PMID- 25527796 TI - Counselling a patient with chronic illness before pregnancy. AB - As the reproductive age of women increases, women of reproductive age are exposed to more diseases and medications that are potentially related to adverse pregnancy outcomes. The approach to primary prevention of such outcomes is discussed. By minimizing the risks related to the diseases and the medications before conception, the best control of the medical condition and optimized pharmacotherapy is achieved when conception eventually occurs. PMID- 25527795 TI - Chronic illness and the breastfeeding mother. AB - Medications taken for chronic illness (e.g., depression, epilepsy, immunological conditions) while breastfeeding pose challenges to risk-assessment. Based on several cases of drug toxicity (or lack thereof) in the breastfeeding infant, individual risk:benefit analyses are discussed. The benefits of human milk are highlighted, together with clinically important principles for patient management, the spectrum of adverse effects in the infant, and emerging concerns regarding the safety of some medications during breastfeeding. A practical guide for patient management is presented. PMID- 25527797 TI - Improving medicines for children in Canada. Findings of the expert panel on therapeutic products for infants, children and youth. AB - With children being largely orphaned from the benefits of drugs, and being managed mostly by medications unapproved by Health Canada, a landmark document was published in September 2014 by the Council of Canadian Academies (CCA) to serve as a blueprint to change this grim reality. The main findings of the panel included: 1. Children take medications, many of which have not been proven safe and effective for their use. 2. Children respond to medications differently from adults; thus, medicines must be studied in children and formulated for children. 3. Studying medicines in children is always possible and in their best interests. 4. In the United States and the European Union, pediatric medicines research is encouraged, required and monitored in ways that offer lessons for Canada. 5. Pediatric medicines research is a Canadian strength, but it requires reinforcement, sustained capacity and infrastructure to realize its full potential. PMID- 25527798 TI - The effects of the new antipsychotic medications on mothers and babies. AB - Second generation antipsychotics are widely used by thousands of pregnant women worldwide in order to control their psychiatric disorders. The clinical profiles of these drugs have improved, specifically the decreased risk of hyperprolactinemia, which has increased fertility in female patients. However, the reproductive safety of second generation antipsychotics remains undefined and controversial. The aim of this presentation is to synthesize the available evidence-based information into a systematic review of the safety in pregnancy of this group of drugs (in mono-and polytherapy). PMID- 25527799 TI - Quality of hypertension pharmacotherapy in Quebec: a population-based study. AB - BACKGROUND: Choosing the initial pharmacotherapy for new antihypertensive users and ensuring adherence to therapy can be problematic. OBJECTIVES: We sought to assess the quality of pharmacotherapy among new users of antihypertensives in Quebec, and to measure persistence with treatment in the short and longer term. METHODS: Using provincial administrative databases, a historical population-based study was conducted with a cohort of Quebec adults who filled their first antihypertensive prescription between January 1, 2007, and December 31, 2009. We described antihypertensive treatment for those with a diagnosis of hypertension (HTN) in the 5 years preceding initiation of drug therapy. Conformity with criteria for optimal use based on the 2006 Canadian Hypertension Education Program (CHEP) was evaluated. Persistence with treatment was estimated at 3 months, 1 year and 2 years after pharmacotherapy initiation. RESULTS: Among the 79,181 new antihypertensive users with HTN who started treatment between 2007 and 2009, 82.5% were first prescribed only one drug, usually an angiotensin II receptor blocker or an angiotensin-converting enzyme inhibitor and rarely a diuretic. 24.2% of newly treated hypertensive persons aged 60 or older in our sample received a beta-blocker, which is not recommended practice. The initial treatment conformed to CHEP recommendations for 72.8% of those with uncomplicated HTN. After 3 months, 69.8% of new users still persisted with their treatment. This proportion remained stable after 1 year (69.1%) and 2 years (69.2%). CONCLUSION: Conformity of antihypertensive treatment with CHEP criteria, and patient persistence with therapy, was fairly high for new users in the province of Quebec. Research is needed, however, on how to further improve pEEharmacotherapy quality and persistence in new users. PMID- 25527800 TI - "Prozac Baby" - 25 years of motherisk research into SSRIs and alcohol in pregnancy. AB - A summary of the debate regarding the safety of antidepressants in pregnancy is presented through the story of Prozac Baby. This is a diary of a fetus who finds out (to his horror) that his mother intends to abort him due to misinformation she has received. The novel, Prozac Baby, was written by Dr. Gideon Koren, based on his experience at Motherisk. An update on the risks of alcohol in pregnancy is also provided. PMID- 25527801 TI - Management of patients with Cushing's disease: a Canadian cost of illness analysis. AB - BACKGROUND: Cushing's disease (CD) is a rare disorder caused by increased pituitary secretion of adrenocorticotropic hormone (ACTH) resulting in elevated production of cortisol. It is associated with multiple adverse cardiovascular, metabolic, musculoskeletal and mental consequences. Patients with CD require substantial health care resources both in terms of treatments with a curative intent and control of disease related co-morbidities. In this study, a cost of illness analysis was conducted to estimate the direct cost of CD care in Canada. METHODS: This was a retrospective cohort study of 86 CD patients. Data collection included patient demographic and disease related information, existing comorbidities, treatments received and all clinical outcomes. In addition, healthcare resource utilization to manage CD was also collected. Once the mean cost per patient was determined, the overall disease prevalence was used to estimate the total direct cost of illness in Canada. RESULTS: The sample included 86 CD patients, with a mean age of 43 years at diagnosis, 72% were female. All received a first line intervention consisting of transsphenoidal pituitary surgery (78%), bilateral adrenalectomy (5%), radiation therapy (5%) or medical therapy +/- radiation (13%). In addition, 18 and 14 patients subsequently received a second and third line intervention, respectively. The mean cost was $85,946 per patient over the first three lines of therapy. Combining this estimate with the reported disease prevalence (5.5 patients per 100,000 [95%CI: 4.2 to 6.8]), the total direct cost of CD in Canada was estimated to be approximately $80.6 million (95%CI: $61.5 to $99.6 million) over the first 3 lines of therapy. CONCLUSIONS: CD is a debilitating condition that is associated with substantial health care costs. Strategies that provide clinical cure or long term disease control need to be identified to reduce patient morbidity and to save health care costs in patients who remain uncontrolled. PMID- 25527802 TI - New method of forced implantation of permanent catheters for hemodialysis into critically stenosed or occluded central veins. AB - The aim of the study was to report a novel technique of forced implantation of catheters for hemodialysis into critically stenosed or occluded central veins, without preceding angioplasty or stenting. MATERIAL AND METHODS: Sixteen patients with central venous occlusive disease, requiring urgent hemodialysis underwent this procedure. Catheterization of stenosis - occlusion was initially performed with soft guidewire, subsequently exchanged to stiff guidewire. Forced insertion of dilators, peel-off sheath throughout the stenosis or occlusion and finally implantation of the catheter completed the procedure. Our technique does not require pre-procedural angioplasty or stent deployment. RESULTS: In all patients postoperative hemodialysis was managed with satisfactory adequacy. No early or late complications related to the procedure occurred. We did not observe any clinically significant aggravation of symptoms of central vein stenosis or occlusion. Complications, not-related to the procedure included one, late skin entry site infection and one, late catheter thrombosis. These were managed without the necessity of catheter exchange. CONCLUSIONS: Our technique of forced implantation of catheters for hemodialysis into critically stenosed or occluded central veins without previous balloon predilatation or stenting is simple and diminishes the total cost of the procedure. Provides quick vascular access for hemodialysis in life threatening situations. PMID- 25527803 TI - Quality of life considering patients with chronic inflammatory bowel diseases - natural and parenteral nutrition. AB - One of the elements of treatment considering inflammatory bowel diseases is nutritional therapy. The duration of the above-mentioned depends on the prevalence of such symptoms as fever, bowel movements, length of the functioning gastrointestinal tract, stoma and intestinal fistula presence. Nutritional therapy is an essential element of successful treatment alongside pharmacological, surgical, and biological therapy, as well as other methods. Crohn's disease and ulcerative colitis considered as chronic diseases, lead towards physical and biopsychosocial disability, being responsible for the reduction in the quality of life. The aim of the study was to determine the quality of life after surgical procedures in case of patients diagnosed with Crohn's disease and ulcerative colitis, subjected to natural and parenteral nutrition. MATERIAL AND METHODS: The study group comprised 52 patients from the Department of Gastroenterology, Military Medical Institute, and Department of Surgery and Clinical Nutrition, Clinical Hospital in Warsaw. The study was performed between October, 2011 and April, 2012. The World Health Organization Quality of Life Instrument - Bref (WHOQOL-BREF) questionnaire was used to deter mine the patients' quality of life. CONCLUSIONS: A lower quality of life was observed in case of patients subjected to parenteral nutrition, poor education, disease symptoms exacerbation, in the majority-rural inhabitants. The quality of life does not depend on gender, type of disease, family status, and additional medical care. PMID- 25527804 TI - Results of laparoscopic appendectomies performed with the use of titanium clips for closure of the appendicular stump. AB - Nowadays laparoscopy is used frequently not only in elective surgery but also in abdominal emergencies, including acute appendicitis. There are several techniques used to close the appendicular stump during laparoscopic appendectomy. The aim of the study was to present the results of minimally invasive appendectomies performed with the use of titanium clips. MATERIAL AND METHODS: Patients operated on laparoscopically for acute appendicitis with the application of titanium clips between October 2012 and December 2013 were included in the study. We reviewed retrospectively patients' data including: age, sex, duration of the surgical procedure and hospital stay, mortality, intraoperative and postoperative complication rates. RESULTS: There were 93 patients (mean age=33.8 years, SD=15.23) in the analyzed group, including 60 men (mean age=33.5 years, SD= 15.07) and 33 women (mean age=33.9 years SD=15.26). The average duration of the surgical procedure was 66 min (SD= 33.15). The average length of hospital stay was 3.38 days (SD=1.62). No intraoperative complications were observed in the analyzed group. Post-operative complication rate was low (6 cases, 6.5%). No mortality was observed. CONCLUSIONS: Laparoscopic appendectomy with the application of titanium clips for closure of the appendicular stump is safe, associated with low complication rates and should be considered as a routine technique in everyday surgical practice. PMID- 25527805 TI - Evaluating the prognostic value of selected prognostic scales in patients operated on due to peritonitis. AB - The aim of the study was to assess the usefulness of prognostic scales: ASA (American Society of Anesthesiologist), MPI (Meinheim Peritonitis Index), MOFS (the Multiple Organ Failure Score) and SPI (the Simple Prognostic Index) in the prognosis of the course of disease in patients operated on for peritonitis. MATERIAL AND METHODS: The study was conducted in the Clinical Department of General and Oncological Surgery of the Medical University in Lodz between January 2009 to December 2010. During this period 263 patients were operated on for peritonitis. Before surgery all patients were classified into particular groups according to the above mentioned prognostic scales according to their criteria. RESULTS: There were 29 (11%) deaths. ASA >=4 (p<0.0001), MPI >30 (p<0.0001) MOFS >=2 (p<0.0001), SPI II, III, IV (p<0.0001) were important risk factors of death. CONCLUSIONS: 1. ASA, MPI, MOFS and SPI scales are of high significance in predicting the outcome in patients operated on for peritonitis. 2. The ASA scale in spite and due to its simplicity is adequate enough to be used in everyday practice in patients operated on for peritonitis. 3. The MPI scale is most suitable in the scientific aims and in comparing the outcomes of patients operated on for peritonitis. PMID- 25527806 TI - Neurilemoma of the median nerve - surgical strategies based on a case report. AB - The study presented a case of a patient with a neurilemoma of the median nerve. It presented as a six centemeters tumor, at the level of the proximal one third of the arm with only mild paraesthesias within first to third ray of the hand. MRI showed the relationship of the tumor and the median nerve, and allowed for the preliminary diagnose of a benign peripheral neural sheath tumor (neurilemoma or neurofibroma). During the first operation the tumor has not been excised, because nerve reconstruction technique was not available. During the second procedure excision of the tumor has been performed without resection of the median nerve trunk with no postoperative deficiencies. The paper provides a detailed description of a surgical procedure. The presented case, like current publications shows that peripheral neural sheath tumor may be usually excised without resection of the nerve trunk, although the possibility of nerve fascicles injury or the need to excise them in the case of neurofibroma clearly suggest that these type of operations should be carried out in centers with microsurgical facilities. PMID- 25527807 TI - Gall-bladder duplication - case report. AB - Gall-bladder duplication is a rare anatomical variation, which can affect safe performance of cholecystectomy and be a cause of persistent symptoms and a need for reoperation in case of accessory gall-bladder omission. A case of successfully performed elective laparoscopic cholecystectomy in a patient with duplicated gall-bladder accidentally intraoperatively disclosed is presented. The identified anomaly was classified according to the Harlaftis Classification of Multiple Gall-bladders. Attention was drawn to the uneffectivenes of ultrasound scanning in multiple gall-bladders preoperative detecting, and presence of other non-biliary anatomical variation in the same individual as well. PMID- 25527808 TI - Calcifying fibrous tumor of the small bowel mesentery in a 27-year old male patient - case report. AB - Calcifying fibrous tumor is a rare disease entity, usually concerning the soft tissues of the limbs, neck, trunk, or scrotum. Cases of the above-mentioned pathology have also been reported considering the pleural and peritoneal cavity, and small bowel mesentery. The essence of the disease, whose etiology and pathogenesis remains unclear, is the fibrous tissue infiltration and diffuse inflammation with focal calcifications. The study presented a case of a 27-year old male patient subjected to surgical intervention, due to an abdominal cavity tumor. The tumor was radically removed, and its character and definitive diagnosis were established postoperatively. After a seven-year follow-up period, recurrence was not observed. PMID- 25527809 TI - Emerging role of ultrasound guided peripheral nerve anaesthesia in surgery of lower extremities. PMID- 25527810 TI - Skin bridge loop stomy - operative technique. PMID- 25527811 TI - Pharmacogenetics of drug-metabolizing enzymes in Italian populations. AB - Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 (CYP) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans. PMID- 25527812 TI - Biological variation of high sensitivity cardiac troponin-T in stable dialysis patients: implications for clinical practice. AB - BACKGROUND: Changes in high sensitivity cardiac troponin-T (hs-cTnT) concentrations may reflect either acute myocardial injury or biological variation. Distinguishing between these entities is essential to accurate diagnosis, however, the biological variation of hs-cTnT in dialysis population is currently unknown. We sought to estimate the within- and between-person coefficients of variation of hs-cTnT in stable dialysis patients, and derive the critical difference between measurements needed to exclude biological variation with 99% confidence. METHODS: Fifty-five prevalent haemo- and peritoneal-dialysis patients attending two metropolitan hospitals were assessed on 10 consecutive occasions; weekly for 5 weeks then monthly for 4 months. Assessments were conducted at the same dialysis cycle time-point and entailed hs-cTnT testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they developed clinical or physiological instability. RESULTS: In total 137 weekly and 114 monthly hs-cTnT measurements from 42 stable patients were analysed. Respective between- and within-person coefficients of variation were 83% and 7.9% for weekly measurements, and 79% and 12.6% for monthly measurements. Within-person variation was unaffected by dialysis modality or cardiac co-morbidity. The bidirectional 99% reference change value was -25% and +33% for weekly measurements, and -37% and +58% for monthly measurements. CONCLUSIONS: The between-person variation of hs-cTnT in the dialysis population is markedly greater than within-person variation indicating that hs-cTnT testing is best applied in this population using a relative change strategy. An increase of 33% or a reduction of 25% in serial hs-cTnT concentrations measured at weekly intervals excludes change due to analytical and biological variation alone with 99% confidence. PMID- 25527813 TI - Role of JAK2 V617F mutation and aberrant expression of microRNA-143 in myeloproliferative neoplasms. AB - BACKGROUND: Myeloproliferative neoplasms (MPNs) are clonal myeloid disorders characterized by the overproduction of mature blood cells. The pathogenetic hallmark of MPNs is the dysregulation of JAK-STAT signaling, usually associated with the JAK2 V617F mutation. Multiple additional genetic and epigenetic alterations that constitutively activate the JAK-STAT signaling pathway have been described, including the modulation of the microRNAs (miRs) expression levels. The aims of our study were to investigate JAK2 V617F mutation allele burden and miR-143 expression levels in MPNs patients and to investigate the correlation between these genetic signatures and hematological parameters. METHODS: In total 78 patients with a clinical diagnosis of polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IM), made according to the WHO 2008 criteria, were included in the study. Twenty healthy subjects were checked as controls. Quantification of JAK2 V617F mutation and miR-143 expression levels were determined by real-time quantitative polymerase chain reaction. RESULTS: The miR-143 expression in MPNs patients was 2.97-fold higher than in controls. JAK2 V617F mutation allele burden and miR-143 expression level resulted higher in PV and IM respect to ET patients. Patients who had V617F allele burden >50% displayed a higher miRNA-143 expression level than patients with allele burden <50%. In MPNs patients, a statistically significant positive correlation was observed between JAK2 V617F mutation allele burden and hemoglobin and hematocrit values and between miR-143 expression levels and platelet count. CONCLUSIONS: Our findings of aberrant miR-143 expression support the concept that factors other than JAK2 V617F mutation may contribute to the pathogenesis and some clinical signs of MPNs. PMID- 25527814 TI - Stroke and inherited thrombophilia in a Tunisian girl with sickle cell anemia. PMID- 25527815 TI - Adenosine deaminase, dipeptidyl peptidase-IV activities and lipid peroxidation are increased in the saliva of obese young adult. AB - BACKGROUND: Obesity is the hallmark of the metabolic syndrome representing a major global health problem. It is considered a state of chronic inflammation with minimal exploration of salivary biomarkers. Thus, the intent of the present study was to assess the activities of salivary dipeptidyl peptidase IV (DPP-IV), adenosine deaminase (ADA) and lipid peroxidation in obese young and overweight young subjects. METHODS: ADA, DPP-IV activities and lipid peroxidation were investigated in saliva, as well as insulin, glucose, HbA1c, HOMA and anthropometric measurements in 149 young adults, including 54 with normal weight, 27 overweight and 68 obese subjects. RESULTS: Salivary ADA and DPP-IV activities as well as lipid peroxidation were higher in patients with obesity compared to the normal weight group. Correlations between ADA/DPP-IV activities, lipid peroxidation/ADA activity, ADA activity/hip circumference and BMI/weight were observed. CONCLUSIONS: Our results indicate that the increase in the salivary ADA and DPP-IV activities as well as in the lipid peroxidation could be related of the regulation to various aspects of adipose tissue function and inflammatory obesity. It is suggested that these salivary biomarkers may be used as biochemical test in clinical abnormalities present in obesity, in the absence of oral inflammatory diseases. PMID- 25527816 TI - Fungal contamination of hyaluronidase solution mimicking fungal joint infection: a preanalytical pitfall in synovial fluid analysis. PMID- 25527817 TI - Osteoporosis management among chronic glucocorticoid users: a systematic review. AB - BACKGROUND: Clinical practice guidelines recommend that all patients starting chronic oral glucocorticoid (GC) therapy receive bone mineral density (BMD) testing and osteoporosis pharmacotherapy. OBJECTIVE: We completed a systematic review of observational studies to examine the proportion of patients on chronic oral GC therapy who receive osteoporosis management. METHODS: Two independent reviewers completed a systematic search of Ovid MEDLINE(r) and EMBASE(r) to identify all English language articles that examined the prevalence of osteoporosis management among chronic oral GC users. Clinical trials, abstracts, reviews, commentaries, and letters to the editor were excluded. Study methods and results (use of BMD testing and osteoporosis pharmacotherapy) were abstracted and summarized by year and region. RESULTS: We identified 29 eligible studies published between 1999 and October 2013: 17 were conducted in North America, 5 in Europe, and 7 in other regions. Heterogeneity between patient populations and methods used to define chronic GC use precluded the direct comparison of results between regions, or over time. Over 80% of studies identified that < 40% of chronic oral GC users received BMD testing or osteoporosis pharmacotherapy. When results of these studies were plotted by year, there was little evidence of improvement in osteoporosis management over time. CONCLUSIONS: Despite consistent recommendations to target osteoporosis prevention at the onset of chronic oral GC therapy, osteoporosis is undermanaged among chronic oral GC users. Targeted interventions are needed to help reduce the burden of fracture-related morbidity associated with GC-induced osteoporosis. PMID- 25527819 TI - A negative correlation between insulin-like peptide 3 and bisphenol A in human cord blood suggests an effect of endocrine disruptors on testicular descent during fetal development. AB - STUDY QUESTION: Does a relationship exist between insulin-like peptide 3 (INSL3) and selected environmental endocrine disruptors (EEDs) in human cord blood (cb)? SUMMARY ANSWER: In the whole population (cryptorchid and control boys) cbINSL3 correlated negatively with cb free bisphenol A (BPA) providing indirect evidence for an impact of EEDs on fetal Leydig cell INSL3 production. WHAT IS KNOWN ALREADY: INSL3 is a major regulator of testicular descent. This hormone has been shown to be decreased in cord blood from boys with idiopathic cryptorchidism, the most frequent male malformation. Fetal exposure to several EEDs has been suspected to be involved in the occurrence of idiopathic cryptorchidism. STUDY DESIGN, SIZE, DURATION: Correlations between cb INSL3 or testosterone and cb free bioactive BPA and maternal milk polychlorinated biphenyls (PCB153), dichlorodiphenyldichloroethylene (DDE), and monobutyl phthalate (mBP) were assessed in newborn boys in a prospective case-control study. All boys (n = 6246) born after 34 weeks of gestation were systematically screened at birth for cryptorchidism over a 3-year period (2002-2005), and a diagnosis of cryptorchidism confirmed by a senior paediatrician. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 52 cryptorchid (26 transient, 26 persistent) and 128 control boys born at two hospitals in southern France. INSL3 was assayed in CB by a modified validated enzyme-linked immunosorbent assay. Testosterone was measured in CB after diethyl-ether extraction by means of ultra-pressure liquid chromatography-tandem mass spectrometry. Free cbBPA was measured after an extraction step with a radioimmunoassay validated after comparison of values obtained by high-pressure liquid chromatography-mass spectrometry. The xenobiotic analysis in mothers' milk was performed after fat extraction by gas chromatography-mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: EED concentrations were not increased in the cryptorchid versus control group although a trend for increased mBP (P = 0.09) was observed. In the whole study population, cb levels of BPA correlated negatively with INSL3 (P = 0.01; R2 = 0.05) but not with testosterone. No other EED correlated with INSL3 or with testosterone. LIMITATIONS, REASONS FOR CAUTION: The levels of BPA and INSL3 in cb may not reflect chronic fetal exposure to EEDs. The deleterious impact of EEDs on fetal testicular descent during specific windows of development has yet to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: The negative correlation between cb free BPA and INSL3 provides indirect evidence for an impact of EEDs on human fetal Leydig cell INSL3 production and points to cbINSL3 as a possible target of EED action during fetal testis development. PMID- 25527820 TI - Incorporating covariates in skewed functional data models. AB - We introduce a class of covariate-adjusted skewed functional models (cSFM) designed for functional data exhibiting location-dependent marginal distributions. We propose a semi-parametric copula model for the pointwise marginal distributions, which are allowed to depend on covariates, and the functional dependence, which is assumed covariate invariant. The proposed cSFM framework provides a unifying platform for pointwise quantile estimation and trajectory prediction. We consider a computationally feasible procedure that handles densely as well as sparsely observed functional data. The methods are examined numerically using simulations and is applied to a new tractography study of multiple sclerosis. Furthermore, the methodology is implemented in the R package cSFM, which is publicly available on CRAN. PMID- 25527821 TI - The Anterior Temporal Face Area Contains Invariant Representations of Face Identity That Can Persist Despite the Loss of Right FFA and OFA. AB - Macaque neurophysiology found image-invariant representations of face identity in a face-selective patch in anterior temporal cortex. A face-selective area in human anterior temporal lobe (fATL) has been reported, but has not been reliably identified, and its function and relationship with posterior face areas is poorly understood. Here, we used fMRI adaptation and neuropsychology to ask whether fATL contains image-invariant representations of face identity, and if so, whether these representations require normal functioning of fusiform face area (FFA) and occipital face area (OFA). We first used a dynamic localizer to demonstrate that 14 of 16 normal subjects exhibit a highly selective right fATL. Next, we found evidence that this area subserves image-invariant representation of identity: Right fATL showed repetition suppression to the same identity across different images, while other areas did not. Finally, to examine fATL's relationship with posterior areas, we used the same procedures with Galen, an acquired prosopagnosic who lost right FFA and OFA. Despite the absence of posterior face areas, Galen's right fATL preserved its face selectivity and showed repetition suppression comparable to that in controls. Our findings suggest that right fATL contains image-invariant face representations that can persist despite the absence of right FFA and OFA, but these representations are not sufficient for normal face recognition. PMID- 25527822 TI - DNA methylation and epigenetics: exploring the terra incognita of the atherosclerotic landscape. PMID- 25527823 TI - Macrophage solubilization and cytotoxicity of indium-containing particles as in vitro correlates to pulmonary toxicity in vivo. AB - Macrophage-solubilized indium-containing particles (ICPs) were previously shown in vitro to be cytotoxic. In this study, we compared macrophage solubilization and cytotoxicity of indium phosphide (InP) and indium-tin oxide (ITO) with similar particle diameters (~ 1.5 um) and then determined if relative differences in these in vitro parameters correlated with pulmonary toxicity in vivo. RAW 264.7 macrophages were treated with InP or ITO particles and cytotoxicity was assayed at 24 h. Ionic indium was measured in 24 h culture supernatants. Macrophage cytotoxicity and particle solubilization in vitro were much greater for InP compared with ITO. To correlate changes in vivo, B6C3F1 mice were treated with InP or ITO by oropharyngeal aspiration. On Days 14 and 28, bronchoalveolar lavage (BAL) and pleural lavage (PL) fluids were collected and assayed for total leukocytes. Cell differentials, lactate dehydrogenase activity, and protein levels were also measured in BAL. All lavage parameters were greatly increased in mice treated with InP compared with ITO. These data suggest that macrophage solubilization and cytotoxicity of some ICPs in vitro are capable of predicting pulmonary toxicity in vivo. In addition, these differences in toxicity were observed despite the two particulate compounds containing similar amounts of indium suggesting that solubilization, not total indium content, better reflects the toxic potential of some ICPs. Soluble InCl3 was shown to be more cytotoxic than InP to macrophages and lung epithelial cells in vitro further suggesting that ionic indium is the primary cytotoxic component of InP. PMID- 25527824 TI - Accessory atrioventricular pathways refractory to catheter ablation: role of percutaneous epicardial approach. AB - BACKGROUND: Epicardial mapping and ablation of accessory pathways through a subxiphoid approach can be an alternative when endocardial or epicardial transvenous mapping has failed. METHODS AND RESULTS: We reviewed acute and long term follow-up of 21 patients (14 males) referred for percutaneous epicardial accessory pathway ablation. There was a median of 2 previous failed procedures. All patients were highly symptomatic, 8 had atrial fibrillation (3 with cardiac arrest) and 13 had frequent symptomatic episodes of atrioventricular reentrant tachycardia. Six patients (28.5%) had a successful epicardial ablation. Five patients (23.8%) underwent a successful repeated endocardial mapping, and ablation after epicardial mapping yielded no early activation site. Epicardial mapping was helpful in guiding endocardial ablation in 2 patients (9.5%), showing that the earliest activation was simultaneous at the epicardium and endocardium. Four patients (19%) underwent successful open-chest surgery after failing epicardial/endocardial ablation. Two patients (9.5%) remained controlled under antiarrhythmic drugs after unsuccessful endocardial/epicardial ablation. Two patients had a coronary sinus diverticulum and one a right atrium to right ventricle diverticulum. Three patients acquired postablation coronary sinus stenosis. There was no major complication related to pericardial access. CONCLUSIONS: Percutaneous epicardial approach is an alternative when conventional endocardial or transvenous epicardial ablation fails in the elimination of the accessory pathway. A new attempt by endocardial approach was successful in a significant number of patients. Open-chest surgery may be required in symptomatic cases refractory to endocardial-epicardial approach. PMID- 25527825 TI - Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation. AB - BACKGROUND: Cardiac sarcoid-related ventricular tachycardia (VT) is a rare disorder; the underlying substrate and response to ablation are poorly understood. We sought to examine the ventricular substrate and outcomes of catheter ablation in this population. METHODS AND RESULTS: Of 435 patients with nonischemic cardiomyopathy referred for VT ablation, 21 patients (5%) had cardiac sarcoidosis. Multiple inducible VTs were observed with mechanism consistent with scar-mediated re-entry in all VTs. Voltage maps showed widespread and confluent right ventricular scarring. Left ventricular scarring was patchy with a predilection for the basal septum, anterior wall, and perivalvular regions. Epicardial right ventricular scar overlay and exceeded the region of corresponding endocardial scar. After >=1 procedures, ablation abolished >=1 inducible VT in 90% and eliminated VT storm in 78% of patients; however, multiple residual VTs remained inducible. Failure to abolish all inducible VTs was because of septal intramural circuits or extensive right ventricular scarring. Multiple procedure VT-free survival was 37% at 1 year, but VT control was achievable in the majority of patients with fewer antiarrhythmic drugs compared with preablation (2.1+/-0.8 versus 1.1+/-0.8; P<0.001). CONCLUSIONS: Patients with cardiac sarcoidosis and VT exhibit ventricular substrate characterized by confluent right ventricular scarring and patchy left ventricular scarring capable of sustaining a large number of re-entrant circuits. Catheter ablation is effective in terminating VT storm and eliminating >=1 inducible VT in the majority of patients, but recurrences are common. Ablation in conjunction with antiarrhythmic drugs can help palliate VT in this high-risk population. PMID- 25527827 TI - Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice. AB - Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy. PMID- 25527826 TI - Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients. AB - Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases. PMID- 25527828 TI - Transcriptional characteristics and differences in Arabidopsis stigmatic papilla cells pre- and post-pollination. AB - Pollination is an important early step in sexual plant reproduction. In Arabidopsis thaliana, sequential pollination events, from pollen adhesion onto the stigma surface to pollen tube germination and elongation, occur on the stigmatic papilla cells. Following successful completion of these events, the pollen tube penetrates the stigma and finally fertilizes a female gametophyte. The pollination events are thought to be initiated and regulated by interactions between papilla cells and pollen. Here, we report the characterization of gene expression profiles of unpollinated (UP), compatible pollinated (CP) and incompatible pollinated (IP) papilla cells in A. thaliana. Based on cell type specific transcriptome analysis from a combination of laser microdissection and RNA sequencing, 15,475, 17,360 and 16,918 genes were identified as expressed in UP, CP and IP papilla cells, respectively, and, of these, 14,392 genes were present in all three data sets. Differentially expressed gene (DEG) analyses identified 147 and 71 genes up-regulated in CP and IP papilla cells, respectively, and 115 and 46 genes down-regulated. Gene Ontology and metabolic pathway analyses revealed that papilla cells play an active role as the female reproductive component in pollination, particularly in information exchange, signal transduction, internal physiological changes and external morphological modification. This study provides fundamental information on the molecular mechanisms involved in pollination in papilla cells, furthering our understanding of the reproductive role of papilla cells. PMID- 25527829 TI - Identification of mRNAs that move over long distances using an RNA-Seq analysis of Arabidopsis/Nicotiana benthamiana heterografts. AB - Phloem is a conductive tissue that allocates nutrients from mature source leaves to sinks such as young developing tissues. Phloem also delivers proteins and RNA species, such as small RNAs and mRNAs. Intensive studies on plant systemic signaling revealed the essential roles of proteins and RNA species. However, many of their functions are still largely unknown, with the roles of transported mRNAs being particularly poorly understood. A major difficulty is the absence of an accurate and comprehensive list of mobile transcripts. In this study, we used a hetero-graft system with Nicotiana benthamiana as the recipient scion and Arabidopsis as the donor stock, to identify transcripts that moved long distances across the graft union. We identified 138 Arabidopsis transcripts as mobile mRNAs, which we collectively termed the mRNA mobilome. Reverse transcription-PCR, quantitative real-time PCR and droplet digital PCR analyses confirmed the mobility. The transcripts included potential signaling factors and, unexpectedly, more general factors. In our investigations, we found no preferred transcript length, no previously known sequence motifs in promoter or transcript sequences and no similarities between the level of the transcripts and that in the source leaves. Grafting experiments regarding the function of ERECTA, an identified transcript, showed that no function of the transcript mobilized. To our knowledge, this is the first report identifying transcripts that move over long distances using a hetero-graft system between different plant taxa. PMID- 25527831 TI - Workflow4Metabolomics: a collaborative research infrastructure for computational metabolomics. AB - SUMMARY: The complex, rapidly evolving field of computational metabolomics calls for collaborative infrastructures where the large volume of new algorithms for data pre-processing, statistical analysis and annotation can be readily integrated whatever the language, evaluated on reference datasets and chained to build ad hoc workflows for users. We have developed Workflow4Metabolomics (W4M), the first fully open-source and collaborative online platform for computational metabolomics. W4M is a virtual research environment built upon the Galaxy web based platform technology. It enables ergonomic integration, exchange and running of individual modules and workflows. Alternatively, the whole W4M framework and computational tools can be downloaded as a virtual machine for local installation. AVAILABILITY AND IMPLEMENTATION: http://workflow4metabolomics.org homepage enables users to open a private account and access the infrastructure. W4M is developed and maintained by the French Bioinformatics Institute (IFB) and the French Metabolomics and Fluxomics Infrastructure (MetaboHUB). CONTACT: contact@workflow4metabolomics.org. PMID- 25527830 TI - MdMYB9 and MdMYB11 are involved in the regulation of the JA-induced biosynthesis of anthocyanin and proanthocyanidin in apples. AB - Anthocyanin and proanthocyanidin (PA) are important secondary metabolites and beneficial to human health. Their biosynthesis is induced by jasmonate (JA) treatment and regulated by MYB transcription factors (TFs). However, which and how MYB TFs regulate this process is largely unknown in apple. In this study, MdMYB9 and MdMYB11 which were induced by methyl jasmonate (MeJA) were functionally characterized. Overexpression of MdMYB9 or MdMYB11 promoted not only anthocyanin but also PA accumulation in apple calluses, and the accumulation was further enhanced by MeJA. Subsequently, yeast two-hybrid, pull-down and bimolecular fluorescence complementation assays showed that both MYB proteins interact with MdbHLH3. Moreover, Jasmonate ZIM-domain (MdJAZ) proteins interact with MdbHLH3. Furthermore, chromatin immunoprecipitation-quantitative PCR and yeast one-hybrid assays demonstrated that both MdMYB9 and MdMYB11 bind to the promoters of ANS, ANR and LAR, whereas MdbHLH3 is recruited to the promoters of MdMYB9 and MdMYB11 and regulates their transcription. In addition, transient expression assays indicated that overexpression of MdJAZ2 inhibits the recruitment of MdbHLH3 to the promoters of MdMYB9 and MdMYB11. Our findings provide new insight into the mechanism of how MeJA regulates anthocyanin and PA accumulation in apple. PMID- 25527832 TI - Population-based structural variation discovery with Hydra-Multi. AB - Current strategies for SNP and INDEL discovery incorporate sequence alignments from multiple individuals to maximize sensitivity and specificity. It is widely accepted that this approach also improves structural variant (SV) detection. However, multisample SV analysis has been stymied by the fundamental difficulties of SV calling, e.g. library insert size variability, SV alignment signal integration and detecting long-range genomic rearrangements involving disjoint loci. Extant tools suffer from poor scalability, which limits the number of genomes that can be co-analyzed and complicates analysis workflows. We have developed an approach that enables multisample SV analysis in hundreds to thousands of human genomes using commodity hardware. Here, we describe Hydra Multi and measure its accuracy, speed and scalability using publicly available datasets provided by The 1000 Genomes Project and by The Cancer Genome Atlas (TCGA). AVAILABILITY AND IMPLEMENTATION: Hydra-Multi is written in C++ and is freely available at https://github.com/arq5x/Hydra. CONTACT: aaronquinlan@gmail.com or ihall@genome.wustl.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25527833 TI - mirPub: a database for searching microRNA publications. AB - SUMMARY: Identifying, amongst millions of publications available in MEDLINE, those that are relevant to specific microRNAs (miRNAs) of interest based on keyword search faces major obstacles. References to miRNA names in the literature often deviate from standard nomenclature for various reasons, since even the official nomenclature evolves. For instance, a single miRNA name may identify two completely different molecules or two different names may refer to the same molecule. mirPub is a database with a powerful and intuitive interface, which facilitates searching for miRNA literature, addressing the aforementioned issues. To provide effective search services, mirPub applies text mining techniques on MEDLINE, integrates data from several curated databases and exploits data from its user community following a crowdsourcing approach. Other key features include an interactive visualization service that illustrates intuitively the evolution of miRNA data, tag clouds summarizing the relevance of publications to particular diseases, cell types or tissues and access to TarBase 6.0 data to oversee genes related to miRNA publications. AVAILABILITY AND IMPLEMENTATION: mirPub is freely available at http://www.microrna.gr/mirpub/. CONTACT: vergoulis@imis.athena innovation.gr or dalamag@imis.athena-innovation.gr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25527834 TI - Biased gene conversion and GC-content evolution in the coding sequences of reptiles and vertebrates. AB - Mammalian and avian genomes are characterized by a substantial spatial heterogeneity of GC-content, which is often interpreted as reflecting the effect of local GC-biased gene conversion (gBGC), a meiotic repair bias that favors G and C over A and T alleles in high-recombining genomic regions. Surprisingly, the first fully sequenced nonavian sauropsid (i.e., reptile), the green anole Anolis carolinensis, revealed a highly homogeneous genomic GC-content landscape, suggesting the possibility that gBGC might not be at work in this lineage. Here, we analyze GC-content evolution at third-codon positions (GC3) in 44 vertebrates species, including eight newly sequenced transcriptomes, with a specific focus on nonavian sauropsids. We report that reptiles, including the green anole, have a genome-wide distribution of GC3 similar to that of mammals and birds, and we infer a strong GC3-heterogeneity to be already present in the tetrapod ancestor. We further show that the dynamic of coding sequence GC-content is largely governed by karyotypic features in vertebrates, notably in the green anole, in agreement with the gBGC hypothesis. The discrepancy between third-codon positions and noncoding DNA regarding GC-content dynamics in the green anole could not be explained by the activity of transposable elements or selection on codon usage. This analysis highlights the unique value of third-codon positions as an insertion/deletion-free marker of nucleotide substitution biases that ultimately affect the evolution of proteins. PMID- 25527835 TI - Contrasting inter- and intraspecies recombination patterns in the "Harveyi clade" vibrio collected over large spatial and temporal scales. AB - Recombination plays an important role in the divergence of bacteria, but the frequency of interspecies and intraspecies recombination events remains poorly understood. We investigated recombination events that occurred within core genomes of 35 Vibrio strains (family Vibrionaceae, Gammaproteobacteria), from six closely related species in the so-called "Harveyi clade." The strains were selected from a collection of strains isolated in the last 90 years, from various environments worldwide. We found a close relationship between the number of interspecies recombination events within core genomes of the 35 strains and the overall genomic identity, as inferred from calculations of the average nucleotide identity. The relationship between the overall nucleotide identity and the number of detected interspecies recombination events was comparable when analyzing strains isolated over 80 years apart, from different hemispheres, or from different ecologies, as well as in strains isolated from the same geographic location within a short time frame. We further applied the same method of detecting recombination events to analyze 11 strains of Vibrio campbellii, and identified disproportionally high number of intraspecies recombination events within the core genomes of some, but not all, strains. The high number of recombination events was detected between V. campbellii strains that have significant temporal (over 18 years) and geographical (over 10,000 km) differences in their origins of isolation. Results of this study reveal a remarkable stability of Harveyi clade species, and give clues about the origins and persistence of species in the clade. PMID- 25527836 TI - Intraisolate mitochondrial genetic polymorphism and gene variants coexpression in arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizal fungi (AMF) are multinucleated and coenocytic organisms, in which the extent of the intraisolate nuclear genetic variation has been a source of debate. Conversely, their mitochondrial genomes (mtDNAs) have appeared to be homogeneous within isolates in all next generation sequencing (NGS)-based studies. Although several lines of evidence have challenged mtDNA homogeneity in AMF, extensive survey to investigate intraisolate allelic diversity has not previously been undertaken. In this study, we used a conventional polymerase chain reaction -based approach on selected mitochondrial regions with a high fidelity DNA polymerase, followed by cloning and Sanger sequencing. Two isolates of Rhizophagus irregularis were used, one cultivated in vitro for several generations (DAOM-197198) and the other recently isolated from the field (DAOM 242422). At different loci in both isolates, we found intraisolate allelic variation within the mtDNA and in a single copy nuclear marker, which highlighted the presence of several nonsynonymous mutations in protein coding genes. We confirmed that some of this variation persisted in the transcriptome, giving rise to at least four distinct nad4 transcripts in DAOM-197198. We also detected the presence of numerous mitochondrial DNA copies within nuclear genomes (numts), providing insights to understand this important evolutionary process in AMF. Our study reveals that genetic variation in Glomeromycota is higher than what had been previously assumed and also suggests that it could have been grossly underestimated in most NGS-based AMF studies, both in mitochondrial and nuclear genomes, due to the presence of low-level mutations. PMID- 25527837 TI - Satellite DNA as a driver of population divergence in the red flour beetle Tribolium castaneum. AB - Tandemly repeated satellite DNAs are among most rapidly evolving sequences in eukaryotic genome, usually differing significantly among closely related species. By inducing changes in heterochromatin and/or centromere, satellite DNAs are expected to drive population and species divergence. However, despite high evolutionary dynamics, divergence of satellite DNA profiles at the level of natural population which precedes and possibly triggers speciation process is not readily detected. Here, we characterize minor TCAST2 satellite DNA of the red flour beetle Tribolium castaneum and follow its dynamics among wild-type strains originating from diverse geographic locations. The investigation revealed presence of three distinct subfamilies of TCAST2 satellite DNA which differ in monomer size, genome organization, and subfamily specific mutations. Subfamilies Tcast2a and Tcast2b are tandemly arranged within pericentromeric heterochromatin whereas Tcast2c is preferentially dispersed within euchromatin of all chromosomes. Among strains, TCAST2 subfamilies are conserved in sequence but exhibit a significant content variability. This results in overrepresentation or almost complete absence of particular subfamily in some strains and enables discrimination between strains. It is proposed that homologous recombination, probably stimulated by environmental stress, is responsible for the emergence of TCAST2 satellite subfamilies, their copy number variation and dispersion within genome. The results represent the first evidence for the existence of population specific satellite DNA profiles. Partial organization of TCAST2 satellite DNA in the form of single repeats dispersed within euchromatin additionally contributes to the genome divergence at the population level. PMID- 25527838 TI - Germline methylation patterns determine the distribution of recombination events in the dog genome. AB - The positive-regulatory domain containing nine gene, PRDM9, which strongly associates with the location of recombination events in several vertebrates, is inferred to be inactive in the dog genome. Here, we address several questions regarding the control of recombination and its influence on genome evolution in dogs. First, we address whether the association between CpG islands (CGIs) and recombination hotspots is generated by lack of methylation, GC-biased gene conversion (gBGC), or both. Using a genome-wide dog single nucleotide polymorphism data set and comparisons of the dog genome with related species, we show that recombination-associated CGIs have low CpG mutation rates, and that CpG mutation rate is negatively correlated with recombination rate genome wide, indicating that nonmethylation attracts the recombination machinery. We next use a neighbor-dependent model of nucleotide substitution to disentangle the effects of CpG mutability and gBGC and analyze the effects that loss of PRDM9 has on these rates. We infer that methylation patterns have been stable during canid genome evolution, but that dog CGIs have experienced a drastic increase in substitution rate due to gBGC, consistent with increased levels of recombination in these regions. We also show that gBGC is likely to have generated many new CGIs in the dog genome, but these mostly occur away from genes, whereas the number of CGIs in gene promoter regions has not increased greatly in recent evolutionary history. Recombination has a major impact on the distribution of CGIs that are detected in the dog genome due to the interaction between methylation and gBGC. The results indicate that germline methylation patterns are the main determinant of recombination rates in the absence of PRDM9. PMID- 25527839 TI - The bimodal distribution of genic GC content is ancestral to monocot species. AB - In grasses such as rice or maize, the distribution of genic GC content is well known to be bimodal. It is mainly driven by GC content at third codon positions (GC3 for short). This feature is thought to be specific to grasses as closely related species like banana have a unimodal GC3 distribution. GC3 is associated with numerous genomics features and uncovering the origin of this peculiar distribution will help understanding the potential roles and consequences of GC3 variations within and between genomes. Until recently, the origin of the peculiar GC3 distribution in grasses has remained unknown. Thanks to the recent publication of several complete genomes and transcriptomes of nongrass monocots, we studied more than 1,000 groups of one-to-one orthologous genes in seven grasses and three outgroup species (banana, palm tree, and yam). Using a maximum likelihood-based method, we reconstructed GC3 at several ancestral nodes. We found that the bimodal GC3 distribution observed in extant grasses is ancestral to both grasses and most monocot species, and that other species studied here have lost this peculiar structure. We also found that GC3 in grass lineages is globally evolving very slowly and that the decreasing GC3 gradient observed from 5' to 3' along coding sequences is also conserved and ancestral to monocots. This result strongly challenges the previous views on the specificity of grass genomes and we discuss its implications for the possible causes of the evolution of GC content in monocots. PMID- 25527840 TI - The mitochondrial genome of the glomeromycete Rhizophagus sp. DAOM 213198 reveals an unusual organization consisting of two circular chromosomes. AB - Mitochondrial (mt) genomes are intensively studied in Ascomycota and Basidiomycota, but they are poorly documented in basal fungal lineages. In this study, we sequenced the complete mtDNA of Rhizophagus sp. DAOM 213198, a close relative to Rhizophagus irregularis, a widespread, ecologically and economical relevant species belonging to Glomeromycota. Unlike all other known taxonomically close relatives harboring a full-length circular chromosome, mtDNA of Rhizophagus sp. reveals an unusual organization with two circular chromosomes of 61,964 and 29,078 bp. The large chromosome contained nine protein-coding genes (atp9, nad5, cob, nad4, nad1, nad4L, cox1, cox2, and atp8), small subunit rRNA gene (rns), and harbored 20 tRNA-coding genes and 10 orfs, while the small chromosome contained five protein-coding genes (atp6, nad2, nad3, nad6, and cox3), large subunit rRNA gene (rnl) in addition to 5 tRNA-coding genes, and 8 plasmid-related DNA polymerases (dpo). Although structural variation of plant mt genomes is well documented, this study is the first report of the presence of two circular mt genomes in arbuscular mycorrhizal fungi. Interestingly, the presence of dpo at the breakage point in intergenes cox1-cox2 and rnl-atp6 for large and small mtDNAs, respectively, could be responsible for the conversion of Rhizophagus sp. mtDNA into two chromosomes. Using quantitative real-time polymerase chain reaction, we found that both mtDNAs have an equal abundance. This study reports a novel mtDNA organization in Glomeromycota and highlights the importance of studying early divergent fungal lineages to describe novel evolutionary pathways in the fungal kingdom. PMID- 25527841 TI - Rooting the domain archaea by phylogenomic analysis supports the foundation of the new kingdom Proteoarchaeota. AB - The first 16S rRNA-based phylogenies of the Archaea showed a deep division between two groups, the kingdoms Euryarchaeota and Crenarchaeota. This bipartite classification has been challenged by the recent discovery of new deeply branching lineages (e.g., Thaumarchaeota, Aigarchaeota, Nanoarchaeota, Korarchaeota, Parvarchaeota, Aenigmarchaeota, Diapherotrites, and Nanohaloarchaeota) which have also been given the same taxonomic status of kingdoms. However, the phylogenetic position of some of these lineages is controversial. In addition, phylogenetic analyses of the Archaea have often been carried out without outgroup sequences, making it difficult to determine if these taxa actually define lineages at the same level as the Euryarchaeota and Crenarchaeota. We have addressed the question of the position of the root of the Archaea by reconstructing rooted archaeal phylogenetic trees using bacterial sequences as outgroup. These trees were based on commonly used conserved protein markers (32 ribosomal proteins) as well as on 38 new markers identified through phylogenomic analysis. We thus gathered a total of 70 conserved markers that we analyzed as a concatenated data set. In contrast with previous analyses, our trees consistently placed the root of the archaeal tree between the Euryarchaeota (including the Nanoarchaeota and other fast-evolving lineages) and the rest of archaeal species, which we propose to class within the new kingdom Proteoarchaeota. This implies the relegation of several groups previously classified as kingdoms (e.g., Crenarchaeota, Thaumarchaeota, Aigarchaeota, and Korarchaeota) to a lower taxonomic rank. In addition to taxonomic implications, this profound reorganization of the archaeal phylogeny has also consequences on our appraisal of the nature of the last archaeal ancestor, which most likely was a complex organism with a gene-rich genome. PMID- 25527850 TI - Recent experience establishing a new pediatric palliative care team. PMID- 25527842 TI - An experienced physiotherapist prescribing and administering corticosteroid and local anaesthetic injections to the shoulder in an Australian orthopaedic service, a non-inferiority randomised controlled trial and economic analysis: study protocol for a randomised controlled trial. AB - BACKGROUND: The early management of orthopaedic outpatients by physiotherapists may be useful in reducing public hospital waiting lists. Physiotherapists in Australia are prevented by legislation and funding models from investigating, prescribing, injecting and referring autonomously. This gap in service is particularly noticeable in the management of shoulder pain in early-access physiotherapy services, as patients needing corticosteroid injection face delays or transfer to other services for this procedure. This trial will investigate the clinical (decision making and outcomes) and economic feasibility of a physiotherapist prescribing and delivering corticosteroid and local anaesthetic injections for shoulder pain in an Australian public hospital setting. METHODS/DESIGN: A double-blinded (patient and assessor) non-inferiority randomised controlled trial will compare an orthopaedic surgeon and a physiotherapist prescribing and delivering corticosteroid injections to the shoulder. Agreement in decision making between the two clinicians will be investigated, and economic information will be obtained for estimating disease burden and an economic evaluation. The surgeon and the physiotherapist will independently assess patients, and 64 eligible participants will be randomised to receive subacromial injection of corticosteroid and local anaesthetic from either the surgeon or the physiotherapist. Post-injection, all participants will receive physiotherapy. The primary outcome measure will be the Shoulder Pain and Disability Index measured at baseline, and at 6 and 12 weeks post-injection. Analysis will be conducted on an intention-to-treat basis and compared to a per protocol analysis. A cost-utility analysis will be undertaken from the perspective of the health funder. DISCUSSION: Findings will assist policy makers and services in improving access for orthopaedic patients. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: 12612000532808 First registered: 21 May 2012. First participant randomized: 16 January 2013. PMID- 25527851 TI - 50 years ago in The Journal of Pediatrics: a nasal mask for premature infants. PMID- 25527852 TI - 50 years ago in The Journal of Pediatrics: Atherosclerosis and pediatrics. PMID- 25527853 TI - High incidence of occult, serious injury in possibly-abused infants presenting with isolated bruising. PMID- 25527854 TI - Professional breastfeeding support enhances breastfeeding continuation. PMID- 25527855 TI - Physical fitness is associated with enhanced academic performance. PMID- 25527856 TI - Multiple-dose hypertonic saline decreases bronchiolitis admissions. PMID- 25527857 TI - In-hospital formula use and early breastfeeding cessation: association not causation. PMID- 25527858 TI - Reply: To PMID 24529621. PMID- 25527860 TI - The overlap method is a safe and feasible for esophagojejunostomy after laparoscopic-assisted total gastrectomy. AB - BACKGROUND: Laparoscopic procedures are increasingly being applied to gastric cancer surgery, including total gastrectomy for tumors located in the upper gastric body. Even for expert surgeons, esophagojejunostomy after laparoscopy assisted total gastrectomy (LATG) can be technically challenging. We perform the overlap method of esophagojejunostomy after LATG for gastric cancer. However, technical questions remain. Is the overlap method safer and more useful than other anastomosis techniques, such as methods using a circular stapler? In addition, while we perform this overlap reconstruction after LATG in a deep and narrow operative field, can the overlap method be performed safely regardless of body habitus? This study aimed to evaluate these issues retrospectively and to review the literature. METHODS: From October 2005 to August 2013, we performed LATG with lymph-node dissection and Roux-en-Y reconstruction using the overlap method in 77 patients with gastric cancer. This study examined pre-, intra- and postoperative data. RESULTS: Mean operation time, time to perform anastomosis, and estimated blood loss were 391.4 min, 36.3 min, and 146.9 ml, respectively. There were no deaths, and morbidity rate was 13%, including one patient (1%) who developed anastomotic stenosis. Mean postoperative hospitalization was 13.4 days. Surgical outcomes did not differ significantly by body mass index. CONCLUSIONS: First, the overlap method for esophagojejunostomy after LATG is safe and useful. Second, this method can be performed irrespective of the body type of the patient. In particular, in a deep and narrow operative field, the overlap method is more versatile than other anastomosis methods. We believe that the overlap method can become a standard reconstruction technique for esophagojejunostomy after LATG. PMID- 25527861 TI - Efinaconazole: Developmental and reproductive toxicity potential of a novel antifungal azole. AB - Efinaconazole is a new triazole antifungal for topical treatment of onychomycosis. The reproductive and developmental toxicity of efinaconazole was characterized in fertility and early embryonic development (rat), embryo-fetal development (rat and rabbit), and peri/post-natal development (rat) studies in accordance with current ICH guidances. In the fertility study, maternal reproductive toxicity was noted as estrous cycle prolongation (NOAEL=5mg/kg/day) but there were no male reproductive effects even in the presence of paternal toxicity (NOAEL=25mg/kg/day). Rat embryo-fetal and perinatal pup lethality was the most sensitive (NOAEL=5mg/kg/day) efinaconazole developmental toxicity and was noted at maternally toxic doses. Efinaconazole did not affect rabbit embryo fetal development at maternally toxic doses (NOAEL=10mg/kg/day). No malformations were induced by efinaconazole in rats or rabbits. When compared with systemic exposures observed in onychomycosis patients, embryo-fetal toxicity in rats was noted at high (>100-fold) multiples of systemic exposure. PMID- 25527862 TI - A high throughput screening system for predicting chemically-induced reproductive organ deformities. AB - There is a great need for alternative testing methods for reproductive toxicants that are practical, fast, cost-effective and easy to interpret. Previously we followed a pragmatic approach using readily available tests, which was successful in predicting reproductive toxicity of chemicals [13]. This initial battery still contained apical tests and is fairly complex and low in its throughput. The current study aimed to simplify this screening battery using a mechanistic approach and a panel of high throughput CALUX reporter gene assays. A mechanistic approach was taken to validate this high throughput test battery. To this end it was challenged with two preselected sets of chemicals addressing two major apical effect classes relevant in reproductive toxicity. We found selectivity in this battery in that 82% of the compounds inducing reproductive organ deformities were predicted correctly, while for compounds inducing neural tube defects this was the case in 47% only. This is consistent with the mechanisms of toxicity covered in the battery. The most informative assays in the battery were ERalpha CALUX to measure estrogenicity and the AR-anti CALUX assay to measure androgen receptor antagonism. PMID- 25527863 TI - Cord blood: a promising source of allogeneic natural killer cells for immunotherapy. PMID- 25527864 TI - Intracellular labeling of mouse embryonic stem cell-derived neural progenitor aggregates with micron-sized particles of iron oxide. AB - BACKGROUND AIMS: Pluripotent stem cell (PSC)-derived neural progenitor cells (NPCs) represent an unlimited source for the treatment of various neurological disorders. NPCs are usually derived from PSCs through the formation of embryoid body (EB), an aggregate structure mimicking embryonic development. This study investigated the effect of labeling multicellular EB-NPC aggregates with micron sized particles of iron oxide (MPIO) for cell tracking using magnetic resonance imaging (MRI). METHODS: Intact and dissociated EB-NPC aggregates were labeled with various concentrations of MPIOs (0, 2.5, 5 and 10 MUg Fe/mL). The labeled cells were analyzed by fluorescent imaging, flow cytometry and in vitro MRI for labeling efficiency and detectability. Moreover, the biological effects of intracellular MPIO on cell viability, cytotoxicity, proliferation and neural differentiation were evaluated. RESULTS: Intact EB-NPC aggregates showed higher cell proliferation and viability compared with the dissociated cells. Despite diffusion limitation at low MPIO concentration, higher concentration of MPIO (i.e., 10 MUg Fe/mL) was able to label EB-NPC aggregates at similar efficiency to the single cells. In vitro MRI showed concentration-dependent MPIO detection in EB-NPCs over 2.0-2.6 population doublings. More important, MPIO incorporation did not affect the proliferation and neural differentiation of EB-NPCs. CONCLUSIONS: Multicellular EB-NPC aggregates can be efficiently labeled and tracked with MPIO while maintaining cell proliferation, phenotype and neural differentiation potential. This study demonstrated the feasibility of labeling EB-NPC aggregates with MPIO for cellular monitoring of in vitro cultures and in vivo transplantation. PMID- 25527865 TI - Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry. AB - BACKGROUND: The echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene rearrangements occur in approximately 5% of lung adenocarcimomas (ACA), leading to ALK overexpression and predicting response to targeted therapy. To the present, few studies have been focused on the expression of ALK protein in lung squamous cell carcinomas (SqCC). Only several cases of lung SqCC were reported expression of ALK protein. No clinical study has been published to explicit the relationship between ALK expression and the response to targeted therapy in SqCC. METHODS: In this study, we analyzed ALK protein expression with a specific rabbit monoclonal Ig antibody (D5F3 clone) in 207 cases of lung SqCC. The positive cases were confirmed with ALK fluorescence in situ hybridization (FISH) and RT-PCR. RESULTS: We found that 3 out of 207 (1.4%) cases of lung SqCC were ALK positive detected by IHC staining, which were confirmed by ALK FISH and RT-PCR. CONCLUSIONS: Our results indicate that ALK protein expression is not a rare molecular event in SqCC. Although the frequency of EML4-ALK rearrangements is lower in lung SqCC than that in lung adenocarcinomas, their presence may provide additional treatment options in lung SqCC. The response of SqCC patients with ALK expression to target therapy of crizotinib should be explored. PMID- 25527867 TI - dNTP deficiency induced by HU via inhibiting ribonucleotide reductase affects neural tube development. AB - Exposure to environmental toxic chemicals in utero during the neural tube development period can cause developmental disorders. To evaluate the disruption of neural tube development programming, the murine neural tube defects (NTDs) model was induced by interrupting folate metabolism using methotrexate in our previous study. The present study aimed to examine the effects of dNTP deficiency induced by hydroxyurea (HU), a specific ribonucleotide reductase (RNR) inhibitor, during murine neural tube development. Pregnant C57BL/6J mice were intraperitoneally injected with various doses of HU on gestation day (GD) 7.5, and the embryos were checked on GD 11.5. RNR activity and deoxynucleoside triphosphate (dNTP) levels were measured in the optimal dose. Additionally, DNA damage was examined by comet analysis and terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) assay. Cellular behaviors in NTDs embryos were evaluated with phosphorylation of histone H3 (PH-3) and caspase-3 using immunohistochemistry and western blot analysis. The results showed that NTDs were observed mostly with HU treatment at an optimal dose of 225 mg/kg b/w. RNR activity was inhibited and dNTP levels were decreased in HU-treated embryos with NTDs. Additionally, increased DNA damage, decreased proliferation, and increased caspase-3 were significant in NTDs embryos compared to the controls. Results indicated that HU induced murine NTDs model by disturbing dNTP metabolism and further led to the abnormal cell balance between proliferation and apoptosis. PMID- 25527866 TI - S-Nitrosylation in neurogenesis and neuronal development. AB - BACKGROUND: Nitric oxide (NO) is a pleiotropic messenger molecule. The multidimensional actions of NO species are, in part, mediated by their redox nature. Oxidative posttranslational modification of cysteine residues to regulate protein function, termed S-nitrosylation, constitutes a major form of redox-based signaling by NO. SCOPE OF REVIEW: S-Nitrosylation directly modifies a number of cytoplasmic and nuclear proteins in neurons. S-Nitrosylation modulates neuronal development by reaction with specific proteins, including the transcription factor MEF2. This review focuses on the impact of S-nitrosylation on neurogenesis and neuronal development. MAJOR CONCLUSIONS: Functional characterization of S nitrosylated proteins that regulate neuronal development represents a rapidly emerging field. Recent studies reveal that S-nitrosylation-mediated redox signaling plays an important role in several biological processes essential for neuronal differentiation and maturation. GENERAL SIGNIFICANCE: Investigation of S nitrosylation in the nervous system has elucidated new molecular and cellular mechanisms for neuronal development. S-Nitrosylated proteins in signaling networks modulate key events in brain development. Dysregulation of this redox signaling pathway may contribute to neurodevelopmental disabilities such as autism spectrum disorder (ASD). Thus, further elucidation of the involvement of S nitrosylation in brain development may offer potential therapeutic avenues for neurodevelopmental disorders. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25527868 TI - Longevity-associated mitochondrial DNA 5178 C/A polymorphism modulates the effects of coffee consumption on erythrocytic parameters in Japanese men: an exploratory cross-sectional analysis. AB - BACKGROUND: Mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism reportedly modulates the effects of coffee consumption on the risk of hypertension, dyslipidemia and abnormal glucose tolerance. The objective of this analysis was to investigate whether Mt5178 C/A polymorphism modifies the effects of coffee consumption on erythrocytic parameters in male Japanese health check-up examinees. METHODS: A total of 436 men (mean age +/- standard deviation, 54.1 +/- 7.8 years) were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, an exploratory cross-sectional analysis assessing the joint effects of Mt5178 C/A polymorphism and coffee consumption on red blood cell counts, hematocrit and hemoglobin was conducted. RESULTS: For Mt5178C genotypic men, after adjustment for age, body mass index, alcohol consumption, habitual smoking and green tea consumption, coffee consumption significantly decreased red blood cell counts (P for trend = 0.022) and hemoglobin (P for trend = 0.035). The risk of anemia, defined as hemoglobin of <14 g/dL, after the aforementioned adjustment, appeared to depend on coffee consumption (P for trend = 0.078), and the adjusted odds ratio for anemia was significantly higher in men who consumed >=4 cups of coffee per day than in those who consumed <1 cup per day (odds ratio = 3.771, 95% confidence interval: 1.088 to 13.06, P = 0.036). For Mt5178A genotypic men, coffee consumption possibly reduced the risk of anemia (P for trend = 0.049). However, after the aforementioned adjustment, the statistical significance disappeared (P for trend = 0.137). CONCLUSIONS: This exploratory cross-sectional analysis suggests that Mt5178 C/A polymorphism modulates the effects of coffee consumption on erythrocytic parameters and the risk of anemia in male Japanese health check-up examinees. PMID- 25527869 TI - The acquisition and retention of urinary catheterisation skills using surgical simulator devices: teaching method or student traits. AB - BACKGROUND: The acquisition of procedural skills is an essential component of learning for medical trainees. The objective of this study was to assess which teaching method of performing urinary catheterisation is associated with most efficient procedural skill acquisition and retention. We evaluated factors affecting acquisition and retention of skills when using simulators as adjuncts to medical training. METHODS: Forty-two second year medical students were taught urinary catheter insertion using different teaching methods. The interactive group (n = 19) were taught using a lecture format presentation and a high fidelity human urinary catheter simulator. They were provided with the use of simulators prior to examination. The observer group (n = 12) were taught using the same method but without with simulator use prior to examination. The didactic group (n = 11) were taught using the presentation alone. Student characteristics such as hand dexterity and IQ were measured to assess for intrinsic differences. All students were examined at four weeks to measure skill retention. RESULTS: Catheter scores were significantly higher in the interactive group (p < 0.005). Confidence scores with catheter insertion were similar at index exam however were significantly lower in the didactic group at the retention testing (p < 0.05). Retention scores were higher in the interactive group (p < 0.001). A significant positive correlation was observed between laparoscopy scores and time to completion with overall catheter score (p < 0.05). Teaching method, spatial awareness and time to completion of laparoscopy were significantly associated with higher catheter scores at index exam (p = 0.001). Retention scores at 4 weeks were significantly associated with teaching method and original catheter score (p = 0.001). CONCLUSION: The importance of simulators in teaching a complex procedural skill has been highlighted. Didactic teaching method was associated with a significantly higher rate of learning decay at retention testing. PMID- 25527870 TI - The relationship between stimulus repetitions and fulfilled expectations. AB - Several neuroimaging studies showed that fulfilled expectations increase the magnitude of repetition suppression (RS) in the face-selective visual cortex. However, previous fMRI studies did not allow a distinction between the reductions of the response due to stimulus repetitions and fulfilled expectations (expectation suppression, ES). In most prior studies repetitions and expectations were not independent from each other as repetitions occurred more often when they were expected and less often when they were not expected, thereby confounding RS with ES. To overcome this confound, we presented pairs of female and male faces that were either repeating or alternating with an overall probability of 50-50%. Orthogonally to this, the gender of the first face in each pair signaled with 75% accuracy whether repetitions or alternations were more likely to occur. We found significant RS in the FFA, the OFA and the LO. In addition, these areas showed a reduction of the response for expected when compared to surprising trials. Moreover, the effects of RS and ES were always additive rather than interactive in our ROIs. This implies that stimulus repetition and fulfilled expectations can be dissociated from one another in terms of their effects on the neural responses. PMID- 25527871 TI - Chest pain out-of-hours - an interview study of primary care physicians' diagnostic approach, tolerance of risk and attitudes to hospital admission. AB - BACKGROUND: Acute chest pain constitutes a considerable diagnostic challenge outside hospitals. This will often lead to uncertainty in choosing the right management, and the physicians' approach may be influenced by their knowledge of diagnostic measures and their tolerance of risk. The aim of this study was to investigate primary care physicians' diagnostic approach, tolerance of risk and attitudes to hospital admission in patients with acute chest pain out-of-hours in Norwegian primary care. METHODS: Data were registered prospectively from four Norwegian casualty clinics. Data from structured telephone interviews with 100 physicians shortly after a consultation with a patient presenting at the casualty clinic with "chest pain" were analysed. Tolerance of risk was measured by the Pearson Risk Scale and the Tolerance of Risk Scale, the latter developed for this study. RESULTS: "Patient history and symptoms" was considered the most important, and "negative ECG" and "effect of sublingual nitroglycerine" the least important aspects in the diagnostic approach. There were no significant differences in length of experience or gender when testing "risk avoiders" against the rest. Almost all physicians felt that their risk assessment out-of-hours was reasonably good, and felt reasonably safe, but only 50% agreed with the statement "I don't worry about my decisions after I've made them". Concerning chest pain patients only, 51% of the physicians were worried about complaints being made about them, 75% agreed that admitting someone to hospital put patients in danger of being "over-tested", and 51% were more likely to admit the patient if the patient herself wanted to be admitted. CONCLUSIONS: Physicians working out-of-hours showed considerable differences in their diagnostic approach, and not all physicians diagnose patients with chest pain according to current guidelines and evidence. Continuous medical education must focus on the diagnostic approach in patients with chest pain in primary care and empowerment of physicians through training and emphasis on risk assessment and "tolerance of risk". PMID- 25527872 TI - A qualitative study of health system barriers to accessibility and utilization of maternal and newborn healthcare services in Ghana after user-fee abolition. AB - BACKGROUND: To reduce financial barriers to access, and improve access to and use of skilled maternal and newborn healthcare services, the government of Ghana, in 2003, implemented a new maternal healthcare policy that provided free maternity care services in all public and mission healthcare facilities. Although supervised delivery in Ghana has increased from 47% in 2003 to 55% in 2010, strikingly high maternal mortality ratio and low percentage of skilled attendance are still recorded in many parts of the country. To explore health system factors that inhibit women's access to and use of skilled maternal and newborn healthcare services in Ghana despite these services being provided free. METHODS: We conducted qualitative research with 185 expectant and lactating mothers and 20 healthcare providers in six communities in Ghana between November 2011 and May 2012. We used Attride-Stirling's thematic network analysis framework to analyze and present our data. RESULTS: We found that in addition to limited and unequal distribution of skilled maternity care services, women's experiences of intimidation in healthcare facilities, unfriendly healthcare providers, cultural insensitivity, long waiting time before care is received, limited birthing choices, poor care quality, lack of privacy at healthcare facilities, and difficulties relating to arranging suitable transportation were important health system barriers to increased and equitable access and use of services in Ghana. CONCLUSION: Our findings highlight how a focus on patient-side factors can conceal the fact that many health systems and maternity healthcare facilities in low-income settings such as Ghana are still chronically under-resourced and incapable of effectively providing an acceptable minimum quality of care in the event of serious obstetric complications. Efforts to encourage continued use of maternity care services, especially skilled assistance at delivery, should focus on addressing those negative attributes of the healthcare system that discourage access and use. PMID- 25527873 TI - Transport and deposition of stabilized engineered silver nanoparticles in water saturated loamy sand and silty loam. AB - It is considered inevitable that the increasing production and application of engineered nanoparticles will lead to their release into the environment. However, the behavior of these materials under environmentally relevant conditions is still only poorly understood. In this study the transport and deposition behavior of engineered surfactant stabilized silver nanoparticles (AgNPs) in water saturated porous media was investigated in transport experiments with glass beads as reference porous medium and in two natural soils under various hydrodynamic and hydrochemical conditions. The transport and retention processes of AgNPs in the porous media were elucidated by inverse modeling and possible particle size changes occurring during the transport through the soil matrix were analyzed with flow field-flow fractionation (FlFFF). A high mobility of AgNPs was observed in loamy sand under low ionic strength (IS) conditions and at high flow rates. The transport was inhibited at low flow rates, at higher IS, in the presence of divalent cations and in a more complex, fine-grained silty loam. The slight decrease of the mean particle size of the AgNPs in almost all experiments indicates size selective filtration processes and enables the exclusion of homoaggregation processes. PMID- 25527874 TI - Augmented reality-assisted bypass surgery: embracing minimal invasiveness. AB - OBJECTIVE: The overlay of virtual images on the surgical field, defined as augmented reality, has been used for image guidance during various neurosurgical procedures. Although this technology could conceivably address certain inherent problems of extracranial-to-intracranial bypass procedures, this potential has not been explored to date. We evaluate the usefulness of an augmented reality based setup, which could help in harvesting donor vessels through their precise localization in real-time, in performing tailored craniotomies, and in identifying preoperatively selected recipient vessels for the purpose of anastomosis. METHODS: Our method was applied to 3 patients with Moya-Moya disease who underwent superficial temporal artery-to-middle cerebral artery anastomoses and 1 patient who underwent an occipital artery-to-posteroinferior cerebellar artery bypass because of a dissecting aneurysm of the vertebral artery. Patients' heads, skulls, and extracranial and intracranial vessels were segmented preoperatively from 3-dimensional image data sets (3-dimensional digital subtraction angiography, angio-magnetic resonance imaging, angio-computed tomography), and injected intraoperatively into the operating microscope's eyepiece for image guidance. RESULTS: In each case, the described setup helped in precisely localizing donor and recipient vessels and in tailoring craniotomies to the injected images. CONCLUSIONS: The presented system based on augmented reality can optimize the workflow of extracranial-to-intracranial bypass procedures by providing essential anatomical information, entirely integrated to the surgical field, and help to perform minimally invasive procedures. PMID- 25527875 TI - PsT1: A Low-Cost Optical Simulator for Psychomotor Skills Training in Neuroendoscopy. AB - BACKGROUND: Well-developed psychomotor skills are important for competence in minimally invasive surgery. Neuroendoscopy is no exception, and adaptation to different visual perspectives and careful handling of the surgical instruments are mandatory. Few training systems, however, focus on developing psychomotor skills for neuroendoscopy. Here, we introduce a new training system called PsT1 that provides visual feedback via the use of simple optics that emulate the endoscope at 0 degrees and 30 degrees . Time and error metrics are generated automatically with integrated software to ensure objective assessment. METHODS: Neuroendoscopic optics were emulated with a low-cost, commercially available universal serial bus 2.0 camera and a light-emitting diode light source. Visual feedback of 30 degrees was obtained by displacing the optical axis of the universal serial bus camera by 30 degrees , and metrics (time, precision, and errors) were generated automatically by the software. Three evaluation modules were developed (spatial adaptation, depth adaptation, and dissection), and 35 expert and nonexpert neurosurgeons performed an initial evaluation of the system. RESULTS: A total of 81% and 90% of surgeons agreed that the visuals were satisfactory and movement and control were accurately replicated, respectively. The advantages and disadvantages of the system were compared. CONCLUSIONS: Here, we present a novel, low-cost, and easy-to-implement training system for developing basic neuroendoscopic psychomotor skills. The use of objective metrics, surgical instruments, and emulation of the neuroendoscope at 0 degrees and 30 degrees are competitive advantages of the current system. PMID- 25527876 TI - Presence of haptoglobin-2 allele is associated with worse functional outcomes after spontaneous intracerebral hemorrhage. AB - OBJECTIVE: To determine if the haptoglobin (Hp) phenotype, which has been shown to be a predictor of clinical outcomes in cerebrovascular disorders, particularly subarachnoid hemorrhage, was predictive of functional outcomes after spontaneous intracerebral hemorrhage (ICH). METHODS: Patients admitted with a diagnosis of ICH were prospectively included and divided into 3 groups based on their genetically determined Hp phenotype: 1-1, 2-1, and 2-2. Outcome measures included mortality and 30-day modified Rankin Scale scores. Demographics and outcomes were compared for each phenotype using multivariate linear regression analysis. RESULTS: The study included 94 patients. The distribution of Hp phenotype was Hp 1-1, 12 (13%); Hp 2-1, 46 (49%); and Hp 2-2, 36 (38%). The 3 Hp subgroups did not differ in terms of demographic variables, comorbidities, or ICH characteristics. There was a nonsignificant trend toward increased mortality in Hp 2-1 and Hp 2-2 compared with Hp 1-1, with mortality of 8% in Hp 1-1, 17% in Hp 2-1, and 25% in Hp 2-2 (P = 0.408). In the regression model adjusted for confounders, Hp 2-1 (odds ratio = 0.05, 95% confidence interval = 0.01-0.47, P < 0.001) and Hp 2-2 phenotypes (odds ratio = 0.14, 95% confidence interval = 0.02-0.86, P = 0.045) had significantly lower odds of modified Rankin Scale scores 0-2 compared with Hp 1-1. CONCLUSIONS: After ICH, individuals with the Hp-2 allele (2-1 and 2-2) had worse functional outcomes than individuals with the Hp-1 allele (Hp 1-1). There was a nonsignificant association between Hp phenotype and mortality. Larger prospective studies with better surrogates of ICH outcomes are warranted. PMID- 25527877 TI - Extent of preoperative depression is associated with return to work after lumbar fusion for spondylolisthesis. AB - BACKGROUND: The ability to understand factors associated with an increased duration of missed work postoperatively could be used to more effectively select patients with the greatest opportunity for a successful outcome. We set out to determine the effect of preoperative depression on postoperative return to work in patients undergoing transforaminal lumbar interbody fusion (TLIF) for degenerative spondylolisthesis. METHODS: Fifty-eight patients undergoing TLIF for symptomatic grade I degenerative lumbar spondylolisthesis were included in this analysis. Patient demographics, clinical presentation, indications for surgery, radiologic studies, and operative variables were assessed for each case. Patient assessed outcome measures were obtained prospectively at baseline and 2 years postoperatively. To understand the factors associated with prolonged return to work, univariate linear regression analysis and stepwise multivariate Cox proportional hazards model was used. RESULTS: All patient-reported outcomes assessed were significantly improved 2 years after TLIF (P < 0.001). Of the 32 patients working preoperatively, 26 (81%) returned to work postoperatively. Median time to return to work was 56 days (range, 10-150 days). Independent of patient age; preoperative pain, disability, and quality of life; and extent of postoperative improvement, increased preoperative Zung depression score remained associated with prolonged return to work (P = 0.02). CONCLUSIONS: Independent of postoperative improvement in pain, disability, and quality of life, the extent of preoperative depression was an independent predictor of time to return to work in patients undergoing TLIF for spondylolisthesis, suggesting that regardless of how successful TLIF surgery may be at improving a patient's pain, disability, or quality of life, greater depression will delay or prohibit their ability to return to work postoperatively. PMID- 25527878 TI - Intracranial aneurysm rupture is predicted by measures of solar activity. AB - OBJECTIVE: The cause precipitating intracranial aneurysm rupture remains unknown in many cases. It has been observed that aneurysm ruptures are clustered in time, but the trigger mechanism remains obscure. Because solar activity has been associated with cardiovascular mortality and morbidity, we decided to study its association to aneurysm rupture in the Swiss population. METHODS: Patient data were extracted from the Swiss SOS database, at time of analysis covering 918 consecutive patients with angiography-proven aneurysmal subarachnoid hemorrhage treated at 7 Swiss neurovascular centers between January 1, 2009, and December 31, 2011. The daily rupture frequency (RF) was correlated to the absolute amount and the change in various parameters of interest representing continuous measurements of solar activity (radioflux [F10.7 index], solar proton flux, solar flare occurrence, planetary K-index/planetary A-index, Space Environment Services Center [SESC] sunspot number and sunspot area) using Poisson regression analysis. RESULTS: During the period of interest, there were 517 days without recorded aneurysm rupture. There were 398, 139, 27, 12, 1, and 1 days with 1, 2, 3, 4, 5, and 6 ruptures per day. Poisson regression analysis demonstrated a significant correlation of F10.7 index and RF (incidence rate ratio [IRR] = 1.006303; standard error (SE) 0.0013201; 95% confidence interval (CI) 1.003719-1.008894; P < 0.001), according to which every 1-unit increase of the F10.7 index increased the count for an aneurysm to rupture by 0.63%. A likewise statistically significant relationship of both the SESC sunspot number (IRR 1.003413; SE 0.0007913; 95% CI 1.001864-1.004965; P < 0.001) and the sunspot area (IRR 1.000419; SE 0.0000866; 95% CI 1.000249-1.000589; P < 0.001) emerged. All other variables analyzed showed no significant correlation with RF. CONCLUSIONS: We found greater radioflux, SESC sunspot number, and sunspot area to be associated with an increased count of aneurysm rupture. The clinical meaningfulness of this statistical association must be interpreted carefully and future studies are warranted to rule out a type-1 error. PMID- 25527879 TI - Risks of in-hospital death and complications after fusion surgery in patients with atlantoaxial subluxation: analysis of 1090 patients using the Japanese Diagnosis Procedure Combination database. AB - OBJECTIVE: To examine in-hospital mortality and postoperative major complications in patients undergoing fusion surgery for atlantoaxial subluxation (AAS) and to examine whether the risk of perioperative complications varies between patients with and without rheumatoid arthritis (RA). METHODS: A retrospective analysis of data from the Diagnosis Procedure Combination database, a nationwide administrative impatient database in Japan, identified 1090 patients who underwent spinal fusion surgery for AAS during 2007-2012. Patients' clinical characteristics were extracted, including age, sex, use of homologous blood transfusion, length of stay, and type of hospital. Clinical outcomes included in hospital death and major complications, including surgical-site infection, sepsis, cardiac events, respiratory disorders, acute renal failure, pulmonary embolism, perioperative stroke, and vertebral injury. Massive blood transfusion was defined as at least 6 units of red blood cells. RESULTS: Four hundred sixty five patients (42.7%) were classified as the RA group. In-hospital mortality after fusion surgery for AAS was 0.5% (5/1090), and major complications occurred in 5% (55/1090). Multivariate analyses showed that patients with RA were more likely to have major complications after surgery than patients without RA (odds ratio: 1.69; 95% confidence interval: 0.96-2.97; P = 0.07), and the rate of massive blood transfusion was significantly greater in patients with RA than in patients without RA (odds ratio: 2.29; 95% confidence interval: 1.12-4.68; P = 0.02). CONCLUSIONS: The in-hospital mortality after fusion surgery for AAS was relatively low. However, patients with RA had an increased risk of postoperative complications and massive blood transfusion compared with patients without RA. PMID- 25527880 TI - Surgical microanatomy of the anterior clinoid process for paraclinoid aneurysm surgery and efficient modification of extradural anterior clinoidectomy. AB - BACKGROUND: Anatomic variations of the anterior clinoid process (ACP) should be recognized before clinoidectomy to ensure a safe approach. This study describes the incidence of caroticoclinoid foramen (CCF), interclinoid osseous bridge, and pneumatization of the ACP during extradural anterior clinoidectomy. The problems and technical issues encountered in such cases are described. METHODS: Using multidetector-row computed tomography, 144 sides in 72 cases of paraclinoid aneurysm treated by extradural anterior clinoidectomy were analyzed preoperatively. RESULTS: CCF, interclinoid osseous bridge, and pneumatization of the ACP were observed in 16.6%, 2.77%, and 27.7% of cases. Pneumatized patterns were divided into 3 groups according to route: pneumatization via the optic strut (in 74.1%), pneumatization via the anterior root (in 14.8%), and pneumatization via optic strut and anterior root (in 11.1%). CCF and interclinoid osseous bridge represent obstacles to complete extradural removal of the ACP. The ACP should not be moved even after drilling the lateral wall of the ACP, orbital roof, and optic strut, so an intradural approach is sometimes needed. A CCF warrants careful removal to open the distal dural ring. Awareness of the routes of pneumatization for the ACP should reduce the risk of tears in the paranasal mucosa. If tears arise in the mucosa, suturing and closure are needed to prevent liquorrhea. CONCLUSIONS: Preoperative computed tomography is useful to detect variations in the anatomy around the ACP. When performing extradural anterior clinoidectomy in such anomalous cases, appropriate modifications are needed to ensure a safe approach. PMID- 25527881 TI - Breach of Posterior Wall of Frontal Sinus: Management with Preservation of the Sinus. AB - OBJECTIVE: To analyze outcomes after the management of mild (<1 mm) and moderately severe (>1 mm and <5 mm) breaches of the posterior wall of the frontal sinus with a goal of maintaining or restoring the functional status of the sinus. METHODS: A retrospective analysis of prospectively accrued data was performed on patients with mild and moderately severe breaches of the posterior wall of their frontal sinus who were managed with the intent to preserve the frontal sinus. Data on presenting features, pathology, details on breaches of the posterior wall, management, outcome, and complications were collected from medical records and neuroimages. RESULTS: Forty-two cases met inclusion criteria. Diagnostic categories included trauma in 34 cases, infection in 3, and other categories in another 5 cases. Five presented with cerebrospinal fluid rhinorrhea, and 26 had radiographic evidence of obstruction of a nasofrontal duct at time of presentation. Fifteen patients were managed without surgical intervention, and 27 underwent surgery. No complications occurred in the patients managed without surgery and 4 postoperative cerebrospinal leaks that were managed successfully with a period of drainage occurred in the surgical group. No patient developed meningitis or mucocele. CONCLUSIONS: Many patients with mild to moderately severe breaches of the posterior wall of the frontal sinus can be managed safely and effectively by techniques that preserve the anatomy and function of the frontal sinus. PMID- 25527882 TI - Deep brain stimulation of the nucleus accumbens and bed nucleus of stria terminalis for obsessive-compulsive disorder: a case series. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric condition defined by the presence of obsessions, compulsions, or both. It has a lifetime prevalence of 2%-3% and causes significant impairment in social and work functioning, as well as a reduced quality of life. Treatment includes pharmacotherapy and psychotherapy, but a significant number of patients fail to respond to treatment. Deep brain stimulation has shown to be a safe and effective procedure for severe, chronic, treatment-resistant OCD, and several surgical targets have been proposed for treatment, including the nucleus accumbens, the anterior limb of the internal capsule, the subthalamic nucleus, the globus pallidus, and the bed nucleus of stria terminalis. OBJECTIVES: To report the first Italian case series of patients who underwent DBS of 2 distinct targets for OCD: nulceus accumbens and bed nulceus of stria terminalis. METHODS: Four patients underwent DBS of the nulceus accumbens, and 4 patients underwent DBS of the bed nucleus of stria terminalis. RESULTS: Six patients showed a significant improvement in OCD symptoms. CONCLUSIONS: DBS of these 2 structures is a safe and effective procedure for the treatment of severe, refractory OCD. PMID- 25527883 TI - Pituitary tumor apoplexy in adolescents. AB - OBJECTIVE: The aim of this study was to determine whether there are differences in pituitary apoplexy and subclinical apoplexy secondary to adenoma hemorrhage in the adolescent population with regard to symptomatology, neuroimaging features, pathology, and outcomes compared with adults. METHODS: A retrospective series of 9 consecutive patients with a diagnosis of pituitary hemorrhage who were surgically treated at Rady's Children's Hospital San Diego, between 2008 and 2013 were evaluated for clinical, endocrine, neuroradiographic, and pathologic features in association with clinical outcomes. RESULTS: Nine patients (6 girls, age 14-21 years) presented to our institution with headache (9/9), nausea (3/9), dizziness (4/9), and visual disturbances (6/9) in the setting of a sellar hemorrhagic tumor on magnetic resonance imaging (MRI). Three patients presented with apoplexy and 6 with subclinical apoplexy. Duration of symptoms ranged from 3 days to 1 year. MRI revealed hemorrhage (9/9), rim enhancement (6/9), sphenoid sinus mucosal thickening (2/9), mass effect on the optic chiasm (8/9), and sellar remodeling (9/9). The percentage of hemorrhage preoperatively observed on MRI ranged from 50% to greater than 95%. On presentation, hyperprolactinemia was recorded in 7 patients, 6 of whom had galactorrhea and/or amenorrhea. Open transsphenoidal decompression was performed in 8/9 patients; 7 of 9 were diagnosed with prolactinoma. Biopsy specimens revealed 10%-90% hemorrhage and no infarction in any of the cases. All patients treated showed improvement of symptoms after surgery (average follow-up, 28.2 months). Postoperative complications included transient diabetes insipidus (n = 5), persistent cerebrospinal fluid rhinorrhea (n = 3), and meningitis (n = 1). Five patients had long-term endocrine sequelae of hyperprolactinemia requiring ongoing medical treatment. CONCLUSIONS: Pituitary hemorrhage resulting in apoplexy or subclinical apoplexy in adolescents may represent a distinct entity with a more indolent symptomatology and more favorable neurologic and endocrine outcome compared with adults that is worthy of further validation in a multi-institutional cohort. PMID- 25527884 TI - Neuro-ophthalmic presentation and surgical results of unruptured intracranial aneurysms-prospective Helsinki experience of 142 patients. AB - OBJECTIVE: To assess prospectively neuro-ophthalmic findings associated with unruptured intracranial aneurysms and treatment morbidity and to identify factors predicting these findings. METHODS: Patients admitted to Helsinki University Central Hospital and treated surgically or endovascularly during 2011 underwent a neuro-ophthalmic examination, including formal visual field testing, before operation, at discharge, and 2-4 months and >=6 months postoperatively. Univariate and multivariate analysis was used to identify factors predicting eye movement disorders. RESULTS: Study participants included 142 patients with 184 treated aneurysms: 7 (5%) had a third, fourth, or sixth nerve palsy or skew deviation preoperatively, and 16 (11%) had a third, fourth, or sixth nerve palsy or skew deviation postoperatively; the frequency was 8 (6%) at the last follow-up evaluation. Other findings included compressive optic neuropathy (n = 4), ischemic optic neuropathy (n = 1), Weber syndrome (n = 3), Benedikt syndrome (n = 1), and Wallenberg syndrome (n = 1). Of the 140 survivors at 6 months, 7 (5%) presented with visual field defects resulting from the aneurysm or its treatment. In the best bivariate model, factors independently predicting postoperative eye movement disorders were aneurysm location in the posterior circulation with an odds ratio of 142.02 (95% confidence interval = 20.13-1002.22) and aneurysm size (odds ratio = 1.28 for each 1-mm increase in diameter, 95% confidence interval = 1.12-1.47). CONCLUSIONS: Management of unruptured intracranial aneurysms is fairly safe from a neuro-ophthalmic perspective, with some treatment-related morbidity being transient and minor. Although rare, an irreversible deficit is possible and should be taken into account when considering preventive treatment. PMID- 25527885 TI - Complication avoidance in the resection of spinal meningiomas. AB - BACKGROUND: Surgical resection is considered the treatment of choice for spinal meningiomas and can be safe and effective; however, neurologic and surgical complications occur. This article reviews the factors that may predict susceptibility to this postoperative decline and addresses therapeutic choices, adjunctive therapies, and technologic applications that may help avoid complications. METHODS: A literature search was conducted for articles related to spinal meningiomas addressing surgical treatment, adjuvant treatment, and technologic applications related to management and minimizing of complications. RESULTS: There were 16 surgical series identified, comprising 1090 patients with median mortality of 1% (range, 0%-4%), nonneurologic surgical morbidity of 4% (range, 0%-24%), and permanent neurologic deterioration of 6% (range, 0%-21%). Common complications were cerebrospinal fluid leaks and fistulas, venous thromboembolic disease, myocardial infarction, and neurologic deterioration with either transient or permanent neurologic deficits. Predictive risk factors of neurologic decline included pathoanatomic features of lesion calcification, anterior dural attachment, infiltrative tumor, and tumoral adherence to the spinal cord and patient-specific factors of preoperative neurologic and advanced age. CONCLUSIONS: Alongside surgery, selection of more direct approaches and use of adjuvant radiotherapy in patients with higher grade lesions and recurrent disease may lead to improved outcomes. New technologies, including microsurgical technique, intraoperative electrophysiologic monitoring, intraoperative ultrasound, and ultrasonic aspiration, may improve the safety and limit the complications of resection. PMID- 25527886 TI - Strategies to minimize complications during intraoperative aneurysmal hemorrhage: a personal experience. AB - BACKGROUND: The occurrence of intraoperative rupture (IOR) of an aneurysm is one of the most precarious moments in microsurgery, and the management of IOR profoundly affects operative outcomes. METHODS: The authors describe their personal experiences during the past decade with managing intraoperative aneurysm rupture for microsurgical treatment of complex cerebral aneurysm procedures. RESULTS: Steps to avoid and manage IOR depend on the stage of the operation or phase of dissection and on aneurysm location and configuration. The point at which IOR occurs dictates the management options available. The rupture of the aneurysm itself usually does not cause death or disability, but the subsequent actions performed by the surgeon can make the difference between a good and poor outcome. Major complications are caused by the surgeon's premature reaction placing a permanent clip in the face of torrential bleeding without adequate visualization, leading to vascular and cranial nerve injuries. Short videos are provided to illustrate the technical nuances to minimize complications. CONCLUSIONS: Accurate knowledge of the anatomy of the aneurysm and surrounding vasculature is the keystone to prevention and treatment of IOR. Most importantly, the surgeon must not rush prematurely to apply a permanent clip blindly in an effort to stop the hemorrhage. PMID- 25527887 TI - Damping and energy dissipation in soft tissue vibrations during running. AB - It has been well accepted that the vibrations of soft tissue cannot be simulated by a single sinusoidal function. In fact, these vibrations are a combination of several vibration modes. In this study, these modes are extracted applying a recently developed method namely, partly ensemble empirical mode decomposition (PEEMD). Then, a methodology for estimating the damping properties and energy dissipation caused by damping for each mode is used. Applying this methodology on simulated signals demonstrates high accuracy. This methodology is applied to the acceleration signals of the gastrocnemius muscle during sprinting and the differences between the damping properties of different vibration modes were identified. The results were 1) the damping property of high-frequency mode was higher than that for low-frequency modes. 2) All identified modes were in under damped condition, therefore, the vibrations had an oscillatory nature. 3) The damping ratios of lower modes are about 100% increased compared to higher modes. 4) The energy dissipation occurred in lower modes were much more than that for higher mode; According to the power spectrum of the ground reaction force (GRF), which is the input force into the body, the recent finding supports the muscle tuning paradigm. It is suggested that the damping properties and energy dissipation can be used to distinguish between different running conditions (surface, fatigue, etc.). PMID- 25527888 TI - Comparison of explicit finite element and mechanical simulation of the proximal femur during dynamic drop-tower testing. AB - Current screening techniques based on areal bone mineral density (aBMD) measurements are unable to identify the majority of people who sustain hip fractures. Biomechanical examination of such events may help determine what predisposes a hip to be susceptible to fracture. Recently, drop-tower simulations of in-vitro sideways falls have allowed the study of the mechanical response of the proximal human femur at realistic impact speeds. This technique has created an opportunity to validate explicit finite element (FE) models against dynamic test data. This study compared the outcomes of 15 human femoral specimens fractured using a drop tower with complementary specimen-specific explicit FE analysis. Correlation coefficient and root mean square error (RMSE) were found to be moderate for whole bone stiffness comparison (R(2)=0.3476 and 22.85% respectively). No correlation was found between experimentally and computationally predicted peak force, however, energy absorption comparison produced moderate correlation and RMSE (R(2)=0.4781 and 29.14% respectively). By comparing predicted strain maps to high speed video data we demonstrated the ability of the FE models to detect vulnerable portions of the bones. Based on our observations, we conclude that there exists a need to extend the current apparent level material models for bone to cover higher strain rates than previously tested experimentally. PMID- 25527889 TI - Biomechanical study on the bladder neck and urethral positions: simulation of impairment of the pelvic ligaments. AB - Excessive mobility of the bladder neck and urethra are common features in stress urinary incontinence. We aimed at assessing, through computational modelling, the bladder neck position taking into account progressive impairment of the pelvic ligaments. Magnetic resonance images of a young healthy female were used to build a computational model of the pelvic cavity. Appropriate material properties and constitutive models were defined. The impairment of the ligaments was simulated by mimicking a reduction in their stiffness. For healthy ligaments, valsalva maneuver led to an increase in the alpha angle (between the bladder neck symphysis pubis and the main of the symphysis) from 91.8 degrees (at rest) to 105.7 degrees , and 5.7 mm of bladder neck dislocation, which was similar to dynamic imaging of the same woman (alpha angle from 80 degrees to 103.3 degrees , and 5mm of bladder neck movement). For 95% impairment, they enlarged to 124.28 degrees and 12 mm. Impairment to the pubourethral ligaments had higher effect than that of vaginal support (115 degrees vs. 108 degrees , and 9.1 vs. 7.3mm). Numerical simulation could predict urethral motion during valsalva maneuver, for both healthy and impaired ligaments. Results were similar to those of continent women and women with stress urinary incontinence published in the literature. Biomechanical analysis of the pubourethral ligaments complements the biomechanical study of the pelvic cavity in urinary incontinence. It may be useful in young women presenting stress urinary incontinence without imaging evidence of urethral and muscle lesions or organ descend during valsalva, and for whom fascial damage are not expected. PMID- 25527890 TI - Biomechanical benefits of the Onion-Skin motor unit control scheme. AB - Muscle force is modulated by varying the number of active motor units and their firing rates. For the past five decades, the notion that the magnitude of the firing rates is directly related to motor unit size and recruitment threshold has been widely accepted. This construct, here named the After-hyperpolarization scheme evolved from observations in electrically stimulated cat motoneurons and from reported observations in voluntary contractions in humans. It supports the assumption that the firing rates of motor units match their mechanical properties to "optimize" force production, so that the firing rate range corresponds to that required for force-twitch fusion (tetanization) and effective graduation of muscle force. In contrast, we have shown that, at any time and force during isometric voluntary constant-force contractions in humans, the relationship between firing rate and recruitment threshold is inversely related. We refer to this construct as the Onion-Skin scheme because earlier-recruited motor units always have greater firing rates than latter-recruited ones. By applying a novel mathematical model that calculates the force produced by a muscle for the two schemes we found that the Onion-Skin scheme is more energy efficient, provides smoother muscle force at low to moderate force levels, and appears to be more conducive to evolutionary survival than the After-hyperpolarization scheme. PMID- 25527891 TI - Quantitative analysis of imprint shape and its relation to mechanical properties measured by microindentation in bone. AB - Microindentation in bone is a micromechanical testing technique routinely used to extract material properties related to bone quality. As the analysis of microindentation data is based on assumptions about the contact between sample and surface, the aim of this study was to quantify the topological variability of indentations in bone and examine its relationship with mechanical properties. Indentations were performed in dry human and ovine bone in axial and transverse directions and their topology was measured by atomic force microscopy. Statistical shape modeling of the residual imprint allowed to define a mean shape and to describe the variability in terms of 21 principal components related to imprint depth, surface curvature and roughness. The indentation profile of bone was found to be highly consistent and free of any pile up while differing mostly by depth between species and direction. A few of the topological parameters, in particular depth, showed significant but rather weak and inconsistent correlations to variations in mechanical properties. The mechanical response of bone as well as the residual imprint shape was highly consistent within each category. We could thus verify that bone is rather homogeneous in its micromechanical properties and that indentation results are not strongly influenced by small deviations from an ideally flat surface. PMID- 25527892 TI - The extent of altered digit force direction correlates with clinical upper extremity impairment in chronic stroke survivors. AB - Many stroke survivors suffer from impaired hand function. Biomechanics of hand grip suggests that abnormally directed grip force can hamper gripping abilities and hand function. This study examined the relation between the ability to precisely direct fingertip force and clinical hand function scores among individuals affected by stroke. Specifically, clinical hand function tests of the Fugl-Meyer, Chedoke McMaster, and Box and Block Test were used, since they involve various hand movements required for activities of daily living. Digit force direction during static grip was recorded using multiaxial load cells. Data for 59 chronic stroke survivors were analyzed. We found that larger angular deviation of digit force from the normal direction was significantly associated with lower hand functional levels (p<.001 for all three clinical tests). Particularly, stroke survivors whose digit force deviated more than 21 degrees from the normal direction could not achieve the normal level of Fugl-Meyer or Chedoke or move more than 4 blocks in a minute. The biomechanics of the way digit force direction affects hand grip function is described. In addition, underlying mechanisms for altered digit force direction post stroke are postulated, including impaired somatosensation and abnormal neural input to muscles. In summary, this study identifies a new biomechanical marker for hand functional level and recovery. Future interventions may focus on correcting digit force direction to improve hand functional outcome. PMID- 25527894 TI - Analytical evaluation of natural radionuclides and their radioactive equilibrium in raw materials and by-products. AB - An investigation into the distribution of natural radionuclides and radioactive secular equilibrium in raw materials and by-products in a domestic distribution was conducted to deduce the optimum conditions for the analytical evaluation of natural radionuclides for (238)U, (226)Ra, and (232)Th using a gamma-ray spectrometer and inductively coupled plasma mass spectrometer (ICP-MS). The range of the specific activities of natural radionuclides was first evaluated by analyzing (228)Ac and (214)Bi, which are (232)Th and (226)Ra indicators, respectively, in about 100 samples of raw materials and by-products through a gamma-ray spectrometer. From further experiments using several samples selected based on the results of the distribution of natural radionuclides, the validation of their analytical evaluations for the indirect measurements using a gamma-ray spectrometer and direct measurements using ICP-MS was assured by comparing their results. Chemically processed products from the raw materials, such as Zr sand and ceramic balls, were generally shown for the type of bead and particularly analyzed showing a definite disequilibrium with above a 50% difference between (238)U and (226)Ra in the uranium series and (232)Th and (228)Ra in the thorium series. PMID- 25527893 TI - Protective variant associated with alcohol dependence in a Mexican American cohort. AB - BACKGROUND: Mexican Americans, particularly those born in the United States, are at greater risk for alcohol associated morbidity and mortality. The present study sought to investigate whether specific genetic variants may be associated with alcohol use disorder phenotypes in a select population of Mexican American young adults. METHODS: The study evaluated a cohort of 427 (age 18 - 30 years) Mexican American men (n = 171) and women (n = 256). Information on alcohol dependence was obtained through interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). For all subjects, DNA was extracted from blood samples, followed by genotyping using an Affymetrix Axiom Exome1A chip. RESULTS: A protective variant (rs991316) located downstream from the ADH7 (alcohol dehydrogenase 7) gene showed suggestive significance in association with alcohol dependence symptom counts derived from DSM-III-R and DSM-IV criteria, as well as to clustered alcohol dependence symptoms. Additional linkage analysis suggested that nearby variants in linkage disequilibrium with rs991316 were not responsible for the observed association with the alcohol dependence phenotypes in this study. CONCLUSIONS: ADH7 has been shown to have a protective role against alcohol dependence in previous studies involving other ethnicities, but has not been reported for Mexican Americans. These results suggest that variants near ADH7 may play a role in protection from alcohol dependence in this Mexican American cohort. PMID- 25527895 TI - Activity determination of (41)Ar using efficiency extrapolation method and 4pibeta(PS)-4pigamma(NaI) coincidence system. AB - Noble gas (41)Ar was measured with a 4pibeta-4pigamma coincidence system, in which gamma- and beta-rays were respectively detected with a well-type NaI(Tl) and plastic scintillator (PS) detector. The activity of (41)Ar was determined from an efficiency extrapolation method, in which the beta detector efficiency was varied by electronic discrimination using the software developed under Visual basic. In addition, high resolution gamma spectroscopy with HPGe detector was also used for activity determination of (41)Ar, and the result was satisfactory in agreement with that obtain by the efficiency extrapolation method. This work demonstrated that the activity of (41)Ar can be accurately measured by efficiency extrapolation method. PMID- 25527896 TI - Gamma-ray spectroscopy in the decay of (83)Se to levels of (83)Br. AB - High-resolution gamma ray spectroscopy experiments have been done to study the emissions from the radioactive decay of 22-min (83g)Se produced from neutron capture using samples of enriched (82)Se. Energy and intensity values have been obtained to roughly an order of magnitude greater precision than in previous studies. Based on energy sums, 2 new levels are proposed in the daughter (83)Br and one previously proposed level is shown to be doubtful. Some 25 new transitions appear to decay with the (83)Se halflife, about half of which can be accommodated among the previous or newly proposed levels. Several previous gamma ray placements are shown to be inconsistent with the new determinations of the (83)Br energy levels, but cannot be accommodated anywhere else among the known levels. As a result of the missing gamma ray placements, some of the beta branchings in the decay to levels of (83)Br appear to be negative. Gamma rays from the 2.4-h decay of the daughter (83)Br to levels of (83)Kr have also been observed, along with decays of (81g)(,m)Se present as a small impurity in the enriched samples and also as a strong component in irradiated samples of natural Se. PMID- 25527897 TI - Self-attenuation as a function of gamma ray energy in naturally occurring radioactive material in the oil and gas industry. AB - Self-attenuation correction factors were experimentally determined using radioactive point sources in combination with a subject material of naturally occurring radioactive material (NORM) obtained from oil exploration waste products. The self-attenuation correction factors were taken across a range of gamma ray energies from 41.73 to 1408.0keV. It is noted that the greatest amount of self-attenuation occurs in the energy regime below 200keV and rises to near zero attenuation at higher energies for these types of samples. For the 46.5keV gamma ray of (210)Pb there can be an underestimation of 62%. PMID- 25527898 TI - Mitochondrial genomes of the Baltic clam Macoma balthica (Bivalvia: Tellinidae): setting the stage for studying mito-nuclear incompatibilities. AB - BACKGROUND: Allopatric divergence across lineages can lead to post-zygotic reproductive isolation upon secondary contact and disrupt coevolution between mitochondrial and nuclear genomes, promoting emergence of genetic incompatibilities. A previous F ST scan on the transcriptome of the Baltic clam Macoma balthica highlighted several genes potentially involved in mito-nuclear incompatibilities (MNIs). As proteins involved in the mitochondrial oxidative phosphorylation (OXPHO) chain are prone to MNIs and can contribute to the maintenance of genetic barriers, the mitochondrial genomes of six Ma. balthica individuals spanning two secondary contact zones were sequenced using the Illumina MiSeq plateform. RESULTS: The mitogenome has an approximate length of 16,806 bp and encodes 13 protein-coding genes, 2 rRNAs and 22 tRNAs, all located on the same strand. atp8, a gene long reported as rare in bivalves, was detected. It encodes 42 amino acids and is putatively expressed and functional. A large unassigned region was identified between rrnS and tRNA (Met) and could likely correspond to the Control Region. Replacement and synonymous mutations were mapped on the inferred secondary structure of all protein-coding genes of the OXPHO chain. The atp6 and atp8 genes were characterized by background levels of replacement mutations, relative to synonymous mutations. However, most nad genes (notably nad2 and nad5) were characterized by an elevated proportion of replacement mutations. CONCLUSIONS: Six nearly complete mitochondrial genomes were successfully assembled and annotated, providing the necessary roadmap to study MNIs at OXPHO loci. Few replacement mutations were mapped on mitochondrial encoded ATP synthase subunits, which is in contrast with previous data on nuclear encoded subunits. Conversely, the high population divergence and the prevalence of non-synonymous mutations at nad genes are congruent with previous observations from the nuclear transcriptome. This further suggest that MNIs between subunits of Complex I of the OXPHO chain, coding for NADH dehydrogenase, may play a role in maintaining barriers to gene flow in Ma. balthica. PMID- 25527899 TI - Parental reactions to children's negative emotions: relationships with emotion regulation in children with an anxiety disorder. AB - Research has demonstrated that parental reactions to children's emotions play a significant role in the development of children's emotion regulation (ER) and adjustment. This study compared parent reactions to children's negative emotions between families of anxious and non-anxious children (aged 7-12) and examined associations between parent reactions and children's ER. Results indicated that children diagnosed with an anxiety disorder had significantly greater difficulty regulating a range of negative emotions and were regarded as more emotionally negative and labile by their parents. Results also suggested that mothers of anxious children espoused less supportive parental emotional styles when responding to their children's negative emotions. Supportive and non-supportive parenting reactions to children's negative emotions related to children's emotion regulation skills, with father's non-supportive parenting showing a unique relationship to children's negativity/lability. PMID- 25527900 TI - Internet-assisted delivery of cognitive behavioural therapy (CBT) for childhood anxiety: systematic review and meta-analysis. AB - AIM: To conduct a systematic review and meta-analysis of the literature to assess efficacy of internet-delivered cognitive behavioural therapy (CBT) for child anxiety disorder. METHOD: A systematic search of 7 electronic databases was conducted to assess CBT intervention for children with anxiety problems with remote delivery either entirely or partly via technology. Six articles reporting 7 studies were included. RESULTS: The findings together suggested that CBT programmes involving computerised elements were well received by children and their families, and its efficacy was almost as favourable as clinic-based CBT. The mixture of children and adolescents included the studies, diverse range of programmes, and lack of consistency between study designs made it difficult to identify key elements of these programmes or draw conclusions on the treatment efficacy. CONCLUSIONS: Analysis supports online delivery for wider access of this evidence-based therapy. Areas in need of improvement for this new method are indicated. PMID- 25527901 TI - Associations between lifetime PTSD symptoms and current substance use disorders using a five-factor model of PTSD. AB - This paper aimed to extend the existing knowledge on the association between PTSD symptoms, alcohol use disorders (AUD) and nicotine dependence (ND) by distinguishing between anxious and dysphoric arousal PTSD symptoms and by considering the putative contribution of additional comorbidity. Data stem from a cross-sectional study in a stratified, representative sample of 1483 recently deployed soldiers using standardized diagnostic interviews. All lifetime PTSD symptom clusters (occurrence of any symptom and number of symptoms) were associated with current AUD and ND in crude models except that anxious arousal was not related to AUD. Associations were reduced in magnitude when controlling for comorbidity. Current ND was related to the occurrence of any emotional numbing and to the number of re-experiencing symptoms above the contribution of other symptom clusters and comorbidity. In conclusion, associations between PTSD symptoms, AUD and ND may be partially attributable to additional comorbidity. Findings also yield further evidence for a role of emotional numbing and re experiencing symptoms in the comorbidity between PTSD and ND and for a distinction between dysphoric and anxious arousal PTSD symptoms. PMID- 25527902 TI - Gender differences in the expression of PTSD symptoms among active duty military personnel. AB - This study examined gender differences in posttraumatic stress disorder (PTSD) symptoms and symptom factors in the total U.S. active duty force. Data were drawn from the 2008 Department of Defense Survey of Health Related Behaviors among Active Duty Military Personnel including 17,939 men and 6751 women from all services. The results indicated that women expressed more distress than men across almost all the symptoms on the PTSD Checklist except for hypervigilance. Women also scored significantly higher on all four factors examined: Re experiencing, Avoidance, Emotionally Numb, Hyperarousal. More women than men were distressed by combat experiences that involved some type of violence, such as being wounded, witnessing or engaging in acts of cruelty, engaging in hand-to hand combat, and, to a lesser extent, handling dead bodies. Men who had been sexually abused had a greater number of symptoms and were consistently more distressed than women on individual symptoms and symptom factors. PMID- 25527903 TI - Which mothers receive a post partum home visit in Queensland, Australia? A cross sectional retrospective study. AB - OBJECTIVE: Although home visiting in the early post partum period appears to have increased, there are limited data defining which women receive a visit and none that include Queensland. We aimed to investigate patterns of post partum home visiting in the public and private sectors in Queensland. METHODS: Data were collected via a retrospective cross-sectional survey of women birthing in Queensland between 1 February and 31 May 2010 at 4 months post partum (n = 6948). Logistic regression was used to assess associations between receiving a home visit and sociodemographic, clinical and hospital variables. Analyses were stratified by public and private birthing sector because of significant differences between sectors. RESULTS: Public sector women were more likely to receive a visit from a nurse or midwife (from the hospital or child health sector) within 10 days of hospital discharge (67.2%) than private sector women (7.2%). Length of hospital stay was associated with home visiting in both sectors. Some vulnerable subpopulations in both sectors were more likely to be visited, whereas others were not. CONCLUSIONS: Home visiting in Queensland varies markedly between the public and private sector and is less common in some vulnerable populations. Further consideration to improving the equity of community post partum care in Queensland is needed. PMID- 25527904 TI - Cell-to-cell movement of viruses via plasmodesmata. AB - Plant viruses utilize plasmodesmata (PD), unique membrane-lined cytoplasmic nanobridges in plants, to spread infection cell-to-cell and long-distance. Such invasion involves a range of regulatory mechanisms to target and modify PD. Exciting discoveries in this field suggest that these mechanisms are executed by the interaction between plant cellular components and viral movement proteins (MPs) or other virus-encoded factors. Striking working analogies exist among endogenous non-cell-autonomous proteins and viral MPs, in which not only do they all use PD to traffic, but also they exploit same regulatory components to exert their functions. Thus, this review discusses on the viral strategies to move via PD and the PD-regulatory mechanisms involved in viral pathogenesis. PMID- 25527905 TI - Validation of triggers and development of a pediatric trigger tool to identify adverse events. AB - BACKGROUND: Little is known about adverse events (AEs) in pediatric patients. Record review is a common methodology for identifying AEs, but in pediatrics the record review tools generally have limited focus. The aim of the present study was to develop a broadly applicable record review tool to identify AEs in pediatric inpatients. METHODS: Using a broad literature review and expert opinion with a modified Delphi process, a pediatric trigger tool with 88 triggers, definitions, and descriptions including AE preventability decision support was developed and tested in a random sample of 600 hospitalized pediatric patients admitted in 2010 to a single university children's hospital. Four registered nurse-physician teams performed complete two-stage retrospective reviews of 150 records each from either neonatal, surgical/orthopedic, medicine, or emergency medicine units. RESULTS: Registered nurse review identified 296 of 600 records with triggers indicating potential AEs. Records (n = 121) with only false positive triggers not indicating any potential AEs were not forwarded to the next review stage. On subsequent physician review, 204 (34.0%) of patients were found to have had 563 AEs, range 1-27 AEs/patient. A total of 442 preventable AEs were found in 161 patients (26.8%), range 1-22. Overall, triggers were found 3,598 times in 417 (69.5%) records, with a mean of 6 (median 1, range 0-176) triggers per patient. The overall positive predictive value of the triggers was 22.9%, (range 0.0-100.0%). The final pediatric trigger tool, developed with a second Delphi round, required 29 triggers. CONCLUSIONS: AEs are common in pediatric patients and most are preventable. The main contributions of this study are to further develop and adapt trigger definitions, including AE preventability decision support, to introduce new triggers in pediatric care, as well as to apply pediatric triggers in different clinical specialties. Our findings resulted in a national pediatric trigger tool, and might also be adapted internationally. The pediatric trigger tool can help healthcare organizations to measure and analyze the AEs occurring in hospitalized children in order to improve patient safety. PMID- 25527906 TI - First molecular detection and characterization of herpesvirus and poxvirus in a Pacific walrus (Odobenus rosmarus divergens). AB - BACKGROUND: Herpesvirus and poxvirus can infect a wide range of species: herpesvirus genetic material has been detected and amplified in five species of the superfamily Pinnipedia; poxvirus genetic material, in eight species of Pinnipedia. To date, however, genetic material of these viruses has not been detected in walrus (Odobenus rosmarus), another marine mammal of the Pinnipedia clade, even though anti-herpesvirus antibodies have been detected in these animals. CASE PRESENTATION: In February 2013, a 9-year-old healthy captive female Pacific walrus died unexpectedly at L'Oceanografic (Valencia, Spain). Herpesvirus was detected in pharyngeal tonsil tissue by PCR. Phylogenetic analysis revealed that the virus belongs to the subfamily Gammaherpesvirinae. Poxvirus was also detected by PCR in skin, pre-scapular and tracheobronchial lymph nodes and tonsils. Gross lesions were not detected in any tissue, but histopathological analyses of pharyngeal tonsils and lymph nodes revealed remarkable lymphoid depletion and lymphocytolysis. Similar histopathological lesions have been previously described in bovine calves infected with an alphaherpesvirus, and in northern elephant seals infected with a gammaherpesvirus that is closely related to the herpesvirus found in this case. Intracytoplasmic eosinophilic inclusion bodies, consistent with poxviral infection, were also observed in the epithelium of the tonsilar mucosa. CONCLUSION: To our knowledge, this is the first molecular identification of herpesvirus and poxvirus in a walrus. Neither virus was likely to have contributed directly to the death of our animal. PMID- 25527907 TI - Evaluation of RECIST in chemotherapy-treated lung cancer: the Pharmacogenoscan Study. AB - BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) are widely used to assess the effect of chemotherapy in patients with cancer. We hypothesised that the change in unidimensional tumour size handled as a continuous variable was more reliable than RECIST in predicting overall survival (OS). METHODS: The prospective Pharmacogenoscan study enrolled consecutive patients with non-small cell lung cancer (NSCLC) at any stage seen between 2005 and 2010 at six hospitals in France, given chemotherapy. After exclusion of patients without RECIST or continuous-scale tumour size data and of those with early death, 464 patients were left for the survival analyses. Cox models were built to assess relationships between RECIST 1.1 categories or change in continuous-scale tumour size and OS. The best model was defined as the model minimising the Akaike Information Criterion (AIC). RESULTS: OS was 14.2 months (IQR, 7.3-28.9 months). According to RECIST 1.1, 146 (31%) patients had a partial or complete response, 245 (53%) stable disease, and 73 (16%) disease progression. RECIST 1.1 predicted better OS than continuous-scale tumour in early (<6 months) predicted survival analyses (p = 0.03) but the accuracy of the two response evaluation methods was similar in late (>=6 months) predicted survival analyses (p = 0.15). CONCLUSION: In this large observational study, change in continuous-scale tumour size did not perform better than RECIST 1.1 in predicting survival of patients given chemotherapy to treat NSCLC. TRIAL REGISTRATION: NCT00222404. PMID- 25527908 TI - Urban greenness and physical activity in a national survey of Canadians. AB - Recent research suggests that urban greenness has important beneficial effects on health. While some epidemiological studies have investigated associations between measures of greenness and participation in physical activities, the findings have been inconsistent and several have relied on self-reported rather than objectively determined measures of greenness. Further, there have been few national studies. Our aim was to characterize associations between residential measures of greenness and physical activity within a nationally representative sample of Canadians. Moreover, we sought to determine to what extent these associations were modified by age, sex and income. Our analyses are based on data collected from participants of the 2001 Canadian Community Health Survey. Analyses were restricted to 69,910 individuals who were: 20 years of age and older, lived in urban areas, and for whom a residential measure of greenness could be assigned. The Normalised Difference Vegetation Index (NDVI), which is an objectively defined measure of greenness based on satellite imaging, was assigned to the residential addresses of the participants. Our NDVI values were based on 30 m and 500 m buffers from the centroid of the provided postal codes. Logistic regression was used to estimate odds ratios (ORs) and their 95% confidence intervals to describe associations between greenness and several measures of physical activity. The ORs were adjusted for age, sex, smoking status, marital status, and income. We found that participants who resided in the highest quartile of greenness, based on a 500 m buffer, were more likely to participate in leisure-time physical activity (adjusted OR=1.34, 95% CI=1.25-1.44) when compared to those in the lowest quartile. Positive associations were observed between greenness and physical activity in all income groupings. A key finding was the observation of a stronger association between greenness and measures of physical activity among younger adults, especially women. Our findings have important public health implications as they suggest that access to urban green environments contributes to increased participation in leisure-time physical activity which has demonstrable health benefits. PMID- 25527909 TI - betaIII-tubulin overexpression is linked to aggressive tumor features and shortened survival in clear cell renal cell carcinoma. AB - AIMS: betaIII-tubulin (TUBB3) is a microtubule component overexpression of which is found in many solid cancer types, often linked to poor patient prognosis, and has been suggested to predict failure of microtubule-targeting chemotherapeutics. This study was designed to determine prevalence and prognostic impact of TUBB3 expression in kidney cancers. METHODS AND RESULTS: A tissue microarray (TMA) containing more than 1,200 renal tumors was analyzed by immunohistochemistry. TUBB3 expression varied markedly between the different histological subtypes and was more frequent in 105 papillary cancers (75.2 %, p < 0.0001), 38 oncocytomas (52.6 %, p < 0.0001), and 22 chromophobic carcinomas (36.4 %, p = 0.1221) than in 555 clear cell RCC (16.4 %). In clear cell cancers, strong TUBB3 positivity was linked to high Fuhrman grade (p < 0.0001), advanced stage (0.002), nodal metastases (p = 0.0433), hematogenous metastases (p = 0.0016), and shortened overall survival (p < 0.0001). Associations with outcome and tumor phenotype were inversely for papillary RCC, where TUBB3 immunostaining was linked to low tumor stage (p = 0.0012) and prolonged survival (p = 0.0043). CONCLUSIONS: TUBB3 expression levels and their effects are strikingly different between ccRCC and papillary RCC. These differences may be caused by differences in VHL function between these RCC subtypes, because VHL (like TUBB3) is another strong regulator of microtubule function. PMID- 25527910 TI - The toxicokinetic profile of curdione in pregnant SD rats and its transference in a placental barrier system detected by LC-MS/MS. AB - The objective of this study was to determine the toxicokinetic profile of curdione in pregnant SD rats as well as the transference of curdione into the fetus through the placental barrier system using LC-MS/MS. Thirteen pregnant SD rats were treated with 7, 21 and 63 mg/kg curdione once daily from gestational day 6 (GD6) to GD15. Blood samples were collected at different time points on GD6 and GD15. Maternal plasma, placental plasma, placenta tissue, amniotic fluid and fetal tissue were collected for concentration analysis after all the animals were sacrificed following one repeated dose on GD19. The results indicated that Cmax, AUC(0-t) and AUC(0-infinity) increased in a dose-dependent manner both on GD6 and GD15. At 7 mg/kg group, the total serum clearance value on GD15 was reduced to approximately 16.4% of that on GD6, and the volume of distribution was also significantly decreased (p<0.05). Curdione could be detected in the maternal plasma, placental plasma, placenta tissue, amniotic fluid and fetal tissue, and its concentration in the fetal tissue reached saturation at 21 mg/kg. In conclusion, curdione presents with the risk of accumulation in pregnant SD rats and may affect the fetus via transference through the placental barrier system. PMID- 25527911 TI - From canonical to non-canonical cyclic nucleotides as second messengers: pharmacological implications. AB - This review summarizes our knowledge on the non-canonical cyclic nucleotides cCMP, cUMP, cIMP, cXMP and cTMP. We place the field into a historic context and discuss unresolved questions and future directions of research. We discuss the implications of non-canonical cyclic nucleotides for experimental and clinical pharmacology, focusing on bacterial infections, cardiovascular and neuropsychiatric disorders and reproduction medicine. The canonical cyclic purine nucleotides cAMP and cGMP fulfill the criteria of second messengers. (i) cAMP and cGMP are synthesized by specific generators, i.e. adenylyl and guanylyl cyclases, respectively. (ii) cAMP and cGMP activate specific effector proteins, e.g. protein kinases. (iii) cAMP and cGMP exert specific biological effects. (iv) The biological effects of cAMP and cGMP are terminated by phosphodiesterases and export. The effects of cAMP and cGMP are mimicked by (v) membrane-permeable cyclic nucleotide analogs and (vi) bacterial toxins. For decades, the existence and relevance of cCMP and cUMP have been controversial. Modern mass-spectrometric methods have unequivocally demonstrated the existence of cCMP and cUMP in mammalian cells. For both, cCMP and cUMP, the criteria for second messenger molecules are now fulfilled as well. There are specific patterns by which nucleotidyl cyclases generate cNMPs and how they are degraded and exported, resulting in unique cNMP signatures in biological systems. cNMP signaling systems, specifically at the level of soluble guanylyl cyclase, soluble adenylyl cyclase and ExoY from Pseudomonas aeruginosa are more promiscuous than previously appreciated. cUMP and cCMP are evolutionary new molecules, probably reflecting an adaption to signaling requirements in higher organisms. PMID- 25527912 TI - Communication: vacuum ultraviolet photoabsorption of interstellar icy thiols. AB - Following the recent identification of ethanethiol in the interstellar medium (ISM) we have carried out Vacuum UltraViolet (VUV) spectroscopy studies of ethanethiol (CH3CH2SH) from 10 K until sublimation in an ultrahigh vacuum chamber simulating astrochemical conditions. These results are compared with those of methanethiol (CH3SH), the lower order thiol also reported to be present in the ISM. VUV spectra recorded at higher temperature reveal conformational changes in the ice and phase transitions whilst evidence for dimer production is also presented. PMID- 25527913 TI - Two new constraints for the cumulant matrix. AB - We suggest new strict constraints that the two-particle cumulant matrix should fulfill. The constraints are obtained from the decomposition of ?S(2)?, previously developed in our laboratory, and the vanishing number of electrons shared by two non-interacting fragments. The conditions impose stringent constraints into the cumulant structure without any need to perform an orbital optimization procedure thus carrying very small or no computational effort. These constraints are tested on the series of Piris natural orbital functionals (PNOF), which are among the most accurate ones available in the literature. Interestingly, even though all PNOF cumulants ensure correct overall ?S(2)? values, none of them is consistent with the local spin structure of systems that dissociate more than one pair of electrons. A careful analysis of the local spin components reveals the most important missing contributions in the cumulant expression thus suggesting a means to improve PNOF5. The constraints provide an inexpensive tool for the construction and testing of cumulant structures that complement previously known conditions such as the N-representability or the square of the total spin angular momentum, ?S(2)?. PMID- 25527914 TI - Orbital-free density functional theory implementation with the projector augmented-wave method. AB - We present a computational scheme for orbital-free density functional theory (OFDFT) that simultaneously provides access to all-electron values and preserves the OFDFT linear scaling as a function of the system size. Using the projector augmented-wave method (PAW) in combination with real-space methods, we overcome some obstacles faced by other available implementation schemes. Specifically, the advantages of using the PAW method are twofold. First, PAW reproduces all electron values offering freedom in adjusting the convergence parameters and the atomic setups allow tuning the numerical accuracy per element. Second, PAW can provide a solution to some of the convergence problems exhibited in other OFDFT implementations based on Kohn-Sham (KS) codes. Using PAW and real-space methods, our orbital-free results agree with the reference all-electron values with a mean absolute error of 10 meV and the number of iterations required by the self consistent cycle is comparable to the KS method. The comparison of all-electron and pseudopotential bulk modulus and lattice constant reveal an enormous difference, demonstrating that in order to assess the performance of OFDFT functionals it is necessary to use implementations that obtain all-electron values. The proposed combination of methods is the most promising route currently available. We finally show that a parametrized kinetic energy functional can give lattice constants and bulk moduli comparable in accuracy to those obtained by the KS PBE method, exemplified with the case of diamond. PMID- 25527915 TI - On the NP-completeness of the Hartree-Fock method for translationally invariant systems. AB - The self-consistent field method utilized for solving the Hartree-Fock (HF) problem and the closely related Kohn-Sham problem is typically thought of as one of the cheapest methods available to quantum chemists. This intuition has been developed from the numerous applications of the self-consistent field method to a large variety of molecular systems. However, as characterized by its worst-case behavior, the HF problem is NP-complete. In this work, we map out boundaries of the NP-completeness by investigating restricted instances of HF. We have constructed two new NP-complete variants of the problem. The first is a set of Hamiltonians whose translationally invariant Hartree-Fock solutions are trivial, but whose broken symmetry solutions are NP-complete. Second, we demonstrate how to embed instances of spin glasses into translationally invariant Hartree-Fock instances and provide a numerical example. These findings are the first steps towards understanding in which cases the self-consistent field method is computationally feasible and when it is not. PMID- 25527916 TI - QM/MM investigation of the concentration effects on the second-order nonlinear optical responses of solutions. AB - A multiscale approach combining quantum mechanics (QM) and molecular mechanics methods has been employed to investigate the effects of solute-solute interactions and therefore of concentration on the first hyperpolarizability of solutions of nitrobenzene in benzene. First, spatial distributions of solute and solvent molecules are generated using Monte Carlo simulations where the intermolecular interactions are described using the Lennard-Jones potentials and Coulomb terms. Then, a reduced number of statistically-uncorrelated configurations are sampled and submitted to time-dependent Hartree-Fock calculations of the first hyperpolarizability. When only one molecule is described quantum-mechanically and is embedded in the electrostatic polarization field of the solution described by point charges, betaHRS and beta// as well as the depolarization ratio increase in parallel with the concentration in nitrobenzene. This effect is attributed to the increase of the polarization field associated with the presence of polar nitrobenzene molecules in the surrounding. Then, the first solvation shell is considered explicitly in the QM calculation to address solute-solute interactions effects. When the number of nitrobenzenes in the first solvation shell increases, betaHRS and beta// normalized to the number of nitrobenzene molecules decrease and this decrease attains roughly 50% when there are 3 nitrobenzene molecules in the first solvation shell. These drastic reductions of the first hyperpolarizability result from (partial) centro symmetric arrangements between the nitrobenzene molecules, as supported by the relationship between beta and the angle between the nitrobenzene charge transfer axes. Moreover, these beta decreases originate mostly from the reduction of the dipolar beta component, whereas the octupolar one is rather constant as a function of the nitrobenzene concentration. PMID- 25527917 TI - Simulated two-dimensional electronic spectroscopy of the eight bacteriochlorophyll FMO complex. AB - The Fenna-Matthews-Olson (FMO) protein-pigment complex acts as a molecular wire conducting energy between the outer antenna system and the reaction center; it is an important photosynthetic system to study the transfer of excitonic energy. Recent crystallographic studies report the existence of an additional (eighth) bacteriochlorophyll a (BChl a) in some of the FMO monomers. To understand the functionality of this eighth BChl, we simulated the two-dimensional electronic spectra of both the 7-site (apo form) and the 8-site (holo form) variant of the FMO complex from green sulfur bacteria, Prosthecochloris aestuarii. By comparing the spectrum, it was found that the eighth BChl can affect two different excitonic energy transfer pathways: (1) it is directly involved in the first apo form pathway (6 -> 3 -> 1) by passing the excitonic energy to exciton 6; and (2) it facilitates an increase in the excitonic wave function overlap between excitons 4 and 5 in the second pathway (7 -> 4,5 -> 2 -> 1) and thus increases the possible downward sampling routes across the BChls. PMID- 25527918 TI - The von Neumann basis in non-Cartesian coordinates: application to floppy triatomic molecules. AB - We extend the periodic von Neumann basis to non-Cartesian coordinates. The bound states of two isomerizing triatomic molecules, LiCN/LiNC and HCN/HNC, are calculated using the vibrational Hamiltonian in Jacobi coordinates. The phase space localization of the basis functions leads to a flexible and accurate representation of the Hamiltonian. This results in significant savings compared to a basis localized just in coordinate space. The favorable scaling of the method with dimensionality makes it promising for applications to larger systems. PMID- 25527919 TI - Dynamics in the quantum/classical limit based on selective use of the quantum potential. AB - A classical limit of quantum dynamics can be defined by compensation of the quantum potential in the time-dependent Schrodinger equation. The quantum potential is a non-local quantity, defined in the trajectory-based form of the Schrodinger equation, due to Madelung, de Broglie, and Bohm, which formally generates the quantum-mechanical features in dynamics. Selective inclusion of the quantum potential for the degrees of freedom deemed "quantum," defines a hybrid quantum/classical dynamics, appropriate for molecular systems comprised of light and heavy nuclei. The wavefunction is associated with all of the nuclei, and the Ehrenfest, or mean-field, averaging of the force acting on the classical degrees of freedom, typical of the mixed quantum/classical methods, is avoided. The hybrid approach is used to examine evolution of light/heavy systems in the harmonic and double-well potentials, using conventional grid-based and approximate quantum-trajectory time propagation. The approximate quantum force is defined on spatial domains, which removes unphysical coupling of the wavefunction fragments corresponding to distinct classical channels or configurations. The quantum potential, associated with the quantum particle, generates forces acting on both quantum and classical particles to describe the backreaction. PMID- 25527920 TI - Geometry-dependent lifetime of Interatomic coulombic decay using equation-of motion coupled cluster method. AB - Electronically excited atom or molecule in an environment can relax via transferring its excess energy to the neighboring atoms or molecules. The process is called Interatomic or Intermolecular coulombic decay (ICD). The ICD is a fast decay process in environment. Generally, the ICD mechanism predominates in weakly bound clusters. In this paper, we have applied the complex absorbing potential approach/equation-of-motion coupled cluster (CAP/EOMCCSD) method which is a combination of CAP and EOMCC approach to study the lifetime of ICD at various geometries of the molecules. We have applied this method to calculate the lifetime of ICD in Ne-X; X = Ne, Mg, Ar, systems. We compare our results with other theoretical and experimental results available in literature. PMID- 25527921 TI - Practical hyperdynamics method for systems with large changes in potential energy. AB - A practical hyperdynamics method is proposed to accelerate systems with highly endothermic and exothermic reactions such as hydrocarbon pyrolysis and oxidation reactions. In this method, referred to as the "adaptive hyperdynamics (AHD) method," the bias potential parameters are adaptively updated according to the change in potential energy. The approach is intensively examined for JP-10 (exo tetrahydrodicyclopentadiene) pyrolysis simulations using the ReaxFF reactive force field. Valid boost parameter ranges are clarified as a result. It is shown that AHD can be used to model pyrolysis at temperatures as low as 1000 K while achieving a boost factor of around 10(5). PMID- 25527922 TI - Local electric dipole moments for periodic systems via density functional theory embedding. AB - We describe a novel approach for the calculation of local electric dipole moments for periodic systems. Since the position operator is ill-defined in periodic systems, maximally localized Wannier functions based on the Berry-phase approach are usually employed for the evaluation of local contributions to the total electric dipole moment of the system. We propose an alternative approach: within a subsystem-density functional theory based embedding scheme, subset electric dipole moments are derived without any additional localization procedure, both for hybrid and non-hybrid exchange-correlation functionals. This opens the way to a computationally efficient evaluation of local electric dipole moments in (molecular) periodic systems as well as their rigorous splitting into atomic electric dipole moments. As examples, Infrared spectra of liquid ethylene carbonate and dimethyl carbonate are presented, which are commonly employed as solvents in Lithium ion batteries. PMID- 25527923 TI - Appointing silver and bronze standards for noncovalent interactions: a comparison of spin-component-scaled (SCS), explicitly correlated (F12), and specialized wavefunction approaches. AB - A systematic examination of noncovalent interactions as modeled by wavefunction theory is presented in comparison to gold-standard quality benchmarks available for 345 interaction energies of 49 bimolecular complexes. Quantum chemical techniques examined include spin-component-scaling (SCS) variations on second order perturbation theory (MP2) [SCS, SCS(N), SCS(MI)] and coupled cluster singles and doubles (CCSD) [SCS, SCS(MI)]; also, method combinations designed to improve dispersion contacts [DW-MP2, MP2C, MP2.5, DW-CCSD(T)-F12]; where available, explicitly correlated (F12) counterparts are also considered. Dunning basis sets augmented by diffuse functions are employed for all accessible zeta levels; truncations of the diffuse space are also considered. After examination of both accuracy and performance for 394 model chemistries, SCS(MI)-MP2/cc-pVQZ can be recommended for general use, having good accuracy at low cost and no ill effects such as imbalance between hydrogen-bonding and dispersion-dominated systems or non-parallelity across dissociation curves. Moreover, when benchmarking accuracy is desirable but gold-standard computations are unaffordable, this work recommends silver-standard [DW-CCSD(T**)-F12/aug-cc-pVDZ] and bronze-standard [MP2C-F12/aug-cc-pVDZ] model chemistries, which support accuracies of 0.05 and 0.16 kcal/mol and efficiencies of 97.3 and 5.5 h for adenine.thymine, respectively. Choice comparisons of wavefunction results with the best symmetry-adapted perturbation theory [T. M. Parker, L. A. Burns, R. M. Parrish, A. G. Ryno, and C. D. Sherrill, J. Chem. Phys. 140, 094106 (2014)] and density functional theory [L. A. Burns, A. Vazquez-Mayagoitia, B. G. Sumpter, and C. D. Sherrill, J. Chem. Phys. 134, 084107 (2011)] methods previously studied for these databases are provided for readers' guidance. PMID- 25527924 TI - Non-stochastic matrix Schrodinger equation for open systems. AB - We propose an extension of the Schrodinger equation for a quantum system interacting with environment. This extension describes dynamics of a collection of auxiliary wavefunctions organized as a matrix m, from which the system density matrix can be reconstructed as rho=mm(?). We formulate a compatibility condition, which ensures that the reconstructed density satisfies a given quantum master equation for the system density. The resulting non-stochastic evolution equation preserves positive-definiteness of the system density and is applicable to both Markovian and non-Markovian system-bath treatments. Our formalism also resolves a long-standing problem of energy loss in the time-dependent variational principle applied to mixed states of closed systems. PMID- 25527925 TI - Time-dependent Jahn-Teller problem: phonon-induced relaxation through conical intersection. AB - A theoretical study of time-dependent dynamical Jahn-Teller effect in an impurity center in a solid is presented. We are considering the relaxation of excited states in the E?e-problem through the conical intersection of the potential energy. A strict quantum-mechanical treatment of vibronic interactions with both the main Jahn-Teller active vibration and the nontotally symmetric phonons causing the energy loss is given. The applied method enables us to calculate the time-dependence of the distribution function of the basic configurational coordinate. We have performed a series of numerical calculations allowing us, among other relaxation features, to visualise the details of the relaxation through the conical intersection. In particular, we elucidate how the Slonczewski quantization of the states in the conical intersection affects the relaxation. PMID- 25527926 TI - Criteria for first- and second-order vibrational resonances and correct evaluation of the Darling-Dennison resonance coefficients using the canonical Van Vleck perturbation theory. AB - The second-order vibrational Hamiltonian of a semi-rigid polyatomic molecule when resonances are present can be reduced to a quasi-diagonal form using second-order vibrational perturbation theory. Obtaining exact vibrational energy levels requires subsequent numerical diagonalization of the Hamiltonian matrix including the first- and second-order resonance coupling coefficients. While the first order Fermi resonance constants can be easily calculated, the evaluation of the second-order Darling-Dennison constants requires more complicated algebra for seven individual cases with different numbers of creation-annihilation vibrational quanta. The difficulty in precise evaluation of the Darling-Dennison coefficients is associated with the previously unrecognized interference with simultaneously present Fermi resonances that affect the form of the canonically transformed Hamiltonian. For the first time, we have presented the correct form of the general expression for the evaluation of the Darling-Dennison constants that accounts for the underlying effect of Fermi resonances. The physically meaningful criteria for selecting both Fermi and Darling-Dennison resonances are discussed and illustrated using numerical examples. PMID- 25527927 TI - The small-voxel tracking algorithm for simulating chemical reactions among diffusing molecules. AB - Simulating the evolution of a chemically reacting system using the bimolecular propensity function, as is done by the stochastic simulation algorithm and its reaction-diffusion extension, entails making statistically inspired guesses as to where the reactant molecules are at any given time. Those guesses will be physically justified if the system is dilute and well-mixed in the reactant molecules. Otherwise, an accurate simulation will require the extra effort and expense of keeping track of the positions of the reactant molecules as the system evolves. One molecule-tracking algorithm that pays careful attention to the physics of molecular diffusion is the enhanced Green's function reaction dynamics (eGFRD) of Takahashi, Tanase-Nicola, and ten Wolde [Proc. Natl. Acad. Sci. U.S.A. 107, 2473 (2010)]. We introduce here a molecule-tracking algorithm that has the same theoretical underpinnings and strategic aims as eGFRD, but a different implementation procedure. Called the small-voxel tracking algorithm (SVTA), it combines the well known voxel-hopping method for simulating molecular diffusion with a novel procedure for rectifying the unphysical predictions of the diffusion equation on the small spatiotemporal scale of molecular collisions. Indications are that the SVTA might be more computationally efficient than eGFRD for the problematic class of non-dilute systems. A widely applicable, user-friendly software implementation of the SVTA has yet to be developed, but we exhibit some simple examples which show that the algorithm is computationally feasible and gives plausible results. PMID- 25527928 TI - A novel combination of DLS-optical microrheology and low frequency Raman spectroscopy to reveal underlying biopolymer self-assembly and gelation mechanisms. AB - The connectivity between gelation and increasing water confinement and structuring within nanopores of a thermally induced gel is demonstrated for the first time through low frequency Raman spectroscopy and optical microrheology measurements. Specifically, the work confirms that increased ordering of individual water molecules can be observed during the gelation of agarose upon cooling. More importantly, it illustrates the ability of the two techniques to provide new insights and a more direct link between intermolecular interactions/microstructure and evolving rheological response in gelling systems. PMID- 25527929 TI - Induced photoemission from driven nonadiabatic dynamics in an avoided crossing system. AB - When vibrational dynamics on an ionic state (large dipole moment) is coupled to that on a neutral state (small dipole moment) such as at an avoided crossing in the alkali halide system, the population transfer between the states cause oscillation of the molecular dipole, leading to dipole emission. Such dynamics may be driven by an external field. We study how the coupled wavepacket dynamics is affected by the parameters (intensity, frequency) of the driving field with the aim of making use of the photoemission as an alternative detection scheme of femtosecond and subfemtosecond vibrational and electronic dynamics or as a characteristic optical source. PMID- 25527930 TI - Survey of the high resolution infrared spectrum of methane ((12)CH4 and (13)CH4): partial vibrational assignment extended towards 12,000 cm(-1.). AB - We have recorded the complete infrared spectrum of methane (12)CH4 and its second most abundant isotopomer (13)CH4 extending from the fundamental range starting at 1000 cm(-1) up to the overtone region near 12,000 cm(-1) in the near infrared at the limit towards the visible range, at temperatures of about 80 K and also at 298 K with Doppler limited resolution in the gas phase by means of interferometric Fourier transform spectroscopy using the Bruker IFS 125 HR prototype (ZP 2001) of the ETH Zurich laboratory. This provides the so far most complete data set on methane spectra in this range at high resolution. In the present work we report in particular those results, where the partial rovibrational analysis allows for the direct assignment of pure (J = 0) vibrational levels including high excitation. These results substantially extend the accurate knowledge of vibrational band centers to higher energies and provide a benchmark for both the comparison with theoretical results on the one hand and atmospheric spectroscopy on the other hand. We also present a simple effective Hamiltonian analysis, which is discussed in terms of vibrational level assignments and (13)C isotope effects. PMID- 25527931 TI - Probing ground and low-lying excited states for HIO2 isomers. AB - We present a computational study on HIO2 molecules. Ground state properties such as equilibrium structures, relative energetics, vibrational frequencies, and infrared intensities were obtained for all the isomers at the coupled-cluster with single and double excitations as well as perturbative inclusion of triples (CCSD(T)) level of theory with the aug-cc-pVTZ-PP basis set and ECP-28-PP effective core potential for iodine and the aug-cc-pVTZ basis set for hydrogen and oxygen atoms. The HOIO structure is confirmed as the lowest energy isomer. The relative energies are shown to be HOIO < HOOI < HI(O)O. The HO(O)I isomer is only stable at the density functional theory (DFT) level of theory. The transition states determined show interconversion of the isomers is possible. In order to facilitate future experimental identification, vibrational frequencies are also determined for all corresponding deuterated species. Vertical excitation energies for the three lowest-lying singlet and triplet excited states were determined using the configuration interaction singles, time-dependent density functional theory (TD-DFT)/B3LYP, TD-DFT/G96PW91, and equation of motion-CCSD approaches with the LANL2DZ basis set plus effective core potential for iodine and the aug-cc-pVTZ basis set for hydrogen and oxygen atoms. It is shown that HOIO and HOOI isomers have excited states accessible at solar wavelengths (<4.0 eV) but these states have very small oscillator strengths (<2 * 10(-3)). PMID- 25527932 TI - Static electric dipole polarizabilities of An(5+/6+) and AnO2 (+/2+) (An = U, Np, and Pu) ions. AB - The parallel components of static electric dipole polarizabilities have been calculated for the lowest lying spin-orbit states of the penta- and hexavalent oxidation states of the actinides (An) U, Np, and Pu, in both their atomic and molecular diyl ion forms (An(5+/6+) and AnO2 (+/2+)) using the numerical finite field technique within a four-component relativistic framework. The four component Dirac-Hartree-Fock method formed the reference for MP2 and CCSD(T) calculations, while multireference Fock space coupled-cluster (FSCC), intermediate Hamiltonian Fock space coupled-cluster (IH-FSCC) and Kramers restricted configuration interaction (KRCI) methods were used to incorporate additional electron correlation. It is observed that electron correlation has significant (~5 a.u.(3)) impact upon the parallel component of the polarizabilities of the diyls. To the best of our knowledge, these quantities have not been previously reported and they can serve as reference values in the determination of various electronic and response properties (for example intermolecular forces, optical properties, etc.) relevant to the nuclear fuel cycle and material science applications. The highest quality numbers for the parallel components (alphazz) of the polarizability for the lowest Omega levels corresponding to the ground electronic states are (in a.u.(3)) 44.15 and 41.17 for UO2 (+) and UO2 (2+), respectively, 45.64 and 41.42 for NpO2 (+) and NpO2 (2+), respectively, and 47.15 for the PuO2 (+) ion. PMID- 25527933 TI - Probing chirality fluctuations in molecules by nonlinear optical spectroscopy. AB - Symmetry breaking caused by geometric fluctuations can enable processes that are otherwise forbidden. An example is a perylene bisimide dyad whose dipole moments are perpendicular to each other. Forster-type energy transfer is thus forbidden at the equilibrium geometry since the dipolar coupling vanishes. Yet, fluctuations of the geometric arrangement have been shown to induce finite energy transfer that depends on the dipole variance, rather than the mean. We demonstrate an analogous effect associated with chirality symmetry breaking. In its equilibrium geometry, this dimer is non-chiral. The linear chiral response which depends on the average geometry thus vanishes. However, we show that certain 2D chiral optical signals are finite due to geometric fluctuations. Furthermore, the correlation time of these fluctuations can be experimentally revealed by the waiting time dependence of the 2D signal. PMID- 25527934 TI - High resolution IR diode laser study of collisional energy transfer between highly vibrationally excited monofluorobenzene and CO2: the effect of donor fluorination on strong collision energy transfer. AB - Collisional energy transfer between vibrational ground state CO2 and highly vibrationally excited monofluorobenzene (MFB) was studied using narrow bandwidth (0.0003 cm(-1)) IR diode laser absorption spectroscopy. Highly vibrationally excited MFB with E' = ~41,000 cm(-1) was prepared by 248 nm UV excitation followed by rapid radiationless internal conversion to the electronic ground state (S1->S0*). The amount of vibrational energy transferred from hot MFB into rotations and translations of CO2 via collisions was measured by probing the scattered CO2 using the IR diode laser. The absolute state specific energy transfer rate constants and scattering probabilities for single collisions between hot MFB and CO2 were measured and used to determine the energy transfer probability distribution function, P(E,E'), in the large DeltaE region. P(E,E') was then fit to a bi-exponential function and extrapolated to the low DeltaE region. P(E,E') and the biexponential fit data were used to determine the partitioning between weak and strong collisions as well as investigate molecular properties responsible for large collisional energy transfer events. Fermi's Golden rule was used to model the shape of P(E,E') and identify which donor vibrational motions are primarily responsible for energy transfer. In general, the results suggest that low-frequency MFB vibrational modes are primarily responsible for strong collisions, and govern the shape and magnitude of P(E,E'). Where deviations from this general trend occur, vibrational modes with large negative anharmonicity constants are more efficient energy gateways than modes with similar frequency, while vibrational modes with large positive anharmonicity constants are less efficient at energy transfer than modes of similar frequency. PMID- 25527935 TI - Modeling of molecular nitrogen collisions and dissociation processes for direct simulation Monte Carlo. AB - The Direct Simulation Monte Carlo (DSMC) method typically used for simulating hypersonic Earth re-entry flows requires accurate total collision cross sections and reaction probabilities. However, total cross sections are often determined from extrapolations of relatively low-temperature viscosity data, so their reliability is unknown for the high temperatures observed in hypersonic flows. Existing DSMC reaction models accurately reproduce experimental equilibrium reaction rates, but the applicability of these rates to the strong thermal nonequilibrium observed in hypersonic shocks is unknown. For hypersonic flows, these modeling issues are particularly relevant for nitrogen, the dominant species of air. To rectify this deficiency, the Molecular Dynamics/Quasi Classical Trajectories (MD/QCT) method is used to accurately compute collision and reaction cross sections for the N2(Sigmag+1)-N2(Sigmag+1) collision pair for conditions expected in hypersonic shocks using a new potential energy surface developed using a ReaxFF fit to recent advanced ab initio calculations. The MD/QCT-computed reaction probabilities were found to exhibit better physical behavior and predict less dissociation than the baseline total collision energy reaction model for strong nonequilibrium conditions expected in a shock. The MD/QCT reaction model compared well with computed equilibrium reaction rates and shock-tube data. In addition, the MD/QCT-computed total cross sections were found to agree well with established variable hard sphere total cross sections. PMID- 25527936 TI - Self-interaction corrected density functional calculations of Rydberg states of molecular clusters: N,N-dimethylisopropylamine. AB - Theoretical calculations of Rydberg excited states of molecular clusters consisting of N,N-dimethylisopropylamine molecules using a Perdew-Zunger self interaction corrected energy functional are presented and compared with results of resonant multiphoton ionization measurements. The binding energy of the Rydberg electron in the monomer is calculated to be 2.79 eV and 2.27 eV in the 3s and 3p state, respectively, which compares well with measured values of 2.88 eV and 2.21 eV. Three different stable configurations of the dimer in the ground state were found using an energy functional that includes van der Waals interaction. The lowest ground state energy conformation has the two N-atoms widely separated, by 6.2 A, while the Rydberg state energy is lowest for a configuration where the N-atoms of the two molecules come close together, separated by 3.7 A. This conformational change is found to lower the Rydberg electron binding energy by 0.2 eV. The self-interaction corrected functional gives a highly localized hole on one of the two molecules, unlike results obtained using the PBE functional or the hybrid B3LYP functional which give a delocalized hole. For the trimer, the self-interaction corrected calculation gives a Rydberg electron binding energy lowered further by 0.13 eV as compared with the dimer. The calculated results compare well with trends observed in experimental measurements. The reduction of the Rydberg electron binding energy with cluster size can be ascribed to an effective delocalization of the positive charge of the hole by the induced and permanent dipole moments of the neighboring molecules. A further decrease observed to occur on a time scale of tens of ps can be ascribed to a structural rearrangement of the clusters in the Rydberg state where molecules rotate to orient their dipoles in response to the formation of the localized hole. PMID- 25527937 TI - Ab initio study of the RbSr electronic structure: potential energy curves, transition dipole moments, and permanent electric dipole moments. AB - Excited states and the ground state of the diatomic molecule RbSr were calculated by post Hartree-Fock molecular orbital theory up to 22 000 cm(-1). We applied a multireference configuration interaction calculation based on multiconfigurational self-consistent field wave functions. Both methods made use of effective core potentials and core polarization potentials. Potential energy curves, transition dipole moments, and permanent electric dipole moments were determined for RbSr and could be compared with other recent calculations. We found a good agreement with experimental spectra, which have been obtained recently by helium nanodroplet isolation spectroscopy. For the lowest two asymptotes (Rb (5s (2)S) + Sr (5s4d (3)P degrees ) and Rb (5p (2)P degrees ) + Sr (5s(2) (1)S)), which exhibit a significant spin-orbit coupling, we included relativistic effects by two approaches, one applying the Breit-Pauli Hamiltonian to the multireference configuration interaction wave functions, the other combining a spin-orbit Hamiltonian and multireference configuration interaction potential energy curves. Using the results for the relativistic potential energy curves that correspond to the Rb (5s (2)S) + Sr (5s4d (3)P degrees ) asymptote, we have simulated dispersed fluorescence spectra as they were recently measured in our lab. The comparison with experimental data allows to benchmark both methods and demonstrate that spin-orbit coupling has to be included for the lowest states of RbSr. PMID- 25527938 TI - Near-infrared and ultraviolet induced isomerization of crotonic acid in N2 and Xe cryomatrices: first observation of two high-energy trans C-O conformers and mechanistic insights. AB - E-crotonic acid was isolated in cryogenic solid N2 and xenon matrices, and subjected to Laser ultraviolet (UV) and near-infrared (NIR) irradiations. In the deposited matrices, the two low-energy cis C-O E-cc and E-ct conformers, which are the only forms significantly populated in the gas phase, were observed. UV irradiation (lambda= 250 nm) of the compound in N2 matrix allows for experimental detection, not just of the two low-energy cis C-O isomers of Z-crotonic acid previously observed in the experiments carried out in argon matrix [Z-cc and Z ct; R. Fausto, A. Kulbida, and O. Schrems, J. Chem. Soc., Faraday Trans. 91, 3755 3770 (1995)] but also of the never observed before high-energy forms of both E- and Z-crotonic acids bearing the carboxylic acid group in the trans arrangement (E-tc and Z-tc conformers). In turn, NIR irradiation experiments in the N2 matrix allow to produce the high-energy E-tc trans C-O conformer in a selective way, from the initially deposited E-cc form. The vibrational signatures of all the 6 rotameric structures of the crotonic acids experimentally observed, including those of the new trans C-O forms, were determined and the individual spectra fully assigned, also with support of theoretically obtained data. On the other hand, as found before for the compound isolated in argon matrix, the experiments performed in xenon matrix failed to experimental detection of the trans C-O forms. This demonstrates that in noble gas matrices these forms are not stable long enough to allow for their observation by steady state spectroscopy techniques. In these matrices, the trans C-O forms convert spontaneously into their cis C-O counterparts, by tunnelling. Some mechanistic details of the studied processes were extracted and discussed. PMID- 25527939 TI - Using a two-capillary viscometer with preheating to measure the viscosity of dilute argon from 298.15 K to 653.15 K. AB - Currently, there exists only one set of experimental results at temperatures up to 680 K with the claimed relative standard uncertainty of (0.15-0.20)%. This paper reports new experimental results using the two-capillary viscometer in the temperature range from 298.15 K to 653.15 K with the claimed relative standard uncertainty of 0.062%. The new measurements agree with the existing high accuracy measurements and ab initio calculations in the overlapping temperature range within the extraordinary low relative differences of +/-0.08%. The good agreement represents a robust proof of the potential models derived from the ab initio calculations, which play the powerful means in obtaining the thermophysical properties of dilute monoatomic gases over wide temperature ranges. In the experiments, the authors observed the occurrence of insufficient preheating existing with the two-capillary viscometer at high temperature. PMID- 25527940 TI - Direct production of OH radicals upon CH overtone activation of (CH3)2COO Criegee intermediates. AB - Ozonolysis of alkenes, a principle non-photolytic source of atmospheric OH radicals, proceeds through unimolecular decay of energized carbonyl oxide intermediates, known as Criegee intermediates. In this work, cold dimethyl substituted Criegee intermediates are vibrationally activated in the CH stretch overtone region to drive the 1,4 hydrogen transfer reaction that leads to OH radical products. IR excitation of (CH3)2COO reveals the vibrational states with sufficient oscillator strength, coupling to the reaction coordinate, and energy to surmount the effective barrier (<= 16.0 kcal mol(-1)) to reaction. Insight on the dissociation dynamics is gleaned from homogeneous broadening of the spectral features, indicative of rapid intramolecular vibrational energy redistribution and/or reaction, as well as the quantum state distribution of the OH X(2)Pi (v = 0) products. The experimental results are compared with complementary electronic structure calculations, which provide the IR absorption spectrum and geometric changes along the intrinsic reaction coordinate. Additional theoretical analysis reveals the vibrational modes and couplings that permit (CH3)2COO to access to the transition state region for reaction. The experimental and theoretical results are compared with an analogous recent study of the IR activation of syn CH3CHOO and its unimolecular decay to OH products [F. Liu, J. M. Beames, A. S. Petit, A. B. McCoy, and M. I. Lester, Science 345, 1596 (2014)]. PMID- 25527941 TI - The crystal structure of methane B at 8 GPa--an alpha-Mn arrangement of molecules. AB - From a combination of powder and single-crystal synchrotron x-ray diffraction data we have determined the carbon substructure of phase B of methane at a pressure of ~8 GPa. We find this substructure to be cubic with space group I4-3m and 58 molecules in the unit cell. The unit cell has a lattice parameter a = 11.911(1) A at 8.3(2) GPa, which is a factor of ?2 larger than had previously been proposed by Umemoto et al. [J. Phys.: Condens. Matter 14, 10675 (2002)]. The substructure as now solved is not related to any close-packed arrangement, contrary to previous proposals. Surprisingly, the arrangement of the carbon atoms is isostructural with that of alpha-manganese at ambient conditions. PMID- 25527942 TI - Massively parallel molecular-dynamics simulation of ice crystallisation and melting: the roles of system size, ensemble, and electrostatics. AB - Ice crystallisation and melting was studied via massively parallel molecular dynamics under periodic boundary conditions, using approximately spherical ice nano-particles (both "isolated" and as a series of heterogeneous "seeds") of varying size, surrounded by liquid water and at a variety of temperatures. These studies were performed for a series of systems ranging in size from ~1 * 10(6) to 8.6 * 10(6) molecules, in order to establish system-size effects upon the nano clusters" crystallisation and dissociation kinetics. Both "traditional" four-site and "single-site" and water models were used, with and without formal point charges, dipoles, and electrostatics, respectively. Simulations were carried out in the microcanonical and isothermal-isobaric ensembles, to assess the influence of "artificial" thermo- and baro-statting, and important disparities were observed, which declined upon using larger systems. It was found that there was a dependence upon system size for both ice growth and dissociation, in that larger systems favoured slower growth and more rapid melting, given the lower extent of "communication" of ice nano-crystallites with their periodic replicae in neighbouring boxes. Although the single-site model exhibited less variation with system size vis-a-vis the multiple-site representation with explicit electrostatics, its crystallisation-dissociation kinetics was artificially fast. PMID- 25527943 TI - Finite-size scaling study of shear viscosity anomaly at liquid-liquid criticality. AB - We study the equilibrium dynamics of a symmetrical binary Lennard-Jones fluid mixture near its consolute criticality. Molecular dynamics simulation results for the shear viscosity, eta, from a microcanonical ensemble are compared with those from a canonical ensemble with various thermostats. It is observed that the Nose Hoover thermostat is a good candidate for this purpose, and is therefore adopted for the quantification of the critical singularity of eta, to avoid the temperature fluctuations (or even drifts) that are often encountered in microcanonical simulations. Via a finite-size scaling analysis of our simulation data we have been able to confirm that the shear viscosity exhibits a weak critical singularity in agreement with the theoretical predictions. PMID- 25527944 TI - Formation of a new archetypal Metal-Organic Framework from a simple monatomic liquid. AB - We report a molecular-dynamics simulation of a single-component system of particles interacting via a spherically symmetric potential that is found to form, upon cooling from a liquid state, a low-density porous crystalline phase. Its structure analysis demonstrates that the crystal can be described by a net with a topology that belongs to the class of topologies characteristic of the Metal-Organic Frameworks (MOFs). The observed net is new, and it is now included in the Reticular Chemistry Structure Resource database. The observation that a net topology characteristic of MOF crystals, which are known to be formed by a coordination-driven self-assembly process, can be reproduced by a thermodynamically stable configuration of a simple single-component system of particles opens a possibility of using these models in studies of MOF nets. It also indicates that structures with MOF topology, as well as other low-density porous crystalline structures can possibly be produced in colloidal systems of spherical particles, with an appropriate tuning of interparticle interaction. PMID- 25527945 TI - Interplay between the structure and dynamics in liquid and undercooled boron: an ab initio molecular dynamics simulation study. AB - In the present work, the structural and dynamic properties of liquid and undercooled boron are investigated by means of ab initio molecular dynamics simulation. Our results show that both liquid and undercooled states present a well pronounced short-range order (SRO) mainly due to the formation of inverted umbrella structural units. Moreover, we observe the development of a medium-range order (MRO) in the undercooling regime related to the increase of inverted umbrella structural units and of their interconnection as the temperature decreases. We also evidence that this MRO leads to a partial crystallization in the beta-rhombohedral crystal below T = 1900 K. Finally, we discuss the role played by the SRO and MRO in the nearly Arrhenius evolution of the diffusion and the non-Arrhenius temperature dependence of the shear viscosity, in agreement with the experiment. PMID- 25527946 TI - Dielectric response from lattices of dipoles with fixed orientation. AB - The properties of dipolar cubic lattices are studied and the paradox of how to obtain a long range polarization in such lattices is resolved by choosing a proper shape of the total system. It has been shown that large but finite number of aligned dipoles prefer to exist as needle shaped macroscopic particles [M. Yoon and D. Tomanek, J. Phys.: Condens. Matter 22, 455105 (2010)]. The total energy for a particle in such a system has one short range contribution depending on the packing (the chosen lattice) and one long range term depending on the dipole density of the system. We show that the latter term corresponds exactly to the polarization term from a dielectric medium embedding a sphere of the considered system. There is no need to include a dielectric medium in this modeling and the "dielectric stabilization" is generated solely by the dipoles of the system. PMID- 25527947 TI - High pressure study of a highly energetic nitrogen-rich carbon nitride, cyanuric triazide. AB - Cyanuric triazide (CTA), a nitrogen-rich energetic material, was compressed in a diamond anvil cell up to 63.2 GPa. Samples were characterized by x-ray diffraction, Raman, and infrared spectroscopy. A phase transition occurring between 29.8 and 30.7 GPa was found by all three techniques. The bulk modulus and its pressure derivative of the low pressure phase were determined by fitting the 300 K isothermal compression data to the Birch-Murnaghan equation of state. Due to the strong photosensitivity of CTA, synchrotron generated x-rays and visible laser radiation both lead to the progressive conversion of CTA into a two dimensional amorphous C=N network, starting from 9.2 GPa. As a result of the conversion, increasingly weak and broad x-ray diffraction lines were recorded from crystalline CTA as a function of pressure. Hence, a definite structure could not be obtained for the high pressure phase of CTA. Results from infrared spectroscopy carried out to 40.5 GPa suggest the high pressure formation of a lattice built of tri-tetrazole molecular units. The decompression study showed stability of the high pressure phase down to 13.9 GPa. Finally, two CTA samples, one loaded with neon and the other with nitrogen, used as pressure transmitting media, were laser-heated to approximately 1100 K and 1500 K while compressed at 37.7 GPa and 42.0 GPa, respectively. In both cases CTA decomposed resulting in amorphous compounds, as recovered at ambient conditions. PMID- 25527948 TI - Molecular simulation of thermodynamic and transport properties for the H2O+NaCl system. AB - Molecular dynamics and Monte Carlo simulations have been carried out to obtain thermodynamic and transport properties of the binary mixture H2O+NaCl at temperatures from T = 298 to 473 K. In particular, vapor pressures, liquid densities, viscosities, and vapor-liquid interfacial tensions have been obtained as functions of pressure and salt concentration. Several previously proposed fixed-point-charge models that include either Lennard-Jones (LJ) 12-6 or exponential-6 (Exp6) functional forms to describe non-Coulombic interactions were studied. In particular, for water we used the SPC and SPC/E (LJ) models in their rigid forms, a semiflexible version of the SPC/E (LJ) model, and the Errington Panagiotopoulos Exp6 model; for NaCl, we used the Smith-Dang and Joung-Cheatham (LJ) parameterizations as well as the Tosi-Fumi (Exp6) model. While none of the model combinations are able to reproduce simultaneously all target properties, vapor pressures are well represented using the SPC plus Joung-Cheathem model combination, and all LJ models do well for the liquid density, with the semiflexible SPC/E plus Joung-Cheatham combination being the most accurate. For viscosities, the combination of rigid SPC/E plus Smith-Dang is the best alternative. For interfacial tensions, the combination of the semiflexible SPC/E plus Smith-Dang or Joung-Cheatham gives the best results. Inclusion of water flexibility improves the mixture densities and interfacial tensions, at the cost of larger deviations for the vapor pressures and viscosities. The Exp6 water plus Tosi-Fumi salt model combination was found to perform poorly for most of the properties of interest, in particular being unable to describe the experimental trend for the vapor pressure as a function of salt concentration. PMID- 25527949 TI - Molecular dynamics investigation of nanoscale cavitation dynamics. AB - We use molecular dynamics simulations to investigate the cavitation dynamics around intensely heated solid nanoparticles immersed in a model Lennard-Jones fluid. Specifically, we study the temporal evolution of vapor nanobubbles that form around the solid nanoparticles heated over ps time scale and provide a detail description of the following vapor formation and collapse. For 8 nm diameter nanoparticles we observe the formation of vapor bubbles when the liquid temperature 0.5-1 nm away from the nanoparticle surface reaches ~90% of the critical temperature, which is consistent with the onset of spinodal decomposition. The peak heat flux from the hot solid to the surrounding liquid at the bubble formation threshold is ~20 times higher than the corresponding steady state critical heat flux. Detailed analysis of the bubble dynamics indicates adiabatic formation followed by an isothermal final stage of growth and isothermal collapse. PMID- 25527950 TI - Energy relaxation of a dissipative quantum oscillator. AB - The dissipative harmonic oscillator is studied as a model for vibrational relaxation in a liquid environment. Continuum limit expressions are derived for the time-dependent average energy, average width of the population, and the vibrational population itself. The effect of the magnitude of the solute-solvent interaction, expressed in terms of a friction coefficient, solvent temperature, and initial energy of the oscillator on the relaxation has been studied. These results shed light on the recent femtosecond stimulated Raman scattering probe of the 1570 cm(-1) -C=C- stretching mode of trans-Stilbene in the first (S1) excited electronic state. When the oscillator is initially cold with respect to the bath temperature, its average energy and width increase in time. When it is initially hot, the average energy and width decrease with time in qualitative agreement with the experimental observations. PMID- 25527951 TI - Coupled slow and fast surface dynamics in an electrocatalytic oscillator: model and simulations. AB - The co-existence of disparate time scales is pervasive in many systems. In particular for surface reactions, it has been shown that the long-term evolution of the core oscillator is decisively influenced by slow surface changes, such as progressing deactivation. Here we present an in-depth numerical investigation of the coupled slow and fast surface dynamics in an electrocatalytic oscillator. The model consists of four nonlinear coupled ordinary differential equations, investigated over a wide parameter range. Besides the conventional bifurcation analysis, the system was studied by means of high-resolution period and Lyapunov diagrams. It was observed that the bifurcation diagram changes considerably as the irreversible surface poisoning evolves, and the oscillatory region shrinks. The qualitative dynamics changes accordingly and the chaotic oscillations are dramatically suppressed. Nevertheless, periodic cascades are preserved in a confined region of the resistance vs. voltage diagram. Numerical results are compared to experiments published earlier and the latter reinterpreted. Finally, the comprehensive description of the time-evolution in the period and Lyapunov diagrams suggests further experimental studies correlating the evolution of the system's dynamics with changes of the catalyst structure. PMID- 25527952 TI - Vibrational lifetimes of hydrogen on lead films: an ab initio molecular dynamics with electronic friction (AIMDEF) study. AB - Using density functional theory and Ab Initio Molecular Dynamics with Electronic Friction (AIMDEF), we study the adsorption and dissipative vibrational dynamics of hydrogen atoms chemisorbed on free-standing lead films of increasing thickness. Lead films are known for their oscillatory behaviour of certain properties with increasing thickness, e.g., energy and electron spillout change in discontinuous manner, due to quantum size effects [G. Materzanini, P. Saalfrank, and P. J. D. Lindan, Phys. Rev. B 63, 235405 (2001)]. Here, we demonstrate that oscillatory features arise also for hydrogen when chemisorbed on lead films. Besides stationary properties of the adsorbate, we concentrate on finite vibrational lifetimes of H-surface vibrations. As shown by AIMDEF, the damping via vibration-electron hole pair coupling dominates clearly over the vibration-phonon channel, in particular for high-frequency modes. Vibrational relaxation times are a characteristic function of layer thickness due to the oscillating behaviour of the embedding surface electronic density. Implications derived from AIMDEF for frictional many-atom dynamics, and physisorbed species will also be given. PMID- 25527953 TI - Ostwald ripening in multiple-bubble nuclei. AB - The Ostwald ripening of bubbles is studied by molecular dynamics simulations involving up to 679 * 10(6) Lennard-Jones particles. Many bubbles appear after depressurizing a system that is initially maintained in the pure-liquid phase, and the coarsening of bubbles follows. The self-similarity of the bubble-size distribution function predicted by Lifshitz-Slyozov-Wagner theory is directly confirmed. The total number of bubbles decreases asymptotically as t(-x) with scaling exponent x. As the initial temperature increases, the exponent changes from x = 3/2 to 1, which implies that the growth of bubbles changes from interface-limited (the t(1/2) law) to diffusion-limited (the t(1/3) law) growth. PMID- 25527954 TI - Intervalence charge transfer luminescence: interplay between anomalous and 5d - 4f emissions in Yb-doped fluorite-type crystals. AB - In this paper, we report the existence of intervalence charge transfer (IVCT) luminescence in Yb-doped fluorite-type crystals associated with Yb(2+)-Yb(3+) mixed valence pairs. By means of embedded cluster, wave function theory ab initio calculations, we show that the widely studied, very broad band, anomalous emission of Yb(2+)-doped CaF2 and SrF2, usually associated with impurity-trapped excitons, is, rather, an IVCT luminescence associated with Yb(2+)-Yb(3+) mixed valence pairs. The IVCT luminescence is very efficiently excited by a two-photon upconversion mechanism where each photon provokes the same strong 4f(14)-1A1g-> 4f(13)((2)F7/2)5deg-1T1u absorption in the Yb(2+) part of the pair: the first one, from the pair ground state; the second one, from an excited state of the pair whose Yb(3+) moiety is in the higher 4f(13)((2)F5/2) multiplet. The Yb(2+) Yb(3+) -> Yb(3+)-Yb(2+) IVCT emission consists of an Yb(2+) 5deg -> Yb(3+) 4f7/2 charge transfer accompanied by a 4f7/2 -> 4f5/2 deexcitation within the Yb(2+) 4f(13) subshell: [(2)F5/25deg,(2)F7/2] -> [(2)F7/2,4f(14)]. The IVCT vertical transition leaves the oxidized and reduced moieties of the pair after electron transfer very far from their equilibrium structures; this explains the unexpectedly large band width of the emission band and its low peak energy, because the large reorganization energies are subtracted from the normal emission. The IVCT energy diagrams resulting from the quantum mechanical calculations explain the different luminescent properties of Yb-doped CaF2, SrF2, BaF2, and SrCl2: the presence of IVCT luminescence in Yb-doped CaF2 and SrF2; its coexistence with regular 5d-4f emission in SrF2; its absence in BaF2 and SrCl2; the quenching of all emissions in BaF2; and the presence of additional 5d-4f emissions in SrCl2 which are absent in SrF2. They also allow to interpret and reproduce recent experiments on transient photoluminescence enhancement in Yb(2+) doped CaF2 and SrF2, the appearance of Yb(2+) 4f-5d absorption bands in the excitation spectra of the IR Yb(3+) emission in partly reduced CaF2:Yb(3+) samples, and to identify the broadband observed in the excitation spectrum of the so far called anomalous emission of SrF2:Yb(2+) as an IVCT absorption, which corresponds to an Yb(2+) 4f5/2 -> Yb(3+) 4f7/2 electron transfer. PMID- 25527955 TI - The adsorption of alpha-cyanoacrylic acid on anatase TiO2 (101) and (001) surfaces: a density functional theory study. AB - The adsorption of alpha-cyanoacrylic acid (CAA) on anatase TiO2 (101) and (001) surfaces, including adsorption energies, structures, and electronic properties, have been studied by means of density functional theory calculations in connection with ultrasoft pseudopotential and generalized gradient approximation based upon slab models. The most stable structure of CAA on anatase TiO2 (101) surface is the dissociated bidentate configuration where the cyano N and carbonyl O bond with two adjacent surface Ti atoms along [010] direction and the dissociated H binds to the surface bridging O which connects the surface Ti bonded with carbonyl O. While for the adsorption of CAA on (001) surface, the most stable structure is the bidentate configuration through the dissociation of hydroxyl in carboxyl moiety. The O atoms of carboxyl bond with two neighbor surface Ti along [100] direction, and the H from dissociated hydroxyl interacts with surface bridging O, generating OH species. The adsorption energies are estimated to be 1.02 and 3.25 eV for (101) and (001) surfaces, respectively. The analysis of density of states not only suggests the bonds between CAA and TiO2 surfaces are formed but also indicates that CAA adsorptions on TiO2 (101) and (001) surfaces provide feasible mode for photo-induced electron injection through the interface between TiO2 and CAA. This is resulted from that, compared with the contribution of CAA orbitals in valence bands, the conduction bands which are mainly composed of Ti 3d orbitals have remarkable reduction of the component of CAA orbitals. PMID- 25527956 TI - Molecular reordering processes on ice (0001) surfaces from long timescale simulations. AB - We report results of long timescale adaptive kinetic Monte Carlo simulations aimed at identifying possible molecular reordering processes on both proton disordered and ordered (Fletcher) basal plane (0001) surfaces of hexagonal ice. The simulations are based on a force field for flexible molecules and span a time interval of up to 50 MUs at a temperature of 100 K, which represents a lower bound to the temperature range of earth's atmosphere. Additional calculations using both density functional theory and an ab initio based polarizable potential function are performed to test and refine the force field predictions. Several distinct processes are found to occur readily even at this low temperature, including concerted reorientation (flipping) of neighboring surface molecules, which changes the pattern of dangling H-atoms, and the formation of interstitial defects by the downwards motion of upper-bilayer molecules. On the proton disordered surface, one major surface roughening process is observed that significantly disrupts the crystalline structure. Despite much longer simulation time, such roughening processes are not observed on the highly ordered Fletcher surface which is energetically more stable because of smaller repulsive interaction between neighboring dangling H-atoms. However, a more localized process takes place on the Fletcher surface involving a surface molecule transiently leaving its lattice site. The flipping process provides a facile pathway of increasing proton-order and stabilizing the surface, supporting a predominantly Fletcher-like ordering of low-temperature ice surfaces. Our simulations also show that eventual proton-disordered patches on the surface may induce significant local reconstructions. Further, a subset of the molecules on the Fletcher surface are susceptible to forming interstitial defects which might provide active sites for various chemical reactions in the atmosphere. PMID- 25527957 TI - Lattice Monte Carlo simulations of polymer melts. AB - We use Monte Carlo simulations to study polymer melts consisting of fully flexible and moderately stiff chains in the bond fluctuation model at a volume fraction 0.5. In order to reduce the local density fluctuations, we test a pre packing process for the preparation of the initial configurations of the polymer melts, before the excluded volume interaction is switched on completely. This process leads to a significantly faster decrease of the number of overlapping monomers on the lattice. This is useful for simulating very large systems, where the statistical properties of the model with a marginally incomplete elimination of excluded volume violations are the same as those of the model with strictly excluded volume. We find that the internal mean square end-to-end distance for moderately stiff chains in a melt can be very well described by a freely rotating chain model with a precise estimate of the bond-bond orientational correlation between two successive bond vectors in equilibrium. The plot of the probability distributions of the reduced end-to-end distance of chains of different stiffness also shows that the data collapse is excellent and described very well by the Gaussian distribution for ideal chains. However, while our results confirm the systematic deviations between Gaussian statistics for the chain structure factor Sc(q) [minimum in the Kratky-plot] found by Wittmer et al. [EPL 77, 56003 (2007)] for fully flexible chains in a melt, we show that for the available chain length these deviations are no longer visible, when the chain stiffness is included. The mean square bond length and the compressibility estimated from collective structure factors depend slightly on the stiffness of the chains. PMID- 25527958 TI - Equilibrium properties of charged microgels: a Poisson-Boltzmann-Flory approach. AB - The equilibrium properties of ionic microgels are investigated using a combination of the Poisson-Boltzmann and Flory theories. Swelling behavior, density profiles, and effective charges are all calculated in a self-consistent way. Special attention is given to the effects of salinity on these quantities. In accordance with the traditional ideal Donnan equilibrium theory, it is found that the equilibrium microgel size is strongly influenced by the amount of added salt. Increasing the salt concentration leads to a considerable reduction of the microgel volume, which therefore releases its internal material - solvent molecules and dissociated ions - into the solution. Finally, the question of charge renormalization of ionic microgels in the context of the cell model is briefly addressed. PMID- 25527959 TI - Advances in the generalized entropy theory of glass-formation in polymer melts. AB - The generalized entropy theory (GET) of polymeric glass-forming liquids is reformulated into a computationally simpler and more natural formalism than the original version of this theory. The new theoretical framework greatly facilitates establishing essential trends in the dependence of the segmental relaxation time tau, fragility, characteristic temperatures of glass-formation, etc., on the combined influences of monomer molecular structure, chain rigidity, and cohesive interaction strength. Special attention is placed on the estimating the parameters of the phenomenological Vogel-Fulcher-Tammann relations for describing segmental relaxation in diverse liquids in the low temperature range of glass-formation, Tg > T > Tc (or Tg < T < Tg + 100 K), where Tg and Tc are, respectively, the glass transition temperature and the crossover temperature separating the high and low temperature regimes of glass-formation. Finally, we discuss how the molecular energetic interaction parameters of the GET can be estimated from experimental data. Illustrative calculations are performed for the stiffness factor sigma and the cohesive energy density u as a first step in this direction. PMID- 25527960 TI - Non-adiabatic dynamics of isolated green fluorescent protein chromophore anion. AB - On-the-fly ab initio molecular dynamics calculations have been performed to investigate the relaxation mechanism of green fluorescent protein chromophore anion under vacuum. The CASSCF surface hopping simulation method based on Zhu Nakamura theory is applied to present the real-time conformational changes of the target molecule. The static calculations and dynamics simulation results suggest that not only the twisting motion around bridging bonds between imidazolinone and phenoxy groups but the strength mode of C=O and pyramidalization character of bridging atom are major factors on the ultrafast fluorescence quenching process of the isolated chromophore anion. The abovementioned factors bring the molecule to the vicinity of conical intersections on its potential energy surface and to finish the internal conversion process. A Hula-like twisting pattern is displayed during the relaxation process and the entire decay process disfavors a photoswitching pattern which corresponds to cis-trans photoisomerization. PMID- 25527961 TI - Citrate synthase proteins in extremophilic organisms: studies within a structure based model. AB - We study four citrate synthase homodimeric proteins within a structure-based coarse-grained model. Two of these proteins come from thermophilic bacteria, one from a cryophilic bacterium and one from a mesophilic organism; three are in the closed and two in the open conformations. Even though the proteins belong to the same fold, the model distinguishes the properties of these proteins in a way which is consistent with experiments. For instance, the thermophilic proteins are more stable thermodynamically than their mesophilic and cryophilic homologues, which we observe both in the magnitude of thermal fluctuations near the native state and in the kinetics of thermal unfolding. The level of stability correlates with the average coordination number for amino acid contacts and with the degree of structural compactness. The pattern of positional fluctuations along the sequence in the closed conformation is different than in the open conformation, including within the active site. The modes of correlated and anticorrelated movements of pairs of amino acids forming the active site are very different in the open and closed conformations. Taken together, our results show that the precise location of amino acid contacts in the native structure appears to be a critical element in explaining the similarities and differences in the thermodynamic properties, local flexibility, and collective motions of the different forms of the enzyme. PMID- 25527962 TI - Hydration and hydrogen bond network of water around hydrophobic surface investigated by terahertz spectroscopy. AB - Water conformation around hydrophobic side chains of four amino acids (glycine, L alanine, L-aminobutyric acid, and L-norvaline) was investigated via changes in complex dielectric constant in the terahertz (THz) region. Each of these amino acids has the same hydrophilic backbone, with successive additions of hydrophobic straight methylene groups (-CH2-) to the side chain. Changes in the degree of hydration (number of dynamically retarded water molecules relative to bulk water) and the structural conformation of the water hydrogen bond (HB) network related to the number of methylene groups were quantitatively measured. Since dielectric responses in the THz region represent water relaxations and water HB vibrations at a sub-picosecond and picosecond timescale, these measurements characterized the water relaxations and HB vibrations perturbed by the methylene apolar groups. We found each successive straight -CH2- group on the side chain restrained approximately two hydrophobic hydration water molecules. Additionally, the number of non-hydrogen-bonded (NHB) water molecules increased slightly around these hydrophobic side chains. The latter result seems to contradict the iceberg model proposed by Frank and Evans, where water molecules are said to be more ordered around apolar surfaces. Furthermore, we compared the water-hydrophilic interactions of the hydrophilic amino acid backbone with those with the water hydrophobic interactions around the side chains. As the hydrophobicity of the side chain increased, the ordering of the surrounding water HB network was altered from that surrounding the hydrophilic amino acid backbone, thereby diminishing the fraction of NHB water and ordering the surrounding tetrahedral water HB network. PMID- 25527964 TI - Potential threat attracts attention and interferes with voluntary saccades. AB - Several studies have shown that threatening stimuli are prioritized by the visual system. In the present study we investigated whether a stimulus associated with a threat of electrical shock attracts attention and accordingly interferes with the execution of voluntary eye movements to other locations. In 2 experiments, we showed that when a fear-conditioned and a neutral stimulus were presented simultaneously, voluntary saccades were initiated faster toward fear-conditioned compared with neutral stimuli. Moreover, saccades often erroneously went to the location of threat even when a saccade to a different location was required. This implies an automatic shift of attention to a fear-conditioned stimulus that interferes with saccade execution. The same pattern of results was found for a neutral stimulus that was always presented together with the fear-conditioned stimulus and consequently itself became associated with threat. The current results indicate that threatening stimuli attract visual attention and subsequently bias saccade target selection in a reflexive fashion. PMID- 25527963 TI - Self-rated health amongst male and female employees in Sweden: a nationally representative study. AB - PURPOSE: Self-rated health (SRH) is a well-established measure within social epidemiology. However, most studies on SRH tend to be amongst the general population, where SRH has been found to be lower in women than in men. Few studies have specifically investigated patterns of SRH just within an employed population. The purpose of this study was to (1) investigate whether there are gender differences in reporting suboptimal SRH in an employed Swedish population and (2) study whether these differences could be explained by socio-economic, work-, health- and/or lifestyle-related factors. METHODS: This study is cross sectional analysis of data from the 2008 wave of Swedish Longitudinal Occupational Survey of Health, a nationally representative cohort of the Swedish working population. This study includes the responses of 9,756 employed individuals. Logistic regression analyses were performed. RESULTS: After adjusting for age, income and working hours (full vs. part time), men had significantly higher odds of suboptimal SRH than women OR 1.38 (95 % CI 1.22 1.55). With stepwise inclusion of health factors such as long-standing disease, sleep quality and fatigue, the OR for men increased to 1.65 (95 % CI 1.44-1.89). Gender differences in reporting suboptimal SRH were attenuated to 1.29 (95 % CI 1.11-1.51) with the inclusion of lifestyle factors. However, they remained significant after inclusion of all explanatory variables. CONCLUSIONS: In contrast to findings in general population studies, our results show that men in employment have higher odds of suboptimal SRH than their female counterparts. As SRH is an important indicator of health with a strong association with mortality, an excess risk of suboptimal SRH amongst employed men shows that more attention should be paid to men's health in the workplace. PMID- 25527965 TI - Mobile eye tracking reveals little evidence for age differences in attentional selection for mood regulation. AB - Two studies are reported representing the first use of mobile eye tracking to study emotion regulation across adulthood. Past research on age differences in attentional deployment using stationary eye tracking has revealed older adults show relatively more positive looking and seem to benefit more moodwise from this looking pattern, compared with younger adults. However, these past studies have greatly constrained the stimuli participants can look at, despite real-world settings providing numerous possibilities for what we choose to look at. The authors therefore used mobile eye tracking to study age differences in attentional selection, as indicated by fixation patterns to stimuli of different valence freely chosen by the participant. In contrast to stationary eye-tracking studies of attentional deployment, Study 1 showed that younger and older individuals generally selected similar proportions of valenced stimuli, and attentional selection had similar effects on mood across age groups. Study 2 replicated this pattern with an adult life span sample including middle-aged individuals. Emotion regulation-relevant attention may thus differ depending on whether stimuli are freely chosen or not. (PsycINFO Database Record PMID- 25527966 TI - Successful adjunctive immunoglobulin treatment in patients affected by leukocyte adhesion deficiency type 1 (LAD-1). AB - Two patients with a severe leukocyte adhesion deficiency type 1 (LAD-1) phenotype were analyzed by flow cytometry and functional assays to demonstrate the improper adhesive and phagocytic responses of their leukocytes. A single homozygous defect that involves a missense mutation (c.817G>A) that encodes for a G273R substitution in CD18 was identified in both patients. The adhesion and phagocytosis assays demonstrated the inability of patients' leukocytes to perform these functions. Expression of the LFA-1 (CD11a/CD18) on the co-transfected HEK 293 cells with the mutated form of CD18 was not detected. Finally, both patients have been treated with immunoglobulin as an adjunctive therapy with positive results. We propose that intravenous immunoglobulin treatment is safe and efficacious in LAD-1 patients before hematopoietic stem cell transplantation and helpful in controlling severe infections. Subcutaneous immunoglobulin appeared to help wound healing in refractory ulcers in these patients. PMID- 25527967 TI - Waterborne beclomethasone dipropionate affects the physiology of fish while its metabolite beclomethasone is not taken up. AB - Asthma is commonly treated with inhalable glucocorticosteroids, including beclomethasone dipropionate (BDP). This is a synthetic prodrug which is metabolized to the more active monopropionate (BMP) and free beclomethasone in humans. To evaluate potential effects of residual drugs on fish, we conducted a 14 day flow-through exposure experiment with BDP and beclomethasone using rainbow trout, and analyzed effects on plasma glucose, hepatic glutathione and catalase activity together with water and body concentrations of the BDP, BMP and beclomethasone. We also analyzed hepatic gene expression in BDP-exposed fish by microarray and quantitative PCR. Beclomethasone (up to 0.65 MUg/L) was not taken up in the fish while BDP (0.65 and 0.07 MUg/L) resulted in accumulation of both beclomethasone, BMP and BDP in plasma, reaching levels up to those found in humans during therapy. Accordingly, exposure to 0.65 MUg/L of BDP significantly increased blood glucose as well as oxidized glutathione levels and catalase activity in the liver. Exposure to beclomethasone or the low concentration of BDP had no effect on these endpoints. Both exposure concentrations of BDP resulted in significantly higher transcript abundance of phosphoenolpyruvate carboxykinase involved in gluconeogenesis, and of genes involved in immune responses. As only the rapidly metabolized prodrug was potent in fish, the environmental risks associated with the use of BDP are probably small. However, the observed physiological effects in fish of BDP at plasma concentrations known to affect human physiology provides valuable input to the development of read-across approaches in the identification of pharmaceuticals of environmental concern. PMID- 25527968 TI - Bioavailability and characterization of dissolved organic nitrogen and dissolved organic phosphorus in wastewater effluents. AB - There is still a great knowledge gap in the understanding of characteristics and bioavailability of dissolved organic nitrogen (DON) and dissolved organic phosphorus (DOP) in wastewater effluents, which surmise implications related to both discharge regulation and treatment practice. In this study, we simultaneously investigated the characteristics and bioavailability of both DON and DOP, with separated hydrophilic versus hydrophobic fractions, in highly treated wastewater effluents for the first time. The tertiary effluents from two wastewater treatment plants were separated into two fractions by XAD-8 resin coupled with anion exchange resin based on the hydrophobicity. Results showed that the majority of DON was present in hydrophilic forms while more DOP existed in hydrophobic forms. Hydrophilic DON contributed to 64.0%-72.2% of whole DON, while hydrophobic DOP accounted for 61.4%-80.7% of total DOP for the two plants evaluated. The effluents and their fractions were then subject to bioavailability assay based on 14-day algae growth. The results indicated that majority (~73-75%) of the effluent DOP, particularly the hydrophobic fraction with lower C/P ratio was more likely to be bioavailable for algal growth. The bioavailable fraction of DON varied widely (28%-61%) for the two plants studied and the hydrophilic fraction with lower C/N ratio seemed to exhibit higher bioavailability than the hydrophobic portion. The differences in bioavailable DON and DOP distributions of effluents from those two plants could be attributed to different receiving effluent compositions and wastewater treatment processes. In addition, fluorescence excitation-emission matrices (EEMs) combined with parallel factor analysis (PARAFAC) were used to characterize the dissolved organic matter (DOM) in wastewater effluent, which provided insights into the nature of organic matter in wastewater samples with different characteristics and originating sources. PMID- 25527969 TI - Endoscopic therapies for gastroesophageal reflux disease: back in the game? PMID- 25527970 TI - To band or not to band.... PMID- 25527971 TI - Discrepancies in liver disease labeling in the package inserts of commonly prescribed medications. PMID- 25527972 TI - Esophageal mucosal impedance: is it time to forgo prolonged gastroesophageal reflux recordings? PMID- 25527973 TI - NF-kappaB signaling pathway confers neuroblastoma cells migration and invasion ability via the regulation of CXCR4. AB - BACKGROUND: Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of tumor metastasis, but the molecular mechanism(s) involved in this process remains largely unknown. In this study, we investigated the role of NF-kappaB signaling pathway in the regulation of CXC chemokine receptor-4 (CXCR4) in neuroblastoma metastasis. MATERIAL AND METHODS: NF-kappaB, CXCR4 mRNA and protein expression were measured by RT-PCR, and Western blot. Tumor necrosis factor-alpha (TNF-alpha) was used to induce the upregulation of NF kappaB and CXCR4. The knockdown of NF-kappaB and CXCR4 was achieved by PDTC. Transwell assay was used to investigate the role of NF-kappaB (P65) in neuroblastoma cell migration and invasion. An in vitro co-culture system was established to investigate the role of tumor microenvironment in regulation of the NF-kappaB signaling pathway. RESULTS: Over-expression of NF-kappaB (p65) promoted tumor migration and invasion through the upregulation of CXCR4; however, knockdown of NF-kappaB(P65) inhibited tumor migration and invasion through blocking the expression of CXCR4. Consistently, in the co-culture system, the expression of CXCR4 was partly dependent on the expression of NF-kappaB (p65). CONCLUSIONS: Our studies reveal critical roles for the NF-kappaB signaling pathway in neuroblastoma migration and invasion. The mechanism may be through up regulation of CXCR4, mediated by the NF-kappaB signaling pathways. Targeting NF kappaB signalling pathways and ultimately CXCR4 could be a strategy in neuroblastoma therapy. PMID- 25527974 TI - Inferring action structure and causal relationships in continuous sequences of human action. AB - In the real world, causal variables do not come pre-identified or occur in isolation, but instead are embedded within a continuous temporal stream of events. A challenge faced by both human learners and machine learning algorithms is identifying subsequences that correspond to the appropriate variables for causal inference. A specific instance of this problem is action segmentation: dividing a sequence of observed behavior into meaningful actions, and determining which of those actions lead to effects in the world. Here we present a Bayesian analysis of how statistical and causal cues to segmentation should optimally be combined, as well as four experiments investigating human action segmentation and causal inference. We find that both people and our model are sensitive to statistical regularities and causal structure in continuous action, and are able to combine these sources of information in order to correctly infer both causal relationships and segmentation boundaries. PMID- 25527975 TI - Structural characterization of alkaline and oxidative stressed degradation products of lurasidone using LC/ESI/QTOF/MS/MS. AB - A selective, accurate, precise and robust stability indicating liquid chromatography assay method was developed for the monitoring of a novel antipsychotic drug, lurasidone, in the presence of its degradation products (DPs). Also, we investigated degradation behavior of the drug under various stressed conditions such as hydrolytic (acidic, basic and neutral), oxidation, photolytic and thermal. The drug was found to be degraded under base hydrolytic and oxidative conditions, while it was stable in acid and neutral hydrolytic, photolytic and thermal conditions. The method showed adequate separation of lurasidone and its DPs on Xterra C18 (150 mm * 4.6 mm i.d., 3.5 MUm) column using 20 mM ammonium formate (pH 3.0): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 0.6 mL/min. This method was extended to liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC/ESI/QTOF/MS/MS) for structural characterization of DPs. A total of five DPs were characterized by LC/ESI/QTOF/MS/MS studies. Most probable mechanisms for the formation of DPs were proposed. The developed method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization Guideline Q2 (R1). PMID- 25527976 TI - Enantiomeric separation of tapentadol by capillary electrophoresis--study of chiral selectivity manipulation by various types of cyclodextrins. AB - The chiral recognition of the centrally acting analgesic agent tapentadol and its isomers with various cyclodextrins (CDs) was studied by capillary electrophoresis, focusing on the migration order of four stereoisomers. In the case of non-charged hydroxypropylated CDs (2-hydroxypropyl-beta-CD, 2 hydroxypropyl-gamma-CD) the beta derivative was able to discriminate the S,R- and R,S-isomers in acidic background electrolyte, whereas the gamma allowed the separation of S,S- and R,R-tapentadol, respectively. Dual CD system containing both hosts was used to separate all of four isomers. Negatively charged sulfated alpha-CD at 1.0% (w/v) concentration in 100mM sodium borate buffer (pH 9.5) was capable of separating the isomers with favorable enantiomer migration order and the optimized method was able to determine 0.15% of chiral impurities of tapentadol in the presence of the last migrating clinically important R,R-isomer. PMID- 25527977 TI - Raman imaging of pharmaceutical materials: refractive index effects on contrast at buried interfaces. AB - Resolution targets composed of bilayer polydimethylsiloxane (PDMS) devices with buried polyethylene glycol (PEG) channels have been fabricated using traditional photolithographic and micromolding techniques to develop resolution targets that mimic pharmaceutical materials. Raman chemical images of the resulting PEG-in PDMS devices composed of varying parallel line widths were investigated by imaging the PEG lines through a thin overlayer of PDMS. Additionally, a scattering agent, Al2O3, was introduced at varying concentrations to each layer of the device to explore the effects of scattering materials on Raman images. Features in the resulting chemical images of the PEG lines suggest that reflection at the PEG/PDMS interface contributes to the Raman signal. A model based on geometric optics was developed to simulate the observed image functions of the targets. The results emphasize the influence of refractive index discontinuities at the PEG/PDMS interface on the apparent size and shape of the PEG features. Such findings have an impact on interpretation of Raman images of nonabsorbing, opaque pharmaceutical samples. PMID- 25527978 TI - Quality evaluation of the Finasteride polymorphic forms I and II in capsules. AB - Finasteride (FNS) is a specific competitive inhibitor of steroid type-II 5alpha reductase and is widely used for the treatment of benign prostatic hyperplasia, prostate cancer, and androgenetic alopecia. FNS has two polymorphic forms identified as Form I and Form II. It is known that polymorphism can cause significant differences in the physicochemical properties of a compound such as melting point, density, morphology, solubility, and color. Thus, proper qualitative and quantitative monitoring of the solid-state forms is crucial to ensure high-quality products. There are no published papers studying the influence of the FNS polymorphs on the physicochemical quality of capsules. Furthermore, the available analytical methods are time-consuming, expensive, use buffer or do not demonstrate stability-indicating capacity. The aim of this work was to validate a rapid high-performance liquid chromatography (HPLC) method to evaluate FNS in capsules and to study the physicochemical properties of polymorphic forms, evaluating their possible influence in the dissolution profile and stability of FNS in capsules. Capsules containing Forms I and II of FNS were prepared and subjected to quality control studies, dissolution profiles and a stability study at 50 degrees C. A significant effect of polymorphism on the FNS solubility and dissolution properties was observed. These results suggest that changes in the effects of FNS can occur if a suitable control study is not performed on the raw material used to produce the capsules. PMID- 25527979 TI - Simultaneous determination of the counter ion and possible impurity from the synthetic route in the pharmaceutical substance prasugrel hydrochloride. AB - A fast and selective capillary electrophoresis method was developed and validated for the simultaneous determination of the hydrochloride and acetic acid content in prasugrel hydrochloride. Because of the poor chromophore, the indirect detection was chosen. Among different compositions studied as the background electrolyte, the pyromellitic acid with diethylamine (DEA) and myristyltrimethylammonium bromide (TTAB) was chosen. During the validation the specificity, linearity, accuracy, precision, range, and stability of the sample solution were confirmed. The results indicate that the method is suitable for the determination of the counter ion and impurity from the synthetic route of the pharmaceutical drug substance in the same assay. PMID- 25527980 TI - A simple LC-MS/MS method using HILIC chromatography for the determination of fosfomycin in plasma and urine: application to a pilot pharmacokinetic study in humans. AB - A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, using hydrophilic interaction liquid chromatography (HILIC) chromatography for the analysis of fosfomycin in human plasma and urine, has been developed and validated. The plasma method uses a simple protein precipitation using a low volume sample (10 MUL) and is suitable for the concentration range of 1 to 2000 MUg/mL. The urine method involves a simple dilution of 10 MUL of sample and is suitable for a concentration range of 0.1 to 10 mg/mL. The plasma and urine results, reported, respectively, are for recovery (68, 72%), inter-assay precision (<=9.1%, <=8.1%) and accuracy (range -7.2 to 3.3%, -1.9 to 1.6%), LLOQ precision (4.7%, 3.1%) and accuracy (1.7% and 1.2%), and includes investigations into the linearity, stability and matrix effects. The method was used in a pilot pharmacokinetic study of a critically ill patient receiving i.v. fosfomycin, which measured a maximum and minimum plasma concentration of 222 MUg/mL and 172 MUg/mL, respectively, after the initial dose, and a maximum and minimum plasma concentration of 868 MUg/mL and 591MUg/mL, respectively, after the fifth dose. The urine concentration was 2.03 mg/mL after the initial dose and 0.29 mg/mL after the fifth dose. PMID- 25527981 TI - Development of a purity control strategy for pemetrexed disodium and validation of associated analytical methodology. AB - Stability-indicating reversed phase HPLC methods have been developed and validated for the determination of 13 potential process and degradation impurities in pemetrexed disodium drug substance (DS) and pemetrexed for injection drug product (DP). This paper describes the development of HPLC-UV impurity methods for drug substance and drug product. Relative response factors (RRF) have been determined using HPLC-UV in tandem with CAD or by NMR detection. Conditions for the generation of system suitability solutions are described and assure adequate chromatographic resolution and peak identification without the need for impurity reference standards. The methods were fully validated and demonstrated to have acceptable specificity, linearity, accuracy, repeatability, intermediate precision, detection/quantitation limit, and robustness. PMID- 25527983 TI - Complete mitochondrial DNA sequence of the endangered giant sable antelope (Hippotragus niger variani): insights into conservation and taxonomy. AB - The giant sable antelope is one of the most endangered African bovids. Populations of this iconic animal, the national symbol of Angola, were recently rediscovered, after many decades of presumed extinction. Even so, their numbers are scarce and hence conservation plans are essential. However, fundamental information such as its taxonomic position, time of divergence and degree of genetic variation are still lacking. Here, we used a museum preserved horn as a source of DNA to describe, for the first time, the complete mitochondrial genome of the giant sable antelope, and provide insights into its evolutionary history. Reads generated by shotgun sequencing were mapped against the mitochondrial genome of common sable antelope and the nuclear genomes of cow and sheep. Phylogenetic reconstruction and divergence time estimate give support to the monophyly of the giant sable and a maximum divergence time of 170 thousand years to the closest subspecies. About 7% of the nuclear genome was mapped against the reference. The genetic resources reported here are now available for future work in the field of conservation genetics and phylogeny, in this and related species. PMID- 25527982 TI - LC-UV/MS methods for the analysis of prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH) and its active chelator salicylaldehyde isonicotinoyl hydrazone (SIH). AB - Salicylaldehyde isonicotinoyl hydrazone (SIH) is an intracellular iron chelator with well documented potential to protect against oxidative injury both in vitro and in vivo. However, it suffers from short biological half-life caused by fast hydrolysis of the hydrazone bond. Recently, a concept of boronate prochelators has been introduced as a strategy that might overcome these limitations. This study presents two complementary analytical methods for detecting the prochelator boronyl salicylaldehyde isonicotinoyl hydrazone-BSIH along with its active metal binding chelator SIH in different solution matrices and concentration ranges. An LC-UV method for determination of BSIH and SIH in buffer and cell culture medium was validated over concentrations of 7-115 and 4-115 MUM, respectively, and applied to BSIH activation experiments in vitro. An LC-MS assay was validated for quantification of BSIH and SIH in plasma over the concentration range of 0.06-23 and 0.24-23 MUM, respectively, and applied to stability studies in plasma in vitro as well as analysis of plasma taken after i.v. administration of BSIH to rats. A Zorbax-RP bonus column and mobile phases containing either phosphate buffer with EDTA or ammonium formate and methanol/acetonitrile mixture provided suitable conditions for the LC-UV and LC-MS analysis, respectively. Samples were diluted or precipitated with methanol prior to analysis. These separative analytical techniques establish the first validated protocols to investigate BSIH activation by hydrogen peroxide in multiple matrices, directly compare the stabilities of the prochelator and its chelator in plasma, and provide the first basic pharmacokinetic data of this prochelator. Experiments reveal that BSIH is stable in all media tested and is partially converted to SIH by H2O2. The observed integrity of BSIH in plasma samples from the in vivo study suggests that the concept of prochelation might be a promising strategy for further development of aroylhydrazone cytoprotective agents. PMID- 25527984 TI - Mitochondrial phylogeny shows multiple independent ecological transitions and northern dispersion despite of Pleistocene glaciations in meadow and steppe vipers (Vipera ursinii and Vipera renardi). AB - The phylogeny and historical demography of small Eurasian vipers of the Vipera ursinii and V. renardi complexes were studied using mitochondrial DNA sequences analysed with Bayesian inference, Maximum Likelihood and Maximum Parsimony approaches, and mismatch distributions. Diversification in the group resulted from an initial dispersion in the later Pliocene - Pleistocene in two directions: north-westwards via the Balkans (V. ursinii complex) and north-eastwards from Asia Minor via the Caucasus (V. renardi complex). An independent, comparatively recent transition occurred from montane habitats to lowland grasslands in different mitochondrial lineages during the Late Pleistocene, when representatives of the both complexes had reached lowland steppes to the north. Effective population size showed clear signs of rapid growth in eastern V. renardi, triggered by colonization of vast lowland steppes, but in western V. ursinii complex grew during the Last Glaciation and experienced stabilization in Holocene. Expansion and population growth in lowland lineages of V. renardi was not strongly affected by Pleistocene climatic oscillations, when cold, dry conditions could have favoured species living in open grasslands. The high diversity of closely related haplotypes in the Caucasus and Tien-Shan could have resulted from repetitive expansion-constriction-isolation events in montane regions during Pleistocene climate fluctuations. The mitochondrial phylogeny pattern conflicts with the current taxonomy. PMID- 25527985 TI - Assessing optimal configurations of multi-paddock grazing strategies in tallgrass prairie using a simulation model. AB - Maintaining or enhancing the productive capacity and resilience of rangeland ecosystems is critical for the continued support of livelihoods and the ecosystem services that benefit society at large. While the benefits of multi-paddock grazing management have been evident for many years in many countries, it is extremely difficult if not impossible to adequately assess the consequences of the different combinations of management options possible when using multi paddock management under constantly varying conditions on rangelands. To investigate grazing scenarios that would be impractical to conduct in the field we developed a simulation model to focus on addressing the impacts of different cattle grazing management options with multi-paddock management on ecological condition (EC) and profitability. Cattle ranching options are simulated over 25 years periods under varying levels of multi-paddock grazing management complexity at low to moderate stocking levels and fixed or variable stocking rates. We examine the likely ecological and economic effects of shortening grazing periods, lengthening recovery periods, using fixed versus adaptive operational decisions and increasing the number of paddocks in the grazing configuration. At initial stocking levels of up to at 70% of forage standing crop, both EC and profitability are increased with increasing number of paddocks. Shorter periods of grazing increase both EC and profitability while increasing recovery periods increases both EC and profitability initially but profitability decreases if recovery periods are too long. Both EC and profitability are positively related to number of paddocks used. PMID- 25527986 TI - Biodecolorization and biodegradation potential of recalcitrant triphenylmethane dyes by Coriolopsis sp. isolated from compost. AB - Triphenylmethane dyes (TPM) are recalcitrant colorants brought into the environment. In this study, a lesser-known white rot fungus Coriolopsis sp. (1c3), isolated from compost of Empty Fruit Bunch (EFB) of oil palm, was explored for its decolorization potential of TPM dyes. The isolate 1c3 demonstrated good decolorization efficiencies in the treatment of Crystal Violet (CV; 100 mg l( 1)), Methyl Violet (MV; 100 mg l(-1)) and Cotton Blue (CB; 50 mg(-1)), with 94%, 97% and 91%, within 7, 7 and 1 day(s), respectively. Malachite Green (MG; 100 mg l(-1)) was the most recalcitrant dye, with 52% decolorization after 9 days. Dye removal by 1c3 was presumably via biosorption, whereby the process was determined to be influenced by fungal biomass, initial dye concentrations and oxygen requirements. Biodegradation was also a likely mechanism responsible for dye removal by 1c3, occurred as indicated by the reduction of dye spectra peaks. Detection of laccase, lignin peroxidase and NADH-DCIP reductase activities further substantiate the possible occurrence of biodegradation of TPM dyes by 1c3. PMID- 25527987 TI - Selective adsorption of lead, copper and antimony in runoff water from a small arms shooting range with a combination of charcoal and iron hydroxide. AB - Metals and metalloids from ammunition residues at small arms shooting ranges leach into the soil and surrounding watercourses and may pose a threat to exposed wildlife and humans. To reduce the potential impact of heavy metal on the environment a field study was performed with different sorbents in order to reduce the metal concentration in polluted water from a shooting range. Two sorbents were tested in situ for their ability to reduce the concentration of Cu, Sb and Pb: Brimac((r)) charcoal and Kemira((r)) iron hydroxide. The mean sorption of Cu, Sb and Pb was 85%, 65%, and 88% respectively when using the charcoal and 60%, 85% and 92% respectively with the iron hydroxide. Even better sorption of the elements was achieved when the two sorbents were combined in order to increase their selectivity. The best results were achieved in the filter in which the water percolated the charcoal first and the iron hydroxide last, with a mean sorption of Cu, Sb and Pb of 89%, 90% and 93% respectively. This preparation gave a significant better sorption of Cu compared to the filter in which the water percolated the iron hydroxide first and the charcoal last. The different effect between the two filters may be due to pH, since charcoal has alkaline properties and iron hydroxide has acidic properties. For large scale experiments or in filter devices we therefore recommend use of a combination of different reactive sorbents. PMID- 25527988 TI - Evaluating the Sustainable Intensification of arable farms. AB - Sustainable Intensification (SI) of agriculture has recently received widespread political attention, in both the UK and internationally. The concept recognises the need to simultaneously raise yields, increase input use efficiency and reduce the negative environmental impacts of farming systems to secure future food production and to sustainably use the limited resources for agriculture. The objective of this paper is to outline a policy-making tool to assess SI at a farm level. Based on the method introduced by Kuosmanen and Kortelainen (2005), we use an adapted Data Envelopment Analysis (DEA) to consider the substitution possibilities between economic value and environmental pressures generated by farming systems in an aggregated index of Eco-Efficiency. Farm level data, specifically General Cropping Farms (GCFs) from the East Anglian River Basin Catchment (EARBC), UK were used as the basis for this analysis. The assignment of weights to environmental pressures through linear programming techniques, when optimising the relative Eco-Efficiency score, allows the identification of appropriate production technologies and practices (integrating pest management, conservation farming, precision agriculture, etc.) for each farm and therefore indicates specific improvements that can be undertaken towards SI. Results are used to suggest strategies for the integration of farming practices and environmental policies in the framework of SI of agriculture. Paths for improving the index of Eco-Efficiency and therefore reducing environmental pressures are also outlined. PMID- 25527989 TI - Enhancing voluntary participation in community collaborative forest management: a case of Central Java, Indonesia. AB - This paper examines voluntary participation in community forest management, and characterizes how more participation may be induced. We implemented a survey of 571 respondents and conducted a case study in Central Java, Indonesia. The study's novelty lies in categorizing the degrees of participation into three levels and in identifying how socio-economic factors affect people's participation at each level. The analysis finds that voluntary participation responds to key determinants, such as education and income, in a different direction, depending on each of the three levels. However, the publicly organized programs, such as information provision of benefit sharing, are effective, irrespective of the levels of participation. Overall, the results suggest a possibility of further success and corrective measures to enhance the participation in community forest management. PMID- 25527991 TI - The association between dietary patterns, diabetes and depression. AB - BACKGROUND: Type 2 diabetes and depression are commonly comorbid high-prevalence chronic disorders. Diet is a key diabetes risk factor and recent research has highlighted the relevance of diet as a possible risk for factor common mental disorders. This study aimed to investigate the interrelationship among dietary patterns, diabetes and depression. METHODS: Data were integrated from the National Health and Nutrition Examination Study (2009-2010) for adults aged 18+ (n=4588, Mean age=43yr). Depressive symptoms were measured by the Patient Health Questionnaire-9 and diabetes status determined via self-report, usage of diabetic medication and/or fasting glucose levels >=126mg/dL and a glycated hemoglobin level >=6.5% (48mmol/mol). A 24-h dietary recall interview was given to determine intakes. Multiple logistic regression was employed, with depression the outcome, and dietary patterns and diabetes the predictors. Covariates included gender, age, marital status, education, race, adult food insecurity level, ratio of family income to poverty, and serum C-reactive protein. RESULTS: Exploratory factor analysis revealed five dietary patterns (healthy; unhealthy; sweets; 'Mexican' style; breakfast) explaining 39.8% of the total variance. The healthy dietary pattern was associated with reduced odds of depression for those with diabetes (OR 0.68, 95% CI [0.52, 0.88], p=0.006) and those without diabetes (OR 0.79, 95% CI [0.64, 0.97], p=0.029) (interaction p=0.048). The relationship between the sweets dietary pattern and depression was fully explained by diabetes status. CONCLUSION: In this study, a healthy dietary pattern was associated with a reduced likelihood of depressive symptoms, especially for those with Type 2 diabetes. PMID- 25527990 TI - Chronotype and seasonality: morningness is associated with lower seasonal mood and behavior changes in the Old Order Amish. AB - BACKGROUND: Several studies documented that lower scores on the Morningness Eveningness Questionnaire (MEQ) are associated with a higher global seasonality of mood (GSS). As for the Modern Man artificial lighting predominantly extends evening activity and exposure to light, and as evening bright light phase is known to delay circadian rhythms, this chronic exposure could potentially lead to both lower Morningness as well as higher GSS. The aim of the study was to investigate if the MEQ-GSS relationship holds in the Old Order Amish of Lancaster County, PA, a population that does not use network electrical light. METHODS: 489 Old Order Amish adults (47.6% women), with average (SD) age of 49.7 (14.2) years, completed both the Seasonal Pattern Assessment Questionnaire (SPAQ) for the assessment of GSS, and MEQ. Associations between GSS scores and MEQ scores were analyzed using linear models, accounting for age, gender and relatedness by including the relationship matrix in the model as a random effect. RESULTS: GSS was inversely associated with MEQ scores (p=0.006, adjusted). LIMITATIONS: include a potential recall bias associated with self-report questionnaires and no actual light exposure measurements. CONCLUSION: We confirmed the previously reported inverse association between MEQ scores and lower seasonality of mood, for the first time in a population that does not use home network electrical lighting. This result suggests that the association is not a byproduct of exposure to network electric light, and calls for additional research to investigate mechanisms by which Morningness is negatively associated with seasonality. PMID- 25527992 TI - Diagnosis of bipolar disorder in primary and secondary care: what have we learned over a 10-year period? AB - BACKGROUND: Studies suggest that misdiagnosis of bipolar disorders (BD) is frequent in primary care. This study aimed to evaluate agreement between referral for BD by general practitioners (GP) and BD diagnosis by secondary care psychiatrists, and to evaluate the impact of age, gender, and BD type on agreement. METHODS: The study was conducted at Hopital du Sacre-Coeur de Montreal's "Module Evaluation/Liaison" (MEL), which establishes/clarifies psychiatric diagnoses requested mainly from GPs and directs patients to appropriate treatment and care. Socio-demographic variables, reason for referral, and psychiatric diagnosis were compiled for patients assessed from 1998 to 2010. GP-psychiatrist agreement was established for BD type, gender, and age group (18 25, 26-35, 36-45, >45) using Cohen's Kappa coefficient (Kappa). RESULTS: From 1998 to 2010, MEL psychiatrists received 18,111 requests and carried out 10,492 (58%) assessments. There were 583 referrals for BD suspicion, while 640 assessments (6.1%) received a BD diagnosis (40.3% type I, 40.5% type II). The overall K was 0.35 (95% CI [0.31, 0.38]), and was significantly higher for type I than type II (I=0.35, 95% CI [0.30, 0.39]; II=0.25, 95% CI [0.21, 0.30]), though age group and gender had no impact. LIMITATIONS: Reasons for referral were converted into keywords and categories to facilitate agreement analyses. Only the main psychiatric diagnosis was available. CONCLUSIONS: Our study suggests diagnosing BD remains strenuous, regardless of age and gender, though BD type I seems better understood by primary care GPs. The true measure of BD diagnosis remains a critical issue in clinical practice. PMID- 25527994 TI - Managing bipolar moods without medication: a qualitative investigation. AB - OBJECTIVES: Although many diagnosed with Bipolar Disorder (BD) choose to manage their moods without medication at some point, their experiences of doing so are not well understood. This paper aims to explore the processes by which people manage bipolar moods without medication. METHODS: Ten people diagnosed with BD who do not use medication were interviewed. Analysing their accounts using grounded theory methods led to developing a model of how they perceive the processes involved in managing moods without medication. RESULTS: Participants engaged in repeated evaluative processes around their strategies for managing moods. Some participants decided not to influence elevated moods due to their perceived advantages. Participants' intentions and actions were influenced by their perceptions of themselves and by the meanings they attached to bipolar moods, which were in turn influenced by feedback from others. CONCLUSIONS: The complexity of the processes described by participants suggests that traditional models of explaining non-adherence may over-simplify some individuals' experiences. Future research could focus on identifying factors predictive of successful attempts to manage moods without medication. Professionals should place more emphasis on non-medication approaches in order to increase engagement with people who do not use medication. This may involve focussing on individual's longer-term goals rather than on modifying moods in shorter-term. Conclusions are based on participants who had experienced significant bipolar moods, but who largely seemed satisfied living without medication. LIMITATIONS: Future research should ascertain whether such processes apply to a wider group of individuals who do not use medication for bipolar moods. PMID- 25527993 TI - Disruption of white matter integrity marks poor antidepressant response in bipolar disorder. AB - BACKGROUND: Changes of white matter (WM) microstructure have been proposed as structural biomarkers of bipolar disorder (BD). The chronotherapeutic combination of repeated total sleep deprivation and morning light therapy (TSD+LT) can acutely reverse depressive symptoms in approximately 60% of patients, and it has been proposed as a model antidepressant treatment to investigate the neurobiological correlates of rapid antidepressant response. METHODS: We tested if baseline DTI measures can predict response to treatment in 70 in-patients affected by a major depressive episode in the course of BD, treated with chronotherapeutics for one week. We performed whole-brain tract-based spatial statistics with threshold-free cluster enhancement for the DTI measures of WM microstructure integrity: fractional anisotropy, axial, radial, and mean diffusivity. RESULTS: Increased mean and radial water diffusivity correlated with poor antidepressant response to TSD+LT in core WM tracts which are crucial for the functional integrity of the brain, including corpus callosum, corona radiata, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and thalamic radiation. LIMITATIONS: Limitations include issues such as generalizability, possible population stratification, medications and their effects on DTI measures, and no placebo control for chronotherapeutics. We could not consider other factors such as gene-environment interactions. CONCLUSIONS: The association of increased radial and mean diffusivity with poor response to chronotherapeutic treatment warrants interest for the study of DTI measures of WM microstructure as markers for treatment response in bipolar depression. PMID- 25527995 TI - Implicit motor learning in bipolar disorder. AB - OBJECTIVES: A growing number of publications describe cerebellar abnormalities in patients with bipolar disorder (BD). The aim of the following paper was to examine the functional aspects of that issue by focusing on implicit learning - a cognitive function with significant cerebellar underpinnings. METHODS: 27 patients with BD and 26 healthy controls (HC), matched for age and sex took part in the study. Implicit motor learning was assessed by the serial reaction time task (SRTT), in which participants were unconsciously learning a sequence of motor reactions. The indicators of procedural learning were the decrease of reaction time (RT) across the repetition of the sequence and the rebound of RT when the sequence changed into a random set of stimuli. RESULTS: BD patients did not present any indicators of the implicit learning, their RT increased across repetitions of the sequence and it decreased when the sequence changed to random. Contrary, in the control group RT decreased across the sequence repetitions and increased when the stimuli begun to appear randomly. LIMITATIONS: A low subject count and a non-drug naive patients group, medicated with atypical antipsychotic and mood stabilizers, are the most significant limitations of this study. CONCLUSIONS: BD patients did not acquire procedural knowledge while performing the task, whereas HC did. To our knowledge this is the first study that shows the impairment of implicit motor learning in patients with BD. This indicates the possible cerebellar dysfunction in this disease and may provide a new neuropsychiatric approach to bipolar disorder. PMID- 25527996 TI - Altered spontaneous neuronal activity in chronic posttraumatic stress disorder patients before and after a 12-week paroxetine treatment. AB - BACKGROUND: Abnormal functional brain activity has been revealed in patients with Posttraumatic Stress Disorder (PTSD) in recent years, while the recovery neuromechanism of PTSD has not yet been elucidated. The aim of this study was to investigate the altered spontaneous brain activity in treatment-naive chronic PTSD patients before and after 12 weeks' treatment with paroxetine. METHODS: Twenty-one earthquake-related PTSD patients and seventeen traumatized controls underwent a resting functional magnetic resonance imaging (Rs-fMRI) scan at baseline. Amplitude of low-frequency fluctuation (ALFF) was calculated and compared between PTSD patients and controls. Then, the PTSD group completed 12 weeks of treatment with paroxetine, and Rs-fMRI was repeated to compare with the baseline. Lastly, correlation analyses of ALFF values within altered brain areas were conducted. RESULTS: Hyperactive function of visual cortex was observed in PTSD patients before and after treatment. After treatment, significantly increased ALFF values were observed in the left orbitofrontal cortex (OFC), while decreased ALFF values were found in the precuneus. Interestingly, a negative correlation between the mean ALFF values of OFC and those of precuneus and visual cortex was only observed in controls, but not in PTSD patients pre- or post treatment. LIMITATIONS: A corresponding control condition was absent in this study. CONCLUSION: The findings showed that manipulating regional spontaneous activity of precuneus and OFC could be a potential prognostic indicator of PTSD. However, hyperactive function of visual cortex and disrupted connections between OFC, precuneus and visual cortex did not reverse after treatment, which could be a potential target for further treatment. PMID- 25527998 TI - Moderators of response to cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care. AB - BACKGROUND: Stratified medicine aims to improve clinical and cost-effectiveness by identifying moderators of treatment that indicate differential response to treatment. Cognitive behavioural therapy (CBT) is often offered as a 'next-step' for patients who have not responded to antidepressants, but no research has examined moderators of response to CBT in this population. We aimed, therefore, to identify moderators of response to CBT in treatment resistant depression. METHODS: We used linear regression to test for interactions between treatment effect and 14 putative moderator variables using data from the CoBalT randomised controlled trial. This trial examined the effectiveness of CBT given in addition to usual care (n=234) compared with usual care alone (n=235) for primary care patients with treatment resistant depression. RESULTS: Age was the only variable with evidence for effect modification (p Value for interaction term=0.012), with older patients benefiting the most from CBT. We found no evidence of effect modification by any other demographic, life, illness, personality trait, or cognitive variable (p>=0.2). CONCLUSIONS: Given the largely null findings, a stratified approach that might limit offering CBT is premature; CBT should be offered to all individuals where antidepressant medication has failed. PMID- 25527999 TI - Mobile health monitoring to characterize depression symptom trajectories in primary care. AB - BACKGROUND: Classification of depression severity can guide treatment decisions. This study examined whether using repeated mobile health assessments to determine symptom trajectories is a potentially useful method for classifying depression severity. METHODS: 344 primary care patients with depression were identified and recruited as part of a program of mobile health symptom monitoring and self management support. Depression symptoms were measured weekly via interactive voice response (IVR) calls using the Patient Health Questionnaire (PHQ-9). Trajectory analysis of weekly IVR PHQ-9 scores from baseline through week 6 was used to subgroup patients according to similar trajectories. Multivariable linear regression was used to determine whether the trajectories predicted 12-week PHQ-9 scores after adjusting for baseline and 6-week PHQ-9 scores. RESULTS: The optimal trajectory analysis model included 5 non-intersecting trajectories. The subgroups of patients assigned to each trajectory had mean baseline PHQ-9s of 19.7, 14.5, 9.5, 5.0, and 2.0, and respective mean decreases in PHQ-9s over six weeks of .3, 2.0, 3.6, 2.3, and 1.9. In regression analyses, each trajectory significantly predicted 12-week PHQ-9 scores (using the modal trajectory as a reference) after adjusting for both baseline and 6-week PHQ-9 scores. LIMITATIONS: Treatment history was unknown, findings may not be generalizable to new episodes of treatment. CONCLUSIONS: Depression symptom trajectories based on mobile health assessments are predictive of future depression outcomes, even after accounting for typical assessments at baseline and a single follow-up time point. Approaches to classify patients' disease status that involve multiple repeated assessments may provide more accurate and useful information for depression management compared to lower frequency monitoring. PMID- 25527997 TI - Affective bias and current, past and future adolescent depression: a familial high risk study. AB - BACKGROUND: Affective bias is a common feature of depressive disorder. However, a lack of longitudinal studies means that the temporal relationship between affective bias and depression is not well understood. One group where studies of affective bias may be particularly warranted is the adolescent offspring of depressed parents, given observations of high rates of depression and a severe and impairing course of disorder in this group. METHODS: A two wave panel design was used in which adolescent offspring of parents with recurrent depression completed a behavioural task assessing affective bias (The Affective Go/No Go Task) and a psychiatric interview. The affective processing of adolescents with current, prior and future depressive disorder was compared to that of adolescents free from disorder. RESULTS: Adolescents with current depression and those who developed depression at follow-up made more commission errors for sad than happy targets compared to adolescents free from disorder. There was no effect of prior depression on later affective processing. LIMITATIONS: Small cell sizes meant we were unable to separately compare those with new onset and recurrent depressive disorder. CONCLUSIONS: Valence-specific errors in behavioural inhibition index future vulnerability to depression in adolescents already at increased risk and may represent a measure of affective control. Currently depressed adolescents show a similar pattern of affective bias or deficits in affective control. PMID- 25528000 TI - The association between childhood maltreatment and emotion regulation: two different mechanisms contributing to depression? AB - BACKGROUND: Childhood maltreatment is an established distal risk factor for later emotional problems, although research suggests this relationship is mediated by proximal factors. However, it is unclear if different forms of childhood maltreatment are related to unique emotion regulation strategies. In this study, we examined whether avoidance and rumination, two emotion regulation strategies strongly associated with depression, were associated with different forms of childhood maltreatment, and whether these strategies, in turn, mediated the relationship between childhood maltreatment and current depressive symptoms. METHODS: Participants were a community sample of pregnant, primarily low-income women, 55 of whom met criteria for Major Depressive Disorder (MDD) and 85 who had elevated levels of depressive symptoms but did not meet criteria for MDD. RESULTS: Significant rates of childhood maltreatment were reported. Childhood emotional neglect was related to behavioural avoidance, and childhood emotional abuse was related to rumination. In path analyses, behavioural avoidance mediated the relationship between childhood emotional neglect and depression. Rumination was a partial mediator of childhood emotional abuse and depression. LIMITATIONS: The data were correlational in nature, and replication with a larger sample will help validate the model. DISCUSSION: In a clinical, community-based sample different types of childhood maltreatment are related to unique emotion regulation strategies. Implications for understanding the developmental antecedents of emotion regulation and depression are discussed. PMID- 25528001 TI - Reliability and validity of a new post-stroke depression scale in Chinese population. AB - BACKGROUND: Nowadays there is still a lack of effective method to evaluate post stroke depression. To distinguish patients with and without depression after stroke reliably, this study proposes a new Post-Stroke Depression Scale (PSDS). METHODS: PSDS was developed based on various depression scales and clinician experiences. 158 stroke patients who were able to finish PSDS and Hamilton Depression Rating Scale (HDRS) were recruited. Cronbach alpha, Spearman rank coefficient and Kruskal-Wallis test were respectively used to examine reliability, internal consistency and discriminate validity. Then the Receiver Operating Characteristic (ROC) curve was used to determine the ability of scale and categorized scales to the range of depression. Finally, the factors of the PSDS were classified by average clustering analysis. RESULTS: The Cronbach alpha of PSDS was 0.797 (95% CI) indicted a good reliability. The Spearman correlation coefficient between PSDS and HDRS was 0.822 (P<0.001) showed an excellent congruent validity. The discriminate validity displayed significant difference between patients with and without depression (P<0.001). 6/24 was set to be the cut-off value by ROC analysis. Moreover, the different severity was distinguished by the value 6/24, 15/24 and 17/24. LIMITATIONS: The small sample size maybe the main limitation, the larger sample used in different fields according sex, age and side-lesion was needed to verity the results. The cut off value calculated by ROC curve maybe react the severity of the disease to some extent, but it is not absolute. CONCLUSIONS: PSDS is a valid, reliable and specific tool for evaluating post-stroke depression patients and can be conveniently utilized. PMID- 25528002 TI - Myeloperoxidase-mediated oxidation targets serum apolipoprotein A-I in diabetic patients and represents a potential mechanism leading to impaired anti-apoptotic activity of high density lipoprotein. AB - BACKGROUND: It is demonstrated that levels of protein-bound chlorotyrosine, nitrotyrosine and myeloperoxidase (MPO), a protein that catalyzes generation of chlorinating and nitrating oxidants, serve as independent predictors of cardiovascular disease. METHODS: Immunoprecipitation and Western blot were used to analyze protein concentration, nitration and chlorination. LC-MS/MS was used to identify nitrated and chlorinated sites of Tyr from immunoprecipitated serum proteins. RESULTS: Apolipoprotein A-I (apoA-I), the primary protein constituent of high density lipoprotein (HDL), was identified as a selective target for MPO catalyzed nitration and chlorination in patients with type 2 diabetes. The serum proteins from diabetic subjects showed that the levels of apoA-I nitration and chlorination were clearly increased, whereas apoA-I concentration and cholesterol efflux activity were significantly decreased. MPO as a likely mechanism for oxidative modification of apoA-I in vivo was apparently facilitated by MPO binding to apoA-I. Subsequently, it was found that Tyr 192 was the major nitration and chlorination site in apoA-I from diabetic serum. Further studies in vitro revealed that besides the classic inhibition in cholesterol efflux activities, MPO-catalyzed oxidation could result in a loss of anti-apoptotic activity of lipoprotein. CONCLUSIONS: ApoA-I undergoes MPO-mediated oxidation in serum from diabetic patients compared to non-diabetic subjects and MPO-catalyzed modification may impair the anti-apoptotic properties of HDL in vitro. PMID- 25528003 TI - Trends over 8 years in quality of diabetes care: results of the AMD Annals continuous quality improvement initiative. AB - OBJECTIVE: Quality of care monitoring is a key strategy for health policy. In Italy, the AMD Annals continuous monitoring and quality improvement initiative has been in place since 2006. Results after 8 years are now available. RESEARCH DESIGN AND METHODS: Quality of diabetes care indicators during the years 2004 2011 were extracted from electronic medical records of 300 diabetes clinics. From 200,000 to 500,000 patients with type 2 diabetes were analyzed per year. Six process indicators, eight intermediate outcome indicators, seven indicators of treatment intensity/appropriateness, and a quality of care summary score (Q score) were evaluated. Previous studies documented that the risk of developing a new cardiovascular event was 80 % higher in patients with a Q score <15 and 20 % higher in those with a score between 15 and 25, as compared to those with a score >25. RESULTS: The proportion of patients with HbA1c <=7 %, LDL cholesterol <100 mg/dl, and blood pressure >=140/90 mmHg increased by 4.8, 21.9, and 10.0 %, respectively. Process and treatment intensity/appropriateness indicators consistently improved. The proportion of patients with a Q score <15 decreased from 13.5 to 6.5 %, while those with a Q score >25 increased from 22.9 to 38.5 %. CONCLUSIONS: AMD Annals document the progress in quality of diabetes care. Longitudinal improvements in Q score can translate into less cardiovascular events, with evident clinical and economic implications. AMD Annals represent a physician-led effort not requiring allocation of extra-economic resources, which is easy to implement and deeply rooted in routine clinical practice. They are a potential case model for other healthcare systems. PMID- 25528004 TI - The minimal promoter region of the dense-core vesicle protein IA-2: transcriptional regulation by CREB. AB - AIMS: IA-2 is a transmembrane protein found in the dense-core vesicles (DCV) of neuroendocrine cells and one of the major autoantigens in type 1 diabetes. DCV are involved in the secretion of hormones (e.g., insulin) and neurotransmitters. Stimulation of pancreatic beta cells with glucose upregulates the expression of IA-2 and an increase in IA-2 results in an increase in the number of DCV. Little is known, however, about the promoter region of IA-2 or the transcriptional factors that regulate the expression of this gene. METHODS: In the present study, we constructed eight deletion fragments from the upstream region of the IA-2 transcription start site and linked them to a luciferase reporter. RESULTS: By this approach, we have identified a short bp region (-216 to +115) that has strong promoter activity. We also identified a transcription factor, cAMP responsive element-binding protein (CREB), which binds to two CREB-related binding sites located in this region. The binding of CREB to these sites enhanced IA-2 transcription by more than fivefold. We confirmed these findings by site directed mutagenesis, chromatin immunoprecipitation assays and RNAi inhibition. CONCLUSION: Based on these findings, we conclude that the PKA pathway is a critical, but not the exclusive signaling pathway involved in IA-2 gene expression. PMID- 25528005 TI - Fear of hypoglycemia: relationship to hypoglycemic risk and psychological factors. AB - OBJECTIVE: The major aims of this study were to examine (1) the association between fear of hypoglycemia (FOH) in adults with type 1 diabetes with demographic, psychological (anxiety and depression), and disease-specific clinical factors (hypoglycemia history and unawareness, A1c), including severe hypoglycemia (SH), and (2) differences in patient subgroups categorized by level of FOH and risk of SH. RESEARCH DESIGN AND METHODS: Questionnaires were mailed to 764 patients with type 1 diabetes including the Swedish translation of the Hypoglycemia Fear Survey (HFS) and other psychological measures including the Perceived Stress Scale, Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index, Social Phobia Scale, and Fear of Complications Scale. A questionnaire to assess hypoglycemia history was also included and A1c measures were obtained from medical records. Statistical analyses included univariate approaches, multiple stepwise linear regressions, Chi-square t tests, and ANOVAs. RESULTS: Regressions showed that several clinical factors (SH history, frequency of nocturnal hypoglycemia, self-monitoring) were significantly associated with FOH but R (2) increased from 16.25 to 39.2 % when anxiety measures were added to the model. When patients were categorized by level of FOH (low, high) and SH risk (low, high), subgroups showed significant differences in non-diabetes-related anxiety, hypoglycemia history, self-monitoring, and glycemic control. CONCLUSION: There is a strong link between FOH and non-diabetes-related anxiety, as well as hypoglycemia history. Comparison of patient subgroups categorized according to level of FOH and SH risk demonstrated the complexity of FOH and identified important differences in psychological and clinical variables, which have implications for clinical interventions. PMID- 25528006 TI - Nationwide reduction in the frequency of severe hypoglycemia by half. AB - AIMS: To examine contemporary rates of severe hypoglycemia (SH) and identify the effect of predictors of SH in a pediatric type 1 diabetes population. METHODS: The national diabetes register provided data on children residing in Denmark from 2008 to 2013 in this register-based population study. Robust Poisson regression models were applied. RESULTS: The study population [n = 2,715 (50.9 % boys), mean (SD) age at onset; 8.1 (4.0) years, diabetes duration; 5.6 (4.9) years] comprised 7,390 person-years of data and 561 events of SH. The overall incidence of SH was 7.6 per 100 person-years. The incidence rate peaked with 16.0 per 100 person years in 2008 reaching a nadir of 4.9 in 2011. Overall, insulin pump reduced the rate of SH with 27 % compared to any pen treatment (P = 0.003). When stratifying pen treatment, premixed insulin increased the rate of SH by 1.9-fold (P = 0.0015) and NPH increased the rate by 1.6-fold (P = 0.003) versus pump treatment, whereas long-acting insulin analogues were comparable with pump treatment (P = 0.1485). We found no association of SH with glycemic control (P > 0.05). CONCLUSIONS: A nationwide halving in rates of severe hypoglycemia was observed during the study period independent of the prevailing average HbA1c level. Changes in diabetes care and successful educational programs may have influenced the lower incidence rate of severe hypoglycemia. PMID- 25528007 TI - Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: "double trouble" overlapping syndrome? PMID- 25528008 TI - Bedside evaluation of smooth pursuit eye movements in acute sensory stroke patients. AB - BACKGROUND AND PURPOSE: Unilateral saccadic pursuit is reported to be suggestive of a pontine lesion in sensory stroke patients. We attempted to verify this eye sign in just-hospitalized pontine sensory stroke patients. METHODS: Horizontal smooth pursuit eye movements were evaluated upon hospital arrival in 4 pontine sensory stroke patients and were compared with those in 6 thalamic sensory stroke patients. Eye movements were evaluated with the patient lying down on the emergency room or stroke care unit bed by means of a newly developed video oculography-based eye movement recording system equipped to project a moving laser pointer onto the ceiling. RESULTS: Laterality of horizontal smooth pursuit gain in pontine sensory stroke patients was evident upon arrival; in thalamic sensory stroke patients, horizontal smooth pursuit gain was equal in both directions. These characteristics were easily detected at bedside. CONCLUSION: Unilateral saccadic pursuit in pontine sensory stroke patients may be a practical diagnostic sign that can be detected even in the emergency room. The video oculography-based recording system equipped to project a moving laser pointer onto the ceiling may be useful for detecting this eye sign. PMID- 25528009 TI - Validation of the hepatoma arterial embolization prognostic score in European and Asian populations and proposed modification. AB - BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is used to treat hepatocellular carcinoma (HCC), but it is a challenge to predict patient survival. The hepatic arterial embolization prognostic (HAP) score has been shown to predict which patients will have shorter survival times and should not undergo TACE. We aimed to validate this scoring system in a prospective study of patients in Europe and Asia. METHODS: We evaluated the prognostic accuracy of the HAP score in estimating overall survival (OS) of 126 patients with HCC who received TACE in the United Kingdom or Italy (training set) from 2001 through 2013. We also analyzed data from 723 patients treated in Korea and Japan (validation set), including 79 with newly diagnosed HCC, who underwent TACE in Korea or Japan from 2004 through 2013. Response to TACE was determined based on computed tomography analysis. OS was calculated from the time of the first TACE until death or the last follow-up evaluation. RESULTS: OS was associated with hypoalbuminemia, alpha fetoprotein level greater than 400 ng/mL, and tumor size greater than 7 cm at diagnosis (P < .01), but not a bilirubin level greater than 17 umol/L (P > .05), in both data sets. The lack of association between OS and bilirubin level was confirmed using receiver operating characteristic analysis. We developed a modified version of the HAP score, based on the level of albumin and alpha fetoprotein and tumor size, which predicted OS with increased accuracy in the training and validation cohorts. CONCLUSIONS: In a multicenter validation study, we developed a modified version of the HAP that predicts survival of patients with HCC treated with TACE in Europe and Asia. This system might be used to identify patients with HCC most likely to benefit from TACE in clinical practice. PMID- 25528010 TI - Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. AB - BACKGROUND & AIMS: Liver biopsy is invasive and associated with complications, sampling errors, and observer variability. Vibration-controlled transient elastography (VCTE) with FibroScan can be used to immediately assess liver stiffness. We aimed to define optimal levels of liver stiffness to identify patients with chronic viral hepatitis and significant fibrosis, advanced fibrosis, or cirrhosis. METHODS: In a prospective, 2-phase study, patients with chronic hepatitis C or B underwent VCTE followed by liver biopsy analysis from January 2005 through May 2008 at 6 centers in the United States. In phase 1 we identified optimal levels of liver stiffness for identification of patients with stage F2-F4 or F4 fibrosis (the development phase, n = 188). In phase 2 we tested these cutoff values in a separate cohort of patients (the validation phase, n = 560). All biopsies were assessed for METAVIR stage by a single pathologist in the phase 1 analysis and by a different pathologist in the phase 2 analysis. Diagnostic performances of VCTE were assessed by area under the receiver operating characteristic curve (AUROC) analyses. RESULTS: In phase 1 of the study, liver stiffness measurements identified patients with >= F2 fibrosis with AUROC value of 0.89 (95% confidence interval, 0.83-0.92) and identified patients with F4 fibrosis with AUROC value of 0.92 (95% confidence interval, 0.87-0.95). Liver stiffness cutoff values (kPa) in phase 1 were 8.4 for >= F2 (82% sensitivity, 79% specificity) and 12.8 for F4 (84% sensitivity, 86% specificity). In the phase 2 analysis, the liver stiffness cutoff values identified patients with >= F2 fibrosis with 58% sensitivity (P < .0001 vs phase 1) and 75% specificity (nonsignificant difference vs phase 1); they identified patients with F4 fibrosis with 76% sensitivity (P < .0001 vs phase 1) and 85% specificity (nonsignificant differences vs phase 1). VCTE had an interobserver agreement correlation coefficient of 0.98 (n = 26) and an intraobserver agreement correlation coefficient of 0.95 (n = 34). CONCLUSIONS: In a large U.S. multicenter study, we confirmed that VCTE provides an accurate assessment of liver fibrosis in patients with chronic viral hepatitis. Our findings are similar to those from European and Asian cohorts. PMID- 25528011 TI - Intraductal papillary mucinous neoplasm presenting as hemosuccus pancreaticus. PMID- 25528013 TI - Referential coding does not rely on location features: Evidence for a nonspatial joint Simon effect. AB - The joint Simon effect (JSE) shows that the presence of another agent can change one's representation of one's task and/or action. According to the spatial response coding approach, this is because another person in one's peri-personal space automatically induces the spatial coding of one's own action, which in turn invites spatial stimulus-response priming. According to the referential coding approach, the presence of another person or event creates response conflict, which the actor is assumed to solve by emphasizing response features that discriminate between one's own response and that of the other. The 2 approaches often make the same predictions, but the spatial response coding approach considers spatial location as the only dimension that can drive response coding, whereas the referential coding approach allows for other dimensions as well. To compare these approaches, the authors ran 2 experiments to see whether a nonspatial JSE can be demonstrated. Participants responded to the geometrical shape of a central colored stimulus by pressing a left or right button, while wearing gloves of the same or different color as the stimuli. Participants performed the task individually, either by responding to either stimulus shapes (Experiment 1) or by responding to only 1 of the 2 shapes (Experiment 2), and in the presence of a coactor. Congruence between stimulus and glove color affected performance in the 2-choice and the joint tasks but not in the individual go/no go task. This demonstration of a nonspatial JSE is inconsistent with the spatial response coding approach but supports the referential coding approach. PMID- 25528014 TI - Eye movements during reading and topic scanning: effects of word frequency. AB - The study examined the nature of eye movement control and word recognition during scanning for a specific topic, compared with reading for comprehension. Experimental trials included a manipulation of word frequency: the critical word was frequent (and orthographically familiar) or infrequent (2 conditions: orthographically familiar and orthographically unfamiliar). First-pass reading times showed effects of word frequency for both reading and scanning, with no interactions between word characteristics and task. Therefore, in contrast to the task of searching for a single specific word (Rayner & Fischer, 1996), there were immediate and localized influences of lexical processing when scanning for a specific topic, indicating that early word recognition processes are similar during reading and topic scanning. In contrast, there were interactions for later measures, with larger effects of word frequency during reading than scanning, indicating that reading goals can modulate later processes such as the integration of words into sentence context. Additional analyses of the distribution of first-pass single fixation durations indicated that first-pass fixations of all durations were shortened during scanning compared with reading, and reading for comprehension produced a larger subset of longer first-pass fixations compared with scanning. The implications for the nature of word recognition and eye movement control are discussed. PMID- 25528012 TI - Identification and Characterization of Cefazolin-Induced Liver Injury. AB - BACKGROUND & AIMS: Cephalosporin antibiotics are popular because they have a broad spectrum of activity and are generally well tolerated; however, cephalosporin-induced liver injury is considered rare. We describe a new syndrome associated with a single intravenous dose of cefazolin and the clinical features of cephalosporin-induced liver injury. METHODS: The Drug-Induced Liver Injury (DILI) Network collected detailed clinical data on 1212 patients with DILI between 2004 and 2012. We analyzed data from 41 patients in whom cephalosporins were implicated as primary agents of liver disease; 33 formally were adjudicated as having cephalosporin-induced DILI. RESULTS: Nineteen patients developed clinically apparent DILI after a single intravenous dose of cefazolin. All patients developed self-limited liver injury 3 to 23 days after receiving cefazolin during surgery-often during a minor outpatient procedure. The latency period was 20 days. Clinical features included itching, jaundice, nausea, fever, and rash. Laboratory abnormalities included a mixed or cholestatic pattern of serum enzyme increases. We identified 14 more patients with DILI attributed to other cephalosporins (5 first-generation, 2 second-generation, 6 third generation, and 1 fourth-generation agent). Although latency and injury patterns were similar for cefazolin and other cephalosporins, the other cephalosporins were associated with more severe courses of injury, including 2 deaths from liver failure. CONCLUSIONS: DILI can develop after a single dose of cefazolin. It is characterized by a latency period of 1 to 3 weeks after exposure, a cholestatic biochemical pattern, and a self-limited moderate to severe clinical course. Other cephalosporins can cause a similar but more severe injury. PMID- 25528015 TI - Two objects or one? Similarity rather than complexity determines objecthood when resolving dynamic input. AB - The human brain is continuously confronted with dynamic visual input, and from this it must infer whether input belongs to a single versus multiple object identities across time. Object substitution masking (OSM), in which perception of a target stimulus is impaired by a temporally trailing 4-dot mask, reflects a failure to segment the target and mask as discrete objects. According to Bouvier and Treisman (2010), OSM only occurs for targets that require binding multiple separate features (e.g., color and orientation) to be identified. In contrast, a target that represents a unique feature is thought to be impervious to masking. Here, however, we show that a single orientation target (a Gabor) is susceptible to masking with an orientation-discrimination task, but only when the mask is similar in orientation to the target. That is, target-mask similarity, rather than target complexity determines masking. A reexamination of Bouvier and Treisman's (2010) results show that they can be explained within this target-mask similarity perspective. This means that the similarity of 2 objects determines whether they will be integrated or segmented across time, rather than the complexity of 1 of the objects in isolation. PMID- 25528017 TI - Uranium isotopes in groundwater occurring at Amazonas State, Brazil. AB - This paper reports the behavior of the dissolved U-isotopes (238)U and (234)U in groundwater providing from 15 cities in Amazonas State, Brazil. The isotope dilution technique accompanied by alpha spectrometry were utilized for acquiring the U content and (234)U/(238)U activity ratio (AR) data, 0.01-1.4ugL(-1) and 1.0 3.5, respectively. These results suggest that the water is circulating in a reducing environment and leaching strata containing minerals with low uranium concentration. A tendency to increasing ARs values following the groundwater flow direction is identified in Manaus city. The AR also increases according to the SW NE directions: Uarini->Tefe; Manacapuru->Manaus; Presidente Figueiredo->Sao Sebastiao do Uatuma; and Boa Vista do Ramos->Parintins. Such trends are possibly related to several factors, among them the increasing acid character of the waters. The waters analyzed are used for human consumption and the highest dissolved U content is much lower than the maximum established by the World Health Organization. Therefore, in view of this radiological parameter they can be used for drinking purposes. PMID- 25528016 TI - Different Physiological and Subjective Responses to the Hyperthermia Between Young and Older Adults: Basic Study for Thermal Therapy in Cardiovascular Diseases. AB - BACKGROUND: Thermal therapy has been used as adjuvant therapy in patients with cardiovascular disease. However, little is known about responses to thermal stress in older adults. We examined the effects of thermal stress in younger and older healthy Japanese individuals. METHODS: The study included 12 young (mean age, 22 years) and 12 older (mean age, 68 years) healthy adults and was performed under strict temperature and humidity control to minimize confounding. Participants lay supine throughout three consecutive 30-minute phases: Phase I (heating at 70 degrees C in a dome-shaped sauna), Phase II (insulation in the sauna), and Phase III (cool down). Physiological parameters and subjective thermal sensations were compared within and between two age groups. RESULTS: Mean skin temperature increased significantly in both age groups (Phase I) and after the first 10 minutes was higher among older adults (by 6.8 degrees C vs 6.0 degrees C among younger; p < .01). Mean rectal temperature increased by 0.6 degrees C in both groups (Phase II). Mean heart rate increased significantly in both age groups (Phase II) and was higher among younger adults (by 21.4 vs 11.3 beats/min among older adults; p < .05). Both systolic (by 15.1 mmHg) and diastolic (by 10.5 mmHg) blood pressure dropped significantly among older adults (Phase I), returning to baseline in Phase III; no changes were noted among those younger. There was no between-group difference in fluid loss or thermal sensations. CONCLUSIONS: Compared with younger adults, older adults are more likely to drop blood pressure in response to thermal stress but had similar fluid loss and subjective responses. PMID- 25528018 TI - Effect of indoor activity size distribution of (222)Rn progeny in-depth dose estimation. AB - In this work, the attached and unattached activity size distribution of (222)Rn progeny ((214)Bi and (218)Po) were measured indoor. The fraction of attached progeny was collected using a low-pressure Berner cascade-impactor technique. A constructed wire screen diffusion battery was used for collecting the fraction of unattached progeny. Most of the attached activities for (214)Bi progeny were associated with the aerosol particles of the accumulation mode. The active median aerodynamic diameter (AMAD) of this mode for (214)Bi was determined to be 350nm with a geometric standard division (GSD) of 3. The GSD of unattached size distributions for (218)Po was 1.3 with an active median aerodynamic diameter (AMTD) of 1.3nm. Given that dose estimation is sensitive to environmental conditions, an analytical method was introduced to compute the local energy deposition of (218)Po alpha particles in a target volume of 1MUm spheres located at different depths in bronchial epithelium. While the depth-dose distributions for nuclides uniformly distributed within the epithelium were found to be practically constant with depth, they decreased in an almost linear fashion with increasing depth for nuclides on the airway surface. PMID- 25528019 TI - Measurements of liquid phase residence time distributions in a pilot-scale continuous leaching reactor using radiotracer technique. AB - An alkaline based continuous leaching process is commonly used for extraction of uranium from uranium ore. The reactor in which the leaching process is carried out is called a continuous leaching reactor (CLR) and is expected to behave as a continuously stirred tank reactor (CSTR) for the liquid phase. A pilot-scale CLR used in a Technology Demonstration Pilot Plant (TDPP) was designed, installed and operated; and thus needed to be tested for its hydrodynamic behavior. A radiotracer investigation was carried out in the CLR for measurement of residence time distribution (RTD) of liquid phase with specific objectives to characterize the flow behavior of the reactor and validate its design. Bromine-82 as ammonium bromide was used as a radiotracer and about 40-60MBq activity was used in each run. The measured RTD curves were treated and mean residence times were determined and simulated using a tanks-in-series model. The result of simulation indicated no flow abnormality and the reactor behaved as an ideal CSTR for the range of the operating conditions used in the investigation. PMID- 25528020 TI - Biological and clinical significance of PARP1 protein expression in breast cancer. AB - Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well characterised cohort of clinically annotated stage I-III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASgamma and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASgamma (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple negative subgroup. PMID- 25528021 TI - Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis. AB - The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20-86 years). Of the patients, 162 patients (37.5 %) had ER positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER negative/HER2-positive (ER-HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER-HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p < 0.001) and ER-HER2+ (p = 0.018) groups. Treatment with trastuzumab before developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p < 0.001). For HER2-positive patients with brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival. PMID- 25528022 TI - A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2 targeted therapies trastuzumab and lapatinib. AB - The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80 6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9-29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation. PMID- 25528023 TI - INPP4B and RAD50 have an interactive effect on survival after breast cancer. AB - Genes sharing similar genomic landscape have the potential to interactively orchestrate certain clinicopathological features of a disease. Deletion of the RAD50 gene is a common event particularly in basal-like breast cancer, and often occurs together with deletions of BRCA1, RB1, TP53, PTEN, and INPP4B. In this study, we investigate whether these co-deleted genes have interactive effects on survival in breast cancer. Using publicly available TCGA data, we employed Cox's proportional hazards models to test whether genomic deletions of these genes, or reduced protein or transcript levels associate with breast cancer patient survival in an interactive manner. Further validation was obtained at the transcriptional level by including 1,596 additional cases from 13 publicly available gene expression data sets from the KM-plotter database. Our results indicate that RAD50 and INPP4B associate interactively with breast cancer survival at the transcriptional, translational, and genomic levels in the TCGA data set (p (interaction) < 0.05). While neither of the genes was independently prognostic on its own, low INPP4B levels in combination with above median RAD50 abundance associated with increased hazard, both at the mRNA (HR 2.39, 95 % CI 1.20-4.76) and protein (HR 2.92, 95 % CI 1.42-6.00) levels, whereas concomitant deletion or low expression of both genes associated with unexpectedly improved survival. A similar pattern was observed in the KM-plotter data set (p (interaction) = 0.0067). We find that RAD50 and INPP4B expression levels have a synergistic influence on breast cancer survival, possibly through their effects on treatment response. PMID- 25528024 TI - Impact of chemotherapy on telomere length in sporadic and familial breast cancer patients. AB - Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that mutations in these genes might be responsible for this event. Given the contradictory results reported in the literature, we tested whether other parameters, such as chemotherapy, could be modifying telomere length (TL). We performed a cross-sectional study measuring leukocyte TL of 266 sporadic breasts cancer patients treated with first-line chemotherapy, with a median follow-up of 240 days. Additionally, we performed both cross-sectional and longitudinal studies in a series of 236 familial breast cancer patients that included affected and non-affected BRCA1/2 mutation carriers. We have measured in leukocytes from peripheral blood: the TL, percentage of short telomeres (<3 kb), telomerase activity levels and the annual telomere shortening speed. In sporadic cases we found that chemotherapy exerts a transient telomere shortening effect (around 2 years) that varies depending on the drug combination. In familial cases, only patients receiving treatment were associated with telomere shortening but they recovered normal TL after a period of 2 years. Chemotherapy affects TL and should be considered in the studies that correlate TL with disease susceptibility. PMID- 25528025 TI - High sensitivity multiplex short tandem repeat loci analyses with massively parallel sequencing. AB - STR typing in forensic genetics has been performed traditionally using capillary electrophoresis (CE). However, CE-based method has some limitations: a small number of STR loci can be used; stutter products, dye artifacts and low level alleles. Massively parallel sequencing (MPS) has been considered a viable technology in recent years allowing high-throughput coverage at a relatively affordable price. Some of the CE-based limitations may be overcome with the application of MPS. In this study, a prototype multiplex STR System (Promega) was amplified and prepared using the TruSeq DNA LT Sample Preparation Kit (Illumina) in 24 samples. Results showed that the MinElute PCR Purification Kit (Qiagen) was a better size selection method compared with recommended diluted bead mixtures. The library input sensitivity study showed that a wide range of amplicon product (6-200ng) could be used for library preparation without apparent differences in the STR profile. PCR sensitivity study indicated that 62pg may be minimum input amount for generating complete profiles. Reliability study results on 24 different individuals showed that high depth of coverage (DoC) and balanced heterozygote allele coverage ratios (ACRs) could be obtained with 250pg of input DNA, and 62pg could generate complete or nearly complete profiles. These studies indicate that this STR multiplex system and the Illumina MiSeq can generate reliable STR profiles at a sensitivity level that competes with current widely used CE-based method. PMID- 25528026 TI - Concordance study between the ParaDNA(r) Intelligence Test, a rapid DNA profiling assay, and a conventional STR typing kit (AmpFlSTR(r) SGM Plus(r)). AB - The ParaDNA(r) Intelligence Test enables STR profiling directly from human biological samples and evidence items collected from crime scene in 75min. Designed for non-expert use this system allows DNA information to be available to investigators before it would typically be available from a laboratory. The ParaDNA Intelligence Test system amplifies D3S1358, D8S119, D16S539, D18S1358 and TH01 STR loci and the gender typing locus amelogenin and detects the alleles present with HyBeacon(r) probes. Individual DNA samples from 381 UK Caucasian individuals were analysed using AmpFlSTR(r) SGM Plus(r) and the ParaDNA Intelligence Test with the derived STR profiles compared. Here we describe the high level of concordance demonstrated between the two systems and discuss this with reference to allele frequencies and the discriminatory power offered by the ParaDNA Intelligence Test. PMID- 25528027 TI - Pancreatic body hydatid cyst: A case report. AB - INTRODUCTION: Hydatid disease is a parasitic infestation caused by the cystic stage of Echinococcus granulosus. Hydatid cysts are commonly located in the liver and lung. Pancreatic affection by hydatid cysts is very rare even in endemic areas. PRESENTATION OF CASE: Our case is a 34-year-old male patient referred to our centre with a pancreatic body cyst diagnosed by abdominal CT scan. The patient gave 3 months history of epigastric pain. He also gave history of travelling to Saudi Arabia and China. His enzyme-linked immunoadsorbent assay (ELIZA) test for echinococcal antigens was positive. Surgical exploration revealed a 7cm cyst in the body of the pancreas separable from the surroundings. Endocystectomy and deroofing of the cyst was done. DISCUSSION: Due to its rarity and similarity with more common pancreatic cystic conditions, diagnosis of pancreatic hydatid cyst may be challenging. Abdmonial sonography and CT scan together with enzyme-linked immunoadsorbent assay (ELIZA) test for echinococcal antigens are helpful diagnostic tools. Therapeutic options include endocystectomy and deroofing, albendazol therapy with percutaneous drainage or laparoscopic excision of the cyst. CONCLUSION: Even in non-endemic areas, past history of travelling abroad in patients with pancreatic cystic lesions should raise the suspicion of hydatid disease as a possible diagnosis. PMID- 25528028 TI - Acute scrotal pain as sole presentation of acute pancreatities. AB - Pancreatitis has a myriad of different presentations although commonly presents with epigastric pain radiating to the back, nausea and vomiting. There are five case reports in the English literature of scrotal pain and swelling in severe alcoholic pancreatitis, two of which underwent surgical exploration. We present the first case of mild pancreatitis presenting with scrotal pain in the absence of any other symptoms or signs. We conclude that in any patient with unexplained scrotal pain, even in the absence of physical signs the possibility of pancreatitis should be considered. PMID- 25528029 TI - Late-onset renal vein thrombosis: A case report and review of the literature. AB - INTRODUCTION: Renal vein thrombosis, a rare complication of renal transplantation, often causes graft loss. Diagnosis includes ultrasound with Doppler, and it is often treated with anticoagulation or mechanical thrombectomy. Success is improved with early diagnosis and institution of treatment. PRESENTATION OF CASE: We report here the case of a 29 year-old female with sudden development of very late-onset renal vein thrombosis after simultaneous kidney pancreas transplant. This resolved initially with thrombectomy, stenting and anticoagulation, but thrombosis recurred, necessitating operative intervention. Intraoperatively the renal vein was discovered to be compressed by a large ovarian cyst. DISCUSSION: Compression of the renal vein by a lymphocele or hematoma is a known cause of thrombosis, but this is the first documented case of compression and thrombosis due to an ovarian cyst. CONCLUSION: Early detection and treatment of renal vein thrombosis is paramount to restoring renal allograft function. Any woman of childbearing age may have thrombosis due to compression by an ovarian cyst, and screening for this possibility may improve long-term graft function in this population. PMID- 25528030 TI - Cerebral venous thrombosis in a breast cancer patient taking tamoxifen: Report of a case. AB - INTRODUCTION: Tamoxifen reduces breast cancer risk, but can cause thromboembolic complications. Cerebral venous thrombosis is a rare form of stroke in which blood clots occlude the dural sinus or cerebral veins. PRESENTATION OF CASE: A 46-year old female presented with a severe headache and nausea of subacute onset. She had undergone masectomy for breast cancer 20 months ago and had been taking tamoxifen. Brain CT and MRI confirmed cerebral venous infarction and venous thrombosis in the superior sagittal sinus and straight sinus. She had elevated D dimer level, decreased levels of protein S activity and antithrombin III. Doppler ultrasound revealed concurrent deep vein thrombosis in her right leg. There was no evidence of breast cancer recurrence. With oral anticoagulation, she discharged without neurological complications. The abnormal laboratory findings of coagulopathy returned to normal after discontinuation of tamoxifen. DISCUSSION: Considering the abnormal findings in the workup of coagulopathy and no other risk factor for venous thrombosis, this thromboembolic complication can be attributed to the coagulopathy with use of tamoxifen. CONCLUSION: Clinicians should warn about the possibility of thromboembolic complications with tamoxifen. PMID- 25528031 TI - Simultaneous bilateral decortications via video-assisted thoracic surgery for bilateral empyema. AB - INTRODUCTION: Bilateral empyema is a rare and life-threatening condition that is difficult to treat. We herein report a case of bilateral empyema that was treated with simultaneous bilateral decortications via video-assisted thoracic surgery (VATS). PRESENTATION OF CASE: A 38-year-old female complained of chest pain, dyspnea, and high grade fever lasting two weeks. Computed tomography revealed bilateral notching pleural effusion and pneumonia with atelectasis. Bilateral thoracic drainage was performed. From the right chest, white pus was drained, and Streptococcus anginosus was identified. The left drainage fluid was serous, and no bacteria were identified. We diagnosed the patient with right empyema and left para-pneumonic effusion consequent to pneumonia. Because conservative therapies could not resolve the inflammatory findings, simultaneous bilateral VATS decortications were performed. Both thoracic cavities had loculated pleural effusion. In contrast to the preoperative findings, white pus was found in not only the right, but also the left thoracic cavity. She had an uncomplicated postoperative course and recovered. DISCUSSION: Bilateral empyema that has developed to the fibrinopleural phase is difficult to treat with drains alone. Bilateral VATS decortications helped to make a definitive diagnosis and treat both sides simultaneously. CONCLUSION: Simultaneous bilateral VATS decortications should be considered as a feasible and effective procedure for bilateral empyema that is refractory to medical treatment. PMID- 25528032 TI - Staging resection and reconstruction with temporary wound VAC coverage in a case of giant cystosarcoma phyllodes of the breast. AB - INTRODUCTION: Cystosarcoma phyllodes (CP) is a rare breast tumor occurring most often in females in their fifth decade. While usually benign, some CP tumors exhibit aggressive growth patterns and extensively invade chest wall structures; resecting these tumors to negative surgical margins can be challenging. We present a case of malignant CP involving the chest wall where using a negative pressure vacuum-assisted closure (VAC) system after resection enabled complete histopathologic margin assessment prior to reconstruction. This is the first known report of staged breast tumor resection and reconstruction with interim VAC coverage. CASE PRESENTATION: A 48 year-old woman presented with rapidly increasing left breast size, fevers, and fatigue. On examination, the left breast was massively enlarged with engorged vessels and skin necrosis. Lab analyses revealed unusual metabolic abnormalities requiring preoperative hospitalization. We performed a left modified radical mastectomy with partial resection of pectoralis major and minor muscles, temporarily sealing the wound with a VAC due to concern for deeper tumor extension that could require further resection. Pathology revealed malignant CP with a negative deep margin. The 38cm defect was then repaired with latissimus myocutaneous flap plus skin graft. At three-year follow up the patient remains free of disease. CONCLUSION: In cases of malignant CP involving the chest wall, minimizing the extent of chest wall resection is critical for reducing morbidity, while completely clearing tumor margins is essential for reducing recurrence risk. Using temporary wound VAC coverage enables cautious debulking followed by histopathologic margin assessment prior to definitively reconstructing the breast. PMID- 25528033 TI - Internal-mesocolic hernia after laparoscopic left colectomy report of case with late manifestation. AB - INTRODUCTION: In contrast to right colectomy, closure of the mesocolic gap after laparoscopic left colectomy is not practiced, and reports of small gut herniation through this gap are scarce. PRESENTATION OF CASE: A 73 year old male was admitted as an emergency with symptoms and clinical signs, suggesting obstruction of the small bowel. Abdominal imaging, including computed tomography confirmed the diagnosis. The patient had undergone laparoscopic left colectomy for cancer, three years ago. At laparotomy small bowel loops were found to herniate through the mesocolic defect at the level of the colonic anastomosis. The small bowel loops were reduced and their viability was ascertained. Because of an iatrogenic perforation of the colon at the anastomosis during small bowel loops mobilization, the colon was temporarily exteriorized in the form of a double barrel colostomy. The postoperative course was uneventful. DISCUSSION: Very few cases have been reported in the liteature indicating the need of sutuing the mesenterium. Despite the limited numbe of the reported cases, there is clearly a risk of intenal hernia after laparoscopic left colectomy. CONCLUSION: Although rare internal hernia after laparoscopic left colectomy may occur, and this brings forward the question of mesocolic gap closure. PMID- 25528034 TI - Choriocarcinoma of the adrenal gland: A case report. AB - INTRODUCTION: Non-gestational, extragonadal choriocarcinoma is a rare clinical entity. PRESENTATION OF CASE: Herein, we report a 56 year old woman who presented with an incidental adrenal mass and was diagnosed with a non-gestational choriocarcinoma of the adrenal gland as the sole site of disease. DISCUSSION: To our knowledge, this is the first case of an ectopic primary adrenal choriocarcinoma. A metastasis from a primary tumor that completely regressed or that could not be identified is an alternate explanation. CONCLUSION: It should be recognized that choriocarcinoma can affect the adrenal gland and it should be considered as a rare cause for an adrenal incidentaloma. PMID- 25528035 TI - Primary colon cancer with a high serum PIVKA-II level. AB - INTRODUCTION: Protein induced by vitamin K absence/antagonist-II (PIVKA-II) is an abnormal protein, and several reports have demonstrated the efficacy of PIVKA-II in the diagnosis of hepatocellular carcinoma (HCC). We report an extremely rare case of adenocarcinoma of the colon with a high serum PIVKA-II level. PRESENTATION OF CASE: A 95-year-old woman presented with right lower quadrant pain and appetite loss. An abdominal computed tomography scan and ultrasonography showed an ascending colon tumor and multiple metastatic tumors in the liver. The serum level of PIVKA-II was extremely high, 11,900ng/mL. Colonoscopic examination revealed a tumor accompanied by an ulcer in the ascending colon, which was highly suspicious for malignancy. Multiple biopsies showed well-differentiated adenocarcinoma of the colon, which was evaluated as colon cancer, stage IV. PIVKA II-productive colon cancer was confirmed. Chemotherapy with TS-1 was administered. The patient died 3 months after initial admission. DISCUSSION: The expression of PIVKA-II was detected in non-cancer areas, with non-specific expression observed in plasma cells in our case. There might be some possibility that hepatoid differentiation exists in other regions of the colon tumor or in the liver tumor, parenchymal cells or lung metastases, which were composed of PIVKA-II-positive and AFP-negative cells. CONCLUSION: To the best of our knowledge, high serum levels of PIVKA-II resulting from colon adenocarcinoma have not been reported previously. We report this rare case together with a review of the literature. PMID- 25528036 TI - Totally extraperitoneal inguinal hernia repair during extraperitoneal laparoscopic radical prostatectomy: Report of a case. AB - INTRODUCTION: The incidence of prostate cancer is increasing, and inguinal hernias are common in the age group of men with prostate cancer. Furthermore, inguinal hernias are now considered to be one of the long-term complications of radical prostatectomy. In this report, we present our experience with the performance of totally extraperitoneal inguinal hernia repair (TEP) along with extraperitoneal laparoscopic radical prostatectomy (ELRP). PRESENTATION OF CASE: A 66-year-old man with prostate cancer and bilateral inguinal hernias was admitted to our hospital for surgery. He had a history of right inguinal hernioplasty without mesh placement and ascending colon diverticulitis. With a diagnosis of prostate cancer and bilateral inguinal hernia, concomitant TEP after ELRP was safely performed. DISCUSSION: TEP combined with ELRP appears to be a rational procedure and easy to perform. The incidence of complications related to either TEP or ELRP might not be increased. TEP combined with ELRP might be safely performed for recurrent inguinal hernia after non-mesh hernioplasty. CONCLUSION: TEP combined with ELRP might be of use in prostate cancer patients with inguinal hernias. PMID- 25528037 TI - Metastatic rhabdoid meningioma of the parotid - Mimicking primary salivary gland neoplasm. AB - INTRODUCTION: Tumors involving the parotid are predominantly primary with metastatic lesions forming a miniscule population. Meningioma metastasizing to the parotid is extremely rare and hence can often be mistaken for the more common primary salivary gland neoplasms. PRESENTATION OF CASE: A 59-year-old male presented with a swelling in the left parotid region. Fine needle aspiration cytology was suggestive of myoepithelial predominant pleomorphic adenoma. A superficial parotidectomy performed revealed a tumor composed of rhabdoid cells with abundant finely granular eosinophilic cytoplasm raising a possibility of myoepithelioma. Immunohistochemistry for myoepithelial markers was negative. A critical review elicited a history of surgical excision of a recurrent rhabdoid meningioma twice. A possibility of metastasis was considered and a second panel of immunomarkers demonstrated vimentin and epithelial membrane antigen positivity. Neuroimaging studies demonstrated a space occupying lesion in the frontal lobe suggestive of a recurrent/residual tumor. In view of the history, neuroradiology, histopathology and immunohistochemistry, a final diagnosis of metastatic rhabdoid meningioma to the parotid was rendered. DISCUSSION: Morphologically, metastatic rhabdoid meningioma may mimic a primary or metastatic carcinoma, melanoma and sarcoma. Accurate diagnosis can be made by careful clinical evaluation and histopathological examination of the tumor. These tumors are composed of rhabdomyoblast like cells with abundant eosinophilic cytoplasm. The present case demonstrated characteristic histopathological features confirmed by immunohistochemistry. CONCLUSION: Rhabdoid meningioma is an aggressive tumor with a high propensity to recur and metastasize. The present case highlights the importance of clinical, radiological and histopathological correlation to accurately diagnose these rare entities. PMID- 25528038 TI - Bilateral femoral neck fractures after an epileptic attack: A case report. AB - INTRODUCTION: Bilateral femoral neck fractures can occur due to high- or low energy trauma, in the presence of various predisposing factors, such as osteoporosis, renal osteodystrophy, hypocalcemic seizures, primary or metastatic tumors, electroconvulsive therapy, epileptic seizures, and hormonal disorders. PRESENTATION OF CASE: This report presents a case of bilateral femoral neck fractures that occurred during an epileptic attack in a 24-year-old male with mental retardation. His complaints had started after a grand mal epileptic attack 10 days earlier. Bilateral displaced femoral neck fractures (Garden type 4) were seen in lateral radiographs of both hips. The patient was operated on urgently, with closed reduction, three stainless steel cannulated screws, and internal fixation applied to both hips. At postoperative week 12, solid joining was achieved and active walking with complete loading was started. DISCUSSION: Bilateral femoral neck fractures can occur following a grand mal epilepsy attack in young patients. The use of antiepileptic drugs can also lead to the development of pathological fractures by reducing bone mineral density. CONCLUSION: Femoral neck fractures should be suspected in patients with epilepsy who present with severe pain in both hips and an inability to walk. Stainless steel implants can be used for treatment. The viability of the femoral head should be evaluated by scintigraphy. Bone mineral density should be monitored in patients who use anti-epileptic drugs, and internal fixation is preferred in the treatment of femoral neck fractures. PMID- 25528039 TI - Bilateral femoral neck fractures secondary to chronic carbamazepine use treated by bilateral dynamic hip screw: A case report. AB - INTRODUCTION: Bilateral femoral neck fractures without major trauma are rare and related to several conditions. Insufficiency fractures due to the use of anti epileptic drug are one of the rare causes. This case study is about bilateral femoral neck insufficiency fractures resulting from chronic use of anti-epileptic drug. PRESENTATION OF CASE: A 26-year-old woman was referred to our emergency department with a complaint of bilateral groin pain and a 12-year history of irregular carbamazepine use. The diagnosis was bilateral femoral neck insufficiency fractures due to irregular long-term carbamazepine use. One-stage bilateral dynamic hip screw osteosynthesis was performed. After 2 years of follow up, good result was obtained. DISCUSSION: There are several risk factors for insufficiency fracture, and antiepileptic drug related osteoporosis is one of the reason. These drugs have negative effect on bone methabolism and bone mineral density. CONCLUSION: To our knowledge, this is the first case in the literature of bilateral femoral neck insufficiency fracture due to chronic carbamazepine use. Joint and bone pain with a history of long-term use of anti-epileptic drug should be investigated carefully, and insufficiency fractures should be kept in mind. PMID- 25528040 TI - Repeated hepatic resection combined with inferior vena cava replacement: Case report and review of literature. AB - INTRODUCTION: Advanced tumors of the liver involving the inferior vena cava (IVC) have always been considered a contraindication to surgery. PRESENTATION OF CASE: We report a case of a patient, who previously underwent right hepatectomy, with recurrence of colorectal liver metastasis invading the IVC. The patient had a liver resection together with replacement of the vena cava using a ringed polytetrafluoroethylene (PTFE) graft tube. The operation was carried out in hepatic vascular exclusion (HVE) without the use of veno-venous bypass. The patient was healthy and tumor-free at 6 months post-surgery. DISCUSSION: In patients with hepatic malignancy involving the IVC, extended hepatic resection and reconstruction of the IVC is often the prerequisite to obtaining a resection margin. CONCLUSION: Extended hepatic resection with IVC reconstruction for hepatic malignancy may offer a chance of cure to selected patients who otherwise have poor survival rates. PMID- 25528041 TI - Abdominal tuberculosis mimicking Crohn's disease's exacerbation: A clinical, diagnostic and surgical dilemma. A case report. AB - INTRODUCTION: Tuberculosis in Europe is a health public problem, which has increased constantly over the last few decades. The most common clinical manifestation of tuberculosis is pulmonary. The diagnosis of extrapulmonary tuberculosis can be challenging and clinical manifestations of gastrointestinal tuberculosis are unspecific and can mimic other pathologies. PRESENTATION OF CASE: A young Chinese man, who had recently been diagnosed with Crohn's disease, was admitted to the emergency room of our hospital with a one-month history of diffuse abdominal pain and weight loss. The patient initially presented with epigastric pain, which had been constantly increasing over the last 48 h. Other symptoms included diarrhea, nausea, and fever. The patient was then admitted with the diagnosis of Crohn's disease exacerbation, and a treatment with corticosteroids, azathioprine, mesalazine, adalimumab, and antibiotic therapy was started. The symptoms were due to an initially misdiagnosed case of abdominal tuberculosis. DISCUSSION: Intestinal tuberculosis is mainly localized at the ileocecal level in 85% of patients. Medical therapy is the treatment of choice and surgery is not required if it is diagnosed at an early stage.? CONCLUSION: The diagnosis of abdominal tuberculosis still remains a challenge for both internists and surgeons. Before starting a therapy with adalimumab, every patient should be tested for latent tuberculosis infection. PMID- 25528042 TI - Subacromial osteochondroma: A rare cause of impingement syndrome. AB - INTRODUCTION: Subacromial impingement syndrome is one of the most common disorders of shoulder. Scapula is a very rare site for osteochondromas, and osteochondromas arising under the acromion cause impingement syndrome. PRESENTATION OF CASE: We presented 34-year old female patient with subacromial impingement syndrome secondary to osteochondroma. She had received conservative treatment several times in other clinics. The osteochondroma causing impingement was not diagnosed. Physical examination of the right shoulder revealed 90 degrees flexion, 70 degrees abduction, 20 degrees external rotation and internal rotation to sacrum. X-ray, CT and MRI of the shoulder was obtained. Osteochondroma of the acromion (35*33*25mm) causing impingement was detected. The osteochondroma of acromion compressed, displaced and ruptured the supraspinatus tendon. Also an osseous prominence of glenoid was detected during shoulder arthroscopy, and it was removed arthroscopically. The giant osteochondroma of acromion could not remove arthroscopically due to the size of the lesion, and it was removed totally through a mini open approach. Histopathological examination confirmed the diagnosis of osteochondroma. DISCUSSION: Scapular, clavicular and humeral osteochondromas cause impingement syndrome. Osteochondroma should be treated with total excision. Recurrences can be seen due to insufficient removal of osteochondromas. We think that, total excision is important to prevent recurrence. Subacromial osteochondroma is a very rare cause of impingement syndrome, and if it isn't diagnosed early it limits shoulder movements, causes severe shoulder impingement and rotator cuff tear. CONCLUSION: The diagnosis of subacromial osteochondroma should be considered in any patient with shoulder impingement syndrome and good functional results can be expected following total excision. PMID- 25528043 TI - Prospective cross-sectional study on faecal immunochemical tests: sex specific cut-off values to obtain equal sensitivity for colorectal cancer? AB - BACKGROUND: Faecal immunochemical tests (FITs) are commonly used in colorectal cancer (CRC) screening. Diagnostic accuracy of FIT differs between males and females. This so far unexplained difference could result in a dissimilarity in screening outcome between both sexes. The aim of this study is to compare sensitivity and specificity of a FIT between males and females, and study potential explanatory variables. METHODS: In this cross-sectional study, data were prospectively collected. 3,022 subjects performed a FIT prior to complete colonoscopy. Sensitivity, specificity, and ROC curves were compared for both sexes. Potential explanatory variables of the relation between sensitivity and sex were explored. RESULTS: At all cut-off values, FIT sensitivity for CRC was higher (range 13-23%) and specificity was lower (range 2-4%) in males compared to females. At 75 ng/ml, sensitivity for CRC was 93% in males compared to 71% in females (p = 0.03), and specificity was 90% in males compared to 93% in females (p = <0.05). For advanced adenomas, males had a slightly higher sensitivity and lower specificity (not significant). At 75 ng/ml, sensitivity for advanced adenomas was 33% in males compared to 29% in females (p = 0.46), and specificity was 93% in males compared to 95% in females (p = 0.22). ROC curves were similar for both sexes, and equal combinations of sensitivity and specificity could be achieved by adjusting the cut-off values. For CRC, the difference in sensitivity could not be explained by age or location of the tumour. CONCLUSIONS: FIT has a higher sensitivity and a lower specificity for CRC in males than in females. Equal test characteristics can be achieved by allowing separate cut-off values for both sexes. Location and age do not explain the observed differences in sensitivity. PMID- 25528044 TI - Effects of a performance and quality improvement intervention on the work environment in HIV-related care: a quasi-experimental evaluation in Zambia. AB - BACKGROUND: Human resource shortages and reforms in HIV-related care make it challenging for frontline health care providers in southern Africa to deliver high-quality services. At health facilities of the Zambian Defence Forces, a performance and quality improvement approach was implemented to improve HIV related care and was evaluated in 2010/2011. Changes in providers' work environment and perceived quality of HIV-related care were assessed to complement data of provider performance. METHODS: The intervention involved on-site training, supportive supervision, and action planning focusing on detailed service delivery standards. The quasi-experimental evaluation collected pre- and post-intervention data from eight intervention and comparison facilities matched on defence force branch and baseline client volume. Overall, 101 providers responded to a 24-item questionnaire on the work environment, covering topics of drugs, supplies, and equipment; training, feedback, and supervision; compensation; staffing; safety; fulfilment; and HIV services quality. In bivariate analysis and multivariate analyses, we assessed changes within each study group and between the two groups. RESULTS: In the bivariate analysis, the intervention group providers reported improvements in the work environment on adequacy of equipment, feeling safe from harm, confidence in clinical skills, and reduced isolation, while the comparison group reported worsening of the work environment on supplies, training, safety, and departmental morale.In the multivariate analysis, the intervention group's improvement and the comparison group's decline were significant on perceived adequacy of drugs, supplies, and equipment; constructive feedback received from supervisor and co-workers; and feeling safe from physical harm (all P <0.01, except P <0.04 for equipment). Further, the item "provider lacks confidence in some clinical skills" declined in the intervention group but increased in the comparison group (P = -0.005). In multivariate analysis, changes in perceived quality of HIV care did not differ between study groups. Provider perceptions were congruent with observations of preparing drugs, supplies, equipment, and in service delivery of prevention of mother-to-child transmission of HIV and antiretroviral therapy follow-up care. CONCLUSIONS: The performance and quality improvement intervention implemented at Zambian Defence Forces' health facilities was associated with improvements in providers' perceptions of work environment consistent with the intervention's focus on commodities, skills acquisition, and receipt of constructive feedback. PMID- 25528045 TI - Management of pregnant and postnatal women with pre-existing diabetes or cardiac disease using multi-disciplinary team models of care: a systematic review. AB - BACKGROUND: More women with an increased risk of poor pregnancy outcome due to pre-existing medical conditions are becoming pregnant. Although clinical care provided through multi-disciplinary team (MDT) working is recommended, little is known about the structure or working practices of different MDT models, their impact on maternal and infant outcomes or healthcare resources. The objectives of this review were to consider relevant international evidence to determine the most appropriate MDT models of care to manage complex medical conditions during and after pregnancy, with a specific focus on pre-existing diabetes or cardiac disease in high income country settings. METHODS: Quantitative and qualitative evidence of MDT models of care for the management of pregnant/postnatal women with pre-existing diabetes and cardiac disease was considered. A search of the literature published between January 2002 - January 2014 was undertaken. Methodological quality was assessed using checklists developed by the Joanna Briggs Institute. Given limited primary and secondary research evidence, guidelines and opinion papers were included. Two independent reviewers conducted critical appraisal of included papers. RESULTS: Nineteen papers were included from UK, Canada, USA, the Netherlands and Singapore. No studies were found which had compared MDT models for pregnant/postnatal women with pre-existing diabetes or cardiac disease. Two small retrospective studies reported better outcomes for women with cardiac disease if an MDT approach was used, although evidence to support this was limited. Due to study heterogeneity it was not possible to meta analyse data. No evidence was identified of MDT management in the postnatal period or impacts of MDT working on healthcare resources. CONCLUSIONS: Despite widespread promotion of MDT models of care for pregnant and postnatal women with pre-existing diabetes or cardiac disease, there is a dearth of primary evidence to inform structure or working practices or beneficial impact on maternal and infant outcomes or healthcare resources. Primary research into if or how MDT models of care improve outcomes for women with complex pregnancies is urgently needed. PMID- 25528046 TI - The fairness, predictive validity and acceptability of multiple mini interview in an internationally diverse student population--a mixed methods study. AB - BACKGROUND: International medical students, those attending medical school outside of their country of citizenship, account for a growing proportion of medical undergraduates worldwide. This study aimed to establish the fairness, predictive validity and acceptability of Multiple Mini Interview (MMI) in an internationally diverse student population. METHODS: This was an explanatory sequential, mixed methods study. All students in First Year Medicine, National University of Ireland Galway 2012 were eligible to sit a previously validated 10 station MMI. Quantitative data comprised: demographics, selection tool scores and First Year Assessment scores. Qualitative data comprised separate focus groups with MMI Assessors, EU and Non-EU students. RESULTS: 109 students participated (45% of class). Of this 41.3% (n = 45) were Non-EU and 35.8% (n = 39) did not have English as first language. Age, gender and socioeconomic class did not impact on MMI scores. Non-EU students and those for whom English was not a first language achieved significantly lower scores on MMI than their EU and English speaking counterparts (difference in mean 11.9% and 12.2% respectively, P<0.001). MMI score was associated with English language proficiency (IELTS) (r = 0.5, P<0.01). Correlations emerged between First Year results and IELTS (r = 0.44; p = 0.006; n = 38) and EU school exit exam (r = 0.52; p<0.001; n = 56). MMI predicted EU student OSCE performance (r = 0.27; p = 0.03; n = 64). In the analysis of focus group data two overarching themes emerged: Authenticity and Cultural Awareness. MMI was considered a highly authentic assessment that offered a deeper understanding of the applicant than traditional tools, with an immediate relevance to clinical practice. Cultural specificity of some stations and English language proficiency were seen to disadvantage international students. Recommendations included cultural awareness training for MMI assessors, designing and piloting culturally neutral stations, lengthening station duration and providing high quality advance information to candidates. CONCLUSION: MMI is a welcome addition to assessment armamentarium for selection, particularly with regard to stakeholder acceptability. Understanding the mediating and moderating influences for differences in performance of international candidates is essential to ensure that MMI complies with the metrics of good assessment practice and principles of both distributive and procedural justice for all applicants, irrespective of nationality and cultural background. PMID- 25528047 TI - The relevance of network prominence and reciprocity of relationships for alcohol use and alcohol-related problems in a college residence hall network. AB - Peer associations are influential for substance use among college students, but relatively few investigations have been conducted on the social network characteristics that are associated with problematic alcohol use in college. This study investigated the association between network characteristics of prestige, expansiveness, and reciprocity and alcohol use variables in a college residence hall network. Undergraduate students in 1 residence hall (N = 129; 51.9% female; 48.1% non-Hispanic White; 84.5% first-year) reported on their alcohol use and alcohol-related problems in the past semester and nominated up to 10 residence hall peers who were important to them. Network autocorrelation modeling evaluated the association between 5 network variables reflecting prestige (indegree and betweenness centrality), expansiveness (outdegree), and relationship agreement (indegree reciprocity and outdegree reciprocity) and 3 indicators of alcohol use (drinks per week, number of heavy drinking days, number of alcohol problems). Moderation by gender of the associations between network characteristics and alcohol variables was also investigated. Models controlled for demographics and network autocorrelation. A higher outdegree and higher betweenness centrality within the residence hall network were significantly related to the number of heavy drinking days and number of alcohol problems, respectively. Higher indegree and higher betweenness centrality were associated with more alcohol problems for women when alcohol use was controlled. Having higher prestige and indicating oneself as having more friends in a college residential network may convey alcohol-related risks, with some risks higher for women. PMID- 25528049 TI - Psychometric properties of the system for coding couples' interactions in therapy -alcohol. AB - Few systems are available for coding in-session behaviors for couples in therapy. Alcohol Behavioral Couple Therapy (ABCT) is an empirically supported treatment, but little is known about its mechanisms of behavior change. In the current study, an adapted version of the Motivational Interviewing for Significant Others coding system was developed into the System for Coding Couples' Interactions in Therapy-Alcohol (SCCIT-A), which was used to code couples' interactions and behaviors during ABCT. Results showed good interrater reliability of the SCCIT-A and provided evidence that the SCCIT-A may be a promising measure for understanding couples in therapy. A 3-factor model of the SCCIT-A (Positive, Negative, and Change Talk/Counter-Change Talk) was examined using a confirmatory factor analysis, but model fit was poor. Because model fit was poor, ratios were computed for Positive/Negative ratings and for Change Talk/Counter-Change Talk codes based on previous research in the couples and Motivational Interviewing literature. Post hoc analyses examined correlations between specific SCCIT-A codes and baseline characteristics, and indicated some concurrent validity. Correlations were run between ratios and baseline characteristics; ratios may be an alternative to using the factors from the SCCIT-A. Reliability and validity analyses suggest that the SCCIT-A has the potential to be a useful measure for coding in-session behaviors of both partners in couples therapy and could be used to identify mechanisms of behavior change for ABCT. Additional research is needed to improve the reliability of some codes and to further develop the SCCIT-A and other measures of couples' interactions in therapy. PMID- 25528048 TI - Coping, PTSD symptoms, and alcohol involvement in trauma-exposed college students in the first three years of college. AB - The objective of the present study was to examine prospective, bidirectional associations among posttraumatic stress disorder (PTSD) symptoms, coping style, and alcohol involvement (use, consequences) in a sample of trauma-exposed students just entering college. We also sought to test the mechanistic role that coping may play in associations between PTSD symptoms and problem alcohol involvement over time. Participants (N = 734) completed measures of trauma exposure, PTSD symptoms, coping, and alcohol use and consequences in September of their first college year and again each September for the next 2 years. We observed reciprocal associations between PTSD and negative coping strategies. In our examination of a mediated pathway through coping, we found an indirect association from alcohol consequences and PTSD symptoms via negative coping, suggesting that alcohol consequences may exacerbate posttraumatic stress over time by promoting negative coping strategies. Trauma characteristics such as type (interpersonal vs. noninterpersonal) and trauma reexposure did not moderate these pathways. Models were also invariant across gender. Findings from the present study point to risk that is conferred by both PTSD and alcohol consequences for using negative coping approaches, and through this, for posttraumatic stress. Interventions designed to decrease negative coping may help to offset this risk, leading to more positive outcomes for those students who enter college with trauma exposure. PMID- 25528050 TI - Correlates of recent drug use among victimized women on probation and parole. AB - Guided by the Comprehensive Health Seeking and Coping Paradigm (CHSCP; Nyamathi, 1989), the present research sought to examine associations between victimization, psychological distress, lawbreaking and recent drug use (past 12 months) among 406 victimized women on probation and parole. Bivariate differences between women who reported recent drug use and those who did not report recent use were compared across the 4 domains of the CHSCP (sociodemographic characteristics, personal resources, lifetime victimization, dynamic crime and drug factors). Variables significantly related to recent drug use at the bivariate level were retained in the multivariate analysis. The final multivariate model, using stepwise logistic regression via backward elimination, retained five candidate variables indicating women who recently used drugs, were younger, were not sexually victimized as children, began using drugs before they were 13 years of age, were on probation, and had engaged in more recent lawbreaking. The final model accounted for approximately 30% of the variance in drug use over the past 12 months. Implications for intervention and future research are discussed. PMID- 25528051 TI - Drinking consequences and subsequent drinking in college students over 4 years. AB - There is some evidence that college student drinkers may continue drinking in the face of adverse consequences. We examined 2 hypotheses: (a) that this seemingly pathological behavior is a phenomenon of university life, occurring with consistency throughout the entirety of college, and (b) that individuals accumulate these consequences over multiple semesters in college. A sample of 3,720 students from a large Midwestern university was asked to complete surveys the summer before college and every semester thereafter for 4 years. Results showed that certain drinking-related consequences (e.g., blackouts, regretted sexual experiences) consistently predicted continued frequent heavy drinking in the following semester, even after controlling for sex, race, age, and previous semester frequent heavy drinking (range of odds ratio = 1.17 to 1.45 across semesters, p < .01). Such potent consequences may predict subsequent drinking for a number of possible reasons that may be examined and addressed as they would pertain to specific protective behavioral strategy-related and cognitive interventions. Furthermore, consequences were accumulated over multiple semesters by notable proportions of students. For example, 13.8% of students reported blacking out 5 time-points or more--describing a full half or more of their college careers. Experimental studies which aim to modify students' perceptions of norms associated with these consequences may aid in developing interventions to reduce the burden of harm to students. In the broader context, and given the prevalence of students' accumulation of consequences, future study might aim to determine how and in what ways these findings describe either pathological or normative processes. PMID- 25528052 TI - Dynamic associations among alcohol use and anxiety symptoms in early adolescence. AB - The relationship between anxiety and alcohol use in adolescence remains unclear, with evidence for no association and for risk and protective effects of anxiety. Considering developmental trajectories may be important for understanding the association between anxiety and alcohol use and may help clarify prior mixed findings. The present study examined trajectories of alcohol use, social anxiety symptoms, and general anxiety symptoms in early to middle adolescence through the use of univariate and parallel process growth models. Social anxiety and general anxiety symptoms declined, while alcohol use increased with age. Parallel process growth models suggested that less rapid declines in social anxiety and general anxiety symptoms were associated with more rapid escalation in alcohol use. These results suggest that young adolescents who do not show normative declines in social anxiety or general anxiety symptoms may be at risk for more rapid increases in alcohol use. PMID- 25528053 TI - Examining the affective tone of alcohol craving in young drinkers. AB - An abundance of research has examined craving and affective responses to alcohol; however, minimal emphasis has been placed on the relationship between craving and affective states at specific time points of alcohol consumption. Fifty-nine university students (28 light drinkers, 31 heavy drinkers) completed assessments of craving, and positive and negative affect at baseline (Time 1), immediately following consumption of a standard drink of alcohol (Time 2), and 20 min post consumption (Time 3). In light drinkers, craving was positively correlated with positive affect at all 3 time points. In heavy drinkers, craving was only correlated with positive affect at Time 2. There were no associations between craving and negative affect at any time point in either group. A subsequent profile analysis revealed parallel profiles of craving and positive affect over time in light drinkers, but not heavy drinkers. At 20 min post alcohol consumption, a moderated regression showed that the relationship between craving and positive affect weakened as level of alcohol use increased. These findings suggest that craving is positively associated with positive affect in light drinkers, but as levels of drinking escalate, this association dissipates. PMID- 25528054 TI - Using motives for smoking to distinguish between different college student smoker typologies. AB - Relatively little is known about how to categorize different types of smokers, especially occasional smokers. Because of the prevalence of occasional smoking among college students, the current study aimed to gain an understanding of the different typologies of smokers on campus. To accomplish this, a latent class analysis (LCA) was conducted using 17 motives for smoking items (N = 327). The LCA revealed that four smoker groups were present: (1) addicted smokers who endorsed smoking due to pleasure and habit/addiction; (2) stress smokers, who endorsed smoking to relax, to reduce levels of stress, and to regulate mood; (3) social smokers, who endorsed smoking because of social factors such as to fit in or because friends smoke; and (4) nonendorsing smokers, who had a low endorsement for all the items. An additional LCA with covariates revealed that age of initiation, current smoking patterns, smoker self-classification, and quit likelihood differentiated these groups of smokers whereas current age and alcohol use did not. These typologies should be considered when designing interventions for occasional smokers. PMID- 25528055 TI - Traumatic spondyloptosis of the lumbar spine: a case report. AB - INTRODUCTION: Spondyloptosis is the most severe of translation spine injuries. It results in complete disruption of the structural elements of the vertebral column and the adjacent paravertebral soft tissues, culminating in severe biomechanical instability. Although several cases of lumbosacral spondyloptosis have been documented, not many cases of traumatic lumbar spondyloptosis have been published in the literature. CASE PRESENTATION: We present a case of a 34-year-old man of Nilo-Hamitic ethnicity who presented to our unit with paraplegia following injury from the collapse of a concrete wall. Radiographic images showed spondyloptosis at the fourth lumbar vertebral level. He underwent surgery where decompression, reduction, posterior instrumentation and bone grafting through a posterior approach were done. He started regaining motor power 48 hours postoperatively. He is currently undergoing rehabilitation and is steadily improving, 2 months postoperatively. CONCLUSIONS: In limited-resource settings there is a tendency of "skilful neglect" of complex injuries. Where resources allow, surgical reconstruction of spondyloptosis should be attempted irrespective of the severity of the initial neurological deficit because there are chances of neurological improvement. PMID- 25528056 TI - Immunohistochemical determination of the miR-1290 target arylamine N acetyltransferase 1 (NAT1) as a prognostic biomarker in breast cancer. AB - BACKGROUND: There are many molecular differences between estrogen receptor alpha (ERalpha)-positive and ER-negative breast cancers. Recent analyses have shown that the former can be divided into two subtypes, luminal A and luminal B. These differ in response to endocrine therapy and chemotherapy, and in prognosis. In a previous study, we found that microRNA (miR)-1290 that was significantly down regulated in luminal A tumors and its potential target arylamine N acetyltransferase 1 (NAT1). The aim of the present study was to determine whether NAT1 is a bona fide target of miR-1290, and to investigate the impact of NAT1 on breast cancer prognosis. METHODS: Luciferase reporter assays were employed to validate NAT1 as a putative miR-1290 target gene. Expression of NAT1, ERalpha, progesterone receptor (PgR) and HER2 was analyzed in 394 breast cancer samples by immunohistochemistry. RESULTS: NAT1 was confirmed to be a direct target of miR 1290. Levels of expression of NAT1 were positively correlated with those of ERalpha (P < 0.0001) and PgR (P < 0.0001), but negatively correlated with both tumor grade and size (P < 0.0001). Kaplan-Meier analysis showed that the presence of NAT1 was significantly associated with increased overall survival (OS) (P = 0.0416) in these patients. Similarly, significant associations of NAT1 with disease-free survival (DFS) (P = 0.0048) and OS (P = 0.0055) in those patients who received adjuvant endocrine therapy with tamoxifen (n = 176) were found. Moreover, NAT1 was also significantly associated with increased DFS (P = 0.0025) and OS (P = 0.0007) in the subset of lymph node-positive patients (n = 147). Univariate and multivariate analyses showed significant associations between levels of NAT1 and DFS (P = 0.0005 and 0.019, respectively). CONCLUSIONS: We report that miR-1290 directly targets the NAT1 3'-UTR and that NAT1 protein expression is correlated with improved OS of breast cancer patients. NAT1 is a possible prognostic biomarker for lymph node-positive breast cancer. Thus, miR 1290 and its target NAT1 are associated with important characteristics of breast cancer. PMID- 25528057 TI - Thriving beyond survival: understanding utilization of perinatal health services as predictors of birth registration: a cross-sectional study. AB - BACKGROUND: There are an estimated 35 million unregistered children in Indonesia. To understand ways to best leverage existing health system-related resources and ensure greater protective measures for these vulnerable children, this study explores the predictive relationship between the utilization of perinatal health services and birth certificate ownership in two Indonesian provinces. METHODS: This study employed a cross-sectional design with interviewer-administered household surveys to heads of households in West Nusa Tenggara and East Nusa Tenggara from May to July of 2013. The primary outcome of interest was birth certificate ownership among children under the age of 5 years old. Bivariate and multivariable regression analyses using Generalized Estimating Equations (GEE) considered a set of covariates that represented child and household socio demographic characteristics along with health services utilization variables during pregnancy and post-pregnancy periods. RESULTS: 389 heads of households were interviewed, yielding data on a sample of 451 children under the age of 5. Fewer than 28% of children in this sample possessed a birth certificate. Nearly 57% (n = 259) of children were delivered in a clinical facility, though only 36% (n = 93) of these were legally registered. Of children born in the home (n = 194), registration dropped to 16% (n = 31). Adjusted analyses accounting for socio-demographic factors suggest that children born in a clinic facility (AOR = 2.33, 95% CI: 1.27, 4.33), hospital (AOR = 2.38, 95% CI: 1.12, 5.09), or in the presence of a skilled birth attendant (AOR = 2.35, 95% CI: 1.31, 4.23) were significantly more likely to be registered. Children whose mothers sought post natal care were 2.99 times more likely to possess a birth certificate (AOR = 2.99, 95% CI: 1.1, 7.57). Pre-natal care was not associated with birth registration. CONCLUSION: These findings suggest that use of perinatal health services increases the likelihood of registering a child's birth despite a lack of formal integration of vital registration with the health sector. Formally leveraging existing community-based health workers and perinatal services may serve to further increase registration rates in hard to reach areas of Indonesia. PMID- 25528058 TI - A realist review of educational interventions to improve the delivery of nutrition care by doctors and future doctors. AB - BACKGROUND: Dietary interventions are considered an important aspect of clinical practice, more so in the face of the rising prevalence of obesity, diabetes and cardiovascular diseases globally. Routinely, most doctors do not provide such intervention to their patients, and several barriers, present during both training and clinical practice, have been identified. Educational interventions to improve nutrition care competencies and delivery have been implemented but with variable success, probably, due to the complex nature of such interventions. Using traditional methods only to investigate whether interventions are effective or not could not provide appropriate lessons. It is therefore pertinent to conduct a realist review that investigates how the interventions work. This realist review aims at determining what sort of educational interventions work, how, for whom, and in what circumstances, to improve the delivery of nutrition care by doctors and future doctors. METHODS/DESIGN: This realist review will be conducted according to Pawson's five practical steps for conducting a realist review: (1) clarifying the scope of the review, (2) determining the search strategy, including adopting broad inclusion/exclusion criteria and purposive snowballing techniques, (3) ensuring proper article selection and study quality assessment using multiple methods, (4) extracting and organising data through the process of note taking, annotation and conceptualization and (5) synthesising the evidence and drawing conclusions through a process of reasoning. This realist review protocol has not been registered in any database before now. DISCUSSION: Findings will be reported according to the publication criteria outlined by the realist and meta-narrative evidence synthesis (RAMESES) group. PMID- 25528059 TI - Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy. AB - Although our recent studies have demonstrated that NOD2 is one of the critical components of a signal transduction pathway that links renal injury to inflammation in diabetic nephropathy (DN), the regulatory mechanisms for NOD2 expression under hyperglycemia have not yet been elucidated. Considering that NOD2 mRNA from different species bears a long 3'-UTR with various AU-rich elements, the present study was designed to investigate the potential contribution of the RNA-binding protein human antigen R (HuR) on the posttranscriptional regulation of NOD2 expression. In this study, we first found upregulation of HuR in the kidney from DN subjects, which was correlated with proteinuria, indicating a role for HuR in the pathogenesis of DN. In vitro, high glucose (HG) induced a distinct increase in cytoplasmic HuR in rat glomerular mesangial cells. By RNA EMSA, we found that HuR bound to the 3'-UTR of NOD2, and HuR silencing reduced HG-induced NOD2 expression and mRNA stability. Mechanistically, we further found that NADPH oxidase-mediated redox signaling contributed to the expression and translocation of HuR and NOD2 mRNA stability. Finally, we evaluated the role of HuR showing that in vivo gene silencing of HuR by intrarenal lentiviral gene delivery ameliorated renal injury as well as reducing NOD2 expression in diabetic rats. Collectively, our studies demonstrate that HuR acts as a key posttranscriptional regulator of NOD2 expression, suggesting that targeting of HuR-NOD2 signaling might be crucial for the treatment of DN. PMID- 25528060 TI - Towards a comprehensive characterization of durum wheat landraces in Moroccan traditional agrosystems: analysing genetic diversity in the light of geography, farmers' taxonomy and tetraploid wheat domestication history. AB - BACKGROUND: Crop diversity managed by smallholder farmers in traditional agrosystems is the outcome of historical and current processes interacting at various spatial scales, and influenced by factors such as farming practices and environmental pressures. Only recently have studies started to consider the complexity of these processes instead of simply describing diversity for breeding purposes. A first step in that aim is to add multiple references to the collection of genetic data, including the farmers' varietal taxonomy and practices and the historical background of the crop. RESULTS: On the basis of interview data collected in a previous study, we sampled 166 populations of durum wheat varieties in two traditional Moroccan agrosystems, in the Pre-Rif and Atlas Mountains regions. Using a common garden experiment, we detected a high phenotypic variability on traits indicative of taxonomical position and breeding status, namely spike shape and plant height. Populations often combined modern (short) with traditional-like (tall) statures, and classical durum squared spike shape (5 flowers/spikelet) with flat spike shape (3 flowers/ spikelet) representative of primitive domesticated tetraploid wheat (ssp. dicoccum). By contrast, the genetic diversity assessed using 14 microsatellite markers was relatively limited. When compared to the genetic diversity found in a large collection of tetraploid wheat, it corresponded to free-threshing tetraploid wheat. Within Morocco, the two studied regions differed for both genetic diversity and variety names. Within regions, neither geography nor variety names nor even breeding status constituted strong barriers to gene exchange despite a few significant patterns. CONCLUSIONS: This first assessment of morphological and genetic diversity allowed pointing out some important factors that may have influenced the structure and evolutionary dynamics of durum wheat in Morocco: the significance of variety names, the occurrence of mixtures within populations, the relative strength of seed exchange between farmers and local adaptation, as well as the fate of modern varieties once they have been introduced. Further, multidisciplinary studies at different spatial scales are needed to better understand these complex agrosystems of invaluable importance for food security. PMID- 25528061 TI - The impact of coronary artery disease risk loci on ischemic heart failure severity and prognosis: association analysis in the COntrolled ROsuvastatin multiNAtional trial in heart failure (CORONA). AB - BACKGROUND: Recent genome-wide association studies have identified multiple loci that are associated with an increased risk of developing coronary artery disease (CAD). The impact of these loci on the disease severity and prognosis of ischemic heart failure due to CAD is currently unknown. METHODS: We undertook association analysis of 7 single nucleotide polymorphism (rs599839, rs17465637, rs2972147, rs6922269, rs1333049, rs501120, and rs17228212) at 7 well established CAD risk loci (1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21, and 15q22.33, respectively) in 3,320 subjects diagnosed with systolic heart failure of ischemic aetiology and participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) trial. The primary outcome was the composite of time to first event of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, secondary outcomes included mortality and hospitalization due to worsening heart failure. RESULTS: None of the 7 loci were significantly associated with the primary composite endpoint of the CORONA trial (death from cardiovascular cases, nonfatal myocardial infarction, and nonfatal stroke). However, the 1p13.3 locus (rs599839) showed evidence for association with all-cause mortality (after adjustment for covariates; HR 0.74, 95%CI [0.61 to 0.90]; P = 0.0025) and we confirmed the 1p13.3 locus (rs599839) to be associated with lipid parameters (total cholesterol (P = 1.1x10(-4)), low-density lipoprotein levels (P = 3.5 * 10(-7)) and apolipoprotein B (P = 2.2 * 10(-10))). CONCLUSION: Genetic variants strongly associated with CAD risk are not associated with the severity and outcome of ischemic heart failure. The observed association of the 1p13.3 locus with all-cause mortality requires confirmation in further studies. PMID- 25528062 TI - Prenatal administration of lipopolysaccharide induces sex-dependent changes in glutamic acid decarboxylase and parvalbumin in the adult rat brain. AB - RATIONALE: Recent clinical studies suggest GABA-ergic system abnormalities as a neuropathological mechanism of schizophrenia. OBJECTIVES: In the present study, we examined the effect of chronic prenatal lipopolysaccharide (LPS) administration on immunohistochemical changes of glutamate decarboxylase (GAD67) and parvalbumin (PV)-expressing neurons in the medial prefrontal cortex and hippocampus of rats. RESULTS: These data demonstrated that prenatal LPS administration during the final 2 weeks of pregnancy induced schizophrenia-like behavioral symptoms, such as deficits in sensorimotor gating (prepulse inhibition) and impairments in social interactions and exploration, in adult offspring. Moreover, immunohistochemical analysis revealed that in our neurodevelopmental model of schizophrenia, decreases in the total number of PV- and GAD67-positive neurons in the medial prefrontal cortices of adult females prenatally exposed to LPS were observed, whereas these immunochemical changes were primarily detected in the hippocampus of males. Additionally, a decrease in PV-labeled axon terminals of GABA-ergic cells, likely reflecting the perisomatic inhibitory innervation of pyramidal neurons, was observed in the medial prefrontal cortices in both sexes. CONCLUSION: This study provided evidence of a key role for the GABA system in neurodevelopment associated with the etiopathogenesis of schizophrenia and showed that the observed changes are sex dependent. Moreover, this study is the first to present a model of schizophrenia based on prenatal LPS administration, which not only produced behavioral abnormalities but also changed the cytoarchitecture of the GABA inhibitory system. PMID- 25528063 TI - Theoretical analyses of cellular transmembrane voltage in suspensions induced by high-frequency fields. AB - A change of the transmembrane voltage is considered to cause biophysical and biochemical responses in cells. The present study focuses on the cellular transmembrane voltage (Deltaphi) induced by external fields. We detail analytical equations for the transmembrane voltage induced by external high-frequency (above the relaxation frequency of the cell membrane) fields on cells of a spherical shape in suspensions and layers. At direct current (DC) and low frequencies, the cell membrane was assumed to be non-conductive under physiologic conditions. However, with increasing frequency, the permittivity of the cytoplasm/extracellular medium and conductivity of the membrane must be accounted for. Our main work is to extend application of the analytical solution of Deltaphi to the high-frequency range. We first introduce the transmembrane voltage generated by DC and low-frequency exposures on a single cell. Then, we focus on cell suspensions exposed to high-frequency fields. Using the effective medium theory and the reasonable assumption, the approximate analytical solution of Deltaphi on cells in suspensions and layers can be derived. Phenomenological effective medium theory equations cannot be used to calculate the local electric field of cell suspensions, so we raised a possible solution based on the Bergman theory. PMID- 25528064 TI - Aging, confidence, and misinformation: recalling information with the cognitive interview. AB - In 2 experiments, younger and older adults witnessed a simulated robbery, received misleading information about the event, and then were interviewed with the Cognitive Interview about their memory for the robbery. In both experiments, older adults were disproportionately more confident than younger adults in the accuracy of incorrect information that they recalled than in the accuracy of correct information. Critically, this age-related increase in high-confidence errors occurred even in comparison with younger adults who were matched with older adults on the overall amount and accuracy of the information remembered about the robbery. In addition, Experiment 2 showed that retrieval warnings to disregard the misinformation were just as effective in older adults as compared with younger adults at reducing the reporting of misleading information. Finally, both experiments showed that across the multiple retrieval stages of the Cognitive Interview, the final retrieval stage is roughly half as effective for older adults relative to younger adults at eliciting previously unreported information. These results indicate that investigators have much less to gain from older adults than they do from younger adults with repeated inquiries (during the same session) about a witnessed event. PMID- 25528065 TI - Age differences and longitudinal change in the effects of data collection mode on self-reports of psychosocial functioning. AB - The current study investigated age differences and longitudinal change in mode effects, wherein individuals report less negative and more positive psychosocial functioning with data collection modes that have greater (vs. less) direct contact with interviewers (e.g., in-person interviews vs. telephone interviews). Using 2 longitudinal datasets, the Later Life Study of Social Exchanges (LLSSE) and Swedish Adoption/Twin Study of Aging (SATSA), we tested how mode effects may vary with cohort (baseline age differences) and maturational development (longitudinal change). In Study 1, LLSSE participants (65-90 years old) completed in-person and telephone interviews assessing negative and positive aspects of psychosocial functioning across 2 years. The data collection mode with greater direct contact with interviewers (in-person interviews) was associated with reporting less negative and more positive psychosocial functioning compared to the mode with less direct contact (telephone interviews). These mode effects were more pronounced with older baseline age, but only for the negative psychosocial measures. Mode effects also became stronger over time for reports of negative affect. In Study 2, SATSA participants (38-86 years old) completed mailed questionnaires and questionnaires collected in-person that assessed depressive symptoms and positive affect across 18 years. Consistent with Study 1, participants reported fewer depressive symptoms and more positive affect with greater (vs. less) direct contact with interviewers (questionnaires collected in person vs. mailed questionnaires). For reports of depressive symptoms, but not positive affect, mode effects were more pronounced with age and time. Together, the results underscore how mode effects may contribute to inconsistent findings in the socioemotional aging literature. PMID- 25528066 TI - Effects of healthy ageing on precision and binding of object location in visual short term memory. AB - Visual short term memory (STM) declines as people get older, but the nature of this deterioration is not well understood. We tested 139 healthy subjects (19-83 years) who were first required to identify a previously seen object and then report its location using a touchscreen. Results demonstrated an age-related decline in both object identification and localization. Deterioration in localization performance was apparent even when only 1 item had to be remembered, worsening disproportionately with increasing memory load. Thus, age-dependent memory degradation cannot be explained simply by a decrease in the number of items that can be held in visual STM but rather by the precision with which they are recalled. More important, there was no evidence for a significant decrease in object-location binding with increasing age. Thus, although precision for object identity and location declines with age, the ability to associate object identity to its location seems to remain unimpaired. As it has been reported that binding deficits in STM might be the first cognitive signs of early Alzheimer's disease (AD), the finding that object-location binding processes are relatively intact with normal aging supports the possible suitability of using misbinding as an index measures for probing early diagnosis of AD. PMID- 25528067 TI - Benchmarking of gastric cancer sensitivity to anti-cancer drugs ex vivo as a basis for drug selection in systemic and intraperitoneal therapy. AB - BACKGROUND: The choice of drugs for treatment of advanced gastric cancer (GC) is empirical. The purpose of the current study was to benchmark ex vivo the sensitivity of GC tumor cells from patients to standard cytotoxic and some newly introduced targeted drugs (TDs), as a basis for drug selection in the treatment of GC. METHODS: Tumor cell samples from patients with GC were analyzed for sensitivity to 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, mitomycin C, doxorubicin and docetaxel as well as for the targeted drugs bortezomib, sorafenib, sunitinib and rapamycin using a short-term in vitro assay based on retention of viable tumor cells of fluorescent fluorescein. Samples of normal mononuclear cells, chronic lymphocytic leukemia, ovarian cancer and colorectal cancer were included for comparison. RESULTS: The GC samples were essentially as sensitive to the standard drugs and the TDs as those from colorectal cancer whereas the ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the clinically used standard drugs. In GC, cisplatin was cross-resistant to oxaliplatin and 5 fluorouracil which, on the other hand, was not cross-resistant to the other cytotoxic drugs. The activity of sunitinib did not obviously correlate to that of the standard drugs. CONCLUSION: Ex vivo assessment of drug sensitivity of tumor cells from patients with GC is feasible and may provide information that could be useful for selection of drugs for treatment. Drug sensitivity varies considerably between and within individual samples arguing for individualized selection of drugs for chemotherapy. PMID- 25528068 TI - Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. AB - BACKGROUND: Thrombophilia is reported to be a candidate etiology of recurrent pregnancy loss (RPL). No conclusive results on the association between prothrombin G20210A mutation and RPL have been reported. METHODS: We undertook a systematic review and meta-analysis of 37 case-control studies using a comprehensive electronic search on papers published by May 2014. We studied 5400 cases and 4640 controls to investigate the potential association between G20210A and RPL. In this review, we define RPL as more than 2 miscarriages. RESULTS: A significant association was found between G20210A and RPL, with a combined odds ratio (OR) of 1.81 (95% confidence interval [CI]: 1.26-2.60). However, the risks differed in the subgroup analyses, categorized by study sites, maternal age, and type of miscarriages. The pooled OR remained significant in European studies (OR: 1.80, 95% CI: 1.35-2.41), whereas in the Middle-Eastern studies, it was not significant (OR: 2.39, 95% CI: 0.96-5.92). The risk of RPL was significantly higher in women older than 29 years (OR: 1.91, 95% CI: 1.61-6.11), and a positive relationship was only observed between prothrombin G20210A mutation and fetal loss, but not embryonic loss. There was no evidence of publication bias in any of the analyses. The sensitivity analyses showed that the findings were quite stable. CONCLUSION: This meta-analysis suggests that the G20210A prothrombin mutation increases the risk of RPL (fetal loss, primary RPL, or secondary RPL), particularly in Europeans and women older than 29 years. We recommend further screening in more specific groups among women. PMID- 25528069 TI - Thrombotic events in acute promyelocytic leukemia. AB - INTRODUCTION: Thrombotic events (TE) appear to be more common in acute promyelocytic leukemia (APL) than in other acute leukemias, with reported prevalence ranging from 2 to 10-15%. MATERIALS AND METHODS: We retrospectively analyzed the data on TE appearance in 63 APL patients. RESULTS: TE occured in 13 (20.6%) cases, four arterial (6.3%) and nine venous (14.3%). TE were more frequently diagnosed after initiation of weekly D-dimer monitoring (7 TE during 20 months vs 6 during 76 months, P=0.032). Patients with and without venous thrombosis were significantly different regarding female/male ratio (P=0.046), PT (P=0.022), aPTT (P=0.044), ISTH DIC score (P=0.001), bcr3 (P=0.02) and FLT3-ITD (P=0.028) mutation. The most significant risk factor for venous TE occurrence in multivariate analysis was FLT3-ITD mutation (P=0.034). PAI-1 4G/4G polymorphism was five times more frequent in patients with venous TE than without it (P=0.05). Regarding risk factors for arterial TE we failed to identify any. CONCLUSIONS: We have demonstrated that APL-related TE rate is higher than previously reported and that weekly D-dimer monitoring might help to identify patients with silent thrombosis. Moreover, our study suggests a possible relationship between venous TE occurrence and several laboratory findings (PT, aPTT, ISTH DIC score, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G). Prophylactic use of heparin might be considered in patients with ISTH DIC score<5, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G. PMID- 25528070 TI - Prevalence and risk factors for post thrombotic syndrome after deep vein thrombosis in children: a cohort study. AB - BACKGROUND: While post thrombotic syndrome (PTS) is increasingly recognized as a frequent and potentially serious complication of deep vein thrombosis (DVT) in children, limited information is available regarding predictors of PTS. METHODS: Using the Mayo Clinic Master Diagnostic Index, all pediatric patients (age 0 to 18 years) with a potential DVT based on ICD-8 codes over the 15-year period, 1995 to 2009 were identified. A validated PTS survey instrument was mailed to eligible patients followed by a second mailing and three reminder phone calls for non responders. Baseline clinical and radiographic characteristics were abstracted from patient medical records and tested as potential predictors of PTS using logistic regression. Associations were summarized by calculating odds ratios (OR) and corresponding 95% confidence intervals. RESULTS: Ninety patients agreed to participate. The mean age (+/-SD) at DVT diagnosis and survey completion were 12.8 (+/-6.1) and 19.3 (+/-7.7) years, respectively. Fifty three respondents (59%) reported mild PTS whereas 12 (13%) reported moderate-to-severe PTS. Pain (34%) and dilated blood vessels (40%) were the most frequent PTS symptom and sign, respectively. On multivariate analysis, predictors of PTS included duration between incident DVT and survey completion (OR 1.75; 95% CI: 1.08-2.84) and number of thrombosed vein segments (OR 1.40; 95% CI: 1.05-1.86). CONCLUSION: Over 70% of children with DVT report subsequent symptoms or signs of PTS, though only 13% report clinically significant, moderate-to-severe PTS. Number of thrombosed vein segments at diagnosis and time duration between incident DVT and survey completion were independent predictors of PTS. PMID- 25528071 TI - Preparation and chromatographic performance evaluation of cucurbit[7]uril immobilized silica. AB - Cucurbit[7]uril (CB7), one host macromolecule, possesses a hydrophobic inner cavity and two identical hydrophilic carbonyl fringe portals, thus interacting with a variety of guest molecules through hydrophobic, hydrogen bonding and ion dipole interactions. These characteristics make CB7 a good candidate as the stationary phase (SP) modifier in high performance liquid chromatography (HPLC). In the present work, CB7 was immobilized onto silica (CB7-SiO2) by a sol-gel approach. The obtained CB7-SiO2 was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis and elemental analysis. The chromatographic performance of CB7-SiO2 was then studied in detail, in both reversed phase (RP) and hydrophilic interaction liquid chromatographic (HILIC) modes. For probe aromatic compounds and dyes, the typical RP behavior was observed, mainly due to the predominant hydrophobic interaction between the analytes and CB7-SiO2. For probe alkaloids, the "U-shape" curves were obtained; in the methanol-rich part, HILIC performance was obvious, probably owing to hydrogen bonding and ion-dipole interactions. Compared to bare SiO2 SP, the stronger retention and different selectivity were observed on CB7-SiO2. The CB7 SiO2 SP remained stable within at least 11,000 column volumes of the MP, revealing the satisfactory stability of it. The proposed method integrated the advantages of CB7 and sol-gel method provided a feasible way for the wider application of CBs in separation science. PMID- 25528072 TI - Magnetomotive room temperature dicationic ionic liquid: a new concept toward centrifuge-less dispersive liquid-liquid microextraction. AB - A new centrifuge-less dispersive liquid-liquid microextraction technique based on application of magnetomotive room temperature dicationic ionic liquid followed by electrothermal atomic absorption spectrometry (ETAAS) was developed for preconcentration and determination of trace amount of gold and silver in water and ore samples, for the first time. Magnetic ionic liquids not only have the excellent properties of ionic liquids but also exhibit strong response to an external magnetic field. These properties provide more advantages and potential application prospects for magnetic ionic liquids than conventional ones in the fields of extraction processes. In this work, thio-Michler's ketone (TMK) was used as chelating agent to form Ag/Au-TMK complexes. Several important factors affecting extraction efficiency including extraction time, rate of vortex agitator, pH of sample solution, concentration of the chelating agent, volume of ionic liquid as well as effects of interfering species were investigated and optimized. Under the optimal conditions, the limits of detection (LOD) were 3.2 and 7.3ngL(-1) with the preconcentration factors of 245 and 240 for Au and Ag, respectively. The precision values (RSD%, n=7) were 5.3% and 5.8% at the concentration level of 0.05MUgL(-1) for Au and Ag, respectively. The relative recoveries for the spiked samples were in the acceptable range of 96-104.5%. The results demonstrated that except Hg(2+), no remarkable interferences are created by other various ions in the determination of Au and Ag, so that the tolerance limits (WIon/WAu or Ag) of major cations and anions were in the range of 250 1000. The validated method was successfully applied for the analysis of Au and Ag in some water and ore samples. PMID- 25528073 TI - Family functioning in the context of parental bipolar disorder: associations with offspring age, sex, and psychopathology. AB - Previous research has shown that families with a parent who has bipolar disorder (BD) may experience family functioning difficulties. However, the association between family functioning and psychopathology among offspring of parents with BD, and offspring characteristics that may moderate this association, remains poorly understood. This study examined the cross-sectional associations between family functioning (cohesion, expressiveness, and conflict) and psychopathology in 117 offspring (ages 5-18) of 75 parents with BD. We also examined whether age and sex differences moderated these associations. We measured offspring psychopathology by examining current dimensional symptoms and DSM-IV emotional and behavioral disorders. Correlational analyses indicated that higher family conflict and lower cohesion were associated with higher internalizing and externalizing symptoms in offspring. Lower family cohesion was also associated with current offspring mood disorders. Moderation analyses indicated, first, that the link between lower family cohesion and internalizing symptoms was stronger for younger offspring compared to older offspring. Second, higher family conflict and current mood disorder were associated in younger males but not in older males or in females. Results remained the same after controlling for parental anxiety or substance use disorder comorbidity. Our study highlights the importance of accounting for family functioning when working with offspring at risk for BD, while also recognizing that the connections between family functioning and offspring outcomes are complex and differ based on offspring sex and developmental stage. PMID- 25528074 TI - Capitalizing on everyday positive events uniquely predicts daily intimacy and well-being in couples coping with breast cancer. AB - Capitalization is the relational process of savoring positive life events by sharing them with responsive relationship partners. The purpose of the present study was to use dyadic intensive longitudinal methods to examine novel hypotheses regarding links between capitalization processes and daily intimacy and well-being in women with breast cancer and their intimate partners. Although couples coping with cancer often experience an increase in negative daily life events, we hypothesized that it would be important for them to share and capitalize on positive events in addition to sharing negative events. Female patients with early stage breast cancer and their intimate partners (99 couples) completed electronic daily diaries for 7 to 10 consecutive days tapping everyday processes of sharing negative and positive events with each other. Dyadic multilevel process modeling revealed that on days when capitalization attempts (i.e., sharing the best event of the day) occurred, daily feelings of intimacy in the sharer were higher for both patients and partners. Moreover, greater perceived partner responsiveness to capitalization attempts was associated with increases in the sharer's daily feelings of intimacy and decreases in the sharer's daily negative affect. When the patient's partner was the sharer, perceived partner responsiveness also was associated with increased daily positive affect. More important, all effects of capitalization were observed above and beyond the effects of event positivity and sharing negative events (i.e., social support attempts). Findings suggest that, even in the midst of significant life adversity, sharing daily good news with intimate partners enhances relationship well-being independently of sharing bad news. PMID- 25528075 TI - Children exposed to intimate partner violence: influences of parenting, family distress, and siblings. AB - The aim of this study was to investigate associations between maternal stress, parenting behavior, and sibling adjustment in relation to child trauma symptoms in families with and without a history of intimate partner violence (IPV). Maternal report was used to measure maternal stress and child trauma symptoms, whereas parenting behavior was assessed through an observational measure. Participants consisted of mothers with 2 school-age siblings recruited from the community. Results indicated that violent families reported higher levels of maternal stress and sibling trauma symptoms than nonviolent families, although no differences were found in parenting behavior. Sibling trauma symptoms and negative maternal behavior toward a sibling were strong predictors of trauma symptoms in younger siblings exposed to IPV but only modest predictors for older siblings. Moderator analyses showed that in IPV-affected families, the trauma symptoms of older siblings were related to the trauma symptoms of younger siblings when maternal stress was high. PMID- 25528076 TI - Saving time and preventing mistakes. PMID- 25528077 TI - Should we include social media in higher education? PMID- 25528078 TI - Nutrition education intervention for women with breast cancer: effect on nutritional factors and oxidative stress. AB - OBJECTIVES: To assess the effect of a nutrition education intervention on nutritional factors and oxidative stress during treatment of breast cancer. DESIGN: Nonrandomized clinical trial conducted in 2010-2011, including an evaluation at baseline and after 12 months. PARTICIPANTS: Women from Brazil who had breast cancer, divided into an intervention group (IG) (n = 18) and comparison group (n = 75). INTERVENTION: To increase intake of fruits and vegetables and reduce red and processed meats, via telephone and printed materials. MAIN OUTCOME MEASURES: Food intake, anthropometry, and levels of lipid hydroperoxide, carbonyl proteins, reduced glutathione, and ferric reducing antioxidant power. ANALYSES: Chi-square, Mann-Whitney or t tests for baseline data; Wilcoxon or paired t tests for intra-group outcomes, linear regression models, and Bonferroni multiplicity adjustment. RESULTS: The researchers observed an increase in fruit and vegetable intake, reduction in red and processed meat intake, no change in body weight, and an increase in glutathione in the IG over the comparison group. However, after Bonferroni adjustment, only the consumption of fruits and vegetables and fruit was significantly higher in IG. CONCLUSIONS AND IMPLICATIONS: This study presents improved dietary changes after a theory driven nutrition education intervention. Although the sample size is small, it has proven to be clinically relevant. PMID- 25528079 TI - Potential population-level nutritional impact of replacing whole and reduced-fat milk with low-fat and skim milk among US children aged 2-19 years. AB - OBJECTIVE: Dietary guidance emphasizes plain low-fat and skim milk over whole, reduced-fat, and flavored milk (milk eligible for replacement [MER]). The objective of this study was to evaluate the population-level impact of such a change on energy, macronutrient and nutrient intakes, and diet cost. DESIGN: Cross-sectional modeling study. SETTING: Data from the 2001-2002 and 2003-2004 National Health and Nutrition Examination Survey. PARTICIPANTS: A total of 8,112 children aged 2-19 years. MAIN OUTCOME MEASURES: Energy, macronutrient, and micronutrient intake before and after replacement of MER with low-fat or skim milk. ANALYSIS: Survey-weighted linear regression models. RESULTS: Milk eligible for replacement accounted for 46% of dairy servings. Among MER consumers, replacement with skim or low-fat milk would lead to a projected reduction in energy of 113 (95% confidence interval [CI], 107-119) and 77 (95% CI, 73-82) kcal/d and percent energy from saturated fat by an absolute value of 2.5% of total energy (95% CI, 2.4-2.6) and 1.4% (95% CI, 1.3-1.5), respectively. Replacement of MER does not change diet costs or calcium and potassium intake. CONCLUSIONS: Substitution of MER has the potential to reduce energy and total and saturated fat intake with no impact on diet costs or micronutrient density. The feasibility of such replacement has not been examined and there may be negative consequences if replacement is done with non-nutrient-rich beverages. PMID- 25528080 TI - Association between pupillary light reflex and sensory behaviors in children with autism spectrum disorders. AB - Atypical pupillary light reflexes (PLR) has been observed in children with autism spectrum disorders (ASD), which suggests potential autonomic nervous system (ANS) dysfunction in ASD. ANS is also involved in modulating sensory processing and sensory dysfunction has been widely reported in children with ASD. However, the potential association between physiological measurements of PLR and behavioral observations (e.g. sensory behaviors) has not been examined extensively in literature. In this study, we investigated the potential correlation between PLR and frequently observed sensory behaviors in children with ASD. We found a significant association between PLR constriction amplitude and a set of sensory behaviors in the ASD group but not in typically developing children. Children with ASD who showed more atypical sensory behaviors also had smaller PLR constriction amplitudes. A smaller PLR constriction amplitude suggests lower parasympathetic modulation. This observation implies that some atypical sensory behaviors in children with ASD could be associated with decreased parasympathetic modulation. PMID- 25528081 TI - When words lead to solutions: executive function deficits in preschool children with specific language impairment. AB - Several studies indicate that school-age children with specific language impairment (SLI) have difficulties with tasks that rely on executive functions. Whether executive function deficits in children with SLI emerge during preschool age remains unclear. Our aim was to fill this gap by investigating executive function performances in two age groups of preschoolers with and without SLI. Children with SLI (N=60; young: 53.6+/-5.3 months; old: 65.4+/-3.8 months) and age-matched control children (N=58) were tested for problem-representation ability, using the Flexible Item Selection Task (FIST), rule-use skills, using a Stroop-like Day-Night test (D/N), and planning skills, using the Tower of London test (TOL). Older children performed better than younger children did across tasks. Children with SLI had poorer performance, compared to typically developing children, on measures of problem representation, planning skills, and use of rules. Our results clearly indicate that executive function impairment is evident during the preschool period. Although old children with SLI performed better than young children with SLI, their performances were still poor, compared to those of control peers. These findings suggest that children with SLI have altered executive functioning at 53.6 months. PMID- 25528082 TI - Effects of declared levels of physical activity on quality of life of individuals with intellectual disabilities. AB - Routine physical fitness improves health and psychosocial well-being of individuals with intellectual and developmental disabilities. The current study investigated impact of physical fitness on quality of life by comparing individuals who maintain a physically active lifestyle with those who do not report exercising. We assessed several indicators of quality of life, including inclusion and community participation; satisfaction with professional services, home life, and day activities; dignity, rights, and respect received from others; fear; choice and control; and family satisfaction. Our data suggested that individuals who regularly exercise reported having more frequent outings into the community than did their peers who reported exercising infrequently; regular exercisers were also more likely to live in intermediate care facilities (ICF) as opposed to living independently or with family members. We discuss possible reasons for this as well as ideas for future research needed to expand on this area. PMID- 25528083 TI - Flexible conflict management: conflict avoidance and conflict adjustment in reactive cognitive control. AB - Conflict processing is assumed to serve two crucial, yet distinct functions: Regarding task performance, control is adjusted to overcome the conflict. Regarding task choice, control is harnessed to bias decision making away from the source of conflict. Despite recent theoretical progress, until now two lines of research addressed these conflict-management strategies independently of each other. In this research, we used a voluntary task-switching paradigm in combination with response interference tasks to study both strategies in concert. In Experiment 1, participants chose between two univalent tasks on each trial. Switch rates increased following conflict trials, indicating avoidance of conflict. Furthermore, congruency effects in reaction times and error rates were reduced following conflict trials, demonstrating conflict adjustment. In Experiment 2, we used bivalent instead of univalent stimuli. Conflict adjustment in task performance was unaffected by this manipulation, but conflict avoidance was not observed. Instead, task switches were reduced after conflict trials. In Experiment 3, we used tasks comprising univalent or bivalent stimuli. Only tasks with univalent revealed conflict avoidance, whereas conflict adjustment was found for all tasks. On the basis of established theories of cognitive control, an integrative process model is described that can account for flexible conflict management. PMID- 25528084 TI - Fast and careless or careful and slow? Apparent holistic processing in mental rotation is explained by speed-accuracy trade-offs. AB - A major debate in the mental-rotation literature concerns the question of whether objects are represented holistically during rotation. Effects of object complexity on rotational speed are considered strong evidence against such holistic representations. In Experiment 1, such an effect of object complexity was markedly present. A closer look on individual performance patterns, however, revealed that only some participants showed this effect. For others, rotational speed was independent of object complexity. The assumption that these fast rotating participants use a holistic representation that equally well holds simple and complex objects would explain these results. Taking error rates into account disproved this explanation: Fast participants simply committed more errors in those conditions for which careful participants invested more rotation time. Whether this speed-accuracy trade-off is a stable personality trait or a somewhat flexible strategic choice was examined in Experiments 2 and 3. In Experiment 2, participants received monetary incentives that encouraged them to minimize errors. In line with a certain degree of flexible strategic control over speed-accuracy trade-offs, a large majority of participants showed effects of object complexity on rotational speed. When, in contrast, time pressure was induced in Experiment 3, error rates increased considerably and most participants' rotational speed became independent of object complexity. Our results indicate that all our participants performed mental rotation on a nonholistic representation and that apparent holistic processing strategies in mental rotation (and potentially also in other spatial tasks) might actually be speed-accuracy trade-offs in disguise. PMID- 25528085 TI - Temporal and statistical information in causal structure learning. AB - Three experiments examined children's and adults' abilities to use statistical and temporal information to distinguish between common cause and causal chain structures. In Experiment 1, participants were provided with conditional probability information and/or temporal information and asked to infer the causal structure of a 3-variable mechanical system that operated probabilistically. Participants of all ages preferentially relied on the temporal pattern of events in their inferences, even if this conflicted with statistical information. In Experiments 2 and 3, participants observed a series of interventions on the system, which in these experiments operated deterministically. In Experiment 2, participants found it easier to use temporal pattern information than statistical information provided as a result of interventions. In Experiment 3, in which no temporal pattern information was provided, children from 6- to 7-years-old, but not younger children, were able to use intervention information to make causal chain judgments, although they had difficulty when the structure was a common cause. The findings suggest that participants, and children in particular, may find it more difficult to use statistical information than temporal pattern information because of its demands on information processing resources. However, there may also be an inherent preference for temporal information. PMID- 25528086 TI - Is it always me first? Effects of self-tagging on third-person perspective taking. AB - Self-relevant information is associated with facilitation of perceptual and memory processes. In 2 experiments, participants verified the number of dots within a virtual room that were visible to a given perspective, corresponding to participants' own first-person perspectives or the third-person perspectives for self- and other-associated avatars. Perspectives were either congruent or incongruent with respect to the number of dots visible to each. In Experiment 1, we examined perspective taking for self- and other-associated avatars relative to one another; both avatars appeared simultaneously in the virtual room, and participants made judgments based on the prompted avatar's perspective. In Experiment 2, we examined perspective taking for each avatar relative to the first-person perspective; only 1 avatar was visible in the virtual room (Self or Other, varying by trial), and participants made judgments based on their first person view or the avatar's perspective. Experiment 2 also included a replication of the third-person paradigm used in Experiment 1. Results from Experiment 1 (replicated in Experiment 2) demonstrated an advantage for judgments of the Self (vs. Other) avatar's perspective; both avatars elicited reliable interference effects of similar magnitude. Results from Experiment 2 further demonstrated that participants prioritized the first-person (vs. third-person) perspective, and that the presence of the Self (vs. Other) avatar improved performance for the first- and third-person perspectives when those perspectives were congruent. Taken together, these findings suggest that self-relevant perspectives are prioritized when they are actively engaged and when they can be subsumed within the first-person view. Such prioritization appears to occur by strategic means. PMID- 25528087 TI - Categorical biases in spatial memory: the role of certainty. AB - Memories for spatial locations often show systematic errors toward the central value of the surrounding region. The Category Adjustment (CA) model suggests that this bias is due to a Bayesian combination of categorical and metric information, which offers an optimal solution under conditions of uncertainty (Huttenlocher, Hedges, & Duncan, 1991). A fundamental assumption of this model is that representations of locations are unbiased but uncertain; during combination, greater metric uncertainty results in relatively greater emphasis on categorical information, ultimately leading to increased bias (but also minimizing error across multiple estimates). Sampaio and Wang (2009) have demonstrated that metric information is not lost during this combination process, supporting the CA model's assumption that underlying spatial representations are undistorted. Here, we examine the 2nd half of the CA model's central assumption: that increasing metric uncertainty drives the combination process. Participants recognized point locations within visually complex images in a 4-choice task. Our results indicate that individuals recognized the correct location over other, biased alternatives, confirming that metric information is unbiased at the time of retrieval. In addition, we found that, when participants make errors, they are more likely to select locations that are biased toward the category prototype. In Experiment 2, we demonstrate that categorically biased locations are most likely to be chosen under conditions of uncertainty. Indeed, under these conditions, categorically biased locations were chosen more frequently than the correct location. These results suggest that systematic errors are the result of combination across multiple levels of spatial representations that are undistorted but somewhat uncertain. PMID- 25528088 TI - The effect of processing fluency on impressions of familiarity and liking. AB - Processing fluency has been shown to have wide-ranging effects on disparate evaluative judgments, including judgments of liking and familiarity. One account of such effects is the hedonic marking hypothesis (Winkielman, Schwarz, Fazendeiro, & Reber, 2003), which posits that fluency is directly linked to affective preferences via a positive emotional reaction that is triggered by fluent processing. The evidence supporting this account suggests that fluency may exert a stronger influence on affective judgments than other judgments. The current study compared the effect of fluency on judgments of familiarity and liking. Contrary to predictions, liking judgments were not more strongly affected by fluency than familiarity judgments. In fact, the balance of the results showed the opposite pattern. When the type of judgment was manipulated between subjects (Experiment 1) or in a blocked design (Experiment 2), fluency had comparable effects on impressions of liking and familiarity. But when the type of judgment was manipulated in a mixed design (Experiments 3 and 6), or when both familiarity and liking judgments were given for all items (Experiments 4 and 5), only familiarity judgments were affected by the fluency manipulation. The dominance of the familiarity interpretation was found when fluency was manipulated artificially, via priming, and when inherent variations in fluency across the stimuli were considered. These results suggest that, within a given context, participants adopt a single interpretation for fluency, and the sense of familiarity that arises from fluent processing overshadows the sense of positivity, thus questioning aspects of the hedonic marking hypothesis. PMID- 25528089 TI - Is it harder to switch among a larger set of tasks? AB - When stimuli afford multiple tasks, switching among them involves promoting one of several task-sets in play into a most-active state. This process, often conceptualized as retrieving task parameters and stimulus-response (S-R) rules into procedural working memory, is a likely source of the reaction time (RT) cost of a task-switch, especially when no time is available for task preparation before the stimulus. We report 2 task-cuing experiments that asked whether the time consumed by task-set retrieval increases with the number of task-sets in play, while unconfounding the number of tasks with their frequency and recency of use. Participants were required to switch among 3 or 5 orthogonal classifications of perceptual attributes of an object (Experiment 1) or of phonological/semantic attributes of a word (Experiment 2), with a 100 or 1,300 ms cue-stimulus interval. For 2 tasks for which recency and frequency were matched in the 3- and 5-task conditions, there was no effect of number of tasks on the switch cost. For the other tasks, there was a greater switch cost in the 5-task condition with little time for preparation, attributable to effects of frequency/recency. Thus, retrieval time for active task-sets is not influenced by the number of alternatives per se (unlike several other kinds of memory retrieval) but is influenced by recency or frequency of use. PMID- 25528090 TI - How does creating a concept map affect item-specific encoding? AB - Concept mapping has become a popular learning tool. However, the processes underlying the task are poorly understood. In the present study, we examined the effect of creating a concept map on the processing of item-specific information. In 2 experiments, subjects learned categorized or ad hoc word lists by making pleasantness ratings, sorting words into categories, or creating a concept map. Memory was tested using a free recall test and a recognition memory test, which is considered to be especially sensitive to item-specific processing. Typically, tasks that promote item-specific processing enhance free recall of categorized lists, relative to category sorting. Concept mapping resulted in lower recall performance than both the pleasantness rating and category sorting condition for categorized words. Moreover, concept mapping resulted in lower recognition memory performance than the other 2 tasks. These results converge on the conclusion that creating a concept map disrupts the processing of item-specific information. PMID- 25528091 TI - Real-time processing of ASL signs: Delayed first language acquisition affects organization of the mental lexicon. AB - Sign language comprehension requires visual attention to the linguistic signal and visual attention to referents in the surrounding world, whereas these processes are divided between the auditory and visual modalities for spoken language comprehension. Additionally, the age-onset of first language acquisition and the quality and quantity of linguistic input for deaf individuals is highly heterogeneous, which is rarely the case for hearing learners of spoken languages. Little is known about how these modality and developmental factors affect real time lexical processing. In this study, we ask how these factors impact real-time recognition of American Sign Language (ASL) signs using a novel adaptation of the visual world paradigm in deaf adults who learned sign from birth (Experiment 1), and in deaf adults who were late-learners of ASL (Experiment 2). Results revealed that although both groups of signers demonstrated rapid, incremental processing of ASL signs, only native signers demonstrated early and robust activation of sublexical features of signs during real-time recognition. Our findings suggest that the organization of the mental lexicon into units of both form and meaning is a product of infant language learning and not the sensory and motor modality through which the linguistic signal is sent and received. PMID- 25528092 TI - First things first: similar list length and output order effects for verbal and nonverbal stimuli. AB - When participants are presented with a short list of unrelated words and they are instructed that they may recall in any order, they nevertheless show a very strong tendency to recall in forward serial order. Thus, if asked to recall in any order: "hat, mouse, tea, stairs," participants often respond "hat, mouse, tea, stairs" even though there was no forward order requirement of the task. In 4 experiments, we examined whether this tendency is language-specific, reflecting mechanisms involved with speech perception, speech production, and/or verbal short-term memory. Specifically, we examined whether we would observe similar findings when participants were asked to recall, in any order, lists of between 1 and 15 nonverbal stimuli, such as visuospatial locations (Experiment 1, Experiment 3, Experiment 4), or touched facial locations (Experiment 2). Contrary to a language-specific explanation, we found corresponding tendencies (albeit somewhat reduced) in the immediate free recall of these nonverbal stimuli. We conclude that the tendency to initiate recall of a short sequence of items with the first item is a general property of memory, which may be augmented by verbal coding. PMID- 25528094 TI - Predicting the unbeaten path through syntactic priming. AB - A number of previous studies showed that comprehenders make use of lexically based constraints such as subcategorization frequency in processing structurally ambiguous sentences. One piece of such evidence is lexically specific syntactic priming in comprehension; following the costly processing of a temporarily ambiguous sentence, comprehenders experience less processing difficulty with the same structure with the same verb in subsequent processing. In previous studies using a reading paradigm, however, the effect was observed at or following disambiguating information and it is not known whether a priming effect affects only the process of resolving structural ambiguity following disambiguating input or it also affects the process before ambiguity is resolved. Using a visual world paradigm, the current study addressed this issue with Japanese relative clause sentences. Our results demonstrated that after experiencing the relative clause structure, comprehenders were more likely to predict the usually dispreferred structure immediately upon hearing the same verb. No compatible effect, in contrast, was observed on hearing a different verb. Our results are consistent with the constraint-based lexicalist view, which assumes the parallel activation of possible structural analyses at the verb. Our study demonstrated that an experience of a dispreferred structure activates the structural information in a lexically specific manner, leading comprehenders to predict another instance of the same structure on encountering the same verb. PMID- 25528093 TI - Test-enhanced learning versus errorless learning in aphasia rehabilitation: testing competing psychological principles. AB - Because individuals with acquired language disorders are frequently unable to reliably access the names of common everyday objects (i.e., naming impairment), rehabilitation efforts often focus on improving naming. The present study compared 2 rehabilitation strategies for naming impairment, reflecting contradictory prescriptions derived from different theoretical principles. The prescription derived from psychological research on test-enhanced learning advocates providing patients opportunities to retrieve target names from long term memory (i.e., retrieval practice) in the course of treatment. In contrast, the errorless learning approach derived from cognitive rehabilitation research eschews retrieval practice in favor of methods that minimize naming errors, and thus the potential for error learning, in the course of treatment. The present study directly compared these approaches and showed that, despite superior (and errorless) performance during errorless treatment, treatment that prioritized retrieval practice produced greater retention 1-day and 1-week following treatment. These findings have implications for clinical practice, as well as theoretical accounts of lexical access and test-enhanced learning. PMID- 25528095 TI - The locus of serial processing in reading aloud: orthography-to-phonology computation or speech planning? AB - Dual-route theories of reading posit that a sublexical reading mechanism that operates serially and from left to right is involved in the orthography-to phonology computation. These theories attribute the masked onset priming effect (MOPE) and the phonological Stroop effect (PSE) to the serial left-to-right operation of this mechanism. However, both effects may arise during speech planning, in the phonological encoding process, which also occurs serially and from left to right. In the present paper, we sought to determine the locus of serial processing in reading aloud by testing the contrasting predictions that the dual-route and speech planning accounts make in relation to the MOPE and the PSE. The results from three experiments that used the MOPE and the PSE paradigms in English are inconsistent with the idea that these effects arise during speech planning, and consistent with the claim that a sublexical serially operating reading mechanism is involved in the print-to-sound translation. Simulations of the empirical data on the MOPE with the dual route cascaded (DRC) and connectionist dual process (CDP++) models, which are computational implementations of the dual-route theory of reading, provide further support for the dual-route account. PMID- 25528096 TI - Beyond decoding: phonological processing during silent reading in beginning readers. AB - In this experiment, the extent to which beginning readers process phonology during lexical identification in silent sentence reading was investigated. The eye movements of children aged seven to nine years and adults were recorded as they read sentences containing either a correctly spelled target word (e.g., girl), a pseudohomophone (e.g., gerl), or a spelling control (e.g., garl). Both children and adults showed a benefit from the valid phonology of the pseudohomophone, compared to the spelling control during reading. This indicates that children as young as seven years old exhibit relatively skilled phonological processing during reading, despite having moved past the use of overt phonological decoding strategies. In addition, in comparison to adults, children's lexical processing was more disrupted by the presence of spelling errors, suggesting a developmental change in the relative dependence upon phonological and orthographic processing in lexical identification during silent sentence reading. PMID- 25528097 TI - Masked primes activate feature representations in reading aloud. AB - Theories of reading aloud are silent about the role of subphonemic/subsegmental representations in translating print to sound. However, there is empirical evidence suggesting that feature representations are activated in speech production and visual word recognition. In the present study, we sought to determine whether masked primes activate feature representations in reading aloud using a variation of the masked onset priming effect (MOPE). We found that target nonwords (e.g., BAF) were read aloud faster when preceded by masked nonword primes that shared their initial phoneme with the target (e.g., bez), or primes whose initial phoneme shared all features except voicing with the first phoneme of the target (e.g., piz), compared with unrelated primes (e.g., suz). We obtained the same result in 2 experiments that used different participants and prime durations (around 60 ms in Experiment 1 and 50 ms in Experiment 2). The significant masked feature priming effect that was observed in both experiments converges with the empirical evidence in the speech production and visual word recognition domains indicating a functional role for features in reading aloud. Our findings motivate the further development of current theories of reading aloud and have important implications for extant theories of speech production. PMID- 25528098 TI - Second-language experience modulates eye movements during first- and second language sentence reading: evidence from a gaze-contingent moving window paradigm. AB - Eye movement measures demonstrate differences in first-language (L1) and second language (L2) paragraph-level reading as a function of individual differences in current L2 exposure among bilinguals (Whitford & Titone, 2012). Specifically, as current L2 exposure increases, the ease of L2 word processing increases, but the ease of L1 word processing decreases. Here, we investigate whether current L2 exposure also relates to more general aspects of reading performance, including global eye movement measures and how bilinguals use parafoveal information to the right of fixation during L1 and L2 sentence-level reading, through use of a gaze contingent moving window paradigm (McConkie & Rayner, 1975). We found that bilinguals with high versus low current L2 exposure exhibited increased L2 reading fluency (faster reading rates, shorter forward fixation durations), but decreased L1 reading fluency (slower reading rates, longer forward fixation durations). We also found that bilinguals with high versus low current L2 exposure were more affected by reductions in window size during L2 reading (indicative of a larger L2 perceptual span), but were less affected by reductions in window size during L1 reading (indicative of a smaller L1 perceptual span). Taken together, these findings suggest that individual differences in current L2 exposure among bilinguals also modulate more general aspects of reading behavior, including global measures of reading difficulty and the allocation of visual attention into the parafovea during both L1 and L2 sentence-level reading. PMID- 25528099 TI - A violation of the conditional independence assumption in the two-high-threshold model of recognition memory. AB - The 2-high-threshold (2HT) model of recognition memory assumes that test items result in distinct internal states: they are either detected or not, and the probability of responding at a particular confidence level that an item is "old" or "new" depends on the state-response mapping parameters. The mapping parameters are independent of the probability that an item yields a particular state (e.g., both strong and weak items that are detected as old have the same probability of producing a highest-confidence "old" response). We tested this conditional independence assumption by presenting nouns 1, 2, or 4 times. To maximize the strength of some items, "superstrong" items were repeated 4 times and encoded in conjunction with pleasantness, imageability, anagram, and survival processing tasks. The 2HT model failed to simultaneously capture the response rate data for all item classes, demonstrating that the data violated the conditional independence assumption. In contrast, a Gaussian signal detection model, which posits that the level of confidence that an item is "old" or "new" is a function of its continuous strength value, provided a good account of the data. PMID- 25528100 TI - Identifying strategy use in category learning tasks: a case for more diagnostic data and models. AB - The strength of conclusions about the adoption of different categorization strategies-and their implications for theories about the cognitive and neural bases of category learning-depend heavily on the techniques for identifying strategy use. We examine performance in an often-used "information-integration" category structure and demonstrate that strategy identification is affected markedly by the range of models under consideration, the type of data collected, and model-selection techniques. We use a set of 27 potential models that represent alternative rule-based and information-integration categorization strategies. Our experimental paradigm includes the presentation of nonreinforced transfer stimuli that improve one's ability to discriminate among the predictions of alternative models. Our model-selection techniques incorporate uncertainty in the identification of individuals as either rule-based or information-integration strategy users. Based on this analysis we identify 48% of participants as unequivocally using an information-integration strategy. However, adopting the standard practice of using a restricted set of models, restricted data, and ignoring the degree of support for a particular strategy, we would typically conclude that 89% of participants used an information-integration strategy. We discuss the implications of potentially erroneous strategy identification for the security of conclusions about the categorization capabilities of various participant and patient groups. PMID- 25528101 TI - Judgments of learning as memory modifiers. AB - A frequent procedure used to study how individuals monitor their own learning is to collect judgments of learning (JOLs) during acquisition, considered to be important, in part, because such judgments are assumed to guide how individuals allocate their future learning resources. In such research, however, a tacit assumption is frequently made: Namely, that asking for such metacognitive judgments does not affect the learning process per se. In 3 experiments, the present research addressed the accuracy of this assumption and tested a possible account--based on aspects of Koriat's cue-utilization approach to JOLs (Koriat, 1997) and de Winstanley, Bjork, and Bjork's (1996) transfer-appropriate multifactor account of generation effects--for why the mere act of making JOLs might enhance later memory for the information so judged. Potential implications of the present findings for the future conduction of research using metacognitive measures as well as for students studying for exams is discussed. PMID- 25528103 TI - 'Right' for publication: strategies for supporting novice writers across health and medical disciplines. AB - The idea that scholarly writing is an integral part of academic and clinical work is not new; however, increasing expectations that health professionals contribute to research output through publication, regardless of level of employment or experience, creates anxiety and dissonance for many novice and sometimes not-so novice writers. Publications and the impact of scholarly work have become the key indicators not only of the performance of individual health academics, but also of health disciplines and universities more broadly. In Australia, as in many other countries, publications as the measure of research impact and outputs are expected in professional disciplines, universities and schools. Research impact is assessed and rated against other institutions and used as a means of allocating scarce research funding. Publishing has become a matter of professional reputation and sustainability. This paper reports on a project designed to enhance publication rates across health disciplines based at a rural university, where many staff members combine academic work with ongoing clinical roles. Without deliberate and focused support to enhance skills and confidence in writing it was unlikely that these academics and clinical staff members would be able to develop the kind of track record required for a successful academic career or promotion. This paper outlines the development, delivery and outcomes of this university-funded project, which drew on evidence in the literature to increase the publication rates across two Schools (Health and Medicine) at a rural university. PMID- 25528104 TI - When pain is not only pain: inserting needles into the body evokes distinct reward-related brain responses in the context of a treatment. AB - The aim of this study was to compare behavioral and functional brain responses to the act of inserting needles into the body in two different contexts, treatment and stimulation, and to determine whether the behavioral and functional brain responses to a subsequent pain stimulus were also context dependent. Twenty-four participants were randomly divided into two groups: an acupuncture treatment (AT) group and an acupuncture stimulation (AS) group. Each participant received three different types of stimuli, consisting of tactile, acupuncture, and pain stimuli, and was given behavioral assessments during fMRI scanning. Although the applied stimuli were physically identical in both groups, the verbal instructions differed: participants in the AS group were primed to consider the acupuncture as a painful stimulus, whereas the participants in the AT group were told that the acupuncture was part of therapeutic treatment. Acupuncture yielded greater brain activation in reward-related brain areas (ventral striatum) of the brain in the AT group when compared to the AS group. Brain activation in response to pain stimuli was significantly attenuated in the bilateral secondary somatosensory cortex and the right dorsolateral prefrontal cortex after prior acupuncture needle stimulation in the AT group but not in the AS group. Inserting needles into the body in the context of treatment activated reward circuitries in the brain and modulated pain responses in the pain matrix. Our findings suggest that pain induced by therapeutic tools in the context of a treatment is modulated differently in the brain, demonstrating the power of context in medical practice. PMID- 25528102 TI - Parity, lactation, bone strength, and 16-year fracture risk in adult women: findings from the Study of Women's Health Across the Nation (SWAN). AB - Our objective was to examine the associations of lifetime parity and accumulated length of lactation with bone strength in women prior to the menopause transition and fracture risk during and after the transition. Participants were 2239 pre- or early peri-menopausal women from the Study of Women's Health Across the Nation (SWAN), ages 42-53 years at baseline, who had no childbirths after age 42. Bone mineral density (BMD) was measured in the femoral neck and the lumbar spine at the baseline SWAN visit using dual-energy x-ray absorptiometry, and the composite indices of femoral neck strength relative to load (in three failure modes: compression, bending, and impact) were calculated from femoral neck BMD, femoral neck size, and body size. Data on fractures after age 42 were collected for a median follow-up of 15.7 years (interquartile range, 11.4-18.5 years). In multiple linear regressions adjusted for covariates, lifetime parity was associated positively with femoral neck strength relative to load (0.024 standard deviation (SD) increment in impact strength index per childbirth, p=0.049), but accumulated length of lactation was associated negatively with lumbar spine BMD (0.018 SD decrement per every additional 6 months of lactation, p=0.040). In Cox proportional hazards regressions adjusted for covariates, neither parity nor lactation was associated with fracture hazard after age 42. In conclusion, parity and lactation have little impact on peak bone strength prior to menopause, and do not affect fracture risk after age 42 over 16-year follow-up. PMID- 25528105 TI - Standardized standing pelvis-to-floor photographs for the assessment of lower extremity alignment. AB - OBJECTIVES: The objective of this cross-sectional study was to assess the intra rater, inter-rater and test-retest reliability and concurrent validity of lower extremity alignment estimated from a photograph [photographic alignment (PA) angle]. METHODS: A convenience sample of participants was recruited from the community. Radiopaque stickers were placed over participants' anterior superior iliac spines. One radiograph and one photograph were taken with the participant standing in a standardized position. The stickers were removed. After 30 min they were reapplied and a second photograph was taken. The hip-knee-ankle (HKA) angle was measured from each radiograph using customized imaging analysis software. The same software was used by three readers to measure the PA angle from each photograph from the first set twice, at least 2 weeks apart. One reader measured the PA angle from the second set of photographs. Reliability was tested using intraclass correlation coefficients (ICC(2,1)), Bland-Altman analyses and the minimal detectable change (MDC95). Concurrent validity was tested using a Pearson's correlation coefficient and Bland-Altman analysis. RESULTS: Fifty adults participated (mean age 41.8 years; mean body mass index 24.7 kg/m(2)). The PA angle was 4.5 degrees more varus than the HKA angle; these measures were highly correlated (r = 0.92). Intra-rater (ICC(2,1) > 0.985), inter-rater (ICC(2,1) = 0.988) and test-retest reliability (ICC(2,1) = 0.903) showed negligible bias (<0.20 degrees ). The MDC95 was 2.69 degrees . CONCLUSIONS: The PA angle may be used in place of the HKA angle if a bias of 4.5 degrees is added. A difference of 3 degrees between baseline and follow-up would be considered a true difference. PMID- 25528111 TI - Visualization of neurotransmitter uptake and release in serotonergic neurons. AB - BACKGROUND: To study serotonergic volume neurotransmission at cellular level it needs to investigate neurotransmitter release and re-uptake sites in serotonergic neurons. However, due to the low number of cell bodies in the raphe nuclei and their widely branching neurites, serotonergic neuronal cultures are not accessible ex vivo. NEW METHOD: We have combined differentiation protocols for the generation of stem cell-derived serotonergic neurons together with confocal microscopy to study the uptake and release of fluorescent substrates known to be selectively taken up by monoaminergic neurons. These substances include: (i) 4-(4 (dimethylamino)styryl)-N-methylpyridiunium (ASP+), an analog of the neurotoxin MPP+; (ii) the fluorescent false neurotransmitter (FFN511); and (iii) serotonin (5-hydroxytryptamine; 5-HT) itself, which is known to emit fluorescence upon excitation at 320-460nm. RESULT: ASP+ is taken up into living serotonergic neurons through the serotonin transporter, but not accumulated into synaptic vesicles; FFN511 diffuses in a SERT-independent way into serotonergic neurons and accumulated into synaptic vesicles. KCl-induced release of FFN511 and 5-HT can be visualized and quantified in living serotonergic neurons. COMPARISON WITH EXISTING METHODS: Application of ASP+ so far has been used to investigate substrate/transporter interactions; studies on FFN511 uptake and release have only been performed in dopaminergic neurons; quantitative studies on uptake and release of 5-HT in living serotonergic neurons have not been reported yet. CONCLUSION: The differentiation protocols for the generation of stem cell-derived serotonergic neurons combined with the application of different fluorescent dyes allow to quantify neurotransmitter uptake and release in living serotonergic neurons in vitro. PMID- 25528106 TI - The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study. AB - BACKGROUND: Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. OBJECTIVE: To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). METHODS: Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean +/- SD age = 74 +/- 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders. RESULTS: Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (>= 1.0 nM). Higher plasma (dp)ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively]. CONCLUSION: Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA. PMID- 25528112 TI - LinkRbrain: multi-scale data integrator of the brain. AB - BACKGROUND: LinkRbrain is an open-access web platform for multi-scale data integration and visualization of human brain data. This platform integrates anatomical, functional, and genetic knowledge produced by the scientific community. NEW METHOD: The linkRbrain platform has two major components: (1) a data aggregation component that integrates multiple open databases into a single platform with a unified representation; and (2) a website that provides fast multi-scale integration and visualization of these data and makes the results immediately available. RESULTS: LinkRbrain allows users to visualize functional networks or/and genetic expression over a standard brain template (MNI152). Interrelationships between these components based on topographical overlap are displayed using relational graphs. Moreover, linkRbrain enables comparison of new experimental results with previous published works. COMPARISON WITH EXISTING METHODS: Previous tools and studies illustrate the opportunities of data mining across multiple tiers of neuroscience and genetic information. However, a global systematic approach is still missing to gather cognitive, topographical, and genetic knowledge in a common framework in order to facilitate their visualization, comparison, and integration. CONCLUSIONS: LinkRbrain is an efficient open-access tool that affords an integrative understanding of human brain function. PMID- 25528113 TI - Assessment of attention threshold in rats by titration of visual cue duration during the five choice serial reaction time task. AB - BACKGROUND: The 5 choice serial reaction time task (5CSRTT) is commonly used to assess attention in rodents. We sought to develop a variant of the 5CSRTT that would speed training to objective success criteria, and to test whether this variant could determine attention capability in each subject. NEW METHOD: Fisher 344 rats were trained to perform a variant of the 5CSRTT in which the duration of visual cue presentation (cue duration) was titrated between trials based upon performance. The cue duration was decreased when the subject made a correct response, or increased with incorrect responses or omissions. Additionally, test day challenges were provided consisting of lengthening the intertrial interval and inclusion of a visual distracting stimulus. RESULTS: Rats readily titrated the cue duration to less than 1s in 25 training sessions or less (mean+/-SEM, 22.9+/-0.7), and the median cue duration (MCD) was calculated as a measure of attention threshold. Increasing the intertrial interval increased premature responses, decreased the number of trials completed, and increased the MCD. Decreasing the intertrial interval and time allotted for consuming the food reward demonstrated that a minimum of 3.5s is required for rats to consume two food pellets and successfully attend to the next trial. Visual distraction in the form of a 3Hz flashing light increased the MCD and both premature and time out responses. COMPARISON WITH EXISTING METHOD: The titration variant of the 5CSRTT is a useful method that dynamically measures attention threshold across a wide range of subject performance, and significantly decreases the time required for training. Task challenges produce similar effects in the titration method as reported for the classical procedure. CONCLUSIONS: The titration 5CSRTT method is an efficient training procedure for assessing attention and can be utilized to assess the limit in performance ability across subjects and various schedule manipulations. PMID- 25528114 TI - Metronomic capecitabine as extended adjuvant chemotherapy in women with triple negative breast cancer. AB - PURPOSE: High interest in triple-negative breast cancers is not surprising as this category of patients benefits neither from hormonal therapies nor from anti HER2 treatments. Blockade of angiogenesis by metronomic chemotherapy as well as other antiangiogenics might improve outcomes in this group of patients. This study aims to evaluate the tolerability and efficacy of metronomic capecitabine as extended adjuvant treatment for women with triple-negative breast cancer. METHODS: This is a prospective phase II study that included 41 patients diagnosed with triple-negative breast cancer and who were indicated for adjuvant chemotherapy. They received capecitabine 500mg PO twice daily and continuously for six months after finishing six cycles of adjuvant FEC100+/-postoperative radiotherapy. RESULTS: Forty-one patients were enrolled in this study between June 2010 and December 2013. Median age was 50years ranging from 27 to 67years. Treatment was well tolerated. Adverse effects were grade 1 palmar-plantar erythrodysesthesia in 13 patients (31.7%); grade 1 diarrhea in five patients (12.2%); and grade 1 vomiting in two patients (4.9%). Estimated median follow-up duration was 34 months. Estimated mean disease-free survival (DFS) was 42.4months (95% CI, 39.02-45.79), while median DFS was not reached. Estimated mean overall survival was 44.34months (95% CI 41.9-46.9). CONCLUSION: Extended adjuvant metronomic capecitabine is well tolerated with patient compliance. These results need to be compared in a study with control arm, larger sample, as well as longer follow-up. PMID- 25528115 TI - Dietary pretreatment with green tea polyphenol, (-)-epigallocatechin-3-gallate reduces the bioavailability and hepatotoxicity of subsequent oral bolus doses of (-)-epigallocatechin-3-gallate. AB - Human case-studies have reported an association between green tea-based dietary supplements and hepatotoxicity. Studies have demonstrated the hepatotoxicity of high-dose oral bolus dosing with the tea polyphenol (-)-epigallocatechin-3 gallate (EGCG) in mice and dogs. We examined the effect of pretreatment with dietary EGCG on the hepatotoxicity and bioavailability of acute oral bolus dosing with EGCG in CF-1 mice. EGCG (750 mg/kg, i.g., once daily for 3 days) increased plasma alanine aminotransferase by 80-fold, decreased both reduced (by 59%) and total (by 33%) hepatic glutathione, and increased hepatic levels of phosphorylated histone 2AX. Pretreatment with dietary EGCG (3.2 mg/g diet) for 2 weeks mitigated hepatotoxicity. Acute oral EGCG also decreased mRNA expression of glutathione reductase. Dietary pretreatment prevented these decreased and increased glutathione peroxidase (Gpx)2, Gpx3, Gpx5, and Gpx7 expression. We found that dietary EGCG reduced the plasma (57% reduction) and hepatic (71% reduction) EGCG exposure following oral bolus dosing compared to mice that were not pre-treated. Overall, it appears that EGCG can modulate its own bioavailability and that dietary treatment may reduce the toxic potential of acute high oral bolus doses of EGCG. These data may partly explain the observed variation in hepatotoxic response to green tea-containing dietary supplements. PMID- 25528116 TI - Free fatty acids enhance the oxidative damage induced by ethanol metabolism in an in vitro model. AB - In recent years, there has been a growing interest to explore the responsiveness to injury in steatotic hepatocyte. VL-17A cells, which express ADH and Cyp2E1 overloaded with free fatty acids (1 mM of oleic and palmitic acid 2:1) showed an increased oxidative damaged after 24 h free fatty acids treatment when exposed to ethanol (100 mM) for 48 h as a second injury. An increment in reactive oxygen species, determined by DCFH-DA, protein oxidation, and apoptosis were observed although an increase in main antioxidant proteins such as superoxide dismutase 1 and glutathione peroxidase were observed, but failed in gamma-glutamylcysteine synthetase, suggesting a decreased capacity of synthesis of glutathione compared with cells treated only with free fatty acids or ethanol. The increased oxidative stress and toxicity in lipid overloaded VL-17A cells subjected to ethanol exposure were accompanied by increases in Cyp2E1 protein expression. Our data show that lipid loaded in an in vitro model, VL-17A cells, is more susceptible to cell damage and oxidative stress when treated with ethanol. PMID- 25528122 TI - Will health care reform rescue families in crisis? PMID- 25528123 TI - The referral and consultation entrustable professional activity: defining the components in order to develop a curriculum for pediatric residents. PMID- 25528124 TI - At-school substance use as a marker for serious health risks. AB - OBJECTIVE: At-school substance use is associated with increased rates of violence and delinquency. However, whether at-school substance use is a useful marker for other serious health risks and whether this association varies by gender or substance is still unclear. METHODS: We analyzed data from the national 2011 Youth Risk Behaviors Survey of 15,698 ninth to 12th grade students. We used multivariate regressions controlling for age and race and evaluated whether at school marijuana and alcohol users were more likely than out-of-school users to exhibit 9 serious health risks (exposure to intoxicated driving, fighting, carrying a weapon at school, substance use with intercourse, experiencing intimate partner violence, being forced to have intercourse, experiencing depression, suicidal ideation, and attempting suicide). We included interaction terms to determine whether this association varied by gender or substance. RESULTS: At-school alcohol and marijuana use were both associated with increased odds of all 9 serious health risks. The association between at-school substance use and fighting and being forced to have sex was greater for boys than for girls. Associations did not vary significantly by substance. Specificity of at school substance use for serious health risks ranged from 0.93 to 0.96, and positive predictive values ranged from 0.23 to 0.69, well above the ranges for out-of-school use and nonuse. CONCLUSIONS: Students found using alcohol or marijuana at school should be immediately and carefully screened for other serious health risks that pose significant present dangers; this might represent a critical opportunity to identify troubled youth. PMID- 25528125 TI - Black versus white differences in rates of addressing parental tobacco use in the pediatric setting. AB - OBJECTIVE: To examine racial differences in rates of screening parents for cigarette smoking during pediatric outpatient visits and to determine if a parental tobacco control intervention mitigates racial variation in whether cigarette smoking is addressed. METHODS: As part of the Clinical Effort Against Secondhand Smoke Exposure (CEASE) randomized controlled trial, exit interviews were conducted with parents at 10 control and 10 intervention pediatric practices nationally. Parents were asked to report if during the visit did anyone ask if they smoke cigarettes. A generalized linear mixed model was used to estimate the effect of black vs white race on asking parents about cigarette smoking. RESULTS: Among 17,692 parents screened at the exit interview, the proportion of black parents who were current smokers (16%) was lower than the proportion of white parents who smoked (20%) (P < .001). In control group practices, black parents were more likely to be asked (adjusted risk ratio 1.23; 95% confidence interval 1.08, 1.40) about cigarette smoking by pediatricians than whites. In intervention group practices both black and white parents were more likely to be asked about smoking than those in control practices and there was no significant difference between black and white parents in the likelihood of being asked (adjusted risk ratio 1.01; 95% confidence interval 0.93, 1.09). CONCLUSIONS: Although a smaller proportion of black parents in control practices smoked than white, black parents were more likely to be asked by pediatricians about smoking. The CEASE intervention was associated with higher levels of screening for smoking for both black and white parents. PMID- 25528126 TI - Risk factors for requiring intensive care among children admitted to ward with bronchiolitis. AB - OBJECTIVE: To examine risk factors for transfer of bronchiolitis patients from the ward to the intensive care unit (ICU) and/or initiation of critical care interventions. METHODS: We performed a 16-center, prospective cohort study of hospitalized children age <2 years with bronchiolitis. During the winters of 2007 to 2010, researchers collected clinical data and nasopharyngeal aspirates from study participants. The primary outcome was late intensive care use, defined as a transfer to the ICU and/or use of mechanical ventilation (regardless of location) after the child's first inpatient day. RESULTS: Among 2104 children hospitalized with bronchiolitis, 1762 (84%) were identified as initial ward patients, comprising the analysis cohort. The median age was 4 months (interquartile range, 2-9 months), and 1048 (59%) were boys. The most frequently detected pathogens were respiratory syncytial virus (72%) and rhinovirus (25%). After the first inpatient day, 47 (3%; 95% confidence interval, 2-4) were subsequently transferred to the ICU or required mechanical ventilation. In the multivariable logistic regression model predicting subsequent transfer to the ICU or mechanical ventilation use, the significant predictors were birth weight <5 pounds (odds ratio, 2.28; 95% confidence interval, 1.30-4.02; P = .004) and respiratory rate high of >= 70 breaths/min on the first inpatient day (odds ratio, 4.64; 95% confidence interval, 2.86-7.53; P < .001). CONCLUSIONS: In this multicenter study of children hospitalized with bronchiolitis, low birth weight and tachypnea were significantly associated with subsequent transfer to the ICU and/or use of mechanical ventilation. PMID- 25528127 TI - Punishment and reward in parental discipline for children aged 5 to 6 years: prevalence and groups at risk. AB - OBJECTIVE: In this study we examined the use and predictors of different discipline practices by parents of children aged 5 to 6 years. METHODS: We obtained cross-sectional data for a nationally representative Dutch sample of children aged 5 to 6 years within the setting of routine well-child visits provided to the entire population. A total of 1630 children participated (response rate, 84%). Before the visit, parents completed a questionnaire with questions about their approach to discipline (punishment and rewards). Chi-square tests and logistic regression analyses were used to examine associations between discipline practices and child, parent, and family factors. RESULTS: Parental punishment prevalence was 21.9% for spanking and 80.3% for other punishment practices, such as time-outs. The prevalence of rewards as a discipline strategy was 32.2% for granting privileges and 86.3% for cuddling/complimenting. Multivariate logistic regression analyses showed that spanking was more likely in families in which the mothers have low and medium levels of education and in families of non-Dutch ethnicity. Other punishment practices (eg, time-outs, verbal reprimands, and holding) were more likely in families of Dutch ethnicity. Granting privileges was more likely in families of non-Dutch ethnicity, who lived in large cities, whose income was below the poverty level, in unemployed families, and in small families. Cuddling and complimenting were more likely in families with a high maternal educational level, in families of Dutch ethnicity, and in small families. CONCLUSIONS: These findings show the importance of considering social and economic factors when identifying and supporting parents with parenting/rearing challenges. PMID- 25528128 TI - Why adolescents fight: a qualitative study of youth perspectives on fighting and its prevention. AB - OBJECTIVE: To identify risk factors for fighting, factors that protect against fighting, and strategies to prevent fighting, among adolescents who fight and those uninvolved in fighting. METHODS: Focus groups were conducted with middle and high school students, stratified by fighting (fighter/nonfighter) status, race/ethnicity, and gender. Groups were audiotaped, transcribed, and analyzed using margin coding and thematic content analysis. Themes were independently identified by 3 coders; disagreements were resolved by consensus. RESULTS: The 65 participants in the 12 focus groups were 13 to 17 years old. Reasons for fighting include self-defense, to gain/maintain respect, or anger; having goals for the future is protective. Nonfighters state that their parents condone fighting only when physically attacked and that they teach adolescents strategies to avoid fighting. Fighters describe mixed messages from parents, and pro-fighting attitudes and modeling of aggressive behavior among some family members. Nonfighters avoid fighting by ignoring insults or walking away. Fighters feel unable to use nonviolent conflict-resolution methods effectively. Peers may instigate or encourage fights. Suggested prevention strategies include anger management and conflict-resolution programs, relationships with caring adults, and physicians counseling youth about the consequences of fighting. CONCLUSIONS: Nonfighters use various strategies to avoid fighting, whereas fighters are aware of few alternatives to fighting. Conflicting parental messages about fighting may enhance the likelihood of fighting. Physicians can counsel youth about the negative consequences of fighting. Interventions that teach anger management and conflict resolution, promote adolescent self-efficacy for using nonviolent strategies, and address parental attitudes about fighting may be effective in preventing fighting. PMID- 25528129 TI - Poor sleep and lower working memory in grade 1 children: cross-sectional, population-based study. AB - OBJECTIVE: Poor sleep and working memory difficulties are both associated with learning difficulties, but it is not known whether they are linked with each other in childhood. We aimed to determine, in a population-based sample of grade 1 children, whether poor sleep is associated with reduced working memory capacity. METHODS: Cross-sectional population-based study. All grade 1 children in 44 elementary schools in metropolitan Melbourne, Australia; 1749 children were included (participation rate 65%, mean age 6.9 years). Parents completed a written questionnaire at home, after which researchers administered one-on-one child computerized assessments at school. Predictor measures were parent-reported 1) perceptions of poor sleep, 2) regularity of bedtime, 3) sleep duration, and 4) sleep onset latency. Outcome measures were backward digit recall (verbal working memory) and Mister X (visuospatial working memory) subtests of the Automated Working Memory Assessment (AWMA). Associations were examined using linear regression, adjusted for duration of schooling, gender, age, and social status. RESULTS: Increasing poor sleep (P = .03), less regularity of bedtime (P < .001), and shorter sleep duration (P = .03) were all associated with poorer verbal working memory, with effect sizes ranging from 0.3 to 1.2. Poor sleep was not associated with visuospatial working memory. CONCLUSIONS: At a population level, poor sleep in early school-age children is associated with poorer verbal working memory, an important predictor of academic difficulties. PMID- 25528130 TI - Neural signatures of conscious and unconscious emotional face processing in human infants. AB - Human adults can process emotional information both with and without conscious awareness, and it has been suggested that the two processes rely on partly distinct brain mechanisms. However, the developmental origins of these brain processes are unknown. In the present event-related brain potential (ERP) study, we examined the brain responses of 7-month-old infants in response to subliminally (50 and 100 msec) and supraliminally (500 msec) presented happy and fearful facial expressions. Our results revealed that infants' brain responses (Pb and Nc) over central electrodes distinguished between emotions irrespective of stimulus duration, whereas the discrimination between emotions at occipital electrodes (N290 and P400) only occurred when faces were presented supraliminally (above threshold). This suggests that early in development the human brain not only discriminates between happy and fearful facial expressions irrespective of conscious perception, but also that, similar to adults, supraliminal and subliminal emotion processing relies on distinct neural processes. Our data further suggest that the processing of emotional facial expressions differs across infants depending on their behaviorally shown perceptual sensitivity. The current ERP findings suggest that distinct brain processes underpinning conscious and unconscious emotion perception emerge early in ontogeny and can therefore be seen as a key feature of human social functioning. PMID- 25528131 TI - Reproductive state affects hiding behaviour under risk of predation but not exploratory activity of female Spanish terrapins. AB - Female investment during reproduction may reduce survivorship due to increased predation risk. During pregnancy, the locomotor performance of gravid females might be diminished due to the additional weight acquired. In addition, egg production may also increase thermoregulatory, metabolic and physiological costs. Also, pregnant females have greater potential fitness and should take fewer risks. Thus, females should ponder their reproductive state when considering their behavioural responses under risky situations. Here, we examine how reproductive state influence risk-taking behaviour in different contexts in female Spanish terrapins (Mauremys leprosa). We simulated predator attacks of different risk levels and measured the time that the turtles spent hiding entirely inside their own shells (i.e. appearance times). We also assessed the subsequent time after emergence from the shell that the turtles spent immobile monitoring for predators before starting to escape actively (i.e. waiting times). Likewise, we performed a novel-environment test and measured the exploratory activity of turtles. We found no correlations between appearance time, waiting time or exploratory activity, but appearance times were correlated across different risk levels. Only appearance time was affected by the reproductive state, where gravid females reappeared relatively later from their shells after a predator attack than non-gravid ones. Moreover, among gravid females, those carrying greater clutches tended to have longer appearance times. This suggests that only larger clutches could affect hiding behaviour in risky contexts. In contrast, waiting time spent scanning for predators and exploratory activity were not affected by the reproductive state. These differences between gravid and non gravid females might be explained by the metabolic-physiological costs associated with egg production and embryo maintenance, as well as by the relatively higher potential fitness of gravid females. PMID- 25528132 TI - Montmorillonite enhanced ciprofloxacin transport in saturated porous media with sorbed ciprofloxacin showing antibiotic activity. AB - Antibiotic ciprofloxacin (CIP) is immobile in the subsurface but it has been frequently detected in the aquatic system. Therefore it is important to investigate the factors impacting CIP's mobilization in aquifer. Laboratory columns packed with sand were used to test colloid-facilitated CIP transport by 1) using kaolinite or montmorillonite to mobilize presorbed-CIP in a column or 2) co-transporting with CIP by pre-mixing them before transport. The Langmuir model showed that CIP sorption by montmorillonite (23gkg(-1)) was 100 times more effective than sand or kaolinite. Even with strong CIP complexation ability to Fe/Al coating on sand surface, montmorillonite promoted CIP transport, but not kaolinite. All presorbed-CIP by sand was mobilized by montmorillonite after 3 pore volumes through co-transporting of CIP with montmorillonite. The majority of CIP was fixed onto the montmorillonite interlayer but still showed inhibition of bacteria growth. Our results suggested that montmorillonite with high CIP sorption ability can act as a carrier to enhance CIP's mobility in aquifer. PMID- 25528133 TI - Spectral induced polarization (SIP) response of mine tailings. AB - Mine tailings impoundments are a source of leachates known as acid mine drainage (AMD) which can pose a contamination risk for surrounding surface and groundwater. Methodologies which can help management of this environmental issue are needed. We carried out a laboratory study of the spectral induced polarization (SIP) response of tailings from the Haveri Au-Cu mine, SW Finland. The primary objectives were, (1) to determine possible correlations between SIP parameters and textural properties associated with oxidative-weathering mechanisms, mineralogical composition and metallic content, and (2) to evaluate the effects of the pore water chemistry on SIP parameters associated with redox inactive and redox-active electrolytes varying in molar concentration, conductivity and pH. The Haveri tailings exhibit well defined relaxation spectra between 100 and 10,000Hz. The relaxation magnitudes are governed by the in-situ oxidative-weathering conditions on sulphide mineral surfaces contained in the tailings, and decrease with the oxidation degree. The oxidation-driven textural variation in the tailings results in changes to the frequency peak of the phase angle, the imaginary conductivity and chargeability, when plotted versus the pore water conductivity. In contrast, the real and the formation electrical conductivity components show a single linear dependence on the pore water conductivity. The increase of the pore water conductivity (dominated by the increase of ions concentration in solution) along with a transition to acidic conditions shifts the polarization peak towards higher frequencies. These findings show the unique sensitivity of the SIP method to potentially discriminate AMD discharges from reactive oxidation zones in tailings, suggesting a significant advantage for monitoring threatened aquifers. PMID- 25528134 TI - Modeling improved ISCO treatment of low permeable zones via viscosity modification: assessment of system variables. AB - A major challenge to successfully using in situ chemical oxidation (ISCO) for groundwater treatment is achieving uniform contact between the oxidant and contaminants in a heterogeneous aquifer. Viscosity modification technology, where a water-soluble polymer is mixed with remedial fluids, has been introduced in recent years to improve oxidant coverage of the target zone (i.e., sweep efficiency) and thus, treatment efficacy. In this work, we developed a numerical model to simulate the remedial fluid coverage from an ISCO injection with viscosity modification. Specifically, solution mixtures of xanthan and NaMnO4 were injected into a two-dimensional (2D) transport flow box that contained heterogeneous layers. Xanthan solutions were simulated as shear-thinning non Newtonian fluids, where viscosity is a function of shear rate, polymer and NaMnO4 concentrations. Reactive transport of the polymer, NaMnO4, TCE, and reaction products were simultaneously modeled using advection dispersion reaction (ADR) equations coupled with the simulated flow field. The numerical model was validated using experimental data from the 2D cell experiments. Sensitivity analysis was conducted to investigate the relative contributions of system variables, such as polymer and permanganate concentrations, flow rate, permeability contrast, and different geometry settings. Results showed that higher concentration of permanganate and slower flow rate of the shear-thinning non-Newtonian fluids improved the oxidants ability to enter low permeable zones and react with the TCE. Higher permeability contrast decreased the velocity of the xanthan-MnO4(-) mixture inside the low permeable zone (LPZ), which increased TCE oxidation and product recovery. Changing the architecture of the LPZ from one zone to two smaller zones separated by a transmissive zone increased the overall product recovery. Thus, viscosity modification can improve both the sweeping efficiencies and TCE removal. PMID- 25528135 TI - Effect of UV light on the inactivation of recombinant human adenovirus and murine norovirus seeded in seawater in shellfish depuration tanks. AB - Shellfish depuration is a process that aims to eliminate pathogens from mollusk tissues. Seawater disinfection during the depuration process is important and ultraviolet (UV) light treatment is the most used method worldwide. Viral models are usually employed as surrogates of fastidious viruses in viability studies. The aim of this study was to employ methods based on green fluorescent protein (GFP) fluorescence and plaque forming units to detect, respectively, recombinant adenovirus (rAdV-GFP) and murine norovirus (MNV) artificially seeded in environmental matrices. These assays were applied to assess the inactivation of rAdV-GFP and MNV in seawater in recirculation shellfish depuration tanks with and without UV light treatment. Kinetics of rAdV GFP-expression was previously measured by UV-spectrophotometer. Flow cytometry (FC), fluorescence microscopy (FM), and plaque assay were used to determine virus titer and detection limits. The influence of the environmental matrix on the performance of the methods was prior determined using either drinking water or filtered seawater seeded with rAdV-GFP. Disinfection of seeded seawater was evaluated with and without UV treatment. The time of 24-h post-infection was established as ideal for fluorescence detection on rAdV-GFP infected cells. FC showed lower sensitivity, when compared to FM, which was similar to plaque assay. Seawater disinfection on depuration tanks was promising and rAdV-GFP declined 99.99 % after 24 and 48 h with and without UV treatment, respectively. MNV was completely inactivated after 24 h in both treatments. As conclusion, the depuration tanks were effective to inactivate rAdV-GFP and MNV and the UV disinfection treatment accelerated the process. PMID- 25528136 TI - X/XO or H2O2 induced IPEC-J2 cell as a new in vitro model for studying apoptosis in post-weaning piglets. AB - We previously demonstrated that intestinal epithelial cell apoptosis in weaned piglets is much more serious than that observed in sucking piglets and is related to oxidative stress during weaning. It is difficult to study the apoptosis mechanisms only using in vivo methods because of the limit of existing research technology. An in vitro cellular system is required for piglet intestinal epithelial cell apoptosis research. In this study, a non-tumorigenic epithelial cell line, IPEC-J2 cells, was employed as a cell model. Hydrogen peroxide and xanthine/xanthine oxidase (X/XO) were both used and compared for apoptosis modeling. The concentrations of hydrogen peroxide and XO were selected and verified using cell viability analysis, the comet assay and flow cytometry. Intracellular ROS were measured using fluorescent probes. Additionally, the expression levels of the apoptosis-related genes Fas, Bcl-2, P53, Caspase 3, Caspase 8, and Caspase 9 were analyzed using quantitative RT-PCR. The results indicated the optimal modeling method is a final concentration of 0.5 mM H2O2 incubated with IPEC-J2 cells for 1 h at 37 degrees C in 5 % CO2 for hydrogen peroxide-induced apoptosis modeling, and a final concentration of 250 MUM X/50 U/L XO incubated with IPEC-J2 cells for 6 h at 37 degrees C in 5 % CO2 for X/XO induced apoptosis modeling. For the apoptotic pathway, the X/XO modeling method is more similar to 21 days weaning piglets. Therefore, we suggest that X/XO modeling with IPEC-J2 cells be used as an in vitro cell culture model for weaning piglet intestinal epithelial cell apoptosis. PMID- 25528137 TI - Genetic, antigenic and pathogenic characterization of four infectious bursal disease virus isolates from China suggests continued evolution of very virulent viruses. AB - Infectious bursal disease virus (IBDV) causes an economically significant disease of young chickens worldwide. The emergence of very virulent IBDV (vvIBDV) strains has brought more challenges for effective prevention and control of this disease. The aim of the present study was to characterize four IBDV isolates from various regions of China between late 1990s and recent years and to compare them with previously isolated European IBDV strains. In this study, one Chinese vvIBDV strain isolated in 1999 and three strains isolated between 2005 and 2011 were analyzed at the genetic, antigenic and pathogenic levels. Strain SH99 was closely related and clustered in the same genetic lineage as the typical vvIBDV based on the genomic sequences of segments A and B. However, the three more recent Chinese vvIBDV (HLJ0504, HeB10 and HuN11) showed several genetic changes in both segments and clustered in a distinct lineage from the typical vvIBDV and the previously known Chinese vvIBDV. Based on the binding to a panel of neutralizing monoclonal antibodies in antigen capture enzyme-linked immunosorbent assays, all Chinese vvIBDVs exhibited similar antigenicity with the European typical vvIBDV strains. Nonetheless, the pathogenicity caused by the recent Chinese vvIBDV was higher than that induced by the European typical vvIBDV. This study calls for a sustained surveillance of IBD situation in China in order to support a better prevention and control of the disease. PMID- 25528138 TI - Finer characterization of Mycobacterium tuberculosis using spoligotyping and 15 loci MIRU-VNTRs reveals phylogeographical specificities of isolates circulating in Guyana and Suriname. AB - In this study we used spoligotyping and 15-loci MIRU-VNTRs for a finer characterization of Mycobacterium tuberculosis strains isolated from patients residing in Guyana (n=74) and Suriname (n=80). The mean age of the patients was 38.5years (36.5 and 40.2years for Guyana vs. Suriname), with a male-to-female sex ratio of 2.25 for Guyana vs. 4.27 in Suriname. Spoligotyping and 15-loci MIRU VNTRs led to a total of 41 and 65 different patterns respectively, with an overall clustering rate of 83.8% vs. 68.8%. Combined spoligotyping and VNTR analysis led to the detection of 18 clusters of 2-41 isolates, with an overall clustering of 67.5% and a recent "n-1" transmission rate of 55.8%. Importantly, Guyana was characterized by a significantly higher percentage of clustered isolates than Suriname (79.7% vs. 56.3%; p=0.0019). Three big spoligo/MIRU (SIT/MIT) clusters containing >10 isolates each were shared between the 2 countries, and concerned: T1 sublineage cluster 53/861 (n=41, 37 in Guyana vs. 4 in Suriname); EAI6-BGD1 sublineage cluster 1340/860 (n=16, 3 in Guyana vs. 13 in Suriname); and T1 sublineage cluster 131/146 (n=11, 6 in Guyana vs. 5 in Suriname); as well as 2 smaller clusters of 2 and 3 isolates respectively. However, the relative phylogeographical specificities of strains in circulation as well as a lack of drug-resistance observed among strains from Suriname suggested that trans-border transmission of drug-resistant isolates occurred less frequently than thought. Tracing and interrupting transmission channels of a specific clone (SIT53/15-MIT861) should become a priority in Guyana, not only because it is by far most abundant but also because it accounts for almost half of the drug resistant isolates (n=8/17, 47.1%) in our study, and clustered 5/12 (41.7%) MDR isolates. PMID- 25528139 TI - Getting to the heart of the matter. PMID- 25528140 TI - Two surgical techniques for transaortic transcatheter aortic valve replacement: is there a preferred technique? PMID- 25528141 TI - Mycotic aortic aneurysm in a child with aortic coarctation. PMID- 25528142 TI - Giant, pedunculated right atrial thrombus formation after surgical atrial septal defect repair. PMID- 25528144 TI - Galactose-1-phosphate uridyltransferase dried blood spot quality control materials for newborn screening tests. AB - OBJECTIVES: We aimed to prepare dried-blood-spot (DBS) quality control (QC) materials for galactose-1-phosphate uridyltransferase (GALT), to evaluate their stability during storage and use, and to evaluate their performance in five DBS GALT test methods. DESIGN AND METHODS: We prepared and characterized GALT-normal and GALT-deficient DBS materials and compared GALT activities in DBSs after predetermined storage intervals at controlled temperatures and humidities. External evaluators documented the suitability of the DBS QC materials for use in five GALT test methods. RESULTS: GALT activity losses from DBSs stored in low (<30%) humidity for 14 days at 45 degrees C, 35 days at 37 degrees C, 91 days at room temperature, 182 days at 4 degrees C, and 367 days at -20 degrees C were 54%, 53%, 52% 23%, and 7% respectively. In paired DBSs stored in high humidity (>50%) for identical intervals, losses were: 45 degrees C-68%; 37 degrees C-79%; room temperature-72%, and 4 degrees C-63%. GALT activities in DBSs stored at 4 degrees C were stable throughout 19 excursions to room temperature. Twenty-five of 26 external evaluators, using five different GALT test methods, classified the GALT-deficient DBSs as "outside normal limits". All evaluators classified the GALT-normal DBSs as "within normal limits". CONCLUSIONS: Most of the GALT activity loss from DBSs stored at elevated or room temperature was attributable to the effects of storage temperature. Most of the loss from DBSs stored at 4 degrees C was attributable to the effects of elevated humidity. Loss from DBSs stored at -20 degrees C was insignificant. The DBS materials were suitable for monitoring performance of all five GALT test methods. PMID- 25528143 TI - Alcohol and energy drink use among adolescents seeking emergency department care. AB - Emergency department (ED) visits due to energy drinks rose drastically from 2007 to 2011. Consuming alcohol mixed with energy drinks by young people is particularly concerning. Among youth (aged 14-20 years) in the ED reporting past year alcohol use, we assessed frequency, reasons, and medical consequences of consuming alcohol and energy drinks in the same beverage or on the same occasion, and relationships with other risk behaviors. The sample included 439 youth (M(age)=18.6 years, SD=1.4; 41% male; 73% Caucasian): those who drank alcohol, but not energy drinks (Non-Users; 41%, n=178), those who drank alcohol and energy drinks on separate occasions (Separate; 23%, n=103), and those who combined alcohol and energy drinks in the same beverage or on the same occasion (Combined; 36%, n=158). Common reasons for combining energy drinks and alcohol were hiding the flavor of alcohol (39%) and liking the taste (36%). Common consequences were feeling jittery (71%) and trouble sleeping (46%). Combined users had the highest rates of risk behaviors (e.g., drug use, sexual risk behaviors, driving after drinking) and alcohol use severity. Multinomial logistic regression indicated that men, those who had sex after substance use, those who had used drugs, and those with higher alcohol severity were more likely to be Combined users than Non Users. Those with higher alcohol severity were also more likely to be Combined users than Separate users. Combining energy drinks and alcohol is associated with higher rates of other risk behaviors among young drinkers. Future studies are needed to determine longitudinal relationships of energy drink use on substance use problem trajectories. PMID- 25528145 TI - Gut transport characteristics in herbivorous and carnivorous serrasalmid fish from ion-poor Rio Negro water. AB - Three closely related characids, Tambaqui (omnivore), black Piranha (carnivore), and Pacu (herbivore), all Serrasalmidae, inhabit the ion-poor, acidic Rio Negro. We compared O2-consumption and N excretion rates in vivo, and sodium, chloride, glucose, and ammonia transport characteristics of gut sac preparations in vitro. The Pacu had a significantly higher weight-specific oxygen consumption, and a lower N/Q ratio than the omnivorous Tambaqui, and a significantly lower urea-N excretion rate than the carnivorous black Piranha, suggesting N-limitation in the herbivorous Pacu. With a value of 2.62 +/- 0.15, gut to fork length ratio in the Pacu was about 2.5 times higher than in the black Piranha, and 2.0 times higher than in the Tambaqui. Anterior intestinal activities of three enzymes involved in N-fixation for amino acid synthesis (glutamate dehydrogenase, glutamate oxaloacetate transferase, and glutamate-pyruvate transferase) were generally greatest in the carnivore and lowest in the herbivore species. In all three species, sodium, chloride, glucose, and ammonia were taken up at high rates from the intestine, resulting in an isosmotic fluid flux. Comparing the area-specific fluid flux of the anterior, mid, and posterior gut sections, no difference was detected between the three sections of the Pacu, while in the Tambaqui, it was highest in the anterior section, and in the black Piranha highest in the middle section. Overall, the area-specific uptake rates for sodium, chloride, glucose, and ammonia of anterior, mid, and posterior sections were similar in all three species, indicating that there is no difference in the area-specific transport rates associated with trophic position. The net ammonia uptake flux from gut interior was not significantly different from the net ammonia efflux to the serosal fluid, so that the ammonia removed from the intestine by the mucosal epithelium was quantitatively transferred through the tissue to the serosal side in all three species. Thus, metabolic activity of gut tissue did not significantly influence the net ammonia transfer. Due to the much higher gut to fork length ratio, the overall transport capacity of the gut of the herbivorous Pacu by far exceeded the transport capacity of their carnivorous and omnivorous relatives, thus compensating for the lower digestibility and the low Na(+), Cl( ), and N-content of the plant diet. Accordingly, in order to cope with the more difficult digestible plant material and the very low nitrogen content of plants, herbivorous fish have not evolved more effective area-specific transport capacities, but rather have increased the length of the gut. PMID- 25528146 TI - Using biochemical markers to assess the effects of imposed temperature stress on freshwater decapod crustaceans: Cherax quadricarinatus as a test case. AB - The effects of thermal stress can impact negatively on the abundance and distribution of temperature-sensitive species, particularly freshwater crustaceans. This study investigated the effects of thermal stress on physiological and biochemical parameters at five treatment temperatures resulting in minimal (25 degrees C), moderate (27, 29 degrees C) or severe (31, 33 degrees C) thermal stress in the common tropical freshwater crayfish Cherax quadricarinatus. The aim was to develop a suite of stress-sensitive assays to use on threatened populations of freshwater crustaceans, particularly those restricted to cooler temperatures and only found in high altitude refugia. Significant increases in indicators of oxidative and metabolic stress were observed at 29 degrees C and were elevated further at 33 degrees C. After a 50 day acclimation to an imposed temperature stress, significant changes in the level of total glutathione, total lipids, muscular protein, total haemocyte count, lipid peroxidation and protein carbonyls were observed between treatments while superoxide dismutase activity and haemolymph protein concentrations did not change. The data provided proof of concept that measuring key biochemical responses to high temperature can provide a means of contrasting the level of thermal stress experienced between individuals of the same species adapted to different temperatures. The methods developed are expected to be of use in research on wild populations of other freshwater poikilothermic organisms, particularly those susceptible to increased environmental temperatures associated with climate change. PMID- 25528147 TI - Targeted mutagenesis using zinc-finger nucleases in perennial fruit trees. AB - MAIN CONCLUSION: Targeting a gene in apple or fig with ZFN, introduced by transient or stable transformation, should allow genome editing with high precision to advance basic science and breeding programs. Genome editing is a powerful tool for precise gene manipulation in any organism; it has recently been shown to be of great value for annual plants. Classical breeding strategies using conventional cross-breeding and induced mutations have played an important role in the development of new cultivars in fruit trees. However, fruit-tree breeding is a lengthy process with many limitations. Efficient and widely applied methods for targeted modification of fruit-tree genomes are not yet available. In this study, transgenic apple and fig lines carrying a zinc-finger nuclease (ZFNs) under the control of a heat-shock promoter were developed. Editing of a mutated uidA gene, following expression of the ZFN genes by heat shock, was confirmed by GUS staining and PCR product sequencing. Finally, whole plants with a repaired uidA gene due to deletion of a stop codon were regenerated. The ZFN-mediated gene modifications were stable and passed onto regenerants from ZFN-treated tissue cultures. This is the first demonstration of efficient and precise genome editing, using ZFN at a specific genomic locus, in two different perennial fruit trees-apple and fig. We conclude that targeting a gene in apple or fig with a ZFN introduced by transient or stable transformation should allow knockout of a gene of interest. Using this technology for genome editing allows for marker gene independent and antibiotic selection-free genome engineering with high precision in fruit trees to advance basic science as well as nontransgenic breeding programs. PMID- 25528148 TI - Two Blast-independent tools, CyPerl and CyExcel, for harvesting hundreds of novel cyclotides and analogues from plant genomes and protein databases. AB - MAIN CONCLUSION: Two high-throughput tools harvest hundreds of novel cyclotides and analogues in plants. Cyclotides are gene-encoded backbone-cyclized polypeptides displaying a diverse range of bioactivities associated with plant defense. However, genome-scale or database-scale evaluations of cyclotides have been rare so far. Here, a novel time-efficient Perl program, CyPerl, was developed for searching cyclotides from predicted ORFs of 34 available plant genomes and existing plant protein sequences from Genbank databases. CyPerl isolated sequences were further analyzed by removing repeats, evaluating their cysteine-distributed regions (CDRs) and comparing with CyBase-collected cyclotides in a user-friendly Excel (Microsoft Office) template, CyExcel. After genome-screening, 186 ORFs containing 145 unique cyclotide analogues were identified by CyPerl and CyExcel from 30 plant genomes tested from 10 plant families. Phaseolus vulgaris and Zea mays were the richest two species containing cyclotide analogues in the plants tested. After screening protein databases, 266 unique cyclotides and analogues were identified from seven plant families. By merging with 288 unique CyBase-listed cyclotides, 510 unique cyclotides and analogues were obtained from 13 plant families. In total, seven novel plant families containing cyclotide analogues and 202 novel cyclotide analogues were identified in this study. This study has established two Blast-independent tools for screening cyclotides from plant genomes and protein databases, and has also significantly widened the plant distribution and sequence diversity of cyclotides and their analogues. PMID- 25528149 TI - Leaf wounding or simulated herbivory in young N. attenuata plants reduces carbon delivery to roots and root tips. AB - MAIN CONCLUSION: In Nicotiana attenuata seedlings, simulated herbivo ry by the specialist Manduca sexta decreases root growth and partitioning of recent photoassimilates to roots in contrast to increased partitioning reported for older plants. Root elongation rate in Nicotiana attenuata has been shown to decrease after leaf herbivory, despite reports of an increased proportion of recently mobilized photoassimilate being delivered towards the root system in many species after similar treatments. To study this apparent contradiction, we measured the distribution of recent photoassimilate within root tissues after wounding or simulated herbivory of N. attenuata leaves. We found no contradiction: herbivory reduced carbon delivery to root tips. However, the speed of phloem transport in both shoot and root, and the delivery of recently assimilated carbon to the entire root system, declined after wounding or simulated herbivory, in contrast with the often-reported increase in root partitioning. We conclude that the herbivory response in N. attenuata seedlings is to favor the shoot and not bunker carbon in the root system. PMID- 25528150 TI - Perinatal factors associated with early neonatal deaths in very low birth weight preterm infants in Northeast Brazil. AB - BACKGROUND: In Brazil, the prevalence of prematurity has increased in recent years and it is a major cause of death in the neonatal period. Therefore, this study aims at assessing perinatal factors associated with early neonatal deaths in very low birth weight preterm infants born in a region of Brazil with low Human Development Index. METHODS: Prospective cohort study of inborns with gestational age 23(0/7)-31(6/7) weeks and birthweight 500-1499 g without malformations in 19 public reference hospitals of the state capitals of Brazil's Northeast Region. Perinatal variables associated with early neonatal death were determined by Cox regression analysis. RESULT: Among 627 neonates, 179 (29%) died with 0-6 days after birth. Early death was associated to: absence of antenatal steroids (HR 1.59; 95% CI 1.11-2.27), multiple gestation (1.95; 1.28-3.00), male sex (2.01; 1.40-2.86), 5th minute Apgar <7 (2.93; 2.03-4.21), birthweight <1000 g (2.58; 1.70-3.88), gestational age <28 weeks (2.07; 1.42-3.02), use of surfactant (1.65; 1.04-2.59), and non-use of a pain scale (1.89; 1.24-2.89). CONCLUSION: Biological variables and factors related to the quality of perinatal care were associated with the high chance of early death of preterm infants born in reference hospitals of Northeast Brazil. PMID- 25528151 TI - Effect of 30 % hydrogen peroxide on mineral chemical composition and surface morphology of bovine enamel. AB - A combination of atomic absorption spectroscopy (AAS), Fourier transform infrared spectroscopy (FTIR), scanning electronic microscopy (SEM), and gas adsorption techniques was used to characterize the effect of 30 % hydrogen peroxide (HP) on enamel surface. To perform the analyses of AAS, 1 ml of 30 % HP was added to 30 mg of a bovine enamel powder sample (150-200 um fractions) for times of 5, 20, 60, 90, and 120 min; then 5 ml of the solution was withdrawn after each time period to measure [Ca(2+)] ions. The remaining powder was recovered and analyzed by FTIR. For SEM and gas adsorption tests, 4 * 4 mm(2) enamel sectioned samples were polished and 30 % HP was applied on the surface for the same time periods. AAS data show that 30 % HP treatment mobilized calcium from the enamel at all times studied. FTIR spectra showed that the total amount of phosphate and carbonate mineral contents such as amide I decreased significantly. SEM revealed that randomly distributed areas throughout the smooth enamel surface treatment became rougher and more irregular. These alterations indicate that surface damage increases with increasing durations of HP treatment. Gas adsorption analysis proved that bleached enamel is a typically non-porous material with a small specific surface area which decreases slightly with the 30 % HP treatment. In sum, 30 % HP induced a significant alteration of the organic and mineral part of the enamel, leading to the release of calcium and a rougher, more irregular enamel surface on randomly distributed areas. PMID- 25528152 TI - Human papillomavirus 16/18 seroprevalence in unvaccinated women over 30 years with normal cytology and with high grade cervical abnormalities in Australia: results from an observational study. AB - BACKGROUND: Australia commenced human papillomavirus (HPV) vaccination in 2007, with a two-year catch-up to the age of 26; catch-up cohorts are thus now entering their thirties. Plans for monitoring vaccine impact involve pre- and post vaccination assessment of cervical HPV DNA in the general population and in high grade abnormalities. Although HPV serology is less sensitive than DNA genotyping, it assesses lifetime exposure and may be easier to measure in the general population. However, benchmark pre-vaccination seroprevalence of vaccine-included types in unvaccinated women with high grade abnormalities has not previously been reported. METHODS: We assessed seroprevalence for HPV16/18 from a population based sample of 3,729 women with normal cytology and 971 women with confirmed high grade abnormalities (CIN2/3), aged 30-64 years, unvaccinated, and recruited in New South Wales in 2006-2010. We examined the variation in HPV16/18 seropositivity by age and in relation to a range of reproductive and behavioural characteristics in the subgroup of normal cytology women with no recent history of high grade cervical disease. RESULTS: The HPV 16, 18 and combined seroprevalence was 19%, 7% and 24% among women with normal cytology, and 39%, 13% and 44% among women with CIN2/3, respectively. For both groups, HPV16/18 seroprevalence was highest at age 30-39 years and decreased with age. In multivariable analysis for women with normal cytology, HPV16 and HPV18 seropositivity were each associated with the number of lifetime sexual partners (p-trend <0.001 and 0.052, respectively) and for HPV16 this was also associated with age (p-trend <0.001) and prior diagnosis of Chlamydia (adjusted OR 1.89, 95% CI 1.27-2.80). CONCLUSIONS: The findings of this study inform pre-vaccination estimates of HPV seropositivity in women with normal cytology and women with high grade abnormalities. Almost a quarter of unvaccinated women aged over 30 years with normal cytology, and more than 40% of those with CIN2/3, had seroconverted to HPV 16 or 18. These findings provide a potential additional benchmark for assessing the effects of HPV vaccination. PMID- 25528153 TI - Measurement of bone marrow lesions by MR imaging in knee osteoarthritis using quantitative segmentation methods--a reliability and sensitivity to change analysis. AB - BACKGROUND: Longitudinal assessment of bone marrow lesions (BMLs) in knee osteoarthritis (KOA) by MRI is usually performed using semi-quantitative grading methods. Quantitative segmentation methods may be more sensitive to detect change over time. The purpose of this study was to evaluate and compare the validity and sensitivity to detect changes of two quantitative MR segmentation methods for measuring BMLs in KOA, one computer assisted (CAS) and one manual (MS) method. METHODS: Twenty-two patients with KOA confined to the medial femoro-tibial compartment obtained MRI at baseline and follow-up (median 334 days in between). STIR, T1 and fat saturated T1 post-contrast sequences were obtained using a 1.5 T system. The 44 sagittal STIR sequences were assessed independently by two readers for quantification of BML. The signal intensities (SIs) of the normal bone marrow in the lateral femoral condyles and tibial plateaus were used as threshold values. The volume of bone marrow with SIs exceeding the threshold values (BML) was measured in the medial femoral condyle and tibial plateau and related to the total volume of the condyles/plateaus.The 95% limits of agreement at baseline were used to determine the sensitivity to change. RESULTS: The mean threshold values of CAS and MS were almost identical but the absolute and relative BML volumes differed being 1319 mm3/10% and 1828 mm3/15% in the femur and 941 mm3/7% and 2097 mm3/18% in the tibia using CAS and MS, respectively. The BML volumes obtained by CAS and MS were significantly correlated but the tissue changes measured were different. The volume of voxels exceeding the threshold values was measured by CAS whereas MS included intervening voxels with normal SI.The 95% limits of agreement were narrower by CAS than by MS; a significant change of relative BML by CAS was outside the limits of -2.0%-4.7% whereas the limits by MS were -6.9%-8.2%. The BML changed significantly in 13 knees using CAS and in 10 knees by MS. CONCLUSION: CAS was a reliable method for measuring BML and more sensitive to detect changes over time than MS. The BML volumes measured by the two methods differed but were significantly correlated. PMID- 25528154 TI - Exostosis of the optic canal in a child--a rare diagnosis in a paediatric ear, nose and throat setting: a case report. AB - INTRODUCTION: Optic nerve compression is an uncommon disorder leading to deterioration or complete loss of vision. CASE PRESENTATION: We describe the case of a 14-year-old Caucasian girl with a gradual deterioration of vision in her right eye. Using modern imaging techniques and endonasal endoscopic surgery, we identified the cause and removed the pathology. CONCLUSIONS: The cause of optic nerve compression was a rare exostosis in the optic canal. An endonasal endoscopic approach is the optimal choice for management of optic nerve pathologies. It is a gentle and minimally invasive surgical technique. Interdisciplinary cooperation, especially with the eye doctor and radiologist, is required in these cases. PMID- 25528155 TI - Current employment characteristics and career intentions of Lithuanian dentists. AB - BACKGROUND: The present survey explored the current employment profile and future career intentions of Lithuanian general dentists and specialists. METHODS: A census sampling method was employed with data collected by means of a structured questionnaire that inquired about demographics, different employment-related aspects (practice type and location, working hours, perceived lack of patients, etc.), and future career intentions (intent to emigrate, to change profession, or the timing of retirement). The final response rate was 67.6% corresponding to 2,008 respondents. RESULTS: The majority of all dentists work full or part-time in the private dental sector, more than one third of them owns a private practice or rents a dental chair. A minority of dentists works in the public dental sector. According to the survey, 26.6% of general dentists and 39.2% of dental specialists works overtime (> 40 hours per week; P < 0.001) and practice in multiple clinics (1.4 +/- 0.6 and 2.0 +/- 1.2, respectively; P < 0.001). One third of general dentists (31.3%) and dental specialists (31.4%) stated to have a low number of patients (P > 0.05). The majority (68.9% of general dentists and 65.9% of dental specialists) plans to work after the retirement age (P > 0.05). Emigration as an option for their professional career is being considered by 10.8% of general dentists and 8.3% of dental specialists (P > 0.05). Working either full or part-time in private practices (OR = 4.3) and younger age (<= 35 years; OR = 2.2) are the two strongest predictors for a perceived insufficient number of patients. CONCLUSIONS: One third of dentists in Lithuania work long hours and lack patients. Many dentists practice in multiple locations and plan to retire after the official retirement age. Some dentists and dental specialists plan to emigrate. The perceived shortcomings within the dental care system and workforce planning of dentists need to be addressed. PMID- 25528156 TI - Long non-coding RNA normalisers in human brain tissue. AB - The family of long non-coding RNA (lncRNA) is of increasing scientific interest as there is emerging evidence, that lncRNAs are of essential importance for transcriptional and translational control, genomic imprinting and regulation of normal development as well as neuronal plasticity. As the generation of reliable expression profiles requires adequate normalisers, it is of fundamental importance to determine suitable references for lncRNA studies. However, to date no systematic analysis of potential lncRNA normalisers has been performed on human postmortem brain tissue samples. In this study, we investigated three different brain regions (cortex, white matter, and cerebellum) of human postmortem tissue and analysed the expression stability of 90 lncRNAs. Bioinformatical analysis was performed to identify stably expressed lncRNAs. Subsequently, lncRNAs were classified according to their stability values using the NormFinder algorithm. We identified 30 suitable normalisers in cortex, 22 in white matter, and 41 in cerebellum. In addition, there were 13 suitable normalisers for studies comparing cortex and white matter, 25 for studies comparing cortex and cerebellum and 7 for studies comparing white matter and cerebellum. 5 lncRNAs (LUST, IGF2AS (family), 7SK, HOXA6as, NDM29) showed stable expression in all investigated brain regions. A subsequent analysis of the influence of postmortem intervals (PMI) on expression of lncRNAs revealed that expression levels of the newly identified 5 universal lncRNA normalisers are stable within PMI of up to 27 h. Thus, these 5 lncRNAs may be applicable as references for accurate normalisation of lncRNA profiling in multiple brain regions during long PMI, enabling the generation of highly reproducible datasets in lncRNA studies of the human brain. PMID- 25528157 TI - Mutation in the Drosophila melanogaster adenosine receptor gene selectively decreases the mosaic hyperplastic epithelial outgrowth rates in wts or dco heterozygous flies. AB - Adenosine (Ado) is a ubiquitous metabolite that plays a prominent role as a paracrine homeostatic signal of metabolic imbalance within tissues. It quickly responds to various stress stimuli by adjusting energy metabolism and influencing cell growth and survival. Ado is also released by dead or dying cells and is present at significant concentrations in solid tumors. Ado signaling is mediated by Ado receptors (AdoR) and proteins modulating its concentration, including nucleoside transporters and Ado deaminases. We examined the impact of genetic manipulations of three Drosophila genes involved in Ado signaling on the incidence of somatic mosaic clones formed by the loss of heterozygosity (LOH) of tumor suppressor and marker genes. We show here that genetic manipulations with the AdoR, equilibrative nucleoside transporter 2 (Ent2), and Ado deaminase growth factor-A (Adgf-A) cause dramatic changes in the frequency of hyperplastic outgrowth clones formed by LOH of the warts (wts) tumor suppressor, while they have almost no effect on control yellow (y) clones. In addition, the effect of AdoR is dose-sensitive and its overexpression leads to the increase in wts hyperplastic epithelial outgrowth rates. Consistently, the frequency of mosaic hyperplastic outgrowth clones generated by the LOH of another tumor suppressor, discs overgrown (dco), belonging to the wts signaling pathway is also dependent on AdoR. Our results provide interesting insight into the maintenance of tissue homeostasis at a cellular level. PMID- 25528159 TI - Students' perspectives on research and assessment of a model template designed to guide beginners in research in a medical school in Cameroon. AB - BACKGROUND: Research activities for medical students and residents (trainees) are expected to serve as a foundation for the acquisition of basic research skills. Some medical schools therefore recommend research work as partial requirement for certification. However medical trainees have many difficulties concerning research, for which reason potential remedial strategies need to be constantly developed and tested. The views of medical trainees are assessed followed by their use and appraisal of a novel "self-help" tool designed for the purposes of this study with potential for improvement and a wider application. METHODS: This study was a cross-sectional survey of volunteering final-year medical students and residents of a medical school in Cameroon. RESULTS: This study surveyed the opinions of a total of 120 volunteers of which 82 (68%) were medical students. Three out of 82 (4%) medical students reported they had participated in research activities with a publication versus 10 out of 38 residents (26%). The reported difficulties in research for these trainees included referencing of material (84%), writing a research proposal (79%), searching for literature (73%) and knowledge of applicable statistical tests (72%) amongst others. All participants declared the "self-help" tool was simple to use, guided them to think and better understand their research focus. CONCLUSION: Medical trainees require much assistance on research and some "self-help" tools such as the template used in this study might be a useful adjunct to didactic lectures. PMID- 25528158 TI - Peripheral residence of naive CD4 T cells induces MHC class II-dependent alterations in phenotype and function. AB - BACKGROUND: As individual naive CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naive CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naive CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences. RESULTS: We examined separated CD4hi and CD4lo subsets of mouse naive CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naive CD4lo and CD4hi cells showed similar differences. Naive CD4lo and CD4hi subsets of thymic single positive CD4 T cells did not show differences whereas peripheral naive CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer mediated parking of naive CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent, at least in part, on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naive CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition. CONCLUSIONS: Our data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naive CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of older people via either anti-oxidant or DUSP inhibitor small molecules. PMID- 25528160 TI - Immuno-pathomechanism of liver fibrosis: targeting chemokine CCL2-mediated HIV:HCV nexus. AB - Even in the era of successful combination antiretroviral therapy (cART), co infection of Hepatitis C virus (HCV) remains one of the leading causes of non AIDS-related mortality and morbidity among HIV-positive individuals as a consequence of accelerated liver fibrosis and end-stage liver disease (ESLD). The perturbed liver microenvironment and induction of host pro-inflammatory mediators in response to HIV and HCV infections, play a pivotal role in orchestrating the disease pathogenesis and clinical outcomes. How these viruses communicate each other via chemokine CCL2 and exploit the liver specific cellular environment to exacerbate liver fibrosis in HIV/HCV co-infection setting is a topic of intense discussion. Herein, we provide recent views and insights on potential mechanisms of CCL2 mediated immuno-pathogenesis, and HIV-HCV cross-talk in driving liver inflammation. We believe CCL2 may potentially serve an attractive target of anti fibrotic intervention against HIV/HCV co-infection associated co-morbidities. PMID- 25528162 TI - Personality Assessment Inventory scores as predictors of misconduct, recidivism, and violence: A meta-analytic review. AB - More than 30 studies have examined the ability of scores on the Personality Assessment Inventory (PAI; Morey, 1991, 2007) to predict violence or misconduct. The Antisocial Features (ANT), Aggression (AGG), and Violence Potential Index (VPI) Scales of the PAI, in particular, have received substantial attention as predictors of institutional infractions and criminal recidivism. The current study used meta-analysis to provide a comprehensive review of the ability of scores on these and other PAI scales to predict misbehavior. Scores on the ANT (d = .26 to .39) and AGG (d = .23 to .40) scales consistently emerged as small to moderate predictors of misbehavior. Effects tended to be larger in correctional than treatment settings (e.g., ANT d = .44 vs. .20), for institutional misconduct than recidivism (e.g., AGG d = .37 vs. .23), and for institutional misconduct studies with follow up periods of at least 1.5 years (e.g., ANT d = .46). Overall, findings provide support for the predictive validity of multiple PAI scales. PMID- 25528161 TI - The GPCR repertoire in the demosponge Amphimedon queenslandica: insights into the GPCR system at the early divergence of animals. AB - BACKGROUND: G protein-coupled receptors (GPCRs) play a central role in eukaryotic signal transduction. However, the GPCR component of this signalling system, at the early origins of metazoans is not fully understood. Here we aim to identify and classify GPCRs in Amphimedon queenslandica (sponge), a member of an earliest diverging metazoan lineage (Porifera). Furthermore, phylogenetic comparisons of sponge GPCRs with eumetazoan and bilaterian GPCRs will be essential to our understanding of the GPCR system at the roots of metazoan evolution. RESULTS: We present a curated list of 220 GPCRs in the sponge genome after excluding incomplete sequences and false positives from our initial dataset of 282 predicted GPCR sequences obtained using Pfam search. Phylogenetic analysis reveals that the sponge genome contains members belonging to four of the five major GRAFS families including Glutamate (33), Rhodopsin (126), Adhesion (40) and Frizzled (3). Interestingly, the sponge Rhodopsin family sequences lack orthologous relationships with those found in eumetazoan and bilaterian lineages, since they clustered separately to form sponge specific groups in the phylogenetic analysis. This suggests that sponge Rhodopsins diverged considerably from that found in other basal metazoans. A few sponge Adhesions clustered basal to Adhesion subfamilies commonly found in most vertebrates, suggesting some Adhesion subfamilies may have diverged prior to the emergence of Bilateria. Furthermore, at least eight of the sponge Adhesion members have a hormone binding motif (HRM domain) in their N-termini, although hormones have yet to be identified in sponges. We also phylogenetically clarified that sponge has homologs of metabotropic glutamate (mGluRs) and GABA receptors. CONCLUSION: Our phylogenetic comparisons of sponge GPCRs with other metazoan genomes suggest that sponge contains a significantly diversified set of GPCRs. This is evident at the family/subfamily level comparisons for most GPCR families, in particular for the Rhodopsin family of GPCRs. In summary, this study provides a framework to perform future experimental and comparative studies to further verify and understand the roles of GPCRs that predates the divergence of bilaterian and eumetazoan lineages. PMID- 25528163 TI - Development of the Abbreviated Masculine Gender Role Stress Scale. AB - Data gathered from 6 independent samples (n = 1,729) that assessed men's masculine gender role stress in college and community males were aggregated used to determine the reliability and validity of an abbreviated version of the Masculine Gender Role Stress (MGRS) Scale. The 15 items with the highest item-to total scale correlations were used to create an abbreviated MGRS Scale. Psychometric properties of each of the 15 items were examined with item response theory (IRT) analysis, using the discrimination and threshold parameters. IRT results showed that the abbreviated scale may hold promise at capturing the same amount of information as the full 40-item scale. Relative to the 40-item scale, the total score of the abbreviated MGRS Scale demonstrated comparable convergent validity using the measurement domains of masculine identity, hypermasculinity, trait anger, anger expression, and alcohol involvement. An abbreviated MGRS Scale may be recommended for use in clinical practice and research settings to reduce cost, time, and patient/participant burden. Additionally, IRT analyses identified items with higher discrimination and threshold parameters that may be used to screen for problematic gender role stress in men who may be seen in routine clinical or medical practice. PMID- 25528164 TI - Internal consistency and stability of the CANTAB neuropsychological test battery in children. AB - The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computer assessed test battery widely use in different populations. The internal consistency and 1-year stability of CANTAB tests were examined in school-age children. Two hundred-thirty children (57% girls) from five schools in the Jyvaskyla school district in Finland participated in the study in spring 2011. The children completed the following CANTAB tests: (a) visual memory (pattern recognition memory [PRM] and spatial recognition memory [SRM]), (b) executive function (spatial span [SSP], Stockings of Cambridge [SOC], and intra-extra dimensional set shift [IED]), and (c) attention (reaction time [RTI] and rapid visual information processing [RVP]). Seventy-four children participated in the follow-up measurements (64% girls) in spring 2012. Cronbach's alpha reliability coefficient was used to estimate the internal consistency of the nonhampering test, and structural equation models were applied to examine the stability of these tests. The reliability and the stability could not be determined for IED or SSP because of the nature of these tests. The internal consistency was acceptable only in the RTI task. The 1-year stability was moderate-to-good for the PRM, RTI, and RVP. The SSP and IED showed a moderate correlation between the two measurement points. The SRM and the SOC tasks were not reliable or stable measures in this study population. For research purposes, we recommend using structural equation modeling to improve reliability. The results suggest that the reliability and the stability of computer-based test batteries should be confirmed in the target population before using them for clinical or research purposes. PMID- 25528165 TI - The validity and scalability of the Theory of Mind Scale with toddlers and preschoolers. AB - Despite the importance of theory of mind (ToM) for typical development, there remain 2 key issues affecting our ability to draw robust conclusions. One is the continued focus on false belief as the sole measure of ToM. The second is the lack of empirically validated measures of ToM as a broad construct. Our key aim was to examine the validity and reliability of the 5-item ToM scale (Peterson, Wellman, & Liu, 2005). In particular, we extended on previous research of this scale by assessing its scalability and validity for use with children from 2 years of age. Sixty-eight typically developing children (aged 24 to 61 months) were assessed on the scale's 5 tasks, along with a sixth Sally-Anne false-belief task. Our data replicated the scalability of the 5 tasks for a Rasch-but not Guttman-scale. Guttman analysis showed that a 4-item scale may be more suitable for this age range. Further, the tasks showed good internal consistency and validity for use with children as young as 2 years of age. Overall, the measure provides a valid and reliable tool for the assessment of ToM, and in particular, the longitudinal assessment of this ability as a construct. PMID- 25528166 TI - Early supported discharge after stroke in Bergen (ESD Stroke Bergen): three and six months results of a randomised controlled trial comparing two early supported discharge schemes with treatment as usual. AB - BACKGROUND: Stroke causes lasting disability and the burden of stroke is expected to increase substantially during the next decades. Optimal rehabilitation is therefore mandatory. Early supported discharge (ESD) has previously shown beneficial, but all major studies were carried out more than ten years ago. We wanted to implement and study the results of ESD in our community today with comparisons between ESD and treatment as usual, as well as between two different ESD models. METHODS: Patients with acute stroke were included during a three year period (2008-11) in a randomised controlled study comparing two different ESD models to treatment as usual. The two ESD models differed by the location of treatment: either in a day unit or in the patients' homes. Patients in the ESD groups were followed by a multi-disciplinary ambulatory team in the stroke unit and discharged home as early as possible. The ESD models also comprised treatment by a multi-disciplinary community health team for up to five weeks and follow-up controls after 3 and 6 months. Primary outcome was modified Rankin Scale (mRS) at six months. RESULTS: Three-hundred-and-six patients were included. mRS scores and change scores were non-significantly better in the two ESD groups at 3 and 6 months. Within-group improvement from baseline to 3 months was significant in the ESD 1 (p = 0.042) and ESD 2 (p = 0.001) groups, but not in the controls. More patients in the pooled ESD groups were independent at 3 (p = 0.086) and 6 months (p = 0.122) compared to controls and there also was a significant difference in 3 month change score between them (p = 0.049). There were no differences between the two ESD groups. Length of stay in the stroke unit was 11 days in all groups. CONCLUSIONS: Patients in the ESD groups tended to be more independent than controls at 3 and 6 months, but no clear statistically significant differences were found. The added effect of supported discharge and improved follow-up seems to be rather modest. The improved stroke treatment of today may necessitate larger patient samples to demonstrate additional benefit of ESD. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT00771771. PMID- 25528167 TI - Deciphering the interactions between chlorambucil and calf thymus DNA: a multi spectroscopic and molecular docking study. AB - Non-covalent interactions of chlorambucil with calf thymus DNA was investigated using multi-spectroscopic techniques and molecular docking study. Binding constant calculated was found to be 1.54*10(4)M(-1) at 290K, significantly lower than various known intercalators. Quenching process was found to be static as evident by biomolecular quenching constant. Thermodynamic parameters revealed the involvement of hydrophobic interactions and hydrogen bonds in the binding. Chlorambucil was found to interact via external binding mode and follow groove binding as it replaces Hoechst (a typical groove binder) from the groove of DNA but does not replace intercalating dyes including ethidium bromide and acridine orange from the DNA helix. These results were further supported by KI quenching experiments, DNA melting studies, CD spectroscopy and molecular docking. PMID- 25528168 TI - The Keap1-Nrf2 system and diabetes mellitus. AB - Nrf2 (NF-E2-related factor 2) plays a key role in the protection of vertebrates against environmental stress by contributing to the inducible expression of detoxification and antioxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1) is a sensor for oxidative and electrophilic stresses. Keap1 also acts as an E3 ubiquitin ligase substrate-recognition subunit that specifically targets Nrf2. Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions. Upon exposure to oxidative or electrophilic stress, Keap1 loses its ability to ubiquitinate Nrf2. Many lines of evidence have recently clarified that the Keap1 Nrf2 system also plays critical roles in the maintenance of cellular homeostasis. One of the most salient examples is the contribution of Keap1-Nrf2 to metabolic and energy-balance regulation. In particular, how the Keap1-Nrf2 system protects the body against diabetes mellitus and how perturbations in this system provoke the disease condition are now under intense investigation. This review will summarize the recent progress made in this area. PMID- 25528170 TI - Editorial: Reflections on being 'founding' Editor-in-Chief of Cellular Signalling. PMID- 25528169 TI - Sequential combination therapy with flavopiridol and autocatalytic caspase-3 driven by amplified hTERT promoter synergistically suppresses human ovarian carcinoma growth in vitro and in mice. AB - BACKGROUND: Induction of cell apoptosis and regulation of cell cycle are very attractive for treatments of tumors including ovarian carcinoma. Flavopiridol is a potent small molecular cyclin-dependent kinase(cdk) inhibitor, but its antitumor efficacy is not satisfied yet. Caspase-3 play a major role in the transduction of apoptotic signals and the execution of apoptosis in mammalian cells. We have successfully constructed the recombinant adenovirues AdHTVP2G5-rev casp3 containing autocatalytic caspase-3 (rev-caspase-3) driven by amplified hTERT promoter system (TSTA-hTERTp). In this study, we applied it with flavopiridol to investigate their antitumor effect on ovarian cancer in vitro and in vivo. METHODS: Cell viabilities were determined using Cell Counting Kit 8 and flow cytometry. RT-PCR and immunoblotting assays were used to detect cellular apoptotic activities. Tumor growth and survival of mice bearing tumors were studied. RESULTS: Flavopiridol or AdHTVP2G5-rev-casp3 at low dosage alone was mildly cytotoxic in vitro with a viability rate of 86.5 +/- 4.7% for 300 nM flavopiridol and 88.9 +/- 5.4% for AdHTVP2G5-rev-casp3 (MOI 20). By contrast, significant synergism of their sequential combination was observed, and the treatment of AdHTVP2G5-rev-casp3 (MOI 20) infection for 72 h, followed by flavopiridol (300 nM) for 48 h, can result in the most synergistic cell death, with cell survival rate and apoptotic rate of 11.6% and 69.7%, respectively. The sequential combination showed synergistic tumor suppression rate of 77.8%, which was significantly higher than that of AdHTVP2G5-rev-casp3 (33.6%) or flavopiridol (40.1%) alone. The mean survival of mice treated with the combination was 286 +/- 8 d, which was synergistically longer than that of mice treated with AdHTVP2G5 rev-casp3 (141 +/- 14d), flavopiridol (134 +/- 10 d) or controls (106 +/- 11 d) (P < 0.01). CONCLUSIONS: The sequential combination of rev-caspase-3 and flavopiridol result in significant synergistic cell killing effects, significant tumor growth suppression and extended survival of mice bearing OVCAR3 cells. The combination should be further explored as a potential clinically useful regimen against ovarian cancer. PMID- 25528171 TI - Expression of prostaglandin synthesizing enzymes (cyclooxygenase 1 and cyclooxygenase 2) in the ovary of the ostrich (Struthio camelus). AB - Cyclooxygenase is the rate limiting enzyme in the production of prostaglandins. In birds two isoforms are present: cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). Despite evidence implicating that cyclooxygenases and PGs are critical factors in female reproduction in birds, little is known about COX expression in the avian ovary. In birds, cyclooxygenases have been studied in very few species only. In this study we report on the expression of COX-1 and COX-2 in the ovary of the ostrich (Struthio camelus) using immunohistochemistry and non-radioactive in situ hybridization techniques. Our results demonstrate that COX-1 is strongly expressed in the cytoplasm of oocytes of previtellogenic follicles, whereas COX-2 shows the strongest immunostaining in the granulosa cells of previtellogenic follicles. The signals of both isoenzymes fade significantly with increasing diameter and finally nearly vanish in the vitellogenic follicles with a size >1.8 cm. This expression pattern in the ostrich (S. camelus) is, therefore, completely different from the localization of COX-1 and COX-2 in the hen (Gallus gallus), a finding which also suggests different functions of the cyclooxygenases in the ostrich species. Non-radioactive in situ hybridization confirmed that COX-1 is synthesized in the ooplasm and COX-2 in the granulosa layers of early previtellogenic follicles. According to the results of this study it appears unlikely that COX-1 or COX-2 play a major role in ovulation and oviposition in the ostrich. PMID- 25528172 TI - Household hazardous waste management: a review. AB - This paper deals with the waste stream of household hazardous waste (HHW) presenting existing management systems, legislation overview and other relevant quantitative and qualitative information. European Union legislation and international management schemes are summarized and presented in a concise manner by the use of diagrams in order to provide crucial information on HHW. Furthermore, sources and types, numerical figures about generation, collection and relevant management costs are within the scope of the present paper. The review shows that the term used to refer to hazardous waste generated in households is not clearly defined in legislation, while there is absence of specific acts regulating the management of HHW. The lack of obligation to segregate HHW from the household waste and the different terminology used makes it difficult to determine the quantities and composition of this waste stream, while its generation amount is relatively small and, therefore, is commonly overlooked in waste statistics. The paper aims to cover the gap in the related literature on a subject that is included within the crucial waste management challenges at world level, considering that HHW can also have impact on other waste streams by altering the redox conditions or causing direct reactions with other non hazardous waste substances. PMID- 25528173 TI - Novel technologies for reverse osmosis concentrate treatment: a review. AB - Global water shortages due to droughts and population growth have created increasing interest in water reuse and recycling and, concomitantly, development of effective water treatment processes. Pressured membrane processes, in particular reverse osmosis, have been adopted in water treatment industries and utilities despite the relatively high operational cost and energy consumption. However, emerging contaminants are present in reverse osmosis concentrate in higher concentrations than in the feed water, and have created challenges for treatment of the concentrate. Further, standards and guidelines for assessment and treatment of newly identified contaminants are currently lacking. Research is needed regarding the treatment and disposal of emerging contaminants of concern in reverse osmosis concentrate, in order to develop cost-effective methods for minimizing potential impacts on public health and the environment. This paper reviews treatment options for concentrate from membrane processes. Barriers to emerging treatment options are discussed and novel treatment processes are evaluated based on a literature review. PMID- 25528174 TI - Effect of surfactant hydrophile-lipophile balance (HLB) value on mineral oxide charging in apolar media. AB - The current work examines the role of surfactant hydrophile-lipophile balance (HLB) on the ability for surfactant reverse micelles to impart charge to particles dispersed in an apolar medium, a study motivated by a number of applications that seek to maximize particle charge in such systems. Previous investigations have shown that relative acid-base properties of the particles and surfactants, as well as surfactant concentration and trace water content, all play a major role in the particle charge obtained. However, the ability of a surfactant to stabilize charge in reverse micelles is also an important aspect of creating charge on a particle surface. It has been previously shown that surfactant HLB value is an important parameter in assessing the size of the polar core of the reverse micelles, thereby impacting the total charge that is generated in the bulk solution as determined by conductivity. In the current study, this theory is extended to investigate the impact on particle charging. To accomplish this, the electrophoretic mobility is determined for a series of mineral oxides dispersed in Isopar-L with either Span 20, Span 80, or Span 85. These three surfactants all have the same head group chemistry, but their HLB value ranges from 1.8 to 8.6. It is found that the maximum observed particle electrophoretic mobility does scale directly with the HLB of the accompanying surfactant. This indicates that there is a direct correlation between a surfactant's ability to stabilize charge and its ability to impart charge to a particle. However, the largest HLB surfactant, Span 20, also exhibited a large amount of charge screening or neutralization at larger surfactant concentrations. This highlights the competition between particle charging and micelle-micelle charging that remains one of the largest obstacles to maximizing particle charge in apolar systems. PMID- 25528175 TI - Current and emerging options for taxol production. AB - Paclitaxel (trademark "Taxol") is a plant-derived isoprenoid natural product that exhibits potent anticancer activity. Taxol was originally isolated from the Pacific yew tree in 1967 and triggered an intense scientific and engineering venture to provide the compound reliably to cancer patients. The choices available for production include synthetic and biosynthetic routes (and combinations thereof). This chapter focuses on the currently utilized and emerging biosynthetic options for Taxol production. A particular emphasis is placed on the biosynthetic production hosts including macroscopic and unicellular plant species and more recent attempts to elucidate, transfer, and reconstitute the Taxol pathway within technically advanced microbial hosts. In so doing, we provide the reader with relevant background related to Taxol and more general information related to producing valuable, but structurally complex, natural products through biosynthetic strategies. PMID- 25528176 TI - Daily physical activity enhances resilient resources for symptom management in middle-aged women. AB - OBJECTIVE: The aim of the present study was to evaluate the direct and indirect associations between physical activity and menopausal symptoms. METHODS: Community-dwelling middle-aged women (N = 103; age range 40-60 years) completed daily Internet surveys at the end of the day and wore an accelerometer for the objective assessment of physical activity for 21-days. 1-1-1 multilevel mediation models were estimated to test whether resilient resources (i.e., positive affect and coping efficacy) mediated the association between physical activity and symptom burden at the between- and within-person level. RESULTS: Analyses demonstrated physical activity had an indirect effect (-0.16) on symptom burden through the enhancement of positive affect at the within-person level (p < .05; 95% confidence interval [CI] based on 20,000 Monte Carlo replications [-0.25, 0.08]). In models that tested coping efficacy as the mediator, it was found that the indirect effect of physical activity on symptom burden at the within-person level was -0.08 (p < .05; 95% CI based on 20,000 Monte Carlo replications [-0.14, -0.03]). CONCLUSIONS: These effects were nonsignificant at the between-person level, suggesting one route in which physical activity may help a woman to cope with her symptoms is through the enhancement of positive affect and coping efficacy on a day-to-day basis. PMID- 25528177 TI - Chronic illness and loneliness in older adulthood: The role of self-protective control strategies. AB - OBJECTIVES: This study examined whether levels of chronic illness predict enhanced feelings of loneliness in older adulthood. In addition, it investigated whether engagement in health-related self-protection (e.g., positive reappraisals), but not in health engagement control strategies (e.g., investment of time and effort), would buffer the adverse effect of chronic illness on older adults' feelings of loneliness. METHOD: Loneliness was examined repeatedly in 2 year intervals over 8 years in a longitudinal study of 121 community-dwelling older adults (Time 1 age = 64 to 83 years). In addition, levels of chronic illness, health-related control strategies, and sociodemographic variables were assessed at baseline. RESULTS: Growth-curve models showed that loneliness linearly increased over time and that this effect was observed only among participants who reported high, but not low, baseline levels of chronic illness. In addition, health-related self-protection, but not health engagement control strategies, buffered the adverse effect of chronic illness on increases in loneliness. CONCLUSIONS: Loneliness increases in older adulthood as a function of chronic illness. Older adults who engage in self-protective strategies to cope with their health threats might be protected from experiencing this adverse effect. PMID- 25528178 TI - Racial and sexual identities as potential buffers to risky sexual behavior for Black gay and bisexual emerging adult men. AB - OBJECTIVE: Emerging adult Black gay and bisexual men represent intersections of social groups that are greatly impacted by the HIV epidemic (i.e., young, Black, gay/bisexual). Given their vulnerability to HIV, it is imperative to understand how these social identities may also promote resilience, and point to protective factors that may aid in our development of population-specific HIV prevention interventions. METHOD: An online survey of the experiences of Black lesbian, gay, and bisexual young adults was administered. The current study assessed the intersection of identities and sexual risk behavior for a subsample of this population; 120 Black gay and bisexual young men (Mage = 21.79, SD = 3.08). RESULTS: Using hierarchical linear regression, higher levels of racial centrality (degree to which being Black is central to ones identity) and racial public regard (perceptions of societal views toward Black Americans) predicted decreases in risky sexual behavior (total anal sex acts and unprotected anal sex acts). CONCLUSION: Researchers and interventionist should consider the ways in which racial centrality may be a critical tool in our efforts to decrease the HIV epidemic among young Black gay and bisexual men in America. PMID- 25528180 TI - Maternal prenatal felt security and infant health at birth interact to predict infant fussing and crying at 12 months postpartum. AB - Infants born with medical problems are at risk for less optimal developmental outcomes. This may be, in part, because neonatal medical problems are associated with maternal distress, which may adversely impact infants. However, the reserve capacity model suggests that an individual's bank of psychosocial resources buffers the adverse effects of later-encountered stressors. This prospective longitudinal study examined whether preexisting maternal psychosocial resources, conceptualized as felt security in close relationships, moderate the association between neonatal medical problems and infant fussing and crying 12 months postpartum. Maternal felt security was measured by assessing its indicators in 5,092 pregnant women. At birth, infants were classified as healthy or having a medical problem. At 12 months, experience sampling was used to assess daily maternal reports of fussing and crying in 135 mothers of infants who were healthy or had medical problems at birth. Confirmatory factor analyses revealed that attachment, relationship quality, self-esteem, and social support can be conceptualized as indicators of a single felt security factor. Multiple regression analyses revealed that prenatal maternal felt security interacts with infant health at birth to predict fussing and crying at 12 months. Among infants born with medical problems, higher felt security predicted decreased fussing and crying. Maternal felt security assessed before birth dampens the association between neonatal medical problems and subsequent infant behavior. This supports the hypothesis that psychosocial resources in reserve can be called upon in the face of a stressor to reduce its adverse effects on the self or others. PMID- 25528179 TI - A minority stress--emotion regulation model of sexual compulsivity among highly sexually active gay and bisexual men. AB - OBJECTIVE: Sexual compulsivity represents a significant public health concern among gay and bisexual men, given its co-occurrence with other mental health problems and HIV infection. The purpose of this study was to examine a model of sexual compulsivity based on minority stress theory and emotion regulation models of mental health among gay and bisexual men. METHOD: Gay and bisexual men in New York City reporting at least nine past-90-day sexual partners (n = 374) completed measures of distal minority stressors (i.e., boyhood gender nonconformity and peer rejection, adulthood perceived discrimination), hypothesized proximal minority stress mediators (i.e., rejection sensitivity, internalized homonegativity), hypothesized universal mediators (i.e., emotion dysregulation, depression, and anxiety), and sexual compulsivity. RESULTS: The hypothesized model fit the data well (RMSEA = 0.05, CFI = 0.98, TLI = 0.95, SRMR = 0.03). Distal minority stress processes (e.g., adulthood discrimination) were generally found to confer risk for both proximal minority stressors (e.g., internalized homonegativity) and emotion dysregulation. Proximal minority stressors and emotion dysregulation, in turn, generally predicted sexual compulsivity both directly and indirectly through anxiety and depression. CONCLUSIONS: The final model suggests that gay-specific (e.g., internalized homonegativity) and universal (e.g., emotion dysregulation) processes represent potential treatment targets to attenuate the impact of minority stress on gay and bisexual men's sexual health. Tests of interventions that address these targets to treat sexual compulsivity among gay and bisexual men represent a promising future research endeavor. PMID- 25528181 TI - Stressful life events and orthostatic blood pressure recovery in older adults. AB - OBJECTIVE: The majority of the literature on stress and blood pressure (BP) concerns the increased risk of cardiovascular morbidity and mortality from high BP. Because the sympathetic nervous system is critical to the maintenance of orthostatic BP, it was hypothesized that older adults who have experienced more stressful life events (SLEs) would be more likely to show impaired recovery of BP in response to orthostatic stress. METHOD: A total of 3,765 participants (Mage = 61.6 years, SD = 8.2; 54% female) from the first wave of The Irish Longitudinal Study on Ageing (TILDA) were included in the current analysis. Exposure to lifetime SLEs was ascertained by self-completion questionnaire, and beat-to-beat orthostatic BP measurement was carried out. Individuals who failed to recover at least 95% of their baseline BP by 60 s post stand were characterized as having impaired orthostatic BP recovery. RESULTS: An independent, dose-response relationship between the number of SLEs reported and the odds of impaired systolic BP recovery was observed after adjustment for covariates (1 event: odds ratio [OR] = 1.19, 95% confidence interval [CI] [0.98, 1.45], p = .078; 2 events: OR = 1.33, 95% CI [1.03, 1.73], p = .031; 3 or more events: OR = 1.56, 95% CI [1.12, 1.73], p = .009). This relationship was not evident for diastolic BP recovery. CONCLUSION: The reporting of a higher number of SLEs is associated with greater risk of impaired systolic BP recovery from orthostatic stress. Potential clinical implications include an increased risk of cerebral hypoperfusion, which predisposes older adults to falls, faints, and changes in cognitive status. PMID- 25528182 TI - Do single and multiple behavior change interventions contain different behavior change techniques? A comparison of interventions targeting physical activity in obese populations. AB - OBJECTIVE: Interventions to increase physical activity (PA) can target this behavior alone or as part of multiple health behavior change (MHBC) interventions. To date, little is known about the content of MHBC interventions compared with single health behavior change (SHBC) interventions. This study sought to compare the number and type of behavior change techniques (BCTs) in SHBC and MHBC interventions using a secondary analysis of studies included in a systematic review of PA interventions in obese populations. METHODS: BCTs used to increase PA (PA BCTs) in intervention descriptions of included studies were double coded using a standardized BCT taxonomy. Interventions were categorized as SHBC (targeting PA) or MHBC (targeting PA and diet) interventions. The mean number of PA BCTs for SHBC and MHBC interventions was compared using an independent-samples t test. Chi-square analyses for each BCT assessed differences in proportions of SHBC and MHBC interventions that contained that BCT. RESULTS: The MHBC obesity interventions contained a greater number of PA BCTs (M = 11.68) than the SHBC obesity interventions (M = 8.71). Six PA BCTs were more common in MHBC interventions. Two PA BCTs were more common in the SHBC interventions. CONCLUSIONS: SHBC and MHBC interventions may systematically differ not only in the number of behaviors targeted, but also in the numbers and type of BCTs used. This study demonstrates that intervention content should also be considered when assessing the relative effectiveness of SHBC and MHBC interventions. PMID- 25528183 TI - Predictors of dental avoidance among Australian adults with different levels of dental anxiety. AB - OBJECTIVES: It has been proposed that avoidance of dental visits might be the main determinant of poor oral health outcomes in people with high dental anxiety (HDA). This study aimed to determine the predictors of dental avoidance among people with HDA and also whether these predictors differed from those found in people with lower dental anxiety (LDA). METHOD: Study participants (n = 596; response rate = 41.1%) comprised a random cross-sectional sample of the Australian adult population who completed a mailed self-complete questionnaire containing items relating to the use and accessibility of dental services, trust in dental professionals, dental anxiety, dental experiences, self-perceived oral health, vulnerability-related perceptions of visiting the dentist, and psychological health. Multiple imputation was used to replace missing values and statistically significant variables in bivariate analyses were entered into a multivariable logistic generalized linear model. RESULTS: More than two-thirds of participants with HDA were currently avoiding or delaying a dental visit. Among people with HDA, dental avoidance was independently and significantly predicted by difficulty paying a $300 dental bill, having no or only little trust in the last-visited dentist, perceived treatment need and dental anxiety. Among people with LDA, only perceived treatment need and dental anxiety predicted avoidance. CONCLUSIONS: In addition to their high anxiety, a number of additional barriers to dental visiting were found for people with HDA. These barriers, especially cost and communication issues with dentists, need to be addressed to assist people with HDA obtain necessary, regular dental care. PMID- 25528184 TI - Psychological distress and intensive care unit stay after cardiac surgery: The role of illness concern. AB - OBJECTIVE: To examine the association between psychological factors and length of intensive care unit (ICU) stay in patients undergoing elective coronary artery bypass graft (CABG) surgery. METHOD: We studied 212 adults undergoing CABG surgery preoperatively to assess depression symptoms, anxiety symptoms, and illness perceptions and then followed them up during the in-hospital stay to measure length of ICU stay. RESULTS: Greater preoperative concern about the illness (B = .200, 95% CI [.094, .305], p = < .001), but not depression or anxiety symptoms, was significantly related to longer ICU stays after controlling for demographic, clinical, and behavioral covariates. CONCLUSIONS: Illness concern may be particularly relevant for CABG recovery, though more work is needed to delineate the exact mechanisms of this effect. PMID- 25528185 TI - Continuing excellence. PMID- 25528186 TI - Latent tuberculosis: interferon and beyond? PMID- 25528187 TI - High-quality genotyping data from formalin-fixed, paraffin-embedded tissue on the drug metabolizing enzymes and transporters plus array. AB - The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array covers 1936 markers in 231 genes involved in drug metabolism and transport. Blood and saliva-derived DNA works well on the DMET array, but the utility of DNA from FFPE tissue has not been reported for this array. As the ability to use DNA from FFPE tissue on the array could open the potential for large retrospective sample collections, we examined the performance and reliability of FFPE-derived DNA on the DMET Plus array. Germline DNA isolated from archived normal FFPE tissue blocks stored for 3 to 19 years and matched blood or saliva from 16 patients with osteosarcoma were genotyped on the DMET Plus array. Concordance was assessed by calculating agreement and the kappa-statistic. We observed high call rates for both the blood- or saliva-derived DNA samples (99.4%) and the FFPE-derived DNA samples (98.9%). Moreover, the concordance among the 16 blood- or saliva-derived DNA and FFPE DNA pairs was high (97.4%, kappa = 0.915). This is the first study showing that DNA from normal FFPE tissue provides accurate and reliable genotypes on the DMET Plus array compared with blood- or saliva-derived DNA. This finding provides an opportunity for pharmacogenetic studies in diseases with high mortality rates and prevents a bias in studies where otherwise only alive patients can be included. PMID- 25528188 TI - Comparison of custom capture for targeted next-generation DNA sequencing. AB - Targeted, capture-based DNA sequencing is a cost-effective method to focus sequencing on a coding region or other customized region of the genome. There are multiple targeted sequencing methods available, but none has been systematically investigated and compared. We evaluated four commercially available custom targeted DNA technologies for next-generation sequencing with respect to on target sequencing, uniformity, and ability to detect single-nucleotide variations (SNVs) and copy number variations. The technologies that used sonication for DNA fragmentation displayed impressive uniformity of capture, whereas the others had shorter preparation times, but sacrificed uniformity. One of those technologies, which uses transposase for DNA fragmentation, has a drawback requiring sample pooling, and the last one, which uses restriction enzymes, has a limitation depending on restriction enzyme digest sites. Although all technologies displayed some level of concordance for calling SNVs, the technologies that require restriction enzymes or transposase missed several SNVs largely because of the lack of coverage. All technologies performed well for copy number variation calling when compared to single-nucleotide polymorphism arrays. These results enable laboratories to compare these methods to make informed decisions for their intended applications. PMID- 25528189 TI - Diagnostic performance of a cytokine and IFN-gamma-induced chemokine mRNA assay after Mycobacterium tuberculosis-specific antigen stimulation in whole blood from infected individuals. AB - Interferon (IFN)-gamma release assays have limited sensitivity and cannot differentiate between active tuberculosis (TB) disease and latent TB infection (LTBI). Numerous cytokines and regulator factors have been implicated in the pathogenesis and control of Mycobacterium tuberculosis infection. Additional cytokines and chemokines associated with M. tuberculosis infection may improve the performance of IFN-gamma release assays. We developed a real-time RT-PCR TaqMan assay for targeting levels of eight human targets [IFN-gamma, tumor necrosis factor (TNF)-alpha, IL-2R, IL-4, IL-10, CXCL9, CXCL10, and CXCL11] and evaluated the assay with three different study groups. Results showed that the sensitivity of TNF-alpha, IL-2R, and CXCL10 in the active pulmonary tuberculosis (PTB) group was 96.43%, 96.43%, and 100%, respectively. The sensitivity of IL-2R and CXCL10 in the latent tuberculosis infection group was 86.36% and 81.82%, respectively. Statistical results showed that TNF-alpha and CXCL9 were the best individual markers for differentiating between the PTB, LTBI, and non-TB groups. For optimal sensitivity and differentiation of M. tuberculosis infection status, the simultaneous detection of multiple targets was attempted. The combination of IFN-gamma, TNF-alpha, and IL-2R, and the combination of TNF-alpha, IL-2R, CXCL9, and CXCL10 showed the best performance for detecting active PTB (both 100% positivity) and LTBI (86.36% and 81.82% positivity, respectively). These results imply that the combination of suitable markers is useful in efficiently diagnosing TB and differentiating M. tuberculosis infection status. PMID- 25528191 TI - DNA binding and cytotoxicity activity of a chiral iron(III) triangle complex based on a natural rosin product. AB - The first chiral trinuclear iron(III) complex [Fe3(MU3-O)(L)6(CH3OH)2(CH3O)]?H2O (2) of a natural rosin product dehydroabietic acid (HL, 1) was synthesized and fully characterized. The interactions of 1 and 2 with salmon sperm DNA were investigated by viscosity measurements, UV, fluorescence and circular dichroism (CD) spectroscopic techniques. Absorption spectral (Kb=1.30*10(5)M(-1) (1), 1.40*10(5)M(-1)(2)), emission spectral (KSV=1.19*10(4)M(-1) (1), 1.79*10(4)M(-1) (2)) and viscosity measurements reveal that 1 and 2 interacted with DNA through intercalation and 2 exhibited a slight higher DNA binding ability. The Stern Volmer quenching constant (KSV) and corresponding thermodynamic parameters (DeltaG, DeltaH and DeltaS) of the binding processes were determined. The negative DeltaH and DeltaG values indicate that the binding reactions were exothermic and spontaneous. 1 and 2 were also screened for their cytotoxic ability and 1 demonstrated higher growth inhibition of the selected cancer cells at concentrations of 25MUM and 50MUM, this result was not identical with their DNA binding ability order. Thus, the involvement of Fe(III) centers had positive effect on DNA binding ability and negative effect on cytotoxicity. PMID- 25528192 TI - The efficacy of Radachlorin-mediated photodynamic therapy in human hepatocellular carcinoma cells. AB - BACKGROUND: Photodynamic therapy (PDT) is a relatively novel modality for the treatment of cancer and some non-malignant lesions. PDT uses a photosensitive drug and light to destroy malignant cells. The aim of this study was to determine in vitro efficacy of Radachlorin-based PDT (Radachlorin-PDT) on human hepatocellular carcinoma (HCC). METHODS: The study used human liver cancer cells (HepG2) and normal liver cells (HFLF-PI4) to evaluate cell viability using the standard 2-(4, 5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The mechanism of cell death following Radachlorin-PDT was determined by DNA agarose gel electrophoresis and flow cytometry. RESULTS: Radachlorin without light irradiation had no toxic effect on HepG2 and HFLF-PI4 cells. Cell survival of HepG2 and HFLF-PI4 cells were decreased following PDT in a concentration dependent manner. However, HepG2 cells were much more sensitive to Radachlorin PDT than HFLF-PI4 cells. Radachlorin LD50 on HepG2 cells was 30MUg/ml and 20MUg/ml, 24h after exposure to doses of 5J/cm(2) and 15, or 25J/cm(2), respectively. Optimal Radachlorin and light dose to kill HepG2 cells with minimal effects on normal HFLF-PI4 cells were 100MUg/ml and 15J/cm(2), respectively. Our results also showed that apoptosis is induced in HepG2 cells following Radachlorin-PDT. CONCLUSION: Our in vitro data suggest that the use of PDT with Radachlorin can be effective in the treatment of HCC. PMID- 25528190 TI - Systems genomics evaluation of the SH-SY5Y neuroblastoma cell line as a model for Parkinson's disease. AB - BACKGROUND: The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used as a cellular model for Parkinson's disease, the relevance of this cellular model in the context of Parkinson's disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated. RESULTS: We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD. CONCLUSIONS: The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson's disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer's disease but lower than for Huntington's disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments. PMID- 25528193 TI - Superoxide mediated photomodification and DNA damage induced apoptosis by Benz(a)anthracene via mitochondrial mediated pathway. AB - Benz(a)anthracene (BA) is an ubiquitous environmental pollutant of polycyclic aromatic hydrocarbon's (PAHs) family. We showed superoxide (O2(-)) catalyzed BA photo modification and apoptosis in HaCaT keratinocytes under sunlight exposure. O2(-) generation was confirmed by quenching through superoxide dismutase (SOD). BA induced photocytotoxicity were investigated through MTT and NRU assay. We proposed DNA insults such as single and double strand breakage and CPDs formation which results in cell cycle arrest and apoptosis by photosensitized BA. BA induced apoptosis was caspase dependent and occurred through a mitochondrial pathway. Reduction of mitochondrial membrane potential, translocation of Bax to mitochondria and cytochrome c release favors involvement of mitochondria in BA phototoxicity. AO/EB double staining and TEM analysis also support apoptotic cell death. We propose a p21 regulated apoptosis via expression of Bax, and cleaved PARP under sunlight exposure. Thus, we conclude that it is imperative to avoid solar radiation during peak hr (between 11A.M. and 3P.M.) when the amount of solar radiation is high, in the light of DNA damage which may lead to mutation or skin cancer through photosensitized BA under sunlight exposure. Concomitantly, investigation is urgently required for the photosafety of BA photoproducts reaching in the environment through photomodification. PMID- 25528194 TI - Spectroscopic study on the interaction between mononaphthalimide spermidine (MINS) and bovine serum albumin (BSA). AB - The interaction mononaphthalimide spermidine (MINS, 1) and bovine serum albumin (BSA) was studied by UV/vis absorption, fluorescence and circular dichroism spectra (CD) under physiological conditions (pH=7.4). The observed spectral quenching of BSA by compound 1 indicated compound 1 could bind to BSA. Further fluorescent tests revealed that the quenching mechanism of BSA by compound 1 was overall static. Meanwhile, the obtained binding constant and thermodynamic parameters on compound-BSA interaction showed that the type of interaction force of compound 1 and BSA was mainly hydrophobic. The analysis of synchronous, three dimensional fluorescence and CD showed that compound 1 had weak influence on the conformational changes in BSA. Molecular docking simulation was performed and docking model in silico suggested that the configuration of compound 1 was localized in enzymatic drug site II in BSA. Furthermore, naphthalimide moiety of compound 1 greatly contributed to the hydrophobic interaction between compound 1 and BSA protein, as confirmed by experimental data. PMID- 25528195 TI - Subergorgiaols A-L, 9,10-secosteroids from the South China Sea gorgonian Subergorgia rubra. AB - Twelve new 9,10-secosteroids designated as subergorgiaols A-L (1-12), along with four known analogues (13-16), were isolated from the gorgonian Subergorgia rubra collected from the South China Sea. Their planar structures and the relative configurations were elucidated by comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of 1 was established by a dimolybdenum tetraacetate [Mo2(AcO)4] induced circular dichroism (ICD) procedure and the modified Mosher's method. Compounds 1-12 represent the first series of 9,10 secosteroids characterized with a hydroxy group at C-8, which are 8-OH derivatives of astrogorgiadiols/calicoferols. Compound 4 exhibited cytotoxicity against the cervical carcinoma cell line (CaSki) with an IC50 value of 2.4 MUM, and 6 showed toxicity toward brine shrimp Artemia salina with an LC50 value of 2.0 MUM. PMID- 25528196 TI - Bioactive steroidal alkaloids from Buxus macowanii Oliv. AB - Chemical investigation of the crude methanolic extract of Buxus macowanii resulted in the isolation of five new steroidal alkaloids, 31-hydroxybuxatrienone (1), macowanioxazine (2), 16alpha-hydroxymacowanitriene (3), macowanitriene (4), macowamine (5), along with five known steroidal bases, Nb-demethylpapillotrienine (6), moenjodaramine (7), irehine (8), buxbodine B (9) and buxmicrophylline C (10). Structures of compounds 1-10 were elucidated with the aid of spectroscopic methods including 1D and 2D NMR techniques and mass spectrometry. Compounds 1, 3, and 4 belong to a rare class of Buxus alkaloids having Delta(1,2) 9(10->19) abeo triene system. All isolates were evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity and found to exhibit moderate to weak anti-AChE activity with IC50 values in the range of 10.8-98MUM. Compounds 1 and 6 were also moderately active in BACE1 inhibitory assay. PMID- 25528197 TI - Validation of the driver behaviour questionnaire using behavioural data from an instrumented vehicle and high-fidelity driving simulator. AB - Data from two previously published studies were used to examine the correlations between scores on the violation, error and lapse sub-scales of the driver behaviour questionnaire, and observed driving speed. One dataset utilised data from an instrumented vehicle, which recorded driver speed on bends on a rural road. The other utilised data from a driving simulator study. Generally in both datasets the DBQ violation subscale was associated with objectively-measured speed, while the error and lapse sub-scales were not. These findings are consistent with the idea that the DBQ is a valid measure of observed behaviour in real driving (its original intended use) and also in simulated driving. The fact that associations were the same in real and simulated driving lends further support to the relative validity of driving simulation. The need for larger and more focused studies examining the role of different motivations in different driving situations is discussed. PMID- 25528198 TI - The influence of diabetes mellitus on midregional proadrenomedullin concentrations and prognostic value in heart failure outpatients. AB - BACKGROUND: Diabetes mellitus (DM) is associated with an adverse outcome in heart failure (HF). Increased concentrations of midregional proadrenomedullin (MR proADM) have been associated with DM and are predictors of mortality in HF patients. The aim of this study was to elucidate the impact of DM on MR-proADM concentrations and the prognostic value regarding all-cause mortality and hospitalization among HF patients. METHODS AND RESULTS: We included 366 patients from an HF clinic; 69 (19%) had a history of DM and 40 (11%) had newly diagnosed DM (HbA1c >=48 mmol/mol). The median MR-proADM concentration was unaffected by DM status (P = .20) but increased in HF patients with impaired renal function (P < .001). During a median follow-up of 55 months, 189 died, and 292 either died or were hospitalized. After adjustment for clinically relevant parameters, MR-proADM was associated with all-cause mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1-1.4; P = .01) and the combined end point of death and hospitalization (HR 1.2, 95% CI 1.1-1.4; P = .02) per 1 SD increment of ln transformed variable. No interaction between DM and MR-proADM was found regarding mortality or hospitalization. CONCLUSIONS: Diabetes status had no impact on MR proADM concentrations or in the predictive ability of MR-proADM in HF patients. PMID- 25528199 TI - Impact of cardiac resynchronization therapy on clinical outcomes in patients with continuous-flow left ventricular assist devices. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) can improve survival in left ventricular assist device (LVAD) recipients. However, the impact of cardiac resynchronization therapy (CRT-D) on outcomes in continuous-flow left ventricular assist device (CF-LVAD) patients is not known. We sought to determine if CRT-D improved clinical outcomes in CF-LVAD patients compared with ICDs alone. METHODS AND RESULTS: Sixty-one consecutive CF-LVAD patients with an ICD or CRT-D were evaluated. Impacts of CRT-D on mortality, all-cause hospitalization, and incidence of atrial (AA) and ventricular (VA) arrhythmias after LVAD implantation was compared with patients with ICD alone. Of the 61 LVAD patients, 31 (age 59.8 +/- 16 years, 84% male) had CRT-D and 30 (age 57.2 +/- 13 years, 74% male) had ICD. Before LVAD implantation, no significant differences were noted between the groups in demographic and clinical characteristics, LVAD indications, and incidence of AA and VA. Over 682 +/- 45 days of LVAD support, 8 patients (25.8%) died in the CRT-D arm versus 5 (16.7%) in the ICD arm (P = .35). No differences were noted between the CRT-D and ICD groups in all-cause (96.8 vs 93.3%; P = .63) and HF (19.4 vs 26.7%; P = .78) hospitalizations, left ventricular (LV) end diastolic diameter (6.4 +/- 1.5 vs 6.2 +/- 1.1 cm, P = .47), and incidence of AA (35.4% vs 33.3%; P = .80), VA (29% vs 26.6%; P = .86), and ICD shocks (22.6% vs 16.7%; P = .93). Beta-blocker and antiarrhythmic drug use after LVAD implantation was similar in both groups. CONCLUSIONS: In patients with refractory HF who received CF-LVADs, CRT-D, compared with ICD, did not significantly improve mortality, all-cause hospitalization, LV dimensions, and incidence of AA and VA. PMID- 25528200 TI - Presence of autoantibody directed against beta1-adrenergic receptors is associated with amelioration of cardiac function in response to carvedilol: Japanese Chronic Heart Failure (J-CHF) Study. AB - BACKGROUND: Autoantibody against beta1-adrenergic receptors (beta1-AAb) exerts agonist-like action inducing receptor uncoupling and myocardial damage. We attempted to determine the significance of beta1-AAb in chronic heart failure (CHF) patients who received carvedilol in a substudy of the Japanese Chronic Heart Failure study. METHODS AND RESULTS: In this prospective, randomized, multicenter trial, 117 patients were assigned to 2.5 mg, 5 mg, and 20 mg (n = 38, 36, and 43) carvedilol groups according to the target dose. beta1-AAb was positive in 51 patients (44%, P) and negative in 66 (56%, N). The percentage increase of left ventricular ejection fraction over 56 weeks (DeltaLVEF) was larger in P than in N (P = .050) and in the high-titer group (H) than in the low titer group (L; P = .04). Left ventricular (LV) volume decreased to a greater extent in H than in L over 56 weeks. beta1-AAb titer was significantly correlated with DeltaLVEF and the percentage change of LV volume and was an independent predictor of them. No difference was seen in the composite end point (all-cause mortality and hospitalization for cardiovascular diseases or heart failure). However, in patients with dilated cardiomyopathy, it was more common in the 2.5 mg group than in the other groups in N, and it was similar among the 3 groups in P. CONCLUSIONS: Our data suggest that the presence of beta1-AAb is associated with favorable response to carvedilol in CHF. PMID- 25528201 TI - Size exclusion-based purification and PCR-based quantitation of MS2 bacteriophage particles for environmental applications. AB - MS2 bacteriophage is the most commonly used surrogate for pathogenic viruses in laboratory and field studies. In order to determine the number of infectious viral particles in samples, the use of accurate quantitation methods is essential. We have optimised a size exclusion chromatography-based method for MS2 purification and a SYBR Green-based single-step quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay for the quantitation of MS2. The qRT-PCR enabled accurate quantitation of viral RNA of the purified stock with a detection limit of 2 genome copy equivalents/MUl. Detection inhibition, if any, was eliminated by reducing sample volume added to the qRT-PCR reaction mix when MS2 was detected in environmental water samples. The purification method eliminated the impurities and the purified stock yielded a high concentration of infectious MS2 particles. The qRT-PCR assay enabled the accurate quantitation of the viral particles thus providing an alternative to the traditional plaque assays. A combined use of purified MS2 stock and PCR-based quantitation gives the opportunity to explore virus characteristics, behaviour and interactions in the environment. PMID- 25528202 TI - In vitro assessment of the effect of vaccine-targeted human papillomavirus (HPV) depletion on detection of non-vaccine HPV types: implications for post-vaccine surveillance studies. AB - In populations where the prevalence of vaccine-targeted HPV types has been reduced significantly due to widespread vaccination of the target population, the sensitivity of some consensus PCR-based assays to detect remaining HPV types may be altered, leading to misrepresentations of prevalence. Importantly, this may lead to false indications of type replacement in vaccinated populations. To assess whether excess vaccine-targeted HPV DNA resulted in reduced detection of other genotypes on the Roche HPV linear array genotype assay, simulated samples containing 1000 copies of one or two high-risk HPV DNA genomes in the presence and the absence of 10,000 copies of the HPV16 genome were tested. HPV16 alone did not affect detection of other high-risk genotypes; however when HPV16 and an additional genotype were present, detection of HPV31, 33, 51 or 59 was impeded, indicating potential for misrepresentation of population-based prevalence of these genotypes and false evidence for type replacement following vaccination. PMID- 25528203 TI - Evaluation of a hepatitis C virus (HCV) antigen assay for routine HCV screening among men who have sex with men infected with HIV. AB - BACKGROUND: For detection of early HCV infection and reinfection, commercial HCV RNA tests are available. However, these tests are relatively time-consuming and expensive. A commercially available test that may supplement current screening methods, targets the HCV core protein. METHODS: During five waves of anonymous surveys at the Amsterdam STI clinic between 2009-2012, all HIV-infected MSM (N=439) were tested for HCV-antibodies (AxSYM HCV 3.0, Abbott), and HCV-RNA (TMA Versant, Siemens). To evaluate the potential value of the ARCHITECT HCV antigen (HCV-Ag) assay (Abbott), all HCV-RNA-positive sera (N=31) were tested with this assay, as well as two HIV-infected HCV-RNA-negative controls. In addition, all included samples were tested for alanine aminotransferase (ALT). RESULTS: Among 439 HIV-infected MSM, 31 (7.1%) tested positive for HCV-RNA; the HCV-Ag assay showed concordant positive results for 31/31 (100%). A substantial number of MSM, i.e., 5/31 (16.1%), had detectable HCV-RNA but were HCV-seronegative at the time of screening and were presumed to have been recently infected. Concordant HCV-RNA negative results were obtained in 57/60 control-samples. Specificity was 95.0% (95% CI: 86.1-99.0). The detection limit was between 3.0 and 3.7 Log10 IU/mL, irrespective of HCV genotype/subtype. ALT concentrations were elevated (i.e.,>40 U/L) in 9/31 (29.0%) HCV-RNA positive MSM, including 1/5 (20.0%) MSM with recent HCV-infection. CONCLUSIONS: The HCV-Ag assay proved a valuable screening tool for detection of active HCV infection among HIV-infected MSM with and without anti HCV. Adding ALT to current screening methods would improve case finding marginally. We therefore recommend implementation of routine HCV-Ag screening for populations at risk for HCV-(re)infection. PMID- 25528204 TI - Beyond H2: exploiting 2-hydroxypyridine as a design element from [Fe]-hydrogenase for energy-relevant catalysis. AB - The unique primary and secondary coordination environments surrounding the active site of hydrogenase enzymes play a crucial role in H2 activation and transfer reactions. [Fe]-hydrogenase contains a 2-hydroxypyridine ligand motif, and many researchers have incorporated this design element into synthetic catalysts. Transition metal complexes supported by 2-hydroxypyridine scaffolds are catalysts for chemical conversion schemes relevant to alternative energy applications and, in addition to hydrogenase-type reactivity, find new uses in other chemical domains. In this review, the current status of 2-hydroxypyridine-derived catalysts is described with an emphasis on design features that lead to lower energy catalytic pathways. PMID- 25528205 TI - Relationship between expression of muscle-specific uncoupling protein 2 messenger RNA and genetic selection toward growth in channel catfish. AB - This study tested the hypothesis that increased growth in channel catfish is associated with expression of the genes that code for uncoupling proteins (UCP) 2 and 3, members of the mitochondrial channel proteins involved in nutrient sensing and metabolism. The specific objective was to contrast the levels of UCP2 messenger RNA (mRNA) in fast vs slow growing catfish as well as in fed vs fasted catfish. Two distinct UCP2 transcripts were identified and named UCP2a and UCP2b, respectively. Nucleotide and amino acid sequence of catfish UCP2s were highly similar to UCP2 and other UCPs from other fish and mammals (>75%). Expression of UCP2a mRNA was detectable at very low levels in various metabolically active tissues, whereas the expression of UCP2b mRNA was readily detectable in the muscle and heart. In a 21-wk feeding study, fish that grew faster had a greater percent body fat at the end of the study (P < 0.01). Expression of UCP2b mRNA tended to be lower (P < 0.10) in fast growing fish in the middle of the study although levels were similar at the beginning and the end of the study. In the fed vs fasted study, expression of UCP2b mRNA in muscle was increased (P < 0.05) in fish assigned to 30 d of fasting. Our results suggest that, based on the nucleotide and amino acid sequence similarities and tissue mRNA distribution, catfish UCP2b may be the analog to UCP3. Moreover, our results suggest selection toward growth and associated fat accumulation appears to be independent of muscle UCP2b mRNA expression and UCP2b-mediated mechanisms. PMID- 25528206 TI - Serotonin receptor expression is dynamic in the liver during the transition period in Holstein dairy cows. AB - Nonneuronal serotonin (5-HT) participates in glucose metabolism, but little is known regarding the actions of 5-HT in the liver during the transition period in dairy cattle. Here, we explore circulating patterns of 5-HT and characterize the hepatic 5-HT receptor and glucose transporter profiles around calving in multiparous Holstein dairy cows (n = 6, average lactation = 4 +/- 1.9). Concentrations of serum 5-HT decreased on day -3 compared with -5 and -7 precalving (167.7 +/- 80 vs 1511.1 +/- 602 ng/mL). 5-HT nadir was on day -1 precalving and remained low postcalving (481.4 +/- 49 ng/mL). Plasma glucose concentrations decreased precalving (P = 0.008) and were positively correlated with 5-HT during the precalving period (r = 0.55, P = 0.043). On day 1, postcalving hepatic messenger RNA expression of 5-HT1D, 2B, 3C, 6, and 7 receptors were decreased compared with day -7 (P < 0.048). The 5-HT3A and 5-HT3B decreased on day 7. The 5-HT2A increased on days 1 and 7 compared with -7 (P < 0.05). The 5-HT1F and 5-HT1A receptors were increased 2.5- and 3.8-fold on day 7, respectively, compared with days -7 and 1 (P < 0.046). The 5-HT5A was not detected, and 5-HT4 was detected on days -7 and 1 only. Expression of Glut-2,-5 and SGLT1 were decreased on days 1 and 7 compared with -7 (P < 0.05), whereas Glut-1 was increased on day 7 compared with -7 (P < 0.05). These results indicate that 5-HT could be important for liver glucose homeostasis possibly through receptor mediated signaling at specific times. Additional research is needed to further explore the functional role of these receptors in the liver during the transition from pregnancy to lactation. PMID- 25528207 TI - Respiratory failure due to a gigantic endothoracic goiter. PMID- 25528208 TI - Adult fibrosarcoma: surgical management in developing countries. PMID- 25528209 TI - Ampular metastasis of a breast lobulillar carcinoma. PMID- 25528210 TI - Do simultaneous colectomy and nephrectomy in synchronous tumours extend hospital stay? PMID- 25528212 TI - Transcriptome characterization and SSR discovery in large-scale loach Paramisgurnus dabryanus (Cobitidae, Cypriniformes). AB - The large-scale loach (Paramisgurnus dabryanus, Cypriniformes) is a bottom dwelling freshwater species of fish found mainly in eastern Asia. The natural germplasm resources of this important aquaculture species has been recently threatened due to overfishing and artificial propagation. The objective of this study is to obtain the first functional genomic resource and candidate molecular markers for future conservation and breeding research. Illumina paired-end sequencing generated over one hundred million reads that resulted in 71,887 assembled transcripts, with an average length of 1465bp. 42,093 (58.56%) protein coding sequences were predicted; and 43,837 transcripts had significant matches to NCBI nonredundant protein (Nr) database. 29,389 and 14,419 transcripts were assigned into gene ontology (GO) categories and Eukaryotic Orthologous Groups (KOG), respectively. 22,102 (31.14%) transcripts were mapped to 302 KEGG pathways. In addition, 15,106 candidate SSR markers were identified, with 11,037 pairs of PCR primers designed. 400 primers pairs of SSR selected randomly were validated, of which 364 (91%) pairs of primers were able to produce PCR products. Further test with 41 loci and 20 large-scale loach specimens collected from the four largest lakes in China showed that 36 (87.8%) loci were polymorphic. The transcriptomic profile and SSR repertoire obtained in this study will facilitate population genetic studies and selective breeding of large-scale loach in the future. PMID- 25528211 TI - The identification of oppA gene homologues as part of the oligopeptide transport system in mycoplasmas. AB - The lack of an annotated oppA gene as part of many oligopeptide permease (opp) operons has questioned the necessity of the oligopeptide-binding domain (OppA) as a part of the Opp transport system in mycoplasmas. This study investigated the occurrence of an oppA gene as part of the oppBCDF operon in 42 mycoplasma genomes. Except for hemoplasma, all mycoplasmas were found to possess one or more copies of the oppBCDF operon and with the help of similarity searches their oppA genes could be identified. Phylogenetic analysis of the combined OppABCDF amino acid sequences allowed them to be grouped into three types. Each type has a unique set of conserved motifs, which are likely to reflect substrate preference and adaption strategies. Our approach allowed the identification of oppA gene homologues for all mycoplasma opp operons and thereby provides a method for re evaluating the current annotation of oppA genes in mycoplasma genomes. PMID- 25528213 TI - Feasibility and acceptability of point-of-care testing for sexually transmissible infections among men and women in mobile van settings. AB - To demonstrate the feasibility and acceptability of mobile point-of-care and near patient testing for sexually transmissible infections, we offered services during an annual community event and surveyed event-goers. Forty-two participants were tested. When provided with options, the majority of participants chose point-of care or near-patient testing. Trichomoniasis, chlamydia and gonorrhea were detected. All but one infected participant were notified and prescribed treatment. Participants responding to a written questionnaire reported sample self-collection and testing in a van as acceptable, although men reported self collection in a van as less acceptable than a doctor's office. Providing mobile point-of-care and near-patient sexually transmitted infection testing to the general population is feasible and acceptable. PMID- 25528214 TI - Investigation of microRNA-155 as a serum diagnostic and prognostic biomarker for colorectal cancer. AB - The aim of the present study was to explore serum microRNA-155 (miR-155) expression in patients with colorectal cancer (CRC) and examined the potential usefulness of this molecule as a biomarker for diagnosis and prognosis in CRC. Serum samples were obtained between May 2007 and March 2013 from 146 CRC patients and 60 healthy controls. Serum miR-155 expression levels were measured by quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR). Survival curves were obtained using the Kaplan-Meier method and assessed by the log-rank test. The receiver operating characteristic (ROC) curve was used for the prediction of cut-off values of the markers. Serum miR-155 expression level on average was upregulated in CRC patients compared with the matched healthy controls (P < 0.001). ROC curve analysis showed that miR-155 was a useful marker for discriminating cases from healthy controls, with an area under the ROC curve (AUC) of 0.776 (95% confidence interval (CI) 0.714 to 0.837, P < 0.001). Kaplan Meier analysis with the log-rank test indicated that high serum miR-155 expression had a significant impact on overall survival (38.2 vs. 69.9%; P < 0.001) and progression-free survival (34.8 vs. 66.0%; P < 0.001). In conclusion, the detection of miR-155 levels in the serum might serve as a new tumor biomarker in the diagnosis and assessment of prognosis of CRC. PMID- 25528215 TI - Antitumor effect of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles on mice bearing breast cancer: a systemic toxicity assay. AB - Breast cancer is one of the most prevalent cancer types among women. The use of magnetic fluids for specific delivery of drugs represents an attractive platform for chemotherapy. In our previous studies, it was demonstrated that maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2Cit) induced in vitro cytotoxicity and in vivo antitumor activity, followed by intratumoral administration in breast carcinoma cells. In this study, our aim was to follow intravenous treatment to evaluate the systemic antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Female Balb/c mice were evaluated with regard to toxicity of intravenous treatments through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine and liver, kidney, and lung histology. The antitumor activity of rhodium (II) citrate (Rh2Cit), Magh-Rh2Cit, and maghemite nanoparticles coated with citrate (Magh-Cit), used as control, was evaluated by tumor volume reduction, histology, and morphometric analysis. Magh-Rh2Cit and Magh-Cit promoted a significant decrease in tumor area, and no experimental groups presented hematotoxic effects or increased levels of serum ALT and creatinine. This observation was corroborated by the histopathological examination of the liver and kidney of mice. Furthermore, the presence of nanoparticles was verified in lung tissue with no morphological changes, supporting the idea that our nanoformulations did not induce toxicity effects. No studies about the systemic action of rhodium (II) citrate-loaded maghemite nanoparticles have been carried out, making this report a suitable starting point for exploring the therapeutic potential of these compounds in treating breast cancer. PMID- 25528216 TI - Loss of MLH1 confers resistance to PI3Kbeta inhibitors in renal clear cell carcinoma with SETD2 mutation. AB - Renal clear cell carcinoma (ccRCC) is characterized by frequent mutation in SETD2, which has recently been shown to regulate mismatch repair (MMR). We aim to investigate the association between MMR machinery genes and SETD2 mutation in ccRCC. We exploited the Genomics of Drug Sensitivity in Cancer (GDSC) database to identify selective inhibitors for SETD2 mutant ccRCC cells. We also exploited the Cancer Genome Atlas (TCGA) database to study the association between SETD2 status and MMR-related genes. In vitro studies were performed to validate the in silico findings. Reproduction of the GDSC database revealed four compounds with significant selectivity for SETD2 mutant ccRCC cells, amongst which two compounds targeted PI3Kbeta. Phosphorylation of AKT at both S473 and T308 was decreased following PI3Kbeta inhibitor treatment in SETD2 mutant ccRCC cells, whereas the basal pAKT level was not changed between mutant and wild-type SETD2. Both decreased MLH1 and increased AKT levels induced lower PMS2, indicating that MMR was mediated by SETD2 via both AKT and MLH1 in ccRCC. Analysis of the TCGA database further revealed high tendency of homozygous co-deletion of SETD2 and MLH1. In the absence of MLH1, suppression of pAKT by PI3Kbeta inhibitor was mitigated and inhibition in cell proliferation, invasiveness, migratory ability and tumourigenesis was partially restored. Besides the reported H3K36 trimethylation pathway, we found that SETD2 mutation also mediated MMR via AKT induced PMS2 decrease and co-loss of MLH1 loss in ccRCC. PMID- 25528217 TI - Estimation of radon prone areas through binary classification, part 2: radon prone geologies. AB - A radon prone geology is one for which the probability is increased that in a house built on it, elevated indoor Rn concentration will be encountered, or that its Rn potential will be increased. Labelling geological units as Rn prone or not can be an important support in deciding whether a geographical or administrative region in which that geological unit occurs, should be called Rn prone area, possibly in absence of other predictors. In this article a method is proposed which, given a set of geological classes, sorts the classes into Rn prone and non Rn prone classes depending on a classification criterion which one can choose according the purpose. The method is computationally simple and is demonstrated on the example of Germany. PMID- 25528218 TI - The UK geochemical environment and cardiovascular diseases: magnesium in food and water. AB - Cardiovascular diseases (CVDs) contribute approximately one-third to noncommunicable diseases in the UK. The central role of magnesium in CVDs (enzyme activity, cardiac signalling, etc.) is well established. Mortality and morbidity rates for CVDs may be inversely related to water hardness, suggesting a role for environmental magnesium. Published official and quasi-official data sources were evaluated to establish a model magnesium intake for a representative adult: standardised reference individual (SRI), standardised reference male (SRM) or standardised reference female (SRF). For typical dietary constituents, only tap water is probably locally derived and bottled water may not be. Fruits and vegetables are imported from many countries, while meat, dairy and cereal products represent a composite of UK source areas. Alcoholic beverages provide magnesium, there is doubt about its absorptive efficiency, and they are not locally derived. A simple model was devised to examine the effect of varying dietary contributions to total daily intake of magnesium. Omitting tap or bottled water, the combined intake, solid food plus alcoholic beverages, is 10.57 mmol Mg (84.5 % RNI) for the SRM and for the SRF, 8.10 mmol Mg (71.7 % RNI). Consumers drinking water derived from reservoirs or rivers, or supplementing it with the purest bottled water, improve their magnesium intake only slightly compared with water containing no magnesium. Choosing bottled water with high magnesium content when the public supply derives from rivers or reservoirs partially satisfies magnesium needs. Real improvement in SRI magnesium nutrition is seen only where water is hard. However, this conclusion cannot be validated until new measurement technologies for body magnesium become available. PMID- 25528219 TI - Giant cell arteritis restricted to the limb arteries: An overlooked clinical entity. AB - OBJECTIVE: Giant cell arteritis (GCA) is a systemic vasculitis typically affecting temporal arteries. In at least 15% of cases, GCA also features inflammation of the aorta and its primary branches. Large-vessel inflammation restricted to proximal limb arteries in the absence of temporal and aortic involvement (Limb Restricted, LR) is rare and not well described in literature. Hence, we aim to characterize this neglected clinical entity. METHODS: We describe a series of three cases of LR-GCA. All patients were older than 50 years, had increased erythrocyte sedimentation rate (ESR), normal cholesterol and triglycerides serum levels, negative temporal artery biopsy, suggestive F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) findings, and responded to immunosuppressive therapy. We also reviewed all published cases of LR-GCA (76 cases), for a total of 79 patients. RESULTS: Limb claudication was reported in 87% of the patients, and cranial symptoms and polymyalgia rheumatica in 20%. Constitutional symptoms were never reported. Median ESR levels were 66.5mm/1h. Upper and lower limb arteries were involved in 86% and 9% of the patients respectively, and the remaining 5% had simultaneous upper and lower limb vessel involvement. Conventional angiography was performed in 63% of the cases, color doppler ultrasound in 20%, FDG-PET in 14%, and computed tomography angiography in 3%. CONCLUSION: If temporal biopsy and aortic imaging are negative for GCA in patients older than 50 years with bilateral limb claudication, elevated ESR, and suggestive vascular radiological findings, LR-GCA should be suspected. Upper limb arteries are more frequently involved. Since constitutional symptoms are typically absent in LR-GCA, differential diagnosis with atherosclerotic plaques may be challenging. PMID- 25528220 TI - Sulfate resupply accentuates protein synthesis in coordination with nitrogen metabolism in sulfur deprived Brassica napus. AB - To investigate the regulatory interactions between S assimilation and N metabolism in Brassica napus, de novo synthesis of amino acids and proteins was quantified by (15)N and (34)S tracing, and the responses of transporter genes, assimilatory enzymes and metabolites pool involving in nitrate and sulfate metabolism were assessed under continuous sulfur supply, sulfur deprivation and sulfate resupply after 3 days of sulfur (S) deprivation. S-deprived plants were characterized by a strong induction of sulfate transporter genes, ATP sulfurylase (ATPS) and adenosine 5'-phosphosulfate reductase (APR), and by a repressed activity of nitrate reductase (NR) and glutamine synthetase (GS). Sulfate resupply to the S-deprived plants strongly increased cysteine, amino acids and proteins concentration. The increase in sulfate and cysteine concentration caused by sulfate resupply was not matched with the expression of sulfate transporters and the activity of ATPS and APR which were rapidly decreased by sulfate resupply. A strong induction of O-acetylserine(thiol)lyase (OASTL), NR and GS upon sulfate resupply was accompanied with the increase in cysteine, amino acids and proteins pool. Sulfate resupply resulted in a strong increase in de novo synthesis of amino acids and proteins, as evidenced by the increases in N and S incorporation into amino acids (1.8- and 2.4-fold increase) and proteins (2.2-and 6.3-fold increase) when compared to S-deprived plants. The results thus indicate that sulfate resupply followed by S-deprivation accelerates nitrate assimilation for protein synthesis. PMID- 25528221 TI - Identification and expression of a stearoyl-ACP desaturase gene responsible for oleic acid accumulation in Xanthoceras sorbifolia seeds. AB - Xanthoceras sorbifolia Bunge is an oilseed tree that grows well on barren lands in dry climate. Its seeds contain a large amount of oil rich in oleic acid (18:1(Delta9)) and linoleic acid (18:2(Delta9, 12)). However, the molecular regulation of oil biosynthesis in X. sorbifolia seeds is poorly understood. Stearoyl-ACP desaturase (SAD, EC 1.14.99.6) is a plastid-localized soluble desaturase that catalyzes the conversion of stearic acid (18:0) to oleic acid, which plays a key role in determining the ratio of saturated to unsaturated fatty acids. In this study, a full-length cDNA of XsSAD was isolated from developing X. sorbifolia embryos. The XsSAD open reading frame had 1194-bp, encoding a polypeptide of 397 amino acids. XsSAD expression in Escherichia coli cells resulted in increased 18:1(Delta9) level, confirming the biological activity of the enzyme encoded by XsSAD. XsSAD expression in Arabidopsis ssi2 mutants partially restored the morphological phenotype and effectively increased the 18:1(Delta9) level. The levels of other unsaturated fatty acids synthesized with 18:1(Delta9) as the substrate also increased to some degree. XsSAD in X. sorbifolia had a much higher expression in embryos than in leaves and petals. XsSAD expression also correlated well with the oleic acid, unsaturated fatty acid, and total fatty acid levels in developing embryos. These data suggested that XsSAD determined the synthesis of oleic acid and contributed to the accumulation of unsaturated fatty acid and total oil in X. sorbifolia seeds. A preliminary tobacco rattle virus-based virus-induced gene silencing system established in X. sorbifolia can also be helpful for further analyzing the functions of XsSAD and other oil synthesis-related genes in woody plants. PMID- 25528222 TI - Sorption kinetics and mechanism of various oils into kapok assembly. AB - Sorption rates of kapok fibers on different oils, such as diesel, cooking oil, used motor oil, and motor oil, were quantitatively evaluated by using a wicking method. Kapok fibers absorbing different oils exhibited large differences in terms sorption coefficients. Microscopic observations of oil wetting on a single kapok showed that the four oils had varying wettability and adhesiveness to kapok, but that all of them penetrated into kapok lumens quickly because of the fiber's low surface energy, which was 40.64 mN/m, and extreme hydrophobicity, with a water contact angle up to 151 degrees . After treatment with chloroform, there were slight changes in oil absorbencies to kapok, but the sorption coefficients for the four oils increased markedly. SEM demonstrated that chloroform treatments caused the smooth surface of the kapok fibers to become highly roughened, with densely vertical grooves that provided more available surface and a larger driving force for oil sorption through the fiber assembly. PMID- 25528223 TI - How much plastic is in the ocean? You tell me! PMID- 25528224 TI - Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination. AB - Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum. PMID- 25528225 TI - Multiparametric mapping of neurological soft signs in healthy adults. AB - Minor motor and sensory deficits or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. Although previous studies have reported that NSS are associated with altered structure and function within fronto-parietal areas, it remains unclear whether the neuroanatomical basis of NSS may be confounded by underlying pathological processes, and by antipsychotic treatment. Morphological brain correlates of NSS in healthy subjects have seldom been investigated. This study evaluated the relationship between NSS levels and abnormalities of subcortical and cortical structures in healthy individuals. High-resolution MRI data at 3 Tesla were obtained from 68 healthy individuals. Automated segmentation of caudate nucleus, putamen, globus pallidus, thalamus, and brainstem was performed using both FSL FIRST and Freesurfer. The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index). NSS were examined on the Heidelberg Scale and related to both subcortical and cortical measurements. Using two fully automated brain segmentations methods, we found no significant association between NSS levels and morphological changes in subcortical structures. Higher NSS scores were associated with morphological changes of cortical thickness, area and folding in multiple areas comprising superior frontal, middle temporal, insular and postcentral regions. Our findings demonstrate the benefit of surface-based approaches when investigating brain correlates of NSS. The data lend further support to the hypothesis that NSS in healthy individuals involve multiple cortical rather than subcortical brain regions. PMID- 25528226 TI - Use of combined microscopic and spectroscopic techniques to reveal interactions between uranium and Microbacterium sp. A9, a strain isolated from the Chernobyl exclusion zone. AB - Although uranium (U) is naturally found in the environment, soil remediation programs will become increasingly important in light of certain human activities. This work aimed to identify U(VI) detoxification mechanisms employed by a bacteria strain isolated from a Chernobyl soil sample, and to distinguish its active from passive mechanisms of interaction. The ability of the Microbacterium sp. A9 strain to remove U(VI) from aqueous solutions at 4 degrees C and 25 degrees C was evaluated, as well as its survival capacity upon U(VI) exposure. The subcellular localisation of U was determined by TEM/EDX microscopy, while functional groups involved in the interaction with U were further evaluated by FTIR; finally, the speciation of U was analysed by TRLFS. We have revealed, for the first time, an active mechanism promoting metal efflux from the cells, during the early steps following U(VI) exposure at 25 degrees C. The Microbacterium sp. A9 strain also stores U intracellularly, as needle-like structures that have been identified as an autunite group mineral. Taken together, our results demonstrate that this strain exhibits a high U(VI) tolerance based on multiple detoxification mechanisms. These findings support the potential role of the genus Microbacterium in the remediation of aqueous environments contaminated with U(VI) under aerobic conditions. PMID- 25528227 TI - Influence of Enteromorpha polysaccharides on variation of coagulation behavior, flocs properties and membrane fouling in coagulation-ultrafiltration process. AB - Enteromorpha polysaccharides (Ep) were used as a new coagulant aid together with polyaluminum chloride (PACl) in coagulation-ultrafiltration process to purify Yellow River water. The evolution of flocs size, growth rate, strength, recoverability and fractal structure due to Ep addition were systematically studied in this paper. On this basis, membrane fouling caused by the coagulation effluents of PACl and Ep were also investigated. Results indicated that Ep addition lead to 20% increase in coagulation performance, and meanwhile generate flocs with bigger sizes, faster growth rates and higher recovery abilities. Additionally, the flocs formed by PACl presented more compact structure with a larger D(f) value, while much looser flocs were obtained when Ep was added. Results of ultrafiltration experiments implied that with Ep addition, membrane fouling could be significantly reduced due to large size and loosely structures of flocs in coagulation effluents. Considering both the coagulation efficiency and ultrafiltration membrane performance, 0.2 mg/L Ep was determined as the optimal dosage in coagulation-ultrafiltration process in this study. PMID- 25528228 TI - Continuous treatments of estrogens through polymerization and regeneration of electrolytic cells. AB - This study proposes a novel electrolytic method for simultaneous removal of trace estrogens and regeneration of electrolytic cells for long-term wastewater treatment. Continuous treatments of estrogens estrone (E1), 17beta-estradiol (E2) and 17alpha-ethinyl estradiol (EE2) were theoretically and experimentally studied using an electrolytic reactor equipped with a multi-packed granular glassy carbon electrode reactor. Experimental results demonstrated that E1, E2 and EE2 were effectively removed through electro-polymerization on the granular glassy carbon (and Pt/Ti) anode counter. Polymer formed during continuous treatment was quickly decomposed and electrodes were regenerated completely by OH radicals produced through the reduction of ozone. Calculated overall energy consumptions were less than 10 Wh/m(3), demonstrating extremely low energy consumptions. In addition, a mathematical model developed based on the limiting mass transfer rate and post regeneration could represent general trends in time series data observed in experiments. PMID- 25528229 TI - Suppression of methane/air explosion by ultrafine water mist containing sodium chloride additive. AB - The suppression effect of ultrafine mists on methane/air explosions with methane concentrations of 6.5%, 8%, 9.5%, 11%, and 13.5% were experimentally studied in a closed visual vessel. Ultrafine water/NaCl solution mist as well as pure water mist was adopted and the droplet sizes of mists were measured by phase doppler particle analyzer (PDPA). A high speed camera was used to record the flame evolution processes. In contrast to pure water mist, the flame propagation speed, the maximum explosion overpressure (DeltaP(max)), and the maximum pressure rising rate ((dP/dt)max) decreased significantly, with the "tulip" flame disappearing and the flame getting brighter. The results show that the suppressing effect on methane explosion by ultrafine water/NaCl solution mist is influenced by the mist amount and methane concentration. With the increase of the mist amount, the pressure, and the flame speed both descended significantly. And when the mist amount reached 74.08 g/m(3) and 37.04 g/m(3), the flames of 6.5% and 13.5% methane explosions can be absolutely suppressed, respectively. All of results indicate that addition of NaCl can improve the suppression effect of ultrafine pure water mist on the methane explosions, and the suppression effect is considered due to the combination effect of physical and chemical inhibitions. PMID- 25528230 TI - Ag-bridged Ag2O nanowire network/TiO2 nanotube array p-n heterojunction as a highly efficient and stable visible light photocatalyst. AB - A unique Ag-bridged Ag2O nanowire network/TiO2 nanotube array p-n heterojunction (Ag-Ag2O/TiO2 NT) was fabricated by simple electrochemical method. Ag nanoparticles were firstly electrochemically deposited onto the surface of TiO2 NT and then were partly oxidized to Ag2O nanowires while the rest of Ag mother nanoparticles were located at the junctions of Ag2O nanowire network. The Ag Ag2O/TiO2 NT heterostructure exhibited strong visible-light response, effective separation of photogenerated carriers, and high adsorption capacity. The integration of Ag-Ag2O self-stability structure and p-n heterojunction permitted high and stable photocatalytic activity of Ag-Ag2O/TiO2 NT heterostructure photocatalyst. Under 140-min visible light irradiation, the photocatalytic removal efficiency of both dye acid orange 7 (AO7) and industrial chemical p nitrophenol (PNP) over Ag-Ag2O/TiO2 NT reached nearly 100% much higher than 17% for AO7 or 13% for PNP over bare TiO2 NT. After 5 successive cycles under 600-min simulated solar light irradiation, Ag-Ag2O/TiO2 NT remained highly stable photocatalytic activity. PMID- 25528231 TI - A review of photochemical approaches for the treatment of a wide range of pesticides. AB - Pesticides are renowned as some of the most pernicious chemicals known to humankind. Nine out of twelve most hazardous and persistent organic chemicals on planet have been identified as pesticides and their derivatives. Because of their strong recalcitrant nature, it often becomes a difficult task to treat them by conventional approaches. It is well perceived that many factors can interfere with the degradation of pesticides under ambient conditions, e.g., media, light intensity, humic content, and other biological components. However, for the effective treatment of pesticides, photochemical methods are viewed as having clear and perceivable advantages. In this article, we provide a review of the fundamental characteristics of photochemical approaches for pesticide treatment and the factors governing their capacity and potential in such a process. PMID- 25528232 TI - Novel reduction of Cr(VI) from wastewater using a naturally derived microcapsule loaded with rutin-Cr(III) complex. AB - The harmfulness of carcinogenic hexavalent chromium (Cr(VI)) is dramatically decreased when Cr(VI) is reduced to trivalent chromium (Cr(III)). Rutin, a natural flavonoid, exhibits excellent antioxidant activity by coordinating metal ions. In this study, a complex containing rutin and Cr(III) (rutin-Cr(III)) was synthesized and characterized. The rutin-Cr(III) complex was much easier to reduce than rutin. The reduction of the rutin-Cr(III) complex was highly pH dependent, with 90% of the Cr(VI) being reduced to Cr(III) in 2h under optimal conditions. A biodegradable, sustained-release system encapsulating the rutin Cr(III) complex in a alginate-chitosan microcapsule (rutin-Cr(III) ACMS) was also evaluated, and the reduction of Cr(VI) was assessed. This study also demonstrated that low-pH solutions increased the reduction rate of Cr(VI). The environmentally friendly microcapsules can reduce Cr(VI) for prolonged periods of time and can easily biodegrade after releasing the rutin-Cr(III) complex. Given the excellent performance of rutin-Cr(III) ACMS, the microcapsule system represents an effective system for the remediation of Cr(VI) pollution. PMID- 25528233 TI - Remediation of trichloroethylene-contaminated soils by star technology using vegetable oil smoldering. AB - Self-sustaining treatment for active remediation (STAR) is an innovative soil remediation approach based on smoldering combustion that has been demonstrated to effectively destroy complex hydrocarbon nonaqueous phase liquids (NAPLs) with minimal energy input. This is the first study to explore the smoldering remediation of sand contaminated by a volatile NAPL (trichloroethylene, TCE) and the first to consider utilizing vegetable oil as supplemental fuel for STAR. Thirty laboratory-scale experiments were conducted to evaluate the relationship between key outcomes (TCE destruction, rate of remediation) to initial conditions (vegetable oil type, oil: TCE mass ratio, neat versus emulsified oils). Several vegetable oils and emulsified vegetable oil formulations were shown to support remediation of TCE via self-sustaining smoldering. A minimum concentration of 14,000 mg/kg canola oil was found to treat sand exhibiting up to 80,000 mg/kg TCE. On average, 75% of the TCE mass was removed due to volatilization. This proof-of-concept study suggests that injection and smoldering of vegetable oil may provide a new alternative for driving volatile contaminants to traditional vapour extraction systems without supplying substantial external energy. PMID- 25528234 TI - Catalytic degradation of Acid Orange 7 by manganese oxide octahedral molecular sieves with peroxymonosulfate under visible light irradiation. AB - In this paper, the photodegradation of Acid Orange 7 (AO7) in aqueous solutions with peroxymonosulfate (PMS) was studied with manganese oxide octahedral molecular sieves (OMS-2) as the catalyst. The activities of different systems including OMS-2 under visible light irradiation (OMS-2/Vis), OMS-2/PMS and OMS 2/PMS/Vis were evaluated. It was found that the efficiency of OMS-2/PMS was much higher than that of OMS-2/Vis and could be further enhanced by visible light irradiation. The catalyst also exhibited stable performance for multiple runs. Results from ESR and XPS analyses suggested that the highly catalytic activity of the OMS-2/PMS/Vis system possible involved the activation of PMS to sulfate radicals meditated by the redox pair of Mn(IV)/Mn(III) and Mn(III)/Mn(II), while in the OMS-2/PMS system, only the redox reaction between Mn(IV)/Mn(III) occurred. Several operational parameters, such as dye concentration, catalyst load, PMS concentration and solution pH, affected the degradation of AO7. PMID- 25528235 TI - Respirable volcanic ash is distinct mineralogically, physicochemically and toxicologically from soils originating from weathered volcanic products. A comment on Cervini-Silva et al. (2014) "Lipid peroxidation and cytotoxicity induced by respirable volcanic ash". PMID- 25528236 TI - Surface acoustic wave ammonia sensor based on ZnO/SiO2 composite film. AB - A surface acoustic wave (SAW) resonator with ZnO/SiO2 (ZS) composite film was used as an ammonia sensor in this study. ZS composite films were deposited on the surface of SAW devices using the sol-gel method, and were characterized using SEM, AFM, and XRD. The performance of the sensors under ammonia gas was optimized by adjusting the molar ratio of ZnO:SiO2 to 1:1, 1:2 and 1:3, and the sensor with the ratio of ZnO to SiO2 equaling to 1:2 was found to have the best performance. The response of sensor was 1.132 kHz under 10 ppm NH3, which was much higher than that of the sensor based on a pristine ZnO film. Moreover, the sensor has good selectivity, reversibility and stability at room temperature. These can be attributed to the enhanced absorption of ammonia and unique surface reaction on composite films due to the existence of silica. PMID- 25528237 TI - Laser ignitibility of insensitive secondary explosive 1,1-diamino-2,2 dinitroethene (FOX-7). AB - An experimental investigation into laser ignitibility of insensitive secondary explosives, 1,1-diamino-2,2-dinitroethene (FOX-7) has been carried out, using a diode laser of continuous wave at the laser wavelength of 974 nm. The direct optical ignition of an insensitive explosive will add more safety features to insensitive munitions (IM) or explosive devices. In this study, effects of laser parameters on the ignitibility were analysed in terms of laser ignition threshold, the times to initiate the ignition and full combustion, and burning sustainability. The results have shown that carbon black (CB) as an optical sensitizer is compatible with FOX-7, and significantly enhances laser ignitibility of the explosive when a small amount of CB is uniformly doped in FOX 7. The delay times for ignition and subsequent development of sustainable burning of the material are mainly determined by ignition laser power, although the other laser parameters have effects. The minimum laser power required to ignite the optically sensitized FOX-7 was found below 10 W and a fast ignition was initiated in as short as 70 MUs by a laser power of 40 W. Also the effect of the mixture uniformity of FOX-7/CB on laser ignition performance was evaluated in this study. PMID- 25528238 TI - Effect of low-concentration rhamnolipid on adsorption of Pseudomonas aeruginosa ATCC 9027 on hydrophilic and hydrophobic surfaces. AB - The effects of low-concentration monorhamnolipid (monoRL) on the adsorption of Pseudomonas aeruginosa ATCC 9027 grown on glucose or hexadecane to glass beads with hydrophobic or hydrophilic surfaces was investigated using batch adsorption experiments. Results showed that adsorption isotherms of the cells on both types of glass beads fitted the Freundlich equation better than the Langmuir equation. The Kf of the Freundlich equation for adsorption of hexadecane-grown cell to glass beads with hydrophobic surface was remarkably higher than that for adsorption of hexadecane-grown cell to glass beads with hydrophilic surface, or glucose-grown cell to glass beads with either hydrophilic or hydrophobic surface. Furthermore, it decreased with the increasing monoRL concentration. For both groups of cells, the zeta potential was close to each other and stable with the increase of monoRL concentration. The surface hydrophobicity of hexadecane-grown cells, however, was significantly higher than that of the glucose-grown cells and it decreased with the increase of monoRL concentration. The results indicate the importance of hydrophobic interaction on adsorption of bacterial cells to surfaces and monoRL plays a role in reducing the bacterial adsorption by affecting cell surface hydrophobicity. PMID- 25528239 TI - Occurrence and distribution of conventional and new classes of per- and polyfluoroalkyl substances (PFASs) in the South China Sea. AB - Concentrations of 23 per- and polyfluoroalkyl substances (PFASs), including new classes of PFASs, in seawater samples were investigated for their occurrence and the interaction of the ocean currents with the distribution of PFASs in the South China Sea. This study revealed that socio-economic development was associated with the PFAS contamination in coastal regions of South China. Significant correlations between concentration of total PFASs with gross domestic product (GDP) per capita and population density were found in the areas, suggesting that the influence of intense human activities in these areas may have resulted in higher PFAS contamination to the adjacent environment. Di-substituted polyfluoroalkyl phosphate (diPAP), one of the potential replacements for PFASs, was only detected in the heavily developed region, namely Pearl River Delta (PRD). Total PFAS concentrations, ranging from 195 to 4925 pg/L, were detected at 51 sampling stations of the South China Sea. The results also confirmed that PFAS contamination in the South China Sea is strongly affected by the ocean currents. In comparison to perfluoroactane sulfonate (PFOS) concentrations measured nine years ago at the same locations, the concentrations in this study were found to be two times higher. This indicated that the use and production of perfluoroalkyl sulfonates (PFSAs) has been continuing in the region. PMID- 25528240 TI - Photocatalytic degradation of recalcitrant organic pollutants in water using a novel cylindrical multi-column photoreactor packed with TiO2-coated silica gel beads. AB - A novel cylindrical multi-column photocatalytic reactor (CMCPR) has been developed and successfully applied for the degradation of methyl orange (MO), amoxicillin (AMX) and 3-chlorophenol (3-CP) in water. Due to its higher adsorption capacity and simpler molecular structure, 3-CP compared with MO and AMX obtained the highest photodegradation (100%) and mineralization (78.1%) after 300-min photocatalytic reaction. Electrical energy consumption for photocatalytic degradation of MO, AMX and 3-CP using CMCPR was 5.79*10(4), 7.31*10(4) and 2.52*10(4) kW h m(-3) order(-1), respectively, which were less than one-thousand of those by reported photoreactors. The higher flow rate (15 mL min(-1)), lower initial concentration (5 mg L(-1)) and acidic condition (pH 3) were more favorable for the photocatalytic degradation of MO using CMCPR. Five repetitive operations of CMCPR achieved more than 97.0% photodegradation of MO in each cycle and gave a relative standard deviation of 0.72%. In comparison with reported slurry and thin-film photoreactors, CMCPR exhibited higher photocatalytic efficiency, lower energy consumption and better repetitive operation performance for the degradation of MO, AMX and 3-CP in water. The results demonstrated the feasibility of utilizing CMCPR for the degradation of recalcitrant organic pollutants in water. PMID- 25528241 TI - Estimation of lower flammability limits of C-H compounds in air at atmospheric pressure, evaluation of temperature dependence and diluent effect. AB - Estimation of the lower flammability limits of C-H compounds at 25 degrees C and 1 atm; at moderate temperatures and in presence of diluent was the objective of this study. A set of 120 C-H compounds was divided into a correlation set and a prediction set of 60 compounds each. The absolute average relative error for the total set was 7.89%; for the correlation set, it was 6.09%; and for the prediction set it was 9.68%. However, it was shown that by considering different sources of experimental data the values were reduced to 6.5% for the prediction set and to 6.29% for the total set. The method showed consistency with Le Chatelier's law for binary mixtures of C-H compounds. When tested for a temperature range from 5 degrees C to 100 degrees C, the absolute average relative errors were 2.41% for methane; 4.78% for propane; 0.29% for iso-butane and 3.86% for propylene. When nitrogen was added, the absolute average relative errors were 2.48% for methane; 5.13% for propane; 0.11% for iso-butane and 0.15% for propylene. When carbon dioxide was added, the absolute relative errors were 1.80% for methane; 5.38% for propane; 0.86% for iso-butane and 1.06% for propylene. PMID- 25528242 TI - Short-term moderate exercise provides long-lasting protective effects against metabolic dysfunction in rats fed a high-fat diet. AB - INTRODUCTION: A sedentary lifestyle and high-fat feeding are risk factors for cardiometabolic disorders. This study determined whether moderate exercise training prevents the cardiometabolic changes induced by a high-fat diet (HFD). MATERIALS AND METHODS: Sixty-day-old rats were subjected to moderate exercise three times a week for 30 days. After that, trained rats received a HFD (EXE-HFD) or a commercial normal diet (EXE-NFD) for 30 more days. Sedentary animals also received the diets (SED-HFD and SED-NFD). Food intake and body weight were measured weekly. After 120 days of life, analyses were performed. Data were analysed with two-way ANOVA and the Tukey post-test. RESULTS: Body weight gain induced by HFD was attenuated in trained animals. HFD reduced food intake by approximately 30% and increased body fat stores by approximately 75%. Exercise attenuated 80% of the increase in fat pads and increased 24% of soleus muscle mass in NFD animals. HFD induced a hyper-response to glucose injection, and exercise attenuated this response by 50%. Blood pressure was increased by HFD, and the beneficial effect of exercise in reducing blood pressure was inhibited by HFD. HFD increased vagal activity by 65% in SED-HFD compared with SED-NFD rats, and exercise blocked this increase. HFD reduced sympathetic activity and inhibited the beneficial effect of exercise on ameliorating sympathetic activity. CONCLUSION: Four weeks of moderate exercise at low frequency was able to prevent the metabolic changes induced by a HFD but not the deleterious effects of diet on the cardiovascular system. PMID- 25528244 TI - Highly parameterized inversion of groundwater reactive transport for a complex field site. AB - In this study a numerical groundwater reactive transport model of a shallow groundwater aquifer contaminated with volatile organic compounds is developed. In addition to advective-dispersive transport, the model includes contaminant release from source areas, natural attenuation, abiotic degradation by a permeable reactive barrier at the site, and dilution by infiltrating rain. Aquifer heterogeneity is parameterized using pilot points for hydraulic conductivity, specific yield and groundwater recharge. A methodology is developed and applied to estimate the large number of parameters from the limited data at the field site (groundwater levels, groundwater concentrations of multiple chemical species, point-scale measurements of soil hydraulic conductivity, and lab-scale derived information on chemical and biochemical reactions). The proposed methodology relies on pilot point parameterization of hydraulic parameters and groundwater recharge, a regularization procedure to reconcile the large number of spatially distributed model parameters with the limited field data, a step-wise approach for integrating the different data sets into the model, and high performance computing. The methodology was proven to be effective in reproducing multiple contaminant plumes and in reducing the prior parameter uncertainty of hydraulic conductivity and groundwater recharge. Our results further indicate that contaminant transport predictions are strongly affected by the choice of the groundwater recharge model and flow parameters should be identified using both head and concentration measurements. PMID- 25528245 TI - Simulation using novel equipment designed to explain spirometric abnormalities in respiratory disease enhances learning in higher cognitive domains. AB - Simulation of disorders of respiratory mechanics shown by spirometry provides insight into the pathophysiology of disease but some clinically important disorders have not been simulated and none have been formally evaluated for education. We have designed simple mechanical devices which, along with existing simulators, enable all the main dysfunctions which have diagnostic value in spirometry to be simulated and clearly explained with visual and haptic feedback. We modelled the airways as Starling resistors by a clearly visible mechanical action to simulate intra- and extra-thoracic obstruction. A narrow tube was used to simulate fixed large airway obstruction and inelastic bands to simulate restriction. We hypothesized that using simulators whose action explains disease promotes learning especially in higher domain educational objectives. The main features of obstruction and restriction were correctly simulated. Simulation of variable extra-thoracic obstruction caused blunting and plateauing of inspiratory flow, and simulation of intra-thoracic obstruction caused limitation of expiratory flow with marked dynamic compression. Multiple choice tests were created with questions allocated to lower (remember and understand) or higher cognitive domains (apply, analyse and evaluate). In a cross-over design, overall mean scores increased after 11/2 h simulation spirometry (43-68 %, effect size 1.06, P < 0.0001). In higher cognitive domains the mean score was lower before and increased further than lower domains (Delta 30 vs 20 %, higher vs lower effect size 0.22, P < 0.05). In conclusion, the devices successfully simulate various patterns of obstruction and restriction. Using these devices medical students achieved marked enhancement of learning especially in higher cognitive domains. PMID- 25528246 TI - Work-family conflict, emotional exhaustion, and displaced aggression toward others: the moderating roles of workplace interpersonal conflict and perceived managerial family support. AB - Taking a resource-based self-regulation perspective, this study examined afternoon emotional exhaustion as a mediator linking the within-person relations between morning work-family conflict and later employee displaced aggression in the work and family domains. In addition, it examined resource-related contextual factors as moderators of these relations. The theoretical model was tested using daily diary data from 125 employees. Data were collected at 4 time points during each workday for 3 consecutive weeks. Multilevel modeling analysis showed that morning family-to-work conflict was positively related to afternoon emotional exhaustion, which in turn predicted displaced aggression toward supervisors and coworkers in the afternoon and displaced aggression toward family members in the evening. In addition, morning workplace interpersonal conflict exacerbated the impact of morning work-to-family conflict on afternoon emotional exhaustion, whereas perceived managerial family support alleviated the impact of morning family-to-work conflict on afternoon emotional exhaustion. These findings indicate the importance of adopting a self-regulation perspective to understand work-family conflict at work and its consequences (i.e., displaced aggression) in both work and family domains. PMID- 25528243 TI - Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort. AB - PURPOSE: The aim of the study was to assess associations between intake of combined soft drinks (sugar sweetened and artificially sweetened) and fruit and vegetable juices and the risk of hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC) using data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries. METHODS: After 11.4 years of follow-up, 191 HCC, 66 IHBC and 236 GBTC cases were identified. Hazard ratios and 95% confidence intervals (HR; 95% CI) were estimated with Cox regression models with multivariable adjustment (baseline total energy intake, alcohol consumption and intake pattern, body mass index, physical activity, level of educational attainment and self-reported diabetes status). RESULTS: No risk associations were observed for IHBC or GBTC. Combined soft drinks consumption of >6 servings/week was positively associated with HCC risk: HR 1.83; 95% CI 1.11-3.02, p trend = 0.01 versus non-consumers. In sub-group analyses available for 91% of the cohort artificially sweetened soft drinks increased HCC risk by 6% per 1 serving increment (HR 1.06, 95% CI 1.03-1.09, n cases = 101); for sugar-sweetened soft drinks, this association was null (HR 1.00, 95% CI 0.95-1.06; n cases = 127, p heterogeneity = 0.07). Juice consumption was not associated with HCC risk, except at very low intakes (<1 serving/week: HR 0.60; 95% CI 0.38-0.95; p trend = 0.02 vs. non-consumers). CONCLUSIONS: Daily intake of combined soft drinks is positively associated with HCC, but a differential association between sugar and artificially sweetened cannot be discounted. This study provides some insight into possible associations of HCC with sugary drinks intake. Further exploration in other settings is required. PMID- 25528247 TI - Regulating and facilitating: the role of emotional intelligence in maintaining and using positive affect for creativity. AB - Although past research has identified the effects of emotional intelligence on numerous employee outcomes, the relationship between emotional intelligence and creativity has not been well established. We draw upon affective information processing theory to explain how two facets of emotional intelligence-emotion regulation and emotion facilitation-shape employee creativity. Specifically, we propose that emotion regulation ability enables employees to maintain higher positive affect (PA) when faced with unique knowledge processing requirements, while emotion facilitation ability enables employees to use their PA to enhance their creativity. We find support for our hypotheses using a multimethod (ability test, experience sampling, survey) and multisource (archival, self-reported, supervisor-reported) research design of early career managers across a wide range of jobs. PMID- 25528248 TI - Timing, rates, and causes of death in a large South African tuberculosis programme. AB - BACKGROUND: Tuberculosis (TB) mortality remains high across sub-Saharan Africa despite integration of TB and HIV/ART programmes. To inform programme design and service delivery, we estimated mortality by time from starting TB treatment. METHODS: Routinely collected data on TB treatment, vital status, and the timing and causes of death, were linked to cardio-respiratory autopsy data, from 1995 2008, from a cohort of male platinum miners in South Africa. Records were expanded into person-months at risk (pm). RESULTS: 4162 TB episodes were registered; 3170 men were treated for the first time and 833 men underwent retreatment. Overall, 509 men died, with a case fatality of 12.2% and mortality rate of 2.0/100 pm. Mortality was highest in the first month after starting TB treatment for first (2.3/100 pm) and retreatment episodes (4.8/100 pm). When stratified by HIV status, case fatality was higher in HIV positive men not on ART (first episode 14.0%; retreatment episode 26.2%) and those on ART (12.0%; 22.0%) than men of negative or unknown HIV status (2.6%; 3.6%). Mortality was also highest in the first month for each of these groups. Mortality risk factors included older age, previous TB, HIV, pulmonary TB, and diagnostic uncertainty. The proportion of deaths attributable to TB was consistently overestimated in clinical records versus cardio-respiratory autopsy. CONCLUSIONS: Programme mortality was highest in those with HIV and during the first month of TB treatment in all groups, and many deaths were not caused by TB. Resource allocation should prioritise TB prevention and accurate earlier diagnosis, recognise the role of HIV, and ensure effective clinical care in the early stages of TB treatment. PMID- 25528249 TI - An epidemiological evaluation of pediatric long bone fractures - a retrospective cohort study of 2716 patients from two Swiss tertiary pediatric hospitals. AB - BACKGROUND: Children and adolescents are at high risk of sustaining fractures during growth. Therefore, epidemiological assessment is crucial for fracture prevention. The AO Comprehensive Injury Automatic Classifier (AO COIAC) was used to evaluate epidemiological data of pediatric long bone fractures in a large cohort. METHODS: Data from children and adolescents with long bone fractures sustained between 2009 and 2011, treated at either of two tertiary pediatric surgery hospitals in Switzerland, were retrospectively collected. Fractures were classified according to the AO Pediatric Comprehensive Classification of Long Bone Fractures (PCCF). RESULTS: For a total of 2716 patients (60% boys), 2807 accidents with 2840 long bone fractures (59% radius/ulna; 21% humerus; 15% tibia/fibula; 5% femur) were documented. Children's mean age (SD) was 8.2 (4.0) years (6% infants; 26% preschool children; 40% school children; 28% adolescents). Adolescent boys sustained more fractures than girls (p < 0.001). The leading cause of fractures was falls (27%), followed by accidents occurring during leisure activities (25%), at home (14%), on playgrounds (11%), and traffic (11%) and school accidents (8%). There was boy predominance for all accident types except for playground and at home accidents. The distribution of accident types differed according to age classes (p < 0.001). Twenty-six percent of patients were classed as overweight or obese - higher than data published by the WHO for the corresponding ages - with a higher proportion of overweight and obese boys than in the Swiss population (p < 0.0001). CONCLUSION: Overall, differences in the fracture distribution were sex and age related. Overweight and obese patients seemed to be at increased risk of sustaining fractures. Our data give valuable input into future development of prevention strategies. The AO PCCF proved to be useful in epidemiological reporting and analysis of pediatric long bone fractures. PMID- 25528250 TI - Use of Floseal(r), a human gelatine-thrombin matrix sealant, in surgery: a systematic review. AB - BACKGROUND: Surgical bleeding can be associated with an increased risk of morbidity and mortality across all surgical areas. Thus, numerous products have been developed to achieve haemostasis. A flowable haemostatic matrix such as Floseal(r) can quickly and reliably stop bleeding across the full spectrum of bleeding scenarios. The aim of this study was to systematically review clinical and economic evidence regarding the use of Floseal(r) in surgical procedures. METHODS: An extensive literature search was conducted in PubMed, EMBASE, and the Cochrane Library over the period spanning 2003-2013 to identify publications related to Floseal(r) use in all types of surgical procedures. Case reports and case series studies were excluded. RESULTS: A total of 27 papers met the selection criteria and were analysed. In the studies, blood loss and the time to achieve haemostasis were the most reported outcomes used to assess the efficacy of Floseal(r). The majority of published studies (64%) examined the use of Floseal(r) compared with conventional methods (such as electrocautery or suturing). The remaining 36% of the studies evaluated the use of Floseal(r) compared with other haemostatic agents, such as Surgicel(r), Gelfoam(r), and Hemostase(r). FloSeal(r) has been demonstrated to be an efficacious method in surgical procedures to reduce the time to achieve haemostasis, the frequency of intra- and postoperative bleeding, and the length of hospital stay, among other primary outcomes, resulting in less consumption of health resources. CONCLUSIONS: The majority of the selected studies confirmed that Floseal(r) showed improvements over other haemostatic agents in achieving haemostasis and reducing blood loss. PMID- 25528251 TI - Postoperative hemostatic efficacy of gauze soaked in tranexamic acid, fibrin sponge, and dry gauze compression following dental extractions in anticoagulated patients with cardiovascular disease: a prospective, randomized study. AB - INTRODUCTION: Oral anticoagulants are widely prescribed drugs. Interruption of anticoagulant therapy prior to oral surgery has been an issue of great controversy. The purpose of this study was to evaluate the incidence of bleeding complications after dental extractions in patients on anticoagulant therapy (warfarin) in whom different local hemostatic methods were used. MATERIAL AND METHODS: Patients using warfarin and requiring extractions of at least two teeth were screened to participate in this prospective, randomized study. Extraction sites were considered as sampling units (statistically representative sample size) and were allocated to one of the three study groups (G1-4.8% tranexamic acid; G2-fibrin sponge; and G3-no local hemostatic agents). RESULTS: Eighty-four extraction sites were obtained from patients with mitral valve prolapse (47.4%), prosthetic cardiac valve (23.7%), venous thromboembolism (21.1%), and pulmonary embolism (5.2%). International normalized ratio (INR) values ranged between 2.1 and 3.1 (mean 2.51 +/- 0.1). Postoperative bleeding was observed in four surgical sites (p < 0.001) and was mainly in older patients (p = 0.005). DISCUSSION: The three local hemostatic protocols were similarly effective in controlling postoperative bleeding in patients undergoing anticoagulant therapy with warfarin. The majority of teeth could be extracted with minimal problems in patients with cardiovascular diseases receiving treatment with anticoagulant therapy. PMID- 25528252 TI - Treatment decisions in a man with Hodgkin lymphoma and Guillian-Barre syndrome: a case report. AB - INTRODUCTION: Guillain-Barre syndrome, or acute inflammatory demyelinating polyneuropathy, has been described in the presence of malignancies such as lymphoma. Guillain-Barre syndrome/acute inflammatory demyelinating polyneuropathy causes paresthesias and weakness, which can make the treatment of lymphoma with chemotherapy challenging. Given the rarity of this co-presentation it is not known if the effects of Guillain-Barre syndrome should be considered when selecting a treatment regimen for Hodgkin lymphoma. To the best of our knowledge, the impact of these treatment modifications has not been previously reported. CASE PRESENTATION: We report the case of a 37-year-old Caucasian man with a diagnosis of stage IIB classical Hodgkin lymphoma with concomitant Guillain-Barre syndrome. Our patient originally presented with an enlarged cervical lymph node and quickly developed distal paresthesia and progressive weakness of all four extremities. He was diagnosed with Hodgkin's lymphoma and initiated on treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine. Doses of bleomycin and vinblastine were held or dose-reduced throughout his initial treatment course due to underlying neuropathy and dyspnea. He continued to have persistent disease after five cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and went on to receive salvage treatments including more chemotherapy, radiation, autologous stem cell transplant and is currently preparing for an allogeneic stem cell transplant. CONCLUSIONS: Paraneoplastic syndromes such as Guillain-Barre syndrome/acute inflammatory demyelinating polyneuropathy can make the treatment of patients with Hodgkin lymphoma more challenging and can interfere with delivering full-dose chemotherapy. Further case series are needed to evaluate the effect that paraneoplastic syndromes, or adjustments made in therapy due to these syndromes, negatively affect the prognosis of patients with Hodgkin lymphoma. PMID- 25528253 TI - In vivo RNAi screen identifies candidate signaling genes required for collective cell migration in Drosophila ovary. AB - Collective migration of loosely or closely associated cell groups is prevalent in animal development, physiological events, and cancer metastasis. However, our understanding of the mechanisms of collective cell migration is incomplete. Drosophila border cells provide a powerful in vivo genetic model to study collective migration and identify essential genes for this process. Using border cell-specific RNAi-silencing in Drosophila, we knocked down 360 conserved signaling transduction genes in adult flies to identify essential pathways and genes for border cell migration. We uncovered a plethora of signaling genes, a large proportion of which had not been reported for border cells, including Rack1 (Receptor of activated C kinase) and brk (brinker), mad (mother against dpp), and sax (saxophone), which encode three components of TGF-beta signaling. The RNAi knock down phenotype was validated by clonal analysis of Rack1 mutants. Our data suggest that inhibition of Src activity by Rack1 may be important for border cell migration and cluster cohesion maintenance. Lastly, results from our screen not only would shed light on signaling pathways involved in collective migration during embryogenesis and organogenesis in general, but also could help our understanding for the functions of conserved human genes involved in cancer metastasis. PMID- 25528254 TI - Cell therapy for macular degeneration--first phase I/II pluripotent stem cell based clinical trial shows promise. PMID- 25528255 TI - Calcium dobesilate for diabetic retinopathy: a systematic review and meta analysis. AB - Many randomized clinical controlled trials have confirmed the efficacy and safety of calcium dobesilate in treating diabetic retinopathy (DR). This systematic review critically evaluated the evidence that links calcium dobesilate to DR. In this fixed-effects meta-analysis, a total of 221 pertinent English-language articles published between January 1975 and October 2013 were identified. Systematic searches of PUBMED, Springer Link and the Cochrane Clinical Trials Database were conducted using the keywords "diabetic retinopathy" and "calcium dobesilate". The extracted information included the study design, inclusion and exclusion criteria, setting, sample size, participant mean age, treatment regime, mean change in best corrected visual acuity, laboratory parameters, capillary fragility, intraocular pressure and fundus manifestations based on the findings of fluorescent angiography. The summary statistics indicated that calcium dobesilate was significantly associated with improving retinal microaneurysms (RR: 0.62, 95%CI: 0.42-0.90, P=0.01), retinal hemorrhages (RR: 0.39, 95% CI: 0.17 0.88, P=0.02); exudates (RR: 0.31, 95% CI: 0.12-0.81, P=0.02), reduction of whole blood viscosity (MD: -0.57 CP, 95% CI: -0.75 to -0.38, P<0.001), plasma viscosity (MD: -0.36 CP, 95% CI: -0.63 to -0.09, P=0.01) and blood cholesterol (MD: -0.48 mg mL(-1), 95% CI: -0.64-0.33, P<0.00001). Intraocular pressure was also significantly reduced (MD: -5.59 mmHg, 95% CI: -6.69 to -4.50, P<0.00001). The results indicate that calcium dobesilate effectively treats DR at the systematic and local ocular levels. PMID- 25528256 TI - Cardiorespiratory Fitness Is Associated With Cognitive Performance in Older But Not Younger Adults. AB - OBJECTIVES: Aging is associated with declines in executive function and episodic memory. Cardiorespiratory fitness (CRF) has been associated with enhanced executive function in older adults (OA), but the relationship with episodic memory remains unclear. The purpose of the study was to examine the relationship between CRF and cognition in young and OA and whether CRF mitigates age-related cognitive decline. METHODS: Participants completed exercise testing to evaluate CRF (peak VO2) and neuropsychological testing to assess cognition. RESULTS: In OA, peak VO2 was positively related to executive function, as well as to accuracy on an experimental face-name memory task and visual episodic memory. In young adults (YA), a relationship between peak VO2 and cognition was not evident. High fit OA performed as well as YA on executive function measures. On episodic memory measures, YA performed better than high-fit OA, who in turn performed better than low-fit OA. CONCLUSIONS: CRF is positively associated with executive function and episodic memory in OA and attenuates age-related cognitive decline. We provide preliminary support for the age-dependence hypothesis, which posits that cognition and CRF relationships may be most readily observed during lifetime periods of significant neurocognitive development. PMID- 25528257 TI - The Association Between Older Israelis' Quality of Relationships With Their Family and Migrant Live-in Caregivers and Their Loneliness. AB - OBJECTIVES: (a) To assess the extent to which there are ambivalent dyadic relationships between older care recipients and their primary family caregivers (PFCs) and migrant care workers (MCWs) and (b) to examine the extent to which ambivalence explains loneliness among the care recipients. METHOD: A sample of 279 triads of respondents (care recipients, their PFCs, and their MCWs) was used and interviewed face-to-face. The Dyadic Relationship Scale was used to assess quality of relationships and ambivalence. The de Jong Gierveld Loneliness Scale was used to assess loneliness. RESULTS: Mean scores for dyadic ambivalence between the care recipients and both types of caregivers were moderate. Lower levels of ambivalence in dyadic relationships with PFCs were associated with decreased loneliness. Ambivalent dyadic relationships explained 6% of the variance in loneliness. DISCUSSION: Some degree of ambivalent relationship exists between care recipients and both types of caregivers. The vigor of ambivalence was significantly associated with the level of loneliness reported by functionally disabled older adults. PMID- 25528258 TI - An Ego Depletion Account of Aging Stereotypes' Effects on Health-Related Variables. AB - OBJECTIVES: This study examined whether stereotypes may predict health outcomes independently from their internalization into the self. Specifically, we tested whether endorsement of negative age stereotypes in the physical activity (PA) domain is related to decreased subjective vitality among active older adults, illustrating ego depletion. METHOD: This longitudinal study included 192 retired individuals aged 60-92 years who regularly participated in organized PA, and who completed the measures on three occasions (9-month period). RESULTS: Multilevel growth models tested whether within-person variation in age stereotypes endorsement across waves predicted subjective vitality, after controlling for self-perceptions of aging and relevant covariates. Results showed that (a) within person increases in endorsement of age stereotypes of self-efficacy (b = 0.17, p < .01) were associated with increases in subjective vitality, (b) between-person mean difference in endorsement of age stereotypes of PA benefits (b = 0.21, p < .05) positively predicted subjective vitality, and (c) subjective vitality mediated the relationship between endorsement of self-efficacy stereotype and self-rated health. DISCUSSION: This study confirmed that endorsement of age stereotypes of PA predicted subjective vitality among active older adults. These results suggest that stereotypes may be related to health-related outcomes notably through ego depletion effects. PMID- 25528259 TI - Nucleosome organizations in induced pluripotent stem cells reprogrammed from somatic cells belonging to three different germ layers. AB - BACKGROUND: Nucleosome organization determines the chromatin state, which in turn controls gene expression or silencing. Nucleosome remodeling occurs during somatic cell reprogramming, but it is still unclear to what degree the re established nucleosome organization of induced pluripotent stem cells (iPSCs) resembles embryonic stem cells (ESCs), and whether the iPSCs inherit some residual gene expression from the parental fibroblast cells. RESULTS: We generated genome-wide nucleosome maps in mouse ESCs and in iPSCs reprogrammed from somatic cells belonging to three different germ layers using a secondary reprogramming system. Pairwise comparisons showed that the nucleosome organizations in the iPSCs, regardless of the iPSCs' tissue of origin, were nearly identical to the ESCs, but distinct from mouse embryonic fibroblasts (MEF). There is a canonical nucleosome arrangement of -1, nucleosome depletion region, +1, +2, +3, and so on nucleosomes around the transcription start sites of active genes whereas only a nucleosome occupies silent transcriptional units. Transcription factor binding sites possessed characteristic nucleosomal architecture, such that their access was governed by the rotational and translational settings of the nucleosome. Interestingly, the tissue-specific genes were highly expressed only in the parental somatic cells of the corresponding iPS cell line before reprogramming, but had a similar expression level in all the resultant iPSCs and ESCs. CONCLUSIONS: The re-established nucleosome landscape during nuclear reprogramming provides a conserved setting for accessibility of DNA sequences in mouse pluripotent stem cells. No persistent residual expression program or nucleosome positioning of the parental somatic cells that reflected their tissue of origin was passed on to the resulting mouse iPSCs. PMID- 25528260 TI - Doctors' views about training and future careers expressed one year after graduation by UK-trained doctors: questionnaire surveys undertaken in 2009 and 2010. AB - BACKGROUND: The UK medical graduates of 2008 and 2009 were among the first to experience a fully implemented, new, UK training programme, called the Foundation Training Programme, for junior doctors. We report doctors' views of the first Foundation year, based on comments made as part of a questionnaire survey covering career choices, plans, and experiences. METHODS: Postal and email based questionnaires about career intentions, destinations and views were sent in 2009 and 2010 to all UK medical graduates of 2008 and 2009. This paper is a qualitative study of 'free-text' comments made by first-year doctors when invited to comment, if they wished, on any aspect of their work, education, training, and future. RESULTS: The response rate to the surveys was 48% (6220/12952); and 1616 doctors volunteered comments. Of these, 61% wrote about their first year of training, 35% about the working conditions they had experienced, 33% about how well their medical school had prepared them for work, 29% about their future career, 25% about support from peers and colleagues, 22% about working in medicine, and 15% about lifestyle issues. When concerns were expressed, they were commonly about the balance between service provision, administrative work, and training and education, with the latter often suffering when it conflicted with the needs of medical service provision. They also wrote that the quality of a training post often depended on the commitment of an individual senior doctor. Service support from seniors was variable and some respondents complained of a lack of team work and team ethic. Excessive hours and the lack of time for reflection and career planning before choices about the future had to be made were also mentioned. Some doctors wrote that their views were not sought by their hospital and that NHS management structures did not lend themselves to efficiency. UK graduates from non-UK homes felt insecure about their future career prospects in the UK. There were positive comments about opportunities to train flexibly. CONCLUSIONS: Although reported problems should be considered in the wider context, in which the majority held favourable overall views, many who commented had been disappointed by aspects of their first year of work. We hope that the concerns raised by our respondents will prompt trainers, locally, to determine, by interaction with junior staff, whether or not these are concerns in their own training programme. PMID- 25528261 TI - Phylogeny of seven Bulinus species originating from endemic areas in three African countries, in relation to the human blood fluke Schistosoma haematobium. AB - BACKGROUND: Snails species belonging to the genus Bulinus (Planorbidae) serve as intermediate host for flukes belonging to the genus Schistosoma (Digenea, Platyhelminthes). Despite its importance in the transmission of these parasites, the evolutionary history of this genus is still obscure. In the present study, we used the partial mitochondrial cytochrome oxidase subunit I (cox1) gene, and the nuclear ribosomal ITS, 18S and 28S genes to investigate the haplotype diversity and phylogeny of seven Bulinus species originating from three endemic countries in Africa (Cameroon, Senegal and Egypt). RESULTS: The cox1 region showed much more variation than the ribosomal markers within Bulinus sequences. High levels of genetic diversity were detected at all loci in the seven studied species, with clear segregation between individuals and appearance of different haplotypes, even within same species from the same locality. Sequences clustered into two lineages; (A) groups Bulinus truncatus, B. tropicus, B. globosus and B. umbilicatus; while (B) groups B. forskalii, B. senegalensis and B. camerunensis. Interesting patterns emerge regarding schistosome susceptibility: Bulinus species with lower genetic diversity are predicted to have higher infection prevalence than those with greater diversity in host susceptibility. CONCLUSION: The results reported in this study are very important since a detailed understanding of the population genetic structure of Bulinus is essential to understand the epidemiology of many schistosome parasites. PMID- 25528262 TI - A randomised controlled trial of an exercise plus behaviour change intervention in people with multiple sclerosis: the step it up study protocol. AB - BACKGROUND: Exercise has consistently yielded short-term, positive effects on health outcomes in people with multiple sclerosis (MS). However, these effects have not been maintained in the long-term. Behaviour change interventions aim to promote long-term positive lifestyle change. This study, namely, "Step it Up" will compare the effect of an exercise plus Social Cognitive Theory (SCT)-based behaviour change intervention with an exercise plus control education intervention on walking mobility among people with MS. METHODS/DESIGN: People with a diagnosis of MS who walk independently, score of 0-3 on the Patient Determined Disease Steps, who have not experienced an MS relapse or change in their MS medication in the last 12 weeks and who are physically inactive will be randomised to one of two study conditions. The experimental group will undergo a 10-week exercise plus SCT-based behavioural change intervention. The control group will undergo a 10-week exercise plus education intervention to control for contact. Participants will be assessed at weeks 1, 12, 24 and 36. The primary outcome will be walking mobility. Secondary outcomes will include: aerobic capacity, lower extremity muscle strength, participant adherence to the exercise programme, self-report exercise intensity, self-report enjoyment of exercise, exercise self-efficacy, outcome expectations for exercise, goal-setting for exercise, perceived benefits and barriers to exercise, perceptions of social support, physical and psychological impact of MS and fatigue. A qualitative evaluation of Step it Up will be completed among participants post-intervention. DISCUSSION: This randomised controlled trial will examine the effectiveness of an exercise plus SCT-based behaviour change intervention on walking mobility among people with MS. To this end, Step it Up will serve to inform future directions of research and clinical practice with regard to sustainable exercise interventions for people with MS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02301442. PMID- 25528263 TI - Work disability functional assessment battery: feasibility and psychometric properties. AB - OBJECTIVE: To assess the feasibility and psychometric properties of 8 scales covering 2 domains of the newly developed Work Disability Functional Assessment Battery (WD-FAB): physical function (PF) and behavioral health (BH) function. DESIGN: Cross-sectional study. SETTING: Community. PARTICIPANTS: Adults (N=973) unable to work because of a physical (n=497) or a mental (n=476) disability. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Each disability group responded to a survey consisting of the relevant WD-FAB scales and existing measures of established validity. The WD-FAB scales were evaluated with regard to data quality (score distribution, percentage of "I don't know" responses), efficiency of administration (number of items required to achieve reliability criterion, time required to complete the scale) by computerized adaptive testing (CAT), and measurement accuracy as tested by person fit. Construct validity was assessed by examining both convergent and discriminant correlations between the WD-FAB scales and scores on same-domain and cross-domain established measures. RESULTS: Data quality was good, and CAT efficiency was high across both WD-FAB domains. Measurement accuracy was very good for PF scales; BH scales demonstrated more variability. Construct validity correlations, both convergent and divergent, between all WD-FAB scales and established measures were in the expected direction and range of magnitude. CONCLUSIONS: The data quality, CAT efficiency, person fit, and construct validity of the WD-FAB scales were well supported and suggest that the WD-FAB could be used to assess PF and BH function related to work disability. Variation in scale performance suggests the need for future work on item replenishment and refinement, particularly with regard to the Self-Efficacy scale. PMID- 25528264 TI - The role of KIF14 in patient-derived primary cultures of high-grade serous ovarian cancer cells. AB - OBJECTIVE: Previously, it has been shown that KIF14 mRNA is overexpressed in ovarian cancer (OvCa), regardless of histological subtype. KIF14 levels are independently predictive of poor outcome and increased rates of recurrence in serous OvCa patients. Furthermore, it has been shown that KIF14 also controls the in vivo tumorigenicity of OvCa cell lines. In this study, we evaluate the potential of KIF14 as a therapeutic target through selective inhibition of KIF14 in primary high-grade serous patient-derived OvCa cells. METHODS: To assess the dependence of primary serous OvCa cultures on KIF14, protein levels in 11 prospective high grade serous ovarian cancer samples were increased (KIF14 overexpression by transfection) or decreased (anti-KIF14 shRNA) in vitro, and proliferative capacity, anchorage independence and xenograft growth were assessed. RESULTS: Seven of eleven samples demonstrated increased/decreased in vitro proliferation in response to KIF14 overexpression/knockdown, respectively. When examining in vitro tumorigenicity (colony formation) and in vivo growth (subcutaneous xenografts) in response to KIF14 manipulation, none of the samples demonstrated growth in soft agar (11 samples), or xenograft growth (4 samples). CONCLUSIONS: Although primary high-grade serous OvCa cells may depend on KIF14 for in vitro proliferation we were unable to demonstrate a role for KIF14 on tumorigenicity or develop an in vivo model for assessment. We have, however developed an effective in vitro method to evaluate the effect of target gene manipulation on the proliferative capacity of primary OvCa cultures. PMID- 25528265 TI - Genetic diversities of 20 novel autosomal STRs in Chinese Xibe ethnic group and its genetic relationships with neighboring populations. AB - In the present study, we investigated the genetic polymorphisms of 20 novel STR loci and one previously studied locus in the Xibe ethnic group from China, as well as its genetic relationships with neighboring populations. Totally 226 unrelated healthy Xibe individuals were involved in the study. At least 5 alleles were observed for each locus, with the minimum and maximum allelic frequencies of 0.0022 and 0.5221, respectively. We obtained the lowest and highest observed heterozygosity and expected heterozygosity at locus D1S1627 and D19S433, respectively. The values of combined power of discrimination and probability of exclusion of all the 21 STR loci were 0.99999999999999999997310 and 0.999998650, respectively. Analyses of interpopulation differentiation, principal component analysis, genetic distance and phylogenetic tree revealed the relationships between Xibe group and its neighboring groups, showing that the studied Xibe group had a close genetic relationship with the Mongolian group. The present results indicated that these 21 STR loci had high genetic polymorphisms in the studied Xibe group, and were capable for the paternity testing and individual identification in forensic application. PMID- 25528266 TI - Identification of microRNAs by small RNA deep sequencing for synthetic microRNA mimics to control Spodoptera exigua. AB - Beet armyworm, Spodoptera exigua, is a major pest of cotton around the world. With the increase of resistance to Bacillus thuringiensis (Bt) toxin in transgenic cotton plants, there is a need to develop an alternative control approach that can be used in combination with Bt transgenic crops as part of resistance management strategies. MicroRNAs (miRNAs), a non-coding small RNA family (18-25 nt), play crucial roles in various biological processes and over expression of miRNAs has been shown to interfere with the normal development of insects. In this study, we identified 127 conserved miRNAs in S. exigua by using small RNA deep sequencing technology. From this, we tested the effects of 11 miRNAs on larval development. We found three miRNAs, Sex-miR-10-1a, Sex-miR-4924, and Sex-miR-9, to be differentially expressed during larval stages of S. exigua. Oral feeding experiments using synthetic miRNA mimics of Sex-miR-10-1a, Sex-miR 4924, and Sex-miR-9 resulted in suppressed growth of S. exigua and mortality. Over-expression of Sex-miR-4924 caused a significant reduction in the expression level of chitinase 1 and caused abortive molting in the insects. Therefore, we demonstrated a novel approach of using miRNA mimics to control S. exigua development. PMID- 25528267 TI - An epigenetic regulatory element of the Nodal gene in the mouse and human genomes. AB - Nodal signaling plays critical roles during embryonic development. The Nodal gene is not expressed in adult tissues but is frequently activated in cancer cells, contributing to progression toward malignancy. Although several regulatory elements of the Nodal gene have been identified, the epigenetic mechanisms by which Nodal expression is regulated over the long term remain unclear. We found a region exhibiting dynamic changes in DNA methylation at approximately -3.0 kb to 0.4 kb upstream from the transcriptional start site (TSS) that we termed the epigenetic regulatory element (ERE). The ERE was unmethylated in mouse embryonic stem cells (mESCs) but became increasingly methylated in differentiated cells and tissues, concomitant with the downregulation of Nodal mRNA expression. In vitro reporter assays identified an Oct3/4 binding motif within the ERE, indicating that the ERE is responsible for the activation of Nodal in mESCs. Furthermore, the ERE was a target of differentiation-associated Polycomb silencing, and the chromatin condensed when mESCs differentiated to embryoid bodies (EBs). Pharmacological inhibition of PRC2 led to the reactivation of Nodal expression in EBs and mouse embryonic fibroblasts (MEFs). The ERE was also targeted by PRC2 in normal human cells. In NODAL-expressing human cancer cells, accumulation of EZH2 and trimethylation of H3K27 at the ERE were diminished. In conclusion, Nodal is epigenetically controlled through the ERE in the mouse embryo and human cells. PMID- 25528268 TI - The release of As, Cr and Cu from contaminated soil stabilized with APC residues under landfill conditions. AB - The aim of this study was to investigate the stability of As, Cr and Cu in contaminated soil treated with air pollution control residues under landfill conditions. The influence of landfill gas and temperature on the release of trace elements from stabilized soil was simulated using a diffusion test. The air pollution control residues immobilized As through the precipitation of Ca-As minerals (calcium arsenate (Ca5H2(AsO4)3 * 5H2O), weilite (CaAsO4) and johnbaumite (Ca5(AsO4)3(OH)), incorporation of As into ettringite (Ca6Al2(SO4)3(OH)12 * 26H2O) and adsorption by calcite (CaCO3). The air pollution control residues generally showed a high resistance to pH reduction, indicating high buffer capacity and stability of immobilized As in a landfill over time. Generation of heat in a landfill might increase the release of trace elements. The release of As from stabilized soil was diffusion-controlled at 60 degrees C, while surface wash-off, dissolution, and depletion prevailed at 20 degrees C. The air pollution control residues from the incineration of municipal solid waste immobilized Cr, indicating its stability in a landfill. The treatment of soil with air pollution control residues was not effective in immobilization of Cu. Contaminated soils treated with air pollution control residues will probably have a low impact on overall leachate quality from a landfill. PMID- 25528269 TI - Barriers to collaborative forest management and implications for building the resilience of forest-dependent communities in the Ashanti region of Ghana. AB - Community resilience, the capacity of a community to adapt to change in ways that result in positive impacts on its well-being, is increasingly used as a framework for understanding and enhancing the sustainability of forest-dependent communities as social-ecological systems. However, studies linking community resilience to the implementation of forest management programs are limited. This study uses community resilience literature and analyzes data collected from interviews to study barriers of forest-dependent communities of collaborative forest management (CFM) in two forest-dependent communities in the Ashanti region of Ghana. Analysis revealed the barriers in community response to CFM programs in these two communities comprise institutional shortfalls in the design and implementation of the CFM program that have constrained the incentives, capacity and opportunities for communities to successfully adapt to the program. The paper offers recommendations on how the CFM program can contribute to building the resilience of communities in managing their forests. The first is to build institutional capacity of communities to play an active role in forest governance, and the second is the prioritization of well-being and livelihood enhancement as forest management goals. PMID- 25528270 TI - Strategic effects of future environmental policy commitments: climate change, solar radiation management and correlated air pollutants. AB - We study the effects of environmental policy commitments in a futuristic world in which solar radiation management (SRM) can be utilized to reduce climate change damages. Carbon and sulfur dioxide emissions (correlated pollutants) can be reduced through tradable permits. We show that if nations simultaneously commit to carbon permit policies, national SRM levels rise with carbon quotas. Alternatively, if they simultaneously commit to SRM policies, the global temperature falls with each unit increase in the global SRM level. A nation always wishes to be a leader in policymaking, but prefers carbon to SRM policymaking. The globe prefers SRM policy commitments. PMID- 25528271 TI - Remote sensing estimation of the total phosphorus concentration in a large lake using band combinations and regional multivariate statistical modeling techniques. AB - Remote sensing has been widely used for ater quality monitoring, but most of these monitoring studies have only focused on a few water quality variables, such as chlorophyll-a, turbidity, and total suspended solids, which have typically been considered optically active variables. Remote sensing presents a challenge in estimating the phosphorus concentration in water. The total phosphorus (TP) in lakes has been estimated from remotely sensed observations, primarily using the simple individual band ratio or their natural logarithm and the statistical regression method based on the field TP data and the spectral reflectance. In this study, we investigated the possibility of establishing a spatial modeling scheme to estimate the TP concentration of a large lake from multi-spectral satellite imagery using band combinations and regional multivariate statistical modeling techniques, and we tested the applicability of the spatial modeling scheme. The results showed that HJ-1A CCD multi-spectral satellite imagery can be used to estimate the TP concentration in a lake. The correlation and regression analysis showed a highly significant positive relationship between the TP concentration and certain remotely sensed combination variables. The proposed modeling scheme had a higher accuracy for the TP concentration estimation in the large lake compared with the traditional individual band ratio method and the whole-lake scale regression-modeling scheme. The TP concentration values showed a clear spatial variability and were high in western Lake Chaohu and relatively low in eastern Lake Chaohu. The northernmost portion, the northeastern coastal zone and the southeastern portion of western Lake Chaohu had the highest TP concentrations, and the other regions had the lowest TP concentration values, except for the coastal zone of eastern Lake Chaohu. These results strongly suggested that the proposed modeling scheme, i.e., the band combinations and the regional multivariate statistical modeling techniques, demonstrated advantages for estimating the TP concentration in a large lake and had a strong potential for universal application for the TP concentration estimation in large lake waters worldwide. PMID- 25528272 TI - The effect of mercury on baseline corticosterone in a breeding songbird. AB - Although songbirds accumulate mercury at rates equivalent to better-studied aquatic avian species, effects of mercury bioaccumulation in songbirds remain understudied. Little is known about the effects of mercury on endocrine physiology, but recent evidence indicates that mercury may disrupt the function of the hypothalamic-pituitary-adrenal axis. Both field-based correlational studies and a recent dosing experiment suggest that mercury exposure alters levels of the primary avian stress hormone, CORT. We sampled zebra finches that had been dosed with 0, 0.5, or 1.0 ppm dietary methylmercury for baseline CORT twice; once during pairing and once after successfully fledging young. Circulating levels of CORT were not significantly affected by mercury exposure. However, our findings indicate potentially important differences in CORT responses between the sexes when exposed to environmentally relevant doses of mercury across the nesting cycle. PMID- 25528273 TI - Concentrations and seasonal variation of ambient PM(2.5) and associated metals at a typical residential area in Beijing, China. AB - In this study, continuous monitoring of PM2.5 was carried out for 1 year period at one of the largest residential areas in Beijing. Annual mean of PM2.5 during sampling period was 100.4 ug/m(3). The seasonal variation trend of PM2.5 was winter > spring > autumn and summer. The total mass concentrations of metals in PM2.5 ranged from 0.4 to 13.2 MUg/m(3). There were significant (p < 0.05) seasonal variations for concentrations of Ca, Al, Mn, As, Rb, Cr, Ni, Cd and Co, seasonal variations in PM-associated metals were not necessarily the same as the seasonal variation in PM2.5, related to differing seasonal trends in source types. The impact of meteorological factors (e.g., wind speed) on metals levels of PM2.5 was found to be significant by regression models. The EFs value of Ag, Ca, Cd, Pb, Zn, As, Cu, and Cr were higher than ten, suggesting that those elements were primarily contributed by anthropogenic sources. Seasonal characteristic of EFs were found for As, Cr, Ca and Ag, which indicating the seasonal pollution sources types for those metals. Overall, these findings indicated that the pollution control of ambient PM2.5 should not be negligible in residential area in Beijing and the local government should pertinent and accurate prevent and control of air pollution as well as protect human health. PMID- 25528274 TI - Transient resolution of chronic right bundle branch block in the acute phase of myocardial infarction. PMID- 25528275 TI - Seeking a reading machine for the blind and discovering the speech code. AB - A machine that can read printed material to the blind became a priority at the end of World War II with the appointment of a U.S. Government committee to instigate research on sensory aids to improve the lot of blinded veterans. The committee chose Haskins Laboratories to lead a multisite research program. Initially, Haskins researchers overestimated the capacities of users to learn an acoustic code based on the letters of a text, resulting in unsuitable designs. Progress was slow because the researchers clung to a mistaken view that speech is a sound alphabet and because of persisting gaps in man-machine technology. The tortuous route to a practical reading machine transformed the scientific understanding of speech perception and reading at Haskins Labs and elsewhere, leading to novel lines of basic research and new technologies. Research at Haskins Laboratories made valuable contributions in clarifying the physical basis of speech. Researchers recognized that coarticulatory overlap eliminated the possibility of alphabet-like discrete acoustic segments in speech. This work advanced the study of speech perception and contributed to our understanding of the relation of speech perception to production. Basic findings on speech enabled the development of speech synthesis, part science and part technology, essential for development of a reading machine, which has found many applications. Findings on the nature of speech further stimulated a new understanding of word recognition in reading across languages and scripts and contributed to our understanding of reading development and reading disabilities. PMID- 25528276 TI - HKT transporters mediate salt stress resistance in plants: from structure and function to the field. AB - Plant cells are sensitive to salinity stress and do not require sodium as an essential element for their growth and development. Saline soils reduce crop yields and limit available land. Research shows that HKT transporters provide a potent mechanism for mediating salt tolerance in plants. Knowledge of the molecular ion transport and regulation mechanisms and the control of HKT gene expression are crucial for understanding the mechanisms by which HKT transporters enhance crop performance under salinity stress. This review focuses on HKT transporters in monocot plants and in Arabidopsis as a dicot plant, as a guide to efforts toward improving salt tolerance of plants for increasing the production of crops and bioenergy feedstocks. PMID- 25528278 TI - New horizons in the management of Alzheimer disease. PMID- 25528277 TI - Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss. AB - BACKGROUND: The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort. RESULTS: Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR=3.91, 95% CI: 1.62-9.40, p=1.45*10(-7)). CONCLUSIONS: We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases. PMID- 25528279 TI - Certified nurse aide scope of practice. PMID- 25528280 TI - SAIDO learning as a cognitive intervention for dementia care: a preliminary study. AB - OBJECTIVES: The purpose of this study was to examine the beneficial effects on cognitive function by a cognitive intervention program designed for dementia care called Learning Therapy in Japan and SAIDO Learning in the United States (hereinafter "SAIDO Learning," as appropriate). SAIDO Learning is a working memory training program that uses systematized basic problems in arithmetic and language, including reading aloud, as well as writing. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Twenty-three nursing home residents with dementia were assigned as an intervention group, and another 24 people with dementia at another nursing home were assigned as a control group. Both nursing homes were operated by the same organization, and residents of both nursing homes received essentially the same nursing care. Thirteen and 6 subjects of the intervention and control groups, respectively, were clinically diagnosed as Alzheimer disease (AD). RESULTS: After the 6-month intervention, the participants with AD of the intervention group showed statistically significant improvement in cognitive function, as measured by the Mini-Mental State Examination (MMSE) compared with the control participants. In addition, post hoc analysis revealed that the Frontal Assessment Battery at Bedside (FAB) scores of the intervention group tended to improve after 6-month intervention. Based on MDS scores, improvements in total mood severity scores also were observed, but only in the intervention group of the participants with AD. CONCLUSION: These results suggest that SAIDO Learning is an effective cognitive intervention and is useful for dementia care. An additional outcome of this intervention, which has not yet been evaluated in detail, appears to be that it promotes greater positive engagement of a diversity of nursing home staff in the residents' individual progress and care needs. PMID- 25528281 TI - Maintenance cognitive stimulation therapy: an economic evaluation within a randomized controlled trial. AB - BACKGROUND: Cognitive Stimulation Therapy (CST) is effective and cost-effective for people with mild-to-moderate dementia when delivered biweekly over 7 weeks. AIMS: To examine whether longer-term (maintenance) CST is cost-effective when added to usual care. METHODS: Cost-effectiveness analysis within multicenter, single-blind, pragmatic randomized controlled trial; subgroup analysis for people taking acetylcholinesterase inhibitors (ACHEIs). A total of 236 participants with mild-to-moderate dementia received CST for 7 weeks. They were randomized to either weekly maintenance CST added to usual care or usual care alone for 24 weeks. RESULTS: Although outcome gains were modest over 6 months, maintenance CST appeared cost-effective when looking at self-rated quality of life as primary outcome, and cognition (MMSE) and proxy-rated quality-adjusted life years as secondary outcomes. CST in combination with ACHEIs offered cost-effectiveness gains when outcome was measured as cognition. CONCLUSIONS: Continuation of CST is likely to be cost-effective for people with mild-to-moderate dementia. PMID- 25528282 TI - The vegetative state: prevalence, misdiagnosis, and treatment limitations. AB - INTRODUCTION: Patients in a vegetative state/unresponsive wakefulness syndrome (VS/UWS) open their eyes spontaneously, but show only reflexive behavior. Although VS/UWS is one of the worst possible outcomes of acquired brain injury, its prevalence is largely unknown. This study's objective was to map the total population of hospitalized and institutionalized patients in VS/UWS in the Netherlands: prevalence, clinical characteristics, and treatment limitations. METHODS: Nationwide point prevalence study on patients in VS/UWS at least 1 month after acute brain injury in hospitals, rehabilitation centers, nursing homes, institutions for people with intellectual disability, and hospices; diagnosis verification by a researcher using the Coma Recovery Scale-revised (CRS-r); gathering of demographics, clinical characteristics, and treatment limitations. RESULTS: We identified 33 patients in VS/UWS, 24 of whose diagnoses could be verified. Patients were on average 51 years old with a mean duration of VS/UWS of 5 years. The main etiology was hypoxia sustained during cardiac arrest and resuscitation. More than 50% of patients had not received rehabilitation services. Most were given life-sustaining treatment beyond internationally accepted prognostic boundaries regarding recovery of consciousness. Seventeen (39%) of 41 patients presumed to be in VS/UWS were found to be at least minimally conscious. CONCLUSIONS: Results translate to a prevalence of 0.1 to 0.2 hospitalized and institutionalized VS/UWS patients per 100,000 members of the general population. This small figure may be related to the legal option to withhold or withdraw life-sustaining treatment, including artificial nutrition and hydration. On the other hand, this study shows that in certain cases, physicians continue life-prolonging treatment for up to 25 years. Patients have poor access to rehabilitation and are at substantial risk for misdiagnosis. PMID- 25528283 TI - Assessment of care problems in Romania: feasibility and exploration. AB - OBJECTIVES: The objective of this study was to study the feasibility of a recently developed instrument, LPZ-International, which assesses care problems in health care, and to describe the prevalence of care problems in Romanian health care institutions. Large differences exist in care services in Europe. Data on quality of care are absent or incomplete in Central-Eastern European countries. These countries, including Romania, have faced dramatic socioeconomic changes, which led to negative changes in quality of care. DESIGN: Cross-sectional study. SETTING: Hospital wards, mental care institutions, and nursing homes. PARTICIPANTS: Nine health care institutions and admitted 394 patients. MEASURES: LPZ-International was introduced in 9 health care institutions in Romania. Assessed care problems included pressure ulcers, urinary and fecal incontinence, malnutrition, falls, and physical restraints. The data were collected between November 2013 and March 2014. Two health care professionals completed the questionnaire by hand at the patient's site. RESULTS: Six of the 9 health care institutions and 90% of the patients participated, which indicates the feasibility of LPZ-International, as did the completeness of the questionnaire. The data showed a high consistency and only a few were missing. The most frequent care problem was urinary and fecal incontinence, especially in the nursing home. Pressure ulcers and malnutrition were less frequent care problems in Romanian patients. Physical restraints were frequently applied in the nursing home and geriatrics and oncology wards. CONCLUSIONS: LPZ-International is a feasible instrument to assess care problems. The differences between wards and countries in the prevalence of care problems indicate differences in quality of care and the need for high-quality, comparative research. PMID- 25528284 TI - Metabolism of UV-filter benzophenone-3 by rat and human liver microsomes and its effect on endocrine-disrupting activity. AB - Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3 OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4 diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes. PMID- 25528285 TI - Lexical and sublexical orthographic processing: an ERP study with skilled and dyslexic adult readers. AB - This ERP study investigated the cognitive nature of the P1-N1 components during orthographic processing. We used an implicit reading task with various types of stimuli involving different amounts of sublexical or lexical orthographic processing (words, pseudohomophones, pseudowords, nonwords, and symbols), and tested average and dyslexic readers. An orthographic regularity effect (pseudowords-nonwords contrast) was observed in the average but not in the dyslexic group. This suggests an early sensitivity to the dependencies among letters in word-forms that reflect orthographic structure, while the dyslexic brain apparently fails to be appropriately sensitive to these complex features. Moreover, in the adults the N1-response may already reflect lexical access: (i) the N1 was sensitive to the familiar vs. less familiar orthographic sequence contrast; (ii) and early effects of the phonological form (words-pseudohomophones contrast) were also found. Finally, the later N320 component was attenuated in the dyslexics, suggesting suboptimal processing in later stages of phonological analysis. PMID- 25528286 TI - Holistic neural coding of Chinese character forms in bilateral ventral visual system. AB - How are Chinese characters recognized and represented in the brain of skilled readers? Functional MRI fast adaptation technique was used to address this question. We found that neural adaptation effects were limited to identical characters in bilateral ventral visual system while no activation reduction was observed for partially overlapping characters regardless of the spatial location of the shared sub-character components, suggesting highly selective neuronal tuning to whole characters. The consistent neural profile across the entire ventral visual cortex indicates that Chinese characters are represented as mutually distinctive wholes rather than combinations of sub-character components, which presents a salient contrast to the left-lateralized, simple-to-complex neural representations of alphabetic words. Our findings thus revealed the cultural modulation effect on both local neuronal activity patterns and functional anatomical regions associated with written symbol recognition. Moreover, the cross-language discrepancy in written symbol recognition mechanism might stem from the language-specific early-stage learning experience. PMID- 25528288 TI - Visuospatial complexity modulates reading in the brain. AB - Neurocognitive processing of orthographic visuospatial complexity was examined through fMRI-based overt naming (n=16) of phonologically transparent, high and low frequency Hindi/Devanagari words that were visually simple (????, ????) or complex (, ????). Participants' overt behavior was modestly influenced by visuospatial complexity (accuracy: main effect p=.01, complexity*frequency interaction p<.07), while neuroimaging data revealed a robust effect of complexity (main effect FWE p<10(-4), complexity*frequency interaction FWE p<7*10(-8)). Interaction-based RoIs showed higher BOLD response in the VWFA to complex and left posterior temporal cortex to simple words, with greater right lingual de-activation to complex than simple words. Subtractions confirmed additional recruitment of VWFA, right frontal, inferior orbitofrontal, mid temporal pole and left cerebellum by visuospatially complex over simple words. Finally, low frequency words activated bilateral occipital and putamen areas, left IPL, SPL, IFG and VWFA, suggesting that effortful phonological processing in alphasyllabic Hindi/Devanagari requires neural resources specialized for both visuospatially simple and complex orthographies. PMID- 25528287 TI - The effect of age of acquisition, socioeducational status, and proficiency on the neural processing of second language speech sounds. AB - This study investigates the role of age of acquisition (AoA), socioeducational status (SES), and second language (L2) proficiency on the neural processing of L2 speech sounds. In a task of pre-attentive listening and passive viewing, Spanish English bilinguals and a control group of English monolinguals listened to English syllables while watching a film of natural scenery. Eight regions of interest were selected from brain areas involved in speech perception and executive processes. The regions of interest were examined in 2 separate two-way ANOVA (AoA*SES; AoA*L2 proficiency). The results showed that AoA was the main variable affecting the neural response in L2 speech processing. Direct comparisons between AoA groups of equivalent SES and proficiency level enhanced the intensity and magnitude of the results. These results suggest that AoA, more than SES and proficiency level, determines which brain regions are recruited for the processing of second language speech sounds. PMID- 25528289 TI - An in vivo microdialysis characterization of the transient changes in the interstitial dialysate concentration of metabolites and cytokines in human skeletal muscle in response to insertion of a microdialysis probe. AB - Skeletal muscle has recently been described as an endocrine organ, capable of releasing cytokines and regulators of metabolism. Microdialysis of the interstitial space of skeletal muscle enables analysis of the release of such cytokines. The purpose of this study was to determine the transient changes in concentration of metabolites and cytokines in human skeletal muscle in a 7h period following the insertion of a microdialysis probe. In total, sixteen microdialysis catheters were inserted into the vastus lateralis of male participants (age 26.2+/-1.35y, height 180.8+/-3.89cm, mass 83.9+/-3.86kg, BMI 25.7+/-0.87kgm(-2), body fat 26.1+/-3.0%). Serial samples were analyzed by micro enzymatic and multiplexed immunoassay. Muscle interstitial glucose and lactate levels remained stable throughout, amino acid concentrations stabilized after 2.5h, however, insertion of a microdialysis catheter induced a 29-fold increase in peak IL-6 (p<0.001) and 35-fold increase in peak IL-8 concentrations (p<0.001) above basal levels 6h post insertion. In contrast to stable amino acid, glucose and lactate concentrations after 2h, commonly reported markers of tissue homeostasis in in vivo microdialysis, the multi-fold increase in IL-6 and IL-8 following insertion of a microdialysis catheter is indicative of a sustained disturbance of tissue homeostasis. PMID- 25528290 TI - Intestinal microbiota diversity and expression of pattern recognition receptors in newly weaned piglets. AB - This study evaluated the gastrointestinal microbial diversity and the expression of pattern recognition receptors (PRRs) of the small intestine during the first week post-weaning in newly weaned piglets. Sixteen piglets were sacrificed on days 0, 1, 4, and 7 post-weaning. Luminal contents from the stomach, ileum, and colon were collected to determine the microbiota diversity; intestinal mucosa from the ileum was collected to assess mRNA expression of PRRs, including toll like receptors (TLRs) and NOD-like receptors (NLRs); sections of ileum were examined immunohistochemically to assess the immunoglobulin-secreting cells. The results showed that the number of denaturing gradient gel electrophoresis (DGGE) bands from the ileum and colon contents were significantly reduced in the d 4 post-weaning group. Biodiversity indexes (Shannon-Wiener index, richness index, and evenness index) were significantly decreased in the ileum of weaning groups. These indexes decreased in the colon of the d 4 post-weaning group. No significant differences were obtained in the stomach. With the exception of TLR5, the mRNA expressions of TLR2, TLR4, and TLR7 increased post-weaning. The mRNA expressions of NOD1 and NOD2 were significantly affected in the d 4 post-weaning group, and there were no significant differences in the d 1 or d 7 post-weaning groups. Analysis of the immunoglobulin-secreting (IgA, IgG, and IgM) cells showed that the ratio of each immunoglobulin was significantly higher on d 7 than d 0. The results revealed that microbial diversity was lower in the ileum and on d 4 post-weaning. Weaning significantly affected the expression of intestinal PRRs mainly on d 1 and d 4 post-weaning. The expression of specific PRRs was triggered by weaning to recognize distinctive microbiota and promote the development and maturation of the intestinal mucosal immunity. PMID- 25528291 TI - Adaptive variable structure hierarchical fuzzy control for a class of high-order nonlinear dynamic systems. AB - In this paper, a novel adaptive hierarchical fuzzy control system based on the variable structure control is developed for a class of SISO canonical nonlinear systems in the presence of bounded disturbances. It is assumed that nonlinear functions of the systems be completely unknown. Switching surfaces are incorporated into the hierarchical fuzzy control scheme to ensure the system stability. A fuzzy soft switching system decides the operation area of the hierarchical fuzzy control and variable structure control systems. All the nonlinearly appeared parameters of conclusion parts of fuzzy blocks located in different layers of the hierarchical fuzzy control system are adjusted through adaptation laws deduced from the defined Lyapunov function. The proposed hierarchical fuzzy control system reduces the number of rules and consequently the number of tunable parameters with respect to the ordinary fuzzy control system. Global boundedness of the overall adaptive system and the desired precision are achieved using the proposed adaptive control system. In this study, an adaptive hierarchical fuzzy system is used for two objectives; it can be as a function approximator or a control system based on an intelligent-classic approach. Three theorems are proven to investigate the stability of the nonlinear dynamic systems. The important point about the proposed theorems is that they can be applied not only to hierarchical fuzzy controllers with different structures of hierarchical fuzzy controller, but also to ordinary fuzzy controllers. Therefore, the proposed algorithm is more general. To show the effectiveness of the proposed method four systems (two mechanical, one mathematical and one chaotic) are considered in simulations. Simulation results demonstrate the validity, efficiency and feasibility of the proposed approach to control of nonlinear dynamic systems. PMID- 25528292 TI - Stabilization of fractional-order singular uncertain systems. AB - This paper focuses on the state and static output feedback stabilization for fractional-order singular (FOS) uncertain linear systems with the fractional commensurate order 0= 50% in the left main coronary artery and >= 70% in one or several of the major coronary arteries. AF recurrences were defined as any atrial arrhythmia lasting >30s and occurring within the first week (early recurrences, ERAF) or between 3 and 12 months (late recurrences, LRAF) after ablation and were assessed with serial 7 day Holter ECG. RESULTS: 152 patients (11.6%) had significant CAD; 89 (59%) had one, 35 (23%) two and 28 (18%) three vessel disease; 72 (47%) patients had RCA involvement. Occurrence of AF recurrences was comparable in CAD (p=0.625 and 0.568 for ERAF and LRAF, respectively). Among patients with CAD, neither the location (RCA versus non-RCA) nor the extent of CAD (single versus multiple vessel disease) was associated with rhythm outcomes after AF catheter ablation (all p>0.05). CONCLUSION: The presence and extent of CAD seem not to impact on rhythm outcome of AF catheter ablation in the entire cohort. PMID- 25528311 TI - Comparison of a morning polypill, evening polypill and individual pills on LDL cholesterol, ambulatory blood pressure and adherence in high-risk patients; a randomized crossover trial. AB - AIMS: Cardiovascular polypills are a novel strategy in the prevention of cardiovascular disease. Based on considerations about the effectiveness, the individual pills of a polypill are taken at different times of the day. This study aimed therefore to compare the use of a polypill in the morning, in the evening or the individual components taken at their usual times on cardiovascular risk factors and patient acceptability. METHODS: The study was a randomized three period crossover trial. Seventy-eight patients with established cardiovascular disease were randomly allocated to the use of polypill (aspirin 75 mg, simvastatin 40 mg, lisinopril 10mg and hydrochlorothiazide 12.5mg) in the morning, in the evening or use of the individual agents taken at different time points (Trial: NCT01506505). RESULTS: Using the polypill in the evening resulted in a 0.2 mmol/L (95%-confidence interval (CI): 0.1 to 0.3) lower fasting LDL cholesterol compared to the use in the morning, and not statistically significantly different mean 24-hour systolic BP (mean difference: 0.7 mmHg; 95% CI; -2.1 to 3.4). Compared to the use of the individual agents, the mean LDL cholesterol was 0.2 mmol/L (95%-CI: 0.1 to 0.3) higher when using the polypill in the morning, but not statistically significantly different when used in the evening (mean difference: -0.1 mmol/L; 95%-CI: -0.1 to 0.0). Furthermore, there were no differences in mean 24-hour systolic BP with morning use (mean difference: 0.4 mmHg; 95%-CI; -1.5 to 2.3) or evening use (mean difference: 1.0mmHg; 95%-CI; -0.8 to 2.8) of the polypill compared to the individual agents. The adherence was 5.2% (95%-CI: 1.4 to 9.1) higher with morning use of the polypill and 5.0% (95%-CI: 1.5 to 8.5) higher with evening use compared to the individual agents. Treatment with the polypill was preferred by 92% of the participants. CONCLUSION: The use of a polypill in the evening was more effective in lowering LDL-cholesterol, and resulted in not statistically significantly different ambulatory BP levels compared to the use of a polypill in the morning. Therapy with a polypill was associated with an increased adherence. The polypill is highly preferred by patients, demonstrating a potential role for the polypill in the prevention of cardiovascular disease. PMID- 25528312 TI - Sitagliptin and cardiovascular outcomes in diabetic patients with chronic kidney disease and acute myocardial infarction: A nationwide cohort study. AB - BACKGROUND: The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients with chronic kidney disease (CKD) after acute myocardial infarction (AMI) are unclear. METHODS: We analyzed data from the Taiwan National Health Insurance Research Database between March 1st, 2009 and December 31st, 2011. A total of 1025 AMI patients with diabetes with chronic kidney disease were selected as the study cohort. The study evaluated the cardiovascular safety and efficacy of sitagliptin by comparing 205 subjects (20%) who use sitagliptin to 820 matched subjects (80%) who do not. The primary outcomes included myocardial infarction, ischemic stroke or cardiovascular death. RESULTS: Primary composite outcomes occurred in 54 patients in the sitagliptin group (26.3%) and in 164 patients in the comparison group (20.0%) (HR, 1.32; 95% CI, 0.97-1.79; P=0.079) during the mean follow-up of 1.02years (SD=0.71years). The sitagliptin group had similar risks of ischemic stroke, all-cause mortality or hospitalization for heart failure (HF) compared to the non-sitagliptin group (P=0.938, 0.523 and 0.795 respectively). However, sitagliptin use was associated with increased risks of recurrent myocardial infarction (HR, 1.73; 95% CI, 1.15-2.58; P=0.008) and percutaneous coronary revascularization (HR, 1.43; 95% CI, 1.04-1.95; P=0.026). CONCLUSIONS: Among type 2 diabetic patients with CKD after AMI, the use of sitagliptin was not associated with an increased risk of cardiovascular death, ischemic stroke or hospitalization for HF but was associated with increased risks of recurrent MI and percutaneous coronary revascularization. PMID- 25528313 TI - The impact of gender and left atrial blood stasis on adiponectin levels in non valvular atrial fibrillation. AB - BACKGROUND: Obesity is a risk factor for non-valvular atrial fibrillation (NVAF), diabetes mellitus, and hypertension. Adiponectin, a unique biomarker of adipose tissue, has antiinflammatory, insulin-sensitizing, and antiatherogenic properties and is known to be higher in women. The relationship between adiponectin, gender, and thromboembolic risk in atrial fibrillation however is unknown. METHODS: The relationship between gender, adiponectin levels, and echocardiographic measures of blood stagnation and left atrial appendage thrombus (LAAT) was assessed in 209 patients with NVAF (55 women and 154 men; mean age 63 +/- 14 years) compared to 70 normal sinus rhythm controls (29 women and 41 men; mean age 64 +/- 14 years). Total adiponectin was measured by solid-phase ELISA. Demographic and clinical variables of CHADS2 and CHA2DS2-VASc were collected, and spontaneous echocardiographic contrast (SEC), left atrial appendage emptying velocity (LAAEV) and left atrium volume index (LAVI) were measured prospectively. RESULTS: Elevated adiponectin was associated with advanced cardiovascular pathology and permanent arrhythmia but only in men with NVAF. In NVAF men, a step-wise increase in adiponectin levels was noted relative to increasing intensity of SEC and decreasing LAAEV. Adiponectin level >16657 ng/ml predicted LAAT (OR: 3.66; 95% Cl: 1.21-11.48; p=0.022) after adjustment for CHADS2 score in men but not in women with NVAF. CONCLUSIONS: There is a direct correlation between elevated adiponectin level and the degree of left atrial blood stasis in men but not in women with NVAF. High adiponectin levels can be used as an important variable in the prediction of LAAT. PMID- 25528314 TI - Geriatric nutritional risk index in hospitalized heart failure patients. PMID- 25528315 TI - Ruptured mitral chordae tendinae induced by acute inferior myocardial infarction. PMID- 25528316 TI - Acceptance and psychological impact of implantable defibrillators amongst adults with congenital heart disease. AB - BACKGROUND: The psychological impact of implantable cardioverter defibrillators (ICDs) in adults with congenital heart disease (ACHD) has not been established. OBJECTIVE: To compare device acceptance, quality of life, anxiety and depression between ACHD patients with ICDs (ICD-Congenital), with pacemakers (PPM Congenital), with no devices (No Device-Congenital) and non-ACHD patients with ICDs (ICD-Non-Congenital). METHODS: A total of 147 ACHD and 46 non-ACHD patients (age 45.0+/-14.7 years, 56.5% males) completed the Florida Patient Acceptance Survey (FPAS), the 36-item Short Form Health Survey (SF-36) and Hospital Anxiety & Depression Scale (HADS). RESULTS: ICD-Congenital patients (n=59) showed lower device acceptance compared to PPM-Congenital patients (n=41), p=0.04, and reported worse quality of life (p=0.001) and higher prevalence of depression (p=0.009) when compared to No Device-Congenital (n=47) patients. ICD-Congenital and ICD-Non-Congenital patients (n=46) showed similar mental and physical health, device acceptance, anxiety and depression. Within ICD-Congenital, patients with poorest device acceptance (FPAS <67, "Non-Acceptors") showed significantly lower mental health scores (p=0.008), and higher levels of anxiety (p=0.02) and depression (p=0.01) compared to "Acceptors" (FPAS >=67). "Non-Acceptors" were younger at survey (p=0.006), younger at ICD implantation (p=0.01) and were less likely to have received appropriate shocks (p=0.03). CONCLUSION: Younger age and lack of appropriate ICD shocks are risk factors for poor ICD acceptance. Device acceptance is lower in adults with congenital heart disease who receive an ICD than those who receive pacemakers. Appropriate screening for anxiety and depression may be warranted for ACHD patients considered for ICD implantation or already living with ICDs. PMID- 25528317 TI - The influence of the external structures in atrial fibrillation patients: Relationship to focal low voltage areas in the left atrium. AB - INTRODUCTION: Left atrial (LA) low voltage areas (LVAs) are suggested as an important factor for maintaining atrial fibrillation (AF). The relationship between focal LVAs and anatomical contact is still unclear. METHODS: Thirty paroxysmal AF (PAF) and 30 persistent AF (PsAF) patients underwent high density voltage mapping during sinus rhythm before any radiofrequency applications were performed. The relationship between the LVA (<0.5mV) and contact area (CoA) demonstrated by enhanced CT and the distance to near external structures were investigated. RESULTS: The anterior region, posterior wall and left pulmonary vein (LPV) antrum were the three most frequent LVA sites that corresponded to CoA sites, and LVAs mostly overlapped with CoAs (PAF 47/61: 77%, PsAF 63/74: 85%). In the PAF group, patients with posterior-LVAs had a shorter distance to the vertebrae than those without (2.8 +/- 1.1 vs. 4.4 +/- 1.9 mm; P=0.0086). The distance to the vertebrae was the only predictive factor of the existence of a posterior-LVA and the cut-off value was <=2.9 mm (P<0.0001). Similarly, an LPV LVA also had the same results (2.0 +/- 0.5 vs. 2.7 +/- 0.8mm, P=0.0127) and the cut-off value was <=2.6mm (P=0.0391). In contrast, the PsAF patients had no difference in the distance when compared to the existence of an LVA. CONCLUSIONS: Anatomical CoAs demonstrated a spatial relationship to the LVAs in AF patients. In PAF patients, the distance to near external structures in the posterior region was a predictive factor for the existence of an LVA and may have had some influence on maintaining AF, while in PsAF patients no relationship was suggested. PMID- 25528318 TI - Approximate kernel competitive learning. AB - Kernel competitive learning has been successfully used to achieve robust clustering. However, kernel competitive learning (KCL) is not scalable for large scale data processing, because (1) it has to calculate and store the full kernel matrix that is too large to be calculated and kept in the memory and (2) it cannot be computed in parallel. In this paper we develop a framework of approximate kernel competitive learning for processing large scale dataset. The proposed framework consists of two parts. First, it derives an approximate kernel competitive learning (AKCL), which learns kernel competitive learning in a subspace via sampling. We provide solid theoretical analysis on why the proposed approximation modelling would work for kernel competitive learning, and furthermore, we show that the computational complexity of AKCL is largely reduced. Second, we propose a pseudo-parallelled approximate kernel competitive learning (PAKCL) based on a set-based kernel competitive learning strategy, which overcomes the obstacle of using parallel programming in kernel competitive learning and significantly accelerates the approximate kernel competitive learning for large scale clustering. The empirical evaluation on publicly available datasets shows that the proposed AKCL and PAKCL can perform comparably as KCL, with a large reduction on computational cost. Also, the proposed methods achieve more effective clustering performance in terms of clustering precision against related approximate clustering approaches. PMID- 25528319 TI - [Obstructive sleep apnea in women]. AB - The prevalence of sleep disturbances and their symptomatic manifestations may be different in men and women. Women with obstructive sleep apnea are less likely to be diagnosed with sleep apnea compared to men, probably due to atypical symptoms such as morning headaches, symptoms of depression and daytime fatigue. There is a great importance of diagnosis and treatment of sleep disorders regarding quality of life, co-morbidity and mortality in both genders. PMID- 25528320 TI - [Complex molecular genetic algorithm in the diagnosis of myeloproliferative neoplasms]. AB - INTRODUCTION: Mutations in Janus kinase 2, calreticulin and thrombopoietin receptor genes have been identified in the genetic background of Philadelphia chromosome negative, "classic" myeloproliferative neoplasms. AIM: The aim of the authors was to identify driver mutations in a large myeloproliferative cohort of 949 patients. METHOD: A complex array of molecular techniques (qualitative and quantitative allele-specific polymerase chain reactions, fragment analyzes, high resolution melting and Sanger sequencing) was applied. RESULTS: All 354 patients with polycythemia vera carried Janus kinase 2 mutations (V617F 98.6%, exon 12: 1.4%). In essential thrombocythemia (n = 468), the frequency of V617F was 61.3% (n = 287), that of calreticulin 25.2% (n = 118), and that of thrombopoietin receptor mutations 2.1% (n = 10), while 11.3% (n = 53) were triple-negative. Similar distribution was observed in primary myelofibrosis (n = 127): 58.3% (n = 74) V617F, 23.6% (n = 30) calreticulin, 6.3% (n = 8) thrombopoietin receptor mutation positive and 11.8% (n = 15) triple-negative. CONCLUSIONS: The recent discovery of calreticulin gene mutations led to definite molecular diagnostics in around 90% of clonal myeloproliferative cases. PMID- 25528321 TI - [Let's save our nurses and doctors!]. AB - INTRODUCTION: Several studies have shown that healthcare service is a dangerous workplace, but the reasons have been remained unexplained. AIM: The aim of the authors was to obtain data on the health condition of health care professionals and identify the underlying risk factors for the increased morbidity. METHOD: Health care data obtained from 276 bedside nurses in 2004 and 1250 hospital employees in 2009 were analysed. In addition, the fate of department directors of Szent Gyorgy University Hospital in Szekesfehervar between 1979 and 2010 was recorded and the data were compared to those obtained from a smaller hospital in Budapest during the same time period. RESULTS: The body mass index of bedside nurses between the age of 30-35 years reached the upper limit of normal (which occurred 5-10 years earlier as compared to the average population) and then it increased continuously above the average value. In hospital employees the increase of body mass index was accompanied by an increase in the frequency of chronic diseases such as hypertension, allergy, thyroid dysfunction, rheumatologic diseases, diabetes, peptic ulcer, cancer and depression. When the cause of death of the department directors who died between 1979 and 2010 was analyzed the authors found that cancer death occurred in 77% and 82% of department directors in Szekesfehervar and Budapest hospitals, respectively, while cancer death rate in 2011 was 25.4% in Hungary. CONCLUSIONS: The authors propose that continuous psychological stress, night shifts, nonstop standby and surcharge may all suppress the activity of the immune system. This proposal seems to be supported by novel psycho-neuro-immunological research data. The solution could be early prevention using stress control. PMID- 25528322 TI - [Information flow between medical and social sciences]. AB - In order to reveal impacts of natural and social sciences on each other, the authors examined connections between fields of medical and social sciences using a search for references and citations of scientific publication. 1. The largest affinity between the medical and social sciences was found between neurosciences and psychology, but there was a significant affinity between clinical sciences and general social sciences, as well. 2. The example of General & Internal Medicine papers in the topics of "diabetes" suggests that in the period 2001-2010 the share of references to social sciences was significantly increased. In the meantime, social science papers in the same topics contained references to Clinical Medicine papers in a constantly high percentage. 3. In the sample under study, the age distribution of social science papers in the references did not differ significantly from that of the other sources. 4. Share of references to social science papers was found to be extremely high among Hungarian General & Internal Medicine papers in the topics of "diabetes". This finding still requires clarification, nevertheless, since e.g. it was not supported by an institutional comparison including the largest Hungarian medical research university. 5. The intensity of the reference/citation mediated information flows between the Hungarian Medical Journal, Orvosi Hetilap and social sciences appears to be in accordance with the current international trends. PMID- 25528323 TI - [Medical opinion about the death of Miklos Zrinyi, the "Hungarian God of War"]. PMID- 25528324 TI - Functional neuropeptidomics in invertebrates. AB - Neuropeptides are key messengers in almost all physiological processes. They originate from larger precursors and are extensively processed to become bioactive. Neuropeptidomics aims to comprehensively identify the collection of neuropeptides in an organism, organ, tissue or cell. The neuropeptidome of several invertebrates is thoroughly explored since they are important model organisms (and models for human diseases), disease vectors and pest species. The charting of the neuropeptidome is the first step towards understanding peptidergic signaling. This review will first discuss the latest developments in exploring the neuropeptidome. The physiological roles and modes of action of neuropeptides can be explored in two ways, which are largely orthogonal and therefore complementary. The first way consists of inferring the functions of neuropeptides by a forward approach where neuropeptide profiles are compared under different physiological conditions. Second is the reverse approach were neuropeptide collections are used to screen for receptor-binding. This is followed by localization studies and functional tests. This review will focus on how these different functional screening methods contributed to the field of invertebrate neuropeptidomics and expanded our knowledge of peptidergic signaling. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology. PMID- 25528325 TI - School-Located Vaccination Clinics for Adolescents: Correlates of Acceptance Among Parents. AB - Four vaccines are recommended by The Advisory Committee for Immunization Practices for adolescents: tetanus, diphtheria, acellular pertussis vaccine (Tdap), meningococcal conjugate vaccine (MCV4), human papillomavirus vaccine (HPV), and annual seasonal influenza vaccine. However, coverage among adolescents is suboptimal. School-located vaccination clinics (SLVCs) offer vaccines to students at school, increasing access. This study seeks to determine the relationship between attitudes of parents of middle- and high-school students and acceptance of SLVCs for all four adolescent recommended vaccines. We conducted a telephone and web-based survey among parents of students enrolled in six middle and five high schools in Georgia. Analyses were conducted to examine associations between parental attitudes and willingness to allow their child to be vaccinated at school. Tdap and influenza vaccine had the highest rates of parental SLVC acceptance while HPV vaccine had the lowest. Parents who accepted SLVCs had higher perceived severity of influenza, meningococcal, and HPV illnesses compared to parents who did not accept SLVC. Intention to vaccinate was associated with SLVC acceptance for Tdap [Adjusted OR (AOR) 7.38; 95% confidence interval (CI) 2.44-22.31], MCV4 (AOR 2.97; 95% CI 1.67-5.28), and HPV vaccines (AOR 7.61; 95% CI 3.43-16.89). Social norms were associated with acceptance of SLVCs for influenza vaccine (AOR 1.44; 95% CI 1.12-1.84). These findings suggest parents of adolescents are generally supportive of SLVCs for recommended adolescent vaccines. Perceived severity of illness and intention to get their adolescent vaccinated were the most consistent correlates of parental SLVC acceptance for all vaccines. Future SLVC planning should focus on perceptions of disease severity and benefits of vaccination. PMID- 25528326 TI - Diet-Related Colorectal Cancer Prevention Beliefs and Dietary Intakes in an Urban Minority Population. AB - In the United States, colorectal cancer (CRC) is the third leading cause of cancer-related death and third most commonly diagnosed cancer among adults. This study is the first to examine the relationship between diet-related beliefs for colorectal cancer prevention and dietary intake among an urban, predominantly Black population (n = 169). More than two-thirds reported diet-related CRC prevention beliefs. Those with diet-related CRC prevention beliefs had healthier intakes for dietary fiber (p = .005), fruit, vegetable, bean (p = .027), red meat (p = .032), vitamin C (p = .039), and cholesterol (p = .045). Most people may already have diet-related CRC prevention beliefs and having them is associated with a more healthful dietary intake. PMID- 25528327 TI - Anti-inflammatory effects of a triple-bond resveratrol analog: structure and function relationship. AB - Resveratrol is a polyphenol found in grapes and red wine, showing well characterized anti-inflammatory and antiproliferative activities. In order to exceed resveratrol's biological effects and to reveal the structural determinants of the molecule's activity, numerous derivatives were synthesized recently. Most of these resveratrol analogs vary from the original molecule in the number, position or identity of the phenolic functional groups. Investigation of the analogs provided important data regarding structure-activity relationship of the molecule. With the exception of cis- and trans-resveratrol and the reduced form dihydroresveratrol, little is known about the molecular effects of the stilbene backbone. In the present study we investigated the anti-inflammatory properties of a new, triple-bond resveratrol analog, 3,4',5-trihydroxy-diphenylacetylene (TDPA) on lipopolysaccharide-stimulated RAW macrophages. We found that the analog had weaker antioxidant activity and stronger inhibitory effect on nuclear factor kappaB activation, and on cyclooxygenase-2, tumor necrosis factor alpha and interleukin-6 production. It also prevented lipopolysaccharide-induced depolarization of the mitochondrial membrane. In contrast to resveratrol, TDPA increased the phosphorylation of c-Jun N-terminal and p38 mitogen activated protein kinases. In summary, we identified a novel compound with better anti inflammatory properties than resveratrol. Our results contributed to a better understanding of the structural determinants of resveratrol's biological activities. PMID- 25528328 TI - Natural and semisynthetic diterpenoids with antiviral and immunomodulatory activities block the ERK signaling pathway. AB - The pathogenesis of many viral infections lies on the damage caused by the immune response against the virus. Current antiviral drugs do not act on the inflammatory component of the disease. Thus, new compounds that inhibit both viral multiplication and the immunopathology elicited by the virus are an approach that should be considered. In the present study, we identified two jatropholones (2A and 5B) and one carnosic acid derivative (9C) that significantly inhibited multiplication of TK+ and TK- strains of HSV-1 in Vero cells. Compounds 2A, 5B and 9C also prevented HSV-1- and TLRs-induced inflammatory response in cultivated murine macrophages. In macrophages infected with HSV-1, the inhibitory effect of compounds 2A, 5B and 9C on TNF-alpha and IL 6 production could be associated with the block of ERK pathway, whereas NF-kappaB pathway was not hampered by any of the compounds. Besides, 2A, 5B and 9C also inhibited ERK pathway and reduced TNF-alpha production in macrophages stimulated with TLR2, TLR4 or TLR9 agonists and were able to hinder IL-6 secretion after activation with TLR2 or TLR4, but not with TLR9. The immunomodulatory effect of 2A, 5B and 9C in macrophages infected with HSV-1 may be a consequence of the inhibition of ERK pathway activated by TLRs. The availability of compounds with both antiviral and immunomodulatory properties which affect TLR signaling pathways might be a useful strategy to control the progress of virus-induced disease. PMID- 25528329 TI - Traumatic brain injury-induced axonal phenotypes react differently to treatment. AB - Injured axons with distinct morphologies have been found following mild traumatic brain injury (mTBI), although it is currently unclear whether they reflect varied responses to the injury or represent different stages of progressing pathology. This complicates evaluation of therapeutic interventions targeting axonal injury. To address this issue, we assessed axonal injury over time within a well-defined axonal population, while also evaluating mitochondrial permeability transition as a therapeutic target. We utilized mice expressing yellow fluorescent protein (YFP) in cortical neurons which were crossed with mice which lacked Cyclophilin D (CypD), a positive regulator of mitochondrial permeability transition pore opening. Their offspring were subjected to mTBI and the ensuing axonal injury was assessed using YFP expression and amyloid precursor protein (APP) immunohistochemistry, visualized by confocal and electron microscopy. YFP(+) axons initially developed a single, APP(+), focal swelling (proximal bulb) which progressed to axotomy. Disconnected axonal segments developed either a single bulb (distal bulb) or multiple bulbs (varicosities), which were APP(-) and whose ultrastructure was consistent with ongoing Wallerian degeneration. CypD knock-out failed to reduce proximal bulb formation but decreased the number of distal bulbs and varicosities, as well as a population of small, APP(+), callosal bulbs not associated with YFP(+) axons. The observation that YFP(+) axons contain several pathological morphologies points to the complexity of traumatic axonal injury. The fact that CypD knock-out reduced some, but not all, subtypes highlights the need to appropriately characterize injured axons when evaluating potential neuroprotective strategies. PMID- 25528330 TI - Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption. AB - Oral absorption of compounds depends on many physiological, physiochemical and formulation factors. Two important properties that govern oral absorption are in vitro permeability and solubility, which are commonly used as indicators of human intestinal absorption. Despite this, the nature and exact characteristics of the relationship between these parameters are not well understood. In this study a large dataset of human intestinal absorption was collated along with in vitro permeability, aqueous solubility, melting point, and maximum dose for the same compounds. The dataset allowed a permeability threshold to be established objectively to predict high or low intestinal absorption. Using this permeability threshold, classification decision trees incorporating a solubility-related parameter such as experimental or predicted solubility, or the melting point based absorption potential (MPbAP), along with structural molecular descriptors were developed and validated to predict oral absorption class. The decision trees were able to determine the individual roles of permeability and solubility in oral absorption process. Poorly permeable compounds with high solubility show low intestinal absorption, whereas poorly water soluble compounds with high or low permeability may have high intestinal absorption provided that they have certain molecular characteristics such as a small polar surface or specific topology. PMID- 25528331 TI - In vitro anticancer activity of gold(III) complexes with some esters of (S,S) ethylenediamine-N,N'-di-2-propanoic acid. AB - Five novel gold(III) complexes of general formulas [AuCl2{(S,S)-R2eddip}]PF6, ((S,S)-eddip = (S,S)-ethylenediamine-N,N'-di-2-propanoate, R = n-Bu, n-Pe, i-Bu, i-Am, cPe; 1-5, respectively) were synthesized and characterized by UV/Vis, IR and NMR spectroscopy and mass spectrometry. DFT calculations indicated that (R,R) N,N'-configuration diastereoisomers were the most stable for 1-5. 3 is stable in DMSO for at least 24 h, but immediate hydrolysis in PBS occurs. 3 is readily reduced with ascorbic acid and forms adducts with bovine serum albumin (BSA). In vitro anticancer activity of the gold(III) complexes against human cervix adenocarcinoma HeLa, human myelogenous leukemia K562, human melanoma Fem-x tumor cell lines, as well as against non-cancerous human embryonic lung fibroblast cell line MRC-5 was determined using MTT assay. Complex 4 showed highest activity and selectivity (IC50(Fem-x) = 1.3 +/- 0.2; IC50(MRC-5)/IC50(Fem-x) = 72.5 +/- 12.4), 4 times more active and 28 times more selective than cisplatin. Complexes induced apoptotic mode of death in a time-dependent manner in HeLa cells. PMID- 25528332 TI - Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines. AB - To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3'-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3'-methoxy moiety on the C-ring phenyl group of AN (6a-e) with 3'-hydroxy (7a-e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g-i) with a 6-hydroxy group (7g-i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H) one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis. In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies. PMID- 25528333 TI - Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase. AB - Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 MUM). PMID- 25528334 TI - Improving selectivity preserving affinity: new piperidine-4-carboxamide derivatives as effective sigma-1-ligands. AB - We report the design, synthesis and binding evaluation against sigma1 and sigma2 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on sigma receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward sigma1 and sigma2 receptors. Very high sigma1 affinity (Ki = 3.7 nM) and Kisigma2/Kisigma1 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4 chlorobenzyl moiety linked to the piperidine nitrogen atom. PMID- 25528335 TI - Multimodal biopanning of T7 phage-displayed peptides reveals angiomotin as a potential receptor of the anti-angiogenic macrolide Roxithromycin. AB - Roxithromycin (RXM) is a semi-synthetic fourteen-membered macrolide antibiotic that shows anti-angiogenic activity in solid tumors. In the present study, we conducted biopanning of T7 phage-displayed peptides either on a 96-well formatted microplate, a flow injection-type quartz-crystal microbalance (QCM) biosensor, or a cuvette-type QCM. RXM-selected peptides of different sequence, length and number were obtained from each mode of screening. Subsequent bioinformatics analysis of the RXM-selected peptides consistently gave positive scores for the extracellular domain (E458-T596) of angiomotin (Amot), indicating that this may comprise a binding region for RXM. Bead pull down assay and QCM analysis confirmed that RXM directly interacts with Amot via the screen-guided region, which also corresponds to the binding site for the endogenous anti-angiogenic inhibitor angiostatin (Anst). Thus, multimodal biopanning of T7PD revealed that RXM binds to the extracellular domain on Amot as a common binding site with Anst, leading to inhibition of angiogenesis-dependent tumor growth and metastasis. These data might explain the molecular basis underlying the mechanism of action for the anti-angiogenic activity of RXM. PMID- 25528336 TI - Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II). AB - In this paper we report the investigation of C-3 and beta-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the beta acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affinities. In particular, the allyl 6b and ethyl 15a represented the more interesting compounds of this series. Furthermore, the introduction of methyl cycloalkyl groups (compounds 11a, 12a) exhibited no change in both MT2 and 5-HT2C binding affinities while a decrease of MT1 binding affinity occurred leading to an MT2 selectivity. Finally, the acetamide modulation has led to methyl thiourea 11h, with a weak MT2 selectivity. PMID- 25528337 TI - Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents. AB - Potent anticancer 4-arylchromene agents 6, as restricted isoCA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substituted 4-chromanones 10 in a one pot procedure which include regioselective arylalkynols hydration, alcohol etherification, MOM-cleavage, and cyclization. Further palladium coupling reactions, using aryl halides and N tosylhydrazones 11 gave access to a small library of functionalized 4 arylchromenes 6 with good yields. From this series of 4-arylchromenes, we have identified compound 6s which inhibit tubulin assembly at a micromolar level and demonstrate a remarkable nanomolar level of cytotoxicity against four human cancer cell lines. Docking studies showed that isoCA-4 and its restricted chromene analogue 6s adopt a similar positioning in the colchicine binding-site of tubulin. PMID- 25528338 TI - Synthesis, cytostatic evaluation and structure activity relationships of novel bis-indolylmethanes and their corresponding tetrahydroindolocarbazoles. AB - BIMs (bis-indolylmethanes) (1a-n) were synthesized using glacial acetic acid as a protic acid for promotion of the condensation reaction of indoles with aldehydes in high yields (86-98 %). Corresponding tetrahydroindolo[2,3-b]carbazoles (2a-m) were synthesized via condensation of BIMs with aldehydes. Ten synthesized compounds have been submitted to the national cancer institute in the USA where all the submitted samples have been selected for one dose screening. As a result of the one dose screening of BIMs (1e,f,h,i,n) and of the indolocarbazoles (2e,f,h,i,j) the average highest cytostatic effects was recorded here for the BIM 1h and the indolocarbazole (2e) that showed the lowest mean values of "47.39%" and of "21.63%" respectively. Both compounds (1h and 2e) were further tested in five dose screening with the tested substance (1h) being significantly more sensitive for several cancers cell line as corresponding to their GI50 values. Furthermore, the basically substituted derivative 2e showed the highest antipoliferative activity in a nanomolar scale towards the three selected cancers cell lines Non small lung cell NCI-H460 with GI50 "616 nM", Ovarian Cancer cell line OVCAR-4 with GI50 "562 nM" and Breast Cancer cell line MCF7 with GI50 "930 nM". PMID- 25528339 TI - Zygosaccharomyces favi sp. nov., an obligate osmophilic yeast species from bee bread and honey. AB - Five yeast strains representing a hitherto undescribed yeast species were isolated from bee bread and honey in Hungary. They are obligate osmophilic, i.e. they are unable to grow in/on high water activity culture media. Following isogamous conjugation, they form 1-4 spheroid or subspheroid ascospores in persistent asci. The analysis of the sequences of their large subunit rRNA gene D1/D2 domain placed the new species in the Zygosaccharomyces clade. In terms of pairwise sequence similarity, Zygosaccharomyces gambellarensis is the most closely related species. Comparisons of D1/D2, internal transcribed spacer and translation elongation factor-1alpha (EF-1alpha) gene sequences of the five strains with that of the type strain of Z. gambellarensis revealed that they represent a new yeast species. The name Zygosaccharomyces favi sp. nov. (type strain: NCAIM Y.01994(T) = CBS 13653(T) = NRRL Y-63719(T) = ZIM 2551(T)) is proposed for this new yeast species, which based on phenotype can be distinguished from related Zygosaccharomyces species by its obligate osmophilic nature. Some intragenomic sequence variability, mainly indels, was detected among the ITS copies of the strains of the new species. PMID- 25528340 TI - Wenyingzhuangia heitensis sp. nov., a new species of the family Flavobacteriaceae within the phylum Bacteroidetes isolated from seawater. AB - A Gram-negative, strictly aerobic, beige-pigmented, non-motile, rod-shaped strain designated H-MN17(T) was isolated from seawater in Japan. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the family Flavobacteriaceae within the phylum Bacteroidetes and that it showed highest sequence similarity (97.5 %) to Wenyingzhuangia marina D1(T). The hybridization values for DNA-DNA relatedness between the strains of H MN17(T) and W. marina D1(T) were lower than 70 %, which is accepted as the phylogenetic definition of a novel species. The DNA G+C content of strain H MN17(T) was 31.8 mol%; MK-6 was the major menaquinone; and anteiso-C15:0, anteiso C17:0 and anteiso-C19:0 were identified as the major (>10 %) cellular fatty acids. A complex polar lipid profile was present consisting of phosphatidylethanolamine, three unidentified lipids, three unidentified glycolipids and three unidentified aminolipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel species of the genus Wenyingzhuangia for which the name Wenyingzhuangia heitensis sp. nov. is proposed. The type strain of W. heitensis sp. nov. is H-MN17(T) (=KCTC 42245(T) = NBRC 110601(T)). PMID- 25528341 TI - Negadavirga shengliensis gen. nov., sp. nov., a novel member of the family Cyclobacteriaceae isolated from oil-contaminated saline soil. AB - Four novel Gram-stain-negative, rod-shaped, and non-motile bacterial strains, SLG210-21(T), SLG210-4, SLG210-5 and SLG210-14, were isolated from oil contaminated saline soil in Shengli Oilfield, China. Growth were observed at 25 42 degrees C (optimum 37 degrees C), in the presence of 0-10 % (w/v) NaCl (optimum 0-1 %) and at pH 4.0-10.0 (optimum pH 7.6-8.6). All the strains were positive for catalase and alpha, beta-galactosidase activities and nitrogen reduction, and negative for oxidase activity, glucose fermentation and hydrolysis of agar, starch, gelatin, Tween 40, 60 and 80. The DNA G+C contents of the four strains were 41.3-43.0 mol% and the predominant respiratory quinones were all menaquinone-7. The major fatty acids were iso-C15:0, anteiso-C15:0, summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), C16:1 omega5c and summed feature 9 (iso-C17:1 omega9c and/or 10-methyl C16:0), while the polar lipids consisted of phosphatidylcholine, phosphatidylethanolamine, glycolipid, two unidentified phospholipids and two unidentified amino lipids. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the four strains clustered together to form a stable branch in the family Cyclobacteriaceae, and were most closely related to the genera Cyclobacterium and Echinicola with the 16S rRNA gene sequence similarities being 88.6-90.3 and 89.6-91.4 %, respectively. DNA-DNA hybridization between SLG210-21(T) and the other three strains showed the relatedness of 93.8 +/- 4.5, 96.2 +/- 4.2 and 82.3 +/- 4.8 %, respectively. Based on the polyphasic analysis, a novel species in a new genus, Negadavirga Shengliensis gen. nov., sp. nov., is proposed with SLG210-21(T) (=LMG 27737(T) = CGMCC1.12768(T)) [corrected] as the type strain. PMID- 25528342 TI - Effectiveness of chitosan against wine-related microorganisms. AB - The antimicrobial action of chitosan against wine related microorganisms, including Lactobacillus plantarum, Saccharomyces cerevisiae, Oeonococcus oeni, Lactobacillus hilgardii, Brettanomyces bruxellensis, Hanseniaspora uvarum and Zygosaccharomyces bailii was examined in laboratory media. In order to assess the potential applicability of chitosan as a microbial control agent for wine, the effect of chitosan, applied individually and/or in combination with sulphur dioxide (SO2), on the growth of microorganisms involved in various stages of winemaking and on the fermentative performance of S. cerevisiae was investigated. Of the seven wine-related microorganisms studied, S. cerevisiae exhibited the strongest resistance to antimicrobial action of chitosan in laboratory media with a minimum inhibitory concentration (MIC) greater than 2 g/L. L. hilgardii, O. oeni and B. bruxellensis were the most susceptible to chitosan since they were completely inactivated by chitosan at 0.2 g/L. The MIC of chitosan for L. plantarum, H. uvarum and Z. bailii was 2, 0.4 and 0.4 g/L, respectively. In wine experiments, it was found that chitosan had a retarding effect on alcoholic fermentation without significantly altering the viability and the fermentative performance of S. cerevisiae. With regard to non-Saccharomyces yeasts (H. uvarum and Z. bailii) involved in winemaking, the early deaths of these yeasts in mixed cultures with S. cerevisiae were not probably due to the antimicrobial action of chitosan but rather due to ethanol produced by the yeasts. The complex interactions between chitosan and wine ingredients as well as microbial interactions during wine fermentation considerably affect the efficacy of chitosan. It was concluded that chitosan was worthy of further investigation as an alternative or complementary preservative to SO2 in wine industry. PMID- 25528343 TI - A longitudinal study of the distance that young people walk to school. AB - Walking or cycling to school has been associated with important health benefits. Distance between home and school is the main correlate of active commuting to school, but how far children walk to school and how this changes as children age is unknown. Mode of commuting and objectively-assessed distance to school were measured at 3 time points: aged 9/10 years, 10/11 years and 13/14 years. Data were analysed using ROC-curve analyses. With age, children walked further to school; the threshold distance that best discriminated walkers from passive commuters was 1421 m in 10-year-olds, 1627 m in 11-year-olds and 3046 m in 14 year-olds. Future interventions should consider the distance that young people actually walk. PMID- 25528344 TI - Intergenerational cultural conflict, mental health, and educational outcomes among Asian and Latino/a Americans: Qualitative and meta-analytic review. AB - Among immigrant Asian and Latino groups, the contrast between collectivism in traditional heritage and individualism in the mainstream American cultures presents unique challenges for their family relationships. This systematic review was designed to answer 3 fundamental questions: to what extent do(es) (a) acculturation mismatch (AM) correlate with intergenerational cultural conflict (ICC); (b) ICC correlate with offspring's mental health and educational outcomes; and (c) demographic and study characteristics moderate these relationships. Sixty one research reports were reviewed, with 68 independent study samples (N = 14,453; 41 and 27 Asian and Latino/a samples, respectively) subjected to 3 meta analyses. AM positively correlated with ICC (r = .23), which in turn negatively correlated with offspring mental health (r = -.20) and educational outcomes (r = .09). Findings provided support for acculturation gap-distress theory. While these effect size estimates were small, participant and methodological variables affected their magnitude. Contrary to findings on intergenerational conflict within mainstream non-immigrant families, the relationships among AM, ICC, and mental health were larger in young adult than adolescent groups within immigrant families. ICC significantly correlated with internalizing problems and adaptive functioning, but not externalizing problems. AM was more closely related to ICC among women and second-generation immigrant offspring. AM and ICC were more problematic among offspring who were low-risk and lived in less ethnically disperse regions, particularly when studied in cross-sectional studies. Effect sizes also differed significantly across measurement tools for the key constructs. Limitations to generalizability (few studies on educational outcomes, relative under-representation of Latino/a to Asian American samples), and implications for intervention and future research are discussed. PMID- 25528347 TI - Spontaneous cerebrospinal fluid leak following a pilates class: a case report. AB - INTRODUCTION: A spinal cerebrospinal fluid leak is the most common cause of spontaneous intracranial hypotension which is an uncommon but increasingly recognized cause of headache. This article describes the first reported case of pilates being associated with a spontaneous spinal cerebrospinal fluid leak whilst also highlighting the key information about spontaneous cerebrospinal fluid leaks that will be useful to the general clinician. CASE PRESENTATION: We present the case of a 42-year-old Caucasian woman who developed a low-pressure headache following a pilates class. A computed tomography scan of her head demonstrated bilateral chronic subdural hematomas and cerebellar descent. Magnetic resonance imaging of her spine revealed the presence of extensive extradural cerebrospinal fluid collections. She responded to conservative management and repeat neuroimaging after symptom resolution revealed no abnormalities. CONCLUSIONS: Awareness and early recognition of spontaneous intracranial hypotension is important to prevent unnecessary investigations and delay in treatment. Pilates may be a risk factor for the development of a spontaneous cerebrospinal fluid leak. PMID- 25528346 TI - Religion and morality. AB - The relationship between religion and morality has long been hotly debated. Does religion make us more moral? Is it necessary for morality? Do moral inclinations emerge independently of religious intuitions? These debates, which nowadays rumble on in scientific journals as well as in public life, have frequently been marred by a series of conceptual confusions and limitations. Many scientific investigations have failed to decompose "religion" and "morality" into theoretically grounded elements; have adopted parochial conceptions of key concepts-in particular, sanitized conceptions of "prosocial" behavior; and have neglected to consider the complex interplay between cognition and culture. We argue that to make progress, the categories "religion" and "morality" must be fractionated into a set of biologically and psychologically cogent traits, revealing the cognitive foundations that shape and constrain relevant cultural variants. We adopt this fractionating strategy, setting out an encompassing evolutionary framework within which to situate and evaluate relevant evidence. Our goals are twofold: to produce a detailed picture of the current state of the field, and to provide a road map for future research on the relationship between religion and morality. PMID- 25528349 TI - Local enhancement and social foraging in a non-social insular lizard. AB - Even in solitary foragers, conspecifics can provide reliable information about food location. The insular lizard Podarcis lilfordi is a solitary species with high population densities that sometimes aggregate around rich food patches. Its diet includes novel and unpredictable resources, such as carcasses or plants, whose exploitation quickly became widespread among the population. We tested the use of social information by lizards through some field experiments in which they had to choose one of the two pieces of fruit. Probably due to local enhancement, lizards preferred to feed on the piece of fruit where conspecifics or lizard shaped models were already present. Conspecifics' behaviour, but also their mere presence, seems to be a valuable source of information to decide where to feed. Lizards also showed a strong attraction to conspecifics, even in the absence of food. Maybe the presence of a group is interpreted as an indirect cue for the presence of food. The group size was not important to females, but males had a significantly higher attraction towards groups with three conspecifics. We discuss some characteristics of P. lilfordi at Aire Island that can explain the development of the observed social foraging, as well as their possible consequences. PMID- 25528345 TI - When it comes to lifestyle recommendations, more is sometimes less: a meta analysis of theoretical assumptions underlying the effectiveness of interventions promoting multiple behavior domain change. AB - A meta-analysis of 150 research reports summarizing the results of multiple behavior domain interventions examined theoretical predictions about the effects of the included number of recommendations on behavioral and clinical change in the domains of smoking, diet, and physical activity. The meta-analysis yielded 3 main conclusions. First, there is a curvilinear relation between the number of behavioral recommendations and improvements in behavioral and clinical measures, with a moderate number of recommendations producing the highest level of change. A moderate number of recommendations is likely to be associated with stronger effects because the intervention ensures the necessary level of motivation to implement the recommended changes, thereby increasing compliance with the goals set by the intervention, without making the intervention excessively demanding. Second, this curve was more pronounced when samples were likely to have low motivation to change, such as when interventions were delivered to nonpatient (vs. patient) populations, were implemented in nonclinic (vs. clinic) settings, used lay community (vs. expert) facilitators, and involved group (vs. individual) delivery formats. Finally, change in behavioral outcomes mediated the effects of number of recommended behaviors on clinical change. These findings provide important insights that can help guide the design of effective multiple behavior domain interventions. PMID- 25528348 TI - Inhibitory effects of Stemona tuberosa on lung inflammation in a subacute cigarette smoke-induced mouse model. AB - BACKGROUND: Stemona tuberosa has long been used in Korean and Chinese medicine to ameliorate various lung diseases such as pneumonia and bronchitis. However, it has not yet been proven that Stemona tuberosa has positive effects on lung inflammation. METHODS: Stemona tuberosa extract (ST) was orally administered to C57BL/6 mice 2 hr before exposure to CS for 2 weeks. Twenty-four hours after the last CS exposure, mice were sacrificed to investigate the changes in the expression of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), chemokines such as keratinocyte-derived chemokine (KC) and inflammatory cells such as macrophages, neutrophils, and lymphocytes from bronchoalveolar lavage fluid (BALF). Furthermore, we compared the effect of ST on lung tissue morphology between the fresh air, CS exposure, and ST treatment groups. RESULTS: ST significantly decreased the numbers of total cells, macrophages, neutrophils, and lymphocytes in the BALF of mice that were exposed to CS. Additionally, ST reduced the levels of cytokines (TNF-alpha, IL-6) and the tested chemokine (KC) in BALF, as measured by enzyme-linked immunosorbent assay (ELISA). We also estimated the mean alveolar airspace (MAA) via morphometric analysis of lung tissues stained with hematoxylin and eosin (H&E). We found that ST inhibited the alveolar airspace enlargement induced by CS exposure. Furthermore, we observed that the lung tissues of mice treated with ST showed ameliorated epithelial hyperplasia of the bronchioles compared with those of mice exposed only to CS. CONCLUSIONS: These results indicate that Stemona tuberosa has significant effects on lung inflammation in a subacute CS-induced mouse model. According to these outcomes, Stemona tuberosa may represent a novel therapeutic herb for the treatment of lung diseases including COPD. PMID- 25528350 TI - Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation (NONSEDA Trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Through many years, the standard care has been to use continuous sedation of critically ill patients during mechanical ventilation. However, preliminary randomised clinical trials indicate that it is beneficial to reduce the sedation level. No randomised trial has been conducted comparing sedation with no sedation, a priori powered to have all-cause mortality as primary outcome.The objective is to assess the benefits and harms of non-sedation versus sedation with a daily wake-up trial in critically ill patients. METHODS/DESIGN: The non-sedation (NONSEDA) trial is an investigator-initiated, randomised, clinical, parallel-group, multinational trial designed to include 700 patients from at least six ICUs in Denmark, Norway and Sweden.Inclusion criteria are mechanically ventilated patients with expected duration of mechanical ventilation >24 hours.Exclusion criteria are non-intubated patients, patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO2/FiO2 < 9 where sedation might be necessary to ensure sufficient oxygenation or place the patient in prone position.Experimental intervention is non-sedation supplemented with pain management during mechanical ventilation.Control intervention is sedation with a daily wake-up trial.The primary outcome will be all cause mortality at 90 days after randomization. Secondary outcomes will be: days until death throughout the total observation period; coma- and delirium-free days; highest RIFLE score; days until discharge from the intensive care unit (within 28 days); days until the participant is without mechanical ventilation (within 28 days); and proportion of patients with a major cardiovascular outcome. Explorative outcomes will be: all cause mortality at 28 days after randomisation; days until discharge from the intensive care unit; days until the participant is without mechanical ventilation; days until discharge from the hospital; organ failure.Trial size: we will include 700 participants (2 * 350) in order to detect or reject 25% relative risk reduction in mortality with a type I error risk of 5% and a type II error risk of 20% (power at 80%). DISCUSSION: The trial investigates potential benefits of non-sedation. This might have large impact on the future treatment of mechanically ventilated critically ill patients. TRIAL REGISTER: ClinicalTrials.gov NCT0196768, 09.01.2014. PMID- 25528351 TI - Child mental health in Jordanian orphanages: effect of placement change on behavior and caregiving. AB - BACKGROUND: To assess the mental health and behavioral problems of children in institutional placements in Jordan to inform understanding of current needs, and to explore the effects of placement change on functioning and staff perceptions of goodness-of-fit. METHODS: An assessment was completed of 134 children between 1.5-12 years-of-age residing in Jordanian orphanages. The Child Behavior Checklist was used to assess prevalence rates of problems across externalizing and internalizing behavior and DSM-IV oriented subscales. Also included was caregiver perceived goodness-of-fit with each child, caregiving behavior, and two placement change-clock variables; an adjustment clock measuring time since last move, and an anticipation clock measuring time to next move. RESULTS: 28% were in the clinical range for the internalizing domain on the CBCL, and 22% for the externalizing domain. The children also exhibited high levels of clinical range social problems, affective disorder, pervasive developmental disorder, and conduct problems. Internalizing problems were found to decrease with time in placement as children adjust to a prior move, whereas externalizing problems increased as the time to their next age-triggered move drew closer, highlighting the anticipatory effects of change. Both behavioral problems and the change clocks were predictive of staff perceptions of goodness-of-fit with the children under their care. CONCLUSIONS: These findings add to the evidence demonstrating the negative effects of orphanage rearing, and highlight the importance of the association between behavioral problems and child-caregiver relationship pathways including the timing of placement disruptions and staff perceptions of goodness of-fit. PMID- 25528352 TI - Salmonella blood stream infections in a tertiary care setting in Ghana. AB - BACKGROUND: Despite the clinical significance of Salmonella infections, surveillance data worldwide remains limited and is more so exemplified by the lack of reports from Africa especially in eastern, central and western Africa. This study reports on Salmonella serotypes as significant causes of blood stream infections (BSI) and multidrug antibiotic resistance at Korle-Bu Teaching Hospital in Accra, Ghana. METHODS: Antibiogram patterns, seasonal variations in disease incidence and predisposing factors for infection with Salmonella serotypes were analyzed retrospectively over a 4-year period from January 2010 to December 2013. Blood cultures were processed with BACTEC 9240 blood culture system. Speciation was done with BBL Crystal Enteric/Nonfermenter identification system(r), and with slide agglutination using specific antisera. Antimicrobial susceptibility testing was carried out by the Kirby-Bauer disc diffusion method according to Clinical and Laboratory Standard Institute guidelines. RESULTS: We report a 6.5% (n = 181/2768) prevalence of Salmonella bacteraemia at the Korle-Bu Teaching Hospital; with a preponderance of non-typhoidal salmonellae (NTS) over typhoidal salmonella (TS) (n = 115/181, 63.5% versus n = 66/181, 36.5%; P-value <0.002). Children under 5 years bore the brunt of the disease (n = 93/174, 53.4%). Resistance to ciprofloxacin (n = 1/127, 0.7%), amikacin (n = 3/81, 3.7%), and cefotaxime (n = 6/99, 6.1%) remained low, despite high levels of multidrug resistant Salmonella phenotypes (n = 81/181, 44.2%). In multivariate analysis, and among patients with Salmonella BSI, those < 1 year old had reduced risk of non-typhoidal infections [Odds ratio, 0.51; 95% confidence interval (95% CI), 0.16-0.92, P-value 0.021]. Similarly, patients with cefuroxime resistant strans were at increased risk of having multidrug resistant Salmonella BSI (OR, 8.97; 95% CI, 3.62-24.15; P-value, 0.001). CONCLUSIONS: Salmonellae, predominantly NTS, account for a reasonable low proportion of positive blood cultures in our tertiary care setting; but with significant multidrug resistant phenotypes and low ciprofloxacin and cefotaxime resistance. PMID- 25528353 TI - Physiological and analgesic effects of continuous-rate infusion of morphine, butorphanol, tramadol or methadone in horses with lipopolysaccharide (LPS) induced carpal synovitis. AB - BACKGROUND: Continuous-rate infusion (CRI) of drugs results in more stable plasma drug concentrations than administration of intermittent boluses, thus providing greater stability of physiological parameters. The aim of this study was to evaluate the physiologic and analgesic effects of the administration of morphine, butorphanol, tramadol or methadone by CRI in horses with induced synovitis of the radiocarpal joint. RESULTS: Increased values of cardiorespiratory parameters and body temperature were observed in all groups after initiation of opioid administration, and these increases were sustained throughout the CRI period. Morphine, butorphanol and methadone each caused a reduction in gut sounds, and this effect was greatest in animals that received morphine. Administration of morphine or methadone reduced the degree of lameness after the end of intravenous infusion. Administration of tramadol did not alter the degree of lameness in the animals. CONCLUSIONS: CRI of morphine or methadone, but not butorphanol or tramadol, provided analgesia in horses with carpal synovitis. All of these opioids increased cardiovascular and respiratory parameters and reduced gut sounds during CRI. PMID- 25528354 TI - Identification of an immuno-dominant protein from Klebsiella pneumoniae strains causing pyogenic liver abscess: implication in serodiagnosis. AB - BACKGROUND: Klebsiella pneumoniae has emerged worldwide as a cause of pyogenic liver abscess (PLA) often complicated by meningitis and endophthalmitis. Early detection of this infectious disease will improve its clinical outcome. Therefore, we tried to isolate immunodominant proteins secreted by K. pneumoniae strains causing PLA. RESULTS: The secreted proteins of the NTUH-K2044 strain were separated by two-dimensional electrophoresis and then immunoblotted using convalescent sera from patients with K. pneumoniae PLA. A ~30-kDa immunodominant protein was then identified. Liquid chromatography-tandem mass spectrometry (LC MS/MS) revealed an open reading frame (KP1_p307) located on the pK2044 plasmid and bioinformatic analysis identified this protein as a signal peptide of unknown function. The KP1_p307 gene was more prevalent in PLA strains and capsular type K1/K2 strains, but disruption of this gene in NTUH-K2044 strain did not decrease virulence in mice. Ten of fourteen (71%) sera from patients with K. pneumoniae PLA were immunoreactive with the recombinant KP1_p307 protein. Seroconversion demonstrated by a rise in serum titer in serial serum samples confirmed that antibodies against the KP1_p307 protein were elicited after infection. CONCLUSIONS: The KP1_p307 protein could be used as an antigen for early serodiagnosis of K. pneumoniae PLA, particularly in K1/K2 PLA strains. PMID- 25528355 TI - Elective anatomy by whole body dissection course: what motivates students? AB - BACKGROUND: Students' motivation provides a powerful tool to maximise learning. The reasons for motivation can be articulated in view of self-determination theory (SDT). This theory proposes that for students to be motivated and hence benefit educationally and professionally from courses, three key elements are needed: autonomy, competence, and relatedness. In this paper we apply SDT theory to consider medical students' motivation to participate throughout a 2014 optional summer intensive eight week elective anatomy by whole body dissection course. The course was designed and facilitated by surgeons, and required small group, active learning. METHODS: At the end of the course, data were collected from all (24/24) students by means of an open ended survey questionnaire. Framework analysis was used to code and categorise data into themes. RESULTS: Utilising self-determination theory as a theoretical framework, students' motivation and experiences of participation in the course were explored. Elements that facilitated students' motivation included the enthusiasm and expertise of the surgeons, the sense of collegiality and community within the course, the challenges of group activities, and sense of achievement through frequent assessments. CONCLUSION: The team learning course design, and facilitation by surgeons, provided an enriched learning environment, motivating students to build on their knowledge and apply a surgical context to their learning. PMID- 25528356 TI - What clinicians want: findings from a psychotherapy practice research network survey. AB - Practice research networks may be one way of advancing knowledge translation and exchange (KTE) in psychotherapy. In this study, we document this process by first asking clinicians what they want from psychotherapy research. Eighty-two psychotherapists in 10 focus groups identified and discussed psychotherapy research topics relevant to their practices. An analysis of these discussions led to the development of 41 survey items. In an online survey, 1,019 participants, mostly practicing clinicians, rated the importance to their clinical work of these 41 psychotherapy research topics. Ratings were reduced using a principal components analysis in which 9 psychotherapy research themes emerged, accounting for 60.66% of the variance. Two postsurvey focus groups of clinicians (N = 22) aided in interpreting the findings. The ranking of research themes from most to least important were-Therapeutic Relationship/Mechanisms of Change, Therapist Factors, Training and Professional Development, Client Factors, Barriers and Stigma, Technology and Adjunctive Interventions, Progress Monitoring, Matching Clients to Therapist or Therapy, and Treatment Manuals. Few differences were noted in rankings based on participant age or primary therapeutic orientation. Postsurvey focus group participants were not surprised by the top-rated items, as they were considered most proximal and relevant to therapists and their work with clients during therapy sessions. Lower ranked items may be perceived as externally imposed agendas on the therapist and therapy. We discuss practice research networks as a means of creating new collaborations consistent with KTE goals. Findings of this study can help to direct practitioner-researcher collaborations. PMID- 25528357 TI - Incidence of multiple sclerosis in Northern Lisbon, Portugal: 1998-2007. AB - BACKGROUND: There are few, recent, well assessed, multiple sclerosis (MS) incidence surveys on European populations. This study sought to measure MS incidence in a Northern Lisbon population and assess it using capture-recapture methods (CRMs). METHODS: Among the population residing in the Northern Lisbon Health Area, registered MS diagnoses were obtained from general practitioners in three primary-care districts covering a population of 196,300, and a neurology unit at the main referral hospital. Cases with onset during the periods 1978-1997 and 2008-2012 were excluded due to perceived poor access to image-supported neurological diagnosis and administrative changes in patient referral respectively. Age- and sex-specific incidences for the period 1998-2007 were calculated using McDonald diagnostic criteria, and CRMs were used to correct age specific incidence rates. The corrected figures were also adjusted for age using the European Standard Population as reference. RESULTS: When applied to 62 MS patients with onset in the period 1998-2007, the rates per 100,000 population were as follows for both sexes: crude, 3.16; age-adjusted, 3.09 (95% CI 2.32 to 3.87); CRM-adjusted, 4.53 (95% CI 3.13 to 5.94); and age- and CRM-adjusted, 4.48 (3.54-5.41). In general, the rates were 3-fold higher among women than among men. Negative source dependency and CRM impact were highest at ages 35-44 years, where a 60% rise led to a peak incidence. CONCLUSIONS: MS incidence in Northern Lisbon, Portugal, is moderately lower than that yielded by surveys on European populations. CRMs, which in this instance suggest undercounts, are a potentially useful tool for case-finding assessment but their application may introduce bias. PMID- 25528358 TI - A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. AB - BACKGROUND: Although promising results have emerged regarding oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) for the treatment of peanut allergy (PA), direct comparisons of these approaches are limited. OBJECTIVE: This study was conducted to compare the safety, efficacy, and mechanistic correlates of peanut OIT and SLIT. METHODS: In this double-blind study children with PA were randomized to receive active SLIT/placebo OIT or active OIT/placebo SLIT. Doses were escalated to 3.7 mg/d (SLIT) or 2000 mg/d (OIT), and subjects were rechallenged after 6 and 12 months of maintenance. After unblinding, therapy was modified per protocol to offer an additional 6 months of therapy. Subjects who passed challenges at 12 or 18 months were taken off treatment for 4 weeks and rechallenged. RESULTS: Twenty-one subjects aged 7 to 13 years were randomized. Five discontinued therapy during the blinded phase. Of the remaining 16, all had a greater than 10-fold increase in challenge threshold after 12 months. The increased threshold was significantly greater in the active OIT group (141- vs 22 fold, P = .01). Significant within-group changes in skin test results and peanut specific IgE and IgG4 levels were found, with overall greater effects with OIT. Adverse reactions were generally mild but more common with OIT (P < .001), including moderate reactions and doses requiring medication. Four subjects had sustained unresponsiveness at study completion. CONCLUSION: OIT appeared far more effective than SLIT for the treatment of PA but was also associated with significantly more adverse reactions and early study withdrawal. Sustained unresponsiveness after 4 weeks of avoidance was seen in only a small minority of subjects. PMID- 25528359 TI - The 3 major types of innate and adaptive cell-mediated effector immunity. AB - The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet(+) IFN-gamma-producing group 1 ILCs (ILC1 and natural killer cells), CD8(+) cytotoxic T cells (TC1), and CD4(+) TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3(+) ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid-related orphan receptor gammat(+) ILC3s, TC17 cells, and TH17 cells producing IL-17, IL 22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. PMID- 25528360 TI - Environmental exposure chambers in allergen immunotherapy trials: Current status and clinical validation needs. AB - As required by the European Medicines Agency and the US Food and Drug Administration for pivotal trials involving allergen immunotherapy (AIT) products, clinical efficacy assessment is currently based on double-blind, placebo-controlled field studies with natural allergen exposure during the allergen season. However, this study design is associated with several drawbacks, such as the high variability of allergen exposure in different trial sites or seasons and the presence of confounding environmental factors. On the contrary, environmental exposure chambers (EECs) aim to operate with a stable and reproducible allergen exposure under highly standardized environmental conditions. Technical validation parameters for different EECs worldwide have been published by several groups. However, full clinical validation of EEC study outcomes is required for their classification as an appropriate alternative to natural allergen exposure for AIT product efficacy assessment. Some clinical validation parameters have already been addressed for EEC units. The reliability of provoked symptoms in repeated EEC sessions is high, but the predictive power of EEC settings for the clinical response on natural exposure and the impact of seasonal priming on test results still have to be validated systematically, as does the inter-EEC variability. Thus the authors recommend a continued in-depth validation of EECs to exploit the potential of this technology for future AIT product development. PMID- 25528362 TI - Obesity and asthma: the chicken or the egg? PMID- 25528361 TI - Early childhood IgE reactivity to pathogenesis-related class 10 proteins predicts allergic rhinitis in adolescence. AB - BACKGROUND: Component-resolved diagnosis might improve the prediction of future allergy in young children. OBJECTIVE: We sought to investigate the association between IgE reactivity to the pathogenesis-related class 10 (PR-10) protein family and allergic rhinitis to birch pollen (ARbp) from early childhood up to age 16 years. METHOD: Questionnaire data and sera obtained at 4, 8, and 16 years of age from the Barn/Children Allergi/Allergy Milieu Stockholm Epidemiologic (BAMSE) study birth cohort were used. Sera from 764 children were analyzed for IgE reactivity to 9 PR-10 allergen proteins at the 3 time points by using an allergen chip based on ISAC technology. ARbp was defined as upper airway symptoms during birch pollen exposure. RESULTS: IgE reactivity to Bet v 1 was found in 12%, 17%, and 25% of children at 4, 8, and 16 years of age. IgE reactivity of PR 10 proteins showed a hierarchic intrarelationship: Bet v 1 > Mal d 1 > Cor a 1.04 > Ara h 8 > Pru p 1 > Aln g 1 > Api g 1 > Act d 8 > Gly m 4. There was an increased risk of incidence and persistence of ARbp up to age 16 years with increasing levels of Bet v 1-specific IgE or increasing numbers of IgE-reactive PR-10 proteins at 4 years. Children with severe ARbp at age 16 years had higher levels of Bet v 1-specific IgE at age 4 years compared with children with mild symptoms. CONCLUSION: ARbp at age 16 years can be predicted by analysis of IgE reactivity to PR-10 proteins in early childhood. PMID- 25528363 TI - Fibroblast growth factor 23 in acute myocardial infarction complicated by cardiogenic shock: a biomarker substudy of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. AB - INTRODUCTION: Cardiogenic shock (CS) is the leading cause of death in patients hospitalized with acute myocardial infarction (AMI). Biomarkers might help in risk stratification and understanding of pathophysiology. Preliminary data suggests that patients with CS face a profound increase in the osteocyte-derived hormone fibroblast growth factor 23 (FGF-23), which acts as a negative regulator of serum phosphate levels. The present study aimed to assess the predictive role of FGF-23 for clinical outcome in a large cohort of CS patients with and without renal dysfunction. METHODS: In the randomized Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, 600 patients with CS complicating AMI were assigned to therapy with or without IABP. Our predefined biomarker substudy included 182 patients. Blood sampling was performed in a standardized procedure at three different time points (day 1 (day of admission), day 2 and day 3). Differences in outcome of patients with FGF-23 levelsmedian were compared by log-rank testing. Stepwise logistic regression modeling was performed to identify predictors of death at 30 days and Cox regression analysis for time to death during the first year. RESULTS: At all three time points, nonsurvivors had significantly higher FGF-23 levels compared to survivors (P<0.001 for all). Patients with FGF-23 levels above the median (395 RU/mL [interquartile range 102;2,395]) were characterized by an increased 30-day mortality and 1-year mortality. In multivariable analysis FGF-23 levels remained independent predictors for 30-day (odds ratio per 10log 1.80, 95% confidence interval (CI) 1.11 to 2.92; P=0.02) and 1-year mortality (hazard ratio 1.50, 95% CI 1.11 to 2.04, P=0.009). After stratifying the patients according to their baseline serum creatinine levels, the negative prognostic association of increased FGF-23 was only significant in those with serum creatinine greater than median. CONCLUSIONS: In CS, high levels of FGF-23 are independently related to a poor clinical outcome. However, this prognostic association appears only to apply in patients with impaired renal function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00491036. Registered 22 June 2007. PMID- 25528364 TI - Preparation and physicochemical properties of chitosan broadleaf holly leaf nanoparticles. AB - OBJECTIVE: To prepare chitosan broadleaf holly leaf nanoparticles and to investigate their physicochemical properties and drug release characteristics in vitro. METHODS: Broadleaf holly leaf total flavonoids were extracted using an ethanol gradient and the determination of their contents was performed using a UV vis spectrophotometer. Nanoparticles were prepared by ionic crosslinking. The morphology and distribution of the particles were examined. In addition, several factors affecting drug-loading and the encapsulation rate were explored. Furthermore, studies on the characteristics of in vitro release were performed. RESULTS: The content of total flavonoids from broadleaf holly leaf was 31.84%. The nanoparticles were spherical in shape, and the size range was between 100 and 600 nm. The polydispersity was 0.137. The optimal preparation process of the nanoparticles was the following: chitosan concentration 1 mg/ml, TPP concentration 1mg/ml, and concentration of broadleaf holly leaf total flavonoids 1 mg/ml. The in vitro release profile showed that the nanoparticles have an initial burst release effect of 45.6-48.9% within the first two hours. The total release was 91.9% in 24 h. CONCLUSIONS: Chitosan nanoparticles are a potential broadleaf holly leaf delivery system. PMID- 25528365 TI - The effect of mixing on the extrusion-spheronisation of a micro-crystalline cellulose paste. AB - The effect of mixer shear strain rate on the performance of a model micro crystalline cellulose pharmaceutical paste undergoing extrusion-spheronisation was studied using a laboratory scale planetary mixer and a screw-based mixer. The maximum shear strain rate in each mixer was estimated. Five pastes were prepared, one each at 97 and 265 s(-1) in the planetary mixer, and one each at 304, 988 and 2220 s(-1) in the screw mixer. The rheology of the pastes was quantified by Benbow-Bridgwater characterisation based on ram extrusion. Each paste was spheronised and pellet size and shape distributions obtained by automated size analysis. Mixer type (rather than shear strain rate) was found to have the strongest influence on the paste properties, with the screw-mixed material having a higher yield strength and forming smaller pellets with a narrower size distribution when spheronised under identical conditions. PMID- 25528366 TI - Plastid intramembrane proteolysis. AB - Progress in the field of regulated intramembrane proteolysis (RIP) in recent years has not surpassed plant biology. Nevertheless, reports on RIP in plants, and especially in chloroplasts, are still scarce. Of the four different families of intramembrane proteases, only two have been linked to chloroplasts so far, rhomboids and site-2 proteases (S2Ps). The lack of chloroplast-located rhomboid proteases was associated with reduced fertility and aberrations in flower morphology, probably due to perturbations in jasmonic acid biosynthesis, which occurs in chloroplasts. Mutations in homologues of S2P resulted in chlorophyll deficiency and impaired chloroplast development, through a yet unknown mechanism. To date, the only known substrate of RIP in chloroplasts is a PHD transcription factor, located in the envelope. Upon proteolytic cleavage by an unknown protease, the soluble N-terminal domain of this protein is released from the membrane and relocates to the nucleus, where it activates the transcription of the ABA response gene ABI4. Continuing studies on these proteases and substrates, as well as identification of the genes responsible for different chloroplast mutant phenotypes, are expected to shed more light on the roles of intramembrane proteases in chloroplast biology. PMID- 25528367 TI - Mothers' and daughters' beliefs about factors affecting preadolescent girls' body satisfaction. AB - Body dissatisfaction is common in preadolescent girls. In this qualitative study, preadolescent girls (N=145) wrote descriptions of factors that made them feel good and bad about their bodies. Their mothers (N=145) also wrote about factors they believed made their daughters feel good and bad about their bodies. Statements were coded using thematic analysis. Chi-square analyses examined mother-daughter dyad agreement, and differences in influential factors based on ethnic identity. Despite general agreement in overall themes, results indicated limited agreement within mother-daughter dyads. Specifically, one significant result was detected: mothers and their daughters agreed on the importance of teasing as a negative influence on body satisfaction. There was one significant difference based on ethnic identity, with Hispanic girls mentioning more frequently than White girls that physical activity/exercise helped them feel good about their bodies. Recommendations are made for family-based interventions to support the body image of preadolescent girls. PMID- 25528368 TI - Factor structure of the Body Image Concern Inventory in a Japanese sample. AB - The purpose of this study was to investigate the factor structure of the Body Image Concern Inventory (BICI) using a Japanese population as a web-based survey. Two thousand and sixty individuals (1030 women, 1030 men) ranging from 20 to 69 years of age (M=40, SD=16) took part in the present research. A confirmatory factor analysis showed that the second-order factor model of the BICI, which had three first-order factors and one second-order factor of dysmorphic appearance concern was an adequate fit to the data. Additionally, the Cronbach's alpha values of the overall and three subscales of the BICI were adequate. Furthermore, measurement invariance tests revealed that the second-order factor model of the BICI had acceptable measurement invariance at the scale and factor-loading levels between genders. These findings suggested that the BICI was reliable, and able to compare its mean scores between women and men in Japan. PMID- 25528369 TI - The effect of thin and muscular images on women's body satisfaction. AB - A substantial body of research documents that exposure to images depicting a "thin ideal" body figure effects women's state-oriented body satisfaction. However, there is evidence that the societal ideal body figure of females is evolving to be not just thin, but also muscular or toned. Therefore, the purpose of this research was to test the effect of exposure to ideal body figures that are both thin and muscular on female state body satisfaction. Researchers recruited female participants (N=366) from an online community (Amazon's Mechanical Turk) and randomly assigned them to view images in one of four conditions: thin, thin and muscular, thin and hypermuscular, and control (images of cars). Results indicated that state-oriented body satisfaction decreased in the thin condition and thin and muscular condition, but not the hypermuscular or control conditions. These findings have implications for clinical initiatives as well as future research. PMID- 25528370 TI - Structure-retention behaviour of biologically active fused 1,2,4-triazinones- correlation with in silico molecular properties. AB - The chromatographic behaviour and significant lipophilicity/hydrophobicity indices (log k(w), S, phi(0)) are presented for 21 biologically active fused 1,2,4-triazinones based on the linear relationship: log k = log k(w)-Sphi established for the retention on LC-18 HPLC column, using as mobile phases mixtures of three organic modifiers with water. The effect of these mobile phase modifiers on the chromatographic behaviour of solutes was established and the organic modifier of choice is suggested. The complex correlation of slopes versus intercepts obtained for acetonitrile, contrary to linear ones obtained for methanol and dioxane are disclosed. The observed difference in retention mechanism for acetonitrile compared to methanol and dioxane is explained by intermolecular interactions encoded in lipophilicity. Linear correlations with statistically significant levels between log kw values determined from three different chromatographic systems were obtained. The relationships between log k(w) constants (derived from the linear model for methanol-water mobile phases) and predicted log P and log S values by the use of various computational methods were investigated and these were established with high correlation coefficients. The predicted log P values plotted against phi(0 (MeOH)) indices showed the best fit. Principal component analysis was used to compare various lipophilicity parameters of the solutes and their in silico biological descriptors relevant to optimal pharmacokinetics profile. The similarities and dissimilarities between all the variables and molecular structures of solutes are presented. Statistically significant correlations were found between the chromatographic lipophilicity indices and the calculated pharmacokinetic descriptors: fraction unbound in brain (f(u, brain)), oral bioavailability (%F), permeability and intestinal absorption in jejunum (Caco-2), skin permeation (log K(p)) and blood/brain concentration (log BB). PMID- 25528371 TI - Endoscope-assisted keyhole surgery via an eyebrow incision for removal of large meningiomas of the anterior and middle cranial fossa. AB - BACKGROUND: Conventional open surgery of large meningiomas has proven to be challenging even in experienced hands. Intense retraction and dissection around neurovascular structures increase morbidity and mortality. In the present study, we retrospectively analyzed the surgical technique, and outcome in 40 patients with large anterior cranial fossa meningiomas extending to the middle fossa. All patients were approached via a supraorbital mini craniotomy. METHODS: It is a retrospective study of 40 patients (12 males, 28 females) who underwent surgery for large anterior cranial fossa meningiomas (diameter >5 cm) extending to the middle fossa in four different neurosurgical centers within 6 years. Depending on the localization of the tumor, the skin incision was between 2.5 and 3 cm long and was made without shaving the patient's eyebrow hair. Subsequently, a keyhole craniotomy was performed of approximately 0.8*1.2-1.4 cm in diameter. Preoperative and postoperative clinical and radiological data were analyzed and discussed. RESULTS: Headache and psycho-organic syndrome were the most common presenting symptom in all patients. Presenting symptoms were associated with psychological changes in 23 cases, visual impairment in 19 patients, and anosmia in 17 patients. In overall, 36 of 40 patients (90%) showed a good outcome and returned at long-term follow-up to their previous occupations. The elderly patients returned to their daily routine. CONCLUSION: With the appropriate keyhole approach as a refinement of the classic keyhole craniotomy to a smaller key"burr"hole, and with use of modern and new designed equipment, it is possible to perform complete resection of large anterior and middle fossa meningiomas with the same safety, efficiency and with less complication rates as described in the literature for large meningiomas even performed with classic keyhole craniotomies. PMID- 25528372 TI - Moyamoya in a patient with Sneddon's syndrome. PMID- 25528373 TI - Thoracic lateral extracavitary corpectomy for anterior column reconstruction with expandable and static titanium cages: clinical outcomes and surgical considerations in a consecutive case series. AB - OBJECTIVE: Many surgical interventions have emerged as effective means of restoring mechanical stability of the anterior column of the spine. The lateral extracavitary approach (LECA) allows for broad visualization and circumferential reconstruction of the spinal column. However, early reports demonstrated significant complication rates, protracted operative times, and prolonged hospitalizations. More recent reports have highlighted concerns for subsidence, particularly with expandable cages. Our work seeks to describe a single-surgeon consecutive series of patients undergoing LECA for thoracic corpectomy. Specifically, the objective was to explore the surgical considerations, clinical and radiographic outcomes, and complication profile of this approach. METHODS: A retrospective study examined data from 17 consecutive patients in whom single or multi-level corpectomy was performed via a LECA by a single surgeon. Vertebral body replacement was achieved with either a static or expandable titanium cage. The Karnofsky Performance Scale (KPS) was utilized to assess patient functional status before and after surgery. Radiographic outcomes, particularly footplate-to body ratio and subsidence, were assessed on CT imaging at 6 weeks after surgery and at follow-up of at least 6 months. RESULTS: The majority of patients had post operative KPS scores consistent with functional independence (>=70, 12/17 patients, 71%). Fourteen patients had improved or maintained function by last follow-up. In both groups, all patients had a favorable footplate-to-body ratio, and rates of subsidence were similar at both time points. Notably, the overall complication rate (24%) was significantly lower than that published in the literature, and no patient suffered a pneumothorax that required placement of a thoracostomy tube. CONCLUSION: The LECA approach for anterior column reconstruction with static or expandable cages is an important surgical consideration with favorable surgical parameters and complication rates. Further, use of expandable cages may allow for reconstruction over a larger segment without increased risk of subsidence. PMID- 25528374 TI - Capsaicin inhibits collagen fibril formation and increases the stability of collagen fibers. AB - Capsaicin is a versatile plant product which has been ascribed several health benefits and anti-inflammatory and analgesic properties. We have investigated the effect of capsaicin on the molecular stability, self-assembly, and fibril stability of type-I collagen. It was found that capsaicin suppresses collagen fibril formation, increases the stability of collagen fibers in tendons, and has no effect on the molecular stability of collagen. Turbidity assay data show that capsaicin does not promote disassembly of collagen fibrils. However, capsaicin moderately protects collagen fibrils from enzymatic degradation. Computational studies revealed the functions of the aromatic group and amide region of capsaicin in the collagen-capsaicin interaction. The results may have significant implications for capsaicin-based therapeutics that target excess collagen accumulation-linked pathology, for example thrombosis, fibrosis, and sclerosis. PMID- 25528376 TI - Role of hematin and sodium nitroprusside in regulating Brassica nigra seed germination under nanosilver and silver nitrate stresses. AB - Silver nanoparticles (AgNPs) are one of the most widely used nanomaterials, although the mechanisms of AgNP toxicity in terrestrial plants is still unclear. We compared the toxic effects of AgNPs and AgNO3 on Brassica nigra seed germination at physiological and molecular levels. Both AgNPs and AgNO3 inhibited seed germination, lipase activity, soluble and reducing sugar contents in germinating seeds and seedlings. These reductions were more pronounced in AgNP treatments than AgNO3 treatments. Application of 200-400mg/L both AgNPs and AgNO3 increased transcription of heme oxygenase-1. However, at 800, 1600 mg/L, AgNPs or AgNO3 suppressed HO-1 expression. At 400mg/L, AgNPs or AgNO3-induced inhibitory effects on seed germination and were ameliorated by the HO-1 inducer, hematin, or NO donor, sodium nitroprusside (SNP). Additionally, 4 MUM hematin and 400 MUM SNP were able to markedly boost the HO/NO system. However, the addition of the HO-1 inhibitor (ZnPPIX) or the specific scavenger of NO (cPTIO) not only reversed the protective effects conferred by hematin, but also blocked the up-regulation of HO activity. In addition, hematin-drived NO production in B. niger seeds under AgNPs was confirmed. Our results at physiological and molecular levels suggested that AgNPs were more toxic than AgNO3. Based on these results, for the first time, we suggest that endogenous HO is needed to alleviate AgNPs-induced germination inhibition, which might have a possible interaction with NO. PMID- 25528375 TI - New members of the mammalian glycerophosphodiester phosphodiesterase family: GDE4 and GDE7 produce lysophosphatidic acid by lysophospholipase D activity. AB - The known mammalian glycerophosphodiester phosphodiesterases (GP-PDEs) hydrolyze glycerophosphodiesters. In this study, two novel members of the mammalian GP-PDE family, GDE4 and GDE7, were isolated, and the molecular basis of mammalian GP PDEs was further explored. The GDE4 and GDE7 sequences are highly homologous and evolutionarily close. GDE4 is expressed in intestinal epithelial cells, spermatids, and macrophages, whereas GDE7 is particularly expressed in gastro esophageal epithelial cells. Unlike other mammalian GP-PDEs, GDE4 and GDE7 cannot hydrolyze either glycerophosphoinositol or glycerophosphocholine. Unexpectedly, both GDE4 and GDE7 show a lysophospholipase D activity toward lysophosphatidylcholine (lyso-PC). We purified the recombinant GDE4 and GDE7 proteins and show that these enzymes can hydrolyze lyso-PC to produce lysophosphatidic acid (LPA). Further characterization of purified recombinant GDE4 showed that it can also convert lyso-platelet-activating factor (1-O-alkyl sn-glycero-3-phosphocholine; lyso-PAF) to alkyl-LPA. These data contribute to our current understanding of mammalian GP-PDEs and of their physiological roles via the control of lyso-PC and lyso-PAF metabolism in gastrointestinal epithelial cells and macrophages. PMID- 25528377 TI - Chromium toxicity tolerance of Solanum nigrum L. and Parthenium hysterophorus L. plants with reference to ion pattern, antioxidation activity and root exudation. AB - Chromium (Cr), being a highly toxic metal, adversely affects the mineral uptake and metabolic processes in plants when present in excess. The current study was aimed at investigating the Cr accumulation in various plant tissues and its relation to the antioxidation activity and root exudation. Plants were grown in soil spiked with different concentrations of Cr for three weeks in pots and analysed for different growth, antioxidants and ion attributes. Furthermore, plants treated with different concentrations of Cr in pots were shifted to rhizobox-like system for 48h and organic acids were monitored in the mucilage dissolved from the plant root surface, mirroring rhizospheric solution. The results revealed that the Cr application at 1mM increased the shoot fresh and dry weight and root dry weight of Solanum nigrum, whereas the opposite was observed for Parthenium hysterophorus when compared with lower levels of Cr (0.5mM) or control treatment. In both plant species, Cr and Cl concentrations were increased while Ca, Mg and K concentrations in root, shoot and root exudates were decreased with increasing levels of Cr. Higher levels of Cr treatments enhanced the activities of SOD, POD and proline content in leaves of S. nigrum, whereas lower levels of Cr treatment were found to have stimulatory effects in P. hysterophorus. P. hysterophorus exhibited highest exudation of organic acid contents. With increasing levels of Cr treatments, citric acid concentration in root exudates increased by 35% and 44% in S. nigrum, whereas 20% and 76% in P. hysterophorus. Cr toxicity was responsible for the shoot growth reduction of S. nigrum and P. hysterophorus, however, shoot growth response was different at different levels of applied Cr. Consequently, Cr stress negatively altered the plant physiology and biochemistry. However, the enhanced antioxidant production, Cl uptake and root exudation are the physiological and biochemical indicators for the plant adaptations in biotic systems polluted with Cr. PMID- 25528378 TI - Spatial and interspecific variation of accumulated trace metals between remote and urbane dwelling birds of Pakistan. AB - The current study was designed to evaluate the hypothesis that birds of urbanized and/or industrialized origin depict higher metal accumulation as compared to remote dwellers. We selected seven representative species from three families (Anatidae, Motacillidae and Sturnidae) at two different locations; Baroghil valley (remote location) and Soan valley (urbanized location) of Pakistan and analyzed the concentrations of 8 metals Pb, Cd, Cr, Ni, Cu, Mn, Fe and Zn in feathers of these species. Feathers from Soan valley which is under higher anthropogenic influence exhibited significantly (P<0.001) higher metal concentrations when compared with the feathers of the same species at Baroghil valley which has negligible anthropogenic input. Terrestrial birds of the Baroghil valley revealed greater metal loads than aquatic birds while at Soan valley it was vice versa. In general, elevated concentrations of metals were recorded in insectivorous species as compared to omnivorous species. Within each location, species belonging to Anatidae and Motacillidae revealed similar metal contamination patterns. Principal component Analysis (PCA) based on correlation matrices depicted a clear tendency of metals towards the species originating from areas with greater pollution load (Soan valley) than relatively undisturbed sites (Baroghil valley) and hence corroborated our hypothesis. The pattern of metal accumulation in feathers of both the locations suggested that there may be a flux of migration between the two regions and/or trans-boundary movement of pollutants/metals, which either singly or synergistically influence the overall metal profile in the studied bird species. PMID- 25528379 TI - Biochemical changes in certain enzymes of Lysapsus limellium (Anura: Hylidae) exposed to chlorpyrifos. AB - Different enzyme biomarkers (AChE: acetylcholinesterase, CbE: carboxylesterase, GST: glutathione-S-transferase, CAT: catalase) were measured in digestive tissues of Lysapsus limellum frogs collected from a rice field (RF: chlorpyriphos sprayed by aircraft) and a non-contaminated area (RS: reference site), immediately (24h) and 168 h after aerial spraying with chlorpyrifos (CPF). CPF degradation was also searched in water samples collected from RF and RS, and found that insecticide concentration was reduced to~6.78% of the original concentration in RF at 168 h. A significant reduction of AChE and CbE activities was detected in L. limellum from RF in stomach and liver at 24 and 168 h, and in intestine only at 24h, with respect to RS individuals. CAT activity decreased in intestine of L. limellum from RF 24h and 168 h after exposure to CPF, whereas GST decreased in that tissue only at 24h. In stomach and liver, a decrease was observed only at 168 h in both CAT and GST. The use of biomarkers (AChE, CbE, GST, and CAT) provides different lines of evidences for ecotoxicological risk assessment of wild frog populations at sites contaminated with pesticides. PMID- 25528380 TI - Assessment of the exposure to heavy metals in Griffon vultures (Gyps fulvus) from the Iberian Peninsula. AB - Griffon vultures (Gyps fulvus), by virtue of their position at the top of the food chain and as obligate scavengers, are at risk of accumulating and concentrating heavy metals in their tissues and may be more predisposed to their toxic effects. The aim of this study is to investigate heavy metal concentrations in Griffon vultures in Portugal and Catalonia, Spain and to determine if heavy metal concentrations in the blood of weak and/or injured Griffon vultures admitted to wildlife rehabilitation centres (WRC) reflect contamination profiles in the local, free-living and outwardly healthy population. Whole-blood samples taken from 121 Griffon vultures caught in the wild or admitted to WRC in Portugal and Catalonia, Spain were examined for cadmium (Cd), mercury (Hg) and lead (Pb) by inductively coupled plasma mass spectrometry (ICP-MS). Cd and Hg were not detected in most samples (98.3% and 95%, respectively), while Pb was detected in all birds in concentrations ranging between 4.97 and 300.23 ug/dl. Birds admitted to WRC had significantly lower Pb concentrations (24.15 +/- 15.07 and 25.98 +/- 18.04 ug/dl in Portugal and Catalonia, Spain, respectively) than animals caught in the wild (29.67 +/- 13.19 and 42.22 +/- 50.08 ug/dl in Portugal and Catalonia, Spain, respectively) (p<0.05). This may be explained by the fact that malnutrition was the main cause of admission of Griffon vultures to WRC, as ingestion has been described as the most significant pathway for Pb exposure in raptors. Therefore Griffon vultures admitted to WRC do not seem to be representative of the local, free-flying populations, so it remains necessary to continue catching when one intends to monitor Pb exposure in this species. The population of vultures captured in Catalonia, Spain showed the highest mean blood Pb concentration, perhaps due to the municipal rubbish dump located near the feeding station, with rubbish providing a significant fraction of their trophic needs. The ingestion of game meat with bullet fragments in carcasses or with Pb shots embedded in their flesh could also be the cause of the high blood Pb concentrations found in some vultures. The potential risk of Pb exposure in Griffon vulture populations must be given consideration, since most individuals evaluated had Pb concentrations between 20 and 100ug/dl, which is considered to be subclinical exposure to Pb, and which is above the threshold level at which Pb can affect antioxidant system in this species (15 ug/dl). PMID- 25528381 TI - Content and comprehensibility of juvenile and adult tender-of-plea forms: implications for knowing, intelligent, and voluntary guilty pleas. AB - The overwhelming majority of criminal convictions in the United States are obtained through guilty pleas. To be constitutionally valid, guilty pleas must be knowing, voluntary, and intelligent. The information the defendant relies on to make a knowing, voluntary, and intelligent plea decision may be conveyed to the defendant through several modes, including but not limited to communication with defense counsel. Here, we address a mode that to our knowledge has previously not been systematically examined-tender-of-plea (ToP) forms. ToP forms are written instruments that inquire into whether the defendant understands and appreciates the plea decision and is capable of entering it. Using content analysis and comprehensibility measures, we examined a national sample of 208 tender-of-plea forms for both juvenile and adult defendants to determine what information they contained and their level of comprehensibility. The ToP forms were coded for several items concerning knowledge and voluntariness including rights waived, direct and collateral consequences, and capacity. Our findings show that the forms (a) are highly variable in their content, (b) exceed the reading comprehension of most defendants, and (c) are available more often to adult than to juvenile defendants. The implications of these findings are the forms should not be used to stand in place of "full and vigorous" judicial plea colloquies or meaningful defender-defendant discussions about plea decision-making. (PsycINFO Database Record PMID- 25528382 TI - Extracellular DNA as a target for biofilm control. AB - Bacterial biofilms endure high concentrations of biocides, and new strategies for biofilm control must therefore replace or complement the use of antibiotics, for example, by targeting the extracellular matrix to cause dispersal or increased antimicrobial susceptibility. Extracellular DNA (eDNA) is a matrix component of most biofilms, and is therefore an attractive target. Enzymatic degradation of eDNA can prevent, disperse, or sensitize biofilm to antimicrobials, but cheaper production is required to realize large-scale application. Replacing mammalian DNase with bacterial nucleases could offer a path to lower production costs. Alternatively, eDNA could be targeted by disrupting its interactions with other matrix components. As new knowledge about eDNA-binding matrix components comes to light, exciting opportunities for targeting the biofilm matrix via eDNA are emerging. PMID- 25528384 TI - The Journal reports progress, notes changes for authors. PMID- 25528383 TI - Serum 25-hydroxyvitamin D levels are associated with carotid atherosclerosis in normotensive and euglycemic Chinese postmenopausal women: the Shanghai Changfeng study. AB - BACKGROUND: The role of serum 25-hydroxyvitamin D (25 (OH) D) in atherogenesis is unclear. We investigated whether the 25 (OH) D is independently associated with the carotid intima-media thickness (CIMT) and carotid plaques in normotensive and euglycemic postmenopausal women. METHODS: A total of 671 normotensive and euglycemic postmenopausal women (mean age, 58.8 years) were enrolled from the Changfeng Study. A standard interview, anthropometrics measurements and laboratory analyses were performed for each participant. Bilateral CIMTs were measured using ultrasonography, and the presence of carotid plaques was assessed. The serum 25 (OH) D was measured using electrochemiluminescence immunoassay. RESULTS: Serum 25 (OH) D was 43.6 +/- 18.2 nmol/L in the postmenopausal women. Compared with subjects with 25 (OH) D in the first, second and third quartiles, subjects with 25 (OH) D in the fourth quartile had decreased CIMT and prevalence of carotid plaque (0.684 +/- 0.009 mm vs 0.719 +/- 0.009 mm, 0.708 +/- 0.009 mm and 0.709 +/- 0.009 mm; 10.8% vs 19.0%, 14.8% and 16.8%, respectively). After adjusting for conventional CVD risk factors, PTH, liver and renal function, postmenopausal women with 25 (OH) D in the fourth quartile still had lower CIMT than those in the first, second and third quartiles (p = 0.039) and the subjects in the fourth quartile had a 0.421-fold decreased risk of carotid plaques relative to those in the lowest quartile (95% confidence interval 0.209 to 0.848). CONCLUSIONS: These results suggest serum 25 (OH) D is independently and inversely associated with carotid atherosclerosis in postmenopausal women with normal blood pressure and normal glucose tolerance. PMID- 25528386 TI - Does toxic defence in Nycticebus spp. relate to ectoparasites? The lethal effects of slow loris venom on arthropods. AB - The venom produced by slow lorises (Nycticebus spp.) is toxic both intra- and inter-specifically. In this study we assessed the ecoparasite repellent properties of their venom. We tested venom from two Indonesian slow loris species: Nycticebus javanicus and Nycticebus coucang. Arthropods directly exposed to brachial gland secretions mixed with saliva from both species were immediately impaired or exhibited reduced activity (76%), and often died as a result (61%). We found no significant difference in the result of 60-min trials between N. coucang and N. javanicus [X(2)(1, n = 140) = 2.110, p = 0.3482]. We found evidence that the degree of lethality of the venom varies according to the arthropod taxa to which it is exposed. While most maggots (84%) were initially impaired from the venom after 10 min, maggots died after a 1 h trial 42% of the time. In contrast, at the end of 1 h trial, spiders died 78% of the time. For all arthropods, the average time to death from exposure was less than 25 min (M = 24.40, SD = 22.60). Ectoparasites including ticks, members of the arachnid order, are known to transmit pathogens to hosts and may be an intended target of the toxic secretions. Our results suggest that one function of slow loris venom is to repel parasites that affect their fitness, and that their topical anointing behaviour may be an adaptive response to ectoparasites. PMID- 25528385 TI - Investigating the therapeutic effects of LASSBio-596 in an in vivo model of cylindrospermopsin-induced lung injury. AB - The cyanotoxin cylindrospermopsin (CYN) has lately been reported with a notorious toxicity to mammals. LASSBio-596 is a compound with anti-inflammatory actions. We aimed at evaluating the therapeutic effects of LASSBio-596 in a model of CYN induced lung injury. Protocol #1: BALB/c mice received intratracheally (i.t.) 50 MUL of saline or semi-purified extract of CYN (70 MUg/kg). 18 h later, animals that received saline were gavaged with saline (SALSAL) or 50 mg/kg of LASSBio-596 (SALLAS), and mice that received CYN were gavaged with either saline (TOXSAL) or 50 mg/kg of LASSBio-596 (TOXLAS). Pulmonary mechanics was measured 6 h after gavage. Lungs were prepared for histology and inflammatory mediators determination. Protocol #2: Mice received 50-MUL of CYN (70 MUg/kg, i.t.) and 18 h later were gavaged with saline (NOT TREATED), or 50 mg/kg of LASSBio-596 (TREATED). Survival rates and pulmonary mechanics of the survivors were assessed. CYN exposure increased mechanical components, alveolar collapse, PMN cells and fiber deposition in the lungs, as well as the production of IL-1beta, IL-6 and KC in Protocol #1. LASSBio-596 attenuated those changes. TREATED mice in Protocol #2 presented significantly higher survival rates and tended to improve lung mechanics. Briefly, LASSBio-596 showed positive effects in mice exposed to CYN. PMID- 25528387 TI - High number of memory t cells is associated with higher risk of acute graft versus-host disease after allogeneic stem cell transplantation. AB - The pathophysiology of acute graft-versus-host disease (GVHD) remains poorly understood in humans. Although T cell subsets have been identified to play a major role in disease initiation in rodents, clinical data on the effect of these different subsets are scarce and conflicting. To address this question, immunophenotyping analyses were performed on the graft in 210 patients. The onset of acute GVHD was retrospectively correlated with these subpopulations. In an adjusted analysis, only the absolute count of CD45lo/CD62Llo CD8(+) T cells (effector memory T cells) was significantly associated with the onset of grade 2 to 4 acute GVHD. Thus, in contrast to experimental data, we found that the number of effector memory but not of naive T cells was associated with the onset of GVHD. These results should be kept in mind while clinical trials, which aim to deplete naive T cells, are underway in several institutions. PMID- 25528389 TI - Radioimmunotherapy in allogeneic nonmyeloablative conditioning for B cell lymphoma: should we use it more often? PMID- 25528388 TI - Comparison of outcomes of allogeneic transplantation for chronic myeloid leukemia with cyclophosphamide in combination with intravenous busulfan, oral busulfan, or total body irradiation. AB - Cyclophosphamide (Cy) in combination with busulfan (Bu) or total body irradiation (TBI) is the most commonly used myeloablative conditioning regimen in patients with chronic myeloid leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase after myeloablative conditioning with Cy in combination with TBI, oral Bu, or intravenous (i.v.) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors (URD) from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors, and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving i.v. Bu compared with TBI (relative risk [RR], .36; P = .022) or oral Bu (RR, .39; P = .028), but nonrelapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving i.v. Bu (RR, .53; P = .025) or oral Bu (RR, .64; P = .017) compared with TBI. In CML in first chronic phase, Cy in combination with i.v. Bu was associated with less relapse than TBI or oral Bu. LFS was better after i.v. or oral Bu compared with TBI. PMID- 25528391 TI - Words of wisdom. Re: Poorly functioning kidneys recover from ischemia after partial nephrectomy as well as strongly functioning kidneys. PMID- 25528392 TI - Words of wisdom. Re: Comparison of 2 transvaginal surgical approaches and perioperative behavioral therapy for apical vaginal prolapse: the OPTIMAL randomized trial. PMID- 25528390 TI - Center for International Blood and Marrow Transplant Research chronic graft versus-host disease risk score predicts mortality in an independent validation cohort. AB - We previously reported a risk score that predicted mortality in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (HCT) between 1995 and 2004 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We sought to validate this risk score in an independent CIBMTR cohort of 1128 patients with CGVHD who underwent transplantation between 2005 and 2007 using the same inclusion criteria and risk score calculations. According to the sum of the overall risk score (range, 1 to 12), patients were assigned to 4 risk groups (RGs): RG1 (0 to 2), RG2 (3 to 6), RG3 (7 to 8), and RG4 (9 to 10). RG3 and RG4 were combined, as RG4 accounted for only 1% of the total cohort. Cumulative incidences of nonrelapse mortality (NRM) and probability of overall survival were significantly different between each RG (all P < .01). NRM and overall survival at 5 years after CGVHD for each RG were 17% and 72% in RG1, 26% and 53% in RG2, and 44% and 25% in RG3, respectively (all P < .01). Our study validates the prognostic value of the CIBMTR CGVHD RGs for overall survival and NRM in a contemporary transplantation population. The CIBMTR CGVHD RGs can be used to predict major outcomes, tailor treatment planning, and enroll patients in clinical trials. PMID- 25528393 TI - Words of wisdom. Re: Risk of incisional hernia after minimally invasive and open radical prostatectomy. PMID- 25528394 TI - Words of wisdom. Re: A randomized trial of robot-assisted laparoscopic radical cystectomy. PMID- 25528395 TI - Words of wisdom. Re: Enzalutamide in metastatic prostate cancer before chemotherapy. PMID- 25528396 TI - Words of wisdom. Re: Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. PMID- 25528398 TI - Quality of life after mild to moderate trauma. AB - INTRODUCTION: To evaluate potential reduction in health-related quality of life (HRQOL) after a mild to moderate trauma. MATERIALS AND METHODS: Follow-up study of a cohort of 153 trauma patients admitted to the High Dependency Unit of the Emergency Department of the University-Hospital of Florence from July 2008 to February 2012. After 6 months from the event, a telephone interview using the Physical (PCS) and Mental (MCS) Health Composite Score (SF12) was conducted. Patients reported their HRQOL both at present and before trauma. Scores >= 50 represent no disability; 40-49, mild disability; 30-39, moderate disability; and below 30, severe disability. RESULTS: Before the event 143 (93%) subjects reported a normal PCS and MCS. After the events, a significantly lower proportion of patients maintained a normal PCS and MCS values (52 and 68%, all p<0.01). One, two, three and four PCS items worsened in 14%, 15%, 18% and 38% of the study population, while one, two, three or four MCS dimensions worsened in 12%, 19%, 19% and 24%. We identified 109 subjects (N+), which showed normal PCS and MCS values before trauma, in the absence of any pre-existing medical condition. After the event, we observed a significant PCS (before: 54, standard deviation, SD 6; after 43, SD 11, p<0.0001) and MCS (before: 55, SD 7; after 47, SD 11, p<0.0001) worsening among N+ subjects. Distribution across the four disability categories was 52, 24, 17 and 6% for MCS score and 38, 25, 27 and 11% for PCS score: overall 8 (7%) patients reported a moderate disability and 5 (5%) reported a severe disability in both dimensions. Compared with subjects with preserved values, patients with an abnormal (<39) HRQOL were older, showed a higher prevalence of female gender and pre-existing medical conditions and a worst Sequential Organ Failure Assessment score. An advanced age (OR 1.033, 95% CI 1.010-1.057, p=0.005) and a higher SOFA T1 score (OR 1.500, 95% CI 1.027-2.190, p=0.036) were independently associated with a worsening PCS. CONCLUSIONS: After a mild trauma, we evidenced a relevant reduction in HRQOL; an advanced age and a higher degree of organ dysfunction were independently associated with HRQOL deterioration. PMID- 25528400 TI - New directions in canine behavior. PMID- 25528399 TI - Association of perioperative blood transfusion and adverse events after operative treatment of proximal humerus fractures. AB - BACKGROUND: The purpose of this study was to assess the relationship between perioperative blood transfusion for proximal humerus fracture and inpatient mortality, adverse events, prolonged hospital stay, and nonroutine disposition. METHODS: Among the >55,000 patients with an operatively treated proximal humerus fracture identified in the Nationwide Inpatient Sample between 2008 and 2011, 17% received a perioperative blood transfusion. Multivariable logistic regression analyses addressed the association of blood transfusion with inpatient mortality, adverse events, hospital stay, and nonroutine discharge, accounting for comorbidities and other known confounders. RESULTS: Perioperative blood transfusion for fracture of the proximal humerus was not associated with inhospital death, but it was independently associated with inpatient adverse events (odds ratio (OR) 4.4, 95% confidence interval (CI) 4.2-4.6), prolonged hospital stay (OR 2.8, 95% CI 2.7-2.9), and increased nonroutine discharge (OR 1.8, 95% CI 1.7-1.9). CONCLUSIONS: Inpatients with fracture of the proximal humerus who receive transfusion are not more likely to die in hospital, but they do stay longer, experience more adverse events, and are less likely to be discharged home. Additional study is merited to determine if the judicious use of blood transfusion in the perioperative period can decrease inpatient morbidity and health-care resource utilisation. LEVEL OF EVIDENCE: Level II, Retrospective Design, Prognosis Study. PMID- 25528401 TI - Vowelling and semantic priming effects in Arabic. AB - In the present experiment we used a semantic judgment task with Arabic words to determine whether semantic priming effects are found in the Arabic language. Moreover, we took advantage of the specificity of the Arabic orthographic system, which is characterized by a shallow (i.e., vowelled words) and a deep orthography (i.e., unvowelled words), to examine the relationship between orthographic and semantic processing. Results showed faster Reaction Times (RTs) for semantically related than unrelated words with no difference between vowelled and unvowelled words. By contrast, Event Related Potentials (ERPs) revealed larger N1 and N2 components to vowelled words than unvowelled words suggesting that visual orthographic complexity taxes the early word processing stages. Moreover, semantically unrelated Arabic words elicited larger N400 components than related words thereby demonstrating N400 effects in Arabic. Finally, the Arabic N400 effect was not influenced by orthographic depth. The implications of these results for understanding the processing of orthographic, semantic, and morphological structures in Modern Standard Arabic are discussed. PMID- 25528402 TI - The efficacy of auditory probes in indexing cognitive workload is dependent on stimulus complexity. AB - We examined whether the utility of a recently developed auditory probe technique for indexing cognitive workload was dependent on the stimulus properties of the probes. EEG was recorded while participants played a videogame under various levels of cognitive workload. At each level of workload, participants were probed with one of four different types of auditory stimuli: novel complex, repeated complex, novel simple, or repeated simple sounds. Probe efficacy at indexing cognitive workload was assessed by determining which probes elicited ERP components that decreased monotonically as a function of workload. Results suggest that complex auditory stimuli were significantly more effective in indexing cognitive workload than simple stimuli. The efficacy of complex stimuli was due to their ability to elicit a robust orienting response, indexed by the early P3a component of the ERP, which decreased monotonically as a function of cognitive workload. PMID- 25528403 TI - Bimanual force variability in chronic stroke: with and without visual information. AB - Visual information is critical to producing and controlling force output to achieve targeted levels. This study investigated bimanual force control in chronic stroke individuals while manipulating visual information. Nine chronic stroke individuals and nine age-matched controls executed bimanual wrist and finger extension at 5% of maximum voluntary contraction. Bimanual force control outcome measures included: (a) coefficient of variation, (b) approximate entropy, and (c) bimanual coordination. Without visual information, chronic stroke individuals displayed less force variability and more regular force production in comparison to age-matched controls. These findings suggest that chronic stroke individuals depended on visual information during bimanual force execution. PMID- 25528404 TI - Modulation of glutamatergic transmission by presynaptic N-methyl-D-aspartate mechanisms in second-order neurons of the rat nucleus tractus solitarius. AB - The present study investigated the physiological function of presynaptic N-methyl d aspartate (NMDA) mechanisms in glutamatergic transmission in the rat nucleus tractus solitarius (NTS). Membrane currents were recorded from the NTS second order neurons by using whole-cell patch pipettes including MK-801 to block postsynaptic NMDA receptors. All experiments were performed under blockade of inhibitory synaptic transmission. Co-application of NMDA and d-serine decreased the tractus solitarius (TS)-evoked excitatory postsynaptic currents (eEPSCs) in 7/12 (58%) of neurons, and increased the paired pulse ratio. The remaining neurons were insensitive to NMDA and d-serine. Application of an NMDA antagonist D-AP5 had no effect on eEPSCs in all 8 neurons tested. Action potential independent EPSCs (miniature EPSCs; mEPSCs) were recorded in the presence of tetrodotoxin. Co-application of NMDA and d-serine increased the mEPSC frequency but had no significant effect on the amplitude in 5/28 (18%) of neurons. D-AP5 decreased the mEPSC frequency without effect on the amplitude in 6/18 (33%) of neurons. This study demonstrated that (1) NMDA receptors were presynaptically distributed in a subset of NTS second-order neurons and that (2) the presynaptic NMDA receptors played an inhibitory role in TS-mediated release of glutamate and a facilitatory role in spontaneous release of glutamate. The present results suggest that the activation of presynaptic NMDA receptors modulates glutamatergic transmissions in the rat NTS second-order neurons. PMID- 25528405 TI - Analysis of several loci from genome-wide association studies in Parkinson's disease in mainland China. AB - Large-scale meta-analyses of genome-wide association studies in Parkinson's disease (PD) have identified a number of susceptibility loci in sporadic PD. Since the characteristics of those loci in a Han Chinese population from mainland China were unknown, we performed a case-control replication study in this population and evaluated several single nucleotide polymorphisms (SNPs) identified in a recent GWAS-meta-analysis. In total, 933 subjects comprised of 460 PD patients and 473 controls were genotyped. We found strong evidence of an association for rs708723 in RAB7L1 in the total sample (genotype p=0.01, allele p=0.01, OR=0.78, 95% CI=0.65-0.94). With rs156429 in GPNMB, there was a significant difference in genotype and allele distribution between male PD patients and the control subgroup (genotype p=0.01, allele p=0.01, OR=0.67, 95% CI=0.49-0.92). However, we did not observe any significant difference in genotype or allele distribution between PD and control for rs34016896 in NMD3 and rs6812193 in STBD1. PMID- 25528406 TI - Post-lesion administration of 7-NI attenuated motor and non-motor deficits in 6 OHDA induced bilaterally lesioned female rat model of Parkinson's disease. AB - The preoperative neuroprotective effect of the 7-nitroindazole (7-NI) in 6 hydroxydopamine (6-OHDA) induced unilateral male animal models of Parkinson's disease (PD) has been widely reported. However, the therapeutic approach to PD pathology would be closely associated with the post-lesion treatment by 7-NI in 6 OHDA-induced bilateral model. Also, there is a scarcity of data on neuroprotective effect of 7-NI in PD in females. We have studied the neuroprotective effects of 7-NI in 6-OHDA-induced bilaterally lesioned female rats after short-term post-lesion treatment. Sprague-Dawley female rats with bilateral intraventricular injection of either 6-OHDA (10.5MUg) (n=8-11/group) or saline (sham; n=8/group) at substantia nigra (SN) were provided with 7-NI (30mg/kg/day) intraperitoneal, once a day during the 3 consecutive days of short term treatment. 6-OHDA lesioned animals developed the motor and non-motor deficits, which were evaluated by behavioral and neuro-biochemical tests from the substantia nigra. Post-lesion administration of 7-NI reduced the motor deficits induced by 6-OHDA in the behavioral tasks such as Rota rod, open field test and forced swim test. Simultaneously, the dopamine levels were restored by 7-NI in post lesion animals up to 76% in comparison to 6-OHDA lesioned animals (23%). Furthermore, antioxidant-like effect of 7-NI was observed in lipid peroxidation, catalase, superoxide dismutase, and reduced glutathione tests. Conclusively, the present study showed that early postoperative administration of 7-NI attenuates the motor deficits induced by 6-OHDA in bilaterally lesioned female rat model of PD. PMID- 25528407 TI - A 2-DE-based proteomic study on the toxicological effects of cisplatin in L02 cells. AB - Cisplatin is a chemotherapeutic agent for the treatment of various cancers. In this study, cisplatin-induced effects were characterized in vitro model of human liver cells (L02) using 2-DE-based proteomics. Results indicated that different cisplatin treatments primarily induced disturbances in protein synthesis and oxidative stress via differential mechanisms. Since the experimental concentrations of cisplatin described a hormesis effect in cell proliferation of L02 cells, it was expected to reveal the hormesis effects using proteomic markers. However, only confilin-1 was commonly up-regulated in three concentrations of cisplatin treatments showing a hormesis effects with a U-shape regulation. These results were highly consistent with many other toxico-proteomic studies, indicating that the toxico-proteomic responses based on dose-dependent protein responses were incongruent with the theoretically linear or hormetic concentration-effect relationship. Our findings suggested that a macroscopic hormesis phenomenon on the cell proliferation could not be reflected by proteomic responses induced by cisplatin treatments. PMID- 25528408 TI - Identification of titanium dioxide nanoparticles in food products: induce intracellular oxidative stress mediated by TNF and CYP1A genes in human lung fibroblast cells. AB - Food grade TiO2 (E171) is a synthetic additive, and widely used as a coloring agent in many foods, pharmaceutical and personal care products. A few reports have highlighted that insoluble particulates (less than 200nm) of food grade TiO2 are found in many foods and confectionary products. However, information regarding the physico-chemical properties (i.e., size and shape)-based food grade TiO2 nanotoxicity related human health issues are limited. The main goal of this study is to examine the presence of nano-sized particulates and its structural characteristics of food grade- TiO2 materials and to assess the acute cellular uptake and metabolic stress induced by these particulates in human lung fibroblast (WI-38) cells. The results of transmission electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction studies indicated that about food grade TiO2 sample contains spherical shaped particulate forms in the nano scale range, <100nm. The intracellular oxidative stress in human lung fibroblast cells (WI-38) was assessed through studies investigating the cellular uptake of the particles, changes in nuclear and cytoplasmic morphology, intracellular ROS, mitochondrial trans-membrane potential, the cell cycle and the expression of genes linked to metabolic stress markers. Altogether our data clearly indicate that primary metabolic stress indicators such as changes in the intracellular ROS, the dose-dependent loss of the mitochondrial membrane potential, alterations in cell cycle progression (G2/M>S>G0/G1) and changes in the TNF and CYP1A gene expression pattern are linked to cellular stress. Thus, food grade TiO2 as nano scaled contaminants could not only be potential human health risk factors, suggesting that safety considerations with special respect to a few crucial factors such as size, and shape should be considered and regulated by food regulators. PMID- 25528409 TI - The effect of catechol on human peripheral blood mononuclear cells (in vitro study). AB - Catechol also known as pyrocatechol or 1,2-dihydroxybenzene is formed endogenously in the organism from neurotransmitters including adrenaline, noradrenaline, and dopamine. It is also a metabolite of many drugs like DOPA, isoproterenol or aspirin and it is also formed in the environment during transformation of various xenobiotics. We evaluated in vitro the effect of catechol on the structure and function of human peripheral blood mononuclear cells (PBMCs). The cells were incubated with xenobiotic at concentration range from 2 to 500MUg/mL for 1h. Human blood mononuclear cells were obtained from leucocyte-platelet buffy coat taken from healthy donors in the Blood Bank of Lodz, Poland. Using flow cytometry we have evaluated necrotic, apoptotic and morphological changes in PBMCs incubated with catechol. Moreover, we have estimated changes in reactive oxygen species (ROS) formation, protein carbonylation and lipid peroxidation in the cells studied. The compound studied provoked necrotic (from 250MUg/mL), apoptotic (from 100MUg/mL), and morphological changes (from 250MUg/mL) in the incubated cells. We have also noted that catechol decreased H2DCF oxidation at 2 and 10MUg/mL but at higher concentrations of 250 and 500MUg/mL it caused statistically significant increase in the oxidation of this probe. We also observed an increase in lipid peroxidation (from 250MUg/mL) and protein carbonylation (from 50MUg/mL) of PBMCs. It was observed that catechol only at high concentrations was capable of inducing changes in PBMCs. The obtained results clearly showed that catechol may induce change in PBMCs only in the caste of poisoning with this compound. PMID- 25528410 TI - Toxic effects upon exposure to benzo[a]pyrene in juvenile white shrimp Litopenaeus vannamei. AB - The purpose of this study was to investigate the toxic effects induced by benzo[a]pyrene (BaP). In the present study, juvenile white shrimp Litopenaeus vannamei were exposed to BaP for 21 days at four different concentrations as 0, 0.03, 0.3 and 3MUg/L. Detoxification system parameters, transcription of metabolism-related genes, and damage indexes were investigated for screening. It showed mRNA expression levels of superoxide dismutase (SOD), cytochrome P450 (CYP) 1A1 and glutathione-S-transferase (GST) in hepatopancreas were significantly induced at day 3 by 0.3 and 3MUg/L BaP, and returned to the initial level afterwards. 7-Ethoxyresorufin O-deethylase (EROD), GST and SOD activities in gill and hepatopancreas were also induced by 0.3 and 3MUg/L BaP, while T-AOC and GSH contents were reduced after BaP exposure. The study also showed that 0.3 and 3MUg/L BaP caused damage effects, while 0.03MUg/L BaP treatment did not exhibit any damage effects. Moreover, according to the correlation analysis results, we conclude that EROD activity, GST activity and GSH content in hepatopancreas can be used as defense biomarkers; DNA strand breaks, lipid peroxidation (LPO) level and protein carbonyl (PC) content in gill and hepatopancreas can be used as damage biomarkers; EROD activity, GST activity, GSH contents and damage effects of DNA strand breaks, LPO level and PC content in hepatopancreas can be used as combined biomarkers. These results will provide information not only on potential biomarkers that could be effectively applied to biomonitor aquatic environment to contamination, but also provide information on toxic effects of this specie. PMID- 25528411 TI - Benchmark dose estimation of cadmium reference level for hypertension in a Chinese population. AB - Cadmium exposure can cause high blood pressure or hypertension. Benchmark dose has been used to estimate the reference point of cadmium for kidney and bone damage. In this study, we observed the association of blood pressure and cadmium in blood (BCd) and evaluated the reference level of cadmium for hypertension using benchmark dose (BMD) approach. A total of 441 subjects were included in this study. Blood samples were collected from each individual for BCd determination. Blood pressure was measured by electronic sphygmomanometer. BMD and BMDL were calculated using BMD software corresponding to additional risk of 10%. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of hypertension increased with the increasing of BCd, especially for SBP (chi(2)=3.9, p=0.047 in men; chi(2)=4.3, p=0.037 in women). With a benchmark response of 10%, the BMDL10 for hypertension (high SBP) was 0.95MUg/L and 1.02MUg/L for women and men, respectively; the BMDL10 for hypertension (high DBP) was 1.8MUg/L and 1.66MUg/L for women and men, respectively. Our data evidenced that BCd was associated with elevation in blood pressure and hypertension, especially for women. The reference level of cadmium for hypertension with high SBP was lower than that of high DBP. PMID- 25528412 TI - Antibiotics exposure and health risks: chloramphenicol. AB - The antibiotic chloramphenicol (CAP) is banned from food production. Besides being a medicinal product, CAP is also a natural product, produced by Streptomyces Venezuelae. The lack of scientific data hampers setting of an Acceptable Daily Intake (ADI). Consequently, a maximum residue limit (MRL) in food could not be established. This was then translated into a zero tolerance using the so-called Minimum Required Performance Limit (MRPL) level, viz. the achievable detection limit in food, to guide the zero tolerance policy. The MRPL is clearly not relevant to food safety and human health but is solely related to analytical technological capabilities. The increase in the latter enables detection at ever-lower levels and ignores toxicological relevance. We here provide arguments to use a Threshold of Toxicological Concern (TTC) for CAP that can accommodate developing toxicological insights. PMID- 25528413 TI - Effects of selenium on lead-induced alterations in Abeta production and Bcl-2 family proteins. AB - Previous studies in humans and animals have suggested that lead (Pb) may increase the expression of amyloid precursor protein (APP) and accumulation of amyloid beta protein (Abeta). Our previous studies have revealed that selenium (Se) can partially improve memory deficits induced by Pb exposure. In this study we sought to investigate the effect of Pb and Se on the endogenous expression of APP, Abeta40 and Bcl-2 family proteins. In vitro, the protein levels of APP and Abeta significantly decreased in SH-SY5Y and PC12 cells co-incubated with Pb-acetate and selenomethionine (SeMet) for 48h, compared with cells treated with Pb-acetate alone. Furthermore, these reductions induced by Se appeared to be concentration dependent. In Wistar rats, we observed that the mRNA and protein levels of APP, the protein level of Bax, and the ratio of Bax/Bcl-2 protein significantly increased after Pb treatment at embryonic stage and in neonates. These increases were significantly reversed by the treatment of Se. Taken together, our results suggest that Se can attenuate the alterations in APP expression and Abeta production as well as Bcl-2 family proteins induced by lead exposure in cells and in animals. PMID- 25528414 TI - Hepatic oxidative stress and inflammatory responses with cadmium exposure in male mice. AB - Cadmium (Cd), a non-essential heavy metal, is one of the major environmental contaminants with grave toxicological consequences globally. In the present study, the effects of Cd on hepatic oxidative stress and inflammatory responses in mice were evaluated. Male adult mice were orally exposed to 3, 10 and 30mg/L CdCl2 supplied in the drinking water for 7 and 21 days. Histopathological changes and the alterations of the main parameters related to oxidative stress and inflammatory responses in the liver were observed. Hepatic malondialdehyde (MDA) contents increased significantly after treatment with 30mg/L CdCl2 for 21 days, and the contents of glutathione (GSH) increased significantly in both 10 and 30mg/L CdCl2 treated groups. The hepatic activities of glutathione peroxidase (GPX), catalase (CAT) and glutathione S-transferase (GST) increased significantly after the treatment with 30mg/L CdCl2 for 21 days. In accordance with the enzyme activities, the transcription status of hepatic superoxide dismutase 1 (Sod1), superoxide dismutase 2 (Sod2), Cat, Gpx, Gstalpha1, glutathione synthetase (Gss), glutathione reductase (Gr) and heme oxygenase 1 (Ho1) were also increased by high dose (30mg/L) or long period (21 days) exposure. In addition, the serum levels of tumor necrosis factor alpha (TNFalpha), interleukin 6 (IL6) and interleukin 1beta (IL1beta) increased significantly in the groups treated with 30mg/L CdCl2 for 21 days. And the genes of TNFalpha, IL6, interleukin 1alpha (IL1alpha), inducible nitric oxide synthase (iNOS) and interferon gamma (IFNgamma) were also increased in the liver of mice when exposed to relative high dose of CdCl2 for 7 or 21 days. Taken together, the results of this study suggested that the exposure to Cd had the potential to induce immunotoxicity accompanied with oxidative stress in the liver of mice. PMID- 25528415 TI - Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception. AB - OBJECTIVES: To further evaluate the effect of weight and body mass index (BMI) on the efficacy of levonorgestrel emergency contraception. METHODS: Data from two large, multicenter, randomized controlled trials designed to assess emergency contraceptive efficacy were pooled to evaluate the effect of weight and BMI on pregnancy rates among women who received levonorgestrel. Descriptive methods (comparison of means and distributions according to pregnancy status and pregnancy rates across weight and BMI categories) as well as cubic spline modeling were used to describe the relationship between pregnancy risk and weight/BMI. RESULTS: The analysis population comprised 1731 women, among whom 38 pregnancies were reported. Women for whom levonorgestrel was not effective in preventing pregnancy had a significantly higher mean body weight and BMI than women who did not become pregnant (76.7 vs. 66.4 kg, p<.0001; 28.1 vs. 24.6 kg/m2, p<.0001). The estimated pregnancy rate increased significantly from 1.4% [95% confidence interval (CI): 0.5%-3.0%] among the group of women weighing 65-75 kg to 6.4% (95% CI: 3.1%-11.5%) and 5.7% (95% CI: 2.9%-10.0%) in the 75-85 kg and >85 kg groups, respectively. Statistical modeling demonstrated a steep increase in pregnancy risk starting from a weight near 70-75 kg to reach a risk of pregnancy of 6% or greater around 80 kg. Similar results were obtained for statistical modeling of BMI as well as when the two studies were analyzed individually. CONCLUSIONS: All analyses showed a significant drop in the efficacy of levonorgestrel emergency contraception with increasing body weight, with pregnancy risk in the higher weight categories similar to expected rates in the absence of contraception. Like body weight, increasing BMI was highly correlated with increased pregnancy risk. PMID- 25528416 TI - Repertoire of virus-derived small RNAs produced by mosquito and mammalian cells in response to dengue virus infection. AB - RNA interference (RNAi) is the major defense of many arthropods against arthropod borne RNA viruses (arboviruses), but the role of RNAi in vertebrate immunity to arboviruses is not clear. RNA viruses can trigger RNAi in vertebrate cells, but the vertebrate interferon response may obscure this interaction. We quantified virus-derived small RNAs (vRNAs) generated by mosquito (U4.4) cells and interferon-deficient (Vero) and interferon-competent (HuH-7) mammalian cells infected with a single isolate of mosquito-borne dengue virus. Mosquito cells produced significantly more vRNAs than mammalian cells, and mosquito cell vRNAs were derived from both the positive- and negative-sense dengue genomes whereas mammalian cell vRNAs were derived primarily from positive-sense genome. Mosquito cell vRNAs were predominantly 21 nucleotides in length whereas mammalian cell vRNAs were between 12 and 36 nucleotides with a modest peak at 24 nucleotides. Hot-spots, regions of the virus genome that generated a disproportionate number of vRNAs, overlapped among the cell lines. PMID- 25528418 TI - Electroencephalography and externalizing behavior: a meta-analysis. AB - Electroencephalography (EEG) has been used to examine the possibility of dysfunctional brain activity in externalizing behavior, but findings across studies have been inconsistent. Furthermore, studies of attention deficit/hyperactivity disorder (ADHD) versus other externalizing behaviors, such as disruptive behavior disorders or antisocial behavior, have developed parallel literatures. The purpose of the present study was to reconcile these two literatures. A meta-analysis of 62 studies of EEG power at rest in relationship to externalizing behaviors was performed. Results of the meta-analyses showed significantly higher delta (Hedges's g=0.25) and theta power (g=0.40) and lower beta power (g=-0.22) in externalizing participants compared to controls. Alpha (g=-0.26) and gamma power (g=-0.26) were marginally lower in externalizing samples. Results were not moderated by type of externalizing behavior. Overall, the results of the meta-analyses were consistent with the hypoarousal theory of externalizing behavior. PMID- 25528417 TI - Structures of minute virus of mice replication initiator protein N-terminal domain: Insights into DNA nicking and origin binding. AB - Members of the Parvoviridae family all encode a non-structural protein 1 (NS1) that directs replication of single-stranded viral DNA, packages viral DNA into capsid, and serves as a potent transcriptional activator. Here we report the X ray structure of the minute virus of mice (MVM) NS1 N-terminal domain at 1.45A resolution, showing that sites for dsDNA binding, ssDNA binding and cleavage, nuclear localization, and other functions are integrated on a canonical fold of the histidine-hydrophobic-histidine superfamily of nucleases, including elements specific for this Protoparvovirus but distinct from its Bocaparvovirus or Dependoparvovirus orthologs. High resolution structural analysis reveals a nickase active site with an architecture that allows highly versatile metal ligand binding. The structures support a unified mechanism of replication origin recognition for homotelomeric and heterotelomeric parvoviruses, mediated by a basic-residue-rich hairpin and an adjacent helix in the initiator proteins and by tandem tetranucleotide motifs in the replication origins. PMID- 25528419 TI - Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. AB - BACKGROUND: Cesarean delivery is one of the most common surgical procedures performed by obstetricians. Infectious morbidity after cesarean delivery can have a tremendous impact on the postpartum woman's return to normal function and her ability to care for her baby. Despite the widespread use of prophylactic antibiotics, postoperative infectious morbidity still complicates cesarean deliveries. OBJECTIVES: To determine if cleansing the vagina with an antiseptic solution before a cesarean delivery decreases the risk of maternal infectious morbidities, including endometritis and wound complications. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 December 2014). SELECTION CRITERIA: We included randomized and quasi-randomized trials assessing the impact of vaginal cleansing immediately before cesarean delivery with any type of antiseptic solution versus a placebo solution/standard of care on post-cesarean infectious morbidity. DATA COLLECTION AND ANALYSIS: We independently assessed eligibility and quality of the studies. MAIN RESULTS: Seven trials randomizing 2816 women (2635 analyzed) evaluated the effects of vaginal cleansing (all with povidone-iodine) on post-cesarean infectious morbidity. The risk of bias was generally low, with the quality of most of the studies being high. Vaginal preparation immediately before cesarean delivery significantly reduced the incidence of post-cesarean endometritis from 8.3% in control groups to 4.3% in vaginal cleansing groups (average risk ratio (RR) 0.45, 95% confidence interval (CI) 0.25 to 0.81, seven trials, 2635 women). The risk reduction was particularly strong for women who were already in labor at the time of the cesarean delivery (7.4% in the vaginal cleansing group versus 13.0% in the control group; RR 0.56, 95% CI 0.34 to 0.95, three trials, 523 women) and for women with ruptured membranes (4.3% in the vaginal cleansing group versus 17.9% in the control group; RR 0.24, 95% CI 0.10 to 0.55, three trials, 272 women). No other outcomes realized statistically significant differences between the vaginal cleansing and control groups. No adverse effects were reported with the povidone iodine vaginal cleansing.The quality of the evidence using GRADE was low for post cesarean endometritis, moderate for postoperative fever, and low for wound infection. AUTHORS' CONCLUSIONS: Vaginal preparation with povidone-iodine solution immediately before cesarean delivery reduces the risk of postoperative endometritis. This benefit is particularly realized for women undergoing cesarean delivery, who are already in labor or who have ruptured membranes. As a simple, generally inexpensive intervention, providers should consider implementing preoperative vaginal cleansing with povidone-iodine before performing cesarean deliveries. PMID- 25528420 TI - Contrasting metal detoxification in polychaetes, bivalves and fish from a contaminated bay. AB - Jinzhou Bay in Bohai, Northern China, is historically contaminated with metals, but the organisms living in such contaminated environments are much less well studied. In this study, we contrasted the different subcellular and detoxification responses of polychaetes, bivalves and fish collected from different contaminated sites in Jinzhou Bay. In polychaete Neanthes japonica, metal-rich granule (MRG) was the main biologically detoxified metal compartment, and metallothionein-like protein (MTLP) detoxified a relatively smaller fraction of accumulated metals. The importance of MRG increased whereas that of MTLP decreased with increasing metal bioaccumulation. Detoxification in the two bivalves was similar to that in the polychaetes. However, the MRG appeared to play only a minor role in metal binding and detoxification in the gills and livers of fish, whereas MTLP was the dominating detoxification pool. Cellular debris was an important pool binding with metals in the three marine animals. Our study highlighted the contrasting cellular binding and detoxification among different marine organisms living in contaminated environments. PMID- 25528421 TI - (1)H NMR based metabolomics approach to study the toxic effects of herbicide butachlor on goldfish (Carassius auratus). AB - Butachlor, one of the most widely used herbicides in agriculture, has been reported with high ecotoxicity to aquatic plants and animals. In this study, a (1)H NMR based metabolomics approach combined with histopathological examination and biochemical assays was applied to comprehensively investigate the toxic effects of butachlor on four important organs (gill, brain, liver and kidney) of goldfish (Carassius auratus) for the first time. After 10 days' butachlor exposure at two dosages of 3.2 and 0.64 MUmol/L, fish tissues (gill, brain, liver and kidney) and serum were collected. Histopathological inspection revealed severe impairment of gill filaments and obvious cellular edema in livers and kidneys. The increase of glutathione peroxidase (GSH-Px) activity in gill and methane dicarboxylic aldehyde (MDA) level in four tissues reflected the disturbance of antioxidative system in the intoxicated goldfish. Serum lactate dehydrogenase (LDH) activity and creatinine (CRE) level were increased in butachlor exposure groups, suggesting liver and kidney injuries induced by butachlor. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of NMR profiles disclosed metabolic changes that were related to the toxic effects of butachlor including oxidative stress, disorder of energy metabolism and amino acids metabolism, and disturbance of neurotransmitter balance in butachlor exposed goldfish. This integrated metabolomics approach provided a molecular basis underlying the toxicity of butachlor and demonstrated that metabolomics was a powerful and highly effective approach to elucidate the toxicity and underlying mechanisms of herbicides and pesticides, applicable for their risk assessment. PMID- 25528422 TI - Quantitative structure-activity relationships for chronic toxicity of alkyl chrysenes and alkyl-benz[a]anthracenes to Japanese medaka embryos (Oryzias latipes). AB - Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are a class of compounds found at significant concentrations in crude oils, and likely the main constituents responsible for the chronic toxicity of oil to fish. Alkyl substituents at different locations on the aromatic rings change the size and shape of PAH molecules, which results in different interactions with tissue receptors and different severities of toxicity. The present study is the first to report the toxicity of several alkylated derivatives of chrysene and benz[a]anthracene to the embryos of Japanese medaka (Oryzias latipes) using the partition controlled delivery (PCD) method of exposure. The PCD method maintained the desired exposure concentrations by equilibrium partitioning of hydrophobic test compounds from polydimethylsiloxane (PDMS) films. Test concentrations declined by only 13% over a period of 17 days. Based on the prevalence of signs of blue sac disease (BSD), as expressed by median effective concentrations (EC50s), benz[a]anthracene (B[a]A) was more toxic than chrysene. Alkylation generally increased toxicity, except at position 2 of B[a]A. Alkyl-PAHs substituted in the middle region had a lower EC50 than those substituted at the distal region. Except for B[a]A and 7-methylbenz[a]anthracene (7-MB), estimated EC50 values were higher than their solubility limits, which resulted in limited toxicity within the range of test concentrations. The regression between log EC50s and logKow values provided a rough estimation of structure-activity relationships for alkyl-PAHs, but Kow alone did not provide a complete explanation of the chronic toxicity of alkyl PAHs. PMID- 25528423 TI - Taming the great: enhanced syphilis screening in HIV-positive men who have sex with men in a hospital clinic setting. AB - Syphilis incidence in HIV-positive men who have sex with men (MSM) continues to increase, with strategies based on early detection and treatment urgently required to control rising infections. There are barriers to enhanced testing in certain settings. At our tertiary referral HIV centre, testing rates before and after a period of enhanced syphilis testing in HIV-positive MSM were assessed. When compared with the control period (pre-enhanced screening), the enhanced syphilis testing was associated with a significant increase in syphilis testing of HIV-positive patients undergoing routine viral load testing (136 out of 574, 23% vs 317 out of 574, 55%; P<0.0001) and a three-fold increase in new syphilis diagnoses (4 out of 574 vs 18 out of 574, P=0.004). PMID- 25528425 TI - Statin therapy and cardiovascular outcomes after coronary revascularization in the elderly. PMID- 25528424 TI - Dietary predictors of arterial stiffness in a cohort with type 1 and type 2 diabetes. AB - OBJECTIVE: To determine the dietary predictors of central blood pressure, augmentation index and pulse wave velocity (PWV) in subjects with type 1 and type 2 diabetes. METHODS: Participants were diagnosed with type 1 or type 2 diabetes and had PWV and/or pulse wave analysis performed. Dietary intake was measured using the Dietary Questionnaire for Epidemiological Studies Version 2 Food Frequency Questionnaire. Serum lipid species and carotenoids were measured, using liquid chromatography electrospray ionization-tandem mass spectrometry and high performance liquid chromatography, as biomarkers of dairy and vegetable intake, respectively. Associations were determined using linear regression adjusted for potential confounders. RESULTS: PWV (n = 95) was inversely associated with reduced fat dairy intake (beta = -0.01; 95% CI -0.02, -0.01; p = 0 < 0.05) in particular yoghurt consumption (beta = -0.04; 95% CI -0.09, -0.01; p = 0 < 0.05) after multivariate adjustment. Total vegetable consumption was negatively associated with PWV in the whole cohort after full adjustment (beta = -0.04; 95% CI -0.07, -0.01; p < 0.05). Individual lipid species, particularly those containing 14:0, 15:0, 16:0, 17:0 and 17:1 fatty acids, known to be of ruminant origin, in lysophosphatidylcholine, cholesterol ester, diacylglycerol, phosphatidylcholine, sphingomyelin and triacylglycerol classes were positively associated with intake of full fat dairy, after adjustment for multiple comparisons. However, there was no association between serum lipid species and PWV. There were no dietary predictors of central blood pressure or augmentation index after multivariate adjustment. CONCLUSION: In this cohort of subjects with diabetes reduced fat dairy intake and vegetable consumption were inversely associated with PWV. The lack of a relationship between serum lipid species and PWV suggests that the fatty acid composition of dairy may not explain the beneficial effect. PMID- 25528426 TI - Increased ambulatory arterial stiffness index in obese children. AB - OBJECTIVE: Altered arterial stiffness is a recognized risk factor of poor cardiovascular health. Ambulatory arterial stiffness index (AASI, defined as one minus the regression slope of diastolic on systolic blood pressure values derived from a 24 h arterial blood pressure monitoring, ABPM) is an upcoming and readily available marker of arterial stiffness. Our hypothesis was that AASI is increased in obese children compared to age- and gender matched healthy subjects. METHODS: AASI was calculated from ABPM in 101 obese children (BMI >= 1.88 SDS according to age- and sex-specific BMI charts), 45% girls, median BMI SDS 2.8 (interquartile range (IQR) 2.5-3.4), median age 11.5 years (9.1-13.4) and compared with an age and gender matched healthy control group of 71 subjects with median BMI SDS 0.0 ( 0.8-0.5). Multivariate regression analysis was applied to identify significant independent factors explaining AASI variability in this population. RESULTS: AASI was significantly higher in obese children compared to controls (0.388 (0.254 0.499) versus 0.190 (0.070-0.320), p < 0.0001), but blood pressure values were similar. In a multivariate analysis including obese children only, AASI was independently predicted by 24-h systolic blood pressure SDS (p = 0.012); in a multivariate analysis including obese children and controls BMI SDS and pulse pressure independently influenced AASI (p < 0.001). CONCLUSIONS: This study shows that AASI, a surrogate marker of arterial stiffness, is increased in obese children. AASI seems to be influenced by BMI and pulse pressure independently of systolic and diastolic blood pressure values, suggesting that other factors are involved in increased arterial stiffness in obese children. PMID- 25528427 TI - Reactive aldehyde-scavenging enzyme activities in atherosclerotic plaques of cigarette smokers and nonsmokers. AB - OBJECTIVE: To investigate enzymatic reactive aldehyde-scavenging enzyme capacity together with lipid peroxidation as expression of oxidative stress in atherosclerotic plaques of cigarette smokers and nonsmokers. METHODS: We have assessed specific enzymatic activities of class 1, 2, and 3 aldehyde dehydrogenase (ALDH1, ALDH2, and ALDH3, respectively), glutathione S-transferase (isozyme A4-4, GSTA4-4), and aldose reductase (AR), namely the major reactive aldehyde-scavenging enzymes, together with lipid peroxidation, i.e., fluorescent damage products of lipid peroxidation (FDPL), in carotid atherosclerotic plaques surgically removed from 17 cigarette smokers and 17 nonsmokers. RESULTS: The enzymatic activities of ALDH1 plus ALDH2, ALDH3, GSTA4-4, and AR were significantly lower in the atherosclerotic plaques of smokers than in those of nonsmokers, while plaque FDPL levels were significantly higher in the smokers than in the nonsmokers. The amount of cigarette smoking was correlated inversely with the aforementioned plaque enzymatic activities and directly with plaque FDPL content. Plaque FDPL levels were inversely correlated with plaque enzymatic activities in smokers and nonsmokers. The degree of carotid atherosclerotic stenosis, as expression of atherosclerosis severity, was correlated inversely with plaque enzymatic activities and directly with plaque FDPL levels in smokers and nonsmokers; moreover, the degree of carotid stenosis was directly correlated with the amount of cigarette smoking. CONCLUSION: atherosclerotic lesions of cigarette smokers are endowed with a depressed enzymatic reactive aldehyde scavenging capacity eventually favoring oxidative stress and the severity of atherosclerosis. PMID- 25528428 TI - Proteomic identification of differentially expressed proteins in vascular wall of patients with ruptured intracranial aneurysms. AB - OBJECTIVE: Intracranial aneurysms (IA) are serious cerebral vascular abnormalities, however, little is known about the mechanisms underlying IA formation, progression and rupture. Therefore, this study aimed to assess protein expression specific to the vascular tissues of IA patients. METHODS: IA samples were intraoperatively collected from 14 patients after microneurosurgical clipping and pooled. Matched superficial temporal artery (STA) tissues collected from the same patients were used as controls. Differentially expressed proteins were identified using isobaric tags for relative and absolute quantification (iTRAQ) and two-dimensional liquid chromatography-tandem mass spectrometry (2D LC MS/MS), validated by immunoblot. RESULTS: 816 proteins were found to be differently expressed in IA and healthy tissues. The expression level of 162 proteins differed by at least two fold. Expression of 80 proteins was up regulated and expression of 82 was down-regulated. According to PANTHER, these proteins were involved in immune responses, cell adhesion, cellular component organization and developmental processes. Azurocidin-1 (AZU1, a known antimicrobial) and Transmembrane 9 superfamily member 1 (TM9SF1, a novel autophagy-related protein) were 8.0 and 8.6 fold up-regulated, respectively, in IA, while Sorbin and SH3 domain-containing protein 2 (SORBS2), involved in signaling complex assembly, was 12.1 fold down-regulated. CONCLUSION: These findings suggest that IA formation and rupture might be related to autophagy and immune responses, which possibly accounts for proteolytic degradation of vessel wall connective tissues and cytoskeleton components. PMID- 25528429 TI - Subclinical carotid atherosclerosis and triglycerides predict the incidence of chronic kidney disease in the Japanese general population: results from the Kyushu and Okinawa Population Study (KOPS). AB - OBJECTIVE: To examine whether or not subclinical atherosclerosis independently predicts the incidence of chronic kidney disease (CKD) in the Japanese general population. METHODS: This study is part of the Kyushu and Okinawa Population Study (KOPS), a survey of vascular events associated with lifestyle-related diseases. Participants who attended both baseline (2004-2007) and follow-up (2009 2012) examinations were eligible. The common carotid intima-media thickness (IMT) was assessed for each participant at baseline. The end point was the incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) during the follow-up of participants without CKD at baseline. RESULTS: During the five-year follow-up, 224 of the 1824 participants (12.3%) who developed CKD had higher carotid IMT (0.74 +/- 0.22 vs. 0.65 +/- 0.14 mm, P < 0.001), higher triglycerides (1.6 +/- 0.8 vs. 1.3 +/- 0.7 mmol/L, P < 0.001), and lower high density lipoprotein cholesterol (1.5 +/- 0.4 vs. 1.6 +/- 0.4 mmol/L, P < 0.001) at baseline than those who did not. In logistic regression analysis adjusted for significant covariates, eGFR (Odds ratio [OR] 0.83, 95% confidence interval (CI) 0.80-0.85, P < 0.001), carotid IMT (0.10 mm increase: OR 1.17, 95% CI 1.04-1.33, P = 0.010), and triglycerides (OR 1.35, 95% CI 1.06-1.73, P = 0.015) at baseline were independent predictors for the development of CKD. CONCLUSIONS: Higher carotid IMT and hypertriglyceridemia were independently associated with the development of CKD in the population studied. PMID- 25528430 TI - Remarkable quantitative and qualitative differences in HDL after niacin or fenofibrate therapy in type 2 diabetic patients. AB - HDL-increasing drugs such as fenofibrate and niacin have failed to decrease the cardiovascular risk in patients with type 2 diabetes. Drug-mediated quantitative and qualitative HDL modifications could be involved in these negative results. To evaluate the quantitative and qualitative effects of niacin and fenofibrate on HDL in patients with type 2 diabetes, a prospective, randomised controlled intervention trial was conducted. Thirty type 2 diabetic patients with low HDL were randomised to receive either fenofibrate (FFB) or niacin + laropiprant (ERN/LPR) as an add-on to simvastatin treatment for 12 weeks according to a crossover design. At the basal point and after each intervention period, physical examinations and comprehensive standard biochemical determinations and HDL metabolomics were performed. Thirty nondiabetic patients with normal HDL were used as a basal control group. ERN/LRP, but not FFB, significantly increased HDL cholesterol. Neither ERN/LRP nor FFB reversed the HDL particle size or particle number to normal. ERN/LRP increased apoA-I but not apoA-II, whereas FFB produced the opposite effect. FFB significantly increased Prebeta1-HDL, whereas ERN/LRP tended to lower Prebeta1-HDL. CETP and LCAT activities were significantly decreased only by ERN/LRP. PAF-AH activity in HDL and plasma decreased with the use of both agents. Despite their different actions on antioxidant parameters, none of the treatments induced detectable antioxidant improvements. ERN/LRP and FFB had strikingly different effects on HDL quantity and quality, as well as on HDL cholesterol concentrations. When prescribing HDL cholesterol increasing drugs, this differential action should be considered. PMID- 25528431 TI - The dark and bright side of atherosclerotic calcification. AB - Vascular calcification is an unfavorable event in the natural history of atherosclerosis that predicts cardiovascular morbidity and mortality. However, increasing evidence suggests that different calcification patterns are associated with different or even opposite histopathological and clinical features, reflecting the dual relationship between inflammation and calcification. In fact, initial calcium deposition in response to pro-inflammatory stimuli results in the formation of spotty or granular calcification ("microcalcification"), which induces further inflammation. This vicious cycle favors plaque rupture, unless an adaptive response prevails, with blunting of inflammation and survival of vascular smooth muscle cells (VSMCs). VSMCs promote fibrosis and also undergo osteogenic transdifferentiation, with formation of homogeneous or sheet-like calcification ("macrocalcification"), that stabilizes the plaque by serving as a barrier towards inflammation. Unfortunately, little is known about the molecular mechanisms regulating this adaptive response. The advanced glycation/lipoxidation endproducts (AGEs/ALEs) have been shown to promote vascular calcification and atherosclerosis. Recent evidence suggests that two AGE/ALE receptors, RAGE and galectin-3, modulate in divergent ways, not only inflammation, but also vascular osteogenesis, by favoring "microcalcification" and "macrocalcification", respectively. Galectin-3 seems essential for VSMC transdifferentiation into osteoblast-like cells via direct modulation of the WNT-beta-catenin signaling, thus driving formation of "macrocalcification", whereas RAGE favors deposition of "microcalcification" by promoting and perpetuating inflammation and by counteracting the osteoblastogenic effect of galectin-3. Further studies are required to understand the molecular mechanisms regulating transition from "microcalcification" to "macrocalcification", thus allowing to design therapeutic strategies which favor this adaptive process, in order to limit the adverse effects of established atherosclerotic calcification. PMID- 25528433 TI - Determinants of the components of arterial pressure among older adults--the role of anthropometric and clinical factors: a multi-continent study. AB - OBJECTIVE: The aim of this study was to evaluate the factors associated with different components of arterial blood pressure in nine nationally-representative samples of people aged >=50 years. METHODS: Data were available for 53,289 people aged >=18 years who participated in the SAGE (WHO Study on global AGEing and adult health) study conducted in China, Ghana, India, Mexico, Russia, and South Africa, and the COURAGE (Collaborative Research on Ageing in Europe) study conducted in Finland, Poland, and Spain, between 2007 and 2012. Standard procedures were used to obtain diastolic and systolic blood pressure (DBP, SBP) measurements to identify hypertensive participants, and to determine mean arterial blood pressure (MAP) and pulse pressure (PP). RESULTS: The analytical sample consisted of 42,116 people aged 50 years or older. South Africa had the highest prevalence of hypertension (78.3%), and the highest measurements of MAP +/- SD (113.6 +/- 36.4 mmHg), SBP +/- SD (146.4 +/- 49.5 mmHg), and DBP +/- SD (97.2 +/- 33.9 mmHg). In the adjusted models, dose-dependent positive associations between Body Mass Index (BMI) and MAP or PP were observed in most countries (p < 0.05). Diabetes was positively associated with PP in most countries but the association between diabetes and MAP was less consistent. Stroke was associated with both higher MAP and PP in China, Ghana, and South Africa (p < 0.05). CONCLUSIONS: Obesity and diabetes remain important modifiable risk factors for arterial peripheral resistance and stiffness as reflected by MAP and PP respectively. Controlling arterial pressure abnormalities after stroke events may be important for secondary prevention, particularly in developing countries. PMID- 25528432 TI - High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans. AB - Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets: 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p = 0.0005 and p = 0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p = 0.0243) and DHA-enriched high oleic canola oil (p = 0.0249), although high-oleic canola oil had the lowest binding at baseline (p = 0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding. PMID- 25528434 TI - Low concentrations of phospholipids and plasma HDL cholesterol subclasses in asymptomatic subjects with high coronary calcium scores. AB - OBJECTIVE: To determine whether HDL size distribution and HDL subclasses are associated with coronary calcium scores. METHODS: We screened 677 apparently healthy individuals by coronary tomography. One hundred twenty subjects were then recruited for the study and grouped by coronary artery calcification scores (CAC). Forty asymptomatic patients with atherosclerosis with CAC scores >=75th percentile for gender and age were placed in the first group. Forty patients with CAC scores <=25th percentile and 40 matched controls (CAC = 0) made up the two remaining groups. HDL samples were separated via sequential ultracentrifugation, followed by electrophoresis: they were then enzymatically stained and densitometrically analyzed to determine the triglycerides (Tg), phospholipids (Ph), and plasma cholesterol (C) concentrations corresponding to each HDL subclass. RESULTS: HDL size distribution, lipid and non-lipid risk factors for atherosclerosis were similar among the three groups: HDL-cholesterol and HDL phospholipids were significantly lower in the CAC >=75th percentile group, whereas HDL-lipids in the CAC <=25th group were comparable to the controls. HDL2b and HDL2a-cholesterol were decreased, whereas phospholipids were lower in patients constituting 4 of the 5 HDL subclasses. The Ph-to-Tg ratios of small HDL were higher in both experimental groups compared with the controls, suggesting that these lipoproteins had abnormal structures. In spite of the significant differences between the high-CAC score subjects and the controls, statistical analyses demonstrated no substantial relationship between CAC scores and HDL parameters: other lipid and non-lipid risk factors for atherosclerosis were not statistically linked to CAC scores. Only male gender and age contributed to CAC scores in our study population. CONCLUSIONS: Our results suggest that CAC scores and traditional lipid profiles are independent aspects of atherosclerosis and that only lipids may be biomarkers of coronary calcification during the asymptomatic stages of the disease; however, HDL subclasses do not contribute to CAC scores. PMID- 25528435 TI - Sex differences on prefrontally-dependent cognitive tasks. AB - There is preliminary evidence to suggest that the prefrontal cortex (PFC) is modulated by sex steroids in humans and other primates. The current study examined whether sex differences in performance could be discerned on two working memory tasks that emphasize monitoring and updating processes, and on two tasks that engage the ventromedial PFC/orbitofrontal cortex (VMPFC/OFC). Healthy young adults (48 females; 45 males) completed the n-back, Self-Ordered Pointing (SOP), Iowa Gambling Task (IGT), and a probabilistic reversal learning task. On the IGT, males selected more cards from the advantageous decks than females. On the reversal learning task, there was no significant sex difference in acquisition of the reinforcement contingencies, but males made fewer errors than females during the reversal phase. The sexes did not differ significantly on the n-back or SOP tasks. These findings provide tentative support for the hypothesis that functions carried out by the VMPFC/OFC are sexually differentiated in humans. PMID- 25528437 TI - Gait and reach-to-grasp movements are mutually modified when performed simultaneously. AB - Typically, prehension and gait behaviors are studied separately. However, little is known about what changes occur in these motor skills when they are combined. We investigated and characterized motor performance during combined walking and prehension at different levels of difficulty of the prehension task. Fifteen right-handed young adults were invited to walk at their self-selected pace and grasp a dowel as they walked. They also grasped the dowel in a stationary condition (upright stance). We combined conditions with/without obstacles and stable/unstable base for dowel prehension. Modifications in gait and prehension were identified when they were combined, especially for the most difficult prehension conditions. The grasping task caused an adaptation in gait because the participants preferred to adopt a more conservative strategy of increasing their dynamic stability during the approach phase and when grasping the dowel. Walking changed the prehension movement by reducing the reaching movement time, peak wrist velocity, and peak grip aperture velocity. In addition, the peak grip aperture was affected by the presence of obstacles close to the dowel. The participants adjusted their gait during the approach phase to facilitate dowel prehension, and they controlled the hand position online to adjust its configuration based on the prehension conditions. PMID- 25528438 TI - Safety effects of traffic signing for left turn flashing yellow arrow signals. AB - In 2010, the left turn flashing yellow arrow (FYA) signal displays were installed at signalized intersections on state routes in the Peoria, Illinois, area. Supplemental traffic signs with text "Left Turn Yield on Flashing Yellow Arrow" were mounted on the mast arm adjacent to the left turn signal at over half of the FYA installations. The purpose of this paper is to present the results of the effectiveness evaluation of the FYA supplemental sign on safety. Analyses are presented on the effects of the FYA supplemental sign for all drivers and a subset of drivers age 65 and older. A crash-based comparison of 164 FYA approaches including 90 approaches with the sign and 74 approaches without the sign showed greater crash reductions when the supplemental FYA sign was present. The results also showed that crashes involving drivers age 65 and older did not experience the same magnitudes of crash reductions as compared to all drivers. The findings of this research indicate that supplemental FYA signs may help in improving safety for left-turning vehicles during the permissive interval. Thus, it is recommended that supplemental signs be used when initially implementing the FYA, and that effort to educate the driving public on new traffic control be made to further improve safety at signalized intersections. PMID- 25528436 TI - Separability of abstract-category and specific-exemplar visual object subsystems: evidence from fMRI pattern analysis. AB - Previous research indicates that dissociable neural subsystems underlie abstract category (AC) recognition and priming of objects (e.g., cat, piano) and specific exemplar (SE) recognition and priming of objects (e.g., a calico cat, a different calico cat, a grand piano, etc.). However, the degree of separability between these subsystems is not known, despite the importance of this issue for assessing relevant theories. Visual object representations are widely distributed in visual cortex, thus a multivariate pattern analysis (MVPA) approach to analyzing functional magnetic resonance imaging (fMRI) data may be critical for assessing the separability of different kinds of visual object processing. Here we examined the neural representations of visual object categories and visual object exemplars using multi-voxel pattern analyses of brain activity elicited in visual object processing areas during a repetition-priming task. In the encoding phase, participants viewed visual objects and the printed names of other objects. In the subsequent test phase, participants identified objects that were either same exemplar primed, different-exemplar primed, word-primed, or unprimed. In visual object processing areas, classifiers were trained to distinguish same-exemplar primed objects from word-primed objects. Then, the abilities of these classifiers to discriminate different-exemplar primed objects and word-primed objects (reflecting AC priming) and to discriminate same-exemplar primed objects and different-exemplar primed objects (reflecting SE priming) was assessed. Results indicated that (a) repetition priming in occipital-temporal regions is organized asymmetrically, such that AC priming is more prevalent in the left hemisphere and SE priming is more prevalent in the right hemisphere, and (b) AC and SE subsystems are weakly modular, not strongly modular or unified. PMID- 25528439 TI - Injuries related to off-road vehicles in Canada. AB - Off-road vehicles (ORVs; this includes snowmobiles, all-terrain vehicles or ATVs and dirt bikes) were once used primarily for work and travel. Such use remains common in Canada, although their recreational use has also gained popularity in recent years. An epidemiological injury profile of ORV users is important for better understanding injuries and their risk factors to help inform injury prevention initiatives. The Traffic Injury Research Foundation (TIRF) partnered with the Public Health Agency of Canada (PHAC) to analyze the epidemiology of ORV related injuries. The primary aim was to assess crashes and injuries in Canada, including the extent of alcohol involvement. Secondly, the burden of injury among children and teen ORV drivers in Canada, as well as passengers, was investigated. Descriptive and inferential epidemiological statistics were generated using the following data sources: first, TIRF's National Fatality Database, which is a comprehensive, pan-Canadian, set of core data on all fatal motor vehicle crashes; second, TIRF's Serious Injury Database, which contains information on persons seriously injured in crashes; and, third, PHAC's Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP), a surveillance system currently operating in the emergency departments of some pediatric and general hospitals across Canada. Exposure data have been used in the analyzes where available. Between 1990 and 2010, fatality rates increased among ATV and dirt bike operators. The fatality rate among snowmobilers declined during this period. Of particular concern, among fatally injured female ATV users, children aged 0-15 years comprised the highest proportion of any age group at 33.8%. Regarding alcohol use, among fatally injured snowmobile and ATV/dirt bike operators tested for alcohol, 66% and 55% tested positive, respectively. Alcohol involvement in adult ORV crashes remains an important factor. In light of the growing popularity of ORVs, prevention and mitigation measures are required to address this issue. PMID- 25528440 TI - Marek's disease virus-encoded analog of microRNA-155 activates the oncogene c-Myc by targeting LTBP1 and suppressing the TGF-beta signaling pathway. AB - Marek's disease virus (MDV) is a representative alpha herpes virus able to induce rapid-onset T-cell lymphoma in its natural host and regarded as an ideal model for the study of virus-induced tumorigenesis. Recent studies have shown that the mdv1-miR-M4-5p, a viral analog of cellular miR-155, is critical for MDV's oncogenicity. However, the precise mechanism whereby it was involved in MD lymphomagenesis remained unknown. We have presently identified the host mRNA targets of mdv1-miR-M4-5 and identified the latent TGF-beta binding protein 1 (LTBP1) as a critical target for it. We found that during MDV infection, down regulation of LTBP1 expression by mdv1-miR-M4-5p led to a significant decrease of the secretion and activation of TGF-beta1, with suppression of TGF-beta signaling and a significant activation of expression of c-Myc, a well-known oncogene which is critical for virus-induced tumorigenesis. Our findings reveal a novel and important mechanism of how mdv1-miR-M4-5p potentially contributes to MDV-induced tumorigenesis. PMID- 25528441 TI - Synthesis of a new class of Betti bases by the Mannich-type reaction: efficient, facile, solvent-free and one-pot protocol. AB - A variety of organocatalysts has been screened for the synthesis of arylaminonaphthols. It has been shown that (N,N-dimethylethanolamine) is a highly efficient organocatalyst for the direct synthesis of a novel class of arylaminonaphthols via three-component condensation of 2-naphthol, aldehydes, and arylamines under solvent-free conditions. Mild, one-pot, and green reaction conditions, relatively short reaction times and good yields make this protocol highly significant. 25 new compounds have been synthesized by this method. PMID- 25528442 TI - Role of p38MAPK in apoptosis and autophagy responses to photodynamic therapy with Chlorin e6. AB - BACKGROUND: Photodynamic therapy (PDT) has been undergoing clinical evaluation for the treatment of colorectal cancer. But the molecular mechanism of photodynamic injury in human colorectal cancer cells still remains unclear. METHODS: Chlorin e6 (Ce6) was used to photosensitize SW620 cells. The inhibitory effect of PDT was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltertrazolium bromide tetrazolium) assay and colony forming assay. Apoptosis was determined by nuclear DAPI (4'-6-diamidino-2-phenylindole) staining and Annexin V-PE/7-AAD assay. Monodansylcadaverine (MDC) staining was used to evaluate the abundance of autophagic vacuoles in PDT treated cells. The apoptosis and autophagy associated proteins were analyzed by western blotting. Moreover, we applied siRNA p38MAPK and p38MAPK inhibitor SB203580 to dissect its effect on cellular response to PDT in SW620 cells. RESULTS: Ce6 mediated PDT (Ce6-PDT) induced apparent autophagy and apoptosis with dependent on ROS (reactive oxygen species) generation. When p38MAPK was inhibited by siRNA or inhibitor SB203580, a marked enhancement of apoptosis and autophagy in SW620 cells was detected after PDT. Moreover, autophagy inhibitor 3-methyladenine/Bafilomycin A1 greatly aggravated PDT induced photodamage in SW620 cells. CONCLUSION: Ce6-PDT induced ROS production to activate p38MAPK probably to prevent SW620 cells from photodamage. Inhibition of p38MAPK activation accelerated cell apoptosis, meanwhile enhanced autophagy may act as a cytoprotective process in SW620 cells. PMID- 25528443 TI - MicroRNA-134 suppresses endometrial cancer stem cells by targeting POGLUT1 and Notch pathway proteins. AB - We aimed to ascertain the role of microRNAs (miRNAs) in regulating human endometrial cancer stem cells (HuECSCs). The expression level of miRNA-134 (miR 134), a member of the DLK1-DIO3 genomic imprinted miRNA cluster, differed significantly between HuECSCs and human endometrial cancer cells (HuECCs). miR 134 inhibited HuECSCs proliferation and migration by targeting protein O glucosyltransferase 1 (POGLUT1) expression. Exogenous miR-134 overexpression downregulated POGLUT1 and Notch pathway proteins in HuECSCs in vitro. miR-134 overexpression affected the G2/M phase of HuECSCs and suppressed the growth of xenograft tumours formed. Thus, endogenous miR-134 regulation in HuECSCs may suppress tumourigenesis in human endometrial carcinoma. PMID- 25528445 TI - Transcriptional profiling analysis of individual kinase-deletion strains of fission yeast in response to nitrogen starvation. AB - Nitrogen starvation (NS) induces sexual development when mating partners are available or enter into quiescent state (G0) in heterothallic background in fission yeast. However, little is known whether the two processes share common signaling molecules or cells defective in the two processes share common transcriptional signatures. To address these questions, we first assessed 77 kinase-deletion strains for NS-induced G0-arrest phenotypes. Our result indicated that 10 out of 77 kinase-deletion strains exhibited defect in G0-arrest, only 3 of which were defective in sexual development based on a previous study, suggesting that the two processes hardly share common signaling components. We subsequently performed transcriptional profiling analysis. Our result indicated that NS-induced transcriptional change was so robust that it prevailed the alteration by individual kinase-deletion alleles. Based on comparison between kinase-deletion strains proficient and deficient in sexual development or G0 arrest, we identified subsets of genes that were associated with sexual development-deficient or G0-arrest-deficient kinase-deletion strains. Multiple pairing analyses allowed grouping of functional related kinases. Furthermore, we showed that Pka1-mediated pathways were required for upregulation of NS-induced genes upon NS and downregulation of the same set of genes under the N-replete conditions. Taken together, our analyses indicate that sexual development and NS induced G0-arrest are unrelated; and sexual development-deficient and G0-arrest deficient kinase-deletion strains possess distinct transcriptional signatures. We propose that Pka1 is a key regulator of nitrogen metabolic pathways and Pka1 mediated signaling pathways play roles in regulation of NS-induced genes under both N-depleted and N-replete conditions. PMID- 25528444 TI - Low levels of lipopolysaccharide modulate mitochondrial oxygen consumption in skeletal muscle. AB - OBJECTIVE: We have previously demonstrated that activation of toll-like receptor 4 (TLR4) in skeletal muscle results in an increased reliance on glucose as an energy source and a concomitant decrease in fatty acid oxidation under basal conditions. Herein, we examined the effects of lipopolysaccharide (LPS), the primary ligand for TLR4, on mitochondrial oxygen consumption in skeletal muscle cell culture and mitochondria isolated from rodent skeletal muscle. MATERIALS/METHODS: Skeletal muscle cell cultures were exposed to LPS and oxygen consumption was assessed using a Seahorse Bioscience extracellular flux analyzer. Mice were also exposed to LPS and oxygen consumption was assessed in mitochondria isolated from skeletal muscle. RESULTS: Acute LPS exposure resulted in significant reductions in Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP)-stimulated maximal respiration (state 3u) and increased oligomycin induced state 4 (state 4O) respiration in C2C12 and human primary myotubes. These findings were observed in conjunction with increased mRNA of uncoupling protein 3 (UCP3), superoxide dismutase 2 (SOD2), and pyruvate dehydrogenase activity. The LPS-mediated changes in substrate oxidation and maximal mitochondrial respiration were prevented in the presence of the antioxidants N-acetylcysteine and catalase, suggesting a potential role of reactive oxygen species in mediating these effects. Mitochondria isolated from red gastrocnemius and quadriceps femoris muscle from mice injected with LPS also demonstrated reduced respiratory control ratio (RCR), and ADP- and FCCP-stimulated respiration. CONCLUSION: LPS exposure in skeletal muscle alters mitochondrial oxygen consumption and substrate preference, which is absent when antioxidants are present. PMID- 25528447 TI - Reviewing the serotonin reuptake inhibitors (SSRIs) footprint in the aquatic biota: uptake, bioaccumulation and ecotoxicology. AB - Selective serotonin re-uptake inhibitors (SSRIs) antidepressants are amongst the most prescribed pharmaceutical active substances throughout the world. Their presence, already described in different environmental compartments such as wastewaters, surface, ground and drinking waters, and sediments, and their remarkable effects on non-target organisms justify the growing concern about these emerging environmental pollutants. A comprehensive review of the literature data with focus on their footprint in the aquatic biota, namely their uptake, bioaccumulation and both acute and chronic ecotoxicology is presented. Long-term multigenerational exposure studies, at environmental relevant concentrations and in mixtures of related compounds, such as oestrogenic endocrine disruptors, continue to be sparse and are imperative to better know their environmental impact. PMID- 25528448 TI - Breeding of ozone resistant rice: relevance, approaches and challenges. AB - Tropospheric ozone concentrations have been rising across Asia, and will continue to rise during the 21st century. Ozone affects rice yields through reductions in spikelet number, spikelet fertility, and grain size. Moreover, ozone leads to changes in rice grain and straw quality. Therefore the breeding of ozone tolerant rice varieties is warranted. The mapping of quantitative trait loci (QTL) using bi-parental populations identified several tolerance QTL mitigating symptom formation, grain yield losses, or the degradation of straw quality. A genome-wide association study (GWAS) demonstrated substantial natural genotypic variation in ozone tolerance in rice, and revealed that the genetic architecture of ozone tolerance in rice is dominated by multiple medium and small effect loci. Transgenic approaches targeting tolerance mechanisms such as antioxidant capacity are also discussed. It is concluded that the breeding of ozone tolerant rice can contribute substantially to the global food security, and is feasible using different breeding approaches. PMID- 25528446 TI - Oxidative stress and mitochondrial dysfunction in Kindler syndrome. AB - BACKGROUND: Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease. METHODS: Patient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy. RESULTS: Patient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state. CONCLUSIONS: This is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS. PMID- 25528449 TI - Concentrations and origins of nitro-polycyclic aromatic hydrocarbons and oxy polycyclic aromatic hydrocarbons in ambient air in urban and rural areas in northern China. AB - Twelve nitro-PAHs (nPAHs) and four oxy-PAHs (oPAHs) were measured in air samples for 12 months at 18 sites in urban settings, rural villages, or rural fields in northern China. The nPAH concentrations were higher in urban areas (1.3 +/- 1.3 ng/m(3)), and nPAH/parent PAH ratios were higher (suggesting important contributions from motor vehicles and secondary formation) in urban sites than in rural villages. oPAHs are primarily emitted from solid fuel combustion and motor vehicles, and similar oPAH concentrations were found in urban areas (23 +/- 20 ng/m(3)) and rural villages (29 +/- 24 ng/m(3)). The high numbers of motor vehicles in Beijing and intensive industrial activity in Taiyuan and Dezhou caused higher nPAH concentrations. No spatial trend in oPAH concentrations was found in the rural villages, because similar oPAH mixtures are emitted from solild fuel combustion. The nPAH and oPAH concentrations were higher in the winter, and correlated with residential energy consumption and precipitation. PMID- 25528450 TI - A New Proposal for the Target Value for Home BP in Type 2 Diabetes Patients: The J-HOP Study. AB - OBJECTIVE: The target levels of home-monitored blood pressure (BP) in patients with type 2 diabetes mellitus (T2DM) have not yet been established. We sought to examine the appropriate target home BP level in T2DM. METHODS: This is a subanalysis of the Japan Morning Surge-Home Blood Pressure (J-HOP) study. We enrolled 4,310 patients who had at least 1 cardiovascular risk factor, and clinic and home BP monitoring was performed. The urinary albumin-to-creatinine ratio (UACR) was measured as a marker of microvascular disease. Quadratic equations of the relationship between clinic/home systolic BP (SBP) and log-transformed UACR were used to determine the home BP value. Home BP levels corresponding to clinic SBP/diastolic BP (DBP) level using the UACR values were calculated separately by the presence/absence of diabetes. RESULTS: The mean age of the patients was 64.9+/-10.9 years; 47.0% were males. Of the 4,310 subjects enrolled, 1,057 (24.5%) had T2DM (the DM group) and 3,253 (75.5%) did not (non-DM group). The home BP levels equivalent to clinic BP 140/90 mm Hg were 135/84 and 135/83 mm Hg in the DM and non-DM groups, respectively. The home SBP levels equivalent to clinic SBP 130/80 mm Hg were 122/79 mm Hg in the non-DM group and 129/78 mm Hg in the DM group. CONCLUSIONS: Regardless of diabetic status, the home BP level that corresponds to the clinic SBP 140/90 mm Hg was 135/85 mm Hg. In patients with T2DM, the home SBP level equivalent to clinic SBP 130/80 mm Hg was 129/78 mm Hg with regard to the extent of microvascular disease. PMID- 25528452 TI - Predicting the timing of first generation egg hatch for the pest redlegged earth mite Halotydeus destructor (Acari: Penthaleidae). AB - Integrated pest management in Australian winter grain crops is challenging, partly because the timing and severity of pest outbreaks cannot currently be predicted, and this often results in prophylactic applications of broad spectrum pesticides. We developed a simple model to predict the median emergence in autumn of pest populations of the redlegged earth mite, Halotydeus destructor, a major field crop and pasture pest in southern Australia. Previous data and observations suggest that rainfall and temperature are critical for post-diapause egg hatch. We evaluated seven models that combined rainfall and temperature thresholds derived using three approaches against previously recorded hatch dates and 2013 field records. The performance of the models varied between Western Australia and south-eastern Australian States. In Western Australia, the key attributes of the best fitting model were more than 5 mm rain followed by mean day temperatures of below 20.5 degrees C for 10 days. In south-eastern Australia, the most effective model involved a temperature threshold reduced to 16 degrees C. These regional differences may reflect adaptation of H. destructor in south-eastern Australia to varied and uncertain temperature and rainfall regimes of late summer and autumn, relative to the hot and dry Mediterranean-type climate in Western Australia. Field sampling in 2013 revealed a spread of early hatch dates in isolated patches of habitat, ahead of predicted paddock scale hatchings. These regional models should assist in monitoring and subsequent management of H. destructor at the paddock scale. PMID- 25528451 TI - Weed management practices affect the diversity and relative abundance of physic nut mites. AB - Crop management practices determine weed community, which in turn may influence patterns of diversity and abundance of associated arthropods. This study aimed to evaluate whether local weed management practices influence the diversity and relative abundance of phytophagous and predatory mites, as well as mites with undefined feeding habits--of the families Oribatidae and Acaridae--in a physic nut (Jatropha curcas L.) plantation subjected to (1) within-row herbicide spraying and between-row mowing; (2) within-row herbicide spraying and no between row mowing; (3) within-row weeding and between-row mowing; (4) within-row weeding and no between-row mowing; and (5) unmanaged (control). The herbicide used was glyphosate. Herbicide treatments resulted in higher diversity and relative abundance of predatory mites and mites with undefined feeding habit on physic nut shrubs. This was probably due to the toxic effects of the herbicide on mites or to removal of weeds. Within-row herbicide spraying combined with between-row mowing was the treatment that most contributed to this effect. Our results show that within-row weeds harbor important species of predatory mites and mites with undefined feeding habit. However, the dynamics of such mites in the system can be changed according to the weed management practice applied. Among the predatory mites of the family Phytoseiidae Amblydromalus sp. was the most abundant, whereas Brevipalpus phoenicis was the most frequent phytophagous mite and an unidentified oribatid species was the most frequent mite with undefined feeding habit. PMID- 25528453 TI - Iterative reconstruction of magnetic induction using Lorentz transmission electron tomography. AB - Intense ongoing research on complex nanomagnetic structures requires a fundamental understanding of the 3D magnetization and the stray fields around the nano-objects. 3D visualization of such fields offers the best way to achieve this. Lorentz transmission electron microscopy provides a suitable combination of high resolution and ability to quantitatively visualize the magnetization vectors using phase retrieval methods. In this paper, we present a formalism to represent the magnetic phase shift of electrons as a Radon transform of the magnetic induction of the sample. Using this formalism, we then present the application of common tomographic methods particularly the iterative methods, to reconstruct the 3D components of the vector field. We present an analysis of the effect of missing wedge and the limited angular sampling as well as reconstruction of complex 3D magnetization in a nanowire using simulations. PMID- 25528454 TI - Prospects of linear reconstruction in atomic resolution electron holographic tomography. AB - Tomography commonly requires a linear relation between the measured signal and the underlying specimen property; for Electron Holographic Tomography this is given by the Phase Grating Approximation (PGA). While largely valid at medium resolution, discrepancies arise at high resolution imaging conditions. We set out to investigate the artefacts that are produced if the reconstruction still assumes the PGA even with an atomic resolution tilt series. To forego experimental difficulties the holographic tilt series was simulated. The reconstructed electric potential clearly shows peaks at the positions of the atoms. These peaks have characterisitic deformations, which can be traced back to the defocus a particular atom has in the holograms of the tilt series. Exchanging an atom for one of a different atomic number results in a significant change in the reconstructed potential that is well contained within the atom's peak. PMID- 25528455 TI - BitTorious: global controlled genomics data publication, research and archiving via BitTorrent extensions. AB - BACKGROUND: Centralized silos of genomic data are architecturally easier to initially design, develop and deploy than distributed models. However, as interoperability pains in EHR/EMR, HIE and other collaboration-centric life sciences domains have taught us, the core challenge of networking genomics systems is not in the construction of individual silos, but the interoperability of those deployments in a manner embracing the heterogeneous needs, terms and infrastructure of collaborating parties. This article demonstrates the adaptation of BitTorrent to private collaboration networks in an authenticated, authorized and encrypted manner while retaining the same characteristics of standard BitTorrent. RESULTS: The BitTorious portal was sucessfully used to manage many concurrent domestic Bittorrent clients across the United States: exchanging genomics data payloads in excess of 500GiB using the uTorrent client software on Linux, OSX and Windows platforms. Individual nodes were sporadically interrupted to verify the resilience of the system to outages of a single client node as well as recovery of nodes resuming operation on intermittent Internet connections. CONCLUSIONS: The authorization-based extension of Bittorrent and accompanying BitTorious reference tracker and user management web portal provide a free, standards-based, general purpose and extensible data distribution system for large 'omics collaborations. PMID- 25528456 TI - Oral Dysesthesia Rating Scale: a tool for assessing psychosomatic symptoms in oral regions. AB - BACKGROUND: The concept of cenesthopathy was first introduced by Dupre and Camus in 1907 to describe clinically unexplainable bodily sensations mainly attributed to psychiatric pathology. If it occurs in oral regions, it is termed oral cenesthopathy and it has been of special interest to psychiatrists and dentists. While there is no independently defined criteria for this condition, which is classified as either a delusional or a somatoform disorder, clinical practice and research require a standard scale to measure and rate its symptoms. In this study, we included any types of psychosomatic symptoms in oral regions as oral dysesthesia, and developed an Oral Dysesthesia Rating Scale (Oral DRS) and evaluated its validity and reliability as an assessment tool. METHODS: The scale was developed based on literature review and extensive clinical experience. Twelve reviewers assessed relevancy of each item to oral dysesthesia symptoms by 1-4 scoring scale and item content validity index was computed. To evaluate the inter-rater reliability of Oral DRS, pairs of raters administered the scale to 40 randomly selected patients with complaints of oral dysesthesia symptoms and Cohen's weighted kappa coefficient was determined for each item. RESULTS: The scale assesses the severity of feelings of foreign body [A1], exudation [A2], squeezing-pulling [A3], movement [A4], misalignment [A5], pain [A6], and spontaneous thermal sensation or tastes [A7], and the degree of impairment in eating [B1], articulation [B2], work [B3], and social activities [B4] on a scale of 0-5. Items A1, A2, A3, A4, B3, and B4 demonstrated acceptable content validity. Inter-rater reliabilities were good or excellent for all items evaluated. CONCLUSION: The Oral DRS can help define the nosography of clinically unexplainable oral dysesthesia through further case evaluation and clinical research and facilitate devising of treatment modalities. PMID- 25528458 TI - Racial discrimination, multiple group identities, and civic beliefs among immigrant adolescents. AB - The present study tested the independent and interactive effects of multiple group identities (i.e., American and ethnic) and racial discrimination on civic beliefs among immigrant adolescents. Seventy-seven participants completed a questionnaire during after-school programs. Ethnic identity was positively associated with civic beliefs whereas racial discrimination was negatively related to civic beliefs, and racial discrimination moderated the relationships between multiple group identities and civic beliefs. Our findings highlight the importance of studying structural and individual factors jointly in the investigation of civic beliefs among immigrant adolescents. (PsycINFO Database Record PMID- 25528457 TI - Trust increases euthanasia acceptance: a multilevel analysis using the European Values Study. AB - BACKGROUND: This study tests how various kinds of trust impact attitudes toward euthanasia among the general public. The indication that trust might have an impact on euthanasia attitudes is based on the slippery slope argument, which asserts that allowing euthanasia might lead to abuses and involuntary deaths. Adopting this argument usually leads to less positive attitudes towards euthanasia. Tying in with this, it is assumed here that greater trust diminishes such slippery slope fears, and thereby increases euthanasia acceptance. METHODS: The effects of various trust indicators on euthanasia acceptance were tested using multilevel analysis, and data from the European Values Study 2008 (N = 49,114, 44 countries). More precisely, the influence of people's general levels of trust in other people, and their confidence in the health care system, were measured--both at the individual and at the country level. Confidence in the state and the press were accounted for as well, since both institutions might monitor and safeguard euthanasia practices. RESULTS: It was shown that the level of trust in a country was strongly positively linked to euthanasia attitudes, both for general trust and for confidence in health care. In addition, within countries, people who perceived their fellow citizens as trustworthy, and who had confidence in the press, were more supportive of euthanasia than their less trusting counterparts. The pattern was, however, not true for confidence in the state and for confidence in the health care system at the individual level. Notably, all confirmative effects held, even when other variables such as religiosity, education, and values regarding autonomy were controlled for. CONCLUSIONS: Trust seems to be a noteworthy construct to explain differences in attitudes towards euthanasia, especially when drawing cross-country comparisons. Therefore, it should be added to the existing literature on correlates of euthanasia attitudes. PMID- 25528459 TI - Prolonged severe immunodeficiency following thymectomy and radiation: a case report. AB - INTRODUCTION: Immunodeficiency can occur both in patients undergoing radiation therapy, as well as in patients who have had thymectomies. However, few studies have examined the immune recovery of a patient following both procedures. We aim to emphasize the need for assessment and consistent monitoring of patients with thymoma prior to and after combined treatment of thymectomy and radiation, both of which are likely to result in an increased risk for immunodeficiency. CASE PRESENTATION: We describe the longitudinal progress of a 59-year-old Asian male who underwent thymectomy followed by radiation therapy and subsequently presented with generalized urticaria. Revelation of a low absolute lymphocyte count (615 cells/mcL) on initial evaluation prompted further analysis of his immunoglobulin levels and antigen response to a polysaccharide pneumococcal vaccine (PneumoVax 23). Although his immunoglobulin levels were unremarkable, he failed to respond to 11 of 12 serotypes of the pneumococcal vaccine. As a result, he was placed on Bactrim(r) (trimethoprim-sulfamethoxazole) prophylaxis to prevent opportunistic infections, and his CD4+ and CD8+ counts were monitored over the course of 8 years. His lymphocyte counts 87 months after thymectomy and 85 months after radiation therapy were as follows: absolute lymphocyte count 956 cells/mcL, absolute CD3+/CD4+ 164/mm3 (16%) and absolute CD3+/CD8+ 257/mm3 (25%). The patient was able to discontinue Bactrim(r) (trimethoprim-sulfamethoxazole) prophylaxis after 9 years of treatment. CONCLUSIONS: The lymphocytopenia, low CD4+ count, and failed response to pneumococcal vaccination that presented in our patient are consistent with immunodeficiency. After radiation alone, a recovery of T-lymphocytes is usually observed after approximately 3 weeks. Over the course of 8 years, he has still not made a full recovery according to laboratory markers, which seem to have stabilized at chronically low levels. To prevent serious complications, we suggest that patients who have undergone both thymectomy and radiation therapy be monitored for immunodeficiency. This case report informs the practices of allergists, oncologists, and neurologists in the continuing care of patients with thymoma. PMID- 25528461 TI - Concurrent use of granulocyte-colony stimulating factor with repetitive transcranial magnetic stimulation did not enhance recovery of function in the early subacute stroke in rats. AB - We investigated the additive effect of repetitive transcranial magnetic stimulation (rTMS) combined with granulocyte-colony stimulating factor (G-CSF) on functional outcome in the early subacute phase of stroke. Seven-week-old male rats were subjected to permanent middle cerebral artery occlusion (MCAo) and were divided into four groups: normal saline administration with sham rTMS (group 1, n = 15), G-CSF administration with sham rTMS (group 2, n = 15), G-CSF with 1 Hz rTMS (group 3, n = 14), and G-CSF with 20 Hz rTMS (group 4, n = 15). Animals received G-CSF or saline for 5 days from the day of MCAo and were concurrently treated with 20-min rTMS on their lesioned hemisphere for 2 weeks. Neurological functional score was worse in group 4 compared to that in group 2 on day 15. In Western blots conducted on day 25, phosphorylation of endothelial nitric oxide synthase was markedly lower in groups 2, 3, and 4 than that in group 1 in the ischemic border zone. PECAM-1 expression at ischemic core was lower in groups 4 than in group 2. Caspase-3 expression was markedly higher in groups 4 than in group 1, 2, 3 at ischemic core. Iba1 expression was higher in groups 4 than in group 1, 2 at ischemic core. G-CSF combined with rTMS administered in the early subacute phase of ischemic stroke may exert a hazardous effect on functional recovery, possibly due to impaired angiogenic mechanism, decreased cell survival, and increased inflammation. PMID- 25528462 TI - Use of a continuous twin screw granulation and drying system during formulation development and process optimization. AB - Since small scale is key for successful introduction of continuous techniques in the pharmaceutical industry to allow its use during formulation development and process optimization, it is essential to determine whether the product quality is similar when small quantities of materials are processed compared to the continuous processing of larger quantities. Therefore, the aim of this study was to investigate whether material processed in a single cell of the six-segmented fluid bed dryer of the ConsiGmaTM-25 system (a continuous twin screw granulation and drying system introduced by GEA Pharma Systems, ColletteTM, Wommelgem, Belgium) is predictive of granule and tablet quality during full-scale manufacturing when all drying cells are filled. Furthermore, the performance of the ConsiGmaTM-1 system (a mobile laboratory unit) was evaluated and compared to the ConsiGmaTM-25 system. A premix of two active ingredients, powdered cellulose, maize starch, pregelatinized starch and sodium starch glycolate was granulated with distilled water. After drying and milling (1000 MUm, 800 rpm), granules were blended with magnesium stearate and compressed using a ModulTM P tablet press (tablet weight: 430 mg, main compression force: 12 kN). Single cell experiments using the ConsiGmaTM-25 system and ConsiGmaTM-1 system were performed in triplicate. Additionally, a 1h continuous run using the ConsiGmaTM-25 system was executed. Process outcomes (torque, barrel wall temperature, product temperature during drying) and granule (residual moisture content, particle size distribution, bulk and tapped density, hausner ratio, friability) as well as tablet (hardness, friability, disintegration time and dissolution) quality attributes were evaluated. By performing a 1h continuous run, it was detected that a stabilization period was needed for torque and barrel wall temperature due to initial layering of the screws and the screw chamber walls with material. Consequently, slightly deviating granule and tablet quality attributes were obtained during the start-up phase of the 1h run. For the single cell runs, granule and tablet properties were comparable with results obtained during the second part of the 1h run (after start-up). Although deviating granule quality (particle size distribution and Hausner ratio) was observed due to the divergent design of the ConsiGmaTM-1 unit and the ConsiGmaTM-25 system (horizontal set-up) used in this study, tablet quality produced from granules processed with the ConsiGmaTM-1 system was predictive for tablet quality obtained during continuous production using the ConsiGmaTM-25 system. PMID- 25528460 TI - Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy. AB - In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers. PMID- 25528463 TI - Use of modified halloysite nanotubes in the feed reduces the toxic effects of zearalenone on sow reproduction and piglet development. AB - A study was conducted to determine the effects of feeding a blend of corn contaminated with Fusarium mycotoxins on the physical condition of pregnant and suckling sows and the development of their offspring. Halloysite nanotubes modified using the surfactant, stearyldimethylbenzylammonium chloride, were tested for its efficacy in protecting against the detrimental effects of zearalenone (ZEN) exposure. A total of 18 pregnant second parity Yorkshire sows (six per treatment) were fed control diet, contaminated grain diet (ZEN, 2.77 mg/kg), and contaminated grain + 1% modified halloysite nanotube (MHNT) diet (ZEN, 2.76 mg/kg) from 35 to 70 days in pregnancy (DIP), which is the critical period in development of fetuses. The results show that consumption of ZEN led to a reduction in sow's mass gain during 35 to 70 DIP and mass at 110 DIP, backfat at 70 DIP and weaning, placenta weight at 70 DIP and farrowing, the lactation average daily feed intake, and an increase in the weight of ovary at 70 DIP of sows (P < 0.05). The total number and average body weight (BW) of fetuses at 70 DIP, the number of piglets born, the litter birth weight, the average BW of piglet at birth, the number of piglets born alive, the born alive litter weight, and born alive piglet BW at farrowing were also decreased by ZEN exposure (P < 0.05). The increased expressions of P53, Bax, Cyto C, caspase 9, and caspase 3 and decreased expression of Bcl-2 were observed in the uterus and placenta of sows at 70 DIP, the placenta and fetal uterus at farrowing, and the piglet uterus at weaning (P < 0.05). Adding 1% MHNTs decreased the residue of ZEN in maternal and fetal tissues. The number of fetuses and the average fetus BW at 70 DIP, the total number of piglets born, the litter birth weight, the born alive piglet BW at farrowing, the average piglet BW, the litter weaned weight, and the average day gain at weaning were increased by adding 1% MHNTs, compared with the ZEN treated group (P < 0.05). The MHNTs significantly reduced the damage to the fat in the colostrum and the protein and lactose in the milk induced by the ZEN contaminated feed (P < 0.05). Modified halloysite nanotubes could be used as adsorbent in the feed to reduce the toxic effects of ZEN. PMID- 25528464 TI - Isolation of Cryptococcus gattii from Oregon soil and tree bark, 2010-2011. AB - BACKGROUND: In Oregon, human and animal infections by C. gattii were first identified in 2004. Cryptococcus gattii is considered to be an emerging non zoonotic infection affecting animals and humans in Oregon. We report a longitudinal environmental isolation of C. gattii after an Oregon dog was diagnosed with the disease in 2009. RESULTS: Cryptococcus gattii was isolated twice from the same location with a span of one year between isolation dates. Cryptococcus gattii molecular types VGIIa and VGI were isolated in 2010 from soil and tree bark near the home of a 9-month-old dog which three months previously had an infection caused by C. gattii genotype VGIIa. The environment featured heavy growth of Douglas Fir trees. In 2011, a second set of soil and tree bark samples was collected in the same area and C. gattii VGIIa was again identified from the environment, along with genotypes VGIIb and VGIIc. CONCLUSIONS: The use of animal surveillance data to identify environmental niches of C. gattii should be considered to expand the understanding of this emerging pathogen. Understanding the ecology and how the environment and other factors might modify the existing niches is important for assessing risk and for designing measures to protect human and animal health. PMID- 25528465 TI - Financial viability, benefits and challenges of employing a nurse practitioner in general practice. AB - This case study examines the financial viability, benefits and challenges of employing a primary healthcare (PHC) nurse practitioner (NP) in a bulk-billing healthcare cooperative in the Australian Capital Territory. There are few empirical case reports in the Australian literature that demonstrate financial sustainability of this type of healthcare professional in primary healthcare. This case study demonstrates that the costs of employing a PHC-NP in general practice are offset by direct and indirect Medicare billings generated by the PHC NP, resulting in a cost-neutral healthcare practitioner. The success of this model relies on bidirectional collaborative working relationships amongst general practitioners and NPs. PHC-NPs should have a generalist scope of practice and specialist expertise in order to maximise their utility within the general practice environment. PMID- 25528466 TI - A Bayesian prediction model between a biomarker and the clinical endpoint for dichotomous variables. AB - BACKGROUND: Early biomarkers are helpful for predicting clinical endpoints and for evaluating efficacy in clinical trials even if the biomarker cannot replace clinical outcome as a surrogate. The building and evaluation of an association model between biomarkers and clinical outcomes are two equally important concerns regarding the prediction of clinical outcome. This paper is to address both issues in a Bayesian framework. METHODS: A Bayesian meta-analytic approach is proposed to build a prediction model between the biomarker and clinical endpoint for dichotomous variables. Compared with other Bayesian methods, the proposed model only requires trial-level summary data of historical trials in model building. By using extensive simulations, we evaluate the link function and the application condition of the proposed Bayesian model under scenario (i) equal positive predictive value (PPV) and negative predictive value (NPV) and (ii) higher NPV and lower PPV. In the simulations, the patient-level data is generated to evaluate the meta-analytic model. PPV and NPV are employed to describe the patient-level relationship between the biomarker and the clinical outcome. The minimum number of historical trials to be included in building the model is also considered. RESULTS: It is seen from the simulations that the logit link function performs better than the odds and cloglog functions under both scenarios. PPV/NPV >=0.5 for equal PPV and NPV, and PPV + NPV >=1 for higher NPV and lower PPV are proposed in order to predict clinical outcome accurately and precisely when the proposed model is considered. Twenty historical trials are required to be included in model building when PPV and NPV are equal. For unequal PPV and NPV, the minimum number of historical trials for model building is proposed to be five. A hypothetical example shows an application of the proposed model in global drug development. CONCLUSIONS: The proposed Bayesian model is able to predict well the clinical endpoint from the observed biomarker data for dichotomous variables as long as the conditions are satisfied. It could be applied in drug development. But the practical problems in applications have to be studied in further research. PMID- 25528468 TI - Does long-term care insurance affect the length of stay in hospitals for the elderly in Korea?: a difference-in-difference method. AB - BACKGROUND: This study examines the effects of long-term care insurance (LTCI) on the length of stay (LoS) of senior citizens under the national health insurance of Korea. METHODS: The subjects include 3,903,448 people aged 65 and over as of July 1, 2008 when the LTCI was introduced in Korea. This study uses their panel data which traced the records of medical services and LTCI services for the same people from 2007 to 2010, and applies a difference-in-difference approach on LTCI users from levels 1, 2, and 3 who are the treatment group and non-LTCI users who are the control group. RESULTS: We found that the LoS of LTCI users is 1.27 days greater than that of non-LTCI users, but the LoS of level 1 and level 2 beneficiaries decreases by 8.35 and 2.84 days, respectively, whereas the LTCI does not reduce the LoS of level 3 beneficiaries. CONCLUSIONS: The reason why there is an effect on the LoS of level 1 and 2 beneficiaries is that these groups could choose to utilize institutional care services provided by the LTCI, and out of-pocket costs of institutions are lower than that of hospitals. However, the reason why there is no effect on the LoS of level 3 beneficiaries is that they are not permitted to use the institutional care services in the Korean LTCI policy. Therefore, we recommend a modification in the LTCI system that facilitates the use of long-term care institutional services by level 3 beneficiaries without conflicting Korea's LTCI principle to promote home-based care services instead of the institutional care services. PMID- 25528467 TI - Resolution of anaemia in a cohort of HIV-infected patients with a high prevalence and incidence of tuberculosis receiving antiretroviral therapy in South Africa. AB - BACKGROUND: Anaemia is frequently associated with both HIV-infection and HIV related tuberculosis (TB) in antiretroviral therapy (ART)-naive patients in sub Saharan Africa and is strongly associated with poor prognosis. However, the effect of ART on the resolution of anaemia in patient cohorts with a high prevalence and incidence of tuberculosis is incompletely defined and the impact of TB episodes on haemoglobin recovery has not previously been reported. We therefore examined these issues using data from a well-characterised cohort of patients initiating ART in South Africa. METHODS: Prospectively collected clinical and haematological data were retrospectively analysed from patients receiving ART in a South African township ART service. TB diagnoses and time updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded. Anaemia severity was classified according to WHO criteria. Multivariable logistic regression analysis was used to determine factors independently associated with anaemia after 12 months of ART. RESULTS: Of 1,140 patients with baseline haemoglobin levels, 814 were alive in care and had repeat values available after 12 months of ART. The majority of patients were female (73%), the median CD4 count was 104 cells/uL and 30.5% had a TB diagnosis in the first year of ART. At baseline, anaemia (any severity) was present in 574 (70.5%) patients and was moderate/severe in 346 (42.5%). After 12 months of ART, 218 (26.8%) patients had anaemia of any severity and just 67 (8.2%) patients had moderate/severe anaemia. Independent predictors of anaemia after 12 months of ART included greater severity of anaemia at baseline, time-updated erythrocyte microcytosis and receipt of an AZT-containing regimen. In contrast, prevalent and/or incident TB, gender and baseline and time-updated CD4 cell count and viral load measurements were not independent predictors. CONCLUSIONS: Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions. However, approximately one-quarter of patients remained anaemic after one year of ART and may require additional investigations and/or interventions. PMID- 25528469 TI - Clinical skills of veterinary students - a cross-sectional study of the self concept and exposure to skills training in Hannover, Germany. AB - BACKGROUND: Students of veterinary medicine should achieve basic professional competences required to practise their profession. A main focus of veterinary education is on developing clinical skills. The present study used the guidelines of the "Day-One Skills" list of European Association of Establishments for Veterinary Education (EAEVE) to create an online questionnaire for assessing the skills acquired by students at the University of Veterinary Medicine Hannover (TiHo). The theoretical and practical veterinary knowledge levels of the students and postgraduates are determined and compared. RESULTS: In two batches, 607 people responded (response batch 1, 23.78%; response batch 2, 23.83%). From 49 defined skills, 28 are actually practised during training at the university and 21 activities are known only theoretically. Furthermore, the students showed great willingness to use simulators and models in a clinical skills lab. CONCLUSIONS: The results of this survey highlight that the opening of a clinical skills lab at the University of Veterinary Medicine Hannover and its incorporation into the study programme are ideal tools to promote practical competences and foster the motivation to learn. PMID- 25528470 TI - Affect and psychiatric symptoms in a veteran polytrauma clinic. AB - Although the relationship between negative affect and psychiatric symptoms has been well-demonstrated in research, less is known about positive affect relative to negative affect, and its relationship to psychiatric symptoms, especially among veterans. This study examined how levels of positive and negative affect are associated with symptoms of depression, anxiety, and posttraumatic stress disorder (PTSD). Data were collected in a veteran polytrauma clinic; analyses were conducted using data from 94 veterans (87 males) with and without a mild traumatic brain injury (mTBI) diagnosis. Results demonstrate that positive and negative affect were separate dimensions and that both were independently related to each symptom measure. After removing the contribution of negative affect from symptom reports, strong relationships remained between positive affect and psychiatric symptoms. Furthermore, the magnitude of the associations for positive affect and for negative affect with symptoms of depression, anxiety, and PTSD were not impacted by a mTBI diagnosis. Altogether, findings suggest that both positive and negative affect should be uniquely considered when conceptualizing, assessing, and treating returning service members; in addition, positive affect may be an appropriate target of assessment and interventions of persons who have experienced polytrauma. PMID- 25528471 TI - Examination of self-regulatory efficacy and pain among individuals challenged by arthritis flares. AB - PURPOSE/OBJECTIVE: Public health guidelines for physical activity (PA) for individuals with arthritis are 150 min/week. Self-regulatory efficacy to plan and schedule activity (SRE-SP) was greater for individuals meeting guidelines in studies when symptoms were usual. Extreme symptoms of a flare presumably challenge or block PA adherence. We found it surprising that the question of whether pain intensity and SRE-SP differ within the same person as a function of symptom severity (i.e., flare vs. no-flare) and PA level has not been addressed. RESEARCH METHOD/DESIGN: Participants (N = 53) reported SRE-SP and SRE to overcome arthritis barriers (SRE-AB) during the following month, average usual and flare pain intensity, and PA volume in the past 6 months. Mixed-model ANOVAs compared those meeting or not meeting PA guidelines in both flare and no-flare conditions. RESULTS: Main effects for SRE (SP and AB) were significant for within flare/no flare comparisons (p < .001) and for SRE-SP were significant between PA groups (p < .05). Individuals meeting PA guidelines have the advantage of greater SRE-SP to motivate adherence than those of the less active. All participants' activity was less efficacious during a flare. For pain intensity, a within-subjects flare versus no-flare effect (p < .001) confirmed that flares are perceived as more of an obstacle or challenge for engaging in PA. CONCLUSION/IMPLICATIONS: Regardless of meeting or not meeting PA guidelines, participants reported lower SRE and higher pain intensity during a flare. PA adherence during a flare may require self-regulation of PA to be active, and in particular, to be able to meet recommended guidelines, relative to symptom severity. PMID- 25528472 TI - Isolation and characterization of the outer membrane of Escherichia coli with autodisplayed Z-domains. AB - "Autodisplay technology" is an expression technique used to display the various recombinant proteins on the outer membrane (OM) of Escherichia coli. The resulting autodisplayed Z-domain has been used to improve the sensitivity of immunoassays. In this work, a facile isolation method of the OM fraction of E. coli with autodisplayed Z-domains was presented using (1) an enzyme reaction for the hydrolysis of the peptidoglycan layer and (2) short centrifugation steps. The purity of the isolated OM fraction was analyzed. For the estimation of contamination with bacterial proteins from other parts of E. coli, Western blots of marker proteins for the OM (OmpA), periplasm (beta-lactamase), inner membrane (SecA), and cytoplasm (beta-galactosidase) were performed. Additionally, assays of marker components or enzymes from each part of E. coli were carried out including the OM (KDO), inner membrane (NADH oxidase), periplasm (beta lactamase), and cytoplasm (beta-galactosidase). The yield of OM isolation using this new method was determined to be 80% of the total OM amount, with less than 1% being contaminants from other parts of E. coli. PMID- 25528473 TI - Computational insight in the role of fusogenic lipopeptides at the onset of liposome fusion. AB - We performed an extensive computational study to obtain insight in the molecular mechanisms that take place prior to membrane fusion. We focused on membrane anchored hybrid macromolecules (lipid-polymer-oligopeptide) that mimic biological SNARE proteins in terms of liposome fusion characteristics [H. Robson Marsden et al., 2009]; efficient micro-second simulation was enabled by combining validated MARTINI force fields for the molecular building blocks in coarse-grained molecular dynamics (CGMD). We find that individual peptide domains in the hybrid macromolecules bind and partially integrate parallel to the membrane surface, in agreement with experimental findings. By varying several experimental design parameters, we observe that peptide domains remain in the solvent phase only in two cases: (1) for solitary lipopeptides (low concentration), below a threshold area per lipid in the membrane, and (2) when the lipopeptide concentration is high enough for the peptide domains to self-assemble into tetrameric homo complexes. The peptide-membrane binding is not affected by solvent-induced peptide unfolding, which we mimicked by relaxing the usual MARTINI helix constraints. Remarkably, in this case, a reverse transition to a helical secondary structure is observed after binding, highlighting the role of the membrane as a template (partitioning-folding coupling). Our findings undermine the current view of the initial stages towards fusion, in which membranes are thought to be kept in close apposition via dimerization of individual complementary peptides in the solvent phase. Although we did not study actual fusion, our simulations show that the formation of homomers, which is suppressed in experimental peptide-pair design and therefore believed to be insignificant for fusion, by peptides anchored to the same membrane does play a key role in this locking mechanism and potentially also in membrane destabilization that precede fusion. PMID- 25528474 TI - Interactions between cognitive and sensory load while planning and controlling complex gait adaptations in Parkinson's disease. AB - BACKGROUND: Recent research has argued that removal of relevant sensory information during the planning and control of simple, self-paced walking can result in increased demand on central processing resources in Parkinson's disease (PD). However, little is known about more complex gait tasks that require planning of gait adaptations to cross over an obstacle in PD. METHODS: In order to understand the interaction between availability of visual information relevant for self-motion and cognitive load, the current study evaluated PD participants and healthy controls while walking toward and stepping over an obstacle in three visual feedback conditions: (i) no visual restrictions; (ii) vision of the obstacle and their lower limbs while in complete darkness; (iii) vision of the obstacle only while in complete darkness; as well as two conditions including a cognitive load (with a dual task versus without a dual task). Each walk trial was divided into an early and late phase to examine changes associated with planning of step adjustments when approaching the obstacle. RESULTS: Interactions between visual feedback and dual task conditions during the obstacle approach were not significant. Patients with PD had greater deceleration and step time variability in the late phase of the obstacle approach phase while walking in both dark conditions compared to control participants. Additionally, participants with PD had a greater number of obstacle contacts when vision of their lower limbs was not available specifically during the dual task condition. Dual task performance was worse in PD compared to healthy control participants, but notably only while walking in the dark regardless of visual feedback. CONCLUSIONS: These results suggest that reducing visual feedback while approaching an obstacle shifts processing to somatosensory feedback to guide movement which imposes a greater demand on planning resources. These results are key to fully understanding why trips and falls occur in those with PD. PMID- 25528475 TI - T11 target structure induced modulations of the pro-inflammatory and anti infammatorycytokine expressions in experimental animals for glioma abrogation. AB - Glioma angiogenesis is the result of the interaction between cancer cells with endothelial cells, and the surrounding inflammatory cells. This interaction plays a crucial role in directing the neo-formation of blood vessels. In the carcinogenic milieu, inflammatory cytokines secreted from inflammatory cells affect endothelial cell functions that are indispensable for tumor growth and metastatic propagation. TNF-alpha, referred to as the 'inflammatory switch', has shown its potential as an inflammatory agent by activation of IL-8 and IL-6 through NF-kappaB mediated pathway. Therefore, inhibitors of angiogenesis appear to be promising therapeutic agents for advanced gliomas. Previous studies from our lab showed that T11TS, a membrane glycoprotein, has antiangiogenic and antineoplastic activities in experimental animals and human samples. The present experimental study was designed to evaluate the effect of T11TS therapy on inflammatory cytokine expression of TNF-alpha, IL-8, IL-6 and their downstream associated molecule NF-kappaB in vivo. Our results revealed that T11TS therapy induced downregulation of TNF-alpha, IL-8, IL-6, and NF-kappaB confirmed by FACS assay and ELISA. In situ-immunofluorescence results hint that T11TS has the efficacy to stop the inflammation related to angiogenesis. Moreover, upregulation of IL-4 and IL-10 in microglia after T11TS therapy helps in complete abrogation of glioma inflammation and angiogenesis. These effects might contribute to the antineoplastic activity of T11TS. PMID- 25528476 TI - A natural flavonoid glucoside icariin inhibits Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an autoimmune disease that is characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. Icariin, a natural flavonoid glucoside isolated from plants in the Epimedium family, has been proved to have various pharmacological activities. However, the effect of icariin on experimental autoimmune encephalomyelitis (EAE) has never been investigated. In our current study, we found that icariin treatment leads to alleviated inflammatory infiltration and reduced blood-brain barrier leakage (BBB) of the paracellular tracer (FITC-dextran) in EAE. Mice that received icariin-treated T cells also displayed lower EAE scores and better clinical recovery from EAE. Icariin administration suppresses the frequencies of Th1 and Th17 cells in the splenocytes and lymph node cells. Icariin-treated mice also show lower frequency of Th17 cells in CNS mononuclear cells. The effect of icariin on Th1 and Th17 cell differentiation may be mediated via modulation of dendritic cells (DCs). Furthermore, icariin suppresses the proliferation of T cells and the differentiation of Th1 and Th17 cells in vitro. In conclusion, icariin ameliorates EAE and this was associated with suppressed Th1 and Th17 cell differentiation. PMID- 25528477 TI - Binding of trivalent chromium to serum transferrin is sufficiently rapid to be physiologically relevant. AB - Transferrin, the major iron transport protein in the blood, also transports trivalent chromium in vivo. Recent in vitro studies have, however, suggested that the binding of chromic ions to apotransferrin is too slow to be biologically relevant. Nevertheless, the in vitro studies have generally failed to adequately take physiological bicarbonate concentrations into account. In aqueous buffer (with ambient (bi)carbonate concentrations), the binding of chromium to transferrin is too slow to be physiologically relevant, taking days to reach equilibrium with the protein's associated conformational changes. However, in the presence of 25mM (bi)carbonate, the concentration in human blood, chromic ions bind rapidly and tightly to transferrin. Details of the kinetics of chromium binding to human serum transferrin and conalbumin (egg white transferrin) in the presence of bicarbonate and other major potential chromium ligands are described and are consistent with transferrin being the major chromic ion transporter from the blood to tissues. PMID- 25528478 TI - Effect of ancillary ligands on the interaction of ruthenium(II) complexes with the triplex RNA poly(U).poly(A)*poly(U). AB - Two new Ru(II) complexes with 1,8-naphthalimide group, [Ru(phen)2(pnip)](2+) (Ru1; phen=1,10-phenanthroline, pnip=2-[N-(p-phenyl)-1,8 napthalimide]imidazo[4',5'-f][1,10]phenanthroline) and [Ru(bpy)2(pnip)](2+) (Ru2; bpy=2,2'-bipyridine), have been synthesized and characterized. The interactions of Ru1 and Ru2 with the triplex RNA poly(U)*poly(A)*poly(U) (where * denotes the Watson-Crick base pairing and * denotes the Hoogsteen base pairing) were studied by various biophysical. Electronic spectra established that the binding affinity for Ru1 was greater than that for Ru2. Fluorescence and viscosity studies gave convincing evidence for a true intercalative binding of both complexes with the RNA triplex. UV melting studies confirmed that the two complexes could stabilize the triplex, whereas the effects of the two complexes on the stability of the Hoogsteen base-paired strand ploy(U) and the Watson-Crick base-paired duplex poly(U)*poly(A) of the triplex were different. In the case of Ru1, the increase of the thermal stability of the Hoogsteen base-paired strand was stronger than that of the Watson-Crick base-paired duplex. However, an opposite effect was observed in the case of Ru2. Circular dichroic studies suggested that the RNA triplex undergoes a conformational transition in the presence of Ru1, whereas the helicity of the RNA triplex still remains A-type in the presence of Ru2. The main results obtained here further advance our knowledge on the interaction of RNA triple-stranded structures with metal complexes, particularly ruthenium(II) complexes. PMID- 25528479 TI - Photoinduced DNA damage and cytotoxicity by a triphenylamine-modified platinum diimine complex. AB - Many planar photosensitizers tend to self-aggregate via van der Waals interactions between pi-conjugated systems. The self-aggregation of the photosensitizer may reduce the efficiency of the photosensitizer to generate singlet oxygen, thereby diminishing its photodynamic activity. Efforts have been made to improve the photodynamic activity of bis-(o diiminobenzosemiquinonato)platinum(II) which has planar geometry by the introduction of the sterically hindered triphenylamine moiety into the ligand. Herein we report the photoinduced DNA damage and cytotoxicity by a triphenylamine modified platinum-diimine complex in red light studied by fluorescence spectra, agarose gel assay and cell viability assay. The results suggest that the triphenylamine-modified platinum-diimine complex has better capability to generate singlet oxygen than bis-(o-diiminobenzosemiquinonato)platinum(II), and it can induce DNA damage in red light, causing high photocytotoxicity in HepG-2 cells in vitro. PMID- 25528480 TI - Structural biology of the lanthanides-mining rare earths in the Protein Data Bank. AB - With its about 100,000 three-dimensional structures, the Protein Data Bank is a copious source of information: it contains also some hundreds of structures of macromolecules complexed with lanthanide cations, which are examined here. These cations, which are found in a wide variety of protein types, were introduced to determine the structures, by exploiting their anomalous dispersion (in crystallographic studies, where they are also used as crystallization additives) or the paramagnetic pseudocontact shifts (in NMR analyses). The coordination numbers in the first coordination sphere are very variable, though they tend to be close to those that are observed in small molecules or in water solution. The coordination polyhedra are also quite variable as it can be expected for large cations. Interestingly, lanthanide cations are frequently observed in packing bridges between symmetry equivalent molecules in crystals, where they tend to form polynuclear complexes, with up to seven cations bridged by water/hydroxide ligands. PMID- 25528481 TI - Cu(II)-dipeptide complexes of 2-(4'-thiazolyl)benzimidazole: synthesis, DNA oxidative damage, antioxidant and in vitro antitumor activity. AB - Two new Cu(II)-dipeptide complexes of 2-(4'-thiazolyl)benzimidazole, [Cu(Gly Gly)(TBZ)(Cl)].4H2O (1) and [Cu(Gly-l-Leu)(TBZ)(Cl)].H2O (2) (Gly-Gly=glycyl glycine anion, Gly-l-Leu=glycyl-l-leucine anion and TBZ=2-(4' thiazolyl)benzimidazole) have been synthesized and characterized by elemental analyses, molar conductance measurements and spectroscopy methods (IR, UV visible, electrospray ionization mass spectra (ESI-MS) and EPR). The DNA binding and cleavage properties of the complexes monitored by multi-spectroscopic techniques (UV absorption, fluorescence and circular dichroism), viscosity determination and agarose gel electrophoresis indicated that the complexes bound to calf thymus (CT)-DNA via a partial intercalative mode with considerable intrinsic binding constants (Kb=1.64*10(5)M(-1) for 1 and 2.59*10(5)M(-1) for 2), and cleaved pBR322 DNA efficiently in the mediation of ascorbic acid (AA), probably via an oxidative damage mechanism induced by OH. The antioxidant activities of the complexes have been evaluated by means of modified nitroblue tetrazolium (NBT) photoreduction and cellular antioxidant activity (CAA) assays using HepG2 cells as a model, and it was found that IC50 values of 1 and 2 for dismutation of O2(-) were 0.172 and 0.247MUM, respectively, and the CAA50 values were 10.57 and 10.74MUM. In addition, the complexes were subjected to in vitro cytotoxicity against three human carcinoma cell lines (HeLa, A549 and HepG2), which revealed that the complexes exhibited effective cytotoxicity (IC50 values varying from 33.17 to 100MUM) and selective inhibition toward HeLa cell lines. These findings indicate that the complexes have the potential to act as effective metallopeptide chemotherapeutic agents. PMID- 25528482 TI - The relation between location of cervical cord compression and the location of myelomalacia. AB - OBJECTIVE: The purpose of this study was to examine the relationship between the location of the cervical cord compression and the increased signal intensity within the cervical cord on T2-weighted imaging (T2WI) in patients with cervical myelopathy and myelomalacia. MATERIALS AND METHODS: We reviewed 1,615 MRI reports from January 2011 to May 2013 from a single institution. Of the 1,615 reports reviewed, 168 patients were diagnosed with increased signal intensity within the cervical spine on T2WI. After applying the exclusion criteria 82 patients were included in the study. The MRIs of these 82 patients were then reviewed and the location of the increased signal intensity on T2WI in relation to the location of the pressure on the spinal cord was recorded. RESULTS: In more than 50 % of the cases the lesions with increased signal intensity on T2WI either were located distal to the pressure on the spinal cord or started at the level of the pressure and extended to an area distal to the pressure. In 26 out of the 92 lesions with increased signal intensity on T2WI, the lesion started proximal to the pressure on the spinal cord and extended distal to it. In only 3 out of the 92 lesions, the lesion with increased signal intensity on T2WI was solely located proximal to the pressure on the spinal cord. In 5 other cases the lesion with increased signal intensity on T2WI started proximal to the level of pressure on the spinal cord and extended into the level of pressure on the spinal cord (p < 0.001; Table 1). CONCLUSION: Cervical myelomalacia may appear proximal, distal or at the level of the compressed cord. It rarely appears solely proximal to the pressure area on the cord. PMID- 25528483 TI - ISS outreach report. PMID- 25528484 TI - The impact of hospital-acquired infections with multidrug-resistant bacteria in an oncology intensive care unit. AB - OBJECTIVE: To describe overall site-specific hospital-acquired infection (HAI) rates and to describe the microbiological and antibiotic resistance profiles of infecting pathogens, together with their impact on multidrug-resistant (MDR) bacteria-associated mortality. METHODS: We conducted a 5-year retrospective descriptive study of HAI in patients in the intensive care unit (ICU) of a cancer center in Mexico from January 2007 to December 2011. The following information was collected: patient characteristics and comorbidities, data related to the neoplasm and its treatment, microbiology, and the resistance pattern of all isolates. RESULTS: During the study period, 1418 patients were admitted to the ICU; 134 of them developed 159 infections, with an incidence of 11.2/100 hospitalized patients and 32.2/per 1000 patient-days. Two hundred sixty-six microorganisms were isolated. The overall prevalence of MDR-HAI was 39.5%. The most frequent organisms were as follows: 54 (20%) Escherichia coli (94.4% of these were extended-spectrum beta-lactamase producers), 32 (12%) Staphylococcus aureus (90.6% of these were methicillin-resistant), 32 (12%) Enterococcus faecium (18.7% of these were vancomycin-resistant), and 20 (6%) Acinetobacter baumannii (all were MDR). Among patients admitted to the ICU, 252 (17.8%) died. Death was related to the HAI in 58 (23%) of these patients (p<0.001) and 51 (88%) had a MDR organism isolated (p=0.05). CONCLUSIONS: The emergence of MDR bacteria poses a difficult task for physicians, who have limited therapeutic options. Critically ill cancer patients admitted to the ICU are at major risk of a bacterial MDR-HAI that will impact adversely on mortality. PMID- 25528485 TI - Use of surfactants for the remediation of contaminated soils: a review. AB - Due to the great harm caused by soil contamination, there is an increasing interest to apply surfactants to the remediation of a variety of contaminated soils worldwide. This review article summarizes the findings of recent literatures regarding remediation of contaminated soils/sites using surfactants as an enhancing agent. For the surfactant-based remedial technologies, the adsorption behaviors of surfactants onto soil, the solubilizing capability of surfactants, and the toxicity and biocompatibility of surfactants are important considerations. Surfactants can enhance desorption of pollutants from soil, and promote bioremediation of organics by increasing bioavailability of pollutants. The removal of heavy metals and radionuclides from soils involves the mechanisms of dissolution, surfactant-associated complexation, and ionic exchange. In addition to the conventional ionic and nonionic surfactants, gemini surfactants and biosurfactants are also applied to soil remediation due to their benign features like lower critical micelle concentration (CMC) values and better biocompatibility. Mixed surfactant systems and combined use of surfactants with other additives are often adopted to improve the overall performance of soil washing solution for decontamination. Worldwide the field studies and full-scale remediation using surfactant-based technologies are yet limited, however, the already known cases reveal the good prospect of applying surfactant-based technologies to soil remediation. PMID- 25528486 TI - Study on the correlation between copper oxide nanoparticles induced growth suppression and enhanced lignification in Indian mustard (Brassica juncea L.). AB - In this study, the morphological, physiological and molecular level effects of copper oxide nanoparticles (CuONPs) were studied in an economically important oil seed crop Brassica juncea L. The possible involvement of lignification on shoot root growth retardation was also studied. The seedlings were exposed to 0, 20, 50, 100, 200, 400 and 500mg/L of CuONPs in semi-solid half strength Murashige and Skoog medium under controlled growth chamber conditions for 14 days. Exposure to CuONPs resulted in suppression of shoot-growth, reduction in total chlorophyll and carotenoids contents as well modification of root system architecture such as shortening of primary and lateral roots. Significant increases in hydrogen peroxide formation, peroxidase enzyme activity and lignification of shoots and roots were observed. The lipid peroxidation levels increased significantly in shoots and roots of B. juncea seedlings. Phloroglucinol-HCl staining revealed enhanced lignification of shoot and roots. Gene expression studies revealed significant activation of CuZn superoxide dismutase (CuZnSOD) in roots at all concentrations of CuONPs exposure. In shoots significant up-regulation of CuZnSOD gene was observed upon exposure to 100, 200 and 400 mg/L of CuONPs exposure. However no change in the expression levels of MnSOD gene was observed in both stem and roots. The expression of catalase (CAT) and ascorbate peroxidase (APX) genes were also not changed in shoots. However, significant inhibition of CAT and APX genes were observed in roots of B. juncea plants under exposure to 100, 200, 400 and 500 mg/L of CuONPs exposure. The SOD enzyme activity significantly increased in roots under exposure to 50-500 mg/L of CuONPs and in shoots as a result of exposure to 100-500 mg/L of CuONPs. The APX activity significantly decreased in roots upon exposure to 50-500 mg/L of CuONPs. In shoots, the APX activity significantly decreased upon exposure to 200-500 mg/L of CuONPs. PMID- 25528487 TI - Direct effects of the algal toxin, domoic acid, on ovarian function: Bovine granulosa and theca cells as an in vitro model. AB - Domoic acid (DA) is a potent neurotoxin produced by alga Pseudo-nitzschia spp. and has been associated with reproductive disorders in mammals. The aim of this study was to investigate if DA can affect the reproductive system via direct action on ovarian function. Bovine granulosa and theca cells were used as in vitro models for evaluating DA effects on ovarian cell proliferation and steroid production. In small-follicle granulosa cells (SMGC), cell proliferation and estradiol (E2) production was not affected (P>0.05) while progesterone (P4) production was inhibited (P<0.05) by DA at all doses tested. In large-follicle granulosa cells (LGGC), DA had no effect (P>0.05) on cell proliferation or P4 production while E2 production was stimulated by 1 and 5 ug/ml DA (P<0.05). DA (1 ug/ml) attenuated (P<0.05) insulin-like growth factor 1 (IGF-1)-induced P4 production by large-follicle theca cells (LGTC), but did not affect androstenedione (A4) production or proliferation of LGTC. In glutamate-free medium, DA inhibited (P<0.05) SMGC E2 production and this inhibition was similar to inhibition of E2 by trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid monohydrate (ACPD; a selective metabotropic glutamate receptor subtype agonist) while kainic acid (KA; an ionotropic glutamate receptor subtype agonist) had no effect (P>0.10) on E2 production. Collectively, these results show for the first time that DA has direct effects on ovarian GC and TC steroidogenesis. Because DA inhibited E2 and P4 production, DA has the potential to be an endocrine disruptor. PMID- 25528488 TI - Environmental concentrations of benz[a]anthracene induce developmental defects and DNA damage and impair photomotor response in Japanese medaka larvae. AB - Benz[a]anthracene (BaA) is a ubiquitous polycyclic aromatic hydrocarbon found in numerous aquatic ecosystems. However, ecotoxicological data in aquatic organisms are scarce. To remedy this lack of data, Japanese medaka (Oryzias latipes) embryos were exposed to BaA and toxic effects were investigated at multiple toxicological endpoints. Japanese medaka embryos were incubated onto BaA-spiked artificial sediment for 9 days at low or moderate environmental concentrations ranging from 0.9 to 12 ugg(-1) dw. BaA-exposed embryos exhibited significant tachycardia. BaA exposure was also shown to increase CYP1A activity in the hepato biliary tissue as well as craniofacial deformities and DNA damage in pro-larvae. The photomotor response of BaA-exposed larvae was reduced in comparison to the control group. According to this set of tests, the lowest tested and observed effect concentration (LOEC) for Japanese medaka early life stages was equivalent to 0.92 ugg(-1) dw of BaA. This concentration fall into the range of concentrations frequently encountered in sediments of polluted aquatic ecosystems. Taking into consideration these results, BaA represents a threat for fish early life stages in particular those developing onto or into contaminated sediments. PMID- 25528489 TI - Microalgae - A promising tool for heavy metal remediation. AB - Biotechnology of microalgae has gained popularity due to the growing need for novel environmental technologies and the development of innovative mass production. Inexpensive growth requirements (solar light and CO2), and, the advantage of being utilized simultaneously for multiple technologies (e.g. carbon mitigation, biofuel production, and bioremediation) make microalgae suitable candidates for several ecofriendly technologies. Microalgae have developed an extensive spectrum of mechanisms (extracellular and intracellular) to cope with heavy metal toxicity. Their wide-spread occurrence along with their ability to grow and concentrate heavy metals, ascertains their suitability in practical applications of waste-water bioremediation. Heavy metal uptake by microalgae is affirmed to be superior to the prevalent physicochemical processes employed in the removal of toxic heavy metals. In order to evaluate their potential and to fill in the loopholes, it is essential to carry out a critical assessment of the existing microalgal technologies, and realize the need for development of commercially viable technologies involving strategic multidisciplinary approaches. This review summarizes several areas of heavy metal remediation from a microalgal perspective and provides an overview of various practical avenues of this technology. It particularly details heavy metals and microalgae which have been extensively studied, and provides a schematic representation of the mechanisms of heavy metal remediation in microalgae. PMID- 25528490 TI - Ability of ambulatory ECG-based T-wave alternans to modify risk assessment of cardiac events: a systematic review. AB - BACKGROUND: Exercise-based spectral T-wave alternans (TWA) has been proposed as a noninvasive tool-identifying patients at risk of sudden cardiac death (SCD) and cardiac mortality. Prior studies have indicated that ambulatory electrocardiogram (AECG)-based TWA is an important alternative platform to exercise for risk stratification of cardiac events. This study sought to review data regarding 24 hour AECG-based TWA and to discuss its potential role in risk stratification of fatal cardiac events across a series of patient risk profiles. METHODS: Prospective clinical studies of the predictive value of AECG-based TWA obtained with daily activity published between January 1990 and November 2014 were retrieved. Major endpoints included composite endpoint of SCD, cardiac mortality, and severe arrhythmic events. RESULTS: Data were accumulated from 5 studies involving a total of 1,588 patients, including 317 positive and 1,271 negative TWA results. Compared with the negative group, positive group showed increased rates of SCD (hazard ratio [HR]: 7.49, 95% confidence interval [CI]: 2.65 to 21.15), cardiac mortality (HR: 4.75, 95% CI: 0.42 to 53.55), and composite endpoint (SCD, cardiac mortality, and severe arrhythmic events, HR: 5.94, 95% CI: 1.80 to 19.63). For the 4 studies evaluating TWA measured using the modified moving average method, the HR associated with a positive versus negative TWA result was 9.51 (95% CI: 4.99 to 18.11) for the composite endpoint. CONCLUSIONS: The positive group of AECG-based TWA has a nearly six-fold risk of severe outcomes compared with the negative group. Therefore, AECG-based TWA provides an accurate means of predicting fatal cardiac events. PMID- 25528491 TI - Current focussing in cochlear implants: an analysis of neural recruitment in a computational model. AB - Several multipolar current focussing strategies are examined in a computational model of the implanted human cochlea. The model includes a realistic spatial distribution of cell bodies of the auditory neurons throughout Rosenthal's canal. Simulations are performed of monopolar, (partial) tripolar and phased array stimulation. Excitation patterns, estimated thresholds, electrical dynamic range, excitation density and neural recruitment curves are determined and compared. The main findings are: (I) Current focussing requires electrical field interaction to induce spatially restricted excitation patterns. For perimodiolar electrodes the distance to the neurons is too small to have sufficient electrical field interaction, which results in neural excitation near non-centre contacts. (II) Current focussing only produces spatially restricted excitation patterns when there is little or no excitation occurring in the peripheral processes, either because of geometrical factors or due to neural degeneration. (III) The model predicts that neural recruitment with electrical stimulation is a three dimensional process; regions of excitation not only expand in apical and basal directions, but also by penetrating deeper into the spiral ganglion. (IV) At equal loudness certain differences between the spatial excitation patterns of various multipoles cannot be simulated in a model containing linearly aligned neurons of identical morphology. Introducing a form of variability in the neurons, such as the spatial distribution of cell bodies in the spiral ganglion used in this study, is therefore essential in the modelling of spread of excitation. This article is part of a Special Issue entitled . PMID- 25528492 TI - Inner ear contribution to bone conduction hearing in the human. AB - Bone conduction (BC) hearing relies on sound vibration transmission in the skull bone. Several clinical findings indicate that in the human, the skull vibration of the inner ear dominates the response for BC sound. Two phenomena transform the vibrations of the skull surrounding the inner ear to an excitation of the basilar membrane, (1) inertia of the inner ear fluid and (2) compression and expansion of the inner ear space. The relative importance of these two contributors were investigated using an impedance lumped element model. By dividing the motion of the inner ear boundary in common and differential motion it was found that the common motion dominated at frequencies below 7 kHz but above this frequency differential motion was greatest. When these motions were used to excite the model it was found that for the normal ear, the fluid inertia response was up to 20 dB greater than the compression response. This changed in the pathological ear where, for example, otosclerosis of the stapes depressed the fluid inertia response and improved the compression response so that inner ear compression dominated BC hearing at frequencies above 400 Hz. The model was also able to predict experimental and clinical findings of BC sensitivity in the literature, for example the so called Carhart notch in otosclerosis, increased BC sensitivity in superior semicircular canal dehiscence, and altered BC sensitivity following a vestibular fenestration and RW atresia. PMID- 25528493 TI - Flashbacks, intrusions, mind-wandering - Instances of an involuntary memory spectrum: A commentary on Takarangi, Strange, and Lindsay (2014). AB - In their paper, Takarangi, Strange, and Lindsay (2014) showed in two experiments that participants who had witnessed a shocking film frequently "mind-wandered without awareness" about the content of the film. More importantly, they equated this effect with the occurrence of traumatic intrusions. In this commentary, we argue that the authors adhered to conceptually ambiguous terms, and thereby unintentionally contribute to an already existing conceptual blur in the trauma memory field. We postulate that clear definitions are urgently needed for phenomena such as intrusions, flashbacks, and mind-wandering, when using them in the context of trauma memory. Furthermore, our proposal is that these phenomena can fall under a spectrum of different involuntary memory instances. We propose that by adopting stricter definitions and viewing them as separate, but interrelated phenomena, different lines of trauma-memory research can be reconciled, which would considerably advance the field. PMID- 25528494 TI - The experience of freedom in decisions - Questioning philosophical beliefs in favor of psychological determinants. AB - Six experiments tested two competing models of subjective freedom during decision making. The process model is mainly based on philosophical conceptions of free will and assumes that features of the process of choosing affect subjective feelings of freedom. In contrast, the outcome model predicts that subjective freedom is due to positive outcomes that can be expected or are achieved by a decision. Results heavily favored the outcome model over the process model. For example, participants felt freer when choosing between two equally good than two equally bad options. Process features including number of options, complexity of decision, uncertainty, having the option to defer the decision, conflict among reasons, and investing high effort in choosing generally had no or even negative effects on subjective freedom. In contrast, participants reported high freedom with good outcomes and low freedom with bad outcomes, and ease of deciding increased subjective freedom, consistent with the outcome model. PMID- 25528495 TI - Acute rectal ischemia following failed uterine artery embolization and emergency hysterectomy for postpartum hemorrhage. PMID- 25528496 TI - Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. AB - OBJECTIVE: Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma. METHODS: This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib. RESULTS: 67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade >=3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%). CONCLUSIONS: Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma. PMID- 25528497 TI - Distribution and case-fatality ratios by cell-type for ovarian carcinomas: a 22 year series of 562 patients with uniform current histological classification. AB - BACKGROUND: Ovarian carcinoma is comprised of several different cell types reflecting different clinicopathologic features. Pathologic criteria for distinguishing cell types have evolved, and therefore non-contemporary literature on ovarian cancer may have limited current relevance. A new dualistic model of pathogenesis that distinguishes type I (endometrioid, mucinous, clear cell and low grade serous carcinomas) from type II (high grade serous carcinomas and carcinosarcomas) tumors has become widely accepted. METHODS: A cohort of 562 patients with invasive ovarian carcinoma from a large community hospital practice was reviewed. Cell type, FIGO stage, mortality and interpathologist diagnostic reproducibility were analyzed. RESULTS: Advanced stage ovarian carcinomas were type II in 86% of cases while low stage tumors were most often type I. Only 1.7% of type II tumors were confirmed to be stage I with comprehensive surgical staging. Type II tumors accounted for 85% of deaths, and clear cell carcinomas, 5% of deaths. Cell type-specific case-fatality ratios for type II tumors were 62% and 79% for high grade serous carcinoma and carcinosarcoma, respectively. For type I tumors, case-fatality ratios were 38%, 36%, 27% and 13% for low grade serous, clear cell, endometrioid and mucinous carcinomas, respectively. The kappa value for diagnostic reproducibility among 3 gynecologic pathologists was 0.83. CONCLUSIONS: Current diagnostic criteria confirm that high grade serous carcinoma and carcinosarcoma account for the vast majority (85%) of ovarian cancer deaths. Cell type designation is highly reproducible among gynecologic pathologists. Type II tumors are rarely stage I (<2%) when comprehensively staged by a gynecologic oncologist. PMID- 25528499 TI - Analyzing person, situation and person * situation interaction effects: Latent state-trait models for the combination of random and fixed situations. AB - Latent state-trait (LST) models (Steyer, Ferring, & Schmitt, 1992) allow separating person-specific (trait) effects from (1) effects of the situation and person * situation interactions, and (2) random measurement error in purely observational studies. Typical LST applications use measurement designs in which all situations are sampled randomly and do not have to be known for any individual. Limitations of conventional LST models for only random situations are that traits are implicitly assumed to generalize perfectly across situations, and that main effects of situations are inseparable from person * situation interaction effects because both are measured by the same latent variable. In this article, we show how these limitations can be overcome by using measurement designs in which two or more random situations are nested within two or more fixed situations that are known for each individual. We present extended LST models for the combination of random and fixed situations (LST-RF approach) and show that the extensions allow (1) examining the extent to which traits are situation-specific and (2) isolating person * situation interactions from situation main effects. We demonstrate that the LST-RF approach can be applied with both homogenous and heterogeneous indicators in either the single- or multilevel structural equation modeling frameworks. Advantages and limitations of the new models as well as their relation to other approaches for studying person * situation interactions are discussed. PMID- 25528500 TI - Non-chromatographic preparative purification of enhanced green fluorescent protein. AB - Recombinant enhanced green fluorescent protein (eGFP) is used as a marker in numerous applications in biomedical research and diagnostics. For these applications, the macromolecule needs to be provided in a highly purified form. The conventional purification process of eGFP usually consists of multiple subsequent preparative chromatography steps. Since this procedure is costly and time-consuming, an alternative chromatography-free purification process was investigated. This process was a combination of three-phase partitioning (TPP) and preparative crystallization including an ultrafiltration/diafiltration (UF/DF) intermediate step. After the TPP step, eGFP with a purity level suitable for preparative crystallization of 82.5-85.0% and a yield of 84-92% was obtained depending on the scale. After cross-flow UF/DF, the crystallization was performed in parallelized mL-scale stirred tanks. A favorable robust crystal morphology was obtained combined with fast crystallization kinetics when two polyethylenglycols and ethanol were used simultaneously as crystallization additives. The crystallization process can easily be scaled-up to obtain large amounts of highly purified, concentrated eGFP with a purity >99% after a crystal wash step and resolubilization. The proposed chromatography-free purification procedure gives reason to expect significant reductions of costs and required process time compared to conventional preparative chromatography. PMID- 25528501 TI - Highly sensitive luciferase reporter assay using a potent destabilization sequence of calpain 3. AB - Reporter assays that use luciferases are widely employed for monitoring cellular events associated with gene expression in vitro and in vivo. To improve the response of the luciferase reporter to acute changes of gene expression, a destabilization sequence is frequently used to reduce the stability of luciferase protein in the cells, which results in an increase of sensitivity of the luciferase reporter assay. In this study, we identified a potent destabilization sequence (referred to as the C9 fragment) consisting of 42 amino acid residues from human calpain 3 (CAPN3). Whereas the half-life of Emerald Luc (ELuc) from the Brazilian click beetle Pyrearinus termitilluminans was reduced by fusing PEST (t1/2=9.8 to 2.8h), the half-life of C9-fused ELuc was significantly shorter (t1/2=1.0h) than that of PEST-fused ELuc when measurements were conducted at 37 degrees C. In addition, firefly luciferase (luc2) was also markedly destabilized by the C9 fragment compared with the humanized PEST sequence. These results indicate that the C9 fragment from CAPN3 is a much more potent destabilization sequence than the PEST sequence. Furthermore, real-time bioluminescence recording of the activation kinetics of nuclear factor-kappaB after transient treatment with tumor necrosis factor alpha revealed that the response of C9-fused ELuc is significantly greater than that of PEST-fused ELuc, demonstrating that the use of the C9 fragment realizes a luciferase reporter assay that has faster response speed compared with that provided by the PEST sequence. PMID- 25528502 TI - The development of an online measure of therapist competence. AB - The topic of therapist training has been relatively neglected in the research literature. Similarly, the related issue of the measurement of the outcome of training, especially therapist competence, has been largely overlooked. Data supporting the effectiveness of various methods of clinician training and those providing estimates of the level of competence achieved by clinicians are scarce. Validated scalable methods for the measurement of clinician outcomes such as competence are required to evaluate both existing and new methods of training. This study focuses on the development and testing of an online measure (eMeasure) to assess therapists' applied knowledge of Enhanced Cognitive Behaviour Therapy (CBT-E), a transdiagnostic evidence-supported treatment for the full range of eating disorders. The eMeasure meets the stringent requirements of the Rasch model and has three equivalent versions making it suitable for repeat testing of trainees in outcome studies. Preliminary best cut points to distinguish between those who are competent and those who are not are identified. While the present work focused on CBT-E, the method described may be used to develop and test other measures relating to therapist competence. PMID- 25528503 TI - Conformational stability, spectroscopic (FT-IR, FT-Raman and UV-Vis) analysis, NLO, NBO, FMO and Fukui function analysis of 4-hexylacetophenone by density functional theory. AB - The experimental and theoretical study on the structures and vibrations of 4 hexylacetophenone (abbreviated as 4HAP) are presented. The FT-IR and FT-Raman spectra of the title compound have been recorded in the region 4000-400cm(-1) and 3500-100cm(-1) respectively. The molecular structures, vibrational wavenumbers, infrared intensities and Raman activities were calculated using DFT (B3LYP and LSDA) method with 6-311++G(d,p) basis set. The most stable conformer of 4HAP is identified from the computational results. The assignments of the vibrational spectra have been carried out with the aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMEF). The linear polarizability (alpha) and the first hyperpolarizability (betatot) values of the investigated molecule have been computed using B3LYP and LSDA with 6 311++G(d,p) basis set. Stability of the molecule arising from hyper conjugative interaction and charge transfer delocalization has been analyzed using natural bond orbital (NBO) analysis. The molecule orbital contributions are studied by density of energy states (DOSs). UV-Vis spectrum and effects of solvents have been discussed effects of solvents have been discussed and the electronic properties such as HOMO and LUMO energies were determined by time-dependent TD DFT approach. Fukui function and Mulliken analysis on atomic charges of the title compound have been calculated. Finally, electrophilic and nucleophilic descriptors of the title molecule have been calculated. PMID- 25528504 TI - An integrated experimental and theoretical investigation of the vibrational modes and molecular structure of a chelate, tetraaqua cysteine aluminum(III). AB - The complex formed by Al(3+) and cysteine in aqueous solution has been studied by potentiometry, Raman spectroscopy and DFT calculations (DFT:B3LYP/6-311++G(**)). Atomic charges, frontier molecular orbitals, electrostatic potential contour surface, electrostatic potential map and donor-acceptor second order perturbative energies were examined. The [Al(Cys)(H2O)4](2+) complex adopts a distorted octahedral geometry. Cysteine should act as a bidentate ligand through the oxygen of the carboxylate and the nitrogen of the amino group. The molecule has high HOMO-LUMO energy gap, intense intramolecular charge transfer and positive electrostatic potential. PMID- 25528505 TI - A combined experimental and DFT study of a novel unsymmetrical azine 2-(4 methoxybenzylidene)-1-(1-(4-isobutylphenyl) ethylidene) hydrazine. AB - A novel unsymmetrical azine 2-(4-methoxybenzylidene)-1-(1-(4-isobutylphenyl) ethylidene) hydrazine (UA) was prepared and characterized by IR, (1)H and (13)C NMR spectral studies. A 2D - potential energy scan (PES) of p isobutylacetophenone (IBAP) was the portal to the conformational analysis of UA by density functional theory (DFT) methods using 6-31G(d,p) basis set by Gaussian 03 program. The theoretical IR frequencies were found to be in good agreement with the experimental values. The IR frequencies of UA were analyzed by means of Potential energy Distribution (PED %) calculation using Vibrational Energy Distribution Analysis (VEDA 4) program. The experimental NMR chemical shift values of UA were compared with the theoretical values obtained by DFT method. Nonlinear optical behavior of the unsymmetrical azine is also examined by the theoretically predicted values of dipole moment (MU), polarizability (alpha0) and first hyperpolarizability (betatot). Stability of the UA molecule has been analyzed using NBO analysis. The electrochemistry of UA studied experimentally by cyclic voltammetry is complemented by the computational analysis of the anionic form of the molecule UA. The determination of various global and local reactivity descriptors in the context of chemical reactivity is also performed and the electrophilicity at the vital atomic sites in UA is revealed. Bader's Atoms in molecules (AIM) theory of UA indicated the presence of intramolecular hydrogen bonding in the molecule. The molecular electrostatic potential (MEP) and HOMO LUMO orbital analysis are also performed for the molecule UA. PMID- 25528506 TI - Artificial neural network assisted kinetic spectrophotometric technique for simultaneous determination of paracetamol and p-aminophenol in pharmaceutical samples using localized surface plasmon resonance band of silver nanoparticles. AB - Spectrophotometric analysis method based on the combination of the principal component analysis (PCA) with the feed-forward neural network (FFNN) and the radial basis function network (RBFN) was proposed for the simultaneous determination of paracetamol (PAC) and p-aminophenol (PAP). This technique relies on the difference between the kinetic rates of the reactions between analytes and silver nitrate as the oxidizing agent in the presence of polyvinylpyrrolidone (PVP) which is the stabilizer. The reactions are monitored at the analytical wavelength of 420nm of the localized surface plasmon resonance (LSPR) band of the formed silver nanoparticles (Ag-NPs). Under the optimized conditions, the linear calibration graphs were obtained in the concentration range of 0.122-2.425MUgmL( 1) for PAC and 0.021-5.245MUgmL(-1) for PAP. The limit of detection in terms of standard approach (LODSA) and upper limit approach (LODULA) were calculated to be 0.027 and 0.032MUgmL(-1) for PAC and 0.006 and 0.009MUgmL(-1) for PAP. The important parameters were optimized for the artificial neural network (ANN) models. Statistical parameters indicated that the ability of the both methods is comparable. The proposed method was successfully applied to the simultaneous determination of PAC and PAP in pharmaceutical preparations. PMID- 25528498 TI - Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study. AB - OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. PMID- 25528507 TI - Synthesis and characterization of perchlorato bridged Cu2(II)Zn(II) heterotrinuclear complexes derived from succinoyldihydrazones. AB - In the present paper three new heterotrimetallic Cu(II)-Zn(II)-Cu(II) complexes have been synthesized and characterized by analytical and spectroscopic studies. The molar conductance values for the complexes fall in the region 1.2-1.7Omega( 1)cm(2)mol(-1) in DMSO solution indicating that all of the complexes are non electrolyte. The dihydrazone ligand is present in enol form in all of the complexes. Both the copper centres have distorted square pyramidal stereochemistry in all of the complexes while the zinc centre in all hetero metal complexes has octahedral stereochemistry. The EPR parameters of the complexes indicate that the copper centre has [Formula: see text] orbital as the ground state. The electron transfer reactions of the complexes have been investigated by cyclic voltammetry. PMID- 25528508 TI - Preparation and characterization of SeO2/TiO2 composite photocatalyst with excellent performance for sunset yellow azo dye degradation under natural sunlight illumination. AB - To improve the solar light induced photocatalytic application performances of TiO2, in this study, the SeO2 modified TiO2 composite photocatalysts with various ratios of SeO2 to TiO2 were prepared by sol-gel method. The catalyst was characterized by X-ray diffraction (XRD), high resolution scanning electron microscope (HR-SEM), energy dispersive spectra (EDS), diffuse reflectance spectra (DRS), photoluminescence spectra (PL), X-ray photoelectron spectroscopy (XPS) and Brunauer-Emmett-Teller (BET) surface area measurement methods. The photocatalytic activity of SeO2/TiO2 was investigated for the degradation of sunset yellow (SY) in aqueous solution using solar light. The SeO2/TiO2 is found to be more efficient than prepared TiO2 and TiO2-P25 at pH 7 for the mineralization of SY. The effects of operational parameters such as the amount of photocatalyst, dye concentration and initial pH on photo mineralization of SY have been analyzed. The degradation was strongly enhanced in the presence of electron acceptors such as oxone, KIO4 and KBrO3. The kinetics of SY photodegradation was found to follow the pseudo-first order rate law and could be described in terms of Langmuir Hinshelwood model. The mineralization of SY has been confirmed by COD measurements. The catalyst is found to be reusable. PMID- 25528509 TI - Interaction between transition metals and phenylalanine: a combined experimental and computational study. AB - Some transition metal complexes of phenylalanine of general formula [M(C9H10NO2)2]; where M=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) are prepared in aqueous medium and characterized by spectroscopic, thermo-gravimetric (TG) and magnetic susceptibility analysis. Density functional theory (DFT) has been employed calculating the equilibrium geometries and vibrational frequencies of those complexes at B3LYP level of theory using 6-31G(d) and SDD basis sets. In addition, frontier molecular orbital and time-dependent density functional theory (TD-DFT) calculations are performed with CAM-B3LYP/6-31+G(d,p) and B3LYP/SDD level of theories. Thermo-gravimetric analysis confirms the composition of the complexes by comparing the experimental and calculated data for C, H, N and metals. Experimental and computed IR results predict a significant change in vibrational frequencies of metal-phenylalanine complexes compared to free ligand. DFT calculation confirms that Mn, Co, Ni and Cu complexes form square planar structure whereas Zn adopts distorted tetrahedral geometry. The metal-oxygen bonds in the optimized geometry of all complexes are shorter compared to the metal-nitrogen bonds which is consistent with a previous study. Cation-binding energy, enthalpy and Gibbs free energy indicates that these complexes are thermodynamically stable. UV-vis and TD-DFT studies reveal that these complexes demonstrate representative metal-to-ligand charge transfer (MLCT) and d-d transitions bands. TG analysis and IR spectra of the metal complexes strongly support the absence of water in crystallization. Magnetic susceptibility data of the complexes exhibits that all except Zn(II) complex are high spin paramagnetic. PMID- 25528510 TI - Ligand sensitized luminescence of uranyl by benzoic acid in acetonitrile medium: a new luminescent uranyl benzoate specie. AB - Benzoic acid (BA) is shown to sensitize and enhance the luminescence of uranyl ion in acetonitrile medium. Luminescence spectra and especially UV-Vis spectroscopy studies reveal the formation of tri benzoate complex of uranyl i.e. [UO2(C6H5COO)3](-) which is highly luminescent. In particular, three sharp bands at 431, 443, 461nm of absorption spectra provides evidence for tri benzoate specie of uranyl in acetonitrile medium. The luminescence lifetime of uranyl in this complex is 68MUs which is much more compared to the lifetime of uncomplexed uranyl (20MUs) in acetonitrile medium. In contrary to aqueous medium where uranyl benzoate forms 1:1 and 1:2 species, spectroscopic data reveal formation of 1:3 complex in acetonitrile medium. Addition of water to acetonitrile results in decrease of luminescence intensity of this specie and the luminescence features implode at 20% (v/v) of water content. For the first time, to the best of our knowledge, the existence of [UO2(C6H5COO)3](-) specie in acetonitrile is reported. Mechanism of luminescence enhancement is discussed. PMID- 25528511 TI - Nano structure zinc (II) Schiff base complexes of a N3-tridentate ligand as new biological active agents: spectral, thermal behaviors and crystal structure of zinc azide complex. AB - In this work, synthesis of some new five coordinated zinc halide/pseudo-halide complexes of a N3-tridentate ligand is presented. All complexes were subjected to spectroscopic and physical methods such as FT-IR, UV-visible, (1)H and (13)C NMR spectra, thermal analyses and conductivity measurements for identification. Based on spectral data, the general formula of ZnLX2 (X=Cl(-), Br(-), I(-), SCN(-) and N3(-)) was proposed for the zinc complexes. Zinc complexes have been also prepared in nano-structure sizes under ultrasonic irradiation. X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were applied for confirmation of nano-structure character for the complexes. Among the complexes, zinc azide complex structure was analyzed by X-ray crystallography. This complex crystallizes as a triplet in trigonal system with space group of P31. The coordination sphere around the zinc center is well shown as a distorted trigonal bipyramidal with three nitrogen atoms from Schiff base ligand and two terminal azide nitrogen atoms attached to zinc ion. Various intermolecular interactions such as NH?N, CH?N and CH?pi hydrogen bonding interactions stabilize crystalline lattice so that they causes a three dimensional supramolecular structure for the complex. In vitro screening of the compounds for their antimicrobial activities showed that ZnLI2, ZnL(N3)2, ZnLCl2 and ZnL(NCS)2 were found as the most effective compound against bacteria of Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli respectively. Also ZnLI2 and ZnLCl2 complexes were found more effective against two selected fungi than others. Finally, thermal behaviors of the zinc complexes showed that they are decomposed via 2-4 thermal steps from room temperature up to 1000 degrees C. PMID- 25528512 TI - Infrared spectrum, structural and optical properties and molecular docking study of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde. AB - The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1 carbaldehyde have been investigated experimentally and theoretically. The title compound was optimized using at HF and DFT levels of calculations. The B3LYP/6 311++G(d,p) (5D,7F) results and in agreement with experimental infrared bands. The normal modes are assigned using potential energy distribution. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using natural bonding orbital analysis. The frontier molecular orbital analysis is used to determine the charge transfer within the molecule. From molecular electrostatic potential map, it is evident that the negative electrostatic potential regions are mainly localized over the carbonyl group and mono substituted phenyl ring and are possible sites for electrophilic attack and, positive regions are localized around all para substituted phenyl and pyrazole ring, indicating possible sites for nucleophilic attack. First hyperpolarizability is calculated in order to find its role in nonlinear optics. The geometrical parameters are in agreement with experimental data. From the molecular docking studies, it is evident that the fluorine atom attached to phenyl ring and the carbonyl group attached to pyrazole ring are crucial for binding and the results draw us to the conclusion that the compound might exhibit phosphodiesterase inhibitory activity. PMID- 25528513 TI - The guanidine and benzoic acid (1:1) complex. The polarized vibrational studies and theoretical investigations. AB - The structure of guanidinium benzoate was discovered by Silva et al. On the basis of these X-ray crystallographic studies the detailed DFT investigation are performed. According to this result the infrared spectrum for one theoretical molecule was calculated. On the basis of potential energy distribution (PED) analysis the clear-cut assignments of observed bands were performed. For the calculated molecule with energy minimum the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were obtained. The energy difference between HOMO and LUMO was analyzed. According to theoretical calculations the direction of dipole moments (TDM) for bands observed in infrared spectra are analyzed. Verification of theoretical TDM behaviors is performed on the basis of experimental polarized specular reflection infrared spectra. The detailed assignments of observed bands is presented. Both theoretical and experimental spectra are compared. Crucial role of three different hydrogen bonds is studied in detail. Additionally, on the basis of differential scanning calorimetric study no phase transition was found in investigated crystal in the range 100-400K. PMID- 25528514 TI - Electronic structure of antibiotic erythromycin. AB - The electronic structure of erythromycin A (ERYMA) molecule has been studied by UV photoelectron spectroscopy and assigned (in the low ionization energy region only) by empirical arguments. The two orbitals with highest energy (lowest ionization energy) are localized on the nitrogen of the desosamine sugar functional group and on the ester group of macrolide (lactone) ring. We discuss how these orbital energies can help to rationalize the known mode of binding of ERYMA to their biological receptors. PMID- 25528515 TI - Regret and disappointment in ASD: the matter of thinking versus feeling: a commentary on "feelings of regret and disappointment in adults with high functioning autism" by Zalla et al., 2014. PMID- 25528517 TI - Draft genome sequence of Pseudomonas oleovorans strain MGY01 isolated from deep sea water. AB - Pseudomonas oleovorans MGY01 isolated from the deep-sea water of the South China Sea could effectively degrade malachite green. The draft genome of P. oleovorans MGY01 was sequenced and analyzed to gain insights into its efficient metabolic pathway for degrading malachite green. The data obtained revealed 109 Contigs (N50; 128,269 bp) with whole genome size of 5,201,892 bp. The draft genome sequence of strain MGY01 will be helpful in studying the genetic pathways involved in the degradation of malachite green. PMID- 25528518 TI - The Keap1-Nrf2-antioxidant response element pathway: a review of its regulation by melatonin and the proteasome. AB - Both melatonin and proteasome inhibitors upregulate antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GP), hemoxygenase 1 (HO-1), and NADPH:quinone oxidoreductase (NQO1). Recent evidence suggests that the antioxidant action of both melatonin and proteasome inhibitors involves the Keap1 ARE (Keap1 antioxidant response element) pathway via the upregulation of Nrf2. Melatonin and proteasome inhibitors suppress the degradation of Nrf2 and also enhance its nuclear translocation. In the nucleus Nrf2, together with a cofactor, stimulates the transcription of antioxidant enzymes and detoxifying enzymes. The ligase (E3) complex (Keap1-Cul3-Rbx1) responsible for ubiquitinating Nrf2, prior to proteasomal degradation, also ubiquitinates IkB kinase and the antiapoptotic factor Bcl-2, and possibly additional proteins. In various systems, NF-kappaB, which is inhibited by IkBalpha, is downregulated by proteasome inhibitors as well as by melatonin. Similarly in leukemic cells, Bcl-2 is down-regulated by the proteasome inhibitor, bortezomib, and also by melatonin. Thus melatonin administration modulates the activity of three separate substrates of the Keap1 Cul3-Rbx1 ubiquitin ligase. These facts could be accounted for by the hypothesis that melatonin interacts with the ubiquitin ligase complex or, more likely, by the hypothesis that melatonin acts as a proteasome inhibitor. A recent study documented that melatonin acts as a proteasome inhibitor in cancer cells as well as inhibiting chymotrypsin-like activity in cell-free systems of these cells. Further studies, however, are needed to clarify the interaction of melatonin and the ubiquitin-proteasome system as they relate to oxidative stress. PMID- 25528519 TI - Transcriptional profiling of five isolated size-matched stages of human preantral follicles. AB - Little is known of the early stages of human follicular development and the complex processes that regulate follicular growth. To identify genes of potential importance, we analysed follicle-related transcripts in five populations of isolated size-matched human preantral follicles by microarray analysis. Oocyte specific genes were found to be the most abundant and differentially expressed transcripts and included germ cell transcription factors LHX8 and SOHLH2 which were significantly down-regulated during preantral follicle development. Differentially expressed genes also included transcription factors of NOTCH signalling, IGF2, orphan nuclear receptor LRH-1, and homeobox gene HOXA7, indicating potentially important regulatory roles for these genes during early human folliculogenesis. We also found that FSHR mRNA and protein were present in the earliest stages of preantral follicles, whereas LHR was absent. In conclusion, our data identify specific oocyte and somatic genes in small human follicles that impact early follicle growth, and provide foundation for further analysis of the signalling pathways involved in early human folliculogenesis. PMID- 25528520 TI - Factors influencing frontline health service providers' likelihood to recommend a future, preventive HIV vaccine to key populations in Karnataka, south India. AB - The HIV epidemic in the south Indian state of Karnataka disproportionately burdens key populations of men who have sex with men and female sex workers. Despite having successfully reduced HIV incidence among certain key populations through the use of targeted intervention, India's HIV epidemic remains one of its greatest public health issues. The best long-term strategy for managing the global HIV epidemic might involve a preventive vaccine; however, vaccine availability cannot guarantee its accessibility or acceptability. Vaccine recommendations from frontline health service providers have previously been identified as useful strategies to enhance vaccine uptake among target groups. This study used structured interviews to explore frontline health service providers' self-identified likelihood to recommend a future, preventive HIV vaccine to key populations in Karnataka. A modified social ecological model was then used to categorise factors that might prevent health service providers from recommending an HIV vaccine. Overall, 83% of health service providers reported that they would be very likely to recommend an HIV vaccine to men who have sex with men and female sex workers, while less than one-third of participants identified one or more barrier to vaccine recommendation. Intrapersonal, interpersonal, and structural/political factors were most commonly reported to act as potential barriers to future HIV vaccine recommendation among health service providers in Karnataka. This study adds to the limited body of literature focussing on future HIV vaccine acceptability in low- and middle-income countries and highlights some of the several complexities surrounding vaccine acceptability and uptake among key populations in Karnataka. PMID- 25528521 TI - Genetic and immunologic relationships between vaccine and field strains for vaccine selection of type A foot-and-mouth disease virus circulating in East Asia. AB - Of the seven known serotypes of foot-and-mouth disease virus (FMDV), type A has the most diverse variations. Genetic variations also occur frequently at VP1, VP2, VP3, and VP4 because these proteins constitute the viral capsid. The structural proteins of FMDV, which are closely related to immunologic correlations, are the most easily analyzed because they have highly accessible information. In this study we analyzed the type A vaccine viruses by alignment of available sequences in order to find appropriate vaccine strains. The matching rate of ASIA topotype-specific sites (20 amino acids) located on the viral surface, which are mainly VP1 and VP2, was highly related to immunologic reactivity. Among the available vaccines analyzed in this study, we suggest that A Malaysia 97 could be used as a vaccine virus as it has the highest genetic similarity and immunologic aspects to field strains originating in East Asia. PMID- 25528522 TI - Protective immune response to liposome adjuvanted high potency foot-and-mouth disease vaccine in Indian cattle. AB - BACKGROUND: Foot-and-mouth disease (FMD) vaccines applied for prophylactic use in endemic areas provide short-lived immunity requiring regular boosters. Indian FMD control program recommends twice a year vaccination. Development of high potency vaccines that provide better immune response can singificantly contribute to control programme by reducing the frequency of vaccination. The present study explores new adjuvants to enhance the protective efficacy of inactivated trivalent FMD vaccines. METHODOLOGY AND PRINCIPAL FINDINGS: VacciMax((r)) is a novel adjuvant which uses a liposome-based oil emulsion platform. Cattle were immunized using VacciMax-A and VacciMax-B FMD vaccines and evaluated for protective efficacy. Similar groups of animals were also boosted after 6 months to study the effect of booster immunisation on protection against homologous challenge. Serum samples from immunized animals were tested by virus neutralization test (VNT) and liquid phase blocking ELISA (LPBE). After challenge, animals were screened for virus load by real-time PCR and reactivity in non-structural protein (3ABC) antibody detection ELISA to corroborate the protection data. A single dose of VacciMax-A formulation elicited higher percentage protection (63%) in VacciMax-A compared to 25% in VacciMax-B upon challenge at one-year post-vaccination. Upon boosting at 6 months also, VacciMax A group showed higher levels of protection (100%) compared to VacciMax-B (86%), even though both the groups elicited comparable VNT titre (p=0.4964). The results also demonstrated that intramuscular route was preferrable over subcutaneous route of administration. CONCLUSION: The study demonstrates that immunization with VacciMax-A-IM adjuvanted FMD vaccine with high antigen payload under boosting regimen could effectively be used as potent vaccine to maintain herd immunity. PMID- 25528523 TI - Randomised field trial to evaluate serological response after foot-and-mouth disease vaccination in Turkey. AB - Despite years of biannual mass vaccination of cattle, foot-and-mouth disease (FMD) remains uncontrolled in Anatolian Turkey. To evaluate protection after mass vaccination we measured post-vaccination antibodies in a cohort of cattle (serotypes O, A and Asia-1). To obtain results reflecting typical field protection, participants were randomly sampled from across Central and Western Turkey after routine vaccination. Giving two-doses one month apart is recommended when cattle are first vaccinated against FMD. However, due to cost and logistics, this is not routinely performed in Turkey, and elsewhere. Nested within the cohort, we conducted a randomised trial comparing post-vaccination antibodies after a single-dose versus a two-dose primary vaccination course. Four to five months after vaccination, only a third of single-vaccinated cattle had antibody levels above a threshold associated with protection. A third never reached this threshold, even at peak response one month after vaccination. It was not until animals had received three vaccine doses in their lifetime, vaccinating every six months, that most (64% to 86% depending on serotype) maintained antibody levels above this threshold. By this time cattle would be >20 months old with almost half the population below this age. Consequently, many vaccinated animals will be unprotected for much of the year. Compared to a single-dose, a primary vaccination course of two-doses greatly improved the level and duration of immunity. We concluded that the FMD vaccination programme in Anatolian Turkey did not produce the high levels of immunity required. Higher potency vaccines are now used throughout Turkey, with a two-dose primary course in certain areas. Monitoring post-vaccination serology is an important component of evaluation for FMD vaccination programmes. However, consideration must be given to which antigens are present in the test, the vaccine and the field virus. Differences between these antigens affect the relationship between antibody titre and protection. PMID- 25528524 TI - [Writing the present and looking to the future]. PMID- 25528525 TI - [CONSORT, STROBE, and STARD. Tools to improve the reporting of research]. PMID- 25528526 TI - The distribution of the obstruction in the pulmonary arteries modifies pulsatile right ventricular afterload in pulmonary hypertension. PMID- 25528527 TI - Digoxin use may increase the relative risk of acute pancreatitis: A population based case-control study in Taiwan. AB - OBJECTIVES: The goal of this study was to evaluate the association between digoxin use and acute pancreatitis in Taiwan. METHODS: Utilizing the database of the Taiwan National Health Insurance Program, this case-control study consisted of 6116 subjects aged 20-84years with a first-attack of acute pancreatitis since 2000 to 2011 as the cases and 24,464 randomly selected subjects without acute pancreatitis as the controls. Both cases and controls were matched by sex, age and index year of diagnosing acute pancreatitis. The absence of digoxin prescription was defined as "never use". Active use of digoxin was defined as subjects who at least received 1 prescription for digoxin within 7days before the date of diagnosing acute pancreatitis. Non-active use of digoxin was defined as subjects who did not receive a prescription within 7days but at least received 1 prescription for digoxin >=8days before the date of diagnosing acute pancreatitis. The odds ratio (OR) and 95% confidence interval (CI) were measured to evaluate the association between digoxin use and acute pancreatitis by a multivariable unconditional logistic regression model. RESULTS: After adjusting for potential confounding factors, the adjusted OR of acute pancreatitis was 5.29 for subjects with active use of digoxin (95% CI 3.61, 7.73), when compared with subjects with never use of digoxin. The adjusted OR of acute pancreatitis decreased to 1.04 for subjects with non-active use of digoxin (95% CI 0.89, 1.21), but no statistical significance. CONCLUSIONS: These data indicate that only persons actively using digoxin may have the high relative odds of acute pancreatitis. Further research or case report is warranted to evaluate the pathophysiological basis underlying the relationship between digoxin use and acute pancreatitis. PMID- 25528528 TI - Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: A meta-analysis. AB - BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4is) improve glucose control in patients with type 2 diabetes mellitus (DM); however, only few studies were properly designed to evaluate their cardiovascular (CV) effects. The purpose of this study was to assess the impact of DPP-4i treatment on CV morbidity and mortality. METHODS: Randomized clinical trials enrolling more than 200 patients, comparing DPP-4 versus placebo or active treatments in patients with DM and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of heart failure (HF) were included in the analysis. RESULTS: Ninety-four trials enrolling 85,224 patients (median follow up=29weeks) were included in the analysis. Compared to control, treatment with DPP-4i did not affect all-cause and CV mortality, as well as stroke, in the short and long terms (< and >=29weeks, respectively). DPP-4i reduced the risk of MI in the short (RR: 0.584 [95% CI: 0.361 to 0.943]; p=0.028), but not in the long term. Additionally, long-term treatment with DPP-4 was associated with a 15.8% increased risk of HF (RR: 1.158 [CI: 1.011 to 1.326]; p=0.034). No heterogeneity among studies or publication bias was detected. CONCLUSIONS: DPP4is do not affect all cause- and CV-mortality and stroke in diabetic patients; the reduction in MI observed with short-term treatment does not persist in the long term. Long-term use of DPP-4i in diabetic patients is associated with increased risk of HF. PMID- 25528529 TI - Does exercise cause atrial fibrillation? PMID- 25528530 TI - Stroke risk reduction with oral anticoagulation using CHA2DS2-VASc in a Japanese AF population: A modeling analysis. AB - BACKGROUND: Current clinical guidelines recommend that risk stratification for ischaemic stroke in patients with nonvalvular AF (NVAF) should be performed using the CHA2DS2-VASc score (Congestive heart failure, Hypertension, Age>= 75years [double], Diabetes mellitus, previous thromboembolism [double], Vascular disease, Age 65-74years, and female gender) to aid decision making for antithrombotic treatment, with a preference for Non-Vitamin K Oral Anticoagulants (NOACs) in those with CHA2DS2-VASc score >=1. However, CHA2DS2-VASc score is not recommended in the 2014 Japanese Circulation Society (JCS) guidelines for patients with NVAF. METHODS: To assess the impact of the JCS approach to stroke prevention in AF, and model the impact of using a CHA2DS2-VASc based 2-step decision making strategy, we calculated the incidence of ischaemic stroke in NVAF patients without OAC on basis of the CHADS2 and CHA2DS2-VASc scores using published Japanese data, and estimated the preventable number of stroke events. RESULTS: Using a CHA2DS2-VASc based approach, the potential annual stroke events based on the estimated total number of NVAF patients in Japan was 889,000, as follows: 4369 for dabigatran 150 mg, 6049 for dabigatran 110mg, 5918 for rivaroxaban (intention-to-treat; ITT), 5302 for apixaban, 5843 for edoxaban 60mg (ITT), and 7598 for edoxaban 30 mg (ITT), respectively. Using a CHADS2 score-based approach, the number of potential stroke events was much greater for each agent. CONCLUSION: Our modelling analysis has shown that when considering antithrombotic treatment for Japanese NVAF patients, using a CHA2DS2-VASc-based approach would allow greater opportunities for stroke prevention. PMID- 25528531 TI - Dual emission from 2-(4'-N,N-dimethylaminophenyl)pyridoimidazole-nanoparticle composite: effect of beta-cyclodextrin. AB - The interactions of the silver nanoparticles with 2-(4'-N,N dimethylaminophenyl)benzimidazole and its nitrogen substituted analogues, 2-(4' N,N-dimethylaminophenyl)pyridoimidazoles are investigated by absorption, steady state and time resolved fluorescence, field emission scanning electron microscope (FESEM) and transmission electron microscope (TEM) techniques. The surface plasmon resonance band, the FESEM and the TEM images of the particles suggest that the fluorophores can stabilize the nanoparticles even in the absence of any other stabilizing agent. On the other hand, in the absence of fluorophores the nanoparticles are unstable and coagulate. In contrary to the earlier literature reports that interactions of nanoparticles with intramolecular charge transfer (ICT) or twisted intramolecular charge transfer (TICT) species quenches their fluorescence, to the best of our knowledge, the first ever formation of TICT state by interactions of nanoparticles with the fluorophores is observed. The formation of TICT state in 2-(4'-N,N-dimethylaminophenyl)pyridoimidazoles results in dual emission. The TICT emissions from the nanoparticle-fluorophore complexes are weak. But the emissions become prominent upon complexation with beta cyclodextrin. PMID- 25528532 TI - Fine tuning the pH triggers the enantiorecognition of underivatized amino acids by silver nanoparticles: a novel approach based on the focused use of solution equilibria. AB - Stereoselective amino acid analysis is still a challenging task. In this work, we report a study on the chiral recognition of D,L-Trp and D,L-His using L-Cys capped silver nanoparticles (AgNPs) and copper(II) ion. The AgNPs have been characterized by TEM, UV-Vis spectra and dynamic light scattering (DLS) measurements and used for chiral discrimination. In the L-Cys capped AgNPs, the alpha-amino and alpha-carboxyl groups of the surface-confined amino acid, besides showing either a negative or a neutral charge as a function of the pH, can coordinate the copper(II) ion, which in turn, binds the L- or D-amino acid present in solution forming diastereoisomeric complexes. The resulting systems have been characterized by UV-Vis spectroscopy, exploiting the zwitterionic nature of the cysteine to obtain enantiodiscrimination by a fine tuning of the pH. The analysis of the UV-Vis data by using a multiwavelength approach allows us to determine the kinetic constants ruling the processes. PMID- 25528533 TI - Zwitterionic glycosyl modified polyethersulfone membranes with enhanced anti fouling property and blood compatibility. AB - In this study, novel zwitterionic glycosyl modified polyethersulfone (PES) ultrafiltration membranes were prepared via in-situ cross-linking polymerization coupled with phase inversion technique, and the following reactions. The membranes were characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), (1)HNMR spectrum, and static water contact angles (WCAs) measurements. The modified membranes showed excellent anti-fouling property, and the flux recovery ratio could reach almost 100%. Meanwhile, the blood compatibility of the membranes was measured by protein adsorption, platelet adhesion, activated partial thromboplastin time (APTT), and thrombin time (TT). The results implied that the zwitterionic glycosyl modified PES membranes had good anti-fouling property and blood compatibility. PMID- 25528534 TI - Engineering a biomimetic three-dimensional nanostructured bone model for breast cancer bone metastasis study. AB - Traditional breast cancer (BrCa) bone metastasis models contain many limitations with regards to controllability, reproducibility and flexibility of design. In this study, a novel biomimetic bone microenvironment was created by integrating hydroxyapatite (HA) and native bioactive factors deposited by osteogenic induction of human bone marrow mesenchymal stem cells (MSCs) within a cytocompatible chitosan hydrogel. It was found that a 10% nanocrystalline HA (nHA) chitosan scaffold exhibited the highest BrCa adhesion and proliferation when compared to chitosan scaffolds with 20% nHA, 10% and 20% microcrystalline HA as well as amorphous HA. This 3-D tunable bone scaffold can provide a biologically relevant environment, increase cell-cell and cell-matrix interactions as found in native bone, and retain the behavior of BrCa cells with different metastasis potential (i.e. highly metastatic MDA-MB-231, less metastatic MCF-7 and transfected MDA-MB-231). The co-culture of MSCs and MDA-MB 231 in this bone model illustrated that MSCs have the capacity to upregulate the expression of the well-known metastasis-associated gene metadherin within BrCa cells. In summary, this study illustrates the ability of our 3-D bone model to create a biomimetic environment conducive to recapitulating the behavior of metastatic BrCa cells, making it a promising tool for in vitro BrCa cell bone metastasis study and for the discovery of potential therapeutics. PMID- 25528535 TI - Characteristics and phylogeny of Bacillus cereus strains isolated from Maari, a traditional West African food condiment. AB - Maari is a spontaneously fermented food condiment made from baobab tree seeds in West African countries. This type of product is considered to be safe, being consumed by millions of people on a daily basis. However, due to the spontaneous nature of the fermentation the human pathogen Bacillus cereus occasionally occurs in Maari. This study characterizes succession patterns and pathogenic potential of B. cereus isolated from the raw materials (ash, water from a drilled well (DW) and potash), seed mash throughout fermentation (0-96h), after steam cooking and sun drying (final product) from two production sites of Maari. Aerobic mesophilic bacterial (AMB) counts in raw materials were of 10(5)cfu/ml in DW, and ranged between 6.5*10(3) and 1.2*10(4)cfu/g in potash, 10(9)-10(10)cfu/g in seed mash during fermentation and 10(7) - 10(9) after sun drying. Fifty three out of total 290 AMB isolates were identified as B. cereus sensu lato by use of ITS-PCR and grouped into 3 groups using PCR fingerprinting based on Escherichia coli phage M13 primer (M13-PCR). As determined by panC gene sequencing, the isolates of B. cereus belonged to PanC types III and IV with potential for high cytotoxicity. Phylogenetic analysis of concatenated sequences of glpF, gmk, ilvD, pta, pur, pycA and tpi revealed that the M13-PCR group 1 isolates were related to B. cereus biovar anthracis CI, while the M13-PCR group 2 isolates were identical to cereulide (emetic toxin) producing B. cereus strains. The M13-PCR group 1 isolates harboured poly-gamma-D-glutamic acid capsule biosynthesis genes capA, capB and capC showing 99-100% identity with the environmental B. cereus isolate 03BB108. Presence of cesB of the cereulide synthetase gene cluster was confirmed by PCR in M13-PCR group 2 isolates. The B. cereus harbouring the cap genes were found in potash, DW, cooking water and at 8h fermentation. The "emetic" type B. cereus were present in DW, the seed mash at 48-72h of fermentation and in the final product, while the remaining isolates (PanC type IV) were detected in ash, at 48-72h fermentation and in the final product. This work sheds light on the succession and pathogenic potential of B. cereus species in traditional West African food condiment and clarifies their phylogenetic relatedness to B. cereus biovar anthracis. Future implementation of GMP and HACCP and development of starter cultures for controlled Maari fermentations will help to ensure a safe product. PMID- 25528536 TI - The microbiological quality of ready-to-eat salads in Turkey: a focus on Salmonella spp. and Listeria monocytogenes. AB - The microbiological safety of ready-to-eat (RTE) foods is of special concern as they are not exposed to further processing before consumption. In the present study, Listeria monocytogenes and Salmonella spp. were isolated from 15(6%) and 21(8%) samples respectively out of 261 RTE foods commercialized in Turkey. Escherichia coli was present in 10(4%) samples analyzed. Psychrotrophic aerobic populations >6logCFU/g were found in 36 (14%) of the samples, while total coliforms were detected in 155 (59%) of samples analyzed. All of the Salmonella spp. and L. monocytogenes isolates tested, exhibited resistance to one or more antimicrobial agents used. For Salmonella spp. isolates, resistance to penicillin (69%), erythromycin (38%), gentamicin (36%), tetracycline (36%) neomycin (33%), ampicillin (33%), amikacin (33%), vancomycin (33%), streptomycin (29%) cefotaxime (9%) and oxacillin (9%) was observed. For L. monocytogenes isolates, resistance to erythromycin (23%) and cephalothin (20%) was evident. The presence of pathogens and the relatively high resistance among the bacteria tested in RTE foods could pose public health and therapeutic problems in consumers. These results indicate the need of implementing hygienic rules in the production chain of RTE foods to ensure microbiological safety and to improve shelf life. PMID- 25528537 TI - Cost-of-illness and disease burden of food-related pathogens in the Netherlands, 2011. AB - To inform risk management decisions on control and prevention of food-related disease, both the disease burden expressed in Disability Adjusted Life Years (DALY) and the cost-of-illness of food-related pathogens are estimated and presented. Disease burden of fourteen pathogens that can be transmitted by food, the environment, animals and humans was previously estimated by Havelaar et al. (2012). In this paper we complement these by cost-of-illness estimates. Together, these present a complete picture of the societal burden of food-related diseases. Using incidence estimates for 2011, community-acquired non-consulting cases, patients consulting their general practitioner, hospitalized patients and the incidence of sequelae and fatal cases, estimates were obtained for DALYs, direct healthcare costs (e.g. costs for doctor's fees, hospitalizations and medicines), direct non-healthcare costs (e.g. travel costs to and from the doctor), indirect non-healthcare costs (e.g. productivity loss, special education) and total costs. The updated disease burden for 2011 was equal to 13,940 DALY/year (undiscounted) or 12,650 DALY/year (discounted at 1.5%), and was of the same magnitude as previous estimates. At the population-level thermophilic Campylobacter spp., Toxoplasma gondii and rotavirus were associated with the highest disease burden. Perinatal listeriosis infection was associated with the highest DALY per symptomatic case. The total cost-of-illness in 2011 of fourteen food-related pathogens and associated sequelae was estimated at ? 468 million/year, if undiscounted, and at ? 416 million/year if discounted by 4%. Direct healthcare costs accounted for 24% of total costs, direct non-healthcare costs for 2% and indirect non-healthcare costs for 74% of total costs. At the population-level, norovirus had the highest total cost-of-illness in 2011 with ? 106 million/year, followed by thermophilic Campylobacter spp. (? 76 million/year) and rotavirus (? 73 million/year). Cost-of-illness per infected case varied from ? 150 for Clostridium perfringens intoxications to ? 275,000 for perinatal listeriosis. Both incident cases and fatal cases are more strongly correlated with COI/year than with DALY/year. More than 40% of all cost-of-illness and DALYs can be attributed to food, in total ? 168 million/year and 5,150 DALY/year for 2011. Beef, lamb, pork and poultry meat alone accounted for 39% of these costs. Products of animal origin accounted for ? 86 million/year (or 51% of the costs attributed to food) and 3,320 DALY/year (or 64% of the disease burden attributed to food). Among the pathogens studied Staphylococcus aureus intoxications accounted for the highest share of costs attributed to food (? 47.1 million/year), followed by Campylobacter spp. (? 32.0 million/year) and norovirus (? 17.7 million/year). PMID- 25528538 TI - Monitoring of learning at the category level when learning a natural concept: will task experience improve its resolution? AB - Researchers have recently begun to investigate people's ability to monitor their learning of natural categories. For concept learning tasks, a learner seeks to accurately monitor learning at the category level - i.e., to accurately judge whether exemplars will be correctly classified into the appropriate category on an upcoming test. Our interest was in whether monitoring resolution at the category level would improve as participants gain task experience across multiple study-test blocks, as well as within each block. In four experiments, exemplar birds (e.g., American Goldfinch, Cassin's Finch) paired with each family name (e.g., Finch) were studied, and participants made a judgment of learning (JOL) for each exemplar. Of most interest, before and after studying the exemplars, participants made category learning judgments (CLJs), which involved predicting the likelihood of correctly classifying novel birds into each family. Tests included exemplars that had been studied or exemplars that had not been studied (novel). This procedure was repeated for either one or two additional blocks. The relative accuracy of CLJs did not improve across blocks even when explicit feedback was provided, whereas item-by-item JOL accuracy improved across blocks. Category level resolution did improve from pre-study to post-study on an initial block, but it did not consistently increase within later blocks. The stable accuracy of CLJs across blocks poses a theoretical and empirical challenge for identifying techniques to improve people's ability to judge their learning of natural categories. PMID- 25528539 TI - Cryptococcosis in patients living with hepatitis C and B viruses. AB - Cryptococcosis, a systemic fungal infection, has become a significant, global public health problem. Patients with liver disease have an increased predisposition to infections, such as Cryptococcosis. To report the underlying disease, the variety of etiologic agents involved and the outcomes of the Cryptococcosis in patients living with HBV and/or HCV, we reviewed 34 medical records of patients who were diagnosed with Cryptococcosis by the Mycology Laboratory of Santa Casa Hospital, Porto Alegre, Brazil. Males corresponded to 79% of the patients, and the average patient age was 46.9 years. The cultures of 26/34 patients were positive: 25 patients were infected with Cryptococcus neoformans and one with C. gattii. A total of 14 deaths (41%) occurred. As a criterion of our study, all patients had viral hepatitis infection: 27 (80%) were infected with HCV, five (15%) were infected with HBV, and two patients were infected with both viruses. Because HBV and/or HCV are transmitted among drug users through infected blood, and the end-stage cirrhotic liver must be transplanted, these two population types were well represented in this study and were analyzed in detail. Cryptococcosis patients living with HCV and/or HBV appear to have the same symptoms, mean age and gender distribution as the general Cryptococcosis population. Once Cryptococcosis affects the brain, a high mortality rate ensues; therefore, physicians must be aware of the possible occurrence of this disease in patients living with HCV and HBV. PMID- 25528540 TI - Design, analysis and validation of a simple dynamic model of a submerged membrane bioreactor. AB - In this study, a simple dynamic model of a submerged membrane bioreactor (sMBR) is proposed, which would be suitable for process control. In order to validate the proposed model structure, informative data sets are generated using a detailed simulator built in a well-established environment, namely GPS-X. The model properties are studied, including equilibrium points, stability, and slow/fast dynamics (three different time scales). The existence of slow-fast dynamics is central to the development of a dedicated parameter estimation procedure. Finally, a nonlinear model predictive control is designed to illustrate the potential of the developed model within a model-based control structure. The problem of water treatment in a recirculating aquaculture system is considered as an application example. PMID- 25528541 TI - Performance of vertical up-flow constructed wetlands on swine wastewater containing tetracyclines and tet genes. AB - Antibiotics and antibiotic resistance genes (ARGs) pollution in animal feeding farms received more public attention recently. Livestock wastewater contains large quantities of antibiotics and ARGs even after traditional lagoon treatment. In this study, the performance of vertical up-flow constructed wetlands (VUF-CWs) on swine wastewater containing tetracycline compounds (TCs) and tet genes was evaluated based on three aspects, TCs and tet genes removal efficiencies, residual TCs and tet genes in soils and plants, and the effect of TCs accumulation on nutrients removal and tet genes development. High removal efficiencies (69.0-99.9%) were achieved for oxytetracycline (OTC), tetracycline (TC) and chlortetracycline (CTC) with or without OTC spiked in the influent additionally. TCs concentrations in surface soils increased at first two sampling periods and then decreased after plants were harvested. Satisfactory nutrients removal efficiencies were also obtained, but TN and NH4-N removal efficiencies were significantly negative correlated with total concentration of TCs (?TCs) in the soils (p < 0.01). The absolute abundances of all the target genes (tetO, tetM, tetW, tetA, tetX and intI1) were greatly reduced with their log units ranging from 0.26 to 3.3. However, the relative abundances of tetO, tetM and tetX in some effluent samples were significantly higher than those in the influent (p < 0.05). The relative abundances of tet genes except for tetO were significantly correlated with ?TCs in the soils (p < 0.05). In summary, the proposed VUF-CWs are effective alternative for the removal of TCs and tet genes. But it is of great importance to prevent large accumulation of TCs in the soils. PMID- 25528542 TI - Effects of coagulation on the removal of natural organic matter, genotoxicity, and precursors to halogenated furanones. AB - Natural organic matter (NOM) in drinking water can react with disinfectants to form disinfection by-products (DBPs). Halogenated furanones are a group of emerging DBPs that can account for 20-60% of the total mutagenicity observed in drinking water. This study examined the impacts of bench-scale coagulation and subsequent chlorination on DBP formation as well as genotoxicity using three source waters located in Ontario, Canada. Two halogenated furanones 3-chloro-4 (dichloromethyl)-2(5H)-furanone (MX) and mucochloric acid (MCA) were analyzed; along with trihalomethanes (THMs), haloacetic acids (HAAs), and absorbable organic halides (AOX). NOM was quantified using liquid chromatography-organic carbon detection (LC-OCD). Measured MX and MCA formation was 6.9-15.3 ng/L and 43.2-315 ng/L following optimized coagulation and subsequent chlorination of the three waters tested. DBP formation and speciation were evaluated as a function of the specific NOM fractions present in the source waters. Humics, building blocks, and biopolymers were highly correlated with DBP formation. Correlations between DBPs were also investigated and a potential relationship between MCA and/or MX vs. HAAs was observed. MX was the only measured DBP that contributed to genotoxicity, representing less than 0.001% of AOX by mass but responsible for 40 67% of the genotoxic response in chlorinated Ottawa River water samples. Genotoxic potential decreased with alum dosages, signifying that coagulation was effective at removing genotoxic DBP precursors. PMID- 25528543 TI - Phosphorus recovery from microbial biofuel residual using microwave peroxide digestion and anion exchange. AB - Sustainable production of microalgae for biofuel requires efficient phosphorus (P) utilization, which is a limited resource and vital for global food security. This research tracks the fate of P through biofuel production and investigates P recovery from the biomass using the cyanobacterium Synechocystis sp. PCC 6803. Our results show that Synechocystis contained 1.4% P dry weight. After crude lipids were extracted (e.g., for biofuel processing), 92% of the intracellular P remained in the residual biomass, indicating phospholipids comprised only a small percentage of cellular P. We estimate a majority of the P is primarily associated with nucleic acids. Advanced oxidation using hydrogen peroxide and microwave heating released 92% of the cellular P into orthophosphate. We then recovered the orthophosphate from the digestion matrix using two different types of anion exchange resins. One resin impregnated with iron nanoparticles adsorbed 98% of the influent P through 20 bed volumes, but only released 23% during regeneration. A strong-base anion exchange resin adsorbed 87% of the influent P through 20 bed volumes and released 50% of it upon regeneration. This recovered P subsequently supported growth of Synechocystis. This proof-of-concept recovery process reduced P demand of biofuel microalgae by 54%. PMID- 25528544 TI - Bioaugmentation of overloaded anaerobic digesters restores function and archaeal community. AB - Adding beneficial microorganisms to anaerobic digesters for improved performance (i.e. bioaugmentation) has been shown to decrease recovery time after organic overload or toxicity upset. Compared to strictly anaerobic cultures, adding aerotolerant methanogenic cultures may be more practical since they exhibit higher methanogenic activity and can be easily dried and stored in ambient air for future shipping and use. In this study, anaerobic digesters were bioaugmented with both anaerobic and aerated, methanogenic propionate enrichment cultures after a transient organic overload. Digesters bioaugmented with anaerobic and moderately aerated cultures recovered 25 and 100 days before non-bioaugmented digesters, respectively. Increased methane production due to bioaugmentation continued a long time, with 50-120% increases 6 to 12 SRTs (60-120 days) after overload. In contrast to the anaerobic enrichment, the aerated enrichments were more effective as bioaugmentation cultures, resulting in faster recovery of upset digester methane and COD removal rates. Sixty days after overload, the bioaugmented digester archaeal community was not shifted, but was restored to one similar to the pre-overload community. In contrast, non-bioaugmented digester archaeal communities before and after overload were significantly different. Organisms most similar to Methanospirillum hungatei had higher relative abundance in well-operating, undisturbed and bioaugmented digesters, whereas organisms similar to Methanolinea tarda were more abundant in upset, non-bioaugmented digesters. Bioaugmentation is a beneficial approach to increase digester recovery rate after transient organic overload events. Moderately aerated, methanogenic propionate enrichment cultures were more beneficial augments than a strictly anaerobic enrichment. PMID- 25528545 TI - Efficient production of optically pure L-lactic acid from food waste at ambient temperature by regulating key enzyme activity. AB - Bio-production of optically pure L-lactic acid from food waste has attracted much interest as it can treat organic wastes with simultaneous recovery of valuable by products. However, the yield of L-lactic acid was very low and no optically pure L-lactic acid was produced in the literature due to (1) the lower activity of enzymes involved in hydrolysis and L-lactic acid generation, and (2) the participation of other enzymes related to D-lactic acid and acetic and propionic acids production. In this paper, a new strategy was reported for effective production of optically pure L-lactic acid from food waste at ambient temperature, i.e. via regulating key enzyme activity by sewage sludge supplement and intermittent alkaline fermentation. It was found that not only optically pure L-lactic acid was produced, but the yield was enhanced by 2.89-fold. The mechanism study showed that the activities of enzymes relevant to food waste hydrolysis and lactic acid production were enhanced, and the key enzymes related to volatile fatty acids and D-lactic acid generations were severally decreased or inhibited. Also, the microbes responsible for L-lactic acid production were selectively proliferated. Finally, the pilot-scale continuous experiment was conducted to testify the feasibility of this new technique. PMID- 25528546 TI - Gravity-driven membrane filtration as pretreatment for seawater reverse osmosis: linking biofouling layer morphology with flux stabilization. AB - In this study gravity-driven membrane (GDM) ultrafiltration is investigated for the pretreatment of seawater before reverse osmosis (RO). The impacts of temperature (21 +/- 1 and 29 +/- 1 degrees C) and hydrostatic pressure (40 and 100 mbar) on dynamic flux development and biofouling layer structure were studied. The data suggested pore constriction fouling was predominant at the early stage of filtration, during which the hydrostatic pressure and temperature had negligible effects on permeate flux. With extended filtration time, cake layer fouling played a major role, during which higher hydrostatic pressure and temperature improved permeate flux. The permeate flux stabilized in a range of 3.6 L/m(2) h (21 +/- 1 degrees C, 40 mbar) to 7.3 L/m(2) h (29 +/- 1 degrees C, 100 mbar) after slight fluctuations and remained constant for the duration of the experiments (almost 3 months). An increase in biofouling layer thickness and a variable biofouling layer structure were observed over time by optical coherence tomography and confocal laser scanning microscopy. The presence of eukaryotic organisms in the biofouling layer was observed by light microscopy and the microbial community structure of the biofouling layer was analyzed by sequences of 16S rRNA genes. The magnitude of permeate flux was associated with the combined effect of the biofouling layer thickness and structure. Changes in the biofouling layer structure were attributed to (1) the movement and predation behaviour of the eukaryotic organisms which increased the heterogeneous nature of the biofouling layer; (2) the bacterial debris generated by eukaryotic predation activity which reduced porosity; (3) significant shifts of the dominant bacterial species over time that may have influenced the biofouling layer structure. As expected, most of the particles and colloids in the feed seawater were removed by the GDM process, which led to a lower RO fouling potential. However, the dissolved organic carbon in the permeate was not be reduced, possibly because some microbial species (e.g. algae) could convert CO2 into organic substances. To further improve the removal efficiency of the organic carbon, combining carrier biofilm processes with a submerged GDM filtration system is proposed. PMID- 25528547 TI - N-nitrosodimethylamine (NDMA) formation at an indirect potable reuse facility. AB - Full-scale experiments to evaluate N-nitrosodimethylamine (NDMA) formation and attenuation were performed within an advanced indirect potable reuse (IPR) treatment system, which includes, sequentially: chloramination for membrane fouling control, microfiltration (MF), reverse osmosis (RO), ultraviolet irradiation with hydrogen peroxide (UV/H2O2), final chloramination, and pH stabilization. Results of the study demonstrate that while RO does effectively remove the vast majority of NDMA precursors, RO permeate can still contain significant concentrations of NDMA precursors resulting in additional NDMA formation during chloramination. Thus, it is possible for this advanced treatment system to produce water with NDMA levels higher than regional requirements for potable applications (10 ng/L). The presence of H2O2 during UV oxidation reduced NDMA photolysis efficiency and increased NDMA formation (~22 ng/L) during the secondary chloramination and lime stabilization. This is likely due to formation of UV/H2O2 degradation by-products with higher NDMA formation rate than the parent compounds. However, this effect was diminished with higher UV doses. Bench scale experiments confirmed an enhanced NDMA formation during chloramination after UV/H2O2 treatment of dimethylformamide, a compound detected in RO permeate and used as model precursor in this study. The effect of pre-ozonation for membrane fouling control on NDMA formation was also evaluated at pilot- (ozone-MF RO) and bench-scale. Relatively large NDMA formation (117-227 ng/L) occurred through ozone application that was dose dependent, whereas chloramination under typical dosages and contact times of IPR systems resulted in only a relatively small increase of NDMA (~20 ng/L). Thus, this research shows that NDMA formation within a potable water reuse facility can be challenging and must be carefully evaluated and controlled. PMID- 25528548 TI - Fate of benzotriazole and 5-methylbenzotriazole in recycled water recharged into an anaerobic aquifer: column studies. AB - The fate of benzotriazole (BTri) and 5-methylbenzotriazole (5-MeBT) was investigated under anaerobic conditions at nano gram per litre concentrations in large-scale laboratory columns to mimic a managed aquifer recharge replenishment strategy in Western Australia. Investigations of BTri and 5-MeBT sorption behaviour demonstrated mobility of the compounds with retardation coefficients of 2.0 and 2.2, respectively. Degradation processes over a period of 220 days indicated first order biodegradation of the BTri and 5-MeBT under anaerobic aquifer conditions after a biological lag-time of approximately 30-60 days. Biodegradation half-lives of 29 +/- 2 and 26 +/- 1 days for BTri and 5-MeBT were respectively observed, with no threshold effect to biodegradation observed at the 200 ng L(-1). The detection of degradation products provided further evidence of BTri and 5-MeBT biodegradation. These results suggested that if BTri and 5-MeBT were present in recycled water recharged to the Leederville aquifer, biodegradation during aquifer passage is likely given sufficient aquifer residence times or travel distances between recycled water injection and groundwater extraction. PMID- 25528549 TI - Corticosterone suppresses vasotocin-enhanced clasping behavior in male rough skinned newts by novel mechanisms interfering with V1a receptor availability and receptor-mediated endocytosis. AB - In rough-skinned newts, Taricha granulosa, exposure to an acute stressor results in the rapid release of corticosterone (CORT), which suppresses the ability of vasotocin (VT) to enhance clasping behavior. CORT also suppresses VT-induced spontaneous activity and sensory responsiveness of clasp-controlling neurons in the rostromedial reticular formation (Rf). The cellular mechanisms underlying this interaction remain unclear. We hypothesized that CORT blocks VT-enhanced clasping by interfering with V1a receptor availability and/or VT-induced endocytosis. We administered a physiologically active fluorescent VT conjugated to Oregon Green (VT-OG) to the fourth ventricle 9 min after an intraperitoneal injection of CORT (0, 10, 40 MUg/0.1mL amphibian Ringers). The brains were collected 30 min post-VT-OG, fixed, and imaged with confocal microscopy. CORT diminished the number of endocytosed vesicles, percent area containing VT-OG, sum intensity of VT-OG, and the amount of VT-V1a within each vesicle; indicating that CORT was interfering with V1a receptor availability and VT-V1a receptor-mediated endocytosis. CORT actions were brain location-specific and season-dependent in a manner that is consistent with the natural and context-dependent expression of clasping behavior. Furthermore, the sensitivity of the Rf to CORT was much higher in animals during the breeding season, arguing for ethologically appropriate seasonal variation in CORT's ability to prevent VT-induced endocytosis. Our data are consistent with the time course and interaction effects of CORT and VT on clasping behavior and neurophysiology. CORT interference with VT-induced endocytosis may be a common mechanism employed by hormones across taxa for mediating rapid context- and season-specific behavioral responses. PMID- 25528550 TI - [An update of the obstetrics hemorrhage treatment protocol: author's reply]. PMID- 25528551 TI - A survey of treatment approaches of malignant ascites in Germany and Austria. AB - BACKGROUND: Malignant ascites (MA) is a common manifestation of advanced cancer. Currently, there are no evidence-based guidelines for the management of MA. We conducted a survey with physicians throughout Germany and Austria, to get an overview of current approaches and opinions in the treatment of MA. METHODS: One hundred and twenty-eight medical oncologists (MO), gastroenterologists (GE), and gynecologists (GYN) completed an electronic questionnaire consisting of 33 questions. RESULTS: Ninety percent of the physicians were from Germany and 10% from Austria; 48% of those were MO, 30% were GYN, and 14% were GE. Most physicians treated an average of 34 patients (pts)/year with MA. Twenty-six percent of these pts suffered from ovarian, 20% from pancreatic, 17% from gastric, and 14% from colorectal cancer. The majority of the physicians associated MA with poor prognosis (92%) and significant reduction in quality of life (87%). One third felt that MA was a contraindication for full dosing of systemic chemotherapy. Paracentesis (PC) was performed in 70% of pts with symptom relieve and quality of life being the main reasons. Almost half of the pts required 3-5 PC, 50% even more than 5 PC during the course of their disease. Only 15% of pts needed multiple PC per week; the majority (79%) needed the procedure either once a week or every 14 days. In 61% of pts, 3-5 L of ascites fluid was drained. Only in 8%, 5 L and more were removed. Volume substitution with IV albumin was performed in 40% of pts. Most pts (55%) had to stay 1-3 h in a healthcare facility for the procedure. However, 21% had to stay >=1 day. While almost all physicians (89%) performed a PC at some point in the treatment of MA, 75% felt that a systemic chemotherapy and 55% thought a concomitant diuretic therapy were a necessary adjunct. Seven percent of the pts received a targeted treatment with catumaxomab. CONCLUSIONS: Repeated PC is the main pillar of treatment of MA; its effect is only temporary and requires significant hospital resources. Further treatment strategies of MA have to be evaluated in prospective studies. Targeted therapies like catumaxomab and VEGF inhibitors should be integrated into these. PMID- 25528553 TI - Adult supraglottitis: changing trends. AB - There is no clinical dynamic staging system which scores according to severity all the anatomical regions in adult supraglottitis. The objective of the study was to describe the demographics, clinical presentation, interventions and outcomes of adult patients diagnosed with acute supraglottitis (AS), and to study the correlation of a new AS classification with the need for airway intervention, in comparison with the current classification. This was a retrospective, cohort study conducted at a secondary medical care center. Adults diagnosed with AS from the years 1990-2013 were identified. Data were extracted for demographic and clinical information and there was no intervention. The main outcome and measures were the need for airway intervention. 288 eligible patients were enrolled. AS incidence rate was 4.3/100,000 patients/year. The mean age was 50 +/- 16 years. Sore throat (94 %) and dysphagia (88 %) were the most common presenting symptoms. Patients were hospitalized either in the Otolaryngology Department (n = 255, 89 %) or in the Intensive Care Unit (n = 33, 11 %). Of the latter, 19 (58 %) had an airway securing intervention procedure. Our suggested classification was more sensitive than the current one for predicting the need for intubation (p = 0.03). Signs and symptoms of AS in adults are different from those in children. Adult patients presenting with oropharyngeal complaints should be suspected for AS and treated appropriately. PMID- 25528552 TI - Skin fibroblasts from individuals with Chediak-Higashi Syndrome (CHS) exhibit hyposensitive immunogenic response. AB - BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by immunodeficiency, oculocutaneous albinism, neurological dysfunction, and early death. Individuals with CHS present with increased susceptibility to infections of the skin, upper-respiratory tract, gastrointestinal tract, and oral tissues. Classical CHS is caused by mutations in the gene encoding lysosomal trafficking regulator (LYST). Although defects in cytotoxic T cell lytic secretory granule secretion and neutrophil phagocytosis are suggested to contribute to the immunodeficiency in CHS, the underlying molecular mechanisms are unknown. We hypothesized that skin fibroblasts from CHS subjects exhibit impaired immune response due to defective trafficking of inflammatory factors. METHODS AND RESULTS: Primary skin fibroblasts from CHS subjects or healthy controls were assessed for genes encoding inflammatory response factors using PCR array. At baseline, we found CD14, IL1R1 and TLR-1 were down-regulated significantly (>=2 fold change) and the genes encoding TLR-3, IL-1beta and IL-6 were up-regulated in CHS cells compared to control cells. When challenged with E. coli lipopolysaccharide (LPS), CHS cells were less responsive than control cells, with only 8 genes significantly up-regulated (3-68 fold change) compared to baseline values, whereas 28 genes in control cells were significantly up-regulated at a much higher magnitude (3-4,629 fold change). In addition, 50% of the genes significantly up-regulated in LPS-treated control cells were significantly lower in LPS-treated CHS cells. IL-6, a fibroblast derived proinflammatory cytokine essential for fighting infections was significantly lower in culture media of CHS cells with or without LPS. Furthermore, Western blot and immunofluorescent staining revealed that TLR-2 and TLR-4 were diminished on cell membranes of CHS cells and dissociated from Rab11a. CONCLUSIONS: For the first time, results from our study indicate defective trafficking of TLR-2 and TLR-4 contributes to the hyposensitive response of CHS skin fibroblasts to immunogenic challenge, providing a potential therapeutic target for clinical intervention in CHS. PMID- 25528554 TI - Hijacking of death receptor signaling by bacterial pathogen effectors. AB - Death receptors such as Tumor necrosis factor receptor 1, FAS and TNF-associated apoptosis-inducing ligand-R1/2 play a major role in counteracting with bacterial pathogen infection through regulation of inflammation and programmed cell death. The highly regulated death receptor signaling is frequently targeted by gram negative bacterial pathogens such as Salmonella, Shigella, enteropathogenic Escherichia coli and enterohamorrhagic Escherichia coli, which harbor a conserved type III secretion system that delivers a repertoire of effector proteins to manipulate host signal transductions for their own benefit. This review focuses on how bacterial gut pathogens hijack death receptor signaling to inhibit host NF kappaB and programmed cell death pathways. PMID- 25528555 TI - A not so happy day after all: excess death rates on birthdays in the U.S. AB - This study estimates average excess death rates on and around birthdays, and explores differences between birthdays falling on weekends and birthdays falling on weekdays. Using records from the U.S. Social Security Administration for 25 million people who died during the period from 1998 to 2011, average excess death rates are estimated controlling for seasonality of births and deaths. The average excess death rate on birthdays is 6.7% (p < 0.0001). No evidence is found of dips in average excess death rates in a +/-10 day neighborhood around birthdays that could offset the spikes on birthdays. Significant differences are found between age groups and between weekend and weekday birthdays. Younger people have greater average excess death rates on birthdays, reaching up to 25.4% (p < 0.0001) for ages 20-29. Younger people also show the largest differences between average excess death rates on weekend birthdays and weekday birthdays, reaching up to 64.5 percentage points (p = 0.0063) for ages 1-9. Over the 13-year period analyzed, the estimated excess deaths on birthdays are 4590. PMID- 25528556 TI - Addressing the unemployment-mortality conundrum: non-linearity is the answer. AB - The effect of unemployment on mortality is the object of a lively literature. However, this literature is characterized by sharply conflicting results. We revisit this issue and suggest that the relationship might be non-linear. We use data for 265 territorial units (regions) within 23 European countries over the period 2000-2012 to estimate a multivariate regression of mortality. The estimating equation allows for a quadratic relationship between unemployment and mortality. We control for various other determinants of mortality at regional and national level and we include region-specific and time-specific fixed effects. The model is also extended to account for the dynamic adjustment of mortality and possible lagged effects of unemployment. We find that the relationship between mortality and unemployment is U shaped. In the benchmark regression, when the unemployment rate is low, at 3%, an increase by one percentage point decreases average mortality by 0.7%. As unemployment increases, the effect decays: when the unemployment rate is 8% (sample average) a further increase by one percentage point decreases average mortality by 0.4%. The effect changes sign, turning from negative to positive, when unemployment is around 17%. When the unemployment rate is 25%, a further increase by one percentage point raises average mortality by 0.4%. Results hold for different causes of death and across different specifications of the estimating equation. We argue that the non-linearity arises because the level of unemployment affects the psychological and behavioural response of individuals to worsening economic conditions. PMID- 25528557 TI - Portraying mental illness and drug addiction as treatable health conditions: effects of a randomized experiment on stigma and discrimination. AB - Despite significant advances in treatment, stigma and discrimination toward persons with mental illness and drug addiction have remained constant in past decades. Prior work suggests that portraying other stigmatized health conditions (i.e., HIV/AIDS) as treatable can improve public attitudes toward those affected. Our study compared the effects of vignettes portraying persons with untreated and symptomatic versus successfully treated and asymptomatic mental illness and drug addiction on several dimensions of public attitudes about these conditions. We conducted a survey-embedded randomized experiment using a national sample (N = 3940) from an online panel. Respondents were randomly assigned to read one of ten vignettes. Vignette one was a control vignette, vignettes 2-5 portrayed individuals with untreated schizophrenia, depression, prescription pain medication addiction and heroin addiction, and vignettes 6-10 portrayed successfully treated individuals with the same conditions. After reading the randomly assigned vignette, respondents answered questions about their attitudes related to mental illness or drug addiction. Portrayals of untreated and symptomatic schizophrenia, depression, and heroin addiction heightened negative public attitudes toward persons with mental illness and drug addiction. In contrast, portrayals of successfully treated schizophrenia, prescription painkiller addiction, and heroin addiction led to less desire for social distance, greater belief in the effectiveness of treatment, and less willingness to discriminate against persons with these conditions. Portrayal of persons with successfully treated mental illness and drug addiction is a promising strategy for reducing stigma and discrimination toward persons with these conditions and improving public perceptions of treatment effectiveness. PMID- 25528558 TI - Lived experience of acute gastrointestinal illness in Rigolet, Nunatsiavut: "just suffer through it". AB - Enteric illness associated with foodborne and waterborne disease is thought to be common in some Canadian Indigenous communities. This study aimed to understand the lived experience of acute gastrointestinal illness (AGI), including symptoms and severity, perceived causes, and healthcare seeking behaviors of AGI in the small Inuit community of Rigolet, Canada. A concurrent mixed quantitative and qualitative methods design was used. Two cross-sectional retrospective surveys provided quantitative data to examine self-reported AGI symptoms and the distribution of potential risk factors in the community. Qualitative data from in depth interviews with one-third of AGI cases were analyzed using a constant comparative method to describe symptoms and severity, identify perceived risk factors, and explore health seeking behavior of AGI in Rigolet. Of the survey respondents reporting AGI, most reported symptoms of diarrhea without vomiting, followed by diarrhea with vomiting, and vomiting without diarrhea. The most common secondary symptoms included stomach cramps and abdominal pain, nausea, and extreme tiredness. Community members identified potential risk factors for AGI that reflect the epidemiology triad (host, agent, and environmental factors), including hygiene, retail food, tap water, boil water advisories, and personal stress. Risk aversion and healthcare seeking behaviors reflected the core constructs of the Health Belief Model (perceived susceptibility, severity, and benefits and barriers to action). Understanding community experience, perspectives, and beliefs related to AGI is useful for public health practitioners and health care providers. This information is important especially considering the relatively high estimated burden of AGI and the relatively low healthcare seeking behaviors in some Indigenous communities compared to national estimates. Moreover, the mixed-methods approach used to understand the burden of AGI could be extended to other health research in Indigenous contexts. PMID- 25528560 TI - On aims and methods of psychiatry - a reminiscence of 50 years of Tinbergen's famous questions about the biology of behavior. AB - BACKGROUND: In 1963, Nicolaas Tinbergen published an article on "the aims and methods of ethology" in which he identified a fundamental framework for the scientific inquiry into the understanding of biological phenomena. In particular, he emphasized to not only study what he called the "proximate" causes, that is, mechanism and ontogeny of a given trait, but to include evolutionary explanations, i.e., the phylogeny and adaptive properties of that trait. DISCUSSION: While influential in the field of biology and to some degree medicine, psychiatry has fallen short of adopting Tinbergen's approach. This article aims at discussing why Tinbergen's precis has lost nothing of its attractiveness to psychiatry as a medical discipline. Examples will be given for the analysis of emotions, attachment and psychotherapy. Tinbergen has bequeathed to us a scientific framework that can greatly advance our understanding of psychiatric conditions and improve diagnosis and treatment of mental disorders, with similar potential for medicine in general. PMID- 25528559 TI - Generation of cell type-specific monoclonal antibodies for the planarian and optimization of sample processing for immunolabeling. AB - BACKGROUND: Efforts to elucidate the cellular and molecular mechanisms of regeneration have required the application of methods to detect specific cell types and tissues in a growing cohort of experimental animal models. For example, in the planarian Schmidtea mediterranea, substantial improvements to nucleic acid hybridization and electron microscopy protocols have facilitated the visualization of regenerative events at the cellular level. By contrast, immunological resources have been slower to emerge. Specifically, the repertoire of antibodies recognizing planarian antigens remains limited, and a more systematic approach is needed to evaluate the effects of processing steps required during sample preparation for immunolabeling. RESULTS: To address these issues and to facilitate studies of planarian digestive system regeneration, we conducted a monoclonal antibody (mAb) screen using phagocytic intestinal cells purified from the digestive tracts of living planarians as immunogens. This approach yielded ten antibodies that recognized intestinal epitopes, as well as markers for the central nervous system, musculature, secretory cells, and epidermis. In order to improve signal intensity and reduce non-specific background for a subset of mAbs, we evaluated the effects of fixation and other steps during sample processing. We found that fixative choice, treatments to remove mucus and bleach pigment, as well as methods for tissue permeabilization and antigen retrieval profoundly influenced labeling by individual antibodies. These experiments led to the development of a step-by-step workflow for determining optimal specimen preparation for labeling whole planarians as well as unbleached histological sections. CONCLUSIONS: We generated a collection of monoclonal antibodies recognizing the planarian intestine and other tissues; these antibodies will facilitate studies of planarian tissue morphogenesis. We also developed a protocol for optimizing specimen processing that will accelerate future efforts to generate planarian-specific antibodies, and to extend functional genetic studies of regeneration to post-transcriptional aspects of gene expression, such as protein localization or modification. Our efforts demonstrate the importance of systematically testing multiple approaches to species-specific idiosyncracies, such as mucus removal and pigment bleaching, and may serve as a template for the development of immunological resources in other emerging model organisms. PMID- 25528562 TI - The contribution of the reach and the grasp to shaping brain and behaviour. AB - Skilled hand use is a striking feature of human behaviour, but in contrast to the view that it recently evolved in the primate lineage, the present paper argues that skilled hand movements have an early phylogenetic origin dating back to the synergies displayed by the pectoral fins of bony fishes. Insights into the function and evolution of hand use stem from the dual visuomotor channel theory, which proposes that prehension is a composite of 2 movements, the reach and the grasp. The reach is in part an egocentric act directed toward the extrinsic (location) features of objects while the grasp is in part an allocentric act directed toward the intrinsic (shape and size) features of objects. Phylogenetic, developmental, and behavioural evidence suggest that the reach and the grasp evolved separately under somatosensory control and were subsequently coordinated with visual control in the primate lineage. Accordingly, parallel pathways from visual cortex came to influence separate reach and grasp systems in parietofrontal cortex, and new descending pathways to the spinal cord came to assist in visually guided reaching. Neural processes related to the "where" of the reach and the "what" of the grasp have had a formative role in shaping cognition more generally. PMID- 25528561 TI - Palmitoleic acid (n-7) increases white adipocytes GLUT4 content and glucose uptake in association with AMPK activation. AB - BACKGROUND: Palmitoleic acid was previously shown to improve glucose homeostasis by reducing hepatic glucose production and by enhancing insulin-stimulated glucose uptake in skeletal muscle. Herein we tested the hypothesis that palmitoleic acid positively modulates glucose uptake and metabolism in adipocytes. METHODS: For this, both differentiated 3 T3-L1 cells treated with either palmitoleic acid (16:1n7, 200 MUM) or palmitic acid (16:0, 200 MUM) for 24 h and primary adipocytes from mice treated with 16:1n7 (300 mg/kg/day) or oleic acid (18:1n9, 300 mg/kg/day) by gavage for 10 days were evaluated for glucose uptake, oxidation, conversion to lactate and incorporation into fatty acids and glycerol components of TAG along with the activity and expression of lipogenic enzymes. RESULTS: Treatment of adipocytes with palmitoleic, but not oleic (in vivo) or palmitic (in vitro) acids, increased basal and insulin-stimulated glucose uptake and GLUT4 mRNA levels and protein content. Along with uptake, palmitoleic acid enhanced glucose oxidation (aerobic glycolysis), conversion to lactate (anaerobic glycolysis) and incorporation into glycerol-TAG, but reduced de novo fatty acid synthesis from glucose and acetate and the activity of lipogenic enzymes glucose 6-phosphate dehydrogenase and ATP-citrate lyase. Importantly, palmitoleic acid induction of adipocyte glucose uptake and metabolism were associated with AMPK activation as evidenced by the increased protein content of phospho(p)Thr172AMPKalpha, but no changes in pSer473Akt and pThr308Akt. Importantly, such increase in GLUT4 content induced by 16:1n7, was prevented by pharmacological inhibition of AMPK with compound C. CONCLUSIONS: In conclusion, palmitoleic acid increases glucose uptake and the GLUT4 content in association with AMPK activation. PMID- 25528563 TI - A shared short-term memory system for stimulus duration and stimulus frequency. AB - Recent research has suggested the existence of a modality-independent memory system that is responsible for storing representations of simple, scalar stimulus attributes, such as the frequency of an auditory pure tone or the duration of a stimulus. In the present study, we modify an existing computational model of short-term memory (STM) for stimulus frequency to allow it to perform STM tasks for both stimulus frequency and stimulus duration, supporting the notion of a common scalar STM system. We further demonstrate the utility of the model by showing that it can reproduce the subjective shortening effect, a classic finding in the psychophysical literature. PMID- 25528564 TI - Short-term memory for the comparative instructions in symbolic comparison. AB - In the current study, a novel paradigm was used in which participants (N = 24) first compared the sizes of pairs of animals and then were asked, on half of the trials, to make a follow-up identification judgment regarding either the form of the comparative instruction that had just been used for the preceding comparison (i.e., smaller? or larger?) or the size of the stimuli in the comparison pair. To selectively enhance the difficulty associated with processing each of these aspects, on a large number of comparison trials, either the comparative instruction or the stimulus pair, respectively, was presented only very briefly. Results indicate that memory for the comparative instructions was dependent on the relative size of the stimulus pair such that participants were more likely to correctly identify the smaller form of the comparative instruction after comparing pairs of small stimulus items, as well as more likely to correctly identify the larger form of the comparative instruction after comparing pairs of large stimulus items. Such results are consistent with the view that the size of the stimulus pair contextually activates the representation of the congruent form of the comparative instruction. PMID- 25528566 TI - Laparoscopic Sleeve-Collis-Nissen Gastroplasty: a Safe Alternative for Morbidly Obese Patients with Gastroesophageal Reflux Disease. AB - BACKGROUND: Some studies have recently suggested that laparoscopic sleeve gastrectomy may exacerbate gastroesophageal reflux disease (GERD) symptoms or even increase the risk of "de novo" post-operative GERD. We herein describe and evaluate the initial response of an alternative technique of sleeve gastroplasty combined with Nissen fundoplication for morbidly obese patients who present significant GERD. METHODS: From January 2008 to December 2013, 122 morbidly obese patients underwent laparoscopic Sleeve-Collis-Nissen gastroplasty (LSCNG). RESULTS: The great majority of the patients were female (97.5 %), with a mean age of 42.4 years old (from 18 to 72). Hiatal hernia and use of proton pump inhibitors (PPIs) were presented in 54.9 and 92 %, respectively. The mean operative time was 91 +/- 6 min. The mean hospitalization stay was 2 +/- 0.3 days. Major complications including stenosis requiring endoscopic dilation and GI bleeding were observed in five patients (4.1 %). No leaks were observed. One-year follow-up showed a significant decrease in the prevalence of esophagitis (100 vs 13.6 %) and the use of PPIs (92 vs 13.6 %). The percentages of excess weight loss 1 and 3 years after the surgery were 64.4 +/- 7.2 and 60.4 +/- 8.1 %, respectively. CONCLUSIONS: LSCNG is a novel, technically feasible surgery with a low incidence of procedure-related complications. However, further prospective studies are required to assess the real impact of this procedure on the improvement of GERD symptoms. PMID- 25528567 TI - Clinical Indications, Utilization, and Funding of Bariatric Surgery in Europe. AB - PURPOSE: The objective of this study was to evaluate the current utilization, the level of endorsement by professional societies, and health technology assessment bodies, as well as the reimbursement levels for bariatric surgery in European countries. MATERIALS AND METHODS: We performed an analysis of the indications for bariatric surgery based on national clinical and commissioning guidelines, current utilization of surgery, characteristics of patients who underwent surgery, and reimbursement tariffs in Belgium, Denmark, England, France, Germany, Italy, and Sweden. Data were obtained from national patient registries, administrative databases, and published literature for the year 2012. RESULTS: Despite clear consensus outlined in clinical guidelines, significant differences were found in the eligibility criteria for surgery. Patients with no significant comorbidities were deemed eligible if they had a body mass index (BMI) of 40 or 50 kg/m(2) in Denmark. Irrespective of the country, patients with comorbidities were eligible if they had a BMI of 35 kg/m(2). The highest utilization of bariatric surgery (number of surgeries per 1 M population) was observed in Belgium (928), Sweden (761), and France (571) while Italy (128), England (117), and Germany (72) had the lowest utilization. There was a strong negative correlation between utilization and average BMI level of the patient population (r = -.909, p = 0.005). The annual per capita spending on surgery differed significantly between countries, ranging from 0.54 in Germany to 4.33 in Belgium. CONCLUSIONS: There are significant variations in the clinical indications, utilization, and funding of bariatric surgery in European countries. PMID- 25528568 TI - Factors influencing 30-day emergency visits and readmissions after sleeve gastrectomy: results from a community bariatric center. AB - INTRODUCTION: Bariatric surgery has proven safe and effective for long-term weight loss in morbidly obese patients. Readmissions within 30 days of discharge have become an important metric for quality of care. Sleeve gastrectomy is a common bariatric procedure, but data regarding early readmission is sparse. The purpose of this study is to determine what, if any, demographic or technical factors influence returns to the hospital or readmission following sleeve gastrectomy. METHODS: All laparoscopic sleeve gastrectomies (n = 200) performed at a single community hospital from February 2009 to November 2012 were retrospectively reviewed. Demographic, technical, length of stay, return to Emergency Department (ED) and readmission data were gathered for each patient. The data were analyzed to determine what factors were related to early return to the Emergency Department or readmission. RESULTS: Demographics were similar to other studies, with a male to female ratio of 1:4. Patients returning to the ED or readmitted within 30 days were statistically younger than those not returning. None of the other demographic, social, technical, or comorbid conditions considered were associated with a statistically significant risk of readmission or return to the ED within 30 days. CONCLUSION: Although the only statistically significant difference among the groups studied was age, trends toward significance exist in minority ethnicity and comorbid asthma. These factors have been associated with increased complications in other types of surgery. Larger, multi-institutional studies are needed to further evaluate these and other risk factors for readmission following bariatric surgery. PMID- 25528570 TI - Tomo3D 2.0--exploitation of advanced vector extensions (AVX) for 3D reconstruction. AB - Tomo3D is a program for fast tomographic reconstruction on multicore computers. Its high speed stems from code optimization, vectorization with Streaming SIMD Extensions (SSE), multithreading and optimization of disk access. Recently, Advanced Vector eXtensions (AVX) have been introduced in the x86 processor architecture. Compared to SSE, AVX double the number of simultaneous operations, thus pointing to a potential twofold gain in speed. However, in practice, achieving this potential is extremely difficult. Here, we provide a technical description and an assessment of the optimizations included in Tomo3D to take advantage of AVX instructions. Tomo3D 2.0 allows huge reconstructions to be calculated in standard computers in a matter of minutes. Thus, it will be a valuable tool for electron tomography studies with increasing resolution needs. PMID- 25528569 TI - Clinical features of vestibular schwannomas in patients who experience hearing improvement after surgery. AB - Postoperative improvements in hearing in patients with vestibular schwannoma are extremely rare. We reviewed nine cases retrospectively to investigate the clinical features of these cases. Hearing improvement was defined as an improvement in hearing class according to American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria. The nine patients comprised five men and four women with a mean age of 40.4 years. Of the nine tumors, three were solid and six cystic; mean tumor size was 29.7 mm. Mean pure tone average (PTA) and mean speech discrimination scores (SDS) were 47.5 dB and 22.8%, respectively, preoperatively and 29.6 dB and 83.9%, respectively, postoperatively. AAO-HNS class distribution was class B:1 and D:8, preoperatively, and class A: 5 and B:4, postoperatively. A lateral suboccipital retrosigmoid approach with a lateral (park bench) position was used in all nine patients. Clinical features of these vestibular schwannomas included (1) large cystic tumors, (2) sudden onset hearing loss, (3) the presence of a valley shape in the middle-pitch area on preoperative audiograms, (4) almost intact preoperative inner ear function, (5) a low SDS relative to PTA preoperatively, (6) surgical treatment via a lateral suboccipital approach within 6 months of the most recent exacerbation of hearing loss, (7) observation of I waves in preoperative, intraoperative, and postoperative auditory brainstem response (ABR) recordings, and (8) postoperative improvement in mainly the middle-pitch range and SDS. For surgical treatment of vestibular schwannomas with the above clinical features, a translabyrinthine approach and cochlear nerve section (unless the I wave on the intraoperative ABR trace disappears) should be avoided, regardless of the patient's preoperative hearing level, if a surgeon hopes to maximize the chances of preserving or improving hearing. PMID- 25528572 TI - Which dimensions of access are most important when rural residents decide to visit a general practitioner for non-emergency care? AB - OBJECTIVE: Access to primary healthcare (PHC) services is key to improving health outcomes in rural areas. Unfortunately, little is known about which aspect of access is most important. The objective of this study was to determine the relative importance of different dimensions of access in the decisions of rural Australians to utilise PHC provided by general practitioners (GP). METHODS: Data were collected from residents of five communities located in 'closely' settled and 'sparsely' settled rural regions. A paired-comparison methodology was used to quantify the relative importance of availability, distance, affordability (cost) and acceptability (preference) in relation to respondents' decisions to utilise a GP service for non-emergency care. RESULTS: Consumers reported that preference for a GP and GP availability are far more important than distance to and cost of the service when deciding to visit a GP for non-emergency care. Important differences in rankings emerged by geographic context, gender and age. CONCLUSIONS: Understanding how different dimensions of access influence the utilisation of PHC services is critical in planning the provision of PHC services. This study reports how consumers 'trade-off' the different dimensions of access when accessing GP care in rural Australia. The results show that ensuring 'good' access requires that policymakers and planners should consider other dimensions of access to services besides geography. PMID- 25528571 TI - Seeing tobacco mosaic virus through direct electron detectors. AB - With the introduction of direct electron detectors (DED) to the field of electron cryo-microscopy, a wave of atomic-resolution structures has become available. As the new detectors still require comparative characterization, we have used tobacco mosaic virus (TMV) as a test specimen to study the quality of 3D image reconstructions from data recorded on the two direct electron detector cameras, K2 Summit and Falcon II. Using DED movie frames, we explored related image processing aspects and compared the performance of micrograph-based and segment based motion correction approaches. In addition, we investigated the effect of dose deposition on the atomic-resolution structure of TMV and show that radiation damage affects negative carboxyl chains first in a side-chain specific manner. Finally, using 450,000 asymmetric units and limiting the effects of radiation damage, we determined a high-resolution cryo-EM map at 3.35A resolution. Here, we provide a comparative case study of highly ordered TMV recorded on different direct electron detectors to establish recording and processing conditions that enable structure determination up to 3.2A in resolution using cryo-EM. PMID- 25528573 TI - Modulation of bacterial outer membrane vesicle production by envelope structure and content. AB - BACKGROUND: Vesiculation is a ubiquitous secretion process of Gram-negative bacteria, where outer membrane vesicles (OMVs) are small spherical particles on the order of 50 to 250 nm composed of outer membrane (OM) and lumenal periplasmic content. Vesicle functions have been elucidated in some detail, showing their importance in virulence factor secretion, bacterial survival, and biofilm formation in pathogenesis. Furthermore, OMVs serve as an envelope stress response, protecting the secreting bacteria from internal protein misfolding stress, as well as external envelope stressors. Despite their important functional roles very little is known about the regulation and mechanism of vesicle production. Based on the envelope architecture and prior characterization of the hypervesiculation phenotypes for mutants lacking the lipoprotein, Lpp, which is involved in the covalent OM-peptidoglycan (PG) crosslinks, it is expected that an inverse relationship exists between OMV production and PG crosslinked Lpp. RESULTS: In this study, we found that subtle modifications of PG remodeling and crosslinking modulate OMV production, inversely correlating with bound Lpp levels. However, this inverse relationship was not found in strains in which OMV production is driven by an increase in "periplasmic pressure" resulting from the accumulation of protein, PG fragments, or lipopolysaccharide. In addition, the characterization of an nlpA deletion in backgrounds lacking either Lpp- or OmpA-mediated envelope crosslinks demonstrated a novel role for NlpA in envelope architecture. CONCLUSIONS: From this work, we conclude that OMV production can be driven by distinct Lpp concentration-dependent and Lpp concentration-independent pathways. PMID- 25528575 TI - Genetic variants in antigen presentation-related genes influence susceptibility to hepatitis C virus and viral clearance: a case control study. AB - BACKGROUND: Genes related to antigen presentation pathway, which are in the non classical class-II region of human leukocyte antigen (HLA), play a vital role during the infection of hepatitis C virus (HCV). METHODS: The current study determined the genotypes of 34 tagging-SNPs (single nucleotide polymorphisms) from 9 candidate genes (HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, TAP1, TAP2, LMP2, LMP7, and tapasin) in a Chinese population of paid blood donors with high risk of HCV infection. The distributions of those SNPs were compared among the 1207 former paid blood donors with different HCV infection outcomes. RESULTS: HLA-DMA rs1063478 and HLA-DOA rs2284191 were independent factors of acquiring HCV infection. Carrying three favorable alleles of rs1063478-T and rs2284191-G offered the highest protective effect (odds ratio = 0.46, 95% confidence intervals = 0.27-0.78). HLA-DOB rs7383287 and LMP2 rs17587 were independent factors of infection chronicity. Subjects carrying two favorable alleles of rs7383287-G and rs17587-A had a decreased risk of HCV chronicity (odds ratio = 0.42, 95% confidence intervals = 0.26-0.66). The interaction analysis showed that experience of plasma donation interacted with the combined effects of rs1063478 and rs2284191 for HCV susceptibility, and the experience of whole blood donation interacted with the association of rs7383287 with HCV clearance. CONCLUSIONS: Our results suggested that genetic variants in antigen presentation pathway had influence on susceptibility to HCV infection and viral clearance. HLA-DMA rs1063478, HLA-DOA rs2284191, and HLA-DOB rs7383287 were identified as novel loci in Chinese population that were involved in HCV infection. PMID- 25528577 TI - Skin rash, dyspnea and bone pain: secondary syphilis. PMID- 25528576 TI - Antiviral and myocyte protective effects of IL-28A in coxsackievirus B3-induced myocarditis. AB - OBJECTIVE: This study aimed to investigate whether interleukin-28A (IL-28A) plays a role in murine myocarditis induced by coxsackievirus B3 (CVB3), and to explore its possible mechanism involved. METHODS: Male BALB/c mice both infected and not infected by CVB3 were randomly divided into four groups (n=40), untreated or treated with different doses of IL-28A for 4 days, and then sacrificed on days 4 and 7 post-infection. The heart samples were collected for histopathologic examination. Cardiac viral load was determined by a plaque assay. Additionally, immunoblot analysis, TUNEL assay, and immunohistochemistry were performed to examine the expression of signal transducer, activator of transcription 1 and 2 (STAT1 and STAT2), CVB3-induced apoptosis and the expression of Bcl-2, BAX and Caspase-3. RESULTS: Compared to uninfected mice, the CVB3 infected mice exhibited higher mortality rate (p<0.001), apparent inflammation and myocardial lesion (p<0.01), and higher cardiac viral load (p<0.01). After CVB3 infection, IL-28A treated mice presented no death (p<0.001), reduced inflammation and myocardial lesion (p<0.01), and lower viral load (p<0.01) compared to untreated mice. Besides, treatment with IL-28A markedly increased the expressions of STAT1 and STAT2, and inhibited CVB3-induced apoptosis in myocardial cells with increased ratio of Bcl-2/BAX. CONCLUSION: The antiviral and myocyte protective effects of IL-28A in CVB3-induced myocarditis are regulated by STAT1 and STAT2. PMID- 25528578 TI - Treatment of genotype one hepatitis C virus (HCV) infection in HIV co-infected patients using telaprevir based regimen. PMID- 25528574 TI - Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury. AB - BACKGROUND: The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes. METHODS: EPO TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05. DISCUSSION: A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012). PMID- 25528579 TI - Breakthrough curves for toluene adsorption on different types of activated carbon fibers: application in respiratory protection. AB - Activated carbon fibers (ACF) are considered viable alternative adsorbent materials in respirators because of their larger surface area, lighter weight, and fabric form. The purpose of this study was to characterize the breakthrough curves of toluene for different types of commercially available ACFs to understand their potential service lives in respirators. Two forms of ACF, cloth (AC) and felt (AF), with three surface areas each were tested. ACFs were challenged with six toluene concentrations (50-500 p.p.m.) at constant air temperature (23 degrees C), relative humidity (50%), and air flow (16 l min-1) at different bed depths. Breakthrough data were obtained using continuous monitoring by gas chromatography using a gas sampling valve. The ACF specific surface areas were measured by an automatic physisorption analyzer. Results showed unique shapes of breakthrough curves for each ACF form: AC demonstrated a gradual increase in breakthrough concentration, whereas AF showed abrupt increase in concentration from the breakpoint, which was attributed to the difference in fiber density between the forms. AF has steeper breakthrough curves compared with AC with similar specific surface area. AC exhibits higher 10% breakthrough times for a given bed depth due to higher mass per bed depth compared with AF, indicating more adsorption per bed depth with AC. ACF in respirators may be appropriate for use as protection in environments with toluene concentration at the Occupational Safety and Health Administration Permissible Exposure Limit, or during emergency escape for higher toluene concentrations. ACF has shown great potential for application in respiratory protection against toluene and in the development of thinner, lighter, and more efficient respirators. PMID- 25528580 TI - Collaborating with front-line healthcare professionals: the clinical and cost effectiveness of a theory based approach to the implementation of a national guideline. AB - BACKGROUND: Clinical guidelines are an integral part of healthcare. Whilst much progress has been made in ensuring that guidelines are well developed and disseminated, the gap between routine clinical practice and current guidelines often remains wide. A key reason for this gap is that implementation of guidelines typically requires a change in the behaviour of healthcare professionals - but the behaviour change component is often overlooked. We adopted the Theoretical Domains Framework Implementation (TDFI) approach for supporting behaviour change required for the uptake of a national patient safety guideline to reduce the risk of feeding through misplaced nasogastric tubes. METHODS: The TDFI approach was used in a pre-post study in three NHS hospitals with a fourth acting as a control (with usual care and no TDFI). The target behavior identified for change was to increase the use of pH testing as the first line method for checking the position of a nasogastric tube. Repeat audits were undertaken in each hospital following intervention implementation. We used Zou's modified Poisson regression approach with robust standard errors to estimate risk ratios for the use of pH testing. The projected return on investment (ROI) was also calculated. RESULTS: Following intervention implementation, the use of pH first line increased significantly across intervention hospitals [risk ratio (95% CI) ranged from 3.1 (1.14 to8.43) p < .05, to 8.14 (3.06 to21.67) p < .001] compared to the control hospital, which remained unchanged [risk ratio (CI) = .77 (.47-1.26) p = .296]. The estimated savings and costs in the first year were L2.56 million and L1.41 respectively, giving an ROI of 82%, and this was projected to increase to 270% over five years. CONCLUSION: The TDFI approach improved the uptake of a patient safety guideline across three hospitals. The TDFI approach is clinically and cost effective in comparison to the usual practice. PMID- 25528581 TI - The deletion of an extra six nucleotides in the 5' -untranslated region of the nucleoprotein gene of Newcastle disease virus NA-1 decreases virulence. AB - BACKGROUND: The virulent Newcastle disease virus (NDV) strain NA-1 (genotype VII) was isolated from an epizootic involving a flock of geese in Jilin Province, Northeast China, in 1999. Compared with the classical NDV strains, which have a genome size of 15,186 bp, the more recently isolated NDV strains, including that involved in the goose outbreak, have an extra six nucleotides in the 5' untranslated region (UTR) of the nucleoprotein (NP) gene. This extra sequence, TCCCAC, is highly conserved and has been found in multiple NDV strains, including ZJ-1, WF00G, JSG0210, and NA-1. In the current study, an infectious clone from strain NA-1 was isolated and designated rNA-1. Subsequently, strain rNA-1 was mutated to delete the six-nucleotide insertion, producing strain rNA-1(-). Virulence of the recombinant virus was then assayed in chickens and geese. RESULTS: The recombinant virus rNA-1(-) showed similar biological characteristics to the parental NA-1 strain in DF-1 chicken fibroblast cells. However, the virulence of rNA-1(-) in 9-day-old embryonated chicken eggs and 1-day-old specific pathogen-free (SPF) chickens was decreased compared with the rNA-1 control. Furthermore, the virulence of the recombinant strain was slightly decreased in 1-day-old SPF chickens when compared with that in 1-day-old geese. CONCLUSION: Following deletion of six nucleotides in the 5'-UTR of the NP gene of NDV strain NA-1, the virulence of the rNA-1(-) recombinant strain was decreased in both chickens and geese. However, rNA-1(-) was more virulent in chickens than geese, as seen by the higher intracerebral pathogenicity index value. PMID- 25528582 TI - First report of Theileria and Anaplasma in the Mongolian gazelle, Procapra gutturosa. AB - BACKGROUND: Theileria and Anaplasma are especially important emerging tick-borne pathogens of animals and humans. Molecular surveys and identification of the infectious agents in Mongolian gazelle, Procapra gutturosa are not only crucial for the species' preservation, but also provide valuable information on parasite and bacterial epidemiology. FINDINGS: A molecular surveillance study was undertaken to assess the prevalence of Theileria spp. and Anaplasma spp. in P. gutturosa by PCR in China. Theileria luwenshuni, A. bovis, A. phagocytophilum, and A. ovis were frequently found in P. gutturosa in China, at a prevalence of 97.8%, 78.3%, 65.2%, and 52.2%, respectively. The prevalence of each pathogens in the tick Haemaphysalis longicornis was 80.0%, 66.7%, 76.7%, and 0%, respectively, and in the tick Dermacentor niveus was 88.2%, 35.3%, 88.2%, and 58.5%, respectively. No other Theileria or Anaplasma species was found in these samples. Rickettsia raoultii was detected for the first time in P. gutturosa in China. CONCLUSIONS: Our results extend our understanding of the epidemiology of theileriosis and anaplasmosis in P. gutturosa, and will facilitate the implementation of measures to control these tick-borne diseases in China. PMID- 25528583 TI - Expression and prognostic value of Mycl1 in gastric cancer. AB - As a member of the Myc proto-oncogene family, MYCL1 has been found to be amplified and overexpressed in some malignancies. However, the clinical significance of Mycl1 expression in gastric cancer is still unknown. Mycl1 expression was detected on tissue microarrays of gastric cancer samples in 176 cases using immunohistochemical staining, and its association with clinicopathological factors and overall survival was also analyzed. Mycl1 showed greater expression in gastric cancer tissue than in adjacent normal tissue (62.5% vs 46.0%, respectively, P=0.002), and its expression was correlated with patient age, tumor differentiation, and TNM stage (P=0.007, 0.003, and 0.002, respectively). The Mycl1 positive group had an unfavorable outcome compared with the negative group (P<0.001). Multivariate analysis showed that Mycl1 expression was an independent prognostic factor of gastric cancer (P=0.009). These results suggest that Mycl1 expression might be useful as a biomarker to predict prognosis and is a promising therapeutic target for patients with gastric cancer. PMID- 25528584 TI - L-Idose: an attractive substrate alternative to D-glucose for measuring aldose reductase activity. AB - Although glucose is one of the most important physio-pathological substrates of aldose reductase, it is not an easy molecule for in vitro investigation into the enzyme. In many cases alternative aldoses have been used for kinetic characterization and inhibition studies. However these molecules do not completely match the structural features of glucose, thus possibly leading to results that are not fully applicable to glucose. We show how aldose reductase is able to act efficiently on L-idose, the C-5 epimer of D-glucose. This is verified using both the bovine lens and the human recombinant enzymes. While the kcat values obtained are essentially identical to those measured for D-glucose, a significant decrease in KM was observed. This can be due to the significantly higher level of the free aldehyde form present in L-idose compared to D-glucose. We believe that L-idose is the best alternative to D-glucose in studies on aldose reductase. PMID- 25528585 TI - SR-BI mediates high density lipoprotein (HDL)-induced anti-inflammatory effect in macrophages. AB - High density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR BI), mediates selective cholesteryl ester uptake from lipoproteins into the liver as well as cholesterol efflux from macrophages to HDL. Recently, strong evidence has demonstrated the anti-inflammatory effect of HDL, although the mechanism of action is not fully understood. In this study, we showed that the anti inflammatory effects of HDL are dependent on SR-BI expression in THP-1 macrophages. Consistent with earlier findings, pretreatment of macrophages with HDL abolished LPS-induced TNFalpha production. HDL also inhibited LPS-induced NF kappaB activation. In addition, knockdown of SR-BI or inhibition of SR-BI ligand binding abolished the anti-inflammatory effect of HDL. SR-BI is a multi-ligand receptor that binds to modified lipoproteins as well as native HDL. Since modified lipoproteins have pro-inflammatory properties, it is unclear whether SR BI activated by modified HDL has an anti- or pro-inflammatory effect. Glycated HDL induced NF-kappaB activation and cytokine production in macrophages in vitro, suggesting a pro-inflammatory effect for modified HDL. Moreover, inhibition of SR BI function or expression potentiated glycated HDL-induced TNF-alpha production, suggesting an anti-inflammatory effect for SR-BI. In conclusion, SR-BI plays an important function in regulating HDL-mediated anti-inflammatory response in macrophages. PMID- 25528586 TI - Generation and characterization of a bispecific diabody targeting both EPH receptor A10 and CD3. AB - The EPH receptor A10 (EphA10) is up-regulated in breast cancer but is not normally expressed in healthy tissue, thus it has been suggested that EphA10 may be a useful target for cancer therapy. This study reports a diabody, an antibody derivative binding two different target molecules, EphA10 expressed in tumor cells and CD3 expressed in T cells, which showed T cell dependent-cytotoxicity. The diabody, which has His-tagged and FLAG-tagged chains, was expressed in Escherichia coli and purified in both heterodimer (Db-1) and homodimer (Db-2) formulations by liquid chromatography. Flow cytometry analysis using EphA10 expressing cells showed that binding activity of heterodimers was stronger than that of homodimers. Addition of diabodies to PBMC cultures resulted in T-cell mediated redirected lysis, and the bioactivity was consistent with the stronger binding activity of heterodimeric diabody formulations. Our results indicate that diabodies recognizing both EphA10 and CD3 could have a range of potential applications in cancer therapy, such as breast cancers that express the EPH receptor A10, especially triple negative breast cancer. PMID- 25528589 TI - Classroom quality and academic skills: Approaches to learning as a moderator. AB - The purpose of this study was to examine whether approaches to learning moderated the association between child care classroom environment and Head Start children's academic skills. The data came from the Head Start Family and Child Experiences Survey (FACES-2003 Cohort). The dataset is a nationally representative longitudinal study of Head Start children. The sample was selected using the stratified 4-stage sampling procedure. Data was collected in fall 2003, spring 2004, spring 2005, and spring 2006 in the first year of kindergarten. Participants included 3- and 4-year-old Head Start children (n = 786; 387 boys, 399 girls; 119 Hispanic children, 280 African American children, 312 Caucasian children). Head Start children's academic skills in letter-word identification, dictation/spelling, and mathematics at the 4 time points were measured by the Woodcock-Johnson Achievement Battery tests. Approaches to learning in fall 2003 was measured by the teacher report of the Preschool Learning Behaviors Scale. Child care classroom quality in fall 2003 was measured by the revised Early Childhood Environment Rating Scale. Results of the linear mixed effects models demonstrated that approaches to learning significantly moderated the effect of child care classroom quality on Head Start children's writing and spelling. Specifically, positive approaches to learning mitigated the negative effect of lower levels of classroom quality on dictation/spelling. Results underscore the important role of approaches to learning as a protective factor. Implications for early childhood educators with an emphasis on learning goals for disengaged children are discussed. PMID- 25528588 TI - Audit of a new model of birth care for women with low risk pregnancies in South Africa: the primary care onsite midwife-led birth unit (OMBU). AB - BACKGROUND: South Africa's health system is based on the primary care model in which low-risk maternity care is provided at community health centres and clinics, and 'high-risk' care is provided at secondary/tertiary hospitals. This model has the disadvantage of delays in the management of unexpected intrapartum complications in otherwise low-risk pregnancies, therefore, there is a need to re evaluate the models of birth care in South Africa. To date, two primary care onsite midwife-led birth units (OMBUs) have been established in the Eastern Cape. OMBUs are similar to alongside midwifery units but have been adapted to the South African health system in that they are staffed, administered and funded by the primary care service. They allow women considered to be at 'low risk' to choose between birth in a community health centre and birth in the OMBU. METHODS: The purpose of this audit was to evaluate the impact of establishing an OMBU at Frere Maternity Hospital in East London, South Africa, on maternity services. We conducted an audit of routinely collected data from Frere Maternity Hospital over two 12 month periods, before and after the OMBU opened. Retrospectively retrieved data included the number of births, maternal and perinatal deaths, and mode of delivery. RESULTS: After the OMBU opened at Frere Maternity Hospital, the total number of births on the hospital premises increased by 16%. The total number of births in the hospital obstetric unit (OU) dropped by 9.3%, with 1611 births out of 7375 (22%) occurring in the new OMBU. The number of maternal and perinatal deaths was lower in the post-OMBU period compared with the pre-OMBU period. These improvements cannot be assumed to be the result of the intervention as observational studies are prone to bias. CONCLUSIONS: The mortality data should be interpreted with caution as other factors such as change in risk profile may have contributed to the death reductions. There are many additional advantages for women, hospital staff and primary care staff with this model, which may also be more cost-effective than the standard (freestanding) primary care model. PMID- 25528587 TI - Cardiac myostatin upregulation occurs immediately after myocardial ischemia and is involved in skeletal muscle activation of atrophy. AB - Myostatin (MSTN), a negative regulator of muscle growth and size, is increased after acute myocardial infarction (AMI) but timing of upregulation after injury is not known. In this study, we investigated the timing of the MSTN/AKT/p38 pathway activation in heart and skeletal muscle after AMI, as well as the potential effect of cardiac injury-related MSTN endocrine signaling on skeletal muscle and other circulating growth factors. METHODS: Coronary artery ligation was performed in C57BL/6 mice at age 8 weeks to induce AMI. Mice were sacrificed at different time points (10 m, 1 h, 2 h, 6 h, 12 h, 24 h, 1 week, 2 weeks, 1 months and 2 months) after surgery (n=3 per time point, n=18 total). RESULTS: Cardiac and circulating MSTN upregulation occurred as early as 10 min after AMI. Two months after AMI, increased cardiac MSTN/SMAD2,3 and p38 together with decreased IGF-1/AKT signaling suggest an anti-hypertrophic profile. In skeletal muscle, an absence of local MSTN increase was accompanied by increased MSTN dependent SMAD2,3 signaling, suggestive of paracrine effects due to cardiac derived MSTN. Protein degradation by the ubiquitin-proteasome system in the skeletal muscle was also evident. Serum from 24h post-MI mice effectively induced a MSTN-dependent increase in atrogin1 and MuRF1. CONCLUSION: Our study shows that cardiac MTSN activation occurs rapidly after cardiac ischemia and may be involved in peripheral protein degradation in the skeletal muscle by activating atrogin1 and MuRF1. PMID- 25528590 TI - Latent profile analysis of sixth graders based on teacher ratings: Association with school dropout. AB - The goal of this study was to identify meaningful groups of sixth graders with common characteristics based on teacher ratings of assets and maladaptive behaviors, describe dropout rates for each group, and examine the validity of these groups using students' self-reports. The sample consisted of racially diverse students (n = 675) attending sixth grade in public schools in Northeast Georgia. The majority of the sample was randomly selected; a smaller group was identified by teachers as high risk for aggression. Based on teacher ratings of externalizing behaviors, internalizing problems, academic skills, leadership, and social assets, latent profile analysis yielded 7 classes that can be displayed along a continuum: Well-Adapted, Average, Average-Social Skills Deficit, Internalizing, Externalizing, Disruptive Behavior with School Problems, and Severe Problems. Dropout rate was lowest for the Well-adapted class (4%) and highest for the Severe Problems class (58%). However, students in the Average Social Skills Deficit class did not follow the continuum, with a large proportion of students who abandoned high school (29%). The proportion of students identified by teachers as high in aggression consistently increased across the continuum from none in the Well-Adapted class to 84% in the Severe Problems class. Students' self-reports were generally consistent with the latent profile classes. Students in the Well-Adapted class reported low aggression, drug use, and delinquency, and high life satisfaction; self-reports went in the opposite direction for the Disruptive Behaviors with School Problems class. Results highlight the importance of early interventions to improve academic performance, reduce externalizing behaviors, and enhance social assets. PMID- 25528591 TI - Psychopharmacological treatment among adolescents with disabilities: Prevalence and predictors in a nationally representative sample. AB - Little is known about psychopharmacological treatment among adolescents with educational disabilities. This study (a) describes pharmacotherapy among adolescents who received special education, and (b) examines the relations to adolescents' disability type and sociodemographic characteristics. The sample was 9,230 adolescents who participated in the National Longitudinal Transition Study 2, a nationally representative study of students with disabilities. Descriptive statistics and logistic regression were used to estimate prevalence and predictors of pharmacotherapy. During the study period, 18.14% of adolescents received pharmacotherapy with 11.75% receiving monopharmacy, 6.39% receiving polypharmacy, and 5.86% simultaneously receiving multiple classes of medications. Stimulants and antidepressants were the most commonly used classes of psychotropic medication. After adjusting for sociodemographics, pharmacotherapy was highest among adolescents with other health impairments, emotional disturbance, and autism. Disability type, race/ethnicity, marital status, head of household education, urbanicity, and private insurance type were significant predictors of polypharmacy. Overall, these results indicated rates of psychopharmacological treatment exceeded those in the general population and disparities across sociodemographic groups existed. Implications for research and practice are discussed. PMID- 25528592 TI - Students' ratings of teacher support and academic and social-emotional well being. AB - Data on students' perceptions of teacher social support, academic functioning, and social-emotional functioning were collected from a sample of 796 7th and 8th grade middle school students using the Child and Adolescent Social Support Scale (CASSS; Malecki, Demaray, & Elliott, 2000), Iowa Tests of Basic Skills (ITBS) and school records, and the Behavior Assessment Scale for Children, Second Edition, Adolescent Version, (BASC-2 SRP-A; Reynolds & Kamphaus, 2004). The purpose of the current study was to examine possible gender differences in perceptions of the frequency and importance of different types of teacher support and the related academic and social-emotional outcomes. Girls rated Emotional and Appraisal Support as more important than did boys. Teacher Emotional Support was significantly and positively related to grade point average (GPA) for boys and girls. For girls only, Emotional and Informational Support were significantly related to ITBS Reading scores, and Emotional, Informational, and Instrumental Support were significantly related to ITBS Math scores. Regarding social emotional variables, Emotional Support was significantly and negatively related to School Problems, Internalizing Problems, Inattention/Hyperactivity, and overall Emotional Symptoms and positively related to Personal Adjustment for both boys and girls. Furthermore, Emotional Support from teachers was more strongly related to Inattention/Hyperactivity for girls than boys. These results emphasize the importance of providing teacher social support, especially emotional support, to students in early adolescence and recognizing gender differences in the function of specific types of teacher support. PMID- 25528593 TI - Cave conservation priority index to adopt a rapid protection strategy: a case study in Brazilian Atlantic rain forest. AB - Cave environments are characterized by possessing specialized fauna living in high environmental stability with limited food conditions. These fauna are highly vulnerable to impacts, because this condition can frequently be easily altered. Moreover, environmental determinants of the biodiversity patterns of caves remain poorly understood and protected. Therefore, the main goal of this work is to propose a cave conservation priority index (CCPi) for a rapid assessment for troglobiotic and troglophile protection. Furthermore, the troglobiotic diversity, distribution and threats have been mapped in the Brazilian Atlantic forest. To propose the CCPi, the human impacts and richness of troglobiotic and troglophile species of 100 caves were associated. Data related to troglomorphic/troglobiotic fauna from another 200 caves were used to map the troglobiotic diversity and distribution. The CCPi reveals extremely high conservation priority for 15% of the caves, high for 36% and average for 46% of the caves. Fourteen caves with extremely high priorities should have urgent conservation and management actions. The geographical distribution of the 221 known troglobiotic/troglomorphic species allowed us to select 19 karst areas that need conservation actions. Seven areas were considered to have urgent priority for conservation actions. The two richest areas correspond to the "iron quadrangle" with iron ore caves (67 spp.) and the "Acungui limestone group" (56 spp.). Both areas have several caves and are important aquifers. The use of the CCPi can prevent future losses because it helps assessors to select caves with priorities for conservation which should receive emergency attention in relation to protection, management and conservation actions. PMID- 25528594 TI - Prioritizing watersheds for conservation actions in the southeastern coastal plain ecoregion. AB - The aim of this study was to apply and evaluate a recently developed prioritization model which uses the synoptic approach to geographically prioritize watersheds in which Best Management Practices (BMPs) can be implemented to reduce water quality problems resulting from erosion and sedimentation. The model uses a benefit-cost framework to rank candidate watersheds within an ecoregion or river basin so that BMP implementation within the highest ranked watersheds will result in the most water quality improvement per conservation dollar invested. The model was developed to prioritize BMP implementation efforts in ecoregions containing watersheds associated with the USDA-NRCS Conservation Effects Assessment Project (CEAP). We applied the model to HUC-8 watersheds within the southeastern Coastal Plain ecoregion (USA) because not only is it an important agricultural area but also because it contains a well studied medium-sized CEAP watershed which is thought to be representative of the ecoregion. The results showed that the three HUC-8 watersheds with the highest rankings (most water quality improvement expected per conservation dollar invested) were located in the southern Alabama, northern Florida, and eastern Virginia. Within these watersheds, measures of community attitudes toward conservation practices were highly ranked, and these indicators seemed to push the watersheds to the top of the rankings above other similar watersheds. The results, visualized as maps, can be used to screen and reduce the number of watersheds that need further assessment by managers and decision-makers within the study area. We anticipate that this model will allow agencies like USDA-NRCS to geographically prioritize BMP implementation efforts. PMID- 25528595 TI - Effects of coal mining, forestry, and road construction on southern Appalachian stream invertebrates and habitats. AB - Coal has been extracted via surface and sub-surface mining for decades throughout the Appalachian Mountains. New interest in ridge-top mining has raised concerns about possible waterway impacts. We examined effects of forestry, mining, and road construction-based disturbance on physico-chemistry and macroinvertebrate communities in east-central Tennessee headwater streams. Although 11 of 30 sites failed Tennessee's biocriteria scoring system, invertebrate richness was moderately high and we did not find significant differences in any water chemistry or habitat parameters between sites with passing and failing scores. However, conductivity and dissolved solid concentrations appeared elevated in the majority of study streams. Principal components (PCs) analysis indicated that six PCs accounted for ~77 % of among-site habitat variability. One PC associated with dissolved oxygen and specific conductance explained the second highest proportion of among-site variability after catchment area. Specific conductance was not correlated with catchment area but was strongly correlated with mining activity. Composition and success of multivariate models using habitat PCs to predict macroinvertebrate metrics was highly variable. PC scores associated with water chemistry and substrate composition were most frequently included in significant models. These results suggest that impacts of historical and current coal mining remain a source of water quality and macroinvertebrate community impairment in this region, but effects are subtle. Our results suggest that surface mining may have chronic and system-wide effects on habitat conditions and invertebrate communities in Cumberland Plateau streams. PMID- 25528596 TI - Synchronised approach for intrauterine insemination in subfertile couples. AB - BACKGROUND: In many countries intrauterine insemination (IUI) is the treatment of first choice for a subfertile couple when the infertility work up reveals an ovulatory cycle, at least one open Fallopian tube and sufficient spermatozoa. The final goal of this treatment is to achieve a pregnancy and deliver a healthy (singleton) live birth. The probability of conceiving with IUI depends on various factors including age of the couple, type of subfertility, ovarian stimulation and the timing of insemination. IUI should logically be performed around the moment of ovulation. Since spermatozoa and oocytes have only limited survival time correct timing of the insemination is essential. As it is not known which technique of timing for IUI results in the best treatment outcome, we compared different techniques for timing IUI and different time intervals. OBJECTIVES: To evaluate the effectiveness of different synchronisation methods in natural and stimulated cycles for IUI in subfertile couples. SEARCH METHODS: We searched for all publications which described randomised controlled trials of the timing of IUI. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (1966 to October 2014), EMBASE (1974 to October 2014), MEDLINE (1966 to October 2014) and PsycINFO (inception to October 2014) electronic databases and prospective trial registers. Furthermore, we checked the reference lists of all obtained studies and performed a handsearch of conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different timing methods for IUI were included. The following interventions were evaluated: detection of luteinising hormone (LH) in urine or blood, single test; human chorionic gonadotropin (hCG) administration; combination of LH detection and hCG administration; basal body temperature chart; ultrasound detection of ovulation; gonadotropin-releasing hormone (GnRH) agonist administration; or other timing methods. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, extracted the data and assessed study risk of bias. We performed statistical analyses in accordance with the guidelines for statistical analysis developed by The Cochrane Collaboration. The overall quality of the evidence was assessed using GRADE methods. MAIN RESULTS: Eighteen RCTs were included in the review, of which 14 were included in the meta-analyses (in total 2279 couples). The evidence was current to October 2013. The quality of the evidence was low or very low for most comparisons . The main limitations in the evidence were failure to describe study methods, serious imprecision and attrition bias.Ten RCTs compared different methods of timing for IUI. We found no evidence of a difference in live birth rates between hCG injection versus LH surge (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.06 to 18, 1 RCT, 24 women, very low quality evidence), urinary hCG versus recombinant hCG (OR 1.17, 95% CI 0.68 to 2.03, 1 RCT, 284 women, low quality evidence) or hCG versus GnRH agonist (OR 1.04, 95% CI 0.42 to 2.6, 3 RCTS, 104 women, I(2) = 0%, low quality evidence).Two RCTs compared the optimum time interval from hCG injection to IUI, comparing different time frames that ranged from 24 hours to 48 hours. Only one of these studies reported live birth rates, and found no difference between the groups (OR 0.52, 95% CI 0.27 to 1.00, 1 RCT, 204 couples). One study compared early versus late hCG administration and one study compared different dosages of hCG, but neither reported the primary outcome of live birth.We found no evidence of a difference between any of the groups in rates of pregnancy or adverse events (multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS)). However, most of these data were very low quality. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether there is any difference in safety and effectiveness between different methods of synchronization of ovulation and insemination. More research is needed. PMID- 25528597 TI - Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection. AB - Although it has been known for decades that patients with type 2 diabetes mellitus (DM) are more susceptible to severe tuberculosis (TB) infection, the underlying immunological mechanisms remain unclear. Resistin, a protein produced by immune cells in humans, causes insulin resistance and has been implicated in inhibiting reactive oxygen species (ROS) production in leukocytes. Recent studies suggested that IL-1beta production in patients with Mycobacteria tuberculosis infection correlates with inflammasome activation which may be regulated by ROS production in the immune cells. By investigating the level of resistin in different patient groups, we found that serum resistin levels were significantly higher in severe TB and DM-only groups when compared with mild TB cases and healthy controls. Moreover, elevation of serum resistin correlated with impairment of ROS production of neutrophils in patients with both DM and TB. In human macrophages, exogenous resistin inhibits the production of ROS which are important in the mycobacterium-induced inflammasome activation. Moreover, macrophages with defective ROS production had poor IL-1beta production and ineffective control of mycobacteria growth. Our results suggest that increased resistin in severe TB and DM patients may suppress the mycobacterium-induced inflammasome activation through inhibiting ROS production by leukocytes. PMID- 25528598 TI - Repeated epinephrine doses during prolonged cardiopulmonary resuscitation have limited effects on myocardial blood flow: a randomized porcine study. AB - BACKGROUND: In current guidelines, prolonged cardiopulmonary resuscitation (CPR) mandates administration of repeated intravenous epinephrine (EPI) doses. This porcine study simulating a prolonged CPR-situation in the coronary catheterisation laboratory, explores the effect of EPI-administrations on coronary perfusion pressure (CPP), continuous coronary artery flow average peak velocity (APV) and amplitude spectrum area (AMSA). METHODS: Thirty-six pigs were randomized 1:1:1 to EPI 0.02 mg/kg/dose, EPI 0.03 mg/kg/dose or saline (control) in an experimental cardiac arrest (CA) model. During 15 minutes of mechanical chest compressions, four EPI/saline-injections were administered, and the effect on CPP, APV and AMSA were recorded. Comparisons were performed between the control and the two EPI-groups and a combination of the two EPI-groups, EPI-all. RESULT: Compared to the control group, maximum peak of CPP (Pmax) after injection 1 and 2 was significantly increased in the EPI-all group (p = 0.022, p = 0.016), in EPI 0.02-group after injection 2 and 3 (p = 0.023, p = 0.027) and in EPI 0.03 group after injection 1 (p = 0.013). At Pmax, APV increased only after first injection in both the EPI-all and the EPI 0.03-group compared with the control group (p = 0.011, p = 0.018). There was no statistical difference of AMSA at any Pmax. Seven out of 12 animals (58%) in each EPI-group versus 10 out of 12 (83%) achieved spontaneous circulation after CA. CONCLUSION: In an experimental CA-CPR pig model repeated doses of intravenous EPI results in a significant increase in APV only after the first injection despite increments in CPP also during the following 2 injections indicating inappropriate changes in coronary vascular resistance during subsequent EPI administration. PMID- 25528599 TI - Pectin enhances rice (Oryza sativa) root phosphorus remobilization. AB - Plants growing in phosphorus (P)-deficient conditions can either increase their exploration of the environment (hence increasing P uptake) or can solubilize and reutilize P from established tissue sources. However, it is currently unclear if P stored in root cell wall can be reutilized. The present study shows that culture of the rice cultivars 'Nipponbare' (Nip) and 'Kasalath' (Kas) in P deficient conditions results in progressive reductions in root soluble inorganic phosphate (Pi). However, Nip consistently maintains a higher level of soluble Pi and lower relative cell wall P content than does Kas, indicating that more cell wall P is released in Nip than in Kas. P-deficient Nip has a greater pectin and hemicellulose 1 (HC1) content than does P-deficient Kas, consistent with the significant positive relationship between pectin and root-soluble Pi levels amongst multiple rice cultivars. These observations suggest that increased soluble Pi might result from increased pectin content during P starvation. In vitro experiments showed that pectin releases Pi from insoluble FePO4. Furthermore, an Arabidopsis thaliana mutant with reduced pectin levels (qua1-2), has less root soluble Pi and is more sensitive to P deficiency than the wild type (WT) Col-0, whereas NaCl-treated WT plants exhibit both an increased root pectin content and an elevated soluble Pi content during P-starvation. These observations indicate that pectin can facilitate the remobilization of P deposited in the cell wall. This is a previously unknown mechanism for the reutilization of P in P-starved plants. PMID- 25528600 TI - Objectively measured physical activity, brain atrophy, and white matter lesions in older adults with mild cognitive impairment. AB - Physical activity may help to prevent or delay brain atrophy. Numerous studies have shown associations between physical activity and age-related changes in the brain. However, most of these studies involved self-reported physical activity, not objectively measured physical activity. Therefore, the aim of this study was to examine the association between objectively measured physical activity, as determined using accelerometers, and brain magnetic resonance imaging (MRI) measures in older adults with mild cognitive impairment (MCI). We analyzed 323 older subjects with MCI (mean age 71.4 years) who were recruited from the participants of the Obu Study of Health Promotion for the Elderly. We recorded demographic data and measured physical activity using a tri-axial accelerometer. Physical activity was classified as light-intensity physical activity (LPA) or moderate-to-vigorous physical activity (MVPA). Brain atrophy and the severity of white matter lesions (WML) were determined by MRI. Low levels of LPA and MVPA were associated with severe WML. Subjects with severe WML were older, had lower mobility, and had greater brain atrophy than subjects with mild WML (all P<0.05). Multivariate analysis revealed that more MVPA was associated with less brain atrophy, even after adjustment for WML (beta=-0.126, P=0.015), but LPA was not (beta=-0.102, P=0.136). Our study revealed that objectively measured physical activity, especially MVPA, was associated with brain atrophy in MCI subjects, even after adjusting for WML. These findings support the hypothesis that physical activity plays a crucial role in maintaining brain health. PMID- 25528601 TI - Criterion-referenced fitness standards for predicting physical independence into later life. AB - OBJECTIVES: The aim of the current study was to develop sex and age-adjusted criterion-referenced fitness standards to predict independent physical functioning into later life. DESIGN: Cross-sectional. SETTING: National Survey of Physical Fitness and Physical Activity, Portugal. PARTICIPANTS: A national representative sample of 3074 non-institutionalized older adults (65-84years). MEASUREMENTS: Projected capacity for physical independence was assessed by the Composite Physical Function (CPF) scale, and physical fitness was assessed using the Senior Fitness Test battery. ROC analyses were used to evaluate the classification accuracy of physical fitness components, and determine the best cutoff values of functional fitness to predict loss of independence. Stepwise multivariate logistic regression was used to identify sex and age category fitness components that were predictors of independence with follow-up ROC analysis to verify the model's discriminative capability. RESULTS: ROC curve analysis showed that the fitness tests were good in diagnosing physical independence (AUC>0.7). Logistic regression models demonstrated that different fitness components should be targeted according to age and sex, but with an emphasis on aerobic endurance and agility/dynamic balance. Overall, models provided higher AUC (males: 0.79-0.86; females: 0.73-0.85) when comparing the best fitness tests for each sex and age category. The sensitivity of newly developed models ranged from 80.5 to 87.7 in males and from 68.2 to 86.3 in females, while the specificity ranged from 62.1 to 73.8 in males and between 58.2 and 82.9 in females. CONCLUSION: The Senior Fitness Test provides a good field tool that allows the identification of fitness levels that older adults need to achieve to be physically independent later in life, and permits the accurate planning and implementation of exercise-based interventions for older adults. PMID- 25528602 TI - Post-trial induction of conditioned apomorphine stimulant and inhibitory response effects: evidence for potent trace conditioning of drug effects. AB - The Pavlovian conditioning of drug effects has frequently been demonstrated using protocols that are variants of Pavlovian delay conditioning. We undertook to determine if drug conditioning could be induced using a Pavlovian trace conditioning procedure. Rats were tested in a novel open-field environment for 5 min and in post-trial phase were injected either with vehicle, 2.0 mg/kg or 0.05 mg/kg apomorphine immediately or after a delay of 15 min. The procedure was repeated three times and subsequently a 30 min non-drug test was given. The vehicle and 15 min post-trial apomorphine groups did not differ and in the 30 min test their locomotion scores were equivalent to another vehicle group tested for the first time. The group that received 2.0 mg/kg apomorphine immediately post trial had a progressive increase in activity over the three sessions and also initially in the 30 min test. The results for the 0.05 mg/kg immediate post-test group were a mirror image of the 2.0 mg/kg apomorphine group. Post-trial apomorphine treatments can induce potent conditioned effects indicative of the efficacy of trace conditioning of drug effects. These finding suggest that trace conditioning may be an important contributor to the potency of conditioned-drug effects in the development of drug addiction. PMID- 25528604 TI - Comparison of direct and indirect pyrolysis of micro-algae Isochrysis. AB - Yield and composition of pyrolysis oil in direct and indirect pyrolysis process were investigated which indicated that pyrolysis of defatted microalgae provided a potential way to convert protein and carbohydrate to biofuels. Defatted microalgae pyrolysis with lipid extraction has higher total oil yield than only microalgae direct pyrolysis. There was an increase for N-heterocyclic compounds and phenols and a decrease for hydrocarbons in defatted microalgae pyrolysis oil. There is an apparent decrease from C12 to C16 and nearly no carbon distribution from C17 to C22 for defatted microalgae pyrolysis. Based on composition of pyrolysis feedstock, pyrolysis oil yields were simulated by Compounds Biofuel Model and their accuracy was less than +/-4.4%. Considering total oil yield and characteristics, microalgae pyrolysis after lipid extraction process is a promising way for microalgae utilization. PMID- 25528603 TI - Emotion dysregulation mediates the relationship between lifetime cumulative adversity and depressive symptomatology. AB - Repeated exposure to stressful events across the lifespan, referred to as cumulative adversity, is a potent risk factor for depression. Research indicates that cumulative adversity detrimentally affects emotion regulation processes, which may represent a pathway linking cumulative adversity to vulnerability to depression. However, empirical evidence that emotion dysregulation mediates the relationship between cumulative adversity and depression is limited, particularly in adult populations. We examined the direct and indirect effects of cumulative adversity on depressive symptomatology in a large community sample of adults (n = 745) who were further characterized by risk status: never-depressed (n = 638) and "at-risk" remitted mood-disordered (n = 107). All participants completed the Cumulative Adversity Inventory (CAI), the Difficulties in Emotion Regulation Scale (DERS), and the Center for Epidemiologic Studies Depression Scale (CES-D). Bootstrapped confidence intervals were computed to estimate the indirect effect of emotion dysregulation on the relationship between cumulative adversity and depressive symptomatology and to test whether this indirect effect was moderated by risk status. Emotion dysregulation partially and significantly mediated the relationship between cumulative adversity and depressive symptomatology independent of risk status. Overall, cumulative adversity and emotion dysregulation accounted for 50% of the variance in depressive symptomatology. These findings support the hypothesis that disruption of adaptive emotion regulation processes associated with repeated exposure to stressful life events represents an intrapersonal mechanism linking the experience of adverse events to depression. Our results support the utility of interventions that simultaneously emphasize stress reduction and emotion regulation to treat and prevent depressive vulnerability and pathology. PMID- 25528605 TI - In situ biodiesel production from greasy sewage sludge using acid and enzymatic catalysts. AB - This study proposes to select the most appropriate sewage sludge (greasy, primary and secondary) for in situ transesterification and to compare the technical, economic and energetic performance of an enzymatic catalyst (Novozym(r)435) with sulfuric acid. Greasy sludge was selected as feedstock for biodiesel production due to its high lipid content (44.4%) and low unsaponifiable matter. Maximum methyl esters yield (61%) was reached when processing the wet sludge using sulfuric acid as catalyst and n-hexane, followed by dried-greasy sludge catalyzed by Novozym(r)435 (57% methyl esters). Considering the economic point of view, the process using acid catalyst was more favorable compared to Novozym(r)435 catalyst due to the high cost of lipase. In general, greasy sludge (wet or dried) showed high potential to produce biodiesel. However, further technical adjustments are needed to make biodiesel production by in situ transesterification using acid and enzymatic catalyst feasible. PMID- 25528606 TI - Comparison of bacterial succession in green waste composts amended with inorganic fertiliser and wastewater treatment plant sludge. AB - Replacing CAN with DWS resulted in a stable product capable of supporting similar levels of plant growth to conventional compost. Proteobacteria was the dominant phylum detected in both CAN- and DWS-amended composts with Actinobacteria, Bacteroidetes, Firmicutes and Chloroflexi present also. Proteobacteria in both composts negatively correlated with pH, NO3 concentration and temperature, but were positively influenced by NH4 levels. Sphaerobacter was the most abundant genus in the mature phase of both CAN- and DWS-amended composts but bacterial community structure in mature DWS-amended compost appeared more diverse than that present in mature compost made using CAN. PMID- 25528607 TI - Influence of ferrous ions on extracellular polymeric substances content and sludge dewaterability during bioleaching. AB - Pretreatment of activated sludge with sulfuric acid and bioleaching using Acidithiobacillus ferrooxidans along with addition of Fe(2+) on sludge dewaterability was investigated. The sludge dewatering efficiency in terms of capillary suction time (CST) and specific resistant to filtration (SRF) was increased with a decrease in sludge pH. A pH of 2.67 was found to be optimum for dewatering, at which 81% and 63% reduction of CST and SRF were achieved, respectively. The dewaterability of sludge was enhanced after the addition of Fe(2+) and A. ferrooxidans. Ideal concentration of Fe(2+) was 2 g/L for sludge dewaterability, which showed 96% and 88% reduction in CST and SRF, respectively. In the control sludge, maximum part of the biopolymeric macromolecules was contributing by the tightly bound extracellular polymeric substances (TB-EPS). At optimum Fe(2+) concentration, total EPS was reduced by 73%, enhancing sludge dewaterability. Bioleaching conducted by A. ferrooxidans could solubilized 88% Cu and 99% Zn within 120 h. PMID- 25528608 TI - Individuals with agenesis of the corpus callosum show sensory processing differences as measured by the sensory profile. AB - OBJECTIVE: Given reports of high pain thresholds and reduced auditory response in individuals with agenesis of the corpus callosum (AgCC), this study investigated whether affected participants report atypical experiences and behaviors on a well established sensory processing measure. METHODS: Fourteen participants with AgCC (ages 11-59) completed the Adolescent/Adult Sensory Profile (Brown & Dunn, 2001). Sensory profile scales were classified as "Atypical" if they were more than 1 standard deviation from the mean. RESULTS: Fifty-seven percent of participants with AgCC reported reduced sensory registration as compared to an expected 16% of the normative sample. Similarly, 50% of the AgCC participants reported atypically increased auditory processing difficulties. CONCLUSIONS: Using a well-established sensory processing questionnaire, participants with AgCC reported measurable differences in multiple aspects of sensory processing. The most notable difference was in the quadrant of low sensory registration, suggesting that individuals with AgCC may require sensory information to be presented more slowly or at a higher intensity for adequate processing. The sensory modality that was most affected was the auditory system, which is consistent with increased rates of language disorders and autism spectrum disorders in this population. Understanding sensory processing in individuals with AgCC can both elucidate the role of interhemispheric transfer in the development of intact sensory processing as well as contribute to our knowledge of the role of the corpus callosum in a range of disorders in which sensory processes are impacted. (PsycINFO Database Record PMID- 25528609 TI - The premotor role of the prefrontal cortex in response consistency. AB - OBJECTIVE: The aim of the present study was to investigate the cortical correlates of the intraindividual coefficient of variation (ICV) in a go/no-go task, focusing on the prefrontal cortex (PFC) contribution and evaluating both pre- and poststimulus brain activity. METHOD: We recorded event-related potentials (ERPs) in 40 subjects, arranged a posteriori in 2 groups on the basis of their ICV values. By this method, we formed the consistent (low ICV; n = 20) and inconsistent (high ICV; n = 20) group: the age, speed, and accuracy performance of the 2 groups were matched. RESULTS: The prestimulus anticipatory PFC activity, as reflected by the prefrontal negativity (pN) wave, and the poststimulus P3 component were larger in the consistent than in the inconsistent group. In contrast, no differences were observed between groups in the brain activities associated to motor preparation and early sensory processing. CONCLUSIONS: Data are interpreted as an enhanced top-down control in consistent performers, likely characterized by a greater sustained attention on the task. PMID- 25528610 TI - Decussation as an axial twist: A comment on Kinsbourne (2013). AB - One of the great mysteries of the brain, which has puzzled all-time students of brain form and function, is the contralateral organization of the forebrain and the crossings of its major afferent and efferent connections. As a novel explanation, two recent studies have proposed that the rostral part of the head, including the forebrain, is rotated by 180 degrees with respect to the rest of the body (de Lussanet and Osse, 2012; Kinsbourne, 2013). Kinsbourne proposes one 180 degrees turn while we consider the 180 degrees being the result of two 90 degrees turns in opposite directions. We discuss the similarities and differences between the two hypotheses. PMID- 25528611 TI - Transcriptomic comparison of thiamethoxam-resistance adaptation in resistant and susceptible strains of Aphis gossypii Glover. AB - A thiamethoxam-resistant strain of cotton aphid (ThR) strain displayed a 19.35 fold greater resistance to thiamethoxam compared to a susceptible cotton aphid (SS) strain. Solexa sequencing technology was used to investigate differentially expressed genes (DEGs) in cotton aphids in the context of thiamethoxam resistance. A total of 22,569,311 and 21,317,732 clean reads were obtained from the ThR and SS transcriptomes, respectively, and assembled into 35,222 non redundant (Nr) consensus sequences. The expression of 620 unigenes changed significantly in the ThR libraries compared to the SS strain; 349 genes were up regulated, and 271 genes were down-regulated (P<=0.001). Expression levels of ribosomal proteins, ATP synthase, cytochrome c oxidase, ecdysteroid UDP glucosyltransferase and esterase were up-regulated significantly in the ThR strain compared to the SS strain. The genes of cuticle proteins, salivary proteins, and fibroin heavy chain decreased dramatically. One nicotinic acetylcholine receptor (nAChR) alpha subunit was down-regulated in the ThR strain. The expression levels of 10 differentially expressed unigenes were confirmed using real-time RT-PCR, and the observed trends in gene expression matched the Solexa expression profiles. Specific single-nucleotide polymorphisms (SNPs) in nAChRs that cause amino acid substitution were found from the ThR and SS stains respectively. These data illustrate that genetic changes in nAChR genes and up-regulated ribosomal proteins, ecdysteroid UDP-glucosyltransferase, cytochrome c oxidase, esterase and peroxidase may confer the tolerance of resistant cotton aphids to thiamethoxam. PMID- 25528612 TI - Acute suppression of TGF-beta with local, sustained release of tranilast against the formation of fibrous capsules around silicone implants. AB - We propose the acute, local suppression of transforming growth factor beta (TGF beta), a major profibrotic cytokine, to reduce fibrosis around silicone implants. To this end, we prepared silicone implants that were able to release tranilast, a TGF-beta inhibitor, in a sustained manner for 5 days or 15 days. We performed histologic and immunohistochemical analyses for 12 weeks after the implantation of the implants in living rats. The capsule thicknesses and collagen densities significantly decreased compared with those around the non-treated silicone implants. Notably, early suppression of TGF-beta affected the fibrogenesis that actually occurs at the late stage of wound healing. This change may be ascribed to the decrease in monocyte recruitment mediated by early TGF-beta during the acute inflammatory reaction. Thus, a significant decrease in differentiated macrophages was observed along with a decrease in the quantity of TGF-beta and fibroblasts during the subsequent inflammation stage; these changes led to a diminished fibrotic capsule formation. PMID- 25528613 TI - Lifecourse epidemiology and molecular pathological epidemiology. PMID- 25528615 TI - Neural oscillations: beta band activity across motor networks. AB - Local field potential (LFP) activity in motor cortical and basal ganglia regions exhibits prominent beta (15-40Hz) oscillations during reaching and grasping, muscular contraction, and attention tasks. While in vitro and computational work has revealed specific mechanisms that may give rise to the frequency and duration of this oscillation, there is still controversy about what behavioral processes ultimately drive it. Here, simultaneous behavioral and large-scale neural recording experiments from non-human primate and human subjects are reviewed in the context of specific hypotheses about how beta band activity is generated. Finally, a new experimental paradigm utilizing operant conditioning combined with motor tasks is proposed as a way to further investigate this oscillation. PMID- 25528614 TI - Neural ensemble communities: open-source approaches to hardware for large-scale electrophysiology. AB - One often-overlooked factor when selecting a platform for large-scale electrophysiology is whether or not a particular data acquisition system is 'open' or 'closed': that is, whether or not the system's schematics and source code are available to end users. Open systems have a reputation for being difficult to acquire, poorly documented, and hard to maintain. With the arrival of more powerful and compact integrated circuits, rapid prototyping services, and web-based tools for collaborative development, these stereotypes must be reconsidered. We discuss some of the reasons why multichannel extracellular electrophysiology could benefit from open-source approaches and describe examples of successful community-driven tool development within this field. In order to promote the adoption of open-source hardware and to reduce the need for redundant development efforts, we advocate a move toward standardized interfaces that connect each element of the data processing pipeline. This will give researchers the flexibility to modify their tools when necessary, while allowing them to continue to benefit from the high-quality products and expertise provided by commercial vendors. PMID- 25528616 TI - Editorial - Orthopedic trauma management in a heterogeneous country. PMID- 25528617 TI - Tertiary survey in trauma patients: avoiding neglected injuries. AB - INTRODUCTION: Medical personnel in trauma centres in several countries have realised that undiagnosed injuries are common and are now focussing their attention on reducing the incidence of these injuries. Tertiary survey is a simple and easy approach to address the issue of undiagnosed injuries in trauma patients. Tertiary survey consists of reevaluating patients 24 hours after admission by means of an anamnesis protocol, physical examination, review of complementary tests and request for new tests when necessary. OBJECTIVE: To show the importance of tertiary survey in trauma patients for diagnosing injuries undetected at the time of initial survey. METHODS: A standardised protocol was used to perform a prospective observational study with patients admitted through the emergency department, Department of Orthopaedics and Trauma, Santa Casa de Sao Paulo. The patients were reevaluated 24 hours after admission or after recovering consciousness. New physical examinations were performed, tests performed on admission were reassessed and new tests were requested, when necessary. RESULTS: Between February 2012 and February 2013, 526 patients were evaluated, 81 (15.4%) were polytraumatised, and 445 (84.6%) had low-energy trauma. A total of 57 new injuries were diagnosed in 40 patients, 61.4% of which affected the lower limb. Diagnosis of 11 new injuries (19.3%) resulted in changes in procedure. CONCLUSION: The application of the protocol for tertiary survey proved to be easy, inexpensive and beneficial to patients (particularly polytraumatised patients) because it enabled identification of important injuries that were not detected on admission in a large group of patients. PMID- 25528618 TI - Reproducibility of classifications for olecranon fractures. AB - INTRODUCTION: Fractures of the olecranon are relatively common injuries in adults and are of great clinical importance. Classification systems have been developed as tools to assist surgeons in grouping different types of fractures, to facilitate communication and to standardise treatment, but none of the systems used today is universally accepted for olecranon fractures. METHODS: Fifty-nine olecranon fractures were classified according to the Schatzker, Colton, Mayo and AO/ASIF systems by four observers with different levels of expertise. Intra- and inter-observer agreement was assessed. Each observer analysed the images at three different times; the images were randomised and presented in a different sequence at each assessment. RESULTS: There was higher mean intra-observer agreement in the AO/ASIF (0.60) and Mayo (0.64) classifications compared with the Schatzker (0.49) and Colton (0.38) classifications. Inter-observer agreement was better with AO/ASIF and Mayo (0.35 and 0.32, respectively) than with Schatzker and Colton (0.29 and 0.12, respectively). CONCLUSION: The results of this study indicate that the most commonly used classifications for olecranon fractures are associated with low reproducibility. PMID- 25528619 TI - Interprosthetic femoral fractures: proposed new classification system and treatment algorithm. AB - Interprosthetic femoral fracture is a rare and challenging fragility fracture issue. Due to aging of the population, the incidence of this type of fracture is gradually and constantly increasing. There is no complete and specific interprosthetic femoral fracture classification system that indicates treatment and prognosis in the literature. The aim of the present study was to describe a new classification system for interprosthetic femoral fractures, and to present a case series and a treatment algorithm derived from the current evidence in the literature. PMID- 25528620 TI - Interlocking screws placed with freehand technique and uni-planar image intensification: the "dip-stick" technique. AB - OBJECTIVE: To report our experience with a novel alternative method of freehand interlocking of intramedullary nails. This method requires the use of only anterior-posterior image intensification and an intramedullary guide wire to verify screw placement. Our results are compared with historical results in the literature. METHODS: A total of 815 patients were treated using this technique from January 2008 to December 2012; 603 patients had fractures of the tibia and 212 had fractures of the femur. RESULTS: The mean duration of surgery for tibial shaft fractures was 55.6 minutes (range 42-60 minutes) and that for fractures of the femur was 78 minutes (range 50-90 minutes). The mean time for each distal locking was 3.8 minutes (2.5-5.1 minutes), with 7.65 seconds of exposure to radiation during each block. CONCLUSIONS: The surgical technique is simple, easy and reproducible. Mean time of surgery and radiation exposure was less than that in the literature. A comparative study should be performed. PMID- 25528621 TI - Functional recovery of elderly patients with surgically-treated intertrochanteric fractures: preliminary results of a randomised trial comparing the dynamic hip screw and proximal femoral nail techniques. AB - INTRODUCTION: Intertrochanteric fractures of the femur are prevalent in the elderly, and leave patients with functional restrictions after surgical treatment. The aim of this study was to compare the functional recovery at 1-year follow-up of elderly patients with intertrochanteric fractures treated surgically with the dynamic hip screw (DHS) or proximal femoral nail (PFN) fixation techniques. MATERIAL AND METHODS: This prospective, randomised, blinded trial included patients aged over 65 years with intertrochanteric fractures classified as AO group 31.A1 or 31.A2. The patients were allocated into one of two treatment groups: one treated with DHS and the other with PFN. Data on functional recovery were obtained using the Functional Recovery Score developed by Zuckerman for elderly patients with hip fracture. Variables were described as means and standard deviations, and the non-parametric Kolmogorov-Smirnov test was used to verify the normality of data distribution. Non-normally distributed variables were compared using the non-parametric Friedman and Mann-Whitney U tests. Data processing and analysis were carried out in SPSS 10.0. Results were deemed significant at the 5% level (p <= 0.05). RESULTS: There were no significant between-group differences in age (p=0.152), sex (p=0.363), or American Society of Anaesthesiologists (ASA) score (p=0.579). Functional recovery scores in the DHS group at 3 and 6 months after surgery were significantly reduced from preoperative baseline scores (p=0.007) compared with in the PFN group. However, there were no statistically significant differences between the two groups in functional recovery scores at baseline (p=0.346) or at 3 months (p=0.880), 6 months (p=0.699), and 12 months (p=0.468) after surgery. There was no between group difference in mortality (p=0.140). CONCLUSION: At 1-year follow-up, functional recovery scores were similar in elderly patients treated with the DHS and PFN techniques. However, DHS-treated patients exhibited significant loss of function in the first 6 months after surgery, which did not occur in the PFN treated group. PMID- 25528622 TI - Bone tissue repair in patients with open diaphyseal tibial fracture treated with biplanar external fixation or reamed locked intramedullary nailing. AB - INTRODUCTION: Open tibial fractures are usually caused by high-energy trauma. There is no consensus about the best treatment for these fractures. Biomechanical studies show that fixing on two planes approaches the rigidity of the bone, whereas the use of interlocking intramedullary nailing is widely used and reported to produce better therapeutic results in fracture healing. OBJECTIVE: To compare bone tissue repair in patients with open diaphyseal tibial fracture treated with biplanar external fixation or reamed locked intramedullary nailing. METHOD: Prospective randomised study with 68 patients undergoing two types of surgical treatment: biplanar external fixation or reamed locked intramedullary nailing. Consolidation, complications (infection, malunion and non-union) and quality of life using the SF-36 Health Survey were assessed 12 months after surgery. RESULTS: Consolidation occurred in 84.6% of patients who underwent reamed intramedullary nailing, and in 90.3% of patients who were treated with biplanar external fixation. In the intramedullary nailing group, there were two cases of non-union, three cases of malunion and two cases of infection. In the patients treated with biplanar fixation, there were three cases of non-union, five cases of malunion and no cases of infection. There were no statistically significant differences between the treatment groups for these results. Patient quality of life was statistically equal for both methods. CONCLUSION: Treatment with biplanar external fixation was associated with statistically similar results compared with intramedullary locking. PMID- 25528623 TI - Influence of time to surgery on the incidence of complications in femoral neck fracture treated with cannulated screws. AB - BACKGROUND: Osteosynthesis of femoral neck fractures is particularly indicated in patients aged under 60 years. A prolonged interval between the fracture and surgical fixation has been associated with avascular necrosis (AVN) of the femoral head. The primary objective of this study was to evaluate the association between the time to surgery and the development of complications in patients with femoral neck fractures. METHODS: Patients with displaced fractures of the femoral neck (Garden III or IV) who underwent fixation with three cannulated screws in the inverted triangle configuration from January 2009 to December 2010 were evaluated retrospectively for the development of orthopaedic complications. Patients were divided into two groups according to the time to surgery (within 7 days or more than 7 days). Complication rates were compared between the two groups. Regression analyses were performed to assess the risk factors for complications. RESULTS: Thirty-one patients were included in the study; the duration of follow-up ranged from 24 to 50 months. The time from fracture to surgery ranged from 3 to 18 days. Fifteen patients underwent surgery within 7 days, and 16 patients underwent surgery after 7 days. There were four cases of femoral head necrosis. One patient had an associated infection; one patient experienced non-union, and another demonstrated osteosynthesis failure. There were no statistically significant differences in the overall rate of complications between the groups (p = 0.999). None of the preoperative parameters or fracture characteristics were predictive factors for complications. The only factor associated with the development of complications was inadequate fracture reduction in the anteroposterior (AP) view (odds ratio [OR] = 35.50, 95% confidence interval [CI] = 2.56 to 548.36, p = 0.008). CONCLUSIONS: The interval between the occurrence of the injury and surgical fixation is not associated with the development of complications in fractures of the femoral neck. Inadequate fracture reduction in the AP view is a predictive factor for complications in these fractures. PMID- 25528624 TI - Surgical treatment for unstable pelvic fractures in skeletally immature patients. AB - OBJECTIVE: To present the results and conclusions of our study on surgical treatment for unstable pelvic fractures in children subjected to surgical reduction and stabilisation. METHODS: We analysed the cases of fourteen skeletally immature patients with unstable pelvic fractures who underwent surgery for this condition between March 2004 and January 2011. The surgical technique used was based on the principle of surgical reduction and stabilisation of anterior and posterior lesions of the pelvic ring. This was a retrospective study, based on clinical assessment and X-ray analyses. RESULTS: The mean age of patients at the time of the condition was 9.4 years (range 2-13 years). Eight patients were female and six were male. The cause of the trauma was being hit by a car in ten cases, falls in three cases and an accident involving a motorcycle in one case. Five patients presented with other associated injuries, including fracture of the clavicle, femur shaft, proximal humerus, tibial shaft or olecranon, and bladder damage. All the patients assessed showed excellent clinical progress. Pelvic asymmetry prior to surgery varied from 1.1 to 2.9 cm (mean 1.5 cm) and dropped to a range of 0.2 to 0.9 cm (mean 0.4 cm) after reduction. In none of the cases was there a change between the pelvic asymmetry measured immediately after surgery and at the end of the follow-up period. CONCLUSION: Pelvic fracture in skeletally immature patients is rare and surgery is not normally indicated. Various authors have questioned this conservative type of treatment due to complications encountered. Bone remodelling does not seem to be sufficient to ensure an improvement in pelvic asymmetry, which justifies opting for surgery to reduce and correct deformities in the pelvic ring. PMID- 25528625 TI - Treatment of pelvic fractures - a national survey. AB - INTRODUCTION: This survey was conducted during the 38(th) Brazilian Congress of Orthopaedics and Traumatology to identify the opinion of Brazilian orthopaedic surgeons on the standard treatment of pelvic fractures. MATERIALS AND METHODS: Participants were randomly selected and invited to voluntarily answer a questionnaire of 10 multiple choice questions addressing the main aspects of the treatment of pelvic fractures: classification, fixation methods in unstable patients, optimal surgical timing in stable patients, and fixation methods in different types of anterior and posterior pelvic injuries. RESULTS/CONCLUSION: Three hundred and fifty-two questionnaires were completed, and the following main observations were made: most orthopaedists prefer to use an external fixator in the iliac crest for the emergency stabilisation of pelvic injuries in haemodynamically unstable patients (79.5%); they consider a period of up to one week as optimal for fixation in stable patients (55.1%); they use a plate for the fixation of fractures of the iliopubic rami through a Pfannenstiel or ilio inguinal approach (53.9%); and they use reconstruction plates for the fixation of fractures of the iliac wing (63.1%). Regarding other studied aspects, there was no predominance of more than 50% of the choices among respondents. PMID- 25528626 TI - The effect of autologous concentrated bone-marrow grafting on the healing of femoral shaft non-unions after locked intramedullary nailing. AB - The aim of this study was to assess the union rates in a series of patients with failed femoral shaft aseptic non-union who were treated with percutaneous concentrated autologous bone marrow grafting. Bone marrow harvesting and cell injection were performed under general anaesthesia in a single surgical procedure. Radiographic union was diagnosed in fractures with a score >= 10 according to the radiographic union scale in tibial fractures (RUST) and confirmed by clinical examination. Eight out of 16 patients progressed to consolidation (RUST score >= 10). Radiographic evidence of fracture union was observed at an average of 4.75 +/- 1.75 months (range 3 to 8 months). All eight patients who did not progress to union within 12 months following the cell grafting procedure had a RUST score <= 10 (range 4 to 9). There were no differences in age, number of previous surgeries, duration of nonunion and preoperative RUST score between the patients that developed solid union and those with failed consolidation. However, a relationship between the number of osteoprogenitors injected and the rate of union was noted, 20.2 +/- 8.6 * 10(8) versus 9.8 +/- 4.3 * 10(8), p<0.005, between the patients with and without union, respectively. The efficacy of percutaneous autologous concentrated bone marrow grafting seems to be related to the number of osteoprogenitors available in the aspirates. Optimisation of the aspiration technique and concentration process is of paramount importance to increase the incidence of a successful outcome. PMID- 25528627 TI - Understanding HIV infection for the design of a therapeutic vaccine. Part II: Vaccination strategies for HIV. AB - HIV infection leads to a gradual loss CD4(+) T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive lifelong adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore, there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. PMID- 25528628 TI - Cytokeratin 20 improves the detection of circulating tumor cells in patients with colorectal cancer. AB - Cytokeratin 20 (CK20) is a well-established marker for colon epithelium. Herein, we suggest that CK20 is a biomarker for detecting circulating tumor cells (CTCs) in patients with metastatic colorectal cancer. Blood specimens (7.5 mL) were collected during surgery after liver mobilization from 25 patients with colorectal cancer. The FDA approved CellSearchTM system and two panels of antibodies against cytokeratins, cytokeratin 8, 18 and 19 (CK8/18/19) and CK8/18/19/20, were used for the detection of CTCs. All the patients' samples were processed using the anti-CK8/18/19 panel. The number of detected CTCs was low, 52% of the patients lacked CTCs and 40% had <= 2 CTCs/7.5 mL blood. Nine of the patients' blood samples were processed with both antibody panels. The detection rate of CTCs was significantly higher using the anti-CK8/18/19/20 panel compared with the anti-CK8/18/19 panel, p-value 0.0078. Our data show that inclusion of CK20 as a biomarker efficiently improves the detection of CTCs in colorectal cancer patients. The finding in our study is of clinical importance since a new prognostic biomarker would provide an important tool in individual clinical decision-making for colorectal cancer patients. PMID- 25528629 TI - SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway. AB - Stearoyl-CoA desaturase 1 (SCD1) is a key regulator in the mechanisms of cell proliferation, survival and transformation to cancer, and autophagy also plays a critical role in hepatocellular carcinoma (HCC). However, whether SCD1 mediates autophagy in HCC remains unknown. In this study, we observed significantly elevated SCD1 expression levels and evident suppression of autophagy in HCC, and the positive SCD1 expression and autophagy defect were independently correlated with poor prognosis of HCC patients. We also found that the inhibition of SCD1 by a pharmacological inhibitor reduced cell viability and induced apoptosis and autophagy of human HCC cells in a dose- and time-dependent manner. Moreover, the pharmacological inhibition of AMPK supported the hypothesis that the induction of autophagy caused by SCD1 inhibition relied on AMPK stimulation. Furthermore, the human HCC cells death triggered by inhibition of SCD1 was partly involved in autophagy-induced apoptosis via AMPK signaling. Our findings reveal a novel role for SCD1 in the regulation of autophagy via AMPK signaling and provide mechanistic input for the clinical exploration that the combination of SCD1 inhibition with autophagy induction may be attractive for the management of HCC. PMID- 25528630 TI - Lactate dehydrogenase 5: an old friend and a new hope in the war on cancer. AB - A hallmark of most cancer cells is an altered metabolism involving a shift to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the main source of energy. Lactate dehydrogenase 5 (LDH-5) catalyzes the reduction of pyruvate by NADH to form lactate, thus determining the availability of NAD(+) to maintain the continuity of glycolysis. It is therefore an important control point in the system of cellular energy release. Its upregulation is common in many malignant tumors. Inhibiting LDH-5 activity has an anti-proliferative effect on cancer cells. It may reverse their resistance to conventional chemo- and radiotherapy. Recent research has renewed interest in LDH 5 as an anticancer drug target. This review summarizes recent studies exploring the role of LDH-5 in cancer growth, its utility as a tumor marker, and developments made in identifying and designing anti-LDH-5 therapeutic agents. PMID- 25528631 TI - DNA damage response--a double-edged sword in cancer prevention and cancer therapy. AB - Genomic stability depends on an efficient DNA damage repair system to keep the chromosomes intact. Unrepaired DNA damage not only causes cell cycle arrest, apoptosis, but also accumulates genome mutations. DNA damage response (DDR) exhibits a critical function on the protection against human cancer, as indicated by the high predisposition to cancer of individuals with germ-line mutations in DDR genes. However, a defective DNA repair is liked intimately with the unchecked proliferation and the intrinsic resistance to clinical DNA-damaging agents. Therefore, abrogation of specific proteins in DNA damage repair pathways is a promising strategy for developing targeted cancer treatments. It may sound paradoxical to inhibit DDR pathway for sensitization of clinical therapy because cancer promotion and malignant transformation are aided by deficient DNA repair pathways. Actually, DDR acts as a positive guardian of genomic stability to prevent from tumorigenesis. On the other hand, DDR also performs as a negative saboteur to resist chemo- and radiotherapy. In this regard, DDR functions as "a double-edged sword" in cancer prevention and cancer therapy. The defective DDR that makes cancer cells of high mutability should alternatively provide therapeutic opportunities that confer the lethality to cancer cells without harming normal cells. PMID- 25528632 TI - Recognizing upper limb movements with wrist worn inertial sensors using k-means clustering classification. AB - In this paper we present a methodology for recognizing three fundamental movements of the human forearm (extension, flexion and rotation) using pattern recognition applied to the data from a single wrist-worn, inertial sensor. We propose that this technique could be used as a clinical tool to assess rehabilitation progress in neurodegenerative pathologies such as stroke or cerebral palsy by tracking the number of times a patient performs specific arm movements (e.g. prescribed exercises) with their paretic arm throughout the day. We demonstrate this with healthy subjects and stroke patients in a simple proof of concept study in which these arm movements are detected during an archetypal activity of daily-living (ADL) - 'making-a-cup-of-tea'. Data is collected from a tri-axial accelerometer and a tri-axial gyroscope located proximal to the wrist. In a training phase, movements are initially performed in a controlled environment which are represented by a ranked set of 30 time-domain features. Using a sequential forward selection technique, for each set of feature combinations three clusters are formed using k-means clustering followed by 10 runs of 10-fold cross validation on the training data to determine the best feature combinations. For the testing phase, movements performed during the ADL are associated with each cluster label using a minimum distance classifier in a multi-dimensional feature space, comprised of the best ranked features, using Euclidean or Mahalanobis distance as the metric. Experiments were performed with four healthy subjects and four stroke survivors and our results show that the proposed methodology can detect the three movements performed during the ADL with an overall average accuracy of 88% using the accelerometer data and 83% using the gyroscope data across all healthy subjects and arm movement types. The average accuracy across all stroke survivors was 70% using accelerometer data and 66% using gyroscope data. We also use a Linear Discriminant Analysis (LDA) classifier and a Support Vector Machine (SVM) classifier in association with the same set of features to detect the three arm movements and compare the results to demonstrate the effectiveness of our proposed methodology. PMID- 25528633 TI - The impact of infrainguinal endovascular interventions on the results of subsequent femoro-tibial bypass procedures: a retrospective cohort study. AB - BACKGROUND: Endovascular recanalization has become the accepted first-line treatment strategy for most lower extremity arterial occlusions, especially in patients with critical limb ischemia (Rutherford 4-6). Prior endovascular interventions have been described as risk factors for the outcome of subsequent lower extremity bypass surgery. The effect on subsequent tibial and peroneal bypasses is controversial. We analyzed the impact of prior endovascular lower extremity revascularization procedures on the short- and mid-term results of femoro-tibial and femoro-peroneal bypasses. METHODS: A retrospective analysis was conducted of all patients who had undergone tibial or peroneal bypass surgery after prior endovascular interventions (PEI-Group, n=40) of the same extremity in our department from October 2007 to October 2012. We compared this group with a group of patients who had received a tibial or peroneal bypass as primary revascularization procedure (BF-Group, n=93) during the same period of time because primary endovascular therapy had been deemed unfeasible in those cases. Indication in all cases was critical limb ischemia; the median age was 78 years (range 50-90 years), 45.1% were diabetics, and 42.9% were female. The graft material was autologous vein in 80 cases and HePTFE in 53 cases. Endpoints of the analysis were primary and secondary patency rates, limb salvage and survival at 2 years postoperatively. RESULTS: At 2 years overall primary patency was 68.4%, secondary patency was 69.5%, limb salvage was 83.6% and survival was 62.6%. Primary patency for the BF-Group was 74.3% vs. 55.1% for the PEI-Group (P=.310) at 2 years; secondary patency was 74.6% vs. 59.1% (P=.268). Prior endovascular intervention did not have any significant effects on limb salvage (83.7% vs. 83.6%; P=.470) or survival rates (61.0% vs. 65.0%; P=.258) at the 2-year mark, either. There were no significant differences in graft occlusion, death and major amputation rates within the first 30 postoperative days. Except for male gender, there were no significant differences in risk factors and indications between the two groups. CONCLUSIONS: Prior endovascular intervention of femoro-tibial vessels does not have a negative impact on the outcome of subsequent tibial or peroneal bypass surgery in patients with critical limb ischemia. PMID- 25528634 TI - Plumbagin induces growth inhibition of human glioma cells by downregulating the expression and activity of FOXM1. AB - Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that plumbagin induced G2/M arrest. Interestingly, we found that plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21(CIP1) and p27(KIP1). Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced plumbagin induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced plumbagin-induced glioma cell growth inhibition. These results suggest that plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas. PMID- 25528636 TI - World Urologic Oncology Federation Bladder Cancer Prevention Program: a global initiative. AB - Bladder cancer is an international public health problem, and the incidence and mortality are closely tied to cigarette smoking. Urologists are, mostly, not involved in smoking cessation with their patients. The World Urologic Oncology Federation has launched a global initiative to incorporate smoking cessation into urological practice. We believe that urologists can readily be influenced to engage their patients, primary care physicians, and communities in bladder cancer prevention. The World Urologic Oncology Federation, a federation of 17 regional/national societies of urologic oncology around the world, is well positioned to lead this global effort. The results would be an extremely cost effective program, which has the potential to substantially improve the health of the world's population. PMID- 25528635 TI - Chloroquine potentiates temozolomide cytotoxicity by inhibiting mitochondrial autophagy in glioma cells. AB - Mitochondrial autophagy eliminates damaged mitochondria and decreases reactive oxygen species (ROS). The autophagy inhibitor chloroquine (CQ) potentiates temozolomide (TMZ) cytotoxicity in glioma cells, but it is not known whether CQ does this by inhibiting mitochondrial autophagy. The effects of CQ and TMZ on MitoSOX Red fluorescence, a mitochondrial ROS indicator, and cell death were examined in rat C6 glioma cells. Mitochondrial autophagy was monitored by the colocalization of MitoTracker Red fluorescence and EGFP-LC3 dots. Mitochondrial content was measured by MitoTracker Green fluorescence and immunoblotting for a mitochondrial protein. Finally, CQ's effects on tumor cells derived from a glioblastoma patient and human U87-MG glioblastoma cells were assessed. TMZ (100 1,000 MUM) alone did not affect mitochondrial ROS or cell death in C6 cells, but when administered with CQ (10 MUM), it increased mitochondrial ROS and cell death. Antioxidants significantly suppressed the CQ-augmented cell death in TMZ treated cells, indicating that mitochondrial ROS were involved in this cell death. TMZ treatment reduced MitoTracker Green fluorescence and mitochondrial protein levels, and these effects were inhibited by CQ. TMZ also increased the colocalization of EGFP-LC3 dots with mitochondria, and CQ enhanced this effect. CQ potentiated TMZ-induced cytotoxicity in patient-derived glioblastoma cells as well as human U87-MG glioblastoma cells. These results suggest that CQ increases cellular ROS and augments TMZ cytotoxicity in glioma cells by inhibiting mitochondrial autophagy. PMID- 25528637 TI - Commentary on "Efficacy and safety of photodynamic therapy for recurrent, high grade nonmuscle invasive bladder cancer refractory or intolerant to bacille Calmette-Guerin immunotherapy." Lee JY, Diaz RR, Cho KS, Lim MS, Chung JS, Kim WT, Ham WS, Choi YD, Department of Urology, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Hospital and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.: J Urol 2013; 190(4):1192-9. doi:10.1016/j.juro.2013.04.077. [Epub 2013 May 3]. PMID- 25528638 TI - Commentary on "The impact of intravesical gemcitabine and 1/3 dose bacillus Calmette-Guerin instillation therapy on the quality of life in patients with nonmuscle invasive bladder cancer: Results of a prospective, randomized, phase II trial." Gontero P, Oderda M, Mehnert A, Gurioli A, Marson F, Lucca I, Rink M, Schmid M, Kluth LA, Pappagallo G, Sogni F, Sanguedolce F, Schiavina R, Martorana G, Shariat SF, Chun F.: J Urol 2013; 190(3):857-62. doi:10.1016/j.juro.2013.03.097. [Epub 2013 Mar 29]. PMID- 25528639 TI - Commentary on "Impact of statin use on oncologic outcomes in patients with urothelial carcinoma ofthe bladder treated with radical cystectomy." da Silva RD, Xylinas E, Kluth L, Crivelli JJ, Chrystal J, Chade D, Guglielmetti GB, Pycha A, Lotan Y, Karakiewicz PI, Sun M, Fajkovic H, Zerbib M, Scherr DS, Shariat SF, Department of Urology and Division of Medical Oncology, Weill Cornell Medical College, New York - Presbyterian Hospital, New York, New York 10065, USA.: J Urol 2013; 190(2):487-92. doi:10.1016/j.juro.2013.02.003. [Epub 2013 Feb 8]. PMID- 25528641 TI - The amyloid precursor protein shows a pH-dependent conformational switch in its E1 domain. AB - The amyloid precursor protein (APP) and its proteolytic cleavage product Abeta are widely believed to be central to the etiology of Alzheimer's disease (AD). APP and its family members are also essential for proper neuronal development and homeostasis. APP is located at the cell surface and within intracellular compartments, cellular regions that exhibit different pH values. The AD associated amyloidogenic processing of APP is initiated predominantly in intracellular acidic compartments, whereas its non-amyloidogenic cleavage is initiated at the cell surface at slightly basic pH. We analyzed the influence of pH on the APP-E1 domain and found that its two constituting subdomains, GFLD and CuBD, interact with each other in a pH-dependent manner. Dynamic light scattering showed that APP-E1 represents a more open conformation at neutral pH and a more closed conformation at acidic pH. Analyzing a 1.4 A, high-resolution X-ray structure of E1 derived from merohedrally twinned crystals resulted in the identification of individual residues that are responsible for these pH-dependent interactions. Mutational studies and dynamic light scattering measurements further proved that specific hydrogen bonds between the two carboxylates of D177 and E87, as well as between N89 and H147, are major determinants of this pH driven conformational switch in APP-E1. These findings show how APP can adopt different conformations depending on pH and suggest that the protein fulfils different functions at distinct localizations within the cell. Additionally, our data suggest a novel strategy for treating AD based on regulating the amyloidogenic processing of APP by the specific interruption of the interaction between the APP-E1 subdomains. PMID- 25528640 TI - Flexible stoichiometry and asymmetry of the PIDDosome core complex by heteronuclear NMR spectroscopy and mass spectrometry. AB - Homotypic death domain (DD)-DD interactions are important in the assembly of oligomeric signaling complexes such as the PIDDosome that acts as a platform for activation of caspase-2-dependent apoptotic signaling. The structure of the PIDDosome core complex exhibits an asymmetric three-layered arrangement containing five PIDD-DDs in one layer, five RAIDD-DDs in a second layer and an additional two RAIDD-DDs. We addressed complex formation between PIDD-DD and RAIDD-DD in solution using heteronuclear nuclear magnetic resonance (NMR) spectroscopy, nanoflow electrospray ionization mass spectrometry and size exclusion chromatography with multi-angle light scattering. The DDs assemble into complexes displaying molecular masses in the range 130-158kDa and RAIDD-DD:PIDD DD stoichiometries of 5:5, 6:5 and 7:5. These data suggest that the crystal structure is representative of only the heaviest species in solution and that two RAIDD-DDs are loosely attached to the 5:5 core. Two-dimensional (1)H,(15)N-NMR experiments exhibited signal loss upon complexation consistent with the formation of high-molecular-weight species. (13)C-Methyl-transverse relaxation optimized spectroscopy measurements of the PIDDosome core exhibit signs of differential line broadening, cross-peak splitting and chemical shift heterogeneity that reflect the presence of non-equivalent sites at interfaces within an asymmetric complex. Experiments using a mutant RAIDD-DD that forms a monodisperse 5:5 complex with PIDD-DD show that the spectroscopic signature derives from the quasi but non-exact equivalent environments of each DD. Since this characteristic was previously demonstrated for the complex between the DDs of CD95 and FADD, the NMR data for this system are consistent with the formation of a structure homologous to the PIDDosome core. PMID- 25528642 TI - An experimental investigation of the indirect transfer and deposition of gunshot residue: further studies carried out with SEM-EDX analysis. AB - Experiments were undertaken in order to explore the potential for gunshot residue (GSR) particles to undergo tertiary transfer, and to be deposited on individuals in the vicinity of a firearm discharge. Samples were taken from hands following a series of test-firings. SEM-EDX with automated detection and analysis software was used to determine the presence of GSR on these samples. As many as 22 particles were found to have undergone tertiary transfer via a series of handshakes following a firearm discharge. In one run, a particle measuring 49.19 MUm was recovered from a tertiary transfer recipient. Significant numbers of particles were also recovered from bystanders, with as many as 36 being detected on a sample taken from an individual who was in the proximity of a firearm discharge. The implications of these observations for forensic investigations are considered. In particular, the need to prevent unwanted transfer during the collection phase is highlighted, and the importance of acknowledging the possibility of secondary and tertiary transfers when reconstructing firearms incidents is also stressed. Experimental studies offer a means of improving our understanding of the dynamics of GSR transfer and deposition, and assisting the forensic reconstruction of firearms incidents. PMID- 25528643 TI - Influence of repeated permanent coloring and bleaching on ethyl glucuronide concentrations in hair from alcohol-dependent patients. AB - BACKGROUND: Ethyl glucuronide (EtG), a minor metabolite of alcohol, is used as a sensitive marker in hair to detect the retrospective consumption of alcohol. The proximal 0-3 cm hair segment is often used for analysis, providing information on alcohol consumption over the past 3 months. Using more distal segments would allow the detection of alcohol consumption over longer time periods, thereby addressing the chronicity of the consumption. In view of this, permanent coloring and bleaching were shown in vitro to alter EtG concentrations in hair, but no in vivo studies are available to prove or disprove this. AIMS: To investigate the influence of repeated bleaching and permanent coloring on EtG concentrations in vivo and to assess the stability of EtG concentrations in distal compared to proximal hair segments. METHODS: Hair samples from alcohol-dependent patients with uncolored/unbleached (N=4), permanent coloration (N=5) and bleached hair (N=5) were analyzed in two to six 3 cm long segments for EtG concentrations, and alcohol consumption and hair cosmetic treatments were assessed. RESULTS: We observed that hair bleaching and permanent coloring reduces EtG concentrations by 82+/-11% and 65+/-24%, respectively, with correlations between the number of cosmetic treatments and the decrease in EtG concentrations. EtG remained stable in untreated hair samples up to 18 cm. CONCLUSIONS: EtG is a sensitive marker to assess chronic alcohol consumption up to 18 months in alcohol-dependent patients with no cosmetic hair treatments. However, in alcohol-dependent patients who color or bleach their hair, care should be taken when interpreting EtG measurements. PMID- 25528644 TI - Differences between the measured blood ethanol concentration and the estimated concentration by Widmark's equation in elderly persons. AB - BACKGROUND: The Widmark's equation (C [BAC]=A/p*r) is the most commonly used formula in legal medicine to estimate the blood alcohol concentration (BAC) from the amount of ingested ethanol and vice versa. Within a drinking experiment with a target BAC of 1.2 g/kg, a 75-year-old participant reached a maximum BAC of 1.83 g/kg and showed signs of severe ethanol intoxication, while the other nine subjects (age: 19-31 years) had BACs close to the target BAC. This incident brought up the question, if the Widmark's equation is an appropriate tool for aged persons. METHODS: A drinking experiment with 50 elderly voluntary test persons (22 males, 28 females, mean age and range [males]: 69.7 years, 60-84 years, mean age and range [females]: 68.5 years, 61-78 years) was performed. The amount of ethanol leading to a BAC of 0.6 g/kg was estimated individually using the Widmark's equation (used Widmark factors: 0.7 for males, 0.6 for females). After drinking, the blood ethanol concentrations were measured using headspace gas chromatography/flame ionization detection. RESULTS: The measured maximum BACs of the elderly participants were significantly higher (alpha=0.01) than the target BAC (mean maximum BAC and range: 0.627 g/kg, 0.3-0.81 g/kg, for males: 0.616 g/kg, 0.32-0.78 g/kg, for females: 0.635 g/kg, 0.3-0.81). The calculated Widmark factors showed a high coefficient of variation (for males: 0.7+/-0.138 [0.55-1.2, CV: 19.7%], for females 0.59+/-0.119 [0.46-1.08, CV: 20.2%]). CONCLUSION: The results demonstrate that BAC calculations by Widmark's equation in elderly individuals may be complicated by a high variation of Widmark factors. There is a tendency to an elevation of the actual BAC with increasing age. PMID- 25528645 TI - Time series analysis of gastric acid secretion over a 20-year period in normal Japanese men. AB - BACKGROUND: The gastric acid secretion level is an important determinant for the manifestation of the gastroesophageal reflux disease spectrum, finally leading to the development of esophageal adenocarcinoma (EAC). Although the incidence of EAC has remained low in Asia, understanding the recent trend in gastric acid secretion should be helpful in estimating future incidences of EAC in that area. We investigated the latest chronological change (1995-2014) in gastric acid secretion in normal Japanese patients. METHODS: A total of 307 asymptomatic Japanese men who attended the clinic for annual endoscopic checkups from 1995 to 2014 were enrolled in this analysis. Gastrin-stimulated gastric acid secretion was estimated with the endoscopic gastrin test. The association between gastric acid secretion and chronological period was assessed with a multivariate linear regression analysis. RESULTS: Overall gastric acid secretion gradually increased over the 20-year period in the entire cohort in the unadjusted analysis (p < 0.05). However, the apparent increase was largely related to the relative decreasing rate of H. pylori infection, which profoundly inhibited gastric acid secretion. Gastric acid secretion did not change over the 20-year period in H. pylori-negative subjects, and it showed only a mild increase during this period in H. pylori-positive subjects. CONCLUSIONS: Considering that gastric acid secretion remained unchanged in H. pylori-negative Japanese men over a 20-year period at a level much lower than that in Occidental subjects, upper gastrointestinal disease profiles in the Japanese population will differ from those in Western countries in the post-H. pylori era. PMID- 25528646 TI - Urinary and faecal N-methylhistamine concentrations do not serve as markers for mast cell activation or clinical disease activity in dogs with chronic enteropathies. AB - BACKGROUND: This study sought to correlate faecal and urinary N-methylhistamine (NMH) concentrations with resting versus degranulated duodenal mast cell numbers in dogs with chronic enteropathies (CE), and investigate correlations between intestinal mast cell activation and clinical severity of disease as assessed by canine chronic enteropathy clinical activity index (CCECAI), and between urinary and faecal NMH concentrations, mast cell numbers, and histopathological scores. Twenty-eight dogs with CE were included. Duodenal biopsies were stained with haematoxylin and eosin (H&E), toluidine blue, and by immunohistochemical labelling for tryptase. Duodenal biopsies were assigned a histopathological severity score, and duodenal mast cell numbers were counted in five high-power fields after metachromatic and immunohistochemical staining. Faecal and urinary NMH concentrations were measured by gas chromatography-mass spectrometry. RESULTS: There was no correlation between the CCECAI and faecal or urinary NMH concentrations, mast cell numbers, or histopathological score - or between faecal or urinary NMH concentration and mast cell numbers. Post hoc analysis revealed a statistically significant difference in toluidine blue positive mast cells between two treatment groups (exclusion diet with/without metronidazole versus immunosuppression (IS)), with higher numbers among dogs not requiring IS. CONCLUSION: Faecal and urinary NMH concentrations and duodenal mast cell numbers were not useful indicators of severity of disease as assessed by the CCECAI or histological evaluation. The number of duodenal mast cells was higher in dogs that did not need IS, i.e. in dogs responding to an exclusion diet (with/without metronidazole), than in dogs requiring IS. Further studies comparing the role of mast cells in dogs with different forms of CE are needed. PMID- 25528648 TI - Pathways to personalized treatment strategies for depressive disorders. PMID- 25528647 TI - Molecular characterization of a homolog of the ferric-uptake regulator, Fur, from the marine bacterium Marinobacter algicola DG893. AB - Full length recombinant iron regulatory protein, Fur, has been isolated and characterized from the algal-associated marine bacterium Marinobacter algicola DG893. Under nondenaturing conditions the Fur protein behaves on size exclusion chromatography as a dimer while it is monomeric under SDS PAGE conditions. ICP-MS and fluorescence quenching experiments show that Mb-Fur binds a single metal ion (Zn, Mn, or Co) per monomer. Electrophoretic mobility shift assays were used to probe the interaction of Mb-Fur with the purported Fur box in the promoter region upstream of the vibrioferrin biosynthetic operon. Interaction of Mb-Fur with a 100 bp DNA fragment containing the Fur box in the presence of 10 uM Mn, Co or Zn(II) resulted in decreased migration of DNA on a 7.5% polyacrylamide gel. In the absence of the Fur protein or the metal, no interaction is seen. The presence of EDTA in the binding, loading or running buffers also abolished all activity demonstrating the importance of the metal in formation of the promoter-repressor complex. Based on a high degree of similarity between Mb-Fur and its homolog from Pseudomonas aeruginosa (PA) whose X-ray structure is known we developed a structural model for the former which suggested that only one of the several metal binding sites found in other Fur's would be functional. This is consistent with the single metal binding stoichiometry we observed. Since the purported metal binding site was one that has been described as "structural" rather than "functional" in PA and yet the monometallic Mb-Fur retains DNA Fur box binding ability it reopens the question of which site is which, or if different species have adapted the sites for different purposes. PMID- 25528649 TI - Improved application of the electrophoretic tissue clearing technology, CLARITY, to intact solid organs including brain, pancreas, liver, kidney, lung, and intestine. AB - BACKGROUND: Mapping of tissue structure at the cellular, circuit, and organ-wide scale is important for understanding physiological and biological functions. A bio-electrochemical technique known as CLARITY used for three-dimensional anatomical and phenotypical mapping within transparent intact tissues has been recently developed. This method provided a major advance in understanding the structure-function relationships in circuits of the nervous system and organs by using whole-body clearing. Thus, in the present study, we aimed to improve the original CLARITY procedure and developed specific CLARITY protocols for various intact organs. RESULTS: We determined the optimal conditions for reducing bubble formation, discoloration, and depositing of black particles on the surface of tissue, which allowed production of clearer organ images. We also determined the appropriate replacement cycles of clearing solution for each type of organ, and convincingly demonstrated that 250-280 mA is the ideal range of electrical current for tissue clearing. We then acquired each type of cleared organs including brain, pancreas, liver, lung, kidney, and intestine. Additionally, we determined the images of axon fibers of hippocampal region, the Purkinje layer of cerebellum, and vessels and cellular nuclei of pancreas. CONCLUSIONS: CLARITY is an innovative biochemical technology for the structural and molecular analysis of various types of tissue. We developed improved CLARITY methods for clearing of the brain, pancreas, lung, intestine, liver, and kidney, and identified the appropriate experimental conditions for clearing of each specific tissue type. These optimized methods will be useful for the application of CLARITY to various types of organs. PMID- 25528651 TI - The social validity of a national assessment centre for selection into general practice training. AB - BACKGROUND: Internationally, recruiting the best candidates is central to the success of postgraduate training programs and the quality of the medical workforce. So far there has been little theoretically informed research considering selection systems from the perspective of the candidates. We explored candidates' perception of the fairness of a National Assessment Centre (NAC) approach for selection into Australian general practice training, where candidates were assessed by a Multiple Mini Interview (MMI) and a written Situational Judgment Test (SJT), for suitability to undertake general practice (GP) training. METHODS: In 2013, 1,930 medical practitioners, who were eligible to work in Australia attended one of 14 NACs in each of 5 states and 2 territories. A survey was distributed to each candidate at the conclusion of their assessment, which included open-ended questions aimed at eliciting candidates' perceived benefits and challenges of the selection process. A framework analysis was informed by the theoretical lens of Social Validity Theory. RESULTS: Qualitative data was available from 46% (n = 886/1,930) of candidates, who found the NAC experience fair and informative for their training and career goals, but wanted to be provided with more information in preparation. Candidates valued being able to communicate their skills during the MMI, but found some difficulty in interpreting the questions. A significant minority had concerns that a lack of relevant GP experience may inhibit their performance. Candidates also expressed concerns about the time limits within the written paper, particularly if English was not their first language. They also expressed a desire for formative feedback during the interview process. CONCLUSION: During any job selection process, not only is the organisation assessing the candidates, but the candidates are also assessing the organisation. However, a focus on the candidate experience throughout an organisation's selection process may provide benefits to both candidates and the organisation, regardless of whether or not candidates secured the job. Social Validity Theory is a useful addition to the methods for demonstrating the reasonableness of any selection system. PMID- 25528650 TI - Predictors of recurrence after a first hepatectomy for colorectal cancer liver metastases: a retrospective analysis. AB - BACKGROUND: Surgical resection is considered the standard therapy in the treatment of liver metastases from colorectal cancer (CRCLM); however, most patients experience tumor recurrence after curative hepatic resection. The objective was to determine potential prognostic factors for tumor recurrence after an initial hepatectomy for CRCLM. METHODS: A study population of 101 patients who had undergone a first curative hepatectomy for CRCLM was retrospectively analyzed. Selected biological tumor markers, and clinical and pathological features were then tested by Cox regression. RESULTS: Synchronous liver metastases occurred in 38 patients (37.6%) and 63 patients (62.3%) presented with metachronous liver metastases. In a median follow-up time of 68 months, recurrence was observed in 64 patients (63.3%). The 5-year cumulative risk of recurrence was 56.7%. The median survival after recurrence was 24.5 months (range 1 to 41 months) and 5-year cumulative overall survival was 31.8%. Of all variables tested by Cox regression, intra- and extrahepatic resectable disease, CEA levels>=50 ng/mL and bilobar liver disease remained significant as predictors of recurrence in the multivariate analysis. CONCLUSIONS: Independent risk factors for recurrence after an initial hepatectomy for CRCLM, such as intra and extrahepatic resectable disease, CEA levels>=50 ng/mL and bilobar liver disease, can eventually help in making decisions in this very complex scenario. PMID- 25528652 TI - Personality dimensions and their behavioral correlates in wild Virunga mountain gorillas (Gorilla beringei beringei). AB - Studies of animal personality improve our understanding of individual variation in measures of life history and fitness, such as health and reproductive success. Using a 54 trait personality questionnaire developed for studying great apes and other nonhuman primates, we obtained ratings on 116 wild mountain gorillas (Gorilla beringei beringei) monitored by the Dian Fossey Gorilla Fund's Karisoke Research Center in Rwanda. There were 8 raters who each had more than 1.5 years of working experience with the subjects. Principal component analyses identified 4 personality dimensions with high interrater reliabilities-Dominance, Openness, Sociability, and Proto-Agreeableness-that reflected personality features unique to gorillas and personality features shared with other hominoids. We next examined the associations of these dimensions with independently collected behavioral measures derived from long-term records. Predicted correlations were found between the personality dimensions and corresponding behaviors. For example, Dominance, Openness, Sociability, and Proto-Agreeableness were related to gorilla dominance strength, time spent playing, rates of approaches, and rates of interventions in intragroup conflicts, respectively. These findings enrich the comparative-evolutionary study of personality and provide insights into how species differences in personality are related to ecology, social systems, and life history. PMID- 25528653 TI - The effect of cane length and step height on muscle strength and body balance of elderly people in a stairway environment. AB - BACKGROUND: It has been reported that 75% of stairway accidents occur while descending stairs. Using a cane can help to prevent older people and those with limited mobility from falling. However, studies have shown that two-thirds of older cane users use a cane that is longer than the recommended length, which may cause unnecessary muscular loads. This study aims to assess balance and muscular load in older people descending different height steps with different cane lengths. METHODS: Nine participants (5 males and 4 females) aged over 65 years participated in this study. Cane length and stair height were independent variables. Electromyography signals were recorded from the biceps brachii of the arm that usually held the cane and from both gastrocnemius muscles. In addition, the center of pressure (CoP) was assessed as an indicator of balance in older people descending a step. RESULTS: Descending from higher steps resulted in the use of greater arm and leg strength at the time of first foot contact. However, cane length did not affect any of the root mean square values. In addition, the CoP Stabilometric Parameters showed that mean distance, antero-posterior mean distance, total excursions, antero-posterior total excursions, mean velocity, and antero-posterior mean velocity were significantly affected by step height, but not by cane length. CONCLUSIONS: If cane length is within the currently suggested range, then it has little effect on the force load on the arm and legs when descending a step. Step height has a greater effect than cane length on the strategies used by older people to maintain stability. PMID- 25528654 TI - Successful resection of recurrent mediastinal liposarcoma using preoperative evaluation of organ invasion by four-dimensional computed tomography. AB - We report the case of a 64-year-old woman with recurrent mediastinal dedifferentiated liposarcoma. She had undergone surgical resection twice. Subsequently, on regular follow-up visits, chest computed tomography demonstrated a third local recurrence of the tumor with invasion into adjacent intrathoracic organs. Adhesion of the heart to the anterior chest wall through a pericardial defect that had been inadvertently created at the second operation was suspected. We decided to use a thoracoabdominal approach with four-dimensional computed tomography (4DCT) for preoperative guidance. The patient had also undergone MRI; however, the result was equivocal regarding adhesion of intrathoracic organs. The use of 4DCT enabled successful en bloc resection of the tumor. Results of the pathology examination showed complete resection of a dedifferentiated liposarcoma. The patient's postoperative course was uneventful, and she was discharged on postoperative day 19. PMID- 25528655 TI - The level of urinary alpha1 microglobulin excretion is a useful marker of peritubular capillaritis in antineutrophil cytoplasmic antibody associated vasculitis. AB - BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis affects small vessels in the kidney (i.e., arterioles, glomerular or peritubular capillaries, or venules). Although crescentic glomerulonephritis is a common histological finding, the incidence of peritubular capillaritis (PTC) or arteriolitis is unclear. Moreover, the laboratory data that reflect the degree of renal histological damage and distinguish between PTC and arteriolitis have not yet been clarified. METHODS: We investigated laboratory data and histological findings from 11 patients diagnosed with ANCA-associated vasculitis (2 men and 9 women, mean age 70.3 +/- 3.3 years) whose renal biopsies were performed between 2009 and 2014. RESULTS: All patients were positive for myeloperoxidase (MPO) ANCA. PTC or arteriolitis was detected in six patients (54.5 %), respectively. The only significant positive relationship between laboratory data and histological findings observed was that between levels of urinary alpha1 microglobulin (u-alpha1MG) excretion and the percentage of tubular atrophy and interstitial fibrosis (r = 0.67, p = 0.035). No significant differences in laboratory data were found between patients with or without arteriolitis. However, the levels of u-alpha1MG excretion were significantly higher in patients with PTC than in those without PTC (75.2 +/- 19.5 vs. 15.0 +/- 3.6 mg/dl, p = 0.035). CONCLUSION: PTC or arteriolitis occurs at a high rate independently of crescentic glomerulonephritis in ANCA-associated vasculitis patients. The levels of u-alpha1MG excretion reflect the degrees of tubular atrophy and interstitial fibrosis. Moreover, high levels of u-alpha1MG excretion suggest that PTC is more likely than arteriolitis in ANCA-associated vasculitis patients. PMID- 25528656 TI - Repetition suppression and repetition enhancement underlie auditory memory-trace formation in the human brain: an MEG study. AB - The formation of echoic memory traces has traditionally been inferred from the enhanced responses to its deviations. The mismatch negativity (MMN), an auditory event-related potential (ERP) elicited between 100 and 250ms after sound deviation is an indirect index of regularity encoding that reflects a memory based comparison process. Recently, repetition positivity (RP) has been described as a candidate ERP correlate of direct memory trace formation. RP consists of repetition suppression and enhancement effects occurring in different auditory components between 50 and 250ms after sound onset. However, the neuronal generators engaged in the encoding of repeated stimulus features have received little interest. This study intends to investigate the neuronal sources underlying the formation and strengthening of new memory traces by employing a roving-standard paradigm, where trains of different frequencies and different lengths are presented randomly. Source generators of repetition enhanced (RE) and suppressed (RS) activity were modeled using magnetoencephalography (MEG) in healthy subjects. Our results show that, in line with RP findings, N1m (~95 150ms) activity is suppressed with stimulus repetition. In addition, we observed the emergence of a sustained field (~230-270ms) that showed RE. Source analysis revealed neuronal generators of RS and RE located in both auditory and non auditory areas, like the medial parietal cortex and frontal areas. The different timing and location of neural generators involved in RS and RE points to the existence of functionally separated mechanisms devoted to acoustic memory-trace formation in different auditory processing stages of the human brain. PMID- 25528657 TI - Theta frontoparietal connectivity associated with proactive and reactive cognitive control processes. AB - Cognitive control involves both proactive and reactive processes. Paradigms that rely on reactive control have shown that frontoparietal oscillatory synchronization in the theta frequency band is associated with interference control. This study examines whether proactive control is also associated with connectivity in the same frontoparietal theta network or involves a distinct neural signature. A task-switching paradigm was used to differentiate between proactive and reactive control processes, involved in preparing to switch or repeat a task and resolving post-target interference, respectively. We confirm that reactive control is associated with frontoparietal theta connectivity. Importantly, we show that proactive control is also associated with theta band oscillatory synchronization but in a different frontoparietal network. These findings support the existence of distinct proactive and reactive cognitive control processes that activate different theta frontoparietal oscillatory networks. PMID- 25528658 TI - Adaptive mechanisms of developing brain: cerebral lateralization in the prematurely-born. AB - Preterm birth results in alterations in neural connectivity, but the impact of prematurity on the functional organization of the developing brain has yet to be explored. To test the hypothesis that preterm birth alters cortical organization during the late second and third trimesters of gestation, we interrogated cerebral lateralization at rest in 26 very preterm subjects (birth weight 500 1500g) with no evidence of brain injury and 25 healthy term control subjects at term equivalent age. Employing an unbiased voxel-based measure of functional connectivity, these data demonstrated that cerebral lateralization is impaired in the prematurely-born. At term equivalent age, preterm neonates showed significantly less lateralization in regions subserving both receptive and expressive language, left Brodmann (BA) areas insula-BA22-BA21 and L BA45-BA47 (p<0.05 corrected for multiple comparisons for both). Exploratory region of interest analyses demonstrated significantly less inter-hemispheric connectivity from L BA22 to R BA22 in preterm infants compared to term controls (p<0.005) and from R BA22 to its homolog (p<0.005). L BA22, Wernicke's area, was more strongly connected to R BA39, foreshadowing neural networks for language in preterm subjects at school age, adolescence and young adulthood. For these very preterm neonates born at less than 30weeks' PMA, the degree of prematurity had no influence on lateralization in these differential regions. PMID- 25528660 TI - Pulmonary veno-occlusive disease: a rare cause of pulmonary hypertension. PMID- 25528659 TI - Chlamydia pneumoniae effector chlamydial outer protein N sequesters fructose bisphosphate aldolase A, providing a benefit to bacterial growth. AB - BACKGROUND: Pathogenic chlamydiae are obligate intracellular pathogens and have adapted successfully to human cells, causing sexually transmitted diseases or pneumonia. Chlamydial outer protein N (CopN) is likely a critical effector protein secreted by the type III secretion system in chlamydiae, which manipulates host cells. However, the mechanisms of its action remain to be clarified. In this work, we aimed to identify previously unidentified CopN effector target in host cells. RESULTS: We first performed a pull-down assay with recombinant glutathione S-transferase (GST) fusion CopN proteins (GST-CpCopN: Chlamydia pneumoniae TW183, GST-CtCopN: Chlamydia trachomatis D/UW-3/CX) as "bait" and soluble lysates obtained from human immortal epithelial HEp-2 cells as "prey", followed by SDS-PAGE with mass spectroscopy (MS). We found that a host cell protein specifically bound to GST-CpCopN, but not GST-CtCopN. MS revealed the host protein to be fructose bisphosphate aldolase A (aldolase A), which plays a key role in glycolytic metabolism. We also confirmed the role of aldolase A in chlamydia-infected HEp-2 cells by using two distinct experiments for gene knockdown with an siRNA specific to aldolase A transcripts, and for assessment of glycolytic enzyme gene expression levels. As a result, both the numbers of chlamydial inclusion-forming units and RpoD transcripts were increased in the chlamydia-infected aldolase A knockdown cells, as compared with the wild-type HEp 2 cells. Meanwhile, chlamydial infection tended to enhance expression of aldolase A. CONCLUSIONS: We discovered that one of the C. pneumoniae CopN targets is the glycolytic enzyme aldolase A. Sequestering aldolase A may be beneficial to bacterial growth in infected host cells. PMID- 25528661 TI - Detection of insertion/deletion polymorphisms from challenged samples using the Investigator DIPplex(r) kit. AB - This research focuses on detection of bi-allelic insertion/deletion polymorphisms (InDels) from challenged samples using the Investigator DIPplex(r) Kit from Qiagen. The study included analyzing body fluids from humans, as well as pristine and degraded samples. For the purpose of assessing species specificity, samples from various animals were included. At first, an analytical threshold (AT) for the detection of alleles was established based on an assessment of the noise in the system. Then, InDel profiles were obtained from samples exposed to detrimental environmental conditions, washed bloodstains, lipsticks, ChapStick(r), ancient Croatian bone samples, and every day products such as toothbrushes and dental floss. Concordant profiles were obtained from different body fluids of the same donor. InDel profiles were also generated successfully when body fluids were deposited on substrates and directly amplified without pre treatment with buffer or washing reagents. InDels can provide additional information when only partial STR profiles are generated from challenged samples. PMID- 25528662 TI - Epidemiology and recent trends of severe sepsis in Spain: a nationwide population based analysis (2006-2011). AB - BACKGROUND: Although severe sepsis constitutes an important burden for healthcare systems, there is limited nationwide data on its epidemiology in European countries. Our objective was to examine the most recent epidemiological characteristics and trends of severe sepsis in Spain, from a population perspective. METHODS: Analysis of the 2006-2011 National Hospital Discharge Registry. Cases were identified by combining specific ICD-9CM codes. We estimated demographics, clinical characteristics and outcomes and calculated age- and sex adjusted estimations of incidence and mortality rates. Trends were assessed in terms of annual percent change (APC) in rates using joinpoint regression analysis. RESULTS: Over the 6-year period we identified 240939 cases of severe sepsis nationwide representing 1.1% of all hospitalisations and 54% of hospitalisations with sepsis. Incidence was 87 cases per 100,000 population. Overall 58% of cases were men, 66% were over the age of 65 and about 67% had associated comorbidities. Bacteremia was coded in 16% of records. Almost 54% of cases had one organ dysfunction, 26% two and around 20% three or more dysfunctions. In-hospital case-fatality was 43% and associated with age, gender, comorbidities and organ dysfunctions, among others. We found significant demographic and clinical changes over time with an increase in the mean age of cases, comorbidities, number of organ dysfunctions and in the number of cases with gram-negative pathogens. Furthermore, even with gender disparities, standardised incidence and mortality rates increased with an overall APC of 8.6% (95% CI 5.1, 12.1) and 6% (95% CI 1.9, 10.3), respectively. Conversely, we detect a significant decrease in case-fatality rates with an overall APC of -3.24% (95% CI: -4.2, -2.2). CONCLUSIONS: This nationwide population-based study shows that hospitalizations with severe sepsis are frequent and associated with substantial in-hospital mortality in Spain. Furthermore it indicates that the incidence and mortality rates of severe sepsis have notably increased in recent years, showing also a significant increase in the age and severity of the affected population. Despite this, there has been a significant decreasing trend in case-fatality rates over time. This information has significant implications for health-care system planning and may prove useful to estimate future care requirements. PMID- 25528664 TI - Sharing of clinical data in a maternity setting: how do paper hand-held records and electronic health records compare for completeness? AB - BACKGROUND: Historically, the paper hand-held record (PHR) has been used for sharing information between hospital clinicians, general practitioners and pregnant women in a maternity shared-care environment. Recently in alignment with a National e-health agenda, an electronic health record (EHR) was introduced at an Australian tertiary maternity service to replace the PHR for collection and transfer of data. The aim of this study was to examine and compare the completeness of clinical data collected in a PHR and an EHR. METHODS: We undertook a comparative cohort design study to determine differences in completeness between data collected from maternity records in two phases. Phase 1 data were collected from the PHR and Phase 2 data from the EHR. Records were compared for completeness of best practice variables collected The primary outcome was the presence of best practice variables and the secondary outcomes were the differences in individual variables between the records. RESULTS: Ninety four percent of paper medical charts were available in Phase 1 and 100% of records from an obstetric database in Phase 2. No PHR or EHR had a complete dataset of best practice variables. The variables with significant improvement in completeness of data documented in the EHR, compared with the PHR, were urine culture, glucose tolerance test, nuchal screening, morphology scans, folic acid advice, tobacco smoking, illicit drug assessment and domestic violence assessment (p = 0.001). Additionally the documentation of immunisations (pertussis, hepatitis B, varicella, fluvax) were markedly improved in the EHR (p = 0.001). The variables of blood pressure, proteinuria, blood group, antibody, rubella and syphilis status, showed no significant differences in completeness of recording. CONCLUSION: This is the first paper to report on the comparison of clinical data collected on a PHR and EHR in a maternity shared-care setting. The use of an EHR demonstrated significant improvements to the collection of best practice variables. Additionally, the data in an EHR were more available to relevant clinical staff with the appropriate log-in and more easily retrieved than from the PHR. This study contributes to an under-researched area of determining data quality collected in patient records. PMID- 25528665 TI - Cross-sectional study of Schmallenberg virus seroprevalence in wild ruminants in Poland at the end of the vector season of 2013. AB - BACKGROUND: In view of recurrent Schmallenberg virus (SBV) infections all over Europe between 2011 and 2013, a lively scientific debate over the importance of the sylvatic transmission cycle of the virus has emerged. The study presents results of serosurvey which included wild ruminants representing species of red deer (Cervus elaphus), roe deer (Capreolus capreolus), European bison (Bison bonasus), fallow deer (Dama dama), mouflon (Ovis orientalis musimon) hunted or immobilized at 34 different locations of Poland in the autumn/winter 2013. RESULTS: Out of 580 sera, 145 (25%) were considered positive for SBV antibodies. The overall SBV seroprevalence calculated using district probability weights was estimated at 27.7% (95% CI: 24.0-31.4). The seroprevalences at the district level varied between 0 and 80.0% (95% CI: 24.5-135.0%) with the mean within-district prevalence of 24.0% (95% CI: 16.5-31.4). Significantly higher seroprevalence was observed in animals from the Eastern provinces (36.6%) compared to the Western provinces (22.8%). SBV infection impact varied significantly between different species (higher SBV seroprevalence in larger species such as European bison), population type (free-ranging; captive), age, body weight, percent of the district forest area, part of Poland, and the densities of wild and domestic ruminants at the district and province level. Using statistical multivariable logistic model, population type, age, part of Poland and domestic ruminant density were identified as the main risk factors for SBV infection in wild ruminants in Poland. CONCLUSIONS: SBV seroprevalence in wild ruminants, similarly to the epizootic situation in domestic ruminants in the country, varied significantly between districts and provinces. Association between SBV seropositivity, species, animal body weight and age group expressed by a higher prevalence in larger ruminants may be explained by more frequent exposure to midge-vector bites of the latter, however it might also be related to the different species susceptibility to SBV infection. The positive effect of higher domestic ruminant density on the risk of SBV infection in wildlife and lower SBV seroprevalences in the latter suggested that the sylvatic cycle of SBV transmission is an effect of the pathogen spillover from the domestic animals. PMID- 25528663 TI - Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial. AB - BACKGROUND: Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded, randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients in the intensive care unit (ICU). E PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial. METHODS/DESIGN: The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect, variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial, and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acute healthcare system perspective, over a data rich time horizon of ICU admission and hospital admission. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping. DISCUSSION: This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00182143 . Date of registration: 10 September 2005. PMID- 25528666 TI - Semaphorin3A-induced axonal transport mediated through phosphorylation of Axin-1 by GSK3beta. AB - The establishment of neuronal polarity is necessary for proper neuronal wiring. Semaphorin3A (Sema3A), originally identified as a repulsive axon guidance molecule, exerts a wide variety of biological functions through signaling pathways including sequential phosphorylation of collapsin response mediator protein by cyclin-dependent kinase-5 (Cdk5) and glycogen synthase kinase-3beta (GSK3beta). Sema3A acts on its receptor neuropilin-1 to regulate axonal transport. To delineate mechanism by which Sema3A induces axonal transport, we investigate whether GSK3beta is involved in mediating Sema3A-induced axonal transport. 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione, an inhibitor of GSK3beta, suppressed Sema3A-induced antero- and retrograde axonal transport. Introduction of either GSK3beta mutants, GSK3beta-L128A or K85M, suppressed Sema3A-induced axonal transport. On the other hand, introduction of GSK3beta-R96A did not affect the Sema3A effect, suggesting that unprimed substrates are primarily involved in Sema3A-induced axonal transport. Overexpression of a partial fragment of frequently rearranged in advanced T-cell lymphomas 1 (FRATtide), which interferes the interaction between GSK3beta and Axis inhibitor 1 (Axin-1), also suppressed Sema3A-induced transport. siRNA knockdown of Axin-1, an unprimed substrate of GSK3beta, suppressed Sema3A-induced antero- and retrograde axonal transport. These results indicate that GSK3beta and Axin-1 are involved in Sema3A-induced bidirectional axonal transport. This finding should provide a clue for understanding of mechanisms of a wide variety of biological activities of Sema3A. PMID- 25528667 TI - Pre-pregnancy Body Mass Index (BMI) and delivery outcomes in a Canadian population. AB - BACKGROUND: Worldwide there has been a dramatic increase in the prevalence of overweight and obesity in women of childbearing age. Growing evidence suggests that maternal overweight and obesity is associated with poor maternal and perinatal outcomes. This study evaluated the impact of maternal pre-pregnancy overweight and obesity on pregnancy, labour and delivery outcomes in a cohort of women with term, singleton pregnancies cared for by family physicians in community based practices. METHODS: This study is a secondary analysis of the All Our Babies Cohort, a prospective, community-based pregnancy cohort in Calgary, Alberta. Maternal self-reported data on height and pre-pregnancy weight from term, singleton, cephalic pregnancies (n = 1996) were linked to clinical data on pregnancy and birth events retrieved from electronic health records. Descriptive and bivariate regression analysis were used to compare pregnancy and birth outcomes between women categorized as normal weight, overweight and obese based on the pre-pregnancy BMI. Multinomial regression analysis stratified by type of labour onset examined the association between pre-pregnancy BMI and mode of delivery controlling for maternal age, pre-existent health conditions, parity, fertility treatments, history of C-section and pregnancy complications. RESULTS: The cohort consisted of 65.8% normal weight, 23.6% overweight and 10.6% obese women. Women with increased pre-pregnancy BMI were more likely to develop pregnancy complications such as preeclampsia (OR 3.5, CI 2.0-4.6 for overweight; OR 5.3, CI 3.3-8.5 for obese) and gestational diabetes (OR 3.0, CI 1.8-5.0 for overweight; OR 6.5, CI 3.7-11.2 for obese) than normal weight women. Spontaneous onset of labour was recorded in 71.2% of women with normal pre-pregnancy BMI, whereas 39.3% of overweight and 49% of obese women had their labour induced. For women with spontaneous labour, pre-pregnancy BMI was not a significant risk factor for mode of delivery, controlling for covariates. Among women with induced labor, obesity was a significant risk factor for delivery by C-section (adjusted OR 2.2; CI 1.2-4.1). CONCLUSIONS: Even among women with term, singleton pregnancies obtaining prenatal care in community-based settings, obese women who undergo labour induction are at increased risk of obstetrical interventions at delivery. These findings highlight the importance of tailored maternal care in pregnancy and at delivery of pregnant women with increased BMI in order to improve the outcomes and wellbeing of these women and their children. PMID- 25528668 TI - The invariance assumption in process-dissociation models: an evaluation across three domains. AB - The class of process-dissociation models, a subset of the class of multinomial processing-tree models, is one of the best understood classes of models used in experimental psychology. A number of prominent debates have addressed fundamental assumptions of process-dissociation models, leading, in many cases, to conceptual clarifications and extended models that address identified issues. One issue that has so far defied empirical clarification is how to evaluate the invariance assumption for the dominant process. Violations of the invariance assumption have, however, the potential to bias conventional process-dissociation analyses in different ways, and they can cause misleading theoretical interpretations and conclusions. Based on recent advances in multinomial modeling, we propose new approaches to examine the invariance assumption empirically and apply them in 6 studies to 3 prominent fields of application of process-dissociation models: to the Stroop task, to the interplay of recollection and habit in cued recall, and to the study of racial bias in the weapon task. In each of these content domains, the invariance assumption is found to be violated to a considerable extent. PMID- 25528669 TI - Priming memories of past wins induces risk seeking. AB - People are often risk averse when making decisions under uncertainty. When those decisions are based on past experience, people necessarily rely on their memories. Thus, what is remembered at the time of the choice should influence risky choice. We tested this hypothesis by priming memory for past outcomes in a simple risky-choice task. In the task, people repeatedly chose between a safe option and a risky option that paid off with a larger or smaller reward with a 50/50 chance. Some trials were preceded by a priming cue that was previously paired with one of the outcomes. We found that priming cues associated with wins caused people to become risk seeking, whereas priming cues associated with relative losses had little effect. These results suggest that people can be induced to be more risk seeking through subtle reminders of previous winning experiences. PMID- 25528670 TI - Noise-optimized virtual monoenergetic images and iodine maps for the detection of venous thrombosis in second-generation dual-energy CT (DECT): an ex vivo phantom study. AB - AIMS AND OBJECTIVES: Deep venous thrombosis (DVT) can be difficult to detect using CT due to poor and heterogeneous contrast. Dual-energy CT (DECT) allows iodine contrast optimization using noise-optimized monoenergetic extrapolations (MEIs) and iodine maps (IMs). Our aim was to assess whether MEI and IM could improve the delineation of thrombotic material within iodine-enhanced blood compared to single-energy CT (SECT). MATERIALS AND METHODS: Six vessel phantoms, including human thrombus and contrast media-enhanced blood and one phantom without contrast, were placed in an attenuation phantom and scanned with DECT 100/140 kV and SECT 120 kV. IM, virtual non-contrast images (VNC), mixed images, and MEI were calculated. Attenuation of thrombi and blood were measured. Contrast and contrast-to-noise-ratios (CNRs) were calculated and compared among IM, VNC, mixed images, MEI, and SECT using paired t tests. RESULTS: MEI40keV and IM showed significantly higher contrast and CNR than SE120kV from high to intermediate iodine concentrations (contrast:pMEI40keV < 0.002,pIM < 0.005;CNR:pMEI40keV < 0.002,pIM < 0.004). At low iodine concentrations, MEI190keV and VNC images showed significantly higher contrast and CNR than SE120kV with inverted contrasts (contrast:pMEI190keV < 0.008,pVNC < 0.002;CNR:pMEI190keV < 0.003,pVNC < 0.002). CONCLUSIONS: Noise-optimized MEI and IM provide significantly higher contrast and CNR in the delineation of thrombosis compared to SECT, which may facilitate the detection of DVT in difficult cases. KEY POINTS: * Poor contrast makes it difficult to detect thrombosis in CT. * Dual-energy-CT allows contrast optimization using monoenergetic extrapolations (MEI) and iodine maps (IM). * Noise-optimized-MEI and IM are significantly superior to single-energy-CT in delineation of thrombosis. * Noise-optimized-MEI and IM may facilitate the detection of deep vein thrombosis. PMID- 25528671 TI - Image quality of low mA CT pulmonary angiography reconstructed with model based iterative reconstruction versus standard CT pulmonary angiography reconstructed with filtered back projection: an equivalency trial. AB - OBJECTIVE: To determine whether CT pulmonary angiography (CTPA) using low mA setting reconstructed with model-based iterative reconstruction (MBIR) is equivalent to routine CTPA reconstructed with filtered back projection (FBP). METHODS: This prospective study was approved by the institutional review board and patients provided written informed consent. Eighty-two patients were examined with a low mA MBIR-CTPA (100 kV, 20 mA) and 82 patients with a standard FBP-CTPA (100 kV, 250 mA). Region of interests were drawn in nine pulmonary vessels; signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. A five-point scale was used to subjectively evaluate the image quality of FBP-CTPA and low mA MBIR-CTPA. RESULTS: Compared to routine FBP-CTPA, low mA MBIR-CTPA showed no differences in the attenuation measured in nine pulmonary vessels, higher SNR (56 +/- 19 vs 43 +/- 20, p < 0.0001) and higher CNR (50 +/- 17 vs 38 +/- 18, p < 0.0001) despite a dose reduction of 93 % (p < 0.0001). The subjective image quality of low mA MBIR-CTPA was quoted as diagnostic in 98 % of the cases for patient with body mass index less than 30 kg/m(2). CONCLUSION: Low mA MBIR CTPA is equivalent to routine FBP-CTPA and allows a significant dose reduction while improving SNR and CNR in the pulmonary vessels, as compared with routine FBP-CTPA. KEY POINTS: * Low mA MBIR-CTPA is equivalent to routine FBP-CTPA. * MBIR-CTPA may be achieved with drastic (93 %) dose reduction. * Low mA MBIR-CTPA should be studied in the setting of suspected PE. PMID- 25528672 TI - Overexpression of the sweet potato IbOr gene results in the increased accumulation of carotenoid and confers tolerance to environmental stresses in transgenic potato. AB - In a previous study, we have evidenced that the overexpression of the IbOr gene isolated from sweet potato conferred a tolerance activity against salinity and methyl viologen (MV) treatment in transgenic sweet potato calli along with an enhanced carotenoid content. In this study, to further examine the function of the IbOr gene in heterologous organism, we transformed the IbOr gene into potato under the direction of SWPA2 promoter, a strong inducible promoter upon treatment with various environmental stresses. Consistently with our previous study of sweet potato calli, the level of total carotenoid was elevated up to 2.7-fold (38.1 MUg g(-1)DW) compared to the non-transgenic control, Atlantic cultivar. However, the composition of carotenoid was not influenced by the overexpression of the IbOr gene since only pre-existing carotenoids in the non-transgenic control including violaxanthin, lutien and beta-carotene were elevated at a similar level of total carotenoids. In general, the transcript levels for most of carotenogenesis-related genes were elevated in transgenic tuber, whereas they remained at similar levels in transgenic leaf tissues compared to those of non transgenic controls. The increased levels of carotenoid content in the leaf or tuber tissue of transgenic lines were correlated with the enhanced tolerance activity against salt- or MV-mediated oxidative stresses and DPPH radical scavenging activity. Our preliminary results suggest that further investigation is required for the development of a crop tolerant to salinity and other environmental stresses through the overexpression of the IbOr gene. PMID- 25528673 TI - Integrated effect of microbial antagonist, organic amendment and fungicide in controlling seedling mortality (Rhizoctonia solani) and improving yield in pea (Pisum sativum L.). AB - The study evaluated the comparative performance of a few microbial antagonists, organic amendments and fungicides and their integration for the management of seedling mortality (Rhizoctonia solani Kuhn) and yield improvement in pea (Pisum sativum L.). Before setting the experiment in field microplots, a series of in vitro and in vivo experiments were conducted to select a virulent isolate of R. solani, an effective antagonistic isolate of Trichoderma harzianum, a fungitoxic organic amendment and an appropriate fungicide. A greenhouse pathogenicity test compared differences in seedling mortality in pea inoculated by four isolates of R. solani and identified the isolate RS10 as the most virulent one. Among the 20 isolates screened in dual culture assay on PDA, T. harzianum isolate T-3 was found to show the highest (77.22%) inhibition of the radial growth of R. solani. A complete inhibition (100.00%) of colony growth of R. solani was observed when fungicide Bavistin 50 WP and Provax-200 at the rate of 100 and 250 ppm, respectively, were used, while Provax-200 was found to be highly compatible with T. harzianum. Mustard oilcake gave maximum inhibition (60.28%) of the radial growth of R. solani at all ratios, followed by sesame oilcake and tea waste. Integration of soil treatment with T. harzianum isolate T-3 and mustard oilcake and seed treatment with Provax-200 appeared to be significantly superior in reducing seedling mortality and improving seed yield in pea in comparison to any single or dual application of them in the experimental field. The research results will help growers develop integrated disease management strategies for the control of Rhizoctonia disease in pea. The research results show the need for an integrating selective microbial antagonist, organic amendment and fungicide to achieve appropriate management of seedling mortality (R. solani) and increase of seed yield in pea. PMID- 25528674 TI - Cadmium effects on the retina of adult Danio rerio. AB - The aim of this work is to describe the effects of cadmium pollution on the vision of adult zebrafish, Danio rerio. Retinal morpho-cytological alterations were investigated by light and electron microscopy, while the functionality of cadmium-exposed retinae was assessed by re-illumination behavioral tests with white or colored light. Our results demonstrate that cadmium toxicity causes significant degeneration and loss of organization at both macro and microscopic levels. These alterations impair functional responses particularly through an increase in light sensitivity. Metallothioneins were not seen to be up-regulated, while the recovery of visual acuity is due to a regenerative process by Muller cells. PMID- 25528675 TI - [Extra-oral signs to look for in patients exhibiting oral warning signs of genetic diseases]. AB - This article is aimed at defining guidelines for dental surgeons to manage patients with warning signs of rare genetic diseases. Anomalies of tooth development may occur as an isolated condition or in association with other symptoms in syndromes. In many cases, dental anomalies may be the first manifestations of a genetic disease. The dentist can contribute to the diagnosis, and hence to an early treatment of this syndrome. When one or more dental anomalies are found, practitioners should refer patients to a genetic clinic or a specialized reference center to diagnose genetic diseases. Therefore, we provide, for the first time, a table of extra-oral signs that dental surgeons can look for in patients exhibiting heritable dental developmental anomalies. PMID- 25528676 TI - New drug discovery: extraordinary opportunities in an uncertain time. AB - The way in which new medicines are discovered has irreversibly changed and the future sustainability of the enterprise is characterized by an unprecedented period of uncertainty. Herein, we convey that these changes provide unprecedented opportunities for many different players within the private and public sectors to work together and develop new models that ensure the sustainability of activities that have had an extraordinary impact; in terms of promoting public health and driving economic value. Specific examples of experiments are provided to demonstrate some of the new thinking that will be needed to ensure continuation of new drug discovery. PMID- 25528677 TI - Hydrogen generation: aromatic dithiolate-bridged metal carbonyl complexes as hydrogenase catalytic site models. AB - The design, syntheses and characteristics of metal carbonyl complexes with aromatic dithiolate linkers reported as bioinspired hydrogenase catalytic site models are described and reviewed. Among these the complexes capable of hydrogen generation have been discussed in detail. Comparisons have been made with carbonyl complexes having alkyl dithiolates as linkers between metal centers. PMID- 25528678 TI - Stereospecific ligands and their complexes. XXII. Synthesis and antitumor activity of palladium(II) complexes with some esters of (S,S)-ethylenediamine N,N'-di-(2,2'-di(4-hydroxy-benzyl))-acetic acid. AB - Four new ligands and their palladium(II) complexes of general formula R2-S,S eddtyr (L1-L4) and [PdCl2(R2-S,S-eddtyr)] (C1-C4) (R=ethyl, n-propyl, n-butyl and n-pentyl; S,S-eddtyr.2HCl=ethylenediamine-N,N'-di-(2,2'-di(4-hydroxy-benzyl)) acetic acid dihydrochloride have been synthesized and characterized by microanalysis, infrared, (1)H and (13)C NMR spectroscopy. Cytotoxicity for ligands and complexes on two different cell lines (human breast cancer, MDA-MB 231 and human lung cancer, A549 cell lines) and human chronic lymphocytic leukemia cells (CLL) was investigated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay. PMID- 25528679 TI - The reaction of dichlorodiammineplatinum(II), [PtCl2(NH3)2], isomers with zinc fingers. AB - The interaction of cis-DDP and trans-DDP (DDP=[PtCl2(NH3)2]) with the C-terminal zinc finger (ZF2) of the HIVNCp7 nucleocapsid protein was investigated by fluorescence, circular dichroism, mass spectrometry, and {(1)H, (15)N} HSQC (heteronuclear single quantum coherence) NMR spectroscopy. The rate of reaction differed significantly for the two compounds, with the trans isomer reacting in a significantly faster manner, as expected. {(1)H, (15)N} HSQC NMR of (15)N-labeled compounds with the ZF2 showed the appearance of several new (15)N peaks, consistent with sulfur binding and formation of Pt-S species. Mass spectrometry confirmed the formation of several different Pt-apopeptide/ZF2 adducts. Circular dichroism and fluorescence spectroscopy also indicated conformational changes upon binding while a 33% decrease in fluorescence of the unique tryptophan residue was seen in 72h upon complexation of the cis isomer, while the trans isomer quenched 50% in just 24h. PMID- 25528680 TI - Prevalence of chronic kidney disease and associated factors among the Chinese population in Taian, China. AB - BACKGROUND: This study was designed to assess the prevalence of chronic kidney disease (CKD) and associated risk factors among the Chinese population in Taian, China. METHODS: A primary care-based cross-sectional study was conducted in Taian, China, from September to December 2012. Participants selected by a multi stage stratified cluster sampling procedure were interviewed and tested for hematuria, albuminuria, estimated glomerular filtration rate (eGFR) and other clinical indices. Factors associated with CKD were analyzed by univariate and multivariate logistic regression analysis. RESULTS: A total of 14,399 subjects were enrolled in this study. The rates of hematuria, albuminuria and reduced eGFR were 4.20%, 5.25% and 1.89%, respectively. Approximately 9.49% (95% CI: 8.93% 10.85%) of the participants had at least one indicator of CKD, with an awareness of 1.4%. Univariate analyses showed that greater age, body mass index, and systolic and diastolic blood pressure; higher levels of serum creatinine, uric acid, fasting blood glucose, triglycerides, total cholesterol and low-density lipoprotein cholesterol; and lower eGFR were associated with CKD (p < 0.05 each). Multivariate analysis showed that age, female gender, educational level, smoking habits, systolic blood pressure, and history of diabetes mellitus, hyperlipidemia, hypercholesterolemia and hyperuricemia were independent risk factors for CKD. CONCLUSIONS: The prevalence of CKD in the primary care population of Taian, China, is high, although awareness is quite low. Health education and policies to prevent CKD are urgently needed among this population. PMID- 25528681 TI - RNA-Seq identifies novel myocardial gene expression signatures of heart failure. AB - Heart failure is a complex clinical syndrome and has become the most common reason for adult hospitalization in developed countries. Two subtypes of heart failure, ischemic heart disease (ISCH) and dilated cardiomyopathy (DCM), have been studied using microarray platforms. However, microarray has limited resolution. Here we applied RNA sequencing (RNA-Seq) to identify gene signatures for heart failure from six individuals, including three controls, one ISCH and two DCM patients. Using genes identified from this small RNA-Seq dataset, we were able to accurately classify heart failure status in a much larger set of 313 individuals. The identified genes significantly overlapped with genes identified via genome-wide association studies for cardiometabolic traits and the promoters of those genes were enriched for binding sites for transcriptions factors. Our results indicate that it is possible to use RNA-Seq to classify disease status for complex diseases such as heart failure using an extremely small training dataset. PMID- 25528682 TI - Proof of prometastatic niche induction by hepatic stellate cells. AB - BACKGROUND: An interaction between tumor cells and the microenvironment, as well as the development of angiogenesis, are required to form liver metastases (LMs). MATERIAL AND METHODS: Immunofluorescence detection of alpha-smooth muscle actin, desmin, Ki67, laminin, and CD31 was used to analyze the kinetics of tumor angiogenesis determinants, especially the contribution of hepatic stellate cells (HSCs) to angiogenesis in hepatic metastasis produced by intrasplenically injected LS174 colorectal cancer cells. Immunostaining was performed at various times (days 9, 14, 28, and 39). RESULTS: At the earliest stage, micrometastases consisted of proliferating cancer cells, a well-organized network of activated HSCs and laminin deposits. No vascular network was observed. As the LMs grew in size, an organized vascular network appeared; the laminin network colocalized with CD31 immunostaining. At the later stages, all the immunostained markers became peripheral as a central necrosis developed. Purified activated HSCs isolated from transgenic mice livers developing hepatocellular carcinoma secreted laminin and showed enhanced human umbilical vein EC network formation in a Matrigel assay. In a coinjection LM experiment, activated HSCs enhanced the metastatic process. Moreover, colorectal LMs from six patients were analyzed, and a pattern of marker distribution similar to the coinjection experiment was found in human LMs. CONCLUSIONS: For the first time, our results show that HSCs play a crucial role in organizing and accelerating the progression of metastasis in modulating the prometastatic niche, interacting with colorectal cancer cell recruitment, and the organization of angiogenesis during colorectal LM development. Therefore, HSCs may be an early therapeutic target in colorectal cancer therapies. PMID- 25528683 TI - Coronary evaluation in patients with stroke: recognizing the risk. PMID- 25528684 TI - Developmental programing of thirst and sodium appetite. AB - Thirst and sodium appetite are the sensations responsible for the motivated behaviors of water and salt intake, respectively, and both are essential responses for the maintenance of hydromineral homeostasis in animals. These sensations and their related behaviors develop very early in the postnatal period in animals. Many studies have demonstrated several pre- and postnatal stimuli that are responsible for the developmental programing of thirst and sodium appetite and, consequently, the pattern of water and salt intake in adulthood in need-free or need-induced conditions. The literature systematically reports the involvement of dietary changes, hydromineral and cardiovascular challenges, renin angiotensin system and steroid hormone disturbances, and lifestyle in these developmental factors. Therefore, this review will address how pre- and postnatal challenges can program lifelong thirst and sodium appetite in animals and humans, as well as which neuroendocrine substrates are involved. In addition, the possible epigenetic molecular mechanisms responsible for the developmental programing of drinking behavior, the clinical implications of hydromineral disturbances during pre- and postnatal periods, and the developmental origins of adult hydromineral behavior will be discussed. PMID- 25528686 TI - Coping styles moderate the relationships between exposure to community violence and work-related outcomes. AB - The purpose of this study was to identify coping strategies used by employees exposed to community violence and their relationships to work-related outcomes. In study 1, Mexican Maquiladora employees who experienced community violence reported their coping strategies. Results identified 3 strategies: social, solitary, and maladaptive coping. In study 2, another sample completed measures of violence exposure, strain, coping, and turnover intention. Supervisors provided performance evaluations. Community violence predicted the use of all 3 strategies. Social coping lessened the effects of community violence on turnover while maladaptive strategies predicted increased psychological strain. Results indicate that workers use a variety of coping strategies in response to community violence that both lessen and magnify the effects of violence exposure and impact their psychological strain, turnover intention, and job performance. (PsycINFO Database Record PMID- 25528687 TI - Effectiveness of total worker health interventions. AB - Total Worker Health (TWH) was introduced and the term was trademarked in 2011 by the National Institute for Occupational Safety and Health (NIOSH) to formally signal the expansion of traditional occupational safety and health (OSH) to include wellness and well-being. We searched PubMed, PsycINFO, and other databases using keywords TWH, health promotion, health protection, and variants for articles meeting the criteria of (a) employing both occupational safety and/or health (OSH, or health protection) and wellness and/or well-being (health promotion, or HP) in the same intervention study, and (b) reporting both OSH and HP outcomes. Only 17 published studies met these criteria. All but 1 of the 17 TWH interventions improved risk factors for injuries and/or chronic illnesses, and 4 improved 10 or more risk factors. Several TWH interventions reported sustained improvements for over a year, although only 1 is readily available for dissemination. These results suggest that TWH interventions that address both injuries and chronic diseases can improve workforce health effectively and more rapidly than the alternative of separately employing more narrowly focused programs to change the same outcomes in serial fashion. These 17 articles provide useful examples of how TWH interventions can be structured. The promise of simultaneous improvements in safety, health, and well-being leads to the call to pursue TWH research to identify and disseminate best practices. PMID- 25528688 TI - An assessment of the overlap between morale and work engagement in a nonoperational military sample. AB - The degree of overlap between two positive motivational constructs-morale and work engagement-was assessed in a random sample of Canadian Armed Forces personnel stationed across Canada (N = 1,224). Based on self-determination theory and past research, job-specific self-efficacy, trust in teammates, and job significance were expected to be associated with morale and work engagement. Structural equation modeling analyses revealed that morale and work engagement were highly positively correlated, but had different patterns of association with predictor and outcome variables. Although trust in teammates and job significance predicted both morale and work engagement, job-specific self-efficacy predicted morale but not work engagement. Willingness to deploy on operations, turnover intentions, and psychological distress were predicted by both morale and work engagement, but morale was a better predictor of psychological distress and work engagement was a stronger predictor of turnover intentions. Together, the results suggest that, despite their overlap, morale and work engagement, as defined and measured herein, are not interchangeable. PMID- 25528689 TI - Relations of negative and positive work experiences to employee alcohol use: testing the intervening role of negative and positive work rumination. AB - This study tested a model linking work experiences to employee alcohol use. The model extended past research in 3 ways. First, it incorporated both negative and positive work experiences. Second, it incorporated a previously unexplored cognitive intervening process involving negative and positive work rumination. Third, it incorporated several important dimensions of alcohol use (heavy use, workday use, and after-work use). Data were collected from a national probability sample of 2,831 U.S. workers. Structural equation modeling revealed that the conceptual model provided an excellent fit to the data. Negative work experiences were positively related to negative work rumination, which was positively related to heavy alcohol use, workday alcohol use, and after work alcohol use. Positive work experiences were positively related to positive work rumination, which was negatively related to heavy alcohol use and after work alcohol use, but was unrelated to workday alcohol use. The study also provided initial support for the psychometric properties and construct validity of the newly developed Negative and Positive Work Rumination Scale (NAPWRS). PMID- 25528690 TI - Study of indentation of a sample equine bone using finite element simulation and single cycle reference point indentation. AB - In an attempt to study the mechanical behavior of bone under indentation, methods of analyses and experimental validations have been developed, with a selected test material. The test material chosen is from an equine cortical bone. Stress strain relationships are first obtained from conventional mechanical property tests. A finite element simulation procedure is developed for indentation analyses. The simulation results are experimentally validated by determining (1) the maximum depth of indentation with a single cycle type of reference point indentation, and (2) the profile and depth of the unloaded, permanent indentation with atomic force microscopy. The advantage of incorporating in the simulation a yield criterion calibrated by tested mechanical properties, with different values in tension and compression, is demonstrated. In addition, the benefit of including damage through a reduction in Young's modulus is shown in predicting the permanent indentation after unloading and recovery. The expected differences in response between two indenter tips with different sharpness are predicted and experimentally observed. Results show predicted indentation depths agree with experimental data. Thus, finite element simulation methods with experimental validation, and with damage approximation by a reduction of Young's modulus, may provide a good approach for analysis of indentation of cortical bone. These methods reveal that multiple factors affect measured indentation depth and that the shape of the permanent indentation contains useful information about bone material properties. Only further work can determine if these methods or extensions to these methods can give useful insights into bone pathology, for example the bone fragility of thoroughbred racehorses. PMID- 25528691 TI - A 3-D constitutive model for pressure-dependent phase transformation of porous shape memory alloys. AB - Porous shape memory alloys (SMAs) exhibit the interesting characteristics of porous metals together with shape memory effect and pseudo-elasticity of SMAs that make them appropriate for biomedical applications. In this paper, a 3-D phenomenological constitutive model for the pseudo-elastic behavior and shape memory effect of porous SMAs is developed within the framework of irreversible thermodynamics. Comparing to micromechanical and computational models, the proposed model is computationally cost effective and predicts the behavior of porous SMAs under proportional and non-proportional multiaxial loadings. Considering the pressure dependency of phase transformation in porous SMAs, proper internal variables, free energy and limit functions are introduced. With the aim of numerical implementation, time discretization and solution algorithm for the proposed model are also presented. Due to lack of enough experimental data on multiaxial loadings of porous SMAs, we employ a computational simulation method (CSM) together with available experimental data to validate the proposed constitutive model. The method is based on a 3-D finite element model of a representative volume element (RVE) with random pores pattern. Good agreement between the numerical predictions of the model and CSM results is observed for elastic and phase transformation behaviors in various thermomechanical loadings. PMID- 25528692 TI - Preventing the pack size effect: exploring the effectiveness of pictorial and non pictorial serving size recommendations. AB - People eat more from large than from small packs, which is known as the pack size effect. We hypothesized that providing a serving size recommendation would reduce the influence of the pack size on consumption and would thus diminish the pack size effect. Moreover, we hypothesized that a pictorial serving size recommendation, displaying food amounts visually, would be more effective than a non-pictorial recommendation that communicates the recommended amount in grams only. We tested these hypotheses in two online experiments (N = 317 and N = 324) and in one lab experiment (N = 89). In the online experiments, participants were shown a small or a large pack of unhealthy snacks, with or without a serving size recommendation. The main outcome measure was expected consumption. Replicating the pack size effect in an online setting, we found that participants expected to consume more food from large than from small packs. Furthermore, the pack size effect was considerably stronger for men than for women. Importantly, when including portion size preferences as a covariate, the pictorial serving size recommendation significantly reduced expected consumption, especially when placed on a large pack, as hypothesized. The non-pictorial serving size recommendation had no effect. In the lab experiment, students received a large bag of M&M's which did or did not contain the pictorial serving size recommendation. We again included general portion size preferences as a covariate. The serving size recommendation significantly lowered the amount of M&M's that participants served themselves, but only when participants reported to have noticed the serving size recommendation. We conclude that providing a pictorial serving size recommendation can be an effective intervention strategy to reduce the pack size effect, if it attracts sufficient attention. PMID- 25528693 TI - The influence of hot and cool executive function on the development of eating styles related to overweight in children. AB - Studies linking executive function (EF) and overweight suggest that a broad range of executive functions might influence weight via obesity-related behaviors, such as particular eating styles. Currently, however, longitudinal studies investigating this assumption in children are rare. We hypothesized that lower hot and cool EF predicts a stronger increase in eating styles related to greater weight gain (food approach) and a weaker increase in eating styles related to less weight gain (food avoidance) over a 1-year period. Hot (delay of gratification, affective decision-making) and cool (attention shifting, inhibition, working memory updating) EF was assessed experimentally in a sample of 1657 elementary-school children (German school classes 1-3) at two time points, approximately one year apart. The children's food-approach and food avoidance behavior was rated mainly via parent questionnaires at both time points. As expected, lower levels of hot and cool EF predicted a stronger increase in several food-approach eating styles across a 1-year period, mainly in girls. Unexpectedly, poorer performance on the affective decision-making task also predicted an increase in certain food-avoidance styles, namely, slowness in eating and satiety responsiveness, in girls. Results implicate that lower EF is not only seen in eating-disordered or obese individuals but also acts as a risk factor for an increase in particular eating styles that play a role in the development of weight problems in children. PMID- 25528694 TI - Neural predictors of chocolate intake following chocolate exposure. AB - Previous studies have shown that one's brain response to high-calorie food cues can predict long-term weight gain or weight loss. The neural correlates that predict food intake in the short term have, however, hardly been investigated. This study examined which brain regions' activation predicts chocolate intake after participants had been either exposed to real chocolate or to control stimuli during approximately one hour, with interruptions for fMRI measurements. Further we investigated whether the variance in chocolate intake could be better explained by activated brain regions than by self-reported craving. In total, five brain regions correlated with subsequent chocolate intake. The activation of two reward regions (the right caudate and the left frontopolar cortex) correlated positively with intake in the exposure group. The activation of two regions associated with cognitive control (the left dorsolateral and left mid dorsolateral PFC) correlated negatively with intake in the control group. When the regression analysis was conducted with the exposure and the control group together, an additional region's activation (the right anterior PFC) correlated positively with chocolate intake. In all analyses, the intake variance explained by neural correlates was above and beyond the variance explained by self-reported craving. These results are in line with neuroimaging research showing that brain responses are a better predictor of subsequent intake than self-reported craving. Therefore, our findings might provide for a missing link by associating brain activation, previously shown to predict weight change, with short-term intake. PMID- 25528695 TI - Comparison of an analog and digital quantitative and qualitative analysis for the fit of dental copings. AB - BACKGROUND: Precision in fit is crucial for dental crowns and bridges. Most analyses of fit are based on analog 2D techniques. Aim of this in-vitro study was to compare an analog and a digital quantitative and qualitative analysis for the fit of CAD/CAM fabricated dental copings. METHODS: A prepared steel canine served as master die. CAD surface models, varying in data density, were purposely enlarged in height (Ez), circumference (Exy) and both of these aspects at once (Exyz). Two titanium copings for each variation were produced. The silicone replica-technique was applied to analyze the fit by means of a 2D analog light microscope measurement (LMM) and a 3D computer-assisted measurement using an optical digitizing system (ODKM97), respectively. RESULTS: In most cases, restorations based on the low data density showed a better fit than those based on high data density. Original size low density data showed the lowest marginal and axial values in the quantitative 2D analyses (LMM and ODKM97). The 3D measurements (ODKM97) revealed best fit of the low density original size specimens, whereas the Ez specimens showed the highest values. Noticeable variations in fit were detected marginally and axially depending on the specific measurement point (mesial, distal, oral, or buccal) for both measurement systems. DISCUSSION: The analog 2D replica technique revealed a loss of information due to the necessary cutting process. By contrast, the digital computer-based method provided 3D quantitative and qualitative results without data loss over the complete surface. PMID- 25528696 TI - Classification of breast regions as mass and non-mass based on digital mammograms using taxonomic indexes and SVM. AB - Breast cancer is the second most common type of cancer in the world. Several computer-aided detection and diagnosis systems have been used to assist health experts identify suspicious areas that are difficult to perceive with the human eye, thus aiding in the detection and diagnosis of cancer. This work proposes a methodology for the discrimination and classification of regions extracted from mammograms as mass and non-mass. The Digital Database for Screening Mammography (DDSM) was used in this work for the acquisition of mammograms. The taxonomic diversity index (Delta) and the taxonomic distinctness (Delta(*)), which were originally used in ecology, were used to describe the texture of the regions of interest. These indexes were computed based on phylogenetic trees, which were applied to describe the patterns in regions of breast images. Two approaches were used for the analysis of texture: internal and external masks. A support vector machine was used to classify the regions as mass and non-mass. The proposed methodology successfully classified the masses and non-masses, with an average accuracy of 98.88%. PMID- 25528698 TI - Oklahoma's success in reducing the toll of tobacco. PMID- 25528697 TI - Pre-operative prediction of surgical morbidity in children: comparison of five statistical models. AB - BACKGROUND: The accurate prediction of surgical risk is important to patients and physicians. Logistic regression (LR) models are typically used to estimate these risks. However, in the fields of data mining and machine-learning, many alternative classification and prediction algorithms have been developed. This study aimed to compare the performance of LR to several data mining algorithms for predicting 30-day surgical morbidity in children. METHODS: We used the 2012 National Surgical Quality Improvement Program-Pediatric dataset to compare the performance of (1) a LR model that assumed linearity and additivity (simple LR model) (2) a LR model incorporating restricted cubic splines and interactions (flexible LR model) (3) a support vector machine, (4) a random forest and (5) boosted classification trees for predicting surgical morbidity. RESULTS: The ensemble-based methods showed significantly higher accuracy, sensitivity, specificity, PPV, and NPV than the simple LR model. However, none of the models performed better than the flexible LR model in terms of the aforementioned measures or in model calibration or discrimination. CONCLUSION: Support vector machines, random forests, and boosted classification trees do not show better performance than LR for predicting pediatric surgical morbidity. After further validation, the flexible LR model derived in this study could be used to assist with clinical decision-making based on patient-specific surgical risks. PMID- 25528699 TI - Detection of in vivo DNA damage induced by very low doses of mainstream and sidestream smoke extracts using a novel assay. AB - BACKGROUND: Mainstream (MS) smoke, the main smoke inhaled by active smokers, and sidestream (SS) smoke, the main component of secondhand smoke, induce a wide range of DNA lesions. Owing to technical limitations, the in vivo levels of tobacco-induced DNA damage are unknown. Recently, the authors developed a highly sensitive primer-anchored DNA damage detection assay (PADDA) to quantify endogenous and induced DNA damage. PURPOSE: To quantify the in vivo levels of DNA damage induced by MS and SS smoke extracts in human cells using PADDA and define the strand-specific patterns of DNA damage and repair following exposure to diverse doses of MS and SS smoke. METHODS: Human epithelial cells were exposed to escalating doses of hydrogen peroxide (H2O2), MS, or SS smoke. TP53 gene DNA damage was quantified using PADDA at various time points. DNA double-strand breaks were detected by immunofluorescence analysis of phosphorylated histone H2AX (gamma-H2AX). Cell viability was determined by 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide (MTT) assay. Data were collected and analyzed by t-test in 2012-2014. RESULTS: A dose-dependent increase in DNA damage was detected in vivo with increasing doses of H2O2, MS, and SS smoke. Even 1 hour of exposure to very low doses of MS or SS smoke resulted in significant DNA damage (p<0.01). MS and SS smoke induced distinctive strand-specific patterns of DNA damage and DNA repair kinetics. CONCLUSIONS: Very low concentrations of MS and SS smoke induce significant DNA damage in human cells. Application of PADDA to population studies has major potential to establish biomarkers of susceptibility to tobacco-induced diseases. PMID- 25528700 TI - Excise tax differences at Oklahoma smoke shops: an opportunity for inter-tribal coordination. AB - BACKGROUND: Oklahoma's tribal tobacco shops are distributed throughout the state, including in urban areas. During the time frame of this study, state excise tax rates for cigarettes varied by tribe and region, and took five distinct levels, ranging from 5.75 cents to $1.03 per pack. PURPOSE: To describe the pricing behavior of these smoke shops in a way that could support potential increases in the tribal taxation of cigarettes within the state. METHODS: Two waves (2010 and 2011) of site visits were conducted, covering nearly all tribal smoke shops in the northeastern quarter of the state, an area containing the city of Tulsa and 60% of all tribal outlets. Researchers recorded representative prices and verified the tax rate paid (via tax stamp) for each shop. Data were analyzed in 2013. RESULTS: Lower-taxed tribal cigarettes tended to be priced at discounts that were even greater than the differential in tax rates. For example, across waves, the average pack of Marlboros from a shop with a 5.75-cent tax stamp sold for 52 cents less than the same pack from a 25.75-cent shop and 60 cents less than from a 51.5-cent shop. The minimal inter-tribal price response to the discontinuation of large quantities of contraband cigarette sales suggests that inter-tribal price competition in the Tulsa area is not as intense as expected. CONCLUSIONS: Ample scope exists for either unilateral or coordinated cross-tribal tax and price increases that will increase tribal cigarette tax revenue collections and improve public health. PMID- 25528701 TI - A neo-strategic planning approach to enhance local tobacco control programs. AB - BACKGROUND: Research in tobacco control demonstrating best practices is widely disseminated; however, application at the local level is often difficult. Translating research into practice requires a concerted effort to develop an understanding of the evidence and how it can be applied within diverse contexts. PURPOSE: A strategic planning infrastructure was developed to support the translation of evidence-based interventions into community practice. This paper highlights the strategic process of turning "know-what" into "know-how" to facilitate the strategic planning and implementation of tobacco control best practices at the local level. DESIGN: The purpose, people, process, and product strategies of knowledge management and translation provided a framework for the strategic planning infrastructure. The knowledge translation concepts of audience, motivations, and mechanisms were synergized in the neo-strategic planning component design. SETTING/PARTICIPANTS: The participants were 20 community coalitions funded to implement local tobacco control programs. INTERVENTION: From 2004 to 2011, the strategic planners facilitated a cyclical process to translate research into practice using a trio of integrated tools, skill-building workshops on strategic planning, and grantee-driven technical assistance and consultation. MAIN OUTCOME MEASURES: In the short term, the usefulness of the strategic planning components to the programs was measured. The intermediate outcome was the successful movement of the community programs from the planning stage to the implementation stage. The achievement of community level changes in planned tobacco control efforts was the overall outcome measure for the success of the local coalitions. RESULTS: Seventeen of 20 communities that began the planning process implemented strategic plans. All 17 of the programs implemented evidence-based practices, resulting in numerous tobacco-free policies, increased cessation, and increased support from the media and community. CONCLUSIONS: Bridging the gap between research and practice can enhance the practicality, efficiency, and effectiveness of tobacco control programs at the local level, maximizing the potential positive health impact. PMID- 25528702 TI - Communities of excellence in tobacco control: changes in local policy and key outcomes. AB - BACKGROUND: The Oklahoma Communities of Excellence in Tobacco Control (CX) program was established in 2004. Thirty-three CX grants have been funded to implement comprehensive tobacco control programs in 50 counties and one tribal nation. PURPOSE: To describe local tobacco policy gains within CX counties and short-term and intermediate outcomes such as Oklahoma Tobacco Helpline registration and awareness, quit attempts, and home smoking bans among adults. METHODS: A before-and-after study design examined outcomes within CX counties and among CX urban and rural counties. Comparisons were made with non-funded counties when possible. Local policy tracking databases were reviewed for the number of policies implemented from 2004 to 2013 in CX counties. Population-level tobacco indicators, using Helpline registration and 2004-2010 Behavioral Risk Factor Surveillance System data, quantified changes over time. Data were collected in 2003-2013 and analyzed in 2013. RESULTS: Eight hundred thirty-one legislated and voluntary policies were implemented in CX counties and high levels of Helpline registration were maintained. Statistically significant increases were observed in CX counties for the proportion of smokers making a quit attempt, Helpline awareness, and home smoking bans among smokers. These observed increases were greater in rural CX counties than urban. Non-CX counties only experienced a statistically significant increase in Helpline awareness. CONCLUSIONS: Using community-based best practices in tobacco control while focusing on social norm change, CX counties experienced positive changes in smoking-related attitudes and behaviors. This study expands the evidence base for statewide tobacco control programming and underscores the value of community-based tobacco control programs. PMID- 25528703 TI - Case studies from community coalitions: advancing local tobacco control policy in a preemptive state. AB - Policies that shield people from the harm of tobacco exposure are essential to protect the health of the population. Coalitions have often led the way in safeguarding community health by promoting social norm change though policy adoption. In some states, tobacco control laws are weak, in part because of a tobacco industry tactic of prohibiting or pre-empting communities from enacting ordinances that are more protective. In spite of strong state-level preemptions, local coalitions in Oklahoma have implemented hundreds of voluntary policies in tobacco control that have improved the protection and health of their communities while not violating preemption. Three case studies of policy change are presented that exemplify the key approach of local coalitions working with strong allies and informed decision makers to establish tobacco-free businesses, schools, and outdoor recreational areas. In each of the cases, the policy changes surpassed the protection provided by the state laws and inspired additional policy changes. The key strategies and lessons learned may help tobacco control coalitions in other states limited by preemption to garner more support and momentum for important policy changes within their communities and states. PMID- 25528704 TI - A brief history of the tobacco settlement in Oklahoma. PMID- 25528705 TI - Oklahoma's youth-driven tobacco policy campaigns: assessment of impacts and lessons learned. AB - BACKGROUND: Youth engagement is an important component of comprehensive tobacco control programs. Oklahoma has dozens of Students Working Against Tobacco (SWAT) teams throughout the state. Traditionally, SWAT has focused more on community and peer education than policy initiatives. To systematically engage SWAT members in high-impact policy work, Oklahoma launched new training materials and policy focused campaigns in October 2011. PURPOSE: To examine initial campaign implementation and impact, including outcomes and lessons learned. METHODS: Youth baseline and post-campaign survey data and program coordinator post-campaign survey data were collected in 2011-2012 and analyzed in 2013. Chi-square analyses and t tests were used to identify differences in youths' attitudes, self efficacy, and activism behavior. Descriptive statistics and thematic analysis of coordinator survey data were used to identify barriers to campaign implementation. Copies of passed policies were collected. RESULTS: Youths' tobacco-related attitudes (p<0.001) and confidence to implement local policy campaigns (p=0.011) and discuss Big Tobacco's lies (p=0.048) were higher at follow-up. Excepting survey collection (p=0.019), youth did not engage in new advocacy behaviors during the study period. Seven policies were partly attributed to the campaigns. Timing, lack of training, and material format were identified as barriers to implementation. CONCLUSIONS: When implementing similar programs, significant planning must go into the timing of the launch. Instruction must be provided to local staff before materials are disseminated. Developed materials must account for short meetings and limited access to technology. With some adjustments, campaigns like these could prove valuable tools for engaging youth in high-impact local tobacco control efforts. PMID- 25528706 TI - Stakeholder engagement: a model for tobacco policy planning in Oklahoma Tribal communities. AB - BACKGROUND: Oklahoma law pre-empts local governments from enacting smoking restrictions inside public places that are stricter than state law, but the sovereign status of Oklahoma's 38 Tribal nations means they are uniquely positioned to stand apart as leaders in the area of tobacco policy. PURPOSE: To provide recommendations for employing university-Tribal partnerships as an effective strategy for tobacco policy planning in tribal communities. METHODS: Using a community-based participatory research approach, researchers facilitated a series of meetings with key Tribal stakeholders in order to develop a comprehensive tobacco policy plan. Ongoing engagement activities held between January 2011 and May 2012, including interdepartmental visits, facility site tours, interviews, and attendance at tribal activities, were critical for fostering constructive and trusting relationships between all partners involved in the policy planning process. RESULTS: The 17-month collaborative engagement produced a plan designed to regulate the use of commercial tobacco in all Tribally owned properties. The extended period of collaboration between the researchers and Tribal stakeholders facilitated: (1) levels of trust between partners; and (2) a steadfast commitment to the planning process, ensuring completion of the plan amid uncertain political climates and economic concerns about tobacco bans. CONCLUSIONS: Extended engagement produced an effective foundation for policy planning that promoted collaboration between otherwise dispersed Tribal departments, and facilitated communication of diverse stakeholder interests related to the goal of tobacco policies. The findings of this study provide useful strategies and best practices for those looking to employ Tribal-university partnerships as strategies for tobacco control planning and policy-based research. PMID- 25528707 TI - Oklahoma Tobacco Helpline utilization and cessation among American Indians. AB - BACKGROUND: American Indians in Oklahoma have higher rates of tobacco use (29.2%) than any other racial group in the state. The Oklahoma Tobacco Helpline provides free cessation services to all Oklahomans and implements strategies specifically aimed at increasing the utilization and effectiveness of cessation services for American Indians. PURPOSE: To explore Helpline utilization patterns as well as outcomes, such as participant satisfaction and success in quitting, for American Indians. The utilization patterns and outcomes for American Indians were compared to that of the white population from July 1, 2010, to June 30, 2013, to determine whether the Helpline is equally effective among American Indians compared to whites. METHODS: Helpline utilization data from July 1, 2010, to June 30, 2013, were analyzed in the fall of 2013 to identify patterns and compare differences between American Indian and white Helpline registrants. Four- and 7-month follow up survey data were used to compare outcomes related to satisfaction with services and quit rates. RESULTS: During the 3-year study period, 10.6% of registrants who enrolled in an intervention were American Indian (11,075) and 71.2% were white (74,493). At the 7-month follow-up survey, 31.7% of American Indians reported having used no tobacco in the past 30 days compared to 36.5% of whites, but the differences were not statistically significant between racial groups. CONCLUSIONS: The Oklahoma Tobacco Helpline is equally effective for American Indian and white tobacco users who register for Helpline services. PMID- 25528708 TI - Predictors of smokeless tobacco cessation among telephone quitline participants. AB - BACKGROUND: The prevalence of smokeless tobacco use in the U.S. is increasing and its use is a risk factor for a number of adverse health outcomes. Currently, there is limited evidence on the effectiveness of quitlines for tobacco cessation among smokeless tobacco users. PURPOSE: To examine factors related to tobacco abstinence among exclusive smokeless tobacco users registering for services with the Oklahoma Tobacco Helpline. METHODS: Participants included 959 male exclusive smokeless tobacco users registering with the Helpline between 2004 and 2012; a total of 374 completed a follow-up survey 7 months post-registration. Data were collected between 2004 and 2013 and included baseline data at Helpline registration, services received, and 7-month follow-up for 30-day point prevalence for tobacco abstinence. Univariate and multiple logistic regression examined associations between abstinence and participant characteristics, intensity of Helpline intervention, and behavioral factors. ORs and 95% CIs were reported. Analyses were completed in 2013. RESULTS: At the 7-month follow-up, 43% of the participants reported 30-day abstinence from tobacco. Each additional completed Helpline call increased the likelihood of tobacco cessation by 20% (OR=1.20, 95% CI=1.05, 1.38). Smokeless tobacco users with higher levels of motivation to quit at baseline were twice as likely to be abstinent than those with low or moderate levels of motivation (OR=2.05, 95% CI=1.25, 3.35). Use of nicotine replacement therapy was not associated with abstinence when adjusted for Helpline calls, income, and level of motivation. CONCLUSIONS: Tobacco quitlines offer an effective intervention to increase smokeless tobacco abstinence. PMID- 25528709 TI - Tobacco control and prevention in Oklahoma: best practices in a preemptive state. AB - For more than a decade, the Oklahoma Tobacco Settlement Endowment Trust and Oklahoma State Department of Health have collaborated to implement best practices in tobacco control through state and community interventions, including legislated and voluntary policy approaches, health communication, cessation programs, and surveillance and evaluation activities. This partnership eliminates duplication and ensures efficient use of public health dollars for a comprehensive tobacco control program based on a systems and social norm change approach. The purpose of this paper is to briefly describe strategies to reduce tobacco use despite a rare policy environment imposed by the presence of near complete state preemption of tobacco-related law. Key outcome indicators were used to track progress related to state tobacco control and prevention programs. Data sources included cigarette excise tax stamp sales, statewide surveillance systems, Oklahoma Tobacco Helpline registration data, and local policy tracking databases. Data were collected in 2001-2013 and analyzed in 2012 and 2013. Significant declines in cigarette consumption and adult smoking prevalence occurred in 2001-2012, and smoking among high school students fell 45%. Changes were also observed in attitudes and behaviors related to secondhand smoke. Community coalitions promoted adoption of local policies where allowable, with 92 ordinances mirroring state clean indoor air laws and 88 ordinances mirroring state youth access laws. Tobacco-free property policies were adopted by 292 school districts and 309 worksites. Moving forward, tobacco use will be prioritized as an avoidable health hazard in Oklahoma as it is integrated into a wellness approach that also targets obesity reduction. PMID- 25528710 TI - Post-cessation weight concerns among women calling a state tobacco quitline. AB - BACKGROUND: Obese and overweight women who smoke are more likely to be concerned about weight gain following cessation, impacting ability to quit and relapse. PURPOSE: To determine differences in weight concerns for underweight, normal weight, overweight, and obese female smokers by race/ethnicity. METHODS: From March to November 2008, female adult tobacco users calling the Oklahoma Tobacco Helpline were asked questions to determine the prevalence of obesity and concern for cessation-related weight gain. A score of 50 or greater, where 0=not at all concerned and 100=very concerned, on one of two weight concerns questions defined the outcome. BMI was calculated from self-reported height and weight. For the current analyses in 2013, race, ethnicity, age, education, marital status, and tobacco use history were examined as covariates. Multiple logistic regression was used to calculate ORs and 95% CIs. RESULTS: A significant interaction between race and BMI was observed; thus, separate models were created for white (n=3,579); black (n=330); American Indian (n=441); and Hispanic (n=125) women. BMI was independently associated with weight concerns among all racial/ethnic groups, but the strength of the association varied. For black and Hispanic women, there was a particularly strong association between BMI and weight concerns among obese women (OR=9.55, 95% CI=5.05, 18.07, and OR=8.46, 95% CI=2.57, 27.83, respectively), although sample sizes were small. CONCLUSIONS: State quitlines should consider tailoring promotional efforts and treatment protocols to include concerns about weight gain, especially for obese African American and Hispanic smokers. PMID- 25528711 TI - Increased evidence-based tobacco treatment through Oklahoma hospital system changes. AB - BACKGROUND: Oklahoma hospitals admit approximately 120,000 tobacco users each year, many for diseases resulting from tobacco use. PURPOSE: To describe a unique partnership between the Oklahoma Hospital Association and Oklahoma Tobacco Settlement Endowment Trust to reach more tobacco users through the implementation of sustainable health system changes within hospitals and clinics to integrate an evidence-based tobacco treatment protocol for all tobacco-using patients. METHODS: The Oklahoma Hospital Association tobacco-cessation model included (1) identifying all tobacco-using patients; (2) assessing addiction level and readiness to quit; (3) prescribing medications to manage withdrawal while in hospital; and (4) proactively faxing a referral to the Oklahoma Tobacco Helpline for all patients ready to quit. Helpline registration patterns and characteristics of fax-referred hospitalized patients were tracked for the 4 years of the initiative (2009-2013); data were analyzed in 2013. RESULTS: Twenty one hospitals and 12 clinics participated in the initiative. Fax referrals to the Helpline increased by >150% in the first year, from about 600 during the year prior to the implementation of the program (July 2009 to June 2010) to 1,581 from Oklahoma Hospital Association facilities alone in the first year following the launch of the initiative. Nearly 5,600 Oklahoma Hospital Association fax referrals were made during the 4-year study period. About 41% of these referrals resulted in Helpline enrollment (n=2,289). CONCLUSIONS: Sustainable, evidence based tobacco treatment interventions embedded in hospital systems can successfully identify tobacco users and provide effective treatment, including increased proactive Helpline referrals for quit coaching. PMID- 25528712 TI - Longitudinal evaluation of the Tobacco Stops With Me campaign. AB - INTRODUCTION: Counter-marketing in tobacco control plays an important role in increasing smoking cessation, reducing overall tobacco use, and reducing exposure to secondhand smoke. PURPOSE: To evaluate the Tobacco Stops With Me campaign in Oklahoma by determining awareness and impact on tobacco-related attitudes, knowledge, and behavior among tobacco users and non-users. METHODS: A 2-year longitudinal population-based study of 4,001 Oklahomans aged 18-54 years was conducted to evaluate campaign-related changes in knowledge, attitudes, and behaviors. Baseline data were collected using landline and cellular phones in 2007 prior to the launch of the campaign, with follow-up surveys at 1 year after baseline (n=2,466) and 2 years after baseline (n=2,266). Data were analyzed in 2012 using methods appropriate for weighted longitudinal data. RESULTS: Overall campaign awareness was 81%. Exposure to Tobacco Stops With Me doubled quit attempts among tobacco users and increased knowledge about the harm of secondhand smoke. Tobacco non-users exposed to the campaign were 1.5 times more likely to help someone quit using tobacco than those not exposed, report that tobacco is a serious problem in Oklahoma, believe that tobacco companies should not be allowed to give away free samples or advertise at public events, and believe that smoking should be banned at public outdoor places. These findings were statistically significant after controlling for potential confounding variables. CONCLUSIONS: This study demonstrates the campaign's impact on tobacco-related attitudes, knowledge, and behaviors among both tobacco users and non-users. PMID- 25528714 TI - Which nicotine products are gateways to regular use? First-tried tobacco and current use in college students. AB - BACKGROUND: The potential for emerging tobacco products (ETPs) to be gateway products for further tobacco use among youth is of significant concern. PURPOSE: To examine use of various nicotine-containing products on a tobacco-free college campus and whether the first product tried predicts subsequent tobacco use. METHODS: Undergraduate students (N=1,304) at a large university completed an online survey of past/current use of cigarettes; smokeless tobacco (SLT); hookah; ETPs (dissolvables, snus, and electronic cigarettes); and nicotine replacement therapy (NRT). Data were collected from September 2012 to May 2013 and analyses were conducted from June to September 2013. Students were classified as single, dual, or poly tobacco users. RESULTS: The sample consisted of 79.5% non-users, 13.8% single, 4.4% dual, and 1.5% poly users. Overall, 49.4% of participants reported trying a tobacco product. Hookah was the most tried product (38%), but cigarettes were most often the first product ever tried (51%). First product tried did not predict current tobacco use and non-use, but individuals who first tried SLT or cigarettes (rather than hookah or ETPs) were more likely to be poly tobacco users. Current tobacco users who first tried ETPs or hookah were largely non-daily users of hookah; current tobacco users who first tried cigarettes or SLT were largely non-daily or daily users of cigarettes/SLT. CONCLUSIONS: Hookah and ETPs are increasingly becoming the first tobacco product ever tried by youth; however, uptake of ETPs is poor, unlike cigarettes and SLT, and does not appear to lead to significant daily/non-daily use of cigarettes and SLT. PMID- 25528713 TI - Wreaking "havoc" on smoking: social branding to reach young adult "partiers" in Oklahoma. AB - BACKGROUND: More than 25% of young adult Oklahomans smoked cigarettes in 2012. Tobacco marketing campaigns target young adults in social environments like bars/nightclubs. Social Branding interventions are designed to compete directly with this marketing. PURPOSE: To evaluate an intervention to reduce smoking among young adult "Partiers" in Oklahoma. The Partier peer crowd was described as follows: attendance at large nightclubs, fashion consciousness, valuing physical attractiveness, and achieving social status by exuding an image of confidence and financial success. DESIGN: Repeated cross-sectional study with three time points. SETTING/PARTICIPANTS: Randomized time location survey samples of young adult Partier bar and club patrons in Oklahoma City (Time 1 [2010], n=1,383; Time 2 [2011], n=1,292; and Time 3 [2012], n=1,198). Data were analyzed in 2013. INTERVENTION: The "HAVOC" Social Branding intervention was designed to associate a smoke-free lifestyle with Partiers' values, and included events at popular clubs, brand ambassador peer leaders who transmit the anti-tobacco message, social media, and tailored anti-tobacco messaging. MAIN OUTCOME MEASURES: Daily and nondaily smoking rates, and binge drinking rates (secondary). RESULTS: Overall, smoking rates did not change (44.1% at Time 1, 45.0% at Time 2, and 47.4% at Time 3; p=0.17), but there was a significant interaction between intervention duration and brand recall. Partiers reporting intervention recall had lower odds of daily smoking (OR=0.30 [0.10, 0.95]) and no difference in nondaily smoking, whereas Partiers who did not recall the intervention had increased odds of smoking (daily AOR=1.74 [1.04, 2.89]; nondaily AOR=1.97 [1.35, 2.87]). Among non-Partiers, those who recalled HAVOC reported no difference in smoking, and those who did not recall HAVOC reported significantly increased odds of smoking (daily AOR=1.53 [1.02, 2.31]; nondaily AOR=1.72 [1.26, 2.36]). Binge drinking rates were significantly lower (AOR=0.73 [0.59, 0.89]) overall. CONCLUSIONS: HAVOC has the potential to affect smoking behavior among Oklahoma Partiers without increasing binge drinking. PMID- 25528715 TI - Prospective associations among youth assets in young adults and tobacco use. AB - BACKGROUND: Developmental assets protect adolescents from tobacco use; however, their influence during the transition to young adulthood is unknown. PURPOSE: To determine the prospective associations among assets and tobacco use in older adolescents and young adults. METHODS: Prospective analyses were conducted using five waves of annual data collected from 467 randomly selected ethnically diverse youth (baseline age, 15-17 years) from 2003 to 2008. Logistic regression was conducted in 2013 to prospectively examine associations between ten Wave 1 assets with no tobacco use in the past 30 days over the five waves of the study (no use). Assets that were significantly associated with no use were included in a second analysis to examine the cumulative effect of Wave 1 assets on no use. RESULTS: Youth who possessed Family Communication, Relationship with Mother, Aspirations for the Future, Parental Monitoring, or Responsible Choices assets had significantly higher odds of no tobacco use. There were significant interactions between Relationship with Father, Non-Parental Adult Role Models, Future Educational Aspirations, and Peer Role Models assets and family structure, gender, or both. There was a significant interaction between cumulative assets and family structure. For youth in two-parent households at Wave 1, those with more assets had significantly greater odds of reporting no tobacco use over five waves compared to those with the fewest assets. CONCLUSIONS: The influence of assets in adolescents can influence tobacco use into young adulthood. Family structure and gender can influence the asset-tobacco use relationship. PMID- 25528716 TI - Confirmatory factor analysis and psychometric properties of the Yale-Brown Cornell Eating Disorders Scale Self-Report version (SR-YBC-EDS) in Spanish clinical and non-clinical samples. AB - OBJECTIVE: The aim of the study was to adapt and validate the Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS) transformed into a self-report format in Spanish clinical and non-clinical samples. METHOD: Eighty-three eating disordered patients and 358 non-clinical participants completed the Self Report-YBC-EDS version (SR-YBC-EDS), the Eating Attitudes Test (EAT), and the Penn State Worry Questionnaire (PSWQ). RESULTS: Confirmatory factor analyses of a two-factor second-order model showed adequate values of goodness-of-fit indices for non clinical (normed chi(2)=13.4578; df =18; NFI=0.980; GFI=1.00; RMSEA=0.00) and clinical samples (normed chi(2)=26.5913; df =18; NFI=0.944; GFI=0.981; RMSEA=0.076). The factor loadings were high (preoccupations range: 0.69-0.91; rituals range: 0.61-0.94). Cronbach's alpha (range alpha=0.85-0.90) and test retest 2weeks later (range: 0.84-0.91) were excellent in both samples. SR-YBC-EDS showed moderate-high indices of convergent validity with PSWQ and EAT. For the total score, a cutoff of 13 showed a sensitivity of 90.4%, a specificity of 91.6%, and a diagnostic accuracy of 91.4%. Positive and negative predictive values were excellent (71.4% and 97.6%, respectively). DISCUSSION: Findings indicate that the SR-YBC-EDS is a reliable and valid instrument to identify symptoms and assess the severity of ED, and it can be used as a faster and less costly alternative to the YBC-EDS interview. PMID- 25528717 TI - A novel measure of compulsive food restriction in anorexia nervosa: validation of the Self-Starvation Scale (SS). AB - The characteristic relentless self-starvation behaviour seen in Anorexia Nervosa (AN) has been described as evidence of compulsivity, with increasing suggestion of transdiagnostic parallels with addictive behaviour. There is a paucity of standardised self-report measures of compulsive behaviour in eating disorders (EDs). Measures that index the concept of compulsive self-starvation in AN are needed to explore the suggested parallels with addictions. With this aim a novel measure of self-starvation was developed (the Self-Starvation Scale, SS). 126 healthy participants, and 78 individuals with experience of AN, completed the new measure along with existing measures of eating disorder symptoms, anxiety and depression. Initial validation in the healthy sample indicated good reliability and construct validity, and incremental validity in predicting eating disorder symptoms. The psychometric properties of the SS scale were replicated in the AN sample. The ability of this scale to predict ED symptoms was particularly strong in individuals currently suffering from AN. These results suggest the SS may be a useful index of compulsive food restriction in AN. The concept of 'starvation dependence' in those with eating disorders, as a parallel with addiction, may be of clinical and theoretical importance. PMID- 25528718 TI - Depression, coping, hassles, and body dissatisfaction: factors associated with disordered eating. AB - The objective was to explore what predicts first-year college women's disordered eating tendencies when they arrive on campus. The 215 first-year college women completed the surveys within the first 2weeks of classes. A structural model examined how much the Helplessness, Hopelessness, Haplessness Scale, the Brief COPE, the Brief College Student Hassle Scale, and the Body Shape Questionnaire predicted eating disordered tendencies (as measured by the Eating Attitudes Test). The Body Shape Questionnaire, the Helplessness, Hopelessness, Haplessness Scale (inversely), and the Denial subscale of the Brief COPE significantly predicted eating disorder tendencies in first-year college women. In addition, the Planning and Self-Blame subscales of the Brief COPE and the Helplessness, Hopelessness, Haplessness Scale predicted the Body Shape Questionnaire. In general, higher levels on the Helplessness, Hopelessness, Haplessness Scale and higher levels on the Brief College Student Hassle Scale related to higher levels on the Brief COPE. Coping seems to remove the direct path from stress and depression to disordered eating and body dissatisfaction. PMID- 25528719 TI - Navigating the obesogenic environment: how psychological sensitivity to the food environment and self-regulatory competence are associated with adolescent unhealthy snacking. AB - PURPOSE: Living in an obesogenic environment may not affect all adolescents to the same extent, depending on their psychological sensitivity to the food environment and their self-regulatory competence. The purpose of the current study was to examine associations of these two factors with unhealthy snacking among adolescents. We also investigated whether self-regulatory competence could attenuate the negative effects of being sensitive to the food environment. METHODS: A survey was completed by 11,392 European adolescents (10-17years old). The survey measured psychological sensitivity to the food environment, self regulatory competence and self-reported unhealthy snack intake. RESULTS: Higher food environment sensitivity and lower self-regulatory competence were associated with more unhealthy snacking. The two factors also interacted, with self regulatory competence attenuating the influence of high food environment sensitivity. DISCUSSION: Adolescents who are sensitive to the food environment reported higher unhealthy snack intake. More frequent use of self-regulation strategies on the other hand was associated with lower unhealthy snack intake. Moreover, self-regulatory competence was found to moderate the influence of psychological sensitivity to the food environment on unhealthy snacking, although the effect size was small. Fostering adolescents' self-regulatory competence can help enable them to better navigate the obesogenic environment. PMID- 25528720 TI - Triazinoindole analogs as potent inhibitors of alpha-glucosidase: synthesis, biological evaluation and molecular docking studies. AB - A new series of triazinoindole analogs 1-11 were synthesized, characterized by EI MS and (1)H NMR, evaluated for alpha-glucosidase inhibitory potential. All eleven (11) analogs showed different range of alpha-glucosidase inhibitory potential with IC50 value ranging between 2.46+/-0.008 and 312.79+/-0.06 MUM when compared with the standard acarbose (IC50, 38.25+/-0.12 MUM). Among the series, compounds 1, 3, 4, 5, 7, 8, and 11 showed excellent inhibitory potential with IC50 values 2.46+/-0.008, 37.78+/-0.05, 28.91+/-0.0, 38.12+/-0.04, 37.43+/-0.03, 36.89+/-0.06 and 37.11+/-0.05 MUM respectively. All other compounds also showed good enzyme inhibition. The binding modes of these analogs were confirmed through molecular docking. PMID- 25528721 TI - Determine the equilibrium mechanical properties of articular cartilage from the short-term indentation response. AB - Indentation testing is widely used to evaluate the mechanical properties of articular cartilage. However, most curve-fitting solutions for indentation analysis require the deformation data of cartilage at the equilibrium state, which often takes the tissue hours to reach. The lengthy testing time reduces the efficiency of indentation, increases the chance of tissue deterioration, and prevents in vivo applications. To overcome these limitations, a novel technique based on principal component analysis (PCA) was developed in this study, which can predict the full indentation creep curve based on the first few minutes' deformation history and the principal components. The accuracy of this technique was confirmed using the indentation data from 40 temporomandibular joint condylar cartilage samples and 17 bovine knee joint samples. The mechanical properties determined by biphasic curve-fitting using predicted and experimental data are in good agreement, with the difference between the two less than 5%. For TMJ and knee cartilages, it is found that any number of full tests beyond eight will not lead to any increase larger than 1% in the accuracy, indicating a low sample number required for prediction. In addition, the principal components of indentation creep curves are consistent for the same type of cartilage tested with identical protocols, but significantly different between two distinct cartilages. Therefore PCA may also represent a new method to compare the mechanical behaviors of different cartilages, as it avoids the assumptions associated with mechanical constitutive models and relies purely on the experimental data. PMID- 25528722 TI - Allopurinol alleviates hypertension and proteinuria in high fructose, high salt and high fat induced model of metabolic syndrome. AB - Metabolic syndrome (MetS) is a global epidemic associated with great socioeconomic and public health impact. Prevalence of the MetS has been consistently associated with cardiorenal mortality. The objective of this study was to investigate the effect of allopurinol treatment on various components of an established MetS in rats. In a first group, MetS was induced in male Wistar rats by the addition of 10% fructose to drinking water and placing the rats on high-fat and high-salt diet for 12 weeks (M). In the second group, MetS was induced for 12 weeks plus allopurinol administration (20 mg/kg/d) orally for 4 weeks starting at week 9 (MA). The third group was control (C) group that received a normal diet. The M group had higher blood pressure (BP) (85.5 +/- 3.17 vs 66.1 +/- 3.3 mm Hg) and proteinuria (1.8 +/- 0.3 vs 0.59 +/- 0.13 g/d) compared with the C group. Allopurinol reversed the BP and proteinuria in MA rats to the control level. Allopurinol administration suppressed the low-grade inflammation associated with MetS and reversed the increases in kidney transforming growth factor beta and urine 8-isoprostane acid observed in the MA group to control levels. In addition, allopurinol reduced angiotensin II and angiotensin receptor type 1 levels in the kidney of MA rats compared with the M group. The administration of allopurinol for short term in an established MetS model reduced features of the MetS especially hypertension and proteinuria. Addition of allopurinol to the therapy of MetS may provide superior means to alleviate hypertension and proteinuria associated with MetS. PMID- 25528723 TI - Impact of adjuvant treatment for microscopic residual disease after non-small cell lung cancer surgery. AB - BACKGROUND: Incomplete resection of non-small cell lung cancer (NSCLC) portends a dramatic decline in survival. Historically, postoperative radiation and chemotherapy have been offered to treat residual disease at the surgical margins, yet the efficacy is unknown. We examined the survival among incompletely resected NSCLC patients to identify the optimal response to positive NSCLC surgical margins. METHODS: The National Cancer Data Base was queried for surgically managed pathologic stage I-III NSCLC between 2003 and 2006 (n = 54,512). The prevalence, predictors, impact, and optimal treatment approaches to positive surgical margins were investigated. RESULTS: A positive surgical margin was identified in 3,102 NSCLC patients (5.7% of resections), including 1,688 with microscopically positive (R1) margins (3.1%). Compared with complete resections, patients with R1 resections had a worse 5-year survival; stage pI (62% vs 37%; p < 0.0001), stage pII (41% vs 29%; p < 0.0001), and stage pIII (33% vs 19%; p < 0.0001). Postoperative administration of both chemotherapy and radiation were associated with superior survival compared with surgery alone at all stages; stage pI (44% vs 35%; p = 0.05), stage pII (33% vs 21%; p = 0.0013), and stage pIII NSCLC (30% vs 12%; p < 0.0001). Administration of chemotherapy or radiation alone was less consistently associated with improved outcome in R1 patients. Of note, radiation alone did not improve survival for stage pI patients with R1 resections (26% vs 35%; p = 0.0399). CONCLUSIONS: The administration of both chemotherapy and radiation is associated with an improved survival in patients with microscopically positive surgical margins, irrespective of stage. Further study is needed to clarify the optimal stage-specific adjuvant approach to incompletely resected NSCLC. PMID- 25528724 TI - Preoperative performance status impacts perioperative morbidity and mortality after lung transplantation. AB - BACKGROUND: The aim of this study was to determine which factors predict poor postoperative performance and to evaluate the impact of these variables on 1-year mortality. METHODS: The United Network for Organ Sharing database was queried for adult patients undergoing lung transplantation (LTx) from 2007 to 2011. Patients were divided based on their preoperative Karnofsky Performance Status score (KPS) into 3 groups. Regression analysis was conducted to determine which factors predicted poor postoperative performance. Cox modeling was utilized to identify which of these factors was associated with an increased risk of mortality after LTx. RESULTS: Of the 7,832 patients included in this study, 30.1% required complete assistance, 57.7% required partial assistance, and 12.3% needed no assistance preoperatively. Postoperative KPS was assessed at a mean of 2.6 +/- 1.5 years after transplant. A number of factors, including primary graft failure, redo and single LTx, and intensive care unit status prior to LTx independently predicted poor performance; whereas a body mass index 18.5 kg/m(2) or greater and some degree of preoperative functional independence were protective. Age greater than 60 years, donor tobacco use, and intensive care unit status, extracorporeal membrane oxygenation support, and mechanical ventilation prior to LTx were associated with an increased risk 1-year mortality, while preoperative functional independence and a body mass index 18.5 to 30 kg/m(2) were protective. CONCLUSIONS: This is the largest known study to examine the issue of disability in LTx and its relationship to mortality. Preoperative performance status significantly impacts post-LTx mortality. Patient optimization may improve outcomes and should alter decisions regarding graft selection and allocation. PMID- 25528725 TI - Creating an arc-shaped aorta: use of the subclavian artery for interrupted aortic arch repair. AB - BACKGROUND: With interrupted aortic arch (IAA), a direct anastomosis may produce an angular-shaped aortic arch instead of the normal arc-shaped aorta, when the discontinuity is considerably long. That may lead to aortic stenosis and to compression of the pulmonary artery or the main bronchus. If a tube graft is used, reoperation for graft exchange is inevitable. We demonstrate the results of using the subclavian artery for creating an arc-shaped aorta in IAA repair. METHODS: Between February 2006 and October 2012, 23 patients underwent IAA repair using the subclavian artery. The subclavian artery was closed distally, divided, and longitudinally incised from the transected end to the aorta. This flap was used to bridge the gap of the IAA, by forming the posterior wall of a new aortic segment. The arch was completed using glutaraldehyde-fixed autologous pericardium (52%) or homograft (48%). RESULTS: Median follow-up time was 4.8 years (range, 1.3 to 6.9). There were no early deaths and 1 late death. On postoperative angiographic imaging, the aorta takes an arc-shaped course in all cases. Aortic arch stenosis developed in 7 patients (30%). Four patients were treated interventionally, and 3 surgically. During follow-up, there was no compression of the pulmonary artery or the main bronchus. CONCLUSIONS: By using the subclavian artery, an arc-shaped aorta can be accomplished without the use of tube grafts. With this technique, compression of the pulmonary artery or the main bronchus can be avoided. This technique is recommended if a direct anastomosis might be not applicable to bridge a long interruption. PMID- 25528726 TI - Analysis of the effect of high hydrostatic pressure treatment and enterocin AS-48 addition on the bacterial communities of cherimoya pulp. AB - In the present study, pulp obtained from cherimoya pulp (Annona cherimola) was inoculated with epiphytic microbiota collected from cherimoya fruits, and supplemented or not with the circular bacteriocin enterocin AS-48 (50MUg/g) and then packed under vacuum. Samples supplemented or not with enterocin were treated by high hydrostatic pressure (600MPa, 8min) and then stored at 5 degrees C for 30days. The single AS-48 treatment only delayed microbial growth non significantly (p>0.05). HHP treatment reduced microbial counts by five log cycles, but it did not prevent further growth of survivors by day 7. The combined treatment (AS-48+HHP) was the most effective, keeping bacterial cell densities at <=1.5 log CFU/g for up to 15days. 16S rRNA gene pyrosequencing analysis was done on amplicon libraries from the growth on TSA plates seeded with ten-fold dilutions of pulp suspensions and incubated at 22 degrees C for 24h. The results obtained are limited by the experimental conditions used in the study, and only concern the bacterial fraction that was selected by the TSA and growth conditions used. Pantoea (Pantoea agglomerans, Pantoea vagans) were the operational taxonomic units (OTUs) detected at highest relative abundance in bacterial biomass grown from control samples for the first 7days of storage, followed by Enterococcus gallinarum and Leuconostoc mesenteroides during late storage. The single HHP treatment significantly reduced the relative abundance of OTUs belonging to Pantoea and strongly increased that of endosporeformers (mainly Bacillus firmus and Bacillus stratosphericus) early after treatment, although Pantoea became again the predominant OTUs during storage. Samples singly treated with enterocin AS-48 revealed a strong inhibition of E. gallinarum as well as an early decrease in the relative abundance of Pantoea and an increased relative abundance of OTUs belonging to other Gram-negative species (mainly from genera Serratia and Pseudomonas). The strong microbial inactivation achieved by the combined treatment with enterocin and HHP reduced the levels of viable cells below detectable limits at days 0 and 1, and survivors recovered on TSA at day 7 were represented in >99% by B. firmus OTU. OTUs from endosporeformers were no longer detected during prolonged incubation, displaced by Pantoea spp., Erwinia billingiae and leuconostocs. Results from the present study indicate that HHP in combination with enterocin AS-48 is more effective in preserving the microbiological quality of cherimoya pulp during storage than the single HHP treatment. PMID- 25528727 TI - Prevalence and characterization of methicillin susceptible Staphylococcus aureus ST398 isolates from retail foods. AB - In this study, we explored the prevalence of Staphylococcus aureus (S. aureus) ST398 in retail foods and then investigated for their virulence and antimicrobial resistance genetic background. Fourteen out of 5103 (0.27%) samples were positive for methicillin susceptible S. aureus (MSSA) ST398. Resistance was most frequently observed to penicillin (PEN) (100%), followed by trimethoprim (TMP), erythromycin (ERY) and ampicillin (AMP) (each 86.7%), clindamycin (CLD, 80.0%), and tetracycline (TET, 26.7%). All ST398 isolates were susceptible to amikacin, chloramphenicol, cefoxitin, gentamicin, oxacillin, and vancomycin. Two predominant resistance patterns including TMP-ERY-CLD-PEN-AMP (60.0%) and TMP-ERY TET-CLD-PEN-AMP (20.0%) were identified. Isolates harbored blaZ (86.7%) gene, followed by tet(L) and linA/linA' (each 46.7%), ermB and msrA (each 33.3%), aph(3')-IIIa and dfrK (each 26.7%), tet(K) (20.0%), ant(4')-Ia, ermA and emrC (each 13.3%) and cat::pC221 (6.7%). No isolate carried mecA, tet(M), tet(O), fexA, aac(6')/aph(2"), cfr, ermT, msrB, cat::pC194, cat::pC223, catpIp-501, dfrD, dfrG and dfrS1 genes. For virulence genes, hld (73.3%), seb and sed (each 66.7%), hla (60.0%), lukPV (33.3%), sej (26.7%), lukED and seg (each 3.3%) were detected. None of isolates contained sea, sec, see, seh, sei, tst, eta, etb, sek-ser, seu, lukM, hlg, and hlgv genes. Four spa types were found, including t571 (6/15), t034 (4/15), t2876 (3/15) and t1250 (2/15). All strains were non-typeable for agr locus. Our findings indicated that MSSA ST398 isolates had a low prevalence rate in retail foods, and these isolates harbored multiple virulence and antimicrobial resistance genes, and exhibited multiple antimicrobial resistance. Further studies are required to elucidate the possible role of MSSA ST398 as a source of human infection. PMID- 25528728 TI - KLF1 stabilizes GATA-1 and TAL1 occupancy in the human beta-globin locus. AB - KLF1 is an erythroid specific transcription factor that binds to regulatory regions of erythroid genes. Binding sites of KLF1 are often found near binding sites of GATA-1 and TAL1. In the beta-globin locus, KLF1 is required for forming active chromatin structure, although its role is unclear. To explore the role of KLF1 in transcribing the human gamma-globin genes, we stably reduced the expression of KLF1 in erythroid K562 cells, compromising its association in the beta-globin locus. The gamma-globin transcription was reduced with disappearance of active chromatin structure of the locus in the KLF1 knockdown cells. Interestingly, GATA-1 and TAL1 binding was reduced in the beta-globin locus, even though their expressions were not affected by KLF1 knockdown. The KLF1-dependent GATA-1 and TAL1 binding was observed in the adult locus transcribing the beta globin gene and in several erythroid genes, where GATA-1 occupancy is independent from TAL1. These results indicate that KLF1 plays a role in facilitating and/or stabilizing GATA-1 and TAL1 occupancy in the erythroid genes, contributing to the generation of active chromatin structure such as histone acetylation and chromatin looping. PMID- 25528729 TI - Structural modeling and docking studies of ribose 5-phosphate isomerase from Leishmania major and Homo sapiens: a comparative analysis for Leishmaniasis treatment. AB - Leishmaniases are caused by protozoa of the genus Leishmania and are considered the second-highest cause of death worldwide by parasitic infection. The drugs available for treatment in humans are becoming ineffective mainly due to parasite resistance; therefore, it is extremely important to develop a new chemotherapy against these parasites. A crucial aspect of drug design development is the identification and characterization of novel molecular targets. In this work, through an in silico comparative analysis between the genomes of Leishmania major and Homo sapiens, the enzyme ribose 5-phosphate isomerase (R5PI) was indicated as a promising molecular target. R5PI is an important enzyme that acts in the pentose phosphate pathway and catalyzes the interconversion of d-ribose-5 phosphate (R5P) and d-ribulose-5-phosphate (5RP). R5PI activity is found in two analogous groups of enzymes called RpiA (found in H. sapiens) and RpiB (found in L. major). Here, we present the first report of the three-dimensional (3D) structures and active sites of RpiB from L. major (LmRpiB) and RpiA from H. sapiens (HsRpiA). Three-dimensional models were constructed by applying a hybrid methodology that combines comparative and ab initio modeling techniques, and the active site was characterized based on docking studies of the substrates R5P (furanose and ring-opened forms) and 5RP. Our comparative analyses show that these proteins are structural analogs and that distinct residues participate in the interconversion of R5P and 5RP. We propose two distinct reaction mechanisms for the reversible isomerization of R5P to 5RP, which is catalyzed by LmRpiB and HsRpiA. We expect that the present results will be important in guiding future molecular modeling studies to develop new drugs that are specially designed to inhibit the parasitic form of the enzyme without significant effects on the human analog. PMID- 25528730 TI - Does ultrasonic advanced energy reduce lymphocele incidence in laparoscopic para aortic lymphadenectomy? AB - OBJECTIVE: To evaluate the use of ultrasonic advanced energy in reducing the occurrence of symptomatic lymphocele and its related complications in laparoscopic extra-peritoneal para-aortic lymphadenectomy in patients with gynecological cancer. STUDY DESIGN: A retrospective cohort study of consecutive patients in a tertiary referral center identified 2 groups of patients, undergoing laparoscopic extra-peritoneal para-aortic lymphadenectomy with or without the use of ultrasonic advanced energy. Surgery time, hospital stay, number of retrieved nodes and lymphocele requiring treatment were studied. Results were also compared between trained and trainee surgeons. RESULTS: 163 patients were scheduled for laparoscopic extra-peritoneal para-aortic lymphadenectomy: 81 treated using bipolar energy (control group: group 1) between August 1999 and January 2005, and 82 treated using ultrasonic advanced energy (study group: group 2) between July 2010 and March 2014. The main indication (90% in group 1, 61% in group 2) was advanced cervical carcinoma (stage IB2 and above). Ultrasonic advanced energy significantly decreased operative time (p=0.001) and intra-operative bleeding (p=0.01) and increased the number of para aortic nodes retrieved (p=0.02). There was no significant difference in hospital stay or lymphocele requiring treatment (8.6% in group 1, 8.5% in group 2: p=0.98). For senior than for junior surgeons, surgery time was shorter but not significantly (p=0.80) and postoperative lymphocele rates were identical. CONCLUSION: Ultrasonic advanced energy may provide benefit in laparoscopic para aortic lymphadenectomy, facilitating surgical ergonomics, but did not decrease post-surgery lymphocele. PMID- 25528731 TI - Systems genetics view of endometriosis: a common complex disorder. AB - Endometriosis is a condition in which cells derived from the endometrium grow outside the uterus, e.g. in the peritoneum (external genital endometriosis). As these cells are under the influence of female hormones, major symptoms of endometriosis are pain, especially during the cycle, and infertility. Numerous hypotheses for the formation of endometriosis can be found in the literature, but there is growing evidence of serious genetic contributions to endometriosis susceptibility. The involvement of genes, steroid hormone metabolism, immunological reactions, receptor formation, inflammation, proliferation, apoptosis, intercellular adhesion, cell invasion and angiogenesis as well as genes regulating the activity of aforementioned enzymes have been suggested. Some more recently suggested candidate genes picked up in genome-wide association studies are involved in oncogenesis, metaplasia of endometrium cells and pathways of embryonic development of the female reproductive system. However, gene mutations proven to be causative for endometriosis have not been identified so far, even though the abnormal expression of candidate genes for endometriosis could be provoked by different epigenetic modifications including DNA methylation, heterochromatization or introduction of regulatory miRNA. We hypothesize that endometriosis is induced by a combination of abnormal genetic and/or epigenetic mutations: the latter pave the way for pathological changes which become irreversible, and according to the "epigenetic landscape" theory, this proceeds to the typical clinical manifestations. Two stages in the endometriosis pathway are suggested: (1) induction of primary endometrial cells toward endometriosis, and (2) implantation and progression of these cells into endometriosis lesions. The model favors endometriosis as an outgrowth of primary cells different in their origin, canalization of pathological processes, manifestation diversity provoked by unique genetic background and epigenetic influences, which result in many different clinical forms of the disease. PMID- 25528732 TI - The evolving role of saline infusion sonography (SIS) in infertility. AB - Saline infusion sonography (SIS) has become a valuable diagnostic modality in gynaecology over the last three decades. SIS is now commonly employed for detailed evaluation of the uterine cavity as part of pre-treatment assessment in infertile women. The objective of this paper is review the scientific literature on SIS in infertility. Medline, Ovid and Cochrane databases were searched for relevant articles. The indications, technical aspects and the potential advantages of SIS are discussed. The efficacy and sensitivity of SIS are compared to hysteroscopy in the evaluation of uterine polyps, fibroids, intrauterine adhesions and uterine anomalies. Increasing evidence suggests the use of SIS prior to an in-vitro fertilization (IVF) cycle as it has increased sensitivity in the detection of intrauterine pathology. SIS is cost-effective and results in better patient satisfaction scores than hysteroscopy. PMID- 25528733 TI - Is vaginal hysterectomy is equally safe for the enlarged and normally sized non prolapse uterus? A cohort study assessing outcomes. AB - OBJECTIVE: Gynecologists are reluctant to perform vaginal hysterectomy if the uterine size exceeds 12 weeks in the belief that complications could be higher in this group. The aim of this cohort control study was to compare demographics, surgical outcomes and safety of vaginal hysterectomy in women with non-prolapsed uteri weighing >280 g (>12 weeks size) to those with uteri weighing <280 g removed vaginally for similar indications. STUDY DESIGN: In this study, classified as Canadian Task Force II (cohort-control), the index group comprised 41 women who underwent vaginal hysterectomy for non-prolapse indications with uterine enlargement >280 g (12 weeks), while the control group consisted of 66 women with uteri <280 g. Demographic data as well as duration of surgery, blood loss, intraoperative complications and readmission rates were compared. RESULTS: Women in the two groups had statistically similar mean age, body mass index and parity (47.7 vs 44.9 yrs, 30.3 vs 32.4 kg m(-3) and 2.8 vs 2.4, respectively; p>0.05). The mean operative time was significantly longer in the index group (123.3+/-43.2 vs 85+/-32.1 min; p=1.47*10(-6)). Women with enlarged uteri had greater mean estimated blood loss (402.8+/-402.2 vs 160.8+/-123.2 ml; p<0.0001) but the mean length of stay was similar (45.4+/-28.7 vs 37.6+/-26.2 h; p>0.05). Two uteri weighing >1000 g were removed vaginally. Intra- and post-operative complications such as bladder injury, blood transfusion and pelvic sepsis were similar in both groups. CONCLUSIONS: Vaginal hysterectomy in larger non-prolapsed uteri takes longer (mean 38 min longer) and is associated with more blood loss (mean increase 242 ml) compared to normal-sized uteri but is not associated with a significant increase in complication rates. PMID- 25528734 TI - Ovarian-sparing local mass excision for ovarian fibroma/fibrothecoma in premenopausal women. AB - OBJECTIVES: To evaluate the recurrence rate of ovarian fibroma/fibrothecoma and reproductive outcomes following ovarian-sparing local mass excision in premenopausal women. STUDY DESIGN: A retrospective cohort study was performed at two gynecologic surgery centers using data collected between January 2005 and December 2011. It included premenopausal patients treated with ovarian-sparing local mass excision and pathologically proven ovarian fibroma/fibrothecoma who were followed up for at least 6 months. The recurrence of fibroma/fibrothecoma and pregnancy outcomes in those who wanted to conceive after local mass excision were collected and analyzed. RESULTS: The mean age of the patients (n=50) was 33.3+/-6.9 years (range, 20-50 years), and the mean follow-up duration was 26.6+/ 19.2 months (range, 6-88 months). Fibroma was present in 40 patients, fibrothecoma in 7, and cellular fibroma in 3. Natural conception occurred in 11 of the 12 patients who became pregnant during the follow-up period. On follow-up ultrasonography, one patient experienced recurrent disease, 50 months after initial surgery, resulting in a crude overall recurrence rate of only 2%. CONCLUSION: Given the 2% recurrence rate of ovarian fibroma/fibrothecoma following ovarian sparing local mass excision, local mass excision appears to be an effective surgical option in women of reproductive age. PMID- 25528735 TI - Characterizing asthma in Qatar. PMID- 25528737 TI - FLG P478S polymorphisms and environmental risk factors for the atopic march in Taiwanese children: a prospective cohort study. AB - BACKGROUND: Little is known about the role of genetic and environmental modifiers in atopic march. OBJECTIVE: To investigate the effects of filaggrin (FLG) P478S polymorphisms and environmental factors on the risk of asthma in a cohort of children with atopic dermatitis (AD). METHODS: In 2010, 3,246 children from Childhood Environment and Allergic Diseases Cohort Study cohort were recruited. There were 485 children with AD who were invited for further clinical evaluation. Environmental exposures and skin prick tests for allergens were collected at 3 years of age and the development of asthma was determined at 6 years. Multivariate logistic regressions were performed to estimate the association between genetic and environmental factors and the development asthma in children with AD. RESULTS: Of 397 children with AD who completed the follow-up, 97 developed asthma. After controlling for potential confounders, only mite sensitizations (odds ratio 1.89, 95% confidence interval 1.10-3.25) and the FLG TT genotype (odds ratio 2.26, 95% confidence interval 1.33-3.84) were significantly associated with the development of asthma in children with AD. Mite sensitizations and FLG variants had a synergistic effect on the development of asthma. When children with FLG variants were exposed to mite, the risk for asthma was compounded compared with those with FLG variants without mite exposure (odds ratio 3.58, 95% confidence interval 1.81-7.08). CONCLUSION: Mite sensitization and the FLG TT genotype couldt be associated with the development of atopic march. PMID- 25528736 TI - Child with atopic dermatitis. PMID- 25528739 TI - Allergen of the month--Stemphylium. PMID- 25528738 TI - Omalizumab therapy for asthma patients with poor adherence to inhaled corticosteroid therapy. AB - BACKGROUND: Omalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy. OBJECTIVE: To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use. METHODS: Patients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV1) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV1 of 20% (PC20) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4 month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC20 was measured before and after each period. RESULTS: Fifteen patients completed the study. The mean baseline PC20 was 14.1 mg/mL (95% CI, 10.8-18.4 mg/mL). The fold change PC20 was 0.9 (95% CI, 0.5-1.7) during placebo and 3.1 (95% CI, 1.6-6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2-9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00-0.33) canisters per month. CONCLUSION: Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133042. PMID- 25528740 TI - ASICs and mammalian mechanoreceptor function. AB - It is well established that some members of the Deg/ENaC super family of amiloride sensitive ion channels can participate directly in the transduction of mechanical stimuli by sensory neurons in invertebrates. A large body of work has also implicated the acid sensing ion channels family (ASIC1-4) as participants in regulating mechanoreceptor sensitivity in vertebrates. In this review we provide an overview of the physiological and genetic evidence for involvement of ASICs in mechanosensory function. On balance, the available evidence favors the idea that these channels have an important regulatory role in mechanosensory function. It is striking how diverse the consequences of Asic gene deletion are on mechanosensory function with both gain and loss of function effects being observed depending on sensory neuron type. We conclude that other, as yet unknown, molecular partners of ASIC proteins may be decisive in determining their precise physiological role in mechanosensory neurons. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. PMID- 25528741 TI - Do tektites really date the bifaces from the Bose (Baise) Basin, Guangxi, southern China? PMID- 25528742 TI - Comparative study of high tibial osteotomy using dynamic axial fixator and locked low-profile plate in medial osteoarthritis of knee. AB - PURPOSE: The purpose of this study was to evaluate the role of medial opening wedge high tibial osteotomy (HTO) in medial unicompartmental osteoarthritis (MCOA) of knee and to compare between the two methods of osteotomy using either dynamic axial fixator (DAF) or locking compression plate (LCP). METHODS: A total of 20 patients with medial osteoarthritis of knee were enrolled in this prospective study who were divided into two groups of 10 each. First group comprising of two males and eight females were treated by HTO using DAF. Second group comprising of five males and five females were treated by HTO using LCP. We assessed various radiological parameters including hip knee ankle angle (HKA), tibiofemoral angle (TFA), weight-bearing line on tibia, Insall Salvati index and tibial slope. Functional outcome of knee at final follow-up was assessed by Oxford knee score (OKS) and visual analogue scale. RESULTS: In first group, mean HKA angle changed from 187 degrees to 178.30 degrees (p = 0.006), mean TFA from 182.40 degrees to 172 degrees (p = 0.003), average position of weight-bearing line from 11.24 to 59.54 % (p = 0.004), and mean OKS 43.3-16.9 (p = 0.004). In second group, mean HKA angle changed from 186 degrees to 178.80 degrees (p = 0.004), mean TFA from 180.90 degrees to 173.60 degrees (p = 0.004), average position of weight-bearing line from 14 to 61.3 % (p = 0.004), and mean OKS 43.2 16.5 (p = 0.002). CONCLUSION: HTO is an established treatment for patients with symptomatic MCOA knee with significant improvement in the clinical and radiographic parameters. There is no significant difference between the two methods; however, external fixator has the complication of pin tract infections. LEVEL OF EVIDENCE: II. PMID- 25528743 TI - A new tool predicting survival after radiosurgery alone for one or two cerebral metastases from lung cancer. AB - Radiosurgery is frequently used for patients with few cerebral metastases. Decisions regarding personalized treatment should include the patient's survival prognosis. Prognostic tools should be available for estimating the remaining lifetime for each primary tumor and treatment. We designed such a tool for patients receiving radiosurgery alone for cerebral metastases from lung cancer. Ten variables were analyzed in 98 patients. On multivariate analysis, extra cranial spread was significantly associated with worse survival (p < 0.001). A trend was observed for poorer performance status (p = 0.08) and greater diameter of cerebral lesions (p = 0.07). Points for the tool were derived from 12-month survival rates of these variables and added, resulting in sum scores of 10-16 points. Three groups were built, 10-12, 14-15, and 16 points with 12-month survival rates of 22, 52, and 79% (p < 0.001). This new tool enables physicians to estimate the survival of lung cancer patients with few cerebral metastases which should impact individualized treatment choices. PMID- 25528744 TI - Intermittency of aeolian saltation. AB - Saltation motion of sand grains in a steady wind was measured using a high-speed camera at very high frequency in a wind tunnel. A Heaviside-type function was defined to quantificationally describe an inherent property of saltation, i.e. intermittency. Kurtosis and periodicity of state function are statistical manifestations of intermittency. In addition, the strong autocorrelation of time series of volume concentration clearly confirms that saltation is not a completely random process at the timescale of subsecond. Formation mechanism, especially turbulent structures responsible for intermittent saltation, remains to be revealed from the viewpoint of classical mechanics. PMID- 25528746 TI - Insects associated with Jatropha curcas Linn. (Euphorbiaceae) in west Niger. AB - Jatropha curcas has been introduced into Niger since 2004 by International Crops Research Institute for the Semi-Arid Tropics (ICRISAT). This plant is cultivated for its oil, which can be used as a Biofuel. Through direct and indirect insect collection methods, an inventory of the insect associated with J. curcas has been conducted in Western Niger during two rainy seasons (from June to October) in 2010 and 2011. We have identified insects belonging to the following families: Acrididae (Oedaleus senegalensis Krauss, Oedaleus nigeriensis Uvarov, Heteracris leani Uvarov, Catantops stramineus Walker, Parga cyanoptera Uvarov, and Acanthacris ruficornis citrina Audinet-Serville), Pyrgomorphidae (Poekilocerus bufonius hieroglyphicus Klug), Cetoniidae (Pachnoda interrupta Olivier, Pachnoda marginata aurantia Herbst, Pachnoda sinuata Heinrich and McClain, and Rhabdotis sobrina Gory and Percheron), Meloidae (Decapotoma lunata Pallas), Pentatomidae (Agonoscelis versicoloratus Dallas, Nezara viridula Linn, and Antestia sp. Kirkaldy), Coreidae (Leptoglossus membranaceus Fabricius and Cletus trigonus Thunberg), and Scutelleridae (Calidea panaethiopica Kirkaldy). Origin and potential impact on J. curcas of all these insect species are presented and discussed. The lower insect's diversity indexes are observed in 2010 and 2011 for Niamey, Saga, and Gaya because of semi-arid character of the Sahelian area. PMID- 25528745 TI - Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. AB - BACKGROUND: This study aimed to determine 5-year efficacy of catheter ablation for persistent atrial fibrillation (AF) using AF termination as a procedural end point. METHODS AND RESULTS: One hundred fifty patients (57+/-10 years) underwent persistent AF ablation using a stepwise ablation approach (pulmonary vein isolation, electrogram-guided, and linear ablation) with the desired procedural end point being AF termination. Repeat ablation was performed for recurrent AF or atrial tachycardia. AF was terminated by ablation in 120 patients (80%). Arrhythmia-free survival rates after a single procedure were 35.3%+/-3.9%, 28.0%+/-3.7%, and 16.8%+/-3.2% at 1, 2, and 5 years, respectively. Arrhythmia free survival rates after the last procedure (mean 2.1+/-1.0 procedures) were 89.7%+/-2.5%, 79.8%+/-3.4%, and 62.9%+/-4.5%, at 1, 2, and 5 years, respectively. During a median follow-up of 58 (interquartile range, 43-73) months after the last ablation procedure, 97 of 150 (64.7%) patients remained in sinus rhythm without antiarrhythmic drugs. Another 14 (9.3%) patients maintained sinus rhythm after reinitiation of antiarrhythmic drugs, and an additional 15 (10.0%) patients regressed to paroxysmal recurrences only. Failure to terminate AF during the index procedure (hazard ratio 3.831; 95% confidence interval, 2.070-7.143; P<0.001), left atrial diameter>=50 mm (hazard ratio 2.083; 95% confidence interval, 1.078-4.016; P=0.03), continuous AF duration>=18 months (hazard ratio 1.984; 95% confidence interval, 1.024-3.846; P<0.04), and structural heart disease (hazard ratio 1.874; 95% confidence interval, 1.037-3.388; P=0.04) predicted arrhythmia recurrence. CONCLUSIONS: In patients with persistent AF, an ablation strategy aiming at AF termination is associated with freedom from arrhythmia recurrence in the majority of patients over a 5-year follow-up period. Procedural AF nontermination and specific baseline factors predict long-term outcome after ablation. PMID- 25528747 TI - Ants of the Florida Keys: species accounts, biogeography, and conservation (Hymenoptera: Formicidae). AB - As a tropical archipelago, the Florida Keys provide an ideal environment to examine the historic and short-term processes that structure and influence biological diversity. Through a new survey of the ants of the Florida Keys, we increase our knowledge of the number of species to 94 representing 34 genera and 8 subfamilies. Through detailed collection information, we provide an in depth picture of the distribution of each species across the Keys. On the basis of these data and information on the native and known distributions of each species, we confirm the historical trend toward continued immigration of nonnative species into the Florida Keys and present these findings in the context of the proportion of native to nonnative species. We find a similar number of species introduced from the Old World and Neotropical mainland and discuss the probable immigration of mainland Florida species during the exposure of the Florida Shelf during the last glacial episode and the subsequent isolation of some populations as sea level rose following the last glaciation. Lastly, we discuss the possible threats to these populations due to rapid climate change and other human influences. PMID- 25528748 TI - Temperature- and CO2-dependent life table parameters of Spodoptera litura (Noctuidae: Lepidoptera) on sunflower and prediction of pest scenarios. AB - Predicted increase in temperature and atmospheric CO2 concentration will influence the growth of crop plants and phytophagous insects. The present study, conducted at the Central Research Institute for Dryland Agriculture, Hyderabad, India, aimed at (1) construction of life tables at six constant temperatures viz., 20, 25, 27, 30, 33, and 35 +/- 0.5 degrees C for Spodoptera litura (Fabricius) (Noctuidae: Lepidoptera) reared on sunflower (Helianthus annus L.) grown under ambient and elevated CO2 (eCO2) (550 ppm) concentration in open top chambers and (2) prediction of the pest status in near future (NF) and distant future (DF) climate change scenarios at major sunflower growing locations of India. Significantly lower leaf nitrogen, higher carbon and higher relative proportion of carbon to nitrogen (C:N) were observed in sunflower foliage grown under eCO2 over ambient. Feeding trials conducted on sunflower foliage obtained from two CO2 conditions showed that the developmental time of S. litura (Egg to adult) declined with increase in temperature and was more evident at eCO2. Finite (lambda) and intrinsic rates of increase (r(m)), net reproductive rate (Ro), mean generation time, (T) and doubling time (DT) of S. litura increased significantly with temperature up to 27-30 degrees C and declined with further increase in temperature. Reduction of 'T' was observed from maximum value of 58 d at 20 degrees C to minimum of 24.9 d at 35 degrees C. The DT of population was higher (5.88 d) at 20 degrees C and lower (3.05 d) at 30 degrees C temperature of eCO2. The data on these life table parameters were plotted against temperature and two nonlinear models were developed separately for each of the CO2 conditions for predicting the pest scenarios. The NF and DF scenarios temperature data of four sunflower growing locations in India is based on PRECIS A1B emission scenario. It was predicted that increased 'rm', 'lambda', and 'Ro' and reduced 'T' would occur during NF and DF scenario over present period at all locations. The present results indicate that temperature and CO2 are vital in influencing the population growth of S. litura and pest incidence may possibly be higher in the future. PMID- 25528749 TI - Attractiveness of native mammal's feces of different trophic guilds to dung beetles (Coleoptera: Scarabaeinae). AB - Mammal feces are the primary food and nesting resource for the majority of dung beetle species, and larval development depends on the quantity and quality of that resource. Physiological necessities, competitive interactions, and resource sharing are common and suggest that dung beetles may show preferences for feces of greater nutritional quality, which may in turn impact beetle assemblages and community structure. This study investigated whether attractiveness of dung beetles to different resource (feces) types varies depending on mammal trophic guild and associated nutritional content. This study was conducted in Atlantic Forest fragments in the Parque Estadual da Serra do Tabuleiro, Santa Catarina, Brazil. To evaluate attractiveness, the feces of the carnivore Puma concolor, the omnivores Cerdocyon thous and Sapajus nigritus, and the herbivore Tapirus terrestris were utilized as bait. Dung was collected from zoo animals fed a standard diet. Sampling was performed in triplicate in five areas in the summer of 2013. Four pitfall traps were established in each area, and each trap was baited with one type of mammal feces. Food preference of the species was analyzed by calculating Rodgers' index for cafeteria-type experiments. In total, 426 individuals from 17 species were collected. Rodgers' index showed that omnivorous mammal feces (C. thous) were most attractive to all dung beetle species, although it is known that dung beetles are commonly opportunistic with respect to search for and allocation of food resources. These results suggest that mammal loss could alter competitive interactions between dung beetles. PMID- 25528750 TI - Identification and expression analysis of QM-like gene from Spodoptera litura after challenge by the entomopathogenic fungus Nomuraea rileyi. AB - A partial sequence of QM homologue was isolated from a Spodoptera litura fatbody suppression subtractive hybridization library. The full-length Spodoptera litura QM (SpLQM) cDNA of 838 bp contains a 5' untranslated region (UTR) of 112 bp, a 3' UTR of 66 bp, and an open reading frame of 660 nucleotides coding for a 219 amino acid peptide with a molecular weight of 25.5 kDa. Analysis of SpLQM sequence revealed the presence of characteristic motifs, including the ribosomal protein L10 signature and SH3-binding motif. Multiple alignment analysis revealed that SpLQM shares an overall identity of 57.1-99.1% with other members of QM family. Phylogenetic analysis confirmed that SpLQM is closely related to other insect QMs. Analysis of the tissue expression pattern showed that the SpLQM mRNA was expressed in all tissues tested, with highest levels measured in hemocytes, followed by fat bodies. Upon Nomuraea rileyi challenge, SpLQM showed significant upregulation in fat bodies and hemocytes, while slightly upregulation in midguts. The results suggest that SpLQM might play an important role in the innate immunity of S. litura in response to N. rileyi infection. SpLQM was also successfully overexpressed in Escherichia coli, and the recombinant fusion protein SpLQM-His has a molecular weight of 32 kDa. PMID- 25528751 TI - Recognition and binding of the PF2 lectin to alpha-amylase from Zabrotes subfasciatus (Coleoptera:Bruchidae) larval midgut. AB - Amylases are an important family of enzymes involved in insect carbohydrate metabolism that are required for the survival of insect larvae. For this reason, enzymes from starch-dependent insects are targets for insecticidal control. PF2 (Olneya tesota) is a lectin that is toxic to Zabrotes subfasciatus (Coleoptera: Bruchidae) larvae. In this study, we evaluated recognition of the PF2 lectin to alpha-amylases from Z. subfasciatus midgut and the effect of PF2 on alpha-amylase activity. PF2 caused a decrease of total amylase activity in vitro. Subsequently, several alpha-amylase isoforms were isolated from insect midgut tissues using ion exchange chromatography. Three enzyme isoforms were verified by an in-gel assay for amylase activity; however, only one isoform was recognized by antiamylase serum and PF2. The identity of this Z. subfasciatus alpha-amylase was confirmed by liquid chromatography-tandem mass spectrometry. The findings strongly suggest that a glycosylated alpha-amylase isoform from larval Z. subfasciatus midgut interacts with PF2, which interferes with starch digestion. PMID- 25528752 TI - Open and disturbed habitats support higher diversity of Syrphidae (Diptera)? A case study during three yr of sampling in a fragment of Araucaria forest in southern Brazil. AB - The diversity of hoverflies in five different habitats of the Parque Estadual de Vila Velha, Ponta Grossa, Parana, Brazil, from September 1999 to August 2002 was studied. These five areas had been exposed to various types of anthropogenic disturbance at different times, which resulted in different stages of plant succession. In total, 2,841 specimens of 151 species of Syrphidae were collected using malaise traps. The highest species richness and abundance were found at the edge of the forest (Forest Edge), whereas the lowest was found in the most conserved areas. Evenness values increased along the succession gradient. The accumulation curve of new occurrences of syrphid species nearly approached an asymptote starting on the third month of the third year. Estimates of syrphid species richness using different methods indicated that between 155 and 288 species are found in the study area, according the Michaelis-Menten and the Chao2 estimators, respectively. The richness and abundance of representatives of the subfamily Syrphinae were higher in more open areas, where herbaceous plants predominate. Nineteen hoverfly species can be considered as environmental indicators, as they were collected exclusively or mainly in one of the defined habitat types. The degree of opening of the vegetation seems to be the factor determining the distribution of Syrphidae species, a conclusion based on the finding that grassy clearings in Araucaria Forests had more species. Hence, we conclude that, to become established, Syrphidae communities need conserved mosaic landscapes. PMID- 25528753 TI - Canopy vegetation influences ant (Hymenoptera: Formicidae) communities in headwater stream riparian zones of central Appalachia. AB - In the eastern United States, eastern hemlock Tusga canadensis (L.) Carriere forests are threatened by the invasive hemlock woolly adelgid, Adelges tsugae, a pest that is causing widespread hemlock mortality. Eastern hemlock is an essential component of forested communities. Adelgid-induced hemlock mortality is causing a shift in forest composition and structure, altering ecosystem function and thereby influencing the arthropod community. Using pitfall traps at three sites, we monitored ground-dwelling arthropods at 30-d intervals in hemlock dominated and deciduous-dominated forests in central Appalachia over 2 yr. Here, we focus on the ant community (Hymenoptera: Formicidae) collected in the summer months. Ants form a ubiquitous and integral component of the invertebrate community, functioning at various trophic levels as predators, herbivores, and omnivores, and fulfilling important roles in forest ecosystems. We found no difference in overall ant abundance between hemlock-dominated and deciduous dominated forests but did detect significant differences in the genera Prenolepis between forest types (P < 0.01) and Aphaenogaster across study locations (P = 0.02). Three genera were unique to deciduous forests; one was unique to hemlock forests. Not surprisingly, total formicids and several genera demonstrated temporal differences in abundance, with greater numbers captured in July than in August. As hemlock woolly adelgid-induced mortality of eastern hemlock becomes more pervasive, changes in forest composition and structure are imminent, accompanied by shifts in hemlock associates. PMID- 25528754 TI - The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis. AB - Perlecan is a major heparan sulfate (HS) proteoglycan in the arterial wall. Previous studies have linked it to atherosclerosis. Perlecan contains a core protein and three HS side chains. Its core protein has five domains (DI-DV) with disparate structures and DII is highly homologous to the ligand-binding portion of LDL receptor (LDLR). The functional significance of this domain has been unknown. Here, we show that perlecan DII interacts with LDL. Importantly, the interaction largely relies on O-linked glycans that are only present in the secreted DII. Among the five repeat units of DII, most of the glycosylation sites are from the second unit, which is highly divergent and rich in serine and threonine, but has no cysteine residues. Interestingly, most of the glycans are capped by the negatively charged sialic acids, which are critical for LDL binding. We further demonstrate an additive effect of HS and DII on LDL binding. Unlike LDLR, which directs LDL uptake through endocytosis, this study uncovers a novel feature of the perlecan LDLR-like DII in receptor-mediated lipoprotein retention, which depends on its glycosylation. Thus, perlecan glycosylation may play a role in the early LDL retention during the development of atherosclerosis. PMID- 25528757 TI - Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. AB - OBJECTIVES: Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia. METHODS: All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I (2) and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure. RESULTS: 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: -0.579 (-0.755 to -0.404); antidepressants: -0.349 (-0.551 to -0.146); combinations of pharmacological agents: -0.518 (-0.757 to -0.279); glutamatergic medications: -0.289 (-0.478 to 0.1); psychological interventions: -0.396 (-0.563 to -0.229). No significant effect was found for first-generation antipsychotics: -0.531 (-1.104 to 0.041) and brain stimulation: -0.228 (-0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale. CONCLUSIONS AND RELEVANCE: Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement. PMID- 25528755 TI - A cancer theory kerfuffle can lead to new lines of research. AB - The standard viewpoint that cancer is a genetic disease is often stated as a fact rather than a theory. By not acknowledging that it is a theory, namely the Somatic Mutation Theory (SMT), researchers are limiting their progress. An attractive alternative to SMT is the tissue organization field theory (TOFT), which is summarized as "development gone awry." To initiate a kerfuffle, I discuss the interpretation of various results under both TOFT and SMT, including recurrent mutations, hereditary cancers, induction of tumors in transgenic experiments, remission of tumors following the inhibition of enzymes activated by mutated genes, nongenotoxic carcinogens, denervation experiments, foreign-body carcinogenesis, transplantation experiments, and tumors with zero mutations. Thinking in terms of TOFT can spur new lines of research; examples are given related to the early detection of cancer. PMID- 25528758 TI - Impact of DSM-5 changes on the diagnosis and acute treatment of schizophrenia. AB - OBJECTIVE: To examine the consequences and validity of changes in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnostic criteria for schizophrenia, eg, omission of subtypes, using a large dataset of double-blind, randomized, placebo-controlled schizophrenia trials. METHODS: Data from 22 short term efficacy registration trials of second generation antipsychotics for the treatment of acute psychotic episodes in patients with schizophrenia (N = 5233), submitted to the Dutch regulatory authority were analyzed. We examined whether patients in these pre-DSM-5 trials met the diagnostic criteria for schizophrenia according to DSM-5. Using linear regression, we examined differences in effect size between DSM-IV subtypes and between DSM-5 symptom dimensions. RESULTS: Over 99.5% of the patients met DSM-5 diagnostic criteria for schizophrenia and no differences in effect size were found between schizophrenia subtypes (P = .65). Symptom dimensions that respond best to treatment with second generation antipsychotics were hallucinations, delusions, disorganized speech, and mania (Hedge's g -0.23 to -0.31). CONCLUSIONS: Results of clinical trials in patients with pre-DSM-5 schizophrenia also apply to patients diagnosed with DSM-5 schizophrenia. Omission of the classic subtypes is justified as they are not predictive of response to treatment. The DSM-5 C-RDPSS scale adds valuable information to the categorical diagnosis of schizophrenia, which is relevant for antipsychotic response. PMID- 25528760 TI - Low testosterone in a young combat veteran with dual diagnosis and suicidal behavior: a case study. AB - Suicide and suicidal behaviors amongst combat veterans is an important public health issue. Exposure to military combat predisposes patients to increased levels of major depression, post-traumatic stress disorder (PTSD), substance abuse, and chronic pain - all of which are important risk factors for suicide. Here, we present a case study of a young combat veteran who presented with an impulsive suicide attempt that had a high potential for lethality in the context of depression, PTSD, and substance use. On routine admission laboratory work, his serum level of testosterone was seen to be low. Given the important role that testosterone plays in the regulation of mood and behavior, we posit that it is a potentially important marker for suicide risk in an already at-risk population. PMID- 25528759 TI - The Stress of the Street for Patients With Persecutory Delusions: A Test of the Symptomatic and Psychological Effects of Going Outside Into a Busy Urban Area. AB - BACKGROUND: For many patients with persecutory delusions, leaving home and going into crowded streets is a key clinical problem. In this study we aimed to inform treatment development by determining the psychological mechanisms whereby busy urban environments increase paranoia. In a randomized design with prespecified mediation analysis, we compared the effects on patients of going outside into a busy social environment with staying inside. METHODS: Fifty-nine patients with current persecutory delusions, in the context of nonaffective psychosis, reporting fears when going outside were assessed on factors from a cognitive model of paranoia. They were then randomized either to enter a busy local shopping street or to complete a neutral task indoors. They were then reassessed on the measures. RESULTS: Compared with staying inside, the street exposure condition resulted in significant increases in paranoia, voices, anxiety, negative beliefs about the self, and negative beliefs about others. There was also a decrease in positive thoughts about the self. There was no alteration in reasoning processes. There were indications that the increase in paranoia was partially mediated by increases in anxiety (45%), depression (38%), and negative beliefs about others (45%). CONCLUSIONS: We found that increases in negative affect may form an important route by which social exposure in urban environments triggers paranoid thoughts. The study provides an illustration of how an experimental approach can be applied to help understand a specific difficulty for patients with psychosis. In future studies the effects of specific elements of the social environment could be tested. PMID- 25528761 TI - Neuroprotective effects of hydrogen sulfide and the underlying signaling pathways. AB - Hydrogen sulfide (H2S) is an endogenously produced gas that represents a novel third gaseous signaling molecule, neurotransmitter and cytoprotectant. Cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), 3 mercaptopyruvate sulfur transferase with cysteine aminotransferase (3-MST/CAT) and 3-mercaptopyruvate sulfur transferase with d-amino acid oxidase (3-MST/DAO) pathways are involved in the generation of endogenous H2S despite the ubiquitous or restricted distribution of those enzymes. CBS, 3-MST/CAT and 3-MST/DAO can be found in the brain, while CSE is widely located in other organs. There also exist up-taking or recycling and scavenging mechanisms in H2S metabolism to maintain its persistence for physiological function. In recent years, investigating the role that H2S plays in the central nervous system and cardiovascular system has always been a hotspot. To date, effects of H2S are at least partially verified in multiple animal models or neuron cell lines of Alzheimer's disease, Parkinson's disease, cerebral ischemia, major depression disorders and febrile seizure, although subsequent studies are still badly needed. This article presents an overview of current knowledge of H2S focusing on its neuroprotective effects and corresponding signaling pathways, together with connections to potential therapeutic strategies in the clinic. PMID- 25528762 TI - Astroglial control of neuroinflammation: TLR3-mediated dsRNA-sensing pathways are in the focus. AB - Neuroinflammation is as an important component of pathogenesis in many types of brain pathology. Immune mechanisms regulate neuroplasticity, memory formation, neurogenesis, behavior, brain development, cognitive functions, and brain metabolism. It is generally believed that essential homeostatic functions of astrocytes - astroglia-neuron metabolic coupling, gliovascular control, regulation of proliferation, and migration of cells in the neurogenic niches - are compromised in neuroinflammation resulting in excitotoxicity, neuronal and glial cell death, and alterations of intercellular communication. Viral neuroinfection, release of non-coding RNAs from the cells at the sites of brain injury or degeneration, and application of siRNA or RNA aptamers as therapeutic agents would require dsRNA-sensing pathways in the cells of neuronal and non neuronal origin. In this review, we analyze the data regarding the role of astrocytes in dsRNA-initiated innate immune response in neuroinflammation and their contribution to progression of neurodegenerative and neurodevelopmental pathology. PMID- 25528763 TI - Inhibition of spontaneous and experimental lung metastasis of soft-tissue sarcoma by tumor-targeting Salmonella typhimurium A1-R. AB - Prognosis of patients with lung metastases of soft-tissue sarcoma is still poor. Therefore, novel systemic therapy is needed to improve the survival of soft tissue sarcoma. In the present study, tumor-targeting therapy with a genetically modified auxotrophic strain of Salmonella typhimurium, termed A1-R, was evaluated. Mouse models of primary soft tissue sarcoma and spontaneous lung metastasis were obtained by orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells. S. typhimurium A1-R was administered from day 14, once a week for two weeks. On day 28, lung samples were excised and observed with a fluorescence imaging system. The number of lung metastasis was 8.8 +/- 3.4 in the untreated group and 0.8 +/- 0.8 in the treated group (P = 0.024). A mouse model of experimental lung metastasis was obtained by tail vein injection of HT1080-RFP cells. The mice were treated with S. typhimurium A1-R (i.v.) on day 7, once a week for three weeks. S. typhimurium A1-R significantly reduced lung metastases and improved overall survival (P = 0.004). S. typhimurium A1-R bacterial therapy has future potential for treating advanced soft tissue sarcoma and improving prognosis of patients with lung metastasis. PMID- 25528764 TI - The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma. AB - New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79-2.13 MUmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5-6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES. PMID- 25528765 TI - The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer. AB - Elucidating the mechanisms that underlie metastasis is of paramount importance to understanding tumor progression and to the development of novel therapeutics. Epithelial to Mesenchymal Transition (EMT) plays a vital role in tumor cell dissemination and is regulated by a core cassette of transcription factors. Despite recent advances, the molecular pathways that regulate the EMT program have not yet been fully delineated. We show that Siah ubiquitin ligases regulate Zeb1 protein, a key EMT transcription factor. The induction of EMT in breast cancer cells leads to the down-regulation of Siah, while the loss of Siah induces a mesenchymal phenotype, concurrent with an up-regulation of Zeb1. Overexpression of Siah in vitro mediates Zeb1 degradation, which can be blocked with a Siah peptide inhibitor. Thus, this work demonstrates that Siah is a novel regulator of EMT. This work is the first to identify a mechanism of post-translational regulation of the key Epithelial to Mesenchymal Transition transcription factor Zeb1. PMID- 25528766 TI - IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment. AB - IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1beta, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis. gp130757FF xIL-1RT1-/- mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130757FF mouse model of gastric tumorigenesis. Gastric lesions in gp130757FF xIL-1RT1-/- mice were increased in incidence and size compared to gp130757FF mice. Proximal gastric lesions originated from the cardiac region and were associated with elevated STAT3 activation, loss of specialized gastric cells and a modulated immune response including increased expression of TNF-alpha and MDSC associated genes. Administration of IL-11 to IL-1RT1-/- mice showed similar changes to gp130757FF xIL-1RT1-/- mice. Spleens from IL-11 treated wildtype mice showed an enrichment of MDSC and gp130757FF xIL-1RT1-/- mice had increased MDSCs in the stomach compared to gp130757FF mice. Furthermore, crossing TNF-alpha-/- to gp130757FF mice resulted in reduced lesion size. We conclude that IL-1 signaling antagonizes IL-11/STAT3 mediated pathology and the genetic deletion of IL-1RT1 results in increased tumor burden. We provide evidence that a likely mechanism is due to IL-11/STAT3 dependent enrichment of MDSCs. PMID- 25528767 TI - Mitochondrial p32 is upregulated in Myc expressing brain cancers and mediates glutamine addiction. AB - Metabolic reprogramming is a key feature of tumorigenesis that is controlled by oncogenes. Enhanced utilization of glucose and glutamine are the best-established hallmarks of tumor metabolism. The oncogene c-Myc is one of the major players responsible for this metabolic alteration. However, the molecular mechanisms involved in Myc-induced metabolic reprogramming are not well defined. Here we identify p32, a mitochondrial protein known to play a role in the expression of mitochondrial respiratory chain complexes, as a critical player in Myc-induced glutamine addiction. We show that p32 is a direct transcriptional target of Myc and that high level of Myc in malignant brain cancers correlates with high expression of p32. Attenuation of p32 expression reduced growth rate of glioma cells expressing Myc and impaired tumor formation in vivo. Loss of p32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal. Finally, we provide evidence that p32 expression contributes to Myc-induced glutamine addiction of cancer cells. Our findings suggest that Myc promotes the expression of p32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells. PMID- 25528768 TI - Higher mortality and impaired elimination of bacteria in aged mice after intracerebral infection with E. coli are associated with an age-related decline of microglia and macrophage functions. AB - Incidence and mortality of bacterial meningitis are strongly increased in aged compared to younger adults demanding new strategies to improve prevention and therapy of bacterial central nervous system (CNS) infections the elderly. Here, we established a geriatric mouse model for an intracerebral E. coli infection which reflects the clinical situation in aged patients: After intracerebral challenge with E. coli K1, aged mice showed a higher mortality, a faster development of clinical symptoms, and a more pronounced weight loss. Elimination of bacteria and systemic inflammatory response were impaired in aged mice, however, the number of infiltrating leukocytes and microglial cells in the CNS of aged and young mice did not differ substantially. In vitro, primary microglial cells and peritoneal macrophages from aged mice phagocytosed less E. coli and released less NO and cyto-/chemokines compared to cells from young mice both without activation and after stimulation by agonists of TLR 2, 4, and 9. Our results suggest that the age-related decline of microglia and macrophage functions plays an essential role for the higher susceptibility of aged mice to intracerebral infections. Strategies to improve the phagocytic potential of aged microglial cells and macrophages appear promising for prevention and treatment of CNS infections in elderly patients. PMID- 25528769 TI - TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer. AB - Tumor budding in colorectal cancer is likened to an epithelial-mesenchymal transition (EMT) characterized predominantly by loss of E-cadherin and up regulation of E-cadherin repressors like TWIST1 and TWIST2. Here we investigate a possible epigenetic link between TWIST proteins and the tumor budding phenotype. TWIST1 and TWIST2 promoter methylation and protein expression were investigated in six cell lines and further correlated with tumor budding in patient cohort 1 (n = 185). Patient cohort 2 (n = 112) was used to assess prognostic effects. Laser capture microdissection (LCM) of tumor epithelium and stroma from low- and high-grade budding cancers was performed. In colorectal cancers, TWIST1 and TWIST2 expression was essentially restricted to stromal cells. LCM results of a high-grade budding case show positive TWIST1 and TWIST2 stroma and no methylation, while the low-grade budding case was characterized by negative stroma and strong hypermethylation. TWIST1 stromal cell staining was associated with adverse features like more advanced pT (p = 0.0044), lymph node metastasis (p = 0.0301), lymphatic vessel invasion (p = 0.0373), perineural invasion (p = 0.0109) and worse overall survival time (p = 0.0226). Stromal cells may influence tumor budding in colorectal cancers through expression of TWIST1. Hypermethylation of the tumor stroma may represent an alternative mechanism for regulation of TWIST1. PMID- 25528772 TI - Massive electrical storm at disease onset in a patient with Brugada syndrome. AB - BACKGROUND: Brugada syndrome (BrS) is a genetic arrhythmogenic disease characterized by ST-segment elevations in the right precordial leads of the electrocardiogram (ECG). These ECG changes may be concealed and BrS may present with electrical storm characterized by recurrent ventricular tachycardia and fibrillation. CASE REPORT: A 49-year-old previously healthy man was admitted with electrical storm. The patient received direct current (DC) cardioversion shocks and only after intravenous lidocaine did the electrical storm slowly subside with a total of 255 DC shocks administered during the first 24 h after admission. He fully recovered and received an implantable cardioverter-defibrillator. Subsequent drug challenge with flecainide revealed type 1 BrS. CONCLUSIONS: Massive electrical storm can be the first symptom of BrS and the diagnostic ECG changes may be concealed at presentation. Although hundreds of DC shocks may be required during initial treatment, full recovery can be achieved. PMID- 25528770 TI - Short-hairpin RNA library: identification of therapeutic partners for gefitinib resistant non-small cell lung cancer. AB - Somatic mutations of the epidermal growth factor receptor often cause resistance to therapy with tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). In this study, we aimed to identify partner drugs and pathways that can induce cell death in combination with gefitinib in NSCLC cells. We undertook a genome wide RNAi screen to identify synthetic lethality with gefitinib in tyrosine kinase inhibitor resistant cells. The screening data were utilized in different approaches. Firstly, we identified PRKCSH as a candidate gene, silencing of which induces apoptosis of NSCLC cells treated with gefitinib. Next, in an in silico gene signature pathway analysis of shRNA library data, a strong correlation of genes involved in the CD27 signaling cascade was observed. We showed that the combination of dasatinib (NF-kappaB pathway inhibitor) with gefitinib synergistically inhibited the growth of NSCLC cells. Lastly, utilizing the Connectivity Map, thioridazine was identified as a top pharmaceutical perturbagen. In our experiments, it synergized with gefitinib to reduce p-Akt levels and to induce apoptosis in NSCLC cells. Taken together, a pooled short hairpin library screen identified several potential pathways and drugs that can be therapeutic targets for gefitinib resistant NSCLC. PMID- 25528771 TI - Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells. AB - Increased glucose metabolism is now recognized as an emerging hallmark of cancer. Recent studies have shown that glucose metabolism is even more active in cancer stem cells (CSCs), a rare population of cancer cells with the capacity to self renew and initiate tumors, and that CSCs are dependent on glycolysis for their survival/growth. However, the role of glucose metabolism in the control of their self-renewal and tumor-initiating capacity per se still remains obscure. Moreover, much remains unknown as to which of the numerous molecules involved in the glucose metabolism is suitable as a target to control CSCs. Here we demonstrate that the facilitative glucose transporter GLUT1 is essential for the maintenance of pancreatic, ovarian, and glioblastoma CSCs. Notably, we found that WZB117, a specific GLUT1 inhibitor, could inhibit the self-renewal and tumor initiating capacity of the CSCs without compromising their proliferative potential in vitro. In vivo, systemic WZB117 administration inhibited tumor initiation after implantation of CSCs without causing significant adverse events in host animals. Our findings indicate GLUT1-dependent glucose metabolism has a pivotal role not only in the growth and survival of CSCs but also in the maintenance of their stemness and suggest GLUT1 as a promising target for CSC directed cancer therapy. PMID- 25528773 TI - [Liver, pancreas, biliary tract cancer]. PMID- 25528774 TI - [Liver, pancreas, biliary tract cancer. II. Current Status of Combined Vascular Resection for Perihilar Cholangiocarcinoma]. PMID- 25528775 TI - [Liver, pancreas, biliary tract cancer. I. Surgical treatment of hepatocellular carcinoma associated with vascular tumor thrombosis]. PMID- 25528776 TI - [Liver, pancreas, biliary tract cancer. III. Pancreatectomy with Vascular Resection for Locally Advanced Pancreatic Cancer]. PMID- 25528777 TI - [Aortic valve replacement: effective office area as a predictor of surgical treatment results]. PMID- 25528778 TI - [Objectifying of investigation results of patients with coronary artery disease]. PMID- 25528779 TI - [Radiofrequency ablation in treatment of thyroid gland nodules]. PMID- 25528780 TI - The upside--and downside--of outpatient surgery: Joan Rivers' death is a reminder that you should carefully look before you book. PMID- 25528781 TI - The truth about gluten. PMID- 25528782 TI - [Modern strategies of surgical treatment of aortic arch aneurysms]. PMID- 25528783 TI - [Accelerated rehabilitation of patients after pancreatic resection]. PMID- 25528784 TI - Findings of research misconduct. PMID- 25528785 TI - Findings of research misconduct. PMID- 25528786 TI - Authors' reply. PMID- 25528787 TI - Authors' reply. PMID- 25528788 TI - Authors' reply. PMID- 25528789 TI - Authors' reply. PMID- 25528790 TI - Authors' reply. PMID- 25528791 TI - [Charlotte Jacobs 1847 - 1916. First female pharmacist in the Netherlands and the Dutch East Indies]. PMID- 25528792 TI - [250 years (city) pharmacists in Dordrecht, the Netherlands]. PMID- 25528793 TI - [Paul Janssen (1926-2003) physician, medical chemist, entrepreneur, active in China]. PMID- 25528794 TI - [Pharmacists and their customers in the Bourgongne realm]. PMID- 25528795 TI - [Actual aspects in the pharmacology of the narcotic analgesics]. PMID- 25528796 TI - [The medical--recovering treatment of pain]. PMID- 25528797 TI - [Up-date in the renin-angiotensin system. 1) Peculiarities in children]. PMID- 25528798 TI - [Epidemiology of the nutritional diseases. IV) Obesity]. PMID- 25528800 TI - [Esophageal motor disturbances in sclerodermia]. AB - By the manometric method the esophageal motility in 14 patients with sclerodermia was studied. All patients presented an esophageal motor dysfunction characterized by the decrease in amplitude of the spohageal contractions, presence of aperistaltic contractions, decrease of basal pressure of the lower esophageal sphincter and its incomplete relaxation at deglutition. These esophageal motor disturbances may appear in association or separately in the same patient. The pathogenesis of the esophageal motor dysfunction in sclerodermia is not yet fully understood. Besides the theoretical interest, the knowledge of the esophageal motor dysfunction in sclerodermia has also a practical value in respect of the tretment which is to be set up. PMID- 25528799 TI - [The Oradea study regarding the epidemiology factors in ischemic cardiopathy]. AB - Cholesterolemia in a population of 100482 inhabitants of the Bihor district, subjected to screening for the risk factors in ischemic cardiopathy were studied. Together with hyperlipidemias other risk factors were detected: arterial hypertension, obesity, diabetes mellitus, smoking, ischemic alterations of the electrocardiogram, the influence of the noxious agents present at the working place, of the blood groups and disturbances of the menstrual cycle. The mean cholesteremia is of 205 +/- 43.7 mgr% (M = 207 +/- 43.7 mgr%; F = 204 +/- 43.5 mgr%). The prevalence of cholesterolemia, in comparison with the higher normal limits in each age group over 15 years of age, is in the entire studied series, of 13.5%. The population in whom cholesterolemia exceeds 250 mgr% represents 13.92%. PMID- 25528801 TI - [Anatomo-clinical observations of the splenic reaction (splenomegaly) occuring in fulminant-comatose forms of acute viral hepatitis]. AB - Statistical analysis of 80 cases of fulminant-comatose forms of acute viral hepatitis revealed a frequency of 13.7% of splenic hypertrophy as compared to a frequency of 50.6% in 87 common forms of illness. The intensity and frequency of the splenic reaction in the two studied series shows an agreement between the data of the clinical examination--splenic palpability--and the anatomo pathological ones--splenic weight in grams at necropsy being in inverse ratio to aging. Thus, between the prognostical benignity of the fulminant-comatose forms and the intensity of the splenic reaction appears to be a direct relation. PMID- 25528802 TI - [Peculiarities of the surgical treatment of thyrotoxicosis in the aged]. AB - With an increasing frequency, recorded by most of the statistics, the thyrotoxicosis of the aged present themselves, most often, under uncharacteristic clinical aspects, often delusive. Out of a series of 37 thyrotoxic patients (representing 9.2% of all cases of thyrotoxicosis admitted to the Ist Surgical Clinic between 1970 and 1980) in 27 cases we performed a the surgical treatmeat with good immediate and late results. As a preliminary, execepting the endocrine balancing the improvement of the respiratory exchanges, the compensation of the possible heart disturbances and the ensurance of a good hydration and restoring of the nutritional state were followed. PMID- 25528803 TI - [Considerations on scolioses recuperation]. AB - The authors present their own experience in the intersomatic arthrodesis for severe scolioses, with or without means of osteosynthesis. The indication for this intervention is justified only as an atribute of absolute "vital indication". This surgery is far-reaching, requires an accurate technique, well adjusted instruments and conditions of advanced intensive care. The results were satisfactory both for the correction of the gibbosity but especially for the functional recuperation of the restrictive, respiratory insufficiency. 45 patients, out of whom 9 required an arthrodesis with an original model of thready rod, benefited from anl intersomatic osteotomy. We noticed that a progressive correction of the primitive upper concavity can be obtained by a osteotomy not larger than 4 disks; the patients to whom a spring for permanent compression was set profited by a satisfactory progressive correction. PMID- 25528804 TI - [Treatment of duodenal ulcer by hyperselective vagotomy]. AB - In the treatment of duodenal ulcer the hyperselective vagotomy is recommended by the authors. On the other hand it has indications and contraindications which must be taken into account. The rational attitude is that of a differentiated surgical treatment, in which the various methods, classical gastrectomy included, find their indication from case to case. PMID- 25528805 TI - [Entero-urinary fistula]. AB - A patient with an entero-urinary fistula who underwent 5 surgical interventions before being admitted to our clinic is presented. At the admittance it was specified that it is an enterourinary fistula, but the repeated investigations showed that it is an ulceration situated on the posterior wall of the descending colon, at its junction with the sigmoid, from which two fistulas come out: one towards the urinary bladder and the other towards the left iliac fossa. After debridement of the fistulas the segmentary colectomy and immediate restoration of the transit were performed. In the immediate evolution a stercoral fistula, closing itself spontaneously, reappeared. The late examination showed normal colon and urinary system without clinical alterations. PMID- 25528806 TI - Lower oesophageal sphincter pressure during early pregnancy: manometric studies before and after abortion. AB - Resting lower oesophageal sphincter pressure (L.O.S.P.) was determined in 14 pregnant women with heartburn and 12 pregnant women without heartburn before (10 to 18 weeks of gestation) and in the first week after an elective abortion. Mean L.O.S.P. in pregnant women with heartburn was 11.5 +/- 1.5 mm Hg before and 17.3 +/- 1.8 mm Hg after abortion, the difference being statistically significant (p < 0.001). In the group of pregnant women without heartburn the mean resting L.O.S.P. before and after abortion was not significantly different. Although the exact mechanism by which gastro-oesophageal reflux occurs during early pregnancy is not entirely understood, it appears that hormonal changes (elevated serum concentrations of progesterone and oestrogens) play a major role by depressing L.O.S., the main antireflux barrier. PMID- 25528807 TI - Anesthetic management of pheochromocytoma. A report on sixteen cases. PMID- 25528808 TI - [The hand, foot and mouth disease. Clinical premiere in our country]. AB - In May 1981 the hand, foot and mouth disease was diagnosed for the first time in Ramaia in a 4 year old child. The onset of the disease was characterized by moderate fever, coryza and spontaneous endobuccal pains followed at a short interval of time by the simultaneous of a papulo-vesicular eruption on hands and feet. The eruption was prevalent on the hands and feet fingers as well as on the palmar and plantar regions. Isolated aphthous lesions were seen on the vestibular mucosa. Morphologically, the intraepidermic site of the lesion with an advanced acantholytic process in the vesicular area was noticed. In the superficial and deep tissue perivascular infiltrate with mononucleares were present. PMID- 25528809 TI - [Sensivity of some enzymes in Guerin tumours after the administration of Nystatin MC]. AB - In the animals with a 24 hours and 15 days transplant of Guerin lymphotropic epithelioma Nystatin MC in a dose of 800 mg/K body weight/day and 1 800 mg/K body weight/day every 3 and 6 hours daily for 8 days was injected subcutaneously. The dosing of the activity of gluthamin-synthetase, MDH and catalase in tumours of 8, 23, and 38 days showed that Nystatin MC disturbed the activity of the enzymes from mythocondries and cytoplasm especially in the 8 and 23 days tumours, influencing the glycolitic process. The gluthamin-synthesis was inhibited during the entire tumoral activity period, reaching after treatment almost normal values. Cytoplasmic MDH was influenced by the treatment in relation with the age of the tumour and the used dose. I PMID- 25528810 TI - The membrane level of procaine pharmacology. AB - In almost all the pharmacological effects of procaine, the biological membranes are invoked as final target of the drug. The membrane impact could be an interaction (generally, a specific one) with a membrane receptor (a protein-like biomolecule-enzyme, carrier, pharmacological or hormonal receptor, etc.) or a nonspecific interaction with membrane lipids, alterring their structure and dynamics. These two different mechanisms are discussed in the light of the experimental results obtained from studies on model systems (artificial membranes liposomes), on neuronal, muscular, erythrocytar and bacterial membranes. Finally, some considerations are made about the connexion with membrane changing in aging organisms. PMID- 25528811 TI - [The activity of certain enzymes of gluconegenesis in rabbit brain and liver intoxicated by CS2]. AB - The carbon disulphide (CS) administrated chronic to rabbit produced an important inhibition of glucose-6-phosphate phosphohyrolase and fructose-1,6-diphosphate phosphoydrolase activity in brain and liver. The decrease of theses two enzymes of gluconeogenetic cycle seem to justify certain physiological and clinical changes of the neuropsychic and hepatic activity observed in the intoxication by CS2. PMID- 25528812 TI - [The effects of dental contacts in terminal occlusion]. PMID- 25528813 TI - [Periodontal alterations in patients with hepatic cirrhosis. Note II]. AB - Following up the evolution of a series of 85 patients with hepatic cirrhosis, a number of alterations concerning the whole maxillo-facial area and especially the marginal periodontium in a proportion of 93%, were noticed. A direct relation between the status of the marginal periodontium and the degree of hepatic affection could be established. The clinical alterations at the level of periodontium were in keeping with the histological and biochemical ones, fact resulting from the complementary examinations (amino-acids, G.D.H. and L.D.H. emzymes and seric proteins determinations) performed at the level of liver and periodontal tissue, both in animals and in cirrhotic patients. PMID- 25528814 TI - Radiological differentiation of renal masses. AB - This study analyse the performance of radiological investigation in differentiation of Renal Masses (R.M.) based on author's experience in 54 verified cases. In autor's technological conditions (Scanner and Ultrasounds absense), the procedures available for the discrimination of R.M. include only: plain radiography, urography, pyelography, nephrotomography and selective renal angiography. The discussion about the value of each procedure is conclusive; urography is a very poor method for discrimination but acceptable as a first step investigation: Renal Angiography--at this moment the better radiological method available for R.M. differentiation, will probably be replaced within a few years by Computer Tomodensimetry, because of its highest preision and innocuity. PMID- 25528815 TI - [Studies reagarding the bioavailability of oxacillin from preconditioned powders]. AB - Previous studies have pointed out a good antimicrobial activity of two oxacillin salts--DBED--oxacillin and calcic oxacillin--which were conditioned as "preconditioned powders" for oral suspensions. The above mentioned preparations were followed up by administration to animals, and similar seric concentrations in DBED oxacillin and sodic oxacillin (with the difference that insoluble salts present a long-time activity) were pointed out. PMID- 25528816 TI - [Adoption and adopted child. Forensic and psychiatric considerations]. AB - The authors analyse child adoption and the problems of the adopted child through briefing the juridic (legal) regulations ot this institution as well as the many medical and psychologic aspects regarding the relationships that condition its success. At the same they present the semiological aspects induced by the failure of adoption investigated under the aspect of motivation and the manifestations of certain reactive psychosyndromes of the adopted child. The authors' intention and the aim of the paper is to institutionalize a certain medical and psychological delivery according to the knowledge of the many relational implications of child adoption and--without the tendency to 'psychiatrize'--in order to promote the success conveyed to the humanistic content of this institution. PMID- 25528817 TI - [Instable angina pectoris]. PMID- 25528818 TI - [Semiological value of the skin colour alterations in internal medicine]. PMID- 25528819 TI - [Escherichia coli: in reality, a conditional pathogenic bacterium]. PMID- 25528820 TI - [Exogenous causes in the etiology of congenital mental deficiency]. PMID- 25528821 TI - [Profiles of Galati physicians. The Filipescu family, three generations of physicians ]. PMID- 25528822 TI - [Dr. Alexandru C. Pavel (1924-1981)]. PMID- 25528823 TI - [Complex artistic experience]. PMID- 25528824 TI - [A peculiar monarch -- the relationship of Wagner and Ludwig II., king of Bavaria]. PMID- 25528825 TI - [Two empty chairs: the story of a tragic friendship -- pictorial encounters]. PMID- 25528826 TI - [Persistence of chronic inflammatory responses, role in the development of chronic pancreatitis, obesity and pancreatic cancer]. AB - The purpose of the review--to analyze the basic data of the role of chronic low intensity inflammatory response as general biological process in the development and progression of chronic pancreatitis, obesity, and pancreatic cancer. Highlighted evidence from epidemiological studies showing that chronic pancreatitis and obesity are independent risk factors for pancreatic cancer, regardless of diabetes. Studied role of adipokines as Cytokines regulating of immune inflammatory response. Draws attention to the staging of pancreatic cancer in obesity. PMID- 25528827 TI - [Gastrointestinal disorders in patients with renal impairment]. AB - In the study the most common gastroenterological disorders among patients with CRF are reviewed. It was shown two main types of such disorders: as a manifestation of the underlying disease (CKD) or as an associated disease. It was determined that anorexia, nausea, vomiting, constipation, gastrointestinal bleeding, and acute abdominal pain are the most common gastroenterological symptoms. The necessity of further studying of the pathogenetic mechanisms of gastroenterological disorders in the case of presence of CRF and the importance of an integrated approach to the screening and management of patients with CRF was shown. PMID- 25528828 TI - [Fecal microbiota transplantation in treatment of inflammatory bowel diseases]. AB - Inflammatory bowel diseases (IBD) are chronic, recurrent disease associated with significant morbidity and disability rates and marked reduction of quality of life. The exact aetiology of these conditions is unknown, however, there is increasing data supporting the influence of gut microbiota in the pathogenesis of IBD. Despite of large number of actively exploring approaches to IBD treatment, some patients remain refractory to standard management or have significant adverse side effects. Given the probably role of the gastrointestinal microbiotain development of IBD, treatments that manipulate the microbiota have been investigated with varying degree of efficacy. Faecal microbiota transplantation (FMT) can be considered as alternative regimen for IBD management, but there is currently a lack of evidence supporting this approach in similar conditions. The comprehensive data are necessary to provide understandable and clear conclusion to guide current practice and future research. PMID- 25528829 TI - [Epidemiology and risk factors of inflammatory bowel diseases]. AB - The paper dedicated to comparative gap of epidemiology data in Ukraine, Europe and North America, review of evidence-based researches of value of particular risk factors of Crohn's disease and ulcerative colitis. PMID- 25528830 TI - [Digestive system disease as manifestation of the pleiotropic action of genes in mitochondrial dysfunction]. AB - Defined involvement lesions of the digestive system of clinical manifestations of mitochondrial dysfunction associated with both point mutations and polymorphism of mitochondrial DNA. The nature of the clinical signs of mtDNA polymorphisms carriers--multi organical, a progressive, clinical polymorphism, genetic heterogeneity with predominant involvement of energotropic bodies (cerebrum, cordis, hepatic). Set individual nosological forms of mitochondrial dysfunctions- syndromes Leia, Leber, Cairns, Sarah, MERRF, MELAS, NARP, MNGIE confirmed by clinical and genetic, morphological, biochemical, enzymatic, molecular genetics methods. It was found that 84-88% of these syndromes involving the violation of the digestive system with varying degrees of injury. This damage will be the first in the complex chain signs recovery which determines the direction of early rehabilitation. PMID- 25528831 TI - [Pathogenesis, diagnosis and treatment of hepatic encephalopathies in patients with liver cirrhosis]. AB - The data on the positive experience with hepatic encephalopathy in patients with cirrhosis liver L-ornithine-L-aspartate (drug larnamyn), the effectiveness of which is provided by its components (amino acids, ornithine and aspartate) which improve metabolism, ammonia detoxification mechanism, production of energy in the Krebs cycle, promote restoration of the cell membrane, and carried out anti inflammatory and detoxicative effect. PMID- 25528832 TI - [CORRECTION OF BILE FLOW CHARACTERISTICS IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE IN COMBINATION WITH HYPERURICEMIA]. AB - Basis on study through integrated comparative assessment of clinical, biochemical survey data revealed that in patients with impaired metabolism of uric acid in a greater percentage of common biliary sludge, a violation of the rheological properties of bile, a violation of cholate-cholesterol ratio index, which indicates an increased risk of bile stones. The study found that despite the high levels of uric acid there is a violation of the spectrum of bile acids, cholic and deoxycholic growth acid reduction taurocholic acid. Thus, application of ursodeoxycholic acid, rosuvastatin and allopurinol in these study patients with NAFLD dosages in combination with hyperuricemia improves the clinical symptoms and normalization of biochemical parameters and normalizes the spectrum of biliary acids. PMID- 25528833 TI - [State of homeostasis links in the children with intestinal colic]. AB - The state of homeostasis links in the children with intestinal colic is represented by the following parameters and clinical characteristics. The data of investigated children's contingent with intestinal colic prevailed by following comorbidities: SARS--12 (18.18% +/- 4.78%), protein-energy malnutrition--9 (12.85% +/- 3.82%), pneumonia--6 (8.57% +/- 3.57%), atopic dermatitis--7 (10.00% +/-.3.57%). All children have a next complaints: flatulence (100%), in the 62 children (88.57% +/- 3.82%) were identificated frequent regurgitation, in the 48 (80.33%)--hyperbilirubinemia. ALT levels were elevated in 25 children (41%) and 31 (51.66%) children had increased levels of AST. IL8 level were elevated in the 40 children (71.42%). The level of antibodies to elastase was greatly increased in all 56 (100%) children. PMID- 25528834 TI - [Psychopharmacological approach with the usage of selective serotonin reuptake inhibitors in functional dyspepsia treatment]. AB - Objective: To assess the efficacy of selective serotonin reuptake inhibitor (SSRI) escitalopram in patients with functional dyspepsia (FD). Treatment results showed reduction of dyspeptic symptoms as well as significant decrease of anxiety and depression and improvement of quality of life in patients, who were additionally prescribed SSRI. PMID- 25528835 TI - [Current prospects for diagnosis and treatment of food intolerance]. AB - In the study we found most frequent symptoms and pathological conditions associated with food intolerance and their changes when using dietary recommendations established on the results of test-FED (FED). We were determined the frequency of responses by type of food intolerance for the most common foods. We have investigated the possibility of the normalization of body weight in patients with high body mass index. PMID- 25528836 TI - [Food sensitization as a factor of formation of functional diseases of the digestive system in children]. AB - 169 children (105 with food sensitization and 64 without it among them) were examined. The presence of combined functional disorders of the digestive system on the background of food sensitization is proved. There are lesions of the biliary tract and of the sphincter of Oddi on pancreatic type among them, which prevailed. It was shown that the food sensitization is pathogenetic factor in the development of functional abnormalities of the pancreas, the maximum effect is marked in pre-school age. PMID- 25528837 TI - [Assessment of microscopic state of stomach mucous membrane in children with functional dyspepsia]. AB - The results of morphological research of stomach's mucouse membrane in children with functional dyspepsia are presented in the article. Microscopic changes were found in all examined children regardless of endoscopic state of the gastric and duodenum mucosa. Microscopic picture of the epithelium damage and regeneration was revealed; in more complicated cases, under the decline of regeneration potential features of interstitial inflammation appear. Actuality of morphological research in differential diagnostic of functional dyspepsia and chronic gastritis in children has been shown. PMID- 25528838 TI - [The clinical application of 13C-breath tests in pancreatic diseases]. AB - Maldigestion persists in most patients with chronic pancreatitis (GP). The objective lipase and amylase insufficiency diagnosis is needed to achieve an adequate clinical response to oral pancreatic enzyme substitution therapy. The novel data is presented in the article about the role of 13C-mixed triglyceride and 13C-corn starch breath tests as a tools for exocrine pancreatic insufficiency diagnosis, for evaluating fat and starch malabsorbtion in CP patients. 135 patients were included in the investigation. It has been shown, that 13C-breath tests could be useful tools in clinical practice for CP diagnosis. They are well correlate with fecal elastase-1 level, has high sensitivity and specificity for diagnosis of lipase and amylase deficiency. Tests make it possible to choose the initial pancreatic enzyme dosage and are beneficial during the treatment for pancreatic enzyme dose correction. PMID- 25528839 TI - [Structural state of the pancreas and coprogram parameters for assessment patients with chronic pancreatitis after cholecystectomy]. AB - Reviewed by a structural condition of the pancreas by ultrasound and scores from the Marseille-Cambridge classification in patients with chronic biliary pancreatitis, including those who had a history of cholecystectomy. Found that after cholecystectomy gland size decreased slightly, but significantly fibrosis is increased. Chronic inflammation and fibrosis of the gland leads to inhibition of both acinar and ductal secretory function, leads to its external and internal secretion deficiency. In assessing coprogram found that most patients with CP present with signs of exocrine insufficiency, including steatorrhea and kreatorrhea that are most pronounced in patients with CP after open cholecystectomy. PMID- 25528840 TI - [Combined pathology of the upper gastrointestinal tract in children: current trends]. AB - The article presents the current views and controversial issues problems comorbidity upper gastrointestinal tract in children and adolescents (gastroesophageal reflux disease and gastroduodenal diseases). Analyzed their own long-term observations, depending on the type of disease, severity of motor disorders, endoscopic and morphological picture, infection Helicobacter pylori. The possible options for the formation of gastroesophageal reflux disease in children and adolescents with gastroduodenal diseases. PMID- 25528841 TI - [Impairments of gastrointestinal tract in autism]. AB - In the article the peculiarities of the gastrointestinal tract in children with autism. Presents the algorithm for evaluation of children with autism in KhSMGC, the statistical data about the frequency of lesions of the gastrointestinal tract. The main directions of correction of digestive disorders and its results. PMID- 25528842 TI - [The role of chronic gastritis in past medical history with NSAID administration in patients with osteoarthrosis]. AB - 122 patients with osteoarthrosis, who have in the past medical history verified chronic gastritis (50 males and 72 females) at the age from 42 to 64 have been examined. Control group was comprised of 40 patients with osteoarthrosis without gastroduodenal zone pathology in the past medical history. For arthralgia relief patients were prescribed meloxicam (average dose--12.5 - 1.39 mg daily) or nimesulide (average dose--150 +/- 14.91 mg daily). As a result of this research it was determined that administration of selective NSAID (meloxicam and nimesulide) in patients with chronic gastritis in the past medical history raised the risk of NSAID gastropathy/dyspepsia 2.9 times (P < 0.03) than in patients without associated gastroduodenal zone pathology. Atrophy of gastric mucosa is associated with higher risks (P > 0.05) of erosive gastropathy. Patients with chronic gastritis in the past medical history when taking NSAID with the purpose of gastropathy prevention are recommended to undergo gastroprotective therapy. PMID- 25528843 TI - [Rational therapy of patients with essential hypertension and abdominal obesity with concomitant subclinical hypothyroidism]. AB - It was determined the characteristics of lipid status of patients with essential hypertension, abdominal obesity with concomitant subclinical hypothyroidism- mostly increased levels of total and LDL cholesterol. In assessing the effectiveness of statin therapy in combination with levothyroxine replacement therapy compared with statin monotherapy, combination therapy showed the best result in terms of achievement of target levels of both total cholesterol and LDL. The obtained results allow us to recommend the use of combination therapy for patients with hypertension, abdominal obesity with concomitant subclinical hypothyroidism in order to achieve the target values of LDL and thus to reduce the cardiovascular risk of these patients. PMID- 25528844 TI - [The efficiency of Lyapko applicators usage in the treatment of patients with comorbidity of hypertension and chronic pancreatitis based on the heart rate variability]. AB - Efficiency of the acupressure methodics of Lyapko applicators including in the treatment of patients with comorbidity of hypertension and chronic pancreatitis is estimated based on the study of the dynamics of the clinic and the state of autonomic nervous system using heart rate variability. The significant autonomic disorders were found in the studied group. More pronounced effect of this method of acupuncture was confirmed for the treatment of comorbidity of the studied pathologies, especially with regard to autonomic disorders. PMID- 25528845 TI - [Negative effects of termination statinotherapy in patients after acute coronary event with concominent non-alcoholic steatohepatitis]. AB - 140 patients with myocardial infarction in combination with non-alcoholic steatohepatitis, 58 patients took medium theraupeutic doses of rosuvastatin of 10 mg/day and 82 patients--torvastatin of 40 mg/day, have been examined. The study found significant progression of dyslipidemia, when the statins (improving blood total cholesterol and TG by 34% and LDL cholesterol by 38%). In patients who continued receiving statins, noted the positive dynamics of lipidohramy: in patients receiving rosuvastatin 10 mg levels of total cholesterol and LDL cholesterol decreased by 36% and 43%, respectively, with atorvastatin 40 mg level indicators fell by 34% and 40% respectively. Therapy rosuvastatin 10 mg had an advantage over the use of atorvastatin 40 mg in raising HDL cholesterol by 21%, and reduction of TG level by 37%. It is proved that the method furthers statins improves disease in patients with acute myocardial infarction, prevents the development of coronary artery disease resistant and recurrent acute coronary events, reduces the incidence of hospitalizations for heart failure progression. PMID- 25528846 TI - [Clinical and paraclinical features of the hepatobiliary system in children with cholelitiasis]. AB - The article is devoted to actual issues of diagnostics of the initial stage of cholelithiasis in children. Special attention is paid to the role of functional disorders of the biliary tract as factors in the pathogenesis of metabolic pathology of the hepatobiliary system. According to the results of the study highlighted the predominant types of functional disorders of the gallbladder and biliary tract stone disease in children. Highlighted the role of diagnostics of the initial manifestations ECB in the prevention of progression and formation of calculous stage of the disease. PMID- 25528847 TI - [Efficiency of etiologic correction of concomitant ascaridosis in the complex treatment of chronic pancreatitis]. AB - The of antihelmintic preparation albendazole using in the complex treatment of patients with chronic pancreatitis with the concomitant ascaridosis was promote regression of clinical demonstration of basic and concomitant diseases (P < 0.05). Options of coprogram and the structural state of pancreas from data of ultrasonography in marks by Marseille-Cambridge classification of chronic pancreatitis, after the conducted treatment became the better (P < 0.05), that established expedience of the use of albendazole in complex treatment of patients with a chronic pancreatitis with a concomitant ascaridosis. PMID- 25528848 TI - [Helicobacter pylori infection in patients with functional dyspepsia, eradication rates in the Donetsk region]. AB - We have investigated 175 patients with Rome III diagnostic criteria for functional dyspepsia. 104 (59%) patients were infected with Helicobacter pylori. Three-component (PPI + clarithromycin + amoxicillin) 7-day therapy with the addition of the probiotic was effective in 92 patients (88.4%). Dyspeptic symptoms were resolved in 37 patients with successful eradication (40%). Persistent effect for 6 months was maintained in 24 patients (26%). Eradication efficacy in eliminating of the dyspepsia symptoms was higher in epigastric pain syndrome than postprandial distress syndrome. PMID- 25528849 TI - [Epidemiology of viral hepatitis C in the Donetsk region]. AB - The article is devoted to the analysis of features of natural history of hepatitis C in Donetsk region, with the purpose to determine the number of patients in need of treatment in the first place, forecast on their cure, determination of the number of patients needing the retreatment. Namely, it is showed the age distribution of acute viral hepatitis B and C among the patients of Donetsk region, the percentage of patients with different severity of fibrosis inthe population of patients with chronic hepatitis C in Donetsk region. The stage of liver fibrosis and the degree of disease activity were compared. Furthermore, it is showed the distribution of genotypes of hepatitis C virus in a population of patients of Donetsk region. PMID- 25528850 TI - [Pathogenetic grounds of trophological impact of chronic pancreatitis complex therapy]. AB - In chronic pancreatitis patients was found persistent state of oxidative stress on the level of malonic aldehyde, which ran against the lowered levels of antioxidant enzymatic and non-enzymatic composition, and it has been found in the state of hypoproteinemia proteinogram indices (P < 0.05). The use of complex treatment of patients with chronic pancreatitis multivitamin-aminoacid drug Moriamin forte contributes to a significant regression effects oxidative stress and reduces the effects of hypoproteinemia (P < 0.05). PMID- 25528851 TI - [The parameters of estimation of the quality of life of patients with chronic pancreatitis and concomitant diabetes mellitus in outpatient practice]. AB - It was estimated quality of life of 62 of patients with chronic pancreatitis, depending on the presence of concomitant diabetes mellitus by SF-36 survey and the classification of M-ANNHEIM. It was established that these indicators in the chronic pancreatitis compared with the control group were significantly lower according to the SF-36 scale on 27.3% by the physical health component, on 12.8% by the mental health, and with diabetes, respectively--on 37.9% and 23.8% to those in chronic pancreatitis. The severity of chronic pancreatitis with concomitant diabetes was deeper than in the patients without endocrine failure: respectively, the average severity (S) prevailed in 72.7% of patients vs 25%, the cases of expressed and severe severity appeared. PMID- 25528852 TI - [Osteodeficiency in chronic pancreatitis: ways of correction]. AB - The expediency of Vitrum Calcium 600 + D400 and Risendros using in the complex treatment of the patients with a chronic pancreatitis and osteodeficiency syndrome has been proved. As a result the status of the bone mineralization is improved, the mineral density of the bone tissue is increased. PMID- 25528854 TI - [Gastric juice calcium content in patients with gastroesophageal reflux disease]. AB - The purpose of this study was to investigate free calcium content of gastric juice in patients with gastroesophageal reflux disease (GERD). After analyzing the calcium levels of gastric juice in patients with GERD and healthy people we found that calcium levels in the gastric juice of patients with GERD was significantly lower than normal. It was also analyzes the relationship between free calcium content of saliva and the same index in the gastric juice. It was revealed increasing the ratio of free calcium saliva and gastric juice in patients with GERD. This ratio increases with the progression of the disease, which may indicate on deep motility disorders of gastro-esophageal connection. PMID- 25528853 TI - [Imbalance of microelements and vitamins in adolescents with diffuse nontoxic goiter and biliary dyskinesia]. AB - The purpose of the present work was to study the level of microelements and vitamins in adolescents with diffuse nontoxic goiter. It has been shown that comorbid biliary dyskinesia leads to significant dysregulation of vitamin and mineral metabolism: the level of essential elements was decreased and the level of toxic elements was increased. Comorbid biliary dyskinesia in adolescents with diffuse nontoxic goiter was accompanied by a disbalance of vitamins. The changes found in micronutrients have sex differences. PMID- 25528855 TI - [Mitochondrial neurogastrointestinal encephalopathy syndrome]. AB - The article presents a case report of clinical observations of syndrome mitochondrial neurogastroenterology encephalomyopathy (MNGIE syndrome). PMID- 25528856 TI - [Gastrointestinal and metabolic impairments in cystic fibrosis]. AB - This article is about the peculiarities of gastrointestinal lesions, and the nature of metabolic disorders in patients with cystic fibrosis. Presented statistical data abouth the frequency of various gastrointestinal disorders in cystic fibrosis, studied the spectrum of ultrasound changes and changes in the biochemical status of patients with cystic fibrosis. PMID- 25528857 TI - [Hyperhomocysteinemia--a predictor of inflammatory changes in the liver]. AB - Studied pathogenetic mechanisms of influence of hyperhomocysteinemia on the formation and progression of nonalcoholic steatohepatitis. PMID- 25528858 TI - Synthesis and Antibacterial Activity of Alkylated Diamines and Amphiphilic Amides of Quinic Acid Derivatives. AB - Different series of N-alkylated diamines and their derivatives condensed to quinic acid were synthesized and tested for antibacterial properties against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The lipophilic chain and carbohydrate moiety modulate the antibacterial activity and the compounds showed a structure-activity relationship. Overall, 11 compounds displayed better activity than chloramphenicol against Gram-positive and Gram-negative bacteria. Monoalkylated amines 2a-h displayed an activity similar to that of ethambutol against Mycobacterium tuberculosis. PMID- 25528859 TI - Multicentric Castleman disease mimicking IgG4-related disease: A case report. AB - A 50-year-old woman was referred to our hospital for shoulder joint stiffness. She had a history of polyclonal hypergammaglobulinemia and an elevated C-reactive protein level. Her laboratory data revealed an elevated serum immunoglobulin G4 (IgG4) level, hypergammaglobulinemia, and rheumatoid factor positivity in the absence of anticyclic citrullinated peptide antibody. [18F]-Fluorodeoxyglucose positron emission tomography showed significant [18F]-fluorodeoxyglucose uptake in multiple lymph nodes (axillary, hilar, para-aortic, and inguinal). Biopsy of the inguinal lymph node showed expansion of the interfollicular areas by heavily infiltrating plasma cells, consistent with multicentric Castleman disease (MCD). Immunohistochemical analysis revealed a 37.3% IgG4-positive:IgG-positive plasma cell ratio, indicating overlapping IgG4-related disease. However, serological cytokine analysis revealed elevated levels of interleukin-6 (9.3 pg/ml) and vascular endothelial growth factor (VEGF) (1210 pg/ml), which are compatible with MCD. Corticosteroid treatment resolved the serological and imaging abnormalities. IgG4-related disease can mimic MCD, and it is crucial to distinguish between these two diseases. Serum interleukin-6 and VEGF levels may help to discriminate MCD from IgG4-related disease. PMID- 25528860 TI - Non-corticosteroid risk factors of symptomatic avascular necrosis of bone in systemic lupus erythematosus: A retrospective case-control study. AB - OBJECTIVE: Avascular necrosis of bone (AVN) is an important complication of systemic lupus erythematosus (SLE). Corticosteroid therapy has been underlined as a main risk factor for osteonecrosis. However, AVN development in patients who have never received corticosteroid and the absence of AVN in the majority of the patients, who received corticosteroid, propose a role for non-corticosteroid risk factors in AVN development. METHODS: This case-control study included two subsets: oral corticosteroid (66 AVN and 248 non-AVN patients) and pulse-therapy subset (39 AVN and 312 non-AVN patients) who have attended our Lupus clinic from 1979 to 2009. Patients received similar cumulative dose corticosteroid, equal maximum dose and 1-year maximum dose of corticosteroid. The demographic data (including sex, age of disease onset, age at the diagnosis of AVN), organs involvement, SLE Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics/American College of Rheumatology-Damage index (SLICC/ACR DI), number of disease flare ups were compared between two subsets. RESULTS: The mean age of SLE onset was younger (P value = 0.04) in the AVN patients. In oral corticosteroid subset, malar rash (P value < 0.001) and oral ulcer (P value = 0.003) were seen more frequently in non-AVN patients, whereas psychosis (P value = 0.03) was significantly more prevalent AVN subset in oral corticosteroid subset. In corticosteroid pulse subset, no significant difference in clinical features was noted. CONCLUSION: In oral corticosteroid subset, younger age of disease onset and psychosis were significantly associated with AVN, whereas malar rash and oral ulcer showed negative association AVN. PMID- 25528861 TI - IL-18 serum concentration is markedly elevated in typical familial Mediterranean fever with M694I mutation and can distinguish it from atypical type. PMID- 25528862 TI - Effects of hip joint center location and femoral offset on abductor muscle strength after total hip arthroplasty. AB - OBJECTIVES: The purposes of this study were 1) to examine the changes in the hip joint center (HJC) position and the femoral offset (FO) after total hip arthroplasty (THA) and 2) to investigate the effects of the HJC and FO on isometric abductor muscle strength. METHODS: We evaluated 51 patients who underwent unilateral primary THA. The FO, and horizontal and vertical distances from the HJC to the tip of the teardrop were measured and isometric hip abductor muscle strength was measured. RESULTS: The HJC of the affected side moved medially postoperatively compared with that of the unaffected side (p < 0.05), and the FO was reconstructed similarly to the unaffected side. There were significant negative correlations between the changes in the horizontal distance from the HJC and FO to the tip of the teardrop. An increase in the FO and infero medial cup position optimized hip abductor muscle strength. CONCLUSION: The HJC was reconstructed medially and superiorly, and the change in the FO after THA was influenced by the change in the horizontal distance of the HJC. Multiple regression analysis revealed that the medial and inferior HJC and increase in the FO constitute an effective procedure for restoring abductor strength. PMID- 25528863 TI - Interleukin-1 targeting treatment in familial Mediterranean fever: an experience of pediatric patients. AB - OBJECTIVES: The aim of this report was to evaluate and discuss treatment of pediatric familial Mediterranean fever (FMF) patients with anti-interleukin1 (IL 1) agents. METHODS: Refractory or colchicine unresponsive FMF was described as severe and frequent attacks and/or having high acute phase reactance levels despite having a maximum dose of colchicine (2 mg/day). Disease course, adverse effects, duration of follow-up, treatment protocols, responses to the therapies were discussed. RESULTS: Eight patients (6 male, 2 female) having refractory FMF were identified. Mediterranean fever (MEFV) gene analyses revealed homozygous M694V mutations in six patients and heterozygote M694V mutations in one patient and no mutation in one patient. They were all treated with anakinra and/or canakinumab. The use of anti-IL-1 drugs was beneficial to all patients. None of them had any severe adverse effects due to the therapy. CONCLUSIONS: Anakinra and canakinumab were effective in patient refractory to colchicine treatment as shown both in our series and in the literature. Therefore, controlled trials are needed to evaluate the safety and long-term efficacy of IL-1 targeting agents in colchicine resistant patients. PMID- 25528864 TI - Travelers with immune-mediated inflammatory diseases: are they different? AB - BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) increasingly benefit from improved health due to new therapeutic regimens allowing increasing numbers of such patients to travel overseas. This study aims to assess the proportion of IMID travelers seeking advice at the Travel Clinic of the University of Zurich, Switzerland, and to determine whether demographics, travel, and vaccination patterns differ between IMID- and non-IMID travelers. METHODS: Pre-travel visits and differences between IMID- and non-IMID travelers were assessed; logistic regression was used to adjust for confounders. RESULTS: Among 22,584 travelers who visited the Zurich Travel Clinic in a 25-month period, 1.8% suffered from an IMID, with gastroenterological and rheumatic conditions being the most common; 34.2% were using immunosuppressive or immunomodulatory medication. The reasons for travel and the destinations did not differ between IMID- and non-IMID travelers, Thailand and India being the most common destinations. IMID travelers stayed less often for longer than 1 month abroad and traveled less frequently on a low budget. Inactivated vaccines were similarly administered to both groups, while live vaccines were given half as often to IMID travelers. CONCLUSIONS: The increasing numbers of IMID patients, many using immunosuppressive or immunomodulatory therapy, show similar travel patterns as non-IMID travelers. Thus, they are exposed to the same travel health risks, vaccine-preventable infections being one among them. Particularly, in view of the fact that live attenuated vaccines are less often administered to IMID patients more data are needed on the safety and immunogenicity of vaccines and on travel specific risks to be able to offer evidence-based pre-travel health advice. PMID- 25528865 TI - Viral vector-mediated transgenic cell therapy in regenerative medicine: safety of the process. AB - INTRODUCTION: There are safety concerns regarding viral vectors in regenerative medicine research because of adverse experiences in conventional gene therapy with systemic delivery of recombinant virus. Transgenic cell therapy emerges as an attractive strategy, in which the genes of interest are delivered in vitro into isolated cells first; instead of transgene vectors, these transgenic cells are then implanted back to the host. This ex vivo strategy enables the examination of cell viability and phenotype before subsequent transplantation and prevents to the most extent the potential delivery-related hazards caused by exposure of viral components to the host. The transgenic implants are often localized, thus traceable for safety monitoring except those cases involving systemic distribution of transgenic cells. AREAS COVERED: The safety of ex vivo process used in viral vector-mediated transgenic cell therapy for regenerative medicine purpose. EXPERT OPINION: Safety concerns related to viral vector delivery can be dispelled in the majority of regenerative medicine applications by transgenic cell therapy. The ex vivo process executes in vitro transfection before subsequent transplantation of transgenic cells so that it avoids the exposure of viral components (particularly capsids or envelops) to the host, while this exposure is inevitable in conventional in vivo gene therapy. Besides, the practice of localized cell implantation and in vitro manipulation also reinforce the safety of transgenic cell therapy. Given the significantly reduced delivery-related hazard, viral vector-mediated transgenic cell therapy can be generally considered as a safe approach for most regenerative medicine applications. PMID- 25528867 TI - [The finale of the 60th decade of the Zeitschrift fur Psychosomatische Medizin und Psychotherapie]. PMID- 25528868 TI - [Blended-learning in psychosomatics and psychotherapy - Increasing the satisfaction and knowledge of students with a web-based e-learning tool]. AB - OBJECTIVES: To improve the synergy of established methods of teaching, the Department of Psychosomatics and Psychotherapy, University Hospital Munster, developed a web-based elearning tool using video clips of standardized patients. The effect of this blended-learning approach was evaluated. METHODS: A multiple choice test was performed by a naive (without the e-learning tool) and an experimental (with the tool) cohort of medical students to test the groups' expertise in psychosomatics. In addition, participants' satisfaction with the new tool was evaluated (numeric rating scale of 0-10). RESULTS: The experimental cohort was more satisfied with the curriculum and more interested in psychosomatics. Furthermore, the experimental cohort scored significantly better in the multiple-choice test. CONCLUSION: The new tool proved to be an important addition to the classical curriculum as a blended-learning approach which improves students' satisfaction and knowledge in psychosomatics. PMID- 25528869 TI - [Attitudes towards euthanasia: The impact of experiencing end-of-life care]. AB - BACKGROUND: It is a matter of debate whether euthanasia should be part of medical practice. OBJECTIVES: The current study investigates the attitudes of bereaved family members of cancer patients towards euthanasia. MATERIALS AND METHODS: We conducted a survey with 211 people who had recently lost a close relative to cancer. Participants were asked whether euthanasia should be part of medical practice.Two logistic regression models were calculated in order to determine the factors influencing the attitude towards active euthanasia and assisted suicide. RESULTS: About 70% and 75% of the respondents approved active euthanasia and assisted suicide, respectively. Religious denomination and psychological distress had a significant impact on the attitude towards active euthanasia. About 10%of the deceased patients had asked for active euthanasia. CONCLUSIONS: There was no difference between bereaved family members and the general population regarding the acceptance of euthanasia. Attitudes towards active euthanasia are associated with psychological distress and shaped by cultural values rather than by the experience of end-of-life care. PMID- 25528870 TI - [Mindfulness, depression, quality of life, and cancer: The nonlinear, indirect effect of mindfulness on the quality of life of cancer patients]. AB - OBJECTIVES: This study investigates the relationships between mindfulness, depression, and quality of life (QoL) in cancer patients. METHODS: A total of 51 cancer patients were assessed with the FreiburgMindfulness Inventory (FFA;Walach et al. 2004), the Hospital Anxiety and Depression Scale (HADS-D; Herrmann et al. 1994), and the Schedule for the Evaluation of Individual Quality of Life -DW (SEI QoLDW; Browne et al. 1997). The nonlinear relationships were analyzed using the instantaneous indirect effect procedure by Hayes and Preacher (2010). RESULTS: The relationship between mindfulness and QoL is mediated by depression. Because the relationship between mindfulness and depression is squared, the total effect of mindfulness on QoL is not constant. Increasing the level of mindfulness results in a decrease in its effect on the QoL of cancer patients. CONCLUSIONS: Cancer patients benefit from mindfulness up to a medium level through a decrease in depression, resulting in higher QoL. Patients with very higher mindfulness show more depressive symptoms, which leads to a neutralization of the effect of mindfulness on QoL. PMID- 25528871 TI - [Psychodynamic psychotherapy, lifestyle and prevention]. AB - OBJECTIVES: Patients with mental disorders frequently manifest unhealthy behavior, which contributes to their increased risk for chronic mental and somatic diseases as well as excess mortality rates of 10 years and more. It also impairs their well-being and the course of mental disorders.We analyzed whether by addressing unhealthy behavior prevention can be integrated into psychodynamic psychotherapy. METHODS: We reviewed the literature on the role of unhealthy behavior for mental disorders, on the role of lifestyle risk factors in psychodynamic theory, and on barriers to the integration of addressing lifestyle in psychodynamic psychotherapy. RESULTS: Smoking, unhealthy dietary habits, and physical inactivity constitute dysfunctional behavior, resulting from maladaptive self-representations and an impairment of emotion-regulation capacities. In psychodynamic psychotherapy this maladaptive behavior can be addressed and treated as a kind of defensive behavior and resistance. CONCLUSION: We believe that by addressing unhealthy behavior prevention can become a crucial task for psychodynamic psychotherapists today. PMID- 25528872 TI - Early Intervention for Borderline Personality Disorder: Psychodynamic Therapy in Adolescents. AB - OBJECTIVES: Borderline personality disorder (BPD) should be understood as a disorder of development (Streeck-Fischer 2008, 2013) that has its first manifestation in late childhood and adolescence. There are only few treatment studies of adolescents meeting the diagnostic criteria of borderline personality disorder, although early interventions for these patients are urgently needed (see Chanen & McCutcheon 2013). We examined the effectiveness of an inpatient psychodynamic therapy (PDT). METHODS: Twenty-eight adolescents fulfilling the DSM IV diagnostic criteria of borderline personality disorder were treated with psychodynamic therapy. The mean duration of treatment was 29.87 weeks (SD = 15.88). Outcomes were remission rates, GAF, GSI, SDQ, IIP and BPI scores. Assessments were made at admission and after treatment. Pre-post comparisons and comparisons with normative data were conducted. RESULTS: At the end of treatment 39.29% of the patients were remitted. We found significant improvements for the GAF, GSI, SDQ, IIP (all p0.001) and the BPI (p = 0.006). CONCLUSIONS: These clinically relevant improvements demonstrate the effectiveness of psychodynamic therapy in adolescents with borderline personality disorder and stress the usefulness of an early intervention for these patients. PMID- 25528874 TI - [Looking into international journals]. PMID- 25528873 TI - [How burdensome is the treatment of patients with somatoform disorders?]. AB - OBJECTIVES: This study examines the influence of self-perceived emotional stress during the treatment of patients with somatoform disorders. It asks whether emotional stress can be influenced by psychosomatic education. METHODS: Via online questionnaire general practitioners were asked about the prevalence of patients presenting with somatoform disorders and emotional stress during treatment. RESULTS: The prevalence of somatoform disorders in general practices was estimated at around 27.7 %. Practitioners educated in psychosomatic medicine estimate the prevalence of patients with somatoform disorders higher than practitioners without such education (n = 79; r = 0.242; p = 0.032). The treatment of patients presenting with somatoform disorders causes 42.6% more emotional stress among general practitioners compared with the treatment of an average patient (n = 79; t = 16.67; p <= 0.001). Doctors with additional education in psychosomatic medicine rate stress 17.2% lower than doctors without such education (n = 79; t = 1.875; p = 0.033). CONCLUSIONS: General practitioners experience the treatment of patients presenting with somatoform disorders as emotionally stressful. This emotional stress is mainly explained by increases in time expenditure, but it can be reduced by additional psychosomatic education. PMID- 25528875 TI - [Obituary for Eduard Kurt Jorswieck (1919 - 2014)]. PMID- 25528882 TI - Predictors of poor outcome among older liver transplant recipients. AB - With the increasing age of recipients undergoing orthotopic liver transplant (OLT), there is need for better risk stratification among them. Our study aims to identify predictors of poor outcome among OLT recipients >= 60 yr of age. All patients who underwent OLT at Cleveland Clinic from January 2004 to April 2010 were included. Baseline patient characteristics and post-OLT outcomes (mortality, graft failure, length of stay, and major post-OLT cardiovascular events) were obtained from prospectively collected institutional registry. Among patients >= 60 yr of age, multivariate regression modeling was performed to identify independent predictors of poor outcome. Of the 738 patients included, 223 (30.2%) were >= 60 yr. Hepatic encephalopathy, platelet counts < 45,000/MUL, total serum bilirubin > 3.5 mg/dL, and serum albumin < 2.65 mg/dL independently predicted poor short-term outcomes. The presence of pre-OLT coronary artery disease and arrhythmia were independent predictors of poor long-term outcomes. Cardiac causes represented the second most common cause of mortality among the elderly cohort. Despite that, this carefully selected cohort of older OLT recipients had outcomes that were comparable with the younger recipients. Thus, our results show the need for better pre-OLT evaluation and optimization, and for closer post-OLT surveillance, of cardiovascular disease among the elderly. PMID- 25528883 TI - Molecular imaging biomarkers for dementia with Lewy bodies: an update. AB - BACKGROUND: Dementia with Lewy body (DLB) is considered to be the second most common form of neurodegenerative disorders after Alzheimer's disease (AD), affecting as many as 100,000 people in the UK and up to 1.3 million in the USA. However, nearly half of patients with DLB remain undiagnosed thus depriving many of them from an early and adequate treatment of their distressing symptoms. Accurate and early diagnosis of DLB is important for both patients and their caregivers, since the neuropsychiatric symptoms require specific management. METHODS: In the current study, we review the most recent developments in the field of molecular nuclear imaging to diagnose DLB. RESULTS: The review addresses, the neurotransmitter based (dopaminergic, cholinergic, and glutamatergic) nuclear imaging techniques, role of the autonomic dysfunction and its visualization in DLB with myocardial sympathetic imaging and vesicular catecholamine uptake, as well as the use of amyloid polypeptides and glial markers as molecular imaging probes in the clinical diagnosis of DLB. CONCLUSIONS: Most of the above nuclear imaging methods are restricted to highly specialized clinical centers, and thus not applicable to a large number of patients requiring dementia (e.g. DLB) diagnosis in routine clinical setting. Validating them against more readily accessible peripheral biomarkers, e.g. CSF and blood biomarkers linked to the DLB process, may facilitate their use in wider clinical settings. PMID- 25528884 TI - Characterization of typical potent odorants in cola-flavored carbonated beverages by aroma extract dilution analysis. AB - The aroma-active compounds in typical cola-flavored carbonated beverages were characterized using gas chromatography-olfactometry and gas chromatography-mass spectrometry. The potent odorants in the top three U.S. brands of regular colas were identified by aroma extract dilution analysis (AEDA). Among the numerous odorants identified, eugenol (spicy, clovelike, sweet) and coumarin (sweet, herbaceous) were predominant in all colas. Other predominant odorants in at least one brand included guaiacol (smoky) and linalool (floral, sweet), while 1,8 cineole (minty, eucalyptus-like) was a moderately potent odorant in all colas. Determination of the enantiomeric compositions indicated that (R)-(-)-linalool (34.5%) was a more potent odorant than the (S)-(+)-enantiomer (65.6%) due to its much lower odor detection threshold. In addition, lemon-lime and cooling attributes determined by sensory descriptive analysis had the highest odor intensities among the eight sensory descriptors. The aroma profiles of the three colas were in good agreement with the potent odorants identified by AEDA. PMID- 25528885 TI - Mechanism of stabilization of helix secondary structure by constrained Calpha tetrasubstituted alpha-amino acids. AB - The theoretical basis behind the ability of constrained Calpha-tetrasubstituted amino acids (CTAAs) to induce stable helical conformations has been studied through Replica Exchange Molecular Dynamics Potential of Mean Force Quantum Theory of Atoms In Molecules calculations on Ac-l-Ala-CTAA-l-Ala-Aib-l-Ala-NHMe peptide models. We found that the origin of helix stabilization by CTAAs can be ascribed to at least two complementary mechanisms limiting the backbone conformational freedom: steric hindrance predominantly in the (+x,+y,-z) sector of a right-handed 3D Cartesian space, where the z axis coincides with the helical axis and the Calpha of the CTAA lies on the +y axis (0,+y,0), and the establishment of additional and relatively strong C-H...O interactions involving the CTAA. PMID- 25528886 TI - Provocative intraocular pressure challenge preferentially decreases venous oxygen saturation despite no reduction in blood flow. AB - PURPOSE: Ocular disease can both alter the retina's oxygen requirements, and decrease its ability to cope with changes in metabolic demand. We examined the influence of a moderate intraocular pressure (IOP) elevation on three outcome measures: arterial and venous oxygen saturation, blood flow, and the pattern electroretinogram (PERG). METHODS: We increased IOP to ~30 mmHg in 23 healthy participants (22-39 years) using a mechanical probe applied to the eyelid, thereby lowering ocular perfusion pressure (OPP) by ~30%. The Oxymap retinal oximeter was used to measure oxygen saturation for arteries and veins. Blood flow, volume and velocity were measured using the Heidelberg retinal flowmeter and steady-state PERG waveforms (8.34 Hz) were recorded bilaterally (200 sweeps). For each outcome measure, data was obtained three times: at baseline, 1 min into sustained IOP elevation, and 1 min after the probe was removed. RESULTS: During IOP elevation, changes in oxygen saturation of retinal arteries failed to reach statistical significance [F(1,30) = 3.69, p = 0.05], whereas venous oxygen saturation was significantly reduced [F(1,21) = 27.43, p < 0.01]. Blood flow increased slightly [F(2,40) = 6.28, p < 0.0001], PERG amplitude significantly reduced [F(2,44) = 24.24, p < 0.0001] and PERG phase was significantly delayed [F(2,44) = 17.00, p < 0.0001]. Contralateral eyes were unchanged. OPP reduction correlated little with PERG amplitude, PERG phase or venous oxygen saturation. CONCLUSIONS: Mild, acute IOP elevation increases arterio-venous oxygen saturation differences primarily through lowering venous oxygen saturation, suggesting increased oxygen consumption by healthy neurons when physiologically stressed. PMID- 25528887 TI - A qualitative study of veterans on long-term opioid analgesics: barriers and facilitators to multimodality pain management. AB - OBJECTIVE: The aim of this study was to examine barriers and facilitators to multimodality chronic pain care among veterans on high-dose opioid analgesics for chronic non-cancer pain. SETTING: A Veterans Health Administration clinic in San Antonio. PARTICIPANTS: Twenty-five veterans taking at least 50 mg morphine equivalent daily oral opioid doses for more than 6 months. METHODS: Three semi structured focus groups, each with seven to nine veterans. Interview guide addressed: chronic pain effects on quality of life, attitudes/experiences with multimodality pain care, social support, and interest in peer support. In an iterative process using grounded theory, three reviewers reviewed de-identified transcripts for themes. The theory of planned behavior (TPB) framework was used to classify barriers and facilitators to multimodal pain management. MAIN RESULTS: The 25 participants had a mean age of 54 years (39-70); 32% were women and 24% non-white. The three TPB dimensions (attitudes, social norms, and perceived behavioral control) were reflected in emergent themes: 1) uncontrollable impact of pain in all aspects of life; 2) reliance on opioids and challenges in obtaining these drugs despite ambivalence about benefits; 3) poor access to and beliefs about non-pharmacologic therapies; 4) frustrations with Department of Veterans Affairs health care; and 5) poor social support and isolation reflected by limited interest in peer support. CONCLUSIONS: Veterans with chronic pain on long-term opioids hold pervasive attitudes that prevent them from using multimodality pain management options, lack social support and social norms for non-opioid-based pain treatment options, and have poor perceived control due to poor access to multimodality care. PMID- 25528888 TI - Index of mechanical efficiency in competitive and recreational long distance runners. AB - The purpose of this investigation was to compare external work and net energy expenditure during a bout of repetitive stretch-shortening cycles between competitive and recreational long-distance runners. Participants were divided into either competitive or recreational runners based on their maximal oxygen consumption and self-reported 1600 m times. The stretch-shortening cycle involved a repetitive hopping protocol on a force plate while measuring oxygen consumption and lactate accumulation for a total of 10 min. External work and net energy expenditure were calculated for 3 min after steady state was achieved and the ratio between these variables was utilised as an index of mechanical efficiency. Lower extremity stiffness was calculated during this interval as well. Net energy expenditure was significantly lower in competitive runners (152.6 +/- 33.3 kJ) in comparison to recreational runners (200.6 +/- 41.4 kJ) (P = 0.02) given similar amounts of external work performed in both groups (competitive runners = 65.6 +/- 20.1 kJ, recreational runners = 68.8 +/- 12.1 kJ) (P = 0.67). Index of mechanical efficiency was significantly different between competitive runners (43.2 +/- 9.0%) and recreational runners (34.8 +/- 5.3%) (P = 0.03). No significant differences were found in lower extremity stiffness (P = 0.64). Competitive distance runners can perform similar levels of external work with lower net energy expenditure and thus a higher index of mechanical efficiency during repetitive stretch-shortening cycles in comparison to recreational runners with similar values of lower extremity stiffness. This ability could possibly be due differences in muscle-tendon length changes, muscle pre-activation, cross-bridge potentiation and short-latency reflex responses as a result of training which should be considered for future investigation. PMID- 25528889 TI - Bone scintigraphy in axial seronegative spondyloarthritis patients: role in detection of subclinical peripheral arthritis and disease activity. AB - AIM: To detect subclinical peripheral arthritis and disease activity in axial seronegative spondyloarthritis (SpA) patients using bone scintigraphy. METHODS: Seronegative SpA patients with an established diagnosis and no clinically evident arthritis at the time of the study were included. After excluding symptomatic cases, 20 patients were recruited; 18 with ankylosing spondylitis (AS) and another two with psoriatic arthritis (PsA). Conventional bone scintigraphy was performed to detect the distribution of increased uptake, blood vascular pool (vascularity) and activity. RESULTS: The peripheral joints in all the patients were asymptomatic with no signs of arthritis on clinical examination. Disease activity was higher in those with hypervascularity and activity (75%) detected by scintigraphy. Scintigraphic activity of the sacroiliac joints was found in 10 patients (50%) with a mean sacroiliac joint index of 2.4 +/- 0.6. Subclinical involvement of the hips, knees, shoulders, ankles, small joints of the hands, ankles and sternoclavicular joints, as well as the small joints of the feet were detected with descending frequencies (25%, 25%, 20%, 20%, 15%, 10% and 10%, respectively). Dorsal spine increased uptake was found in 35% and hypervascularity of the skull in two cases. Avascular necrosis of the hip was present in one case with hypovascularity. CONCLUSION: The spectrum of joint involvement in seronegative SpAs should not be limited to sacroiliitis. Bone scintigraphy provides a cost-effective method for detecting the extent of involvement in this group of autoimmune systemic diseases (axial SpA) without clinical evidence of peripheral arthritis. PMID- 25528890 TI - Clinical presentation of placenta percreta with uterine incarceration in the second trimester. PMID- 25528891 TI - Reversible posterior encephalopathy syndrome in pregnancy without pre-eclampsia. PMID- 25528892 TI - Analysis of gene expression identifies candidate markers and pathways in pre eclampsia. AB - Pre-eclampsia is a serious multisystem disorder and causes significant increase in both maternal and foetal morbidity and perinatal mortality globally. Due to the limited understanding of the molecular mechanism of pre-eclampsia, the current study conducted bioinformatic analyses to screen key regulators involved in pre-eclampsia. The gene expression profiling dataset GSE44711 containing 8 early-onset pre-eclampsia placentas and 8 gestational-age-matched control placentas was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened by limma software package, which were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the Database for Annotation, Visualization, and Integrated Discovery website. Finally, protein-protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes database. In total, 192 DEGs including 106 upregulated and 86 downregulated genes were obtained. Proteoglycan 2 and podoplanin were the most significantly up- and downregulated genes, respectively. In addition, three potential pathways and their related DEGs: spermidine/spermine N1-acetyltransferase 1, amiloride-binding protein 1 and adenosylmethionine decarboxylase 1 were associated with arginine and proline metabolism. Vascular endothelial growth factor C; phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit beta; collagen, type I, alpha 1 (COL1A1); and fibronectin 1 (FN1) were associated with focal adhesion. COL6A1 as well as COL1A1 and FN1 were involved in extra-cellular matrix-receptor interaction. The current study identified several potential genes and three pathways which may be considered as candidate targets for diagnosis and therapy of pre-eclampsia. PMID- 25528893 TI - Cervical prolapse in pregnancy and varied outcomes - a report of three cases. PMID- 25528894 TI - Comparison of the effects of PMDD and pre-menstrual syndrome on mood disorders and quality of life: a cross-sectional study. AB - In this study, we compared psychiatric symptoms, quality of life and disability in patients with pre-menstrual dysphoric disorder (PMDD) and pre-menstrual syndrome (PMS). Forty-nine women with PMDD were compared with 43 women with PMS. All participants were asked to complete a socio-demographic data collection form, a Brief Disability Questionnaire, a medical study short form-36 (SF-36) and Hospital Anxiety and Depression Scale (HADS) forms. The patients with PMDD had higher HAD-A and HAD-D scores than the patients in PMS group (p < 0.01). No statistically significant differences were found on brief disability between two groups (p > 0.05), but both groups had medium level of brief disability. The PMDD group had a lower SF-36 scoring than the PMS group in every compared parameters (p < 0.01). PMS and PMDD may lead to brief disability, and PMDD may cause loss of quality of life and psychological problems. The evaluation of patients with PMS and PMDD pre-menstrual disorders should be more detailed. PMID- 25528895 TI - Bridging the gap between molecular and elemental mass spectrometry: higher energy collisional dissociation (HCD) revealing elemental information. AB - Molecular mass spectrometry has been applied to simultaneously obtain molecular and elemental information from metal-containing species. Energy tuning of the higher-energy collision dissociation (HCD) fragmentation cell allows the controlled production of typical peptide fragments or elemental reporter ions informing about the metallic content of the analyzed species. Different instrumental configurations and fragmentation techniques have been tested, and the efficiency extracting the elemental information has been compared. HCD fragmentation operating at very high energy led to the best results. Platinum, lanthanides, and iodine reporter ions from peptides interacting with cisplatin, peptides labeled with lanthanides-MeCAT-IA, and iodinated peptides, respectively, were obtained. The possibility to produce abundant molecular and elemental ions in the same analysis simplifies the correlation between both signals and open pathways in metallomics studies enabling the specific tracking of metal containing species. The proposed approach has been successfully applied to in solution standards and complex samples. Moreover, interesting preliminary MALDI imaging experiments have been performed showing similar metal distribution compared to laser ablation (LA)-ICPMS. PMID- 25528896 TI - Differential expression of candidate salivary effector proteins in field collections of Hessian fly, Mayetiola destructor. AB - Evidence is emerging that some proteins secreted by gall-forming parasites of plants act as effectors responsible for systemic changes in the host plant, such as galling and nutrient tissue formation. A large number of secreted salivary gland proteins (SSGPs) that are the putative effectors responsible for the physiological changes elicited in susceptible seedling wheat by Hessian fly, Mayetiola destructor (Say), larvae have been documented. However, how the genes encoding these candidate effectors might respond under field conditions is unknown. The goal of this study was to use microarray analysis to investigate variation in SSGP transcript abundance amongst field collections from different geographical regions (southeastern USA, central USA, and the Middle East). Results revealed significant variation in SSGP transcript abundance amongst the field collections studied. The field collections separated into three distinct groups that corresponded to the wheat classes grown in the different geographical regions as well as to recently described Hessian fly populations. These data support previous reports correlating Hessian fly population structure with micropopulation differences owing to agro-ecosystem parameters such as cultivation of regionally adapted wheat varieties, deployment of resistance genes and variation in climatic conditions. PMID- 25528897 TI - Optimisation of isolation procedure for pyrrolizidine alkaloids from Rindera umbellata Bunge. AB - Procedure for isolation of pyrrolizidine alkaloids (PAs) from Rindera umbellata Bunge plant species was optimised. Different extraction media (methanol, ethanol and sulphuric acid), concentration and volume of sulphuric acid, pH of PA solution for alkaline extraction, extraction time and techniques (maceration, ultrasonic and overhead rotary mixer assisted extraction) were investigated. The yields of six PAs (7-angeloyl heliotridane, 7-angeloyl heliotridine, lindelofine, 7-angeloyl rinderine, punctanecine and heliosupine) were monitored by GC-MS/FID. The best results for the isolation all of six PAs were obtained when the extraction was performed with 1 M sulphuric acid (30 mL per 1.00 g of dried sample) by overhead rotary mixer during three days. Optimal pH value for alkaline extraction of PAs with CH2Cl2 was 9, and the extraction should be performed with four portions of 30 mL of CH2Cl2. This procedure could be also useful for a plant sample preparation for GC and LC analyses of PAs. PMID- 25528899 TI - Serological survey of Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum, and Ehrlichia canis infections in rural and urban dogs in Central Italy. AB - INTRODUCTION: Borrelia burgdorferi sensu lato (s.l.) and Anaplasma phagocytophilum are well known zoonotic pathogens, whereas Ehrlichia canis is usually considered to be of veterinary concern, although on the basis of recent reports it also seems to be able to infect humans. OBJECTIVE: The aim of the study was to determine the seroprevalence of B. burgdorferi s.l., A. phagocytophilum and E. canis in an Italian canine population, and to verify if there are differences between dogs living in urban areas and those from a rural environment. MATERIALS AND METHOD: Blood sera of 1,965 dogs, 1,235 from cities and 730 from rural areas, were tested by indirect immunofluorescent assay (IFAT). RESULTS: The overall seroprevalence was highest for E. canis (7.07%), followed by A. phagocytophilum (4.68%), and B. burgdorferi s.l. (1.47%). Rural dogs showed the highest seroprevalence to B. burgdorferi s.l. and A. phagocytophilum. No significant differences were observed between rural and urban E. canis-positive dogs. A low percentage (1.32%) of dogs with dual seropositivity was detected, and no triple positive reactions were observed. No significant differences were detected in the seroprevalence of the three agents in relationship to the age and gender of the dogs. Seroprevalence in the five years considered were not statistically different, except for the lowest rate for E. canis observed in 2012. CONCLUSIONS: The results confirm the presence of B. burgdorferi s.l., A. phagocytophilum and E. canis in Italian dogs in both urban and rural areas. Monitoring pet dogs, which share the same environment with their owners, is useful for identifying the presence of tick-borne disease agents of both veterinary and public health significance. PMID- 25528898 TI - Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: Results of a phase III, double-blind, randomized, placebo controlled trial. AB - OBJECTIVE: To evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures. METHODS: This randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged >=16 years and had uncontrolled partial-onset seizures despite treatment with 1-2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n = 226), ESL 800 mg (n = 216), or ESL 1,200 mg (n = 211). Following a 2-week titration period, patients received ESL 800 or 1,200 mg once-daily for 12 weeks. Seizure data were captured and documented using event-entry or daily entry diaries. RESULTS: Standardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200 mg (p = 0.004), and there was a trend toward improvement with ESL 800 mg (p = 0.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800 mg (p = 0.001) and 1,200 mg (p < 0.001) both reduced SSF. There were no statistically significant interactions between treatment response and geographical region (p = 0.38) or diary version (p = 0.76). Responder rate (>=50% reduction in SSF) was significantly higher with ESL 1,200 mg (42.6%, p < 0.001) but not ESL 800 mg (30.5%, p = 0.07) than placebo (23.1%). Incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation increased with ESL dose. The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia. SIGNIFICANCE: Adjunctive ESL 1,200 mg once-daily was more efficacious than placebo in adult patients with refractory partial-onset seizures. The once-daily 800 mg dose showed a marginal effect on SSF, but did not reach statistical significance. Both doses were well tolerated. Efficacy assessment was not affected by diary format used. PMID- 25528900 TI - Reduction of ochratoxin A in chicken feed using probiotic. AB - Mycotoxins present in fodders may evoke health problems of animals and people. The data published by FAO in 2001 show that 25% of raw materials are contaminated with mycotoxins, while their type and concentration are to a great extent dependable on the climatic zone. Biological detoxification of mycotoxins by the use of microorganisms is one of the well-known strategies for the management of mycotoxins in foods and feeds. The aim of this study was to determine the influence of spontaneous fermentation and that with the use of probiotic bacteria and yeast on ochratoxin A (OTA) concentration and the microbiota pattern during fermentation. The probiotic preparation is a natural product containing bacteria resistant to gastric juice and bile: Lactobacillus paracasei LOCK 0920, Lactobacillus brevis LOCK 0944, Lactobacillus plantarum LOCK 0945, as well as live yeasts Saccharomyces cerevisiae LOCK 0140 of high fermenting capacity. After 6-hour fermentation with the probiotic, in feed with a low concentration of ochratoxin A (1 mg/kg) the amount of ochratoxin A decreased by 73%. In the case of high a concentration (5 mg/kg) the decrease in ochratoxin A was lower at about 55%. This tendency was sustained during the following hours of incubation (12th and 24th hours). The application of probiotic bacteria and yeasts resulted in the reduction of aerobic spore forming bacteria. It can be concluded that the probiotic preparation containing bacteria of Lactobacillus strains and yeasts Saccharomyces cerevisiae used in the study was conducive to detoxification of ochratoxin A added to a feed. PMID- 25528901 TI - Pollen grains as allergenic environmental factors--new approach to the forecasting of the pollen concentration during the season. AB - INTRODUCTION AND OBJECTIVES: It is important to monitor the threat of allergenic pollen during the whole season, because of practical application in allergic rhinitis treatment, especially in the specific allergen immunotherapy. The aim of the study was to propose the forecast models predicting the pollen occurrence in the defined pollen concentration categories related to the patient exposure and symptom intensity. MATERIAL AND METHODS: The study was performed in Cracow (southern Poland), pollen data were collected using the volumetric method in 1991 2012. For all independent variables (meteorological elements) and the daily pollen concentrations the running mean for periods: 2-, 3-, 4-, 5-, 6- and 7 days before the predicted day were calculated. The multinomial logistic regression was used to find the relation between the probability of the pollen concentration occurrence in the selected categories and meteorological elements and pollen concentration in days preceding the predicted daily concentration. The models were constructed for each taxon using data in 1991-2011 (without 1992 and 1996 due to missing data in these years) and 1998-2011 pollen seasons. RESULTS: The days classified among the lowest category (0-10 PG/m3) (pollen grains/m 3 of air) dominated for all the studied taxa. The percentage of the obtained predictions of the pollen occurrence fluctuated between 35-78% which is a sufficient value of model predictions. Considering the studied taxon, the best model accuracy was obtained for models forecasting Betula pollen concentration (both data series), and Poaceae (both data series). CONCLUSIONS: The application of the recommended threshold values during the predictive models construction seems to be really useful to estimate the real threat of allergen exposure. It was indicated that the polynomial logistic regression models could be a practical tool for effective forecasting in biological monitoring of pollen exposure. PMID- 25528902 TI - Detection of TBEV RNA in Ixodes ricinus ticks in north-eastern Poland. AB - TBEV (Flaviviridae, Flavivirus) is an etiologic agent of tick-borne encephalitis (TBE), the most important arboviral human infection involving the central nervous system. The disease is endemic in a zone extending from central and eastern Europe to Siberia and Japan, and corresponds to the distribution of the ixodid ticks, which act both as the vectors and reservoir of TBEV. Humans acquire infection mainly by the bite of an infected tick. A continuous increase of TBE cases throughout Europe has been observed over a period of 30 years. The objective of this study was a preliminary determination of the infection level of ticks collected in North-Eastern Poland, the endemic area of TBE. Questing Ixodes ricinus ticks (adults, nymphs and larvae) were collected by flagging the lower vegetation in 55 locations in Poland in 2006-2009. A total of 2075 ticks (676 females, 555 males, 799 nymphs and 45 larvae) were collected and examined for the presence of RNA TBEV by nested RT-PCR. The average number of ticks in one pool was 6.98. The minimum infection rate of ticks with TBEV was estimated in total area as 0.96%. TBEV RNA was detected in all of the investigated developmental stages of ticks. The prevalence of viral infection in ticks is a useful indicator of TBE virus circulation and may be used for risk assessment of the degree of natural focus activity and of the risk to contact TBE in a particular natural habitat. PMID- 25528903 TI - Plant pollen content in the air of Lublin (central-eastern Poland) and risk of pollen allergy. AB - Pollen monitoring was carried out in Lublin in 2001-2012 by the volumetric method using a Hirst-type spore trap (Lanzoni VPPS 2000). Daily pollen concentrations considerably differed in the particular years. The pollen counts with the biggest variability were observed in the first half of a year when woody plants flowering. The highest annual pollen index were noted for the following taxa: Betula, Urtica, Pinaceae, Poaceae and Alnus. Betula annual total showed the greatest diversity in the study years. The number of days on which the pollen concentration exceeded the threshold values, thereby inducing allergies, was determined for the taxa producing the most allergenic pollen. The above-mentioned taxa primarily included the following: Poaceae, in the case of which the highest number of days with the risk of occurrence of pollen allergy was found (35), Betula (18), and Artemisia (10). The following taxa: Alnus (14 days), Populus (11 days), Fraxinus (10 days), and Quercus (8 days), were also characterized by a large number of days on which their pollen concentrations exceeded the threshold values. The occurrence of periods of high concentration of particular pollen types were also noted. Risk of pollen allergy appeared the earliest at the beginning of February during Alnus and Corylus blooming. High concentrations of other woody plants were recorded from the last ten days of March to about 20 May, and of herbaceous plants from the first/last half of May-beginning of October. PMID- 25528904 TI - Effects of climatic conditions on the biting density and relative abundance of Simulium damnosum complex in a rural Nigerian farm settlement. AB - INTRODUCTION AND OBJECTIVE: The effect of climatic conditions on the biting density and relative abundance of Simulium damnosum complex at Adani, Nigeria, from August 2010-January 2011 was investigated. MATERIALS AND METHODS: The classical method of collecting blackflies for a period of 11 hours using human attractants was employed in the study. Monthly climatic data, such as rainfall, relative humidity and temperature were collected for the period of study. RESULTS: Rainfall, relative humidity, temperature, harmattan (cold, dry wind) and deforestation were observed to affect the biting density and relative abundance of blackflies at the site. A total of 548 female adult blackflies were collected. The biting density of the flies ranged from 0.5 Flies/Man/Hour (FMH) in December to 5.5 FMH in January. The relative abundance of the flies ranged from 21 in December to 243 in January. Regression analysis showed that temperature and relative humidity had a positive correlation with relative abundance of Simulium damnosum complex (y=-0.0006x+5.593, r=0.0519) and (y=-0.1213x+78.794, r=0.505), respectively. CONCLUSIONS: The risk of getting infected with Onchocerca volvulus increased during the dry season with its associated weather conditions. PMID- 25528905 TI - The prevalence and distribution of Dirofilaria repens in dogs in the Mazovian Province of central-eastern Poland. AB - The aim of this study was to determine the prevalence and distribution of canine dirofilariosis from different districts of the Mazovian Province in central eastern Poland. 462 dogs aged from 1.5-14 years were examined for dirofilariosis. Blood samples were examined for the presence of microfilariae using the Knott method, as well as the method of Kingston and Morton, after centrifugation in haematocrit microtubes in order to determine the intensity of infection as the number of microfilariae in 60 microliters of blood. The species of microfilariae found were determined after staining on the basis of the morphological characters. Samples were also examined using Canine Heartworm Antigen Test Kit SNAP HTWM (IDEXX, USA) that allows the detection of circulating antigens of females of Dirofilaria immitis. The positive samples were examined using multiplex PCR assay for species confirmation. Microfilariae belonging to the species D. repens were found in the blood samples of dogs originating from the city of Warsaw and from 18 districts of Mazovian Province. The mean prevalence of that species observed in the province was 25.8%. The range of intensity counted with the number of microfilariae found in 60 microliters of blood amounted to between 1-150; median intensity 9 microfilariae. The highest prevalence, reaching 52.9% and the highest median intensity of infection reaching 28 microfilariae, was found in Radom district. The lowest prevalence, amounting to 4.2%, was registered in Grojec district; however, the lowest median intensity reaching 6 microfilariae was noted in Zyrardow district. The infected dogs had not been outside of Poland, which means that this is an autochthonous infection. Microfilariae and antigens of D. immitis were not found in any examined blood samples. Results of the presented study show that autochthonous dirofilariosis caused by nematodes D. repens commonly occurs in the area of the Mazovian Province. PMID- 25528906 TI - Prevalence of and relationship between rhinoconjunctivitis and lower airway diseases in compost workers with current or former exposure to organic dust. AB - INTRODUCTION AND OBJECTIVE: The relationship between allergic rhinitis and allergic asthma is well characterized. However, it remains unknown whether an association exists between symptoms of upper and lower airway diseases and occupational bioaerosol exposure beyond the scope of allergy. MATERIALS AND METHODS: The current cross-sectional study focuses on 190 current and 59 former compost workers exposed to bioaerosols. Work-related symptoms indicative of conjunctivitis, rhinitis and lower airway irritation were assessed and compared with 38 non-exposed control subjects. Allergic asthma was diagnosed using a calculated score, and chronic obstructive pulmonary disease (COPD) was spirometrically determined. RESULTS: 12 current, 8 former and 5 non-exposed subjects were diagnosed with allergic asthma and excluded from further analysis. Multivariate logistic regression models suggested that cough and chronic bronchitis in current compost workers were associated with eye irritation (OR 2.75 (0.93-8.07); OR 7.22 (1.12-46.5)). Chronic bronchitis in former workers was strongly associated with work-related eye irritation (OR 38.6 (1.33->1000) and nose irritation (OR 25.0 (1.21-513)). CONCLUSIONS: After excluding allergic asthmatics, there was no evidence that eye or nose irritation was due to an underlying atopic disease, but rather to non-allergic mucous membrane irritation syndrome. Therefore, the higher incidence of chronic bronchitis in former compost workers may reflect a chronic irritative process triggered by exposure to bioaerosols. PMID- 25528907 TI - Protective efficacy of permethrin-treated trousers against tick infestation in forestry workers. AB - INTRODUCTION AND OBJECTIVE: Prevention of tick borne diseases in forestry workers is essentially based on the use of appropriate clothing. The objective of this pragmatic, randomized, controlled trial was to assess the potential benefit of permethrin-treated working trousers for the prevention of tick infestation during forestry work. MATERIALS AND METHODS: N=164 male forestry workers were equipped for a period of 16 weeks with permethrin-treated (intervention group-I) or untreated work trousers (control group-II). Subgroups, according to the use of trousers with (I-1, II-1) or without cut protection lining (I-2, II-2) were constituted. Tick infestation (quantity of ticks on the body surface) was assessed by questionnaire after 16 workdays. Control and intervention groups were compared by calculating the infestation rate (percentage of subjects with ticks) and the average number of ticks per workday. RESULTS: The infestation rate in the intervention group was significantly lower than in the control group (36.6 vs. 63.4%, p=0.001; Fisher-test). Further analysis revealed a significant reduction of tick infestation by permethrin treatment only for subjects wearing trousers without the cut protection lining (I-2: 34.2 vs. II-2: 80.0%, p<0.001), while users of cut protection trousers did not benefit from such treated trousers (I-1: 38.6 vs. II-1: 47.6%, n.s.). Similar results were found for comparisons based on the average number of ticks per workday. CONCLUSIONS: The use of permethrin treated trousers does not completely prevent tick infestations. Improvement of tick protection has been shown only for some applications, but not in general. Additional prevention measures are therefore still indispensable. PMID- 25528908 TI - Evaluation of working conditions of workers engaged in tending horses. AB - INTRODUCTION: A growing interest in the horse business has resulted in the increased engagement of many people in this area, and the health problems occurring among workers create the need to search for prophylactic measures. OBJECTIVE: The objective of the study was evaluation of the level of exposure to air pollution in a stable, and estimation of the degree of work load among workers engaged in tending horses. MATERIAL AND METHODS: The study was conducted twice, during the winter season, in a stable maintaining race horses, and in a social room. In order to evaluate workers' exposure, air samples were collected by the aspiration method. After the incubation of material, the total number of bacteria and fungi in the air was determined, as well as the number of aerobic mesophilic and thermophilic bacteria, expressed as the number of colony forming units per cubic meter of air (CFU/m3). The measurement of total dust concentration in the air was also performed, simultaneously with the measurement of microclimatic parameters. The study of work load also covered the measurement of energy expenditure, evaluation of static physical load, and monotony of movements performed. CONCLUSIONS: The stable may be considered as a workplace with considerable risk of the occurrence of unfavourable health effects. PMID- 25528909 TI - Prevalence of tick-borne pathogens in an urban park in Rome, Italy. AB - INTRODUCTION: Limited information is available about the presence of tick-borne pathogens in urban parks in Italy. To fill this gap, ticks were collected in a public park in Rome over a 1-year period and screened by molecular methods for tick-borne pathogens. RESULTS AND CONCLUSION: The most abundant tick species were Rhipicephalus turanicus and Ixodes ricinus. The predominant pathogens detected were Borrelia. burgdorferi sensu lato (36%), Rickettsia spp. (36%), and Coxiella burnetii (22%). Among less frequently detected pathogens, Babesia microti was detected for the first time in Italy, with a prevalence of 4%. Neither Bartonella spp. nor Francisella tularensis were detected. With regard to co-infections, the most frequent double and triple infections involved Rickettsia spp., B. burgdorferi sl., and C. burnetii.. A positive correlation was detected between pathogens and I. ricinus. Further studies are needed in order to assess risk associated with tick-borne pathogens in urban areas. PMID- 25528910 TI - Isolation of Listeria monocytogenes from milks used for Iranian traditional cheese in Lighvan cheese factories. AB - Traditional Lighvan cheese is a semi-hard cheese which has a popular market in Iran and neighboring countries. The aim of this study was evaluating the contamination of milks used for Lighvan cheese making with Listeria monocytogenes. Raw milk samples were randomly collected from different cheese producing factories (sampling carried out from large milk tanks used cheese making in factories). Isolation of L. monocytogenes was performed according to ISO 11290 and biochemical tests were done to identify and confirm L. monocytogenes. 9 samples (50%) of the 18 collected samples from milk tanks in Lighvan cheese producing factories were contaminated with L. monocytogenes. The concentration of L. monocytogenes in all 9 positive samples was 40 CFU/ml. This study is the first report of L. monocytogenes contamination in raw milks used for Lighvan cheese production in Iran. Regarding the fact that these cheeses are produced from raw milk and no heating process is performed on them its milk contamination can be a potential risk for consumers. PMID- 25528911 TI - Occurrence of Leptospira DNA in water and soil samples collected in eastern Poland. AB - Leptospira is an important re-emerging zoonotic human pathogen, disseminated by sick and carrier animals, water and soil. Weather calamities, such as flooding or cyclones favour the spreading of these bacteria. To check a potential role of natural water and soil in the persistence and spread of Leptospira on the territory of eastern Poland, 40 samples of natural water and 40 samples of soil were collected from areas exposed to flooding, and 64 samples of natural water and 68 samples of soil were collected from areas not exposed to flooding. Samples of water were taken from various reservoirs (rivers, natural lakes, artificial lakes, canals, ponds, farm wells) and samples of soils were taken at the distance of 1-3 meters from the edge of the reservoirs. The samples were examined for the presence of Leptospira DNA by nested-PCR. Two out of 40 samples of water (5.0%) collected from the area exposed to flooding showed the presence of Leptospira DNA, while all 40 samples of soil from this area were negative. All samples of water and soil (64 and 68, respectively) collected from the areas not exposed to flooding were negative. No significant difference were found between the results obtained in the areas exposed and not exposed to flooding. In conclusion, these results suggest that water and soil have only limited significance in the persistence and dissemination of Leptospira in eastern Poland. PMID- 25528912 TI - Effect of isopropyl methylphosphonofluoridate (IMPF) poisoning on selected immunological parameters of angiogenesis. AB - INTRODUCTION AND OBJECTIVE: Acetylcholinesterase (AChE) and cholinergic receptors play an important role in the immune system, including lymphocyte-induced angiogenesis. However, their exact role is not fully understood. The presented work tests the influence of isopropyl methylphosphonofluoridate (IMPF), an irreversible inhibitor of AChE, on selected immune parameters associated with angiogenesis in mice. The levels of VEGF, bFGF, TNF-alpha, and IFN-gamma production were measured, together with the ability of lymphoid spleen cells to induce local GvH reaction after a single dose of IMPF. MATERIALS AND METHOD: Experiments were performed in male BALB/c mice. Acetylcholinesterase activity in erythrocytes was determined by the Ellman's procedure. Levels of cytokines were measured in serum using standard commercial ELISA kits. Influence of IMPF intoxication upon angiogenesis was examined by the LIA test, according to the Sidky and Auerbach procedure. RESULTS: The results showed a 6- and 8-fold increase in VEGF at days 1 and 7 of the experiment, respectively, as well as a decrease (at days 14 and 21 after administration), followed by a significant increase (day 1) in bFGF levels. A statistically significant decrease in the concentration of IFN-gamma was observed throughout all experiments. The maximum decrease in the level of TNF-alpha was found at days 1 and 7 after administration of IMPF. Additionally, a significant decrease was found in the ability to form new blood vessels following IMPF administration. CONCLUSIONS: This study revealed that IMPF has a significant effect on the regulation of lymphocyte-induced angiogenesis, which is related with the modulation of angiogenic and pro inflammatory cytokines secretion. The observed differences suggest a possible derangement of certain elements of the neuronal and/or non-neuronal cholinergic system. PMID- 25528913 TI - Disturbance of posture in children with very low lead exposure, and modification by VDR FokI genotype. AB - INTRODUCTION AND OBJECTIVE: Lead has a negative effect on the central nervous system (CNS), inter alia indicated by disturbance of posture. However, knowledge of the CNS effects at low exposure is insufficient. Individuals differ in vulnerability, possibly because of genetic predisposition. Polymorphisms in the delta-aminolevulinic acid dehydratase (ALAD) and vitamin D receptor (VDR) genes may modify lead metabolism and neurotoxicity. The objective of the study was to determine whether very low lead exposure affects posture in children, and whether ALAD and VDR genotypes modify the effect. MATERIALS AND METHODS: In 1996-2001, 108 (age 5-13, mean 6.9), and in 2008-2010 231 (age 5-11, mean 7.9) children from Poland were tested by posturography and blood-lead concentration (B-Pb; medians 50 and 36 ug/L, respectively). The children were genotyped for ALAD (RsaI, MspI) and VDR (FokI, BsmI, TaqI). RESULTS: There were correlations between posture and B-Pb (sway area with closed eyes: rS=0.24, P<0.001; velocity: rS=0.21, P<0.001). Significant effects (adjusted for the potential confounders height and mother's education) were present already at (ln-transformed) B-Pb<50 ug/L [beta (regression coefficient) for sway area 0.025, p=0.001), and even stronger than at higher levels (beta=0.006, p=0.06, respectively)]. The ff carriers in VDR FokI polymorphism were more susceptible to the effect of lead on the balance system, while other VDR or ALAD genotypes did not significantly modify the effect. CONCLUSIONS: Effects on CNS, as reflected by disturbances of posture, were present at very low lead exposure (B-Pb<50 ug/L), and the effect was significantly greater at such low B-Pbs than at higher. VDR FokI significantly modified the effect. PMID- 25528914 TI - Relative efficiencies of the Burkard 7-Day, Rotorod and Burkard Personal Samplers for Poaceae and Urticaceae pollen under field conditions. AB - INTRODUCTION: In aerobiological studies it is often necessary to compare concentration data recorded with different models of sampling instrument. Sampler efficiency typically varies from device to device, and depends on the target aerosol and local atmospheric conditions. To account for these differences inter sampler correction factors may be applied, however for many pollen samplers and pollen taxa such correction factors do not exist and cannot be derived from existing published work. MATERIALS AND METHODS: In this study, the relative efficiencies of the Burkard 7-Day Recording Volumetric Spore Trap, the Sampling Technologies Rotorod Model 20, and the Burkard Personal Volumetric Air Sampler were evaluated for Urticaceae and Poaceae pollen under field conditions. The influence of wind speed and relative humidity on these efficiency relationships was also assessed. Data for the two pollen taxa were collected during 2010 and 2011-2012, respectively. RESULTS: The three devices were found to record significantly different concentrations for both pollen taxa, with the exception of the 7-Day and Rotorod samplers for Poaceae pollen. Under the range of conditions present during the study, wind speed was found to only have a significant impact on inter-sampler relationships involving the vertically orientated Burkard Personal sampler, while no interaction between relative efficiency and relative humidity was observed. CONCLUSIONS: Data collected with the three models of sampler should only be compared once the appropriate correction has been made, with wind speed taken into account where appropriate. PMID- 25528915 TI - Pre- and postnatal exposure of children to tobacco smoke during the first four years of life--observations of the authors. AB - INTRODUCTION: Environmental exposure to tobacco smoke is a significant threat for human health, where the higher is its degree, the more immature the human organism is. Therefore, the exposure to Tobacco smoke in foetal life exerts unfavourable effects on developing foetus and may cause early and distant results in children. MATERIAL AND METHODS: The study comprised 318 children in their first four years of life, treated for various medical conditions. The examined children were divided into two groups, Group 1--children exposed to Tobacco smoke -and Group 2--a control group with children from non-smoking families. History data were obtained on the basis of a specially designed questionnaire, used by the doctor in an individual conversation with parent. In each third child from the group 1 cotinine concentration in urine was assayed by the method of high performance liquid chromatography-UV-VIS and the cotinine/creatinine ratio was calculated. RESULTS OF STUDY: Results demonstrated environmental exposure to tobacco smoke in 173 children (Group 1). Out of them 31.2% were the children whose mothers had smoked also during pregnancy (Subgroup A). The other 119 children from Group 1 were accounted to Subgroup B, i.e., children, where other household members had been smoking cigarettes. A comparative group comprised 143 children from non-smoking families. The results demonstrated then that 17% of all the examined children were those, exposed to tobacco smoke effects already in their foetal life, predisposing them to prematurity and low birth weight. Moreover, it was observed that the young age and lower education level of their parents, together with worse housing conditions, may suggest a predisposing character and role of the mentioned factors. PMID- 25528916 TI - Residential proximity to major roadways is associated with increased prevalence of allergic respiratory symptoms in children. AB - INTRODUCTION AND OBJECTIVE: Numerous epidemiologic studies have reported increased risk of allergic rhinitis and asthma in relation to 'western life style', which represents diversity of factors. We hypothesized that residential proximity to major roadways, reflecting an exposure to traffic-related air pollution, is associated with prevalence of allergic respiratory symptoms in children. MATERIALS AND METHODS: A total of 8290 individuals of two age groups: 16 year olds and 7 year olds from Krakow, Poland were included. We used the Polish version of the International Study of Asthma and Allergy in Childhood supplemented with a question concerning the distance between a responder's house and a high traffic density road: below 200 m, from 200-500 m, or more than 500 m. RESULTS: Children and adolescents with a residential proximity closer to a major roadway had more frequent asthma-related symptoms in the last 12 months and at any time in the past. Consistent with the increased frequency of asthmatic symptoms, responders residing within 200 meters complained more often of sneezing, runny or blocked nose accompanied by itchy-watery eyes and hay fever in comparison to responders who resided 200-500 meters from a major roadway. The lowest rate of nasal symptoms was observed in residents living in the distance to major roads (> 500 meters). The rate of positive answers decreased in a distant dependent manner. CONCLUSIONS: Our findings suggest an important spatial relationship between the distance from a major roadway and the evaluated respiratory symptoms. The results emphasize the need for more comprehensive air quality policies within urban areas with increased motor vehicle density. PMID- 25528917 TI - Prevalence of antibodies against selected zoonotic agents in forestry workers from eastern and southern Poland. AB - INTRODUCTION AND OBJECTIVE: Due to the nature of their work, foresters are exposed to many infectious pathogens from the wildlife reservoir. The primary aim of this study was to assess their contact with these pathogens. MATERIAL AND METHODS: Sera and antibodies, mainly of IgG class against selected infectious factors, collected from a group of 216 employees of National Forests from eastern and southern Poland, were investigated. RESULTS: Antibodies to Anaplasma phagocytophilum were detected in 64 sera (29.6%), to Bartonella spp. in 133 sera (61.6%), to Babesia microti in 50 sera (23.1%), and to Coxiella burnetii in 14 sera (6.4%); 7 sera (3.2%) were positive to Francisella tularensis. In studies of diseases not carried by ticks positive results were found in 28 sera (12.9%) to Toxocara canis, 13 sera (6.0 %) to Trichinella spiralis, and in 7 sera (3.2%) to Echinococcus granulosus. Antibodies to Hanta viruses were detected with antigens from Puumala and Dobrava/Hantaan strains in both IgM and IgG class. In 9 foresters, positive results were found, including one positive result to 2 antigens, 5 to Dobrava/Hantaan antigen and 3 to Puumala antigen. CONCLUSION: Frequently higher percentages of positive results were found in people working utdoors, and in men when compared with women. PMID- 25528918 TI - Transmission of second-hand smoke sensitivity and smoking attitude in a family. AB - INTRODUCTION AND OBJECTIVE: The role of genetic factors in nicotine dependence is well understood, but no information is available on the inheritability of second hand smoke (SHS) exposure sensitivity and their co-variance. MATERIALS AND METHODS: 186 adult same-gender pairs of twin (146 monozygotic, 40 dizygotic; 44+/ 17 years+/-SD) completed a questionnaire. RESULTS: The model showed a significant role of unshared environmental factors influencing the co-variance between smoking habit and SHS sensitivity (re=-0.191, 95% CI, -0.316 to -0.056, or the total phenotypic correlation of rph=-0.406, p<0.001) without evidence for genetic covariation. Age, gender and country-adjusted analysis indicated 51.5% heritability for smoking habit (95% confidence interval/CI/, 6.2 to 89.8%), 49.7% for SHS sensitivity (95%CI, 19.1-72.0%), 35.5% for general opinions on SHS exposure in restaurants/cafes (95%CI, 10.7-58.6%), and 16.9% in pubs/bars (95%CI, 0.0-49.0%). CONCLUSIONS: The co-variance between SHS sensitivity and smoking habits is driven mainly by the unshared environment. SHS sensitivity is moderately inheritable. The considerable influence of environmental factors on general opinions on SHS exposure in designated indoor public venues emphasizes the importance of smoking bans and health behaviour interventions at the individual level in developing an anti-smoking attitude. PMID- 25528919 TI - Psychoactive substances use experience and addiction or risk of addiction among by Polish adolescents living in rural and urban areas. AB - The objective of the study was to determine the similarities and differences between adolescents with psychoactive substances use experience living in urban and rural areas as regards the intensity of Internet addiction symptoms as well as the evaluation of prevalence of psychoactive substances use among adolescents depending on the place of residence. The examined group consisted of 1 860 people (1 320 girls and 540 boys) their average age being 17 years. In the study the following research methods were used: the Sociodemographic Questionnaire designed by the authors, the Internet Addiction Questionnaire by Potembska, the Internet Addiction test by Young, the Internet Addiction Questionnaire (KBUI) designed by Pawlowska and Potembska. Statistically significant differences were found as regards the prevalence of psychoactive substances use by the adolescents living in urban and rural areas and as regards the intensity of Internet addiction symptoms in adolescents, both from the urban and rural areas, who use and do not use illegal drugs. Significantly more adolescents living in urban areas as compared to their peers living in rural areas use psychoactive substances, mainly marihuana. The adolescents who use psychoactive substances, as compared to the adolescents with no experience using illegal drugs, living both in urban and rural areas significantly more often play online violent games and use web pornography. The adolescents living in rural areas who use psychoactive substances significantly more often as compared to the adolescents who do not use these substances claim that it is only thanks to the interactions established on the Internet that they can get acceptance, understanding and appreciation. PMID- 25528920 TI - Quality of life and occurrence of depression under chemotherapy in patients suffering from lung carcinoma. AB - INTRODUCTION AND OBJECTIVE: In Poland, lung carcinoma is the most frequent malignant neoplasm in men and the third most frequent in women. The neoplastic disease causes enormous psychic stress and may lead to depressive reactions. The purpose of this research was to assess the quality of life and the occurrence of depression in patients suffering from lung neoplasms and undergoing chemotherapy. MATERIALS AND METHOD: The research covered 102 patients (test group TG) with lung carcinoma and undergoing chemotherapy. In the research, standardised questionnaires: EORTC-QLQ-C30, Beck Depression Inventory and a matrix developed by the researcher were applied. The control group (CG) consisted of 60 healthy people who were examined by the Beck Depression Inventory. RESULTS: A highly statistically significant dependency was found (p<0.01) between the general quality of life and the occurrence of depression. 51.5% of those examined with a very low level of general quality of life had the symptoms of severe depression. Those examined who had a very high level of general quality of life did not have features of severe depression. A statistically significant dependency (p<0.01) was ascertained between the occurrence of depression and the health condition of those examined. CONCLUSIONS: Depression symptoms occur more frequently and with greater intensity in patients suffering from lung neoplasm, compared to the group of healthy people (p<0.01). A statistically significant connection between marital status, place of residence, and assessment of quality of life was found out (p<0.05). PMID- 25528921 TI - Dysfunctions associated with dementia and their treatment. AB - International UnderstAID project shows the role of physiotherapist in patients with dementia as divided into two branches: helping to resolve the physical problems and solving the problems related to dementia. The role of physiotherapist in dementia treatment may be divided into two branches: helping to resolve the physical problems and solving the problems related to dementia. The physical problems consider such aspects as musculoskeletal disorders, mobility dysfunction and pain. Referring to musculoskeletal problems, the interventions of physical therapists should included whole-body progressive resistance exercise training, strengthening, "range-of-motion" and stretching exercises and transfer training. Mobility disorders are associated with physical symptoms such as: rigidity, balance problem, shuffling gait. Decreased mobility can be based on unrelieved pain. These are some crucial scales which are designed to detected the pain. For instance, The Pain Assessment in Advanced Dementia. Transcutaneous Electrical Nerve Stimulation, massage or exercises can be provide to reduce the pain in patients with dementia. Physiotherapy in dementia treatment influences not only physical functions but also the maintenance or progression of cognitive abilities of demented elderly subjects. PMID- 25528922 TI - Selected breast cancer risk factors and early detection of the neoplasm in women from Lublin region attending screening program in St. John's Cancer Center, years 2005-2006. AB - INTRODUCTION AND OBJECTIVE: In Poland, consulting is offered to women about risk factors of breast cancer, breast symptoms and early cancer detection. Study aims were to evaluate the correlation between some risk factors and women's attendance to breast checkups, and to assess links between risk factors and detection of early breast cancer. MATERIALS AND METHODS: The study involved 8014 women aged 50 69 years, participating in breast cancer screening program. The frequency of breast checkups (mammography, CBE and BSE) and occurrence of breast cancer risk factors in studied women were evaluated as well as clinical stage of detected tumors. Odds ratios were used to compare relative odds of breast cancer with exposure to risk factors. RESULTS: 47.11% studied women had regularly undergone MMG, 30.82% had CBE within the previous year, 14.26% regularly performed BSE. The incidence of risk factors varied from 2.94% (menarche at <=11 years) to 12.38% (current use of HRT). In 47.82% women, no evidence of studied risk factors was found. Women with history of breast biopsies and current users of HRT had MMG, CBE and BSE significantly more often (p<0.0001). 29.27% early breast cancers (pTis, pT1abN0) were found among 82 detected tumors. Relative odds of breast cancer occurrence in women without the risk factors were significantly lower (OR=0.55, 95% CI [0.35; 0.86]). Only nulliparous women had significantly higher odds of early breast cancer (OR=7.37, 95% CI [1.32; 41.17]). CONCLUSIONS: Women using HRT and women after breast biopsy were significantly more likely to attend breast checkups. There were no significant links between most risk factors and odds of early stages of breast cancer. Women should have preventive checkups irrespective of their breast cancer risk factors. PMID- 25528924 TI - Influence of caffeine administered at 45 degrees C on bone tissue development. AB - INTRODUCTION AND OBJECTIVE: Caffeine is one of the world's most commonly ingested alkaloids which easily permeates the placenta. The teratogenic and embryotoxic influence of large doses of caffeine has been established in many experimental studies on animals. The objective of this work was to assess the influence of caffeine, administered at 45 degrees C, on the development of the bone tissue of rats, with particular reference to elemental bone composition using an X-ray microprobe. MATERIALS AND METHODS: The research was conducted on white rats of the Wistar strain. The fertilized females were divided into two groups: an Experimental Group (Group E) and a Control Group (Group C). The females in Group E were given caffeine orally (at 45 degrees C) in 30 mg/day doses from the 8th to the 21st day of pregnancy. The females in Group C were given water at the same temperature. The fetuses were used to assess the growth and mineralization of the skeleton. A qualitative analysis of the morphology and mineralization of bones was conducted using the alcian-alizarin method. For calcium and potassium analysis, an X-ray microprobe was used. RESULTS: By staining the skeleton using the alcian-alizarin method, changes in 52 of Group E fetuses were observed. The frequency of the development variants in the Group E rats was statistically higher, compared with Group C. CONCLUSIONS: Receiving caffeine at a higher temperature may result in different pharmacodynamics and significantly change tolerance to it. In Group E, a significant decrease in the calcium level, as well as an increase in the potassium level, was observed. The X-ray microprobe can be a perfect complement to the methods which enable determination of the mineralization of osseous tissue. PMID- 25528923 TI - Methods of analysis of gut microorganism--actual state of knowledge. AB - INTRODUCTION: Microbiota plays an integral part in maintaining organism homeostasis, through eliminat pathogens, anti-cancer activity, synthesis of digestive enzymes and vitamins, maintaining the continuity of the intestinal epithelium and stimulation of the gastrointestinal immune system, and encourage a quicker and more efficient immune response. Changes in the microbiota composition is often observed in patients with allergy, atopy, irritable bowel syndrome and other diseases, which is the reason for a growing interest in methods of identification of the gut microbial complex. OBJECTIVE: The aim of the study was to compare the state of current knowledge about two methods used in the study of intestinal microorganisms complex: the traditional culture method and genetic analysis. DESCRIPTION OF THE STATE OF KNOWLEDGE: Both techniques have advantages and disadvantages. The biggest limitation of the culture method is its inability to detect a significant number of the intestinal microbes. Using the microbiological technique we can only detect identifiable bacteria that can be grown on available substrates. For an accurate quantitative and qualitative investigation of the total microbiota, the more expensive genetic method is required. Due to genetic analysis it is possible to identify the vast number of new microorganisms and identify the dominant bacterial groups in different parts of the gastrointestinal tract. SUMMARY: Each of the presented techniques plays specific role in medicine and science. The combination of both methods may become a critical element for understanding the ecosystem of intestinal bacteria. PMID- 25528925 TI - Evaluation of relations between body posture parameters with somatic features and motor abilities of boys aged 14 years. AB - INTRODUCTION: Body posture is an individual characteristic for everyone, it shows great differentiation - especially in people during their progressive development. As a result, the variability of the development and lack of physical activity impose body posture defects in children and youth. In the literature there is a great lack of measureable data on the relations between correct body posture with somatic features, especially motor features in children at the developing age. The aim of this study was to evaluate the relations between correct body posture parameters, measured with the photogrammetric method, with some of the somatic features and motor abilities of boys at the age of 14. MATERIAL AND METHODS: The study included 133 boys aged 14 attending junior secondary schools in the Krakow area of Poland. Only boys with the correct body posture were examined. Posture was examined by the Moire method, through which six parameters were obtained in the sagittal plane, seven in the frontal plane, and one in the transverse plane. The somatic measurements included basic parameters, such as body weight and body height. The measurements of motor features included: marching balance test, speed movement test of the arms and their functional strength. To evaluate the relationships between correct body posture with the characteristics of somatic and motor abilities, the Spearman rank correlation was used. The lowest level of statistical significance was accepted at p<=0,05. RESULTS: No correlations were noted between some of the correct body posture features and the somatic features, and some of the motor abilities of the examined boys at the level of p<=0.05 and p<=0.01. CONCLUSIONS: The irregular correlation between the correct body posture and somatic and motor features probably results from the rather big development variability of the boys during puberty. PMID- 25528926 TI - Mental illness and metabolic syndrome--a literature review. AB - INTRODUCTION AND OBJECTIVE: Researchers' opinions are divided on whether metabolic syndrome is a separate clinical entity. Undoubtedly, the components of the syndrome, such as abdominal obesity, hypertension, impaired glucose tolerance, hypertriglyceridaemia, adversely affect metabolism, bringing with it a number of consequences, including type 2 diabetes and cardiovascular disease which significantly impair the quality of life. ABBREVIATED DESCRIPTION OF THE STATE OF KNOWLEDGE: In recent years, much attention has been paid to research on the prevalence of metabolic disorders in mentally ill patients. This is due to a growing awareness that some antipsychotic medications contribute to weight gain in patients suffering from mental illness, and consequently lead to the development of a number of interrelated somatic factors, such as abdominal obesity, impaired glucose tolerance, hypertriglyceridaemia, and hypertension. Weight gain and other metabolic syndrome components have been noticed not only in patients, but also in their families. This paper presents current research on the prevalence of metabolic syndrome in people with mental illness. An analysis of the causes of metabolic disorders in this population has been conducted, including the role of the hypothalamic-pituitary-adrenal axis and cortisol secretion in the development of components of metabolic syndrome. CONCLUSIONS: Components of the metabolic syndrome are especially observed in mentally ill people. The mechanisms of their formation are not fully understood. A large role in their formation besides the negative effects of antipsychotic medication and specific lifestyle, play a specific dysregulation of the hypothalamic-pituitary adrenal axis. Undoubtedly, further research and analysis in this area is necessary. PMID- 25528927 TI - Prevalence of human papillomavirus (HPV) in upper respiratory tract mucosa in a group of pre-school children. AB - INTRODUCTION: Human Papillomavirus (HPV) is a group of DNA viruses which is an etiological factor of many benign and malignant diseases of the upper respiratory tract mucosa, female genital tract and the skin. HPV infection is considered a sexually-transmitted infection, but can also be transmitted by non-sexual routes, including perinatal vertical transmission, physical contact, iatrogenic infection and autoinoculation. Recurrent Respiratory Papillomatosis (RRP) in children is connected with HPV infection transmitted vertically from mother to child during the passage of the foetus through an infected birth canal. OBJECTIVE: The aim of this study was to establish the level of Human Papillomaviruses carrier state in upper respiratory tract mucosa in healthy pre-school children, and to identify potential risk factors for HPV infection. MATERIALS AND METHOD: After obtaining consent from their parents, 97 pre-school children were examined--51 girls and 46 boys between the ages of 3-5 years; average age--4 years and 5 months. 68 children were urban dwellers and 29 came from a rural environment. A questionnaire with detailed history was taken including parents' and child's personal data, as well as perinatal risk factors in pregnancy. Socio-demographic information was also obtained, including the standard of living, and chosen environmental factors. Routine ENT examination was performed. Exfoliated oral squamous cells were collected from swabs and analysed for the presence of DNA papillomaviruses by polymerase chain reaction. RESULTS: The presence of HPV in the respiratory tract in children was detected in 19.6% cases. 'High oncogenic potential' HPVs, such as HPV-16 and HPV-18, were not observed in squamous cell mucosa of the respiratory tract in the children. No significant differences were observed between the HPV carrier state in urban and rural inhabitants. PMID- 25528928 TI - Dietary exposure to cadmium, lead and nickel among students from south-east Poland. AB - The dietary intake of cadmium, lead and nickel was determined among students from three universities in the city of Lublin in south-east Poland to assess the levels of exposure to these contaminants, compared to PTWI and TDI values. The study was performed in 2006-2010 and involved 850 daily food rations of students. The technique of 24-hour dietary recall and diet duplicates was used. Cadmium, lead and nickel complexes with ammonium-pyrrolidindithiocarbamate were formed and extracted to the organic phase with 4-methylpentan-2-one-MIBK, in which their content was measured by flame atomic absorption spectrometry. The highest intake of the elements studied was observed in 2008. The data show that in none of the cases, the level of intake reached 70% of PTWI/TDI values, and thus the risk of developing diseases related to high exposure to these toxic metals absorbed from foodstuffs was low. The parameters of methods were checked during determinations by adding standard solutions to the samples before mineralization and by using two reference materials: Total diet ARC/CL HDP and Bovine muscle RM NIST 8414. The dietary exposure to lead and cadmium has significantly decreased in recent years, whereas the exposures to nickel remains on a stable level. PMID- 25528929 TI - Assessment of diet in chronic kidney disease female predialysis patients. AB - INTRODUCTION AND OBJECTIVE: Nutrition is important in the therapy of predialysis patients. The aim of the presented single-centre descriptive study was to assess the diet in chronic kidney disease female predialysis patients with no previous dietary intervention, in comparison with recommendations, as well as the analysis of the energy, protein and phosphate intake in correlation with chosen laboratory measurements. MATERIALS AND METHODS: The research was carried out in 31 female predialysis patients with CKD of different etiology, aged 29-79 years (GFR: 19.4+/-9.7 ml/min/1.73 m2). Main outcome measures were self-reported data from three-day dietary recall. Nutrients content and energy value of diet were compared with guidelines for chronic kidney disease patients or, in case of nutrients when they are not settled, with the recommendations for healthy women. RESULTS: All patients had a lower energy intake than the recommended level. At the same time, 35.8% of patients were characterised by improper protein intake- too low or too high. The majority of patients had low intake of most of vitamins and minerals. The total, animal and plant protein were positively correlated with the energy value of diet and with amount of most of the nutrients. Values of GFR were positively correlated with animal protein intake, while phosphate and creatinine in blood were negatively correlated with total and animal protein intake. CONCLUSIONS: The study highlights that diet of CKD predialysis patients with no previous dietary intervention is not properly balanced. PMID- 25528930 TI - Biological psychological and social determinants of old age: bio-psycho-social aspects of human aging. AB - The aging of humans is a physiological and dynamic process ongoing with time. In accordance with most gerontologists' assertions it starts in the fourth decade of life and leads to death. The process of human aging is complex and individualized, occurs in the biological, psychological and social sphere. Biological aging is characterized by progressive age-changes in metabolism and physicochemical properties of cells, leading to impaired self-regulation, regeneration, and to structural changes and functional tissues and organs. It is a natural and irreversible process which can run as successful aging, typical or pathological. Biological changes that occur with age in the human body affect mood, attitude to the environment, physical condition and social activity, and designate the place of seniors in the family and society. Psychical ageing refers to human awareness and his adaptability to the ageing process. Among adaptation attitudes we can differentiate: constructive, dependence, hostile towards others and towards self attitudes. With progressed age, difficulties with adjustment to the new situation are increasing, adverse changes in the cognitive and intellectual sphere take place, perception process involutes, perceived sensations and information received is lowered, and thinking processes change. Social ageing is limited to the role of an old person is culturally conditioned and may change as customs change. Social ageing refers to how a human being perceives the ageing process and how society sees it. PMID- 25528931 TI - Physical activity of Poles--critical analysis of research 2010-2014. AB - The aim of the study was an analysis of research on the physical activity (PA) carried out among Poles from 2010 - 2014 on a national scale. The obtained results concerning PA and recommended levels of PA, in particular those issued by the World Health Organization (WHO), were taken into consideration. The research articles were obtained through searching English-language scientific databases and common search engines. National-level research conducted within the Polish population aged 10 years and above were taken into account. Studies presenting the PA of Poles without division into age categories were excluded. Seven research papers presenting studies on children and adolescents (aged 10-18 years), adults (aged 19-64 years) and older adults (aged 65+ years) were included into the subsequent analysis. When referring to the accepted criteria within the PA research satisfactory levels of PA were observed in: a) 4.2%-91.4% of female subjects and 17.9%-93.8% of male subjects aged 10-18 years, b) 9.2%-77.6% of male subjects and 12.0%-77.6% of female subjects aged 19-64 years, c) 11.9%-50.7% of male subjects and 11.1%-50.7% of female subjects aged 65 years and above. The results obtained in the study demonstrate a very wide variability of PA levels, thus rendering these results implausible. Recommendations issued by the WHO for the PA were assumed in only two cases. The study was conducted by use of the self reported method, primarily with research tools which did not meet psychometric standards were employed. It is necessary to perform systematic studies on the methodological correctness of research on the PA of Poles. On the basis of the study carried out from 2010-2014 it is difficult to answer reliably the question: 'What are the levels of PA of Polish subjects?' PMID- 25528932 TI - Effects of aerobic interval training versus continuous moderate exercise programme on aerobic and anaerobic capacity, somatic features and blood lipid profile in collegate females. AB - INTRODUCTION: Regular physical activity has many positive health benefits, including reducing the risk of cardiovascular diseases, metabolic diseases and some cancers, as well as improving the quality of life. objectives. The aim of the study was to examine the effects of 8-week aerobic interval cycle exercise training (AIT) compared to continuous cycle exercises of moderate intensity (CME) on the aerobic and anaerobic capacity, somatic features and lipid profile. MATERIAL AND METHODS: The research was conducted in 88 volunteers aged 19.5+/-0.6 years, who were randomized to three groups of organized physical activity (OPA), who exercised 3 times per week in 47 min sessions: (I) AIT (n=24) comprising 2 series of 6x10 s sprinting with maximal pedalling cadence and active rest pedalling with intensity 65%-75% HRmax, (II) CME (n=22) corresponding to 65%-75% HRmax, (III) regular collegiate physical education classes of programmed exercises (CON; n=42). Before and after OPA anthropometrics, aero- and anaerobic capacity and lipid profile indices were measured. RESULTS: In AIT, a significantly greater decrease of waist circumference and WHR was noted when compared to CON, and a significantly greater reduction of sum of skinfolds than in CON and CME. Improvement in relative and absolute VO2max (L/min and ml/kg/min) was significantly higher in AIT than CON. Work output and peak power output in the anaerobic test improved significantly in AIT, CME and CON, but independently of training type. OPA was effective only in reducing triglyceride concentrations in CME and CON groups, without interaction effects in relation to training type. CONCLUSION: It was found that 8 weeks of OPA was beneficial in improving somatic and aerobic capacity indices, but AIT resulted in the greatest improvement in somatic indices (waist circumference, WHR, sum of skinfolds) and in VO2max, compared to CME and CON programmes. PMID- 25528933 TI - Postpartum adiponectin changes in women with gestational diabetes. AB - INTRODUCTION AND OBJECTIVE: Current literature provides contradictory information on the role of adiponectin (AdipoQ) in the course of gestational diabetes mellitus (GDM) and the changes after delivery. The aim of the study was to measure AdipoQ concentration in blood of women with GDM, and to conduct a comparative analysis of AdipoQ concentrations in gestation at 3 and 12 months after delivery. MATERIAL AND METHODS: The study group consisted of 50 women diagnosed with GDM between 24 and 28 weeks of gestation. Three months after delivery, 41 women underwent further tests, while 12 months after delivery 30 patients. All patients underwent clinical and laboratory evaluation at GDM diagnosis at 3 and 12 months after delivery. Laboratory evaluation included fasting glucose, fasting insulin, OGTT and lipid parameters in serum. Serum AdipoQ concentration was measured at GDM diagnosis as well as at 3 and 12 months after delivery. RESULTS: AdipoQ concentrations did not differ significantly between the groups during gestation (p=0.7054) and 3 months after delivery (p=0.9732), while a significant rise was observed 12 months after delivery, compared to the values during pregnancy (p=0.0006). AdipoQ in the GDM group 12 months after delivery inversely correlated with fasting glucose and 2-hour post load plasma glucose after a 75-g oral glucose tolerance test (r=-0.37*; p<0.05 and r=-0.42, p<0.05, respectively). CONCLUSIONS: An increased level of AdipoQ after delivery in the comparison to women with GDM may be a marker for reversibility of carbohydrate metabolism disorders, while a negative correlation between AdipoQ and glucose levels suggests that this parameter may be a predictor In the future of disturbances in glucose tolerance in women with GDM. PMID- 25528934 TI - Care concept in medical and nursing students' descriptions--philosophical approach and implications for medical education. AB - INTRODUCTION: Care is seen as something that is peculiar to the medical sciences but its meaning and status for physicians and nurses differs. OBJECTIVES: The aim of this research was to learn how nursing and medical students understand and define care, and how their definition and views on their practice of caring change as they advance through their studies. MATERIAL AND METHODS: The study was conducted among two groups of students: before and after their first practicum (n=102). Analysis of the students' answers was carried out using Colaizzi's phenomenological descriptive methodology, which means that a qualitative approach was used. RESULTS: The qualitative analysis shows that the medical and nursing students define care in the same way, using 9 main categories: compassion, commitment, competence, confidence, conscience, communication, patience, courage and support. The nursing students viewed their caring to be within both practical and emotional dimensions and this was a core feature of their identity as nurses. Medical students, on the other hand, viewed the practical dimension of care as an additional activity. All the students in the study underlined the importance of having time to care and showed that, for them, 'time' in this context has a moral meaning. What was interesting to the research team centered on the initial attitudes to 'caring' from both medical and nursing students. CONCLUSIONS: We found that students of both nursing and medicine do not begin their studies with different attitudes and concepts of care. However, after their initial exposure to practical placements a process begins which forges different identities around the concept of care. This implies trends in the division of professional roles during their initial education. PMID- 25528935 TI - Evaluation of differences in health-related quality of life during the treatment of post-burn scars in pre-school and school children. AB - OBJECTIVE: The aim of the research was an assessment of the differences in the self-evaluation of health-related quality of life during the treatment of post burn scars on the upper limbs of pre-school and school children. MATERIALS AND METHOD: a group of 120 children were examined--66 boys and 54 girls, divided into a pre-school group of 60 children (average age 4.3+/-1.7) and a primary school group of 60 children (average age 10.4+/-1.2). The structured interview and an adopted Visual Analog Anxiety Scale and Visual Analog Unpleasant Events Tolerance Scale were used to evaluate the level of plaster tolerance, and anxiety caused by the removal of dressings during treatment. RESULTS: In the first test, In both groups, a low tolerance was noted to the pressure plaster, with the pre-school aged children obtaining worse results (x=18.9+/-SD 10.16) than those of school age (x=33.65+/-SD 13,21), regardless of gender. Pre-school children were afraid (x=47.5+/-SD 24.26), while school-aged children were not afraid of having the plaster removed (x=20.5+/-SD 9.46). The differences between the groups were statistically significant. In the fourth and final test on pre-school aged children, the tolerance of plasters had improved (x=23.24+/-SD 15.43) obtaining a value somewhat lower than for school-aged children (32.4+/-SD 6.45), as well as a noted fall in the anxiety level (30.83+/-SD 23.38) with an average value insignificantly higher than that recorded for the children of school age (15.83+/ SD 6.19). CONCLUSIONS: The tests confirmed the appearance of differences in the self-evaluation of health-related life quality in pre-school and school-aged children. PMID- 25528936 TI - Validation of the Polish language version of the SF-36 Health Survey in patients suffering from lumbar spinal stenosis. AB - INTRODUCTION AND OBJECTIVE: Patient-reported outcome (PRO) questionnaires have become the standard measure for treatment effectiveness after spinal surgery. One of the most widely used generic PROs is the SF-36 Health Survey. The aim of this study was to specifically focus on validating the SF-36 Health Survey to confirm that the tool is an acceptable and psychometrically robust measure to collect HRQoL data in Polish patients with spinal stenosis. MATERIALS AND METHODS: Patients were eligible if they were above 18 years of age and had been qualified for spine surgery of the lumbar region due to either discopathy or non-traumatic spinal stenosis. All patients filled-in the Polish version of the SF-36 and a demographic questionnaire. Standard validity and reliability analyses were performed. RESULTS: 192 patients (83 women--43.2%) agreed to take part in the study (mean age: 57.5+/-11.4 years). In 47 patients (24.5%), using MRI, ossification of the ligamenta flava were found. Cronbach's alpha coefficients showed positive internal consistency (0.70-0.92). Interclass correlations for the SF-36 ranged from 0.72-0.86 and proved appropriate test-retest reliability. Satisfactory convergent and discriminant validity in multi-trait scaling analyses was seen. CONCLUSIONS: The Polish version of the SF-36 is a reliable and valid tool for measuring HRQoL in patients with spinal stenosis. It can be recommended for use in clinical and epidemiological settings in the Polish population. However, caution is warranted when interpreting the results of the 'role limitations due to physical health problems' and the 'role limitations due to emotional problems' scales because of floor and ceiling effects. PMID- 25528937 TI - Neurofeedback training for peak performance. AB - AIM: One of the applications of the Neurofeedback methodology is peak performance in sport. The protocols of the neurofeedback are usually based on an assessment of the spectral parameters of spontaneous EEG in resting state conditions. The aim of the paper was to study whether the intensive neurofeedback training of a well-functioning Olympic athlete who has lost his performance confidence after injury in sport, could change the brain functioning reflected in changes in spontaneous EEG and event related potentials (ERPs). CASE STUDY: The case is presented of an Olympic athlete who has lost his performance confidence after injury in sport. He wanted to resume his activities by means of neurofeedback training. His QEEG/ERP parameters were assessed before and after 4 intensive sessions of neurotherapy. Dramatic and statistically significant changes that could not be explained by error measurement were observed in the patient. CONCLUSION: Neurofeedback training in the subject under study increased the amplitude of the monitoring component of ERPs generated in the anterior cingulate cortex, accompanied by an increase in beta activity over the medial prefrontal cortex. Taking these changes together, it can be concluded that that even a few sessions of neurofeedback in a high performance brain can significantly activate the prefrontal cortical areas associated with increasing confidence in sport performance. PMID- 25528939 TI - Assessment of differences in psychosocial resources and state of health of rural and urban residents--based on studies carried out on students during examination stress. AB - INTRODUCTION: Civilization changes of the environment shaping the psychosocial resources from rural to urban influence human health. AIM: The study aimed to identify the differences due to the place of residence (rural, urban) as far as health resources are concerned (social support, sense of coherence, dehydroepiandrosterone sulfate concentration in plasma) and health in examination stress situations. The study also determined the concentration of dehydroepiandrosterone sulfate (health resource) and cortisol (stress indicator). MATERIAL AND METHODS: The psychosocial variables were assessed using the scales: ISEL-48v. Coll., SOC-29, SF-36v.2TM o and analogue scale (perception of examination stress). The study included, based on a stratified sampling (year of study) and purposive sampling (written examination, major), 731 students representing the six universities in Lublin, south-east Poland. Among the respondents, 130 students were rural residents. RESULTS: Health resources of students living in rural and urban areas generally differ statistically significantly in social support and the subscales of availability of tangible support, availability of appreciative support, the availability of cognitive evaluative support and a sense of resourcefulness. The study recorded a sstatistically significantly larger network of family ties among students living in rural areas. The demonstrated diversity of resources did not substantially affect the perceived health, with the exception of pain sensation. Examination stress assessed by subjective opinion of the respondents and plasma cortisol levels vary relative to the place of residence. Students residing in rural areas showed significantly lower cortisol levels values, but subjectively perceived the situation of examation as more stressful. CONCLUSIONS: Differences in health resources and their mechanism of impact on health, to a limited extent, were conditioned by the place of residence, but they are so important in the light of human choices that they require further analysis. PMID- 25528938 TI - Disease-related social situation in family of children with chronic kidney disease--parents' assessment. A multicentre study. AB - INTRODUCTION AND OBJECTIVE: Chronic kidney disease (CKD) in children burdens life of patients and their families. Little is known about parents' assessment of families' social situation. However, the knowledge of the details of a patient's and his family's life standards might influence modification and optimization of applied therapy. Therefore, the main goal of the present study was to explore the selected elements of life situation of patients suffering with CKD as well as their parents, depending on the CKD stage and appropriate treatment. MATERIALS AND METHODS: Cross-sectional national study was conducted. A total of 203 children with CKD and 388 their parent-proxies (196 women and 192 men) were enrolled into this study. Patient data and questionnaires filled by both parents, concerning social-demographic parameters and assessment of changes in families after CKD diagnosis in the child, were analysed. RESULTS: CKD children are being brought up in proper families whose financial situation is not good. Children need help in process of education. Perception of current situation differed between both parents in the change of the income source, taking care of CKD child, change in social relations and evaluating relations with medical staff. Parents do not obtain proper support from social workers. CONCLUSION: Families of CKD children require support in area of financial and educational help for school children. The discrepancies in evaluation of family situation between mothers and fathers of ill children might be the source of conflicts possibly resulting in worsening the outcome for CKD children. PMID- 25528940 TI - Prostate cancer in patients from rural and suburban areas--PSA value, Gleason score and presence of metastases in bone scan. AB - INTRODUCTION: Prostate cancer is the second most common neoplasm among men both worldwide and in Poland. In prostate cancer, bone metastasis is related to a poorer prognosis. A diagnosis of metastatic bone disease is important in prostate cancer patients prior to therapy. Prostate specific antigen (PSA) serum value is used both as a screening tool and for staging of prostate cancer. AIM: To evaluate whether there is a link between symptoms presented by patients, pain in particular, and the presence, number and location of bone metastases as assessed by bone scan scintigraphy in concordance with PSA values and Gleason scores. MATERIAL: A group of 186 patients (aged: 68.38+/-6.16) diagnosed with prostate cancer, from rural and suburban areas of Malopolska province, that was directed for bone scan scintigraphy to the Nuclear Medicine Dept, John Paul II Hospital in Krakow. METHODS: Analysis of all laboratory findings (including PSA value) and a biopsy were performed. Then, bone scan scintigraphy was done with the use of methylene disphosphonate (MDP) labeled with Tc-99m. RESULTS: In patients with a Gleason value<=7 and a PSA value<=20 ng/ml, the cutoff value for a negative bone scan with a confidence interval of 0.95 was established at a PSA value below 10 ng/ml (p<0.01). Correlations were established between PSA value and presence of metastases in bone scan (r=0.45, p=0.05), the number of metastases (r=0.66, p<0.01), and their presence in particular body regions. CONCLUSIONS: The correlation between PSA value and both presence and number of metastases confirms the usefulness of bone scan scintigraphy in prostate cancer staging. The cutoff value for negative bone scan with a 95% confidence interval was established at PSA=10 ng/ml. PMID- 25528941 TI - Limited usefulness of the test of spontaneous growth hormone (GH) nocturnal secretion as a screening procedure in diagnosing GH deficiency in children with short stature. AB - INTRODUCTION AND OBJECTIVE: In Poland, the assessment of nocturnal GH secretion has gained the status of screening test; however, this procedure is not included in international recommendations. The aim of the study was to assess the accuracy and predictive value of the test of nocturnal GH secretion as a screening procedure in diagnosing GHD, and to check the adequacy of the cut-off value for GH peak in this test on the level of 10 ng/ml. MATERIALS AND METHODS: The analysis comprised the data of 1,000 children with short stature. In all the patients, GH secretion was assessed in a screening test (after falling asleep) and in 2 stimulating tests (reference tests), with simultaneous assessment of IGF I secretion before stimulating tests. The indices of screening test accuracy, likelihood ratios and predictive values were assessed. The cut-off level of GH peak after falling asleep, ensuring its 95% sensitivity, was calculated in ROC curve analysis. RESULTS: Sensitivity of the screening test was 70.4%, while the specificity--61.2%, positive likelihood ratio--1.842, negative likelihood ratio- 0.482, positive predictive value--0.462, negative predictive value--0.812. The sensitivity of the test of GH secretion after falling asleep is too low with respect to the requirements for screening test. The ROC curve analysis showed 95% sensitivity for the screening test on the level of 19.0 ng/ml; however, with a very low specificity--below 25%, thus making this test completely useless as a screening procedure. CONCLUSIONS: The obtained results strongly contradict the opinion that the assessment of GH secretion after falling asleep should be a screening test in diagnosing GHD in children with short stature. PMID- 25528942 TI - Visual assessment of voice disorders in patients with occupational dysphonia. AB - INTRODUCTION: In a group of persons using the voice occupationally, the frequent symptoms are hoarseness, voice fatigability and aphonia. Pathological changes in the larynx may have organic or functional character which require different methods of treatment and rehabilitation. Visualization of vibrations of the vocal folds is an essential condition for an appropriate assessment of the causes of dysphonia. OBJECTIVE: The purpose of the study is assessment of the usefulness of a high-speed imaging (HSI) system in the diagnosis of functional and organic dysphonia of occupational character, compared with digital kymography (DKG) and digital stroboscopy (DS) with a high resolution module. MATERIAL AND METHODS: The study group consisted of 64 patients with voice quality disorders with features of occupational dysphonia. The control group consisted of 15 patients with euphonic voice. Analysis of the voice quality parameters during phonation of the 'e' vowel was performed using HSI, DKG and stroboscopy of high resolution, by means of a digital HS camera (HRES Endocam, Richard Wolf GmbH, Knittlingen, Germany). Vocal folds vibrations were registered at the rate of 4,000 frames per second. RESULTS: HSI is the most reliable diagnostic tool giving the possibility of an analysis of the true vibrations of the vocal folds. It also enables an observation of the aperiodicity of vibrations of the vocal folds, while DS with high resolution allows diagnosis of the periodicity of the vibrations. CONCLUSIONS: HSI is particularly useful in the diagnosis of neurologically-based pathology of the voice (paralytic dysphonia) and organic dysphonia. The quickest method of diagnosing the phonatory paresis of the glottis is DKG. The advantage of both HSI and DKG is the non-invasiveness of examinations; however, their limitations are time-consuming and the high cost of equipment. PMID- 25528943 TI - NT-proBNP: a useful marker of cardiovascular function in patients on chronic haemodialysis treatment. PMID- 25528944 TI - The ADP antagonist MRS2179 regulates the phenotype of smooth muscle cells to limit intimal hyperplasia. AB - PURPOSE: ADP plays an important part in platelet aggregation by activating P2Y1 and P2Y12 receptors. The ADP antagonist MRS2179 has been used in thrombosis related treatments but its effects on vein graft (VG) remodeling is undefined. We examined the effect of MRS2179 on VG intimal hyperplasia and explored the mechanism of action. METHODS: A mouse model of VG transplantation was established. Mice underwent surgery and received MRS2179 by intraperitoneal injection every other day for 3 weeks. VG remodeling was assessed 4-weeks later. Vascular smooth muscle cells (VSMCs) were isolated and treated with MRS2179. The effect of MRS2179 on the proliferation, migration and inflammatory-cytokine expression of VSMCs was also evaluated. RESULTS: MRS2179 significantly inhibited VSMC proliferation compared with the control group. Significant inhibitory effects of MRS2179 on VSMC migration was observed in two-dimensional and three dimensional models. The extent of intimal hyperplasia was significantly less in MRS2179 treated mice than in controls. Reduced migration of macrophage was found in MRS2179 treated mice. Expression of the inflammatory cytokines IL-1beta and TNF-alpha was decreased significantly in the MRS2179 treated group. In addition, decreased phosphorylation was found on Akt, Erk1/2 and p38. CONCLUSIONS: These data demonstrate that MRS2179 inhibits neointima formation in VGs by regulating the proliferation, and migration of VSMCs, macrophage migration, inflammatory cytokine secretion and related signaling pathway. Our study provides novel insights regarding purinergic signaling in SMCs in vivo. The P2Y1 receptor may serve as a therapeutic target in neointima formation. PMID- 25528947 TI - Contribution of siloxanes to COD loading at wastewater treatment plants: phase transfer, removal, and fate at different treatment units. AB - Cyclic volatile methylsiloxanes (cVMSs) are entering to waste stream in increasing quantities due to their increasing use in personal care products (i.e., shampoos, creams). The cVMSs have high vapor pressures and low solubilities and are mostly transferred into the gaseous phase via volatilization; however, some are sorbed onto biosolids. The purpose of this study was to track and estimate the phase transfer (water, solids, gas), fate, and contribution to COD loading of selected siloxanes (D4, D5 and D6) which are the most commonly found cVMSs in the wastewater systems. Removal efficiencies of the wastewater treatment units were evaluated based on the partitioning characteristics of the cVMSs in gas, liquid, and biosolids phases. The contributions of the siloxanes present in the influent and effluent were estimated in terms of COD levels based on the theoretical oxygen demand (ThOD) of the siloxanes. Siloxanes constitute approximately 39 and 0.001mgL(-1) of the COD in the influents and effluent. Oxidation systems showed higher removal efficiencies based COD loading in comparison to the removal efficiencies achieved aeration tanks and filtration systems. Treatment systems effectively remove the siloxanes from the aqueous phase with over 94% efficiency. About 50% of the siloxanes entering to the wastewater treatment plant accumulate in biosolids. PMID- 25528948 TI - Subjects with COPD and productive cough have an increased risk for exacerbations and death. AB - BACKGROUND: Chronic bronchitis is related to worse general health status, exacerbations and mortality among subjects with COPD. Also less longstanding cough and phlegm may be related to worse prognosis in COPD but this has rarely been evaluated in population-based studies. AIM: To evaluate the relationship between productive cough, exacerbations and mortality among subjects with and without COPD. METHOD: All subjects with COPD (n = 993) were identified together with sex- and age matched reference subjects without obstructive lung function impairment from four population-based cohorts in 2002-04. Baseline spirometry and structured interview including data on exacerbations last 12 months were used in this study (n = 1986) together with mortality data collected until February 2012. RESULTS: Productive cough was more common in COPD than non-COPD (42.8 vs. 23.5%, p < 0.001), more common in men than women, but associated to exacerbations in both sexes. COPD-subjects with productive cough had the highest risk for exacerbations in both sexes and they had a significantly increased risk for death (HR 1.48, 95% CI 1.13-1.94) also when adjusted for sex, age, BMI, smoking habits and heart disease. CONCLUSION: Productive cough was common and increased the risk for exacerbations in both sexes, in both COPD and non-COPD. COPD-subjects with productive cough had the highest risk for exacerbations and a significantly higher risk for death also after adjustment for common risk factors. PMID- 25528949 TI - Several siblings with Cystic Fibrosis as a risk factor for poor outcome. AB - BACKGROUND: Occurrence of Cystic Fibrosis (CF) in more than one member in a family is not uncommon. The aim of our study was to assess the influence of multiple siblings with CF on disease expression and outcome. METHODS: Study group consisted of 2-siblings (2-sibs, n = 42) or 3/4 siblings (3/4-sibs, n = 22) with CF in one family. Each sibling was matched by age, mutation, and gender to a single CF patient. RESULTS: 3/4-sibs subgroup compared to singles showed a lower mean FEV1 with a faster decline rate (58.4 +/- 27.5 vs. 72.7 +/- 25.4 and -5 +/- 6.4 vs. -1.7 +/- 2.8 %predicted decline/year respectively, p < .05), more airway colonization by Pseudomonas aeruginosa and Mycobacterium abscessus (15 (68%) vs. 8 (36%) and 7 (32%) vs. 4 (18%), respectively, p < .05) and more lung transplants (5 (23%) vs. 2 (9%), respectively, p < .02). Last mean FEV1 within 3/4-sibs was significantly lower for the youngest sib (p < .05). CONCLUSIONS: Three or more CF patients in one family may be a risk factor for more severe disease and poor prognosis. In our view this reflects the burden of disease on the patients and families. PMID- 25528950 TI - Making sense of 'lower' and 'upper' stem-group Euarthropoda, with comments on the strict use of the name Arthropoda von Siebold, 1848. AB - The ever-increasing number of studies that address the origin and evolution of Euarthropoda - whose extant representatives include chelicerates, myriapods, crustaceans and hexapods - are gradually reaching a consensus with regard to the overall phylogenetic relationships of some of the earliest representatives of this phylum. The stem-lineage of Euarthropoda includes numerous forms that reflect the major morphological transition from a lobopodian-type to a completely arthrodized body organization. Several methods of classification that aim to reflect such a complex evolutionary history have been proposed as a consequence of this taxonomic diversity. Unfortunately, this has also led to a saturation of nomenclatural schemes, often in conflict with each other, some of which are incompatible with cladistic-based methodologies. Here, I review the convoluted terminology associated with the classification of stem-group Euarthropoda, and propose a synapomorphy-based distinction that allows 'lower stem-Euarthropoda' (e.g. lobopodians, radiodontans) to be separated from 'upper stem-Euarthropoda' (e.g. fuxianhuiids, Cambrian bivalved forms) in terms of the structural organization of the head region and other aspects of overall body architecture. The step-wise acquisition of morphological features associated with the origins of the crown-group indicate that the node defining upper stem-Euarthropoda is phylogenetically stable, and supported by numerous synapomorphic characters; these include the presence of a deutocerebral first appendage pair, multisegmented head region with one or more pairs of post-ocular differentiated limbs, complete body arthrodization, posterior-facing mouth associated with the hypostome/labrum complex, and post-oral biramous arthropodized appendages. The name 'Deuteropoda' nov. is proposed for the scion (monophyletic group including the crown-group and an extension of the stem-group) that comprises upper stem Euarthropoda and Euarthropoda. A brief account of common terminological inaccuracies in recent palaeontological studies evinces the utility of Deuteropoda nov. as a reference point for discussing aspects of early euarthropod phylogeny. PMID- 25528951 TI - Acute blastocystis-associated appendicular peritonitis in a child, Casablanca, Morocco. AB - Despite increasing reports that Blastocystis infection is associated with digestive symptoms, its pathogenicity remains controversial. We report appendicular peritonitis in a 9-year-old girl returning to France from Morocco. Only Blastocystis parasites were detected in stools, appendix, peritoneal liquid, and recto-uterine pouch. Simultaneous gastroenteritis in 26 members of the child's family suggested an outbreak. PMID- 25528952 TI - Child sexual abuse in the Roman Catholic Church in Germany: comparison of victim impact data collected through church-sponsored and government-sponsored programs. AB - At around the same time in 2010, the German government and the Roman Catholic Church in Germany each set up a critical incident reporting system (CIRS) to gather information on child sexual abuse that had taken place within the Church. The objective in both cases was to solicit stories from victims and former victims and allow them to have input into a review process. The existence of these two similar systems, one initiated by the institution involved in the abuse and the other by an independent entity, provided an opportunity to compare the background and motivation of victims who chose to communicate through one channel or the other. Data were obtained on a total of 927 individuals, 571 through the church CIRS and 356 through the government CIRS, who had reported that they had experienced childhood sexual abuse within the Roman Catholic Church. Some differences were found between the two groups in terms of gender, the reported frequency of abuse, and the desire for compensation. These differences highlight the need for an effective complaint management system to offer not just one but complementary channels of communication. In addition, the findings confirm the feasibility and value of a CIRS approach and the use of so-called 'citizen science' in politically driven review processes. PMID- 25528953 TI - Expert witness testimony in ophthalmology malpractice litigation. AB - PURPOSE: To examine the relative qualifications of expert witnesses testifying on behalf of plaintiffs vs defendants in ophthalmology malpractice litigation. DESIGN: Correlational and descriptive study; analysis of expert witness and physician demographic data available on several databases. METHODS: The Westlaw legal database was searched for ophthalmologist expert witness testimony from January 2006 to June 2014. Physician demographic data were used as the main outcome measures, including length of experience, scholarly impact (as measured by the h-index), practice setting, and fellowship training status and were obtained from state medical licensing board sites and online medical facility and practice sites. H-indices were obtained from the Scopus database. RESULTS: Defendant and plaintiff expert witnesses had comparable mean years of experience (32.9 and 35.7, respectively) (P = .12) and scholarly impact (h-index = 8.6 and 8.3, respectively) (P = .42). Cases tended to resolve on the side of the expert witness with the higher h-index (P = .04). Significantly higher proportions of defendant witnesses were in academic practice (P < .05) and underwent fellowship training (P < .001). CONCLUSION: Ophthalmologist expert witnesses testifying for both plaintiffs and defendants had over 30 years of experience and high scholarly impact. Practitioners testifying on behalf of plaintiffs were statistically less likely to work in an academic setting and have subspecialty training. Scholarly impact of expert witnesses appeared to affect trial outcomes. Surgical societies should stringently police for appropriate expert witness testimony given by both plaintiff and defense experts in malpractice litigation. PMID- 25528954 TI - Histopathologic grading of anaplasia in retinoblastoma. AB - PURPOSE: To determine whether the degree of tumor anaplasia has prognostic value by evaluating its correlation with high-risk histopathologic features and clinical outcomes in a series of retinoblastoma patients. DESIGN: Retrospective clinicopathologic study. METHODS: The clinical and pathologic findings in 266 patients who underwent primary enucleation for retinoblastoma were reviewed. The histologic degree of anaplasia was graded as retinocytoma, mild, moderate, or severe as defined by increasing cellular pleomorphism, number of mitoses, nuclear size, and nuclear hyperchromatism. Nuclear morphometric characteristics were measured. The clinical and pathologic data of 125 patients were compared using Kaplan-Meier estimates of survival. Fisher exact test and multivariate regression were used to analyze the association between anaplasia grade and high-risk histologic features. RESULTS: Increasing grade of anaplasia was associated with decreased overall survival (P = .003) and increased risk of metastasis (P = .0007). Histopathologic features that were associated with anaplasia included optic nerve invasion (P < .0001), choroidal invasion (P < .0001), and anterior segment invasion (P = .04). Multivariate analysis considering high-risk histopathology and anaplasia grading as predictors of distant metastasis and death showed that high-risk histopathology was statistically significant as an independent predictor (P = .01 for metastasis, P = .03 for death) but anaplasia was not (P = .63 for metastasis, P = .30 for death). In the absence of high-risk features, however, severe anaplasia identified an additional risk for metastasis (P = .0004) and death (P = .01). CONCLUSION: Grading of anaplasia may be a useful adjunct to standard histopathologic criteria in identifying retinoblastoma patients who do not have high-risk histologic features but still have an increased risk of metastasis and may need adjuvant therapy. PMID- 25528955 TI - En face imaging of the choroid in polypoidal choroidal vasculopathy using swept source optical coherence tomography. AB - OBJECTIVE: To define morphologic features of polypoidal choroidal vasculopathy (PCV) using en face images from swept-source optical coherence tomography (SS OCT). DESIGN: Prospective cross-sectional study. METHODS: The study included 10 eyes from 6 patients with PCV and 10 eyes from 5 age-matched normal subjects. All subjects were prospectively scanned with a prototype SS OCT system. A motion correction algorithm was applied to correct and merge scans into a single volumetric dataset. En face images were generated at intervals of 4.13 MUm (1 pixel) relative to the Bruch membrane. RESULTS: Age +/- standard deviation for the normal group was 62.4 (+/-12.1) years and for the PCV group was 68.3 (+/-5.2) years. En face SS OCT imaging of PCV eyes demonstrated the relationship between larger pigment epithelial detachments (PEDs) and small adjoining PEDs that correlated with the polypoidal lesions seen on indocyanine green angiography in all PCV eyes. En face SS OCT demonstrated choroidal vascular abnormalities in 7 out of 7 eyes with PCV, and in 2 out of 3 enrolled fellow eyes in patients with unilateral PCV. Out of 7 PCV eyes, focal choroidal vascular dilation was noted in 3 eyes and diffuse choroidal vascular dilation was noted in 1 eye. In addition, a branching vascular network was noted above the Bruch membrane in 1 eye, below the Bruch membrane within the choriocapillaris in 1 eye, and in the larger choroidal vascular layer in 1 eye. CONCLUSIONS: En face SS OCT provides an in vivo tool to visualize the pathologic features and the choroidal vasculature in PCV. PMID- 25528957 TI - Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. AB - Astaxanthin (ATX) has been proven to ameliorate early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH) by modulating cerebral oxidative stress. This study was performed to assess the effect of ATX on the Nrf2-ARE pathway and to explore the underlying molecular mechanisms of antioxidant properties of ATX in EBI after SAH. A total of 96 male SD rats were randomly divided into four groups. Autologous blood was injected into the prechiasmatic cistern of the rat to induce an experimental SAH model. Rats in each group were sacrificed at 24 h after SAH. Expressions of Nrf2 and heme oxygenase-1 (HO-1) were measured by Western blot and immunohistochemistry analysis. The mRNA levels of HO-1, NAD (P) H: quinone oxidoreductase 1 (NQO-1), and glutathione S transferase-alpha1 (GST-alpha1) were determined by real-time polymerase chain reaction (PCR). It was observed that administration of ATX post-SAH could up regulate the cortical expression of these agents, mediated in the Nrf2-ARE pathway at both pretranscriptional and posttranscriptional levels. Meanwhile, oxidative damage was reduced. Furthermore, ATX treatment significantly attenuated brain edema, blood-brain barrier (BBB) disruption, cellular apoptosis, and neurological dysfunction in SAH models. This study demonstrated that ATX treatment alleviated EBI in SAH model, possibly through activating the Nrf2-ARE pathway by inducing antioxidant and detoxifying enzymes. PMID- 25528956 TI - Ciliary neurotrophic factor for macular telangiectasia type 2: results from a phase 1 safety trial. AB - PURPOSE: To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. DESIGN: An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. METHODS: The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. RESULTS: The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. CONCLUSIONS: The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. PMID- 25528959 TI - Briarane diterpenoids from the gorgonian Dichotella gemmacea. AB - Seven new briarane diterpenoids, gemmacolides AS-AY (1-7), were isolated together with ten known analogues (8-17) from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data and comparison with reported data. The absolute configuration of compounds was determined based on electronic circular dichroism (ECD) experiments and genetic correlations as well. Compounds 15 and 16 were reported for the first time for the gorgonian. In the preliminary in vitro bioassays, compound 5 showed potential growth inhibitory activity against MG63 cells. PMID- 25528958 TI - Synthetic approaches to the lamellarins--a comprehensive review. AB - The present review discusses the known synthetic routes to the lamellarin alkaloids published until 2014. It begins with syntheses of the structurally simpler type-II lamellarins and then focuses on the larger class of the 5,6 saturated and -unsaturated type-I lamellarins. The syntheses are grouped by the strategy employed for the assembly of the central pyrrole ring. PMID- 25528961 TI - Multimodality imaging in adnexal torsion. AB - Adnexal torsions are one among the causes of acute pelvic pain in females. Commonly occurring adnexal torsions are ovarian either involving the normal ovary with functional cysts or an associated mass. Fallopian tube torsions, torsions involving paraovarian, fimbrial cysts and subserosal fibroids are rare. Here we discuss the multimodality imaging approach for the diagnosis of adnexal torsion, its limitations and mimics. PMID- 25528962 TI - Putting program evaluation into practice: enhancing the Girls Just Wanna Have Fun program. AB - In recent years there has been a call for increased community physical activity and sport programs for female youth that are deliberately structured to foster positive developmental outcomes. In addition, researchers have recognized the need to empirically evaluate such programs to ensure that youth are provided with optimal opportunities to thrive. This study represents a utilization-focused evaluation of Girls Just Wanna Have Fun, a female-only physical activity-based life skills community program. A utilization-focused evaluation is particularly important when the evaluation is to help stakeholders utilize the findings in practice. The purpose of this study was twofold: (a) to gain an understanding of the ongoing successes and challenges after year two of program implementation and (b) to examine how the adaptations made based on feedback from the first year evaluation were perceived as impacting the program. From interviews with youth participants and program leaders, three main themes with eight sub-themes emerged. The main themes were: (a) applying lessons learned can make a significant difference, (b) continually implementing successful strategies, and (c) ongoing challenges. Overall, this evaluation represents an important step in understanding how to improve program delivery to better meet the needs of the participants in community-based programming. PMID- 25528960 TI - Impact of DHA on metabolic diseases from womb to tomb. AB - Long chain polyunsaturated fatty acids (LC-PUFAs) are important mediators in improving and maintaining human health over the total lifespan. One topic we especially focus on in this review is omega-3 LC-PUFA docosahexaenoic acid (DHA). Adequate DHA levels are essential during neurodevelopment and, in addition, beneficial in cognitive processes throughout life. We review the impact of DHA on societal relevant metabolic diseases such as cardiovascular diseases, obesity, and diabetes mellitus type 2 (T2DM). All of these are risk factors for cognitive decline and dementia in later life. DHA supplementation is associated with a reduced incidence of both stroke and atherosclerosis, lower bodyweight and decreased T2DM prevalence. These findings are discussed in the light of different stages in the human life cycle: childhood, adolescence, adulthood and in later life. From this review, it can be concluded that DHA supplementation is able to inhibit pathologies like obesity and cardiovascular disease. DHA could be a dietary protector against these metabolic diseases during a person's entire lifespan. However, supplementation of DHA in combination with other dietary factors is also effective. The efficacy of DHA depends on its dose as well as on the duration of supplementation, sex, and age. PMID- 25528963 TI - Is implementation fidelity associated with improved access to care in a school based Child and Family Team model? AB - Effective child and family centered service planning is crucial to addressing vulnerable children's needs. However, there is limited evidence about what facets of these processes improve service use and outcomes. The current study used a Poisson random effects hazard model to test correlations between fidelity to NC's Child and Family Support Team model and time to service receipt, using case management data for 3396 children served by that program during the 2008-2009 school year. Students were more likely to receive recommended services more quickly when caregivers and the students attended planning meetings, when their plans included services for caregivers, and when child and family team leaders followed up after meetings to verify service receipt. Contrary to the Child and Family Support Team theory of change, match between student needs and the lead agency of the meeting was not associated with the odds of quicker service receipt, nor was attendance by natural supports. Findings from this study demonstrate the potential effectiveness of using case management systems to measure service planning process fidelity, as well as how results thereof can both inform process improvement and potential refinements to models' theories of change. PMID- 25528964 TI - RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. AB - Atherosclerosis, a syndrome with abnormal arterial walls, is one of the major causes that lead to the development of various cardiovascular diseases. The key initiator of atherosclerosis is cholesterol accumulation. The uncontrolled cholesterol deposition, mainly involving low-density lipoprotein (LDL), causes atheroma plaque formation, which initiates chronic inflammation due to the recruitment of inflammatory cells such as macrophages. Macrophages scavenge excess peripheral cholesterol and transport intracellular cholesterol to high density lipoprotein (HDL) for excretion or storage. Cholesterol-laden macrophage derived foam cell formation is the main cause of atherogenesis. It is critical to understand the regulatory mechanism of cholesterol homeostasis in the macrophage in order to prevent foam cells formation and further develop novel therapeutic strategies against atherosclerosis. Here we identified a protein, RIP140 (receptor interacting protein 140), which enhances macrophage-derived foam cell formation by reducing expression of reverse cholesterol transport genes, A TP binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1). In animal models, we found that reducing RIP140 levels by crossing macrophage-specific RIP140 knockdown (MphiRIP140KD) mice with ApoE null mice effectively ameliorates high-cholesterol diet-induced atherosclerosis. Our data suggest that reducing RIP140 levels in macrophages significantly inhibits atherosclerosis, along with markers of inflammation and the number of macrophages in a western diet fed ApoE null mouse. This study provides a proof-of-concept for RIP140 as a risk biomarker of, and a therapeutic target for, atherosclerosis. PMID- 25528966 TI - Segmental absence of intestinal musculature -presentation in a 10-year-old boy with an extensive involved segment. AB - Segmental absence of the intestinal musculature is a rare cause of acute abdomen most likely associated with intestinal perforation and sepsis in neonates and adults. We present a case of a 10-year-old boy who developed acute abdomen and was treated with right hemicolectomy and partial resection of the ileum. The ileum showed a 20-cm-long stenotic segment showing prominent thinning of the intestinal wall. This case occurred in an older child, which appears to be rare when comparing the literature. The bowel defect was also the largest described to date, indicating the potential effect of an atonic segment leading to obstructive disease. PMID- 25528965 TI - Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling. AB - Differentiation of human pluripotent stem cells as embryoid bodies (EBs) has been achieved previously with p38alfa MAPK inhibitors such as SB203580 with moderate efficiency of 10-15%. We synthesized and screened 42 compounds that are 2,4,5 trisubstituted azole analogues of SB203580 for efficient cardiomyocyte differentiation. Our screen identified novel compounds that have similar cardiac differentiation activity as SB203580. However, the cardiac differentiation did not correlate with p38alfa MAPK inhibition, indicating an alternative mechanism in cardiac differentiation. Upon profiling several 2,4,5-trisubstituted azole compounds against a panel of 97 kinases we identified several off targets, among them casein kinases 1 (CK1). The cardiomyogenic activities of SB203580 and its analogues showed a correlation with post mesoderm Wnt/beta-catenin pathway inhibition of CK1 epsilon and delta. These findings united the mechanism of 2,4,5 trisubstituted azole with the current theory of Wnt/beta-catenin regulated pathway of cardiac differentiation. Consequently an efficient cardiomyocyte protocol was developed with Wnt activator CHIR99021 and 2,4,5-trisubstituted azoles to give high yields of 50-70% cardiomyocytes and a 2-fold increase in growth. PMID- 25528967 TI - Uninformed and disinformed society and the GMO market. AB - The EU has a complicated regulatory framework, and this is slowing down the approval process of new genetically modified (GM) crops. Currently, labeling of GM organisms (GMOs) is mandatory in all Member States. However, the USA, in which GMO labeling is not mandatory, continues to lead the production of biotech crops, biopharmaceuticals, biomaterials, and bioenergy. PMID- 25528968 TI - Internal organization of macromonomers and dendronized polymers based on thiophene dendrons. AB - The internal organization of macromonomers (MGs) consisting of all-thiophene dendrons of generation g = 2 and 3 attached to a phenyl core, as well as of the dendronized polymers resulting from polymerization of these macromonomers (PG2 and PG3, respectively), has been investigated using theoretical methods. The conformational preferences of the MGs, determined using density functional theory calculations, are characterized by the relative orientation between dendrons and core. We find that the strain of the MGs increases with the generation number and is alleviated by small conformational re-arrangements of the peripheral thiophene rings. The conformations obtained for the MGs have subsequently been used to construct models for the dendronized polymers. Classical molecular dynamics simulations have evidenced that the interpenetration of dendrons belonging to different repeat units is very small for PG2. In contrast, the degree of interpenetration is found to be very high for PG3, which also shows a significant degree of backfolding (i.e. occurrence of peripheral methyl groups approaching the backbone). Consequently, PG2 behaves as a conventional linear flexible polymer bearing bulk pendant groups, whereas PG3 is better characterized as a semirigid homogeneous cylinder. The two polymers are stabilized by pi-pi stacking interactions, even though these are significantly more abundant for PG3 than for PG2; the average numbers of interactions per repeat unit are 3.0 and 8.8 for PG2 and PG3, respectively. While in these interactions the thiophene rings can adopt either parallel (sandwich) or perpendicular (T-shaped) dispositions, the former scenario turns out to be the most abundant. PMID- 25528969 TI - Ovarian follicular activity during late gestation and postpartum in guanaco (Lama guanicoe). AB - This study evaluated ovarian activity in late gestation and post-partum in guanacos in captivity. Follicular dynamics was monitored every second day from 40 days before and other 40 after delivery by transrectal sonography and by plasma steroids concentrations. Seven out of eight (87.5%) of gestating females presented ovarian follicular activity under progesterone levels >3 nmol/l with maximum follicular size of 8.42 +/- 0.83 mm from days 23 to 1 before delivery. After delivery, all females have follicular wave development from day 0 to 38, with larger follicular size and longer follicular wave phases and interwave interval when compared with pre-partum data. During post-partum period, there was a close relationship between follicle size and estradiol-17beta concentration, with r = 0.69 at the beginning of growth phase and r = 0.86 in association with the largest dominant follicle. Plasma estradiol-17beta concentration varied from 11.92 to 198.55 pmol/l. Plasma estrone sulfate, free estrone and progesterone returned to baseline concentrations during peripartal period and remained basal thereafter. The results described follicular activity during late gestation and early post-partum period. These findings provide relevant information to understand physiological changes occurring during this reproductive key period in seasonal breeders with long gestation duration as New and Old World camelids. PMID- 25528970 TI - Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators. AB - Snake venom neurotoxins and lymphocyte antigen 6 (Ly6) proteins, most of the latter being membrane tethered by a glycosylphosphatidylinositol (GPI) anchor, have a variety of biological activities, but their three-finger (3F) folding combines them in one Ly6/neurotoxin family. Subsets of two groups, represented by alpha-neurotoxins and Lynx1, respectively, interact with nicotinic acetylcholine receptors (nAChR) and, hence, are of therapeutic interest for the treatment of neurodegenerative diseases, pain, and cancer. Information on the mechanisms of action and 3D structure of the binding sites, which is required for drug design, is available from the 3D structure of alpha-neurotoxin complexes with nAChR models. Here, I compare the structural and functional features of alpha neurotoxins versus Lynx1 and its homologs to get a clearer picture of Lynx1-nAChR interactions that is necessary for fundamental science and practical applications. PMID- 25528971 TI - [Cardiac troponin beyond acute coronary syndrome]. PMID- 25528972 TI - Cochrane Corner: Corticosteroids for viral myocarditis. AB - The causes of myocarditis are diverse, but a viral etiology is the most common. In this systematic review by the Cochrane Collaboration, the authors assessed the efficacy of corticosteroid therapy in patients with viral myocarditis. Eight randomized controlled trials with 719 patients (two trials in pediatric populations) were included for analysis. Pooled results did not show significant differences in mortality with the use of corticosteroids. Patients on corticosteroid therapy had significantly higher post-treatment left ventricular ejection fraction values compared to control. These results are limited by the significant heterogeneity associated with clinical trials. The best available evidence does not support the routine use of corticosteroids in patients with viral myocarditis. PMID- 25528973 TI - Economic evaluation of ticagrelor for secondary prevention following acute coronary syndromes. AB - INTRODUCTION AND OBJECTIVES: To estimate the cost-effectiveness and cost-utility of ticagrelor in the treatment of patients with acute coronary syndromes (unstable angina or myocardial infarction with or without ST-segment elevation), including patients treated medically and those undergoing percutaneous coronary intervention or coronary artery bypass grafting. METHODS: A short-term decision tree and a long-term Markov model were used to simulate the evolution of patients' life-cycles. Clinical effectiveness data were collected from the PLATO trial and resource use data were obtained from the Hospital de Santa Marta database, disease-related group legislation and the literature. RESULTS: Ticagrelor provides increases of 0.1276 life years and 0.1106 quality-adjusted life years (QALYs) per patient. From a societal perspective these clinical gains entail an increase in expenditure of ?610. Thus the incremental cost per life year saved is ?4780 and the incremental cost per QALY is ?5517. CONCLUSIONS: The simulation results show that ticagrelor reduces events compared to clopidogrel. The costs of ticagrelor are partially offset by lower costs arising from events prevented. The use of ticagrelor in clinical practice is therefore cost-effective compared to generic clopidogrel. PMID- 25528974 TI - Effusive-constrictive pericarditis as the manifestation of an unexpected diagnosis. AB - Constrictive pericarditis is a clinical condition characterized by the appearance of signs and symptoms of right heart failure due to loss of pericardial compliance. Cardiac surgery is now one of the most frequent causes in developed countries, while tuberculosis remains the most prevalent cause in developing countries. Malignancy is a rare cause but usually has a poor prognosis. The diagnosis of constrictive pericarditis remains a clinical challenge and requires a combination of noninvasive diagnostic methods (echocardiography, cardiac magnetic resonance and computed tomography); in some cases, cardiac catheterization is needed to confirm the diagnosis. The authors present the case of a 51-year-old man, hospitalized due to cardiac tamponade. Diagnostic investigation was suggestive of tuberculous etiology. Despite directed medical therapy, the patient developed effusive-constrictive physiology. He underwent pericardiectomy and anatomopathologic study suggested a neoplastic etiology. The patient died in the postoperative period from biventricular failure. PMID- 25528975 TI - Twenty years after International Conference on Population and Development: where are we with adolescent sexual and reproductive health and rights? AB - The International Conference on Population and Development in Cairo in 1994 laid out a bold, clear, and comprehensive definition of reproductive health and called for nations to meet the educational and service needs of adolescents to enable them to deal in a positive and responsible way with their sexuality. In the context of the ongoing review of the International Conference on Population and Development Programme of Action and the considerations for a post-2015 development agenda, this article summarizes the findings of the articles presented in this volume and identifies key challenges and critical answers that need to be tackled in addressing adolescent sexual and reproductive health and rights. The key recommendations are to link the provision of sexuality education and sexual and reproductive health (SRH) services; build awareness, acceptance, and support for youth-friendly SRH education and services; address gender inequality in terms of beliefs, attitudes, and norms; and target the early adolescent period (10-14 years). The many knowledge gaps, however, point to the pressing need for further research on how to best design effective adolescent SRH intervention packages and how best to deliver them. PMID- 25528976 TI - Sexuality education: emerging trends in evidence and practice. AB - The International Conference on Population and Development and related resolutions have repeatedly called on governments to provide adolescents and young people with comprehensive sexuality education (CSE). Drawing from these documents, reviews and meta-analyses of program evaluations, and situation analyses, this article summarizes the elements, effectiveness, quality, and country-level coverage of CSE. Throughout, it highlights the matter of a gender and rights perspective in CSE. It presents the policy and evidence-based rationales for emphasizing gender, power, and rights within programs--including citing an analysis finding that such an approach has a greater likelihood of reducing rates of sexually transmitted infections and unintended pregnancy--and notes a recent shift toward this approach. It discusses the logic of an "empowerment approach to CSE" that seeks to empower young people--especially girls and other marginalized young people--to see themselves and others as equal members in their relationships, able to protect their own health, and as individuals capable of engaging as active participants in society. PMID- 25528977 TI - Effective strategies to provide adolescent sexual and reproductive health services and to increase demand and community support. AB - Access to youth friendly health services is vital for ensuring sexual and reproductive health (SRH) and well-being of adolescents. This study is a descriptive review of the effectiveness of initiatives to improve adolescent access to and utilization of sexual and reproductive health services (SRHS) in low- and middle-income countries. We examined four SRHS intervention types: (1) facility based, (2) out-of-facility based, (3) interventions to reach marginalized or vulnerable populations, (4) interventions to generate demand and/or community acceptance. Outcomes assessed across the four questions included uptake of SRHS or sexual and reproductive health commodities and sexual and reproductive health biologic outcomes. There is limited evidence to support the effectiveness of initiatives that simply provide adolescent friendliness training for health workers. Data are most ample (10 initiatives demonstrating weak but positive effects and one randomized controlled trial demonstrating strong positive results on some outcome measures) for approaches that use a combination of health worker training, adolescent-friendly facility improvements, and broad information dissemination via the community, schools, and mass media. We found a paucity of evidence on out-of-facility-based strategies, except for those delivered through mixed-use youth centers that demonstrated that SRHS in these centers are neither well used nor effective at improving SRH outcomes. There was an absence of studies or evaluations examining outcomes among vulnerable or marginalized adolescents. Findings from 17 of 21 initiatives assessing demand generation activities demonstrated at least some association with adolescent SRHS use. Of 15 studies on parental and other community gatekeepers' approval of SRHS for adolescents, which assessed SRHS/commodity uptake and/or biologic outcomes, 11 showed positive results. Packages of interventions that train health workers, improve facility adolescent friendliness, and endeavor to generate demand through multiple channels are ready for large-scale implementation. However, further evaluation of these initiatives is needed to clarify mechanisms and impact, especially of specific program components. Quality research is needed to determine effective means to deliver services outside the facilities, to reach marginalized or vulnerable adolescents, and to determine effective approaches to increase community acceptance of adolescent SRHS. PMID- 25528978 TI - Addressing intimate partner violence and sexual violence among adolescents: emerging evidence of effectiveness. AB - Intimate partner violence (IPV) and sexual violence (SV) are widespread among adolescents and place them on a lifelong trajectory of violence, either as victims or perpetrators. The aim of this review was to identify effective approaches to prevent adolescent IPV and SV and to identify critical knowledge gaps. The interventions reviewed in this article reflect the global focus on interventions addressing violence perpetrated by men against women in the context of heterosexual relationships. Interventions for girls and boys (10-19 years) were identified through electronic searches for peer-reviewed and gray literature such as reports and research briefs. Studies were excluded if they were published before 1990 or did not disaggregate participants and results by age. Programs were classified as "effective," "emerging," "ineffective," or "unclear" based on the strength of evidence, generalizability of results to developing country settings, and replication beyond the initial pilot. Programs were considered "effective" if they were evaluated with well-designed studies, which controlled for threats to validity through randomization of participants. A review of 142 articles and documents yielded 61 interventions, which aimed to prevent IPV and SV among adolescents. These were categorized as "parenting" (n = 8), "targeted interventions for children and adolescents subjected to maltreatment" (n = 3), "school based" (n = 31; including 10 interventions to prevent sexual assault among university students), "community based" (n = 16), and "economic empowerment" (n = 2). The rigor of the evaluations varies greatly. A good number have relatively weak research designs, short follow-up periods, and low or unreported retention rates. Overall, there is a lack of robust standardized measures for behavioral outcomes. Three promising approaches emerge. First, school-based dating violence interventions show considerable success. However, they have only been implemented in high-income countries and should be adapted and evaluated in other settings. Second, community-based interventions to form gender equitable attitudes among boys and girls have successfully prevented IPV or SV. Third, evidence suggests that parenting interventions and interventions with children and adolescents subjected to maltreatment hold promise in preventing IPV or SV by addressing child maltreatment, which is a risk factor for later perpetration or experience of IPV or SV. Results suggest that programs with longer term investments and repeated exposure to ideas delivered in different settings over time have better results than single awareness-raising or discussion sessions. However, lack of rigorous evidence limits conclusions regarding the effectiveness of adolescent IPV and SV prevention programs and indicates a need for more robust evaluation. PMID- 25528979 TI - Ensuring youth's right to participation and promotion of youth leadership in the development of sexual and reproductive health policies and programs. AB - The purpose of this article was to reflect on the concepts of adolescence and youth, summarize models and frameworks developed to conceptualize youth participation, and assess research that has attempted to evaluate the implementation and impact of youth participation in the field of sexual and reproductive health and rights (SRHR). We searched and critically reviewed relevant published reports and "gray literature" from the period 2000-2013. "Young people" are commonly defined as those between the ages of 10 and 24 years, but what it means to be a young person varies largely across cultures and depends on a range of socioeconomic factors. Several conceptual frameworks have been developed to better understand youth participation, and some frameworks are designed to monitor youth development programs that have youth participation as a key component. Although none of them are SRHR specific, they have the potential to be adapted and applied also for adolescents' SRHR programs. The most monitored and evaluated intervention type is peer education programs, but the effectiveness of the approach is questioned. There are few attempts to systematically evaluate youth participation, and clear indicators and better methodologies still need to be developed. More research and documentation as well as the adoption of innovative practices for involving youth in sexual and reproductive health programs are needed. Participation is a right and should not only be evaluated in terms of effectiveness and impact. Youth participation in program and policy development should still be a priority. PMID- 25528980 TI - Creating an enabling environment for adolescent sexual and reproductive health: a framework and promising approaches. AB - This article provides a conceptual framework and points out the key elements for creating enabling environments for adolescent sexual and reproductive health (ASRH). An ecological framework is applied to organize the key elements of enabling environments for ASRH. At the individual level, strategies that are being implemented and seem promising are those that empower girls, build their individual assets, and create safe spaces. At the relationship level, strategies that are being implemented and seem promising include efforts to build parental support and communication as well as peer support networks. At the community level, strategies to engage men and boys and the wider community to transform gender and other social norms are being tested and may hold promise. Finally, at the broadest societal level, efforts to promote laws and policies that protect and promote human rights and address societal awareness about ASRH issues, including through mass media approaches, need to be considered. PMID- 25528981 TI - Structure and thermodynamics of Mg:phosphate interactions in water: a simulation study. AB - The association of Mg(2+) and H2 PO4 (-) in water can give insights into Mg:phosphate interactions in general, which are very widespread, but for which experimental data is surprisingly sparse. It is studied through molecular dynamics simulations (>100 ns) by using the polarizable AMOEBA force field, and the association free energy is computed for the first time. Explicit consideration of outer-sphere and two types of inner-sphere association provides considerable insight into the dynamics and thermodynamics of ion pairing. After careful assessment of the computational approximations, the agreement with experimental values indicates that the methodology can be extended to other inorganic and biological Mg:phosphate interactions in solution. PMID- 25528985 TI - Geneticists offer recommendations for sharing unexpected consanguinity findings with parents: guidance on approaching counseling sessions, protecting child's best interests. PMID- 25528982 TI - Modulation of p53 and met expression by Kruppel-like factor 8 regulates zebrafish cerebellar development. AB - Kruppel-like factor 8 (Klf8) is a zinc-finger transcription factor implicated in cell proliferation, and cancer cell survival and invasion; however, little is known about its role in normal embryonic development. Here, we show that Klf8 is required for normal cerebellar development in zebrafish embryos. Morpholino knockdown of klf8 resulted in abnormal cerebellar primordium morphology and the induction of p53 in the brain region at 24 hours post-fertilization (hpf). Both p53-dependent reduction of cell proliferation and augmentation of apoptosis were observed in the cerebellar anlage of 24 hpf-klf8 morphants. In klf8 morphants, expression of ptf1a in the ventricular zone was decreased from 48 to 72 hpf; on the other hand, expression of atohla in the upper rhombic lip was unaffected. Consistent with this finding, Purkinje cell development was perturbed and granule cell number was reduced in 72 hpf-klf8 morphants; co-injection of p53 MO(sp) or klf8 mRNA substantially rescued development of cerebellar Purkinje cells in klf8 morphants. Hepatocyte growth factor/Met signaling is known to regulate cerebellar development in zebrafish and mouse. We observed decreased met expression in the tectum and rhombomere 1 of 24 hpf-klf8 morphants, which was largely rescued by co injection with klf8 mRNA. Moreover, co-injection of met mRNA substantially rescued formation of Purkinje cells in klf8 morphants at 72 hpf. Together, these results demonstrate that Klf8 modulates expression of p53 and met to maintain ptf1a-expressing neuronal progenitors, which are required for the appropriate development of cerebellar Purkinje and granule cells in zebrafish embryos. PMID- 25528986 TI - NIH policy supports broader sharing of genomic data, strengthens informed-consent rules: research participants must give consent for secondary sharing, even if data are de-identified. PMID- 25528988 TI - Ultrasonication-dependent formation and degradation of alpha-synuclein amyloid fibrils. AB - Ultrasonication can be used to break the supersaturation of alpha-synuclein, a protein associated with Parkinson's disease, at pH7.4 above the critical concentration of fibrillation, thereby inducing the formation of amyloid fibrils. We speculated that ultrasonication could also be used to depolymerize preformed fibrils below the critical concentration. However, extensive ultrasonic irradiation transformed preformed fibrils into amorphous aggregates even above the critical concentration. Exposing preformed fibrils to the hydrophobic air water interface of cavitation bubbles may have destabilized the fibrils and stabilized amorphous aggregates. Upon extensive ultrasonic irradiation, the accompanying decomposition of chemical structures was suggested when monitored by analytical ultracentrifugation. Amorphous aggregates produced by extensive ultrasonication showed higher cytotoxicity, suggesting that, although ultrasonication might be a useful approach for inactivating amyloid fibrils, potential cytotoxicity of amorphous aggregates should be considered. PMID- 25528989 TI - Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study: comment. PMID- 25528990 TI - Clinical implication of the preoperative GSA index in 99mTc-GSA scintigraphy in hepatitis C virus-related hepatocellular carcinoma. AB - We aimed to examine the relationship between the preoperative GSA index [uptake ratio of the liver to the liver plus heart at 15 min (LHL15) to uptake ratio of the heart at 15 min to that at 3 min (HH15) ratio] calculated from 99mTc-labeled diethylene triamine pentaacetate-galactosyl human serum albumin (99mTc-GSA) scintigraphy and background liver fibrosis and to investigate whether the GSA index can be a useful predictor in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) patients treated with surgical resection (SR). A total of 213 HCV related HCC patients were analyzed. Receiver operating characteristic (ROC) curve analysis was performed for calculating the area under the ROC (AUROC) for nine noninvasive parameters including GSA index, indocyanine green retention at 15 min, aspartate aminotransferase (AST) to platelet ratio index, FIB-4 index, AST to alanine aminotransferase ratio, serum albumin, total bilirubin, platelet count and prothrombin time for cirrhosis. We also examined predictive factors associated with overall survival (OS) and recurrence-free survival (RFS) after SR in univariate and multivariate analyses. There were 153 males and 60 females with the mean age of 69.9 years. The median observation periods were 2.8 years. The mean maximum tumor size was 4.1 cm. HH15 ranged from 0.452 to 0.897. LHL15 ranged from 0.669 to 0.982. The mean value of the GSA index was 1.41. Among the nine parameters, the GSA index yielded the highest AUROC for cirrhosis with a level of 0.786 at an optimal cut-off value of 1.37 (sensitivity, 65.9%; specificity, 79.0%). In multivariate analyses, the GSA index was an independent predictor (P<0.001) linked to RFS and it had a marginal significance in terms of OS (P=0.074). In conclusion, the preoperative GSA index can be a useful predictor in HCV-related HCC patients treated with SR. PMID- 25528991 TI - Lipopolysaccharide stimulation improves the odontoblastic differentiation of human dental pulp cells. AB - Lipopolysaccharide (LPS) is one of the causative agents of pulpitis and previous studies have demonstrated that the LPS stimulation of human aortic valve interstitial cells induces inflammatory mediators and the gene expression of osteogenic factors. Therefore, in the present study, it was hypothesized that LPS affects the odontoblastic differentiation of human dental pulp cells (hDPCs). In order to investigate this, an in vitro study using hDPCs was performed. Increased alkaline phosphatase (ALP) activity was observed in the hDPCs treated with LPS, which was more marked when the cells were costimulated with odontogenic induction medium (OM). LPS also appeared to increase the gene expression levels of dentin sialophosphoprotein and dentin matrix protein-1 and the protein expression level of dental sialoprotein in the hDPCs, particularly in combination with OM. In addition, the size and the number of nodules formed in the hDPCs exposed to OM and LPS were increased compared to those stimulated by OM alone. To determine the role of nuclear factor kappaB (NF-kappaB) during the LPS-induced odontoblastic differentiation of hDPCs, immunofluorescence was performed. The nuclear translocation of NF-kappaB, induced by LPS was confirmed, suggesting its involvement in the LPS-induced increase in odontoblastic differentiation of hDPCs. In conclusion, there may be an association between LPS stimulation, with or without OM, and odontoblastic differentiation. PMID- 25528992 TI - Different types of intermittent pneumatic compression devices for preventing venous thromboembolism in patients after total hip replacement. AB - BACKGROUND: Total hip replacement (THR) is an effective treatment for reducing pain and improving function and quality of life in patients with hip disorders. While this operation is very successful, deep vein thrombosis (DVT) and pulmonary embolism (PE) are significant complications after THR. Different types of intermittent pneumatic compression (IPC) devices have been used for thrombosis prophylaxis in patients following THR. Available devices differ in compression garments, location of air bladders, patterns of pump pressure cycles, compression profiles, cycle length, duration of inflation time and deflation time, or cycling mode such as automatic or constant cycling devices. Despite the widely accepted use of IPC for the treatment of arterial and venous diseases, the relative effectiveness of different types of IPC systems as prophylaxis against thrombosis after THR is still unclear. OBJECTIVES: To assess the comparative effectiveness and safety of different IPC devices with respect to the prevention of venous thromboembolism in patients after THR. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator searched the Specialised Register (November 2014), CENTRAL (2014, Issue 10). Clinical trial databases were searched for details of ongoing and unpublished studies. Reference lists of relevant articles were also screened. There were no limits imposed on language or publication status. SELECTION CRITERIA: Randomized and quasi-randomized controlled studies were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. Disagreement was resolved by discussion or, if necessary, referred to a third review author. MAIN RESULTS: Only one quasi-randomized controlled study with 121 study participants comparing two types of IPC devices met the inclusion criteria. The authors found no cases of symptomatic DVT or PE in either the calf-thigh compression group or the plantar compression group during the first three weeks after the THR. The calf-thigh pneumatic compression was more effective than plantar compression for reducing thigh swelling during the early postoperative stage. The strength of the evidence in this review is weak as only one trial was included and it was classified as having a high risk of bias. AUTHORS' CONCLUSIONS: There is a lack of evidence from randomized controlled trials to make an informed choice of IPC device for preventing venous thromboembolism (VTE) following total hip replacement. More research is urgently required, ideally a multicenter, properly designed RCT including a sufficient number of participants. Clinically relevant outcomes such as mortality, imaging-diagnosed asymptomatic VTE and major complications must be considered. PMID- 25528995 TI - Reviving the protein quality control system: therapeutic target for cardiac disease in the elderly. AB - It has been firmly established that ageing constitutes a principal risk factor for cardiac disease. Currently, the underlying mechanisms of ageing that contribute to the initiation or acceleration of cardiac disease are essentially unresolved. Prevailing theories of ageing center on the loss of cellular protein homeostasis, by either design (genetically) or "wear and tear" (environmentally). Either or both ways, the normal protein homeostasis in the cell is affected, resulting in aberrant and misfolded proteins. Should such misfolded proteins escape the protein quality control (PQC) system, they become proteotoxic and accelerate the loss of cellular integrity. Impairment of PQC plays a prominent role in the pathophysiology of ageing-related neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. The concept of an impaired PQC driving ageing-related diseases has recently been expanded to cardiac diseases, including atrial fibrillation, cardiac hypertrophy, and cardiomyopathy. In this review, we provide a brief overview of the PQC system in relation to ageing and discuss the emerging concept of the loss of PQC in cardiomyocytes as a trigger for cardiac disease. Finally, we discuss the potential of boosting the PQC system as an innovative therapeutic target to treat cardiac disease in the elderly. PMID- 25528993 TI - Optimism and barriers to colonoscopy in low-income Latinos at average risk for colorectal cancer. AB - OBJECTIVES: Colorectal cancer (CRC) screening continues to be underused, particularly by Latinos. CRC and colonoscopy fear, worry, and fatalism have been identified as screening barriers in Latinos. The study purpose was to examine the relationship of optimism, fatalism, worry, and fear in the context of Latinos referred for CRC screening. METHODS: Our sample included 251 Latinos between the ages of 50 and 83 years who had no personal or immediate family history of CRC, no personal history of gastrointestinal disorder, no colonoscopy in the past 5 years, and received a referral for a colonoscopy. Face-to-face interviews were performed, and data were analyzed using regression models. RESULTS: Greater optimism (beta = -1.72, p < 0.000), lower fatalism (beta = 0.29, p < 0.01), and absence of family history of cancer (beta = 1, p < 0.01) were associated with decreased worry about the colonoscopy. Being female (beta = 0.85, p < 0.05) and born in the USA (beta = 1.1, p < 0.01) were associated with greater worry about colonoscopy and the possibility of having CRC. Family history of cancer (beta = 2.6, p < 0.01), female gender (beta = 2.9, p < 0.000), not following the doctor's advice (beta = 2.7, p < 0.01), and putting off medical problems (beta = 1.9, p < 0.05) were associated with greater fear. In the multiple regression model, lower optimism (beta = -0.09, p < 0.05), higher fatalism (beta = 0.28, p < 0.01), and female gender (beta = 0.9, p < 0.05) were associated with greater worry. CONCLUSIONS: Interventions that address fatalism and promote optimistic beliefs may reduce worry among Latinos referred for colonoscopy. Interventions that alleviate colonoscopy fear because of family history of cancer particularly among Latino women may help improve distress about CRC screening. PMID- 25528996 TI - At the heart of matters: the role of the heart team in transcatheter aortic valve replacement. PMID- 25528997 TI - In silico and in vitro interrogation of a widely used HEV RT-qPCR assay for detection of the species Orthohepevirus A. AB - Hepatitis E virus (HEV) infection is a public health concern worldwide, associated with waterborne outbreaks in developing countries and reported as an emerging zoonotic infection in high-income countries. A recent consensus proposal classified the isolates from human, swine, wild boar, deer, mongoose, rabbit and camel in seven genotypes within the species Orthohepevirus A. In this report a popular HEV RT-qPCR assay was assessed for the detection of the species Orthohepevirus A. In silico analysis of 189 complete genome sequences showed that the assay targets a highly conserved region in the Orthohepevirus A genome. Additionally, plasmid standards were constructed to test the effect of probe- and primer-binding site mutations in the assay performance. The assay proved robust enough to detect strains with mutations in the probe-binding site and in the 3' end primer-binding site regions. A degenerate version of the reverse primer improves the performance of the assay particularly in the detection of HEV-5 and 6. The addition and detection of MS2 RNA in each RT-qPCR reaction monitored for amplification inhibition and did not affect the performance of the assay in the detection of the HEV RNA international standard. Therefore, the RT-qPCR assay can be confidently used for the RNA detection of the seven genotypes within the species Orthohepevirus A. PMID- 25528994 TI - Kruppel-like factors in muscle health and disease. AB - Kruppel-like factors (KLF) are zinc-finger DNA-binding transcription factors that are critical regulators of tissue homeostasis. Emerging evidence suggests that KLFs are critical regulators of muscle biology in the context of cardiovascular health and disease. The focus of this review is to provide an overview of the current state of knowledge regarding the physiologic and pathologic roles of KLFs in the three lineages of muscle: cardiac, smooth, and skeletal. PMID- 25528998 TI - Importance of very early HCV RNA kinetics for prediction of treatment outcome of highly effective all oral direct acting antiviral combination therapy. AB - Interferon-free combination therapies lead to rapid suppression of HCV RNA early during treatment. The potential to predict virologic response and failure as well as to guide treatment duration with measurement of HCV RNA very early during treatment by highly sensitive assays is not well known. In 11 IL28B CC (rs12979860) patients infected with HCV genotype 1, who received DAA combination therapy with the NS3 protease inhibitor ABT-450/r together with the non nucleoside NS5B polymerase inhibitor ABT-072 and ribavirin for 12 weeks, HCV RNA was assessed frequently by the RealTime HCV (ART) and the High-Pure-System/Cobas TaqMan (HPS) assays during and after treatment. Overall, at 33 of 131 time points during treatment residual HCV RNA was detectable by ART but undetectable by HPS while the converse was observed in only two samples. Of the two patients who experienced virologic relapse, one patient had residual viremia at week 6 of treatment by ART only while the other patient never had undetectable HCV RNA by the ART assay. However, residual viremia was also observed by ART as late as therapy weeks 9, 10 and 12 in patients with subsequent sustained virologic response. In patients with sustained response no viremia was observed at multiple time points during post-treatment follow up by either assay. The higher sensitivity of the ART in comparison to the HPS assay may be associated with more frequent detection of residual viremia during highly effective, interferon-free combination therapies. However, the significance of this finding in predicting virologic failure appears to be limited. PMID- 25528999 TI - Pharmacological properties of native CaCCs and TMEM16A. PMID- 25529000 TI - Growth of polypyrrole ultrathin films on MoS2 monolayers as high-performance supercapacitor electrodes. AB - A scalable solution-based approach is developed to controllably grow PPy ultrathin films on 2D MoS2 monolayers. When these sandwiched nanocomposites are utilized as supercapacitor electrodes, a record high specific capacitance, remarkable rate capability, and improved cycling stability are achieved, offering a feasible solution to create the next generation of energy-storage device with superior power density and energy density. PMID- 25529001 TI - Rapid detection of the Klebsiella pneumoniae carbapenemase (KPC) gene by loop mediated isothermal amplification (LAMP). AB - Klebsiella pneumoniae carbapenemases (KPC), which are associated with resistance to carbapenem, have recently spread worldwide and have become a global concern. It is necessary to detect KPC-producing organisms in clinical settings to be able to control the spread of this resistance. We have developed a loop-mediated isothermal amplification (LAMP) method for rapid detection of KPC producers. LAMP primer sets were designed to recognize the homologous regions of blaKPC-2 to blaKPC-17 and could amplify blaKPC rapidly. The specificity and sensitivity of the primers in the LAMP reactions for blaKPC detection were determined. This LAMP assay was able to specifically detect KPC producers at 68 degrees C, and no cross-reactivity was observed for other types of beta-lactamase (class A, B, C, or D) producers. The detection limit for this assay was found to be 10(0) CFU per tube, in 25 min, which was 10-fold more sensitive than a PCR assay for blaKPC detection. Then, the sensitivity of the LAMP reactions for blaKPC detection in human specimens (sputum samples, urine samples, fecal samples and blood samples) was analyzed; it was observed that the LAMP assay had almost the same sensitivity in these samples as when using purified DNA. The LAMP assay is easy to perform and rapid. It may therefore be routinely applied for detection of KPC producers in the clinical laboratory. PMID- 25529002 TI - The power of philanthropy: message from the president. PMID- 25529004 TI - Clinical evaluation of 121 lithium disilicate all-ceramic crowns up to 9 years. AB - OBJECTIVE: The aim of this prospective clinical study was to evaluate the clinical performance of lithium disilicate allceramic crowns for a period from 12 to 156 months. METHOD AND MATERIALS: One hundred and twenty five lithium disilicate all-ceramic crowns were placed in 35 patients between 2001 and 2007. One patient who received four all-ceramic crowns was excluded from the study. The remaining 34 patients received 121 all-ceramic crowns and were recalled. Ninety eight anterior and 23 posterior crowns were inserted. All crowns were applied on vital teeth except for 11 crowns which were placed on endodontically treated teeth. Follow-up appointments were performed 6 months after insertion, then annually. Replacement of a restoration was defined as failure. Marginal integrity, marginal discoloration, secondary caries, sensitivity, color match, and ceramic surface were evaluated following modified California Dental Association/Ryge criteria. The survival rate of the crowns was determined using Kaplan- Meier statistical analysis and log-rank test (P = .05). RESULTS: Ten crowns were fractured. The cumulative survival rate according to Kaplan-Meier was 87.1% after mean 104.6 months (range 12 to 156 months). Location (anterior vs posterior) of all-ceramic crown did not significantly affect the survival rate according to log-rank test (P = .89). Endodontically treated teeth without post and-core restorations exhibited a higher failure rate after all-ceramic crown application according to log-rank test (P < .001). CONCLUSION: In this in vivo study, lithium disilicate all-ceramic crowns exhibited a satisfactory clinical performance with an estimated survival probability of 87.1% over 104.6 months and they can be used clinically in the anterior and posterior region. Restoring endodontically treated teeth with post-and-core restorations should be considered before all-ceramic crown application. PMID- 25529005 TI - Clinical comparison of submucosal injection of dexamethasone and triamcinolone acetonide on postoperative discomfort after third molar surgery. AB - OBJECTIVE: The aim of the study was to compare the effect of submucosal injection of dexamethasone and triamcinolone acetonide on postoperative pain, swelling, and trismus occurring after impacted mandibular third molar surgery. METHOD AND MATERIALS: A total of 78 patients (aged 18 to 35) with asymptomatic, unilateral, impacted mandibular third molar, and without any systemic disease were included in this study. Patients were divided into three groups randomly (control, dexamethasone, and triamcinolone acetonide). In the experimental groups, dexamethasone and triamcinolone acetonide were injected into submucosa at about 1 cm above the surgical area submucosally. The control group of patients did not take any drug submucosally but the same surgical procedure was applied. Pain evaluation was performed by visual analog scale (VAS). Swelling was measured using a flexible standard ruler measuring the dimensions of the axes between certain points on the face. For trismus evaluation, maximum mouth opening was measured. Measurements taken on the preoperative, and on postoperative first, third, and seventh days were compared with each other and statistically evaluated. RESULTS: There were statistically significant differences between the control and experimental groups on the different days of the postoperative period. The effect of triamcinolone acetonide on pain started on the first day postoperatively and the effect of triamcinolone acetonide on trismus and pain was better than other groups at the third and seventh days. However, there was no statistically significant difference between the effects of dexamethasone and triamcinolone acetonide regarding postoperative complications. CONCLUSION: The submucosal injection of dexamethasone or triamcinolone acetonide might be an effective treatment for postoperative discomfort occurring following impacted mandibular third molar surgery, and triamcinolone acetonide could be applied as an alternative to dexamethasone. PMID- 25529003 TI - Phase-resetting as a tool of information transmission. AB - Models of information transmission in the brain largely rely on firing rate codes. The abundance of oscillatory activity in the brain suggests that information may be also encoded using the phases of ongoing oscillations. Sensory perception, working memory and spatial navigation have been hypothesized to use phase codes, and cross-frequency coordination and phase synchronization between brain areas have been proposed to gate the flow of information. Phase codes generally require the phase of the oscillations to be reset at specific reference points for consistent coding, and coordination between oscillators requires favorable phase resetting characteristics. Recent evidence supports a role for neural oscillations in providing temporal reference windows that allow for correct parsing of phase-coded information. PMID- 25529006 TI - Effect of endodontic sealers on push-out bond strength of cemented fiber posts. AB - OBJECTIVE: The purpose of this study was to compare the effect of eugenol-based and resin-based endodontic sealers on the push-out bond strengths of prefabricated fiber posts luted with different resin cements. METHOD AND MATERIALS: Ninety prefabricated fiber posts were luted into extracted singlerooted teeth with one of three resin cements (Variolink II, ParaCore, or Rely X Unicem). Each group was subdivided into three groups with 10 teeth each. The first two groups were obturated with gutta percha and one of two eugenol based endodontic sealers (Endofil or TubliSeal) each. The third group was obturated with gutta percha and (AH26) resin-based root canal sealer. Push-out tests were performed in a universal testing machine by applying a load speed at 0.5 mm/min by using a 1-mm-diameter metallic plunger which induced a load in an apical to coronal direction. The maximum value for post dislodgement (in Newtons) was recorded. Data were collected and statistically analyzed using two-way ANOVA and Tukey multiple comparison tests (alpha = .05). RESULTS: The highest mean bond strength values were recorded for the AH26 sealer group (non-eugenol sealer) luted with Rely X Unicem resin cement (mean +/- SD = 326.1 +/- 66.1 N), while the lowest mean bond strength values were observed with posts luted with Variolink II resin cement into canals obturated with gutta-percha and Endofil (eugenol-based) sealer (90.3 +/- 25.2 N). There was no significant difference between the means of push-out strengths for the Endofil and TubliSeal groups (P = .745). CONCLUSION: Eugenol-based sealers (Endofil and TubliSeal) significantly reduced the push-out bond strength of prefabricated fiber posts luted with resin cement. PMID- 25529008 TI - Introduction of a fluorescent probe to amyloid-beta to reveal kinetic insights into its interactions with copper(II). AB - The kinetics of the interactions between amyloid-beta (Abeta) and metal ions are crucial to understanding the physiological and pathological roles of Abeta in the normal brain and in Alzheimer's disease. Using the quenching of a fluorescent probe by Cu(2+), the mechanism of Abeta/Cu(2+) interactions in physiologically relevant conditions has been elucidated. Cu(2+) binds to Abeta at a near diffusion-limited rate, initially forming component I. The switching between component I and II occurs on the second timescale, with a significant energy barrier. Component I is much more reactive towards Cu(2+) ligands and likely responsible for initial Abeta dimer formation. Clioquinol (CQ) is shown to sequester Cu(2+) more effectively than other tested ligands. These findings have implications for the potential roles of Abeta in regulating neurotransmission, and for the screening of small molecules targeting Abeta-metal interactions. PMID- 25529007 TI - Structure predicts function: combining non-invasive electrophysiology with in vivo histology. AB - We present an approach for combining high resolution MRI-based myelin mapping with functional information from electroencephalography (EEG) or magnetoencephalography (MEG). The main contribution to the primary currents detectable with EEG and MEG comes from ionic currents in the apical dendrites of cortical pyramidal cells, aligned perpendicularly to the local cortical surface. We provide evidence from an in-vivo experiment that the variation in MRI-based myeloarchitecture measures across the cortex predicts the variation of the current density over individuals and thus is of functional relevance. Equivalent current dipole locations and moments due to pitch onset evoked response fields (ERFs) were estimated by means of a variational Bayesian algorithm. The myeloarchitecture was estimated indirectly from individual high resolution quantitative multi-parameter maps (MPMs) acquired at 800MUm isotropic resolution. Myelin estimates across cortical areas correlated positively with dipole magnitude. This correlation was spatially specific: regions of interest in the auditory cortex provided significantly better models than those covering whole hemispheres. Based on the MPM data we identified the auditory cortical area TE1.2 as the most likely origin of the pitch ERFs measured by MEG. We can now proceed to exploit the higher spatial resolution of quantitative MPMs to identify the cortical origin of M/EEG signals, inform M/EEG source reconstruction and explore structure-function relationships at a fine structural level in the living human brain. PMID- 25529009 TI - The alpha2beta1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: a preclinical study. AB - cyclicCHAD is a peptide representing the alpha2beta1 integrin binding sequence of the matrix protein chondroadherin (CHAD), which in our hands proved effective at counteracting bone loss in ovariectomised mice by inhibiting osteoclastogenesis. Given that bone metastases are characterised by exacerbated osteoclast activity as well, we tested this therapy in mice intracardiacally injected with the osteotropic human breast cancer cell line MDA-MB-231. Treatment with cyclicCHAD significantly decreased cachexia and incidence of bone metastases, and induced a trend of reduction of visceral metastasis volume, while in orthotopically injected mice cyclicCHAD reduced tumour volume. In vitro studies showed its ability to impair tumour cell motility and invasion, suggesting a direct effect not only on osteoclasts but also on the tumour cell phenotype. Interestingly, when administered together with a suboptimal, poorly effective, dose of doxorubicin (DXR), cyclicCHAD improved survival and reduced visceral metastases volume to a level similar to that of the optimal dose of DXR alone. Taken together, these preclinical data suggest that cyclicCHAD is a new inhibitor of bone metastases, with an appreciable direct effect also on tumour growth and a synergistic activity in combination with low dose chemotherapy, underscoring an important translational impact. PMID- 25529010 TI - Therapeutic approach to the management of HER2-positive breast cancer metastatic to the brain. AB - HER2 positive breast cancers have been shown to have a greater propensity to metastasise to the brain. This may be due to several reasons, including the creation of a "sanctuary-site" for tumour in the brain following trastuzumab therapy. Elucidating the mechanism of this phenomenon may aid the prevention or intervention and treatment of such metastases, but research is limited by the deficiency and diminished access of CNS tissue. However, CNS penetrable HER2 receptor antagonists such as lapatinib and intrathecal administration of trastuzumab might benefit patients, and are worthy of further investigation. New avenues of molecular approach have focused on manipulating signal transduction system involved in HER2 function. The importance of systemic therapies and those targeted to metastatic lesions is emphasised and evaluated here. PMID- 25529011 TI - Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive growth, early metastasis and high resistance to chemotherapy. Salinomycin is a promising compound eliminating cancer stem cells and retarding cancer cell migration. The present study investigated the effectiveness of salinomycin against PDAC in vivo and elucidated the mechanism of PDAC growth inhibition. Salinomycin treatment was well tolerated by the mice and significantly reduced tumor growth after 19 days compared to the control group (each n = 16). There was a trend that salinomycin also impeded metastatic spread to the liver and peritoneum. Whereas salinomycin moderately induced apoptosis and retarded proliferation at 5-10 uM, it strongly inhibited cancer cell migration that was accompanied by a marked loss of actin stress fibers after 6-9 h. Salinomycin silenced RhoA activity, and loss of stress fibers could be reversed by Rho activation. Moreover, salinomycin dislocated fascin from filopodia and stimulated Rac-associated circular dorsal ruffle formation. In conclusion, salinomycin is an effective and promising compound against PDAC. Besides its known stem cell-specific cytotoxic effects, salinomycin blocks cancer cell migration by disrupting stress fiber integrity and affecting the mutual Rho-GTPase balance. PMID- 25529013 TI - Large-scale virtual high-throughput screening for the identification of new battery electrolyte solvents: computing infrastructure and collective properties. AB - A volunteer computing approach is presented for the purpose of screening a large number of molecular structures with respect to their suitability as new battery electrolyte solvents. Collective properties like melting, boiling and flash points are evaluated using COSMOtherm and quantitative structure-property relationship (QSPR) based methods, while electronic structure theory methods are used for the computation of electrochemical stability window estimators. Two application examples are presented: first, the results of a previous large-scale screening test (PCCP, 2014, 16, 7919) are re-evaluated with respect to the mentioned collective properties. As a second application example, all reasonable nitrile solvents up to 12 heavy atoms are generated and used to illustrate a suitable filter protocol for picking Pareto-optimal candidates. PMID- 25529012 TI - Semaphorin-3F suppresses the stemness of colorectal cancer cells by inactivating Rac1. AB - Tumor cell stemness has been recognized as a key contributor to tumor initiation, progression and recurrence. Our previous studies have found that semaphorin-3F (SEMA3F), an axon guidance molecule in the development of central nervous system, inhibited the growth and metastasis of colorectal cancer (CRC). However, a possible role for SEMA3F in regulating cancer cell stemness remains unknown. Here, we report a novel mechanism of the acquirement of stemness of CRC cells regulated by SEMA3F. Knockdown of SEMA3F significantly promoted the self-renewal and tumorigenicity of CRC cells, and increased the expression of stemness associated genes, while overexpressing SEMA3F reduced the stemness of CRC cells. Mechanistically, GTP-Rac1 was involved in SEMA3F mediated regulation of CRC cell stemness by targeting the Wnt/beta-catenin pathway. Clinically, GTP-Rac1 expression was inversely correlated with SEMA3F levels in CRC samples and patients with SEMA3F(low)/GTP-Rac1(high) CRC showed poorer prognosis. Our findings demonstrate the ability of SEMA3F to inhibit the stemness of human CRC cells by suppressing Rac1 activation, which suggests a novel therapeutic approach for CRC. PMID- 25529014 TI - Very Late Treatment-Related Alterations in Brain Function of Breast Cancer Survivors. AB - Although adjuvant chemotherapy (CT) for breast cancer (BC) is associated with very late side-effects on cognition and brain function, studies on adverse effects of specific treatment regimens are scarce. Here, neurotoxicity profiles after different treatment strategies were compared in BC survivors randomized to high-dose (HI) or conventional-dose (CON-) CT, in women treated with radiotherapy (RT) -only and a healthy control (HC) group. We administered a neurocognitive test battery, a planning fMRI task (Tower of London) and episodic memory fMRI task (Paired Associates paradigm) in BC survivors who received CON-CT (n=24) and HC (n=27). Data were compared to BC survivors who received HI-CT (n=17) and RT only (n=15) and who were previously assessed. Testing took place +/-11.5 years post-CT. Furthermore, neurocognitive data were compared to neurocognitive data acquired <=2 years post-treatment. Cognitive assessment revealed sustained cognitive decline in 10.5% of HI-CT, 8.3% of CON-CT, 6.7% of RT-only patients and 0% in the HC. Hypoactivation was found in task-related prefrontal and parietal areas for both CT-groups versus RT-only, with HI-CT showing more pronounced hypoactivation than CON-CT, combined with worse task performance. RT-only survivors performed at a similar level to HC while showing hyperactivation in task-related brain areas. Long after treatment, CT is associated with cognitive problems and task-related hypoactivation that depend on the specific cytotoxic regimen. This worse performance in patients who received CT could be explained by impaired brain functioning that is more severe with more intense CT. PMID- 25529015 TI - Recurrence pattern analysis after re-irradiation with bevacizumab in recurrent malignant glioma patients. AB - BACKGROUND: The aim of the present analysis was to evaluate the recurrence pattern in patients with recurrent malignant glioma after re-irradiation in combination with bevacizumab as there is limited data on how to optimally choose dose, fractionation and delineation margins. METHODS: Thirty-one patients with recurrent malignant glioma treated with re-irradiation and bevacizumab after previous chemoradiotherapy (concurrent temozolomide 75 mg/m(2)/d according to the EORTC/NCIC trial) and [(18) F]FET-PET and/or MRI confirmed recurrence were retrospectively analyzed. Bevacizumab was applied twice during fractionated re irradiation (10 mg/kg, d1+d15, median 36 Gy, conventionally fractionated). Recurrence patterns were assessed by means of [(18) F]FET-PET and/or MRI. RESULTS: Median follow-up was 34.0 months for all patients [95%-CI, 27.7-40.3] and median post-recurrence survival 10.8 months [95%-CI, 9.2-12.4]. Concerning the recurrence patterns, 61.3% of these were located in-field (19 patients), 22.6% were marginal (7 patients) and 16.1% ex-field (5 patients). No influence on the recurrence pattern was observed according to sex, WHO grade, maintenance chemotherapy or MGMT methylation status whereas planning target volume (PTV) size had a significant influence on the recurrence pattern (p=0.032). PTV sizes>75 ml were associated with a higher in-field recurrence rate and lower median post recurrence progression-free survival (8.5 vs. 4.9 months, p=0.016). CONCLUSIONS: After the administration of re-irradiation with bevacizumab the recurrence pattern seems to be mainly centrally located. The PTV size was the main predictor for a marginal/ex-field recurrence. PMID- 25529016 TI - Characterization of a multidrug-resistant, novel Bacteroides genomospecies. AB - Metronidazole- and carbapenem-resistant Bacteroides fragilis are rare in the United States. We isolated a multidrug-resistant anaerobe from the bloodstream and intraabdominal abscesses of a patient who had traveled to India. Whole-genome sequencing identified the organism as a novel Bacteroides genomospecies. Physicians should be aware of the possibility for concomitant carbapenem- and metronidazole-resistant Bacteroides infections. PMID- 25529017 TI - Applications of solid-phase microextraction and gas chromatography/mass spectrometry (SPME-GC/MS) in the study of grape and wine volatile compounds. AB - Volatile compounds are responsible for the wine "bouquet", which is perceived by sniffing the headspace of a glass, and of the aroma component (palate-aroma) of the overall flavor, which is perceived on drinking. Grape aroma compounds are transferred to the wine and undergo minimal alteration during fermentation (e.g., monoterpenes and methoxypyrazines); others are precursors of aroma compounds which form in winemaking and during wine aging (e.g., glycosidically-bound volatile compounds and C13-norisoprenoids). Headspace solid phase microextraction (HS-SPME) is a fast and simple technique which was developed for analysis of volatile compounds. This review describes some SPME methods coupled with gas chromatography/mass spectrometry (GC/MS) used to study the grape and wine volatiles. PMID- 25529018 TI - Effects of high hydrostatic pressure on Escherichia coli ultrastructure, membrane integrity and molecular composition as assessed by FTIR spectroscopy and microscopic imaging techniques. AB - High hydrostatic pressure (HHP) is a novel food processing technology that is considered as an attractive alternative to conventional heat treatments for the preservation of foods, due to its lethal effects on pathogenic and spoilage microorganisms, while causing minor effects on food quality and sensorial attributes. This study is aimed at investigating how HHP treatments at varying intensities in the range 50-900 MPa affect the viability, membrane integrity, ultrastructure and molecular composition of Escherichia coli. Results of membrane integrity tests (measurement of cellular leakage and monitoring of propidium iodide uptake through fluorescence microscopy) and ultrastructural observations by transmission electron microscopy demonstrated that HHP gave rise to cellular enlargement, membrane damage or detachment, DNA and protein denaturation and loss of intracellular contents. Fourier-transform infrared (FTIR) spectroscopy analyses evidenced minor changes in molecular composition in response to high pressures, which were mostly observed on the spectral region w4 (1200-900 cm-1), mainly informative of carbohydrates and polysaccharides of the cell wall. These findings suggest that exposure of E. coli cells to HHP causes alterations in their physical integrity while producing minor modifications in biochemical cellular composition. The current study increases the knowledge on the mechanisms of E. coli inactivation by HHP and provides valuable information for the design of more effective food preservation regimes based on the integration of mild HHP in combination with other food preservation strategies into a multi-target hurdle technology approach. PMID- 25529019 TI - Synthesis, characterisation and reactions of phosphine-substituted alkynylboronates and alkynyltrifluoroborate salts. AB - The synthesis and structural characterisation of phosphine-substituted alkynylboronates is reported. A P(III)-centred alkynylboronate (2) was prepared that showed little evidence for the conjugation of the P-lone pair to the boron via the alkyne pi-system, as judged by X-ray crystallography studies of 2 and a related P(V) compound, 3. In addition, corresponding alkynyltrifluoroborate salts were prepared that showed improved stability by comparison to their boronic ester counterparts. These salts undergo Pd-catalysed cross-coupling reactions with aryl halides. PMID- 25529020 TI - Lignin hydrolysis and phosphorylation mechanism during phosphoric acid-acetone pretreatment: a DFT study. AB - The study focused on the structural sensitivity of lignin during the phosphoric acid-acetone pretreatment process and the resulting hydrolysis and phosphorylation reaction mechanisms using density functional theory calculations. The chemical stabilities of the seven most common linkages (beta-O-4, beta-beta, 4-O-5, beta-1, 5-5, alpha-O-4, and beta-5) of lignin in H3PO4, CH3COCH3, and H2O solutions were detected, which shows that alpha-O-4 linkage and beta-O-4 linkage tend to break during the phosphoric acid-acetone pretreatment process. Then alpha O-4 phosphorylation and beta-O-4 phosphorylation follow a two-step reaction mechanism in the acid treatment step, respectively. However, since phosphorylation of alpha-O-4 is more energetically accessible than phosphorylation of beta-O-4 in phosphoric acid, the phosphorylation of alpha-O-4 could be controllably realized under certain operational conditions, which could tune the electron and hole transfer on the right side of beta-O-4 in the H2PO4- functionalized lignin. The results provide a fundamental understanding for process-controlled modification of lignin and the potential novel applications in lignin-based imprinted polymers, sensors, and molecular devices. PMID- 25529021 TI - Synthesis and Bio-Evaluation of New (18) F-Labeled Pyridaben Analogs with Improved Stability for Myocardial Perfusion Imaging in Mice. AB - To improve the stability of (18) F-labeled pyridaben analogs for myocardial perfusion imaging, three new analogs of pyridaben ([(18) F]FPTP2, [(18) F]FPTP P2, and [(18) F]FPTP-P3) were synthesized with 'side chain' modifications. The radiolabeled tracers and corresponding non-radioactive compounds were obtained by substituting tosyl group with (18/19) F. The effect of structure modification on myocardial targeting and physicochemical properties of new tracers were evaluated in vitro and in vivo. The total radiosynthesis time of these tracers was approximately 70-90 min with high decay-corrected radiochemical yields (36-65%) and good radiochemical purity (> 98%). These lipophilic tracers exhibited obvious improved stability in water. Studies of their biodistribution in normal Kunming mice demonstrated that [(18) F]FPTP2 exhibited very high initial heart uptake (39.70 +/- 2.81 %ID/g at 2 min after injection) and low background in the liver, blood, and soft tissues. The heart-to-liver, heart-to-lung, and heart-to-blood ratios were 3.59, 19.34, and 67.34 at 15 min postinjection, respectively. Favorable myocardial targeting property and remarkable improvement of stability of [(18) F]FPTP2 suggest that the substitution of the phenyl 'sidechain' with other non-phenyl rings has no effect on the myocardial targeting property of (18) F-labeled pyridaben analogs. PMID- 25529022 TI - Control of eight predominant Eimeria spp. involved in economic coccidiosis of broiler chicken by a chemically characterized essential oil. AB - AIM: To control eight most predominant Eimeria spp. involved in the economic disease of coccidiosis in broiler chicken, by a chemically characterized essential oil of eucalyptus and peppermint. METHODS AND RESULTS: The experimental design consisted of 160 day-old-broiler chicks, divided into four equal groups (G1 , G2 , G3 and G4 ), with 40 birds per group. Each group was divided into four equal subgroups. Birds in G1 were deprived of essential oil treatment and of Eimeria challenge. Birds in G2 were unchallenged, and administered the essential oil in drinking water at 0.69 ml kg(-1) body weight. Birds in G3 were untreated with essential oil, and each of its four subgroups was challenged at a different age (14, 21, 28 and 35 days). Birds in G4 were treated with essential oil, and challenged in the same manner as for G3 . Equal number of birds from all subgroups (n = 10) were sacrificed at the sixth day after the time allocated for each challenge. The 6 day incubation period post challenge resulted in respective mean per cent weight increase in G2 and G1 birds equivalent to 57.8 and 53.1% (P < 0.05). In addition, the essential oil improved the per cent weight increase in challenged birds (54.6%) compared to the challenged-untreated birds (18.6%) (P < 0.05). The mean feed conversion, mortality, intestinal lesion scores and oocyst counts were significantly reduced in the challenged-treated birds compared to the challenged-untreated birds (P < 0.05). CONCLUSIONS: The results support the hypothesis of using the essential oils of eucalyptus and peppermint to control the most prevalent Eimeria spp. involved in coccidiosis of broiler chicken, helping in improvement of their production, alleviation of lesions and reduction in intestinal oocyst counts. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information about the possibility of using this blend of essential oil as a coccidiostat for the protection of broiler chickens against the prevalent eight Eimeria spp. of coccidiosis. PMID- 25529023 TI - Leptopyrine, new alkaloid from Leptopyrum fumarioides L. (Ranunculaceae). AB - A new type of isoquinoline alkaloid leptopyrine was isolated from the aerial parts of Leptopyrum fumarioides L. (Ranunculaceae) of Mongolian origin. The known alkaloids protopine and thalifoline were isolated for the first time from this the species. All structures were established by physical and spectral analyses. PMID- 25529024 TI - Chronic intraocular pressure elevation impairs autoregulatory capacity in streptozotocin-induced diabetic rat retina. AB - PURPOSE: To assess ocular blood flow responses to acute IOP stress following 4 weeks of chronic IOP elevation in streptozotocin (STZ)-induced diabetic and control rats. We hypothesise that chronic IOP elevation for 4 weeks will further impair blood flow regulation in STZ-induced diabetic rats eyes. METHODS: Two weeks following citrate buffer or STZ-injections chronic IOP elevation was induced in Long Evans rats via fortnightly intracameral injections of microspheres (15 MUm) suspended in 5% polyethylene glycol. IOP was monitored daily. Electroretinography (ERG, -6.79-2.07 log cd s m(-2) ) was undertaken at Week 4 to compare photoreceptor (RmPIII ), ON-bipolar cell (Vmax ) and ganglion cell dominant ERG [scotopic threshold response (STR)] components. 4 weeks post chronic IOP induction, ocular blood flow (laser Doppler flowmetry) was measured in response to acute IOP challenge (10-100 mmHg, in 5 mmHg steps, each 3 min). RESULTS: Four weeks of chronic IOP (mean +/- S.E.M., citrate: 24.0 +/- 0.3 to 30.7 +/- 1.3 and STZ-diabetes: 24.2 +/- 0.2 to 31.1 +/- 1.2 mmHg) was associated with reduced photoreceptor amplitude in both groups (-25.3 +/- 2.2% and -17.2 +/- 3.0%, respectively). STZ-diabetic eyes showed reduced photoreceptor sensitivity (citrate: 0.5 +/- 1.8%, STZ-diabetic: -8.1 +/- 2.4%). Paradoxically ON-bipolar cell sensitivity was increased, particularly in citrate control eyes (citrate: 166.8 +/- 25.9%, STZ-diabetic: 64.8 +/- 18.7%). The ganglion cell dominant STR was not significantly reduced in STZ-diabetic rats. Using acute IOP elevation to probe autoregulation, we show that STZ-diabetes impaired autoregulation compared with citrate control animals. The combination of STZ-diabetes and chronic IOP elevation further impaired autoregulation. CONCLUSIONS: STZ-diabetes and chronic IOP elevation appear to be additive risk factors for impairment of ocular blood flow autoregulation. PMID- 25529025 TI - Non-diagnostic use of oral Gastrografin: a frequent source of conflict, with a practical solution. PMID- 25529027 TI - Polymerase-chain reaction/electrospray ionization-mass spectrometry for the detection of bacteria and fungi in bronchoalveolar lavage fluids: a prospective observational study. AB - PLEX-ID uses polymerase chain reaction-electrospray ionization/mass spectrometry for rapid identification of infectious agents in clinical samples. We evaluated its concordance with our centre's standard methods (SM) for bacterial and fungal detection in bronchoalveolar lavage (BAL) fluid in a prospective observational cohort study. The primary outcome was concordance (%) between SM and PLEX-ID. Secondary outcomes included concordance when excluding commensal oral flora, detection of resistance genes, and PLEX-ID's potential impact on clinical management, as determined by two independent reviewers. Included were 101 specimens from 94 patients. BALs were performed primarily for suspected pneumonia (76/101, 75%) and lung transplant work-ups (12/101, 12%). Most specimens yielded at least one organism by either method (92/101, 91%). Among all microorganisms detected (n = 218), 83% and 17% were bacterial and fungal, respectively. Overall concordance between SM and PLEX-ID was 45% (45/101). Concordance increased to 66% (67/101) when discordance for commensal flora was excluded. PLEX-ID failed to detect 21% of all 183 SM-identified organisms, while SM did not identify 28% of the 191 PLEX-ID-identified organisms (p <0.001). There was low concordance for mecA detection. Two infectious-disease specialists' analyses concluded that in most of the 31 discordant, non-commensal cases, PLEX-ID results would have had little or no impact on patient management; in eight cases, however, PLEX-ID would have led to 'wrong decision-making'. The tested version of PLEX-ID concurred weakly with standard methods in the detection of bacteria and fungi in BAL specimens, and is not likely to be useful as a standalone tool for microbiological diagnosis in suspected respiratory infections. PMID- 25529028 TI - Selective processing of buildings and faces during working memory: the role of the ventral striatum. AB - The ventral striatum seems to play an important role during working memory (WM) tasks when irrelevant information needs to be filtered out. However, the concrete neural mechanisms underlying this process are still unknown. In this study, we investigated these mechanisms in detail. Eighteen healthy human participants were presented with multiple items consisting of faces or buildings. They either had to maintain two or four items from one category (low- and high-memory-load condition), or two from one category and suppress (filter out) two items from the other category (distraction condition). Striatal activity was increased in the distraction as compared with the high-load condition. Activity in category specific regions in the inferior temporal cortex [fusiform face area (FFA) and parahippocampal place area (PPA)] was reduced when items from the other category needed to be selectively maintained. Furthermore, functional connectivity analysis showed significant reduction of striatal-PPA correlations during selective maintenance of faces. However, striatal-FFA connectivity was not reduced during maintenance of buildings vs. faces, possibly because face stimuli are more salient. Taken together, our results suggest that the ventral striatum supports selective WM maintenance by reduced gating of task-irrelevant activity via attenuating functional connectivity without increasing task-relevant activity correspondingly. PMID- 25529030 TI - Pseudo-SLE by human immunodeficiency virus infection. AB - A 61-year-old woman was admitted for long-lasting fever and recurrent opportunistic infections during the treatment of SLE. She had been diagnosed as SLE and type-IV nephritis based on a renal biopsy and serological findings. A colonoscopy and liver biopsy revealed disseminated Mycobacterium avium complex infection. Human immunodeficiency virus (HIV) infection status was then examined and found to be positive. From the clinical course, the first symptoms were inferred to have been those of HIV infection. PMID- 25529026 TI - Conserved proline-directed phosphorylation regulates SR protein conformation and splicing function. AB - The alternative splicing of human genes is dependent on SR proteins, a family of essential splicing factors whose name derives from a signature C-terminal domain rich in arginine-serine dipeptide repeats (RS domains). Although the SRPKs (SR specific protein kinases) phosphorylate these repeats, RS domains also contain prolines with flanking serines that are phosphorylated by a second family of protein kinases known as the CLKs (Cdc2-like kinases). The role of specific serine-proline phosphorylation within the RS domain has been difficult to assign since CLKs also phosphorylate arginine-serine dipeptides and, thus, display overlapping residue specificities with the SRPKs. In the present study, we address the effects of discrete serine-proline phosphorylation on the conformation and cellular function of the SR protein SRSF1 (SR protein splicing factor 1). Using chemical tagging and dephosphorylation experiments, we show that modification of serine-proline dipeptides broadly amplifies the conformational ensemble of SRSF1. The induction of these new structural forms triggers SRSF1 mobilization in the nucleus and alters its binding mechanism to an exonic splicing enhancer in precursor mRNA. These physical events correlate with changes in the alternative splicing of over 100 human genes based on a global splicing assay. Overall, these studies draw a direct causal relationship between a specific type of chemical modification in an SR protein and the regulation of alternative gene splicing programmes. PMID- 25529029 TI - The safety of hand-assisted laparoscopic living donor nephrectomy: the Ohio State University experience with 1500 cases. AB - Hand-assisted laparoscopic donor (HALD) nephrectomy has been performed at our institution since December 1999. Through May 2014, a total of 1500 HALD procedures have been performed. We have evaluated the outcomes of HALD. The HALD procedure consists of a hand-port incision as well as two 12-mm ports. Mean donor age was 40.8 +/- 10.8 yr, BMI was 27.9 +/- 5.0, there were 541 males, 1271 Caucasians, and the left kidney was removed in 1236 patients. All procedures were successfully completed. Four donors (0.27%) were converted to an open technique due to bleeding. Four donors required blood transfusions. 53 donors (3.5%) were readmitted in the first month post-donation; almost half were due to gastrointestinal complaints. Six donors required reoperation; three for SBO and three for wound dehiscence. 27 patients (1.8%) developed incisional hernias. Seven donors (0.47%) developed bowel obstruction. All donors recovered well with a mean hospital stay after donation of 2.1 +/- 0.3 d. All except one kidney were successfully implanted. Twenty-one recipients (1.4%) experienced DGF. Ureter complications occurred in 17 (1.1%) recipients. Early graft loss occurred in 13 patients (0.9%). In conclusion, HALD is a safe procedure for the donor with good recipient outcomes. PMID- 25529031 TI - Prophylactic effect of fondaparinux and enoxaparin for preventing pulmonary embolism after total hip or knee arthroplasty: A retrospective observational study using the Japanese Diagnosis Procedure Combination database. AB - OBJECTIVES: The aim of this study was to estimate the effect of fondaparinux and enoxaparin combined with mechanical prophylaxis (MP) after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We also investigated the occurrence of pulmonary embolism (PE) and its associated risk factors. METHODS: Data were retrospectively collected on patients who underwent THA or TKA between 2008 and 2010 from the Japanese Diagnosis Procedure Combination database (n = 49,678). We extracted information on sex, age, main diagnosis, types of anesthesia, duration of anesthesia, comorbidities, hospital volume, the use of MP, and the use of anticoagulant drugs. RESULTS: The overall occurrence of PE was 0.41%. Multivariate logistic regression analysis showed that the occurrence of PE was significantly higher in females (odds ratio, 2.17; p < 0.001, compared with males), TKA (1.47; p = 0.039, compared with THA), and longer-duration anesthesia (2.63; p = 0.008 in the >= 240-min. group compared with the <= 119-min. group). Compared with the MP-alone group, the occurrence of PE was significantly reduced in the fondaparinux group (0.58; p = 0.025) and the enoxaparin group (0.59; p = 0.046). CONCLUSIONS: Fondaparinux or enoxaparin combined with MP decreased the occurrence of PE. The risk factors for PE were female patients, TKA, and longer duration anesthesia (>= 240 min.). PMID- 25529032 TI - Echocardiographic evaluation of diastolic dysfunction in rheumatoid arthritis - a case-control study. AB - OBJECTIVES: To assess left ventricular diastolic dysfunction (LVDD) and its predictors in rheumatoid arthritis (RA). METHODS: This cross-sectional case control study assessed 100 RA patients and 100 healthy controls for LVDD by M mode, two-dimensional, colour Doppler echocardiography. RESULTS: RA patients had higher prevalence of LVDD than controls (43% vs. 14%; p < 0.001). LVDD had significant association with duration (p = 0.033), severity of disease activity (p < 0.0001), Steinbrocker stage and functional class (p < 0.0001 each) and non adherence to treatment (p = 0.047). Peak of late diastolic (A) mitral flow velocity and isovolumic relaxation time (IVRT) were higher (p < 0.05 each), whereas left ventricular ejection fraction, peak of early diastolic (E) mitral flow velocity and E/A ratio were lower (p < 0.05 each) in RA patients than in controls. Deceleration time (DT) was not significantly different in the two groups (p = 0.623). E/A ratio had significant correlation with anti-cyclic citrullinated peptide antibody (ACPA) (r = 0.233, p = 0.019) and age (r = 0.203, p = 0.042). IVRT had significant negative correlation with ACPA (r = -0.196, p = 0.044), while DT had significant correlation with Disease Activity Score with 28 joint (DAS28) counts (r = 0.244, p = 0.014). ACPA was an independent predictor of E/A ratio (p = 0.031). DAS28 was the only independent predictor of LVDD (odds ratio [OR] = 6.01; p = 0.007). CONCLUSIONS: LVDD occurred commonly in RA patients and depended on severity of disease activity. PMID- 25529033 TI - Efficacy at 52 weeks of daily clinical use of iguratimod in patients with rheumatoid arthritis. AB - OBJECTIVE: In recent years, the use of one or more conventional synthetic disease modifying antirheumatic drugs has been recommended for the treatment of rheumatoid arthritis (RA). We performed a 52-week study on the efficacy and safety of iguratimod (IGU) against patients with RA in daily clinical use. METHODS: Forty-one patients were enrolled in this study, and the clinical course of RA was regularly evaluated during the 52 weeks of treatment. RESULTS: The survival rate at week 52 was 53.7%. The disease activity score (DAS) 28 erythrocyte sedimentation rate, DAS28-C-reactive protein, simplified disease activity index, and clinical disease activity index were all significantly decreased at week 52. The matrix metalloproteinase-3 level was significantly decreased at week 52 by combination therapy of IGU and methotrexate. There were one case of the onset of interstitial pneumonia (IP), one exacerbation of IP, and one case of the onset of Pneumocystis jiroveci pneumonia. CONCLUSIONS: IGU is effective for RA patients when used for daily clinical treatment for 52 weeks. PMID- 25529042 TI - Frontal midline theta as a neurophysiological correlate for deficits of attentional orienting in children with developmental coordination disorder. AB - Children with developmental coordination disorder (DCD) have been demonstrated to show attentional orienting deficits. The neural mechanism, however, has thus far remained elusive. Here, we measure oscillations in the EEG associated with attentional orienting to address this issue. The EEG was recorded from DCD children and typical developing (TD) controls during an eye-gaze cueing paradigm. DCD group responded more slowly than TD group across all conditions. Additionally, TD group showed higher frontal midline theta activities in both valid and invalid conditions relative to a neutral condition, with such an effect absent in the DCD group. Theta oscillations might reflect attentional processing in relation to the cues being performed in TD group, with the lessened modulation of theta in DCD group possibly reflecting a deficit in attentional orienting. Possible explanations for the DCD-TD differences in theta oscillation and attentional orienting are discussed. PMID- 25529043 TI - Learning curves for cardiothoracic and vascular surgical procedures--a systematic review. AB - OBJECTIVES: The aim of this systematic review is to evaluate the learning curve (LC) literature and identify the LC of cardiothoracic and vascular surgical procedures. SUMMARY AND BACKGROUND: The LC describes an observation that a learner's performance improves over time during acquisition of new motor skills. Measuring the LC of surgical procedures has important implications for surgical innovation, education, and patient safety. Numerous studies have investigated LCs of isolated operations in cardiothoracic and vascular surgeries, but a lack of uniformity in the methods and variables used to measure LCs has led to a lack of systematic reviews. METHODS: The MEDLINE(r), EMBASETM, and PsycINFO(r) databases were systematically searched until July 2013. Articles describing LCs for cardiothoracic and vascular procedures were included. The type of procedure, statistical analysis, number of participants, procedure setting, level of participants, outcomes, and LCs were reviewed. RESULTS: A total of 48 studies investigated LCs in cardiothoracic and vascular surgeries. Based on operating time, the LC for coronary artery bypass surgery ranged between 15 and 100 cases; for endoscopic vessel harvesting and other cardiac vessel surgery between 7 and 35 cases; for valvular surgery, which included repair and replacement, between 20 and 135 cases; for video-assisted thoracoscopic surgery, between 15 and 35 cases; for vascular neurosurgical procedures between 100 and 500 cases, based on complications; for endovascular vessel repairs between 5 and 40 cases; and for ablation procedures between 25 and 60 cases. However there was a distinct lack of standardization in the variables/outcome measures used, case selection, prior experience, and supervision of participating surgeons and a range of statistical analyses to compute LCs was noted. CONCLUSION: LCs in cardiothoracic and vascular procedures are hugely variable depending on the procedure type, outcome measures, level of prior experience, and methods/statistics used. Uniformity in methods, variables, and statistical analysis is needed to derive meaningful comparisons of LCs. Acknowledgment and application of learning processes other than those reliant on volume-outcomes relationship will benefit LC research and training of surgeons. PMID- 25529044 TI - Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. AB - INTRODUCTION: Adenoviruses (Ads) have attracted researchers from across the disciplines for several reasons. Their ability to recombine with and express the heterologous genes encouraged their development as gene/vaccine delivery vectors. Preclinical and clinical trials using these vectors have shown significant promise for their future development while highlighting certain limitations. AREAS COVERED: Ad vector development, clinical application of these vectors in gene therapy and vaccine development, and promises that these vectors offered for future development are discussed. Also, various factors affecting their in vivo efficacy as well as the strategies being pursued to overcome these obstacles are described. EXPERT OPINION: Decades of efforts have resulted in understanding various aspects of human Ad 5 biology as well as the in vivo behavior of vectors derived from this serotype. While this vector has shown great potential, some of the limitations highlighted in recent studies have reinforced the quest for an ideal vector derived from novel Ads. Combinatorial approaches to address the various limitations of the existing vectors must be pursued to develop novel vectors with enhanced clinical potential. PMID- 25529046 TI - Species are hypotheses: avoid connectivity assessments based on pillars of sand. AB - Connectivity among populations determines the dynamics and evolution of populations, and its assessment is essential in ecology in general and in conservation biology in particular. The robust basis of any ecological study is the accurate delimitation of evolutionary units, such as populations, metapopulations and species. Yet a disconnect still persists between the work of taxonomists describing species as working hypotheses and the use of species delimitation by molecular ecologists interested in describing patterns of gene flow. This problem is particularly acute in the marine environment where the inventory of biodiversity is relatively delayed, while for the past two decades, molecular studies have shown a high prevalence of cryptic species. In this study, we illustrate, based on marine case studies, how the failure to recognize boundaries of evolutionary-relevant unit leads to heavily biased estimates of connectivity. We review the conceptual framework within which species delimitation can be formalized as falsifiable hypotheses and show how connectivity studies can feed integrative taxonomic work and vice versa. Finally, we suggest strategies for spatial, temporal and phylogenetic sampling to reduce the probability of inadequately delimiting evolutionary units when engaging in connectivity studies. PMID- 25529045 TI - Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane. AB - OBJECTIVE: To investigate MK-467 as part of premedication in horses anaesthetized with isoflurane. STUDY DESIGN: Experimental, crossover study with a 14 day wash out period. ANIMALS: Seven healthy horses. METHODS: The horses received either detomidine (20 MUg kg(-1) IV) and butorphanol (20 MUg kg(-1) IV) alone (DET) or with MK-467 (200 MUg kg(-1) IV; DET + MK) as premedication. Anaesthesia was induced with ketamine (2.2 mg kg(-1) ) and midazolam (0.06 mg kg(-1) ) IV and maintained with isoflurane. Heart rate (HR), mean arterial pressure (MAP), end tidal isoflurane concentration, end-tidal carbon dioxide tension, central venous pressure, fraction of inspired oxygen (FiO2 ) and cardiac output were recorded. Blood samples were taken for blood gas analysis and to determine plasma drug concentrations. The cardiac index (CI), systemic vascular resistance (SVR), ratio of arterial oxygen tension to inspired oxygen (Pa O2 /FiO2 ) and tissue oxygen delivery (DO2 ) were calculated. Repeated measures anova was applied for HR, CI, MAP, SVR, lactate and blood gas variables. The Student's t-test was used for pairwise comparisons of drug concentrations, induction times and the amount of dobutamine administered. Significance was set at p < 0.05. RESULTS: The induction time was shorter, reduction in MAP was detected, more dobutamine was given and HR and CI were higher after DET+MK, while SVR was higher with DET. Arterial oxygen tension and Pa O2 /FiO2 (40 minutes after induction), DO2 and venous partial pressure of oxygen (40 and 60 minutes after induction) were higher with DET+MK. Plasma detomidine concentrations were reduced in the group receiving MK-467. After DET+MK, the area under the plasma concentration time curve of butorphanol was smaller. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 enhances cardiac function and tissue oxygen delivery in horses sedated with detomidine before isoflurane anaesthesia. This finding could improve patient safety in the perioperative period. The dosage of MK-467 needs to be investigated to minimise the effect of MK-467 on MAP. PMID- 25529047 TI - Overview of dermatologic disorders of neonates in a central regional intensive care unit in Hungary. AB - The immaturity and vulnerability of the skin and epidermal barrier function and the frequent iatrogenic complications following diagnostic and therapeutic procedures are often associated with skin manifestations in infants in neonatal intensive care units (NICUs). The aim of the current study was to investigate dermatologic disorders in neonates in our NICU. A prospective cohort study was conducted in the NICU at the Department of Pediatrics at the University of Szeged between January 2012 and January 2013. All full- and preterm infants hospitalized in the NICU underwent whole-body skin examinations and all dermatologic disorders and treatment modalities were recorded. Eighty-nine dermatologic conditions were detected in 64 of the 211 neonates admitted to the NICU. A wide variety of clinical symptoms accompanied these conditions in these preterm and severely ill full-term infants. A considerable proportion of the disorders that were seen resulted from the immaturity of the skin and various iatrogenic complications. Dermatologic disorders are frequent in neonates requiring intensive care. Prevention, early detection, and optimal treatment of these disorders with modern, standardized skin care management strategies can result in significant improvements in barrier function and in the integrity of the skin, increasing the overall efficacy of neonatal intensive care. PMID- 25529049 TI - Protective role of autophagy and autophagy-related protein 5 in early tumorigenesis. AB - Autophagy, a fundamental cellular catabolic process, is involved in the development of numerous diseases including cancer. Autophagy seems to have an ambivalent impact on tumor development. While increasing evidence indicates a cytoprotective role for autophagy that can contribute to resistance against chemotherapy and even against the adverse, hypoxic environment of established tumors, relatively few publications focus on the role of autophagy in early tumorigenesis. However, the consensus is that autophagy is inhibitory for the genesis of tumors. To understand this apparent contradiction, more detailed information about the roles of the individual participants in autophagy is needed. This review will address this topic with respect to autophagy-related protein 5 (ATG5), which in several lines of investigation has been ascribed special significance in the autophagic pathway. Furthermore, it was recently shown that an ATG5 deficiency in melanocytes interferes with oncogene-induced senescence, thus promoting melanoma tumorigenesis. Similarly, an ATG5 deficiency resulted in tumors of the lung and liver in experimental mouse models. Taken together, these findings indicate that ATG5 and the autophagy to which it contributes are essential gatekeepers restricting early tumorigenesis in multiple tissues. PMID- 25529048 TI - The influence of the human microbiome and probiotics on cardiovascular health. AB - Cardiovascular disease (CVD) is a major cause of death worldwide. Of the many etiological factors, microorganisms constitute one. From the local impact of the gut microbiota on energy metabolism and obesity, to the distal association of periodontal disease with coronary heart disease, microbes have a significant impact on cardiovascular health. In terms of the ability to modulate or influence the microbes, probiotic applications have been considered. These are live microorganisms which when administered in adequate amounts confer a benefit on the host. While a number of reports have established the beneficial abilities of certain probiotic bacterial strains to reduce cholesterol and hypertension, recent research suggests that their use could be more widely applied. This review presents an up-to-date summary of the known associations of the microbiome with CVD, and potential applications of probiotic therapy. PMID- 25529050 TI - beta-1 tubulin R307H SNP alters microtubule dynamics and affects severity of a hereditary thrombocytopenia. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) in platelet-associated genes partly explain inherent variability in platelet counts. Patients with monoallelic Bernard Soulier syndrome due to the Bolzano mutation (GPIBA A156V) have variable platelet counts despite a common mutation for unknown reasons. OBJECTIVES: We investigated the effect of the most common SNP (R307H) in the hematopoietic specific tubulin isotype beta-1 in these Bernard Soulier patients and potential microtubule-based mechanisms of worsened thrombocytopenia. PATIENTS/METHODS: Ninety-four monoallelic Bolzano mutation patients were evaluated for the R307H beta-1 SNP and had platelet counts measured by three methods; the Q43P SNP was also evaluated. To investigate possible mechanisms underlying this association, we used molecular modeling of beta-1 tubulin with and without the R307H SNP. We transfected SNP or non-SNP beta-1 tubulin into MCF-7 and CMK cell lines and measured microtubule regrowth after nocodazole-induced depolymerization. RESULTS: We found that patients with at least one R307H SNP allele had significantly worse thrombocytopenia; manual platelet counting revealed a median platelet count of 124 in non-SNP patients and 76 in SNP patients (both *10(9) L(-1) ; P < 0.01). The Q43P SNP had no significant association with platelet count. Molecular modeling suggested a structural relationship between the R307H SNP and microtubule stability via alterations in the M-loop of beta tubulin; in vitro microtubule recovery assays revealed that cells transfected with R307H SNP beta-1 had significantly impaired microtubule recovery. CONCLUSIONS: Our data show that the R307H SNP is significantly associated with the degree of thrombocytopenia in congenital and acquired platelet disorders, and may affect platelets by altering microtubule behavior. PMID- 25529051 TI - Metabolic optimisation of the basketball free throw. AB - The free throw (FT) is a fundamental basketball skill used frequently during a match. Most of actual play occurs at about 85% of maximum heart rate (HR). Metabolic intensity, through fatigue, may influence a technically skilled move as the FT is. Twenty-eight under 17 basketball players were studied while shooting FTs on a regular indoor basketball court. We investigated FT accuracy in young male basketball players shooting at three different HRs: at rest, at 50% and at 80% of maximum experimentally obtained HR value. We found no significant FT percentage difference between rest and 50% of the maximum HR (FT percentage about 80%; P > 0.05). Differently, at 80% of the maximum HR the FT percentage decreased significantly by more than 20% (P < 0.001) down to about 60%. No preliminary warm up is needed before entering game for the FT accuracy. Furthermore, we speculate that time-consuming, cooling-off routines usually performed by shooters before each FT may be functional to improve its accuracy. PMID- 25529052 TI - Prevalence of joint hypermobility in Kuwait. AB - AIM: To determine the prevalence of joint hypermobility (JH) among young Kuwaiti adults. METHODS: This was a cross-sectional study of 390 randomly selected healthy undergraduate university students, aged 18-29 years from the Health Sciences Centre, Kuwait University, Safat, Kuwait. Beighton score at four peripheral sites bilaterally (knees, elbows, thumbs and fifth fingers) and forward flexion of the trunk were used to evaluate joint hypermobility. Any student who met four out of the nine criteria was considered hypermobile. Joint pain was documented in all subjects through personal interview. RESULTS: A total of 390 subjects (male : female ratio 1.0 : 0.9) were assessed. Of those, 87 (22.3%) were found to have JH: 60 (29.4%) males and 27 (14.5%) females, showing a significantly higher male predominance (P < 0.001). Beighton score was inversely correlated with age (rho = -0.15, P = 0.003). A higher incidence of finger signs was noted in comparison to elbow-knee hyperextension and hands-to-floor. Knee joint, back, neck and shoulder pains, in descending order, were the commonest type of joint complaints, although not statistically significant (P > 0.05) in subjects with and without joint hypermobility. It was also observed that the left side, at all the sites, was slightly more hypermobile in comparison to the right side in hypermobile subjects. CONCLUSIONS: The prevalence of joint hypermobility is not uncommon among young Kuwaiti adults, and was comparable to the data published in other Asian-Pacific regions. General practitioners should therefore be familiar with the condition and its clinical associations, while assessing musculoskeletal complaints. PMID- 25529053 TI - Remarkable proanthocyanidin adsorption properties of monastrell pomace cell wall material highlight its potential use as an alternative fining agent in red wine production. AB - The existence of interactions between the polysaccharides of vegetal cell walls and proanthocyanins makes this cell wall material an interesting option for its use as a fining agent to reduce the level of proanthocyanins in wines. Pomace wastes from the winery are widely available and a source of cell wall material, and the identification of varieties whose pomace cell walls present high proanthocyanin binding capacity and of processing methods that could enhance their adsorption properties could be of great interest. This study compared the proanthocyanin adsorption properties of pomace cell wall material from three different grape varieties (Monastrell, Cabernet Sauvignon, and Syrah), and the results were compared with those obtained using fresh grape cell walls. Also, the effect of the vinification method has been studied. Analysis of the proanthocyanidins in the solution after reaction with the cell wall material, using phloroglucinolysis and size exclusion chromatography, provided quantitative and qualitative information on the adsorbed and nonadsorbed compounds. A highlight of this study was the observation that Monastrell pomace cell wall material showed a strong affinity for proanthocyanidins, with values similar to that obtained for fresh grapes cell walls, and a preferential binding of high molecular mass proanthocyanidins, so these pomace cell walls could be used in wines to reduce astringency. The use of maceration enzymes during vinification had little effect on the retention capacity of the pomace cell walls obtained from this vinification, although an increase in the retention of low molecular mass proanthocyanidins was observed, and this might have implications for wine sensory properties. PMID- 25529054 TI - Composition and antioxidant activity of water-soluble oligosaccharides from Hericium erinaceus. AB - Oligosaccharide are carbohydrate molecules, comprising repeating units joined together by glycosidic bonds. In recent years, an increasing number of oligosaccharides have been reported to exhibit various biological activities, including antitumor, immune-stimulation and antioxidation effects. In the present study, crude water-soluble oligosaccharides were extracted from the fruiting bodies of Hericium erinaceus with water and then successively purified by diethylaminoethyl-cellulose 52 and Sephadex G-100 column chromatography, yielding one major oligosaccharide fraction: Hericium erinaceus oligosaccharide (HEO-A). The structural features of HEO-A were investigated by a combination of monosaccharide component analysis by thin layer chromatography, infrared spectroscopy, nuclear magnetic resonance spectroscopy, scanning electron microscopy and high-performance gel permeation chromatography. The results indicated that HEO-A was composed of D-xylose and D-glucose, and the average molecular size was ~1,877 Da. The antioxidant activity of HEO-A was evaluated using three biochemical methods to determine the scavenging activity of HEO-A on 1,1-diphenyl-2-picrylhydrazyl, hydrogen peroxide and 2,2'-azino-bis(3 ethylbenzthiazoline-6-sufonic acid) diammonium radicals. The results indicated that HEO-A may serve as an effective healthcare food and source of natural antioxidant compounds. PMID- 25529055 TI - Impact of endocrine-disrupting chemicals on reproductive function in zebrafish (Danio rerio). AB - The prevalence of endocrine-disrupting chemicals (EDCs) in the aquatic environment has been associated with the wide detection of alterations in the development and physiology of vertebrates. Zebrafish, as a model species, has been extensively used in toxicological research. In this review, we focus on recent published evidence of the harmful effects of EDCs on reproductive function in zebrafish, including skewed sex ratio, immature gonads, diminished sexual behaviour, decreased sperm count, reduced spawning and fertilization. These impairments mostly result from disruption to sex-steroid hormones induced by endocrine disruptors. We also discuss other effects of exposure to EDCs. In EDC exposure research, despite incomplete assessments of altered gonad histopathology and sexual behaviour, these present potential effective biomarkers or pathways for evaluating the reproductive function in zebrafish on EDC exposure. To date, the pernicious effects of some EDCs on the reproductive performance in laboratory zebrafish are well understood; however, similar alterations remain for further determination in wild-type fish and more kinds of EDCs. More studies should be performed under established scientific regulatory criteria to investigate the impact of EDCs on reproduction in zebrafish. Moreover, further research is required to explain the definite mechanism of sexual differentiation, which helps in understanding the shift of sexual phenotype with EDC exposure. PMID- 25529056 TI - Correction to Radiolabeled Mannosylated Dextran Derivatives Bearing a NIR Fluorophore for Sentinel Lymph Node Imaging. PMID- 25529058 TI - In response to Dr. Verdolin. PMID- 25529057 TI - Technology use in linking criminal justice reentrants to HIV care in the community: a qualitative formative research study. AB - Innovative interventions increasing linkage, adherence, and retention in care among HIV-infected persons in the criminal justice system are needed. The authors conducted a qualitative study to investigate technology-based tools to facilitate linkage to community-based care and viral suppression for HIV-infected jail detainees on antiretroviral medications being released to the community. The authors conducted 24 qualitative interview-12 in Rhode Island and 12 in Washington, DC-among recently incarcerated HIV-infected persons to elicit their perceptions on the use of technology tools to support linkage to HIV care among criminal justice populations. This article discusses participants' perceptions of the acceptability of technological tools such as (a) a computer-based counseling and (b) text messaging interventions. The participants reported positive experiences when previewing the technology-based tools to facilitate linkage to HIV care and adherence to HIV medications. Successful linkage to care has been shown to improve HIV-associated and non-HIV-associated health outcomes, as well as prevent criminal recidivism and facilitate reentrants' successful and meaningful transition. These findings can be used to inform the implementation of interventions aimed at promoting adherence to antiretroviral medications and linkage to care for HIV-infected persons being released from the correctional setting. PMID- 25529059 TI - A flexible and low-cost polypropylene pouch for naked-eye detection of herpes simplex viruses. AB - Effective viral detection is a key goal in the development of point of care (POC) diagnostic devices. Loop-mediated isothermal amplification (LAMP) could potentially be a valuable tool for rapid viral detection and diagnosis in commercial and hospital laboratories and resource limited settings. Here, we present a novel polypropylene pouch (PP) for detection of HSV-1 and HSV-2. With this plastic pouch we could detect up to 6.08 * 10(1) copies per MUL of HSV-1 DNA and 0.598 copies per MUL of HSV-2 DNA within 45 minutes. Since LAMP itself is less sensitive to inhibitory substances present in the real sample, we could also detect viral DNA without the need for viral DNA extraction and purification. The result from LAMP could be evaluated by naked eye due to the addition of hydroxy naphthol blue (HNB) dye in the reaction mixture. Since this proposed device is easy to handle, portable, user friendly and low cost, it offers a tremendous potential to be a perfect candidate for POC diagnostic device for use in resource limited settings. PMID- 25529060 TI - Prevalence of iron deficiency on ICU discharge and its relation with fatigue: a multicenter prospective study. AB - INTRODUCTION: Prevalence of iron deficiency (ID) at intensive care (ICU) admission is around 25 to 40%. Blood losses are important during ICU stay, leading to iron losses, but prevalence of ID at ICU discharge is unknown. ID has been associated with fatigue and muscular weakness, and may thus impair post-ICU rehabilitation. This study assessed ID prevalence at ICU discharge, day 28 (D28) and six months (M6) after and its relation with fatigue. METHODS: We conducted this prospective, multicenter observational study at four University hospitals ICUs. Anemic (hemoglobin (Hb) less than 13 g/dL in male and less than 12 g/dL in female) critically ill adult patients hospitalized for at least five days had an iron profile taken at discharge, D28 and M6. ID was defined as ferritin less than 100 ng/L or less than 300 ng/L together with a transferrin saturation less than 20%. Fatigue was assessed by numerical scale and the Multidimensional Fatigue Inventory-20 questionnaire at D28 and M6 and muscular weakness by a hand grip test at ICU discharge. RESULTS: Among 107 patients (men 77%, median (IQR) age 63 (48 to 73) years) who had a complete iron profile at ICU discharge, 9 (8.4%) had ID. At ICU discharge, their hemoglobin concentration (9.5 (87.7 to 10.3) versus 10.2 (92.2 to 11.7) g/dL, P =0.09), hand grip strength (52.5 (30 to 65) versus 49.5 (15.5 to 67.7)% of normal value, P =0.61) and visual analog scale fatigue scale (57 (40 to 80) versus 60 (47.5 to 80)/100, P =0.82) were not different from non-ID patients. At D28 (n =80 patients) and M6 (n =78 patients), ID prevalence increased (to 25 and 35% respectively) while anemia prevalence decreased (from 100% to 80 and 25% respectively, P <0.0001). ID was associated with increased fatigue at D28, after adjustment for main confounding factors, including anemia (regression coefficient (95%CI), 3.19 (0.74 to 5.64), P =0.012). At M6, this association disappeared. CONCLUSIONS: The prevalence of ID increases from 8% at discharge to 35% six months after prolonged ICU stay (more than five days). ID was associated with increased fatigue, independently of anemia, at D28. PMID- 25529061 TI - Breakfast intake among adults with type 2 diabetes: influence on daily energy intake. AB - OBJECTIVE: To assess the association between breakfast energy and total daily energy intake among individuals with type 2 diabetes. DESIGN: Cross-sectional study. Daily energy intake was computed from a 24 h dietary recall. Multiple regression models were used to estimate the association between daily energy intake (dependent variable) and quartiles of energy intake at breakfast (independent variable), expressed in either absolute or relative (percentage of total daily energy intake) terms. Orthogonal polynomial contrasts were used to test for linear and quadratic trends. Models were controlled for sex, age, race/ethnicity, BMI, physical activity and smoking. In addition, we used separate multiple regression models to test the effect of quartiles of absolute and relative breakfast energy on energy intake at lunch, dinner and snacks. SETTING: The 1999-2004 National Health and Nutrition Examination Survey (NHANES). SUBJECTS: Participants aged >=30 years with self-reported history of diabetes (n 1146). RESULTS: Daily energy intake increased as absolute breakfast energy intake increased (linear trend, P<0.0001; quadratic trend, P=0.02), but decreased as relative breakfast energy intake increased (linear trend, P<0.0001). In addition, while higher quartiles of absolute breakfast intake had no associations with energy intake at subsequent meals, higher quartiles of relative breakfast intake were associated with lower energy intake during all subsequent meals and snacks (P<0.05). CONCLUSIONS: Consuming a breakfast that provided less energy or comprised a greater proportion of daily energy intake was associated with lower total daily energy intake in adults with type 2 diabetes. PMID- 25529063 TI - Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health. AB - AIM: The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells (PBMCs) was influenced by gender, pregnancy or mental health. METHODS: We used RT-qPCR to determine the mRNA expression level in PBMCs from men (n = 16), non-pregnant women (n = 19), healthy pregnant women (n = 27) and depressed pregnant women (n = 15). RESULTS: The rho2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The delta and rho2 subunits were up regulated by pregnancy, whereas the epsilon subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in turn, commonly expressed the alpha6 and the gamma2 subunits. The beta1 and epsilon subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women, while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs. CONCLUSION: The results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMCs. PMID- 25529062 TI - Distribution and determinants of plasma homocysteine levels in rural Chinese twins across the lifespan. AB - Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10-66 years, a subset of a community based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome. PMID- 25529064 TI - Rapid diagnostic tests for identifying avian influenza A(H7N9) virus in clinical samples. AB - To determine sensitivity of rapid diagnostic tests for detecting influenza A(H7N9) virus, we compared rapid tests with PCR results and tested different types of clinical samples. Usefulness of seasonal influenza rapid tests for A(H7N9) virus infections is limited because of their low sensitivity for detecting virus in upper respiratory tract specimens. PMID- 25529065 TI - Production and characterisation of hyaluronidase and elastase inhibitory protein hydrolysates from Venus clam. AB - The hydrolysates of fresh and boiled Venus clams with five different proteases for the production of low-molecular protein hydrolysates were optimised by response surface methodology. Alcalase hydrolysates exhibited the strongest hyaluronidase inhibitory activity. The optimum hydrolysis conditions of fresh and boiled clams were< enzyme-to-substrate ratio (E/S), 2.15%; time, 150 min; water to-substrate ratio (W/S), 83.84 mL g(-1) for fresh clam, and E/S, 2.02%; time, 4.11 h; W/S, 69.74 mL g(-1) for boiled clam. The fresh and boiled clam protein hydrolysates were fractionated by S-200 HR size-exclusion chromatography, which resulted in one (FH1) and two (BH1 and BH2) fractions, respectively. BH1 exhibited the highest hyaluronidase and elastase inhibitory activities with specific activities of 141.15 and 81.36% mL mg(-1), respectively. Therefore, the boiled Venus clam hydrolysate might be developed as a cosmeceutical agent because of its strong hyaluronidase and elastase inhibitory activities. PMID- 25529067 TI - The electronic structure calculations of two-dimensional transition-metal dichalcogenides in the presence of external electric and magnetic fields. AB - Transition-metal dichalcogenides TX2 (T = W, Mo; X = S, Se, Te) are layered materials that are available in ultrathin forms such as mono-, bi- and multilayers, which are commonly known as two-dimensional materials. They have an intrinsic band gap in the range of some 500 meV to 2 eV, depending on the composition and number of layers, and giant intrinsic spin-orbit splittings for odd layer numbers, and, in conjunction with their high chemical and mechanical stability, they qualify as candidate materials for two-dimensional flexible electronics and spintronics. The electronic structure of each TX2 material is very sensitive to external factors, in particular towards electric and magnetic fields. A perpendicular electric field reduces the band gap, and for some structures semiconductor-metal transitions could be possible. Moreover, the electric field triggers the spin-orbit splitting for bilayers. A magnetic field applied normal to the layers causes the Hall effect, which in some cases may result in a quantum (spin) Hall effect and thus in magnetic switches. Finally, we discuss how valleytronics is possible in these materials by selective interaction of electrons in the different valleys using polarized light. PMID- 25529069 TI - Ion association in aqueous and non-aqueous solutions probed by diffusion and electrophoretic NMR. AB - The results of diffusion and electrophoretic NMR (eNMR) measurements are reported for a series of tetramethylammonium (TMA) electrolytes (with sulphate, fluoride, acetate, chloride, bromide, nitrate, iodide and perchlorate as anions) in deuterated solvents such as water, dimethylsulphoxide (DMSO), acetonitrile, methanol and ethanol. In addition, similar data are presented for aqueous solutions of tetraalkylammonium salts with increasing alkyl chain length. The combination of diffusion NMR and eNMR yields the effective charge for the TMA cation. Relative to the nominal charge of znom = 1 of TMA, the effective charge in the different solvents is found to be progressively smaller in the order water > DMSO > methanol > acetonitrile > ethanol. A part of this observed trend is ascribed to regular ion-ion interactions incorporated in the Onsager limiting law. Indeed, in solvents with high dielectric constants such as water, DMSO and methanol, the Onsager limiting law describes well the observations for all tetraalkylammonium ions. For ethanol and acetonitrile, there is a significant difference between the experimental data and the expected limiting-law behavior that is attributed to ion association (ion pairing) not taken into consideration by the Onsager limiting law. PMID- 25529068 TI - Long term effect of trabeculectomy on retrobulbar haemodynamics in glaucoma. AB - PURPOSE: Previous reports showed increased flow velocities in retrobulbar vessels after glaucoma surgery in the first weeks. Colour Doppler imaging was performed to investigate the long-term effects of trabeculectomy on retrobulbar haemodynamics in patients with primary open-angle glaucoma (POAG). METHODS: In a prospective study 30 patients (mean age 63.2 +/- 15.4 years) with POAG were included. Colour Doppler imaging was performed before 1-2 weeks, after 2 months, after 4-6 months, and up to 3 years after trabeculectomy to determine the peak systolic and end-diastolic velocities in the ophthalmic artery, central retinal artery, and the short nasal and temporal posterior ciliary arteries. RESULTS: Mean follow-up was 416 +/- 246 days. In the first postsurgical period mean intraocular pressure (IOP) decreased after trabeculectomy from 25 +/- 6 mmHg to 9 +/- 4 mm Hg (p < 0.0001) and then increased in the further follow-up to 13 +/- 3 mmHg (p < 0.05) without any anti-glaucomatous medication. Colour Doppler imaging revealed a significant increase of the end-diastolic velocities of the central retinal artery at all postoperative visits compared to pre-surgery (p < 0.003) and of the end-diastolic velocities in the temporal posterior ciliary arteries (p < 0.003). The change of blood flow parameters that increased during follow-up was significantly correlated to the change in ocular perfusion pressure and IOP. CONCLUSIONS: End-diastolic velocities of the central retinal artery and of the temporal posterior ciliary arteries increased after successful trabeculectomy and remained stable in a longer period - even if IOP rose significantly in the follow up. PMID- 25529070 TI - Ultrasonography, laboratory, and cholangiography correlation of biliary complications in pediatric liver transplantation. AB - The aim of this study is to correlate the US, laboratory, and cholangiography findings in pediatric liver transplant patients with biliary complications, trying to identify reliable decision-making tools for the management of these complications. Retrospective review was carried out of US results in 39 consecutive patients, from 2011 to 2013, with biliary complications after LT, documented by PTC. According to US biliary dilation, patients were classified as: mild, moderate, and severe, and according to laboratory findings as: normal or abnormal serum bilirubin and level of serum GGT. Data were correlated with PTC findings, divided in three groups: mild, moderate, and severe/occlusive BDS. There was no statistically significant correlation between the US findings and the laboratory findings and between US findings with PTC. There was a statistically significant correlation between GGT and cholangiography. In our series, abnormal US could not predict the severity of BDS on PTC. Bilirubin results were not able to predict the US findings either. GGT results demonstrated a statistically significant correlation with the severity of BDS found on PTC. These findings emphasize the role of GGT in the evaluation and decision of biliary interventions in pediatric liver transplant recipients. PMID- 25529073 TI - Looking inside the seasonal clock. PMID- 25529071 TI - Remarkable efficacy of tocilizumab for treating rheumatoid arthritis in patients with high platelet counts. AB - OBJECTIVES: To optimize the efficacy of treatment with tocilizumab for rheumatoid arthritis (RA), we comparatively analyzed the outcome of tocilizumab treatment in patients with normal background changes associated closely with IL-6. PATIENTS AND METHODS: The study involved 87 patients with RA satisfying the diagnostic criteria of the American College of Rheumatology (ACR) and receiving continuous tocilizumab treatment for 24 weeks or longer. The outcome of tocilizumab treatment in these patients was comparatively analyzed in relation to the baseline platelet count (the high platelet count group and the normal group), pretreatment hemoglobin levels (the low group and the normal platelet count group), and speed of bone destruction (the rapid progression group and slow progression group). RESULTS: Treatment with tocilizumab significantly improved the 28-joint disease activity score using the erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI), regardless of baseline platelet count, hemoglobin level, or annual speed of bone destruction (DeltaTSS). The margins of improvement in DAS28-ESR and CDAI did not differ depending on baseline hemoglobin level or DeltaTSS, but the improvement was significantly greater in the high platelet count group than in the normal platelet count group. CONCLUSIONS: These results suggest that in patients with high platelet count, IL 6 is a more important factor involved in RA pathogenesis and that tocilizumab is suitable as a first-line biologic for the treatment of RA patients with high platelet count. PMID- 25529080 TI - Viral hepatitis: towards the eradication of HCV and a cure for HBV. PMID- 25529081 TI - Current and future HCV therapy: do we still need other anti-HCV drugs? AB - Eradication of hepatitis C virus (HCV) infection, at least in compensated patients, can help improve the outcomes of liver disease such as cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation, as well as perhaps extra-hepatic complications such as diabetes and cardiovascular risk. In the past few years, the landscape of antiviral therapy has evolved at a breathtaking pace from pegylated interferon (PEG-IFN) plus ribavirin (RBV) (PEG-IFN/RBV) to IFN based strategies combining direct acting antivirals (DDAs) with PEG-IFN/RBV and finally IFN-free combinations of DAAs. In particular with these most recent developments, treatment regimens have become shorter, safer and even more effective, with a wide range of indications. Nevertheless, research continues and newer antiviral drugs are still under development. At a point when a >90% sustained virological response (SVR) is being claimed with all new available regimens, pharmacological and clinical research should be addressing unresolved areas, such as cases of suboptimal SVR or to increase effectiveness rather than pursuing the development of new 'me-too' drugs. The issues which should be given priority for further development include the following: Improving the results of IFN-free regimens in patients with genotype 3 (HCV-3) infection. Identifying the indications for the treatment in patients with compensated and decompensated cirrhosis. Identifying standardized or personalized backup strategies in patients who do not respond to IFN-free regimens. Finally, because of financial constraints, the high cost of IFN-free strategies prevents their universal use in CHC patients and coverage by national healthcare systems. Thus, efforts must be made to document cost-effectiveness in all clinical scenarios and to develop more affordable IFN-free regimens. PMID- 25529082 TI - Pegylated interferon based therapy with second-wave direct-acting antivirals in genotype 1 chronic hepatitis C. AB - Within the last few years, treatment of chronic hepatitis C infection has progressed beyond regimens containing the first-wave direct-acting antiviral agents (DAAs) boceprevir and telaprevir, which had high pill burdens as well as low efficacy and safety in treatment-experienced patients. Triple therapy regimens with newer second-wave DAAs combined with pegylated interferon (PEG-IFN) and ribavirin (RBV), have shown rates of sustained virological response never before achieved with previous regimens in treatment-naive genotype 1 (HCV-1) patients. Additionally, increased response rates have been found with quadruple agent therapy in prior non-responders, partial-responders, and relapsers, including those with cirrhosis. This review will focus on the second-wave DAAs including protease inhibitors (PI), nucleotide inhibitors, and NS5B inhibitors combined with PEG-IFN and RBV for both treatment-naive and treatment-experienced genotype 1 hepatitis C virus (HCV-1) infected patients. The current standard of care for treatment-naive HCV-1 is the second-wave PI, sofosbuvir, plus PEG IFN/RBV and sofosbuvir plus the second-wave nucleotide inhibitor simeprevir with or without RBV in treatment-experienced HCV-1 patients. These recommendations could change, especially for treatment-experienced patients based on the positive results obtained with the newest quadruple therapy studies. PMID- 25529083 TI - How to optimize current therapy in hepatitis C virus genotype 1 patients. Predictors of response to interferon-based therapy with second wave direct acting antivirals. AB - Second wave direct acting antivirals such as sofosbuvir, simeprevir and daclatasvir can be combined with pegylated interferon alpha and ribavirin (PEG IFN/RBV) as triple therapy in patients with hepatitis C virus (HCV) infection. In patients with HCV genotype 1 (HCV-1), a PEG-IFN/RBV-based regimen with sofosbuvir is highly effective but the presence of cirrhosis and the non-CC IFNL3 genotype have been associated with a poorer response. A PEG-IFN/RBV-based regimen with simeprevir or daclatasvir is based on response-guided therapy and its efficacy depends on predictors of response to IFN. HCV-1 subtype is also a major predictor of response. In HCV-1a infected patients, the K80Q mutation in NS3 or the presence of NS5A variants at baseline are associated with poor response with simeprevir- or daclatasvir-containing regimens respectively. Thus, these regimens should be only used in HCV-1b patients with good predictors of response to IFN. PMID- 25529084 TI - Optimal therapy of genotype-2 chronic hepatitis C: what's new? AB - The standard of care (SOC) for the treatment of HCV genotype 2 (HCV-2) was pegylated interferon alpha plus ribavirin (PEG-IFN/RBV) at weight-based doses for a response-guided duration. The launches of sofosbuvir and daclatasvir in 2014 have resulted in new, better tolerated and shorter treatment. The combination of sofosbuvir and RBV for 12 weeks appears to be the new SOC in both European and American guidelines. The cost and therefore the access to this treatment remains a problem in many countries because of major economic constraints. For the few more difficult-to-treat patients, a combination of direct acting antivirals may be suitable and is being studied in ongoing trials. Because of rapidly changing treatment recommendations, the decision to treat HCV-2 patients with currently approved drugs or to wait until a better option is available in the future, must be made according to the stage of fibrosis. PMID- 25529085 TI - Optimal therapy in genotype 4 chronic hepatitis C: finally cured? AB - Optimal therapy for patients with hepatitis C virus (HCV) genotype 4 (HCV-4) infection is changing rapidly, and the possibility of a total cure is near. The standard of care has been combination pegylated interferon (PEG-IFN)-ribavirin (RBV), with modest response rates and considerable adverse events. Since the introduction of sofosbuvir (SOF), simeprevir (SIM), and daclatasvir (DCV), the duration of treatment has been significantly shortened and response rates have increased. The recommended treatment for IFN-eligible patients is PEG-IFN/RBV plus SOF, SIM or DCV. In IFN ineligible patients, the optimal regimen is a 24 week course of SOF/RBV, or a 12-week course of SOF-SIM or SOF-DCV with or without RBV. The pipeline for patients with chronic HCV is highly active. IFN-free combinations with paritaprevir-ombitasvir, SOF-ledipasvir, or DCV-asunaprevir (ASV)-beclabuvir (BMS-791325) for 12 weeks or less with close to 100% cure rates will soon become the optimal therapy. PMID- 25529086 TI - Optimal management of patients with chronic hepatitis C and comorbidities. AB - Although HCV infection mainly induces liver injury, chronic disease is systemic. Moreover, host and viral factors, as well as comorbidities, may influence the chance of achieving a sustained virological response or disease outcome. Although there are sufficient data on the use of peg-interferon and ribavirin in patients with comorbidities, there is very little data on first generation protease inhibitors, which include significant drug-drug interactions and have therefore been administered with caution in these patients. The availability of new, more effective direct acting antivirals should significantly change this scenario. All these issues are discussed in this review. PMID- 25529087 TI - Optimal therapy of HIV/HCV co-infected patients with direct acting antivirals. AB - The development of direct acting antivirals (DAAs) against the hepatitis C virus (HCV) has revolutionized treatment paradigms for HCV in HIV co-infected subjects. In the era of DAAs, HIV/HCV co-infected patients have the same cure rates of over 90% with interferon (IFN)-free DAA combinations. Therefore, guidelines no longer separate mono- and co-infected subjects. Indications for HCV therapy and DAA drug selection have become the same for all patients. The only special consideration in HIV/HCV co-infected subjects is the need to check for drug-drug interactions between HIV and HCV drugs, especially HIV and HCV protease inhibitors which have a high risk of clinically significant drug interactions. Because of the faster progression of fibrosis and the higher risk of hepatic decompensation in co infected subjects, even with combination antiretroviral (ART) therapy, the availability of modern HCV treatments needs to be extended and HCV therapy should be discussed in all co-infected patients. PMID- 25529088 TI - Optimal IFN-free therapy in treatment-naive patients with HCV genotype 1 infection. AB - There has been a revolution in the treatment of chronic hepatitis C. Several oral regimens combining direct-acting antivirals (DAAs) from different families [NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors (PI)] are under development. These regimens result in an increase in sustained virological response (SVR) rates to above 90% and reduce the duration of treatment to twelve weeks or less. As of 2015 several regimens will be approved with additive potencies, without cross resistance and with a good safety profile. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide. This review summarizes results obtained with oral DAAs combinations, that have been approved and/or have completed phase III clinical trials for HCV genotype 1 (HCV-1) treatment-naive patients. PMID- 25529089 TI - Optimal interferon-free therapy in treatment-experienced chronic hepatitis C patients. AB - Over the past year, interferon (IFN) free dosing regimens have become available to treat chronic hepatitis C. Offering high rates of sustained virological response (SVR), short treatment and improved tolerability, IFN-free treatment now represents the paradigm for both treatment-naive and -experienced patients. Patients with prior treatment failure, in particular those with cirrhosis, still represent some of the most difficult to treat, but the availability of multiple agents that can interrupt several steps of the HCV lifecycle affords providers and patients with options that can be combined and individually tailored to each patient's unique needs to obtain high rates of SVR. PMID- 25529090 TI - Cure of HCV related liver disease. AB - Chronic hepatitis C virus (HCV) causes chronic liver injury and can lead to cirrhosis and hepatocellular carcinoma (HCC). HCV can also interact with the immune system to cause several HCV related disorders including essential mixed cryoglobulinemia, vasculitis, dermatitis, glomerulonephritis and lymphoma. A strong association between HCV and diabetes mellitus also exists. These extrahepatic features may lead to increased fatigue and a reduced quality of life. It is now possible to cure most patients with chronic HCV using oral antiviral therapy. Many of these HCV-related disorders and symptoms can be cured when HCV is eradicated. However, some patients may have irreversible injury to extrahepatic sites, cirrhosis that cannot resolve, an increased risk for HCC, persistent fatigue and a reduced quality of life, despite achieving sustained virological response. PMID- 25529091 TI - Reversibility of hepatitis B virus cirrhosis after therapy: who and why? AB - The end point of liver fibrosis in almost all chronic liver diseases including HBV chronic hepatitis is cirrhosis. Progression to cirrhosis is associated with annular deposition of fibrous tissue and vascular remodeling with a shift from a lobular to nodular organization. Although advanced liver fibrosis was previously thought to be irreversible, today there is compelling evidence that cirrhosis can be reversed if the underlying cause of liver injury is eliminated. Indeed, most clinical trials with antiviral therapy and histological follow-up have shown that fibrosis can regress and that in some cases even cirrhosis can reverse following long-term HBV-DNA suppression, although the return to a fully normal liver is rarely observed and difficult to prove. Nevertheless, a marked percentage of cirrhosis will not reverse even after effective antiviral therapy. Generally cirrhosis is more likely to regress if it is recent, there is effective and long lasting viral suppression, an internal capacity to regenerate and no vascular thrombosis. HBV treatment in patients with cirrhosis is associated with an improved clinical outcome although there may still be a risk of hepatocellular carcinoma. Nevertheless it has not yet been determined if a favorable outcome depends on histological regression or whether the reversal of cirrhosis is merely a surrogate marker of viral suppression. The significance of the reversal of cirrhosis is still a subject of debate because neither the histological scoring systems nor non-invasive markers to evaluate the reversal of cirrhosis have been validated. PMID- 25529092 TI - HBsAg quantification to optimize treatment monitoring in chronic hepatitis B patients. AB - Hepatitis B surface antigen (HBsAg) levels in serum have been shown to reflect active intrahepatic covalently closed circular DNA (cccDNA) and to have additional value as a marker of on-treatment efficacy. In the past few years, immunoassays to quantify HBsAg have been developed to monitor HBsAg kinetics during treatment. Although HBsAg quantification cannot replace HBV DNA measurement in clinical practice, the combined use of HBsAg quantification and HBV DNA measurements could help predict treatment outcome. One of the most important results of the studies in this new marker is that a decline in HBsAg titres during pegylated-interferon (PEG-IFN) treatment is a strong predictor of response so that a 'week 12 stopping rule' could be established for both Hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. However, the positive predictive value (PPV) for a sustained viral response (SVR) remains low. The role of HBsAg measurements during nucloes(t)ides analogue (NAs) treatment is unclear. It may be a useful marker for stopping NAs by limiting the chance of relapse or for add-on strategies. Monitoring serum HBsAg levels in chronic hepatitis B (CHB) patients during treatment may provide significant complementary information to HBV DNA measurements. PMID- 25529093 TI - What can we learn from hepatitis B virus clinical cohorts? AB - Chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) are considered to be sequential adverse outcomes in patients with persistent hepatitis B virus (HBV) infection. HBV infection is endemic in Taiwan and most HBV carriers acquire the virus early in life. The impact of HBV factors on the natural course of patients with chronic HBV infection has been investigated in three cohort studies. The first Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) cohort study revealed that HBV viral load is a strong predictive factor for the risk of cirrhosis and HCC and baseline serum HBV DNA levels >2000 IU/ml may increase the risk of cirrhosis and HCC in adult HBV carriers. In the second Study of E Antigen seRoClearance of Hepatitis B (SEARCH-B), HBsAg level <100 IU/ml at 1-year post HBeAg seroconversion was shown to be a predictor of HBsAg seroclearance over time. Recently, the third Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers (ERADICATE-B) cohort study also suggested that HBsAg levels were a complementary predictive risk factor to HBV DNA levels for predicting HBV-related adverse events in patients with low viral load (HBV DNA level <2000 IU/ml). An HBsAg level >1000 IU/ml in HBeAg-negative patients with low viral load, is associated with higher risks of HCC, cirrhosis, and HBeAg-negative hepatitis. Based on results of the REVEAL-HBV cohort study, a risk calculator to predict HCC in non-cirrhotic patients was developed and validated by independent international cohorts (REACH-B). In the recent update of the REVEAL-HBV study, HBsAg level was incorporated into the HCC risk prediction model with excellent accuracy. In conclusion, evidence from these HBV clinical cohorts confirms the progression and integration of viral biomarkers for the prediction of the prognosis of Asian chronic hepatitis B (CHB) patients. If the predictive power of the HCC risk calculator could be validated in non-Asian populations, it could be used in clinical practice to individualize the management of HBV carriers with different levels of HCC risk. PMID- 25529094 TI - Optimal therapy of chronic hepatitis B: how do I treat HBeAg-positive patients? AB - Current agents for the treatment of chronic hepatitis B (CHB) can be classified into interferon-alpha (standard or pegylated) (IFN) and nucleos(t)ide analogues (NAs). IFN therapy has the advantage of a finite duration (48 weeks) with a chance for durable sustained off-treatment response in HBeAg positive CHB patients. However, these benefits are limited to approximately 30% of HBeAg positive patients, while parenteral administration and potential side effects are common patient concerns. Thus, patients who can benefit from IFN therapy must be carefully selected and monitored. Recently, stopping rules for IFN non-responders were developed based on 12-week HBsAg levels. NAs are currently used in most CHB patients. They are administered in one tablet daily and can be used in all patients with excellent tolerability and a good safety profile. The current first line options, entecavir (ETV) and tenofovir (TDF), are highly potent with a minimal risk of resistance during long-term monotherapy. Prolongation of entecavir or tenofovir maintains the initially high virological remission rates in adherent HBeAg positive patients and modifies the long-term outcomes. The need for a long-term, perhaps indefinite, treatment duration is the main limitation of ETV or TDF, which may sometimes be safely discontinued in HBeAg positive patients who achieve stable HBeAg seroconversion. Since there will always be safety concerns and family planning issues with long-term therapy, NAs should be used carefully particularly in young HBeAg positive patients with minimal-mild liver disease. PMID- 25529095 TI - Optimal therapy of chronic hepatitis B: how do I treat my HBeAg-negative patients? AB - HBeAg negative chronic hepatitis B (CHB) is a frequent, progressive and difficult to-cure phase of CHB. The end-point of therapy is to persistently suppress viral replication to halt progression of liver disease. Two different treatment strategies are currently available: a short-term course of pegylated interferon alpha (PEG-IFN) or long-term therapy with nucleot(s)ide analogues (NA), i.e. entecavir or tenofovir. Young patients with mild-to-moderate stages of liver disease can benefit from a 48-week course of PEG-IFN, while NA may be preferred in patients with more severe liver disease, in older patients, and in those who do not respond, are unwilling or have contraindications to PEG-IFN. Nucleot(s)ide analogues provide persistent viral suppression and biochemical normalization in almost all patients, together with the regression of fibrosis and the prevention of decompensation, but the effect on hepatocellular carcinoma rates is limited. Thus, NAs have become the most popular treatment strategy worldwide but lifelong administration is associated with high cost, unknown safety and adherence issues and an unknown risk of drug-resistance over time as well as limited rates of HBsAg seroclearance. On the other hand, PEG-IFN treatment may achieve a SVR in nearly a quarter of patients ultimately leading to HBsAg loss in almost 30-50%. Interestingly, response rates to PEG-IFN may further increase with more careful patient selection based on age, ALT and HBV DNA levels at baseline and by applying early on-treatment stopping rules based on HBV DNA and HBsAg kinetics. The combination of NA and PEG-IFN is not currently recommended but numerous studies are ongoing. PMID- 25529096 TI - Optimal therapy for chronic hepatitis B: hepatitis B virus combination therapy? AB - Currently available antiviral treatment for chronic hepatitis B can be divided into two classes of therapeutic agents: pegylated interferon alpha (PEG-IFN) and nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment, either simultaneously, as sequential combination therapy (add-on), or even as an immediate switch from one agent to the other. Different NAs have also been combined in certain clinical situations. At present, several studies have confirmed certain virological advantages to combination therapies, but pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing. Therefore, combination treatment, especially with PEG-IFN plus NAs, is not indicated and was not recommended by the European Association for the Study of the Liver Clinical Practice Guidelines written in 2012, while the guidelines for the use of combination NAs is limited to very few clinical situations. PMID- 25529097 TI - HBV and the immune response. AB - Hepatitis B virus (HBV) infection acquired in adult life is generally self limited while chronic persistence of the virus is the prevalent outcome when infection is acquired perinatally. Both control of infection and liver cell injury are strictly dependent upon protective immune responses, because hepatocyte damage is the price that the host must pay to get rid of intracellular virus. Resolution of acute hepatitis B is associated with functionally efficient, multispecific antiviral T-cell responses which are preceded by a poor induction of intracellular innate responses at the early stages of infection. Persistent control of infection is provided by long-lasting protective memory, which is probably sustained by continuous stimulation of the immune system by trace amounts of virus which are never totally eliminated, persisting in an occult episomic form in the nucleus of liver cells even after recovery from acute infection. Chronic virus persistence is instead characterized by a lack of protective T-cell memory maturation and by an exhaustion of HBV-specific T-cell responses. Persistent exposure of T cells to high antigen loads is a key determinant of functional T-cell impairment but also other mechanisms can contribute to T-cell inhibition, including the tolerogenic effect of the liver environment. The degree of T-cell impairment is variable and its severity is related to the level of virus replication and antigen load. The antiviral T-cell function is more efficient in patients who can control infection either partially, such as inactive HBsAg carriers with low levels of virus replication, or completely, such as patients who achieve HBsAg loss either spontaneously or after antiviral therapy. Thus, understanding the features of the immune responses associated with control of infection is needed for the successful design of novel immune modulatory therapies based on the reconstitution of efficient antiviral responses in chronic HBV patients. PMID- 25529098 TI - Treatment of hepatocellular carcinoma: beyond international guidelines. AB - The management of hepatocellular carcinoma (HCC) is decided according to evidence based recommendations generated by international societies: according to these recommendations, the tumour stage, as determined by the Barcelona clinical liver cancer (BCLC) score, divides patients into five prognostic categories, each with a distinct treatment indication. Radical therapies such as hepatic resection, orthotopic liver transplantation and percutaneous local ablation are strongly indicated in patients with very early and early stage tumours (BCLC O and A), a choice which mainly depends on a combination of tumour volume, status of underlying liver disease, the presence of comorbidities and the patient's age. Although radical therapies provide a survival rate of between 50% and 75% at year five in well selected patients, tumour recurrence is frequent following resection and ablation compared to transplantation (70% vs. 10% respectively), which has the additional advantage of preventing morbidity and mortality from portal hypertension. Generally, while radical therapies are contraindicated in patients with a large tumour burden, such as those with intermediate stage BCLC B, survival in the subset of these patients with well compensated cirrhosis may improve from 16 to 20 months, on average, following repeated treatments with transarterial chemoembolization (TACE). Survival may also improve in patients who are in poor condition or who do not respond to TACE and in those with an advanced HCC (BCLC C) following oral therapy with the multikinase inhibitor sorafenib. However, because most recommendations are based on uncontrolled studies and expert opinions rather than well designed, high powered randomized controlled trials, treatment criteria need to be adapted to special groups because real life cohorts do not match the selection criteria suggested by the guidelines. Indeed, up to one-third of patients with early stage tumours who are unfit for radical therapy because of advanced age, the presence of significant comorbidities or a strategic location of the nodule, are forced to receive palliative care. BCLC A patients with moderate portal hypertension and certain BCLC B patients could still be eligible for hepatic resection if a chance for 50% survival at 5 years is still perceived as being cost-effective by both the patient and caregivers. PMID- 25529099 TI - The coagulation system in patients with end-stage liver disease. AB - In patients with cirrhosis, routine laboratory tests for primary hemostasis and coagulation usually show anomalies that are associated with excess bleeding in other settings, in particular low platelet counts and prolonged prothrombin time. However, under conditions similar to those in vivo, primary hemostasis and thrombin production do not appear to be decreased in patients with cirrhosis, particularly when the platelet count is above 75,000/MUl. Furthermore, there is laboratory and epidemiological evidence of a mild procoagulant and prothrombotic state in patients with cirrhosis. Bleeding is mainly because of portal hypertension rather than defective hemostasis. There is some evidence that anticoagulation therapy is not associated with an excess of severe bleeding and that it could improve the outcome in patients without portal vein thrombosis. At present, there is no clear evidence that portal vein thrombosis is responsible for the progression of liver disease and that anticoagulation therapy would improve the outcome of patients with portal vein thrombosis. PMID- 25529100 TI - The cost of major complications associated with immediate two-stage expander/implant-based breast reconstruction. AB - Previous studies assessing the costs associated with two stage expander/implant (E/I) reconstruction rarely include the cost of complications. The purpose of this study is to analyze the complication costs associated with a single institution experience with immediate E/I reconstruction. All immediate two stage E/I reconstructions at a single institution between March 2005-April 2011 were reviewed. The reconstruction database was retrospectively queried for reconstructive details, complications, and cost. Statistical analyses were performed to determine which complications significantly increased reconstructive cost. 327 E/I reconstructions in 195 patients were analyzed. The major complications analyzed included haematoma requiring evacuation (1.2% of reconstructions), major infection (6.1% of reconstructions), E/I exposure (3.1% of reconstructions), and E/I rupture (2.4% of reconstructions); 2.1% of patients experienced reconstructive failure. The mean reconstructive cost was $22,323 +/- 9,072. Costs were increased $12,554 by E/I infection (p < 0.001) and $17,153 by prosthetic exposure (p < 0.001). Pre- or postoperative radiation or chemotherapy did not significantly affect reconstructive costs. Unplanned readmissions or unplanned visits to the operative room significantly increased total reconstructive costs (p < 0.001 and p < 0.001, respectively). In conclusion, prosthetic infection and prosthetic exposure significantly increased costs associated with immediate two-stage E/I reconstruction, as did unplanned readmissions and unplanned visits to the operative room. In the current state of the US healthcare system, it is becoming more important for surgeons to be conscious of the economic burden associated with poor reconstructive outcomes. PMID- 25529101 TI - Microvascular anastomosis using fibrin glue and venous cuff in rat carotid artery. AB - Conventional anastomosis with interrupted sutures can be time-consuming, can cause vessel narrowing, and can lead to thrombosis at the site of repair. The amount of suture material inside the lumen can impair the endothelium of the vessel, triggering thrombosis. In microsurgery, fibrin sealants have the potential beneficial effects of reducing anastomosis time and promoting accurate haemostasis at the anastomotic site. However, there has been a general reluctance to use fibrin glue for microvascular anastomoses because the fibrin polymer is highly thrombogenic and may not provide adequate strength. To overcome these problems, a novel technique was defined for microvascular anastomosis with fibrin glue and a venous cuff. Sixty-four rats in two groups are included in the study. In the experimental group (n = 32), end-to-end arterial anastomosis was performed with two stay sutures, fibrin glue, and a venous cuff. In the control group (n = 32), conventional end-to-end arterial anastomosis was performed. Fibrin glue assisted anastomosis with a venous cuff took less time, caused less bleeding at the anastomotic site, and achieved a patency rate comparable to that provided by the conventional technique. Fibrin sealant assisted microvascular anastomosis with venous cuff is a rapid, easy, and reliable technique compared to the end-to end arterial anastomosis. PMID- 25529102 TI - Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine. AB - This work presents the first NMR metabolomics study of maternal plasma during pregnancy, including correlation between plasma and urine metabolites. The expected decrease in circulating amino acids early in pregnancy was confirmed with six amino acids being identified as required by the fetus in larger extents. Newly observed changes in citrate, lactate, and dimethyl sulfone suggested early adjustments in energy and gut microflora metabolisms. Alterations in creatine levels were also noted, in addition to creatinine variations reflecting alterations in glomerular filtration rate. Regarding plasma macromolecules, HDL and LDL+VLDL levels were confirmed to increase throughout pregnancy, although at different rates and accompanied by increases in fatty acid chain length and degree of unsaturation. Correlation studies suggested (a) an inverse relationship between lipoproteins (HDL and LDL+VLDL) and albumin, with a possible direct correlation to excreted (unassigned) pregnancy markers resonating at delta 0.55 and delta 0.63, (b) a direct link between LDL+VLDL and N-acetyl-glycoproteins, together with excreted marker at delta 0.55, and (c) correlation of plasma albumin with particular circulating and excreted metabolites. These results have unveiled specific lipoprotein/protein metabolic aspects of pregnancy with impact on the excreted metabolome and, therefore, provide an interesting lead for the further understanding of pregnancy metabolism. PMID- 25529104 TI - Why are anti-obesity drugs stigmatized? AB - Obesity is a common and morbid disease, but its treatment remains far from ideal. Many doctors, regulatory agencies, media outlets and patients consider lifestyle modification as the only possible intervention. Pharmacological agents, although with limitations, are useful weapons but are highly stigmatized. Some reasons for this stigma are discussed in this editorial and include: the failure of short term medication use to achieve long-term results (due to the chronic and recurrent condition of obesity); common perception of obesity as a lifestyle choice; difficulty to treat obesity in the primary care setting; less than desired weight-loss results with medications; misuse of medications for cosmetic reasons; and unfavorable history of other anti-obesity drugs that were withdrawn in previous decades. PMID- 25529103 TI - Hepatitis C seroconversion in methadone maintenance treatment programs in Wuhan, China. AB - BACKGROUND AND AIMS: To decrease infectious disease transmission, China is expanding methadone maintenance treatment (MMT). This study evaluated the prevalence of hepatitis C virus (HCV) infection at MMT entry, seroconversion rates after admission and potential risk factors for HCV seroconversion during MMT in Wuhan, China. DESIGN: Cross-sectional survey of all patients entering MMT and prospective follow-up of patients HCV seronegative at admission. SETTING: All MMT clinics in Wuhan, China. PARTICIPANTS: A total of 12 755 opiate-dependent individuals entering MMT between May 2006 and June 2011; 1200 participants HCV seronegative at admission were followed. MEASUREMENTS: Serological tests for HCV and self-report data on risk behaviors at MMT admission; urine toxicology results and repeated assessments of serological status and risk behaviors during treatment on patients HCV seronegative at admission. FINDINGS: HCV seroprevalence at admission was 72.1% [95% confidence interval (CI) = 71.3-72.9%] and 555/1200 (46.3%, 95% CI = 43.5-49.1%) patients seroconverted to HCV during MMT. The mean time to HCV seroconversion was 3 (95% CI = 2.84-3.07) years with a cumulative seroconversion rate of 34.5 (95% CI = 31.5-36.9) per 100 person-years. Significant predictors of HCV conversion included injection drug use in the past 30 days [relative hazard (RH) 2.0, 95% CI: 1.6 - 2.4, P=0.002] and the rate of opiate-positive urine tests during MMT (RH 2.0, 95% CI = 1.3-3.1, P<0.001). CONCLUSIONS: Methadone maintenance treatment patients in Wuhan, China show a high prevalence of hepatitis C virus at admission (72.1%) and a high rate of seroconversion during treatment (46.3%). Seroconversion is associated with continuing injection drug use. PMID- 25529105 TI - Ventral midline blanching in the setting of segmental infantile hemangiomas: clinical observations and pathogenetic implications. AB - Areas of blanched skin in children may be seen as an independent finding or in association with vascular birthmarks. We performed a retrospective chart review to identify and describe infants with areas of ventral midline blanching in the presence of segmental infantile hemangiomas. We identified nine full-term infants with partial or full segmental hemangiomas and areas of midline ventral blanching. Additional ventral wall defects were seen in five patients. Six had cardiac anomalies and six had intracranial anomalies. Five were diagnosed with definite PHACE (posterior fossa, hemangioma, arterial, cardiac, and eye abnormalities) syndrome and three had possible PHACE syndrome. Eight were complicated by ulceration. Treatment varied according to the case. Ventral blanching, even in the absence of overt midline defects, can be seen in infants with segmental hemangiomas at risk for PHACE syndrome. We hypothesize that midline blanching may represent a minor manifestation of a developmental ventral defect. PMID- 25529107 TI - Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality. AB - BACKGROUND: In studies on cancer-associated venous thromboembolism (VTE), patients not only are at risk for VTE but also may die from their underlying malignancy. OBJECTIVES: In this competing-risk (CR) scenario, we systematically compared the performance of standard (Kaplan-Meier estimator [1-KM]), log-rank test, and Cox model) and specific CR methods for time-to-VTE analysis. PATIENTS AND METHODS: Cancer patients (1542) were prospectively followed for a median of 24 months. VTE occurred in 112 (7.3%) patients, and 572 (37.1%) patients died. RESULTS: In comparison with the CR method, 1-KM slightly overestimated the cumulative incidence of VTE (cumulative VTE incidence at 12 and 24 months [1-KM vs. CR]: 7.22% vs. 6.74%, and 8.40% vs. 7.54%, respectively). Greater bias was revealed in tumor entities with high early mortality (e.g., pancreatic cancer, n = 99, 24-month cumulative VTE incidence: 28.37% vs. 19.30%). Comparing the (subdistribution) hazard of VTE between patients with low and high baseline D dimer, the Cox model yielded a higher estimate than the corresponding CR model (hazard vs. subdistribution hazard ratio [95% CI] 2.85 [1.92-4.21] vs. 2.47 [1.67 3.65]). For this comparison, the log-rank test yielded a higher test statistic and smaller P-value than Gray's test (chi(2) on 1 degree of freedom: 29.88 vs. 21.34). CONCLUSION: In patients with cancer who are at risk for VTE and death, standard and CR methods for time-to-VTE analysis can generate differing results. For 1-KM, the magnitude of bias is a direct function of competing mortality. Consequently, bias tends to be negligible in cancer patient populations with low mortality but can be considerable in populations at high risk of death. PMID- 25529106 TI - Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making. AB - Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions. PMID- 25529108 TI - Specific labeling of climbing fibers shows early synaptic interactions with immature Purkinje cells in the prenatal cerebellum. AB - During development, growing axons must locate target cells to form synapses. This is not easy, since target cells are also growing and even actively migrating. In some brain regions, such axons have been reported to wait for the timing when target cells become mature, without invading their target region. However, in the cerebellum climbing fibers (CFs), major afferent axons, arrive near their target neurons, Purkinje cells, when the neurons are still actively migrating. We, therefore, examined whether synaptic contacts are established at such early stages. To specifically label CFs, we introduced by in utero electroporation a mixture of genes encoding for Ptf1a-enhancer-driven Cre recombinase and Cre dependent fluorescent protein into the mouse hindbrain at embryonic day (E) 10.5 and observed them during development. The earliest stages at which labeled CFs were observed in the cerebellar primordium were E15.5-E16.5. These fibers were fasciculated in the dorsal region and entered the cerebellar primordium. Some fibers defasciculated and reached the caudal region. At E17.5 and E18.5, fasciculated fibers were also found in the mantle region, and some grew toward the surface of the primordium to penetrate a mass of Purkinje cells. Interestingly, as early as E16.5, labeled fibers were found to run in close apposition to Purkinje cell dendrites and to express a presynaptic marker. These observations suggest that CFs form synapses with Purkinje cells as soon as the fibers enter the cerebellum. PMID- 25529109 TI - Luminescence properties of Ca2 Ga2 SiO7 :RE phosphors for UV white-light-emitting diodes. AB - A series of Eu(2+) -, Ce(3+) -, and Tb(3+) -doped Ca2 Ga2 SiO7 phosphors is synthesized by using a high-temperature solid-state reaction. The powder X-ray diffraction and structure refinement data indicate that our prepared phosphors are single phased and the phosphor crystalizes in a tetrahedral system with the ${P?bar 42m}$ (113) space group. The Eu(2+) - and Ce(3+) -doped phosphors both have broad excitation bands, which match well with the UV light-emitting diodes chips. Under irradiation of lambda=350 nm, Ca2 Ga2 SiO7 :Eu(2+) and Ca2 Ga2 SiO7 :Ce(3+) , Li(+) have green and blue emissions, respectively. Luminescence of Ca2 Ga2 SiO7 :Tb(3+) , Li(+) phosphor varies with the different Tb(3+) contents. The thermal stability and energy-migration mechanism of Ca2 Ga2 SiO7 :Eu(2+) are also studied. The investigation results indicate that the prepared Ca2 Ga2 SiO7 :Eu(2+) and Ca2 Ga2 SiO7 :Ce(3+) , Li(+) samples show potential as green and blue phosphors, respectively, for UV-excited white-light-emitting diodes. PMID- 25529110 TI - A threader technique using an 11-0 loop needle for supermicrosurgery. PMID- 25529111 TI - Experimental study of endothelial progenitor cells labeled with superparamagnetic iron oxide in vitro. AB - Endothelial progenitor cells (EPCs) have an essential role in counteracting risk factor-induced endothelial injury and protecting against the development of vascular injury, such as myocardial infarction. Magnetic resonance imaging (MRI) was reported to be effective in tracking transplanted stem cells following cell labeling with superparamagnetic iron oxide (SPIO) nanoparticles. SPIO has previously been used to label and track EPCs; however, the safest concentration of SPIO for labeling EPCs on a cellular level has remained to be elucidated. In addition, the optimum number of SPIO-labeled cells required to produce the highest quality magnetic resonance images has not yet been determined. In the present study, EPCs were isolated from the bone marrow of minipigs using density gradient centrifugation. Their biological activity was then studied using flow cytometric analysis. Cells were incubated at different concentrations of SPIO for different durations and then the growth curve, apoptosis, morphology and labeling efficiency of the EPCs were detected using optical and electron microscopy. T2 weighted fast spin-echo (T2WITSE) MRI of the different numbers of SPIO-labeled EPCs (35 ug/ml) were then obtained in axial and sagittal planes. The results of the present study demonstrated that EPCs were efficiently labeled with SPIO, with a labeling efficiency in each group of ~100% following incubation for 24 h. SPIO was found to be localized in the endosomal vesicles of EPCs, which was confirmed by electron microscopy. When the concentration of SPIO was <70 ug/ml, no significant differences were observed in cell viability, proliferative capability (P>0.05) and morphology between labeled and unlabeled EPCs. Furthermore, the T2WITSE signal intensity was significantly decreased in the groups of 5.0x105/ml and 1.0x105/ml compared with that of the control (P<0.05). In conclusion, the results of the present study indicated that 35 ug/ml was the most effective concentration of SPIO to label EPCs in vitro and acquire a high quality MRI. These findings may therefore contribute to the development of a promising novel therapeutic method for the treatment of myocardial infarction following autograft with SPIO-labeled EPCs in vivo. PMID- 25529112 TI - Automated analysis of flow cytometric data for measuring neutrophil CD64 expression using a multi-instrument compatible probability state model. AB - BACKGROUND: Leuko64TM (Trillium Diagnostics) is a flow cytometric assay that measures neutrophil CD64 expression and serves as an in vitro indicator of infection/sepsis or the presence of a systemic acute inflammatory response. Leuko64 assay currently utilizes QuantiCALC, a semiautomated software that employs cluster algorithms to define cell populations. The software reduces subjective gating decisions, resulting in interanalyst variability of <5%. We evaluated a completely automated approach to measuring neutrophil CD64 expression using GemStoneTM (Verity Software House) and probability state modeling (PSM). METHODS: Four hundred and fifty-seven human blood samples were processed using the Leuko64 assay. Samples were analyzed on four different flow cytometer models: BD FACSCanto II, BD FACScan, BC Gallios/Navios, and BC FC500. A probability state model was designed to identify calibration beads and three leukocyte subpopulations based on differences in intensity levels of several parameters. PSM automatically calculates CD64 index values for each cell population using equations programmed into the model. GemStone software uses PSM that requires no operator intervention, thus totally automating data analysis and internal quality control flagging. Expert analysis with the predicate method (QuantiCALC) was performed. Interanalyst precision was evaluated for both methods of data analysis. RESULTS: PSM with GemStone correlates well with the expert manual analysis, r(2) = 0.99675 for the neutrophil CD64 index values with no intermethod bias detected. The average interanalyst imprecision for the QuantiCALC method was 1.06% (range 0.00-7.94%), which was reduced to 0.00% with the GemStone PSM. The operator-to-operator agreement in GemStone was a perfect correlation, r(2) = 1.000. CONCLUSION: Automated quantification of CD64 index values produced results that strongly correlate with expert analysis using a standard gate-based data analysis method. PSM successfully evaluated flow cytometric data generated by multiple instruments across multiple lots of the Leuko64 kit in all 457 cases. The probability-based method provides greater objectivity, higher data analysis speed, and allows for greater precision for in vitro diagnostic flow cytometric assays. PMID- 25529114 TI - Acute effect of different minimalist shoes on foot strike pattern and kinematics in rearfoot strikers during running. AB - Despite the growing interest in minimalist shoes, no studies have compared the efficacy of different types of minimalist shoe models in reproducing barefoot running patterns and in eliciting biomechanical changes that make them differ from standard cushioned running shoes. The aim of this study was to investigate the acute effects of different footwear models, marketed as "minimalist" by their manufacturer, on running biomechanics. Six running shoes marketed as barefoot/minimalist models, a standard cushioned shoe and the barefoot condition were tested. Foot-/shoe-ground pressure and three-dimensional lower limb kinematics were measured in experienced rearfoot strike runners while they were running at 3.33 m . s-1 on an instrumented treadmill. Physical and mechanical characteristics of shoes (mass, heel and forefoot sole thickness, shock absorption and flexibility) were measured with laboratory tests. There were significant changes in foot strike pattern (described by the strike index and foot contact angle) and spatio-temporal stride characteristics, whereas only some among the other selected kinematic parameters (i.e. knee angles and hip vertical displacement) changed accordingly. Different types of minimalist footwear models induced different changes. It appears that minimalist footwear with lower heel heights and minimal shock absorption is more effective in replicating barefoot running. PMID- 25529113 TI - Identification of character-impact odorants in a cola-flavored carbonated beverage by quantitative analysis and omission studies of aroma reconstitution models. AB - Thirty aroma-active components of a cola-flavored carbonated beverage were quantitated by stable isotope dilution assays, and their odor activity values (OAVs) were calculated. The OAV results revealed that 1,8-cineole, (R)-(-) linalool, and octanal made the greatest contribution to the overall aroma of the cola. A cola aroma reconstitution model was constructed by adding 20 high-purity standards to an aqueous sucrose-phosphoric acid solution. The results of headspace solid-phase microextraction and sensory analyses were used to adjust the model to better match authentic cola. The rebalanced model was used as a complete model for the omission study. Sensory results indicated that omission of a group consisting of methyleugenol, (E)-cinnamaldehyde, eugenol, and (Z)- and (E)-isoeugenols differed from the complete model, while omission of the individual components of this group did not differ from the complete model. These results indicate that a balance of numerous odorants is responsible for the characteristic aroma of cola-flavored carbonated beverages. PMID- 25529115 TI - Communicative social capital and collective efficacy as determinants of access to health-enhancing resources in residential communities. AB - This article contributes to the burgeoning literature on the social determinants of health disparities. The authors investigate how communication resources and collective efficacy, independently and in combination, shape residents' access to health enhancing resources (including healthcare services, sources of healthier food options, and public recreation spaces) in their communities. Using random digit dial telephone survey data from 833 residents of South Los Angeles communities the authors show that communicative social capital-that is, an information and problem-solving resource that accrues to residents as they become more integrated into their local communication network of neighbors, community organizations, and local media-plays a significant role in access to health resources. This relationship is complicated by individuals' health insurance and health status, as communicative social capital magnifies the sense of absence of resources for those who are in worse health and lack insurance. Communicative social capital builds collective efficacy, which is positively related to access to health-enhancing resources, but it also mediates the negative relationship between communicative social capital and access to health resources. Residents with richer stores of communicative social capital and collective efficacy report better access to health resources. The authors conclude with a discussion of implications of these findings and suggestions for future research. PMID- 25529117 TI - Impact of lymph node ratio on survival in patients with pancreatic and periampullary cancer. AB - BACKGROUND: According to some studies, the number of lymph nodes with metastases in relation to the total number of removed lymph nodes, the lymph node ratio (LNR), is one of the most powerful predictors of survival after resection in patients with pancreatic cancer. However, contradictory results have been reported, and small sample sizes of the cohorts and different definitions of a microscopic positive resection margin (R1) hamper the interpretation of data. METHODS: The predictive value of LNR for 3-year survival was assessed using a Cox proportional hazards model. From 1992 to 2012, all patients with pancreatic and periampullary cancer operated on with pancreatoduodenectomy were selected from a database. Clinicopathological characteristics were analysed. Microscopic positive resection margin was defined as the microscopic presence of tumour cells within 1 mm of the margins. A nomogram was created. RESULTS: Some 760 patients were included. Predictive factors for death in 350 patients with pancreatic ductal adenocarcinoma included in the nomogram were: R1 resection (hazard ratio (HR) 1.55, 95 per cent c.i. 1.07 to 2.25), poor tumour differentiation (HR 2.78, 1.40 to 5.52), LNR above 0.18 (HR 1.75, 1.13 to 2.70) and no adjuvant therapy (HR 1.54, 1.01 to 2.34). The C statistic was 0.658 (0.632 to 0.698), and calibration was good (Hosmer-Lemeshow chi(2) = 5.67, P =0.773). LNR and poor tumour differentiation (HR 4.51 and 3.30 respectively) were also predictive in patients with distal common bile duct (CBD) cancer. LNR, R1 resection and jaundice were predictors of death in patients with ampullary cancer (HR 7.82, 2.68 and 1.93 respectively). CONCLUSION: LNR is a common predictor of poor survival in pancreatic, distal CBD and ampullary cancer. PMID- 25529116 TI - Effect of reproductive seasonality on gamete quality in the North American bison (Bison bison bison). AB - The objective was to investigate the effects of reproductive seasonality on gamete quality in plains bison (Bison bison bison). Epididymal sperm (n = 61 per season), collected during the breeding season (July-September), had significantly higher post-thaw total motility (36.76 +/- 14.18 vs 31.24 +/- 12.74%), and lower linearity (0.36 +/- 0.06 vs 0.39 +/- 0.04) and wobbliness (0.49 +/- 0.04 vs 0.51 +/- 0.03; mean +/- SD) compared to non-breeding season (January-March) samples. Representative samples (n = 4) from each season were used in heterologous IVF trials using cattle oocytes. Cleavage, morulae and blastocyst percentage were higher for breeding vs non-breeding season sperm samples (81.88 +/- 6.8 vs 49.94 +/- 6.77; 41.89 +/- 13.40 vs 27.08 +/- 23.21; and 30.49 +/- 17.87 vs 13.72 +/- 18.98%, respectively). Plains bison ovaries collected during the breeding (n = 97 pairs) and non-breeding (n = 100 pairs) seasons were classified as luteal or follicular. Oocytes recovered from these ovaries were classified into five grades based on morphology. There was no significant difference in the number of luteal ovaries or grades of oocytes recovered. Oocytes were matured, fertilized (with frozen sperm from three bison bulls) and cultured in vitro. Cleavage percentage was higher for oocytes collected during breeding vs non-breeding season (83.72 +/ 6.42 vs 73.98 +/- 6.43), with no significant difference in subsequent development to blastocysts. In summary, epididymal sperm from non-breeding season had decreased total motility and resulted in reduced embryo production in vitro. Oocytes collected during non-breeding season had reduced ability to be matured, fertilized and/or undergo cleavage in vitro. Data suggested that season influenced gamete quality in plains bison. PMID- 25529119 TI - B(C6F5)3-catalyzed transfer hydrogenation of imines and related heteroarenes using cyclohexa-1,4-dienes as a dihydrogen source. AB - The strong boron Lewis acid tris(pentafluorophenyl)borane, B(C6F5)3, is shown to abstract a hydride from suitably donor-substituted cyclohexa-1,4-dienes, eventually releasing dihydrogen. This process is coupled with the FLP-type (FLP = frustrated Lewis pair) hydrogenation of imines and nitrogen-containing heteroarenes that are catalyzed by the same Lewis acid. The net reaction is a B(C6F5)3-catalyzed, i.e., transition-metal-free, transfer hydrogenation using easy-to-access cyclohexa-1,4-dienes as reducing agents. Competing reaction pathways with or without the involvement of free dihydrogen are discussed. PMID- 25529118 TI - Entamoeba histolytica RacC selectively engages p21-activated kinase effectors. AB - Rho family GTPases modulate actin cytoskeleton dynamics by signaling through multiple effectors, including the p21-activated kinases (PAKs). The intestinal parasite Entamoeba histolytica expresses ~20 Rho family GTPases and seven isoforms of PAK, two of which have been implicated in pathogenesis-related processes such as amoebic motility and invasion and host cell phagocytosis. Here, we describe two previously unstudied PAK isoforms, EhPAK4 and EhPAK5, as highly specific effectors of EhRacC. A structural model based on 2.35 A X-ray crystallographic data of a complex between EhRacC(Q65L).GTP and the EhPAK4 p21 binding domain (PBD) reveals a fairly well-conserved Rho/effector interface despite deviation of the PBD alpha-helix. A structural comparison with EhRho1 in complex with EhFormin1 suggests likely determinants of Rho family GTPase signaling specificity in E. histolytica. These findings suggest a high degree of Rho family GTPase diversity and specificity in the single-cell parasite E. histolytica. Because PAKs regulate pathogenesis-related processes in E. histolytica, they may be valid pharmacologic targets for anti-amoebiasis drugs. PMID- 25529120 TI - Tunable rigidity of (polymeric core)-(lipid shell) nanoparticles for regulated cellular uptake. AB - Core-shell nanoparticles (NPs) with lipid shells and varying water content and rigidity but with the same chemical composition, size, and surface properties are assembled using a microfluidic platform. Rigidity can dramatically alter the cellular uptake efficiency, with more-rigid NPs able to pass more easily through cell membranes. The mechanism accounting for this rigidity-dependent cellular uptake is revealed through atomistic-level simulations. PMID- 25529121 TI - Response to letter by Verdolin. PMID- 25529122 TI - Fluorescence chemosensors for hydrogen sulfide detection in biological systems. AB - A comprehensive review of the development of H2S fluorescence-sensing strategies, including sensors based on chemical reactions and fluorescence resonance energy transfer (FRET), is presented. The advantages and disadvantages of fluorescence sensing strategies are compared with those of traditional methods. Fluorescence chemosensors, especially those used in FRET sensing, are highly promising because of their low cost, technical simplicity, and their use in real-time sulfide imaging in living cells. Potential applications based on sulfate reduction to H2S, the relationship between sulfate-reducing bacteria activity and H2S yield, and real-time detection of sulfate-reducing bacteria activity using fluorescence sensors are described. The current challenges, such as low sensitivity and poor stability, are discussed. PMID- 25529123 TI - Characterization and biofilm forming ability of diarrhoeagenic enteroaggregative Escherichia coli isolates recovered from human infants and young animals. AB - Enteroaggregative Escherichia coli (EAEC) is an important pathotype that causes infection in humans and animals. EAEC isolates (n=86) recovered from diarrhoeal cases in human infants (37) and young animals (49) were characterized as 'typical' and/or 'atypical' EAEC strains employing PCR for virulence associated genes (cvd432, aaiA, astA, pilS, irp2, ecp, pic, aggR, aafA, aggA, and agg3A). Besides, biofilm formation ability of human and animal EAEC isolates was assessed using microtiter plate assay. In addition, the transcriptional profile of biofilm associated genes (fis and ecp) was also evaluated and correlated with biofilm formation assay for few selected EAEC isolates of human and animal origins. Overall, a diverse virulence gene profile was observed for the EAEC isolates of human and animal origins as none of the EAEC isolates revealed the presence of all the genes that were targeted. Nine 'typical' EAEC isolates were identified (6 from humans and 3 from animals) while, the majority of the isolates were 'atypical' EAEC strains. Isolation and identification of three 'typical' EAEC isolates from animals (canines) appears to be the first report globally. Further, based on the observations of the biofilm formation assay, the study suggested that human EAEC isolates in particular were comparatively more biofilm producers than that of the animal EAEC isolates. The fis gene was highly expressed in majority of 'typical' EAEC isolates and the ecp gene in 'atypical' EAEC isolates. PMID- 25529125 TI - Lymphoblastic transformation of follicular lymphoma: a clinicopathologic and molecular analysis of 7 patients. AB - Approximately 30% of patients with follicular lymphoma (FL) transform to a more aggressive malignancy, most commonly diffuse large B cell lymphoma. Rarely, FL transformation results in clinical findings, histology, and immunophenotype reminiscent of B-lymphoblastic leukemia/lymphoma. We report the largest series to date with detailed analysis of 7 such patients. Lymphoblastic transformation occurred on average 2 years after initial diagnosis of FL. Five patients had prior intensive chemotherapy. Two patients developed mature high-grade lymphoma, followed by the lymphoblastic transformation. FL had BCL2 gene rearrangement in 4 of 5 cases. High-grade transformation was accompanied by MYC gene rearrangement (5 of 5). Transformation was characterized by expression of TdT, loss of Bcl6, variable loss of immunoglobulin light chain, and persistence of Pax-5, Bcl2, and CD10. Whole-exome sequencing in 1 case revealed presence of several actionable mutations (CD79B, CCND3, CDK12). FL, aggressive mature B cell lymphoma, and lymphoblastic transformation were clonally related in 6 evaluable cases. After transformation, survival ranged from 1 to 14 months. Four patients died of disease, 2 were in remission after stem cell transplant, and 1 was alive with disease. PMID- 25529132 TI - Utilisation of psychosocial and informational services in immigrant and non immigrant German cancer survivors. AB - OBJECTIVE: We examined psychosocial and informational services used by long-term survivors of breast, colon and prostate cancer in immigrants versus non immigrants. METHODS: Patients were sampled from population-based cancer registries in Germany. They completed a questionnaire assessing immigration biography, service use and socio-demographic characteristics. RESULTS: Data of 6143 cancer survivors were collected of whom 383 (6%) were immigrants. There was no evidence of an association between immigration status and service use. However, immigration biography played a role when patients' and their parents' birthplace were taken into account. When parents were born outside Europe, survivors less frequently used information from the Internet (ORadj 0.4, 95% CI 0.2; 0.8). Web-based information (ORadj 0.7, 95% CI 0.5; 0.9) was less frequently used when the participant was born outside Germany. CONCLUSION: The differences in the use of psychosocial and informational services between immigrants and non immigrants seem to be generally small. Acculturation may play a role in service uptake. In survey-based health services research, investigators should not stratify by census-defined immigration status, but rather by cultural background. PMID- 25529124 TI - Prevalence of low central venous oxygen saturation in the first hours of intensive care unit admission and associated mortality in septic shock patients: a prospective multicentre study. AB - INTRODUCTION: In septic shock patients, the prevalence of low (<70%) central venous oxygen saturation (ScvO2) on admission to the intensive care unit (ICU) and its relationship to outcome are unknown. The objectives of the present study were to estimate the prevalence of low ScvO2 in the first hours of ICU admission and to assess its potential association with mortality in patients with severe sepsis or septic shock. METHODS: This was a prospective, multicentre, observational study conducted over a one-year period in ten French ICUs. Clinicians were asked to include patients with severe sepsis or septic shock preferably within 6 hours of ICU admission and as soon as possible without changing routine practice. ScvO2 was measured at inclusion and 6 hours later (H6), by blood sampling. RESULTS: We included 363 patients. Initial ScvO2 below 70% was present in 111 patients and the pooled estimate for its prevalence was 27% (95% Confidence interval (95%CI): 18% to 37%). At time of inclusion, among 166 patients with normal lactate concentration (<=2 mmol/L), 55 (33%) had a low initial ScvO2 (<70%), and among 136 patients who had already reached the classic clinical endpoints for mean arterial pressure (>=65 mmHg), central venous pressure (>=8 mmHg), and urine output (>=0.5 mL/Kg of body weight), 43 (32%) had a low initial ScvO2 (<70%). Among them, 49% had lactate below 2 mmol/L. The day 28 mortality was higher in case of low initial ScvO2 (37.8% versus 27.4%; P = 0.049). When adjusted for confounders including the Simplified Acute Physiology Score and initial lactate concentration, a low initial ScvO2 (Odds ratio (OR) = 3.60, 95%CI: 1.76 to 7.36; P = 0.0004) and a low ScvO2 at H6 (OR = 2.18, 95%CI: 1.12 to 4.26; P = 0.022) were associated with day-28 mortality by logistic regression. CONCLUSIONS: Low ScvO2 was common in the first hours of admission to the ICU for severe sepsis or septic shock even when clinical resuscitation endpoints were achieved and even when arterial lactate was normal. A ScvO2 below 70% in the first hours of ICU admission and six hours later was associated with day-28 mortality. PMID- 25529133 TI - Composition variability of the organic fraction of municipal solid waste and effects on hydrogen and methane production potentials. AB - The composition of the Organic Fraction of Municipal Solid Waste (OFMSW) strongly depends on the place and time of collection for a specific municipality or area. Moreover synthetic food waste or organic waste from cafeterias and restaurants may not be representative of the overall OFMSW received at treatment facilities for source-separated waste. This work is aimed at evaluating the composition variability of OFMSW, the potential productions of hydrogen and methane from specific organic waste fractions typically present in MSW and the effects of waste composition on overall hydrogen and methane yields. The organic waste fractions considered in the study were: bread-pasta, vegetables, fruits, meat fish-cheese and undersieve 20mm. Composition analyses were conducted on samples of OFMSW that were source segregated at household level. Batch tests for hydrogen and methane productions were carried out under mesophilic conditions on selected fractions and OFMSW samples. Results indicated that the highest production of hydrogen was achieved by the bread-pasta fraction while the lowest productions were measured for the meat-fish-cheese fraction. The results indicated that the content of these two fractions in organic waste had a direct influence on the hydrogen production potentials of OFMSW. The higher the content of bread-pasta fraction, the higher the hydrogen yields were while the contrary was observed for the meat-fish-cheese fraction. The definition of waste composition therefore represents fundamental information to be reported in scientific literature to allow data comparison. The variability of OFMSW and its effects on hydrogen potentials might also represents a problematic issue in the management of pilot or full-scale plants for the production of hydrogen by dark fermentation. PMID- 25529134 TI - Micro-scale energy valorization of grape marcs in winery production plants. AB - The Biochemical Methane Potential (BMP) of winery organic waste, with reference to two Italian red and white grapes (i.e. Nero Buono and Greco) by-products was investigated. The study was carried out to verify the possibility to reduce the production impact in a green-waste-management-chain-perspective. The possibility to efficiently utilize wine-related-by-products for energy production at a micro scale (i.e. small-medium scale winery production plant) was also verified. Results showed as a good correlation can be established between the percentage of COD removal and the biogas production, as the winery can produce, from its waste methanization, about 7800 kW h year(-1) electrical and 8900 kW h year(-1) thermal. A critical evaluation was performed about the possibility to utilize the proposed approach to realize an optimal biomass waste management and an energetic valorization in a local-energy-production-perspective. PMID- 25529136 TI - Collagen crosslinking does not dictate stiffness in a transgenic mouse model of skeletal muscle fibrosis. AB - Skeletal muscle fibrosis is characterized by increases in tissue stiffness and collagen content. However, a very weak correlation exists between collagen content and stiffness in skeletal muscle. Recently, it has been hypothesized that collagen crosslinking explains tissue stiffness in fibrotic skeletal muscle. Therefore, we addressed this hypothesis by correlating tissue stiffness with lysyl-pyridinoline, hydroxylysyl-pyridinoline, and pentosidine collagen crosslinks. Stepwise regression revealed that, separate or together, collagen crosslinks did not correlate with tissue stiffness. Our result demonstrates that increased tissue stiffness in skeletal muscle fibrosis is not simply explained by increased collagen crosslinks and/or collagen crosslink density. We suggest that collagen organization may affect tissue stiffness. PMID- 25529137 TI - Female patient-specific finite element modeling of pelvic organ prolapse (POP). AB - Pelvic organ prolapse (POP) occurs only in women and becomes more common as women age. However, the surgical practices remain poorly evaluated. The realization of a simulator of the dynamic behavior of the pelvic organs is then identified as a need. It allows the surgeon to estimate the functional impact of his actions before his implementation. In this work, the simulation will be based on a patient-specific approach in which each geometrical model will be carried out starting from magnetic resonance image (MRI) acquisition of pelvic organs of one patient. To determine the strain and stress in the soft biological tissues, hyperelastic constitutive laws are used in the context of finite element analysis. The Yeoh model has been implemented into an in-house finite element code FER to model these organ tissues taking into account large deformations with multiple contacts. The 2D and 3D models are considered in this preliminary study and the results show that our method can help to improve the understanding of different forms of POP. PMID- 25529135 TI - Design and characterization of a photo-activatable hedgehog probe that mimics the natural lipidated form. AB - We have generated a photoactivatable form of sonic hedgehog protein by modifying the N-terminal cysteine with the heterobifunctional photocrosslinker 4 maleimidobenzophenone (Bzm). The Bzm modification on ShhN imparted a significant increase in activity as assessed in the C3H10T1/2 functional assay with potency comparable to that of the endogenous dual-lipidated form of ShhN (ShhNp). Reversed-phase HPLC analysis indicated that the increase in activity compared to unmodified ShhN may be due in part to the hydrophobic nature of the benzophenone group. In contrast to the fully processed ShhNp, Bzm-ShhN is monomeric as assessed by analytical SEC and does not require detergent to be soluble. Further, we demonstrated that the Bzm-ShhN was able to crosslink in vitro in the presence of a known binding partner, heparin. We suggest that Bzm-ShhN can serve as a relatively facile and preferred source of ShhNp for in vitro assays and as a probe to identify novel Hh protein interactions. PMID- 25529138 TI - Quantifying skeletal muscle recovery in a rat injury model using ultrasound imaging. AB - Monitoring skeletal muscle health during recovery or degeneration is of great interest both clinically and in research settings. This type of monitoring requires health measurements be taken at multiple time points. Contraction strength is a commonly used metric for quantifying muscle health, but it requires invasive in vitro or in situ procedures that may further damage the tissue. Ultrasound imaging can be used to visualize muscle damage, and semi-quantitative grading scales have been shown to be effective at characterizing abnormalities. Using an established functional testing procedure in a rat model as a baseline measurement of muscle strength, we show that ultrasound imaging combined with a semi-quantitative grading scale can be used to monitor recovery after contusion injury. Although additional work is needed to refine the imaging and grading procedures, ultrasound promises a fast and non-invasive alternative to functional testing for characterizing skeletal muscle health. PMID- 25529139 TI - Cardiac fluid dynamics anticipates heart adaptation. AB - Hemodynamic forces represent an epigenetic factor during heart development and are supposed to influence the pathology of the grown heart. Cardiac blood motion is characterized by a vortical dynamics, and it is common belief that the cardiac vortex has a role in disease progressions or regression. Here we provide a preliminary demonstration about the relevance of maladaptive intra-cardiac vortex dynamics in the geometrical adaptation of the dysfunctional heart. We employed an in vivo model of patients who present a stable normal heart function in virtue of the cardiac resynchronization therapy (CRT, bi-ventricular pace-maker) and who are expected to develop left ventricle remodeling if pace-maker was switched off. Intra-ventricular fluid dynamics is analyzed by echocardiography (Echo-PIV). Under normal conditions, the flow presents a longitudinal alignment of the intraventricular hemodynamic forces. When pacing is temporarily switched off, flow forces develop a misalignment hammering onto lateral walls, despite no other electro-mechanical change is noticed. Hemodynamic forces result to be the first event that evokes a physiological activity anticipating cardiac changes and could help in the prediction of longer term heart adaptations. PMID- 25529140 TI - Identification of intrinsic and reflexive contributions to low-back stiffness: medium-term reliability and construct validity. AB - This study aimed at testing the reliability and construct validity of a trunk perturbation protocol (TPP) that estimates the intrinsic and reflexive contributions to low-back stiffness. The TPP consists of a series of pseudorandom position-controlled trunk perturbations in an apparatus measuring forces and displacements at the harness surrounding the thorax. Intrinsic and reflexive contributions to low-back stiffness were estimated using a system identification procedure, leading to 12 parameters. Study 1 methods (reliability): 30 subjects performed five 75-s trials, on each of two separate days (eight weeks apart). Reliability was assessed using the generalizability theory, which allowed computing indexes of dependability (phi, analogous to intraclass correlation coefficient) and standard errors of measurement (SEM). Study 2 methods (validity): 20 healthy subjects performed three 75-s trials for each of five experimental conditions assumed to provide different lumbar stiffness; testing the construct validity of the TPP using four conditions with different lumbar belt designs and one control condition without. Study 1 results (reliability): Learning was seen between the first and following trials. Consequently, reliability analyses were performed without the first trial. Simulations showed that averaging the scores of three trials can lead to acceptable reliability results for some TPP parameters. Study 2 results (validity): All lumbar belt designs increased low-back intrinsic stiffness, while only some of them decreased reflex stiffness, which support the construct validity of the TPP. Overall, these findings support the use of the TPP to test the effect of rehabilitation or between-groups differences with regards to trunk stiffness. PMID- 25529142 TI - Bayesian estimation of diagnostic accuracy of a new bead-based antibody detection test to reveal Toxoplasma gondii infections in pig populations. AB - The success of a Toxoplasma gondii surveillance program in European pig production systems depends partly on the quality of the test to detect infection in the population. The test accuracy of a recently developed serological bead based assay (BBA) was investigated earlier using sera from experimentally infected animals. In this study, the accuracy of the BBA was determined by the use of sera from animals from two field subpopulations. As no T. gondii infection information of these animals was available, test accuracy was determined through a Bayesian approach allowing for conditional dependency between BBA and an ELISA test. The priors for prevalence were based on available information from literature, whereas for specificity vague non-informative priors were used. Priors for sensitivity were based either on available information or specified as non-informative. Posterior estimates for BBA sensitivity and specificity were (mode) 0.855 (Bayesian 95% credibility interval (bCI) 0.702-0.960) and 0.913 (bCI 0.893-0.931), respectively. Comparing the results of BBA and ELISA, sensitivity was higher for the BBA while specificity was higher for ELISA. Alternative priors for the sensitivity affected posterior estimates for sensitivity of both BBA and ELISA, but not for specificity. Because the difference in prevalence between the two subpopulations is small, and the number of infected animals is small as well, the precision of the posterior estimates for sensitivity may be less accurate in comparison to the estimates for specificity. The estimated value for specificity of BBA is at least optimally defined for testing pigs from conventional and organic Dutch farms. PMID- 25529141 TI - Cerebral cortex assembly: generating and reprogramming projection neuron diversity. AB - The mammalian cerebral cortex is responsible for the highest levels of associative, cognitive and motor functions. In the central nervous system (CNS) the cortex stands as a prime example of extreme neuronal diversity, broadly classified into excitatory projection neurons (PNs) and inhibitory interneurons (INs). We review here recent progress made in understanding the strategies and mechanisms that shape PN diversity during embryogenesis, and discuss how PN classes may be maintained, postnatally, for the life of the organism. In addition, we consider the intriguing possibility that PNs may be amenable to directed reprogramming of their class-specific features to allow enhanced cortical plasticity in the adult. PMID- 25529143 TI - Fasciola hepatica: a comparative survey of adult fluke resistance to triclabendazole, nitroxynil and closantel on selected upland and lowland sheep farms in Northern Ireland using faecal egg counting, coproantigen ELISA testing and fluke histology. AB - In order to investigate the incidence and distribution of adult fluke resistance to the fasciolicide tricalbendazole (TCBZ) amongst populations of Fasciola hepatica in sheep flocks in Northern Ireland (NI), individual rectal faeces samples were collected from 3 groups of 20 sheep, before (pre-dose), and 21 days after (post-dose) treatment of the animals with TCBZ, nitroxynil or closantel, on each of 13 well-managed sheep farms distributed across the province. The efficacy of each flukicide was determined for each farm, using faecal egg count reduction (FECRT) and F. hepatica coproantigen ELISA testing. In certain flocks, 2 sheep with high pre-dose faecal egg counts (FEC) were killed 3 days and 21 days respectively after TCBZ treatment, and the histology of the fluke reproductive organs was compared with that of flukes from untreated sheep, and from sheep treated with nitroxynil or closantel 2 days prior to death, using haematoxylin and eosin (H&E) staining and an in situ hybridisation method (TdT-mediated dUDP nick end labelling [TUNEL]) to demonstrate apoptosis. Results from FECRT revealed that in all flocks with a high fluke burden, TCBZ was ineffective in treating chronic fasciolosis, and this finding was generally supported by the results of the coproantigen reduction test (CRT). The histology of reproductive organs of flukes from TCBZ-treated sheep in these flocks was normal, when compared with untreated flukes, and this, together with the FECRT and CRT findings, indicated a likely diagnosis of TCBZ resistance in all the flocks with a high fluke burden. In contrast, nitroxynil and closantel were found to be fully effective against TCBZ-resistant flukes in each of the flocks bearing a high chronic fluke burden. All of the flocks with a high fluke burden and TCBZ resistance were managed on lowland in the South and East of NI. Upland flocks, in the North and West, had low fluke burdens, or were clear of infection; and FECs were too low to allow valid resistance testing. The study highlights the high level of penetration of TCBZ resistance throughout F. hepatica populations in areas of intensively managed sheep production with a high level of fluke challenge. Further, it emphasises the importance of pre-emptive chemotherapeutic action against chronic fasciolosis, using flukicides effective against the egg-producing adult flukes to minimise pasture contamination for the next season's lamb crop. This study also exemplifies the use of several complementary methods (FECRT; CRT; fluke histology; comparative anthelmintic efficacy testing) for confirmation of a diagnosis of fluke drug resistance. PMID- 25529144 TI - On the interplay between mathematics and biology: hallmarks toward a new systems biology. AB - This paper proposes a critical analysis of the existing literature on mathematical tools developed toward systems biology approaches and, out of this overview, develops a new approach whose main features can be briefly summarized as follows: derivation of mathematical structures suitable to capture the complexity of biological, hence living, systems, modeling, by appropriate mathematical tools, Darwinian type dynamics, namely mutations followed by selection and evolution. Moreover, multiscale methods to move from genes to cells, and from cells to tissue are analyzed in view of a new systems biology approach. PMID- 25529145 TI - Neuroprotective activity and acetylcholinesterase inhibition of five Amaryllidaceae species: a comparative study. AB - AIMS: Amaryllidaceae alkaloids exhibit a wide range of physiological effects, of which the acetylcholinesterase (AChE) inhibitory activity is the most relevant. However, scientific evidence related to their neuroprotective effectiveness against glutamate-induced toxicity has been lacking. Thus, the purpose of this study was to conduct a comparative study of the neuroprotective activity and the AChE inhibitory activity of species of Amaryllidaceae. MAIN METHODS: The neuroprotective activity against glutamate-induced toxicity was measured in rat cortical neurons and the Ellman method was employed for the quantification of acetylcholinesterase inhibitory activity of alkaloidal extracts of five species of Amaryllidaceae (Crinum jagus, Crinum bulbispermum, Hippeastrum barbatum, Hippeastrum puniceum and Zephyranthes carinata). The alkaloid Amaryllidaceae patterns based on GC/MS analyses were also investigated. KEY FINDINGS: The results showed that the alkaloidal extract from C. jagus presented a high neuroprotective activity in both pre- and post-treatments against a glutamate excitotoxic stimulus. Furthermore, the alkaloid extracts from C. jagus and Z. carinata revealed an inhibitory activity of AChE from the electric eel with IC50 values of 18.28+/-0.29 and 17.96+/-1.22MUg/mL, respectively. In addition, 46 alkaloids were detected by GC/MS, and 20 of them were identified based on their mass spectra and retention index. The results suggest that the neuroprotective effects might be associated with lycorine and crinine-type alkaloids, whereas the acetylcholinesterase enzyme inhibitory activity could be related to galanthamine and lycorine-type alkaloids, although not based on synergistic processes. SIGNIFICANCE: In summary, Amaryllidaceae species are sources of alkaloids with potential use for Alzheimer's disease. PMID- 25529146 TI - Dexmedetomidine protects against apoptosis induced by hypoxia/reoxygenation through the inhibition of gap junctions in NRK-52E cells. AB - AIMS: The alpha2-adrenoceptor inducer dexmedetomidine (Dex) provides renoprotection against ischemia/reperfusion (I/R) injury, but the mechanism of this effect is largely unknown. The present study investigated the effect of Dex on apoptosis induced by hypoxia/reoxygenation (H/R) and the relationship between this effect and gap junction intercellular communication (GJIC). MAIN METHODS: In vitro, two cell lines of normal rat kidney proximal tubular cells (NRK-52E) and HeLa cells that were transfected with a connexin 32 (Cx32) plasmid were exposed to H/R. The role of Dex in the modulation of H/R-induced apoptosis was explored by the manipulation of connexin expression, and hence gap junction (GJ) function, using a GJIC inhibitor, heptanol, and a GJIC inducer, retinoic acid. GJ function and the Cx32 protein level were determined by the parachute dye-coupling assay and Western blotting, respectively. KEY FINDINGS: Dex and heptanol significantly reduced H/R-induced apoptosis in NRK-52E cells. The anti-apoptosis effect of Dex was exhibited only in Cx32-expressing HeLa cells. One hour Dex exposure inhibited GJ function mainly via a decrease in Cx32 protein levels in NRK-52E cells. SIGNIFICANCE: Our data suggest that Dex reduced H/R-induced apoptosis through the inhibition of GJ activity by reducing Cx32 protein levels. PMID- 25529147 TI - Slow-releasing rapamycin-coated bionic peripheral nerve scaffold promotes the regeneration of rat sciatic nerve after injury. AB - AIMS: To investigate the effect of locally slow-released rapamycin (RAPA) from the bionic peripheral nerve scaffold on rat sciatic nerve regeneration in the early phase of nerve injury. MAIN METHODS: Slow-releasing RAPA-polyhydroxy alcohol (PLGA) microspheres were prepared and tested for microsphere diameter and slow-release effect in vitro after loading onto nerve scaffold. A total of 48 male SD rats were randomly divided into control group and 3 experimental groups as follows: group 1: RAPA-PLGA scaffold; group 2: RAPA scaffold; and group 3: scaffold alone. In the control group, a 15mm sciatic nerve was excised and religated reversely. In the experimental groups, the scaffolds were used to bridge a defect of 15mm sciatic nerve. The outcome of nerve regeneration was evaluated using neurophysiological and neuromuscular morphological techniques. KEY FINDINGS: The RAPA-PLGA microspheres displayed a smooth exterior. The slow release of RAPA in group 1 lasted for 14days. The sciatic nerve function index (SFI) and electrophysiological and morphological features were examined 12weeks after the surgery in all groups to reveal various degrees of ipsilateral sciatic nerve regeneration. The SFI values at 12weeks showed no significant difference between the RAPA-PLGA scaffold and control groups; morphological observations revealed that the outcomes of nerve regeneration in the above 2 groups were similar and significantly better than those in the RAPA scaffold and scaffold alone groups. SIGNIFICANCE: RAPA-PLGA microsphere-loaded bionic peripheral nerve scaffold gradually released RAPA locally in the early phase of sciatic nerve regeneration, reduced the secondary nerve injury, and evidently promoted the regeneration of peripheral nerve. PMID- 25529148 TI - TNF-alpha confers resistance to Fas-mediated apoptosis in rheumatoid arthritis through the induction of soluble Fas. AB - AIMS: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that is characterized by hyperplastic synovial tissue containing activated synovial fibroblasts. Contradictory findings in the apoptosis of fibroblast-like synoviocytes (FLS) have been described elsewhere, showing that RA FLS have an enhanced susceptibility to Fas (also known as CD95)-mediated apoptosis in vitro in contrast to the observed lack of apoptosis in the RA synovium in vivo. However, the potential mechanisms responsible for this discrepancy remain under investigation. The soluble form of Fas (sFas) was found to inhibit Fas-induced apoptosis by binding to Fas ligand (FasL), thereby preventing the interaction between FasL and membrane-bound Fas. MAIN METHODS: We determined the levels of soluble FasL (sFasL) and sFas in patients with RA and the effects of proinflammatory mediators, including TNF-alpha, on the induction of apoptotic mediators in RA FLS. KEY FINDINGS: The levels of sFasL and sFas were significantly elevated in the synovial fluids of RA patients compared with control subjects. In addition, we found that the sFas is substantially induced in RA FLS by TNF-alpha, which were abundantly present in the synovial fluid of RA. SIGNIFICANCE: These findings suggest that TNF-alpha confers resistance to Fas mediated apoptosis through sFas induction, which could explain the apparent resistance of RA synovial cells to apoptosis in vivo. PMID- 25529149 TI - Cooperative effects of EGF, FGF, and TGF-beta1 in prostate stromal cells are different from responses to single growth factors. AB - AIMS: Stromal growth is critical for prostate enlargement during benign prostatic hyperplasia (BPH). While responses of prostate cells to single growth factors have been well characterized, responses to multiple growth factors at once are poorly understood. Here, we examined the effects of combinations between epidermal growth factor (EGF), fibroblast growth factor (FGF), and transforming growth factor-beta1 (TGF-beta1) in human prostate stromal cells. MAIN METHODS: EGF, FGF, and TGF-beta1 were applied to WPMY-1 cells, an immortalized, non malignant line of stromal cells from the human prostate. Hypertrophic responses were assessed by protein/DNA ratio, and cyclin D1 mRNA by RT-PCR. Expression of EGF, FGF, and TGF-beta1 and their receptors in human prostate tissue was analyzed by RT-PCR, Western blot, and fluorescence staining. KEY FINDINGS: Hypertrophic responses to single growth factors and combinations were similar. Combinations showed additive effects on cyclin D1 mRNA. Combination of EGF with TGF-beta1, but not EGF or TGF-beta1 alone, caused assembly of cells to a new two-dimensional structure, being characterized by dense aggregates connected by branches of few cells. EGF and TGF-beta1 were detected together in human prostates. Receptors for EGF and TGF-beta colocalized on stromal cells in human prostates. SIGNIFICANCE: Responses of prostate stromal cells to combinations of EGF, FGF, and TGF-beta1 may be quantitatively different, qualitatively different, or similar to responses to single growth factors. The combination of EGF and TGF-beta1, but not EGF or TGF-beta1 alone, induces aggregation of prostate stromal cells, which may be relevant for morphogenesis. PMID- 25529150 TI - Molecular and functional characterization of TRPV4 channels in pregnant and nonpregnant mouse uterus. AB - AIMS: The aim of the present study was to characterize TRPV4 channels in pregnant and nonpregnant mouse uterus and examine their functional role in spontaneous and agonist-induced contractions. MAIN METHODS: We used RT-PCR, Western blot and immunohistochemistry experiments to demonstrate the presence of TRPV4 mRNA and protein, respectively in both pregnant and nonpregnant mouse uterus. Tension experiments were conducted for functional characterization of the TRPV4 channels. KEY FINDINGS: TRPV4 mRNA and protein were detected in both pregnant and nonpregnant mouse uterus with distribution in both endometrium and myometrium. The TRPV4 channel agonist GSK1016790A (GSK) increased myometrial contraction in pregnant (Emax 336.8+/-21.35%; pD2 7.79+/-0.29) and nonpregnant (Emax 238+/ 28.13%; pD2 7.61+/-0.57) animals. HC067047 (1MUM), a selective blocker of the TRPV4 channel, antagonized the contractions to GSK in pregnant (Emax 171+/ 18.26%; pD2 6.58+/-0.37) and nonpregnant (Emax 78.12+/-9.32%; pD2 7.54+/-0.9) uteri. Further, HC067047 (1MUM) inhibited contractions induced by PGF2alpha in the pregnant (Emax 183.2+/-13.94%; pD2 7.01+/-0.30 versus control Emax 495.7+/ 42.49%; pD2 7.12+/-0.24) and nonpregnant (Emax 105.3+/-7.10%; pD2 7.24+/-0.34 versus control Emax 232.5+/-12.27%; pD2 7.83+/-0.29) uteri. SIGNIFICANCE: TRPV4 channels are present in the pregnant and nonpregnant mouse uteri, and their activation by endogenous ligands like prostaglandin increases myometrial contractility. Thus, the TRPV4 channel can be an important target in reducing myometrial contractility in preterm labor. PMID- 25529151 TI - Exogenous Oct4 in combination with valproic acid increased neural progenitor markers: an approach for enhancing the repair potential of the brain. AB - AIMS: Attempts are aimed to introduce new approaches toward enhancing the brain's potential for repair in neurodegenerative diseases and traumatic injuries. Here we report an increased expression of pluripotency and progenitor markers within the brain following pretreatment with valproic acid (VPA) and in vivo transfection of inducible Oct4-expressing viral particles. MATERIALS AND METHODS: Systemic administration of VPA was performed for one week prior to an intracerebroventricular injection of the Oct4-expressing vector into the right side of the brain. Oct4 expression was induced by doxycycline from day 1 post transfection for an additional week. Real time-PCR and immunohistofluorescence were used for evaluation of marker expression. KEY FINDINGS: Real time-PCR analyses of samples collected from the area of transfection within the injected lateral ventricle revealed increased expression of some stem cell and progenitor markers, which included endogenous Oct4, Nanog, Klf4, c-Myc, Pax6 and Sox1. Expressions of Oct4, SSEA1 and Nanog were further confirmed by immunohistofluorescence. The increased neural progenitor and pluripotency markers due to Oct4 overexpression did not lead to teratoma formation during a 100day follow-up. SIGNIFICANCE: Our findings suggest that the application of Oct4 as a reprogramming factor in conjunction with VPA, an epigenetic modifier, might be a potential strategy for increasing the brain's capability to repair itself. PMID- 25529152 TI - Images in emergency medicine. Woman with cough and dyspnea. Pulmonary-renal syndrome caused by microscopic polyangiitis. PMID- 25529153 TI - Clinical policy: critical issues in the evaluation and management of adult patients with suspected acute nontraumatic thoracic aortic dissection. PMID- 25529154 TI - Expert opinion: supplementing the gaps in evidence-based medicine. PMID- 25529155 TI - Commentary. PMID- 25529156 TI - Change of shift. I was just looking at the stars. PMID- 25529157 TI - Laboring under the stone: January 2015 Annals of Emergency Medicine Journal Club. PMID- 25529158 TI - Images in emergency medicine. Teenage male with sudden left hemiparesis. Ischemic stroke as a result of vertebral artery thrombosis. PMID- 25529159 TI - Latrodectism and effectiveness of antivenom. PMID- 25529160 TI - In reply. PMID- 25529161 TI - The integration of social media into residency curriculum has obstacles. PMID- 25529162 TI - In reply. PMID- 25529163 TI - In reply. PMID- 25529164 TI - Lipid emulsion for cocaine toxicity: more questions for investigation. PMID- 25529165 TI - Support for nursing mothers. Policy statement. PMID- 25529166 TI - Supporting political advocacy in the emergency department. Policy statement. PMID- 25529167 TI - Responsibility for admitted patients. Policy statement. PMID- 25529168 TI - Emergency department patient advocate role and training. Policy statement. PMID- 25529169 TI - Deferral of care after medical screening of emergency department patients. Policy statement. PMID- 25529170 TI - The impact of front-of-pack nutrition labels on consumer product evaluation and choice: an experimental study. AB - OBJECTIVE: The present research was an experimental test that aimed to quantify the impact of two dominant front-of-pack (FOP) nutritional label formats on consumer evaluations of food products that carried them. The two FOP label types tested were the traffic light label and the Percentage Daily Intake. DESIGN: A 4*5 partially replicated Latin square design was used that allowed the impact of the FOP labels to be isolated from the effects of the product and the consumers who were performing the evaluations. SETTING: The experiment was conducted on campus at the University of Otago, New Zealand. SUBJECTS: The participants were 250 university students selected at random who met qualifying criteria of independent living and regular purchase of the products used in the research. They were not aware of the purpose of the research. RESULTS: The presence of FOP labels led to significant and positive changes in consumer purchase intentions towards the products that carried them. These changes were not affected by the nature of FOP labels used, their size or the product nutritional status (good/bad) that they were reporting. CONCLUSIONS: The result is consistent with the participants paying attention to the FOP label and then using it as an adimensional cue indicating product desirability. As such, it represents a complete functional failure of both of these FOP label types in this specific instance. This result supports calls for further research on the performance of these FOP labels before any move to compulsory deployment is made. PMID- 25529171 TI - Workload of on-call emergency room neurologists in a Spanish tertiary care centre. A one-year prospective study. Reply to a letter. PMID- 25529172 TI - Ischaemic stroke in patients treated with oral anticoagulants. AB - INTRODUCTION: Cardioembolic stroke is associated with poorer outcomes. Prevention is based on oral anticoagulant (OAC) therapy. Haemorrhage is the main complication of OACs, which are sometimes ineffective. PATIENTS AND METHODS: We retrospectively reviewed 1014 consecutive patients who suffered an ischaemic stroke between 2011 and 2013, analysing those who were receiving OAC treatment at stroke onset (107 patients in total) with special attention to aetiology, outcomes, and INR value in the acute phase. RESULTS: The mean age (SD) was 71.9 (10) years. Patients had been treated with OACs for 5.9 (5.5) years; 98.1% of them were being treated for heart disease. INR was <2 in 77 patients (72%), and 30 patients (28%) had an INR>=2. Nine patients (8.4%) had INR values within the therapeutic range. According to TOAST classification criteria, 88.8% of strokes were cardioembolic and 1.9% were atherothrombotic. Anticoagulation therapy was discontinued in 48 patients (44.9%) due to haemorrhagic transformation (24 patients), extensive infarction (23), or endarterectomy (1). Therapy was resumed in 24 patients (50%) after a mean lapse of 36 days. This was not possible in the remaining patients because of death or severe sequelae. New OACs (NOACs) were prescribed to 9 patients (18.7% of all potential candidates). At 3 months, patients with INR>1.7 in the acute phase exhibited better outcomes than patients with INR<=1.7 (mRS 0-2 in 62% vs 30.8%; death in 10% vs 38.4%; P=.0004). CONCLUSIONS: Some patients taking OACs suffer ischaemic strokes that are usually cardioembolic, especially if INR is below the therapeutic range. OACs can be resumed without complications, and NOACs are still underused. Despite cases in which treatment is ineffective, outcomes are better when INR is above 1.7 at stroke onset. PMID- 25529173 TI - Motor and non-motor symptoms of Parkinson's disease and their impact on quality of life and on different clinical subgroups. AB - INTRODUCTION: The aim of the present study is to analyse the influence that motor and non-motor symptoms have on the quality of life (QoL) of patients with Parkinson's disease (PD), and to study the relationship between the two types of symptoms. MATERIAL AND METHODS: This cross-sectional study included 103 patients with PD (55 men and 48 women). Quality of life was measured on the PDQ-39 scale. The UPDRS scale (I-IV) was also used, and different items were grouped to analyse the presence of tremor, rigidity, bradykinesia, and axial symptoms. The non-motor symptoms scale (NMSS) was administered to assess non-motor symptoms. We performed correlation analyses between different scales to analyse the influence of motor and non-motor symptoms on QoL. RESULTS: Correlations were observed between the PDQ-39 summary index (PDQ39_SI) and the NMSS (correlation coefficient [cc], 0.56; p<.001), UPDRS III (cc, 0.44; p< .001) and UPDRS IV (cc, 0.37; p<.001) scores. The strongest correlation was between cognitive symptoms and mood. The analysis pointed to a direct relationship between the NMSS score and axial symptoms (cc, 0.384; p<.01), bradykinesia (cc, 0.299; p<.01), and to a lesser extent, rigidity (cc, 0.194; p<.05). No relationship was observed between presence of tremor and the NMSS score. CONCLUSION: Cognitive symptoms and mood exert the most influence on QoL of patients with PD. We found at least two phenotypes; one with predominantly axial symptoms, with significant involvement of non-motor symptoms, and a tremor-associated phenotype in which these symptoms are less prevalent. PMID- 25529174 TI - Validation of the Spanish-language version of Mini-Addenbrooke's Cognitive Examination as a dementia screening tool. PMID- 25529175 TI - Cerebrospinal fluid hypotension as a cause of cortical vein thrombosis. PMID- 25529176 TI - Impulsivity among migraine patients: Study in a series of 155 cases. AB - INTRODUCTION: Impulsivity is a psychological phenomenon that has not been extensively studied in headache patients. We aim to assess the presence of impulsivity in patients with chronic migraine (CM) and medication overuse (MO). PATIENTS: All patients examined in an outpatient headache clinic between January 2013 and March 2014 were included. Episodic migraine, CM, and MO were diagnosed according to ICHD-III beta criteria. We prospectively gathered demographic and clinical characteristics. Mood disorders were evaluated using the Hospital Anxiety and Depression Scale (HADS) and impulsiveness was assessed with the Plutchik impulsivity scale. RESULTS: A total of 155 patients were included (22 men, 133 women). The mean age (SD) was 38.2 (11.7) years (range, 18-70); 104 patients (67.1%) presented CM and, among them, 74 (71.1%) had MO. Of the patient total, 28.4% met criteria for anxiety, 7.1% for depression and 16.1% for impulsivity. The CM group showed higher scores for HADS-anxiety (8.5 [SD 4.5] vs. 6.4 [SD 3.6], p=0.003) and HADS-depression (4.4 [4.3] vs. 1.9 [2.3], p<0.001). Among CM cases only, scores for HADS-anxiety (9.3 [4.4] vs. 6.8 [4.3], p=0.01) and HADS-Depression (5.1 [4.6] vs. 2.7 [2.9], p=0.002) were higher in patients who also had MO. We found no associations between Plutchik scale scores or presence of impulsivity with either CM or MO. CONCLUSION: Impulsivity is a common trait in our population of migraine patients, but unlike mood disorders, it is not correlated with either CM or MO. PMID- 25529177 TI - Has clinical activity in paediatric neurology changed in the past 11 years? AB - INTRODUCTION: We believe that the demand for paediatric neurology (PN) care has increased over the past decade, and that reasons for requesting consultations have also changed. The objective of this study is to complete a registry study to profile the demand for PN care in 2013 and compare results to those from a study performed in 2002. METHODS: A prospective registry of PN healthcare activities was completed at Hospital Universitario de Getafe in 2013. Results were compared with those from a prospective registry study conducted in 2002. RESULTS: The number of visits increased from 1,300 in 2002 to 1,982 in 2013 (a 52.46% increase), and from 32.6 visits per 1,000 children to 57.48 (a 76.32% increase). Outpatient consultations accounted for 92.2% of all PN consultations in 2013. Currently, attention deficit-hyperactivity disorder (ADHD) is the most frequent diagnosis (27.6% in 2013 vs. 8.1% in 2002). Although the percentage of headache consultations has decreased (19% in 2013 vs. 22% in 2002), headache was still the most common reason for an initial visit in 2013 (32.1%), followed by ADHD (19.1%). Epilepsy remains the most frequent diagnosis in hospitalised patients (30.3% in 2013 vs. 36.7% in 2002). CONCLUSIONS: PN is fundamentally an outpatient activity that has increased considerably in recent years. This increase is mainly due to neurodevelopmental disorders, especially ADHD. We might state that the role of ADHD in PN is comparable to that of dementia in general neurology. PMID- 25529179 TI - Workload of on-call emergency room neurologists in a Spanish tertiary care centre. A one-year prospective study. Response to a reply. PMID- 25529178 TI - Analysis of macular and nerve fiber layer thickness in multiple sclerosis patients according to severity level and optic neuritis episodes. AB - INTRODUCTION: Quantitative assessment of macular and nerve fibre layer thickness in multiple sclerosis patients with regard to expanded disability status scale (EDSS) and presence or absence of previous optic neuritis episodes. METHODS: We recruited 62 patients with multiple sclerosis (53 relapsing-remitting and 9 secondary progressive) and 12 disease-free controls. All patients underwent an ophthalmological examination, including quantitative analysis of the nerve fibre layer and macular thickness using optical coherence tomography. Patients were classified according to EDSS as A (lower than 1.5), B (between 1.5 and 3.5), and C (above 3.5). RESULTS: Mean nerve fibre layer thickness in control, A, B, and C groups was 103.35+/-12.62, 99.04+/-14.35, 93.59+/-15.41, and 87.36+/-18.75MUm respectively, with statistically significant differences (P<.05). In patients with no history of optic neuritis, history of episodes in the last 3 to 6 months, or history longer than 6 months, mean nerve fibre layer thickness was 99.25+/ 13.71, 93.92+/-13.30 and 80.07+/-15.91MUm respectively; differences were significant (P<.05). Mean macular thickness in control, A, B, and C groups was 220.01+/-12.07, 217.78+/-20.02, 217.68+/-20.77, and 219.04+/-24.26MUm respectively. Differences were not statistically significant. CONCLUSIONS: The mean retinal nerve fibre layer thickness in multiple sclerosis patients is related to the EDSS level. Patients with previous optic neuritis episodes have a thinner retinal nerve fibre layer than patients with no history of these episodes. Mean macular thickness is not correlated to EDSS level. PMID- 25529180 TI - Clinical practice guidelines for subarachnoid haemorrhage. Diagnosis and treatment. PMID- 25529181 TI - Clinical, molecular, and pharmacological aspects of FMR1 related disorders. AB - BACKGROUND: Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. DEVELOPMENT: This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). CONCLUSIONS: Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments. PMID- 25529182 TI - Imaging protocol for suspected ureteric calculi in patients presenting to the emergency department. AB - AIM: To ensure diagnostic yields were adequate in patients with suspected ureteric calculi with and without haematuria, and to assess whether there was a significant difference between these two groups in men and women. MATERIALS AND METHODS: A retrospective analysis was undertaken of 513 patient records who attended the Emergency Department with suspected ureteric colic over 8 months. RESULTS: 513 patient records were evaluated. The overall positive rate for calculi was 45.4%, with an alternative diagnosis in 14.4%. Of the patients scanned with haematuria 49.36% were positive. The positive scan rate in males was significantly higher than in females (56% v. 31%, p < 0.0001). 32.79% of patients scanned without haematuria had a proven calculus. The positive rate in males without haematuria was 40.39% versus 27.14% in females. CONCLUSION: The overall diagnostic yield of 45.4% is acceptable according to national guidelines. A large number of patients scanned without haematuria were found to have a calculus. This review suggests that in males a negative urine dipstick should not preclude CT investigation for renal colic in the presence of a "classical" history. However, the number of female patients with negative scans suggests that further randomized studies are needed to identify the ideal investigation pathway in women. PMID- 25529184 TI - Corticomotor excitability changes during mirrored or asynergistic wrist movements. AB - The current study used transcranial magnetic stimulation (TMS) of the right primary motor cortex (M1) during bimanual contractions to examine facilitatory and inhibitory influences on the contralateral, target extensor carpi radialis muscle (ECR) during changes in the task demands of the ipsilateral (task) ECR. The bimanual contractions were either mirrored (isometric wrist extension bilaterally) or more difficult asynergistic (asymmetric [wrist extension paired with wrist radial deviation]) contractions. TMS-induced motor evoked potentials (MEPs) and cortical silent periods (CSPs) were recorded during the execution of visually guided ramp and hold tasks. It was of interest to determine whether or not asynergistic contractions, representing a more difficult bimanual coordination task, resulted in differing patterns of activation and inhibition than mirrored movements. Asynergistic contractions were found to have differing effects on the target ECR than mirrored contractions. Foremost among these differences were the presence of enhanced inhibitory mechanisms. During asynergistic bimanual contractions the MEPs of the target ECR did not increase to the same degree and cortical silent period durations were longer. Findings indicate that bimanual mirrored and asynergistic contractions result in differing patterns of corticomotor excitability. PMID- 25529183 TI - Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats. AB - Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 days, with each infusion of cocaine being paired with a cue light. After 21 days of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer. PMID- 25529185 TI - Memory loss in chemotherapy-treated rats is exacerbated in high-interference conditions and related to suppression of hippocampal neurogenesis. AB - Drugs used to treat cancer have neurotoxic effects that often produce memory loss and related cognitive deficits. In a test of the hypothesis that chemotherapy induced cognitive impairment is related to a loss of inhibitory control, rats injected with a combination of methotrexate+5-fluouracil or equal volumes of saline, were administered a retroactive interference task in which memory for a learned discrimination problem was tested under conditions of high- and low interference. The drugs had no effect on original learning or on re-learning the discrimination response when there was little interference, but the chemotherapy group was severely impaired in the hippocampus-sensitive, high-interference memory test. The impaired performance correlated significantly with reduced neurogenesis in the hippocampus. The failure to suppress interfering influences is consistent with a breakdown in pattern separation, a process that distinguishes and separates overlapping neural representations of experiences that have a high degree of similarity. PMID- 25529186 TI - Scopolamine and amphetamine produce similar decision-making deficits on a rat gambling task via independent pathways. AB - Disorders characterized by disturbed cholinergic signaling, such as schizophrenia, exhibit impaired performance on measures of real-world cost/benefit decision-making. Whether the cholinergic system contributes to the choice deficits observed is currently unknown. We therefore determined the effects of broad-acting agonists and antagonists at the nicotinic and muscarinic receptor on decision making, as measured by the rodent gambling task (rGT). Given the anatomical and functional connectivity of the cholinergic and dopaminergic systems, we also sought to modulate amphetamine's previously reported effect on rGT performance via the cholinergic system. Male rats were trained on the rGT, during which animals chose from four different options. The optimal strategy on the rGT is to favor options associated with smaller immediate rewards and less punishment/loss. Impulsive action was also measured by recording the number of premature responses made. Performance on the rGT was assessed following acute treatment with the muscarinic receptor agonist oxotremorine, the muscarinic receptor antagonist scopolamine, nicotine, and the nicotinic receptor antagonist mecamylamine. Similar to the effect produced by amphetamine, muscarinic receptor antagonism with scopolamine (0.1mg/kg) impaired decision making, albeit to a lesser degree. Prior muscarinic agonism with oxotremorine was unable to attenuate amphetamine's effects on rGT performance. Oxotremorine, nicotine, and mecamylamine did not affect the choice profile. We therefore conclude that modulation of the muscarinic, but not nicotinic, receptor system can affect decision making under conditions of risk and uncertainty. Such findings contribute to a broader understanding of the cognitive deficits observed in disorders in which cholinergic signaling is compromised. PMID- 25529188 TI - Safety and efficacy of percutaneous cecostomy/colostomy for treatment of large bowel obstruction in adults with cancer. AB - PURPOSE: To assess the safety and efficacy of image-guided percutaneous cecostomy/colostomy (PC) in the management of colonic obstruction in patients with cancer. MATERIALS AND METHODS: Twenty-seven consecutive patients underwent image-guided PC to relieve large bowel obstruction at a single institution between 2000 and 2012. Colonic obstruction was the common indication. Patient demographics, diagnosis, procedural details, and outcomes including maximum colonic distension (MCD; ie, greatest transverse measurement of the colon on radiograph or scout computed tomography image) were recorded and retrospectively analyzed. RESULTS: Following PC, no patient experienced colonic perforation; pain was relieved in 24 of 27 patients (89%). Catheters with tip position in luminal gas rather than mixed stool/gas or stool were associated with greater decrease in MCD (-40%, -12%, and -16%, respectively), with the difference reaching statistical significance (P = .002 and P = .013, respectively). Catheter size was not associated with change in MCD (P = .978). Catheters were successfully removed from six of nine patients (67%) with functional obstructions and two of 18 patients (11%) with mechanical obstructions. One patient underwent endoscopic stent placement after catheter removal. Three patients required diverting colostomy after PC, and their catheters were removed at the time of surgery. One major complication (3.7%; subcutaneous emphysema, pneumomediastinum, and sepsis) occurred 8 days after PC and was successfully treated with cecostomy exchange, soft-tissue drainage, and intravenous antibiotic therapy. CONCLUSIONS: Image guided PC is safe and effective for management of functional and mechanical bowel obstruction in patients with cancer. For optimal efficacy, catheters should terminate within luminal gas. PMID- 25529187 TI - Multifunctional calcium phosphate nanoparticles for combining near-infrared fluorescence imaging and photodynamic therapy. AB - Photodynamic therapy (PDT) of tumors causes skin photosensitivity as a result of unspecific accumulation behavior of the photosensitizers. PDT of tumors was improved by calcium phosphate nanoparticles conjugated with (i) Temoporfin as a photosensitizer, (ii) the RGDfK peptide for favored tumor targeting and (iii) the fluorescent dye molecule DY682-NHS for enabling near-infrared fluorescence (NIRF) optical imaging in vivo. The nanoparticles were characterized with regard to size, spectroscopic properties and uptake into CAL-27 cells. The nanoparticles had a hydrodynamic diameter of approximately 200 nm and a zeta potential of around +22mV. Their biodistribution at 24h after injection was investigated via NIRF optical imaging. After treating tumor-bearing CAL-27 mice with nanoparticle PDT, the therapeutic efficacy was assessed by a fluorescent DY-734-annexin V probe at 2 days and 2 weeks after treatment to detect apoptosis. Additionally, the contrast agent IRDye(r) 800CW RGD was used to assess tumor vascularization (up to 4 weeks after PDT). After nanoparticle-PDT in mice, apoptosis in the tumor was detected after 2 days. Decreases in tumor vascularization and tumor volume were detected in the next few days. Calcium phosphate nanoparticles can be used as multifunctional tools for NIRF optical imaging, PDT and tumor targeting as they exhibited a high therapeutic efficacy, being capable of inducing apoptosis and destroying tumor vascularization. PMID- 25529189 TI - Comparison of midterm outcomes between surgical treatment and endovascular reconstruction for chronic infrarenal aortoiliac occlusion. AB - PURPOSE: To compare the midterm results of aortoiliac stent (AIS) placement with those of surgical treatment in patients with chronic infrarenal aortoiliac occlusion. MATERIALS AND METHODS: Midterm outcomes in patients treated at a single center from 2005 to 2010 were retrospectively reviewed. Correlations between baseline clinical factors and midterm outcomes were assessed. RESULTS: The technical success rate was significantly lower in the AIS group than in the surgery group (83.3% vs 100%; P = .016). Of 68 technically successfully treated patients, 33 underwent surgical revascularization and 35 received AIS placement. There were no significant differences in patient demographics, Rutherford classification, cardiovascular risk factors, and 30-day mortality rates. Surgically treated patients had a longer average postoperative hospital stay (P = .001) and higher rates of postoperative complications, including respiratory failure (P = .010), transient renal dysfunction (P = .002), and multiple organ dysfunction (P = .023). Mean ankle-brachial index increased significantly in both groups (P < .001), but to the same extent. The primary 1-, 3-, and 5-year patency rates were 93.6%, 90.2%, and 90.2%, respectively, in the surgery group, and 91.4%, 81.8%, and 64.2%, respectively, in the AIS group (P = .054). No differences were observed in survival rate (P = .945), limb salvage (P = .860), or secondary patency (P = .916). CONCLUSIONS: AIS for chronic infrarenal aortoiliac occlusion is associated with a shorter hospital stay and lower postoperative morbidity rates. Although midterm primary patency rate was lower than for traditional open surgery, AIS appears to be a safe, minimally invasive, and reliable procedure for patients with chronic infrarenal aortoiliac occlusion. PMID- 25529190 TI - Association of radiographic osteoarthritis, pain on passive movement and knee range of motion: a cross-sectional study. AB - BACKGROUND: Knee pain is associated with radiographic knee osteoarthritis, but the relationships between physical examination, pain and radiographic features are unclear. OBJECTIVE: To examine whether deficits in knee extension or flexion were associated with radiographic severity and pain during clinical examination in persons with knee pain or radiographic features of osteoarthritis. DESIGN: Cross-sectional data of the Somerset and Avon Survey of Health (SASH) cohort study. METHODS: Participants with knee pain or radiographic features of osteoarthritis were included. We assessed the range of passive knee flexion and extension, pain on movement and Kellgren and Lawrence (K/L) grades. Odds ratios were calculated for the association between range of motion and pain as well as radiographic severity. RESULTS/FINDINGS: Of 1117 participants with a clinical assessment, 805 participants and 1530 knees had complete data and were used for this analysis. Pain and radiographic changes were associated with limited range of motion. In knees with pain on passive movement, extension and flexion were reduced per one grade of K/L by -1.4 degrees (95% CI -2.2 to -0.5) and -1.6 degrees (95% CI -2.8 to -0.4), while in knees without pain the reduction was 0.3 degrees (95% CI -0.6 to -0.1) (extension) and -1.1 degrees (-1.8 to -0.3) (flexion). The interaction of pain with K/L was significant (p = 0.021) for extension but not for flexion (p = 0.333). CONCLUSIONS: Pain during passive movement, which may be an indicator of reversible soft-tissue changes, e.g., reversible through physical therapy, is independently associated with reduced flexion and extension of the knee. PMID- 25529191 TI - The effect of end-range cervical rotation on vertebral and internal carotid arterial blood flow and cerebral inflow: A sub analysis of an MRI study. AB - INTRODUCTION: Cervical spine manual therapy has been associated with a small risk of serious adverse neurovascular events, particularly to the vertebral arteries. Sustained end-range rotation is recommended clinically as a pre-manipulative screening tool; however ultrasound studies have yielded conflicting results about the effect of rotation on blood flow in the vertebral arteries. There has been little research on internal carotid arterial flow or utilising the reference standard of angiography. OBJECTIVES: To evaluate the mean effect of cervical rotation on blood flow in the craniocervical arteries and blood supply to the brain, as well as individual variation. DESIGN: This was an observational study. METHOD: Magnetic resonance angiography was used to measure average blood flow volume in the vertebral arteries, internal carotid arteries, and total cerebral inflow, in three neck positions: neutral, end-range left rotation and end-range right rotation in healthy adults. RESULTS: Twenty participants were evaluated. There was a decrease in average blood flow volume in the vertebral and internal carotid arteries on contralateral rotation, compared to neutral. This was statistically significant on left rotation only. Ipsilateral rotation had no effect on average blood flow volume in any artery. Total cerebral inflow was not significantly affected by rotation in either direction. CONCLUSIONS: It appears that in healthy adults the cerebral vasculature can compensate for decreased flow in one or more arteries by increasing flow in other arteries, to maintain cerebral perfusion. Sustained end-range rotation may therefore reflect the compensatory capacity of the system as a whole rather than isolated vertebrobasilar function. PMID- 25529192 TI - Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-beta receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. AB - Purpose Transforming growth factor-beta (TGF-beta) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-beta signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15%) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD >=6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation. PMID- 25529194 TI - Brain expression of pCREB in rats exposed to consummatory successive negative contrast. AB - A 32-to-4% sucrose devaluation leads to suppression of consummatory behavior relative to unshifted 4% sucrose controls. This is accompanied by an emotional response inducing memory consolidation. Expression levels of phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB, a marker of synaptic plasticity) were higher after the first devaluation session than after the second in prelimbic cortex, anterior cingulate cortex, and dorso-medial striatum. The central nucleus of the amygdala showed a tendency to differential pCREB expression. This evidence contributes to identifying the brain circuit for one form of traumatic memory involving reward loss. PMID- 25529193 TI - A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors. AB - Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008 001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade >=3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors. PMID- 25529195 TI - Stress-induced alterations in prefrontal dendritic spines: Implications for post traumatic stress disorder. AB - The medial prefrontal cortex (mPFC) is involved in a variety of important functions including emotional regulation, HPA axis regulation, and working memory. It also demonstrates remarkable plasticity in an experience-dependent manner. There is extensive evidence that stressful experiences can produce profound changes in the morphology of neurons within mPFC with a variety of behavioral consequences. The deleterious behavioral outcomes associated with mPFC dysfunction have been implicated in multiple psychopathologies, including post traumatic stress disorder (PTSD). Given the prevalence of these disorders, a deeper understanding of the cellular mechanisms underlying stress-induced morphological changes in mPFC is critical, and could lead to improved therapeutic treatments. Here we give a brief review of recent studies examining the mechanisms underlying changes in mPFC pyramidal neuron dendritic spines - the primary sites of excitatory input in cortical pyramidal neurons. We begin with an overview of the effects of chronic stress on mPFC dendritic spine density and morphology followed by proposed mechanisms for these changes. We then discuss the time course of stress effects on mPFC as well as potential intercellular influences. Given that many psychopathologies, including PTSD, have different prevalence rates among men and women, we end with a discussion of the sex differences that have been observed in morphological changes in mPFC. Future directions and implications for PTSD are discussed throughout. PMID- 25529196 TI - Oxidative stress accelerates amyloid deposition and memory impairment in a double transgenic mouse model of Alzheimer's disease. AB - Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimer's disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12-15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment. PMID- 25529197 TI - Classification of prefrontal and motor cortex signals for three-class fNIRS-BCI. AB - Functional near-infrared spectroscopy (fNIRS) is an optical imaging method that can be used for a brain-computer interface (BCI). In the present study, we concurrently measure and discriminate fNIRS signals evoked by three different mental activities, that is, mental arithmetic (MA), right-hand motor imagery (RI), and left-hand motor imagery (LI). Ten healthy subjects were asked to perform the MA, RI, and LI during a 10s task period. Using a continuous-wave NIRS system, signals were acquired concurrently from the prefrontal and the primary motor cortices. Multiclass linear discriminant analysis was utilized to classify MA vs. RI vs. LI with an average classification accuracy of 75.6% across the ten subjects, for a 2-7s time window during the a 10s task period. These results demonstrate the feasibility of implementing a three-class fNIRS-BCI using three different intentionally-generated cognitive tasks as inputs. PMID- 25529198 TI - TGF-beta is a potent inducer of Nerve Growth Factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain? AB - OBJECTIVE: Pain is the main problem for patients with osteoarthritis (OA). Pain is linked to inflammation, but in OA a subset of patients suffers from pain without inflammation, indicating an alternative source of pain. Nerve Growth Factor (NGF) inhibition is very efficient in blocking pain during OA, but the source of NGF is unclear. We hypothesize that damaged cartilage in OA releases Transforming Growth Factor-beta (TGF-beta), which in turn stimulates chondrocytes to produce NGF. DESIGN: Murine and human chondrocyte cell lines, primary bovine and human chondrocytes, and cartilage explants from bovine metacarpal joints and human OA joints were stimulated with TGF-beta1 and/or Interleukin-1 (IL-1)beta. We analyzed NGF expression on mRNA level with QPCR and stained human OA cartilage for NGF immunohistochemically. Cultures were additionally pre-incubated with inhibitors for TAK1, Smad2/3 or Smad1/5/8 signaling to identify the TGF-beta pathway inducing NGF. RESULTS: NGF expression was consistently induced in higher levels by TGF-beta than IL-1 in all of our experiments: murine, bovine and human origin, in cell lines, primary chondrocytes and explants cultures. TAK1 inhibition consistently reduced TGF-beta-induced NGF whereas it fully blocked IL 1beta-induced NGF expression. In contrast, ALK5-Smad2/3 inhibition fully blocked TGF-beta-induced NGF expression. Despite the large variation in basal NGF in human OA samples (mRNA and histology), TGF-beta exposure led to a consistent high level of NGF induction. CONCLUSION: We show for the first time that TGF-beta induces NGF expression in chondrocytes, in a ALK5-Smad2/3 dependent manner. This reveals a potential alternative non-inflammatory source of pain in OA. PMID- 25529199 TI - Dynamics and modulation of metabotropic glutamate receptors. AB - The metabotropic glutamate receptors (mGluRs) are glutamate-activated G protein coupled receptors widely expressed in the central nervous system. The eight mGluRs subtypes modulate transmission at many synapses, and are interesting therapeutic targets for the treatment of many neurological and psychiatric diseases. In particular, their organization in multiple domains and subunits offers various possibilities for the development of drugs that modulate mGluRs activity with different efficacies. Recent structural, biophysical and functional analyses have provided new insights into the mechanism of mGluR activation and dynamics. They also revealed the structural bases of ligand efficacy then providing possible mechanism of action of partial agonists and allosteric modulators. These new findings are of great interest for the development of novel mGluR subtype-selective compounds. PMID- 25529202 TI - Natural occurring 2-(2-phenylethyl) chromones, structure elucidation and biological activities. AB - 2-(2-Phenylethyl) chromone (PEC), an uncommon class of chromones, possesses a phenylethyl substituent at the C2 position. They have been isolated from a few plant species. They have promising biological activities such as neuro protective, cytotoxic, acetylcholinesterase inhibitory, antibacterial and anti inflammatory. This review focuses on the naturally occurring PEC derivatives, their sources, physical and spectral data, as well as biological activities. PMID- 25529200 TI - Synaptic localization of neurotransmitter receptors: comparing mechanisms for AMPA and GABAA receptors. AB - Ionotropic neurotransmitter receptors mediate fast synaptic transmission by localizing at postsynapses. Changes in receptor number at synapses induce synaptic plasticity. Thus, mechanisms for the synaptic localization of receptors in basal transmission and synaptic plasticity have been investigated extensively. Recent findings reveal that synaptic localization of tetrameric AMPA receptors in basal transmission requires the PDZ binding of TARP auxiliary subunits, which modulate receptor properties and pharmacology. On the other hand, pentameric GABAA receptors require multiple receptor subunits for their synaptic localization in basal transmission. AMPA receptors seem to utilize distinct mechanisms for basal synaptic localization and synaptic insertion during plasticity. Revealing precise mechanisms for receptor synaptic localization may establish new approaches to control synaptic transmission. PMID- 25529204 TI - Improved one-way hash chain and revocation polynomial-based self-healing group key distribution schemes in resource-constrained wireless networks. AB - Self-healing group key distribution (SGKD) aims to deal with the key distribution problem over an unreliable wireless network. In this paper, we investigate the SGKD issue in resource-constrained wireless networks. We propose two improved SGKD schemes using the one-way hash chain (OHC) and the revocation polynomial (RP), the OHC&RP-SGKD schemes. In the proposed OHC&RP-SGKD schemes, by introducing the unique session identifier and binding the joining time with the capability of recovering previous session keys, the problem of the collusion attack between revoked users and new joined users in existing hash chain-based SGKD schemes is resolved. Moreover, novel methods for utilizing the one-way hash chain and constructing the personal secret, the revocation polynomial and the key updating broadcast packet are presented. Hence, the proposed OHC&RP-SGKD schemes eliminate the limitation of the maximum allowed number of revoked users on the maximum allowed number of sessions, increase the maximum allowed number of revoked/colluding users, and reduce the redundancy in the key updating broadcast packet. Performance analysis and simulation results show that the proposed OHC&RP SGKD schemes are practical for resource-constrained wireless networks in bad environments, where a strong collusion attack resistance is required and many users could be revoked. PMID- 25529203 TI - Sex-dependent differences in renal angiotensinogen as an early marker of diabetic nephropathy. AB - AIM: The renal renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic nephropathy. The aim of this study was to investigate sex differences in renal renin-angiotensin system (RAS) and the roles of androgens in diabetes-associated renal injury. METHODS: Renal injury and fibrosis were studied in streptozotocin-induced diabetic rats by albuminuria and by gene expression of collagen I and fibronectin. RAS was investigated by analysing the plasma angiotensinogen (AOGEN) and renin activity (PRA) and their renal gene expression. Also, a group of diabetic rats was treated with the anti-androgen flutamide. RESULTS: Albuminuria was significantly lower in diabetic females than in males (1.2 [0.8-1.5] versus 4.4 [2.2-6.1] mg/24 h, data are median [IQR] values, P < 0.05). Renal AOGEN mRNA levels were increased by diabetes in males (8.1 +/- 0.8% in diabetes versus 0.8 +/- 0.2% in control, P < 0.001) but not in females (1.0 +/- 0.1% in diabetes versus 0.8 +/- 0.1% in control, P > 0.05), as were collagen I and fibronectin mRNAs. Furthermore, AOGEN mRNA levels were strongly correlated with albuminuria (Spearman r = 0.64, 95% [CI] 0.36-0.81, P < 0.0001). Diabetes decreased PRA, renal renin mRNA and plasma AOGEN in both females and males. Anti-androgen treatment decreased albuminuria only in diabetic males without affecting the endocrine or renal RAS. CONCLUSIONS: These data indicate that renal but not hepatic AOGEN or renin is positively associated with diabetic albuminuria and contribute to the sex-dependent differences in renal injury. Androgens may contribute to albuminuria in male independently of the RAS. PMID- 25529205 TI - Moving target tracking through distributed clustering in directional sensor networks. AB - The problem of moving target tracking in directional sensor networks (DSNs) introduces new research challenges, including optimal selection of sensing and communication sectors of the directional sensor nodes, determination of the precise location of the target and an energy-efficient data collection mechanism. Existing solutions allow individual sensor nodes to detect the target's location through collaboration among neighboring nodes, where most of the sensors are activated and communicate with the sink. Therefore, they incur much overhead, loss of energy and reduced target tracking accuracy. In this paper, we have proposed a clustering algorithm, where distributed cluster heads coordinate their member nodes in optimizing the active sensing and communication directions of the nodes, precisely determining the target location by aggregating reported sensing data from multiple nodes and transferring the resultant location information to the sink. Thus, the proposed target tracking mechanism minimizes the sensing redundancy and maximizes the number of sleeping nodes in the network. We have also investigated the dynamic approach of activating sleeping nodes on-demand so that the moving target tracking accuracy can be enhanced while maximizing the network lifetime. We have carried out our extensive simulations in ns-3, and the results show that the proposed mechanism achieves higher performance compared to the state-of-the-art works. PMID- 25529206 TI - A smart city application: a fully controlled street lighting isle based on Raspberry-Pi card, a ZigBee sensor network and WiMAX. AB - A smart city application has been realized and tested. It is a fully remote controlled isle of lamp posts based on new technologies. It has been designed and organized in different hierarchical layers, which perform local activities to physically control the lamp posts and transmit information with another for remote control. Locally, each lamp post uses an electronic card for management and a ZigBee tlc network transmits data to a central control unit, which manages the whole isle. The central unit is realized with a Raspberry-Pi control card due to its good computing performance at very low price. Finally, a WiMAX connection was tested and used to remotely control the smart grid, thus overcoming the distance limitations of commercial Wi-Fi networks. The isle has been realized and tested for some months in the field. PMID- 25529207 TI - Multi-sensor fusion of Landsat 8 thermal infrared (TIR) and panchromatic (PAN) images. AB - Data fusion is defined as the combination of data from multiple sensors such that the resulting information is better than would be possible when the sensors are used individually. The multi-sensor fusion of panchromatic (PAN) and thermal infrared (TIR) images is a good example of this data fusion. While a PAN image has higher spatial resolution, a TIR one has lower spatial resolution. In this study, we have proposed an efficient method to fuse Landsat 8 PAN and TIR images using an optimal scaling factor in order to control the trade-off between the spatial details and the thermal information. We have compared the fused images created from different scaling factors and then tested the performance of the proposed method at urban and rural test areas. The test results show that the proposed method merges the spatial resolution of PAN image and the temperature information of TIR image efficiently. The proposed method may be applied to detect lava flows of volcanic activity, radioactive exposure of nuclear power plants, and surface temperature change with respect to land-use change. PMID- 25529208 TI - The benefits of soft sensor and multi-rate control for the implementation of Wireless Networked Control Systems. AB - Recent advances in wireless networking technology and the proliferation of industrial wireless sensors have led to an increasing interest in using wireless networks for closed loop control. The main advantages of Wireless Networked Control Systems (WNCSs) are the reconfigurability, easy commissioning and the possibility of installation in places where cabling is impossible. Despite these advantages, there are two main problems which must be considered for practical implementations of WNCSs. One problem is the sampling period constraint of industrial wireless sensors. This problem is related to the energy cost of the wireless transmission, since the power supply is limited, which precludes the use of these sensors in several closed-loop controls. The other technological concern in WNCS is the energy efficiency of the devices. As the sensors are powered by batteries, the lowest possible consumption is required to extend battery lifetime. As a result, there is a compromise between the sensor sampling period, the sensor battery lifetime and the required control performance for the WNCS. This paper develops a model-based soft sensor to overcome these problems and enable practical implementations of WNCSs. The goal of the soft sensor is generating virtual data allowing an actuation on the process faster than the maximum sampling period available for the wireless sensor. Experimental results have shown the soft sensor is a solution to the sampling period constraint problem of wireless sensors in control applications, enabling the application of industrial wireless sensors in WNCSs. Additionally, our results demonstrated the soft sensor potential for implementing energy efficient WNCS through the battery saving of industrial wireless sensors. PMID- 25529209 TI - ReaxFF molecular dynamics simulations on lithiated sulfur cathode materials. AB - Sulfur is a very promising cathode material for rechargeable energy storage devices. However, sulfur cathodes undergo a noticeable volume variation upon cycling, which induces mechanical stress. In spite of intensive investigation of the electrochemical behavior of the lithiated sulfur compounds, their mechanical properties are not very well understood. In order to fill this gap, we developed a ReaxFF interatomic potential to describe Li-S interactions and performed molecular dynamics (MD) simulations to study the structural, mechanical, and kinetic behavior of the amorphous lithiated sulfur (a-LixS) compounds. We examined the effect of lithiation on material properties such as ultimate strength, yield strength, and Young's modulus. Our results suggest that with increasing lithium content, the strength of lithiated sulfur compounds improves, although this increment is not linear with lithiation. The diffusion coefficients of both lithium and sulfur were computed for the a-LixS system at various stages of Li-loading. A grand canonical Monte Carlo (GCMC) scheme was used to calculate the open circuit voltage profile during cell discharge. The Li-S binary phase diagram was constructed using genetic algorithm based tools. Overall, these simulation results provide insight into the behavior of sulfur based cathode materials that are needed for developing lithium-sulfur batteries. PMID- 25529211 TI - The distribution of kisspeptin (Kiss)1- and Kiss2-positive neurones and their connections with gonadotrophin-releasing hormone-3 neurones in the zebrafish brain. AB - Kisspeptin is a neuroendocrine hormone with a critical role in the activation of gonadotrophin-releasing hormone (GnRH) neurones, which is vital for the onset of puberty in mammals. However, the functions of kisspeptin neurones in non mammalian vertebrates are not well understood. We have used transgenics to labell kisspeptin neurones (Kiss1 and Kiss2) with mCherry in zebrafish (Danio rerio). In kiss1:mCherry transgenic zebrafish, Kiss1 cells were located in the dorsomedial and ventromedial habenula, with their nerve fibres contributing to the fasciculus retroflexus and projecting to the ventral parts of the interpeduncular and raphe nuclei. In kiss2:mCherry zebrafish, Kiss2 cells were primarily located in the dorsal zone of the periventricular hypothalamus and, to a lesser extent, in the periventricular nucleus of the posterior tuberculum and the preoptic area. Kiss2 fibres formed a wide network projecting into the telencephalon, the mesencephalon, the hypothalamus and the pituitary. To study the relationship of kisspeptin neurones and GnRH3 neurones, these fish were crossed with gnrh3:EGFP zebrafish to obtain kiss1:mCherry/gnrh3:EGFP and kiss2:mCherry/gnrh3:EGFP double transgenic zebrafish. The GnRH3 fibres ascending to the habenula were closely associated with Kiss1 fibres projecting from the ventral habenula. On the other hand, GnRH3 fibres and Kiss2 fibres were adjacent but scarcely in contact with each other in the telencephalon and the hypothalamus. The Kiss2 and GnRH3 fibres in the ventral hypothalamus projected into the pituitary via the pituitary stalk. In the pituitary, Kiss2 fibres were directly in contact with GnRH3 fibres in the pars distalis. These results reveal the pattern of kisspeptin neurones and their connections with GnRH3 neurones in the brain, suggesting distinct mechanisms for Kiss1 and Kiss2 in regulating reproductive events in zebrafish. PMID- 25529219 TI - A practical guide to the use of thiopurines in oral medicine. AB - Thiopurines are widely used as first-line immunosuppressive therapies in the management of chronic inflammatory oral disease. However, despite over half a century of clinical experience, the evidence base for their use is limited. The aims of this paper were to review the evidence for the use of thiopurines in oral medicine and provide a contemporary model of thiopurine metabolism and mechanism of action and a rationale for clinical use and safe practice. PMID- 25529220 TI - No pain no gain: The positive impact of punishment on the strategic regulation of accuracy. AB - Previous studies have shown that punishing people through a large penalty for volunteering incorrect information typically leads them to withhold more information (metacognitive response bias), but it does not appear to influence their ability to distinguish between their own correct and incorrect answers (metacognitive accuracy discrimination). The goal of the current study was to demonstrate that punishing people for volunteering incorrect information-versus rewarding volunteering correct information-produces more effective metacognitive accuracy discrimination. All participants completed three different general knowledge tests: a reward test (high points for correct volunteered answers), a baseline test (equal points/penalties for volunteered correct/incorrect answers) and a punishment test (high penalty for incorrect volunteered answers). Participants were significantly better at distinguishing between their own correct and incorrect answers on the punishment than reward test, which has implications for situations requiring effective accuracy monitoring. PMID- 25529221 TI - Spatial control of calcineurin in response to heat shock in fission yeast. AB - In fission yeast, Ppb1, the Ca2+/calmodulin-dependent protein phosphatase calcineurin regulates multiple biological processes, such as cytokinesis, Ca2+ homeostasis, membrane trafficking and cell wall integrity. Calcineurin dephosphorylates the Prz1 transcription factor, leading to its nuclear translocation and gene expression under the control of CDRE (calcineurin dependent response element). Although the calcineurin-mediated spatial control of downstream transcription factors has been intensively studied in many organisms, less is known about the spatial regulation of calcineurin on stresses. Here, we show that heat shock stimulates calcineurin-dependent nuclear translocation of Prz1 and CDRE-dependent gene expression. Notably, calcineurin exhibited a dramatic change in subcellular localization, translocating from diffuse cytoplasmic to dot-like structures on heat shock. The calcineurin dots colocalized with Dcp2 or Pabp, the constituent of P-bodies or stress granules, respectively, thus suggesting that calcineurin is a component of RNA granules under heat shock. Importantly, the calcineurin inhibitor FK506 markedly inhibited the accumulation of calcineurin granules, whereas the constitutively active calcineurin strongly accumulated in the granules on heat shock, suggesting that phosphatase activity is important for calcineurin localization. Notably, the depletion of calcineurin induced a rapid appearance of Nrd1- and Pabp-positive RNA granules. The possible roles of calcineurin in response to heat shock will be discussed. PMID- 25529222 TI - Evaluation of Novel Microabrasion Paste as a Dental Bleaching Material and Effects on Enamel Surface. AB - PURPOSE: Dental fluorosis is an enamel dysplasia that can cause serious aesthetic and psychological problems. An examination of the literature shows that the microabrasion method is the most effective way to treat fluorosis. This study aimed to produce a prototype microabrasion paste for the treatment of fluorosis stains and to examine the effects of the paste on tooth structure and color in vitro. MATERIAL AND METHODS: Forty extracted upper incisor teeth were used in this study. The teeth were divided into four treatment groups: a prototype microabrasion paste group (N = 10), an Opalustre paste group (N = 10), a 37% phosphoric acid gel group (N = 10), and a distilled water (control) group (N = 10). Following treatment, all specimens in each of the four groups were examined by scanning electron microscopy for changes in their surface enamel. Changes in tooth color changes of the 1st and 2nd groups were measured before and after treatment by a VITA Easyshade Advance spectrophotometer. RESULTS: In scanning electron microscopy evaluations, significant differences were not observed between the 1st and 2nd groups. Differences in three color-measuring coordinates between the 1st and 2nd were also not statistically significant (p > 0.05). CONCLUSIONS: The study demonstrated that the prototype paste is a viable treatment option for dental fluorosis. CLINICAL SIGNIFICANCE: The findings in this study demonstrated that the tested prototype microabrasion paste is extremely harmless, minimally invasive agent, and able to improve the color, shine and chrome values of the teeth. PMID- 25529223 TI - Changes in management and outcomes for children and adolescents with type 1 diabetes over the last 50 years. AB - Over the 50 years from 1964 to 2014, outcomes for children with type 1 diabetes have improved significantly, because of both technological advancements and changes in management philosophy. For the child with type 1 diabetes in 2014, intensive management with multiple daily injections or insulin pump therapy and the support of a specialist multidisciplinary team is now standard care. The main treatment goal is no longer the avoidance of hypoglycaemia, but the minimisation of hyperglycaemia and glucose variability, thereby reducing the risk of microvascular complications. However, the inherent burden of care and diligence required by patients and families, if they are to maintain optimal diabetes control, have not changed and may even have increased. While the long sought after cure for diabetes remains elusive, artificial pancreas or closed-loop systems hold the most promise for improving the burden of care in the near term for children and adolescents with type 1 diabetes. PMID- 25529224 TI - Criticisms of drugs in early development for the treatment of depression: what can be improved? AB - Major depressive disorder (MDD) is a common and debilitating mental illness, which leads to serious functional impairment in patients, and treatment-wise, there are currently a number of different classes of antidepressants already on the market. However, emerging evidence from numerous clinical trials has confirmed that there is still an unmet need for antidepressant efficacy in terms of response and remission. Approximately only 30% of patients with MDD may remit after adequate treatment with antidepressants in clinical practice. The drawbacks of the currently available antidepressants also include inadequate overall efficacy, safety issues and the lag prior to onset of clinical improvement. The need for new agents with novel mechanisms of action has led to the development of several newer antidepressants including vilazodone, edivoxetine, ketamine, atomoxetine and vortioxetine, which have been approved for the treatment of MDD. However, the efficacy and safety of these next-generation antidepressants, in clinical trials, are still unsatisfactory. This paper provides a brief updated overview of the progress and critical limitations in the development of novel antidepressants. PMID- 25529225 TI - Drug-drug interaction software in clinical practice: a systematic review. AB - PURPOSE: Several electronic databases which report the prevalence of drug-drug interactions (DDIs) are used as a tool for evaluation of potentially harmful DDIs. The aim of our review was to evaluate the usability and appropriateness of commercially available electronic databases which assess the prevalence of potential DDIs. METHODS: The systematic electronic literature search was conducted with the following search terms: "database" AND "software," and "drug drug interactions" AND "database," and the inclusion and exclusion criteria were applied in order to identify the publications of interest. RESULTS: A total of 3766 papers were identified by systematic search. After applying inclusion and exclusion criteria, 38 publications were included in the analysis. The most commonly used software in the included studies was Micromedex(r) Drug-Reax, for which some authors argue to be the most reliable due to highest sensitivity. It gives information about clinical consequences of DDIs, classifies underlying mechanism and onset of the adverse outcome (either rapid, or delayed) as well as severity (such as minor, moderate, or major), and provides the level of evidence which supports this information. This data is also provided by Drug Interaction Facts(r), Lexi-Interact(r), and Pharmavista(r). A small number of studies which compared assessment of DDIs with electronic database and the clinician's assessment showed large discrepancy in number and relevance of detected DDIs. The overlap was in some cases as low as 11 %. CONCLUSION: The deficiency of clinical relevance of detected DDIs should be addressed in the upcoming research as it would provide more relevant information to the prescribers' in clinical practice. PMID- 25529226 TI - Does age modify the relationship between adherence to secondary prevention medications and mortality after acute myocardial infarction? A nested case control study. AB - PURPOSE: Clinical trials have shown that evidence-based secondary prevention medications reduce mortality after acute myocardial infarction (AMI). Yet, these medications are generally underused in daily practice, and older people are often excluded from drug trials. The purpose of this study was to examine whether the relationship between adherence to evidence-based drugs and post-AMI mortality varies with increasing age. METHODS: The study population was defined as all residents in the Local Health Authority of Bologna (Italy) hospitalized for AMI between January 1, 2008 and June 30, 2011, and followed up until December 31, 2012. Medication adherence was calculated as the proportion of days covered (PDC) for filled prescriptions of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, antiplatelet drugs, and statins; patients were classified as adherent (PDC >=75 %) or nonadherent (PDC <75 %). We used incidence density sampling, and the moderating effect of age on the relationship between adherence and mortality was investigated through conditional multiple logistic regression analysis. RESULTS: The study population comprised 3963 patients. During the 5-year study period, 1085 deaths (27.4 %) were observed. For both younger and older patients, adherence to polytherapy (three or four medications) was associated with lower mortality (adj. rate ratio = 0.41; P < 0.001). A significant inverse relationship was found between adherence to each of the four medications and mortality, although the risk reduction associated with antiplatelet therapy declined after the age of 70-75. CONCLUSIONS: The beneficial effect of evidence-based polytherapy on mortality following AMI is observed also in older populations. Nevertheless, the risk-benefit ratio associated with antiplatelet therapy is less favorable with increasing age. PMID- 25529227 TI - Side effects related to potentially inappropriate medications in elderly psychiatric patients under everyday pharmacotherapy. AB - PURPOSE: Potentially inappropriate medication (PIM) is suggested to give rise to adverse drug events. To study this suggestion for elderly psychiatric patients, an observational analysis related prescription of PRISCUS PIMs and drug-induced side effects in old aged (>=65 years) psychiatric inpatients and outpatients under conditions of everyday pharmacotherapy. METHODS: Request forms from a therapeutic drug monitoring (TDM) survey and medical files were screened for medication to identify PIMs of the PRISCUS list and assessed using the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale. RESULTS: From 914 TDM request forms, data were available for 168 patients (64.3 % female). Patients (mean +/- SD age 73.0 +/- 5.5 years) received by mean 6.4 +/- 3.9 drugs per day. More than half of them (53.0 %, n = 89) had at least one PIM, inpatients 0.9 +/- 0.8 and outpatients 0.5 +/- 0.7. Predominant PIMs were hypnotic drugs (69 %) in inpatients and antipsychotic drugs (35.6 %) in outpatients. The number of PIMs correlated with the total number of drugs administered per day (Spearman correlation coefficient 0.225, p < 0.01, CI 95 %). Side effects were documented for 106 patients (63 %). Severity of side effects did not correlate significantly (p > 0.05) with number of PIMs. However, only 6 of 77 patients who took no PRISCUS PIMs but 2 of 3 patients who took 3 PRISCUS PIMs exhibited severe side effects. CONCLUSIONS: Though the prevalence for PIMs and side effects was high in old aged psychiatric inpatients and outpatients, PIMs could not be identified as major determinants of overall unwanted side effects. Nevertheless, prescription of PIMs should be minimized, especially of hypnotic drugs, to improve safety. PMID- 25529228 TI - Old and new immunophenotypic markers in multiple myeloma for discrimination of responding and relapsing patients: The importance of "normal" residual plasma cell analysis. AB - BACKGROUND: Multiple myeloma is an incurable disease characterized by proliferation of clonal malignant plasma cells (CPCs), which can be immunophenotypically distinguished from polyclonal plasma cells (PPCs) by multiparameter flow cytometry (MFC). The utility of PPCs analysis in detecting prognostic and predictive information is still a matter of debate. METHODS: we tested the ability of 11 MFC markers in detecting differences in the immunophenotype of CPCs and PPCs among patients in various disease stages; we verified if these markers could be associated with disease stage/response to therapy despite the role of clinical parameters. RESULTS: significant changes in the expression of markers occurred both in CPCs and PPCs. CD58 on PPCs of responding patients was downregulated compared with PPC of relapsing group. Fraction of CD200 expressing PCs was lower in control subjects than in PPCs from MGUS and myeloma groups. CD11a levels of expression on both CPCs and PPCs showed an upregulation in newly diagnosed and relapsing patients versus PCs of controls; CD20 was less expressed on control PCs than on MGUS CPCs and PPCs. CD49d revealed to be advantageous in discrimination of PPCs from CPCs. In our multiple regression model, CD19 and CD49d on CPCs, and CD45, CD58 and CD56 on PPCs maintained their association with groups of patients independently of other prognostic variables. CONCLUSIONS: we provide a feasible start point to put in order ranges of expression on PPCs in healthy and myeloma subjects; we propose a new approach based on PPC analysis to monitor the stages of the disease. PMID- 25529230 TI - Controlling the reactivity of the Se-Se bond by the supramolecular chemistry of cucurbituril. AB - We describe a new strategy to control the reactivity of Se?Se bond by using supramolecular chemistry of cucurbituril. We have demonstrated that selenocystamine (SeCy) and cucurbit[6]uril (CB[6]) can form a stable supramolecular complex (Ka =5.5*10(6) M(-1) ). Before complexation, the free Se?Se bond in SeCy is rather sensitive to redox stimuli and gets disrupted quickly with addition of reductant or oxidant. However, after binding with CB[6], the Se?Se bond becomes quite inert and hardly reacts with reductant or oxidant. One advantage of this supramolecular protection is that it can be applied in a wide pH range from weakly acidic to basic. Additionally, the supramolecular complex formed by SeCy and CB[6] can be reversibly dissociated simply with addition of Ba(2+) . PMID- 25529229 TI - Meeting report VLPNPV: Session 3: Immune responses. AB - Virus-like particles (VLPs) and nano-particles (NP) are increasingly considered for both prophylactic and therapeutic vaccines for a wide variety of human and animal diseases. Indeed, 2 VLPs have already been licensed for use in humans, the human papilloma virus vaccine and the hepatitis B virus vaccine. (1) Reflecting this increased interest, a second international conference with a specific focus on VLPs and NP was held at the Salk Institute for Biological Studies in La Jolla, California, in June 2014. Approximately 100 attendees, hailing from many nations, came from academic institutions, research institutes, and biotech companies. A wide variety of topics were discussed, ranging from development and characterization of specific VLP and NP vaccine candidates to methods of production of these particles. Session three was focused on the general question of immune responses to VLPs. PMID- 25529231 TI - Suppression of graft-versus-host disease and retention of graft-versus-tumour reaction by murine genetically engineered dendritic cells following bone marrow transplantation. AB - The effect of infusion of lentiviral vector-mediated, genetically engineered dendritic cells (DCs) following allogeneic bone marrow transplantation (allo-BMT) on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) was investigated in a mouse model. Lentivirus-mediated expression of soluble tumor necrosis factor receptor 1 (sTNFR1) converted immature DCs (imDCs) from BABL/c mice into engineered DCs in vitro. An EL4 leukemia allo-BMT model of BABL/c to C57BL/6 mice was established. Engineered DCs with donor bone marrow cells and splenocytes were subsequently transplanted into myeloablatively irradiated recipients. The average survival duration in the sTNFR1- and pXZ9-imDC groups was significantly prolonged compared with that of the allo-BMT group (P<0.05). Mild histological changes in GVHD or leukemia were observed in the recipients in the sTNFR1-imDC group and clinical GVHD scores in this group were significantly decreased compared with those of the transplantation and pXZ9-imDC groups. Serum interferon-gamma levels were decreased in the pXZ9-imDC and sTNFR1-imDC groups compared with those in the allo-BMT group (P<0.05), with the reduction being more significant in the sTNFR1-imDC group (P<0.05). Serum interleukin-4 expression levels were decreased in the allo-BMT group, but gradually increased in the pXZ9 imDC and sTNFR1-imDC groups (P<0.05). Co-injection of donor genetically engineered imDCs was able to efficiently protect recipient mice from lethal GVHD while preserving GVL effects during allo-BMT. PMID- 25529232 TI - An innovative oat-based sterile emollient cream in the maintenance therapy of childhood atopic dermatitis. AB - Although emollients are recommended in the management of atopic dermatitis (AD), regimens for emollient maintenance therapy are awaiting validation. We conducted an international, multicenter, open-label trial to assess the effects of a 3 month maintenance treatment regimen with a sterile, preservative-free emollient cream containing oat plantlets in children (ages 6 mos-6 yrs) with moderate AD. After a 14-day run-in stabilization phase using a topical corticosteroid (TCS) treatment of medium potency, 108 children with a SCORing Atopic Dermatitis (SCORAD) index of 20 or less were included in the study. Emollient was applied twice daily for 3 months. Rescue TCS treatment was used only in cases of flare ups. The SCORAD index, Patient-Oriented SCORAD (PO-SCORAD) index, number of flares, TCS use, and tolerance were assessed at months 1, 2, and 3 (M1, M2, M3). AD severity improved, with a highly significant decrease in the SCORAD and PO SCORAD indexes at M2 and M3 (p < 0.001). Changes from baseline to M3 were 48.6 +/ 73.6% for SCORAD and 29.6 +/- 125.3% for PO-SCORAD. The number of flares and TCS use significantly decreased by M3 (both p < 0.001). Very good tolerance was recorded in 100% of children at M2 and M3. Notwithstanding the limitations inherent in open-label trials, twice daily application of the oat-based sterile emollient cream led to a significant improvement of clinical symptoms, evidenced by parallel changes in the SCORAD and PO-SCORAD indexes and fewer flare-ups. Clinical benefit and less TCS use were maintained at M3. Tolerance was very good. PMID- 25529233 TI - Differentiating the evolution of female song and male-female duets in the New World blackbirds: can tropical natural history traits explain duet evolution? AB - Female bird song and combined vocal duets of mated pairs are both frequently associated with tropical, monogamous, sedentary natural histories. Little is known, however, about what selects for duetting behavior versus female song. Female song likely preceded duet evolution and could drive apparent relationships between duets and these natural histories. We compared the evolution of female song and male-female duets in the New World blackbirds (Icteridae) by investigating patterns of gains and losses of both traits and their relationships with breeding latitude, mating system, nesting pattern, and migratory behavior. We found that duets evolved only in lineages in which female song was likely ancestral. Both female song and duets were correlated with tropical breeding, social monogamy, territorial nesting, and sedentary behavior when all taxa were included; however, correlations between duets and these natural history traits disappeared when comparisons were limited to taxa with female song. Also, likelihood values supported stronger relationships between the natural history traits and female song than between these traits and duets. Our results suggest that the natural histories thought to favor the evolution of duetting may in fact be associated with female song and that additional selection pressures are responsible for the evolution of duets. PMID- 25529235 TI - Intraoral reconstruction with "thinned" peroneal artery perforator flaps: An alternative to classic donor areas in comorbid patients. AB - Free fasciocutaneous flaps like the radial forearm free flap (RFFF) and the anterolateral thigh (ALT) are the most commonly used flaps in intraoral reconstruction. However, certain conditions preclude the use of either of these flaps. The aim of this report was to show applicability of "thinned" peroneal artery perforator (PAP) flaps in intraoral reconstruction. We report two cases of squamous cell carcinoma involving the tongue and floor of the mouth, where one patient had advanced scleroderma with tight forearm skin and the other with a history of Reynaud's disease precluding the use of RFFF. In addition, both patients were morbidly obese with thick adipose tissue in the thigh making ALT flap not a suitable option. Instead, a PAP flap was chosen. After the harvest, the subcutaneous tissue thickness was measured to be 2.2 and 1.8 cm, respectively. The thinning was performed by removing the deep fat lobules of the superficial fat layer down to a final thickness of 0.4 and 0.3 cm, respectively. A 2 * 2 cm area surrounding the perforators were kept untouched. Both patients had uneventful postoperative course with one patient having a small donor area dehiscence that healed with local wound care. The functional outcomes at 1 year were good. "Thinned" PAP flap is a unique and novel application that may be an alternative in intraoral reconstruction when primary choices are not available. PMID- 25529236 TI - The Anatomical Record by the numbers: seeing anatomy through the lens of mathematics and geometry. PMID- 25529234 TI - The compact mitochondrial genome of Zorotypus medoensis provides insights into phylogenetic position of Zoraptera. AB - BACKGROUND: Zoraptera, generally regarded as a member of Polyneoptera, represents one of the most enigmatic insect orders. Although phylogenetic analyses based on a wide array of morphological and/or nuclear data have been performed, the position of Zoraptera is still under debate. Mitochondrial genome (mitogenome) information is commonly considered to be preferable to reconstruct phylogenetic relationships, but no efforts have been made to incorporate it in Zorapteran phylogeny. To characterize Zoraptera mitogenome features and provide insights into its phylogenetic placement, here we sequenced, for the first time, one complete mitogenome of Zoraptera and reconstructed the phylogeny of Polyneoptera. RESULTS: The mitogenome of Zorotypus medoensis with an A+T content of 72.50% is composed of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a noncoding A+T-rich region. The gene content and arrangement are identical to those considered ancestral for insects. This mitogenome shows a number of very unusual features. First, it is very compact, comprising 14,572 bp, and is the smallest among all known polyneopteran mitogenomes. Second, both noncoding sequences and coding genes exhibit a significant decrease in size compared with those of other polyneopterans. Third, Z. medoensis mitogenome has experienced an accelerated substitution rate. Fourth, truncated secondary structures of tRNA genes occur with loss of dihydrouridine (DHU) arm in trnC, trnR, and trnS(AGN) and loss of TPsiC arm in trnH and trnT. The phylogenetic analyses based on the mitogenome sequence information indicate that Zoraptera, represented by Z. medoensis, is recovered as sister to Embioptera. However, both Zoraptera and Embioptera exhibit very long branches in phylogenetic trees. CONCLUSIONS: Characterization of Z. medoensis mitogenome contributes to our understanding of the enigmatic Zoraptera. Mitogenome data demonstrate an overall strong resolution of deep-level phylogenies of Polyneoptera but not Insecta. It is preferable to expand taxon sampling of Zoraptera and other poorly represented orders in future to break up long branches. PMID- 25529237 TI - Through the eyes of Galileo's heirs: deciphering the laws of nature through the language of mathematics. PMID- 25529238 TI - Three-dimensional geometric morphometric analysis of the nasopharyngeal boundaries and its functional integration with the face and external basicranium among extant hominoids. AB - The nasopharynx is a centrally located but understudied upper respiratory tract component. This study tested hypotheses related to the functional integration of the nasopharyngeal boundaries with the facial skeleton and external basicranium over the course of development in humans and nonhuman hominoids. It was hypothesized that facial morphology (width, length, and kyphosis) is related to nasopharyngeal width and choanal morphology, whereas relative external basicranial proportions are related to nasopharyngeal depth. Human infants were used as models of extreme orthognathy and external basicranial retroflexion, whereas nonhuman hominoids were used to model greater relative prognathism and external basicranial retroflexion. Both of these groups were contrasted against adult humans, who exhibit both extreme orthognathy and external basicranial flexion. Three-dimensional landmark coordinate data were collected from age graded series of Homo, Pan, Gorilla, Pongo, and Hylobates. Generalized Procrustes Analysis was performed, and multivariate shape differences were evaluated via principal components analysis. Additionally, linear measures were extracted from the Procrustes-corrected sets of landmark data. Results indicate that human adults are indeed distinct from all groups in possessing a relatively shallow nasopharyngeal roof and shorter, more flexed external basicranial axis. Human adults and infants both exhibit greater relative choanal and nasopharyngeal width. Nonhuman hominoid faces tended to become airorhynch into adulthood, whereas humans exhibited the opposite trend. When pooling all the hominoids, facial width and palate length were strongly correlated with choanal and nasopharyngeal width, whereas facial kyphosis was strongly correlated with choanal orientation. The hypotheses were supported as the results indicated a morphologic relationship among nasopharyngeal boundaries, the facial skeleton, and the external basicranium. PMID- 25529241 TI - Phenetic and functional analyses of the distal ulna of Australopithecus afarensis and Australopithecus africanus. AB - The morphology of the distal portion of the hominoid ulna is poorly studied despite its important functional role at the wrist joint. There are five qualitatively well-described fossil hominin distal ulnae belonging to Australopithecus afarensis and Australopithecus africanus, but there have been few efforts to quantify their morphology or relate it to their functional abilities. This article presents an effort to do so, using three-dimensional geometric morphometrics to analyze the shape of the distal ulna of the Plio Pleistocene hominins and an extant comparative sample of great apes and humans. For the extant taxa, results show that the morphology of Pan and Pongo is distinct from that of Homo, and that these differences are likely related to climbing, clambering and below-branch suspension in the former, and the release of the limbs from locomotion and (potentially) tool manufacture in the latter. For the australopiths, results indicate that the A. afarensis sample is relatively heterogeneous. These results are driven by the morphology of A.L. 333 12, which is the largest ulna in the sample and has a unique combination of traits when compared with the other two A. afarensis specimens. Overall, the morphology of all the hominins was most consistent with the pattern displayed by extant great apes, and specifically Pan and Pongo; however, large overlap in shape in the distal ulna in the extant sample indicates that other areas of the skeleton may be more informative for functional analyses. PMID- 25529239 TI - Biomechanical implications of intraspecific shape variation in chimpanzee crania: moving toward an integration of geometric morphometrics and finite element analysis. AB - In a broad range of evolutionary studies, an understanding of intraspecific variation is needed in order to contextualize and interpret the meaning of variation between species. However, mechanical analyses of primate crania using experimental or modeling methods typically encounter logistical constraints that force them to rely on data gathered from only one or a few individuals. This results in a lack of knowledge concerning the mechanical significance of intraspecific shape variation that limits our ability to infer the significance of interspecific differences. This study uses geometric morphometric methods (GM) and finite element analysis (FEA) to examine the biomechanical implications of shape variation in chimpanzee crania, thereby providing a comparative context in which to interpret shape-related mechanical variation between hominin species. Six finite element models (FEMs) of chimpanzee crania were constructed from CT scans following shape-space Principal Component Analysis (PCA) of a matrix of 709 Procrustes coordinates (digitized onto 21 specimens) to identify the individuals at the extremes of the first three principal components. The FEMs were assigned the material properties of bone and were loaded and constrained to simulate maximal bites on the P(3) and M(2) . Resulting strains indicate that intraspecific cranial variation in morphology is associated with quantitatively high levels of variation in strain magnitudes, but qualitatively little variation in the distribution of strain concentrations. Thus, interspecific comparisons should include considerations of the spatial patterning of strains rather than focus only on their magnitudes. PMID- 25529242 TI - Exploring phylogenetic and functional signals in complex morphologies: the hamate of extant anthropoids as a test-case study. AB - Three-dimensional geometric morphometrics (3DGM) is a powerful tool for capturing and visualizing the "pure" shape of complex structures. However, these shape differences are sometimes difficult to interpret from a functional viewpoint, unless specific approaches (mostly based on biomechanical modeling) are employed. Here, we use 3DGM to explore the complex shape variation of the hamate, the disto ulnar wrist bone, in anthropoid primates. Major trends of shape variation are explored using principal components analysis along with analyses of shape and size covariation. We also evaluate the phylogenetic patterning of hamate shape by plotting an anthropoid phylogenetic tree onto the shape space (i.e., phylomorphospace) and test against complete absence of phylogenetic signal using posterior permutation. Finally, the covariation of hamate shape and locomotor categories is explored by means of 2-block partial least squares (PLS) using shape coordinates and a matrix of data on arboreal locomotor behavior. Our results show that 3DGM is a valuable and versatile tool for characterizing the shape of complex structures such as wrist bones in anthropoids. For the hamate, a significant phylogenetic pattern is found in both hamate shape and size, indicating that closely related taxa are typically the most similar in hamate form. Our allometric analyses show that major differences in hamate shape among taxa are not a direct consequence of differences in hamate size. Finally, our PLS indicates a significant covariation of hamate shape and different types of arboreal locomotion, highlighting the relevance of this approach in future 3DGM studies seeking to capture a functional signal from complex biological structures. PMID- 25529240 TI - The feeding biomechanics and dietary ecology of Paranthropus boisei. AB - The African Plio-Pleistocene hominins known as australopiths evolved derived craniodental features frequently interpreted as adaptations for feeding on either hard, or compliant/tough foods. Among australopiths, Paranthropus boisei is the most robust form, exhibiting traits traditionally hypothesized to produce high bite forces efficiently and strengthen the face against feeding stresses. However, recent mechanical analyses imply that P. boisei may not have been an efficient producer of bite force and that robust morphology in primates is not necessarily strong. Here we use an engineering method, finite element analysis, to show that the facial skeleton of P. boisei is structurally strong, exhibits a strain pattern different from that in chimpanzees (Pan troglodytes) and Australopithecus africanus, and efficiently produces high bite force. It has been suggested that P. boisei consumed a diet of compliant/tough foods like grass blades and sedge pith. However, the blunt occlusal topography of this and other species suggests that australopiths are adapted to consume hard foods, perhaps including grass and sedge seeds. A consideration of evolutionary trends in morphology relating to feeding mechanics suggests that food processing behaviors in gracile australopiths evidently were disrupted by environmental change, perhaps contributing to the eventual evolution of Homo and Paranthropus. PMID- 25529243 TI - A new fully automated approach for aligning and comparing shapes. AB - Three-dimensional geometric morphometric (3DGM) methods for placing landmarks on digitized bones have become increasingly sophisticated in the last 20 years, including greater degrees of automation. One aspect shared by all 3DGM methods is that the researcher must designate initial landmarks. Thus, researcher interpretations of homology and correspondence are required for and influence representations of shape. We present an algorithm allowing fully automatic placement of correspondence points on samples of 3D digital models representing bones of different individuals/species, which can then be input into standard 3DGM software and analyzed with dimension reduction techniques. We test this algorithm against several samples, primarily a dataset of 106 primate calcanei represented by 1,024 correspondence points per bone. Results of our automated analysis of these samples are compared to a published study using a traditional 3DGM approach with 27 landmarks on each bone. Data were analyzed with morphologika(2.5) and PAST. Our analyses returned strong correlations between principal component scores, similar variance partitioning among components, and similarities between the shape spaces generated by the automatic and traditional methods. While cluster analyses of both automatically generated and traditional datasets produced broadly similar patterns, there were also differences. Overall these results suggest to us that automatic quantifications can lead to shape spaces that are as meaningful as those based on observer landmarks, thereby presenting potential to save time in data collection, increase completeness of morphological quantification, eliminate observer error, and allow comparisons of shape diversity between different types of bones. We provide an R package for implementing this analysis. PMID- 25529245 TI - Enhanced jump performance when providing augmented feedback compared to an external or internal focus of attention. AB - Factors such as an external focus of attention (EF) and augmented feedback (AF) have been shown to improve performance. However, the efficacy of providing AF to enhance motor performance has never been compared with the effects of an EF or an internal focus of attention (IF). Therefore, the aim of the present study was to identify which of the three conditions (AF, EF or IF) leads to the highest performance in a countermovement jump (CMJ). Nineteen volunteers performed 12 series of 8 maximum CMJs. Changes in jump height between conditions and within the series were analysed. Jump heights differed between conditions (P < 0.001), resulting in best performance with AF (32.04 +/- 7.11 cm), followed by EF (31.21 +/- 6.67 cm) and IF (30.77 +/- 6.87 cm). Significantly different (P < 0.001) within-series effects of higher jump heights at the end of the series in AF (+1.60%) and lower jump heights at the end of the series in EF (-1.79%) and IF ( 1.68%) were observed. Muscle activity did not differ between conditions. The differences between conditions and within the series provide evidence that AF leads to higher performance and better progression within one series than EF and IF. Consequently, AF seems to outperform EF and IF when maximising jump height. PMID- 25529246 TI - Screening for sulfate in distillers dried grains and solubles by FT-IR spectroscopy. AB - Distillers Dried Grains and Solubles (DDGS) are an animal feed containing varying levels of sulfur. As ruminants are susceptible to high sulfur diets, sulfur content is of major interest to the parties involved. The variation in levels of sulfur in DDGS is mainly due to sulfate derived from the addition of sulfuric acid during the production. ATR/FT-IR spectroscopy was used to determine sulfate levels in 90 DDGS samples from various origins (Canada, China, EU, and U.S.A.). Specific absorption bands for sulfate at 615 and 1107 cm(-1) enabled the analysis of sulfate in the DDGS matrix. Besides direct quantification (using band at 615 cm(-1)), PLS regression was applied for the prediction of sulfate using FT-IR spectra and calibration with reference values analyzed by capillary electrophoresis. An extended calculation on the total sulfur estimated that 11% of the DDGS samples analyzed in this study featured sulfur contents higher than 0.80%. PMID- 25529247 TI - Outcome after liver resection in patients presenting with simultaneous hepatopulmonary colorectal metastases. AB - BACKGROUND: The most common sites of metastasis from colorectal cancer (CRC) are hepatic and pulmonary; they can present simultaneously (hepatic and pulmonary metastases) or sequentially (hepatic then pulmonary metastases, or vice versa). Simultaneous disease may be aggressive, and thus may be approached with caution by the clinician. The aim of this study was to determine the outcomes following hepatic and pulmonary resection for simultaneously presenting metastatic CRC. METHODS: A retrospective review was undertaken of a prospectively maintained database to identify patients presenting with simultaneous hepatopulmonary disease who underwent hepatic resection. Patients' electronic records were used to identify clinicopathological variables. The log rank test was used to determine survival, and chi(2) analysis to determine predictors of failure of intended treatment. RESULTS: Fifty-nine patients were identified and underwent hepatic resection; median survival was 45.4 months and the 5-year survival rate 38 per cent. Twenty-two patients (37 per cent) did not have the intended pulmonary intervention owing to progression or recurrence of disease. Thirty seven patients who progressed to hepatopulmonary resection had a median survival of 54.2 months (5-year survival rate 43 per cent). Those who had hepatic resection alone had a median survival of 24.0 months (5-year survival rate 30 per cent). Failure to progress to pulmonary resection was predicted by heavy nodal burden of primary colorectal disease and bilobar hepatic metastases. Redo pulmonary surgery following pulmonary recurrence did not confer a survival benefit. CONCLUSION: Selected patients with simultaneous hepatopulmonary CRC metastases should be considered for attempted curative resection, but some patients may not receive the intended treatment owing to progression of pulmonary disease after hepatic resection. PMID- 25529248 TI - Inverse kinetic solvent isotope effect in TiO2 photocatalytic dehalogenation of non-adsorbable aromatic halides: a proton-induced pathway. AB - An efficient redox reaction between organic substrates in solution and photoinduced h(+) vb /e(-) cb on the surface of photocatalysts requires the substrates or solvent to be adsorbed onto the surface, and is consequentially marked by a normal kinetic solvent isotope effect (KSIE >= 1). Reported herein is a universal inverse KSIE (0.6-0.8 at 298 K) for the reductive dehalogenation of aromatic halides which cannot adsorb onto TiO2 in a [D0 ]methanol/[D4 ]methanol solution. Combined with in situ ATR-FTIR spectroscopy investigations, a previously unknown pathway for the transformation of these aromatic halides in TiO2 photocatalysis was identified: a proton adduct intermediate, induced by released H(+) /D(+) from solvent oxidation, accompanies a change in hybridization from sp(2) to sp(3) at a carbon atom of the aromatic halides. The protonation event leads these aromatic halides to adsorb onto the TiO2 surface and an ET reaction to form dehalogenated products follows. PMID- 25529254 TI - A systematic review of mindfulness and acceptance-based treatments for social anxiety disorder. AB - CONTEXT: The cultivation of mindfulness and acceptance has been theoretically and empirically associated with psychological ancillary well-being and has demonstrated efficacy in the treatment of various disorders. Hence, mindfulness and acceptance-based treatments (MABTs) have recently been explored for the treatment of social anxiety disorder (SAD). This review aims to evaluate the benefits of MABTs for SAD. METHODS: Systematic review of studies investigating an MABT for individuals with SAD, using PsycInfo, Medline, PubMed, and Cochrane Central Register of Controlled Trials. RESULTS: Nine studies were identified. Significant improvements in symptomatology were demonstrated following the MABT, but benefits were equivalent or less than yielded by cognitive-behavioral therapy (CBT). LIMITATIONS: The few treatment studies available were compromised by significant methodological weaknesses and high risk of bias across domains. Studies were largely uncontrolled with small sample sizes. The hybrid nature of these interventions creates ambiguity regarding the specific utility of treatment components or combinations. CONCLUSIONS: MABTs demonstrate significant benefits for reducing SAD symptomatology; however, outcomes should be interpreted with caution until appropriate further research is conducted. Furthermore, the benefit of MABTs above and beyond CBT must be considered tentative at best; thus, CBT remains best practice for first-line treatment of SAD. PMID- 25529255 TI - Dorsal root ganglion pulsed radiofrequency for the management of intractable vertebral metastatic pain: a case series. AB - OBJECTIVE: Metastatic bone pain is characteristic of cancer pain and is a form of refractory cancer pain, as the pain includes not only nociceptive but also neuropathic pain. Although some drugs are effective in the management of painful bone metastases, pain while moving is one of the most refractory forms of pain. Although pulsed radiofrequency (RF) dramatically reduces neuropathic pain, chronic pain, and vertebral metastatic pain, the number of cases reported in these studies was very small (five or less). DESIGN: Case report. SETTING: Single pain center. PATIENTS: Fifteen patients suffering from intractable vertebral metastatic pain. INTERVENTIONS: Dorsal root ganglion (DRG) pulsed RF. OUTCOME MEASURES: A numerical rating scale (NRS) of pain at rest and while moving. RESULTS: Almost all patients experienced sound pain relief after the pulsed RF treatment. There were no severe side effects reported. CONCLUSION: DRG pulsed RF procedure provided sound pain relief for patients with intractable vertebral metastatic pain. Metastatic bone pain is characteristic of cancer pain and is a form of refractory cancer pain, as the pain includes not only nociceptive but also neuropathic pain. Although some drugs are effective in the management of painful bone metastases, pain while moving is one of the most refractory forms of pain. DRG pulsed RF procedure provided sound pain relief for patients with intractable vertebral metastatic pain. PMID- 25529256 TI - Marker-free automated histopathological annotation of lung tumour subtypes by FTIR imaging. AB - By integration of FTIR imaging and a novel trained random forest classifier, lung tumour classes and subtypes of adenocarcinoma are identified in fresh-frozen tissue slides automated and marker-free. The tissue slices are collected under standard operation procedures within our consortium and characterized by current gold standards in histopathology. In addition, meta data of the patients are taken. The improved standards on sample collection and characterization results in higher accuracy and reproducibility as compared to former studies and allows here for the first time the identification of adenocarcinoma subtypes by this approach. The differentiation of subtypes is especially important for prognosis and therapeutic decision. PMID- 25529257 TI - The stages of recovery in relation to the other subjective and objective aspects of psychosis. AB - The Stages of Recovery Instrument (STORI; Andresen et al., 2006) was used among 110 patients with psychosis. Recovery stages relationship with attribution, the way of experiencing illness and its phase and symptoms were analyzed. The samples were drawn from treatment facility including in-patient unit. The subgroups of recovering patients were identified: moratorium (27%), awareness (32%), preparation (30%) and rebuilding (11%). The achievement of higher stages of the recovery was correlated with: less severe symptoms of psychosis (with the exception of anxiety and depression, which have no impact on the stages of recovery), medical attribution (I am ill), integrative attitude toward the experience of psychosis, and the absence of involuntary hospitalizations. The logistic regression analysis model indicated the independent significance of the medical attribution, the integrating attitude toward psychotic experience and the remission of symptoms. Other clinical variables and social characteristics did not differentiate between the stages of recovery in any significant way. No juxtaposition as such was found between the processes of recovery and being ill, but rather a complementary relation. Recovery has been found to be enhanced by the remission of psychotic symptoms, medical attribution and integrative attitude toward the experience of psychotic crisis. PMID- 25529258 TI - Plasma catecholamine levels before and after paroxetine treatment in patients with panic disorder. AB - Catecholamines such as norepinephrine, epinephrine, and dopamine are closely related to the autonomic nervous system, suggesting that panic disorder may involve elevated catecholamine levels. This study investigated basal and posttreatment catecholamine levels in patients with panic disorder. A total of 29 patients with panic disorder and 23 healthy controls participated in the study. Panic disorder patients received paroxetine treatment for 12 weeks after clinical tests and examination had been conducted. We investigated the difference in basal levels of catecholamine and measured the changes in catecholamine levels before and after drug treatment in panic disorder patients. The basal plasma epinephrine (48.87+/-6.18 pg/ml) and dopamine (34.87+/-3.57 pg/ml) levels of panic disorder patients were significantly higher than those (34.79+/-4.72 pg/ml and 20.40+/ 3.53 pg/ml) of the control group. However, basal plasma norepinephrine levels did not show statistically significant differences between patients and controls. After drug therapy, plasma catecholamine levels were nonsignificantly decreased and norepinephrine levels showed a tendency toward a decrease that did not reach significance. In conclusion, this study suggests the possibility of a baseline increase of plasma catecholamine levels and activation of sympathetic nervous systems in patients with panic disorder which may normalize after treatment with paroxetine. PMID- 25529259 TI - Arginine vasopressin 1a receptor RS3 promoter microsatellites in schizophrenia: a study of the effect of the "risk" allele on clinical symptoms and facial affect recognition. AB - We studied AVPR1A RS3 polymorphism in schizophrenic patients and controls. AVPR1A RS3 was not associated with schizophrenia. The allele 327bp implicated in autism and social behavior was associated with negative symptoms and tended to be linked to patient facial affect recognition suggesting its impact on schizophrenia social phenotypes. PMID- 25529260 TI - Relationship between alexithymia and dependent personality disorder: a dimensional analysis. AB - The present study had two aims and used two different samples. The first aim was to determine if alexithymia and dependent personality disorder (DPD) are distinct or overlapping constructs. The second aim was to determine the specificity and the stability of the relationship between alexithymia and DPD. The first study used exploratory principal components analysis (PCA) in a sample of 477 non clinical subjects who completed three questionnaires measuring alexithymia (Twenty item Toronto Alexithymia Scale, i.e. TAS-20), dependent personality disorder (Dependent Personality Questionnaire, i.e. DPQ) and depression (Beck Depression Inventory-II, i.e. BDI-II). The second study used a sample of 305 subjects consecutively admitted to an outpatient department of legal medicine. The subjects completed (at admission and 3 months later) the Structured Clinical Interview for DSM-IV, screen questionnaire (SCID-II-SQ), the TAS-20 and the BDI. Multiple regressions were done. For the first study, the PCA yielded a four factor solution with no overlap of the significant factor loadings for the items from each scale and with the factors corresponding to their respective construct. For the second study, multiple regressions showed that only avoidant personality disorder was an independent predictor of the TAS-20 scores. Alexithymia is a construct that is distinct and separate from DPD and depression. Alexithymia is not a stable feature of DPD while it is a core feature of avoidant personality disorder. PMID- 25529261 TI - The inter-relationship between mood, self-esteem and response styles in adolescent offspring of bipolar parents: an experience sampling study. AB - The response styles theory of depression (Nolen-Hoeksema, 1991) proposes three main strategies individuals employ in response to low mood: rumination, active coping (distraction and problem-solving) and risk taking. Although recent research has suggested this theory has utility in understanding the symptoms of bipolar disorder (BD), the role of these processes in conferring vulnerability to the condition is poorly understood. Twenty-three adolescent children of patients with BD and 25 offspring of well parents completed the Experience Sampling Method (ESM; Csikszentmihalyi and Larson, 1987) diary for six days. Longitudinal analyses were carried out to examine inter-relationships between mood, self esteem and response styles. Increased negative as well as positive mood resulted in greater rumination in both groups. Low self-esteem triggered greater risk taking at the subsequent time point in the at-risk group, while negative affect instigated increased active coping in the control group. In both groups, engagement in risk-taking improved mood at the subsequent time point, whilst rumination dampened self-esteem. Differential longitudinal associations between mood, self-esteem and response styles between at-risk and control children suggest early psychological vulnerability in the offspring of BD parents, with important indications for early intervention. PMID- 25529262 TI - Effect of Ramadan fasting on anthropometric, metabolic, inflammatory and psychopathology status of Egyptian male patients with schizophrenia. AB - Ramadan fasting is believed to be beneficial. We assessed a random sample of 100 Egyptian male schizophrenia outpatients using the Positive and Negative Syndrome Scale (PANSS) and dietary, anthropometric, clinical, and laboratory measures at baseline (T1) before Ramadan of 2014 and during the fourth week of Ramadan (T2). The metabolic syndrome was identified in 31 patients and these showed a reduction of high-density lipoprotein cholesterol (HDLc) and brain-derived neurotrophic factor (BDNF) concentrations and increase in the levels of dietary intakes, body mass index (BMI), waste circumference, systolic and diastolic blood pressure, all PANSS subscales, glucose, insulin, HOMA-IR, total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-c), white blood cells, granulocytes, lymphocytes, monocytes, fibrinogen and high-sensitivity C-reactive protein (hs CRP). In a multiple regression analysis, total energy intake and body mass index (BMI) emerged as the main independent predictors of deterioration in most inflammatory and psychopathology parameters. These findings did not support our hypothesis but suggested that Ramadan fasting has a negative impact on schizophrenia patients, especially those with metabolic syndrome. This could draw attention to the need in the psycho-education management of such patients to focus more on nutrition education for safe fasting. PMID- 25529264 TI - Editorial overview: analytical biotechnology. PMID- 25529263 TI - A systematic review of adult admissions to ICUs related to adverse drug events. AB - Adverse drug events (ADE) may lead to hospital admission, and in some cases admission to an ICU is mandatory. We conducted a systematic review dealing with the incidence of ADE requiring ICU admission in adult patients, the reference population being all ICU admissions. Medline, Embase and Web of Science databases were screened from January 1982 to July 2014, using appropriate key words. Only original articles in English reporting the incidence of ADE requiring ICU admission in adult patients among total ICU admissions were included. Article eligibility was assessed by two independent reviewers, a third being involved in cases of disagreement. All reported characteristics (type of ICU, characteristics of patients, incidence of ADE, severity and preventability, drugs involved, causality) in the selected articles were collected for the review. The quality of studies was independently assessed by two reviewers with a specific score that we developed. A meta-analysis was conducted. Inclusion criteria were fulfilled by 11 studies out of the 4,311 identified in the initial literature search. The median (interquartile) quality score was 0.61 (0.44; 0.69). The reported incidences of ADE requiring ICU admission in adult patients ranged from 0.37 to 27.4%, with an associated mortality rate ranging from 2 to 28.1% and a mean length of stay ranging from 2.3 to 6.4 days. Preventable events accounted for 17.5 to 85.7% of the events. Costs and mechanisms at the root of ADE were investigated in only two and five studies, respectively. The forest plot examining the incidence of ADE requiring ICU admission in adult patients was associated with high heterogeneity (I (2) statistic > 98%), and the shape of the corresponding funnel plot was asymmetric. Heterogeneity across studies concerned many features, including studied populations, events considered, causality assessment methods, definitions of preventability and severity. Despite the heterogeneity of the reports, our review indicates that ICU admission due to ADE is a significant issue that should deserve further interest. The review led us to propose a list of items devoted to the reporting of future studies on ADE requiring ICU admissions. PMID- 25529265 TI - Walking exercise for chronic musculoskeletal pain: systematic review and meta analysis. AB - OBJECTIVE: To systematically review the evidence examining effects of walking interventions on pain and self-reported function in individuals with chronic musculoskeletal pain. DATA SOURCES: Six electronic databases (MEDLINE, CINAHL, PsychINFO, PEDro, Sport Discus, and the Cochrane Central Register of Controlled Trials) were searched from January 1980 to March 2014. STUDY SELECTION: Randomized and quasi-randomized controlled trials in adults with chronic low back pain, osteoarthritis, or fibromyalgia comparing walking interventions to a nonexercise or nonwalking exercise control group. DATA EXTRACTION: Data were independently extracted using a standardized form. Methodological quality was assessed using the U.S. Preventive Services Task Force system. DATA SYNTHESIS: Twenty-six studies (2384 participants) were included, and suitable data from 17 studies were pooled for meta-analysis, with a random effects model used to calculate between-group mean differences and 95% confidence intervals (CIs). Data were analyzed according to the duration of follow-up (short-term, <=8wk postrandomization; medium-term, >2mo to 12mo; long-term, >12mo). Interventions were associated with small to moderate improvements in pain at short-term (mean difference , -5.31; 95% CI, -8.06 to -2.56) and medium-term (mean difference, 7.92; 95% CI, -12.37 to -3.48) follow-up. Improvements in function were observed at short-term (mean difference, -6.47; 95% CI, -12.00 to -0.95), medium-term (mean difference, -9.31; 95% CI, -14.00 to -4.61), and long-term (mean difference, -5.22; 95% CI, -7.21 to -3.23) follow-up. CONCLUSIONS: Evidence of fair methodological quality suggests that walking is associated with significant improvements in outcome compared with control interventions but longer-term effectiveness is uncertain. With the use of the U.S. Preventive Services Task Force system, walking can be recommended as an effective form of exercise or activity for individuals with chronic musculoskeletal pain but should be supplemented with strategies aimed at maintaining participation. Further work is required for examining effects on important health-related outcomes in this population in robustly designed studies. PMID- 25529266 TI - A chiral stationary phase coated by surface molecularly imprinted polymer for separating 1,1'-binaphthalene-2,2'-diamine enantiomer by high performance liquid chromatography. AB - This report describes novel pathway for the development of a new type of CSP. A chiral stationary phase (CSP) prepared by coating a molecularly imprinted polymer (MIP) on the surface of silica gel (SMIP-CSP) showed a high separation factor (3.39) in separating racemic 1,1'-binaphthalene-2,2'-diamine (DABN) by high performance liquid chromatography (HPLC). Being the crosslinking agent, ethylene glycol dimethacrylate (EGDMA) was copolymerized with the monomer, methacrylic acid (MAA), in the presence of (R)-DABN as the template molecules on the surface of the silica gel particles to produce the SMIP-CSPs. The effects of the pretreatment temperature, the (R)-DABN content and the type of silica gel and monomer in the SMIP-CSPs on the separation of the racemic DABN were systematically investigated. PMID- 25529267 TI - Present state of microchip electrophoresis: state of the art and routine applications. AB - Microchip electrophoresis (MCE) was one of the earliest applications of the micro total analysis system (MU-TAS) concept, whose aim is to reduce analysis time and reagent and sample consumption while increasing throughput and portability by miniaturizing analytical laboratory procedures onto a microfluidic chip. More than two decades on, electrophoresis remains the most common separation technique used in microfluidic applications. MCE-based instruments have had some commercial success and have found application in many disciplines. This review will consider the present state of MCE including recent advances in technology and both novel and routine applications in the laboratory. We will also attempt to assess the impact of MCE in the scientific community and its prospects for the future. PMID- 25529269 TI - Early excision and grafting, an alternative approach to the surgical management of large body surface area levamisole-adulterated cocaine induced skin necrosis. AB - Levamisole-adulterated cocaine as a cause of retiform purpura progressing to full thickness skin necrosis was first documented in 2003 and currently comprises over 200 reported cases. Whereas, its presentation, pathophysiology, and diagnostic workup have been reasonably well-defined, only one publication has significantly detailed its surgical management. For this reason there exists a relative absence of data in comparison to its reported incidence to suggest a preferred treatment strategy. In the case mentioned, treatment emphasized delayed surgical intervention while awaiting lesion demarcation and the monitoring of autoantibodies. At our institution we offer an alternative approach and present the case of a 34 year old female who presented with 49% TBSA, levamisole-induced skin necrosis managed with early surgical excision and skin grafting. The patient presented three days following cocaine exposure with painful, purpura involving the ears, nose, buttocks, and bilateral lower extremities which quickly progressed to areas of full-thickness necrosis. Lab analysis demonstrated elevated p-ANCA and c-ANCA, as well as leukopenia, decreased C4 complement, and urinalysis positive for levamisole, corroborating the diagnosis. Contrasting the most thoroughly documented case in which the patient underwent first surgical excision on hospital day 36 and underwent 18 total excisions, our patient underwent first excision on hospital day 10 and received only one primary excision prior to definitive autografting. To our knowledge, this is the largest surface area surgically treated that did not result in surgical amputation or autoamputation of limbs or appendages, respectively. We contend that early excision and grafting provides optimal surgical management of this syndrome while avoiding the morbidity seen with delayed intervention. PMID- 25529268 TI - Vitamin D status after a high dose of cholecalciferol in healthy and burn subjects. AB - BACKGROUND: Burn patients are at risk of vitamin D (VD) deficiency and may benefit from its pleiotropic effects as soon as acute phase. Aim of this observational study was to assess effects of a cholecalciferol (VD3) bolus on VD status in adult burn patients (Group B, GB) after admission, compared to healthy subjects (Group H, GH). METHODS: Both groups received an oral dose of 100,000 IU VD3. Blood samples were collected before (D0) and 7 days (D7) after bolus to measure 250H-D, 1,25(OH)2-D, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Albumin (ALB) and VD binding protein (DBP) were measured and used to calculate free 25OH-D level. Data were expressed as median (min-max) or proportions. RESULTS: A total of 49 subjects were included: 29 in GH and 20 in GB. At D0, prevalence of VD deficiency was higher in GB: 25OH-D was 21.5 (10.1 46.3) ng/ml in GH vs 11 (1.8-31.4) ng/ml in GB. DBP and ALB were lower in GB. At D7, DBP was stable in both groups while ALB decreased in GB. 25OH-D increased by 66.6 (13.5-260.3)% in GH. In GB, changes in 25OH-D extended from -36.7% to 333.3% with a median increase of 33.1%. Similar changes were observed in each group for free 25OH-D. High FGF23 levels were observed in GB. CONCLUSIONS: This study highlighted the differences in VD status and in response to a high dose VD3 in burn patients when compared to healthy patients. Pitfalls in VD status assessment are numerous during acute burn care: 25OH-D measurement needs cautious interpretation and interest of free 25OH-D is still questionable. They should not prevent burn patients to receive VD supplements during acute care. Higher doses than general recommendations should probably be considered. PMID- 25529270 TI - Exposure and body burden of polychlorinated biphenyls (PCB) and metals in a historically contaminated community. AB - There are many small villages where environmental contamination is substantial due to historical industrial activities. The aim of the present study was to investigate if long-term or current consumption of local foods, as reported in food frequency questionnaires, co-vary with measured concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), lead (Pb), cadmium (Cd) and mercury (Hg) in blood, urine and hair from a population living in a historically contaminated village. Blood, urine and hair were provided by men (n=38) and women (n=57), who had participated in a previous case-control study in the contaminated area, and were analyzed for PCB, OCPs, Pb, Cd and Hg. A detailed food frequency questionnaire, used in the previous epidemiological study, was repeated, and up-dated information of life-style, exposure factors and other covariates was collected. Associations between reported consumption of local foods and exposure biomarkers were explored in relation to age, gender, life-style factors and other covariates. A large part of the population in the area reported consumption of local food, and thus, was potentially exposed to the contaminants. Despite the limited number of participants and other weaknesses described, it was possible to link reported consumption of different foods to biomarker concentrations. Reported consumption of local vegetables, forest berries and mushrooms co-varied with urinary Cd, indicating an influence from the contaminated area on the Cd exposure. We found no associations between PCB plasma concentrations with reported consumption of local fish, but with consumption of herring (non-local sea fish) which is typically high in PCB. Pesticide (HCB, p,p' DDE, trans-nonachlor) exposure was mainly associated with agricultural work and having a private well the first five years of life, but we found no associations between pesticide concentrations in plasma and consumption of local vegetables or fish. Exposure to Hg was associated with consumption of fish, both local and non local, and Pb exposure was associated with the consumption of game. Overall, the contaminant concentrations measured in blood, urine and hair varied substantially among study participants, but on average, the concentrations were similar to concentrations measured in other groups of the general Swedish population in the same age range. Larger studies are needed to evaluate health risks (and causality) associated with historical environmental contamination. PMID- 25529271 TI - External morphology and calling song characteristics in Tibicen plebejus (Hemiptera: Cicadidae). AB - Tibicen plebejus is the largest cicada native to the ecosystem in northern Iran. The male cicada produces a loud calling song for attracting females from a long distance. It is presumed that the female selects a mate based on a combination of passive and active mechanisms, but it is not known if she selects for size, nor if the male's size correlates with any characteristic of the advertisement call. In this study, we report the relationship between calling song features and morphological characters in the male of T. plebejus. Research was conducted in northern Iran during the summer of 2010. Seventeen males were collected and their calling songs were recorded in a natural environment. Two morphological characters were measured: length and weight. Maximum, minimum and average of values of 10 key acoustic variables of the calling song were analyzed: phrase duration, phrase part 1, phrase part 2, number of phrases per minute, echeme duration, echeme period, interecheme interval, number of echeme per second, echeme/intereheme ratio, and dominant frequency. The data were tested for the level of association between morphology and acoustic variables using simple linear regression. In conclusion, in terms of song structure, three significant positive correlations existed between length and (1) mean echeme duration, (2) mean echeme/interecheme ratio, (3) maximum echeme/interecheme ratio. We found out also four significant negative correlations between both length and weight with (1) minimum interecheme intervals, (2) mean dominant frequency, (3) minimum dominant frequency, (4) maximum dominant frequency, and between weight and (1) minimum interecheme intervals, (2) mean dominant frequency, (3) minimum dominant frequency, (4) maximum dominant frequency. It can be found that larger males of T. plebejus produce songs of lower frequency and are less silent between echemes. PMID- 25529272 TI - The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation. AB - Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communications in the nervous system by converting the binding of a chemical messenger - a neurotransmitter - into an ion flux through the postsynaptic membrane. Here, we present an overview of the most recent advances on the signal transduction mechanism boosted by X-ray crystallography of both prokaryotic and eukaryotic homologues of the nicotinic acetylcholine receptor (nAChR) in conjunction with time-resolved analyses based on single-channel electrophysiology and Molecular Dynamics simulations. The available data consistently point to a global mechanism of gating that involves a large reorganization of the receptor mediated by two distinct quaternary transitions: a global twisting and a radial expansion/contraction of the extracellular domain. These transitions profoundly modify the organization of the interface between subunits, which host several sites for orthosteric and allosteric modulatory ligands. The same mechanism may thus mediate both positive and negative allosteric modulations of pLGICs ligand binding at topographically distinct sites. The emerging picture of signal transduction is expected to pave the way to new pharmacological strategies for the development of allosteric modulators of nAChR and pLGICs in general. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25529273 TI - Neurobehavioral consequences of small molecule-drug immunosuppression. AB - 60 years after the first successful kidney transplantation in humans, transplant patients have decent survival rates owing to a broad spectrum of immunosuppressive medication available today. Not only transplant patients, but also patients with inflammatory autoimmune diseases or cancer benefit from these life-saving immunosuppressive and anti-proliferative medications. However, this success is gained with the disadvantage of neuropsychological disturbances and mental health problems such as depression, anxiety and impaired quality of life after long-term treatment with immunosuppressive drugs. So far, surprisingly little is known about unwanted neuropsychological side effects of immunosuppressants and anti-proliferative drugs from the group of so called small molecule-drugs. This is partly due to the fact that it is difficult to disentangle whether and to what extent the observed neuropsychiatric disturbances are a direct result of the patient's medical history or of the immunosuppressive treatment. Thus, here we summarize experimental as well as clinical data of mammalian and human studies, with the focus on selected small-molecule drugs that are frequently employed in solid organ transplantation, autoimmune disorders or cancer therapy and their effects on neuropsychological functions, mood, and behavior. These data reveal the necessity to develop immunosuppressive and anti proliferative drugs inducing fewer or no unwanted neuropsychological side effects, thereby increasing the quality of life in patients requiring long term immunosuppressive treatment. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25529274 TI - Food neophobia associates with lower dietary quality and higher BMI in Finnish adults. AB - OBJECTIVE: Food neophobia has been associated with decreased consumption of vegetables mainly among children. We hypothesized that food neophobia in adults is also associated with lower overall dietary quality and higher BMI. DESIGN: Data for the present cross-sectional analyses were derived from parents in a follow-up family study. SETTING: The STEPS study, a longitudinal study of health and development of a cohort of children born in south-west Finland. SUBJECTS: The parents, 1178 women (age 19-45 years, mean 32.2 years) and 1013 men (age 18-57 years, mean 34.1 years), completed a questionnaire at home when their child was 13 months old. The questionnaire included the Food Neophobia Scale (FNS; range 10 70), the Index of Diet Quality (IDQ; range 0-16) and a measure of fruit and vegetable consumption. At that time the participants' height and weight were also measured by a research nurse to calculate BMI. RESULTS: Compared with the food neophilics (FNS score 10-24), the food neophobics (FNS score 40-70) consumed fewer vegetables (women: 15 v. 10 portions/week; men: 13 v. 7 portions/week), scored lower on the IDQ (women: 9.7 v. 8.5; men: 8.8 v. 7.8) and had higher BMI (women: 24.2 v. 26.0 kg/m2; men: 26.5 v. 27.5 kg/m2) as tested by one-way ANOVA, with all P values <0.001 in women and <0.05 in men. The food neophobics followed a diet lower in nutritional quality than did the food neophilics, especially regarding vegetables. CONCLUSIONS: Food neophobia may complicate adaptation to dietary recommendations and predispose to overweight. PMID- 25529276 TI - Hepatic angiosarcoma: a suggestive pattern of enhancement on dynamic MR imaging. PMID- 25529275 TI - Cystic mesothelioma of the gallbladder: MR imaging findings. PMID- 25529277 TI - A new approach to determine the susceptibility of bacteria to antibiotics directly from positive blood culture bottles in two hours. AB - The rapid identification and antibiotic susceptibility test of bacteria causing bloodstream infections are given a very high priority by clinical laboratories. In an effort to reduce the time required for performing antibiotic susceptibility test (AST), we have developed a new method to be applied from positive blood culture bottles. The design of method was performed using blood culture bottles prepared artificially with five strains which have a known susceptibility. An aliquot of the blood culture was subcultured in the presence of specific antibiotics and bacterial counts were monitored using the Sysmex UF-1000i flow cytometer at different times up to 180min. Receiver operating curve (ROC) analysis allowed us to find out the cut-off point for differentiating between sensitive and resistant strains to the tested antibiotic. This procedure was then validated against standard commercial methods on a total of 100 positive blood culture bottles from patients. First, bacterial identification was performed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) directly from positive blood culture bottles as we have previously reported. Secondly, antibiotic susceptibility test was performed in the same way that was carried out in artificially prepared blood culture bottles. Our results indicate that antibiotic susceptibility test can be determined as early as 120min since a blood culture bottle is flagged as positive. The essential agreement between our susceptibility test and commercial methods (E-test, MicroScan and Vitek) was 99%. In summary, we conclude that reliable results on bacterial identification and antibiotic susceptibility test performed directly from positive blood culture bottles can be obtained within 3h. PMID- 25529279 TI - Rectus sheath hematoma: a review of the literature. AB - Rectus sheath hematoma (RSH) is a relatively rare clinical condition, strongly associated among others, with abdominal trauma and anticoagulation. Although well documented over the years, it still seems to be often misdiagnosed. Estimations of further increase in incidence are made, based on the increasing use of anticoagulants. Thus it was of interest to us to perform a literature review on the available literature of this entity with the aim to facilitate a better understanding and management in primary and secondary care settings. This review intends to present a synthesis on the main topics of this condition such as pathophysiology, epidemiology, predisposing factors, clinical presentation, diagnosis and basic treatment instructions. The initial search resulted in 146 articles. Additional citations from the reference list of the relevant publication were also included. Every physician in the field of primary/emergency medicine and surgery must be familiar with it, as misdiagnosis may lead to unnecessary laparotomy or death. In contrast, faster and more accurate diagnosis can lead to mortality rate reduction and cost containment. PMID- 25529278 TI - Mass spectrometry identification of potential mediators of progestin-only contraceptive-induced abnormal uterine bleeding in human endometrial stromal cells. AB - OBJECTIVE: Thrombin and hypoxia each target human endometrial stromal cells (HESCs) to mediate long-acting progestin-only contraceptive (LAPC)-induced abnormal uterine bleeding (AUB). Thus, the secretome resulting from treatment of primary cultures of HESCs with thrombin or hypoxia was screened by mass spectrometry (MS) to detect potential protein mediators that lead to AUB. STUDY DESIGN: Cultured HESCs were primed with estradiol+/-medroxyprogesterone acetate (MPA) or etonogestrel (ETO), the respective progestins in MPA-injected and ETO implanted LAPCs, and then treated by incubation with thrombin or under hypoxia. Collected conditioned medium supernatants were used for protein identification and quantitation of potential AUB mediators by liquid chromatography combined with tandem mass spectrometry analysis. Microarray analysis of parallel cultures and immunostaining of endometrial biopsies of LAPC users vs. nonusers corroborated MS results. RESULTS: MS identified several proteins displaying changes in expression levels from either thrombin or hypoxia treatments that are integral to angiogenesis or extracellular matrix formation. Several MS-identified proteins were confirmed by mRNA microarray analysis. Overexpressed stanniocalcin 1 (STC-1) was observed in endometrium of LAPC users. Unlike controls, all LAPC users displayed endometrial tubal metaplasia (ETM). CONCLUSIONS: MS analysis identified many proteins that can affect angiogenesis or vessel integrity, thereby contributing to AUB. Confirmation of STC-1 overexpression in LAPC users and microarray data supports the validity of the MS data and suggests STC-1 involvement in AUB. The discovery of ETM in LAPC users indicates that LAPC related side effects extend beyond AUB. The results presented here demonstrate a complex biological response to LAPC use. IMPLICATIONS: MS identified several HESC secreted proteins deregulated by thrombin and hypoxia that may mediate LAPC induced AUB. The revelation of overexpressed STC-1 by combined in vivo and in vitro observations identifies a potential target for future studies to prevent or minimize LAPC-induced AUB. PMID- 25529281 TI - Correspondence to: "Predictors of in-hospital mortality amongst octogenarians undergoing emergency general surgery: a retrospective cohort study". PMID- 25529280 TI - A prospective cross-sectional study of laparoscopic subtotal Lind fundoplication for gastro-oesophageal reflux disease--a durable and effective anti-reflux procedure. AB - INTRODUCTION: Laparoscopic partial fundoplication for gastro-oesophageal reflux disease (GORD) is reported to have fewer side effects when compared to Nissen fundoplication, but doubts remain over its long term durability in controlling reflux. The aim of this study was to assess outcome of symptoms for all patients presenting with GORD undergoing routine laparoscopic subtotal Lind fundoplication. MATERIALS & METHODS: All patients undergoing laparoscopic fundoplication between August, 1999 and November, 2007 performed by a single surgeon were included in the study. The anti-reflux procedure studied was laparoscopic Lind (300 degrees ) fundoplication with crural repair in all cases. Patients completed pre and post-operative questionnaires containing validated scoring systems for heartburn, gas bloat, dysphagia and overall patient satisfaction. RESULTS: Over the 100-month period, 320 consecutive patients underwent laparoscopic subtotal Lind fundoplication. Of these, 256 (80%) replied to the questionnaire at a mean of 31 months (range 3-96 months) following surgery. 91.4% of respondents had an improvement in heartburn symptom score with a significant reduction in score from 7.74 preoperatively to 1.25 postoperatively (p<0.001). There was also a significant reduction of mean modified Visick score for reflux control (heartburn and regurgitation) from 3.49 preoperatively to 1.48 after surgery (p<0.001). In total, 22 patients developed recurrent reflux symptoms with half of these reporting their recurrence within two years following surgery. Because of this all were tested with post-operative pH testing, yet only one had a 24-h pH time outside the normal range. Overall patient satisfaction was high with a visual analogue score of 9 and 88% of the patients claimed they would have the operation again. CONCLUSION: Laparoscopic Lind fundoplication demonstrates excellent reflux control when performed routinely for all patients presenting with GORD. This technique is both durable and efficacious in controlling reflux symptoms. PMID- 25529282 TI - Erythropoiesis-stimulating agents: dose and mortality risk. AB - Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality in end-stage renal disease patients. It is not clear if this effect is related to the elevated ESAs dosage for targeting hemoglobin levels or underlying morbid conditions that lead to ESA resistance. We retrospectively evaluated from 2008 to death or December 2011, 28 consecutive incident hemodialysis patients. We identified 2 cohort of patients based on their mean annual ESAs dosage. The correlation between data was evaluated with the Spearman's rho test. Kaplan-Meier curves were generated to assess survival in subjects with high and low ESAs mean dose. Median ESAs dosage, used as a cutoff point between patients at high and low ESAs dose, was at 11.000 IU/week for epoetin alfa and beta, 55 mcg/week for darbopoietin, and 220 mcg/month for cera. Mean hemoglobin (Hb) level was 10.58 +/- 0.13 g/dL. Of 28 patients, during follow up, 6 (21,4%) died of all causes. High-dose ESA therapy was associated with increased all-cause mortality (P = .047). Moreover, there was a negative correlation between ESAs dose and Hb levels (rho = -0.825; P < .001). Higher ESAs dose for the treatment of anemia in incident hemodialysis patients was associated with higher mortality risk. ESAs and Hb serum levels were inversely correlated with mortality. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner or an interactive effect that adversely affects mortality. PMID- 25529283 TI - Nef, the shuttling molecular adaptor of HIV, influences the cytokine network. AB - Several viruses manipulate host innate immune responses to avoid immune recognition and improve viral replication and spreading. The viral protein Nef of Human Immunodeficiency Virus is mainly involved in this "hijacking" activity and is a well established virulence factor. In the last few years there have been remarkable advances in outlining a defined framework of its functions. In particular Nef appears to be a shuttling molecular adaptor able to exert its effects both on infected and non infected bystander cell. In addition it is emerging fact that it has an important impact on the chemo-cytokine network. Nef protein represents an interesting new target to develop therapeutic drugs for treatment of seropositive patients. In this review we have tried to provide a unifying view of the multiple functions of this viral protein on the basis of recently available experimental data. PMID- 25529284 TI - Assessing the utility of routine first annual follow-up visits after primary total knee arthroplasty. AB - The combination of increased TKA utilization and a decreased number of arthroplasty specialists has resulted in a growing need to maximize efficiency without sacrificing the level of care being provided. The purpose of this study was to evaluate the utility of routine first annual follow-up visits for patients that have undergone primary TKA. Of 339 TKAs performed by a single surgeon in 2012, 23% failed to attend scheduled first annual visits. Furthermore, none of the revisions performed at our facility since 2003 were the direct result of information gained at a patient's routine first annual visit. As such, we question the clinical utility of the first annual visit. PMID- 25529285 TI - Inpatient mortality after primary total hip arthroplasty: analysis from the National Inpatient Sample database. AB - Although inpatient mortality rates following total hip arthroplasty are low, understanding factors that influence inpatient mortality rates is important. Discharge data from the 2007-2008 HCUP Nationwide Inpatient Sample database were used in this study. Patients were identified based on whether they were admitted for a primary total hip arthroplasty and grouped based on their mortality status. All hip and acetabular fracture patients were excluded. Discharge data revealed 508,150 primary total hip arthroplasties with an inpatient mortality rate of 0.13%. The most significant pre-operative predictors of inpatient mortality were increasing age, weekend admission, increased Charlson co-mobidity score, Medicare payer status, race and a Southern hospital region. The two most significant complications post-operatively leading to increased mortality were pulmonary and cardiovascular complications. PMID- 25529286 TI - Effects of ractopamine administration and castration method on muscle fiber characteristics and sensory quality of the longissimus muscle in two Pietrain pig genotypes. AB - Single and combined effects of ractopamine supplementation (RAC, 7.5 vs. 0 ppm), castration method (surgical castration: SC vs. immuno-castration: IM) and genotype (genotype A: GA vs. GB containing 25% or 50% Pietrain) were determined on longissimus muscle (LM) fiber traits and quality of pork (n=512). RAC increased fiber IIX cross-sectional area (P=0.009) and decreased glycolytic potential (P=0.02) and pork tenderness (P<0.001). Fiber traits indicated that LM of IM pigs was more oxidative (P<0.05) and meat had slightly higher (P=0.04) off flavor score and WBSF than SC. LM from GB pigs was paler (P<0.05) and had greater (P<0.05) glycolytic potential, IIX fiber cross sectional area and pork off-flavor than GA. RAC supplementation, castration method and genotype or their combination affected some fiber traits and some quality parameters but differences reported were small indicating these treatments or their combination could be used without major prejudice to meat quality. PMID- 25529287 TI - Meat quality of lamb frozen stored up to 21 months: instrumental analyses on thawed meat during display. AB - The study analysed the effect of frozen storage duration (FSD: 0, 1, 9, 15 or 21 months) and display duration (DD: 0-24 h post-slaughter-, 3 and 6 days) in modified atmosphere packaging (MAP) on lamb quality. pH, colour, lipid oxidation, water holding capacity and instrumental texture were performed on Longissimus muscle in displayed fresh and thawed meat. FSD affected all the variables showing lower differences between fresh and 1 month storage than among them and longer FSD. Only cooking losses were not affected by DD in thawed meats. It was observed a general decrease in quality (lower redness and water holding capacity; higher yellowness and lipid oxidation) as FSD or DD increased and only texture was improved over DD being thawed meat more tender. In conclusion, lamb storage at 18 degrees C should not exceed 1 month if thawed meat would be later displayed in MAP while meat would have an acceptable quality up to 21 months without subsequent display. PMID- 25529288 TI - The functionality of plum ingredients in meat products: a review. AB - Dried plums (prunes) have been marketed to consumers for consumption directly from the package as a convenient snack and have been reported to have broad health benefits. Only recently have fractionated, dried plum ingredients been investigated for their functionality in food and feed products. Dried plum puree, dried plum fiber, dried plum powder, dried plum concentrate, and fresh plum concentrate have been investigated to date. They have been evaluated as fat replacers in baked goods, antioxidants in meat formulations, phosphate replacers in chicken marinades, and antimicrobials in food systems. Overall, dried plum products have been shown to be effective at reducing lipid oxidation and show promise as antimicrobials. PMID- 25529289 TI - Age at HPV vaccine initiation and completion among US adolescent girls: trend from 2008 to 2012. AB - OBJECTIVE: To examine the trend of provider-verified HPV vaccine initiation (>=1 dose) and completion (>=3 doses) among adolescent girls at the Advisory Committee on Immunization Practices (ACIP) recommended age (11-12 years). METHODS: We analyzed National Immunization Survey of Teens 2008-2012 data and examined the trend of provider-verified HPV vaccine initiation and completion among <13 year old girls. RESULTS: Data on age at HPV vaccine initiation and completion were available for 24,466 and 15,972 girls, respectively. The weighted proportion of girls who initiated the vaccine at <13 years of age was 14.1%, 24.1%, 35.9%, 47.7% and 55.9% in 2008, 2009, 2010, 2011 and 2012, respectively (p for trend <.001). The similar trend was also observed for mean age at HPV vaccine initiation and completion (p<.001). CONCLUSIONS: Additional efforts are needed to increase HPV vaccine uptake among adolescent girls as only half of them receive this vaccine at ACIP recommended age. PMID- 25529291 TI - Factors that affect voluntary vaccination of children in Japan. AB - Some important vaccinations are not included in the routine childhood immunization schedule in Japan. Voluntary vaccinations are usually paid as an out of-pocket expense. Low voluntary vaccination coverage rates and high target disease incidence are assumed to be a consequence of voluntary vaccination. Therefore, this study aimed to explore factors associated with voluntary vaccination patterns in children. We conducted an online survey of 1243 mothers from a registered survey panel who had at least one child 2 months to <3 years of age. The voluntary vaccination mainly correlated positively with annual household income and mothers' positive opinions about voluntary vaccinations, but negatively with number of children. Financial support, especially for low income households and households with more than one child, may motivate parents to vaccinate their children. Communication is also an important issue. More opportunities for education and information about voluntary vaccinations should be provided to mothers without distinguishing between voluntary and routine vaccination. PMID- 25529290 TI - Visualizing knowledge and attitude factors related to influenza vaccination of physicians. AB - PURPOSE: To characterize groups of primary healthcare physicians according to sociodemographic data, years of professional experience and knowledge of and attitudes to influenza, and to evaluate differences between groups with respect to influenza vaccination in the 2011-2012 season. METHODS: We carried out an anonymous web survey of Spanish primary healthcare physicians in 2012. Information on vaccination, and knowledge of and attitudes to influenza was collected. Multiple correspondence analysis and cluster analysis were used to define groups of physicians. RESULTS: We included 835 physicians and identified three types. Type B were physicians with low professional experience of influenza. Types A and C were physicians with high professional experience with influenza, type A also had a high awareness of influenza and seasonal vaccination. Types A and C were older and more often male than type B (p<0.0001). Knowledge of influenza was greatest in type A and lowest in type B. Awareness of influenza was greatest in type A and lowest in type C. In type A, 71.0% of physicians were vaccinated in the 2011-2012 season, compared with 48.1% and 33.6% from types B and C, respectively (p<0.001). CONCLUSIONS: Additional efforts should be made to increase interest and concerns about preventing the transmission of influenza in physicians who do not believe influenza is a severe disease and are not concerned about its transmission. PMID- 25529293 TI - The role of parental attitudes and provider discussions in uptake of adolescent vaccines. AB - The purpose of this study was to examine the relationship between parental vaccine attitudes, the number of specific vaccines discussed with a provider, and immunization outcomes including discussing immunization with their teen, knowledge of adolescent vaccine schedule, and their son or daughter being up-to date on recommended vaccines using a nationally weight sample. Parents completed an internet-based survey between December 2012 and January 2013 and we computed a vaccine attitude scale (higher scores indicating stronger and more positive attitudes toward vaccination of teen) for each parent and categorized them into one of three groups: low (n=76), medium (n=207) or high (n=215). We also constructed a vaccine discussion scale representing the number of vaccines discussed with their adolescent's physician. Parents who were identified as having high vaccine attitudes were significantly more likely to report their physician talked with them about a particular vaccine. Using logistic regression and controlling for respondent's gender and age, income, and teen's gender, we found medium as compared to low-attitude parents had a 6.21 (95%CI=3.08, 12.51) greater odds of reporting that their teen had all recommended vaccines. Similarly, high as compared to low-attitude parents reported a 23.02 (95% CI=11.27, 46.99) greater odds of having a teen who was up-to-date on recommended vaccines. We detected that for each additional vaccine discussed, there was a 1.24 (95%CI=1.11, 1.39) increase in odds of the teen having all recommended vaccines. Parental immunization attitudes and provider discussion about vaccines are key ingredients to improving immunization rates among adolescents. While some parents may be reluctant to immunize their son or daughter with a recommended vaccine, vaccine-specific discussions between physicians and parents represent an important first step to continued discussions with providers regarding vaccination. Moreover, vaccine discussions must occur within the context of ongoing conversations about health and disease prevention. PMID- 25529295 TI - Molecular characterisation of ABC-type multidrug efflux systems in Bifidobacterium longum. AB - Administration of probiotic bacteria such as Bifidobacterium spp. can prevent antibiotic associated diarrhoea since they can survive the often harsh conditions of the gut. In Bifidobacterium longum subsp. longum(T) NCIMB 702259, two gene clusters, with homology to the ATP-binding cassette (ABC) family of efflux transporters, were identified and studied to assess their functional contribution to antibiotic resistance. Both gene clusters contained two genes encoding putative efflux transporters and a regulator gene, upstream of the structural genes. Reverse transcriptase analysis indicated that the genes in each cluster were transcribed as operons, one where all three genes, including a putative MarR type regulator were transcribed together (BLLJ_1496/1495/1494), and the other where the two ABC-type transporter genes (BLLJ_1837/1836) were co-transcribed, but excluded the putative regulator (BLLJ_1838). Heterologous expression of the cloned BLLJ_1837/1836 transporter genes in Lactococcus lactis conferred resistance to erythromycin and tetracycline by increasing the minimum inhibitory concentration between 1.5 and 3 fold. The presence of these genes also allowed a 16% increase in the efflux of Hoechst 33342 from L. lactis cells containing the two transporter genes, BLLJ_1837-6. In B. longum, an increase in the levels of transcription of 3.3 fold was observed for BLLJ_1837 in the presence of erythromycin, as measured by multiplex quantitative PCR. In contrast to this, the expression of the genes of the BLLJ_1495/1494 operon in L. lactis did not show significant drug resistance functionality. Gel shift experiments showed that in the BLLJ_1495/1494 operon, the putative MarR-type regulator protein (BLLJ_1496) bound with high affinity to the DNA sequence upstream of the operon in which it was located but this was not erythromycin dependent. This study demonstrated the occurrence of a drug inducible, ABC-type transporter system (BLLJ_1837/1836) in B. longum as well as a putative MarR-type DNA binding protein (BLLJ_1496). PMID- 25529294 TI - The constitution of visual perceptual units in the functional architecture of V1. AB - In this paper we show that the emergence of perceptual units in V1 can be explained in terms of a physical mechanism of simmetry breaking of the mean field neural equation. We consider a mean field neural model which takes into account the functional architecture of the visual cortex modeled as a group of rotations and translations equipped with a degenerate metric. The model generalizes well known results of Bressloff and Cowan which, in absence of input, accounts for hallucination patterns. The main result of our study consists in showing that in presence of a visual input, the stable eigenmodes of the linearized operator represent perceptual units of the visual stimulus. The result is strictly related to dimensionality reduction and clustering problems. PMID- 25529292 TI - Factors associated with tuberculosis infection, and with anti-mycobacterial immune responses, among five year olds BCG-immunised at birth in Entebbe, Uganda. AB - BACKGROUND: BCG is used widely as the sole licensed vaccine against tuberculosis, but it has variable efficacy and the reasons for this are still unclear. No reliable biomarkers to predict future protection against, or acquisition of, TB infection following immunisation have been identified. Lessons from BCG could be valuable in the development of effective tuberculosis vaccines. OBJECTIVES: Within the Entebbe Mother and Baby Study birth cohort in Uganda, infants received BCG at birth. We investigated factors associated with latent tuberculosis infection (LTBI) and with cytokine response to mycobacterial antigen at age five years. We also investigated whether cytokine responses at one year were associated with LTBI at five years of age. METHODS: Blood samples from age one and five years were stimulated using crude culture filtrates of Mycobacterium tuberculosis in a six-day whole blood assay. IFN-gamma, IL-5, IL-13 and IL-10 production was measured. LTBI at five years was determined using T-SPOT.TB((r)) assay. Associations with LTBI at five years were assessed using multivariable logistic regression. Multiple linear regression with bootstrapping was used to determine factors associated with cytokine responses at age five years. RESULTS: LTBI prevalence was 9% at age five years. Only urban residence and history of TB contact/disease were positively associated with LTBI. BCG vaccine strain, LTBI, HIV infection, asymptomatic malaria, growth z-scores, childhood anthelminthic treatment and maternal BCG scar were associated with cytokine responses at age five. Cytokine responses at one year were not associated with acquisition of LTBI by five years of age. CONCLUSION: Although multiple factors influenced anti myocbacterial immune responses at age five, factors likely to be associated with exposure to infectious cases (history of household contact, and urban residence) dominated the risk of LTBI. PMID- 25529296 TI - FKBPs in bacterial infections. AB - BACKGROUND: FK506-binding proteins (FKBPs) contain a domain with peptidyl-prolyl cis/trans-isomerase (PPIase) activity and bind the immunosuppressive drugs FK506 and rapamycin. FKBPs belong to the immunophilin family and are found in eukaryotes and bacteria. SCOPE OF REVIEW: In this review we describe two major groups of bacterial virulence-associated FKBPs, the trigger factor and Mip-like PPIases. Moreover, we discuss the contribution of host FKBPs in bacterial infection processes. MAJOR CONCLUSIONS: Since PPIases are regarded as alternative antiinfective drug targets we highlight current research strategies utilizing pipecolinic acid and cycloheximide derivatives as well as substrate based inhibitors. GENERAL SIGNIFICANCE: The current research strategies suggest a beneficial synergism of drug development and basic research. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25529297 TI - Changes to both cardiac metabolism and performance accompany acute reductions in functional capillary supply. AB - BACKGROUND: The relative importance of arteriole supply or ability to switch between substrates to preserve cardiac performance is currently unclear, but may be critically important in conditions such as diabetes. METHODS: Metabolism of substrates was measured before and after infusion of polystyrene microspheres in the perfused working heart to mimic random capillary loss due to microvascular disease. The effect of acute loss of functional capillary supply on palmitate and glucose metabolism together with function was quantified, and theoretical tissue oxygen distribution calculated from histological samples and ventricular VO(2) estimated. RESULTS: Microsphere infusion led to a dose-dependent decrease in rate pressure product (RPP) and oxygen consumption (P<0.001). Microsphere infusion also increased work/unit oxygen consumption of hearts ('efficiency') by 25% (P<0.01). When corrected for cardiac work palmitate oxidation remained tightly coupled to very low workloads (RPP<2500 mmHg/min), illustrating a high degree of metabolic control. Arteriole occlusion by microspheres decreased the density of patent capillaries (P<0.001) and correspondingly increased the average capillary supply area by 40% (P<0.01). Calculated rates of oxygen consumption declined from 16.6+/-7.2 ml/100 ml/min to 12.4+/-9 ml/100 ml/min following arteriole occlusion, coupled with increases in size of regions of myocardial hypoxia (Control=22.0% vs. Microspheres=42.2%). CONCLUSIONS: Cardiac mechanical performance is very sensitive to arteriolar blockade, but metabolite switching from fatty acid to glucose utilisation may also support cardiac function in regions of declining PO(2). GENERAL SIGNIFICANCE: Preserving functional capillary supply may be critical for maintenance of cardiac function when metabolic flexibility is lost, as in diabetes. PMID- 25529298 TI - Access channels to the buried active site control substrate specificity in CYP1A P450 enzymes. AB - BACKGROUND: A cytochrome P450 active site is buried within the protein molecule and several channels connect the catalytic cavity to the protein surface. Their role in P450 catalysis is still matter of debate. The aim of this study was to understand the possible relations existing between channels and substrate specificity. METHODS: Time course studies were carried out with a collection of polycyclic substrates of increasing sizes assayed with a library of wild-type and chimeric CYP1A enzymes. This resulted in a matrix of activities sufficiently large to allow statistical analysis. Multivariate statistical tools were used to decipher the correlation between observed activity shifts and sequence segment swaps. RESULTS: The global kinetic behavior of CYP1A enzymes toward polycyclic substrates is significantly different depending on the size of the substrate. Mutations which are close or lining the P450 channels significantly affect this discrimination, whereas mutations distant from the P450 channels do not. CONCLUSIONS: Size discrimination is taking place for polycyclic substrates at the entrance of the different P450 access channels. It is thus hypothesized that channels differentiate small from large substrates in CYP1A enzymes, implying that residues located at the surface of the protein may be implied in this differential recognition. GENERAL SIGNIFICANCE: Catalysis thus occurs after a two step recognition process, one at the surface of the protein and the second within the catalytic cavity in enzymes with a buried active site. PMID- 25529299 TI - Plant immunophilins: a review of their structure-function relationship. AB - BACKGROUND: Originally discovered as receptors for immunosuppressive drugs, immunophilins consist of two major groups, FK506 binding proteins (FKBPs) and cyclosporin A binding proteins (cyclophilins, CYPs). Many members in both FKBP and CYP families are peptidyl prolyl isomerases that are involved in protein folding processes, though they share little sequence homology. It is not surprising to find immunophilins in all organisms examined so far, including viruses, bacteria, fungi, plants and animals, as protein folding represents a common process in all living systems. SCOPE OF REVIEW: Studies on plant immunophilins have revealed new functions beyond protein folding and new structural properties beyond that of typical PPIases. This review focuses on the structural and functional diversity of plant FKBPs and CYPs. MAJOR CONCLUSIONS: The differences in sequence, structure as well as subcellular localization, have added on to the diversity of this family of molecular chaperones. In particular, the large number of immunophilins present in the thylakoid lumen of the photosynthetic organelle, promises to deliver insights into the regulation of photosynthesis, a unique feature of plant systems. However, very little structural information and functional data are available for plant immunophilins. GENERAL SIGNIFICANCE: Studies on the structure and function of plant immunophilins are important in understanding their role in plant biology. By reviewing the structural and functional properties of some immunophilins that represent the emerging area of research in plant biology, we hope to increase the interest of researchers in pursuing further research in this area. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25529303 TI - Features of autism spectrum disorder (ASD) in childhood epilepsy: a population based study. AB - In a defined geographical area in the south of the UK, 115 children with active epilepsy (i.e., children who had seizures in the last year and/or children who were taking antiepileptic drugs (AEDs)) were identified via a computerized database and liaison with local pediatricians. Eighty-five (74%) of the children (5-15years of age) underwent a comprehensive psychological assessment. Twenty-one percent of the children met the DSM-IV-TR criteria for ASD, and 61% of those with ASD had another DSM-IV-TR behavioral or motor disorder. The Autism Spectrum Screening Questionnaire (ASSQ) was completed by parents (n=69) and by teachers (n=67) of children with an IQ>34. Only 9% of children on parent ratings and 15% of children on teacher ratings had no features of ASD. Parents reported significantly (p<.05) more features of ASD on the ASSQ compared with teachers. Factors significantly associated with responses on the ASSQ included respondent (parents reported more features), school placement (more features in specialized settings), and respondent by school placement interaction. Effective screening for ASD in children with epilepsy will need a consideration of the impact of informant and school placement on ratings. In conclusion, features of ASD were common in children with epilepsy regardless of cognitive ability. The ASSQ was a useful screening instrument in this population, and combining parent and teacher forms was optimal in terms of screening properties. PMID- 25529305 TI - Inhibiting reactions to emotional versus non-emotional response cues in schizophrenia: Insights from a motor-process paradigm. AB - Recent models of schizophrenia suggest deficient use of contextual response cues when confronted with countermanding emotional cues. It is important to clinically validate these models by testing patients diagnosed with schizophrenia on tasks with competing emotional and contextual response determinants. Control and schizophrenia groups completed a novel task that elicited motor responses consistent with, or in opposition to, pre-potent emotional actions (i.e., approach vs. avoidance). An analogous non-emotional task was also used to examine cue-conflict impairment more generally. The groups demonstrated statistically equivalent performance decrements on incongruent versus congruent trials on both tasks. However, within the schizophrenia group, the incongruency effect was significantly greater in the emotional versus non-emotional task. These data suggest that, while patients with schizophrenia were able to employ contextual response cues to override competing emotional responses, they were slower to resolve emotional versus non-emotional response conflict. When patients were subdivided according to the presence or absence of disorganized symptoms, this effect was confined to patients with disorganized symptoms. PMID- 25529306 TI - Systematic study of binding of MU-conotoxins to the sodium channel NaV1.4. AB - Voltage-gated sodium channels (NaV) are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the NaV channels in the nervous system has been exploited by venomous animals for preying purposes, which have developed toxins that can block the NaV channels, thereby disabling their function. Because of their potency, such toxins could provide drug leads for the treatment of neurological disorders associated with NaV channels. However, most toxins lack selectivity for a given target NaV channel, and improving their selectivity profile among the NaV1 isoforms is essential for their development as drug leads. Computational methods will be very useful in the solution of such design problems, provided accurate models of the protein-ligand complex can be constructed. Using docking and molecular dynamics simulations, we have recently constructed a model for the NaV1.4-MU-conotoxin-GIIIA complex and validated it with the ample mutational data available for this complex. Here, we use the validated NaV1.4 model in a systematic study of binding other MU-conotoxins (PIIIA, KIIIA and BuIIIB) to NaV1.4. The binding mode obtained for each complex is shown to be consistent with the available mutation data and binding constants. We compare the binding modes of PIIIA, KIIIA and BuIIIB to that of GIIIA and point out the similarities and differences among them. The detailed information about NaV1.4-MU-conotoxin interactions provided here will be useful in the design of new NaV channel blocking peptides. PMID- 25529308 TI - Investigation of solvent dynamic effects on the electron self-exchange in two thianthrene couples with large inner reorganization energies. AB - The large structural difference between thianthrene radical cations and their neutral parent molecules can possibly affect their electron self-exchange reactions. Before this can be investigated experimentally, it is necessary to first understand the influence of the solvent on such electron transfer reactions. To achieve this, the rate constants of the electron self-exchange reactions of the Th(+)/Th and MTh(+)/MTh (Th = thianthrene, MTh = 2,3,7,8 tetramethoxythianthrene) couples were investigated by means of ESR line broadening experiments in different solvents at 293 K. The diffusion corrected rate constants cover a range of 7.2 * 10(8)<=ket<= 44 * 10(8) M(-1) s(-1) for Th(+)/Th and 2.0 * 10(8)<=ket<= 11.6 * 10(8) M(-1) s(-1) for MTh(+)/MTh, respectively. The results were analysed within the framework of the Marcus Theory and the characteristic reorganization energy, lambda, was determined. Both couples clearly show a solvent dynamic effect controlled by the longitudinal relaxation time tauL of the solvents. However, the influence of the structural changes, in terms of lambda, was smaller than expected at room temperature. PMID- 25529307 TI - The finding of a group IIE phospholipase A2 gene in a specified segment of Protobothrops flavoviridis genome and its possible evolutionary relationship to group IIA phospholipase A2 genes. AB - The genes encoding group IIE phospholipase A2, abbreviated as IIE PLA2, and its 5' and 3' flanking regions of Crotalinae snakes such as Protobothrops flavoviridis, P. tokarensis, P. elegans, and Ovophis okinavensis, were found and sequenced. The genes consisted of four exons and three introns and coded for 22 or 24 amino acid residues of the signal peptides and 134 amino acid residues of the mature proteins. These IIE PLA2s show high similarity to those from mammals and Colubridae snakes. The high expression level of IIE PLA2s in Crotalinae venom glands suggests that they should work as venomous proteins. The blast analysis indicated that the gene encoding OTUD3, which is ovarian tumor domain-containing protein 3, is located in the 3' downstream of IIE PLA2 gene. Moreover, a group IIA PLA2 gene was found in the 5' upstream of IIE PLA2 gene linked to the OTUD3 gene (OTUD3) in the P. flavoviridis genome. It became evident that the specified arrangement of IIA PLA2 gene, IIE PLA2 gene, and OTUD3 in this order is common in the genomes of humans to snakes. The present finding that the genes encoding various secretory PLA2s form a cluster in the genomes of humans to birds is closely related to the previous finding that six venom PLA2 isozyme genes are densely clustered in the so-called NIS-1 fragment of the P. flavoviridis genome. It is also suggested that venom IIA PLA2 genes may be evolutionarily derived from the IIE PLA2 gene. PMID- 25529309 TI - Design and participant baseline characteristics of 'A Clinical Trial of IntensiVE Dialysis': the ACTIVE Dialysis Study. AB - AIMS: Observational reports suggest extended dialysis hours are associated with improved outcomes. These findings are confounded by better prognostic characteristics among people practising extended hours. The aim of this article is to provide an overview of the methods and baseline characteristics for ACTIVE Dialysis Study participants. METHODS: This multicentre, randomized, open-label, blinded endpoint-assessment trial randomized participants receiving maintenance haemodialysis therapy to either extended (>=24 h) or standard (12-18 h) weekly haemodialysis for 12 months. A web-based randomization system used minimization to ensure balanced allocation across regions, dialysis setting and dialysis vintage. The primary outcome is the change in quality of life over 12 months of study treatment assessed by EQ-5D. Secondary outcomes include change in left ventricular mass index assessed by magnetic resonance imaging and safety outcomes including dialysis access events. RESULTS: A total of 200 participants were recruited between 2009 and 2013 from Australia (29.0%), China (62.0%), Canada (5.5%) and New Zealand (3.5%). Participants had a mean age of 52 (+/- 12) years and 11.5% were dialysing at home, with a mean duration of 13.9 h per week over a median of three sessions. At baseline, 32.5% had a history of cardiovascular disease and 36.5% had diabetes. CONCLUSION: The ACTIVE Dialysis Study has met its planned recruitment target. The participant population are drawn from a range of health service settings in a global context. The study will contribute important evidence on the benefits and harms of extending weekly dialysis hours. The trial is registered at clinicaltrials.gov (NCT00649298). PMID- 25529312 TI - Changes in Quality of Health Care Delivery after Vertical Integration. AB - OBJECTIVES: To fill an empirical gap in the literature by examining changes in quality of care measures occurring when multispecialty clinic systems were acquired by hospital-owned, vertically integrated health care delivery systems in the Twin Cities area. DATA SOURCES/STUDY SETTING: Administrative data for health plan enrollees attributed to treatment and control clinic systems, merged with U.S. Census data. STUDY DESIGN: We compared changes in quality measures for health plan enrollees in the acquired clinics to enrollees in nine control groups using a differences-in-differences model. Our dataset spans 2 years prior to and 4 years after the acquisitions. We estimated probit models with errors clustered within enrollees. DATA COLLECTION/EXTRACTION METHODS: Data were assembled by the health plan's informatics team. PRINCIPAL FINDINGS: Vertical integration is associated with increased rates of colorectal and cervical cancer screening and more appropriate emergency department use. The probability of ambulatory care sensitive admissions increased when the acquisition caused disruption in admitting patterns. CONCLUSIONS: Moving a clinic system into a vertically integrated delivery system resulted in limited increases in quality of care indicators. Caution is warranted when the acquisition causes disruption in referral patterns. PMID- 25529313 TI - The structure and component characteristics of partial nitrification biofilms under autotrophic and heterotrophic conditions. AB - The differences in the structure and component characteristics of partial nitrification biofilms between autotrophic and heterotrophic conditions were investigated in this work. Three-dimensional excitation-emission matrix fluorescence spectroscopy (EEM), fluorescence staining, and confocal laser scanning microscopy (CLSM) were used to determine differences in the architecture and extracellular polymeric substance (EPS) distribution of the autotrophic and heterotrophic biofilms. Partial nitrification was successfully achieved, and the results demonstrated that an appropriate amount of organic carbon (chemical oxygen demand (COD)/N = 2.6) is advantageous for obtaining better partial nitrification. The final ammoniation and nitrosation rates achieved were 97 and 99 %, respectively. Proteins (PN) and polysaccharides (PS) were dominant in the tightly bound EPS (TB-EPS) of autotrophic and heterotrophic biofilms, with PN/PS ratios of 0.96 and 0.69, respectively. Proteins, lipids, alpha-D-glucopyranose polysaccharides, and nucleic acids were mostly present within the layers of biofilms, but they were distributed in the upper-middle portion of the autotrophic biofilm and increased with depth from the upper layer in the heterotrophic biofilms. PMID- 25529314 TI - Tyramine biosynthesis is transcriptionally induced at low pH and improves the fitness of Enterococcus faecalis in acidic environments. AB - Enterococcus faecalis is a commensal bacterium of the human gut that requires the ability to pass through the stomach and therefore cope with low pH. E. faecalis has also been identified as one of the major tyramine producers in fermented food products, where they also encounter acidic environments. In the present work, we have constructed a non-tyramine-producing mutant to study the role of the tyramine biosynthetic pathway, which converts tyrosine to tyramine via amino acid decarboxylation. Wild-type strain showed higher survival in a system that mimics gastrointestinal stress, indicating that the tyramine biosynthetic pathway has a role in acid resistance. Transcriptional analyses of the E. faecalis V583 tyrosine decarboxylase cluster showed that an acidic pH, together with substrate availability, induces its expression and therefore the production of tyramine. The protective role of the tyramine pathway under acidic conditions appears to be exerted through the maintenance of the cytosolic pH. Tyramine production should be considered important in the adaptability of E. faecalis to acidic environments, such as fermented dairy foods, and to survive passage through the human gastrointestinal tract. PMID- 25529315 TI - Genome-wide identification, expression analysis of GH3 family genes in Medicago truncatula under stress-related hormones and Sinorhizobium meliloti infection. AB - Auxin plays a pivotal role in the regulation of plant growth and development by controlling the expression of auxin response genes rapidly. As one of the major auxin early response gene families, Gretchen Hagen 3 (GH3) genes are involved in auxin homeostasis by conjugating excess auxins to amino acids. However, how GH3 genes function in environmental stresses and rhizobial infection responses in Medicago truncatula are largely unknown. Here, based on the latest updated M. truncatula genome, a comprehensive identification and expression profiling analysis of MtGH3 genes were performed. Our data showed that most of MtGH3 genes were expressed in tissue-specific manner and were responsive to environmental stress-related hormones. To understand the possible roles of MtGH3 genes involved in symbiosis establishment between M. truncatula and symbiotic bacteria, quantitative real-time polymerase chain reaction (qRT-PCR) was used to test the expressions of MtGH3 genes during the early phase of Sinorhizobium meliloti infection. The expression levels of most MtGH3 genes were upregulated in shoots and downregulated in roots by S. meliloti infection. The differences in expression responses to S. meliloti infection between roots and shoots were in agreement with the results of free indoleacetic acid (IAA) content measurements. The identification and expression analysis of MtGH3 genes at the early phase of S. meliloti infection may help us to understand the role of GH3-mediated IAA homeostasis in the regulation of nodule formation in model legumes M. truncatula. PMID- 25529316 TI - A novel homozygous nonsense mutation in the PVRL4 gene and expansion of clinical spectrum of EDSS1. AB - Ectodermal dysplasias (EDs) belong to a group of genetic diseases which result from alterations in ectoderm-derived appendages including hair, nail, teeth and sweat glands. Ectodermal dysplasia syndactyly syndrome (EDSS1) is one of the rare forms of ED caused by mutations in nectin-4, encoded by the PVRL4 gene. The present study described clinical investigation of the EDSS1 identified in a large consanguineous family. Furthermore, DNA sequence analysis revealed a novel homozygous nonsense mutation (181C>T, p.Asp61*) in the PVRL4 gene. PMID- 25529317 TI - Influence of transrectal and transabdominal ultrasound examination on salivary cortisol, heart rate, and heart rate variability in mares. AB - Pregnancy diagnostics in equine reproduction are routinely performed using transrectal ultrasonography, although it is also possible to visualize the fetus by transabdominal ultrasound examinations from the 90th day of gestation onward. We hypothesized that ultrasound examinations may stress the mare and that the gestational stage status and lactation may influence the mare's stress reaction. To investigate the stress reaction, 25 thoroughbred mares of different age, pregnancy and lactational status underwent a transrectal examination. In pregnant mares, an additional transabdominal examination was performed. Salivary cortisol concentration, mean heart rate, and heart rate variability of mares were assessed to evaluate the reactions of hypothalamic-pituitary-adrenal (HPA) axis and of the autonomic nervous system. Significant differences were observed between lactating and nonlactating mares; with a lower responsiveness to stress in lactating mares. The transrectal ultrasound examination in nonlactating mares induced a significant increase in salivary cortisol (P < 0.05), and in the heart rate variability parameter, ratio of low to high frequencies (P < 0.05). This reflects an activation of the HPA axis and a shift to more sympathetic dominance. In contrast, a transabdominally performed pregnancy check did not induce an activation of the HPA axis over basal level but increased the mean heart rate and low to high frequency ratio. The results of this study indicate that checks of advanced pregnancies can be easily performed by transabdominal ultrasonography. With regard to animal welfare, this technique should be preferred during midgestation in nonlactating mares. PMID- 25529318 TI - 46,XX testicular disorder of sexual development with SRY-negative caused by some unidentified mechanisms: a case report and review of the literature. AB - BACKGROUND: 46,XX testicular disorder of sex development is a rare genetic syndrome, characterized by a complete or partial mismatch between genetic sex and phenotypic sex, which results in infertility because of the absence of the azoospermia factor region in the long arm of Y chromosome. CASE PRESENTATION: We report a case of a 14-year-old male with microorchidism and mild bilateral gynecomastia who referred to our hospital because of abnormal gender characteristics. The patient was treated for congenital scrotal type hypospadias at the age of 4 years. Semen analysis indicated azoospermia by centrifugation of ejaculate. Levels of follicle-stimulating hormone and luteinizing hormone were elevated, while that of testosterone was low and those of estradiol and prolactin were normal. The results of gonadal biopsy showed hyalinization of the seminiferous tubules, but there was no evidence of spermatogenic cells. Karyotype analysis of the patient confirmed 46,XX karyotype and fluorescent in situ hybridization analysis of the sex-determining region Y (SRY) gene was negative. Molecular analysis revealed that the SRY gene and the AZFa, AZFb and AZFc regions were absent. No mutation was detected in the coding region and exon/intron boundaries of the RSPO1, DAX1, SOX9, SOX3, SOX10, ROCK1, and DMRT genes, and no copy number variation in the whole genome sequence was found. CONCLUSION: This study adds a new case of SRY-negative 46,XX testicular disorder of sex development and further verifies the view that the absence of major regions from the Y chromosome leads to an incomplete masculine phenotype, abnormal hormone levels and infertility. To date, the mechanisms for induction of testicular tissue in 46,XX SRY-negative patients remain unknown, although other genetic or environmental factors play a significant role in the regulation of sex determination and differentiation. PMID- 25529319 TI - Epidermal Choristoma of the Tongue Mimicking a Congenital Melanotic Macule. AB - We report the fifth case of epidermal choristoma of the oral cavity in a Caucasian newborn with a congenital melanotic macule on the dorsum of the tongue. Epidermal choristoma is an exceedingly rare and benign condition probably caused by a developmental abnormality. It is identified according to the presence of normal skin in an abnormal location. Histologically it is identified according to areas of stratified epithelium and hyperpigmentation of the basal layer along with cutaneous adnexal structures (hair follicles, sebaceous or sweat glands). The clinical presentation is variable, but most of the cases described presented with a congenital lingual pigmented macule. These lesions should be included within the differential diagnosis of congenital lingual macules and distinguished from other entities such as congenital lingual melanotic macules and melanocytic lesions. Surgical excision is the treatment of choice. Epidermal choristoma is a benign condition that probably is underdiagnosed because it is a new and rare entity, and dermatologists should be aware of it. PMID- 25529320 TI - Women's experiences, preferences and perceptions regarding vaginal products: Results from a cross-sectional web-based survey in Portugal. AB - OBJECTIVE: We aimed to identify Portuguese women's experiences, preferences and perceptions regarding vaginal products. METHODS: A descriptive cross-sectional study was conducted (February-May 2013) among Portuguese women (aged 18 to 65 years) using an online questionnaire. Descriptive and chi-squared statistics were applied. RESULTS: Among 2529 women, 85.4% had used vaginal products, mostly to manage vulvovaginal infections (75.3%). Gels, creams and ointments (semi-solids) were the most frequently used (82%), followed by vaginal suppositories (56.5%) and tablets/capsules (41.8%), while vaginal rings were used by 10% of women. Semi solids were preferred as an intravaginal medication both by women who had previously used them and by women who had never used an intravaginal product, while preference for vaginal rings was higher only among women who had previously used them. Even though 87.1% of all women considered vaginal drug delivery to be advantageous, the majority preferred to use oral products. Leakage (84.8%) and insertion difficulties (58.4%) were the main problems reported for vaginal products. CONCLUSIONS: Overall, semi-solids were the most used and preferred vaginal products, while vaginal rings were highly acceptable for women who had previously used them. Although they considered the vaginal route to be more efficient and safe, many women felt it to be less appealing than the oral route, particularly due to comfort issues. PMID- 25529327 TI - The reminiscence bump in autobiographical memory and for public events: A comparison across different cueing methods. AB - The reminiscence bump has been found for both autobiographical memories and memories of public events. However, there have been few comparisons of the bump across each type of event. In the current study, therefore, we compared the bump for autobiographical memories versus the bump for memories of public events. We did so between-subjects, through two cueing methods administered within-subjects, the cue word method and the important memories method. For word-cued memories, we found a similar bump from ages 5 to 19 for both types of memories. However, the bump was more pronounced for autobiographical memories. For most important memories, we found a bump from ages 20 to 29 in autobiographical memory, but little discernible age pattern for public events. Rather, specific public events (e.g., the Fall of the Berlin Wall) dominated recall, producing a chronological distribution characterised by spikes in citations according to the years these events occurred. Follow-up analyses suggested that the bump in most important autobiographical memories was a function of the cultural life script. Our findings did not yield support for any of the dominant existing accounts of the bump as underlying the bump in word-cued memories. PMID- 25529328 TI - Silencing miR-106b improves palmitic acid-induced mitochondrial dysfunction and insulin resistance in skeletal myocytes. AB - MicroRNA-106b (miR-106b) is reported to correlate closely with skeletal muscle insulin resistance. In the current study the effect of miR-106b on palmitic acid (PA)-induced mitochondrial dysfunction and insulin resistance was investigated in C2C12 myotubes via the silencing of miR-106b. MiR-106b expression was increased under PA treatment, while miR-106b loss of function improved insulin sensitivity by upregulating its target mitofusin-2 (Mfn2) in C2C12 myocytes. Furthermore, miR 106b loss of function partly improved mitochondrial morphological lesions and increased the levels of mitochondial DNA and intracellular adenosine triphosphate that had been impaired by PA exposure in C2C12 myocytes. MiR-106b loss of function attenuated the levels of intracellular reactive oxygen species (ROS), and upregulated the expression levels of the estrogen-related receptor (ERR) alpha/peroxisome proliferative activated receptor gamma coactivator (PGC) 1alpha/Mfn2 axis under PA exposure. In addition, miR-106b negatively regulated skeletal muscle mitochondrial function and insulin sensitivity under PA-induced insulin resistance by targeting Mfn2, which may be associated with reduced ROS and upregulation of the ERR-alpha/PGC-1alpha/Mfn2 axis. PMID- 25529329 TI - Color assimilation of resin composites with adjacent color according to the distance. AB - STATEMENT OF PROBLEM: Color of esthetic restorative materials shifts toward color of adjacent material. PURPOSE: The purposes were to determine the amount of distance-dependent color shift in resin composites toward the color of adjacent materials and to define a color shift parameter (CSP) that can quantify this phenomenon. METHODS: Three brands of resin composites, two shades for each, were investigated. Specimens of 2 (thickness) * 4 (width) * 16 (length) mm(3) were fixed in an adjustable XY stage in contact with black and white ceramic tiles at each end. Color was measured by a spectroradiometer at seven separated points in 2-mm intervals, in which P1 was 2 mm away from the black tile. Mean value of the color differences (DeltaE*ab ) between P1 and each of the other measurement points (P2-P6) was defined as the CSP, in which higher CSP value indicated smaller color assimilation toward P1 color. RESULTS: The range of the CSP was 7.5 12.4, which was influenced by the brand and shade of resin composites (p < 0.05). CONCLUSIONS: The CSP defined in this study provided the amount of color shift of esthetic materials toward adjacent color, which indicated the color assimilation effect of these materials. CLINICAL SIGNIFICANCE: The CSP investigated in the present study might be used to compare the tendency of color assimilation of esthetic restorative materials, and proper CSP ranges for optimal color assimilation or color blocking should be further determined. PMID- 25529333 TI - Structure of an electric double layer containing a 2:2 valency dimer electrolyte. AB - The structure of a planar electric double layer formed by a 2:2 valency dimer electrolyte in the vicinity of a uniformly charged planar hard electrode is investigated using density functional theory and Monte Carlo simulations. The dimer electrolyte consists of a mixture of charged divalent dimers and charged divalent monomers in a dielectric continuum. A dimer is constructed by two tangentially tethered rigid spheres, one of which is divalent and positively charged and the other neutral, whereas the monomer is a divalent and negatively charged rigid sphere. The density functional theory reproduces well the simulation results for (i) the singlet distributions of the various ion species with respect to the electrode, and (ii) the mean electrostatic potential. Comparison with earlier results for a 2:1/1:2 dimer electrolyte shows that the double layer structure is similar when the counterion has the same valency. PMID- 25529330 TI - Arecoline increases basic fibroblast growth factor but reduces expression of IL 1, IL-6, G-CSF and GM-CSF in human umbilical vein endothelium. AB - BACKGROUND: Areca nut chewing is associated with oral submucous fibrosis (OSF). Raised vascular basic fibroblast growth factor may induce fibrosis. Arecoline is a muscarinic alkaloid in areca nut, which we earlier reported causes injury and necrosis of human endothelium. MATERIALS AND METHODS: Human umbilical vein endothelial cells were exposed to arecoline with or without tumor necrosis factor alpha, and separately to acetylcholine, muscarine, or nicotine. Protein levels of basic fibroblast growth factor, as well as the inflammatory cytokines: granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor, and Interleukins-6, 1-alpha and 1-beta, were determined by enzyme-linked immunosorbent assay. mRNA levels were established by real-time reverse transcription polymerase chain reaction. RESULTS: Basic fibroblast growth factor was released into the culture medium at arecoline levels causing necrosis (P < 0.05). This contrasted with an opposite effect of arecoline on levels of the inflammatory cytokines (P < 0.05). Tumor necrosis factor-alpha increased IL-6 and granulocyte-macrophage colony stimulated factor, but arecoline reduced this stimulated expression (P < 0.05). Arecoline had no effect on mRNA for basic fibroblast growth factor, although there was reduced mRNA for the separate inflammatory cytokines studied. The effect of acetylcholine, muscarine, and nicotine was minimal and dissimilar to that of arecoline. CONCLUSIONS: Data raise the possibility that arecoline-induced, vascular basic fibroblast growth factor contributes to OSF, by combining increased growth factor expression with endothelial necrosis, and thus driving fibroblast proliferation. PMID- 25529334 TI - Nano-micro structured superhydrophobic zinc coating on steel for prevention of corrosion and ice adhesion. AB - Thin films of zinc have been deposited on steel substrates by electrodeposition process and further functionalized with ultra-thin films of commercial silicone rubber, in order to obtain superhydrophobic properties. Morphological feature, by scanning electron microscope (SEM), shows that the electrodeposited zinc films are composed of micro-nano rough patterns. Furthermore, chemical compositions of these films have been analyzed by X-ray diffraction (XRD) and infra-red (IRRAS). An optimum electrodeposition condition, based on electrical potential and deposition time, has been obtained which provides superhydrophobic properties with a water contact angle of 155+/-1 degrees . The corrosion resistance properties, in artificial seawater, of the superhydrophobic zinc coated steel are found to be superior to bare steel. Similarly, the measured ice adhesion strength on superhydrophobic surfaces, using the centrifugal adhesion test (CAT), is found to be 6.3 times lower as compared to bare steel. This coating has promising applications in offshore environment, to mitigate corrosion and reduce ice adhesion. PMID- 25529335 TI - On the stability of Pt(IV) pro-drugs with haloacetato ligands in the axial positions. AB - The design of Pt(IV) pro-drugs as anticancer agents is predicated on the assumption that they will not undergo substitution reactions before entering the cancer cell. Attempts to improve the cytotoxic properties of Pt(IV) pro-drugs included the use of haloacetato axial ligands. Herein, we demonstrate that Pt(IV) complexes with trifluoroacetato (TFA) or dichloroacetato (DCA) ligands can be unstable under biologically relevant conditions and readily undergo hydrolysis, which results in the loss of the axial TFA or DCA ligands. The half-lives for Pt(IV) complexes with two TFA or DCA ligands at pH 7 and 37 degrees C range from 6 to 800 min, which is short relative to the duration of cytotoxicity experiments that last 24-96 h. However, complexes with two monochloroacetato (MCA) or acetato axial ligands are stable under biologically relevant conditions. The loss of the axial ligands depends primarily on the electron-withdrawing strength of the axial ligands, but also upon the nature of the equatorial ligands. We were unable to find obvious correlations between the structures of the Pt(IV) complexes and the rates of decay of the parent compounds. The X-ray crystal structures of the bis DCA and bis-MCA Pt(IV) derivatives of oxaliplatin did not reveal any significant structural differences that could explain the observed differences in stability. PMID- 25529336 TI - Neutral Pectin side chains of Amaranth (Amaranthus hypochondriacus) contain long, partially branched Arabinans and short galactans, both with terminal arabinopyranoses. AB - Amaranth is a pseudocereal of high nutritional value, including a high dietary fiber content. Amaranth dietary fiber was suggested to contain large amounts of neutral rhamnogalacturonan I side chains. In this study, endo-arabinanase and endo-galactanase were used to liberate arabinan and galactan oligosaccharides from amaranth fiber. The liberated oligosaccharides were identified by high performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and HPLC-MS(n) using standard compounds, which were isolated from amaranth, sugar beet, potato, and red clover sprouts and characterized by one- and two-dimensional NMR spectroscopy. It was demonstrated that insoluble amaranth arabinans have linear and branched areas, with the O-3 position being the dominant branching point. Minor amounts of branches at position O-2 and double substitution were also found. Amaranth arabinans were also demonstrated to contain terminal alpha-(1->5)-linked l-arabinopyranose units. In addition, it was evidenced that galactans from amaranth seeds are composed of beta-(1->4)-linked d galactopyranose units, which can also be terminated with l-arabinopyranose units. In direct comparison to structural elucidation of amaranth fiber by using methylation analysis, the advantage of the enzymatic approach over methylation analysis was demonstrated. PMID- 25529337 TI - Human cell lines for the production of recombinant proteins: on the horizon. AB - The market of recombinant proteins as human pharmaceuticals has surpassed annual revenues of more than 150 billion dollars. The marketed proteins are often complex in terms of post-translational modifications and conventional hosts have shown weaknesses in terms of quality of these recombinant proteins. Especially the non-human glycopatterns leading to immunogenicity or shortened in vivo half life have gained attention over the past decade. Therefore, production cell lines with better or novel characteristics are required and human cell lines seem to be the most genuine and logical choice. Thus, several human cell lines have been used to generate biopharmaceuticals. We here present an overview of such examples and highlight their promise for biopharmaceutical production processes of the future. PMID- 25529338 TI - Targeted prodrug approaches for hormone refractory prostate cancer. AB - Due to the propensity of relapse and resistance with prolonged androgen deprivation therapy (ADT), there is a growing interest in developing non-hormonal therapeutic approaches as alternative treatment modalities for hormone refractory prostate cancer (HRPC). Although the standard treatment for HRPC consists of a combination of ADT with taxanes and anthracyclines, the clinical use of chemotherapeutics is limited by systemic toxicity stemming from nondiscriminatory drug exposure to normal tissues. In order to improve the tumor selectivity of chemotherapeutics, various targeted prodrug approaches have been explored. Antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) strategies leverage tumor-specific antigens and transcription factors for the specific delivery of cytotoxic anticancer agents using various prodrug-activating enzymes. In prostate cancer, overexpression of tumor-specific proteases such as prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) is being exploited for selective activation of anticancer prodrugs designed to be activated through proteolysis by these prostate cancer-specific enzymes. PSMA- and PSA-activated prodrugs typically comprise an engineered high specificity protease peptide substrate coupled to a potent cytotoxic agent via a linker for rapid release of cytotoxic species in the vicinity of prostate cancer cells following proteolytic cleavage. Over the past two decades, various such prodrugs have been developed and they were effective at inhibiting prostate tumor growth in rodent models; several of these prodrug approaches have been advanced to clinical trials and may be developed into effective therapies for HRPC. PMID- 25529340 TI - Sexual and reproductive health in cystic fibrosis: a life-course perspective. AB - Adolescents and adults with cystic fibrosis now approach developmental milestones, including sexual and reproductive ones, at a similar time to their healthy peers. Yet, their sexual and reproductive health (SRH) is profoundly affected by their disease, and their SRH decisions can substantially affect their health. Navigation of SRH milestones in the context of cystic fibrosis needs education, guidance, and access to SRH services. In this Review, we discuss scientific knowledge of SRH in patients with cystic fibrosis across the life course and clinical practices for SRH within cystic fibrosis care. We identify crucial gaps in SRH education of patients and their access to resources and then present a model of care for provision of developmentally appropriate SRH education and care within cystic fibrosis services across the life course. This model emphasises the central importance of the cystic fibrosis team and service links to primary and specialist SRH care. PMID- 25529339 TI - Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. AB - BACKGROUND: No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow derived MSCs in patients with moderate-to-severe ARDS. METHODS: The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774. FINDINGS: No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related. INTERPRETATION: A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints. FUNDING: The National Heart, Lung, and Blood Institute. PMID- 25529341 TI - Cell therapies for ARDS: a promising start. PMID- 25529342 TI - Educational campaigns at point of purchase in rural supermarkets improve stroke knowledge. AB - BACKGROUND: The number of elderly people is dramatically increasing, and this trend is especially pronounced in rural populations. The aim of the present study was to verify the effectiveness of stroke education in a rural area. METHODS: The stroke educational flyers were distributed for 3 weeks at the point of purchase within supermarkets. Questionnaires were used to determine knowledge about stroke and appropriate emergent action on identifying stroke. RESULTS: A total of 882 people responded to the questionnaires before (n = 409) and 3 months after (n = 473) the campaign. Of these, 686 (77.8%) were aged 65 years or older. The percentages of correct answers for hemiplegia and one-sided numbness (P < .05 for both) and calling emergency medical services (EMS) on identifying stroke occurrence (P < .001) were higher after the campaign compared with those before the campaign. Of the respondents aged 65 years or older, the percentages of correct answers for numbness on one side and calling for EMS on identifying stroke were higher after the campaign (P < .05 and P < .001, respectively). CONCLUSIONS: A simple point-of-purchase stroke campaign using educational flyers could meaningfully affect stroke knowledge among elderly persons in a rural community. PMID- 25529343 TI - CYP2C19 genotype and early ischemic lesion recurrence in stroke patients treated with clopidogrel. AB - BACKGROUND: Early recurrent ischemic lesions detected on diffusion-weighted imaging (DWI) have been proposed as a surrogate marker for clinical recurrence. We hypothesized that cytochrome P450 2C19 (CYP2C19) genotype influences the incidence of early recurrence on DWI in acute stroke patients treated with clopidogrel. METHODS: We enrolled 76 Korean patients with acute ischemic stroke due to large artery atherosclerosis who were treated with clopidogrel. Early ischemic lesion recurrence was defined as new lesions separate from the index lesion. We compared the rates of early ischemic lesion recurrence on DWI based on the CYP2C19 genotypes. RESULTS: Early recurrence on DWI was observed in 36 patients (47.4%). A total of 76 patients were classified into 3 phenotypic groups: extensive metabolizers (EMs; n = 27, 35.5%), intermediate metabolizers (IMs; n = 36, 47.4%), and poor metabolizers (PMs; n = 13, 17.1%). Early recurrence on DWI was more common in PMs (84.6%), followed by IMs (50.0%), and EMs (25.9%; P < .001). PMs had a significantly higher recurrence rate than EMs (P < .001). In multivariate analysis, CYP2C19 genotypes were independently associated with early DWI recurrence (for PMs: odds ratio, 19.3; 95% confidence interval, 3.15-117.56). CONCLUSIONS: CYP2C19 genotypes are significantly associated with early lesion recurrence in Korean acute stroke patients treated with clopidogrel. PMID- 25529344 TI - Determination of the maximum operating range of hydrodynamic stress in mammalian cell culture. AB - Application of quality by design (QbD) requires identification of the maximum operating range for parameters affecting the cell culture process. These include hydrodynamic stress, mass transfer or gradients in dissolved oxygen and pH. Since most of these are affected by the impeller design and speed, the main goal of this work was to identify a maximum operating range for hydrodynamic stress, where no variation of cell growth, productivity and product quality can be ensured. Two scale-down models were developed operating under laminar and turbulent condition, generating repetitive oscillating hydrodynamic stress with maximum stress values ranging from 0.4 to 420Pa, to compare the effect of the different flow regimes on the cells behavior. Two manufacturing cell lines (CHO and Sp2/0) used for the synthesis of therapeutic proteins were employed in this study. For both cell lines multiple process outputs were used to determine the threshold values of hydrodynamic stress, such as cell growth, morphology, metabolism and productivity. They were found to be different in between the cell lines with values equal to 32.4+/-4.4Pa and 25.2+/-2.4Pa for CHO and Sp2/0, respectively. Below the measured thresholds both cell lines do not show any appreciable effect of the hydrodynamic stress on any critical quality attribute, while above, cells responded negatively to the elevated stress. To confirm the applicability of the proposed method, the obtained results were compared with data generated from classical small-scale reactors with a working volume of 3L. PMID- 25529345 TI - Heterologous expression of an orphan NRPS gene cluster from Paenibacillus larvae in Escherichia coli revealed production of sevadicin. AB - The Gram-positive bacterium Paenibacillus larvae is the causative agent of the fateful honey bee disease American Foulbrood (AFB). Sequence analysis of P. larvae genomic DNA showed the presence of numerous nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding gene clusters, not correlating with secondary metabolite production. As NRPS and PKS derived metabolites are known to exhibit diverse biological activities, their identification is of particular interest for infection and drug research. Here an 11.6kb orphan NRPS gene cluster was directly cloned from the genomic DNA of P. larvae and expressed in Escherichia coli resulting in the production of sevadicin. Isolation of the metabolite was followed by structural characterization, synthesis and bioactivity studies. PMID- 25529346 TI - Limitations in the process of transcription and translation inhibit recombinant human chorionic gonadotropin expression in CHO cells. AB - Human chorionic gonadotropin (hCG) is a glycoprotein hormone that exists as a heterodimer with a alpha subunit and beta subunit assembled together with disulfide bridges. This hormone plays an important role in the detection of ovulation induction and in the treatment of certain diseases that cause female infertility. The effects of transcription, subunit expression, assembling and secretion on recombinant hCG expression in CHO cells were studied using stable high-producing and low-producing cell lines generated by the FLP-InTM system. The results indicated that the mRNA and polypeptide levels of the beta subunit were always higher than those of the alpha subunit. Further study confirmed that the differences were caused by the transcription rate rather than by mRNA stability. In the high-producing cell lines, there was obvious transcription level limitation of the alpha subunit in contrast to the beta subunit. In addition, there was obvious limitation of the synthetic steps from mRNA to polypeptide for both the alpha subunit and the beta subunit, especially the beta subunit. Significant limitations of the assembly and secretion levels were not observed in this research. This study presents a research methodology for double subunit protein expression and provides valuable evidence for the enhancement of recombinant hCG productivity. PMID- 25529347 TI - Two-hybrid-based systems: powerful tools for investigation of membrane traffic machineries. AB - Protein-protein interactions regulate biological processes and are fundamental for cell functions. Recently, efforts have been made to define interactomes, which are maps of protein-protein interactions that are useful for understanding biological pathways and networks and for investigating how perturbations of these networks lead to diseases. Therefore, interactomes are becoming fundamental for establishing the molecular basis of human diseases and contributing to the discovery of effective therapies. Interactomes are constructed based on experimental data present in the literature and computational predictions of interactions. Several biochemical, genetic and biotechnological techniques have been used in the past to identify protein-protein interactions. The yeast two hybrid system has beyond doubt represented a revolution in the field, being a versatile tool and allowing the immediate identification of the interacting proteins and isolation of the cDNA coding for the interacting peptide after in vivo screening. Recently, variants of the yeast two-hybrid assay have been developed, including high-throughput systems that promote the rapidly growing field of proteomics. In this review we will focus on the role of this technique in the discovery of Rab interacting proteins, highlighting the importance of high throughput two-hybrid screening as a tool to study the complexity of membrane traffic machineries. PMID- 25529348 TI - Gateway-compatible vectors for high-throughput protein expression in pro- and eukaryotic cell-free systems. AB - Although numerous techniques for protein expression and production are available the pace of genome sequencing outstrips our ability to analyze the encoded proteins. To address this bottleneck, we have established a system for parallelized cloning, DNA production and cell-free expression of large numbers of proteins. This system is based on a suite of pCellFree Gateway destination vectors that utilize a Species Independent Translation Initiation Sequence (SITS) that mediates recombinant protein expression in any in vitro translation system. These vectors introduce C or N terminal EGFP and mCherry fluorescent and affinity tags, enabling direct analysis and purification of the expressed proteins. To maximize throughput and minimize the cost of protein production we combined Gateway cloning with Rolling Circle DNA Amplification. We demonstrate that as little as 0.1 ng of plasmid DNA is sufficient for template amplification and production of recombinant human protein in Leishmania tarentolae and Escherichia coli cell-free expression systems. Our experiments indicate that this approach can be applied to large gene libraries as it can be reliably performed in multi well plates. The resulting protein expression pipeline provides a valuable new tool for applications of the post genomic era. PMID- 25529349 TI - Potential challenges facing distributed leadership in health care: evidence from the UK National Health Service. AB - The discourse of leaderism in health care has been a subject of much academic and practical debate. Recently, distributed leadership (DL) has been adopted as a key strand of policy in the UK National Health Service (NHS). However, there is some confusion over the meaning of DL and uncertainty over its application to clinical and non-clinical staff. This article examines the potential for DL in the NHS by drawing on qualitative data from three co-located health-care organisations that embraced DL as part of their organisational strategy. Recent theorising positions DL as a hybrid model combining focused and dispersed leadership; however, our data raise important challenges for policymakers and senior managers who are implementing such a leadership policy. We show that there are three distinct forms of disconnect and that these pose a significant problem for DL. However, we argue that instead of these disconnects posing a significant problem for the discourse of leaderism, they enable a fantasy of leadership that draws on and supports the discourse. PMID- 25529350 TI - The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice. AB - Diabetic encephalopathy has recently been recognized late complication of diabetes resulting in progressive cognitive deficits. Emerging evidence has indicated that endoplasmic reticulum (ER) stress-mediated apoptosis is involved in the pathogenesis of diabetic eye and kidney as well as non-diabetic neurodegeneration. However, there was little direct evidence for the involvement of ER stress in diabetic encephalopathy up to now. In the present work, we investigated the role of ER stress in the pathogenesis of diabetic encephalopathy. Our results have demonstrated the existence of ER stress in the hippocampus of streptozotocin (STZ)-induced diabetic mice. STZ injection i.p. rapidly induced up-regulation of the ER stress marker, the prosurvival chaperone glucose-regulated protein 78 (GRP78), as early as 6-24h and persisted at least for up to 72h in the hippocampus of mice, indicating the UPR activation soon after STZ administration. The increased expression of GRP78 in hippocampal cells is to relieve the ER stress. With the development of diabetes, the expression of GRP78 decreases while the expression of UPR-associated proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) increases significantly in the hippocampal neurons of diabetic mice from 1 week after STZ administration to 12 weeks/the end of the study. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells in the hippocampus of diabetic mice were largely colocalized with NeuN- and CHOP-positive cells, indicating that the up regulation of CHOP in hippocampal neurons of diabetic mice may promote neuronal apoptosis and account for the damaged learning and memory ability of diabetic mice. Therefore, our study provides evidence that ER stress may play an important role in the pathogenesis of neuronal degeneration and may contribute to cognitive dysfunction of diabetic encephalopathy. PMID- 25529352 TI - Effects of oxygen concentration and pressure on Drosophila melanogaster: oxidative stress, mitochondrial activity, and survivorship. AB - Organisms are known to be equipped with an adaptive plasticity as the phenotype of traits in response to the imposed environmental challenges as they grow and develop. In this study, the effects of extreme changes in oxygen availability and atmospheric pressure on physiological phenotypes of Drosophila melanogaster were investigated to explore adaptation mechanisms. The changes in citrate synthase activity (CSA), lifespan, and behavioral function in different atmospheric conditions were evaluated. In the CAS test, hyperoxia significantly increased CSA; both hypoxia and hyperbaric conditions caused a significant decrease in CSA. In the survivorship test, all changed atmospheric conditions caused a significant reduction in lifespan. The lifespan reduced more after hypoxia exposure than after hyperbaria exposure. In behavioral function test, when mechanical agitation was conducted, bang-sensitive flies showed a stereotypical sequence of initial muscle spasm, paralysis, and recovery. The percentage of individuals that displayed paralysis or seizure was measured on the following day and after 2 weeks from each exposure. The majority of flies showed seizure behavior 15 days after exposure, especially after 3 h of exposure. The percentage of individuals that did not undergo paralysis or seizure and was able to move in the vial, was also tested. The number of flies that moved and raised the higher level of the vial decreased after exposure. Animal's speed decreased significantly 15 days after exposure to extreme environmental conditions. In summary, the alteration of oxygen availability and atmospheric pressure may lead to significant changes in mitochondria mass, lifespan, and behavioral function in D. melanogaster. PMID- 25529351 TI - High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy--a prospective randomised trial. AB - INTRODUCTION: Critically ill patients with respiratory failure undergoing bronchoscopy have an increased risk of hypoxaemia-related complications. Previous studies have shown that in awake, hypoxaemic patients non-invasive ventilation (NIV) is helpful in preventing gas exchange deterioration during bronchoscopy. An alternative and increasingly used means of oxygen delivery is its application via high-flow nasal cannula (HFNC). This study was conducted to compare HFNC with NIV in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy. METHODS: Prospective randomised trial randomising 40 critically ill patients with hypoxaemic respiratory failure to receive either NIV or HFNC during bronchoscopy in the intensive care unit. RESULTS: After the initiation of NIV and HFNC, oxygen levels were significantly higher in the NIV group compared to the HFNC group. Two patients were unable to proceed to bronchoscopy after the institution of HFNC due to progressive hypoxaemia. During bronchoscopy, one patient on HFNC deteriorated due to intravenous sedation requiring non-invasive ventilatory support. Bronchoscopy was well tolerated in all other patients. There were no significant differences between the two groups regarding heart rate, mean arterial pressure and respiratory rate. Three patients in the NIV group and one patient in the HFNC group were intubated within 24 hours after the end of bronchoscopy (P = 0.29). CONCLUSIONS: The application of NIV was superior to HFNC with regard to oxygenation before, during and after bronchoscopy in patients with moderate to severe hypoxaemia. In patients with stable oxygenation under HFNC, subsequent bronchoscopy was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01870765. Registered 30 May 2013. PMID- 25529353 TI - How cytochrome c oxidase can pump four protons per oxygen molecule at high electrochemical gradient. AB - Experiments have shown that the A-family cytochrome c oxidases pump four protons per oxygen molecule, also at a high electrochemical gradient. This has been considered a puzzle, since two of the reduction potentials involved, Cu(II) and Fe(III), were estimated from experiments to be too low to afford proton pumping at a high gradient. The present quantum mechanical study (using hybrid density functional theory) suggests a solution to this puzzle. First, the calculations show that the charge compensated Cu(II) potential for CuB is actually much higher than estimated from experiment, of the same order as the reduction potentials for the tyrosyl radical and the ferryl group, which are also involved in the catalytic cycle. The reason for the discrepancy between theory and experiment is the very large uncertainty in the experimental observations used to estimate the equilibrium potentials, mainly caused by the lack of methods for direct determination of reduced CuB. Second, the calculations show that a high energy metastable state, labeled EH, is involved during catalytic turnover. The EH state mixes the low reduction potential of Fe(III) in heme a3 with another, higher potential, here suggested to be that of the tyrosyl radical, resulting in enough exergonicity to allow proton pumping at a high gradient. In contrast, the corresponding metastable oxidized state, OH, is not significantly higher in energy than the resting state, O. Finally, to secure the involvement of the high energy EH state it is suggested that only one proton is taken up via the K channel during catalytic turnover. PMID- 25529354 TI - Detection of ALK rearrangements in malignant pleural effusion cell blocks from patients with advanced non-small cell lung cancer: a comparison of Ventana immunohistochemistry and fluorescence in situ hybridization. AB - BACKGROUND: Surgical resections or tumor biopsies are often not available for patients with late-stage non-small cell lung cancer (NSCLC). Cytological specimens, such as malignant pleural effusion (MPE) cell blocks, are critical for molecular testing. Currently, diagnostic methods to identify anaplastic lymphoma kinase (ALK) rearrangements include fluorescence in situ hybridization (FISH), real-time reverse transcriptase-polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). In the current study, the authors compared Ventana ALK IHC assays and ALK FISH to detect ALK rearrangements in MPE cell blocks from patients with advanced NSCLC. METHODS: The ALK IHC assay and ALK FISH were performed on 63 MPE cell blocks. RT-PCR analysis was performed as additional validation in cases in which a discrepancy was observed between the IHC assay and FISH results. RESULTS: The Ventana ALK IHC assay was found to be informative for all 63 samples, and 8 cases were positive. Fifty-eight cases were interpretable for FISH detection, and 6 were positive. The concordance between IHC and FISH was 100% among the 58 cases. Of the 5 uninterpretable ALK FISH cases, 2 cases and 3 cases, respectively, were ALK IHC positive and negative. One of the 2 ALK IHC positive cases also demonstrated a positive result in the RT-PCR assay and the patient benefited from crizotinib treatment. CONCLUSIONS: MPE cell blocks can be used successfully for the detection of ALK rearrangement when tumor tissue is not available. The Ventana ALK IHC assay is an effective screening method for ALK rearrangement in MPE cell blocks from patients with advanced NSCLC, demonstrating high agreement with FISH results. PMID- 25529355 TI - The beneficial effect of growth hormone treatment on islet mass in streptozotocin treated mice. AB - BACKGROUND: Type 1 diabetes is an autoimmune disease, characterized by a loss of pancreatic beta-cell mass and function, which results in dramatic reductions in insulin secretion and circulating insulin levels. Patients with type 1 diabetes are traditionally treated with insulin injections and insulin pumps ex vivo or undergo transplantation. Growth hormone (GH) has been shown to be involved in beta-cell function and survival in culture. METHODS: Twelve-week-old female C57BL/6 mice were treated with streptozotocin and monitored for their weight and blood glucose levels. Fourteen days post-initial injection, these mice were separated into two groups at random. One group was treated with GH while the other treated with vehicle for up to 3 weeks. These mice were compared with mice not treated with streptozotocin. RESULTS: Under our experimental conditions, we observed that mice treated with GH had larger islets and higher serum insulin levels than streptozotocin-treated mice treated with saline (0.288 vs. 0.073 ng/mL, p < 0.01). CONCLUSIONS: Our data demonstrate that GH may rescue islets and therefore may possess therapeutic potential in the treatment of type 1 diabetes, although consideration should be made regarding GH's effect on insulin resistance. PMID- 25529356 TI - The importance of platelet markers on hospital mortality in intensive care unit patients. PMID- 25529357 TI - Platelet indices in the prognostication of critically ill patients: another piece of the puzzle. PMID- 25529358 TI - [Optic nerve infarction in Sneddon's syndrome]. AB - CLINICAL CASE: We report a case of a 26 year old woman with Raynaud's phenomenon and livedo reticularis 2 years onset, who presented with visual field defects accompanied by hypertension, hematuria, and headache. The examination revealed multiple retinal and optic nerve head infarcts in both eyes. DISCUSSION: Sneddon's syndrome is a vasculitis that produces livedo reticularis, neurological symptoms, and less frequently myocardial, renal and retinal infarction. After reviewing the literature, this is the first case described of Sneddon's syndrome presenting with optic nerve infarction. PMID- 25529360 TI - A ferromagnetically coupled (S = 1) peroxodicopper(II) complex. AB - Copper enzymes play important roles in the binding and activation of dioxygen in biological systems. Key copper/dioxygen intermediates have been identified and studied in synthetic analogues of the metalloprotein active sites, including the MU-eta(2):eta(2)-peroxodicopper(II) motif relevant to type III dicopper proteins. Herein, we report the synthesis and characterization of a bioinspired dicopper system that forms a stable MU-eta(1):eta(1)-peroxo complex whose Cu-O-O-Cu torsion is constrained to around 90 degrees by ligand design. This results in sizeable ferromagnetic coupling between the copper(II) ions, which is detected by magnetic measurements and HF-EPR spectroscopy. The new dicopper peroxo system is the first with a triplet ground state, and it represents a snapshot of the initial stages of O2 binding at type III dicopper sites. PMID- 25529361 TI - In situ TEM imaging of defect dynamics under electrical bias in resistive switching rutile-TiO2. AB - In this study, in situ electrical biasing was combined with transmission electron microscopy (TEM) in order to study the formation and evolution of Wadsley defects and Magneli phases during electrical biasing and resistive switching in titanium dioxide (TiO2). Resistive switching devices were fabricated from single-crystal rutile TiO2 substrates through focused ion beam milling and lift-out techniques. Defect evolution and phase transformations in rutile TiO2 were monitored by diffraction contrast imaging inside the TEM during electrical biasing. Reversible bipolar resistive switching behavior was observed in these single-crystal TiO2 devices. Biased induced reduction reactions created increased oxygen vacancy concentrations to such an extent that shear faults (Wadsley defects) and oxygen deficient phases (Magneli phases) formed over large volumes within the TiO2 TEM specimen. Nevertheless, the observed reversible formation/dissociation of Wadsley defects does not appear to correlate to resistive switching phenomena at these length scales. These defect zones were found to reversibly reconfigure in a manner consistent with charged oxygen vacancy migration responding to the applied bias polarity. PMID- 25529362 TI - Subperiosteal orbital abscess: volumetric criteria for surgical drainage. AB - OBJECTIVE: To investigate predictive factors of surgical management of subperiosteal orbital abscess in children. METHODS: A retrospective monocentric study was conducted between 2000 and 2011 with children hospitalized for acute pediatric orbital cellulitis (APOC). Clinical, biological and radiological data as well as medical and surgical management were collected and analyzed. All patients received intravenous antibiotics and underwent a CT-scan. Orbit and subperiosteal intraorbital abscess dimensions were measured on axial and coronal planes and the abscess volume was calculated using a spheroid model. RESULTS: Eighty-three children with APOC (mean age: 4.5 years) were included, 53 were boys (63.9%). Thirty-two children (38.6%) presented with a subperiosteal orbital abscess. Mean abscess volume was 570mm(3) and mean exophthalmos was 4.7mm. Twenty patients were treated surgically, 11 of which by an endoscopic approach. A positive correlation was observed between the volume of the abscess or exophthalmos and surgical drainage: 57.9% of patients underwent surgery when exophthalmos was >4mm, 29.4% between 2 and 4mm, and none when <2mm. All patients with an abscess volume >500mm(3) or >5% of orbital volume were operated on whereas only 30% or 39% of patients, respectively, in case of smaller volumes (P<0.05). CONCLUSION: Surgery for subperiosteal orbital abscess is usually performed in case of visual complications or unfavorable medical outcome. The importance of the exophthalmos and the volume of the abscess measured on the CT scan are predictive factors of surgery in children with subperiosteal orbital abscess without visual complications. PMID- 25529363 TI - Pressure algometry with a rotational fanning probe improves the detection of experimental muscle hyperalgesia. AB - OBJECTIVE: Muscle hyperalgesia is typically evaluated by pressure algometry applying linear stimulation. Combining linear pressure stimulation with additional minor variations of the pressure in different directions may optimize the detection of pain sensitivity in hyperalgesic muscle. METHODS: Pressure pain thresholds (PPTs) to linear pressure stimulations were assessed on the extensor carpi radialis brevis (ECRB) muscle in 18 healthy subjects with a computer controlled pressure algometer. During constant pressure stimulation (5 seconds) equal to the PPT, rotational (45 to 180 degrees ), linear vibrational (15 to 50 Hz), or radial vibrational (5 to 25 Hz) stimulations were applied via regular and fanning rounded probes (1 cm2). The pressure pain intensity was rated on an electronic visual analogue scale (VAS). Muscle hyperalgesia was induced in nine subjects by injections of nerve growth factor (NGF) into the ECRB muscle, and isotonic saline was injected as a control condition in other nine subjects on day 0. The PPT and related pressure pain sensitivity were assessed on day -1, day +1, and day +4. RESULTS: The PPT at day +1 was decreased in the NGF group compared with day -1 and the controls (P < 0.01). Preinjection (day -1) analysis showed that VAS scores were increased for rotation compared with linear stimulation alone (P < 0.001). During NGF-induced muscle, hyperalgesia linear pressure stimulation with rotation of the fanning probe induced higher VAS scores than with the regular probe within the NGF group as well as between NGF and control groups (P < 0.02). CONCLUSIONS: Rotational stimulation together with pressure stimulation was more efficient than classical pressure algometry in detecting muscle hyperalgesia. PMID- 25529364 TI - Risk factors for surgical site infection following cesarean section in a Brazilian Women's Hospital: a case-control study. AB - The present study evaluated patients with diagnosis of surgical site infection (SSI) following cesarean section and their controls to determinate risk factors and impact of antibiotic prophylaxis on this condition. METHODS: All cesareans performed from January 2009 to December 2012 were evaluated for SSI, based on criteria established by CDC/NHSN. Control patients were determined after inclusion of case patients. Medical records of case and control patients were reviewed and compared regarding sociodemographic and clinical characteristics. RESULTS: Our study demonstrated an association following univariate analysis between post-cesarean SSI and number of internal vaginal examinations, time of membrane rupture, emergency cesarean and improper use of antibiotic prophylaxis. This same situation did not repeat itself in multivariate analysis with adjustment for risk factors, especially with regard to antibiotic prophylaxis, considering the emergency cesarean factor only. CONCLUSION: The authors of the present study not only question surgical antimicrobial prophylaxis use based on data presented here and in literature, but suggest that the prophylaxis is perhaps indicated primarily in selected groups of patients undergoing cesarean section. Further research with greater number of patients and evaluated risk factors are fundamental for better understanding of the causes and evolution of surgical site infection after cesarean delivery. PMID- 25529365 TI - Ratio of monocytes to lymphocytes in peripheral blood in patients diagnosed with active tuberculosis. AB - OBJECTIVE: The ratio of monocytes to lymphocytes in peripheral blood could reflect an individual's immunity to Mycobacterium tuberculosis. The objective of this study was to evaluate the relationship between ratio of monocytes to lymphocytes and clinical status of patients with active tuberculosis. METHODS: This was a retrospective review of data collected from the clinical database of The Fifth People's Hospital of Wuxi, Medical College of Jiangnan University. A total of 419 patients who had newly diagnosed active tuberculosis and 108 cases from 419 patients with tuberculosis therapy either near completion or completed were selected. Controls were 327 healthy donors. RESULTS: Median ratio of monocytes to lymphocytes was 0.36 (IQR, 0.22-0.54) in patients before treatment, and 0.16 (IQR, 0.12-0.20) in controls (p<0.001). Ratio of monocytes to lymphocytes <9% or >25% was significant predictors for active tuberculosis (OR=114.73, 95% CI, 39.80-330.71; OR=89.81, 95% CI, 53.18-151.68, respectively). After treatment, the median ratio of monocytes to lymphocytes recovered to be nearly normal. Compared to other patients, patients with extrapulmonary tuberculosis and of age >60 years were more likely to have extreme ratio of monocytes to lymphocytes (AOR=2.57, 95% CI, 1.08-6.09; AOR=4.36, 95% CI, 1.43 13.29, respectively). CONCLUSIONS: Ratio of monocytes to lymphocytes <9% or >25% is predictive of active tuberculosis. PMID- 25529366 TI - Risk of vancomycin-resistant enterococci bloodstream infection among patients colonized with vancomycin-resistant enterococci. AB - BACKGROUND: Vancomycin-resistant enterococci colonization has been reported to increase the risk of developing infections, including bloodstream infections. AIM: In this study, we aimed to share our experience with the vancomycin resistant enterococci bloodstream infections following gastrointestinal vancomycin-resistant enterococci colonization in pediatric population during a period of 18 months. METHOD: A retrospective cohort of children admitted to a 400 bed tertiary teaching hospital in Izmir, Turkey whose vancomycin-resistant enterococci colonization was newly detected during routine surveillances for gastrointestinal vancomycin-resistant enterococci colonization during the period of January 2009 and December 2012 were included in this study. All vancomycin resistant enterococci isolates found within 18 months after initial detection were evaluated for evidence of infection. FINDINGS: Two hundred and sixteen patients with vancomycin-resistant enterococci were included in the study. Vancomycin-resistant enterococci colonization was detected in 136 patients (62.3%) while they were hospitalized at intensive care units; while the remaining majority (33.0%) were hospitalized at hematology-oncology department. Vancomycin resistant enterococci bacteremia was present only in three (1.55%) patients. All these patients were immunosuppressed due to human immunodeficiency virus (one patient) and intensive chemotherapy (two patients). CONCLUSION: In conclusion, our study found that 1.55% of vancomycin-resistant enterococci-colonized children had developed vancomycin-resistant enterococci bloodstream infection among the pediatric intensive care unit and hematology/oncology patients; according to our findings, we suggest that immunosupression is the key point for developing vancomycin-resistant enterococci bloodstream infections. PMID- 25529367 TI - Exercise interventions and peripheral arterial function: implications for cardio metabolic disease. AB - Physical inactivity is a major risk factor for the development of obesity and other cardiovascular (CV) disease (CVD). Vascular endothelial dysfunction is a key event in the development of CVD and is associated with a sedentary lifestyle in otherwise healthy adults. In addition, vascular endothelial dysfunction may be exacerbated in sedentary individuals who are obese and insulin resistant, since excess body fat is associated with elevated levels of pro-atherogenic inflammatory adipokines and cytokines that reduce the nitric oxide (NO) and other upstream paracrine signaling substances which reduces vascular health. Since blood flow-related shear stress is a major stimulus to NO release from the endothelium, disturbed flow or low shear stress is the likely mechanism by which vascular endothelial function is altered with inactivity. Evidence shows that regular physical exercise has beneficial effects on CVD and the risk factors that promote peripheral arterial function and health. Both aerobic and resistance exercise training are generally believed to improve endothelial function and are commonly recommended for CV health, including the management of obesity, hypertension, and insulin resistance. However, many factors including age, disease status, and race appear to influence these outcomes. Although evidence supporting the health benefits of exercise is compelling, the optimum prescription (volume and intensity) and the exact mechanism underlying the effects of exercise training on arterial function and cardiometabolic risk has yet to be identified. The focus of this review will be on the evidence supporting exercise interventions for peripheral arterial function. PMID- 25529368 TI - The vasculature in cardiovascular diseases: will the vasculature tell us what the future holds? PMID- 25529369 TI - A FRET-based DNA nano-tweezer technique for the imaging analysis of specific mRNA. AB - A DNA nano-tweezer (DNA-NT) structure-based target mRNA detection probe, which uses fluorescence resonance energy transfer (FRET) as a detection signal and works as a single molecule, has been developed. This FRET-paired fluorescent dye modified DNA-NT, self-assembled from three single-stranded DNAs, alters its structure from open to closed states and produces a FRET signal in response to in vitro transcripts of Hes-1 mRNA. Our results showed that the FRET-based DNA-NT detected both GLUT1 mRNA as a pre-fixed target mRNA model and Hes-1 mRNA as a model expressed inside a living cell. These results confirm the feasibility of using the FRET-based DNA-NT for imaging analysis of target mRNA. PMID- 25529370 TI - Treatment modifications in tumour necrosis factor-alpha (TNF)-based isolated limb perfusion in patients with advanced extremity soft tissue sarcomas. AB - BACKGROUND: Tumour necrosis factor-alpha (TNF) and melphalan based isolated limb perfusion (TM-ILP) is an attractive treatment option for advanced extremity soft tissue sarcomas (STS). This study reports on a 20-year single centre experience and discusses the evolution and changes in methodology since the introduction of TNF in ILP. PATIENTS AND METHODS: We performed 306 TM-ILPs in 275 patients with extremity STS. All patients were candidates for amputation or mutilating surgery in order to achieve local control. Clinical response evaluation consisted of clinical examination and magnetic resonance imaging. To evaluate the importance of TNF-dose, treatment results of two periods (1991-2003 high dose (3-4 mg) TNF; 2003-2012 reduced dose (1-2mg) TNF) were compared. RESULTS: During the study period, more femoral perfusions were done instead of iliac perfusions. Reduction of TNF dose and reduction of total ILP time did not lead to different clinical response rates (70% and 69% for periods 1 and 2 respectively) or different local recurrence rates, but was associated with less local toxicity (23% and 14% for periods 1 and 2 respectively). Hospital stay was significantly reduced during the study period. There was an improved pathological response in the high dose TNF group without consequences for clinical outcome. CONCLUSION: TM-ILP remains a very effective treatment modality for limb threatening extremity STS. Moreover, reduction of dose and the growing experience in ILP led to less local toxicity and shorter hospital stay. PMID- 25529372 TI - Hip range of motion and scapula position in youth baseball pitching pre and post simulated game. AB - Lower to upper extremity sequencing of energy and force is linked by virtue of the scapula. It was the purpose of this study to examine the relationship between passive hip rotational range of motion and scapular kinematics during baseball pitching. Nineteen youth baseball players (11.3 +/- 0.6 years; 151.8 +/- 8.8 cm; 45.9 +/- 10.9 kg) with no history of injury participated. Bilateral hip passive rotational range of motion was measured pre and post pitching a simulated game. Scapular kinematics at the position of shoulder maximum external rotation during the pitching cycle were recorded in the first and last innings of the simulated game. Post simulated game, stance leg hip passive internal rotation revealed significant correlations (r = -0.57, P = 0.01) with scapula anterior/posterior tilt at the pitching event of maximum humeral external rotation. The current study reveals that pitching a simulated game results in alterations throughout the kinetic chain. Specifically, this study strengthens the notion that lumbopelvic-hip complex parameters play a significant role in shoulder motion. With this link identified, it is suggested that clinical focus be directed musculature about the lumbopelvic-hip complex as well as muscles that work to stabilise the scapula during dynamic movement. PMID- 25529371 TI - Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. AB - BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations. PATIENTS AND METHODS: Specialist centres collaborated to report prognostic factors and outcome for 113 patients. RESULTS: Median age was 30 years (range: 11-80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1-34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3-28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03-10.96) and 20 (95% CI: 12.63-27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P=0.046; hazard ratio (HR)=0.482 95% CI: 0.213-0.996) and death (P=0.004; HR=0.445 95% CI: 0.256 0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P=0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P<0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3 years (95% CI: 0-4.25). CONCLUSIONS: Prognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease. PMID- 25529373 TI - Are we ready for back-to-nature crop breeding? AB - Sustainable agriculture in response to increasing demands for food depends on development of high-yielding crops with high nutritional value that require minimal intervention during growth. To date, the focus has been on changing plants by introducing genes that impart new properties, which the plants and their ancestors never possessed. By contrast, we suggest another potentially beneficial and perhaps less controversial strategy that modern plant biotechnology may adopt. This approach, which broadens earlier approaches to reverse breeding, aims to furnish crops with lost properties that their ancestors once possessed in order to tolerate adverse environmental conditions. What molecular techniques are available for implementing such rewilding? Are the strategies legally, socially, economically, and ethically feasible? These are the questions addressed in this review. PMID- 25529374 TI - [Laryngeal tuberculosis and coadjuvant corticosteroid treatment]. PMID- 25529375 TI - [Child health and international cooperation: A paediatric approach]. AB - The international development cooperation in child health arouses special interest in paediatric settings. In the last 10 10 years or so, new evidence has been presented on factors associated with morbidity and mortality in the first years of life in the least developed countries. This greater knowledge on the causes of health problems and possible responses in the form of interventions with impact, leads to the need to disseminate this information among concerned professional pediatricians. Serious efforts are needed to get a deeper insight into matters related to global child health and encourage pediatricians to be aware and participate in these processes. This article aims to provide a social pediatric approach towards international cooperation and child health-related matters. PMID- 25529376 TI - [Emergency antidotes and services]. PMID- 25529377 TI - Loss of SPARC dysregulates basal lamina assembly to disrupt larval fat body homeostasis in Drosophila melanogaster. AB - BACKGROUND: SPARC is a collagen-binding glycoprotein whose functions during early development are unknown. We previously reported that SPARC is expressed in Drosophila by hemocytes and the fat body (FB) and enriched in basal laminae (BL) surrounding tissues, including adipocytes. We sought to explore if SPARC is required for proper BL assembly in the FB. RESULTS: SPARC deficiency leads to larval lethality, associated with remodeling of the FB. In the absence of SPARC, FB polygonal adipocytes assume a spherical morphology. Loss-of-function clonal analyses revealed a cell-autonomous accumulation of BL components around mutant cells that include collagen IV (Col lV), Laminin, and Perlecan. Ultrastructural analyses indicate SPARC-deficient adipocytes are surrounded by an aberrant accumulation of a fibrous extracellular matrix. CONCLUSIONS: Our data indicate a critical requirement for SPARC for the proper BL assembly in Drosophila FB. Since Col IV within the BL is a prime determinant of cell shape, the rounded appearance of SPARC-deficient adipocytes is due to aberrant assembly of Col IV. PMID- 25529378 TI - [Delayed haemolytic transfusion reaction: About 3 patients with sickle cell disease]. AB - INTRODUCTION: The use of a red blood cell transfusion in a patient with major sickle cell disease is sometimes necessary. The occurrence of delayed haemolytic transfusion reaction is a rare but potentially serious complication. This event can occur at any age. It is probably under diagnosed due to the difficulty in diagnosis with few specific signs. CASE REPORTS: We describe in this article the clinical, biological, and hazards of therapeutic management of three cases of delayed haemolytic transfusion reaction in sickle cell disease patients. The high performance chromatography, which evaluates the percentage of HbA1, is the biological investigation used to establish the diagnosis of this event. The pathophysiology of this event remains still poorly understood. Several treatments have been used during this event. However, the therapeutic management remains controversial. CONCLUSION: Transfusion in any patient likely to suffer from delayed haemolytic transfusion reaction is not recommended because of the risk of worsening this reaction. Prevention of recurrence is essential. PMID- 25529379 TI - Some fallacies of human-subjects protection, and some solutions. PMID- 25529381 TI - Second autologous stem cell transplant: an effective therapy for relapsed multiple myeloma. AB - Therapeutic options for patients with multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (ASCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second ASCT, with no clear standard of care. We retrospectively analyzed the outcomes of 75 patients who underwent salvage melphalan-based ASCT for relapsed MM at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Conditioning was performed with melphalan 200 mg/m(2) (n = 43), 180 mg/m(2) (n = 1), 140 mg/m(2) (n = 22), and 100 mg/m(2) (n = 9). The median age at second ASCT was 59 years (range, 36 to 75), and 58% (n = 35) were men. Of those with available data, 19% had high-risk cytogenetics (including t (4;14), p53 loss, or del 13q by karyotype) at the time of second ASCT. Median interval between first and salvage ASCT was 37.5 months (range, 6.9 to 111.4). Of 72 assessable patients, 57% had chemotherapy-sensitive disease before to salvage ASCT and 43% were chemoresistant. Four patients died within 100 days of ASCT. Response was assessed at 2 to 3 months post-ASCT, and of 71 assessable patients, 82% achieved at least a partial response, 15% had stable disease, and 3% progressed despite salvage ASCT. After salvage ASCT, 38 patients received maintenance therapy and 14 went on to allogeneic ASCT. The median progression free survival (PFS) after second autograft was 10.1 months (95% confidence interval [CI], 7.6 to 13.4) and median overall survival (OS) 22.7 months (95% CI, 19.2 to 41.2). Patients with chemosensitive relapse had a trend toward better PFS (hazard ratio [HR], .60 [95% CI, .36 to 1.02]; P = .058) and significantly longer OS (HR, .49 [95% CI, .27 to .88]; P = .017) than patients with resistant relapse. Those with high-risk cytogenetics at the time of second ASCT had higher risk of death (HR, 2.98 [95% CI, 1.28 to 6.97]; P = .012) compared with patients with standard-risk cytogenetics. Salvage ASCT is an effective strategy for relapsed MM with chemosensitive disease and results in comparable PFS and OS to other salvage strategies. PMID- 25529380 TI - Fungal infections in liver transplant patients admitted to the intensive care unit. AB - BACKGROUND: Fungal infections have a significant impact on patient survival after liver transplantation, mostly caused by Candida and Aspergillus. The clinical manifestations vary, and range from colonization, active local infection, to severe invasive form. A high degree of suspicion is required for the early diagnosis and, accordingly, the optimal management of these infections. This study aimed to evaluate fungal infection in the Intensive care Unit (ICU) in admitted liver transplant patients, focussing of etiologic agent, clinical/laboratory presentation (including mortality), and risk factors. MATERIAL AND METHODS: This retrospective study included living related liver transplanted patients admitted to the ICU. Clinical data was collected, thorough clinical evaluation was done, and laboratory tests were performed. Microbiological examination detecting the presence of fungus in various samples, using cultures and serology, and imaging investigations were carried out in all patients. RESULTS: This study included 23 cases of ICU-admitted liver transplant patients who were diagnosed with fungal infection. Candida was the most common fungal infection and occurred at a mean of 2 months after transplantation; while Aspergillus was less common and occurred later with worse laboratory findings. Invasive fungal infection constituted 43% of the diagnosed cases. Difference in mortality between Aspergillus and Candida was insignificant, as was difference between patients with and without fungal infection. CONCLUSIONS: Fungal infection among LT patients was common, including the invasive forms. PMID- 25529382 TI - Comparison of unrelated cord blood and peripheral blood stem cell transplantation in adults with myelodysplastic syndrome after reduced-intensity conditioning regimen: a collaborative study from Eurocord (Cord blood Committee of Cellular Therapy & Immunobiology Working Party of EBMT) and Chronic Malignancies Working Party. AB - Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in patients with higher risk myelodysplastic syndrome (MDS), but the choice of the optimal alternative stem cell source is still a subject of debate in patients lacking an HLA-matched sibling donor. Here, we report on a large series of patients with MDS (N = 631) transplanted either with mobilized peripheral stem cells (PBs) from unrelated donors (n = 502) or with umbilical cord blood transplant (UCB, n = 129) as alternative grafts after reduced intensity conditioning. Neutrophil engraftment was higher after PB (98% versus 78%, P < .0001). Acute graft-versus-host disease (GVHD) was similar after PB (31%) and UCB (29%), and chronic GVHD incidence was higher after PB (41% versus 23%). Two-year nonrelapse mortality was lower after PB (31% versus 42% P = .03). There was a better overall survival (OS) and disease-free survival (DFS) after PB (49% +/- 2% versus 30% +/- 4%, P < .0001 and 44% +/- 2% versus 28% +/- 4%, P < .0001). Multivariate analysis confirmed the advantage of PB for treatment-related mortality, OS, and DFS, whereas relative risk of chronic GVHD was similar. A multivariate analysis comparing PB from a 10/10 HLA-matched donor, PB from a 9/10 HLA-matched donor, and UCB showed an advantage on treatment-related mortality, DFS, and OS only in 10/10 PB. We conclude that in MDS patients lacking an HLA matched sibling donor, PB from a 10/10 HLA-matched unrelated donor is the preferred source of hematopoietic stem cells. HLA-mismatched unrelated donor or cord blood seem to give similar inferior results except for neutrophil engraftment, which is delayed after UCB. PMID- 25529384 TI - Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS: Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS: In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34 0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS: Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy. PMID- 25529386 TI - Comparing diagrammatic recording versus traditional written account of tympanomastoid procedures: completion of a second audit cycle of 25 cases: Our experience. PMID- 25529385 TI - Financial analysis of brucellosis control for small-scale goat farming in the Bajio region, Mexico. AB - Brucellosis is an endemic disease in small-scale goat husbandry systems in Mexico. It is a zoonosis and the economic consequences can be large, although estimates are not available for the Mexican goat sector. Our objective was to conduct a financial analysis of brucellosis control in a prominent dairy goat production area of the Bajio region, Mexico. We used three models: (1) a brucellosis transmission model at village flock level (n=1000 head), (2) a flock growth model at smallholder flock level (n=23 head) using output of model 1 and (3) cost-benefit analysis of several brucellosis control scenarios based on output of model 2. Scenarios consisted of test-and-slaughter or vaccination or a combination of both compared to the base situation (no control). The average net present values (NPV) of using vaccination over a 5-year period was 3.8 US$ (90% CI: 1.3-6.6) and 20 US$ (90% CI: 11.3-28.6) over a 10-year period per goat. The average benefit-cost ratios over a 5-year period and 10-year period were 4.3 US$ (90% CI: 2.2-6.9) and 12.3 US$ (90% CI: 7.5-17.3) per goat, respectively. For the total dairy goat population (38,462 head) of the study area (the Bajio of Jalisco and Michoacan) the NPV's over a 5-year and 10-year period were 0.15 million US$ and 0.8 million US$. However, brucellosis prevalence was predicted to remain relatively high at about 12%. Control scenarios with test-and-slaughter predicted to reduce brucellosis prevalence to less than 3%, but this produced a negative NPV over a 5-year period ranging from -31.6 to -11.1 US$ and from -31.1 to 7.5 US$ over a 10-year period. A brucellosis control campaign based on vaccination with full coverage is economically profitable for the goat dairy sector of the region although smallholders would need financial support in case test-and slaughter is applied to reduce the prevalence more quickly. PMID- 25529383 TI - National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. AB - The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies. PMID- 25529387 TI - Co(III) protoporphyrin IX chloride in solution: spin-state and metal coordination revealed from resonant inelastic X-ray scattering and electronic structure calculations. AB - The local electronic structure of the cobalt centre-ion of Co(III) protoporphyrin IX chloride dissolved in dimethyl sulfoxide (DMSO) liquid solution is studied by resonant inelastic X-ray scattering (RIXS) spectroscopy at the cobalt L-edge. The resulting cobalt 2p partial-fluorescence-yield (PFY) X-ray absorption (XA) spectrum, integrated from RIXS spectra, is simulated for various possible spin states and coordination of the cobalt centre by using the newly developed density functional theory/restricted open shell single excitation configuration interaction (DFT/ROCIS) method. Comparison between experiment and calculation shows that the cobalt ion (3d(6) electronic configuration) adopts a low-spin state with all six 3d electrons paired, and the cobalt centre is either 5 coordinated by its natural ligands (one chloride ion and four nitrogen atoms), or 6-coordinated, when binding to an oxygen atom of a DMSO solvent molecule. Analysis of the measured RIXS spectra reveals weak 3d-3d electron correlation, and in addition a value of the local HOMO-LUMO gap at the Co sites is obtained. PMID- 25529389 TI - Relationship between socioeconomic status and general practitioner visits for children in the first 12 months of life: an Australian study. AB - OBJECTIVE: The aim of the present study was to examine the relationship between socioeconomic status (SES) and child general practitioner (GP) visits in the first 12 months of life. METHODS: A longitudinal analysis of 1202 mother and child dyads was conducted as part of the Environments for Healthy Living study from south-east Queensland, Australia, for participants enrolled between 2006 and 2009. Maternally reported survey data (sociodemographic and child health information) were linked with individual Medical Benefits Scheme data from birth to 12 months, identifying GP service use. RESULTS: On average, children visited the GP 10.2 times in the first 12 months of life. An inverse relationship was found for SES and child GP visits, with maternal education and child gender the strongest predictors of the total number of GP visits. Almost 70% of participants had all GP consultations bulk billed and only 3.5% paid more than A$100 in total. CONCLUSIONS: Children from lower SES families may have a greater need for health services due to higher rates of illness and injury. Bulk billing and low-cost access to GP services, regardless of length of consultation, improve equity of access; however, indirect costs may prevent low-income mothers from accessing care for their child when needed. PMID- 25529388 TI - Choroidal thickness and high myopia: a case-control study of young Chinese men in Singapore. AB - PURPOSE: To determine the distribution of choroidal thickness (CT) and ocular factors associated with CT in high myopic eyes in comparison with emmetropic eyes of young healthy adults. METHODS: A case-control study of 648 young, male subjects, including 520 high myopes and 128 emmetropes. Choroidal imaging was performed using enhanced depth imaging spectral domain optical coherence tomography. Images were postprocessed using adaptive compensation for quality enhancement. CT was measured at nine locations, including subfovea and 1.5 and 3 mm nasal, temporal, superior and inferior to fovea. RESULTS: The CT at the subfovea was significantly thinner (mean +/- standard error: 225.87 +/- 5.51 MUm) for high myopes compared to emmetropes (375.15 +/- 6.58 MUm, p < 0.001). Likewise, CT in high myopic group was significantly thinner than emmetropic control group at all locations (p for trend <0.001 for all locations). Distribution of CT showed a markedly different pattern in high myopic eyes (thickest superiorly at 3 mm, 265.97 +/- 5.97 MUm) and emmetropic eyes (thickest subfoveally, 375.15 +/- 6.58 MUm). Choroid was thinnest at nasal 3 mm location in both the myopic (108.85 +/- 3.97 MUm) and emmetropic (238.25 +/- 6.72 MUm) groups. Among the ocular factors studied, axial length, posterior staphyloma and chorio-retinal atrophy were the significant predictors of CT. CONCLUSIONS: Highly myopic eyes have significantly thinner choroid and showed different distribution pattern, compared to emmetropes. Axial length, posterior staphyloma and chorio retinal atrophy are the strongest determinants of CT. PMID- 25529391 TI - The effectiveness of a rehabilitation programme for Chinese cancer survivors: A pilot study. AB - Cancer survivors have experienced high stress which impairs psychological functioning and decreases quality of life (QOL). This study aims to assess the mediating effect of self-efficacy on mood disturbance and QOL, and determine the effectiveness of a 12 week rehabilitation programme to improve self-efficacy as well as improve mood disturbance and QOL in Chinese cancer survivors. A total of 47 cancer patients were randomly assigned into the experimental (n = 24) and control (n = 23) groups. The participants in the experimental group received cancer-related education, progressive muscle relaxation and emotional support. Self-reported questionnaires, including General Self-efficacy Scale (GSES), Profile of Mood States Scale-Short Form (POMS-SF) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) were collected in pre- and post-intervention. Findings from this study indicated that self-efficacy was a complete mediator between mood disturbance and QOL, and the 12 week rehabilitation programme had a positive effect on self efficacy, mood disturbance and QOL for Chinese cancer survivors. PMID- 25529390 TI - School victimization and substance use among lesbian, gay, bisexual, and transgender adolescents. AB - Lesbian, gay, bisexual, and transgender (LGBT) adolescents are at increased risk for substance use, relative to their heterosexual counterparts. Although previous research has demonstrated that experiences of anti-LGBT harassment, discrimination, and victimization may explain some of this disparity, little is known about the mechanisms whereby such mistreatment leads to substance abuse. This study aimed to examine whether mechanisms suggested by the Social Development Model might explain the links between school-based victimization and substance use in this population. Five hundred and four ethnically diverse LGBT adolescents ages 14-19 reported their experiences with school victimization, substance abuse, school bonding, and deviant peer group affiliation. Anti-LGBT victimization in school was associated with substance abuse, and although causality cannot be established, structural equation modeling confirmed that the data are consistent with a theoretical model in which this association was mediated by increased affiliation with deviant peers. Preventive interventions for LGBT adolescents must not only attempt to make schools safer for these youth, but also help keep them engaged in healthy peer groups when they are confronted with mistreatment in school. PMID- 25529392 TI - Living with antipsychotic medication side-effects: the experience of Australian mental health consumers. AB - The present study explores people's experience of living with antipsychotic medication side-effects. Qualitative data were gathered through semistructured interviews with 10 mental health consumers in a community care setting in Australia. The interview transcriptions were content analysed, and enhanced by combining manifest and latent content. Important contextual cues were identified through replaying the audio-recordings. Several main themes emerged from the analysis, including the impact of side-effects, attitudes to the use of medication and side-effects, and coping strategies to manage medication side effects. Each participant reported between six and seven side-effects on average, which were often pronounced and had a major disruptive impact on their lives. Of these effects, the most commonly mentioned was sedation, which the participants described as leaving them in a 'zombie'-like state. Most participants expressed an attitude of acceptance about the side-effects. The participants' most common strategy to manage side-effects was to change the dosage of the medication. Other common side-effect management strategies involved using other medications to control side-effects, and diverse self-help techniques, the most common of which was relaxation/distraction techniques. PMID- 25529393 TI - Editorial: Process to progress? Investigative trials, mechanism and clinical science. AB - In 2002 Helena Kraemer and colleagues published an important article on the analysis of clinical trials in mental health, which advocated a planned focus on mechanisms to investigate the processes behind treatment effects. Kraemer et al. considered not only new approaches to mediation analysis, but also a theoretical approach to factors, both pre-treatment and during treatment, that might moderate this mediation. Trials should not just be about whether a treatment 'worked', but how it worked; with the results informing modification of the intervention for the next trial by discarding aspects that were not effective and reinforcing aspects that were - an iterative procedure towards greater effectiveness. Can we enjoy similar ambitions for complex interventions within mental health? It is not so long ago when the received wisdom within the clinical and much of the research community was that it was simply impossible in practice to mount randomised controlled trials relevant to the kind of psychosocial interventions we use in child and adolescent mental health (CAMHS). How different the situation is now, with burgeoning interest in a systematic evidence base for psychological treatment and the possibilities for unexpected advances (as well as unexpected harms). Nevertheless it is probably still fair to say that the systematic use of process and mechanism study within trials in our field is the exception rather than the rule. What are the possibilities and implications for our field? PMID- 25529394 TI - First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid. PMID- 25529395 TI - Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study. AB - OBJECTIVE: Prediction of long-term outcomes in patients with community-acquired pneumonia (CAP) is incompletely understood. We investigated the value of clinical risk scores [pneumonia severity index (PSI) and CURB-65] (Confusion, Urea, Respiratory rate, Blood Pressure, Age >65 years) and blood biomarkers of different physiopathological pathways in predicting long-term survival in a well characterized cohort of patients with CAP enrolled in an antibiotic stewardship trial. DESIGN, SETTING AND SUBJECTS: Patients admitted with CAP to six medical centres in Switzerland were prospectively followed for 6 years. Cox regression models and area under the receiver operating characteristics curve (AUC) were used to investigate associations between initial risk assessment and all-cause mortality. MAIN OUTCOME MEASURE: All-cause mortality during a 6-year follow-up period. RESULTS: Six-year mortality in the present cohort (median age 73 years) was 45.1% [95% confidence interval (CI) 41.8-48.3%]. Initial PSI and CURB-65 scores both had excellent long-term prognostic accuracy, with a stepwise increase in mortality per risk class. The hazard ratios (95% CI) of the highest PSI and CURB-65 classes (reference: lowest class) were 38.0 (14.0-103.0) and 7.8 (2.2 14.5), respectively, after 6 years. The addition of inflammatory (pro adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers measured upon hospital admission further improved the prognostic capabilities of the PSI (AUC increase from 0.79 to 0.83; P < 0.0001) and the CURB-65 score (AUC increase from 0.73 to 0.80; P < 0.001). CONCLUSION: Risk assessment using clinical scores allowed accurate long-term prognostication, which was further improved by the addition of two inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers. These data provide a rationale for a more risk-adapted, 'personalized' strategy for long-term management of patients with CAP. PMID- 25529403 TI - Arthroplasty compared to internal fixation by locking plate osteosynthesis in comminuted fractures of the distal humerus. AB - PURPOSE: The purpose of this study was to evaluate and compare the results after double locking plate osteosynthesis (ORIF) and total elbow arthroplasty (TEA) in AO type C fractures of the distal humerus. METHODS: This retrospective study includes clinical results of 29 patients (9xTEA, 20xORIF) with a mean age of 62 years. The male to female ratio was 8:21. Range of motion, MEPS, DASH and complications were evaluated. Patients older than 60 years (n = 19) were filtered and compared statistically. RESULTS: After a mean follow-up of 25 months the ORIF group reached an extension-flexion of 99 degrees +/-23 degrees and the TEA-group of 111 degrees +/-13 degrees . The ORIF-group vs. the TEA-group had a mean MEPS of 85+/-17 vs. 94+/-11 and DASH of 34+/-24 vs. 24+/-12. In patients older than 60 years extension-flexion was 97 degrees +/-23 degrees after ORIF and 110 degrees +/-14 after TEA (p = 0.237). The ORIF-group vs. the TEA-group had a mean MEPS of 82+/-21 vs. 94+/-11 (p = 0.078) and DASH of 45+/-18 vs. 26+/-11 (p = 0.023). The ORIF-group had a 4.4 times higher risk for major complications. CONCLUSION: TEA and ORIF lead to comparable functional results, but major complications are more common after ORIF. Despite this, ORIF remains the gold standard for younger and older patients because of the lifelong loading limitation after TEA, unknown implant survival and problematic revision surgery. For patients older than 60 years a primary TEA can be recommended in exceptional cases, if the loading limitation is acceptable for the individual or the fracture is not reconstructable. PMID- 25529404 TI - Easter egg hunt dermatitis: systemic allergic contact dermatitis associated with chocolate ingestion. AB - Pediatric systemic allergic contact dermatitis to nickel has previously been reported in association with cocoa. We present four clinical cases of hypersensitivity temporally associated with chocolate consumption at Easter. Clinicians should be aware of the potential for foods high in nickel to provoke patients with known nickel sensitivity and systemic dermatitis. PMID- 25529406 TI - Influence of gender, anxiety and depression symptoms, and use of oral contraceptive in color perception. AB - OBJECTIVE: The color is a psychophysical phenomenon, and much has been studied about its physical components. However, the psychological part is poorly investigated, except for the difference between genders in the literature shows that more men are color deficient than women. Dental students are trained to better understand the differences in color, so we became interested in studying whether psychological variables such as anxiety and depression and use of hormonal contraceptives may interfere with this ability. The aim of this in vitro study was to investigate if factors, such as, hormonal contraceptive use, depressive symptoms, anxiety and quality of life, influence on the ability of color discrimination of dental school students. MATERIALS AND METHODS: Sixty-one subjects participated and the following instruments apply: (1) test that consists in the observation of a set of 25 labels (Pantones) with values of known colors, (2) scales of depression, anxiety, and quality of life assessments, and (3) Ishihara test. RESULTS: No difference was observed between genders as color perception (p = 0.868). Symptoms of anxiety and depression were significantly more frequent in the female population that showed worse quality of life (p < 0.000) but did not interfere with color perception. Women using hormonal contraceptives had lower color perception than men (p = 0.04). CONCLUSION: No difference between the genders in the perception of colors was observed, contrary to common sense that women discriminate more colors than men, but women using hormonal contraceptives showed more difficulty in color perception. CLINICAL SIGNIFICANCE: The ability to understand and distinguish color differences is extremely important in clinical dentistry. There could be differences in color perception between men and women that would influence clinical performance. PMID- 25529405 TI - EEG potentials associated with artificial grammar learning in the primate brain. AB - Electroencephalography (EEG) has identified human brain potentials elicited by Artificial Grammar (AG) learning paradigms, which present participants with rule based sequences of stimuli. Nonhuman animals are sensitive to certain AGs; therefore, evaluating which EEG Event Related Potentials (ERPs) are associated with AG learning in nonhuman animals could identify evolutionarily conserved processes. We recorded EEG potentials during an auditory AG learning experiment in two Rhesus macaques. The animals were first exposed to sequences of nonsense words generated by the AG. Then surface-based ERPs were recorded in response to sequences that were 'consistent' with the AG and 'violation' sequences containing illegal transitions. The AG violations strongly modulated an early component, potentially homologous to the Mismatch Negativity (mMMN), a P200 and a late frontal positivity (P500). The macaque P500 is similar in polarity and time of occurrence to a late EEG positivity reported in human AG learning studies but might differ in functional role. PMID- 25529407 TI - Increasing radiosensitivity with the downregulation of cofilin-1 in U251 human glioma cells. AB - The aim of the present study was to examine the association between cofilin-1 (CFL1) and radioresistance in human glioma U251 cells. CFL1 expression was downregulated and upregulated in U251 cells through the transfection of CFL1 small interfering (si)RNA and pcDNA3.1-CFL1, respectively. The radiosensitivity of U251 cells and established radioresistant U251 cells (RR-U251) was evaluated using cell viability, migration and invasion ability assays. Cell cycle distribution was also examined. The results showed that CFL1 expression was significantly increased in RR-U251 cells; in addition, the cell viability, migration and invasion ability of RR-U251 cells were significantly enhanced compared to those of the normal U251 cells, whereas the number of cells arrested in G2 phase was markedly decreased. In CFL1-silenced RR-U251 and CFL1-silenced U251 cells, the cell viability, migration and invasion abilities were significantly downregulated and the number of cells arrested in G2 phase was increased compared to that of the untransfected cells. In U251 cells overexpressing CFL1, cell viability, migration and invasion abilities were markedly upregulated and the number of cells arrested in G2 phase was decreased. In conclusion, the results of the present study suggested that downregulation of CFL1 may increase radiosensitivity in U251 cells. PMID- 25529409 TI - Community fitness programs: what is available for children and youth with motor disabilities and what do parents want? AB - BACKGROUND: Physical activity is recognized as a rehabilitation approach for individuals with motor disabilities. OBJECTIVES: To determine whether community fitness programs were accommodating children and youth with motor disabilities, and to understand family perspectives on important outcomes related to fitness programs. DESIGN: Telephone survey and qualitative interviews. PARTICIPANTS AND SETTINGS: Representatives of 61 fitness programs/facilities and 13 parents of children with motor disabilities. METHODS: Telephone survey (facilities) and qualitative interviews (parents). RESULTS: 24.6% of programs reported lack of wheelchair accessibility. Only 9.8% of programs and facilities required their staff to have training to support individuals with disabilities. Parents discussed barriers, including lack of staff support and challenges with finding information about community programs. Parents focused on the social benefits of fitness programs. CONCLUSIONS/SIGNIFICANCE: Additional efforts toward reducing access barriers are needed. Parents' focus on social outcomes has direct implications on the design and evaluation of fitness programs. PMID- 25529410 TI - Electrical Stimulation Following Botulinum Toxin A in Children With Spastic Diplegia: A Within-Participant Randomized Pilot Study. AB - AIMS: To determine whether electrical stimulation (ES) following botulinum toxin A (BoNT/A) injection increases passive extensibility of the hamstring muscles in children with spastic diplegia. METHODS: Six children undergoing bilateral BoNT/A injections to the hamstrings participated in this within-participant single blind randomized controlled trial. One leg of each child was randomised to the experimental condition and the other to the control condition. The experimental leg received daily stretch and ES to the hamstrings for 12 weeks, while the control leg received only daily stretch. The primary outcome was passive hamstring extensibility reflected by popliteal angle measured with a standardised torque. Secondary outcomes were two goniometric measures of popliteal angle using the Modified Tardieu Scale (R1 and R2), and parents' perceptions of treatment effectiveness. Outcomes were measured at baseline, 4 weeks, 12 weeks and 6 months. RESULTS: The mean between-group difference (95% CI) at 4 weeks was 2 degrees (-2 to 5) for popliteal angle measured with a standardised torque, favouring the experimental leg. Tardieu results for R1 and R2 were 0 degrees (-4 to 3) and 7 degrees (0 to 14), respectively. CONCLUSION: ES does not improve passive extensibility of the hamstring muscles at 4 weeks over any possible effects of BoNT/A alone. PMID- 25529408 TI - An estimate of pocket closure and avoided needs of surgery after scaling and root planing with systemic antibiotics: a systematic review. AB - BACKGROUND: Relevant benefits of adjunctive medication of antibiotica after conventional root surface debridement in terms of enhanced pocket depth (PD) reduction have been shown. However, means and standard deviations of enhanced reductions are difficult to translate into clinical relevant treatment outcomes such as pocket resolution or avoidance of additional surgical interventions. Accordingly, the aim of this systematic review was to calculate odds ratios for relevant cut-off values of PD after mechanical periodontal treatment with and without antibiotics, specifically the combination of amoxicilline and metronidazol, from published studies. As clinical relevant cut-off values "pocket closure" for PD <= 3mm and "avoidance of surgical intervention" for PD <= 5 mm were determined. METHODS: The databases PubMed, Embase and Central were searched for randomized clinical studies assessing the beneficial effect of the combination of amoxicillin and metronidazole after non-surgical mechanical debridement. Titles, abstracts and finally full texts were scrutinized for possible inclusion by two independent investigators. Quality and heterogeneity of the studies were assessed and the study designs were examined. From published means and standard deviations for PD after therapy, odds ratios for the clinically relevant cut-off values were calculated using a specific statistical approach. RESULTS: Meta-analyses were performed for the time points 3 and 6 month after mechanical therapy. Generally, a pronounced chance for pocket closure from 3 to 6 months of healing was shown. The administration of antibiotics resulted in a 3.55 and 4.43 fold higher probability of pocket closure after 3 and 6 months as compared to mechanical therapy alone. However, as the estimated risk for residual pockets > 5 mm was 0 for both groups, no odds ratio could be calculated for persistent needs for surgery. Generally, studies showed a moderate to high quality and large heterogeneity regarding treatment protocol, dose of antibiotic medication and maintenance. CONCLUSION: With the performed statistical approach, a clear benefit in terms of an enhanced chance for pocket closure by co administration of the combination of amoxicillin and metronidazole as an adjunct to non-surgical mechanical periodontal therapy has been shown. However, data calculation failed to show a benefit regarding the possible avoidance of surgical interventions. PMID- 25529411 TI - Concurrent validity of the School Outcomes Measure (SOM) and Pediatric Evaluation of Disability Inventory (PEDI) in preschool-age children. AB - AIMS: The purpose of this study was to examine the concurrent validity of the School Outcomes Measure (SOM) compared with the Pediatric Evaluation of Disability Inventory (PEDI) in preschool-age children. This study also examined the consistency of children's motor performance across the home and school settings. METHODS: Five school-based physical therapists collected data on 44 preschool-age children with physical or combined physical and cognitive disability. Correlation coefficients analyzed the strength of association between SOM and PEDI subscale scores, while participant group mean scores analyzed agreement between measures regarding level of motor performance. RESULTS: Correlations between homologous PEDI and SOM subscale scores varied from rs = .53 to rs = .92 supporting concurrent validity. With some exceptions, group mean SOM scores showed agreement with group mean PEDI scores when children were categorized by age, gross motor function level, or PEDI cutoff score (1 or 2 SD below the mean). CONCLUSIONS: The results partially support concurrent validity between the SOM and PEDI, and suggest that the children's motor performance was similar across home and school settings. The findings also suggest that as a minimal database the SOM can reliably assess motor performance in the school setting; the disadvantage is difficulty interpreting SOM scores. PMID- 25529412 TI - "You gotta try it all": Parents' Experiences with Robotic Gait Training for their Children with Cerebral Palsy. AB - AIMS: Innovative robotic technologies hold strong promise for improving walking abilities of children with cerebral palsy (CP), but may create expectations for parents pursuing the "newest thing" in treatment. The aim of this qualitative study was to explore parents' values about walking in relation to their experiences with robotic gait training for their children. METHODS: Semi structured interviews were conducted with parents of five ambulatory children with CP participating in a randomized trial investigating robotic gait training effectiveness. RESULTS: Parents valued walking, especially "correct" walking, as a key component of their children's present and future well-being. They continually sought the "next best thing" in therapy and viewed the robotic gait trainer as a potentially revolutionary technology despite mixed experiences. CONCLUSIONS: The results can help inform rehabilitation therapists' knowledge of parents' values and perspectives, and guide effective collaborations toward meeting the therapeutic needs of children with CP. PMID- 25529413 TI - Technical note: The use of a sonomicrometry system for monitoring uterine involution in postpartum dairy cows. AB - Sonomicrometry allows the measurement of the distance between 2 piezoelectric crystals and has been widely used to investigate the contractility of the heart and gastrointestinal tract. The objective of this study was to determine whether this method can be used to quantify the reduction in uterine size in cows postpartum. Seven healthy pluriparous Holstein Friesian cows (3.7+/-0.7 yr old, parity 2.4+/-0.5, mean+/-SD) were used. Three weeks before calving, 4 piezoelectric crystals were implanted via laparotomy in the myometrium of the greater curvature of the pregnant uterine horn in a longitudinal direction. Sonometric measurements were conducted daily from 2 d before parturition until 14 d after calving, followed by measurements every other day until d 28. Changes in the distance between neighboring crystals were presented as relative changes (%) from baseline values before parturition. The diameter of the previously pregnant uterine horn was measured using transrectal B-mode sonography from d 10 to 28 after calving. The cows were slaughtered 39+/-6 d postpartum and the uterus was evaluated for fixation of the crystals. The distances between neighboring crystals underwent changes with a reduction of greater than 50% until d 1 postpartum, but no further changes were recorded from d 1 to 7. In the second week, changes in all distances were affected by day postpartum. One distance was affected by day postpartum in wk 3 and 4. There was a positive correlation between the diameter of the previously pregnant horn and the distances between the crystals. Examination of the uterus after slaughter of the cows revealed that 8 crystals (29%) were no longer fixed in the myometrium. Seven of these (25%) could be evaluated completely or partially and 1 (4%) could not be analyzed. Sonomicrometry seems to be suitable for the objective measurement of reduction in uterine length in cows. PMID- 25529414 TI - Variation in the interservice intervals of dairy cows in the United Kingdom. AB - An understanding of the normal estrous-cycle length of the cow is important when managing and monitoring dairy-herd fertility. Although the normal interovulatory interval is widely considered to be 21 d, some studies have found alternative intervals to be more prevalent; previously, most of the variation in interval length was expected to be between cows. The aim of this study was to assess the time between inseminations (interservice interval, ISI) in a large number of dairy cows and to explore possible associations between cow factors and estrous cycle length. The study used ISI data from 42,252 cows in 159 herds across England and Wales. Univariate analysis of the subset of 114,572 intervals between 15 and 30 d (a range covering the increased frequency of ISI occurring at the expected time of the first return to estrus) following an insemination revealed a modal ISI of 22d. Primiparous heifers had a modal ISI of 21 d. Significant differences existed between the distribution of ISI for different yield groups, parity numbers, and the number of inseminations. Multilevel regression modeling was used to evaluate the associations between cow factors and ISI, while accounting for clustering at the herd and cow level. This revealed significant associations between predicted ISI and insemination number, days in milk, lactation 305-d milk yield, and month and year of insemination. Variance partition coefficients indicated that only 1% of variation in ISI was at the herd level, 12% at the animal level, and 87% at the insemination level, indicating that cycle length varies substantially more between cycles within a cow than between cows or herds. These findings suggest the normal range of ISI for modern UK dairy cows is longer than expected and cycle length has a large amount of unexplained variation within individual animals over time. PMID- 25529415 TI - Analysis method for determination of nisin A and nisin Z in cow milk by using liquid chromatography-tandem mass spectrometry. AB - Nisin, a polypeptide with antimicrobial properties, is known as a natural preservative. It is used in various foods, including dairy products. This study validated a novel procedure using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of nisin A and nisin Z in cow milk. An extraction solution of 0.1 M acetate buffer containing 1 M NaCl (pH 2.0) and MeOH (1:1) was used to extract nisin A and nisin Z from milk samples. After the addition of extraction buffers, the samples were homogenized and centrifuged. The supernatant was filtered and injected for LC-MS/MS analysis. The linearity of the analytical method had a high correlation coefficient (r>=0.9987). The limits of quantitation of nisin A and nisin Z were approximately 12.9 and 10.9 ug/kg, respectively. The accuracy of the analytical method in milk ranged from 90.6 to 103.4% for nisin A and from 83.8 to 104.4% for nisin Z. The coefficient of variation values of intra- and interday in milk determined to be less than 5% in both nisin A and nisin Z. Because the proposed method has comparatively high recovery and low coefficient of variation, it seems appropriate for the determination of nisin A and nisin Z in milk samples. As the quantification of nisin A and nisin Z in milk samples by using LC-MS/MS has only been rarely reported until now, this study provides a meaningful technological advance for the dairy industry. PMID- 25529416 TI - Short communication: Importance of introgression for milk traits in the German Vorderwald and Hinterwald cattle. AB - The subject of the present study was to analyze the influence of genetic introgression on milk yield performance of the German local Vorderwald and Hinterwald cattle breeds. Deviations of milk yield, fat yield, and protein yield of cows as well as pedigree information were analyzed. A sire model was used to estimate genetic trend and effects of the migrant breeds. Migrant contributions to Vorderwald cattle were high and have been rising even in the recent past. The effects of these breeds on milk yield performance were positive. Montbeliarde cattle not only had the largest effect on milk production of Vorderwald cattle but also the highest genetic contribution to this breed. Genetic introgression with Montbeliarde continued until recently. This suggests that introgression of high-yielding breeds is still a preferred method for genetic improvement of local breeds, even though it diminishes their value for conservation. Hence, the current population management has too little focus on the preservation of genetic uniqueness. In comparison, migrant breed contributions to the Hinterwald cattle, a breed with a unique phenotype and an own niche, were moderate and almost constant over the time. For the Hinterwald cattle, no significant effect of migrant breeds could be detected, which suggests that population management has different priorities in different endangered breeds. We conclude that not only the registration of animals from local breeds but also the breeding programs themselves should be supported and need to be controlled. PMID- 25529417 TI - Bovine chromosomal regions affecting rheological traits in acid-induced skim milk gels. AB - The production of fermented milk products has increased worldwide during the last decade and is expected to continue to increase during the coming decade. The quality of these products may be optimized through breeding practices; however, the relations between cow genetics and technological properties of acid milk gels are not fully known. Therefore, the aim of this study was to identify chromosomal regions affecting acid-induced coagulation properties and possible candidate genes. Skim milk samples from 377 Swedish Red cows were rheologically analyzed for acid-induced coagulation properties using low-amplitude oscillation measurements. The resulting traits, including gel strength, coagulation time, and yield stress, were used to conduct a genome-wide association study. Single nucleotide polymorphisms (SNP) were identified using the BovineHD SNPChip (Illumina Inc., San Diego, CA), resulting in almost 621,000 segregating markers. The genome was scanned for putative quantitative trait loci (QTL) regions, haplotypes based on highly associated SNP were inferred, and the additive genetic effects of haplotypes within each QTL region were analyzed using mixed models. A total of 8 genomic regions were identified, with large effects of the significant haplotype explaining between 4.8 and 9.8% of the phenotypic variance of the studied traits. One major QTL was identified to overlap between gel strength and yield stress, the QTL identified with the most significant SNP closest to the gene coding for kappa-casein (CSN3). In addition, a chromosome-wide significant region affecting yield stress on BTA 11 was identified to be colocated with PAEP, coding for beta-lactoglobulin. Furthermore, the coagulation properties of the genetic variants within the 2 genes were compared with the coagulation properties identified by the patterns of the haplotypes within the regions, and it was discovered that the haplotypes were more diverse and in one case slightly better at explaining the phenotypic variance. Besides these significant QTL comprising the 2 milk proteins, 3 additional genes are proposed as possible candidates, namely RAB22A, CDH13, and STAT1, and all have previously been found to be expressed in the mammary gland. To our knowledge, this is the first attempt to map QTL regions for acid-induced coagulation properties. PMID- 25529418 TI - Short communication: Milk fat depression induced by conjugated linoleic acid and a high-oil and low-fiber diet occurs equally across the day in Holstein cows. AB - Recently, a circadian rhythm of milk and milk component synthesis has been characterized that is partially dependent on the timing of feed intake. Our objective was to determine if inhibition of milk fat synthesis during diet induced milk fat depression occurred to a higher degree during certain phases of the day. A retrospective analysis was conducted on 2 experiments that induced milk fat depression while milking cows 3 times per day at equal intervals. The response at each milking was analyzed using mixed model ANOVA with repeated measures. In experiment 1, nine multiparous Holstein cows were arranged in a 3*3 Latin square design, and treatments were control, 3-d intravenous infusion of 10 g/d of trans-10,cis-12 conjugated linoleic acid (CLA), and a low-forage and high fat diet for 10 d. In experiment 2, ten multiparous ruminally cannulated cows were arranged in a replicated design and milk samples were collected during a control period or after 5 d of abomasal infusion of 10 g/d of CLA. The daily pattern of milk fat concentration and yield did not differ between treatments in either experiment. In experiment 1, an effect was found of treatment and milking time on milk fat concentration and yield. Similarly, in experiment 2, main effects were found of treatment and milking time on milk fat concentration and an effect of treatment, but no effect of milking time on milk fat yield. Milk fat percent was increased from 3.41 to 4.06% and 3.25 to 3.48% from the morning to the afternoon milking in experiments 1 and 2, respectively. Additionally, milk fatty acid profile, including trans intermediates, was changed over the day in experiment 1, but the magnitude of the changes were small and the pattern did not differ among treatments. A daily rhythm of milk fat concentration and yield was observed in cows milked 3 times a day, but milk fat depression decreases milk fat yield equally over the day. PMID- 25529419 TI - An investigation of the efficacy of a polyvalent mastitis vaccine using different vaccination regimens under field conditions in the United Kingdom. AB - Vaccination can play a useful role in mastitis control programs, although there is a relative dearth of large, well-controlled field efficacy studies. This paper presents the findings on the use of a commercially available vaccine (Startvac, Hipra UK Ltd., Nottingham, UK) on commercial units under UK field conditions. In total, 3,130 cows were recruited from 7 farms and were randomly allocated, within farm, to 1 of 3 groups. The first group received the vaccine following the label regimen, the second group was vaccinated every 90 d following an initial vaccination course, and the third group was left unvaccinated to act as controls. Vaccine efficacy was assessed in the first 120 d of lactation. Data were available for analysis from 1,696 lactations in 1,549 cows. In total, 779 cases of clinical mastitis occurred in the 3 study groups, and we detected no significant difference in the incidence or prevalence of clinical or subclinical mastitis between any of the 3 groups. Mastitis vaccination following the label regimen was associated with a significant reduction in the severity of clinical cases. Cows in this group were at significantly decreased odds of developing clinical mastitis presenting with more than just milk changes [odds ratio: 0.58; 95% confidence interval (CI): 0.35-0.98]. Similarly, each additional vaccination resulted in a cow being at decreased odds of developing clinical mastitis presenting with more than just milk changes (odds ratio: 0.87; 95% CI: 0.77 0.98). Although no cows were culled because of severe mastitis in either of the vaccinated groups, we detected no significant difference in the mastitis-related culling rate between groups. Analysis of milk production data demonstrated that, on average, cows on the label regimen produced a higher volume of milk (231 L; 95% CI: 104.1-357.4) and more milk solids (12.36 kg; 95% CI: 3.12-21.60) than unvaccinated cows in the first 120 d of lactation. Conservative analysis suggested that a return on investment of 2.57:1 could be expected under UK conditions based on increased milk yield alone. PMID- 25529421 TI - Chemical composition and nutritive value of corn silage harvested in the northeastern United States after Tropical Storm Irene. AB - In the fall of 2011, Hurricane (Tropical Storm) Irene caused significant damage to the forage corn crop in the northeastern United States. Compromised crops were subjected to various degrees of flooding, lodging, and contamination with sediment. The objective of this study was to determine if compromised plants harvested for silage fermented normally and if the nutritive value of these silages was adversely affected. The chemical and nutrient composition of compromised silages was compared with that from silages made from unaffected plants from the same region. The concentration of NEL and in vitro digestibility of NDF were lower in plants compromised by the hurricane. In addition, the ash content of compromised silages was higher than that of unaffected silages. Specifically, concentrations of Al, Co, Fe, and Mn were higher in compromised silages. Overall, silage fermentation appeared to be normal; the final silage pH, and concentrations of fermentation acids, alcohols, and esters were similar between compromised and unaffected silages. Numbers of yeasts (but not molds) tended to be higher in compromised silage than in unaffected silage. Pathogenic microorganisms were not detected in any silage. The incidences and concentrations of mycotoxins were similar between compromised and normal silage. Several farms that fed compromised silage reported subsequent health issues with their animals. PMID- 25529420 TI - Lactobacillus gasseri requires peptides, not proteins or free amino acids, for growth in milk. AB - Lactobacillus gasseri is a widespread commensal lactic acid bacterium inhabiting human mucosal niches and has many beneficial effects as a probiotic. However, L. gasseri is difficult to grow in milk, which hurts usability for the food industry. It had been previously reported that supplementation with yeast extract or proteose peptone, including peptides, enables L. gasseri to grow well in milk. In this study, our objective was to confirm peptide requirement of L. gasseri and evaluate efficacy of peptide release by enzymatic proteolysis on growth of L. gassei in milk. Three strains of L. gasseri did not grow well in modified DeMan, Rogosa, Sharpe broth without any nitrogen sources (MRS-N), but addition of a casein-derived peptide mixture, tryptone, promoted growth. In contrast, little effect was observed after adding casein or a casein-derived amino acid mixture, casamino acids. These results indicate that L. gasseri requires peptides, not proteins or free amino acids, among milk-derived nitrogen sources for growth. Lactobacillus gasseri JCM 1131T hardly had growth capacity in 6 kinds of milk based media: bovine milk, human milk, skim milk, cheese whey, modified MRS-N (MRSL-N) supplemented with acid whey, and MRSL-N supplemented with casein. Moreover, treatment with digestive proteases, particularly pepsin, to release peptides made it grow well in each milk-based medium. The pepsin treatment was the most effective for growth of strain JCM 1131T in skim milk among the tested food-grade proteases such as trypsin, alpha-chymotrypsin, calf rennet, ficin, bromelain, and papain. As well as strain JCM 1131T, pepsinolysis of milk improved growth of other L. gasseri strains and some strains of enteric lactobacilli such as Lactobacillus crispatus, Lactobacillus gallinarum, Lactobacillus johnsonii, and Lactobacillus reuteri. These results suggest that some relatives of L. gasseri also use peptides as desirable nitrogen sources, and that milk may be a good supplier of nutritious peptides to enteric lactobacilli including L. gasseri after peptic digestion in the gastrointestinal tract. This is the first report showing peptide requirement of L. gasseri and efficacy of pepsinolysis on the growth of L. gasseri and its relatives in milk. This study would contribute to increasing usability of L. gasseri and its relatives as probiotics in dairy foods. PMID- 25529422 TI - Sugar reduction of skim chocolate milk and viability of alternative sweetening through lactose hydrolysis. AB - Milk consumption by Americans has not met the standards of the Dietary Guidelines for Americans. Chocolate milk can improve milk consumption, especially by children, due to its color and taste. However, the high sugar content of chocolate milk is a cause for concern about its healthfulness, resulting in its removal from some school lunch programs. It is important to reduce the sugar content of chocolate milk and still maintain acceptability among consumers. It is also important to investigate other natural alternatives to sweetening. The objectives of this study were to identify the different sweetness intensity perceptions of sucrose in water and various dairy matrices, to identify the acceptable reduction in sweet taste for chocolate milk for both young adults (19 35 yr) and children (5-13 yr), and to determine if lactose hydrolysis is a viable alternative. Threshold and power function studies were used to determine the benchmark concentration of sucrose in chocolate milk. The acceptability of sugar reduction from the benchmark concentration for both young adults and children and the acceptability of lactose hydrolyzed chocolate milk (4 degrees C for 24 h) with added lactose for young adults were evaluated. Acceptability results demonstrated that sugar reduction in chocolate milk is possible for both young adults and children as long as it does not exceed a 30% reduction (from 205 mM). Lactose hydrolysis of added lactose was used to achieve the sweetness of sucrose in chocolate milk but required >7.5% (wt/vol) added lactose, which contributed undesirable calories, indicating that lactose hydrolysis may be more suitable for other dairy beverages that require less added sugar. The findings of this study demonstrate consumer acceptance of reduced-sugar chocolate milk and a possible way to use lactose hydrolysis in dairy beverages. PMID- 25529423 TI - Milk production responses to dietary stearic acid vary by production level in dairy cattle. AB - Effects of stearic acid supplementation on feed intake and metabolic and production responses of dairy cows with a wide range of milk production (32.2 to 64.4 kg/d) were evaluated in a crossover design experiment with a covariate period. Thirty-two multiparous Holstein cows (142+/-55 d in milk) were assigned randomly within level of milk yield to treatment sequence. Treatments were diets supplemented (2% of diet dry matter) with stearic acid (SA; 98% C18:0) or control (soyhulls). The diets were based on corn silage and alfalfa and contained 24.5% forage neutral detergent fiber, 25.1% starch, and 17.3% crude protein. Treatment periods were 21 d with the final 4 d used for data and sample collection. Compared with the control, SA increased dry matter intake (DMI; 26.1 vs. 25.2 kg/d) and milk yield (40.2 vs. 38.5 kg/d). Stearic acid had no effect on the concentration of milk components but increased yields of fat (1.42 vs. 1.35 kg/d), protein (1.19 vs. 1.14 kg/d), and lactose (1.96 vs. 1.87 kg/d). The SA treatment increased 3.5% fat-corrected milk (3.5% FCM; 40.5 vs. 38.6 kg/d) but did not affect feed efficiency (3.5% FCM/DMI, 1.55 vs. 1.53), body weight, or body condition score compared with the control. Linear interactions between treatment and level of milk yield during the covariate period were detected for DMI and yields of milk, fat, protein, lactose, and 3.5% FCM; responses to SA were positively related to milk yield of cows. The SA treatment increased crude protein digestibility (67.4 vs. 65.5%), tended to increase neutral detergent fiber digestibility (43.6 vs. 42.3%), decreased fatty acid (FA) digestibility (56.6 vs. 76.1%), and did not affect organic matter digestibility. Fatty acid yield response, calculated as the additional FA yield secreted in milk per unit of additional FA intake, was only 13.3% for total FA and 8.2% for C18:0 plus cis 9 C18:1. Low estimated digestibility of the SA supplement was at least partly responsible for the low FA yield response. Treatment did not affect plasma insulin, glucagon, glucose, and nonesterified FA concentrations. Results show that stearic acid has the potential to increase DMI and yields of milk and milk components, without affecting conversion of feed to milk, body condition score, or body weight. Moreover, effects on DMI and yields of milk and milk components were more pronounced for higher-yielding cows than for lower-yielding cows. PMID- 25529424 TI - The relationship between activity clusters detected by an automatic activity monitor and endocrine changes during the periestrous period in lactating dairy cows. AB - The aim of this study was to determine the relationship between observed estrous related behavior, activity clusters (AC; detected by automatic activity monitor), endocrine profiles, and ovulation time. Twenty-one cows in estrus (after 2 cloprostenol treatments, 11 d apart) and 12 nonsynchronized cows, to establish Heatime (SCR Engineers Ltd., Netanya, Israel) herd baseline activity, were enrolled. Cows had Heatime monitors applied 3 wk before the trial to establish their own baseline activity level. Cows in standing estrus had ultrasonography and phlebotomy carried out every 4 h to determine dominant follicle size, endocrine profiles, and ovulation time. After ovulation, these procedures were repeated once on d 3 to 6. Heatime alerted estrus in 90% of cows, and incorrectly alerted 17% of AC. The mean+/-SEM duration for standing estrus was 9+/-1 and 13+/ 1 h for estrous-related behavior. Estrous-related behavior began after the start of the proestrous estradiol-17beta (E2) increase (59+/-6.5 h). Cows with longer durations of raised proestrous E2 had longer intervals from its onset to the start of standing estrus and AC. The AC duration increased with longer durations of estrous-related behavior. Higher peak E2 occurred with longer standing estrus and estrous-related behavior. As E2 concentration decreased after the peak, 90% of cows still had estrous-related behavior. Duration of estrous-related behavior increased with higher average E2 concentration during the last 8 h before the start of the LH surge. During this surge 90% of cows had all of their standing estrus. As yields increased, so did the magnitude of the preovulatory FSH surges. Higher surges occurred with shorter standing estrus and estrous-related behavior. Cows with shorter LH surges had longer standing estrus. Peak LH preceded the AC peak (6.6+/-0.8 h). Duration of overlap between the AC start and the LH surge end ranged between 0 and 14 h; 1 cow had none. No association was found between the AC characteristics with the E2, LH, or FSH profiles. In conclusion, the relationship between the timing of the E2 increase and estrous activity may be mediated by other factors (GnRH surge). Estrous-related behavior, but not endocrine profiles, was related to AC duration. Timing of standing estrus during the LH surge ensures that mating allows sperm maturation before ovulation. Based on the interval from the start of an AC to ovulation (27+/-1 h), the optimum time to artificial insemination is, on average, between 9 and 15 h after the AC start. PMID- 25529425 TI - Potential of milk fatty acid composition to predict diet composition and authenticate feeding systems and altitude origin of European bulk milk. AB - The aims of this work were to elucidate the potential of using milk fatty acid (FA) concentration to predict cow diet composition and altitude of bulk milk collected in 10 different European countries and to authenticate cow-feeding systems and altitude of the production area using a data set of 1,248 bulk cow milk samples and associated farm records. The predictions based on FA for cow diet composition were excellent for the proportions of fresh herbage [coefficient of determination (R2)=0.81], good for hay, total herbage-derived forages, and total preserved forages (R2>0.73), intermediate for corn silage and grass silage (R2>0.62), and poor for concentrates (R2<0.51) in the cow diet. Milk samples were assigned to groups according to feeding system, level of concentrate supplementation, and altitude origin. Milk FA composition successfully authenticated cow-feeding systems dominated by a main forage (>93% of samples correctly classified), but the presence of mixed diets reduced the discrimination. Altitude prediction reliability was intermediate (R2<0.62). Milk FA composition was not able to authenticate concentrate supplementation level in the diet (<58% of samples correctly classified). Similarly, the altitude origin was not successfully authenticated by milk FA composition (<76% of samples correctly classified). The potential of milk FA composition to authenticate cow feeding was confirmed using a data set representative of the diversity of European production conditions. PMID- 25529426 TI - Short communication: Use of single nucleotide polymorphism genotypes and health history to predict future phenotypes for milk production, dry matter intake, body weight, and residual feed intake in dairy cattle. AB - As feed prices have increased, the efficiency of feed utilization in dairy cattle has attracted increasing attention. In this study, we used residual feed intake (RFI) as a measurement of feed efficiency along with its component traits, adjusted milk energy (aMilkE), adjusted dry matter intake (aDMI), and adjusted metabolic body weight (aMBW), where the adjustment was for environmental factors. These traits may also be affected by prior health problems. Therefore, the carryover effects of 3 health traits from the rearing period and 10 health traits from the lactating period (in the same lactation before phenotype measurements) on RFI, aMilkE, aDMI, and aMBW were evaluated. Cows with heavier birth weight and greater body weight at calving of this lactation had significant increases in aMilkE, aDMI, and aMBW. The only trait associated with RFI was the incidence of diarrhea early in the lactation. Mastitis and reproductive problems had negative carryover effects on aMilkE. The aMBW of cows with metabolic disorders early in the lactation was lower than that of unaffected cows. The incidence of respiratory disease during lactating period was associated with greater aMBW and higher aDMI. To examine the contribution of health traits to the accuracy of predicted phenotype, genomic predictions were computed with or without information regarding 13 health trait phenotypes using random forests (RF) and support vector machine algorithms. Adding health trait phenotypes increased prediction accuracies slightly, except for prediction of RFI using RF. In general, the accuracies were greater for support vector machine than RF, especially for RFI. The methods described herein can be used to predict future phenotypes for dairy replacement heifers, thereby facilitating culling decisions that can lead to decreased feed costs during the rearing period. For these decisions, prediction of the animal's own phenotype is of greater importance than prediction of the genetic superiority or inferiority that will transmit to its offspring. PMID- 25529428 TI - Mechanism of [3+2] cycloaddition of alkynes to the [Mo3 S4 (acac)3 (py)3 ][PF6 ] cluster. AB - A study, involving kinetic measurements on the stopped-flow and conventional UV/Vis timescales, ESI-MS, NMR spectroscopy and DFT calculations, has been carried out to understand the mechanism of the reaction of [Mo3 S4 (acac)3 (py)3 ][PF6 ] ([1]PF6 ; acac=acetylacetonate, py=pyridine) with two RC?CR alkynes (R=CH2 OH (btd), COOH (adc)) in CH3 CN. Both reactions show polyphasic kinetics, but experimental and computational data indicate that alkyne activation occurs in a single kinetic step through a concerted mechanism similar to that of organic [3+2] cycloaddition reactions, in this case through the interaction with one Mo(MU-S)2 moiety of [1](+) . The rate of this step is three orders of magnitude faster for adc than that for btd, and the products initially formed evolve in subsequent steps into compounds that result from substitution of py ligands or from reorganization to give species with different structures. Activation strain analysis of the [3+2] cycloaddition step reveals that the deformation of the two reactants has a small contribution to the difference in the computed activation barriers, which is mainly associated with the change in the extent of their interaction at the transition-state structures. Subsequent frontier molecular orbital analysis shows that the carboxylic acid substituents on adc stabilize its HOMO and LUMO orbitals with respect to those on btd due to better electron withdrawing properties. As a result, the frontier molecular orbitals of the cluster and alkyne become closer in energy; this allows a stronger interaction. PMID- 25529427 TI - Serosal-to-mucosal urea flux across the isolated ruminal epithelium is mediated via urea transporter-B and aquaporins when Holstein calves are abruptly changed to a moderately fermentable diet. AB - Urea transport (UT-B) proteins are known to facilitate urea movement across the ruminal epithelium; however, other mechanisms may be involved as well because inhibiting UT-B does not completely abolish urea transport. Of the aquaporins (AQP), which are a family of membrane-spanning proteins that are predominantly involved in the movement of water, AQP-3, AQP-7, and AQP-10 are also permeable to urea, but it is not clear if they contribute to urea transport across the ruminal epithelium. The objectives of this study were to determine (1) the functional roles of AQP and UT-B in the serosal-to-mucosal urea flux (Jsm-urea) across rumen epithelium; and (2) whether functional adaptation occurs in response to increased diet fermentability. Twenty-five Holstein steer calves (n=5) were assigned to a control diet (CON; 91.5% hay and 8.5% vitamin and mineral supplement) or a medium grain diet (MGD; 41.5% barley grain, 50% hay, and 8.5% vitamin and mineral) that was fed for 3, 7, 14, or 21 d. Calves were killed and ruminal epithelium was collected for mounting in Ussing chambers under short-circuit conditions and for analysis of mRNA abundance of UT-B and AQP-3, AQP-7, and AQP-10. To mimic physiologic conditions, the mucosal buffer (pH 6.2) contained no urea, whereas the serosal buffer (pH 7.4) contained 1 mM urea. The fluxes of (14)C-urea (Jsm urea; 26 kBq/10 mL) and (3)H-mannitol (Jsm-mannitol; 37 kBq/10 mL) were measured, with Jsm-mannitol being used as an indicator of paracellular or hydrophilic movement. Serosal addition of phloretin (1 mM) was used to inhibit UT-B-mediated urea transport, whereas NiCl2 (1 mM) was used to inhibit AQP-mediated urea transport. Across treatments, the addition of phloretin or NiCl2 reduced the Jsm urea from 116.5 to 54.0 and 89.5 nmol/(cm(2) * h), respectively. When both inhibitors were added simultaneously, Jsm-urea was further reduced to 36.8 nmol/(cm(2) * h). Phloretin-sensitive and NiCl2-sensitive Jsm-urea were not affected by diet. The Jsm-urea tended to increase linearly as the duration of adaptation to MGD increased, with the lowest Jsm-urea being observed in animals fed CON [107.7 nmol/(cm(2) * h)] and the highest for those fed the MGD for 21 d [144.2 nmol/(cm(2) * h)]. Phloretin-insensitive Jsm-urea tended to increase linearly as the duration of adaptation to MGD increased, whereas NiCl2 insensitive Jsm-urea tended to be affected by diet. Gene transcript abundance for AQP-3 and UT-B in ruminal epithelium increased linearly as the duration of MGD adaptation increased. For AQP-7 and AQP-10, gene transcript abundance in animals that were fed the MGD was greater compared with that of CON animals. These results demonstrate that both AQP and UT-B play significant functional roles in urea transport, and they may play a role in urea transport during dietary adaptation to fermentable carbohydrates. PMID- 25529429 TI - The interrelation between aPKC and glucose uptake in the skeletal muscle during contraction and insulin stimulation. AB - Contraction and insulin increase glucose uptake in skeletal muscle. While the insulin pathway, better characterized, requires activation of phosphoinositide 3 kinase (PI3K) and atypical protein kinase (aPKC), muscle contraction seems to share insulin-activated components to increase glucose uptake. This study aimed to investigate the interrelation between the pathway involved in glucose uptake evoked by insulin and muscle contraction. Isolated muscle of rats was treated with solvent (control), insulin, wortmannin (PI3K inhibitor) and the combination of insulin plus wortmannin. After treatment, muscles were electrically stimulated (contracted) or remained at rest. Glucose transporter 4 (GLUT4) localization, glucose uptake and phospho-aPKC (aPKC activated form) were assessed. Muscle contraction and insulin increased glucose uptake in all conditions when compared with controls not stimulating an effect that was accompanied by an increase in GLUT4 and of phospho-aPKC at the muscle membrane. Contracted muscles treated with insulin did not show additive effects on glucose uptake or aPKC activity compared with the response when these stimuli were applied alone. Inhibition of PI3K blocked insulin effect on glucose uptake and aPKC but not in the contractile response. Thus, muscle contraction seems to stimulate aPKC and glucose uptake independently of PI3K. Therefore, aPKC may be a convergence point and a rate limit step in the pathway by which, insulin and contraction, increase glucose uptake in skeletal muscle. PMID- 25529431 TI - Quantitation of 47 human tear proteins using high resolution multiple reaction monitoring (HR-MRM) based-mass spectrometry. AB - Tear proteins are intimately related to the pathophysiology of the ocular surface. Many recent studies have demonstrated that the tear is an accessible fluid for studying eye diseases and biomarker discovery. This study describes a high resolution multiple reaction monitoring (HR-MRM) approach for developing assays for quantification of biologically important tear proteins. Human tear samples were collected from 1000 subjects with no eye complaints (411 male, 589 female, average age: 55.5+/-14.5years) after obtaining informed consent. Tear samples were collected using Schirmer's strips and pooled into a single global control sample. Quantification of proteins was carried out by selecting "signature" peptides derived by trypsin digestion. A 1-h nanoLC-MS/MS run was used to quantify the tear proteins in HR-MRM mode. Good reproducibility of signal intensity (using peak areas) was demonstrated for all 47 HR-MRM assays with an average coefficient of variation (CV%) of 4.82% (range: 1.52-10.30%). All assays showed consistent retention time with a CV of less than 0.80% (average: 0.57%). HR-MRM absolute quantitation of eight tear proteins was demonstrated using stable isotope-labeled peptides. BIOLOGICAL SIGNIFICANCE: In this study, we demonstrated for the first time the technique to quantify 47 human tear proteins in HR-MRM mode using approximately 1MUl of human tear sample. These multiplexed HR-MRM based assays show great promise of further development for biomarker validation in human tear samples. Both discovery-based and targeted quantitative proteomics can be achieved in a single quadrupole time-of-flight mass spectrometer platform (TripleTOF 5600 system). PMID- 25529432 TI - Preferential interactions between protein and arginine: effects of arginine on tertiary conformational and colloidal stability of protein solution. AB - The purpose of this study was to better understand the preferential binding behavior of arginine to protein as well as the impact of arginine on the conformational and colloidal stability of protein solution. Physical stabilities of model proteins, bovine serum albumin (BSA) and ovalbumin (OVA), were investigated by fluorescence-based and dynamic light scattering techniques in the absence and presence of arginine. We investigated the interactions between arginine and tryptophan or tyrosine residues by conducting solubility and fluorescence studies of two amino acid derivatives, N-acetyl-l-tryptophanamide (NATA) and N-acetyl-l-tyrosinamide (NAYA), in arginine solutions. The result showed that arginine preferentially bond to the aromatic amino acids of proteins mainly through hydrogen bonds and Van der Waals' forces, while the binding constant K of arginine with BSA and OVA at 298K was 41.92 and 5.77L/mol, respectively. The fluorescence quenching, the decreased fluorescence lifetime and the red-shifted ANS peak position revealed that arginine perturbed the local environment of tryptophan and tyrosine residues. We also found the attenuated electrostatic repulsion among BSA and OVA molecules after adding arginine. These findings provided strong evidence that arginine possessed negative effects on tertiary conformational and colloidal stability of BSA and OVA during the preferential binding process. PMID- 25529433 TI - Epithelial cell adhesion molecule aptamer conjugated PEG-PLGA nanopolymersomes for targeted delivery of doxorubicin to human breast adenocarcinoma cell line in vitro. AB - Targeted delivery of anti-cancer agents exclusively to tumor cells introduces an attractive strategy because it increases the therapeutic index compared with untargeted drugs. Aptamer conjugated nanoparticles that can specifically bind to the proteins on a tumor cell surface are capable nanoscale delivery systems for enhancing cellular uptake of chemotherapeutic agents. The epithelial cell adhesion molecule (EpCAM) as a cancer stem cell marker emerges as a versatile target for aptamer-based cancer therapy due to its high expression level in various adenocarcinoma cell lines and its very low expression level in normal cells. We developed EpCAM-targeted PEG-PLGA nanopolymersomes by covalently coupling the EpCAM aptamer to the surface of nanopolymersomes loaded with the anticancer agent doxorubicin via pH gradient method. The results indicated that doxorubicin was entrapped in PEG-PLGA nanopolymersomes with encapsulation efficiency and loading content of 91.25+/-4.27% and 7.3+/-0.34%, respectively. Over a period of 5 days, up to 8% of the DOX was released through this system. The doxorubicin-loaded aptamer conjugated nanopolymersomes exhibited efficient cell uptake and internalization, and were significantly more cytotoxic (P<0.01) toward EpCAM-positive tumor cells (MCF-7) than non-targeted nanopolymersomes. Our data suggest that EpCAM-targeted nanopolymersomes will lead to an improved therapeutic index of doxorubicin to EpCAM positive cancer cells. PMID- 25529434 TI - Trichotomous gastric retention of amorphous capecitabine: an attempt to overcome pharmacokinetic gap. AB - Capecitabine (CAP) is an oral drug of choice for treatment of colorectal cancer. But its short plasma half-life limits clinical utility and the usually prescribed dosing regimen results in significant periods of therapeutically irrelevant concentration. To overcome this pharmacokinetic void a trichotomous gastroretentive (TRGDDS) system made up of CAP housed in xanthan gum microparticles (CXGMP) has been developed for extending CAP's gastric residence time thereby prolonging the subsequent elimination. TRGDDS was evaluated for particle size (243+/-25MUm), surface morphology (porous) entrapment efficiency (87.72+/-7.31%), buoyancy (86.32+/-2.3%), mucoadhesiveness (88+/-4.3%), swelling index (80.37+/-4.65). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) of CXGMP suggested CAP had been rendered amorphous, a property which unconventionally slows its dissolution. Significant control was offered by CXGMP compared to crystalline CAP in terms of drug release. Pharmacokinetic studies in Wistar rat further revealed that CXGMP increased the MRT (three times), elimination half-life (roughly 4 fold) and AUC (1.44 folds) of CAP at a dose of 5mg/kg in comparison to CAP solution of same strength. Conclusively the employment of TRGDDS had extended the duration for which CAP stayed in the rodent model, providing evidence for potentially obtaining a more efficacious dosing regimen in actual disease models. PMID- 25529435 TI - Shell-crosslinked hybrid nanoparticles for direct cytosolic delivery for tumor therapy. AB - To obtain efficient therapeutics, drug release into the cytosol is required because drug targets are often located in the cytosol or have active sites that require intracellular machinery in the cytosolic compartment. However, typical nanocarriers gain cellular entry by endocytic mechanisms, confining the internalized nanocarriers to the endosomal-lysosomal system, thus resulting in the rapid destruction of active drugs without release into the cytosol. Herein, hybrid nanoparticles (HNs) with a core-shell structure, which was based on nanoemulsion-templates stabilized by both beta-lactoglobulin (beta-LG) and lecithin, were developed. Additionally, its formation mechanism and structure were also studied. Importantly, the HNs could directly penetrate the cell membrane and enter the cytosol, without entrapment within the endosomal-lysosomal system via the lipid raft-like pathway, thus enhancing its antitumor activities. We therefore concluded that HNs are promising targeting delivery systems for drugs, especially for pharmaceutical proteins and gene-targeting drugs. PMID- 25529436 TI - Aerosil as a novel co-crystal co-former for improving the dissolution rate of hydrochlorothiazide. AB - Co-crystallization of drugs with benign co-formers is promising for enhancing dissolution rate of poorly soluble drugs. The selection of safe and pharmacologically inert co-formers is a critical step in this process. Accordingly, the objective of this work was to investigate aerosil 200 as a potential co-former for the preparation of hydrochlorothiazide co-crystal. Co crystal formation involved acetone assisted co-grinding after mixing hydrochlorothiazide with increasing molar ratios of aerosil (1:1, 1:2 and 1:4). The prepared formulations were subjected to Fourier transform infrared spectroscopy, differential thermal analysis, and powder X-ray diffraction studies. These investigations provided evidence for co-crystal formation between the drug and aerosil. Complete co-crystallization was even achieved at the lowest tested concentration of aerosil suggesting that the stoichiometric ratio of co crystal formation is 1:1 molar ratio. The dissolution studies revealed faster dissolution rate of the drug from co-crystals compared to the pure unprocessed drug or that which was subjected to wet grinding in absence of aerosil. Increasing the molar ratio of aerosil increased the amount dissolved in the first 5 min. This may be attributed to adsorption of the formed co-crystal on the surface of excess aerosil. In conclusion, aerosil can be considered as co-crystal co-former with potential future application. PMID- 25529437 TI - Elevated arterial lactate concentrations early after coronary artery bypass grafting are associated with increased anaerobic metabolism in skeletal muscle. AB - OBJECTIVE: To assess the effect of coronary artery bypass grafting with cardiopulmonary bypass on muscle perfusion, oxygen extraction, and lactate release during postoperative rest and exercise. DESIGN: Prospective observational study. SETTING: University hospital. PARTICIPANTS: Patients undergoing planned coronary artery bypass grafting. INTERVENTION: Knee-extensor exercise before and after coronary artery bypass grafting. MEASUREMENTS AND MAIN RESULTS: Femoral artery blood flow was measured with ultrasound. Femoral vein blood and arterial blood were sampled at rest and during light exercise and were analyzed for hemoglobin, lactate, oxygen saturation, and oxygen partial pressure. Fourteen patients were tested before and after surgery. The arterial lactate concentrations were increased after surgery, both at rest and during light exercise. Resting arterial lactate increased from 0.65 (0.5-0.8) to 1.0 (0.9-1.3) mmol/L (p=0.01) (median and interquartile range). Furthermore, lactate was released from the leg even during postoperative rest, and the release of lactate was increased during postoperative exercise. There were no significant differences between the preoperative and postoperative femoral artery blood flow. Femoral vein oxygen partial pressure was reduced significantly after surgery, indicating reduced muscle cell oxygen partial pressure. CONCLUSIONS: The patients had elevated anaerobic metabolism in skeletal muscle after surgery to compensate for anemia. Lactate was released from the leg into the general circulation during postoperative rest and exercise. The postoperatively reduced hemoglobin concentration of 11.4 mg/dL (10.6-12.3) resulted in increased anaerobic metabolism and release of lactate from skeletal muscle. The authors concluded that coronary artery bypass grafting patients are susceptible to anaerobic metabolism even with maintained peripheral blood flow. PMID- 25529438 TI - Prediction of bleeding after cardiac surgery: comparison of model performances: a prospective observational study. AB - OBJECTIVES: Primary aims were to (1) perform external validation of the Papworth Bleeding Risk Score, and (2) compare the usefulness of the Dyke et al universal definition of perioperative bleeding with that used in the Papworth Bleeding Risk Score. A secondary aim was to use a locally developed logistic prediction model for severe postoperative bleeding to investigate whether prediction could be improved with inclusion of the variable "surgeon" or selected intraoperative variables. DESIGN: Single-center prospective observational study. SETTING: University hospital. PARTICIPANTS: 7,030 adults undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Papworth Bleeding Risk Score could identify the group of patients with low risk of postoperative bleeding, with negative predictive value of 0.98, when applying the Papworth Score on this population. The positive predictive value was low; only 15% of the patients who were rated high risk actually suffered from increased postoperative bleeding when using the Papworth Score on this population. Using the universal definition of perioperative bleeding proposed by Dyke et al, 28% of patients in the Papworth high-risk group exceeded the threshold of excessive bleeding in this population. The local models showed low ability for discrimination (area under the receiver operating characteristics curve<0.75). Addition of the factor "surgeon" or selected intraoperative variables did not substantially improve the models. CONCLUSION: Prediction of risk for excessive bleeding after cardiac surgery was not possible using clinical variables only, independent of endpoint definition and inclusion of the variable "surgeon" or of selected intraoperative variables. These findings may be due to incomplete understanding of the causative factors underlying excessive bleeding. PMID- 25529439 TI - Interaction of VP8 with mRNAs of bovine herpesvirus-1. AB - The UL47 gene product, VP8, is one of the most abundant tegument proteins of bovine herpesvirus-1 (BoHV-1). Deletion of VP8 leads to impaired growth in tissue culture, and VP8 is indispensable for BHV-1 replication in cattle. To elucidate the biological functions of VP8, we explored its interaction with mRNAs of immediate early (bICP0), early (gB, gD) and late (gC) genes of BoHV-1. FLAG tagged VP8 was pulled down from COS-7 cells co-transfected with plasmids encoding VP8 and either gB, gC, gD or bICP0. This was followed by RNA extraction, cDNA synthesis and qPCR, which demonstrated binding of VP8 to bICP0, gB, gC and gD mRNAs in the cytoplasm and nucleus. These results were supported by co localization of VP8 with bICP0, gB, gC and gD mRNAs in the nucleus as determined by confocal microscopy. Amino acids 259-342, located in the conserved portion of UL47 homologues, were found to contain the RNA binding region on VP8. To further characterize these interactions, Northwestern blotting was performed by immobilizing VP8 on a nitrocellulose membrane followed by hybridization with in vitro transcribed bICP0 mRNA. The results demonstrated binding of VP8 to intron less mRNA but not intron-containing mRNA of bICP0. In addition, the interaction of VP8 with bICP0 mRNA was confirmed in vitro by RNA electrophoretic mobility shift assay, which also showed that the zinc finger and acidic domains both interact with VP8. Based on these results, we concluded that VP8 binds to intron less mRNAs of bICP0, gB, gC and gD. PMID- 25529440 TI - Construction and characterization of novel fowlpox virus shuttle vectors. AB - Viral vectors are important vehicles in vaccine research. Avipoxviruses including fowlpox virus (FPV) play major roles in viral vaccine vector development for the prevention and therapy of human and other veterinary diseases due to their immunomodulatory effects and safety profile. Recently, we analyzed the genomic and proteomic backgrounds of the Chinese FPV282E4 strain. Based on analysis of the whole genome of FPV282E4, the FPV150 and FPV193 loci were chosen as insertion sites for foreign genes, and two shuttle vectors with a triple-gene expression cassette were designed and constructed. Homologous recombination between the FPV virus genome and sequences within the shuttle plasmids in infected cells was confirmed. The recombinants were obtained through several rounds of plaque purification using enhanced green fluorescent protein as a reporter and evaluated for the correct expression of foreign genes in vitro using RT-PCR, real-time PCR and Western blotting. Morphogenesis and growth kinetics were assayed via transmission electron microscopy and viral titering, respectively. Results showed that recombinant viruses were generated and correctly expressed foreign genes in CEF, BHK-21 and 293T cells. At least three different exogenous genes could be expressed simultaneously and stably over multiple passages. Additionally, the FPV150 mutation, FPV193 deletion and insertion of foreign genes did not affect the morphogenesis, replication and proliferation of recombinant viruses in cells. Our study contributes to the improvement of FPV vectors for multivalent vaccines. PMID- 25529441 TI - Regulation of host responses and viral replication by the mitogen-activated protein kinases in intestinal epithelial cells infected with Enterovirus 71. AB - Enterovirus 71 (EV71) has become an important neurotropic enterovirus in children since the eradication of the poliovirus. A cytokine storm with elevated levels of proinflammatory cytokines is proposed as critical to the pathogenesis of EV71 induced brain stem encephalitis with pulmonary edema, often a fatal complication. Mitogen-activated protein kinases (MAPK) are involved in cellular processes including immune responses and apoptosis. EV71 infection can trigger MAPK activation in human cells, and extracellular signal-regulated kinase (ERK) signaling is essential for EV71 replication. In this study, we report that in EV71-infected human intestinal epithelial cells (HT-29), both ERK1/2 and Jun-N terminal kinase 1/2 (JNK1/2) were phosphorylated and activated. While MAPK was not involved in the induction of IL-1beta, the expressions of IL-6 and IL-8 were positively regulated by both ERK1/2 and JNK1/2, which were also responsible for type I IFN induction. HT-29 cells underwent apoptosis in EV71 infection, but the activation of ERK1/2 and JNK1/2 signaling appeared to suppress induction of TNF alpha and FasL and inhibit extrinsic apoptosis in infected cells. Activation of NF-kappaB was also observed in HT-29 cells in EV71 infection, leading to increased viral replication and proinflammatory cytokine induction. However, the activation of NF-kappaB was inhibited by the inhibitors of ERK1/2, p38 and JNK1/2, indicating that a cross-talk may exist between MAPK and NF-kappaB pathways in EV71-infected intestinal epithelial cells. Understanding host responses and their underlying mechanisms may help develop effective therapeutics against EV71 and tools for control of future EV71 outbreaks. PMID- 25529442 TI - Regulation and evasion of antiviral immune responses by porcine reproductive and respiratory syndrome virus. AB - Virus infection of mammalian cells triggers host innate immune responses to restrict viral replication and induces adaptive immunity for viral elimination. In order to survive and propagate, viruses have evolved sophisticated mechanisms to subvert host defense system by encoding proteins that target key components of the immune signaling pathways. Porcine reproductive and respiratory syndrome virus (PRRSV), a RNA virus, impairs several processes of host immune responses including interfering with interferon production and signaling, modulating cytokine expression, manipulating apoptotic responses and regulating adaptive immunity. In this review, we highlight the molecular mechanisms of how PRRSV interferes with the different steps of initial antiviral host responses to establish persistent infection in pigs. Dissection of the PRRSV-host interaction is the key in understanding PRRSV pathogenesis and will provide a basis for the rational design of vaccines. PMID- 25529443 TI - Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage. AB - Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague-Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH+RR, and SAH+Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron-sulfur cluster dependent aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH. PMID- 25529444 TI - Glatiramer acetate (GA) prevents TNF-alpha-induced monocyte adhesion to primary endothelial cells through interfering with the NF-kappaB pathway. AB - Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) is considered to be the major one contributing to the process of development of endothelial dysfunction. Exposure to TNF-alpha induces the expression of a number of proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1), and adhesion molecules, including vascular adhesion molecule-1 (VCAM-1) and E selectin, which mediate the interaction of invading monocytes with vascular endothelial cells. Glatiramer acetate (GA) is a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). The effects of GA in vascular disease have not shown before. In this study, we found that GA significantly inhibited TNF-alpha-induced binding of monocytes to endothelial cells. Mechanistically, we found that GA ameliorated the upregulation of MCP-1, VCAM-1, and E-selectin induced by TNF-alpha. Notably, this process is mediated by inhibiting the nuclear translocation and activation of NF-kappaB. Our results also indicate that GA pretreatment attenuates the up-regulation of COX-2 and iNOS. These data suggest that GA might have a potential benefit in therapeutic endothelial dysfunction related diseases. PMID- 25529445 TI - Eicosapentaenoic acid (EPA) induced apoptosis in HepG2 cells through ROS-Ca(2+) JNK mitochondrial pathways. AB - Eicosapentaenoic acid (EPA), a well-known dietary n-3 PUFAS, has been considered to inhibit proliferation of tumor cells. However, the molecular mechanism related to EPA-induced liver cancer cells apoptosis has not been reported. In this study, we investigated the effect of EPA on HepG2 cells proliferation and apoptosis mechanism through mitochondrial pathways. EPA inhibited proliferation of HepG2 cells in a dose-dependent manner and had no significant effect on the cell viability of humor normal liver L-02 cells. It was found that EPA initially evoked ROS formation, leading to [Ca(2+)]c accumulation and the mitochondrial permeability transition pore (MPTP) opening; EPA-induced HepG2 cells apoptosis was inhibited by N-acetylcysteine (NAC, an inhibitor of ROS), 1,2-bis (2 aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM, a chelator of calcium) and CsA (inhibitor of MPTP). The relationship between ROS production, the increase of cytoplasmic Ca and MPTP opening was detected. It seems that ROS may act as an upstream regulator of EPA-induced [Ca(2+)]c generation, moreover, generation of ROS, overload of mitochondrial [Ca(2+)]c, and JNK activated cause the opening of MPTP. Western blotting results showed that EPA elevated the phosphorylation status of JNK, processes associated with the ROS generation. Simultaneously, the apoptosis induced by EPA was related to release of cytochrome C from mitochondria to cytoplasm through the MPTP and activation of caspase-9 and caspase-3. These results suggest that EPA induces apoptosis through ROS-Ca(2+) JNK mitochondrial pathways. PMID- 25529446 TI - MiR-378a-3p enhances adipogenesis by targeting mitogen-activated protein kinase 1. AB - Previous studies showed that miR-378a plays important roles in adipogenesis and obesity; however, the precise mechanisms of action remain unknown. Here, we found that miR-378a-3p expression is up-regulated in adipose tissues of high fat diet induced obese mice, as well as during the differentiation of 3T3-L1 preadipocytes. Mir-378a-3p induced adipogenesis by targeting mitogen-activated protein kinase 1 (MAPK1). Overexpression of miR-378a-3p or silencing MAPK1 reduced MAPK1 expression and enhanced adipogenesis, whereas blockage of endogenous miR-378a-3p had the opposite effect, suggesting that miR-378a-3p promotes the adipogenesis of 3T3-L1 cells by targeting MAPK1. PMID- 25529448 TI - A functional variant in the exon 5 of PLIN1 reduces risk of central obesity by possible regulation of lipid storage. AB - PURPOSE: Perilipin coats lipid droplets in adipocytes and steroidogenic cells. Its major role is in the regulation of intracellular lipolysis in adipocytes. Our aim was to examine the association between common variants at the PLIN1 gene and central obesity in unrelated Chinese adults. METHODS: A case-control study was carried out on 869 patients with central obesity and 869 age- and gender-matched individuals without central obesity. Two PLIN1 variants (rs6496589 and rs8179078) were genotyped by PCR and restriction enzyme analysis. In addition, the association of the variant with central obesity was replicated in an independent population of 629 central obesity patients and 518 controls. Finally, the relationship between rs6496589 and enhancing lipid accumulation in THP-1-derived macrophages was assessed. RESULTS: PLIN1 rs6496589 allele frequencies and genotype frequencies of CG+GG in the patients' group were much lower than those in the control group. After adjustment for conventional risk factors using multiple logistical regression analysis, rs6496589G allele frequencies were significantly associated with a lower risk of central obesity (OR 0.71, 95% CI: 0.59-0.86, P=0.001). These results were confirmed in an independent study. No association was found between PLIN1 rs8179078 and central obesity. Furthermore, in vitro assays revealed that homozygous rs6496589G alleles presented lower lipid droplet accumulation in THP-1-derived macrophages, compared with non-carriers. CONCLUSIONS: The functional PLIN1 rs6496589 may influence the risk of central obesity through possible regulation of lipid storage. PMID- 25529447 TI - miR-143 inhibits interleukin-13-induced inflammatory cytokine and mucus production in nasal epithelial cells from allergic rhinitis patients by targeting IL13Ralpha1. AB - Allergic rhinitis (AR) is a common chronic inflammatory condition of the nasal mucosal tissue. The interleukin-13 (IL-13) signaling pathway is of great importance in the pathogenesis of AR. However, how the signaling molecules in this pathway are regulated, particularly through microRNAs (miRNAs), remains unclear. In the present study, we investigated the regulatory role and mechanism of miRNA-143 (miR-143) in IL-13-induced inflammatory cytokine and mucus production in nasal epithelial cells (NECs) from AR patients. Our results showed that forced expression of miR-143 significantly decreased the mRNA and protein expression levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), eotaxin and mucin 5AC (MUC5AC) in IL-13-stimulated NECs. Moreover, we confirmed that miR-143 directly targeted and significantly suppressed IL-13 receptor alpha1 chain (IL13Ralpha1) gene expression. This study thus suggests that miR-143 regulation of IL-13-induced inflammatory cytokine and mucus production in NECs from AR patients probably partly depends on inhibition of IL13Ralpha1. Therefore, the IL13Ralpha1 signaling pathway may be a potential target for the prevention and treatment of AR by miR-143. PMID- 25529449 TI - Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-gamma activation. AB - The peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARgamma in macrophages. However, it is not yet known whether statins activate PPARgamma in other vascular cells. In the present study, we investigated whether statins activate PPARgamma in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARgamma in HASMCs, but not in HUVECs. Statins induced cyclooxygenase 2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2 siRNA abrogated statin-mediated PPARgamma activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP 1) and tumor necrosis factor-alpha (TNF-alpha) in HASMCs. These effects of statins were abrogated by treatment with PPARgamma-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe(-/-) mice. In addition, transcriptional activity of PPARgamma and CD36 expression were increased, and the expression of MCP-1 and TNF-alpha was decreased, in the aorta of statin-treated Apoe(-/-) mice. In conclusion, statins mediate anti-atherogenic effects through PPARgamma activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis. PMID- 25529450 TI - Deficiency of the 15-kDa selenoprotein led to cytoskeleton remodeling and non apoptotic membrane blebbing through a RhoA/ROCK pathway. AB - The 15-kDa selenoprotein (Sep15) has been implicated in etiology of some types of cancer. Herein, inducible RNAi cell lines were established and cell morphology and motility were analyzed. The majority of Sep15-deficient cells (>95%) formed membrane blebs in a dynamic manner. Blebbing cells transformed cell morphology from a normal flat spindle shape to a spherical morphology. In blebbing cells, actin fibers moved to the cell periphery, covering and obscuring visualization of alpha-tubulin. Bleb formation was suppressed by the inhibitors of Rho-associated protein kinase (ROCK), RhoA or myosin light chain (MLC), restoring blebbing cells to wild-type morphology. RhoA activation and phosphorylation of myosin phosphatase target subunit 1 was induced by Sep15 knockdown. Sep15-deficient cells were non-apoptotic, and displayed a distinct relative localization of F actin and alpha-tubulin from typical apoptotic blebbing cells. Our data suggest that Sep15 in Chang liver cells regulates the pathway that antagonizes RhoA/ROCK/MLC-dependent non-apoptotic bleb formation. PMID- 25529451 TI - Silk gland-specific proteinase inhibitor serpin16 from the Bombyx mori shows cysteine proteinase inhibitory activity. AB - Serpins (serine proteinase inhibitors) are widely distributed in different species and are well known for their inhibitory activities towards serine proteinases. Here, we report the functional characterization of Bombyx mori serpin16. Expression analysis showed that serpin16 was specifically expressed at high levels in the silk gland at both the transcriptional and translational levels. Moreover, homology modeling and multi-sequence alignment suggested that serpin16 had a canonical serpin fold, but it contained a unique reactive center loop, which was obviously shorter than that of typical serpins. Inhibitory activity analyses revealed that the target proteinase of serpin18 is a cysteine proteinase, rather than a serine proteinase. Furthermore, a Michaelis complex model of serpin16 with its target proteinase was constructed to explain the structural basis of how serpin16 recognizes the cysteine proteinase and its target specificity. PMID- 25529452 TI - Prox1 expression in the endolymphatic sac revealed by whole-mount fluorescent imaging of Prox1-GFP transgenic mice. AB - This study describes a technical breakthrough in endolymphatic sac research, made possible by the use of the recently generated Prox1-GFP transgenic mouse model. Whole-mount imaging techniques through the decalcified temporal bone and three dimensional observations of Prox1-GFP mouse tissue revealed the positive labeling of the endolymphatic sac in adult stage, and allowed, for the first time, the GFP based identification of endolymphatic sac epithelial cells. Prox1 expression was observed in all parts of the endolymphatic sac epithelia. In intermediate portion of the endolymphatic sac, mitochondria-rich cells did not express Prox1, although ribosome-rich cells showed strong GFP labeling. The anatomical relationship between the endolymphatic sac and the surrounding vasculature was directly observed. In the endolymphatic sac, expression of Prox1 may suggest progenitor cell-like pluripotency or developmental similarity to systemic lymphatic vessels in other organs. This whole-mount imaging technique of the endolymphatic sac can be combined with other conventional histological, sectioning, and labeling techniques and will be very useful for future endolymphatic sac research. PMID- 25529453 TI - Chronic effects of neuroendocrine regulatory peptide (NERP-1 and -2) on insulin secretion and gene expression in pancreatic beta-cells. AB - Neuroendocrine regulatory peptides (NERP-1 and -2) are novel amidated peptides derived from VGF, a polypeptide secreted from neurons and endocrine cells through a regulated pathway. Dr. Nakazato Masamitsu reported that NERP-1 and -2 may have a local modulator function on the human endocrine system, and clearly showed expression of NERP-1 and -2 in human pancreas islets. Based on these data, we investigated the alteration of insulin secretion, insulin granule-related protein, and pancreas-specific transcription factors in response to NERPs expression. We confirmed the expression of NERP-1 and -2 in the pancreas of a human diabetes patient, in addition to diabetic animal models. When INS1 cells and primary rat islets were incubated with 10nM NERPs for 3 days, glucose stimulated insulin secretion levels were blunted by NERP-1 and -2. The number of insulin granules released from the readily releasable pool, which is associated with the first phase of glucose-stimulated insulin release, was decreased by NERP 1 and -2. Insulin granule-related proteins and mRNAs were down-regulated by NERP 2 treatment. NERP-2 decreased the expression of BETA2/NeuroD and insulin and controlled the nucleo-cytoplasmic translocation of FOXO1 and Pdx-1. We observed that NERP-2 levels were dramatically increased in diabetic pancreas. In conclusion, NERP-2 may play an important role in insulin secretion through the regulation of insulin secretory granules and beta-cell transcription factors. In addition, NERP-2 expression is increased in diabetic conditions. Therefore, we suggest that NERPs may be potent endogenous suppressors of glucose-dependent insulin secretion. PMID- 25529456 TI - Lower-limb amputation following foot ulcers in patients with diabetes: classification systems, external validation and comparative analysis. AB - BACKGROUND: This study aimed to validate and compare the existing systems developed to stratify subjects with diabetic foot ulcers by risk of consequent lower extremity amputation. METHODS: We conducted a prospective cohort study on a consecutive series of patients (mean age of 68 years; 64% male) with active ulcer who were attending our Hospital Diabetic Foot Clinic (n = 293) from January 2010 to March 2013. At baseline, we collected information on the participants' characteristics and the relevant variables. Afterwards, we assessed the predictive value of each variable and each system's prognostic accuracy for amputation occurrence. RESULTS: During a median follow-up of 91 days (interquartile range of 98), ulcers healed in 62% of the subjects. Major amputation occurred in 7% and minor occurred in 17%. Previous ulcer or amputation, ulcer area, and gangrene were associated with amputation occurrence. Nephropathy, pulses number, ulcer aetiology, depth, and number were associated with risk of amputation. Systems typically presented sensitivity values >=80% and negative likelihood ratios <=0.5 for the highest risk group; area under the receiver operating characteristic curve ranged from 0.56 to 0.83 and positive likelihood ratios from 1.0 to 5.9. If one chose only major amputation as an outcome, positive predictive values were lower, and negative predictive values tended to be higher. CONCLUSIONS: System stages, grades, scores, and/or prognostics were generally associated with amputation, presenting overall substantial accuracy values. Nevertheless, great improvement is possible. A multicentre study validating and refining the existing systems is needed to improve clinical decision-making in this area. PMID- 25529455 TI - PTH Signaling During Exercise Contributes to Bone Adaptation. AB - Improving the structural integrity of bone reduces fracture risk and development of osteoporosis later in life. Exercise can increase the mechanical properties of bone, and this increase is often attributed to the dynamic loading created during exercise. However, the increase in systemic parathyroid hormone (PTH) levels during exercise gives reason to hypothesize that PTH signaling also regulates bone adaptation in response to exercise. Therefore, the first aim of this study was to establish the impact PTH signaling has on bone adaptation during exercise by inhibiting PTH signaling with PTH(7-34); the second aim was to determine whether increasing PTH levels during exercise with PTH(1-34) can augment bone adaptation. Thirty minutes after a single bout of running on a treadmill, mice exhibited a twofold increase in systemic PTH levels. Under the same exercise regimen, the influence of PTH signaling on bone adaptation during exercise was then evaluated in mice after 21 consecutive days of exercise and treatment with PTH(7-34), PTH(1-34), or vehicle. Exercise alone caused a significant increase in trabecular bone volume with adaptation to a more platelike structure, which was inhibited with PTH(7-34) during exercise. Changes in structural-level and tissue level mechanical properties during exercise occurred in the absence of significant changes to cortical bone geometry. Inhibition of PTH signaling during exercise attenuated the changes in structural-level mechanical properties, but not tissue-level properties. Enhanced PTH signaling during exercise with PTH(1 34) increased trabecular and cortical bone volume, but had little effect on the structural-level and tissue-level mechanical properties compared to exercise alone. Our study is the first to demonstrate that bone adaptation during exercise is not only a function of dynamic loading, but also PTH release, and that PTH signaling contributes differently at the structural and tissue levels. PMID- 25529454 TI - Identification of heat shock protein 27 as a novel autoantigen of Behcet's disease. AB - OBJECTIVE: The aim of this study was to identify candidate pathogenic autoantigens of Behcet's disease (BD) in pathogen-stimulated target cells. METHODS: First, three cell lines were used as target cells to screen autoantibody. Second, selected target cells were simulated with pathogens. Third, western blotting was used for detecting the auto-antigens in cell extracts. Next, immunoprecipitation was performed and the amino-acid sequences of target antigens were analyzed by LC-MALDI-TOF/TOF. Then, the potential target antigen was expressed, purified, and immunologically confirmed. And finally, an ELISA kit was developed and clinically validated through the assessments of 456 clinical samples with BD. RESULTS: One antigen with a molecular weight of approximately 27 kDa was identified as heat shock protein 27 (HSP27). The reactivity of serum IgG against recombinant human HSP27 was detected in 52 of 91 BD patients (57%), 66 of 92 rheumatoid arthritis (RA) patients (72%), 32 of 90 Sjogren syndrome (SS) patients (36%), 22 of 92 systemic lupus erythematosus (SLE) patients (24%) and 0 of 91 healthy controls (HC). The reactivity of BD serum IgG antibodies against HSP27 was significantly higher than SLE (P<0.0001) SS (P<0.0001) and HC (P<0.0001). CONCLUSIONS: This study identified HSP27 as a candidate endothelial cell autoantigen of BD, which is interesting and probably worth further exploration. PMID- 25529457 TI - Symbolic boundaries, subcultural capital and prescription drug misuse across youth cultures. AB - Prescription drug misuse among young adults has surged over the past decade. Yet the contexts surrounding this misuse remain unclear, particularly the subcultural contexts. Many young urban adults participate in youth cultures. This article describes the subcultural contexts of prescription drug misuse in youth subcultures. Drawing on ethnographic data collected over 12 months from different youth cultural scenes, the authors describe the subcultural bases of prescription drug misuse. The symbolic boundaries and subcultural capital inherent in these scenes shape the ways youth think about drugs and behave accordingly. While young adults are often lumped together by theorists, ethnographic data show considerable variation across these subcultures with regard to what may enable or inhibit prescription drug misuse. The broader subcultural ethos in each scene, as well as attitudes towards other types of drugs, frame the ways that prescription drugs are perceived and used in each of these settings. The findings highlight the role of symbolic boundaries and subcultural capital in shaping routine practices of drug use among young adults. These data show that education campaigns about prescription drug misuse should take into account the variability in youth cultural scenes to maximise the efficacy of these messages aimed at young adults. PMID- 25529458 TI - [A rare case of caudal appendage]. AB - Caudal appendage is a rare malformation which has since ever been interesting. We present the case of a girl in which a caudal appendage was discovered before birth. A throughout checking found an extension from this abnormality to the cordal spine. The baby is operated when 2months old. Differential diagnosis are spina bifida, teratoma and pilonidal sinus. Caudal appendage is one of the typical cutaneous finding with underlying spinal dysraphism, such as hair tuft or pigmented macule. The risk is a tethered cord syndrome that can lead to severe complication. The treatment is either surgery or expectation. PMID- 25529459 TI - A rare case of subglottic embryonal rhabdomyosarcoma: managed with the aim of organ preservation. AB - BACKGROUND: Rhabdomyosarcoma is a malignant mesenchymal neoplasm rarely diagnosed in the larynx. Traditionally, it has been treated by radical surgery (i.e. total laryngectomy), followed by radiation and/or chemotherapy. Recent advances suggest that it may be treated with combination therapy comprising high-dose radiation and pulse chemotherapy, with a high success rate. CASE REPORT: We report the first documented case of subglottic embryonal rhabdomyosarcoma in an adolescent female treated with chemoradiation alone, and review the literature reflecting a move towards organ preservation. CONCLUSION: While surgery has been successfully used to treat this neoplasm, combination therapy, as described in our study, also seems effective and has the added advantage of preserving laryngeal function. PMID- 25529460 TI - Assessment of EGFR and KRAS mutation status from FNAs and core-needle biopsies of non-small cell lung cancer. AB - BACKGROUND: Molecular testing to determine gene mutation status is now the recommended standard of care for patients with advanced or metastatic Non-small cell lung cancer (NSCLC). Because the majority of patients with NSCLC present with metastatic disease, minimally invasive procedures are necessary for diagnosis, staging, and molecular analysis. However, the resulting samples have perceived limitations in the oncology community, and most commercially available tests have not been validated for these sample types. The current study was undertaken to assess the feasibility of determining epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status in fine-needle aspirates (FNAs) and core-needle biopsies (CNBs) after staining with Papanicolaou or hematoxylin and eosin, respectively. METHODS: Gene mutation status was determined in 140 NSCLC tumor samples with proprietary tests for EGFR and KRAS mutations (cobas tests) followed by Sanger sequencing of exons 18 through 21 of the EGFR gene and exon 2 of the KRAS gene. The results were analyzed based on FNA (n = 91) or CNB (n = 49) sampling. RESULTS: The cobas tests yielded valid results in the majority of FNA and CNB samples for both EGFR (97.9%) and KRAS (93.6%). Moreover, valid results were obtained for 90% of samples that had DNA concentrations below the values recommended by the manufacturer. For samples with valid results from both cobas testing and Sanger sequencing, 95.7% and 93% agreement were observed for EGFR status and KRAS status, respectively. CONCLUSIONS: Gene mutation testing can be successfully performed on cytology and CNB samples, expanding the potential of personalized cancer treatment to patients who have limited tissue samples. PMID- 25529461 TI - Adsorption-driven self-sorting of dynamic imine libraries. AB - Differences in adsorption among the components of complex mixtures play a role in separations, surface-based sensing, and heterogeneous catalysis, and have been implicated in theories of the origin of life. Herein, we consider mixtures of imines and we show that if such complex mixtures are also dynamic-that is, if their components equilibrate among themselves-then they can dramatically simplify in composition during the course of column chromatography. As they travel down the column, imines continuously trade their aldehyde and amine constituents, favoring the formation of molecules with extremes of polarity at the expense of species with intermediate polarities. Iterative application of this principle leads to simplification of imine libraries containing up to 16 members into 4 major products. PMID- 25529462 TI - Thrombin generation and rotational thromboelastometry in the healthy adult population. AB - AIM: Published data on thrombin generation variables and their correlation with thromboelastometry in the healthy population are scarce. This study aimed at assessing thrombin generation in adults and its correlation to classical rotational thromboelastometry (ROTEM). METHODS: Thrombin generation was measured in platelet-poor plasma from healthy volunteers using the calibrated automated thrombogram (CAT) with 1 and 5 pmol/l tissue factor final concentration. Lag time, thrombin peak, time to thrombin peak and endogenous thrombin potential (ETP) were analyzed. ROTEM was performed without activator (NATEM) and data for clotting time, alpha angle, clot formation time and maximum clot firmness were correlated with those of thrombin generation. RESULTS: Altogether 132 persons (72 men, 60 women; median age: 48.0 years) were included. There was a positive non linear correlation for age versus lag time (p < 0.001) and time to peak (p = 0.001), and almost linear correlation for age versus thrombin peak (p = 0.024) and ETP (p = 0.001), although with a moderate regression slope. Regarding ROTEM, there was a positive correlation between age and maximum clot firmness and alpha angle (p = 0.001), but a negative correlation between age and clotting time (p = 0.039). Comparing both assays, thrombin peak and ETP measured with a final tissue factor concentration of 5 pmol/l correlated significantly with alpha angle and maximum clot firmness. CONCLUSION: The age-related changes in CAT and ROTEM variables among adults are not linear. There is a significant correlation, although with a moderate slope, between data from CAT measured with 5 pmol/l tissue factor and ROTEM. PMID- 25529463 TI - Etanercept combined with systemic drugs or phototherapy for treatment of psoriasis. AB - Biologic drugs have provided excellent results in the treatment of moderate to severe psoriasis. Nevertheless, in routine clinical practice, combinations of biologic drugs with phototherapy or systemic drugs can increase efficacy, diminish toxicity, and reduce the cost of treatment. Published experience with these combinations is scarce, although the results are often satisfactory. This review examines the most relevant published experience in the combination of the most studied drug in this field-etanercept-with methotrexate, acitretin, ciclosporin, and narrowband UV-B phototherapy. Findings reported in the literature can help when taking major decisions on the management of biologic and systemic drugs in moderate to severe psoriasis. PMID- 25529464 TI - Gastric mucosa-associated lymphoid tissue lymphoma in a patient with severe psoriasis receiving ustekinumab. PMID- 25529465 TI - Dowling-Degos disease associated with hidradenitis suppurativa: a case report. PMID- 25529466 TI - Vertically orientated telangiectasias and pruritus on the thorax of a patient with early superior vena cava syndrome secondary to a malignant thymoma. PMID- 25529467 TI - Multivariate modeling of body mass index, pulse pressure, systolic and diastolic blood pressure in Chinese twins. AB - Systolic and diastolic blood pressure, pulse pressure (PP), and body mass index (BMI) are heritable traits in human metabolic health but their common genetic and environmental backgrounds are not well investigated. The aim of this article was to explore the phenotypic and genetic associations among PP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. The studied sample contained 615 twin pairs (17-84 years) collected in the Qingdao municipality. Univariate and multivariate structural equation models were fitted for assessing the genetic and environmental contributions. The AE model combining additive genetic (A) and unique environmental (E) factors produced the best fit for each four phenotypes. Heritability estimated in univariate analysis ranged from 0.42 to 0.74 with the highest for BMI (95% CI 0.70-0.78), and the lowest for PP (95% CI 0.34-0.49). The multivariate model estimated (1) high genetic correlations for DBP with SBP (0.87), PP with SBP (0.75); (2) low-moderate genetic correlations between PP and DBP (0.32), each BP component and BMI (0.24-0.37); (3) moderate unique environmental correlation for PP with SBP (0.68) and SBP with DBP (0.63); (4) there was no significant unique environmental correlation between PP and BMI. Overall, our multivariate analyses revealed common genetic and environmental backgrounds for PP, BP, and BMI in Chinese twins. PMID- 25529468 TI - Eye-tracking measurements and their link to a normative model of monitoring behaviour. AB - Increasing automation necessitates operators monitoring appropriately (OMA) and raises the question of how to identify them in future selections. A normative model was developed providing criteria for the identification of OMA. According to this model, the monitoring process comprises distinct monitoring phases (orientation, anticipation, detection and recheck) in which attention should be focused on relevant areas. The current study tests the normative model on the basis of eye tracking. The eye-tracking data revealed increased concentration on relevant areas during the orientation and anticipation phase in comparison to the other phases. For the assessment of monitoring behaviour in the context of personnel selection, this implies that the anticipation and orientation phases should be considered separately as they appear to be more important in the context of monitoring than the other phases. PRACTITIONER SUMMARY: A normative model was developed for the assessment of monitoring behaviour. Using the eye tracking method, this model was tested with applicants for an Air Traffic Controller training programme. The results are relevant for the future selection of human operators, who will have to monitor highly automated systems. PMID- 25529469 TI - The use of moderate sedation for the secondary prevention of adverse vasovagal reactions. AB - BACKGROUND: Vasovagal reactions can occur with spine procedures and may result in premature procedure termination or other adverse events. OBJECTIVE: To evaluate if moderate sedation is an effective means of secondary prevention for vasovagal reactions. METHODS: Prospectively collected data on 6,364 consecutive spine injections. RESULTS: Of the 6,364 spine injections, 6,150 spine injections were done without moderate sedation and resulted in 205 vasovagal reactions (3.3% [95% confidence interval {CI} 2.9-3.8%]). One hundred thirty-four spine procedures were performed on patients that had a history of prior vasovagal reaction during a spine procedure. Of these, 90 procedures were performed without moderate sedation, and 21/90 (23.3% [95% CI 15.2-32.1%]) were complicated by a repeat vasovagal reaction. None of 44 repeat injections that utilized moderate sedation experienced a repeat vasovagal reaction (0% [95% CI 0-9.6%]) (chi(2) = 12.17, P < 0.00048). The rate of vasovagal reaction in patients with a history of prior reaction undergoing repeat injection without conscious sedation was significantly higher (23.3% [95% CI 15.2-32.1%]) than the rate in patients with no such history (3.0% [95% CI 2.6-3.5%] [chi(2) = 113.4, P < 1.78E-26]). CONCLUSIONS: A history of vasovagal reaction is a strong predictor of experiencing a vasovagal reaction on subsequent procedures. No vasovagal reactions occurred with the use of moderate sedation, including in the 44 injections in patients that had a history of vasovagal reaction during spine procedures. The overall low rate of vasovagal reactions is low, and greater benefits of moderate sedation were observed when utilized as secondary prevention of repeat vasovagal reactions. PMID- 25529470 TI - Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: a case study of lindane-induced neurotoxicity. AB - Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans. Time- and concentration-dependent lindane dosimetry was determined in primary cultures of rat cortical neurons in vitro using "faux" (without electrodes) microelectrode arrays (MEAs). In vivo data were derived from literature values, and physiologically based pharmacokinetic (PBPK) modeling was used to extrapolate from rat to human. The previously determined EC50 for increased firing rates in primary cultures of cortical neurons was 0.6MUg/ml. Media and cell lindane concentrations at the EC50 were 0.4MUg/ml and 7.1MUg/ml, respectively, and cellular lindane accumulation was time- and concentration-dependent. Rat blood and brain lindane levels during seizures were 1.7-1.9MUg/ml and 5-11MUg/ml, respectively. Brain lindane levels associated with seizures in rats and those predicted for humans (average=7MUg/ml) by PBPK modeling were very similar to in vitro concentrations detected in cortical cells at the EC50 dose. PBPK model predictions matched literature data and timing. These findings indicate that in vitro MEA results are predictive of in vivo responses to lindane and demonstrate a successful modeling approach for IVIVE of rat and human neurotoxicity. PMID- 25529471 TI - A multi-enzyme microreactor-based online electrochemical system for selective and continuous monitoring of acetylcholine. AB - This study demonstrates an online electrochemical system (OECS) for selective and continuous measurements of acetylcholine (ACh) through efficiently integrating in vivo microdialysis, a multi-enzyme microreactor and an electrochemical detector. A multi-enzyme microreactor was prepared first by co-immobilizing two kinds of enzymes, i.e. choline oxidase (ChOx) and catalase (Cat), onto magnetite nanoparticles and then confining the as-formed nanoparticles into a fused-silica capillary with the assistance of an external magnet. The multi-enzyme microreactor was settled between an in vivo microdialysis sampling system and an electrochemical detector to suppress the interference from choline toward ACh detection. Selective detection of ACh was accomplished using the electrochemical detector with ACh esterase (AChE) and ChOx as the recognition units for ACh and Prussian blue (PB) as the electrocatalyst for the reduction of hydrogen peroxide (H2O2). The current recorded with the OECS was linear with the concentration of ACh (I/nA = -3.90CACh/MUM + 1.21, gamma = 0.998) within a concentration range of 5 MUM to 100 MUM. The detection limit, based on a signal-to-noise ratio of 3, was calculated to be 1 MUM. Interference investigation demonstrates that the OECS did not produce an observable current response toward physiological levels of common electroactive species, such as ascorbic acid (AA), dopamine (DA), 3,4 dihydroxyphenylacetic acid (DOPAC), and uric acid (UA). The high selectivity and the good linearity in combination with the high stability may enable the OECS developed here as a potential system for continuous monitoring of cerebral ACh release in some physiological and pathological processes. PMID- 25529472 TI - The loading of coordination complex modified polyoxometalate nanobelts on activated carbon fiber: a feasible strategy to obtain visible light active and highly efficient polyoxometalate based photocatalysts. AB - To enhance the photocatalytic properties of coordination complex modified polyoxometalates (CC/POMs) in the visible light region, its nanobelts (CC/POMNBs) were loaded on activated carbon fiber (ACF) through a simple colloidal blending process. The resulting coordination complex modified polyoxometalate nanobelts loaded activated carbon fiber composite materials (CC/POMNBs/ACF) exhibited dramatic photocatalytic activity for the degradation of rhodamine B (RhB) under visible light irradiation. Optical and electrochemical methods illustrated the enhanced photocatalytic activity of CC/POMNBs/ACF, which originates from the high separation efficiency of the photogenerated electrons and holes on the interface of the CC/POMNBs and ACF, which results from the synergistic effects between them. In the composite material, the role of ACF could be described as a photosensitizer and a good electron transporter. Furthermore, the influence of the mass ratio between the CC/POMNBs and ACF on the photocatalytic performance of the resulting composite material was discussed, and an ideal value to obtain highly efficient photocatalysts was obtained. The results suggested that the loading of CC/POMNBs on the surface of ACF would be a feasible strategy to enhance their photocatalytic activity. PMID- 25529473 TI - LC-MS/MS simultaneous quantitation of 2-hydroxyethylated, oxidative, and unmodified DNA nucleosides in DNA isolated from tissues of mice after exposure to ethylene oxide. AB - 2-Hydroxyethylated and oxidative DNA nucleosides (DNA adduct biomarkers), such as O6-(2-hydroxyethyl)-2'-deoxyguanosine (O6HEdG), N6-(2-hydroxyethyl)-2' deoxyadenosine (N6HEdA), 1-(2-hydroxyethyl)-2'-deoxyadenosine (N1HEdA), and 8 hydroxy-2'-deoxyguanosine (8-OHdG), N2,3-etheno-2'-deoxyguanosine (N2,3 ethenodG), alpha-methyl-gamma-hydroxy-1,N2-propano-2'-deoxyguanosine (CrotondG), are important proposed biomarkers for exploring the genotoxicity mechanism of ethylene oxide (EO) in vivo. A liquid chromatography-tandem mass spectrometric method was developed for the simultaneous determination of O6HEdG, N6HEdA, N1HEdA, 8-OHdG, CrotondG, and N2,3-ethenodG together with regular 2' deoxyguanosine (dG), and 2'-deoxyadenosine (dA) nucleosides in the DNA extracted from mouse lung tissues for the assessment of exposure to EO after inhalation. The lower limits of quantitation for 8-OHdG, CrotondG, N2,3-EthenodG, O6HEdG, N1HEdA, N6HEdA, dG, and dA were 0.025, 0.00125, 0.025, 0.00125, 0.025, 0.01, 2342, and 2500ng/mL, respectively. The linearity of the calibration curves for all analytes were >0.989. The intra-day assay precision relative standard deviation (RSD) values for quality control (QC) samples for all analytes were <=13.5% with accuracy values ranging from 86.5% to 111%. The inter-day assay precision (RSD) values for all analytes were <=18.8% with accuracy values ranging from 87.9% to 119%. This method was used for simultaneous determination of the levels of 8-OHdG, CrotondG, N2,3-EthenodG, O6HEdG, dG, N1HEdA, N6HEdA, and dA in DNA enzymatic hydrolysates from DNA extracted from mouse lung after 12 weeks' inhalation exposure to EO at atmospheric concentrations of 0, 100, and 200ppm. Overall, N2,3-ethenodG was not detected in any samples. 8-OHdG, CrotondG, dG, and dA were all quantifiable in all samples. O6HEdG, N1HEdA, and N6HEdA were quantifiable in most samples and the ratio of the corresponding adduct versus their corresponding DNA base (dG or dA) [*10 (e6)] was increased as the EO exposure concentration increased. PMID- 25529474 TI - Peripheral refraction with eye and head rotation with contact lenses. AB - PURPOSE: To evaluate the impact of eye and head rotation in the measurement of peripheral refraction with an open-field autorefractometer in myopic eyes wearing two different center-distance designs of multifocal contact lenses (MFCLs). METHODS: Nineteen right eyes from 19 myopic patients (average central M +/- SD = 2.67 +/- 1.66 D) aged 20-27 years (mean +/- SD = 23.2 +/- 3.3 years) were evaluated using a Grand-Seiko autorefractometer. Patients were fitted with one multifocal aspheric center-distance contact lens (Biofinity Multifocal D((r))) and with one multi-concentric MFCL (Acuvue Oasys for Presbyopia). Axial and peripheral refraction were evaluated by eye rotation and by head rotation under naked eye condition and with each MFCL fitted randomly and in independent sessions. RESULTS: For the naked eye, refractive pattern (M, J0 and J45) across the central 60 degrees of the horizontal visual field values did not show significant changes measured by rotating the eye or rotating the head (p > 0.05). Similar results were obtained wearing the Biofinity D, for both testing methods, no obtaining significant differences to M, J0 and J45 values (p > 0.05). For Acuvue Oasys for presbyopia, also no differences were found when comparing measurements obtained by eye and head rotation (p > 0.05). Multivariate analysis did not showed a significant interaction between testing method and lens type neither with measuring locations (MANOVA, p > 0.05). There were significant differences in M and J0 values between naked eyes and each MFCL. CONCLUSION: Measurements of peripheral refraction by rotating the eye or rotating the head in myopic patients wearing dominant design or multi-concentric multifocal silicone hydrogel contact lens are comparable. PMID- 25529475 TI - New biennial BCLA conference. PMID- 25529477 TI - Transcriptional profiling of rat hypothalamus response to 2,3,7,8 tetrachlorodibenzo-rho-dioxin. AB - In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23h after exposure to TCDD (100MUg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions. PMID- 25529478 TI - Circulating microRNA as a diagnostic marker in populations with type 2 diabetes mellitus and diabetic complications. AB - Diabetes mellitus (DM) is a global health care issue resulting from hyperglycemia mediated life-threatening complications. Although the use of glucose-lowering agents is routinely practiced, high dependence on medication leads to poor quality of life for DM patients. While it is still not feasible to precisely determine the critical timing when DM is truly established, perhaps the best way to reduce DM-associated mortality is to prevent it. To this end, an exploration of prognostic molecules sensitive enough to detect early physiological alteration at the initiating stage would be required. Recently discovered small noncoding molecules, microRNAs (miRs), in body fluid seem promising to be utilized as a biomarker to monitor DM initiation and progression, as it is believed that expression of circulating miRs reflects disease pathology. Current DM-related miRs were often referred to miRs differentially expressed in insulin target organs (liver, muscle, and adipose tissues) or circulating blood (peripheral blood) in diabetic patients compared to their control counterparts, although these miRs could merely be resultant nucleotides from DM-induced organ impairment instead of the indicators of onset/progression of DM. In the current review, studies showing circulating miRs associated with type 2 DM and its complications are summarized, and future scope of using miRs as biomarkers for disease prognosis/diagnosis is also emphasized. PMID- 25529476 TI - Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. AB - Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy. PMID- 25529480 TI - Cystine improves survival rates in a LPS-induced sepsis mouse model. AB - BACKGROUND & AIMS: The control of inflammation is important for suppressing severe sepsis. Oral administration of cystine and theanine have been shown to suppress inflammatory responses due to invasion. Furthermore, the uptake of cystine into monocytes is promoted by exposure to lipopolysaccharide (LPS). In the present study, the effects of cystine were examined in the context of inflammatory responses. METHODS: Cystine was orally administered to mice, and the levels of interleukin (IL)-6 in the blood and spleen and the survival rates were calculated after the administration of LPS. The effects of cystine as well as neutralising anti-IL-10 antibodies on the LPS-induced production of IL-6 and IL 10 were examined in a monocyte cell line. RESULTS: The oral administration of cystine reduced IL-6 levels in the blood and spleen after LPS stimulation and improved survival rates. The addition of cystine to monocytes suppressed LPS induced IL-6 production but enhanced IL-10 production. A neutralising anti-IL-10 antibody eliminated the inhibitory effects of cystine on the LPS-induced production of IL-6. CONCLUSIONS: The oral administration of cystine suppressed IL 6 production following LPS stimulation and improved survival rates in mice with LPS-induced sepsis. The enhanced production of IL-10 by monocytes may be involved in this anti-inflammatory response. PMID- 25529479 TI - The C. elegans NR4A nuclear receptor gene nhr-6 promotes cell cycle progression in the spermatheca lineage. AB - BACKGROUND: NR4A nuclear receptors are a conserved, functionally diverse group of nuclear receptors that regulate multiple cellular processes including proliferation and differentiation. The gene nhr-6 encodes the sole Caenorhabditis elegans NR4A nuclear receptor homolog with an essential role in reproduction by regulating morphogenesis of the spermatheca, a somatic gonad organ involved in ovulation and fertilization. RESULTS: Here, we identify the spermatheca cell lineage defects that occur in nhr-6 mutants. Utilizing cell marker analysis, we find that nhr-6 is required for cell cycle progression and that the cell proliferation phenotype is not due to premature cell cycle exit. We also show that loss of the negative cell cycle regulators fzr-1 and lin-35 suppresses the cell proliferation defects. We further demonstrate that NHR-6 activity intersects with Eph receptor signaling during spermatheca cell proliferation. CONCLUSIONS: NHR-6 has an essential function in promoting cell cycle progression during G1 phase in a specific spermatheca cell lineage. Genetic suppression of the proliferation phenotype does not affect the differentiation phenotypes observed in nhr-6 mutants, indicating a dualistic role for nhr-6 in regulating cell proliferation and cell differentiation during spermatheca organogenesis. PMID- 25529482 TI - The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants. AB - The chemical interaction of sodium sulfide (Na2S) with the NO-donor S nitrosoglutathione (GSNO) has been described to generate new reaction products, including polysulfides and nitrosopersulfide (SSNO(-)) via intermediacy of thionitrous acid (HSNO). The aim of the present work was to investigate the vascular effects of the longer-lived products of the Sulfide/GSNO interaction. Here we show that the products of this reaction relax precontracted isolated rings of rat thoracic aorta and mesenteric artery (but to a lesser degree rat uterus) with a >2-fold potency compared with the starting material, GSNO (50 nM), whereas Na2S and polysulfides have little effect at 1-5 uM. The onset of vasorelaxation of the reaction products was 7-10 times faster in aorta and mesenteric arteries compared with GSNO. Relaxation to GSNO (100-500 nM) was blocked by an inhibitor of soluble guanylyl cyclase, ODQ (0.1 and 10 uM), and by the NO scavenger cPTIO (100 uM), but less affected by prior acidification (pH 2 4), and unaffected by N-acetylcysteine (1 mM) or methemoglobin (20 uM heme). By contrast, relaxation to the Sulfide/GSNO reaction products (100-500 nM based on the starting material) was inhibited to a lesser extent by ODQ, only slightly decreased by cPTIO, more markedly inhibited by methemoglobin and N acetylcysteine, and abolished by acidification before addition to the organ bath. The reaction mixture was found to generate NO as detected by EPR spectroscopy using N-(dithiocarboxy)-N-methyl-D-glucamine (MGD2)-Fe(2+) as spin trap. In conclusion, the Sufide/GSNO reaction products are faster and more pronounced vasorelaxants than GSNO itself. We conclude that in addition to NO formation from SSNO(-), reaction products other than polysulfides may give rise to nitroxyl (HNO) and be involved in the pronounced relaxation induced by the Sulfide/GSNO cross-talk. PMID- 25529483 TI - Reflections on esophageal columnar metaplasia (Barrett)-ANNO 2015. AB - Esophageal columnar metaplasia (ECM) (Barrett's esophogus) continues to generate clinical and basic attention. Yet many questions remain unanswered and global consensus on important issues is often still lacking. This article discusses a selection of certain recent findings and reflects on some remaining uncertainties of this intriguing disease. PMID- 25529481 TI - Frailty in childhood cancer survivors. AB - Young adult childhood cancer survivors are at an increased risk of frailty, a physiologic phenotype typically found among older adults. This phenotype is associated with new-onset chronic health conditions and mortality among both older adults and childhood cancer survivors. Mounting evidence suggests that poor fitness, muscular weakness, and cognitive decline are common among adults treated for childhood malignancies, and that risk factors for these outcomes are not limited to those treated with cranial radiation. Although the pathobiology of this phenotype is not known, early cellular senescence, sterile inflammation, and mitochondrial dysfunction in response to initial cancer or treatment-related insults are hypothesized to play a role. To the authors' knowledge, interventions to prevent or remediate frailty among childhood cancer survivors have not been tested to date. Pharmaceutical, nutraceutical, and lifestyle interventions have demonstrated some promise. PMID- 25529485 TI - Synergistic effects of nonmetal co-doping with sulfur in anatase TiO2: a DFT + U study. AB - Using DFT + U calculations, the crystal structure and electronic properties of nonmetal co-doping with sulfur in anatase TiO2 are systematically investigated. The initial purpose of this work is to improve the photocatalytic performance of S mono-doped TiO2, in which S occupies the lattice Ti site and acts as a recombination center. Among eight nonmetal impurities that occupy the interstitial site of a TiO6 octahedron, the synergistic effects of B, C, and O with S could achieve this purpose: suppressing the recombination of photogenerated electron-hole pairs by inducing a local inner built-in electric field and eliminating the deep impurity energy bands of S mono-doped TiO2. Furthermore, the photon absorption could be extended to the visible-light region, owing to the overlap of impurity energy bands with the top of the valence band or the bottom of the conduction band. Thus, Ti1-xO2SxBy, Ti1-xO2SxCy and Ti1-xO2SxOy could be considered as promising efficient photocatalysts. Furthermore, the underlying mechanism and tendency of these synergistic effects have been discussed, according to the relationship between the photocatalytic performance and the crystal or electronic structure. PMID- 25529486 TI - Storiform-pleomorphic type of multifocal malignant fibrous histiocytoma of the lumbar spine. AB - BACKGROUND: We present the extremely rare case of a 67-year-old male with malignant fibrous histiocytoma, arising in the lumbar spine, demonstrated with radiological and pathological studies. CASE REPORT: The patient and his relatives refused open surgical approach and we performed transpedicular vertebral corpus biopsy and vertebroplasty under spinal anesthesia. His pathological result was malignant fibrous histiocytoma. The spine is a very uncommon site for malignant fibrous histiocytoma. CONCLUSIONS: The management of malignant fibrous histiocytoma relies on the combination of maximum decompression surgery, chemotherapy and radiotherapy. Total removal is unrealistic and diagnosis is difficult. The prognosis in terms of continuing neurological deficit after surgery appears to be poor. PMID- 25529484 TI - Optogenetic control of intracellular signaling pathways. AB - Cells employ a plethora of signaling pathways to make their life-and-death decisions. Extensive genetic, biochemical, and physiological studies have led to the accumulation of knowledge about signaling components and their interactions within signaling networks. These conventional approaches, although useful, lack the ability to control the spatial and temporal aspects of signaling processes. The recently emerged optogenetic tools open exciting opportunities by enabling signaling regulation with superior temporal and spatial resolution, easy delivery, rapid reversibility, fewer off-target side effects, and the ability to dissect complex signaling networks. Here we review recent achievements in using light to control intracellular signaling pathways and discuss future prospects for the field, including integration of new genetic approaches into optogenetics. PMID- 25529487 TI - Molecular structure-adsorption study on current textile dyes. AB - This study was performed to investigate the adsorption of a diverse set of textile dyes onto granulated activated carbon (GAC). The adsorption experiments were carried out in a batch system. The Langmuir and Freundlich isotherm models were applied to experimental data and the isotherm constants were calculated for 33 anthraquinone and azo dyes. The adsorption equilibrium data fitted more adequately to the Langmuir isotherm model than the Freundlich isotherm model. Added to a qualitative analysis of experimental results, multiple linear regression (MLR), support vector regression (SVR) and back propagation neural network (BPNN) methods were used to develop quantitative structure-property relationship (QSPR) models with the novel adsorption data. The data were divided randomly into training and test sets. The predictive ability of all models was evaluated using the test set. Descriptors were selected with a genetic algorithm (GA) using QSARINS software. Results related to QSPR models on the adsorption capacity of GAC showed that molecular structure of dyes was represented by ionization potential based on two-dimensional topological distances, chromophoric features and a property filter index. Comparison of the performance of the models demonstrated the superiority of the BPNN over GA-MLR and SVR models. PMID- 25529489 TI - The quality and usability of smartphone and hand-held fundus photography, compared to standard fundus photography. PMID- 25529491 TI - Removal of oil droplets from water using carbonized rice husk: enhancement by surface modification using polyethylenimine. AB - Carbonized rice husk (CRH) is a promising material to separate oil from water owing to its abundance, low-cost, and environmentally benign characteristics. However, CRH's performance is somewhat limited by its similar surface charge to that of oil, leading to repulsive interactions. To improve the separation efficiency of CRH, CRH was modified via impregnation with a cationic biocompatible polymer, polyethlyenimine (PEI) to form PEI-CRH. The modified sample exhibits a remarkably higher (10-50 times) oil/water (O/W) separation efficiency than that of the unmodified one. Small PEI-CRH particles (about 64 MUm) are found to adsorb oil droplets faster and larger quantities than bigger particles (about 113 and 288 MUm). PEI-CRH exhibits higher separation efficiency at high temperatures owing to the destabilization of the emulsion. It is also found that the oil adsorption mechanism involves a chemical interaction between PEI-CRH and oil droplets. The addition of NaCl considerably improves the separation efficiency, while the addition of a cationic surfactant has the opposite effect. In acidic emulsions, PEI-CRH adsorbs more oil than in neutral or basic conditions owing to favorable attractive forces between oil droplets and the surface of PEI-CRH. PEI-CRH can be easily regenerated by washing with ethanol. These promising features of PEI-CRH indicate that PEI-CRH could be an efficient and low-cost adsorbent for the O/W separation applications. PMID- 25529490 TI - Urbanization in China changes the composition and main sources of wet inorganic nitrogen deposition. AB - Nowadays, nitrogen (N) deposition has become a growing global concern due to urbanization activities increasing the large amount of reactive N in the atmosphere. However, it remains unclear whether urbanization affects the composition and main sources of N deposition in rapidly urbanizing areas such as in China. One-year measurement of wet inorganic N deposition was conducted using ion-exchange resin (IER) columns in the range of 260 km from urban to rural areas in the Pearl River Delta (PRD) region, south China. An increasing pattern of wet inorganic deposition along the urbanization gradient was observed and it increased in the order: rural (15.26 +/- 0.20 kg N ha(-1) year(-1)) < suburban/rural (21.45 +/- 3.73 kg N ha(-1) year(-1)) < urban (31.16 +/- 0.44 kg N ha(-1) year(-1)) < urban/suburban sites (34.15 +/- 5.73 kg N ha(-1) year(-1)). Nitrate N (NO3 (-)-N) accounted for 53.5-79.1 % of total wet inorganic N deposition, indicating a significant negative correlation with distance from the urban core. Based on moss delta(15)N-values the main source of NO3 (-)-N was considered to be emitted from vehicles. Our results demonstrate that urbanization has large impacts on the regional pattern of wet inorganic N deposition. Thus, controlling NOx emission, especially vehicle emission will become an effective strategy for N pollution abatement in China. PMID- 25529492 TI - Copper uptake by Eichhornia crassipes exposed at high level concentrations. AB - The objective of this study was to assess the growth of water hyacinth (Eichhornia crassipes) and its ability to accumulate Cu from polluted water with high Cu concentrations and a mixture of other contaminants under short-term exposure, in order to use this species for the remediation of highly contaminated sites. Two hydroponic experiments were performed under greenhouse conditions for 7 days. One of them consisted of growing water hyacinth in Hoagland solution supplemented with 15 or 25 mg Cu/L and a control. The other one contained water hyacinth growing in polluted river water supplemented with 15 mg Cu/L and a control. Cu was accumulated principally in roots. The maximum Cu concentration was 23,387.2 mg/kg dw in the treatment of 25 mg Cu/L in Hoagland solution. Cu translocation from roots to leaves was low. The mixture of 15 mg Cu/L with polluted water did not appear to have toxic effects on the water hyacinth. This plant showed a remarkable uptake capacity under elevated Cu concentrations in a mixture of pollutants similar to pure industrial effluents in a short time of exposure. This result has not been reported before, to our knowledge. This species is suitable for phytoremediation of waters subject to discharge of mixed industrial effluents containing elevated Cu concentrations (>=15 mg Cu/L), as well as nutrient-rich domestic wastewaters. PMID- 25529493 TI - Characterization of (241)Pu occurrence, distribution, and bioaccumulation in seabirds from northern Eurasia. AB - The paper presents unique data of plutonium (241)Pu study in seabirds from northern Eurasia, permanently or temporally living at the southern Baltic Sea coast. Together, ten marine birds species were examined, as follows: three species that permanently reside at the southern Baltic, four species of wintering birds, and three species of migrating birds; 366 samples were analyzed. The obtained results indicated plutonium was non-uniformly distributed in organs and tissues of analyzed seabirds. The highest (241)Pu content was found in the digestion organs and feathers, the lowest in muscles. Also, the internal radiation doses from (241)Pu were evaluated. PMID- 25529494 TI - Enhancement of nitrate-induced bioremediation in marine sediments contaminated with petroleum hydrocarbons by using microemulsions. AB - The effect of microemulsion on the biodegradation of total petroleum hydrocarbons (TPH) in nitrate-induced bioremediation of marine sediment was investigated in this study. It was shown that the microemulsion formed with non-ionic surfactant polyoxyethylene sorbitan monooleate (Tween 80), 1-pentanol, linseed oil, and either deionized water or seawater was stable when subjected to dilution by seawater. Desorption tests revealed that microemulsion was more effective than the Tween 80 solution or the solution containing Tween 80 and 1-pentanol to desorb TPH from marine sediment. In 3 weeks of bioremediation treatment, the injection of microemulsion and NO3 (-) seems to have delayed the autotrophic denitrification between NO3 (-) and acid volatile sulfide (AVS) in sediment compared to the control with NO3 (-) injection alone. However, after 6 weeks of treatment, the delaying effect of microemulsion on the autotrophic denitrification process was no longer observed. In the meantime, the four injections of microemulsion and NO3 (-) resulted in as high as 29.73 % of TPH degradation efficiency, higher than that of two injections of microemulsion and NO3 (-) or that of four or two injections of NO3 (-) alone. These results suggest that microemulsion can be potentially applied to enhance TPH degradation in the nitrate-induced bioremediation of marine sediment. PMID- 25529495 TI - Ultra-high performance liquid chromatography tandem high-resolution mass spectrometry study of tricyclazole photodegradation products in water. AB - This paper reports the study of the photodegradation reactions that tricyclazole can naturally undergo, under the action of sunlight, in aqueous solutions of standard tricyclazole and of the commercial BEAM(TM) formulation. The analyses are carried out by ultra-high performance liquid chromatography technique coupled with high-resolution tandem mass spectrometry. Analysis of both tricyclazole and BEAM(TM) water solutions undergone to hydrolysis does not evidence new chromatographic peaks with respect to the not treated solutions. On the contrary, analysis of the same samples subjected to sunlight irradiation shows a decreased intensity of tricyclazole signal and the presence of new chromatographic peaks. Two photodegradation products of tricyclazole have been identified, one of which has been also quantified, being the commercial standard available. The pattern is similar for the solutions of the standard fungicide and of the BEAM(TM) formulation. The results obtained from eco-toxicological tests show that toxicity of tricyclazole standard solutions is greater than that of the irradiated ones, whereas toxicity levels of all the BEAM(TM) solutions investigated (non irradiated, irradiated, and hydrolyzed) are comparable and lower than those shown by tricyclazole standard solutions. Experiments performed in paddy water solution show that there is no difference in the degradation products formed. PMID- 25529497 TI - Neural bases of event knowledge and syntax integration in comprehension of complex sentences. AB - Comprehension of complex sentences is necessarily supported by both syntactic and semantic knowledge, but what linguistic factors trigger a readers' reliance on a specific system? This functional neuroimaging study orthogonally manipulated argument plausibility and verb event type to investigate cortical bases of the semantic effect on argument comprehension during reading. The data suggest that telic verbs facilitate online processing by means of consolidating the event schemas in episodic memory and by easing the computation of syntactico-thematic hierarchies in the left inferior frontal gyrus. The results demonstrate that syntax-semantics integration relies on trade-offs among a distributed network of regions for maximum comprehension efficiency. PMID- 25529496 TI - Rehabilitation following hospitalization in patients with COPD: can it reduce readmissions? AB - Exacerbations of chronic obstructive pulmonary disease (COPD) are one of the commonest causes of emergency hospital admission and are associated with high rates of readmission. Rehabilitation in the peri- and early post-hospitalization setting may counteract the deleterious consequences of an acute hospital admission and target modifiable risk factors for readmission such as physical inactivity, reduced exercise capacity and impaired physical function. Pulmonary rehabilitation in the peri-hospitalization period can improve exercise capacity and health-related quality of life and can also reduce rates of readmission. Consequently, guidelines have recommended the provision of pulmonary rehabilitation in the acute setting. However, recent trials showing less positive results and observational data questioning acceptability may challenge prevailing enthusiasm. This review examines the role of pulmonary rehabilitation in the peri and early post-hospitalization setting, considering the modifiable risk factors for readmission, the latest evidence regarding rehabilitation in the acute setting, issues around acceptability and uptake, and alternative strategies to help deliver rehabilitation to more patients. The acceptability and effectiveness of pulmonary rehabilitation offered that post-exacerbation could be improved by overcoming issues around the setting, timing and format of rehabilitation approaches, including their integration with self-management interventions. PMID- 25529498 TI - Preparatory behaviours and condom use during receptive and insertive anal sex among male-to-female transgenders (waria) in Jakarta, Indonesia. AB - INTRODUCTION: The male-to-female transgender (waria) is part of a key population at higher risk for HIV. This study aims to test whether psychosocial determinants as defined by the theory of planned behaviour (TPB) can explain behaviours related to condom use among waria. Three preparatory behaviours (getting, carrying, and offering a condom) and two condom use behaviours (during receptive and insertive anal sex) were assessed. METHODS: The study involved 209 waria, recruited from five districts in Jakarta and interviewed by using structured questionnaires. Specific measures were developed to study attitudes, subjective norms and perceived behavioural control (PBC) in order to predict intentions and behaviours. RESULTS: The explained variance between intentions with regard to three preparatory behaviours and two condom uses ranged between 30 and 57%, and the variance between the actual preparatory behaviours of three preparatory and two condom uses ranged between 21 and 42%. In our study, as with several previous studies of the TPB on HIV protection behaviours, the TPB variables differed in their predictive power. With regard to intention, attitude and PBC were consistently significant predictors; attitude was the strongest predictor of intention for all three preparatory behaviours, and PBC was the strongest predictor of intention for condom use, both during receptive and insertive anal sex. TPB variables were also significantly related to the second parameter of future behaviour: actual (past) behaviour. TPB variables were differentially related to the five behaviours. Attitude was predictive in three behaviours, PBC in three behaviours and subjective norms in two behaviours. CONCLUSIONS: Our results have implications for the development of interventions to target preparatory behaviours and condom use behaviours. Five behaviours and three psychological factors as defined in the TPB are to be targeted. PMID- 25529499 TI - The role of global trade and transport network topology in the human-mediated dispersal of alien species. AB - More people and goods are moving further and more frequently via many different trade and transport networks under current trends of globalisation. These networks can play a major role in the unintended introduction of exotic species to new locations. With the continuing rise in global trade, more research attention is being focused on the role of networks in the spread of invasive species. This represents an emerging field of research in invasion science and the substantial knowledge being generated within other disciplines can provide ecologists with new tools with which to study invasions. For the first time, we synthesise studies from several perspectives, approaches and disciplines to derive the fundamental characteristics of network topology determining the likelihood of spread of organisms via trade and transport networks. These characteristics can be used to identify critical points of vulnerability within these networks and enable the development of more effective strategies to prevent invasions. PMID- 25529500 TI - A retrospective evaluation of zirconia-fixed partial dentures in general practices: an up to 13-year study. AB - OBJECTIVES: To evaluate zirconia-based fixed partial dentures (FPDs) after more than 8 years in clinical service. METHODS: Patients treated between 2000 and 2004 with zirconia FPDs were identified from the records of a manufacturer of FPD substructures. Of the 45 patients who met the inclusion criteria 30 attended the appointment and 33 FPDs were evaluated using modified California Dental Association (CDA) criteria. In addition, plaque and the bleeding index were registered. Patient satisfaction with the restorations was evaluated using a 10 point visual analog scale (VAS). RESULTS: All the FPDs were made using CAD/CAM and hot isostatic pressed yttria-tetragonal zirconia polycrystal (HIPed Y-TZP) ceramic (Denzir) and were placed within general practices. The mean observation period was 9.6+/-1.6 years (range 3.0-13.1 years). The CDA rating was 90% satisfactory for the surface. Corresponding figures for anatomic form, color and margin integrity were 94%, 100% and 94%, respectively. Regarding surface three (9.7%) FPDs exhibited veneer chipping and were rated 'not acceptable'. For margin integrity two (6.5%) were rated 'not acceptable' because of caries. For anatomic form two (6.1%) were rated 'not acceptable' due to two lost FPDs. No significant differences were seen between the FPDs and controls for plaque and bleeding. The Kaplan-Meier survival rate (still in clinical function) was 94%, the success rate (technical events accounted for) 91% and (biological events accounted for) 73%. Based on the VAS the mean value for patient satisfaction was 9.3+/-1.2. SIGNIFICANCE: Ninety-four percent of the FPDs were still in clinical function. HIPed Y-TZP could serve as an alternative for FPD treatments similar to those in the current study. PMID- 25529501 TI - Effect of long-term storage on nanomechanical and morphological properties of dentin-adhesive interfaces. AB - INTRODUCTION: To evaluate the influence of storage time on the elastic modulus, micromorphology, nanoleakage, and micromechanical behavior of the dentin-adhesive interfaces of five adhesive systems (Scotchbond Multi-Purpose, Clearfil SE Bond, One Up Bond F, Adper Easy One, and Filtek LS Adhesive) after 24h (T0) and 12 months (T1). METHODS: Fifty teeth were restored and distributed according to each adhesive system (n=10). At least four specimens were obtained from each tooth. One specimen was evaluated under SEM to obtain the micromorphology of dentin adhesive interface (DAI). Two specimens were used to assess nanoleakage, one tested in T0 and the other in T1. The last specimen was used for nanoindentation, in T0 and T1, to obtain the initial and final mechanical properties of DAI structures. Two non-restored teeth were evaluated under SEM to obtain the dentin morphology. Laboratorial data were used to build 15 finite element models to assess the maximum principal stress in each time of analysis. RESULTS: Storage resulted in hydrolysis of the dentin-adhesive interfaces for all groups. Silver impregnation increased for all groups after 1 year storage (p<.05), except for Clearfil SE Bond. In general, a decrease in elastic modulus values was observed for all groups from T0 to T1 (p<.05), mainly at the hybrid layer. The FEAs showed higher stress levels at T1 than T0 simulations for all adhesives. CONCLUSION: At T1, degradation occurred at the dentin-adhesive interface formed by all adhesives, and the intensity of degradation differed depending on the type of adhesive system used. The interface formed by the self-etching primer containing the 10-MDP functional monomer showed the highest stability among the adhesive systems after 12 months of storage. PMID- 25529502 TI - Using diagrams versus text for spaced restudy: Effects on learning in 10th grade biology classes. AB - BACKGROUND AND AIM: Spaced restudy has been typically tested with written learning materials, but restudy with visual representations in actual classrooms is under-researched. We compared the effects of two spaced restudy interventions: A Diagram-Based Restudy (DBR) warm-up condition and a business-as-usual Text Based Restudy (TBR) warm-up condition. SAMPLE: One hundred and twenty-eight consented high school students in 15 classes. METHODS: Students completed daily warm-ups over a 4-week period. Students were randomly assigned to conditions within classrooms. Warm-ups were independently completed at the start of class meetings and consisted of questions about content covered 1-10 days prior to each warm-up. Students received feedback on their answers each week. A series of ANOVAs and ANCOVAs was conducted. RESULTS AND CONCLUSIONS: Results showed equal and significant growth from pre- to post-test for both conditions (d = .31-.67) on three outcomes: Biology knowledge, biology diagram comprehension (near transfer), and geology diagram comprehension (far transfer). ANCOVA results suggested that the magnitude of this increase was linked to the number of questions attempted during the intervention. For the DBR condition only, there were interactions with content knowledge on diagram comprehension gain scores and interactions with spatial scores on biology knowledge gain scores. Students with lower biology knowledge and lower Paper Folding Test scores were disadvantaged in the DBR condition, whereas the TBR condition was equitable across all levels of knowledge and spatial ability. PMID- 25529503 TI - Characterization of conventional, biodynamic, and organic purple grape juices by chemical markers, antioxidant capacity, and instrumental taste profile. AB - The objectives of this study were to characterize organic, biodynamic, and conventional purple grape juices (n = 31) produced in Europe based on instrumental taste profile, antioxidant activity, and some chemical markers and to propose a multivariate statistical model to analyze their quality and try to classify the samples from the 3 different crop systems. Results were subjected to ANOVA, correlation, and regression analysis, principal component analysis (PCA), hierarchical cluster analysis (HCA), soft independent modeling of class analogy (SIMCA), and partial least-squares discriminant analysis (PLSDA). No statistical significant differences (P > 0.05) were observed among juices from the 3 crop systems. Using PCA and HCA, no clear separation among crop systems was observed, corroborating the ANOVA data. However, PCA showed that the producing region highly affects the chemical composition, electronic tongue parameters, and bioactivity of grape juices. In this sense, when organic and biodynamic were grouped as "nonconventional" juices, SIMCA model was able to discriminate 12 out of 13 organic/biodynamic juices and 17 out of 18 conventional juices, presenting an efficiency of 93.5%, while 11 out of 13 non-conventional and 100% conventional grape juices were correctly classified using PLSDA. The use of electronic tongue and the determination of antioxidant properties and major phenolic compounds have shown to be a quick and accurate analytical approach to assess the quality of grape juices. PMID- 25529504 TI - Development of quality indicators to evaluate antibiotic treatment of patients with community-acquired pneumonia in Indonesia. AB - OBJECTIVE: To develop an instrument for evaluating the quality of antibiotic management of patients with community-acquired pneumonia (CAP) applicable in a middle-income developing country. METHOD: A previous study and Indonesian guidelines were reviewed to derive potential quality of care indicators (QIs). An expert panel performed a two-round Delphi consensus procedure on the QI's relevance to patient recovery, reduction of antimicrobial resistance and cost containment. Applicability in practice, including reliability, feasibility and opportunity for improvement, was determined in a data set of 128 patients hospitalised with CAP in Semarang, Indonesia. RESULTS: Fifteen QIs were selected by the consensus procedure. Five QIs did not pass feasibility criteria, because of inappropriate documentation, inefficient laboratory services or patient factors. Three QIs provided minor opportunity for improvement. Two QIs contradicted each other; one of these was considered not valid and excluded. A final set of six QIs was defined for use in the Indonesian setting. CONCLUSION: Using the Delphi method, we defined a list of QIs for assessing the quality of care, in particular antibiotic treatment, for CAP in Indonesia. For further improvement, a modified Delphi method that includes discussion, a sound medical documentation system, improvement of microbiology laboratory services, and multi center applicability tests are needed to develop a valid and applicable QI list for the Indonesian setting. PMID- 25529505 TI - Does policy grow on trees? AB - Policymaking is both an art and a science. It is a long process of research, debate and consensus (where possible). The elaboration of the Framework for Responsible Sharing of Genomic and Health-Related Data serves as an illustration of this process. PMID- 25529506 TI - Short- and long-term effects of gestational diabetes mellitus on healthcare cost: a cross-sectional comparative study in the ATLANTIC DIP cohort. AB - AIMS: This paper examines the association between gestational diabetes mellitus and costs of care during pregnancy and 2-5 years post pregnancy. METHODS: Healthcare utilization during pregnancy was measured for a sample of 658 women drawn from the Atlantic Diabetes in Pregnancy (ATLANTIC DIP) network. Healthcare utilization 2-5 years post pregnancy was assessed for a subsample of 348 women via a postal questionnaire. A vector of unit costs was applied to healthcare activity to calculate the costs of care at both time points. Differences in cost for women with gestational diabetes mellitus compared with those with normal glucose tolerance during the pregnancy were examined using univariate and multivariate regression analyses. RESULTS: Gestational diabetes mellitus was independently associated with an additional ?817.60 during pregnancy (?1192.1 in the gestational diabetes mellitus group, ?511.6 in the normal glucose tolerance group), in the form of additional delivery and neonatal care costs, and an additional ?680.50 in annual healthcare costs 2-5 years after the index pregnancy (?6252.4 in the gestational diabetes mellitus group, ?5434.8 in the normal glucose tolerance group). CONCLUSIONS: These results suggest that gestational diabetes mellitus is associated with increased costs of care during and post pregnancy. They provide indication of the associated cost that can be avoided or reduced by the screening, prevention and management of gestational diabetes mellitus in pregnancy. These estimates are useful for further studies that examine the cost and cost-effectiveness of such programmes. PMID- 25529507 TI - Advances in treating drug-resistant hepatitis B virus in HIV-infected patients. AB - INTRODUCTION: Treatment of HIV infection with nucleos(t)ide analogs active against hepatitis B virus (HBV) highly improves hepatic outcomes in HIV-HBV coinfected patients, especially when tenofovir (TDF) is part of the antiviral regimen. Drug resistance has been the major drawback and must remain as the most important caveat when planning to treat dually or HIV and HBV independently in coinfected patients. AREAS COVERED: The use of lamivudine (LAM) as the only active anti-HBV agent should strongly be discouraged in HIV-HBV coinfected patients, although it might be considered for individuals with low serum HBV-DNA and in the absence of liver cirrhosis as an exception. In any other case drug resistance may cause any clinical benefit of this antiviral HBV therapy to disappear, and lead to cross-resistance with other antivirals and even occasionally select for HBV vaccine escape mutants. In cirrhotics, liver enzyme flares may be accompanied by life-threatening decompensation. Entecavir is generally not recommended as an anti-HBV agent in HIV-HBV coinfected patients given its low residual antiretroviral activity and potential for selection of resistance mutations in HIV. Adefovir is not active against HIV using HBV dosing and is no longer recommended as HBV therapy given its limited antiviral effect. Finally, telbivudine is not active against HIV, it is less potent than TDF against HBV and depicts low barrier to resistance and cross-resistance to LAM or emtricitabine. EXPERT OPINION: The introduction of TDF has drastically reduced the clinical relevance of hepatitis B drug resistance in HIV-HBV coinfected individuals. The use of LAM as the only active anti-HBV agent should strongly be discouraged in this population. PMID- 25529508 TI - Propofol pretreatment attenuates remote kidney injury induced by orthotopic liver autotransplantation, which is correlated with the activation of Nrf2 in rats. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular-defense response in protection against oxidative injury. Several studies have demonstrated that propofol ameliorates ischemia/reperfusion injury in a number of organs. However, whether propofol exerts renal protection against liver transplantation via Nrf2 activation remains to be elucidated. The aim of the present study was to investigate the effects of orthotopic liver autotransplantation (OLAT) on renal Nrf2 expression and to determine whether propofol protects against kidney injury induced by OLAT via Nrf2 activation. A total of 24 male Sprague Dawley rats were randomly divided into four groups: sham surgery + normal saline (sham group); OLAT + normal saline (OLAT group); OLAT + propofol 50 mg/kg (L-Prop group) and OLAT + propofol 100 mg/kg (H-Prop group). Normal saline and propofol were administered for 3 consecutive days through an intraperitoneal injection prior to surgery. Kidney pathology, blood urea nitrogen (BUN), creatinine (Cr), superoxide anion (O2*-), hydroxyl radical (.OH), maleic dialdehyde (MDA) and expression levels of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1) and NADP quinine oxidoreductase 1 (NQO1) were assessed 8 h after OLAT. It was demonstrated that OLAT induced remote kidney damage. Pretreatment with propofol significantly ameliorated renal pathology and abrogated the increase of the Cr and BUN concentrations, O2*- and .OH activities, and MDA levels induced by OLAT. In the H-Prop group, Keap1 expression in the cytoplasm was decreased and Nrf2 expression in the nucleus was upregulated, accompanied by an increase of HO-1 and NQO1 expression. The present results suggest that propofol pretreatment exerted renal protection against OLAT, with the upregulation of nuclear Nrf2 expression as a potential mechanism. PMID- 25529510 TI - The Effect of Dental Adhesive on Final Color Match of Direct Laminate Veneer (DLV): In Vitro Study. AB - AIM: To evaluate the influence of dental adhesive on the color match of direct laminate veneer. MATERIALS AND METHOD: Specimens were prepared in the form of discs. B1 nano-filled composite Filtek Z-350 XT (3M-ESPE) and single-bond universal adhesive were used. Twenty discs of each test group with a diameter of 10 +/- 0.1 mm and thickness of 0.7 +/- 0.1 mm were prepared. The specimens were divided into three groups: control group that has composite material only (C), a group that has adhesive with composite material (AC), and a group that has adhesive with composite and re-bonding technique (ACR). The samples were placed in viewing port for color measurement. Spectrophotometer was used in this study. Descriptive statistical analysis was performed for the CIE L*, a*, and b* values. Statistical software IBM SPSS 16.0 was used for analyzing the data, with a significance level of 0.05 (p < 0.05). RESULTS: In this study, both groups where bonding agent was applied had significant change in color of the samples (p < 0.05). AC and ACR showed a change along the "a" coordinate and the "b" coordinate with using adhesive and re-bonding technique. There were significant differences when comparing the values of a* and b* of the control group C with AC group and ACR on using adhesive and re-bonding technique. ACR specimens presented the lowest "L" value. CONCLUSION: Within the limitations of this study, despite the fact that the change of color is not extensive, the dental adhesive changes the color of direct composite restoration in a way that may warrant caution. Additional studies are essential to substantiate the findings of this study. CLINICAL SIGNIFICANCE: Dental adhesive play an important role in changing the color of direct composite restoration. PMID- 25529515 TI - Impact of implant support on mandibular free-end base removable partial denture: theoretical study. AB - OBJECTIVES: This study investigated the impact of implant support on the development of shear force and bending moment in mandibular free-end base removable partial dentures (RPDs). MATERIAL AND METHODS: Three theoretical test models of unilateral mandibular free-end base RPDs were constructed to represent the base of tooth replacement, as follows: Model 1: first and second molars (M1 and M2); Model 2: second premolar (P2), M1, and M2; and Model 3: first premolar (P1), P2, M1, and M2. The implant support located either at M1 or M2 sites. The occlusal loading was concentrated at each replacement tooth to calculate the stress resultants developed in the RPD models using the free-body diagrams of shear force and bending moment. RESULTS: There was a trend of reduction in the peak shear force and bending moment when the base was supported by implant. However, the degree of reduction varied with the location of implant support. The moment reduced by 76% in Model 1, 58% in Model 2, and 42% in Model 3, when the implant location shifted from M1 to M2 sites. CONCLUSIONS: The shear forces and bending moments subjected to mandibular free-end base RPDs were found to decrease with the addition of implant support. However, the impact of implant support varied with the location of implant in this theoretical study. PMID- 25529509 TI - Prostate hyperplasia caused by long-term obesity is characterized by high deposition of extracellular matrix and increased content of MMP-9 and VEGF. AB - Recent studies have shown a positive association of cancer and obesity, but the morphological and molecular mechanisms involved in this relationship are still unknown. This study analysed the impact of long-term obesity on rat prostate, focusing on stromal changes. Male adult Wistar rats were treated with high-fat diet to induce obesity, while the control group received a balanced diet. After 30 weeks of feeding, the ventral prostate was analysed by immunohistochemistry for cell proliferation, smooth muscle alpha-actin, vimentin, chondroitin sulphate and metalloproteinases (MMP-2 and 9). The content of androgen receptor (AR), oestrogen receptors (ERs) and vascular endothelial growth factor (VEGF) was measured by Western blotting, and activity of catalase and Glutathione-S Transferase (GST) were quantified by enzymatic assay. Long-term obesity decreased testosterone plasma levels by 70% and resulted in stromal prostate hyperplasia, as evidenced by increased collagen fibres. Such stromal hyperplasia was associated with increased number of blood vessels and raised VEGF content, and increased expression of chondroitin sulphate, vimentin, alpha-actin and MMP-9. In spite of the high cell density in prostate, the proliferative activity was lower in the prostates of obese rats, indicating that hyperplasia was established during the early phases in this obesity model. AR levels increased significantly, whereas the ERalpha decreased in this group. Moreover, the levels of catalase and GST were changed considerably. These findings indicate that long-term obesity, besides disturbing the antioxidant control, causes intense stromal remodelling and release of factors that create an environment that can promote proliferative disorders in the gland, culminating with diffuse hyperplasia. PMID- 25529516 TI - First-year dental students' motivation and attitudes for choosing the dental profession. AB - OBJECTIVE: To determine first-year dental students' current motivation and attitudes for choosing the dental profession at the Faculty of Dental Medicine, Medical University - Sofia, Bulgaria. MATERIAL AND METHODS: An anonymous questionnaire, consisting of 12 questions about students' socio-demographic profile and their motivation for choosing dentistry, was administered to 119 first-year dental students at the Faculty of Dental Medicine of the Medical University of Sofia. The study was conducted at the beginning of the 2012-2013 academic year. The data was processed and analyzed with the following software: Microsoft Windows Server 2008 R2; Microsoft SQL Server 2008; Internet Information Server 7.5.; Microsoft SharePoint Server 2010. RESULTS: The majority of the students (73%) were self-motivated for choosing dentistry as a career; 61% of them did not have relatives in the medical profession; 43% chose dental medicine because it is a prestigious, humane and noble profession; 50% - for financial security; 59% - because of the independence that it provides. There were no significant differences in the motivation between males and females. CONCLUSION: Independence, financial security and 'prestige' were the predominant motivating factors in this group of first-year dental students. Determining the reasons for choosing dentistry has important implications for the selection and training of students as well as for their future job satisfaction. PMID- 25529517 TI - The effects of diabetes mellitus and hypertension on work productivity. AB - OBJECTIVE: The primary objective of this paper is to examine the impact of diabetes mellitus on the ability to work in patients with diabetes mellitus. The second objective of this paper is to examine the differences in the ability to work between patients with diabetes mellitus and patients with other chronic diseases, such as hypertension. MATERIAL AND METHODS: A study was conducted in 10 family medicine practices from two primary health care centers, Pale and East Sarajevo, in the period between July 2009 and May 2010, utilising a retrospective medical records review and a cross sectional survey. The outcomes used to portray respondent's health status included functional measures and ability to work. Functional measures were analyzed using SF-36 and a general questionnaire. Absenteeism and productivity loss were retrospectively analyzed for the past ten years from a regional sick-leave database and the administrative records of the Commission for the assessment of work capacity for the Pension and Disability Insurance Fund of the Republika Srpska respectively. RESULTS: Out of the total number of patients with diabetes, 24.6% had some form of disability. A statistically significant difference was found between the two groups; patients with diabetes mellitus were much more likely to have problems meeting the required standards at the workplace due to emotional and physical health issues compared to hypertensive patients. CONCLUSION: Diabetes mellitus appears to reduce an individual's ability to work in comparison to patients with hypertension. There is a need to set up a diabetes mellitus prevention program and to develop and implement effective targeted intervention to help workers to manage their disease better. PMID- 25529518 TI - Prognostic factors of overall survival for patients with stage II colon cancer. AB - OBJECTIVE: To analyze factors influencing survival of patients with stage II colon cancer treated at our cancer center (Sparrow Hospital) from February 1996 through December 2006. PATIENTS AND METHODS: Survival analyses on 197 patients' age 71.1+/-0.9 years (29 to 97) were done using SAS system (V9.3, Cary NC). Analysis included age, gender, stage, surgery type, number of examined lymph nodes, pathological grade, tumor size and the use of adjuvant chemotherapy. RESULTS: Mean follow up length was 48.1+/-2.3 months (0.1-133) and 56+/-3.3 (0.2 133) for survivors. The average number of removed lymph nodes was 18+/-13 (1 103). Adjuvant chemotherapy treatment (5-FU+/- leucovorin) was given to 49 patients, while others (148) were followed expectantly. There were 90 deaths during follow up. Only age exhibits a statistically significant relationship to survival (Hazard Ratio (HR) =1.06, 95% CI=1.03-1.08, p<0.001). Adjuvant chemotherapy possibly reduced the risk of death by 42% approaching a borderline advantage for survival (HR=0.58, CI=0.33-1.03, p=0.06. The number of removed lymph nodes also showed a possible relationship to survival (HR=0.98, CI= 0.62 1.56, p=0.07). Other investigated factors (gender, type of surgery, etc.) were not significant correlates. CONCLUSION: In this study we found that the most important factor for survival of patients with Stage II colon cancer is the patient's age. Adjuvant chemotherapy showed a borderline significance while the number of resected lymph nodes seemed to be an important survival factor. However, in our study statistical significance was not achieved. PMID- 25529519 TI - The relationship of Bradykinin B2 receptor gene variation with obesity, hypertension and lipid variables in obese patients. AB - OBJECTIVE: This study examined the association of C-58T genotypes with obesity/hypertension related parameters and serum lipids in obese (n=108) and non obese (n=80) patients. MATERIALS AND METHODS: Bradykinin receptor (B2R) C-58T genotypes were determined by PCR-RFLP. RESULTS: B2R gene C-58T frequencies for T/T (homozygous wild type), T/C (heterozygous) and C/C (homozygous polymorphic) genotypes for obese and non-obese patients were respectively: 36.1%, 37.5%; 45.4%, 52.5% and 18.5%, 10%. Obese patients using diuretic medication had lower C/C genotype frequency compared to T/T and T/C genotypes. Total cholesterol (T Chol) (p=0.035) levels were found to be associated with B2R C-58T polymorphism, where the T/T genotype had higher total cholesterol levels compared to the T/C genotype in obese patients. Non-obese patients using oral antidiabetic medication had higher C/C genotype frequency than that of T/T and T/C genotypes. Waist circumference (p=0.016) and diastolic blood pressure (p=0.01) levels were elevated in the non-obese subjects with the C/C genotype compared to T/C and T/T. CONCLUSION: Although B2R C-58T gene polymorphism was not found to be effective on obesity with logistic regression analysis in the whole study population in obese subjects, the T-Chol decreasing effect of the B2R gene C allele and the higher waist circumference measurements in the non-obese subjects may indicate there may be a link between B2R gene C-58T polymorphism and obesity in study populations of higher numbers. PMID- 25529520 TI - Only a minority of patients in the urological emergency unit need urgent urology care. AB - OBJECTIVE: To present patients who were examined, monitored and admitted at the urological emergency unit (UEU) at the University Hospital, Split during the summer and winter of 2010 and to establish who of them were really in need of immediate urological care. METHODS: A retrospective study of patients and diagnoses of patients examined at the UEU was undertaken during two winter and two summer months 2010. We compared the total number of patients, the number of patients with urological issues, patients with urological emergencies, patients with non-urological issues, patients who were briefly monitored at the UEU, and patients admitted to the urology department, within these two periods. Descriptive statistic and chi squared tests were used. RESULTS: During the winter period 465 patients were examined at the UEU and during the summer 733 patients. During the summer period there were statistically more urological issues (chi2=12.3; p=0.005) and urological emergencies (chi2=4.14; p=0.042) while in the winter period there were more non-urological issues and more patients were monitored at the UEU (chi2=33.9; p<0.001). The most common diagnoses are: renal colic and urine retention, in both periods. Only 8% of patients in both the winter and summer periods were admitted to hospital after examination at the UEU, which represents the actual number of patients who needed immediate urological care. CONCLUSION: Of all the patients examined at the UEU, only a fraction constituted real, life-threatening urological emergencies. Primary care physicians and general emergency departments should be more educated in urological emergencies so that they can resolve more nonemergency patients themselves. PMID- 25529521 TI - Congenital cardiac anomalies in myelomeningocele patients. AB - OBJECTIVE: Myelomeningocele may be isolated but more frequently is associated with other anomalies. Congenital heart disease occurs with different incidence rate in myelomeningocele which is observed more frequently with skeletal malformations. METHODS: This study was undertaken in the Children's Hospital Medical Center between 2010 to 2012 to evaluate 75 myelomeningocele patients for cardiac anomalies, with electrocardiography and echocardiography in addition to clinical examination of the cardiopulmonary system. Demographic information, myelomeningocele location and characteristics, orthopedic deformities, neurological deficits and radiographic findings were studied besides cardiologic assessments. RESULTS: The ages of the patients ranged from 1 day to 4 years. The myelomeningocele locations were lumbosacral, lumbar and sacral area in most cases. Physical examination of the heart was abnormal in 6 children, but echocardiography revealed cardiac anomalies in only two children. Both children were female patients with severe scoliosis, multiple rib deficiencies and associated vertebral anomalies. CONCLUSION: Congenital heart defects are not very common in MMC patients. Female patients with suspicious clinical examinations for cardiac anomalies and associated rib and vertebral anomalies are advised to be investigated by echocardiography to rule out associated cardiac anomalies. PMID- 25529522 TI - Mitral valve replacement in a patient with infective endocarditis and aneurysm of the cerebral artery: a case report. AB - OBJECTIVE: Endocarditis can have profound and devastating neurological consequences, with the vast majority of these complications in patients with left sided valvular disease. The approach to the acute management of stroke in children with infective endocarditis is limited by the inadequacy of published data on their clinical course and outcome. CASE REPORT: This case report presents a 12 year old girl with diagnosed endocarditis, complicated with intracranial hemorrhage, due to the rupture of an aneurysm of the peripheral branch medial cerebral artery and gradient therapeutic approach, with an excellent final result. CONCLUSION: Congestive heart failure resulting from valvular insufficiency required mitral valve replacement, after cerebral aneurysm clipping. PMID- 25529523 TI - Double superior vena cava: two cases in Thai cadavers. PMID- 25529524 TI - A call for greater power in an era of publishing negative results. AB - Historically, medical journals published only positive results from experimentation. With the growth of electronic media, many journals are now able to publish negative results as well. Because most medical experiments are designed to have different thresholds of significance for positive and negative results, this can lead readers to misunderstand the level of significance of a published negative result. We propose a technical shift - setting alpha equal to beta - to avoid this potential for misunderstanding. PMID- 25529525 TI - The thematic hierarchy in sentence comprehension: A study on the interaction between verb class and word order in Spanish. AB - Linking is the theory that captures the mapping of the semantic roles of lexical arguments to the syntactic functions of the phrases that realize them. At the sentence level, linking allows us to understand "who did what to whom" in an event. In Spanish, linking has been shown to interact with word order, verb class, and case marking. The current study aims to provide the first piece of experimental evidence about the interplay between word order and verb type in Spanish. We achieve this by adopting role and reference grammar and the extended argument dependency model. Two different types of clauses were examined in a self paced reading task: clauses with object-experiencer psychological verbs and activity verbs. These types of verbs differ in the way that their syntactic and semantic structures are linked, and thus they provide interesting evidence on how information that belongs to the syntax-semantics interface might influence the predictive and integrative processes of sentence comprehension with alternative word orders. Results indicate that in Spanish, comprehension and processing speed is enhanced when the order of the constituents in the sentence mirrors their ranking on a semantic hierarchy that encodes a verb's lexical semantics. Moreover, results show that during online comprehension, predictive mechanisms based on argument hierarchization are used rapidly to inform the processing system. Our findings corroborate already existing cross-linguistic evidence on the issue and are briefly discussed in the light of other sentence-processing models. PMID- 25529526 TI - Enantioselective Michael addition of water. AB - The enantioselective Michael addition using water as both nucleophile and solvent has to date proved beyond the ability of synthetic chemists. Herein, the direct, enantioselective Michael addition of water in water to prepare important beta hydroxy carbonyl compounds using whole cells of Rhodococcus strains is described. Good yields and excellent enantioselectivities were achieved with this method. Deuterium labeling studies demonstrate that a Michael hydratase catalyzes the water addition exclusively with anti-stereochemistry. PMID- 25529527 TI - Men's Intentions to Have Sex With a New Partner: Sexual and Emotional Responding, Alcohol, and Condoms. AB - Findings regarding the relation between alcohol and intentions to have sex have been mixed, and little research has examined the role of condom availability on intentions to have sex. Sexual and emotional responding may influence subsequent sexual decisions. Thus, a better understanding of sexual and emotional responding combined with situational factors such as condom presence could help explain the discrepancies in findings regarding alcohol's effect on intentions to have sex. The effects of alcohol and condom presence on men's intentions to have sex were examined using an experimental paradigm involving an alcohol administration study and a second-person eroticized scenario. The effects of sexual and emotional responding were also examined in relation to intentions to have sex. It was found that alcohol increased positive mood, which was associated with higher intentions to have sex. In addition, condom presence was directly associated with higher intentions to have sex. More sexual desire was related to increased likelihood of sexual intentions. These findings increase understanding of mechanisms underlying the relation between alcohol and intentions to have sex. PMID- 25529528 TI - Regulation of Trek1 expression in nasal mucosa with allergic rhinitis by specific immunotherapy. AB - Epithelial barrier dysfunction is involved in the pathogenesis of allergic disorders, such as nasal allergy. TWIK-related K(+) 1 (Trek1) potassium channels are required in the maintenance of the epithelial barrier function. This study aims to investigate the role of antigen-specific immunotherapy (SIT) in the regulation of Trek1 expression in the nasal mucosa. In this study, patients with nasal allergy were treated with SIT and/or Clostridium butyricum. The expression of Trek1 and histone demethylase 1 (HDAC1) in the nasal epithelia was assessed by real-time reverse transcription polymerase chain reaction and Western blotting. Serum cytokines were assessed by enzyme-linked immunosorbent assay. The results showed that Trek1 and HDAC1 were detected in the nasal epithelia. Trek1 was lower, whereas HDAC1 was higher in patients with allergic rhinitis as compared with healthy controls. Trek1-null RPMI2650 monolayers showed a markedly compromised epithelial barrier function. Treatment with SIT significantly increased the Trek1 levels in the nasal epithelia of allergic rhinitis patients that were further improved in conjunction of SIT and administration of probiotic C. butyricum. In conclusion, nasal epithelia express Trek1 that can be suppressed by allergic response. SIT can restore the expression of Trek1 in the nasal epithelia and can be further improved by conjunction with administration of C. butyricum. PMID- 25529529 TI - A behavioral audiogram of the red fox (Vulpes vulpes). AB - We determined the absolute hearing sensitivity of the red fox (Vulpes vulpes) using an adapted standard psychoacoustic procedure. The animals were tested in a reward-based go/no-go procedure in a semi-anechoic chamber. At 60 dB sound pressure level (SPL) (re 20 MUPa) red foxes perceive pure tones between 51 Hz and 48 kHz, spanning 9.84 octaves with a single peak sensitivity of -15 dB at 4 kHz. The red foxes' high-frequency cutoff is comparable to that of the domestic dog while the low-frequency cutoff is comparable to that of the domestic cat and the absolute sensitivity is between both species. The maximal absolute sensitivity of the red fox is among the best found to date in any mammal. The procedure used here allows for assessment of animal auditory thresholds using positive reinforcement outside the laboratory. PMID- 25529530 TI - Eye color as a risk factor for acquired sensorineural hearing loss: a review. AB - Eye color may be an indicator of inner ear melanin content and has been associated with hearing loss. There is controversy as to whether eye color has an effect on acquired causes of sensorineural hearing loss. This review was conducted to analyze the literature evaluating the relationship between eye color and causes of sensorineural hearing loss. Six databases were searched to identify eligible studies. Included articles were independently assessed for quality by two authors. Eighteen articles were eligible for review. Eye color was not found to have an effect in the non-exposed population or in presbycusis. In noise induced sensorineural hearing loss, light-eyed patients had more significant loss following noise exposure, although the variability reported due to eye color was modest (r(2) = 0.01-0.14). Two out of three studies reported that dark eye color is associated with cisplatin ototoxicity. In one study, green-eyed patients were found to be at higher risk of radiation-induced hearing loss. Eye color does not appear to play a role in hearing loss in non-exposed individuals or presbycusis. It is possible that dark-eyed individuals, with greater inner ear melanin content, are better protected against noise-induced hearing loss. Evidence suggests that melanin can be protective against radiation-induced sensorineural hearing loss, but may predispose individuals to cisplatin ototoxicity. Future studies are required to support these conclusions. PMID- 25529531 TI - Distribution and characteristics of severe traumatic brain injury at Mulago National Referral Hospital in Uganda. AB - OBJECTIVE: Road traffic accidents are a leading cause of injury in low- and middle-income countries, where mortality rates are disproportionately higher. Patients with severe traumatic brain injury (TBI) tend to have very poor outcomes. To reduce the burden from severe TBI, we describe its distribution at Mulago National Referral Hospital (Kampala, Uganda) and identify the associations between outcomes and patient characteristics, offering insights into prevention and future research efforts to improve clinical care. METHODS: This is a single institution, retrospective chart review including patients of all ages with a Glasgow Coma Scale (GCS) score of 8 or less (measured upon admission). A database was compiled to maximize all available clinical variables. Descriptive statistics and univariable and multivariable regression models were fitted to identify significant associations with outcome (died or discharged). RESULTS: One hundred twenty patients were identified between July 1, 2008, and June 30, 2009. The cumulative incidence of admissions is 89 per 100,000. Thirty-one patients died in the hospital, yielding a 25.8% mortality rate. Motorcycle road traffic accident was the leading mechanism of injury, and males ages 15-29 years comprised the predominant demographic (42.5% of patients). Initial GCS, change in GCS score during hospital stay, and the presence of hematoma were strongest predictors of outcome. CONCLUSIONS: Severe TBI was a common condition for injury-related hospital admissions at Mulago Hospital. The capacity for neurosurgery may have explained the relatively lower mortality rate than previously reported from Sub Saharan Africa. Further investigations are needed. Targeted prevention programs focused on motorcycle users and helmet law enforcement should decrease the incidence of severe TBI. PMID- 25529532 TI - Surgical disconnection of the cortical venous reflux for high-grade intracranial dural arteriovenous fistulas. AB - OBJECTIVES: To assess the clinical outcome, complications, and angiographic outcomes after surgical disconnection of intracranial dural arteriovenous fistulas (DAVFs). METHODS: Analysis of prospectively collected data, including clinical presentation, preoperative angiographic findings, postoperative complications, clinical, and angiographic outcomes. RESULTS: Between January 2002 and January 2012, 25 patients underwent surgery for DAVFs. The anatomical locations included tentorial (8), ethmoidal (8), foramen magnum (5), middle fossa (2), torcular (1), and parafalcine (1). All had cortical venous reflux (CVR) and all were treated with craniotomy and disconnection of CVR. Two patients required repeat surgery for residual CVR. One patient had a postoperative seizure. There were no other complications. All patients had complete disconnection of CVR confirmed by digital subtraction angiography. None of the patients have had hemorrhage or recurrence of CVR on follow-up. CONCLUSIONS: Surgical disconnection of CVR for high-grade intracranial DAVFs is highly effective and can be performed with very low complication rates. Where embolization cannot be performed safely, surgical disconnection (rather than stereotactic radiosurgery) is the treatment of choice for high grade DAVFs. PMID- 25529533 TI - Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(L glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy. AB - Platinum-based polymeric nano-drugs, especially cisplatin-loaded polymeric nanoparticles (CDDP-NPs), have been extensively exploited for the treatment of solid tumors. However, it is still unclear what role the processing procedure and the properties of the polymeric carrier materials may play in influencing the plasma pharmacokinetics, biodistribution and in vivo efficacy of CDDP-NPs. In this study, a series of poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) copolymers were synthesized for the preparation of CDDP-loaded PLG-g mPEG (CDDP/PLG-g-mPEG) nanoparticles. All of the parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length, ultrafiltration purification and cisplatin loading content, were found to have a significant influence on the plasma pharmacokinetics of the CDDP/PLG-g-mPEG nanoparticles. The blood circulation time of the nanoparticles was prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and CDDP loading content. The use of ultrafiltration purification could prolong the blood circulation time of the nanoparticles as well. Experiments to measure the pharmacokinetics and biodistribution demonstrated that the selected CDDP/PLG-g mPEG nanoparticles, NP10, had a long blood circulation time and could achieve selective and significant accumulation in Lewis lung carcinoma (LLC) tumors. The platinum plasma concentrations in the LLC tumor-bearing mice receiving NP10 remained up to 46-fold higher than that of mice receiving equivalent doses of free CDDP. In addition, the plasma area under the concentration time curve (AUC) of NP10 was 31-fold higher than that of free CDDP in 48h. The platinum concentration ratio of NP10 to free CDDP in tumors reached as high as 9.4. The tumor AUC ratio of NP10 to CDDP was 6. Using a mouse C26 tumor model, here we demonstrate that NP10 improves the safety and tolerance in vivo when compared to CDDP and effectively inhibits the growth of C26 tumors. Furthermore, increasing the dosage of NP10 by 2 or 3-fold of free CCDP improved its anticancer efficacy to comparable or higher levels. These results indicate that CDDP/PLG-g-mPEG nanoparticles have greater potential for the treatment of solid tumors in clinical application. PMID- 25529534 TI - Bone volume fraction and fabric anisotropy are better determinants of trabecular bone stiffness than other morphological variables. AB - As our population ages, more individuals suffer from osteoporosis. This disease leads to impaired trabecular architecture and increased fracture risk. It is essential to understand how morphological and mechanical properties of the cancellous bone are related. Morphology-elasticity relationships based on bone volume fraction (BV/TV) and fabric anisotropy explain up to 98% of the variation in elastic properties. Yet, other morphological variables such as individual trabeculae segmentation (ITS) and trabecular bone score (TBS) could improve the stiffness predictions. A total of 743 micro-computed tomography (MUCT) reconstructions of cubic trabecular bone samples extracted from femur, radius, vertebrae, and iliac crest were analyzed. Their morphology was assessed via 25 variables and their stiffness tensor (CFE) was computed from six independent load cases using micro finite element (MUFE) analyses. Variance inflation factors were calculated to evaluate collinearity between morphological variables and decide upon their inclusion in morphology-elasticity relationships. The statistically admissible morphological variables were included in a multiple linear regression model of the dependent variable CFE. The contribution of each independent variable was evaluated (ANOVA). Our results show that BV/TV is the best determinant of CFE(r(2) adj = 0.889), especially in combination with fabric anisotropy (r(2) adj = 0.968). Including the other independent predictors hardly affected the amount of variance explained by the model (r(2) adj = 0.975). Across all anatomical sites, BV/TV explained 87% of the variance of the bone elastic properties. Fabric anisotropy further described 10% of the bone stiffness, but the improvement in variance explanation by adding other independent factors was marginal (<1%). These findings confirm that BV/TV and fabric anisotropy are the best determinants of trabecular bone stiffness and show, against common belief, that other morphological variables do not bring any further contribution. These overall conclusions remain to be confirmed for specific bone diseases and postelastic properties. PMID- 25529535 TI - Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells. AB - Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger signalling resulting in surface mobilization of crucial damage-associated molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib resistant metastatic melanoma. PMID- 25529536 TI - Transcatheter device occlusion of the left ventricular outflow tract as treatment for severe aortic regurgitation in hypoplastic left heart syndrome. AB - Aortic regurgitation is a rare but dangerous condition in patients with hypoplastic left heart syndrome (HLHS). We report the case of a 2-year-old girl with HLHS with aortic/mitral stenosis (AS-MS) subtype after stage II palliation via the bilateral bidirectional Glenn (BBDG) procedure, when aortic regurgitation presented with the clinical manifestation of a paroxysmal coronary steal phenomenon provoked by exertion. Transcatheter closure of the left ventricular outflow tract (LVOT) with an Amplatzer(TM) Vascular Plug 4 minimized and finally abolished aortic reflux without compromising either coronary perfusion or atrioventricular (AV) conduction. Midterm follow-up over 3 years revealed complete disappearance of her symptoms, and follow-up catheterization displayed complete LVOT closure. This case illustrates the promising potential of modern cardiac catherization techniques in certain cases and emphasizes that precise assessment of the native aorta and coronary system is critical in HLHS patients. PMID- 25529537 TI - Factorial design of essential oil extraction from Fagraea fragrans Roxb. flowers and evaluation of its biological activities for perfumery and cosmetic applications. AB - OBJECTIVE: To optimize the extraction yields of essential oil from Fagraea fragrans Roxb. flowers in hydro-distillation using a central composite design (CCD) and to evaluate its biological activities for perfumery and cosmetic applications. METHODS: Central composite design was applied to study the influences of operational parameters [water to flower weight (X(1)) and distillation time (X(2))] on the yields of essential oil (Y). Chemical compositions of the essential oil extracted from the optimized condition were identified by gas chromatography-mass spectrometry. Antioxidant activities of the essential oil were determined against ABTS(*+) and DPPH(*) radicals, and the cytotoxic effects were assessed on human embryonic kidney (HEK293) cells by the use of the MTT assay. Also, the aromatic properties of the essential oil were evaluated by five healthy trained volunteers. RESULTS: The best conditions to obtain the maximum essential oil yield were 7.5 mL g(-1) (X(1)) and 215 min (X(2)). The experimental yield of the essential oil (0.35 +/- 0.02% v/w) was close to the value predicted by a mathematical model (0.35 +/- 0.01% v/w). 3 Octadecyne, Z,Z,Z-7,10,13-hexadecatrienal, E-nerolidol, pentadecanal and linalool were the major constituents of the essential oil. The essential oil showed moderate antioxidant capacities with no toxic effects on HEK293 cells at 1-250 MUg mL(-1). Also, the essential oil exhibited a very strong aroma and was classified to be top- to middle-notes. CONCLUSION: The results offer the effectively operational conditions in the extraction of essential oil from F. fragrans using hydro-distillation. The essential oil could be used as a natural fragrance, having antioxidant activity with slight cytotoxicity, for perfumery and cosmetic applications. PMID- 25529539 TI - An overview of the nutrition transition in West Africa: implications for non communicable diseases. AB - The nutrition landscape in West Africa has been dominated by the programmes to address undernutrition. However, with increasing urbanisation, technological developments and associated change in dietary patterns and physical activity, childhood and adult overweight, and obesity are becoming more prevalent. There is an evidence of increasing intake of dietary energy, fat, sugars and protein. There is low consumption of fruit and vegetables universally in West Africa. Overall, the foods consumed are predominantly traditional with the component major food groups within recommended levels. Most of the West African countries are at the early stages of nutrition transition but countries such as Cape Verde, Ghana and Senegal are at the latter stages. In the major cities of the region, children consume energy-dense foods such as candies, ice cream and sweetened beverages up to seven times as frequently as fruit and vegetables. Adult obesity rates have increased by 115 % in 15 years since 2004. In Ghana, the prevalence of overweight/obesity in women has increased from 12.8 % in 1993 to 29.9 % in 2008. In Accra, overweight/obesity in women has increased from 62.2 % in 2003 to 64.9 % in 2009. The age-standardised proportion of adults who engage in adequate levels of physical activity ranges from 46.8 % in Mali to 94.7 % in Benin. The lingering stunting in children and the rising overweight in adults have resulted to a dual burden of malnutrition affecting 16.2 % of mother-child pairs in Cotonou. The prevalence of hypertension has been increased and ranges from 17.6 % in Burkina Faso to 38.7 % in Cape Verde. The prevalence is higher in the cities: 40.2 % in Ougadougou, 46.0 % in St Louis and 54.6 % in Accra. The prevalence of diabetes ranges from 2.5 to 7.9 % but could be as high as 17.9 % in Dakar, Senegal. The consequences of nutrition transition are not only being felt by the persons in the high socioeconomic class, but also in cities such as Accra and Ouagadougou, where at least 19 % of adults from the poorest households are overweight and 19 28 % have hypertension. Concerted national action involving governments, partners, private sector and civil society is needed to re-orient health systems and build capacity to address the dual burden of malnutrition, to regulate the food and beverage industry and to encourage healthy eating throughout the life course. PMID- 25529541 TI - Direct in situ investigation of milling reactions using combined X-ray diffraction and Raman spectroscopy. AB - The combination of two analytical methods including time-resolved in situ X-ray diffraction (XRD) and Raman spectroscopy provides a new opportunity for a detailed analysis of the key mechanisms of milling reactions. To prove the general applicability of our setup, we investigated the mechanochemical synthesis of four archetypical model compounds, ranging from 3D frameworks through layered structures to organic molecular compounds. The reaction mechanism for each model compound could be elucidated. The results clearly show the unique advantage of the combination of XRD and Raman spectroscopy because of the different information content and dynamic range of both individual methods. The specific combination allows to study milling processes comprehensively on the level of the molecular and crystalline structures and thus obtaining reliable data for mechanistic studies. PMID- 25529538 TI - Single-molecule bioelectronics. AB - Experimental techniques that interface single biomolecules directly with microelectronic systems are increasingly being used in a wide range of powerful applications, from fundamental studies of biomolecules to ultra-sensitive assays. In this study, we review several technologies that can perform electronic measurements of single molecules in solution: ion channels, nanopore sensors, carbon nanotube field-effect transistors, electron tunneling gaps, and redox cycling. We discuss the shared features among these techniques that enable them to resolve individual molecules, and discuss their limitations. Recordings from each of these methods all rely on similar electronic instrumentation, and we discuss the relevant circuit implementations and potential for scaling these single-molecule bioelectronic interfaces to high-throughput arrayed sensing platforms. PMID- 25529540 TI - Cannabis smoking and serum C-reactive protein: a quantile regressions approach based on NHANES 2005-2010. AB - BACKGROUND: Pre-clinical studies link cannabinoid-1 receptor activation to inflammation and atherosclerotic effects; anti-inflammation and immunosuppression seem to be mediated by cannabinoid-2 receptor activation. In this epidemiological study, we aim to present estimates on suspected cannabis-attributable immunomodulation as manifest in serum C-reactive protein (CRP) levels as non specific inflammatory markers with interpretable clinical values. With strength of data from recent large nationally representative community sample surveys, the research approach illustrates value of a quantile regressions approach in lieu of the commonly used but relatively arbitrary cutpoints for CRP values. METHODS: The study population encompasses 20-59 year old participants from the National Health and Nutrition Examination Surveys, 2005-2010 (n=1115 recently active cannabis smokers and 8041 non-smokers, identified via confidential Audio Computer Assisted Self-Interviews). Age, sex, race, education, income-poverty ratio, alcohol consumption, and tobacco smoking also were measured, together with body mass index (BMI), which actually might be on a mediational path. Quantile regressions, with bootstrapping for variance estimation, made it possible to hold these covariates constant while estimating cannabis-CRP associations. RESULTS: Evidence suggesting possible cannabis-attributable immunomodulation emerges at CRP levels below the median (p<0.05). Whereas BMI might help explain a cannabis link with serum CRP, but BMI-stratified analyses disclosed no appreciable variation of the cannabis-CRP relationship across BMI subgroups. CONCLUSIONS: Extending pre clinical research on cannabis-attributable immunomodulation, this study's CRP evidence points toward possible anti-inflammatory effects of cannabis smoking. More definitive evidence can be derived by combining pre-clinical research, studies of patients, and epidemiological research approaches. PMID- 25529542 TI - Outcomes in patients with high-degree atrioventricular block as the initial manifestation of cardiac sarcoidosis. AB - Although high-degree atrioventricular block (AVB) is a common initial manifestation of cardiac sarcoidosis, little is known about the outcomes. The aim of this study was to assess outcomes in patients with AVB as an initial manifestation of cardiac sarcoidosis compared with those in patients with ventricular tachyarrhythmia (VT) and/or heart failure (HF). Fifty-three consecutive patients with cardiac sarcoidosis, who had high-degree AVB (n = 22) or VT and/or HF (n = 31), were enrolled. The end point was defined as major adverse cardiac events, including cardiac death, ventricular fibrillation, sustained VT, and hospitalization for HF. Over a median follow-up period of 34 months, the outcomes of major adverse cardiac events were better in patients with high-degree AVB than in those with VT and/or HF (log-rank test, p = 0.046). However, this difference was due mainly to HF hospitalization. The outcomes of fatal cardiac events, including cardiac death, ventricular fibrillation, and sustained VT, were comparable between the 2 groups (log-rank test, p = 0.877). The fatal cardiac events in patients with high-degree AVB were not associated with the initiation of steroid treatment or left ventricular dysfunction. In conclusion, the outcomes of major adverse cardiac events are better in patients with high-degree AVB than in those with VT and/or HF. However, patients with high degree AVB have a high rate of fatal cardiac events, similar to those with VT and/or HF. An indication for an implantable cardioverter-defibrillator, but not a pacemaker system, can be considered in patients with cardiac sarcoidosis manifested by high-degree AVB. PMID- 25529543 TI - Effect of obstructive sleep apnea on frequency of stroke in patients with atrial fibrillation. AB - Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke that is not included in the usual cardioembolic risk assessments for patients with atrial fibrillation (AF). The aim of this study was to investigate the impact of OSA on stroke rate in patients with AF. Patients with AF and new diagnoses of OSA were identified from retrospective chart review. Those with histories of stroke at the time of the sleep study were excluded. The primary outcome was the incidence of stroke, determined by a physician investigator blinded to the results of polysomnography. Subgroup analysis was performed among different CHADS2 and CHA2DS2-VASc scores. Of 5,138 patients screened for OSA, 402 (7.7%) had AF and 332 (6.4%) met the inclusion criteria. Among the study population, the occurrence of first-time stroke was 22.9%. Ischemic stroke was more common in patients with OSA compared with patients without (25.4% vs 8.2% respectively, p = 0.006). After controlling for age, male gender, and coronary artery disease, the association between OSA and stroke remained statistically significant, with an adjusted odds ratio of 3.65 (95% confidence interval 1.252 to 10.623). A positive dose effect of the apnea-hypopnea index on the rate of stroke was observed (p = 0.0045). Subgroup analysis showed significantly higher rates of stroke in patients with CHADS2 scores of 0 and CHA2DS2-VASc scores of 0 and 1 and co-morbid OSA. In conclusion, OSA in patients with AF is an independent predictor of stroke. This association may have important clinical implications in ischemic stroke risk stratification. PMID- 25529544 TI - Vascular inflammation in metabolically abnormal but normal-weight and metabolically healthy obese individuals analyzed with 18F-fluorodeoxyglucose positron emission tomography. AB - Recent studies have suggested that body size phenotype may contribute to atherosclerosis and cardiovascular disease. (18)F-fluorodeoxyglucose (FDG) positron emission tomography is a useful imaging technique for detecting vascular inflammation that may reflect plaque vulnerability. Therefore, we analyzed which body size phenotypes cause the increased vascular inflammation using FDG positron emission tomography. We compared (18)F-FDG uptake, measured using the blood normalized standardized uptake value, known as the target-to-background ratio (TBR), along with various cardiometabolic risk parameters in 250 participants without a history of cardiovascular disease. Body size phenotypes were classified according to body mass index and the presence/absence of metabolic syndrome. Cardiometabolic risk factors were significantly different among the body size phenotype groups. In particular, the maximum TBR (maxTBR) values in the metabolically abnormal but normal-weight, metabolically healthy obese (MHO), and metabolically abnormal obese groups were significantly greater than those of the metabolically healthy normal-weight (MHNW) group. Components of metabolic syndrome, insulin resistance, high-sensitivity C-reactive protein, and Framingham Risk Score were associated with maxTBR value. Interestingly, although the Framingham Risk Score of the MHO group was almost similar to that of the MHNW group, maxTBR value of MHO subjects was significantly higher than that of MHNW subjects (1.38 [1.20, 1.50] vs 1.22 [1.12, 1.37], p = 0.006). In conclusion, the present study suggests that unique subsets of body size phenotype, such as MHO or metabolically abnormal but normal weight, may have distinct effects on vascular inflammation. PMID- 25529545 TI - Comparison of outcomes of percutaneous MitraClip versus surgical repair or replacement for degenerative mitral regurgitation in octogenarians. AB - Octogenarians affected by mitral regurgitation (MR) are an increasing high-risk population. MitraClip repair is emerging as a promising option for this kind of patients. In this retrospective study, the outcomes of patients aged >=80 years, affected by isolated degenerative MR, who underwent isolated transcatheter (n = 25) or surgical (n = 35, 29 repairs and 6 replacements) mitral intervention from September 2008 to February 2014 were compared. MitraClip patients had higher mean age (84.5 +/- 3.2 vs 81.9 +/- 2.0 years, p <0.01), median Logistic Euroscore 19.4 (11.1 to 29.0) versus 8.4 (7.0 to 10.1) (p <0.01), median Society of Thoracic Surgeons predicted mortality 5.3 (3.5 to 6.6) versus 2.7 (2.3 to 3.9) (p <0.01), and more advanced New York Heart Association class (III to IV in 68% vs 37%, p = 0.02). At 30 days, 1 death occurred in the MitraClip group (p = 0.2). MitraClip was associated with significantly less complications (p <0.05) but more residual MR >2 (p <0.01). Two-year actuarial survival rate was 90% for MitraClip versus 97% for surgery (p <0.01). Higher Society of Thoracic Surgeons mortality was associated with reduced follow-up survival rate (p = 0.01). Two-year actuarial freedom from MR >2 was 70% versus 100%, respectively (p <0.01). New York Heart Association class and quality of life improved after MitraClip and were similar to surgical patients. Recurrent MR >2 was not significantly associated with follow-up mortality in this elderly setting. After the introduction of MitraClip, octogenarian patients with isolated degenerative MR receiving mitral treatment significantly increased (p <0.01). In conclusion, MitraClip patients, despite being older, more symptomatic, and affected by more co-morbidities showed significantly reduced postoperative complications. Two-year mortality was higher in the MitraClip group likely because of co-morbidities. Transcatheter mitral repair resulted in more octogenarians being treated compared with the past. PMID- 25529546 TI - Epidemiology of human plague in the United States, 1900-2012. AB - We summarize the characteristics of 1,006 cases of human plague occurring in the United States over 113 years, beginning with the first documented case in 1900. Three distinct eras can be identified on the basis of the frequency, nature, and geographic distribution of cases. During 1900-1925, outbreaks were common but were restricted to populous port cities. During 1926-1964, the geographic range of disease expanded rapidly, while the total number of reported cases fell. During 1965-2012, sporadic cases occurred annually, primarily in the rural Southwest. Clinical and demographic features of human illness have shifted over time as the disease has moved from crowded cities to the rural West. These shifts reflect changes in the populations at risk, the advent of antibiotics, and improved detection of more clinically indistinct forms of infection. Overall, the emergence of human plague in the United States parallels observed patterns of introduction of exotic plants and animals. PMID- 25529547 TI - The process of processing: exploring the validity of Neisser's perceptual cycle model with accounts from critical decision-making in the cockpit. AB - The perceptual cycle model (PCM) has been widely applied in ergonomics research in domains including road, rail and aviation. The PCM assumes that information processing occurs in a cyclical manner drawing on top-down and bottom-up influences to produce perceptual exploration and actions. However, the validity of the model has not been addressed. This paper explores the construct validity of the PCM in the context of aeronautical decision-making. The critical decision method was used to interview 20 helicopter pilots about critical decision-making. The data were qualitatively analysed using an established coding scheme, and composite PCMs for incident phases were constructed. It was found that the PCM provided a mutually exclusive and exhaustive classification of the information processing cycles for dealing with critical incidents. However, a counter-cycle was also discovered which has been attributed to skill-based behaviour, characteristic of experts. The practical applications and future research questions are discussed. Practitioner Summary: This paper explores whether information processing, when dealing with critical incidents, occurs in the manner anticipated by the perceptual cycle model. In addition to the traditional processing cycle, a reciprocal counter-cycle was found. This research can be utilised by those who use the model as an accident analysis framework. PMID- 25529549 TI - Analgesic effects of botulinum neurotoxin type A in a model of allyl isothiocyanate- and capsaicin-induced pain in mice. AB - We evaluate analgesic effects of BoNT/A in relation to the two main transient receptor potentials (TRP), the vanilloid 1 (TRPV1) and the ankyrin 1 (TRPA1), having a role in migraine pain. BoNT/A (15 pg/mouse) was injected in the inner side of the medial part of hindlimb thigh of mice, where the superficial branch of femoral artery is located. We chosen this vascular structure because it is similar to other vascular structures, such as the temporal superficial artery, whose perivascular nociceptive fibres probably contributes to migraine pain. After an interval, ranging from 7 to 30 days, capsaicin (agonist of TRPV1) or allyl isothiocyanate (AITC; agonist of TRPA1) were injected in the same region previously treated with BoNT/A and nocifensive response to chemicals-induced pain was recorded. In absence of BoNT/A, capsaicin and AITC induced extensive nocifensive response, with a markedly different temporal profile: capsaicin induced maximal pain during the first 5 min, while AITC induced maximal pain at 15-30 min after injection. Pretreatment with BoNT/A markedly reduced both the capsaicin- and AITC-induced pain for at least 21 days. These data suggest a long lasting analgesic effect of BoNT/A exerted via prevention of responsiveness of TRPV1 and TRPA1 toward their respective agonists. PMID- 25529550 TI - Selective rearrangement of terminal epoxides into methylketones catalysed by a nucleophilic rhodium-NHC-pincer complex. AB - An efficient Rh(I)-NHC-pincer catalyst for the highly regioselective Meinwald rearrangement of monoalkylated epoxides into methylketones under mild conditions is presented. The nucleophilic epoxide opening is assisted by Lewis acids. PMID- 25529548 TI - Dose escalation during the first year of long-term opioid therapy for chronic pain. AB - OBJECTIVE: To identify patient factors and health care utilization patterns associated with dose escalation during the first year of long-term opioid therapy for chronic pain. DESIGN: Retrospective cohort study using electronic health record data. SETTING: University health system. SUBJECTS: Opioid naive adults with musculoskeletal pain who received a new outpatient opioid prescription between July 1, 2011 and June 30, 2012 and stayed on opioids for 1 year. METHODS: Mixed-effects regression was used to estimate patients' rate of opioid dose escalation. Demographics, clinical characteristics, and health care utilization for patients with and without dose escalation were compared. RESULTS: Twenty three (9%) of 246 patients in the final cohort experienced dose escalation (defined as an increase in mean daily opioid dose of >=30-mg morphine equivalents over 1 year). Compared with patients without dose escalation, patients with escalation had higher rates of substance use diagnoses (17% vs 1%, P = 0.01) and more total outpatient encounters (51 vs 35, P = 0.002) over 1 year. Differences in outpatient encounters were largely due to more non face-to-face encounters (e.g., telephone calls, emails) among patients with dose escalation. Differences in age, race, concurrent benzodiazepine use, and mental health diagnoses between patients with and without dose escalation were not statistically significant. Primary care clinicians prescribed 89% of opioid prescriptions. CONCLUSIONS: Dose escalation during the first year of long-term opioid therapy is associated with higher rates of substance use disorders and more frequent outpatient encounters, especially non face-to-face encounters. PMID- 25529551 TI - Pretreatment of Miscanthus stalk with organic alkali guanidine and amino guanidine. AB - Organic alkali guanidine and amino-guanidine were used as catalysts to pretreat Miscanthus stalks. The effects of catalyst loadings, pretreatment temperature and time, on pretreatment results were studied. Between guanidines and amino guanidines, guanidines were of benefit to produce hexose and amino-guanidines were in favor of producing pentose in stalk enzymolysis process. SEM images showed that the stalk surface after pretreatment were porous, cracked, and corroded. XRD data showed that the relative crystallinity index of cellulose after pretreatment was increased. FTIR spectra illustrated that both guanidine and amino-guanidine were effective to remove lignin and degrade hydrogen bonds of cellulose. TG data indicated that the initial temperature of rapid weight loss of Miscanthus stalks pretreated by the guanidine was higher than that by the amino guanidine. The maximum sugar yields of Miscanthus stalks pretreated by the guanidine and the amino-guanidine after enzymolysis for 24 h were 350 and 370 mg/g stalks, respectively. PMID- 25529552 TI - Contaminant classification using cosine distances based on multiple conventional sensors. AB - Emergent contamination events have a significant impact on water systems. After contamination detection, it is important to classify the type of contaminant quickly to provide support for remediation attempts. Conventional methods generally either rely on laboratory-based analysis, which requires a long analysis time, or on multivariable-based geometry analysis and sequence analysis, which is prone to being affected by the contaminant concentration. This paper proposes a new contaminant classification method, which discriminates contaminants in a real time manner independent of the contaminant concentration. The proposed method quantifies the similarities or dissimilarities between sensors' responses to different types of contaminants. The performance of the proposed method was evaluated using data from contaminant injection experiments in a laboratory and compared with a Euclidean distance-based method. The robustness of the proposed method was evaluated using an uncertainty analysis. The results show that the proposed method performed better in identifying the type of contaminant than the Euclidean distance based method and that it could classify the type of contaminant in minutes without significantly compromising the correct classification rate (CCR). PMID- 25529553 TI - Characterization of a novel thermostable N-acylhomoserine lactonase from the thermophilic bacterium Thermaerobacter marianensis. AB - Thermaerobacter marianensis is an extremely thermophilic bacterium, which was isolated from the Mariana Trench, with an optimal growth temperature of approximately 75 degrees C. N-Acylhomoserine lactone (AHL) is a quorum-sensing signal molecule used by many gram-negative bacteria. Here, we report the identification of an AHL-degrading gene homolog (designated aiiT) in the genome of T. marianensis JCM 10246. AiiT has 59.7%, 21.2%, and 11.2% identity to AhlS from Solibacillus silvestris, AiiA from Bacillus cereus, and AidC from Chryseobacterium sp., respectively. Homologs of aiiT were also found in Thermaerobacter nagasakiensis, T. composti, and T. subterraneus. A purified AiiT maltose binding fusion showed high AHL-degrading activity against N-hexanoyl-L homoserine lactone, N-octanoyl-L-homoserine lactone, and N-decanoyl-L-homoserine lactone at temperatures ranging from 40 to 80 degrees C. HPLC analysis revealed that AiiT functions as an AHL-lactonase that catalyzes AHL ring opening by hydrolyzing lactones. AiiT displayed maximal activity at high temperatures (60-80 degrees C) and showed higher thermostability than other AHL lactonases. PMID- 25529554 TI - Exploring Outcomes Related to Anxiety and Depression in Completers of a Randomized Controlled Trial of Complicated Grief Treatment. AB - The present study examines a more fine-grained analysis of anxiety-related and depression-related outcomes amongst a sample of treatment completers who were assigned to complicated grief treatment (CGT) (n = 35) or interpersonal psychotherapy (IPT) (n = 34) in a previously reported randomized controlled trial. We examined effects of antidepressant use and measures of anxiety and depression, focusing especially on guilt related to the death or deceased and grief-related avoidance in order to further understand the differential effectiveness of CGT and IPT amongst participants who received the full course of treatment. Analyses showed that CGT produced greater reductions in anxiety and depressive symptoms including negative thoughts about the future and grief related avoidance. CGT's advantage over IPT in lowering depression was most pronounced amongst those not taking antidepressants. Our results further elucidate CGT effects and support the idea that CG and major depressive disorder are distinct conditions. KEY PRACTITIONER MESSAGE: Targeted treatment for complicated grief (CG) produces benefits in associated mood and anxiety symptoms and CG symptoms. Amongst patients with CG, interpersonal psychotherapy seems relatively ineffective in ameliorating depressive symptoms. Grief-related depressive symptoms may not respond to standard treatments unless CG symptoms are also addressed. Reducing grief-related symptoms, such as anxieties about the future, guilt related to the death or deceased and avoidance of reminders of the loss may be important aspects in reducing CG. PMID- 25529555 TI - Level of adherence and predictors of adherence to the Option B+ PMTCT programme in Tigray, northern Ethiopia. AB - OBJECTIVE: The aim of this study was to determine the level of adherence to Option B+ PMTCT drugs and factors associated with adherence among HIV-positive pregnant women in public hospitals of Tigray, northern Ethiopia. METHODS: A cross sectional study was conducted among 277 HIV-positive pregnant women in 2014. A two-stage cluster sampling technique was used to select the study participants. Individual consent was obtained from each participant. Multivariate logistic regression was used to estimate the net effect sizes of factors associated with adherence to Option B+ PMTCT drugs. RESULTS: The level of adherence of respondents to Option B+ PMTCT drugs was 87.1% (95% confidence interval (CI) 82.6 90.7%). Controlling for the effect of other factors, the odds of adhering to Option B+ PMTCT were 4.7 times higher among women who received counselling on medication as compared to those who did not (adjusted odds ratio (aOR) 4.7, 95% CI 1.98-11.35). Similarly, disclosing HIV status was positively associated with good adherence (aOR 4.2, 95% CI 1.07-16.33). CONCLUSIONS: The adherence level was found to be reasonably good. Counselling on medication and HIV status disclosure were positive predictors of adherence to Option B+ PMTCT drugs. PMID- 25529556 TI - Emergence of norovirus GI.2 outbreaks in military camps in Singapore. AB - BACKGROUND: Simultaneous acute gastroenteritis (AGE) outbreaks occurred at two military camps. This study details the epidemiological findings, explores possible origins, and discusses preventive measures. METHODS: Investigations included attack rate surveys, symptom surveys, hygiene inspections, and the testing of water, food, and stool samples. DNA/RNA was extracted from stool samples and amplified via real-time reverse transcription PCR (RT-PCR). Partial and full-length capsid nucleotide sequences were obtained, phylogenetic relationships inferred, and homology modelling of antigenic sites performed. RESULTS: The military outbreaks involved 775 persons and were preceded by two AGE outbreaks at restaurants in the local community. The outbreak was longer and larger in the bigger camp (21 days, attack rate 15.0%) than the smaller camp (6 days, attack rate 8.3%). Of 198 stool samples, norovirus GI.2 was detected in 32.5% (larger camp) and 28.6% (smaller camp). These were essentially identical to preceding community outbreaks. Antigenic site homology modelling also showed differences between identified and more common AGE outbreak strains (norovirus GII.4). CONCLUSION: Differences observed highlight difficulties in controlling person-to-person outbreaks among large groups in close proximity (e.g., military trainees). Distinct differences in antigenic sites may have contributed to increased immunological susceptibility of the soldiers to infection. PMID- 25529557 TI - [Parvovirus B19 seroprevalence in a group of schizophrenic patients]. AB - BACKGROUND: Schizophrenia is a highly disabling chronic mental illness. It is considerded as a neurodeveloppemental illness resulting from the interaction of genetic and environmental factors. Growing evidence supports the major role of prenatal infections and inflammation in the genesis of schizophrenia. The hypothesis including viral infections has been the subject of several studies and the role of parvovirus B19 (PB19) in the onset of the disease has been suggested. However, there is, up till now, no seroepidemiological evidence of his involvement. OBJECTIVE: To determine the prevalence of parvovirus B19 (PB19) in schizophrenic patients and in control subjects and to examine clinical associations between viral prevalence, risk factors of infectious disease and clinical features. METHOD: We carried out a case-control seroepidemiological study in the Psychiatry department of Farhat-Hached general hospital of Sousse (Tunisia). We recruited108 schizophrenic patients and 108 healthy controls free from any psychotic disorder and matched for age and sex. We collected sociodemographic data, medical history, axis I comorbid disorders and infectious risk factors. We assessed patients for psychopathology and severity of illness using respectively the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions (CGI). For each study participant, blood sample was collected and levels of IgG and IgM anti-PB19 were measured using the ELISA technique. RESULTS: The prevalence of IgG antibodies to PB19 was significantly higher in schizophrenic patients than in controls (73.1% vs 60.2%; P=0.04). There were no statistical differences between the two groups regarding the prevalence of IgM antibodies to PB19. No association was found between viral prevalence and sociodemographic data, risk factors for infection or clinical characteristics. The presence of PB19 antibodies was associated with a lower score on the PANSS negative subscale (P=0.04). No other signficative association were found. CONCLUSIONS: In our study, prevalence of IgG antibodies to PB19 was significantly higher in schizophrenic patients than in controls. This finding supports the hypothesis of the involvement of PB19 in schizophrenia. Further studies including both virological and immunological aspects are needed to better clarify the etiopathogenic mechanisms of schizophrenia which would challenge the management of this disease. PMID- 25529559 TI - Establishing an external quality assessment scheme for point-of-care international normalized ratio in Thailand. AB - INTRODUCTION: Effective warfarin therapy management has gained national interest, resulting in the increased use of point-of-care testing (POCT) for international normalized ratio (INR). External quality assessment (EQA) is recommended to ensure quality of the testing. CoaguChek XS and CoaguChek XS Plus are the only commonly available POCT INR monitors in Thailand. Therefore, Thailand NEQAS for Blood Coagulation initiated the scheme for POCT INR in 2013, including only hospitals using these devices. METHODS: Questionnaires were sent to the hospitals, enquiring about their interest in EQA participation. Two surveys were distributed; each included five certified European Concerted Action on Anticoagulation (ECAA) INR plasma sets. Unsatisfactory performance was indicated by a 15% deviation from the certified mean INR value. RESULTS: There were 156 hospitals using the devices. Thirty-five hospitals responded to the questionnaires. Medical personnel undertaking POCT INR were limited to laboratory staff in 29 (83%) of these centers, and 31 hospitals actually participated. The medians of results from participants were the same or nearly the same as the certified mean INRs. CONCLUSION: External quality assessment for POCT INR in Thailand is feasible using the ECAA plasmas as control materials. The results therefore appear encouraging to other developing countries to establish their own EQA schemes. PMID- 25529558 TI - TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN. AB - Agonists for TLR9 and Stimulator of IFN Gene (STING) act as vaccine adjuvants that induce type-1 immune responses. However, currently available CpG oligodeoxynucleotide (ODN) (K-type) induces IFNs only weakly and STING ligands rather induce type-2 immune responses, limiting their potential therapeutic applications. Here, we show a potent synergism between TLR9 and STING agonists. Together, they make an effective type-1 adjuvant and an anticancer agent. The synergistic effect between CpG ODN (K3) and STING-ligand cyclic GMP-AMP (cGAMP), culminating in NK cell IFN-gamma (type-II IFN) production, is due to the concurrent effects of IL-12 and type-I IFNs, which are differentially regulated by IRF3/7, STING, and MyD88. The combination of CpG ODN with cGAMP is a potent type-1 adjuvant, capable of inducing strong Th 1-type responses, as demonstrated by enhanced antigen-specific IgG2c and IFN-gamma production, as well as cytotoxic CD8(+) T-cell responses. In our murine tumor models, intratumoral injection of CpG ODN and cGAMP together reduced tumor size significantly compared with the singular treatments, acting as an antigen-free anticancer agent. Thus, the combination of CpG ODN and a STING ligand may offer therapeutic application as a potent type-II IFN inducer. PMID- 25529560 TI - Visual function and retinal nerve fibre layer degeneration in patients with Alzheimer disease: correlations with severity of dementia. PMID- 25529561 TI - Hierarchically ordered self-lubricating superhydrophobic anodized aluminum surfaces with enhanced corrosion resistance. AB - Herein, we report a facile method for the fabrication of self-lubricating superhydrophobic hierarchical anodic aluminum oxide (AAO) surfaces with improved corrosion protection, which is greatly anticipated to have a high impact in catalysis, aerospace, and the shipping industries. This method involves chemical grafting of as-formed AAO using low surface free energy molecules like long chain saturated fatty acids, perfluorinated fatty acid (perfluorooctadecanoic acid, PFODA), and perfluorosulfonicacid-polytetrafluoroethylene copolymer. The pre and post treatment processes in the anodization of aluminum (Al) play a vital role in the grafting of fatty acids. Wettability and surface free energy were analyzed using a contact angle meter and achieved 161.5 degrees for PFODA grafted anodized aluminum (PFODA-Al). This study was also aimed at evaluating the surface for corrosion resistance by Tafel polarization and self-lubricating properties by tribological studies using a pin-on-disc tribometer. The collective results showed that chemically grafted AAO nanostructures exhibit high corrosion resistance toward seawater and low frictional coefficient due to low surface energy and self-lubricating property of fatty acids covalently linked to anodized Al surfaces. PMID- 25529564 TI - The immune system likes nanotechnology. PMID- 25529562 TI - Mast cells and neuroinflammation. AB - It has been determined that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. There is an emerging realization that glia and microglia, in particular, (which are the brain's resident macrophages), are an important source of inflammatory mediators and may have fundamental roles in CNS disorders. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin, such as mast cells. Mast cells reside in the CNS and are capable of migrating across the blood-brain barrier (BBB) in situations where the barrier is compromised as a result of CNS pathology. Mast cells are both sensors and effectors in communication among nervous, vascular, and immune systems. In the brain, they reside on the brain side of the BBB, and interact with astrocytes, microglia, and blood vessels via their neuroactive stored and newly synthesized chemicals. They are first responders, acting as catalysts and recruiters to initiate, amplify, and prolong other immune and nervous responses upon activation. Mast cells both promote deleterious outcomes in brain function and contribute to normative behavioral functioning, particularly cognition and emotion. Mast cells may play a key role in treating systemic inflammation or blockade of signaling pathways from the periphery to the brain. PMID- 25529565 TI - Highlights from the latest articles on vaccine development using nanoparticles. PMID- 25529563 TI - Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice. AB - Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and beta-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. PMID- 25529566 TI - Group A Streptococcal vaccine candidate: contribution of epitope to size, antigen presenting cell interaction and immunogenicity. AB - AIM: Utilize lipopeptide vaccine delivery system to develop a vaccine candidate against Group A Streptococcus. MATERIALS & METHODS: Lipopeptides synthesized by solid-phase peptide synthesis-bearing carboxyl (C)-terminal and amino (N) terminal Group A Streptococcus peptide epitopes. Nanoparticles formed were evaluated in vivo. RESULTS: Immune responses were induced in mice without additional adjuvant. We demonstrated for the first time that incorporation of the C-terminal epitope significantly enhanced the N-terminal epitope-specific antibody response and correlated with forming smaller nanoparticles. Antigen presenting cells had increased uptake and maturation by smaller, more immunogenic nanoparticles. Antibodies raised by vaccination recognized isolates. CONCLUSION: Demonstrated the lipopeptidic nanoparticles to induce an immune response which can be influenced by the combined effect of epitope choice and size. PMID- 25529567 TI - A stable nanoparticulate DDA/MMG formulation acts synergistically with CpG ODN 1826 to enhance the CD4+ T-cell response. AB - AIM: To combine the dimethyldioctadecyl ammonium/monomycoloyl glycerol (DDA/MMG) liposomal vaccine adjuvant with the Toll-like receptor (TLR) ligands poly(I:C) (TLR3), flagellin (TLR5) or CpG oligodeoxynucleotide 1826 (TLR9) and investigate their physicochemical properties as well as their CD4(+) T-cell-inducing capacity. MATERIALS & METHODS: Formulations were investigated by dynamic light scattering and differential scanning calorimetry. Their CD4(+) T-cell induction with a tuberculosis antigen was analyzed by multiplex cytokine analysis, ELISA and intracellular cytokine staining. RESULTS: DDA/MMG/CpG was the best combination for obtaining increased CD4(+) T-cell responses. However, coformulating CpG and DDA/MMG liposomes led to instability and the formulation was therefore optimized systematically using a design of experiment. CONCLUSION: The nanoparticulate DDA/MMG/CpG adjuvant can be stabilized and synergistically enhances CD4(+) T-cell responses compared with DDA/MMG liposomes. PMID- 25529568 TI - Development of functionalized nanoparticles for vaccine delivery to dendritic cells: a mechanistic approach. AB - AIM: Produce biodegradable nanoparticles to target antigen-presenting cells (APCs) and evaluate their potential to be used as a vaccine delivery system. MATERIALS & METHODS: Untargeted PEGylated poly(d,l-lactic-co-glycolide)-based nanoparticles and mannose-grafted nanoparticles were formulated and physicochemically characterized. Immortalized and primary APCs were used to study nanoparticle internalization patterns. The endocytic pathways and intracellular trafficking followed by nanoparticles were also investigated. RESULTS & DISCUSSION: Nanoparticles displayed mannose residues available for binding at the nanoparticle surface. Different nanoparticle internalization patterns by immortalized and primary APCs were verified. Macropinocytosis, clathrin-mediated endocytosis, caveolin- and lipid raft-dependent endocytosis are involved in nanoparticles internalization. Nanoparticles demonstrate both endolysosomal and cytosolic localizations and a tendency to accumulate nearby the endoplasmic reticulum. CONCLUSION: The developed nanoparticles might drive antigens to be presented through MHC class I and II molecules to both CD8(+) and CD4(+) T cells, favoring a complete and coordinated immune response. PMID- 25529569 TI - Recent advances in peptide-based subunit nanovaccines. AB - Vaccination is the most efficient way to protect humans against pathogens. Peptide-based vaccines offer several advantages over classical vaccines, which utilized whole organisms or proteins. However, peptides alone are not immunogenic and need a delivery system that can boost their recognition by the immune system. In recent years, nanotechnology-based approaches have become one of the most promising strategies in peptide vaccine delivery. This review summarizes knowledge on peptide vaccines and nanotechnology-based approaches for their delivery. The recently reported nano-sized delivery platforms for peptide antigens are reviewed, including nanoparticles composed of polymers, peptides, lipids, inorganic materials and nanotubes. The future prospects for peptide-based nanovaccines are discussed. PMID- 25529570 TI - The impact of size on particulate vaccine adjuvants. AB - Particulate adjuvants have been successful at inducing increased immune responses against many poorly immunogenic antigens. However, the mechanism of action of these adjuvants often remains unclear. As more potential vaccine targets are emerging, it is becoming necessary to broaden our knowledge on the factors involved in generating potent immune responses to recombinant antigens with adjuvants. While composition of adjuvants is integral in defining the overall performance of an adjuvant, some physical parameters such as particle size, surface charge and surface modification may also contribute to the potency. In this review, we will try to highlight the role of particle size in controlling the immune responses to adjuvanted vaccines, with a focus on insoluble aluminum salts, oil-in-water emulsions, polymeric particles and liposomes. PMID- 25529571 TI - Dendrimers as nonviral vectors in dendritic cell-based immunotherapies against human immunodeficiency virus: steps toward their clinical evaluation. AB - Although the antiretroviral therapy has led to a long-term control of HIV-1, it does not cure the disease. Therefore, several strategies are being explored to develop an effective HIV vaccine, such as the use of dendritic cells (DCs). DC based immunotherapies bear different limitations, but one of the most critical point is the antigen loading into DCs. Nanotechnology offers new tools to overcome these constraints. Dendrimers have been proposed as carriers for targeted delivery of HIV antigens in DCs. These nanosystems can release the antigens in a controlled manner leading to a more potent specific immune response. This review focuses on the first steps for clinical development of dendrimers to assess their safety and potential use in DC-based immunotherapies against HIV. PMID- 25529572 TI - Poly(lactic acid) and poly(lactic-co-glycolic acid) particles as versatile carrier platforms for vaccine delivery. AB - The development of safe and effective vaccines for cancer and infectious diseases remains a major goal in public health. Over the last two decades, controlled release of vaccine antigens and immunostimulant molecules has been achieved using nanometer or micron-sized delivery vehicles synthesized using biodegradable polymers. In addition to achieving a depot effect, enhanced vaccine efficacy using such delivery vehicles has been attributed to efficient targeting of antigen presenting cells such as dendritic cells. Biodegradable and biocompatible poly(lactic acid) and poly(lactic-co-glycolic acid) polymers belong to one such family of polymers that have been a popular choice of material used in the design of these delivery vehicles. This review summarizes research findings from ourselves and others highlighting the promise of poly(lactic acid)- and poly(lactic-co-glycolic acid)-based vaccine carriers in enhancing immune responses. PMID- 25529573 TI - Association between quality of the diet and cardiometabolic risk factors in postmenopausal women. AB - BACKGROUND: Climateric is a phase of women's life marked by the transition from the reproductive to the non-reproductive period. In addition to overall weight gain, the menopause is also associated with the increase of abdominal fat. We used The Healthy Eating Index as a summary measure to evaluate the major components and the quality of women's diet after the onset of the menopause. This study aims at examining the association between the quality of the diet and cardiometabolic risk factors in postmenopausal women. METHODS: Cross-sectional study including 215 postmenopausal women attending a public outpatient clinic. The 24-hour dietary recall method was used to assess the food intake and to establish the Healthy Eating Index. Diets were then classified as appropriate diet (>80 points), diet "requiring improvement" (80-51 points), and poor diet (<51 points). Cardiometabolic risk factors included abdominal obesity, dyslipidemia, diabetes mellitus, and hypertension. The Fisher's exact test was utilized for the Statistical analysis. RESULTS: The analysis of the food intake showed that the average daily intake of lipids (36.7%) and sodium (2829.9 mg) were above the recommended. Only 8.8% of the women performed moderate or intense physical exercises on a regular basis. The diet was considered poor in 16.3%, "requiring improvement" in 82.8%, and appropriate for only 0.9% of the women. The study detected increased waist circumference in 92.1% of the participants. The mean concentration of triglycerides was of 183.3 mg/dl, and 130.7 mg/dl for cholesterol (Low Density Lipoprotein). CONCLUSION: Women consume a low quality diet, possibly due to the low intake of vegetables and fruits and excessive consumption of sodium. These inappropriate eating habits are associated with and, have a negative impact on the cardiometabolic risk factors such as abdominal obesity. PMID- 25529575 TI - A clinician's guide to double hit lymphomas. AB - Double hit lymphomas (DHL) represent a subset of highly aggressive B-cell malignancies characterized by the presence of recurrent cytogenetic rearrangements affecting MYC and either BCL2 and/or BCL6. Recent studies have expanded the concept to include MYC/BCL2 protein co-expressing lymphomas. Around 5-10% of diffuse large B-cell lymphomas are 'double hit' using the cytogenetic definition, whilst around 30-40% are MYC/BCL2 protein co-expressing. In this review, we provide a comprehensive overview of this condition written with the practicing clinician in mind, covering the definition and classification, when DHL should be suspected and how to make the diagnosis, the prognostic factors and a detailed discussion of recent evidence regarding optimal therapy. In particular, we discuss choice of induction regimen, the role of central nervous system-directed prophylaxis, stem cell transplantation and relapsing or refractory disease and provide our opinions based on the currently available evidence. Finally, we highlight some of the more exciting therapies currently in development for this highly aggressive disease. PMID- 25529576 TI - Implementing WHO hospital guidelines improves quality of paediatric care in central hospitals in Lao PDR. AB - OBJECTIVES: To evaluate the impact of implementing a multifaceted intervention based on the WHO Pocketbook of Hospital Care for Children on the quality of case management of common childhood illnesses in hospitals in Lao PDR. METHODS: The quality of case management of four sentinel conditions was assessed in three central hospitals before and after the implementation of the WHO Pocketbook as part of a broader mixed-methods study. Data on performance of key steps in case management in more than 600 admissions were collected by medical record abstraction pre- and post-intervention, and change was measured according to the proportion of cases which key steps were performed as well as an overall score of case management for each condition. RESULTS: Improvements in mean case management scores were observed post-intervention for three of the four conditions, with the greatest change in pneumonia (53-91%), followed by diarrhoea and low birthweight. Rational drug prescribing, appropriate use of IV fluids and appropriate monitoring all occurred more frequently post-intervention. Non-recommended practices such as prescription of antitussives became less frequent. CONCLUSIONS: A multifaceted intervention based on the WHO Pocketbook of Hospital Care for children led to better paediatric care in central Lao hospitals. The degree of improvement was dependent on the condition assessed. PMID- 25529574 TI - Host endoplasmic reticulum COPII proteins control cell-to-cell spread of the bacterial pathogen Listeria monocytogenes. AB - Listeria monocytogenes is a food-borne pathogen that uses actin-dependent motility to spread between human cells. Cell-to-cell spread involves the formation by motile bacteria of plasma membrane-derived structures termed 'protrusions'. In cultured enterocytes, the secreted Listeria protein InlC promotes protrusion formation by binding and inhibiting the human scaffolding protein Tuba. Here we demonstrate that protrusions are controlled by human COPII components that direct trafficking from the endoplasmic reticulum. Co precipitation experiments indicated that the COPII proteins Sec31A and Sec13 interact directly with a Src homology 3 domain in Tuba. This interaction was antagonized by InlC. Depletion of Sec31A or Sec13 restored normal protrusion formation to a Listeria mutant lacking inlC, without affecting spread of wild type bacteria. Genetic impairment of the COPII component Sar1 or treatment of cells with brefeldin A affected protrusions similarly to Sec31A or Sec13 depletion. These findings indicated that InlC relieves a host-mediated restriction of Listeria spread otherwise imposed by COPII. Inhibition of Sec31A, Sec13 or Sar1 or brefeldin A treatment also perturbed the structure of cell-cell junctions. Collectively, these findings demonstrate an important role for COPII in controlling Listeria spread. We propose that COPII may act by delivering host proteins that generate tension at cell junctions. PMID- 25529577 TI - The potential role of nemonoxacin for treatment of common infections. AB - INTRODUCTION: Nemonoxacin , a novel non-fluorinated quinolone, exhibits potent activity against Gram-positive bacteria, including MRSA and fluoroquinolone resistant MRSA, Gram-negative and atypical pathogens. This agent also has a reduced propensity for resistance development in many kinds of pathogens. AREAS COVERED: This article reviews currently available clinical and in vitro data that support the potential role of nemonoxacin for the treatment of common infectious diseases, including community-acquired pneumonia (CAP), Clostridium difficile infections (CDIs), acute bacterial skin and skin structure infections (ABSSSIs) and sexually transmitted diseases (STDs). One recent Phase II trial comparing either 500 mg or 750 mg oral nemonoxacin with 500 mg oral levofloxacin for mild to moderate CAP demonstrated that nemonoxacin had comparable clinical success with levofloxacin. Nemonoxacin showed lower MICs against clinical C. difficile isolates than commercially available fluoroquinolones, making it a potential therapeutic agent if novel formulations are developed to maintain a higher concentration in the human gut. For STDs, nemonoxacin also showed good activity against some common pathogens, such as Chlamydia trachomatis and Neisseria gonorrhoeae. EXPERT OPINION: Although in vitro studies have shown promising results regarding the susceptibility to nemonoxacin of common pathogens causing CDIs, ABSSSIs and STDs, further clinical trials are needed to prove its efficacy. PMID- 25529578 TI - Sunitinib does not attenuate contractile force following a period of ischemia in isolated human cardiac muscle. AB - Concerns have been raised about the development of heart failure in patients treated for cancer with angiogenesis inhibitors, such as the tyrosine kinase inhibitor sunitinib. Patients with previous coronary artery disease and hypertension have an increased risk of developing heart failure. Therefore, we studied the effect of sunitinib on the contractility of isolated human atrial trabeculae and the effect on recovery after ischemic stimulation. After informed consent, the atrial appendage of patients undergoing cardiac surgery was harvested and isolated trabeculae were placed in an organ bath with a force transducer. During electrical stimulation, contractile force was measured during normal pacing or after simulated ischemia. Of each patient, one trabecula was perfused with control and one with sunitinib. Contractile force (expressed as percentage of baseline force) declined over time to 57 +/- 8 and 73 +/- 20% after 150 min of stimulation for solvent- and sunitinib-treated trabeculae, respectively (mean +/- SE; n = 8; p > 0.1). After simulated ischemia and reperfusion, contractile force was 40 +/- 6% in the control compared to 39 +/- 6% in the sunitinib-treated trabeculae during the last final 5 min of reperfusion (n = 12; p > 0.1). Sunitinib at low, but clinically relevant, concentrations does not have a direct effect on function of human atrial cardiomyocytes nor does it attenuate the recovery in contractile force of atrial cardiomyocytes after a period of ischemia. A direct and acute toxic effect on cardiomyocytes does not explain the development of heart failure in patients treated with sunitinib. PMID- 25529579 TI - Alginate-based emulsion template containing high oil loading stabilized by nonionic surfactants. AB - Oil-in-water (O/W) emulsion-gel systems containing high oil payloads are of increasing interest for food applications because of the reduction in encapsulation cost, consumption frequency or volume of food products. This study shows a facile approach to prepare stable alginate-based O/W emulsions at high oil loading using a mixture of nonionic surfactants (Tween 80 and Span 20) as a template to form gelled-emulsions. The synergistic effects of alginate and surfactants on the O/W emulsion properties were evaluated in terms of oil droplet size and emulsion stability. At 2% (w/v) of alginate and 1% (w/v) of surfactants, the size distribution of oil droplets was narrow and monomodal, even at an oil loading of 70% (v/v). The emulsions formed were stable against phase separation. The oil droplet size could be further reduced to below 1 MUm using a high-shear homogenizer. The emulsions formed could be easily molded and gelled into solids of different shapes via ionic gelation. The findings of this study create possible avenues for applications in food industries. PMID- 25529580 TI - Induction and treatment of anergy in murine leprosy. AB - Leprosy is a disease consisting of a spectrum of clinical, bacteriological, histopathological and immunological manifestations. Tuberculoid leprosy is frequently recognized as the benign polar form of the disease, while lepromatous leprosy is regarded as the malignant form. The different forms of leprosy depend on the genetic and immunological characteristics of the patient and on the characteristics of the leprosy bacillus. The malignant manifestations of lepromatous leprosy result from the mycobacterial-specific anergy that develops in this form of the disease. Using murine leprosy as a model of anergy in this study, we first induced the development of anergy to Mycobacterium lepraemurium (MLM) in mice and then attempted to reverse it by the administration of dialysable leucocyte extracts (DLE) prepared from healthy (HLT), BCG-inoculated and MLM-inoculated mice. Mice inoculated with either MLM or BCG developed a robust cell-mediated immune response (CMI) that was temporary in the MLM inoculated group and long-lasting in the BCG-inoculated group. DLE were prepared from the spleens of MLM- and BCG-inoculated mice at the peak of CMI. Independent MLM intradermally-inoculated groups were treated every other day with HLT-DLE, BCG-DLE or MLM-DLE, and the effect was documented for 98 days. DLE administered at a dose of 1.0 U (1 * 10(6) splenocytes) did not affect the evolution of leprosy, while DLE given at a dose of 0.1 U showed beneficial effects regardless of the DLE source. The dose but not the specificity of DLE was the determining factor for reversing anergy. PMID- 25529581 TI - India's sterilisation scandal. PMID- 25529583 TI - Developmental disorders: deciphering exomes on a grand scale. PMID- 25529584 TI - No expectation to share incidental findings in genomic research. PMID- 25529585 TI - Apparently abnormal Wechsler Memory Scale index score patterns in the normal population. AB - Interpretation of the Wechsler Memory Scale-Fourth Edition may involve examination of multiple memory index score contrasts and similar comparisons with Wechsler Adult Intelligence Scale-Fourth Edition ability indexes. Standardization sample data suggest that 15-point differences between any specific pair of index scores are relatively uncommon in normal individuals, but these base rates refer to a comparison between a single pair of indexes rather than multiple simultaneous comparisons among indexes. This study provides normative data for the occurrence of multiple index score differences calculated by using Monte Carlo simulations and validated against standardization data. Differences of 15 points between any two memory indexes or between memory and ability indexes occurred in 60% and 48% of the normative sample, respectively. Wechsler index score discrepancies are normally common and therefore not clinically meaningful when numerous such comparisons are made. Explicit prior interpretive hypotheses are necessary to reduce the number of index comparisons and associated false positive conclusions. Monte Carlo simulation accurately predicts these false positive rates. PMID- 25529586 TI - Assessing frontal behavioral syndromes and cognitive functions in traumatic brain injury. AB - This study examined the relationship between individual and family ratings on a measure of frontal behaviors using the Frontal Systems Behavior Scale (FrSBe). Additionally, this study investigated whether self-reported symptoms of frontal lobe dysfunction correspond to neuropsychological performance, particularly those tests measuring executive functions. Thirty-three individuals with moderate-to severe traumatic brain injury (TBI) and 19 healthy individuals completed the FrSBe and neuropsychological measures. Results indicated that the self-ratings of individuals' apathy, disinhibition, and executive dysfunction significantly increased from before to after injury, as did the family members' ratings, with no significant difference between the patients' and family members' reports for any of the three FrSBe subscales. Although individuals with TBI demonstrated impairments in neuropsychological measures, including measures of executive functioning, few significant correlations were found between the patients' FrSBe ratings and measures of cognitive functioning. This suggests that information from the FrSBe may differ from information gathered during a cognitive evaluation and may enhance our understanding of the behavioral sequelae following TBI that may not be captured by neuropsychological assessment alone. PMID- 25529587 TI - Exaggerating psychopathology produces residual effects that are resistant to corrective feedback: an experimental demonstration. AB - We explored the effects of feedback on symptom reporting. Two experimental groups (n=15 each) were given a scenario with the option to exaggerate symptoms. Compared with a control condition (n=15), both groups scored significantly higher on the Structured Inventory of Malingered Symptomatology. Next, one group was confronted in a sympathetic way about their symptom validity test failure, whereas the other group was confronted in a neutral manner. Both groups subsequently completed the Brief Symptom Inventory (BSI). BSI scores of both feedback groups remained significantly higher than those of control participants. Participants who had been provided with sympathetic feedback or neutral feedback did not differ in their BSI scores. Even participants who indicated during the exit interview that they had given up symptom exaggeration attained significantly higher BSI scores than those of controls, indicating that exaggeration has residual effects that are resistant to corrective feedback. We discuss cognitive dissonance as a model for understanding the residual effects of symptom exaggeration. PMID- 25529588 TI - Welcoming a paradigm shift in occupational therapy: symptom validity measures and cognitive assessment. AB - Until now, occupational therapists have been limited in their ability to access methods designed to ensure that formal cognitive and psychosocial testing results were valid. These standardized symptom validity tests (SVTs) are now considered mandatory during neuropsychological testing, particularly within a medical-legal context. The purpose of this study was to evaluate the use of symptom validity testing by occupational therapists involved in a medical-legal setting and to determine whether data obtained are in keeping with findings from other professions. Thirty-six consecutive medical-legal clients were administered the Nonverbal Medical Symptom Validity Test, the Medical Symptom Validity Test, or both during the course of standardized testing. Test administration revealed a failure rate on SVTs of 48%, indicating other occupational therapy formal cognitive or psychosocial test results within those assessments were invalid. These findings are in keeping with a vast international body of research on use of symptom validity measures. We recommend implementation of symptom validity measures in all cognitive and psychosocial test situations. PMID- 25529589 TI - Improving the diagnostic accuracy of the RBANS in mild cognitive impairment with construct-consistent measures. AB - Research on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has suggested that it has somewhat limited sensitivity in the differentiation of patients with mild cognitive impairment (MCI) from patients with dementia and elderly patients with no neurologic or psychiatric diagnoses. This study sought to increase the diagnostic utility of the RBANS in differentiating between patients with Alzheimer's disease (AD), MCI, and no diagnosis (ND) with the addition of construct comparable neuropsychological test measures. Diagnostic utility was assessed by comparing patients diagnosed with MCI to patients diagnosed with AD as well as to the ND group. The following cognitive domains were investigated: short-term memory, retention and long-term memory, language, attention, visuoconstruction, and overall cognitive functioning. Stepwise logistic regressions found that in the comparisons between MCI and ND, the Step 2 addition of construct comparable neuropsychological measures provided a significant diagnostic increase in the short-term memory and overall cognitive functioning models. In the comparisons between MCI and AD, the Step 2 additions provided a significant diagnostic increase in the short-term memory, visuoconstruction, and overall cognitive functioning models. Results suggested that the inclusion of construct similar neuropsychological tests significantly increases the diagnostic accuracy of the RBANS when attempting to identify more subtle cognitive deficits inherent in MCI. PMID- 25529590 TI - WAIS-IV administration errors: effects of altered response requirements on Symbol Search and violation of standard surface-variety patterns on Block Design. AB - This study utilized a sample of 50 college students to assess the possibility that responding to the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Symbol Search subtest items with an "x" instead of a "single slash mark" would affect performance. A second sample of 50 college students was used to assess the impact on WAIS-IV Block Design performance of presenting all the items with only red surfaces facing up. The modified Symbol Search and Block Design administrations yielded mean scaled scores and raw scores that did not differ significantly from mean scores obtained with standard administrations. Findings should not be generalized beyond healthy, well-educated young adults. PMID- 25529591 TI - Normatization of the symbol digit modalities test-oral version in a Latin American country. AB - The aim of this study was to standardize the Symbol Digit Modalities Test (SDMT) Oral version in a healthy population living in Argentina and to analyze the influence that age, gender, and education have on the SDMT. Secondarily, it is intended to analyze the performance of patients with multiple sclerosis (MS) on this test. Two hundred ninety-seven healthy participants were evaluated; they had an average age of 39.28 years and 13.87 years of schooling; 77.8% were women. The sample was segmented according to age in three groups: younger than 35 years old, 36 to 50 years old, and 51 to 70 years old. The sample was also segmented according to years of schooling in three groups: 11 years or less, 12 to 16 years, and more than 16 years. All participants were evaluated with the oral version of the SDMT. A clinical sample of 111 patients with MS was also assessed. The mean on the SDMT for the total sample was 51.34 (SD=12.76). The differences were significant between all groups, p<.05, according to age. The participants with a higher level of education performed better than did those with moderate education and those with less schooling, p<.05. There was a significant difference between patients with MS and healthy controls, p<.01. The SDMT is influenced by age as well as by schooling, although not by gender. The norms displayed here will be useful to accurately evaluate the yield of the patients in the neuropsychological clinic when comparing them with their group of reference. It was also demonstrated that the SDMT can discriminate between patients with MS and healthy people. PMID- 25529592 TI - WAIS-IV Verbal Comprehension Index and Perceptual Reasoning Index performance is unaffected by cold-pressor pain induction. AB - Cognitive complaints are frequently reported by patients with chronic pain, but studies of the effects of pain on different forms of cognition have been inconsistent. In two studies, cold-pressor pain was induced in nonclinical undergraduate volunteers who, under normal conditions, took Verbal Comprehension Index (VCI) subtests (Study 1, n=57) or Perceptual Reasoning Index (PRI) subtests (Study 2, n=59) followed by a different VCI or PRI subtest taken during either cold-pressor pain induction or a nonpainful control condition. Pain was not associated with significant reduction in subtest scaled score performance. Results indicate that cold-pressor pain in nonclinical volunteers does not impair Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) VCI or PRI performance and suggest that pain per se should not be expected to substantially influence these cognitive abilities. Viewed together with previous Processing Speed Index and Working Memory Index studies, no cognitive or intellectual functions measured by the WAIS-IV are affected by induced pain. Generalizability of these findings may be limited by the fact that patients with chronic pain may differ in their pain experience from nonclinical volunteers with induced pain. PMID- 25529593 TI - The relation between cognitive control and risky driving in young novice drivers. AB - This study investigated if decreased cognitive control, reflected in response inhibition and working-memory performance, is an underlying mechanism of risky driving in young novice drivers. Thirty-eight participants aged 17 to 25 years old, with less than 1 year of driving experience, completed a simulated drive that included several risky driving measures. Measures of response inhibition and verbal working memory were negatively associated with the standard deviation of the lateral lane position. Response inhibition, but not working memory, was also negatively related with the detection of, reaction to, and crashes with road hazards. Unexpectedly, increased cognitive control did not always relate to decreased risky driving. Visuospatial working-memory performance related positively with yellow-light running and negatively with the minimal following distance inside the city center. The findings evidence the role of cognitive control in explaining risky driving in young novice drivers. This relationship, however, differed per cognitive function and per driving parameter. Implications for future research and traffic safety interventions are discussed. PMID- 25529594 TI - Cognitive rehabilitation in a visual variant of Alzheimer's disease. AB - Alzheimer's disease (AD) is commonly associated with marked memory deficits; however, nonamnestic variants have been consistently described as well. Posterior cortical atrophy (PCA) is a progressive degenerative condition in which posterior regions of the brain are predominantly affected, therefore resulting in a pattern of distinctive and marked visuospatial symptoms, such as apraxia, alexia, and spatial neglect. Despite the growing number of studies on cognitive and neural bases of the visual variant of AD, intervention studies remain relatively sparse. Current pharmacological treatments offer modest efficacy. Also, there is a scarcity of complementary nonpharmacological interventions with only two previous studies of PCA. Here we describe a highly educated 57-year-old patient diagnosed with a visual variant of AD who participated in a cognitive intervention program (comprising reality orientation, cognitive stimulation, and cognitive training exercises). Neuropsychological assessment was performed across moments (baseline, postintervention, follow-up) and consisted mainly of verbal and visual memory. Baseline neuropsychological assessment showed deficits in perceptive and visual constructive abilities, learning and memory, and temporal orientation. After neuropsychological rehabilitation, we observed small improvements in the patient's cognitive functioning, namely in verbal memory, attention, and psychomotor abilities. This study shows evidence of small beneficial effects of cognitive intervention in PCA and is the first report of this approach with a highly educated patient in a moderate stage of the disease. Controlled studies are needed to assess the potential efficacy of cognition-focused approaches in these patients, and, if relevant, to grant their availability as a complementary therapy to pharmacological treatment and visual aids. PMID- 25529595 TI - Multiple asymptomatic colon plasmacytomas: a diagnostic and therapeutic dilemma. PMID- 25529582 TI - Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. AB - BACKGROUND: Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. METHODS: The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. FINDINGS: Around 80,000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. INTERPRETATION: Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. FUNDING: Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health. PMID- 25529596 TI - Amlodipine+benazepril is superior to hydrochlorothiazide+benazepril irrespective of baseline pulse pressure: subanalysis of the ACCOMPLISH trial. AB - Pulse pressure (PP) is an independent risk factor for cardiovascular (CV) disease and death but few studies have investigated the effect of antihypertensive treatments in relation to PP levels before treatment. The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed that the combination of benazepril+amlodipine (B+A) is superior to benazepril+hydrochlorothiazide (B+H) in reducing CV events. We aimed to investigate whether the treatment effects in the ACCOMPLISH trial were dependent on baseline PP. High-risk hypertensive patients (n=11,499) were randomized to double-blinded treatment with single-pill combinations of either B+A or B+H and followed for 36 months. Patients were divided into tertiles according to their baseline PP and events (CV mortality/myocardial infarction or stroke) were compared. Hazard ratios (HRs) for the treatment effect (B+A over B+H) were calculated in a Cox regression model with age, coronary artery disease, and diabetes mellitus as covariates and were compared across the tertiles. The event rate was increased in the high tertile of PP compared with the low tertile (7.2% vs 4.4% P<.01). In the high and medium PP tertiles, HRs were 0.75 (95% confidence interval [CI], 0.60-0.95; P=.018) and 0.74 (CI, 0.56-0.98, P=.034), respectively, in favor of B+A. There was no significant difference between the treatments in the low tertile and no significant differences in treatment effect when comparing the HRs between tertiles of PP. B+A has superior CV protection over B+H in high-risk hypertensive patients independent of baseline PP although the absolute treatment effect is enhanced in the higher tertiles of PP where event rates are higher. PMID- 25529603 TI - Analysis of P. gingivalis, T. forsythia and S. aureus levels in edentulous mouths prior to and 6 months after placement of one-piece zirconia and titanium implants. AB - BACKGROUND: It has been suggested that completely edentulous patients harbour fewer periodontopathic bacteria compared with dentate patients, due to the removal of the subgingival periodontal environment. However, reappearance of certain microbes has been reported after the placement of implants in these patients. AIM: The aim of this study was to determine whether the periodontopathic bacteria Porphyromonas gingivalis and Tannerella forsythia, as well as the non-periodontopathic bacterium, Staphylococcus aureus, emerged in edentulous patients 6 months after placement of one-piece zirconia and titanium implants. MATERIALS AND METHODS: Twenty-six patients were included in the study (titanium = 13, zirconia = 13). Microbial samples were collected from the tongue prior to implant placement and 6 months after implant placement from both the tongue and from around the implants. A qRT-PCR assay using SYBR green/ROX chemistry was used for the detection and quantification of rgp, nuc and karilysin single-copy gene of P. gingivalis, T. forsythia and S. aureus, respectively. Positive controls used in the study were pure bacterial gDNA purified from cultures of P. gingivalis and S. aureus, a cloned sequence of the karilysin gene for T. forsythia, a plaque sample positive for P. gingivalis and T. forsythia, and nasal gDNA for S. aureus. RESULTS: The results show that prior to implant placement, all three bacterial species were below the lower limit of quantification in all edentulous patients. The samples collected from the tongue and around the implants remained below the lower limit of quantification for each of the three species. However, all positive controls used in the study were detectable in the samples. qPCR standard curves showed correlation coefficients >0.97 and efficiencies >94.5% (slope range -3.19 to -3.46) for each of the SYBR green PCR assays. CONCLUSION: The results of this study indicate that the tested organisms did not emerge 6 months after implant placement irrespective of the nature of the implant biomaterial. A further follow-up of at least 2 years post implantation of these patients is suggested to determine whether there are any changes in the oral microbiota and whether such changes are associated with the development of peri-implant disease. PMID- 25529604 TI - MicroRNA-139-5p regulates C2C12 cell myogenesis through blocking Wnt/beta-catenin signaling pathway. AB - MicroRNAs (miRNAs) are novel and potent regulators in myogenesis. However, the molecular mechanisms that many miRNAs regulate myoblast proliferation and differentiation which are largely unknown. Here, we found that miR-139-5p increased during C2C12 myoblast proliferation, while presenting an inverse trend during C2C12 myoblast differentiation. Flow cytometry and EdU incorporation assay showed that miR-139-5p slowed down the growth of C2C12 cells. Additional study demonstrated that ectopic introduction of miR-139-5p into C2C12 cells blocked myoblast differentiation. Importantly, we demonstrated for the first time that Wnt1, which is associated with the Wnt/beta-catenin signaling pathway, was a direct target of miR-139-5p. Moreover, we found that the expression level of Wnt1 was suppressed significantly (p < 0.01) by miR-139-5p, which triggered inhibition of Wnt/beta-catenin signaling through upregulation of glycogen synthase kinase 3 beta (GSK-3beta; p < 0.05) and downregulation of p-GSK-3beta (p < 0.01), beta catenin (p < 0.05), and nuclear beta-catenin (p < 0.01). Taken together, these results suggest that miR-139-5p is an important negative regulator in myogenesis through blocking the Wnt1-mediated Wnt/beta-catenin signaling pathway. PMID- 25529605 TI - Caudal duplication syndrome. PMID- 25529606 TI - Practical route to the left wing of CTX1B and total syntheses of CTX1B and 54 deoxyCTX1B. AB - Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant sensitive bisallylic ether moiety, by a 6-exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B. PMID- 25529607 TI - A Cross-National Tool for Assessing and Studying Suicidal Behaviors. AB - Current methodologies employed in collecting data for suicide research present several limitations. In this article, we describe a novel method and tool to prospectively study suicidal behavior and its related risk and protective factors in different countries. This tool is a web-based database, which will initially be developed and piloted by suicide research groups from Austria, Brazil, Chile, France, Italy, Mexico, Spain, Sweden, and the US. The database will develop and integrate research tools key to collaboration, permit exploration of ethical considerations, and provide a universal interface in English, Spanish, French, Portuguese, Italian, and German that will make it possible to incorporate new groups from different countries to the network. The common database resulting of this cross-national effort will allow researchers to share and compare data across countries in a large sample of patients. Using anonymous electronic records of patients, we will: 1) determine the impact of risk and protective factors (viz. aggression and religious affiliation) in different socio-cultural environments; 2) develop a clinical model of suicidal behavior that integrates the multiple dimensions implicated; 3) try differentiating the effects of biological, environmental, and cultural factors on suicidal behavior, and 4) offer the global psychiatric research community a tool that will standardize assessment across nations, allowing for better generalization. PMID- 25529608 TI - Preconception care has the potential for a high return on investment. PMID- 25529609 TI - Novel diagnostic tests of ectopic pregnancy, if at first you don't succeed... PMID- 25529610 TI - Nonmedically indicated induction of labor: are the benefits worth the costs? PMID- 25529611 TI - Perhydroxylcucurbit[6]uril as a highly selective gas chromatographic stationary phase for analytes of wide-ranging polarity. AB - This work describes the separation performance of a perhydroxylcucurbit[6]uril stationary phase for capillary gas chromatography. The perhydroxylcucurbit[6]uril stationary phase exhibits higher resolving capabilities for critical analytes with better peak shapes than cucurbit[6]uril and conventional stationary phases. The advantageous separation feature of the perhydroxylcucurbit[6]uril stationary phase may originate from its unique structure and favorably balanced interactions with the analytes. Also, the perhydroxylcucurbit[6]uril column shows good separation repeatability with relative standard deviations in the range of 0.01 0.13% for intraday, 0.37-0.82% for interday, and 1.0-4.7% for column-to-column repeatability. PMID- 25529613 TI - A New Version of the Impairment and Functioning Inventory for Patients With Chronic Pain (IFI-R). AB - BACKGROUND: Few instruments are available that have adequate psychometric properties for assessing daily functioning in patients with musculoskeletal pain. In addition, none of these instruments assesses the perceived decrease in levels of daily activities after the onset of pain. OBJECTIVE: To review the psychometric qualities of the Impairment and Functioning Inventory (IFI) for patients with chronic pain. DESIGN: Cross-sectional study. SETTING: Four public primary care centers and a public pain clinic. PATIENTS: A total of 483 patients with back pain who were treated at primary care centers and 137 patients with various pain conditions who were treated at a pain clinic. METHODS: To analyze factorial validity, a confirmatory factor analysis was performed via structural equation modeling. To measure internal consistency, Cronbach's alpha coefficients were calculated. To assess convergent validity, Pearson correlation coefficients were computed between the 2 scales of the IFI and the measures of the Roland Morris Questionnaire. Criterion validity and generalizability were analyzed by regression analysis via structural equation modeling using the LISREL 8.30 software package. MAIN OUTCOME MEASURES: The IFI for patients with chronic pain. RESULTS: A revised version of the IFI (IFI-R) is presented that consists of 30 items with 2 related subscales: Daily Functioning and Impairment (perceived current level of functioning compared with the level of functioning before pain onset). Both subscales were significantly correlated with disability. Depression, pain intensity, and pain anxiety had a negative association with functioning and a positive association with impairment. On the other hand, pain catastrophizing had a negative association with functioning and pain hypervigilance had a positive association with impairment due to pain. CONCLUSIONS: The IFI-R appears to be a valid and reliable measurement tool for the assessment of perceived daily functioning and impairment in people with chronic pain. PMID- 25529614 TI - Prevention of Pressure Ulcers Among People With Spinal Cord Injury: A Systematic Review. AB - OBJECTIVES: To evaluate the literature on the effectiveness of bed and wheelchair positioning and repositioning in the prevention of pressure ulcers (PUs) in both the spinal cord injury (SCI) and non-SCI populations. DESIGN: Systematic review. METHODS: PubMed, CINAHL, PsycINFO, and EMBASE were queried with the subject heading terms "pressure sore," "pressure ulcer," "position or turn in bed, wheelchair," "pressure relief," and "pressure release." All study design types that assessed the effectiveness of bed and wheelchair positioning and pressure relief maneuvers in any patient group and in any setting were sought. Three independent reviewers extracted and summarized details of eligible trials using a standardized method. Two independent reviewers assessed the methodological quality of each trial using the American Academy of Neurology guidelines. When reviewers were not able to reach consensus, a third independent reviewer served as tiebreaker. RESULTS: We identified 2820 publications, of which 49 met inclusion criteria. Of these publications, the subject population was 2834 (923 persons with SCI, 717 persons without SCI, and 1194 healthy control subjects). Among studies examining pressure related to position or repositioning in bed or sitting, procedures for measuring skin pressure and metabolism were highly variable by anatomic location, measurement technique, outcome measure, study site, participant characteristics, and description of position/turning for bed and seated interventions. Numerous factors can influence tissue interface pressures, and no prospective studies had been performed to determine a causal relationship between interface pressure and skin breakdown. Several studies suggest that skin response to pressure differs between subjects with and without SCI. Conflicting results and insufficient evidence for optimal bed and seated positioning and turning and pressure relief maneuvers to prevent PUs in both SCI and non-SCI populations were limiting factors. CONCLUSIONS: Although there is no clear optimal positioning or turning frequency in bed, the evidence suggests avoiding the 90 degrees lateral position because of high pressures and PU risk over the trochanters. During sitting, pressures are linearly redistributed from the sitting area during recline and tilt; however, reclining carries with it an increased risk of shear forces on this skin. The evidence does not support conclusive guidelines on positioning or repositioning techniques for PU prevention in bed or during sitting. We conclude that PU risk is highly individualized, with the SCI population at a higher risk, which demands flexible PU prevention strategies for bed/seated positioning and pressure relief maneuvers. Education has and will remain our most powerful ally to thwart this pervasive public health problem. PMID- 25529615 TI - Cancer survivorship: a growing role for physiatric care. PMID- 25529612 TI - The role of nuclear hormone receptors in cutaneous wound repair. AB - The cutaneous wound repair process involves balancing a dynamic series of events ranging from inflammation, oxidative stress, cell migration, proliferation, survival and differentiation. A complex series of secreted trophic factors, cytokines, surface and intracellular proteins are expressed in a temporospatial manner to restore skin integrity after wounding. Impaired initiation, maintenance or termination of the tissue repair processes can lead to perturbed healing, necrosis, fibrosis or even cancer. Nuclear hormone receptors (NHRs) in the cutaneous environment regulate tissue repair processes such as fibroplasia and angiogenesis. Defects in functional NHRs and their ligands are associated with the clinical phenotypes of chronic non-healing wounds and skin endocrine disorders. The functional relationship between NHRs and skin niche cells such as epidermal keratinocytes and dermal fibroblasts is pivotal for successful wound closure and permanent repair. The aim of this review is to delineate the cutaneous effects and cross-talk of various nuclear receptors upon injury towards functional tissue restoration. PMID- 25529616 TI - Quantitative ethnomedicinal study of plants used in the Nelliyampathy hills of Kerala, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Inspite of tremendous advances made in allopathic medical practices, medicinal plants have played an important role throughout the world in treating and preventing a variety of diseases and hence there is urgency in recording such data. This is the first ethnobotanical study in which statistical calculations about plants are done by the Pearson correlation coefficient (PCC) method. The present study was aimed to identify plants collected for medicinal purposes by the traditional healers of Nelliyampathy hills, located in Palakkad district of Kerala, India and to document the traditional names, preparation and uses of these plants. METHODS: The field study was carried out over a period of 2 years (2011-2013) using semi-structured interviews with 66 informants (most of the informants belonged to an age between 50 and 70 years) in six remote locations in the hills. Ethnomedicinal data was analyzed using frequency citation (FC), relative frequency of citation (RFC) and use value (UV) along with a Pearson correlation coefficient (PCC). Demographic characteristics of participants, ethnobotanical inventory of plants and data on medicinal application and administration were recorded. RESULTS: A total of 85 medicinal plants belonging to 49 families were reported to be used against 19 different ailments in the hills. The maximum reported medicinal plant families were Cucurbitaceae with 6 species followed by Acanthaceae, Malvaceae and Fabaceae (each 5 species), Asteraceae, Lamiaceae, Moraceae and Myrtaceae (each 3 species), the most dominant life form of the species includes herbs (42) followed by tree (20), climber (15) and shrub (8), the most frequent used part was leaves (40%) followed by root (14%), seed and flowers (each12%), fruit (9%), bark (7%), stem (2%), latex (2%), rhizome and whole plant (each 1%), the most common preparation and administration methods were paste (32%), powder (22%), decoction and juice (each 20%) and raw (4%), infusion and inhalation (each1% ). The Pearson correlation coefficient between RFC and UV was 0.638 showing highly positive significant association. CONCLUSIONS: In this study, we have documented considerable indigenous knowledge about the native medicinal plants in Nelliyampathy hills for treating common ailments. The plants such as further investigated phytochemically and pharmacologically which leads to natural drug discovery development may be based on the present study. The study has various socioeconomic dimensions which are associated with the local communities. PMID- 25529617 TI - Traditional local medicines in the republic of Palau and non-communicable diseases (NCD), signs of effectiveness. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of this survey was to describe which traditional medicines (TM) are most commonly used for non-communicable diseases (NCD - diabetes, hypertension related to excess weight and obesity) in Pacific islands and with what perceived effectiveness. NCD, especially prevalent in the Pacific, have been subject to many public health interventions, often with rather disappointing results. Innovative interventions are required; one hypothesis is that some local, traditional approaches may have been overlooked. MATERIALS AND METHODS: The method used was a retrospective treatment-outcome study in a nation wide representative sample of the adult population (about 15,000 individuals) of the Republic of Palau, an archipelago of Micronesia. RESULTS: From 188 respondents (61% female, age 16-87, median 48,), 30 different plants were used, mostly self-prepared (69%), or from a traditional healer (18%). For excess weight, when comparing the two most frequent plants, Morinda citrifolia L. was associated with more adequate outcome than Phaleria nishidae Kaneh. (P=0.05). In case of diabetes, when comparing Phaleria nishidae (=Phaleria nisidai) and Morinda citrifolia, the former was statistically more often associated with the reported outcome "lower blood sugar" (P=0.01). CONCLUSIONS: Statistical association between a plant used and reported outcome is not a proof of effectiveness or safety, but it can help select plants of interest for further studies, e.g. through a reverse pharmacology process, in search of local products which may have a positive impact on population health. PMID- 25529618 TI - Secondhand smoke exposure among never-smoking youth in 168 countries. AB - PURPOSE: To estimate the prevalence of secondhand smoke (SHS) exposure among never-smoking adolescents and identify key factors associated with such exposure. METHODS: Data were obtained from nationally representative Global Youth Tobacco Surveys conducted in 168 countries during 1999-2008. SHS exposure was ascertained in relation to the location-exposure inside home, outside home, and both inside and outside home, respectively. Independent variables included parental and/or peer smoking, knowledge about smoke harm, attitudes toward smoking ban, age, sex, and World Health Organization region. Simple and multiple logistic regression analyses were conducted. RESULTS: Of 356,414 never-smoking adolescents included in the study, 30.4%, 44.2%, and 23.2% were exposed to SHS inside home, outside home, and both, respectively. Parental smoking, peer smoking, knowledge about smoke harm, and positive attitudes toward smoke ban were significantly associated with increased odds of SHS exposure. Approximately 14% of adolescents had both smoking parents and peers. Compared with never-smoking adolescents who did not have both smoking parents and peers, those who had both smoking parents and peers had 19 (adjusted odds ratio [aOR], 19.0; 95% confidence interval [CI], 16.86 21.41), eight (aOR, 7.71; 95% CI, 7.05-8.43), and 23 times (aOR, 23.16; 95% CI, 20.74-25.87) higher odds of exposure to SHS inside, outside, and both inside and outcome home, respectively. CONCLUSIONS: Approximately one third and two fifths of never-smoking adolescents were exposed to SHS inside or outside home, and smoking parents and/or peers are the key factors. Study findings highlight the need to develop and implement comprehensive smoke-free policies consistent with the World Health Organization Framework Convention on Tobacco Control. PMID- 25529619 TI - Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring. AB - BACKGROUND & AIMS: During pregnancy, acetaminophen is one of the very few medications recommended by physicians to treat fever or pain. Recent insights from epidemiological studies suggest an association between prenatal acetaminophen medication and an increased risk for development of asthma in children later in life. The underlying pathogenesis of such association is still unknown. METHODS: We aimed to develop a mouse model to provide insights into the effect of prenatal acetaminophen on maternal, fetal and adult offspring's health. The toxic effect of acetaminophen was studied in mice on 1) maternal liver; mirrored by biomarkers of liver injury, centrilobular necrosis, and infiltration of granulocytes; 2) fetal liver; reflected by the frequency of hematopoietic stem cells, and 3) postnatal health; evaluated by the severity of allergic airway inflammation among offspring. RESULTS: We observed an increased susceptibility towards acetaminophen-induced liver damage in pregnant mice compared to virgins. Moreover, hematopoietic stem cell frequency in fetal liver declined in response to acetaminophen. Furthermore, a greater severity of airway inflammation was observed in offspring of dams upon prenatal acetaminophen treatment, identified lung infiltration by leukocytes and eosinophil infiltration into the airways. CONCLUSION: Our newly developed mouse model on prenatal use of acetaminophen reflects findings from epidemiological studies in humans. The availability of this model will allow improvement in our understanding of how acetaminophen related hepatotoxicity is operational in pregnant individuals and how an increased risk for allergic diseases in response to prenatal acetaminophen is mediated. Such insights, once available, may change the recommendations for prenatal acetaminophen use. PMID- 25529620 TI - Solutions to the discrepancies in the extent of liver damage following ischemia/reperfusion in standard mouse models. PMID- 25529621 TI - Development and validation of a polycystic liver disease complaint-specific assessment (POLCA) - use of the Delphi technique for content validation. PMID- 25529622 TI - Liver resection for hepatocellular carcinoma in 313 Western patients: tumor biology and underlying liver rather than tumor size drive prognosis. AB - BACKGROUND & AIMS: Treatment decisions for hepatocellular carcinoma are mostly guided by tumor size. The aim of this study was to analyze resection outcomes according to tumor size and characterize prognostic factors. METHODS: Patients resected at a Western center between 1989 and 2010 were grouped by largest tumor size: <50mm, 50-100mm, and >100mm. The primary end points were overall- and recurrence-free survival. Univariate associations with primary endpoints were entered into a Cox proportional hazard regression model. RESULTS: Three hundred thirteen patients underwent resection: 111 (36%) had tumors <50mm, 113 (36%) had tumors between 50 and 100mm, and 89 (28%) had tumors >100mm. Five-year overall and disease-free survival rates for the three groups were 67%, 46%, and 34%, and 32%, 27%, and 27%, respectively. Thirty-five patients, mostly from <50mm group, underwent transplantation which was associated with a 91% 5 year survival rate. Tumor size was not an independent predictor of overall or recurrence-free survival on multivariate analyses. Independent predictors of decreased overall survival were: intraoperative transfusion (HR=2.60), cirrhosis (HR=2.42), poorly differentiated tumor (HR=2.04), satellite lesions (HR=1.69), alpha-fetoprotein >200 (HR=1.53), and microvascular invasion (HR=1.48). The use of salvage transplantation was an independent predictor of improved survival (HR=0.21). Recurrence-free survival was predicted by intraoperative transfusion (HR=2.15), poorly differentiated tumor (HR=1.87), microvascular invasion (HR=1.71) and cirrhosis (HR=1.69). CONCLUSION: By studying a large group of patients across a distribution of tumor sizes and background liver diseases, it is demonstrated that size alone is a limited prognostic factor. Tumor biology and condition of the underlying liver are better prognosticators and should be given closer attention. Although hampered by recurrence rates, resection is safe and offers good overall survival. In addition, it may allow for better selection for salvage transplantation after consideration of histopathological risk factors. PMID- 25529623 TI - Non-hypervascular hepatobiliary phase hypointense nodules on gadoxetic acid enhanced MRI: risk of HCC recurrence after radiofrequency ablation. AB - BACKGROUND & AIMS: Hepatobiliary phase images (HBPI) of gadoxetic acid-enhanced MRI can depict borderline hepatocellular nodules that have the potential to progress into hypervascular hepatocellular carcinomas (HCCs), as non hypervascular hypointense nodules. We retrospectively evaluated the impact of the presence of non-hypervascular hypointense nodules at HBPI of gadoxetic acid enhanced MRI on the patient's prognosis after radiofrequency ablation (RFA) for early stage HCCs. METHODS: A total of 139 patients who underwent pre-procedural gadoxetic acid-enhanced MRI followed by RFA were included. After a mean follow-up of 44.6+/-13.2 months, we compared the results of tumor recurrence as well as overall and recurrence-free survival (RFS) with the presence of non-hypervascular hypointense nodules on HBPI. RESULTS: The presence of non-hypervascular hypointense nodules on HBPI did not affect overall survival (p=0.136). However, the estimated 5-year RFS rate was 71.3% in 29 patients without non-hypervascular hypointense nodules on HBPI compared to 27.9% in 110 patients with non hypervascular hypointense nodules on HBPI, indicating a significant difference (hazard ratio=2.84 [1.39-5.98], p=0.006). When we classified recurrence into local tumor progression [LTP], intrahepatic distant recurrence [IDR], and extra hepatic metastasis [EM], five-year cumulative incidences (CI) of IDR in patients with non-hypervascular hypointense nodules on HBPI were significantly higher than those in patients without non-hypervascular hypointense nodules on HBPI (17.9% vs. 67.5%, p<0.001). Five-year CIs of LTP and EM showed no significant difference (p>0.05). CONCLUSIONS: The presence of non-hypervascular hypointense hepatocellular nodules on HBPI of gadoxetic acid-enhanced MRI taken prior to RFA is a significant predictive factor of recurrence after RFA of early stage HCCs, particularly IDR. PMID- 25529624 TI - Reply to: "Chronic kidney disease (CKD) and NAFLD: time for awareness and screening". PMID- 25529625 TI - Reply to: "Development and validation of a polycystic liver disease complaint specific assessment (POLCA) - use of the Delphi technique for content validation". PMID- 25529626 TI - Optimal methods for measuring eligibility for liver transplant in hepatocellular carcinoma patients undergoing transarterial chemoembolization. AB - BACKGROUND & AIMS: We investigated the optimal radiologic method for measuring hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) in order to assess suitability for liver transplantation (LT). METHODS: 271 HCC patients undergoing TACE prior to LT were classified according to both Milan and up-to-seven criteria after TACE by using the enhancement or size method on computed tomography images. The cumulative incidence function curves with competing risks regression was used in post-LT time-to-recurrence analysis. The predictive accuracy for recurrence was compared using area under the time dependent receiver operating characteristic curves (AUC) estimation. RESULTS: Of the 271 patients, 246 (90.8%) and 164 (60.5%) fell within Milan and 252 (93.0%) and 210 (77.5%) fell within up-to-seven criteria, when assessed by enhancement and size methods, respectively. Competing risks regression analyses adjusting for covariates indicated that meeting the criteria by enhancement and by size methods was independently related to post-LT time-to-recurrence in the Milan or up-to seven model. Higher AUC values were observed with the size method only in the up to-seven model (p<0.05). Mean differences in the sum of tumor diameter and number of tumors between pathologic and radiologic findings were significantly less by the enhancement method (p<0.05). Cumulative incidence curves showed similar recurrence results between patients with and without prior TACE within the criteria based on either method, except for the within up-to-seven by the enhancement method (p=0.017). CONCLUSIONS: The enhancement method is a reliable tool for assessing the control or downstaging of HCC within Milan after TACE, although the size method may be preferable when applying the up-to-seven criterion. PMID- 25529627 TI - Chronic kidney disease (CKD) and NAFLD: time for awareness and screening. PMID- 25529629 TI - Emergent use of Impella CPTM during transcatheter aortic valve replacement: Transaortic access. AB - Sudden onset of hypotension is a rare but emergent event in patients undergoing transcatheter aortic valve replacement (TAVR). This primarily occurs due to coronary artery obstruction, valve misplacement/migration, ventricular perforation, cardiac tamponade, severe paravalvular regurgitation, stunned myocardium, ventricular arrhythmia, and annulus rupture. While the operator makes an attempt to identify and correct the underlying problem, an emergent placement of mechanical hemodynamic assist device may be necessary and crucial for a successful outcome. We describe a unique and challenging case of complete circulatory collapse in a patient undergoing transaortic TAVR with Edwards SAPIEN prosthesis (Edwards Lifesciences, CA) who required rescue Impella CPTM (Abiomed, Danvers, MA) placement directly through the ascending aorta due to unfavorable femoral access. PMID- 25529628 TI - MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway. AB - Growth plate chondrocytes go through multiple differentiation steps and eventually become hypertrophic chondrocytes. The parathyroid hormone (PTH) related peptide (PTHrP) signaling pathway plays a central role in regulation of hypertrophic differentiation, at least in part, through enhancing activity of histone deacetylase 4 (HDAC4), a negative regulator of MEF2 transcription factors that drive hypertrophy. We have previously shown that loss of the chondrocyte specific microRNA (miRNA), miR-140, alters chondrocyte differentiation including mild acceleration of hypertrophic differentiation. Here, we provide evidence that miR-140 interacts with the PTHrP-HDAC4 pathway to control chondrocyte differentiation. Heterozygosity of PTHrP or HDAC4 substantially impaired animal growth in miR-140 deficiency, whereas these mutations had no effect in the presence of miR-140. miR-140-deficient chondrocytes showed increased MEF2C expression with normal levels of total and phosphorylated HDAC4, indicating that the miR-140 pathway merges with the PTHrP-HDAC4 pathway at the level of MEF2C. miR-140 negatively regulated p38 mitogen-activated protein kinase (MAPK) signaling, and inhibition of p38 MAPK signaling reduced MEF2C expression. These results demonstrate that miR-140 ensures the robustness of the PTHrP/HDAC4 regulatory system by suppressing MEF2C-inducing stimuli. (c) 2014 American Society for Bone and Mineral Research (c) 2015 American Society for Bone and Mineral Research. PMID- 25529630 TI - A novel analytical brain block tool to enable functional annotation of discriminatory transcript biomarkers among discrete regions of the fronto-limbic circuit in primate brain. AB - Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these circuits are associated with many important psychiatric and neurological disorders. While high quality gene expression profiles can be identified in brains from model organisms, primate brains have unique features such as Brodmann Area 25, which is absent in rodents, yet profoundly important in primates, including humans. The potential insights to be gained from studying the human brain are complicated by the fact that the post-mortem interval (PMI) is variable, and most repositories keep solid tissue in the deep frozen state. Consequently, sampling the important medial and internal regions of these brains is difficult. Here we describe a novel method for obtaining discrete regions from the fronto-limbic circuits of a 4 year old and a 5 year old, male, intact, frozen non-human primate (NHP) brain, for which the PMI is exactly known. The method also preserves high quality RNA, from which we use transcriptional profiling and a new algorithm to identify region-exclusive RNA signatures for Area 25 (NFkappaB and dopamine receptor signaling), the anterior cingulate cortex (LXR/RXR signaling), the amygdala (semaphorin signaling), and the hippocampus (Ca(++) and retinoic acid signaling). The RNA signatures not only reflect function of the different regions, but also include highly expressed RNAs for which function is either poorly understood, or which generate proteins presently lacking annotated functions. We suggest that this new approach will provide a useful strategy for identifying changes in fronto-limbic system biology underlying normal development, aging and disease in the human brain. PMID- 25529631 TI - Hypothalamic, feeding/arousal-related peptidergic projections to the paraventricular thalamic nucleus in the rat. AB - Based on the importance of paraventricular thalamic nucleus (PVT) as a relay station of energy balance, arousal, and food reward, we aimed in the present study to determine projection patterns of neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and orexin (ORX)-ergic fibers to the PVT. First, the distribution of peptidergic axon terminals within the PVT was examined. NPY and CART terminals were confined within the boundary of the thalamic nucleus, exhibiting almost identical distribution. MCH terminals were rarely observed. In contrast, ORX terminals were as extensive as NPY/CART terminals, but spread into the peri-PVT region. Second, neuronal origin of feeding/arousal-related peptides projecting to the PVT was investigated. NPY neurons were observed in the medial subdivision of the arcuate nucleus (Arc), whereas CART cells were in the lateral Arc as well as other hypothalamic regions including the paraventricular hypothalamic nucleus, lateral hypothalamus (LH), dorsal hypothalamic area, and zona incerta. Both NPY- and CART fiber projections to the PVT were bilateral; ipsilateral proportion was 54.0% +/- 3.6% (n = 6) for NPY and 57.1% +/- 2.5% (n = 6) for CART. The total number of CART neurons projecting to the PVT exceeded that of NPY cells; the ratio of labeled CART neurons to NPY cells was 2.4 +/- 0.2 (n = 6). In contrast, ORX-ergic fiber projection to the PVT exhibited a slight ipsilateral dominance (62.7% +/- 1.6%, n = 6), with majority of labeled cells located in the LH medial to the fornix (72.2% +/- 2.3%, n = 6). Third, based on heavy projection from the PVT to the nucleus accumbens shell (NAcSh), the convergence of NPY and CART terminals on a single PVT neuron was identified; the proportion of labeled PVT neurons that received converging NPY/CART terminals compared with the total PVT neurons projecting to the NAcSh was 2.7% +/- 0.6% (n = 3). Finally, PVT cells receiving NPY, CART, or ORX terminals provided divergent axon collaterals to NAcSh and medial prefrontal cortex. The present observations provided the anatomical evidence that the PVT might play an essential role in the integration of antagonistically-acting, feeding/arousal-related peptidergic inputs on their way to the cortical reward circuit. PMID- 25529633 TI - Toward biosensors for the detection of circulating microRNA as a cancer biomarker: an overview of the challenges and successes. AB - Considerable attention has been dedicated to developing feasible point-of-care tests for cancer diagnosis and prognosis. An ideal biomarker for clinical use should be easily assayed with minimally invasive medical procedures but possess high sensitivity and specificity. The role of microRNAs (miRNAs) in the regulation of different cellular processes, the unique altered patterns in cancer patients and presence in body fluids in the stable form, points to their clinical utility as blood-based biomarkers for diagnosis, prognosis, and treatment of cancer. Although a variety of selective and sensitive laboratory-based methods are already exist for the detection of circulating miRNA, having a simple, low cost and rapid assay, which could be routinely used in clinical practice, is still required. Among different approaches that have developed for circulating miRNA detection, biosensors, due to the high sensitivity, ease of use, short assay time, non-toxic experimental steps, and adaptability to point-of-care testing, exhibit very attractive properties for developing portable devices. With this view, we present an overview of some of the challenges that still need to be met to be able to use circulating miRNAs in clinical practice, including their clinical significance, sample preparation, and detection. In particular, we highlight the recent advances in the rapidly developing area of biosensors for circulating miRNA detection, along with future prospects and challenges. PMID- 25529634 TI - Bed bug aggregation pheromone finally identified. AB - Bed bugs have become a global epidemic and current detection tools are poorly suited for routine surveillance. Despite intense research on bed bug aggregation behavior and the aggregation pheromone, which could be used as a chemical lure, the complete composition of this pheromone has thus far proven elusive. Here, we report that the bed bug aggregation pheromone comprises five volatile components (dimethyl disulfide, dimethyl trisulfide, (E)-2-hexenal, (E)-2-octenal, 2 hexanone), which attract bed bugs to safe shelters, and one less-volatile component (histamine), which causes their arrestment upon contact. In infested premises, a blend of all six components is highly effective at luring bed bugs into traps. The trapping of juvenile and adult bed bugs, with or without recent blood meals, provides strong evidence that this unique pheromone bait could become an effective and inexpensive tool for bed bug detection and potentially their control. PMID- 25529632 TI - Differential roles of medial prefrontal subregions in the regulation of drug seeking. AB - The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction. This dichotomy of mPFC function may be a general attribute, as similar dorsal ventral distinctions exist for expression vs. extinction of fear conditioning. However, other results indicate that the role of mPFC neurons in reward processing is more complex than a simple PL-seek vs. IL-extinguish dichotomy. Both PL and IL have been shown to drive and inhibit drug seeking (and other types of behaviors) depending on a range of factors including the behavioral context, the drug-history of the animal, and the type of drug investigated. This heterogeneity of findings may reflect multiple subcircuits within each of these PFC areas supporting unique functions. It may also reflect the fact that the mPFC plays a multifaceted role in shaping cognition and behavior, including those overlapping with cocaine seeking and extinction. Here we discuss research leading to the hypothesis that dorsal and ventral mPFC differentially control drug seeking and extinction. We also present recent results calling the absolute nature of a PL vs. IL dichotomy into question. Finally, we consider alternate functions for mPFC that correspond less to response execution and inhibition and instead incorporate the complex cognitive behavior for which the mPFC is broadly appreciated. PMID- 25529638 TI - Heterobimetallic complexes of rhodium dibenzotetramethylaza[14]annulene [(tmtaa)Rh-M]: formation, structures, and bond dissociation energetics. AB - A rhodium(II) dibenzotetramethylaza[14]annulene dimer ([(tmtaa)Rh]2) undergoes metathesis reactions with [CpCr(CO)3]2, [CpMo(CO)3]2, [CpFe(CO)2]2, [Co(CO)4]2, and [Mn(CO)5]2 to form (tmtaa)Rh-M complexes (M = CrCp(CO)3, MoCp(CO)3, FeCp(CO)2, Co(CO)4, or Mn(CO)5). Molecular structures were determined for (tmtaa)Rh-FeCp(CO)2, (tmtaa)Rh-Co(MU-CO)(CO)3, and (tmtaa)Rh-Mn(CO)5 by X-ray diffraction. Equilibrium constants measured for the metathesis reactions permit the estimation of several (tmtaa)Rh-M bond dissociation enthalpies (Rh-Cr = 19 kcal mol(-1), Rh-Mo = 25 kcal mol(-1), and Rh-Fe = 27 kcal mol(-1)). Reactivities of the bimetallic complexes with synthesis gas to form (tmtaa)Rh-C(O)H and M-H are surveyed. PMID- 25529636 TI - The genetic ancestry of African Americans, Latinos, and European Americans across the United States. AB - Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical events, such as early Spanish colonization, waves of immigration from many regions of Europe, and forced relocation of Native Americans within the US. This study sheds light on the fine-scale differences in ancestry within and across the United States and informs our understanding of the relationship between racial and ethnic identities and genetic ancestry. PMID- 25529637 TI - Connexin expression in human acute myeloid leukemia cells: identification of patient subsets based on protein and global gene expression profiles. AB - Bone marrow stromal cells support both normal and malignant hematopoiesis. Tauhis support is mediated through the local cytokine network and by direct cell-cell interactions mediated via adhesion molecules and the formation of gap junctions by connexins. Previous studies on connexins in human acute myeloid leukemia (AML) have mainly focused on the investigation of leukemia cell lines. In the present study, we therefore investigated the expression of various connexins at the protein (i.e., cell surface expression) and mRNA level in primary human AML cells. The cell surface expression of the connexins, Cx26, Cx32, Cx37, Cx43 and Cx45, varied considerably between patients, and detectable levels were observed only for subsets of patients. On the whole, Cx43 and Cx45 showed the highest cell surface expression. Connexin expression was dependent on AML cell differentiation, but showed no association with cytogenetic abnormalities or mutations of the fms-related tyrosine kinase 3 (FLT3) or nucleophosmin (NPM)-1 genes. By contrast, only Cx45 showed a significant variation between patients at the mRNA level. A high Cx45 expression was associated with the altered regulation of the mitogen-activated protein kinase (MAPK) pathway and the release of pro inflammatory cytokines [interleukin (IL)-17, tumor necrosis factor (TNF), interferon-gamma], whereas a low Cx45 expression was associated with the altered regulation of protein functions (i.e., ligase activity, protein folding and catabolism). There was no significant correlation observed between the connexin mRNA and protein levels. Thus, differences in connexin expression can be used to subclassify AML patients. Differences in connexin cell surface expression profiles are not reflected at the mRNA level and have to be directly examined, whereas variations in Cx45 mRNA expression are associated with differences in cell signaling and the regulation of protein functions. PMID- 25529640 TI - Phantom pain in a patient with brachial plexus avulsion injury. AB - OBJECTIVE: Phantom limb pain is a painful sensation perceived in the absent limb following surgical or traumatic amputation. Phantom limb sensations, which are nonpainful, occur in nearly all amputees. Deafferentation can also produce similar symptoms. Here we report the presence of phantom pain in a deafferented limb. DESIGN: Case report. SETTING: Hospital-based outpatient clinic. PATIENT: A 65-year-old man was referred to the pain clinic for management of upper extremity pain secondary to brachial plexus avulsion (BPA) following a motor vehicle accident. Initially he noticed a feeling of growing and shrinking of his arm. Following this, the pain started gradually from his elbow extending to his fingertips covering all dermatomes. He described the pain as continuous, severe, and sharp. He also described the arm as being separate from his existing insensate arm and felt as though the fist was closed with the thumb pointing out. On physical examination, he had no sensation to fine touch or pressure below the elbow. There were no consistent areas of allodynia. He had diffuse muscle wasting in all the muscle groups of his left upper extremity, besides winging of the scapula. Electrodiagnostic studies showed a left brachial plexopathy consistent with multilevel nerve root avulsion sparing the dorsal rami. CONCLUSION: This is a report of phantom limb sensations and phantom pain following BPA in an intact but flaccid and insensate limb. PMID- 25529639 TI - Tularemia in children, Turkey, September 2009-November 2012. AB - Tularemia, a zoonotic disease caused by Francisella tularensis, is found throughout most of the Northern Hemisphere. It is not well known and is often misdiagnosed in children. Our aim with this study was to evaluate the diagnosis, treatment, and prognosis for 100 children with tularemia in Turkey. The mean patient age was 10.1 +/- 3.5 years (range 3-18 years), and most (63%) patients were male. The most common physical signs and laboratory findings were cervical lymphadenopathy (92%) and elevated erythrocyte sedimentation rate (89%). Treatment response was higher and rate of relapse lower for children 5-10 years of age than for those in other age groups. Associated with treatment failure were female sex, treatment delay of >=16 days, and use of doxycycline. Tularemia is endemic to Turkey, and the number of cases has been increasing among children as well as adults. PMID- 25529641 TI - Localisation of luminal epithelium edge in digital histopathology images of IHC stained slides of endometrial biopsies. AB - Diagnosis of recurrent miscarriage due to abnormally high number of uterine natural killer (uNK) cells has recently been made possible by a protocol devised by Quenby et al. Hum Reprod 2009;24(1):45-54. The diagnosis involves detection and counting of stromal and uNK cell nuclei in endometrial biopsy slides immunohistochemically stained with haematoxylin for staining cell nuclei and CD56 as a marker for the uNK cells. However, manual diagnosis is a laborious process, fraught with subjective errors. In this paper, we present a novel method for detection of uterine natural killer (uNK) cells in the human female uterus lining and localisation of the luminal epithelium edge in endometrial biopsies. Specifically, we employ a local phase symmetry based method to detect stromal cell nuclei and propose an adaptive background removal method that significantly eases the segmentation of uNK cell nuclei regions. We also propose a novel method using alpha shapes for the identification of epithelial cell nuclei and B-Spline curve fitting on identified cell nuclei to localise the luminal epithelium edge. The objective of edge localisation is to avoid cell nuclei near the luminal epithelium edge being counted in the diagnosis process due to their non-relevance to the calculation of stromal to uNK cell ratio that determines the diagnosis of recurrent miscarriages in the end. The resulting algorithm offers a promising potential for computer-assisted diagnosis of recurrent miscarriage due to its high accuracy. PMID- 25529642 TI - The dry-heat loss effect of melt-spun phase change material fibres. AB - Phase change materials (PCM) have the ability to store latent heat when they change phases, a property that gives clothing that incorporates PCM its cooling effect. This study investigated the effect of dry-heat loss (cooling) of a novel melt-spun PCM fibre on the basis of the area covered, mass, the latent heat of fusion and melting temperature, compared to a known PCM clothing product. PCM fibres with melting temperatures of 28.4 and 32.0 degrees C and PCM packs with melting temperatures of 28.0 and 32.0 degrees C were studied. The results showed that the PCM fibres had a larger initial peak cooling effect than that of the PCM packs. The duration of the cooling effect of PCM fibres was primarily dependent on the PCM mass and the latent heat of fusion capacity, and secondly on the covered area and melting temperature of the PCM. PRACTITIONER SUMMARY: This study investigates the cooling effect of PCM fibres on a thermal manikin. The PCM fibres had a high but short-lasting cooling effect. This study contributes to the knowledge of how the body's temperature regulation may be affected by the cooling properties of clothing that incorporates PCM. PMID- 25529643 TI - Occlusion therapy improves phase-alignment of the cortical response in amblyopia. AB - The visual evoked potential (VEP) generated by the amblyopic visual system demonstrates reduced amplitude, prolonged latency, and increased variation in response timing (phase-misalignment). This study examined VEPs before and after occlusion therapy (OT) and whether phase-misalignment can account for the amblyopic VEP deficits. VEPs were recorded to 0.5-4cycles/degree gratings in 10 amblyopic children (2-6years age) before and after OT. Phase-misalignment was measured by Fourier analysis across a limited bandwidth. Signal-to-noise ratios (SNRs) were estimated from amplitude and phase synchrony in the Fourier domain. Responses were compared to VEPs corrected for phase-misalignment (individual epochs shifted in time to correct for the misalignment). Before OT, amblyopic eyes (AE) had significantly more phase-misalignment, latency prolongation, and lower SNR relative to the fellow eye. Phase-misalignment contributed significantly to low SNR but less so to latency delay in the AE. After OT, phase alignment improved, SNR improved and latency shortened in the AE. Raw averaged waveforms from the AE improved after OT, primarily at higher spatial frequencies. Correcting for phase-misalignment in the AE sharpened VEP peak responses primarily at low spatial frequencies, but could not account for VEP waveform improvements in the AE after OT at higher spatial frequencies. In summary, VEP abnormalities from the AE are associated with phase-misalignment and reduced SNR possibly related to desynchronization of neuronal activity. The effect of OT on VEP responses is greater than that accounted for by phase-misalignment and SNR alone. PMID- 25529644 TI - Rapid detection of whey in milk powder samples by spectrophotometric and multivariate calibration. AB - A rapid method for the detection and quantification of the adulteration of milk powder by the addition of whey was assessed by measuring glycomacropeptide protein using mid-infrared spectroscopy (MIR). Fluid milk samples were dried and then spiked with different concentrations of GMP and whey. Calibration models were developed using multivariate techniques, from spectral data. For the principal component analysis and discriminant analysis, excellent percentages of correct classification were achieved in accordance with the increase in the proportion of whey samples. For partial least squares regression analysis, the correlation coefficient (r) and root mean square error of prediction (RMSEP) in the best model were 0.9885 and 1.17, respectively. The rapid analysis, low cost monitoring and high throughput number of samples tested per unit time indicate that MIR spectroscopy may hold potential as a rapid and reliable method for detecting milk powder frauds using cheese whey. PMID- 25529645 TI - Anthocyanin yield and skin softening during maceration, as affected by vineyard row orientation and grape ripeness of Vitis vinifera L. cv. Shiraz. AB - Anthocyanin and mechanical properties were evaluated on Shiraz grapes, picked from both sides of North-South and East-West vineyard row orientations at two harvest dates. Wines were made from each combination. The evaluation and evolution of crushed skin mechanical properties during maceration-fermentation, as also affected by grape ripeness, are shown for the first time. No significant differences in anthocyanin content were found in the grapes between the two vineyard row orientations. However, a significant decrease in anthocyanins and berry skin break force (also referred as skin hardness or strength) was found between the two harvest dates. During maceration, a reduction in the crushed berry skin break force of more than 15% occurred. The intact berries and macerated skins showed similarity in skin break energy values. The anthocyanin profile of the grapes and of the wines prominently displayed malvidin forms, changed mainly by the ripeness level of the grapes. PMID- 25529646 TI - Effect of whey protein isolate and beta-cyclodextrin wall systems on stability of microencapsulated vanillin by spray-freeze drying method. AB - Vanillin flavour is highly volatile in nature and due to that application in food incorporation is limited; hence microencapsulation of vanillin is an ideal technique to increase its stability and functionality. In this study, vanillin was microencapsulated for the first time by non-thermal spray-freeze-drying (SFD) technique and its stability was compared with other conventional techniques such as spray drying (SD) and freeze-drying (FD). Different wall materials like beta cyclodextrin (beta-cyd), whey protein isolate (WPI) and combinations of these wall materials (beta-cyd + WPI) were used to encapsulate vanillin. SFD microencapsulated vanillin with WPI showed spherical shape with numerous fine pores on the surface, which in turn exhibited good rehydration ability. On the other hand, SD powder depicted spherical shape without pores and FD encapsulated powder yielded larger particle sizes with flaky structure. FTIR analysis confirmed that there was no interaction between vanillin and wall materials. Moreover, spray-freeze-dried vanillin + WPI sample exhibited better thermal stability than spray dried and freeze-dried microencapsulated samples. PMID- 25529647 TI - Surface energy analysis (SEA) and rheology of powder milk dairy products. AB - Results of inverse gas chromatography adsorption/desorption experiments using selected probes on skimmed milk, whey and demineralised whey powder materials are presented. The dispersive component of surface energy was found to be dominant, indicating a low polarity character. Surface energy profiles of demineralised whey and skimmed milk showed a characteristic steep exponential decrease from approximately 170 mJ/m(2) to 60 mJ/m(2) and 140 mJ/m(2) to 45 mJ/m(2), respectively, whereas whey powder exhibited a constant (non-exponential) surface energy at approximately 45 mJ/m(2). The dispersive surface energy of demineralised whey and skimmed milk powder showed a broad distribution ranging from 40 mJ/m(2) to 120 mJ/m(2) and 175 mJ/m(2), respectively. In contrast, the dispersive surface energy distribution for whey was very narrow, ranging from only 42.8 mJ/m(2) to 45 mJ/m(2). The determined yield locus and Mohr's circles indicated that demineralised whey exhibited free flowing powder characteristics, whereas skimmed milk and whey exhibited cohesive powder flow behaviour. PMID- 25529648 TI - Effects of continuous and intermittent retrogradation treatments on in vitro digestibility and structural properties of waxy wheat starch. AB - The effects of continuous retrogradation (CR) and intermittent retrogradation (IR) treatments under 4 degrees C and 25 degrees C or temperature-cycled condition of 4/25 degrees C on the digestibility and structural properties of waxy wheat starch were investigated. The results indicated that IR treatment under temperature cycles of 4/25 degrees C (IR-4/25) was more beneficial to the formation of slowly digestible starch (SDS, 42.24%). Moreover, the gelatinisation enthalpy of IR-4/25-treated starch sample was lower than that of CR-4/25-treated sample. Variation in infrared absorbance ratio of 1047 cm(-1)/1022 cm(-1) of IR treated starch samples was consistent with relative crystallinity. Through retrogradation treatment under 4/25 degrees C or 4 degrees C, starch samples exhibited X-ray diffraction pattern of B-type, while CR-25 and IR-25-treated samples showed a mixed A+B type pattern. Besides, the swelling power of CR-4/25 treated starch sample was higher than that of IR-4/25-treated sample. The pasting temperatures of IR-treated starch samples were higher than those of the CR treated samples. PMID- 25529635 TI - Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. AB - Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 * 10(-44)) and estrogen receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 * 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 * 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 * 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. PMID- 25529649 TI - Angiotensin-I converting enzyme inhibitory peptides from antihypertensive skate (Okamejei kenojei) skin gelatin hydrolysate in spontaneously hypertensive rats. AB - The aim of this study was to investigate antihypertensive effect of bioactive peptides from skate (Okamejei kenojei) skin gelatin. The Alcalase/protease gelatin hydrolysate below 1 kDa (SAP) exhibited the highest angiotensin-I converting enzyme (ACE) inhibition compared to other hydrolysates. SAP can decrease systolic blood pressure significantly in spontaneously hypertensive rats. SAP inhibited vasoconstriction via PPAR-gamma expression, activation and phosphorylation of eNOS in lungs. Moreover, the expression levels of endothelin 1, RhoA, alpha-smooth muscle actin, cleaved caspase 3 and MAPK were decreased by SAP in lungs. Vascularity, muscularization and cellular proliferation in lungs were detected by immunohistochemical staining. Finally, two purified peptides (LGPLGHQ, 720Da and MVGSAPGVL, 829Da) showed potent ACE inhibition with IC50 values of 4.22 and 3.09 MUM, respectively. These results indicate that bioactive peptides isolated from skate skin gelatin may serve as candidates against hypertension and could be used as functional food ingredients. PMID- 25529650 TI - Effects of photoperiod, growth temperature and cold acclimatisation on glucosinolates, sugars and fatty acids in kale. AB - Curly kale is a robust, cold tolerant plant with a high content of health promoting compounds, grown at a range of latitudes. To assess the effects of temperature, photoperiod and cold acclimatisation on levels of glucosinolates, fatty acids and soluble sugars in kale, an experiment was set up under controlled conditions. Treatments consisted of combinations of the temperatures 15/9 or 21/15 degrees C, and photoperiods of 12 or 24h, followed by a cold acclimatisation period. Levels of glucosinolates and fatty acid types in leaves were affected by growth conditions and cold acclimatisation, being generally highest before acclimatisation. The effects of growth temperature and photoperiod on freezing tolerance were most pronounced in plants grown without cold acclimatisation. The results indicate that cold acclimatisation can increase the content of soluble sugar and can thereby improve the taste, whilst the content of unsaturated fatty and glucosinolates acids may decrease. PMID- 25529651 TI - Changes in carotenoid profiles and in the expression pattern of the genes in carotenoid metabolisms during fruit development and ripening in four watermelon cultivars. AB - Changes in carotenoid profiles during fruit ripening were investigated in four watermelon cultivars: red-fleshed "CN66", pink-fleshed "CN62", yellow-fleshed "ZXG381" and white-fleshed "ZXG507". The expression pattern of twelve genes (GGPS, PSY, PSY-A, PDS, ZDS, CRTISO, LCYB, CHYB, ZEP, NCED1, NCED2 and NCED3) was analysed. In "CN66" and "CN62", lycopene appeared at 12 DAP and became a main carotenoid increased at the later stages. The transcript levels of carotenogenic genes in "CN66" sharply increased during 18-30 DAP, and concomitantly, fruit accumulated the massive amounts of carotenoids. In "ZXG381", violaxanthin and lutein contents were positively correlated, respectively, with CHYB and ZEP transcript levels during fruit ripening. The trace amounts of carotenoids in "ZXG507" were accompanied with the low transcript levels of most biosynthetic genes. The results suggest that differential transcriptional regulation of carotenoid metabolic genes is very important in determining the amount and type of specific carotenoids accumulated during fruit development and ripening. PMID- 25529652 TI - Enzymatic degradation of phytate, polyphenols and dietary fibers in Ethiopian injera flours: effect on iron bioaccessibility. AB - The effect of removing phytate (IP6), iron-binding polyphenols, and dietary fibers on iron bioaccessibility in wheat-red sorghum (WrS) and teff-white sorghum (TwS) flour blends used in Ethiopia to make injera, a fermented pancake, was evaluated through the application of exogenous enzymes. Phytase treatment led to >90% reduction in IP6 and to an IP6:Fe molar ratio <1, but iron bioaccessibility was not improved (P > 0.05). Phytase + xylanase + cellulase (P + X + C) treatment increased iron bioaccessibility in TwS (non-detectableto1.6%) and WrS (1.9-3.2%), whereas phytase + polyphenol oxidase (P + PPO) treatment only showed improvement in the TwS blend. P + X + C + PPO treatment of the WrS blend increased the soluble non-dialysable iron fraction (6.7%) more than P + PPO treatment (3.9%). Although responses to enzyme treatments and iron bioaccessibility were matrix dependent, a positive effect of dietary fiber hydrolysis with X + C was obtained, irrespective of the blend. Dietary fibers had a negative effect on iron bioaccessibility independent of phytates. PMID- 25529653 TI - Evaluation of physicochemical properties, proximate and nutritional composition of Gracilaria edulis collected from Palk Bay. AB - Gracilaria edulis, a red alga present in southeast coast of India was evaluated for its nutritional composition. FT-IR analysis of soluble polysaccharides revealed the presence of galactans, 3,6-anhydro-alpha-L-galactopyranose, sulphated galactose and the gelling agent agar, with the sulphate content estimated as 51.01 MUg/mg of polysaccharide. Results of physicochemical properties and nutritional profile reveal the presence of dietary fibre (8.9 +/- 0.62% DW), carbohydrate (101.61 +/- 1.8 mg/g DW), crude protein (6.68 +/- 0.94 mg/g DW) and lipid content (8.3 +/- 1.03 mg/g DW). G. edulis contains biologically important fatty acids like palmitic acid (2.06%), linolenic acid (2.56%), and oleic acid (1.98%). The other nutritional components present in high amounts are proline, chlorophyll A and B, all the essential amino acids and vitamin A, E and C. These findings suggest that G. edulis has potent nutritional value which might be used as a source of nutrients for human and animals. PMID- 25529654 TI - Validation and comparison of two commercial ELISA kits and three in-house developed real-time PCR assays for the detection of potentially allergenic mustard in food. AB - The study compares the applicability of two commercial mustard ELISA kits (Mustard ELISA Kit-specific and Mustard ELISA Kit-total) and three in-house developed real-time PCR assays (singleplex assay for white mustard, singleplex assay for black/brown mustard and duplex assay for the detection of white, black and brown mustard). Analyses of raw and brewed model sausages containing white and black/brown mustard in the range from 1 to 50 ppm indicate that both ELISAs and the three real-time PCR assays allow the detection of traces of mustard in raw and in brewed sausages. The ELISAs were found to be more sensitive than the real-time PCR assays. When the ELISAs and real-time PCR assays were applied to the analysis of 15 commercial foodstuffs differing in their labelling concerning mustard, in one sample mustard was detected with both ELISAs and the three real time PCR assays although mustard was not indicated on the food ingredient list. PMID- 25529655 TI - Characterisation of corn starch-based films reinforced with taro starch nanoparticles. AB - Taro starch nanoparticles (TSNPs) obtained by hydrolysis with pullulanase and the recrystallisation of gelatinised starch were used as reinforcing agents in corn starch films. The influence of TSNPs contents (0.5-15%) on the physical, mechanical, thermal, and structural properties of starch films was investigated. An increase in the concentration of TSNPs led to a significant decrease in the water vapour permeability (WVP) of films. The addition of TSNPs increased the tensile strength (TS) of films from 1.11 MPa to 2.87 MPa. Compared with pure starch films, the surfaces of nanocomposite films became uneven. The onset temperature (To) and melting temperature (Tm) of films containing TSNPs were higher than those of pure starch films. The addition of TSNPs improved the thermal stability of starch films. PMID- 25529657 TI - Isolation of micro- and nano-crystalline cellulose particles and fabrication of crystalline particles-loaded whey protein cold-set gel. AB - Micro- and nano-crystalline cellulose (MCC and NCC, respectively) particles isolated from cellulose filter papers via acid digestion were characterised and loaded into a heat-denatured whey protein isolate (WPI) solution which was subsequently cold-set-gelled. Both the MCC and NCC particles were rod-shaped and had higher crystallinity degrees than had the cellulose source they were isolated from. The hydrodynamic diameter of NCC particles was ~ 15 nm. Fourier transform infrared (FTIR) spectroscopy suggested more surface hydroxyl groups on the NCC than the MCC particles and complete digestion of hemicellulose on the cellulosic substrate by acid. MCC- and NCC-loaded WPI gel matrices were topographically less uniform and contained many more undulations in comparison to the crystal-free counterpart. It was found, using dynamic rheometry and penetration tests, that the crystal loading into WPI gels weakened the texture. Non-covalent interactions between the cellulose crystals and whey protein strands were proposed in the gel structure according to FTIR results. PMID- 25529656 TI - Lipid-derived aldehyde degradation under thermal conditions. AB - Nucleophilic degradation produced by reactive carbonyls plays a major role in food quality and safety. Nevertheless, these reactions are complex because reactive carbonyls are usually involved in various competitive reactions. This study describes the thermal degradation of 2-alkenals (2-pentenal and 2-octenal) and 2,4-alkadienals (2,4-heptadienal and 2,4-decadienal) in an attempt to both clarify the stability of aldehydes and determine new compounds that might also play a role in nucleophile/aldehyde reactions. The obtained results showed that alkenals and alkadienals decomposed rapidly in the presence of buffer and air to produce formaldehyde, acetaldehyde, and the aldehydes corresponding to the breakage of the carboncarbon double bonds: propanal, hexanal, 2-pentenal, 2 octenal, glyoxal, and fumaraldehyde. The activation energy of double bond breakage was relatively low (~ 25 kJ/mol) and the yield of alkanals (10-18%) was higher than that of 2-alkenals (~ 1%). All these results indicate that these reactions should be considered in order to fully understand the range of nucleophile/aldehyde adducts produced. PMID- 25529658 TI - Quantification of total pigments in citrus essential oils by thermal wave resonant cavity photopyroelectric spectroscopy. AB - A general theory of thermal wave resonant cavity photopyroelectric spectroscopy (TWRC-PPE) was recently proposed by Balderas-Lopez (2012) for the thermo-optical characterisation of substances in a condensed phase. This theory is used to quantify the total carotenoids and chlorophylls in several folded and un-folded citrus essential oils to demonstrate the viability of using this technique as an alternative analytical method for the quantification of total pigments in citrus oils. An analysis of variance (ANOVA) reveals significant differences (p < 0.05) among the means of optical absorption coefficient data for the folding degree and fruit type in citrus oils. The experimental results show that TWRC-PPE spectroscopy can be used to quantify concentrations up to five times higher of total carotenoids and chlorophylls in citrus oils than UV-Vis spectroscopy without sample preparation or dilution. The optical limits of this technique and possible interference are also described. PMID- 25529659 TI - Chemical, chromatic, and sensory attributes of 6 red wines produced with prefermentative cold soak. AB - Six red grape cultivars, Barbera D'Asti, Cabernet Sauvignon, Malbec, Merlot, Pinot Noir and Syrah, were produced with or without prefermentative cold soak (CS). Cold soak had no effect on the basic chemical composition of the wines. At pressing, CS wines were more saturated and with a higher red component than control wines. After 1 year of bottle aging, CS wines retained 22% more anthocyanins than control wines, but tannins and total phenolics remained unaffected. Both saturation and the red component of colour were slightly higher in CS wines. From a sensory standpoint, CS only enhanced colour intensity in Barbera D'Asti and Cabernet Sauvignon wines, whereas it diminished colour intensity in Pinot Noir. Cold soak had no effect on perceived aroma, bitterness, astringency, and body of the wines. Principal Component Analysis suggested that the outcome of CS is contingent upon the specific cultivar to which the CS technique is applied. PMID- 25529660 TI - A universally calibrated microplate ferric reducing antioxidant power (FRAP) assay for foods and applications to Manuka honey. AB - The ferric reducing antioxidant power (FRAP) assay was recently adapted to a microplate format. However, microplate-based FRAP (mFRAP) assays are affected by sample volume and composition. This work describes a calibration process for mFRAP assays which yields data free of volume effects. From the results, the molar absorptivity (epsilon) for the mFRAP assay was 141,698 M(-1) cm(-1) for gallic acid, 49,328 M(-1) cm(-1) for ascorbic acid, and 21,606 M(-1) cm(-1) for ammonium ferrous sulphate. The significance of epsilon (M(-1) cm(-1)) is discussed in relation to mFRAP assay sensitivity, minimum detectable concentration, and the dimensionless FRAP-value. Gallic acid showed 6.6 mol of Fe(2+) equivalents compared to 2.3 mol of Fe(+2) equivalents for ascorbic acid. Application of the mFRAP assay to Manuka honey samples (rated 5+, 10+, 15+, and 18+ Unique Manuka Factor; UMF) showed that FRAP values (0.54-0.76 mmol Fe(2+) per 100g honey) were strongly correlated with UMF ratings (R(2)=0.977) and total phenols content (R(2) = 0.982)whilst the UMF rating was correlated with the total phenols (R(2) = 0.999). In conclusion, mFRAP assay results were successfully standardised to yield data corresponding to 1-cm spectrophotometer which is useful for quality assurance purposes. The antioxidant capacity of Manuka honey was found to be directly related to the UMF rating. PMID- 25529661 TI - Effects of flavonoid glycosides obtained from a Ginkgo biloba extract fraction on the physical and oxidative stabilities of oil-in-water emulsions prepared from a stripped structured lipid with a low omega-6 to omega-3 ratio. AB - In this study, we have produced a structured lipid with a low omega6/omega3 ratio by lipase-catalysed interesterification with perilla and grape seed oils (1:3, wt/wt). A Ginkgo biloba leaf extract was fractionated in a column packed with HP 20 resin, producing a flavonoid glycoside fraction (FA) and a biflavone fraction (FB). FA exhibited higher antioxidant capacity than FB, showing 58.4 mmol gallic acid equivalent (GAE)/g-of-total-phenol-content, 58.8 mg quercetin equivalent (QUE)/g-of-total-flavonoid-content, 4.5 mmol trolox/g-of-trolox-equivalent antioxidant capacity, 0.14 mg extract/mL-of-free-radical-scavenging-activity (DPPH assay, IC50), and 2.3 mmol Fe2SO4 . 7H2O/g-of-ferric-reducing-antioxidant power. The oil-in-water emulsion containing the stripped structured lipid as an oil phase with FA exhibited the highest stability and the lowest oil globule diameters (d43 and d32), where the aggregation was unnoticeable by Turbiscan and particle size analyses during 30 days of storage. Furthermore, FA was effective in retarding the oxidation of the emulsions. PMID- 25529662 TI - DNA degradation in genetically modified rice with Cry1Ab by food processing methods: implications for the quantification of genetically modified organisms. AB - Food processing methods contribute to DNA degradation, thereby affecting genetically modified organism detection and quantification. This study evaluated the effect of food processing methods on the relative transgenic content of genetically modified rice with Cry1Ab. In steamed rice and rice noodles, the levels of Cry1Ab were ? 100% and <83%, respectively. Frying and baking in rice crackers contributed to a reduction in Pubi and Cry1Ab, while microwaving caused a decrease in Pubi and an increase in Cry1Ab. The processing methods of sweet rice wine had the most severe degradation effects on Pubi and Cry1Ab. In steamed rice and rice noodles, Cry1Ab was the most stable, followed by SPS and Pubi. However, in rice crackers and sweet rice wine, SPS was the most stable, followed by Cry1Ab and Pubi. Therefore, Cry1Ab is a better representative of transgenic components than is Pubi because the levels of Cry1Ab were less affected compared to Pubi. PMID- 25529663 TI - Monitoring the physicochemical degradation of coconut water using ESI-FT-ICR MS. AB - Fresh and aged coconut water (CW) samples were introduced directly into the electrospray ionisation (ESI) source, and were combined with the Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) technique to characterise in situ chemical compounds produced during natural ageing (from 0 to 15 days) at room temperature (23 degrees C). The ESI-FT-ICR MS readings were acquired and the data were correlated to conventional methodologies: pH, total titratable acidity (TA), total soluble solids, microbial analyses, and ultraviolet visibility (UV-vis) spectroscopy analysis. In general, the pH and TA values changed after 3 days of storage making the CW unsuitable for consumption. The ESI(-)-FT-ICR data also showed a clear and evident change in the chemical profile of CW after 3 days of ageing in the m/z 150-250 and 350-450 regions. Initially, the relative intensity of the natural markers (the m/z 215 and 377 ions-sugar molecules) decreases as a function of ageing time, with the last marker disappearing after 3 days of ageing. New chemical species were then identified such as: citric (m/z 191), galacturonic (m/z 193), gluconic (m/z 195), and saccharic (m/z 209) acids. ESI(-)-FT-ICR MS is a powerful tool to predict the physicochemical properties of CW, such as the pH and TA, where species such as fructose, glucose, sucrose, and gluconic acid can be used as natural markers to monitor the quality of the fruits. PMID- 25529664 TI - Contribution of SO2 to antioxidant potential of white wine. AB - The reactivity of SO2 with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and in Folin Ciocalteu (FC) assays was analysed under different experimental conditions. There was significantly higher reactivity between SO2 and DPPH in buffered methanol than in methanol alone. When DPPH and FC assays were performed in a mixture of caftaric acid and SO2, there were synergistic effects that were more pronounced with the FC assay. Phenolics are an important parameter of wine quality, and their accurate characterisation in wine is essential. Analysis of white wines with DPPH and FC assays overestimates the contribution of phenolics to the antioxidant potential (AOP). SO2 contributes (from 20% to 45%) to the AOP of the white wines analysed. As SO2 reactivity depends highly on buffer composition, pH, time of incubation and other compounds, e.g. phenolics and aldehydes, different experimental protocols can produce large variations in AOPs, and therefore control of experimental conditions is extremely important. PMID- 25529665 TI - Application of handheld and portable spectrometers for screening acrylamide content in commercial potato chips. AB - The most common methods for acrylamide analysis in foods require the use of LC MS/MS and GC-MS. Although these methods have great analytical performance, they need intensive sample preparation, highly specialised instrumentation, and are time consuming. In this study, portable and handheld infrared spectrometers were evaluated as rapid methods for screening acrylamide in potato chips and their performances were compared to those of benchtop infrared systems. The acrylamide content of 64 commercial potato chips (169-2453 MUg/kg) was determined by LC MS/MS. Spectral data were collected using mid-infrared (MIR) and near-infrared (NIR) spectrometers. Partial least squares regression (PLSR) calibration models were developed to predict acrylamide levels. Overall, good linear correlation was found between the predicted acrylamide levels and actual measured acrylamide concentrations by LC-MS/MS (rPred > 0.90 and SEP < 100 MUg/kg). Our results indicate that portable and handheld spectrometers can be used as simple and rapid alternatives for acrylamide analysis in potato chips. PMID- 25529666 TI - A NMR-based, non-targeted multistep metabolic profiling revealed L-rhamnitol as a metabolite that characterised apples from different geographic origins. AB - This study utilises (1)H NMR-based metabolic profiling to characterise apples of five cultivars grown either in Japan (Fuji, Orin, and Jonagold) or New Zealand (Fuji, Jazz, and Envy). Principal component analysis (PCA) showed a clear separation between the Fuji-Orin-Jonagold class and the Jazz-Envy class, primarily corresponding to the differences in sugar signals, such as sucrose, glucose, and fructose. Multistep PCA removed the influence of dominant sugars and highlighted minor metabolites such as aspartic acid, 2-methylmalate, and an unidentified compound. These minor metabolites separated the apples into two classes according to different geographical areas. Subsequent partial least squares discriminant analysis (PLS-DA) indicated the importance of the unidentified metabolite. This metabolite was isolated using charcoal chromatography, and was identified as L-rhamnitol by 2D NMR and LC/MS analyses. The remarkable contribution of L-rhamnitol to geographic discrimination suggests that apples may be characterised according to various factors, including storage duration, cultivation method, and climate. PMID- 25529667 TI - Optimisation of the reaction conditions for the production of cross-linked starch with high resistant starch content. AB - The optimum reaction conditions (temperature and pH) for the preparation of cross linked (CL) corn and wheat starches with maximum resistant starch (RS) content were investigated by using response surface methodology (RSM). According to the preliminary results, five levels were selected for reaction temperature (38-70 degrees C) and pH (10-12) in the main study. RS contents of the CL corn and wheat starch samples increased with increasing temperature and pH, and pH had a greater influence on RS content than had temperature. The maximum RS content (with a maximum p value of 0.4%) was obtained in wheat starch cross-linked at 38 degrees C and pH 12. In the case of CL corn starch, the optimum condition was 70 degrees C and pH 12. CL corn and wheat starch samples were also produced separately under the optimum conditions and their RS contents were 80.4% and 83.9%, respectively. These results were also in agreement with the values predicted by RSM. PMID- 25529668 TI - Occurrence and assessment of perfluorinated compounds in fish from the Danjiangkou reservoir and Hanjiang river in China. AB - Residues of eight perfluorinated compounds (PFCs) were investigated in 15 fish samples from the Danjiangkou reservoir and Hanjiang river (Xiangyang and Zhongxiang sections). The total concentrations of PFCs in fish muscles ranged from 2.01 to 43.8 ng g(-)(1) dry weight. The mean concentration of total PFCs from related muscles showed the following trend in various regions: Zhongxiang section < Xiangyang section < Danjiangkou reservoir. Perfluorooctane sulphonate (PFOS) was the dominant PFC in the fish liver samples from the Danjiangkou reservoir. The calculated hazard ratio (HR) of PFCs, for all fish muscle samples, was less than 1.0, and could be classified at safe levels for the general population. However, yellow croaker fish from the Danjiangkou reservoir and Hanjiang river-Xiangyang section had HRs of 0.2, indicating that frequent consumption of this contaminated fish may pose an unacceptable risk to human health. PMID- 25529669 TI - Post-harvest nutraceutical behaviour during ripening and senescence of 8 highly perishable fruit species from the Northern Brazilian Amazon region. AB - The post-harvest nutraceutical characteristics of highly perishable native fruits species from the Northern Brazilian Amazon region were studied during 12 day at 15 +/- 1 degrees C and 95 +/- 3% RH. Uxi and caja fruit showed climacteric behaviour while caju, acai de terra firme, camu-camu, inaja, murici and araca-boi were non-climacteric. Soluble solids and sugars increased for climacteric fruit while total acidity remained constant for all fruits. In general, all fruit species had high levels of total phenolics (121-9889 mg GAE 100 g(-1) dry weight pulp), vitamin C (31-1532 mg AA 100 mL(-1) juice) and antioxidant activity (AOX) (75-288 1 MUmol Trolox Eq 100 g(-1) dry weight, ORAC value), however, camu-camu, acai and murici were among the highest. All fruits showed an increase in phenolic content (15-82%), a simultaneous decrease in ascorbic acid in both peel (88-98%) and pulp (89-97%), while AOX increased or decreased depending on the fruit species, very likely due to the specific phenolic profile being synthesized. We propose a hypothetical model where ripening/senescence induced a redox homeostasis imbalance which in turn triggered the responses. PMID- 25529670 TI - The application of stable isotope ratio analysis to determine the geographical origin of wheat. AB - In this work, in order to discriminate the geographical origin of wheat, delta(13)C and delta(15)N values of 35 wheat samples originated from different regions were determined, using the method of element analyser-stable isotope ratio mass spectrometry. The results indicated that wheat from Australia, the USA, Canada and China could be potentially discriminated by using analyte delta(13)C and delta(15)N. delta(13)C values of wheat were ranged from 25.6470/00 to -22.3260/00, the delta(15)N values of 35 wheat samples were calculated between 1.8590/00 and 7.7120/00. Moreover, the results illustrated regional distributions of delta(15)N values of wheat as Australia>The USA>Jiangsu province of China>Shandong province of China>Canada. So delta(13)C and delta(15)N analysis would be potentially useful for rapid and routine analyses of geographical origin of wheat, even the cereal grains. In order to confirm the discrimination capability of delta(13)C and delta(15)N, a follow-up work will use this method to analyse a larger set of samples. PMID- 25529671 TI - A systematic, comparative study on the beneficial health components and antioxidant activities of commercially fermented soy products marketed in China. AB - The objectives of this study are to systematically assess the bioactive substances and overall antioxidant capacities of commercially fermented soy products and to find the relationships between the presence of beneficial components in different types of soybean fermented products. The results show that phenolic profiles increased significantly after fermentation as compared with raw yellow soybeans. Among all the samples, the douchi and fermented black bean sauce had the highest detected antioxidant profiles. Even though the total isoflavone content was reduced in fermented soybean products (794.84 MUg/g on average) as compared with raw yellow soybeans (3477.6 MUg/g), there was an obvious trend of conversion of the glucoside form in raw soybeans into the aglycone-form isoflavones in the fermented soybean products. The highest daidzein and genistein values were found in the "Yangfan" black bean douchi, i.e. 860.3 MUg/g and 1025.9 MUg/g, respectively. The amounts of essential amino acids also were improved in most fermented soybean products. The douchi and black bean fermented products are recommended for consumption due to their abundant bioactive substances. PMID- 25529672 TI - Effects of bioactive constituents in functional cocoa products on cardiovascular health in humans. AB - Cocoa manufacturers are producing novel products increasing polyphenols, methylxanthines or dietary fibre to improve purported health benefits. We attempt to explain the contribution of cocoa bioactive compounds to cardiovascular effects observed in previous studies, placing particular emphasis on methylxanthines. We focused on a soluble cocoa product rich in dietary fibre (DFCP) and a product rich in polyphenols (PPCP). Effects of regularly consuming DFCP (providing daily 10.17 g, 43.8 mg and 168.6 mg of total-dietary-fibre, flavanols and methylxanthines, respectively) as well as PPCP (providing daily 3.74 g, 45.3 mg and 109.8 mg of total-dietary-fibre, flavanols and methylxanthines, respectively) on cardiovascular health were assessed in two controlled, cross-over studies in free-living normocholesterolemic and moderately hypercholesterolemic subjects. Both products increased HDL-cholesterol concentrations, whereas only DFCP decreased glucose and IL-1beta levels in all subjects. Flavanols appeared to be responsible for the increase in HDL cholesterol, whereas insoluble-dietary-fibre and theobromine in DFCP were associated with the hypoglycemic and anti-inflammatory effects observed. PMID- 25529673 TI - Digestibility of pasta made with three wheat types: a preliminary study. AB - The aim of this study was to assess the digestibility of the protein and starch in pasta made with different cereals, i.e. Triticum durum, Triticum polonicum and Triticum dicoccum, and to measure the glycemic index (GI) of the different types of pasta. The digestibility of the starch in T.polonicum pasta differed significantly from the others. It seemed to be less digested than dicoccum and durum wheat pasta. T.polonicum pasta also had a lower glycemic index, while there were no significant differences in the protein digestibility of the three types of pasta. PMID- 25529674 TI - Discrimination and characterisation of extra virgin olive oils from three cultivars in different maturation stages using Fourier transform infrared spectroscopy in tandem with chemometrics. AB - A methodology based on Fourier transform infrared (FTIR) spectroscopy, combined with multivariate analysis methods, was applied in order to monitor extra virgin olive oils produced from three distinct cultivars on different maturation stages. For the first time, this kind of methodology is used for the simultaneous discrimination of the maturation stage, and different cultivars. Principal component analysis and discriminant analysis were utilised to create a model for the discrimination of olive oil samples. Partial least squares regression was employed to design calibration models for the determination of chemical parameters. The performance of these models was based on the multiple coefficient of determination (R(2)), the root mean square error of calibration (RMSEC) and root mean square error of cross validation (RMSECV). The prediction models for the chemical parameters resulted in a R(2) ranged from 0.93 to 0.99, a RMSEC ranged from 1% to 4% and a RMSECV from 2% to 5%. It has been shown that this kind of approach allows to distinguish the different cultivars, and to clearly discern the different maturation stages, in each one of these distinct cultivars. Furthermore, the results demonstrated that FTIR spectroscopy in tandem with chemometric techniques allows the creation of viable and accurate models, suitable for correlating the data collected by FTIR spectroscopy, with the chemical composition of the EVOOs, obtained by standard methods. PMID- 25529675 TI - Determination of alditols by capillary electrophoresis with indirect laser induced fluorescence detection. AB - A novel method was developed based on capillary electrophoresis with indirect laser-induced fluorescence detection for the determination of alditols including xylitol, sorbitol, arabinitol and mannitol. The baseline separation was achieved with a capillary with 30 MUm inner diameter and running buffer (pH 9.6) composed of 40 mM sodium tetraborate, 5% (v/v) methanol, 10(-5)M sodium fluorescein as background fluorescence. Calibration curves (0.2-2.0 mg mL(-1)) showed good linear correlations (r>0.999). The detection limits of the alditols were in the range of 19.0-24.4 MUg mL(-1). The intra-day and inter-day RSDs for migration times and peak areas were less than 1.6% and 4.3%, respectively. The average recoveries were in the range of 99.6-105.5%. The developed method was successfully applied to determination of alditols in different real samples, and the results were compared with those of capillary electrophoresis with indirect ultraviolet detection method. PMID- 25529676 TI - Monitoring endogenous enzymes during olive fruit ripening and storage: correlation with virgin olive oil phenolic profiles. AB - The ability of olive endogenous enzymes beta-glucosidase, polyphenol oxidase (PPO) and peroxidase (POX), to determine the phenolic profile of virgin olive oil was investigated. Olives used for oil production were stored for one month at 20 degrees C and 4 degrees C and their phenolic content and enzymatic activities were compared to those of ripening olive fruits. Phenolic and volatile profiles of the corresponding oils were also analysed. Oils obtained from fruits stored at 4 degrees C show similar characteristics to that of freshly harvested fruits. However, the oils obtained from fruits stored at 20 degrees C presented the lowest phenolic content. Concerning the enzymatic activities, results show that the beta-glucosidase enzyme is the key enzyme responsible for the determination of virgin olive oil phenolic profile as the decrease in this enzyme activity after 3 weeks of storage at 20 degrees C was parallel to a dramatic decrease in the phenolic content of the oils. PMID- 25529677 TI - Dynamic behaviour and residual pattern of thiamethoxam and its metabolite clothianidin in Swiss chard using liquid chromatography-tandem mass spectrometry. AB - A simultaneous method was developed to analyse thiamethoxam and its metabolite clothianidin in Swiss chard using tandem mass spectrometry (in the positive electrospray ionisation mode using multiple reaction monitoring mode) to estimate the dissipation pattern and the pre-harvest residue limit (PHRL). Thiamethoxam (10%, WG) was sprayed on Swiss chard grown in two different areas under greenhouse conditions at the recommended dose rate of 10 g/20 L water. Samples were collected randomly up to 14 days post-application, extracted using quick, easy, cheap, effective, rugged, safe (QuEChERS) acetate-buffered method and purified via a dispersive solid phase extraction (d-SPE) procedure. Matrix matched calibration showed good linearity with determination coefficients (R(2)) ? 0.998. The limits of detection (LOD) and quantification (LOQ) were 0.007 and 0.02 mg/kg. The method was validated in triplicate at two different spiked concentration levels. Good recoveries (n=3) of 87.48-105.61% with relative standard deviations (RSDs) < 10 were obtained for both analytes. The rate of disappearance of total thiamethoxam residues in/on Swiss chard was best described by first-order kinetics with half-lives of 6.3 and 4.2 days. We predicted from the PHRL curves that if the residues were <19.21 or 26.98 mg/kg at 10 days before harvest, then total thiamethoxam concentrations would be below the maximum residue limits during harvest. PMID- 25529678 TI - Flavanols, proanthocyanidins and antioxidant activity changes during cocoa (Theobroma cacao L.) roasting as affected by temperature and time of processing. AB - The effect of roasting on the content of flavanols and proanthocyanidins and on the antioxidant activity of cocoa beans was investigated. Cocoa beans were roasted at three temperatures (125, 135 and 145 degrees C), for different times, to reach moisture contents of about 2 g 100 g(-1). Flavanols and proanthocyanidins were determined, and the antioxidant activity was tested by total phenolic index (TPI), ferric reducing antioxidant power (FRAP) and total radical trapping antioxidant parameter (TRAP) methods. The rates of flavanol and total proanthocyanidin loss increased with roasting temperatures. Moisture content of the roasted beans being equal, high temperature-short time processes minimised proanthocyanidins loss. Moisture content being equal, the average roasting temperature (135 degrees C) determined the highest TPI and FRAP values and the highest temperature (145 degrees C) determined the lowest TPI values. Moisture content being equal, low temperature-long time roasting processes maximised the chain-breaking activity, as determined by the TRAP method. PMID- 25529679 TI - In vitro bioaccessibility and monolayer uptake of lutein from wholegrain baked foods. AB - Lutein-enriched foods would contribute towards promoting the consumption of this important carotenoid. In the current study cookies, muffins, and flatbreads were produced at three enrichment levels (0.5, 1.0 and 2.0mg lutein per serving) to investigate lutein bioavailability in vitro. Foods were subjected to in vitro simulation of human upper gastrointestinal digestion coupled with a Caco-2 monolayer absorption assay. Digestive conditions representative of the fed state conditions associated with significantly higher lutein bioaccessibility compared with the fasted state (p < 0.001). Lutein bioaccessibility of cookies and muffins was higher than flatbreads due to their elevated fat content, measured under either fed or fasted conditions. Lutein concentration in the aqueous phase was the most important factor in determining apical cell uptake of lutein, with cookies and muffins exhibiting a higher lutein uptake than flatbreads (p < 0.05). As commonly consumed foods, lutein-enriched cookies, muffins, and flatbreads have the potential to improve lutein intake. PMID- 25529680 TI - Formulation of oil-in-water beta-carotene microemulsions: effect of oil type and fatty acid chain length. AB - The impact of oil type and fatty acid chain length on the development of food grade microemulsions for the entrapment of beta-carotene was investigated. The microemulsion region of a ternary phase diagram containing short chain monoglycerides was larger than for di- and triglycerides when Tween 80 was used as surfactant. The cytotoxicity of microemulsions composed of a 30% monoglyceride oil, 20% Tween 80 and 50% aqueous buffer were evaluated using an in vitro cell culture model (human epithelial colorectal adenocarcinoma, Caco-2). The cytotoxicity test showed that the viability of Caco-2 cells against beta-carotene microemulsions at concentrations of 0.03125% (v/v) was higher than 90%. This study suggests that short chain monoglycerides could be used with Tween 80 to prepare transparent beta-carotene-encapsulated O/W microemulsions in the particle size range of 12-100 nm. PMID- 25529681 TI - Interrelationship between myoglobin and lipid oxidations in oxeye scad (Selar boops) muscle during iced storage. AB - The interrelationship between myoglobin oxidation, lipid oxidation and discolouration in oxeye scad fish during iced storage were investigated. The myoglobin autoxidation rate increased with increasing storage time up to 12 days (p < 0.05) and remained constant thereafter (p > 0.05). Increase in metmyoglobin correlated well with a blue shift from 410 to 408 nm for myoglobin. The soret band of myoglobin decreased with a concomitant decrease in the redness index (p < 0.05). During storage, the extractable haem iron decreased (p < 0.05), while the non-haem iron increased (p < 0.05). Hydrogen peroxide and ferrylmyoglobin concentrations had increased at the end of storage (p < 0.05). The conjugated diene (CD) and peroxide value (PV) of oxeye scad lipids tended to stabilise during the initial phase of storage, increased in the differentiation phase and had declined at the end of storage. However, thiobarbituric acid reactive substances (TBARS) increased markedly (p < 0.05). Overall, lipid and myoglobin oxidations in oxeye scad occurred in a concurrent manner and each process appeared to enhance the other. PMID- 25529682 TI - Purification and characterisation of arabinoxylan arabinofuranohydrolase I responsible for the filterability of barley malt. AB - Dan'er is a widely grown malt barley cultivar in China, but its filterability defects have severely impeded its application in beer brewing. Previous investigations have suggested that we should identify the malt filterability correlated proteins, one of which was postulated to be arabinoxylan arabinofuranohydrolase I (AXAH-I). To verify this hypothesis, we purified AXAH-I from Dan'er malt, characterised its enzyme performance, and investigated its influence on filterability by adding different amounts of purified enzyme to the mash. With 6 mU g(-1) malt AXAH-I supplemented, the wort separation rate increased by 31.8%, viscosity decreased by 3.6%, and the endosperm reserve contents declined concomitantly. Unexpectedly, the wort turbidity increased with increasing AXAH-I. We also tried to optimise the use of currently available commercial enzyme products for filterability improvement in beer brewing, by supplementing them with purified AXAH-I and beta-amylase. AXAH-I could be a functional component for novel commercial enzyme products in the beer industry. PMID- 25529683 TI - The mechanism study in the interactions of sorghum procyanidins trimer with porcine pancreatic alpha-amylase. AB - To examine the mechanisms in the interaction of sorghum procyanidins trimer (SPT) with porcine pancreatic alpha-amylase (PPA), fluorescence quenching, circular dichroism, and UV spectra methods were adopted. The procyanidins binding mode, binding constant and effect of procyanidins on protein stability and conformation were determined. The fluorescence spectroscopy results showed that the Stern Volmer quenching constant K(SV) of SPT on PPA, bimolecular quenching constant k(q), and apparent static quenching constant K were 2639.5 M(-1), 2.6395 * 10(11) M(-1) s(-1), and 495.19 M(-1), respectively. In addition, binding constant KA and number of binding sites were 872.971 M(-1) and 1, respectively. Circular dichroism study revealed that PPA conformation was altered by SPT with a major reduction of beta-sheet, increase of beta-turn, minor change of random coil. UV spectra indicated that SPT influenced the micro-environment of aromatic amino acid residues in PPA. These findings directly elucidate the mechanisms of high molecular weight SPT in interaction with PPA. PMID- 25529684 TI - Impact of additives on thermally-induced trans isomers in 9c,12c linoleic acid triacylglycerol. AB - Trilinolein, with or without additives, was placed in glass ampoules and subjected to thermal treatment at 180 degrees C or 240 degrees C for 8h. Thermal treatment of trilinolein at 180 degrees C and 240 degrees C produced twice the amount of trans nonconjugated linoleic acids (NLAs) compared to conjugated linoleic acids (CLAs), and nitrogen stream reduced the amount of both trans NLA and CLA products. The presence of additives resulted in the suppression or induction of trans NLAs and CLAs, depending on the type of additive, the concentration of the additive, and the heating temperature. Our analysis indicates that TBHQ is an effective additive for reducing trans NLA formation and inducing trans CLA formation in frying oil. Glutathione and L-cysteine at 0.1% may also be used as additives for frying oil. At suitable concentrations, Fe(3+) and Al(3+) ions derived from oils can reduce trans NLAs and induce trans CLAs during frying. PMID- 25529685 TI - Isolation of maltol glucoside from the floral nectar of New Zealand manuka (Leptospermum scoparium). AB - Maltol glucoside (3-(beta-D-glucopyranosyloxy)-2-methyl-4H-pyran-4-one), 1, was isolated from a preparation of the floral nectar from the New Zealand manuka tree (Leptospermum scoparium). 1 eluted just after dihydroxyacetone in HPLC of underivatized nectar and showed a UV absorbance maximum of 258 nm. The structure of 1 was confirmed by NMR and high resolution mass spectrometry. PMID- 25529686 TI - Quantitative analysis of volatiles in edible oils following accelerated oxidation using broad spectrum isotope standards. AB - Analysis of food volatiles generated by processing are widely reported but comparisons across studies is challenging in part because most reports are inherently semi-quantitative for most analytes due to limited availability of chemical standards. We recently introduced a novel strategy for creation of broad spectrum isotopic standards for accurate quantitative food chemical analysis. Here we apply the principle to quantification of 25 volatiles in seven thermally oxidised edible oils. After extended oxidation, total volatiles of high n-3 oils (flax, fish, cod liver) were 120-170 mg/kg while low n-3 vegetable oils were <50mg/kg. Separate experiments on thermal degradation of d5-ethyl linolenate indicate that off-aroma volatiles originate throughout the n-3 molecule and not solely the n-3 terminal end. These data represent the first report using broad spectrum isotopically labelled standards for quantitative characterisation of processing-induced volatile generation across related foodstuffs, and verify the origin of specific volatiles from parent n-3 fatty acids. PMID- 25529687 TI - Total phenolics, flavonoids, antioxidant activity, crude fibre and digestibility in non-traditional wheat flakes and muesli. AB - The five different types of muesli composed of non-traditional wheat flakes were prepared and analysed. Dickkopf wheat, red wheat, kamut and spelt were compared with commercial wheat flakes. Wheat flakes and muesli were assessed for basic analyses (dry matter, ash, protein, starch and fat content), total phenolic and flavonoid content, antioxidant activity (ABTS and DPPH assays), crude fibre content and in vitro digestibility. Furthermore, sensory evaluation of muesli involving scale and ranking preference tests was provided. Flakes and muesli made from Dickkopf wheat and red wheat showed the highest total phenolic and flavonoid content and, consequently, the highest antioxidant activity. Moreover, these cereals were high in crude fibre and thus were less digestible. On the other hand, the lowest total phenolic and flavonoid contents and antioxidant activity were determined in commercial flakes and muesli produced from these flakes. The flakes made from non-traditional wheat were sensorially comparable to commercial products. PMID- 25529688 TI - Detection of the causal agents of Keriorrhea (Lepidocybium flavobrunneum and Ruvettus pretiosus) by means of Real Time PCR. AB - Consumption of Lepidocybium flavobrunneum and Ruvettus pretiosus is related with the gastrointestinal disease called Keriorrhea. Sometimes, intentionally or not, these species are mislabelled as other harmless species, causing severe disruptions to consumers. The correct identification of these species helps to avoid food fraud and health problems. For this reason, a multiplex Real Time-PCR method based on TaqMan technology for the correct authentication of L. flavobrunneum and R. pretiosus has been developed. The method is based on a species-specific set of primers and TaqMan probe which amplifies a 276 bp fragment of the cytochrome oxidase I (COI) mitochondrial DNA region. This methodology allows your application to any type of product, regardless of the degree of processing it has undergone with high specificity, sensitivity and rapidity. Also, it might be a useful tool in monitoring and verifying labelling regulation and protect consumer rights. PMID- 25529689 TI - Role of major wine constituents in the foam properties of white and rose sparkling wines. AB - The chemical composition of sparkling wines is directly related to their foam quality, but the compounds responsible are not yet completely established. This work aims at identifying the contribution of the different wine compounds to the foaming properties of white and rose sparkling wines. Our results demonstrated the positive contribution of anthocyanins and amino acids to the foamability parameters HM (maximum height reached by foam after CO2 injection) and HS (foam stability height during CO2 injection), and the negative contribution of proanthocyanidins. Mannoproteins and polysaccharides rich in arabinose and galactose (PRAG) were poor foam formers but good foam stabilizers. The different forms of malvidin showed the highest influence on the HM and HS parameters, followed by amino acid compounds, mainly beta-alanine. The model to explain foam stability was only predicted by polysaccharides from grapes, concretely PRAG. To our knowledge, this is the first time these correlations in sparkling wines have been described. PMID- 25529690 TI - Reassociation of dissociated caseins upon acidification of heated pH-adjusted skim milk. AB - Milk was heated at different pH (pH 6.5-7.1) and temperatures (20-120 degrees C/10 min). This resulted in different levels of casein and denatured whey proteins to be distributed between the colloidal and serum phases. The milks were subsequently acidified and the distribution of protein between colloidal and serum was monitored at different pH. On acidification to pH 5.4, the serum phase caseins and denatured whey proteins partially reassociated with the caseins, although a complex behaviour was observed at ~ pH 5.4 where additional casein dissociation occurred in some samples. At pH below 5.4 the caseins and denatured whey proteins rapidly aggregated. No separate aggregation of kappa casein/denatured whey protein complexes or kappa-casein depleted micelles was observed. The earlier gelation of milks heated at higher pH was likely to be due to the destabilisation of the entire milk protein system rather than a preferential aggregation of the serum phase proteins. PMID- 25529691 TI - Analysis of free nucleotide monophosphates in human milk and effect of pasteurisation or high-pressure processing on their contents by capillary electrophoresis coupled to mass spectrometry. AB - A simple, efficient and green analytical method for the determination of free nucleotide monophosphates in human milk is proposed. It involves centrifugal ultrafiltration (CUF) as sample treatment and capillary electrophoresis electrospray mass spectrometry (CE-ESI-MS) for separation and simultaneous quantification. The optimised method, applied to the analysis of human milk samples, included their dilution (1:5) with water followed by CUF treatment. No matrix effects were found. The method provided limits of detection between 0.08 and 0.13 MUg mL(-1) and limits of quantification between 0.26 and 0.43 MUg mL( 1). The intralaboratory repeatability and reproducibility afforded relative standard deviation values lower than 10%. The method was applied to the study of the effects of Holder pasteurisation and high-pressure processing on the nucleotide contents in samples from a human milk bank. The results showed concentration values between 0.5 and 10 MUg mL(-1), with higher concentrations for the samples treated by pasteurisation. The effect of freezing time on the content of nucleotides was also assessed. PMID- 25529692 TI - Effects of different sorbic acid and moisture levels on chemical and microbial qualities of sun-dried apricots during storage. AB - Effects of different sorbic acid (SA) (0, 488-530 and 982-1087 mg/kg) and moisture [intermediate (271-278 g/kg) and high (341-344 g/kg)] levels on the chemical and microbiological qualities of sun-dried apricots during storage at different temperatures (4, 10, 20 and 30 degrees C) for 10 months were evaluated. Moisture content and SA concentration showed significant effect on brown colour formation, beta-carotene oxidation and microbial load (p < 0.05). As moisture content increased, brown colour formation decreased. Moreover, SA oxidation protected beta-carotene from oxidation. Although no microbial spoilage was observed in the samples with intermediate moisture content, control group with high moisture was spoiled by yeast and mould in 1-3 months of storage at all temperatures studied; 488 mg SA/kg was sufficient to prevent the spoilage. Regardless of moisture content, 500 mg SA/kg was found to be effective for the prevention of brown colour formation and inhibition of microbial growth. PMID- 25529693 TI - Novel in situ evaluation of the role minerals play in the development of the hard to-cook (HTC) defect of cowpeas and its effect on the in vitro mineral bioaccessibility. AB - Cowpea is a nutritionally important drought-resistant legume in sub-Saharan Africa. It is, however, underutilised, in part due to the hard-to-cook (HTC) defect caused by adverse storage conditions resulting in seeds not softening during cooking. This study introduced a novel evaluation of the potential role that minerals play in the development of the HTC defect. The mineral distribution in the cotyledons of normal and HTC cowpeas were analysed by Proton Induced X-ray Emission (PIXE) spectrometry. The phytate, tannin and total phenolic contents were analysed together with in vitro mineral bioaccessibility. In HTC cowpeas, Ca and Mg were more concentrated in the cell wall-middle lamella area of the parenchyma cells. This, together with the reduction in phytate content, confirmed the 'phytase-phytate-mineral' hypothesis as a mechanism for development of the HTC defect. Despite the phytate reduction in stored cowpeas, the HTC defect decreased the bioaccessibility of Ca, Fe and Zn in cowpeas. PMID- 25529694 TI - Quantitative assessment of moniliformin in cereals via alternative precipitation pathways, aided by LC-LIT-MS and LC-Q-TOF-MS. AB - The availability of a simple chemical precipitation workflow aided by targeted and untargeted mass spectrometry would provide an accurate diagnostic platform for the direct determination of moniliformin in cereals for food safety control. In-house method validation was performed at six concentration levels of 8, 40, 80, 200, 400, and 600 ng g(-1) in cereal flours of wheat, corn, rye, oats and barley. Spiking experiments were made at three concentration levels of 20, 40 and 100 ng g(-1). Protein precipitation and "PHREE" column cleanup strategy provided recoveries of 81-108% for all cereals matrices using external calibrants. "PHREE" purification provided significant (p < 0.05) ion signal enhancement reduction advantage for all matrices except corn flour. Moniliformin underwent significant (p < 0.05) degradation over 2 weeks when prepared in acidified water. A simple, low-cost and fit-for-purpose procedure for the identification and quantitation of moniliformin in cereals becomes available to support prospective regulatory function. PMID- 25529695 TI - Aqueous two-phase based on ionic liquid liquid-liquid microextraction for simultaneous determination of five synthetic food colourants in different food samples by high-performance liquid chromatography. AB - A rapid and effective method of aqueous two-phase systems based on ionic liquid microextraction for the simultaneous determination of five synthetic food colourants (tartrazine, sunset yellow, amaranth, ponceau 4R and brilliant blue) in food samples was established. High-performance liquid chromatography coupled with an ultraviolet detector of variable wavelength was used for the determinations. 1-alkyl-3-methylimidazolium bromide was selected as the extraction reagent. The extraction efficiency of the five colourants in the proposed system is influenced by the types of salts, concentrations of salt and [CnMIM]Br, as well as the extracting time. Under the optimal conditions, the extraction efficiencies for these five colourants were above 95%. The phase behaviours of aqueous two-phase system and extraction mechanism were investigated by UV-vis spectroscopy. This method was applied to the analysis of the five colourants in real food samples with the detection limit of 0.051-0.074 ng/mL. Good spiked recoveries from 93.2% to 98.9% were obtained. PMID- 25529696 TI - Determination of sulphite in wines using suppressed ion chromatography. AB - Suppressed ion chromatography with the use of a conductivity detector was developed for the determination of sulphite ions in wine samples. When a mixed solution of sodium carbonate, sodium bicarbonate, and acetone was used as the mobile phase, simultaneous determination of eight inorganic anions (i.e., fluoride, chloride, nitrite, nitrate, sulphite, phosphate, sulphate, and thiosulphate) was completed in approximately 25 min. Linearity, reproducibility, and detection limits were determined for the proposed method. In the case of sulphite detection, a linear calibration curve with a good correlation coefficient of 0.9992 was obtained from the peak height of sulphite with a relative standard deviation (n = 6) 1.48%. In addition, the detection limit of sulphite was 0.27 mg/L at a signal-to-noise ratio of 3. Further, the developed method was applied for the determination of sulphite contained in several wine samples. PMID- 25529697 TI - Assessment of the stability of proanthocyanidins and other phenolic compounds in cranberry syrup after gamma-irradiation treatment and during storage. AB - Shelf life of commercial cranberry syrup irradiated with gamma radiation at a rate of 5 kGy and stored for 6 months at 25 degrees C and 60% relative humidity (RH) and under accelerated stability conditions was investigated. High performance liquid chromatography coupled to electrospray ionisation quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF-MS) was used to characterise cranberry syrup. Afterwards, these compounds were quantified by HPLC-ESI-QTOF-MS and 4-dimethylaminocinnamaldehyde (DMAC) assay. A significant increase in the content of procyanidin B isomer 1 (from 4.4 to 7.0 MUg/ml) and procyanidin A2 (from 83 to 93 MUg/ml) was observed after irradiation and compared with the non irradiated syrup. Procyanidin B isomers and prodelphinidin were stable at 25 degrees C during the first month of storage, whereas quercetin and some derivatives remained constant for 3 months of storage at this temperature. In short, after gamma-irradiation in dose of 5 kGy, most compounds were highly stable for a month at 25 degrees C. PMID- 25529698 TI - Lipoxygenase activity in different species of sweet lupin (Lupinus L.) seeds and flakes. AB - Lipoxygenase (LOX)-catalysed degradation of polyunsaturated fatty acids is supposed to be a major cause of undesirable off-flavour development in legumes. In the present study, a photometric LOX assay including adequate sample workup was adapted to lupin seeds, kernels and flakes, respectively. Optimum reaction conditions were at pH 7.5 using a phosphate buffer concentration of 150 mmol l( 1) without the addition of sodium chloride. The LOX activities of different lupin species and varieties were compared. Significant variations among the species and varieties ranging from 50 to 1004 units mg(-1) protein were determined, being significantly lower than soybean LOX activity. Hulling and flaking of the seeds resulted in a 15% increase of LOX activity. In contrast to soy and other legumes, LOX from lupin only converted free fatty acids, whereas trilinolein and beta carotene were not oxidised. Consequently, according to the established classification, lupin LOX activity may be assigned to the LOX type-1, which, to the best of our knowledge, was demonstrated for the first time. PMID- 25529699 TI - A straightforward method to determine flavouring substances in food by GC-MS. AB - A straightforward GC-MS method was developed to determine the occurrence of fourteen flavouring compounds in food. It was successfully validated for four generic types of food (liquids, semi-solids, dry solids and fatty solids) in terms of limit of quantification, linearity, selectivity, matrix effects, recovery (53-120%) and repeatability (3-22%). The method was applied to a survey of 61 Dutch food products. The survey was designed to cover all the food commodities for which the EU Regulation 1334/2008 set maximum permitted levels. All samples were compliant with EU legislation. However, the levels of coumarin (0.6-63 mg/kg) may result in an exposure that, in case of children, would exceed the tolerable daily intake (TDI) of 0.1mg/kg bw/day. In addition to coumarin, estragole, methyl-eugenol, (R)-(+)-pulegone and thujone were EU-regulated substances detected in thirty-one of the products. The non-EU regulated alkenylbenzenes, trans-anethole and myristicin, were commonly present in beverages and in herbs-containing products. PMID- 25529700 TI - Pomegranate peel and peel extracts: chemistry and food features. AB - The present review focuses on the nutritional, functional and anti-infective properties of pomegranate (Punica granatum L.) peel (PoP) and peel extract (PoPx) and on their applications as food additives, functional food ingredients or biologically active components in nutraceutical preparations. Due to their well known ethnomedical relevance and chemical features, the biomolecules available in PoP and PoPx have been proposed, for instance, as substitutes of synthetic food additives, as nutraceuticals and chemopreventive agents. However, because of their astringency and anti-nutritional properties, PoP and PoPx are not yet considered as ingredients of choice in food systems. Indeed, considering the prospects related to both their health promoting activity and chemical features, the nutritional and nutraceutical potential of PoP and PoPx seems to be still underestimated. The present review meticulously covers the wide range of actual and possible applications (food preservatives, stabilizers, supplements, prebiotics and quality enhancers) of PoP and PoPx components in various food products. Given the overall properties of PoP and PoPx, further investigations in toxicological and sensory aspects of PoP and PoPx should be encouraged to fully exploit the health promoting and technical/economic potential of these waste materials as food supplements. PMID- 25529701 TI - Comparative HPLC/ESI-MS and HPLC/DAD study of different populations of cultivated, wild and commercial Gentiana lutea L. AB - The root of Gentiana lutea L., famous for its bitter properties, is often used in alcoholic bitter beverages, food products and traditional medicine to stimulate the appetite and improve digestion. This study presents a new, fast, and accurate HPLC method using HPLC/ESI-MS and HPLC/DAD for simultaneous analysis of iridoids (loganic acid), secoiridoids (gentiopicroside, sweroside, swertiamarin, amarogentin) and xanthones (isogentisin) in different populations of G.lutea L., cultivated in the Monti Sibillini National Park, obtained wild there, or purchased commercially. Comparison of HPLC/ESI-MS and HPLC/DAD indicated that HPLC/ESI-MS is more sensitive, reliable and selective. Analysis of twenty samples showed that gentiopicroside is the most dominant compound (1.85-3.97%), followed by loganic acid (0.11-1.30%), isogentisin (0.03-0.48%), sweroside (0.05-0.35%), swertiamarin (0.08-0.30%), and amarogentin (0.01-0.07%). The results confirmed the high quality of the G.lutea cultivated in the Monti Sibillini National Park. PMID- 25529702 TI - Comparison of the performance of different silica hydride particles for the solid phase extraction of non-volatile analytes from dark chocolate with analysis by gas chromatography-quadrupole mass spectrometry. AB - The extraction capabilities of a Diamond HydrideTM phase, as well as silica hydride phases modified with bidentate octadecyl (BDC(18)), phenyl or cholesteryl groups, were evaluated for the analysis of fatty acids, amino acids, sugars and sterols in a dark chocolate extract. These batch adsorption performances were investigated using either methanol or aqueous methanol as the solvent. The compositions of the extracted fractions were assessed by gas chromatography interfaced with quadrupole mass spectrometry (GC-qMS). The batch binding propensities of the various compound classes with silica hydride particles modified with immobilised phenyl groups or larger ligands followed trends predicted from linear solvation energy relationships. Both prediction and experiment revealed that better extraction results could be obtained with the phenyl, BDC(18) and cholesteryl hydride particles for the major chocolate components. Based on these results, separations in micro-pipette tip format with these three types of stationary phase particles have been undertaken. PMID- 25529703 TI - Influence of dietary components on Aspergillus niger prolyl endoprotease mediated gluten degradation. AB - Celiac disease (CD) is caused by intolerance to gluten. Oral supplementation with enzymes like Aspergillus niger propyl-endoprotease (AN-PEP), which can hydrolyse gluten, has been proposed to prevent the harmful effects of ingestion of gluten. The influence of meal composition on AN-PEP activity was investigated using an in vitro model that simulates stomach-like conditions. AN-PEP optimal dosage was 20 proline protease units (PPU)/g gluten. The addition of a carbonated drink strongly enhanced AN-PEP activity because of its acidifying effect. While fat did not affect gluten degradation by AN-PEP, the presence of food proteins slowed down gluten detoxification. Moreover, raw gluten was degraded more efficiently by AN-PEP than baked gluten. We conclude that the meal composition influences the amount of AN-PEP needed for gluten elimination. Therefore, AN-PEP should not be used to replace a gluten free diet, but rather to support digestion of occasional and/or inadvertent gluten consumption. PMID- 25529704 TI - Determination of chlorophenols in honey samples using in-situ ionic liquid dispersive liquid-liquid microextraction as a pretreatment method followed by high-performance liquid chromatography. AB - In-situ ionic liquid-dispersive liquid-liquid microextraction (IL-DLLME) method was developed as a pretreatment method for the detection of six chlorophenols (CPs) in honey samples. The hydrophobic ionic liquid [C4MIM][NTf2], formed in situ by the hydrophilic ionic liquid [C4MIM][BF4] and the ion exchange reagent LiNTf2 was used as the microextractant solvent of CPs from honey sample. Then the enriched analytes were back-extracted into 40 MUL of 0.14 M NaOH solution and finally subjected to analysis by high-performance liquid chromatography. The method showed low limit of detection of CPs, 0.8-3.2 MUg/L and high enrichment factor, 34-65 with the recoveries range from 91.60% to 114.33%. The method is simple, rapid, environmentally friendly and with high extraction efficiency. PMID- 25529705 TI - Metabolomic unveiling of a diverse range of green tea (Camellia sinensis) metabolites dependent on geography. AB - Numerous factors such as geographical origin, cultivar, climate, cultural practices, and manufacturing processes influence the chemical compositions of tea, in the same way as growing conditions and grape variety affect wine quality. However, the relationships between these factors and tea chemical compositions are not well understood. In this study, a new approach for non-targeted or global analysis, i.e., metabolomics, which is highly reproducible and statistically effective in analysing a diverse range of compounds, was used to better understand the metabolome of Camellia sinensis and determine the influence of environmental factors, including geography, climate, and cultural practices, on tea-making. We found a strong correlation between environmental factors and the metabolome of green, white, and oolong teas from China, Japan, and South Korea. In particular, multivariate statistical analysis revealed strong inter-country and inter-city relationships in the levels of theanine and catechin derivatives found in green and white teas. This information might be useful for assessing tea quality or producing distinct tea products across different locations, and highlights simultaneous identification of diverse tea metabolites through an NMR based metabolomics approach. PMID- 25529706 TI - Chemical properties in fruits of mulberry species from the Xinjiang province of China. AB - Mulberries are a widely cultivated foodstuff both in China and worldwide. However, there are stark differences in the nutritional values of mulberry species. To better appreciate these differences, we here describe the chemical characteristics of white (Morus alba L.), Russian (M. alba var. tatarica L.), and black (Morus nigra L.) mulberry fruits cultivated in the Xinjiang province of China. The chemical composition analysis was performed by official methods procedures. The amino acids were analysed by the phenyl isothiocyanate method. The 2,6-dichloroindophenol titrimetric method, the aluminium chloride colorimetric method, and the pH differential method were also used in measuring the content of reduced ascorbic acid, total flavonoids, and total monomeric anthocyanins, respectively. The black mulberry fruits had the highest content of reduced ascorbic acid (48.4 mg/100 g fw), titratable acidity (47.1 mg/g fw), and Fe (11.9 mg/100 g fw) of these 3 species. The Russian mulberry fruits had the highest EAA/TAA (essential amino acid/total amino acid) ratio at 44% followed by the white mulberry (42%) and the black mulberry (29%). The black mulberry fruits had found to be richest in terms of total flavonoids and total monomeric anthocyanins. These results are helpful for selecting mulberry species with abundant nutrients and phytochemicals for commercial cultivation. PMID- 25529707 TI - Food types and frying frequency affect the lipid oxidation of deep frying oil for the preparation of school meals in Korea. AB - 200 soybean oils used in school meals for deep frying were investigated to elucidate factors influencing lipid oxidation in the oils. The mean levels of moisture along with primary and secondary lipid oxidation products were significantly different among the oils used by the six schools. When comparing lipid oxidation products of frying oils used for four different food groups (vegetables, fish, meat or carbohydrate-rich foods), differences were found among them, with the values for the carbohydrate-rich group being the lowest. The vegetable group was higher in the contents of conjugated dienes and trienes, and lower for those of hydroperoxides and malondialdehyde. The mean values of malondialdehyde and p-anisidine value for the fish group were greater than those of the other groups. The levels of conjugated trienes and malondialdehyde increased with the frying frequency. These findings indicate that food types and frequency of frying play a role in determining the oil oxidation in deep fried foods in schools. PMID- 25529708 TI - Colorimetric detection of melamine based on methanobactin-mediated synthesis of gold nanoparticles. AB - A simple and rapid field-portable colorimetric method for the detection of melamine in liquid milk was reported. Methanobactin (Mb) could reduce Au (III) to Au (0) and mediate the synthesis of gold nanoparticles (Au-NPs). Upon the addition of melamine, melamine interacted with oxazolone ring of Mb, which interrupted the formation of Au-NPs. Melamine could also stimulate the aggregation of formed Au-NPs. In this paper, these characteristics have been used to detect melamine in liquid milk by naked eyes observation with a detection limit of 5.56 * 10(-6)M (0.7 mg/kg). Further, the plasmon absorbance of the formed Au-NPs allowed the quantitative detection of melamine by UV-vis spectrometer. A linear correlation was existed between the absorbance and the melamine concentration ranging from 3.90 * 10(-7)M to 3.97 * 10(-6)M with a correlation coefficient of 0.9685. The detection limit (3sigma) obtained by UV vis spectrum was as low as 2.38 * 10(-7)M (i.e., 0.03 mg/kg). PMID- 25529709 TI - Synthesis, characterisation and antioxidant features of procyanidin B4 and malvidin-3-glucoside stearic acid derivatives. AB - The acylation of procyanidin B4 with a saturated fatty acid chloride containing 18 carbon atoms was studied in order to obtain procyanidin B4 3-O-di-stearic acid conjugate. This compound was structurally characterised by mass spectrometry and 1D and 2D NMR techniques. Derivatization of malvidin-3-glucoside using stearoyl chloride in acetonitrile was also performed yielding mono-, di- and tri-stearic ester derivatives. The novel derivatives obtained revealed significant antioxidant activity, although lower than the respective precursors. However, the chemical modification of anthocyanins and procyanidins (water soluble pigments) to more lipophilic compounds has the advantage of increased bioavailability in biological matrices, and to potentiate their application in food matrices and cosmetic products. PMID- 25529710 TI - Effective clean-up and ultra high-performance liquid chromatography-tandem mass spectrometry for isoflavone determination in legumes. AB - Legumes are an excellent source of macronutrients and phytochemicals as isoflavones. The aim of this work was to develop a new analytical method for determining five isoflavone compounds, three of which are aglycons, namely daidzein, genistein, biochanin A, and two of which, daidzin and genistin, are glycosilated, in lentils and other pulses, using an effective clean-up system and UHPLC-MS/MS (triple quadrupole) method. The recoveries obtained by spiking the lentil samples with a standard mixture of isoflavones at three levels of fortification (5, 25 and 100 MUg kg(-1)) were in the range of 54.4-111.1%, 68.6 91.1%, and 84.4-114%, respectively. The method was applied to analyse 48 lentil samples from central Italy and pulses for determining the isoflavone content, which was found to range from 1.1 to 95.6 MUg kg(-1). PMID- 25529711 TI - Phenolic and carotenoid profiles and antiproliferative activity of foxtail millet. AB - Commonly consumed foxtail millet varieties Jingu28 and Jingu34 were compared in terms of phytochemical composition, antioxidant property, and antiproliferative activity. The cellular antioxidant activity (CAA) was evaluated based on HepG2 cell cultivation. Antiproliferative properties against HepG2 and MDA cell were assayed by methylene blue assay. Total phenolic content (TPC) was 78.79 and 114.22 mg gallic acid equiv/100 g DW in Jingu28 and Jingu34. Both varieties contained ferulic acid, chlorogenic acid, caffeic acid and p-coumaric acid, syringic acid. Xanthophylls and zeaxanthin were also detected. Peroxyl radical scavenging capacity of the foxtail millet were 228.13 (Jingu28) and 355.03 (Jingu34) MUmol of vitamin C equiv/100 g, respectively. CAA values of the foxtail millet varieties ranged from 1.52 to 8.97 MUmol quercetin equiv/100 g DW. The proliferation of MDA and HepG2 cancer cells were significantly inhibited in a dose-dependent manner after exposure to Jingu28 and Jingu34 extractions. PMID- 25529712 TI - Characterisation of fatty acid, carotenoid, tocopherol/tocotrienol compositions and antioxidant activities in seeds of three Chenopodium quinoa Willd. genotypes. AB - Composition of fatty acids, tocopherols, tocotrienols, and carotenoids, and their contribution to antioxidant activities were investigated in seeds of three coloured quinoa cultivars (white, red and black). The major components and individual compounds were significantly different, and their concentrations were higher in darker seeds (p < 0.05). The oil yield was 6.58-7.17% which contained predominantly unsaturated fatty acids (89.42%). The ratio of omega-6/omega-3 fatty acid was ca. 6/1. The total tocopherol content ranged from 37.49 to 59.82 MUg/g and mainly consisted of gamma-tocopherol. Trace amount of alpha- and beta tocotrienols was also found. Black quinoa had the highest vitamin E followed by red and white quinoas. Carotenoids, mainly trans-lutein (84.7-85.6%) and zeaxanthin were confirmed for the first time in quinoa seeds, and the concentration was also the highest in black seeds. The antioxidant activities of lipophilic extracts were positively correlated with polyunsaturated fatty acids, total carotenoids and total tocopherols. PMID- 25529713 TI - Isothermal DNA amplification strategies for duplex microorganism detection. AB - A valid solution for micro-analytical systems is the selection of a compatible amplification reaction with a simple, highly-integrated efficient design that allows the detection of multiple genomic targets. Two approaches under isothermal conditions are presented: recombinase polymerase amplification (RPA) and multiple displacement amplification (MDA). Both methods were applied to a duplex assay specific for Salmonella spp. and Cronobacter spp., with excellent amplification yields (0.2-8.6 . 10(8) fold). The proposed approaches were successfully compared to conventional PCR and tested for the milk sample analysis as a microarray format on a compact disc (support and driver). Satisfactory results were obtained in terms of resistance to inhibition, selectivity, sensitivity (10(1) 10(2)CFU/mL) and reproducibility (below 12.5%). The methods studied are efficient and cost-effective, with a high potential to automate microorganisms detection by integrated analytical systems working at a constant low temperature. PMID- 25529714 TI - Formation and mitigation of N-nitrosamines in nitrite preserved cooked sausages. AB - Literature on formation and mitigation of N-nitrosamine (NA) and especially non volatile NA (NVNA) in meat products is scarce and the present study is therefore a relevant contribution to the field. We found positive correlation between the levels of N-nitrosopiperidine (NPIP), N-nitrosohydroxyproline (NHPRO), N nitrosoproline (NPRO), N-nitrosothiazolidine-4-carboxylic acid (NTCA) and N nitroso-2-methyl-thiazolidine-4-carboxylic acid (NMTCA) and the amount of nitrite added to cooked pork sausages. The levels studied were 0, 60, 100, 150, 250 and 350 mg kg(-)(1). The levels of N-nitrosodimethylamine (NDMA) and N nitrosopyrrolidine (NPYR) remained at or below limit of quantification. Erythorbic acid inhibited the formation of NHPRO, NPRO, NPIP and NTCA. This inhibition was for NTCA and NMTCA counteracted by addition of free iron. Ascorbyl palmitate had less inhibitory effect than erythorbic acid and a combination of the two provided no further protection. Increasing the black pepper content increased the levels of NPIP and NMTCA. Only slight effects of increased fat content and addition of tripolyphosphate were observed. PMID- 25529715 TI - Variation of volatile compounds among wheat varieties and landraces. AB - Analysis of volatile compounds was performed on 81 wheat varieties and landraces, grown under controlled greenhouse conditions, in order to investigate the possibility of differentiating wheat varieties according to their volatile compound profiles. Volatile compounds from wheat samples were extracted by dynamic headspace extraction and analysed by gas chromatography-mass spectrometry. Seventy-two volatile compounds were identified in the wheat samples. Multivariate analysis of the data showed a large diversity in volatile profiles between samples. Differences occurred between samples from Austria compared to British, French and Danish varieties. Landraces were distinguishable from modern varieties and they were characterised by higher averaged peak areas for esters, alcohols, and some furans. Modern varieties were characterised by higher averaged peak areas for terpenes, pyrazines and straight-chained aldehydes. Differences in volatile profiles are demonstrated between wheat samples for the first time, based on variety. These results are significant to plant breeders and commercial users of wheat. PMID- 25529716 TI - Dieckol enhances the expression of antioxidant and detoxifying enzymes by the activation of Nrf2-MAPK signalling pathway in HepG2 cells. AB - Dieckol was previously reported to exhibit antioxidant and anticancer activities in vitro studies. In this study, we characterised the mechanism underlying the dieckol-mediated expression of antioxidant and detoxifying enzymes. Dieckol suppressed the production of intracellular reactive oxygen species in the presence or absence of H2O2 and increased glutathione level in HepG2 cells. Dieckol enhanced the activities of antioxidant enzymes, and the expression of detoxifying enzymes including heme oxygenase-1 (HO-1), NAD(P)H:quinine oxidoreductase 1 (NQO1), and glutathione S-transferase (GST) in HepG2 cells. Enhanced expression of antioxidant and detoxifying enzymes by dieckol was presumed to be the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2) demonstrated by its nuclear translocation and transcriptional activity via activation of mitogen-activated protein kinases in HepG2 cells. Furthermore, we demonstrated dieckol induced the expression of HO-1 in mouse liver. These results demonstrate that the dieckol-mediated cytoprotection in HepG2 cells is mediated through a ROS-independent up-regulation of antioxidant and detoxifying enzymes via Nrf2 activation as well as its intrinsic antioxidant activity, suggesting that dieckol may be used as a natural cytoprotective agent. PMID- 25529717 TI - Detection of peanut (Arachis hypogaea) allergen by Real-time PCR method with internal amplification control. AB - Specific primer sets were designed based on the DNA sequence of Ara h 1, one of the major peanut (Arachis hypogaea) allergens, and a competitive internal amplification control (IAC) was designed by compound primer technology. By choosing 314 copies/PCR as the IAC dosage, a Real-time PCR method with IAC was established for detecting peanut allergen Ara h 1 DNA. The method showed high specificity with a detection limit of 0.005% peanut. A series of commercial food products with/without peanut components were tested. Among these products, the peanut allergen Ara h 1 DNA could be detected in 12 products labelled containing peanut ingredients, in two without a declaration of peanut and one labelled that was produced in a facility that produced peanut-containing foods. This indicates that the method is highly sensitive for the detection of peanut ingredients in foods. PMID- 25529718 TI - Geographical origin of cereal grains based on element analyser-stable isotope ratio mass spectrometry (EA-SIRMS). AB - The stable carbon and nitrogen isotopic compositions (delta(13)C and delta(13)N) of different cereal grains from different regions were determined, using element analyser-stable isotope ratio mass spectrometry (EA-SIRMS) as the key method. Systematically, delta(13)C and delta(13)N of 5 kinds of cereal grains of different origins, 30 wheat samples from different cultivation areas and 160 rice samples of different cultivars from Guangdong province of China were examined. The results indicated that the delta(13)C values of rice, soybean, millet, wheat and corn were significantly (P < 0.05) different within different origins (Heilongjiang, Shandong and Jiangsu province of China), respectively, while delta(13)N values were not. Interestingly, there exists discrimination between these 5 kinds of cereals grains, no matter C-3 or C-4 plants. Further study showed that the delta(13)C values of wheat from Australia, the USA, Canada, and Jiangsu and Shandong province of China were also significantly (P < 0.01) different. Furthermore, the P-value test for 160 rice samples of 5 cultivars was not significant (P > 0.05), which indicated that the cultivar of cereal grains was not significant based on delta(13)C value. Thus, the comparison of delta(13)C would be potentially useful for rapid and routine discrimination of geographical origin of cereal grains. PMID- 25529719 TI - Postharvest chitosan-g-salicylic acid application alleviates chilling injury and preserves cucumber fruit quality during cold storage. AB - The effect of salicylic acid with and without chitosan, or a chitosan-g-salicylic acid complex, on chilling injury and post-harvest quality of cucumber stored at 2 degrees C for 12 days plus 2 days at 20 degrees C was investigated. The results showed the chitosan-g-salicylic acid coating inhibited chilling injury better than salicylic acid alone or with chitosan. Chitosan-g-salicylic acid also reduced weight loss and respiration rate, limited increases in malondialdehyde content and electrolyte leakage, and maintained higher total soluble solids, chlorophyll and ascorbic acid content. Furthermore, this coating increased the endogenous salicylic acid concentrations and antioxidant enzyme activities including superoxide dismutase, catalase, ascorbate peroxidase and glutathione reductase in cucumber during storage. Our study suggests that chitosan-g salicylic acid alleviated chilling injury in cucumber through sustained-release of salicylic acid and the higher antioxidant enzymes concentrations. PMID- 25529720 TI - Investigation of the solubility enhancement mechanism of rebaudioside D using a solid dispersion technique with potassium sorbate as a carrier. AB - Rebaudioside (Reb) D is a high intensity, natural sweetener that shows great potential for substituting sugar in sweetened beverages. However, Reb D is poorly water soluble, and thus, a solid dispersion technique was recently established to enhance its solubility. The purpose of this study was to elucidate the solubility enhancement mechanism of this solid dispersion material by employing Scanning Electron Microscopy (SEM), Raman spectroscopy, Fourier Transform Infrared spectroscopy (FT-IR) and X-ray Diffraction (XRD). Potassium sorbate (KS) was chosen as the carrier and two different concentration ratios were investigated as solid dispersions (SD) and as physical mixtures (PM). Our data demonstrated the possible mechanism for enhancing solubility through solid dispersion through increased surface area/volume ratio and hydrogen bonding between Reb D and KS. The interaction between the two components were also related to the different concentration ratios, therefore an optimisation of the ratio is important to produce a soluble and stable complex. PMID- 25529721 TI - Simple analytical strategy for MALDI-TOF-MS and nanoUPLC-MS/MS: quantitating curcumin in food condiments and dietary supplements and screening of acrylamide induced ROS protein indicators reduced by curcumin. AB - Curcumin is the major active ingredient of turmeric and is widely used as a preservative, flavouring and colouring agent. Curcumin is a potent substance with several functions, including antioxidant, antitumor, anti-inflammatory, antimicrobial, antiparasitic, antimutagenic, chemopreventive and chemotherapeutic activities. Matrix-assisted laser desorption/ionisation coupled with time-of flight mass spectrometry (MALDI-TOF-MS) has been used to analyse various molecules (including natural antioxidants). This study established an expeditious method that couples MALDI-TOF-MS with a simple dilution method to quantify curcumin in food condiments and dietary supplements. The linear range of curcumin detection ranged from 1 to 100 MUg/mL. In further experiments, liver cells were treated with curcumin after exposure to acrylamide. Nano ultra performance liquid chromatographic system (nanoUPLC) coupled with tandem mass spectrometry (MS/MS) was used to evaluate the potential proteins and protein modifications induced by acrylamide. The results indicate that curcumin reduces the effects of reactive oxygen species induced by acrylamide. PMID- 25529722 TI - Determination of phytochemicals and antioxidant activity of methanol extracts obtained from the fruit and leaves of Tunisian Lycium intricatum Boiss. AB - A comparative analysis of methanol extracts from fruit and leaves of Lycium intricatum Boiss., a Solanaceous shrubbery with the potential to become a high value crop, was performed by means of liquid chromatography with photodiode array and electrospray ionisation mass spectrometric detection (LC/PDA/ESI-MS). The total phenolic (TPC), anthocyanin (TAC) and flavonoid (TFC) contents as well as the antioxidant capacity measured by four complementary methods were performed for each sample. The results showed the tested extracts to be rich sources of phenolics; in leaves polyphenols and flavonoids dominate, while in fruit anthocyanins dominate. Nineteen phenolic compounds were detected and fifteen were identified or tentatively characterised based on Photodiode-array ultraviolet visible (PDA) UV-Vis spectra, ESI-MS spectrometric data and spiking experiments with authentic standards. Rutin and chlorogenic acid are the major constituents of the leaves and fruit, respectively. Results obtained in this study have revealed that leaves exhibit better performance in all antioxidant assays. From these results it has been shown that extracts of L. intricatum have great potential as a source of phenolics for natural health products. PMID- 25529723 TI - Nano-encapsulation of coenzyme Q10 using octenyl succinic anhydride modified starch. AB - Octenyl succinic anhydride modified starch (OSA-ST) was used to encapsulate coenzyme Q10 (CoQ10). CoQ10 was dissolved in rice bran oil and incorporated into an aqueous OSA-ST solution. High pressure homogenisation of the mixture was conducted at 170 MPa for 56 cycles. The resulting emulsion had a particle size range of 200-300 nm and the absolute zeta potential varied between 8.4 and 10.6 mV. CoQ10 retention of the emulsion and freeze dried products, determined by a hexane rinse, was 98.2%. Reconstitution of the freeze dried product in Mcllvaine citrate-phosphate buffers with pH values of 3-5 and temperatures at 4 and 25 degrees C had very little effect on the range and distribution of the nanoparticles' size. The inflection point of the zeta potential and pH plot occurred at the first pKa of succinic acid (pH 4.2), indicating succinate as the main influence over zeta potential. PMID- 25529724 TI - A solid phase extraction procedure for the determination of Cd(II) and Pb(II) ions in food and water samples by flame atomic absorption spectrometry. AB - A relatively rapid, accurate and precise solid phase extraction method is presented for the determination of cadmium(II) and lead(II) in various food and water samples. Quantitation is carried out by flame atomic absorption spectrometry (FAAS). The method is based on the retention of the trace metal ions on Dowex Marathon C, a strong acid cation exchange resin. Some important parameters affecting the analytical performance of the method such as pH, flow rate and volume of the sample solution; type, concentration, volume, flow rate of the eluent; and matrix effects on the retention of the metal ions were investigated. Common coexisting ions did not interfere on the separation and determination of the analytes. The detection limits (3 sigmab) for Cd(II) and Pb(II) were found as 0.13 and 0.18 MUg L(-1), respectively, while the limit of quantification values (10 sigmab) were computed as 0.43 and 0.60 MUg L(-1) for the same sequence of the analytes. The precision (as relative standard deviation was lower than 4% at 5 MUg L(-1) Cd(II) and 10 MUg L(-1) Pb(II) levels, and the preconcentration factor was found to be 250. The accuracy of the proposed procedure was verified by analysing the certified reference materials, SPS-WW2 Batch 108 wastewater level 2 and INCT-TL-1 tea leaves, with the satisfactory results. In addition, for the accuracy of the method the recovery studies (? 95%) were carried out. The method was applied to the determination of the analytes in the various natural waters (lake water, tap water, waste water with boric acid, waste water with H2SO4) and food samples (pomegranate flower, organic pear, radish leaf, lamb meat, etc.), and good results were obtained. While the food samples almost do not contain cadmium, they have included lead at low levels of 0.13-1.12 MUg g(-1). PMID- 25529725 TI - Residues investigation of fluoroquinolones and sulphonamides and their metabolites in bovine milk by quantification and confirmation using ultra performance liquid chromatography-tandem mass spectrometry. AB - A novel UPLC-MS/MS method for quantification and confirmation of eight fluoroquinolones, five sulphonamides (SAs) and four acetyled metabolites in milk is developed. Their main fragmentation pathways were presented. The limits of quantification were in the range of 0.01-0.29 MUg kg(-1) for FQs and 0.13-1.68 MUg kg(-1) for SAs. Mean recoveries ranging from 61% to 115% were achieved at spiked level of 0.5-100 MUg kg(-1). The intra- and inter-day precisions were in the range of 6.3-10.7% and 9.0-13.4%, respectively. This novel approach has high speed and sensitivity, and can ensure the multiclass and multiresidue analysis of bovine milk at low MUg kg(-1) level. The content of each analyte residue is much lower than the maximum residue limits. Some residues in milk were confirmed in according to the Commission Decision 657/2002/EC. PMID- 25529726 TI - Comparative study of the bioconversion process using R-(+)- and S-(-)-limonene as substrates for Fusarium oxysporum 152B. AB - This study compared the bioconversion process of S-(-)-limonene into limonene-1,2 diol with the already established biotransformation of R-(+)-limonene into alpha terpineol using the same biocatalyst in both processes, Fusarium oxysporum 152B. The bioconversion of the S-(-)-isomer was tested on cell permeabilisation under anaerobic conditions and using a biphasic system. When submitted to permeabilisation trials, this biocatalyst has shown a relatively high resistance; still, no production of limonene-1,2-diol and a loss of activity of the biocatalyst were observed after intense cell treatment, indicating a complete loss of cell viability. Furthermore, the results showed that this process can be characterised as an aerobic system that was catalysed by limonene-1,2-epoxide hydrolase, had an intracellular nature and was cofactor-dependent because the final product was not detected by an anaerobic process. Finally, this is the first report to characterise the bioconversion of R-(+)- and S-(-)-limonene by cellular detoxification using ultra-structural analysis. PMID- 25529727 TI - Nutrient content in the muscle and skin of fillets from farmed rainbow trout (Oncorhynchus mykiss). AB - The nutrient content in the muscle and edible skin parts of rainbow trout (Oncorhynchus mykiss) fillets, sampled at two growth stages, was evaluated. The average concentrations of protein and essential amino acids were higher in the muscle than in the skin. The chemical scores reached a value of 1.0 for the amino acids in the muscle and ranged from 0.40 (tryptophan) to 0.94 (threonine) in the skin. The average lipid content and the saturated fatty acids/polyunsaturated fatty acids and n-6/n-3 ratios were higher in the skin than in the muscle, whereas the proportion of docosahexaenoic acid (C22:6 n-3) was higher in the muscle. Significant differences were found for the essential minerals analysed, except for Cu. The concentrations of Na, K and Mg were higher and those of Ca, P, Fe, Mn and Zn were lower in the muscle than in the skin. Significant effects of the fish growth on the composition were detected. PMID- 25529728 TI - Isolation and characterisation of sericin antifreeze peptides and molecular dynamics modelling of their ice-binding interaction. AB - This study aimed to isolate and characterise a novel sericin antifreeze peptide and investigate its ice-binding molecular mechanism. The thermal hysteresis activity of ice-binding sericin peptides (I-SP) was measured and their activity reached as high as 0.94 degrees C. A P4 fraction, with high hypothermia protective activity and inhibition activity of ice recrystallisation, was obtained from I-SP, and a purified sericin peptide, named SM-AFP, with the sequence of TTSPTNVSTT and a molecular weight of 1009.50 Da was then isolated from the P4 fraction. Treatment of Lactobacillus delbrueckii Subsp. bulgaricus LB340 LYO with 100 MUg/ml synthetic SM-AFP led to 1.4-fold increased survival (p < 0.05). Finally, an SM-AFP/ice binding model was constructed and results of molecular dynamics simulation suggested that the binding of SM-AFP with ice and prevention of ice crystal growth could be attributed to hydrogen bond formation, hydrophobic interaction and non-bond interactions. Sericin peptides could be developed into beneficial cryoprotectants and used in frozen food processing. PMID- 25529729 TI - Thermal and UV stability of beta-carotene dissolved in peppermint oil microemulsified by sunflower lecithin and Tween 20 blend. AB - Microemulsions are suitable for simultaneous delivery of flavour oils and lipophilic bioactive compounds in transparent beverages. In the present study, the feasibility of delivering beta-carotene in microemulsions formulated with peppermint oil and a blend of Tween(r) 20 and various amounts of sunflower lecithin was investigated. The poorly water- and oil-soluble beta-carotene was dissolved in the transparent microemulsions that had particles smaller than 10nm and were stable during ambient storage for 65 d. The inclusion of beta-carotene did not change the flow-behaviour and Newtonian viscosity. The degradation of beta-carotene in microemulsions during ambient storage, ultraviolet radiation, and thermal treatments at 60 and 80 degrees C followed first order kinetics and was greatly suppressed when compared to the solution control. The antioxidant potential of peppermint oil and a greater content of lecithin in microemulsions enabled the better protection of beta-carotene. The studied microemulsions may find various applications in manufacturing transparent beverages. PMID- 25529730 TI - Differentiation of degrees of ripeness of Catuai and Tipica green coffee by chromatographical and statistical techniques. AB - The quality of green coffee is influenced by the degree of ripeness of the fruit at harvest. The aim of this study was to identify chemical markers differentiating between degrees of ripeness. Two coffee varieties, Catuai and Tipica, from the same farm were analysed using the following parameters and methods: caffeine and chlorogenic acid content using high-performance liquid chromatography (HPLC), sucrose content using hydrophilic interaction chromatography, high-molecular weight fraction (HMW) using high-performance size exclusion chromatography (HPSEC) and volatile compounds using headspace solid phase micro extraction gas chromatography/mass spectrometry. The best method for differentiating between degrees of ripeness was found to be principal component analysis (PCA) based on HPLC data. HPSEC showed differences in the HMW fraction for different degrees of ripeness and both coffee varieties. Volatile profiles allowed separation of both varieties; yet, except for ripe Catuai, no separation was achieved for the degree of ripeness. PMID- 25529731 TI - NIRS and iSPA-PLS for predicting total anthocyanin content in jaboticaba fruit. AB - The aim of this study was to evaluate the potential of the successive projection algorithm for interval selection in partial least squares (iSPA-PLS) together with near-infrared reflectance spectroscopy (NIRS) as a feasible method to determine the total anthocyanin content (TAC) of intact jaboticaba fruit [Myrciaria jaboticaba (Vell.) O. Berg]. A total of 579 jaboticaba fruit were collected in three different harvests in three separate years (2011 and 2013). The correlation coefficients between the predicted and measured TAC were between 0.65 and 0.89, the RMSEPs were 7.55 g kg(-1) and 9.35 g kg(-1) (good accuracy) for prediction set, respectively. The RPD ratios for TAC were in the range of 2.57-3.19 with iSPA-PLS, which showed better predictive performance (acceptable precision). These results suggest that the NIR spectroscopy and wavelength selection (iSPA-PLS) algorithm can be used to determine the TAC of intact jaboticaba fruit. PMID- 25529732 TI - Modelling and optimising of physicochemical features of walnut-oil beverage emulsions by implementation of response surface methodology: effect of preparation conditions on emulsion stability. AB - The major purpose of this study is to apply response surface methodology to model and optimise processing conditions for the preparation of beverage emulsions with maximum emulsion stability and viscosity, minimum particle size, turbidity loss rate, size index and peroxide value changes. A three-factor, five-level central composite design was conducted to estimate the effects of three independent variables: ultrasonic time (UT, 5-15 min), walnut-oil content (WO, 4-10% (w/w)) and Span 80 content (S80, 0.55-0.8). The results demonstrated the empirical models were satisfactorily (p < 0.0001) fitted to the experimental data. Evaluation of responses by analysis of variance indicated high coefficient determination values. The overall optimisation of preparation conditions was an UT of 14.630 min, WO content of 8.238% (w/w), and S80 content of 0.782% (w/w). Under this optimum region, responses were found to be 219.198, 99.184, 0.008, 0.008, 2.43 and 16.65 for particle size, emulsion stability, turbidity loss rate, size index, viscosity and peroxide value changes, respectively. PMID- 25529733 TI - Triazolo-beta-aza-epsilon-amino acid and its aromatic analogue as novel scaffolds for beta-turn peptidomimetics. AB - Triazolo-beta-aza-epsilon-amino acid and its aromatic analogue ((Al)TAA/(Ar)TAA) in the peptide backbone mark a novel class of conformationally constrained molecular scaffolds to induce beta-turn conformations. This was demonstrated for (Al)TAA in a Leu-enkephalin analogue and in a designed pentapeptide wherein the FRET process was established. Restricted rotation induced chirality and turn conformation into the achiral aromatic amino acid scaffold, (Ar)TAA, which in a short tripeptide backbone acted as a beta-turn mimic as a beta-sheet folding nucleator. PMID- 25529734 TI - Development of constrained tamoxifen mimics and their antiproliferative properties against breast cancer cells. AB - An efficient synthesis of a new series of tamoxifen mimics is described by employing iodine catalyzed ipsocyclization strategy followed by Suzuki coupling. A molecular docking studies of the synthesized compounds 11a-n and 12 in estrogen receptor (ER-alpha) showed that the scaffolds are fitting well in the groove, thereby suggesting them as promising antiproliferative agents for estrogen dependent breast cancer lines. All compounds were tested in vitro against breast cancer cell lines-ER positive, MCF-7; ER negative, MDA-MB-231; and control mammary epithelial cells, MEpiC. The biological results showed that most of the compounds are active against MCF-7 with IC50 values less than 6.5MUM which corroborate the results of molecular docking studies. PMID- 25529735 TI - Synthesis and biological evaluation of picolinamides as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). AB - Synthesis of a series of 6-substituted picolinamide derivatives and their inhibitory activities against 11beta-hydroxysteroid dehydrogenase type 1 are described. Optimization of the initial hit compound, N-cyclohexyl-6-(piperidin-1 yl)picolinamide (1) from high throughput screening of in-house library resulted in the discovery of the highly potent and metabolically stable compound 25, which was efficacious in a mouse ex vivo pharmacodynamic model and reduced the fasting blood glucose and insulin levels in a HF/STZ mouse model after oral dosing. PMID- 25529736 TI - Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors. AB - Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process. PMID- 25529737 TI - Microwave-assisted synthesis and biological evaluation of 3,4-diaryl maleic anhydride/N-substituted maleimide derivatives as combretastatin A-4 analogues. AB - A series of new CA-4 analogues bearing maleic anhydride/N-substituted maleimide moiety were synthesized via a microwave-assisted process. They were evaluated for the anti-proliferative activities against three tumor cell lines (SGC-7901, HT 1080 and KB). Most compounds showed moderate potencies in micromolar range, with the most promising analogue 6f showing active at submicromolar concentration against HT-1080 cancer cells which was selected to investigate the antitumor mechanisms. In addition, molecular docking studies within the colchicine binding site of tubulin were also in good agreement with the tubulin polymerization inhibitory data and provided a basis for further structure-guided design of novel CA-4 analogues. PMID- 25529738 TI - 5Z-7-Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner. AB - 5Z-7-Oxozeaenol (5Z7O) is a covalent bonding inhibitor against the several protein kinases (e.g., ERK2 and TAK1) that possess a free cysteine at the gatekeeper-2 position. In addition to this cysteine, MAP2K7 has three other cysteine residues that are candidate for covalent bonding by the inhibitor 5Z7O. The crystal structure of the MAP2K7/5Z7O complex revealed that the inhibitor binds to MAP2K7 at a cysteine residue located at the end of the hinge region and not at the gatekeeper-2 residue. The structural insights into the interaction of 5Z7O with MAP2K7 should aid the development of 5Z7O derivatives with improved potency and selectivity. PMID- 25529739 TI - Discovery and SAR study of 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-ones as soluble and highly potent PDE7 inhibitors. AB - The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4 pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3 piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility. PMID- 25529740 TI - Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization. AB - Starting from our previously identified novel c-Met kinase inhibitors bearing 1H imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1 dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations. PMID- 25529741 TI - Production of bacteriopurpurin-18 phytyl ester from bacteriopheophytin a via allomerization by contact with titanium oxides in the presence of molecular oxygen. AB - Incubation of bacteriopheophytin (BPhe) a, which was a demetalated pigment of bacteriochlorophyll a in photosynthetic bacteria, in CH2Cl2 in the presence of TiO2 particles with bubbling O2 in the dark produced a pigment absorbing 814nm. Detailed characterization of the novel pigment isolated from the CH2Cl2 suspension revealed that bacteriopurpurin-18 phytyl ester possessing an anhydride type six-membered exocyclic E-ring was majorly formed by the treatment with TiO2 particles under oxygenic conditions. Oxidation of the bacteriochlorin ring in BPhe a, namely formations of derivatives of 3-acetyl pheophytin a and 3-acetyl protopheophytin a, can barely be detected through the conversion processes. PMID- 25529742 TI - Synthesis, in vitro and in vivo antitumor activity of pyrazole-fused 23 hydroxybetulinic acid derivatives. AB - A collection of pyrazole-fused 23-hydroxybetulinic acid derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited significant antiproliferative activity. Especially compound 15e displayed the most potent activity with the IC50 values of 5.58 and 6.13MUM against B16 and SF763 cancer cell lines, respectively. Furthermore, the significant in vivo antitumor activity of 15e was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation. PMID- 25529743 TI - Intention-behavior gap is wider for walking and moderate physical activity than for vigorous physical activity in university students. AB - OBJECTIVES: The theory of planned behavior proposes that physical activity is the result of intentions; however little is known about whether the relation between intentions and behavior differs between vigorous, moderate physical activity, and walking. For university students, vigorous physical activity is oftentimes enacted as a goal-directed behavior; whereas walking is oftentimes a means to achieving a goal other than physical activity (e.g., transportation). DESIGN: The study was a one-week prospective study. METHODS: Undergraduate students (N=164) reported intentions for walking, moderate physical activity, and vigorous physical activity and self-reported these behaviors one week later. RESULTS: Hierarchical linear modeling revealed that intentions were more strongly related to vigorous physical activity than to moderate physical activity or walking. CONCLUSIONS: Intention-enhancing interventions may effectively promote vigorous physical activity, but other motivational processes may be more appropriate to target in interventions of walking and moderate physical activity. PMID- 25529744 TI - Injuries in community-level Australian football: Results from a club-based injury surveillance system. AB - OBJECTIVES: Far fewer injury surveillance systems exist within community sport than elite sport. As a result, most epidemiological data on sports injuries have limited relevance to community-level sporting populations. There is potential for data from community club-based injury surveillance systems to provide a better understanding of community sports injuries. This study aimed to describe the incidence and profile of community-level Australian football injuries reported using a club-based injury surveillance system. DESIGN: Prospective, epidemiological study. METHODS: Sports trainers from five community-level Australian football leagues recorded injury data during two football seasons using the club-based system. An online surveillance tool developed by Sports Medicine Australia ('Sports Injury Tracker') was used for data collection. The injury incidence, profile and match injury rate were reported. RESULTS: Injury data for 1205 players were recorded in season one and for 823 players in season two. There was significant variability in injury incidence across clubs. However, aggregated data were consistent across football seasons, with an average of 0.7 injuries per player per season and 38-39 match injuries per 1000 h match exposure. A large proportion of injuries occurred during matches, involved the lower limb and resulted from contact. CONCLUSIONS: Data from the club-based system provided a profile of injuries consistent with previous studies in community-level Australian football. Moreover, injury incidence was consistent with other studies using similar personnel to record data. However, injury incidence was lower than that reported in studies using player self-report or healthcare professionals and may be an underestimate of true values. PMID- 25529745 TI - Preparation of multi-coloured different sized fluorescent gold clusters from blue to NIR, structural analysis of the blue emitting Au7 cluster, and cell-imaging by the NIR gold cluster. AB - Blue, green, orange-red, red and NIR emitting gold quantum clusters have been prepared in aqueous media by using a bioactive peptide glutathione (reduced) at physiological pH. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) analyses show that the core structure sizes of the five different gold clusters are Au7 (blue), Au16 (green), Au19 (orange-red), Au21 (red) and Au22 (NIR). The photo-stability and pH-stability of these quantum clusters have been measured, and these are photo-stable against continuous UV irradiation for a few hours. They also exhibit moderate to good pH-stability within the pH range of 5-12.5. A computational study reveals the organisation of gold atoms in the thiolate-protected blue quantum cluster and its several structural parameters, including the mode of interaction of ligand molecules with Au atoms in the Au7 cluster. Interestingly, it has been found that NIR emitting gold quantum cluster can easily be internalized into the adenocarcinomic human alveolar basal epithelial cell line (A549 cell line). Moreover, a MTT assay indicates that our NIR emitting gold quantum cluster show very low cytotoxicy to A549 cancer cells. PMID- 25529746 TI - Nurses' experiences of caring for the older adult in the emergency department: a focused ethnography. AB - The purpose of this study was to explore nurses' experience of caring for the older adult within the ED. This focused ethnographic study used a combination of semi-structured interviews and non-participant observation. Seven registered nurses participated, detailing their experiences of caring for the older adult in the ED. Data were transcribed verbatim and analyzed thematically. Findings revealed three themes: the culture, which focused on priority setting and throughput of patients, lack of fit between the older adult and the ED, and managing lack of fit. Nurses relied on a default orientation of priority setting, recognizing this put the older adult at risk of substandard care. Lack of fit was accentuated by the need to 'puzzle through' atypical presentations of many older adults. It is concluded that consideration needs to be given on how to mitigate lack of fit and how to support nurses to give the care the older adult requires. PMID- 25529747 TI - Emergency nurses' knowledge, attitude and clinical decision making skills about pain. AB - INTRODUCTION: Pain is the most common reason that patients come to the emergency department. Emergency nurses have an indispensable role in the management of this pain. AIM: The aim of this study was to examine emergency nurses' knowledge, attitude and clinical decision-making skills about pain. METHODS: This descriptive study was conducted in a state and a university hospital between September and October 2012 in Malatya, Turkey. Of 98 nurses working in the emergency departments of these two hospitals, 57 returned the questionnaires. The response rate was 58%. Data were collected using the Demographic Information Questionnaire, Knowledge and Attitude Questionnaire about Pain and Clinical Decision Making Survey. Frequency, percentage, mean and standard deviation were used to evaluate data. RESULTS: 75.4% of participant nurses knew that patients' own statement about their pain was the most reliable indicator during pain assessment. Almost half of the nurses believed that patients should be encouraged to endure the pain as much as possible before resorting to a pain relief method. The results also indicate that most of nurses think that a sleeping patient does not have any pain and pain relief should be postponed as it can influence the diagnosis negatively. It is determined that the pain scale was not used frequently. Only 35.1% of nurses reported keeping records of pain. CONCLUSION: Despite all the recommendations of substantial past research the results of this study indicate that emergency nurses continue to demonstrate inadequate knowledge, clinical decision-making skills and negative attitudes about pain. PMID- 25529748 TI - Neural correlates of visual motion processing without awareness in patients with striate cortex and pulvinar lesions. AB - Patients with striate cortex lesions experience visual perception loss in the contralateral visual field. In few patients, however, stimuli within the blind field can lead to unconscious (blindsight) or even conscious perception when the stimuli are moving (Riddoch syndrome). Using functional magnetic resonance imaging (fMRI), we investigated the neural responses elicited by motion stimulation in the sighted and blind visual fields of eight patients with lesions of the striate cortex. Importantly, repeated testing ensured that none of the patients exhibited blindsight or a Riddoch syndrome. Three patients had additional lesions in the ipsilesional pulvinar. For blind visual field stimulation, great care was given that the moving stimulus was precisely presented within the borders of the scotoma. In six of eight patients, the stimulation within the scotoma elicited hemodynamic activity in area human middle temporal (hMT) while no activity was observed within the ipsilateral lesioned area of the striate cortex. One of the two patients in whom no ipsilesional activity was observed had an extensive lesion including massive subcortical damage. The other patient had an additional focal lesion within the lateral inferior pulvinar. Fiber-tracking based on anatomical and functional markers (hMT and Pulvinar) on individual diffusion tensor imaging (DTI) data from each patient revealed the structural integrity of subcortical pathways in all but the patient with the extensive subcortical lesion. These results provide clear evidence for the robustness of direct subcortical pathways from the pulvinar to area hMT in patients with striate cortex lesions and demonstrate that ipsilesional activity in area hMT is completely independent of conscious perception. PMID- 25529749 TI - Study of differential properties of fibrochondrocytes and hyaline chondrocytes in growing rabbits. AB - We aimed to build a culture model of chondrocytes in vitro, and to study the differential properties between fibrochondrocytes and hyaline chondrocytes. Histological sections were stained with haematoxylin and eosin so that we could analyse the histological structure of the fibrocartilage and hyaline cartilage. Condylar fibrochondrocytes and femoral hyaline chondrocytes were cultured from four, 4-week-old, New Zealand white rabbits. The production of COL2A1, COL1OA1, SOX9 and aggrecan was detected by real time-q polymerase chain reaction (RT-qPCR) and immunoblotting and the differences between them were compared statistically. Histological structures obviously differed between fibrocartilage and hyaline cartilage. COL2A1 and SOX9 were highly expressed within cell passage 2 (P2) of both fibrochondrocytes and hyaline chondrocytes, and reduced significantly after cell passage 4 (P4). The mRNA expressions of COL2A1 (p=0.05), COL10A1 (p=0.04), SOX9 (p=0.03), and aggrecan (p=0.04) were significantly higher in hyaline chondrocytes than in fibrochondrocytes, whereas the expression of COL1A1 (p=0.02) was the opposite. Immunoblotting showed similar results. We have built a simple and effective culture model of chondrocytes in vitro, and the P2 of chondrocytes is recommended for further studies. Condylar fibrocartilage and femoral hyaline cartilage have unique biological properties, and the regulatory mechanisms of endochondral ossification for the condyle should be studied independently in the future. PMID- 25529750 TI - Customised reconstruction of the orbital wall and engineering of selective laser melting (SLM) core implants. PMID- 25529751 TI - Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. AB - If diagnosed at early stages, patients with hepatocellular carcinoma (HCC) can receive curative therapies, whereas therapeutic options at later stages are very limited. Here, we addressed the potential of soluble Axl (sAxl) as a biomarker of early HCC by analyzing levels of sAxl in 311 HCC and 237 control serum samples from centers in Europe and China. Serum concentrations of sAxl were significantly increased in HCC (18.575 ng/mL) as compared to healthy (13.388 ng/mL) or cirrhotic (12.169 ng/mL) controls. Receiver operating characteristic curve analysis of sAxl in very early stage HCC patients (BCLC 0) showed an area under the curve (AUC) of 0.848, with a sensitivity of 76.9% and a specificity of 69.2%. alpha-Fetoprotein (AFP)-negative HCC patients displayed an AUC of 0.803, with sensitivity and specificity of 73% and 70.8%. Combination of sAxl and AFP improved diagnostic accuracy to 0.936 in very early HCC patients and to 0.937 in all HCC. Differential diagnosis of very early HCC versus liver cirrhosis showed a combined performance for sAxl and AFP of 0.901 with a sensitivity of 88.5% and a specificity of 76.7%. Furthermore, sAxl levels failed to be elevated in primary ovarian, colorectal and breast carcinomas as well as in secondary hepatic malignancies derived from colon. In summary, sAxl outperforms AFP in detecting very early HCC as compared to healthy or cirrhotic controls and shows high diagnostic accuracy for AFP-negative patients. sAxl is specific for HCC and suggested as a biomarker for routine clinical use. PMID- 25529754 TI - Combating the emerging viral infectious diseases. PMID- 25529752 TI - Gender differences in cadmium and cotinine levels in prepubertal children. AB - Susceptibility to environmental stressors has been described for fetal and early childhood development. However, the possible susceptibility of the prepubertal period, characterized by the orchestration of the organism towards sexual maturation and adulthood has been poorly investigated and exposure data are scarce. In the current study levels of cadmium (Cd), cotinine and creatinine in urine were analyzed in a subsample 216 children from 12 European countries within the DEMOCOPHES project. The children were divided into six age-sex groups: boys (6-8 years, 9-10 years and 11 years old), and girls (6-7 years, 8-9 years, 10-11 years). The number of subjects per group was between 23 and 53. The cut off values were set at 0.1 ug/L for Cd, and 0.8 ug/L for cotinine defined according to the highest limit of quantification. The levels of Cd and cotinine were adjusted for creatinine level. In the total subsample group, the median level of Cd was 0.180 ug/L (range 0.10-0.69 ug/L), and for cotinine the median wet weight value was 1.50 ug/L (range 0.80-39.91 ug/L). There was no significant difference in creatinine and cotinine levels between genders and age groups. There was a significant correlation between levels of cadmium and creatinine in all children of both genders. This shows that even at such low levels the possible effect of cadmium on kidney function was present and measurable. An increase in Cd levels was evident with age. Cadmium levels were significantly different between 6-7 year old girls, 11 year old boys and 10-11 year old girls. As there was a balanced distribution in the number of subjects from countries included in the study, bias due to data clustering was not probable. The impact of low Cd levels on kidney function and gender differences in Cd levels needs further investigation. PMID- 25529756 TI - Efficacy of ranitidine in olanzapine-induced weight gain: a dose-response study. AB - AIM: Weight gain has long been recognized as a side-effect of atypical antipsychotic drugs. Numerous new approaches have been tried for prevention of weight gain, the H2 blockers being one of them. The study was conducted with the aim to evaluate the efficacy of ranitidine in olanzapine-induced weight gain at two fixed doses of 150 and 300 mg day-1 . METHODS: Seventy-five inpatients with an ICD-10-DCR diagnosis of schizophrenia as their first episode were randomized into three groups of 25 patients each, receiving 150 mg day-1 ranitidine, 300 mg day-1 ranitidine and third group receiving only olanzapine. Their weight and body mass index (BMI) were measured at baseline and at intervals of 4 and 8 weeks. RESULTS: All patients were comparable with respect to their weight and BMI at baseline. When a change in the weight and BMI was assessed at 4 and 8 weeks from baseline, no significant difference was observed between the three groups. CONCLUSION: Ranitidine at doses of 150 and 300 mg day-1 when combined with olanzapine was ineffective in attenuating olanzapine-induced weight gain. The likely reasons could be the use of low doses for a shorter period of time, or mechanisms other than H2 receptors might play an important role in weight gain. PMID- 25529753 TI - Advancements in the development of subunit influenza vaccines. AB - The ongoing threat of influenza epidemics and pandemics has emphasized the importance of developing safe and effective vaccines against infections from divergent influenza viruses. In this review, we first introduce the structure and life cycle of influenza A viruses, describing major influenza A virus-caused pandemics. We then compare different types of influenza vaccines and discuss current advancements in the development of subunit influenza vaccines, particularly those based on nucleoprotein (NP), extracellular domain of matrix protein 2 (M2e) and hemagglutinin (HA) proteins. We also illustrate potential strategies for improving the efficacy of subunit influenza vaccines. PMID- 25529757 TI - Negative hemodynamic effects of pantoprazole at high infusion rates in mice. AB - BACKGROUND: Pantoprazole has been shown to exert a negative inotropic effect in isolated myocardium. The purpose of this study was to evaluate the hemodynamic effects of pantoprazole in vivo in healthy myocardium and in the setting of heart failure. METHODS AND RESULTS: Healthy mice and mice with heart failure 4 weeks after myocardial infarction induced by permanent LAD ligation were instrumented with a Millar Mikrotip conductance catheter to record pressure-volume loops. Pantoprazole was infused at rates of 3 and 10 mg/kg/min intravenously, and hemodynamic parameters were recorded. Infusion of pantoprazole at increasing rates lead to a significant decline of end systolic LV pressure by decreasing heart rate, myocardial contractility and arterial elastance. These effects were quick, beginning immediately with the infusion and usually reaching a plateau after 2 or 3 min of infusion. The effects on blood pressure and heart rate were of comparable size in healthy mice and mice with MI. However, in sham-operated mice, there was a compensatory increase in stroke volume that sufficed to maintain cardiac output at a constant level, which was missing in mice with MI. In 4 of 13 mice with MI infusion of 10 mg/kg/min pantoprazole lead to pump failure, which was lethal in 2 of these animals. CONCLUSION: At higher infusion rates, pantoprazole is able to induce negative hemodynamic responses. In particular, in the setting of heart failure, these effects can lead to significant impairment of cardiac function. Therefore, high infusion rates of pantoprazole should be avoided especially in heart failure patients. PMID- 25529755 TI - Sexual reproduction and genetic exchange in parasitic protists. AB - A key part of the life cycle of an organism is reproduction. For a number of important protist parasites that cause human and animal disease, their sexuality has been a topic of debate for many years. Traditionally, protists were considered to be primitive relatives of the 'higher' eukaryotes, which may have diverged prior to the evolution of sex and to reproduce by binary fission. More recent views of eukaryotic evolution suggest that sex, and meiosis, evolved early, possibly in the common ancestor of all eukaryotes. However, detecting sex in these parasites is not straightforward. Recent advances, particularly in genome sequencing technology, have allowed new insights into parasite reproduction. Here, we review the evidence on reproduction in parasitic protists. We discuss protist reproduction in the light of parasitic life cycles and routes of transmission among hosts. PMID- 25529758 TI - Statin therapy decreased the recurrence frequency of atrial fibrillation after electrical cardioversion: a meta-analysis. AB - BACKGROUND: It is unclear whether statin agents provide clinical benefit in preventing the relapse of atrial fibrillation (AF) after electrical cardioversion (EC). The purpose of this study was to assess the effect of statin agents on the recurrence of AF after EC by conducting a meta-analysis of randomized controlled trials (RCTs). MATERIAL AND METHODS: We conducted a systematic literature search of Medline, EMBASE, ISI Web of Science, and Cochrane databases. RCTs comparing clinical endpoint of the recurrence of AF associated with statin administration vs. no statin treatment (placebo or conventional medical therapy) in patients with AF after EC were eligible. Combined results are presented as risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: A total of 5 trials with 524 patients were available for analysis. The pooling analysis showed that statin agents significantly reduced the recurrence of AF after EC compared with no statin treatment (RR=0.76, 95% CI 0.63-0.92; p=0.004; I2=44%). The beneficial effect was shown both in AF subjects receiving atorvastatin or rosuvastatin treatment (atorvastatin 80 mg: RR=0.82, p=0.05; atorvastatin 10 mg: RR=0.27, p=0.03; rosuvastatin: RR=0.38, p=0.04) and in younger patients (<65 years; RR=0.58, p=0.0005). Furthermore, the benefit of statin agents on preventing AF recurrence after EC was demonstrated within 3-month follow-up (p=0.03), and the clinical benefit seemed likely to remain until no less than 12 months after EC (p=0.05). CONCLUSIONS: Based on the currently available data, administration of statin agents, especially atorvastatin or rosuvastatin, is beneficial in lowering the frequency of AF recurrence after EC. PMID- 25529759 TI - Highly selective and reversible chemosensor for Pd(2+) detected by fluorescence, colorimetry, and test paper. AB - A "turn-on" fluorescent and colorimetric chemosensor (RBS) for Pd(2+) has been designed and synthesized through introduction of sulfur as a ligand atom to Rhodamine B. RBS exhibits high selectivity (freedom from the interference of Hg(2+ )in particular) and sensitivity toward Pd(2+) with a detection limit as low as 2.4 nM. RBS is also a reversible sensor, and it can be made into test paper to detect Pd(2+) in pure water. Compared to the chemosensors that introduced phosphorus to Rhodamine to detect Pd(2+), RBS can be synthesized more simply and economically. PMID- 25529762 TI - Successful long-term management of choroidal neovascularization secondary to angioid streaks in a patient with pseudoxanthoma elasticum: a case report. AB - INTRODUCTION: We describe the long-term effectiveness and tolerability of intravitreal vascular endothelial growth factor inhibitor ranibizumab in a patient with pseudoxanthoma elasticum with bilateral macular choroidal neovascularization secondary to angioid streaks. CASE PRESENTATION: A 54-year-old Caucasian man with history of heart disease presented with visual loss in his right eye. An examination revealed choroidal neovascularization and reduced visual acuity, while no abnormalities were seen in his left eye. He was diagnosed with angioid streaks associated with pseudoxanthoma elasticum. Off-label treatment with intravitreal bevacizumab once a month initiated in December 2007 was discontinued after 3 months due to lack of efficacy. In September 2008, the patient reported reduced visual acuity in his left eye and an examination revealed changes. Left eye treatment was initiated in October 2008 with a loading dose (three consecutive monthly intravitreal injections of ranibizumab 0.5mg/50 MUL) followed by 0.5mg/50 MUL followed by treatment as needed until May 2014. After 21 ranibizumab injections, an examination revealed angioid streaks and choroidal neovascularization in both eyes. His right eye showed retinal layer deterioration with outer limiting membrane and photoreceptor inner/outer segment junction involvement. His left eye had a smaller foveal scar, with other areas preserved. Visual acuity was stable in his treated left eye, but had deteriorated in his right eye. Ranibizumab treatment was well tolerated with no adverse events reported. CONCLUSIONS: In the present case, an as-needed regimen of ranibizumab after an initial loading dose, achieved maintenance of visual function and was well tolerated over a period of almost 6 years in a patient with pseudoxanthoma elasticum and high cardiovascular risk. As anti-vascular endothelial growth factor agents are associated with increased risk of systemic effects, particularly arterial thromboembolic events, following intravenous administration, the absence of serious thromboembolic or cardiovascular adverse events throughout the 6-year treatment period is particularly encouraging considering our patient's high cardiovascular risk status. PMID- 25529763 TI - Human neutrophils are activated by a peptide fragment of Clostridium difficile toxin B presumably via formyl peptide receptor. AB - Clostridium difficile may induce antibiotic-associated diarrhoea and, in severe cases, pseudomembranous colitis characterized by tremendous neutrophil infiltration. All symptoms are caused by two exotoxins: TcdA and TcdB. We describe here the activation of isolated human blood neutrophils by TcdB and, moreover, by toxin fragments generated by limited proteolytical digestion. Kinetics and profiles of TcdB-induced rise in intracellular-free Ca(2+) and reactive oxygen species production were similar to that induced by fMLF, which activates the formyl peptide receptor (FPR) recognizing formylated bacterial peptide sequences. Transfection assays with the FPR-1 isoform hFPR26 in HEK293 cells, heterologous desensitization experiments and FPR inhibition via cyclosporine H strongly suggest activation of cells via FPR-1. Domain analyses revealed that the N-terminal glucosyltransferase domain of TcdB is a potent activator of FPR pointing towards an additional mechanism that might contribute to pathogenesis. This pro-inflammatory ligand effect can be triggered even by cleaved and, thus, non-cytotoxic toxin. In summary, we report (i) a ligand effect on neutrophils as completely new molecular mode of action, (ii) pathogenic potential of truncated or proteolytically cleaved 'non-cytotoxic' fragments and (iii) an interaction of the N-terminal glucosyltransferase domain instead of the C-terminal receptor binding domain of TcdB with target cells. PMID- 25529761 TI - Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin. AB - Previously, we prepared a pirarubicin (THP)-encapsulated micellar drug using styrene-maleic acid copolymer (SMA) as the drug carrier, in which active THP was non-covalently encapsulated. We have now developed covalently conjugated SMA-THP (SMA-THP conjugate) for further investigation toward clinical development, because covalently linked polymer-drug conjugates are known to be more stable in circulation than drug-encapsulated micelles. The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one-fifth of the maximum tolerable dose). Although SMA-THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor targeting properties in vivo. PMID- 25529764 TI - Uniquely human self-control begins at school age. AB - Human beings have remarkable skills of self-control, but the evolutionary origins of these skills are unknown. Here we compare children at 3 and 6 years of age with one of humans' two nearest relatives, chimpanzees, on a battery of reactivity and self-control tasks. Three-year-old children and chimpanzees were very similar in their abilities to resist an impulse for immediate gratification, repeat a previously successful action, attend to a distracting noise, and quit in the face of repeated failure. Six-year-old children were more skillful than either 3-year-olds or chimpanzees at controlling their impulses. These results suggest that humans' most fundamental skills of self-control - as part of the overall decision-making process - are a part of their general great ape heritage, and that their species-unique skills of self-control begin at around the age at which many children begin formal schooling. PMID- 25529765 TI - Ceftolozane/tazobactam for the treatment of complicated intra-abdominal infections. AB - INTRODUCTION: Decisions regarding empirical antimicrobial therapy for complicated intra-abdominal infections (cIAIs) are increasingly difficult because of the threat of antimicrobial resistance. Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae are a particular challenge, as is multidrug resistant (MDR) Pseudomonas aeruginosa, both of which are encountered in cIAI. Ceftolozane/tazobactam is a new antimicrobial that provides an effective solution for treating cIAI. AREAS COVERED: Evidence concerning the mechanism of action of ceftolozane/tazobactam, its in vitro activity against common cIAI pathogens, and pharmacokinetic and pharmacodynamic properties are reviewed. The clinical efficacy and safety of ceftolozane/tazobactam plus metronidazole, as determined by the Phase II and III clinical trials in hospitalized adults with cIAI, are discussed. EXPERT OPINION: Ceftolozane/tazobactam has demonstrated efficacy and safety in patients with cIAI, including those who are infected with ESBL producing Enterobacteriaceae and P. aeruginosa. High rates of clinical cure by ceftolozane/tazobactam in Phase II and III trials suggest that this antimicrobial will be valuable for treating infections caused by MDR Gram-negative bacteria. In recent years, clinicians have become dependent on carbapenems for treating MDR infections. There is concern that this could lead to emergence of carbapenem resistant strains, emphasizing the importance of antimicrobial stewardship. Ceftolozane/tazobactam appears to be an effective carbapenem-sparing alternative for treating cIAI. PMID- 25529766 TI - Proteome alterations in cortex of mice exposed to fluoride and lead. AB - Both fluoride and lead can cross the blood-brain barrier and produce toxic effects on the central neural system, resulting in low learning and memory abilities, especially in children. In order to identify the proteomic pattern in the cortex of young animals, from the beginning of fertilization to the age of postnatal day 56, pregnant female mice and pups were administrated with 150 mg sodium fluoride/L and/or 300 mg lead acetate/L in their drinking water. Two dimensional electrophoresis (2-DE) combined with mass spectrometry (MS) was applied to identify differently expressed protein spots. Results showed that there were eight proteins in the cortex that significantly changed, whose biological functions were involved in (1) energy metabolism (Ndufs1, Atp5h, Atp6v1b2), (2) cytoskeleton (Spna2, Tuba1a, Tubb2a), (3) glycation repair (Hdhd2), and (4) cell stress response (Hspa8). Based on the previous and current studies, ATPase, Spna2, and Hspa8 were shared by fluoride and lead both as common target molecules. PMID- 25529767 TI - Failure of gastroenterologists to apply intestinal ultrasound in inflammatory bowel disease in the Asia-Pacific: a need for action. AB - Intestinal ultrasound (IUS) is a cheap, noninvasive, risk-free procedure that is significantly underutilized in the diagnosis and management of patients with inflammatory bowel disease (IBD) in the Asia-Pacific region. More cost-effective methods of monitoring disease activity are required in light of the increasing global burden of IBD (especially in Asia), the advent of personalized medicine, and the rising cost of healthcare. IUS is a prime example of a technique that meets these needs. Its common clinical applications include assessing the activity and complications of IBD. In continental Europe, countries such as Germany and Italy use this imaging tool as the standard of care and have integrated it into management protocols. There are formal training programs in these countries to train gastroenterologists in IUS, and it is used in an outpatient setting during patient consultations. Barriers to its use in the Asia Pacific region include lack of experience and research data, and there are few established centers with active training programs. These concerns can be addressed by investing more in IUS service provision and by increasing allocation of resources toward local research and training. Increased uptake of IUS will ultimately benefit patients with IBD. PMID- 25529768 TI - Investigation of microstructured chitosans by coherent anti-Stokes Raman microscopy. AB - This work describes application of coherent anti-Stokes Raman scattering (CARS) microscopy technique for analytical characterization of microstructured materials based on chitosan. We demonstrate that nitrogen-hydrogen vibration band in the high wavenumber region of CARS spectrum prevails over response from oxygen hydrogen vibrations and can be used as a spectral marker of chitosan. The chemically selective imaging is experimentally demonstrated by applying CARS microscopy to discriminate between chitosan and polystyrene microparticles. CARS microscopy was shown to be a valuable tool for characterization of polluted chitosan fibre from utilized engine filter material. A possibility to observe foreign material pieces on the surface of the polluted chitosan fibre is demonstrated and discussed. PMID- 25529769 TI - Tea consumption reduces the risk of de novo myelodysplastic syndromes. AB - Epidemiologic data suggest that green tea consumption may protect against certain cancers, but no previous study has examined myelodysplastic syndromes (MDS). A hospital-based case-control study was conducted in China in 2012-2013 to investigate the association between tea intake and the risk of de novo MDS in adults. The study included 208 cases aged 19-85 years with MDS and 208 controls individually matched to the cases by gender, 5-year age group and residential locality. Odds ratios (ORs) were estimated using conditional logistic regression. Compared with non-tea drinkers, the adjusted ORs (95% confidence intervals) for all MDS combined were 0.39 (0.20-0.74), 0.45 (0.25-0.79), and 0.40 (0.21-0.77) for those who consumed tea >20 years, >=2 cups daily, and dried tealeaves >=750g per annum, respectively. Significant dose-response trends were observed across all the measures. The inverse association existed in both genders, in the refractory anemia with excessive blasts subtype, in cytogenetic 'good' and 'intermediated/poor' prognosis groups, and in the International Prognostic Scoring System lower and higher risk groups, but not in the refractory cytopenia with multilineage dysplasia subtype. The study suggests that regular tea consumption reduces the risk of de novo MDS in the Chinese population. PMID- 25529772 TI - A healthy lifestyle could reduce the onset of first heart attack by 80. PMID- 25529771 TI - Sphingosine kinase 1 enhances the invasion and migration of non-small cell lung cancer cells via the AKT pathway. AB - Sphingosine kinase 1 (SphK1) has been shown to play an important role in the progression of a number of human cancers. It has been reported that the expression of SphK1 is greatly elevated in non-small cell lung cancer (NSCLC) tissues. However, its role and underlying mechanisms in NSCLC have not been fully elucidated. In the present study, we found that SphK1 was highly expressed in NSCLC cells. Overexpression of SphK1 promoted the invasion and migration of NSCLC cells, while knockdown of SphK1 suppressed the invasion and migration. Furthermore, we demonstrated that SphK1 decreased the protein level of E cadherin, yet increased the protein level of Snail. In addition, SphK1 was able to stimulate the activation of AKT. Inhibition of the AKT pathway attenuated the biological functions of NSCLC cells induced by overexpression of SphK1. Taken together, our findings suggest that SphK1 can enhance the invasion and migration of NSCLC cells via activation of the AKT pathway and regulation of E-cadherin and Snail expression. Thus, SphK1 could be a potential target for the detection and treatment of NSCLC. PMID- 25529770 TI - Exogenous connexin43-expressing autologous skeletal myoblasts ameliorate mechanical function and electrical activity of the rabbit heart after experimental infarction. AB - Acute myocardial infarction is one of the major causes of mortality worldwide. For regeneration of the rabbit heart after experimentally induced infarction we used autologous skeletal myoblasts (SMs) due to their high proliferative potential, resistance to ischaemia and absence of immunological and ethical concerns. The cells were characterized with muscle-specific and myogenic markers. Cell transplantation was performed by injection of cell suspension (0.5 ml) containing approximately 6 million myoblasts into the infarction zone. The animals were divided into four groups: (i) no injection; (ii) sham injected; (iii) injected with wild-type SMs; and (iv) injected with SMs expressing connexin43 fused with green fluorescent protein (Cx43EGFP). Left ventricular ejection fraction (LVEF) was evaluated by 2D echocardiography in vivo before infarction, when myocardium has stabilized after infarction, and 3 months after infarction. Electrical activity in the healthy and infarction zones of the heart was examined ex vivo in Langendorff-perfused hearts by optical mapping using di-4 ANEPPS, a potential sensitive fluorescent dye. We demonstrate that SMs in the coculture can couple electrically not only to abutted but also to remote acutely isolated allogenic cardiac myocytes through membranous tunnelling tubes. The beneficial effect of cellular therapy on LVEF and electrical activity was observed in the group of animals injected with Cx43EGFP-expressing SMs. L-type Ca(2+) current amplitude was approximately fivefold smaller in the isolated SMs compared to healthy myocytes suggesting that limited recovery of LVEF may be related to inadequate expression or function of L-type Ca(2+) channels in transplanted differentiating SMs. PMID- 25529785 TI - Brackish Eutrophic Water Treatment by Iris pseudacorus L.-Planted Microcosms: Physiological Responses of Iris pseudacorus L. to Salinity. AB - Iris pseudacorus L. has been widely used in aquatic ecosystem to remove nutrient and has achieved positive effects. However, little is known regarding the nutrient-removal performance and physiological responses of I. pseudacorus for brackish eutrophic water treatment due to high nutrients combined with certain salinity levels. In this study, I. pseudacorus-planted microcosms were established to evaluate the capacity of I. pseudacorus to remove excessive nutrients from fresh (salinity 0.05%) and brackish (salinity 0.5%) eutrophic waters. The degradation of total nitrogen and ammonia nitrogen were not affected by 0.5% salinity; 0.5% salinity promoted the degradation of nitrate nitrogen while severely inhibited the degradation of total phosphorus. Additionally, 0.5% salinity was found to induce stress responses quantified by measuring six physiological indexes. Compared to 0.05% salinity, 0.5% salinity resulted in significant decreases in the chlorophyll a, b and total chlorophyll contents of I. pseudacorus which closely related to photosynthesis (p < 0.05). Furthermore, the higher proline, malondialdehyde contents and antioxidant enzyme activities were detected in I. pseudacorus exposed to 0.5% salinity, which provided protection against reactive oxygen species. The results highlight that the cellular stress assays are efficient for monitoring the health of I. pseudacorus in salinity shock-associated constructed wetlands. PMID- 25529786 TI - Remembering the past and imagining the future: Selective effects of an episodic specificity induction on detail generation. AB - According to the constructive episodic simulation hypothesis, remembering past experiences and imagining future experiences both rely heavily on episodic memory. However, recent research indicates that nonepisodic processes such as descriptive ability also influence memory and imagination. We recently found that an episodic specificity induction--brief training in recollecting details of past experiences--enhanced detail generation on memory and imagination tasks but not a picture description task and thereby concluded that the induction can dissociate episodic processes involved in remembering the past and imagining the future from those nonepisodic processes involved in description. To evaluate the generality of our previous findings and to examine the role of generative search in producing those findings, we modified our paradigm so that word cues replaced picture cues, and a word comparison task that requires generation of sentences and word definitions replaced picture description. Young adult participants received either a specificity induction or one of two control inductions before completing the memory, imagination, and word comparison tasks. Replicating and extending our previous work, we found that the specificity induction increased detail generation in memory and imagination without having an effect on word comparison. The induction's selective effect on memory and imagination stemmed from an increase in internal (i.e., on-topic and episodic) details and had no effect on external (e.g., off-topic or semantic) details. The results point to the efficacy of the specificity induction for isolating episodic processes involved in remembering the past and imagining the future even when a nonepisodic task requires generative search. PMID- 25529787 TI - Sleep quality in patients with dental anxiety. AB - BACKGROUND: Psychological distress is associated with sleep disturbances; however there is little research on sleep quality in dental anxiety (DA) patients. OBJECTIVES: To measure the sleep quality in patients with DA compared to patients with an exacerbated gag reflex (GAG) and controls and to analyze its association with various demographic and behavioral parameters. METHODS: 67 DA patients, 54 GAG patients and 100 controls with no history of DA or GAG participated in the study. Data regarding: demographic details, smoking habits, the Pittsburgh Sleep Quality Index (PSQI), Numeric Rating Scale (NRS) for pain assessment, Corah's dental anxiety scale (DAS) and Oral Health Impact Profile-14 (OHIP-14), plaque index (PI) and Decay, Missing and Filled Teeth (DMFT) scores were collected. RESULTS: 49.3% of the DA group and 38.9% of the GAG group were poor sleepers (mean PSQI score > 5), compared to 29.0% of the controls (PSQI mean scores: 5.8 +/- 3.4, DA group; 5.2 +/- 3.6 GAG group vs. 4.5 +/- 2.7, control group; p = 0.029). Compared to controls, DA and GAG patients exhibited poorer scores in the sleep disturbances PSQI component (p = 0.001). DA patients exhibited poorer scores in the sleep duration PSQI component compared to the control (p = 0.002) and GAG groups (p = 0.033). Female gender (p = 0.039), higher current (p = 0.046) and maximal NRS (p = 0.019), higher DAS (p < 0.001) and OHIP-14 (p < 0.001) scores and more missing teeth (p = 0.003) were positively associated with higher PSQI scores. CONCLUSIONS: DA patients suffered more from impaired sleep than controls and GAGs. Impaired sleep in DA patients is multidimensional phenomenon influenced by the specific diagnosis, gender, pain, dental anxiety levels, dental experience and oral health related quality of life. PMID- 25529788 TI - Resident physicians using modern practices for excellent documentation and care in heart failure (PUMPED CHF). AB - The most common indication for readmission among Medicare patients is congestive heart failure (CHF). Prior studies underscore the use of residents to bolster hospital-wide programs and reduce CHF readmissions. The authors assessed the effectiveness of a novel online training program designed to improve resident documentation and knowledge related to CHF. The findings suggest that despite a significant increase in knowledge scores following the online educational course, there was only a slight increase in documentation scores. Additional teaching modalities need to be identified to foster resident education and create sustained behavior change. PMID- 25529773 TI - Nucleosome positioning in yeasts: methods, maps, and mechanisms. AB - Eukaryotic nuclear DNA is packaged into nucleosomes. During the past decade, genome-wide nucleosome mapping across species revealed the high degree of order in nucleosome positioning. There is a conserved stereotypical nucleosome organization around transcription start sites (TSSs) with a nucleosome-depleted region (NDR) upstream of the TSS and a TSS-aligned regular array of evenly spaced nucleosomes downstream over the gene body. As nucleosomes largely impede access to DNA and thereby provide an important level of genome regulation, it is of general interest to understand the mechanisms generating nucleosome positioning and especially the stereotypical NDR-array pattern. We focus here on the most advanced models, unicellular yeasts, and review the progress in mapping nucleosomes and which nucleosome positioning mechanisms are discussed. There are four mechanistic aspects: How are NDRs generated? How are individual nucleosomes positioned, especially those flanking the NDRs? How are nucleosomes evenly spaced leading to regular arrays? How are regular arrays aligned at TSSs? The main candidates for nucleosome positioning determinants are intrinsic DNA binding preferences of the histone octamer, specific DNA binding factors, nucleosome remodeling enzymes, transcription, and statistical positioning. We summarize the state of the art in an integrative model where nucleosomes are positioned by a combination of all these candidate determinants. We highlight the predominance of active mechanisms involving nucleosome remodeling enzymes which may be recruited by DNA binding factors and the transcription machinery. While this mechanistic framework emerged clearly during recent years, the involved factors and their mechanisms are still poorly understood and require future efforts combining in vivo and in vitro approaches. PMID- 25529789 TI - Triple aim program: assessing its effectiveness as a hospital management tool. AB - According to a recent national survey of Hospital chief executive officers, financial challenges are their top concern, especially government reimbursement. Moreover, the patient faces greater deductibles forcing hospitals to prioritize price transparency. The Triple Aim program is a tool available to hospital management to help address these challenges. This study indicates that the Triple Aim is valuable to healthcare providers and patients by reducing medical errors, improving healthcare quality, and reducing costs on a per capita basis. Managerial implications are discussed for hospitals and health systems considering this approach to addressing financial challenges. PMID- 25529790 TI - Quality improvement in healthcare delivery utilizing the patient-centered medical home model. AB - Despite the fact that the United States dedicates so much of its resources to healthcare, the current healthcare delivery system still faces significant quality challenges. The lack of effective communication and coordination of care services across the continuum of care poses disadvantages for those requiring long-term management of their chronic conditions. This is why the new transformation in healthcare known as the patient-centered medical home (PCMH) can help restore confidence in our population that the healthcare services they receive is of the utmost quality and will effectively enhance their quality of life. Healthcare using the PCMH model is delivered with the patient at the center of the transformation and by reinvigorating primary care. The PCMH model strives to deliver effective quality care while attempting to reduce costs. In order to relieve some of our healthcare system distresses, organizations can modify their delivery of care to be patient centered. Enhanced coordination of services, better provider access, self-management, and a team-based approach to care represent some of the key principles of the PCMH model. Patients that can most benefit are those that require long-term management of their conditions such as chronic disease and behavioral health patient populations. The PCMH is a feasible option for delivery reform as pilot studies have documented successful outcomes. Controversy about the lack of a medical neighborhood has created concern about the overall sustainability of the medical home. The medical home can stand independently and continuously provide enhanced care services as a movement toward higher quality care while organizations and government policy assess what types of incentives to put into place for the full collaboration and coordination of care in the healthcare system. PMID- 25529791 TI - Managed care and organizational influences on hospitalist program adoption. AB - Hospitalists help improve healthcare efficiency, but less is known about the factors that influence hospitals to utilize hospitalists. The purpose of this research was to investigate the influence of managed care and hospital case mix on hospitalist program adoption in general hospitals. Maximum likelihood estimation was used to estimate a nonlinear binary response model to predict hospitalist program adoption. Hospital case mix was positively and significantly associated with the adoption of a hospitalist program while health maintenance organization market share was negatively related to hospitalist program adoption. Managers may want to consider these factors when planning to adopt a hospitalist program. PMID- 25529793 TI - Isosteric substitutions of urea to thiourea and selenourea in aliphatic oligourea foldamers: site-specific perturbation of the helix geometry. AB - Nearly isosteric oxo to thioxo substitution was employed to interrogate the structure of foldamers with a urea backbone and explore the relationship between helical folding and hydrogen-bonding interactions. A series of oligomers with urea bonds substituted by thiourea bonds at discrete or all positions in the sequence have been prepared and their folding propensity was studied by using a combination of spectroscopic methods and X-ray diffraction. The outcome of oxo to thioxo replacements on the helical folding was found to depend on whether central or terminal ureas were modified. The canonical helix geometry was not affected upon insertion of thioureas close to the negative end of the helix dipole, whereas thioureas close to the positive pole were found to increase the terminal flexibility and cause helix fraying. Perturbation was amplified when a selenourea was incorporated instead, leading to a structure that is only partly folded. PMID- 25529794 TI - Science isn't science if it isn't reproducible. AB - This Editorial introduces readers to the US National Institutes of Health's Proposed Principles and Guidelines for Reporting Preclinical Research. PMID- 25529797 TI - Ultrasound-assisted extraction and solid-phase extraction as a cleanup procedure for organochlorinated pesticides and polychlorinated biphenyls determination in aquatic samples by gas chromatography with electron capture detection. AB - The feasibility of developing a quick, easy, efficient procedure for the simultaneous determination of organochlorinated pesticides and polychlorinated biphenyls in aquatic samples using gas chromatography with electron capture detection based on solid-phase extraction was investigated. The extraction solvent (n-hexane/acetone, cyclohexane/ethyl acetate, n-hexane/dichloromethane, n hexane) for ultrasound-assisted solid-liquid extraction and solid-phase extraction columns (florisil, neutral alumina, acidic alumina, aminopropyl trimethoxy silane, propyl ethylenediamine, aminopropyl trimethoxy silane/propyl ethylenediamine, graphitized carbon black and silica) for cleanup procedure were optimized. The gas chromatography with electron capture detection method was validated in terms of linearity, sensitivity, reproducibility, and recovery. Mean recoveries ranged from 75 to 115% with relative standard deviations <13%. Quantification limits were 0.20-0.40 ng/g for organochlorinated pesticides and polychlorinated biphenyls. The satisfactory data demonstrated the good reproducibility of the method with relative standard deviations lower than 13%. In comparison to other related methods, this method requires less time and solvent and allows for rapid isolation of the target analytes with high selectivity. This method therefore allows for the screening of numerous samples and can also be used for routine analyses. PMID- 25529795 TI - p120-catenin down-regulation and epidermal growth factor receptor overexpression results in a transformed epithelium that mimics esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis due to its highly invasive and metastatic potential. The molecular pathogenesis underlying the invasive mechanism of ESCC is not well known because of the lack of existing models to study this disease. p120-Catenin (p120ctn) and the epidermal growth factor receptor (EGFR) have each been implicated in several cancers, including ESCC. p120ctn is down-regulated in 60% of ESCC tumors, whereas EGFR is the most commonly overexpressed oncogene in ESCC. For these reasons, we investigated the cooperation between p120ctn and EGFR and its effect on ESCC invasion. We show that p120ctn down-regulation is commonly associated with EGFR overexpression. By using a three-dimensional culture system, we demonstrate that the inverse relationship between p120ctn and EGFR has biological implications. Specifically, p120ctn down-regulation coupled with EGFR overexpression in human esophageal keratinocytes (EPC1-PE) was required to promote invasion. Morphological comparison of EPC1-PE cells grown in three-dimensional culture and human ESCC revealed identical features, including significantly increased cellularity, nuclear grade, and proliferation. Molecular characteristics were measured by keratin expression patterns, which were nearly identical between EPC1 PE cells in three-dimensional culture and ESCC samples. Altogether, our analyses have demonstrated that p120ctn down-regulation and EGFR overexpression are able to mimic human ESCC in a relevant three-dimensional culture model. PMID- 25529798 TI - Editor's perspectives - December 2014. PMID- 25529796 TI - Loss of Sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays PARK2 translocation to mitochondria. AB - Prostatic intraepithelial neoplasia is a precursor to prostate cancer. Herein, deletion of the NAD(+)-dependent histone deacetylase Sirt1 induced histological features of prostatic intraepithelial neoplasia at 7 months of age; these features were associated with increased cell proliferation and enhanced mitophagy. In human prostate cancer, lower Sirt1 expression in the luminal epithelium was associated with poor prognosis. Genetic deletion of Sirt1 increased mitochondrial superoxide dismutase 2 (Sod2) acetylation of lysine residue 68, thereby enhancing reactive oxygen species (ROS) production and reducing SOD2 activity. The PARK2 gene, which has several features of a tumor suppressor, encodes an E3 ubiquitin ligase that participates in removal of damaged mitochondria via mitophagy. Increased ROS in Sirt1(-/-) cells enhanced the recruitment of Park2 to the mitochondria, inducing mitophagy. Sirt1 restoration inhibited PARK2 translocation and ROS production requiring the Sirt1 catalytic domain. Thus, the NAD(+)-dependent inhibition of SOD2 activity and ROS by SIRT1 provides a gatekeeper function to reduce PARK2-mediated mitophagy and aberrant cell survival. PMID- 25529799 TI - Increased Risk of Depression in Patients with Parkinson Disease: A Nationwide Cohort Study. AB - OBJECTIVE: The association between Parkinson disease (PD) and depression remains unclear, particularly in the Asian population. The purpose of this study is to investigate the risk of depression in patients with PD using population-based data. METHODS: Based on the National Health Insurance Research Database of Taiwan, we identified 1,698 patients with PD aged 40 years or older diagnosed in 2000-2003. With frequency matching procedure, we randomly selected 6,792 subjects without PD stratified by sex and age. Both cohorts were followed until the end of 2008 or diagnosis of depression. Risk of depression associated with PD was estimated in the multivariate Cox hazards regressions. Diabetes, hypertension, and hyperlipidemia were more prevalent at baseline in patients with PD. RESULTS: Compared with the cohort without PD, the hazard ratio (HR) for depression in PD patients was 4.06 (95% CI: 3.15-5.23), which increased to 4.26 (95% CI: 3.29 5.51) after adjustment for age, sex, urbanization, income, and coexisting medical conditions. In the sex stratification, the HR of depression for men with PD was 4.42 (95% CI: 2.93-6.67) compared with men without PD. The HR for the association between PD and depression in women was 4.22 (95% CI: 3.02-5.88). CONCLUSION: This study suggests that patients with PD are at an elevated risk of depression, particularly for men. Integrated care for early identification and treatment of depression are crucial for patients with PD. PMID- 25529804 TI - Treatment of recurrent hepatitis C with interferon-free regimens: better starting early. PMID- 25529801 TI - Comparative endothelial profiling of doxorubicin and daunorubicin in cultured endothelial cells. AB - Although anthracycline antibiotics have been successfully used for nearly half a century in the treatment of various malignancies, their use is limited by their cardiac and vascular toxicities, and the mechanisms of these toxicities are still not entirely clear. Herein, we comprehensively characterized cytotoxic effects of two structurally related anthracyclines, doxorubicin and daunorubicin. In nanomolar concentrations, both drugs induced DNA damage and increased nuclear area that were associated with their accumulation in the nucleus (doxorubicin ?50 nM and daunorubicin ?25 nM) as evidence by Raman microspectroscopy at 3820-4245 cm(-1). At low micromolar concentrations, doxorubicin (?5 MUM) and daunorubicin (?1 MUM) increased the generation of reactive oxygen species, decreased intracellular reduced glutathione, induced an alteration in endothelial elasticity and caused a reorganization of the F-actin cytoskeleton. In isolated mouse aortic rings, doxorubicin (?50 MUM) was less potent than daunorubicin (?5 MUM) in impairing the endothelium-dependent response. In summary, using a comprehensive endothelial profiling approach, we demonstrated clear-cut differences in the potencies to induce endotheliotoxic responses for two structurally similar chemotherapeutics, at a nuclear, cytosolic and membrane levels. Furthermore, our results suggest that the differences in the endothelial toxicities of doxorubicin and daunorubicin are linked to differences in their nuclear accumulation and the DNA damage-triggered response of the endothelium. PMID- 25529802 TI - Augmenter of liver regeneration links mitochondrial function to steatohepatitis and hepatocellular carcinoma. PMID- 25529805 TI - Recurring rare liver tumor presenting with hypoglycemia. PMID- 25529806 TI - Multiple masses in the colon of a patient with ulcerative colitis. PMID- 25529800 TI - Impulsive traits and unplanned suicide attempts predict exaggerated prefrontal response to angry faces in the elderly. AB - OBJECTIVE: Abnormal responses to social stimuli are seen in people vulnerable to suicidal behavior, indicating possible disruptions in the neural circuitry mediating the interpretation of socioemotional cues. These disruptions have not been empirically related to psychological and cognitive pathways to suicide. In the present study of older suicide attempters, we examined neural responses to emotional faces and their relationship to impulsivity, one of the components of the suicidal diathesis. METHODS: Using functional magnetic resonance imaging, we recorded neurohemodynamic responses to angry faces in a carefully characterized sample of 18 depressed elderly with history of suicide attempts, 13 depressed nonsuicidal patients, and 18 healthy individuals, all aged 60+. Impulsivity was assessed with the Social Problem Solving Inventory Impulsivity/Carelessness Style subscale and Barratt Impulsiveness Scale. The Suicide Intent Scale planning subscale was used to describe the degree of planning associated with the most lethal attempt. RESULTS: Depression and history of attempted suicide were not associated with neural responses to angry faces, failing to replicate earlier studies. Higher impulsivity, however, predicted exaggerated responses to angry faces in fronto-opercular and dorsomedial prefrontal cortex (pcorr <0.05). Poorly planned suicide attempts also predicted increased fronto-opercular responses. Results were robust to effects of medication exposure, comorbid anxiety and addiction, severity of depression, burden of physical illness, and possible brain injury from suicide attempts. CONCLUSION: Impulsive traits and history of unplanned suicide attempts partly explain the heterogeneity in neural responses to angry faces in depressed elderly. Displays of social emotion command excessive cortical processing in impulsive suicide attempters. PMID- 25529807 TI - An unexpected cause of intestinal obstruction in an uncommon site. PMID- 25529808 TI - Melena and hyperammonemic seizures in a turner syndrome patient. PMID- 25529809 TI - Liver sinusoidal endothelial cells: an antiviral "defendothelium". PMID- 25529810 TI - Multifocal pancreatic tumors in a young woman. PMID- 25529811 TI - Long noncoding RNAs and hepatocellular carcinoma. PMID- 25529812 TI - Two wrongs, one right. PMID- 25529813 TI - No risk of malignancy with biologics in inflammatory bowel disease: is the debate over? PMID- 25529814 TI - Abdominal pain and ileocolitis in a 51-year-old woman. PMID- 25529816 TI - Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans. AB - An estimated 4 million Americans have been exposed to the hepatitis C virus (HCV). The risks of incident and progressive chronic kidney disease and of mortality in patients with normal kidney function infected with HCV are unclear. In a nationally representative cohort of 100,518 HCV(+) and 920,531 HCV(-) US veterans with normal baseline estimated glomerular filtration rate (eGFR), we examined the association of HCV infection with (1) all-cause mortality, (2) incidence of decreased kidney function (defined as eGFR <60 mL/min/1.73 m(2) and 25% decrease in eGFR), (3) end-stage renal disease, and (4) rate of kidney function decline. Associations were examined in naive and adjusted Cox models (for time-to-event analyses) and logistic regression models (for slopes), with sequential adjustments for important confounders. Propensity-matched cohort analysis was used in sensitivity analyses. The patients' age was 54.5 +/- 13.1 (mean +/- standard deviation) years, 22% were black, 92% were male, and the baseline eGFR was 88 +/- 16 mL/min/1.73 m(2) . In multivariable adjusted models HCV infection was associated with a 2.2-fold higher mortality (fully adjusted hazard ratio = 2.17, 95% confidence interval [CI] 2.13-2.21), a 15% higher incidence of decreased kidney function (adjusted hazard ratio = 1.15, 95% CI 1.12 1.17), a 22% higher risk of steeper slopes of eGFR (adjusted odds ratio = 1.22, 95% CI 1.19-1.26), and a 98% higher hazard of end-stage renal disease (adjusted hazard ratio = 1.98, 95% CI 1.81-2.16). Quantitatively similar results were found in propensity-matched cohort analyses. CONCLUSIONS: Infection with HCV is associated with higher mortality risk, incidence of decreased kidney function, and progressive loss of kidney function; randomized controlled trials are warranted to determine whether treatment of HCV infection can prevent the development and progression of chronic kidney disease and improve patient outcomes. PMID- 25529817 TI - Validity of a questionnaire measuring motives for choosing foods including sustainable concerns. AB - Since the 1990s, sustainability of diet has become an increasingly important concern for consumers. However, there is no validated multidimensional measurement of motivation in the choice of foods including a concern for sustainability currently available. In the present study, we developed a questionnaire that measures food choice motives during purchasing, and we tested its psychometric properties. The questionnaire included 104 items divided into four predefined dimensions (environmental, health and well-being, economic and miscellaneous). It was administered to 1000 randomly selected subjects participating in the Nutrinet-Sante cohort study. Among 637 responders, one-third found the questionnaire complex or too long, while one-quarter found it difficult to fill in. Its underlying structure was determined by exploratory factor analysis and then internally validated by confirmatory factor analysis. Reliability was also assessed by internal consistency of selected dimensions and test-retest repeatability. After selecting the most relevant items, first-order analysis highlighted nine main dimensions: labeled ethics and environment, local and traditional production, taste, price, environmental limitations, health, convenience, innovation and absence of contaminants. The model demonstrated excellent internal validity (adjusted goodness of fit index = 0.97; standardized root mean square residuals = 0.07) and satisfactory reliability (internal consistency = 0.96, test-retest repeatability coefficient ranged between 0.31 and 0.68 over a mean 4-week period). This study enabled precise identification of the various dimensions in food choice motives and proposed an original, internally valid tool applicable to large populations for assessing consumer food motivation during purchasing, particularly in terms of sustainability. PMID- 25529818 TI - Well, that's what came with it. A qualitative study of U.S. mothers' perceptions of healthier default options for children's meals at fast-food restaurants. AB - INTRODUCTION: Using a qualitative design, this study investigated mothers' perceptions of food choices and default options, for children, at fast-food restaurants. STUDY DESIGN: Mothers of 3- to 8-year-old children (n = 40) participated in phone interviews. RESULTS: Mothers praised fast-food restaurants for offering healthier choices, but voiced concerns about quality of the food. Half worried about meat products and several were distressed by the processing involved with food and beverages. Many said that their children wanted to visit fast-food restaurants because of advertised toys and not food offerings. Half liked bundled meals, as long as they could choose the specific items that were included. Having healthier defaults might eliminate battles, reduce forgetfulness and facilitate ordering. Most mothers favored healthier defaults because it would help "other parents." CONCLUSION: This small study provides strong support for offering healthier options at fast-food restaurants. Restaurants, schools and other food venues should design children's meals that make the healthy choice the easy choice. PMID- 25529819 TI - Underlying differences between conscientious omnivores and vegetarians in the evaluation of meat and animals. AB - As criticisms of factory farming continue to mount, an increasing number of individuals have changed their existing dietary practices. Perhaps the two most important options for those reacting against industrial farming are (1) vegetarianism/veganism (i.e., veg*nism), the avoidance of animal flesh/all animal products; and (2) conscientious omnivorism (CO), the consumption of meat or fish only when it satisfies certain ethical standards. While the former group has recently received much attention in the social science literature, studies specifically examining those who identify themselves as COs have been virtually nonexistent. The present research sought to investigate possible underlying attitudinal differences between the two groups. Results indicated that relative to veg*ns, COs evaluated animals less favorably, meat more favorably, and were lower in idealism, misanthropy, and ingroup identification. Mediation analysis demonstrated that differences between COs and veg*ns in the perceived acceptability of killing animals for food were mediated by beliefs about animals and meat. The discussion largely speculates on the causal direction of these effects. PMID- 25529820 TI - Role of the Parathyroid Hormone Type 1 Receptor (PTH1R) as a Mechanosensor in Osteocyte Survival. AB - Osteocytes have a major role in the control of bone remodeling. Mechanical stimulation decreases osteocyte apoptosis and promotes bone accrual, whereas skeletal unloading is deleterious in both respects. PTH1R ablation or overexpression in osteocytes in mice produces trabecular bone loss or increases bone mass, respectively. The latter effect was related to a decreased osteocyte apoptosis. Here, the putative role of PTH1R activation in osteocyte protection conferred by mechanical stimulation was assessed. Osteocytic MLO-Y4 cells were subjected to mechanical stimuli represented by hypotonic shock (216 mOsm/kg) or pulsatile fluid flow (8 Hz, 10 dynes/cm(2)) for a short pulse (10 min), with or without PTH1R antagonists or after transfection with specific PTHrP or PTH1R siRNA. These mechanical stimuli prevented cell death induced within 6 hours by etoposide (50 MUM), related to PTHrP overexpression; and this effect was abolished by the calcium antagonist verapamil (1 MUM), a phospholipase C (PLC) inhibitor (U73122; 10 MUM), and a PKA activation inhibitor, Rp-cAMPS (25 MUM), in these cells. Each mechanical stimulus also rapidly induced beta-catenin stabilization and nuclear ERK translocation, which were inhibited by the PTH1R antagonist PTHrP(7-34) (1 MUM), or PTH1R siRNA, and mimicked by PTHrP(1-36) (100 nM). Mechanical stretching by hypotonic shock did not affect cAMP production but rapidly (<1 min) stimulated Ca(i)(2+) transients in PTH1R-overexpressing HEK-293 cells and in MLO-Y4 cells, in which calcium signaling was unaffected by the presence of a PTHrP antiserum or PTHrP siRNA but inhibited by knocking down PTH1R. These novel findings indicate that PTH1R is an important component of mechanical signal transduction in osteocytic MLO-Y4 cells, and that PTH1R activation by PTHrP-independent and dependent mechanisms has a relevant role in the prosurvival action of mechanical stimulus in these cells. PMID- 25529821 TI - Percutaneous bi-atrial extracorporeal membrane oxygenation for acute circulatory support in advanced heart failure. AB - Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) may improve survival after cardiac arrest by providing cardiopulmonary support. However, VA-ECMO increases left ventricular (LV) afterload, which can promote progressive LV distension and often requires a secondary approach to reduce LV pressure and volume in patients with left heart failure. We report a case of biventricular unloading via biatrial cannulation in the presence of LV thrombus using a TandemHeart percutaneous trans-septal cannula for VA-ECMO in an adult patient with refractory ventricular fibrillation. PMID- 25529823 TI - Simulation of one-dimensional blood flow in networks of human vessels using a novel TVD scheme. AB - An extension of a total variation diminishing (TVD) scheme to solve one dimensional (1D) blood flow for human circulation is proposed. This method is simple as it involves only a few modifications to existing shock-capturing TVD schemes. We have applied the method to a wide range of test cases including a complete simulation of the human vascular network. Excellent solutions have been demonstrated for problems involving varying and discontinuous mechanical properties of blood vessels. For 1D network simulations, the method has been shown to agree well with the reported computational results. Finally, the method has been demonstrated to compare favorably with in vivo experiments set up to study the impact of circle of Willis anomalies on flow patterns in the cerebral arterial system. PMID- 25529822 TI - 3-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,2,5-selenadiazole (G 1103), a novel combretastatin A-4 analog, induces G2/M arrest and apoptosis by disrupting tubulin polymerization in human cervical HeLa cells and fibrosarcoma HT-1080 cells. AB - Microtubule is a popular target for anticancer drugs. In this study, we describe the effect 3-(3-hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,2,5 selenadiazole (G-1103), a newly synthesized analog of combretastatin A-4 (CA-4), showing a strong time- and dose-dependent anti-proliferative effect on human cervical cancer HeLa cells and human fibrosarcoma HT-1080 cells. We demonstrated that the growth inhibitory effects of G-1103 in HeLa and HT-1080 cells were associated with microtubule depolymerization and proved that G-1103 acted as microtubule destabilizing agent. Furthermore, cell cycle analysis revealed that G 1103 treatment resulted in cell cycle arrest at the G2/M phase in a time dependent manner with subsequent apoptosis induction. Western blot analysis revealed that down-regulation of cdc25c and up-regulation of cyclin B1 was related with G2/M arrest in HeLa and HT-1080 cells treatment with G-1103. In addition, G-1103 induced HeLa cell apoptosis by up-regulating cleaved caspase-3, Fas, cleaved caspase-8 expression, which indicated that G-1103 induced HeLa cell apoptosis was mainly associated with death receptor pathway. However, G-1103 induced HT-1080 cell apoptosis by up-regulating cleaved caspase-3, Fas, cleaved caspase-8, Bax and cleaved caspase-9 expression and down-regulating anti apoptotic protein Bcl-2 expression, which indicated that G-1103 induced HT-1080 cell apoptosis was associated with both mitochondrial and death receptor pathway. Taken together, all the data demonstrated that G-1103 exhibited its antitumor activity through disrupting the microtubule assembly, causing cell cycle arrest and consequently inducing apoptosis in HeLa and HT-1080 cells. Therefore, the novel compound G-1103 is a promising microtubule inhibitor that has great potentials for therapeutic treatment of various malignancies. PMID- 25529824 TI - The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway. AB - Aging causes phenotypic changes in skeletal muscle progenitor cells that lead to the progressive loss of myogenic differentiation and thus a decrease in muscle mass. The naturally occurring triterpene, ursolic acid, has been reported to be an effective agent for the prevention of muscle loss by suppressing degenerative muscular dystrophy. Leucine, a branched-chain amino acid, and its metabolite, beta-hydroxy-beta-methylbutyric acid, have been reported to enhance protein synthesis in skeletal muscle. Therefore, the aim of the present study was to investigate whether the combination of ursolic acid and leucine promotes greater myogenic differentiation compared to either agent alone in C2C12 murine myoblasts. Morphological changes were observed and creatine kinase (CK) activity analysis was performed to determine the conditions through which the combination of ursolic acid and leucine would exert the most prominent effects on muscle cell differentiation. The effect of the combination of ursolic acid and leucine on the expression of myogenic differentiation marker genes was examined by RT-PCR and western blot analysis. The combination of ursolic acid (0.5 uM) and leucine (10 uM) proved to be the most effective in promoting myogenic differentiation. The combination of ursolic acid and leucine significantly increased CK activity than treatment with either agent alone. The level of myosin heavy chain, a myogenic differentiation marker protein, was also enhanced by the combination of ursolic acid and leucine. The combination of ursolic acid and leucine significantly induced the expression of myogenic differentiation marker genes, such as myogenic differentiation 1 (MyoD) and myogenin, at both the mRNA and protein level. In addition, the number of myotubes and the fusion index were increased. These findings indicate that the combination of ursolic acid and leucine promotes muscle cell differentiation, thus suggesting that this combination of agents may prove to be beneficial in increasing muscle mass. PMID- 25529825 TI - Health care response to CCHF in US soldier and nosocomial transmission to health care providers, Germany, 2009. AB - In 2009, a lethal case of Crimean-Congo hemorrhagic fever (CCHF), acquired by a US soldier in Afghanistan, was treated at a medical center in Germany and resulted in nosocomial transmission to 2 health care providers (HCPs). After his arrival at the medical center (day 6 of illness) by aeromedical evacuation, the patient required repetitive bronchoscopies to control severe pulmonary hemorrhage and renal and hepatic dialysis for hepatorenal failure. After showing clinical improvement, the patient died suddenly on day 11 of illness from cerebellar tonsil herniation caused by cerebral/cerebellar edema. The 2 infected HCPs were among 16 HCPs who received ribavirin postexposure prophylaxis. The infected HCPs had mild or no CCHF symptoms. Transmission may have occurred during bag-valve mask ventilation, breaches in personal protective equipment during resuscitations, or bronchoscopies generating infectious aerosols. This case highlights the critical care and infection control challenges presented by severe CCHF cases, including the need for experience with ribavirin treatment and postexposure prophylaxis. PMID- 25529826 TI - Oxo-anion recognition by mono- and bisurea pendant-arm macrocyclic complexes. AB - The novel macrocyclic copper(II) complexes [2](2+) and [3](2+), carrying one or two (nitrophenyl)urea fragments appended to an azacyclam or diazacyclam framework, exploit the hydrogen-bond-forming abilities of the urea subunits, along with the metal-ligand interaction, in the recognition of anionic species. Equilibrium studies in acetonitrile performed on [2](2+) and [3](2+) show that (nitrophenyl)urea pendant arms strongly interact with anionic species such as carboxylates and phosphates, which display both coordinating tendencies toward copper(II) and good affinity toward urea subunits. Stability constants of the adducts are considerably higher than those determined for the interaction of the same anions with a "plain urea" reference compound, confirming the synergistic action of metallomacrocyclic and urea subunits. Complex [2](2+) forms 1:1 adducts with acetate, benzoate, hydrogendiphosphate, and dihydrogen phosphate, while complex [3](2+) interacts with the same anions according to both 1:1 and 1:2 stoichiometries, with the exception of hydrogendiphosphate, which forms only the 1:1 adduct with a distinctly high association constant (log K > 7). Spectrophotometric investigations suggest that oxoanionic species interact with the complexes according to a "bridged" mode, inducing the macrocyclic systems to adopt a scorpionate-like conformation, as confirmed by crystallographic studies on the [3](2+)/succinate adduct. PMID- 25529827 TI - Acyl-chain elongation drives ketosynthase substrate selectivity in trans acyltransferase polyketide synthases. AB - Type I modular polyketide synthases (PKSs), which are responsible for the biosynthesis of many biologically active agents, possess a ketosynthase (KS) domain within each module to catalyze chain elongation. Acylation of the KS active site Cys residue is followed by transfer to malonyl-ACP to yield an extended beta-ketoacyl chain (ACP = acyl carrier protein). To date, the precise contribution of KS selectivity in controlling product fidelity has been unclear. Six KS domains from trans-acyltransferase (trans-AT) PKSs were subjected to a mass spectrometry based elongation assay, and higher substrate selectivity was identified for the elongating step than in preceding acylation. A close correspondence between the observed KS selectivity and that predicted by phylogenetic analysis was seen. These findings provide insights into the mechanism of KS selectivity in this important group of PKSs, can serve as guidance for engineering, and show that targeted mutagenesis can be used to expand the repertoire of acceptable substrates. PMID- 25529828 TI - Re-emerging of porcine respiratory and reproductive syndrome virus (lineage 3) and increased pathogenicity after genomic recombination with vaccine variant. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) was first reported in China since late 1995 and several variants were further reported in subsequence years, causing huge economic losses to the Chinese swine industry. To date, three major lineages (lineage 3, 5.1 and 8.7) of Type 2 PRRSV were reported in China based on our global genotyping. The present study provides the epidemiology of the PRRSV in South China based on the isolates collected during 2009-2012, indicating three lineages (lineage 3, 5.1 and 8.7) of Type 2 PRRSV were still circulating in this area. Our phylogenetic reconstruction indicated that lineage 3 re-emerged in 2010 formed a huge cluster with closely related to the 2004 isolates from Hong Kong. Furthermore, the inter-lineage genomic recombination between MLV vaccine strain (lineage 5) and a recently re-emerged lineage 3 virus (QYYZ) has also been found in a farm practicing MLV vaccination. Our in vivo experiment comparing the pathogenicity and clinical presentations among currently isolated viruses indicated that pigs infected with recombinant lineage 3 virus (GM2) showed persistent higher fever compared to pigs infected by its wild counterpart (QYYZ). This study enhanced our understanding on potential importance of the recombination of PRRSV along with their evolution. PMID- 25529829 TI - Measuring dwell time percentage from head-mounted eye-tracking data--comparison of a frame-by-frame and a fixation-by-fixation analysis. AB - Although analysing software for eye-tracking data has significantly improved in the past decades, the analysis of gaze behaviour recorded with head-mounted devices is still challenging and time-consuming. Therefore, new methods have to be tested to reduce the analysis workload while maintaining accuracy and reliability. In this article, dwell time percentages to six areas of interest (AOIs), of six participants cycling on four different roads, were analysed both frame-by-frame and in a 'fixation-by-fixation' manner. The fixation-based method is similar to the classic frame-by-frame method but instead of assigning frames, fixations are assigned to one of the AOIs. Although some considerable differences were found between the two methods, a Pearson correlation of 0.930 points out a good validity of the fixation-by-fixation method. For the analysis of gaze behaviour over an extended period of time, the fixation-based approach is a valuable and time-saving alternative for the classic frame-by-frame analysis. PMID- 25529830 TI - Time to improvement of pain and sleep quality in clinical trials of pregabalin for the treatment of fibromyalgia. AB - OBJECTIVE: To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia. DESIGN: A post hoc analysis of four 8- to 14-week phase 2-3, placebo-controlled trials of fixed-dose pregabalin (150-600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms. PATIENTS: A total of 2,747 patients with fibromyalgia, aged 18-82 years. METHODS: Pain and sleep quality scores, recorded daily on 11-point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of >=2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a >=1-point reduction of the baseline NRS score of patient responders who had a >=30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at endpoint. RESULTS: Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo. CONCLUSIONS: Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo. PMID- 25529831 TI - Performance characteristics of a brief Family History Questionnaire to screen for Lynch syndrome in women with newly diagnosed endometrial cancer. AB - OBJECTIVE: The brief Family History Questionnaire (bFHQ) was developed to identify endometrial cancer patients whose family histories suggest Lynch syndrome (LS). We compared the bFHQ, extended Family History Questionnaire (eFHQ) and dictated medical records (DMRs) to determine which family history screening strategy is superior in identifying LS in unselected women with newly diagnosed endometrial cancer that have undergone universal germline testing. METHODS: Prospective cohort study recruited women with newly diagnosed endometrial cancer to evaluate screening strategies to identify LS. Participants completed bFHQ and eFHQ, had tumor assessed with immunohistochemistry (IHC) for mismatch repair proteins (MMR) and micro-satellite instability testing and underwent universal germline testing for LS. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) were compared between the family history screening strategies as well as IHC. RESULTS: 118 of 182 eligible patients (65%) consented; 87 patients (74%) were evaluable with both family history and germline mutation status. Median age was 61years (range 26-91). All 7 patients with confirmed LS were correctly identified by bFHQ, compared to 5 and 4 by eFHQ and DMR, respectively. The sensitivity, specificity, PPV and NPV values of bFHQ were 100%, 76.5%, 25.9% and 100%, respectively, performing similar to IHC testing. While eFHQ was more specific than bFHQ (86.7% vs. 76.5%, P=0.007), 2 cases of LS were missed. CONCLUSIONS: The patient-administered bFHQ effectively identified women with confirmed LS and is a good screening tool to triage women with endometrial cancer for further genetic assessment. PMID- 25529834 TI - On-chip read-out of picomechanical motion under ambient conditions. AB - Monitoring the nanomechanical movement of suspended cantilever structures has found use in applications ranging from biological/chemical sensing to atomic force microscopy. Interrogating these sensors relies on the ability to accurately determine the sub-nanometre movements of the cantilever. Here we investigate a technique based on the combination of integrated silicon photonics and microelectromechanical systems (MEMS) to create an optically resonant microcavity and demonstrate its use for monitoring of the position of cantilevers on the picometer scale under ambient conditions with dynamic range extending over several microns. The technique is interferometric, and we show it to be sufficiently sensitive to measure both the first and second modes of cantilever Brownian motion. We anticipate that application of this technique will provide a physically robust, picometer precision, integrated cantilever movement read-out technology which can take cantilever sensors from laboratory controlled environments into real world conditions, allowing everyday applications. PMID- 25529832 TI - Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study. AB - OBJECTIVES: To describe characteristics associated with neurotoxicity (NT) in advanced ovarian cancer patients treated on Gynecologic Oncology Group 218 and examine effect of substituting docetaxel for paclitaxel in these patients. METHODS: The development of NT was defined as Common Toxicity Criteria grade (G)>=1. The association between substitution with docetaxel and NT improvement was explored with generalized estimating equations adjusting for treatment cycle and NT grading at previous cycle. RESULTS: Of 1864 evaluable patients, 1329 (71%) developed G>=1 NT during the study. Nearly half appeared within the first two cycles of chemotherapy, with 31% experiencing G>=2. Older patients or those with worse quality of life (QoL) scores at baseline (p<0.05) were more likely to experience NT. One-hundred-six patients received docetaxel as substitute for paclitaxel. Of them, 47 patients started with docetaxel at cycle one due to reaction to paclitaxel (n=32), fear of NT (n=4), and other reasons (n=11), whereas 59 patients switched to docetaxel during cycle 2-6 due to NT (n=32), reaction to paclitaxel (n=19), and other reasons (n=8). Although the protocol instructed otherwise, the majority continued paclitaxel despite G>=2 NT symptoms. There was no evidence that substitution with docetaxel improved NT (Odds Ratio: 1.57; 95% CI 0.98-2.54; p>0.05). Of 59 patients who switched to docetaxel, only seven (12%) discontinued taxane prior to chemotherapy completion. A roughly equal chance of worsening NT was reported on paclitaxel (6%) as on docetaxel (5%). CONCLUSIONS: Age and worse QoL at baseline are associated with NT. Substitution of docetaxel did not improve NT symptoms. PMID- 25529835 TI - Synthesized ultrathin MoS2 nanosheets perpendicular to graphene for catalysis of hydrogen evolution reaction. AB - We synthesize the ultrathin MoS2 nanosheets perpendicular to reduced graphene oxides (MoS2?RGO) as an electro-catalyst, which exhibits excellent catalytic activity and good stability for the hydrogen evolution reaction (HER) in acidic medium. PMID- 25529833 TI - 204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24 26 January 2014, Naarden, The Netherlands. PMID- 25529837 TI - Improved quality of life two-years post Transcatheter Aortic Valve Replacement for a regurgitant aortic homograft. AB - The limited durability of prosthetic cardiac valves together with an aging population will present ongoing management challenges. This paper describes the case of an 82 year-old male with symptomatic severe regurgitation in an aortic homograft which remains successfully treated with Transcatheter Aortic Valve Replacement (TAVR) at two-year follow-up. PMID- 25529836 TI - Walking training with cueing of cadence improves walking speed and stride length after stroke more than walking training alone: a systematic review. AB - QUESTION: After stroke, is walking training with cueing of cadence superior to walking training alone in improving walking speed, stride length, cadence and symmetry? DESIGN: Systematic review with meta-analysis of randomised or controlled trials. PARTICIPANTS: Adults who have had a stroke. INTERVENTION: Walking training with cueing of cadence. OUTCOME MEASURES: Four walking outcomes were of interest: walking speed, stride length, cadence and symmetry. RESULTS: This review included seven trials involving 211 participants. Because one trial caused substantial statistical heterogeneity, meta-analyses were conducted with and without this trial. Walking training with cueing of cadence improved walking speed by 0.23 m/s (95% CI 0.18 to 0.27, I(2)=0%), stride length by 0.21 m (95% CI 0.14 to 0.28, I(2)=18%), cadence by 19 steps/minute (95% CI 14 to 23, I(2)=40%), and symmetry by 15% (95% CI 3 to 26, random effects) more than walking training alone. CONCLUSIONS: This review provides evidence that walking training with cueing of cadence improves walking speed and stride length more than walking training alone. It may also produce benefits in terms of cadence and symmetry of walking. The evidence appears strong enough to recommend the addition of 30 minutes of cueing of cadence to walking training, four times a week for 4 weeks, in order to improve walking in moderately disabled individuals with stroke. REVIEW REGISTRATION: PROSPERO (CRD42013005873). PMID- 25529838 TI - Spontaneous Coronary Artery Dissection: once is never enough. AB - Spontaneous Coronary Artery Dissection (SCAD) is a rare and potentially life threatening cause of Acute Coronary Syndrome. Recurrence of SCAD in patients, other than peripartum women, has been discussed infrequently in the literature. We report a case of patient who suffered recurrent SCAD in different coronary arteries. Her history was significant for a likely SCAD five years earlier. We briefly review the literature on SCAD and its recurrence. PMID- 25529840 TI - Pain anticipation: an activation likelihood estimation meta-analysis of brain imaging studies. AB - The anticipation of pain has been investigated in a variety of brain imaging studies. Importantly, today there is no clear overall picture of the areas that are involved in different studies and the exact role of these regions in pain expectation remains especially unexploited. To address this issue, we used activation likelihood estimation meta-analysis to analyze pain anticipation in several neuroimaging studies. A total of 19 functional magnetic resonance imaging were included in the analysis to search for the cortical areas involved in pain anticipation in human experimental models. During anticipation, activated foci were found in the dorsolateral prefrontal, midcingulate and anterior insula cortices, medial and inferior frontal gyri, inferior parietal lobule, middle and superior temporal gyrus, thalamus, and caudate. Deactivated foci were found in the anterior cingulate, superior frontal gyrus, parahippocampal gyrus and in the claustrum. The results of the meta-analytic connectivity analysis provide an overall view of the brain responses triggered by the anticipation of a noxious stimulus. Such a highly distributed perceptual set of self-regulation may prime brain regions to process information where emotion, action and perception as well as their related subcategories play a central role. Not only do these findings provide important information on the neural events when anticipating pain, but also they may give a perspective into nocebo responses, whereby negative expectations may lead to pain worsening. PMID- 25529839 TI - Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells. AB - Epalrestat (EPS) is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs), an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress. PMID- 25529841 TI - Higher prevalence of childbirth related fear in foreign born pregnant women- findings from a community sample in Sweden. AB - OBJECTIVE: to investigate the prevalence of childbirth related fear (CBRF) in early pregnancy among both Swedish born and foreign born women living in Sweden. DESIGN: a cross sectional prevalence study. Data was collected by a questionnaire, which was available in Swedish and eight other languages. SETTING: a university hospital in the middle of Sweden. PARTICIPANTS: the recruitment took place during a two month period where the participating women completed the Fear of Birth Scale (FOBS) in mid-pregnancy. MEASUREMENTS: prevalence of CBRF, the cut point of 60 and above. Odds ratios with a 95% confidence interval were calculated between women born in Sweden and women born in a foreign country. Stratified analyses were also performed separately for Swedish born and foreign born women. FINDINGS: in total 606 women completed the survey, 78% were born in Sweden and 22% were born in a foreign country. About 22% of the total sample scored 60 or more on the FOBS-scale. Almost 18% (n=85) of the women born in Sweden reported CBRF whereas 37 % (n=49) of the foreign born women reported CBRF. Being born outside Sweden (OR 2.7; CI 1.7-4.0) and expecting the first baby (OR 1.9; CI 1.3 2.8) were associated with CBRF. There were no differences in age, civil status or level of education between women with or without FOBS>=60. However, a stratified analysis showed that primiparas born in a foreign country (OR 3.8; CI 1.8-8.0) were more likely to score 60 or more on the FOBS-scale compared to multiparas born in a foreign country. KEY CONCLUSIONS: childbirth related fear was almost three times as common among foreign born women when compared to Swedish women. Foreign born childbearing women are an extremely vulnerable group who need culturally sensitive and targeted support from caregivers. Further research is needed to clearly identify the components of women's childbirth related fear in various ethnic groups. PMID- 25529842 TI - Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses. AB - OBJECTIVES: The transient receptor potential vanilloid type-1 channel (TRPV1) is expressed in the midbrain periaqueductal grey (PAG), a region of the brain related to aversive responses. TRPV1 antagonism in the dorsolateral PAG (dlPAG) induces anxiolytic-like effects in models based on conflict situations. No study, however, has investigated whether these receptors could contribute to fear responses to proximal threat. Thus, we tested the hypothesis that TRPV1 in the PAG could mediate fear response in rats exposed to a predator. METHODS: We verified whether exposure to a live cat (a natural predator) would activate TRPV1 expressing neurons in the PAG. Double-staining immunohistochemistry was used as a technique to detect c-Fos, a marker of neuronal activation, and TRPV1 expression. We also investigated whether intra-dlPAG injections of the TRPV1 antagonist, capsazepine (CPZ), would attenuate the behavioural consequences of predator exposure. RESULTS: Exposure to a cat increased c-Fos expression in TRPV1-positive neurons, mainly in the dorsal columns of the PAG, suggesting that TRPV1 expressing neurons are activated by threatening stimuli. Accordingly, local injection of CPZ inhibited the fear responses. CONCLUSION: These data support the hypothesis that TRPV1 channels mediate fear reactions in the dlPAG. This may have an implication for the development of TRPV1-antagonists as potential drugs for the treatment of certain psychiatric disorders. PMID- 25529844 TI - The conundrum of aortic valve surgery in octogenarians. PMID- 25529845 TI - Rhabdomyolysis and acute renal failure associated with influenza virus type A infection. PMID- 25529843 TI - Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. AB - In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5% (4/266) of all patients, 4% (3/77) of all familial cases and 7% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes. PMID- 25529846 TI - Carcinoembryonic antigen as a cancer screening marker by primary care physicians. PMID- 25529847 TI - Factor analysis of the Scale of Prodromal Symptoms: data from the Early Detection and Intervention for the Prevention of Psychosis Program. AB - AIM: The Scale of Prodromal Symptoms (SOPS) was developed to identify individuals experiencing early signs of psychosis, a critical first step towards early intervention. Preliminary dimension reduction analyses suggested that psychosis risk symptoms may deviate from the traditional symptom structure of schizophrenia, but findings have been inconsistent. This study investigated the phenomenology of psychosis risk symptoms in a large sample from a multi-site, national study using rigorous factor analysis procedure. METHODS: Participants were 334 help-seeking youth (age: 17.0 +/- 3.3) from the Early Detection and Intervention for the Prevention of Psychosis Program, consisting of 203 participants at clinically higher risk (sum of P scores >= 7), 87 with clinically lower risk (sum of P scores < 7) and 44 in very early first-episode psychosis (<30 days of positive symptoms). Baseline SOPS data were subjected to principal axis factoring (PAF), estimating factors based on shared variance, with Oblimin rotation. RESULTS: PAF yielded four latent factors explaining 36.1% of total variance: positive symptoms; distress; negative symptoms; and deteriorated thought process. They showed reasonable internal consistency and good convergence validity, and were not orthogonal. CONCLUSIONS: The empirical factors of the SOPS showed similarities and notable differences compared with the existing SOPS structure. Regrouping the symptoms based on the empirical symptom dimensions may improve the diagnostic validity of the SOPS. Relative prominence of the factors and symptom frequency support early identification strategies focusing on positive symptoms and distress. Future investigation of long-term functional implications of these symptom factors may further inform intervention strategies. PMID- 25529849 TI - Quality of diabetes care in low- and middle-income Asian and Middle Eastern countries (1993-2012): 20-year systematic review. AB - OBJECTIVE: To assess the extent to which people with diabetes in low- and middle income countries (LMIC) of Asia and the Middle East met evidence-based care recommendations through a systematic review of published literature. METHODS: Electronic searches of Medline and Embase were carried out for studies assessing quality of care among people with diabetes in Asia and the Middle East between 1993 and 2012. Benchmarking against American Diabetes Association guidelines, we reported level and proportions meeting recommended risk factor control (glycated hemoglobin [HbA1c], blood pressure, and low density lipoprotein-cholesterol [LDL]) and preventive care processes across different settings. RESULTS: One hundred and fifteen publications met eligibility for inclusion (91 reported risk factor control, 7 reported preventive processes, and 17 reported both). Only China, Thailand, Malaysia and Philippines had nationally representative data. Mean HbA1c (6.5-11% or 48-97 mmol/mol), SBP (120-152 mm Hg), and LDL (2.4-3.8 mmol/l) varied greatly. Despite variation in availability of data, studies consistently showed that recommended care goals were not being achieved. CONCLUSIONS: The practice of auditing and benchmarking against evidence-based guidelines appears to be uncommon in Asia and the Middle East and there was heterogeneity of reporting across studies, populations, and methods used. The available data showed inadequate care. PMID- 25529850 TI - Usual interstitial pneumonia following resolution of cavitated pulmonary masses in a patient with ANCA-associated vasculitis. AB - A 72-year-old woman with slight pulmonary interstitial reticular markings was initially diagnosed with microscopic polyangiitis (MPA). Two years later, cavitated pulmonary masses appeared, and a biopsy specimen revealed granulomas. Granulomatosis with polyangiitis (GPA) was diagnosed. The masses resolved with treatment. Ten years later, the usual interstitial pneumonia (UIP) pattern appeared on chest computed tomography (CT). The diagnosis of lung toxicity from methotrexate (MTX) or cyclophosphamide (CYC) was precluded by the clinical course. Despite treatment with prednisolone (PSL), the UIP progressed. The change of pulmonary pathology from masses to UIP is rare in patients with GPA. PMID- 25529852 TI - Deep carious lesions and other consequences of caries among 18-year-olds at Public Dental Health Service in Northern Norway: A cross-sectional age cohort study. AB - OBJECTIVES: To document deep carious lesions and other consequences of caries (DCL-CC) in molars of 18-year olds leaving the free-of-charge Public Dental Health Service (PDHS). To explore the association between background factors and DCL-CC. MATERIALS AND METHODS: The final study sample (n=1876) comprised 95% of individuals born in 1993 and registered in the PDHS in Troms County, Northern Norway. The most recent digital bitewing radiographs of each subject were examined for DCL-CC (deep untreated carious lesions, deep restorations, root canal obturations or extractions due to caries). Inter- and intra-observer kappa scores were 0.62 and 0.87, respectively. Information on background factors (gender, clinic location, history of medical problems, bitewing examination interval, DMFT score and planned recalls) were retrieved from dental records. RESULTS: About one-quarter of subjects (488) had at least one molar with DCL-CC. There were 848 molars in total with DCL-CC; the majority were deep restorations (70%), but 4% were deep untreated carious lesions. More than a quarter of DCL-CC were either root canal obturations (14%) or extractions (12%). Multivariable logistic regression analyses showed that a 1-unit increase in DMFT score was associated with deep untreated carious lesions and extractions due to caries. There was no association between urban/rural clinic location, which indicated socio-economic status, and either DMFT score or DCL-CC. CONCLUSIONS: Despite the existence of a free-of-charge dental service, more than one-quarter of the subjects in the present study had at least one molar with DCL-CC. PMID- 25529851 TI - Low-dose intramuscular dexmedetomidine as premedication: a randomized controlled trial. AB - BACKGROUND: Dexmedetomidine-induced bradycardia or hypotension has recently attracted considerable attention because of potentially grave consequences, including sinus arrest and refractory cardiogenic shock. A route other than intravenous injection or a low dose may help minimize cardiovascular risks associated with dexmedetomidine. However, few studies have addressed the clinical effects of low-dose intramuscular dexmedetomidine as premedication. MATERIAL AND METHODS: Forty American Society of Anesthesiologists physical status I adult patients undergoing suspension laryngoscopic surgery were randomized to receive intramuscular dexmedetomidine (1 ug.kg-1) or midazolam (0.02 mg.kg-1) 30 minutes prior to anaesthesia induction. The sedative, hemodynamic, and adjuvant anaesthetic effects of both premedications were assessed. RESULTS: The levels of sedation (Observer's Assessment of Alertness/Sedation scales) and anxiety (visual analog score) at pre-induction, and the times to eye-opening and extubation, were not different between the groups. The heart rate response following tracheal intubation and extubation, and mean arterial pressure responses after extubation, were attenuated in the dexmedetomidine group compared to the midazolam group. No bradycardia or hypotension was noted in any patients. Propofol target concentrations at intubation and at start and completion of surgery were decreased in the dexmedetomidine group, whereas no difference in respective remifentanil levels was detected. CONCLUSIONS: This study provides further evidence that dexmedetomidine premedication in low dose (1 MUg.kg-1) by intramuscular route can induce preoperative sedation and adjuvant anaesthetic effects without clinically significant bradycardia or hypotension. PMID- 25529854 TI - Preschool children favor copying a successful individual over an unsuccessful group. AB - The human aptitude for imitation and social learning underpins our advanced cultural practices. While social learning is a valuable evolutionary survival strategy, blind copying does not necessarily facilitate survival. Copying from the majority allows individuals to make rapid judgments on the value of a trait, based on its frequency. This is known as the majority bias: an individual's tendency to copy the behavior elicited by the largest number of individuals in a population. An alternative approach is to follow those who are the most proficient. While there is evidence that children do show both processes, no study has directly pitted them against each other. To do this, in the current experiment 36 children aged between 4 and 5 years watched live actors demonstrate, as a group or individually, how to open novel puzzle boxes. Children exhibited a bias to the majority when group and individual methods were successful, but favored the individual if the group method was unsuccessful. Affiliating children with the unsuccessful majority group did not impact on this pattern. PMID- 25529848 TI - The unfolded protein response in retinal vascular diseases: implications and therapeutic potential beyond protein folding. AB - Angiogenesis is a complex, step-wise process of new vessel formation that is involved in both normal embryonic development as well as postnatal pathological processes, such as cancer, cardiovascular disease, and diabetes. Aberrant blood vessel growth, also known as neovascularization, in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues. Understanding the mechanisms of retinal neovascularization is an urgent unmet need for developing new treatments for these devastating diseases. Accumulating evidence suggests a vital role for the unfolded protein response (UPR) in regulation of angiogenesis, in part through coordinating the secretion of pro-angiogenic growth factors, such as VEGF, and modulating endothelial cell survival and activity. Herein, we summarize current research in the context of endoplasmic reticulum (ER) stress and UPR signaling in retinal angiogenesis and vascular remodeling, highlighting potential implications of targeting these stress response pathways in the prevention and treatment of retinal vascular diseases that result in visual deficits and blindness. PMID- 25529853 TI - Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells. AB - Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF 1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis. PMID- 25529855 TI - Multiple metastases of soft tissue visualized by technetium-99m-methylene diphosphonate scintigraphy: a case report. AB - INTRODUCTION: Lungs and liver are the most common sites of colorectal cancer metastases after regional lymph nodes, but metastases to unusual sites are reported. Heterotopic bone formation in soft tissues from colorectal cancer is a rare metastatic occurrence. CASE PRESENTATION: We present the case of a 29-year old Caucasian man affected by colon adenocarcinoma with multiple soft tissue metastases visualized by magnetic resonance imaging, computed tomography scan and scintigraphic bone scan. We suppose that these findings can be due to the fact that the tracer is concentrated in the ossification nidus of soft metastases. CONCLUSIONS: Our experience suggests that, in the presence of colon adenocarcinoma, a bone scan could be a sensible tool to highlight bone lesions or heterotopic bone nidus in soft tissues and that any subcutaneous lesion should be resected to avoid underestimating a potential malignancy. PMID- 25529856 TI - Genetic variability testing of neurodevelopmental genes in schizophrenic patients. AB - This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In Schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia. PMID- 25529857 TI - Comparison of the antidiabetic effects of linagliptin among groups with a normal renal function and a mild or severe renal impairment - retrospective observation study of Japanese patients with type 2 diabetes mellitus. AB - OBJECTIVE: The clinical course > 6 months after the initiation of linagliptin in patients with type 2 diabetes was compared among the groups divided by their renal function. METHODS: Two hundred and sixteen Japanese patients with type 2 diabetes treated with 5 mg once daily linagliptin were studied as the treated set. One hundred and forty-five subjects whose medications were not changed during the observation period were investigated as the full analysis set to assess the effectiveness. The subjects were divided into three groups based on an eGFR: eGFR >= 60, 59 - 45 and < 45 ml/min/1.73 m(2). The parameters were analyzed separately in the patients receiving monotherapy and additional therapy of linagliptin. RESULTS: The HbA1c (NGSP) levels significantly improved in both the patients receiving monotherapy and additional therapy. The changes in the HbA1c levels at 6 months were not significantly different between the groups with an eGFR >= 60, 59 - 45 and < 45 ml/min/1.73 m(2) receiving monotherapy (-1.0, -0.8 and -0.8%, respectively). Similarly, those were not significantly different between the different groups receiving additional therapy (-0.6, -0.5 and -0.7%, respectively). CONCLUSIONS: Linagliptin is considered to be effective for patients with type 2 diabetes and renal impairment in the present analysis performed at our institution. PMID- 25529858 TI - Assessment of periostin levels in serum and gingival crevicular fluid of patients with periodontal disease. AB - BACKGROUND AND OBJECTIVE: Periostin, a secreted adhesion molecule essential for periodontal tissue integrity, is highly expressed in the periodontal ligament and plays a critical role in tooth and bone development. The purpose of this study was to investigate periostin levels in the gingival crevicular fluid and serum of patients with periodontal disease and compare them with those of healthy individuals. MATERIAL AND METHODS: Eighty individuals (41 males and 39 females; age range: 25-48 years) were enrolled in the study. Individuals were divided into three groups following clinical and radiographic examinations: the periodontal healthy group (n = 20), gingivitis group (n = 30) and chronic periodontitis group (n = 30). Gingival crevicular fluid and serum samples were collected and periostin levels were determined using the enzyme-linked immunosorbent assay. RESULTS: The total amount and concentration of periostin decreased in gingival crevicular fluid with the progression and severity of the disease from healthy controls to gingivitis and to chronic periodontitis groups and differed significantly (p < 0.05). However, there was no significant difference in serum periostin concentration within all groups (p > 0.05). Periostin in gingival crevicular fluid negatively correlated with the gingival index in the periodontal disease groups, whereas it is inversely correlated with the clinical attachment level only in the periodontitis group (p < 0.05). When all the clinical groups were examined together, the periostin concentration negatively correlated with clinical attachment level and gingival index; moreover, total periostin positively correlated with periostin concentration and clinical attachment level (p < 0.05). CONCLUSIONS: The periostin levels in gingival crevicular fluid decreased proportionally with the progression and severity of periodontal disease, and negatively correlated with the clinical parameters. Within the limits of the study, the periostin level in gingival crevicular fluid can be considered a reliable marker in the evaluation of periodontal disease susceptibility and activity. PMID- 25529859 TI - Examining gender based violence and abuse among Liberian school students in four counties: An exploratory study. AB - The purpose of this article is to uncover the extent of sexual gender based violence (GBV) experienced by a convenience sample of students from select counties in Liberia and to understand the disclosure experiences of those victims willing to come forward. Girls (n=758) and boys (n=1,100) were asked about their sexual GBV experiences including their disclosure experiences, if applicable. Results indicated that sexual violation (i.e., peeping or inappropriate touching) was found among both girls and boys. Sexual coercion (i.e., forced sex) was more prevalent than transactional sex (i.e., trading sex for grades or money). Both sexual coercion and transactional sex were reported by more girls than boys, yet the rates for the most severe form of sexual violence (i.e., sexual coercion) were high for both girls (30%) and boys (22%). When students were asked if they told anyone, 38% reported that they did disclose their experiences. This study contributes to a small but growing body of research to document the prevalence and types of sexual violence against children in Liberia. Consistent with other studies, the evidence shows that sexual violence against boys and girls is occurring at alarming rates. PMID- 25529860 TI - Nomogram to predict the likelihood of upgrade of atypical ductal hyperplasia diagnosed on a core needle biopsy in mammographically detected lesions. AB - AIMS: To estimate the likelihood of the upgrade for atypical ductal hyperplasia (ADH) diagnosed on a core needle biopsy of a mammographically detected lesion. METHODS AND RESULTS: A total of 203 consecutive ADH cases diagnosed on core biopsy in mammographically detected lesions and having subsequent surgical excision were reviewed. The pathological features of ADH were assessed with multivariable logistic regression to predict the likelihood of upgrade for these patients. A nomogram was created using statistically significant variables. A corresponding formula was created to calculate the risk of upgrade. This risk was divided further into low, intermediate and high. A total of 57 (28.1%) cases had upgrade. A nomogram was created that included age, menopausal status, hormone therapy status, personal history of breast cancer, number of involved cores, solid growth pattern, size of largest focus and mammographic mass versus calcifications. The nomogram had an area under the receiver operating characteristic curve of 0.775. CONCLUSIONS: We have developed a user-friendly nomogram that uses easily recognized variables to calculate the likelihood of upgrade for ADH. The nomogram could assist the treating surgeon in decision making, particularly when the patient is at risk for surgical intervention. PMID- 25529861 TI - Beneficial effect of T follicular helper cells on antibody class switching of B cells in prostate cancer. AB - Prostate cancer is the most common malignancy in males and easily develops to be aggressive which is closely related to the chronic inflammatory tumor microenvironment in situ. This study aimed to assess the immunoglobulin G (IgG) subclass of B cells and explore their interactions with T follicular helper (Tfh) subsets in prostate cancer patients. The percentages of peripheral blood naive B cells, memory B cells and mature B cells, as well as Tfh1, Tfh2 and Tfh17 cells were analyzed or sorted by FACSAria. The ratios of the different IgG subclasses (IgG1, IgG2, IgG3 and IgG4) were detected by ELISA, and the expression levels of CXCR3 and CCR6 were measured using RT-PCR and western blot analysis. Meanwhile a co-culture system of B and Tfh cells was to assess the effect of each Tfh subset on the antibody subclass switching of B cells in vitro. We observed higher percentages of 3 Tfh subsets and IgG4+ B cells in the patients with prostate cancer than that in the health controls and proved a positive correlation between Tfh2 and IgG4+ B cells. Then we verified that IL-4, IL-6, IL-10 and prostaglandin E2 (PGE2) effectively promoted antibody class switching of B cells, which may be mediated by inducing Tfh2 cells, yet the study was not completely dependent on Tfh cells. The results provide evidence of the B cell response to an immune suppressive environment by evaluating IgG4 antibodies, and established a relationship between IgG4+ B cells and Tfh2 cells. Clarification of lymphocyte functions in the inflammatory microenvironment of tumors will be of potential therapeutic value. PMID- 25529862 TI - Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat. AB - Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcgamma-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID- 25529863 TI - Adherence to prescription opioid monitoring guidelines among residents and attending physicians in the primary care setting. AB - OBJECTIVE: The aim of this study was to compare adherence to opioid prescribing guidelines and potential opioid misuse in patients of resident vs attending physicians. DESIGN: Retrospective cross-sectional study. SETTING: Large primary care practice at a safety net hospital in New England. SUBJECTS: Patients 18-89 years old, with at least one visit to the primary care clinic within the past year and were prescribed long-term opioid treatment for chronic noncancer pain. METHODS: Data were abstracted from the electronic medical record by a trained data analyst through a clinical data warehouse. The primary outcomes were adherence to any one of two American Pain Society Guidelines: (1) documentation of at least one opioid agreement (contract) ever and (2) any urine drug testing in the past year, and evidence of potential prescription misuse defined as >=2 early refills. We employed logistic regression analysis to assess whether patients' physician status predicts guideline adherence and/or potential opioid misuse. RESULTS: Similar proportions of resident and attending patients had a controlled substance agreement (45.1% of resident patients vs. 42.4% of attending patient, P = 0.47) or urine drug testing (58.6% of resident patients vs. 63.6% of attending patients, P = 0.16). Resident patients were more likely to have two or more early refills in the past year relative to attending patients (42.8% vs. 32.5%; P = 0.004). In the adjusted regression analysis, resident patients were more likely to receive early refills (odds ratio 1.82, 95% confidence interval 1.26-2.62) than attending patients. CONCLUSIONS: With some variability, residents and attending physicians were only partly compliant with national guidelines. Residents were more likely to manage patients with a higher likelihood of opioid misuse. PMID- 25529864 TI - Developmental dyscalculia. AB - Numerical skills are essential in our everyday life, and impairments in the development of number processing and calculation have a negative impact on schooling and professional careers. Approximately 3 to 6 % of children are affected from specific disorders of numerical understanding (developmental dyscalculia (DD)). Impaired development of number processing skills in these children is characterized by problems in various aspects of numeracy as well as alterations of brain activation and brain structure. Moreover, DD is assumed to be a very heterogeneous disorder putting special challenges to define homogeneous diagnostic criteria. Finally, interdisciplinary perspectives from psychology, neuroscience and education can contribute to the design for interventions, and although results are still sparse, they are promising and have shown positive effects on behaviour as well as brain function. CONCLUSION: In the current review, we are going to give an overview about typical and atypical development of numerical abilities at the behavioural and neuronal level. Furthermore, current status and obstacles in the definition and diagnostics of DD are discussed, and finally, relevant points that should be considered to make an intervention as successful as possible are summarized. PMID- 25529866 TI - Fli1 deficiency and beyond: a unique pathway linking peripheral vasculopathy and dermal fibrosis in systemic sclerosis. PMID- 25529865 TI - Involvement of multiple taste receptors in umami taste: analysis of gustatory nerve responses in metabotropic glutamate receptor 4 knockout mice. AB - KEY POINTS: The taste receptor T1R1 + T1R3 heterodimer and metabotropic glutamate receptors (mGluR) may function as umami taste receptors. Here, we used mGluR4 knockout (mGluR4-KO) mice and examined the function of mGluR4 in peripheral taste responses of mice. The mGluR4-KO mice showed reduced responses to glutamate and L AP4 (mGluR4 agonist) in the chorda tympani and glossopharyngeal nerves without affecting responses to other taste stimuli. Residual glutamate responses in mGluR4-KO mice were suppressed by gurmarin (T1R3 blocker) and AIDA (group I mGluR antagonist). The present study not only provided functional evidence for the involvement of mGluR4 in umami taste responses, but also suggested contributions of T1R1 + T1R3 and mGluR1 receptors in glutamate responses. ABSTRACT: Umami taste is elicited by L-glutamate and some other amino acids and is thought to be initiated by G-protein-coupled receptors. Proposed umami receptors include heterodimers of taste receptor type 1, members 1 and 3 (T1R1 + T1R3), and metabotropic glutamate receptors 1 and 4 (mGluR1 and mGluR4). Accumulated evidences support the involvement of T1R1 + T1R3 in umami responses in mice. However, little is known about the in vivo function of mGluR in umami taste. Here, we examined taste responses of the chorda tympani (CT) and the glossopharyngeal (GL) nerves in wild-type mice and mice genetically lacking mGluR4 (mGluR4-KO). Our results indicated that compared to wild-type mice, mGluR4 KO mice showed significantly smaller gustatory nerve responses to glutamate and L (+)-2-amino-4-phosphonobutyrate (an agonist for group III mGluR) in both the CT and GL nerves without affecting responses to other taste stimuli. Residual glutamate responses in mGluR4-KO mice were not affected by (RS)-alpha-cyclopropyl 4-phosphonophenylglycine (an antagonist for group III mGluR), but were suppressed by gurmarin (a T1R3 blocker) in the CT and (RS)-1-aminoindan-1,5-dicarboxylic acid (an antagonist for group I mGluR) in the CT and GL nerve. In wild-type mice, both quisqualic acid (an agonist for group I mGluR) and L-(+)-2-amino-4 phosphonobutyrate elicited gustatory nerve responses and these responses were suppressed by addition of (RS)-1-aminoindan-1,5-dicarboxylic acid and (RS)-alpha cyclopropyl-4-phosphonophenylglycine, respectively. Collectively, the present study provided functional evidences for the involvement of mGluR4 in umami taste responses in mice. The results also suggest that T1R1 + T1R3 and mGluR1 are involved in umami taste responses in mice. Thus, umami taste would be mediated by multiple receptors. PMID- 25529872 TI - Lipid signalling dynamics at the beta-cell plasma membrane. AB - Pancreatic beta-cells are clustered in islets of Langerhans and secrete insulin in response to increased concentrations of circulating glucose. Insulin in turn acts on liver, muscle and fat tissue to store energy and normalize the blood glucose level. Inappropriate insulin release may lead to impaired glucose tolerance and diabetes. In addition to glucose, other nutrients, neural stimuli and hormonal stimuli control insulin secretion. Many of these signals are perceived at the plasma membrane, which is also the site where insulin granules undergo exocytosis. Therefore, it is not surprising that membrane lipids play an important role in the regulation of insulin secretion. beta-cells release insulin in a pulsatile fashion. Signalling lipids integrate the nutrient and neurohormonal inputs to fine-tune, shape and co-ordinate the pulsatility. An important group of signalling lipids are phosphoinositides and their downstream messengers. This MiniReview will discuss new insights into lipid signalling dynamics in beta-cells obtained from live-cell imaging experiments with fluorescent translocation biosensors. The plasma membrane concentration of several phosphoinositides and of their downstream messengers changes rapidly upon nutrient or neurohormonal stimulation. Glucose induces the most complex spatio temporal patterns, typically involving oscillations of messenger concentrations, which sometimes are locally restricted. The tightly controlled levels of lipid messengers can mediate specific binding of downstream effectors to the plasma membrane, contributing to the appropriate regulation of insulin secretion. PMID- 25529873 TI - Feasibility for detecting liver metastases in dogs using gadobenate dimeglumine enhanced magnetic resonance imaging. AB - Early detection of liver metastases may improve the prognosis for successful treatment in dogs with primary tumors. Hepatobiliary-specific contrast agents have been shown to allow an increase in magnetic resonance imaging (MRI) detection of liver metastases in humans. The purpose of this prospective study was to test the feasibility for using one of these agents, gadobenate dimeglumine, to detect liver metastases in dogs. Ten consecutive dogs known to have a primary tumor were recruited for inclusion in the study. All dogs were scanned using the same protocol that included a T2-weighted respiratory-triggered sequence, T1 VIBE, diffusion-weighted imaging, and 3D-FLASH before and after dynamic injection of gadobenate dimeglumine contrast medium. Delayed imaging was performed less than 30 min after injection and up to 60 min in two cases. Histological analysis of liver lesions identified in delayed phases was performed for each case and confirmed metastatic origin. In all cases, lesion number detected in hepatobiliary contrast-enhanced sequences was statistically higher than in other sequences. Optimal lesion detection occurred with a 3D-FLASH sequence acquired in the transverse plane and less than 30 min after injection. Findings indicated that gabobenate dimeglumine enhanced MRI is a feasible technique for detecting liver metastases in dogs. PMID- 25529874 TI - Special bioanalysis for special populations? PMID- 25529875 TI - What are the main considerations for bioanalysis of estrogens and androgens in plasma and serum samples from postmenopausal women? PMID- 25529876 TI - Bioanalysis in special populations. AB - As part of this special focus issue, Bioanalysis invited a selection of leading researchers to express their views on bioanalysis in special populations. The topics covered include a discussion of specific population-related factors that can affect sample analysis, technological advances and challenges relating to matrix effects. Their responses provide a valuable insight into current considerations, as well as future developments in the field. PMID- 25529878 TI - Challenges in application of bioanalytical method on different populations and effect of population on PK. AB - Prashant Kale has 22 years of immense experience in the analytical and bioanalytical domain. He is Senior Vice President, Bioequivalence Operations of Lambda Therapeutic Research, India which includes Bioanalytical, Clinics, Clinical data management, Pharmacokinetics and Biostatistics, Protocol writing, Clinical lab and Quality Assurance departments. He has been with Lambda for over 14 years. By qualification he is a M.Sc. and an MBA. Mr. Kale is responsible for the management, technical and administrative functions of the BE unit located at Ahmedabad and Mumbai, India. He is also responsible for leading the process of integration between bioanalytical laboratories and services offered by Lambda at global locations (India and Canada). Mr. Kale has faced several regulatory audits and inspections from leading regulatory bodies including but not limited to DCGI, USFDA, ANVISA, Health Canada, UK MHRA, Turkey MoH, WHO. There are many challenges involved in the application of bioanalytical method on different populations. This includes difference in equipment, material and environment across laboratories, variations in the matrix characteristics in different populations, differences in techniques between analysts such as sample processing and handling and others. Additionally, there is variability in the PK of a drug in different populations. This article shows the effect of different populations on validated bioanalytical method and on the PK of a drug. Hence, the bioanalytical method developed and validated for a specific population may need required modification when applied to another population. Critical consideration of all such aspects is the key to successful implementation of a validated method on different populations. PMID- 25529879 TI - The importance of choosing the appropriate matrix to validate a bioanalytical method according to the study needs. AB - Sylvain Lachance is a Bioanalytical Scientific Expert in the Bioanalytical Division of inVentiv Health Clinical Quebec City's (Canada) site, a CRO offering clinical, commercial and consulting services to the healthcare industry. He is responsible for following up on the conduct of bioanalytical method development activities by enhancing the scientific and technical knowledge of the researchers, bioanalytical project coordinators and of the laboratory technicians. He assists bioanalytical project coordinators in investigations during bioanalyses and method validations. He has been working in the Bioanalytical Division of inVentiv Health Clinical for over 16 years, working as a Research Scientist, Chromatographic Specialist and Scientific Expert. He has worked on multiple method developments in HPLC and LC-MS/MS, specifically on troubleshooting. He has been involved in more than 70 posters and publications in the bioanalytical field for different scientific meetings. Ann Levesque obtained her PhD in Biochemistry at the Universite Laval in Quebec City in 1994 studying the biological actions of peptide analogs of the gastrin releasing peptide in the growth inhibition of cancer cells. Prior to joining inVentiv Health Clinical, she held management positions at other Contract Research Organizations. Her publications include over 100 posters, 17 scientific articles and book chapters in the clinical biochemistry and bioanalytical fields. Within inVentiv Health, Dr. Levesque is responsible for managing the R&D and sample analysis teams performing bioanalytical analysis of small molecules and peptides. She is also acting as the Biomedical Laboratory Director accountable for the oversight of all activities related to the safety testing of samples from subjects enrolled in early stage clinical trials. Since joining the Bioanalytical Division, Dr. Levesque has been instrumental in the great success of the laboratory by developing a culture of quality, innovation and value. Validation guidelines from different agencies mainly recommend that matrix effect should be studied with hemolyzed and hyperlipidemic samples, while the European agency requires also to investigate matrix effect on special population. When studies are done in countries with different dietary habits, or when a medication is administered to decrease the concentration of the endogenous compounds, should the matrix effect in these conditions be evaluated? Herein, three case studies are described to show the importance of choosing the appropriate matrix for the bioanalytical method validations and for their use to analyze the study samples according to the conditions required by the clinical trials. The case studies presented are related to the use of the testosterone, Omega-3 and cortisol methods. PMID- 25529877 TI - Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC-MS/MS. AB - AIM: Determination of piperaquine (PQ) in pediatric plasma requires a method with a small sample volume. RESULTS: We report a sensitive LC-MS/MS method for quantitation of PQ with only 25 ul human plasma. Using a deuterated internal standard (PQ-d6), an analytical PFP column, APCI(+) as the ion source and MRM (535/288 for PQ and 541/294 for the IS) for detection, the method has a linear calibration range of 1.5-250 ng/ml with a runtime of 3.0 min per sample. The method was applied to plasma samples from children. CONCLUSION: The developed LC MS/MS method is suitable for pediatric studies with small volume plasma samples collected via capillary tubes. One limitation was the performance of PFP columns varied among different brands. PMID- 25529880 TI - European Bioanalysis Forum: recommendation on dealing with hemolyzed and hyperlipidemic matrices. AB - Recent guidelines on bioanalytical method validation have recommended to investigate matrix effects in special matrices such as hemolytic and hyperlipidemic plasma. However, these guidelines were not clear on how to implement these recommendations. The European Bioanalysis Forum has discussed this topic in depth and has asked for feedback from member companies. Those discussions have resulted in more specific guidance on how to define hemolytic and hyperlipidemic plasma, how to validate bioanalytical methods for these matrices and how to deal with hemolytic and hyperlipidemic study samples. These recommendations are presented in this manuscript. PMID- 25529881 TI - Role of dried blood spots in health and disease diagnosis in older adults. AB - Older adults represent a substantial number of the world population, which is set to grow considerably in the coming years. The health challenges faced by the older adults are unique. Several age-related changes in them make phlebotomy difficult. Application of dried blood has been demonstrated to be useful in the other similarly vulnerable population, the neonates. Similar approach of standardization and demonstration of use of dried blood spots (DBS) for analytes of interest in older adult population would be highly appreciated. There are very few reports of use of DBS in older adults. There are several potential areas of interest for older adults in which DBS assays are available but have not been applied for screening in them. This review describes a brief general overview of DBS, its advantages and disadvantages and potential use in disease diagnosis in older adults. PMID- 25529883 TI - Metabolomics of drugs of abuse: a more realistic view of the toxicological complexity. PMID- 25529882 TI - Bioanalysis during pregnancy: recent advances and novel sampling strategies. AB - Consumption of drugs of abuse, tobacco and alcohol throughout pregnancy is a serious public health problem and results in an important economic cost to the health system. Drug and/or metabolites determination in biological matrices from mother and newborn is an objective measure of in utero drug exposure. We reviewed methods published for the determination of in utero drug exposure from 2007 to 2014, with special focus on meconium, placenta, umbilical cord and newborn hair. Accurate bioanalytical procedures are essential to obtain high-quality data to perform interventions and to establish correlations between analytical measures and clinical outcomes. We included a brief overview of clinical implications of in utero drug exposure to better understand the importance of this serious health issue. PMID- 25529884 TI - A sensitive and rapid method for quantification of lacosamide and desmethyl lacosamide by LC-MS/MS. AB - BACKGROUND: Monitoring lacosamide (LCM) helps optimize therapeutic dosing in some clinical settings. We developed a novel LC-MS/MS method for measuring serum LCM and O-desmethyl lacosamide (ODL). RESULTS/DISCUSSION: The sample preparation was protein precipitation with methanol. The total CV was less than 4.7%. Calibration range was 0.95-30.29 ug/ml and 0.95-30.41 ug/ml while the expanded linear range was 0.41-47.49 ug/ml and 0.34-48.17 ug/ml for LCM and ODL, respectively with analytical accuracy of 87.2-106.0%. 45 random serum samples collected from 23 individuals on either 200 mg/day or 400 mg/day of LCM therapy showed concentrations of 2.2-19.8 ug/ml for LCM and up to 2.5 ug/ml for ODL. CONCLUSION: A simple and sensitive LC-MS/MS assay was validated for quantification of LCM and ODL in human serum. PMID- 25529886 TI - Retrospective monitoring of long-term recreational and dependent cocaine use in toenail clippings/scrapings as an alternative to hair. AB - BACKGROUND: Toenails were assessed as an alternative matrix to hair for retrospective monitoring of cocaine consumption of recreational and dependent users. Results/methodology: Toenail clippings, scrapings and hair samples from recreational and dependent cocaine users were analyzed for cocaine and metabolites. Dependent users displayed significantly higher concentrations in hair and toenail samples compared to recreational users. Cocaine abstinence could be monitored in hair and toenail samples. One postmortem fingernail was analyzed in layers to investigate the cocaine and metabolite concentration profile. Highest concentrations were observed in the dorsal layer, being indicative of contamination. CONCLUSION: Having led to comparable results, toenails may be an alternative for retrospective monitoring of cocaine consumption/abstinence. Hair should remain the first choice for assessment of temporal evidence of drug intake. PMID- 25529885 TI - Quantitative determination of free/bound atazanavir via high-throughput equilibrium dialysis and LC-MS/MS, and the application in ex vivo samples. AB - AIM: The determination of drug-protein binding is important in the pharmaceutical development process because of the impact of protein binding on both the pharmacokinetics and pharmacodynamics of drugs. Equilibrium dialysis is the preferred method to measure the free drug fraction because it is considered to be more accurate. The throughput of equilibrium dialysis has recently been improved by implementing a 96-well format plate. Results/methodology: This manuscript illustrates the successful application of a 96-well rapid equilibrium dialysis (RED) device in the determination of atazanavir plasma-protein binding. DISCUSSION/CONCLUSION: This RED method of measuring free fraction was successfully validated and then applied to the analysis of clinical plasma samples taken from HIV-infected pregnant women administered atazanavir. Combined with LC-MS/MS detection, the 96-well format equilibrium dialysis device was suitable for measuring the free and bound concentration of pharmaceutical molecules in a high-throughput mode. PMID- 25529887 TI - Generation and application of polyclonal IgY antibodies specific for full-length and nicked prostate-specific antigen. AB - BACKGROUND: The prostate-specific antigen (PSA) is considered an important serum marker for prostate cancer detection, monitoring and staging. The purpose of this study was to generate IgY class antibodies that recognize native PSA and selected epitopes. METHODOLOGY: Hens immunized with either full-length human PSA or its peptidyl fragment-conjugates produced specific antibodies that were isolated from egg yolks. We developed a monoclonal/IgY sandwich ELISA with a PSA detection limit of 50 pg/ml and a linear range of 0.05-1.0 ng/ml. CONCLUSION: Because the signal observed for the PSA-specific IgY antibodies by ELISA and the reactivity profile of the epitope-derived IgYs were comparable to those of mouse monoclonal IgG antibodies, avian antibodies may be a cost-effective alternative to mammalian antibodies for prostate cancer diagnostics. PMID- 25529888 TI - Quantifying vemurafenib in dried blood spots using high-performance LC-MS/MS. AB - BACKGROUND: To further investigate the pharmacokinetics of vemurafenib and to support therapeutic drug monitoring an LC-MS/MS method was developed and validated for the quantification of vemurafenib in dried blood spots. RESULTS: Vemurafenib was extracted from the dried blood spots by methanol:acetonitrile (50:50, v/v) and separated on a C18 column with gradient elution and analyzed with triple quadrupole mass spectrometry in positive ion mode. The validated calibration range is linear from 1 to 100 ug/ml. Intra- and inter-assay accuracies and precisions were within +/-13.6% and <=6.5%. The applicability of the assay was tested by analyzing dried blood spots samples of melanoma patients receiving vemurafenib. CONCLUSION: This assay met all predefined validation criteria and is considered suitable to quantify vemurafenib in dried blood samples. PMID- 25529889 TI - Use of generic LC-MS/MS assays to characterize atypical PK profile of a biotherapeutic monoclonal antibody. AB - BACKGROUND: The fully human monoclonal antibody mAb123, which binds to and neutralizes chemokine motif ligand-21 (CCL21) displays a faster clearance in cynomolgus monkey compared with typical IgG kinetics. A direct and an immunoaffinity LC-MS/MS assays were developed to compare with the previously established ligand-binding assays (LBAs). RESULTS: A strong correlation of LC MS/MS pharmacokinetic data with LBA data confirmed the rapid drug disposition of mAb123 is an intrinsic property of the molecule, rather than interference of anti mAb123 antibodies in the LBA. CONCLUSION: The data illustrate that in cases of unexpected results from LBA, application of orthogonal bioanalytical techniques such as LC-MS/MS can help in in interpretation of pharmacokinetic as determined by LBAs. PMID- 25529891 TI - Application of quality by design and statistical quality control concepts in immunoassays. AB - Quality by design (QbD) expanded in recent years from pharmaceutical processing into analytical chemistry. Beyond online process analytical technology, off-line assays including immunoassays are also starting to benefit from QbD. Although analytical QbD is still a relatively new development, underlying concepts, such as target-oriented development and statistical quality control have been applied to diagnostic assays under the term 'design control' for several years. We reviewed how QbD and statistical quality control concepts have been applied both to diagnostic and bioanalytical immunoassays ranging from the use of individual tools to end-to-end QbD-based workflows. We will discuss some of the results of the different approaches to immunoassays, how they fit into the QbD framework and how individual tools may complement a QbD workflow. PMID- 25529890 TI - 2014 White Paper on recent issues in bioanalysis: a full immersion in bioanalysis (Part 2 - hybrid LBA/LCMS, ELN & regulatory agencies' input). AB - The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years' editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies' Input. Part 1 (Small molecules bioanalysis using LCMS) was published in the Bioanalysis issue 6(22) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the Bioanalysis issue 6(24). PMID- 25529894 TI - Statement of removal. Projected impact of Cervarix(r) vaccination on oncogenic human paillomvirus infection and cervical cancer in the United Kingdom. PMID- 25529892 TI - Off-premise alcohol outlets on and around tribal land: risks for rural California Indian youth. AB - Investigating the alcohol environment for rural American Indian youth, we conducted 70 interviews with leading members and youth representatives of nine Southern California tribes. We also conducted brief observations in all 13 stores licensed to sell alcohol on and close to the reservation lands of the nine tribes. Underage youth may obtain alcoholic beverages at stores either directly through illegal sales to minors or indirectly through social sources. Stores are also environments within which alcoholic beverages and heavy drinking may become normalized for youth. Limitations and implications for convenience store-based prevention research on alcohol retail environment for youth in rural populations areas are discussed. PMID- 25529895 TI - Role of T helper lymphokines in the immune-inflammatory pathophysiology of schizophrenia: Systematic review and meta-analysis. AB - BACKGROUND: Schizophrenia is highly complex multifactorial psychiatric disorder with poorly defined etiopathophysiology, which also has manifestations in the immune system. AIMS: The aim of this review is to meta-analyze the available evidence regarding the role of immune activation indicated by the T helper cells in order to evaluate etiopathophysiological links between the immune system and schizophrenia. METHODS: A literature search was performed in multiple electronic databases for relevant research papers published between 1990 and May 2014. Meta analyses were conducted under both random- (REM) and fixed-effect models (FEM) by calculating weighted mean differences with 95% confidence intervals. Heterogeneity was assessed with the I(2) index. RESULTS: Twenty-one studies were selected after observing inclusion and exclusion criteria. In vitro interferon gamma (INF-gamma) and interleukin (IL)-2 production was significantly lower in the schizophrenic patients compared with non-schizophrenic control individuals under both FEM and REM. Serum levels of IL-2 and serum/in vitro IL-4 were not significantly different in both groups under both FEM and REM. Overall Th1:Th2 ratio (INF-gamma:IL-4 and IL-2:IL-4) in the serum samples was significantly deflected towards Th2 under both models in the serum samples (- 0.33 [- 0.59 to - 0.06]; P < 0.03, FEM and - 2.44 [- 4.27 to - 0.60]; P < 0.009, REM) but in vitro production Th1:Th2 ratio (INF-gamma:IL-4 and IL-2:IL-4) was deflected towards Th1 under both the models (1.11 [0.45-1.78]; P < 0.002, FEM and 6.68 [0.72-12.64]; P < 0.03, REM). CONCLUSIONS: Whereas the Th1:Th2 ratio in the serum samples deflected towards T2, in vitro Th1:Th2 ratio favored Th1 when the individual study data were meta-analyzed. PMID- 25529896 TI - A study of muscle involvement in scrub typhus. AB - OBJECTIVES: Patients with scrub typhus often complain of myalgia, but a comprehensive study on muscle dysfunction is lacking. We therefore report the clinical, electromyographic and muscle biopsy findings in patients with scrub typhus. METHODS: Consecutive patients with scrub typhus were included, and their clinical and laboratory findings were noted. The patients with myalgia or weakness and elevated serum creatine kinase (CK) were considered to have muscle involvement. Electromyography (EMG) and muscle biopsy were done in some patients. Patients were treated with doxycycline 200mg daily for 7 days, and their clinical and biochemical outcome on discharge and one month were evaluated. RESULTS: 13 out of 33 (39.4%) patients had muscle involvement and their CK levels ranged between 287 and 3166 (859 +/- 829) U/L. EMG revealed short duration polyphasic potentials, and muscle histopathology revealed evidence of vasculitis. There were significant correlations between severity of weakness and CK levels (r = -0.6; p < 0.001), platelet counts (r = 0.4; p = 0.04), duration of illness (r = -0.4; p = 0.01) and disability on discharge (r = -0.4; p = 0.04). Patients with muscle involvement had more severe illness evidenced by a lower Glasgow Coma Scale score (p < 0.001), thrombocytopenia (p = 0.05) and greater disability on discharge (p = 0.007), when compared to those without muscle involvement. All the patients had complete recovery following doxycycline therapy, and CK levels also normalized. CONCLUSION: Muscle dysfunction was present in 39% patients with scrub typhus. Although muscle histopathology showed evidence of vasculitis, patients responded to doxycycline. PMID- 25529898 TI - Protein tyrosine nitration: a signaling mechanism conserved from yeast to man. AB - Although protein nitration had already been reported in the late forties and found to specifically affect tyrosine residues 20 years later, it was not until the early nineties that this post-translational modification was reported to occur in vivo in mammalian cells. Over the years, this protein modification has increasingly proven to play a major role in a variety of physiological mechanisms through redox signaling and pathological conditions through nitro-oxidative stress, from protozoan parasites to humans. In this issue (Proteomics 2015, 15, 580-590), Kang et al. report the identification of the nitroproteome during mating in the yeast Saccharomyces cerevisiae and most interestingly on the changes in nitration induced by the mating signal alpha-factor of several of these proteins. The correlation of these modifications with the biological functions of these proteins strongly suggests a role for protein nitration in mating signal transduction in yeast, thereby confirming the conservation of this pathway throughout the evolution from unicellular eukaryotes to man. The ubiquity of protein tyrosine nitration, whose importance is now also recognized in plants, further highlights its significance as an essential signaling mechanism in eukaryotes. PMID- 25529897 TI - Chebulagic acid from Terminalia chebula enhances insulin mediated glucose uptake in 3T3-L1 adipocytes via PPARgamma signaling pathway. AB - The thiazolidinedione (TZDs) class of drugs are very effective for the treatment of type 2 diabetes mellitus (T2DM). But due to the adverse effects of synthetic TZDs, their use is strictly regulated. The therapeutic actions of TZDs are mediated via modulation of peroxisome proliferator-activated receptor gamma (PPARgamma). Naturally occurring PPARgamma modulators are more desirable as they lack the serious adverse effects caused by TZDs. This has prompted the exploitation of medicinal plants used in traditional medicine, for their potential PPARgamma activity. In the present work, we studied chebulagic acid (CHA) isolated from fruits of Terminalia chebula with respect to its effect on adipogenesis, glucose transport, and endocrine function of adipocyte. The mRNA expression profile of PPARgamma target gene CCAAT/enhancer-binding protein alpha (C/EBP-alpha) was analyzed by qRT-PCR. The putative binding mode and the potential ligand-target interactions of CHA, with PPARgamma was analyzed using docking software (Autodock and iGEMDOCKv2). The results showed that CHA enhances PPARgamma signaling and adipogenesis dose dependently but in a moderate way, less than rosiglitazone. GLUT4 expression and adiponectin secretion was increased by CHA treatment. The mRNA expression of PPARgamma target gene C/EBP-alpha was increased in CHA -treated adipocytes. The comparison of results of various parameters of adipogenesis, insulin sensitivity, endocrine function and molecular docking experiments of roziglitazone and chebulagic acid indicate that the latter behaves like partial PPARgamma agonist which could be exploited for phytoceutical development against T2DM. PMID- 25529899 TI - Effects of a diverting stoma on symptomatic anastomotic leakage after low anterior resection for rectal cancer: a propensity score matching analysis of 1,014 consecutive patients. AB - BACKGROUND: Routine creation of a diverting stoma (DS) in every patient who undergoes low anterior resection (LAR) remains controversial. We aimed to investigate the effect of DS on symptomatic anastomotic leakage (AL) after LAR. STUDY DESIGN: Patients with rectal cancer within 10 cm from the anal verge were eligible for this prospective, multicenter, cohort study (UMIN-CTR, number 000004017). Propensity score matching (PSM) was used to compare groups of patients with and without DS. RESULTS: One thousand fourteen consecutive patients were registered, of whom 936 patients who underwent LAR were analyzed. Before PSM, the overall rate of symptomatic AL was 13.2% (52 of 394) in patients with DS vs. 12.7% (69 of 542) in cases without DS (p = 0.84). Symptomatic AL requiring re laparotomy occurred in 4.7% (44 of 936) of all patients, occurring in 1.0% (4 of 394) of patients with DS vs. 7.4% (40 of 542) of patients without DS (p < 0.001). After PSM, the 2 groups were nearly balanced, and the incidence rates of symptomatic AL in patients with and without DS were 10.9% and 15.8% (p = 0.26). The incidences of AL requiring re-laparotomy in patients with and without DS were 0.6% and 9.1% (p < 0.001). Multivariate analysis identified male sex (p < 0.001; odds ratio [OR] 3.2; 95% confidence interval [CI] 1.8 to 5.7) and tumor size (p < 0.001; OR 1.2; 95% CI 1.1 to 1.4) as independent risk factors of symptomatic AL. CONCLUSIONS: Diverting stoma did not have a significant relationship with symptomatic AL before and after PSM. However, DS does seem to mitigate the consequences of leakage, reducing the need for urgent abdominal reoperation. PMID- 25529900 TI - Hospital costs by cost center of inpatient hospitalization for medicare patients undergoing major abdominal surgery. AB - BACKGROUND: This study aims to describe the magnitude of hospital costs among patients undergoing elective colectomy, cholecystectomy, and pancreatectomy, determine whether these costs relate as expected to duration of care, patient case-mix severity and comorbidities, and whether risk-adjusted costs vary significantly by hospital. Correctly estimating the cost of production of surgical care may help decision makers design mechanisms to improve the efficiency of surgical care. STUDY DESIGN: Patient data from 202 hospitals in the ACS-NSQIP were linked to Medicare inpatient claims. Patient charges were mapped to cost center cost-to-charge ratios in the Medicare cost reports to estimate costs. The association of patient case-mix severity and comorbidities with cost was analyzed using mixed effects multivariate regression. Cost variation among hospitals was quantified by estimating risk-adjusted hospital cost ratios and 95% confidence intervals from the mixed effects multivariate regression. RESULTS: There were 21,923 patients from 202 hospitals who underwent an elective colectomy (n = 13,945), cholecystectomy (n = 5,569), or pancreatectomy (n = 2,409). Median cost was lowest for cholecystectomy ($15,651) and highest for pancreatectomy ($37,745). Room and board costs accounted for the largest proportion (49%) of costs and were correlated with length of stay, R = 0.89, p < 0.001. The patient case-mix severity and comorbidity variables most associated with cost were American Society of Anesthesiologists (ASA) class IV (estimate 1.72, 95% CI 1.57 to 1.87) and fully dependent functional status (estimate 1.63, 95% CI 1.53 to 1.74). After risk-adjustment, 66 hospitals had significantly lower costs than the average hospital and 57 hospitals had significantly higher costs. CONCLUSIONS: The hospital costs estimates appear to be consistent with clinical expectations of hospital resource use and differ significantly among 202 hospitals after risk adjustment for preoperative patient characteristics and procedure type. PMID- 25529901 TI - A comparative study of laparoscopic vs. open distal pancreatectomy for left-sided ductal adenocarcinoma: a propensity score-matched analysis. AB - BACKGROUND: Although laparoscopic surgery has many advantages, its application in pancreatic ductal adenocarcinoma has not been sufficiently studied. The objective of this study was to compare the surgical outcomes of laparoscopic distal pancreatectomy (LDP) to those of open distal pancreatectomy (ODP) for left-sided ductal adenocarcinoma. STUDY DESIGN: Among 167 consecutive patients between December 2006 and August 2013, 150 patients were included. Unmatched and propensity score-matched analyses were performed to compare the primary (oncologic adequacy) and secondary outcomes (hospital course and complications) between ODP and LDP groups. RESULTS: In unmatched patients, LDP was associated with an earlier return to diet and a shorter hospital stay compared with ODP. The 5-year survival rates were 27.6% in unmatched ODP (n = 80) and 32.5% in unmatched LDP (n = 70). Fifty-one patients from each group were selected by propensity score matching. In this matched patient comparison, LDP was again associated significantly with a shorter median postoperative time to restarting diet and a shorter hospital stay. The 2 groups did not differ significantly in terms of primary outcomes of operative time, number of harvested lymph nodes, resection margin status, and secondary outcomes of frequency of pancreatic fistula and complications. The 2 groups also had comparable patient survival (p = 0.91). CONCLUSIONS: This large single-center study of laparoscopic surgery for left sided pancreatic ductal adenocarcinoma indicated that LDP was safe and more efficacious than OPD after propensity score adjustment for presurgical variables of return to diet and length of stay. PMID- 25529902 TI - Application of the aviation black box principle in pediatric cardiac surgery: tracking all failures in the pediatric cardiac operating room. AB - BACKGROUND: Cardiac surgical procedures are complex and require the coordinated action of many. This creates the potential for small failures that could be the substrate for subsequent morbidity or mortality. High-reliability science suggests that preoccupation with small failures can lead to improved outcomes. STUDY DESIGN: Failures of all magnitudes (ie, events) were captured within the pediatric cardiac operating room starting with a single surgeon in April 2008. As the surgical team became more familiar with the process, failure recording was extended to all surgeons and all surgical procedures performed until the conclusion of the study in December 2010. New recording processes were developed and used on a rolling basis during this study. RESULTS: With systematic capture, event rates increased (from occurring within 20% to 50% of operative procedures). Although we identified 9 recurrent patterns, 2 categories (ie, Equipment and Patient Instability) accounted for almost half of the events (45%). The greatest number of events occurred during the prebypass period (40.2%), compared with bypass (20.1%) and postbypass (32.3%) periods. These events were mainly difficulties in access (31.8%), equipment (42.4%), and patient instability (33.3%) in each of the epochs, respectively. Of all events, 7.3% occurred during nonbypass cases, 30.6% of these were communication events. Implementation of this initiative led to recognition of major system-wide issues (eg, need for change in the blood-product acquisition process). CONCLUSIONS: Preoccupation with all failures in the operating room can reveal important information about the operating room and perioperative microenvironment that can prompt substantive process changes both locally and within the larger health system. PMID- 25529903 TI - Is a low readmission rate indicative of a good hospital? AB - BACKGROUND: Hospital readmissions are an increasing focus of health care policy. This study explores the association between 30-day readmissions and 30-day mortality for surgical procedures. STUDY DESIGN: California longitudinal statewide data from 1995 to 2009 were analyzed for 7 complex procedures: abdominal aortic aneurysm repair, aortic valve replacement, bariatric surgery, coronary artery bypass grafting, esophagectomy, pancreatectomy, and percutaneous coronary intervention. Hospitals were categorized based on observed-to-expected (O/E) ratios for 30-day mortality and 30-day readmissions. Hospitals were considered "high" or "low" outliers if the 95% confidence intervals of their O/E ratios excluded 1 and "expected" if they included 1. Hospitals that were outliers in at least 1 metric were classified as "discordant" if their readmission and mortality rates were not both "high" or both "low," and "poorly discordant" in the particular scenario of high mortality with "expected" or "low" readmission rates. RESULTS: A total of 1,090,071 patients and 299 hospitals were analyzed for 7 procedures, representing a total of 1,150 clinical encounters. The overall 30 day mortality was 3.79% and the 30-day readmission was 12.69%. Of the total, 729 (63.3%) had "expected" O/E ratios for both outcomes. Among outliers, 358 (85.0%) were "discordant" and 100 (23.8%) were "poorly discordant." CONCLUSIONS: Hospital readmission rate alone is a limited measure of quality given the poor correlation between hospital readmission and mortality rates. In this study, 85% of hospital outliers were "discordant" for readmission and mortality. Furthermore, almost a quarter of these discordant hospitals had "expected" or "low" readmission but "high" mortality rates. Quality metrics that focus exclusively on readmission rates overlook these discrepancies. PMID- 25529905 TI - Disability intervention model for older adults with arthritis: an integration of theory of symptom management and disablement process model. AB - To evolve a management plan for rheumatoid arthritis, it is necessary to understand the patient's symptom experience and disablement process. This paper aims to introduce and critique two models as a conceptual foundation from which to construct a new model for arthritis care. A Disability Intervention Model for Older Adults with Arthritis includes three interrelated concepts of symptom experience, symptom management strategies, and symptom outcomes that correspond to the Theory of Symptom Management. These main concepts influence or are influenced by contextual factors that are situated within the domains of person, environment, and health/illness. It accepts the bidirectional, complex, dynamic interactions among all components within the model representing the comprehensive aspects of the disablement process and its interventions in older adults with rheumatoid arthritis. In spite of some limitations such as confusion or complexity within the model, the Disability Intervention Model for Older Adults with Arthritis has strengths in that it encompasses the majority of the concepts of the two models, attempts to compensate for the limitations of the two models, and aims to understand the impact of rheumatoid arthritis on a patient's physical, cognitive, and emotional health status, socioeconomic status, and well being. Therefore, it can be utilized as a guiding theoretical framework for arthritis care and research to improve the functional status of older adults with rheumatoid arthritis. PMID- 25529906 TI - Factors affecting aggression in South Korean middle school students. AB - PURPOSE: The study was undertaken to assess levels of aggression, and to determine factors affecting aggression among South Korean middle school students. METHODS: A descriptive study was conducted using self-report questionnaires. The participants were 340 girls and boys from two middle schools and 302 questionnaires were used for the final data analysis. Aggression, academic stress, depression, self esteem, decision-making competency, and happiness were measured. Data were analyzed using descriptive statistics including t tests, one way analysis of variance, Pearson's correlation coefficients and multiple regressions. RESULTS: Aggression had significant correlations with academic stress (r = .21, p < .001), depression (r = .43, p < .001), self esteem (r = .25, p < .001), decision-making competency (r = -.25, p < .001), and happiness (r = -.21, p < .001). Mean score for aggression was 2.49 out of 5. Significant explanatory variables for aggression were grade (t = 4.39, p < .001), academic stress (t = 2.78, p = .006), and depression (t = 5.03, p < .001). The explanatory power of these factors was 26.9%, and this was statistically significant (F = 16.06, p < .001). CONCLUSION: Findings indicate that depression, academic stress, and grade (second grade) influence aggression. To decrease aggressive behavior, it is necessary to provide systematic and political programs in schools and local communities that can ameliorate negative emotional factors like depression and academic stress. Additionally, development of positive factors such as self esteem, decision-making skills, and happiness in middle school students is important to reduce aggression. PMID- 25529904 TI - Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. AB - Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n=17). Markers of inflammation including c-reactive protein (CRP) and TNF and its soluble receptors were also assessed along with depression measured by the 17-item Hamilton Depression Rating Scale. No differences in sleep parameters were found as a function of infliximab treatment over time. Nevertheless, wake after sleep onset (WASO), the spontaneous arousal index and sleep period time significantly decreased, and sleep efficiency significantly increased, from baseline to week 8 in infliximab-treated patients with high (CRP>5mg/L) (n=9) versus low inflammation (CRP?5mg/L) (n=10), controlling for changes in scores of depression. Stage 2 sleep also significantly decreased in infliximab-treated patients with high versus low inflammation. Decreases in soluble TNF receptor 1 (sTNFR1) significantly correlated with decreases in WASO and increases in sleep efficiency in infliximab-treated subjects with high inflammation. Placebo-treated subjects exhibited no sleep changes as a function of inflammation, and no correlations between inflammatory markers and sleep parameters in placebo-treated patients were found. These data suggest that inhibition of inflammation may be a viable strategy to improve sleep alterations in patients with depression and other disorders associated with increased inflammation. PMID- 25529907 TI - Effect of mentoring program on ways of coping with stress and locus of control for nursing students. AB - PURPOSE: This study evaluated the effectiveness of a 14-week mentoring program for first year nursing students and their ways of coping with stress and locus of control. METHODS: The study was designed as a quasi-experimental study. Sixty-six first year students (mentees) and 66 fourth year students (mentors) were eligible to be in the mentoring program. Mentors and mentees contacted each other weekly, as required, to provide information and support. In order to determine the efficiency of the mentoring program, a Locus of Control Scale, the Ways of Coping Inventory and Mentoring Assessment Form were filled out by mentees. RESULTS: In this study the mentoring program increased students' internal locus of control and active coping with stress. The increase in internal locus of control showed parallelism with students' behaviors of seeking social support. CONCLUSION: It is recommended that in nursing schools, the mentoring program be used as an additional program. PMID- 25529908 TI - Perceptions on pain management among Korean nurses in neonatal intensive care units. AB - PURPOSE: The present survey was conducted to investigate the perceptions among nurses of neonatal pain and the associated use of pharmacologic measures (PMs) and nonpharmacologic comfort measures (CMs) in neonatal intensive care units (NICUs). Pain perception, the necessity and actual use of PMs and CMs, and their relationships were investigated and compared according to nurses' positions, educational levels, the existence of guidelines, and prior education on neonatal pain management. METHODS: Participants were 141 nurses from five NICUs at university hospitals. A questionnaire was developed by researchers based on previous studies of neonatal pain management and current practices in surveyed NICUs. Five-point Likert scales were used to assess nurses' perceptions of pain, the necessity of PMs and CMs, and their actual use in 29 painful procedures. RESULTS: The mean scores of perceived pain and the necessity of PMs and CMs were 3.68, 2.96, and 3.79 points, respectively. The actual use of PMs and CMs was 1.67 and 2.63 points, respectively. The perceived necessity of PMs correlated with the actual use of PMs (r = .316, p < .001), and CMs were performed (r = .390, p < .001). Keeping or reading guidelines, or receiving education on pain management resulted in a higher perception of the necessity of PMs. CONCLUSION: Korean nurses in NICUs often underestimate the necessity of pain relief measures and use few PMs or CMs. Therefore, systematic approaches to implement guidelines, such as adaptation of guidelines for each NICU, dissemination of guideline content to all NICU staff, and regular measurements of compliance with the guidelines, are recommended. PMID- 25529909 TI - Effects of hypertension, diabetes, and/or cardiovascular disease on health related quality of life in elderly Korean individuals: a population-based cross sectional survey. AB - PURPOSE: This study explored health-related quality of life (QoL) in Korean elderly individuals with hypertension, diabetes, and/or cardiovascular disease (CVD). METHODS: This study used a population-based cross-sectional design. Data were obtained from the Fourth Korean National Health and Nutrition Examination Survey 2008, which involved a nationally representative sample. Data on health related QoL were collected using the EuroQoL-5 Dimension instrument and via health interviews. The sample consisted of 1,467 Korean individuals aged 60 years and older. A multiple linear regression model was used to analyze health-related QoL. RESULTS: After controlling for sociodemographic and lifestyle variables, individuals with one of the aforementioned chronic diseases had lower EuroQoL-5 Dimension scores, ranging from 0.186 among those with only hypertension to 0.469 among those with hypertension plus CVD, compared with those without a chronic disease (higher scores are indicative of more limitations). The impact of comorbid diseases was greater than that of any single disease except diabetes. CVD had a stronger negative impact on QoL than did any other single disease studied. Whereas the physical elements of QoL were influenced by all diseases, the psychological components were influenced only by hypertension plus diabetes and hypertension plus CVD. CONCLUSION: We found that both the number and the type of diseases affected QoL scores. Efforts to prevent or manage diabetes, CVD, and related risk factors should include psychological support. PMID- 25529910 TI - Case management for medical aid beneficiaries in Korea: findings from case control study. AB - PURPOSE: This study was to evaluate effects of case management provided for 7 months for medical aid in Korea. METHODS: This study was a retrospective comparative study using secondary data analysis. Data from two pre-existing survey were reanalyzed. The data were collected through door to-door interviews using the structured questionnaire. For the medical service use, claims data from the Korea National Health Insurance Corporation was used. Subjects were 73 in the intervention group and 118 in the control group. RESULTS: There was no significant change in the intervention group in self-care ability (p = .296), medication adherence (p = .194) or quality of life (p = .903) compared to those of the control group. For hospital visiting days, it appeared to decrease in the intervention group (p = .038) but with no significant difference from that of the control group (p = .157). Neither were there significant differences in medical expenditures (p = .605). CONCLUSION: Although the effect of case management in this study appeared extremely limited, the short intervention period and characteristics of the medical aid beneficiaries and the limit of controlling only the demand side were discussed as factors to be considered. Nurses have been carrying out professional roles in case management in Korea. However more efforts are needed to develop case management as an area for nursing specialization. PMID- 25529911 TI - Impact of regular nursing rounds on patient satisfaction with nursing care. AB - PURPOSE: The purpose of the study was to determine the impact of regular nursing rounds on patient satisfaction with nursing care. METHODS: This was a controlled clinical trial in which 100 hospitalized patients in a medical surgical ward were allocated to control and experimental groups through convenience sampling. The experimental group received regular nursing rounds every 1-2 hours. Routine care was performed for the control group. Patient satisfaction with the quality of nursing care was assessed on the second and fifth days of hospitalization in both groups using Patient Satisfaction with Nursing Care Quality Questionnaire. RESULTS: On the second day, patient satisfaction scores of the two groups had no significant difference (p = .499). However, the intervention was associated with statistically significant increased patient satisfaction in the experimental group compared to the control group (p < .001). CONCLUSION: Implementing regular nursing rounds had a positive impact on patient satisfaction. This method may hence improve patient-nurse interactions and promote the quality of nursing care and patient satisfaction. PMID- 25529912 TI - Effects of autogenic training on stress response and heart rate variability in nursing students. AB - PURPOSE: This study was undertaken to confirm the effects of autogenic training (AT) on stress response and heart rate variability in nursing school students experiencing stress related to clinical training. METHODS: The study was carried out from September 2012 to April 2013 in a quasi-experimental nonequivalent control group using a pretest-posttest design. The participants were 40 nursing students in their third year at either of two nursing colleges. All consented to participate. Nineteen nursing students at one college were assigned to the experimental group and underwent the 8-week AT program, and the other 21 were assigned to the control group and did not undergo any training. Stress response was assessed by questionnaire and HRV was measured three times, that is, before the program, at the end of the program, and 6 months after the end of the AT program. RESULTS: A significant time/group interaction was found for stress response (F = 4.68, p = .012), a subjective indicator. However, no significant interaction was found for the objective indicators of heart rate variability, normalized low frequency (F = 2.59, p = .090), normalized high frequency (F = 2.59, p = .090), or low frequency to high frequency ratio (F = 1.38, p = .257). CONCLUSION: The results suggest that AT provides an acceptable approach to stress reduction in nursing students. PMID- 25529913 TI - Estimation of effects of factors related to preschooler body mass index using quantile regression model. AB - PURPOSE: The purpose of this study was to investigate Korean preschoolers' obesity-related factors through an ecological approach and to identify Korean preschoolers' obesity-related factors and the different effects of ecological variables on body mass index and its quantiles through an ecological approach. METHODS: The study design was cross-sectional. Through convenience sampling, 241 cases were collected from three kindergartens and seven nurseries in the Seoul metropolitan area and Kyunggi Province in April 2013 using self-administered questionnaires from preschoolers' mothers and homeroom teachers. RESULTS: Results of ordinary least square regression analysis show that mother's sedentary behavior (p < .001), sedentary behavior parenting (p = .039), healthy eating parenting (p = .027), physical activity-related social capital (p = .029) were significant factors of preschoolers' body mass index. While in the 5% body mass index distribution group, gender (p = .031), preference for physical activity (p = .015), mother's sedentary behavior parenting (p = .032), healthy eating parenting (p = .005), and teacher's sedentary behavior (p = .037) showed significant influences. In the 25% group, the effects of gender and preference for physical activity were no longer significant. In the 75% and 95% group, only mother's sedentary behavior showed a statistically significant influence (p < .001, p = .012 respectively). CONCLUSION: Efforts to lower the obesity rate of preschoolers should focus on their environment, especially on the sedentary behavior of mothers, as mothers are the main nurturers of this age group. PMID- 25529914 TI - Factors affecting unused remaining volume of intravenous patient-controlled analgesia in patients following laparoscopic gynecologic surgery. AB - PURPOSE: This study was undertaken to evaluate the factors affecting the unused remaining volume of intravenous patient-controlled analgesia (IV PCA) in patients who had undergone laparoscopic gynecologic surgery. METHODS: We retrospectively collected patient records from pre-existing PCA log sheets from 98 patients. Surgical factors and IV PCA-related data including remaining volume, administration duration, early discontinuation (yes or no), and adverse reactions were recorded. Chi-square test, one-way analysis of variance, and multiple linear regression were applied for data analysis. RESULTS: The average age of the 98 patients was 40.0 +/- 8.24 years. The incidence of postoperative nausea and vomiting (PONV) and early discontinuation were not statistically significant among the different surgical groups (p = .540 and p = .338, respectively). Twenty eight patients wanted discontinuation of IV PCA and the remaining volume was 33.6 +/- 7.8 mL (range 20-55 mL). The significant determinants of remaining volume were whether IV PCA was discontinued due to PONV and duration of surgery (p < .001). The surgical duration was inversely correlated with the remaining volume. CONCLUSION: Early discontinuation of IV PCA due to PONV is a major contributing factor to wastage of medicine. Prevention and treatment of PONV is needed to encourage patients to maintain PCA use for pain control. PMID- 25529915 TI - Development and psychometric evaluation of the Korean version of the cultural competence scale for clinical nurses. AB - PURPOSE: To develop and psychometrically test the Korean version of the Cultural Competence Scale for Nurses (K-CCSN). METHODS: A multi-phase questionnaire development method was used to develop the scale from November 2012 to April 2013. The item pool was generated based on literature review, existing scales and in-depth interviews. The content validity was evaluated twice by an expert panel. The scale validation was conducted with a convenience sample of 456 general hospital nurses recruited from five general hospitals and a nursing college in the Seoul Metropolitan Area of South Korea. The construct-related and criterion related validity and internal consistency reliability of the scale were tested. RESULTS: The 33-item K-CCSN comprised four subscales-cultural awareness, cultural knowledge, cultural sensitivity and cultural skills-explaining 53.96% of the total variance. The criterion-related validity was supported by a known-group comparison. The reliability analysis showed an acceptable-to-high Cronbach's alpha in total and for subscales ranging from .879 to .932. CONCLUSION: This preliminary evaluation of psychometric scale properties demonstrated acceptable validity and reliability. The K-CCSN is able to provide scientific and empirical data regarding the cultural competence of clinical nurses. However, further studies are needed to test the applicability of the scale in different settings and contexts. PMID- 25529916 TI - Changes in and factors affecting second-hand smoke exposure in nonsmoking Korean Americans in California: a panel study. AB - PURPOSE: We evaluated changes in and factors affecting second-hand smoke (SHS) exposure in a panel study of nonsmokers. METHODS: This study was based on data from a larger study of tobacco use among a representative sample of adults of Korean descent residing in California. Participants included 846 males and 1,399 females who were nonsmokers at baseline (2005-2006) and at follow-up (2007-2009). Participants were selected by probability sampling and were interviewed by telephone. RESULTS: At baseline, 50.0% were exposed to any SHS, and at follow-up 2 years later, 60.4% were exposed to any SHS (p < .001). SHS exposure at baseline was associated with acculturation, employment, spousal smoking, and having a friend who smoked (p < .001). Employment, spousal smoking, and other family members smoking were associated with SHS at follow-up (p < .001). The odds ratio of SHS in the employed group declined from 2.01 at baseline to 1.53 at follow-up, that of the group having a smoking spouse increased from 1.88 to 2.36, and that of the group having other family members smoking increased from 1.20 to 1.69. CONCLUSIONS: We showed that SHS exposure increased among Korean American nonsmokers in California, and the most important variables explaining the change in SHS exposure involved smoking among others with whom the subject is associated. These findings could be used as objective evidence for developing public health policies to reduce SHS exposure. PMID- 25529918 TI - Opposing roles of glutaminase isoforms in determining glioblastoma cell phenotype. AB - Glutamine (Gln) and glutamate (Glu) play pivotal roles in the malignant phenotype of brain tumors via multiple mechanisms. Glutaminase (GA, EC 3.5.1.2) metabolizes Gln to Glu and ammonia. Human GA isoforms are encoded by two genes: GLS gene codes for kidney-type isoforms, KGA and GAC, whereas GLS2 codes for liver-type isoforms, GAB and LGA. The expression pattern of both genes in different neoplastic cell lines and tissues implicated that the kidney-type isoforms are associated with cell proliferation, while the liver-type isoforms dominate in, and contribute to the phenotype of quiescent cells. GLS gene has been demonstrated to be regulated by oncogene c-Myc, whereas GLS2 gene was identified as a target gene of p53 tumor suppressor. In glioblastomas (GBM, WHO grade IV), the most aggressive brain tumors, high levels of GLS and only traces or lack of GLS2 transcripts were found. Ectopic overexpression of GLS2 in human glioblastoma T98G cells decreased their proliferation and migration and sensitized them to the alkylating agents often used in the chemotherapy of gliomas. GLS silencing reduced proliferation of glioblastoma T98G cells and strengthen the antiproliferative effect evoked by previous GLS2 overexpression. PMID- 25529917 TI - CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. AB - Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8(+) T-lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand-1 and accumulation of T-regulatory cells and M2 type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia-induced up-regulation of stromal cell-derived 1 alpha. Inhibition of the stromal cell-derived 1 alpha receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8(+) T lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand 1 receptor programmed death receptor-1 (PD-1) showed antitumor effects in treatment-naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. CONCLUSION: Anti-PD-1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti-PD-1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors. PMID- 25529919 TI - Chronic rhinosinusitis osteoblasts differ in cellular properties from normal bone. AB - BACKGROUND: Osteitis, characterized by bony thickening and remodeling, is often considered a hallmark of recalcitrant rhinosinusitis. However, there is limited literature examining the bone in chronic rhinosinusitis (CRS) pathology. In this study we cultured osteoblasts from bone harvested during sinus surgery as well as from nondiseased controls to compare their cellular properties. METHODS: Sinus bone was collected during sinus and skull-base surgery and placed in proliferation media. Outgrowth of cells occurred at 2 weeks and the cells were confirmed to be osteoblasts by alkaline phosphatase staining. Cellular adhesion was determined by replating and counting adhered cells at 4 hours. Proliferation of cells plated for 24 hours was assayed by measuring [(3) H]-thymidine incorporation. Calcium content was measured by changing cells to differentiation media and measuring the calcium content on days 7, 14, and 21. RESULTS: Alkaline phosphatase assay showed more than 90% of osteoblasts staining in all samples. Osteoblasts from patients with CRS had significant decreases in adhesion (p < 0.01) compared to osteoblasts from skull-base patients. There was a significant (p < 0.05) increase in calcium content in rhinosinusitis samples compared with the nondiseased sinus bone samples. CONCLUSION: To date, this is the first known study that shows a direct comparison of osteoblast properties between patients with and without CRS. Our results indicate that there are fundamental phenotypic differences in adhesion and mineralization between osteoblasts in patients with CRS compared to controls. PMID- 25529921 TI - Effect of annealing on down-conversion properties of monoclinic Gd2O3:Er3+ nanophosphors. AB - Erbium-doped nano-sized Gd2O3 phosphor was prepared by a solution combustion method in the presence of urea as a fuel. The phosphor was characterized by X-ray diffractometry (XRD), Fourier transform infra-red spectroscopy, energy dispersive X-ray analysis (EDX) and transmission electron microscopy (TEM). The results of the XRD shows that the phosphor has a monoclinic phase, which was further confirmed by the TEM results. Particle size was calculated by the Debye-Scherrer formula. The erbium-doped Gd2O3 nanophosphor was revealed to have good down conversion (DC) properties and the intensity of phosphor could be modified by annealing. The effects of annealing at 900 degrees C on the particle size and luminescence properties were studied and compared with freshly prepared Gd2O3:Er(3+) nanoparticles. The average particle sizes were calculated as 8 and 20 nm for the freshly prepared samples and samples annealed at 900 degrees C for 1 h, respectively. The results show that both freshly prepared and annealed Gd2O3:Er(3+) have monoclinic structure. PMID- 25529922 TI - The relationship between synovial fluid VEGF and serum leptin with ultrasonographic findings in knee osteoarthritis. AB - AIM: This study aimed to determine synovial fluid and serum biomarkers which could accord with radiological and ultrasonographic findings in knee osteoarthritis. METHODS: Thirty-four patients with knee osteoarthritis were detected with joint effusion by clinical examination. Both knee joints were examined using plain radiographs and ultrasonography. Questions were obtained for visual analog scale (VAS), Western Ontario McMaster Universities Osteoarthritis Index and Health Assessment Questionnaire (HAQ). Synovial fluid (SF) and serum levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-13, leptin, resistin and cartilage oligomeric matrix protein (COMP) were measured using enzyme-linked immunosorbent assay. RESULTS: Synovial fluid VEGF level was positively correlated with Kellgren-Lawrence (KL) grades and it was higher in patients with KL grade 4 than those with KL grade 2. SF VEGF correlated with ultrasonographic findings, such as the length of medial osteophytes. The amount of effusion was positively correlated with SF resistin. Serum leptin level had positive correlation with HAQ and the length of medial osteophytes. MMP-13 or COMP levels were not correlated with radiographic or ultrasonographic findings. CONCLUSION: Synovial fluid VEGF level was correlated with radiographic grading, ultrasonographic findings and functional statues in knee osteoarthritis, and serum leptin level also correlated with the ultrasonographic findings and functional status of knee osteoarthritis. PMID- 25529920 TI - Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. AB - Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxide-dependent impairment of lysosomal acidification and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidification and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifically PKCbetaII. These findings reveal a novel mechanism linking lipotoxicity with a PKCbeta-Nox2-mediated impairment in pH dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs. PMID- 25529923 TI - The susceptibility vessel sign at the proximal M1: a strong predictor for poor outcome after intravenous thrombolysis. AB - BACKGROUND: Half of acute stroke patients have poor outcomes at 3 months even when treated with intravenous thrombolysis using tissue-plasminogen activator (t PA) therapy. The aim of the present study was to evaluate the impact of the susceptibility vessel sign (SVS) on magnetic resonance imaging (MRI) T2* at the proximal portion of the middle cerebral artery (M1 proximal SVS) on clinical outcome in anterior circulation stroke patients treated with t-PA. METHODS: The presence of the M1 proximal SVS was assessed before t-PA therapy. Good outcome and poor outcome at 3 months were defined as a modified Rankin Scale score of 0 to 2 and 4 to 6, respectively. The predictive values of the M1 proximal SVS for a good and poor outcome were calculated. RESULTS: 161 patients (median age [interquartile], 76 [67-83] years; male, 91 [57%]) were enrolled. At 3 months after stroke, 68 (42%) patients achieved a good outcome, and 75 (47%) had a poor outcome. The M1 proximal SVS was found in 17 (11%) patients, of whom none (0%) achieved a good outcome, and 16 (94%) had a poor outcome. The sensitivity and positive predictive value of the M1 proximal SVS for good outcome were very low (0.000 and 0.000, respectively). Furthermore, the specificity and positive predictive value of the M1 proximal SVS for poor outcome were very high (0.988 and 0.941, respectively). CONCLUSION: The M1 proximal SVS appears to be a strong predictor for poor outcome after t-PA therapy. PMID- 25529924 TI - Ten-year retrospective assessment of the performance of the Food Contact Notification (FCN) programme. AB - The Food Contact Notification (FCN) programme was authorised by the US Food and Drug Administration (USFDA) Modernization Act of 1997. Manufacturers may file FCNs for food contact substances (FCSs) not already authorised or pre-sanctioned by the USFDA by demonstrating a reasonable certainty of no harm for their intended uses. The Division of Food Contact Notifications (DFCN) 10-year Retrospective Assessment Group was formed to collect and develop metrics associated with the first decade of the FCN Programme and determine the extent selected aspects of the review process contributed to the effective FCN. Comparative analysis of 924 FCNs revealed that 76% become effective, 23% were withdrawn and 1% received a not accepted status. The focus of the Group was to identify factors impacting the likelihood of an FCN becoming effective. PMID- 25529925 TI - Do genetic defects of DNA repair relevant proteins alter susceptibility to hypertension? A case-control study in northeastern Han Chinese. AB - The aim of this study was to examine the individual and interactive associations of five non-synonymous variants of four DNA repair relevant genes (XRCC1, XRCC3, hOGG1, NQO1) with hypertension in a large northeastern Han Chinese population. This was a hospital-based study involving 1009 hypertensive patients and 756 normotensive controls. All five variants satisfied the Hardy-Weinberg equilibrium. With a Bonferroni corrected alpha of 0.05/5, significance was only attained in the genotype (P=0.007) and allele (P=0.006) distributions of rs25487 in XRCC1 gene between patients and controls, with its mutant allele conferring 29% (95% CI: 1.09-1.53; P=0.003), 31% (95% CI: 1.05-1.62; P=0.015) and 66% (95%CI: 1.10-2.52; P=0.016) increased risks of hypertension under the additive, dominant and recessive models, respectively after adjusting for confounders. The frequency of allele combination C-A-C-G-C (alleles in order of rs1799782, rs25487, rs861539, rs1052133 and rs1800566) was significantly higher in patients than in controls (P=0.003), while that of C-G-C-C-C was significantly lower (P=0.001). Interaction analysis failed to identify any suggestive evidence of synergism across five examined variants. Our findings provide evidence for a contributory role of XRCC1 gene rs25487 variant in the development of hypertension, and this variant possibly acted in a recessive pattern. PMID- 25529926 TI - Lipoid proteinosis: phenotypic heterogeneity in Iranian families with c.507delT mutation in ECM1. AB - Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by loss-of-function mutations in the ECM1 gene, and previous studies have noted phenotypic variability. In this study, we examined 12 patients representing three Iranian families for clinical manifestations and genotyped them for mutations in ECM1. LP was diagnosed with characteristic mucocutaneous and neurologic manifestations. Five patients were also subjected to magnetic resonance imaging (MRI)/computed tomography (CT) scan of the central nervous system. DNA was isolated from peripheral blood from patients and their clinically unaffected relatives, and mutations in ECM1 were sought by PCR-based amplification of all exons and flanking intronic sequences, followed by bidirectional Sanger sequencing. Significant phenotypic variability in this multisystem disorder, including presence of convulsions and epilepsy in about half of the patients was noted. In most cases, this was associated with calcifications in the brain detected by MRI/CT scans. Genotyping of the affected individuals in three families from the central region of Iran revealed presence of homozygous c.507delT mutation in ECM1, reflecting the observed consanguinity in these families. This large cohort revealed extensive phenotypic variability in individuals with the same mutation in ECM1. This observation suggests a role for genetic and epigenetic as well as environmental modulation of the phenotype. Identification of mutations allows screening of unaffected individuals for presence or absence of this mutation in extended LP families, with implications for genetic counseling. PMID- 25529927 TI - Metal-free nitrative cyclization of N-aryl imines with tert-butyl nitrite: dehydrogenative access to 3-nitroindoles. AB - We describe here a new metal-free route for the synthesis of 3-nitroindoles by the nitrative cyclization of N-aryl imines with tert-butyl nitrite. The radical transformation allows the assembly of the indole framework through oxidative cleavage of multi C-H bonds, a nitration, cyclization and isomerization cascade. PMID- 25529928 TI - Children infer affiliative and status relations from watching others imitate. AB - We investigated whether young children are able to infer affiliative relations and relative status from observing others' imitative interactions. Children watched videos showing one individual imitating another and were asked about the relationship between those individuals. Experiment 1 showed that 5-year-olds assume that individuals imitate people they like. Experiment 2 showed that children of the same age assume that an individual who imitates is relatively lower in status. Thus, although there are many advantages to imitating others, there may also be reputational costs. Younger children, 4-year-olds, did not reliably make either inference. Taken together, these experiments demonstrate that imitation conveys valuable information about third party relationships and that, at least by the age of 5, children are able to use this information in order to infer who is allied with whom and who is dominant over whom. In doing so, they add a new dimension to our understanding of the role of imitation in human social life. PMID- 25529929 TI - Oxatriphyrins(2.1.1) incorporating an ortho-phenylene motif. AB - An understanding of fundamental aspects of archetypal organic structural motifs remains a key issue faced by the experimental and theoretical chemists. Two possible bonding modes for a disubstituted benzene ring, that is a meta and para, determines the pi delocalization for oligomeric structures. When the less abundant ortho-substituted variant is introduced into a triphyrin(2.1.1) skeleton an aromatic molecule is obtained and the carbocyclic ring participates in the conjugation of the macrocycle. The two-electron reduction and introduction of boron(III) changes the aromatic character and results in an anti-aromatic structure which has been confirmed by single-crystal analysis and supported by theoretical calculations. PMID- 25529931 TI - Identification of genomic signatures in circulating tumor cells from breast cancer. AB - Levels of circulating tumor cells (CTCs) in blood have prognostic value in early and metastatic breast cancer. CTCs also show varying degrees of concordance with molecular markers of primary tumors they originate from. It is expected that individual cells reflect the heterogeneity and evolution of tumor cells as they acquire new functions and differential responses to chemotherapy. However, a degree of commonality is also plausible, highlighting alterations that allow tumor cells to perform CTC-defining activities such as invasion and intravasation. Using a matched tumor-normal approach, we performed high resolution copy number profiling of CTCs from breast cancer to identify occult changes occurring during progression to metastasis. We identified a signature of recurrent gain in CTCs, consisting of 90 minimal common regions (MCRs) of copy number gain. These were predominantly found across chromosome 19 and were identified at low frequencies (3-4%) in 787 primary breast carcinomas examined. CTC genomic signatures clustered into two groups independent of subtype: a dormancy-related signature with 16 MCRs (AKT2, PTEN, CADM2); and a tumor aggressiveness related signature with 358 MCRs (ANGPTL4, BSG, MIR-373). There were two MCRs in common between the groups on 19q13 and 21q21, containing genes involved in resistance to anoikis, TGFbeta-signaling and metastasis (TFF3, LTBP4, NUMBL). Furthermore, a region harboring the ERBB2 gene was gained in a majority of patients. Regions 20q13 and 15q24 were associated with distant metastasis. The distinctiveness of CTC signatures highlights cell populations with different functional or metastatic potential. Such novel targets could help to specifically identify and block dissemination. PMID- 25529932 TI - A new classification for temporomandibular joint arthrocentesis techniques. PMID- 25529934 TI - A Swedish perspective on nursing and psychosocial research in paediatric oncology: A literature review. AB - PURPOSE: A dramatic improvement in outcomes of survival rates of childhood cancer has been seen. Caring science research is central in providing skills and knowledge to the health care sector, but few overviews of the content of published research have been carried out. The aim of this review was to investigate the content and methodology of published studies in paediatric oncology relevant to caring science, and also to compare possible differences in content and method of the published studies from the nursing and psychosocial perspectives. METHOD: A systematic literature review was performed of 137 published articles on paediatric oncology relevant to caring science in Sweden. RESULTS: The results show that most of the studies were descriptive or comparative ones with a quantitative design. Most of them focused on parents (43%) or children (28%). Most of the studies investigated wellbeing (88%), using questionnaires (54%) or interviews (38%). Several different measurement instruments had been used. While the results were often clearly presented, the clinical implications were more diffuse. The most acknowledged research fund was the Swedish Childhood Foundation (75%). CONCLUSIONS: To reflect the children' perspectives in paediatric oncology require that future researchers take on the challenge of including children (even young ones) in research. The use of a limited number of agreed measurement instruments is desirable. The biggest challenge for the future is to make a shift from explorative to intervention studies. There is an urgent need to transform research results into clinical practice. PMID- 25529935 TI - Symptoms of hormonal therapy and social support: Is there a connection? Comparison of symptom severity, symptom interference and social support among breast cancer patients receiving and not receiving adjuvant hormonal treatment. AB - BACKGROUND: Although there has been a significant reduction in mortality, breast cancer is the most frequent cancer among women worldwide. This decline in mortality has created a significant survivor population that must manage the post curative treatment phase, in order to have an increased quality of life and well being. This study examined the relationship between symptom interference and severity with the perception of social support in the lives of women receiving or not receiving, hormonal therapy after initial treatment. METHODS AND SAMPLE: Participants completed symptom severity and interference questionnaires, (MDASI and BCPT), a social support survey (MSPSS) and demographic and comorbidity questionnaires. RESULTS: Of the 210 women participants, higher symptom severity correlated with unemployment, living alone or being religious. Participants who were currently taking hormonal treatment (n = 84), reported a significant negative correlation between symptom severity, measured by MDASI, and social support (p = 0.006). Consequently, as symptom severity increased, perceived social support decreased. In the BCPT assessment, decreased cognitive functioning (p < 0.05), pain (p < 0.05), bladder dysfunction (p = 0.001), and reduced self image (p < 0.01) were significantly negatively correlated with social support for those participants currently taking hormonal therapy. Participants who had not previously received hormonal therapy (n = 64), cognitive dysfunction and bladder dysfunction were negatively correlated with social support. Women with preexisting heart or pulmonary dysfunction and arthritis reported statistically significant higher levels of symptom severity and decreased perceptions of social support. CONCLUSIONS: Identifying socio-demographic variables and comorbidities that affect hormonal therapy symptom burden is essential for offering adequate support for breast cancer survivors. PMID- 25529933 TI - Regulation of tissue morphogenesis by endothelial cell-derived signals. AB - Endothelial cells (ECs) form an extensive network of blood vessels that has numerous essential functions in the vertebrate body. In addition to their well established role as a versatile transport network, blood vessels can induce organ formation or direct growth and differentiation processes by providing signals in a paracrine (angiocrine) fashion. Tissue repair also requires the local restoration of vasculature. ECs are emerging as important signaling centers that coordinate regeneration and help to prevent deregulated, disease-promoting processes. Vascular cells are also part of stem cell niches and have key roles in hematopoiesis, bone formation, and neurogenesis. Here, we review these newly identified roles of ECs in the regulation of organ morphogenesis, maintenance, and regeneration. PMID- 25529936 TI - Perceived factors influencing nurses' use of evidence-informed protocols for remote cancer treatment-related symptom management: A mixed methods study. AB - PURPOSE: To assess factors perceived to influence nurses' use of symptom protocols when providing remote management for oncology patients. METHOD: A mixed methods descriptive study was guided by the Knowledge-to-Action Framework. In 2013, 8 focus groups and 7 interviews were conducted with 49 nurses or patients/family members in three ambulatory oncology programs within different provincial healthcare systems. Role-play with a protocol was used during nurse focus groups/interviews. Nurses who provided remote symptom support received a survey. Data was triangulated using thematic analysis guided by the Ottawa Model of Research Use. RESULTS: Over 90% of nurses provide telephone support during regular hours only. These symptom protocols were being used by 14% of nurses at one program. Nurses rated the protocols positively for content and format (>85%) but 20% indicated too complex. Protocol facilitators were systematic approach, comprehensive, and evidence-based. Protocol barriers were too long, not for symptom clusters, and inadequate space for documenting. To facilitate use, nurses need to enhance their knowledge (73%) and skills (58%), get access to resources, and obtain performance feedback. Nurse barriers included the learning curve, being unaware of protocols, and feeling tied to a script. Organizational barriers were communication challenges with patients, lack of electronic charting, and no clear direction to use them (54%). CONCLUSIONS: Several barriers and facilitators were perceived to influence the use of symptom protocols. Nurses and patients/family members identified similar factors. Interventions are needed to overcome barriers to nurses using the protocols such as education, clear organizational mandate, and integration with documentation. PMID- 25529937 TI - Patient experiences of nurse-led telephone follow-up following treatment for colorectal cancer. AB - PURPOSE: Colorectal cancer is the third most prevalent cancer worldwide, although mortality rates across most of Europe have decreased in recent years. Historically, patients are asked to return to hospital outpatient clinics following treatment to monitor for disease progression. However, new approaches are being called for that focus on meeting the information and support needs of patients. Telephone follow-up (TFU) by specialist nurses is an alternative approach; this study aimed to explore patient views of TFU. METHODS: Qualitative interviews were conducted with 26 colorectal cancer patients who had received TFU. One interview was also conducted with the specialist nurse who had used a structured intervention to provide TFU. Data were analysed using content analysis. RESULTS: All patients found TFU to be a positive experience and all stated a preference for continuing with TFU. Three main themes emerged from the patient interviews; 1) accessible and convenient care, 2) personalised care, and 3) relationship with the specialist nurse. The themes from the specialist nurse interview were 1) knowing the patient, 2) the benefits of TFU and 3) the challenges of TFU. CONCLUSIONS: TFU was well received by patients; it was perceived as highly convenient and had distinct advantages over hospital follow up. Continuity of care was an important factor in building a trusting relationship between patient and nurse. Training in the use of the intervention is recommended and it may be useful for specialist nurses to initially meet eligible patients face to face to establish rapport before implementing TFU. PMID- 25529938 TI - Spanish consensus on vulvar disorders in postmenopausal women. AB - INTRODUCTION: The consequences of vulvar disorders in terms of health, sexuality, and quality of life are usually undervalued, with disparities in the conceptual, diagnosis and treatment criteria. AIM: The objective of this guide will be to analyse the factors associated with the diagnosis and treatment of vulvar disorders and to provide recommendations for the most appropriate diagnostic and therapeutic measures. METHODOLOGY: A panel of experts from various Spanish scientific societies related to sexual health (Spanish Menopause Society [SMS] and the Asociacion Espanola de Patologia Cervical y Colposcopia [AEPCC]) met to reach a consensus on these issues and to decide the optimal timing and methods based on the best evidence available. RESULTS: We recommend a biopsy of all vulvar lesions with an uncertain diagnosis, especially with asymmetry, irregular borders, variegated and irregular colour and diameter >6mm. For vulvodynia, we recommend the use of lubricants or topical treatments with lidocaine or bupivacaine, amitriptyline, baclofen or triamcinolone. For vulvar epithelial disorders, we recommend beginning with topical corticosteroids of moderate to high potency. For sexual dysfunction, a multidisciplinary approach is the best management strategy in these patients. PMID- 25529939 TI - Different levels of awareness and knowledge of male climacteric in female nurses and female office workers. AB - OBJECTIVE: The objective of this study was to examine levels of awareness and knowledge regarding male climacteric or andropause in Japanese women. We also examined whether there are differences in these levels between nurses as a health profession group and office workers as a general population group. METHODS: Two thousand and eight hundred female registered nurses and women with office-related general occupations aged 20-65 years in Japan completed health questionnaires regarding awareness and knowledge of male climacteric, including male menopausal symptoms and treatments. RESULTS: The proportion in women who had heard of the term male climacteric in nurses was significantly higher than that in office workers. Nurses with past or current experience of menopausal symptoms were likely to recognize male climacteric. Nurses also had a higher level of knowledge than did office workers regarding male menopausal symptoms. High proportions of both nurses and office workers acknowledged depressed mood, irritability, nervousness and sleep problems as male menopausal symptoms. The proportions of women with sympathy for men with male climacteric were high in women with experience of past or current menopausal symptoms and in women who were close to men who suffered from menopausal symptoms. CONCLUSIONS: Nurses with past or current experience of menopausal symptoms had high levels of awareness and knowledge of male climacteric. To spread more information and knowledge regarding male climacteric, provision of education for these nurses may be needed. PMID- 25529940 TI - Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2. AB - An MYH2 mutation p.(Glu706Lys) was originally described in a family with autosomal dominant inheritance, where the affected family members presented with multiple congenital contractures and ophthalmoplegia, progressing to a proximal myopathy in adulthood. Another patient with a dominant mutation p.(Leu1870Pro) was described, presenting as a congenital myopathy with ophthalmoplegia. Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia. Initially, clinically classified as oculopharyngodistal myopathy, the patient was found to carry a novel, de novo MYH2 mutation c.5630T>C p.(Leu1877Pro). This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum. PMID- 25529942 TI - [Focus on the diagnosis and treatment of benign anorectal diseases]. AB - In recent years, researches regarding benign anorectal diseases have experienced unprecedented boom in China, but also exposed a series of problems, such as lack of attention of medical professionals and patients on benign anorectal diseases, lack of basic and clinical researches, and lack of standard diagnosis and treatment etc. This article discusses the problems of current diagnosis and treatment of benign anorectal diseases in China. Clinician should pay close attention to the diagnosis and treatment of benign anorectal disease. PMID- 25529943 TI - [Surgical treatment of anal fistula]. AB - Anal fistula is a common disease. It is also quite difficult to be solved without recurrence or damage to the anal sphincter. Several techniques have been described for the management of anal fistula, but there is no final conclusion of their application in the treatment. This article summarizes the history of anal fistula management, the current techniques available, and describes new technologies. Internet online searches were performed from the CNKI and Wanfang databases to identify articles about anal fistula management including seton, fistulotomy, fistulectomy, LIFT operation, biomaterial treatment and new technology application. Every fistula surgery technique has its own place, so it is reasonable to give comprehensive individualized treatment to different patients, which may lead to reduced recurrence and avoidance of damage to the anal sphincter. New technologies provide promising alternatives to traditional methods of management. Surgeons still need to focus on the invention and improvement of the minimally invasive techniques. Besides, a new therapeutic idea is worth to explore that the focus of surgical treatment should be transferred to prevention of the formation of anal fistula after perianal abscess. PMID- 25529944 TI - [Pay attention to the functional protection during operation for benign anal diseases]. AB - Benign anorectal diseases are common. Hemorrhoids, anal fissure and anal fistula are the top three of colorectal surgery for benign anrorectal clinical practice. Postoperative fecal incontinence or stool seepage has not yet got enough attention by specialists. This article elaborates on the clinical status, evaluation process, functional protection and treatment strategies etc. Following the continence protection principle requires specialists to focus on not only the disease itself but the patient-centered quality of life. PMID- 25529941 TI - Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. In order to advance the field of NAFLD, noninvasive imaging methods for measuring liver fat are needed. Advanced magnetic resonance imaging (MRI) has shown great promise for the quantitative assessment of hepatic steatosis but has not been validated in children. Therefore, this study was designed to evaluate the correlation and diagnostic accuracy of MRI-estimated liver proton density fat fraction (PDFF), a biomarker for hepatic steatosis, compared to histologic steatosis grade in children. The study included 174 children with a mean age of 14.0 years. Liver PDFF estimated by MRI was significantly (P < 0.01) correlated (0.725) with steatosis grade. The correlation of MRI-estimated liver PDFF and steatosis grade was influenced by both sex and fibrosis stage. The correlation was significantly (P < 0.01) stronger in girls (0.86) than in boys (0.70). The correlation was significantly (P < 0.01) weaker in children with stage 2-4 fibrosis (0.61) than children with no fibrosis (0.76) or stage 1 fibrosis (0.78). The diagnostic accuracy of commonly used threshold values to distinguish between no steatosis and mild steatosis ranged from 0.69 to 0.82. The overall accuracy of predicting the histologic steatosis grade from MRI-estimated liver PDFF was 56%. No single threshold had sufficient sensitivity and specificity to be considered diagnostic for an individual child. CONCLUSIONS: Advanced magnitude-based MRI can be used to estimate liver PDFF in children, and those PDFF values correlate well with steatosis grade by liver histology. Thus, magnitude-based MRI has the potential for clinical utility in the evaluation of NAFLD, but at this time no single threshold value has sufficient accuracy to be considered diagnostic for an individual child. PMID- 25529945 TI - [Three types of abdominoperineal excision procedures for the rectal cancer based on anatomic landmarks classification]. AB - Abdominoperineal excision (APE) procedure is still the main approach to low rectal cancer patients with short distance from the anal verge, obvious invasion of adjacent organs and narrow pelvis. Although the principle of TME (total mesorectal excision) needs to be obeyed in the abdominal phase of APE procedure, it does not reach the consensus for the perineal phase. The important reason is the lack of definite anatomic landmarks in the perineal phase, thus the standardization of the procedure remains hard. In 2014, Swedish surgeon, professor Holm, proposed the new conception to classify the APE procedure into three types, which were intersphincteric APE, the extralavator APE and the ischioanal APE, based on the anatomic landmarks with perineal fascias, nervous and blood vessels. In this paper, we combine the review of literatures and our experiences of treatment to introduce and discuss these three types of APE procedures. This new concept is based on anatomic landmarks which makes the category of APE procedure more definitive, the anatomic dissection more clear and the standardization and adoption of APE procedure much easier. PMID- 25529946 TI - [Sacral neuromodulation in the treatment of intractable constipation]. AB - OBJECTIVE: To assess the efficacy of sacral neuromodulation (SNM) in patients with intractable constipation. METHODS: A total of 7 patients with intractable constipation were treated with pereutaneous test stimulation of the S3 nerve root and were assessed by sacral never stimulation system in our department from January 2013 to January 2014. Four of these 7 patients received operation for constipation before. The efficacy was assessed by bowel habit diary, clinic constipation scores, subjective questionnaire and clinical signs. RESULTS: The constipation symptoms were improved significantly in all the 7 patients. The frequency and volume of defecation per week were increased obviously, and the average urine was increased. Six patients underwent permanent implantation of the SNS system. After a median 4 months follow-up, the defecation frequency increased from 0.6 +/- 0.5 to 8.0 +/- 2.5 per week (P<0.01), and the defecation time decreased from (22.9 +/- 11.5) to (3.7 +/- 0.8) min (P<0.01). The Cleveland clinic constipation score decreased from 24.6 +/- 4.2 to 9.0 +/- 0.9 (P<0.01), and the visual analogue scale(VAS) score increased from 8.1 +/- 0.9 to 82.5 +/- 5.2 (P<0.01). CONCLUSION: SNM is a clinically efficacious, minimally invasive and safe new technique, which offers an alternative treatment for the patients with intractable constipation resistant to conservative treatment, especially for the patients refractory to traditional operations. PMID- 25529947 TI - [Laparoscopy assisted with transanal endoscopic microsurgery in the treatment of severe functional constipation]. AB - OBJECTIVE: To investigate the feasibility and efficacy of laparoscopic subtotal colectomy and modified Duhamel procedure combined with transanal endoscopic microsurgery (TEM) in the treatment of severe functional constipation(SFC). METHODS: The clinical data of 10 patients with SFC treated by laparoscopic surgery combined with TEM between May 2010 and October 2012 in Ruijin Hospital of Shanghai Jiaotong University School of Medicine were retrospectively analyzed. The gastrointestinal quality of life index(GIQLI), Wexner constipation scale and daily frequency of defecation postoperatively during follow-up were collected. RESULTS: All the 10 operations were successfully accomplished laparoscopic subtotal colectomy combined with TEM without abdominal incision. There was no conversion to open procedure. One case had preventive terminal ileum stoma. The mean operative time was (256 +/- 58) min. The mean blood loss was (178 +/- 67) ml. The mean time to first flatus was (40 +/- 11) h. There were no ureteric injury, anastomotic leak, pelvic sepsis and other complications postoperatively. There was one case of insufficient small bowel obstruction which was released by conservative treatments. The patients were discharged from the hospital in (9.0 +/- 1.5) d postoperatively. The GIQLI in one year postoperatively was (112 +/- 10) points, which indicated good results compared to (75 +/- 12) points preoperatively (P=0.000). The Wexner constipation scale was 20.8 +/- 2.2 preoperatively and decreased to 5.2 +/- 1.8 at one year follow-up(P=0.000). CONCLUSION: Laparoscopic subtotal colectomy and modified Duhamel procedure combined with TEM provides SFC patients a safe and feasible minimally invasive surgery. PMID- 25529948 TI - [Value of three-dimensional endoanal ultrasonography for anal fistula assessment]. AB - OBJECTIVE: To explore the value of preoperative evaluation with three-dimensional endoanal ultrasonography (3D-EAUS) for anal fistula in order to provide preoperative assessment for anal fistula. METHODS: One hundred patients diagnosed with anal fistula undergoing surgery between March 2012 and March 2013 in our department were prospectively enrolled. All the patients were randomly divided into the ultrasound group and the control group with fifty patients in each group. The ultrasound group received 3D-EAUS and the control group received routine examinations (digital examination and probe) to assess the position of the internal opening, the type of fistula and secondary tracks, respectively. The concordance rate of the preoperative assessment and intraoperative exploration was evaluated between the two groups. RESULTS: The accuracy of identifying internal opening was 96.0% for the ultrasound group and 82.0% for the control group with statistically significant difference (P=0.02). The accuracy of identifying internal opening for simple anal fistula was similar (95.0% vs. 91.3%, P=1). For complex anal fistula, the accuracy was also higher in the ultrasound group (96.7% vs. 74.1%, P=0.025). The accuracy of fistula classification was 78.0% for the ultrasound group and 96.0% for the control group with significant difference (P=0.01). The accuracy of identifying a second track was higher in the ultrasound group (96.0% vs. 82.0%, P=0.025). CONCLUSIONS: It is significantly superior for 3D-EAUS to detect the internal opening, fistula classification and identification of a second track in complex anal fistulas as compared to conventional examination. 3D-EAUS should be recommended as a preoperative assessment for anal fistula, especially for complex one. PMID- 25529949 TI - [Comparison of two-dimensional ultrasound and three-dimensional endoanal ultrasound in the diagnosis of perianal fistula]. AB - OBJECTIVE: To compare the accuracy of two-dimensional endoanal ultrasound (2D EAUS) and three-dimensional endoanal ultrasound (3D-EAUS) in the diagnosis of perianal fistulas. METHODS: Image data of 47 perianal fistula patients undergoing surgery in our department between January 2012 and December 2012 were collected. All the patients underwent 2D-EAUS and 3D-EAUS, and the results were compared to intraoperative findings (gold standard) by kappa concordance test. RESULTS: Both 2D-EAUS and 3D-EAUS showed good concordance with intraoperative findings in internal opening (kappa: 0.776 vs. 0.636). 3D-EAUS had better concordance with intraoperative finding in the diagnosis of intersphincteric, high transsphincteric and suprasphincteric fistulas as compared to 2D-EAUS (kappa: 0.810 vs. 0.592, kappa: 0.863 vs. 0.548, kappa: 1.000 vs. 0.672). 3D-EAUS showed better concordance with intraoperative findings in secondary tract compared to 2D EAUS(kappa: 0.659 vs. 0.535). Both 2D-EAUS and 3D-EAUS had good concordance with intraoperative findings in complicated abscesses (kappa: 0.881 vs. 0.816). CONCLUSION: 3D-EAUS can show the relationship of fistula with anal sphincter, especially in diagnosing high fistula and fistula with secondary tracts, and has a higher diagnostic accuracy than 2D-EAUS. PMID- 25529950 TI - [Ligation of intersphincteric fistula tract in the treatment of complicated fistula-in-ano]. AB - OBJECTIVE: To evaluate the efficacy of ligation of intersphincteric fistula tract (LIFT) in the treatment of complex fistula-in-ano. METHODS: Clinical data of 24 patients with complex fistula-in-ano who treated with LIFT in the Affiliated Hospital of Nanjing University of Chinese Medicine from September 2009 to February 2012 were analyzed retrospectively. The operative efficacy and postoperative continence were evaluated. RESULTS: The prime success rate of fistula healing was 66.7% (16/24) after the LIFT procedure. Two patients presented with intersphincteric incision infection which was successfully treated with topical of silver nitrate. Four patients had intersphincteric fistula with infection and managed with the complete laying open approach. The total clinical healing rate was 91.7% (22/24). Another 2 patients had persistent external opening with discharge. During follow-up of 6 to 44 (median 16) months, The Cleveland Clinic Florida Fecal Incontinence score revealed that no patient developed decreased continence. CONCLUSION: LIFT is a safe and effective sphincter-preserve procedure for complex fistula-in-ano. PMID- 25529951 TI - [Modified ligation of the intersphincteric fistula tract in the treatment of simple transsphincteric perianal fistula]. AB - OBJECTIVE: To assess the efficacy and safety of modified ligation of the intersphincteric fistula tract for simple transsphincteric perianal fistula. METHODS: Seventy patients with simple transsphincteric perianal fistula between October 2012 and January 2014 in our department were prospectively enrolled. According to the random number table, patients were divided into two groups: modified-LIFT group (37 cases, from the external opening close to the fistula, dissect the external sphincter fistula to the intersphincteric groove by tunneling technique, resect the lateral free fistula) and LIFT group (33 cases). Clinical parametres before and after operation were compared, and results of pelvic electromyogram (EMG) and anorectal manometry three months after operation were analyzed to evaluated anal function. RESULTS: The operative time, pain score, hospital stay, and healing time were not significantly different between the two groups (all P>0.05). During the median follow-up of 12 months (3-20 months), the healing rate in modified-LIFT group was 83.8% (31/37), which was significantly higher than 60% (20/33) in LIFT group (P=0.029). After operation, 4 patients had persistent unhealed wound, 2 recurred in modified-LIFT group, while 8 patients had persistent unhealed wound, and 5 recurred in LIFT group. No patients developed anal incontinence. By the pelvic EMG and anorectal manometry 3 months after operation, the duration of motor unit potential, occurrence of simple phase, mean resting pressure and maximun squeeze pressure were not significantly different. CONCLUSION: Modified-LIFT procedure for the management of simple transsphincteric perianal fistulas is a simple and effective operation with higher healing rate and similar anal function as LIFT. PMID- 25529952 TI - [Application of laparoscopic technique in the treatment of traumatic colorectal perforation]. AB - OBJECTIVE: To explore the efficacy and the security of laparoscopic technique in patients with traumatic colorectal perforation. METHODS: Clinical data of 42 patients with traumatic colorectal perforation in our hospital during March of 2005 to March of 2013 were retrospectively analyzed. Twenty-two patients received traditional open operation, and 20 patients received laparoscopic treatment. RESULTS: As compared to open group, laparoscopic group had shorter operation time [(72 +/- 36) min vs. (128 +/- 52) min], less blood loss during operation [(21.2 +/- 3.6) ml vs. (62.6 +/- 8.8) ml], faster postoperative bowel function return[(1.7 +/- 0.6) d vs. (3.5 +/- 1.2) d], shorter hospital stay after operation [(7.3 +/- 1.8) d vs. (13.6 +/- 3.9) d], and lower incidence of postoperative complication [35.0% (7/20) vs. 72.7% (16/22)]. The differences between two were statistically significant (all P<0.05). CONCLUSION: Laparoscopic operation has advantages in the treatment of traumatic colorectal perforation with short operation time, small trauma, rapid recovery and low incidence of complications. PMID- 25529953 TI - [Clinical study of Ruiyun procedure for hemorrhoids combined with Xiaozhiling injections in treatment of hemorrhoids complicated with human immunodeficiency virus infection]. AB - OBJECTIVE: To explore the efficacy of Ruiyun procedure for hemorrhoids (RPH) combined with Xiaozhiling injection in the treatment of hemorrhoids complicated with human immunodeficiency virus (HIV) infection and its influence on cellular immune function. METHODS: Clinical data of 76 hemorrhoid patients, including 36 positive HIV and 40 negative HIV, undergoing RPH combined with Xiaozhiling injections in our center from January 2010 to December 2012 were retrospectively analyzed. Clinical efficacy and cellular immune function preoperative day 1, postoperative day 7, 30 were compared between positive and negative groups. RESULTS: Recurrence rates of positive group and negative group postoperative 6 months were 22.2% (8/36) and 22.5% (9/40), postoperative 1 year were 30.6% (11/36) and 30.0% (12/40) without significant differences (all P>0.05). Morbidity of postoperative complication was also not significantly different between two groups (P>0.05). According to HIV classification, peripheral lymph cell ratio, CD4 count, CD4/CD8, white blood cell count and neutrophil ratio were not significantly different between preoperative day 1 and postoperative day 7 in both groups (all P>0.05). Decreasing velocity and amplitude of CD4 in both groups from high to low was HIV III, HIV II, HIV I, HIV-, while after 30 days the increase of CD4 from high to low was HIV-, HIV I, HIV II, HIV III, which were significantly different as compared to postoperative day 7 (all P<0.05). CONCLUSIONS: RPH combined with Xiaozhiling injection in the treatment of hemorrhoids complicated with HIV infection is effective and safe. Postoperative inhibited cellular immune function can recover quickly. PMID- 25529954 TI - [Efficacy of retained rectal posterior mucosa in procedure for prolapse and hemorrhoids]. AB - OBJECTIVE: To evaluate the efficacy and necessity of retained rectal posterior mucosa in procedure for prolapse and hemorrhoids (PPH). METHODS: Clinical data of 260 cases with severe hemorrhoids in our hospital from January 2010 to May 2012 were analyzed retrospectively. A total of 132 cases with severe hemorrhoids excluding in rectal posterior wall were enrolled in retained rectal posterior mucosa in PPH (improvement group), other 128 cases of severe hemorrhoids were assigned to PPH (conventional group). Operative parameters, efficacy and complication after operation were compared. RESULTS: Two groups of patients received successful operations. Postoperative pain duration, frequency of analgesic drugs and postoperative hospital stay in improvement group were significantly reduced [(1.3 +/- 0.5) d vs. (4.8 +/- 0.7) d, 1.1 +/- 0.3 vs. 5.9 +/- 0.6, (5.2 +/- 0.8) d vs. (5.8 +/- 0.5) d, all P<0.01]. Incidence of anastomotic stenosis, heavy feeling in the anus and delayed bleeding in improvement group were significantly lower than those in conventional group (0 vs. 7.8%, 0.8% vs. 14.1%, 0 vs.7.8%, all P<0.01). CONCLUSIONS: The application of retained rectal posterior mucosa in PPH to patients with severe hemorrhoids excluding in rectal posterior wall can significantly reduce postoperative complications. But long-term efficacy needs further observation. PMID- 25529955 TI - [Application of complete mesocolic excision in stage III colon cancer]. AB - To evaluate the efficacy of complete mesocolic excision (CME) for stage III colon cancer. METHODS: Clinical data of 100 patients diagnosed as stage III colon cancer in our hospital from July 2011 to July 2013 were analyzed retrospectively. Fifty-four patients in CME group underwent complete mesocolic excision and 46 patients in control group underwent traditional radical surgery. Lymphadenectomy, postoperative specimen quality and short-term clinical efficacy were compared between two groups. RESULTS: The number of gross dissected lymph nodes and positive dissected lymph nodes in CME group were 26.7 +/- 2.6 and 4.3 +/- 1.4, which were significantly higher than those in control group (22.9 +/- 3.7 and 2.8 +/- 1.2) (all P<0.01). There was statistical significance in surgical C-class specimens of CME group were found in 45 cases (83.3%), which were significantly higher than those of control group (29 cases, 63.0%) (P<0.05). The postoperative complication rate of two groups was the same without significant difference(both 13.0%, P>0.05). CONCLUSION: CME is safe and effective for stage III colon cancer, which can improve the quality of surgical specimen and increase the number of dissected lymph nodes, but do not elevate the morbidity of postoperative complication. PMID- 25529956 TI - [Clinical study of reduced-port laparoscopy-assisted resection for cancer at the sigmoid colon and upper rectum]. AB - OBJECTIVE: To explore the safety and feasibility of reduced-port laparoscopic assisted resection for cancer at the sigmoid colon and upper rectum. METHODS: Clinical data of 70 patients with sigmoid colon or upper rectal cancer undergoing laparoscopic-assisted resection in our department from February 2013 to July 2014 were retrospectively reviewed. Patients were divided into reduced-port group (44 cases, 3 or 4 ports) and conventional group (26 cases, 5 ports). The operative time, blood loss, retrieved lymph nodes, postoperative exhaust recovery, dietary recovery, hospital stay and morbidity of complication were compared between two the groups. RESULTS: No significant differences were observed in operative time [(144.0 +/- 40.1) min vs. (115.8 +/- 30.8) min], blood loss [(72.9 +/- 50.2) ml vs. (45.5 +/- 52.4) ml], number of retrieved lymph nodes [(10.2 +/- 8.4) vs. (12.0 +/- 5.6)], time to bowel function return [(3.2 +/- 0.7) d vs. (2.8 +/- 0.8) d], time to liquid diet [(4.2 +/- 1.1) d vs. (3.8 +/- 0.9) d], time to semisolid diet [(8.6 +/- 2.1) d vs (8.1 +/- 1.7) d], and postoperative hospital stay [(13.0 +/- 3.4) d vs. (12.8 +/- 7.2) d] between two groups (all P>0.05). Complication rate of conventional group and the reduced-port group was 15.4% and 7.2% without significant difference (P=0.233). CONCLUSIONS: For cancer at the sigmoid colon and upper rectum, reduced-port laparoscopic surgery is feasible, safe and radical as the five-port in terms of technical and oncologic issues. These two procedures have the same short-term outcome. PMID- 25529957 TI - [Modification and efficacy observation of laparoscopic dual anastomosis for mid low rectal cancer]. AB - OBJECTIVE: To explore a new procedure of laparoscopic dual anastomosis for mid low rectal cancer to reduce postoperative complications. METHODS: Clinical data of 56 patients with mid-low rectal cancer undergoing laparoscopic rectal cancer resection(modified double-stapling technique, MDST, modification group) in the Department of General Surgery, the First Affiliated Hospital of Soochow University from February 2010 to June 2014 were compared with the data of 64 patients with mid-low rectal cancer (conventional double-stapling technique, DST, convention group) in the same period based on gender, age, tumor size, the distance from lower edge to the dentate line and tumor staging, etc. Patients in the modification group received operation as follows: (1) the rectum distal end was closed vertically instead of horizontally. (2) the anastomosis was conducted in an "end-corner" approach. (3) upper corner of the closed line in the distal end of rectum was removed. (4) the lower corner of closed line in the distal end of rectum was removed using vascular occlusion clamp method. (5) two T-shaped interchanges ("dangerous triangle") of stapled sutures formed after anastomosis were strengthened with absorbable suture. Patients in the convention group received laparoscopic dual anastomosis using conventional method: two corners and "dangerous triangles" were kept without any treatment. The clinical outcomes of two groups were analyzed retrospectively. RESULTS: The intraoperational blood loss, postoperative drainage volume, postoperative anastomotic stoma bleeding, bowel function return and hospital stay were not significantly different between the two groups (all P>0.05). As compared to the convention group, the modification group had longer operation time [(211 +/- 91) min vs. (174 +/- 57) min, P<0.05], lower incidence of postoperative anastomotic leakage [1.8%(1/56) vs. 12.5% (8/64), P=0.030], lower tenesmus rate [3.6% (2/56) vs. 14.1% (9/64), P<0.05], less postoperative stoma re-creation [0 vs. 9.4% (6/64), P<0.05]. CONCLUSION: Modified laparoscopic dual anastomosis for mid-low rectal cancer can significantly reduce the incidence of post-surgical complications such as anastomotic leakage. PMID- 25529958 TI - [Diagnostic values of pressure aggravation test and breath aggravation test in the early acute appendicitis]. AB - OBJECTIVE: To compare the applied value of the pressure aggravation test and breath aggravation test in the diagnosis of early acute appendicitis. METHODS: A total of 101 cases with epigastralgia, middle or upper abdomen pain, disease duration within 6 hours undergoing pressure aggravation test and breath aggravation test respectively in our hospital between October 2010 and December 2012 were prospectively enrolled. By comparing with the postoperative pathological diagnosis (early acute appendicitis and other abdominal pain), the sensitivity and specificity of these two tests were calculated. Through analyzing the receiver operating characteristic (ROC) curve, the diagnostic value of early acute appendicitis was evaluated. RESULTS: Fifty-two cases of early acute appendicitis and 49 cases of other abdominal pain were diagnosed by postoperative pathologic results. The sensitivity and specificity of the pressure aggravation test were 87.5% and 72.1% and of the breath aggravation test were 53.8% and 83.7% respectively. The area under the ROC curve of the pressure aggravation test was 0.786 (95% CI: 0.693-0.878), similar to that of the breath aggravation test (0.688, 95% CI: 0.583-0.792). CONCLUSION: The pressure aggravation test has higher value to diagnose early acute appendicitis, while the breath aggravation test has better specificity. PMID- 25529959 TI - [Effect of fast tract surgery on immune and inflammatory reaction of elder patients with colorectal cancer]. AB - OBJECTIVE: To compare the effect of rapid rehabilitation surgery (FTS) with the traditional operation method on postoperative immune function recovery, inflammatory reaction and the clinical efficacy in elderly patients with colorectal cancer. METHODS: A total of 144 elderly patients (older than 65 years) diagnosed as colorectal cancer in our department from February 2010 to August 2013 were prospectively enrolled in the study. According to the order of admission, patients were randomly divided into the fast track surgery group (72 cases, study group), and the traditional operation group (72 cases, control group). Preoperative and postoperative T cell subsets, inflammatory index and organ functional parameters were detected and compared. RESULT: Basal clinical data of the two groups had no significant differences (all P>0.05). Three days after operation, CD4+ and CD8+ in both groups increased compared to preoperative levels (P<0.05), while the study group had greater increasing amplitude of CD4+ (t=1.685, P=0.003), and lower CD8+(t=1.145, P=0.005) than the control group. CD4+/CD8+ increased in the study group compared to preoperation and significantly higher than that in the control group (P=0.001). Inflammatory stress indexes were significantly increased, while study group had smaller amplitude than the control group. Serum creatinine, B-natriuretic peptide and Troponin-T increased after operation, while the study group had smaller amplitude than the control group (P<0.05). The study group showed faster resumption of oral intake, quicker bowel function return, time to first defecation, hospital stay, lower incidences of nausea, vomiting, incision infection, and less cost of hospitalization. All the differences were significant (all P<0.05). CONCLUSION: Fast track surgery can effectively protect the perioperative organ function, increase postoperative immune function, decrease inflammation stress reaction, reduce perioperative morbidity of complication, improve efficacy for elderly colorectal cancer patients. PMID- 25529960 TI - [A systematic evaluation on the quality of Meta-analysis in articles published in the Chinese Journal of Gastrointestinal Surgery from 1998 to 2014]. AB - OBJECTIVE: To assess the methodological quality and reporting quality on Meta analysis being published in the Chinese Journal of Gastrointestinal Surgery. METHODS: Computerized literature searching was carried out in Wanfang Medical Online to collect articles that Meta-analysis was used in the Chinese Journal of Gastrointestinal Surgery since it was founded till July, 2014. Manual retrieval was also conducted. Two researchers independently screened for literature and extracted data. Qualities on methodologies or on the processes of reporting and reviewing were evaluated by both AMSTAR and PRISMA scales. RESULTS: Forty-two papers on meta-analyses were included in this study. Results on the quality of methodology evaluation showed that the lowest and highest scores were 6 and 9 respectively, the median score was 7. Two articles (4.8%) were rated as high, 40 articles (95.2%) as moderate and 0 articles (0%) as low. Although the quality of methodology was above the average, however, there were still some problems seen in some papers as the conflict of interest was not stated, the list of studies (included and excluded) was not provided, a comprehensive literature search was not performed, the likelihood of publication bias was not assessed, etc. Results on the quality of reporting evaluation showed that the lowest and highest scores were 14 and 22 respectively, the average score was 18.43 +/- 2.03, 3 articles (7.1%) scored less than 15 points, 35 articles (83.3%) scored 15.5-21 points, and 4 articles (9.6%) scored 21.5-27 points. The included reviews had high quality on the titles of the report, inclusion criteria, rationale of introduction, synthesis of results, results of individual. However, the abstract, objectives of introduction, scheme and registered, inclusion criteria, research screening, additional analysis, conclusion limitations, funding support etc. were lack of comprehensive reports. CONCLUSIONS: Articles on Meta-analysis published in the Chinese Journal of Gastrointestinal Surgery are of high quality. The Chinese Journal of Gastrointestinal Surgery can provide better evidence for clinical decision to gastrointestinal surgeons. However, both of qualities on methodology and reports sill call for continuous improvement. PMID- 25529961 TI - [Current status of the treatments of fecal incontinence]. AB - Fecal incontinence is common. It may have dramatic negative impacts on patients' quality of life. During the past two decades, new treatments with effective outcomes and less complications have been developed. Non-operative treatments include dietary modifications, medications, and biofeedback therapy. Operative treatments include repair (sphincteroplasty), stimulation (sacral nerve stimulation), artificial bowel sphincter implantation, muscle transposition and fecal diversion. The latest reported treatments such as radiofrequency energy delivery and injectable materials are still controversial. But those therapies, having a minimal invasive profile, may be the options before considering a surgery in some patients with mild fecal incontinence. In general, physicians have to make an individualized choice of treatment considering anal function, the quality of life and potential complications. A more invasive operative treatment must be seriously selected in patients with severe fecal incontinence. Indications, outcomes and strategy of current treatments for fecal incontinence are sufficiently discussed by authors in this article. PMID- 25529962 TI - [Research progress of the treatment of rectovaginal fistulas]. AB - Treatment of rectovaginal fistula (RVF) is extremely difficult. Successful performing operation to treat RVF is a major challenge, because recurrence has remained common. RVF has significant negative influence on the patient's quality of life and causes social embarrassment. Up to now, no standard surgical technique is accepted worldwide, no ideal treatment option is suitable for all the patients, and no recommendation of clinical treatment guideline of RVF is available. English literatures were reviewed in this article, from the causes of rectovaginal fistula, classification, diagnosis, surgical methods, surgical approach, minimally invasive technology application, perioperative management and the cause of operation failure aspects were reviewed in detail. PMID- 25529963 TI - [Clinical management of pilonidal diseas-interpretation of practice parameters for the management of pilonidal disease from American Society of Colon and Rectal Surgeons]. AB - Pilonidal disease is a common clinical condition which is not sufficiently recognized with regard to the clinical manifestation and treatment by colorectal surgeons in China, resulting in high misdiagnosis rate and recurrent rate. With reference to the Practice Parameters for the Management of Pilonidal Disease published in 2013 by The American Society of Colon and Rectal Surgeons, we discuss the management of pilonidal disease in four aspects, including etiology, diagnoses, nonoperative and operative management. PMID- 25529964 TI - [Advances in controllable artificial anus device]. AB - Artificial anus is the important surgical treatment for low colorectal cancer. However, fecal incontinence caused by artificial anus has significant influence on quality of life of patients. A series of novel therapy devices have been invented to solve the problem. According to the different applying methods, these devices can be divided into artificial sphincter and occluder. Artificial sphincter is implanted surgically and more automatic but its complicated design increased risk of complications such as infection and gastrointestinal symptoms. By comparison, occluder is less automatic and needs daily cleaning or replacement, but more comfortable, concealed and safer. For most of occluder are disposable or replaced frequently, advanced devices will greatly increase the economic burden on patients. With the progress of science and technology, artificial anal devices will become more intelligent, automatic and miniaturization. PMID- 25529965 TI - [Role of sacral nerve stimulation in anorectal diseases]. AB - Anorectal diseases pose significant impact on patients' physical and mental health. Specially, the living standard of the people is significantly reduced by fecal incontinence, constipation and anorectal pain. Meanwhile there is no radical treatment for these diseases. But sacral nerve stimulation (SNS) provides us with new ideas and methods to treat these diseases and achieves good curative effect. In this article, we review the current application of SNS. PMID- 25529966 TI - Nitrergic function is lost but endothelial function is preserved in the corpus cavernosum and penile resistance arteries of men after radical prostatectomy. AB - INTRODUCTION: Radical prostatectomy (RP) frequently results in erectile dysfunction (ED). It has been hypothesized that alterations of cavernosal tissue subsequent to RP contribute to ED but functional evaluation of the impact of RP on human erectile structures is lacking. AIM: This study aims to evaluate endothelial function of human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) and neurogenic responses of HCC from patients with ED secondary to RP (ED-RP). METHODS: HCC strips and HPRA were obtained from organ donors without history of ED (No-ED) and patients with ED who were segregated depending on ED etiology: ED-RP or vasculogenic (ED-VASC). Functional evaluation of HCC and HPRA was performed in organ chambers and wire myographs, respectively. Histological evaluation of cavernosal tissue consisted of trichrome staining for fibrosis quantification and TUNEL assay for determination of apoptosis. MAIN OUTCOME MEASURES: Endothelium-dependent and endothelium-independent relaxation, electrical field stimulation (EFS)-induced neurogenic contraction and relaxation, and cavernosal fibrosis and apoptosis. RESULTS: Endothelium-dependent relaxations were significantly impaired in HCC and HPRA from ED-VASC patients while these responses in ED-PR patients were not different to No-ED. Similarly, sildenafil induced relaxations were reduced in HCC and HPRA from ED-VASC but were preserved in ED-RP. Adrenergic contractions induced by EFS in HCC were potentiated in both ED-RP and ED-VASC. EFS-induced nitrergic relaxation was significantly reduced in HCC from ED-VASC but was almost abolished in ED-RP. Fibrous tissue content and cavernosal apoptosis in HCC from ED-RP were not significantly different from No ED. CONCLUSIONS: Endothelial function and cavernosal sensitivity to phosphodiesterase type 5 inhibitors are preserved in erectile tissue from ED-RP while a marked imbalance in neurogenic modulation of cavernosal tone favoring adrenergic contractile responses over nitrergic relaxation is manifested. Fibrotic and apoptotic processes in cavernosal tissue are not specifically associated to ED-RP. These evidences could help to retarget therapeutic strategies in the management of ED after RP. PMID- 25529967 TI - Surgical strategies for spontaneous basal ganglia hemorrhages. PMID- 25529968 TI - The pathogenesis of migrating pseudomeningocele. PMID- 25529970 TI - The importance of peer reviewers for advancing the field. PMID- 25529969 TI - The history of neurosurgery at the Royal Free Hospital London: Some corrections. PMID- 25529971 TI - Long term and excessive use of 900 MHz radiofrequency radiation alter microRNA expression in brain. AB - PURPOSE: We still do not have any information on the interaction between radiofrequency radiation (RF) and miRNA, which play paramount role in growth, differentiation, proliferation and cell death by suppressing one or more target genes. The purpose of this study was to bridge this gap by investigating effects of long-term 900 MHz mobile phone exposure on some of the miRNA in brain tissue. MATERIALS AND METHODS: The study was carried out on 14 Wistar Albino adult male rats by dividing them into two groups: Sham (n = 7) and exposure (n = 7). Rats in the exposure group were exposed to 900 MHz RF radiation for 3 h per day (7 days a week) for 12 months (one year). The same procedure was applied to the rats in the sham group except the generator was turned off. Immediately after the last exposure, rats were sacrificed and their brains were removed. rno-miR-9-5p, rno miR-29a-3p, rno-miR-106b-5p, rno-miR-107 and rno-miR-125a-3p in brain were investigated in detail. RESULTS: Results revealed that long-term exposure of 900 MHz RF radiation only decreased rno-miR107 (adjP* = 0.045) value where the whole body (rms) SAR value was 0.0369 W/kg. However, our results indicated that other microRNA evaluated in this study was not altered by 900 MHz RF radiation. CONCLUSION: 900 MHz RF radiation can alter some of the miRNA, which, in turn, may lead to adverse effects. Therefore, further studies should be performed. PMID- 25529972 TI - Dependence of radiation-induced H2AX phosphorylation on histone methylation: evidence from the chromatin immunoprecipitation assay. AB - PURPOSE: To evaluate ionizing radiation (IR)-induced DNA damage response within euchromatic and heterochromatic regions. MATERIAL AND METHODS: Chromatin immunoprecipitation (ChIP) and immunofluorescence analysis were used to explore the distribution of phosphorylated H2AX (gammaH2AX). RESULTS: ChlP experiments after IR at 30 and 60 Gy showed by a factor of 1.28 (1.08-1.53, 95% confidence interval) higher gammaH2AX signal at 45 min after IR in histone H3 trimethylated lysine 4 (H3K4me3) compared to lysine 9 (H3K9me3) enriched chromatin fragments. Halving the radiation dose from 60-30 Gy led to a reduction of gammaH2AX signal by a factor of 0.49 (0.37-0.64), independent of the chromatin region. Repair incubation for 240 min led to a decrease of the gammaH2AX signal by a factor of 0.55 (0.45-0.67) in both regions. The fraction of H3K9me3 was determined with immunofluorescent microscopy to be 30.5 +/- 3.8% of the whole chromatin. The fraction of gammaH2AX foci within H3K9me3 regions was shown to be 12.9 +/- 0.4% and 13.9 +/- 0.6% at 45 min and 4 h after 0.5 Gy, respectively, and thus by a factor of about 2.2 lower than the fraction expected from an isotropic distribution. CONCLUSION: These data strengthen the dependence of IR-induced DNA damage response on the chromatin region. PMID- 25529973 TI - DNA damage at respiratory distress, but not acute time-points, correlates with tissue fibrosis following thoracic radiation exposure in mice. AB - PURPOSE: Radiation exposure can result in DNA damage but whether the extent of DNA damage correlates with the radiation-induced tissue injury in the lung is not known. We aimed to determine whether numbers of gammaH2AX foci, representing histone H2AX phosphorylation a marker of DNA damage, measured within days of radiation exposure, correlated with known later lung injury responses in eight inbred mouse strains. MATERIALS AND METHODS: Mice received 18 Gy pulmonary irradiation and numbers of gammaH2AX positive nuclei in the lung were immunohistochemically determined. RESULTS: Numbers of gammaH2AX foci, assessed up to seven days post irradiation did not correlate with pulmonary fibrosis. gammaH2AX counts from mice in respiratory distress, however, significantly correlated with fibrosis and lungs from mice treated with a fibrosis-reducing antagonist had fewer gammaH2AX foci. CONCLUSIONS: Acute response measures of pulmonary DNA damage did not predict for pathology, but levels of this marker in distressed mice were correlative of fibrosis. PMID- 25529974 TI - Susceptibility of linear and nonlinear otoacoustic emission components to low dose styrene exposure. AB - OBJECTIVE: To investigate potential susceptibility of active cochlear mechanisms to low-level styrene exposure by comparing TEOAEs in workers and controls. DESIGN: Two advanced analysis techniques were applied to detect sub-clinical changes in linear and nonlinear cochlear mechanisms of OAE generation: the wavelet transform to decompose TEOAEs into time-frequency components and extract signal-to-noise ratio and latency of each component, and the bispectrum to detect and extract nonlinear TEOAE contributions as quadratic frequency couplings (QFCs). STUDY SAMPLE: Two cohorts of workers were examined: subjects exposed exclusively to styrene (N = 9), and subjects exposed to styrene and noise (N = 6). The control group was perfectly matched by age and sex to the exposed group. RESULTS: Exposed subjects showed significantly lowered SNR in TEOAE components at mid-to-high frequencies (above 1.6 kHz) and a shift of QFC distribution towards lower frequencies than controls. No systematic differences were observed in latency. CONCLUSION: Low-level styrene exposure may have induced a modification of cochlear functionality as concerns linear and nonlinear OAE generation mechanisms. The lack of change in latency seems to suggest that the OAE components, where generation region and latency are tightly coupled, may not have been affected by styrene and noise exposure levels considered here. PMID- 25529975 TI - Electrophysiologic vestibular evaluation in type 2 diabetic and prediabetic patients: Air conduction ocular and cervical vestibular evoked myogenic potentials. AB - OBJECTIVE: Chronically increased blood glucose levels may affect the vestibular system by damaging cells and neural structures in diabetes mellitus (DM). We aimed to search the effects of neurovascular degeneration on the vestibular system in type 2 DM and prediabetic patients by using air-conducted ocular (oVEMP) and cervical (cVEMP) vestibular evoked myogenic potentials. DESIGN: Prospective study. STUDY SAMPLE: Thirty diabetic, 30 prediabetic patients, and 31 age- and sex-matched controls having no peripheral or central vestibular disease, were enrolled. All participants were evaluated by audiovestibular tests, oVEMP, and cVEMP. RESULTS: In the diabetic group, mean values of both oVEMP and cVEMP p1, n1 latencies were significantly longer compared to the prediabetic group and the control group, whereas latencies were similar in prediabetic and the control groups. Bilateral neural dysfunction was recognized in both tests and lateralization was not seen in VEMP asymmetric ratios. In the diabetic group, prevalence of pathological p1 and n1 latencies in oVEMP were 30.4% and 37.5%, whereas they were 53.7%, 59.3% in cVEMP, respectively. p1 latencies of cVEMP and oVEMP were positively correlated with HbA1c and fasting plasma glucose level in the diabetic group. CONCLUSION: Subclinical vestibular neuropathy can be a newly defined diabetes-related complication. PMID- 25529976 TI - A template for writing radiotherapy protocols. AB - BACKGROUND: Well-specified and unambiguous treatment protocols are essential both for current practice and for the future development of radiation therapy. In order to provide assistance for writing good protocols, irrespective of treatment intention and complexity, up-to-date guidelines are highly desirable. METHODS: We have analysed the radiotherapy work-flow, including clinical and physical aspects, such as preparatory imaging, treatment planning, delivery and evaluation, with the aim to outline a consistent framework covering the entire radiotherapy process. RESULTS: Based on the analysis, a recipe-style template for specifying the description of the radiotherapy process has been designed. The template is written in a general format, which allows for modified phrasing, and should be customised for the specific clinical situation and diagnosis, as well as facility resources. CONCLUSIONS: The template can be used as a tool to ensure a consistent and comprehensive description of the radiotherapy section of clinical guidelines, care programmes and clinical trial protocols. PMID- 25529977 TI - Chronic pain in "probable" vascular dementia: preliminary findings. AB - BACKGROUND: In a previous study, the levels of pain reported by patients with "possible" vascular dementia (VaD) were higher than those reported by older individuals without dementia. OBJECTIVE: To examine experienced pain in patients with "probable" VaD, confirmed by brain imaging. STUDY DESIGN: Observational, cross sectional. SETTING: Nursing home. METHODS: The participants were 20 nursing home residents (14 females, 6 males) who met the NINDS-AIREN criteria for "probable" VaD and 22 nursing home residents with a normal mental status (18 females, 4 males). The patients were in a mild to moderate stage of dementia. All of the participants were suffering from arthritis/arthrosis or osteoporosis. Global cognitive functioning was measured by the Mini-Mental State Examination. Pain was assessed by the Coloured Analogue Scale (CAS: original and modified version) and the Faces Pain Scale. The Geriatric Depression Scale and the Symptom Checklist-90 were used to assess mood. RESULTS: The main finding was that, after controlling for mood, the pain levels indicated by patients with "probable" VaD (M = 102.32; standard deviation [SD] = 53.42) were significantly higher than those indicated by the control group (M = 59.17; SD = 38.75), only according to the CAS modified version (F[1,29]) = 5.62, P = 0.01, eta2 = 0.16). CONCLUSION: As VaD patients may experience greater pain than controls, it is essential for prescribers to be aware of the presence of this neuropathology if these patients are to receive adequate treatment. PMID- 25529978 TI - Epidemiology and ecology of tularemia in Sweden, 1984-2012. AB - The zoonotic disease tularemia is endemic in large areas of the Northern Hemisphere, but research is lacking on patterns of spatial distribution and connections with ecologic factors. To describe the spatial epidemiology of and identify ecologic risk factors for tularemia incidence in Sweden, we analyzed surveillance data collected over 29 years (1984-2012). A total of 4,830 cases were notified, of which 3,524 met all study inclusion criteria. From the first to the second half of the study period, mean incidence increased 10-fold, from 0.26/100,000 persons during 1984-1998 to 2.47/100,000 persons during 1999-2012 (p<0.001). The incidence of tularemia was higher than expected in the boreal and alpine ecologic regions (p<0.001), and incidence was positively correlated with the presence of lakes and rivers (p<0.001). These results provide a comprehensive epidemiologic description of tularemia in Sweden and illustrate that incidence is higher in locations near lakes and rivers. PMID- 25529979 TI - LX4211 therapy reduces postprandial glucose levels in patients with type 2 diabetes mellitus and renal impairment despite low urinary glucose excretion. AB - PURPOSE: We sought to assess the efficacy and safety profile of LX4211, a dual inhibitor of sodium-glucose cotransporter1 (SGLT1) and SGLT2, in patients with type 2 diabetes and renal impairment. METHODS: Thirty-one patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) were randomly assigned to receive 400 mg of LX4211 or placebo for 7 days. The primary end point was the change from baseline to day 7 in postprandial glucose (PPG) levels. Other end points included changes in fasting plasma glucose levels, glucagon-like peptide 1 levels, urinary glucose excretion (UGE), and blood pressure. FINDINGS: LX4211 therapy significantly reduced PPG levels relative to placebo in the total population and in patients with an eGFR <45 mL/min/1.73 m(2), with a placebo adjusted decrease in incremental AUCpredose-4 of 73.5 mg.h/dL (P = 0.009) and 137.2 mg.h/dL (P = 0.001) for the total population and the eGFR <45 mL/min/1.73 m(2) subgroup, respectively. There was a significant reduction in fasting plasma glucose levels relative to baseline of -27.1 mg/dL (P < 0.001). Total and active glucagon-like peptide 1 levels were significantly elevated relative to placebo with LX4211 dosing, and UGE was significantly elevated with placebo-subtracted measures of 38.7, 53.5, and 20.4 g/24 h (P <= 0.007 for all 3) in the total population, eGFR 45 to 59 mL/min/1.73 m(2), and eGFR <45 mL/min/1.73 m(2) subgroups, respectively. IMPLICATIONS: The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m(2) despite the expected reduction in UGE, suggesting that dual SGLT1 and SGLT2 inhibition with LX4211 could prove useful for the treatment of patients with type 2 diabetes and renal impairment. ClinicalTrials.gov identifier: NCT01555008. PMID- 25529980 TI - The galactolipase activity of Fusarium solani (phospho)lipase. AB - The purified (phospho)lipase of Fusarium solani (FSL), was known to be active on both triglycerides and phospholipids. This study aimed at assessing the potential of this enzyme in hydrolyzing galactolipids. FSL was found to hydrolyze at high rates of synthetic medium chains monogalactosyldiacylglycerol (4658+/-146U/mg on DiC8-MGDG) and digalactosyldiacylglycerol (3785+/-83U/mg on DiC8-DGDG) and natural long chain monogalactosyldiacylglycerol extracted from leek leaves (991+/ 85U/mg). It is the microbial enzyme with the highest activity on galactolipids identified so far with a level of activity comparable to that of pancreatic lipase-related protein 2. FSL maximum activity on galactolipids was measured at pH8. The analysis of the hydrolysis product of natural MGDG from leek showed that FSL hydrolyzes preferentially the ester bond at the sn-1 position of galactolipids. To investigate the structure-activity relationships of FSL, a 3D model of this enzyme was built. In silico docking of medium chains MGDG and DGDG and phospholipid in the active site of FSL reveals structural solutions which are in concordance with in vitro tests. PMID- 25529982 TI - A novel PALB2 truncating mutation in an Italian family with male breast cancer. AB - Male breast cancer (MBC) is a rare disease, accounting for ~1% of all breast cancer cases worldwide. Although other genes are also involved, predisposing genetic factors to MBC include germline mutations in the BRCA genes (BRCA2). Among the other genes, partner and localizer of BRCA2 (PALB2) is considered a moderate-penetrance breast cancer susceptibility gene that may also play a role in MBC predisposition. Thus, the aim of the present study was to determine the PALB2 gene status in 8 MBC cases selected from a cohort of 181 hereditary breast and/or ovarian cancer probands. We performed PALB2 mutational analysis by direct sequencing of 13 exons and adjacent intronic regions. This study showed the presence of a PALB2 truncating mutation in 1/8 (12.5%) cases. This novel mutation was named c.1285_1286delAinsTC (p.I429SfsX12) and is localized in exon 4 of PALB2, in the region encoding for the ChAM motif which is important for the efficient association of PALB2 to chromatin and for recruitment of the BRCA complex to accumulate RAD51 at double-strand break sites. Our findings indicate that PALB2 could be added to the list of breast cancer susceptibility genes also in families with MBC cases. PMID- 25529983 TI - Lipopeptides as main ingredients for inhibition of fungal phytopathogens by Bacillus subtilis/amyloliquefaciens. AB - Some isolates of the Bacillus subtilis/amyloliquefaciens species are known for their plant protective activity against fungal phytopathogens. It is notably due to their genetic potential to form an impressive array of antibiotics including non-ribosomal lipopeptides (LPs). In the work presented here, we wanted to gain further insights into the relative role of these LPs in the global antifungal activity of B. subtilis/amyloliquefaciens. To that end, a comparative study was conducted involving multiple strains that were tested against four different phytopathogens. We combined various approaches to further exemplify that secretion of those LPs is a crucial trait in direct pathogen ward off and this can actually be generalized to all members of these species. Our data illustrate that for each LP family, the fungitoxic activity varies in function of the target species and that the production of iturins and fengycins is modulated by the presence of pathogens. Our data on the relative involvement of these LPs in the biocontrol activity and modulation of their production are discussed in the context of natural conditions in the rhizosphere. PMID- 25529986 TI - Bodyweight and body condition score in rabbits on four different feeding regimes. AB - OBJECTIVES: The aim of this study was to assess the effects of four diet regimes (extruded diet with ad lib hay, muesli with ad lib hay, ad lib hay only, ad lib muesli only) on bodyweight and body condition score in rabbits. METHODS: Thirty two Dutch rabbits were studied over 9 months. Bodyweight and body condition score were recorded weekly. RESULTS: All groups gained weight with age, but relative to the ad lib hay only group (mean, 1 . 77 +/- 0 . 13 kg), after 9 months rabbits in the ad lib muesli only group were 146% heavier (2 . 59 +/- 0 . 32 kg); extruded diet with ad lib hay group 125% heavier (2 . 21 +/- 0 . 10 kg); and muesli with ad lib hay group 123% heavier (2 . 18 +/- 0 . 13 kg). Median body condition score of the ad lib muesli only group was obese (4 . 5) and was higher than that in both the extruded diet with ad lib hay and muesli with ad lib hay (median = 3 . 5) groups (P < 0 . 001). Both the extruded diet with ad lib hay and muesli with ad lib hay groups had above-ideal body condition score despite having bodyweights within the breed standard range. The ad lib hay only group had a median body condition score of 3 (ideal). There was an overall positive correlation between body condition score and weight (qs = 0 . 814, P < 0 . 001). CLINICAL SIGNIFICANCE: The feeding of muesli without hay should be avoided, to prevent obesity. PMID- 25529987 TI - Permeabilization of brain tissue in situ enables multiregion analysis of mitochondrial function in a single mouse brain. AB - KEY POINTS: Mitochondrial function in the brain is traditionally assessed through analysing respiration in isolated mitochondria, a technique that possesses significant tissue and time requirements while also disrupting the cooperative mitochondrial reticulum. We permeabilized brain tissue in situ to permit analysis of mitochondrial respiration with the native mitochondrial morphology intact, removing the need for isolation time and minimizing tissue requirements to ~2 mg wet weight. The permeabilized brain technique was validated against the traditional method of isolated mitochondria and was then further applied to assess regional variation in the mouse brain with ischaemia-reperfusion injuries. A transgenic mouse model overexpressing catalase within mitochondria was applied to show the contribution of mitochondrial reactive oxygen species to ischaemia reperfusion injuries in different brain regions. This technique enhances the accessibility of addressing physiological questions in small brain regions and in applying transgenic mouse models to assess mechanisms regulating mitochondrial function in health and disease. ABSTRACT: Mitochondria function as the core energy providers in the brain and symptoms of neurodegenerative diseases are often attributed to their dysregulation. Assessing mitochondrial function is classically performed in isolated mitochondria; however, this process requires significant isolation time, demand for abundant tissue and disruption of the cooperative mitochondrial reticulum, all of which reduce reliability when attempting to assess in vivo mitochondrial bioenergetics. Here we introduce a method that advances the assessment of mitochondrial respiration in the brain by permeabilizing existing brain tissue to grant direct access to the mitochondrial reticulum in situ. The permeabilized brain preparation allows for instant analysis of mitochondrial function with unaltered mitochondrial morphology using significantly small sample sizes (~2 mg), which permits the analysis of mitochondrial function in multiple subregions within a single mouse brain. Here this technique was applied to assess regional variation in brain mitochondrial function with acute ischaemia-reperfusion injuries and to determine the role of reactive oxygen species in exacerbating dysfunction through the application of a transgenic mouse model overexpressing catalase within mitochondria. Through creating accessibility to small regions for the investigation of mitochondrial function, the permeabilized brain preparation enhances the capacity for examining regional differences in mitochondrial regulation within the brain, as the majority of genetic models used for unique approaches exist in the mouse model. PMID- 25529988 TI - Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression. AB - OBJECTIVE: Severe depression may be a risk factor for diagnostic conversion into bipolar disorder (BD), and psychotic depression (PD) has been consistently associated with BD. The aims of the present study were to investigate the stability of the diagnosis of severe depression and the differences between PD and non-psychotic severe depression (non-PD), as well as to assess the effectiveness of electroconvulsive therapy (ECT). METHODS: Patients who were hospitalised for severe depression (diagnosed according to ICD-10) both with and without psychotic symptoms (n=89; mean age=55.6 years, SD=13.9) from 2001 to 2010 were retrospectively assessed. RESULTS: By the 75th month of follow-up assessments, 11(12.4%) patients had developed BD. Among these 11 converters, nine had developed BD within 1 year after admission. Only sub-threshold hypomanic symptoms were significantly related to developing BD. The number of depressive episodes and history of physical diseases were significantly increased in non-PD compared with PD patients, whereas ECT was significantly increased in PD compared with non-PD patients. There was a significant association between length of stay at the hospital and the number of days between admission and ECT. CONCLUSION: Sub threshold hypomanic symptoms may represent a prodrome of BD or an indicator of an already manifest phenotype, especially in older patients, which suggests cautious use of antidepressants. In severe depression, non-PD may often occur secondary to physical diseases and patients may experience increased recurrences compared with PD patients, which may be a more 'primary' disorder and often requires ECT treatments. ECT is effective for severe depression regardless of the presence of any psychotic feature; the earlier ECT is introduced, the better the expected treatment outcome. PMID- 25529989 TI - Cognitive, cultural, and linguistic sources of a handshape distinction expressing agentivity. AB - In this paper the cognitive, cultural, and linguistic bases for a pattern of conventionalization of two types of iconic handshapes are described. Work on sign languages has shown that handling handshapes (H-HSs: those that represent how objects are handled or manipulated) and object handshapes (O-HSs: those that represent the class, size, or shape of objects) express an agentive/non-agentive semantic distinction in many sign languages. H-HSs are used in agentive event descriptions and O-HSs are used in non-agentive event descriptions. In this work, American Sign Language (ASL) and Italian Sign Language (LIS) productions are compared (adults and children) as well as the corresponding groups of gesturers in each country using "silent gesture." While the gesture groups, in general, did not employ an H-HS/O-HS distinction, all participants (signers and gesturers) used iconic handshapes (H-HSs and O-HSs together) more often in agentive than in no-agent event descriptions; moreover, none of the subjects produced an opposite pattern than the expected one (i.e., H-HSs associated with no-agent descriptions and O-HSs associated with agentive ones). These effects are argued to be grounded in cognition. In addition, some individual gesturers were observed to produce the H-HS/O-HS opposition for agentive and non-agentive event descriptions-that is, more Italian than American adult gesturers. This effect is argued to be grounded in culture. Finally, the agentive/non-agentive handshape opposition is confirmed for signers of ASL and LIS, but previously unreported cross-linguistic differences were also found across both adult and child sign groups. It is, therefore, concluded that cognitive, cultural, and linguistic factors contribute to the conventionalization of this distinction of handshape type. PMID- 25529990 TI - CRISPR/Cas9-mediated genome modification in the mollusc, Crepidula fornicata. AB - The discovery and application of the CRISPR/Cas9 genome editing method has greatly enhanced the ease with which transgenic manipulation can occur. We applied this technology to the mollusc, Crepidula fornicata, and have successfully created transgenic embryos expressing mCherry fused to endogenous beta-catenin. Specific integration of the fluorescent reporter was achieved by homologous recombination with a beta-catenin-specific donor DNA containing the mCherry coding sequence. This fluorescent gene knock-in strategy permits in vivo observations of beta-catenin expression during embryonic development and represents the first demonstration of CRISPR/Cas9-mediated transgenesis in the Lophotrochozoa superphylum. The CRISPR/Cas9 method is a powerful and economical tool for genome modification and presents an option for analysis of gene expression in not only major model systems, but also in those more diverse species that may not have been amenable to the classic methods of transgenesis. This approach will allow one to generate transgenic lines of snails for future studies. PMID- 25529991 TI - The new Y Chromosome Haplotype Reference Database. AB - After opening the first version of an internet-accessible worldwide reference database of Y chromosome profiles 14 years ago and six years after the last major relaunch the new YHRD 4.0 repository and website has been rolled-out. By November 2014 about 136k 9-locus haplotypes, among these 84k 17-locus haplotypes, 25k 23 locus haplotypes and 15k Y SNP profiles from 917 sampling locations in 128 countries have been submitted by more than 250 institutes and laboratories. In geographic terms, about 39% of the YHRD samples are from Europe, 32% from Asia, 16% from South America, 6% from North America, 4% from Africa and 2% from Oceania/Australia. Worldwide collaboration is the driving force for the rapid growth of the database and this, in turn, allows the evaluation and implementation of enhanced interpretation tools (variable frequency estimators, LR-based mixture and kinship analysis, Y-SNP-based ancestry assessment). PMID- 25529992 TI - Clinical treatment of orthostatic hypotension after spinal cord injury with training based on electric uprise bed coupled with remote ECG and BP monitor. AB - BACKGROUND: The treatment for orthostatic hypotension (OH) after spinal cord injury (SCI) is an important part of rehabilitation in late-stage SCI. Electric uprise bed training is a relatively commonly used method in treating OH, and how to carry out uprise bed training safely and effectively is an urgent problem. In the early stage of SCI, we used a remote monitoring system to monitor the whole process of uprise bed training, and we explored a safe and efficient method of electric uprise bed training. MATERIAL AND METHODS: The experimental group consisted of 36 patients diagnosed with orthostatic hypotension (OH) after SCI and who received training with an electric uprise bed coupled with remote monitoring system, and the control group of 18 subjects who used a traditional training method. RESULTS: There were no differences in baseline data between the 2 groups. There were no severe symptoms during training in the experimental group, but 3 patients had severe symptoms in the control group. Among the 32 enrolled subjects reaching upright training status within 30 days (17 subjects in the experimental group and 15 subjects in the control group), time interval of training from horizontal position to erect position in the experimental group was 18.00+/-3.12 days and 21.40+/-4.95 days in the control group. Time interval in the experimental group was significantly less than in the control group. However, among all 36 subjects, by combining results of follow-up, there was no significant difference of time interval of training from horizontal position to erect position between the experimental group and the control group. In the experimental group 90.52% of patients finished training compared to 78.19% in the control group (P<0.01). After training, values of OCs and OCd of the experimental group were lower than in the control group. There was no significant difference between groups in number of re-diagnosed OH. CONCLUSIONS: Implementation of training with electric uprise bed coupled with remote monitoring system is generally safe for patients with OH after SCI. For patients who could reach standing training status within 30 days, implementation can improve efficiency of training by shortening time interval of training from horizontal position to erect position. It can increase orthostatic blood pressure change during position change. PMID- 25529993 TI - RETRACTED: Pierisformoside B exhibits neuroprotective and anti-inflammatory effects in murine hippocampal and microglial cells via the HO-1/Nrf2-mediated pathway. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor.The authors have found multiple errors with the submission including but not limited to the incorporation of a figure (figure 6C) previously published in the Korean Journal of Pharmacognosy 2014. Apr, 45(2):161 167, http://kpubs.org/article/articleMain.kpubs?articleANo=HKSOBF_2014_v45n2_161.The authors extend an apology to readers and editors for this matter. PMID- 25529994 TI - Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7. AB - Recently, the traditional Chinese medicine Tripterygium wilfordii Hook f (TwHF) of the Celastraceae family has attracted increasing attention for its potential therapeutic application in patients with rheumatoid arthritis (RA). It is well accepted that TwHF exerts the antirheumatic activity and mainly depends on its potent anti-inflammatory property. To further explore the therapeutic potential of the well-defined TwHF-derived single compound - celastrol in RA, we study the therapeutic efficacy of celastrol on bone erosion in collagen-induced arthritis (CIA) mice and delineate its effects on osteoclast differentiation and functions in RANKL-induced osteoclast precursors RAW264.7 cell line. In CIA mice, daily injection of celastrol (beginning on day 28 after arthritis induction) markedly suppressed arthritis, and reduced bone damage in the joints as demonstrated by histology and bone micro-computed tomography (CT). The effects were accompanied by reductions of osteoclast cells in joints, serum tartrate-resistant acid phosphatase (TRAP) 5b, and expression of osteoclastic genes (Trap, Ctsk, Ctr, Mmp 9) and transcriptional factors (c-Fos, c-Jun and NFATc1). When RAW264.7 cells were treated with RANKL, celastrol inhibited the formation of TRAP+ multinucleated cells and the bone-resorbing activity in dose-dependent manners. Furthermore, celastrol reduced the RANKL-induced expression of osteoclastic genes and transcriptional factors, as well as phosphorylation of NF-kB and mitogen activated protein kinases (MAPK). These findings show that celastrol could directly inhibit osteoclast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction. PMID- 25529995 TI - Text messaging reduces analgesic requirements during surgery. AB - OBJECTIVE: This study aims to determine whether communicating via short message service text message during surgery procedures leads to decreased intake of fentanyl for patients receiving regional anesthesia below the waist compared with a distraction condition and no intervention. METHODS: Ninety-eight patients receiving regional anesthesia for minor surgeries were recruited from a hospital in Montreal, QC, between January and March 2012. Patients were randomly assigned to text message with a companion, text message with a stranger, play a distracting mobile phone game, or receive standard perioperative management. Participants who were asked to text message or play a game did so before receiving the anesthetic and continued until the end of the procedure. RESULTS: The odds of receiving supplemental analgesia during surgery for patients receiving standard perioperative management were 6.77 (P=0.009; N=13/25) times the odds for patients in the text a stranger condition (N=22/25 of patients), 4.39 times the odds for those in the text a companion condition (P=0.03; N=19/23), and 1.96 times the odds for those in the distraction condition (P=0.25; N=17/25). CONCLUSION: Text messaging during surgery provides analgesic-sparing benefits that surpass distraction techniques, suggesting that mobile phones provide new opportunities for social support to improve patient comfort and reduce analgesic requirements during minor surgeries and in other clinical settings. PMID- 25529996 TI - The therapeutic monoclonal antibody market. AB - Since the commercialization of the first therapeutic monoclonal antibody product in 1986, this class of biopharmaceutical products has grown significantly so that, as of November 10, 2014, forty-seven monoclonal antibody products have been approved in the US or Europe for the treatment of a variety of diseases, and many of these products have also been approved for other global markets. At the current approval rate of ~ four new products per year, ~ 70 monoclonal antibody products will be on the market by 2020, and combined world-wide sales will be nearly $125 billion. PMID- 25529997 TI - Effect of LIM kinase 1 overexpression on behaviour of endometriosis-derived stromal cells. AB - LIM kinase 1 (LIMK1) has been implicated in tumour invasion and migration in several tumour types. However, its role in the progression of endometriosis has not yet been studied. Our aim is to analyse LIMK1 expression in endometriosis derived stromal cells and to explore the effects of LIMK1 overexpression on their biological behaviour. The mRNA and protein expression levels of LIMK1 of eutopic endometrial stromal cells (ESCs) separated from 30 endometriosis patients and normal endometrial stromal cells (NSCs) separated from 30 patients without endometriosis were analysed by real-time polymerase chain reaction and Western blot. Lentiviral particles containing human LIMK1 short interfering RNA were used to silence the LIMK1 gene in ESCs and LIMK1-expressing lentiviral particles containing the total LIMK1 cDNA was transfected into NSCs to upregulate LIMK1 expression. Cell migration, invasion, proliferation and expression of markers of adhesion, invasion and angiogenesis of ESCs and NSCs were evaluated under basal conditions and after transfection in vitro. The mRNA and protein expression levels of LIMK1 in ESCs were higher than those in NSCs. Under basal conditions, ESCs exhibited greater cell migration, invasion and proliferation and higher levels of markers of adhesion, invasion and angiogenesis than NSCs. The behaviour of ESCs was decreased after LIMK1 gene silencing and that of NSCs was elevated after LIMK1 gene upregulation. Thus, LIMK1 is overexpressed in ESCs thereby facilitating malignant-like behaviour, including enhanced migration, invasion, proliferation and angiogenesis, all of which contribute to the occurrence and development of endometriosis. PMID- 25529998 TI - Panel of monoclonal antibodies to sperm surface proteins as a tool for monitoring localization and identification of sperm-zona pellucida receptors. AB - Primary binding of the sperm to the zona pellucida (ZP) is one of the many steps necessary for successful fertilization. Sperm bind ZP by means of membrane receptors which recognize carbohydrate moieties on ZP glycoproteins according to a well-defined sequential process. Primary binding receptors, many of which have been disclosed in various mammals, are localized throughout the acrosomal region of the sperm surface. A panel of monoclonal antibodies against proteins from the sperm surface was prepared. Antibodies were screened by immunofluorescence for protein localization and Western blotting. Proteins localized on the sperm head and simultaneously detected by Western blotting were further studied in terms of immunolocalization in reproductive tissues and fluids, binding to ZP, immunoprecipitation and sequencing. Of 17 prepared antibodies, 8 recognized proteins localized on the sperm head and also detected proteins of interest by Western blotting. Only three other antibodies recognized proteins that also coincided in binding to ZP. These three antibodies were used for immunoprecipitation, and further protein sequencing of immunoprecipitates revealed that these antibodies distinguished acrosin precursor, RAB-2A protein, and lactadherin P47. This is not the first time we have detected acrosin on the surface of ejaculated and capacitated sperm. However, to our knowledge, this is the first time RAB-2A has been detected on the sperm surface. Lactadherin P47 has already been characterized and its physiological function in reproduction has been proposed. PMID- 25529999 TI - Ventricular assist devices and increased blood product utilization for cardiac transplantation. AB - BACKGROUND AND AIM OF STUDY: The purpose of this study was to examine whether blood product utilization, one-year cell-mediated rejection rates, and mid-term survival significantly differ for ventricular assist device (VAD patients compared to non-VAD (NVAD) patients following cardiac transplantation. METHODS: From July 2004 to August 2011, 79 patients underwent cardiac transplantation at a single institution. Following exclusion of patients bridged to transplantation with VADs other than the HeartMate II(r) LVAD (n = 10), patients were stratified by VAD presence at transplantation: VAD patients (n = 35, age: 54.0 [48.0-59.0] years) vs. NVAD patients (n = 34, age: 52.5 [42.8-59.3] years). The primary outcomes of interest were blood product transfusion requirements, one-year cell mediated rejection rates, and mid-term survival post-transplantation. RESULTS: Preoperative patient characteristics were similar for VAD and NVAD patients. NVAD patients presented with higher median preoperative creatinine levels compared to VAD patients (1.3 [1.1-1.6] vs. 1.1 [0.9-1.4], p = 0.004). VAD patients accrued higher intraoperative transfusion of all blood products (all p <= 0.001) compared to NVAD patients. The incidence of clinically significant cell-mediated rejection within the first posttransplant year was higher in VAD compared to NVAD patients (66.7% vs. 33.3%, p = 0.02). During a median follow-up period of 3.2 (2.0, 6.3) years, VAD patients demonstrated an increased postoperative mortality that did not reach statistical significance (20.0% vs. 8.8%, p = 0.20). CONCLUSIONS: During the initial era as a bridge to transplantation, the HeartMate II(r) LVAD significantly increased blood product utilization and one-year cell-mediated rejection rates for cardiac transplantation. Further study is warranted to optimize anticoagulation strategies and to define causal relationships between these factors for the current era of cardiac transplantation. PMID- 25530000 TI - Synthesis and characterization of iron oxide/cellulose nanocomposite film. AB - Iron oxide/cellulose high-performance nanocomposite film is successfully prepared by impregnation of iron oxide nanoparticles into a regenerated cellulose film. The structure, thermal stability and mechanical properties of the nanocomposite films are investigated by the wide-angle X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis, and mechanical pull test. The investigation results reveal that the iron oxide is bound to hydroxyl groups of the regenerated cellulose film by hydrogen bonding. Compared with the regenerated cellulose, the tensile strength and elastic modulus of iron oxide/cellulose high-performance films are significantly improved by about 39% and 57%, respectively. PMID- 25530001 TI - Expression of A. niger US368 xylanase in E. coli: purification, characterization and copper activation. AB - The XAn11 cDNA was cloned in pET-28a(+) and the recombinant plasmid was transformed in Escherichia coli. The His-tagged r-XAn11 was purified using Ni-NTA affinity and anion exchange chromatography. The enzyme showed a specific activity of 415.1 U mg(-1) and a molecular mass of 25 kDa. It had an optimal activity at pH 5 and 50 degrees C. It was stable in a wide range of pH and in the presence of some detergents and organic solvents. In the presence of 3mM Cu2+, the relative activity of the His-tagged r-XAn11 was enhanced by 54%. This is the first work reporting that copper is a strong activator for xylanase activity making this enzyme very attractive for future industrial applications. Molecular modeling suggests that the contact region between the catalytic site and the N-terminal His-tag fusion peptide could be responsible for the different behavior of the native and recombinant enzyme toward copper. PMID- 25530002 TI - With routine air leak testing of low colorectal anastomosis is routine intra operative flexible sigmoidoscopy necessary? PMID- 25530003 TI - Endoplasmic reticulum proteins quality control and the unfolded protein response: the regulative mechanism of organisms against stress injuries. AB - The endoplasmic reticulum is the cellular compartment in which secretory proteins are synthesized and folded. Perturbations of endoplasmic reticulum homeostasis lead to the accumulation of unfolded proteins. The activation of the unfolded protein response during endoplasmic reticulum stress transmits information about the status of protein folding to the cytosol and nucleus. The unfolded protein response leads to the upregulation of genes encoding endoplasmic reticulum chaperones, attenuation of translation, and initiation of the endoplasmic reticulum quality control system to restore endoplasmic reticulum homeostasis. When the unfolded protein response is insufficient to rebuild the steady state in endoplasmic reticulum, the programmed cell death or apoptosis would be initiated, by triggering cell injuries, even to cell death through apoptosis signals. In this review, we briefly outline research on the chaperones and foldases conserved in eukaryotes and plants, and describe the general principles and mechanisms of the endoplasmic reticulum quality control and the unfolded protein response. We describe the current models for the molecular mechanism of the unfolded protein response in plants, and emphasize the role of inositol requiring enzyme-1 dependent network in the unfolded protein response. Finally, we give a general overview of the directions for future research on the unfolded protein response in plants and its role in the response to environmental stresses. PMID- 25530004 TI - Diagnostic profile on the IFA 40: HEp-20-10 - an immunofluorescence test for reliable antinuclear antibody screening. AB - Indirect immunofluorescence assay is the recommended gold standard to test for antinuclear antibodies (ANA), which are important biomarkers for systemic rheumatic autoimmune diseases. It is internationally accepted that indirect immunofluorescence assay ANA screening is most sensitive on human epithelial (HEp 2) cells. The cells present a multitude of antigens that display distinguishable localization patterns in interphase and mitotic cells in indirect immunofluorescence analysis. Here, we present the IFA 40: HEp-20-10 test kit (Euroimmun AG, Lubeck, Germany), which is cleared for sale on the US market by the FDA. The test has been designed for qualitative and semiquantitative screening of ANA in human sera. It uses the commonly applied 1:40 cutoff dilution and the enhanced HEp-20-10 cell line for more efficient pattern recognition and has been validated in various studies and by method comparison. The IFA 40: HEp 20-10 test fulfills the essential criteria for reliable application in autoimmune diagnostics. PMID- 25530005 TI - Jan Evangelista Purkynje (1787-1869): first to describe fingerprints. AB - Fingerprints have been used for years as the accepted tool in criminology and for identification. The first system of classification of fingerprints was introduced by Jan Evangelista Purkynje (1787-1869), a Czech physiologist, in 1823. He divided the papillary lines into nine types, based on their geometric arrangement. This work, however, was not recognized internationally for many years. In 1858, Sir William Herschel (1833-1917) registered fingerprints for those signing documents at the Indian magistrate's office in Jungipoor. Henry Faulds (1843-1930) in 1880 proposed using ink for fingerprint determination and people identification, and Francis Galton (1822-1911) collected 8000 fingerprints and developed their classification based on the spirals, loops, and arches. In 1892, Juan Vucetich (1858-1925) created his own fingerprint identification system and proved that a woman was responsible for killing two of her sons. In 1896, a London police officer Edward Henry (1850-1931) expanded on earlier systems of classification and used papillary lines to identify criminals; it was his system that was adopted by the forensic world. The work of Jan Evangelista Purkynje (1787-1869) (Figure 1), who in 1823 was the first to describe in detail fingerprints, is almost forgotten. He also established their classification. The year 2013 marked the 190th anniversary of the publication of his work on this topic. Our contribution is an attempt to introduce the reader to this scientist and his discoveries in the field of fingerprint identification. PMID- 25530006 TI - Clarifying the Relationship of Parental Bonding to Suicide Ideation and Attempts. AB - Suicide and suicidal behavior are major public health problems, especially among adolescents and young adults. Previous research has established links between parental bonding and suicidality; however, it remains unclear whether parental bonding is associated with suicide ideation, the progression from suicide ideation to suicide attempts, or both. This study examined the relation of parental bonding to suicide ideation and suicide attempts in adolescents from two settings: (1) acute psychiatric care (n = 172) and (2) high school (n = 426). All participants were administered validated measures of parental bonding, suicide ideation, and suicide attempts, as well as emotion dysregulation, loneliness, and self-worth. In the psychiatric sample, lower parental care significantly differentiated adolescents with a history of suicide attempts from those with suicide ideation only or without histories of suicidality. This pattern remained even after controlling for other known correlates of suicidality (i.e., emotional dysregulation, loneliness, and low self-worth). Similar effects were found in the community sample, although these findings failed to reach statistical significance. In both samples, parental overprotection was not associated with suicide ideation or suicide attempts. Results suggest that parental care may be an important risk factor for youth suicidal behavior and may help differentiate suicide attempters from suicide ideators. PMID- 25530007 TI - Satisfaction with rural rheumatology telemedicine service. AB - AIM: To assess patient satisfaction with the rheumatology telemedicine service provided to a rural town in northern Australia. METHODS: A prospective, questionnaire-based exploratory study of patients seen at the Mount Isa (rural town) rheumatology telemedicine clinics during 2012 was undertaken. Control groups included patients travelling over 3 h to be seen face-to-face in Townsville (tertiary referral centre), and patients seen at the infrequent face to-face clinic in Mount Isa. A 5-point Likert scale was used to explore themes of communication, confidentiality, physical examination, rapport, medication safety and access. RESULTS: This study evaluated 107 rheumatology outpatients (49 telemedicine, 46 face-to-face Townsville, 12 face-to-face Mount Isa). Patients seen in Mount Isa travelled a median of < 10 km for either the telemedicine or local face-to-face appointments. The patients attending the Townsville face-to face clinic travelled a median of 354 km. New patients comprised 14% of consultations. Satisfaction with themes related to quality-of-care was high with over 90% selecting 'agree' or 'strongly agree' to these questions. Comparing models of care, there were no statistically significant differences in the rates of those selecting 'strongly agree' across questions, apart from a single question related to rapport which favored the Mount Isa face-to-face model (P = 0.018). When asked whether they would rather travel to Townsville than participate in a telemedicine consultation, 63% of patients selected 'disagree' (17%) or 'strongly disagree' (46%). CONCLUSIONS: These results suggest that patients are satisfied with a rheumatology telemedicine service, and may prefer this to extensive travelling. Evaluation in other settings is recommended before generalizing this finding. PMID- 25530008 TI - Anaerobic oxidation of methane: an "active" microbial process. AB - The anaerobic oxidation of methane (AOM) is an important sink of methane that plays a significant role in global warming. AOM was first found to be coupled with sulfate reduction and mediated by anaerobic methanotrophic archaea (ANME) and sulfate-reducing bacteria (SRB). ANME, often forming consortia with SRB, are phylogenetically related to methanogenic archaea. ANME-1 is even able to produce methane. Subsequently, it has been found that AOM can also be coupled with denitrification. The known microbes responsible for this process are Candidatus Methylomirabilis oxyfera (M. oxyfera) and Candidatus Methanoperedens nitroreducens (M. nitroreducens). Candidatus Methylomirabilis oxyfera belongs to the NC10 bacteria, can catalyze nitrite reduction through an "intra-aerobic" pathway, and may catalyze AOM through an aerobic methane oxidation pathway. However, M. nitroreducens, which is affiliated with ANME-2d archaea, may be able to catalyze AOM through the reverse methanogenesis pathway. Moreover, manganese (Mn(4+) ) and iron (Fe(3+) ) can also be used as electron acceptors of AOM. This review summarizes the mechanisms and associated microbes of AOM. It also discusses recent progress in some unclear key issues about AOM, including ANME-1 in hypersaline environments, the effect of oxygen on M. oxyfera, and the relationship of M. nitroreducens with ANME. PMID- 25530009 TI - The development of dose-dense adjuvant chemotherapy. AB - Dose-dense chemotherapy has made a significant contribution to the adjuvant treatment of breast cancer. One way of achieving dose-density is through the use of sequential therapy with noncross resistant therapies to cause cell kill in tumors composed of heterogeneous cells. Another way to achieve this is to shorten the inter-treatment interval to minimize the re-growth of tumor cells, thus allowing for more effective cell killing. Several trials have tested this concept with the majority demonstrating improved efficacy with a dose-density when compared with the traditional schedule. One such notable trial was CALGB 9741 that showed that when dose size and cycle numbers were kept constant, shortening the interval between each chemotherapy dose, with granulocyte-colony stimulating factor support, significantly improved disease-free and overall survival. This important and practice-changing trial led to the wide adoption of dose-dense chemotherapy and formed the basis of many subsequent studies, including allowing for the addition of biologic and targeted agents with excellent safety profile. PMID- 25530010 TI - High vitamin D and calcium intakes increase bone mineral (Ca and P) content in high-fat diet-induced obese mice. AB - Vitamin D and calcium are essential for bone formation, mineralization, and remodeling. Recent studies demonstrated that an increased body mass can be detrimental to bone health. However, whether an increase in dietary vitamin D and calcium intakes in obesity is beneficial to bone health has not been established. The aim of this study was to examine the effects of increased vitamin D and calcium intakes, alone or in combination, on bone status in a high-fat diet induced obesity (DIO) mouse model. We hypothesized that DIO in growing mice affects bone mineral status and that high vitamin D and calcium intakes will promote mineralization of the growing bone in obesity via Ca(2+) regulatory hormones, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (PTH). Male mice were fed high vitamin D3 (10 000 IU/kg), high calcium (1.2%), or high vitamin D3 plus high-calcium diets containing 60% energy as fat for 10 weeks. Bone weight, specific gravity, mineral (Ca and P), and collagen (hydroxyproline) content were measured in the femur and the tibia. Regulators of Ca(2+) metabolism and markers of bone status (PTH, 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D3, and osteocalcin) were measured in blood plasma. Diet-induced obese mice exhibited lower bone Ca and P content and relative bone weight compared with the normal-fat control mice, whereas collagen (hydroxyproline) content was not different between the two groups. High vitamin D3 and calcium intakes significantly increased bone Ca and P content and relative bone weight in DIO mice, which was accompanied by an increase in 1,25(OH)2D3 and a decrease in PTH and osteocalcin concentrations in blood. The findings obtained indicate that increased vitamin D and calcium intakes are effective in increasing mineral (Ca and P) content in the growing bone of obese mice and that the hormonal mechanism of this effect may involve the vitamin D-PTH axis. PMID- 25530012 TI - Adult consumers of cranberry juice cocktail have lower C-reactive protein levels compared with nonconsumers. AB - Flavonoids are important bioactive plant constituents found in abundance in berries, including cranberries. Cranberry beverages have been shown to beneficially impact urinary and cardiovascular health in clinical and observational studies, but their association with anthropometric outcomes is unknown. We examined the association between cranberry juice cocktail (CJC) consumption with flavonoid intake, and cardiometabolic and anthropometric outcomes among adults in the US data for adults (>=19 years, n = 10334) were drawn from cross-sectional National Health and Nutrition Examination Survey combined 2005-2008 survey. We hypothesized that CJC consumers will have lower anthropometric measures and healthier cardiometabolic profiles, including lower cholesterol and C-reactive protein (CRP). A CJC consumer (n = 330) was defined as anyone consuming CJC for 2 nonconsecutive 24-hour dietary recalls. We used multivariate linear regression models to examine differences in anthropometric and cardiometabolic outcomes comparing CJC consumers to nonconsumers controlling for important confounders. Consumers drank an average 404 mL (14 fl oz) of CJC for 2 days and did not have higher total energy intakes compared with nonconsumers (mean [SD], 2259 [79] vs 2112 [24], respectively). In fully adjusted models, adult CJC consumers had significantly lower levels of CRP (mean [SD], 0.13 [0.05]; P = .015), results that were strengthened after further adjustment for body mass index (mean [SD], -0.98 [0.04]; P = .027). Trends toward lower weights and lower levels of cholesterol did not reach statistical significance. Intake of cranberry polyphenols may play a role in promoting anti-inflammatory markers among CJC consumers, specifically lowering CRP levels. PMID- 25530011 TI - No difference in fecal levels of bacteria or short chain fatty acids in humans, when consuming fruit juice beverages containing fruit fiber, fruit polyphenols, and their combination. AB - This study examined the effect of a Boysenberry beverage (750 mg polyphenols), an apple fiber beverage (7.5 g dietary fiber), and a Boysenberry plus apple fiber beverage (750 mg polyphenols plus 7.5 g dietary fiber) on gut health. Twenty-five individuals completed the study. The study was a placebo-controlled crossover study, where every individual consumed 1 of the 4 treatments in turn. Each treatment phase was 4-week long and was followed by a 2-week washout period. The trial beverages were 350 g taken in 2 doses every day (ie, 175 mL taken twice daily). The hypothesis for the study was that the combination of polyphenols and fiber would have a greater benefit on gut health than the placebo product or the fiber or polyphenols on their own. There were no differences in fecal levels of total bacteria, Bacteroides-Prevotella-Porphyromonas group, Bifidobacteriumspecies, Clostridium perfringens, or Lactobacillus species among any of the treatment groups. Fecal short chain fatty acid concentrations did not vary among treatment groups, although prostaglandin E2 concentrations were higher after consumption of the Boysenberry juice beverage. No significant differences were found in quantitative measures of gut health between the Boysenberry juice beverage, the apple fiber beverage, the Boysenberry juice plus apple fiber beverage, and the placebo beverage. PMID- 25530013 TI - Blood redox status is associated with the likelihood of nonalcoholic fatty liver disease irrespectively of diet's total antioxidant capacity. AB - It is well established that oxidative stress is implicated in nonalcoholic fatty liver disease pathogenesis, whereas the dietary intake of antioxidants has been reported to be low in patients with the disease. We hypothesized that blood redox status measurements would be associated with nonalcoholic fatty liver disease presence and severity, and that diet's total antioxidant capacity could moderate the aforementioned association. The study sample consisted of 73 patients with nonalcoholic fatty liver disease, of which 58 were matched by age, sex, and body mass index with 58 controls. Diet's total antioxidant capacity was estimated through the ferric-reducing antioxidant power, the total radical-trapping antioxidant parameter, and the Trolox equivalent antioxidant capacity scores, whereas blood redox status was assessed by measuring thiobarbituric acid reactive substances levels, the enzymatic activity of glutathione peroxidase, and serum resistance to oxidation. Diet's total antioxidant capacity scores and glutathione peroxidase activity were not significantly associated with the disease presence or severity. Both thiobarbituric acid reactive substances and serum resistance to oxidation were significantly associated with the likelihood of nonalcoholic fatty liver disease (odds ratios [ORs], 7.769 [P= .007] and 0.936 [P= .033], respectively), independently of abdominal fat level, degree of insulin resistance, blood lipid levels, markers of subclinical inflammation, and diet's total antioxidant capacity, but not with the disease histologic severity or stage. Our results support the association between blood redox status and the likelihood of nonalcoholic fatty liver disease regardless of diet's total antioxidant capacity. PMID- 25530014 TI - Evaluation of metals and hydrocarbons in sediments from a tropical tidal flat estuary of Southern Brazil. AB - Although the Passagem Channel estuary, Espirito Santo State, Brazil, is located in an urbanized and industrialized region, it has a large mangrove system. Here we examined natural and anthropogenic inputs that may influence trace metal (Cd, Cr, Cu, Ni, Sc, Pb and Zn) and hydrocarbon (n-alkane and terpane) deposition in three sediment cores collected in the tidal flat zone of the estuary. The cores were also analyzed for carbonate, grain size and stable isotopic composition (delta(13)Corg. and delta(15)Ntotal). Metal enrichment and its association to petroleum hydrocarbons in the surficial sediments of one of the cores, indicate crude oil and derivative inputs, possibly from small vessels and road run-off from local heavy automobile traffic. At the landward sites, the major contributions for metals and hydrocarbons are from natural sources, but in one case, Cu may have been enriched by domestic effluent inputs. PMID- 25530015 TI - Major hydrogeochemical processes in an acid mine drainage affected estuary. AB - This study provides geochemical data with the aim of identifying and quantifying the main processes occurring in an Acid Mine Drainage (AMD) affected estuary. With that purpose, water samples of the Huelva estuary were collected during a tidal half-cycle and ion-ion plots and geochemical modeling were performed to obtain a general conceptual model. Modeling results indicated that the main processes responsible for the hydrochemical evolution of the waters are: (i) the mixing of acid fluvial water with alkaline ocean water; (ii) precipitation of Fe oxyhydroxysulfates (schwertmannite) and hydroxides (ferrihydrite); (iii) precipitation of Al hydroxysulfates (jurbanite) and hydroxides (amorphous Al(OH)3); (iv) dissolution of calcite; and (v) dissolution of gypsum. All these processes, thermodynamically feasible in the light of their calculated saturation states, were quantified by mass-balance calculations and validated by reaction path calculations. In addition, sorption processes were deduced by the non conservative behavior of some elements (e.g., Cu and Zn). PMID- 25530016 TI - A damage assessment model of oil spill accident combining historical data and satellite remote sensing information: a case study in Penglai 19-3 oil spill accident of China. AB - Oil spills are one of the major sources of marine pollution; it is important to conduct comprehensive assessment of losses that occur as a result of these events. Traditional methods are required to assess the three parts of losses including cleanup, socioeconomic losses, and environmental costs. It is relatively slow because assessment is complex and time consuming. A relatively quick method was developed to improve the efficiency of assessment, and then applied to the Penglai 19-3 accident. This paper uses an SAR image to calculate the oil spill area through Neural Network Classification, and uses historical oil spill data to build the relationship between loss and other factors including sea surface wind speed, and distance to the coast. A multiple regression equation was used to assess oil spill damage as a function of the independent variables. Results of this study can be used for regulating and quickly dealing with oil spill assessment. PMID- 25530017 TI - Sweating the small stuff: adequacy and accuracy in sweat chloride determination. AB - OBJECTIVES: Sweat chloride testing is the gold standard for diagnosis of cystic fibrosis (CF). Our objectives were to: 1) describe variables that determine sweat rate; 2) determine the analytic and diagnostic capacity of sweat chloride analysis across the range of observed sweat rates; and 3) determine the biologic variability of sweat chloride concentration. METHODS: A retrospective analysis was performed using data from all sweat chloride tests performed at St. Louis Children's Hospital over a 21-month period. RESULTS: A total of 1397 sweat chloride tests (1155 sufficient [>=75 mg], 242 insufficient [<75 mg]), were performed on 904 individuals. The sweat weight collected from forearms was statistically greater than that collected from legs. There was a negligible correlation between sweat weight and chloride concentration (r=-0.06). The mean individual biologic CV calculated from individuals with two or more sweat collections >=75 mg was 13.1% (95% CI: 11.3-14.9%; range 0-88%) yielding a reference change value of 36%. Using 60 mmol/L as the diagnostic chloride cutoff, 100% of CF cases were detected whether a minimum sweat weight of 75, 40, or 20 mg was required. CONCLUSIONS: 1) Collection of sweat from forearms is preferable to upper legs, particularly in very young infants; 2) sweat chloride concentrations are not highly dependent upon sweat rate; 3) a change in sweat chloride concentration exceeding 36% may be considered a clinically significant response to cystic fibrosis transmembrane receptor targeted therapy, and 4) sweat collections of less than 75 mg provide clinically accurate information. PMID- 25530018 TI - Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models. AB - Heparin and its derivatives are known to attenuate cancer metastasis in preclinical models, but have not been used clinically due to adverse bleeding effects. This study compared the efficacy of S-NACH (a sulfated non-anticoagulant heparin) versus tinzaparin (a low molecular weight heparin) in inhibiting metastasis of a growing primary tumor and following surgical excision of primary tumor in a pancreatic cancer mouse model. The efficacy of S-NACH versus tinzaparin on metastasis of the primary tumor was evaluated in each experiment using IVIS imaging. Athymic female mice were treated with S-NACH or tinzaparin, and 30 min later luciferase-transfected pancreatic cancer cells (Mpanc96) were implanted into the spleen; treatment was continued daily until termination. Next we studied the effect of S-NACH versus tinzaparin on metastasis after surgical excision of the primary tumor after 3 weeks of daily treatment with S-NACH or tinzaparin. S-NACH reduced surgically induced metastasis (p<0.01) and tumor recurrence (p<0.05) relative to control. Histopathological studies demonstrated significant increase in tumor necrosis mediated by S-NACH and to lesser extent by tinzaparin as compared to control group. Furthermore, either S-NACH or tinzaparin upregulated the expression of the junctional adhesion molecule E-cadherin in pancreatic cancer cells where its low expression enhances cancer cell migration and invasion. In terms of bleeding time (BT), S-NACH did not affect BT as compared to tinzaparin, which doubled BT. These data suggest that S-NACH is an effective and safe anti-metastatic agent and warrants further clinical evaluation. PMID- 25530019 TI - The medial forebrain bundle as a deep brain stimulation target for treatment resistant depression: A review of published data. AB - INTRODUCTION: Despite a wide variety of therapeutic interventions for major depressive disorder (MDD), treatment resistant depression (TRD) remains to be prevalent and troublesome in clinical practice. In recent years, deep brain stimulation (DBS) has emerged as an alternative for individuals suffering from TRD not responding to combining antidepressants, multiple adjunctive strategies and electroconvulsive therapy (ECT). Although the best site for TRD-DBS is still unclear, pilot data suggests that the medial forebrain bundle (MFB) might be a key target to accomplish therapeutic efficacy in TRD patients. OBJECTIVE: To explore the anatomic, electrophysiologic, neurocognitive and treatment data supporting the MFB as a target for TRD-DBS. RESULTS: The MFB connects multiple targets involved in motivated behavior, mood regulation and antidepressant response. Specific phenomenology associated with TRD can be linked specifically to the superolateral branch (sl) of the MFB (slMFB). TRD patients who received DBS-slMFB reported high response/remission rates with an improvement in functioning and no significant adverse outcomes in their physical health or neurocognitive performance. DISCUSSION: The slMFB is an essential component of a network of structural and functional pathways connecting different areas possibly involved in the pathogenesis of mood disorders. Therefore, the slMFB should be considered as an exciting therapeutic target for DBS therapy to achieve a sustained relief in TRD patients. CONCLUSION: There is an urgent need for clinical trials exploring DBS-slMFB in TRD. Further efforts should pursue measuring baseline pro-inflammatory cytokines, oxidative stress, and cognition as possible biomarkers of DBS-slMFB response in order to aid clinicians in better patient selection. PMID- 25530020 TI - Trapping bound water within a polymer electrolyte membrane of calcium phosphotungstate for efficient CO2 capture. AB - Calcium phosphotungstate is synthesized and utilized to fabricate a polymer electrolyte membrane for the first time. The strong hygroscopicity of both Ca(2+) and PW12O40(3-) is found to "trap" bound water within the membrane, resulting in an appealing CO2 capture performance. PMID- 25530021 TI - Night shift work, chronotype and prostate cancer risk in the MCC-Spain case control study. AB - Night shift work has been classified as a probable human carcinogen based on experimental studies and limited human evidence on breast cancer. Evidence on other common cancers, such as prostate cancer, is scarce. Chronotype is an individual characteristic that may relate to night work adaptation. We evaluated night shift work with relation to prostate cancer, taking into account chronotype and disease severity in a population based case-control study in Spain. We included 1,095 prostate cancer cases and 1,388 randomly selected population controls. We collected detailed information on shift schedules (permanent vs. rotating, time schedules, duration, frequency), using lifetime occupational history. Sociodemographic and lifestyle factors were assessed by face-to-face interviews and chronotype through a validated questionnaire. We used unconditional logistic regression analysis adjusting for potential confounders. Subjects who had worked at least for one year in night shift work had a slightly higher prostate cancer risk [Odds Ratio (OR) 1.14; 95%CI 0.94, 1.37] compared with never night workers; this risk increased with longer duration of exposure (>= 28 years: OR 1.37; 95%CI 1.05, 1.81; p-trend = 0.047). Risks were more pronounced for high risk tumors [D'Amico classification, Relative Risk Ratio (RRR) 1.40; 95%CI 1.05, 1.86], particularly among subjects with longer duration of exposure (>=28 years: RRR 1.63; 95%CI 1.08, 2.45; p-trend = 0.027). Overall risk was higher among subjects with an evening chronotype, but also increased in morning chronotypes after long-term night work. In this large population based study, we found an association between night shift work and prostate cancer particularly for tumors with worse prognosis. PMID- 25530022 TI - Observed distribution of radiocaesium contamination in shiitake lots and variability of test results. AB - Shiitake mushrooms (Lentinula edodes) cultivated on bed-log are known to accumulate radiocaesium. Since the Fukushima-Diichi nuclear power plant accident (2011), the violation rate has been higher for log-cultivated shiitake than that for agricultural products or other foodstuffs. When testing shiitake mushrooms for radionuclide contamination, the validation of the sampling plan can be severely compromised by the heterogeneous contamination within shiitake lots. Currently, few data are available on the statistical properties of the radiocaesium contamination of log-cultivated shiitake. In this paper, shiitake lots contaminated by radiocaesium were identified and the distribution of the radiocaesium concentration within the lots investigated. The risk of misclassifying shiitake lots was predicted from the operating characteristic curve generated from Monte Carlo simulations and the performance of various sampling plans was evaluated. This study provides useful information for deciding on an acceptable level of misclassification risk. PMID- 25530023 TI - Changing trends in prognostic factors for patients with multiple myeloma after autologous stem cell transplantation during the immunomodulator drug/proteasome inhibitor era. AB - We evaluated the clinical significance of prognostic factors including the International Staging System (ISS) and modified European Group for Blood and Marrow Transplantation response criteria in 1650 Japanese patients with multiple myeloma (MM) who underwent upfront single autologous stem cell transplantation (ASCT). We categorized patients into two treatment cohorts: pre-novel agent era (1995-2006) and novel agent era (2008-2011). The combined percentage of pre-ASCT complete response and very good partial response cases (463 of 988, 47%) significantly increased during the novel agent era compared with the pre-novel agent era (164 of 527, 31%; P < 0.0001). The 2-year overall survival (OS) rate of 87% during the novel agent era was a significant improvement relative to that of 82% during the pre-novel agent era (P = 0.019). Although significant differences in OS were found among ISS stages during the pre-novel agent era, no significant difference was observed between ISS I and II (P = 0.107) during the novel agent era. The factors independently associated with a superior OS were female gender (P = 0.002), a good performance status (P = 0.024), lower ISS (P < 0.001), pre ASCT response at least partial response (P < 0.001) and ASCT during the novel agent era (P = 0.017). These results indicate that the response rate and OS were significantly improved, and the ISS could not clearly stratify the prognoses of Japanese patients with MM who underwent upfront single ASCT during the novel agent era. PMID- 25530024 TI - Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain. AB - This study explored the use of the alpha2C -adrenoceptor PET tracer [(11) C]ORM 13070 to monitor alpha2C -AR occupancy in the human brain. The subtype nonselective alpha2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to alpha2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of alpha2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by alpha2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies. PMID- 25530025 TI - Liquid-phase epitaxial growth of two-dimensional semiconductor hetero nanostructures. AB - Although many two-dimensional (2D) hybrid nanostructures are being prepared, the engineering of epitaxial 2D semiconductor hetero-nanostructures in the liquid phase still remains a challenge. The preparation of 2D semiconductor hetero nanostructures by epitaxial growth of metal sulfide nanocrystals, including CuS, ZnS and Ni3S2, is achieved on ultrathin TiS2 nanosheets by a simple electrochemical approach by using the TiS2 crystal and metal foils. Ultrathin CuS nanoplates that are 50-120 nm in size and have a triangular/hexagonal shape are epitaxially grown on TiS2 nanosheets with perfect epitaxial alignment. ZnS and Ni3S2 nanoplates can be also epitaxially grown on TiS2 nanosheets. As a proof-of concept application, the obtained 2D CuS-TiS2 composite is used as the anode in a lithium ion battery, which exhibits a high capacity and excellent cycling stability. PMID- 25530026 TI - Concentration-dependent and surface-assisted self-assembly properties of a bioactive estrogen receptor alpha-derived peptide. AB - We have synthesized a 17-mer peptide (ERalpha17p) that is issued from the hinge region of the estrogen receptor alpha and which activates the proliferation of breast carcinoma cells in steroid-deprived conditions. In the present paper, we show that at a concentration of ~50 MUM, it rapidly forms amyloid-like fibrils with the assistance of electrostatic interactions and that at higher concentrations, it spontaneously forms a hydrogel. By using biophysical, spectral and rheological techniques, we have explored the structural, biophysical and mechanical characteristics of ERalpha17p with respect to fibril formation and gelation. PMID- 25530027 TI - Inexperienced newborn chicks use geometry to spontaneously reorient to an artificial social partner. AB - A fundamental process underlying navigation behaviour, shown to occur in every species tested, uses geometric properties of the environment for location memory and orientation. Here we employ a new method to ask whether this basic geometric orientation ability is innately predisposed in the brain or depends on specific experiences navigating in a geometrically rich environment. Using the newborn domestic chick as a model system, we present a working memory task testing reorientation towards a filial imprinting object under rigorous controlled rearing conditions. In the absence of any previous exposure to a geometrically rich environment, newly hatched chicks spontaneously recovered their bearings by making use of distances and directional relations to reorient themselves to an artificial social partner. These findings provide evidence for an innate capacity to navigate by the geometric structure of the environment. PMID- 25530028 TI - In situ nanofabrication of hybrid PEG-dendritic-inorganic nanoparticles and preliminary evaluation of their biocompatibility. AB - An in situ template fabrication of inorganic nanoparticles using carboxylated PEG dendritic block copolymers of the GATG family is described as a function of the dendritic block generation, the metal (Au, CdSe) and metal molar ratio. The biocompatibility of the generated nanoparticles analysed in terms of their aggregation in physiological media, cytotoxicity and uptake by macrophages relates to the PEG density of the surface of the hybrids. PMID- 25530029 TI - SCA27 is a cause of early-onset ataxia and developmental delay. PMID- 25530030 TI - Impaired slow wave sleep downscaling in patients with infantile spasms. AB - BACKGROUND: West syndrome is a severe epileptic encephalopathy of infancy, characterized by infantile spasms, global retardation, and a severely abnormal electroencephalogram (EEG) pattern known as hypsarrhythmia, which is most prominent during slow waves sleep. The restorative function of slow wave sleep has been linked to downscaling, a neuronal process ensuring a balance of global synaptic strength, which is important for normal cortical functioning and development. A key electrophysiological marker for this downscaling is the reduction of the slope of slow waves across the night. METHODS: We retrospectively compared the slope of slow waves between 14 untreated patients with infantile spasms and healthy age and gender matched controls. Patients were examined in one all-night sleep EEG before treatment, and in two follow-up nap recordings, under and after treatment with corticosteroids. RESULTS: In patients with infantile spasms the overnight reduction in the slope of slow waves was significantly diminished compared to controls (p = 0.009). Moreover, untreated patients revealed overall steeper slopes. During corticosteroid treatment the slope was reduced compared to controls (p = 0.001). After successful treatment the slope was similar between patients and controls. CONCLUSION: Our results provide evidence for reduced downscaling in patients with infantile spasms. Moreover, the marked reduction of the slope during corticosteroid treatment may reflect a loss of synaptic connections due to the effect of glucocorticoids. This altered sleep dependent regulation of synaptic strength in infantile spasms may contribute the underlying pathomechanism of the developmental regression. Furthermore the normalization of synaptic strength due to corticosteroids might provide a potential mechanistic explanation for this treatment strategy. PMID- 25530031 TI - Replication and extension of a hierarchical model of social anxiety and depression: fear of positive evaluation as a key unique factor in social anxiety. AB - Wang, Hsu, Chiu, and Liang (2012, Journal of Anxiety Disorders, 26, 215-224) recently proposed a hierarchical model of social interaction anxiety and depression to account for both the commonalities and distinctions between these conditions. In the present paper, this model was extended to more broadly encompass the symptoms of social anxiety disorder, and replicated in a large unselected, undergraduate sample (n = 585). Structural equation modeling (SEM) and hierarchical regression analyses were employed. Negative affect and positive affect were conceptualized as general factors shared by social anxiety and depression; fear of negative evaluation (FNE) and disqualification of positive social outcomes were operationalized as specific factors, and fear of positive evaluation (FPE) was operationalized as a factor unique to social anxiety. This extended hierarchical model explicates structural relationships among these factors, in which the higher-level, general factors (i.e., high negative affect and low positive affect) represent vulnerability markers of both social anxiety and depression, and the lower-level factors (i.e., FNE, disqualification of positive social outcomes, and FPE) are the dimensions of specific cognitive features. Results from SEM and hierarchical regression analyses converged in support of the extended model. FPE is further supported as a key symptom that differentiates social anxiety from depression. PMID- 25530032 TI - Repro-sexual intersections: sperm donation, HIV prevention and the public interest in semen. AB - In the scientific literature on fertility and assisted reproduction, and in the corresponding area of clinical practice, increasing attention has been paid to two groups: people living with the human immunodeficiency virus (HIV) and gay men. However, research on fertility in the context of HIV focuses almost exclusively on heterosexual couples, whereas studies on non-heterosexual reproduction rarely mention HIV, despite the fact that, in many western countries, HIV prevalence among men who have sex with men is higher than ever before and men who have sex with men are the only group in which new HIV infections are on the rise. This review identifies links between reproduction, HIV and homosexuality, showing that, historically, they are closely intertwined, which has important implications for current issues facing HIV care and fertility services. Considering sex and parenthood as two different but related kinds of intimacy and kinship, the dual role semen plays in sexually transmitted infection and in assisted reproduction is discussed. The review reflects on the future of sperm donation and HIV prevention, asking whether two challenges that potentially face healthcare and medicine today - the shortage of 'high-quality' sperm and the 'surplus' of infected semen - could be addressed by a greater exchange of knowledge. PMID- 25530033 TI - Reporting of embryo transfer methods in IVF research: a cross-sectional study. AB - The reporting of embryo transfer methods in IVF research was assessed through a cross-sectional analysis of randomized controlled trials (RCTs) published between 2010 and 2011. A systematic search identified 325 abstracts; 122 RCTs were included in the study. Embryo transfer methods were described in 42 out of 122 articles (34%). Catheters (32/42 [76%]) or ultrasound guidance (31/42 [74%]) were most frequently mentioned. Performer 'blinding' (12%) or technique standardization (7%) were seldom reported. The description of embryo transfer methods was significantly more common in trials published by journals with lower impact factor (less than 3, 39.6%; 3 or greater, 21.5%; P = 0.037). Embryo transfer methods were reported more often in trials with pregnancy as the main end-point (33% versus 16%) or with positive outcomes (37.8% versus 25.0%), albeit not significantly. Multivariate logistic regression confirmed that RCTs published in higher impact factor journals are less likely to describe embryo transfer methods (OR 0.371; 95% CI 0.143 to 0.964). Registered trials, trials conducted in an academic setting, multi-centric studies or full-length articles were not positively associated with embryo transfer methods reporting rate. Recent reports of randomized IVF trials rarely describe embryo transfer methods. The under reporting of research methods might compromise reproducibility and suitability for meta-analysis. PMID- 25530034 TI - Comparison of progesterone measurement on day of, and day after, HCG administration in IVF-embryo transfer cycles. AB - The aim of this study was to identify whether progesterone measurement on the day after HCG administration has any additional clinical value, over that obtained from progesterone measurement on the day of HCG administration. This was a single centre, non-interventional retrospective, observational, cohort of a consecutive series of 1457 ovarian stimulation cycles leading to fresh embryo transfer cycles between January 2011 and May 2013. Progesterone was found to rise and increase rapidly by about five-fold over a 24-h period. The result of logistic regression analysis suggests that progesterone measurement around the time of HCG administration is one of the three significant (P <0.001) variables affecting clinical pregnancy rate. The predictive value of progesterone measurement on the day of HCG administration could be improved by having a further measurement 24-h later. If the progesterone levels on both days were normal, the implantation rate was 36%, but if the progesterone level on both days were high, the implantation rate dropped to 22%. Progesterone measurement should be considered on the day of HCG administration and also the day after HCG administration to provide clinically useful information on whether or not embryos should be frozen and transfer deferred to a subsequent cycle. PMID- 25530035 TI - Follicles of various maturation stages react differently to enzymatic isolation: a comparison of different isolation protocols. AB - Isolation of human follicles is based on digestion of the tissue by combinations of enzymes. Follicle vitality and morphology are often based on the analysis of pooled follicles of different maturation stages. Information is therefore lacking on the effect of the isolation protocol to individual follicles of different maturation stages. A study was conducted using five protocols combining different enzymes and varying concentrations. Isolated follicles were classified according to their maturation stages, counted and characterized for vitality, morphology, early apoptosis and organization of transzonal projections. No statistical differences were found between the protocols when outcome parameters were analysed on a pool of follicles regardless of their maturation status. Differences were observed in quality when the follicles were analysed separately according to their maturation status. Combining morphologic characteristics and vitality, both Liberase DH and Liberase TM combined with collagenase IV were better at isolating high-quality primordial follicles, compared with collagenase IV. No statistical difference between the isolation protocols was found for primary follicles. If only high-quality isolated secondary follicles are needed, collagenase IV is found to be most advantageous. Follicles of different maturation stages react differently when enzymatic isolation protocols are compared. PMID- 25530036 TI - The effect of sperm DNA fragmentation on live birth rate after IVF or ICSI: a systematic review and meta-analysis. AB - A systematic review and meta-analysis was conducted to evaluate the relationship between the extent of sperm DNA damage and live birth rate (LBR) per couple and the influence of the method of fertilization on treatment outcome. Searches were conducted on MEDLINE, EMBASE and Cochrane Library. Six studies were eligible for inclusion in the meta-analysis. Overall, LBR increased signficantly in couples with low sperm DNA fragmentation compared with those with high sperm DNA fragmentation (RR 1.17, 95% CI 1.07 to 1.28; P = 0.0005). After IVF and intracytoplasmic sperm injection (ICSI), men with low sperm DNA fragmentation had significantly higher LBR (RR 1.27, 95% CI 1.05 to 1.52; P = 0.01) and (RR 1.11, 95% CI 1.00 to 1.23, P = 0.04), respectively. A sensitivity analysis showed no statistically significant difference in LBR between low and high sperm DNA fragmentation when ICSI treatment was used (RR 1.08, 95% CI 0.39 to 2.96; P = 0.88). High sperm DNA fragmentation in couples undergoing assisted reproduction techniques is associated with lower LBR. Well-designed randomized studies are required to assess the role of ICSI over IVF in the treatment of men with high sperm DNA fragmentation. PMID- 25530037 TI - Patterns of barbell acceleration during the snatch in weightlifting competition. AB - The purpose of this study was to determine the association between weightlifting performance and vertical barbell acceleration patterns. Barbell kinematic time series data were tracked from 18 snatches from six weightlifters during a regional weightlifting competition. These data were used to calculate vertical barbell accelerations. Time-series data were normalised to 100% of lift phase, defined as the time interval between barbell lift-off and maximum height of the barbell during each snatch lift. The time-series data were then entered into a pattern recognition algorithm that extracted principal patterns and calculated principal pattern scores. Body mass-normalised lift weight, which was used to quantify weightlifting performance, was significantly correlated (r = 0.673; P = 0.033) with a pattern that captured a difference in peak vertical barbell acceleration between the transition and the second pull phase. This correlation indicated that barbell acceleration profiles of higher weight snatch lifts were characterised by smaller decreases in acceleration during the second knee bend and smaller peak acceleration during the second pull phase. Weightlifting coaches and sports scientist should monitor and track vertical acceleration of the barbell, with focus on acceleration profiles that limit (1) deceleration during the transition phase between the first and second pull and (2) peak acceleration during the second pull phase of the snatch. PMID- 25530038 TI - In utero exposure to the endocrine disruptor di(2-ethylhexyl) phthalate targets ovarian theca cells and steroidogenesis in the adult female rat. AB - Di-2-ethylhexyl phthalate (DEHP) is an endocrine disruptor used in industry as an additive to polyvinyl chloride-based products. Pregnant dams were gavaged with oil, 1, 20, 50, or 300mg of DEHP/kg/day from gestational day 14 until birth in order to characterize the effects of DEHP in the adult female offspring. In utero exposure to DEHP resulted in reduced estrogen levels at proestrus. Theca cell layer thickness was decreased starting at 50mg DEHP/kg/day dose. Follicle stimulating hormone levels were significantly increased at proestrus and estrus. F1 reproduction using a known breeder was not affected. F3 generation showed a decreased pregnancy rate and weight, and increased litter size in the animals exposed to 20mg DEHP/kg/day. The data presented herein suggest that in utero exposure to DEHP targets the theca cell layer and decreases the estrus cycle steroid surge, but despite these effects, does not cause infertility. PMID- 25530039 TI - Nonclinical reproductive and developmental safety evaluation of the MAGE-A3 Cancer Immunotherapeutic, a therapeutic vaccine for cancer treatment. AB - We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100MUL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500MUL of saline (n=2) or the MAGE-A3 Cancer Immunotherapeutic (n=6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected. PMID- 25530040 TI - Letter to the Editor in response to Hostetler. PMID- 25530041 TI - Deleterious effects of benomyl and carbendazim on human placental trophoblast cells. AB - Benomyl and carbendazim are benzimidazole fungicides that are used throughout the world against a wide range of fungal diseases of agricultural products. There is as yet little information regarding the toxicity of benzimidazole fungicides to human placenta. In this study, we utilized human placental trophoblast cell line HTR-8/SVneo (HTR-8) to access the toxic effects of benomyl and carbendazim. Our data showed that these two fungicides decreased cell viability and the percentages of cells in G0/G1 phase, as well as induced apoptosis of HTR-8 cells. The invasion and migration of HTR-8 cells were significantly inhibited by benomyl and carbendazim. We further found that benomyl and carbendazim altered the expression of protease systems (MMPs/TIPMs and uPA/PAI-1) and adhesion molecules (integrin alpha5 and beta1) in HTR-8 cells. Our present study firstly shows the deleterious effects of benomyl and carbendazim on placental cells and suggests a potential risk of benzimidazole fungicides to human reproduction. PMID- 25530042 TI - Birthweight, body composition, and motor performance in 7- to 10-year-old children. AB - AIM: The aim of this study was to analyse the influence of birthweight on motor performance and body composition in children. Further, we investigated whether associations between birthweight and motor performance changed after adjustment for current height, body mass index (BMI), fat-free mass (FFM), and % body fat. METHOD: A total of 483 children (251 males and 232 females) aged 7 to 10 years (mean 8.78, SD 1.0y) born in Vitoria Santo Antao (northeast Brazil) were sampled. Motor performance was operationalized using different physical fitness components and gross motor coordination. Physical fitness was measured by handgrip strength, muscle endurance, explosive power, flexibility, agility, running speed, and maximal oxygen consumption (VO2max). Gross motor coordination was evaluated by means of the Korper Koordination Test fur Kinder (KTK). RESULTS: Positive correlations between birthweight and height, BMI, and FFM were found. Birthweight was positively correlated with handgrip strength and negatively correlated with 20-meter sprint time, even after controlling for age, height, BMI, FFM, and % body fat. Birthweight was negatively associated with relative VO2max (mL/kg/min); however, the association was no longer significant after inclusion of BMI or FFM in the model. INTERPRETATION: Birthweight significantly predicted height, BMI, FFM, and performance in strength and velocity tests, but did not influence gross motor coordination. PMID- 25530043 TI - Stop gambling with your hearing. PMID- 25530044 TI - Morphology of the mouthparts of the spittlebug Philagra albinotata Uhler (Hemiptera: Cercopoidea: Aphrophoridae). AB - Mouthparts associated with feeding behavior and feeding habits are important sensory and feeding structures in insects. To obtain a better understanding of feeding in Cercopoidea, the morphology of mouthparts of the spittlebug, Philagra albinotata Uhler was examined using scanning electron microscopy. The mouthparts of P. albinotata are of the typical piercing-sucking type found in Hemiptera, comprising a cone-shaped labrum, a tube-like, three-segmented labium with a deep groove on the anterior side, and a stylet fascicle consisting of two mandibular and two maxillary stylets. The mandibles consist of a dorsal smooth region and a ventral serrate region near the apical half of the external convex region, and bear five nodules or teeth on the dorsal external convex region on the distal extremity; these are regarded as unique features that distinguish spittlebugs from other groups of Hemiptera. The externally smooth maxillary stylets, interlocked to form a larger food canal and a smaller salivary canal, are asymmetrical only in the internal position of longitudinal carinae and grooves. One dendritic canal is found in each maxilla and one in each mandible. Two types of sensilla trichodea, three types of sensilla basiconica and groups of multi-peg structures occur in different locations on the labium, specifically the labial tip with two lateral lobes divided into anterior sensory fields with ten small peg sensilla arranged in a 5+4+1 pattern and one big peg sensillum, and posterior sensory fields with four sensilla trichodea. Compared with those of previously studied Auchenorrhyncha, the mouthparts of P. albinotata may be distinguished by the shape of the mandibles, the multi-peg structures and a tooth between the salivary canal and the food canal on the extreme end of the stylets. The mouthpart morphology is illustrated using scanning electron micrographs, and the taxonomic and putative functional significance of the different structures is briefly discussed. PMID- 25530045 TI - Diagnosing primary immunodeficiency: a practical approach for the non immunologist. AB - OBJECTIVE: This review will provide an overview of the most common clinical presentations of primary immunodeficiency (PI), navigating through various affected organ systems. The goal is to accurately portray the high variability of this disease and provide a resource that helps to raise the index of suspicion of PI among physicians, aid in recognition of various PI disorders, and trigger more frequent screenings with appropriate referrals to immunologists for further evaluation and treatment. SUMMARY: Patients with PI comprise more than 200 defined genetic abnormalities. Patients have an array of clinical manifestations, ranging from the most widely associated recurrent and chronic bacterial infections to other associated comorbid conditions involving many organ systems. There is still considerable delay between the onset of symptoms and the time of diagnosis of PI. This review will present an overview of the clinical manifestations that will enhance a physician's recognition of a possible PI. Particular emphasis is placed on the pathogens associated with the specific arm of the immune system that is related to each particular type of PI. The initial immune evaluation is described, which together with the history and physical exam can help focus the physician on the immune compartment most likely associated with a PI. CONCLUSIONS: Understanding the types of PI and the related clinical manifestations can help physicians see beyond the presenting symptoms and lead to improved recognition and diagnosis of PI. Timely diagnosis is of utmost importance in PI, as recent advances in bone transplantation and immunoglobulin replacement therapy, as well as future gene therapies, provide effective ways to prevent significant mortality and morbidity. PMID- 25530046 TI - Poor mental health in severely obese patients is not explained by the presence of comorbidities. AB - The prevalence of obesity, especially severe obesity where body mass index (BMI) exceeds 40 kg m(-2) and where the physical risks are greatest, is increasing. However, little is known about the impact of severe obesity on psychological well being and self-rated health (SRH). We aimed to investigate this relationship in patients attending an Irish weight management clinic. SRH was measured with a single-item inventory (excellent = 1, poor = 5). Well-being was measured with the validated World Health Organization-Five Well-being Index (WHO-5), in which scores <13 indicate poor well-being. Previous studies of the Irish population have reported mean SRH = 2.56 (males) and 2.53 (females) and mean well-being = 16.96. One hundred eighty-two (46.8%) completed questionnaires were returned. The sample was representative of the clinic population with a mean age of 47.1, mean baseline BMI of 51.9 kg m(-2) and 64.3% females. Mean SRH was 3.73 in males and 3.30 in females; mean well-being was 10.27 in males and 10.52 in females. In the final multivariable models, number of medications, depression and obstructive sleep apnoea, WHO-5 and current BMI were significant predictors of SRH, and secondary level education, social support and mindfulness scores were significant predictors of psychological well-being. Number of medications was not significant. The results suggest that the poor psychological well-being seen is not explained by the presence of comorbidities and that social support and mindfulness may be important targets for improving psychological well-being. Improving psychological well-being in addition to weight loss and effective management of comorbidities may be important for improving SRH. PMID- 25530047 TI - Protective effect of magnesium and selenium on cadmium toxicity in the isolated perfused rat liver system. AB - The isolated perfused rat liver (IPRL) model has been used into toxicology study of rat liver. This model provides an opportunity at evaluation of liver function in an isolated setting. Studies showed that Cd, in a dose-dependent manner, induced toxic effects in IPRL models, and these effects were associated with aminotransferase activity and lipid peroxidation. The aim of this study was to investigate whether Mg and/or Se could have protective effects against the Cd toxicity in the IPRL model. Male Wistar rats (9-10 weeks) weighing 260-300 gr were used in this study. They were randomly divided into 8 groups of 4-6 rats per cage. In group 1, liver was perfused by Krebs-Henseleit buffer without MgSO4 (Control). Groups 2-8 were exposed to Mg, Se, Cd, Mg +Se, Cd + Mg, Cd + Se, Cd + Mg + Se respectively in Krebs-Henseleit buffer with no added MgSo4. Biochemical changes in the liver were examined within 90 minutes, and the result showed that the exposure to Cd, lowered glutathione level, while it increased malondialdehyde level and aminotransferase activities in IPRL model. Mg administration during exposure to Cd reduces the toxicity of Cd in the liver isolated while Se administration during exposure to Cd did not decrease Cd hepatotoxicity. Nevertheless, simultaneous treatment with Se and Mg on Cd toxicity have strengthened protective effects than the supplementation of Se alone in the liver. PMID- 25530048 TI - Osteoporosis in patients with Pemphigus Vulgaris before steroid therapy. AB - Pemphigus Vulgaris (PV) is often complicated by osteoporosis. Although corticosteroid therapy undoubtedly plays a causative role, inflammation associated with PV may also contribute to osteoporosis. This study was designed to determine the prevalence of osteoporosis in patients with PV before corticosteroid therapy and to compare these findings with those reported previously in healthy volunteers. Newly diagnosed patients with PV, who had not received systemic corticosteroids, were enrolled. Bone mineral density (BMD) was measured both in the lumbar spine (L1-L4) and hip region. Data were compared with those of a healthy Iranian population. The association between the disease duration and severity and BMD was evaluated. A total of 50 patients (27 women) with a mean age of 42.6+/-14.5 years were enrolled. Osteoporosis was seen in 7 (14%) patients, 3 (11.1%) women, 4 (17.4%) men, and in both genders it was more common when compared to the population of healthy Iranians (8.2% in women and 4.9% in men). Osteopenia was found in 26 (52%) patients, 13 women and 13 men. Although both osteopenia and osteoporosis were more common in severe disease, neither the duration nor the severity of PV showed a statistically significant association with osteopenia or osteoporosis. The presence of a higher than expected rate of osteoporosis in patients with PV argues for osteoporosis screening and efforts aimed at prevention and early initiation of treatment to prevent unnecessary morbidity. PMID- 25530049 TI - Mean right and left carotid intima-media thickness measures in cases with/without coronary artery disease. AB - One of the important factors which should be considered in (Coronary artery disease) CAD cases is increased carotid intima-media thickness (IMT) which has been considered to be associated with coronary artery disease severity and cardiovascular events. The goal of this study was to compare risk factors and carotid IMT in cases with CAD and healthy subjects and to determine the association between severity of CAD and IMT. In this case-control study, 250 proved CAD cases and 250 healthy ones were enrolled. Ultrasound evaluation of carotid IMT Ultrasound quantification of the right and left carotid IMTs was obtained. Demographic characteristics (age and sex), risk factors (presence of diabetes, hyperlipidemia (HLP), hypertension (HTN) and smoking) were recorded for all participants. Presence of diabetes, HTN, HLP and mean age was significantly higher in patients than controls. There was positive correlation between IMTs and advancing CAD (for right IMT, rho=0.34, P<0.001, for IMT rho=0.47, P<0.001). Sex, HTN, HLP, right and left IMT measures were independent predictors of CAD. The best cutoff point for right IMT to differentiate patients from controls was 0.82 with sensitivity and specificity of 70% and 50% (AUC=0.70, P<0.001). The best cutoff point for left IMT to differentiate patients from controls was 0.85 with sensitivity and specificity of 80% and 55% (AUC=0.70, P<0.001). Carotid IMT increase should be considered as a surrogate factor for CAD. PMID- 25530050 TI - Anxiety in patients with multiple sclerosis: association with disability, depression, disease type and sex. AB - The aim of the current study was to evaluate anxiety in patients with multiple sclerosis (MS) and factors which are associated with this symptom. Eighty totals of 180 patients with MS were enrolled in this cross-sectional study. They were asked to answer the valid and reliable Persian version of the Beck depression inventory (BDI) and Beck anxiety inventory (BAI) questionnaires. Demographic characteristics (sex and age), duration of the disease, disease course and Kurtzke Expanded Disability Status Scale (EDSS) were recorded for all participants. Mean BDI was 17.5 +/- 11.4 in patients while mean BAI was17.7 +/- 12.5 in all participants, respectively. Mean BDI and BAI were not statistically different between male and female participants. Patients with higher levels of disability (higher EDSS) had significant higher BDI and BAI scores and there was significant positive correlation between EDSS and BDI and BAI scores (rho=0.42, P<0.001, rho=0.35, P<0.001). Patients with SP (Secondary progressive) type of disease had significant higher BDI and BAI score. Multiple linear regression analysis showed that depression and disability level were independent predictors of anxiety in patients. Anxiety and factors which are related with this symptom should be considered in MS patients. PMID- 25530051 TI - Evaluation of plasma concentrations of homocysteine, IL-6, TNF-alpha, hs-CRP, and total antioxidant capacity in patients with end-stage renal failure. AB - It has been proved that hyperhomocysteinemia has a high prevalence in patients with end-stage renal disease (ESRD), which may contribute to the high cardiovascular risk in these patients. Cardiovascular disease is the first cause of high mortality rate in ESRD patients. The aim of the present study was to assess five important factors in patients with ESRD (the amount of homocysteine, IL-6, TNF-alpha, hs-CRP, and Total Antioxidant Capacity). These factors were surveyed in ESRD patients to compare with healthy subjects. In a cross-sectional study, we enrolled 80 patients on maintenance hemodialysis and measured the inflammatory and oxidative stress indicators. The plasma samples were assayed for five above mentioned variables using standard protocols. Two-hour post hemodialysis plasma samples were also assayed for TAC. Plasma levels of inflammation markers, IL-6 and hs-CRP, homocysteine were significantly increased in ESRD group versus control group. This increase was also found in TNF-alpha levels as compared to the controls, but the differences were not statistically significant. Also, the post dialysis samples had significantly lower levels of TAC as compared to predialysis ones. PMID- 25530052 TI - The effect of oral sensorimotor stimulations on feeding performance in children with spastic cerebral palsy. AB - Oral feeding difficulties are common in children with cerebral palsy (CP). The effect of oral-motor dysfunction on feeding problems has been proved in several studies. The purpose of the present study was to evaluate the effect of oral sensorimotor stimulations on feeding performance in children with spastic cerebral palsy. A total of 12 children with spastic cerebral palsy underwent 24 sessions of oral-motor stimulations (3 days per week). The effect of the intervention was assessed after the 12 and 24 sessions. Feeding skills were assessed using Oral Motor Assessment Scale (OMAS). Data were analyzed using Friedman test and intra class correlation coefficient (ICC). The results of the study revealed a significant improvement in feeding skills including mouth closure, lip closure on the utensil, lip closure during deglutition, control of the food during swallowing, mastication, straw suction and control of liquid during deglutition. There were more improvement in mouth closure and less in straw suction. This study showed sensorimotor stimulation is useful for the treatment of the feeding problems, but the progress was not perfect. This could be due to the role of the position and cognitive skills in feeding functions. Thus, other strategies should be considered to achieve more improvement in feeding performance. PMID- 25530053 TI - Coincidence of asthma and bronchospasm during anesthesia in tympanomastoidectomy. AB - High prevalence of asthma and bronchospasm was observed during induction of anesthesia in patients with chronic suppurative otitis mMedia (CSOM) who underwent tympanomastoidectomy. Although several studies have proposed association of allergic diseases with CSOM but no consensus about it has been established. Current study was designed to determine the coincidence of asthma in CSOM patients. In a cross-sectional study, authors investigated medical records of 106 CSOM patients underwent tympanomastoidectomy, aged 15 to 65 years, and 95 controls, which were matched by age and sex. Participants were admitted to Valiasr Hospital, Tehran, Iran, from April of 2011 to March of 2013. Required information, such as demographic characteristics and history of allergic rhinitis (AR) and asthma were obtained from patients' medical records. The prevalence of AR in the CSOM group was higher than controls' group (19.8% and 15.8%, respectively) (P>0.05). Asthma prevalence was significantly higher in patients with CSOM (P=0.03) (OR=7.67, 95% CI: 0.9-62.5). No significant association was found between history of AR and chronic ear infections. However, asthma was significantly more common in CSOM patients. Current study indicates that asthma and risk of bronchospasm need particular attention in patients with CSOM underwent tympanomastoidectomy before and during anesthesia. PMID- 25530054 TI - The effects of religion and spirituality on postoperative pain, hemodynamic functioning and anxiety after cesarean section. AB - Spiritual elements play an important role in the recovery process from acute postoperative pain. This study was conducted to assess the effect of pray meditation on postoperative pain reduction and physiologic responds among muslim patients who underwent cesarean surgery under spinal anesthesia. This double blinded randomized clinical trial study was conducted among muslim patients who underwent cesarean surgery under spinal anesthesia during 2011-2013 at tertiary regional and teaching hospital in Lorestan, Iran. The patients were randomly divided into interventional group (n=80) and control group (n=80). For about 20 minutes using a disposable phone mentioned and listened to pray meditation "Ya man esmoho davaa va zekroho shafa, Allahomma salle ala mohammad va ale mohammad" in interventional group and phone off in control group. Before and during pray meditation, 30, 60 minutes, 3 and 6 hours after pray meditation pain intensity, blood pressure, heart rate and respiratory rate were measured. No statistically significant improvement in pain score was found before and during pray meditation, 30, 60 minutes after pray meditation (P>0.05). Statistically significant improvement in pain score was found at 3 and 6 hours after pray meditation than control group (1.5 +/- 0.3 vs. 3 +/- 1.3, P=0.030) and (1.3 +/- 0.8 vs. 3 +/- 1.1, P=0.003). However, there was no significant difference in the physiological responses (systolic and diastolic blood pressure, respiration, and heart rate) any time between the groups. Religion and spirituality intervention such as pray meditation could be used as one of non-pharmacological pain management techniques for reducing pain after cesarean surgery. Also, Pray meditation provides less postoperative nausea and vomiting (PONV) and more relaxation. PMID- 25530055 TI - Seroprevalence of Epstein-Barr virus among HIV positive patients moreover and its association with CD4 positive lymphocyte count. AB - Opportunistic infections are the leading cause of hospitalization and morbidity in human immunodeficiency virus (HIV) positive patients and are the most common cause of death between them. We aimed to measure IgG antibody against EBV viral capsid antigen (EBV-VCA IgG) to determine the seroprevalence of this infection in HIV-positive population. A case-control study between September 2011 and October 2012 was conducted in a teaching hospital enrolling 114 HIV-positive patients as case group and 114 healthy individuals as control with similar age and sex. Enzyme-linked immunosurbant assay (ELISA) technique was used for determination of EBV-VAC IgG in obtained samples. Of 114 serum samples obtained from HIV-positive patients, 103 (90.4%) samples were found positive for EBV-VCA IgG antibody. There was no significant difference in seroprevalence of EBV VCA IgG antibody between patients received antiretroviral therapy and naive patients (91.5% vs. 87.5%, P>0.05). There was no statistically significant difference in EBV-VCA IgG seroprevalence between three groups of CD4+ in HIV positive group. In conclusion current study showed that seroprevalence of EBV in HIV-positive patients is higher than HIV-negative healthy participants; however, administration of HAART and CD4+ lymphocyte count did not reveal a significant effect in seroprevalence of EBV. Due to the significance of this virus in mortality and morbidity and causing certain malignancies in patients with AIDS, these patients are strongly recommended to be tested for this virus. PMID- 25530056 TI - Selecting emergency medicine: rationales from perspective of Iranian residents. AB - Emergency medicine is a relatively new specialty in Iran. Therefore, the general public and the medical community do not have enough information on its duties, capabilities, its nature, and its work schedule or its degree of occupational difficulty compared to other specialties. Hence, an insight from the early group of residents who selected this specialty can help identify the strengths and weaknesses of this field in order to promote the scientific quality of this field, and attract medical students. It can also help to alleviate deficiencies and strengthen positive aspects of emergency medicine. The aim of this study was to identify the reasons behind choosing emergency medicine as a specialty. A qualitative study was conducted using semi-structured interviews. Maximum variation opportunistic sampling was done, and face-to-face interviews were held with 23 emergency medicine residents and fellows (4 faculty members and 19 residents). Data were analyzed through thematic analysis, and categories and themes were extracted. The main levels extracted were: 1) Individual priorities, 2) the nature of work and the field of study, and 3) professional future. The themes of each main level were extracted and encoded. This study showed that the majority of residents choose emergency medicine specialty to achieve a better social and professional status in one of the most challenging fields of medicine. PMID- 25530057 TI - Vertical infraclavicular block with local anesthetic injections at different currents. AB - Injecting local anesthetic at the seeking current would be appealing.It would save time and avoid potentially dangerous manipulations of the needle. This study aimed to test the hypotheses that in vertical infraclavicular block, injecting local anesthetic at a seeking current of 0.8 mA would produce the same quality of block as injecting at <=0.5mA. A total of sixty ASA I -III adult patients scheduled for elective surgery on the hand, wrist and forearm in two equal groups of 30 patients, were enrolled in this study. The technique described by Kilka & Geiger used in both groups. After eliciting a clear and visible motor response of all fingers in either extension or flexion, injection was performed at a current of 0.8 mA and <=0.5 mA in study and control groups respectively. Duration of time to analgesia and to anesthesia was evaluated. The mean duration of onset of analgesia in radial, median and ulnar nerves in both groups, were similar. The onset of anesthesia took a mean of 13.5 minutes in the control group and 15.6 minutes in study group (P=0.064). The onset of analgesia was 4.2 minutes in the control group and 4.3 minutes in study group. (P=0.508). The success rate in both groups was 100%. We had patients in both groups who developed complete anesthesia of the hand within 25 minutes. We conclude that the injection at 0.8 mA would result in a similar quality of block to one injected at <=0.5 mA. The difference between two groups was not statistically significant. PMID- 25530058 TI - Are Iranians aware of carbon monoxide poisoning: symptoms and its prevention strategies? AB - Carbon monoxide (CO) poisoning is still a health problem all over the world. Informing users about symptoms and suggesting annual inspection of CO producing devices will result in CO poisoning reduction. The goal of this study was to evaluate awareness about CO poisoning symptoms and its prevention ways in Iranian population. In this study, a total of 700 patients' family members attended Imam Khomeni hospital were asked to enroll in the study. A structured questionnaire was used including demographic characteristics, devices which were used at home, awareness of CO poisoning symptoms, awareness of CO detectors, the last time that tubal patency of devices are checked, if it is helpful to open the window to fix gas leak and if surveying devices by an expert at the beginning of the cold season is recommended. A total of 635 participants completed questionnaires. The most used device was gas water heater followed by gas heater. Five hundred and nine reported that they are aware of CO poisoning symptoms (80.1%), 398 (62.6%) stated that it is possible to detect CO leak and 566 (89.1%) told CO detectors would be helpful for reduction of mortality from CO poisoning. Fifty percent of participants had not checked their devices since they have bought their devices. Five hundred and thirty-six (84.4%) reported that opening window could help CO leak, and 596 (93.8%) agreed that an expert checked their fuel-burning devices at the beginning of the winter. Iranian people are not aware of all CO poisoning symptoms. Developing a national strategy for CO surveillance and people education will be helpful. PMID- 25530059 TI - Iranian nursing students' perspectives of educational equity. AB - Around the world there is a growing consensus that students' rights must be protected, regardless of race, creed, color, sex, religion, and socioeconomic status. One of these rights is the educational equity. However, little is known about these phenomena in nursing education. The aim of this study was to explore the educational equity from the perspective of nursing students. A qualitative study was conducted. Thus, we purposefully recruited for in-depth interviews 13 nursing students (8 female and 5 male). All interviews were transcribed verbatim and analyzed by thematic analysis approach to identify categories and themes. Four main themes emerged from the data: Fair Educational Opportunity, fair evaluation, attempts to combat discrimination, and employing qualified teachers. It is argued that educational equity should be developed in higher education. Principles of equity and students' rights may form the most basic rationale for all formal and informal efforts to extend the right of equal access to education. PMID- 25530060 TI - Principles of primary survey and resuscitation in cases of pediatric trauma. AB - Trauma is a common cause of death and disability in children. Proper approach to pediatric trauma involves adherence to ABCDE sequence in the primary survey and resuscitation in order to promptly recognize and manage immediately life threatening conditions. This readily reviewed sequence includes A: establishment and maintenance of a patent airway while maintaining cervical spine immobilization; B: evaluation of breathing, ventilation and oxygenation, immediate treatment of tension pneumothorax, open pneumothorax and massive hemothorax; C: evaluation and treatment of circulatory compromise and shock; D: Disability and Neurologic Status, assessment of signs of increased intracranial pressure and impending cerebral herniation; and E: Exposure while preventing hypothermia. Implementing these assessment and management priorities can result in more favorable outcomes. PMID- 25530061 TI - Ischemic stroke as a rare manifestation of aluminum phosphide poisoning: a case report. AB - Aluminum phosphide (AlP) is a solid fumigant which is widely used for a suicide attempt in Iran. Although neurologic symptoms are commonly reported, cerebrovascular stenosis is rare in AlP poisoning. We described ischemic stroke as a delayed complication of AlP intoxication. A 30-year-old man was admitted because of sudden onset left side hemiplegia, 11 days after intentional ingestion of three rice tablets. Investigations revealed in situ thrombosis in right middle cerebral artery (MCA) while other causes of stroke in young adults were excluded. Ischemic stroke should be considered as a delayed complication of AlP intoxication even after the acute phase of intoxication. PMID- 25530062 TI - Local facial edema: a novel presentation of subcutaneous panniculitis-like T-cell lymphoma in a 30-year-old Iranian woman. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an infrequent cytotoxic T-cell lymphoma of the skin with a unique immunophenotypic profile. Here we describe this lymphoma in a 30-year-old Iranian woman. She presented with periorbital edema, mandibular swelling with edematous areas on her face and two small lymph nodes (6-7mm) in the cervical area. Histopathological findings revealed lobular infiltration of atypical lymphoid cells in subcutaneous tissue, especially around individual fat cells. Immunohistochemical evaluation of the atypical lymphocytes showed CD3 and CD8 immunoreactivity and CD4 and CD56 negativity. She was diagnosed as SPTCL based on clinical, histopathological and immunohistochemical findings. This report suggests that SPTCL should be considered in the differential diagnosis of any atypical skin lesion involving subcutaneous fat. Suitable deep skin biopsy and immunohistochemical staining are essential to differentiate between SPTCL and other more common diagnoses. PMID- 25530065 TI - Effect of the knockdown of death-associated protein 1 expression on cell adhesion, growth and migration in breast cancer cells. AB - Death-associated protein 1 (DAP1) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP1 expression and clinicopathological parameters of human breast cancer. In the present study, we aimed to determine the role of DAP1 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sublines of MCF7 and MDA-MB-231, and performed growth, adhesion and invasion assays and electric cell-substrate impedance sensing (ECIS) studies of the post-wound migration of cells. In addition, we studied the mRNA expression of caspase 8 and 9, DELE, IPS1, cyclin D1 and p21 in the control and knockdown sublines. Knockdown was associated with increased adhesion and migration, significantly so in the MDA-MB-231DAP1kd cell subline (p=0.029 and p=0.001, respectively). Growth in MCF7 cells showed a significant suppression on day 3 (p=0.029), followed by an increase in growth matching the controls on day 5. While no change in the apoptotic response to serum starvation could be attributed to DAP1 knockdown, the expression of known components of the apoptosis pathway (caspase 8) and cell cycle (p21) was significantly reduced in the MCF7DAP1kd cell subline (p<=0.05), while in MDA-MB-231DAP1kd the expression of a pro-apoptotic molecule, IPS1, was suppressed (p<=0.05). DAP1 may have an important role in cell adhesion, migration and growth in the context of breast cancer and has significant associations with the apoptosis pathway. Furthermore, we believe that delayed increase in growth observed in the MCF7DAP1kd cell subline may indicate activation of a strongly pro-oncogenic pathway downstream of DAP1. PMID- 25530066 TI - Performance of a one-step fecal sample-based test for diagnosis of Helicobacter pylori infection in primary care and mass screening settings. AB - BACKGROUND/PURPOSE: An alternative screening test is needed to efficiently eradicate Helicobacter pylori from a population with prevalent upper gastrointestinal lesions. We evaluated the performance of a new one-step fecal test for H. pylori for diagnosis of H. pylori infection in Taiwan. METHODS: We developed a fecal test to detect H. pylori based on the immunochronomatographic assay and a mixture of monoclonal antibodies. We first recruited symptomatic patients from the primary care setting to evaluate fecal test performance using a reference standard consisting of (13)C urea breath test, rapid urease test, and histology. We also compared the performance of the fecal test with that of others. Next, we recruited asymptomatic participants from the mass screening setting to evaluate population attendance for the fecal test and compared its performance with that of (13)C urea breath test. RESULTS: In the primary care setting, 117 patients were recruited; H. pylori infection was confirmed in 58 (49.6%). Fecal test sensitivity, specificity, positive and negative predictive values, and accuracy were 88.0% [95% confidence interval (CI): 79.6-96.4%], 100%, 100%, 89.4% (95% CI, 82.0-96.8%), and 94% (95% CI, 89.7-98.3%), respectively. Fecal test specificity and positive predictive value were significantly higher than those of the serological test, whereas the sensitivity and negative predictive value were lower than those of the (13)C urea breath test (p < 0.05). In the mass screening setting, 2720 of 3520 invited individuals participated (77.3%; 95% CI, 76-78.7%); 649 (23.9%) showed positive results. Concordance rate and kappa statistic between the fecal test and (13)C urea breath test were 91.7% (563/614; 95% CI, 89.9-94.1%) and 0.78 (95% CI, 0.73-0.84), respectively. CONCLUSION: Given the acceptable sensitivity, excellent specificity, and high participation rate to screening, the one-step H. pylori stool antigen test is feasible for wide application in the community. PMID- 25530067 TI - Differences in IL-8 in serum and exhaled breath condensate from patients with exacerbated COPD or asthma attacks. AB - BACKGROUND/PURPOSE: The collection of exhaled breath condensate (EBC) is a noninvasive method that can be used to monitor the inflammatory status of patients with chronic airway diseases. We aimed to study differences in cytokine expression between patients with exacerbations of chronic obstructive pulmonary disease (COPD) and patients with asthma attacks. METHODS: Using a custom-made device and methods based on American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations, EBC samples were collected from nine COPD patients, 12 asthma patients and 10 healthy individuals. Cytokine concentrations in serum and EBC were measured via commercial ELISA kits. RESULTS: Of four cytokines measured in EBC [interleukin-8 (IL-8), IL-17, IL-4 and tumor necrosis factor-alpha (TNF-alpha)], only IL-8 was significantly higher in COPD than in asthma patients (5.27 +/- 0.18 vs. 4.36 +/- 0.34 pg/mL, p = 0.001). Moreover, COPD patients had higher serum IL-8 than asthma patients (10.57 +/- 0.55 vs. 5.15 +/- 0.24 pg/mL, p < 0.001). No significant correlation between serum and EBC cytokine concentrations was observed in each subgroup of patients. CONCLUSION: Compared with patients with asthma attacks, patients with exacerbated COPD had increased IL-8 expression in both serum and EBC. These results suggest that IL-8 may be more important in airway and systemic inflammation in COPD exacerbations than in asthma attacks. PMID- 25530064 TI - Covariate-adjusted measures of discrimination for survival data. AB - MOTIVATION: Discrimination statistics describe the ability of a survival model to assign higher risks to individuals who experience earlier events: examples are Harrell's C-index and Royston and Sauerbrei's D, which we call the D-index. Prognostic covariates whose distributions are controlled by the study design (e.g. age and sex) influence discrimination and can make it difficult to compare model discrimination between studies. Although covariate adjustment is a standard procedure for quantifying disease-risk factor associations, there are no covariate adjustment methods for discrimination statistics in censored survival data. OBJECTIVE: To develop extensions of the C-index and D-index that describe the prognostic ability of a model adjusted for one or more covariate(s). METHOD: We define a covariate-adjusted C-index and D-index for censored survival data, propose several estimators, and investigate their performance in simulation studies and in data from a large individual participant data meta-analysis, the Emerging Risk Factors Collaboration. RESULTS: The proposed methods perform well in simulations. In the Emerging Risk Factors Collaboration data, the age-adjusted C-index and D-index were substantially smaller than unadjusted values. The study specific standard deviation of baseline age was strongly associated with the unadjusted C-index and D-index but not significantly associated with the age adjusted indices. CONCLUSIONS: The proposed estimators improve meta-analysis comparisons, are easy to implement and give a more meaningful clinical interpretation. PMID- 25530068 TI - Efficacy and safety of pregabalin in patients with neuropathic cancer pain undergoing morphine therapy. AB - AIM: To evaluate the efficacy and the safety of pregabalin (PGB)-morphine combination for the treatment of neuropathic cancer pain (NCP). METHODS: In this double-blind, randomized, placebo (PL)-controlled crossover study, 40 cancer patients with severe NCP were randomized into two groups (20 per group): PGB-PL and PL-PGB. Patients in the PGB-PL group received PGB plus oral morphine in phase I, and PL plus oral morphine in phase II. The treatment sequence for the PL-PGB group was PL plus oral morphine in phase I, and PGB plus oral morphine in phase II. These 2-week treatment periods were separated by a 1-week washout period. The primary outcome measure was the decrements in morphine dose; secondary outcomes included quantitative assessments of sleep (rated according to the Medical Outcomes Study Sleep Scale), the Constipation Assessment Scale and adverse effects. RESULTS: The mean minimal effective dose of morphine was 184.4 +/- 69.9 mg/day in the period of PGB treatments, which was significantly lower than that of PL-controls (228.7 +/- 66.9 mg/day; P < 0.001) and baseline (247.5 +/- 80.0 mg/day; P < 0.001). Compared with PL, PGB resulted in a significant sleep improvement as measured by sleep disturbance, sleep quantity, and sleep problems index (P < 0.001), as well as a Constipation Assessment Scale reduction (P < 0.001). PGB resulted in a higher frequency of dry mouth and somnolence than PL (P < 0.05). CONCLUSION: PGB enhances the efficacy of oral morphine and reduces dose related adverse reactions. The PGB-morphine combination is an effective approach to controlling NCP. PMID- 25530069 TI - Switching benefits and costs in competitive health insurance markets: A conceptual framework and empirical evidence from the Netherlands. AB - Competitive health insurance markets will only enhance cost-containment, efficiency, quality, and consumer responsiveness if all consumers feel free to easily switch insurer. Consumers will switch insurer if their perceived switching benefits outweigh their perceived switching costs. We developed a conceptual framework with potential switching benefits and costs in competitive health insurance markets. Moreover, we used a questionnaire among Dutch consumers (1091 respondents) to empirically examine the relevance of the different switching benefits and costs in consumers' decision to (not) switch insurer. Price, insurers' service quality, insurers' contracted provider network, the benefits of supplementary insurance, and welcome gifts are potential switching benefits. Transaction costs, learning costs, 'benefit loss' costs, uncertainty costs, the costs of (not) switching provider, and sunk costs are potential switching costs. In 2013 most Dutch consumers switched insurer because of (1) price and (2) benefits of supplementary insurance. Nearly half of the non-switchers - and particularly unhealthy consumers - mentioned one of the switching costs as their main reason for not switching. Because unhealthy consumers feel not free to easily switch insurer, insurers have reduced incentives to invest in high-quality care for them. Therefore, policymakers should develop strategies to increase consumer choice. PMID- 25530070 TI - Stability of self-referent encoding task performance and associations with change in depressive symptoms from early to middle childhood. AB - Depressed individuals exhibit memory biases on the self-referent encoding task (SRET), such that those with depression exhibit poorer recall of positive, and enhanced recall of negative, trait adjectives (referred to as positive and negative processing biases). However, it is unclear when SRET biases emerge, whether they are stable, and if biases predict, or are predicted by, depressive symptoms. To address this, a community sample of 434 children completed the SRET and a depressive symptoms measure at ages 6 and 9. Negative and positive processing exhibited low, but significant, stability. At ages 6 and 9, depressive symptoms correlated with higher negative, and lower positive, SRET processing. Importantly, lower positive processing at age 6 predicted increased symptoms at age 9. However, negative processing at age 6 did not predict depressive symptoms at age 9, and depressive symptoms at age 6 did not predict SRET processing scores at age 9. This suggests that less positive processing may reflect vulnerability for future depressive symptoms. PMID- 25530071 TI - [Of hair and genes: The continuing story of Dowling-Degos disease]. PMID- 25530072 TI - All failures count. PMID- 25530073 TI - Rearrangement reactions of 1,1-divinyl-2-phenylcyclopropanes. AB - 1,1-Divinyl-2-phenylcyclopropanes are entry points to a rich area of rearrangement chemistry. With N,N-diallyl amide substrates, tandem radical cyclizations can be initiated at room temperature. Warming provides products of pure thermal rearrangements with acids, ester, and amides. These isomerizations give vinylcyclopentenes resulting from divinylcyclopropane rearrangements and more deeply rearranged tricyclic spirolactams resulting from aromatic Cope rearrangements followed by ene reactions. Conversion of the carbonyl group to an alcohol or ether opens retro-ene pathways followed by either tautomerization or Claisen rearrangement. PMID- 25530074 TI - Separate norovirus outbreaks linked to one source of imported frozen raspberries by molecular analysis, Denmark, 2010-2011. AB - Norovirus outbreaks occur frequently in Denmark and it can be difficult to establish whether apparently independent outbreaks have the same origin. Here we report on six outbreaks linked to frozen raspberries, investigated separately over a period of 3 months. Norovirus from stools were sequence-typed; including extended sequencing of 1138 bp encompassing the hypervariable P2 region of the capsid gene. Norovirus was detected in 27 stool samples. Genotyping showed genotype GI.Pb_GI.6 (polymerase/capsid) with 100% identical sequences. Samples from five outbreaks were furthermore identical over the variable capsid P2 region. In one outbreak at a hospital canteen, frozen raspberries was associated with illness by cohort investigation (relative risk 6.1, 95% confidence interval 3.2-11). Bags of raspberries suspected to be the source were positive for genogroup I and II noroviruses, one typable virus was genotype GI.6 (capsid). These molecular investigations showed that the apparently independent outbreaks were the result of one contamination event of frozen raspberries. The contaminated raspberries originated from a single producer in Serbia and were originally not considered to belong to the same batch. The outbreaks led to consultations and mutual visits between producers, investigators and authorities. Further, Danish legislation was changed to make heat-treatment of frozen raspberries compulsory in professional catering establishments. PMID- 25530076 TI - Lost as we are translating? Informing transitional interventions with data from the adult side. PMID- 25530075 TI - The family of K2P channels: salient structural and functional properties. AB - Potassium channels participate in many biological functions, from ion homeostasis to generation and modulation of the electrical membrane potential. They are involved in a large variety of diseases. In the human genome, 15 genes code for K(+) channels with two pore domains (K2P ). These channels form dimers of pore forming subunits that produce background conductances finely regulated by a range of natural and chemical effectors, including signalling lipids, temperature, pressure, pH, antidepressants and volatile anaesthetics. Since the cloning of TWIK1, the prototypical member of this family, a lot of work has been carried out on their structure and biology. These studies are still in progress, but data gathered so far show that K2P channels are central players in many processes, including ion homeostasis, hormone secretion, cell development and excitability. A growing number of studies underline their implication in physiopathological mechanisms, such as vascular and pulmonary hypertension, cardiac arrhythmias, nociception, neuroprotection and depression. This review gives a synthetic view of the most noticeable features of these channels. PMID- 25530078 TI - Cough-variant asthma: a diagnostic dilemma in the occupational setting. AB - BACKGROUND: Cough-variant asthma (Corrao's syndrome) is defined as the presence of chronic non-productive cough in patients with bronchial hyperresponsiveness (BHR) and response to bronchodilator therapy. This variant of asthma may present a diagnostic problem in occupational medicine. AIMS: To describe additional evaluation of cough-variant asthma in a cyanoacrylate-exposed worker in whom standard diagnostic testing was negative. METHODS: A female beautician was evaluated for suspected occupational allergic rhinitis and asthma. A specific inhalation challenge test (SICT) was performed with cyanoacrylate glues used for applying artificial eyelashes and nails. Spirometry and peak expiratory flow (PEF) measurements were recorded hourly for 24h; methacholine challenge testing was performed and nasal lavage (NL) samples were analysed for eosinophilia. RESULTS: After SICT, the patient developed sneezing, nasal airflow obstruction and cough. Declines in forced expiratory volume in 1 s and PEF were not observed. Eosinophil proportions in NL fluid increased markedly at 4 and 24h after SICT. A significant increase in BHR also occurred 24h after SICT. CONCLUSIONS: Clinical symptoms, post-challenge BHR and increased NL eosinophil counts confirmed a positive response to SICT and validated the diagnosis of cough-variant occupational asthma. SICT may be useful in cases where history and clinical data suggest cough-variant asthma and spirometric indices are negative. PMID- 25530077 TI - Clinical, environmental, and serologic surveillance studies of melioidosis in Gabon, 2012-2013. AB - Burkholderia pseudomallei, an environmental gram-negative bacillus, is the causative agent of melioidosis and a bio-threat agent. Reports of B. pseudomallei isolation from soil and animals in East and West Africa suggest that melioidosis might be more widely distributed than previously thought. Because it has been found in equatorial areas with tropical climates, we hypothesized that B. pseudomallei could exist in Gabon. During 2012-2013, we conducted a seroprevalance study in which we set up microbiology facilities at a large clinical referral center and prospectively screened all febrile patients by conducting blood cultures and testing for B. pseudomallei and related species; we also determined whether B. pseudomallei could be isolated from soil. We discovered a novel B. pseudomallei sequence type that caused lethal septic shock and identified B. pseudomallei and B. thailandensis in the environment. Our data suggest that melioidosis is emerging in Central Africa but is unrecognized because of the lack of diagnostic microbiology facilities. PMID- 25530079 TI - Post-traumatic stress disorder among bank employee victims of robbery. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) in the occupational context, especially following workplace robbery, is still under-investigated. AIMS: To evaluate PTSD incidence and risk factors among bank employee victims of robbery voluntarily joining an employer-sponsored post-robbery support programme. METHODS: The programme entailed a structured support interview with robbery victims within 15 days of the robbery and a follow-up psychological assessment 45 days after. A self-reported questionnaire on personal variables and robbery characteristics was administered to participants at the first support session (T1). Interviews on employees' psychophysical health and their opinion about the support programme were administered individually at follow-up (T2). The Impact of Event Scale (IES) was administered both at T1 and T2. RESULTS: There were 383 participants. At T2, 13% of subjects had an IES score >34, a cut-off suggestive of PTSD. In a multi-variate model, feelings of helplessness and terror during the robbery and the number of previous robberies were associated with a PTSD diagnosis. After including IES score at T1, other variables lost statistical significance. CONCLUSIONS: Our findings showed that PTSD is common among employee victims of workplace robbery. Our results also suggest the importance of subjective variables, such as personal perception of robbery severity and early emotional reaction, in identifying people at higher risk of developing PTSD. PMID- 25530080 TI - Resection of calcified aortic heart leaflets in vitro by Q-switched 2 um microsecond laser radiation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) can result in paravalvular leakage and stent deformation in the presence of severe calcification. This study was undertaken to determine the efficacy of laser assisted resection of calcific aortic valve leaflets as a method to minimize the effects of calcium on perivalvular leakage during TAVI. METHODS: A Q-switched Tm:YAG laser emitting at a wavelength of 2.01 MUm was used to evaluate the cutting efficiency on highly calcified human aortic leaflets in vitro (N = 10). A pulse energy of 4.3 mJ, a pulse duration of 0.8-1 MUs, and a repetition rate of 1 kHz were used. The radiation was transmitted via a 200 um core diameter quartz fiber. Resection was performed in a fiber-tissue contact mode on water-covered samples in a dish. The remnant particles were analyzed with respect to quantity and size by light microscopy. RESULTS: A resection rate of 40.4 +/- 22.2 mg/min on highly calcified aortic leaflets was achieved. This corresponds to a cutting speed of approximately 1 cm/min; a laser dissection time of 3 min per leaflet is expected. The majority of the remnant particles (85.4%) were <6 MUm in diameter, with only 0.1% exceeding 300 MUm. CONCLUSIONS: The Q-switched Tm:YAG laser system showed promising results in cutting calcified aortic valves, by transmitting sufficient energy through a small flexible fiber. Catheter-based removal of aortic valve calcification may help to improve TAVI technology. PMID- 25530081 TI - Screening for neuropathic characteristics in failed back surgery syndromes: challenges for guiding treatment. AB - OBJECTIVE: Neuropathic pain screening tools have shown promise in identifying common neuropathic pain characteristics that derive from diverse etiologies (e.g., diabetic peripheral neuropathy, postherpetic neuralgia). However, no prior studies have specifically assessed whether these tools are capable of discerning the underlying pain mechanisms in the vast, heterogeneous group of patients diagnosed with failed back surgery syndrome (FBSS). DESIGN: In this clinical observational study, two tests for neuropathic pain characteristics, the Douleur Neuropathique en 4 (DN4) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaires, were performed on 43 subjects with FBSS. Subjects underwent physical or neurosensory exam components of the DN4 and LANSS in the region of most severe pain (e.g., axial low back or lower extremities). DN4 and LANSS scores were correlated with clinical history and neurologic exam, pain related quality of life questionnaires, and compared to an independent assessment of pain distribution. RESULTS: The presence of neuropathic characteristics, determined by the DN4 (62% sensitivity, 44% specificity), LANSS (38% sensitivity, 75% specificity; cut-offs of 4 and 12, respectively), or their combination (20% sensitivity, 58% specificity) was associated with higher pain intensity as measured by the visual analog scale (DN4 > 4, P = 0.001; LANSS >= 12, P = 0.042), modified Brief Pain Inventory-Short Form (DN4 > 4, P = 0.001; LANSS >= 12, P = 0.082), and Neuropathic Pain Symptom Inventory (DN4 > 4, P = 0.001; LANSS >= 12, P = 0.001), and greater pain-related functional impairment as measured by the Roland-Morris Disability Questionnaire (DN4 > 4, P = 0.006; LANSS >= 12, P = 0.018). The percentage of subjects characterized as neuropathic by the DN4 and LANSS lacked concordance (67.4 vs. 25.6), and the distribution of most severe symptoms (i.e., axial vs radicular) did not correlate with subjects determined to have neuropathic pain. CONCLUSIONS: Unlike other neuropathic syndromes, the neuropathic component of FBSS is less reliably identified by the LANSS and DN4. PMID- 25530082 TI - Recombinant renewable polyclonal antibodies. AB - Only a small fraction of the antibodies in a traditional polyclonal antibody mixture recognize the target of interest, frequently resulting in undesirable polyreactivity. Here, we show that high-quality recombinant polyclonals, in which hundreds of different antibodies are all directed toward a target of interest, can be easily generated in vitro by combining phage and yeast display. We show that, unlike traditional polyclonals, which are limited resources, recombinant polyclonal antibodies can be amplified over one hundred million-fold without losing representation or functionality. Our protocol was tested on 9 different targets to demonstrate how the strategy allows the selective amplification of antibodies directed toward desirable target specific epitopes, such as those found in one protein but not a closely related one, and the elimination of antibodies recognizing common epitopes, without significant loss of diversity. These recombinant renewable polyclonal antibodies are usable in different assays, and can be generated in high throughput. This approach could potentially be used to develop highly specific recombinant renewable antibodies against all human gene products. PMID- 25530083 TI - The effect of iron in MRI and transverse relaxation of amyloid-beta plaques in Alzheimer's disease. AB - Dysregulation of neural iron is known to occur during the progression of Alzheimer's disease. The visualization of amyloid-beta (Abeta) plaques with MRI has largely been credited to rapid proton relaxation in the vicinity of plaques as a result of focal iron deposition. The goal of this work was to determine the relationship between local relaxation and related focal iron content associated with Abeta plaques. Alzheimer's disease (n=5) and control tissue (n=3) sample slices from the entorhinal cortex were treated overnight with the iron chelator deferoxamine or saline, and microscopic gradient-echo MRI datasets were taken. Subsequent to imaging, the same slices were stained for Abeta and iron, and then compared with regard to parametric R2 * relaxation maps and gradient-echo weighted MR images. Abeta plaques in both chelated and unchelated tissue generated MR hypo-intensities and showed relaxation rates significantly greater than the surrounding tissue. The transverse relaxation rate associated with amyloid plaques was determined not to be solely a result of iron load, as much of the relaxation associated with Abeta plaques remained following iron chelation. The data indicate a dual relaxation mechanism associated with Abeta plaques, such that iron and plaque composition synergistically produce transverse relaxation. PMID- 25530084 TI - New perspectives for leishmaniasis chemotherapy over current anti-leishmanial drugs: a patent landscape. AB - INTRODUCTION: Although leishmaniasis is estimated to cause the ninth largest disease burden among individual infectious diseases, it is still one of the most neglected diseases in terms of drug development. Current drugs are highly toxic, resistance is common and compliance of patients to treatment is low, as treatment is long and drug price is high. AREAS COVERED: In this review, the authors carried out a patent landscape in search for new perspectives for leishmaniasis therapy. This search encompassed patent documents having priority date between 1994 and 2014. Selected compounds were compared to current anti-leishmanial drugs regarding efficacy and toxicity, when experimental data were available. EXPERT OPINION: Most patents related to drugs for leishmaniasis have not been produced by the pharmaceutical industry but rather by public research institutes or by universities, and the majority of the inventions disclosed are still in preclinical phase. There is an urgent need to find new ways of funding research for leishmaniasis drugs, incentivizing product development partnerships and pushing forward innovation. PMID- 25530085 TI - Clinical phenotype of APOL1 nephropathy in young relatives of patients with end stage renal disease. AB - BACKGROUND: Two coding variants--G1 and G2--in the apolipoprotein L-1 (APOL1) gene are associated with increased incidence of end-stage renal disease (ESRD) in the adult African American population. These variants associate with hypertension attributed renal disease, focal segmental glomerulosclerosis (FSGS), and HIV associated nephropathy. We hypothesized that as a genetic disease, APOL1 nephropathy has a pediatric phenotype. METHODS: We investigated the incidence of APOL1 variants in young African Americans with hypertension or FSGS and a family history of ESRD by conducting a case-control study of 93 pediatric and young adult African Americans with hypertension or FSGS to determine the association with APOL1 risk variants, G1, and G2 using custom-made TaqMan-based allelic discrimination assays. RESULTS: Forty of the 61 cases (66 %) with a family history of kidney disease had two APOL1 risk variants, significantly higher than the prevalence in controls and the general African American population (p < 0.001); 24 of 29 patients with hypertension-attributed kidney disease had two APOL1 risk variants, while none of nine hypertensive patients without kidney disease had more than one risk allele. CONCLUSIONS: Although it was a small study cohort, our findings strongly suggest for the first time that two APOL1 risk alleles in young hypertensive African Americans with a family history of ESRD are strongly associated with kidney disease. PMID- 25530086 TI - Virulence and in planta movement of Xanthomonas hortorum pv. pelargonii are affected by the diffusible signal factor (DSF)-dependent quorum sensing system. AB - Xanthomonas hortorum pv. pelargonii (Xhp), the causal agent of bacterial blight in pelargonium, is the most threatening bacterial disease of this ornamental worldwide. To gain an insight into the regulation of virulence in Xhp, we have disrupted the quorum sensing (QS) genes, which mediate the biosynthesis and sensing of the diffusible signal factor (DSF). Mutations in rpfF (encoding the DSF synthase) and rpfC (encoding the histidine sensor kinase of the two-component system RfpC/RpfG) and overexpression of rpfF showed a significant reduction in incidence and severity of the disease on pelargonium. Confocal laser scanning microscopy images of inoculated plants with a green fluorescent protein (GFP) labelled wild-type strain showed that the pathogen is homogeneously dispersed in the lumen of xylem vessels, reaching the apex and invading the intercellular spaces of the leaf mesophyll tissue within 21 days. In contrast, the rpfF and rpfC knockout mutants, as well as the rpfF-overexpressing strain, remained confined to the vicinity of the inoculation site. The rpfF and rpfC mutants formed large incoherent aggregates in the xylem vessels that might interfere with upward movement of the bacterium within the plant. Both mutants also formed extended aggregates under in vitro conditions, whereas the wild-type strain formed microcolonies. Expression levels of putative virulence genes in planta were substantially reduced within 48 h after inoculation with the QS mutants when compared with the wild-type. The results presented indicate that an optimal DSF concentration is crucial for successful colonization and virulence of Xhp in pelargonium. PMID- 25530087 TI - A look into the future of cardiology: perspectives from the Montreal Heart Institute. PMID- 25530088 TI - An Examination of the Interpersonal Psychological Theory of Suicidal Behavior in Physicians. AB - Physicians are commonly reported to die by suicide more frequently than individuals in the general population. Thus far, few reasons for this elevated suicide risk have been empirically investigated. Although the interpersonal psychological theory of suicidal behavior (IPTS) has been suggested as a fruitful means of explaining physician suicidality, it has yet to be examined quantitatively. Four hundred nineteen Pennsylvania physicians were assessed on a number of demographics, as well as all components of the IPTS. Findings indicated that physician scores on IPTS components are comparable to other groups displaying increased suicidality (e.g., military populations, prior attempters). Perceived burdensomeness was a significant predictor of suicidal ideation, while thwarted belongingness predicted prior suicide attempts. Acquired capability did not distinguish between prior attempters and nonattempters. Preliminary findings indicate the IPTS may be a useful framework for understanding and predicting physician suicidality. PMID- 25530089 TI - Evolution and impact of ventricular assist device program on children awaiting heart transplantation. AB - BACKGROUND: We sought to evaluate the impact of the evolution of a pediatric mechanical circulatory support (MCS) program on outcomes of children listed for heart transplantation at our institution. METHODS: All patients listed for isolated heart transplantation from 1995 to 2013 were included. The use of MCS while on the wait-list was recorded. Wait-list and posttransplant outcomes were compared before and after 2005, which was when we became capable of providing long-term MCS without size limitation. RESULTS: In total, 259 patients were listed for transplant and 201 (78%) reached transplant. The use of MCS was significantly increased between the eras (13% and 37%, p = 0.0001). Wait-list mortality was significantly decreased (25% and 11%, p = 0.0006). Among transplant recipients, the proportion of patients who underwent MCS was significantly increased (13% and 37%, p = 0.0002). Of these MCS patients, the use of long-term devices was significantly increased (50% and 98%, p = 0.0004). Median duration of MCS was significantly increased (12 and 78 days, p = 0.004). Kaplan-Meier estimates showed a trend (p = 0.08) toward improved survival after bridge-to transplant both at 1 year (70% in the early era and 88% in the late era) and at 5 years (60% and 78%, respectively). CONCLUSIONS: Outcomes of pediatric heart transplantation have significantly improved over the last 2 decades. We believe such improvement is, at least in part, attributable to maturation of MCS strategy, characterized by avoiding the use of temporary devices such as extracorporeal membrane oxygenation as a bridge-to-transplant and a more aggressive use of long-term devices. PMID- 25530090 TI - Audit of lymphadenectomy in lung cancer resections using a specimen collection kit and checklist. AB - BACKGROUND: Audits of operative summaries and pathology reports reveal wide discordance in identifying the extent of lymphadenectomy performed (the communication gap). We tested the ability of a prelabeled lymph node specimen collection kit and checklist to narrow the communication gap between operating surgeons, pathologists, and auditors of surgeons' operation notes. METHODS: We conducted a prospective single cohort study of lung cancer resections performed with a lymph node collection kit from November 2010 to January 2013. We used the kappa statistic to compare surgeon claims on a checklist of lymph node stations harvested intraoperatively with pathology reports and an independent audit of surgeons' operative summaries. Lymph node collection procedures were classified into four groups based on the anatomic origin of resected lymph nodes: mediastinal lymph node dissection, systematic sampling, random sampling, and no sampling. RESULTS: From the pathology reports, 73% of 160 resections had a mediastinal lymph node dissection or systematic sampling procedure, 27% had random sampling. The concordance with surgeon claims was 80% (kappa statistic 0.69, 95% confidence interval: 0.60 to 0.79). Concordance between independent audits of the operation notes and either the pathology report (kappa 0.14, 95% confidence interval: 0.04 to 0.23) or surgeon claims (kappa 0.09, 95% confidence interval: 0.03 to 0.22) was poor. CONCLUSIONS: A prelabeled specimen collection kit and checklist significantly narrowed the communication gap between surgeons and pathologists in identifying the extent of lymphadenectomy. Audit of surgeons' operation notes did not accurately reflect the procedure performed, bringing its value for quality improvement work into question. PMID- 25530091 TI - Single ventricle palliation in low weight patients is associated with worse early and midterm outcomes. AB - BACKGROUND: While low weight is an established risk factor for operative mortality after single ventricle (SV) palliation, its influence on late outcomes is not well understood. We examined current-era effects of low weight at time of surgery on hospital mortality, progression through palliative stages, and survival. METHODS: Five hundred and thirty infants with SV underwent first-stage palliation (2002 to 2012). Competing risk analysis modeled events after initial surgery and after Glenn. Regression models examined the effect of low weight 2.5 kg or less (n = 77 of 530, 14.5%) on early and late outcomes. RESULTS: Initial palliation was Norwood (n = 284, 54%), modified Blalock-Taussig shunt (n = 173, 33%), and pulmonary artery band (n = 73, 14%). Competing risk analysis showed that at 6 months after initial palliation the proportion of patients who had died or received transplantation was 40% in patients 2.5 kg or less and 20% in patients greater than 2.5 kg (p < 0.001). Consequently, the proportion of patients who had progressed to Glenn was 33% in patients 2.5 kg or less and 59% in patients greater than 2.5 kg (p < 0.001). Subsequent to Glenn, progression toward Fontan was unaffected by initial weight. In addition to increased hospital mortality (odds ratio 1.86, 95% confidence interval [CI] 0.93% to 3.70%, p = 0.08); adjusted hazard analysis showed that weight 2.5 kg or less was associated with diminished late survival (hazard ratio 1.65, 95% CI 1.085% to 2.53%, p = 0.02) and that was evident for all palliation types and most SV morphologies. CONCLUSIONS: Low weight at time of first-stage SV palliation is associated with an increase in both hospital mortality and interstage attrition, with subsequently fewer patients progressing toward the Glenn operation. The increased death hazard in low weight SV patients persists for almost 1 year after initial palliation, suggesting the need for more vigilant monitoring and out-patient care in those high-risk patients. PMID- 25530092 TI - IgA deficiency in wolves from Canada and Scandinavia. AB - Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in both humans and selected breeds of domestic dogs. In both species, IgAD is associated with recurrent infections and immune mediated diseases. Previous results imply that IgAD is also common in the wild ancestor of domestic dogs, the gray wolf. Here, we report that serum IgA concentrations are significantly different in Scandinavian and Canadian wolves (p = 3.252e-15) with an increased prevalence for IgAD in Scandinavian wolves (60%), which is as high as those found in high-risk dog breeds. PMID- 25530093 TI - Identification of a c-Jun homolog from Litopenaeus vannamei as a downstream substrate of JNK in response to WSSV infection. AB - c-Jun, a major substrate of c-Jun N-terminal kinase (JNK), participates in regulating gene transcription in response to various stimuli, including cytokines, stress signals, bacterial and viral infection. Results from our previous studies suggested that Litopenaeus vannamei JNK (LvJNK) could be utilized by white spot syndrome virus (WSSV) to facilitate viral replication and gene expression. In this article, a c-Jun homolog from Litopenaeus vannamei (designated as Lvc-Jun) was cloned and its role in WSSV infection was studied. Sequence analysis displayed that Lvc-Jun was a novel homolog of c-Jun family, which contained characteristic Jun and basic leucine zipper (bZIP) domains, and two conserved serine phosphorylation sites (Ser49/59). Semi-quantitative RT-PCR analysis showed that Lvc-Jun mRNAs were expressed in all examined tissues. Further investigation determined that Lvc-Jun was located in the nucleus through self-interaction and its phosphorylation levels could be reduced by JNK inhibitor, suggesting that Lvc-Jun could be regulated by LvJNK through phosphorylation and function as a transcription regulator in a homodimer. During the process of WSSV infection, the transcription levels of Lvc-Jun were up regulated associating with the raising expression and phosphorylation levels of its protein. Moreover, TPA (12-O-tetradecanoylphorbol-13-acetate), a potent inducer of c-Jun, could remarkably promote viral immediate-early gene wsv069 transcription in crayfish hemocytes. Conclusively, our results provided experimental evidences that Lvc-Jun was engaged in WSSV infection and further implied that JNK-c-Jun signaling pathway might be important for WSSV replication and viral gene expression. PMID- 25530094 TI - The Megalobrama amblycephala transferrin and transferrin receptor genes: molecular cloning, characterization and expression during early development and after Aeromonas hydrophila infection. AB - Both transferrin (TF) and transferrin receptor (TFR) play vital roles in iron homeostasis, which is essential for cellular growth and survival. Besides, TF and TFR are also reported to be involved in immune response against bacterial infection. In the present study, we cloned and characterized the Tf and TfR genes in Megalobrama amblycephala. The M. amblycephala Tf gene contained 17 exons and 16 introns, encoding 651 amino acids, while the M. amblycephala TfR gene contained 18 exons and 17 introns, encoding 768 amino acids. In healthy fish, Tf mRNA was most abundant in the liver, and TfR was highly expressed in the blood and brain. During early development, the expression of Tf increased from 12 hpf (hour post fertilization) to 26 hpf, followed by a diminution at 32 hpf, then increased significantly to the peak level at 2 dph (day post hatching). The expression pattern of TfR was similar to that of Tf, fluctuating from 0 hpf to 32 hpf and dramatically increasing to the peak at 2 dph. Additionally, both Tf and TfR genes responded to Aeromonas hydrophila infection, by increasing their expression in the liver, spleen and kidney at both mRNA and protein levels, indicating that they were involved in M. amblycephala immune response. Immunohistochemical analysis and Prussian blue staining verified the internalization of TF-receptor system with bound-iron in the liver of M. amblycephala. PMID- 25530095 TI - Evolution of the complement system in protostomes revealed by de novo transcriptome analysis of six species of Arthropoda. AB - To elucidate the evolutionary history of the complement system in Arthropoda, de novo transcriptome analysis was performed with six species among the Chelicerata, Myriapoda, and Crustacea, and complement genes were identified based on their characteristic domain structures. Complement C3 and factor B (FB) were identified from a sea spider, a jumping spider, and a centipede, but not from a sea firefly or two millipede species. No additional complement components identifiable by their characteristic domain structures were found from any of these six species. These results together with genome sequence information for several species of the Hexapoda suggest that the common ancestor of the Arthropoda possessed a simple complement system comprising C3 and FB, and thus resembled the alternative pathway of the mammalian complement system. It was lost at least twice independently during the evolution of Arthropoda in the millipede lineage and in the common ancestor of Crustacea and Hexapoda. PMID- 25530096 TI - Late-onset primary antiphospholipid syndrome in the elderly: a report of seven cases. AB - AIM: We describe the clinical profile of elderly with primary antiphospholipid syndrome (APS). METHODS: Charts of seven elderly patients diagnosed with APS between 1996 and 2012 were retrospectively assessed. RESULTS: The mean age at diagnosis was 77 +/- 6 years (67-84 years). Two patients had experienced frequent miscarriages. Five patients presented with deep venous thrombosis of the lower limb, one had venous thrombosis of the upper limb and brachiocephalic vein and another had a cerebral ischemic stroke. The antiphospholipid antibodies tests revealed the presence of significant amounts of anticardiolipin antibodies, 12 weeks apart, twice in four patients. The antibodies to beta2-glycoprotein 1 were positive twice in two patients and lupus anticoagulant in one of these. All patients were treated with heparin and long-term anti-vitamin K and thrombosis was cleared in all cases. Two patients presented with bleeding complications: hematuria and hematoma of the buttock in one patient and rectal bleeding in another case. Two elderly developed a colon cancer and lymphoma 1 year later. CONCLUSION: In this report, we report on primary APS in the elderly, to discuss its prevalence and the clinical significance of positive antiphospholipid antibodies in subjects over the age of 65 years. PMID- 25530097 TI - Myocardial bridging: a review with emphasis on electrocardiographic findings. AB - BACKGROUND: Myocardial bridging (MB) occurs when a segment of an epicardial coronary artery takes an intra- myocardial course, thus leading to systolic compression. Most myocardial bridges involve the left anterior descending artery and are observed in 14-35% of patients. Different pathophysiological mechanisms can induce symptoms secondary to myocardial ischemia: systolic coronary compression, diastolic dysfunction associated with aging and coronary atherosclerosis, LV hypertrophy, vasospasm, microvascular and endothelial dysfunction, plaque development proximal to the bridge. METHODS: We performed a literature review of MB, with a particular emphasis on electrocardiographic manifestations. RESULTS: Stable angina-like chest pain is the usual presentation and MB should be suspected in patients at low risk for coronary atherosclerosis which refer this symptom or which present myocardial ischemia at instrumental examinations. ECG changes are not specific for MB and resting ECG is often normal or presents ST segment anomalies. Exercise stress test often shows non specific signs of ischemia, conduction disturbances or arrhythmias which do not allow the distinction between myocardial bridging and other causes of myocardial ischemia; angina often appears during exercise, even in the absence of ECG changes. Myocardial perfusion deficits at scintigraphy are neither obligatory nor specific. Although the clinical significance of MB is still debated, MB has been associated with acute coronary syndrome, coronary vasospasm, and even sudden cardiac death. CONCLUSION: Although MB may lead to myocardial ischemia during stress, its clinical presentation and electrocardiographic findings are not specific. PMID- 25530098 TI - Shikonin, dually functions as a proteasome inhibitor and a necroptosis inducer in multiple myeloma cells. AB - Shikonin (SHK), a natural small agent (MW 288.3), reportedly induces cell death in various tumor cells. We have found that SHK also exerts potent cytocidal effects on human multiple myeloma (MM) cells, but its anticancer mechanism in MM cells remains to be elucidated. SHK at 2.5-5 uM induced apoptosis in seven MM cell lines, including the bortezomib-resistant cell line KMS11/BTZ. The IC50 value of SHK against KMS11/BTZ was comparable to that of a parental cell line KMS11 (1.1 and 1.56 uM, respectively). SHK induces accumulation of ubiquitinated proteins and activates XBP-1 in MM cells, suggesting that SHK functions as a proteasome inhibitor, eventually inducing ER stress-associated apoptosis. SHK increases levels of HSP70/72, which protects cells from apoptosis, and exerts greater cytocidal effects in combination with the HSP70/72 inhibitor VER-155008. At higher concentrations (10-20 uM), SHK induced cell death, which was completely inhibited by a necroptosis inhibitor, necrostatin-1 (Nec-1), while the cytocidal activity was unaffected by Z-VAD-FMK, strongly suggesting that cell death is induced by SHK at high concentrations through necroptosis. The present data show for the first time that SHK induces cell death in MM cells. SHK efficiently induces apoptosis and combination of heat shock protein inhibitor with low dose SHK enhances apoptosis, while high dose SHK induces necroptosis in MM cells. These findings together support the use of SHK as a potential therapeutic agent for MM. PMID- 25530099 TI - Spatial control of cell gene expression by siRNA gradients in biodegradable hydrogels. AB - The extracellular environment exposes cells to numerous biochemical and physical signals that regulate their behavior. Strategies for generating continuous gradients of signals in biomaterials may allow for spatial control and patterning of cell behavior, and ultimately aid in the engineering of complex tissues. Short interfering RNA (siRNA) can regulate gene expression by silencing specific mRNA molecules post-transcriptionally, which may be valuable when presented in a continuous gradient for regenerative or therapeutic applications. Here, a biodegradable hydrogel system containing a gradient of siRNA is presented, and its capacity to regulate protein expression of encapsulated cells in a spatially continuous manner is demonstrated. Photocross-linkable dextran hydrogels containing a gradient of siRNA have been successfully fabricated using a dual programmable syringe pump system, and differential gene silencing in incorporated cells that is sustained over time has been shown using green fluorescent protein as a reporter. This platform technology may be applied in tissue engineering to spatially control biologically relevant cellular processes. PMID- 25530100 TI - Author response to letter to the editor: response to commentary titled "Global family planning metrics--time for new definitions". PMID- 25530101 TI - Response to commentary titled "Global family planning metrics--time for new definitions". PMID- 25530102 TI - Which young adults are most likely to use withdrawal? The importance of pregnancy attitudes and sexual pleasure. AB - OBJECTIVES: Use of withdrawal (coitus interruptus) has consequences for reproductive health, but few nationally representative studies exist. We (1) examined patterns of withdrawal among 15- to 24-year-old women and men, and (2) explored withdrawal's associations with sociodemographic, psychological, and sexual factors. STUDY DESIGN: Using data from the 2006-2010 National Survey of Family Growth, we assessed reports of any and only withdrawal use at last sexual episode in the last month from 3517 sexually active 15 to 24 year-old women and men at risk of unintended pregnancy. Logistic regression documented associations with withdrawal. RESULTS: Fourteen percent of young women and 17% of young men reported any use of withdrawal at last sex; 7% and 6%, respectively, reported only use of withdrawal. Though associated with few sociodemographic factors, withdrawal was significantly linked with pregnancy- and condom attitudes. In regression models, compared to those who said they would be upset if they discovered they were pregnant, young women who said they would be pleased about a pregnancy were 2.2-2.6 times as likely to have used any/only withdrawal (p<.01). For both women and men, those who felt that condoms were likely to diminish sexual pleasure were more likely to have used any/only withdrawal (odds ratio=1.8 2.6, p<.05). CONCLUSIONS: At their last sexual episode, a greater proportion of young adults used withdrawal in conjunction with other methods than by itself. The psychological and sexual variables of orientation toward pregnancy and attitudes about condoms and pleasure were more strongly linked with withdrawal practices than most sociodemographic variables. IMPLICATIONS STATEMENT: Since a substantial minority of young adults use withdrawal, providers may wish to speak directly to contraceptive clients about this method, though they should distinguish between only versus any withdrawal use. Practitioners may also be well served by assessing and responding to pregnancy orientation and pleasure attitudes in contraceptive counseling. PMID- 25530103 TI - Thyminate(2-)-bridged cyclic tetranuclear rhodium(III) complexes formed by a template of a sodium, calcium or lanthanoid ion. AB - In the thyminate(2-)-bridged tetranuclear Cp*Rh(III) complexes incorporating a Na(+), Ca(2+) or Ln(3+) cation, homochiral aggregation of four Rh(III) centres was achieved to form metallacalix[4]arene-type clusters. The thyminate(2-) bridged two Rh(III) and the third metal ion with a MU3 1kappaN(1):2kappa(2)N(3),O(2):3kappaO(2) mode in the Na(+) and Ca(2+) complexes, while in the Ln(3+) analogues it exhibited a different bridging mode, MU3 1kappaN(1):2kappa(2)N(3),O(4):3kappaO(2). PMID- 25530104 TI - Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay. AB - Aflatoxin B1 (AFB1) and Ochratoxin A (OTA) are genotoxic mycotoxins that can contaminate a variety of foodstuffs, the liver and the kidney being their target organs, respectively. The micronucleus (MN) assay (bone marrow) and the comet assay (liver and kidney) were performed simultaneously in F344 rats, treated with AFB1 (0.25 mg/kg b.w.), OTA (0.5 mg/kg b.w.) or both mycotoxins. After AFB1 treatment, histopathology and biochemistry analysis showed liver necrosis, focal inflammation and an increase in Alanine Aminotransferase and Aspartate Aminotransferase. OTA alone did not cause any alteration. The acute hepatotoxic effects caused by AFB1 were less pronounced in animals treated with both mycotoxins. With regard to the MN assay, after 24 h, positive results were obtained for AFB1 and negative results were obtained for OTA, although both toxins caused bone marrow toxicity. In the combined treatment, OTA reduced the toxicity and the number of MN produced by AFB1. In the comet assay, after 3 h, positive results were obtained for AFB1 in the liver and for OTA in the kidney. The combined treatment reduced DNA damage in the liver and had no influence in the kidney. Altogether, these results may be indicative of an antagonistic relationship regarding the genotoxicity of both mycotoxins. PMID- 25530105 TI - Allergenic response to squid (Todarodes pacificus) tropomyosin Tod p1 structure modifications induced by high hydrostatic pressure. AB - The structural and allergenic modifications of tropomyosin Tod p1 (TMTp1) in fresh squids induced by high hydrostatic pressure (HHP) were investigated. The alpha-helix in TMTp1 decreased along with increasing pressure from 200 to 600 MPa, where almost 53% alpha-helix was converted into beta-sheet and random coils at 600 MPa. The free sulfhydryl group dropped significantly as pressure went up, but the surface hydrophobicity increased at 200 and 400 MPa, while it slightly decreased at 600 MPa. Based on in vitro gastrointestinal digestion test, digestibility of TMTp1 was promoted by HHP treatment, in which 400 and 600 MPa were more effective in reducing the allergenicity than 200 MPa based on indirect ELISA. This study suggested that HHP can decrease allergenicity of TMTp1 by protein unfolding and secondary structure modification, thus providing potential for alleviating allergenicity of squid. PMID- 25530106 TI - Peritoneal effluent MMP-2 and PAI-1 in encapsulating peritoneal sclerosis. AB - BACKGROUND: Recently, the use of effluent matrix metalloproteinase 2 (MMP-2) and plasminogen activator inhibitor 1 (PAI-1) as potential biomarkers of peritoneal fibrosis has been demonstrated during longitudinal follow-up of incident peritoneal dialysis (PD) patients. This study focuses on effluent MMP-2 and PAI-1 as early diagnostic markers in the preceding years of patients who develop encapsulating peritoneal sclerosis (EPS). STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: PD patients who developed EPS were compared with controls using a 1:3 case-control design with a minimum PD duration of 57 months. INDEX TESTS: Dialysate appearance rates of MMP-2 and PAI-1. REFERENCE TEST: EPS cases identified by 2 experienced nephrologists and a radiologist based on predefined criteria. RESULTS: 11 patients developed EPS within our center. The time course of MMP-2 appearance rates, studied by means of a linear repeated measures model 4 years prior to the diagnosis of EPS, showed no difference between long-term controls and patients with EPS. In contrast, higher PAI-1 appearance rates were found in patients with EPS compared with controls (P=0.01). At a lag time of 1 year prior to EPS diagnosis, time-specific receiver operating characteristic curve analyses indicated a discriminative ability for PAI-1 appearance rate of 0.77 (95% CI, 0.63-0.91). A discriminative capacity was absent for those of MMP-2. LIMITATIONS: Low event rate of EPS prevented independent validation in this single-center study. CONCLUSIONS: Elevated levels of PAI-1 appearance rates are present in patients who develop EPS, pointing to progressive peritoneal fibrosis and sclerosis. The PAI-1 appearance rate has fair discriminative capacity from 3 years prior to EPS diagnosis. Therefore, effluent PAI-1 may aid in monitoring peritoneal fibrosis and serve as a biomarker for EPS. PMID- 25530107 TI - Effect of low versus high dialysate sodium concentration on blood pressure and endothelial-derived vasoregulators during hemodialysis: a randomized crossover study. AB - BACKGROUND: Intradialytic hypertension affects ~15% of hemodialysis patients and is associated with increased morbidity and mortality. While intradialytic hypertension is associated with increases in endothelin 1 relative to nitric oxide (NO), the cause of these imbalances is unknown. In vitro evidence suggests that altering plasma sodium levels could affect endothelial-derived vasoregulators and blood pressure (BP). Thus, we hypothesized that compared to high dialysate sodium, low dialysate sodium concentration would lower endothelin 1 levels, increase NO release, and reduce BP. STUDY DESIGN: 3-week, 2-arm, randomized, crossover study. SETTING & PARTICIPANTS: 16 patients with intradialytic hypertension. INTERVENTION: Low (5 mEq/L below serum sodium) versus high (5 mEq/L above serum sodium) dialysate sodium concentration. OUTCOMES: Endothelin 1, nitrite (NO2(-)), and BP. MEASUREMENTS: Mixed linear regression was used to compare the effect of dialysate sodium (low vs high) and randomization arm (low-then-high vs high-then-low) on intradialytic changes in endothelin 1, NO2(-), and BP values. RESULTS: The average systolic BP throughout all hemodialysis treatments in a given week was lower with low dialysate sodium concentrations compared with treatments with high dialysate sodium concentrations (parameter estimate, -9.9 [95% CI, -13.3 to -6.4] mm Hg; P < 0.001). The average change in systolic BP during hemodialysis also was significantly lower with low vs high dialysate sodium concentrations (parameter estimate, -6.1 [95% CI, -9.0 to -3.2] mm Hg; P < 0.001). There were no significant differences in intradialytic levels of endothelin 1 or NO2(-) with low vs high dialysate sodium concentrations. LIMITATIONS: Carryover effects limited the power to detect significant changes in endothelial-derived vasoregulators, and future studies will require parallel trial designs. CONCLUSIONS: Low dialysate sodium concentrations significantly decreased systolic BP and ameliorated intradialytic hypertension. Longer studies are needed to determine the long-term effects of low dialysate sodium concentrations on BP and clinical outcomes. PMID- 25530108 TI - Eculizumab for treatment of rapidly progressive C3 glomerulopathy. AB - C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. Rapidly progressive forms of C3G usually respond poorly to conventional treatments. We report on the efficacy of the terminal complement inhibitor eculizumab in 3 adult patients with rapidly progressive C3G. In all 3 patients, serum creatinine levels had increased by >50% in the 2 months preceding initiation of eculizumab treatment despite the use of conventional immunosuppressive drugs and/or plasma exchanges in 2 of these individuals. Of note, 2 patients had long-standing nephrotic syndrome. Kidney biopsy performed prior to eculizumab treatment disclosed marked glomerular inflammatory changes and increased C5b-9 deposition in all patients. Eculizumab use was associated with significant improvement in kidney function, with estimated glomerular filtration rates of patients increasing 22 to 38 mL/min/1.73 m(2). Eculizumab use also was associated with remission of nephrotic syndrome in the 2 affected patients, an effect observed as early as one week after treatment initiation. Repeat kidney biopsy disclosed regression of glomerular inflammatory changes and decreases in glomerular staining for C5b-9 in all patients. These results warrant further assessment of eculizumab for treatment of rapidly progressive forms of C3G with markedly increased glomerular C5b-9 deposits. PMID- 25530109 TI - Biogeography of Fusarium graminearum species complex and chemotypes: a review. AB - Differences in the geographic distribution of distinct trichothecene mycotoxins in wheat and barley were first recorded two decades ago. The different toxicological properties of deoxynivalenol (DON), nivalenol (NIV) and their acetylated derivatives require careful monitoring of the dynamics of these mycotoxins and their producers. The phylogenetic species concept has become a valuable tool to study the global occurrence of mycotoxin-producing Fusarium species. This has revolutionised our views on the terrestrial distribution of trichothecene-producing Fusaria in the context of agronomics, climatic conditions, and human interference by the global trade and exchange of agricultural commodities. This paper presents an overview of the dynamics of the different trichothecene-producing Fusarium species as well as their chemotypes and genotypes across different continents. Clearly not one global population exists, but separate ones can be distinguished, sometimes even sympatric in combination with different hosts. A population with more pathogenic strains and chemotypes can replace another. Several displacement events appear to find their origin in the inadvertent introduction of new genotypes into new regions: 3 acetyl-DON-producing F. graminearum in Canada; 3-acetyl-DON-producing F. asiaticum in Eastern China; 15-acetyl-DON F. graminearum in Uruguay; and NIV producing F asiaticum in the southern United States. PMID- 25530110 TI - Permissive expansion and homing of adoptively transferred T cells in tumor bearing hosts. AB - Activated T cells expressing endogenous or transduced TCRs are two cell types currently used in clinical adoptive T-cell therapy. The ability of these cells to recognize their antigen, expand and traffic to the tumor site are the initial steps necessary for successful therapy. In this study, we used in vivo bioluminescent imaging (BLI) of Renilla luciferase (RLuc) expressing T cells to evaluate the ability of adoptively transferred T cells to survive, expand and home to tumor site in vivo. Using this method, termed RT-Rack (Rluc T cell tracking), we followed T-cell response against tumors in vivo. Expansion and homing of adoptively transferred T cells were antigen dependent, but independent of the host immune status. Moreover, we successfully detected T-cell response to small and large tumors, including autochthonous liver tumors. The adoptively transferred T cells were not ignorant or excluded in a partially tolerant host, which expressed low level of the target in the periphery. Using T cell receptor (TCR)-engineered T cells, we showed the ability of these cells to respond in tumor-bearing hosts by expanding and homing to the tumor site. In all these models, the host immune status, the nature of the tumor or of the antigen, the tumor size and the presence of the targeted antigen in the periphery did not prevent the adoptively transferred T cells from responding by expanding and homing to the tumor. However, T cells had higher expression of the inhibitory receptor PD1 and reduced functional activity when a self-antigen was targeted. PMID- 25530111 TI - Randomized clinical trial: effect of the 5-HT4 receptor agonist revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment. AB - BACKGROUND: Approximately, 20-30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI. METHODS: This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires. KEY RESULTS: In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed. CONCLUSIONS & INFERENCES: No clear differences were seen in reflux parameters between the placebo and revexepride groups. PMID- 25530112 TI - Brazilian porcupine quill injuries. PMID- 25530113 TI - Temporo-spatial gait parameters during street crossing conditions: a comparison between younger and older adults. AB - Most traffic accidents involving pedestrians happen during street crossing. Safe street crossing by older adults requires complex planning and imposes high cognitive demands. Understanding how street crossing situations affect younger and older adults' gait is important to create evidence-based policies, education and training. The objective of this study was to develop and test a method to evaluate temporo-spatial gait parameters of younger and older adults during simulated street crossing situations. Twenty-two younger (25+/-2 years old) and 22 older adults (73+/-6 years old) who lived independently in the community completed 3 walking trials at preferred gait speed and during simulated street crossing with regular and with reduced time. There were significant differences between groups (p<0.001) and conditions (p<0.001). Older adults' street crossing walking speed was higher than their preferred speed (p<0.001). Gait during simulated street crossing resulted in significant and progressive gait changes. The methods developed and tested can be used to (1) evaluate if people are at risk of falls and accidents during street crossing situations, (2) to compare among different groups, and (3) to help establish appropriate times for older pedestrians to cross streets safely. The current time to cross streets is too short even for healthy older adults. PMID- 25530114 TI - Do patients with knee osteoarthritis perform sit-to-stand motion efficiently? AB - The sit-to-stand motion (STS) is a frequently executed activity that is affected by weakness in the quadriceps femoris muscle and knee joint pain in patients with knee osteoarthritis (OA). We investigated whether patients with knee OA can efficiently perform STS through mechanical energy transfer assessments. Participants were 20 women with knee OA and 17 age-matched asymptomatic controls. The center of mass (COM), segment angles, joint moments, and powers during STS were measured. The negative mechanical work in the proximal portion of the shank, negative mean powers in the distal portion of the pelvis and proximal portion of the shank, and the positive mean power in the proximal and distal portions of the thigh were significantly lower in the knee OA group than in the control group. Patients with knee OA primarily performed thoracic forward lean movement, shifting their COM closer to the base of support provided by the feet alone, in an attempt to achieve stability at and after buttocks-off. However, control ability, which generates and absorbs kinetic energy quickly, was not enhanced in these patients, and their motion was unable to increase absorption of the mechanical energy in hip extensors and reduce the load on knee extensors. Furthermore, STS in patients with knee OA had reduced energy absorption in the knee extensors from the shank forward lean movement after buttocks-off, had reduced knee extensor efficiency, and made greater use of physiological energy. These findings suggest that, from the standpoint of mechanical energy transfer, patients with knee OA do not perform STS efficiently. PMID- 25530115 TI - The PDE4 inhibitor, apremilast, suppresses experimentally induced alopecia areata in human skin in vivo. PMID- 25530116 TI - Oculocutaneous albinism: developing novel antibodies targeting the proteins associated with OCA2 and OCA4. AB - BACKGROUND: Patients with oculocutaneous albinism (OCA) have severely decreased pigmentation of their skin, hair and eyes. OCA2 and OCA4 result from mutations of the OCA2 and SLC45A2 genes, respectively, both of which disrupt the trafficking of the critical melanogenic enzyme tyrosinase to melanosomes. Both proteins encoded by those loci (termed P and MATP, respectively) have 12 putative transmembrane regions and are thought to function as transporters, although their functions and subcellular localizations remain to be characterized. OBJECTIVE: To generate specific antibodies against unique synthetic peptides encoded by P and MATP that could be used to characterize their functions and subcellular localizations. METHODS: Western blotting and immunohistochemistry were used to assess the specificity of antibodies and to colocalize P and MATP proteins with various subcellular markers. RESULTS: Specific antibodies to the P and MATP proteins were generated that work well for Western blotting and immunohistochemistry. The localizations of P and MATP with various subcellular organelles were characterized using confocal microscopy, which revealed that they colocalize to some extent with LAMP2, but do not significantly colocalize with markers of the ER, Golgi or melanosomes. Interestingly, both P and MATP colocalize significantly with BLOC-1, a sorting component involved in the intracellular trafficking of melanosomal/lysosomal constituents. CONCLUSION: These results provide a basis to understand how disrupted functions of P or MATP result in the misrouting of tyrosinase and cause the hypopigmentation seen in OCA2 and OCA4. PMID- 25530117 TI - Real-time imaging of interaction between macrophages and lymphatic vessels in an in vitro model to study inflammatory resolution. PMID- 25530118 TI - Plectin-related skin diseases. AB - Plectin has been characterized as a linker protein that is expressed in many cell types and is distinctive in various isoforms in the N-terminus and around the rod domain due to complicated alternative splicing of PLEC, the gene encoding plectin. Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein. In addition, a point mutation in the rod domain of plectin leads to autosomal dominant EBS, called as EBS-Ogna. Plectin can be targeted by circulating autoantibodies in subepidermal autoimmune blistering diseases. This review summarizes plectin-related skin diseases, from congenital to autoimmune disorders. PMID- 25530119 TI - TIP30 inhibits oligodendrocyte precursor cell differentiation via cytoplasmic sequestration of Olig1. AB - Differentiation of oligodendrocyte precursor cells (OPCs) is a prerequisite for both developmental myelination and adult remyelination in the central nervous system. The molecular mechanisms underlying OPC differentiation remain largely unknown. Here, we show that the thirty-kDa HIV-1 Tat interacting protein (TIP30) is a negative regulator in oligodendrocyte development. The TIP30(-/-) mice displayed an increased myelin protein level at postnatal day 14 and 21. By using a primary OPC culture system, we demonstrated that overexpression of TIP30 dramatically inhibited the stage progression of differentiating OPCs, while knockdown of TIP30 enhanced the differentiation of oligodendroglial cells remarkably. Moreover, overexpression of TIP30 was found to sequester the transcription factor Olig1 in the cytoplasm and weaken its nuclear translocation due to the interaction between TIP30 and Olig1, whereas knockdown of TIP30 led to more Olig1 localized in the nucleus in the initiation stage during OPC differentiation. In the cuprizone-induced demyelination model, there was a dramatic increase in NG2-expressing cells with nuclear location of Olig1 in the corpus callosum during remyelination. In contrast, within chronic demyelinated lesions in multiple sclerosis, TIP30 was abnormally expressed in NG2-expressing cells, and few nuclear Olig1 was observed in these cells. Taken together, our findings suggest that TIP30 plays a negative regulatory role in oligodendroglial differentiation. PMID- 25530120 TI - Rapid Automatized Naming in Children with Dyslexia: Is Inhibitory Control Involved? AB - Rapid automatized naming (RAN) is widely seen as an important indicator of dyslexia. The nature of the cognitive processes involved in rapid naming is however still a topic of controversy. We hypothesized that in addition to the involvement of phonological processes and processing speed, RAN is a function of inhibition processes, in particular of interference control. A total 86 children with dyslexia and 31 normal readers were recruited. Our results revealed that in addition to phonological processing and processing speed, interference control predicts rapid naming in dyslexia, but in contrast to these other two cognitive processes, inhibition is not significantly associated with their reading and spelling skills. After variance in reading and spelling associated with processing speed, interference control and phonological processing was partialled out, naming speed was no longer consistently associated with the reading and spelling skills of children with dyslexia. Finally, dyslexic children differed from normal readers on naming speed, literacy skills, phonological processing and processing speed, but not on inhibition processes. Both theoretical and clinical interpretations of these results are discussed. PMID- 25530121 TI - Constraints on statistical computations at 10 months of age: the use of phonological features. AB - Recently, several studies have argued that infants capitalize on the statistical properties of natural languages to acquire the linguistic structure of their native language, but the kinds of constraints which apply to statistical computations remain largely unknown. Here we explored French-learning infants' perceptual preference for labial-coronal (LC) words over coronal-labial words (CL) words (e.g. preferring bat over tab) to determine whether this phonotactic preference is based on the acquisition of the statistical properties of the input based on a single phonological feature (i.e. place of articulation), multiple features (i.e. place and manner of articulation), or individual consonant pairs. Results from four experiments revealed that infants had a labial-coronal bias for nasal sequences (Experiment 1) and for all plosive sequences (Experiments 2 and 4) but a coronal-labial bias for all fricative sequences (Experiments 3 and 4), independently of the frequencies of individual consonant pairs. These results establish for the first time that constellations of multiple phonological features, defining broad consonant classes, constrain the early acquisition of phonotactic regularities of the native language. PMID- 25530122 TI - From gold nanobipyramids to nanojavelins for a precise tuning of the plasmon resonance to the infrared wavelengths: experimental and theoretical aspects. AB - Anisotropic gold nanoparticles and in particular with shapes exhibiting tips are known to present an extremely strong localized electromagnetic field. This field is mostly located at the top of the tips and can be used in various optical applications. Moreover, as a consequence of their anisotropy, they present two plasmon resonance bands corresponding to the transverse and longitudinal resonance modes. Tuning the aspect ratio it becomes possible to display SPR bands near the near infrared region. This was particularly investigated in the case of nanorods and also for bipyramids. In this paper we report a high yield synthesis approach that allows one to precisely control the aspect ratio of bipyramids and to elongate the structure until they adopt a javelin-like aspect. We were able to prepare nano-javelins with surface plasmon resonances up to 1850 nm, opening important perspectives in terms of optical applications in the NIR and IR regions. The synthetic methods are fully reported and the optical properties were correlated with the theoretical approach, taking into consideration not only the aspect ratio but also the truncation of the nano-objects. PMID- 25530123 TI - Characterization of three putative xylulose 5-phosphate/fructose 6-phosphate phosphoketolases in the cyanobacterium Anabaena sp. PCC 7120. AB - Xylulose 5-phosphate/fructose 6-phosphate phosphoketolase (Xfp) is a key enzyme in the central carbohydrate metabolism in heterofermentative bacteria, in which enzymatic property of Xfps is well characterized. This is not the case in other microbes. The cyanobacterium Anabaena sp. PCC 7120 possesses three putative genes encoding Xfp, all1483, all2567, and alr1850. We purified three putative Xfps as recombinant proteins. The results of gel filtration indicated that these proteins form homomultimer complex. All1483 and All2567 showed phosphoketolase activity, whereas Alr1850 did not show the activity. Kinetic analyses demonstrated that substrates, fructose 6-phosphate and inorganic phosphate, are cooperatively bound to enzymes positively and negatively, respectively. PMID- 25530124 TI - Effectiveness of the Nursing Methodology in Pain Management after Major Ambulatory Surgery. AB - Patients undergoing a surgical intervention for the first time are unfamiliar with the perioperative context, and they usually have no knowledge of postoperative pain management. In the preoperative circuit, there is no time to educate the patient in these terms. The professional profile of nurses allows this need to be addressed, and provides a regulated language to evaluate their effectiveness. This study evaluates the effectiveness of nursing counseling during a preoperative consultation for the management of postoperative pain and its effects on patient satisfaction at hospital discharge. This quasi experimental study assesses the efficacy of preoperative nursing intervention in two groups, control (n = 185) and intervention (n = 195). Those in the intervention group attended a preoperative session during which they received information from nursing staff and took part in activities to learn about postoperative pain management and the perioperative circuit. Control group patients underwent the standard preoperative protocol. Data were compiled from January to December 2009. Statistically significant differences existed between the two groups regarding postoperative pain (visual analogue scale >3, 20.5% versus 11.5%; p = .023), patient satisfaction (87.1% versus 78.7%; p = .041), and surgical wound complications (13.9% versus 5.5%; p = .010). The results confirm the benefits of applying the nursing methodology in preoperative clinics. PMID- 25530125 TI - Repeated sprint ability in young basketball players: one vs. two changes of direction (Part 1). AB - The present study aimed to compare the changes of direction on repeated sprint ability (RSA) vs. intensive repeated sprint ability (IRSA) protocols in basketball. Eighteen young male basketball players performed on RSA [10 * 30-m (15 + 15-m, one change of direction)] and IRSA [10 * 30-m (10 + 10 + 10-m, two changes of direction)]. A correlation matrix between RSA, IRSA, "squat jump (SJ) countermovement jump (CMJ)", footstep analysis and total distance in Yo-Yo intermittent recovery level 1 was performed. The best time, worst time, total time and the number of footsteps were significantly smaller in the RSA test compared to IRSA test (P < 0.001), even though they were significantly correlated with each other (r > 0.80, P < 0.05). Blood lactate level and fatigue index did not show any difference between tests. The sensibility of the two tests assessed by the Bland-Altman analysis revealed a small bias (<1.5%) for almost all variables. Moreover, almost all time variables of the two tests were significantly correlated with the SJ (r > 0.478, P < 0.05), CMJ (r > 0.515, P < 0.05) and Yo-Yo (r > 0.489, P < 0.05) performances. The IRSA provided a reliable method for assessing specific sprint ability (with 10-m legs for IRSA ~2.3 s vs. 15 m for RSA ~3 s) with a closer link to basketball game's actions (~2 s). Besides, IRSA could be an appropriate choice for assessing both RSA and changes of direction capacities in basketball players. PMID- 25530126 TI - Phase-locked theta activity evoked in patients with severe motor and intellectual disabilities upon hearing own names. AB - BACKGROUND: Severe motor and intellectual disability (SMID) patients cannot express their feelings with language. Understanding what they are thinking about or how they feel is thus difficult. This study focused on brain responses to hearing their own names to clarify the situation in these patients. METHODS: We performed and analyzed electroencephalography (EEG) for six patients with SMID and eleven healthy subjects. All subjects were presented with auditory stimuli including calling the subject's own name (SON) and reading words. EEG was analyzed by time-frequency analysis, event-related spectral perturbation (ERSP) to detect EEG power changes caused by EEG amplitude, and inter-trial coherence (ITC) to investigate phase-locked changes. RESULTS: ERSP results from healthy subjects showed significant theta power increases as a specific response to SON. While we could not identify a similar pattern in the responses of patients with SMID, analysis of ITC revealed that theta phase-locked activity increased in response to SON not only in all healthy subjects, but also in four patients. DISCUSSION: These results indicate that theta phase-locked activity in some patients with SMID was strongly associated with SON, as in healthy subjects. Our study suggests the existence of specific neural markers that signal an attentional shift in patients upon hearing SON. PMID- 25530127 TI - Cerebral hypoxia-ischemia increases toll-like receptor 2 and 4 expression in the hippocampus of neonatal rats. AB - AIM OF THE STUDY: Recent reports provide evidence that Toll-like receptors (TLRs) play a crucial role in cerebral ischemic injuries and neuronal cell death. The precise role of TLRs in mediating neuronal damage remains to be fully elucidated. In this study, we investigated the expression of TLR2 and TLR4 in the hippocampus of the neonatal rats. MATERIALS AND METHODS: Postnatal day 7 Sprague-Dawley rats were used. The hypoxia-ischemia brain injury models were made by ligature of the left common carotid artery and then inhalation of 8%O(2)/92%N(2) for 2 h. TLR2 and TLR4 expression was assessed with immunohistochemical staining and Western blot assays at 3d, 7d, and 14d after injury. RESULTS: At the 3d and 7d time points, we found a significant increase in the number of TLR2 and TLR4 positive cells in the hippocampus of the HI group when compared with the sham group (P<0.01). Western blot showed similar results. CONCLUSIONS: The study indicates that TLR2 and TLR4 are involved in the hypoxic-ischemic injury of full-term neonatal brains. PMID- 25530128 TI - Understanding antigay bias from a cognitive-affective-behavioral perspective. AB - In general, United States citizens have become increasingly more accepting of lesbians and gay men over the past few decades. Despite this shift in public attitudes, antigay bias remains openly tolerated, accepted, practiced, and even defended by a substantial portion of the population. This article reviews why and how antigay bias persists using a cognitive-affective-behavioral perspective that touches on sociocognitive factors such as prejudice and stereotyping, as well as features unique to antigay bias, such as its concealable nature. The article concludes with a discussion of how understanding modern antigay bias through a cognitive-affective-behavioral lens can be applied to reduce discrimination against gays and lesbians. PMID- 25530129 TI - The impact of asthma exacerbations and preventive strategies. AB - OBJECTIVE: To review the pathophysiologic mechanisms underlying asthma exacerbations, the impact of exacerbations, and both current and future treatment strategies to establish asthma control and reduce the risk of future exacerbations. RESEARCH DESIGN AND METHODS: Relevant adult data were identified via PubMed, with additional references obtained by reviewing bibliographies from selected articles. RESULTS: Asthma exacerbations or 'attacks' are acute episodes of progressive worsening of symptoms which occur in patients with all degrees of asthma severity and are an important cause of morbidity and mortality. For patients, these asthma attacks constitute a considerable part of the disease burden in terms of both personal suffering and economic impact. Exacerbations are characterized in part by decreases in expiratory flow or lung function. The pathophysiologic mechanism underlying these changes is likely to be different depending on the specific asthma phenotype. Asthma exacerbations are commonly initiated by upper respiratory tract infections and/or environmental allergens, although there are other known factors which increase the risk of a patient developing exacerbations, such as cigarette smoking. Establishing asthma control and reducing the risk of future exacerbations is the main goal of asthma treatment. Inhaled corticosteroids alone or in combination with long-acting beta2 agonists, in addition to other step-up strategies such as leukotriene receptor antagonists and theophylline, are recommended. The anti-immunoglobulin E monoclonal antibody omalizumab should also be considered in difficult-to-treat allergic asthma. CONCLUSIONS: Despite the currently available treatments, many patients with asthma remain symptomatic and experience exacerbations regardless of disease severity. New therapies, including long-acting anticholinergics, anti cytokines, and chemoattractant receptor-homologous molecules, are under investigation with some promising results. In addition to increased education and use of self-management plans, these novel therapies are essential to help improve asthma control and reduce exacerbation risk. PMID- 25530130 TI - Autoimmune epilepsy: the search for a definition. PMID- 25530131 TI - Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: Results of the D-first study of Kanto CML study group. AB - To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the "D-First study." Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100 mg dasatinib once daily. A deep molecular response (DMR) was defined as <50 copies/MUg RNA of BCR-ABL1 transcript value corrected by GAPDH, which ensures <0.01% of BCR-ABL1 transcript value according to International Scale (BCR-ABL1(IS)). The halving time for BCR ABL1 transcripts was calculated using transcript levels before dasatinib treatment, transcript levels after 3 months of treatment, and the treatment time between these two points. In terms of molecular response, 38 of 51 (75%) patients reached major molecular response (MMR) by 12 months, and the rate of DMR by 18 months was 59% (30/51). While both BCR-ABL1 transcript levels before treatment and a shorter halving time of BCR-ABL1 transcripts (<=14 days) were significant factors affecting achievement of MMR by 12 months, the Sokal score at diagnosis was not associated with MMR. Importantly, the halving time was the only factor that predicted achievement of DMR by 18 months. We showed that patients with CML CP treated with dasatinib can be stratified according to the early treatment response as determined by the halving time of BCR-ABL1 transcripts. These data emphasize the significance of the early response from dasatinib treatment in achieving a DMR. (ClinicalTrials.gov; NCT01464411). PMID- 25530132 TI - MiR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1. AB - Although the 5-year survival rate of osteosarcoma (OS) has risen to ~60-70%, a substantial portion of patients still respond poorly to chemotherapy and have a high risk of relapse or metastasis even after curative resection. In this study, we found that the expression of miR-142 was significantly reduced in OS tissues and OS cell lines, while Ras-related C3 botulinum toxin substrate 1 (Rac1) expression was increased in the OS tissues and OS cell lines compared with expression in the controls. We then demonstrated that miR-142 regulated Rac1 expression at the transcriptional and translational levels by directly targeting its 3'-untranslated region (3'UTR). In addition, by loss- and gain-of function experiments, we investigated the role of miR-142 in OS cell lines and found that miR-142 acted as a tumor suppressor in the OS cell lines and inhibited cell proliferation and cell invasion and arrested cell cycle in the S phase. Furthermore, miR-142 inhibited osteosarcoma cell invasion by inducing E-cadherin expression and reducing expression of matrix metalloproteinase 2 (MMP2) and MMP9. Thus, overexpression of miR-142 and/or knockdown of Rac1 would be a novel target for OS therapy in the future. PMID- 25530133 TI - Association between FcepsilonRIbeta and IFN-gamma Polymorphisms and Asthma in Asian Population: a Meta-Analysis. AB - Polymorphisms in the beta subunit of the high affinity receptor for IgE (FcepsilonRIbeta) and interferon-gamma (IFN-gamma) genes may influence the risk of asthma. However, the results in Asian population are still debatable. We performed a meta-analysis to ascertain the association between the FcepsilonRIbeta E237G, FcepsilonRIbeta -109C/T, and IFN-gamma 874T/A polymorphisms and asthma in an Asian population. Databases including PubMed, Chinese National Knowledge Infrastructure (CNKI), Weipu, and Wan Fang (Chinese) databases were searched to find the relevant studies. The effect summary odds ratio (OR) with 95% confidence interval (CI) was calculated. There was no significant difference in dominant model and allele model (EG + GG vs. EE: OR = 1.14, 95%CI = 0.94-1.40; G vs. E: OR = 1.13, 95%CI = 0.95-1.34) for FcepsilonRIbeta E237G, and no significant association was observed in the subgroup analysis by age and atopic status. A significantly decreased risk of asthma was observed in allelic model (C vs. T: OR=0.88, 95%CI=0.80-0.98) for FcepsilonRIbeta -109C/T, significant association was found in dominant model (AT+TT vs. AA: OR=0.56, 95% CI=0.33-0.97) for IFN-gamma 874T/A. This meta analysis suggested that FcepsilonRIbeta E237G is not an influencing factor for asthma in Asian population. FcepsilonRIbeta -109C/T and IFN-gamma 874T/A polymorphisms may be influencing factors for asthma in the Asian population. PMID- 25530134 TI - Flow cytometry applications in the study of immunological lung disorders. AB - The use of flow cytometry in the clinical laboratory has grown substantially in the past decade. Flow cytometric analysis provides a rapid qualitative and quantitative description of multiple characteristics of individual cells. For example, it is possible to detect the cell size and granularity, aspects of DNA and RNA content and the presence of cell surface and nuclear markers which are used to characterize the phenotype of single cells. Flow cytometry has been used for the immunophenotyping of a variety of specimens including whole blood, bone marrow, serous cavity fluids, (cerebrospinal fluid) CSF, urine and all types of body fluids. The technique has also been applied to human bronchoalveolar lavage (BAL) fluid, peritoneal fluids and blood. In this review, we describe the current status of the application of flow cytometry as a diagnostic tool in various lung diseases. We focus on the analysis of BAL cell composition in chronic obstructive lung disease (COPD), asthma, lung cancer, sarcoidosis, tuberculosis and idiopathic eosinophilic pneumonia (IEP). PMID- 25530135 TI - Odor-related Chronic Somatic Symptoms Are Associated with Self-Reported Asthma and Hay Fever: The Hordaland Health Study. AB - The aetiology behind odor-related chronic somatic symptoms (O-RCSS) is unknown, although both immunological and psychiatric causes have been suggested. The aim of this study was to investigate the occurrence of self-reported asthma and hay fever and psychiatric symptoms in individuals having O-RCSS compared to individuals with similar chronic somatic symptoms (CSS) which were not odors related, and also compared to healthy controls. Data from the Hordaland Health Study were used. 13,799 individuals, 40-45 years, answered a questionnaire including 16 questions related to somatic symptoms. They also indicated if the symptoms were odor-related, and answered questions about asthma and hay fever. Anxiety and depression were measured with the Hospital Anxiety and Depression Scale. 38 (0.6%) men and 106 (1.4%) women had O-RCSS, whereas 88 (1.5%) men and 192 (2.5%) women had CSS. Adjusted logistic regression analyses showed increased odds of self-reported asthma in those with O-RCSS compared to those with CSS (males: 3.81, 1.06-13.8, females: 2.60, 1.05-6.93) and compared to male and female controls (3.56, 1.89-6.68 and 4.81, 1.92-12.1 respectively). Increased odds of self-reported hay fever were in addition seen in females with O-RCSS. There were no differences in psychiatric symptoms between individuals with O-RCSS and CSS, although individuals in both groups showed increased odds compared to male and female controls. Increased occurrence of self-reported asthma was exclusively found among male and females with O-RCSS, compared to CSS and controls. Increased occurrence of psychiatric symptoms was seen both in individuals with O-RCSS and CSS. PMID- 25530136 TI - Clinical and immunological effects of a forest trip in children with asthma and atopic dermatitis. AB - Asthma and atopic dermatitis are common allergic diseases, and their prevalence has increased in urban children. Recently, it is becoming understood that forest environment has favorable health effects in patients with chronic diseases. To investigate favorable clinical and immunologic effects of forest, we examined changes in clinical symptoms, indirect airway inflammatory marker, and serum chemokines before and after a short-term forest trip. The forest trips were performed with 21 children with asthma and 27 children with atopic dermatitis. All participating children were living in air polluted urban inner-city. We measured spirometry and fractional exhaled nitric oxide (FeNO) in children with asthma and measured scoring atopic dermatitis (SCORAD) index and Thymus and Activation-Regulated Chemokine (TARC)/CCL17 and Macrophage-Derived Chemokine (MDC)/CCL22 levels in children with atopic dermatitis before and after the forest trip. Indoor air pollutants such as indoor mold, particulate matter 10 (PM10) and total volatile organic compounds (TVOCs) of each child's home and the accommodations within forest were measured. A significant increase in forced vital capacity (FVC) and a significant decrease in FeNO were observed after the forest trip in children with asthma. SCORAD indices and MDC/CCL22 levels were significantly decreased after the forest trip in children with atopic dermatitis. Airborne mold and PM10 levels in indoor were significantly lower in the forest accommodations than those of children's homes; however, TVOC levels were not different between the two measured sites. Short-term exposure to forest environment may have clinical and immunological effects in children with allergic diseases who were living in the urban community. PMID- 25530137 TI - Emotional Freedom Technique (EFT) Effects on Psychoimmunological Factors of Chemically Pulmonary Injured Veterans. AB - Emotional Freedom Technique (EFT) as a new therapeutic technique in energy psychology has positive effects on psychological and physiological symptoms, and quality of life. In this research we studied the effect of this treatment on immunological factors. This study tested whether 8-week group sessions of EFT (compared to a wait-list control group) with emphasis on patient's respiratory, psychological and immunological problems in chemically pulmonary injured veterans (N=28) can affect on immunological and psychological factors. Mixed effect linear models indicated that EFT improved mental health (F=79.24, p=0) and health related quality of life (F=13.89, p=0.001), decreased somatic symptoms (F=5.81, p=0.02), anxiety/insomnia (F=24.03, p<0.001), social dysfunction (F=21.59, p<0.001), frequency and severity of respiratory symptoms (F=20.38, p<0.001), and increased lymphocyte proliferation with nonspecific mitogens Concanavalin A (Con A) (F=14.32, p=0.001) and Phytohemagglutinin (PHA) (F=12.35, p=0.002), and peripheral blood IL-17 (F=9.11, p=0.006). This study provides an initial indication that EFT may be a new therapeutic approach for improving psychological and immunological factors. PMID- 25530138 TI - Lack of Association between Toll Like Receptor-2 and Toll Like Receptor-4 Gene Polymorphisms and Other Feature in Iranian Asthmatics Patients. AB - Asthma as a chronic inflammatory airway disease is considered to be the most common chronic disease that is involving genetic and environmental factors. Toll like receptors (TLRs) and other inflammatory mediators are important in modulation of inflammation. In this study, we evaluated the role of TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms in the asthma susceptibility, progress, control levels and lung functions in Iranian patients. On 99 asthmatic patients and 120 normal subjects, TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms were evaluated by PCR-RFLP method recruiting Msp1 and Nco1 restriction enzymes, respectively. IgE serum levels by ELISA technique were determined and asthma diagnosis, treatment and control levels were considered using standard schemes and criteria. Our results indicated that the genotype and allele frequencies of the TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms were not significantly different between control subjects and asthmatics and were not related to in asthma features such as IgE levels, asthma history and pulmonary factors. Wherease some previous studies indicated TLRs and their polymorphisms might have some role in asthma incidence and features, our data demonstrated that TLR2 Arg753Gln and TLR4 Asp299Gly gene variants were not risk factors for asthma or its features in Iranian patients. Genetic complexity, ethnicity, influence of other genes or polymorphisms may overcome these polymorphisms in our asthmatics. PMID- 25530139 TI - Association between Interleukin-1 Receptor Antagonist (IL1RN) Variable Number of Tandem Repeats (VNTR) Polymorphism and Pulmonary Tuberculosis. AB - Macrophages and T-lymphocytes are involved in immune response to Mycobacterium tuberculosis. Macrophage produces interleukin (IL)-1 as an inflammatory mediator. IL-1 receptor antagonist (IL1-Ra) is a natural antagonist of IL-1 receptors. In this study we aimed to examine the possible association between the variable number of tandem repeats (VNTR) of the IL-1 receptor antagonist (IL1RN) gene and pulmonary tuberculosis (TB) in a sample of Iranian population. Our study is a case-control study and we examined the VNTR of the IL1RN gene in 265 PTB and 250 healthy subjects by PCR. Neither the overall chi-square comparison of PTB and control subjects nor the logistic regression analysis indicated any association between VNTR IL1RN polymorphism and PTB. Our data suggest that VNTR IL1RN polymorphism may not be associated with the risk of PTB in a sample of Iranian population. Larger studies with different ethnicities are needed to find out the impact of IL1RN VNTR polymorphism on risk of developing TB. PMID- 25530140 TI - Paraoxonase 1 phenotype and paraoxonase activity in asthmatic patients. AB - Oxidative stress is involved in the pathogenesis of asthma. Paraoxonase 1 (PON1) and arylesterase are esterase enzymes displaying antioxidant characteristics. PON1 activity varies widely among individuals and ethnic groups, partly related to polymorphisms. The aim of this study was to determine the activities of PON1 and arylesterase including the phenotype distribution of PON1 in asthmatic patients and healthy subjects. Forty-nine asthmatic patients and 41 healthy people were included in this study. Serum PON1 and arylesterase activities were determined by spectrophotometric assays, as well as the lipid profiles. The PON1 ratio (salt stimulated paraoxonase/arylesterase) was trimodally distributed and this ratio was used to determine the individual phenotypes of all subjects. The PON1 activity in the asthmatic patients was significantly lower (p=0.024) when compared to the healthy control group, however no significant difference in the activity of arylesterase was observed between the two groups. The prevalence of the PON1 phenotypes in the asthmatic population were 26.5%, 16.3% and 57.2 % for QQ, QR and RR, respectively. PON1 activity was significantly lower in asthmatic patients; in addition, the results of this investigation indicated that PON1 RR phenotype may be an important risk factor in asthma disease. PMID- 25530141 TI - Cotinine level is associated with asthma severity in passive smoker children. AB - Asthma environmental triggers play important roles in severity of disease. Passive smoking could exacerbate asthma symptoms and enhance the decrease in lung function. Cotinine levels could be a reflection of passive exposure to the cigarette both in adults and pediatrics. The aim of this study was to determine degree of association of asthma severity and cotinine level as a marker of passive smoking. In a cross-sectional study, 100 pediatric patients (under 10 years old) with asthma were enrolled, 50 of whom, had been exposed to passive smoking and 50 others included as controls. A complete clinical history, lab exam, and spirometry were performed. A sample of urine, serum and saliva was collected from all attendant patients and controls in the study after confirmation of diagnosis and determination of severity of asthma. The results revealed that age, sex, age of onset of asthma, family history and allergic history were not significantly different between two groups of patients. According to GINA classification, percentage of patients with severe asthma was significantly higher in passive smoker group (p=0.001). Cotinine was significantly higher in passive smoker group compared to control group in serum (p=001), saliva (p=0.001), and urine (p=0.0014). In passive smoker group, cotinine levels were significantly higher in serum (p=0.001), urine (p=0.007), and saliva (p=0.01) of patients with severe asthma than moderate and mild asthma. Serum cotinine (OR: 1.81, 95% CI: 1.35-2.32, p=0.024), urine cotinine (OR: 3.56,95% CI = 1.29-5.53, p=0.01) and saliva cotinine (OR: 1.66, 95% CI: 1.23 1.98, p=0.031) were also significantly associated with higher risk of severe asthma. Cotinine levels were higher in passive smokers compared to non-passive smokers. Besides, cotinine was a predictive risk factor for severe asthma. PMID- 25530142 TI - Immunochemical characterization of prosopis juliflora pollen allergens and evaluation of cross-reactivity pattern with the most allergenic pollens in tropical areas. AB - Allergy to Prosopis juliflora (mesquite) pollen is one of the common causes of respiratory allergy in tropical countries. Mesquite is widely used as street trees in towns and ornamental shade trees in parks and gardens throughout arid and semiarid regions of Iran. The inhalation of mesquite pollen and several species of Amaranthus/Chenopodiaceae family is the most important cause of allergic respiratory symptoms in Khuzestan province. This study was designed to evaluate IgE banding proteins of mesquite pollen extract and its IgE cross reactivity with other allergenic plants. Twenty patients with allergic symptoms and positive skin prick tests (SPT) for mesquite pollen extract participated in the study. Crude pollen extract was prepared from local mesquite trees and used for the evaluation of allergenic profiles of P. juliflora pollen extract by Sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and IgE immunoblotting. There were several protein bands in mesquite pollen extract using SDS-PAGE with the approximate range of molecular weight of 10-85 kDa. The most frequent IgE reactive bands among the patients' sera were approximately 20 and 66 kDa. However, there were other IgE reactive protein bands among the patients' sera with molecular weights of 10, 15, 35, 45, 55 and 85 kDa. Inhibition experiments revealed high IgE cross-reactivity between mesquite and acacia. There are several IgE-binding proteins in P. juliflora pollen extract. Results of this study indicate that proteins with a molecular weight of 10 to 85 kDa are the major allergens in P. juliflora pollen extract. PMID- 25530143 TI - Impact and correlation of environmental conditions on pollen counts in Karachi, Pakistan. AB - A quantitative and qualitative survey of airborne pollen was performed in the city of Karachi, and the pollen counts were correlated with different climatic conditions. The aim of the study was to determine the possible effect of meteorological factors on airborne pollen distribution in the atmosphere of Karachi city. Pollen sampling was carried out by using Burkard spore Trap for the period of August 2009 to July 2010, and a total of 2,922 pollen grains/m(3) were recorded. In this survey, 22 pollen types were recognized. The highest pollen count was contributed by Poaceae pollen type (1,242 pollen grains/m(3)) followed by Amaranthaceae/Chenopodiaceae (948 pollen grains/m(3)), Cyperus rotundus (195 pollen grains/m(3)) and Prosopis juliflora (169 pollen grains/m(3)). Peak pollen season was in August showing a total of 709 pollen grains/m(3) and lowest pollen count was observed in January-2010. Pearson's chi-square test was performed for the possible correlation of pollen counts and climatic factors. The test revealed significant positive correlation of wind speed with pollen types of Amaranthaceae/Chenopodiaceae; Brassica campestris; Asteraceae; and Thuja orientalis. While the correlation of "average temperature" showed significant positive value with Asteraceae and Tamarix indica pollen types. Negative correlation was observed between humidity/ precipitation and pollen types of Brassica campestris; Daucus carota; Ephedra sp.; and Tamarix indica. In the light of above updated data one could identify various aeroallergens present in the air of Karachi city. PMID- 25530144 TI - Decreased urinary level of melatonin as a marker of disease severity in patients with multiple sclerosis. AB - Melatonin has both pro-inflammatory and anti-inflammatory properties depending on the stage of inflammation. Despite its therapeutic effect in alleviation of some symptoms of multiple sclerosis; the precise role of melatonin in MS pathogenesis remains a topic of debate. The aim of this study was to measure the urine level of one of melatonin products which is an index of serum melatonin level, in MS patients in the acute phase of relapse and control patients. We also analyzed different clinical and cognitive indices in order to find any correlation with melatonin level. Twenty eight patients who were diagnosed as relapsing-remitting MS, according to the revised McDonald criteria, along with 10 age- and sex matched control subjects were recruited in our study. Here we showed that urine 6 sulphatoxymelatonin levels (aMT6s; the major metabolite of melatonin) were significantly lower in MS patients compared to control group. Interestingly, urine aMT6s levels significantly correlated with MS Functional Composite score, but not Expanded Disability Severity Score. Based on above findings, there might be new hope in developing a quantitative and objective measure to assess the MS severity especially in neurodegenerative diseases. However, our results should be analyzed cautiously. We didn't evaluate simultaneous level of 25-OH Vitamin D. It has been recently reported that there is a negative correlation between melatonin and vitamin D levels. Further studies are needed to confirm this hypothesis. PMID- 25530145 TI - Seroprevalence of NMO-IgG Antibody in Neuromyelitis optica (NMO) and Its Specificity in Differentiating NMO from Other Demyelinating Diseases with Overlap Symptoms: An Iranian Experience. AB - Neuromyelitis optica is an inflammatory demyelinating disease (IDD) of the CNS, which mainly affects optic nerve and spinal cord. Autoantibodies against aquaporin-4 also known as NMO-IgG have been implicated in the pathogenesis of NMO. We evaluated the sensitivity and specificity of NMO-IgG assay for diagnosing NMO patients and differentiating them from MS patients and those with undifferentiated IDD with overlap symptoms.Eligibility of patients with demyelinating disorders was evaluated based on physical examination, laboratory and imaging studies. Thirty four definite NMO patients (disregarding NMO-IgG status), 34 multiple sclerosis (MS) patients with a history of optic neuritis (ON) or myelitis that were matched for age and disease activity and 44 patients with ON or myelitis attacks fulfilling neither criteria of MS or NMO (NMO spectrum) were selected as undifferentiated group. NMO-IgG was measured in the serum of the included patients by cell-based indirect immunofluorescence assay (IFA). NMO antibody was positive in 11 (32.3%), and 4 (9.09%) patients in NMO and undifferentiated groups, but was undetctable in MS patients. NMO antibody was 32% (95%Cl: 19-49%) sensitive in detecting NMO patients. Its specificity in differentiating NMO from MS subjects was 100 % (95% Cl: 90-!00%). NMO antibody was 95% (95% Cl: 0.88-0.98) specific in differentiating NMOs from other demyelinating diseases. Our results showed that although NMO antibody is highly specific for NMO, current method of measuring it with cell-based IFA is not highly sensitive for diagnosing NMO patients. PMID- 25530146 TI - Development of a new immunochromatographic assay using gold nanoparticles for screening of IgA deficiency. AB - A new competitive immunochromatography (ICG) strip test based on polyclonal antibody (pAb) conjugated with gold nanoparticles (NPs) was developed and its applications for primary screening of immunoglobulin (Ig) A in serum were evaluated. Nanocolloidal gold as the detection reagent, with an average particle diameter of 20 nm, was synthesized and labelled pAb. The antibody-nanocolloidal gold probe was applied on the conjugate pad, and human IgA was immobilized on a nitrocellulose membrane as the capture reagent to prepare the ICG strip test. It took only 10 minutes to accomplish a semi-quantitative detection of serum IgA in this assay. In the optimized investigational conditions, the ICG strip test could distinguish human serum IgA in the range from 1 to 270 ng/mL with a detection limit of 5 ng/mL. The reliability of testing procedures was examined by performing the ICG strip test with 11 serum samples and comparing the results with those obtained via enzyme-linked immunosorbent assay (ELISA). The ICG strip was sufficiently sensitive and accurate for a rapid screening of IgA in human serum. PMID- 25530147 TI - Characteristics of 26 kDa antigen of H. Pylori by Monoclonal Antibody. AB - Alkylhydroperoxide reductase (AhpC, the 26 kDa antigen) is one of the abundant antioxidant enzymes in Helicobacter pylori and seems to have a good potential for use in development of immunoassays to detect H. pylori infection in clinical specimens. This study aimed to investigate some properties of this antigen by the produced monoclonal antibodies. Five established hybridoma cell lines secreting monoclonal antibodies (MAbs) against 26 kDa antigen of H. pylori were cultivated and MAbs were purified by affinity chromatography. Subsequently, MAbs were conjugated with biotin, and different combinations of capture and tracer antibodies used in sandwich ELISA. Immunoblotting of bacterial extracts were performed to estimate aggregation status of the antigen. Release of antigen from the cultivated bacteria on solid media was examined by sandwich ELISA, and also, existence of interference in fecal extract was investigated by immunoblotting and sandwich ELISA. Our findings showed that the MAbs against 26 kDa antigen of H. pylori could recognize three bands of nearly 25 kDa, 50 kDa, and 75 kDa in immunoblotting. This study also indicated presence of more antigens in the culture medium around the bacteria than the bacterial extract itself. The results of sandwich ELISA and immunoblotting on fecal extracts suggest the presence of interfering agents that prevent detection of antigen by antibody in ELISA but not in immunoblotting. In this study the oligomerization of the 26 kDa antigen, presence of interfering agents in stool matrix, and release of antigen to outside of bacteria, were demonstrated. PMID- 25530148 TI - Randomized controlled trial examining expectancy effects on the accuracy of weight measurement. AB - BACKGROUND: Researchers and participants' expectations can influence treatment response. Less is known about the effects of researchers' expectations on the accuracy of data collection in the context of a weight loss trial. METHODS: Student raters (N = 58; age = 20.1 +/- 2.3 years) were recruited to weigh individuals who they thought were completing a 12-month weight loss trial, although these 'participants' were actually standardized patients (SPs) playing these roles. Prior to data collection, student raters were provided information suggesting that the tested treatment had been effective. Each student rater received a list of 9-10 'participants' to weigh. While the list identified each person as 'treatment' or 'control', this assignment was at random, which allowed us to examine the effects of non-blinding and expectancy manipulation on weight measurement accuracy. We hypothesized that raters would record the weights of 'treatment participants' as lower than those of 'control participants'. RESULTS: Contrary to our hypothesis, raters recorded weights that were 0.293 kg heavier when weighing 'treatment' vs. 'control' SPs, although this difference was not significant (P = 0.175). CONCLUSIONS: This pilot study found no evidence that manipulating expectancies about treatment efficacy or not blinding raters biased measurements. Future work should examine other biases which may be created by not blinding research staff who implement weight loss trials as well as the participants in those trials. PMID- 25530149 TI - Myopericarditis associated with Fusobacterium nucleatum-caused liver abscess. AB - A wide clinical spectrum of bacteremic disease caused by Fusobacterium has been presented in this journal. We wish to extend this spectrum by presenting a case of myopericarditis resulting from a liver abscess caused by F. nucleatum. While F. nucleatum plays an important role in periodontal disease, and has been isolated from skin ulcers, liver abscesses, urinary tract infections, and endocarditis, a single case of F. nucleatum-induced pericarditis is documented in the literature. PMID- 25530150 TI - Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk. A large body of evidence supports the contention that oxidative stress, which characterizes DM, may be responsible, at least in part, for less-than-expected response to aspirin, with multiple mechanisms acting at several levels. This review discusses the pathophysiological mechanisms related to oxidative stress and contributing to suboptimal aspirin action or responsiveness. These include: (1) mechanisms counteracting the antiplatelet effect of aspirin, such as reduced platelet sensitivity to the antiaggregating effects of NO, due to high-glucose-mediated oxidative stress; (2) mechanisms interfering with COX acetylation especially at the platelet level, e.g., lipid hydroperoxide-dependent impaired acetylating effects of aspirin; (3) mechanisms favoring platelet priming (lipid hydroperoxides) or activation (F2-isoprostanes, acting as partial agonists of thromboxane receptor), or aldose-reductase pathway mediated oxidative stress, leading to enhanced platelet thromboxane A2 generation or thromboxane receptor activation; (4) mechanisms favoring platelet recruitment, such as aspirin-induced platelet isoprostane formation; (5) modulation of megakaryocyte generation and thrombopoiesis by oxidative HO-1 inhibition; and (6) aspirin-iron interactions, eventually resulting in impaired pharmacological activity of aspirin, lipoperoxide burden, and enhanced generation of hydroxyl radicals capable of promoting protein kinase C activation and platelet aggregation. Acknowledgment of oxidative stress as a major contributor, not only of vascular complications, but also of suboptimal response to antiplatelet agents in T2DM, may open the way to designing and testing novel antithrombotic strategies, specifically targeting oxidative stress-mediated mechanisms of less than-expected response to aspirin. PMID- 25530151 TI - Interactions between cocoa flavanols and inorganic nitrate: additive effects on endothelial function at achievable dietary amounts. AB - Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. We aimed to study interactions between cocoa flavanols (CF) and nitrate, focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose-response crossover study, flow mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4 h after consumption of CF (1.4-10.9 mg/kg bw) or nitrate (0.1-10 mg/kg bw). To study flavanol-nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0 h) and at 1h after ingestion of nitrate (3 or 8.5 mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9 mg/kg bw) or a micro- and macronutrient-matched CF-free drink. FMD was measured at 1, 2, and 4 h thereafter. Blood and urine samples were collected and assessed for CF and nitric oxide (NO) metabolites with HPLC and gas-phase reductive chemiluminescence. Finally, intragastric formation of NO after CF and nitrate consumption was investigated. Both CF and nitrate induced similar intake-dependent increases in FMD. Maximal values were achieved at 1 h postingestion and gradually decreased to reach baseline values at 4 h. These effects were additive at low intake levels, whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion, but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial function when ingested together. PMID- 25530152 TI - Genetic research on biospecimens poses minimal risk. AB - Genetic research on human biospecimens is increasingly common. However, debate continues over the level of risk that this research poses to sample donors. Some argue that genetic research on biospecimens poses minimal risk; others argue that it poses greater than minimal risk and therefore needs additional requirements and limitations. This debate raises concern that some donors are not receiving appropriate protection or, conversely, that valuable research is being subject to unnecessary requirements and limitations. The present paper attempts to resolve this debate using the widely-endorsed 'risks of daily life' standard. The three extant versions of this standard all suggest that, with proper measures in place to protect confidentiality, most genetic research on human biospecimens poses minimal risk to donors. PMID- 25530153 TI - Mild caloric restriction reduces blood pressure and activates endothelial AMPK PI3K-Akt-eNOS pathway in obese Zucker rats. AB - Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n=8) or 80% of AL (CR, n=8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10(-9) to 10(-4) M) was reduced in fa/fa AL compared to control lean AL rats (p<0.001), and restored by CR. The AMPK activator AICAR (10(-5) to 8.10(-3) M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p<0.001). Inhibition of PI3K (wortmannin, 10(-7) M), Akt (triciribine, 10(-5) M), or eNOS (L-NAME, 10(-4) M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK-PI3K-Akt-eNOS pathway. PMID- 25530154 TI - Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways. AB - Thrombolysis is recommended for reperfusion following acute ischemic stroke (AIS), but its effects on stroke-associated injury remain to be clarified. Here, we investigated the effects of recombinant tissue plasminogen activator (r-tPA) on neutrophil pathophysiology in vitro and in a case-control study with AIS patients submitted (n=60) or not (n=30) to thrombolysis. Patients underwent radiological and clinical examination as well as blood sampling at admission and after 1, 7 and 90days. In vitro, 30-min incubation with 0.1-1 mg/ml r-tPA induced neutrophil degranulation in different substrate cultures. Pre-incubation with kinase inhibitors and Western blot documented that degranulation was associated with activation of PI3K/Akt and ERK1/2 pathways in Teflon dishes and PI3K/Akt in polystyrene. In thrombolysed patients, a peak of neutrophil degranulation products (matrix metalloproteinase [MMP]-9, MMP-8, neutrophil elastase and myeloperoxidase), was shown during the first hours from drug administration. This was accompanied by serum augmentation of protective tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. An increased rate of haemorrhagic transformations on day 1 after AIS was shown in thrombolysed patients as compared to non-thrombolysed controls. In conclusion, r-tPA treatment was associated with in vitro neutrophil degranulation, indicating these cells as potential determinants in early haemorrhagic complications after thrombolysis in AIS patients. PMID- 25530155 TI - Selective renal arterial embolization in the treatment of hemodialysis patients complicated with Wunderlich syndrome: a case report. PMID- 25530156 TI - Toll-like receptors recognize distinct proteinase-resistant glycoconjugates in Campylobacter jejuni and Escherichia coli. AB - Campylobacter jejuni causes gastroenteritis and autoimmune neuropathy Guillain Barre syndrome. The mechanism by which C. jejuni infection results in such the hyperimmunity is not completely understood. Host immunity plays an important role in the disease pathogenesis; however, little is known how immune system recognizes this human pathogen. In this study, we report that Toll-like receptors recognize distinct proteinase K-resistant glycoconjugates in C. jejuni and Escherichia coli. Lipopolysaccharide is solely proteinase-resistant glycoconjugate in E. coli. In contrast, C. jejuni possesses at least five different components that are resistant to proteinase digestion and are capable of inducing NF-kappaB activation through TLR2 and TLR4. Possession of multiple activators of Toll-like receptors may be the unique strategy of C. jejuni to trigger hyperimmunity. PMID- 25530157 TI - Internal versus external auditory hallucinations in schizophrenia: symptom and course correlates. AB - INTRODUCTION: The auditory hallucinations associated with schizophrenia are phenomenologically diverse. "External" hallucinations classically have been considered to reflect more severe psychopathology than "internal" hallucinations, but empirical support has been equivocal. METHODS: We examined associations of "internal" versus "external" hallucinations with (1) other characteristics of the hallucinations, (2) severity of other symptoms and (3) course of illness variables, in a sample of 97 stable outpatients with schizophrenia or schizoaffective disorder who experienced auditory hallucinations. RESULTS: Patients with internal hallucinations did not differ from those with external hallucinations on severity of other symptoms. However, they reported their hallucinations to be more emotionally negative, distressing and long-lasting, less controllable and less likely to remit over time. They also were more likely to experience voices commenting, conversing or commanding. However, they also were more likely to have insight into the self-generated nature of their voices. Patients with internal hallucinations were not older, but had a later age of illness onset. CONCLUSIONS: Differences in characteristics of auditory hallucinations are associated with differences in other characteristics of the disorder, and hence may be relevant to identifying subgroups of patients that are more homogeneous with respect to their underlying disease processes. PMID- 25530158 TI - The liverwort Pellia endiviifolia shares microtranscriptomic traits that are common to green algae and land plants. AB - Liverworts are the most basal group of extant land plants. Nonetheless, the molecular biology of liverworts is poorly understood. Gene expression has been studied in only one species, Marchantia polymorpha. In particular, no microRNA (miRNA) sequences from liverworts have been reported. Here, Illumina-based next generation sequencing was employed to identify small RNAs, and analyze the transcriptome and the degradome of Pellia endiviifolia. Three hundred and eleven conserved miRNA plant families were identified, and 42 new liverwort-specific miRNAs were discovered. The RNA degradome analysis revealed that target mRNAs of only three miRNAs (miR160, miR166, and miR408) have been conserved between liverworts and other land plants. New targets were identified for the remaining conserved miRNAs. Moreover, the analysis of the degradome permitted the identification of targets for 13 novel liverwort-specific miRNAs. Interestingly, three of the liverwort microRNAs show high similarity to previously reported miRNAs from Chlamydomonas reinhardtii. This is the first observation of miRNAs that exist both in a representative alga and in the liverwort P. endiviifolia but are not present in land plants. The results of the analysis of the P. endivifolia microtranscriptome support the conclusions of previous studies that placed liverworts at the root of the land plant evolutionary tree of life. PMID- 25530159 TI - Can global longitudinal strain predict reduced left ventricular ejection fraction in daily echocardiographic practice? AB - BACKGROUND: Transthoracic echocardiography (TTE) is the most commonly used method for measuring left ventricular ejection fraction (LVEF), but its reproducibility remains a matter of controversy. Speckle tracking echocardiography assesses myocardial deformation and left ventricular systolic function by measuring global longitudinal strain (GLS), which is more reproducible, but is not used routinely in hospital practice. AIM: To investigate the feasibility of on-line two dimensional GLS in predicting LVEF during routine echocardiographic practice. METHODS: The analysis involved 507 unselected consecutive patients undergoing TTE between August 2012 and November 2013. Echocardiograms were performed by a single sonographer. Echogenicity was noted as good, moderate or poor. Simple linear regression was used to assess the relationship between LVEF and GLS, overall and according to quality of echogenicity. Receiver operating curve (ROC) analysis was used to identify the threshold GLS that predicts LVEF<=40%. RESULTS: Mean LVEF was 64+/-11% and GLS was -18.0+/-4.0%. A reasonable correlation was found between LVEF and GLS (r=-0.53; P<0.001), which was improved when echogenicity was good (r=-0.60; P<0.001). GLS explained 28.1% of the variation in LVEF, and for one unit decrease in GLS, a 1.45 unit increase in LVEF was expected. Correlations between LVEF and GLS were -0.51 for patients in sinus rhythm (n=490) and -0.86 in atrial fibrillation (n=17). Based on ROC analysis, the area under the curve was 0.97 for GLS>=-14%, allowing detection of LVEF<=40% with a sensitivity of 95% and specificity of 86%. CONCLUSION: Two-dimensional GLS is easy to obtain and accurately detects LVEF<=40% in unselected patients. GLS may be especially helpful when a suboptimal acoustic window makes LVEF measurement by Simpson's biplane method difficult and in atrial fibrillation patients with low heart rate variability. PMID- 25530160 TI - A randomized, double-blind, crossover study to evaluate the depth response relationship of intradermal capsaicin-induced pain and hyperalgesia in healthy adult volunteers. AB - OBJECTIVE: The purpose of this study was to evaluate pain and hyperalgesia in response to different depths of intradermal (ID) capsaicin injections in healthy volunteers. DESIGN: Double-blind, cross-over study. SETTING: Clinical Research Laboratory. SUBJECTS: Fifteen healthy male subjects received ID capsaicin injections into the volar aspect of each forearm at depths of 1 mm, 3 mm, 5 mm, and 7 mm. After injection, spontaneous pain, elicited pain, flare response, heat thresholds, and area of hyperalgesia were measured at various time points. OUTCOMES MEASURE: Spontaneous pain, elicited pain (pinprick, stroking, and hot pain), hyperalgesia area, and allodynia area. RESULTS: No significant difference was found between any depths in spontaneous pain, elicited pain (pinprick, stroking, hot pain), hyperalgesia area, or allodynia area. A significant difference was found in the change in heat threshold between 5 mm and 1 mm, 7 mm and 1 mm, 5 mm and 3 mm, 7 mm and 3 mm depths. A significant difference was found in flare area between 5 mm and 3 mm depths. A significant difference was found in systolic blood pressure area under the curve (AUC) between 7 mm and 1 mm depths, and for both systolic and diastolic pressures for 5 mm and 1 mm depths, and 5 mm and 3 mm depths. A significant difference was found in pulse AUC between 5 mm and 1 mm depths and 5 mm and 3 mm depths. CONCLUSIONS: Injection of capsaicin at different depths in the skin had different effects on heart rate and blood pressure but no effect on pain. These results may have implications on the pharmacology and analgesic predictive value of the model of ID capsaicin. PMID- 25530161 TI - Evidence for increasing severity of community-onset boils and abscesses in UK General Practice. AB - In England, hospital admissions for severe staphylococcal boils and abscesses trebled between 1989 and 2004. We investigated this trend using routine data from primary and secondary care. We used The Health Improvement Network (THIN), a large primary-care database and national data on hospital admissions from Hospital Episode Statistics (HES). Time trends in the incidence of primary-care consultations for boils and abscesses were estimated for 1995-2010. HES data were used to calculate age-standardized hospital admission rates for boils, abscesses and cellulitis. The incidence of boil or abscess was 450 [95% confidence interval (CI) 447-452] per 100 000 person-years and increased slightly over the study period (incidence rate ratio 1.005, 95% CI 1.004-1.007). The rate of repeat consultation for a boil or abscess increased from 66 (95% CI 59-73) per 100 000 person-years in 1995 to peak at 97 (95% CI 94-101) per 100 000 person-years in 2006, remaining stable thereafter. Hospital admissions for abscesses, carbuncles, furuncles and cellulitis almost doubled, from 123 admissions per 100 000 in 1998/1999 to 236 admissions per 100 000 in 2010/2011. Rising hospitalization and recurrence rates set against a background of stable community incidence suggests increased disease severity. Patients may be experiencing more severe and recurrent staphylococcal skin disease with limited treatment options. PMID- 25530162 TI - Reversible solid-to-liquid phase transition of coordination polymer crystals. AB - The solid-to-liquid phase transition, a fundamental process commonly observed for various types of substances with significant potential for application, has been given little attention in the field of coordination polymers (CPs) despite the rich functionality of these compounds. In this article, we report the reversible solid-to-liquid phase transition of crystalline CPs. These CPs are composed of zinc ions, phosphate, and azoles, and a well-balanced composition, ionicity, and bond strength afford "melting" CPs. We examined the structure of one such melting framework in the liquid and glass states and found that the coordination bonds are not fully preserved in the liquid state but are re-formed in the glass state. As a demonstration, we fabricated, via phase transition, a thin film with an aligned crystal orientation and a monolith crystal of the CP. PMID- 25530163 TI - Diosgenin reorganises hyperglycaemia and distorted tissue lipid profile in high fat diet-streptozotocin-induced diabetic rats. AB - BACKGROUND: Diabetes is often connected with significant morbidity, mortality and also has a pivotal role in the development of cardiovascular diseases. Diet intervention, particularly naturaceutical antioxidants have anti-diabetic potential and avert oxidative damage linked with diabetic pathogenesis. The present study investigated the effects of diosgenin, a saponin from fenugreek, on the changes in lipid profile in plasma, liver, heart and brain in high-fat diet streptozotocin (HFD-STZ)-induced diabetic rats. Diosgenin was administered to HFD STZ induced diabetic rats by orally at 60 mg kg(-1) body weight for 30 days to assess its effects on body weight gain, glucose, insulin, insulin resistance and cholesterol, triglycerides, free fatty acids and phospholipids in plasma, liver, heart and brain. RESULTS: The levels of body weight, glucose, insulin, insulin resistance, cholesterol, triglycerides, free fatty acids, phospholipids, VLDL-C and LDL-C were increased significantly (P < 0.05) whereas HDL-C level decreased in the HFD/STZ diabetic rats. Administration of diosgenin to HFD-STZ diabetic rats caused a decrease in body weight gain, blood glucose, insulin, insulin resistance and also it modulated lipid profile in plasma and tissues. CONCLUSION: The traditional plant fenugreek and its constituents mediate its anti-diabetic potential through mitigating hyperglycaemic status, altering insulin resistance by alleviating metabolic dysregulation of lipid profile in both plasma and tissues. PMID- 25530164 TI - Resveratrol ameliorates experimental periodontitis in diabetic mice through negative regulation of TLR4 signaling. AB - AIM: To investigate the therapeutic effects of resveratrol (RSV) on periodontitis in diabetic mice and to explore the underlying mechanisms in vitro. METHODS: Experimental periodontitis was induced in db/db mice by ligature application of porphyromonas gingivalis. The mice were treated with RSV (20 mg/kg, p.o.) daily for 4 weeks. Alveolar bone loss, proinflammatory cytokines and TLR4 expression in the gingival tissue were measured. Cultured gingival epithelial cells (GECs) were used for in vitro studies. The transcriptional activity of TLR4 downstream signaling was analyzed using Western blotting. RESULTS: RSV administration significantly decreased the blood glucose levels, and ameliorated alveolar bone loss in db/db mice with experimental periodontitis. RSV administration also suppressed the high levels of IL-1beta, IL-6, IL-8, TNF-alpha, and TLR4 in gingival tissue of the mice. In the GECs incubated in high glucose medium, TLR4 expression was substantially upregulated, which was partly blocked in the presence of RSV. Lipopolysaccharides markedly increased the expression and secretion of IL-1beta, IL-6, IL-8, and TNF-alpha in the GECs cultured in high glucose medium, which was also partly blocked in the presence of RSV. Furthermore, RSV significantly suppressed the phosphorylation of TLR4 downstream factors NF-kappaB p65, p38MAPK, and STAT3. CONCLUSION: RSV exerts protective effects against experimental periodontitis in db/db mice via negative regulation of TLR4 signaling. PMID- 25530165 TI - Reply: To PMID 25045002. PMID- 25530166 TI - Neurotropic threat characterization of Burkholderia pseudomallei strains. AB - The death rate for neurologic melioidosis is high. Whether certain Burkholderia pseudomallei strains are more likely than other strains to cause central nervous system infection and whether route of infection influences the neurotropic threat remain unclear. Therefore, we compared the virulence and dissemination of Australian clinical isolates collected during October 1989-October 2012 from patients with neurologic and nonneurologic melioidosis after intranasal and subcutaneous infection of mice in an experimental model. We did not observe neurotropism as a unique characteristic of isolates from patients with neurologic melioidosis. Rather, a distinct subset of B. pseudomallei strains appear to have heightened pathogenic potential for rapid dissemination to multiple tissues, including the central nervous system, irrespective of the infection route. This finding has valuable public health ramifications for initiating appropriate and timely therapy after exposure to systemically invasive B. pseudomallei strains. Increasing understanding of B. pseudomallei pathology and its influencing factors will further reduce illness and death from this disease. PMID- 25530167 TI - Competition between organics and bromide at the aqueous solution-air interface as seen from ozone uptake kinetics and X-ray photoelectron spectroscopy. AB - A more detailed understanding of the heterogeneous chemistry of halogenated species in the marine boundary layer is required. Here, we studied the reaction of ozone (O3) with NaBr solutions in the presence and absence of citric acid (C6H8O7) under ambient conditions. Citric acid is used as a proxy for oxidized organic material present at the ocean surface or in sea spray aerosol. On neat NaBr solutions, the observed kinetics is consistent with bulk reaction-limited uptake, and a second-order rate constant for the reaction of O3 + Br(-) is 57 +/- 10 M(-1) s(-1). On mixed NaBr-citric acid aqueous solutions, the uptake kinetics was faster than that predicted by bulk reaction-limited uptake and also faster than expected based on an acid-catalyzed mechanism. X-ray photoelectron spectroscopy (XPS) on a liquid microjet of the same solutions at 1.0 * 10(-3)-1.0 * 10(-4) mbar was used to obtain quantitative insight into the interfacial composition relative to that of the bulk solutions. It revealed that the bromide anion becomes depleted by 30 +/- 10% while the sodium cation gets enhanced by 40 +/- 20% at the aqueous solution-air interface of a 0.12 M NaBr solution mixed with 2.5 M citric acid in the bulk, attributed to the role of citric acid as a weak surfactant. Therefore, the enhanced reactivity of bromide solutions observed in the presence of citric acid is not necessarily attributable to a surface reaction but could also result from an increased solubility of ozone at higher citric acid concentrations. Whether the acid-catalyzed chemistry may have a larger effect on the surface than in the bulk to offset the effect of bromide depletion also remains open. PMID- 25530168 TI - The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. AB - OBJECTIVE: As an analgesic and N-methyl-D-aspartate receptor antagonist, ketamine has been increasingly used as an adjunct in the management of acute perioperative pain. Although several meta-analyses have examined low-dose intravenous (i.v.) ketamine, they do not distinguish between different types of infusions. Additionally, the many clinical trials published on ketamine vary by regimen of administration and surgical site. This review seeks to exclusively examine the evidence supporting the use of low-dose i.v. infusion of ketamine for the management of perioperative pain. METHODS: We searched Medline for any clinical trials or meta-analyses that were conducted on low-dose i.v. infusion of ketamine between 1966 and November 2013. Using six equations, we were left with 695 references. Of those, five meta-analyses and 39 clinical trials met the criteria to be included our review. These clinical trials represent 2,482 patients, 1,403 of whom received ketamine. We then examined the efficacy of low-dose i.v. ketamine by regimen and site of surgery using pain scores and opioid consumption as endpoints. Finally, we assessed the safety and long-term impact of low-dose ketamine. RESULTS: Low-dose i.v. ketamine reduces opioid consumption by 40%. It also lowers pain scores, but these findings are less clear. No major complications have been reported with low-dose i.v. infusion of ketamine when given up to 48 hours after surgery. While our review lends support to using low dose i.v. infusion of ketamine in the management of perioperative pain, its optimal dose and regimen remain to be determined. CONCLUSIONS: Thirty-nine clinical trials assessed a continuous infusion or a bolus of low-dose ketamine for postoperative analgesia using reduction of pain scores or reduction of the opioid consumption as the primary endpoint. The mean reduction of opioid consumption when using low-dose i.v. infusion ketamine (infusion rate less than 1.2 mg/kg/h) is 40%. Ketamine also reduces pain scores, but the amplitude of the effect is less clear. No major complications have been reported with low-dose i.v. infusion of ketamine up to 48 hours following surgery. PMID- 25530169 TI - Recognition and management of an embolized balloon expandable bovine transcatheter heart valve: treatment of an inverted valve in the aorta. PMID- 25530170 TI - Characterization of monoclonal antibody's binding kinetics using oblique incidence reflectivity difference approach. AB - Monoclonal antibodies (mAbs) against human proteins are the primary protein capture reagents for basic research, diagnosis, and molecular therapeutics. The 2 most important attributes of mAbs used in all of these applications are their specificity and avidity. While specificity of a mAb raised against a human protein can be readily defined based on its binding profile on a human proteome microarray, it has been a challenge to determine avidity values for mAbs in a high-throughput and cost-effective fashion. To undertake this challenge, we employed the oblique-incidence reflectivity difference (OIRD) platform to characterize mAbs in a protein microarray format. We first systematically determined the Kon and Koff values of 50 mAbs measured with the OIRD method and deduced the avidity values. Second, we established a multiplexed approach that simultaneously measured avidity values of a mixture of 9 mono-specific mAbs that do not cross-react to the antigens. Third, we demonstrated that avidity values of a group of mAbs could be sequentially determined using a flow-cell device. Finally, we implemented a sequential competition assay that allowed us to bin multiple mAbs that recognize the same antigens. Our study demonstrated that OIRD offers a high-throughput and cost-effective platform for characterization of the binding kinetics of mAbs. PMID- 25530171 TI - Targeting defective Toll-like receptor-3 function and idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a disease of the lung parenchyma that is invariably fatal with a median survival of 2 - 3 years. Despite considerable progress in defining the natural history of the disease, many features of IPF pathogenesis remain poorly understood. Several recent studies have highlighted links between pattern recognition receptors of innate immunity termed 'Toll-like receptors' (TLRs) and the aberrant fibrogenesis that characterizes IPF. AREAS COVERED: In this paper, we discuss the natural history of IPF and the identification of several distinct clinical phenotypes in recent years. TLRs are receptors that recognize pathogen- and/or danger-associated molecular patterns and promote an appropriate immune response. We describe in detail some of the recent works linking defective TLR3 function and an aggressive phenotype in IPF and explore the mechanisms and potential clinical implications of this initial observation. EXPERT OPINION: We explore the potential role of TLRs in this setting. We discuss recent genetic studies and the implications for future research. We propose a model of dysregulated innate immune recognition and aberrant lung healing. The potential role of research in aiding the design of clinical trials and the evidence for targeting defective TLR3 function in IPF is presented. PMID- 25530172 TI - Determination of the type and quantity of sialic acid in the egg jelly coat of the sea urchin Paracentrotus lividus using capillary LC-ESI-MS/MS. AB - Sialic acid is a terminal sugar of carbohydrate chains that participates in numerous biological events. Recent studies have explored the mechanism of carbohydrate-mediated fertilisation to understand the biochemistry of fertilisation, although the type and quantity of sialic acid and the role of sialic acid during fertilisation remain unknown. Echinoderm fertilisation in particular has been studied extensively, yet our understanding of the mechanisms of carbohydrate-mediated fertilisation and the role of sialic acid remains incomplete. In this study, we characterised the sialic acid types in the egg jelly coat of the sea urchin, Paracentrotus lividus, using the sensitive analytical system capillary liquid chromatography electro-spray ionisation tandem mass spectrometry (capLC-ESI-MS/MS). First, we isolated the egg jelly coat and released its sialic acid using acid treatment. These sialic acids were derivatised with 1,2-diamino-4,5-methylenediaoxy-benzene dihydrochloride (DMB) and injected into the capLC-ESI-MS/MS system. When compared with standards, we identified twelve different types of sialic acid according to their retention times and collision-induced dissociation fragments. The mass spectral data revealed that Neu5Gc, Neu5Ac, Neu5GcS, and Neu5Gc9Ac were the predominant types of sialic acid in the sea urchin jelly coat, with Neu5Gc being the most abundant. Other types of sialic acid detected included Neu5AcS, Neu5Gc7,9Ac2, Neu5,9Ac2, Neu5Gc8Ac, Neu5Gc7Ac, Neu5,7Ac2, Neu5Gc8,9Ac2, and Neu5,8Ac2. The types and quantities of sialic acid that we detected in the egg jelly coat will aid in the discovery of new sialic acid-specific receptors on the sperm membrane. PMID- 25530173 TI - Erratum to: dosimetric comparison of different treatment modalities for stereotactic radiosurgery of meningioma. PMID- 25530174 TI - Assessing the Awareness and Behaviors of U.S. High School Nurses With Respect to the Female Athlete Triad. AB - Female high school athletes are an at-risk population for the Female Athlete Triad-a syndrome including low energy availability (with or without disordered eating), menstrual dysfunction, and low bone mineral density. School nurses can play an important role in reducing the health burden of this syndrome, by educating coaches and athletes, and by referring symptomatic student-athletes to appropriate community resources for evaluation and treatment. This study assessed knowledge, attitudes, communication, and referral behaviors of U.S. high school nurses about the Female Athlete Triad. Participants were a random sample of 370 U.S. high school nurses. The results indicated that only 19% of the nurses were able to identify the three components of the Triad and only 25% reported that they work proactively with coaches to help prevent health issues among their female athletes. Over 95% expressed interest in learning more about the Triad. Implications for educational program design are discussed. PMID- 25530175 TI - Ronald Allen Bell, 1947-2014. PMID- 25530176 TI - Sexual Assault, Overweight, and Suicide Attempts in U.S. Adolescents. AB - Associations between overweight, sexual assault history, and suicide attempts were examined among 31,540 adolescents from the combined 2009 and 2011 nationally representative Youth Risk Behavior Surveys samples. These variables have not previously been studied concurrently. It was hypothesized that overweight and sexual assault, together, would interact and result in increased suicide attempts. Findings across analyses included (a) no significant associations between sexual assault and overweight in females or males (p = .65 and p = .90, respectively), (b) statistically significant associations between female (but not male) overweight status and suicide attempts (p = .001), (c) a strong association between sexual assault and suicide risk in males (p < .001) and females (p < .001), and (d) an elevated risk for suicide in overweight males with co-occurring sexual assault, with over 33% of males with such histories attempting suicide. Preliminary findings have powerful implications for research and secondary prevention. PMID- 25530177 TI - Genotyping of BMPR1B, BMP15 and GDF9 genes in Chilean sheep breeds and association with prolificacy. PMID- 25530178 TI - Counter-transcribed RNAs of Rhizobium leguminosarum repABC plasmids exert incompatibility effects only when highly expressed. AB - The six plasmids of Rhizobium leguminosarum VF39SM comprise nearly 35% of the bacterium's genome and are all repABC replicons. The repABC operons of the three largest plasmids of VF39SM were found to have strong incompatibility determinants in the non-protein coding regions. However, in all three repABC operons, the intergenic region between repB and repC was the strongest incompatibility factor; this intergenic region has been shown, for most repABC plasmids, to encode a counter-transcribed RNA (ctRNA) that regulates RepC abundance and therefore also rate of initiation of replication. To understand the way in which the ctRNA regulates replication and incompatibility, we carried out mutagenesis on this region from all three plasmids, using error-prone PCR. Mutants with altered incompatibility were detected by screening for their ability to co-exist in the same cell as the parent plasmid. Mutations that abolished the strong incompatibility phenotype were nearly all localized to the predicted ctRNA promoter regions. RT-PCR analysis confirmed that ctRNA was still produced in these promoter mutants, but transcriptional fusions of these mutated promoters to a gusA reporter gene showed a 10- to 50-fold decrease in activity when compared with the wild type promoter. For the repABC operons in this study, the intergenic region is critical in establishing incompatibility, and this appears to require a high level of transcription of the ctRNA. PMID- 25530179 TI - A multifunctional probe with aggregation-induced emission characteristics for selective fluorescence imaging and photodynamic killing of bacteria over mammalian cells. AB - A multifunctional probe aggregation-induced emission-Zinc(II)-dipicolylamine (AIE ZnDPA) is developed for selective targeting, fluorescence imaging, and photodynamic killing of both Gram-positive and Gram-negative bacteria over mammalian cells. The probe has significant advantages in simple probe design, enhanced fluorescence upon bacteria binding, excellent photostability, and broad spectrum antibacterial activity with almost no harm to mammalian cells. PMID- 25530180 TI - The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells. AB - Triple negative breast cancer (TNBC) patients cannot be treated with endocrine therapy or targeted therapies due to lack of related receptors. These patients overexpress the epidermal growth factor receptor (EGFR), but are resistant to tyrosine kinase inhibitors (TKIs) and anti-EGFR therapies. Mechanisms suggested for resistance to TKIs include EGFR independence, mutations and alterations in EGFR and in its downstream signalling pathways. Ligand-induced endocytosis and degradation of EGFR play important roles in the downregulation of the EGFR signal suggesting that its activity could be regulated by targeting its trafficking. Evidence in normal cells showing that the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) can associate with EGFR to regulate its trafficking, led us to hypothesize that NHERF1 expression levels could regulate EGFR trafficking and functional expression in TNBC cells and, in this way, modulate its role in progression and response to treatment. We investigated the subcellular localization of NHERF1 and its interaction with EGFR in a metastatic basal like TNBC cell model, MDA-MB-231, and the role of forced NHERF1 overexpression and/or stimulation with EGF on the sensitivity to EGFR specific TKI treatment with gefitinib. Stimulation with EGF induces an interaction of NHERF1 with EGFR to regulate its localization, degradation and function. NHERF1 overexpression is sufficient to drive its interaction with EGFR in non-stimulated conditions, inhibits EGFR degradation and increases its retention time in the plasma membrane. Importantly, NHERF1 overexpression strongly sensitized the cell to the pharmacological inhibition by gefitinib of EGFR-driven growth, motility and invadopodia-dependent ECM proteolysis. The further determination of how the NHERF1-EGFR interaction is regulated may improve our understanding of TNBC resistance to the action of existing anticancer drugs. PMID- 25530181 TI - Heixuedian (heix), a potential melanotic tumor suppressor gene, exhibits specific spatial and temporal expression pattern during Drosophila hematopoiesis. AB - The Drosophila heixuedian (heix) is the ortholog of human UBIAD1 gene (a.k.a TERE1). The protein product of UBIAD1/heix has multiple enzymatic activities, including the vitamin K2 and the non-mitochondrial CoQ10 biosynthesis. However, the expression pattern of UBIAD1/Heix during metazoan development has not been systematically studied. In this paper, we found that loss of function of heix resulted in pathological changes of larval hematopoietic system, including lymph gland hypertrophy, hemocyte overproliferation and aberrant differentiation, and melanin mass formation. Overexpression of heix cDNA under the tubulin Gal4 driver rescued the above hematopoietic defects. Interestingly, Heix was specifically expressed in plasmatocyte/macrophage lineage in srp driven EGFP positive cells on the head mesoderm during embryogenesis, while it was highly expressed in crystal cells in the primary lobes of the third instar larval lymph gland. Using qRT-PCR analysis, loss of function of heix caused aberrant activation of multiple hemocyte proliferation-related as well as immune-related pathways, including JAK/STAT pathway, Ras/MAPK pathway, IMD pathway and Toll pathway. These data suggested that heix is a potential melanotic tumor suppressor gene and plays a pivotal role in both hemocytes proliferation and differentiation in Drosophila. PMID- 25530183 TI - A case of ectopic cilia. PMID- 25530182 TI - Motor neuron cell bodies are actively positioned by Slit/Robo repulsion and Netrin/DCC attraction. AB - Motor neurons differentiate from a ventral column of progenitors and settle in static clusters, the motor nuclei, next to the floor plate. Within these cell clusters, motor neurons receive afferent input and project their axons out to muscle targets. The molecular mechanisms that position motor neurons in the neural tube remain poorly understood. The floor plate produces several types of guidance cues with well-known roles in attracting and repelling axons, including the Slit family of chemorepellents via their Robo receptors, and Netrin1 via its DCC attractive receptor. In the present study we found that Islet1(+) motor neuron cell bodies invaded the floor plate of Robo1/2 double mutant mouse embryos or Slit1/2/3 triple mutants. Misplaced neurons were born in their normal progenitor column, but then migrated tangentially into the ventral midline. Robo1 and 2 receptor expression in motor neurons was confirmed by reporter gene staining and anti-Robo antibody labeling. Mis-positioned motor neurons projected their axons longitudinally within the floor plate, and failed to reach their normal exit points. To test for potential counteracting ventral attractive signals, we examined Netrin-1 and DCC mutants, and found that motor neurons shifted dorsally in the hindbrain and spinal cord, suggesting that Netrin-1/DCC signaling normally attracts motor neurons closer to the floor plate. Our results show that motor neurons are actively migrating cells, and are normally trapped in a static position by Slit/Robo repulsion and Netrin-1/DCC attraction. PMID- 25530184 TI - Electrocardiographic diagnosis of atrial tachycardia: classification, P-wave morphology, and differential diagnosis with other supraventricular tachycardias. AB - Atrial tachycardia is defined as a regular atrial activation from atrial areas with centrifugal spread, caused by enhanced automaticity, triggered activity or microreentry. New ECG classification differentiates between focal and macroreentrant atrial tachycardia. Macroreentrant atrial tachycardias include typical atrial flutter and other well characterized macroreentrant circuits in right and left atrium. Typical atrial flutter has been described as counterclockwise reentry within right atrial and it presents a characteristic ECG "sawtooth" pattern on the inferior leads. The foci responsible for focal atrial tachycardia do not occur randomly throughout the atria but tend to cluster at characteristic anatomical locations. The surface ECG is a very helpful tool in directing mapping to particular areas of interest. Atrial tachycardia should be differentiated from other supraventricular tachycardias. We propose a diagnostic algorithm in order to help the physician to discriminate among those. Holter analysis could offer further details to differentiate between atrial tachycardia and another supraventricular tachycardia. However, if the diagnosis is uncertain, it is possible to utilize vagal maneuvers or adenosine administration. In conclusion, in spite of well-known limits, a good interpretation of ECG is very important and it could help the physician to manage and to treat correctly patients with atrial tachycardia. PMID- 25530185 TI - Drift in children's categories: when experienced distributions conflict with prior learning. AB - Psychological intuitions about natural category structure do not always correspond to the true structure of the world. The current study explores young children's responses to conflict between intuitive structure and authoritative feedback using a semi-supervised learning (Zhu et al., 2007) paradigm. In three experiments, 160 children between the ages of 4 and 8 learned a one-dimensional decision criterion for distinguishing yummy and yucky 'alien fruits'. They then categorized a large number of new fruits without corrective feedback. The distribution of the new fruits was manipulated such that the natural boundary in the stimuli did not always correspond to the learned boundary. Children changed their decision criteria to reflect the structure of the new stimuli, effectively unlearning the original boundary. Younger children were especially swayed by the distributional information, being relatively insensitive to feedback that the original non-natural boundary was, in fact, still correct. Results are discussed in terms of children's ability to selectively attend to specific information (i.e. feedback vs. distribution), and their interests in forming generally useful representations of experience. PMID- 25530186 TI - A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. AB - Protein- and peptide-based tumor vaccines depend on strong adjuvants to induce potent immune responses. Here, we demonstrated that a recently developed novel adjuvant based on a non-coding, long-chain RNA molecule, termed RNAdjuvant((r)) , profoundly increased immunogenicity of both antigen formats. RNAdjuvant((r)) induced balanced, long-lasting immune responses that resulted in a strong anti tumor activity. A direct comparison to Poly(I:C) showed superior efficacy of our adjuvant to enhance antigen-specific multifunctional CD8(+) T-cell responses and mediate anti-tumor responses induced by peptide derived from HPV-16 E7 protein in the syngeneic TC-1 tumor, a murine model of human HPV-induced cervical cancer. Moreover, the adjuvant was able to induce functional memory responses that mediated complete tumor remission. Despite its remarkable immunostimulatory activity, our RNA-based adjuvant exhibited an excellent pre-clinical safety profile. It acted only locally at the injection site where it elicited a transient but strong up-regulation of pro-inflammatory and anti-viral cytokines as well as cytoplasmic RNA sensors without systemic cytokine release. This was followed by the activation of immune cells in the draining lymph nodes. Our data indicate that our RNA-based adjuvant is a safe and potent immunostimulator that may profoundly improve the efficacy of a variety of cancer vaccines. PMID- 25530187 TI - Eosinophilic fasciitis: clinical characteristics and response to methotrexate. AB - AIM: To describe our experience with 16 patients with eosinophilic fasciitis (EF) treated in our clinic over 14 years. METHODS: We retrospectively reviewed the charts of all patients with biopsy-proven EF. We collected data regarding demographics, clinical presentations, possible triggers, labs, imaging, treatment and response to therapy on follow-up. RESULTS: Eight women and eight men with a mean age of 52 years were included in the study. Three patients related the onset to prior strenuous exercise and one was exposed to vibratory machinery. Fourteen patients had a gradual onset and presented with induration of the skin. Two other patients presented with acute-onset and significant edema and weight gain. All patients required immunosuppressive therapy. Methotrexate (MTX) was used in all of our patients. The rate of complete remission was ~60%. Although the recurrence rate after stopping MTX was 70%, these patients responded well to re-treatment with MTX. CONCLUSION: We believe that MTX represents an effective treatment option for EF. The rarity of this disease would make a double-blind controlled trial study difficult to perform. PMID- 25530188 TI - [Recommendations for radiological diagnosis and assessment of treatment response in lung cancer: a national consensus statement by the Spanish Society of Medical Radiology and the Spanish Society of Medical Oncology]. AB - The last decade has seen substantial progress in the diagnostic and therapeutic approach to lung cancer, thus meaning that its prognosis has improved. The Spanish Society of Medical Radiology (SERAM) and the Spanish Society of Medical Oncology (SEOM) have therefore produced a national consensus statement in order to make recommendations for radiological diagnosis and assessment of treatment response in patients with lung cancer. This expert group recommends multi detector computed tomography (MDCT) as the technique of choice for investigating this disease. The radiology report should include a full assessment by the TNM staging system. Lastly, when the patient is on immunotherapy, response evaluation should employ not only Response Evaluation Criteria in Solid Tumours (RECIST 1.1) but also Immune-Related Response Criteria (irRC). PMID- 25530189 TI - Developmental logics: Brain science, child welfare, and the ethics of engagement in Japan. AB - This article explores the unintended consequences of the ways scholars and activists take up the science of child development to critique the Japanese child welfare system. Since World War II, Japan has depended on a system of child welfare institutions (baby homes and children's homes) to care for state wards. Opponents of institutional care advocate instead for family foster care and adoption, and cite international research on the developmental harms of institutionalizing newborns and young children during the "critical period" of the first few years. The "critical period" is understood as the time during which the caregiving a child receives shapes neurological development and later capacity to build interpersonal relationships. These discourses appear to press compellingly for system reform, the proof resting on seemingly objective knowledge about child development. However, scientific evidence of harm is often mobilized in tandem with arguments that the welfare system is rooted in Japanese culture, suggesting durability and resistance to change. Further, reform efforts that use universalizing child science as "proof" of the need for change are prone to slip into deterministic language that pathologizes the experiences of people who grew up in the system. This article explores the reasons why deterministic models of child development, rather than more open-ended models like neuroplasticity, dominate activist rhetorics. It proposes a concept, "ethics of engagement," to advocate for attention to multiple scales and domains through which interpersonal ties are experienced and embodied over time. Finally, it suggests the possibility of child welfare reform movements that take seriously the need for caring and transformative relationships throughout life, beyond the first "critical years," that do not require deterministic logics of permanent delay or damage. PMID- 25530190 TI - Significance of the vacuum phenomenon in patients with trauma evaluated by whole body computed tomography. AB - BACKGROUND: Severely traumatized patients undergo whole-body computed tomography (WCT) to detect lethal anatomical injuries. When checking the images, we have sometimes recognized minute gas (the vacuum phenomenon [VP]) near the traumatized lesions. Accordingly, we investigated the significance of the VP in patients with trauma. BASIC PROCEDURES: From April to October 2013, a medical record review was retrospectively performed for all patients with trauma. The exclusion criteria included an age more than 60 years, patients who did not receive the WCT, scan and those in cardiopulmonary arrest on arrival. The subjects were divided into 2 groups: a VP group (n=19), which included patients who had the VP, and a control group (n=49). MAIN FINDINGS: There were no significant differences between the 2 groups with regard to age, the mechanism of injury, or the survival rate. In contrast, the ratio of women, the Injury Severity Score, and the duration of hospitalization in the VP group were significantly higher than those in the control group. The greatest number of the VP was located at or near rib fractures, followed by joint spaces that experienced a traumatic impact. PRINCIPAL CONCLUSION: This study demonstrated that the VP tended to be observed most often in severely traumatized female cases. The VP is observed at locations that experience a traumatic impact, so an analysis of the VP may be useful to elucidate the mechanism of injuries. The presence of traumatic VP itself does not influence the final outcome. PMID- 25530191 TI - A hair-raising diagnosis: goose bumps as sign of herpes simplex encephalitis. PMID- 25530192 TI - Succesfull treatment of supralethal caffeine overdose with a combination of lipid infusion and dialysis. PMID- 25530193 TI - Measures to facilitate endotracheal tube-assisted orogastric tube insertion. PMID- 25530195 TI - Development of a sensitive method for the determination of acrylamide in coffee using high-performance liquid chromatography coupled to a hybrid quadrupole Orbitrap mass spectrometer. AB - The emerging trend towards high-resolution mass spectrometry (MS) alternatives was evaluated by the application of Orbitrap MS for the determination of acrylamide in coffee samples. The high resolving power of the Orbitrap MS provided the high selectivity and sensitivity that enabled quantitative analysis of acrylamide in complex matrices, such as coffee. Several sample preparation methods and scanning modes of the MS (full MS, t-SIM, t-MS2) were assessed in order to optimise parameters of the analytical method. The final procedure involved the extraction of acrylamide with acetonitrile, solid-phase extraction with dispersive primary secondary amine (PSA) and amino columns, and the detection by ultra-performance liquid chromatography coupled to a hybrid quadrupole-Orbitrap MS (HPLC-Q-Orbitrap) operated in targeted MS2 scanning mode. The repeatability of the method at the lowest calibration level (10 MUg kg(-1)), expressed as relative standard deviation, was 7.8% and the average recovery of acrylamide was 111%. The proposed method was applied to the determination of acrylamide in 22 samples of roasted coffee obtained from the Latvian retail market. Acrylamide concentration in coffee samples was in the range of 166-503 MUg kg(-1). PMID- 25530194 TI - Lack of evidence for intravenous vasodilators in ED patients with acute heart failure: a systematic review. AB - There are nearly 700,000 annual US emergency department (ED) visits for acute heart failure (AHF). Although blood pressure is elevated on most of these visits, acute therapy remains focused on preload and not afterload reduction. Data from recent prospective studies suggest that patients with AHF with concomitant acute hypertension benefit from intravenous (IV) vasodilators. To better understand the use of vasodilators for such patients, we conducted a systematic review of (1) currently available intravenous vasodilators for ED patients with AHF, or (2) intravenous vasodilators that are not yet available, but have completed phase III clinical trials in AHF, and may be available for ED use in the future. We used multiterm search queries to retrieve research involving nitroglycerin, nitroprusside, enalaprilat, hydralazine, relaxin, and nesiritide. A total of 2001 unique citations were identified from 3 databases: PubMed, EMBASE, and CINAHL. Of these, 1966 were excluded on the basis of established review criteria, leaving 35 published articles for inclusion. Our primary finding was that intravenous nitrovasodilators, when used in the treatment of AHF in ED and ED-like settings, do improve short-term symptoms and appear safe to administer. There are no data suggesting that they impact mortality. Other commonly used vasodilators such as hydralazine and enalaprilat have very little published data about their safety and efficacy. Of note, few studies enrolled patients early in their course of treatment. Thus, to assess the specific impact of vasodilator therapy on both short- and long-term outcomes, future research efforts should focus on patient recruitment in the ED setting. PMID- 25530196 TI - Developmental dyslexia and phonological processing in European Portuguese orthography. AB - This study analysed the performance of phonological processing, the diagnostic accuracy and the influence on reading in children who were native speakers of an orthography of intermediate depth. Portuguese children with developmental dyslexia (DD; N=24; aged 10-12 years), chronological age (CA)-matched controls (N=24; aged 10-12 years) and reading level (RL)-matched controls (N=24; aged 7-9 years) were tested on measures of phonological processing (phonological awareness, naming speed and verbal short-term memory) and reading. The results indicated that the children with DD performed significantly poorer in all measures compared with the CA and RL. Phonological awareness and naming speed showed a high accuracy (receiver operating characteristics curve analysis) for discriminating the children with DD from the CA and RL, whereas the presence of abnormally low scores in phonological awareness and naming speed was more frequent in the DD group than in the controls and the normative population. Hierarchical linear regression analyses revealed that phonological awareness was the most important predictor of all reading accuracy measures, whereas naming speed was particularly related to text reading fluency. PMID- 25530197 TI - [Cross-cultural adaptation of the Mishel uncertainty in illness scale, in a population with chronic kidney disease treated with hemodialysis]. AB - OBJECTIVE: The aim of this article is to translate and adapt the Mishel uncertainty scale to the Spanish context. METHOD: A cross-sectional study for transcultural adaptation and validation of the Mishel uncertainty scale. The study population were patients with chronic renal disease treated with hemodialysis. The original English version of the "Mishel uncertainty in illness scale" was translated into Spanish, then back-translated into English, and all the discrepancies were resolved after consulting with experts. A panel including 11 experts in renal care assessed this culturally adapted Spanish version, in order to score the content validity. It was administered to 116 patients in order to calculate the psychometric properties scale. Construct validity was calculated using factor analysis, and internal consistency using Cronbach's alpha coefficient. Relationships between variables related to the main theory were analyzed. RESULTS: The Spanish version has 17 items, distributed in 2 dimensions: ambiguity and complexity. A content validity index average of 0.7 and a Cronbach's alpha 0.72. Statistically significant association was found between uncertainty, gender, educational level and disease relapse. CONCLUSIONS: Cross cultural adaptation of the Mishel uncertainty in illness scale preserves equivalence with the original. Content validation identified most useful items for chronic renal patients. The multidimensional nature of the scale is reaffirmed. The association between uncertainty and the level of education is also confirmed. PMID- 25530198 TI - The best of both worlds: active enzymes by grafting-to followed by grafting-from a protein. AB - Hydrophilic polymers were attached to lysozyme by a combination of grafting-to and grafting-from approaches using RAFT polymerization. A hydrophilic oligomer was synthesized, and attached to the protein. The protein-oligomer hybrid contained the RAFT end group, enabling chain extension in solution. Lysozyme maintained activity throughout this process. PMID- 25530199 TI - Implementing an ally development model to promote safer schools for LGB youth: a trans-disciplinary approach. AB - Lesbian, gay, and bisexual (LGB) students experience ongoing bullying, harassment, and lack of safety in school. Specialized instructional support personnel (SISPs), such as school counselors, school social workers, and school psychologists, are in a unique position to advocate for LGB students and to implement an ally development model. The purpose of this article is to describe the current climate for LGB students, to discuss the current barriers facing SISPs in advocating for change, and to provide a model of ally development for use at each level of the K-12 system. PMID- 25530200 TI - Design of hyperthermophilic lipase chimeras by key motif-directed recombination. AB - Recombination of diverse natural evolved domains within a superfamily offers greater opportunity for enzyme function leaps. How to recombine protein modules from distant parents with less disruption in cross-interfaces is a challenging issue. Here, we identified the existence of a key motif, the sequence VVSVN(D)YR, within a structural motif psi loop in the alpha/beta-hydrolase fold superfamily, by using a MEME server and the PROMOTIF program. To obtain thermostable lipase like enzymes, two chimeras were engineered at the key motif regions through recombination of domains from a mesophilic lipase and a hyperthermophilic esterase/peptidase with amino acid identity less than 21 %. The chimeras retained the desirable substrate preference of their mesophilic parent and exhibited more than 100-fold increased thermostability at 50 degrees C. Through site-directed mutation, we further improved activity of the chimera by 4.6-fold. The recombination strategy presented here enables the creation of novel catalysts. PMID- 25530201 TI - Polymorphic variation in the epigenetic gene DNMT3B modulates the environmental impact on cognitive ability: a twin study. AB - BACKGROUND: Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors. METHODS: Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance. RESULTS: MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs. CONCLUSIONS: Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity. PMID- 25530202 TI - A reason to celebrate! PMID- 25530205 TI - Multicolor analysis of oligodendrocyte morphology, interactions, and development with Brainbow. AB - Oligodendrocytes are the myelinating cells of the central nervous system. Multiple markers are available to analyze the populations of oligodendroglial cells and their precursors during development and in pathological conditions. However, the behavior of oligodendrocytes remains poorly characterized in vivo, especially at the level of individual cells. Studying this aspect has been impaired so far by the lack of suitable methods for visualizing single oligodendrocytes, their processes, and their interactions during myelination. Here, we have used multicolor labeling technology to single-out simultaneously many individual oligodendrocytes in the postnatal mouse optic nerve. This method is based on Brainbow, a transgenic system for stochastic expression of multiple fluorescent protein genes through Cre-lox recombination, previously used for visualizing axons and neurons. We used tamoxifen-inducible recombination in myelinating cells of Brainbow transgenic mice to obtain multicolor labeling of oligodendrocytes. We show that the palette of colors expressed by labeled oligodendrocytes is tamoxifen dependent, with the highest doses producing the densest and most colorful labeling. At low doses of tamoxifen, the morphology of single or small clusters of fluorescent oligodendrocytes can be studied during postnatal development and in adult. Internodes are labeled to their extremities, revealing nodes of Ranvier. The new mouse model presented here opens new possibilities to explore the organization and development of the oligodendrocyte network with single-cell resolution. PMID- 25530206 TI - The behavioralist as nutritionist: leveraging behavioral economics to improve child food choice and consumption. AB - We leverage behavioral economics to explore new approaches to tackling child food choice and consumption. Using a field experiment with >1500 children, we report several key insights. We find that incentives have large influences: in the control, 17% of children prefer the healthy snack, whereas introduction of small incentives increases take-up of the healthy snack to ~75%. There is some evidence that the effects continue post-treatment, consistent with a model of habit formation. We find little evidence that the framing of incentives (loss vs. gain) matters. Educational messaging alone has little effect, but we observe a combined effect of messaging and incentives: together they provide an important influence on food choice. PMID- 25530207 TI - Effects of an aglycone-rich biotransformed soybean extract in human endothelial cells. AB - Estrogen replacement therapy is not thought to be a safe treatment for prevention of cardiovascular disease in menopausal women; isoflavones are a possible alternative. Estrogen produces beneficial effects on the cardiovascular system by enhancing production of nitric oxide, a vasoprotective and antiatherosclerotic agent. Estrogen-like compounds such as isoflavones are also suggested for increasing nitric oxide production. Isoflavones are present mainly in soy foods as glucosides, but soy isoflavone aglycones, the biologically active estrogen like compounds, are absorbed faster and in higher amounts than their glucoside derivatives and show higher biological activity, implying that they may be more effective in preventing chronic diseases such as coronary heart disease. We evaluated an extract of soybeans fermented by Aspergillus awamori on which polyphenol glucosides were biotransformed to aglycone forms on production of nitric oxide, prostaglandin E2 and endothelin-1 in vitro in human endothelial cells, comparing it with a non-fermented extract. Bioconverted soybean extracts enhanced endothelin-1, nitric oxide and prostaglandin E2 production, while the unfermented extract only enhanced endothelin-1 production. Thus, only the aglycone-rich forms of soybean extracts were able to increase nitric oxide and prostaglandin E2 production, demonstrating that, in endothelial cells in vitro, they may be usable as therapeutic agents against the development of atherosclerosis. PMID- 25530208 TI - A flexible spiral-type supercapacitor based on ZnCo2O4 nanorod electrodes. AB - Fiber electrochemical capacitors show advantages such as light weight and flexibility, and may also be easily integrated or woven into various electronic devices with low cost and high efficiency. In this work, we report the preparation of ZnCo2O4 nanorods on a Ni wire as the fiber electrodes, using a simple and rapid single-step hydrothermal process. The electrochemical properties of the free-standing supercapacitor were analyzed using a two electrode system. The supercapacitor achieved a specific capacitance of 10.9 F g(-1). An energy density of 76 mWh kg(-1) and a power density of up to 1.9 W kg(-1) were also obtained for the fiber supercapacitors. The flexible supercapacitor exhibited remarkable electrochemical stability when subjected to bending at various angles, illustrating the promise for use as electrodes for wearable energy storage. PMID- 25530209 TI - Donald M. Wieland, Ph.D. PMID- 25530210 TI - Assessing activation of hepatic stellate cells by (99m)Tc-3PRGD2 scintigraphy targeting integrin alphavbeta3: a feasibility study. AB - OBJECTIVE: Hepatic stellate cell (HSC) activation, which is accompanied by increased expression of integrin alphavbeta3, is an important factor in liver fibrogenesis. Molecular imaging targeting the integrin alphavbeta3 could provide a non-invasive method for evaluating the expression and the function of the integrin alphavbeta3 on the activated HSCs (aHSCs) in the injured liver, and then provide important prognostic information. (99m)Tc-3PRGD2 is such a radiotracer specific for integrin alphavbeta3. In this study, we aimed to compare the differences in liver uptake and retention of the (99m)Tc-3PRGD2 between normal liver and injured liver to evaluate the feasibility of (99m)Tc-3PRGD2 scintigraphy for this purpose. METHODS: We used planar scintigraphy to assess changes in integrin alphavbeta3 binding of intravenously-administered (99m)Tc 3PRGD2 in the livers of rats with thioacetamide (TAA)-induced liver fibrosis compared with the controls. We co-injected cold c(RGDyK) with (99m)Tc-3PRGD2 to assess the specific binding of the radiotracer. We performed Sirius red staining to assess liver fibrosis, immunofluorescent colocalization to identify the location of integrin alphavbeta3 expressed in the fibrotic liver, and we measured protein and messenger RNA expression of integrin alphavbeta3 and alpha smooth muscle actin (alpha-SMA) in the control and fibrotic livers. RESULTS: The fibrotic livers showed enhanced (99m)Tc-3PRGD2 uptake and retention. The radiotracer was demonstrated to bind specifically with the integrin alphavbeta3 mainly expressed on the aHSCs. The liver-to-heart ratio at 30 min post-injection was higher in the fibrotic livers than in the control livers (TAA, 1.98+/-0.08 vs. control, 1.50+/-0.12, p<0.01). The liver t1/2 was longer than in the controls (TAA, 27.07+/-10.69 min vs. control, 12.67+/-4.10 min, p<0.01). The difference of heart t1/2 between the two groups was not statistically significant (TAA, 3.13+/ 0.63 min vs. control, 3.41+/-0.77 min, p=0.94). CONCLUSIONS: (99m)Tc-3PRGD2 molecular imaging can provide a non-invasive method for assessing activation of HSCs. PMID- 25530211 TI - Instruments to assess sarcopenia and physical frailty in older people living in a community (care) setting: similarities and discrepancies. AB - OBJECTIVES: Both sarcopenia and physical frailty are geriatric syndromes causing loss of functionality and independence. This study explored the association between sarcopenia and physical frailty and the overlap of their criteria in older people living in different community (care) settings. Moreover, it investigated the concurrent validity of the FRAIL scale to assess physical frailty, by comparison with the widely used Fried criteria. DESIGN: Data were retrieved from the cross-sectional Maastricht Sarcopenia Study (MaSS). SETTING: The study was undertaken in different community care settings in an urban area (Maastricht) in the south of the Netherlands. PARTICIPANTS: Participants were 65 years or older, gave written informed consent, were able to understand Dutch language, and were not wheelchair bound or bedridden. INTERVENTION: Not applicable. MEASUREMENTS: Sarcopenia was identified using the algorithm of the European Working Group on Sarcopenia in Older People. Physical frailty was assessed by the Fried criteria and by the FRAIL scale. Logistic regression was performed to assess the association between sarcopenia and physical frailty measured by the Fried criteria. Spearman correlation was performed to assess the concurrent validity of the FRAIL scale compared with the Fried criteria. RESULTS: Data from 227 participants, mean age 74.9 years, were analyzed. Sarcopenia was identified in 23.3% of the participants, when using the cutoff levels for moderate sarcopenia. Physical frailty was identified in 8.4% (>=3 Fried criteria) and 9.3% (>=3 FRAIL scale criteria) of the study population. Sarcopenia and physical frailty were significantly associated (P = .022). Frail older people were more likely to be sarcopenic than those who were not frail. In older people who were not frail, the risk of having sarcopenia increased with age. Next to poor grip strength (78.9%) and slow gait speed (89.5%), poor performance in other functional tests was common in frail older people. The 2 physical frailty scales were significantly correlated (r = 0.617, P < .001). CONCLUSION: Sarcopenia and physical frailty were associated and partly overlap, especially on parameters of impaired physical function. Some evidence for concurrent validity between the FRAIL scale and Fried criteria was found. Future research should elicit the value of combining sarcopenia and frailty measures in preventing disability and other negative health outcomes. PMID- 25530212 TI - Surface softening in metal-ceramic sliding contacts: an experimental and numerical investigation. AB - This study investigates the tribolayer properties at the interface of ceramic/metal (i.e., WC/W) sliding contacts using various experimental approaches and classical atomistic simulations. Experimentally, nanoindentation and micropillar compression tests, as well as adhesion mapping by means of atomic force microscopy, are used to evaluate the strength of tungsten-carbon tribolayers. To capture the influence of environmental conditions, a detailed chemical and structural analysis is performed on the worn surfaces by means of XPS mapping and depth profiling along with transmission electron microscopy of the debris particles. Experimentally, the results indicate a decrease in hardness and modulus of the worn surface compared to the unworn one. Atomistic simulations of nanoindentation on deformed and undeformed specimens are used to probe the strength of the WC tribolayer and despite the fact that the simulations do not include oxygen, the simulations correlate well with the experiments on deformed and undeformed surfaces, where the difference in behavior is attributed to the bonding and structural differences of amorphous and crystalline W-C. Adhesion mapping indicates a decrease in surface adhesion, which based on chemical analysis is attributed to surface passivation. PMID- 25530213 TI - Confounding compression: the effects of posture, sizing and garment type on measured interface pressure in sports compression clothing. AB - The purpose of this investigation was to measure the interface pressure exerted by lower body sports compression garments, in order to assess the effect of garment type, size and posture in athletes. Twelve national-level boxers were fitted with sports compression garments (tights and leggings), each in three different sizes (undersized, recommended size and oversized). Interface pressure was assessed across six landmarks on the lower limb (ranging from medial malleolus to upper thigh) as athletes assumed sitting, standing and supine postures. Sports compression leggings exerted a significantly higher mean pressure than sports compression tights (P < 0.001). Oversized tights applied significantly less pressure than manufacturer-recommended size or undersized tights (P < 0.001), yet no significant differences were apparent between different-sized leggings. Standing posture resulted in significantly higher mean pressure application than a seated posture for both tights and leggings (P < 0.001 and P = 0.002, respectively). Pressure was different across landmarks, with analyses revealing a pressure profile that was neither strictly graduated nor progressive in nature. The pressure applied by sports compression garments is significantly affected by garment type, size and posture assumed by the wearer. PMID- 25530214 TI - Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. AB - We investigated the combination of midostaurin and azacitidine (AZA) in patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Patients received AZA 75 mg m(-2) on days 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (P = 0.05) and in patients not previously transplanted (P = 0.01). Thirty-two (59%) patients have died, all of complications related to disease progression. G3 4 nonhematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high-risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted. PMID- 25530215 TI - Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex. AB - The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents. PMID- 25530216 TI - ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions. AB - Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to beta1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as beta1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. PMID- 25530217 TI - A protein kinase A (PKA)/beta-catenin pathway sustains the BMP2/DLX3-induced osteogenic differentiation in dental follicle cells (DFCs). AB - The directed expression of osteogenic transcription factors via a balanced activation of signaling pathways is an important prerequisite for the development of mineralized tissues. A positive-feedback loop of the BMP2-dependent SMAD signaling pathway and the DLX3 transcription factor (BMP2/DLX3 pathway) directs the osteogenic differentiation of periodontal precursor cells from the dental follicle (DFCs). However, little is known how this BMP2/DLX3 pathway interacts with other crucial signaling pathways such as the WNT/beta-catenin signaling pathway. This study investigated the interaction between the BMP2/DLX3 pathway and the WNT pathway during the osteogenic differentiation of DFCs. BMP2 induced the WNT/beta-catenin pathway in DFCs and phosphorylates beta-catenin via protein kinase A (PKA). Moreover, only BMP2 facilitated the binding of LEF1/SMAD4/beta catenin complex to the DLX3 promoter, while an inducer of the canonical WNT pathway, WNT3A, act as an inhibitor. Although WNT3A inhibits the osteogenic differentiation of DFCs the expression of beta-catenin was crucial for both the expression of DLX3 and for the osteogenic differentiation. In conclusion, while the activation of the canonical WNT pathway inhibits the osteogenic differentiation of DFCs, beta-catenin sustains the BMP2/DLX3-mediated osteogenic differentiation via the activation of PKA. PMID- 25530218 TI - Nitidine chloride induces apoptosis in human hepatocellular carcinoma cells through a pathway involving p53, p21, Bax and Bcl-2. AB - Nitidine chloride (NC), a novel benzo[c]phenanthridine alkaloid, induces the growth inhibition of cancer cells. Previously it was demonstrated that SMMC-7721 human hepatocellular carcinoma (HCC) cells are highly susceptible to the antiproliferative effects of NC. However, the specific mechanisms remained unclear. In the present study the pathways of growth inhibition induced by NC in SMMC-7721 cells were investigated. The effects of NC on SMMC-7721 cell proliferation were characterized by MTT and colony formation assays. Additionally, BALB/c nude mice were transplanted with SMMC-7721 cells to verify the inhibition of HCC by NC in vivo. The results showed that NC inhibited the proliferation of SMMC-7721 cells in vitro in a time- and dose-dependent manner and identified efficacy in vivo in a mouse model of HCC. Acridine orange (AO) staining, transmission electron microscopy, Annexin V/PI staining, TUNEL assay and caspase-3 activation assays were used to investigate apoptosis and the cell cycle distribution. Inhibition was mediated in part by cell cycle arrest in G2/M, leading to chromatin condensation, DNA fragmentation and the formation of apoptotic bodies. Apoptosis was also verified by Annexin V/PI staining, TUNEL assay and caspase-3 activation. To assess the levels of the cell cycle and apoptotic regulators, immunohistochemical staining, ELISA, real-time PCR and RNA interference (RNAi) were employed. The apoptotic process triggered by NC involved the upregulation of p53, p21 and Bax, and the downregulation of Bcl-2. These data elucidate a pathway of apoptosis in SMMC-7721 cells that involves G2/M arrest, upregulation of p53, Bax, caspase-3 and p21, and downregulation of Bcl-2. PMID- 25530219 TI - Homotypic receptor-receptor interactions regulating Eph signaling. AB - The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, and mediate many other cell-cell communication events. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. Recent structural, biochemical and cell-biological studies revealed that these assemblies are generated not only via Eph-ephrin interactions, but also via homotypic interactions between neighboring receptor molecules. In addition, Eph Eph interactions mediate receptor pre-clustering, which ensures fast and efficient activation once ligands come into contact range. Here we summarize the current knowledge about the homotypic Eph-Eph interactions and discuss how they could modulate the initiation of Eph/ephrin signaling. PMID- 25530220 TI - Trends in outcomes, complications, and hospitalization costs for hemispherectomy in the United States for the years 2000-2009. AB - OBJECTIVE: Hemispherectomy is an established surgical treatment for carefully selected pediatric patients with intractable epilepsy. Published perioperative data report low mortality rates and seizure reduction rates of 50-89%. This study investigates trends in the demographics, hospital utilization, and in-hospital complication rates of patients undergoing hemispherectomy over the past decade in the United States, using the nationally representative Kids' Inpatient Database (KID). METHODS: The KID was queried for all discharges with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure code for hemispherectomy in the years 2000, 2003, 2006, and 2009. The patient cohorts from these four time points were compared, analyzing differences in demographic data, insurance and payer status, total cost, length of stay, in hospital mortality, and complications. National estimates and 95% confidence intervals are reported given the weighted sample design of KID. RESULTS: This study identified an estimated total of 552 hospital admissions for hemispherectomy surgery during the years studied in this cohort. The incidence of this procedure increased from 1.2/100,000 admissions in 2000 to 2.2/100,000 in 2009 (p=0.05). Mean age was 6.7 years (range 0-20). There were no significant changes in demographics (age, gender, or race), hospital descriptors (size or type), insurance type, or zip code income quartile. There was a significant increase in total cost, from $42,807 in 2003 to $57,443 in 2009 (p=0.015) (adjusted to 2009 dollars). There were no trends in postoperative complications. In-hospital mortality occurred in five subjects (0.9%). Ventricular shunt placement during hemispherectomy hospitalizations increased over time from 6.7% to 16.5% (p=0.056). Hospitals that performed two or more hemispherectomies yearly had a significantly decreased incidence of in-hospital mortality (odds ratio [OR] 0.08, p=0.04) and an increased incidence of blood transfusion (OR 3.7, p=0.01) compared to hospitals that performed 0-1 procedures a year. SIGNIFICANCE: Hemispherectomy procedures increased slightly in frequency over the past decade, with no change in demographic characteristics of the patients over time. Rates of mortality and perioperative complications remained low. Total costs have increased significantly over time. In-hospital mortality was lower in higher volume hospitals. PMID- 25530221 TI - Outcomes and ventricular tachycardia recurrence characteristics after epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - BACKGROUND: Variable success rates have been reported after epicardial radiofrequency catheter ablation (RFA) in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The details of the electroanatomic substrate are limited to a few studies, and the characteristics of the recurrent ventricular tachycardia (VT) in ARVD/C remain largely unknown. OBJECTIVE: The purpose of this study was to report procedural strategy, safety, and efficacy of epicardial RFA at a tertiary single center with a focus on the characteristics of the substrate and recurrent VT. METHODS: We included 30 ARVD/C patients (mean age 33.1 +/- 11.1 years, 53% male) who underwent endocardial/epicardial mapping and epicardial catheter ablation of VT at the Johns Hopkins Hospital. Implantable cardioverter-defibrillator interrogations were evaluated for VT recurrence. RESULTS: The majority of critical VT circuits (69%) were on the epicardial surface, mostly in the subtricuspid region. Eight patients (27%) experienced VT recurrence after epicardial RFA, and the VT-free survival was 83%, 76%, and 70% at 6,12, and 24, months respectively. A significant reduction of VT burden was observed (P <.001), even among those with VT recurrence. No complications occurred except for acute pericarditis in 1 patient. The majority of VT recurrences occurred during the first year after RFA, during exercise, had fast cycle lengths, and required implantable cardioverter-defibrillator shock for termination. CONCLUSION: The vast majority of critical VT circuits were epicardial, mostly in the subtricuspid region. Epicardial RFA of VT appears to be both safe and effective in achieving arrhythmia control in ARVD/C. The features of the recurrent VT suggest a possible catecholamine-mediated mechanism with an origin in a region not targeted for ablation. PMID- 25530222 TI - Use of vitamin D receptor activator, incident cardiovascular disease and death in a cohort of hemodialysis patients. AB - The use of vitamin D receptor activators (VDRAs) is an independent predictor of a lower risk of death from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). We examined whether the use of VDRAs and other CKD-mineral bone disorder (MBD)-related factors are associated with incident CVD or death after CVD in hemodialysis patients. This is a historical cohort study of 37 690 prevalent hemodialysis patients without previous history of CVD at the end of 2004 extracted from a nationwide registry in Japan. The key exposure was the use of VDRAs, and the outcomes were incident CVD (myocardial infarction, cerebral infarction, cerebral hemorrhage, and sudden death) and death after CVD during the 1-year follow-up. VDRAs were used in 57% of the subjects at baseline. We identified 2433 patients with incident CVD and 397 deaths after the events. In multivariate logistic regression models, independent predictors of incident CVD were non-use of VDRA, higher intact PTH, non-use of calcium-based phosphate binder, and non-use of non-calcium-based phosphate binder. Risk of death after CVD was not significantly associated with VDRA, whereas it was lower in those with lower corrected calcium, and the risk was higher in those with higher phosphate and in non-users of calcium-based phosphate binders. The use of VDRAs was associated with a lower risk of incident CVD but not with death after CVD in this large cohort of hemodialysis patients. The CKD-MBD-related predictors of poor outcomes are associated with the risk of incident CVD, the risk of death after CVD, or both. PMID- 25530223 TI - As old as the mountains: the radiations of the Ericaceae. AB - Mountains are often more species-rich than lowlands. This could be the result of migration from lowlands to mountains, of a greater survival rate in mountains, or of a higher diversification rate in mountains. We investigated this question in the globally distributed family Ericaceae, which includes c. 4426 species ranging from sea level to > 5000 m. We predict that the interaction of low specific leaf area (SLA) and montane habitats is correlated with increased diversification rates. A molecular phylogeny of Ericaceae based on rbcL and matK sequence data was built and dated with 18 fossil calibrations and divergence time estimates. We identified radiations using bamm and correlates of diversification rate changes using binary-state speciation and extinction (BiSSE) and multiple-state speciation and extinction (MuSSE) analyses. Analyses revealed six largely montane radiations. Lineages in mountains diversified faster than nonmountain lineages (higher speciation rate, but no difference in extinction rate), and lineages with low SLA diversified faster than high-SLA lineages. Further, habitat and trait had a positive interactive effect on diversification. Our results suggest that the species richness in mountains is the result of increased speciation rather than reduced extinction or increased immigration. Increased speciation in Ericaceae was facilitated by low SLA. PMID- 25530224 TI - Spectral-domain optical coherence tomography in hydroxychloroquine retinopathy. PMID- 25530225 TI - Gastric residuals, feeding intolerance, and necrotizing enterocolitis in preterm infants. PMID- 25530226 TI - Were There "Additional Foreseeable Risks" in the SUPPORT Study? Lessons Not Learned from the ARDSnet Clinical Trials. AB - Even though the interventions were adapted from standard clinical practice, the way they were provided meant that the care given infants in the study was distinctly different from standard care, with different risk profiles. Parents should have been informed about those differences. PMID- 25530227 TI - Brucella suis infection in domestic pigs in Sardinia (Italy). AB - During a 4-year (2007-2010) survey, the presence of Brucella suis infection in domestic pigs in Sardinia was investigated. Serum samples were collected from breeding pigs located on 108 commercial farms with documented reproductive problems and analysed using the Rose Bengal (RBT) and complement fixation (CFT) tests for screening and confirmation of Brucella, respectively. Of the 1251 serum samples analysed by RBT, 406 sera, originating from 36 farms, were positive for B. suis. CFT was positive in 292/748 sera analysed, confirming positivity in all 36 pig herds. Pigs with international complement fixation test units per ml (ICFTU/ml) values ?160 were slaughtered, and their organs collected for bacteriological examination and testing by polymerase chain reaction (PCR). Brucella spp. strains were isolated in culture from 13/502 organs analysed, and subsequently identified as B. suis biovar 2. PCR detected positivity to Brucella spp. in 19/285 organs analysed. These results confirm the presence and emergence of B. suis infection in domestic pigs in Sardinia. PMID- 25530228 TI - Predominant role of water in native collagen assembly inside the bone matrix. AB - Bone is one of the most intriguing biomaterials found in nature consisting of bundles of collagen helixes, hydroxyapatite, and water, forming an exceptionally tough, yet lightweight material. We present here an experimental tool to map water-dependent subtle changes in triple helical assembly of collagen protein in its absolute native environment. Collagen being the most abundant animal protein has been subject of several structural studies in last few decades, mostly on an extracted, overexpressed, and synthesized form of collagen protein. Our method is based on a (1)H detected solid-state nuclear magnetic resonance (ssNMR) experiment performed on native collagen protein inside intact bone matrix. Recent development in (1)H homonuclear decoupling sequences has made it possible to observe specific atomic resolution in a large complex system. The method consists of observing a natural-abundance two-dimensional (2D) (1)H/(13)C heteronuclear correlation (HETCOR) and(1)H double quantum-single quantum (DQ-SQ) correlation ssNMR experiment. The 2D NMR experiment maps three-dimensional assembly of native collagen protein and shows that extracted form of collagen protein is significantly different from protein in the native state. The method also captures native collagen subtle changes (of the order of ~1.0 A) due to dehydration and H/D exchange, giving an experimental tool to map small changes. The method has the potential to be of wide applicability to other collagen containing biomaterials. PMID- 25530229 TI - A nationwide study of chronic pain prevalence in the general spanish population: identifying clinical subgroups through cluster analysis. AB - OBJECTIVE: This study aims to assess the prevalence of chronic pain, its characteristics, and its impact on the general Spanish population. Also, to establish chronic pain patient subgroups according to the characteristics of pain and to identify variables specifically associated with each subgroup. DESIGN: Telephone-based, cross-sectional nationwide study. SUBJECTS: A sample of 1,957 individuals representative of the Spanish population. METHODS: Data were collected through telephone interviews. A subject was considered to have chronic pain if they had suffered pain (at least 4 days a week) during the last 3 months. The subjects were divided into two subgroups through a cluster analysis, and a regression model was established to determine the variables most specifically associated with these subgroups. RESULTS: The prevalence of chronic pain was 16.6% (95% confidence interval: 14.9-18.3) and among these subjects, more than 50% referred to limitations in their daily activities, 30% felt sad and/or anxious, and 47.2% indicated that their pain was affecting their family life. Two subgroups of subjects with pain were identified: 1) characterized by generalized pain in more than one location and of a long evolution (150 months); and 2) characterized by pain localized to only one site with a shorter duration (100 months). Individuals who felt anxious because of their pain and those who considered that their pain was affecting their family were more likely to belong to group 1. CONCLUSIONS: Pain affects an important proportion of the Spanish adult population and that it has a strong personal impact. Two pain groups were clearly distinguished by their clinical characteristics. PMID- 25530230 TI - Assessment of empathy via self-report and behavioural paradigms: data on convergent and discriminant validity. AB - INTRODUCTION: Research on empathy has a long tradition in clinical research, as deficits in empathy have been found in many mental disorders. Over decades, a large amount of measures for empathy have been developed, but in many cases these have not been analysed with respect to validity. Therefore, this paper aims to relate various assessment methods for empathy, schizotypy and autistic traits to gain knowledge on their convergent and discriminant validity. METHODS: A total of N = 108 participants were tested with two of the most widespread empathy questionnaires (Interpersonal Reactivity Index, Empathy Quotient), two behavioural paradigms (Reading the Mind in the Eyes Test, Cambridge Face-Voice Battery) and a rotation task. Furthermore, questionnaires assessing schizotypal and autistic traits were administered. RESULTS: Results indicate convergent validity of the applied empathy self-report measures, although their association with measures of schizotypal and autistic traits is inconsistent. However, results of the behavioural testing barely correlate either with the self-report measures or among each other. CONCLUSIONS: The questionnaire measures of empathy seem valid and exchangeable, and therefore suitable for capturing self-reported empathy in clinical research. The behavioural paradigms cover distinct endophenotypes of empathy and should only be used for very specific research questions. PMID- 25530231 TI - Molecular epidemiology and genetic diversity of Orientia tsutsugamushi from patients with scrub typhus in 3 regions of India. AB - Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus-endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010-August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development. PMID- 25530232 TI - Skin cancer evaluation in transplant patients: a physician opinion survey with recommendations. AB - BACKGROUND: Non-melanoma skin cancer is the most common malignancy in transplant patients. However, routine skin cancer evaluation is currently not the standard of care. OBJECTIVE: To investigate the current barriers among transplant physicians to skin cancer screening in their patients. To provide recommendations for appropriate routine skin surveillance. METHODS: A web-based survey was conducted among Baylor, Dallas transplant physicians. Thirty-seven of 46 responses were received, and 13 physicians (28%) were classified as "high screeners." RESULTS: The univariate analysis revealed three main barriers including the perception of difficulty in seeing a dermatologist (p = 0.017), skin cancer evaluation is not an important aspect of transplant care (p = 0.038), and thirdly, the belief that there is insufficient evidence to warrant universal skin cancer screening in transplant patients (p = 0.013). The fully adjusted multivariable analysis resulted in two significant conclusions; the most important predictor was the perceived lack of medical evidence for skin cancer screening. LIMITATIONS: The small sample size and all responses being from the same institution in Texas. CONCLUSION: The dermatologic evidence for regular skin cancer screening in transplant patients needs dissemination to our transplant colleagues. This is a significant practice gap which can be appropriately closed by integrating dermatologists into the transplant team. PMID- 25530233 TI - Can a psychologically based treatment help people to live with chronic pain when they are seeking a procedure to reduce it? AB - OBJECTIVE: At present, the potential benefits of psychologically oriented approaches to pain management for patients waiting to undergo medical interventions, such as neuromodulation, remain unclear. Therefore, this study aimed to examine the results of an interdisciplinary treatment based on principles of Acceptance and Commitment Therapy (ACT) delivered to a group of patients being considered for a neuromodulation procedure. DESIGN: Participants were 86 adults with chronic pain. All were referrals to a 2-week, interdisciplinary, residential pain management course for people being considered for a later neuromodulation procedure. Patients completed standard self-report measures of outcome and treatment process at the beginning and end of the 2-week treatment. Data on progression on the neuromodulation pathway were extracted from medical records. RESULTS: After the 2-week ACT-based interdisciplinary treatment, the majority of patients showed a clinically significant improvement on pain, depression, physical functioning, social functioning, and pain acceptance. Regression analyses indicated that change in pain acceptance related to improvements in depression, mental health, physical function, and social function. Results with regard to the trial of neuromodulation revealed that patients who did not proceed to the trial at their physician's request (n = 13) reported significantly worse depression and mental health, and lower levels of pain acceptance and committed action following the 2-week program compared with those who went for the trial. CONCLUSION: People seeking medical interventions to reduce pain appear able to benefit from an interdisciplinary treatment aimed to improve daily functioning and mental health through increased psychological flexibility. PMID- 25530235 TI - Abstracts of Toxins 2015: Basic Science and Clinical Aspects of Botulinum and Other Neurotoxins International Conference, January 14-17, 2015, Lisbon, Portugal. PMID- 25530234 TI - Nano-gold corking and enzymatic uncorking of carbon nanotube cups. AB - Because of their unique stacked, cup-shaped, hollow compartments, nitrogen-doped carbon nanotube cups (NCNCs) have promising potential as nanoscale containers. Individual NCNCs are isolated from their stacked structure through acid oxidation and subsequent probe-tip sonication. The NCNCs are then effectively corked with gold nanoparticles (GNPs) by sodium citrate reduction with chloroauric acid, forming graphitic nanocapsules with significant surface-enhanced Raman signature. Mechanistically, the growth of the GNP corks starts from the nucleation and welding of gold seeds on the open rims of NCNCs enriched with nitrogen functionalities, as confirmed by density functional theory calculations. A potent oxidizing enzyme of neutrophils, myeloperoxidase (MPO), can effectively open the corked NCNCs through GNP detachment, with subsequent complete enzymatic degradation of the graphitic shells. This controlled opening and degradation was further carried out in vitro with human neutrophils. Furthermore, the GNP-corked NCNCs were demonstrated to function as novel drug delivery carriers, capable of effective (i) delivery of paclitaxel to tumor-associated myeloid-derived suppressor cells (MDSC), (ii) MPO-regulated release, and (iii) blockade of MDSC immunosuppressive potential. PMID- 25530236 TI - Special issue: Healthy eating and physical activity in out-of-school time settings. Issue Editors' notes. PMID- 25530238 TI - 4-H Healthy Living programs with impact: a national environmental scan. AB - The 4-H youth development program of the nation's 109 land-grant universities and the Cooperative Extension System is one of the largest youth development organization in the United States serving approximately six million youth. The 4 H Healthy Living initiative began in 2008 to promote achievement of optimal physical, social, and emotional well-being for youth and families. In 2013, the National 4-H Council sought to identify 4-H Healthy Living programs in the domains of healthy eating and physical activity that adhered to the national 4-H Healthy Living mission and were ready for comprehensive outcome evaluation or replication at a national level. This chapter shares findings from an environmental scan of 4-H programs and (a) identifies programs with evidence of promoting a healthy diet and physical activity, (b) describes program impacts related to healthy diet and physical activity, and (c) clarifies select program characteristics associated with reported healthy eating and/or physical activity outcomes. The RE-AIM evaluation framework is introduced as an effective approach to assessing program impact for 4-H Healthy Living and similar out-of-school time programs. PMID- 25530239 TI - Concerns in measurement of healthy eating and physical activity standards implementation. AB - As part of its 2011 commitment to the Partnership for Healthier America, the YMCA of the USA (Y-USA) pledged that by 2015, 85 percent of its local Y associations with early childhood or afterschool programs would have at least one program site that met 100 percent of the Y-USA's healthy eating and physical activity (HEPA) standards. To inform the measurement and monitoring of HEPA standards, the Y-USA designed a thirty-three-item online survey to assess which HEPA standards were being met in afterschool program sites each year in order to track progress over time. Verification activities including direct observation, key informant interviews, and document review generated overall compliance ratings for each standard. Compliance ratings were then compared to the self-reported survey results to determine the validity of the survey for assessing each HEPA standard. The survey had variable accuracy when compared to the validation methods. This chapter aims to inform the measurement and monitoring of HEPA standards implementation in larger afterschool networks by reporting on learnings from the Y-USA's early efforts in its network. PMID- 25530240 TI - Creating healthier afterschool environments in the Healthy Eating Active Communities program. AB - Afterschool programs in California have the potential to play a major role in obesity prevention given that they serve close to a million low-income children. A five-year initiative called the Healthy Eating Active Communities (HEAC) was funded in 2005 by the California Endowment to demonstrate that disparities related to childhood obesity and diabetes could be reduced in communities that offered families accessible and affordable opportunities for healthy eating and physical activity. The afterschool program setting constituted one of five key settings targeted in the initiative. This chapter describes the HEAC afterschool program initiative, reviews findings from the HEAC afterschool program nutrition and physical activity evaluation, and shares strategies that were used to implement the five-year training and technical assistance intervention. PMID- 25530241 TI - Effects of a competency-based professional development training on children's physical activity and staff physical activity promotion in summer day camps. AB - The YMCA of the USA serves more than nine million youth in its summer day camping programs nationwide. In spring 2011, the YMCA of Columbia, SC, with support from the University of South Carolina, adopted a competency-based staff-level training approach in an attempt to align staff behaviors with the YMCA of the USA new physical activity standards for summer camp programs. This chapter presents findings from a multiyear evaluation of a competency-based training approach using a single group design with preassessments and multiple postassessments. Training consisted of participatory exercises and video demonstrations. Data on staff physical activity promotion behaviors were collected using SOSPAN, an instrument that utilizes momentary time sampling to record instances of staff physical activity promotion behaviors consistent with physical activity standards. This chapter describes how a competency-based professional development training may be effective at increasing physical activity promoting and decreasing physical activity discouraging staff behaviors and related child activity levels. PMID- 25530242 TI - Impact of implementation factors on children's water consumption in the Out-of School Nutrition and Physical Activity group-randomized trial. AB - National data suggest that children are not consuming enough water. Experimental evidence has linked increased water consumption to obesity prevention, and the National AfterSchool Association has named serving water as ones of its standards for healthy eating and physical activity in out-of-school time settings. From fall 2010 to spring 2011, twenty Boston afterschool program sites participated in the Out-of-School Nutrition and Physical Activity (OSNAP) initiative, a group randomized trial investigating nutrition and physical activity policies and practices that promote child health. Researchers used data from OSNAP to study the key factors that influence the implementation of practices that promote water intake. Aspects of the organizational capacity of the afterschool programs, characteristics of the providers, and the community context were hypothesized to impact changes in children's water consumption. This chapter demonstrates the effectiveness of an afterschool intervention on increases in children's water consumption. It also outlines the substantial influence that implementation factors can have on the effectiveness of an obesity prevention intervention, highlighting the importance of understanding how interventions are delivered in real-world settings. PMID- 25530243 TI - Evidence-based fitness promotion in an afterschool setting: implementation fidelity and its policy implications. AB - Little is known about how the adoption of evidence-based physical activity (PA) curricula by out-of-school time (OST) programs affects children's physical fitness, and there are no clear guidelines of what constitutes reasonable gains given the types of PA instruction currently offered in these programs. Using a three-wave, quasi-experimental, naturalistic observation design, this study evaluated the implementation of an evidence-based PA instruction curriculum (Sports, Play, and Active Recreation for Kids [SPARK]) and examined whether the potential health benefits of evidence-based PA instruction can be replicated in this context when compared to OST programs that do not use evidence-based PA curricula. Quality of PA instruction and SPARK implementation fidelity were also assessed. Results indicated that children in the non-evidence-based/standard PA instruction programs engaged in higher levels of moderate-to-vigorous PA (MVPA) and showed greater improvements in fitness levels over time. The findings from this chapter suggest that while it is generally accepted that evidence-based approaches yield higher levels of PA when implemented by researchers under controlled conditions, findings are inconsistent when evidence-based PA instruction is implemented in the field, under presumably less controlled conditions. It appears that when it comes to PA instruction in afterschool, either less structured activities or well-implemented evidence-based practices could be the key to promoting higher PA levels and greater health and fitness for school-aged children. PMID- 25530244 TI - Active summers matter: evaluation of a community-based summertime program targeting obesogenic behaviors of low-income, ethnic minority girls. AB - Low-income minority females are disproportionately affected by obesity. The relevance of summer months to weight gain is often overlooked. Some evidence suggests that summer programming, such as day camps, may offer increased opportunities for structured physical activities resulting in less weight gain. This study examined the effectiveness of Girls in the Game, a six-hour four-week sports and fitness summer camp program, in increasing physical activity (PA) and reducing body mass index and media use. Statistically significant increases were observed in four physical activity measures including total PA, MVPA, average number of ten-minute bouts of MVPA, and minutes participants spent in bouts of at least ten minutes of MVPA. This chapter highlights the importance of investigating the potential relationships among weight, physical activity, sedentary time, media use, and participation in summer camp programming. PMID- 25530245 TI - A prospective study of ceramic-on-metal bearings in total hip arthroplasty at four-year follow-up: clinical results, metal ion levels, inflammatory factor levels, and liver-kidney function. AB - BACKGROUND: Despite the theoretical advantages of ceramic-on-metal (CoM) bearings observed in laboratory settings, limited clinical data are available to support in vitro results. Our present study prospectively investigated the clinical results, serum metal ion levels, inflammatory factor levels, and liver-kidney function in a cohort of patients who received total hip arthroplasty (THA) with CoM bearings. METHODS: The cohort comprised 82 THAs in 71 patients (41 men and 30 women), with a mean age of 54 (range 22-77) years. The mean follow-up was four years. All patients completed pre- and postoperative clinical assessment using the Harris Hip Score, Short Form-12, Western Ontario and McMaster Universities Osteoarthritis Index, and radiographic analysis. The serum metal ion levels of cobalt, chromium, molybdenum, and titanium were measured using high-resolution inductively coupled plasma mass spectrometry, and were compared with normal reference values. Inflammatory factors including C-reactive protein, erythrocyte sedimentation, and interleukin-6 levels, and liver-kidney function including alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine, and blood urea nitrogen, were measured in our hospital clinical key laboratory. RESULTS: At the end of the follow-up period, all clinical assessments showed a statistically significant improvement. Although the inflammatory factor levels and liver-kidney function were within normal ranges, the serum levels of metal ion were significantly elevated compared with normal values: cobalt, 2.8 MUg/L; chromium, 2.2 MUg/L; molybdenum, 0.9 MUg/L; and titanium, 2.1 MUg/L. Spearman's correlation analysis showed an association between cobalt, chromium, and titanium metal ion levels and BMI values. CONCLUSIONS: Our study demonstrated that the use of a CoM THA was clinically effective and that metal ion levels were significantly elevated at midterm follow-up. Whether the elevated metal ion levels may reduce adverse reactions is unknown, and long-term follow-up is needed. PMID- 25530247 TI - Sling suspension using the anterior third of the temporalis muscle extended with tendon graft to correct oral incontinence after free flap reconstruction in cases of a major defect of the lower lip muscle. AB - BACKGROUND: Oral incontinence is a common complication after free flap reconstruction after ablation of oral cancers. The postoperative incontinence was corrected with strong suspension to the temporalis muscle in cases of major or total defect of lower lip muscles. METHODS: Eight patients with oral cancer with previous skin flaps for reconstruction of the lower lip had incontinence because of major or total loss of the lower lip muscle. A tendon graft was used as a suspension sling sutured to the anterior third of the bilateral temporalis muscle. RESULTS: Oral continence without drooling was achieved by suspension of the temporalis muscle with free movement of the lower lip. CONCLUSION: This is a good option for correcting the incontinence after major or total loss of lower lip muscles in patients with oral cancer. PMID- 25530246 TI - The syntaxin 31-induced gene, LESION SIMULATING DISEASE1 (LSD1), functions in Glycine max defense to the root parasite Heterodera glycines. AB - Experiments show the membrane fusion genes alpha soluble NSF attachment protein (alpha-SNAP) and syntaxin 31 (Gm-SYP38) contribute to the ability of Glycine max to defend itself from infection by the plant parasitic nematode Heterodera glycines. Accompanying their expression is the transcriptional activation of the defense genes ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1) and NONEXPRESSOR OF PR1 (NPR1) that function in salicylic acid (SA) signaling. These results implicate the added involvement of the antiapoptotic, environmental response gene LESION SIMULATING DISEASE1 (LSD1) in defense. Roots engineered to overexpress the G. max defense genes Gm-alpha-SNAP, SYP38, EDS1, NPR1, BOTRYTIS INDUCED KINASE1 (BIK1) and xyloglucan endotransglycosylase/hydrolase (XTH) in the susceptible genotype G. max[Williams 82/PI 518671] have induced Gm-LSD1 (Gm-LSD1-2) transcriptional activity. In reciprocal experiments, roots engineered to overexpress Gm-LSD1-2 in the susceptible genotype G. max[Williams 82/PI 518671] have induced levels of SYP38, EDS1, NPR1, BIK1 and XTH, but not alpha-SNAP prior to infection. In tests examining the role of Gm-LSD1-2 in defense, its overexpression results in ~52 to 68% reduction in nematode parasitism. In contrast, RNA interference (RNAi) of Gm LSD1-2 in the resistant genotype G. max[Peking/PI 548402] results in an 3.24 10.42 fold increased ability of H. glycines to parasitize. The results identify that Gm-LSD1-2 functions in the defense response of G. max to H. glycines parasitism. It is proposed that LSD1, as an antiapoptotic protein, may establish an environment whereby the protected, living plant cell could secrete materials in the vicinity of the parasitizing nematode to disarm it. After the targeted incapacitation of the nematode the parasitized cell succumbs to its targeted demise as the infected root region is becoming fortified. PMID- 25530248 TI - The Lion King and the Hyaena Queen: large carnivore interactions and coexistence. AB - Interactions among species, which range from competition to facilitation, have profound effects on ecosystem functioning. Large carnivores are of particular importance in shaping community structure since they are at the top of the food chain, and many efforts are made to conserve such keystone species. Despite this, the mechanisms of carnivore interactions are far from understood, yet they are key to enabling or hindering their coexistence and hence are highly relevant for their conservation. The goal of this review is thus to provide detailed information on the extents of competition and facilitation between large carnivores and their impact in shaping their life histories. Here, we use the example of spotted hyaenas (Crocuta crocuta) and lions (Panthera leo) and provide a comprehensive knowledge of their interactions based on meta-analyses from available literature (148 publications). Despite their strong potential for both exploitation and interference competition (range and diet overlap, intraguild predation and kleptoparasitism), we underline some mechanisms facilitating their coexistence (different prey-age selection and scavenging opportunities). We stress the fact that prey abundance is key to their coexistence and that hyaenas forming very large groups in rich ecosystems could have a negative impact on lions. We show that the coexistence of spotted hyaenas and lions is a complex balance between competition and facilitation, and that prey availability within the ecosystem determines which predator is dominant. However, there are still many gaps in our knowledge such as the spatio-temporal dynamics of their interactions. As both species' survival becomes increasingly dependent on protected areas, where their densities can be high, it is critical to understand their interactions to inform both reintroduction programs and protected area management. PMID- 25530253 TI - Determinants of Scanpath Regularity in Reading. AB - Scanpaths have played an important role in classic research on reading behavior. Nevertheless, they have largely been neglected in later research perhaps due to a lack of suitable analytical tools. Recently, von der Malsburg and Vasishth (2011) proposed a new measure for quantifying differences between scanpaths and demonstrated that this measure can recover effects that were missed with the traditional eyetracking measures. However, the sentences used in that study were difficult to process and scanpath effects accordingly strong. The purpose of the present study was to test the validity, sensitivity, and scope of applicability of the scanpath measure, using simple sentences that are typically read from left to right. We derived predictions for the regularity of scanpaths from the literature on oculomotor control, sentence processing, and cognitive aging and tested these predictions using the scanpath measure and a large database of eye movements. All predictions were confirmed: Sentences with short words and syntactically more difficult sentences elicited more irregular scanpaths. Also, older readers produced more irregular scanpaths than younger readers. In addition, we found an effect that was not reported earlier: Syntax had a smaller influence on the eye movements of older readers than on those of young readers. We discuss this interaction of syntactic parsing cost with age in terms of shifts in processing strategies and a decline of executive control as readers age. Overall, our results demonstrate the validity and sensitivity of the scanpath measure and thus establish it as a productive and versatile tool for reading research. PMID- 25530254 TI - A polymorphism in the porcine miR-208b is associated with microRNA biogenesis and expressions of SOX-6 and MYH7 with effects on muscle fibre characteristics and meat quality. AB - MicroRNAs (miRNAs) encoded by the myosin heavy chain (MHC) genes are muscle specific miRNAs (myomiRs) and regulate the expression of MHC isoforms in skeletal muscle. These miRNAs have been implicated in muscle fibre types and their characteristics by affecting the heterogeneity of myosin. In pigs, miR-208b and miR-499 are embedded in introns of MYH7 and MYH7b respectively. Here, we identified a novel single nucleotide polymorphism (SNP) in intron 30 of MYH7 by which porcine miR-208b is encoded. Based on the association study using a total of 487 pigs including Berkshire (n = 164), Landrace (n = 121) and Yorkshire (n = 202), the miR-208b SNP (g.17104G>A) had significant effects on the proportions of types I and IIb fibre numbers (P < 0.010) among muscle fibre characteristics and on drip loss (P = 0.012) in meat quality traits. Moreover, the SNP affected the processing of primary miR-208b into precursor miR-208b with a marginal trend towards significance (P = 0.053), thereby leading to significant changes in the levels of mature miR-208b (P = 0.009). These SNP-dependent changes in mature miR 208b levels were negatively correlated with the expression levels of its target gene, SOX-6 (P = 0.038), and positively associated with the expression levels of its host gene, MYH7 (P = 0.046). Taken together, our data suggest that the porcine miR-208b SNP differentially represses the expression of SOX-6 by regulating miRNA biogenesis, thereby affecting the expression of MYH7 and the traits of muscle fibre characteristics and meat quality. PMID- 25530255 TI - Emotion regulation model in binge eating disorder and obesity--a systematic review. AB - Deficits in emotion regulation processes are a common and widely used explanation for the development and maintenance of binge eating disorder (BED). It is assumed that BED patients - as they have difficulty regulating their negative emotions - use binge eating to cope with these emotions and to find relief. However, the number of experimental studies investigating this assumption is scarce and the differentiation of obese individuals with and without BED regarding the emotion regulation model is not verified. We reviewed literature for experimental studies investigating the emotion regulation model in obese patients (OB) with and without BED. Our search resulted in 18 experimental studies examining the triggering effect of negative emotions for binge eating or its effects on subsequent relief. We found evidence indicating that negative emotion serves as a trigger for binge eating in the BED group unlike the obese group without BED. Considering the small number of studies, we found evidence for a (short-term) improvement of mood through food intake, irrespective of group. PMID- 25530256 TI - A new adaptive configuration of PID type fuzzy logic controller. AB - In this paper, an adaptive configuration for PID type fuzzy logic controller (FLC) is proposed to improve the performances of both conventional PID (C-PID) controller and conventional PID type FLC (C-PID-FLC). The proposed configuration is called adaptive because its output scaling factors (SFs) are dynamically tuned while the controller is functioning. The initial values of SFs are calculated based on its well-tuned counterpart while the proceeding values are generated using a proposed stochastic hybrid bacterial foraging particle swarm optimization (h-BF-PSO) algorithm. The performance of the proposed configuration is evaluated through extensive simulations for different operating conditions (changes in reference, load disturbance and noise signals). The results reveal that the proposed scheme performs significantly better over the C-PID controller and the C PID-FLC in terms of several performance indices (integral absolute error (IAE), integral-of-time-multiplied absolute error (ITAE) and integral-of-time-multiplied squared error (ITSE)), overshoot and settling time for plants with and without dead time. PMID- 25530257 TI - Simple method of designing centralized PI controllers for multivariable systems based on SSGM. AB - A method is given to design multivariable PI/PID controllers for stable and unstable multivariable systems. The method needs only the steady state gain matrix (SSGM). The method is based on the static decoupler design followed by SISO PI/PID controllers design and combining the resulted decoupler and the diagonal PI(D) controllers as the centralized controllers. The result of the present method is shown to be equivalent to the empirical method proposed by Davison EJ. Multivariable tuning regulators: the feed-forward and robust control of general servo-mechanism problem. IEEE Trans Autom Control 1976;21:35-41. Three simulation examples are given. The performance of the controllers is compared with that of the reported centralized controller based on the multivariable transfer function matrix. PMID- 25530258 TI - Fuzzy modeling and predictive control of superheater steam temperature for power plant. AB - This paper develops a stable fuzzy model predictive controller (SFMPC) to solve the superheater steam temperature (SST) control problem in a power plant. First, a data-driven Takagi-Sugeno (TS) fuzzy model is developed to approximate the behavior of the SST control system using the subspace identification (SID) method. Then, an SFMPC for output regulation is designed based on the TS-fuzzy model to regulate the SST while guaranteeing the input-to-state stability under the input constraints. The effect of modeling mismatches and unknown plant behavior variations are overcome by the use of a disturbance term and steady state target calculator (SSTC). Simulation results for a 600 MW power plant show that an offset-free tracking of SST can be achieved over a wide range of load variation. PMID- 25530259 TI - Light-mediated activation of siRNA Release in diblock copolymer assemblies for controlled gene silencing. AB - Controllable release is particularly important for the delivery of small interfering RNA (siRNA), as siRNAs have a high susceptibility to enzymatic degradation if release is premature, yet lack silencing activity if they remain inaccessible within the cytoplasm. To overcome these hurdles, novel and tailorable mPEG-b-poly(5-(3-(amino)propoxy)-2-nitrobenzyl methacrylate) (mPEG-b P(APNBMA)) diblock copolymers containing light-sensitive o-nitrobenzyl moieties and pendant amines are employed to provide both efficient siRNA binding, via electrostatic and hydrophobic interactions, as well as triggered charge reversal and nucleic acid release. In particular, siRNA/mPEG-b-P(APNBMA)23.6 polyplexes show minimal aggregation in physiological salt and serum, and enhanced resistance to polyanion-induced unpackaging compared to polyethylenimine preparations. Cellular delivery of siRNA/mPEG-b-P(APNBMA)23.6 polyplexes reveals greater than 80% cellular transfection, as well as rapid and widespread cytoplasmic distribution. Additionally, UV irradiation indicates ~70% reduction in targeted gene expression following siRNA/mPEG-b-P(APNBMA)23.6 polyplex treatment, as compared to 0% reduction in polyplex-treated cells without UV irradiation, and only ~30% reduction for Lipofectamine-treated cells. The results here highlight the potential of these light-sensitive copolymers with a well-defined on/off switch for applications including cellular patterning for guided cell growth and extension, and cellular microarrays for exploring protein and drug interactions that require enhanced spatiotemporal control of gene activation. PMID- 25530260 TI - Association between serum levels and pentanucleotide polymorphism in the sex hormone binding globulin gene and cardiovascular risk factors in females with polycystic ovary syndrome. AB - The objective of the present study was to evaluate the influence of TAAAA repeat allele length on the levels of serum sex hormone binding globulin (SHBG) and cardiovascular risk factors in patients with polycystic ovary syndrome (PCOS). The study included 91 females with PCOS and 99 healthy controls. Phenotypic hyperandrogenism, body mass index and waist-to-hip ratio (WHR) were recorded. Hormonal profiles, fasting insulin and glucose levels, lipid profiles and C reactive protein (CRP) levels were measured. Genotyping of TAAAA repeat polymorphisms in the SHBG gene was performed. No significant difference was found in the frequency and distribution of TAAAA repeat alleles between PCOS patients and controls (P=0.739). In PCOS patients, SHBG levels were inversely correlated with serum C-reactive protein (CRP) levels (R=-0.489, P<0.001). PCOS patients with long TAAAA repeat alleles had significantly lower serum SHBG and free testosterone levels, yet higher CRP levels than patients with short allele repeats. A multiple linear regression model using the number of TAAAA repeats, waist-to-hip ratio, a homeostatic model assessment of insulin resistance and age as independent predictors explained 44.8% of the variability in serum SHBG levels. In this model, TAAAA repeat polymorphism was found to be the only reliable predictor of serum SHBG levels (P<0.001). In conclusion, the TAAAA repeat polymorphism was shown to not be a major determinant of the PCOS status, although it influenced serum SHBG levels in females with PCOS. A strong independent association existed between serum SHBG and CRP levels. CRP is an established risk factor of cardiovascular disease and a marker of low-grade inflammation, typical of atherogenesis. This may be one of the pathways by which low SHBG levels affect cardiovascular risk. PMID- 25530261 TI - mRNAs that specifically interact with eukaryotic ribosomal subunits. AB - The accuracy of start codon selection is determined by the translation initiation process. In prokaryotes the initiation step on most mRNAs relies on recruitment of the small ribosomal subunit onto the initiation codon by base pairing between the mRNA and the 16S rRNA. Eukaryotes have evolved a complex molecular machinery involving at least 11 initiation factors, and mRNAs do not directly recruit the small ribosomal subunit. Instead the initiation complex is recruited to the 5' end of the mRNA through a complex protein network including eIF4E that interacts with the 5' cap structure and poly-A binding protein that interacts with the 3'end. However, some viral and cellular mRNAs are able to escape this pathway by internal recruitment of one or several components of the translation machinery. Here we review those eukaryotic mRNAs that have been reported to directly recruit the 40S ribosomal subunit internally. In the well characterized cases of viral IRESes, a specific RNA structure is involved in this process, and in addition to recruitment of the ribosome, the mRNA also manipulates the ribosome structure to stimulate the first translocation step. We also review recently described IRES/ribosome interactions in cases where the molecular mechanism leading to translation initiation has yet to be described. Finally we evaluate the possibility that mRNA may recruit the 40S ribosomal subunit through base pairing with the 18S rRNA. PMID- 25530263 TI - The M1 family of vertebrate aminopeptidases: role of evolutionarily conserved tyrosines in the enzymatic mechanism of aminopeptidase B. AB - Aminopeptidase B (Ap-B), a member of the M1 family of Zn(2+)-aminopeptidases, removes basic residues at the NH2-terminus of peptides and is involved in the in vivo proteolytic processing of miniglucagon and cholecystokinin-8. M1 enzymes hydrolyze numerous different peptides and are implicated in many physiological functions. As these enzymes have similar catalytic mechanisms, their respective substrate specificity and/or catalytic efficiency must be based on subtle structural differences at or near the catalytic site. This leads to the hypothesis that each primary structure contains a consensus structural template, strictly necessary for aminopeptidase activity, and a specific amino acid environment localized in or outside the catalytic pocket that finely tunes the substrate specificity and catalytic efficiency of each enzyme. A multiple sequence alignment of M1 peptidases from vertebrates allowed to identify conserved tyrosine amino acids, which are members of this catalytic backbone. In the present work, site-directed mutagenesis and 3D molecular modeling of Ap-B were used to specify the role of four fully (Y281, Y229, Y414, and Y441) and one partially (Y409) conserved residues. Tyrosine to phenylalanine mutations allowed confirming the influence of the hydroxyl groups on the enzyme activity. These groups are implicated in the reaction mechanism (Y414), in substrate specificity and/or catalytic efficiency (Y409), in stabilization of essential amino acids of the active site (Y229, Y409) and potentially in the maintenance of its structural integrity (Y281, Y441). The importance of hydrogen bonds is verified by the Y229H substitution, which preserves the enzyme activity. These data provide new insights into the catalytic mechanism of Ap-B in the M1 family of aminopeptidases. PMID- 25530262 TI - Evolution, energy landscapes and the paradoxes of protein folding. AB - Protein folding has been viewed as a difficult problem of molecular self organization. The search problem involved in folding however has been simplified through the evolution of folding energy landscapes that are funneled. The funnel hypothesis can be quantified using energy landscape theory based on the minimal frustration principle. Strong quantitative predictions that follow from energy landscape theory have been widely confirmed both through laboratory folding experiments and from detailed simulations. Energy landscape ideas also have allowed successful protein structure prediction algorithms to be developed. The selection constraint of having funneled folding landscapes has left its imprint on the sequences of existing protein structural families. Quantitative analysis of co-evolution patterns allows us to infer the statistical characteristics of the folding landscape. These turn out to be consistent with what has been obtained from laboratory physicochemical folding experiments signaling a beautiful confluence of genomics and chemical physics. PMID- 25530264 TI - Spectrum of Fusarium infections in tropical dermatology evidenced by multilocus sequencing typing diagnostics. AB - Fusarium species are emerging causative agents of superficial, cutaneous and systemic human infections. In a study of the prevalence and genetic diversity of 464 fungal isolates from a dermatological ward in Thailand, 44 strains (9.5%) proved to belong to the genus Fusarium. Species identification was based on sequencing a portion of translation elongation factor 1-alpha (tef1-alpha), rDNA internal transcribed spacer and RNA-dependent polymerase subunit II (rpb2). Our results revealed that 37 isolates (84%) belonged to the Fusarium solani species complex (FSSC), one strain matched with Fusarium oxysporum (FOSC) complex 33, while six others belonged to the Fusarium incarnatum-equiseti species complex. Within the FSSC two predominant clusters represented Fusarium falciforme and recently described F. keratoplasticum. No gender differences in susceptibility to Fusarium were noted, but infections on the right side of the body prevailed. Eighty-nine per cent of the Fusarium isolates were involved in onychomycosis, while the remaining ones caused paronychia or severe tinea pedis. Comparing literature data, superficial infections by FSSC appear to be prevalent in Asia and Latin America, whereas FOSC is more common in Europe. The available data suggest that Fusarium is a common opportunistic human pathogens in tropical areas and has significant genetic variation worldwide. PMID- 25530265 TI - Randomised, multicentre trial of micafungin vs. an institutional standard regimen for salvage treatment of invasive aspergillosis. AB - Invasive aspergillosis remains associated with significant morbidity and mortality, necessitating new options for salvage therapy. The objective of this study was to evaluate the efficacy and safety of micafungin as salvage monotherapy in patients with invasive aspergillosis. Patients with proven or probable invasive aspergillosis, who were refractory or intolerant to previous systemic antifungal therapy, were randomised 2 : 1 to receive 300 mg day(-1) intravenous micafungin monotherapy or an intravenous control monotherapy [lipid amphotericin B (5 mg kg(-1) day(-1)), voriconazole (8 mg kg(-1) day(-1)) or caspofungin (50 mg day(-1))] for 3-12 weeks. Patients underwent final assessment 12 weeks after treatment start. Seventeen patients with invasive aspergillosis (proven, n = 2; probable, n = 14; not recorded, n = 1) participated in the study (micafungin arm, n = 12; control arm, n = 5). Three patients each in the micafungin (25.0%; 95% CI: 5.5-57.2) and control arm (60.0%; 95% CI: 14.7-94.7) had successful therapy at end of treatment as assessed by an Independent Data Review Board. Eleven patients died; six due to invasive aspergillosis. No deaths were considered related to study treatment. During this study it became increasingly common to use combination treatment for salvage therapy. Consequently, enrolment was low and the study was discontinued early. No clear trends in efficacy and safety can be concluded. PMID- 25530266 TI - Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats. AB - In preclinical research on pain and analgesia, noxious stimuli can stimulate expression of some behaviors (e.g. withdrawal reflexes) and depress others (e.g. feeding, locomotion, and positively reinforced operant responding). Tolerance to morphine antinociception is a robust and reliable phenomenon in preclinical assays of pain-stimulated behavior, but development of morphine tolerance in assays of pain-depressed behavior has not been studied. This study compared morphine antinociceptive tolerance in parallel assays of pain-stimulated and pain depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response in one group of rats and to depress operant responding for electrical brain stimulation (intracranial self-stimulation; ICSS) in another group of rats. Antinociception produced by morphine (1.0 mg/kg) was determined after a regimen of chronic treatment with either saline or morphine in separate subgroups of rats in each procedure. In rats receiving chronic saline, acid alone stimulated a stretching response and depressed ICSS, and both acid effects were blocked by 1.0 mg/kg morphine. Rats receiving chronic morphine displayed hyperalgesic responses to the acid noxious stimulus in both procedures. Complete tolerance developed to morphine antinociception in the assay of acid-stimulated stretching, but morphine retained full antinociceptive effectiveness in the assay of acid-depressed ICSS. These results suggest that morphine antinociception in an assay of pain-depressed behavior is relatively resistant to tolerance. More broadly, these results suggest that antinociceptive tolerance can develop at different rates or to different degrees for different measures of antinociception. PMID- 25530267 TI - Deoxysappanone B, a homoisoflavone from the Chinese medicinal plant Caesalpinia sappan L., protects neurons from microglia-mediated inflammatory injuries via inhibition of IkappaB kinase (IKK)-NF-kappaB and p38/ERK MAPK pathways. AB - Caesalpinia sappan L. (Lignum Sappan) is a Chinese medicinal plant for treating ischemic cerebral apoplexy. Deoxysappanone B (DSB), a homoisoflavone compound isolated from C. sappan L. (Lignum Sappan), was studied for anti neuroinflammatory and neuroprotective properties using lipopolysaccharide (LPS) induced BV-2 microglia neuroinflammation model and LPS-induced microglia-neuron co-culture system. Our findings showed that DSB effectively inhibited BV-2 microglia-mediated neuroinflammatory mediators' release including NO, PGE2, TNF alpha, IL-6 and reactive oxygen species. Moreover, DSB markedly protected neurons against inflammatory microglia-mediated neurotoxicity in a microglia-neuron co culture system. Mechanism study revealed that DSB blocked two major neuroinflammation-related signaling pathways including IKK-IkappaB-nuclear factor kappaB (NF-kappaB) and p38/ERK mitogen-activated protein kinase (MAPK) cascades, further leading to the inhibition of neuroinflammatory mediators' production. The present study provides evidence that the anti-neuroinflammatory and neuroprotective effect of DSB are due to the suppression of neuroinflammatory mediators' production as well as inflammation-induced neurotoxicity through regulation of multi-targets. Therefore, DSB may serve as a neuroprotective agent for the treatment of neuroinflammatory disorders and inflammation-related neuronal injury. PMID- 25530268 TI - Epicatechin breaks preformed glycated serum albumin and reverses the retinal accumulation of advanced glycation end products. AB - The accumulation of advanced glycation end products (AGEs) is associated with many of the complications of diabetes mellitus, including diabetic retinopathy. AGE-breakers, such as N-phenacylthiazolium and alagebrium, have been proposed as therapeutic agents for reversing the increase in protein crosslinking in diabetes. (-)-Epicatechin is a major dietary flavonoid with a wide range of health-promoting biological activities. The aim of this study was to determine the potential effect of (-)-epicatechin in reducing the burden of AGEs in vitro and in vivo and to evaluate whether the reduced AGE burden could translate into improvement in retinal vascular function in exogenously AGE-injected rats. Glycated human serum albumin was purified from patients with diabetes. The breakdown of the already formed AGEs was studied by treating glycated human serum albumin with (-)-epicatechin. To study the effect of (-)-epicatechin on retinal vascular function, exogenously AGE-injected rats were treated with (-) epicatechin (50 and 100 mg/kg i.p.) for two weeks. Apoptosis of retinal vascular cells was quantified using TUNEL staining. The AGE load in the retinas was determined via immunohistochemical staining and western blot analysis. (-) Epicatechin was able to break preformed glycated human serum albumin in vitro as well as reduce AGE accumulation in retinas in vivo in a dose dependent manner. In exogenously AGE-injected rats, treatment with (-)-epicatechin was evidenced by an improved retinal vascular apoptosis. AGE burden in retinas was also reduced upon treatment. This study suggests that (-)-epicatechin could represent a valuable drug for the treatment of diabetic retinopathy by reducing the AGE burden. PMID- 25530269 TI - Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model: influence of non-cardiac alpha1-adrenergic receptors. AB - Torsades de Pointes (TdP) is a potentially lethal cardiac arrhythmia and a known adverse effect of many drugs secondary to block of the rapidly activating delayed rectifier potassium current (IKr). In animal models antipsychotic drugs have shown reduced pro-arrhythmic potential compared to drugs with comparable IKr blocking characteristics. The reduced pro-arrhythmic properties of antipsychotic drugs has been attributed to a variety of different causes e.g., effects on alpha1-adrenergic receptors, beta-adrenergic receptors, muscarinic receptors or cardiac ion channels like Ca(2+)- and Na(+)-channels. Since only limited experimental information exists about the effects of alpha1-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this. In this study we show that four antipsychotic drugs all have high affinity for alpha1-adrenergic receptor (sertindole>risperidone>haloperidol>olanzapine) and all block IKr (sertindole>haloperidol>risperidone>olanzapine). In canine Purkinje fibres, alpha1-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed for the first time in an in vivo pro-arrhythmic rabbit model that several antipsychotic drugs in accordance with their known alpha1-adrenergic receptor blocking properties reduced the incidence of drug-induced TdP and that the overall ability of the antipsychotic drugs to prevent TdP was associated with prevention of methoxamine induced increase in blood pressure. Further investigations are required to clarify the relative importance of alpha1-adrenergic receptor antagonism in conjunction with the additional effects of antipsychotic drugs on various receptors and ion channels. PMID- 25530270 TI - Early Repolarization Pattern Is Associated with Increased Risk of Early Ventricular Arrhythmias during Acute ST Segment Elevation Myocardial Infarction. AB - BACKGROUND: Early repolarization (ER) and acute ST segment elevation myocardial infarction (STEMI) are sharing the pathophysiology of J wave syndromes. It is speculated that early ventricular arrhythmias (VAs) during STEMI may be predisposed by ER. Our aim was to study the association between ER pattern and risk of VAs during acute STEMI. METHODS: The study included 102 male patients with acute STEMI who were divided into two groups: cases and controls. Cases included 52 patients with sustained VAs during the first 48 hours from the onset of STEMI, while controls included 50 patients with no VAs. On 12-lead surface electrocardiogram, ER was defined as >= 1 mm elevation of J point in at least two inferior or lateral leads with or without ST segment elevation. RESULTS: Mean age was 48.44 +/- 10.08 years and mean left ventricular ejection fraction (LVEF) was 42.25 +/- 11.1%. ER pattern was more frequent in cases than controls (29 vs 14 patients, P = 0.008). Notched J wave (P = 0.0007) and horizontal ST segment (P = 0.033) were more frequent in cases than controls. On adjusted regression model, LVEF (OR: 0.95, 95% CI: 0.91-0.99, P = 0.015) and ER (OR: 3.39, 95% CI: 1.41 8.12, P = 0.006) could predict VAs, while QTc interval (P = 0.24) and QTd (P = 0.86) did not have predictive effect. Inferior/inferolateral and global ER pattern (P = 0.044 and 0.031 respectively), notched J wave (P = 0.001), increasing J wave amplitude (P = 0.042), and ST segment elevation (P = 0.001) were associated with a higher risk of VAs. CONCLUSIONS: ER is associated with increased risk of VAs in the setting of acute STEMI. PMID- 25530271 TI - NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma-Very good response predominantly in patients with intestinal type tumors. AB - Perioperative treatment is a standard of care in locally advanced gastroesophageal cancer (GEC) (gastric adenocarcinoma and gastroesophageal junction (GEJ) adenocarcinoma). While preoperative treatment can be applied to the majority of patients, postoperative chemotherapy can be given only to a fraction. The NeoFLOT-study therefore investigates the application of prolonged neoadjuvant chemotherapy (NACT). Patients with T3, T4, and/or node-positive adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m(2) , leucovorin 200 mg/m(2) , 5 fluorouracil 2600 mg/m(2) and docetaxel 50 mg/m(2) (FLOT) applied q 2 wks. Application of adjuvant chemotherapy was explicitly not part of the protocol. R0 resection rate was evaluated as a primary endpoint. Of 59 enrolled patients, 50 patients underwent surgery and were assessable for the primary endpoint. R0 resection rate was 86.0% (43/50). Pathologic complete response (pCR) was 20.0% (10/50) and a further 20% (10/50) of patients achieved near complete histological remission (<10% residual tumor). Among these very good responders, 85% (17/20) had intestinal type tumors, 10% (2/20) had diffuse and 5% (1/20) had mixed type tumors. After 3 cycles of NACT, 6.9% (4/58) of patients developed progressive disease. Median disease-free survival was 32.9 months. The 1-year survival-rate was 79.3%. Grade 3-4 toxicities included neutropenia 29.3%, febrile neutropenia 1.7%, diarrhea 12.1% and mucositis 6.9%. This study indicates that intensified NACT with 6 cycles of FLOT is highly effective and tolerable in resectable GEC. Very good response (pCR and <10% residual tumor) was predominantly observed in patients with intestinal type tumors. PMID- 25530272 TI - A novel histone deacetylase 6-selective inhibitor suppresses synovial inflammation and joint destruction in a collagen antibody-induced arthritis mouse model. AB - AIM: To investigate the effects of Tubastatin A, a selective histone deacetylase 6 inhibitor, on synovial inflammation and joint destruction in a collagen antibody-induced arthritis (CAIA) mouse model. METHODS: Collagen antibody-induced arthritis mice were given daily intraperitoneal injections of various concentrations of Tubastatin A (0, 10, 50, 100 mg/kg). The clinical score and paw thickness were measured. Mice were sacrificed on day 15, and the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 in the serum were analyzed using enyme-linked immunosorbent assay (ELISA). Two pathologists independently measured the synovitis score. Micro-computed tomography (CT) scans of the joints were performed to quantify joint destruction. The expression of IL 6 from human fibroblast-like synoviocytes (FLSs) after incubation with various doses of Tubastatin A (0, 0.75, 1.5, 3 MUmol/L) was measured using ELISA. RESULTS: The clinical arthritis score was significantly attenuated and paw thickness was lower in the group treated with 100 mg/kg Tubastatin A compared with those treated with vehicle alone. The synovitis score was significantly reduced in the 100 mg/kg Tubastatin A-treated group compared with the control group. Micro-CT showed that quantitative measures of joint destruction were significantly attenuated in the 100 mg/kg Tubastatin A-treated group compared with the control. The expression of IL-6 in the sera was lower in the mice treated with Tubastatin A compared with the control. The expression of IL-6 in human FLSs decreased dose-dependently after incubation with Tubastatin A without affecting cell viability. CONCLUSIONS: Tubastatin A successfully ameliorated synovial inflammation and protected against joint destruction in CAIA mice, at least in part, by modulating IL-6 expression. PMID- 25530273 TI - [In vitro evaluation of the method effectiveness to limit inflation pressure cuffs of endotracheal tubes]. AB - BACKGROUND AND OBJECTIVE: Cuffs of tracheal tubes protect the lower airway from aspiration of gastric contents and facilitate ventilation, but may cause many complications, especially when the cuff pressure exceeds 30cm H2O. This occurs in over 30% of conventional insufflations, so it is recommended to limit this pressure. In this study we evaluated the in vitro effectiveness of a method of limiting the cuff pressure to a range between 20 and 30cm H2O. METHOD: Using an adapter to connect the tested tube to the anesthesia machine, the relief valve was regulated to 30cm H2O, inflating the cuff by operating the rapid flow of oxygen button. There were 33 trials for each tube of three manufacturers, of five sizes (6.5 to 8.5), using three times inflation (10, 15 and 20seconds), totaling 1485 tests. After inflation, the pressure obtained was measured with a manometer. Pressure >30cm H2O or <20cm H2O were considered failures. RESULTS: There were eight failures (0.5%, 95% CI: 0.1-0.9%), with all by pressures <20cm H2O and after 10seconds inflation (1.6%, 95% CI: 0 5-2.7%). One failure occurred with a 6.5 tube (0.3%, 95% CI: -0.3-0.9%), six with 7.0 tubes (2%, 95% CI: 0.4 to 3.6%), and one with a 7.5 tube (0.3%, 95% CI: -0.3-0.9%). CONCLUSION: This method was effective for inflating tracheal tube cuffs of different sizes and manufacturers, limiting its pressure to a range between 20 and 30cm H2O, with a success rate of 99.5% (95% CI: 99.1-99.9%). PMID- 25530274 TI - International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Progress to Date and Future Plans. AB - The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice proposal (INHAND) has been operational since 2005. A Global Editorial Steering Committee manages the overall objectives of the project, and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups, drawing upon experts from North America, Europe, and Japan. Great progress has been made with 9 systems published to date--respiratory, hepatobiliary, urinary, central/peripheral nervous systems, male reproductive and mammary, zymbals, clitoral, and preputial glands in Toxicologic Pathology and the integument and soft tissue and female reproductive in the Journal of Toxicologic Pathology as supplements and on a Web site- www.goReni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photomicrographs of morphologic changes, information regarding pathogenesis, and key references. The purpose of this brief communication is to provide an update on the progress of INHAND. PMID- 25530275 TI - A prospective, randomized controlled trial of conscious sedation using propofol combined with inhaled nitrous oxide for dental treatment. AB - PURPOSE: Adverse reactions during propofol sedation include a decrease in arterial blood pressure, propofol-induced pain on injection, and airway complications. The purpose of this study was to investigate whether combined use of intravenous propofol and inhaled nitrous oxide could decrease the hypotensive and other adverse effects of propofol. PATIENTS AND METHODS: We designed and implemented a prospective, randomized controlled trial. Patients undergoing dental procedures requiring intravenous sedation were randomly allocated to 2 groups: group P comprised those receiving sedation with propofol alone, and group N+P comprised those receiving sedation with 40% nitrous oxide inhalation and propofol. During the dental procedures, the sedation level was maintained at an Observer's Assessment of Alertness/Sedation scale score of 4 by adjusting propofol's target plasma concentration. Nitrous oxide inhalation was the predictor variable, whereas the hemodynamic changes, amount and concentration of propofol, and adverse events were the outcome variables. RESULTS: Eighty-eight patients were successfully analyzed without any complications. The total amount of propofol was significantly less in group N+P (249.8 +/- 121.7 mg) than in group P (310.3 +/- 122.4 mg) (P = .022), and the mean concentration of propofol was significantly less in group N+P (1.81 +/- 0.34 MUg/mL) than in group P (2.05 +/- 0.44 MUg/mL) (P = .006). The mean blood pressure reduction in group N+P (11.0 +/- 8.0 mm Hg) was significantly smaller than that in group P (15.8 +/- 10.2 mm Hg) (P = .034). Pain associated with the propofol injection and memory of the procedure were less in group N+P (P = .011 and P = .048, respectively). Nitrous oxide did not affect respiratory conditions or recovery characteristics. CONCLUSIONS: The results of this study suggest that nitrous oxide inhalation combined with propofol sedation attenuates the hypotensive effect and pain associated with propofol injections, along with potentiating the amnesic effect. PMID- 25530276 TI - Bifid mandibular canals: prevalence and implications. AB - PURPOSE: Bifid mandibular canals (BMCs) are variations of the normal anatomy, with a reported prevalence ranging from 0.08 to 65%. Aberrations of the mandibular canal can have important clinical implications. We therefore sought to assess the prevalence of BMCs and discuss several surgical implications that may be associated with this variation. MATERIALS AND METHODS: A retrospective chart study of available digital panoramic images from our file archives from 2011 to 2013 was performed to search for the prevalence of BMCs; to this end, 5,000 consecutive panoramic radiographs of patients aged 18 to 80 years were studied. Detection of BMCs was based on visualization of 2 radiolucent lines and at least 3 radiopaque borders on the monitor and confirmed by 2 oral and maxillofacial surgeons and 2 dentists. The types of bifidity also were assessed and recorded. Data analysis was performed using the chi(2) test. RESULTS: BMCs were observed in 61, or 1.2%, of 5,000 digital panoramic images. There were no statistically significant correlations found regarding age or gender. The most frequently encountered type of bifid canal was type 2 (82%). CONCLUSIONS: The prevalence of BMCs seen on panoramic images in this study was 1.2% and was not correlated with age or gender. PMID- 25530277 TI - Arthroscopic discopexy is effective in managing temporomandibular joint internal derangement in patients with Wilkes stage II and III. AB - PURPOSE: Disc repositioning for temporomandibular joint (TMJ) internal derangement (ID) is a well-established surgical technique with variable success. The purpose of the present study was to assess the outcomes after arthroscopic disc repositioning (discopexy) for TMJ ID. PATIENTS AND METHODS: This was a prospective, cohort, single-institutional clinical study. The study included patients with TMJ ID in whom diagnostic arthroscopy had failed. These patients were presented and treated at Miami Oral and Maxillofacial Surgery, Baptist Hospital (Miami FL). The predictive variable was the Wilkes diagnostic categories, presented in 2 groups: II and III versus IV and V. The primary outcome variable was the absence of joint pain at 12 months postoperatively. The secondary outcome variables included joint function, maximum interincisal opening, medication use, joint loading sign, and muscle pain. The patients were followed for 1 year postoperatively. The statistical analyses included paired and independent sample Student's t test, chi(2) test, and logistic regression analysis. RESULTS: A total of 32 subjects (42 joints), with a mean age of 31 years, were included in the present study; 28 (87.5%) were women. Of the 42 joints, 71.4% were classified as Wilkes stage II and III. A successful outcome was seen in 69% of the studied subjects and in 86.7% of the Wilkes II and III group versus 25% of the Wilkes IV and V group (P = .001). CONCLUSION: The results of the present study have shown that TMJ arthroscopic discopexy is an effective and predictable treatment of patients with TMJ ID in whom primary TMJ arthroscopy failed. Our results have also shown that patients with Wilkes II or III TMD will have the most successful outcome. PMID- 25530278 TI - Pleomorphic adenoma of the accessory parotid gland: case report and reappraisal of intraoral extracapsular dissection for management. AB - Pleomorphic adenoma is the most common tumor of the major and minor salivary glands. Rarely is it found evolving from an ectopic location of major salivary glandular tissue in the mid cheek. A healthy 56-year-old woman presented to our institution with a 20-year duration of a slowly growing right cheek soft tissue mass that was causing facial asymmetry. No significant functional or neurosensory dysfunction was appreciated. Radiologic examination showed a heterogeneous, hyperintense, well-delineated mass within the region of the right buccal fat pad. Fine-needle aspiration biopsy showed benign salivary gland elements consistent with pleomorphic adenoma. The decision was made to perform intraoral extracapsular dissection for removal. Discussion of the clinical assessment and magnetic resonance imaging evaluation with an emphasis on intraoral extracapsular dissection for definitive surgical therapy of longstanding benign salivary gland tumors is emphasized. PMID- 25530279 TI - Sensory outcomes after reconstruction of lingual and inferior alveolar nerve discontinuities using processed nerve allograft--a case series. AB - PURPOSE: The present study describes the results of using a processed nerve allograft, Avance Nerve Graft, as an extracellular matrix scaffold for the reconstruction of lingual nerve (LN) and inferior alveolar nerve (IAN) discontinuities. PATIENTS AND METHODS: A retrospective analysis of the neurosensory outcomes for 26 subjects with 28 LN and IAN discontinuities reconstructed with a processed nerve allograft was conducted to determine the treatment effectiveness and safety. Sensory assessments were conducted preoperatively and 3, 6, and 12 months after surgical reconstruction. The outcomes population, those with at least 6 months of postoperative follow-up, included 21 subjects with 23 nerve defects. The neurosensory assessments included brush stroke directional sensation, static 2-point discrimination, contact detection, pressure pain threshold, and pressure pain tolerance. Using the clinical neurosensory testing scale, sensory impairment scores were assigned preoperatively and at each follow-up appointment. Improvement was defined as a score of normal, mild, or moderate. RESULTS: The neurosensory outcomes from LNs and IANs that had been microsurgically repaired with a processed nerve allograft were promising. Of those with nerve discontinuities treated, 87% had improved neurosensory scores with no reported adverse experiences. Similar levels of improvement, 87% for the LNs and 88% for the IANs, were achieved for both nerve types. Also, 100% sensory improvement was achieved in injuries repaired within 90 days of the injury compared with 77% sensory improvement in injuries repaired after 90 days. CONCLUSIONS: These results suggest that processed nerve allografts are an acceptable treatment option for reconstructing trigeminal nerve discontinuities. Additional studies will focus on reviewing the outcomes of additional cases. PMID- 25530280 TI - The diagnostic value of technetium 99m pertechnetate salivary gland scintigraphy in patients with certain salivary gland diseases. AB - PURPOSE: To evaluate the diagnostic value of technetium 99m pertechnetate salivary gland scintigraphy in patients with certain salivary gland diseases. MATERIALS AND METHODS: We evaluated 47 patients: 25 with chronic obstructive parotitis, 12 with sialolithiasis, and 10 with Sjogren syndrome. All of the patients underwent preoperative (99m)Tc-pertechnetate salivary gland scintigraphy. Patients with chronic obstructive parotitis also underwent ultrasonography, sialography, and sialoendoscopy; patients with sialolithiasis also underwent ultrasonography and computed tomography; and patients with Sjogren syndrome also underwent ultrasonography and sialography. We made comparisons between (99m)Tc-pertechnetate salivary gland scintigraphy and the other aforementioned diagnostic tests to investigate the role of (99m)Tc-pertechnetate salivary gland scintigraphy in diseases of the salivary glands. RESULTS: In patients with chronic obstructive parotitis, (99m)Tc-pertechnetate salivary gland scintigraphy showed reduced excretion by the affected glands, whereas uptake was nearly normal. Among patients with sialolithiasis, (99m)Tc-pertechnetate salivary gland scintigraphy showed reduced excretion by the affected glands and decreased uptake in 5 patients. In patients with Sjogren syndrome, (99m)Tc-pertechnetate salivary gland scintigraphy showed a decrease in both excretion and uptake by the 4 glands. CONCLUSIONS: Technetium 99m pertechnetate salivary gland scintigraphy played a substantial role in the diagnosis and differential diagnosis of salivary gland diseases. PMID- 25530281 TI - Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis. AB - BACKGROUND AND PURPOSE: Vitamin D deficiency is a recognized risk factor for multiple sclerosis (MS) and is associated with increased disease activity. It has also been proposed that the lower the vitamin D levels are, the higher is the handicap. METHODS: To refine the links between vitamin D insufficiency and disability in MS patients, a retrospective cohort analysis was performed including 181 patients prospectively followed without previous vitamin D supplementation, and age, gender, age at MS onset, MS type, MS activity, Expanded Disability Status Scale (EDSS) were analysed in correlation with plasma vitamin D levels. RESULTS: Vitamin D levels were significantly higher in relapsing remitting MS than in progressive forms of MS in multivariate analyses adjusted for age, ethnicity, gender, disease duration and season (P = 0.0487). Overall, there was a negative correlation between vitamin D level and EDSS score (P = 0.0001, r = -0.33). In relapsing-remitting MS, vitamin D levels were only correlated with disability scores for EDSS < 4 (P = 0.0012). Patients with >20 ng/ml of vitamin D were 2.78 times more likely to have an EDSS < 4 (P = 0.0011, 95% confidence interval 1.49-5.00). CONCLUSION: Data support previous work suggesting that vitamin D deficiency is associated with higher risk of disability in MS. Vitamin D levels also correlated with the degree of disability in fully ambulatory patients with relapsing-remitting MS. These additional results support the pertinence of randomized controlled trials analysing the interest of an early vitamin D supplementation in MS patients to influence evolution of disability. PMID- 25530282 TI - Surgical management of small intestinal intussusception associated with jejunal adenocarcinoma in a dairy cow. PMID- 25530283 TI - Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions. AB - BACKGROUND: Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. METHODS: An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to >=50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. RESULTS: Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. CONCLUSIONS: At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions. PMID- 25530284 TI - Construction of tetralin skeletons based on rhodium-catalysed site-selective ring opening of benzocyclobutenols. AB - Tetralins (tetrahydronaphthalenes) are synthesised from benzocyclobutenols based on the rhodium-catalysed site-selective ring opening followed by intermolecular/intramolecular conjugate addition of the resulting arylrhodium species to electron-deficient alkenes. The produced structures make a remarkable contrast with those available from the same compounds under thermal reaction conditions. PMID- 25530285 TI - Free tubularised vesical mucosa graft for congenital stenosis of the urethra in children. AB - BACKGROUND: Reconstruction of urethral strictures in children remains a challenge to the pediatric surgeon as these are often related to different rare congenital anomalies with various clinical presentations that endanger renal function and should be repaired in young children. Multiple techniques have been described for their repair. We aimed to determine whether the use of a free tubularised bladder mucosal graft associated to a prior tubeless vesicostomy was feasible and sure, as this technique of reconstruction using tubularised grafts has not been described yet in young children. RESULTS: Two newborn male patients were referred to our department. Both presented a congenital stenosis of the urethra as a part of a complex urethral malformation. Surgery involved prior tubeless vesicostomy, free bladder mucosal graft for urethral reconstruction, and vesicostomy closure for both children. Postoperative evolution was satisfying in both children and cystourethroscopy showed permeable urethra. Satisfying cosmetic and functional results have been obtained in the two cases. CONCLUSIONS: The prior vesicostomy prevents kidney damage in the context of complex genital and urinary malformations. Bladder mucosa's immunohistological properties are the most similar to those of the urethral tissue, and are appropriate for this type of correction, making our technique feasible and sure. LEVEL OF EVIDENCE: 5. PMID- 25530286 TI - Another issue comes out: gay rights policy voting in recent U.S. presidential elections. AB - Drawing from the theory of policy voting, this study examines the impact of opinions about gay rights on voting for presidential candidates. Qualitative analysis of the major party platforms and candidate campaign rhetoric from the six presidential elections held between 1988 and 2008 indicates that Democratic and Republican presidential candidates began openly expressing opposing positions on gay rights issues in 1992. Quantitative analysis of public opinion shows that, starting in 1992 and continuing through 2008, gay rights issues became more salient to the public, and opinions about gay rights began to exert a significant effect on vote choice. The study concludes with a discussion of the partisan forces that shaped the electoral significance of gay rights issues during the period from 1988 to 2008 and speculation about the role of gay rights issues in shaping future partisan electoral strategy. PMID- 25530287 TI - Structure, genetics and function of an exopolysaccharide produced by a bacterium living within fungal hyphae. AB - The rice seedling blight fungus Rhizopus microsporus has an unusual symbiosis with a bacterium, Burkholderia rhizoxinica, which lives within the fungal cytosol and produces a potent phytotoxin that causes severe losses in agriculture. To gain insight into symbiosis factors we investigated the endosymbiont's exopolysaccharide (EPS), a secreted matrix that plays pivotal roles in mediating cell-environment interactions. By a combination of homo- and heteronuclear 2D NMR experiments, we elucidated a previously unknown EPS structure: a repeating tetrasaccharide unit bearing a nonstoichiometric acetyl group on a mannose residue. We also analyzed the EPS biosynthesis gene cluster and generated a targeted mutant to compare the phenotypes. Scanning electron microscope images revealed a reduced ability of the mutant to form extracellular polymers around cell aggregates. Phylogenetic analyses suggest that the symbiont's EPS genes are retained through evolutionary processes. PMID- 25530288 TI - JCEHP's new-and first-social media editor. PMID- 25530289 TI - Social media, evidence-based tweeting, and JCEHP. AB - Medical practice and medical journals must adapt to a constantly changing environment, in which social media plays an ever-increasing role. Social media platforms such as Twitter can provide an opportunity to disseminate information in innovative ways. The concept of evidence-based tweeting is introduced, especially as "tweeting the meeting" continues to expand within medical conferences and other venues important for continuing education for health care providers. Future social media strategies for the journal are outlined. PMID- 25530290 TI - Improving asthma care in rural primary care practices: a performance improvement project. AB - INTRODUCTION: Rural areas are often underserviced health areas, lack specialty care services, and experience higher levels of asthma-related burden. A primary care, asthma-focused, performance improvement program was provided to a 6-county, rural-frontier region in Colorado to determine whether asthma care practices could be enhanced to become concordant with evidence-based asthma care guidelines. METHODS: A pre-post, quasi-experimental design was used. A complex, multifaceted intervention was provided to multidisciplinary primary care teams in practices serving children and adults with asthma. Intervention elements included face-to-face trainings, clinical support tools, patient education materials, a website, and clinic visits. Performance improvement and behavior change indicators were collected through chart audits and surveys from the entire health care team. RESULTS: Participants included three health care organizations and their staff in 13 primary care practices. Overall, all team members reported statistically significant improvements in confidence levels for providing quality asthma care. Chart reviews of asthma patient encounters completed before and after the program demonstrated statistically significant improvements in asthma care practices for asthma control assessment (1% vs 20%), provision of asthma action plans (2% vs 29%), controller prescription (39% vs 71%), inhaler technique assessment (1% vs 18%), and arrangement of follow-up appointment (20% vs 37%). CONCLUSION: The asthma care-focused, multifaceted, complex, performance improvement intervention provided to rural primary health care teams lead to significant improvements in all indicators of quality asthma care provision to adults and children with asthma. However, significant barriers exist for rural practices to adopt evidence-based asthma care practices. PMID- 25530291 TI - An online community of practice to support evidence-based physiotherapy practice in manual therapy. AB - INTRODUCTION: The purpose of this study was to explore how a community of practice promoted the creation and sharing of new knowledge in evidence-based manual therapy using Wenger's constructs of mutual engagement, joint enterprise, and shared repertoire as a theoretical framework. METHODS: We used a qualitative approach to analyze the discussion board contributions of the 19 physiotherapists who participated in the 10-week online continuing education course in evidence based practice (EBP) in manual therapy. The course was founded on community of practice, constructivism, social, and situated learning principles. RESULTS: The 1436 postings on 9 active discussion boards revealed that the community of practice was a social learning environment that supported strong participation and mutual engagement. Design features such as consistent facilitation, weekly guiding questions, and collaborative assignments promoted the creation and sharing of knowledge. Participants applied research evidence to the contexts in which they worked through reflective comparison of what they were reading to its applicability in their everyday practice. Participants' shared goals contributed to the common ground established in developing collective knowledge about different study designs, how to answer research questions, and the difficulties of conducting sound research. DISCUSSION: An online longitudinal community of practice utilized as a continuing education approach to deliver an online course based on constructivist and social learning principles allowed geographically dispersed physiotherapists to be mutually engaged in a joint enterprise in evidence-based manual therapy. Advantages included opportunity for reflection, modeling, and collaboration. Future studies should examine the impact of participation on clinical practice. PMID- 25530292 TI - Not enough time or a low priority? Barriers to evidence-based practice for allied health clinicians. AB - INTRODUCTION: Evidence-based practice (EBP) is a key principle in the delivery of effective and high-quality health care. Existing research suggests that allied health professionals are generally supportive of EBP but rarely participate in activities associated with EBP. METHODS: This mixed-method study used 8 focus groups of allied health professionals and managers and a questionnaire of all participants to explore the attitudes and barriers to EBP in a large metropolitan health service. Qualitative data were analyzed using a thematic analysis of focus group transcriptions. Questionnaire data were analyzed descriptively. RESULTS: Fifty clinicians and 10 managers across 7 allied health disciplines participated in the study. The questionnaire identified that clinicians have a positive attitude but low participation in EBP. Qualitative data revealed that EBP was not highly valued by clinicians and managers or viewed as a core component of clinical care, with activities directly related to maintaining patient flow viewed as higher priorities. Lack of skills and resources and difficulty associated with implementing evidence into practice were further barriers. DISCUSSION: Achieving higher uptake of EBP among allied health clinicians requires a cultural shift, placing higher value on these activities despite the challenging context of constant pressures to increase patient flow. Addressing EBP through small group projects rather than considering it to be an individual responsibility may be more acceptable to both clinicians and managers, with added benefits of peer support for both evaluating evidence and translation into practice. PMID- 25530293 TI - The Communication AssessmenT Checklist in Health (CATCH): a tool for assessing the quality of printed educational materials for clinicians. AB - INTRODUCTION: There is little guidance available on strategies to improve the communication quality of printed educational materials (PEMs) for clinicians. The purposes of this study were to conceptualize PEM communication quality, develop a checklist based on this conceptualization, and validate the checklist with a selection of PEMs. METHODS: From a literature review of the strategies influencing communication quality, we generated a conceptual map and developed the Communication AssessmenT Checklist in Health (CATCH) consisting of 55 items nested in 12 concepts. Two raters independently applied CATCH to 45 PEMs evaluated in the studies included in a Cochrane systematic review. From these results, we conducted an item analysis and assessed content validity of CATCH using a hierarchical cluster analysis to explore the extent to which our CATCH operationalization truly represented the communication quality concepts. RESULTS: Some concepts were better covered in the studied PEMs, whereas others were not covered consistently. We observed 3 contrasting PEM clusters. A first cluster (n = 22) was characterized by longer PEMs and comprised mostly high-impact peer reviewed scientific articles or clinical practice guidelines. A second cluster (n = 22) consisted of PEMs shorter than 4 pages that used special fonts, color, pictures, and graphics. A third cluster consisted of a single brief PEM. DISCUSSION: With CATCH it is possible to categorize and understand the mechanisms that can trigger a change in behavior in health care providers. Additional research is needed to validate CATCH before it can be recommended for use. PMID- 25530294 TI - Effects of 2 educational interventions on the management of hypertensive patients in primary health care. AB - INTRODUCTION: Experimental studies on the effectiveness of educational interventions to improve patient care are scarce, especially for low-resources settings. This study investigated the effects of 2 educational interventions on the treatment of hypertensive patients in primary health care in Brazil. METHODS: Forty-one physicians were randomly assigned either to an "active educational intervention" (21 physicians) or to a "passive educational intervention" (20 physicians). The former comprised 1 small group discussion of routine practices, 1 outreach visit, and 3 reminders. The latter consisted of delivery of printed guidelines. Measures of quality of treatment provided for hypertensive patients (181 patients of physicians from the active intervention; 136 patients of physicians from the passive intervention) were obtained through patient interview and charts review, before and 3 months after the intervention. Chi-square and independent t-tests were performed for comparison between the conditions. RESULTS: The groups did not differ before the study. After the intervention, the active intervention group outperformed the passive intervention group in several measures, such as improved prescription of antihypertensive drugs (80% of patients of physicians from the active intervention vs 51% patients of physicians from the passive intervention; p < .01), prescription of aspirin (18% vs 6%; p < .01) and hypolipidemic drugs for high-risk patients (39% vs 21%; p < .01), dietary counseling (76% vs 61%; p < .01), guidance on cardiovascular risk (20% vs 3%; p < .01). Patient outcomes did not differ. DISCUSSION: A multifaceted intervention based on review of practices improved treatment of hypertensive patients in a low-resource setting whereas delivery of guidelines did not help. None of the interventions affected patient outcomes. PMID- 25530295 TI - Facilitating physician reentry to practice: perceived effects of deployments on US army pediatricians' clinical and procedural skills. AB - INTRODUCTION: US Army pediatricians regularly deploy for 6 to 12 months or longer and many are deployed multiple times during their career. Prolonged breaks in pediatric clinical practice may result in skill degradation, requiring a physician reentry process to prepare pediatricians to return to clinical practice. This study sought to identify which specific pediatric clinical skills were felt to be most affected by deployment. METHODS: Army pediatricians on active duty between January 2012 and March 2012 were surveyed via e-mail to determine their comfort level and experience with clinical encounters and procedural skills prior to and after military deployment. RESULTS: Eighty-three pediatricians were eligible, and 75 responded (90% response rate). Of those received, 65 surveys (78%) were complete and included in the statistical analysis. Over half (54%) of the respondents were deployed longer than 6 months, and 32% were deployed for 12 months or longer. The largest changes in reported comfort were seen in neonatal, pediatric, and adolescent acute care and neonatal routine care, including neonatal and pediatric procedures. There was a significant negative correlation (r = .64; p = .003) between provider's reported exposure to neonatal and pediatric clinical encounters during deployment and provider's comfort with those clinical encounters after deployment. DISCUSSION: US Army pediatricians are required to deploy for extended periods of time and have limited opportunities to practice the full range of their pediatric skills. This break in clinical practice is associated with a significant decline in perceived comfort with both routine and acute pediatric care. PMID- 25530296 TI - Workplace-based assessment for vocational registration of international medical graduates. AB - INTRODUCTION: Medical regulatory authorities need efficient and effective methods of ensuring the competence of immigrating international medical graduates (IMGs). Not all IMGs who apply for specialist vocational registration will have directly comparable qualifications to those usually accepted. As general licensure examinations are inappropriate for these doctors, workplace-based assessment (WBA) techniques would appear to provide a solution. However, there is little published data on such outcomes. METHODS: All cases of WBA (n = 81) used for vocational registration of IMGs in New Zealand between 2008 and 2013 were collated and analyzed. RESULTS: The successful completion rate of IMGs through the pathway was 87%. The majority (64%) undertook the year of supervised practice and the final assessment in a provincial center. For those unsuccessful in the pathway, inadequate clinical knowledge was the most common deficit found, followed by poor clinical reasoning. DISCUSSION: A WBA approach for assessing readiness of IMGs for vocational registration is feasible. The constructivist theoretical perspective of WBA has particular advantages in assessing the standard of practice for experienced practitioners working in narrow scopes than traditional methods of assessment. The majority of IMGs undertook both the clinical year and the assessment in provincial hospitals, thus providing a workforce for underserved areas. PMID- 25530297 TI - Trends of psychology-related research on euthanasia: a qualitative software-based thematic analysis of journal abstracts. AB - Euthanasia has received increasing attention in both academic and public debates as one of the most controversial issues. However, the contribution of psychology related themes to the topic has had little role on these ongoing debates. The aim of the present study is twofold: (1) to explore the main themes relating to euthanasia as provided by psychology-related research; (2) to analyze the temporal trends of psychology-related research on euthanasia over the last decades. A comprehensive search of academic literature was conducted on PsychINFO database. A qualitative software-based thematic analysis was carried out on 602 journal abstracts published from 1935 to 2014. This study highlighted four different thematic areas which characterized the scientific discourse on euthanasia: (1) moral values, in terms of religious, philosophical, and social implications concerning the individual's decision to die; (2) professional ethics, in terms of health and social workers' legal responsibility in death assistance; (3) end-of-life care, with regard to medical options provided to support individuals nearing death; and (4) patient's right to healthcare, in terms of access to palliative care and better quality of dying. Euthanasia discourse over the last decades seems to be overall characterized by two main dimensions: (1) the increasing trend of social legitimacy and acceptability of euthanasia over time, which moved from ethical to healthcare issues; and (2) the curvilinear temporal trend about the request/provision process in euthanasia, which moved from patient's decision for ending life (mainly characterizing the most past and recent research) to the role of health professionals (with a peak in the 1990s). The results suggest palliative care as a potential future research area which can provide healthcare providers with skills to 'connect' with patients, understand patients' hidden agendas, and grant a good quality of life and dying process. PMID- 25530298 TI - Rapid detection of hydrazine in a naphthol-fused chromenyl loop and its effectiveness in human lung cancer cells: tuning remarkable selectivity via the reaction altered pathway supported by theoretical studies. AB - Our designed and synthesized chemosensor naphthalene based chromenyl derivative (NAC) [1-(3-hydroxy-3 methyl-3H-benzo[f]chromen-2-yl) ethanone] has been used for fast (<30 s, DL = 0.22 ppb) and selective detection of N2H4 by a new way via the chromenyl ring opening followed by the pyrazole ring formation giving a strong blue fluorescence. The DFT study and the real application in different water samples along with the dipstick method in low cost devices have also been performed here. Human lung cancer cells (NCI-H460) have been used for hydrazinolysis of the NAC in vivo system for detection by the appearance of blue fluorescence and also for the MTT assay showing its remarkable cancer sensitivity. PMID- 25530299 TI - [Empiric antibiotic therapy for neonatal infections: time to change]. PMID- 25530300 TI - Synthesis and systematic evaluation of dark resonance energy transfer (DRET) based library and its application in cell imaging. AB - In this paper, we report a new strategy for constructing a dye library with large Stokes shifts. By coupling a dark donor with BODIPY acceptors of tunable high quantum yield, a novel dark resonance energy transfer (DRET)-based library, named BNM, has been synthesized. Upon excitation of the dark donor (BDN) at 490 nm, the absorbed energy is transferred to the acceptor (BDM) with high efficiency, which was tunable in a broad range from 557 nm to 716 nm, with a high quantum yield of up to 0.8. It is noteworthy to mention that the majority of the non-radiative energy loss of the donor was converted into the acceptor's fluorescence output with a minimum leak of donor emission. Fluorescence imaging tested in live cells showed that the BNM compounds are cell-permeable and can also be employed for live-cell imaging. This is a new library which can be excited through a dark donor allowing for strong fluorescence emission in a wide range of wavelengths. Thus, the BNM library is well suited for high-throughput screening or multiplex experiments in biological applications by using a single laser excitation source. PMID- 25530301 TI - HtrA1 loss is related to aggressive behavior parameters in sentinel node positive breast cancer. AB - AIM: HtrA1, a member of the High Temperature Requirement Factor A family of oxidative stress-response proteases seems to play a role as a tumor suppressor, being down-regulated in a series of human cancers during their progression. Particularly, low HtrA1 mRNA levels have been observed in breast cancer patients with more aggressive clinical features. These have been shown to relate to a longer disease free and overall survival, with more pronounced effects in axillary nodes positive patients. SUBJECTS AND METHODS: We have analyzed for immunohistochemical HtrA1 expression a series of 66 sentinel node positive breast cancers through Tissue Micro Array technology. RESULTS: HtrA1 was absent to low in 29 cases, medium in 19 cases and high in 18 cases. Our data revealed a positive significant relation between HtrA1 expression level and estrogen (p=0,002) and progestinic receptor expression (p=0.003) and a negative correlation with histological grading (p=0.028), proliferation index (p=0.05), common BC histotypes (p=0.040), luminal A and B subtypes (p=0.001), metastasis development (p<0.0001) and local relapse (p<0.0001). Finally, no correlation was recorded between HtrA1 expression level and breast cancer histology type and metastasis to non sentinel nodes. Interestingly HtrA1 loss in SLN metastasis was able to predict positive non sentinel nodes (p=0.001). CONCLUSIONS: Low HtrA1 expression is significantly related to breast cancer poor prognosis parameters, and HtrA1 loss in sentinel nodes is related to metastasis of non sentinel nodes, offering a further marker useful for BC prognostic stratification. PMID- 25530302 TI - Clonality analysis in primary oral squamous cell carcinoma and related lymph-node metastasis revealed by TP53 and mitochondrial DNA next generation sequencing analysis. AB - The chance of developing a neck nodal metastasis after initial treatment of oral squamous cell carcinoma varies from 12.4% to 62%. Despite being the main reason for cancer-related mortality, nodal metastases are still rarely subjected to molecular analyses, and our knowledge of the clonal heterogeneity of multiple lesions within the same patient is limited. The aim of the present study was to evaluate the relationship between primary oral cancer and lymph node metastasis in a series of patients with synchronous and metachronous metastases by 2 clonality tests: mt-DNA and TP53 sequence analysis. The study population consisted of 10 consecutive patients. Data identified in this study demonstrate that our assay based on next-generation analysis of TP53 and mt-DNA is simple, is reliable, allows high throughput, and may be applied to retrospective cases. The combination of mt-DNA and TP53 data analysis helped us to evaluate more precisely and consistently the genetic relationship among different tumor clones. PMID- 25530303 TI - Transoral vs. extraoral approach in the treatment of condylar neck fractures. AB - PURPOSE: The aim of this study was to assess a non-endoscopic transoral versus extraoral technique in the open reduction and internal fixation of displaced or dislocated fractures of the condylar neck. MATERIAL AND METHODS: A total of 104 patients, treated from 2007 to 2012 with 114 class II or class IV fractures according to Spiessl and Schroll were included in this study. Facial nerve function, scarring, pain and functional clinical parameters, such as protrusion, mediotrusion and maximum interincisal distance, were judged clinically (at 21 +/- 12.1 months); repositioning and reossification were measured upon preoperative, postoperative and follow-up (at 8.8 +/- 7 months) radiographs. Patient satisfaction was evaluated using the OHIP-G 14 questionnaire. RESULTS: In all, 36 patients (35%) with 43 fractures (38%) presented for clinical follow-up. Both treatment groups showed clinically and radiologically comparable results. Scarring was obvious in all extraorally treated patients, and hypertrophic scars occurred in four class IV cases (24%). One class IV patient (6%) had a persistent facial nerve palsy; temporary pareses were more frequent (n = 4; 24%). CONCLUSION: The transoral approach did not jeopardize facial nerve function, and extraoral scars were avoided. Repositioning and fixation results and the frequency of revision operations were comparable. The transoral approach can be recommended generally in class II and class IV cases. PMID- 25530304 TI - Rare orbital cystic lesions in children. AB - PURPOSE: To analyze the clinical features, imaging findings and surgical management of rare orbital cystic lesions in children. MATERIALS AND METHODS: Clinical records of 5 Chinese children with rare orbital cystic lesions including cystic teratoma, congenital cystic eye, optic nerve sheath cyst, parasitic cyst, and meningoencephalocele were reviewed. Their clinical history, symptoms and signs, ultrasonography or computed tomography/magnetic resonance imaging (CT/MRI), surgical management were presented in detail. RESULTS: Among the 5 patients, 2 were male and 3 female. The right orbit was involved in 2 patients and the left orbit in 3 patients. Ages ranged from 2 months to 11 years (mean, 4.2 years). Cystic teratoma showed a well-outlined cystic mass with a focal bone like structure (or calcific densities) in their lumens as revealed with CT scan. Congenital cystic eye was a rare ocular malformation that existed at birth and showed a cystic lesion with no definite ocular structures in the orbit. With MRI examination, the optic nerve sheath cyst demonstrated a clear figure of the central optic nerve and the surrounding sheath cyst. Patients with parasitic cysts usually had frequent animal contact and high levels of blood eosinophils. Meningoencephalocele, the herniation into the orbit of brain tissue, had the typical CT/MRI features, with bone defect and soft tissue mass in the orbit and a homogenous appearance that was isodense with brain. CONCLUSIONS: Besides common dermoid/epidermoid cyst, rare orbital cystic lesions such as cystic teratoma, congenital cystic eye, optic nerve sheath cyst, parasitic cyst, and meningoencephalocele should be considered in children. PMID- 25530305 TI - Effect of mechanical stretching on DNA conductance. AB - Studying the structural and charge transport properties in DNA is important for unraveling molecular scale processes and developing device applications of DNA molecules. Here we study the effect of mechanical stretching-induced structural changes on charge transport in single DNA molecules. The charge transport follows the hopping mechanism for DNA molecules with lengths varying from 6 to 26 base pairs, but the conductance is highly sensitive to mechanical stretching, showing an abrupt decrease at surprisingly short stretching distances and weak dependence on DNA length. We attribute this force-induced conductance decrease to the breaking of hydrogen bonds in the base pairs at the end of the sequence and describe the data with a mechanical model. PMID- 25530306 TI - Anger self-management in chronic traumatic brain injury: protocol for a psycho educational treatment with a structurally equivalent control and an evaluation of treatment enactment. AB - Anger and irritability are important and persistent clinical problems following traumatic brain injury (TBI). Treatment options include medications, behavioral modification, and psychotherapies, but some are impractical and none have proven efficacy with this population. We describe a randomized multi-center clinical trial testing a novel, one-on-one, 8-session psychoeducational treatment program, Anger Self-Management Training (ASMT), designed specifically for people with TBI who have significant cognitive impairment. The trial is notable for its use of a structurally equivalent comparison treatment, called Personal Readjustment and Education (PRE), which was created for the study and is intended to maximize equipoise for both participants and treaters. Fidelity assessment is conducted in real time and used in therapist supervision sessions. The primary outcome is change in self-reported anger on validated measures from pre-treatment to 1 week after the final session. Secondary outcomes include participant anger as reported by a significant other; emotional distress in domains other than anger/irritability; behavioral functioning; and quality of life. An interim assessment after the 4th session will allow examination of the trajectory of any observed treatment effects, and a follow-up assessment 2 months after the end of intervention will allow examination of persistence of effects. A treatment enactment phase, in which participants are interviewed several months after the last therapy session, is designed to provide qualitative data on whether and to what extent the principles and techniques learned in treatment are still carried out in daily life. PMID- 25530307 TI - Payment expectations for research participation among subjects who tell the truth, subjects who conceal information, and subjects who fabricate information. AB - Multiple models guide researchers' payment practices but few studies have assessed subjects' expectations for payment. Payments in excess of subjects' expectations may result in undue inducement, while payments below these expectations may be associated with exploitation. Data on subjects' payment expectations will help inform practices to avoid undue inducement and exploitation. This study examined subjects' expectations for payment for common research procedures and explored the relationship between subjects' honesty and payment expectations. One-hundred subjects who participated in two or more studies in the last year reported the minimum payment they expect for completing study procedures. They were also asked about their use of deception while screening for studies. Subjects expected $20 on average to complete the least risky and least burdensome procedure. Subjects' expectations for payment consistently increased with greater procedure risks. Subjects who denied using deception to enroll in studies refused more procedures than subjects who reported using deception. Among subjects who used deception, the rate of procedure refusal increased with procedure risks, suggesting that these subjects have some risk aversion and may act to protect themselves from undue inducement. Although subjects expect greater payments for more risky procedures, ethical considerations for limiting undue inducement may prevent researchers from meeting subjects' expectations. Subjects who use deceptive practices appear to be more risk-tolerant than subjects who deny using deception; nonetheless, these deceptive subjects also exercise some risk aversion when they refuse higher-risk procedures. These subjects may be able to protect themselves from undue inducement by refusing procedures that exceed their risk tolerance. PMID- 25530308 TI - Vancomycin-Resistant Staphylococcus hemolyticus Bacteremia Treated Successfully by Intravenous Daptomycin and Catheter Removal in a Hemodialysis Patient. PMID- 25530309 TI - Condom use preferences among Latinos in Miami-Dade: emerging themes concerning men's and women's culturally-ascribed attitudes and behaviours. AB - Among Latinos, cultural values such as machismo and marianismo may promote inconsistent condom use representing a significant risk factor for HIV infection. Yet there continues to be a need for additional research to explore the influence these cultural values have on Latino men and women's condom use attitudes and behaviours given increasing HIV rates of HIV infection among Latinos. The purpose of this study was to explore further Latino traditional culturally-ascribed attitudes and behaviour for emerging themes toward condom use among a diverse group of adult Latino men and women living in Miami-Dade County, Florida, USA. The study used a qualitative study-design and collected data from 16 focus groups with a total of 67 Latino men and women. Findings from the focus groups described attitudes and behaviours that counter traditional gender roles towards sex and expected sexual behaviours informed by machismo and marianismo. Common attitudes noted in the study include men's classification of women as dirty-clean to determine condom use and women's assertiveness during sexual encounters negotiating condom use--in favour and against it. As the findings of this study suggest, the process differ greatly between Latino men and women, having an impact on the risk behaviours in which each engage. PMID- 25530311 TI - PdbrlA, PdabaA and PdwetA control distinct stages of conidiogenesis in Penicillium digitatum. AB - Penicillium digitatum is one of the most important citrus postharvest pathogens worldwide. Reproduction of massive asexual spores is the primary factor contributing to the epidemic of citrus green mold. To understand the molecular mechanisms underlying conidiogenesis in P. digitatum, we functionally characterized the Aspergillus nidulans orthologs of brlA, abaA and wetA. We showed that deletion of PdbrlA completely blocked formation of conidiophores, whereas deletion of PdabaA led to the formation of aberrant and non-functional phialides. The PdwetA mutant showed various defective phenotypes, such as abnormal conidia with loose cell walls, delayed germination and reduced tolerance to osmotic, detergent, heat shock and menadione stresses, but elevated resistance to H2O2. PdbrlA-influenced genes were identified by comparing global gene expression profiles between the wild-type and the PdbrlA deletion mutant during conidiation. Gene ontology analysis of these differentially expressed genes (DEGs) revealed the diverse roles of PdbrlA in metabolism, transportation and cell structure. Moreover, out of 39 genes previously reported to be involved in conidiogenesis in Aspergillus, mRNA levels of 14 genes were changed in DeltaPdbrlA. Our results confirm the roles of brlA, abaA and wetA in P. digitatum conidiogenesis and provide new insights into the genetics of conidiation in filamentous fungi. PMID- 25530312 TI - Modulating the level of the Rpb7 subunit of RNA polymerase II affects cell separation in Schizosaccharomyces pombe. AB - The rpb7(+) gene encodes the seventh largest subunit of RNA polymerase II and is essential for survival of yeast cells. To gain insight into its functions, we expressed rpb7(+) under the control of the nmt1 promoter and investigated its role in regulating multiple phenotypes in Schizosaccharomyces pombe. We observed that low rpb7(+) levels resulted in slow growth of cells under optimum growth conditions. However, no growth defect was observed under different stress conditions tested in this study. Our results also showed that the most prominent phenotype of cells expressing reduced rpb7(+) is a defect in cell separation. Quantitative real-time PCR analysis further revealed that the transcription of specific cell septation genes was significantly reduced in these cells. Collectively, results presented in this study highlight the distinct role of Rpb7p in regulating cell separation in S. pombe. PMID- 25530313 TI - Diversity and biotransformative potential of endophytic fungi associated with the medicinal plant Kadsura angustifolia. AB - This study investigated the diversity and host component-transforming activity of endophytic fungi in medicinal plant Kadsura angustifolia. A total of 426 isolates obtained were grouped into 42 taxa belonging to Fungi Imperfecti (65.96%), Ascomycota (27.00%), Zygomycota (1.64%), Basidiomycota (0.47%) and Mycelia Sterilia (4.93%). The abundance, richness, and species composition of endophytic assemblages were significantly dependent on the tissue and the sampling site. Many phytopathogenic species associated with healthy K. angustifolia were found prevalent. Among them, Verticillium dahliae was dominant with 16.43% abundance. From 134 morphospecies selected, 39 showed remarkable biocatalytic activity and were further identified as species belonging to the genera Colletotrichum, Eupenicillium, Fusarium, Hypoxylon, Penicillium, Phomopsis, Trametes, Trichoderma, Umbelopsis, Verticillium and Xylaria on the basis of the sequence analysis of the internal transcribed spacer (ITS1-5.8S-ITS2). The results obtained in this work show that K. angustifolia is an interesting reservoir of pathogenic fungal species, and could be a community model for further ecological and evolutionary studies. Additionally, the converting potency screening of some endophytic fungi from this specific medicinal plant may provide an interesting niche on the search for novel biocatalysts. PMID- 25530314 TI - Large-scale analysis of viral nucleic acid spectrum in temporal lobe epilepsy biopsies. AB - OBJECTIVE: Chronic inflammatory processes are important promotors of temporal lobe epilepsy (TLE) development. Based on human herpesvirus 6 (HHV-6) DNA detection in brain tissue from patients with TLE, an association of persistent viral infection with TLE has been discussed. Individual studies reported increased HHV-6 DNA in patients with clinical signs of previous inflammatory brain reaction, that is, febrile seizures or meningoencephalitis. However, detection rates vary considerably between different studies. Here we performed a large-scale analysis of viral DNA/RNA spectrum in high-quality TLE biopsies. In addition to all Herpesviridae, we addressed potentially relevant neurotropic RNA viruses. METHODS: DNA and RNA were extracted from 346 fresh-frozen tissue samples removed by epilepsy surgery. Real-time polymerase chain reaction (PCR) and nested PCR were performed for Herpesviridae and RNA viruses, respectively. Clinical data were analyzed for earlier signs of inflammatory brain reactions. Fresh-frozen hippocampal tissue samples from patients without chronic central nervous system (CNS) disease served as controls (n = 62). Seven previous PCR studies with overall 178 TLE patients were additionally analyzed regarding a correlation of clinical parameters and HHV-6 detection. RESULTS: PCR revealed HHV-6B DNA in 34 specimens (9.8%) from TLE patients. HHV-6B DNA was also present in eight control samples (12.9%; p > 0.05), but showed a lower virus concentration (p < 0.001). Other herpesviruses and RNA viruses were virtually absent. In patients with clinical signs of previous brain inflammation, HHV-6B DNA was observed in 15.0%, whereas only 6.3% of the samples from patients without febrile seizures or meningoencephalitis were positive for HHV-6B DNA (p < 0.05). A meta-analysis of the eight HHV-6 PCR studies revealed similar results. SIGNIFICANCE: This biopsy based study shows no differences in frequency of HHV-6B DNA detection between TLE patients and controls. These results do not support the hypothesis of a persistent HHV-6B infection as a major pathogenetic factor in TLE. However, the higher virus load in TLE patients and the increased detection rate of HHV-6B DNA in patients with previous inflammatory brain reactions require further investigations. PMID- 25530315 TI - Synthesis of Bi2WO6/Bi2O3 composite with enhanced photocatalytic activity by a facile one-step hydrothermal synthesis route. AB - In this study, the characterization and photocatalytic activity of Bi2WO6/Bi2O3 under visible-light irradiation was investigated in detail. The results suggested that Bi2WO6/Bi2O3 can be synthesized by a facile one-pot hydrothermal route using a super big 200 mL Teflon-lined autoclave with optimal sodium oleate/Bi molar ratio of 1.25. Through the characterization of Bi2WO6/Bi2O3 by X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared, UV-vis diffuse reflectance spectra and Photoluminescence spectra, it was found that the as-prepared composite possessed smaller crystallite size and higher visible-light responsive than the pure Bi2WO6. Moreover, it was expected that the as-prepared composites exhibited enhanced photocatalytic activity for the degradation of Rhodamine B under visible-light irradiation, which could be ascribed to their improved light absorption property and the reduced recombination of the photogenerated electrons and holes during the photocatalytic reaction. In general, this study could provide a principle method to synthesize Bi2WO6/Bi2O3 with enhanced photocatalytic activity by one-step hydrothermal synthesis route for environmental purification. PMID- 25530316 TI - SUPPORT and the Ethics of Study Implementation: Lessons for Comparative Effectiveness Research from the Trial of Oxygen Therapy for Premature Babies. AB - The design of SUPPORT has been widely misunderstood. This confusion has driven much of the debate about the trial - and threatens the whole enterpise of comparative effectiveness research. PMID- 25530317 TI - Omega-6 and omega-3 fatty acids metabolism pathways in the body of pigs fed diets with different sources of fatty acids. AB - This study was carried out on 24 gilts (? Polish Large White * ? Danish Landrace) grown with body weight (BW) of 60 to 105 kg. The pigs were fed diets designed on the basis of a standard diet (appropriate for age and BW of pigs) where a part of the energy content was replaced by different fat supplements: linseed oil in Diet L, rapeseed oil in Diet R and fish oil in Diet F (6 gilts per dietary treatment). The fat supplements were sources of specific fatty acids (FA): in Diet L alpha linolenic acid (C18:3 n-3, ALA); in Diet R linoleic acid (C18:2 n-6, LA) and in Diet F eicosapentaenoic acid (C20:5 n-3, EPA), docosapentaenoic acid (C22:5 n-3, DPA) and docosahexaenoic acid (C22:6 n-3, DHA). The protein, fat and total FA contents in the body did not differ among groups of pigs. The enhanced total intake of LA and ALA by pigs caused an increased deposition of these FA in the body (p < 0.01) and an increased potential body pool of these acids for further metabolism/conversions. The conversion efficiency of LA and ALA from the feed to the pig's body differed among groups (p < 0.01) and ranged from 64.4% to 67.2% and from 69.4% to 81.7%, respectively. In Groups L and R, the level of de novo synthesis of long-chain polyunsaturated FA was higher than in Group F. From the results, it can be concluded that the efficiency of deposition is greater for omega-3 FA than for omega-6 FA and depends on their dietary amount. The level of LA and ALA intake influences not only their deposition in the body but also the end products of the omega-3 and omega-6 pathways. PMID- 25530318 TI - Cost per patient-year in response using a claims-based algorithm for the 2 years following biologic initiation in patients with rheumatoid arthritis. AB - OBJECTIVE: To estimate cost per patient-year in response during 2 years following biologic initiation among patients with rheumatoid arthritis (RA). METHODS: Adults newly initiating biologics for RA (etanercept, abatacept, adalimumab, certolizumab, golimumab, or infliximab) between January 2009 and July 2011 were identified in the MarketScan Commercial Database. Eligible patients were continuously enrolled 6 months before (pre-index) and 24 months after (post index) their first (index) biologic claim. Biologic effectiveness was assessed using six criteria during 2-year follow-up: treatment adherence >=80%, no biologic dose escalation, no biologic switch, no new disease-modifying anti rheumatic drug, no new/increased glucocorticoid dose, and limited intra-articular joint injections (<=2). After a 90-day period of non-response for a treatment failure, effectiveness or failure of subsequent treatment was assessed again for the index biologic or new biologic (after switching). Post-index RA-related medical, pharmacy, and drug administration costs were attributed to the index biologic. Cost per patient-year in response was calculated as RA-related costs divided by duration of response. RESULTS: Overall, 15.0% of patients (1229/8193) did not fail any criterion for 2 years and were effectively treated. Mean duration of response was highest for etanercept (538.3 days), followed by golimumab (537.0 days; p = 0.864), adalimumab (534.7 days; p = 0.301), certolizumab (524.0 days; p = 0.165), infliximab (480.0 days; p < 0.001), and abatacept (482.3 days; p < 0.001). Total disease-related cost per patient-year in response was lower for patients initiated on etanercept ($25,086) than for patients initiated on adalimumab ($25,960), certolizumab ($26,339), golimumab ($26,332), abatacept ($35,581), or infliximab ($36,107). LIMITATIONS: This study was limited to employer-paid commercial insurance. Database analyses cannot determine reasons for failing criteria. The algorithm was not designed and validated for 2 years of follow-up. CONCLUSIONS: An effectiveness algorithm estimated that initiating etanercept was the most effective treatment during 2 years of follow-up, with the lowest cost per patient-year in response. PMID- 25530319 TI - Influence of sex and specialty on the prediction of middle-distance running performances using the Mercier et al.'s nomogram. AB - The aim was to test the influence of sex and specialty (3000, 5000 and 10000 m) on the validity of middle-distance running performance predictions obtained from the Mercier et al.'s nomogram. Consequently, we examined all official French track running rankings for the 3000-, 5000- and 10000-m events (men and women) from 2006 to 2012. A scoring table was used to determine the runners' specialties. Only runners who performed in the three distance events within the same year were included (75 women and 400 men). The Mercier et al.'s nomogram was used to predict one running performance from the other two. The results showed no significant difference between actual and predicted running performances (P = 0.77). Female runners had significantly lower performances than male runners (P < 0.001). Specialty did not influence performances (P = 0.11). Very high correlations were found between actual and predicted performances (0.91 < r < 0.99), with the exception of women (r = 0.85) in 5000 m. Moreover, low limits of agreement were obtained for male and female runners, whatever the specialty. These results support the validity of the nomogram to predict running performance in the 3000-, 5000- and 10000-m events for male and female runners, whatever the specialty. The predicted running performances may be used in training programmes (e.g., to prescribe tempo runs) and competitions (e.g., to establish split times). PMID- 25530320 TI - Avian influenza surveillance in Central and West Africa, 2010-2014. AB - Avian influenza virus (AIV) is an important zoonotic pathogen, resulting in global human morbidity and mortality and substantial economic losses to the poultry industry. Poultry and wild birds have transmitted AIV to humans, most frequently subtypes H5 and H7, but also different strains and subtypes of H6, H9, and H10. Determining which birds are AIV reservoirs can help identify human populations that have a high risk of infection with these viruses due to occupational or recreational exposure to the reservoir species. To assess the prevalence of AIV in tropical birds, from 2010 to 2014, we sampled 40 099 birds at 32 sites in Central Africa (Cameroon, Central African Republic, Congo Brazzaville, Gabon) and West Africa (Benin, Cote d'Ivoire, Togo). In Central Africa, detection rates by real-time RT-PCR were 16.6% in songbirds (eight passerine families, n = 1257), 16.4% in kingfishers (family Alcedinidae, n = 73), 8.2% in ducks (family Anatidae, n = 564), and 3.65% in chickens (family Phasianidae, n = 1042). Public health authorities should educate human cohorts that have high exposure to these bird populations about AIV and assess their adherence to biosecurity practices, including Cameroonian farmers who raise small backyard flocks. PMID- 25530321 TI - Effect of ionic size on solvate stability of glyme-based solvate ionic liquids. AB - A series of binary mixtures composed of glymes (triglyme, G3; tetraglyme, G4; pentaglyme, G5) and alkali-metal bis(trifluoromethanesulfonyl)amide salts (M[TFSA]; M = Li, Na, and K) were prepared, and the correlation between the composition and solvate stability was systematically investigated. Their phase diagrams and Raman spectra suggested complexation of the glymes with M[TFSA] in 1:1 and/or 2:1 molar ratio(s). From isothermal stability measurements, it was found that the formation of structurally stable complexes in the solid state did not necessarily ensure their thermal stability in the liquid state, especially in the case of 2:1 complexes, where uncoordinating or highly exchangeable glyme ligands existed in the molten complexes. The phase-state-dependent Raman spectra also supported the presence of free glymes in certain liquid complexes. The effect of the electric field induced by the alkali-metal cations on the oxidative stability of certain glyme complexes was examined by linear sweep voltammetry and quantum chemical calculations. Although the actual oxidative stability of complexes did not necessarily reflect the calculated HOMO energy levels of the glymes, the strong electric field induced by the smaller M(+) cations and proper coordination structures impart high stability to the glyme complexes. The results of thermogravimetry of complexes with different M(+) cations revealed that a balance of competitive interactions of the M(+) ions with the glymes and [TFSA]( ) anions predominates the thermal stability. PMID- 25530322 TI - Analysis of runs of homozygosity and their relationship with inbreeding in five cattle breeds farmed in Italy. AB - Increased inbreeding is an inevitable consequence of selection in livestock populations. The analysis of high-density single nucleotide polymorphisms (SNPs) facilitates the identification of long and uninterrupted runs of homozygosity (ROH) that can be used to identify chromosomal regions that are identical by descent. In this work, the distribution of ROH of different lengths in five Italian cattle breeds is described. A total of 4095 bulls from five cattle breeds (2093 Italian Holstein, 749 Italian Brown, 364 Piedmontese, 410 Marchigiana and 479 Italian Simmental) were genotyped at 54K SNP loci. ROH were identified and used to estimate molecular inbreeding coefficients (FROH ), which were compared with inbreeding coefficients estimated from pedigree information (FPED ) and using the genomic relationship matrix (FGRM ). The average number of ROH per animal ranged from 54 +/- 7.2 in Piedmontese to 94.6 +/- 11.6 in Italian Brown. The highest number of short ROH (related to ancient consanguinity) was found in Piedmontese, followed by Simmental. The Italian Brown and Holstein had a higher proportion of longer ROH distributed across the whole genome, revealing recent inbreeding. The FPED were moderately correlated with FROH > 1 Mb (0.662, 0.700 and 0.669 in Italian Brown, Italian Holstein and Italian Simmental respectively) but poorly correlated with FGRM (0.134, 0.128 and 0.448 for Italian Brown, Italian Holstein and Italian Simmental respectively). The inclusion of ROH > 8 Mb in the inbreeding calculation improved the correlation of FROH with FPED and FGRM . ROH are a direct measure of autozygosity at the DNA level and can overcome approximations and errors resulting from incomplete pedigree data. In populations with high linkage disequilibrium (LD) and recent inbreeding (e.g. Italian Holstein and Italian Brown), a medium-density marker panel, such as the one used here, may provide a good estimate of inbreeding. However, in populations with low LD and ancient inbreeding, marker density would have to be increased to identify short ROH that are identical by descent more precisely. PMID- 25530323 TI - Aerobic glycolysis, motility, and cytoskeletal remodeling. PMID- 25530324 TI - Detection of Zika virus in urine. AB - We describe the kinetics of Zika virus (ZIKV) detection in serum and urine samples of 6 patients. Urine samples were positive for ZIKV >10 days after onset of disease, which was a notably longer period than for serum samples. This finding supports the conclusion that urine samples are useful for diagnosis of ZIKV infections. PMID- 25530325 TI - Antibiotic treatment of signs and symptoms of pulmonary exacerbations: a comparison by care site. AB - BACKGROUND: Antibiotic treatment of cystic fibrosis pulmonary exacerbations is inconsistent. Previous research has indicated that intravenous antibiotics are used more frequently at sites with better pulmonary function but it is not clear under what circumstances they are prescribed. METHOD: Pediatric care sites enrolled in the Epidemiologic Study of Cystic Fibrosis were ranked by median FEV1 % predicted of children they followed. Reported presence of new signs and symptoms of a pulmonary exacerbation (PEx) and antibiotic treatment within 21 days were compared between those in the highest vs. those in the other quartiles, and adjusted for sociodemographic and clinical characteristics of patients. RESULT: Highest quartile sites had a total of 2,454 children eligible for this analysis; lower quartile sites had a total of 5,487. The odds of having a PEx at highest vs. lower sites varied with how the PEx was defined, but high quartile sites were uniformly more likely to treat PEx with antibiotics. The adjusted odds ratio for treatment with any antibiotics of a PEx defined by the occurrence of one or two new signs and symptoms was 1.24 (95% CI 1.10, 1.40); for treatment of a PEx defined by the occurrence of three or four new signs and symptoms was 1.50 (95% CI 1.06, 2.11); and for treatment of a PEx defined by a drop of FEV(1) by >= 15% was 1.33 (1.10, 1.60). The adjusted OR for treatment of these PEx with IV antibiotics was 1.11 (0.94, 1.32), 1.90 (1.32, 2.72), and 1.33 (1.10, 1.60), respectively. CONCLUSION: ESCF care sites in the highest quartile for FEV(1) were more likely to prescribe antibiotics when patients present with either mild or overt evidence of PEx. While this may not be the only reason that their patients have superior median FEV(1), it is likely an important contributor. PMID- 25530326 TI - Food in schools: targeting versus the right to food. PMID- 25530327 TI - Are New Zealand's cancer services second best? PMID- 25530328 TI - Comparison of cancer survival in New Zealand and Australia, 2006-2010. AB - BACKGROUND AND AIMS: Previous studies have shown substantially higher mortality rates from cancer in New Zealand compared to Australia, but these studies have not included data on patient survival. This study compares the survival of cancer patients diagnosed in 2006-10 in the whole populations of New Zealand and Australia. METHOD: Identical period survival methods were used to calculate relative survival ratios for all cancers combined, and for 18 cancers each accounting for more than 50 deaths per year in New Zealand, from 1 to 10 years from diagnosis. RESULTS: Cancer survival was lower in New Zealand, with 5-year relative survival being 4.2% lower in women, and 3.8% lower in men for all cancers combined. Of 18 cancers, 14 showed lower survival in New Zealand; the exceptions, with similar survival in each country, being melanoma, myeloma, mesothelioma, and cervical cancer. For most cancers, the differences in survival were maximum at 1 year after diagnosis, becoming smaller later; however, for breast cancer, the survival difference increased with time after diagnosis. CONCLUSION: The lower survival in New Zealand, and the higher mortality rates shown earlier, suggest that further improvements in recognition, diagnosis, and treatment of cancer in New Zealand should be possible. As the survival differences are seen soon after diagnosis, issues of early management in primary care and time intervals to diagnosis and treatment may be particularly important. PMID- 25530329 TI - Health and wellbeing of older Pacific Peoples in New Zealand. AB - AIM: Ethnic group membership has a robust association with health in New Zealand. To understand this relationship with particular attention to the health of older Pacific peoples, an analysis was undertaken using the Health, Work and Retirement Study. METHOD: The study was initiated in 2006 with 2-year re-assessment intervals. The sample consisted of 6653 individuals aged 55-70 randomly sampled from the electoral roll. Of these, 108 identified as belonging to a Pacific ethnic group. The rest of the sample comprised New Zealand European, Maori, Asian and other ethnic groups. RESULTS: Older Pacific people scored lower on measures of physical and mental health, and reported higher rates of health conditions. The relationship between ethnicity and health was partially explained by lower socioeconomic status, less physical activity, and greater alcohol consumption. After controlling for multiple health risks, socioeconomic and demographic variables, ethnicity continued to predict lower levels of physical health, suggesting that there are other factors which contribute to higher rates of poor health for people of Pacific ethnicity. NZ-born Pacific people had better health than those born outside NZ. CONCLUSION: Taken together, this indicates that ethnicity intersects with structural variables which restrict access to resources related to good health and expose older Pacific people to risk factors for poor health. Combined with the effects of migration this contributes to health disparities found between Pacific and other ethnic groups in in New Zealand. PMID- 25530330 TI - Late-onset rheumatoid arthritis in the Counties Manukau District Health Board region of New Zealand: an observational study of treatment. AB - AIM: The aim of this retrospective study was to investigate whether there are differences in the early treatment of Rheumatoid Arthritis (RA) depending on the age of the patient at diagnosis. METHODS: The electronic records of 127 newly diagnosed RA patients presenting to the Counties Manukau District Health Board Rheumatology outpatient clinic between January 2008 and December 2010 were reviewed. Demographics, disease severity, relevant investigations, and medication use were analysed using Pearson's Chi squared test, Fisher's exact test and t test. RESULTS: The cohort included 32 aged greater than or equal to 60 years with Late Onset RA (LORA) and 95 aged <60 years with Young Onset RA (YORA). No significant differences in baseline disease severity, disease modifying anti rheumatic drug or prednisone use rates were observed between the LORA and YORA groups, with methotrexate use rates of 26/32 (81.25%) and 74/95 (77.89%) respectively. Nonsteroidal anti-inflammatory (NSAID) rate was significantly lower (p=0.013) in the LORA group 14/32 (43.75%) compared to the YORA group 65/95 (68.42%), reflecting an awareness of the adverse effects of these drugs in an older population. CONCLUSION: Patients with new onset rheumatoid arthritis at our institution received similar disease modifying anti-rheumatic drug treatment irrespective of their age. PMID- 25530331 TI - Diagnostic category agreement and malignancy rates in clinician-categorised, non standardised thyroid cytology reports. AB - AIM: Standardised reporting of thyroid cytology is recommended but not universally practiced. We compared agreement between clinicians categorising non standardised thyroid cytology reports, and determined malignancy rates in clinician-assigned cytology categories. METHODS: We identified all thyroid cytology reports from 2008-9 and any reports prior to histology samples from 2008 9 at Middlemore Hospital. Two clinicians independently classified these cytology reports using the Bethesda System, and we assessed agreement between their classifications. We classified histology results following the cytology sample as benign or malignant according to the primary diagnosis in the histology report, and calculated malignancy rates for each cytology category. RESULTS: Agreement between the classifications of 259 cytology results from 227 patients was moderate (kappa=0.67, 95% confidence interval 0.61-0.74), with good agreement (>80%) for only 3 of the 6 Bethesda categories. 122 patients had subsequent thyroid histology samples. 88% had benign primary diagnoses, with 15 (12%) primary thyroid cancers and an additional 11 (9%) incidental cancers. Malignancy rates for each Bethesda category varied from published rates for the majority of clinician-assigned categories. CONCLUSIONS: Low agreement between interpretation of non-standardised thyroid cytology reports suggests that standardised reporting should be universally adopted. Malignancy rates for thyroid cytology categories should be reported to inform local clinical practice. PMID- 25530332 TI - Herpes zoster (shingles) at a large New Zealand general practice: incidence over 5 years. AB - AIM: The objective of this study, in a large group practice in Lower Hutt with a stable population of around 19,000 patients, was to describe the retrospective incidence of shingles over a 5-year period so that it could be compared to international data. METHOD: The practice database was interrogated for patients whose disease code indicated they suffered shingles, herpes zoster, or post herpetic neuralgia between January 1 2009 and December 31 2013. The charts of the identified patients were reviewed to assess whether the diagnosis was confirmed, to ascertain that onset occurred within the specified time period, to describe the site of the rash and the age, sex and ethnicity of the patients. Rates of disease were calculated using a denominator derived from a comparison of patients registered during the 5 years studied. RESULTS: The results indicate that incidence of shingles rose with age, females were more frequently affected than males and that the thorax was the commonest site. CONCLUSION: The incidence at this New Zealand medical centre was similar to that reported internationally. PMID- 25530333 TI - Impact of improved treatment on disease burden of chronic hepatitis C in New Zealand. AB - BACKGROUND: We describe the burden of HCV infection and estimate the effect of four different treatment strategies to reduce HCV-related morbidity and mortality. METHODS: Baseline model parameters were based upon literature review and expert consensus, focusing on New Zealand data. Four scenarios were modelled: Scenario 1 estimated the impact of increased treatment efficacy, while Scenario 2 estimated the effect of increased treatment efficacy and gradual increases in numbers treated. Scenarios 3 and 4 estimated the impact of deferred introduction of new DAAs for either 1 or 2 years. RESULTS: Prevalence of HCV infection peaked in 2010 (50,480 cases). Peak prevalence of cirrhosis and HCC will occur after 2030. Scenario 2 resulted in sizeable decreases in HCV-related morbidity and mortality. The impact of Scenario 1 was smaller. Deferring funding for new DAA treatments for a further 1 or 2 years resulted in an 18-36% increase in liver related deaths in 2030. CONCLUSIONS: While prevalence of chronic HCV infection may have peaked, disease burden continues to grow. Increased treatment uptake and efficacy combined with efforts to reduce disease transmission, will help prevent advanced liver disease and deaths. PMID- 25530334 TI - An uncommon side effect in a common procedure: a case report of an adverse reaction to prilocaine during a Bier's block. AB - This case report describes a rare side effect during a Bier's block. During local anaesthetic injection, the patient suffered a sudden onset painful petechial rash localised to the upper limb, distal to the tourniquet, without systemic effect. After deflation of the tourniquet, the pain resolved and no systemic effects were seen. The skin changes settled without treatment over one week. The discussion summarises standard technique and precautions required for a Bier's block. It also evaluates risks and complications. PMID- 25530335 TI - Medical image. Pain and swelling in a child's thumb. Ewing sarcoma. PMID- 25530336 TI - Options for expanding community water fluoridation in New Zealand. PMID- 25530337 TI - Health effects of water fluoridation--how "effectively settled" is the science? PMID- 25530338 TI - Crisis checklists at every hospital bedside? PMID- 25530339 TI - New Zealand Emergency Medicine Network (NZEMN): collaboration for acute care research in New Zealand. PMID- 25530340 TI - Nucleosome-binding protein HMGN2 exhibits antitumor activity in human SaO2 and U2 OS osteosarcoma cell lines. AB - High mobility group N (HMGNs) are members of the high mobility group protein family, and are involved in the development and progression of several tumors. HMGN1 and HMGN5 were previously shown to be associated with the bioactivities of osteosarcoma. However, the effects and molecular mechanisms of HMGN2 on osteosarcoma progression remain to be determined. In order to characterize the endogenous expression of HMGN2 in osteosarcoma cell lines, RT-PCR and western blot analysis were performed. Recombinant HMGN2 lentivirus was used to infect the osteosarcoma cell lines with relatively low HMGN2 expression to determine the functional relevance of HMGN2 overexpression in osteosarcoma cell growth and migration in vitro and in vivo, and to investigate the expression levels of Ki 67, PCNA, cyclin D1 and cyclin E. The results showed that osteosarcoma cell proliferation and migration were significantly reduced by HMGN2, as indicated by cell count and wound-healing assays. Cell apoptosis was markedly induced and HMGN2 increased the sensitivity to chemotherapy. When HMGN2 expression was enhanced, the expression of cyclin D1 and PCNA was downregulated in osteosarcoma cells. In addition, the tumor volumes in SaO2 and U2-OS subcutaneous nude mouse models treated with HMGN2 lentivirus were significantly decreased as compared to those of the GFP group. These results suggested that the enhanced expression of HMGN2 in osteosarcoma cells by HMGN2 lentivirus, exerts inhibitory effects on growth and migration of osteosarcoma cells. PMID- 25530341 TI - Aerobic exercise and cold pressor test induce hypoalgesia in active and inactive men and women. AB - BACKGROUND: Physical inactivity is a risk factor for chronic pain. Several mechanisms play a role in pain chronification including impairment of pain inhibition. OBJECTIVE: This study compared the efficiency of pain inhibitory systems between physical active and inactive healthy subjects. It was hypothesized that active subjects had more efficient pain inhibition compared with inactive subjects. DESIGN: A randomized, crossover study with 2 days of data collection. METHODS: Fifty-six (28 females) subjects participated in this study. Subjects were subgrouped into active (n = 30) and inactive (n = 26). Conditioned pain modulation (CPM) was assessed by cold pressor testing. Exercise-induced hypoalgesia (EIH) was assessed after 15 minutes bicycling at a heart rate corresponding to 75% VO2max. A control session of 15 minutes quiet rest was also included. Pressure pain thresholds (PPTs) were recorded at the dominant arm and leg before, immediately after, and 15 minutes after conditioning and exercise as well as before and after rest. PPTs were also recorded during conditioning. RESULTS: At baseline, PPTs in inactive men were increased compared with inactive women (P < 0.003). During cold pressor test and after exercise, PPTs increased to the same degree in active and inactive subjects, and the CPM and EIH responses were correlated (P < 0.05). The CPM response immediately after cold pressor test was maintained in women but not in men. CONCLUSIONS: Cold pressor stimulation and aerobic exercise caused comparable multisegmental increases in PPT in active and inactive men and women. The CPM and EIH responses were correlated, but they have different temporal manifestation of hypoalgesia. PMID- 25530342 TI - Dysbindin gene variability is associated with cognitive abnormalities in first episode non-affective psychosis. AB - INTRODUCTION: Dystrobrevin-binding protein 1 gene (dysbindin or DTNBP1) has been associated with schizophrenia and cognitive performance. Its expression in areas implicated in cognition such as the dorsolateral prefrontal cortex, as well as its role in dopaminergic and glutamatergic system, has been replicated by several studies. The main aim of this study was to examine the association between DTNBP1 variability and cognitive performance in a sample of 238 patients with a first episode of a non-affective psychosis. METHODS: Patients, and a comparison sample of 47 healthy subjects, completed an extensive neuropsychological battery. Five single nucleotide polymorphisms (SNPs) within DTNBP1 (rs2619528, rs2619538, rs3213207, rs2619539 and rs760761) and three haplotypes (GACAC, GAGAC and GTGAC) were analysed. RESULTS: In the group of patients, we found a significant association between two of the DTNBP1 SNPs and one of the haplotypes (rs2619539, rs3213207 and GACAC) and a measure of premorbid IQ [Wechsler Adult Intelligence Scale-3rd Edition (WAIS-III) Vocabulary subtest]. Moreover, one of these SNPs, rs2619539, was also associated with our measure of working memory (WAIS-III Backward digits subtest) and two haplotypes, GAGAC and GTGAC, with our measure of verbal memory (Rey Auditory Verbal Learning Test), of visual memory (Rey Complex Figure Test) in the case of GAGAC, and of speed of processing (WAIS-III Digit Symbol-coding) in the case of GTGAC. CONCLUSIONS: Our findings add further evidence suggesting an association between dysbindin gene variability and cognitive abnormalities in schizophrenia, providing preliminary evidence of this association since the time of illness onset among minimally medicated patients. PMID- 25530344 TI - Temozolomide-associated myelodysplasia 6 years after treatment of a patient with pancreatic neuroendocrine tumor. PMID- 25530343 TI - Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss. AB - Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of beta-amyloid (Abeta) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Abeta or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD. PMID- 25530345 TI - Relationships between chemotherapy, chemotherapy dose intensity and outcomes of follicular lymphoma in the immunochemotherapy era: a report from the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. AB - The optimal treatment of follicular lymphoma (FL) is not established. Rituximab's value potentially dilutes the impact of chemotherapy on FL. We reviewed 337 cases of FL treated initially with rituximab as monotherapy or with chemotherapy at the University of Iowa/Mayo Clinic from 2002 to 2009, investigating the association between chemotherapy delivery of cyclophosphamide or doxorubicin and survival. With median follow-up duration of 52.7 months, event-free survival (EFS) and overall survival (OS) were similar between the two groups, with a trend toward better EFS in the R-chemotherapy cohort (hazard ratio [HR]=1.24, p=0.28). In the R-chemotherapy group, increased total dose delivery and delivered dose intensity of doxorubicin were associated with improved EFS only in patients who did not receive R-maintenance (HR=0.81; p=0.02 and HR=0.94; p=0.04). Cyclophosphamide delivery was not associated with EFS. Thus, in the immunochemotherapy era, chemotherapy delivery strategy requires re-evaluation. PMID- 25530346 TI - A novel chemosensitivity profiling platform for small acute lymphoblastic leukemia cell populations. PMID- 25530347 TI - Treatment of chronic lumbosacral radicular pain using adjuvant pulsed radiofrequency: a randomized controlled study. AB - OBJECTIVES: The objective of this study was to determine the effects of combining pulsed radiofrequency (PRF) treatment and transforaminal epidural injection (TFEI) to treat patients with chronic refractory lumbar radicular pain caused by lumbar spinal stenosis. STUDY DESIGN: Randomized control trial. SETTINGS: Interventional pain management practice. METHOD: Sixty-two patients were assigned to the study groups (PRF group = 31; control group = 31). Under fluoroscopic guidance, the RF needle was positioned close to the lumbar dorsal root ganglion. The PRF group received 3 cycles of PRF treatment, and sensory stimulation without RF lesioning was applied to the control group. After PRF or sham lesioning, a local anesthetic with steroid was injected. The primary outcome of a successful response was defined as: 1) >=50% or 4-point pain reduction in the numerical rating scale (NRS) without an increase in the Oswestry disability index (ODI) or medication quantification scale (MQS), or mean score <4 in the global perceived effect (GPE) scale; or 2) >=30% or 2-point pain reduction in NRS with a simultaneous decrease in ODI, MQS, or >=6 points in the GPE scale. RESULT: The number of patients with successful treatment results was higher in the PRF group at 2 months (P = 0.032) and 3 months (P = 0.018). No significant differences were observed in terms of the secondary outcome variables between the 2 groups. CONCLUSION: The TFEI provided significant short-term pain relief and PRF can be applied in conjunction with TFEI to achieve higher treatment efficacy compared with TFEI alone. PMID- 25530348 TI - Effects of physicochemical properties of nanomaterials on their toxicity. AB - Due to their unique size and properties, nanomaterials have numerous applications, which range from electronics, cosmetics, household appliances, energy storage, and semiconductor devices, to medical products such as biological sensors, drug carriers, bioprobes, and implants. Many of the promising properties of nanomaterials arise from their large surface to volume ratio and, therefore, nanobiomaterials that are implantable have a large contact area with the human body. Before, therefore, we can fully exploit nanomaterials, in medicine and bioengineering; it is necessary to understand how they can affect the human body. As a step in this direction, this review paper provides a comprehensive summary of the effects that the physicochemical properties of commonly used nanobiomaterials have on their toxicity. Furthermore, the possible mechanisms of toxicity are described with the aim to provide guidance concerning the design of the nanobiomaterials with desirable properties. PMID- 25530349 TI - [Epidemiological and clinical characteristics of primary ocular cancers in blacks: our experience with 111 cases]. AB - INTRODUCTION: In this work, the authors aim to study clinical and epidemiological characteristics of ocular and orbital primary cancers in sub-Saharan African. PATIENTS AND METHODS: This is a retrospective study over a period of 21 years, from 1984 to 2004, including all cases of ocular cancer, histologically proven after surgery of the globe or the orbit. For each patient, we studied the following parameters: age, sex, reason(s) for consultation, the affected eye, and histological result of the operative specimen. These data were collected by studying the departmental surgical registry, patient medical records and the tumor registry of the anatomicopathology laboratory of a tertiary care hospital in sub-Saharan Africa. RESULTS: We collected data on 111 black patients, among whom 15 cases (13.5%) presented with bilateral involvement, for a total of 126 eyes. The sex ratio was 1.17. Presenting signs showed a predominance of leukocoria (30.2%) followed by proptosis (21.7%) and in third place, protruding conjunctival mass (10.8%). Retinoblastoma was found most frequently, representing 66.6% of the oculo-orbital tumors and 95.45% of the tumors of the globe; followed by epidermoid carcinoma, representing 15.08% of cases. Malignant melanoma was third most common, representing 4.76%, with 83% arising in the anterior uvea and 7% in the choroid. Basal cell carcinoma and rhabdomyosarcoma follow in fourth place. Basal cell carcinoma constituted half (50%) of the eyelid tumors. Rhabdomyosarcoma was the most common orbital tumor in our series (57%). Next were lymphomas with conjunctival localization (2.38%), acute leukemia with orbital localization (1.59%) and rare tumors, palpebral dermatofibrosarcoma (0.79%), an orbital angiosarcoma (0.79%), a glioblastoma of the globe (0.79%) and a malignant solitary fibrous tumor of the orbit (0.79%). CONCLUSION: Ocular and orbital primary cancers in blacks remain tumors of the young, equally distributed between the sexes. Retinoblastoma is the most frequent, followed by epidermoid carcinoma. The globe is the preferential localization of these cancers. PMID- 25530350 TI - [Description of a new method of changing eye color: case report of aesthetic annular keratopigmentation (AAK)]. PMID- 25530351 TI - Highly ordered n/p-co-assembled materials with remarkable charge mobilities. AB - Controlling self-organization and morphology of chemical architectures is an essential challenge in the search for higher energy-conversion efficiencies in a variety of optoelectronic devices. Here, we report a highly ordered donor/acceptor functional material, which has been obtained using the principle of ionic self-assembly. Initially, an electron donor pi-extended tetrathiafulvalene and an electron-acceptor perylene-bisimide were self-organized separately obtaining n- and p-nanofibers at the same scale. These complementary n and p-nanofibers are endowed with ionic groups with opposite charges on their surfaces. The synergic interactions establish periodic alignments between both nanofibers resulting in a material with alternately segregated donor/acceptor nanodomains. Photoconductivity measurements show values for these n/p-co assembled materials up to 0.8 cm(2) V(-1) s(-1), confirming the effectiveness in the design of these heterojunction structures. This easy methodology offers great possibilities to achieve highly ordered n/p-materials for potential applications in different areas such as optoelectonics and photovoltaics. PMID- 25530352 TI - Evaluation of the understanding of antibiotic resistance among Malaysian pharmacy students at public universities: an exploratory study. AB - BACKGROUND: Infectious diseases are a great threat to humankind, and antibiotics are a viable proposition to numerous pathologies. However, antibiotic resistance is a global concern. Therefore, the aims of this survey were to explore the understanding and attitudes of pharmacy students regarding antibiotic use and resistance. METHODS: This is a cross-sectional study conducted on final-year undergraduate pharmacy students from 5 public universities. A validated, self administered questionnaire written in English was used to collect data. It was made up of six domains and forty-five questions. Raosoft software was used to determine the minimum required sample size. Descriptive and inferential data analyses were carried out using SPSS version 20 software. RESULTS: Out of 346 students, only 59.5% showed a strong understanding of antibiotic usage, while 84.4% of students demonstrated a good level of understanding regarding the issue of antibiotic resistance. However, only 34.1% of students demonstrated a positive attitude toward this issue. CONCLUSION: This survey reveals that final-year pharmacy students at Malaysian public universities have a relatively good understanding of antibiotic resistance. However, their attitudes did not strongly correlate to their knowledge. PMID- 25530353 TI - Drug-dependent behaviors and nicotinic acetylcholine receptor expressions in Caenorhabditis elegans following chronic nicotine exposure. AB - Nicotine, the major psychoactive compound in tobacco, targets nicotinic acetylcholine receptors (nAChRs) and results in drug dependence. The nematode Caenorhabditis elegans' (C. elegans) genome encodes conserved and extensive nicotinic receptor subunits, representing a useful system to investigate nicotine induced nAChR expressions in the context of drug dependence. However, the in vivo expression pattern of nAChR genes under chronic nicotine exposure has not been fully investigated. To define the role of nAChR genes involved in nicotine induced locomotion changes and the development of tolerance to these effects, we characterized the locomotion behavior combining the use of two systems: the Worm Tracker hardware and the WormLab software. Our results indicate that the combined system is an advantageous alternative to define drug-dependent locomotion behavior in C. elegans. Chronic (24-h dosing) nicotine exposure at 6.17 and 61.7MUM induced nicotine-dependent behaviors, including drug stimulation, tolerance/adaption, and withdrawal responses. Specifically, the movement speed of naive worms on nicotine-containing environments was significantly higher than on nicotine-free environments, suggesting locomotion stimulation by nicotine. In contrast, the 24-h 6.17MUM nicotine-treated worms exhibited significantly higher speeds on nicotine-free plates than on nicotine-containing plates. Furthermore significantly increased locomotion behavior during nicotine cessation was observed in worms treated with a higher nicotine concentration of 61.7MUM. The relatively low locomotion speed of nicotine-treated worms on nicotine-containing environments also indicates adaption/tolerance of worms to nicotine following chronic nicotine exposure. In addition, this study provides useful information regarding the comprehensive in vivo expression profile of the 28 "core" nAChRs following different dosages of chronic nicotine treatments. Eleven genes (lev-1, acr-6, acr-7, acr-11, lev-8, acr-14, acr-16, acr-20, acr-21, ric-3, and unc-29) were significantly up-regulated following 61.7MUM nicotine treatment, in which worms showed significantly increased locomotion behavior. This study provides insights into the linkage between nicotine-induced locomotion behavior and the regulation of nicotinic acetylcholine receptors. PMID- 25530355 TI - Animated respiratory movement of a spinal intradural arachnoid cyst visualized by intraoperative ultrasonography. AB - This study aims to describe the animated respiratory movement of a spinal intradural arachnoid cyst visualized by intraoperative ultrasonography. A 69-year old man with a spinal arachnoid cyst of the thoracic spine presented with gait disturbance. Magnetic resonance images showed a mild anterior displacement and flattening of the spinal cord at T4-T5. We performed ultrasonography before incision of the dura during the operation and observed the movement of the cyst consisting of not only pulsation in accordance with the cardiac cycle but also rhythmic expansion and contraction in accordance with the respiratory cycle. In the inspiratory phase, the cyst gradually expanded and pulsated in accordance with the cardiac cycle. In the expiratory phase, the cyst gradually contracted with the same pulsation. After resection of the cyst, the patient's neurological improvements were excellent. To our knowledge, this is the first report of animated respiratory movement of a spinal arachnoid cyst visualized by intraoperative ultrasonography. Although cine magnetic resonance imaging can detect spinal intradural arachnoid cysts preoperatively, intraoperative ultrasonography is useful for close analysis of their movement and pathology. Considering the dynamic compression mechanism revealed in this study, we think that an early operation should be performed for such cysts. PMID- 25530354 TI - Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead. AB - Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day 21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend toward negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice. PMID- 25530356 TI - Effects of Causal Structure on Decisions About Where to Intervene on Causal Systems. AB - We investigated how people design interventions to affect the outcomes of causal systems. We propose that the abstract structural properties of a causal system, in addition to people's content and mechanism knowledge, influence decisions about how to intervene. In Experiment 1, participants preferred to intervene at specific locations (immediate causes, root causes) in a causal chain regardless of which content variables occupied those positions. In Experiment 2, participants were more likely to intervene on root causes versus immediate causes when they were presented with a long-term goal versus a short-term goal. These results show that the structural properties of a causal system can guide the design of interventions. PMID- 25530358 TI - It's time to understand the dynamics of "do not attempt cardiopulmonary resuscitation" orders. PMID- 25530357 TI - Molecular characterization of mouse lens epithelial cell lines and their suitability to study RNA granules and cataract associated genes. AB - The discovery of cytosolic RNA granule (RG) component proteins associated with human cataract has initiated investigations on post-transcriptional mechanisms of gene expression control in the lens. Application of established mouse lens epithelial cell lines (LECs) can provide rapid insights on RG function in lens cells, especially because mouse mutants in several RG components are not available. However, although these LECs represent potential reagents for such analyses, they are uncharacterized for lens gene expression or RG formation. Therefore, a detailed molecular and cellular characterization of three permanent mouse LECs 17EM15, 21EM15 and alphaTN4 is performed in this study. Comparative analysis between microarray gene expression datasets on LEC 21EM15 and iSyTE lens tissue demonstrates that 30% of top 200 iSyTE identified lens-enriched genes are expressed in these cells. Majority of these candidates are independently validated to either have lens expression, function or linkage to cataract. Moreover, analysis of microarray data with genes described in Cat-Map, an online database of cataract associated genes and loci, demonstrates that 131 genes linked to cataract loci are expressed in 21EM15 cells. Furthermore, gene expression in LECs is compared to isolated lens epithelium or fiber cells by qRT PCR and by comparative analyses with publically available epithelium or fiber specific microarray and RNA-seq (sequencing) datasets. Expression of select candidate genes was validated by regular and real-time quantitative RT-PCR. Expression of lens epithelium-enriched genes Foxe3, Pax6, Anxa4 and Mcm4 is up regulated in LEC lines, compared to isolated lens fiber cells. Moreover, similar to isolated lens epithelium, all three LECs exhibit down-regulation of fiber cell expressed genes Crybb1, Mip and Prox1 when compared to fiber cells. These data indicate that the LEC lines exhibit greater similarity to lens epithelium than to fiber cells. Compared to non-lens cell line NIH3T3, LECs exhibit significantly enriched expression of transcription factors with important function in the lens, namely Pax6, Foxe3 and Prox1. In addition to these genes, all three LECs also express key lens- and cataract-associated genes, namely Dkk3, Epha2, Hsf4, Jag1, Mab21l1, Meis1, Pknox1, Pou2f1, Sfrp1, Sparc, Tdrd7 and Trpm3. Additionally, 21EM15 microarrays indicate expression of Chmp4b, Cryab and Tcfap2a among others important genes. Immunostaining with makers for Processing bodies (P-bodies) and Stress granules (SGs) demonstrates that these classes of RGs are robustly expressed in all three LECs. Moreover, under conditions of stress, 17EM15 and alphaTN4 exhibit significantly higher numbers of P-bodies and SGs compared to NIH3T3 cells. In sum, these data indicate that mouse LECs 21EM15, 17EM15 and alphaTN4 express key lens or cataract genes, are similar to lens epithelium than fiber cells, and exhibit high levels of P-bodies and SGs, indicating their suitability for investigating gene expression control and RG function in lens derived cells. PMID- 25530359 TI - Anatomic features involved in technical complexity of partial nephrectomy. AB - Nephrometry score systems, including RENAL nephrometry, preoperative aspects and dimensions used for an anatomical classification system, C-index, diameter-axial polar nephrometry, contact surface area score, calculating resected and ischemized volume, renal tumor invasion index, surgical approach renal ranking score, zonal NePhRO score, and renal pelvic score, have been reviewed. Moreover, salient anatomic features like the perinephric fat and vascular variants also have been discussed. We then extract 7 anatomic characteristics, namely tumor size, spatial location, adjacency, exophytic/endophytic extension, vascular variants, pelvic anatomy, and perinephric fat as important features for partial nephrectomy. For novice surgeons, comprehensive and adequate anatomic consideration may help them in their early clinical practice. PMID- 25530360 TI - Editorial comment. PMID- 25530361 TI - Reply: To PMID 25444632. PMID- 25530362 TI - Surgical competency for urethrovesical anastomosis during robot-assisted radical prostatectomy: development and validation of the robotic anastomosis competency evaluation. AB - OBJECTIVE: To develop and validate an assessment tool for the performance of urethrovesical anastomosis (UVA). METHODS: A multicenter, prospective, observational study was conducted in 2 phases. Phase 1, development and content validation, used a panel of 5 experienced robotic surgeons to develop a 6-domain scoring system, Robotic Anastomosis Competence Evaluation (RACE), to assess technical skills for performing UVA. Phase 2, construct validation and reliability, used 5 blinded experienced robotic surgeons to rate UVA recordings of expert, advanced beginner, and novice groups. Content validation index was determined to report consensus in phase 1. Phase 2 involved comparison of RACE scores among the 3 groups. Wilcoxon rank-sum tests were used to compare RACE scores. RESULTS: Two rounds of Delphi methodology achieved consensus on language and content of RACE. Eight experts, 10 advanced beginners, and 10 novice robotic surgeons participated in the validation study. The overall score for the expert group (27.3) was higher than that of the advanced beginner (19.5; P = .04) and novice groups (13.6; P = .001). The advanced beginner and novice groups differed in overall scores (P = .03). CONCLUSION: RACE allows evaluation of surgical competence to perform UVA for robot-assisted radical prostatectomy, when using an inanimate model. PMID- 25530363 TI - Editorial comment. PMID- 25530364 TI - Role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). AB - OBJECTIVE: To evaluate the role of 2 different alpha-1 blockers and 1 phosphodiesterase-5 inhibitor as medical expulsive therapy for distal ureteric calculi. MATERIALS AND METHODS: Between January 2011 and December 2012, 285 patients presenting with distal ureteric stones of size 5-10 mm were on consent randomly assigned to 1 of 3 outpatient treatment arms: tamsulosin (group A), silodosin (group B), and tadalafil (group C). Therapy was given for a maximum of 4 weeks. Stone expulsion rate, time to stone expulsion, analgesic use, number of hospital visits for pain, follow-up, and endoscopic treatment and adverse effects of drugs were noted. All 3 groups were compared for normally distributed data by the analysis of variance, Bonferroni or Kruskal-Wallis test, and Mann-Whitney U test, as required. All the classified and categorical data were analyzed for all 3 groups by using the chi-square test. RESULTS: There was a statistically significant expulsion rate of 83.3% in group B compared with 64.4% and 66.7% in groups A and C, respectively, with lower time of stone expulsion (P value = .006 and P value = .016, respectively). Statistically significant differences were noted in colicky episodes and analgesic requirement in group B than groups A and C. There was no serious adverse event. CONCLUSION: Medical expulsive therapy for the distal ureteric stones using tamsulosin, silodosin, and tadalafil is safe, efficacious, and well tolerated. The result of this pilot study showed that silodosin increases ureteric stone expulsion quite significantly along with better control of pain with significantly lesser analgesic requirement. PMID- 25530365 TI - Antimicrobial resistance patterns in cases of obstructive pyelonephritis secondary to stones. AB - OBJECTIVE: To characterize the local antimicrobial resistance pattern in patients with obstructing ureteral stones and fever, compare this with our local antibiograms, and guide recommendations for empiric antibiotic regimens. METHODS: A retrospective chart review was performed of patients who underwent ureteroscopic intervention for the management of ureteral stones at a neighboring private hospital and a public hospital to identify those patients who had undergone prior decompression for obstructing ureteral stones and fever between 2004 and 2011. Urine culture results were captured to identify uropathogens and sensitivity patterns to antibiotics. These were compared with respective hospital antibiograms. RESULTS: Sixty-five patients were identified, of which 35 had positive urine culture results. More than 25% of the voided urine and upper urinary tract urine cultures differed. Antimicrobial resistance patterns were higher for patients at the public hospital than the hospital antibiogram. The opposite was true at the private hospital. The public hospital demonstrated an overall higher resistance pattern than the private hospital. CONCLUSION: Antimicrobial resistance makes the selection of empiric antibiotic treatment challenging in patients with obstructive pyelonephritis secondary to ureteral stones. Because of discordance between voided urine cultures and those captured at the time of decompression, it is imperative to obtain both voided urine and urine from the kidney to ensure adequate antibiotic coverage. Local population specific antimicrobial guidelines that are frequently updated are essential to ensure adequate coverage and treatment of obstructive pyelonephritis, and condition-specific antibiograms would be recommended in the future. PMID- 25530366 TI - Prediction of single procedure success rate using S.T.O.N.E. nephrolithometry surgical classification system with strict criteria for surgical outcome. AB - OBJECTIVE: To evaluate the S.T.O.N.E. nephrolithometry scoring system for percutaneous nephrolithotomy using computerized tomography (CT) imaging with strict criteria for stone clearance. MATERIALS AND METHODS: We analyzed a cohort of 122 patients who consecutively underwent primary percutaneous nephrolithotomy from July 2010 to March 2012 at our university-based referral hospital. All patients routinely have preoperative and postoperative CT imaging for stone burden determination. Primary outcome (residual stone) was scored as 0-2, 3-4, and >4 mm. All S.T.O.N.E. nephrolithometry parameters were recorded and scored as per published definition. The t test was used for continuous variables, and the chi-square testing or the Fisher exact test (when counts were small) was used for categorical covariates. S.T.O.N.E. score correlation with stone-free status was analyzed by logistic regression. RESULTS: Nephrolithometry score ranged from 5 to 13 with a mean of 9.5. Postoperative CT for residual stone showed 67 (54.9%), 26 (21.3%), and 29 (23.8%) patients had 0-2, 3-4, and >4 mm residual stone, respectively. Mean nephrolithometry scores for residual stone of 0-2, 3-4, and >4 mm were 8.87, 9.73, and 10.79 respectively (P <.0001). There were 11 (9.8%) complications. CONCLUSION: With use of strict CT imaging criteria for assessment of residual stone status, the S.T.O.N.E. scoring system is reproducible and predictive of treatment success. Further investigation is required to both validate this model and to determine if other predictive parameters will improve it as a predictive model. PMID- 25530367 TI - Midterm efficacy and complications of readjustable midurethral sling (Remeex system) in female stress urinary incontinence with recurrence or intrinsic sphincter deficiency. AB - OBJECTIVE: To evaluate the efficacy, complications, and managements of the readjustable midurethral sling (Remeex system) for the treatment of recurrent stress urinary incontinence (SUI) after previous anti-incontinence surgeries or intrinsic sphincter deficiency (ISD). METHODS: Between March 2008 and February 2012, 102 women, who presented with previous failed surgery or ISD, were treated with the Remeex system at 4 different institutions. We retrospectively reviewed medical history, physical examination, urodynamic study, postvoiding residual volume, and/or 1-hour pad test of the patients. Surgical outcomes were evaluated using the Severity Index for Urinary Incontinence. The degree of patient satisfaction was assessed, and all complications were classified according to the modified Clavien classification system. RESULTS: After a mean follow-up of 27.6 months (range, 14-56 months), 91 patients (89.2%) were cured and 6 patients (5.9%) were improved. The patient's satisfaction rate was 87.2% (89 of 102 patients). Overall, 41 patients (40.2%) experienced 53 complications; 15 patients (14.7%) presented de novo urgency, which was properly managed with anticholinergics, and 14 patients (13.7%) underwent delayed sling readjustment for recurrent SUI (n = 13) and urinary retention (n = 1) during follow-up. Among 6 patients (5.9%) with wound infection, 4 patients were successfully treated by daily dressing with antibiotics, and 2 patients underwent removal of the Remeex system owing to intractable infection. Most complications were classified as grade 1 (54.8%) or 2 (15.1%) and were successfully treated with minimal conservative measures. CONCLUSION: The Remeex system is a valuable adjunct for recurrent SUI after previous anti-incontinence surgeries or ISD, considering most complications are Clavien grade I or II. PMID- 25530368 TI - Reply: To PMID 25440819. PMID- 25530369 TI - Editorial comment. PMID- 25530371 TI - Editorial comment. PMID- 25530370 TI - Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. AB - OBJECTIVE: To establish a score threshold that constitutes a clinically relevant change for each domain of the Expanded Prostate Cancer Index Composite (EPIC) Short Form (EPIC-26). Although its use in clinical practice and clinical trials has increased worldwide, the clinical interpretation of this 26-item disease specific patient-reported quality of life questionnaire for men with localized prostate cancer would be facilitated by characterization of score thresholds for clinically relevant change (the minimally important differences [MIDs]). METHODS: We used distribution- and anchor-based approaches to establish the MID range for each EPIC-26 domain (urinary, sexual, bowel, and vitality/hormonal) based on a prospective multi-institutional cohort of 1201 men treated for prostate cancer between 2003 and 2006 and followed up for 3 years after treatment. For the anchor based approach, we compared within-subject and between-subject score changes for each domain to an external "anchor" measure of overall cancer treatment satisfaction. RESULTS: We found the bowel and vitality/hormonal domains to have the lowest MID range (a 4-6 point change should be considered clinically relevant), whereas the sexual domain had the greatest MID values (10-12). Urinary incontinence appeared to have a greater MID range (6-9) than the urinary irritation/obstruction domain (5-7). CONCLUSION: Using 2 independent approaches, we established the MIDs for each EPIC-26 domain. A definition of these MID values is essential for the researcher or clinician to understand when changes in symptom burden among prostate cancer survivors are clinically relevant. PMID- 25530372 TI - Evolution of laparoscopic donor nephrectomy technique and outcomes: a single center experience with more than 1300 cases. AB - OBJECTIVE: To describe and illustrate the evolution of surgical technique, emphasizing technical modifications of laparoscopic donor nephrectomy (LDN) and the impact on complication outcome. METHODS: This is a retrospective observational study of prospectively collected data on all consecutive purely LDN surgeries performed at a tertiary academic medical center (n = 1325), performed between March 2000 and October 2013. RESULTS: Over time, LDN was performed on older patients, changing from a mean of 35.7 years in 2000 to 41.2 years in 2013 (P <.001). Additionally, mean blood loss decreased from 75 mL in 2000 to 21.6 mL in 2013 (P <.001). However, body mass index, operative time, and length of stay remained similar. Overall, there were 105 (7.9%) complications: Clavien grade 1 (n = 81, 6.1%) and grade 2 or higher (n = 23, 1.8%). Procedure duration, blood loss, surgeon, year of procedure, laterality, body mass index, age, and gender did not significantly predict complications. There was no significant difference for Clavien complication rates between the early learning period (first 150 cases) and the rest of the series. CONCLUSION: With continual refinement with LDN techniques based on intraoperative observations and technological advances, complication rates remain consistently low, despite increasing donor age. PMID- 25530373 TI - Penile Mondor disease and its effect on erectile function: results of 30 patients. AB - OBJECTIVE: To investigate the treatment outcomes among patients diagnosed with penile Mondor disease and to evaluate the effect of the disease on erectile function. METHODS: A total of 30 patients diagnosed with penile Mondor disease were enrolled in the study. All patients underwent physical examination and penile Doppler ultrasonography and filled in the International Index of Erectile Function (IIEF-5) questionnaire at regular intervals. Pharmacotherapy was started when penile Mondor disease was diagnosed. After the data were confirmed to be normally distributed using Kolmogorov-Smirnov test, the differences between the 3 IIEF-5 scores were evaluated using repeated measures analysis of variance and post hoc Bonferroni tests. RESULTS: The mean age of the patients was 34.3 years (range, 25-48 years). Ten patients had prolonged sexual intercourse, 4 had recent intestinal infection history, 2 had recent long-haul flights, 1 had sickle cell anemia, and 2 had penile trauma caused by sexual intercourse. Nine patients were considered idiopathic. Mean IIEF-5 scores at the baseline and at 1- and 2-month follow-ups were 20.87, 20.07, and 20.93, respectively. Although no significant difference was found between the baseline and the 2-month follow-up IIEF-5 scores, significant differences between the baseline and the 1-month (P = .004) and the 1- and 2-month follow-up IIEF-5 scores (P = .0001) were detected. CONCLUSION: Penile Mondor disease is a rare complication that can be successfully treated with medical therapy and conservative approach. Our series showed that penile Mondor's disease does not lead to permanent deformation of the penis or erectile dysfunction. PMID- 25530374 TI - Cross-cultural differences in women's sexuality and their perception and impact of premature ejaculation. AB - OBJECTIVE: To assess the cross-cultural differences in women's perception of premature ejaculation (PE). METHODS: A total of 1463 sexually active women from 3 different countries-Mexico, South Korea, and Italy-reporting being or having been in a relationship with a man who suffers from PE were included in the study. A mix of self-constructed questions and questions taken from validated instruments were used, including the Female Sexual Function Index, the Female Sexual Distress Scale, and the Relationship Assessment Scale. RESULTS: Significant differences in importance of ejaculatory control and the degree of distress caused by PE were detected between the 3 countries (P < .001 for both). Lack of control was the most commonly reported reason for distress for Mexico, short latency for Italy, and lack of control for South Korea. Mexico reported the highest rates of previous relationship breakups due to PE (28.9%), whereas Italian women reported the lowest relationship satisfaction and South Korean women the highest. CONCLUSION: It is important to get a better understanding of which sexual issues are important for individuals across different cultures, and whether the same aspects of the problem are considered distressing. This can have implications on nosology, on types of treatments offered, and hence, the likelihood of their efficiency when a couple's sexual perspective is carefully considered. PMID- 25530375 TI - Pancreatic metastasis from clear cell renal cell carcinoma: outcome of an aggressive approach. AB - OBJECTIVE: To evaluate the long-term results of patients surgically treated for metastatic clear cell renal cell carcinoma (CCRCC) with a unique pancreatic secondary localization to assess the importance of radical treatment in this rare group of patients. PATIENTS AND METHODS: This is a retrospective monocentric study including 20 surgically treated patients between 1997 and 2012 for a unique pancreatic metastasis of a CCRCC. The main objective was to evaluate the outcome after surgical resection. RESULTS: Twenty patients were followed up for a CCRCC. The M/F ratio was 1.2. The average age of onset of kidney cancer was 57.05 +/- 7.78 years. Two patients who had synchronous pancreatic metastasis and 18 patients who had metachronous metastasis appeared after an average of 130 +/- 59 months (24-240 months). The average size of the metastases was 20 +/- 11.6 mm. Pancreatic metastasis was unique in all patients, with 35% of patients having multiple lesions of the pancreas. All patients underwent a pancreatic resection of metastasis. Histologic examination confirmed the location of a secondary CCRCC in all patients. Median follow-up after pancreatectomy was 69 months (1-150 months). Disease-free survival at 2 years was 60%. Overall survival rates at 2 and 4 years were 79% and 72%, respectively. There was no difference found between patients with multiple and unique pancreatic metastases in overall survival. CONCLUSION: Unique pancreatic metastasis of CCRCC is rare. The literature on this subject is limited. Surgical resection might be an option and can be associated with long-term disease-free intervals in highly selected patients. PMID- 25530376 TI - Comparative analysis of the risk of radiation exposure and cost of reduced imaging intensity for surveillance of early-stage nonseminomatous germ cell tumors. AB - OBJECTIVE: To evaluate the surveillance recommendations for early-stage testis cancer and the risk of secondary malignancies due to increased radiation exposure. MATERIALS AND METHODS: Using National Comprehensive Cancer Network (NCCN) guidelines 2012 and 2014 for early-stage testicular cancer, the numbers of abdominal and pelvic computed tomography scans (CTAPs) and chest radiographies were calculated, and lifetime attributable risk for secondary malignancy was estimated using Biologic Effects of Ionizing Radiation VII organ-specific model for solid organ malignancy based on the initial age of exposure. Cost was based on the Centers for Medicare and Medicaid Services' cost estimates of CTAP and magnetic resonance imaging (MRI). RESULTS: The 2012 NCCN protocol uses a maximum of 17 CTAPs over 6 years, whereas 2014 guidelines suggest a maximum of 13 CTAPs. The radiation dosage in 2014 guidelines is decreased by 25% compared to the 2012 NCCN guidelines. The minimum number of CTAPs under the 2014 NCCN protocol reduced radiation dose by 38% compared to the maximum number, this compared to about 50% decrease from the 2012 NCCN guidelines. The median cost for a single CTAP with contrast is $369.30; median cost for a single MRI with contrast is $772.18. As compared to the 2012 protocol, the 2014 guidelines reduced CTAP cost by approximately 24%-54% for minimum and maximum CTAPs allowed. CONCLUSION: There is low, however nonzero, risk of secondary malignancy for surveillance in stage I testicular cancer. There is also a significant cost difference between protocols as well as between CT and MRI modalities. PMID- 25530377 TI - Editorial comment. PMID- 25530378 TI - Reply: To PMID 25440986. PMID- 25530379 TI - Impact of prostate-specific antigen on a baseline prostate cancer risk assessment including genetic risk. AB - OBJECTIVE: To determine to what extent prostate cancer (PCa) risk prediction is improved by adding prostate-specific antigen (PSA) to a baseline model including genetic risk. METHODS: Peripheral blood deoxyribonucleic acid was obtained from Caucasian men undergoing prostate biopsy at the University of Toronto (September 1, 2008 to January 31, 2010). Thirty-three PCa risk-associated single nucleotide polymorphisms were genotyped to generate the prostate cancer genetic score 33 (PGS-33). Primary outcome is PCa on study prostate biopsy. Logistic regression, area under the receiver-operating characteristic curves (AUC), and net reclassification improvement were used to compare models. RESULTS: Among 670 patients, 323 (48.2%) were diagnosed with PCa. The PGS-33 was highly associated with biopsy-detectable PCa (odds ratio, 1.66; P = 5.86E-05; AUC, 0.59) compared with PSA (odds ratio, 1.33; P = .01; AUC, 0.55). PSA did not improve risk prediction when added to a baseline model (age, family history, digital rectal examination, and PGS-33) for overall risk (AUC, 0.66 vs 0.66; P = .86) or Gleason score >=7 PCa (AUC, 0.71 vs 0.73; P = .15). Net reclassification improvement analyses demonstrated no appropriate reclassifications with the addition of PSA to the baseline model for overall PCa but did show some benefit for reclassification of men thought to be at higher baseline risk in the high-grade PCa analysis. CONCLUSION: In a baseline model of PCa risk including the PGS-33, PSA does not add to risk prediction for overall PCa for men presenting for "for cause" biopsy. These findings suggest that PSA screening may be minimized in men at low baseline risk. PMID- 25530380 TI - Editorial comment. PMID- 25530381 TI - Reply: To PMID 25530379. PMID- 25530382 TI - Prevalence of prostatic calcification subtypes and association with prostate cancer. AB - OBJECTIVE: To evaluate the prevalence and to classify prostatic calcification on transrectal ultrasonography (TRUS) and correlate the findings with histology. METHODS: A prospective, blinded study of men undergoing TRUS and prostatic biopsy was designed. A standardized reproducible technique was used with a BK 7.5- to 12.5-MHz multiplanar probe. Representative images of the calcification in the sagittal and transverse planes were captured. Blind analysis by an experienced observer was performed. TRUS findings were categorized using a novel classification and correlated with histologic data. RESULTS: A total of 274 patients (58.8%) had prostate cancer, 88 patients (18.9%) inflammation, and 104 patients (22.3%) had benign pathology. Interface calcification was present in 42.3% of patients. Peripheral or transitional zone calcification was unusual (6.8% and 9.0%, respectively). Of the peripheral zone calcification group patients, 78.1% had cancer on histology examination (P = .020). CONCLUSION: Prevalence and characteristics of prostatic calcification have been described using this novel and practical classification. Although interface calcification is common and not associated with any particular pathology, peripheral zone calcification appears to be strongly associated with prostate cancer. PMID- 25530383 TI - Analysis of early morbidity and functional outcome of thulium: yttrium-aluminum garnet laser enucleation for benign prostate enlargement: patient age and prostate size determine adverse surgical outcome. AB - OBJECTIVE: To evaluate complications and functional outcome and to identify patient-associated risk factors, we analyzed consecutive patients undergoing thulium:yttrium-aluminum-garnet laser enucleation of the prostate (ThuLEP) in our department. METHODS: A total of 234 patients were prospectively analyzed. Preoperative data, postoperative complications, and outcome at 6, 12, and 24 months were recorded. Individual risk factors for complications and treatment failure were assessed by univariate and multivariate analyses. RESULTS: Mean age at surgery was 72.88 +/- 7.83 years. Mean preoperative prostate size was 84.8 +/- 34.9 mL. Thirty-day complication rate was 19.7%. Functional treatment failure occurred in 9.0% of all patients. Decline of mean International Prostate Symptom Score was -75%, quality of life index -76%, and postvoid residual -86% at 24 months. Maximum urine flow at 24 months was improved at +231%. In univariate analysis, age >80 years and prostate size <50 mL were significant predictors of complications, which was confirmed by multivariate analysis (P = .0277 and .0409, respectively). Age >80 years, prostate size <80 mL or <50 mL, and American Society of Anesthesiologists classification were significant predictors of functional treatment failure in univariate analysis. Prostate size <80 mL or <50 mL was significantly associated with treatment failure (P < .001) in multivariate analysis. CONCLUSION: ThuLEP is a safe and efficient surgical procedure, even in a patient cohort with high prostate volumes, age, and comorbidities. However, high patient age and small prostate size were significant determinants of adverse outcomes after surgery. To address the question of optimal therapy selection for patients with prostates smaller than 80 mL, further prospective randomized evaluation of ThuLEP and alternative surgical interventions is needed. PMID- 25530384 TI - Determination of the efficiency of 8 mg doxazosin XL treatment in patients with an inadequate response to 4 mg doxazosin XL treatment for benign prostatic hyperplasia. AB - OBJECTIVE: To compare the efficacy of 4 mg and 8 mg doxazosin XL treatments in patients with benign prostatic hyperplasia-related lower urinary tract symptoms and determine the efficiency of 8 mg in those patients with inadequate response to 4 mg. METHODS: A total of 162 patients were included in this study. Of the patients, 108 were randomized to receive 4 mg doxazosin XL (group 1), and 54 were randomized to receive 8 mg (group 2) treatments. After 1 month of treatment, 31 patients in group 1 whose quality of life (QoL) score was unchanged or had deteriorated were switched to 8 mg doxazosin XL treatment (group 1b). RESULTS: The mean age was 59.8 years. After 1 month of treatment, the mean alteration in the International Prostate Symptom Score was 3.9 and 5.2 (P = .028), for the maximum urinary flow rate (Q(max)), it was 3.0 and 3.6 mL/s (P = .206), and for the QoL score it was 1.3 and 1.7 (P = .038) in groups 1 and 2, respectively. For group 1b, during the period in which the patients were receiving 4 and 8 mg doxazosin XL treatments; the International Prostate Symptom Score changes were 1.3 and 3.6 (P <.001), the Q(max) changes were 1.6 and 3.2 mL/s (P <.019), and the QoL changes were 0.4 and 1.8 (P <.001) in groups 1 and 2, respectively. CONCLUSION: With no changes in side effects, 8 mg doxazosin XL treatment is an efficient choice for patients who did not have an adequate response to 4 mg doxazosin XL treatment. PMID- 25530385 TI - Temporal trend of newly diagnosed incidence, medical utilization, and costs for pediatric urolithiasis, 1998-2007: a nationwide population-based study in Taiwan. AB - OBJECTIVE: To investigate the trends of newly diagnosed incidence, medical utilization, and medical costs for pediatric urolithiasis in Taiwan. MATERIALS AND METHODS: The present study uses the National Health Insurance Research Database, which contains the data of all medical benefit claims from the individuals enrolled in the national and single-payer insurance program in Taiwan. The National Health Insurance covered 22,717,053 enrollees, nearly 99% of Taiwan's population. Our analysis includes all subjects aged <18 years with a primary diagnosis of urolithiasis. We analyzed the temporal trend for annual newly diagnosed incidence, medical care visits, and medical costs for pediatric urolithiasis from 1998 to 2007. RESULTS: A total of 1474 patients aged <18 years with newly diagnosed urolithiasis were identified, including 719 (48.8%) boys and 755 (51.2%) girls. The overall newly diagnosed rate of urolithiasis in pediatric population was 0.038% in 2007. The peak age stratum of urolithiasis occurrence in 2007 was 15-18 years. The trend of annual newly diagnosed incidences for boys, girls, and all children declined from 1998 to 2007. Furthermore, there were declining trends both in medical costs and annual medical care visits during the study period. CONCLUSION: This is the first nationwide population-based study to indicate the declining trends in newly diagnosed rate, medical care visits, and medical costs for pediatric urolithiasis. These findings help to quantify and establish the burden of pediatric urolithiasis. These findings help to quantify and establish the burden of medical care for pediatric urolithiasis and to further refine the medical policy. PMID- 25530386 TI - The effect of untethering on urologic symptoms and urodynamic parameters in children with primary tethered cord syndrome. AB - OBJECTIVE: To evaluate urinary system symptoms (USSs) and urodynamic parameters (UPs) before and after untethering in children with primary tethered cord syndrome (pTCS). METHODS: USSs and UPs of patients undergoing untethering for pTCS during the period January 2008-July 2012 were evaluated preoperatively and at the postoperative third and 12th months. For analysis, patients were separated into 4 groups according to the presence of USSs: group 1, USSs preoperative positive and postoperative negative; group 2, USSs preoperative positive and postoperative positive; group 3, USSs preoperative negative and postoperative positive; group 4, USSs preoperative negative and postoperative negative. Preoperative and postoperative USSs and UPs were compared. RESULTS: Forty patients (average age, 7.2 years, follow-up of 2.8 years) were included. There were 13 patients in group 1, 11 in group 2, 3 in group 3, and 13 in group 4. All patients showed improvement when preoperative and postoperative USSs and UPs were compared. There was no correlation between USSs and UPs, both preoperatively and postoperatively. USSs and UPs at the postoperative third and 12th months were similar. Patients with no USS showed the most significant improvement in UP after untethering. CONCLUSION: Our study has demonstrated that untethering in patients with pTCS improves urologic symptoms and UPs. However, there is no correlation between improvement in symptoms and urodynamic findings. Urodynamic changes are similar at the postoperative third and 12th months. As the most significant improvement was seen in patients without USSs, it is important that these patients undergo urodynamic studies preoperatively and postoperatively. PMID- 25530387 TI - Congenital prepubic sinus in an adolescent female: a case report and review of the literature. AB - Congenital prepubic sinus is a rare anomaly, especially in women; only 17 cases in 13 reports were found in the English literature after a search in the PubMed during 1990-2013. We report the diagnosis and successful minimally invasive excision of a congenital prepubic sinus in an adolescent female patient. Our experience and a review of the literature suggest the most likely etiology to be a variant of dorsal urethral duplication. PMID- 25530388 TI - Calyceal diverticulum with a large extra-renal extension in a 5-year-old child. AB - Calyceal diverticula are rare findings in children, often identified due to symptomatic presentation. We present the unique case of an incidentally found calyceal diverticula in a 5-year-old girl with a large extra-renal component, which was successfully excised in a robot-assisted laparoscopic procedure that was without complication. PMID- 25530389 TI - Sports-related genitourinary injuries presenting to United States emergency departments. AB - OBJECTIVE: To describe epidemiologic features of sports-related genitourinary (GU) injuries and determine patient cohorts and particular sporting activities associated with increased GU injury risk. MATERIALS AND METHODS: The National Electronic Injury Surveillance System, a data set validated to provide a probability sample of injury-related US emergency department (ED) presentations, was analyzed to characterize GU injuries between 2002 and 2010. A total of 13,851 observations were analyzed to derive national estimates. RESULTS: Between 2002 and 2010, an estimated 137,525 individuals (95% confidence interval, 104,490 170,620) presented to US EDs with GU injuries sustained during sporting activities. Nearly three-quarters of injuries occurred in the pediatric population. The most common product involved was a bicycle, representing approximately one-third of injuries in both adult and pediatric populations. Injuries related to team sports such as football, baseball or softball, basketball, and soccer were also common, particularly among boys where they represented a combined third of all injuries. Eighty-nine percent of all patients were evaluated and treated in the ED without inpatient admission. The large majority of injuries involved the external genitalia (60%), and significant injuries of paired GU organs (kidneys and testicles) requiring inpatient admission were rare (8.5%). CONCLUSION: Sports-related GU injuries are most commonly sustained during the use of a bicycle. However, there are other associated activities with identifiable high-risk cohorts, products, and situations. Consumers, practitioners, and injury-prevention experts can use our epidemiologic data to prioritize and develop strategies aimed at the prevention and limitation of such injuries, particularly when counseling at-risk cohorts, such as those with solitary kidneys or testicles. PMID- 25530390 TI - Editorial comment. PMID- 25530391 TI - Reply: To PMID 25530389. PMID- 25530392 TI - Is routine postoperative diuresis renography indicated in all adult patients after pyeloplasty for ureteropelvic junction obstruction? AB - OBJECTIVE: To determine if routine follow-up diuresis renography is indicated in all adult patients after pyeloplasty for ureteropelvic junction obstruction (UPJO). METHODS: A multicenter retrospective analysis was conducted in adults who underwent pyeloplasty for symptomatic UPJO between January 2002 and August 2012. Patients with unilateral UPJO demonstrated on diuresis renography, treated with pyeloplasty, and aged >18 years at time of surgery were included in the study. Patients with contralateral renal abnormalities, genitourinary anomalies, and those who declined renography during follow-up were excluded. All eligible patients underwent diuresis renography approximately 3 months postoperatively. Minimal follow-up was 12 months. Patients were divided into 2 groups: patients with persistent pain at 3 months after pyeloplasty and patients who became asymptomatic. Treatment failures in each cohort were identified. Comparisons were performed using the Fisher exact test. RESULTS: A total of 100 pyeloplasties were performed. Of them, 90 were eligible for the study. Mean age was 40 years. Mean follow-up was 21 months. Seventy-three patients (81.1%) became pain free after pyeloplasty. One patient (1.4%) had worsening of differential renal function despite unobstructed drainage on diuresis renogram. None of the patients in the asymptomatic cohort was identified to have unequivocal drainage obstruction on postoperative renogram. Seventeen patients (18.9%) remained symptomatic with pain at 3 months after pyeloplasty; 3 (17.6%) of those patients with loin pain after pyeloplasty were confirmed to have persistent obstructed drainage postoperatively on diuresis renogram (P <.001). All 3 patients required insertion of ureteric stents and/or revision surgery (P <.007). CONCLUSION: In our series, adult patients who became pain free after unilateral pyeloplasty for UPJO did not have persistent obstruction of renal drainage on renography. Routine diuresis renogram to assess drainage and differential renal function in patients who become pain free after pyeloplasty for UPJO may not be necessary. If objective evidence of postoperative outcome is required, then a single renogram at 3 months is recommended. PMID- 25530393 TI - Review of single-surgeon 10-year experience with artificial urinary sphincter with report of sterile cuff erosion managed nonsurgically. AB - OBJECTIVE: To review our experience with artificial urinary sphincter (AUS) and to consider the role of nonsurgical management of sterile AUS cuff erosion. METHODS: We retrospectively reviewed our 10-year experience with AUS implantation, including complication rates. We focus on the outcomes of eroded sphincters including 2 unique patients who were managed nonsurgically for sterile cuff erosion. RESULTS: Between 2002 and 2012, 126 AUS units were implanted in 79 adult male patients by single surgeon (A.K.S.). Twenty-five patients (31.6%) required at least 1 additional procedure because of urethral atrophy (22.8%) or erosion or infection (8.9%). In addition, 2 patients with congenital anomalies underwent AUS implantation at bladder neck and were followed up nonsurgically for several years after cuff erosion. Both refused surgical management and have since remained continent and infection-free despite chronic erosion for 15 years' duration in 1 patient and for 5 years' duration in the other. Of note, the patient with the longer duration of erosion developed bladder stones requiring surgical removal. CONCLUSION: Our AUS complication rates are consistent with those of prior series. Our unique experience with 2 patients suggests that immediate removal of AUS after sterile cuff erosion may occasionally be instituted only in difficult cases where repeat AUS implantation is not possible. To our knowledge, this is the first report of nonsurgical management of eroded AUS cuff in the literature. Larger prospective series concerning patient selection for salvaging eroded AUS may be warranted. PMID- 25530394 TI - Editorial comment. PMID- 25530395 TI - Reply: To PMID 25530393. PMID- 25530396 TI - Long-term outcomes of urethroplasty with abdominal wall skin grafts. AB - OBJECTIVE: To report the long-term outcomes of urethroplasty using abdominal wall skin (AWS) grafts. Men with long-segment strictures, prior urethroplasty, and lichen sclerosus (LS) pose challenges in surgical management, including the choice of graft tissue for urethral reconstruction. AWS grafts are an alternative when buccal mucosa or penile grafts are not feasible or chosen by the patient. METHODS: We retrospectively reviewed 238 patients who underwent urethroplasty (2000-2010) with at least 1 year of follow-up. Demographics, etiology, comorbidities, prior procedures, and surgical technique were analyzed for correlation with recurrence. RESULTS: Mean age was 42.9 years (range, 15-79 years), mean stricture length 5.6 cm (1-24 cm), and median follow-up of 59.3 months (12.5-147 months). A total of 58.4% patients had prior intervention, of which 15 patients (6.3%) had urethroplasty and 41 patients (17.2%) had hypospadias repair. Twenty-six patients (10.9%) underwent urethroplasty with AWS graft, whereas 107 (45.0%) and 12 (5.0%) patients were augmented with buccal mucosa or genital skin. Sixty-six patients (27.7%) had stricture recurrence at a mean of 34.5 months (range, 1.87-87.1 months). On univariate analysis, patients with AWS graft had longer strictures (P = .0001), were more likely to have LS (P = .0002), prior urethroplasty (P = .007), and recurrence (P = .002). On multivariate analysis, prior urethroplasty (odds ratio [OR], 5.3; P = .009), diabetes (OR, 2.6; P = .04), and LS (OR, 2.8; P = .05) were significantly associated with recurrence, whereas AWS graft was not (OR, 2.0; P = .28). CONCLUSION: AWS grafts are an alternative tissue source for urethral stricture, but may be associated with greater risk of recurrence. This may be secondary to patient selection, with this population often having other risk factors for recurrence. PMID- 25530397 TI - Editorial comment. PMID- 25530398 TI - Reply: To PMID 25530396. PMID- 25530399 TI - A modified suture technique for transperitoneal laparoscopic dismembered pyeloplasty of pelviureteric junction obstruction. AB - OBJECTIVE: To describe a modified suture technique for transperitoneal laparoscopic dismembered pyeloplasty (TPLDP) that can be consistently replicated. METHODS: Between June 2010 and April 2014, 21 men and 7 women with primary pelviureteric junction obstruction underwent our modified TPLDP suture technique performed by the same surgeon. In our method, the dismembering should be performed after performing half of anastomosis to achieve the maintenance of correct orientation and the prevention of torsion of anastomosis. We defined the success criteria as complete clinical resolution of flank pain for the patients with flank pain and complete radiologic resolution for the asymptomatic patients. RESULTS: The mean overall operative time for our technique was 137.3 minutes. The mean operative time for procedures on the left side was longer than on the right side (P = .02). The mean suture time was 37.2 minutes. The mean estimated blood loss was 29.4 mL, and the crossing vessel was found in 7 of 28 patients (25.0%). No open conversion was required. The mean follow-up time was 21.0 months. Only 1 patient still had frequent and intolerable flank pain after surgery whose treatment was unsuccessful. The rest of the patients got complete clinical or radiologic resolution. The success rate was 27 of 28 (96.4%). CONCLUSION: Our modified TPLDP suture technique is feasible and seems to be safe and to allow high success rate for the treatment of pelviureteric junction obstruction. Sizable sample and further analysis about technique will be completed in the future. PMID- 25530400 TI - Comparison of optics and performance of single channel and a novel dual-channel fiberoptic ureteroscope. AB - OBJECTIVE: To evaluate performance characteristics and optics of a novel dual working channel fiberoptic ureteroscope (Wolf Cobra) with 2 single-channel fiberoptic ureteroscopes and to a single-channel distal sensor standard definition digital ureteroscope URF-V (SD-DS). METHODS: Four new ureteroscopes (Cobra, Viper, X(2), and SD-DS) were compared for active deflection, irrigation flow, and optical characteristics. We performed a porcine ureteroscopy and measured the time for cleaning the middle calyx after injection of 10 cc of a standardized bloody solution. RESULTS: The SD-DS showed a higher resolution (7.42 lines/mm; P = .0001) compared with the fiberoptic ureteroscopes; among the fiberoptic ureteroscopes, the Cobra had the highest resolution than the Viper and X(2) (P = .0001). Grayscale distribution and color representation were identical for the fiberoptic ureteroscopes, whereas the SD-DS provided a superior color representation and a significant higher depth of field. The Cobra provided superior flow with empty working channel (86 cc/min vs 68 cc/min [Viper] vs 62.5 cc/min [X(2)] vs 62 cc/min [SD-DS]; P = .0001) and with various accessories (P <.0001). With regard to deflection, the Storz X(2) and the Cobra provided superior deflection up and down (P <.0001). When evacuating a standardized bloody field, the Cobra provided significant shorter evacuation times compared with those of the Viper, X(2), and SD-DS (36.6 vs 72 vs 65.6 vs 72.6 seconds, respectively; P = .0001). CONCLUSION: The additional working channel of the Wolf Cobra may improve vision and performance during challenging ureteroscopic cases by providing an increased flow. The enhanced irrigation capabilities of the Cobra have to be balanced with a larger diameter of this ureteroscope. PMID- 25530401 TI - Reply by the authors. PMID- 25530402 TI - Re: Han et al.: Factors associated with continuing medical therapy after transurethral resection of prostate (Urology 2014;84:675-680). PMID- 25530403 TI - Reply: To PMID 25530404. PMID- 25530404 TI - Editorial comment. PMID- 25530405 TI - The effect of intraurethral dexpanthenol on healing and fibrosis in rats with experimentally induced urethral trauma. AB - OBJECTIVE: To determine the efficacy of dexpanthenol applied early after urethral trauma for preventing inflammation and spongiofibrosis. MATERIALS AND METHODS: Twenty-seven rats were randomized and divided into 3 groups, with 9 rats in each group. The urethras of all rats were traumatized with a pediatric urethrotome knife at 6-o' clock. For 14 days, group I was given 0.9% saline twice a day (control group), group II was given dexpanthenol 500 mg/kg ampules once a day and 0.9% saline once a day, and group III was given dexpanthenol 500 mg/kg ampules twice a day intraurethrally using a 22 ga catheter sheath. On day 15, the penises of the rats were degloved to perform penectomy. RESULTS: The mean fibrosis scores were 2.4, 2.2, and 1.4, and mean inflammation scar scores were 2, 1.4, and 1.3 in groups I, II, and III, respectively. There was a significant difference between groups I and II for inflammation (P = .011); however, the difference for fibrosis was not significant (P = .331). The differences between groups I and III were statistically significantly different both for inflammation and fibrosis (P = .004 and P = .003, respectively). Groups II and III were not different significantly for inflammation (P = .638); however, there was less fibrosis in group III, in which high-dose dexpanthenol was administered. CONCLUSION: We showed that dexpanthenol applied early after urethral trauma significantly decreased inflammation and spongiofibrosis. We hope that our study will help to decrease strictures after urethral trauma and contribute to pharmaceutical investigations aiming to improve the success of the surgery for urethral strictures. PMID- 25530406 TI - Nephropleural fistula after percutaneous nephrolithotomy in a pediatric patient: diagnosis and management. AB - Nephropleural fistula is a direct and persistent communication between the intrarenal collecting system and the intrathoracic cavity and is a rare complication of supracostal puncture during percutaneous nephrolithotomy. We report a case of a 4-year-old male child who underwent percutaneous removal of a right renal stone. He developed a nephropleural fistula and displacement of double J stent into the pleural cavity. Decompression of the pelvicalyceal system with percutaneous nephrostomy and repositioning of the double J stent allowed for healing of the fistulous connection. PMID- 25530407 TI - Managing failed fixation: valgus osteotomy for femoral neck nonunion. AB - Femoral neck non union is a relatively uncommon complication following intracapsular hip fracture in the young patient. Almost all patients with femoral neck non union are symptomatic for which they will require some form of revision surgery. This review discusses the role of valgus osteotomy in managing the younger patient with femoral neck non union. PMID- 25530408 TI - The role of external fixation in the treatment of humeral shaft fractures: a retrospective case study review on 85 humeral fractures. AB - There is no consensus among surgeons on the treatment for humeral fractures: the best it is still a matter of some debate. The aim of our work was to demonstrate that external fixation may be considered a valid method not only in emergencies but also for the definitive treatment of such fractures. We perform a retrospective case study review on 85 humeral fractures, 62 shaft fractures, and 23 extrarticular distal third fractures treated with external fixation. Clinical (Disabilities of the Arm, Shoulder and Hand (DASH) score and SF-36) and radiographic follow-up lasted on average 30 months (minimum 12 to maximum 36). Complete healing of fractures was achieved in 97.6% of cases (83 patients), with an average consolidation time of about 12 weeks (83.2 days). One case of delayed union and one case of refracture were encountered. Eighty-one patients demonstrated SF-36 scores at or above the national average and an average DASH score of 8.9. External fixation of humeral shaft fractures is considered a valid treatment method as it provides good results in terms of stability of reduction, tolerability, healing times, and functional recovery. PMID- 25530409 TI - An alarming presentation of Creutzfeldt-Jakob disease following a self-inflicted gunshot wound to the head. AB - Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are characterized by rapid and fatal neurological decline. They not only detrimentally affect the patient, but also present additional challenges to healthcare systems due to the infectivity of the tissues and the difficulty of inactivating the prion. The most common TSE is Creutzfeldt-Jakob disease (CJD), which can occur after familial, spontaneous or acquired transmission. TSEs received more attention after the development of variant CJD (vCJD), also known as Mad Cow Disease, in the UK during the mid-1990s. Unlike familial or spontaneous CJD, this variant was connected to consumption of cattle contaminated with the prion disease, bovine spongiform encephalopathy.This development increased interest in the etiology of CJD and other TSEs and the risk it presents as an infectious disease. The following details the case of a 59-year-old male infected with CJD presented to our level II trauma center for treatment following a self-inflicted gunshot wound to the head. PMID- 25530410 TI - Long-term clinical outcomes of war-related bilateral lower extremities amputations. AB - In a cross-sectional study, 291 out of 500 veterans with war-related bilateral lower limb amputations from Iran-Iraq war (1980-1988) accepted to participate in our study. Information related to amputees and amputated limbs were gathered and a Persian version of the Medical Outcomes Study Short Form 36 (SF-36) was filled. To evaluate the effect of amputation level on health related quality of life, we classified patients to seven types according to the functional remainder of major joints (ankles, knees, hips). 97% of patients were male and the average age at the time of injury was 20 years. The major cause of war injury was shells in 50. 54% of amputees were involved in sport activities. The most common amputation level was transtibial (48%).The major stump complaint was muscle spasm. History of being hospitalized for a psychiatric disorder was reported in 5.6%. The average SF-36 score in type 2 to type 6 were 68, 60, 60, 56, and 62, respectively. Except Energy/Fatigue domain, all the other domains were different from normal population. There was not any significant statistical correlation between amputation type and any domain of the SF-36. Type 6 amputees showed an increase in physical health domains compared with former types. PMID- 25530411 TI - Management of young femoral neck fractures: is there a consensus? AB - BACKGROUND: Femoral neck fractures in young adults (ages <60) are high-energy injuries that are associated with major fracture healing complications such as avascular necrosis, nonunion, and significant shortening. Historically, evidence from small trials has suggested multiple cannulated screws were the optimal implant; however, newer studies and implant designs warrant reevaluation of screws as the gold standard among surgeons. In addition, controversies surrounding reduction technique and urgency of surgical fixation have been previously identified. We aimed to survey surgeon treatment preferences for these challenging fractures. METHODS: A 17-item survey was developed and tested for validity and reliability prior to administration. The questionnaire characterised surgeon demographics, treatment preferences for displaced and undisplaced fractures, and controversies for future clinical trials. The target population consisted of surgeons from the Canadian Orthopaedic Association, the Orthopaedic Trauma Association, and attendees at an international fracture course. RESULTS: 540 surgeons completed the survey, exceeding our sample size requirement. There was a similar proportion of respondents from academic and community hospitals. Most surgeons (61%) treat 1-5 young adult femoral neck fractures per year. For undisplaced fractures, 78% of respondents prefer to use multiple cannulated screws. For displaced fractures, equal preference for multiple screws (46%) and the sliding hip screw (SHS, 49%) was reported. The majority of surgeons perform an open reduction in less than 25% of cases, and the time to fixation was typically between 8 and 24h. CONCLUSIONS: Multiple cannulated screws remain the preferred treatment for most surgeons treating undisplaced fractures; however, there is an equal divide in preference between multiple screws and the SHS for displaced fractures. This increased preference for the SHS contradicts previous survey and small trial data recommending multiple screws for all fracture patterns. The lack of surgeon consensus and the high rates of fracture complications associated with fixation of young femoral neck fractures supports the need for definitive clinical trials to optimise patient important outcomes. PMID- 25530412 TI - Evolution of angiosperm seed disperser mutualisms: the timing of origins and their consequences for coevolutionary interactions between angiosperms and frugivores. AB - The origins of interactions between angiosperms and fruit-eating seed dispersers have attracted much attention following a seminal paper on this topic by Tiffney (1984). This review synthesizes evidence pertaining to key events during the evolution of angiosperm-frugivore interactions and suggests some implications of this evidence for interpretations of angiosperm-frugivore coevolution. The most important conclusions are: (i) the diversification of angiosperm seed size and fleshy fruits commenced around 80 million years ago (Mya). The diversity of seed sizes, fruit sizes and fruit types peaked in the Eocene around 55 to 50 Mya. During this first phase of the interaction, angiosperms and animals evolving frugivory expanded into niche space not previously utilized by these groups, as frugivores and previously not existing fruit traits appeared. From the Eocene until the present, angiosperm-frugivore interactions have occurred within a broad frame of existing niche space, as defined by fruit traits and frugivory, motivating a separation of the angiosperm-frugivore interactions into two phases, before and after the peak in the early Eocene. (ii) The extinct multituberculates were probably the most important frugivores during the early radiation phase of angiosperm seeds and fleshy fruits. Primates and rodents are likely to have been important in the latter part of this first phase. (iii) Flying frugivores, birds and bats, evolved during the second phase, mainly during the Oligocene and Miocene, thus exploiting an existing diversity of fleshy fruits. (iv) A drastic climate shift around the Eocene-Oligocene boundary (around 34 Mya) resulted in more semi-open woodland vegetation, creating patchily occurring food resources for frugivores. This promoted evolution of a 'flying frugivore niche' exploited by birds and bats. In particular, passerines became a dominant frugivore group worldwide. (v) Fleshy fruits evolved at numerous occasions in many angiosperm families, and many of the originations of fleshy fruits occurred well after the peak in the early Eocene. (vi) During periods associated with environmental change altering coevolutionary networks and opening of niche space, reciprocal coevolution may result in strong directional selection formative for both fruit and frugivore evolution. Further evidence is needed to test this hypothesis. Based on the abundance of plant lineages with various forms of fleshy fruits, and the diversity of frugivores, it is suggested that periods of rapid coevolution in angiosperms and frugivores occurred numerous times during the 80 million years of angiosperm-frugivore evolution. PMID- 25530414 TI - Hyperscanning and avoidance in social anxiety disorder: the visual scanpath during public speaking. AB - Social anxiety disorder (SAD) is a debilitating mental illness which is thought to be maintained in part by the aberrant attentional processing of socially relevant information. Critically however, research has not assessed whether such aberrant attentional processing occurs during social-evaluative contexts characteristically feared in SAD. The current study presents a novel approach for the assessment of the visuocognitive biases operating in SAD during a social evaluative stressor. For this task, clinically socially anxious participants and controls were required to give a brief impromptu speech in front of a pre recorded audience who intermittently displayed socially positive or threatening gestures. Participant gaze at the audience display was recorded throughout the speech. Socially anxious participants exhibited a significantly longer visual scanpath, relative to controls. In addition, socially anxious participants spent relatively longer time fixating at the non-social regions in between and around the confederates. The findings of the present study suggest that SAD is associated with hyperscanning and the attentional avoidance of social stimuli. PMID- 25530415 TI - Metamemory in schizophrenia: retrospective confidence ratings interact with neurocognitive deficits. AB - Prior studies with schizophrenia patients described a reduced ability to discriminate between correct and false memories in terms of confidence compared to control groups. This metamemory bias has been associated with the emergence and maintenance of delusions. The relation to neuropsychological performance and other clinical dimensions is incompletely understood. In a cross-sectional study, metamemory functioning was explored in 32 schizophrenia patients and 25 healthy controls. Metamemory was assessed using a verbal recognition task combined with retrospective confidence level ratings. Associations of metamemory performance with six neuropsychological domains (executive functioning/problem solving, speed of processing, working memory, verbal and visual learning, and attention/vigilance) and psychopathological measures were analyzed. Results revealed a significantly smaller discrepancy between confidence ratings for correct and incorrect recognitions in the patient group. Furthermore, patients showed significantly lower recognition accuracy in the metamemory task and marked deficits in all neuropsychological domains. Across all participants, metamemory performance significantly correlated with executive functioning and working memory. No associations with delusions were found. This data confirms prior findings of metamemory biases in schizophrenia. Selective neuropsychological abilities seem to be modulating factors of metamemory functioning. Longitudinal studies in at risk mental state and first-episode patients are needed to reveal causal interrelations. PMID- 25530416 TI - Gender differences in suicide and suicide attempts among US Army soldiers. AB - In order to best tailor suicide prevention initiatives and programs, it is critical to gain an understanding of how service members' suicide risk factors may differ by gender. We aimed to better understand gender differences in suicide and suicide attempts among soldiers, including demographic, military, mental health, and other risk factors. We also examined risk factors uniquely associated with suicide and suicide attempts. We conducted a retrospective study of 1857 US Army soldiers who died by suicide or attempted suicide between 2008 and 2010 and had a Department of Defense Suicide Event Report. Female and male soldiers had more similarities than differences when examining risk factors associated with suicide. The only gender difference approaching significance was workplace difficulties, which was more strongly associated with suicide for female soldiers, compared to their male counterparts. Among suicide decedents, the most common risk factor was having a failed intimate relationship in the 90 days prior to suicide. Among those who attempted suicide, the most common risk factor was a major psychiatric diagnosis. Better understanding both gender differences and risk factors uniquely associated with suicide has critical prevention and public health implications as we work to better understand preventable mortality in our youngest generation of service members. PMID- 25530417 TI - Fasting and acquired capability for suicide: a test of the interpersonal psychological theory of suicide in an undergraduate sample. AB - Though some preliminary research within the framework of the interpersonal psychological theory of suicide (IPTS; Joiner, 2005) has postulated that restrictive eating may contribute to increased risk for suicide through its effect on the acquired capability for suicide (ACS; i.e., increased fearlessness about death and heightened physical pain tolerance), existing studies have not conducted direct tests of this relationship. To enhance understanding of this relationship, we compared undergraduates who endorsed one form of restrictive eating, fasting, (n = 99) to controls endorsing no forms of eating pathology over the lifetime (n = 94). We hypothesized that the fasting group would have higher ACS and higher likelihood of suicide attempt history. Contrary to hypotheses, no differences emerged between groups on ACS, and frequency of fasting within the fasting group was not significantly associated with ACS. Consistent with hypotheses, the fasting group was more likely to have suicide attempt history. Though results were not entirely consistent with hypotheses, the current study represents the first attempt at isolating and examining one form of restrictive eating (i.e., fasting) within the context of the IPTS. Results suggest that, in isolation, fasting may not be directly contributing to increases in ACS. PMID- 25530418 TI - A Persian version of the parental bonding instrument: factor structure and psychometric properties. AB - The Parental Bonding Instrument (PBI) is a widely used self-report measure for quantifying key parenting styles as perceived by the child during its first 16 years. While its development study identified two key parental dimensions, subsequent studies have variably confirmed those two or argued for one or more additional parental constructs. We developed a Persian translation of the PBI and administered it to a sample of 340 high school students. The construct validity of the Persian PBI was examined by Exploratory Factor Analysis while Confirmatory Factor Analysis was used to identify the most adequate model. Analyses of the Persian PBI favored a four-factor model for both parental forms. The Persian PBI has a factorial structure consistent with constructs identified in western cultures, as well as high internal consistency and test-retest reliability. Multivariate analyses indicated significant differences between boys and girls across some factors. The PBI appears an acceptable and appropriate measure for quantifying parent-child bonding in Iranian samples. PMID- 25530419 TI - Accept, distract, or reframe? An exploratory experimental comparison of strategies for coping with intrusive body image thoughts in anorexia nervosa and body dysmorphic disorder. AB - Negative body image is the hallmark of anorexia nervosa (AN) and body dysmorphic disorder (BDD). One aspect of body image, appearance-related thoughts, have shown to be a major contributor to relapse, thus further investigation of successful treatment strategies targeting these maladaptive thoughts are warranted. The present study tested an acceptance/mindfulness (AC), a cognitive restructuring (CR), and a distraction strategy with regard to their short-term effectiveness of reducing the frequency of thought occurrence and associated outcomes in participants with AN (n=20), BDD (n=21), and healthy controls (HC; n=22). Although all strategies led to a significant reduction of thought frequency, there was no group * strategy interaction effect in their reduction. Positive affect increased in the BDD group through the AC strategy, but decreased in healthy controls. Acceptance of the thought increased in the CR strategy in AN, whereas that strategy seemed to work least for BDD. Healthy controls showed most acceptance when using distraction. Taken together, the study suggests that all strategies might have their benefits and that it might be worthwhile further investigating differential indication of the strategies with regard to diagnosis and individual factors. PMID- 25530420 TI - A change in anticoagulation monitoring improves safety, reduces transfusion, and reduces costs in infants on cardiopulmonary bypass. AB - BACKGROUND: An immature coagulation system coupled with the hypothermia and hemodilution associated with cardiopulmonary bypass (CPB) in infants makes the activated clotting time (ACT) an ineffective monitor for anticoagulation in this population. The Medtronic HMS Plus Hemostasis Management System (HMS; Medtronic, Inc., Minneapolis, MN, USA) is shown to decrease thrombin generation and blood product requirements. AIM: We conducted a quality improvement initiative to test our hypothesis that the use of HMS results in reduced incidence of subtherapeutic ACT values, blood product usage, and operating room time for infants undergoing cardiac surgery. METHODS: Fifty consecutive patients weighing <10 kg having cardiac surgery requiring CPB had anticoagulation managed by the HMS. Data were compared to that of 50 consecutive patients weighing <10 kg having cardiac surgery who had their anticoagulation monitored by the ACT alone. Comparisons between categorical variables were performed with chi-square tests. Comparisons between continuous variables were performed with the Wilcoxon rank-sum test. Statistical significance was defined as two-tailed P value < 0.05. RESULTS: The HMS group had a 61% decrease in incidence of ACT values <480 s and elimination of ACT values < 400 s at any time on bypass. The HMS group received fewer blood products and spent fewer minutes in the operating room after protamine administration, translating to fewer donor exposures and a savings of $403 in transfusion costs and $440 in operating room time costs. CONCLUSION: Our findings highlight the benefits of individualized heparinization for pediatric patients undergoing CPB with a monitored heparinization system. PMID- 25530421 TI - MicroRNA-103a inhibits gastric cancer cell proliferation, migration and invasion by targeting c-Myb. AB - OBJECTIVES: There have been no previous reports concerning functions of miR-103a in gastric cancer (GC) cells. Thus the aim of the study was to investigate its expression and role in development of this tumour. MATERIALS AND METHODS: Real time RT-PCR was performed to detect expression of miR-103a in GC cell lines and clinical cancer specimens. To further understand its role, we restored expression of miR-103a in MGC-803 cell line by transfection with miR-103a mimics or inhibitors. Effects of miR-103a on cell proliferation, migration and invasion on targets were also determined. RESULTS: miR-103a was down-regulated in both GC cell lines and clinical cancer specimens. Meanwhile, its level was closely associated with pM or pTNM stage of GC. Overexpression of miR-103a markedly suppressed proliferation, migration, and invasion of GC cells, while its inhibition significantly accelerated cell proliferation, migration and invasion. Moreover, c-Myb was identified to be a functional downstream target of miR-103a, ectopic expression of which partially reversed suppression of cell proliferation and invasion. CONCLUSIONS: Thus our observations suggest that miR-103a functioned as a tumour suppressor by targeting c-Myb. These findings indicate that miR-103a might play a significant role in pathogenesis of GC. PMID- 25530422 TI - The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer. AB - Around 70% of breast cancers express the estrogen receptor alpha (ERalpha) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant anti-endocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ERalpha and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ERalpha and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ERalpha+ breast cancer patients and induces cell death in ER+ breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ERalpha+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERalpha+ breast cancer cells through suppression of ERalpha expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ERalpha+ breast cancers independently of their p53 status. PMID- 25530423 TI - Morphological and physiological features of Arthroderma benhamiae anamorphs isolated in northern Germany. AB - The anamorph of Arthroderma benhamiae is an upcoming zoophilic dermatophyte that only in recent years has gained importance as a cause of tinea in humans. Its identification by conventional methods can cause problems. In this study we have subjected seven genetically confirmed strains of A. benhamiae anamorphs from northern Germany recently identified in our laboratory to a comprehensive assessment. Their macroscopic and microscopic morphology was checked on various agars and enzyme release stimulated by substrates with keratin, hair perforation and other physiological characteristics were tested. All strains were related to the previously described yellow phenotype of the A. benhamiae anamorph and showed a high resemblance among themselves. Coherent features were their uniform thallus morphology on Sabouraud glucose agar with yellow pigmentation, the formation of circuit-like hyphal structures and hyphal connections that had not been described previously, a lack of conidia, thiamine dependence, the spectrum of released enzymes and a good growth on human stratum corneum. With exception of the latter two these criteria are suggested for the identification of this anamorph phenotype that should be evaluated by future observations. Different phenotypes of the A. benhamiae anamorph may prevail in other geographic regions. PMID- 25530424 TI - Use of bladder dose points for assessment of the spatial dose distribution in the posterior bladder wall in cervical cancer brachytherapy and the impact of applicator position. AB - PURPOSE: To validate the feasibility and use of dose points to characterize the bladder wall dose distribution and investigate potential impact of the applicator position in cervical cancer brachytherapy. METHODS AND MATERIALS: One hundred twenty-eight optimized MRI plans were evaluated. The International Commission of Radiation Units and Measurements (ICRU-38) point doses (B(ICRU)), surrogate for bladder base doses, were compared with D(2cc). Vaginal source to superior anterior border of the symphysis distances were measured and compared within two groups, namely Group 1-B(ICRU)/D(2cc) >=1 and Group 2-B(ICRU)/D(2cc) <1. Additionally, points at 1.5 and 2 cm cranial to the B(ICRU), parallel to the tandem and the body axis were analyzed. RESULTS: Thirty-seven percent of the patients had the ratio B(ICRU)/D(2cc) of 1 or higher, with the 2cc subvolume at the bladder base (Group 1). In 63%, BICRU/D2cc ratio was lower than 1 and the 2cc, cranial to the bladder base (Group 2). Median vaginal source-to-superior anterior border of the symphysis line distance was -2 cm (range, -3.7 to +1.2 cm) in Group 1 and +1.8 cm (range, -2 to +4.8 cm) in Group 2 (+ cranial/- caudal direction). There was a high correlation between vaginal sources near the symphysis and the 2cc subvolume at the bladder base. The additional points provided no added value. CONCLUSIONS: Location of the 2cc subvolume varies in cervical cancer brachytherapy. Maximum doses are at the bladder base if vaginal sources are also in the vicinity of the bladder base indicated by B(ICRU)/D(2cc) ratio of 1 or higher. Such variation should be considered in dose-effect analyses and intercomparisons, as the same D(2cc) at different bladder locations may correlate with different morbidity profiles and severity Reporting D(2cc) and B(ICRU) doses together therefore remains essential. PMID- 25530425 TI - Patient and program factors that bridge the detoxification-treatment gap: a structured evidence review. AB - Although completion of detoxification (detox) and a successful transition from detox to substance use disorder (SUD) treatment and/or mutual-help groups are associated with better SUD outcomes, many patients do not complete detox or do not receive SUD care following detox. The purpose of this structured evidence review, summarizing data extraction on a yield of 26 articles, is to identify patient, program, and system factors associated with the outcomes of completion of alcohol detox and successful transitions from alcohol detox to SUD treatment and mutual-help group participation. The review found wide variability among studies in the rates at which patients complete a detox episode (45 to 95%) and enter SUD treatment or mutual-help groups after detox (14 to 92%). Within program factors, behavioral practices that contribute to both detox completion and transitioning to SUD care after detox entail involving the patient's family and utilizing motivational-based approaches. Such practices should be targeted at younger patients, who are less likely to complete detox. Although more studies using a randomized controlled trial design are needed, the evidence suggests that barriers to detox completion and transition to SUD care can be overcome to improve patient outcomes. PMID- 25530426 TI - Depressive symptoms among patients receiving varenicline and bupropion for smoking cessation. AB - While the combination therapy of varenicline and sustained release bupropion (bupropion SR) for cigarette smoking cessation can increase smoking abstinence rates, it has also been associated with increases in self-reported depressive symptoms. We conducted an analysis of the Beck Depression Inventory, second edition (BDI-II), data completed by 505 patients from a large randomized clinical trial, evaluating the efficacy of 12 weeks of combination therapy (varenicline+bupropion SR) compared to varenicline alone. At medication treatment week 2 (1 week after target quit date [TQD]), increased depressive symptoms were observed in patients receiving combination therapy (effect estimate=0.61, 95% CI [0.03, 1.19], P=.039) and those with a history of depression (effect estimate=0.82, 95% CI [0.07, 1.57], P=.033). For treatment weeks 2 to 4, smokers with a history of depression on combination therapy had a greater decline in depressive symptoms compared to those on varenicline alone (effect estimate= 1.99, 95% CI [-3.99, 0.00], P=.050). After treatment week 4, no significant effects of treatment or depression history on BDI-II scores were observed. A history of depression did not moderate the efficacy of combination therapy for smoking abstinence. Our study suggests that for combination therapy with varenicline and bupropion SR, an increase in depressive symptoms over the first 2 weeks may be observed; however, the effects on depressive symptoms do not last beyond 4 weeks. We conclude that among smokers without active moderate or severe depression, the decision to use this combination treatment approach should not be based upon a self-reported history of depression. PMID- 25530427 TI - Common therapeutic factors in bereavement groups. AB - Group therapy remains a popular treatment format for individuals experiencing bereavement. Although many innovative group treatments for grief are being developed, common therapeutic factors can also contribute to outcomes. The author integrates research on group therapy processes and treatment for grief, and examines evidence regarding group therapeutic factors that may influence bereavement group outcomes. Specifically, research on therapeutic factors related to sharing and support, interpersonal learning, and meaning-making is highlighted where it has relevance to bereavement groups. Potential research examining the interactions of these processes, their effects on group functioning and outcomes, and the moderators of these effects are discussed. PMID- 25530428 TI - Cell-free fetal DNA and pregnancy-related complications (review). AB - Cell-free fetal DNA (cff-DNA) is a novel promising biomarker that has been applied in various aspects of obstetrical research, notably in prenatal diagnosis and complicated pregnancies. It is easily detected by semi-quantitative PCR for the SRY target gene. It is well recognized that the levels of circulating cff-DNA play a role in various complications of pregnancy. In this review, we explore the implications of the detection of cff-DNA in a range of pregnancy-related complications, such as preeclampsia, intrauterine growth restriction (IUGR), preterm labor, placenta previa and hyperemesis gravidarum. cff-DNA is released due to apoptotic mechanisms occurring on trophoblastic cells, although recent in vivo studies support the existence of additional mechanisms. The increase in the levels of cff-DNA can be used to predict pregnancy-related complications and has great value in the field of prenatal diagnosis and in common pregnancy-related complications, as it precedes the clinical symptoms of the disease. Gestational age is a factor that determines the elevation in cff-DNA levels in response to pathological conditions. In conclusion, the detection of cff-DNA levels has a number of valuable applications in prenatal screening; however, the detection of cff-DNA levels has not yet been applied in clinical practice for the diagnosis of pregnancy-related disorders. Thus, studies are focusing on unraveling the etiology of alterations in its levels under pathological conditions during pregnancy, in order to determine the potential predictive and diagnostic applications of this biomarker. PMID- 25530429 TI - [Neurogenic stunned myocardium in Pediatrics. A case report]. AB - Neurogenic stunned myocardium is an unusual clinical entity. It mimics an acute coronary syndrome with electrocardiographic abnormalities, cardiac dysfunction and elevated cardiac enzymes with absence of obstructive coronary disease. It may occur after a neurosurgical procedure. A case is presented of neurogenic stunned myocardium occurring in a child after removal of a posterior fossa medulloblastoma. The patient developed nodal tachycardia with hemodynamic impairment. The clinical course was satisfactory due to antiarrhythmic therapy, with biochemical, echocardiographic, and clinical improvement within a week. PMID- 25530430 TI - [Comment to the article: "Unintended intraoperative extubation in a patient with Treacher Collins syndrome: Usefullness of Glidescope videolaryngoscope"]. PMID- 25530431 TI - [Lung herniation as a complication after cardiopulmonary resuscitation]. PMID- 25530432 TI - [Reply to the letter on the article "Comment to the article: "Unintended intraoperative extubation in a patient with Treacher Collins syndrome: Usefullness of GlideScope videolaryngoscope""]. PMID- 25530433 TI - [Diagnose of traqueomalacia with nuclear magnetic resonance]. PMID- 25530434 TI - Real-time ultrasound detection of correct intravenous placement of central venous catheters after ultrasound cannulation. PMID- 25530435 TI - Multi-locus analysis of Giardia duodenalis from nonhuman primates kept in zoos in China: geographical segregation and host-adaptation of assemblage B isolates. AB - Only a few studies based on single locus characterization have been conducted on the molecular epidemiology of Giardia duodenalis in nonhuman primates (NHPs). The present study was conducted to examine the occurrence and genotype identity of G. duodenalis in NHPs based on multi-locus analysis of the small-subunit ribosomal RNA (SSU rRNA), triose phosphate isomerase (tpi), glutamate dehydrogenase (gdh), and beta-giardin (bg) genes. Fecal specimens were collected from 496 animals of 36 NHP species kept in seven zoos in China and screened for G. duodenalis by tpi based PCR. G. duodenalis was detected in 92 (18.6%) specimens from 18 NHP species, belonging to assemblage A (n=4) and B (n=88). In positive NHP species, the infection rates ranged from 4.8% to 100%. In tpi sequence analysis, the assemblage A included subtypes A1, A2 and one novel subtype. Multi-locus analysis of the tpi, gdh, and bg genes detected 11 (8 known and 3 new), 6 (3 known and 3 new) and 9 (2 known and 7 new) subtypes in 88, 47 and 35 isolates in assemblage B, respectively. Thirty-two assemblage B isolates with data at all three loci yielded 15 multi-locus genotypes (MLGs), including 2 known and 13 new MLGs. Phylogenetic analysis of concatenated sequences of assemblage B showed that MLGs found here were genetically different from those of humans, NHPs, rabbit and guinea pig in Italy and Sweden. It further indicated that assemblage B isolates in ring-tailed lemurs and squirrel monkeys might be genetically different from those in other NHPs. These data suggest that NHPs are mainly infected with G. duodenalis assemblage B and there might be geographical segregation and host adaptation in assemblage B in NHPs. PMID- 25530436 TI - Prevalence and complete genome characterization of turkey picobirnaviruses. AB - The "light turkey syndrome" (LTS), in which birds weigh less than their standard breed character at the marketing time, is believed to be a consequence of viral enteritis at an early age (3-5 weeks) from which the birds never fully recover. In a previously published study, we collected fecal pools from 2, 3, 5 and 8 week old turkey poults (80 pools from LTS farms and 40 from non-LTS farms) and examined them for the presence of astro-, rota-, reo-, and coronaviruses. To determine the presence of additional enteric viruses, we analyzed a fecal pool by Illumina sequencing and found picobirnavirus (PBV). Segments 1 and 2 of this virus shared 45.8%aa and 60.9-64.5%aa identity with genogroup I of human PBV, respectively. Primers based on RNA-dependent RNA polymerase and capsid genes were designed for detection and molecular characterization of PBVs in the 120 fecal pools described above. From LTS farms, 39 of 80 (48.8%) pools were PBV positive while 23 of 40 (57.5%) were positive from non-LTS farms. The phylogenetic analysis of 15 randomly selected strains divided them into four subgroups within genogroup I (subgroups 1A-D). Nine strains were in subgroup IA showing 69.9 76.4%nt identity with human PBV GI strainVS111 from the Netherlands. Strains in subgroup IB (n=2) had 91.4-91.7%nt identity with chicken PBV GI strain AVE 42v1 from Brazil. Two strains in subgroup IC had 72.3-74.2%nt identity with chicken PBV strain AVE 71v3 from Brazil. In subgroup ID, two strains showed 72.4-81.8%nt identity with chicken PBV GI strain AVE 57v2 from Brazil. Subgroup IC and ID were the most divergent. Five of the 15 strains were typed using capsid gene primers. They showed 32.6-33.4%nt and 39.5-41.3%aa identity with VS10 human PBV strain. These results indicate co-circulation of divergent strains of PBVs among Minnesota turkeys. PMID- 25530437 TI - Next-generation sequencing reveals low-dose effects of cationic dendrimers in primary human bronchial epithelial cells. AB - Gene expression profiling has developed rapidly in recent years with the advent of deep sequencing technologies such as RNA sequencing (RNA Seq) and could be harnessed to predict and define mechanisms of toxicity of chemicals and nanomaterials. However, the full potential of these technologies in (nano)toxicology is yet to be realized. Here, we show that systems biology approaches can uncover mechanisms underlying cellular responses to nanomaterials. Using RNA Seq and computational approaches, we found that cationic poly(amidoamine) dendrimers (PAMAM-NH2) are capable of triggering down-regulation of cell-cycle-related genes in primary human bronchial epithelial cells at doses that do not elicit acute cytotoxicity, as demonstrated using conventional cell viability assays, while gene transcription was not affected by neutral PAMAM-OH dendrimers. The PAMAMs were internalized in an active manner by lung cells and localized mainly in lysosomes; amine-terminated dendrimers were internalized more efficiently when compared to the hydroxyl-terminated dendrimers. Upstream regulator analysis implicated NF-kappaB as a putative transcriptional regulator, and subsequent cell-based assays confirmed that PAMAM-NH2 caused NF-kappaB dependent cell cycle arrest. However, PAMAM-NH2 did not affect cell cycle progression in the human A549 adenocarcinoma cell line. These results demonstrate the feasibility of applying systems biology approaches to predict cellular responses to nanomaterials and highlight the importance of using relevant (primary) cell models. PMID- 25530438 TI - Downregulation of connexin 32 attenuates hypoxia/reoxygenation injury in liver cells. AB - Gap junction intercellular communication is involved in ischemia-reperfusion (IR) injury of organs. Connexins are proteins that are critical to the function of gap junctions. To clarify the role of gap junctions in IR injury in liver cells, the function of gap junctions was modulated in an in vitro hypoxia/reoxygenation (H/R) model. BRL-3A rat liver cells, endogenously expressing connexins Cx32 and Cx43, were used to model the process of hepatic IR injury. Suppression of gap junction activity was achieved genetically, using Cx32-specific small interfering RNA (siRNA), or chemically, with pharmacological inhibitors, oleamide, and 18 alpha-GA. BRL-3A cells subjected to H/R exhibited reduced cell survival and pathologies indicative of IR injury. Cx32-specific siRNA, oleamide, and 18-alpha GA, respectively, decreased gap junction permeability, as assessed by the parachute assay. Pretreatment with Cx32-specific siRNA increased cell survival. Pretreatment with oleamide or 18-alpha-GA did not improve cell survival. Modulating gap junction by Cx32 gene silencing protected BRL-3A liver cells from H/R. PMID- 25530439 TI - A comparison of attitudes toward lesbians and gay men among students of helping professions in Crete, Greece: the cases of social work, psychology, medicine, and nursing. AB - This study investigated the attitudes toward lesbians and gay men among social work, psychology, medical, and nursing students in Crete, Greece, using Herek's ATLG scale. No respondents held completely heterosexist attitudes; only 1.6% held completely non-heterosexist attitudes. The 44.96 total ATLG score indicates a slightly positive attitude toward lesbians and gay men. Psychology students scored higher than all others on positive attitudes, followed by social work students, medical students, and nursing students. Gender, having lesbian or gay acquaintances or friends, and religiosity were significant factors influencing students' attitudes, while no impact on attitudes due to the effects of higher education could be discerned. Implications for curriculum design and teaching methods are discussed. PMID- 25530440 TI - Sierra Leone doctors call for better Ebola care for colleagues. PMID- 25530441 TI - Global health metrics needs collaboration and competition. PMID- 25530443 TI - Elucidating pH-dependent collagen triple helix formation through interstrand hydroxyproline-glutamic acid interactions. AB - Here, we describe systematic explorations into the molecular basis underlying hydroxyproline-mediated interstrand interactions on the triple-helical stability of collagen-mimetic peptides containing glutamic acid residues. Our studies reveal that the triple-helical stability of these peptides relies on the existence of interstrand interactions between hydroxyprolines and glutamic acid residues that are pH dependent. These unique interactions have been used to engineer collagen peptides that form triple helices on demand through pH control. PMID- 25530444 TI - (1)H chemical shift differences of Prelog-Djerassi lactone derivatives: DFT and NMR conformational studies. AB - This work reports an experimental and theoretical study of the conformational preferences of several Prelog-Djerassi lactone derivatives, to elucidate the (1)H NMR chemical shift differences in the lactonic core that are associated with the relative stereochemistry of these derivatives. The boat-like conformation of explains the anomalous (1)H chemical shift between H-5a and H-5b, in which the two methyl groups (C-8 and C-9) face H-5b, leading to its higher shielding effect. PMID- 25530445 TI - Obesity interacts with infectious mononucleosis in risk of multiple sclerosis. AB - BACKGROUND AND PURPOSE: The possible interaction between adolescent obesity and past infectious mononucleosis (IM) was investigated with regard to multiple sclerosis (MS) risk. METHODS: This report is based on two population-based case control studies, one with incident cases (1780 cases, 3885 controls) and one with prevalent cases (4502 cases, 4039 controls). Subjects were categorized based on adolescent body mass index (BMI) and past IM and compared with regard to occurrence of MS by calculating odds ratios with 95% confidence intervals (CIs) employing logistic regression. A potential interaction between adolescent BMI and past IM was evaluated by calculating the attributable proportion due to interaction. RESULTS: Regardless of human leukocyte antigen (HLA) status, a substantial interaction was observed between adolescent obesity and past IM with regard to MS risk. The interaction was most evident when IM after the age of 10 was considered (attributable proportion due to interaction 0.8, 95% CI 0.6-1.0 in the incident study, and attributable proportion due to interaction 0.7, 95% CI 0.5-1.0 in the prevalent study). In the incident study, the odds ratio of MS was 14.7 (95% CI 5.9-36.6) amongst subjects with adolescent obesity and past IM after the age of 10, compared with subjects with none of these exposures. The corresponding odds ratio in the prevalent study was 13.2 (95% CI 5.2-33.6). CONCLUSIONS: An obese state both impacts the cellular immune response to infections and induces a state of chronic immune-mediated inflammation which may contribute to explain our finding of an interaction between adolescent BMI and past IM. Measures taken against adolescent obesity may thus be a preventive strategy against MS. PMID- 25530446 TI - The effect of surface topography on the micellisation of hexadecyltrimethylammonium chloride at the silicon-aqueous interface. AB - Amphiphilic aggregation at solid-liquid interfaces can generate mesostructured micelles that can serve as soft templates. In this study we have simulated the self-assembly of hexadecyltrimethylammonium chloride (C16TAC) surfactants at the Si(1 0 0)- and Si(1 1 1)-aqueous interfaces. The surfactants are found to form semicylindrical micelles on Si(1 0 0) but hemispherical micelles on Si(1 1 1). This difference in micelle structure is shown to be a consequence of the starkly different surface topographies that result from the reconstruction of the two silicon surfaces, and reveals that micelle structure can be governed by epitaxial matching even with non-polar substrates. PMID- 25530448 TI - Evidence of ERBB3 gene association with rheumatoid arthritis predisposition. AB - AIM: ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3) gene was reported to be related with susceptibility to several autoimmune diseases. Taking this into account, we searched, for the first time, the ERBB3 gene association with rheumatoid arthritis liability. METHODS: One hundred and eighty-six RA patients and 147 controls were enrolled in the study. Polymerase chain reaction - restriction fragment length polymorphism assay was conducted in rs2271189 and rs2292239 genotyping. RESULTS: A statistically significant difference was observed in rs2271189 allele distribution between RA patients and controls (P = 0.029, odds ratio: 1.460, 95% confidence interval: 1.040-2.050). CONCLUSION: As far as we know, this is the first study which correlates ERBB3 gene with RA susceptibility, adding to a previous report of chromosome 12q13 association with RA liability. Furthermore, we confirmed that polymorphism rs2271189 can predict better ERBB3 gene association with disorders than the previously reported ERBB3 variants. More studies in other ethnic groups of patients are needed so as to reveal the extent of the herein observed genetic association. PMID- 25530447 TI - Weight training, aerobic physical activities, and long-term waist circumference change in men. AB - OBJECTIVE: Findings on weight training and waist circumference (WC) change are controversial. This study examined prospectively whether weight training, moderate to vigorous aerobic activity (MVAA), and replacement of one activity for another were associated with favorable changes in WC and body weight (BW). METHODS: Physical activity, WC, and BW were reported in 1996 and 2008 in a cohort of 10,500 healthy U.S. men in the Health Professionals Follow-up Study. Multiple linear regression models (partition/substitution) to assess these associations were used. RESULTS: After adjusting for potential confounders, a significant inverse dose-response relationship between weight training and WC change (P-trend <0.001) was observed. Less age-associated WC increase was seen with a 20-min/day activity increase; this benefit was significantly stronger for weight training ( 0.67 cm, 95% CI -0.93, -0.41) than for MVAA (-0.33 cm, 95% CI -0.40, -0.27), other activities (-0.16 cm, 95% CI -0.28, -0.03), or TV watching (0.08 cm, 95% CI 0.05, 0.12). Substituting 20 min/day of weight training for any other discretionary activity had the strongest inverse association with WC change. MVAA had the strongest inverse association with BW change (-0.23 kg, 95% CI -0.29, 0.17). CONCLUSIONS: Among various activities, weight training had the strongest association with less WC increase. Studies on frequency/volume of weight training and WC change are warranted. PMID- 25530449 TI - Recognizing lexical and semantic change patterns in evolving life science ontologies to inform mapping adaptation. AB - BACKGROUND: Mappings established between life science ontologies require significant efforts to maintain them up to date due to the size and frequent evolution of these ontologies. In consequence, automatic methods for applying modifications on mappings are highly demanded. The accuracy of such methods relies on the available description about the evolution of ontologies, especially regarding concepts involved in mappings. However, from one ontology version to another, a further understanding of ontology changes relevant for supporting mapping adaptation is typically lacking. METHODS: This research work defines a set of change patterns at the level of concept attributes, and proposes original methods to automatically recognize instances of these patterns based on the similarity between attributes denoting the evolving concepts. This investigation evaluates the benefits of the proposed methods and the influence of the recognized change patterns to select the strategies for mapping adaptation. RESULTS: The summary of the findings is as follows: (1) the Precision (>60%) and Recall (>35%) achieved by comparing manually identified change patterns with the automatic ones; (2) a set of potential impact of recognized change patterns on the way mappings is adapted. We found that the detected correlations cover ~66% of the mapping adaptation actions with a positive impact; and (3) the influence of the similarity coefficient calculated between concept attributes on the performance of the recognition algorithms. CONCLUSIONS: The experimental evaluations conducted with real life science ontologies showed the effectiveness of our approach to accurately characterize ontology evolution at the level of concept attributes. This investigation confirmed the relevance of the proposed change patterns to support decisions on mapping adaptation. PMID- 25530450 TI - Screening for gestational diabetes in the Lombardy region: A population-based study. AB - AIM: As the treatment of hyperglycaemia during pregnancy with diet or insulin reduces the risk of adverse maternal outcomes and perinatal complications, screening for gestational diabetes mellitus (GDM) is included, albeit to variable extents, in all guidelines of care for pregnant women. The aim of the present investigation was to estimate the proportion of pregnancies screened for GDM in Lombardy between 2007 and 2010, and to identify predictors of screening. METHODS: A retrospective cross-sectional study using regional healthcare utilization databases of Lombardy was conducted. The study included all residents of Lombardy without pregestational diabetes who delivered between 1 January 2007 and 31 December 2010. The proportion of pregnancies with at least one screening test for GDM was calculated, along with the odds ratios and 95% confidence intervals associated with selected covariates for GDM screening. RESULTS: Of the 362,818 pregnancies included in the sample, 30% were screened for GDM. The proportion of pregnancies screened increased slightly from 2007 (27%) to 2010 (33%) and with maternal age (from 28% among women<25 years to 32% among those >=35 years), and varied widely across local health management organizations (HMOs) of residence (range: 20% to 68%). Socioeconomic indicators (education, immigrant status), obstetric history and prepregnancy hypertension were independent predictors of GDM screening. CONCLUSION: The study finding of a low rate of pregnant women screened for GDM among residents of Lombardy supports the need for programmes to improve training of healthcare professionals, to raise women's awareness of GDM and to eliminate barriers to GDM screening. PMID- 25530451 TI - NADH-linked metabolic plasticity of MCF-7 breast cancer cells surviving in a nutrient-deprived microenvironment. AB - Characteristic of the tumor microenvironment are fluctuating gradients of reduced nutrient levels and released lactate. A fundamental issue is how tumor cells modulate their metabolic activity when both glucose and glutamine levels become limiting in the presence of high exogenous lactate. For functional analyses, the activities of pyruvate kinase, lactate dehydrogenase (LDH) and plasma membrane NADH oxidase (NOX) as well as cell growth were measured in breast cancer MCF-7 cells cultured in medium containing various concentrations of these metabolites. After 3 days at glucose concentrations below 2.5 mM, cell number was higher with 0.1 mM than with 1.0 mM glutamine, indicating that the glucose/glutamine balance is important for growth. On the other hand, NOX activity increased with increasing glucose >2.5 mM, but only with low glutamine (0.1 mM). Pyruvate kinase activity also increased, with LDH activity remaining 2-3-fold lower. Here NOX could have a complementary role in reoxidizing NADH for glycolysis. Exogenous lactate supported cell survival at limiting concentrations of glucose and glutamine while increasing NOX and pyruvate kinase activities as well as NADH levels. It is proposed that lactate supports cell survival by fuelling gluconeogenesis and/or the TCA cycle in mitochondria, from where NADH could be shuttled to the cytosol and reoxidized by NOX. Cell survival and the metabolic phenotype are thus interrelated to the dynamics of NADH and plasma membrane NOX activity, which are regulated by the balance of glucose/glutamine levels, in conjunction with lactate in a precarious tumor microenvironment. PMID- 25530452 TI - Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats. AB - Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 +/- 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 +/- 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 +/- 0.09 MUg/ml and 3.188 +/- 0.71 MUg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 +/- 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 +/- 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio. PMID- 25530453 TI - Chondrogenic regeneration using bone marrow clots and a porous polycaprolactone hydroxyapatite scaffold by three-dimensional printing. AB - Scaffolds play an important role in directing three-dimensional (3D) cartilage regeneration. Our recent study reported the potential advantages of bone marrow clots (MC) in promoting extracellular matrix (ECM) scaffold chondrogenic regeneration. The aim of this study is to build a new scaffold for MC, with improved characteristics in mechanics, shaping, and biodegradability, compared to our previous study. To address this issue, this study prepared a 3D porous polycaprolactone (PCL)-hydroxyapatite (HA) scaffold combined with MC (Group A), while the control group (Group B) utilized a bone marrow stem cell seeded PCL-HA scaffold. The results of in vitro cultures and in vivo implantation demonstrated that although an initial obstruction of nutrient exchange caused by large amounts of fibrin and erythrocytes led to a decrease in the ratio of live cells in Group A, these scaffolds also showed significant improvements in cell adhesion, proliferation, and chondrogenic differentiation with porous recanalization in the later culture, compared to Group B. After 4 weeks of in vivo implantation, Group A scaffolds have a superior performance in DNA content, Sox9 and RunX2 expression, cartilage lacuna-like cell and ECM accumulation, when compared to Group B. Furthermore, Group A scaffold size and mechanics were stable during in vitro and in vivo experiments, unlike the scaffolds in our previous study. Our results suggest that the combination with MC proved to be a highly efficient, reliable, and simple new method that improves the biological performance of 3D PCL-HA scaffold. The MC-PCL-HA scaffold is a candidate for future cartilage regeneration studies. PMID- 25530454 TI - The ingestion of a caffeinated energy drink improves jump performance and activity patterns in elite badminton players. AB - The aim of this study was to investigate the effectiveness of a caffeine containing energy drink to enhance physical and match performance in elite badminton players. Sixteen male and elite badminton players (25.4 +/- 7.3 year; 71.8 +/- 7.9 kg) participated in a double-blind, placebo-controlled and randomised experiment. On two different sessions, badminton players ingested 3 mg of caffeine per kg of body mass in the form of an energy drink or the same drink without caffeine (placebo). After 60 min, participants performed the following tests: handgrip maximal force production, smash jump without and with shuttlecock, squat jump, countermovement jump and the agility T-test. Later, a 45 min simulated badminton match was played. Players' number of impacts and heart rate was measured during the match. The ingestion of the caffeinated energy drink increased squat jump height (34.5 +/- 4.7 vs. 36.4 +/- 4.3 cm; P < 0.05), squat jump peak power (P < 0.05), countermovement jump height (37.7 +/- 4.5 vs. 39.5 +/ 5.1 cm; P < 0.05) and countermovement jump peak power (P < 0.05). In addition, an increased number of total impacts was found during the badminton match (7395 +/- 1594 vs. 7707 +/- 2033 impacts; P < 0.05). In conclusion, the results show that the use of caffeine-containing energy drink may be an effective nutritional aid to increase jump performance and activity patterns during game in elite badminton players. PMID- 25530455 TI - Heterologous expression of highly reducing polyketide synthase involved in betaenone biosynthesis. AB - A unique highly reducing polyketide synthase (HR-PKS) with a reductase domain was identified in a betaenone biosynthetic gene cluster. Successful heterologous expression and characterization of the HR-PKS and trans-acting enoyl reductase (ER) provide insights into the core structure formation with a decalin scaffold and allow reconstitution of the betaenone biosynthetic machinery. PMID- 25530457 TI - Voice dosimetry and monitoring, with emphasis on professional voice diseases: Critical review and framework for future research. AB - Professional voice has become an important issue in the field of occupational health. Similarly, voice diseases related to occupations gain interest in insurance medicine, particularly within the frame of specific insurance systems for occupational diseases. Technological developments have made possible dosimetry of voice loading in the work-place, as well as long-term monitoring of relevant voice parameters during professional activities. A critical review is given, with focus on the specificity of occupational voice use and on the point of view of insurance medicine. Remaining questions and suggestions for future research are proposed. PMID- 25530456 TI - Observational study of differences in head position for high notes in famous classical and non-classical male singers. AB - INTRODUCTION: Differences in classical and non-classical singing are due primarily to aesthetic style requirements. The head position can affect the sound quality. This study aimed at comparing the head position for famous classical and non-classical male singers performing high notes. METHOD: Images of 39 Western classical and 34 non-classical male singers during live performances were obtained from YouTube. Ten raters evaluated the frontal rotational head position (depression versus elevation) and transverse head position (retraction versus protraction) visually using a visual analogue scale. RESULTS: The results showed a significant difference for frontal rotational head position. DISCUSSION AND CONCLUSION: Most non-classical singers in the sample elevated their heads for high notes while the classical singers were observed to keep it around the neutral position. This difference may be attributed to different singing techniques and phonatory system adjustments utilized by each group. PMID- 25530458 TI - Seizure freedom score: a new simple method to predict success of epilepsy surgery. AB - OBJECTIVE: We aim to develop a new scale that predicts seizure outcomes after resective epilepsy surgery. METHODS: We retrospectively reviewed patients who underwent surgery for medically refractory epilepsy at our center between 1999 and 2012. Four predictive outcome indicators were selected: preoperative seizure frequency, history of generalized tonic-clonic seizures, brain magnetic resonance imaging (MRI), and epilepsy duration. A score of 0 or 1 was given if the indicator was associated with poor or good outcome, respectively. A seizure freedom score (SFS) was calculated by adding these four categories (total score ranged from 0 to 4). A modified SFS (m-SFS) was then calculated with two additional outcome indicators: invasive electroencephalography (EEG) evaluation (IEI) (performed or not performed) and lobe of resection (temporal vs. extratemporal), for a score ranging from 0 to 6. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom in the overall group. Statistical significance was tested using the log-rank test and comparison of 95% confidence intervals (CIs). RESULTS: The study population included 466 patients with 244 (52%) male. Seizure freedom rates were directly correlated with the SFS score: at 10 years, 36.9% of patients with SFS of 0 were seizure-free, as opposed to 45% for SFS = 1, 60% for SFS = 2, 72% for SFS 3 or above (p = 0.002). When calculated including the IEI and the localization, the score's performance improved: 24% of patients with a m-SFS of 0 were seizure-free at 10 years, as opposed to 38-59% for m-SFS = 1-3, and 75-79% for m-SFS of 4-6 (p < 0.001). SIGNIFICANCE: An easily measurable seizure freedom score could be a reliable tool to synthesize multiple seizure outcome predictors into a single simple score to predict postoperative seizure freedom. This tool will help with patient and family counseling and estimation of surgical candidacy at both early (SFS) and advanced (m-SFS) stages of a surgical evaluation. PMID- 25530459 TI - Importance of domain purity and molecular packing in efficient solution-processed small-molecule solar cells. AB - Connections are delineated between solar-cell performance, charge-carrier mobilities, and morphology in a highperformance molecular solar cell. The observations show that maximizing the relative phase purity and structural order while simultaneously limiting the domain size may be essential for achieving optimal solar-cell performances in solution-processed small-molecule solar cells . PMID- 25530460 TI - Reduction of Pain Sensitivity is Associated with the Response to Treatment in Women with Chronic Pelvic Pain. AB - OBJECTIVE: The objective of this study was to evaluate whether pain thresholds to electrical stimulation of the skin change in the response to treatment in women with chronic pelvic pain (CPP). METHODS: Fifty-eight women with persistent pelvic pain for at least 6 months, from a tertiary care setting, were included in this study. All women were evaluated before the therapeutic intervention and at 6 months of multidisciplinary treatment. To estimate the pain threshold, we used transcutaneous electrical nerve stimulation on the anterior surface of the nondominant arm. The intensity of clinical pain was estimated by a visual analog scale and by the McGill questionnaire. RESULTS: The mean of pain threshold increased from 14.2 to 17.4 after 6 months of treatment (P < 0.0001). The effect sizes of the increase of electrical pain threshold were 0.86 (95% CI, 0.38 to 1.34) in the group with pain reduction and 0.53 (95% CI, -0.08 to 1.15) in the group without pain reduction. CONCLUSION: The sensitivity to experimental pain was reduced after 6 months of multidisciplinary treatment for CPP. Our data provided additional evidence of central sensitization in women with CPP. PMID- 25530461 TI - Novel immune function for the TRPV1 channel in T lymphocytes. PMID- 25530462 TI - Heat capacity of molten halides. AB - The heat capacities of molten salts are very important for their practical use. Experimental investigation of this property is challenging because of the high temperatures involved and the corrosive nature of these materials. It is preferable to combine experimental investigations with empirical relationships, which allows for the evaluation of the heat capacity of molten salt mixtures. The isobaric molar heat capacities of all molten alkali and alkaline-earth halides were found to be constant for each group of salts. The value depends on the number of atoms in the salt, and the molar heat capacity per atom is constant for all molten halide salts with the exception of the lithium halides. The molar heat capacities of molten halides do not change when the anions are changed. PMID- 25530442 TI - Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. AB - BACKGROUND: Up-to-date evidence on levels and trends for age-sex-specific all cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. METHODS: We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. FINDINGS: Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100,000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. INTERPRETATION: For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade. FUNDING: Bill & Melinda Gates Foundation. PMID- 25530463 TI - Geographic inequity results in disparate mortality: a multivariate intent-to treat analysis of liver transplant data. AB - CONTEXT: The distribution of livers to listed transplant candidates shows substantial geographic inequity. OBJECTIVE: To compare mortality between the 11 UNOS (United Network of Organ Sharing) regions from the time of listing and to show that the geographic region impacts survival. DESIGN, SETTING, AND PATIENTS: We studied the data of 1930 adults listed with a Model for End-Stage Liver Disease (MELD) score of 18 for a liver transplant from March 1, 2002 through December 31, 2007. We calculated one- and three-yr survival rates and performed multivariate Cox regression analysis to determine significant risk factors for mortality. MAIN OUTCOME MEASURES: Patient survival from the time of listing for transplantation. RESULTS: Actual one-yr mortality rate from the time of listing ranged from 30.5% (Region 2) to 12.9% (Region 4). The three-yr mortality rate ranged from 42.0% (Region 2) to 21.6% (Region 4). Multivariate analysis showed a significant increase in mortality in Region 2 (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.21 to 1.83) and a significant decrease in mortality in Region 3 (OR, 0.74; 95% CI, 0.59 to 0.93). CONCLUSIONS: We found significant differences in one- and three-yr mortality rates among UNOS regions. Regional disparities significantly affect patient survival and result in national inequality. PMID- 25530464 TI - Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells. AB - Many biologically active compounds, including macromolecules that are used as various kinds of drugs, must be delivered to the interior of cell or organelles such as mitochondria or nuclei to achieve a therapeutic effect. However, very often, lipophilic cell membrane is impermeable for these molecules. A new method in the transport of macromolecules through the cell membrane is the one based on utilizing cell-penetrating peptides (CPPs). Invented 25 years ago, CPPs are currently the subject of intensive research in many laboratories all over the world. CPPs are short compounds comprising up to 30 amino acid residues, which penetrate the cell membrane but do not cause cell damage. Additionally, CPPs can transfer hydrophilic molecules (peptides, proteins, nucleic acids) which exceed their mass, and for which the cell membrane is generally impermeable. In this review, we concentrate on the cellular uptake mechanism of CPPs and a method of conjunction of CPPs to the transported molecules. We also highlight the potential of CPPs in delivering various kinds of macromolecules into cells, including compounds of therapeutic interest. PMID- 25530465 TI - Interrupted orthodontic force results in less root resorption than continuous force in human premolars as measured by microcomputed tomography. AB - INTRODUCTION: Root resorption is an undesirable but very frequently occurring sequel of orthodontic treatment. The aim of this study was to compare root resorption caused by either continuous (CF) or interrupted (IF) orthodontic force. MATERIAL AND METHODS: The study was performed on human subjects on 30 first upper and lower premolars scheduled for extraction for orthodontic reasons. During four weeks before extraction 12 teeth were subjected to either CF or IF. The force was generated by a segmental titanium-molybdenum alloy cantilever spring that was activated in buccal direction. Initially a force of 60 CentiNewton was used in both CF and IF groups, the force in the former, however, was reactivated every week for 4 weeks. There was no reactivation of force in the IF group after initial application. A morphometric analysis of root resorption was performed by microcomputed tomography and the extent of tooth movement was measured on stone casts. Furthermore, a Tartarate-Resistant Acidic Phosphatase activity (TRAP), the marker enzyme of osteoclasts and cementoclasts, was determined by histochemical method. The Mann-Whitney U test was used to compare the difference in measured parameters between treatment and control tooth groups. RESULTS: The number of resorption craters was significantly higher and their average volume almost twice as large in the CF compared to the IF group (p < 0.05). However, the distance of tooth displacement was similar for both groups. Cementoclasts were detected with the TRAP technique on the surface of two teeth only; both were subjected to continuous force. CONCLUSIONS: The use of IF leads to less destruction of root structure as opposed to continuous force while the same tooth movement was achieved. PMID- 25530466 TI - Pneumonic plague outbreak, Northern Madagascar, 2011. AB - Yersinia pestis, the causative agent of plague, is endemic to Madagascar, particularly to the central highlands. Although plague has not been previously reported in northern Madagascar, an outbreak of pneumonic plague occurred in this remote area in 2011. Over a 27-day period, 17 suspected, 2 presumptive, and 3 confirmed human cases were identified, and all 15 untreated 20 patients died. Molecular typing of Y. pestis isolated from 2 survivors and 5 Rattus rattus rat samples identified the Madagascar-specific 1.ORI3-k single-nucleotide polymorphism genotype and 4 clustered regularly interspaced short palindromic repeat patterns. This outbreak had a case-fatality rate of 100% for nontreated patients. The Y. pestis 1.ORI3-k single-nucleotide polymorphism genotype might cause larger epidemics. Multidrug-resistant strains and persistence of the pathogen in natural foci near human settlements pose severe risks to populations in plague-endemic regions and require outbreak response strategies. PMID- 25530467 TI - Key data elements for use in cost-utility modeling of biological treatments for rheumatoid arthritis. AB - OBJECTIVES: Economic evaluation is becoming more common and important as new biologic therapies for rheumatoid arthritis (RA) are developed. While much has been published about how to design cost-utility models for RA to conduct these evaluations, less has been written about the sources of data populating those models. The goal is to review the literature and to provide recommendations for future data collection efforts. METHODS: This study reviewed RA cost-utility models published between January 2006 and February 2014 focusing on five key sources of data (health-related quality-of-life and utility, clinical outcomes, disease progression, course of treatment, and healthcare resource use and costs). It provided recommendations for collecting the appropriate data during clinical and other studies to support modeling of biologic treatments for RA. RESULTS: Twenty-four publications met the selection criteria. Almost all used two steps to convert clinical outcomes data to utilities rather than more direct methods; most did not use clinical outcomes measures that captured absolute levels of disease activity and physical functioning; one-third of them, in contrast with clinical reality, assumed zero disease progression for biologic-treated patients; little more than half evaluated courses of treatment reflecting guideline-based or actual clinical care; and healthcare resource use and cost data were often incomplete. CONCLUSIONS: Based on these findings, it is recommended that future studies collect clinical outcomes and health-related quality-of-life data using appropriate instruments that can convert directly to utilities; collect data on actual disease progression; be designed to capture real-world courses of treatment; and collect detailed data on a wide range of healthcare resources and costs. PMID- 25530468 TI - Immediate incubation of blood cultures is critical to bring about better bacteremia outcomes. PMID- 25530469 TI - Genotype shift in human coronavirus OC43 and emergence of a novel genotype by natural recombination. AB - BACKGROUND: Human coronavirus (HCoV) OC43 is the most prevalent HCoV in respiratory tract infections. Its molecular epidemiological characterization, particularly the genotyping, was poorly addressed. METHODS: The full-length spike (S), RNA-dependent RNA polymerase (RdRp), and nucleocapsid (N) genes were amplified from each respiratory sample collected from 65 HCoV-OC43-positive patients between 2005 and 2012. Genotypes were determined by phylogenetic analysis. Recombination was analyzed based on full-length viral genome sequences. Clinical manifestations of each HCoV genotype infection were compared by reviewing clinical records. RESULTS: Sixty of these 65 samples belong to genotypes B, C and D. The remaining five strains had incongruent positions in the phylogenetic trees of the S, RdRp and N genes, suggesting a novel genotype emerging, designated as genotype E. Whole genome sequencing and bootscan analysis indicated that genotype E is generated by recombination between genotypes B, C and D. Temporal analysis revealed a sequential genotype replacement of C, B, D and E over the study period with genotype D being the dominant genotype since 2007. The novel genotype E was only detected in children younger than three years suffering from lower respiratory tract infections. CONCLUSIONS: Our results suggest that HCoV-OC43 genotypes are evolving. Such genotype shift may be an adapting mechanism for HCoV-OC43 maintaining its epidemic. PMID- 25530470 TI - Aeromonas spp as a causative agent for nosocomial infection in trauma patients. PMID- 25530471 TI - Bacterial patterning controlled by light exposure. AB - Patterning of multiple bacterial strains in one system is achieved by employing a single photo-activated antibiotic. Varying the light-exposure time results in zones with mixed and single populations. PMID- 25530472 TI - Potential role of ATP-binding cassette transporters against acaricides in the brown dog tick Rhipicephalus sanguineus sensu lato. AB - ATP-binding cassette (ABC) transporters have been shown to be involved in pesticide detoxification in arthropod vectors and are thought to contribute to the development of drug resistance. Little is currently known about the role they play in ticks, which are among the more important vectors of human and animal pathogens. Here, the role of ABC transporters in the transport of fipronil and ivermectin acaricides in the tick Rhipicephalus sanguineus (Ixodida: Ixodidae) was investigated. Larvae were treated with acaricide alone and acaricide in combination with a sub-lethal dose of the ABC transporter inhibitor cyclosporine A. The LC50 doses and 95% confidence intervals (CIs) estimated by mortality data using probit analysis were 67.930 p.p.m. (95% CI 53.780-90.861) for fipronil and 3741 p.p.m. (95% CI 2857-4647) for ivermectin. The pre-exposure of larvae to a sub-lethal dose of cyclosporine A reduced the LC50 dose of fipronil to 4.808 p.p.m. (95% CI 0.715-9.527) and that of ivermectin to 167 p.p.m. (95% CI 15-449), which increased toxicity by about 14- and 22-fold, respectively. The comparison of mortality data for each separate acaricide concentration showed the synergic effect of cyclosporine A to be reduced at higher concentrations of acaricide. These results show for the first time a strong association between ABC transporters and acaricide detoxification in R.sanguineus s.l. PMID- 25530473 TI - Influence of peripheral blood microparticles of pregnant women with preeclampsia on the phenotype of monocytes. AB - Platelet- and endothelial-derived microparticles influence the phenotype of peripheral blood leukocytes and induce production of proinflammatory cytokines. The influence of blood plasma microparticles of pregnant women on the surface receptor expression on intact or activated monocytes is still unexplored. This study was carried out to test the hypothesis that peripheral blood microparticles of women with normal pregnancy and women with preeclampsia have different influence on the expression of surface molecules on monocytes. The objective of the study was to evaluate the influence of blood plasma microparticles of pregnant women on the phenotypic properties of intact and activated THP-1 monocytes. Microparticles were isolated from peripheral blood samples of nonpregnant women, healthy pregnant women, and women with preeclampsia. THP-1 cell line was used as a model of monocytes. Microparticles of nonpregnant women decreased CD18, CD49d, and CD54 expressions and increased CD11c, CD31, CD47, and vascular endothelial growth factor receptor 2 expressions. Microparticles of healthy pregnant women increased CD18, CD54, and integrin beta7 expressions and decreased CD11a and CD29 expressions. Microparticles of women with preeclampsia decreased CD18 expression on tumor necrosis factor alpha (TNF-alpha)-activated TNR-1 cells. Microparticles of nonpregnant women, women with normal pregnancy, and pregnant women with preeclampsia decreased CD181 expression on intact and TNF alpha-activated THP-1 cells. Therefore, blood plasma microparticles of women with normal pregnancy and women with preeclampsia have different influences on the expression of surface molecules on THP-1 monocytes. PMID- 25530474 TI - The c-Jun N-terminal kinase signaling pathway mediates chrysotile asbestos induced alveolar epithelial cell apoptosis. AB - Exposure to chrysotile asbestos exposure is associated with an increased risk of mortality in combination with pulmonary diseases including lung cancer, mesothelioma and asbestosis. Multiple mechanisms by which chrysotile asbestos fibers induce pulmonary disease have been identified, however the role of apoptosis in human lung alveolar epithelial cells (AEC) has not yet been fully explored. Accumulating evidence implicates AEC apoptosis as a crucial event in the development of both idiopathic pulmonary fibrosis and asbestosis. The aim of the present study was to determine whether chrysotile asbestos induces mitochondria-regulated (intrinsic) AEC apoptosis and, if so, whether this induction occurs via the activation of mitogen-activated protein kinases (MAPK). Human A549 bronchoalveolar carcinoma-derived cells with alveolar epithelial type II-like features were used. The present study showed that chrysotile asbestos induced a dose- and time-dependent decrease in A549 cell viability, which was accompanied by the activation of the MAPK c-Jun N-terminal kinases (JNK), but not the MAPKs extracellular signal-regulated kinase 1/2 and p38. Chrysotile asbestos was also shown to induce intrinsic AEC apoptosis, as evidenced by the upregulation of the pro-apoptotic genes Bax and Bak, alongside the activation of caspase-9, poly (ADP-ribose) polymerase (PARP), and the release of cytochrome c. Furthermore, the specific JNK inhibitor SP600125 blocked chrysotile asbestos induced JNK activation and subsequent apoptosis, as assessed by both caspase-9 cleavage and PARP activation. The results of the present study demonstrated that chrysotile asbestos induces intrinsic AEC apoptosis by a JNK-dependent mechanism, and suggests a potential novel target for the modulation of chrysotile asbestos associated lung diseases. PMID- 25530475 TI - Intravenous lidocaine for neuropathic pain: a retrospective analysis of tolerability and efficacy. AB - OBJECTIVES: This study was designed to describe the efficacy and toxicity of intravenous (i.v.) lidocaine infusions for the treatment of neuropathic pain initially administered at a flat-rate trial dose of 500 mg over 30 minutes. SETTING: Academic, tertiary care hospital and infusion center. METHODS: Data were retrospectively collected and analyzed for efficacy, correlations between infusion rates with adverse effects, patterns of infusion rate adjustments, and infusion frequencies. RESULTS: The average rate for all infusions was 9.1 mg/min. Efficacy was seen in 45 patients (65%), and all but eight patients (12%) required infusion rate reductions from the initial test rate of 16.7 mg/min due to adverse effects. Fifty-five patients experienced adverse effects, with light-headedness as the most frequently reported side effect. CONCLUSION: The flat-dose trial used under the University of Wisconsin Health protocol for i.v. lidocaine administration did not cause serious adverse events, but few patients who responded to this trial dose tolerated subsequent infusions at the trial rate. Due to the lack of serious adverse events, administering an aggressive trial dose to elicit an analgesic response appears to be rational. If patients show a benefit from the trial dose, the need for reductions in infusion rate of subsequent doses should be anticipated. PMID- 25530476 TI - Cloning and expression of recombinant equine interleukin-3 and its effect on sulfidoleukotriene and cytokine production by equine peripheral blood leukocytes. AB - Interleukin-3 is a growth and differentiation factor for various hematopoietic cells. IL-3 also enhances stimulus-dependent release of mediators and cytokine production by mature basophils. Function of IL-3 has not been studied in horses because of lack of horse-specific reagents. Our aim was to produce recombinant equine IL-3 and test its effect on sulfidoleukotriene and cytokine production by equine peripheral blood leukocytes (PBL). Equine IL-3 was cloned, expressed in E. coli and purified. PBL of 19 healthy and 20 insect bite hypersensitivity (IBH) affected horses were stimulated with Culicoides nubeculosus extract with or without IL-3. Sulfidoleukotriene (sLT) production was measured in supernatants by ELISA and mRNA expression of IL-4, IL-13 and thymic stromal lymphopoietin (TSLP) assessed in cell lysate by quantitative real-time PCR. Recombinant equine IL-3 (req-IL-3) had a dose dependent effect on sLT production by stimulated equine PBL and significantly increased IL-4, IL-13 and TSLP expression compared to non primed cells. IL-3 priming significantly increased Culicoides-induced sLT production in IBH-affected but not in non-affected horses and was particularly effective in young IBH-affected horses (<= 3 years). A functionally active recombinant equine IL-3 has been produced which will be useful for future immunological studies in horses. It will also allow improving the sensitivity of cellular in vitro tests for allergy diagnosis in horses. PMID- 25530477 TI - Post-training, intrahippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice. AB - Converging evidence indicates that pharmacologically elevating histone acetylation using post-training, systemic or intrahippocampal, administration of histone deacetylase inhibitor (HDACi) can enhance memory consolidation processes in young rodents but it is not yet clear, whether such treatment is sufficient to prevent memory impairments associated with aging. To address this question, we used a 1-day massed spatial learning task in the water maze to investigate the effects of immediate post-training injection of the HDACi trichostatin A (TSA) into the dorsal hippocampus on long-term memory consolidation in 3-4 and 18-20 month-old mice. We show that TSA improved the 24 h-memory retention for the hidden platform location in young-adults, but failed to rescue memory impairments in older mice. The results further indicate that Young-TSA mice sacrificed 1 h after training had a robust increase in histone H4 acetylation in the dorsal hippocampal CA1 region (dCA1) and the dorsomedial part of the striatum (DMS), a structure important for spatial information processing. Importantly, TSA infusion in aged mice completely rescued altered H4 acetylation in the dCA1 but failed to alleviate age-associated decreased H4 acetylation in the DMS. Moreover, intrahippocampal TSA infusion produced concomitant decreases (in adults) or increases (in older mice) of acetylated histone levels in the ventral hippocampus (vCA1 and vCA3) and the lateral amygdala, two structures critically involved in stress and emotional responses. These data suggest that the failure of post training, intrahippocampal TSA injection to reverse age-associated memory impairments may be related to an inability to recruit appropriate circuit specific epigenetic patterns during early consolidation processes. PMID- 25530478 TI - Evolutionary perspectives on human height variation. AB - Human height is a highly variable trait, both within and between populations, has a high heritability, and influences the manner in which people behave and are treated in society. Although we know much about human height, this information has rarely been brought together in a comprehensive, systematic fashion. Here, we present a synthetic review of the literature on human height from an explicit evolutionary perspective, addressing its phylogenetic history, development, and environmental and genetic influences on growth and stature. In addition to presenting evidence to suggest the past action of natural selection on human height, we also assess the evidence that natural and sexual selection continues to act on height in contemporary populations. Although there is clear evidence to suggest that selection acts on height, mainly through life-history processes but perhaps also directly, it is also apparent that methodological factors reduce the confidence with which such inferences can be drawn, and there remain surprising gaps in our knowledge. The inability to draw firm conclusions about the adaptiveness of such a highly visible and easily measured trait suggests we should show an appropriate degree of caution when dealing with other human traits in evolutionary perspective. PMID- 25530479 TI - Evolution of cerebral cortico-cortical communication during visuomotor adaptation to a cognitive-motor executive challenge. AB - Cortical dynamics were examined during a cognitive-motor adaptation task that required inhibition of a familiar motor plan. EEG coherence between the motor planning (Fz) and left hemispheric region was progressively reduced over trials (low-beta, high-beta, gamma bands) along with faster, straighter reaching movements during both planning and execution. The major reduction in coherence (delta, low/high-theta, low/high-alpha bands) between Fz and the left prefrontal region during both movement planning and execution suggests gradual disengagement of frontal executive following its initial role in the suppression of established visuomotor maps. Also, change in the directionality of phase lags (delta, high alpha, high-beta, gamma bands) reflects a progressive shift from feedback to feedforward motor control. The reduction of cortico-cortical communication, particularly in the frontal region, and the strategic feedback/feedforward mode shift translated as higher quality motor performance. This study extends our understanding of the role of frontal executive beyond purely cognitive tasks to cognitive-motor tasks. PMID- 25530480 TI - Medial patellofemoral ligament reconstruction: clinical and radiographic results in a series of 90 cases. AB - INTRODUCTION: Among the numerous techniques available, medial patellofemoral ligament (MPFL) reconstruction is increasingly used for the surgical treatment of objective patellar instability. The main objective of the present study was to assess efficacy in preventing recurrence of patellar dislocation and in correcting radiographic patellar tilt. The study hypothesis was that MPFL reconstruction, isolated or with associated bone surgery, by restoring "favorable" graft anisometry, provides a good trade-off between patellar stability and absence of postoperative stiffness. MATERIALS AND METHODS: Eighty seven patients (90 reconstructions) presenting with objective patellar instability were prospectively included. The standardized procedure comprised MPFL reconstruction using the gracilis tendon. Femoral fixation used an interference screw in a blind tunnel between the adductor magnus tubercle and the medial epicondyle; patellar fixation used 2 anchors. Complementary distal bone graft was associated in 21 patients due to a preoperative tibial tubercle trochlear groove (TT-TG) distance exceeding 20mm or to patella alta. Functional IKDC and Kujala scores and radiographic measurement of patellar tilt and femoral tunnel position were assessed preoperatively and at end of follow-up. RESULTS: Mean follow-up was 24.3months (range, 6-49months). Three patients showed recurrence of patellar dislocation. Mean Kujala score rose from 53.88 preoperatively to 86.24 postoperatively, and mean real IKDC score from 45.15 to 73.92 (P<0.001). Patellar tilt decreased significantly between pre- and postoperative X-ray (P<0.001). DISCUSSION: MPFL gracilis reconstruction provides good clinical results and good radiologic correction of patellar tilt, making it a technique of choice in the treatment of objective patellar instability. LEVEL OF EVIDENCE: Level IV. Retrospective case series study. PMID- 25530481 TI - Surgical management of knee dislocations with ligament reconstruction associated with a hinged external fixator. AB - INTRODUCTION: Knee dislocations are defined as ligament injuries involving at least two of the four most important knee ligaments. Results from recent studies have shown a tendency towards improvement of the functional outcomes with use of an articulated external fixator during the postoperative period following multiligament reconstruction. Our hypothesis was that good knee stability and early gain of range of motion could be achieved with the use of the external fixator after ligament reconstructions. METHODS: Fourteen patients with knee dislocations were evaluated after multiligament reconstruction in association with use of a lateral monoplanar external fixator for six weeks. Reconstructions were performed using grafts from a tissue bank. Range of motion was measured after one, two, three, six, twelve months and at the final evaluation at a mean time of 49 months. The assessments were made using objective and subjective IKDC, Lysholm and Tegner scales. RESULTS: The mean scores were 71.7 for the subjective IKDC score, 81.5 for the Lysholm score. No patient was able to return to previous Tegner score. Out of the 45 ligament reconstructions performed, only four failed during the follow-up time. The mean range of motion of the knee presented a progressive increase from the first to the twelfth month, from 67.8 degrees to 115.7 degrees . Two cases of superficial infection on the site of the external fixator pins were observed. CONCLUSION: The use of an external fixator enabled early rehabilitation with range of motion gains starting from the first postoperative month, a low rate of reconstruction failure and minimal complications. Nevertheless, none of the patients returned to the level of activity prevailing prior to the injury. LEVEL OF EVIDENCE: Level IV, retrospective therapeutic case series. PMID- 25530482 TI - Revision single-bundle anterior cruciate ligament reconstruction with over-the top route procedure. AB - PURPOSE: In revision anterior cruciate ligament reconstruction (ACLR), the single stage technique and the over-the-top route (OTTR) procedure were usually selected for cases where the bone tunnel cannot be created at an anatomical position due to tunnel enlargement and overlap with the mal-positioned tunnel of primary reconstruction. The purpose of this study was to evaluate the clinical results of revision single-bundle ACL reconstruction using OTTR procedure and to compare the clinical results of OTTR procedure with those of anatomical single-bundle revision reconstruction (SBR). HYPOTHESIS: The results of OTTR procedure are equivalent to that of SBR. METHODS: Seventy-six revision ACL reconstruction knees from April 2002 to December 2012 were involved in our study. We focused on 21 knees which underwent surgery with SBR and 22 knees with OTTR using hamstring tendon. The clinical results were evaluated by means of the Lysholm score and the knee stability was assessed by the Lachman test, pivot-shift test and side-to side difference by KT-2000 pre-operatively and after 1 year post-operatively. AP translation and rotational laxity using a navigation system were evaluated before and after revision ACL reconstruction under anesthesia in 8 cases of OTTR and in 6 cases of SBR. RESULTS: There was no statistically significant difference between the OTTR and SBR regarding Lysholm score, Lachman test, pivot-shift test, ATT by KT-2000, and AP translation and rotational laxity with a navigation system. CONCLUSIONS: The clinical results of OTTR are almost equivalent to those of SBR. For the cases in which it is impossible to create the femoral tunnel in an anatomical position, OTTR is a valuable revision ACL reconstruction method. LEVEL OF EVIDENCE: Case-control study. Level III. PMID- 25530483 TI - Risk of hepatitis A decreased among Dutch travelers to endemic regions in 2003 to 2011. AB - We divided the number of travel-related hepatitis A cases notified in Dutch surveillance (2003-2011) by travel data obtained from an annual holiday survey to estimate the risk of hepatitis A among Dutch travelers. Of the 2,094 cases notified, 931 (44%) were imported. Morocco (n = 272, 29%), Turkey (n = 98, 11%), and Egypt (n = 87, 9%) accounted for the largest proportion of cases. Attack rates in returnees from high or intermediate endemic regions declined from 7.5 per 100,000 travelers (95% CI 6.7-8.4) in 2003-2005 to 3.5 (95% CI 3.0-4.0) in 2009-2011 (p < 0.01). Despite the decrease in risk, vaccination remains important, and routine risk monitoring should also be considered. PMID- 25530484 TI - Assessment of clonality of multisegmental main duct intraductal papillary mucinous neoplasms of the pancreas based on GNAS mutation analysis. AB - BACKGROUND: Main duct intraductal papillary mucinous neoplasms (MD-IPMNs) may occur in 1 or multiple segments of the pancreatic duct. Unlike multifocal branch duct (BD)-IPMNs, the clonality of multisegmental MD-IPMNs remains unclear. GNAS mutations are common and specific for IPMNs, and mutational assessment might be useful to determine the clonality of IPMNs as well as to detect high-risk IPMN with distinct ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]). Our aim was to clarify clonality using GNAS status in multisegmental MD-IPMNs. METHODS: We retrospectively reviewed the medical records of 70 patients with MD IPMN. Histologic subtypes and KRAS/GNAS mutations were investigated, and the clonal relationships among multisegmental MD-IPMNs were assessed. Mutational analysis was performed using high-resolution melting analysis and subsequent Sanger/pyrosequencing. RESULTS: Thirteen patients had multiple synchronous and/or metachronous lesions. Seven of these 13 patients had multiple MD-IPMNs; 3 had multiple MD-IPMNs and distinct BD-IPMNs; 1 had multiple MD-IPMNs and a distinct PDAC; 1 had a solitary MD-IPMN, BD-IPMN, and PDAC; and 1 had a solitary MD-IPMN and PDAC. KRAS/GNAS mutations were consistent in 10 of 11 multisegmental MD IPMNs, whereas MD-IPMNs, BD-IPMNs, and PDACs tended to show different mutational patterns. The frequency of malignant IPMNs was significantly higher in the multisegment cohort; malignant IPMNs constituted 90% (9/10) of the multiple cohort and 56% (32/57) of the solitary cohort (P = .04). Mutant GNAS was more frequently observed in the intestinal subtype (94%) than the others. CONCLUSION: MD-IPMNs can be characterized by monoclonal skip progression. Close attention should be paid to the possible presence of skip areas during or after partial pancreatectomy. PMID- 25530485 TI - Study of the population pharmacokinetic characteristics of nimorazole in head and neck cancer patients treated in the DAHANCA-5 trial. AB - AIMS: To study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma. MATERIALS AND METHODS: The pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables. RESULTS: HPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m(2)) was 32.2 +/- 0.9 MUg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 +/- 0.09 h and was not significantly altered as a function of dose. There was a well-established linear linear relationship between area under the concentration-time curve (AUC; mean 191 +/- 6 MUg.h/ml) and administered dose, especially when expressed as g/m(2). The mean apparent volume of distribution was 0.77 +/- 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77-0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients. CONCLUSION: The study supports the current nimorazole dose scheduling in patients. PMID- 25530486 TI - Oxytocin induces positive expectations about ambivalent stimuli (cognitive bias) in dogs. AB - Expectancy bias towards positive outcomes is a potential key to subjective well being, and has been widely investigated in different species. Here we test whether oxytocin, suggested to play a role in human optimism and emotional processing, influences how dogs judge ambivalent situations (in a cognitive bias paradigm). Subjects first learned in a location discrimination task that a bowl either contained food (at the 'positive' location) or was empty (at the 'negative' location). Then, after receiving oxytocin or placebo nasal spray, they were presented with the bowl located halfway between the positive and negative positions in communicative or non-communicative contexts (N=4*16). A Positive Expectancy Score was calculated for each subject using the latency to approach this ambivalent location. Compared to placebo groups, subjects that received oxytocin pretreatment showed a positive expectation bias in both contexts, and this effect was more pronounced in the communicative context. Our study provides the first evidence for the impact of oxytocin on dogs' judgement bias and also shows that the social-communicative nature of the task situation modulates the effect of oxytocin. PMID- 25530487 TI - Sex difference in the relationship between salivary testosterone and inter temporal choice. AB - Humans often prefer a small immediate reward to large reward in the future. This myopic tendency in inter-temporal choice is termed delay discounting, and has been the focus of intensive research in the past decades. Recent studies indicate that the neural regions underlying delay discounting are influenced by the gonadal steroids. However, the specific relationship between the testosterone levels and delay discounting is unclear at this point, especially in females. The present study investigated the relationship between salivary testosterone concentrations and discounting rates in delay- and probability-discounting tasks with healthy males and females. The results revealed a positive correlation between testosterone concentrations and delay-discounting rates in females and a negative correlation in males. Testosterone concentrations were unrelated to probability-discounting rates. Although causal effects of testosterone cannot be certain in this correlational study, if testosterone directly influenced this behavior, observed sex differences in delay discounting may be evidence of a curvilinear effect of testosterone. Alternatively, the findings may reflect inverse pattern of responsiveness to testosterone between male and female neural systems, or basic sex-difference in the neural mechanism underlying delay discounting independent of testosterone itself. PMID- 25530491 TI - Mitochondrial changes in endometrial carcinoma: possible role in tumor diagnosis and prognosis (review). AB - Endometrial carcinoma (EC) is a solid neoplasia for which a role for mitochondria in cancer progression is currently emerging and yet represents a diagnostic and prognostic challenge. EC is one of the most frequently occurring gynecological malignancies in the Western world whose incidence has increased significantly during the last decades. Here, we review the literature data on mitochondrial changes reported in EC, namely, mitochondrial DNA (mtDNA) mutations, increase in mitochondrial biogenesis and discuss whether they may be used as new cancer biomarkers for early detection and prognosis of this cancer. PMID- 25530492 TI - Mitochondrial calcium handling in normotensive and spontaneously hypertensive rats: correlation with systolic blood pressure levels. AB - The aim was to study the mitochondrial Ca(2+) handling of mitochondria isolated from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) hearts and to establish a possible correlation with systolic blood pressure (SBP). Mitochondrial swelling after Ca(2+) addition, Ca(2+)-retention capacity (CRC) by calcium green method, and membrane potential (DeltaPsim) were assessed. SBP was 124+/-1 (WKY) and 235+/-6mmHg (SHR). CRC, Ca(2+) response and DeltaPsim were lower in SHR than WKY mitochondria. The conclusion is: the more depolarized state of SHR than WKY mitochondria results in an abnormal Ca(2+) handling and this event is closely associated with the SBP. PMID- 25530493 TI - Comparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegans. AB - Single-gene mutations that disrupt mitochondrial respiratory chain function in Caenorhabditis elegans change patterns of protein expression and metabolites. Our goal was to develop useful molecular fingerprints employing adaptable techniques to recognize mitochondrial defects in the electron transport chain. We analyzed mutations affecting complex I, complex II, or ubiquinone synthesis and discovered overarching patterns in the response of C. elegans to mitochondrial dysfunction across all of the mutations studied. These patterns are in KEGG pathways conserved from C. elegans to mammals, verifying that the nematode can serve as a model for mammalian disease. In addition, specific differences exist between mutants that may be useful in diagnosing specific mitochondrial diseases in patients. PMID- 25530495 TI - Effect of silver nanoparticles and hydroxyproline, administered in ovo, on the development of blood vessels and cartilage collagen structure in chicken embryos. AB - It has been considered that concentrations of certain amino acids in the egg are not sufficient to fully support embryonic development of modern broilers. In this study we evaluated embryo growth and development with particular emphasis on one of the major components of connective tissue, collagen. Experiments were performed on Ross 308 chicken embryos from 160 fertilised eggs. Experimental solutions of silver nanoparticles (Ag), hydroxyproline solution (Hyp) and a complex of silver nanoparticles with hydroxyproline (AgHyp) were injected into albumen, and embryos were incubated until day 20. An assessment of the mass of embryo and selected organs was carried out followed by measurements of the expression of the key signalling factors' fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-A (VEGF-A). Finally, an evaluation of collagen microstructure using scanning electron microscopy was performed. Our results clearly indicate that Hyp, Ag and AgHyp administered in ovo to chicken embryos did not harm embryos. Comparing to the control group, Hyp, Ag and the AgHyp complex significantly upregulated expression of the FGF-2 at the mRNA and protein levels. Moreover, Hyp, Ag and, in particular, the complex of AgHyp significantly increased blood vessel size, cartilage collagen fibre lattice size and bundle thickness. The general conclusion from this study is that AgHyp treatment may help to build a stronger and longer lasting form of collagen fibres. PMID- 25530496 TI - Hairpin DNA as a biobarcode modified on gold nanoparticles for electrochemical DNA detection. AB - Hairpin DNA (hpDNA) as a novel biobarcode was conjugated with gold nanoparticles (AuNPs) and a reporter DNA (rpDNA) to form hpDNA/AuNP/rpDNA nanoparticles for the detection of an oligonucleotide sequence associated with Helicobacter pylori as a model target. The rpDNA is complementary to about a half-portion of the target DNA sequence (tDNA). A capture DNA probe (cpDNA), complementary to the other half of the tDNA, was immobilized on the surface of a gold electrode. In the presence of tDNA, a sandwich structure of (hpDNA/AuNP/rpDNA)/tDNA/cpDNA was formed on the electrode surface. The differential pulse voltammetry (DPV) detection was based on [Ru(NH3)5(3-(2-phenanthren-9-yl-vinyl)-pyridine)](2+), an electroactive complex that binds to the sandwich structure by its intercalation with the hpDNA and the double-stranded DNA (dsDNA) of the sandwich structure. The several factors--high density of biobarcode hpDNA on the surface of AuNPs, multiple electroactive complex molecules intercalated with each hpDNA and dsDNA molecule, and the intercalation binding mode of the electroactive complex with the DNA sandwich structure--contribute to the DNA sensor with highly selective and sensitive sensing properties. The DNA sensor exhibited a detection limit of 1 * 10(-15) M (i.e., 1 fM), the DNA levels in physiological samples, with linearity down to 2 * 10(-15) M. It can differentiate even one single mismatched DNA from the complementary tDNA. This novel biobarcode-based DNA sensing approach should provide a general platform for development of direct, simple, repetitive, sensitive, and selective DNA sensors for various important applications in analytical, environmental, and clinical chemistry. PMID- 25530497 TI - MicroRNA expression and its clinical implications in Ewing's sarcoma. AB - Ewing's sarcoma (EWS) is the second most common primary bone cancer, and is a predominant childhood malignant disease. Due to limited understanding of its pathogenesis and frequent occurrence of resistance to conventional types of treatment, its management remains difficult, and mortality is frequent. Development of EWS is a multistep process involving genetic and epigenetic alterations of protein-coding proto-oncogenes and tumour-suppressor genes. MicroRNAs (miRNAs) have recently been discovered as a new category of non-protein coding; small RNA molecules that regulate gene expression at the post transcriptional level. Substantial numbers of deregulated miRNAs have been documented in EWS and their biological significance has been confirmed in multiple functional experiments. Several studies have confirmed involvement of miRNAs in various steps of EWS pathogenesis, from occurrence to metastasis. Functionally, miRNA dysregulation may promote cell-cycle progression, confer resistance to apoptosis, and enhance invasiveness and metastasis. These miRNAs have opened a novel field in cancer research with potential clinical utilization for screening, diagnosis, prognostics and prediction of response to treatment. Elucidating biological aspects of miRNA dysregulation may help better understand pathogenesis of EWS and promote development of miRNA directed-therapeutics against it. PMID- 25530498 TI - Grooming and cultural socialization: a mixed method study of caregiving practices in Burma (Myanmar) and the United States. AB - Grooming behaviours are thought to be a crucial aspect of parenting and integral to the sociality of non-human mammals, but there have been few empirical studies on how grooming might be relevant to parenting and socialization processes in humans. Study 1 is a quantitative cross-cultural comparison of grooming practices in two cultural settings: an urban centre in Burma (Myanmar) and an urban centre in the United States. The study uses naturalistic video data of 57 families to analyse grooming behaviours directed at children. A broad range of ages was sampled in each culture to examine the developmental trajectory of grooming behaviours. Results indicate that significant cultural differences exist between Burma and the United States, with Burmese children being groomed by their caregivers more often than U.S. children. Results also indicate that cultural differences in grooming practices begin early and remain constant across age. An unexpected finding was that Burmese families were more variable in their behaviour than U.S. families. Study 2 attempts to explain this variability by using ethnography to describe how sociodemographic changes in Burma are leading to changes in parental values and socialization practices in the schools, but how embodied primary care in the homes appear resistant to change. PMID- 25530499 TI - Pharmacological inhibition of MIF interferes with trophoblast cell migration and invasiveness. AB - INTRODUCTION: Macrophage migration inhibitory factor (MIF) is expressed by villous and extravillous cytotrophoblast. This study was aimed to investigate functional relevance of MIF for human trophoblast. METHODS: MIF mRNA and protein were documented in cytotrophoblast (CT) and extravillous trophoblast cell line HTR-8/SVneo by RT-PCR, Western blot (WB), and immunocytochemistry. Recombinant human MIF (rhMIF), or its specific inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5 dihydro-5-isoxazole acetic acid methyl ester (ISO-1) were used in Wound healing migration and Matrigel invasion tests. Potential effectors, integrin subunits and matrix metalloproteinases (MMP) were studied using WB and gelatin zymography, respectively. RESULTS: Blocking endogenous MIF by ISO-1 decreased HTR-8/SVneo cell migration dose dependently, most significantly with 200 MUg/ml to 65% of control. Supplementation with rhMIF induced a significant stimulation to 129% of control with 200 ng/ml. In CT cell invasion test, ISO-1 at 200 MUg/ml reduced invasion to 59% of control, while rhMIF (200 ng/ml) induced stimulation to 159% of control. In HTR-8/SVneo cells, invasion was significantly inhibited by ISO-1 to 40%, and increased to 150% of control by rhMIF (200 ng/ml). Integrin alpha1 was reduced by ISO-1 in both cell types, while integrins alpha5 and beta1 were not changed. Addition of rhMIF increased integrin alpha1. In the presence of ISO 1, levels of MMP-2 and MMP-9 were reduced in CT and HTR-8/SVneo, while rhMIF stimulated MMP-2 in CT and MMP-9 in HTR-8/SVneo cells. CONCLUSION: Reported findings provide the first insight into the cellular effects of MIF in human trophoblast, which acts to promote cell migration and invasion. PMID- 25530500 TI - How the Eyes Tell Lies: Social Gaze During a Preference Task. AB - Social attention is thought to require detecting the eyes of others and following their gaze. To be effective, observers must also be able to infer the person's thoughts and feelings about what he or she is looking at, but this has only rarely been investigated in laboratory studies. In this study, participants' eye movements were recorded while they chose which of four patterns they preferred. New observers were subsequently able to reliably guess the preference response by watching a replay of the fixations. Moreover, when asked to mislead the person guessing, participants changed their looking behavior and guessing success was reduced. In a second experiment, naive participants could also guess the preference of the original observers but were unable to identify trials which were lies. These results confirm that people can spontaneously use the gaze of others to infer their judgments, but also that these inferences are open to deception. PMID- 25530501 TI - Light control of cellular processes by using photocaged abscisic acid. AB - Abscisic acid (ABA) was chemically modified with a photocaging group to promote photo-induced protein dimerization. This photocontrolled chemically induced dimerization (CID) method based on caged ABA enables dose-dependent light regulation of cellular processes, including transcription, protein translocation, signal transduction, and cytoskeletal remodeling, without the need to perform extensive protein engineering. Caged ABA can be easily modified to respond to different wavelengths of light. Consequently, this strategy should be applicable to the design of light-regulated protein dimerization systems and potentially be used orthogonally with other light-controlled CID systems. PMID- 25530502 TI - Impact of a Neonatal-Bereavement-Support DVD on Parental Grief: A Randomized Controlled Trial. AB - This study tested the effect of a neonatal-bereavement-support DVD on parental grief after their baby's death in a Neonatal Intensive Care Unit compared with standard bereavement care (controls). Following a neonatal death, the authors measured grief change from a 3- to 12-month follow-up using a mixed-effects model. Intent-to-treat analysis was not significant, but only 18 parents selectively watched the DVD. Thus, we subsequently compared DVD viewers with DVD nonviewers and controls. DVD viewers reported higher grief at 3-month interviews compared with DVD nonviewers and controls. Higher grief at 3 months was negatively correlated with social support and spiritual/religious beliefs. These findings have implications for neonatal-bereavement care. PMID- 25530504 TI - Functionalization of platinum nanoparticles with L-proline: simultaneous enhancements of catalytic activity and selectivity. AB - In this work we present the successful application of functionalizing Pt nanoparticles (NPs) with hydrophilic organic ligands as a strategy for enhancing their catalytic activity and selectivity. In the first step, Pt NPs were prepared by a colloidal approach and subsequently functionalized in a separate synthesis step with L-proline (PRO). The functionalized NPs were supported onto Al2O3 and investigated as heterogeneous catalysts for the selective hydrogenation of acetophenone. Whereas significant amounts of side products are formed by supported, "unprotected" (ligand-free) NPs, the PRO-functionalized Pt NPs are highly chemoselective even at 100% conversion. Experiments under kinetically controlled conditions reveal that this high chemoselectivity is not accompanied by a loss of catalytic activity. In contrast, an enhanced rate toward the desired product was found for PRO-Pt in comparison to the "unprotected" Pt NPs. This finding demonstrates that the use of ligands in heterogeneous catalysis allows for simultaneous enhancements of activity and selectivity. PMID- 25530503 TI - Sequence conservation, phylogenetic relationships, and expression profiles of nondigestive serine proteases and serine protease homologs in Manduca sexta. AB - Serine protease (SP) and serine protease homolog (SPH) genes in insects encode a large family of proteins involved in digestion, development, immunity, and other processes. While 68 digestive SPs and their close homologs are reported in a companion paper (Kuwar et al., in preparation), we have identified 125 other SPs/SPHs in Manduca sexta and studied their structure, evolution, and expression. Fifty-two of them contain cystine-stabilized structures for molecular recognition, including clip, LDLa, Sushi, Wonton, TSP, CUB, Frizzle, and SR domains. There are nineteen groups of genes evolved from relatively recent gene duplication and sequence divergence. Thirty-five SPs and seven SPHs contain 1, 2 or 5 clip domains. Multiple sequence alignment and molecular modeling of the 54 clip domains have revealed structural diversity of these regulatory modules. Sequence comparison with their homologs in Drosophila melanogaster, Anopheles gambiae and Tribolium castaneum allows us to classify them into five subfamilies: A are SPHs with 1 or 5 group-3 clip domains, B are SPs with 1 or 2 group-2 clip domains, C, D1 and D2 are SPs with a single clip domain in group-1a, 1b and 1c, respectively. We have classified into six categories the 125 expression profiles of SP-related proteins in fat body, brain, midgut, Malpighian tubule, testis, and ovary at different stages, suggesting that they participate in various physiological processes. Through RNA-Seq-based gene annotation and expression profiling, as well as intragenomic sequence comparisons, we have established a framework of information for future biochemical research of nondigestive SPs and SPHs in this model species. PMID- 25530505 TI - The Use of Cuff Weights for Aquatic Gait Training in People Post-Stroke with Hemiparesis. AB - BACKGROUND AND PURPOSE: This study aimed to examine how spatiotemporal and kinematic gait variables are influenced by the application of a cuff weight during aquatic walking in people post-stroke. The secondary purpose was to compare the differences in gait responses between the placements of cuff weights on the proximal (knee weight) and distal end (ankle weight) of the shank. METHODS: Twenty-one participants post-stroke with hemiparesis aged 66.3 +/- 11.3 years participated in a cross-sectional comparative study. Participants completed two aquatic walking trials at their self-selected maximum walking speed across an 8-m walkway under each of the three conditions: 1) walking with a knee weight; 2) walking with an ankle weight; and 3) walking with no weight. Cuff weights were worn on the paretic leg of each participant. Gait speed, cadence, step width and joint kinematics of the hip, knee and ankle joints were recorded by a customized three-dimensional underwater motion analysis system. RESULTS: Mean aquatic walking speeds significantly increased with the use of cuff weights when compared to walking with no weight. Changes in gait variables were found in the non paretic leg with the addition of weight, while no significant changes were found in the paretic leg. CONCLUSION: The results suggest that the use of additional weight can be helpful if the goal of gait training is to improve walking speed of people post-stroke during pool floor walking. However, it is interesting to note that changes in gait variables were not found in the paretic limb where favourable responses were expected to occur. PMID- 25530506 TI - Highly efficient tandem polymer solar cells with a photovoltaic response in the visible light range. AB - Highly efficient polymer solar cells with a tandem structure are fabricated by using two excellent photovoltaic polymers and a highly transparent intermediate recombination layer. Power conversion -efficiencies over 10% can be realized with a photovoltaic response within 800 nm. PMID- 25530507 TI - PPARbeta/delta and gamma in a rat model of Parkinson's disease: possible involvement in PD symptoms. AB - Parkinson's disease is one of the most common neurologic disorder, affecting about 1-4% of persons older than 60 years. Among the proposed mechanisms of PD generation, free radical damage is believed to play a pivotal role in the development and/or progression of the disease. Recently, PPARs, a class of transcription factors involved in several pathways both in physiological and pathological conditions, have been linked by us and others to neurodegeneration. Particularly, PPARgamma and its ligands have been indicated as potential therapeutic targets for the treatment of several pathological conditions associated with neuroinflammation within the CNS. The anti-inflammatory function of PPARgamma has attracted attention since agonists exert a broad spectrum of protective effects in several animal models of neurological diseases, including psychiatric diseases. On the other hand a detrimental role for PPARbeta/delta has been proposed in Alzheimer, being closely related to the decrease of BDNF and Trkfl. On these bases, in this work we used a 6-OHDA hemi-lesioned rat model, inducing loss of dopaminergic neurons, to study the effects of the lesion at three time points from the lesion (1, 2, and 3 weeks), in relevant areas of PD motor symptoms, such as substantia nigra and globus pallidus and in the area of reward and mood control, the nucleus accumbens. In particular, it was studied: (i) the expression of BDNF and its downstream signals; (ii) the modulation of PPARs levels. The results obtained indicate the possible use of a dual PPARbeta/delta antagonist/PPARgamma agonist to counteract primary and secondary signs of PD neurodegeneration. PMID- 25530508 TI - High prevalence of inclusion body myositis in Norway; a population-based clinical epidemiology study. AB - BACKGROUND AND PURPOSE: Knowledge about the occurrence of sporadic inclusion body myositis (sIBM) in the general population is limited. Here, our aim was to identify and characterize every sIBM patient living in southeast Norway (population 2.64 million) from 2003 to 2012. METHOD: Two sIBM case finding strategies were applied. First, all hospital databases in southeast Norway were screened to identify cases with sIBM-compatible International Classification of Diseases 10 (ICD-10) codes. These cases were then manually chart reviewed. Secondly, all muscle histology reports encoded with inflammation were independently reviewed. Finally, cases were classified according to the 1997 and the 2011 European Neuro-Muscular Centre (ENMC) Research Diagnostic Criteria for sIBM. RESULTS: The combined case finding strategy identified 3160 patients with sIBM compatible ICD-10 codes, and a largely overlapping cohort of 500 patients having muscle biopsies encoded with inflammation. Detailed retrospective review of chart and histology data showed that 95 patients met the 2011 ENMC sIBM criteria and 92 met the 1997 criteria. Estimated point prevalence of sIBM was 33/1 000 000, equal with both criteria sets. Mean age at diagnosis was 66.9 years and mean diagnostic delay was 5.6 years. Chart review revealed higher frequencies of dysphagia (94% vs. 65%) and anti-Sjogren syndrome A antibodies (39% vs. 12%) in female sIBM patients (n = 40) than in males. Coexisting rheumatic diseases were present in 25% of sIBM cases, with Sjogren's syndrome in 10%. CONCLUSION: An estimated point prevalence of sIBM seven times higher than previously observed in Europe is reported. Our data show considerable diagnostic delay, a major challenge with new sIBM treatments in the pipeline. PMID- 25530510 TI - Prospective comparisons of femoral tunnel enlargement with 3 different postoperative immobilization periods after double-bundle anterior cruciate ligament reconstruction with hamstring grafts. AB - PURPOSE: To determine the effect of differing postoperative immobilization periods on femoral bone tunnel enlargement and clinical outcome after double bundle anterior cruciate ligament (ACL) reconstruction with hamstring grafts. METHODS: Fifty-one patients undergoing primary double-bundle ACL reconstruction with hamstring grafts were divided into 3 postoperative immobilization protocol groups: 2-day immobilization with the knee in 20 degrees of flexion postoperatively (group A, n = 18); 1-week immobilization (group B, n = 17); and 2 week immobilization (group C, n = 16). Bone tunnel enlargement was determined by computed digital radiographs taken on the first postoperative day and at 24 months in the anteroposterior (AP) and lateral views. Each tunnel diameter was shown as a percentage of the maximum joint width of the proximal tibia on the AP view or a percentage of the maximum diameter of the patella on the lateral view. To determine the incidence of tunnel enlargement, a percentage diameter change of more than 10% was defined as an enlarged tunnel. The standard clinical evaluation was also performed. This study used nonrandomized procedures. RESULTS: In each group there were no significant differences in the incidence and magnitude of anteromedial and posterolateral bone tunnel enlargement on both the AP and lateral views (1-factor analysis of variance). Group C showed significantly less muscle strength in knee extension compared with the contralateral knee (85.3% +/- 18.4%) than group A (93.7% +/- 13.1%, P = .049) and group B (96.8% +/- 12.9%, P = .044). CONCLUSIONS: This prospective radiographic study showed that femoral bone tunnel enlargement, in both the anteromedial and posterolateral tunnels, may occur after double-bundle ACL reconstruction with hamstring grafts despite different postoperative immobilization periods, with no significant difference in the incidence and magnitude among groups with differing postoperative immobilization periods. In addition, a 2-week immobilization period after surgery showed harmful effects, such as significantly less quadriceps muscle strength. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 25530509 TI - The role of fibers in the femoral attachment of the anterior cruciate ligament in resisting tibial displacement. AB - PURPOSE: The purpose was to clarify the load-bearing functions of the fibers of the femoral anterior cruciate ligament (ACL) attachment in resisting tibial anterior drawer and rotation. METHODS: A sequential cutting study was performed on 8 fresh-frozen human knees. The femoral attachment of the ACL was divided into a central area that had dense fibers inserting directly into the femur and anterior and posterior fan-like extension areas. The ACL fibers were cut sequentially from the bone: the posterior fan-like area in 2 stages, the central dense area in 4 stages, and then the anterior fan-like area in 2 stages. Each knee was mounted in a robotic joint testing system that applied tibial anteroposterior 6-mm translations and 10 degrees or 15 degrees of internal rotation at 0 degrees to 90 degrees of flexion. The reduction of restraining force or moment was measured after each cut. RESULTS: The central area resisted 82% to 90% of the anterior drawer force; the anterior fan-like area, 2% to 3%; and the posterior fan-like area, 11% to 15%. Among the 4 central areas, most load was carried close to the roof of the intercondylar notch: the anteromedial bundle resisted 66% to 84% of the force and the posterolateral bundle resisted 16% to 9% from 0 degrees to 90 degrees of flexion. There was no clear pattern for tibial internal rotation, with the load shared among the posterodistal and central areas near extension and mostly the central areas in flexion. CONCLUSIONS: Under the experimental conditions described, 66% to 84% of the resistance to tibial anterior drawer arose from the ACL fibers at the central-proximal area of the femoral attachment, corresponding to the anteromedial bundle; the fan-like extension fibers contributed very little. This work did not support moving a single-bundle ACL graft to the side wall of the notch or attempting to cover the whole attachment area if the intention was to mimic how the natural ACL resists tibial displacements. CLINICAL RELEVANCE: There is ongoing debate about how best to reconstruct the ACL to restore normal knee function, including where is the best place for ACL graft tunnels. This study found that the most important area on the femur, in terms of resisting displacement of the tibia, was in the central anterior part of the femoral ACL attachment, near the roof of the intercondylar notch. The testing protocol did not lead to data that would support using a large ACL graft tunnel that attempts to cover the whole natural femoral attachment area. PMID- 25530511 TI - Influence of capsular repair versus unrepaired capsulotomy on 2-year clinical outcomes after arthroscopic hip preservation surgery. AB - PURPOSE: The primary objective of this study was to determine whether capsular management technique influences clinical outcomes at a minimum of 2 years after arthroscopic hip preservation surgery. METHODS: A retrospective review of prospectively collected data was conducted to determine the relative influence of 2 capsular management strategies on clinical outcomes: unrepaired capsulotomy (group A) and capsular repair (group B). Four hundred three patients who had undergone arthroscopic hip preservation surgery met the inclusion criteria and had 2-year outcome data available. All patients completed 4 patient-reported outcome (PRO) questionnaires preoperatively and at a minimum of 2 years' follow up. These included the Hip Outcome Score-Activities of Daily Living (HOS-ADL) and Hip Outcome Score-Sport-Specific Subscale (HOS-SSS) subsets, Non-Arthritic Hip Score (NAHS), and modified Harris Hip Score (mHHS). RESULTS: Group A included 235 patients and group B, 168. The mean age of all patients at final follow-up was 36.9 years. Patients in group A were significantly older (42.3 years v 29.4 years, P < .0001) and had a significantly higher body mass index (26.8 kg/m(2)v 22.9 kg/m(2), P < .0001) compared with group B. In addition, female patients were more likely than male patients to undergo capsular repair (136 female patients v 32 male patients, P < .0001). Patients in group A also showed greater chondral damage by acetabular labrum articular disruption classification (P = .0081) and reduced preoperative PROs (HOS-ADL of 60.5 v 66.0, P = .087; HOS-SSS of 37.0 v 46.4, P = .0002; NAHS of 54.6 v 62.2, P < .0001; mHHS of 58.7 v 64.4, P = .0009; and visual analog scale score of 6.3 v 5.84, P = .028). All PROs showed statistically significant improvements for both groups at a minimum follow-up of 2 years (HOS-ADL, 60.5 to 82.2 in group A and 66 to 86.1 in group B; HOS-SSS, 36.9 to 67.3 and 46.4 to 71.2, respectively; NAHS, 54.6 to 79 and 62.2 to 82.8, respectively; visual analog scale score, 6.3 to 3.1 and 5.8 to 2.9, respectively; and mHHS, 58.7 to 81 and 64.4 to 83.8, respectively; P < .0001 for all differences). Furthermore, group B showed greater overall improvements than group A for the HOS-ADL (P = .03) and NAHS (P = .03) on uncorrected univariate analysis, but significance was lost once we controlled for confounding variables. CONCLUSIONS: Arthroscopic capsular repair, used in conjunction with arthroscopic hip preservation surgery, appears to be safe and did not negatively influence clinical outcomes in this study. When confounding variables were controlled for, the use of capsular repair did not show clinically relevant superiority over the use of unrepaired capsulotomy. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25530512 TI - Patient-related risk factors for the extrusion of lateral meniscal allograft transplants. AB - PURPOSE: The objective of this study was to identify the patient-related risk factors for lateral meniscal extrusion after lateral meniscal allograft transplantation (MAT) regarding demographic characteristics, alignment, and pre existing arthrosis. METHODS: Seventy-one patients who underwent arthroscopic lateral MAT with bone bridge fixation between 2008 and 2011 were assessed. Lateral meniscal subluxation was measured on mid-coronal sections of magnetic resonance images 1 year postoperatively. Subluxation of more than 3 mm was considered to be extrusion. Age, gender, body mass index, time from previous meniscectomy, mechanical axis deviation, Kellgren-Lawrence grade on preoperative radiographs, and intraoperative International Cartilage Repair Society grade were assessed as possible patient-related factors. RESULTS: The mean lateral subluxation in the coronal plane was 2.6 +/- 1.6 mm. Among our patients, 23 transplants (32.4%) showed extrusion. The intraoperative cartilage status of the femoral condyle and tibial plateau showed significant differences between the nonextruded (<=3 mm) and extruded (>3 mm) groups (P = .010 and P = .001, respectively). There were no differences in other factors between these 2 groups. Binary logistic regression analysis showed that tibial-side cartilage wear of International Cartilage Repair Society grade 3 or more was a significant risk factor for meniscal extrusion. CONCLUSIONS: Lateral meniscal extrusion 1 year after lateral MAT is affected by the degree of intraoperative cartilage wear, most notably on the tibial side. Patient demographic characteristics, alignment, and radiographic arthritic changes did not differ between nonextruded and extruded MAT cases. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25530513 TI - Association between educational level and access to safe abortion in a Brazilian population. AB - OBJECTIVE: To evaluate sociodemographic factors associated with induced abortion. METHODS: As part of a cross-sectional, descriptive study, 15 800 civil servants from Campinas, Brazil, were invited to complete a self-administered questionnaire about absolutely unwanted pregnancies in January 2010. Bivariate analysis and multivariate Poisson regression analysis were used to explore the associations between induced abortion and sociodemographic characteristics. RESULTS: Overall, 1660 questionnaires were returned. Unwanted pregnancy was reported by 296 (17.8%) respondents, of whom 165 (55.7%) resorted to abortion. Multiple regression analysis showed that college education was the only variable associated with an increased chance of abortion. Among 157 participants who answered questions about the abortion procedure, 97 (61.8%) reported that it had been performed by a physician. Following abortion, 35 (22.9%) of 153 reported that medical care was required and 26 (16.6%) of 157 reported hospitalization, principally those with a lower level of education and those whose abortion had been performed by a nonphysician. CONCLUSION: Compared with women with a college education, those with a lower education level were less likely to terminate an absolutely unwanted pregnancy and to have an abortion performed by a physician, and they were more likely to have complications. These findings confirm the social inequalities associated with abortion in Brazil. PMID- 25530514 TI - On models of the genetic code generated by binary dichotomic algorithms. AB - In this paper we introduce the concept of a BDA-generated model of the genetic code which is based on binary dichotomic algorithms (BDAs). A BDA-generated model is based on binary dichotomic algorithms (BDAs). Such a BDA partitions the set of 64 codons into two disjoint classes of size 32 each and provides a generalization of known partitions like the Rumer dichotomy. We investigate what partitions can be generated when a set of different BDAs is applied sequentially to the set of codons. The search revealed that these models are able to generate code tables with very different numbers of classes ranging from 2 to 64. We have analyzed whether there are models that map the codons to their amino acids. A perfect matching is not possible. However, we present models that describe the standard genetic code with only few errors. There are also models that map all 64 codons uniquely to 64 classes showing that BDAs can be used to identify codons precisely. This could serve as a basis for further mathematical analysis using coding theory, for example. The hypothesis that BDAs might reflect a molecular mechanism taking place in the decoding center of the ribosome is discussed. The scan demonstrated that binary dichotomic partitions are able to model different aspects of the genetic code very well. The search was performed with our tool Beady-A. This software is freely available at http://mi.informatik.hs mannheim.de/beady-a. It requires a JVM version 6 or higher. PMID- 25530515 TI - Bio-Pick, Place, and Perfuse: A New Instrument for Three-Dimensional Tissue Engineering. AB - A grand challenge of tissue engineering is the fabrication of large constructs with a high density of living cells. By adapting the principles of pick-and-place machines used in the high-speed assembly of electronics, we have developed an innovative instrument, the Bio-Pick, Place, and Perfuse (Bio-P3), which picks up large complex multicellular building parts, transports them to a build area, and precisely places the parts at desired locations while perfusing the parts. These assembled parts subsequently fuse to form a larger contiguous tissue construct. Multicellular microtissues were formed by seeding cells into nonadhesive micro molds, wherein cells self-assembled scaffold-free parts in the shape of spheroids, toroids, and honeycombs. After removal from the molds, the parts were gripped, transported (using an x, y, z controller), and released using the Bio-P3 with little to no effect on cell viability or part structure. As many as 16 toroids were stacked over a 170 MUm diameter post where they fused over the course of 48 h to form a single tissue. Larger honeycomb parts were also gripped and stacked onto a build head that, like the gripper head, provided fluid suction to hold and perfuse the parts during assembly. Scaffold-free building parts help to address several of the engineering and biological challenges to large tissue biofabrication, and the Bio-P3 described in this article is a novel instrument for the controlled gripping, placing, stacking, and perfusing of living building parts for solid organ fabrication. PMID- 25530516 TI - Cell membrane wrapping of a spherical thin elastic shell. AB - Nanocapsules that can be tailored intelligently and specifically have drawn considerable attention in the fields of drug delivery and bioimaging. Here we conduct a theoretical study on cell uptake of a spherical nanocapsule which is modeled as a linear elastic solid thin shell in three dimensions. It is found that there exist five wrapping phases based on the stability of three wrapping states: no wrapping, partial wrapping and full wrapping. The wrapping phase diagrams are strongly dependent on the capsule size, adhesion energy, cell membrane tension, and bending rigidity ratio between the capsule and membrane. Discussion is made on similarities and differences between the cell uptake of solid nanocapsules and fluid vesicles. The reported results may have important implications for biomedical applications of nanotechnology. PMID- 25530518 TI - [Bone and Calcium Research Update 2015. Metabolic crosstalk bone and other organs]. AB - Bone homeostasis is maintained by bone formation and bone resorption. The identification that nervous system controls bone metabolism through leptin deficient mice studies opened a new field in bone biology. Notably, sympathetic and parasympathetic nerve system regulate bone metabolism. In addition, sensory nerve system also has been shown to be involved in the regulation of bone homeostasis. On the other hand, recent studies reported that bone derived hormones, such as osteocalcin or fibroblast growth factor 23, regulate systemic metabolism. Based on these findings, currently the bone-organ crosstalk has been noted. PMID- 25530519 TI - [Bone and Calcium Research Update 2015. Regulation of bone remodeling by osteocytes]. AB - Bone is constantly renewed by the balanced action of bone formation and bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. An imbalance of bone remodeling is often linked to various bone diseases. During bone remodeling, resorption by osteoclasts precedes bone formation by osteoblasts. Based on the osteocyte location within the bone matrix and the cellular morphology, it is proposed that osteocytes potentially contribute to the controls of bone remodeling by sensing mechanical stress and hormones. Furthermore, bone has been traditionally regarded as a part of the skeletal and locomotor system, but recent studies suggest that osteocytes regulate systemic biological functions based on the inseparable link between bone and other systems. PMID- 25530520 TI - [Bone and Calcium Research Update 2015. The regulation of proliferation and differentiation by the ER stress transducer in chondrocytes]. AB - BBF2H7 is an ER-resident transmembrane transcription factor which is structurally similar to ATF6, one of the canonical ER stress transducers, and preferentially expresses in chondrocytes. This molecule is processed at the transmembrane region in response to ER stress or differentiation stimuli. The cleaved amino (N) terminal cytoplasmic domain promotes transcription of the ER-Golgi trafficking protein Sec23a, and plays a crucial role in secretion of extracellular matrix proteins from chondrocytes during cartilage formation. On the contrary, the cleaved C-terminal luminal domain of BBF2H7 is secreted from chondrocytes. The secreted BBF2H7 C-terminus directly binds to both Indian Hedgehog and its receptor Patched-1, and facilitates complex formation of the ligand-receptor followed by activation of Hedgehog signaling to promote proliferation in neighbouring chondrocytes. The dual N- and C-terminal functions of BBF2H7 triggered by physiological ER stress could allow chondrocytes to promote simultaneously distinct cellular events for differentiation and proliferation in developing cartilage. PMID- 25530521 TI - [Bone and Calcium Research Update 2015. Novel treatment for FGF23-related hypophosphatemic diseases]. AB - Fibroblast growth factor 23 (FGF23) is a hormone mainly produced by osteocytes and regulates phosphate and vitamin D metabolism by binding to Klotho-FGF receptor complex. Most diseases previously called vitamin D-resistant rickets/osteomalacia or familial hypophosphatemic rickets/osteomalacia have been shown to be caused by excess actions of FGF23. Therefore, several methods to inhibit the actions of FGF23 are now considered as new treatment methods for these FGF23-related hypophosphatemic diseases. It has been reported that anti FGF23 antibody increases serum phosphate in patients with FGF23-related hypophosphatemic disease. PMID- 25530517 TI - Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity. AB - The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression of BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation. PMID- 25530522 TI - [Bone and Calcium Research Update 2015. Basic mechanisms underlying calcium signaling and their biological potentiality]. AB - Calcium ion (Ca2+) is the only second messenger well recognized for the established biological role among various inorganic ions. When cellular Ca2+ controls diverse biological phenomena, it is regulated under exquisitely precise mechanisms. Many proteins have been identified as Ca2+ signal-regulating factors, and still new "players" are added to the repertory. In this review, we will focus on Ca2+ channels, Ca2+-binding proteins,and signaling pathways controlled by these Ca2+ signal-regulating proteins, in order to discuss on molecular bases, biological significance, and possible future developments of Ca2+ signaling. PMID- 25530523 TI - [Bone and Calcium Research Update 2015. Role of calcium in the regulation of smooth muscle function]. AB - The vascular smooth muscle plays a physiological role in the regulation of the organ blood flow and blood pressure by modulating vascular resistance. The contraction of vascular smooth muscle is regulated by both Ca2+ signal and changes in the sensitivity of the contractile apparatus to Ca2+. The influx of the extracellular Ca2+ and the release of Ca2+ from the intracellular store sites play an important role in generating Ca2+ signal. The regulation of activity of myosin light chain phosphatase plays a critical role in regulating the myofilament Ca2+ sensitivity. It is conceivable that any contractile stimulants or vasorelaxant agents exert their vascular effects by affecting either Ca2+ signal or myofilament Ca2+ sensitivity. PMID- 25530524 TI - [Bone and Calcium Research Update 2015. Intracellular Ca2+ regulation in endothelial cells]. AB - Endothelial cells regulates vascular tonus and exerts anti-atherosclerotic effects in response to external stimulation via Ca2+-dependent production of vasoactive substances such as NO. Agonists such as ATP hydrolyze membrane PIP2 and release soluble IP3 into the cell. IP3 then binds to the IP3 receptor and mobilizes Ca2+ from endoplasmic reticulum Ca2+ stores, followed by Ca2+ influxes from the extracellular space. Such store-operated Ca2+ entry comprises organization of a Ca2+ signal complex at the local subplasmalemmal domain involving TRPC4, caveolin1, and STIM1, a Ca2+ sensor protein for intracellular Ca2+ stores. Genetic deletion of any component of these three proteins can lead to depressed Ca2+ influxes and changes of endothelial function. Further elucidation of spatiotemporally organized endothelial Ca2+ signaling is critical for understanding pathophysiology of cardiovascular diseases. PMID- 25530525 TI - [Bone and Calcium Research Update 2015. Regulation of calcium in CKD]. AB - Chronic kidney disease (CKD) patients have a high risk of developing cardiovascular diseases. In addition, they exhibit mineral and bone laboratory abnormalities, bone diseases and vascular calcification, which are the component of new concept "chronic kidney disease-mineral bone disorder". Several organs including kidney, parathyroid, bone, and intestine regulate calcium concentration in orchestration. Parathyroid hormone, phosphate, vitamin D and uremia affect the regulation in serum calcium concentration. PMID- 25530526 TI - [Bone and Calcium Research Update 2015. Recent advances in clinical assessment of trabecular bone architecture: trabecular bone score (TBS)]. AB - Although dual-energy X-ray absorptiometry (DXA) is regarded as the gold-standard technique for diagnosing osteoporosis, bone mineral density (BMD) alone by DXA is not sufficient for bone strength assessment. Trabecular bone score (TBS) is a texture analysis parameter that evaluates pixel gray-level variations in DXA images of the lumbar spine and allows to assess bone microarchitectural status that is one of the determinants of bone strength. Recent clinical evidences show that TBS is associated with fracture risk in primary and secondary osteoporosis, has a complementary role to lumbar spine BMD and responds to osteoporosis medications somewhat differently than BMD. Thus TBS has the potential to become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment. PMID- 25530527 TI - [Bone and Calcium Research Update 2015. Clinical update of urolithiasis--ESWL (extracorporeal shock wave lithotripsy)]. AB - ESWL (extracorporeal shock wave lithotripsy) is widely used for upper urinary stones and successfully treats most patients with uncomplicated kidney stones. ESWL is still of high strategic importance despite ureteroscopy and PNL occupy an essential place in the treatment of urinary stones by technologic advancements. However ESWL is just one of treatment tool and the best procedure should be selected for the patients. Moreover urolithiasis is one of lifestyle-related diseases and should be treated as systemic illness in the daily medical practice. PMID- 25530528 TI - [Bone and Calcium Research Update 2015. Therapy of osteoporosis--Now and future consideration of long-term therapy]. AB - The target to treat osteoporosis is prevention for future fractures. After the evaluation of cathepsin K inhibitors (CKIs) which was developed as antresorptive agents, there is evidence that these agents also possess anabolic activity, suggesting that CKIs differ from so called antiresorptive agents such as bisphosphonates and denosumab. The classification of agents for treatment of osteoporosis has been changed. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) and Atypical femoral fractures (AFFs) have been the problems when the therapy continues relatively for a long period. However, there is no clear guidance on when fracture risk has been reduced to an acceptably low level. As a consequence, some patients at low risk for fracture may be treated for longer than necessary, whereas others at high risk for fracture may have treatment stopped when they might benefit from continuation of the same treatment or a change to a more potent therapeutic agent. Therefore, a "treat-to-target" strategy for the management of patients with osteoporosis has been developed to describe the potential clinical utility of evaluating changes bone density and bone turnover markers, and events of fractures. PMID- 25530532 TI - Jejuno-gastric invagination after Billroth II gastrectomy. PMID- 25530533 TI - Septic limb necrosis, secondary to a brown recluse spider bite. PMID- 25530534 TI - Electrocochleography in children with auditory synaptopathy/neuropathy: diagnostic findings and characteristic parameters. AB - INTRODUCTION: The early diagnosis of AS/AN in children remains challenging because it exclusively relies on the detection of OAE and/or CM, while ABR are pathologically changed or missing. The aim of our study was to ensure the diagnosis of AS/AN, demarcate it to an outer hair cell damage and possibly differentiate between pre- and postsynaptic pathologies. METHODS: We retrospectively evaluated the transtympanic ECochG results of ten children with AS/AN and compared them to a matched group with SNHL and without any signs of AS/AN. We analyzed the thresholds, latencies and - as a new parameter - the amplitude ratio between CAP and SP. RESULTS: CM and SP thresholds were significantly lower than CAP thresholds in AS/AN patients and significantly lower than SP and CM thresholds in SNHL patients with comparable CAP thresholds. The CAP/SP ratio of amplitudes in SNHL children was more than three times (significantly) higher than in AS/AN children. The cutoff value was set at 1.0 in order to differentiate between both groups with a 80-90% sensitivity and specificity. It was not possible to differentiate between a pre- and postsynaptic type of AS/AN in our collective. SUMMARY AND CONCLUSION: The ECochG can add valuable information for a precise differential diagnosis of AS/AN, especially in babyhood. We identified the CAP/SP ratio as a new parameter for differentiation between AS/AN and SNHL. When the CAP/SP ratio falls below 1.0, patients can be diagnosed AS/AN with high specificity and sensitivity. Significantly smaller SPL are needed to evoke SP and CM in the AS/AN group, thus showing the preserved hair cell function. PMID- 25530535 TI - CuO-induced signal amplification strategy for multiplexed photoelectrochemical immunosensing using CdS sensitized ZnO nanotubes arrays as photoactive material and AuPd alloy nanoparticles as electron sink. AB - In this work, multiplexed photoelectrochemical (PEC) immunoassays are introduced into an indium tin oxide (ITO) device. Firstly, the ITO device is fabricated using a simple acid etch treatment method. Secondly, AuPd alloy nanoparticles are electro-deposited on ITO working electrodes as electron sink to construct the immunosensor platform. After that, ZnO nanotubes (ZNTs) arrays are synthesized via chemical etching of ZnO nanorods that are grown on AuPd surface by electrochemical deposition method. Subsequently, CdS is electro-deposited on ZNTs arrays and used as photoactive material. Then, CuO nanoseeds are labeled with signal antibodies and firstly used as PEC signal amplification label. The introduction of CuO brings signal amplification because of the conduction band (CB) of both CuO and ZnO are lower than that of CdS, CuO will compete the photo induced electrons in CB of CdS with ZnO, leading to the decrease of the photocurrent intensity. Using cancer antigen 125, prostate specific antigen and alpha-fetoprotein as model analytes, the proposed immunoassay exhibits excellent precision and sensitivity. Meanwhile, this work provides a promising, addressable and simple strategy for the multi-detection of tumor markers. PMID- 25530536 TI - Detection of 5-hydroxytryptamine (5-HT) in vitro using a hippocampal neuronal network-based biosensor with extracellular potential analysis of neurons. AB - 5-hydroxytryptamine (5-HT) is an important neurotransmitter in regulating emotions and related behaviors in mammals. To detect and monitor the 5-HT, effective and convenient methods are demanded in investigation of neuronal network. In this study, hippocampal neuronal networks (HNNs) endogenously expressing 5-HT receptors were employed as sensing elements to build an in vitro neuronal network-based biosensor. The electrophysiological characteristics were analyzed in both neuron and network levels. The firing rates and amplitudes were derived from signal to determine the biosensor response characteristics. The experimental results demonstrate a dose-dependent inhibitory effect of 5-HT on hippocampal neuron activities, indicating the effectiveness of this hybrid biosensor in detecting 5-HT with a response range from 0.01MUmol/L to 10MUmol/L. In addition, the cross-correlation analysis of HNNs activities suggests 5-HT could weaken HNN connectivity reversibly, providing more specificity of this biosensor in detecting 5-HT. Moreover, 5-HT induced spatiotemporal firing pattern alterations could be monitored in neuron and network levels simultaneously by this hybrid biosensor in a convenient and direct way. With those merits, this neuronal network-based biosensor will be promising to be a valuable and utility platform for the study of neurotransmitter in vitro. PMID- 25530537 TI - QCM-D providing new horizon in the domain of sensitivity range and information for haemostasis of human plasma. AB - Monitoring of the haemostasis status is significant for proper therapeutic directions and decisions in surgery and innate coagulation disorders. In this regard, to gain a general overview of the plasmatic coagulation, prothrombin time (PT) tests are frequently combined with tests for activated partial thromboplastin time (aPTT). For aPTT we report for the first time that a QCM-D (Quartz Crystal Microbalances with Dissipation) based technique offers a better alternative to the standard coagulometer method in the perspective of range and information. We used heparin as anticoagulant to generate different coagulation times for human plasma. QCM-D astonishingly proved to be more sensitive and reliable than the standard coagulometer for aPTT range of upper limits of coagulation times. The established platform can monitor the fibrinogen concentration ranging from 1-6g/L (yielding R(2)=0.98 in calibration curves) along with aPTT from frequency and dissipation shifts together in a single set of measurements. Additionally the sensor layers have been tested for reusability, demonstrating no loss in sensor characteristics up to ten times measurements. PMID- 25530538 TI - A label-free electrochemical aptasensor based on the catalysis of manganese porphyrins for detection of thrombin. AB - A novel manganese porphyrin (MnPP)-catalyzed aerobic oxidation of l-cysteine to disulfides (RSSR) was firstly found and applied into electrochemical aptasensor with a label-free technique for signal amplification. The possible catalytic mechanism of the catalytic reaction where MnPP catalyzed l-cysteine with thiol (RSH) structure to RSSR was discussed in detail. For fabrication of the aptasensor, thionine (Thi), which served as an electron mediator, was mixed with MnPP and immobilized on the nafion coated carbon electrode through ion exchange adsorption. Gold nanoparticle (nano-Au) was assembled on the Thi for immobilizing thrombin binding aptamer (TBA). In the presence of thrombin (TB), TBA will capture TB and form TBA-TB composite thus perturbed electron transfer, leading to decrease of the current for quantitatively detecting TB. Under optimal condition, the electrochemical aptasensor exhibited a linear range of 0.1-25nM with a detection limit of 0.02nM. This work opens a novel way for signal amplification study about porphyrins that served as mimetic enzyme to thiol in electrochemical aptasensor. PMID- 25530539 TI - Electrochemical sensor based on molecularly imprinted film at Au nanoparticles carbon nanotubes modified electrode for determination of cholesterol. AB - A novel electrochemical sensor for cholesterol (CHO) detection based on molecularly imprinted polymer (MIP) membranes on a glassy carbon electrode (GCE) modified with multi-walled carbon nanotubes (MWNTs) and Au nanoparticles (AuNPs) was constructed. p-Aminothiophenol (P-ATP) and CHO were assembled on the surface of the modified GCE by the formation of Au-S bonds and hydrogen-bonding interactions, and polymer membranes were formed by electropolymerization in a polymer solution containing p-ATP, HAuCl4, tetrabutylammonium perchlorate (TBAP) and the template molecule CHO. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) measurements were used to monitor the electropolymerization process and its optimization, which was further characterized by scanning electron microscopy (SEM). The linear response range of the MIP sensor was between 1*10(-13) and 1*10(-9)molL(-1), and the limit of detection (LOD) were 3.3*10(-14)molL(-1). The proposed system has the potential for application in clinical diagnostics of cholesterol with high-speed real-time detection capability, low sample consumption, high sensitivity, low interference and good stability. PMID- 25530540 TI - A competitive photoelectrochemical assay for estradiol based on in situ generated CdS-enhanced TiO2. AB - A novel and simple photoelectrochemical (PEC) bioassay protocol for estradiol was proposed based on in situ generated CdS-enhanced TiO2 film via competitive strategy. The CdS was generated in situ by immediately dropping S(2-) onto the Cd(2+)-functionalized titanium phosphate nanoparticles (TiP@Cd(2+)). The TiO2 photoactive sensing film with countless active sites was obtained by calcination and further explored for estradiol (E2) capture. The TiP@Cd(2+) was used as labels and immobilized through affinity-specific binding with E2 on the surface of the electrode. Greatly enhanced sensitivity was achieved by using porous TiP nanoparticles as carriers to load a large amount of Cd(2+) and further for more CdS production through the S(2-) deposition. What's more, the photocurrent of CdS generated on the electrode surface could be significantly amplified by the coupling of CdS and TiO2, which could enhance the excitation and photo-to electric conversion efficiency. Through the application of a competitive binding assay, the proposed biosensor showed high sensitivity with a detection limit down to 2pg/mL. This simple and fast PEC E2-sensing approach offers great promise to extend its application for the assay of small molecules of biomedical, food and environmental interest. Additionally, the strategy of employing in situ generated narrow-band gap semiconductors paves a new way for PEC sensing. PMID- 25530541 TI - Cyano-substituted oligo(p-phenylene vinylene) single-crystal with balanced hole and electron injection and transport for ambipolar field-effect transistors. AB - High and balanced hole and electron mobilities were achieved in OFETs based on the high photoluminescence of a 1,4-bis(2-cyano-2-phenylethenyl)benzene single crystal with symmetric electrodes. For electron and hole, the operation voltage in the OFETs based on symmetric gold electrodes was 30 and -20 V, respectively. The accumulation threshold voltage is low enough for the OFETs to operate in an ambipolar model with the source/drain voltage (Vds) around 50 V despite the high injection barrier. The highest electron and hole mobility was 0.745 cm(2) V(-1) s(-1) and 0.239 cm(2) V(-1) s(-1), and the current density reached 90.7 and 27.4 A cm(-2), respectively with an assumed 10 nm accumulation layer. The high mobility comes from the strong pi-pi interactions. In addition, the highly ordered hydrogen bonding matrix may create an efficient route to pump the charge to the inner layer which can improve the injection ability. PMID- 25530542 TI - Molecular detection of the blood meal source of sand flies (Diptera: Psychodidae) in a transmission area of American cutaneous leishmaniasis, Parana State, Brazil. AB - The feeding behavior of sand flies provides valuable information about the vector/host interactions and elucidates the epidemiological patterns of American cutaneous leishmaniasis (ACL) transmission. The aim of this study was to identify the blood meal sources of sand flies in endemic areas of leishmaniasis in Parana State through polymerase chain reaction (PCR) amplification of a prepronociceptin (PNOC) gene fragment and its subsequent DNA sequencing. Moreover, molecular assays were conducted to evaluate the sensitivity and reproducibility of the PNOC gene amplification. Besides that, a time-course digestion test of the blood using sand flies that fed artificially on BALB/c mice was performed. Of 1263 female sand flies collected in the field, 93 (3.6%) specimens were engorged and 27 allowed efficient amplification of the PNOC gene. These flies had fed on equine (Equus caballus), porcine (Sus scrofa) and canine (Canis lupus familiaris) species. The results also showed that the identification of the blood meal sources of the sand flies using the molecular method was directly linked to the level of digestion of the blood (time-course) and not to the amount of blood that had been ingested or to the presence of inhibitors in the blood. PMID- 25530543 TI - Efficacy of SynriamTM, a new antimalarial combination of OZ277 and piperaquine, against different developmental stages of Schistosoma mansoni. AB - Control of schistosomiasis relies on a single drug, praziquantel (PZQ). Given the rising concerns about the potential emergence of PZQ-resistant strains, it has now become necessary to search for novel therapeutics. However, the current pace for anti-schistosomal drug discovery is slow; hence, repositioning of existing approved drugs can offer a safe, rapid and cost-effective solution. The anti malarial synthetic artemisinin-derivatives trioxolanes demonstrated anti schistosomal efficacies against the three major species infecting humans and, unlike PZQ, showed activities against both juvenile and adult worm stages. The 1,2,4-trioxolane/OZ277 (arterolane maleate) in combination with a partner drug: piperaquine phosphate was recently developed as an anti-malarial drug and manufactured by Ranbaxy (India) as SynriamTM (SYN). Herein, the in vivo activities of SYN were investigated in a mouse model of Schistosoma mansoni (S. mansoni), compared to PZQ. We show that a single fixed dose of 240mg/kg SYN (40mg/kg arterolane and 200mg/kg piperaqine) induced significant protective effects in mice, in terms of reduction in worm and tissue egg burdens, which were evident against all schistosome developmental stages. Extensive alterations in the tegument and subtegumental tissues of SYN-exposed worms were revealed by both scanning and transmission electron microscopes. Progressive decrease in worm activity and occurrence of death were noticed in vitro upon exposure to the drug more pronounced in the presence of haemin. This report provides the first evidence of the efficacy of a combination of 1,2,4-trioxolane and piperaquine against S. mansoni in mice. Being effective against young stages, SYN could be used to prevent early Schistosoma infection. PMID- 25530544 TI - [Impact of end-stage renal disease and kidney transplantation on the reproductive system]. AB - Chronic renal failure leads to many metabolic disorders affecting reproductive function. For men, hypergonadotropic hypogonadism, hyperprolactinemia, spermatic alterations, decreased libido and erectile dysfunction are described. Kidney transplantation improves sperm parameters and hormonal function within 2 years. But sperm alterations may persist with the use of immunosuppressive drugs. In women, hypothalamic-pituitary-ovarian axis dysfunction due to chronic renal failure results in menstrual irregularities, anovulation and infertility. After kidney transplantation, regular menstruations usually start 1 to 12 months after transplantation. Fertility can be restored but luteal insufficiency can persist. Moreover, 4 to 20% of women with renal transplantation suffer from premature ovarian failure syndrome. In some cases, assisted reproductive technologies can be required and imply risks of ovarian hyperstimulation syndrome and must be performed with caution. Pregnancy risks for mother, fetus and transplant are added to assisted reproductive technologies ones. Only 7 authors have described assisted reproductive technologies for patients with kidney transplantation. No cases of haemodialysis patients have been described yet. So, assisted reproductive technologies management requires a multidisciplinary approach with obstetrics, nephrology and reproductive medicine teams' agreement. PMID- 25530546 TI - Puerarin attenuates airway inflammation by regulation of eotaxin-3. AB - Puerarin is an isoflavonoid isolated from the root of the plant Pueraria lobata and has been used as a prescribed drug in China for the treatment of many diseases in the clinical practice. The present study aimed to determine the protective effects and the underlying mechanisms of puerarin on ovalbumin (OVA) induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (2 mg/kg), and puerarin (10 mg/kg, 20 mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Th1/Th2 cytokines were measured by enzyme linked immunosorbent assay, eotaxin-3 was evaluated by western blotting. Our study demonstrated that, compared with model group, puerarin inhibited OVA induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN gamma level in bronchoalveolar lavage fluid; histological studies demonstrated that puerarin substantially inhibited OVA-induced eosinophilia in lung tissue compared with model group. Western blotting studies demonstrated that puerarin substantially inhibited eotaxin-3 compared with model group. Our findings support puerarin can prevent some signs of allergic asthma in the mouse model. PMID- 25530545 TI - Hcmv-miR-UL112 attenuates NK cell activity by inhibition type I interferon secretion. AB - Viral microRNAs (miRNAs) can regulate the host innate immune response. In particular, the human cytomegalovirus (HCMV) miRNA hcmv-miR-UL112 evades the host immune system by downregulating host immune gene and immediate-early viral gene expression. Natural killer (NK) cells are important innate immune cells with potent cytotoxicity, and are activated by type I interferons (IFNs) upon infection. It remains unclear how HCMV persists in the host despite the strongly antagonistic host immune system. A lentiviral vector was used to stably express hcmv-miR-UL112 in peripheral blood mononuclear cells (PBMCs). Hcmv-miR-UL112 expression levels were detected by TaqMan miRNA assay. The effects of hcmv-miR UL112 on NK cell cytotoxicity were assessed with CD107a mobilization assay and CytoTox 96 non-radioactive cytotoxicity assay. Enzyme-linked immunosorbent assays (ELISA) were performed to detect type I IFNs levels in culture supernatants. To confirm the role of type I IFN in hcmv-miR-UL112-mediated NK cell cytotoxicity, PBMCs were incubated with antagonizing antibodies against IFN receptor (IFNAR) before lenti-hcmv-miR-UL112 treatment and recombinant type I IFN was added back into miR-transduced PBMC. Ectopically expressed hcmv-miR-UL112 functionally attenuated NK cell-mediated cytotoxicity, associated with decreased type I IFN expression. Hcmv-miR-UL112-transfected cells did not reduce the CD107-expression further than the IFNAR neutralizing mAbs-treatment alone, and adding back of recombinant type I IFN restored CD107a expression from the miR-transduced PBMC. Taken together, our results suggest that hcmv-miR-UL112 subverts innate immunity by downregulating type I IFN signaling to inhibit NK cell cytotoxicity. These results provide a new miRNA-based immunoevasion mechanism that may be exploited by HCMV. PMID- 25530547 TI - Challenges with delivering gender-specific and comprehensive primary care to women veterans. AB - BACKGROUND: The growing presence of women veterans in Veterans Administration (VA) settings has prompted the need for greater attention to clinical proficiency related to women's health (WH) primary care needs. Instead of making appointments for multiple visits or referring patients to a WH clinic or alternate site for gender-specific care, a comprehensive primary care model now allows for women veteran patients be seen by primary care providers (PCPs) who have WH training/experience and can see patients for both primary and WH care in the context of a single visit. However, little is currently known about the barriers and facilitators WH-PCPs face in using this approach to incorporate gender specific services into women veterans' primary care services. METHODS: We conducted qualitative in-depth interviews with 22 WH-PCPs at one Midwestern VA Medical Center. All participants were members of one of four outpatient primary care clinics within the main medical center, one off-site satellite clinic, or two off-site community-based outpatient clinics. RESULTS: Inductive thematic analysis identified six themes: 1) Time constraints, 2) importance of staff support, 3) necessity of sufficient space and equipment/supplies, 4) perceptions of discomfort among patients with trauma histories, 5) lack of education/training, and 6) challenges with scheduling/logistics. CONCLUSION: Although adequate staff was a key facilitator, the findings suggest that there may be barriers that undermine the ability of VA WH-PCPs to provide high-quality, comprehensive primary and gender-specific care. The nature of these barriers is multifactorial and multilevel in nature, and may therefore require special policy and practice action. PMID- 25530548 TI - Estimating attributable fractions: principles and applications. PMID- 25530549 TI - Complex carbohydrates of red wine: characterization of the extreme diversity of neutral oligosaccharides by ESI-MS. AB - The major neutral oligosaccharides of a Carignan red wine have been characterized for the first time. The oligosaccharides were prepared after removal of phenolic compounds by polyamide chromatography and of polysaccharides by alcohol precipitation and then were fractionated by anion exchange and size-exclusion chromatography. In a second step, the glycosyl composition and linkages of wine oligosaccharides were determined. Oligosaccharide fractions were analyzed by mass spectrometry (MS) with an electrospray ionization (ESI) source and an ion trap mass analyzer after separation by hydrophilic interaction liquid chromatography on a Nucleodur HILIC column (zwitterionic sulfoalkyl betaine stationary phase). Glycosyl residue composition analysis showed the predominant presence of arabinose, with galactose, rhamnose, and mannose in lower proportion. Neutral oligosaccharides were present at a concentration of 185 mg/L in this wine. The MS spectra in the negative ion mode of the oligosaccharide fractions showed a series of oligosaccharidic structures corresponding to oligo-arabinans often linked to the basic unit alpha-l-Rhap-(1 -> 4)-alpha-d-GalpA. The wine oligosaccharides identified correspond to arabino-oligosaccharides, rhamno-arabino oligosaccharides, and different rhamnogalacturonan-arabino-oligosaccharides with DP ranging from 5 to 49, resulting from the degradation of grape cell wall pectins. Oligosaccharides have an extreme diversity, with more than 100 peaks detected in HPLC-ESI-MS spectra corresponding each to at least one oligosaccharidic structure. PMID- 25530550 TI - Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study: reply. PMID- 25530551 TI - Prostate cancer prevalence in New South Wales Australia: a population-based study. AB - BACKGROUND: Information on the current and future numbers of Australian men living with prostate cancer is limited. We describe a method for estimating complete prevalence of prostate cancer to provide a measure of the burden of prostate cancer in Australia. METHODS: Prostate cancer data from the New South Wales (NSW) Central Cancer Registry were used with PIAMOD (Prevalence and Incidence Analysis MODel) software to estimate future prostate cancer prevalence in NSW. We first fitted parametric incidence and survival models then used the modelled incidence and survival estimates to calculate complete prevalence. The estimated and projected prevalence incorporate past observed trends and take into account different assumptions about future survival trends. These models were validated against observed prevalence from the counting method. RESULTS: Based on data for 1996-2007, the number of men living with prostate cancer in NSW was estimated to rise by 59% to 73%, from 38,322 in 2007 to 60,910-66,160 in 2017. The increasing incidence rates and the ageing population were the major contributors to this estimated increase. Validation suggested that these projections were reasonable, as the estimated prevalence in 1996-2007 was in good agreement with the corresponding prevalence calculated using the direct counting method, and the incidence models were supported by the recent data on prostate specific antigen testing. CONCLUSIONS: As the number of men living with prostate cancer is expected to increase dramatically in the next decade in Australia, representing a significant challenge to the health system, careful planning and development of a healthcare system able to respond to this increased demand is required. These projections are useful for addressing the challenge in meeting the cancer care needs of men with prostate cancer. PMID- 25530552 TI - Development and testing of a tool to assess patient preferences for phase I clinical trial participation. PMID- 25530553 TI - Improving quality of data extractions for the computation of patient-days and admissions. AB - We describe how admissions/discharges/transfers datasets were carefully reviewed for the computation of patient days and admissions used to monitor resistance and antimicrobial use in 9 intensive care units. A visual inspection of datasets and comparisons with other data sources improved accuracy, completeness, and consistency of computations. PMID- 25530554 TI - Hospital unit safety climate: relationship with nurses' adherence to recommended use of facial protective equipment. AB - BACKGROUND: Despite the existence of formal guidelines for the acute health care sector, nurses' adherence to recommended use of facial protective equipment (FPE) to prevent occupational transmission of communicable respiratory disease remains suboptimal. In addition to individual factors such as knowledge and education, group factors such as shared perceptions of organizational support for safety may influence adherence. These group safety climate perceptions can differ depending on the pace and type of work, local leadership, and organizational structure of each unit. METHODS: An analysis of a data set from a cross-sectional survey of 1,074 nurses in 45 units of 6 acute care hospitals was conducted. Variance components analysis was performed to examine the variance in perceptions of safety climate and adherence between units. Hierarchical linear modeling using unit-level safety climate dimensions was conducted to determine if unit-level safety climate dimensions were predictors of nurses' adherence to FPE. RESULTS: Findings revealed statistically significant unit variances in adherence and 5 of the 6 unit-level safety climate dimensions (P < .05). Furthermore, a hierarchical model suggested that tenure and unit-level communication were significantly associated with increased adherence to FPE (P < .05). CONCLUSION: Unit-level safety climate measures varied significantly between units. Strategies to improve unit-level communication regarding safety should assist in improving adherence to FPE. PMID- 25530555 TI - Coliform bacteria, fabrics, and the environment. AB - BACKGROUND: People come into contact with coliform bacteria at recreational sites. Previous research on bacteria adhering to fabrics and surfaces focused on the viability of clinically significant microbes, but did not examine the quantity of bacteria. This study examined the viability and quantity of coliform bacteria adhered to common fabrics. METHODS: The fabrics of 100% cotton, blended cotton, and silk were exposed to a mixture of environmental coliform isolates. Fabrics were incubated in the dark at 25 degrees C or 37 degrees C or in direct sunlight at room temperature for 30, 60, 90, and 120 days. The quantity and viability of the bacteria were determined by the Most Probable Number technique using Colilert reagent (IDEXX Laboratories, Westbrook, ME) and eosin methylene blue agar, respectively. RESULTS: The highest numbers of bacteria were detected for each type of fabric when stored in the dark at 25 degrees C, whereas the lowest numbers of bacteria were detected when fabrics were stored in the dark at 37 degrees C. Low numbers of bacteria were detected on silk and blended cotton exposed to sunlight at room temperature, but not 100% cotton. CONCLUSION: It appears that coliform bacteria can survive on fabrics longer than previous studies have reported. Coliform bacteria survive better in the dark, at lower temperatures, and on fabrics that can retain moisture. These findings can be applied directly to the viability of bacteria on clothing and potential human exposure to fecal pathogens. PMID- 25530556 TI - A gap in patient tape storage and use practices puts patients at risk for cutaneous fungal infections. AB - We report a case of a cutaneous fungal infection in a 12-year-old oncology patient related to patient tape. Our facility had no established guidelines for patient tape. A survey conducted of multiple local healthcare facilities revealed no existing policies or standards of care related to tape storage or use. This reveals a gap in practice. We call for formal recommendations for tape storage and use to enhance patient safety. PMID- 25530557 TI - Lower infection rates after introduction of a photocatalytic surface coating. AB - Health care facilities contain potentially contaminated surfaces that are either difficult to sanitize or prone to recontamination. Photocatalytic materials exhibit antimicrobial activity when exposed to light and provide a safe, durable coating on a wide range of surfaces. We assessed infection rates before and after introduction of a photocatalytic coating in our facility. Infection rates decreased overall by 30%, a change that was statistically significant (P = .02). Similar changes to the built environment merit additional investigation. PMID- 25530558 TI - Surveillance of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae at a comprehensive cancer center in Japan, 2009-2013. AB - We examined the results of surveillance of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, which are pathogens known to cause nosocomial outbreaks, at a comprehensive cancer center in Japan over a 5-year period. We found that the admission prevalence and the incidence of ESBL-producing E coli increased during the study period, in contrast with ESBL producing K pneumoniae, in which the parameters remained low throughout the study period. PMID- 25530559 TI - Lessons learned from the Great East Japan Earthquake: The need for disaster preparedness in the area of disaster mental health for children. AB - The Great East Japan Earthquake on March 11, 2011 brought unprecedented challenges to individuals, families, and communities of the Tohoku region in Japan. Children are especially vulnerable to the postdisaster risk factors that impact their ability to heal. The destruction of the infrastructure by the disasters made it more challenging to reach out to children in an area where the stigma against mental illness is persistent. The authors share their experiences, what they heard from patients, and their reflections on lessons learned. The authors recommend the development of a coordinated mental health response system in preparation for the next disaster. PMID- 25530560 TI - Information and communication technology: connecting the public and first responders during disasters. AB - Lack of success in disaster recovery occurs for many reasons, with one predominant catalyst for catastrophic failure being flawed and inefficient communication systems. Increased occurrences of devastating environmental hazards and human-caused disasters will continue to promulgate throughout the United States and around the globe as a result of the continuous intensive urbanization forcing human population into more concentrated and interconnected societies. With the rapid evolutions in technology and the advent of Information and communication technology (ICT) interfaces such as Facebook, Twitter, Flickr, Myspace, and Smartphone technology, communication is no longer a unidirectional source of information traveling from the newsroom to the public. In the event of a disaster, time critical information can be exchanged to and from any person or organization simultaneously with the capability to receive feedback. A literature review of current information regarding the use of ICT as information infrastructures in disaster management during human-caused and natural disasters will be conducted. This article asserts that the integrated use of ICTs as multidirectional information sharing tools throughout the disaster cycle will increase a community's resiliency and supplement the capabilities of first responders and emergency management officials by providing real-time updates and information needed to assist and recover from a disaster. PMID- 25530561 TI - Problems of preparedness and its promotion in Germany. AB - The official strategy in Germany to promote preparedness is the appliance of mass communication instruments to inform the population about hazards and protection measures as well as to influence the risk perception of people. This is thought to be an appropriate method to raise the level of preparedness. A research project running from 2005 to 2010 investigated central assumptions of the current promotion measures. The results show that a change of paradigm is urgently needed. PMID- 25530562 TI - Volunteers and professional rescue workers: traumatization and adaptation after an avalanche disaster. AB - OBJECTIVE: To compare the degree of traumatization and adaptation in professional and volunteer rescue workers after two snow avalanches. METHOD: Questionnaires including demographic questions, the Social Readjustment Rating Scale, the Rescue Workers Questionnaire, the General Health Questionnaire, the Impact of Event Scale, and the Coping Styles Questionnaire were answered by rescue workers (n = 168). RESULTS: In several areas, professional rescuers had stronger fears than volunteers, all the same, volunteers were significantly more anxious and met criteria for PTSD caseness more often than professionals. CONCLUSION: The findings suggest that voluntary rescue workers suffer from post-traumatic stress disorder symptoms more often than professionals following demanding rescue missions. PMID- 25530563 TI - Category change and risk perception: Hurricane Irene and coastal North Carolina. AB - OBJECTIVE: This research explores variations in risk perception with location and changes in the intensity of a hurricane (Hurricane Irene in 2011). DESIGN: Surveys were mailed to a random sample of 601 year-round residents of two counties in coastal North Carolina. Within each county, areas were chosen based on their risk with respect to wind or storm surge; an equal number of surveys were sent to each area. A 31 percent return rate was achieved. SETTING: Dare County on the Outer Banks of North Carolina and Beaufort County on the Inner Banks were chosen as study areas because of the nature and extent of damage incurred from Hurricane Irene. MAIN OUTCOME MEASURE: Because Hurricane Irene was downgraded before it made landfall in North Carolina, it was anticipated that residents would perceive themselves to be at less risk to hurricane-related hazards with differences related to location on the Atlantic Ocean or on the Sound. RESULTS: Little difference was found between the Inner and Outer Banks locations such that all reported the change in intensity influenced their perceptions by reducing the sense of risk. This varied somewhat, but not significantly, by hazard area. CONCLUSIONS: The downgrading of Hurricane Irene created a false sense of security. Residents of the study area believed themselves to be at low risk and were unlikely to evacuate, despite warnings. The long duration of the event, however, led to significant damages, surprising many, and suggesting the need to emphasize impacts in messaging, no matter the storm intensity. PMID- 25530564 TI - Modeling operators' emergency response time for chemical processing operations. AB - Operators have a crucial role during emergencies at a variety of facilities such as chemical processing plants. When an abnormality occurs in the production process, the operator often has limited time to either take corrective actions or evacuate before the situation becomes deadly. It is crucial that system designers and safety professionals can estimate the time required for a response before procedures and facilities are designed and operations are initiated. There are existing industrial engineering techniques to establish time standards for tasks performed at a normal working pace. However, it is reasonable to expect the time required to take action in emergency situations will be different than working at a normal production pace. It is possible that in an emergency, operators will act faster compared to a normal pace. It would be useful for system designers to be able to establish a time range for operators' response times for emergency situations. This article develops a modeling approach to estimate the time standard range for operators taking corrective actions or following evacuation procedures in emergency situations. This will aid engineers and managers in establishing time requirements for operators in emergency situations. The methodology used for this study combines a well-established industrial engineering technique for determining time requirements (predetermined time standard system) and adjustment coefficients for emergency situations developed by the authors. Numerous videos of workers performing well-established tasks at a maximum pace were studied. As an example, one of the tasks analyzed was pit crew workers changing tires as quickly as they could during a race. The operations in these videos were decomposed into basic, fundamental motions (such as walking, reaching for a tool, and bending over) by studying the videos frame by frame. A comparison analysis was then performed between the emergency pace and the normal working pace operations to determine performance coefficients. These coefficients represent the decrease in time required for various basic motions in emergency situations and were used to model an emergency response. This approach will make hazardous operations requiring operator response, alarm management, and evacuation processes easier to design and predict. An application of this methodology is included in the article. The time required for an emergency response was roughly a one-third faster than for a normal response time. PMID- 25530565 TI - Correlation between FLT3-ITD status and clinical, cellular and molecular profiles in promyelocytic acute leukemias. AB - Internal tandem duplications (ITD) of FLT3 gene occur in about a third of acute promyelocytic leukemias (APL). We investigated the patterns of blood count, surface antigen, expression, chromosome aberrations, PML-RARa isoform, gene expression profile (GEP) and survival in 34 APL patients according to FLT3-ITD status. 97% had a t(15;17) and all of them carried PML-RARa gene fusion, 8 (23.5%) had a FLT3-ITD mutation. Presence of ITD was associated with higher Hb and WBC levels, bcr3 isoform, CD34 expression, CD2 or CD2/CD34 expression. In a multivariate analysis, Hb>9.6g/dL and WBC>=20 * 10(9)/L were important factors for predicting ITD presence. GEP showed that FLT3-ITD carriers clustered separately, even when as few as 5 genes were considered. This study provides further evidence that FLT3-ITDs carriers constitute a biologically distinct group of APL patients. PMID- 25530566 TI - Low expressions of ARS2 and CASP8AP2 predict relapse and poor prognosis in pediatric acute lymphoblastic leukemia patients treated on China CCLG-ALL 2008 protocol. AB - ARS2 protein is important to early development and cell proliferation, in which ARS2-CASP8AP2 interaction is implicated. However, the predictive significance of ARS2 in childhood acute lymphoblastic leukemia (ALL) is unknown. Here we evaluate the predictive values of ARS2 expression and combined ARS2 and CASP8AP2 expression in relapse. We showed that ARS2 expression in ALL bone marrow samples at initial diagnosis was markedly lower than that in complete remission (CR). Likewise, the levels of ARS2 expression in the patients suffering from relapse were significantly lower than that of patients in continuous CR. Furthermore, low expression of ARS2 was closely correlated to poor treatment response including poor prednisone response and high minimal residual disease (MRD), and the patients with high MRD (>=10(-4)) and low ARS2 were more subject to relapse. The multivariate analyses for relapse free survival and event free survival revealed that ARS2 expression remained an independent prognostic factor after adjusting other risk factors. In addition, combined assessment of ARS2 and CASP8AP2 expression was more accurate to predict relapse, based on which an algorithm composed of ARS2 and CASP8AP2 expression, prednisone response and MRD (day 78) was proposed. Together, ARS2 and CASP8AP2 expressions can precisely predict high risk of relapse and ALL prognosis. PMID- 25530567 TI - A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis. AB - The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination. PMID- 25530568 TI - Calorie restriction mimetics: can you have your cake and eat it, too? AB - Strong consensus exists regarding the most robust environmental intervention for attenuating aging processes and increasing healthspan and lifespan: calorie restriction (CR). Over several decades, this paradigm has been replicated in numerous nonhuman models, and has been expanded over the last decade to formal, controlled human studies of CR. Given that long-term CR can create heavy challenges to compliance in human diets, the concept of a calorie restriction mimetic (CRM) has emerged as an active research area within gerontology. In past presentations on this subject, we have proposed that a CRM is a compound that mimics metabolic, hormonal, and physiological effects of CR, activates stress response pathways observed in CR and enhances stress protection, produces CR-like effects on longevity, reduces age-related disease, and maintains more youthful function, all without significantly reducing food intake, at least initially. Over 16 years ago, we proposed that glycolytic inhibition could be an effective strategy for developing CRM. The main argument here is that inhibiting energy utilization as far upstream as possible provides the highest chance of generating a broad spectrum of CR-like effects when compared to targeting a singular molecular target downstream. As an initial candidate CRM, 2-deoxyglucose, a known anti-glycolytic, was shown to produce a remarkable phenotype of CR, but further investigation found that this compound produced cardiotoxicity in rats at the doses we had been using. There remains interest in 2DG as a CRM but at lower doses. Beyond the proposal of 2DG as a candidate CRM, the field has grown steadily with many investigators proposing other strategies, including novel anti glycolytics. Within the realm of upstream targeting at the level of the digestive system, research has included bariatric surgery, inhibitors of fat digestion/absorption, and inhibitors of carbohydrate digestion. Research focused on downstream sites has included insulin receptors, IGF-1 receptors, sirtuin activators, inhibitors of mTOR, and polyamines. In the current review we discuss progress made involving these various strategies and comment on the status and future for each within this exciting research field. PMID- 25530569 TI - Editorial: Health inequity: from evidence to action. PMID- 25530570 TI - Health inequity in people with intellectual disabilities: from evidence to action applying an appreciative inquiry approach. AB - BACKGROUND: The current understanding of health inequities in people with intellectual disabilities does not readily translate into improvements in health status or health care. To identify opportunities for action, the 2013 IASSIDD health SIRG conference organized ten intensive workshops. MATERIALS AND METHODS: The workshops each addressed separate topics, a workshop of self advocated was included as well. Workshop reports were analyzed using a qualitative thematical analysis approach. RESULTS: A total of 134 participants attended the workshops. The analysis of the workshop reports resulted in three main themes: approach, know-how and visibility and a pervasive theme, that of person-centered support. CONCLUSION: Everyone that can contribute to better care should be empowered and facilitated to do so, environments should be accessible and inclusive in nature. Sharing experiences, expertise and data sources within and outside intellectual disabilities care and research were mentioned as ways forward. Strong (policy) visions, felt urgency and shared responsibility are required. PMID- 25530571 TI - Health and disability: partnerships in health care. AB - BACKGROUND: Despite awareness of the health inequalities experienced by people with intellectual disability, their health status remains poor. Inequalities in health outcomes are manifest in higher morbidity and rates of premature death. Contributing factors include the barriers encountered in accessing and receiving high-quality health care. AIMS: This paper outlines health inequalities experienced by people with intellectual disability and focuses on the opportunities medical education provides to address these. Strategies to ensure that health professional education is inclusive of and relevant to people with disabilities are highlighted. CONCLUSIONS: The barriers experienced by people with intellectual disabilities to the receipt of high-quality health care include the attitudes, knowledge and skills of doctors. Improving medical education to ensure doctors are better equipped is one strategy to address these barriers. Improving health enhances quality of life, enables engagement and optimizes opportunities to participate in and contribute to the social and economic life of communities. ACCESSIBLE ABSTRACT: People with intellectual disabilities sometimes find it difficult to get the healthcare they need to stay well. Teaching student doctors about what people with disabilities want and need can help these students become better doctors. Good doctors help people get well and stay healthy and active. When people feel well they can enjoy their lives and join in activities in their community. This article talks about some of the things doctors need to learn, and some ways to teach them. People with disabilities have a very important role in teaching student doctors. PMID- 25530572 TI - Supporting primary healthcare professionals to care for people with intellectual disability: a research agenda. AB - BACKGROUND: The vast health inequities experienced by people with intellectual disability remain indisputable. Persistent and contemporary challenges exist for primary healthcare providers and researchers working to contribute to improvements to the health and well-being of people with intellectual disability. Over two decades after the only review of supports for primary healthcare providers was published, this paper contributes to an evolving research agenda that aims to make meaningful gains in health-related outcomes for this group. METHODS: The present authors updated the existing review by searching the international literature for developments and evaluations of multinational models of care. RESULTS: Based on our review, we present three strategies to support primary healthcare providers: (i) effectively using what we know, (ii) considering other strategies that offer support to primary healthcare professionals and (iii) researching primary health care at the system level. CONCLUSIONS: Strengthening primary care by supporting equitable provision of health-related care for people with intellectual disability is a much needed step towards improving health outcomes among people with intellectual disability. More descriptive quantitative and qualitative research, as well as intervention-based research underpinned by rigorous mixed-methods evaluating these strategies at the primary care level, which is sensitive to the needs of people with intellectual disability will assist primary care providers to provide better care and achieve better health outcomes. ACCESSIBLE ABSTRACT: Many people with intellectual disability have poor health. The authors reviewed what has been written by other researchers about how to improve the health of people with intellectual disability. In the future, people who support adults with intellectual disability should continue doing what they do well, think of other ways to improve health, and do more research about health. At all times, the needs of people with intellectual disability should be the greatest concern for those trying to support them. PMID- 25530573 TI - The uptake of secondary prevention by adults with intellectual and developmental disabilities. AB - BACKGROUND: Secondary prevention involves the early detection of disease while it is asymptomatic to prevent its progression. For adults with intellectual and developmental disabilities, secondary prevention is critical as they may not have the ability to recognize the early signs and symptoms of disease or lack accessible information about these. METHODS: Linked administrative health and social service data were used to document uptake related to four secondary prevention guidelines among adults with intellectual and developmental disabilities. Rates were compared to those from a general population sample representing the same age ranges. RESULTS: Of 22% of adults with intellectual and developmental disabilities had a periodic health examination in a two-year period (compared to 26.4% of adults without intellectual and developmental disabilities). Adults with intellectual and developmental disabilities were less likely to undergo recommended age and gender-specific screening for the three types of cancer studied (colorectal, breast and cervical). CONCLUSIONS: Adults with intellectual and developmental disabilities in Ontario experience disparities in secondary prevention. As changes to primary care delivery and secondary prevention recommendations in the province and elsewhere continue to evolve, close monitoring of the impacts on adults with intellectual and developmental disabilities combined with dedicated efforts to increase access is warranted. PMID- 25530575 TI - [Graves' disease and liver abnormalities: antithyroid drugs are not the only factors involved!]. PMID- 25530576 TI - [Nevus comedonicus]. PMID- 25530577 TI - Muscular adaptations in low- versus high-load resistance training: A meta analysis. AB - There has been much debate as to optimal loading strategies for maximising the adaptive response to resistance exercise. The purpose of this paper therefore was to conduct a meta-analysis of randomised controlled trials to compare the effects of low-load (<=60% 1 repetition maximum [RM]) versus high-load (>=65% 1 RM) training in enhancing post-exercise muscular adaptations. The strength analysis comprised 251 subjects and 32 effect sizes (ESs), nested within 20 treatment groups and 9 studies. The hypertrophy analysis comprised 191 subjects and 34 ESs, nested with 17 treatment groups and 8 studies. There was a trend for strength outcomes to be greater with high loads compared to low loads (difference = 1.07 +/- 0.60; CI: -0.18, 2.32; p = 0.09). The mean ES for low loads was 1.23 +/- 0.43 (CI: 0.32, 2.13). The mean ES for high loads was 2.30 +/- 0.43 (CI: 1.41, 3.19). There was a trend for hypertrophy outcomes to be greater with high loads compared to low loads (difference = 0.43 +/- 0.24; CI: -0.05, 0.92; p = 0.076). The mean ES for low loads was 0.39 +/- 0.17 (CI: 0.05, 0.73). The mean ES for high loads was 0.82 +/- 0.17 (CI: 0.49, 1.16). In conclusion, training with loads <=50% 1 RM was found to promote substantial increases in muscle strength and hypertrophy in untrained individuals, but a trend was noted for superiority of heavy loading with respect to these outcome measures with null findings likely attributed to a relatively small number of studies on the topic. PMID- 25530578 TI - A miniaturized flexible antenna printed on a high dielectric constant nanopaper composite. AB - A high-dielectric-constant and flexible cellulose nanopaper composite is prepared by mixing a small amount of silver nanowires with cellulose nanofibers. The nanopaper antenna is downsized by about a half when using the nanopaper substrate. The nanopaper antenna has potential in wearable wireless communication devices. PMID- 25530579 TI - Phenotypic characterization of multidrug-resistant Pseudomonas aeruginosa strains isolated from pediatric patients associated to biofilm formation. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that has acquired several mechanisms of resistance to multiple groups of antibiotic agents and has been widely employed as a model organism for the study of biofilm formation. Many P. aeruginosa structures embedded in the extracellular matrix, such as exopolysaccharides (EPS), flagella, and type-IV pili (T4P), have been associated with biofilm formation. In this study, we assess biofilm formation by crystal violet quantification in clinical strains of multidrug-resistant (MDR) P. aeruginosa isolated from the Hospital Infantil de Mexico Federico Gomez (HIMFG) associated to total and reducing EPS production (quantification by the anthrone and DNS method, respectively), twitching motility activity by T4P, and flagellar mediated motility. RESULTS: The determination of Minimum Inhibitory Concentration (MIC) showed that >50% of P. aeruginosa strains were resistant to 12 different antibiotics (TIC, CAZ, CTX, CRO, FEP, AZT, GM, CIP, LEV, PZT, IMP, and MEM). Total and reducing EPS analysis of the 58 biofilm-forming MDR P. aeruginosa strains showed heterogeneous values ranging from OD600 9.06 to 212.33, displaying a linear correlation with the production of total EPS (59.66MUg/ml to 6000.33MUg/ml; R(2)=0.89), and a higher correlation with reducing EPS (88.33MUg/ml to 1100.66MUg/ml; R(2)=0.96). T4P twitching motility showed a moderated linear correlation (2.00mm to 28.33mm; R(2)=0.74). Even though it has been demonstrated that flagella contribute to the initial stages of biofilm formation, crystal violet analysis showed a moderate correlation (R(2)=0.49) with flagellar-mediated motility in MDR P. aeruginosa under the tested conditions. In addition, PFGE profiles revealed two subgroups generating profiles group A, consisting of 89.63% (52/58) of the strains, and group B, consisting of 13.09% (6/58) of the strains. CONCLUSIONS: Phenotypic analysis showed a correlation among the biofilms developed in the MDR P. aeruginosa strains with EPS (total and reducing) production, T4P-activity by twitching motility and flagellar-mediated motility. PMID- 25530580 TI - Rational design of alpha-helical antimicrobial peptides: do's and don'ts. AB - Antimicrobial peptides (AMPs) are promising candidates for battling multiresistant bacteria. Despite extensive research, structure-activity relationships of AMPs are not fully understood, and there is a lack of structural data relating to AMPs in lipids. Here we present the NMR structure of anoplin (GLLKRIKTLL-NH2 ) in a micellar environment. A vast library of substitutions was designed and tested for antimicrobial and hemolytic activity, as well as for changes in structure and lipid interactions. This showed that improvement of antimicrobial activity without concomitant introduction of strong hemolytic activity can be achieved through subtle increases in the hydrophobicity of the hydrophobic face or through subtle increases in the polarity of the hydrophilic face of the helix, or-most efficiently-a combination of both. A set of guidelines based on the results is given, for assistance in how to modify cationic alpha helical AMPs in order to control activity and selectivity. The guidelines are finally tested on a different peptide. PMID- 25530581 TI - Dietary supplementation with Bacillus subtilis, Saccharomyces cerevisiae and Aspergillus oryzae enhance immunity and disease resistance against Aeromonas hydrophila and Streptococcus iniae infection in juvenile tilapia Oreochromis niloticus. AB - A feeding trial was conducted to investigate the effects of dietary administration of probiotic with Bacillus subtilis, Aspergillus oryzae and Saccharomyces cerevisiae on growth, innate immune response, Hemato-immunological parameters and disease resistance of Nile tilapia, Oreochromis niloticus. Animals were distributed in three equal groups, each of five replicates and received one of the following experimental diets for four weeks: Control, non-supplemented diet; 5 g kg(-1) probiotic mixture (B. subtilis 1.5 * 10(9) CFU g(-1), S. cerevisiae 10(9) CFU g(-1) and A. oryzae 2 * 10(9) CFU g(-1)); and 10 g kg(-1) probiotic mixture (B. subtilis 3.0 * 10(9) CFU g(-1), S. cerevisiae 2.0 * 10(9) CFU g(-1) and A. oryzae 4.0 * 10(9) CFU g(-1)). The respiratory burst activity, white blood cells and hematological parameters were evaluated after four, five and six weeks of feeding. At the end of the growth trial, fish were sampled for intestinal microbiology and challenged by intraperitoneal injection of LD50 concentration of Aeromonas hydrophila and Streptococcus iniae. Mortality was recorded for the following 3 weeks. Results showed that administration of the probiotic had no significant effect on the growth rates of Nile tilapias, although the fish fed probiotics had better feed conversion. Respiratory burst activity, erythrocyte fragility and levels of white blood cells were significantly improved in tilapias fed diet supplemented with probiotic levels (P < 0.05), which may exhibit up-regulating effects on tilapia immune parameters. The cumulative mortality after A. hydrophila and S. iniae challenge decreased in tilapias fed with probiotic (P < 0.05). The present study demonstrated the potential of B. subtilis, S. cerevisiae and A. oryzae combined as beneficial dietary probiotic in juvenile O. niloticus. PMID- 25530582 TI - Effects of dihydroquercetin obtained from deodar (Cedrus deodara) on immune status of gilthead seabream (Sparus aurata L.). AB - The use of medicinal plants as prophylactic method in fish is considered safe and a very promising alternative to the use of chemicals in aquaculture practices. The prospective mode of action of dihydroquercetin, fraction of the medical plant deodar (Cedrus deodara), was evaluated on immune status of gilthead seabream (Sparus aurata L.). Fish were divided into 4 groups before being fed for 14 days with commercial diets supplemented with 0% (control), 0.1%, 0.5% and 1% of dihydroquercetin. Cellular (phagocytosis and respiratory burst activities) and humoral (seric complement activity, antiprotease, total protein, peroxidase, bactericidal activity and IgM level) immune parameters were investigated. The results recorded enhancement in all the tested parameters and in all the dihydroquercetin supplemented groups compared to the control. Interestingly, the fish received the lowest dose of dihydroquercetin (0.1%) showed a highly significant difference (p < 0.05) in phagocytosis, respiratory burst, IgM level, total protein, complement, antiprotease and bactericidal activities compared to the control. Direct effect of different doses of dihydroquercetin on head-kidney leucocytes was also studied in a previous in vitro assay. Again, the lowest doses tested provoked the highest immune cellular activities, where, the highest phagocytic and respiratory bust activities were recorded in leucocytes incubated with 0.025% and 0.0125% doses, respectively. Therefore, the results suggest that low concentrations of dihydroquercetin as food supplements are able to increase the immune status of gilthead seabream. PMID- 25530583 TI - [Quality improvement of gastrointestinal endoscopy in Korea: past, present, and future]. AB - The motivation for improving quality of gastrointestinal endoscopy begins with the desire to provide patients with the best possible care. Gastrointestinal endoscopy is an excellent area for quality improvement because of its high volume, significant associated risk and expense, and variability in its performance affecting outcomes. Therefore, the assurance that high-quality endoscopic procedures are performed has taken increased importance. The 'Korean Gastrointestinal Endoscopy Research Foundation' and 'Korean Society of Gastrointestinal Endoscopy', as ladders in promoting the highest quality patient care, formed endoscopy quality evaluation in 'National Cancer Screening Program' and'Endoscopy Unit Accreditation' in Korea. However, both new systems have not settled down despite efforts of many years and support by the government. In this article, the past and present of quality improvement of gastrointestinal endoscopy will be reviewed, and the future of quality improvement of gastrointestinal endoscopy will be illuminated. PMID- 25530584 TI - Current status and clinical impact of pediatric endoscopy in Korea. AB - BACKGROUND/AIMS: In pediatrics, endoscopic examination has become a common procedure for evaluation of gastrointestinal presentations. However, there are limited data on pediatric endoscopy in Korea. The aim of this study was to analyze the current status and clinical impacts of endoscopic examination in children and adolescents. METHODS: We retrospectively reviewed the medical records of outpatients who visited the tertiary hospital. Patients under 18 years of age who underwent endoscopy were included. Endoscopic findings were classified as specific and normal based on gross findings. Specific endoscopic findings were reflux esophagitis, peptic ulcers, and Mallory-Weiss tear. Other findings included acute gastritis classified according to the updated Sydney system. RESULTS: In 722 of 330,350 patients (0.2%), endoscopic examination (554 esophagogastroduodenoscopies [EGDs], 121 colonos-copies, 47 sigmoidoscopies) was performed between January 2008 and January 2013. In EGD, abdominal pain was the most frequent presentation (64.1%). The most common diagnosis was gastritis (53.2%), followed by reflux esophagitis. The frequency of peptic ulcer disease was 12.8%. Frequent symptoms leading to colonoscopic examination were abdominal pain, diarrhea, and hematochezia. In colonoscopy, a negative result was more likely in children younger than 7 years old. After the procedure, the diagnostic yield of EGD and colonoscopy was 88.1% and 45.8%, respectively, and the rate of change in management was 67.1%. CONCLUSIONS: In pediatrics, endoscopic examination was useful for the choice of therapeutic strategy and it would be a standard method for evaluation of gastrointestinal presentation. PMID- 25530585 TI - The clinical value of 18F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography for predicting regional lymph node metastasis and non-curative surgery in primary gastric carcinoma. AB - BACKGROUND/AIMS: Accurate preoperative detection of regional lymph nodes and evaluation of tumor resectability is critical to determining the most adequate therapy for gastric cancer. The aim of this study is to identify a possible link between 18F-fluorodeoxyglucose (18F-FDG) uptake on PET scan combined with CT scan (PET/CT) and predictions of lymph node metastasis and non-curative surgery. METHODS: This study included 156 gastric cancer patients who underwent preoperative 18F-FDG PET/CT and surgery. In cases with perceptible FDG uptake in the primary tumor or lymph nodes, the maximum standardized uptake value (SUVmax) was calculated. RESULTS: In multivariate analysis, non-curative surgery (OR, 11.05; 95% CI, 1.10-111.08; p=0.041), tumor size (>=3 cm) (OR, 7.39; 95% CI, 2.41 22.70; p<0.001), and lymph node metastasis (OR, 5.47; 95% CI, 2.05-14.64; p=0.001) were significant independent predictors for 18F-FDG uptake in the primary tumors. Tumor size (tumor size >=3 cm) (OR, 3.15; 95% CI, 1.16-8.58; p=0.025) and lymph node metastasis (OR, 3.36; 95% CI, 1.23-9.14; p=0.018) showed significant association with 18F-FDG uptake in lymph node. When the SUVmax of the primary gastric tumor was greater than 3.75, the sensitivity and specificity of PET/CT with regard to the diagnosis of metastatic lymph node were 73.5% and 74.5%. When the SUVmax of the primary gastric tumor was greater than 4.35 and the FDG uptake of lymph nodes was positive, non-curative surgery was predicted with a sensitivity of 58.8% and specificity of 91.6%. CONCLUSIONS: A high FDG uptake of the gastric tumor was related to histologic positive lymph nodes and non-curative surgery. PMID- 25530586 TI - Differences in the adverse effects of azathioprine between inflammatory bowel disease and autoimmune hepatitis in Korean patients. AB - BACKGROUND/AIMS: Azathioprine (AZA) has been widely used in the therapy of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). However, studies evaluating the adverse effects of AZA in these two diseases are lacking. The aim of this study was to compare the adverse effects of AZA in Korean IBD and AIH patients. METHODS: Patients with IBD or AIH who were treated with AZA at Keimyung University Dongsan Medical Center (Daegu, Korea) between January 2002 and March 2011 were enrolled. Their medical records were reviewed retrospectively in terms of clinical characteristics and adverse effects of AZA. RESULTS: A total of 139 IBD patients and 55 AIH patients were finally enrolled. Thirty IBD patients (21.6%) and eight AIH patients (14.5%) experienced adverse effects of AZA. In particular, the prevalence of leukopenia was significantly higher in the IBD group than in the AIH group (p=0.026). T474C mutation was observed in three of 10 patients who were assessed for thiopurine methyltransferase (TPMT) genotype. CONCLUSIONS: IBD patients are at increased risk for the adverse effects of AZA compared with AIH patients, of which leukopenia was the most commonly observed. Therefore, IBD patients receiving AZA therapy should be carefully monitored. PMID- 25530587 TI - [Prognostic factors in patients with advanced pancreatic cancer treated with gemcitabine chemotherapy: clinical characteristics of long-term survivors]. AB - BACKGROUND/AIMS: Gemcitabine-based chemotherapy has been used as a standard treatment in patients with unresectable pancreatic cancer. However, the clinical outcomes of this regimen are still unsatisfactory in prolonging survival. We retrospectively analyzed clinical characteristics of patients with advanced pancreatic cancers who received gemcitabine-based chemotherapy and showed long term survival. METHODS: We enrolled 49 patients who underwent treatment with more than three cycles of gemcitabine-based chemotherapy. Long-term survivor was defined as patient who has survived more than 12 months after diagnosis. The clinical characteristics were analyzed to compare the differences between long term and short-term survivors. Univariate or multivariate analyses were performed to identify prognostic factors associated with chemo-responses. RESULTS: Twenty patients (41%) survived more than 12 months. Long-term survivors had smaller tumor size (OR 2.190, p=0.049, 95% CI 1.005-4.773) and higher serum BUN level (OR 0.833, p=0.039, 95% CI 0.701-0.990) compared to short-term survivors. Overall median and progression-free survivals were 11 and 4 months, respectively. Presence of distant metastasis (hazard ratio 1.441, p=0.035, 95% CI 1.002-2.908) was a significant independent predictor of progression-free survival. Tumor size (hazard ratio 1.534, p=0.004, 95% CI 1.150-2.045) was associated with overall survival. CONCLUSIONS: Gemcitabine chemotherapy may be more effective and allow longer survivals in patients with clinical characters of smaller tumor size and normal serum BUN level at diagnosis. We suggest a well-designed large controlled study to evaluate the prognostic factors such as clinical characteristics and molecular biological features in patients with advanced pancreatic cancers who receive gemcitabine-based chemotherapy. PMID- 25530588 TI - A case of metachronous development of esophageal squamous cell carcinoma in the patient with esophageal carcinosarcoma. AB - Esophageal carcinosarcoma is a rare malignant esophageal neoplasm consisting of both carcinomatous and sarcomatous elements, with an incidence of 0.5%. There have been only a few case reports of carcinosarcoma and squamous cell carcinoma coexisting in the esophagus. However, all of these are cases of synchronous or metachronous development of carcinosarcoma after chemoradiotherapy in patients of esophageal squamous cell carcinoma. A 53-year-old man underwent esophagogas troduodenoscopy because of chest pain for several months. Endoscopic examination revealed a huge pedunculated esophageal polypoid mass. Endoscopic submucosal dissection (ESD) was performed and histopathologic examination confirmed spindle cell carcinoma (carcinosarcoma). He refused additional esophagectomy. After 21 months, third follow-up endoscopy showed poorly-demarcated flat, faint discolored lesions at different location from the previous ESD site and endoscopic biopsies confirmed squamous cell carcinoma. To the best of our knowledge, this is the first case of metachronous development of esophageal squamous cell carcinoma in a patient with esophageal carcinosarcoma. PMID- 25530589 TI - Jackhammer esophagus treated by a peroral endoscopic myotomy. AB - A 49-year-old woman visited our hospital with dysphagia and chest pain. In another hospital, she was diagnosed as reflux esophagitis. Although she had taken proton pump inhibitor and prokinetics drugs for a long time, she was not relieved of any symptoms. On the basis of high resolution manometry and endoscopic ultrasonography findings, Jackhammer esophagus was diagnosed. In this patient, peroral endoscopic myotomy (POEM) was performed for long myotomy of thickened circular muscle. During the procedure, there were no significant complications and she was discharged uneventfully. Symptoms were completely improved during three months after POEM. Here, we report on a case of Jackhammer esophagus treated by POEM. PMID- 25530590 TI - [A case of low-grade fibromyxoid sarcoma of the colon]. AB - Low-grade fibromyxoid sarcoma is a slowly growing soft tissue neoplasm that shows benign histologic features but may have clinical course of malignant disease. It has been reported to occur in the thigh, inguinal area, axilla, shoulder, neck, perineum or buttock. However, there have been few cases of abdominal organ involvement. A 21-year-old woman presented with a large palpable abdominal mass. A 7*4 cm sized round soft tissue tumor at right upper quadrant area was identified by abdominopelvic CT scan. Percutaneous ultrasound-guided biopsy revealed features of spindle cell tumor. On exploration, the tumor originated from transvers colon and was attached to gastrocolic ligament, transverse mesocolon and stomach. The tumor could be dissected with transverse colectomy and partial gastrectomy. The excised tumor, measuring 7*5*5 cm, was well demarcated and appeared as an ovoid mass with firm and myxoid cut surface. She was diagnosed with low-grade fibromyxoid sarcoma arising from transverse colon, and is currently being followed-up without recurrence or metastasis. PMID- 25530591 TI - [A case of splenic hamartoma diagnosed by contrast-enhanced ultrasonography and magnetic resonance imaging]. AB - Splenic hamartoma is a very rare benign tumor, which is usually found incidentally after splenectomy or autopsy. Although percutaneous needle biopsy can be performed, it carries a high risk of bleeding after the procedure. Therefore, diagnosis is usually made by surgical resection. Herein, we report a case of splenic hamartoma diagnosed by magnetic resonance imaging and contrast enhanced ultrasonography, which enables visualization of the unique signals of microbubbles in the vessels in real time. Relevant literature is also reviewed. PMID- 25530592 TI - Suture versus staples for skin closure after cesarean: a metaanalysis. AB - OBJECTIVE: We sought to perform a metaanalysis to synthesize randomized clinical trials of cesarean skin closure by subcuticular absorbable suture vs metal staples for the outcomes of wound complications, pain perception, patient satisfaction, cosmesis, and operating time. STUDY DESIGN: A systematic search was performed using MEDLINE, Cochrane Databases, and ClinicalTrials.gov registries. We included randomized trials comparing absorbable suture vs metal staples for cesarean skin closure. Data were abstracted regarding wound complications, patient pain perception, patient satisfaction, cosmesis as assessed by the physician and patient, and operating time. RESULTS: Twelve randomized trials with data for the primary outcome on 3112 women were identified. Women whose incisions were closed with suture were significantly less likely to have wound complications than those closed with staples (risk ratio, 0.49; 95% confidence interval [CI], 0.28-0.87). This difference remained significant even when wound complications were stratified by obesity. The decrease in wound complications was largely due to the lower incidence of wound separations in those closed with suture (risk ratio, 0.29; 95% CI, 0.20-0.43), as there were no significant differences in infection, hematoma, seroma, or readmission. There were also no significant differences in pain perception, patient satisfaction, and cosmetic assessments between the groups. Operating time was approximately 7 minutes longer in those closed with suture (95% CI, 3.10-11.31). CONCLUSION: For patients undergoing cesarean, closure of the transverse skin incision with suture significantly decreases wound morbidity, specifically wound separation, without significant differences in pain, patient satisfaction, or cosmesis. Suture placement does take 7 minutes longer than staples. PMID- 25530593 TI - Safe vaginal uterine morcellation following total laparoscopic hysterectomy. PMID- 25530594 TI - Reply: To PMID 24949539. PMID- 25530595 TI - Reply: To PMID 25460836. PMID- 25530596 TI - Physicians' obligations to patients infected with Ebola: echoes of acquired immune deficiency syndrome. AB - Physicians across the United States are engaged in training in the identification, isolation, and initial care of patients with Ebola. Some will be asked to do more. The issue this viewpoint will address is the moral obligation of physicians to participate in these activities. In order to do so the implicit contract between society and its physicians will be considered, as will many of the arguments that are redolent of those that were litigated 30 years ago when acquired immune deficiency syndrome (AIDS) was raising public fears to similar levels, and some physicians were publically proclaiming their unwillingness to render care to those individuals. We will build the case that if steps are taken to reduce risks-optimal personal protective equipment and training-to what is essentially the lowest possible level then rendering care should be seen as obligatory. If not, as in the AIDS era there will be an unfair distribution of risk, with those who take their obligations seriously having to go beyond their fair measure of exposure. It would also potentially undermine patients' faith in the altruism of physicians and thereby degrade the esteem in which our profession is held and the trust that underpins the therapeutic relationship. Finally there is an implicit contract with society. Society gives tremendously to us; we encumber a debt from all society does and offers, a debt for which recompense is rarely sought. The mosaic of moral, historical, and professional imperatives to render care to the infected all echoes the words of medicine's moral leaders in the AIDS epidemic. Arnold Relman perhaps put it most succinctly, "the risk of contracting the patient's disease is one of the risks that is inherent in the profession of medicine. Physicians who are not willing to accept that risk...ought not be in the practice of medicine." PMID- 25530597 TI - Resident participation in laparoscopic hysterectomy. PMID- 25530598 TI - Evaluation of ethics education in obstetrics and gynecology residency programs. AB - OBJECTIVE: The objective of the study was to assess the current status of ethics education in obstetrics-gynecology residency programs. STUDY DESIGN: A cross sectional, web-based survey was designed in conjunction with a professional survey laboratory at the University of Chicago. The survey was piloted with a convenience sample of clinical medical ethics fellows to assess question content and clarity. The survey was deployed by e-mail to all obstetrics-gynecology residency program directors. Descriptive statistics were used to analyze participant responses. The University of Chicago's Institutional Review Board deemed this study exempt from institutional review board formal review. RESULTS: Of 242 eligible obstetrics-gynecology residency program directors, 118 (49%) completed the survey. Most respondents were from university-based programs (n = 78, 66%) that were not religiously affiliated (n = 98, 83%) and trained 4-6 residents per postgraduate year (n = 64, 70%). Although 50% of program directors (n = 60) reported having ethics as part of their core curriculum, most programs teach ethics in an unstructured manner. Fifty-seven percent of respondents (n = 66) stated their program dedicated 5 or fewer hours per year to ethics. The majority of program directors (n = 80, 73%) responded they would like more to a lot more ethics education and believed that ethics education should be required (n = 93, 85%) for residents to complete their training. Respondents identified that crowding in the curriculum was a significant barrier to increased ethics training (n = 50, 45%) and two-thirds (n = 74, 67%) reported a lack of faculty expertise as a moderate barrier to providing ethics education in the residency curriculum. CONCLUSION: This study found that a lack of structured curricula, inadequate faculty expertise, and limited time were important barriers for ethics education in obstetrics-gynecology programs across the nation. Despite these existing challenges, program directors have a strong interest in increasing ethics education in residency training. Therefore, additional resources are needed to assist program directors in enhancing resident ethics education. PMID- 25530599 TI - Temporal trends in maternal medical conditions and stillbirth. AB - OBJECTIVE: The objective of this study was to estimate the prevalence and temporal trends of medical conditions among women with stillbirth and to determine the effect of medical comorbidities on the trend of stillbirth. STUDY DESIGN: The Nationwide Inpatient Sample (NIS) for the years 2008-2010 was first queried for all delivery-related discharges. A multivariable logistic regression model was constructed with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) calculated for medical conditions among women with stillbirth. The NIS was then queried for the years 2000-2010, and the effect of maternal medical conditions on the stillbirth rate was estimated. RESULTS: From 2008 to 2010, there were 51,080 deliveries to women with stillbirth, giving a rate of 4.08 per 1000 live births. Women with stillbirth were more likely to be African American (OR, 2.12; 95% CI, 2.07-2.17), with an age less than 25 years (OR, 1.19; 95% CI, 1.16-1.22) or older than 35 years (OR, 1.40; 95% CI, 1.37-1.44) compared with women without stillbirth. Medical conditions such as cardiac, rheumatological, and renal disorders; hypertension; diabetes; thrombophilia; and drug, alcohol and tobacco use, were independent predictors of fetal demise in multivariable logistic regression modeling. From 2000 to 2010, despite an increase in the total number of births to women with comorbidities, there was a significant decrease in the stillbirth rate, which was more pronounced among women with comorbidities compared with women without comorbidities (P=.021). CONCLUSION: From 2000 to 2010, there was a significantly greater decrease in the stillbirth rate among women with maternal medical conditions than there was among women without comorbidities. These findings occurred despite an overall increase in the number of pregnancies to women with medical comorbidities over the time period. Because the NIS does not include information on gestational age, birthweight, or whether subjects had antepartum testing, we are not able to determine the effect of these variables on the observed outcomes. PMID- 25530600 TI - Higher weight status and restrictive eating disorders: an overlooked concern. PMID- 25530601 TI - Health for the world's adolescents: a second chance in the second decade. AB - The World Health Organization has produced a multimedia, interactive online report entitled Health for the World's Adolescents: A Second Chance in the Second Decade. The report provides an overview of global and regional estimates of adolescent mortality and disability-adjusted life years, disaggregated by age, sex, and cause, and country-level data on health-related behaviors and conditions among adolescents. It outlines the reasons why adolescence is a unique period in the life course requiring special attention and synthesizes current thinking about the determinants that underlie the differences in health status between adolescents. For the first time, this new report pulls together recommendations and guidance from across the World Health Organization relating to interventions directed to a range of priority health problems, including use of alcohol and other psychoactive substances, AIDS, injuries, mental health, nutrition, sexual and reproductive health, tobacco use, and violence, focusing on four core functions of the health sector: supportive policies, service provision, strategic information, and working with other sectors. The report concludes with 10 key actions that would strengthen national responses to adolescent health, and outlines the approaches that are needed to overcome the obstacles to accelerating evidence-informed actions to improve the health of adolescents worldwide--with all the benefits that this will have for public health in the present and across the life course, for this generation and the next. PMID- 25530602 TI - Options for assuring access to confidential care for adolescents and young adults in an explanation of benefits environment. AB - The Affordable Care Act (ACA) has expanded the enrollment of young people in insurance plans and aims to increase access to preventive health services. For adolescents and young adults to fully utilize these services, access to confidential care is critical, especially for sensitive services, like sexual and reproductive health care. With this expansion, the ACA inadvertently exposes more individuals (especially those with private insurance) to confidentiality breaches through routine communications in the form of Explanation of Benefits (EOBs) sent to policyholders (typically the parent). This commentary is based on a qualitative study of individual, semi-structured telephone interviews with 31 health care administrators, policy experts, clinicians, and health plan representatives. The study identified and examined five main policy options aimed at reconciling confidentiality protections and EOBs. While no one solution emerged, approaches that incorporate automatic system changes that do not require action from the patient or provider for protections to take effect were considered most effective for protecting confidentiality. The review of these policy options are designed to inform states and health care advocates confronting this issue. In addition, since many of these approaches are new, a better understanding of how they are operationalized and enforced is necessary to truly evaluate their effectiveness. PMID- 25530604 TI - Factors that do not inform HIV providers' decisions to start antiretroviral therapy for young people living with behaviorally acquired HIV. PMID- 25530603 TI - The impact of school subsidies on HIV-related outcomes among adolescent female orphans. AB - PURPOSE: We examine effects of school support as a structural HIV prevention intervention for adolescent female orphans in Zimbabwe after 5 years. METHODS: Three hundred twenty-eight orphan adolescent girls were followed in a clustered randomized controlled trial from 2007 to 2010. The experimental group received school fees, uniforms, and school supplies and were assigned a school-based "helper." In 2011-2012, the control group received delayed partial treatment of school fees only. At the final data point in 2012, survey, HIV, and Herpes Simplex Virus Type 2 (HSV-2) biomarker data were collected from approximately 88% of the sample. Bivariate and multivariate analyses were conducted on end point outcomes, controlling for age, religious affiliation, and baseline socioeconomic status. RESULTS: The two groups did not differ on HIV or HSV-2 biomarkers. The comprehensive 5-year intervention continued to reduce the likelihood of marriage, improve school retention, improve socioeconomic status (food security), and marginally maintain gains in quality of life, even after providing school fees to the control group. CONCLUSIONS: Paying school fees and expenses resulted in significant improvements in life outcomes for orphan adolescent girls. Biological evidence of HIV infection prevention, however, was not observed. Our study adds to the growing body of research on school support as HIV prevention for girls in sub-Saharan Africa, but as yet, no clear picture of effectiveness has emerged. PMID- 25530605 TI - Position Paper of the Society for Adolescent Health and Medicine: medical management of restrictive eating disorders in adolescents and young adults. PMID- 25530606 TI - A review of improved fixation methods for dental implants. Part I: Surface optimization for rapid osseointegration. AB - PURPOSE: Titanium is a primary metallic biomaterial used in load-bearing orthopedic or dental implants because of its favorable mechanical properties and osseointegration capability. This article reviews the current status of surface optimization techniques for titanium implants, whether such concepts are in the form of sufficiently evidence-based, and highlights the related experimental tools. STUDY SELECTION: A strong emphasis was placed on the enhanced biological responses to titanium implants by modifying the surface finishing process. On this basis, a clear partition of surface chemistry and topography was critical. RESULTS: The intrinsic host tissue response to titanium implants is facilitated by the chemistry or topography of a passive oxide film, although the extent to which the surface characteristics enable rapid osseointegration is still uncertain. CONCLUSION: Besides the fundamental requirements, such as the promotion of osteogenic differentiation, the titanium implant surface should accelerate wound-healing phenomena prior to bone ingrowth toward the surface. Moreover, because initial bacterial attachment to the implant surface is unavoidable, infection control by surface modification is also an important determinant in reducing surgical failure. A desirable surface-biological relationship often needs to be characterized at the nanoscale by means of advanced technologies. PMID- 25530607 TI - The prostate urethral lift: will it be uplifting or downgraded as a treatment strategy for benign prostatic hyperplasia? PMID- 25530608 TI - Trends in operative caseload and mortality rates after radical cystectomy for bladder cancer in England for 1998-2010. AB - BACKGROUND: The Improving Outcomes in Urological Cancers guidelines recommended centralisation of cystectomy services to improve outcomes for bladder cancer (BCa) patients. OBJECTIVE: To investigate trends in all-cause and cause-specific survival to see if there was an improvement in survival after centralisation was implemented. To analyse trends in the number of acute hospital trusts undertaking cystectomy. DESIGN, SETTING, AND PARTICIPANTS: We used routine data to capture information on radical cystectomy (RC) in BCa patients aged 20 yr and older between 1998 and 2010 (n=16,033). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We calculated 30-d and 90-d mortality, and 30-d, 90-d, 1-yr, and 5-yr survival. The average number of RCs per trust was derived. Trends were identified using regression analysis. RESULTS AND LIMITATIONS: The 30-d crude mortality decreased from 5.2% to 2.1% (p<0.001) and 90-d crude mortality decreased from 10.3% to 5.1% (p<0.001). There was an increase in 30-d relative survival from 96% to 98% (p<0.001), in 90-d relative survival from 91% to 96% (p<0.001), in 1-yr relative survival from 71% to 80% (p<0.001), and in 5-yr relative survival from 49% to 56% (2004-2006 data; p<0.001). The mean number of RCs performed by trusts in England increased from six to 24 (p<0.001). Smoking status and stage at diagnosis were not available. CONCLUSIONS: Survival after RC has increased alongside decreases in short-term mortality. There is little evidence of a cohort effect. The trends in survival are linear and we conclude that the continued survival improvements are a result of a combination of service improvements that include service reconfiguration, improved surgical training, neoadjuvant chemotherapy, enhanced recovery principles, and continued improvements in perioperative care. PATIENT SUMMARY: We analysed routinely collected hospital data. Outcomes for patients who undergo cystectomy have improved for all age groups. This is likely to be due to a combination of changes in practice. PMID- 25530609 TI - Re: Oliver W. Hakenberg, Eva M. Comperat, Suks Minhas, Andrea Necchi, Chris Protzel, Nick Watkin. EAU Guidelines on Penile Cancer: 2014 Update. Eur Urol 2015;67:142-50. PMID- 25530610 TI - Reply to Kamran Zargar-Shoshtari, Pranav Sharma and Philippe E. Spiess' Letter to the Editor re: Oliver W. Hakenberg, Eva M. Comperat, Suks Minhas, Andrea Necchi, Chris Protzel, Nick Watkin. EAU Guidelines on Penile Cancer: 2014 Update. Eur Urol 2015;67:142-50. PMID- 25530611 TI - Re: Jodi A. Antonelli, Naim M. Maalouf, Margaret S. Pearle, Yair Lotan. Use of the National Health and Nutrition Examination Survey to calculate the impact of obesity and diabetes on cost and prevalence of urolithiasis in 2030. Eur Urol 2014;66:724-9. PMID- 25530612 TI - pi-Helicenes truncated to a minimum: access through a domino approach involving multiple carbopalladations and a Stille coupling. AB - A novel type of pi-helicenes is reported, in which the pi-system is truncated to an all-s-cis all-Z oligoene chain. A domino sequence was developed, consisting of up to four consecutive carbopalladation reactions and a terminal Stille cross coupling, to generate these entities in one step from the respective linear oligoynes. Despite the minimal pi-system, very high optical rotation values were encountered for the single enantiomers. X-ray crystallography confirmed their screw-shaped structure. PMID- 25530613 TI - The sesquiterpene biosynthesis and vessel-occlusion formation in stems of Aquilaria sinensis (Lour.) Gilg trees induced by wounding treatments without variation of microbial communities. AB - As widely recognized, agarwood formation in Aquilaria trees is induced by external wounding. Because agarwood usually harbors specific microbes, the function of microbes in agarwood formation has been debated for almost a century. In this study, two wounding methods, the burning-chisel-drilling method (BCD) and the whole-tree agarwood-inducing method (Agar-Wit), were used under the non contamination of environmental microorganisms. After pyrosequencing the small rRNA subunits of the wounds induced by the BCD and Agar-Wit, no substantial variation was observed either in fungal and bacterial enrichment and diversity or in the relative abundances of taxa. By contrast, significant variations in fungal and bacterial communities were detected following the partial tree pruning (PTP) wounding. The wound-induced sesquiterpene biosynthesis and vessel-occlusion formation, however, were found to be similar in all types of wounded trunks. We thus infer that wounding in the absence of variations in microbial communities may induce agarwood formation. This result does not support the long-standing notion that agarwood formation depends on microbes. PMID- 25530614 TI - Nano-scale spatial assessment of calcium distribution in coccolithophores using synchrotron-based nano-CT and STXM-NEXAFS. AB - Calcified coccolithophores generate calcium carbonate scales around their cell surface. In light of predicted climate change and the global carbon cycle, the biomineralization ability of coccoliths has received growing interest. However, the underlying biomineralization mechanism is not yet well understood; the lack of non-invasive characterizing tools to obtain molecular level information involving biogenic processes and biomineral components remain significant challenges. In the present study, synchrotron-based Nano-computed Tomography (Nano-CT) and Scanning Transmission X-ray Microscopy-Near-edge X-ray Absorption Fine Structure Spectromicroscopy (STXM-NEXAFS) techniques were employed to identify Ca spatial distribution and investigate the compositional chemistry and distinctive features of the association between biomacromolecules and mineral components of calcite present in coccoliths. The Nano-CT results show that the coccolith scale vesicle is similar as a continuous single channel. The mature coccoliths were intracellularly distributed and immediately ejected and located at the exterior surface to form a coccoshpere. The NEXAFS spectromicroscopy results of the Ca L edge clearly demonstrate the existence of two levels of gradients spatially, indicating two distinctive forms of Ca in coccoliths: a crystalline-poor layer surrounded by a relatively crystalline-rich layer. The results show that Sr is absorbed by the coccoliths and that Sr/Ca substitution is rather homogeneous within the coccoliths. Our findings indicate that synchrotron based STXM-NEXAFS and Nano-CT are excellent tools for the study of biominerals and provide information to clarify biomineralization mechanism. PMID- 25530615 TI - Contrast agents for photoacoustic and thermoacoustic imaging: a review. AB - Photoacoustic imaging (PAI) and thermoacoustic imaging (TAI) are two emerging biomedical imaging techniques that both utilize ultrasonic signals as an information carrier. Unique advantages of PAI and TAI are their abilities to provide high resolution functional information such as hemoglobin and blood oxygenation and tissue dielectric properties relevant to physiology and pathology. These two methods, however, may have a limited detection depth and lack of endogenous contrast. An exogenous contrast agent is often needed to effectively resolve these problems. Such agents are able to greatly enhance the imaging contrast and potentially break through the imaging depth limit. Furthermore, a receptor-targeted contrast agent could trace the molecular and cellular biological processes in tissues. Thus, photoacoustic and thermoacoustic molecular imaging can be outstanding tools for early diagnosis, precise lesion localization, and molecular typing of various diseases. The agents also could be used for therapy in conjugation with drugs or in photothermal therapy, where it functions as an enhancer for the integration of diagnosis and therapy. In this article, we present a detailed review about various exogenous contrast agents for photoacoustic and thermoacoustic molecular imaging. In addition, challenges and future directions of photoacoustic and thermoacoustic molecular imaging in the field of translational medicine are also discussed. PMID- 25530616 TI - Emerging regulation and function of betatrophin. AB - Betatrophin, also known as TD26/RIFL/lipasin/ANGPTL8/C19orf80, is a novel protein predominantly expressed in human liver. To date, several betatrophin orthologs have been identified in mammals. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes. Stimulators of betatrophin, such as insulin, thyroid hormone, irisin and caloric intake, are usually relevant to energy expenditure or thermogenesis. In murine models, serum triglyceride levels as well as pancreatic cell proliferation are potently enhanced by betatrophin. Intriguingly, conflicting phenomena have also been reported that betatrophin suppresses hepatic triglyceride levels, suggesting that betatrophin function is mediated by complex regulatory processes. However, its precise physiological role remains unclear at present. In this review, we have summarized the current findings on betatrophin and their implications. PMID- 25530617 TI - Refolded scFv antibody fragment against myoglobin shows rapid reaction kinetics. AB - Myoglobin is one of the early biomarkers for acute myocardial infarction. Recently, we have screened an antibody with unique rapid reaction kinetics toward human myoglobin antigen. Antibodies with rapid reaction kinetics are thought to be an early IgG form produced during early stage of in vivo immunization. We produced a recombinant scFv fragment for the premature antibody from Escherichia coli using refolding technology. The scFv gene was constructed by connection of the V(H)-V(L) sequence with a (Gly4Ser)3 linker. The scFv fragment without the pelB leader sequence was expressed at a high level, but the solubility was extremely low. A high concentration of 8 M urea was used for denaturation. The dilution refolding process in the presence of arginine and the redox reagents GSH and GSSH successfully produced a soluble scFv protein. The resultant refolded scFv protein showed association and dissociation values of 9.32 * 10-4 M-1.s-1 and 6.29 * 10-3 s-1, respectively, with an affinity value exceeding 107 M-1 (k(on)/k(off)), maintaining the original rapid reaction kinetics of the premature antibody. The refolded scFv could provide a platform for protein engineering for the clinical application for diagnosis of heart disease and the development of a continuous biosensor. PMID- 25530620 TI - Genetic Diversity of Talpa Europaea and Nova Hanta Virus (NVAV) in France. AB - Nova hantavirus (NVAV) was first identified in a single European mole (Talpa europaea), captured in Hungary. Analysis of lung tissues from 94 moles captured in France revealed NVAV in 50%. Based on the genetic diversity of the cytochrome b mtDNA, moles collected in Poitiers and Bordeaux were more closely related to the Iberian mole (T. occidentalis), a species previously assumed to be restricted to the Iberian Peninsula. Several hypotheses are discussed to explain these observations: 1) presence of hitherto unnoticed T. occidentalis in southwestern France; 2) existence of an ancient mitochondrial introgression phenomenon between the two Talpa species, producing a particular phenotype in some hybrids; 3) existence of a hybrid zone between the two species; and 4) existence of a new Talpa species. NVAV was not detected in the southwestern moles, which begs the question of the potential presence of a particular Hantavirus sp. in this population and/or in the Iberian moles. PMID- 25530621 TI - Wealth and Health Behavior: Testing the Concept of a Health Cost. AB - Wealthier individuals engage in healthier behavior. This paper seeks to explain this phenomenon by exploiting both inheritances and lottery winnings to test a theory of health behavior. We distinguish between the direct monetary cost and the indirect health cost (value of health lost) of unhealthy consumption. The health cost increases with wealth and the degree of unhealthiness, leading wealthier individuals to consume more healthy and moderately unhealthy, but fewer severely unhealthy goods. The empirical evidence presented suggests that differences in health costs may indeed partially explain behavioral differences, and ultimately health outcomes, between wealth groups. PMID- 25530619 TI - Lunasin sensitivity in non-small cell lung cancer cells is linked to suppression of integrin signaling and changes in histone acetylation. AB - Lunasin is a plant derived bioactive peptide with both cancer chemopreventive and therapeutic activity. We recently showed lunasin inhibits non-small cell lung cancer (NSCLC) cell proliferation in a cell-line-specific manner. We now compared the effects of lunasin treatment of lunasin-sensitive (H661) and lunasin insensitive (H1299) NSCLC cells with respect to lunasin uptake, histone acetylation and integrin signaling. Both cell lines exhibited changes in histone acetylation, with H661 cells showing a unique increase in H4K16 acetylation. Proximity ligation assays demonstrated lunasin interacted with integrins containing alphav, alpha5, beta1 and beta3 subunits to a larger extent in the H661 compared to H1299 cells. Moreover, lunasin specifically disrupted the interaction of beta1 and beta3 subunits with the downstream signaling components phosphorylated Focal Adhesion Kinase (pFAK), Kindlin and Intergrin Linked Kinase in H661 cells. Immunoblot analyses demonstrated lunasin treatment of H661 resulted in reduced levels of pFAK, phosphorylated Akt and phosphorylated ERK1/2 whereas no changes were observed in H1299 cells. Silencing of alphav expression in H661 cells confirmed signaling through integrins containing alphav is essential for proliferation. Moreover, lunasin was unable to further inhibit proliferation in alphav-silenced H661 cells. This indicates antagonism of integrin signaling via alphav-containing integrins is an important component of lunasin's mechanism of action. PMID- 25530618 TI - P2X and P2Y receptors-role in the pathophysiology of the nervous system. AB - Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a number of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus devoted to role of P2 family receptors, in epilepsy, depression, neuropathic pain, nervous system neoplasms, such as glioma and neuroblastoma, neurodegenerative diseases like Parkinson's disease, Alzheimer's disease and multiple sclerosis. The above mentioned conditions are associated with changes in expression of extracellular ectonucleotidases, P2X and P2Y receptors in neurons and glial cells, as well as releasing considerable amounts of nucleotides from activated or damaged nervous tissue cells into the extracellular space, which contributes to disturbance in purinergic signalling. The numerous studies indicate a potential possibility of using synthetic agonists/antagonists of P2 receptors in treatment of selected nervous system diseases. This is of particular significance, since numerous available agents reveal a low effectiveness and often produce side effects. PMID- 25530622 TI - To Wait in Tier 1 or Intervene Immediately: A Randomized Experiment Examining First Grade Response to Intervention (RTI) in Reading. AB - This randomized controlled experiment compared the efficacy of two Response to Intervention (RTI) models - Typical RTI and Dynamic RTI - and included 34 first grade classrooms (n = 522 students) across 10 socio-economically and culturally diverse schools. Typical RTI was designed to follow the two-stage RTI decision rules that wait to assess response to Tier 1 in many districts, whereas Dynamic RTI provided Tier 2 or Tier 3 interventions immediately according to students' initial screening results. Interventions were identical across conditions except for when intervention began. Reading assessments included letter-sound, word, and passage reading, and teacher-reported severity of reading difficulties. An intent to-treat analysis using multi-level modeling indicated an overall effect favoring the Dynamic RTI condition (d = .36); growth curve analyses demonstrated that students in Dynamic RTI showed an immediate score advantage, and effects accumulated across the year. Analyses of standard score outcomes confirmed that students in the Dynamic condition who received Tier 2 and Tier 3 ended the study with significantly higher reading performance than students in the Typical condition. Implications for RTI implementation practice and for future research are discussed. PMID- 25530623 TI - Quantum Blobs. AB - Quantum blobs are the smallest phase space units of phase space compatible with the uncertainty principle of quantum mechanics and having the symplectic group as group of symmetries. Quantum blobs are in a bijective correspondence with the squeezed coherent states from standard quantum mechanics, of which they are a phase space picture. This allows us to propose a substitute for phase space in quantum mechanics. We study the relationship between quantum blobs with a certain class of level sets defined by Fermi for the purpose of representing geometrically quantum states. PMID- 25530624 TI - Feasibility of recruiting peer educators for an online social networking-based health intervention. AB - OBJECTIVE: This study aims to determine the feasibility of recruiting peer leaders to deliver a community-based health intervention using social media. METHOD: We recruited sixteen African American and Latino men who have sex with men (MSM) as peer leaders for either an HIV prevention or general health intervention using social media. Inclusion criteria required that peer leaders were African American or Latino MSM health communication experts experienced using social media. To receive certification, peer leaders attended 3 training sessions on using social media for public health. Questionnaires asking about health knowledge and comfort using social media to discuss health-related topics were provided at baseline and post-training to ensure that peer leaders were qualified post-training. Repeated measures ANOVA models and chi2 tests tested for differences in peer leader knowledge and comfort using social media pre- and post training. RESULTS: After training, peer leaders were significantly more comfortable using social media to discuss sexual positions. There were no significant differences pre- and post-training on other comfort or knowledge measures, as at baseline, almost all peer leaders were already comfortable using social media. CONCLUSION: Results suggest that peer leaders can be recruited who are qualified to conduct health interventions without needing additional training. The discussed training plan can further ensure that any unqualified peer leaders will be prepared after training. To our knowledge, this is the first study to suggest that peer leaders can be recruited as peer health educators to communicate using social media. PMID- 25530625 TI - Developing a Community-Based Definition of Needs for Persons Living with Chronic HIV. AB - With the advent of antiretroviral therapy, HIV has become a chronic illness for those who have access to the medication. But unlike our understanding of acute disease experience which can be grasped within parameters defined by categories of medical diagnosis and treatment, understanding the experience of chronic illness requires that we expand our analytic frame to include variables and perspectives created by the beliefs, behaviors, context, and culture of the participants. Drawing on focus groups conducted among African American, Hispanic, and white people with HIV in Detroit, Michigan, we show that expressions of needs related to the lived experience of HIV vary among racial and ethnic groups and between genders, resulting in an experientially distinct set of needs. PMID- 25530626 TI - Timing and Energy Resolution of new near-UV SiPMs coupled to LaBr3:Ce for TOF PET. AB - The high light output and fast decay time of LaBr3:Ce scintillation detectors leads to excellent timing performance. To realize the potential of timing resolution with LaBr3:Ce we have investigated the performance with SiPMs, which enable 1-to-1 coupling to individual crystals, and which have been optimized for the near-ultraviolet (NUV) scintillation light emission of LaBr3:Ce. Coincidence timing resolution (CTR) of 100 ps was measured for a 4*4*5 mm3 LaBr3:30%Ce crystal directly coupled to a large-area 4*4 mm2 NUV-SiPM. Results show very little dependence on temperature, in the range of -20 degrees to 20 degrees C, and bias voltage, from 2 V to 5 V over breakdown. Optimal performance was achieved at an over-voltage (OV) range of 3 V - 5 V, at which high gain and high photon detection efficiency are achieved. Though saturation was evident at 511 keV, an energy resolution of 6.8% was measured after correcting for non linearity. We also measured a CTR of 110 ps for a 4*4*5mm3 LaBr3:5%Ce crystal and 245 ps for a 4*4*30 mm3 LaBr3:5%Ce crystal using the NUV-SIPM. The poorer timing measurement for the 30-mm long crystal is due mainly to a systematic shift in the time pick-off as a function of the depth-of-interaction. The excellent temperature stability, fast rise time, high gain, and low noise of the NUV-SiPM make it a practical and highly appealing photodetector for the readout of a LaBr3:Ce TOF-PET detector. PMID- 25530627 TI - Socioeconomic Disparities in Fatalistic Beliefs About Cancer Prevention and the Internet. AB - Given the importance of public information environment in cancer control, it is theoretically and practically important to explore how people's media use to acquire health information influences their beliefs about cancer prevention. In the current research, we focus on the role of the Internet in shaping fatalistic beliefs about cancer prevention (cancer fatalism). To be more specific, we examine the effect of Internet use for health information on changes in cancer fatalism using a 2-wave nationally representative survey. We then investigate whether the effect of Internet use on cancer fatalism is moderated by education and health knowledge. Health-related Internet use reduced cancer fatalism only among those with average and lower than the average levels of education and health knowledge. PMID- 25530628 TI - The Moderating Effects of Peer and Parental Support on the Relationship Between Vicarious Victimization and Substance Use. AB - General strain theory (GST) hypothesizes that youth are more likely to engage in delinquency when they experience vicarious victimization, defined as knowing about or witnessing violence perpetrated against others, but that this relationship may be attenuated for those who receive social support from significant others. Based on prospective data from youth aged 8 to 17 participating in the Project on Human Development in Chicago Neighborhoods (PHDCN), this article found mixed support for these hypotheses. Controlling for prior involvement in delinquency, as well as other risk and protective factors, adolescents who reported more vicarious victimization had an increased likelihood of alcohol use in the short term, but not the long term, and victimization was not related to tobacco or marijuana use. Peer support did not moderate the relationship between vicarious victimization and substance use, but family support did. In contrast to strain theory's predictions, the relationship between vicarious victimization and substance use was stronger for those who had higher compared with lower levels of family support. Implications of these findings for strain theory and future research are discussed. PMID- 25530630 TI - Text Comprehension Mediates Morphological Awareness, Syntactic Processing, and Working Memory in Predicting Chinese Written Composition Performance. AB - The goal of the present study was to test opposing views about four issues concerning predictors of individual differences in Chinese written composition: (a) Whether morphological awareness, syntactic processing, and working memory represent distinct and measureable constructs in Chinese or are just manifestations of general language ability; (b) whether they are important predictors of Chinese written composition, and if so, the relative magnitudes and independence of their predictive relations; (c) whether observed predictive relations are mediated by text comprehension; and (d) whether these relations vary or are developmentally invariant across three years of writing development. Based on analyses of the performance of students in grades 4 (n = 246), 5 (n = 242) and 6 (n = 261), the results supported morphological awareness, syntactic processing, and working memory as distinct yet correlated abilities that made independent contributions to predicting Chinese written composition, with working memory as the strongest predictor. However, predictive relations were mediated by text comprehension. The final model accounted for approximately 75 percent of the variance in Chinese written composition. The results were largely developmentally invariant across the three grades from which participants were drawn. PMID- 25530629 TI - Relationship between Low-Income Patient Census and Substance Use Disorder Treatment Programs' Availability of Tobacco Cessation Services. AB - Low income adults with substance use disorders (SUDs) have a high prevalence of tobacco use and often limited access to tobacco cessation treatment. This study examines the relationship between low-income SUD patient census (i.e., percentage of patients whose treatment costs are covered by Medicaid and Federal block grants) and SUD programs' availability of three evidence-based tobacco cessation services: behavioral treatments, system-level support, and pharmacotherapy. Data were collected from a random sample of 1,006 program administrators in 2010. Mixed-effects models results show that the percentage of low-income patients is significantly positively associated with the availability of behavioral treatments and system-level support but not pharmacotherapy. Thus, low-income patients may have similar access to tobacco cessation pharmacotherapy but greater access to behavioral treatments and system-level support. However, the availability of tobacco cessation services is not widespread overall, which may hamper access to extensive services to address low-income SUD patients' high smoking rates. PMID- 25530631 TI - Maternal Employment and Parenting Through Middle Childhood: Contextualizing Factors. AB - The authors used data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (N = 1,364) to examine maternal work hour status and parenting (sensitivity and learning opportunities) from infancy through middle childhood. Work hour status was conceptualized as nonemployment, part time, and full time. Adjusting for covariates, mothers employed part time had higher sensitivity scores and higher provision of child learning opportunity scores than did mothers who were not employed, and these differences characterized families during early childhood rather than middle childhood. Mothers' provision of child learning opportunities was greater when employed full time (vs. part time) during early childhood. In addition to child age, mothers' ethnic minority status and partner status moderated the association between maternal work hour status and mothers' parenting. In general, the findings supported ideas forwarded by role expansionist theory. PMID- 25530632 TI - Ethnic-Racial Stigma and Health Disparities: From Psychological Theory and Evidence to Public Policy Solutions. AB - The presence of diverse ethnic-racial groups in the United States today is a source of national pride. However, this cultural sentiment is overshadowed by the reality that those ethnic-racial groups that are stigmatized carry a disproportionate burden of negative physical health outcomes. These systematic differences are referred to as health disparities. Although this phenomenon is fairly well documented, relatively little is understood about the social contexts and the psychological processes they activate that contribute to poor health. More importantly, to demonstrate the processes underlying health disparities does not single-handedly address the issue of social injustice in the health of disadvantaged people. Scientists must assume the burden of facilitating the translation of their laboratory and community-based research to public policy recommendations. This volume of the Journal of Social Issues brings together social, developmental, cognitive, and clinical psychological research on the physical health of ethnic-racial stigmatized individuals in the United States. Each contribution explicitly discusses the implications of research for public health policy. PMID- 25530634 TI - Poverty, Material Hardship and Depression. AB - OBJECTIVE: Mental health disorders are of great social, economic, and policy concern. A higher incidence of major depressive disorder has been reported among those living in or near poverty. Our study examines the extent to which the relationship between income and depression is mediated by measures of material hardship. METHODS: We use measures of depression at two points in time from the longitudinal Fragile Families Survey to better discern the causal direction of the relationship between income poverty, hardship, and depression. More specifically, we use conditional logistic fixed-effect models that control for time-invariant unmeasured heterogeneity in the sample. RESULTS: We found a strong relationship between hardships and depression. The most prominent hardships were problems paying bills and phone turned off. We also found that hardship helped mediate much, though not all, of the link between poverty and depression in the conditional fixed effect logistic regression models. CONCLUSION: Our policy simulations suggest that public health efforts to reduce depression may be enhanced from efforts that focus on specific forms of material hardship. PMID- 25530633 TI - Coupled Segmentation of Nuclear and Membrane-bound Macromolecules through Voting and Multiphase Level Set. AB - Membrane-bound macromolecules play an important role in tissue architecture and cell-cell communication, and is regulated by almost one-third of the genome. At the optical scale, one group of membrane proteins expresses themselves as linear structures along the cell surface boundaries, while others are sequestered; and this paper targets the former group. Segmentation of these membrane proteins on a cell-by-cell basis enables the quantitative assessment of localization for comparative analysis. However, such membrane proteins typically lack continuity, and their intensity distributions are often very heterogeneous; moreover, nuclei can form large clump, which further impedes the quantification of membrane signals on a cell-by-cell basis. To tackle these problems, we introduce a three step process to (i) regularize the membrane signal through iterative tangential voting, (ii) constrain the location of surface proteins by nuclear features, where clumps of nuclei are segmented through a delaunay triangulation approach, and (iii) assign membrane-bound macromolecules to individual cells through an application of multi-phase geodesic level-set. We have validated our method using both synthetic data and a dataset of 200 images, and are able to demonstrate the efficacy of our approach with superior performance. PMID- 25530635 TI - The Neighborhood Contexts in Which Low-Income Families Navigate Welfare Reform: Evidence from the Three-City Study. AB - We investigate the neighborhood contexts in which low-income families negotiate the new environment created by welfare reform. Using data from the Three-City Study and U.S. Census, we follow 1,059 low-income women from 1999 to 2005tracking their neighborhood quality, employment, and welfare use. Despite living in similar neighborhoods in 1999, women who left welfare experienced larger reductions in neighborhood disadvantage than women who remained on welfare. Likewise, women who left welfare with employment achieved larger increases in neighborhood quality than those who left welfare without work; the latter experiencing neighborhood change no different than those who stayed on welfare. Results indicate that neighborhood conditions are, at minimum, associated with welfare outcomes. We evaluate whether improvements in residential contexts facilitate transitions to economic self-sufficiency, but also test the reverse possibility. Findings suggest that neighborhood quality increases after women leave welfare, though we cannot reject the possibility that better neighborhoods lead to better outcomes. PMID- 25530636 TI - A Model-Free Machine Learning Method for Risk Classification and Survival Probability Prediction. AB - Risk classification and survival probability prediction are two major goals in survival data analysis since they play an important role in patients' risk stratification, long-term diagnosis, and treatment selection. In this article, we propose a new model-free machine learning framework for risk classification and survival probability prediction based on weighted support vector machines. The new procedure does not require any specific parametric or semiparametric model assumption on data, and is therefore capable of capturing nonlinear covariate effects. We use numerous simulation examples to demonstrate finite sample performance of the proposed method under various settings. Applications to a glioma tumor data and a breast cancer gene expression survival data are shown to illustrate the new methodology in real data analysis. PMID- 25530637 TI - (2302) Proposal to reject the name Gonyaulax catenella (Alexandrium catenella) (Dinophyceae). PMID- 25530638 TI - Total synthesis of trifluorobutyryl-modified, globally protected sialyl Lewis x by a convergent [2+2] approach. AB - Structural and quantitative changes in the expression of sialic acid residues on the surface of eukaryotic cells profoundly influence a broad range of biological processes including inflammation, antigen recognition, microbial attachment, and tumor metastasis. Uptake and incorporation of sialic acid analogues in mammalian cells enable structure-function studies and perturbation of specific recognition events. Our group has recently shown that a trifluorobutyryl-modified sialic acid metabolite diminishes the adhesion of mammalian cells to E and P-selectin, presumably by leading to the expression of fluorinated sLex epitopes on cell surfaces, and interfering with the sLex-selectin interactions that are well known in mediating tumor cell migration.1 For studies directed towards understanding the molecular basis of this reduced adhesion, chemical synthesis of trifluorobutyrylated sialyl Lewis x (C4F3--sLex) was crucial. We have developed a highly efficient [2+2] approach for the assembly of C4F3-sLex on a preparative scale that contains versatile protective groups allowing the glycan to be surface immobilized or solubilized as needed for biophysical studies to investigate selectin interactions. This strategy can, in principle, be used for preparation of other N-modified sLex analogues. PMID- 25530639 TI - The Influence of Weather Anomalies on Mercury Cycling in the Marine Coastal Zone of the Southern Baltic-Future Perspective. AB - Despite the decreased emission loads of mercury, historical deposits of this metal in various compartments of the environment may become an additional diffuse source in the future. Global climate change manifests itself in the temperate zone in several ways: warmer winters, shorter icing periods, increased precipitation and heightened frequency of extreme events such as strong gales and floods, all of which cause disturbances in the rate and direction of mercury biogeochemical cycling. The present study was conducted at two sites, Oslonino and Gdynia Orlowo (both in the coastal zone of the Gulf of Gdansk), from which samples were collected once a month between January 2012 and December 2012. In the Southern Baltic region, climate changes can certainly enhance coast to basin fluxes of mercury and the transfer of bioavailable forms of this metal to the food web. They may also, in the future, contribute to uncontrollable increases of mercury in the seawater. PMID- 25530640 TI - Dye Decolourisation Using Two Klebsiella Strains. AB - This study aimed to decolourise different dyes using two Klebsiella strains (Bz4 and Rz7) in different concentrations and incubation conditions. Azo (Evans blue (EB)) and triphenylmethane (brilliant green (BG)) dyes were used individually and in mixture. The toxicity of the biotransformation products was estimated. Both strains had a significant potential to decolourise the dyes in the fluorone, azo and triphenylmethane classes. The type and concentration of dye affects the decolourisation effectiveness. Differences in the dye removal potential were observed particularly in the main experiment. The best results were obtained for Bz4 in the samples with EB (up to 95.4 %) and dye mixture (up to 99 %) and for Rz7 with BG (100 %). The living and dead biomass of the strain Bz4 highly absorbs the dyes. Significant effect of the process conditions was noticed for both strains. The best results were obtained in static and semistatic samples (89-99 %) for the removal of EB and a mixture of dyes and in static samples (100 %) for BG. The decrease in zootoxicity (from class IV/V) was noticed in all samples with living biomass of the strain Bz4 (to class III/IV) and in samples with single dyes for Rz7 (to class III/IV). The decrease in phytotoxicity (from class III/IV) was noticed for Bz4 in the samples with BG and a mixture (to class III) and for Rz7 in the samples with BG (to class III). The process conditions did not affect the changes in toxicity after the process. PMID- 25530641 TI - Advantages and Challenges of Relaxor-PbTiO3 Ferroelectric Crystals for Electroacoustic Transducers- A Review. AB - Relaxor-PbTiO3 (PT) based ferroelectric crystals with the perovskite structure have been investigated over the last few decades due to their ultrahigh piezoelectric coefficients (d33 > 1500 pC/N) and electromechanical coupling factors (k33 > 90%), far outperforming state-of-the-art ferroelectric polycrystalline Pb(Zr,Ti)O3 ceramics, and are at the forefront of advanced electroacoustic applications. In this review, the performance merits of relaxor PT crystals in various electroacoustic devices are presented from a piezoelectric material viewpoint. Opportunities come from not only the ultrahigh properties, specifically coupling and piezoelectric coefficients, but through novel vibration modes and crystallographic/domain engineering. Figure of merits (FOMs) of crystals with various compositions and phases were established for various applications, including medical ultrasonic transducers, underwater transducers, acoustic sensors and tweezers. For each device application, recent developments in relaxor-PT ferroelectric crystals were surveyed and compared with state-of-the art polycrystalline piezoelectrics, with an emphasis on their strong anisotropic features and crystallographic uniqueness, including engineered domain - property relationships. This review starts with an introduction on electroacoustic transducers and the history of piezoelectric materials. The development of the high performance relaxor-PT single crystals, with a focus on their uniqueness in transducer applications, is then discussed. In the third part, various FOMs of piezoelectric materials for a wide range of ultrasound applications, including diagnostic ultrasound, therapeutic ultrasound, underwater acoustic and passive sensors, tactile sensors and acoustic tweezers, are evaluated to provide a thorough understanding of the materials' behavior under operational conditions. Structure-property-performance relationships are then established. Finally, the impacts and challenges of relaxor-PT crystals are summarized to guide on-going and future research in the development of relaxor-PT crystals for the next generation electroacoustic transducers. PMID- 25530642 TI - Assessment of Adult Age differences in Task Engagement: The Utility of Systolic Blood Pressure. AB - The constructs of effort and engagement are central to many theoretical frameworks associated with the study of aging. Age differences in the effort associated with effortful cognitive operations have been hypothesized to account for aging effects in ability, and shifting goals and motivation have been hypothesized to be associated with differential levels of engagement across situations in younger and older adults. Unfortunately, the assessment of effort and engagement-constructs that we view as relatively synonymous-has suffered in the field of aging due to the lack of well-validated measures. We suggest that systolic blood pressure might provide an easy and valid means for examining age differences in mental effort, and present evidence in support of its usage. Existing findings clearly support its potential utility, but further empirical and theoretical work is necessary. PMID- 25530643 TI - Longitudinal Patterns of Women's Marital Quality: The Case of Divorce, Cohabitation, and Race-Ethnicity. AB - Previous work on marital quality has compared average levels of marital quality by demographic characteristics, such as cohabitation, divorce, or race-ethnicity. Less work has examined whether such differences persist over time. To begin to answer this question, this paper uses multigroup latent growth curves to examine changes in marital quality over time in addition to measuring differences in levels of reported marital quality among cohabitors vs. non-cohabitors, divorced vs. stably married women, and members of different racial-ethnic groups. Although many of the differences are small and statistically insignificant, the results show that non-normative and traditionally disadvantaged groups experience not only lower levels of marital quality but that these differences also persist throughout the life course. I also show that using marital instead of relationship duration for cohabitors has substantive implications when interpreting the results. PMID- 25530644 TI - Spatially resolved estimation of ozone-related mortality in the United States under two Representative Concentration Pathways (RCPs) and their uncertainty. AB - The spatial pattern of the uncertainty in air pollution-related health impacts due to climate change has rarely been studied due to the lack of high-resolution model simulations, especially under the Representative Concentration Pathways (RCPs), the latest greenhouse gas emission pathways. We estimated future tropospheric ozone (O3) and related excess mortality and evaluated the associated uncertainties in the continental United States under RCPs. Based on dynamically downscaled climate model simulations, we calculated changes in O3 level at 12 km resolution between the future (2057-2059) and base years (2001-2004) under a low to-medium emission scenario (RCP4.5) and a fossil fuel intensive emission scenario (RCP8.5). We then estimated the excess mortality attributable to changes in O3. Finally, we analyzed the sensitivity of the excess mortality estimates to the input variables and the uncertainty in the excess mortality estimation using Monte Carlo simulations. O3-related premature deaths in the continental U.S. were estimated to be 1,312 deaths/year under RCP8.5 (95% confidence interval (CI): 427 to 2,198) and -2,118 deaths/year under RCP4.5 (95% CI: -3,021 to -1,216), when allowing for climate change and emissions reduction. The uncertainty of O3 related excess mortality estimates was mainly caused by RCP emissions pathways. Excess mortality estimates attributable to the combined effect of climate and emission changes on O3 as well as the associated uncertainties vary substantially in space and so do the most influential input variables. Spatially resolved data is crucial to develop effective community level mitigation and adaptation policy. PMID- 25530646 TI - Testing the Value of Probability Forecasts for Calibrated Combining. AB - We combine the probability forecasts of a real GDP decline from the U.S. Survey of Professional Forecasters, after trimming the forecasts that do not have "value", as measured by the Kuiper Skill Score and in the sense of Merton (1981). For this purpose, we use a simple test to evaluate the probability forecasts. The proposed test does not require the probabilities to be converted to binary forecasts before testing, and it accommodates serial correlation and skewness in the forecasts. We find that the number of forecasters making valuable forecasts decreases sharply as the horizon increases. The beta-transformed linear pool combination scheme, based on the valuable individual forecasts, is shown to outperform the simple average for all horizons on a number of performance measures, including calibration and sharpness. The test helps to identify the good forecasters ex ante, and therefore contributes to the accuracy of the combined forecasts. PMID- 25530645 TI - Evaluations of Interracial Peer Encounters by Majority and Minority U.S. Children and Adolescents. AB - U.S. majority (European-American) and minority (African-American, Latin-American, Asian-American) students were interviewed regarding race-based and non-race based reasons for exclusion in interracial peer dyads (N = 685), evenly divided by gender at 4th, 7th, and 10th grades attending 20 public schools. All students judged race-based exclusion as the most wrong followed by non-raced based reasons such as lack of shared interests, parental discomfort, and peer pressure. Minority students were more likely to judge non-race based exclusion as wrong than were majority students, and were more likely to expect that racial exclusion occurs, indicating that ethnic background and social experience are significantly related to interpretations of interracial peer dyadic reasons for exclusion. PMID- 25530647 TI - Determination of Chlorinated Solvent Sorption by Porous Material-Application to Trichloroethene Vapor on Cement Mortar. AB - Experiments have been performed to investigate the sorption of trichloroethene (TCE) vapor by concrete material or, more specifically, the cement mortar component. Gas-flow experiments were conducted using columns packed with small pieces of cement mortar obtained from the grinding of typical concrete material. Transport and retardation of TCE at high vapor concentrations (500 mg L-1) was compared to that of a non-reactive gas tracer (Sulfur Hexafluoride, SF6). The results show a large magnitude of retardation (retardation factor = 23) and sorption (sorption coefficient = 10.6 cm3 g-1) for TCE, compared to negligible sorption for SF6. This magnitude of sorption obtained with pollutant vapor is much bigger than the one obtained for aqueous-flow experiments conducted for water-saturated systems. The considerable sorption exhibited for TCE under vapor flow conditions is attributed to some combination of accumulation at the air water interface and vapor-phase adsorption, both of which are anticipated to be significant for this system given the large surface area associated with the cement mortar. Transport of both SF6 and TCE was simulated successfully with a two-region physical non-equilibrium model, consistent with the dual-medium structure of the crushed cement mortar. This work emphasizes the importance of taking into account sorption phenomena when modeling transport of volatile organic compounds through concrete material, especially in regard to assessing vapor intrusion. PMID- 25530648 TI - Applying a dual process model of self-regulation: The association between executive working memory capacity, negative urgency, and negative mood induction on pre-potent response inhibition. AB - This study tested a dual-process model of self-control where the combination of high impulsivity (negative urgency - NU), weak reflective / control processes (low executive working memory capacity - E-WMC), and a cognitive load is associated with increased failures to inhibit pre-potent responses on a cued go/no-go task. Using a within-subjects design, a cognitive load with and without negative emotional load was implemented to consider situational factors. Results suggested that: (1) high NU was associated with low E-WMC; (2) low E-WMC significantly predicted more inhibitory control failures across tasks; and (3) there was a significant interaction of E-WMC and NU, revealing those with low E WMC and high NU had the highest rates of inhibitory control failures on all conditions of the task. In conclusion, results suggest that while E-WMC is a strong independent predictor of inhibitory control, NU provides additional information for vulnerability to problems associated with self-regulation. PMID- 25530649 TI - Mindfulness and Emotional Outcomes: Identifying Subgroups of College Students using Latent Profile Analysis. AB - In non-meditating samples, distinct facets of mindfulness are found to be negatively correlated, preventing the meaningful creation of a total mindfulness score. The present study used person-centered analyses to distinguish subgroups of college students based on their mindfulness scores, which allows the examination of individuals who are high (or low) on all facets of mindfulness. Using the Lo-Mendell-Rubin Adjusted LRT test, we settled on a 4-class solution that included a high mindfulness group (high on all 5 facets, N = 245), low mindfulness group (moderately low on all 5 facets, N = 563), judgmentally observing group (high on observing, but low on non-judging and acting with awareness, N =63), and non-judgmentally aware group (low on observing, but high on non-judging and acting with awareness, N =70). Consistent across all emotional outcomes including depressive symptoms, anxiety symptoms (i.e., worry), affective instability, and distress intolerance, we found that the judgmentally observing group had the most maladaptive emotional outcomes followed by the low mindfulness group. Both the high mindfulness group and the non-judgmentally aware group had the most adaptive emotional outcomes. We discuss the implications of person centered analyses to exploring mindfulness as it relates to important psychological health outcomes. PMID- 25530650 TI - Temperament in context: Infant temperament moderates the relationship between perceived neighborhood quality and behavior problems. AB - Hypotheses that positive affect and fear in infancy moderate later relationships between neighborhood quality and behavior problems were examined in a sample of children from the National Longitudinal Survey of Youth. Results suggested that poor neighborhood quality was associated with antisocial behavior at age 6 for children who in infancy were characterized by either high positive affect and low fear or by low positive affect and high fear. Depression/anxiety increased from age 6 to age 12 for children in poor quality neighborhoods who were characterized in infancy by low positive affect. A combination of low fear and high positive affect in infancy appeared to be protective, as it was associated with decreases in depression/anxiety during childhood. These findings suggest the utility of examining multiple dimensions of temperament and of integrating multiple levels of influence into moderational models to understand and prevent the development of childhood symptomatology. PMID- 25530651 TI - Evaluating the NIH Library Editing Service: Pilot Study Used to Analyze Service Impact. AB - Evidence-based librarianship drives initiatives and priorities in today's research centers. To evaluate the effectiveness of the National Institutes of Health (NIH) Library's Editing Service, librarians conducted a pilot study comparing edited manuscripts with the published versions. Using a random number generator, five published journal articles were chosen for evaluation from a pool of NIH manuscripts (n=147) edited between January 2008 and February 2012. A rubric delineating categories of frequently-checked writing elements was used to facilitate quantitative analysis. Findings showed that 84% of editors' suggestions were accepted for three of the published papers that were submitted to the originally intended journal. PMID- 25530652 TI - "Just a Typical Teenager": The Social Ecology of "Normal Adolescence"-Insights from Diabetes Care. AB - In Western society "normal adolescence" is understood to be a biologically driven phase characterized by emotional turmoil and irrational behavior. Despite being discredited within academic literature this discourse persists both in formal theory and everyday use. Drawing on the case of diabetes care, I argue that the discourse of "normal adolescence" derives its power from its value as a vocabulary of motive through which to navigate the contradictions inherent in the social order at this stage of the life-course. While helping us to comprehend sociologically the ecological niche in which "normal adolescence" is sustained, this analysis raises questions about the persistence of this discourse for social action. PMID- 25530653 TI - Exploring Culturally Based Intrafamilial Stressors Among Latino Adolescents. AB - Despite the profound impact that intrafamilial stressors, including parent - adolescent acculturation discrepancies, may have on Latino adolescent behavioral and mental health, this line of research remains underdeveloped. The purpose of this study is to obtain rich descriptions from Latino adolescents of the most salient intrafamilial stressors. The authors employ focus group methodology with a grounded theory approach. A total of 25 focus groups were conducted with 170 Latino adolescents in the Northeast and Southwest United States. Findings indicate that Latino adolescents experience significant stressors related to parent - adolescent acculturation discrepancies. From this qualitative study the authors derive a series of testable hypotheses aimed at fully understanding the role of parent - adolescent acculturation discrepancies on Latino adolescent behavioral and mental health and informing the development of culturally responsive preventive interventions for this population. PMID- 25530655 TI - Do Antioxidant Enzymes and Glutathione Play Roles in the Induction of Hepatic Oxidative Stress in Mice upon Subchronic Exposure to Mixtures of Dichloroacetate and Trichloroacetate? AB - Dichloroacetate (DCA) and trichloroacetate (TCA) are water chlorination byproducts, and their mixtures were previously found to induce additive to greater than additive effects on hepatic oxidative stress (OS) induction in mice after subchronic exposure. To investigate the roles of antioxidant enzymes and glutathione (GSH) in those effects, livers of B6C3F1 mice treated by gavage with 7.5, 15, or 30 mg DCA/kg/day, 12.5, 25, or 50 mg TCA/kg/day, and mixtures (Mix I, Mix II and Mix III) at DCA:TCA ratios corresponding to 7.5:12.5, 15:25 and 25:50 mg/kg/day, respectively, for 13 weeks. Livers were assayed for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), as well as for GSH levels. In general, DCA suppressed SOD and GSH-Px activities and GSH levels but caused no changes in CAT activity; TCA increased SOD and CAT activities, suppressed GSH-Px activity, but did not change GSH levels; mixtures of DCA and TCA increased SOD and CAT activities and suppressed GSH-Px activity and GSH levels. In conclusion, antioxidant enzymes contribute to DCA-, TCA- and mixtures induced OS, but not to changes from additive to greater than additive effects produced by different mixture compositions of the compounds. GSH on the hand may contribute to these changes. PMID- 25530654 TI - INTEGRATING COMPUTATIONAL PROTEIN FUNCTION PREDICTION INTO DRUG DISCOVERY INITIATIVES. AB - Pharmaceutical researchers must evaluate vast numbers of protein sequences and formulate innovative strategies for identifying valid targets and discovering leads against them as a way of accelerating drug discovery. The ever increasing number and diversity of novel protein sequences identified by genomic sequencing projects and the success of worldwide structural genomics initiatives have spurred great interest and impetus in the development of methods for accurate, computationally empowered protein function prediction and active site identification. Previously, in the absence of direct experimental evidence, homology-based protein function annotation remained the gold-standard for in silico analysis and prediction of protein function. However, with the continued exponential expansion of sequence databases, this approach is not always applicable, as fewer query protein sequences demonstrate significant homology to protein gene products of known function. As a result, several non-homology based methods for protein function prediction that are based on sequence features, structure, evolution, biochemical and genetic knowledge have emerged. Herein, we review current bioinformatic programs and approaches for protein function prediction/annotation and discuss their integration into drug discovery initiatives. The development of such methods to annotate protein functional sites and their application to large protein functional families is crucial to successfully utilizing the vast amounts of genomic sequence information available to drug discovery and development processes. PMID- 25530656 TI - The clinicopathologic importance of serum lactic dehydrogenase in patients with gastric cancer. AB - BACKGROUND: To explore possible correlation between serum lactate dehydrogenase (SLDH) levels and gastric cancer. MATERIALS AND METHODS: We retrospectively reviewed 365 patients with gastric cancer. The correlation of SLDH levels with clinicopathologic features and survival rate was studied. RESULTS: SLDH levels were closely associated with the pathological (p) T stage (P = 0.011), metastasis (P = 0.012), pTNM stage (P = 0.001), and recurrence (P = 0.012). Moreover, we found a significant SLDH level difference among Borrmann type (P = 0.027), pT stage (P = 0.004), lymph node metastasis (P = 0.027), metastasis (P < 0.001), pTNM stage (P = 0.006), and recurrence (P = 0.002). In addition, we detected a significant SLDH level difference between alive and dead subgroups (P = 0.001). In addition, both univariate analysis and multivariate analysis showed that high SLDH levels were independent prognostic factor. For the subgroup with normal LDH (median point of 157.0 U/L), we detected that the subset with SLDH levels >=157 U/L (158-245 U/L) showed poorer OS (P = 0.005) and DFS (P = 0.01) than that of <=157 subgroup. CONCLUSIONS: Our results suggest that high SLDH level could be an independent poor prognostic biomarker. Gastric cancer patients with relative high SLDH level (158-245 U/L) were prone to develop a shorter OS and DFS. PMID- 25530657 TI - Functional polymorphisms of matrix metalloproteinases 1 and 9 genes in women with spontaneous preterm birth. AB - OBJECTIVE: The aim of this study was to investigate the association of functional MMP-1-1607 1G/2G and MMP-9-1562 C/T gene polymorphisms with spontaneous preterm birth (SPTB; preterm birth with intact membranes) in European Caucasian women, as well as the contribution of these polymorphisms to different clinical features of women with SPTB. METHODS AND PATIENTS: A case-control study was conducted in 113 women with SPTB and 119 women with term delivery (control group). Genotyping of MMP-1-1607 1G/2G and MMP-9-1562 C/T gene polymorphisms was performed using the combination of polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: There were no statistically significant differences in the distribution of neither individual nor combinations of genotype and allele frequencies of MMP-1-1607 1G/2G and MMP-9-1562 C/T polymorphisms between women with SPTB and control women. Additionally, these polymorphisms do not contribute to any of the clinical characteristics of women with SPTB, including positive and negative family history of SPTB, gestational age at delivery, and maternal age at delivery, nor fetal birth weight. CONCLUSION: We did not find the evidence to support the association of MMP-1-1607 1G/2G and MMP-9-1562 C/T gene polymorphisms with SPTB in European Caucasian women. PMID- 25530659 TI - There's an App for That: Information Technology Applications for Cognitive Behavioral Practitioners. PMID- 25530658 TI - A disease modification effect of APOE E4 on the association between urinary albumin excretion and cognition in Korean adults. AB - BACKGROUND: No previous study examined a disease modifying effect of APOE E4 status on the association between the urinary albumin-to-creatinine ratio (UACR) and cognition. This study aimed to investigate whether APOE E4 modified the association in Korean adults. METHODS: We performed a cross-sectional study in adults aged 45 to 74 who were living in Namwon City, Republic of Korea. Cognitive function was measured with the Korean version of modified Mini-Mental State Examination (K-mMMSE) and cognitive impairment was defined as scores falling below the 25th percentile of the K-mMMSE according to age, sex, and educational attainments. RESULTS: A total of 10,190 participants (4006 men and 6184 women) were analyzed in the present study. Of these, 1698 subjects (16.7%) were APOE E4 carriers. The UACR values were negatively associated with the K-mMMSE scores, even after adjusting for potential confounders including age, sex, education, and vascular risk factors. APOE E4 modified the association significantly, resulting in a steeper decline of cognitive function with the increase in UACR in E4 carriers (P for interaction = 0.021). CONCLUSION: Higher UACR values were significantly associated with cognitive dysfunction in the general Korean population, with cognition in APOE E4 carriers being more severely affected by increased UACR. PMID- 25530661 TI - Sample Size Requirements and Study Duration for Testing Main Effects and Interactions in Completely Randomized Factorial Designs When Time to Event is the Outcome. AB - In this paper we develop the methodology for designing clinical trials with any factorial arrangement when the primary outcome is time to event. We provide a matrix formulation for calculating the sample size and study duration necessary to test any effect with a pre-specified type I error rate and power. Assuming that a time to event follows an exponential distribution, we describe the relationships between the effect size, the power, and the sample size. We present examples for illustration purposes. We provide a simulation study to verify the numerical calculations of the expected number of events and the duration of the trial. The change in the power produced by a reduced number of observations or by accruing no patients to certain factorial combinations is also described. PMID- 25530660 TI - Worker senescence and the sociobiology of aging in ants. AB - Senescence, the decline in physiological and behavioral function with increasing age, has been the focus of significant theoretical and empirical research in a broad array of animal taxa. Preeminent among invertebrate social models of aging are ants, a diverse and ecologically dominant clade of eusocial insects characterized by reproductive and sterile phenotypes. In this review, we critically examine selection for worker lifespan in ants and discuss the relationship between functional senescence, longevity, task performance, and colony fitness. We did not find strong or consistent support for the hypothesis that demographic senescence in ants is programmed, or its corollary prediction that workers that do not experience extrinsic mortality die at an age approximating their lifespan in nature. We present seven hypotheses concerning how selection could favor extended worker lifespan through its positive relationship to colony size and predict that large colony size, under some conditions, should confer multiple and significant fitness advantages. Fitness benefits derived from long worker lifespan could be mediated by increased resource acquisition, efficient division of labor, accuracy of collective decision-making, enhanced allomaternal care and colony defense, lower infection risk, and decreased energetic costs of workforce maintenance. We suggest future avenues of research to examine the evolution of worker lifespan and its relationship to colony fitness, and conclude that an innovative fusion of sociobiology, senescence theory, and mechanistic studies of aging can improve our understanding of the adaptive nature of worker lifespan in ants. PMID- 25530662 TI - Polyculturalism and Sexist Attitudes: Believing Cultures are Dynamic Relates to Lower Sexism. AB - In cultural contexts in which sexist beliefs are considered traditional, shifts toward gender equality represent an example of cultural change. Polyculturalism is defined as the belief that cultures change constantly through different racial and ethnic groups' interactions, influences, and exchanges with each other and, therefore, are dynamic and socially constructed rather than static. Thus, polyculturalism may involve openness to cultural change and, thereby, would be expected to be associated with lower sexist attitudes. Four studies (both cross sectional and longitudinal) with undergraduate and community samples in the Northeastern United States tested whether endorsement of polyculturalism is inversely associated with sexism, above and beyond potentially confounding belief systems. Across studies, for both women and men, endorsement of polyculturalism was associated with lower sexist attitudes for two classes of sexism measures: (a) attitudes toward the rights and roles of women and (b) ambivalent sexist attitudes toward women. Associations remained significant while controlling for potentially confounding variables (colorblindness, conservatism, egalitarianism, gender and ethnic identity, gender and race essentialism, multiculturalism, right wing authoritarianism, and social dominance orientation). Greater openness to criticizing one's culture mediated polyculturalism's association with attitudes toward the rights and roles of women but not with ambivalent sexist attitudes toward women. Studying polyculturalism may provide unique insights into sexism, and more work is needed to understand the mechanisms involved. PMID- 25530663 TI - Assessment of Surgical Effects on Patients with Obstructive Sleep Apnea Syndrome Using Computational Fluid Dynamics Simulations. AB - Obstructive sleep apnea syndrome is one of the most common sleep disorders. To treat patients with this health problem, it is important to detect the severity of this syndrome and occlusion sites in each patient. The goal of this study is to test the hypothesis that the cure of obstructive sleep apnea syndrome by maxillomandibular advancement surgery can be predicted by analyzing the effect of anatomical airway changes on the pressure effort required for normal breathing using a high-fidelity, 3-D numerical model. The employed numerical model consists of: 1) 3-D upper airway geometry construction from patient-specific computed tomographic scans using an image segmentation technique, 2) mixed-element mesh generation of the numerically constructed airway geometry for discretizing the domain of interest, and 3) computational fluid dynamics simulations for predicting the flow field within the airway and the degree of severity of breathing obstruction. In the present study, both laminar and turbulent flow simulations were performed to predict the flow field in the upper airway of the selected patients before and after maxillomandibular advancement surgery. Patients of different body mass indices were also studied to assess their effects. The numerical results were analyzed to evaluate the pressure gradient along the upper airway. The magnitude of the pressure gradient is regarded as the pressure effort required for breathing, and the extent of reduction of the pressure effort is taken to measure the success of the surgery. The description of the employed numerical model, numerical results from simulations of various patients, and suggestion for future work are detailed in this paper. PMID- 25530664 TI - Does Proximity Matter? Distance Dependence of Adolescent Friendships. AB - Geographic proximity is a determinant factor of friendship. Friendship datasets that include detailed geographic information are scarce, and when this information is available, the dependence of friendship on distance is often modelled by pre-specified parametric functions or derived from theory without further empirical assessment. This paper aims to give a detailed representation of the association between distance and the likelihood of friendship existence and friendship dynamics, and how this is modified by a few basic social and individual factors. The data employed is a three-wave network of 336 adolescents living in a small Swedish town, for whom information has been collected on their household locations. The analysis is a three-step process that combines 1) nonparametric logistic regressions to unravel the overall functional form of the dependence of friendship on distance, without assuming it has a particular strength or shape; 2) parametric logistic regressions to construct suitable transformations of distance that can be employed in 3) stochastic models for longitudinal network data, to assess how distance, individual covariates, and network structure shape adolescent friendship dynamics. It was found that the log odds of friendship existence and friendship dynamics decrease smoothly with the logarithm of distance. For adolescents in different schools the dependence is linear, and stronger than for adolescents in the same school. Living nearby accounts, in this dataset, for an aspect of friendship dynamics that is not explicitly modelled by network structure or by individual covariates. In particular, the estimated distance effect is not correlated with reciprocity or transitivity effects. PMID- 25530665 TI - EPIBATIDINE ANALOGS SYNTHESIZED FOR CHARACTERIZATION OF NICOTINIC PHARMACOPHORES A REVIEW. AB - In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200-400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine's unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the alpha4beta2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction. PMID- 25530666 TI - Modern contraceptive use among women in Uganda: An analysis of trend and patterns (1995-2011). AB - There is an extensive body of literature concerning modern contraceptive use among women in Uganda. A questionable aspect however is whether the impact of factors associated with modern contraceptive use has remained the same in the recent past. Demographic Health Survey (DHS) data of women in the period 1995 2011 was adopted to establish an understanding of this issue. The focus in the investigations was none pregnant sexually active women. Variations in patterns of modern contraceptive use were assessed by socio-economic and demographic characteristics of women using a logistic regression based on a complex survey design. In the results, an upward trend in modern contraceptive use - from 11.6% in 1995 to 32.1% in 2011 - shows that progress has been made in this regard. Increased odds of modern contraceptive use across the study period were noted among women with primary and post-primary education, those in urban areas, women in the higher wealth quartiles and those with a higher number of surviving children (p < 0.01). Further, reduced odds of modern contraceptive use across the study period were noted among married women and those in cohabiting relationships (p < 0.05). The study however demonstrates variations in the impact of these factors across the study period. All the same, efforts towards enhancing modern contraceptive use in the near future should focus on enhancing: (i) literacy levels of woman particularly, (ii) access to and affordability of the services, and (iii) awareness campaigns on family planning use targeting both men and women. PMID- 25530667 TI - The Role of Internet Engagement in the Health-knowledge Gap. AB - The current research posits that education leads to differential levels of Internet engagement, which moderate the association between Internet use for health information and general health knowledge. Using a nationally representative survey that covers adults between the ages of 40 and 70 in the United States, it is found that education is positively related to Internet engagement. Also, Internet use has stronger associations with health knowledge for people exhibiting high Internet engagement than for people exhibiting low Internet engagement. The implications of these findings for research on both Internet use and knowledge gaps are discussed. PMID- 25530668 TI - Identifying Baseline and Ceiling Thresholds within the Qualistar Early Learning Quality Rating and Improvement System. PMID- 25530669 TI - Examining Spouse/Partner Presence as a Moderator in the Relationship between Mental Health Symptoms and Alcohol Use in OEF/OIF Veterans. AB - Veterans from the conflicts in Afghanistan (Operation Enduring Freedom; OEF) and Iraq (Operation Iraqi Freedom; OIF) have reported elevated rates of alcohol consumption, and greater depression and posttraumatic stress disorder (PTSD) symptoms are associated with increased alcohol use. Presence of a spouse/partner, which has been associated with reduced drinking, may buffer the relationship between mental health symptoms and alcohol consumption. To examine this hypothesis, the current study utilized baseline survey data from OEF/OIF veterans (N=325) enrolled in a brief alcohol intervention. Spouse/partner presence moderated the relationship between depression symptoms and alcohol consumption such that depression was positively associated with drinking for veterans without a spouse/partner. Exploratory analyses indicated that the relationship between depression and alcohol use may be particularly salient for veterans without a spouse/partner and a lower number of deployments. Spouse/partner presence did not moderate the relationship between PTSD symptoms and alcohol consumption. Implications of the findings are discussed. PMID- 25530670 TI - Reflection-mode micro-spherical fiber-optic probes for in vitro real-time and single-cell level pH sensing. AB - pH sensing at the single-cell level without negatively affecting living cells is very important but still a remaining issue in the biomedical studies. A 70 MUm reflection-mode fiber-optic micro-pH sensor was designed and fabricated by dip coating thin layer of organically modified aerogel onto a tapered spherical probe head. A pH sensitive fluorescent dye 2', 7'-Bis (2-carbonylethyl)-5(6) carboxyfluorescein (BCECF) was employed and covalently bonded within the aerogel networks. By tuning the alkoxide mixing ratio and adjusting hexamethyldisilazane (HMDS) priming procedure, the sensor can be optimized to have high stability and pH sensing ability. The in vitro real-time sensing capability was then demonstrated in a simple spectroscopic way, and showed linear measurement responses with a pH resolution up to an average of 0.049 pH unit within a narrow, but biological meaningful pH range of 6.12-7.81. Its novel characterizations of high spatial resolution, reflection mode operation, fast response and high stability, great linear response within biological meaningful pH range and high pH resolutions, make this novel pH probe a very cost-effective tool for chemical/biological sensing, especially within the single cell level research field. PMID- 25530671 TI - Spermine detection via metal-mediated ethynylarene 'turn-on' fluorescence signaling. AB - A dicarboxylated ethynylarene was shown to behave as a fluorescent chemosensor for millimolar concentrations of polyamines when mixed with Cd(II), Pb(II) or Zn(II) ions at micromolar concentrations. A bathochromic shift and intensification of fluorescence emission was observed with increasing amounts of metal ion in the presence of aqueous polyamines buffered at pH = 7.6. Such perturbations manifested as 'turn-on' signals from a ratiometric comparison of emission intensities at 390 nm versus 340 nm. Using Pb(II) as the metal mediator, spermine was selectively detected as a 40-fold signal enhancement relative to spermidine, putrescine, cadaverine and several other non-biogenic diamines. Evaluation of additional triamine and tetraamine analytes showed the influence that amine group quantity and spacing had on signal generation. By increasing the ratio of Pb(II) relative to ethynylarene, the detection limit for spermine was successfully lowered to a 25 micromolar level. Noncovalent association between ethynylarene, metal ion and polyamine are believed to promote the observed spectroscopic changes. This study exploits the subtle impact that polyamine structural identity has on transition metal chelation to define a new approach towards polyamine chemosensor development. PMID- 25530672 TI - A novel feature selection method and its application. AB - In this paper, a novel feature selection method based on rough sets and mutual information is proposed. The dependency of each feature guides the selection, and mutual information is employed to reduce the features which do not favor addition of dependency significantly. So the dependency of the subset found by our method reaches maximum with small number of features. Since our method evaluates both definitive relevance and uncertain relevance by a combined selection criterion of dependency and class-based distance metric, the feature subset is more relevant than other rough sets based methods. As a result, the subset is near optimal solution. In order to verify the contribution, eight different classification applications are employed. Our method is also employed on a real Alzheimer's disease dataset, and finds a feature subset where classification accuracy arrives at 81.3%. Those present results verify the contribution of our method. PMID- 25530673 TI - Proton-Electron Double-Resonance Imaging of pH using phosphonated trityl probe. AB - Variable Radio Frequency Proton-Electron Double-Resonance Imaging (VRF PEDRI) enables extracting a functional map from a limited number of images acquired at pre-selected EPR frequencies using specifically designed paramagnetic probes with high quality spatial resolution and short acquisition times. In this work we explored potential of VRF PEDRI for pH mapping of aqueous samples using recently synthesized pH-sensitive phosphonated trityl radical, pTR. The ratio of Overhauser enhancements measured at each pixel at two different excitation frequencies corresponding to the resonances of protonated and deprotonated forms of pTR probe allows for a pH map extraction. Long relaxation times of pTR allow for pH mapping at EPR irradiation power as low as 1.25 W during 130 s acquisition time with spatial resolution of about 1 mm. This is particularly important for in vivo applications enabling one to avoid sample overheating by reducing RF power deposition. PMID- 25530674 TI - Predictors of children's food selection: The role of children's perceptions of the health and taste of foods. AB - Food selection, decisions about which foods to eat, is a ubiquitous part of our everyday lives. The aim of this research was to investigate the role of taste versus health perceptions in 4- and 6-year-old children's food selection. In this study, children and young adults were asked to rate the health and presumed taste of foods. Participants were also asked to indicate whether they would eat these foods in a food selection task. Overall, the results showed that taste was a strong predictor of individuals' food selection above and beyond the variance associated with age, health ratings, and interactions between age and presumed taste ratings as well as age and health ratings. These results contribute to our understanding of children's food selection, and the relative importance of a food's taste versus health in the development of these decisions. PMID- 25530675 TI - Effect of anodal transcranial direct current stimulation on autism: a randomized double-blind crossover trial. AB - The aim of this study was to evaluate the Childhood Autism Rating Scale (CARS), Autism Treatment Evaluation Checklist (ATEC), and Children's Global Assessment Scale (CGAS) after anodal transcranial direct current stimulation (tDCS) in individuals with autism. Twenty patients with autism received 5 consecutive days of both sham and active tDCS stimulation (1 mA) in a randomized double-blind crossover trial over the left dorsolateral prefrontal cortex (F3) for 20 minutes in different orders. Measures of CARS, ATEC, and CGAS were administered before treatment and at 7 days posttreatment. The result showed statistical decrease in CARS score (P < 0.001). ATEC total was decreased from 67.25 to 58 (P < 0.001). CGAS was increased at 7 days posttreatment (P = 0.042). Our study suggests that anodal tDCS over the F3 may be a useful clinical tool in autism. PMID- 25530676 TI - Memory and representation in young children with Down syndrome: Exploring deferred imitation and object permanence. AB - Deferred imitation and object permanence (OP) were tested in 48 young children with Down syndrome (DS), ranging from 20 to 43 months of age. Deferred imitation and high-level OP (invisible displacements) have long been held to be synchronous developments during sensory-motor "Stage 6" (18-24 months of age in unimpaired children). The results of the current study demonstrate deferred imitation in young children with DS, showing they can learn novel behaviors from observation and retain multiple models in memory. This is the first demonstration of deferred imitation in young children with DS. The average OP level passed in this sample was A-not-B, a task passed at 8-12 months of age in normally developing infants. Analyses showed that individual children who failed high-level OP (invisible displacements) could still perform deferred imitation. This indicates that deferred imitation and OP invisible displacements are not synchronous developments in children with DS. This asynchrony is compatible with new data from unimpaired children suggesting that deferred imitation and high-level OP entail separate and distinctive kinds of memory and representation. PMID- 25530677 TI - Potassium channel agonists cause penile erection in cats. AB - Using a feline model, erections caused by a new class of vasodilator agents that specifically activate potassium (K+-ATP) channels (lemakalim, nicorandil, and pinacidil) were compared to baseline and maximal erections induced by a standard drug combination (1.65 mg papaverine, 25 MUg phentolamine and 0.5 MUg PGE1) injected intracavernosally. The responses were characterized by the maximal intracavernosal pressure, the duration of maximal pressure, the total duration of drug effect, the change in penile length, and alterations in systemic arterial blood pressure. All three K+-ATP channel openers caused erections in a dose dependent manner. All agents caused similar increases in penile length with full erection, but the duration of maximal pressure and duration of action were significantly shorter (P<0.01) than with the standard drug combination. Lemakalim did not decrease systemic blood pressure as did nicorandil, pinacidil, and the standard drug combination. This study supports the use of an in-vivo feline model for the evaluation of vasoactive agents and suggests that a new class of agents can pharmacologically activate the erectile response selectively by an alternate pathway. PMID- 25530678 TI - An adaptive algorithm for tracking 3D bead displacements: application in biological experiments. AB - This paper presents a feature-vector-based relaxation method (FVRM) to track bead displacements within a three-dimensional (3D) volume. FVRM merges the feature vector method, a technique used in tracking bead displacements in biological gels, with the relaxation method, an algorithm employed successfully in tracking bead pairs in fluids. More specifically, FVRM evaluates the probability of a bead pairing event based on the quasi-rigidity condition between the feature vectors of a bead and its candidate positions within a searching domain. Computational efficiency is improved via the introduction of an adaptive searching domain size and mismatches are reduced via a two-directional matching strategy. The algorithm is validated using simulated 3D bead displacements caused by a force dipole within a linear elastic gel. Results demonstrate a consistently high recovery ratio (above 98%) and low mismatch ratio (below 0.1%) for tracking parameter (mean bead distance/maximum bead displacement) greater than 0.73. PMID- 25530679 TI - Gas-Assisted Annular Microsprayer for Sample Preparation for Time-Resolved Cryo Electron Microscopy. AB - Time-resolved cryo electron microscopy (TRCEM) has emerged as a powerful technique for transient structural characterization of isolated biomacromolecular complexes in their native state within the time scale of seconds to milliseconds. For TRCEM sample preparation, microfluidic device [9] has been demonstrated to be a promising approach to facilitate TRCEM biological sample preparation. It is capable of achieving rapidly aqueous sample mixing, controlled reaction incubation, and sample deposition on electron microscopy (EM) grids for rapid freezing. One of the critical challenges is to transfer samples to cryo-EM grids from the microfluidic device. By using microspraying method, the generated droplet size needs to be controlled to facilitate the thin ice film formation on the grid surface for efficient data collection, while not too thin to be dried out before freezing, i.e., optimized mean droplet size needs to be achieved. In this work, we developed a novel monolithic three dimensional (3D) annular gas assisted microfluidic sprayer using 3D MEMS (MicroElectroMechanical System) fabrication techniques. The microsprayer demonstrated dense and consistent microsprays with average droplet size between 6-9 MUm, which fulfilled the above droplet size requirement for TRCEM sample preparation. With droplet density of around 12-18 per grid window (window size is 58*58 MUm), and the data collectible thin ice region of >50% total wetted area, we collected ~800-1000 high quality CCD micrographs in a 6-8 hour period of continuous effort. This level of output is comparable to what were routinely achieved using cryo-grids prepared by conventional blotting and manual data collection. In this case, weeks of data collection process with the previous device [9] has shortened to a day or two. And hundreds of microliter of valuable sample consumption can be reduced to only a small fraction. PMID- 25530680 TI - Myeloperoxidase oxidized LDL interferes with endothelial cell motility through miR-22 and heme oxygenase 1 induction: possible involvement in reendothelialization of vascular injuries. AB - Cardiovascular disease linked to atherosclerosis is the leading cause of death worldwide. Atherosclerosis is mainly linked to dysfunction in vascular endothelial cells and subendothelial accumulation of oxidized forms of LDL. In the present study, we investigated the role of myeloperoxidase oxidized LDL (Mox LDL) in endothelial cell dysfunction. We studied the effect of proinflammatory Mox-LDL treatment on endothelial cell motility, a parameter essential for normal vascular processes such as angiogenesis and blood vessel repair. This is particularly important in the context of an atheroma plaque, where vascular wall integrity is affected and interference with its repair could contribute to progression of the disease. We investigated in vitro the effect of Mox-LDL on endothelial cells angiogenic properties and we also studied the signalling pathways that could be affected by analysing Mox-LDL effect on the expression of angiogenesis-related genes. We report that Mox-LDL inhibits endothelial cell motility and tubulogenesis through an increase in miR-22 and heme oxygenase 1 expression. Our in vitro data indicate that Mox-LDL interferes with parameters associated with angiogenesis. They suggest that high LDL levels in patients would impair their endothelial cell capacity to cope with a damaged endothelium contributing negatively to the progression of the atheroma plaque. PMID- 25530681 TI - The effect of IL-4 gene polymorphisms on cytokine production in patients with chronic periodontitis and in healthy controls. AB - Chronic periodontitis (CP) is an inflammatory disease of the teeth-supporting tissues in which genetic predisposition, dental plaque bacteria, and immune mechanisms all play important roles. The aim of this study was to evaluate the occurrence of IL-4 gene polymorphisms in chronic periodontitis and to investigate the association between polymorphisms and cytokines production after bacterial stimulation. Sixty-two subjects (47 CP patients and 15 healthy controls) with detected two polymorphisms in the IL-4 gene (-590C/T and intron 3 VNTR) were examined. Production of cytokines (IL-1alpha, IL-1beta, IL-4, IL-5, IL-6, IL-10, IL-17, TNFalpha, INFgamma, and VEGF) was studied after in vitro stimulation of isolated peripheral blood by mitogens (Pokeweed mitogen, Concanavalin A), dental plaque bacteria (Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, and Prevotella intermedia), and Heat Shock Protein (HSP) 70 by the Luminex multiplex cytokine analysis system. The results were correlated with IL-4 genotypes in patients with CP and healthy controls. The mononuclear cells isolated from peripheral blood of CP patients with selected IL 4 polymorphisms significantly altered the production of IFNgamma, IL-10, IL 1beta, IL-1alpha, TNFalpha, and IL-6 after stimulation by HSP 70 or selected bacteria (from P < 0.001 to P < 0.05). IL-4 gene polymorphisms may influence the function of mononuclear cells to produce not only interleukin-4 but also other cytokines, especially in patients with CP. PMID- 25530682 TI - LPS- and LTA-induced expression of IL-6 and TNF-alpha in neonatal and adult blood: role of MAPKs and NF-kappaB. AB - As nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) seem to be critical mediators in the inflammatory response, we studied the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) on (a) the activation of NF-kappaB and MAPKs and (b) the expression of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) with or without the specific inhibitors of these intracellular signal transduction pathways in neonatal cord and adult blood. TNF-alpha and IL-6 concentrations showed a sharp increase in the supernatants of cord and adult whole blood after stimulation. TNF-alpha concentrations were significantly higher, whereas IL-6 concentrations were tendentially lower in adult blood after stimulation. Stimulation with LPS or LTA resulted in a significantly decreased activation of p38 MAPK in neonatal compared with adult blood. Although LTA failed to induce additional ERK1/2 phosphorylation, LPS stimulation mediated the moderately increased levels of activated ERK1/2 in neonatal monocytes. The addition of the p38 MAPK inhibitor SB202190 significantly decreased IL-6 and TNF-alpha production upon LPS or LTA stimulation. Furthermore, the inhibition of ERK1/2 was able to reduce LPS stimulated TNF-alpha production in neonatal blood. We conclude that p38 MAPK as well as ERK1/2 phosphorylation is crucially involved in LPS activation and could explain the differences in early cytokine response between neonatal and adult blood. PMID- 25530683 TI - Pentraxin 3 as a prognostic biomarker in patients with systemic inflammation or infection. AB - PURPOSE: The long pentraxin 3 (PTX3) is a key component of the humoral arm of the innate immune system. PTX3 is produced locally in response to proinflammatory stimuli. We reviewed the usefulness of systemic levels of PTX3 in critically ill patients with systemic inflammatory response syndrome (SIRS), sepsis, and bacteremia, focusing on its diagnostic and prognostic value. METHODS: A PubMed search on PTX3 was conducted. The list of papers was narrowed to original studies of critically ill patients. Eleven papers on original studies of critically ill patients that report on PTX3 in SIRS, sepsis, or bacteremia were identified. RESULTS: Systematic levels of PTX3 have little diagnostic value in critically ill patients with SIRS, sepsis, or bacteremia. Systemic levels of PTX3, however, have superior prognostic power over other commonly used biological markers in these patients. Systemic levels of PTX3 correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of PTX3 remain elevated in the acute phase and decreased on recovery. Notably, the age of the patients and underlying disease affect systemic levels of PTX3. CONCLUSIONS: The diagnostic value of PTX3 is low in patients with sepsis. Systemic levels of PTX3 have prognostic value and may add to prognostication of patients with SIRS or sepsis, complementing severity-of disease classification systems and other biological markers. PMID- 25530685 TI - The importance of ignoring: Alpha oscillations protect selectivity. AB - Selective attention is often thought to entail an enhancement of some task relevant stimulus or attribute. We discuss the perspective that ignoring irrelevant, distracting information plays a complementary role in information processing. Cortical oscillations within the alpha (8-14 Hz) frequency band have emerged as a marker of sensory suppression. This suppression is linked to selective attention for visual, auditory, somatic, and verbal stimuli. Inhibiting processing of irrelevant input makes responses more accurate and timely. It also helps protect material held in short-term memory against disruption. Furthermore, this selective process keeps irrelevant information from distorting the fidelity of memories. Memory is only as good as the perceptual representations on which it is based, and on whose maintenance it depends. Modulation of alpha oscillations can be exploited as an active, purposeful mechanism to help people pay attention and remember the things that matter. PMID- 25530684 TI - Decreased inflammatory responses of human lung epithelial cells after ethanol exposure are mimicked by ethyl pyruvate. AB - BACKGROUND AND PURPOSE: Leukocyte migration into alveolar space plays a critical role in pulmonary inflammation resulting in lung injury. Acute ethanol (EtOH) exposure exerts anti-inflammatory effects. The clinical use of EtOH is critical due to its side effects. Here, we compared effects of EtOH and ethyl pyruvate (EtP) on neutrophil adhesion and activation of cultured alveolar epithelial cells (A549). EXPERIMENTAL APPROACH: Time course and dose-dependent release of interleukin- (IL-) 6 and IL-8 from A549 were measured after pretreatment of A549 with EtP (2.5-10 mM), sodium pyruvate (NaP, 10 mM), or EtOH (85-170 mM), and subsequent lipopolysaccharide or IL-1beta stimulation. Neutrophil adhesion to pretreated and stimulated A549 monolayers and CD54 surface expression were determined. KEY RESULTS: Treating A549 with EtOH or EtP reduced substantially the cytokine-induced release of IL-8 and IL-6. EtOH and EtP (but not NaP) reduced the adhesion of neutrophils to monolayers in a dose- and time-dependent fashion. CD54 expression on A549 decreased after EtOH or EtP treatment before IL-1beta stimulation. CONCLUSIONS AND IMPLICATIONS: EtP reduces secretory and adhesive potential of lung epithelial cells under inflammatory conditions. These findings suggest EtP as a potential treatment alternative that mimics the anti inflammatory effects of EtOH in early inflammatory response in lungs. PMID- 25530686 TI - The Role of Ambulatory Assessment in Psychological Science. AB - We describe the current use and future promise of an innovative methodology, ambulatory assessment (AA), that can be used to investigate psychological, emotional, behavioral, and biological processes of individuals in their daily life. The term AA encompasses a wide range of methods used to study people in their natural environment, including momentary self-report, observational, and physiological. We emphasize applications of AA that integrate two or more of these methods, discuss the smart phone as a hub or access point for AA, and discuss future applications of AA methodology to the science of psychology. We pay particular attention to the development and application of Wireless Body Area Networks (WBANs) that can be implemented with smart phones and wireless physiological monitoring devices, and we close by discussing future applications of this approach to matters relevant to psychological science. PMID- 25530687 TI - Foreword. PMID- 25530688 TI - Controlling the Actuation Rate of Low-Density Shape-Memory Polymer Foams in Water. AB - SMPs have been shown to actuate below their dry glass transition temperatures in the presence of moisture due to plasticization. This behavior has been proposed as a self-actuating mechanism of SMPs in water/physiological media. However, control over the SMP actuation rate, a critical factor for in vivo transcatheter device delivery applications, has not been previously reported. Here, a series of polyurethane SMPs with systematically varied hydrophobicity is described that permits control of the time for their complete shape recovery in water from under 2 min to more than 24 h. This control over the SMP actuation rate can potentially provide significant improvement in their delivery under conditions, which may expose them to high-moisture environments prior to actuation. PMID- 25530689 TI - Composite Bloom Filters for Secure Record Linkage. AB - The process of record linkage seeks to integrate instances that correspond to the same entity. Record linkage has traditionally been performed through the comparison of identifying field values (e.g., Surname), however, when databases are maintained by disparate organizations, the disclosure of such information can breach the privacy of the corresponding individuals. Various private record linkage (PRL) methods have been developed to obscure such identifiers, but they vary widely in their ability to balance competing goals of accuracy, efficiency and security. The tokenization and hashing of field values into Bloom filters (BF) enables greater linkage accuracy and efficiency than other PRL methods, but the encodings may be compromised through frequency-based cryptanalysis. Our objective is to adapt a BF encoding technique to mitigate such attacks with minimal sacrifices in accuracy and efficiency. To accomplish these goals, we introduce a statistically-informed method to generate BF encodings that integrate bits from multiple fields, the frequencies of which are provably associated with a minimum number of fields. Our method enables a user-specified tradeoff between security and accuracy. We compare our encoding method with other techniques using a public dataset of voter registration records and demonstrate that the increases in security come with only minor losses to accuracy. PMID- 25530690 TI - C-plane Reconstructions from Sheaf Acquisition for Ultrasound Electrode Vibration Elastography. AB - This paper presents a novel algorithm for reconstructing and visualizing ablated volumes using radiofrequency ultrasound echo data acquired with the electrode vibration elastography approach. The ablation needle is vibrated using an actuator to generate shear wave pulses that are tracked in the ultrasound image plane at different locations away from the needle. This data is used for reconstructing shear wave velocity maps for each imaging plane. A C-plane reconstruction algorithm is proposed which estimates shear wave velocity values on a collection of transverse planes that are perpendicular to the imaging planes. The algorithm utilizes shear wave velocity maps from different imaging planes that share a common axis of intersection. These C-planes can be used to generate a 3D visualization of the ablated region. Experimental validation of this approach was carried out using data from a tissue mimicking phantom. The shear wave velocity estimates were within 20% of those obtained from a clinical scanner, and a contrast of over 4 dB was obtained between the stiff and soft regions of the phantom. PMID- 25530691 TI - Risk and Protective Factors Associated with Personal Mastery Among Sexual Minority African American Female Sex Workers. AB - Research among sexual minorities has traditionally examined problems such as substance use, HIV risk, mental health problems, and victimization. Among sexual minority street-based female sex workers, these vulnerabilities can be magnified. Grounded in theories of resilience, this study examines risk and protective factors associated with a high level of personal mastery among a vulnerable population of women. Data are drawn from baseline interviews from street-based African American female sex workers enrolled in a randomized intervention trial in Miami, Florida. We compare sexual minority (N=197) and heterosexual (N=365) women on measures of risk and protective factors; among sexual minority women we present logistic regression analyses which reveal that severe mental distress and HIV transmission risk are associated with low levels of personal mastery, while protective factors of transportation access and social support are associated with high levels of personal mastery. These findings suggest that these protective factors may potentially facilitate the development of personal mastery and represent beneficial avenues for intervention efforts. PMID- 25530692 TI - Sociocultural Factors Shaping Technology Usage: Fulfilling the Promise. PMID- 25530693 TI - Patient-Specific Pluripotent Stem Cells in Doxorubicin Cardiotoxicity: A New Window Into Personalized Medicine. PMID- 25530694 TI - Sasaki Metrics for Analysis of Longitudinal Data on Manifolds. AB - Longitudinal data arises in many applications in which the goal is to understand changes in individual entities over time. In this paper, we present a method for analyzing longitudinal data that take values in a Riemannian manifold. A driving application is to characterize anatomical shape changes and to distinguish between trends in anatomy that are healthy versus those that are due to disease. We present a generative hierarchical model in which each individual is modeled by a geodesic trend, which in turn is considered as a perturbation of the mean geodesic trend for the population. Each geodesic in the model can be uniquely parameterized by a starting point and velocity, i.e., a point in the tangent bundle. Comparison between these parameters is achieved through the Sasaki metric, which provides a natural distance metric on the tangent bundle. We develop a statistical hypothesis test for differences between two groups of longitudinal data by generalizing the Hotelling T 2 statistic to manifolds. We demonstrate the ability of these methods to distinguish differences in shape changes in a comparison of longitudinal corpus callosum data in subjects with dementia versus healthily aging controls. PMID- 25530695 TI - Suspended, micron-scale corner cube retroreflectors as ultra-bright optical labels. AB - Corner cube retroreflectors are objects with three mutually perpendicular reflective surfaces that return light directly to its source and are therefore extremely bright and easy to detect. In this work, we have fabricated suspended corner cube retroreflectors, 5 microns in size, consisting of a transparent epoxy core and three surfaces coated with gold as ultra-bright labels for use in a rapid, low-labor diagnostic platform. The authors have demonstrated that individual cubes are easily imaged using low-cost, low numerical aperture objectives in suspension and that they remain suspended over long periods of time. Moreover, we have demonstrated that the gold outer surfaces can be decorated with proteins, and that individual cubes can be bound to magnetic sample preparation particles bearing antibodies which recognize these proteins. The bound cubes can be imaged and tracked as they move through solution in response to an external magnetic field, and we have, as such, demonstrated the principle of the new biosensing approach. PMID- 25530696 TI - Older Adults' Needs for Home Health Care and the Potential for Human Factors Interventions. AB - Demand for home health care is expected to increase as more people are living longer and because older adults rely on home health services to a greater extent than any other population (CDC, 2000). This paper provides an overview of older adults' home health care needs as well as guidance for potential human factors interventions to reduce medical errors and improve quality of care and independence for older patients. Factors discussed include reducing transition and handoff errors, ensuring proper use of medical devices, managing medication, and optimizing home health settings. The importance of considering the role of normal age-related changes in abilities when evaluating patients' needs is highlighted. The goal of this analysis is to provide guidance for human factors interventions in home health care. PMID- 25530697 TI - "Raising the Bar" for Educational Science. PMID- 25530698 TI - Extraneous color affects female macaques' gaze preference for photographs of male conspecifics. AB - Humans find members of the opposite sex more attractive when their image is spatially associated with the color red. This effect even occurs when the red color is not on the skin or clothing (i.e. is extraneous). We hypothesize that this extraneous color effect could be at least partially explained by a low-level and biologically innate generalization process, and so similar extraneous color effects should be observed in non-humans. To test this possibility, we examined the influence of extraneous color in rhesus macaques (Macaca mulatta). Across two experiments, we determined the influence of extraneous red on viewing preferences (assessed by looking time) in free-ranging rhesus monkeys. We presented male and female monkeys with black and white photographs of the hindquarters of same and opposite sex conspecifics on either a red (experimental condition) or blue (control condition) background. As a secondary control, we also presented neutral stimuli (photographs of seashells) on red and blue backgrounds. We found that female monkeys looked longer at a picture of a male scrotum, but not a seashell, on a red background (Experiment 1), while males showed no bias. Neither male nor female monkeys showed an effect of color on looking time for female hindquarters or seashells (Experiment 2). The finding for females viewing males suggests that extraneous color affects preferences among rhesus macaques. Further, it raises the possibility that evolutionary processes gave rise to extraneous color effects during human evolution. PMID- 25530699 TI - RECIPROCAL RESPONSIBILITY AND SOCIAL SUPPORT AMONG WOMEN IN SUBSTANCE USE RECOVERY. AB - This study sought to identify individual- and house-level predictors of women's employment, education, and retention in self-run recovery homes. Data from a national study of 292 women in Oxford House, an international organization of recovery homes grounded on self-help/mutual aid and 12-step principles were analyzed. Results indicated that the house's Reciprocal Responsibility predicted number of days of paid work. Individual and house variables did not predict participation in education. The presence of recovery home members in personal social networks was statistically significant in predicting retention in the recovery home. Lastly, results indicated that number of days of paid work were not predictive of likelihood of substance use in the next 12 months. The findings of this study indicate that the ability to develop social networks and Reciprocal Responsibility in recovery homes can contribute to positive outcomes for women. PMID- 25530700 TI - Genome-Wide Mapping of Chromatin State of Mouse Forelimbs. AB - BACKGROUND: Cell types are defined at the molecular level during embryogenesis by a process called pattern formation and created by the selective utilization of combinations of sequence specific transcription factors. Developmental programs define the sets of genes that are available to each particular cell type, and real-time biochemical signaling interactions define the extent to which these sets are used at any given time and place. Gene expression is regulated through the integrated action of many cis-regulatory elements, including core promoters, enhancers, silencers, and insulators. The chromatin state in developing body parts provides a code to cellular populations that direct their cell fates. Chromatin profiling has been a method of choice for mapping regulatory sequences in cells that go through developmental transitions. RESULTS: We used antibodies against histone H3 lysine 4 trimethylations (H3K4me3) a modification associated with promoters and open/active chromatin, histone H3 lysine 27 trimethylations (H3K27me3) associated with Polycomb-repressed regions and RNA polymerase II (Pol2) associated with transcriptional initiation to identify the chromatin state signature of the mouse forelimb during mid-gestation, at embryonic day 12 (E12). The families of genes marked included those related to transcriptional regulation and embryogenesis. One third of the marked genes were transcriptionally active while only a small fraction were bivalent marked. Sequence specific transcription factors that were activated were involved in cell specification including bone and muscle formation. CONCLUSION: Our results demonstrate that embryonic limb cells do not exhibit the plasticity of the ES cells but are rather programmed for a finer tuning for cell lineage specification. PMID- 25530701 TI - Master Regulators in Plant Glucose Signaling Networks. AB - The daily life of photosynthetic plants revolves around sugar production, transport, storage and utilization, and the complex sugar metabolic and signaling networks integrate internal regulators and environmental cues to govern and sustain plant growth and survival. Although diverse sugar signals have emerged as pivotal regulators from embryogenesis to senescence, glucose is the most ancient and conserved regulatory signal that controls gene and protein expression, cell cycle progression, central and secondary metabolism, as well as growth and developmental programs. Glucose signals are perceived and transduced by two principal mechanisms: direct sensing through glucose sensors and indirect sensing via a variety of energy and metabolite sensors. This review focuses on the comparative and functional analyses of three glucose-modulated master regulators in Arabidopsis thaliana, the hexokinase1 (HXK1) glucose sensor, the energy sensor kinases KIN10/KIN11 inactivated by glucose, and the glucose-activated target of rapamycin (TOR) kinase. These regulators are evolutionarily conserved, but have evolved universal and unique regulatory wiring and functions in plants and animals. They form protein complexes with multiple partners as regulators or effectors to serve distinct functions in different subcellular locales and organs, and play integrative and complementary roles from cellular signaling and metabolism to development in the plant glucose signaling networks. PMID- 25530702 TI - Occurrence and characterization of livestock-associated methicillin-resistant Staphylococcus aureus in pig industries of northern Thailand. AB - This study was conducted to determine the prevalence of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in pigs, farm workers, and the environment in northern Thailand, and to assess LA-MRSA isolate phenotypic characteristics. One hundred and four pig farms were randomly selected from the 21,152 in Chiang Mai and Lamphun provinces in 2012. Nasal and skin swab samples were collected from pigs and farm workers. Environmental swabs (pig stable floor, faucet, and feeder) were also collected. MRSA was identified by conventional bacterial culture technique, with results confirmed by multiplex PCR and multi locus sequence typing (MLST). Herd prevalence of MRSA was 9.61% (10 of 104 farms). Among pigs, workers, and farm environments, prevalence was 0.68% (two of 292 samples), 2.53% (seven of 276 samples), and 1.28% (four of 312 samples), respectively. Thirteen MRSA isolates (seven from workers, four from environmental samples, and two from pigs) were identified as Staphylococcal chromosomal cassette mec IV sequences type 9. Antimicrobial sensitivity tests found 100% of the MRSA isolates resistant to clindamycin, oxytetracycline, and tetracycline, while 100% were susceptible to cloxacillin and vancomycin. All possessed a multidrug-resistant phenotype. This is the first evidence of an LA-MRSA interrelationship among pigs, workers, and the farm environment in Thailand. PMID- 25530705 TI - Using propensity scores in difference-in-differences models to estimate the effects of a policy change. AB - Difference-in-difference (DD) methods are a common strategy for evaluating the effects of policies or programs that are instituted at a particular point in time, such as the implementation of a new law. The DD method compares changes over time in a group unaffected by the policy intervention to the changes over time in a group affected by the policy intervention, and attributes the "difference-in-differences" to the effect of the policy. DD methods provide unbiased effect estimates if the trend over time would have been the same between the intervention and comparison groups in the absence of the intervention. However, a concern with DD models is that the program and intervention groups may differ in ways that would affect their trends over time, or their compositions may change over time. Propensity score methods are commonly used to handle this type of confounding in other non-experimental studies, but the particular considerations when using them in the context of a DD model have not been well investigated. In this paper, we describe the use of propensity scores in conjunction with DD models, in particular investigating a propensity score weighting strategy that weights the four groups (defined by time and intervention status) to be balanced on a set of characteristics. We discuss the conceptual issues associated with this approach, including the need for caution when selecting variables to include in the propensity score model, particularly given the multiple time point nature of the analysis. We illustrate the ideas and method with an application estimating the effects of a new payment and delivery system innovation (an accountable care organization model called the "Alternative Quality Contract" (AQC) implemented by Blue Cross Blue Shield of Massachusetts) on health plan enrollee out-of-pocket mental health service expenditures. We find no evidence that the AQC affected out-of-pocket mental health service expenditures of enrollees. PMID- 25530704 TI - Network-based association of hypoxia-responsive genes with cardiovascular diseases. AB - Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct an hypoxia CVD bipartite network and find several interesting hypoxia-CVD modules with significant Gene Ontology (GO) similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology. PMID- 25530703 TI - Materials approaches for modulating neural tissue responses to implanted microelectrodes through mechanical and biochemical means. AB - Implantable intracortical microelectrodes face an uphill struggle for widespread clinical use. Their potential for treating a wide range of traumatic and degenerative neural disease is hampered by their unreliability in chronic settings. A major factor in this decline in chronic performance is a reactive response of brain tissue, which aims to isolate the implanted device from the rest of the healthy tissue. In this review we present a discussion of materials approaches aimed at modulating the reactive tissue response through mechanical and biochemical means. Benefits and challenges associated with these approaches are analyzed, and the importance of multimodal solutions tested in emerging animal models are presented. PMID- 25530706 TI - ADDRESSING CONFOUNDING WHEN ESTIMATING THE EFFECTS OF LATENT CLASSES ON A DISTAL OUTCOME. AB - Confounding is widely recognized in settings where all variables are fully observed, yet recognition of and statistical methods to address confounding in the context of latent class regression are slowly emerging. In this study we focus on confounding when regressing a distal outcome on latent class; extending standard confounding methods is not straightforward when the treatment of interest is a latent variable. We describe a recent 1-step method, as well as two 3-step methods (modal and pseudoclass assignment) that incorporate propensity score weighting. Using simulated data, we compare the performance of these three adjusted methods to an unadjusted 1-step and unadjusted 3-step method. We also present an applied example regarding adolescent substance use treatment that examines the effect of treatment service class on subsequent substance use problems. Our simulations indicated that the adjusted 1-step method and both adjusted 3-step methods significantly reduced bias arising from confounding relative to the unadjusted 1-step and 3-step approaches. However, the adjusted 1 step method performed better than the adjusted 3-step methods with regard to bias and 95% CI coverage, particularly when class separation was poor. Our applied example also highlighted the importance of addressing confounding - both unadjusted methods indicated significant differences across treatment classes with respect to the outcome, yet these class differences were not significant when using any of the three adjusted methods. Potential confounding should be carefully considered when conducting latent class regression with a distal outcome; failure to do so may results in significantly biased effect estimates or incorrect inferences. PMID- 25530707 TI - A convergent synthesis of carbocyclic sinefungin and its C5 epimer. AB - A convergent synthesis of carbocyclic sinefungin 2 and its C5 epimer 3 is described. The key features in our synthesis include the use of commercial available L-methionine and readily available (1R, 4S)-4-hydroxy-2-cyclopentenyl acetate as starting materials, cross-metathesis coupling, enzymatic kinetic resolution and Staudinger reduction. The current synthesis is flexible and therefore provides convenient access to the synthesis of various carbocyclic SIN analogues for biological evaluation. PMID- 25530708 TI - Three-Dimensional Flexible Electronics Enabled by Shape Memory Polymer Substrates for Responsive Neural Interfaces. AB - Planar electronics processing methods have enabled neural interfaces to become more precise and deliver more information. However, this processing paradigm is inherently 2D and rigid. The resulting mechanical and geometrical mismatch at the biotic-abiotic interface can elicit an immune response that prevents effective stimulation. In this work, a thiol-ene/acrylate shape memory polymer is utilized to create 3D softening substrates for stimulation electrodes. This substrate system is shown to soften in vivo from more than 600 to 6 MPa. A nerve cuff electrode that coils around the vagus nerve in a rat and that drives neural activity is demonstrated. PMID- 25530709 TI - Development of a Spatial and Temporal Agent-Based Model for Studying Water and Health Relationships: The Case Study of Two Villages in Limpopo, South Africa. AB - Diarrhea, the second leading cause of child morbidity and mortality, can have detrimental effects in the physical and cognitive development of children in developing countries. Health interventions (e.g., increased access to health services and safe water) designed to address this problem are difficult to implement in resource-limited settings. In this paper, we present a tool for understanding the complex relationship between water and public health in rural areas of a developing country. A spatial and temporal agent-based model (ABM) was developed to simulate the current water, sanitation, and health status in two villages in Limpopo Province, South Africa. The model was calibrated using empirical data and published sources. It was used to simulate the effects of poor water quality on the frequency of diarrheal episodes in children, and consequently on child development. Preliminary simulation results show that at the current total coliform levels in the water sources of the studied villages, children are expected to experience stunting by as much as -1.0 standard deviations from the World Health Organization height norms. With minor modifications, the calibrated ABM can be used to design and evaluate intervention strategies for improving child health in these villages. The model can also be applied to other regions worldwide that face the same environmental challenges and conditions as the studied villages. PMID- 25530711 TI - Dehalogenation of Functionalized Alkyl Halides in Water at Room Temperature. AB - Alkyl bromides and chlorides can be reduced to the corresponding hydrocarbons utilizing zinc in the presence of an amine additive. The process takes place in water at ambient temperatures, enabled by a commercially available designer surfactant. The reaction medium can be readily recycled, and the amount of organic solvent invested for product isolation is minimal, leading to very low E Factors. PMID- 25530712 TI - The Quest for Ubuntu: Water and Health in Limpopo (WHIL) Partnership. AB - Internationally, efforts to improve health in under-resourced areas of the world frequently involve coalitions, often with at least one partner from the "outside," such as when NGOs or universities from Europe or the US work with institutions and communities in Africa or Asia. Little has been written about applying successful principles to multinational university collaborations as the unit of analysis and where challenges may be magnified by cultural differences and resource imbalances. The purpose of this article is to share the findings from an evaluation of the multi-year interdisciplinary public health Water and Health in Limpopo (WHIL) collaboration between the University of Venda (South Africa) and the University of Virginia (United States). We believe the learnings described easily transfer to collaborative educational endeavors because at their root they speak to the practices that enhance respectful engagement and partnership sustainability. PMID- 25530710 TI - Smoking at the workplace: Effects of genetic and environmental causal accounts on attitudes towards smoking employees and restrictive policies. AB - People hold diverse beliefs regarding the etiologies of individual and group differences in behaviors which, in turn, might affect their attitudes and behaviors. It is important to establish how perceived etiologies for smoking might affect the effectiveness of policy initiatives and prevention efforts. The present study assessed whether exposure to genetic vs. environmental accounts for smoking affects attitudes towards a) workplace-related smoking policies and b) smokers at the workplace. Results indicate that exposure to a genetic explanation led to stronger objections to a smoking restrictive policy compared with a non genetic explanation. Additionally, participants in the genetic condition were more accepting of a smoker in the workplace than in the environmental condition. Evidently, beliefs about the etiology of smoking influence a range of attitudes related to smokers and smoking related policies. PMID- 25530713 TI - Are care workers appropriate mentors for nursing students in residential aged care? AB - BACKGROUND: The aged care sector is increasingly dominated by a less-qualified workforce at a time of increasing prevalence of complex health concerns, such as dementia. An Australian program to develop teaching aged care facilities is being undertaken to build the sector's capacity and provide nursing students with positive experiences of engaging with vulnerable clients. This research aimed to examine care staff potential to facilitate nursing student engagement with clinically relevant knowledge in the performance of hygiene care in a residential aged care facility. METHODS: This study was designed as an action research study. A cycle of reflection, planning, action, and evaluation is described to illustrate the carer mentor capacity to engage with and contribute to the learning of nursing students. Participants were second year student nurses (n = 10) on a four-week placement in a Tasmanian aged care facility in 2013 and their nurse/carer mentors (n = 17). Mentors participated in six action research meetings, and nursing students engaged in a parallel series of four feedback meetings during the placement. RESULTS: At the beginning of the placement, nursing students exhibited a disregard for the clinical value of care provision. Students considered provision of hygiene care, in particular, the preserve of care workers and an inappropriate training exercise in the context of an undergraduate nursing qualification. To assist students to make links between core nursing competencies and hygiene care as well as to engender respect for their role within the aged care facility, carer mentors developed the Carer Assessment and Reporting Guide. Once implemented during the final weeks of the placement, the Guide improved student perceptions of resident hygiene care (reframed as assessment) and the role of facility care workers, as well as reinforcing carer self-esteem. CONCLUSION: Hygiene care is replete with nursing competencies that are valuable for undergraduate learners, including assessments of skin integrity, mobility, cognitive function, bowels and urine, and basic hygiene. Nurse education programs should strive to address student misconceptions about care work in facilities to account for population level increases in care needs. PMID- 25530714 TI - Optimization of a therapeutic electromagnetic field (EMF) to retard breast cancer tumor growth and vascularity. AB - BACKGROUND: This study provided additional data on the effects of a therapeutic electromagnetic field (EMF) device on growth and vascularization of murine 16/C mammary adenocarcinoma cells implanted in C3H/HeJ mice. METHODS: The therapeutic EMF device generated a defined 120 Hz semi sine wave pulse signal of variable intensity. Murine 16/C mammary adenocarcinoma tumor fragments were implanted subcutaneously between the scapulae of syngeneic C3H mice. Once the tumor grew to 100 mm(3), daily EMF treatments were started by placing the cage of mice within the EMF field. Treatment ranged from 10 to 20 milli-Tesla (mT) and was given for 3 to 80 minutes either once or twice a day for 12 days. Tumors were measured and volumes calculated each 3-4 days. RESULTS: Therapeutic EMF treatment significantly suppressed tumor growth in all 7 EMF treated groups. Exposure to 20mT for 10 minutes twice a day was the most effective tumor growth suppressor. The effect of EMF treatment on extent of tumor vascularization, necrosis and viable area was determined after euthanasia. The EMF reduced the vascular (CD31 immunohistochemically positive) volume fraction and increased the necrotic volume of the tumor. Treatment with 15 mT for 10 min/d gave the maximum anti-angiogenic effect. Lack of a significant correlation between tumor CD 31 positive area and tumor growth rate indicates a mechanism for suppression of tumor growth in addition to suppression of tumor vascularization. CONCLUSION: It is proposed that EMF therapy aimed at suppression of tumor growth and vascularization may prove a safe alternative for patients whether they are or are not candidates for conventional cancer therapy. PMID- 25530715 TI - The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway. AB - BACKGROUND: The mechanism underlying the differential cytotoxicity of curcumin in various cancer types, however, remains largely unclear. The aims of this study is to examine the concentration- and time-related effects of curcumin on two different breast cancer cells, MCF-7 and MDA-MB-231, and investigated the functional changes induced by curcumin treatment, as well as their relationship to the PI3K/Akt-SKP2-Cip/Kips pathway. METHODS: First, WST-1 and clonogenic assay were performed to determine the cytotoxicity of curcumin in MCF-7 and MDA-MB-231 cells. Then, the expression of CDK interacting protein/Kinase inhibitory protein (Cip/Kips) members (p27, p21 and p57) and S-phase kinase-associated protein-2 (SKP2) was investigated by QRT PCR and Western Blotting. Curcumin's effect on PI3K (phosphatidylinositol 3-kinase) /Akt and its substrates Foxo1 and Foxo3a were then studied by Western Blotting. Small interfering RNAs (siRNAs) targeting SKP2 was used to explore the relationship between SKP2 and Cip/Kips members. Finally, WST-1 assay was tested to explore the concomitant treatment with curcumin and the inhibition of PKB or SKP2 signaling on curcumin sensitivity in MCF-7 and MDA-MB-231 cells. RESULTS: We demonstrated MCF-7 and MDA-MB-231 cells exhibited differential responses to curcumin by WST-1 and clonogenic assay (MDA MB-231 cells was sensitive, and MCF-7 cells was resistant), which were found to be related to the differential curcumin-mediated regulation of SKP2-Cip/Kips (p21 and p27 but not p57) signaling. The differential cellular responses were further linked to the converse effects of curcumin on PI3K/Akt and its substrates Foxo1 and Foxo3a. Importantly, PI3K inhibitor wortmannin could counteract both curcumin induced phosphorylation of Akt and up-regulation of SKP2 in MCF-7 cells. Subsequent WST-1 assay demonstrated concomitant treatment with curcumin and wortmannin or SKP2 siRNA not only further augmented curcumin sensitivity in MDA MB-231 cells but also overcame curcumin resistance in MCF-7 cells. CONCLUSIONS: Our study established PI3K/Akt-SKP2-Cip/Kips signaling pathway is involved in the mechanism of action of curcumin and revealed that the discrepant modulation of this pathway by curcumin is responsible for the differential susceptibilities of these two cell types to curcumin. PMID- 25530716 TI - A polymethoxyflavone from Laggera pterodonta induces apoptosis in imatinib resistant K562R cells via activation of the intrinsic apoptosis pathway. AB - BACKGROUND: Treatment with imatinib mesylate (IM) (a tyrosine kinase inhibitor) is the first line of standard care for patients newly diagnosed with CML. Despite the success of IM and other tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains largely incurable, and a number of CML patients die due to Abl mutation-related drug resistance and blast crisis. 3, 5-Dihydroxy-6, 7, 3'4' tetramethoxyflavone (DHTMF) is a polymethoxyflavone isolated from Laggera pterodonta which is a herbal medicine used to treat cancer in the Chinese folk. In the previous study, we found DHTMF demonstrated good antiproliferative activities against a number of cancer cell lines and induced the apoptosis of CNE cells in vitro in a time- and dose-dependent manner while exhibiting low cytotoxicity in the two normal cell lines Vero and EVC304. The aim of the present study was to evaluate the proliferation inhibition and apoptosis induced by DHTMF alone and in combination with IM in the IM-resistant CML cell line K562R. METHODS: Cell proliferation was assayed with the cell counting kit-8 (CCK8) method. The apoptosis percentage was determined by flow cytometry (FCM). Mitochondrial transmembrane potential was detected using FCM and confocal laser scanning microscopy. The level of proteins involved in apoptosis was detected by Western blotting. RESULTS: DHTMF suppressed K562R cell viability in both time- and dose-dependent manners. DHTMF combined with IM enhanced the inhibitory effects and apoptosis in K562R cells as compared with DHTMF alone. DHTMF alone and in combination with IM significantly decreased the mitochondrial membrane potential and increased the levels of cleaved caspase-9, caspase-7, caspase-3, and PARP in K562R cells. CONCLUSIONS: We demonstrated that DHTMF could inhibit IM resistant K562R cell proliferation and induces apoptosis via the intrinsic mitochondrial apoptotic pathway. These results suggest that DHTMF may be a potential therapeutic drug with lower side effects against IM resistance in CML cells. PMID- 25530717 TI - Induction of H2AX phosphorylation in tumor cells by gossypol acetic acid is mediated by phosphatidylinositol 3-kinase (PI3K) family. AB - BACKGROUND: H2AX is phosphorylated (gammaH2AX) by members of the phosphatidylinositol 3-kinase (PI3K) family, including Ataxia telangiectasia mutated (ATM), ATM- and Rad3-related (ATR) and DNA-PK in response to DNA damage. Our study shows that gossypol acetic acid (GAA) alone can induce gammaH2AX in Human mucoepidermoid carcinoma cell line (MEC-1) in vitro. Thus, we further examined the possible mechanisms of GAA to induce gammaH2AX in tumor cells. MATERIALS AND METHODS: The PI3K inhibitors caffeine and wortmannin were used in an effort to identify the kinase(s) responsible for GAA -induced gammaH2AX in MEC 1 cells. DNA dependent protein kinase (DNA-PK) - proficient and -deficient cells, human glioma cell lines M059K and M059J, were also used to evaluate the kinases responsible for GAA induced H2AX phosphorylation. gammaH2AX expression was detected by immunofluorescent microscopy. Flow cytometry assay was used to assay gammaH2AX and cell cycle. RESULTS: GAA induced H2AX phosphorylation in a cell cycle-dependent manner and a significant G0/G1 phase arrest in MEC-1 cells was shown. Caffeine and wortmannin significantly inhibited GAA-induced H2AX phosphorylation in MEC-1 cells. GAA induced H2AX phosphorylation in M059K, but not in M059J. Taken together, these data suggested that GAA treatment alone could induce H2AX phosphorylation in a cell cycle dependent manner in MEC-1 and M059K, but not in M059J cells. A significant G0/G1 phase arrest was shown in MEC-1. CONCLUSIONS: The member of PI3K family, DNA-PK, ATM and ATR are involved in the H2AX phosphorylation of MEC-1 cells. PMID- 25530718 TI - Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats. AB - BACKGROUND: Sepsis causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Radix Ginseng (RG), a traditional herb used as herbal remedy in eastern Asia for thousands of years, which has been traditionally used in China to improve blood circulation and ameliorate pathological hemostasis. This study investigated whether Ginsenoside Rb1, the main components of RG, can attenuate ALI induced by LPS. METHODS: In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Ginsenoside Rb1 (5 mg/kg) treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, the number of myeloperoxidase (MPO) positive cells, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), gene expression of ICAM-1, ultrastructure changes of pulmonary microvasculature, concentration of inflammatory markers and in plasma. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Ginsenoside Rb1 (50 mM), nuclear factor-kappaB (NF kappaB) p65 was measured by immunocytochemistry staining and western blotting. RESULTS: Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils and hemorrhage, the increase in lung W/D ratio, the number of MPO positive cells, the level of inflammatory markers such as TNF-alpha, MCP-1 and IL-8, enhanced expression of ICAM-1 and ICAM 1 gene. Moreover, resulted in the changes of intercellular junctions in the endothelial cells of pulmonary microvasculature. In vitro, the significant increased release of NF-kappaB p65 and its subsequent translocation into the nucleus in PMVECs were observed. In contrast, Ginsenoside Rb1 treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. CONCLUSIONS: These results indicate that Ginsenoside Rb1 attenuated LPS-induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on proinflammatory molecules. PMID- 25530719 TI - Evaluation of the usefulness of a D dimer test in combination with clinical pretest probability score in the prediction and exclusion of Venous Thromboembolism by medical residents. AB - INTRODUCTION: Venous thromboembolism (VTE) requires urgent diagnosis and treatment to avoid related complications. Clinical presentations of VTE are nonspecific and require definitive confirmation by imaging techniques. A clinical pretest probability (PTP) score system helps predict VTE and reduces the need for costly imaging studies. d-dimer (DD) assay has been used to screen patients for VTE and has shown to be specific for VTE. The combined use of PTP and DD assay may improve exclusion of VTE and safely avoid imaging studies. MATERIALS AND METHODS: We prospectively used the Wells PTP score and a DD test to evaluate 230 consecutive patients who presented with VTE symptoms. The receiver operating characteristic curve was used to identify a new DD cutoff value, which was applied to VTE diagnosis and compared with the upper limit of locally established reference range for prediction of thrombosis alone and in combination with the clinical PTP score. RESULTS: We evaluated 118 patients with VTE symptoms fulfilling the inclusion criteria, 64 (54.2%) with clinically suspected deep vein thrombosis (DVT) and 54 (45.8%) with symptoms of pulmonary embolism (PE). The PTP was low in 28 (43.8%) and moderate/high in 36 (56.25%) of the suspected DVT patients, and low in 29 (53.7%) and moderate/high in 25 (46.3%) of the suspected PE patients. Eighteen cases were confirmed by imaging studies: 9 DVT and 9 PE. The agreement between confirmed cases and PTP was significant with PE but not DVT. The negative predictive value for both DVT and PE with current DD cutoff value of <250 MUg/L DDU was 100%, whereas with the calculated cutoff the NPV was 88%. CONCLUSIONS: We confirm that PTP score is valuable tool for medical residents to improve the detection accuracy of VTE, especially for PE. The DD cutoff value of 250 MUg/L FEU is ideal for excluding most cases of low PTP; however, the calculated cutoff was less specific for the exclusion of VTE. PMID- 25530720 TI - Genetic loci associated with Alzheimer's disease. AB - The article by Lambert et al. reports the identification of 11 novel susceptibility loci for late-onset Alzheimer's disease. The observations of this study significantly enhance the field since they further disentangle the genetic causes and pathways underlying Alzheimer's disease by identifying novel disease associated variants clustering in specific pathways. These pathways include APP processing, lipid metabolism, inflammation/immune response, intracellular trafficking/endocytosis, tau metabolism, synaptic function. All of the newly identified disease-associated variants have small effect sizes with increases in risk of 10-20%. The cumulative population attributable fraction associated with known genetic variants amounts now to approximately 80%. This article also underlines the ongoing value of genome-wide association studies for identification of causative common variants in the era of whole-exome and whole genome sequencing studies. PMID- 25530721 TI - Animal models of stroke: translational potential at present and in 2050. AB - Translation from basic science bench research in ischemic stroke to bedside treatment of patients suffering ischemic stroke remains a difficult challenge. Despite literally hundreds of compounds and interventions that provide benefit in experimental models of cerebral ischemia, efficacy in humans remains to be demonstrated. The reasons for failure to translate the extensive positive basic science findings to successful clinical trials have been the focus of discussion for years. Some attribute the failure to flaws in clinical trial design, others question the predictive value of current animal models and some question the quality of preclinical data. It is likely that a combination of all these shortcomings have ultimately led to the failure. The purpose of this review is to analyze the commonly used animal models used in the field today, provide a framework for understanding the current state of basic science research in the ischemic stroke field and discuss a path forward. PMID- 25530722 TI - Relationship with God, Loneliness, Anger and Symptom Distress in Patients with Cancer Who are Near the End of Life. PMID- 25530724 TI - Testing for Measurement Invariance in the Conformity to Masculine Norms-46 Across White and Asian American College Men: Development and Validity of the CMNI-29. AB - The Conformity to Masculine Norms Inventory (CMNI; Mahalik et al., 2003) and revised CMNI-46 (Parent & Moradi, 2009) have received a great deal of empirical attention and support for their strong psychometric properties and evidence of construct validity. However, one important area that remains unexplored is how adherence to these masculine norms may vary across race and ethnicity. The current investigation examines the possible racial measurement noninvariance in the CMNI-46 among Asian American and White American college students (N = 893). The results revealed significant measurement differences across groups; specifically, the CMNI-46 was more theoretically consistent for the White American men than the Asian American men. Through exploratory and multigroup confirmatory factor analysis, an 8-factor, 29-item version of the CMNI emerged, displaying an excellent overall model fit for both racial groups. This study provides strong evidence for the use of a streamlined 29-item version of the CMNI, validated with Asian American and White American men. The findings also lend further empirical and psychometric evidence regarding the variance of masculine norms among ethnic groups as well as the variance of the multidimensional construct of masculinity. PMID- 25530723 TI - Residual Paralysis: Does it Influence Outcome After Ambulatory Surgery? AB - Neuromuscular blocking agents are used to facilitate tracheal intubation in patients undergoing ambulatory surgery. The use of high-dose neuromuscular blocking agents to achieve muscle paralysis throughout the case carries an increased risk of residual post-operative neuromuscular blockade, which is associated with increased respiratory morbidity. Visually monitoring the train-of four (TOF) fade is not sensitive enough to detect a TOF fade between 0.4 and 0.9. A ratio <0.9 indicates inadequate recovery. Quantitative neuromuscular transmission monitoring (e.g., acceleromyography) should be used to exclude residual neuromuscular blockade at the end of the case. Residual neuromuscular blockade needs to be reversed with neostigmine, but it's use must be guided by TOF monitoring results since deep block cannot be reversed, and neostigmine administration after complete recovery of the TOF-ratio can induce muscle weakness. The development and use of new selectively binding reversal agents (sugammadex and calabadion) warrants reevaluation of this area of clinical practice. PMID- 25530725 TI - The Effects of Early Institutionalization on the Discrimination of Facial Expressions of Emotion in Young Children. AB - The current study examined the effects of institutionalization on the discrimination of facial expressions of emotion in 3 groups of 42-month-old children. One group consisted of children abandoned at birth who were randomly assigned to Care as Usual (institutional care) following a baseline assessment. Another group consisted of children abandoned at birth who were randomly assigned to high-quality foster care following a baseline assessment. A third group consisted of never-institutionalized children who were reared by their biological parents. All children were familiarized to happy, sad, fearful, and neutral facial expressions and tested on their ability to discriminate familiar versus novel facial expressions. Contrary to our prediction, all three groups of children were equally able to discriminate among the different expressions. Furthermore, in contrast to findings at 13-30 months of age, these same children showed familiarity rather than novelty preferences toward different expressions. There were also asymmetries in children's discrimination of facial expressions depending on which facial expression served as the familiar versus the novel stimulus. Collectively, early institutionalization appears not to impact the development of the ability to discriminate facial expressions of emotion, at least when preferential looking serves as the dependent measure. These findings are discussed in the context of the myriad domains that are affected by early institutionalization. PMID- 25530727 TI - Cluster Analysis of the Klein Sexual Orientation Grid in Clinical and Nonclinical Samples: When Bisexuality Is Not Bisexuality. AB - We used a cluster analysis to empirically address whether sexual orientation is a continuum or can usefully be divided into categories such as heterosexual, homosexual, and bisexual using scores on the Klein Sexual Orientation Grid (KSOG) in three samples: groups of men and women recruited through bisexual groups and the Internet (Main Study men; Main Study women), and men recruited for a clinical study of HIV and the nervous system (HIV Study men). A five-cluster classification was chosen for the Main Study men (n = 212), a four-cluster classification for the Main Study women (n = 120), and a five-cluster classification for the HIV Study men (n = 620). We calculated means and standard deviations of these 14 clusters on the 21 variables composing the KSOG. Generally, the KSOG's overtly erotic items (Sexual Fantasies, Sexual Behavior, and Sexual Attraction), as well as the Self Identification items, tended to be more uniform within groups than the more social items were (Emotional Preference, Socialize with, and Lifestyle). The result is a set of objectively identified subgroups of bisexual men and women along with characterizations of the extent to which their KSOG scores describe and differentiate them. The Bisexual group identified by the cluster analysis of the HIV sample was distinctly different from any of the bisexual groups identified by the clustering process in the Main Sample. Simply put, the HIV sample's bisexuality is not like bisexuality in general, and attempts to generalize (even cautiously) from this clinical Bisexual group to a larger population would be doomed to failure. This underscores the importance of recruiting non-clinical samples if one wants insight into the nature of bisexuality in the population at large. Although the importance of non clinical sampling in studies of sexual orientation has been widely and justly asserted, it has rarely been demonstrated by direct comparisons of the type conducted in the present study. PMID- 25530728 TI - Homogeneous Gynephiles and Heterogeneous Androphiles: A Factor Analysis of Differences and Similarities in Attractions to the Sexes as a Function of Sexual Orientation. AB - What is it about men and women that make them sexually attractive to those people who find them attractive? Which parts of the body? Which sexual acts? We address this question empirically through a factor analysis of people's ratings of the attractiveness of women's and men's body parts, and of particular sex acts with men and women. Participants of a wide variety of sexual orientations (including a rich sample of bisexuals) rated body parts (by sex) and sex acts (by sex) on 1-to 5 scales. We factor-analyzed answers to these 50 questions to reveal the factor structure of people's attractions as a function of their sexual orientation (itself derived from a previously reported cluster analysis of the Klein Sexual Orientation Grid), then calculated average responses of the male and female clusters on the factors that had emerged. The data showed: (1) The factor structure of men's and women's attractions to women were remarkably similar. (2) The factor structure of men's and women's attractions to men's bodies were remarkably different, identifying an attraction to adult masculinity that differed from attraction to adult boyishness. (3) Lesbian group variability was usually much higher than in any of the other groups. (4) Even though our sample was intentionally diverse, many of our participants only reported attractions to members of one sex. (5) Bisexuals were neither consistently intermediate between homosexuals and heterosexuals nor consistently similar to homosexuals and heterosexuals. (6) Bi-heterosexuals (one of 3 bisexual subgroups) seemed to be more sexually adventurous than might be expected from their position in the progression from pure heterosexual to pure homosexual, especially with regard to anal sex (albeit moderately so). (7) Homosexual men were not intrinsically attracted to anal sex per se. (8) Among men, nonsexual body parts and non-sexual acts were picked out in factor analyses and explained somewhat more variance between men of different sexual orientations than explicitly erotic variables do. (9) Among female respondents, the biggest differences in attractions to men by sexual orientation pertained to specifically erotic differences, not affectionate or bodily stimuli. (10) Although oral-anal contacts generally received low ratings by all the groups of women, ratings of oral-anal contacts were particularly low among lesbians. We believe that this is the first empirical study to report what it is about women and men that forms the basis for attractions to them, and the first to identify significant subgroups among men who are attracted to men. PMID- 25530729 TI - Military Beliefs and PTSD in Active Duty U.S. Army Soldiers. AB - Post-traumatic distress after military combat is a major cost of war. One under investigated factor potentially associated with PTSD symptoms is specific beliefs about one's military service. This study examined post-deployment self-reports from 272 active-duty U.S. Army soldiers, to investigate potential associations between military-related PTSD symptom severity and three beliefs about the military: the importance and value ascribed to one's own work in the Army, to current military operations in Iraq and Afghanistan, and to military service in general. Higher scores on these three beliefs were negatively correlated with military-related PTSD symptom severity. However, in a combined regression model that controlled for recent combat exposure, only the belief about current military operations had a significant, unique association with PTSD symptom severity. That is, more positive beliefs about the value of operations in Iraq or Afghanistan were associated with lower PTSD symptoms. PMID- 25530730 TI - Interpretational Confounding or Confounded Interpretations of Causal Indicators? AB - In measurement theory causal indicators are controversial and little-understood. Methodological disagreement concerning causal indicators has centered on the question of whether causal indicators are inherently sensitive to interpretational confounding, which occurs when the empirical meaning of a latent construct departs from the meaning intended by a researcher. This article questions the validity of evidence used to claim that causal indicators are inherently susceptible to interpretational confounding. Further, a simulation study demonstrates that causal indicator coefficients are stable across correctly specified models. Determining the suitability of causal indicators has implications for the way we conceptualize measurement and build and evaluate measurement models. PMID- 25530726 TI - The Science of Sex Differences in Science and Mathematics. AB - Amid ongoing public speculation about the reasons for sex differences in careers in science and mathematics, we present a consensus statement that is based on the best available scientific evidence. Sex differences in science and math achievement and ability are smaller for the mid-range of the abilities distribution than they are for those with the highest levels of achievement and ability. Males are more variable on most measures of quantitative and visuospatial ability, which necessarily results in more males at both high- and low-ability extremes; the reasons why males are often more variable remain elusive. Successful careers in math and science require many types of cognitive abilities. Females tend to excel in verbal abilities, with large differences between females and males found when assessments include writing samples. High level achievement in science and math requires the ability to communicate effectively and comprehend abstract ideas, so the female advantage in writing should be helpful in all academic domains. Males outperform females on most measures of visuospatial abilities, which have been implicated as contributing to sex differences on standardized exams in mathematics and science. An evolutionary account of sex differences in mathematics and science supports the conclusion that, although sex differences in math and science performance have not directly evolved, they could be indirectly related to differences in interests and specific brain and cognitive systems. We review the brain basis for sex differences in science and mathematics, describe consistent effects, and identify numerous possible correlates. Experience alters brain structures and functioning, so causal statements about brain differences and success in math and science are circular. A wide range of sociocultural forces contribute to sex differences in mathematics and science achievement and ability-including the effects of family, neighborhood, peer, and school influences; training and experience; and cultural practices. We conclude that early experience, biological factors, educational policy, and cultural context affect the number of women and men who pursue advanced study in science and math and that these effects add and interact in complex ways. There are no single or simple answers to the complex questions about sex differences in science and mathematics. PMID- 25530731 TI - HIV sexual risk behavior among emerging adults in psychiatric treatment in Brazil. AB - HIV infection among young populations is increasing worldwide. Adolescents in mental health treatment have demonstrated higher rates of HIV risk behavior than their peers. This first risk behavior study of youth in psychiatric treatment in Brazil reports findings from a cross-sectional national sample of emerging adult psychiatric patients (18-25 years old). The prevalence of lifetime unprotected sex was 65.9%. Multiple logistic regression indicated that being married/in union; sex under the influence of alcohol/drugs; physical violence; earlier sexual debut; and depressive/substance use disorders were associated with unsafe sex. Interventions and services that address these risks during this critical developmental window are urgently needed. PMID- 25530732 TI - Fe2O3 nanoparticle mediated molecular growth and soot inception from the oxidative pyrolysis of 1-methylnaphthalene. AB - While it is well documented iron oxide can reduce soot through burnout in the oxidative regions of flames, it may also impact molecular growth and particle inception. The role of Fe2O3 nanoparticles in mass growth of soot from 1 methylnapthalene (1-MN) was studied in a dual-zone, high-temperature flow reactor. An iron substituted, dendrimer template was oxidized in the first zone to generate ~5 nm Fe2O3 nanoparticles, which were seeded into the second zone of the flow reactor containing 1-MN at 1100 degrees C and phi = 1.4-5.0. Enhanced molecular growth in the presence of Fe2O3 nanoparticles resulted in increased yields of polycyclic aromatic hydrocarbons (PAH) and soot compared to purely gas phase reactions of 1-MN at identical fuel-air equivalence ratios. This also resulted in an increase in soot-number concentration and a slight shift to smaller particles with increasing addition (from no addition to 3 mM) of Fe2O3. Introduction of Fe2O3 nanoparticles resulted in the formation of stabilization of environmentally persistent free radicals (EPFRs), including benzyl, phenoxyl, or semiquinone-type radicals as well as carbon-centered radicals, such as cyclopentadienyl or a delocalized electron in a carbon matrix. At the high concentrations in the flow reactor, these resonance-stabilized free radicals can undergo surface-mediated, radical-radical, molecular growth reactions which may contribute to molecular growth and soot particle inception. PMID- 25530733 TI - Male Veterans Coping With the Pendulum Swing of Rheumatiod Arthritis Pain: A Qualitative Study. AB - This study describes the physical, psychological and social context of rheumatoid arthritis (RA) pain from the male veterans. A qualitative, descriptive design was employed using a purposive sampling to ensure representation of male veterans. Interviews were conducted with 12 male veterans of the VA Greater Los Angeles Healthcare System. Socio-demographic characteristics, clinical profiles and descriptors of rheumatoid pain experienced by male veterans' since their diagnoses were gathered. Interviews were audio recorded and transcribed verbatim. Grounded Theory analysis techniques were used to identify concepts related to living with RA Pain. Six concepts related to RA pain adaptation emerged. Three concepts were associated with movement (keep moving, consequences of not moving, staying physically active) and three were related to emotion (thinking positive thoughts, doing jobs, focusing on male identity). The "keep moving" concept explained coping with chronic RA pain through three activity types: physical, cognitive and socio-economic activities. These activities fluctuated in intensity depending upon the disease stage and RA symptoms. The forward and backward pendulum swing described the unpredictable course and pain coping strategy of the veterans. Further studies are recommended to determine the transferability of our findings to other populations and to confirm the impact of continuous motion as an effective pain management strategy for RA. PMID- 25530734 TI - Pediatric Sedation: Using Secondary Data to Describe Registered Nurse Practice in Radiology. AB - Children, often require sedation for procedures due to their developmental level and difficulty complying with positioning. There are few studies that describe nurse sedation practices or adverse events. Studies of pediatric sedation care have small sample sizes that are inadequate to detect adverse events. This study reports practices and outcomes of sedation delivered to children from infancy up to 14 years of age, that were monitored only by registered nurses (RNs) during diagnostic radiology procedures drawn from a sample of 12,584 cases from the Pediatric Sedation Research Consortium (PSRC) database. There were 727 adverse events (5.78%). However, no deaths, cardiac arrests, intubations or aspirations were reported in this sample. The most common adverse event was inadequate sedation/agitation/delirium 196 (155.8/10,000) and desaturation below baseline for greater than 30 seconds 173 (138/10,000). Further research comparing sedation practices and outcomes by type of providers, including nurses, are necessary to improve practice. PMID- 25530735 TI - FlexE: Using elastic network models to compare models of protein structure. AB - It is often valuable to compare protein structures to determine how similar they are. Structure comparison methods such as RMSD and GDT-TS are based solely on fixed geometry and do not take into account the intrinsic flexibility or energy landscape of the protein. We propose a method, which we call FlexE, that is based on a simple elastic network model and uses the deformation energy as measure of the similarity between two structures. FlexE can distinguish biologically relevant conformational changes from random changes, while existing geometry based methods cannot. Additionally, FlexE incorporates the concept of thermal energy, which provides a rational way to determine when two models are "the same". FlexE provides a unique measure of the similarity between protein structures that is complementary to existing methods. PMID- 25530737 TI - When the Medium Illustrates the Content: Exploiting the Unique Features of Online Communication. PMID- 25530738 TI - An Exploratory Study of Trauma and Religious Factors in Predicting Drinking Outcomes in African American Sexual Assault Survivors. AB - This exploratory study examined the relationships between religious factors, trauma histories and life satisfaction to alcohol-related outcomes in adult sexual assault survivors. A mail survey was administered to a community sample of African American survivors (N = 836) in the Chicago metropolitan area. Hierarchical regression analyses showed that for non-religious women, interpersonal trauma was related to greater frequency of heavy drinking. For moderately religious women, interpersonal and contextual traumas were related to more frequent heavy drinking. For highly religious women, religious coping was related to less frequent heavy drinking. Implications are drawn for research and treatment of female survivors. PMID- 25530736 TI - Amino acid supplementation and impact on immune function in the context of exercise. AB - Moderate and chronic bouts of exercise may lead to positive metabolic, molecular, and morphological adaptations, improving health. Although exercise training stimulates the production of reactive oxygen species (ROS), their overall intracellular concentration may not reach damaging levels due to enhancement of antioxidant responses. However, inadequate exercise training (i.e., single bout of high-intensity or excessive exercise) may result in oxidative stress, muscle fatigue and muscle injury. Moreover, during the recovery period, impaired immunity has been reported, for example; excessive-inflammation and compensatory immunosuppression. Nutritional supplements, sometimes referred to as immuno nutrients, may be required to reduce immunosuppression and excessive inflammation. Herein, we discuss the action and the possible targets of key immuno-nutrients such as L-glutamine, L-arginine, branched chain amino acids (BCAA) and whey protein. PMID- 25530739 TI - A Mixed Methods Mapping of Church versus Secular School Messages to Influence Sexual Decision-Making as Perceived by Zimbabwean Orphan Girl Students. AB - This study examined the messages perceived by adolescent girls with orphanhood to influence their sexual decision-making. Participants were 125 students (mean age =14.7 years), 54% of whom attended church schools in a rural district of eastern Zimbabwe. We collected and analyzed data using concept mapping, a mixed method approach that enabled the construction of message clusters, with weighting for their relative importance. Messages that clustered under Biblical Teachings and Life Planning ranked highest in salience among students in both church and secular schools. Protecting Family Honor, HIV Prevention, and Social Stigma messages ranked next, respectively. Contrary to study hypotheses, the messages that orphan adolescent girls perceived to influence their sexual decisions did not vary by type of school attended. PMID- 25530740 TI - DTN routing in body sensor networks with dynamic postural partitioning. AB - This paper presents novel store-and-forward packet routing algorithms for Wireless Body Area Networks (WBAN) with frequent postural partitioning. A prototype WBAN has been constructed for experimentally characterizing on-body topology disconnections in the presence of ultra short range radio links, unpredictable RF attenuation, and human postural mobility. On-body DTN routing protocols are then developed using a stochastic link cost formulation, capturing multi-scale topological localities in human postural movements. Performance of the proposed protocols are evaluated experimentally and via simulation, and are compared with a number of existing single-copy DTN routing protocols and an on body packet flooding mechanism that serves as a performance benchmark with delay lower-bound. It is shown that via multi-scale modeling of the spatio-temporal locality of on-body link disconnection patterns, the proposed algorithms can provide better routing performance compared to a number of existing probabilistic, opportunistic, and utility-based DTN routing protocols in the literature. PMID- 25530741 TI - Biochemical and Cellular Specificity of Peptide Inhibitors of G Protein-Coupled Receptor Kinases. AB - Identifying novel allosteric inhibitors of G protein-coupled receptor kinases (GRKs) would be of considerable use in limiting both the extent of desensitization of GPCRs as well as downstream positive regulation through GRKs. Several peptides have previously been identified as inhibitors of specific GRKs, but to date there have been few comparisons of the selectivities of these materials on the seven GRKs, modifications to allow cell penetration, or off target activities. The goal of this study was to determine if a panel of peptides mimicking domains on either GPCRs or GRKs would exhibit selective inhibition of GRKs 2, 5, 6 and 7 phosphorylation of rhodopsin. Peptides included sequences from GRK5; helices 3, 9, and 10 (alpha3, alpha9, and alpha10) in the RH domain, and the N-terminal peptide (N-Ter), as well as the intracellular loop 1 (iL1) of the beta2-adrenergic receptor (beta2AR), and the Galpha transducin C-tail (TCT). While some selectivity for individual GRKs was found, overall selectivity was limited and often not reflective of structural predictions. Off-target effects were probed by determining peptide inhibition of adenylyl cyclase (AC) and PKA, and while peptides had no effect on AC activity, N-Ter, iL1, and alpha10 were potent inhibitors of PKA. To probe inhibition of GRK activity in intact cells, we synthesized TAT-tagged peptides, and found that TAT-alpha9-R169A and TAT-TCT inhibited isoproterenol-stimulated GRK phosphorylation of the beta2AR; however, the TAT peptides also inhibited isoproterenol and forskolin stimulation of AC activity. Our findings demonstrate potent peptide inhibition of GRK activities in vitro, highlight the differences in the environments of biochemical and cell based assays, and illustrate the care that must be exercised in interpreting results of either assay alone. PMID- 25530742 TI - Meta-analysis of global metabolomic data identifies metabolites associated with life-span extension. AB - The manipulation of distinct signaling pathways and transcription factors has been shown to influence life span in a cell-non-autonomous manner in multicellular model organisms such as Caenorhabditis elegans. These data suggest that coordination of whole-organism aging involves endocrine signaling, however, the molecular identities of such signals have not yet been determined and their potential relevance in humans is unknown. Here we describe a novel metabolomic approach to identify molecules directly associated with extended life span in C. elegans that represent candidate compounds for age-related endocrine signals. To identify metabolic perturbations directly linked to longevity, we developed metabolomic software for meta-analysis that enabled intelligent comparisons of multiple different mutants. Simple pairwise comparisons of long-lived glp-1, daf 2, and isp-1 mutants to their respective controls resulted in more than 11,000 dysregulated metabolite features of statistical significance. By using meta analysis, we were able to reduce this number to six compounds most likely to be associated with life-span extension. Mass spectrometry-based imaging studies suggested that these metabolites might be localized to C. elegans muscle. We extended the metabolomic analysis to humans by comparing quadricep muscle tissue from young and old individuals and found that two of the same compounds associated with longevity in worms were also altered in human muscle with age. These findings provide candidate compounds that may serve as age-related endocrine signals and implicate muscle as a potential tissue regulating their levels in humans. PMID- 25530743 TI - Colorectal Cancer-Associated Fibroblasts are Genotypically Distinct. AB - Cells in the stromal microenvironment facilitate colorectal cancer (CRC) progression and "co-evolve" with the epithelial cancer cells. Genetic and epigenetic differences between normal colorectal mucosa fibroblasts (NF) and carcinoma-associated fibroblasts (CAF) are not known. The aim of this study is to identify differentially expressed genes and promoter methylation between NF and CAF in human CRC. RNA and DNA were extracted from cultured NF and CAF from CRC resections. Genome-wide gene expression and methylation analyses were performed using the Illumina Human HT-12 v4.0 Expression and Illumina Human Methylation 27 BeadChips. Gene expression values between NF and CAF were compared and correlated with methylation patterns. Data was analyzed using Partek Genomics Suite using one-way ANOVA and p<0.05 as significant. Ingenuity iReportTM was performed to identify potential differences in biological functions and pathways between the NF and CAF. Paired methylation and gene expression analyses from 11 NF and 10 CAF colorectal samples are reported. Unsupervised analysis of differentially expressed genes using iReportTM identified "Top Diseases" as "Cancer" and "Colorectal Cancer". Previous genome wide studies have focused on the cancer cells. We have identified differentially expressed genes and differentially methylated promoter regions that are CAF-specific in CRC. PMID- 25530744 TI - Experimental and Theoretical Investigations of Phonation Threshold Pressure as a Function of Vocal Fold Elongation. AB - The relationship between the vocal fold elongation and the phonation threshold pressure (PTP) was experimentally and theoretically investigated. The PTP values of seventeen excised canine larynges with 0% to 15% bilateral vocal fold elongations in 5% elongation steps were measured using an excised larynx phonation system. It was found that twelve larynges exhibited a monotonic relationship between PTP and elongation; in these larynges, the 0% elongation condition had the lowest PTP. Five larynges exhibited a PTP minimum at 5% elongation. To provide a theoretical explanation of these phenomena, a two-mass model was modified to simulate vibration of the elongated vocal folds. Two pairs of longitudinal springs were used to represent the longitudinal elastin in the vocal folds. This model showed that when the vocal folds were elongated, the increased longitudinal tension would increase the PTP value and the increased vocal fold length would decrease the PTP value. The antagonistic effects contributed by these two factors were found to be able to cause either a monotonic or a non-monotonic relationship between PTP and elongation, which were consistent with experimental observations. Because PTP describes the ease of phonation, this study suggests that there may exist a nonzero optimal vocal fold elongation for the greatest ease for phonation in some larynges. PMID- 25530745 TI - Gold-Coated Fe3O4 Nanoroses with Five Unique Functions for Cancer Cell Targeting, Imaging and Therapy. AB - The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Molecular imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate diagnosis and targeted therapy. Here, we demonstrate gold-coated iron oxide (Fe3O4@Au) nanoroses with five distinct functions, which integrate aptamer-based targeting, magnetic resonance imaging (MRI), optical imaging, photothermal therapy and chemotherapy into one single probe. The inner Fe3O4 core functions as an MRI agent, while the photothermal effect is achieved through near-infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin carried by the nanoroses. Where the doxorubicin is released is monitored by its fluorescent. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging and photothermal effect with high specificity. The five-function-embedded nanoroses show great advantages in multimodality. PMID- 25530746 TI - Deconstructing the Effects of Matrix Elasticity and Geometry in Mesenchymal Stem Cell Lineage Commitment. AB - A wide variety of environmental factors including physical and biochemical signals are responsible for stem cell behavior and function. In particular, matrix elasticity and cell shape have been shown to determine stem cell function, yet little is known about the interplay between how these physical cues control cell differentiation. For the first time, by using ultraviolet (UV) lithography to pattern poly(ethylene) glycol (PEG) hydrogels we are able to manufacture microenvironments capable of parsing the effects of matrix elasticity, cell shape, and cell size in order to explore the relationship between matrix elasticity and cell shape in mesenchymal stem cell (MSC) lineage commitment. Our data shows that cells cultured on 1,000 MUm2 circles, squares, and rectangles were primarily adipogenic lineage regardless of matrix elasticity, while cells cultured on 2,500 and 5,000 MUm2 shapes more heavily depended on shape and elasticity for lineage specification. We further went on to characterize how modifying the cell cytoskeleton through pharmacological inhibitors can modify cell behavior. By showing MSC lineage commitment relationships due to physical signals, this study highlights the importance of cell shape and matrix elasticity in further understanding stem cell behavior for future tissue engineering strategies. PMID- 25530747 TI - Dynamic Optimal Strategy for Monitoring Disease Recurrence. AB - Surveillance to detect cancer recurrence is an important part of care for cancer survivors. In this paper we discuss the design of optimal strategies for early detection of disease recurrence based on each patient's distinct biomarker trajectory and periodically updated risk estimated in the setting of a prospective cohort study. We adopt a latent class joint model which considers a longitudinal biomarker process and an event process jointly, to address heterogeneity of patients and disease, to discover distinct biomarker trajectory patterns, to classify patients into different risk groups, and to predict the risk of disease recurrence. The model is used to develop a monitoring strategy that dynamically modifies the monitoring intervals according to patients' current risk derived from periodically updated biomarker measurements and other indicators of disease spread. The optimal biomarker assessment time is derived using a utility function. We develop an algorithm to apply the proposed strategy to monitoring of new patients after initial treatment. We illustrate the models and the derivation of the optimal strategy using simulated data from monitoring prostate cancer recurrence over a 5-year period. PMID- 25530748 TI - Positive matrix factorization of PM2.5 - eliminating the effects of gas/particle partitioning of semivolatile organic compounds. AB - Gas-phase concentrations of semi-volatile organic compounds (SVOCs) were calculated from gas/particle (G/P) partitioning theory using their measured particle-phase concentrations. The particle-phase data were obtained from an existing filter measurement campaign (27 January 2003-2 October 2005) as a part of the Denver Aerosol Sources and Health (DASH) study, including 970 observations of 71 SVOCs (Xie et al., 2013). In each compound class of SVOCs, the lighter species (e.g. docosane in n alkanes, fluoranthene in PAHs) had higher total concentrations (gas + particle phase) and lower particle-phase fractions. The total SVOC concentrations were analyzed using positive matrix factorization (PMF). Then the results were compared with source apportionment results where only particle-phase SVOC concentrations were used (particle only-based study; Xie et al., 2013). For the particle only-based PMF analysis, the factors primarily associated with primary or secondary sources (n alkane, EC/sterane and inorganic ion factors) exhibit similar contribution time series (r = 0.92-0.98) with their corresponding factors (n alkane, sterane and nitrate+sulfate factors) in the current work. Three other factors (light n alkane/PAH, PAH and summer/odd n alkane factors) are linked with pollution sources influenced by atmospheric processes (e.g. G/P partitioning, photochemical reaction), and were less correlated (r = 0.69-0.84) with their corresponding factors (light SVOC, PAH and bulk carbon factors) in the current work, suggesting that the source apportionment results derived from particle-only SVOC data could be affected by atmospheric processes. PMF analysis was also performed on three temperature stratified subsets of the total SVOC data, representing ambient sampling during cold (daily average temperature < 10 degrees C), warm (>= 10 degrees C and <= 20 degrees C) and hot (> 20 degrees C) periods. Unlike the particle only-based study, in this work the factor characterized by the low molecular weight (MW) compounds (light SVOC factor) exhibited strong correlations (r = 0.82-0.98) between the full data set and each sub-data set solution, indicating that the impacts of G/P partitioning on receptor-based source apportionment could be eliminated by using total SVOC concentrations. PMID- 25530749 TI - Modeling On-Body DTN Packet Routing Delay in the Presence of Postural Disconnections. AB - This paper presents a stochastic modeling framework for store-and-forward packet routing in Wireless Body Area Networks (WBAN) with postural partitioning. A prototype WBANs has been constructed for experimentally characterizing and capturing on-body topology disconnections in the presence of ultrashort range radio links, unpredictable RF attenuation, and human postural mobility. Delay modeling techniques for evaluating single-copy on-body DTN routing protocols are then developed. End-to-end routing delay for a series of protocols including opportunistic, randomized, and two other mechanisms that capture multiscale topological localities in human postural movements have been evaluated. Performance of the analyzed protocols are then evaluated experimentally and via simulation to compare with the results obtained from the developed model. Finally, a mechanism for evaluating the topological importance of individual on body sensor nodes is developed. It is shown that such information can be used for selectively reducing the on-body sensor-count without substantially sacrificing the packet delivery delay. PMID- 25530750 TI - Study of the bus dynamic coscheduling optimization method under urban rail transit line emergency. AB - As one of the most important urban commuter transportation modes, urban rail transit (URT) has been acting as a key solution for supporting mobility needs in high-density urban areas. However, in recent years, high frequency of unexpected events has caused serious service disruptions in URT system, greatly harming passenger safety and resulting in severe traffic delays. Therefore, there is an urgent need to study emergency evacuation problem in URT. In this paper, a method of bus dynamic coscheduling is proposed and two models are built based on different evacuation destinations including URT stations and surrounding bus parking spots. A dynamic coscheduling scheme for buses can be obtained by the models. In the model solution process, a new concept-the equivalent parking spot is proposed to transform the nonlinear model into an integer linear programming (ILP) problem. A case study is conducted to verify the feasibility of models. Also, sensitivity analysis of two vital factors is carried out to analyze their effects on the total evacuation time. The results reveal that the designed capacity of buses has a negative influence on the total evacuation time, while an increase in the number of passengers has a positive effect. Finally, some significant optimizing strategies are proposed. PMID- 25530751 TI - Valuation of travel time savings in viewpoint of WTA. AB - In order to investigate the issues in measurement of value of travel time savings (VTTS), the willingness-to-accept (WTA) for the private car owner is studied by using surveyed data. It is convincing that trip purpose, trip length, time savings, cost savings, income, and allowance from employee have effects on the WTA. Moreover, influences of these variables are not the same for different trip purposes. For commuting trips, effects of income and allowance from employee are significant while time savings and cost savings are dominated for leisure and shopping trips. It is also found that WTA is much higher than expected which implies that there are a group of drivers who are not prone to switching to other trip modes other than passenger car. PMID- 25530752 TI - Gradient learning algorithms for ontology computing. AB - The gradient learning model has been raising great attention in view of its promising perspectives for applications in statistics, data dimensionality reducing, and other specific fields. In this paper, we raise a new gradient learning model for ontology similarity measuring and ontology mapping in multidividing setting. The sample error in this setting is given by virtue of the hypothesis space and the trick of ontology dividing operator. Finally, two experiments presented on plant and humanoid robotics field verify the efficiency of the new computation model for ontology similarity measure and ontology mapping applications in multidividing setting. PMID- 25530753 TI - Incident duration modeling using flexible parametric hazard-based models. AB - Assessing and prioritizing the duration time and effects of traffic incidents on major roads present significant challenges for road network managers. This study examines the effect of numerous factors associated with various types of incidents on their duration and proposes an incident duration prediction model. Several parametric accelerated failure time hazard-based models were examined, including Weibull, log-logistic, log-normal, and generalized gamma, as well as all models with gamma heterogeneity and flexible parametric hazard-based models with freedom ranging from one to ten, by analyzing a traffic incident dataset obtained from the Incident Reporting and Dispatching System in Beijing in 2008. Results show that different factors significantly affect different incident time phases, whose best distributions were diverse. Given the best hazard-based models of each incident time phase, the prediction result can be reasonable for most incidents. The results of this study can aid traffic incident management agencies not only in implementing strategies that would reduce incident duration, and thus reduce congestion, secondary incidents, and the associated human and economic losses, but also in effectively predicting incident duration time. PMID- 25530754 TI - Analysis of the contribution of the road traffic industry to the PM2.5 emission for different land-use types. AB - Road dust and vehicle exhaust are the main sources of air pollution in cities, especially in recent years with the quantity of vehicles and transportation construction continuously soaring; the hazy weather has been a dominant urban pollution form which is widely concerned by the Chinese society. By establishing a relationship model between traffic and land use, then applying analytic hierarchy process on the data from air quality monitoring station, this paper concludes the influence of different traffic behavior on air pollution which provides support to abate urban air pollution caused by traffic reasons through taking measures to control traffic. PMID- 25530755 TI - Modeling pedestrian's conformity violation behavior: a complex network based approach. AB - Pedestrian injuries and fatalities present a problem all over the world. Pedestrian conformity violation behaviors, which lead to many pedestrian crashes, are common phenomena at the signalized intersections in China. The concepts and metrics of complex networks are applied to analyze the structural characteristics and evolution rules of pedestrian network about the conformity violation crossings. First, a network of pedestrians crossing the street is established, and the network's degree distributions are analyzed. Then, by using the basic idea of SI model, a spreading model of pedestrian illegal crossing behavior is proposed. Finally, through simulation analysis, pedestrian's illegal crossing behavior trends are obtained in different network structures and different spreading rates. Some conclusions are drawn: as the waiting time increases, more pedestrians will join in the violation crossing once a pedestrian crosses on red firstly. And pedestrian's conformity violation behavior will increase as the spreading rate increases. PMID- 25530756 TI - Research on assessment methods for urban public transport development in China. AB - In recent years, with the rapid increase in urban population, the urban travel demands in Chinese cities have been increasing dramatically. As a result, developing comprehensive urban transport systems becomes an inevitable choice to meet the growing urban travel demands. In urban transport systems, public transport plays the leading role to promote sustainable urban development. This paper aims to establish an assessment index system for the development level of urban public transport consisting of a target layer, a criterion layer, and an index layer. Review on existing literature shows that methods used in evaluating urban public transport structure are dominantly qualitative. To overcome this shortcoming, fuzzy mathematics method is used for describing qualitative issues quantitatively, and AHP (analytic hierarchy process) is used to quantify expert's subjective judgment. The assessment model is established based on the fuzzy AHP. The weight of each index is determined through the AHP and the degree of membership of each index through the fuzzy assessment method to obtain the fuzzy synthetic assessment matrix. Finally, a case study is conducted to verify the rationality and practicability of the assessment system and the proposed assessment method. PMID- 25530757 TI - Prevalence of Gastroesophageal Reflux Disease in Type II Diabetes Mellitus. AB - Background/Aims. Patients with type II diabetes mellitus (DM) were known to have higher prevalence of gastroesophageal reflux disease (GERD) in the Western countries, but data on the impact of GERD on DM patients in our country are scarce. The aim of this study was to evaluate the prevalence of GERD in type II DM patients in Shanghai, China, and to explore its possible risk factors. Methods. 775 type II DM cases were randomly collected. Reflux Disease Questionnaire (RDQ) was used to check the presence of GERD. Patients' characteristics, laboratory data, face-to-face interview, nerve conduction study, and needle electromyogram (EMG) test were analyzed. Results. 16% patients were found with typical GERD symptoms. Pathophysiological factors such as peripheral neuropathy, metabolism syndrome, and obesity were found to have no significant differences between GERD and non-GERD type II DM patients in the present study. Conclusion. The prevalence of GERD in type II DM patients is higher than that in adult inhabitants in Shanghai, China. No difference in pathophysiological factors, such as peripheral neuropathy, and metabolism syndrome was found in DM GERD patients, suggesting that further study and efforts are needed to explore deeper the potential risk factors for the high prevalence rate of GERD in DM patients. PMID- 25530758 TI - Cost analysis of three techniques of administering sevoflurane. AB - Background. This study aimed to evaluate and compare total cost of sevoflurane and propofol for 1.0 MAC-hour of anaesthesia, employing three anaesthetic techniques. Methods. Adult patients scheduled for surgical procedures under general anaesthesia anticipated to last approximately an hour were randomized into three groups (n = 15 each), to receive anaesthesia using one of the following techniques: low flow technique involving induction with propofol, followed by sevoflurane delivered using initial fresh gas flows of 6 L/min till MAC reached 1.0 and then reduced to 0.5 L/min; alternate method of low flow entailing only a difference in fresh gas flow rates being maintained at 1 L/min throughout; the third technique involving use of sevoflurane for both induction and maintenance of anaesthesia. Results. Cost of sevoflurane to maintain 1 MAC hour of anaesthesia was clinically least with low flow anaesthesia, though statistically similar amongst the three techniques. Once the cost of propofol used for induction in two of the three groups was added to that of sevoflurane, cost incurred was least with the technique using sevoflurane both for induction and maintenance of anaesthesia, as compared to low flow and alternative low flow techniques, a 26% and 32% cost saving, respectively (P < 0.05). PMID- 25530759 TI - Alpha Lipoic Acid Modulated High Glucose-Induced Rat Mesangial Cell Dysfunction via mTOR/p70S6K/4E-BP1 Pathway. AB - The aim of this study was to investigate whether alpha lipoic acid (LA) regulates high glucose-induced mesangial cell proliferation and extracellular matrix production via mTOR/p70S6K/4E-BP1 signaling. The effect of LA on high glucose induced cell proliferation, fibronectin (FN), and collagen type I (collagen-I) expression and its mechanisms were examined in cultured rat mesangial cells by methylthiazol tetrazolium (MTT) assay, flow cytometry, ELISA assay, and western blot, respectively. LA at a relatively low concentration (0.25 mmol/L) acted as a growth factor in rat mesangial cells, promoted entry of cell cycle into S phase, extracellular matrix formation, and phosphorylated AKT, mTOR, p70S6K, and 4E-BP1. These effects disappeared when AKT expression was downregulated with PI3K/AKT inhibitor LY294002. Conversely, LA at a higher concentration (1.0 mmol/L) inhibited high glucose-induced rat mesangial cell proliferation, entry of cell cycle into S phase, and extracellular matrix exertion, as well as phosphorylation of mTOR, p70S6K, and 4E-BP1 but enhanced the activity of AMPK. However, these effects disappeared when AMPK activity was inhibited with CaMKK inhibitor STO 609. These results suggest that LA dose-dependently regulates mesangial cell proliferation and matrix protein secretion by mTOR/p70S6K/4E-BP1 signaling pathway under high glucose conditions. PMID- 25530760 TI - The Association between the Epicardial Adipose Tissue Thickness and Oxidative Stress Parameters in Isolated Metabolic Syndrome Patients: A Multimarker Approach. AB - The risk for cardiovascular diseases and type 2 diabetes mellitus significantly increases in the patient population with metabolic syndrome (MeS). The present study aimed to investigate the association between the epicardial adipose tissue thickness (EATT) and the oxidative stress parameters in MeS patients. The study included 181 patients as a patient group of 92 consecutive patients with MeS and a control group of 89 consecutive patients with similar age and gender. EATT was evaluated by transthoracic echocardiography. Serum levels of total oxidant status (TOS), total antioxidative capacity (TAS), paraoxonase-1 (PON-1), and arylesterase activities were measured. EATT was higher in the MeS group compared to the control group (6.0 +/- 2.0 mm and 4.0 +/- 1.0 mm, resp.; P < 0.001). The level of TOS was higher in the MeS group compared to the control group (P < 0.001). Additionally, the TAS level was higher in the MeS group compared to the control group (P < 0.001). Furthermore, the serum levels of PON-1 and arylesterase were lower in the MeS group compared to the control group (P < 0.001). EAT may cause an increased risk of cardiovascular diseases by leading to increased oxidative stress in patients with MeS. PMID- 25530761 TI - The number of roots and canals in the maxillary second premolars in a group of jordanian population. AB - Objectives. The aim of this study was to investigate the number of roots and root canals in the maxillary second premolar in a group of Jordanian population. Materials and Methods. A total of 217 patients, 100 female (46%) and 117 male (54%), received root canal treatment of maxillary second premolar from January 2012 to January 2014. The mean age of the patients was 32.7, ranging from 18 to 60 years. The teeth included in the study were examined clinically and radiographically for the number of roots and root canals using magnifying loupes. Results. Out of the total of 217 maxillary second premolars, 120 teeth had one root (55.3%), 96 teeth had two roots (44.2%), and one tooth had three roots (0.46%). Regarding root canal configuration, 30 teeth (13.8%) had one canal, 54 teeth (24.9%) had two canals shared in one apical foramen, 132 teeth (60.8%) had two canals with two separate apical foramina, and one tooth (0.46%) had three canals with separate apical foramina. Conclusion. The incidence of two canals (either with shared or separate apical foramina) is very high in the maxillary second premolars in Jordanian population; therefore inspection should be done for the presence of second canal whenever endodontic treatment is planned for this tooth. PMID- 25530762 TI - Acroparesthesia in a female: diagnostic dilemma. AB - Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of a-galactosidase A (also known as ceramide trihexosidase) and resultant accumulation of globotriaosylceramide (Gb3) and related glycophospholipids. The disease affects nearly all major organ systems, with the primary sites damaged by Gb3 including renal glomeruli, myocardium, neurons of the dorsal ganglion and autonomic nervous system, and vascular endothelial and smooth muscle. Progressive deposition in these organ systems leads to renal and heart failure; debilitating pain as a result of nervous system involvement also occurs. PMID- 25530763 TI - Spontaneous aching pain and peculiar involuntary movements: a case report of painful legs and moving toes and review of the literature. AB - Painful legs and moving toes (PLMT) is a rare syndrome characterized by spontaneous neuropathic pain and peculiar involuntary movements in the lower limbs, especially the toes and feet. As it is a relatively rare disorder worldwide, the exact pathophysiology still remains a mystery. Until recently, numerous methods of clinical treatments have been tried; however, the success rate of the therapies is still very low. Here, we report a case of PLMT and also summarize the recent clinical and research literatures regarding clinical presentation, electrophysiological features, etiology, treatment methods, and prognosis of this disorder. Doctors should be aware of this rare syndrome in a patient with painful and/or restless legs. On the other hand, multiple clinical treatments should be tried, even those which usually produce a poor outcome. PMID- 25530766 TI - Luteal Phase Support in the Intrauterine Insemination (IUI) Cycles: A Randomized Double Blind, Placebo Controlled Study. AB - OBJECTIVE: To evaluate the impact of luteal phase support with vaginal progesterone on pregnancy rates in the intrauterine insemination (IUI) cycles, stimulated with clomiphene citrate and human menopausal gonadotropin (hMG), in sub fertile couples. MATERIALS AND METHODS: This prospective, randomized, double blind study was performed in a tertiary infertility center from March 2011 to January 2012. It consisted of 253 sub fertile couples undergoing ovarian stimulation for IUI cycles. They underwent ovarian stimulation with clomiphene citrate (100 mg) and hMG (75 IU) in preparation for the IUI cycle. Study group (n = 127) received luteal phase support in the form of vaginal progesterone (400 mg twice a day), and control group (n = 126) received placebo. Clinical pregnancy and abortion rates were assessed and compared between the two groups. RESULTS: The clinical pregnancy rate was not significantly higher for supported cycles than that for the unsupported ones (15.75% vs. 12.69%, p = 0.3). The abortion rate in the patients with progesterone luteal support compared to placebo group was not statistically different (10% vs. 18.75%, p = 0.45). CONCLUSION: It seems that luteal phase support with vaginal progesterone was not enhanced the success of IUI cycles outcomes, when clomiphene citrate and hMG were used for ovulation stimulation. PMID- 25530764 TI - Lifestyle behaviors and self-rated health: the living for health program. AB - BACKGROUND: Lack of adherence to dietary and physical activity guidelines has been linked to an increase in chronic diseases in the United States (US). The aim of this study was to assess the association of lifestyle behaviors with self rated health (SRH). METHODS: This cross-sectional study used self-reported data from Living for Health Program (N = 1,701) which was conducted from 2008 to 2012 in 190 health fair events in South Florida, US. RESULTS: Significantly higher percent of females as compared to males were classified as obese (35.4% versus 27.0%), reported poor/fair SRH (23.4% versus 15.0%), and were less physically active (33.9% versus 25.4%). Adjusted logistic regression models indicated that both females and males were more likely to report poor/fair SRH if they consumed <=2 servings of fruits and vegetables per day (OR = 2.14, 95% CI 1.30-3.54; OR = 2.86, 95% CI 1.12-7.35, resp.) and consumed mostly high fat foods (OR = 1.58, 95% CI 1.03-2.43; OR = 3.37, 95% CI 1.67-2.43, resp.). The association of SRH with less physical activity was only significant in females (OR = 1.66, 95% CI 1.17 2.35). CONCLUSION: Gender differences in health behaviors should be considered in designing and monitoring lifestyle interventions to prevent cardiovascular diseases. PMID- 25530767 TI - Fundamental Movement Skills among Iranian Primary School Children. AB - OBJECTIVE: To determine the relationship between anthropometric indicators, physical activity (PA) and socioeconomic status (SES) with fundamental movement skills (FMS) among Iranian male students. MATERIALS AND METHODS: In this descriptive study, based on SES scores, 241 students (7-10 years) were randomly selected and classified in high, medium and low groups. All children were measured by 8 morphology anthropometric measures. In order to examine a subset of manipulative skills and to measure physical activity and socioeconomic status, Test of Gross Motor Development (TGMD2) and, interviewer-administered questionnaires were used, respectively. The data were analyzed using Pearson correlation and multiple regression. RESULTS: There was a significant positive correlation between SES and body mass index (BMI), while a significant negative correlation existed between PA and BMI. Object control skills were significantly correlated with height, foot length, forearm length, hand length and physical activity. CONCLUSION: Students with low socioeconomic status were more qualified in movements than other students who were in medium and high socioeconomic status. Therefore, parents need to encourage students to be more active in order to prevent obesity and to facilitate development of object control skills in high socioeconomic status. PMID- 25530765 TI - The influence of pregnancy and lactation on maternal bone health: a systematic review. AB - Osteoporosis is considered as an important public health problem especially in postmenopausal women. There are some hypotheses support the contributory effect of pregnancy and lactation on osteoporosis later in life. High calcium demand during pregnancy and lactation and low estrogenic state support those hypotheses. Numerous studies have investigated on the issue but there is no consensus about the contributory effect of pregnancy and lactation on osteoporosis. To explore the current state of fact, in the present study, all bibliographic databases were searched and all relevant studies on the topic of osteoporosis, lactation, and pregnancy were reviewed. The review shows that despite of controversial results, pregnancy may have protective effect on bone especially if followed by lactation. PMID- 25530768 TI - Nutritional Status among the Children of Age Group 5-14 Years in Selected Arsenic Exposed and Non-Exposed Areas of Bangladesh. AB - OBJECTIVE: To assess and compare the nutritional status of children aged 5-14 years in arsenic exposed and non- exposed areas. MATERIALS AND METHODS: It was a cross sectional study conducted on 600 children of age 5-14 years from arsenic exposed and non-exposed areas in Bangladesh. Designed questionnaire and check list were used for collection of data. To estimate BMI necessary anthropometric measurements of the studied children were done. Dietary intakes of the study children were assessed using 24-hours recall method. RESULTS: The difference of socio-economic conditions between the children of exposed area and non-exposed area was not significant. On an average the body mass index was found to be significantly (p < 0.01) lower among the children of arsenic exposed area (49%) in comparison to that of children in non-exposed area (38%). Stunting (p < 0.01), wasting (p < 0.05) and underweight (p < 0.05) were significantly higher in exposed group in comparison to non-exposed group. No significant difference of nutrition intake was found between exposed and non-exposed children as well as thin and normal children. CONCLUSION: In this study children exposed to arsenic contaminated water were found to be suffered from lower nutritional status. PMID- 25530769 TI - Association between Angiotensinogen M235T Polymorphism and Preeclampsia in Iranian Pregnant Women. AB - OBJECTIVE: To determine the possible association between the M235T variant of angiotensinogen gene and preeclampsia in Iranian preeclamtic women with hypertension during pregnancy. MATERIALS AND METHODS: During a case control study, we used polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis to investigate the association between M235T polymorphism in preeclamtic women compared to normotensive controls. RESULTS: The M235T polymorphism was significantly associated with increased preeclampsia risk in the studied population as supported by a p value of 0.017 and chi-square value of 8.12. The frequency of mutated allele and genotype distribution showed a significant difference between preeclamtic women and control groups. CONCLUSION: The result indicates that the AGT M235T polymorphism plays a significant role in preeclampsia observed in selected Iranian preeclamtic women, and it can be considered as a major risk factor for preeclampsia. PMID- 25530770 TI - Quality of antenatal care in primary health care centers of bangladesh. AB - OBJECTIVE: To find out the quality of ANC in the Upazila Health Complexes (PHC centres) of Bangladesh. MATERIALS AND METHODS: This cross sectional study was done in purposively selected three upazilas among the clients receiving antenatal care (ANC). Data were collected with questionnaire cum checklist in the context of two aspects of quality issues, namely assessment of physical arrangements for ANC (input) and services rendered by the providers (process). RESULTS: The mean age of respondents was 24.6+/-4.5 years. Majority of the respondents were with primary level education (60.3%). About half (52.8%) of the families had monthly income ranging from 3000-5000 taka (38-64 US$). Nearly half (48.9%) had no child, little more than one third (42.3%) were primigravida and 528 (57.7%) were multigravida. Out of 528 multigravid respondents 360 (68.2%) took ANC in their previous pregnancy whereas 168 (31.8%) did not take ANC Pregnancy outcome was found to be associated with receiving ANC (chi(2)=73.599; p=0.000). Respondents receiving ANC had more good pregnancy outcome. The mean waiting time for receiving ANC was 0.77+/-.49 hours. Out of the 13 centers, only 3 (23.1%) have sufficient instruments to render ANC services. Findings showed that where the modes of ANC service delivery in the ANC centers are fairly satisfactory. Though some of the points of standard operation procedures (SOPs) on ANC are not covered by some ANC centers, those were not considered necessary. But, regarding the physical facilities available for rendering ANC services, it is seen that facilities are not quite satisfactory. Number of doctors and nurses are not very satisfactory. One of the centers under this study has no doctor, where ANC services are given by nurses. CONCLUSION: It can be concluded that the ANC services at the primary health care level is not adequate in Bangladesh. To ensure further improvement of the quality of ANC services, instruments used in logistics and supplies should be enhanced. PMID- 25530771 TI - Maternal Healthcare Providers in Uttar Pradesh, India: How to Position Informal Practitioners within the System? AB - OBJECTIVE: To understand the knowledge and services of informal providers and to explore their role in addressing the human resource gap in Uttar Pradesh, India, within the context of maternal health. MATERIALS AND METHODS: The study is exploratory in nature, conducted in four blocks of four districts of Uttar Pradesh state, India. Semi-structured interviews were conducted with 114 informal providers. RESULTS: More than one-third (38%) providers have some formal education and unrecognized degrees. Approximately three-fourths (74%) of them have more than 5 years of work experience. They also provide delivery and in patient services and have basic equipment available. However, they lack essential knowledge about maternal health. They have mixed opinion about their contribution towards maternal health but the only ones available. Therefore, despite lacking requisite knowledge, training and services, they become indispensable due to lack of emergency and timely public health services, and being the only ones existing in the community. CONCLUSION: Informal sector practitioners are a critical link in reaching out to population for health services in developing countries. As opposed to the general notion, they possess years of formal education, experience, informal trainings along with trust of communities. Thus, it becomes important to accept their presence and manage them to the best of their abilities even for specialized care like maternal health. PMID- 25530772 TI - Consanguinity and neonatal death: a nested case-control study. AB - OBJECTIVE: Although numerous studies have found higher rates of abortion and still births following consanguinity (familial marriages), the question of whether consanguinity significantly increases the risk of neonatal death has inadequately been addressed.This study aims to evaluate familial marriage effects on neonatal death in rural areas in Iran. MATERIALS AND METHODS: In this nested case-control study, 6900 newbornswho were born in rural areas of Kohgiluyeh and Boyerahmad Province (South-West of Iran)were followed till the end of neonatal period, and neonatal death was the outcome of interest. Subsequently 97 cases and 97 controls were selected in study cohort by using risk set sampling model. Crude and adjusted odds ratios (OR) were estimated by usinga conditional logistic regression model. RESULTS: In the final model, prematurity (OR = 5.57), low birthweight (LBW) (OR = 7.68), consanguinity (first cousins) (OR = 5.23), C section (OR = 7.27), birth rank more than 3 (OR = 6.95) and birthsinterval less than 24 months (OR = 4.65) showed significant statistical association with neonatal mortality (p < 0.05). CONCLUSION: According to our findings, after adjusting the effects of other significant risk factors, familial marriageto first cousins is considered asan important risk factor for neonatal death. PMID- 25530773 TI - Towards the genetic control of insect vectors: An overview. AB - Insects are responsible for the transmission of major infectious diseases. Recent advances in insect genomics and transformation technology provide new strategies for the control of insect borne pathogen transmission and insect pest management. One such strategy is the genetic modification of insects with genes that block pathogen development. Another is to suppress insect populations by releasing either sterile males or males carrying female-specific dominant lethal genes into the environment. Although significant progress has been made in the laboratory, further research is needed to extend these approaches to the field. These insect control strategies offer several advantages over conventional insecticide-based strategies. However, the release of genetically modified insects into the environment should proceed with great caution, after ensuring its safety, and acceptance by the target populations. PMID- 25530774 TI - Protective Effect of Sundarban Honey against Acetaminophen-Induced Acute Hepatonephrotoxicity in Rats. AB - Honey, a supersaturated natural product of honey bees, contains complex compounds with antioxidant properties and therefore has a wide a range of applications in both traditional and modern medicine. In the present study, the protective effects of Sundarban honey from Bangladesh against acetaminophen- (APAP-) induced hepatotoxicity and nephrotoxicity in experimental rats were investigated. Adult male Wistar rats were pretreated with honey (5 g/kg) for 4 weeks, followed by the induction of hepatotoxicity and nephrotoxicity via the oral administration of a single dose of APAP (2 g/kg). Organ damage was confirmed by measuring the elevation of serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), total protein (TP), total bilirubin (TB), urea, creatinine, and malondialdehyde (MDA). Histopathological alterations observed in the livers and the kidneys further confirmed oxidative damage to these tissues. Animals pretreated with Sundarban honey showed significantly markedly reduced levels of all of the investigated parameters. In addition, Sundarban honey ameliorated the altered hepatic and renal morphology in APAP-treated rats. Overall, our findings indicate that Sundarban honey protects against APAP-induced acute hepatic and renal damage, which could be attributed to the honey's antioxidant properties. PMID- 25530775 TI - Effect of rat medicated serum containing you gui wan on mouse oocyte in vitro maturation and subsequent fertilization competence. AB - You Gui Wan (YGW) is a classic herbal formula in traditional Chinese medicine (TCM) used for the clinical treatment of infertility. This study was to explore whether YGW has an impact on mouse oocyte maturation in vitro and subsequent fertilization competence. Rat medicated serum containing YGW was prepared by orally administrating YGW. Mouse immature oocytes were cultured with YGW medicated serum and compared to those cultured with or without normal rat serum or follicle-stimulating hormone (FSH). YGW medicated serum significantly increased the percentages of matured oocytes when compared to the groups with or without normal rat serum (P < 0.01). Furthermore, YGW medicated serum increased the rate of in vitro fertilization (IVF) when compared to the groups treated with FSH and with or without normal rat serum (P < 0.001). YGW medicated serum also had significant effects on the mRNA expressions of PKA, CREB, MAPK, PKC, PKG, and MPF and the concentrations of cAMP, cGMP, and NO in matured oocytes. These results indicate that YGW can promote mouse oocyte maturation and IVF in vitro. Signaling pathways, such as the cAMP/PKA/MAPK, the PKC-MAPK, and the NO-cGMP-PKG pathway, which are similar to those induced by FSH, may be responsible for this action. PMID- 25530776 TI - Dual Effect of Chrysanthemum indicum Extract to Stimulate Osteoblast Differentiation and Inhibit Osteoclast Formation and Resorption In Vitro. AB - The risk of bone-related diseases increases due to the imbalance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively. The goal in the development of antiosteoporotic treatments is an agent that will improve bone through simultaneous osteoblast stimulation and osteoclast inhibition without undesirable side effects. To achieve this goal, numerous studies have been performed to identify novel approaches using natural oriental herbs to treat bone metabolic diseases. In the present study, we investigated the effect of Chrysanthemum indicum extract (CIE) on the differentiation of osteoclastic and osteoblastic cells. CIE inhibited the formation of TRAP-positive mature osteoclasts and of filamentous-actin rings and disrupted the bone resorbing activity of mature osteoclasts in a dose-dependent manner. CIE strongly inhibited Akt, GSK3beta, and IkappaB phosphorylation in RANKL-stimulated bone marrow macrophages and did not show any effects on MAP kinases, including p38, ERK, and JNK. Interestingly, CIE also enhanced primary osteoblast differentiation via upregulation of the expression of alkaline phosphatase and the level of extracellular calcium concentrations during the early and terminal stages of differentiation, respectively. Our results revealed that CIE could have a potential therapeutic role in bone-related disorders through its dual effects on osteoclast and osteoblast differentiation. PMID- 25530777 TI - Alteration of behavioral changes and hippocampus galanin expression in chronic unpredictable mild stress-induced depression rats and effect of electroacupuncture treatment. AB - To explore new noninvasive treatment options for depression, this study investigated the effects of electric acupuncture (EA) for depression rat models. Depression in rats was induced by unpredictable chronic mild stress (UCMS) combined with isolation for 21 days. Eighteen male Sprague-Dawley rats were randomly assigned into three groups: control, model, and EA groups. Rats were treated by EA once daily for 21 days. The results showed that body weight and sucrose consumption were significantly increased in EA group than in the model group. The crossing numbers and rearing numbers in the open field test significantly decreased in the model group but not in the EA group. And EA treatments upregulated levels of hippocampus galanin (Gal) in UCMS rats back to relative normal levels. The present study suggested that EA had antidepressant effects on UCMS model rats. The potential antidepressant effect may be related to upregulating Gal expression in hippocampus. PMID- 25530778 TI - Effect of ASF (a Compound of Traditional Chinese Medicine) on Behavioral Sensitization Induced by Ethanol and Conditioned Place Preference in Mice. AB - ASF composed by semen and epimedium herbal is a traditional plant compound that is widely used in the treatment of insomnia. Studies have shown that saponins and flavonoids contained in semen can significantly decrease the content of excitatory neurotransmitter Glu in mice. And the total flavone of YinYangHuo can increase the release of GABA in the anterior periventricular system of rat and increase the affinity of GABA for the receptors GABAA. It can be inferred that their synergism may have effect on the neurotransmitter that causes behavioral sensitization and conditioned place preference in experimental animals and affects their drinking behaviors, which is the starting point of this research. The present study found that ASF can inhibit development and expression of behavioral sensitization induced by ethanol and the development of CPP in mice. We demonstrate the inhibition of ASF on behavioral sensitization partly due to its effect on the mesolimbic neurotransmitter system, including decreasing level of DA and Glu and increasing the content of GABA. It suggested that the ASF may have pharmacological effects in the treatment of alcohol addiction. PMID- 25530779 TI - Efficacy of acupuncture for psychological symptoms associated with opioid addiction: a systematic review and meta-analysis. AB - This review systematically assessed the clinical evidence for and against acupuncture as a treatment for psychological symptoms associated with opioid addiction. The database was accessed from MEDLINE and China Knowledge Resource Integrated Database. We included all randomized clinical trials published in Chinese and English regardless of their controls. Meta-analysis was performed using the RevMan software, version 5.2. We conducted a literature search of 16 databases from their inception to January 2014. Four studies from Western countries did not report any clinical gains in the treatment of psychological symptoms associated with opioid addiction. 10 of 12 studies from China have reported positive findings regarding the use of acupuncture to treat the psychological symptoms associated with opioid addiction. The methodological quality of the included studies was poor. The meta-analysis indicated that there was a significant difference between the treatment group and the control group for anxiety and depression associated with opioid addiction, although groups did not differ on opioid craving. This review and meta-analysis could not confirm that acupuncture was an effective treatment for psychological symptoms associated with opioid addiction. However, considering the potential of acupuncture demonstrated in the included studies, further rigorous randomized controlled trials with long followup are warranted. PMID- 25530780 TI - Immunosuppressive Effects of A-Type Procyanidin Oligomers from Cinnamomum tamala. AB - Cinnamon barks extracts have been reported to regulate immune function; however, the component(s) in cinnamon barks responsible for this effect is/are not yet clear. The aim of this study is to find out the possible component(s) that can be used as therapeutic agents for immune-related diseases from cinnamon bark. In this study, the immunosuppressive effects of fraction (named CT-F) and five procyanidin oligomers compounds, cinnamtannin B1, cinnamtannin D1 (CTD-1), parameritannin A1, procyanidin B2, and procyanidin C1, from Cinnamomum tamala or Cinnamomum cassia bark were examined on splenocytes proliferation model induced by ConA or LPS. Then, the effects of activated compound CTD-1 on cytokine production and 2,4-dinitrofluorobenzene (DNFB) induced delayed-type hypersensitivity (DTH) response were detected to evaluate the immunosuppressive activity of CTD-1. It was found that CT-F and CTD-1 significantly inhibited the splenocyte proliferation induced by ConA or LPS. CTD-1 dose-dependently reduced the level of IFN-gamma and IL-2 and intensively suppressed DNFB-induced DTH responses. These findings suggest that the immunosuppressive activities of cinnamon bark are in part due to procyanidin oligomers. CTD-1 may be a potential therapeutic agent for immune-related diseases. PMID- 25530781 TI - Pharmacokinetic alteration of baclofen by multiple oral administration of herbal medicines in rats. AB - The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42-4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C max) and longer time to reach C max (T max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F urine). The absorption rate (K a ) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance. PMID- 25530782 TI - Musculoskeletal strength, balance performance, and self-efficacy in elderly ving tsun chinese martial art practitioners: implications for fall prevention. AB - Objectives. To (1) compare the bone strength, lower limb muscular strength, functional balance performance, and balance self-efficacy between Ving Tsun (VT) martial art practitioners and nonpractitioners and (2) identify the associations between lower limb muscular strength, functional balance performance, and balance self-efficacy among the VT-trained participants. Methods. Thirty-five VT practitioners (mean age +/- SD = 62.7 +/- 13.3 years) and 49 nonpractitioners (mean age +/- SD = 65.9 +/- 10.5 years) participated in the study. The bone strength of the distal radius, lower limb muscular strength, functional balance performance, and balance self-efficacy were assessed using an ultrasound bone sonometer, the five times sit-to-stand test (FTSTS), the Berg balance scale (BBS), and the Chinese version of the activities-specific balance confidence scale, respectively. A multivariate analysis of covariance was performed to compare all the outcome variables between the two groups. Results. Elderly VT practitioners had higher radial bone strength on the dominant side (P < 0.05), greater lower limb muscular strength (P = 0.001), better functional balance performance (P = 0.003), and greater balance confidence (P < 0.001) than the nonpractitioners. Additionally, only the FTSTS time revealed a significant association with the BBS score (r = -0.575, P = 0.013). Conclusions. VT may be a suitable health-maintenance exercise for the elderly. Our findings may inspire the development of VT fall-prevention exercises for the community-dwelling healthy elderly. PMID- 25530783 TI - Isolation, Characterization, Crystal Structure Elucidation, and Anticancer Study of Dimethyl Cardamonin, Isolated from Syzygium campanulatum Korth. AB - Syzygium campanulatum Korth is an equatorial, evergreen, aboriginal shrub of Malaysia. Conventionally it has been used as a stomachic. However, in the currently conducted study dimethyl cardamonin or 2',4'-dihydroxy-6'-methoxy-3',5' dimethylchalcone (DMC) was isolated from S. campanulatum Korth, leaf extract. The structural characterization of DMC was carried out by making use of various techniques including UV, IR, NMR spectral followed by LC-MS, and X-ray crystallographic techniques. For determining the purity of compound, highly effective techniques including TLC, HPLC, and melting point were used. The cytotoxicity of DMC and three different extracts of S. campanulatum was evaluated against human colon cancer cell line (HT-29) by three different assays. DMC and ethanolic extract revealed potent and dose-dependent cytotoxic activity on the cancer cell line with IC50 12.6 and 90.1 ug/mL, respectively. Quite astonishingly to our knowledge, this is the very first report on S. campanulatum as being a rich source (3.5%) of DMC, X-ray crystallography, and anticancer activity on human colon cancer cells. PMID- 25530784 TI - The Inhibition of the Components from Shengmai Injection towards UDP Glucuronosyltransferase. AB - The mechanism of shengmai injection- (SMI-) related drug-drug interaction remains unclear. Evaluation of the inhibition potential of SMI's ingredients towards UDP glucuronosyltransferases (UGTs) activity will provide a new insight to understand SMI-related drug-drug interaction. In vitro incubation system to model UGT reaction was used. Recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4 MU) glucuronidation and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reactions were employed to phenotype the inhibition profile of maidong's components towards the activity of UGT isoforms. Different inhibition potential of maidong's components towards various UGT isoforms was observed. Based on the inhibition kinetic investigation results, ophiopogonin D (OD) noncompetitively inhibited UGT1A6 and competitively inhibited UGT1A8, ophiopogonin D' (OD') noncompetitively inhibited UGT1A6 and UGT1A10, and ruscorectal (RU) exhibited competitive inhibition towards UGT1A4. The inhibition kinetic parameters were calculated to be 20.6, 40.1, 5.3, 9.0, and 0.02 MUM, respectively. In combination with our previous results obtained for the inhibition of UGT isoforms by ginsenosides and wuweizi components, the important SMI ingredients exhibiting strong inhibition towards UGT isoforms were highlighted. All the results obtained in the present study provide a new insight to understand SMI-related drug-drug interaction. PMID- 25530785 TI - Brazilian red propolis induces apoptosis-like cell death and decreases migration potential in bladder cancer cells. AB - Natural products continue to be an invaluable resource of anticancer drug discovery in recent years. Propolis is known for its biological activities such as antimicrobial and antitumor effects. This study assessed the effects of Brazilian red propolis (BRP) on apoptosis and migration potential in human bladder cancer cells. The effect of BRP ethanolic extract (25, 50, and 100 MUg/mL) on 5637 cells was determined by MTT, LIVE/DEAD, and migration (scratch assay) assays. Apoptosis induction was investigated through flow cytometry and gene expression profile was investigated by qRT-PCR. Results showed cytotoxicity on MTT and LIVE/DEAD assays, with IC50 values of 95 MUg/mL in 24 h of treatment. Cellular migration of 5637 cells was significantly inhibited through lower doses of BRP ethanolic extract (25 and 50 MUg/mL). Flow cytometry analyses showed that BRP induced cytotoxicity through apoptosis-like mechanisms in 5637 cells and qRT PCR revealed increased levels of Bax/Bcl-2 ratio, p53, AIF, and antioxidant enzymes genes. Data suggest that BRP may be a potential source of drugs to bladder cancer treatment. PMID- 25530787 TI - Demographic characteristics and medical service use of failed back surgery syndrome patients at an integrated treatment hospital focusing on complementary and alternative medicine: a retrospective review of electronic medical records. AB - Objective. To report the patient demographics and nonsurgical complementary and alternative medicine treatment used at a Korean medicine hospital for low back pain (LBP) and/or sciatica after surgery. Methods. Medical records of patients who visited a spine-specialized Korean medicine hospital at 2 separate sites for continuous or recurrent LBP or sciatica following back surgery were reviewed. The demographics, MRI and/or CT scans, and treatments were assessed. Results. Of the total 707 patients, 62% were male and the average age was 50.20 years. Ninety percent of patients presented with LBP and 67% with sciatica. Eighty-four percent were diagnosed with herniated nucleus pulposus at time of surgery. Of these patients, 70% had pain recurrence 6 months or later, but 19% experienced no relief or immediate aggravation of pain after surgery. Many patients selected traditional Korean medicine treatment as primary means of postsurgery care (47%). When time to pain recurrence was short or pain persisted after surgery, return of symptoms at the same disc level and side was frequent. Conclusion. An integrative treatment model focusing on Korean medicine and used in conjunction with radiological diagnostics and conventional medicine is currently used as a treatment option for patients with pain after lumbar spine surgery. PMID- 25530786 TI - Comparison of electroacupuncture and morphine-mediated analgesic patterns in a plantar incision-induced pain model. AB - Electroacupuncture (EA) is a complementary therapy to improve morphine analgesia for postoperative pain, but underlying mechanism is not well-known. Herein, we investigated EA-induced analgesic effect in a plantar incision (PI) model in male Sprague-Dawley rats. PI was performed at the left hind paw. EA of 4 Hz and high intensity or sham needling was conducted at right ST36 prior to PI and repeated for another 2 days. Behavioral responses to mechanical and thermal stimuli, spinal phospho-ERK, and Fos expression were all analyzed. In additional groups, naloxone and morphine were administered to elucidate involvement of opioid receptors and for comparison with EA. EA pretreatment significantly reduced post PI tactile allodynia for over 1 day; repeated treatments maintained analgesic effect. Intraperitoneal naloxone could reverse EA analgesia. Low-dose subcutaneous morphine (1 mg/kg) had stronger inhibitory effect on PI-induced allodynia than EA for 1 h. However, analgesic tolerance appeared after repeated morphine injections. Both EA and morphine could equally inhibit PI-induced p-ERK and Fos inductions. We conclude that though EA and morphine attenuate postincision pain through opioid receptor activations, daily EA treatments result in analgesic accumulation whereas daily morphine injections develop analgesic tolerance. Discrepant pathways and mechanisms underlying two analgesic means may account for the results. PMID- 25530788 TI - Safety Evaluation of Oral Toxicity of Carica papaya Linn. Leaves: A Subchronic Toxicity Study in Sprague Dawley Rats. AB - The subchronic toxicity effect of the leaf extract of Carica papaya Linn. in Sprague Dawley (SD) rats was investigated in this study. The extract was prepared by dissolving the freeze dried extract of the leaves in distilled water and was administered orally to SD rats (consisted of 10 rats/sex/group) at 0 (control), 0.01, 0.14, and 2 g/kg body weight (BW) for 13 weeks. General observation, mortality, and food and water intake were monitored throughout the experimental period. Hematological and biochemical parameters, relative organ weights, and histopathological changes were evaluated. The study showed that leaf extract when administered for 13 weeks did not cause any mortality and abnormalities of behavior or changes in body weight as well as food and water intake. There were no significant differences observed in hematology parameters between treatment and control groups; however significant differences were seen in biochemistry values, for example, LDH, creatinine, total protein, and albumin. However, these changes were not associated with histopathological changes. In conclusion, the results suggested that daily oral administration of rats with C. papaya leaf extract for 13 weeks at a dose up to fourteen times the levels employed in traditional medicine practice did not cause any significant toxic effect. PMID- 25530789 TI - Preliminary study of quercetin affecting the hypothalamic-pituitary-gonadal axis on rat endometriosis model. AB - In this study, the endometriosis rats model was randomly divided into 6 groups: model control group, ovariectomized group, Gestrinone group, and quercetin high/medium/low dose group. Rats were killed after 3 weeks of administration. The expression levels of serum FSH and LH were detected by ELISA. The localizations and quantities of ERalpha, ERbeta, and PR were detected by immunohistochemistry and western blot. The results showed that the mechanism of quercetin inhibiting the growth of ectopic endometrium on rat endometriosis model may be through the decreasing of serum FSH and LH levels and then reducing local estrogen content to make the ectopic endometrium atrophy. Quercetin can decrease the expression of ERalpha, ERbeta, and PR in hypothalamus, pituitary, and endometrium, thereby inhibiting estrogen and progesterone binding to their receptors to play the role of antiestrogen and progesterone. PMID- 25530790 TI - Synergistic effects of clopidogrel and fufang danshen dripping pills by modulation of the metabolism target and pharmacokinetics. AB - Background and Objective. The aim was to evaluate the synergistic effects of clopidogrel and FDDP by modulating the metabolism target and the pharmacokinetics. Methods. The inhibition effect of FDDP on the CES1 was first investigated by the molecular simulation method, and the synergistic effects on the pharmacokinetics of CPGS were studied as follows: SD rats were treated with oral clopidogrel alone at a dosage of 30 mg/kg or the combination of clopidogrel and FDDP at dosages of 30 mg/kg and 324 mg/kg, respectively, for 21 days. The concentrations of CPGS in the blood plasma samples were determined and the calculated concentrations were used to determine the pharmacokinetic parameters. Results. 20 compounds in FDDP potentially interacted with CES1 target. The CPGS showed a two-compartment model pharmacokinetic profile. The concentration-time course of CPGS was not changed by FDDP, but FDDP decreased the peak plasma concentration and area under the curve of CPGS. Conclusion. The CES1's activity could be partly inhibited by FDDP through the molecular simulation investigation. The concentration-time course of CPGS was altered slightly by FDDP. The results demonstrated the synergistic effects of clopidogrel and FDDP by modulating both the pharmacokinetics and the target metabolism. PMID- 25530791 TI - An alternative to current therapies of functional dyspepsia: self-administrated transcutaneous electroacupuncture improves dyspeptic symptoms. AB - Functional dyspepsia is of high prevalence with little treatment options. The aim of this study was to develop a new treatment method using self-management transcutaneous electroacupuncture (TEA) for functional dyspepsia (FD). Twenty eight patients with FD were enrolled and underwent a crossover clinical trial with 2-week TEA at ST36 and PC6 and 2-week sham-TEA at nonacupuncture sham points. Questionnaires were used to assess symptoms of dyspepsia and quality of life. Physiological testing included gastric emptying and electrogastrography. It was found that (1) TEA but not sham-TEA significantly improved dyspeptic symptoms and 4 domains in quality of life; improvement was also noted in self-rated anxiety and depression scores; (2) gastric emptying was significantly and substantially increased with 2-week TEA but not sham-TEA; and (3) gastric accommodation was also improved with TEA but not sham-TEA, reflected as increased ingested nutrient volumes at the levels of satiety and maximum tolerance. These findings suggest a therapeutic potential of self-administrated TEA method for functional dyspepsia, possibly attributed to improvement in gastric motility. PMID- 25530792 TI - Association between Disease-Specific Quality of Life and Complementary Medicine Use in Patients with Rhinitis in Taiwan: A Cross-Sectional Survey Study. AB - Rhinitis is a common medical condition and can seriously impact patients' quality of life. The objective of this study was to investigate the association between disease-specific quality of life and use of complementary and alternative medicine (CAM) modalities among Taiwanese rhinitis patients. A cross-sectional survey was undertaken at the outpatient department of otolaryngology in a medical center in Taiwan. Sociodemographic information, disease-specific quality of life (Chinese version of the 31-item Rhinosinusitis Outcome Measure, CRSOM-31), and previous use of CAM modalities for treatment of rhinitis of the patients were ascertained. Factor analysis was performed to reduce the number of CAM modalities. The resulting factors were analyzed for their association with CRSOM 31 score using linear regression analyses. Results from the multiple linear regression analyses indicated that Factor 1 (traditional Chinese medicine), Factor 2 (mind-body modalities), Factor 3 (manipulative-based modalities), female sex, and smoking were significantly associated with a worse disease-specific quality of life. In conclusion, various CAM modalities, female sex, and smoking were independent predictors of a worse disease-specific quality of life in Taiwanese patients with rhinitis. PMID- 25530793 TI - Opponent familiarity and contest experience jointly influence contest decisions in Kryptolebias marmoratus. AB - INTRODUCTION: Individual recognition and winner/loser effects both play important roles in animal contests, but how their influences are integrated to affect an individual's contest decisions in combination remains unclear. Individual recognition provides an animal with relatively precise information about its ability to defeat conspecifics that it has fought previously. Winner/loser effects, conversely, rely on sampling information about how an animal's ability to win compares with those of others in the population. The less precise information causing winner/loser effects should therefore be more useful to an individual facing an unfamiliar opponent. In this study, we used Kryptolebias marmoratus, a hermaphroditic mangrove killifish, to test whether winner/loser effects do depend on opponent familiarity. In addition, as previous studies have shown that subordinates that behave aggressively sometimes suffer post-retreat retaliation from contest winners, we also explored this aspect of contest interaction in K. marmoratus. RESULTS: In the early stages of a contest, subordinates facing an unfamiliar dominant were more likely to signal their aggressiveness with either gill displays or attacks rather than retreating immediately. A winning experience then increased the likelihood that the most aggressive behavioral pattern the subordinates exhibited would be attacks rather than gill displays, irrespective of their opponents' familiarity. Dominants that received a losing experience and faced an unfamiliar opponent were less likely than others to launch attacks directly. And subordinates that challenged dominants with more aggressive tactics but still lost received more post-retreat attacks from their dominant opponents. CONCLUSIONS: Subordinates' contest decisions were influenced by both their contest experience and the familiarity of their opponents, but these influences appeared at different stages of a contest and did not interact significantly with each other. The influence of a losing experience on dominants' contest decisions, however, did depend on their subordinate opponents' familiarity. Subordinates and dominants thus appeared to integrate information from the familiarity of their opponents and the outcome of previous contests differently, which warrants further investigation. The higher costs that dominants imposed on subordinates that behaved more aggressively toward them may have been to deter them from either fighting back or challenging them in the future. PMID- 25530794 TI - Breast milk donation after neonatal death in Australia: a report. AB - Lactation and breast milk can hold great value and meaning for grieving mothers who have experienced a recent death of an infant. Donation to a human milk bank (HMB) as an alternative to discarding breast milk is one means of respecting the value of breast milk. There is little research, national policy discussion, or organizational representation in Australia on the subject of breast milk donation after infant death. On 29 November 2013 the Mercy Hospital for Women in Melbourne, Australia hosted Australia's first National Stakeholder Meeting (NSM) on the topic of milk donation after neonatal death. The NSM drew together representatives from Australian HMBs, neonatal intensive care units (NICUs) currently using donor human milk, and Australia's chief NICU parent support organization. The NSM was video-recorded and transcribed, and analyzed thematically by researchers. This article reports the seven dominant themes discussed by stakeholders during the NSM: the spectrum of women's lactation and donation experiences after infant death; the roles of the HMB and NICU in meeting the needs of the bereaved donor; how bereaved mothers' lactation autonomy may interface with a HMB's donation guidelines; how milk donation may be discussed with bereaved mothers; the variation between four categories of milk donation after neonatal death; the impact of limited resources and few HMBs on providing donation programs for bereaved mothers in Australia. This article provides evidence from researchers and practitioners that can assist HMB staff in refining their bank's policy on milk donation after infant death, and provides national policy makers with key considerations to support lactation, human milk banking, and bereavement services nation-wide. PMID- 25530796 TI - ADLD: a novel graphical representation of protein sequences and its application. AB - To facilitate the intuitional analysis of protein sequences, a novel graphical representation of protein sequences called ADLD (Alignment Diagonal Line Diagram) is introduced in this paper first, and then a new ADLD based method is proposed and utilized to analyze the similarity/dissimilarity of protein sequences. Comparing with existing methods, our ADLD based method is proved to be effective in the similarity/dissimilarity analysis of protein sequences and have the merits of good intuition, visuality, and simplicity. The examinations of the similarities/dissimilarities for both the 16 different ND5 proteins and the 29 different spike proteins illustrate the utility of our ADLD based approach. PMID- 25530797 TI - Time-reversed adapted-perturbation (TRAP) optical focusing onto dynamic objects inside scattering media. AB - The ability to steer and focus light inside scattering media has long been sought for a multitude of applications. To form optical foci inside scattering media, the only feasible strategy at present is to guide photons by using either implanted1 or virtual2-4 guide stars, which can be inconvenient and limits potential applications. Here, we report a scheme for focusing light inside scattering media by employing intrinsic dynamics as guide stars. By time reversing the perturbed component of the scattered light adaptively, we show that it is possible to focus light to the origin of the perturbation. Using the approach, we demonstrate non-invasive dynamic light focusing onto moving targets and imaging of a time-variant object obscured by highly scattering media. Anticipated applications include imaging and photoablation of angiogenic vessels in tumours as well as other biomedical uses. PMID- 25530795 TI - Surgical Materials: Current Challenges and Nano-enabled Solutions. AB - Surgical adhesive biomaterials have emerged as substitutes to sutures and staples in many clinical applications. Nano-enabled materials containing nanoparticles or having a distinct nanotopography have been utilized for generation of a new class of surgical materials with enhanced functionality. In this review, the state of the art in the development of conventional surgical adhesive biomaterials is critically reviewed and their shortcomings are outlined. Recent advancements in generation of nano-enabled surgical materials with their potential future applications are discussed. This review will open new avenues for the innovative development of the next generation of tissue adhesives, hemostats, and sealants with enhanced functionality for various surgical applications. PMID- 25530798 TI - How Do Children Perceive and Act on Dynamic Affordances in Crossing Traffic Filled Roads? AB - Successfully perceiving and acting on dynamic affordances is critical for children and adults to function. In our work, we look at how children cross roads as a model for understanding how they learn to perceive and act on dynamic affordances. Ten- to 14-year-old children and adults ride an interactive bicycling simulator through an immersive virtual environment where they cross intersections with continuous cross traffic. We consistently find developmental and individual differences in children's ability to tightly time their entry into the roadway relative to the lead car in the gap. Given that children do not adjust their gap choices to match their less precise timing abilities, children take more risks when crossing roads than adults. We conclude by discussing possible reasons for these developmental differences in movement timing. PMID- 25530801 TI - Beyond the Local Agenda: International Perspectives in Community-based Arts and Health. PMID- 25530799 TI - Hair-based rapid analyses for multiple drugs in forensics and doping: application of dynamic multiple reaction monitoring with LC-MS/MS. AB - BACKGROUND: Considerable efforts are being extended to develop more effective methods to detect drugs in forensic science for applications such as preventing doping in sport. The aim of this study was to develop a sensitive and accurate method for analytes of forensic and toxicological nature in human hair at sub-pg levels. RESULTS: The hair test covers a range of different classes of drugs and metabolites of forensic and toxicological nature including selected anabolic steroids, cocaine, amphetamines, cannabinoids, opiates, bronchodilators, phencyclidine and ketamine. For extraction purposes, the hair samples were decontaminated using dichloromethane, ground and treated with 1 M sodium hydroxide and neutralised with hydrochloric acid and phosphate buffer and the homogenate was later extracted with hexane using liquid-liquid extraction (LLE). Following extraction from hair samples, drug-screening employed liquid chromatography coupled to tandem mass spectrometric (LC-MS/MS) analysis using dynamic multiple reaction monitoring (DYN-MRM) method using proprietary software. The screening method (for > 200 drugs/metabolites) was calibrated with a tailored drug mixture and was validated for 20 selected drugs for this study. Using standard additions to hair sample extracts, validation was in line with FDA guidance. A Zorbax Eclipse plus C18 (2.1 mm internal diameter * 100 mm length * 1.8 MUm particle size) column was used for analysis. Total instrument run time was 8 minutes with no noted matrix interferences. The LOD of compounds ranged between 0.05-0.5 pg/mg of hair. 233 human hair samples were screened using this new method and samples were confirmed positive for 20 different drugs, mainly steroids and drugs of abuse. CONCLUSIONS: This is the first report of the application of this proprietary system to investigate the presence of drugs in human hair samples. The method is selective, sensitive and robust for the screening and confirmation of multiple drugs in a single analysis and has potential as a very useful tool for the analysis of large array of controlled substances and drugs of abuse. PMID- 25530800 TI - Potential predictors of delay in initial treatment contact after the first onset of depression in Japan: a clinical sample study. AB - BACKGROUND: A growing body of evidence shows that reducing the duration of untreated illness (DUI) correlates with improved clinical outcome and course of depression. However, the factors involved in delaying treatment contact after the first onset of lifetime depression are not fully understood. This cross-sectional study aims to identify the characteristics that may predict the delay in initial treatment contact after the first onset of lifetime depression by comparing the socio-demographics and clinical characteristics between those with longer and shorter DUI in a well-characterized Japanese clinical sample. METHODS: Ninety five patients with depression with longer (>12 months) and shorter DUI (<=12 months) at three Japanese outpatient clinics were studied. Subjects received a comprehensive evaluation, including semi-structured clinical interviews and assessment battery, and their clinical charts were reviewed. RESULTS: Of the total sample, the median of DUI was 4 months (interquartile range (IQR) 25th-75th percentile, 2-13). We found that 72.6% of patients seek treatment contact within the first year of depression onset. Multivariate logistic regression analysis showed that longer DUI in patients was associated with marital status (never married). Further, the DSM-IV melancholic features approached significance. CONCLUSIONS: Our findings suggest that most Japanese patients with depression are likely to seek treatment within 1 year of onset, and that marital status and melancholia may be potential predictors of the delay in the initial treatment contact after the first onset of lifetime depression. PMID- 25530802 TI - Arts practice and disconnected youth in Australia: Impact and domains of change. AB - Background: This paper describes research conducted with Big hART, Australia's most awarded participatory arts company. It considers three projects, LUCKY, GOLD and NGAPARTJI NGAPARTJI across separate sites in Tasmania, Western NSW and Northern Territory, respectively, in order to understand project impact from the perspective of project participants, Arts workers, community members and funders. Methods: Semi-structured interviews were conducted with 29 respondents. The data were coded thematically and analysed using the constant comparative method of qualitative data analysis. Results: Seven broad domains of change were identified: psychosocial health; community; agency and behavioural change; the Art; economic effect; learning and identity. Conclusions: Experiences of participatory arts are interrelated in an ecology of practice that is iterative, relational, developmental, temporal and contextually bound. This means that questions of impact are contingent, and there is no one path that participants travel or single measure that can adequately capture the richness and diversity of experience. Consequently, it is the productive tensions between the domains of change that are important and the way they are animated through Arts practice that provides sign posts towards the impact of Big hART projects. PMID- 25530803 TI - Lignin triggers irreversible cellulase loss during pretreated lignocellulosic biomass saccharification. AB - BACKGROUND: Non-productive binding of enzymes to lignin is thought to impede the saccharification efficiency of pretreated lignocellulosic biomass to fermentable sugars. Due to a lack of suitable analytical techniques that track binding of individual enzymes within complex protein mixtures and the difficulty in distinguishing the contribution of productive (binding to specific glycans) versus non-productive (binding to lignin) binding of cellulases to lignocellulose, there is currently a poor understanding of individual enzyme adsorption to lignin during the time course of pretreated biomass saccharification. RESULTS: In this study, we have utilized an FPLC (fast protein liquid chromatography)-based methodology to quantify free Trichoderma reesei cellulases (namely CBH I, CBH II, and EG I) concentration within a complex hydrolyzate mixture during the varying time course of biomass saccharification. Three pretreated corn stover (CS) samples were included in this study: Ammonia Fiber Expansion(a) (AFEXTM-CS), dilute acid (DA-CS), and ionic liquid (IL-CS) pretreatments. The relative fraction of bound individual cellulases varied depending not only on the pretreated biomass type (and lignin abundance) but also on the type of cellulase. Acid pretreated biomass had the highest levels of non recoverable cellulases, while ionic liquid pretreated biomass had the highest overall cellulase recovery. CBH II has the lowest thermal stability among the three T. reesei cellulases tested. By preparing recombinant family 1 carbohydrate binding module (CBM) fusion proteins, we have shown that family 1 CBMs are highly implicated in the non-productive binding of full-length T. reesei cellulases to lignin. CONCLUSIONS: Our findings aid in further understanding the complex mechanisms of non-productive binding of cellulases to pretreated lignocellulosic biomass. Developing optimized pretreatment processes with reduced or modified lignin content to minimize non-productive enzyme binding or engineering pretreatment-specific, low-lignin binding cellulases will improve enzyme specific activity, facilitate enzyme recycling, and thereby permit production of cheaper biofuels. PMID- 25530804 TI - Multiplex ligation-dependent probe amplification and array comparative genomic hybridization analyses for prenatal diagnosis of cytogenomic abnormalities. AB - BACKGROUND: The aims of this study were to evaluate the clinical utility of multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH) analyses on prenatal cases and to review prenatal ultrasound findings of cytogenomic syndromes. RESULTS: Of the 54 prenatal cases analyzed, cytogenomic abnormalities were characterized in 14 cases. In four fetuses with abnormal ultrasound findings, a 40.701 Mb duplication of 8q22.3 q24.3 and a 23.839 Mb deletion of 7q33-q36.3 derived from a paternal balanced translocation, a de novo 13.062 Mb deletion of 11q24.1-q25 for Jacobsen syndrome, a de novo 19.971 Mb deletion of 7q11.23-q21.3 for type 1 split-hand/foot malformation (SHFM1), and a de novo 28.909 Mb duplication of 3q21.1-q25.1 were detected. A 699.8 Kb deletion at 5p15.33 for Cri du Chat syndrome was confirmed in a fetus with abnormal MLPA result. A fetus with abnormal maternal screening was detected with a de novo distal 1.747 Mb duplication at 2q37.1-q37.2 and a 6.664 Mb deletion at 2q37.2-q37.3. Of the eight cases referred by history of spontaneous abortions, derivative chromosomes 11 from paternal carriers of a balanced 8q/11q and a 10q/11q translocation were noted in two cases, simple aneuploids of trisomy 2 and trisomy 21 were seen in three cases, and compound aneuploids of two or three chromosomes were found in three cases. Post-test genetic counseling was performed with detailed genomic information and well characterized postnatal syndromic features. CONCLUSIONS: These results demonstrated that coupling MLPA screening and aCGH analysis are a cost-effective approach to detect cytogenomic abnormalities in a prenatal setting. The aCGH analysis provided not only genomic maps of breakpoints and gene content of imbalanced regions but also better inference of related phenotypes for genetic counseling. Prenatal ultrasound findings reported in the literature for Jacobsen syndrome, SHFM and Cri du Chat syndrome were summarized for use as diagnostic references. PMID- 25530805 TI - Clinical utility of chromosomal microarray analysis in the diagnosis and management of monosomy 7 mosaicism. AB - There have been dramatic improvements in our ability to more accurately diagnose the underlying genetic causes of developmental delay/intellectual disability; however, there is less known about the treatment trajectory and whether or not patient management and outcomes have changed due to the information gained from genetic testing. Here we report a case study of a 20-month-old male first referred to the genetics clinic in 2008 for interhemispheric cysts, agenesis of the corpus callosum, left cortical dysplasia, and developmental delay of unknown etiology. The diagnostic work-up for this patient included chromosomal microarray which detected >20% mosaicism for monosomy 7, which raised concern for a possible myelodysplastic syndrome. The clone was not detected in stimulated peripheral blood cultures and his karyotype was reported as a normal male. Because of this microarray finding, he was referred to pediatric hematology/oncology where he was confirmed to have a pre-symptomatic diagnosis of myelodysplastic syndrome and was treated with chemotherapy and a bone-marrow transplant. This case illustrates the clinical utility of microarray testing and the importance of long-term follow-up to assess patient outcomes. PMID- 25530807 TI - Fiber type composition of the human quadratus plantae muscle: a comparison of the lateral and medial heads. AB - BACKGROUND: The human quadratus plantae muscle has been attributed a variety of functions, however no consensus has been reached on its significance to foot functioning. The architecture of the human quadratus plantae consists of an evolutionarily conserved lateral head, and a medial head thought to be unique to Man. Surveys of human anatomy have demonstrated the absence of either the medial or lateral head in 20% of the population, which may have implications for foot functioning if each muscle head performs a discrete function. METHODS: We investigated the quadratus plantae from eleven formalin-embalmed specimens with a mean age of 84 +/- 9 years. Immunohistochemical methods were used to determine the percentage of Type I and Type II muscle fibers in the medial and lateral heads of the quadratus plantae from these specimens. RESULTS: Results showed striking homogeneity in fiber type composition within an individual, with an average difference in Type I fiber content of 4.1% between lateral and medial heads. Between individuals, however, the ratio of fiber types within the quadratus plantae was highly variable, with Type I fiber percentages ranging from 19.1% to 91.6% in the lateral head, and 20.4% to 97.0% within the medial head. CONCLUSIONS: Our finding of similar fiber type composition of lateral and medial heads within an individual supports the hypothesis that the two heads have a singular function. PMID- 25530808 TI - The role of the Cronobacter sakazakii ProP C-terminal coiled coil domain in osmotolerance. AB - BACKGROUND: We investigate the role of the C-terminal coiled coil of the secondary proline porter ProP in contributing to Cronobacter sakazakii osmotolerance. FINDINGS: The extended C-terminal domain of ProP1 (encoded by ESA_02131) was spliced onto the truncated C-terminal end of ProP2 (encoded by ESA_01706); creating a chimeric protein (ProPc) which exhibits increased osmotolerance relative to the wild type. CONCLUSIONS: It appears that the C terminal coiled coil domain tunes ProP at low osmolality, whereas ProP transporters lacking the coiled coil domain are more active at a higher osmolality range. PMID- 25530806 TI - Systematic identification and quantification of phase variation in commensal and pathogenic Escherichia coli. AB - Bacteria have been shown to generate constant genetic variation in a process termed phase variation. We present a tool based on whole genome sequencing that allows detection and quantification of coexisting genotypes mediated by genomic inversions in bacterial cultures. We tested our method on widely used strains of Escherichia coli, and detected stable and reproducible phase variation in several invertible loci. These are shown here to be responsible for maintaining constant variation in populations grown from a single colony. Applying this tool on other bacterial strains can shed light on how pathogens adjust to hostile environments by diversifying their genomes. PMID- 25530809 TI - Circulating levels of irisin in middle-aged first-degree relatives of type 2 diabetes mellitus - correlation with pancreatic beta-cell function. AB - BACKGROUND: Irisin is a novel myokine secreted in response to peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) activation through exercise. The first-degree relatives (FDRs) of type 2 diabetes mellitus (T2DM) patients bear a lifetime risk for developing T2DM, especially after 40 years old. However, the circulating irisin levels in middle-aged FDRs of T2DM is unclear. We therefore investigated the association between circulating irisin and pancreatic beta-cell function in normal-glucose-tolerance (NGT) subjects. METHODS: In this cross-sectional study, we recruited 412 supposed healthy subjects aged 40-60 who were FDRs of T2DM patients but without previous diagnosis of T2DM. Of the 412 individuals, 254 had NGT and 60 were newly diagnosed T2DM based on the results of a 75 g oral glucose tolerance test (OGTT- World Health Organization diagnostic criteria). We measured irisin in the newly diagnosed T2DM group (n = 60) and in an age- and sex-matched NGT subgroups (n = 62). Serum irisin was quantified by ELISA, and its association with metabolic parameters was analysed by Pearson's correlation and multiple linear regression analyses. RESULTS: There was no significant difference in serum irisin between middle-aged newly diagnosed T2DM patients and the NGT control group. Circulating irisin was correlated with haemoglobin A1c (r = 0.202, p = 0.026) and estimated glomerular filtration rate (r = 0.239, p = 0.010). Multiple linear regression revealed that only homeostasis model assessment-beta (HOMA-beta) was associated with irisin in NGT subjects after adjusting for confounding factors. However, similar analysis in T2DM did not reveal a significant association between circulating irisin and metabolic parameters. CONCLUSIONS: There was no significant difference in serum irisin between middle-aged newly diagnosed T2DM patients and the NGT controls. Serum irisin level was closely related to HOMA-beta in NGT, suggesting that irisin may play a crucial role in pancreatic beta-cell function. PMID- 25530810 TI - Differential association between obesity and coronary artery disease according to the presence of diabetes in a Korean population. AB - BACKGROUND: Coronary artery disease (CAD) is a major cardiovascular complication in diabetic patients. Despite the significant association between obesity and diabetes, the majority of the diabetic subjects are not obese in an Asian population. This study evaluated the association between obesity and coronary artery disease (CAD) according to the diabetes status in a Korean population. METHODS: The association between obesity and CAD using the parameters of any plaque, obstructive plaque, and coronary artery calcium score (CACS) >100 according to the presence of diabetes was evaluated in 7,234 Korean adults who underwent multi-detector computed tomography for general health evaluations. Obesity was defined as a body mass index (BMI) >=25 kg/m(2). RESULTS: The prevalence of obesity was significantly higher in diabetic subjects than in non diabetic subjects, but the majority of the diabetic subjects were non-obese (48% vs. 37%, p <0.001). The incidence of any plaque (58% vs. 29%), obstructive plaque (20% vs. 6%), and CACS >100 (20% vs. 6%) were significantly higher in diabetic patients than in non-diabetic subjects (p <0.001, respectively). Incidence of any plaque (33% vs. 26%, p <0.001), obstructive plaque (7% vs. 6%, p = 0.014), and CACS >100 (8% vs. 6%, p = 0.002) was significantly higher in non-diabetic subjects with obesity than in those without obesity, but the incidence of all coronary parameters was not different in diabetic subjects according to the obesity status. After adjusting for confounding risk factors including age, gender, hypertension, dyslipidemia, current smoking, and mild renal dysfunction, obesity was independently associated with increased risks of any plaque (OR 1.14) and CACS >100 (OR 1.31) only in non-diabetic subjects (p <0.05, respectively). Multiple logistic regression models revealed that diabetes was independently associated with all coronary parameters. CONCLUSION: Despite a significantly higher prevalence of obesity in diabetic subjects than in non-diabetic subjects, obesity is associated with the presence of any plaque and severe coronary calcification only in subjects without established diabetes among Korean population. PMID- 25530811 TI - The relationship between glycemic variability and diabetic peripheral neuropathy in type 2 diabetes with well-controlled HbA1c. AB - BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications of diabetes. Glycemic variability could be an independent risk factor for diabetes complications in addition to average glucose. Type 2 diabetes with well-controlled glycosylated hemoglobin A1c (HbA1c) may have different terms of glycemic variability and vascular complication consequences. The aim of the study is to investigate the relationship between glycemic variability and DPN in type 2 diabetes with well-controlled HbA1c (HbA1c < 7.0%). METHODS: 45 type 2 diabetes with well-controlled HbA1c(HbA1c < 7.0%) and with DPN (DM/DPN group) were recruited in the study, and 45 type 2 diabetes with well-controlled HbA1c and without DPN (DM/-DPN group) were set as controls. The two groups were also matched for age and diabetic duration. Blood pressure, body mass index(BMI), insulin sensitivity index (Matsuda index, ISI), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDLC), and low density lipoprotein cholesterol (LDLC) were tested in the two groups. And all patients were monitored using the continuous glucose monitoring (CGM) system for consecutive 72 hours. The multiple parameters of glycemic variability included the standard deviation of blood glucose (SDBG), mean of daily differences (MODD) and mean amplitude of glycemic excursions (MAGE). RESULTS: The DM/DPN group had a greater SDBG, MODD and MAGE, when compared to the DM/-DPN group (p < 0.05). BMI, TC, and LDLC of DM/DPN group were lower than those of DM/ DPN group (p < 0.05). The patients with hypoglycemia were comparable between the two groups (p > 0.05). Univariate analysis showed DPN was closely associated with BMI (OR 0.82, CI 0.72-0.94, p = 0.005), TC (OR 0.63, CI 0.42-0.93, p = 0.02), LDLC (OR 0.4, CI 0.20-0.80, p = 0.009), SDBG (OR 2.95, CI 1.55-5.61, p = 0.001), MODD (OR 4.38, CI 1.48-12.93, p = 0.008), MAGE (OR 2.18, CI 1.47-3.24, p < 0.001). Multivariate logistic regression analysis showed that MAGE (OR 2.05, CI 1.36-3.09, p = 0.001) and BMI (OR 0.85, CI 0.73-0.99, p = 0.033) were significantly correlating with DPN. Glycemic variability, evaluated by MAGE, was the most significantly independent risk factor for DPN. CONCLUSIONS: There was a close relationship between glycemic variability evaluated by MAGE and DPN in type 2 diabetes with well-controlled HbA1c. PMID- 25530812 TI - Delays reducing waterborne and water-related infectious diseases in China under climate change. AB - Despite China's rapid progress improving water, sanitation and hygiene (WSH) access, in 2011, 471 million people lacked access to improved sanitation and 401 million to household piped water. Because certain infectious diseases are sensitive to changes in both climate and WSH conditions, we projected impacts of climate change on WSH-attributable diseases in China in 2020 and 2030 by coupling estimates of the temperature sensitivity of diarrheal diseases and three vector borne diseases, temperature projections from global climate models, WSH infrastructure development scenarios, and projected demographic changes. By 2030, climate change is projected to delay China's rapid progress toward reducing WSH attributable infectious disease burden by 8-85 months. This development delay summarizes the adverse impact of climate change on WSH-attributable infectious diseases in China, and can be used in other settings where a significant health burden may accompany future changes in climate even as the total burden of disease falls due to non-climate reasons. PMID- 25530814 TI - MICROFLUIDIC DEVICES FOR LABEL-FREE AND NON-INSTRUMENTED QUANTITATION OF UNAMPLIFIED NUCLEIC ACIDS BY FLOW DISTANCE MEASUREMENT. AB - Timely biomarker quantitation has potential to improve human health but current methods have disadvantages either in terms of cost and complexity for benchtop instruments, or reduced performance in quantitation and/or multiplexing for point of-care systems. We previously developed microfluidic devices wherein visually observed flow distances correlated with a model analyte's concentration.1 Here, we significantly expand over this prior result to demonstrate the measurement of unamplified DNA analogues of microRNAs (miRNAs), biomarkers whose levels can be altered in disease states. We have developed a method for covalently attaching nucleic acid receptors on poly(dimethylsiloxane) microchannel surfaces by silane and cross-linker treatments. We found a flow distance dependence on target concentrations from 10 MUg/mL to 10 pg/mL for DNA in both buffer and synthetic urine. Moreover, flow time in addition to flow distance is correlated with target concentration. We also observed longer flow distances for single-base mismatches compared to the target sequence at the same concentration, indicating that our approach can be used to detect point mutations. Finally, experiments with DNA analogues of miRNA biomarkers for kidney disease (mir-200c-3p) and prostate cancer (mir-107) in synthetic urine showed the ability to detect these analytes near clinically relevant levels. Our results demonstrate that these novel microfluidic assays offer a simple route to sensitive, amplification-free nucleic acid quantitation, with strong potential for point-of-care application. PMID- 25530815 TI - Innovative Use of Technology for HIV Prevention and Care: Evidence, Challenges and the Way Forward. PMID- 25530813 TI - Carbohydrate force fields. AB - Carbohydrates present a special set of challenges to the generation of force fields. First, the tertiary structures of monosaccharides are complex merely by virtue of their exceptionally high number of chiral centers. In addition, their electronic characteristics lead to molecular geometries and electrostatic landscapes that can be challenging to predict and model. The monosaccharide units can also interconnect in many ways, resulting in a large number of possible oligosaccharides and polysaccharides, both linear and branched. These larger structures contain a number of rotatable bonds, meaning they potentially sample an enormous conformational space. This article briefly reviews the history of carbohydrate force fields, examining and comparing their challenges, forms, philosophies, and development strategies. Then it presents a survey of recent uses of these force fields, noting trends, strengths, deficiencies, and possible directions for future expansion. PMID- 25530816 TI - Shrink Wrapping Cells in a Defined Extracellular Matrix to Modulate the Chemo Mechanical Microenvironment. AB - Cell-matrix interactions are important for the physical integration of cells into tissues and the function of insoluble, mechanosensitive signaling networks. Studying these interactions in vitro can be difficult because the extracellular matrix (ECM) proteins that adsorb to in vitro cell culture surfaces do not fully recapitulate the ECM-dense basement membranes to which cells such as cardiomyocytes and endothelial cells adhere to in vivo. Towards addressing this limitation, we have developed a surface-initiated assembly process to engineer ECM proteins into nanostructured, microscale sheets that can be shrink wrapped around single cells and small cell ensembles to provide a functional and instructive matrix niche. Unlike current cell encapsulation technology using alginate, fibrin or other hydrogels, our engineered ECM is similar in density and thickness to native basal lamina and can be tailored in structure and composition using the proteins fibronectin, laminin, fibrinogen, and/or collagen type IV. A range of cells including C2C12 myoblasts, bovine corneal endothelial cells and cardiomyocytes survive the shrink wrapping process with high viability. Further, we demonstrate that, compared to non-encapsulated controls, the engineered ECM modulates cytoskeletal structure, stability of cell-matrix adhesions and cell behavior in 2D and 3D microenvironments. PMID- 25530818 TI - Multiscale Particle-Based Modeling of Flowing Platelets in Blood Plasma Using Dissipative Particle Dynamics and Coarse Grained Molecular Dynamics. AB - We developed a multiscale particle-based model of platelets, to study the transport dynamics of shear stresses between the surrounding fluid and the platelet membrane. This model facilitates a more accurate prediction of the activation potential of platelets by viscous shear stresses - one of the major mechanisms leading to thrombus formation in cardiovascular diseases and in prosthetic cardiovascular devices. The interface of the model couples coarse grained molecular dynamics (CGMD) with dissipative particle dynamics (DPD). The CGMD handles individual platelets while the DPD models the macroscopic transport of blood plasma in vessels. A hybrid force field is formulated for establishing a functional interface between the platelet membrane and the surrounding fluid, in which the microstructural changes of platelets may respond to the extracellular viscous shear stresses transferred to them. The interaction between the two systems preserves dynamic properties of the flowing platelets, such as the flipping motion. Using this multiscale particle-based approach, we have further studied the effects of the platelet elastic modulus by comparing the action of the flow-induced shear stresses on rigid and deformable platelet models. The results indicate that neglecting the platelet deformability may overestimate the stress on the platelet membrane, which in turn may lead to erroneous predictions of the platelet activation under viscous shear flow conditions. This particle based fluid-structure interaction multiscale model offers for the first time a computationally feasible approach for simulating deformable platelets interacting with viscous blood flow, aimed at predicting flow induced platelet activation by using a highly resolved mapping of the stress distribution on the platelet membrane under dynamic flow conditions. PMID- 25530817 TI - Fluid Mechanical Forces and Endothelial Mitochondria: A Bioengineering Perspective. AB - Endothelial cell dysfunction is the hallmark of every cardiovascular disease/condition, including atherosclerosis and ischemia/reperfusion injury. Fluid shear stress acting on the vascular endothelium is known to regulate cell homeostasis. Altered hemodynamics is thought to play a causative role in endothelial dysfunction. The dysfunction is associated with/preceded by mitochondrial oxidative stress. Studies by our group and others have shown that the form and/or function of the mitochondrial network are affected when endothelial cells are exposed to shear stress in the absence or presence of additional physicochemical stimuli. The present review will summarize the current knowledge on the interconnections among intracellular Ca2+ - nitric oxide - mitochondrial reactive oxygen species, mitochondrial fusion/fission, autophagy/mitophagy, and cell apoptosis vs. survival. More specifically, it will list the evidence on potential regulation of the above intracellular species and processes by the fluid shear stress acting on the endothelium under either physiological flow conditions or during reperfusion (following a period of ischemia). Understanding how the local hemodynamics affects mitochondrial physiology and the cell redox state may lead to development of novel therapeutic strategies for prevention or treatment of the endothelial dysfunction and, hence, of cardiovascular disease. PMID- 25530819 TI - The relationship between sleep and behavior in autism spectrum disorder (ASD): a review. AB - Although there is evidence that significant sleep problems are common in children with autism spectrum disorder (ASD) and that poor sleep exacerbates problematic daytime behavior, such relationships have received very little attention in both research and clinical practice. Treatment guidelines to help manage challenging behaviors in ASD fail to mention sleep at all, or they present a very limited account. Moreover, limited attention is given to children with low-functioning autism, those individuals who often experience the most severe sleep disruption and behavioral problems. This paper describes the nature of sleep difficulties in ASD and highlights the complexities of sleep disruption in individuals with low functioning autism. It is proposed that profiling ASD children based on the nature of their sleep disruption might help to understand symptom and behavioral profiles (or vice versa) and therefore lead to better-targeted interventions. This paper concludes with a discussion of the limitations of current knowledge and proposes areas that are important for future research. Treating disordered sleep in ASD has great potential to improve daytime behavior and family functioning in this vulnerable population. PMID- 25530820 TI - Nucleosome positioning is unaltered at MLH1 splice site mutations in cells derived from Lynch syndrome patients. AB - BACKGROUND: Splicing is more efficient when coupled with transcription and it has been proposed that nucleosomes enriched in exons are important for splice site recognition. Lynch syndrome is a familial cancer syndrome that can be caused by the autosomal dominant inheritance of splice site mutations in the MutL homolog 1 (MLH1) gene. To better understand the role of nucleosomes in splicing, we used MLH1 splice site mutations in Lynch syndrome cases as a model to investigate if abnormal splicing was associated with altered nucleosome positioning at exon intron boundaries. FINDINGS: Nucleosome Occupancy and Methylome sequencing (NOMe seq) was used to determine the allele-specific positioning of nucleosomes around heterozygous splice site mutations in lymphoblastoid cells lines (LCLs) derived from six Lynch syndrome patients. These mutations were previously shown to cause exon skipping in five of the six patients. Allele-specific high-resolution nucleosome mapping across exons and exon-intron boundaries revealed high levels of nucleosomes across all regions examined. Alleles containing donor or acceptor splice site mutations showed no consistent alteration in nucleosome positioning or occupancy. CONCLUSION: Nucleosomes were enriched at MLH1 exons in LCLs derived from Lynch syndrome patients, and in this model system the positioning of nucleosomes was unaltered at exon-intron boundaries containing splice site mutations. Thus, these splice site mutations alone do not significantly change the local organisation of nucleosomes. PMID- 25530821 TI - Increased Wnt5a mRNA Expression in Advanced Atherosclerotic Lesions, and Oxidized LDL Treated Human Monocyte-Derived Macrophages. AB - OBJECTIVE: Wnt5a is a secreted glycoprotein highly present in atherosclerotic lesions. Uptake of oxidized-low density lipoprotein (ox-LDL) by monocytes/macrophages plays a critical role in atherosclerosis. The objective of this study was to determine if Wnt5a mRNA expression correlates with the severity of atherosclerotic lesions, and if, ox-LDL can induce Wnt5a mRNA in macrophages. METHODS: Wnt5a mRNA in tissue sections from carotid arteries of patients undergoing endarterectomy was quantified via RT-PCR and correlated with plaque severity. Human monocyte-derived macrophages and differentiated THP-1 cells, a human monocytic cell line, were treated with ox-LDL or native-LDL. Subsequently, Wnt5a transcripts were quantified by RT-PCR. RESULTS: Regions of the arteries with more severe plaques had detectable and significant levels of Wnt5a mRNA, while regions of the arteries containing less vulnerable plaques had low or non detectable Wnt5a. Ox-LDL, but not native-LDL, induced Wnt5a mRNA in both human monocyte-derived macrophages and differentiated THP-1 cells. CONCLUSION: Our results demonstrate that the expression of Wnt5a correlates with the severity of atherosclerotic lesions, and that ox-LDL induces Wnt5a mRNA expression in human macrophages. These findings are consistent with the hypothesis that Wnt5a plays a critical role in atherosclerosis progression and that a source of Wnt5a is ox-LDL stimulated macrophages. PMID- 25530823 TI - Connecting Cultures: A training model promoting evidence-based psychological services for refugees. AB - Training clinical psychology graduate students in providing effective psychological services to refugees can be extremely complex. The training approach requires a culturally sensitive framework, potential modification of empirically validated techniques, and flexibility on the part of trainees and supervisors. Connecting Cultures is a program that creates a culturally sensitive context from which trainees can learn to effectively work with refugees within a social justice framework and the ecological model of human development. Connecting Cultures graduate students provide both community-based outreach and direct clinical services to meet the mental health needs of refugees in the Northeast region of the United States. The primary aim of this manuscript is to provide an overview of Connecting Cultures' training and supervision model, highlight the importance of working with cultural consultants, interpreters, and community elders, and discuss the impact this work has on clinical psychology graduate students. A secondary aim is to describe our method for evidence-based psychological assessment and to present preliminary outcome data from our graduate students. Strengths of the Connecting Cultures program include its clinical and research efforts with refugees from over 20 countries, and its ability to flexibly incorporate alternative therapeutic frameworks such as Acceptance and Commitment Therapy. Finally, the manuscript concludes by providing the implications of our work in attempting to meet the mental health needs of refugees after resettlement. PMID- 25530822 TI - A new intuitionism: Meaning, memory, and development in Fuzzy-Trace Theory. AB - Combining meaning, memory, and development, the perennially popular topic of intuition can be approached in a new way. Fuzzy-trace theory integrates these topics by distinguishing between meaning-based gist representations, which support fuzzy (yet advanced) intuition, and superficial verbatim representations of information, which support precise analysis. Here, I review the counterintuitive findings that led to the development of the theory and its most recent extensions to the neuroscience of risky decision making. These findings include memory interference (worse verbatim memory is associated with better reasoning); nonnumerical framing (framing effects increase when numbers are deleted from decision problems); developmental decreases in gray matter and increases in brain connectivity; developmental reversals in memory, judgment, and decision making (heuristics and biases based on gist increase from childhood to adulthood, challenging conceptions of rationality); and selective attention effects that provide critical tests comparing fuzzy-trace theory, expected utility theory, and its variants (e.g., prospect theory). Surprising implications for judgment and decision making in real life are also discussed, notably, that adaptive decision making relies mainly on gist-based intuition in law, medicine, and public health. PMID- 25530824 TI - Spatial Bayesian Variable Selection Models on Functional Magnetic Resonance Imaging Time-Series Data. AB - A common objective of fMRI (functional magnetic resonance imaging) studies is to determine subject-specific areas of increased blood oxygenation level dependent (BOLD) signal contrast in response to a stimulus or task, and hence to infer regional neuronal activity. We posit and investigate a Bayesian approach that incorporates spatial and temporal dependence and allows for the task-related change in the BOLD signal to change dynamically over the scanning session. In this way, our model accounts for potential learning effects in addition to other mechanisms of temporal drift in task-related signals. We study the properties of the model through its performance on simulated and real data sets. PMID- 25530827 TI - Three-dimensional display technologies. AB - The physical world around us is three-dimensional (3D), yet traditional display devices can show only two-dimensional (2D) flat images that lack depth (i.e., the third dimension) information. This fundamental restriction greatly limits our ability to perceive and to understand the complexity of real-world objects. Nearly 50% of the capability of the human brain is devoted to processing visual information [Human Anatomy & Physiology (Pearson, 2012)]. Flat images and 2D displays do not harness the brain's power effectively. With rapid advances in the electronics, optics, laser, and photonics fields, true 3D display technologies are making their way into the marketplace. 3D movies, 3D TV, 3D mobile devices, and 3D games have increasingly demanded true 3D display with no eyeglasses (autostereoscopic). Therefore, it would be very beneficial to readers of this journal to have a systematic review of state-of-the-art 3D display technologies. PMID- 25530825 TI - Combat-Related Invasive Fungal Wound Infections. AB - Combat-related invasive fungal (mold) wound infections (IFIs) have emerged as an important and morbid complication following explosive blast injuries among military personnel. Similar to trauma-associated IFI cases among civilian populations, as in agricultural accidents and natural disasters, these infections occur in the setting of penetrating wounds contaminated by environmental debris. Specific risk factors for combat-related IFI include dismounted (patrolling on foot) blast injuries occurring mostly in southern Afghanistan, resulting in above knee amputations requiring resuscitation with large-volume blood transfusions. Diagnosis of IFI is based upon early identification of a recurrently necrotic wound following serial debridement and tissue-based histopathology examination with special stains to detect invasive disease. Fungal culture of affected tissue also provides supportive information. Aggressive surgical debridement of affected tissue is the primary therapy. Empiric antifungal therapy should be considered when there is a strong suspicion for IFI. Both liposomal amphotericin B and voriconazole should be considered initially for treatment since many of the cases involve not only Mucorales species but also Aspergillus or Fusarium spp., with narrowing of regimen based upon clinical mycology findings. PMID- 25530828 TI - ? AB - Dominant gender roles contribute to the risk of contracting HIV, for that reason the integration of social norms regarding gender into HIV prevention interventions has been urged. This study aims to adapt and develop an intervention to facilitate the transformation of social norms related to gender and sexual practices in Puerto Rican men. The intervention aims to transform social norms related to gender and sexuality in community bars using the Popular Opinion Leaders Model. After being selected, opinion leaders disseminate messages that stress the importance of equitable relationships between men and women for HIV prevention. The first phase of this intervention is discussed in this article. This phase includes a process of rapid ethnography to identify community settings in which we could develop the intervention and allow us to understand the culture of these community bars. From ethnographic observations we: developed a security protocol, developed a profile of the culture of these bars, chose the bars that participate in the two study conditions, and adapted the intervention instruments to respond to the particularities of our participants. PMID- 25530829 TI - Subjective and Objective Hierarchies and Their Relations to Psychological Well Being: A U.S/Japan Comparison. AB - Hierarchy can be conceptualized as objective social status (e.g., education level) or subjective social status (i.e., one's own judgment of one's status). Both forms predict well-being. This is the first investigation of the relative strength of these hierarchy-well-being relationships in the U.S. and Japan, cultural contexts with different normative ideas about how social status is understood and conferred. In probability samples of Japanese (N=1027) and U.S. (N=1805) adults, subjective social status more strongly predicted life satisfaction, positive affect, sense of purpose, and self acceptance in the U.S. than in Japan. In contrast, objective social status more strongly predicted life satisfaction, positive relations with others, and self acceptance in Japan than in the U.S. These differences reflect divergent cultural models of self. The emphasis on independence characteristic of the U.S. affords credence to one's own judgment (subjective status) and the interdependence characteristic of Japan to what others can observe (objective status). PMID- 25530830 TI - Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response. AB - Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathway facilitates the clearance of the undesired proteins; however, if overwhelmed, cells trigger apoptosis by upregulating transcription factors such as C/EBP homologous protein (CHOP). A high throughput screen was performed directed at identifying compounds that selectively upregulate the apoptotic CHOP pathway while avoiding adaptive signaling cascades, resulting in a sulfonamidebenzamide chemotype that was optimized. These efforts produced a potent and selective CHOP inducer (AC50 = 0.8 MUM; XBP1 > 80 MUM), which was efficacious in both mouse embryonic fibroblast cells and a human oral squamous cell cancer cell line, and demonstrated antiproliferative effects for multiple cancer cell lines in the NCI 60 panel. PMID- 25530831 TI - Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase, MitoEbselen-2, as a Radiation Mitigator. AB - Ionizing radiation (IR) triggers mitochondrial overproduction of H2O2 and accumulation of lipid hydroperoxides leading to the induction of apoptotic and necroptotic cell death pathways. Given the high catalytic efficiency of the seleno-enzyme glutathione peroxidase (Gpx) toward reduction of lipid hydroperoxides and H2O2, we tested the potential of mitochondria-targeted derivatives of ebselen to mitigate the deleterious effects of IR. We report that 2-[[2-[4-(3-oxo-1,2-benzoselenazol-2-yl)phenyl]acetyl]amino]ethyl-triphenyl phosphonium chloride (MitoPeroxidase 2) was effective in reducing lipid hydroperoxides, preventing apoptotic cell death, and, when administered 24 h postirradiation, increased the survival of mice exposed to whole body gamma irradiation. PMID- 25530832 TI - Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines. AB - Neuroendocrine (NE) lung tumors comprise 20-25% of all invasive lung malignancies. Currently, no effective treatments are available to cure these tumors, and it is necessary to identify a molecular alteration(s) that characterizes NE lung tumor cells. We aimed to identify a kinase mutation(s) associated with NE lung tumor by screening 517 kinase-encoding genes in human lung cancer cell lines. Our next-generation sequencing analysis of six NE lung tumor cell lines (four small cell lung cancer lines and two non-small cell lung cancer lines) and three non-NE lung tumor lines revealed various kinase mutations, including a nonsynonymous mutation in the proto-oncogene RET (c.2071G>A; p.G691S). Further evaluation of the RET polymorphism in total 15 lung cancer cell lines by capillary sequencing suggested that the frequency of the minor allele (A-allele) in NE lung tumor lines was significantly higher than its frequency in a reference population (p = 0.0001). However, no significant difference between non-NE lung tumor lines and a reference group was detected (p = 1.0). Nevertheless, neither RET expression levels were correlated with the levels of neuron-specific enolase (NSE), a key NE marker, nor vandetanib and cabozantinib, small molecule compounds that inhibit RET, affected NSE levels in lung cancer cells. Our data suggest a potential association of G691S RET polymorphism with NE lung tumor, proposing the necessity of more thorough evaluation of this possibility. The dataset of kinase mutation profiles in this report may help choosing cell line models for study of lung cancer. PMID- 25530834 TI - Mechanistic Studies on Covalent Assemblies of Metal-Mediated Hemi-Aminal Ethers. AB - The use of reversible covalent-bonding in a four-component assembly incorporating chiral alcohols was recently reported to give a method for determining the enantiomeric excess of the alcohols via CD spectroscopy. Experiments that probe the mechanism of this assembly, which consists of 2-formylpyridine (2-PA), dipicolylamine (DPA), Zn(II), and alcohols, to yield zinc-complexes of tren-like ligands, are presented. The studies focus upon the mechanism of conversion of a hemi-aminal (1) to a hemi-aminal ether (3), thereby incorporating the fourth component. It was found that molecular sieves along with 3 to 4 equivalents of alcohol are required to drive the conversion of 1 to 3. Attempts to isolate an intermediate in this reaction via addition of strong Lewis-acids led to the discovery of a five-membered ring pyridinium salt (5), but upon exposure to Zn(II) and alcohols gave different products than the assembly. This was interpreted to support the intermediacy of an iminium species. Kinetic studies reveal that the conversion of 1 to 3 is zero-order in alcohol in large excesses of alcohol, supporting rate-determining formation of an intermediate prior to reaction with alcohol. Further, the magnitude of the rate constant for interconversion of 1 and 3 are similar, supporting the notion that there are similar rate-determining steps (rds's) for the forward and reverse reactions. Hammett plots show that the rds involves creation of a negative charge (interpreted as the loss of positive charge), supporting the notion that decomplexation of Zn(II) from the assemblies to generate apo-forms of 1 and 3 is rate-determining. The individual mechanistic conclusions are combined to create a qualitative reaction coordinate diagram for the interconversion of 1 and 3. PMID- 25530833 TI - Prenyltransferase Inhibitors: Treating Human Ailments from Cancer to Parasitic Infections. AB - The posttranslational modification of protein prenylation is a covalent lipid modification on the C-terminus of substrate proteins that serves to enhance membrane affinity. Oncogenic proteins such as Ras have this modification and significant effort has been placed into developing inhibitors of the prenyltransferase enzymes for clinical therapy. In addition to cancer therapy, prenyltransferase inhibitors have begun to find important therapeutic uses in other diseases, including progeria, hepatitis C and D, parasitic infections, and other maladies. This review will trace the evolution of prenyltransferase inhibitors from their initial use as cancer therapeutics to their expanded applications for other diseases. PMID- 25530836 TI - Opportunities to Strengthen Childhood Obesity Prevention in Two Mexican Health Care Settings. AB - BACKGROUND: The purpose of this study was to examine Mexican caregivers' perceptions of the role of primary care in childhood obesity management, understand the barriers and facilitators of behavior change, and identify opportunities to strengthen obesity prevention and treatment in clinical settings. METHODS: We conducted 52 in-depth interviews with parents and caregivers of overweight and obese children age 2-5 years in 4 Ministry of Health (public, low SES) and 4 Social Security Institute (insured, higher SES) primary care clinics in Mexico City and did systematic thematic analysis. RESULTS: In both health systems, caregivers acknowledged childhood overweight but not its adverse health consequences. Although the majority of parents had not received nutrition or physical activity recommendations from health providers, many were open to clinician guidance. Despite knowledge of healthful nutrition and physical activity, parents identified several barriers to change including child feeding occurring in the context of competing priorities (work schedules, spouses' food preferences), and cultural norms (heavy as healthy, food as nurturance) that take precedence over adherence to dietary guidelines. Physical activity, while viewed favorably, is not a structured part of most preschooler's routines as reported by parents. CONCLUSIONS: The likelihood of success for clinic-based obesity prevention among Mexican preschoolers will be higher by addressing contextual barriers such as cultural norms regarding children's weight and support of family members for behavior change. Similarities in caregivers' perceptions across 2 health systems highlight the possibility of developing comprehensive interventions for the population as a whole. PMID- 25530835 TI - Structural study of a small molecule receptor bound to dimethyllysine in lysozyme. AB - Lysine is a ubiquitous residue on protein surfaces. Post translational modifications of lysine, including methylation to the mono-, di- or trimethylated amine result in chemical and structural alterations that have major consequences for protein interactions and signalling pathways. Small molecules that bind to methylated lysines are potential tools to modify such pathways. To make progress in this direction, detailed structural data of ligands in complex with methylated lysine is required. Here, we report a crystal structure of p sulfonatocalix[4]arene (sclx4) bound to methylated lysozyme in which the lysine residues were chemically modified from Lys-NH3+ to Lys-NH(Me2)+. Of the six possible dimethyllysine sites, sclx4 selected Lys116-Me2 and the dimethylamino substituent was deeply buried in the calixarene cavity. This complex confirms the tendency for Lys-Me2 residues to form cation-pi interactions, which have been shown to be important in protein recognition of histone tails bearing methylated lysines. Supporting data from NMR spectroscopy and MD simulations confirm the selectivity for Lys116-Me2 in solution. The structure presented here may serve as a stepping stone to the development of new biochemical reagents that target methylated lysines. PMID- 25530837 TI - Palladium Catalyzed Aryl C-H Amination with O2 via In Situ Formation of Peroxide Based Oxidant(s) from Dioxane. AB - (DAF)Pd(OAc)2 (DAF = 4,5-diazafluorenone) catalyzes aerobic intramolecular aryl C H amination with N-benzenesulfonyl-2-aminobiphenyl in dioxane to afford the corresponding carbazole product. Mechanistic studies show that the reaction involves in situ generation of peroxide species from 1,4-dioxane and O2, and the reaction further benefits from the presence of glycolic acid, an oxidative decomposition product of dioxane. An induction period observed for the formation of the carbazole product correlates with the formation of 1,4-dioxan-2 hydroperoxide via autoxidation of 1,4-dioxane, and the in situ-generated peroxide is proposed to serve as the reactive oxidant in the reaction. These findings have important implications for the palladium-catalyzed aerobic oxidation reactions conducted in ethereal solvents. PMID- 25530839 TI - The miR-206/133b cluster is dispensable for development, survival and regeneration of skeletal muscle. AB - BACKGROUND: Three different gene clusters code for the muscle-specific miRNAs miR 206, miR-1 and miR-133a/b. The two miR-1/133a clusters generate identical mature miR-1 and miR-133a miRNAs in heart and skeletal muscle, while the cognate miR 206/133b cluster is exclusively expressed in skeletal muscle. Since sequences of the miRNAs miR-133a and miR-133b are almost identical, it seems likely that they share potential targets. Similarly, miR-1 and miR-206 are structurally related and contain identical seed sequences important for miRNA-target recognition. In the past, different functions of these miRNAs were suggested for development, function and regeneration of skeletal muscle using different in vivo and in vitro models; however, mutants lacking the complete miR-206/133b cluster, which generates a single pri-miRNA constituting a functional unit, have not been analyzed. METHODS: We generated miR-206/133b knock-out mice and analyzed these mice morphologically; at the transcriptome and proteome level to elucidate the contribution of this miRNA cluster for skeletal muscle development, differentiation, regeneration in vivo; and by systematic analysis. In addition, we studied the consequences of a genetic loss of miR-206/133b for expression of Pax7 and satellite cell differentiation in vitro. RESULTS: Deletion of the miR 206/133b cluster did not reveal any obvious essential function of the miRNA cluster for development and differentiation of skeletal muscle. Careful examination of skeletal muscles of miR-206/133b mutants revealed no structural alterations or molecular changes at the transcriptome and proteome level. In contrast to previous studies, deletion of the miR-206/133b cluster did not impair regeneration of skeletal muscle in mdx mice. Likewise, differentiation of miR 206/133b deficient satellite cells in vitro was unaffected and no change in Pax7 protein concentration was apparent. CONCLUSIONS: We conclude that the miR 206/133b cluster is dispensable for development, function and regeneration of skeletal muscle, probably due to overlapping functions of the related miR-1/133a clusters, which are strongly expressed in skeletal muscle. We reason that the miR 206/133b cluster alone is not an essential regulator of skeletal muscle regeneration, although more subtle functions might exist that are not apparent under laboratory conditions. PMID- 25530838 TI - Deficient nitric oxide signalling impairs skeletal muscle growth and performance: involvement of mitochondrial dysregulation. AB - BACKGROUND: Nitric oxide (NO), generated in skeletal muscle mostly by the neuronal NO synthases (nNOSMU), has profound effects on both mitochondrial bioenergetics and muscle development and function. The importance of NO for muscle repair emerges from the observation that nNOS signalling is defective in many genetically diverse skeletal muscle diseases in which muscle repair is dysregulated. How the effects of NO/nNOSMU on mitochondria impact on muscle function, however, has not been investigated yet. METHODS: In this study we have examined the relationship between the NO system, mitochondrial structure/activity and skeletal muscle phenotype/growth/functions using a mouse model in which nNOSMU is absent. Also, NO-induced effects and the NO pathway were dissected in myogenic precursor cells. RESULTS: We show that nNOSMU deficiency in mouse skeletal muscle leads to altered mitochondrial bioenergetics and network remodelling, and increased mitochondrial unfolded protein response (UPR(mt)) and autophagy. The absence of nNOSMU is also accompanied by an altered mitochondrial homeostasis in myogenic precursor cells with a decrease in the number of myonuclei per fibre and impaired muscle development at early stages of perinatal growth. No alterations were observed, however, in the overall resting muscle structure, apart from a reduced specific muscle mass and cross sectional areas of the myofibres. Investigating the molecular mechanisms we found that nNOSMU deficiency was associated with an inhibition of the Akt-mammalian target of rapamycin pathway. Concomitantly, the Akt-FoxO3-mitochondrial E3 ubiquitin protein ligase 1 (Mul-1) axis was also dysregulated. In particular, inhibition of nNOS/NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent-protein kinases induced the transcriptional activity of FoxO3 and increased Mul-1 expression. nNOSMU deficiency was also accompanied by functional changes in muscle with reduced muscle force, decreased resistance to fatigue and increased degeneration/damage post-exercise. CONCLUSIONS: Our results indicate that nNOSMU/NO is required to regulate key homeostatic mechanisms in skeletal muscle, namely mitochondrial bioenergetics and network remodelling, UPR(mt) and autophagy. These events are likely associated with nNOSMU-dependent impairments of muscle fibre growth resulting in a deficit of muscle performance. PMID- 25530840 TI - Chemical chaperone 4-phenylbutyrate prevents endoplasmic reticulum stress induced by T17M rhodopsin. AB - BACKGROUND: Rhodopsin mutations are associated with the autosomal dominant form of retinitis pigmentosa. T17M mutation in rhodopsin predisposes cells to endoplasmic reticulum (ER) stress and induces cell death. This study aimed to examine whether chemical chaperone 4-phenylbutyrate prevents ER stress induced by rhodopsin T17M. RESULTS: ARPE-19 cells were transfected with myc-tagged wild-type (WT) and T17M rhodopsin constructs. Turnover of WT and T17M rhodopsin was measured by cycloheximide chase analysis. The activity of ubiquitin-proteasome system was evaluated by GFPU reporter. We found that T17M rhodopsin was misfolded, ubiqutinated and eliminated by ER-associated degradation pathway (ERAD) in ARPE-19 cells. Accumulated T17M rhodopsin induced unfolded protein response, but had no effect on the activity of ubiquitin proteasome system. Moreover, chemical chaperone 4-phenylbutyrate facilitated the turnover of T17M rhodopsin and prevented apoptosis and ER stress induced by T17M rhodopsin. CONCLUSIONS: Chemical chaperone could attenuate UPR signaling and ER stress induced by T17M rhodopsin and has potential therapeutic significance for retinitis pigmentosa. PMID- 25530841 TI - Epithelium-Specific ETS (ESE)-1 upregulated GP73 expression in hepatocellular carcinoma cells. AB - BACKGROUND: Golgi protein-73 (GP73) is a Golgi transmembrane glycoprotein elevated in numerous liver diseases. Clinically, GP73 is strongly elevated in the serum of HCC patients and is thus regarded as a novel potential biomarker for HCC. However, the mechanism leading to GP73 dysregulation in liver diseases remains unknown. RESULTS: This study determined that epithelium-specific ETS (ESE)-1, an epithelium-specific transcription factor, and GP73 expressions were induced by IL-1beta stimulation in vitro, and both were triggered during liver inflammation in vivo. In hepatocellular carcinoma cells, the overexpression of ESE-1 induced GP73 expression, whereas its knock-down did the opposite. Mechanistically, ESE-1 activated GP73 expression by directly binding to its promoter. CONCLUSIONS: Our findings supported a novel paradigm for ESE-1 as a transcriptional mediator of GP73. This study provided a possible mechanism for GP73 upregulation in liver diseases. PMID- 25520778 TI - Cytoscape tools for the web age: D3.js and Cytoscape.js exporters. AB - In this paper we present new data export modules for Cytoscape 3 that can generate network files for Cytoscape.js and D3.js. Cytoscape.js exporter is implemented as a core feature of Cytoscape 3, and D3.js exporter is available as a Cytoscape 3 app. These modules enable users to seamlessly export network and table data sets generated in Cytoscape to popular JavaScript library readable formats. In addition, we implemented template web applications for browser-based interactive network visualization that can be used as basis for complex data visualization applications for bioinformatics research. Example web applications created with these tools demonstrate how Cytoscape works in modern data visualization workflows built with traditional desktop tools and emerging web based technologies. This interactivity enables researchers more flexibility than with static images, thereby greatly improving the quality of insights researchers can gain from them. PMID- 25530842 TI - Aberrant amygdala functional connectivity at rest in pediatric anxiety disorders. AB - BACKGROUND: Childhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP). RESULTS: Compared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age. CONCLUSIONS: Our findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood. PMID- 25520776 TI - Learning intrinsic excitability in medium spiny neurons. AB - We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parameterization of individual ion channels on the neuronal membrane potential-curent relationship (activation function). We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal modulation on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how modulation and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic modulation determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction. PMID- 25530845 TI - Improving the design of the agarose spot assay for eukaryotic cell chemotaxis. AB - Migration of cells along gradients of effector molecules, i.e., chemotaxis, is necessary in immune response and is involved in development and cancer metastasis. The experimental assessment of chemotaxis thus is of high interest. The agarose spot assay is a simple tissue culture system used to analyze chemotaxis. Although direction sensing requires gradients to be sufficiently steep, how the chemical gradients developed in this assay change over time, and thus, under what conditions chemotaxis is plausible, has not yet been determined. Here, we use numerical solution of the diffusion equation to determine the chemoattractant gradient produced in the assay. Our analysis shows that, for the usual spot size, the lifetime of the assay is optimized if the chemoattractant concentration in the spot is initially 30 times the dissociation constant of the chemoattractant-receptor bond. This result holds regardless of the properties of the chemoattractant. With this initial concentration, the chemoattractant gradient falls to the minimum threshold for directional sensing at the same time that the concentration drops to the optimal level for detecting gradient direction. If a higher initial chemoattractant concentration is used, the useful lifetime of the assay is likely to be shortened because receptor saturation may decrease the cells' sensitivity to the gradient; lower initial concentrations would result in too little chemoattractant for the cells to detect. Moreover, chemoattractants with higher diffusion coefficients would sustain gradients for less time. Based on previous measurements of the diffusion coefficients of the chemoattractants EGF and CXCL12, we estimate that the assay will produce gradients that cells can sense for a duration of 10 h for EGF and 5 h for CXCL12. These gradient durations are comparable to what can be achieved with the Boyden chamber assay. The analysis presented in this work facilitates determination of suitable parameters for the assay, and can be used to assess whether observed cell motility is likely due to chemotaxis or chemokinesis. PMID- 25530846 TI - Central C-C Bonding Increases Optical and Chemical Stability of NIR Fluorophores. AB - Functional near-infrared (NIR) fluorophores have played a major role in the recent advances in bioimaging. However, the optical and physicochemical stabilities of NIR fluorophores in the biological and physiological environment are still a challenge. Especially, the ether linkage on the meso carbon of heptamethine core is fragile when exposed to serum proteins or other amine-rich biomolecules. To solve such a structural limitation, a rigid carbon-carbon bond was installed onto the framework of ether-linked NIR fluorophores through the Suzuki coupling. The robust fluorophores replaced as ZW800-1C and ZW800-3C displayed enhanced optical and chemical stability in various solvents and a 100% warm serum environment (> 99%, 24 h). The biodistribution and clearance of C-C coupled ZW800 compounds were almost identical to the previously developed oxygen substituted ZW800 compounds. When conjugated with a small molecule ligand, ZW800 1C maintained the identical stable form in warm serum (>98%, 24 h), while ZW800 1A hydrolyzed quickly after 4 h incubation (34%, 24 h). PMID- 25530847 TI - The strength of coughing may forecast the likelihood of spread of multi-drug resistant microorganisms from the respiratory tract of colonized patients. AB - BACKGROUND: Current recommendations indicate that patients who are coughing and have multidrug resistant microorganisms (MDROs) in their sputum are considered to be shedders and should be cared for in single room isolation at least until symptoms resolve. Airborne spread and subsequent contamination of surfaces adjacent to patients may contribute to transmission. Hence, isolation measures for patients colonized or infected with MDRO at their respiratory tract are intended to interrupt such transmission. However, the potential for microbial shedding in patients with MDRO-positive microbiological reports from their respiratory tract and factors justifying the need for single room isolation are viewed controversially. METHODS: Cough aerosol produced by patients colonized with MDROs was measured for viable counts. Descriptive analysis together with logistic regression analysis was performed to assess the impact of strength of cough on growth of MDRO on culture plates. RESULTS: In 18% (23/128) MDRO were transmitted. Multivariate analysis revealed that strength of cough significantly predicts the yield of MDRO on culture plates (P = 0.012). CONCLUSION: Based on these results it can be concluded that risk stratification for decision of single room isolation of patients colonized or infected with MDROs at their respiratory tract may also take the severity of cough into consideration. However, more work is required in order to assess the severity of cough objectively. PMID- 25530848 TI - The Instructive Role of the Vasculature in Stem Cell Niches. AB - An important hallmark of many adult stem cell niches is their proximity to the vasculature in vivo, a feature common to neural stem cells (NSCs), mesenchymal stem cells (MSCs) from bone marrow, adipose, and other tissues, hematopoietic stem cells (HSCs), and many tumor stem cells. This review summarizes key studies supporting the vasculature's instructive role in adult stem cell niches, and the putative underlying molecular mechanisms by which blood vessels in these niches exert control over progenitor cell fates. The importance of the perivascular niche for pathology, notably tumor metastasis and dormancy, is also highlighted. Finally, the implications of the perivascular regulation of stem and progenitor cells on biomaterial design and the impact on future research directions are discussed. PMID- 25530849 TI - Synergistic regulation of cerebellar Purkinje neuron development by laminin epitopes and collagen on an artificial hybrid matrix construct. AB - The extracellular matrix (ECM) creates a dynamic environment around the cells in the developing central nervous system, providing them with the necessary biochemical and biophysical signals. Although the functions of many ECM molecules in neuronal development have been individually studied in detail, the combinatorial effects of multiple ECM components are not well characterized. Here we demonstrate that the expression of collagen and laminin-1 (lam-1) are spatially and temporally correlated during embryonic and post-natal development of the cerebellum. These changes in ECM distribution correspond to specific stages of Purkinje neuron (PC) migration, somatic monolayer formation and polarization. To clarify the respective roles of these ECM molecules on PC development, we cultured cerebellar neurons on a hybrid matrix comprised of collagen and a synthetic peptide amphiphile nanofiber bearing a potent lam-1 derived bioactive IKVAV peptide epitope. By systematically varying the concentration and ratio of collagen and the laminin epitope in the matrix, we could demonstrate a synergistic relationship between these two ECM components in controlling multiple aspects of PC maturation. An optimal ratio of collagen and IKVAV in the matrix was found to promote maximal PC survival and dendrite growth, while dendrite penetration into the matrix was enhanced by a high IKVAV to collagen ratio. In addition, the laminin epitope was found to guide PC axon development. By combining our observations in vivo and in vitro, we propose a model of PC development where the synergistic effects of collagen and lam-1 play a key role in migration, polarization and morphological maturation of PCs. PMID- 25530850 TI - Cell-derived matrices for tissue engineering and regenerative medicine applications. AB - The development and application of decellularized extracellular matrices (ECM) has grown rapidly in the fields of cell biology, tissue engineering and regenerative medicine in recent years. Similar to decellularized tissues and whole organs, cell-derived matrices (CDMs) represent bioactive, biocompatible materials consisting of a complex assembly of fibrillar proteins, matrix macromolecules and associated growth factors that often recapitulate, at least to some extent, the composition and organization of native ECM microenvironments. The unique ability to engineer CDMs de novo based on cell source and culture methods makes them an attractive alternative to conventional allogeneic and xenogeneic tissue-derived matrices that are currently harvested from cadaveric sources, suffer from inherent heterogeneity, and have limited ability for customization. Although CDMs have been investigated for a number of biomedical applications, including adhesive cell culture substrates, synthetic scaffold coatings, and tissue engineered products, such as heart valves and vascular grafts, the state of the field is still at a relatively nascent stage of development. In this review, we provide an overview of the various applications of CDM and discuss successes to date, current limitations and future directions. PMID- 25530851 TI - Silk Nanofiber Hydrogels with Tunable Modulus to Regulate Nerve Stem Cell Fate. AB - Reconstruction of damaged nerves remains a significant unmet challenge in clinical medicine. To foster improvements, the control of neural stem cell (NSC) behaviors, including migration, proliferation and differentiation are critical factors to consider. Topographical and mechanical stimulation based on the control of biomaterial features is a promising approach, which are usually studied separately. The synergy between topography and mechanical rigidity could offer new insights into the control of neural cell fate if they could be utilized concurrently in studies. To achieve this need, silk fibroin self-assembled nanofibers with a beta-sheet-enriched structure are formed into hydrogels. Stiffness is tuned using different annealing processes to enable mechanical control without impacting the nanofiber topography. Compared with nonannealed nanofibers, NSCs on methanol annealed nanofibers with stiffness similar to nerve tissues differentiate into neurons with the restraint of glial differentiation, without the influence of specific differentiation biochemical factors. These results demonstrate that combining topographic and mechanical cues provides the control of nerve cell behaviors, with potential for neurogenerative repair strategies. PMID- 25530852 TI - A Benzothiazole-Based Sensor for Pyrophosphate (PPi) and ATP: Mechanistic Insight for Anion-Induced ESIPT Turn-On. AB - A benzothiazole derivative 2 bearing two 2,2'-dipicolylamine (DPA) groups was examined for its zinc-binding and subsequent anion sensing properties. The study revealed the anion sensing mechanism of polyphosphate anions via sequential binding to two zinc centers, on the basis of both 1H NMR and mass spectral evidences. The mechanistic insight would provide valuable information for the future design of new excited state intramolecular proton transfer (ESIPT) sensors. In addition, the zinc complex exhibited the solvent-switchible selectivity, responding to pyrophosphate (PPi) in EtOH but adenosine 5' triphosphate (ATP) in water. PMID- 25530853 TI - Shape Transformation Following Reduction-Sensitive PEG Cleavage of Polymer/DNA Nanoparticles. AB - PEGylated polycation/DNA micellar nanoparticles have been developed that can undergo shape transformation upon cleavage of the PEG grafts in response to an environmental cue. As a proof-of-principle, DNA nanoparticles with higher PEG grafting density adopting long, worm- and rod-like morphologies, transition to more condensed nanoparticles with spherical and short-rod morphologies upon cleavage of a fraction of the PEG grafts from the copolymer. This shape transformation leads to increased surface charges, correlating with improved transfection efficiency. PMID- 25530854 TI - Improved cell infiltration of highly porous nanofibrous scaffolds formed by combined fiber-fiber charge repulsions and ultra-sonication. AB - A significant problem affecting electrospun nanofibrous tissue scaffolds is poor infiltration of cells into their three-dimensional (3D) structure. Environmental and physical manipulation, however, can enhance cellular infiltration into electrospun scaffolds. In this work, RGD-modified alginate mats with increased thickness and porosity were achieved by pairing high humidity electrospinning with post-processing ultra-sonication. RGD-modified alginate, polyethylene oxide (PEO), and an FDA-approved, nonionic surfactant blends were electrospun in 20 and 50% relative humidity conditions. Mats electrospun in high humidity conditions resulted in significantly increased mat thickness and decreased fiber diameters. The mats' alginate content was then isolated via ionic crosslinking and PEO/surfactant extraction. Finally, the alginate-only mat was post-processed by ultra-sonication to further enhance its cross-sectional thickness. Cell morphology, proliferation, and infiltration into the scaffolds were evaluated by seeding fibroblasts onto the alginate mat. Cell spreading, growth and infiltration improved with increased humidity and ultra-sonication. This approach shows great promise for the design of cell-permeable nanofibrous scaffolds for tissue-engineering applications. PMID- 25530855 TI - Lacritin-mediated regeneration of the corneal epithelia by protein polymer nanoparticles. AB - The avascular corneal epithelium plays an important role in maintaining normal vision and protecting the corneal interior from environmental infections. Delayed recovery of ocular wounds caused by trauma or refractive surgery strengthens the need to accelerate corneal wound healing and better restore the ocular surface. To address this need, we fused elastin-like polypeptide (ELP) based nanoparticles SI with a model mitogenic protein called lacritin. Lacritin fused at the N terminus of the SI diblock copolymer is called LSI. This LSI fusion protein undergoes thermo-responsive assembly of nanoparticles at physiologically relevant temperatures. In comparison to ELP nanoparticles without lacritin, LSI showed potent signs of lacritin specific effects on a human corneal epithelial cell line (HCE-T), which included enhancement of cellular uptake, calcium-mediated signaling, and closure of a scratch. In vivo, the corneas of non-obese diabetic mice (NOD) were found to be highly responsive to LSI. Fluorescein imaging and corneal histology suggested that topical administration of LSI onto the ocular surface significantly promoted corneal wound healing and epithelial integrity compared to mice treated with or without plain ELP. Most interestingly, it appears that ELP-mediated assembly of LSI is essential to produce this potent activity. This was confirmed by comparison to a control lacritin ELP fusion called LS96, which does not undergo thermally-mediated assembly at relevant temperatures. In summary, fusion of a mitogenic protein to ELP nanoparticles appears to be a promising new strategy to bioengineer more potent biopharmaceuticals with potential applications in corneal wound healing. PMID- 25530856 TI - Enhanced Performance of Plasmid DNA Polyplexes Stabilized by a Combination of Core Hydrophobicity and Surface PEGylation. AB - Nonviral gene therapy has high potential for safely promoting tissue restoration and for treating various genetic diseases. One current limitation is that conventional transfection reagents such as polyethylenimine (PEI) form electrostatically stabilized plasmid DNA (pDNA) polyplexes with poor colloidal stability. In this study, a library of poly(ethylene glycol-b-(dimethylaminoethyl methacrylate-co-butyl methacrylate)) [poly(EG-b-(DMAEMA-co-BMA))] polymers were synthesized and screened for improved colloidal stability and nucleic acid transfection following lyophilization. When added to pDNA in the appropriate pH buffer, the DMAEMA moieties initiate formation of electrostatic polyplexes that are internally stabilized by hydrophobic interactions of the core BMA blocks and sterically stabilized against aggregation by a PEG corona. The BMA content was varied from 0% to 60% in the second polymer block in order to optimally tune the balance of electrostatic and hydrophobic interactions in the polyplex core, and polymers with 40 and 50 mol% BMA achieved the highest transfection efficiency. Diblock copolymers were more stable than PEI in physiologic buffers. Consequently, diblock copolymer polyplexes aggregated more slowly and followed a reaction-limited colloidal aggregation model, while fast aggregation of PEI polyplexes was governed by a diffusion-limited model. Polymers with 40% BMA did not aggregate significantly after lyophilization and produced up to 20-fold higher transfection efficiency than PEI polyplexes both before and after lyophilization. Furthermore, poly(EG-b-(DMAEMA-co-BMA)) polyplexes exhibited pH dependent membrane disruption in a red blood cell hemolysis assay and endosomal escape as observed by confocal microscopy.Lyophilized polyplexes made with the lead candidate diblock copolymer (40% BMA) also successfully transfected cells in vitro following incorporation into gas-foamed polymeric scaffolds. In summary, the enhanced colloidal stability, endosomal escape, and resultant high transfection efficiency of poly(EG-b-(DMAEMA-co-BMA))-pDNA polyplexes underscores their potential utility both for local delivery from scaffolds as well as systemic, intravenous delivery. PMID- 25530857 TI - Tuning nano-architectures and improving bioactivity of conducting polypyrrole coating on bone implants by incorporating bone-borne small molecules. AB - Citric acid, a molecule present in fresh bone, was introduced into template-free electrochemical polymerization to form biocompatible coating made of polypyrrole (PPy) nano-cones on bone implants. It served not only as a dopant to tune the nano-architectures but also as a promoter to enhance bioactivity of the PPy coated implants. PMID- 25530858 TI - Laryngeal aspergilloma: a complication of inhaled fluticasone therapy for asthma. AB - Primary laryngeal aspergillosis in immunocompetent patients is rare. We describe a case of a 59-year-old woman with laryngeal aspergillosis thought to be secondary to long-term inhaled fluticasone therapy. Laryngeal aspergillosis may be an underrecognized complication of inhaled corticosteroid therapy. PMID- 25530859 TI - Fatal pneumomediastinum associated with use of noninvasive mechanical ventilation. AB - We present a case of fatal pneumomediastinum in a patient with acute respiratory failure caused by acute exacerbated chronic obstructive pulmonary disease (AECOPD) and interstitial lung disease (ILD) precipitated by noninvasive mechanical ventilation (NIMV). To our knowledge, this is the first case reported in the literature. NIMV is very useful to treat acute respiratory failure due to AECOPD improving survival and avoiding endotracheal intubation. Use of NIMV in end stage ILD is not standardized and efficacy is to be proven. No data are reported to manage patient with concomitant COPD and ILD. Pathophysiological mechanisms underlying this fatal complication are explained and suggestions to treat this subgroup of patients discussed. PMID- 25530861 TI - Uterine myoma as a cause of iliac vein thrombosis and pulmonary embolism: common disease, rare complication. AB - Uterine myoma is a common condition among women, which may very rarely be associated with deep venous thrombosis (VT). Few reports of myoma with associated VT have been reported in the English language and, of those, only three were associated with embolic events. This manuscript reports the case of a 29-year-old patient who presented with pulmonary embolism due to iliac VT secondary to extrinsic compression by a uterine myoma. Considering the high prevalence of myoma in the population, it is advisable to specifically consider this hypothesis in the case of female patients with pulmonary embolism or limb VT and menstrual abnormalities. This will help to avoid extensive thrombophilia investigation and to accurately determine the correct cause of VT. PMID- 25530860 TI - Discordance between clinical, physiological, and radiological measures in cystic fibrosis. AB - There are several methods available to the clinician to assess severity of lung disease in cystic fibrosis (CF). Here we present a case where several of these modalities appeared to be discordant. As in this case, many assessments of respiratory status may be necessary to fully evaluate patients with CF. Spirometry may be insensitive to significant changes that are apparent both clinically and radiologically, but remains an important marker of short-term change, response to intervention, and prognosis. Chest computed tomography can provide valuable detailed information on the health of the lungs and is more sensitive than spirometry to the changes seen in CF. Longitudinal studies of subjects with disproportionately severe radiological changes may be important to assess whether they are more at risk of precipitous declines in pulmonary function. PMID- 25530862 TI - Severe airflow obstruction in vertically acquired HIV infection. AB - It is becoming increasingly clear that human immunodeficiency virus (HIV) infection, either independently or in concert with opportunistic infections like pulmonary tuberculosis, is a risk factor for the development of chronic airflow limitation. In the majority of patients the etiology of this obstructive ventilatory defect is multifactorial. Post-infectious obliterative bronchiolitis, post-tuberculous lung damage (including bronchiectasis), immune reconstitution and the direct effects of HIV viral infection may all play a role. With increases in life expectancy and decreases in infectious complications in patients taking antiretroviral medications, the importance of HIV-associated chronic lung disease as a cause of pulmonary disability is likely to increase. This is particularly relevant in regions like sub-Saharan Africa, where both HIV infection and tuberculosis are highly prevalent. Here, to illustrate the complexity of this interaction, we present the case of a 15-year-old girl with vertically acquired HIV infection, multiple episodes of pulmonary infection, and severe airflow obstruction. PMID- 25530863 TI - Henoch-Schonlein purpura in mesothelioma. AB - Henoch-Schonlein purpura (HSP) is primarily a childhood immunoglobulin A (IgA) mediated illness. When adults are affected, malignancy can be associated. We present a rare case of HSP in a 75-year-old man with malignant pleural mesothelioma. He presented with episodes of dizziness and subsequently developed non-palpable purpura across his legs, arthralgia, hematuria, proteinuria, and acute renal impairment. HSP was diagnosed based on clinical and histological findings on biopsy specimens from the skin and kidney that showed a leukocytoclastic vasculitis and mesangioproliferative glomerulonephritis with IgA deposits, respectively. He was treated with high-dose oral steroids with resolution of the skin and renal manifestations of the disease. HSP is rare in adults but has been linked to cancers. This is the first report of HSP in a patient with known malignant pleural mesothelioma. PMID- 25530864 TI - Lung function testing in COPD: when everything is not so simple. AB - Combined pulmonary fibrosis and emphysema is a condition occurring mainly in male smokers, presenting different lung mechanics and gas exchange abnormalities than emphysema or pulmonary fibrosis alone. We report the case of an elderly man, former heavy smoker, who presented with progressive exertional dyspnea for 1 year. Lung function tests showed near normal spirometry and lung volumes but marked reduction of diffusing capacity for carbon monoxide and even more nitric oxide. The arterial partial pressure of oxygen was reduced with a markedly increased alveolar-to-arterial difference. High-resolution computed tomography of the chest showed a pattern consistent with upper lobe emphysema and lower lobe pulmonary fibrosis. In conclusion, this case report confirms the limitations of a simplistic approach to lung function in the diagnosis of symptomatic smokers. PMID- 25530865 TI - Unintentional intramuscular administration of tPA/DNase for pleural infection. AB - Intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) therapy has recently been shown to improve outcomes in pleural infection in a randomized trial. Published literature, to date, consists of only ~50 patients who had received tPA/DNase. Safety data of this regimen remain limited. Pleural contents often track along chest drains, but the effect of tPA/DNase on subcutaneous tissues is unknown. We report a patient treated in another center who was unintentionally administered up to six instillations of tPA (10 mg) and DNase (5 mg) intramuscularly via a malpositioned chest drain. The patient experienced minimal discomfort, and there were no signs of tissue inflammation or necrosis on computed tomography. No complications were detected over a 2-month follow-up. Upon transfer, a new pleural drain was inserted and tPA/DNase administered with clearance of his loculated complicated parapneumonic effusion. This case adds to the safety profile of intrapleural tPA/DNase therapy and highlights the importance of correct tube placement. PMID- 25530866 TI - Primary inflammatory myofibroblastic tumor of the trachea. AB - Inflammatory myofibroblastic tumors (IMTs) are rare neoplasms that can involve the airway. Recent studies have shown their malignant behavior with local recurrence and potential metastatic spread; half of the cases are associated with anaplastic lymphoma kinase gene rearrangement. Complete surgical resection is recommended, when feasible. We present a case of a 26-year-old woman admitted to our institution with severe respiratory failure; she was affected with primary IMT of the trachea and underwent complete surgical resection. PMID- 25530867 TI - Swyer-James syndrome associated with asthma and a giant bulla. AB - Swyer-James syndrome was first described in 1953 as unilateral pulmonary emphysema in a 6-year-old boy. The characteristic feature of this syndrome is unilateral pulmonary hyperlucency on a chest X-ray film. Typical symptoms include recurrent chest infections, chronic cough, wheezing, and exertional dyspnea. Although there have been a few reports of pneumothorax in patients with Swyer James syndrome, there have been no reports about an association with giant bullae. Here, we report a case of Swyer-James syndrome associated with a giant bulla and asthma, in which surgery achieved marked improvement of dyspnea. PMID- 25530868 TI - Severe tracheal stenosis with tracheopathia osteoplastica-like changes due to traumatic blunt injury. AB - A 17-year-old man was injured in a motorcycle accident, leading to a complex cerebral contusion and hepatic injury. Approximately one month after being discharged from the hospital, the patient experienced gradually progressive dyspnea on exertion. Chest computed tomography revealed severe upper tracheal stenosis; thus, emergency tracheotomy and subsequent tracheoplasty were performed. Microscopically, the deformation of tracheal cartilage and extensive interstitial ossification/fibro-elastic changes were observed. To our knowledge, this is the first report documenting the ossification of the trachea that rapidly progressed after injury, which was confirmed by surgical resection of the upper trachea. PMID- 25530870 TI - Diesel biodegradation capacities of indigenous bacterial species isolated from diesel contaminated soil. AB - Petroleum based products are the major source of energy for industries and daily life. Leaks and accidental spills occur regularly during the exploration, production, refining, transport, and storage of petroleum and petroleum products. In the present study we isolated the bacteria from diesel contaminated soil and screened them for diesel biodegradation capacity. One monoculture isolate identified by 16S rRNA gene sequence analysis to be Acinetobacter baumannii was further studied for diesel oil biodegradation. The effects of various culture parameters (pH, temperature, NaCl concentrations, initial hydrocarbon concentration, initial inoculum size, role of chemical surfactant, and role of carbon and nitrogen sources) on biodegradation of diesel oil were evaluated. Optimal diesel oil biodegradation by A. baumanii occurred at initial pH 7, 35 degrees C and initial hydrocarbon concentration at 4%. The biodegradation products under optimal cultural conditions were analyzed by GC-MS. The present study suggests that A. baumannii can be used for effective degradation of diesel oil from industrial effluents contaminated with diesel oil. PMID- 25530871 TI - A review of decisional balance research and directions for brief alcohol intervention among college students. AB - This paper provides a review of decisional balance (DB) and proposes strategies for improving DB measurement with respect to alcohol interventions for college students. Although existing alcohol interventions for college drinking are widely available, many undergraduates do not perceive any need to change their drinking. Intervention strategies that encourage students to consciously consider reasons for changing problem behaviors and resolve ambivalence may provide unique benefit. The DB and alcohol literature suggest; 1) a relationship exists between DB and motivation to change (MTC); 2) the decisional balance proportion (DBP) represents a promising new way to conceptualize MTC; and 3) while the DBP is a step forward in DB measurement, it can be improved. Alternative strategies proposed for improving the DBP include; 1) a weighted DBP, which may increase predictive ability and provide a closer approximation of an individual's MTC compared to the original DBP; 2) a coded DBP, which may allow for identification of common reasons why college students choose to drink or not drink; and 3) personalized DBP feedback, which may increase intervention efficacy by further highlighting the discrepancy between behaviors and goals. These strategies can be applied separately or in conjunction, and represent a potentially promising new avenue for DB research. PMID- 25530872 TI - Alterations in skin temperature and sleep in the fear of harm phenotype of pediatric bipolar disorder. AB - In children diagnosed with pediatric bipolar disorder (PBD), disturbances in the quality of sleep and wakefulness are prominent. A novel phenotype of PBD called Fear of Harm (FOH) associated with separation anxiety and aggressive obsessions is associated with sleep onset insomnia, parasomnias (nightmares, night-terrors, enuresis), REM sleep-related problems, and morning sleep inertia. Children with FOH often experience thermal discomfort (e.g. feeling hot, excessive sweating) in neutral ambient temperature conditions, as well as no discomfort during exposure to the extreme cold, and alternate noticeably between being excessively hot in the evening and cold in the morning. We hypothesized that these sleep- and temperature-related symptoms were overt symptoms of an impaired ability to dissipate heat, particularly in the evening hours near the time of sleep onset. We measured sleep/wake variables using actigraphy, and nocturnal skin temperature variables using thermal patches and a wireless device, and compared these data between children with PBD/FOH and a control sample of healthy children. The results are suggestive of a thermoregulatory dysfunction that is associated with sleep onset difficulties. Further, they are consistent with our hypothesis that alterations in neural circuitry common to thermoregulation and emotion regulation underlie affective and behavioral symptoms of the FOH phenotype. PMID- 25530873 TI - Reducing X-Ray Induced Oxidative Damages in Fibroblasts with Graphene Oxide. AB - A major issue of X-ray radiation therapy is that normal cells can be damaged, limiting the amount of X-rays that can be safely delivered to a tumor. This paper describes a new method based on graphene oxide (GO) to protect normal cells from oxidative damage by removing free radicals generated by X-ray radiation using grapheme oxide (GO). A variety of techniques such as cytotoxicity, genotoxicity, oxidative assay, apoptosis, gamma-H2AX expression, and micro-nucleus assay have been used to assess the protective effect of GO in cultured fibroblast cells. It is found that although GO at higher concentration (100 and 500 MUg/mL) can cause cell death and DNA damage, it can effectively remove oxygen free radicals at a lower concentration of 10 MUg/mL. The level of DNA damage and cell death is reduced by 48%, and 39%, respectively. Thus, low concentration GO can be used as an effective radio-protective agent in occupational and therapeutic settings. PMID- 25530874 TI - Use of a Wireless Network of Accelerometers for Improved Measurement of Human Energy Expenditure. AB - Single, hip-mounted accelerometers can provide accurate measurements of energy expenditure (EE) in some settings, but are unable to accurately estimate the energy cost of many non-ambulatory activities. A multi-sensor network may be able to overcome the limitations of a single accelerometer. Thus, the purpose of our study was to compare the abilities of a wireless network of accelerometers and a hip-mounted accelerometer for the prediction of EE. Thirty adult participants engaged in 14 different sedentary, ambulatory, lifestyle and exercise activities for five minutes each while wearing a portable metabolic analyzer, a hip-mounted accelerometer (AG) and a wireless network of three accelerometers (WN) worn on the right wrist, thigh and ankle. Artificial neural networks (ANNs) were created separately for the AG and WN for the EE prediction. Pearson correlations (r) and the root mean square error (RMSE) were calculated to compare criterion-measured EE to predicted EE from the ANNs. Overall, correlations were higher (r = 0.95 vs. r = 0.88, p < 0.0001) and RMSE was lower (1.34 vs. 1.97 metabolic equivalents (METs), p < 0.0001) for the WN than the AG. In conclusion, the WN outperformed the AG for measuring EE, providing evidence that the WN can provide highly accurate estimates of EE in adults participating in a wide range of activities. PMID- 25530876 TI - Emergency surgery for metastatic melanoma. AB - Visceral metastases from malignant melanoma (stage M1c) confer a very poor prognosis, as documented on the most recent revised version of the TNM/AJCC staging system. Emergency surgery for intra-abdominal complications from the disease is rare. We report on our 5-year single institution experience with surgical management of metastatic melanoma to the viscera in the emergent setting. From 2009 to 2013, 14 patients with metastatic melanoma were admitted emergently due to an acute abdomen. Clinical manifestations encompassed intestinal obstruction and bleeding. Surgical procedures involved multiple enterectomies with primary anastomoses in 8 patients, and one patient underwent splenectomy, one adrenalectomy, one right colectomy, one gastric wedge resection, one gastrojejunal anastomosis, and one transanal debulking, respectively. The 30 day mortality was 7 percent. Median follow-up was 14 months. Median overall survival was 14 months. Median disease free survival was 7.5 months. One-year overall survival was 64.2 percent and 2-year overall survival was 14.2 percent. Emergency surgery for metastatic melanoma to the viscera is rare. Elective curative surgery combined with novel cytotoxic systemic therapies is under investigation in an attempt to grant survival benefit in melanoma patients with visceral disease. PMID- 25530877 TI - Personnel's Experiences of Phlebotomy Practices after Participating in an Educational Intervention Programme. AB - Background. Blood specimen collection is a common procedure in health care, and the results from specimen analysis have essential influence on clinical decisions. Errors in phlebotomy may lead to repeated sampling and delay in diagnosis and may jeopardise patient safety. This study aimed to describe the experiences of, and reflections on, phlebotomy practices of phlebotomy personnel working in primary health care after participating in an educational intervention programme (EIP). Methods. Thirty phlebotomists from ten primary health care centres participated. Their experiences were investigated through face-to-face interviews. Findings were analysed using qualitative content analysis. Results. The participants perceived the EIP as having opened up opportunities to reflect on safety. The EIP had made them aware of risks in relation to identification procedures, distractions from the environment, lack of knowledge, and transfer of information. The EIP also resulted in improvements in clinical practice, such as a standardised way of working and increased accuracy. Some said that the training had reassured them to continue working as usual, while others continued as usual regardless of incorrect procedure. Conclusions. The findings show that EIP can stimulate reflections on phlebotomy practices in larger study groups. Increased knowledge of phlebotomy practices improves the opportunities to revise and maximise the quality and content of future EIPs. Educators and safety managers should reflect on and pay particular attention to the identification procedure, distractions from the environment, and transfer of information, when developing and implementing EIPs. The focus of phlebotomy training should not solely be on improving adherence to practice guidelines. PMID- 25530878 TI - Palliative reconstructive surgery: contextualizing palliation in resource-poor settings. AB - Introduction. Palliative care in Kenya and the larger Sub-Saharan Africa is considered a preserve of hospices, where these exist. Surgical training does not arm the surgeon with the skills needed to deal with the care of palliative patients. Resource constraints demand that the surgeon be multidiscipline trained so as to be able to adequately address the needs of a growing population of patients that could benefit from surgical palliation. Patients and Methods. The author describes his experience in the management of a series of 31 palliative care patients, aged 8 to 82 years. There were a total of nine known or presumed mortalities in the first year following surgery; 17 patients experienced an improved quality of life for at least 6 months after surgery. Fourteen of these were disease-free at 6 months. Conclusion. Palliative reconstructive surgery is indicated in a select number of patients. Although cure is not the primary intent of palliative surgery, the potential benefits of an improved quality of life and the possibility of cure should encourage a more proactive role for the surgeon. The need for palliative care can be expected to increase significantly in Africa, with the estimated fourfold increase of cancer patients over the next 50 years. PMID- 25530879 TI - Experiences of dental care and dental anxiety in adults with autism spectrum disorder. AB - Dental anxiety is associated with previous distressing dental experiences, such as lack of understanding of the dentist intentions, perceptions of uncontrollability and experiences of pain during dental treatment. People with autism spectrum disorder (ASD) are impaired in building flexible predictions and expectations, which is very much needed during a dental visit. The aims of the study were to investigate if people with ASD have more negative dental experiences and a higher level of dental anxiety compared to a matched control group. Forty-seven adults with ASD and of normal intellectual performance, and 69 age- and sex-matched typically developing controls completed questionnaires on previous dental experiences and dental anxiety, the Dental Anxiety Scale, and the Dental Beliefs Survey. The ASD group experienced pain during dental treatments more often than the controls and 22% had repeatedly experienced being forced to dental treatment they were not prepared for, compared to 3% of the controls. A higher level of dental anxiety was reported by the ASD group. Dental treatment and methods for supporting the communication with patients with ASD need to be developed, in order to reduce the negative dental experiences and dental anxiety in people with ASD. PMID- 25530880 TI - Evaluation of Contrast Extravasation as a Diagnostic Criterion in the Evaluation of Arthroscopically Proven HAGL/pHAGL Lesions. AB - Purpose. The validity of preoperative MRI in diagnosing HAGL lesions is debated. Various investigations have produced mixed results with regard to the utility of MRI. The purpose of this investigation is to apply a novel method of diagnosing HAGL/pHAGL lesions by looking at contrast extravasation and to evaluate the reliability of such extravasation of contrast into an extra-articular space as a sign of HAGL/pHAGL lesion. Methods. We utilized specific criteria to define contrast extravasation. We evaluated these criteria in 12 patients with arthroscopically proven HAGL/pHAGL lesion. We also evaluated these criteria in a control group. Results. Contrast extravasation occurred in over 83% of arthroscopically positive cases. Contrast extravasation as a diagnostic criterion in the evaluation of HAGL/pHAGL lesions demonstrated a high interobserver degree of agreement. Conclusions. In conclusion, extra-articular contrast extravasation may serve as a valid and reliable sign of HAGL and pHAGL lesions, provided stringent criteria are maintained to assure that the contrast lies in an extra articular location. In cases where extravasation is not present, the "J" sign, though nonspecific, may be the only evidence of subtle HAGL and pHAGL lesions. Level of Evidence. Level IV, Retrospective Case-Control series. PMID- 25530875 TI - ASYMMETRIC CELL DIVISION: IMPLICATIONS FOR GLIOMA DEVELOPMENT AND TREATMENT. AB - Glioma is a heterogeneous disease process with differential histology and treatment response. It was previously thought that the histological features of glial tumors indicated their cell of origin. However, the discovery of continuous neuro-gliogenesis in the normal adult brain and the identification of brain tumor stem cells within glioma have led to the hypothesis that these brain tumors originate from multipotent neural stem or progenitor cells, which primarily divide asymmetrically during the postnatal period. Asymmetric cell division allows these cell types to concurrently self-renew whilst also producing cells for the differentiation pathway. It has recently been shown that increased symmetrical cell division, favoring the self-renewal pathway, leads to oligodendroglioma formation from oligodendrocyte progenitor cells. In contrast, there is some evidence that asymmetric cell division maintenance in tumor stem like cells within astrocytoma may lead to acquisition of treatment resistance. Therefore cell division mode in normal brain stem and progenitor cells may play a role in setting tumorigenic potential and the type of tumor formed. Moreover, heterogeneous tumor cell populations and their respective cell division mode may confer differential sensitivity to therapy. This review aims to shed light on the controllers of cell division mode which may be therapeutically targeted to prevent glioma formation and improve treatment response. PMID- 25530882 TI - Comparison of Two Methods for the Measurement of Medial and Lateral Metapodial Bones in Karagouniko Sheep (Ovis aries, L. 1758) and Hellenic Goat (Capra hircus, L. 1758). AB - The objective of this study was to compare the metapodial lengths of sheep and goats measured with a caliper with those measured using a 2-dimensional digital method. Complementarily, the lengths of medial and lateral metapodials in these species were compared. The limbs of 30 ewes and 30 goats were used. After preparation, the lateral and medial length of the metacarpals and metatarsals were measured twice with a caliper. Afterwards, each bone was scanned and the same lengths were digitally measured twice using commercial software. Data analysis revealed strong linear relationship between the two methods but the absolute relative deviation of the measurements with the caliper was significantly higher than those with the 2-dimensional method (P < 0.05). All lengths measured with the caliper were significantly higher compared to those measured with the 2-dimensional method (P < 0.05). In goats, the lateral length of both metacarpals and metatarsals was significantly higher than medial length (P < 0.05); in sheep the lateral length was significantly higher compared to the medial one only in metatarsal bones (P < 0.05). In conclusion, the 2-dimensional method is more accurate for the measurement of the metapodials' length than the caliper and there is asymmetry between the medial and lateral metapodials in these species. PMID- 25530881 TI - Associates of cardiopulmonary arrest in the perihemodialytic period. AB - Cardiopulmonary arrest during and proximate to hemodialysis is rare but highly fatal. Studies have examined peridialytic sudden cardiac event risk factors, but no study has considered associates of cardiopulmonary arrests (fatal and nonfatal events including cardiac and respiratory causes). This study was designed to elucidate patient and procedural factors associated with peridialytic cardiopulmonary arrest. Data for this case-control study were taken from the hemodialysis population at Fresenius Medical Care, North America. 924 in-center cardiopulmonary events (cases) and 75,538 controls were identified. Cases and controls were 1 : 5 matched on age, sex, race, and diabetes. Predictors of cardiopulmonary arrest were considered for logistic model inclusion. Missed treatments due to hospitalization, lower body mass, coronary artery disease, heart failure, lower albumin and hemoglobin, lower dialysate potassium, higher serum calcium, greater erythropoietin stimulating agent dose, and normalized protein catabolic rate (J-shaped) were associated with peridialytic cardiopulmonary arrest. Of these, lower albumin, hemoglobin, and body mass index; higher erythropoietin stimulating agent dose; and greater missed sessions had the strongest associations with outcome. Patient health markers and procedural factors are associated with peridialytic cardiopulmonary arrest. In addition to optimizing nutritional status, it may be prudent to limit exposure to low dialysate potassium (<2 K bath) and to use the lowest effective erythropoietin stimulating agent dose. PMID- 25530883 TI - A study of Basal cell carcinoma in South asians for risk factor and clinicopathological characterization: a hospital based study. AB - Objectives. Although the incidence of skin cancers in India (part of South Asia) is low, the absolute number of cases may be significant due to large population. The existing literature on BCC in India is scant. So, this study was done focusing on its epidemiology, risk factors, and clinicopathological aspects. Methods. A hospital based cross-sectional study was conducted in Punjab, North India, from 2011 to 2013. History, examination and histopathological confirmation were done in all the patients visiting skin department with suspected lesions. Results. Out of 36 confirmed cases, 63.9% were females with mean +/- SD age being 60.9 +/- 14.2 years. Mean duration of disease was 4.7 years. Though there was statistically significant higher sun exposure in males compared to females (P value being 0.000), BCC was commoner in females, explainable by intermittent sun exposure (during household work in the open kitchens) in women. Majority of patients (88.9%) had a single lesion. Head and neck region was involved in 97.2% of cases, with nose being the commonest site (50%) with nodular/noduloulcerative morphology in 77.8% of cases. Pigmentation was evident in 22.2% of cases clinically. Nodular variety was the commonest histopathological variant (77.8%). Conclusions. This study highlights a paradoxically increasing trend of BCC with female preponderance, preferential involvement of nose, and higher percentage of pigmentation in Indians. PMID- 25530884 TI - Comparative Studies of Oleaginous Fungal Strains (Mucor circinelloides and Trichoderma reesei) for Effective Wastewater Treatment and Bio-Oil Production. AB - Biological wastewater treatment typically requires the use of bacteria for degradation of carbonaceous and nitrogenous compounds present in wastewater. The high lipid containing biomass can be used to extract oil and the contents can be termed as bio-oil (or biodiesel or myco-diesel after transesterification). The separate experiments were conducted on actual wastewater samples with 5% v/v inoculum of Mucor circinelloides MTCC1297 and Trichoderma reesei NCIM992 strains. The observed reductions in chemical oxygen demand (COD) were 88.72% and 86.75% in 96 hrs and the observed substrate based biomass yields were 0.21 mg VSS/mg COD and 0.22 mg VSS/mg COD for M. circinelloides reactor and for T. reesei reactor, respectively. The resulted bio-oil production from wastewater treatment by M. circinelloides and T. reesei reactors was 142.2 mg/L and 74.1 mg/L, whereas biomass containing bio-oil contents (%w/w) were 22.11% and 9.82%, respectively. In this experiment, the fungal wastewater treatment was also compared with conventional bacterial process with respect to specific growth rate, biomass production, and oil content. This study suggests that wastewater can be used as a potential feedstock for bio-oil production with the use of oleaginous fungal strains and which could be a possible route of waste to energy. PMID- 25530885 TI - Ethanol Production from Extruded Thermoplastic Maize Meal by High Gravity Fermentation with Zymomonas mobilis. AB - A comparative study of extruded and ground maize meals as raw materials for the production of regular (12 degrees P) and high gravity (20 degrees P) worts was devised. Extruded water solubility index (WSI) was higher (9.8 percentage units) and crude fat was lower (2.64 percentage units) compared to ground maize. Free amino nitrogen compounds (FAN), pH, and glucose were evaluated in regular and high gravity worts produced from ground or extruded maize. Extrusion improved glucose content and ethanol yield. In 20 degrees P mashes, extrusion is enhanced by 2.14% initial glucose compared with regular ground mashes. The 12 degrees P and 20 degrees P extruded treatments averaged 12.2% and 8.4% higher ethanol, respectively, compared to the uncooked counterpart. The 20 degrees P worts fermented with Zymomonas mobilis produced 9.56% more ethanol than the 12 degrees P counterpart. The results show that the combination of extrusion and fermentation of 20 degrees P worts improved ethanol yield per kg flour until 20.93%. This pretreatment stimulates Z. mobilis fermentation efficiency. PMID- 25530886 TI - Factors associated with the incidence of local recurrences of breast cancer in women who underwent conservative surgery. AB - Conservative surgery is considered the procedure of choice for women who are affected by early stage tumours. The local recurrence of cancer as a consequence of breast tissue conservation is a growing concern. This study aimed to describe the sociodemographic and clinical profiles of women who had local recurrences of breast cancer after conservative surgery and to examine the associations between sociodemographic and clinical variables and the incidence of tumour recurrence in these women. The retrospective cohort included 880 women who were diagnosed with breast cancer and underwent conservative surgery between January 2000 and December 2010. Recurrences occurred in 60 patients, and the mean age of the women at diagnosis was 48.8 years. Predictive factors for local recurrence were young age (<39 years) (P = 0.028 and OR = 10.93), surgical margin involvement (P = 0.001 and OR = 3.66), and Her-2 overexpression (P = 0.045 and OR = 1.94). The establishment of sociodemographic and clinical characteristics might help to select optimum treatments, which is a crucial challenge for public health in Brazil, especially with regard to reductions of surgery and hospitalisation expenditures in the Unified Health System (Sistema Unico de Saude-SUS). PMID- 25530887 TI - Usage of EMBRACE(TM) in Gujarat, India: Survey of Paediatricians. AB - Aim. EMBRACE(TM) is an innovative, low cost infant warmer for use in neonates. It contains phase change material, which stays at constant temperature for 6 hours. We surveyed paediatricians using EMBRACE(TM) regarding benefits, risks, and setup in which it was used in Gujarat. Methods. Questionnaire was administered telephonically to 52 out of 53 paediatricians. Results. EMBRACE(TM) was used for an average of 8.27 (range of 3-18, SD = 3.84) months by paediatricians. All used it for thermoregulation during transfers, for average (SD) duration of 42 (0.64) m per transfer, 62.7% used it at mother's side for average (SD) 11.06 (7.89) h per day, and 3.9% prescribed it at home. It was used in low birth weight neonates only by 56.9% while 43.1% used it for all neonates. While hyperthermia was not reported, 5.9% felt that EMBRACE(TM) did not prevent hypothermia. About 54.9% felt that they could not monitor the newborn during EMBRACE(TM) use. Of paediatricians who practiced kangaroo mother care (KMC), 7.7% have limited/stopped/decreased the practice of KMC and substituted it with EMBRACE(TM). Conclusions. EMBRACE(TM) was acceptable to most but concerns related to monitoring neonates and disinfection remained. Most paediatricians felt that it did not hamper KMC practice. PMID- 25530888 TI - Compelled Body Weight Shift Technique to Facilitate Rehabilitation of Individuals with Acute Stroke. AB - BACKGROUND: The study evaluates the effectiveness of Compelled Body Weight Shift (CBWS) approach in the rehabilitation of individuals with stroke. CBWS involves a forced shift of body weight towards a person's affected side by means of a shoe insert that establishes a lift of the nonaffected lower extremity. METHODS: Eleven patients with acute stroke were randomly assigned to experimental and control groups. The experimental group received a two-week conventional physical therapy combined with CBWS and the control group received only a two-week conventional therapy. Weight bearing, Gait velocity, Berg's Balance, and Fugl Meyer's Scores were recorded before and after the intervention. RESULTS: Weight bearing on the affected side increased in the experimental group and decreased in the control group. The increase in gait velocity with treatment was significant in both the groups (P < 0.05). However, experimental group (P = 0.01) demonstrated larger improvements in gait velocity compared to the control group (P = 0.002). Berg Balance and Fugl-Meyer scores increased for both the groups. CONCLUSION: The implementation of a two-week intervention with CBWS resulted in the improvement in weight bearing and gait velocity of individuals with acute stroke. The present preliminary study suggests that CBWS technique could be implemented as an adjunct to conventional rehabilitation program for individuals with acute stroke. PMID- 25530889 TI - Reattachment of fractured tooth fragment with fiber post: a case series with 1 year followup. AB - Coronal fractures of the anterior teeth are common sequelae of dental trauma. In case of complex fractures, where the fractured segment is available and there is close approximation of the segment to the remaining tooth, root canal treatment followed by reattachment of the fractured segment with fiber post reinforcement is a feasible option. The procedure is simple and economic and needs less chair side time as compared to many conventional methods. In addition, the procedure provides good and long-lasting esthetics, because the original morphology, color, and surface texture are maintained. This paper reports three cases of complex coronal tooth fracture successfully managed using tooth fragment reattachment. PMID- 25530890 TI - Regenerative endodontic treatment of an infected immature dens invaginatus with the aid of cone-beam computed tomography. AB - Dens invaginatus is a developmental anomaly that results in an enamel-lined cavity intruding into the crown or root before the mineralization phase. This report presents regenerative endodontic treatment of a necrotic immature tooth with Oehler's type III dens invaginatus of a nine-year-old female patient. A diagnosis of dens invaginatus (Oehler's type III) and a large periapical lesion was established with the aid of cone-beam computed tomography (CBCT). In the presented case contrary to the classic revascularization protocol, mechanical instrumentation was performed which apparently did not interfere with the regeneration process. After mechanical instrumentation of the invaginated canal by manual K-files, the invaginated canal space was disinfected by triple antibiotic paste followed by blood clot induction from the periapical tissues and the placement of mineral trioxide aggregate. At one-year follow-up, the tooth remained clinically asymptomatic. Radiographic examination revealed complete healing of the periapical lesion. At the 20-month follow-up, the radiographic examination also showed that the open apex was closed and the walls of the root canal were thickened. PMID- 25530891 TI - Out-of-Hospital Perimortem Cesarean Section as Resuscitative Hysterotomy in Maternal Posttraumatic Cardiac Arrest. AB - The optimal treatment of a severe hemodynamic instability from shock to cardiac arrest in late term pregnant women is subject to ongoing studies. However, there is an increasing evidence that early "separation" between the mother and the foetus may increase the restoration of the hemodynamic status and, in the cardiac arrest setting, it may raise the likelihood of a return of spontaneous circulation (ROSC) in the mother. This treatment, called Perimortem Cesarean Section (PMCS), is now termed as Resuscitative Hysterotomy (RH) to better address the issue of an early Cesarean section (C-section). This strategy is in contrast with the traditional treatment of cardiac arrest characterized by the maintenance of cardiopulmonary resuscitation (CPR) maneuvers without any emergent surgical intervention. We report the case of a prehospital perimortem delivery by Caesarean (C) section of a foetus at 36 weeks of gestation after the mother's traumatic cardiac arrest. Despite the negative outcome of the mother, the choice of performing a RH seems to represent up to date the most appropriate intervention to improve the outcome in both mother and foetus. PMID- 25530892 TI - Unique presentation of akinetic mutism and coexisting thyroid storm relating to stroke. AB - Akinetic mutism is described in various clinical presentations but typically is defined as a state wherein the patient appears awake but does not move or speak. It can be divided into two different subtypes; the most common subtypes depend on the lesion location, mesencephalic-diencephalic region, also called apathetic akinetic mutism (somnolent mutism), and those involving the anterior cingulate gyrus and adjacent frontal lobes called hyperpathic akinetic mutism. The pathway of akinetic mutism is believed to originate from circuits that link the frontal and subcortical structures. This case reports a 48-year-old African American female with bilateral anterior cerebral artery stroke and akinetic mutism with coexisting thyroid storm. This patient with bilateral anterior cerebral artery infarcts presented with characteristics that are typical for akinetic mutism such as having intact eye movements but an inability to respond to auditory or visual commands. With the incidence of bilateral anterior cerebral artery (ACA) ischemic stroke being rare and the incidence of akinetic mutism secondary to ischemic stroke even rarer, we suspect that this patient potentially had a unilateral occlusion of anomalous anterior cerebral vasculature. PMID- 25530893 TI - Anton's Syndrome due to Bilateral Ischemic Occipital Lobe Strokes. AB - We present a case of a patient with Anton's syndrome (i.e., visual anosognosia with confabulations), who developed bilateral occipital lobe infarct. Bilateral occipital brain damage results in blindness, and patients start to confabulate to fill in the missing sensory input. In addition, the patient occasionally becomes agitated and talks to himself, which indicates that, besides Anton's syndrome, he might have had Charles Bonnet syndrome, characterized by both visual loss and hallucinations. Anton syndrome, is not so frequent condition and is most commonly caused by ischemic stroke. In this particular case, the patient had successive bilateral occipital ischemia as a result of massive stenoses of head and neck arteries. PMID- 25530894 TI - Clear cell carcinoma arising from cesarean section scar endometriosis: case report and review of the literature. AB - Introduction. The incidence of endometriosis affecting skin tissue represents only 0.5-1.0% of all endometriosis cases. A malignancy in the abdominal wall arising from endometriosis following cesarean section is even rarer; only 21 cases have previously been reported. The therapeutic strategy has not been determined because of the limited cases. We report a case of clear cell adenocarcinoma arising in the abdominal wall from endometriosis tissues following cesarean section and review previous literature to achieve the optimal treatment and better prognosis. Case Presentation. A 60-year-old woman presented with a growing mass at the left side of a cesarean section scar. Radical resection of the abdominal wall mass was performed. Histopathological examination showed a clear cell adenocarcinoma. Benign endometrium-like tissues were found adjacent to the cancer lesion in the excised specimen, suggesting malignant transformation from endometriosis of the abdominal wall. Discussion. Local resection was performed in 10 cases (47.6%) and total abdominal hysterectomy or oophorectomy was conducted in 11 cases (52.4%). No malignant lesions were observed in either the uterus or adnexa that were resected. These cases may be expected to increase with increasing incidence of cesarean section. The significance of the extensional resection should be further elucidated. PMID- 25530895 TI - Acute cardiogenic shock induced by infusional 5-Fluorouracil. AB - A 49-year-old patient with metastatic carcinoma of the bladder and no prior history of heart disease presented with diffuse ST elevation, elevated troponins, and biventricular dysfunction requiring intensive care unit admission and inotropic support after receiving her first course of infusional 5-fluorouracil (5-FU). Over the course of several days, the patient's cardiac function and clinical status returned to baseline. A follow-up echocardiogram performed 5 days after initial presentation revealed an ejection fraction of 59 percent, with no evidence of wall motion abnormalities. Subsequent 5-FU chemotherapy was discontinued, and the patient went on to receive second-line chemotherapy. PMID- 25530896 TI - The utility and limitations of the transfibular approach in ankle trauma surgery. AB - The commonly used extensive approaches to the distal tibia include the posteromedial and anterolateral approaches. The current report describes several cases performed using this technique establishing a rationale and safe zone for performing a transfibular approach to the distal tibia. The advantages of such approach are the excellent visualization of the lateral tibia and the articular space. The utilization of this approach involves the risk of injury to the anterior tibial vessels and to the superficial peroneal nerve as well as a requirement for syndesmosis reconstruction. The recommendation is to utilize this approach in cases of severe comminution of the lateral tibia with a relatively intact medial tibia. PMID- 25530897 TI - Tug-of-War Injuries: A Case Report and Review of the Literature. AB - We report a case of a 10-year-old boy presenting with radial nerve palsy due to injury during a tug-of-war game. Patient was managed nonoperatively and regained radial nerve function. Tug-of-war is a globally popular noncontact sport. Injuries during this game are inevitable and may range from simple sprains to life and limb threatening trauma. Combined hip and knee injuries and soft-tissue injuries involving the back are most frequent. Most injuries occur when tug-of war was played in an informal setting and where the tug-of-war International Federation rules were less likely to be followed. Measures should be taken to increase the awareness about these safety rules and prevention of consequent injuries. Sports physicians, pediatricians, orthopedic surgeons, general physicians, and athletic trainers should be aware of potential injuries resulting from this game while caring for these athletes, so as to be well prepared for apt management of the injuries associated with TOW. PMID- 25530898 TI - Proximal Row Carpectomy for Coexisting Kienbock's Disease and Giant Intraosseous Ganglion of the Scaphoid: A Case Report and Review of the Literature. AB - The etiologies of Keinbock's disease and intraosseous ganglion remain unknown. Both entities are rare and the coexistence of these two pathologies in the same patient and hand is even less frequent. We report the case of a 40-year-old man with a longstanding history of martial arts practice (karate) who developed an avascular necrosis of the lunate concomitant with a giant intraosseous ganglion of the scaphoid bone successfully managed by proximal row carpectomy. We review the literature of these two diseases. PMID- 25530899 TI - Oncocytoma of oral cavity mimicking as jaw tumor. AB - Oncocytoma of major salivary gland is a fairly common benign tumour encountered, but its occurrence in oral minor salivary gland is a rare entity. Here we report a case of a giant minor salivary gland oncocytoma mimicking a jaw tumour which was successfully excised along with a review of literature. PMID- 25530900 TI - QT Interval Prolongation Associated with Intramuscular Ziprasidone in Chinese Patients: A Case Report and a Comprehensive Literature Review with Meta-Analysis. AB - Intramuscular (IM) ziprasidone has been associated with QTc interval prolongations in patients with preexisting risk factors. A 23-year-old male Chinese schizophrenia patient experienced an increase of QTc interval of 83 milliseconds (ms) after receiving 20 mg IM ziprasidone (baseline and increased QT/QTc were, respectively, 384/418 and 450/501). This was rated as a probable adverse drug reaction (ADR) by the Liverpool ADR causality assessment tool. A systematic review including all types of trials reporting the effect of IM ziprasidone on the QTc interval prolongation identified 19 trials with a total of 1428 patients. Mean QTc change from baseline to end of each study was -3.7 to 12.8 ms after IM ziprasidone. Four randomized trials (3 of 4 published in Chinese) were used to calculate a meta-analysis of QTc interval prolongation which showed no significant differences between IM ziprasidone and IM haloperidol groups (risk ratio 0.49 to 4.31, 95% confidence interval 0.09 to 19.68, P = 0.06 to 0.41). However, our review included two cases of patients who experienced symptoms probably related to QTc prolongation after IM ziprasidone. Thus, careful screening and close monitoring, including baseline ECG, should be considered in patients receiving IM ziprasidone for the first time. PMID- 25530901 TI - Treating methamphetamine-induced resistant psychosis with clozapine. AB - Background. Methamphetamine-induced psychosis (MIP) in Iran has turned into a serious issue in terms of health and treatment, lacking any obvious treatment methods for its resistant cases. Aims of Case Report. In the present study, a number of two cases of treatment of MIP with clozapine, which were resistant to the treatment with other antipsychotics, have been reported. Both cases completely responded to the treatment in only 2 weeks and no signs of psychosis relapse were seen in an 8-9 follow-up. Conclusion. Because of its particular pharmacologic features, clozapine may be effective in treating MIP. PMID- 25530902 TI - Pulmonary Embolism following Cessation of Infliximab for Treatment of Miliary Tuberculosis. AB - We report a case of a 41-year-old male who presented with tachycardia and swelling of his left arm six weeks after he started antituberculosis treatment and stopped his rheumatoid arthritis infliximab treatment. He was diagnosed with pulmonary embolism by chest CT and initially treated with warfarin, which interacted with his antituberculosis treatment. This presentation of deep vein thrombosis and pulmonary embolism as part of immune reconstitution inflammatory syndrome has not been previously reported for infliximab treated patients. PMID- 25530903 TI - Predictors of dropout from inpatient opioid detoxification with buprenorphine: a chart review. AB - Inpatient withdrawal treatment (detoxification) is common in opioid dependence, although dropout against medical advice often limits its outcome. This study aimed to assess baseline predictors of dropout from inpatient opioid detoxification with buprenorphine, including age, gender, current substance use, and type of postdetoxification planning. A retrospective hospital chart review was carried out for inpatient standard opioid detoxifications using buprenorphine taper, in a detoxification ward in Malmo, Sweden (N = 122). Thirty-four percent of patients (n = 42) dropped out against medical advice. In multivariate logistic regression, dropout was significantly associated with younger age (OR 0.93 [0.89 0.97]) and negatively predicted by inpatient postdetoxification plan (OR 0.41 [0.18-0.94]), thus favouring an inpatient plan as opposed to outpatient treatment while residing at home. Dropout was unrelated to baseline urine toxicology. In opioid detoxification, patients may benefit from a higher degree of postdetoxification planning, including transition to residential treatment, in order to increase the likelihood of a successful detoxification and treatment entry. Young opioid-dependent patients may need particular attention in the planning of detoxification. PMID- 25530904 TI - Clinical Profile of Plasmodium vivax Malaria in Children and Study of Severity Parameters in relation to Mortality: A Tertiary Care Centre Perspective in Mumbai, India. AB - Background. While research on P. vivax is scarce because it is considered benign, it has become evident with implementation of molecular diagnosis that it can also cause multiple organ dysfunction and severe life-threatening disease. Objective. To study clinical presentations and complications of P. vivax malaria and mortality correlation to severity parameters as defined by WHO criteria for severe malaria. Materials and methods. This study was conducted in a tertiary care centre in Mumbai. Confirmed P. vivax cases were enrolled and studied for their clinical profile, and WHO severity parameters were tested for their frequency and association to mortality. Result. The most common presentation was fever followed by pallor. 26% of the cases satisfied one or more criteria of WHO severity parameters. 2 cases died; both had pulmonary edema and bleeding. The major predictor of mortality among these predefined severity criteria was pulmonary edema/ARDS. Patients with severe anemia, circulatory collapse, and repeated generalized convulsion had 100% survival rate. Leukopenia was present in 10% of the cases. Both cases with mortality had leukopenia. Conclusion. P. vivax monoinfection tends to have severe complications in children. There is a need to review severity criteria for P. vivax malaria. PMID- 25530905 TI - Impact of serum nutritional status on physical function in african american and caucasian stroke survivors. AB - Background. The purpose of this study is to compare serum nutritional profiles in chronic stroke survivors to a representative sample of US Adults (NHANESIII) and determine whether these serum markers differed by race and impact physical function in stroke. Methods. Fasting serum samples were collected for analysis of lipids, uric acid, and albumin in 145 African American (AA) and 111 Caucasian (C) stroke survivors (age: 60 +/- 1 years [mean +/- SEM]). A six-minute walk was performed in a subset of stroke survivors (N = 134). Results. Triglycerides were higher and HDL-cholesterol and albumin lower in C than AA women stroke survivors (Ps < 0.05). Uric acid was lower in C than AA stroke survivors (P < 0.05). Compared to NHANESIII, HDL-cholesterol, albumin, and hemoglobin generally were lower (Ps < 0.05) and lipids were more favorable in stroke (Ps < 0.01). Uric acid was related to six-minute walk performance among a subset of stroke survivors (P < 0.05). Conclusion. In stroke, racial differences exist with regard to serum nutritional risk, but these differences are similar to that observed in the general population. Regardless of race, nutritional risk appears elevated above that of the general population with regard to many of the serum markers. As a modifiable biomarker, uric acid should be monitored closely as it may provide insight into the functional risk of stroke survivors. PMID- 25530906 TI - Elevated Cardiac Troponin in Acute Stroke without Acute Coronary Syndrome Predicts Long-Term Adverse Cardiovascular Outcomes. AB - Background. Elevated cardiac troponin in acute stroke in absence of acute coronary syndrome (ACS) has unclear long-term outcomes. Methods. Retrospective analysis of 566 patients admitted to Temple University Hospital from 2008 to 2010 for acute stroke was performed. Patients were included if cardiac troponin I was measured and had no evidence of ACS and an echocardiogram was performed. Of 200 patients who met the criteria, baseline characteristics, electrocardiograms, and major adverse cardiovascular events (MACE) were reviewed. Patients were characterized into two groups with normal and elevated troponins. Primary end point was nonfatal myocardial infarction during follow-up period after discharge. The secondary end points were MACE and death from any cause. Results. For 200 patients, 17 patients had positive troponins. Baseline characteristics were as follows: age 63.1 +/- 13.8, 64% African Americans, 78% with hypertension, and 22% with previous CVA. During mean follow-up of 20.1 months, 7 patients (41.2%) in elevated troponin and 6 (3.3%) patients in normal troponin group had nonfatal myocardial infarction (P = 0.0001). MACE (41.2% versus 14.2%, P = 0.01) and death from any cause (41.2% versus 14.5%, P = 0.017) were significant in the positive troponin group. Conclusions. Elevated cardiac troponin in patients with acute stroke and no evidence of ACS is strong predictor of long-term cardiac outcomes. PMID- 25530907 TI - Identification of the related substances in ampicillin capsule by rapid resolution liquid chromatography coupled with electrospray ionization tandem mass spectrometry. AB - Rapid Resolution Liquid Chromatography coupled with Electrospray Ionization Tandem Mass Spectrometry (RRLC-ESI-MS(n)) was used to separate and identify related substances in ampicillin capsule. The fragmentation behaviors of related substances were used to identify their chemical structures. Finally, a total of 13 related substances in ampicillin capsule were identified, including four identified components for the first time and three groups of isomers on the basis of the exact mass, fragmentation behaviors, retention time, and chemical structures in the literature. This study avoided time-consuming and complex chemosynthesis of related substances of ampicillin and the results could be useful for the quality control of ampicillin capsule to guarantee its safety in clinic. In the meantime, it provided a good example for the rapid identification of chemical structures of related substances of drugs. PMID- 25530908 TI - Testing for Partial RhD with a D-Screen Diagast Kit in Moroccan Blood Donors with Weak D Expression. AB - The aim of this study was to search for the partial D phenotype in Moroccan blood donors with weak D expression. The study included 32 samples with weak D phenotype, and partial D category red blood cells were detected with the D-Screen Diagast kit, which consists in 9 monoclonal anti-D antibodies specific for the most common categories of partial D. Among the 32 samples studied, we identified 13 specific reactions to a partial D antigen (3 DVI, 2 DVa, 2 DIII((a,b,c)), and 6 DVII), with 8 reactions suggesting a weak D and 11 reactions providing no formal argument in favor of a partial D antigen. This work can be used to validate the performance of the anti-D reagent and to improve the safety of transfusion of red blood cells from donors expressing the partial D antigen by integrating the finding into the recipient file with a recommendation concerning the appropriate care. PMID- 25530909 TI - How to motivate whole blood donors to become plasma donors. AB - This study tested the efficacy of interventions to recruit new plasma donors among whole blood donors. A sample of 924 donors was randomized to one of three conditions: control; information only by nurse; and information plus self positive image message by nurse (SPI). Participants in the control condition only received a leaflet describing the plasma donation procedure. In the two experimental conditions the leaflet was explained face-to-face by a nurse. The dependent variables were the proportion of new plasma donors and the number of donations at six months. Overall, 141 (15.3%) new plasma donors were recruited at six months. There were higher proportions of new plasma donors in the two experimental conditions compared to the control condition (P < .001); the two experimental conditions did not differ. Also, compared to the control condition, those in the experimental conditions (all Ps < .001) gave plasma more often (information only by nurse: d = .26; SPI: d = .32); the SPI intervention significantly outperformed (P < .05) the information only by nurse condition. The results suggest that references to feelings of SPI such as feeling good and being proud and that giving plasma is a rewarding personal experience favor a higher frequency of plasma donation. PMID- 25530910 TI - Medical genetics of ciliopathies. PMID- 25530911 TI - Wearable Networked Sensing for Human Mobility and Activity Analytics: A Systems Study. AB - This paper presents implementation details, system characterization, and the performance of a wearable sensor network that was designed for human activity analysis. Specific machine learning mechanisms are implemented for recognizing a target set of activities with both out-of-body and on-body processing arrangements. Impacts of energy consumption by the on-body sensors are analyzed in terms of activity detection accuracy for out-of-body processing. Impacts of limited processing abilities in the on-body scenario are also characterized in terms of detection accuracy, by varying the background processing load in the sensor units. Through a rigorous systems study, it is shown that an efficient human activity analytics system can be designed and operated even under energy and processing constraints of tiny on-body wearable sensors. PMID- 25530912 TI - Nicotine Absorption from Smokeless Tobacco Modified to Adjust pH. AB - INTRODUCTION: Nicotine delivery from smokeless tobacco (ST) products leads to addiction and the use of ST causes pathology that is associated with increased initiation of cigarette smoking. The rapid delivery of nicotine from ST seems to be associated with the pH of the aqueous suspension of the products - high pH is associated with high nicotine absorption. However, early studies compared nicotine absorption from different commercial products that not only differed in pH but in flavoring, nicotine content, and in format-pouches and loose tobacco. METHODS: The present study compared nicotine absorption from a single unflavored referent ST product (pH 7.7) that was flavored with a low level of wintergreen (2 mg/g) and the pH was amended to either high (8.3) or low (5.4) pH with sodium carbonate or citric acid, respectively. RESULTS: In a within-subject clinical study, the higher pH products delivered more nicotine. No significant differences were seen between perceived product strengths and product experience in all conditions. Heart rate increased by 4 to 6 beats per minute after the high pH flavored and the un-amended product but did not change after the low pH flavored product. CONCLUSIONS: These results indicate that pH is a primary determinant of buccal nicotine absorption. The role of flavoring and other components of ST products in nicotine absorption remain to be determined. PMID- 25530913 TI - Analysis of Multivariate Disease Classification Data in the Presence of Partially Missing Disease Traits. AB - In modern cancer epidemiology, diseases are classified based on pathologic and molecular traits, and different combinations of these traits give rise to many disease subtypes. The effect of predictor variables can be measured by fitting a polytomous logistic model to such data. The differences (heterogeneity) among the relative risk parameters associated with subtypes are of great interest to better understand disease etiology. Due to the heterogeneity of the relative risk parameters, when a risk factor is changed, the prevalence of one subtype may change more than that of another subtype does. Estimation of the heterogeneity parameters is difficult when disease trait information is only partially observed and the number of disease subtypes is large. We consider a robust semiparametric approach based on the pseudo-conditional likelihood for estimating these heterogeneity parameters. Through simulation studies, we compare the robustness and efficiency of our approach with that of the maximum likelihood approach. The method is then applied to analyze the associations of weight gain with risk of breast cancer subtypes using data from the American Cancer Society Cancer Prevention Study II Nutrition Cohort. PMID- 25530914 TI - An Interactive, Web-based High Performance Modeling Environment for Computational Epidemiology. AB - We present an integrated interactive modeling environment to support public health epidemiology. The environment combines a high resolution individual-based model with a user-friendly web-based interface that allows analysts to access the models and the analytics back-end remotely from a desktop or a mobile device. The environment is based on a loosely-coupled service-oriented-architecture that allows analysts to explore various counter factual scenarios. As the modeling tools for public health epidemiology are getting more sophisticated, it is becoming increasingly hard for non-computational scientists to effectively use the systems that incorporate such models. Thus an important design consideration for an integrated modeling environment is to improve ease of use such that experimental simulations can be driven by the users. This is achieved by designing intuitive and user-friendly interfaces that allow users to design and analyze a computational experiment and steer the experiment based on the state of the system. A key feature of a system that supports this design goal is the ability to start, stop, pause and roll-back the disease propagation and intervention application process interactively. An analyst can access the state of the system at any point in time and formulate dynamic interventions based on additional information obtained through state assessment. In addition, the environment provides automated services for experiment set-up and management, thus reducing the overall time for conducting end-to-end experimental studies. We illustrate the applicability of the system by describing computational experiments based on realistic pandemic planning scenarios. The experiments are designed to demonstrate the system's capability and enhanced user productivity. PMID- 25530915 TI - FDG and Amyloid PET in Cognitively Normal Individuals at Risk for Late-Onset Alzheimer's Disease. AB - : Having a parent affected by late-onset Alzheimer's disease (AD) is a major risk factor for cognitively normal (NL) individuals. This study explores the potential of PET with 18F-FDG and the amyloid- beta (Abeta) tracer 11C-Pittsburgh Compound B (PiB) for detection of individual risk in NL adults with AD-parents. METHODS: FDG- and PiB-PET was performed in 119 young to late-middle aged NL individuals including 80 NL with positive family history of AD (FH+) and 39 NL with negative family history of any dementia (FH-). The FH+ group included 50 subjects with maternal (FHm) and 30 with paternal family history (FHp). Individual FDG and PiB scans were Z scored on a voxel-wise basis relative to modality-specific reference databases using automated procedures and rated as positive or negative (+/-) for AD-typical abnormalities using predefined criteria. To determine the effect of age, the cohort was separated into younger (49 +/- 9 y) and older (68 +/- 5 y) groups relative to the median age (60 y). RESULTS: Among individuals of age >60 y, as compared to controls, NL FH+ showed a higher frequency of FDG+ scans vs. FH (53% vs. 6% p < 0.003), and a trend for PiB+ scans (27% vs. 11%; p = 0.19). This effect was observed for both FHm and FHp groups. Among individuals of age <=60 y, NL FHm showed a higher frequency of FDG+ scans (29%) compared to FH- (5%, p = 0.04) and a trend compared to FHp (11%) (p = 0.07), while the distribution of PiB+ scans was not different between groups. In both age cohorts, FDG+ scans were more frequent than PiB+ scans among NL FH+, especially FHm (p < 0.03). FDG-PET was a significant predictor of FH+ status. Classification according to PiB status was significantly less successful. CONCLUSIONS: Automated analysis of FDG- and PiB-PET demonstrates higher rates of abnormalities in at-risk FH+ vs FH- subjects, indicating potentially ongoing early AD-pathology in this population. The frequency of metabolic abnormalities was higher than that of Abeta pathology in the younger cohort, suggesting that neuronal dysfunction may precede major aggregated Abeta burden in young NL FH+. Longitudinal follow-up is required to determine if the observed abnormalities predict future AD. PMID- 25530916 TI - Obesity Prevention for Children with Developmental Disabilities. AB - The prevention of obesity in children with DD is a pressing public health issue, with implications for health status, independent living, and quality of life. Substantial evidence suggests that children with developmental disabilities (DD), including those with intellectual disabilities (ID) and autism spectrum disorder (ASD), have a prevalence of obesity at least as high if not higher than their typically developing peers. The paper reviews what is known about the classic and unique risk factors for childhood obesity in these groups of children, including dietary, physical activity, sedentary behavior, and family factors, as well as medication use. We use evidence from the literature to make the case that primary prevention at the individual/family, school and community levels will require tailoring of strategies and adapting existing intervention approaches. PMID- 25530918 TI - Role of Shiga/Vero toxins in pathogenesis. AB - Shiga toxin (Stx) is the primary cause of severe host responses including renal and central nervous system (CNS) disease in Shiga toxin-producing E. coli (STEC) infections. The interaction of Stx with different eukaryotic cell types is described. Host responses to Stx and bacterial lipopolysaccharide (LPS) are compared as related to the features of the STEC-associated Hemolytic Uremic Syndrome (HUS). Data derived from animal models of HUS and CNS disease, in vivo, and eukaryotic cells, in vitro, are evaluated in relation to HUS disease of humans. PMID- 25530920 TI - Toxoplasmosis, Pancreatitis, Obesity and Drug Discovery. AB - Toxoplasmosis, an infectious and inflammatory syndrome, is one of the most important foodborne diseases causing hospitalization and death in U.S.A. Toxoplasma infects nucleated cells including pancreatic and destroys the beta cells. Toxoplasma is a Category B classified infection by CDC and NIH, which once infected the organisms reside in tissues in cysts form for the host's lifelong awaiting reactivation. Congenital toxoplasmosis occurs by transplacental transmission during maternal infection or reactivation of organisms and manifests with spontaneous abortion, or severe physical and mental defects. Currently, there is no safe and effective therapeutic modality against congenital toxoplasmosis or the persistent chronic infection. Here, toxoplasmosis and possible involvement of infection in induction of pancreatitis, and an experimental drug efficacy is discussed. PMID- 25530917 TI - Shiga Toxin (Stx) Classification, Structure, and Function. AB - Shiga toxin (Stx) is one of the most potent bacterial toxins known. Stx is found in Shigella dysenteriae 1 and in some serogroups of Escherichia coli (called Stx1 in E. coli). In addition to or instead of Stx1, some E. coli strains produce a second type of Stx, Stx2, that has the same mode of action as Stx/Stx1 but is antigenically distinct. Because subtypes of each toxin have been identified, the prototype toxin for each group is now designated Stx1a or Stx2a. The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits. The A subunit of the toxin injures the eukaryotic ribosome and halts protein synthesis in target cells. The function of the B pentamer is to bind to the cellular receptor, globotriaosylceramide, Gb3, found primarily on endothelial cells. The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum. In humans infected with Stx-producing E. coli, the most serious manifestation of the disease, hemolytic-uremic syndrome, is more often associated with strains that produce Stx2a rather than Stx1a, and that relative toxicity is replicated in mice and baboons. Stx1a and Stx2a also exhibit differences in cytotoxicity to various cell types, bind dissimilarly to receptor analogs or mimics, induce differential chemokine responses, and have several distinctive structural characteristics. PMID- 25530919 TI - Mechanisms of Pyrazinamide Action and Resistance. AB - PZA is a unique anti-tuberculosis drug that plays a key role in shortening the TB therapy. PZA kills non-replicating persisters that other TB drugs fail to kill, and thus making it an essential drug for inclusion in any drug combinations for treating drug susceptible and drug-resistant TB such as MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation and perhaps pantothenate /coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase involved in conversion of the prodrug PZA to the active form POA. Mutations in the drug target RpsA are also found in some PZA resistant strains. The recent finding that panD mutations are found in some PZA resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype based PZA susceptibility testing is not reliable due to false resistance, and sequencing of the pncA gene represents a more rapid, cost-effective and more reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a 'tipping point' that inspires new efforts at developing a new type of antibiotics or drugs that target non replicating persisters for improved treatment of not only TB but also other persistent bacterial infections. PMID- 25530921 TI - To Test or Not to Test: Barriers and Solutions to Testing African American College Students for HIV at a Historically Black College/University. AB - Young African Americans are disproportionately affected by sexually transmitted infections, including HIV. The purpose was to identify reasons that African American college students at a historically Black college/university (HBCU) identified as barriers to HIV testing, and how these barriers can be removed. Fifty-seven heterosexual-identified undergraduate students (ages 18-25) attending an HBCU in the southeastern US participated in a mixed method study. Latent content analytic techniques were used to code the transcripts for themes and categories, and representative quotations were used in the findings. Quantitative data indicates high levels of perceived knowledge about HIV transmission, low perception of risk and concern of contracting HIV, yet continued sexual risk behavior. Qualitative data indicates three main themes used to avoid testing and three themes to encourage testing. Students were forthcoming in discussing the themes around avoidance of HIV testing (being scared to know, preferring not to know, and lack of discussion about HIV) and encouraging testing (group testing, increasing basic knowledge, and showing the reality of HIV). It is important for college healthcare professionals, researchers, and officials to identify appropriate ways to encourage HIV testing, and promote testing as part of overall health. PMID- 25530922 TI - Gentle Massage Improves Disease- and Treatment-Related Symptoms in Patients with Acute Myelogenous Leukemia. AB - OBJECTIVE: Cancer treatment is reported to be stressful, and patients diagnosed with hematologic cancers often exhibit higher levels of anxiety and emotional distress than individuals with other malignancies. Management of these symptoms in patients with hematologic cancer presents significant challenges, as many of them are in and out of the hospital while undergoing high dose chemotherapy. Oncology patients use complementary modalities such as therapeutic massage in an attempt to alleviate disease and treatment-related symptoms, including anxiety and emotional distress. In the current study, the feasibility of a novel massage intervention delivered over the continuum of care, as well as assessment of the immediate and cumulative effects of massage, was examined in patients with acute myelogenous leukemia. METHODS: A mixed-methods, unmasked, prospective, randomized study was conducted with two groups: a usual care alone control group and a massage therapy intervention plus usual care group. RESULTS: Significant improvements in levels of stress and health-related quality of life were observed in the massage therapy group versus the usual care alone group, after adjusting for anxiety level, including both immediate and cumulative effects of massage. CONCLUSIONS: While the findings of the current study regarding acceptability, feasibility, and potential efficacy of therapeutic massage as a complementary health-enhancing intervention in patients diagnosed with acute myelogenous leukemia are very promising, the relatively small size of the study sample limits generalizability. PMID- 25530925 TI - Automated Cognitive Health Assessment Using Smart Home Monitoring of Complex Tasks. AB - One of the many services that intelligent systems can provide is the automated assessment of resident well-being. We hypothesize that the functional health of individuals, or ability of individuals to perform activities independently without assistance, can be estimated by tracking their activities using smart home technologies. In this paper, we introduce a machine learning-based method for assessing activity quality in smart homes. To validate our approach we quantify activity quality for 179 volunteer participants who performed a complex, interweaved set of activities in our smart home apartment. We observed a statistically significant correlation (r=0.79) between automated assessment of task quality and direct observation scores. Using machine learning techniques to predict the cognitive health of the participants based on task quality is accomplished with an AUC value of 0.64. We believe that this capability is an important step in understanding everyday functional health of individuals in their home environments. PMID- 25530923 TI - Implications of Mesenchymal Cells in Cancer Stem Cell Populations: Relevance to EMT. AB - The epithelial to mesenchymal transition (EMT) generates tumor cells having stem cell characteristics with phenotypes similar to cancer stem cells (CSCs). Evidence suggests CSCs are in an intermediate state of EMT expressing reduced levels of E-cadherin and exhibiting mesenchymal features including invasiveness associated with metastasis. These findings suggest mechanisms regulating EMT and stemness are closely integrated. Recent reports from multiple laboratories have identified novel mechanisms regulating EMT and stemness involving epigenetics, microenvironment, and dedifferentiation. Circulating tumor cells (CTCs) have also been shown to exhibit features of EMT, but it is unclear what fraction has CSCs properties. EMT characteristics of both CSCs and CTCs are associated with resistance to current clinical treatments, indicating therapies targeting the CSC in addition to the more differentiated tumor cells are required for durable responses. Thus, EMT characteristics of CTCs may prove useful biomarkers for effective therapies for many cancers. PMID- 25530924 TI - Factors Influencing Dating Experiences Among African American Emerging Adults. AB - This study examined sociocultural factors that impact dating and sexual experiences of heterosexual African American undergraduate college students attending a historically Black institution in the Southeastern United States. Specifically, mate availability and relationship involvement were analyzed to document students' experiences, and how these influences may be associated with sexual decision making and behavior. Data from nine focus groups (N = 57) were aggregated and four subthemes were identified: competition among women, acceptability of mates, high prevalence of casual relationships, and lowered expectations for commitment. Power dynamics emerged as a contributing factor to the types of relationship involvement, sexual decision-making, and behavior among participants. The importance of prevention programs focusing on situational and cultural variables is highlighted. Additionally, implications for professionals working with emerging adults to consider the impact of the gender ratio imbalance, and perceived power distributions on perceptions of dating relationships, and sexual decision making and behavior are addressed. PMID- 25530927 TI - Simulation-based process windows simultaneously considering two and three conflicting criteria in injection molding. AB - Process windows in injection molding are habitually built with only one performance measure in mind. In reality, a more realistic picture can be obtained when considering multiple performance measures at a time, especially in the presence of conflict. In this work, the construction of process windows for injection molding (IM) is undertaken considering two and three performance measures in conflict simultaneously. The best compromises between the criteria involved are identified through the direct application of the concept of Pareto dominance in multiple criteria optimization. The aim is to provide a formal and realistic strategy to set processing conditions in IM operations. The resulting optimization approach is easily implementable in MS Excel. The solutions are presented graphically to facilitate their use in manufacturing plants. PMID- 25530926 TI - Excipients of preservative-free latanoprost induced inflammatory response and cytotoxicity in immortalized human HCE-2 corneal epithelial cells. AB - Various preservative-free eye drop formulations for glaucoma treatment have been marketed intending to decrease ocular surface side effects and improve tolerability. However, preservative-free eye drops including different solubilizers to dissolve the antiglaucoma drugs may induce detrimental effects in the eye. In this study, we exposed human corneal epithelial cells (HCE-2) for 1, 6, 12, 24 and 48 hours to the first preservative-free (PF) tafluprost (Taflotan(r)), the recently-launched preservative-free (PF) latanoprost (Monoprost(r)), preservative benzalkonium chloride (BAK) and the excipient macrogolglycerol hydroxystearate 40 (MGHS40) using dilutions 0.1%, 0.3%, 1.0%, 3.0% and 10.0% of the original products. The cells also were exposed to undiluted PF tafluprost and PF latanoprost once a day for 9 days. Cellular morphology was examined by light microscopy and cell proliferation by Ki-67 fluorescent staining with cell viability being determined by erythrosine staining and the release of lactate dehydrogenase (LDH). Mitochondrial metabolic activity was evaluated with the colorimetric MTT assay. The secretion of interleukin 6 (IL-6) was measured with ELISA. HCE-2 cells displayed no significant morphological changes after PF tafluprost treatment, but PF latanoprost caused clear cell loss. Moreover, PF latanoprost, BAK and MGHS40 evoked cellular damage and inflammation with increasing concentrations and time. Furthermore, undiluted daily PF latanoprost application significantly increased LDH release and IL-6 secretion as compared to PF tafluprost. MGHS40 was observed to be associated with the toxicity of PF latanoprost. Excipients in ocular drops should receive more attention in the future, since they seem to trigger similar detrimental effects in cells as preservatives. PMID- 25530928 TI - SART-Type Half-Threshold Filtering Approach for CT Reconstruction. AB - The [Formula: see text] regularization problem has been widely used to solve the sparsity constrained problems. To enhance the sparsity constraint for better imaging performance, a promising direction is to use the [Formula: see text] norm (0 < p < 1) and solve the [Formula: see text] minimization problem. Very recently, Xu et al. developed an analytic solution for the [Formula: see text] regularization via an iterative thresholding operation, which is also referred to as half-threshold filtering. In this paper, we design a simultaneous algebraic reconstruction technique (SART)-type half-threshold filtering framework to solve the computed tomography (CT) reconstruction problem. In the medical imaging filed, the discrete gradient transform (DGT) is widely used to define the sparsity. However, the DGT is noninvertible and it cannot be applied to half threshold filtering for CT reconstruction. To demonstrate the utility of the proposed SART-type half-threshold filtering framework, an emphasis of this paper is to construct a pseudoinverse transforms for DGT. The proposed algorithms are evaluated with numerical and physical phantom data sets. Our results show that the SART-type half-threshold filtering algorithms have great potential to improve the reconstructed image quality from few and noisy projections. They are complementary to the counterparts of the state-of-the-art soft-threshold filtering and hard-threshold filtering. PMID- 25530929 TI - Towards Measuring Stress with Smartphones and Wearable Devices During Workday and Sleep. AB - Work should be a source of health, pride, and happiness, in the sense of enhancing motivation and strengthening personal development. Healthy and motivated employees perform better and remain loyal to the company for a longer time. But, when the person constantly experiences high workload over a longer period of time and is not able to recover, then work may lead to prolonged negative effects and might cause serious illnesses like chronic stress disease. In this work, we present a solution for assessing the stress experience of people, using features derived from smartphones and wearable chest belts. In particular, we use information from audio, physical activity, and communication data collected during workday and heart rate variability data collected at night during sleep to build multinomial logistic regression models. We evaluate our system in a real work environment and in daily-routine scenarios of 35 employees over a period of 4 months and apply the leave-one-day-out cross-validation method for each user individually to estimate the prediction accuracy. Using only smartphone features, we get an accuracy of 55 %, and using only heart rate variability features, we get an accuracy of 59 %. The combination of all features leads to a rate of 61 % for a three-stress level (low, moderate, and high perceived stress) classification problem. PMID- 25530930 TI - Structure-activity-relationship study of N-acyl-N-phenylpiperazines as potential inhibitors of the Excitatory Amino Acid Transporters (EAATs): improving the potency of a micromolar screening Hit is not truism. AB - The excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate from the synaptic cleft. To date, five subtypes EAAT1-5 have been identified for which selective inhibitors have been discovered for EAAT1 and EAAT2. By screening of a commercially available compound library consisting of 4,000 compounds, N-acyl-N-phenylpiperazine analog (+/-)- exo -1 was identified to be a non-selective inhibitor at EAAT1-3 displaying IC50 values in the mid-micromolar range (10 MUM, 40 MUM and 30 MUM at EAAT1, 2 and 3, respectively). Subsequently, we designed and synthesized a series of analogs to explore the structure-activity-relationship of this scaffold in the search for analogs characterized by increased inhibitory potency and/or EAAT subtype selectivity. Despite extensive efforts, all analogs of (+/-)- exo -1 proved to be either inactive or to have least 3-fold lower inhibitory potency than the lead, and furthermore none of the active analogs displayed selectivity for a particular subtype amongst the EAAT1-3. On the basis of our findings, we speculate that (+/-)- exo -1 binds to a recess (deepening) on the EAAT proteins than a well-defined pocket. PMID- 25530931 TI - Quantitative correlation between transcriptional levels of ER chaperone, peroximal protein and FVIII productivity in human Hek-293 cell line. AB - Hek-293 cell line presents good production platform for recombinant therapeutic proteins, however little is known about the components that contribute to the cellular control of recombinant protein production. In this study, we generated a Hek-293 producing recombinant factor VIII (FVIII) and we evaluated the immunoglobulin-binding protein (BiP) and phytanoil-CoA alpha-hydroxylase (PAHX) expression levels which are known for diminishing FVIII production. Our analyses showed that the recombinant cell population expresses 3.1 +/- 1.4 fold of BIP mRNA (P = 0.0054) and 97.8 +/- 0.5 fold of PAHX mRNA (P = 0.0016) compared to nontransduced cells. The amount of these proteins was inversely correlated to the secreted FVIII. In conclusion, BIP and PAHX expression are augmented in human cells producing FVIII and they antagonize the amount of therapeutic factor VIII in the cell culture. PMID- 25530932 TI - Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. AB - BACKGROUND: In a previous meta-analysis of randomized controlled trials comparing lithium with placebo as a long-term treatment in bipolar disorders, we observed a clear preventative effect for manic episodes; however, the effect was equivocal for depressive episodes. Since then, the evidence base has grown further. In this update, we furthermore present the data on efficacy of lithium in comparison to alternative drug treatments. In addition, we analyze the data comparing lithium with placebo and other treatments regarding drop-outs due to reasons other than a mood episode and completion of study (no mood episode and no drop-out to reasons other than a mood episode). METHODS: Randomized controlled trials (RCTs) were sought comparing lithium with placebo and lithium with an alternative treatment in bipolar disorders where the stated intent of treatment was prevention of mood episodes. To this purpose, the Cochrane Central Register of Controlled Trials (CENTRAL) was searched. Reference lists of relevant papers and major textbooks of mood disorders were examined. Authors, other experts in the field, and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. RESULTS: For the comparison of lithium with placebo, seven trials (1,580 participants) were included. Lithium was more effective than placebo in preventing overall mood episodes (random effects RR 0.66, 95% CI 0.53 to 0.82), manic episodes (random effects RR 0.52, 95% CI 0.38 to 0.71), and, dependent on the type of analyses applied, depressive episodes (random effects RR 0.78, 95% CI 0.59 to 1.03; fixed effect RR 0.73, 95% CI 0.60 to 0.88). Lithium was inferior to placebo in leading to drop-outs for reasons other than a mood episode (random effects RR 1.33, 95% CI 1.07 to 1.65) but superior to placebo on study completion (random effects RR 1.69, 95% CI 1.12 to 2.55). For the comparison of lithium with anticonvulsants, seven trials were included (n = 1,305). In prevention of manic episodes, lithium showed superiority compared to anticonvulsants (random effects RR 0.66, 95% CI 0.44 to 1.00). However, there was no significant difference regarding prevention of overall mood episodes, depressive episodes, dropping-out to reasons other than a mood episode, or study completion. CONCLUSIONS: The evidence base for lithium in the long-term treatment of bipolar disorders has strengthened. With no other drug available having such ample and consistent evidence for its efficacy lithium remains the most valuable treatment option in this indication. PMID- 25530933 TI - A cluster randomized trial of utilizing a local change team approach to improve the delivery of HIV services in correctional settings: study protocol. AB - BACKGROUND: Persons held in correctional facilities are at high risk for HIV infection and their prevalence of HIV is substantially higher than in the general population. Thus, the need for proper surveillance and care of this high risk population is a paramount public health issue. This study aims to evaluate an organization-level intervention strategy for improving HIV services for persons in prison or jail. METHODS/DESIGN: HIV Services and Treatment Implementation in Corrections (HIV-STIC) is using a cluster randomized trial design to test an organization-level intervention designed to implement improvements in preventing, detecting, and treating HIV for persons under correctional supervision. Matched pairs of prison or jail facilities were randomized using a SAS algorithm. Facility staff members in both Experimental and Control conditions involved in HIV service delivery are recruited to receive training on HIV infection, the HIV services continuum, and relevant web-based resources. Staff members in both conditions are tasked to implement improvements in HIV prevention, testing, or treatment in their facility. In the Control condition facilities, staff participants use existing techniques for implementing improvement in a selected area of HIV services. In contrast, the Experimental condition staff participants work as a Local Change Team (LCT) with external coaching and use a structured process improvement approach to improve a selected part of the HIV services continuum. The intervention period is 10 months during which data are obtained using survey instruments administered to staff members and aggregate services delivery data. The study is being implemented in 13 pairs of correctional facilities across nine states in the US. Experimental sites are hypothesized to show improvements in both staff attitudes toward HIV services and the number and quality of HIV services provided for inmates. DISCUSSION: The current study examines a range of process and outcome data relevant to the implementation of a Change Team approach across diverse correctional settings in the United States. This initial study represents an important step toward a national best practices approach to implementing change in U.S. correctional settings and could serve as an exemplar for designing similar implementation studies. PMID- 25530934 TI - Does gender matter? Exploring mental health recovery court legal and health outcomes. AB - BACKGROUND: Based upon therapeutic justice principles, mental health courts use legal leverage to improve access and compliance to treatment for defendants who are mentally ill. Justice-involved women have a higher prevalence of mental illness than men, and it plays a greater role in their criminal behavior. Despite this, studies examining whether women respond differently than men to mental health courts are lacking. Study goals were to examine gender-related differences in mental health court participation, and in criminal justice, psychiatric and health-related outcomes. METHODS: This study utilized a quasi-experimental pre posttest design without a control group. The data were abstracted from administrative records of Kalamazoo Community Mental Health and Substance Abuse agency, the county jail and both county hospitals, 2008 through 2011. Generalized estimating equation regression was used to assess gender-differences in pre-post program outcomes (jail days, psychiatric and medical hospitalization days, emergency department visits) for the 30 women and 63 men with a final mental health court disposition. RESULTS: Program-eligible females were more likely than males to become enrolled in mental health court. Otherwise they were similar on all measured program-participation characteristics: treatment compliance, WRAP participation and graduation rate. All participants showed significant reductions in emergency department visits, but women-completers had significantly steeper drops than males: from 6.7 emergency department visits to 1.3 for women, and from 4.1 to 2.4 for men. A similar gender pattern emerged with medical-hospitalization days: from 2.2 medical hospital days down to 0.1 for women, and from 0.9 days up to 1.8 for men. While women had fewer psychiatric hospitalization days than men regardless of program involvement (2.5 and 4.6, respectively), both genders experienced fewer days after MHRC compared to before. Women and men showed equal gains from successful program completion in reduced jail days. CONCLUSIONS: Despite similar participation characteristics, findings point to greater health gains by female compared to male participants, and to lower overall psychiatric acuity. Mental-health-court participation was associated with decreased psychiatric hospitalization days and emergency department visits. Successful program completion correlated to fewer jail days for both women and men. PMID- 25530935 TI - Behavioral Interventions for Individuals Dually-Diagnosed with a Severe Mental Illness and a Substance Use Disorder. AB - The prevalence of substance abuse among severely mentally ill individuals (SMI) with a schizophrenia-spectrum or bipolar disorder is about three times the rate of the general population. However, few effective interventions exist to address the problem. In this paper, we evaluate recent studies of behavioral interventions for substance abuse among SMI individuals. These include cognitive behavioral, motivational interviewing, and contingency management interventions, as well as combinations thereof. Consistent with prior systematic reviews, ours indicates that no behavioral intervention has clearly demonstrated efficacy beyond that of usual care. Unfortunately, most of the reviewed studies suffer from methodological problems that hamper detection of treatment effects. Also, it can be argued that interventions tested thus far may not be well-suited for this cognitively-impaired population. A programmatic series of studies is needed to further develop and test behavioral interventions for treating substance abuse in this population. PMID- 25530936 TI - Standardizing MELD Exceptions: Current Challenges and Future Directions. AB - Since MELD-based allocation was implemented in 2002, a system of exception points has been in place in order to award increased waitlist priority to those patients whose severity of illness or risk of complications are not captured by the MELD score. These exceptions, categorized as standardized and non-standardized, have been used with increasing frequency over time. Several challenges to the exception point system have emerged, including lack of standardization in the criteria used to approve such exceptions, geographic variability in the use and approval of such exceptions, and limited evidence base to support certain exceptions. Herein, we summarize the current implementation of exception points, the challenges facing the transplant community, and suggestions for improving and standardizing the current exception point system. PMID- 25530938 TI - Oral Health Knowledge and Dental Visits in Community Living Older Adults in Rural Appalachia-West Virginia: A Cross-Sectional Analysis. AB - INTRODUCTION: The purpose of this study was to investigate the relationship between oral health knowledge and dental visits of older adults in an Appalachian county. METHODS: A cross-sectional study design was used. Surveys were returned from 205 older adults (50 years and above) from an Appalachian county. Questions were asked about oral health, last dental visit and sociodemographics. RESULTS: The variable of interest, oral health knowledge, was associated with dental visit. Having low oral health knowledge increased odds of having delayed a dental visit beyond a year (unadjusted odds ratio: 2.99; 95% Confidence interval: 1.70, 5.28). Even after considering the number of existing teeth, and controlling for age, sex, education and smoking, the association remained positive and independently significant (adjusted odds ratio: 2.25; 95% Confidence interval: 1.05, 4.82). Education was the only sociodemographic variable associated with last dental visit. CONCLUSION: The surveyed older adults have a need for increasing dental visits within the previous year. Increasing dental knowledge was associated with odds of increased dental visits. Improving dental knowledge may be a strategy to improve the number of older adults having a dental visit within the year. PMID- 25530937 TI - Developmental Exposure to Polybrominated Diphenyl Ethers and Neurodevelopment. AB - Exposure to polybrominated diphenyl ethers (PBDE) during sensitive developmental windows can interfere with cognitive function and behavior, which are critical components of neurodevelopment. The association between developmental exposure to PBDEs and neurodevelopment has been extensively studied using animal models. In this review, we focus on the accumulating evidence in humans. Despite methodological, geographical, and temporal differences between studies, the majority of the epidemiologic evidence supports that early life exposure to PBDEs measured during pregnancy and/or during childhood is detrimental to child neurodevelopment in domains related to child behavior, cognition, and motor skills. While the precise mechanism of action of PBDEs on neurodevelopment is unknown, PBDE-induced neurotoxicity via thyroid hormone disruption and direct action of PBDEs on the developing brain have been proposed and tested. Additional studies are suggested to better understand how early life and/or childhood PBDE exposures, including exposure to specific PBDE congeners, impact neurodevelopmental indices. PMID- 25530940 TI - Adverse events Following Computed Tomographic Colonography compared to Optical Colonoscopy in the Elderly. AB - OBJECTIVE: To evaluate gastrointestinal and cardiovascular adverse event risks associated with optical colonoscopy (OC) among Medicare outpatients who received computed tomography colonography (CTC) as their initial method of colorectal evaluation. METHODS: Medicare claims were compared between 6,114 outpatients >= 66 years who received initial CTC and 149,202 outpatients who received initial OC between January 2007 and December 2008. OC patients were matched on county of residence and year of evaluation. Outcomes included lower gastrointestinal bleeding, gastrointestinal perforation, other gastrointestinal events and cardiovascular events resulting in an emergency department visit or hospitalization within 30 days. RESULTS: Among 1,000 outpatients undergoing initial CTC, 12.4 experienced lower gastrointestinal bleeding, 0.7 perforation, 18.0 other gastrointestinal events and 45.5 cardiovascular events within 30 days. After multivariate adjustment, risks of lower gastrointestinal bleeding, other gastrointestinal events and cardiovascular events were higher with initial OC than CTC, with or without subsequent OC (OR 1.91 95CI [1.47,2.49], OR 1.35 95CI [1.07,1.69] and OR 1.38 95CI [1.18,1.62], respectively); however, perforation risk did not differ (p=0.10). This pattern is similar in older and symptomatic populations. CONCLUSION: Rates of gastrointestinal bleeding, other gastrointestinal events and cardiovascular events are lower following initial CTC than OC, but rates of perforation do not differ. PMID- 25530939 TI - Potentiated gene regulation by methylphenidate plus fluoxetine treatment: Long term gene blunting (Zif268, Homer1a) and behavioral correlates. AB - Use of psychostimulants such as methylphenidate (Ritalin) in medical treatments and as cognitive enhancers in the healthy is increasing. Methylphenidate produces some addiction-related gene regulation in animal models. Recent findings show that combining selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine with methylphenidate potentiates methylphenidate-induced gene regulation. We investigated the endurance of such abnormal gene regulation by assessing an established marker for altered gene regulation after drug treatments - blunting (repression) of immediate-early gene (IEG) inducibility - 14 days after repeated methylphenidate+fluoxetine treatment in adolescent rats. Thus, we measured the effects of a 6-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or their combination on the inducibility (by cocaine) of neuroplasticity-related IEGs (Zif268, Homer1a) in the striatum, by in situ hybridization histochemistry. Repeated methylphenidate treatment alone produced modest gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine given in conjunction with methylphenidate produced pronounced potentiation of methylphenidate-induced blunting for both genes. This potentiation was seen in many functional domains of the striatum, but was most robust in the lateral, sensorimotor striatum. These enduring molecular changes were associated with potentiated induction of behavioral stereotypies in an open field test. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs such as fluoxetine may increase the addiction liability of methylphenidate. Key words: cognitive enhancer, dopamine, serotonin, gene expression, psychostimulant, SSRI antidepressant, striatum. PMID- 25530941 TI - Regional Disparities in Adult Height, Educational Attainment and Gender Difference in Late- Life Cognition: Findings from the Longitudinal Aging Study in India (LASI). AB - State policies over time in India may have led to significant differences by sex in population health and cognition. In this paper, we use data from the pilot wave of the Longitudinal Aging Study in India, conducted in Karnataka, Kerala, Punjab, and Rajasthan, to examine state variations in health, educational attainment, and male preference, and how these variations contribute to gender differences in late-life cognition in India. We find men and women born in Punjab are taller than those elsewhere, but do not find any gender differences in height across states with differential male preference. We do find a significant gap in educational attainment that correlates with male preference. We find paternal education benefits both sons and daughters, while maternal education contributes to daughters' educational attainment. Finally, we find that paternal education benefits daughters' late-life cognition, while maternal education benefits sons' late-life cognition, and that children's education has positive association with older adults' cognitive functioning as well. PMID- 25530942 TI - Gender Differences in Cognition in China and Reasons for Change over Time: Evidence from CHARLS. AB - In this paper, we model gender differences in cognitive ability in China using a new sample of middle-aged and older Chinese respondents. Modeled after the American Health and Retirement Survey (HRS), CHARLS respondents are 45 years and older and are nationally representative of the Chinese population in this age span. Our measures of cognition in CHARLS rely on two measures that proxy for different dimensions of adult cognition-episodic memory and intact mental status. We relate these cognitive measures to adult health and SES outcomes during the adult years. We find large cognitive differences to the detriment of women that were mitigated by large gender differences in education among these generations of Chinese people. These gender differences in cognition are especially concentrated in the older age groups and poorer communities within the sample. We also investigated historical, geographical, and cultural characteristics of communities to understand how they impact cognition. Economic development and environmental improvement such as having electricity, increases in wage per capita and green coverage ratio generally contribute to higher cognition ability. Women benefit more from the fruits of development -electricity and growth of green coverage ratio are conducive to lessening female disadvantage in cognition. PMID- 25530943 TI - The enigmatic reception of DEET - the gold standard of insect repellents. AB - Repellents are important prophylactic tools for travelers and populations living in endemic areas of malaria, dengue, encephalitis, and other vector-borne diseases. DEET is a safe, broad spectrum repellent, which provides complete protection over a long period of time. Despite its low cost, more affordable alternatives are highly desirable, particularly for those in endemic areas where cost is an impediment. Alternative compounds like IR 3535 and picaridin have been developed using molecular modeling, but the lack of knowledge of the molecular target(s) for DEET has retarded progress towards low cost alternatives. It is known that DEET acts at a distance as an odorant as well as by direct contact, i.e., as a tastant, although DEET reception is primarily mediated by the olfactory system. There is unambiguous evidence that olfactory receptor neurons are involved, and that an odorant receptor co-receptor Orco is essential for DEET reception. In the southern house mosquito, Culex quinquefasciatus, DEET triggers repellence by direct activation of an odorant receptor, CquiOR136, which is also sensitive to a plant defense compound, methyl jasmonate. PMID- 25530944 TI - Full genome sequence analysis of a novel adenovirus of rhesus macaque origin indicates a new simian adenovirus type and species. AB - Multiple novel simian adenoviruses have been isolated over the past years and their potential to cross the species barrier and infect the human population is an ever present threat. Here we describe the isolation and full genome sequencing of a novel simian adenovirus (SAdV) isolated from the urine of two independent, never co-housed, late stage simian immunodeficiency virus (SIV)-infected rhesus macaques. The viral genome sequences revealed a novel type with a unique genome length, GC content, E3 region and DNA polymerase amino acid sequence that is sufficiently distinct from all currently known human- or simian adenovirus species to warrant classifying these isolates as a novel species of simian adenovirus. This new species, termed Simian mastadenovirus D (SAdV-D), displays the standard genome organization for the genus Mastadenovirus containing only one copy of the fiber gene which sets it apart from the old world monkey adenovirus species HAdV-G, SAdV-B and SAdV-C. PMID- 25530945 TI - Piperlongumine induces pancreatic cancer cell death by enhancing reactive oxygen species and DNA damage. AB - Pancreatic cancer is one of the most deadly cancers with a nearly 95% mortality rate. The poor response of pancreatic cancer to currently available therapies and the extremely low survival rate of pancreatic cancer patients point to a critical need for alternative therapeutic strategies. The use of reactive oxygen species (ROS)-inducing agents has emerged as an innovative and effective strategy to treat various cancers. In this study, we investigated the potential of a known ROS inducer, piperlongumine (PPLGM), a bioactive agent found in long peppers, to induce pancreatic cancer cell death in cell culture and animal models. We found that PPLGM inhibited the growth of pancreatic cancer cell cultures by elevating ROS levels and causing DNA damage. PPLGM-induced DNA damage and pancreatic cancer cell death was reversed by treating the cells with an exogenous antioxidant. Similar to the in vitro studies, PPLGM caused a reduction in tumor growth in a xenograft mouse model of human pancreatic cancer. Tumors from the PPLGM-treated animals showed decreased Ki-67 and increased 8-OHdG expression, suggesting PPLGM inhibited tumor cell proliferation and enhanced oxidative stress. Taken together, our results show that PPLGM is an effective inhibitor for in vitro and in vivo growth of pancreatic cancer cells, and that it works through a ROS-mediated DNA damage pathway. These findings suggest that PPLGM has the potential to be used for treatment of pancreatic cancer. PMID- 25530946 TI - Sustained expression of CYPs and DNA adduct accumulation with continuous exposure to PCB126 and PCB153 through a new delivery method: Polymeric implants. AB - A new delivery method via polymeric implants was used for continuous exposure to PCBs. Female Sprague-Dawley rats received subcutaneous polymeric implants containing PCB126 (0.15% load), PCB153 (5% load), or both, for up to 45 days and release kinetics and tissue distribution were measured. PCB153 tissue levels on day 15 were readily detected in lung, liver, mammary and serum, with highest levels in the mammary tissue. PCB126 was detected only in liver and mammary tissues. However, a completely different pharmacokinetics was observed on co exposure of PCB153 and PCB126, with a 1.8-fold higher levels of PCB153 in the liver whereas a 1.7-fold lower levels in the mammary tissue. PCB126 and PCB153 caused an increase in expression of key PCB-inducible enzymes, CYP 1A1/2 and 2B1/2, respectively. Serum and liver activities of the antioxidant enzymes, PON1 and PON3, and AhR transcription were also significantly increased by PCB126. 32 P Postlabeling for polar and lipophilic DNA-adducts showed significant quantitative differences: PCB126 increased 8-oxodG, an oxidative DNA lesion, in liver and lung tissues. Adduct levels in the liver remained upregulated up to 45 days, while some lung DNA adducts declined. This is the first demonstration that continuous low-dose exposure to PCBs via implants can produce sustained tissue levels leading to the accumulation of DNA-adducts in target tissue and induction of indicator enzymes. Collectively, these data demonstrate that this exposure model is a promising tool for long-term exposure studies. PMID- 25530947 TI - The Impact of Moderate Intensity Physical Activity on Cardiac Structure and Performance in Older Sedentary Adults. AB - BACKGROUND: Sedentary aging leads to adverse changes in vascular function and cardiac performance. We published improvements in vascular function with moderate intensity physical activity (PA) in continuous bouts. Whether moderate intensity PA also impacts cardiac structure and cardiovascular performance of the aging left ventricle (LV) is unknown. METHODS: We recruited and analyzed results from 102 sedentary older adults ages >= 50 from a randomized controlled trial with 3 study groups: control (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase habitual physical activity (PA, group 3) for 12 weeks. Transthoracic echocardiograms were performed prior to and following the 12 week intervention period to assess cardiac morphology, left ventricular (LV) systolic performance, LV diastolic function, arterial and LV ventricular elastance. Step count and PA intensity/distribution were measured by pedometer and accelerometer. RESULTS: We found no significant changes in cardiac morphology. Further, we found no improvement in the aforementioned cardiac functional parameters. Comparing those who achieved the following benchmarks to those who did not showed no significant changes in cardiac structure or performance: 1)10,000 steps/day, 2) >= 30 minutes/day of moderate intensity physical activity, or 3) moderate intensity PA in bouts >= 10 minutes for >= 20 minutes/day. CONCLUSIONS: In sedentary older adults, increasing moderate intensity PA to currently recommend levels does not result in favorable changes in LV morphology or performance over 12 weeks. More prolonged exposure, higher PA intensity, or earlier initiation of PA may be necessary to see benefits. PMID- 25530948 TI - POSITIVE AND NEGATIVE SUBCLINICAL SYMPTOMS AND MCCB PERFORMANCE IN NON PSYCHIATRIC CONTROLS. AB - Considerable data support the phenomenological and temporal continuity between subclinical psychosis and psychotic disorders. In recent years, neurocognitive deficits have increasingly been recognized as a core feature of psychotic illness but there are few data seeking to elucidate the relationship between subclinical psychosis and neurocogntive deficits in non-clinical samples. The goal of the present study was to examine the relationship between subclinical positive and negative symptoms, as measured by the Community Assessment of Psychic Experiences (CAPE) and performance on the MATRICS Consensus Cognitive Battery (MCCB) in a large (n=303) and demographically diverse non-clinical sample. We found that compared to participants with low levels of subclinical positive symptoms, participants with high levels of subclinical positive symptoms performed significantly better in the domains of working memory (p<.001), verbal learning (p=.007) and visual learning (p=.014). Although comparison of participants with high and low levels of subclinical negative symptoms revealed no differences in MCCB performance, we found that individuals with high levels of subclinical negative symptoms performed significantly better on a measure of estimated IQ (WRAT-3 Reading subtest; p=.02) than those with low levels of subclinical negative symptoms. These results are at odds with prior reports that have generally shown a negative relationship between neurocognitive functioning and severity of subclinical psychotic symptoms, and suggest some potential discontinuities between clinically significant psychotic symptoms and sub syndromal manifestations of psychosis. PMID- 25530949 TI - Optimized DPPH assay in a detergent-based buffer system for measuring antioxidant activity of proteins. AB - The 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) assay is well established for the in vitro determination of antioxidant activity in food and biological extracts. The standard DPPH assay uses methanol or ethanol as solvents, or buffered alcoholic solutions in a ratio of 40%/60% (buffer/alcohol, v/v) to keep the hydrophobic hydrazyl radical and phenolic test compounds soluble while offering sufficient buffering capacity at different pHs tested. Following this protocol, we were unable to keep proteinaceous antioxidants soluble at different pHs to test for their antioxidant activity. Thus, the assay protocol was modified as follows to improve its utility: Non-ionic detergents were added to keep the DPPH radical soluble and to provide a mild and non-denaturing environment for the antioxidant protein.Maximal concentration of DPPH was limited to 100 MUM to stay within the sensitivity range of the detector at the given wavelength (515 nm) and to increase the dynamic range of the assay.0.1 M citrate phosphate buffer was introduced to prevent experimental artifacts due to changing buffer compositions at different pHs. PMID- 25530950 TI - Computational methods and opportunities for phosphorylation network medicine. AB - Protein phosphorylation, one of the most ubiquitous post-translational modifications (PTM) of proteins, is known to play an essential role in cell signaling and regulation. With the increasing understanding of the complexity and redundancy of cell signaling, there is a growing recognition that targeting the entire network or system could be a necessary and advantageous strategy for treating cancer. Protein kinases, the proteins that add a phosphate group to the substrate proteins during phosphorylation events, have become one of the largest groups of 'druggable' targets in cancer therapeutics in recent years. Kinase inhibitors are being regularly used in clinics for cancer treatment. This therapeutic paradigm shift in cancer research is partly due to the generation and availability of high-dimensional proteomics data. Generation of this data, in turn, is enabled by increased use of mass-spectrometry (MS)-based or other high throughput proteomics platforms as well as companion public databases and computational tools. This review briefly summarizes the current state and progress on phosphoproteomics identification, quantification, and platform related characteristics. We review existing database resources, computational tools, methods for phosphorylation network inference, and ultimately demonstrate the connection to therapeutics. Finally, many research opportunities exist for bioinformaticians or biostatisticians based on developments and limitations of the current and emerging technologies. PMID- 25530951 TI - Growing burden of diabetes in Pakistan and the possible role of arsenic and pesticides. AB - This review is undertaken to address the possible role of arsenic and pesticides in the prevalence of diabetes in Pakistan and to highlight a resourceful targeted research in this area. A bibliographic search of scientific databases was conducted with key words of "epidemics of diabetes in Pakistan", "diabetes in Asia", "diabetes mellitus and environmental pollutants", "diabetes mellitus and heavy metals", "diabetes mellitus and pesticides", "prevalence of pesticides in Pakistan", and "heavy metals contamination of drinking water, "vegetables and fruits in Pakistan". More than 200 articles were examined. Studies reporting the prevalence of diabetes mellitus (DM), pesticides and heavy metal contamination of drinking water, fruits and vegetables were included in the study. According to WHO 2011 report, about 12.9 million people are suffering from DM and the number is constantly increasing. Water pollution is a major public health threat in Pakistan. Most of the people in Pakistan are exposed to arsenic and pesticides either in drinking water or through vegetables, fruits, and other edible items with various concentrations above the WHO/FAO permissible limits. Being an agricultural country, a 1169% increase has been recorded with the use of different types of pesticides since last two decades, and almost similar rise in the burden of diabetes. There is a growing global concern of arsenic and pesticides exposure with the incidence of DM. Besides other factors, the environmental attributors in the incidence of DM in Pakistan have not been conclusively elucidated yet which in turn deserve a resourceful targeted research. PMID- 25530952 TI - A cross-sectional assessment to detect type 2 diabetes with endothelial and autonomic nervous system markers using a novel system. AB - BACKGROUND: Type 2 diabetes mellitus is frequently unrecognized until complications appear. Diabetic autonomic neuropathy is one of the early complications of type 2 diabetes mellitus, resulting in autonomic nervous system (ANS) dysfunction. The purpose of this study was to determine the validity of ANS function indicators to screen for type 2 diabetes mellitus, as measured by the TM Oxi and SudoPath system. METHODS: All enrolled participants completed a basic sociodemographic and medical history questionnaire including current medications. Healthy controls (n = 25) underwent a 2-hour oral glucose tolerance test (OGTT) to evaluate glucose, insulin, and insulin C-peptide. Patients with type 2 diabetes mellitus (n = 24) were assessed with fasting plasma glucose (FPG) and glycosylated hemoglobin. The TM-Oxi and SudoPath system evaluation was completed by all subjects. Data were analyzed using SPSS 22. Frequency and descriptive statistics were calculated on all variables. The criterion for statistical significance was alpha = 0.05. RESULTS: The twenty-five healthy controls had a mean age of 37.0 years. The twenty-four type 2 diabetes mellitus patients currently undergoing standard treatment had a mean age of 48.9 years. Based on the American Diabetes Association guidelines, we detected pre-diabetes in 4 subjects and diabetes in 1 subject, while all other subjects had normal FPG values. At 120 minutes, the correlations between the OGTT and cardiometabolic risk score (CMRS) were: r = 0.56 (p = 0.004) for glucose and r = 0.53 (p = 0.006) for insulin. At 120 minutes, the correlations between the OGTT and photoplethysmography index (PTGi) were: r = -0.56 (p = 0.003) for glucose and r = -0.41 (p = 0.04) for insulin. The CMRS, PTGi, and plethysmography total power index (PTGVLFi) differed significantly between the diabetes patients and healthy participants. The specificity and sensitivity for the CMRS, PTGi, and PTVLFi comparing the diabetes patients with healthy controls were high. CONCLUSION: The TM-Oxi and SudoPath system shows promise as a valid, convenient, and non-invasive screening method for type 2 diabetes mellitus. The ANS function and CMR indicators measured by this system may be useful in guiding diabetes and cardiovascular health screening, treatment, and monitoring. PMID- 25530953 TI - A Novel Study Paradigm for Long-term Prevention Trials in Alzheimer Disease: The Placebo Group Simulation Approach (PGSA): Application to MCI data from the NACC database. AB - INTRODUCTION: The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample. METHODS: Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB. RESULTS: The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score. CONCLUSION: An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration. PMID- 25530954 TI - Lipolytic potential of Aspergillus japonicus LAB01: production, partial purification, and characterisation of an extracellular lipase. AB - Lipolytic potential of Aspergillus japonicus LAB01 was investigated by describing the catalytic properties and stability of a secreted extracellular lipase. Enzyme production was considered high under room temperature after 4 days using sunflower oil and a combination of casein with sodium nitrate. Lipase was partially purified by 3.9-fold, resulting in a 44.2% yield using ammonium sulphate precipitation (60%) quantified with Superose 12 HR gel filtration chromatography. The activity of the enzyme was maximised at pH 8.5, and the enzyme demonstrated stability under alkaline conditions. The optimum temperature was found to be 45 degrees C, and the enzyme was stable for up to 100 minutes, with more than 80% of initial activity remaining after incubation at this temperature. Partially purified enzyme showed reasonable stability with triton X 100 and was activated in the presence of organic solvents (toluene, hexane, and methanol). Among the tested ions, only Cu(2+), Ni(2+), and Al(3+) showed inhibitory effects. Substrate specificity of the lipase was higher for C14 among various p-nitrophenyl esters assayed. The KM and V max values of the purified enzyme for p-nitrophenyl palmitate were 0.13 mM and 12.58 umol/(L.min), respectively. These features render a novel biocatalyst for industrial applications. PMID- 25530955 TI - Clinical outcome of bortezomib retreatment in patients with relapsed or refractory multiple myeloma. AB - This retrospective study investigated the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory multiple myeloma (MM). A total of 30 patients who relapsed or progressed after >=6 months since the last dose of their previous bortezomib therapy were included in this study. During the median 6 cycles (range: 2-12) of bortezomib retreatment, 10 (33.3%), 2 (6.7%), and 6 (20.0%) patients achieved complete response, very good partial response, and partial response, respectively. Grade 3 or 4 neutropenia (47.0%), thrombocytopenia (43.0%), anemia (10.0%), and peripheral sensory neuropathy (3.0%) were observed. The median time to progression, progression-free survival, and overall survival were 5.8 months (95% CI: 2.6-9.0), 5.5 months (95% CI: 4.2 6.8), and 13.4 months (95% CI: 6.1-20.7), respectively. Patients who received bortezomib retreatment >=12 months from initial last therapy had a 1-year OS rate of 65.8% (95% CI: 43.5-88.1) while patients receiving retreatment after 6-12 months interval had a 1-year OS rate of 41.7% (95% CI: 13.9-69.5) (P = 0.038). In conclusion, this study demonstrates that retreatment with bortezomib is an effective strategy for patients with MM who relapsed at a long interval after initial bortezomib therapy. PMID- 25530956 TI - Clinical significance of resistin expression in osteoarthritis: a meta-analysis. AB - BACKGROUND: The objective of this study was to conduct a systematic review of literature evaluating human resistin expression as a diagnostic factor in osteoarthritis development and to quantify the overall diagnostic effect. METHOD: Relevant studies were identified and evaluated for quality through multiple search strategies. Studies analyzing resistin expression in the development of OA were eligible for inclusion. Data from eligible studies were extracted and included into the meta-analysis using a random-effects model. RESULTS: Four case control studies consisting of a total of 375 OA patients and 214 controls as well as three sex-stratified analyses composed of 53 males and 104 females were incorporated into our meta-analysis. Our results revealed that resistin levels were significantly higher in male OA subjects and OA patients overall. Country stratified analysis yielded significantly different estimates in resistin levels between male OA subjects and female OA subjects in the Canadian subgroup but not among the French and USA subgroups. Based on the resistin levels in OA cases and controls, resistin levels were heightened in OA patients in the Dutch population. CONCLUSION: These results support the hypothesis that high expression of resistin represents a significant and reproducible marker of poor progression in OA patients, especially in males. PMID- 25530958 TI - A comparison between characterization and biological properties of Brazilian fresh and aged propolis. AB - OBJECTIVE: As propolis is a highly valued bee product, we aimed to verify the quality of aged propolis, investigating their phenolic and flavonoid composition, levels of toxic metals, radical scavenging and antimicrobial activities. MATERIAL AND METHODS: Samples of fresh and aged propolis of six different beekeepers, from the same geographical location, were investigated in terms of their phenolic and flavonoid composition and levels of Pb, Cd, and Cr, as well as radical scavenging and antimicrobial activities. RESULTS: The two groups of propolis had similar qualitative composition by HPLC-PDA and ESI(-)-MS. Fresh propolis and aged propolis show no differences when average values of extraction yield, flavonoids, EC50, or MIC were compared and both types of propolis showed good antimicrobial activity at low concentrations. Only levels of phenolic compounds were higher in fresh propolis. CONCLUSION: The propolis samples considered in this study, aged or fresh, had similar qualitative composition, although they were collected in different periods. Samples only differed in their levels of total phenolic content. Moreover, aged propolis conserves significant radical scavenging and antimicrobial properties. We suggest that aged propolis should not be discarded but explored for alternative applications. PMID- 25530957 TI - Somatostatin negatively regulates parasite burden and granulomatous responses in cysticercosis. AB - Cysticercosis is an infection of tissues with the larval cysts of the cestode, Taenia solium. While live parasites elicit little or no inflammation, dying parasites initiate a granulomatous reaction presenting as painful muscle nodules or seizures when cysts are located in the brain. We previously showed in the T. crassiceps murine model of cysticercosis that substance P (SP), a neuropeptide, was detected in early granulomas and was responsible for promoting granuloma formation, while somatostatin (SOM), another neuropeptide and immunomodulatory hormone, was detected in late granulomas; SOM's contribution to granuloma formation was not examined. In the current studies, we used somatostatin knockout (SOM(-/-)) mice to examine the hypothesis that SOM downmodulates granulomatous inflammation in cysticercosis, thereby promoting parasite growth. Our results demonstrated that parasite burden was reduced 5.9-fold in SOM(-/-) mice compared to WT mice (P < 0.05). This reduction in parasite burden in SOM(-/-) mice was accompanied by a 95% increase in size of their granulomas (P < 0.05), which contained a 1.5-fold increase in levels of IFN-gamma and a 26-fold decrease in levels of IL-1beta (P < 0.05 for both) compared to granulomas from WT mice. Thus, SOM regulates both parasite burden and granulomatous inflammation perhaps through modulating granuloma production of IFN-gamma and IL-1beta. PMID- 25530959 TI - Rapid and accurate detection of bacteriophage activity against Escherichia coli O157:H7 by propidium monoazide real-time PCR. AB - Conventional methods to determine the efficacy of bacteriophage (phage) for biocontrol of E. coli require several days, due to the need to culture bacteria. Furthermore, cell surface-attached phage particles may lyse bacterial cells during experiments, leading to an overestimation of phage activity. DNA-based real-time quantitative polymerase chain reaction (qPCR) is a fast, sensitive, and highly specific means of enumerating pathogens. However, qPCR may underestimate phage activity due to its inability to distinguish viable from nonviable cells. In this study, we evaluated the suitability of propidium monoazide (PMA), a microbial membrane-impermeable dye that inhibits amplification of extracellular DNA and DNA within dead or membrane-compromised cells as a means of using qPCR to identify only intact E. coli cells that survive phage exposure. Escherichia coli O157:H7 strain R508N and 4 phages (T5-like, T1-like, T4-like, and O1-like) were studied. Results compared PMA-qPCR and direct plating and confirmed that PMA could successfully inhibit amplification of DNA from compromised/damaged cells E. coli O157:H7. Compared to PMA-qPCR, direct plating overestimated (P < 0.01) phage efficacy as cell surface-attached phage particles lysed E. coli O157:H7 during the plating process. Treatment of samples with PMA in combination with qPCR can therefore be considered beneficial when assessing the efficacy of bacteriophage for biocontrol of E. coli O157:H7. PMID- 25530960 TI - Pathophysiology of spasticity: implications for neurorehabilitation. AB - Spasticity is the velocity-dependent increase in muscle tone due to the exaggeration of stretch reflex. It is only one of the several components of the upper motor neuron syndrome (UMNS). The central lesion causing the UMNS disrupts the balance of supraspinal inhibitory and excitatory inputs directed to the spinal cord, leading to a state of disinhibition of the stretch reflex. However, the delay between the acute neurological insult (trauma or stroke) and the appearance of spasticity argues against it simply being a release phenomenon and suggests some sort of plastic changes, occurring in the spinal cord and also in the brain. An important plastic change in the spinal cord could be the progressive reduction of postactivation depression due to limb immobilization. As well as hyperexcitable stretch reflexes, secondary soft tissue changes in the paretic limbs enhance muscle resistance to passive displacements. Therefore, in patients with UMNS, hypertonia can be divided into two components: hypertonia mediated by the stretch reflex, which corresponds to spasticity, and hypertonia due to soft tissue changes, which is often referred as nonreflex hypertonia or intrinsic hypertonia. Compelling evidences state that limb mobilisation in patients with UMNS is essential to prevent and treat both spasticity and intrinsic hypertonia. PMID- 25530961 TI - Effects of various antibiotics alone or in combination with doripenem against Klebsiella pneumoniae strains isolated in an intensive care unit. AB - Colistin, tigecycline, levofloxacin, tobramycin, and rifampin alone and in combination with doripenem were investigated for their in vitro activities and postantibiotic effects (PAEs) on Klebsiella pneumoniae. The in vitro activities of tested antibiotics in combination with doripenem were determined using a microbroth checkerboard technique. To determine the PAEs, K. pneumoniae strains in the logarithmic phase of growth were exposed for 1 h to antibiotics, alone and in combination. Recovery periods of test cultures were evaluated using viable counting after centrifugation. Colistin, tobramycin, and levofloxacin produced strong PAEs ranging from 2.71 to 4.23 h, from 1.31 to 3.82 h, and from 1.35 to 4.72, respectively, in a concentration-dependent manner. Tigecycline and rifampin displayed modest PAEs ranging from 1.18 h to 1.55 h and 0.92 to 1.19, respectively. Because it is a beta-lactam, PAEs were not exactly induced by doripenem (ranging from 0.10 to 0.18 h). In combination, doripenem scarcely changed the duration of PAE of each tested antibiotic alone. The findings of this study may have important implications for the timing of doses during K. pneumoniae therapy with tested antibiotics. PMID- 25530962 TI - Type 2C phosphatase 1 of Artemisia annua L. is a negative regulator of ABA signaling. AB - The phytohormone abscisic acid (ABA) plays an important role in plant development and environmental stress response. Additionally, ABA also regulates secondary metabolism such as artemisinin in the medicinal plant Artemisia annua L. Although an earlier study showed that ABA receptor, AaPYL9, plays a positive role in ABA induced artemisinin content improvement, many components in the ABA signaling pathway remain to be elucidated in Artemisia annua L. To get insight of the function of AaPYL9, we isolated and characterized an AaPYL9-interacting partner, AaPP2C1. The coding sequence of AaPP2C1 encodes a deduced protein of 464 amino acids, with all the features of plant type clade A PP2C. Transcriptional analysis showed that the expression level of AaPP2C1 is increased after ABA, salt, and drought treatments. Yeast two-hybrid and bimolecular fluorescence complementation assays (BiFC) showed that AaPYL9 interacted with AaPP2C1. The P89S, H116A substitution in AaPYL9 as well as G199D substitution or deletion of the third phosphorylation site-like motif in AaPP2C1 abolished this interaction. Furthermore, constitutive expression of AaPP2C1 conferred ABA insensitivity compared with the wild type. In summary, our data reveals that AaPP2C1 is an AaPYL9-interacting partner and involved in the negative modulation of the ABA signaling pathway in A. annua L. PMID- 25530963 TI - Application of design of experiment for polyox and xanthan gum coated floating pulsatile delivery of sumatriptan succinate in migraine treatment. AB - Migraine follows circadian rhythm in which headache is more painful at the awakening time. This needs administration of dosage form at night time to release drug after lag period when pain gets worse. Sumatriptan succinate is a drug of choice for migraine. Sumatriptan succinate has bitter taste, low oral bioavailability, and shorter half-life. Present work deals with application of design of experiment for polyox and xanthan gum in development of press coated floating pulsatile tablet. Floating pulsatile concept was applied to increase gastric residence of the dosage form. Burst release was achieved through immediate release tablet using crospovidone as superdisintegrant (10%). Pulse lag time was achieved using swellable polymer polyox WSR 205 and xanthan gum. 3(2) experimental design was applied. Optimized formulation was evaluated for physical characteristics and in-vitro and in-vivo study. From results, it can be concluded that optimized batch F8 containing polyox WSR205 (72.72%) and xanthan gum (27.27%) of total weight of polymer has shown floating lag time of 55 +/- 2 sec, drug content of 100.35 +/- 0.4%, hardness of 6 +/- 0.1 Kg/cm(2), and 98.69 +/- 2% drug release in pulse manner with lag time of 7 +/- 0.1 h. Optimized batch showed prolong gastric residence which was confirmed by in-vivo X-ray study. PMID- 25530964 TI - Detection of free-living amoebae using amoebal enrichment in a wastewater treatment plant of Gauteng Province, South Africa. AB - Free-living amoebae pose a potential health risk in water systems as they may be pathogenic and harbor potential pathogenic bacteria known as amoebae resistant bacteria. Free-living amoebae were observed in 150 (87.2%) of the environmental water samples. In particular, Acanthamoeba sp. was identified in 22 (12.8%) using amoebal enrichment and confirmed by molecular analysis. FLA were isolated in all 8 stages of the wastewater treatment plant using the amoebal enrichment technique. A total of 16 (9.3%) samples were positive for FLA from influent, 20 (11.6%) from bioreactor feed, 16 (9.3%) from anaerobic zone, 16 (9.3%) from anoxic zone, 32 (18.6%) from aerators, 16 (9.3%) from bioreactor effluent, 11 (6.4%) from bioreactor final effluent, and 45 (26.2%) from maturation pond. This study provides baseline information on the occurrence of amoebae in wastewater treatment plant. This has health implications on receiving water bodies as some FLA are pathogenic and are also involved in the transmission and dissemination of pathogenic bacteria. PMID- 25530965 TI - Prepubertal exposure to genistein alleviates di-(2-ethylhexyl) phthalate induced testicular oxidative stress in adult rats. AB - Di-(2-ethylhexyl) phthalate (DEHP) is the most widely used plastizer in the world and can suppress testosterone production via activation of oxidative stress. Genistein (GEN) is one of the isoflavones ingredients exhibiting weak estrogenic and potentially antioxidative effects. However, study on reproductive effects following prepubertal multiple endocrine disrupters exposure has been lacking. In this study, DEHP and GEN were administrated to prepubertal male Sprague-Dawley rats by gavage from postnatal day 22 (PND22) to PND35 with vehicle control, GEN at 50 mg/kg body weight (bw)/day (G), DEHP at 50, 150, 450 mg/kg bw/day (D50, D150, D450) and their mixture (G + D50, G + D150, G + D450). On PND90, general morphometry (body weight, AGD, organ weight, and organ coefficient), testicular redox state, and testicular histology were studied. Our results indicated that DEHP could significantly decrease sex organs weight, organ coefficient, and testicular antioxidative ability, which largely depended on the dose of DEHP. However, coadministration of GEN could partially alleviate DEHP-induced reproductive injuries via enhancement of testicular antioxidative enzymes activities, which indicates that GEN has protective effects on DEHP-induced male reproductive system damage after prepubertal exposure and GEN may have promising future in its curative antioxidative role for reproductive disorders caused by other environmental endocrine disruptors. PMID- 25530966 TI - Study on the relationship between manganese concentrations in rural drinking water and incidence and mortality caused by cancer in Huai'an city. AB - BACKGROUND: Cancer is a significant disease burden in the world. Many studies showed that heavy metals or their compounds had connection with cancer. But the data conflicting about the relationship of manganese (Mn) to cancer are not enough. In this paper, the relationship was discussed between Mn concentrations in drinking water for rural residents and incidence and mortality caused by malignant tumors in Huai'an city. METHODS: A total of 158 water samples from 28 villages of 14 towns were, respectively, collected during periods of high flow and low flow in 3 counties of Huai'an city, along Chinese Huai'he River. The samples of deep groundwater, shallow groundwater, and surface water were simultaneously collected in all selected villages. Mn concentrations in all water samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS 7500a). The correlation analysis was used to study the relationship between the Mn concentration and cancer incidence and mortality. RESULTS: Mn concentrations detectable rate was 100% in all water samples. The mean concentration was 452.32 MUg/L +/- 507.76 MUg/L. There was significant difference between the high flow period and low flow period (t = -5.23, P < 0.05) and also among deep groundwater, shallow groundwater, and surface water (F = 5.02, P < 0.05). The ratio of superscale of Mn was 75.32%. There was significant difference of Mn level between samples in the high flow period and low flow period (chi(2) = 45.62, P < 0.05) and also among deep groundwater, shallow groundwater, and surface water (chi(2) = 10.66, P < 0.05). And also we found that, during the low flow period, Mn concentration has positive correlation with cancer incidence and mortality; for a 1 MUg/L increase in Mn concentration, there was a corresponding increase of 0.45/100000 new cancer cases and 0.35/100000 cancer deaths (P < 0.05). CONCLUSIONS: In Huai'an city, the mean concentration of Mn in drinking water was very high. Mn concentration correlated with cancer incidence and mortality. PMID- 25530968 TI - Influence of orthotropy on biomechanics of peri-implant bone in complete mandible model with full dentition. AB - OBJECTIVE: The study was to investigate the impact of orthotropic material on the biomechanics of dental implant, based on a detailed mandible with high geometric and mechanical similarity. MATERIALS AND METHODS: Multiple data sources were used to elaborate detailed biological structures and implant CAD models. In addition, an extended orthotropic material assignment methodology based on harmonic fields was used to handle the alveolar ridge region to generate compatible orthotropic fields. The influence of orthotropic material was compared with the commonly used isotropic model and simplified orthotropic model. RESULTS: The simulation results showed that the values of stress and strain on the implant-bone interface almost increased in the orthotropic model compared to the isotropic case, especially for the cancellous bone. However, the local stress concentration was more obvious in the isotropic case compared to that in orthotropic case. The simple orthotropic model revealed irregular stress and strain distribution, compared to the isotropic model and the real orthotropic model. The influence of orthotropy was little on the implant, periodontal ligament, tooth enamel, and dentin. CONCLUSION: The orthotropic material has significant effect on stress and strain of implant-bone interface in the mandible, compared with the isotropic simulation. Real orthotropic mechanical properties of mandible should be emphasized in biomechanical studies of dental implants. PMID- 25530967 TI - Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders. AB - A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities. PMID- 25530969 TI - Genetic identification and risk factor analysis of asymptomatic bacterial colonization on cardiovascular implantable electronic devices. AB - Asymptomatic bacterial colonization of cardiovascular implantable electronic devices (CIEDs) is widespread and increases the risk of clinical CIED infection. The aim of the study was to evaluate the incidence of bacterial colonization of generator pockets in patients without signs of infection and to analyze the relationship with clinical infection and risk factors. From June 2011 to December 2012, 78 patients underwent CIED replacement or upgrade. Exclusion criteria included a clinical diagnosis of CIED infection, bacteremia, or infective endocarditis. All patients were examined for evidence of bacterial 16S rDNA on the device and in the surrounding tissues. Infection cases were recorded during follow-up. The bacterial-positive rate was 38.5% (30 cases); the coagulase negative Staphylococcus detection rate was the highest (9 cases, 11.5%). Positive bacterial DNA results were obtained from pocket tissue in 23.1% of patients (18 cases), and bacterial DNA was detected on the device in 29.5% of patients (23 cases). During follow-up (median 24.6 months), two patients (6.7%, 2/30) became symptomatic with the same species of microorganism, S. aureus and S. epidermidis. Multivariable logistic regression analysis found that the history of bacterial infection, use of antibiotics, application of antiplatelet drugs, replacement frequency, and renal insufficiency were independent risk factors for asymptomatic bacterial colonization. PMID- 25530970 TI - Comparison of the health implications on the use of As and Cd contaminated water supply between urban and rural communities. AB - A cross-sectional study was carried out to determine the arsenic (As) and cadmium (Cd) concentrations in blood, urine, and drinking water as well as the health implications on 100 residents in an urban and a rural community. Results showed the blood As, urinary Cd, DNA damage, and water As and Cs were significantly (P < 0.001) higher in the rural community. Findings showed significant (P < 0.005) correlations between blood As and DNA damage with household income, years of residence, and total glasses of daily water consumption among the rural residents. The urinary NAG concentrations, years of residence, milk powder intake (glass/week), and seafood intake (per week) were significantly correlated (P < 0.005) with urinary Cd concentrations among respondents. In addition, urinary Cd level significantly influenced the urinary NAG concentrations (P < 0.001). The rural respondents experienced significantly higher lymphocyte DNA damage and blood As influenced by their years of residence and water consumption. The Cd in drinking water also resulted in the rural respondents having significantly higher urinary NAG which had a significant relationship with urinary Cd. PMID- 25530971 TI - Prospect of stem cell conditioned medium in regenerative medicine. AB - BACKGROUND: Stem cell-derived conditioned medium has a promising prospect to be produced as pharmaceuticals for regenerative medicine. OBJECTIVE: To investigate various methods to obtain stem cell-derived conditioned medium (CM) to get an insight into their prospect of application in various diseases. METHODS: Systematic review using keywords "stem cell" and "conditioned medium" or "secretome" and "therapy." Data concerning treated conditions/diseases, type of cell that was cultured, medium and supplements to culture the cells, culture condition, CM processing, growth factors and other secretions that were analyzed, method of application, and outcome were noted, grouped, tabulated, and analyzed. RESULTS: Most of CM using studies showed good results. However, the various CM, even when they were derived from the same kind of cells, were produced by different condition, that is, from different passage, culture medium, and culture condition. The growth factor yields of the various types of cells were available in some studies, and the cell number that was needed to produce CM for one application could be computed. CONCLUSION: Various stem cell-derived conditioned media were tested on various diseases and mostly showed good results. However, standardized methods of production and validations of their use need to be conducted. PMID- 25530972 TI - Sex cord tumor with annular tubules: an incidental finding in an endometriotic cyst--the first known cooccurrence. AB - Sex cord tumor with annular tubules (SCTATs) is a relatively rare ovarian neoplasm often having a syndromic association with Peutz-Jeghers syndrome (PJS). Other associations described with this rare neoplasm include adenoma malignum of cervix, Turners syndrome, dysgerminoma, gonadoblastoma, endometrial carcinoma, and endometriosis of fallopian tube. We describe for the first time to the best of our literature search the incidental detection of SCTAT coexisting with an endometriotic cyst of ovary. Meticulous histological scanning and awareness is mandatory for detection of such unusual incidental lesions. Non-PJS SCTATs tend to be larger and could be more prone to distant metastasis, warranting subsequent follow-up. PMID- 25530973 TI - A clinically oriented introduction and review on finite element models of the human cochlea. AB - Due to the inaccessibility of the inner ear, direct in vivo information on cochlear mechanics is difficult to obtain. Mathematical modelling is a promising way to provide insight into the physiology and pathology of the cochlea. Finite element method (FEM) is one of the most popular discrete mathematical modelling techniques, mainly used in engineering that has been increasingly used to model the cochlea and its elements. The aim of this overview is to provide a brief introduction to the use of FEM in modelling and predicting the behavior of the cochlea in normal and pathological conditions. It will focus on methodological issues, modelling assumptions, simulation of clinical scenarios, and pathologies. PMID- 25530975 TI - Comment on "Impact of diabetic foot on selected psychological or social characteristics". PMID- 25530974 TI - The unfolded protein response and diabetic retinopathy. AB - Diabetic retinopathy, a common complication of diabetes, is the leading cause of blindness in adults. Diabetes chronically damages retinal blood vessels and neurons likely through multiple pathogenic pathways such as oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. To relieve ER stress, the cell activates an adaptive mechanism known as the unfolded protein response (UPR). The UPR coordinates the processes of protein synthesis, protein folding, and degradation to ensure proteostasis, which is vital for cell survival and activity. Emerging evidence suggests that diabetes can activate all three UPR branches in retinal cells, among which the PERK/ATF4 pathway is the most extensively studied in the development of diabetic retinopathy. X-box binding protein 1 (XBP1) is a major transcription factor in the core UPR pathway and also regulates a variety of genes involved in cellular metabolism, redox state, autophagy, inflammation, cell survival, and vascular function. The exact function and implication of XBP1 in the pathogenesis of diabetic retinopathy remain elusive. Focusing on this less studied pathway, we summarize recent progress in studies of the UPR pertaining to diabetic changes in retinal vasculature and neurons, highlighting the perspective of XBP1 as a potential therapeutic target in diabetic retinopathy. PMID- 25530976 TI - Comparative microRNA expression profiles of cynomolgus monkeys, rat, and human reveal that mir-182 is involved in T2D pathogenic processes. AB - Type 2 diabetes (T2D) is a prevalent disease that happens around the world and usually happens with insulin resistance. MicroRNAs (miRNAs) represented important roles in the suppression of gene expression and were proven to be related to human diseases. In this study, we used cynomolgus monkey fed with normal and high fatty diet (HFD), respectively, to analyze the miRNA expression profile in whole blood by deep sequencing. Finally in total 24 miRNAs with differential expression were filtered. Among them, miR-182 related to the insulin resistance by modulating FOXO1 and PI3K/AKT cascade and had the greatest copy number in the whole blood. Decrease of miR-182 in T2D cynomolgus individuals is completely consistent with the previous studies in human and rat. Integrating miR-182 tissue expression profile, target genes, and copy number in blood reveals that miR-182 plays a key role in crucial genes modulation, such as FOXO1 and BHLHE22, which leads to potential hyperglycemia and modulates the insulin secretion. In addition, miR-182 might regulate the processes of both cell proliferation and apoptosis that play crucial role in determining the cells' fate. Therefore, miR 182 can be a biomarker in diagnosis of the potential T2D that has benefits for medical purpose. PMID- 25530977 TI - Obstructive Sleep Apnea and Multiple Anthropometric Indices of General Obesity and Abdominal Obesity among Young Adults. AB - This study aimed to examine the association between obstructive sleep apnea (OSA) and obesity among young adults. A total of 2911 college students in Thailand participated in the study. Anthropometric measurements and blood pressure were taken by trained research staff. Overall, 6.3% of college students had OSA determined by the Berlin Questionnaire, 9.6% were overweight (BMI: 25-29 kg/m2), 4.5% were obese (BMI>=30 kg/m2); 12.4% had abdominal obesity (men: waist circumference>=90 cm; women: waist circumference>=80 cm). There were significant associations between OSA and overweight (odds ratio (OR)=1.72; 95% confidence interval (CI)=1.04-1.85) and obesity (OR=24.23; 95% CI=15.20-38.61), independent of demographic and lifestyle factors, blood pressure, and psychological distress. Students with OSA were more likely to have abdominal obesity than those without OSA (OR=2.09; 95% CI=1.19-3.67). OSA was significantly related to joint effects of general and abdominal obesity. The OSA-obesity associations were robust and evident for both genders, individuals with normal and elevated blood pressure, and those with and without psychological distress. This study shows independent associations of OSA with general and abdominal obesity among young adults. OSA could be a risk factor for obesity and consequent cardiovascular morbidities. OSA screening and treatment might be important for young adults. PMID- 25530978 TI - Synovial Fluid Lubricant Properties are Transiently Deficient after Arthroscopic Articular Cartilage Defect Repair with Platelet-Enriched Fibrin Alone and with Mesenchymal Stem Cells. AB - BACKGROUND: Following various types of naturally-occurring traumatic injury to an articular joint, the lubricating ability of synovial fluid is impaired, with a correlated alteration in the concentration and/or structure of lubricant molecules, hyaluronan and proteoglycan-4. However, the effect of arthroscopic cartilage repair surgery on synovial fluid lubricant function and composition is unknown. HYPOTHESIS: Arthroscopic treatment of full-thickness chondral defects in horses with (1) platelet-enriched fibrin or (2) platelet-enriched fibrin+mesenchymal stem cells leads to equine synovial fluid with impaired lubricant function and hyaluronan and proteoglycan-4 composition. STUDY DESIGN: Controlled Laboratory Study. METHODS: Equine synovial fluid was aspirated from normal joints at a pre-injury state (0 days) and at 10 days and 3 months following fibrin or fibrin+mesenchymal stem cell repair of full thickness chondral defects. Equine synovial fluid samples were analyzed for friction lowering boundary lubrication of normal articular cartilage (static and kinetic friction coefficients) and concentrations of hyaluronan and proteoglycan-4, as well as molecular weight distribution of hyaluronan. Experimental groups deficient in lubrication function were also tested for the ability of exogenous high-molecular weight hyaluronan to restore lubrication function. RESULTS: Lubrication and biochemical data varied with time after surgery but generally not between repair groups. Relative to pre-injury, kinetic friction was higher (+94%) at 10 days but returned to baseline levels at 3 months while static friction was not altered. Correspondingly, hyaluronan concentration was transiently lower ( 64%) and shifted towards lower molecular weight forms, while proteoglycan-4 concentration was increased (+210%) in 10-day samples relative to pre-injury levels. Regression analysis revealed that kinetic friction decreased with increasing total and high molecular weight hyaluronan. Addition of high molecular weight hyaluronan to bring 10-day hyaluronan levels to 2.0mg/ml restored kinetic friction to pre-injury levels. CONCLUSION: Following arthroscopic surgery for cartilage defect repair, synovial fluid lubrication function is transiently impaired, in association with decreased hyaluronan concentration. This functional deficiency in synovial fluid lubrication can be counteracted in vitro by addition of high molecular weight hyaluronan. CLINICAL RELEVANCE: Synovial fluid lubrication is deficient shortly following arthroscopic cartilage repair surgery, and supplementation with high molecular weight hyaluronan may be beneficial. PMID- 25530979 TI - A stepwise procedure to test contractility and susceptibility to injury for the rodent quadriceps muscle. AB - In patients with muscle injury or muscle disease, assessment of muscle damage is typically limited to clinical signs, such as tenderness, strength, range of motion, and more recently, imaging studies. Biological markers can also be used in measuring muscle injury, such as increased creatine kinase levels in the blood, but these are not always correlated with loss in muscle function (i.e. loss of force production). This is even true of histological findings from animals, which provide a "direct measure" of damage, but do not account for loss of function. The most comprehensive measure of the overall health of the muscle is contractile force. To date, animal models testing contractile force have been limited to the muscle groups moving the ankle. Here we describe an in vivo animal model for the quadriceps, with abilities to measure torque, produce a reliable muscle injury, and follow muscle recovery within the same animal over time. We also describe a second model used for direct measurement of force from an isolated quadriceps muscle in situ. PMID- 25530980 TI - COPING AS A MEDIATOR OF INTERNALIZED HOMOPHOBIA AND PSYCHOLOGICAL DISTRESS AMONG YOUNG ADULT SEXUAL MINORITY WOMEN. AB - Sexual minorities have higher rates of depression and anxiety than their heterosexual counterparts. This elevated risk of psychological distress has generally been hypothesized to be a result of the effects of discrimination including internalized negative beliefs about sexual minorities. However, little research has examined the role of various types of coping in mediating between internalized homophobia and mental health. We tested the direct relationship between internalized homophobia and psychological distress and evaluated general and sexual minority-specific coping strategies as potential mediators using structural equation modeling. Data are from a national sample of 1,099 young adult sexual minority women who were on average 20.86 (SD= 2.12) years old, participating in a study on mental health and substance use. The model demonstrated acceptable fit, chi2 (83) = 402.9, p <.001, CFI=.94, TLI=.92, SRMR= .07, and RMSEA=.06, accounting for 73% of variance in psychological distress. Greater use of maladaptive coping and less use of sexual minority-specific coping were associated with higher psychological distress. Although maladaptive coping mediated the relationship between internalized homophobia and psychological distress, sexual minority-specific coping did not. Our findings support previous studies that have demonstrated the impact of internalized homophobia on psychological distress as well as the role of coping as a protective/risk factor in this relationship. PMID- 25530981 TI - Trans-diagnostic Psychopathology Factors and Sexual Minority Mental Health: Evidence of Disparities and Associations with Minority Stressors. AB - Research on mental health disparities between sexual minority individuals and heterosexuals has traditionally taken a disorder-by-disorder approach. Recently developed trans-diagnostic approaches provide a new method to frame such investigations; however, trans-diagnostic factors have yet to be applied to sexual minority mental health disparities research. The current study applied this methodology to investigate mental health disparities between lesbian, gay, bisexual, and heterosexual individuals in a large national probability sample (N = 34,653). Twelve-month diagnoses of 13 common mood, anxiety, substance use, and personality disorders were modeled, and multi-group analysis indicated a sexual orientation-invariant trans-diagnostic latent structure. Significant disparities at the latent trans-diagnostic factor level were observed; these factor-level disparities are manifested as observed mental disorder disparities. Gender differences typically seen in trans-diagnostic research were not present between sexual minority women and men. Trans-diagnostic internalizing and externalizing factors were then used as outcomes in a minority stress framework and were positively predicted by lifetime history of sexual orientation-related minority stressors (i.e., discrimination and victimization). Implications for using trans diagnostic approaches to frame intervention efforts, supplement disorder-by disorder disparities methodologies, and synthesize piecemeal disparities literatures are discussed. PMID- 25530982 TI - Transmissive Nanohole Arrays for Massively-Parallel Optical Biosensing. AB - A high-throughput optical biosensing technique is proposed and demonstrated. This hybrid technique combines optical transmission of nanoholes with colorimetric silver staining. The size and spacing of the nanoholes are chosen so that individual nanoholes can be independently resolved in massive parallel using an ordinary transmission optical microscope, and, in place of determining a spectral shift, the brightness of each nanohole is recorded to greatly simplify the readout. Each nanohole then acts as an independent sensor, and the blocking of nanohole optical transmission by enzymatic silver staining defines the specific detection of a biological agent. Nearly 10000 nanoholes can be simultaneously monitored under the field of view of a typical microscope. As an initial proof of concept, biotinylated lysozyme (biotin-HEL) was used as a model analyte, giving a detection limit as low as 0.1 ng/mL. PMID- 25530983 TI - Oral health information for Appalachia-West Virginia children: a cross-sectional analysis. AB - INTRODUCTION: Time demands often impact the presentation of heath related educational material/information in rural dental practices. The purpose of this study was to determine if parents/guardians were receiving information with respect to a child's dental needs, and if there were a relationship between the delivery of the information and the utilization of dental servicesin Appalachia West Virginia. METHODS: A survey was presented to parents/guardians of Appalachia West Virginia children [n=62] regarding dental information provided by their dentist/dental hygienist. The data were analyzed with Chi-square, and logistic regression. RESULTS: Summative score of the questions on the survey (Adjusted odds ratio=6.2 [95% CI=1.1, 35.4]; p=0.057), and parental education (p=0.057) remained associated in a logistic regression with a child having had a dental visit within the previous year. CONCLUSIONS: Exposure of parents to dentally related educational material/information provided by a dentist/dental hygienist was independently associated with dental visits. The implication is that there remains a need for dental professionals to actively educate their patients. PMID- 25530984 TI - A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment. AB - Perturbations in the prenatal and early life environment can contribute to the development of offspring stress dysregulation, a pervasive symptom in neuropsychiatric disease. Interestingly, the vertical transmission of maternal microbes to offspring and the subsequent bacterial colonization of the neonatal gut overlap with a critical period of brain development. Therefore, environmental factors such as maternal stress that are able to alter microbial populations and their transmission can thereby shape offspring neurodevelopment. As the neonatal gastrointestinal tract is primarily inoculated at parturition through the ingestion of maternal vaginal microflora, disruption in the vaginal ecosystem may have important implications for offspring neurodevelopment and disease risk. Here, we discuss alterations that occur in the vaginal microbiome following maternal insult and the subsequent effects on bacterial assembly of the neonate gut, the production of neuromodulatory metabolites, and the developmental course of stress regulation. PMID- 25530985 TI - Synaptic rewiring of stress-sensitive neurons by early-life experience: a mechanism for resilience? AB - Genes and environment interact to influence cognitive and emotional functions throughout life. Early-life experiences in particular contribute to vulnerability or resilience to a number of emotional and cognitive illnesses in humans. In rodents, early-life experiences directly lead to resilience or vulnerability to stress later in life, and influence the development of cognitive and emotional deficits. The mechanisms for the enduring effects of early-life experiences on cognitive and emotional outcomes are not completely understood. Here, we present emerging information supporting experience-dependent modulation of the number and efficacy of synaptic inputs onto stress-sensitive neurons. This synaptic 'rewiring', in turn, may influence the expression of crucial neuronal genes. The persistent changes in gene expression in resilient versus vulnerable rodent models are likely maintained via epigenetic mechanisms. Thus, early-life experience may generate resilience by altering synaptic input to neurons, which informs them to modulate their epigenetic machinery. PMID- 25530987 TI - Understanding the HIV disparities between black and white men who have sex with men in the USA using the HIV care continuum: a modeling study. AB - BACKGROUND: Black/white disparities in HIV incidence and prevalence among men who have sex with men (MSM) in the United States remain largely unexplained. We examined the impact on HIV prevalence and incidence of interventions that decrease disparities in HIV care. Deciding which interventions have most impact on reducing disparities is critical. METHODS: Using available US Centers for Disease Control and Prevention (CDC) estimates, we constructed HIV care continua for black and white MSM for 2009-2010. These estimates were used as parameters in a deterministic model to yield estimated race-specific transmissions, transmission rates, incidence rates, and rate-ratios (RR). We examined the impact of changes in the care continuum for black MSM on transmission and incidence rates. FINDINGS: Marked disparities were found throughout the care continuum: ultimately, 16% of black and 34% of white MSM achieved viral suppression. Based on these care continua, 9,833 and 9,710 new HIV transmissions were estimated annually respectively from HIV-positive black and white MSM (transmission RR=1.36 and incidence RR=7.92). In a model where black and white MSM have identical care outcomes, transmission RR=1.00 and incidence RR=5.80. Scenarios of 95% diagnosis, 95% retention, and concurrent 95% diagnosis and 95% retention respectively yield transmission RR=1.00, 1.02, 0.56, and incidence RR=5.81, 5.93, 3.28. INTERPRETATION: Disparities in HIV transmission rates may be reduced by improving the HIV care continuum outcomes, but existing racial disparities in HIV prevalence will likely continue to drive higher incidence among black MSM for decades to come. PMID- 25530988 TI - Clinical course of light-chain smouldering multiple myeloma (idiopathic Bence Jones proteinuria): a retrospective cohort study. AB - BACKGROUND: Bence Jones proteinuria is a disorder that is defined by the excretion of monoclonal light-chain protein. About 15-20% of patients with multiple myeloma secrete monoclonal light chains only, without expression of the normal immunoglobulin heavy chain, which constitutes light-chain multiple myeloma. The definition, prevalence, and progression of these premalignant phases of light-chain multiple myeloma have not been fully characterised. We aimed to identify a subset of patients with idiopathic Bence Jones proteinuria who had a high risk of progression to light-chain multiple myeloma analogous to that seen in patients with smouldering multiple myeloma. METHODS: In this retrospective cohort study, we studied all patients seen at the Mayo Clinic (Rochester, MN, USA) within 30 days of diagnosis of idiopathic Bence Jones proteinuria between Jan 1, 1960, and June 30, 2004. Inclusion criteria were monoclonal light chain in the urine (>=0.2 g/24 h), absence of intact monoclonal immunoglobulin (M protein) in the serum, and no evidence of multiple myeloma, light-chain amyloidosis, or other related plasma-cell proliferative disorders. The primary endpoint was progression to symptomatic multiple myeloma or light-chain amyloidosis. We examined the cumulative probability of progression and the association of potential risk factors on progression rates to identify patients with a high risk of progression to multiple myeloma or light-chain amyloidosis. FINDINGS: We identified 101 patients with idiopathic Bence Jones proteinuria. During 901 total person-years of follow-up, 27 (27%) patients developed multiple myeloma and seven (7%) developed light-chain amyloidosis. The major risk factors for progression were amount of urinary excretion of M protein per 24 h, proportion of bone marrow plasma cells, presence of a markedly abnormal free-light-chain ratio (<0.01 or >100), and reduction of all three uninvolved immunoglobulins. Based on the risk of progression, monoclonal light-chain excretion of 0.5 g/24 h or greater or at least 10% bone marrow plasma cells, or both, in the absence of end-organ damage was used to define light-chain smouldering multiple myeloma. The cumulative probability of progression to active multiple myeloma or light-chain amyloidosis in patients with light-chain smouldering multiple myeloma was 27.8% (95% CI 14.2 39.2) at 5 years, 44.6% (27.9-57.4) at 10 years, and 56.5% (36.3-70.2) at 15 years. INTERPRETATION: Light-chain smouldering multiple myeloma as defined in this study is associated with a high risk of progression to symptomatic light chain multiple myeloma, and this subset of patients needs careful observation and could benefit from clinical trials of early intervention. FUNDING: Jabbs Foundation (Birmingham, UK), US National Cancer Institute, and Henry J Predolin Foundation (Madison, WI, USA). PMID- 25530986 TI - The influence of acute stress on the regulation of conditioned fear. AB - Fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress-related psychopathology. Fear expression can be modulated using a number of regulatory strategies, including extinction, cognitive emotion regulation, avoidance strategies and reconsolidation. In this review, we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques. We focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through Pavlovian fear conditioning. Our primary aim is to explore the impact of stress on fear regulation in humans. Given this, we focus on techniques where stress has been linked to alterations of fear regulation in humans (extinction and emotion regulation), and briefly discuss other techniques (avoidance and reconsolidation) where the impact of stress or stress hormones have been mainly explored in animal models. These investigations reveal that acute stress may impair the persistent inhibition of fear, presumably by altering prefrontal cortex function. Characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress-related psychopathology. PMID- 25530989 TI - Proximal femoral morphology and the relevance to design of anatomically precontoured plates: a study of the Chinese population. AB - Adequately shaped femoral plate is critical for the fixation of fracture in the pertrochanteric regions. Lateral aspect of greater trochanter is an important region where the proximal femoral plate anchored. However, little is known regarding the morphology of greater trochanter. The objective of this study was to measure main dimensions of greater trochanter and other regions in the proximal end of the femur to provide an anatomical basis for the design of the proximal femoral plate. Anthropometric data on the proximal femur were performed utilizing three-dimensional computational modeling. Computed tomography images of healthy femurs in 53 women and 47 men were contributed to three-dimensional femur modeling. All data were compared between male and female femora. The results showed that mean values for male group were found to be greater in most of measured femoral dimensions. Oppositely, females demonstrated higher neck-shaft angle on anteroposterior view and femoral anteversion angle. The anthropometric data can be used for the anatomical shape design of femoral plates for osteosynthesis of fractures in the trochanteric regions. A distinct plate design may be necessary to accommodate differences between the genders. PMID- 25530990 TI - Measurements of soil carbon dioxide emissions from two maize agroecosystems at harvest under different tillage conditions. AB - In this study a comparison of the soil CO2 fluxes emitted from two maize (Zea mays L.) fields with the same soil type was performed. Each field was treated with a different tillage technique: conventional tillage (30 cm depth ploughing) and no-tillage. Measurements were performed in the Po Valley (Italy) from September to October 2012, covering both pre- and postharvesting conditions, by means of two identical systems based on automatic static soil chambers. Main results show that no-tillage technique caused higher CO2 emissions than conventional tillage (on average 2.78 and 0.79 MUmol CO2 m(-2) s(-1), resp.). This result is likely due to decomposition of the organic litter left on the ground of the no-tillage site and thus to an increased microbial and invertebrate respiration. On the other hand, fuel consumption of conventional tillage technique is greater than no-tillage consumptions. For these reasons this result cannot be taken as general. More investigations are needed to take into account all the emissions related to the field management cycle. PMID- 25530991 TI - On some growth properties of entire functions using their maximum moduli focusing (p, q)th relative order. AB - We discuss some growth rates of composite entire functions on the basis of the definition of relative (p, q)th order (relative (p, q)th lower order) with respect to another entire function which improve some earlier results of Roy (2010) where p and q are any two positive integers. PMID- 25530992 TI - The role of disease activity score 28 in the evaluation of articular involvement in systemic lupus erythematosus. AB - OBJECTIVES: To evaluate the application of Disease Activity Score 28 (DAS28) to assess joint involvement in Systemic Lupus Erythematosus (SLE). METHODS: Sixty nine SLE patients, complaining of joint symptoms, and 44 rheumatoid arthritis (RA) patients were enrolled. In SLE patients disease activity was assessed with SLEDAI-2K. DAS28 was calculated in all the patients. RESULTS: Thirty SLE patients (43.5%) showed clinical signs of arthritis. Mean DAS28 was 4.0+/-1.4, 22 patients (31.9%) had low disease activity, 29 (42.0%) moderate, and 18 (26.1%) high. We dichotomized SLE patients according to the presence (Group 1) or absence (Group 2) of articular involvement according to SLEDAI-2K: 56.3% of the patients of the second group had a moderate/high activity according to DAS28. We compared SLE patients with 44 RA patients (M/F 9/35, mean age 55.6+/-14.5 years; mean disease duration 140.4+/-105.6 months). No significant differences were found regarding the values of DAS28 between SLE and RA patients. On the contrary, the values of tender and swollen joint count were significantly higher in RA compared to SLE patients (P=0.0002 and P=0.0001, resp.). CONCLUSIONS: We suggest the use of the DAS28 in the assessment of joint involvement in SLE patients. PMID- 25530993 TI - Variations in stable carbon isotope composition and leaf traits of Picea schrenkiana var. tianschanica along an altitude gradient in Tianshan Mountains, northwest China. AB - To understand the morphological and physiological responses of leaves to changes in altitudinal gradients, we examined ten morphological and physiological characteristics in one-year-old needles of Picea schrenkiana var. tianschanica at ten points along an altitudinal gradient from 1420 to 2300 m a.s.l. on the northern slopes of the Tianshan Mountains in northwest China. Our results indicated that LA, SD, LPC, and LKC increased linearly with increasing elevation, whereas leaf delta13C, LNC, Chla+b, LDMC, LMA, and Narea varied nonlinearly with changes in altitude. With elevation below 2100 m, LNC, Narea, and Chla+b increased, while LDMC and LMA decreased with increasing altitude. When altitude was above 2100 m, these properties showed the opposite patterns. Leaf delta13C was positively correlated with Narea and LNC and negatively correlated with SD and LA, suggesting that leaf delta13C was indirectly controlled by physiological and morphological adjustments along altitudinal gradients. Based on the observed maximum values in LNC, Narea, Chla+b, and LA and the minimum values in LMA and LDMC at the elevation of 2100 m, suggesting higher photosynthetic capacity and greater potential for fast growth under superior optimum zone, we concluded that the best growing elevation for P. schrenkiana var. tianschanica in the Tianshan Mountains was approximately 2100 m. PMID- 25530994 TI - Rate sensitive continuum damage models and mesh dependence in finite element analyses. AB - The experiences from orthogonal machining simulations show that the Johnson-Cook (JC) dynamic failure model exhibits significant element size dependence. Such mesh dependence is a direct consequence of the utilization of local damage models. The current contribution is an investigation of the extent of the possible pathological mesh dependence. A comparison of the resulting JC model behavior combined with two types of damage evolution is considered. The first damage model is the JC dynamic failure model, where the development of the "damage" does not affect the response until the critical state is reached. The second one is a continuum damage model, where the damage variable is affecting the material response continuously during the deformation. Both the plasticity and the damage models are rate dependent, and the damage evolutions for both models are defined as a postprocessing of the effective stress response. The investigation is conducted for a series of 2D shear tests utilizing different FE representations of the plane strain plate with pearlite material properties. The results show for both damage models, using realistic pearlite material parameters, that similar extent of the mesh dependence is obtained and that the possible viscous regularization effects are absent in the current investigation. PMID- 25530995 TI - Seroprevalence and risk factors associated with hepatitis E virus infection in three species of pet birds in northwest China. AB - Hepatitis E virus (HEV), the causative agent of hepatitis E, has been reported in a wide variety of animals, including birds, but little is known of HEV infection in pet birds in northwest China. The objective of the present investigation was to examine HEV seroprevalence in three species of pet birds, namely, Eurasian siskin, Oriental skylark, and black-tailed grosbeak from Gansu. Serum samples collected from 685 pet birds from August 2011 to September 2012 were examined independently for the presence of antibodies against HEV. A total of 59 (8.31%) pet birds were tested positive for HEV antibodies by the commercially available enzyme immunoassay kits. Of these, the seroprevalence was diverse in different species pet birds; the most frequent level was 10.83% (39/360) in Eurasian siskin, followed by 6.57% (19/289) in Oriental skylark, and 2.29% (1/36) in black tailed grosbeak. Age and collecting region of pet birds were the main risk factors associated with HEV infection. The present study firstly revealed the seroprevalence of HEV infection in three species of pet birds in northwest China, which provided the baseline data for taking comprehensive countermeasures and measures for effectively preventing and controlling HEV infection in birds. PMID- 25530996 TI - Levenberg-Marquardt method for the eigenvalue complementarity problem. AB - The eigenvalue complementarity problem (EiCP) is a kind of very useful model, which is widely used in the study of many problems in mechanics, engineering, and economics. The EiCP was shown to be equivalent to a special nonlinear complementarity problem or a mathematical programming problem with complementarity constraints. The existing methods for solving the EiCP are all nonsmooth methods, including nonsmooth or semismooth Newton type methods. In this paper, we reformulate the EiCP as a system of continuously differentiable equations and give the Levenberg-Marquardt method to solve them. Under mild assumptions, the method is proved globally convergent. Finally, some numerical results and the extensions of the method are also given. The numerical experiments highlight the efficiency of the method. PMID- 25530997 TI - Antibacterial activity of Mulinum spinosum extracts against slime-producing Staphylococcus aureus and methicillin-resistant Staphylococcus aureus isolated from nasal carriers. AB - Nasal carriers of Staphylococcus aureus are important reservoirs with risk of developing endogenous infections or transmitting infections to susceptible individuals. Methicillin-resistant S. aureus (MRSA) are associated with higher rates of treatment failure. Some strains of S. aureus produce slime which is believed to make the microorganisms more resistant to antibiotics and host defenses. The antibacterial activity of ethyl acetate:n-hexane (EtOAc:HEX) extracts of Mulinum spinosum (5:95% EtOAc:HEX, 50:50% EtOAc:HEX, 70:30% EtOAc:HEX and mix 20:80/30:70% EtOAc:HEX, 50:50/70:30/100:0% EtOAc:HEX) were assayed against 3 slime-producing S. aureus strains and 2 MRSA strains isolated from nasal carriers. S. aureus ATCC 35556 slime-producing strain and MRSA ATCC 43300 strain were used as controls. The extracts were prepared using flash chromatography. M. spinosum 5:95% AcOEt:HEX showed antibacterial effect against all slime-producing strains (MIC: 500 ug/mL) and the highest activity against MRSA strains (MIC: 500 to 1000 ug/mL). All M. spinosum extracts assayed were active against slime-producing S. aureus and MRSA at doses between 500 and 4000 ug/mL. Both, slime-producing S. aureus and MRSA are highly contagious and hardly eradicated by antibiotic therapies. So, there is an increasing need to find new substances with the ability to inhibit these strains. PMID- 25530998 TI - Analysis of the influence of cracked sleepers under static loading on ballasted railway tracks. AB - The principal causes of cracking in prestressed concrete sleepers are the dynamic loads induced by track irregularities and imperfections in the wheel-rail contact and the in-phase and out-of-phase track resonances. The most affected points are the mid-span and rail-seat sections of the sleepers. Central and rail-seat crack detection require visual inspections, as legislation establishes, and involve sleepers' renewal even though European Normative considers that thicknesses up to 0.5 mm do not imply an inadequate behaviour of the sleepers. For a better understanding of the phenomenon, the finite element method constitutes a useful tool to assess the effects of cracking from the point of view of structural behaviour in railway track structures. This paper intends to study how the cracks at central or rail-seat section in prestressed concrete sleepers influence the track behaviour under static loading. The track model considers three different sleeper models: uncracked, cracked at central section, and cracked at rail-seat section. These models were calibrated and validated using the frequencies of vibration of the first three bending modes obtained from an experimental modal analysis. The results show the insignificant influence of the central cracks and the notable effects of the rail-seat cracks regarding deflections and stresses. PMID- 25530999 TI - Evaluation of cytotoxicity and genotoxicity of Acacia aroma leaf extracts. AB - Acacia aroma, native plant from San Luis, Argentina, is commonly used as antiseptic and for healing of wounds. The present study was conducted to investigate the in vitro cytotoxicity and genotoxicity of hot aqueous extract (HAE) and ethanolic extract (EE) of A. aroma. The cytotoxic activity was assayed by neutral red uptake assay on Vero cell. Cell treatment with a range from 100 to 5000 MUg/mL of HAE and EE showed that 500 MUg/mL and 100 MUg/mL were the maximum noncytotoxic concentrations, respectively. The CC50 was 658 MUg/mL for EE and 1020 MUg/mL for HAE. The genotoxicity was tested by the single-cell gel electrophoresis comet assay. The results obtained in the evaluation of DNA cellular damage exposed to varied concentrations of the HAE showed no significant genotoxic effect at range of 1-20 mg/mL. The EE at 20 mg/mL showed moderate genotoxic effect related to the increase of the DNA percentage contained in tail of the comet; DNA was classified in category 2. At concentrations below 5 mg/mL, the results of cytotoxicity and genotoxicity of aqueous and ethanolic extracts of Acacia aroma guarantee the safety at cell and genomic level. However further studies are needed for longer periods including animal models to confirm the findings. PMID- 25531000 TI - Experimental study on properties of methane diffusion of coal block under triaxial compressive stress. AB - Taking the standard size coal block samples defined by ISRM as research objects, both properties of methane diffusion of coal block under triaxial compressive stress and characteristic influences caused by methane pressure were systematically studied with thermo-fluid-solid coupling with triaxial servocontrolled seepage equipment of methane-containing coal. The result shows the methane diffusion property of coal block under triaxial compressive stress was shown in four-stage as follow, first is sharply reduce stage, second is hyperbolic reduce stage, third is close to a fixed value stage, fourth stage is 0. There is a special point making the reduced rate of characteristic curve of methane diffusion speed become sharply small; the influences of shape of methane diffusion speed characteristic curve caused by methane pressure are not obvious, which only is shown in numerical size of methane diffusion speed. Test time was extended required by appear of the special point makes the reduce rate of methane diffusion speed become sharply small. The fitting four-phase relation of methane diffusion of coal block under triaxial compressive stress was obtained, and the idea is proposed that influences of the fitting four-phase relation caused by methane pressure were only shown in value of fitting parameters. PMID- 25531001 TI - Endovascular intervention for acute ischemic stroke in light of recent trials. AB - Three recently published trials, MR RESCUE, IMS III, and SYNTHESIS Expansion, evaluating the efficacy and safety of endovascular treatment of acute ischemic stroke have generated concerns about the future of endovascular approach. However, the tremendous evolution that imaging and endovascular treatment modalities have undergone over the past several years has raised doubts about the validity of these trials. In this paper, we review the role of endovascular treatment strategies in acute ischemic stroke and discuss the limitations and shortcomings that prevent generalization of the findings of recent trials. We also provide our experience in endovascular treatment of acute ischemic stroke. PMID- 25531002 TI - Linear discrete pursuit game with phase constraints. AB - We consider a linear pursuit game of one pursuer and one evader whose motions are described by different-type linear discrete systems. Position of the evader satisfies phase constraints: y?G, where G is a subset of Rn. We considered two cases: (1) controls of the players satisfy geometric constraints, and (2) controls of the players satisfy total constraints. Terminal set M is a subset of Rn and it is assumed to have a nonempty interior. Game is said to be completed if y(k)-x(k)?M at some step k; thus, the evader has not the right to leave set G. To construct the control of the pursuer, at each step i, we use the value of the control parameter of the evader at the step i. We obtain sufficient conditions of completion of pursuit from certain initial positions of the players in finite time interval and construct a control for the pursuer in explicit form. PMID- 25531003 TI - Burnout in medical residents: a study based on the job demands-resources model. AB - PURPOSE: Burnout is a prolonged response to chronic emotional and interpersonal stressors on the job. The purpose of our cross-sectional study was to estimate the burnout rates among medical residents in the largest Greek hospital in 2012 and identify factors associated with it, based on the job demands-resources model (JD-R). METHOD: Job demands were examined via a 17-item questionnaire assessing 4 characteristics (emotional demands, intellectual demands, workload, and home-work demands' interface) and job resources were measured via a 14-item questionnaire assessing 4 characteristics (autonomy, opportunities for professional development, support from colleagues, and supervisor's support). The Maslach Burnout Inventory (MBI) was used to measure burnout. RESULTS: Of the 290 eligible residents, 90.7% responded. In total 14.4% of the residents were found to experience burnout. Multiple logistic regression analysis revealed that each increased point in the JD-R questionnaire score regarding home-work interface was associated with an increase in the odds of burnout by 25.5%. Conversely, each increased point for autonomy, opportunities in professional development, and each extra resident per specialist were associated with a decrease in the odds of burnout by 37.1%, 39.4%, and 59.0%, respectively. CONCLUSIONS: Burnout among medical residents is associated with home-work interface, autonomy, professional development, and resident to specialist ratio. PMID- 25531004 TI - Clinicopathologic correlation of oral lichen planus and oral lichenoid lesions: a preliminary study. AB - Oral lichen planus (OLP) and oral lichenoid lesions (OLL) are clinically and histologically similar lesions but their treatment planning and prognosis are different. The review of the literature indicates numerous criteria to distinguish these two lesions; however there is a lot of inconsistency. Thus, the aim of this study was to determine the correlation of histopathology and clinical OLP and OLL diagnosis and to clarify which histopathologic criteria could best distinguish these two diagnoses. A retrospective study showed that clinically diagnosed 92 OLPs and 14 OLLs have been confirmed histopathologically in 52.2% and 42.9% of cases, respectively. In addition, histopathology showed statistically significant more eosinophils (P<0.0005), plasma cells (P<0.0005), and granulocytes (P<0.05) in OLL than OLP. To establish histopathological diagnosis of OLP and OLL it should be mandatory to define the type of cells in mononuclear infiltrate, which can be associated more accurately with clinical feature and patient history. Therefore, currently accepted diagnostic criteria for OLP and OLL should be modified and validated on a larger number of patients taking into account particular distinguishing histopathological features. PMID- 25531005 TI - The feasibility of using CT-guided ROI for semiquantifying striatal dopamine transporter availability in a hybrid SPECT/CT system. AB - A hybrid SPECT/CT system provides accurate coregistration of functional and morphological images. CT-guided region of interest (ROI) for semiquantifying striatal dopamine transporter (DAT) availability may be a feasible method. We therefore assessed the intra- and interobserver reproducibility of manual SPECT and CT-guided ROI methods and compared their semiquantitative data with data from MRI-guided ROIs. We enrolled twenty-eight patients who underwent Tc-99m TRODAT-1 brain SPECT/CT and brain MRI. ROIs of the striatal, caudate, putamen, and occipital cortex were manually delineated on the SPECT, CT, and MRI. ROIs from CT and MRI were transferred to the coregistered SPECT for semiquantification. The striatal, caudate, and putamen nondisplaceable binding potential (BPND) were calculated. Using CT-guided ROIs had higher intra- and interobserver concordance correlation coefficients, closer Bland-Altman biases to zero, and narrower limits of agreement than using manual SPECT ROIs. The correlation coefficients of striatal, caudate, and putamen BPND were good between manual SPECT and MRI-guided ROI methods and even better between CT-guided and MRI-guided ROI methods. Conclusively, CT-guided ROI delineation for semiquantifying striatal DAT availability in a hybrid SPECT/CT system is highly reproducible, and the semiquantitative data correlate well with data from MRI-guided ROIs. PMID- 25531006 TI - The effect of different parameters on the development of compressive strength of oil palm shell geopolymer concrete. AB - This paper presents the experimental results of an on-going research project on geopolymer lightweight concrete using two locally available waste materials--low calcium fly ash (FA) and oil palm shell (OPS)--as the binder and lightweight coarse aggregate, respectively. OPS was pretreated with three different alkaline solutions of sodium hydroxide (NaOH), potassium hydroxide, and sodium silicate as well as polyvinyl alcohol (PVA) for 30 days; afterwards, oil palm shell geopolymer lightweight concrete (OPSGPC) was cast by using both pretreated and untreated OPSs. The effect of these solutions on the water absorption of OPS, and the development of compressive strength in different curing conditions of OPSGPC produced by pretreated OPS were investigated; subsequently the influence of NaOH concentration, alkaline solution to FA ratio (A/FA), and different curing regimes on the compressive strength and density of OPSGPC produced by untreated OPS was inspected. The 24-hour water absorption value for OPS pretreated with 20% and 50% PVA solution was about 4% compared to 23% for untreated OPS. OPSGPC produced from OPS treated with 50% PVA solution produced the highest compressive strength of about 30 MPa in ambient cured condition. The pretreatment with alkaline solution did not have a significant positive effect on the water absorption of OPS aggregate and the compressive strength of OPSGPC. The result revealed that a maximum compressive strength of 32 MPa could be obtained at a temperature of 65 degrees C and curing period of 4 days. This investigation also found that an A/FA ratio of 0.45 has the optimum amount of alkaline liquid and it resulted in the highest level of compressive strength. PMID- 25531007 TI - Mechanisms of Heart Failure in Type 2 Diabetes Mellitus. PMID- 25531008 TI - Robust and Effective Component-based Banknote Recognition by SURF Features. AB - Camera-based computer vision technology is able to assist visually impaired people to automatically recognize banknotes. A good banknote recognition algorithm for blind or visually impaired people should have the following features: 1) 100% accuracy, and 2) robustness to various conditions in different environments and occlusions. Most existing algorithms of banknote recognition are limited to work for restricted conditions. In this paper we propose a component based framework for banknote recognition by using Speeded Up Robust Features (SURF). The component-based framework is effective in collecting more class specific information and robust in dealing with partial occlusion and viewpoint changes. Furthermore, the evaluation of SURF demonstrates its effectiveness in handling background noise, image rotation, scale, and illumination changes. To authenticate the robustness and generalizability of the proposed approach, we have collected a large dataset of banknotes from a variety of conditions including occlusion, cluttered background, rotation, and changes of illumination, scaling, and viewpoints. The proposed algorithm achieves 100% recognition rate on our challenging dataset. PMID- 25531009 TI - Pilot of a Behavioral Activation-Enhanced Smoking Cessation Program for Substance Users With Elevated Depressive Symptoms in Residential Treatment. PMID- 25531010 TI - Identifying Drug (Cocaine) Intake Events from Acute Physiological Response in the Presence of Free-living Physical Activity. AB - A variety of health and behavioral states can potentially be inferred from physiological measurements that can now be collected in the natural free-living environment. The major challenge, however, is to develop computational models for automated detection of health events that can work reliably in the natural field environment. In this paper, we develop a physiologically-informed model to automatically detect drug (cocaine) use events in the free-living environment of participants from their electrocardiogram (ECG) measurements. The key to reliably detecting drug use events in the field is to incorporate the knowledge of autonomic nervous system (ANS) behavior in the model development so as to decompose the activation effect of cocaine from the natural recovery behavior of the parasympathetic nervous system (after an episode of physical activity). We collect 89 days of data from 9 active drug users in two residential lab environments and 922 days of data from 42 active drug users in the field environment, for a total of 11,283 hours. We develop a model that tracks the natural recovery by the parasympathetic nervous system and then estimates the dampening caused to the recovery by the activation of the sympathetic nervous system due to cocaine. We develop efficient methods to screen and clean the ECG time series data and extract candidate windows to assess for potential drug use. We then apply our model on the recovery segments from these windows. Our model achieves 100% true positive rate while keeping the false positive rate to 0.87/day over (9+ hours/day of) lab data and to 1.13/day over (11+ hours/day of) field data. PMID- 25531011 TI - Using Computer Vision to Access Appliance Displays. AB - People who are blind or visually impaired face difficulties accessing a growing array of everyday appliances, needed to perform a variety of daily activities, because they are equipped with electronic displays. We are developing a "Display Reader" smartphone app, which uses computer vision to help a user acquire a usable image of a display, to address this problem. The current prototype analyzes video from the smartphone's camera, providing real-time feedback to guide the user until a satisfactory image is acquired, based on automatic estimates of image blur and glare. Formative studies were conducted with several blind and visually impaired participants, whose feedback is guiding the development of the user interface. The prototype software has been released as a Free and Open Source (FOSS) project. PMID- 25531012 TI - Tracking on the Product Manifold of Shape and Orientation for Tractography from Diffusion MRI. AB - Tractography refers to the process of tracing out the nerve fiber bundles from diffusion Magnetic Resonance Images (dMRI) data acquired either in vivo or ex vivo. Tractography is a mature research topic within the field of diffusion MRI analysis, nevertheless, several new methods are being proposed on a regular basis thereby justifying the need, as the problem is not fully solved. Tractography is usually applied to the model (used to represent the diffusion MR signal or a derived quantity) reconstructed from the acquired data. Separating shape and orientation of these models was previously shown to approximately preserve diffusion anisotropy (a useful bio-marker) in the ubiquitous problem of interpolation. However, no further intrinsic geometric properties of this framework were exploited to date in literature. In this paper, we propose a new intrinsic recursive filter on the product manifold of shape and orientation. The recursive filter, dubbed IUKFPro, is a generalization of the unscented Kalman filter (UKF) to this product manifold. The salient contributions of this work are: (1) A new intrinsic UKF for the product manifold of shape and orientation. (2) Derivation of the Riemannian geometry of the product manifold. (3) IUKFPro is tested on synthetic and real data sets from various tractography challenge competitions. From the experimental results, it is evident that IUKFPro performs better than several competing schemes in literature with regards to some of the error measures used in the competitions and is competitive with respect to others. PMID- 25531013 TI - An Active Patch Model for Real World Texture and Appearance Classification. AB - This paper addresses the task of natural texture and appearance classification. Our goal is to develop a simple and intuitive method that performs at state of the art on datasets ranging from homogeneous texture (e.g., material texture), to less homogeneous texture (e.g., the fur of animals), and to inhomogeneous texture (the appearance patterns of vehicles). Our method uses a bag-of-words model where the features are based on a dictionary of active patches. Active patches are raw intensity patches which can undergo spatial transformations (e.g., rotation and scaling) and adjust themselves to best match the image regions. The dictionary of active patches is required to be compact and representative, in the sense that we can use it to approximately reconstruct the images that we want to classify. We propose a probabilistic model to quantify the quality of image reconstruction and design a greedy learning algorithm to obtain the dictionary. We classify images using the occurrence frequency of the active patches. Feature extraction is fast (about 100 ms per image) using the GPU. The experimental results show that our method improves the state of the art on a challenging material texture benchmark dataset (KTH-TIPS2). To test our method on less homogeneous or inhomogeneous images, we construct two new datasets consisting of appearance image patches of animals and vehicles cropped from the PASCAL VOC dataset. Our method outperforms competing methods on these datasets. PMID- 25531014 TI - Understanding of xerostomia and strategies for the development of artificial saliva. AB - Xerostomia is becoming a major issue in dental and medical clinics with an increase of aged population. Medication is the most common etiology of xerostomia, while the most severe xerostomia generally occurs in patients with a history of head and neck radiotherapy. Xerostomic patients usually suffer from diminished quality of life due to various symptoms and complications. Decreased salivary output is a definite objective sign, but oral mucosal wetness is a more reliable factor for the evaluation of xerostomia. At present there are no effective therapeutic methods for the treatment of xerostomia. Sialogogues may have problematic side effects and their therapeutic effects last only brief duration. Artificial saliva typically does not produce satisfactory results in therapeutic efficacy. Therefore, further research and development of better therapeutic modalities are necessary. The basic concept for the development of ideal and functional artificial saliva is the mimicry of natural human saliva. We need proper candidate molecules and antimicrobial supplements to simulate the rheological and biological properties of human saliva. We also need better understanding of the interactions between the ingredients of artificial saliva themselves and between the ingredients and components of human saliva both in solution and on surface phases. In addition, we need accepted measures to evaluate the efficacy of artificial saliva. In conclusion, for the development of ideal artificial saliva, research based on the understanding of pathophysiology of xerostomia and knowledge about rheological and biological functions of human saliva are necessary. PMID- 25531015 TI - A practical guide for diagnosis and treatment of arteriovenous malformations in the oral and maxillofacial region. AB - Arteriovenous malformations (AVMs) are congenital vascular malformations (CVMs) resulting from birth defects of the vasculature. It is rarely seen, only accounting for 1.5% of all vascular anomalies, and 50% of the lesions are located in the oral and maxillofacial region. Regardless of the type, AVMs may ultimately lead to significant anatomical, pathophysiological and hemodynamic consequences. Therefore, despite their relative rarity, AVMs still remain the most challenging and/or life-threatening form of vascular anomalies. Transarterial coil embolisation or ligation of feeding arteries are incorrect approaches and may result in progress of the lesion. Furthermore, such procedures would prevent future endovascular access to the lesions via the arterial route, and should be abandoned. Interventional embolisation using various sclerosants is currently the mainstay of treatment for AVMs, and elimination of the nidus (if present) is the key to success. Among various embolosclerotherapy agents, ethanol sclerotherapy produces the best long-term outcomes, with minimal complications. For more complex cases, multidisciplinary approaches and interventions may provide an excellent potential for a curative result. Based on the published literature and clinical experiences, a practical treatment guideline was established in order to provide a criterion for the management of oral and maxillofacial AVMs. This protocol will be renewed and updated to reflect cutting edge knowledge, and provide the newest treatment modalities for oral and maxillofacial AVMs. PMID- 25531016 TI - Attenuation of inflammatory response by 25- hydroxyvitamin D3-loaded polylactic acid microspheres in treatment of periodontitis in diabetic rats. AB - OBJECTIVE: To investigate the inhibitory effects of 25-hydroxyvitamin D3 (25(OH)D3)-loaded polylactic acid (PLA) microspheres on inflammatory response in diabetic periodontitis. METHODS: 25(OH)D3-loaded PLA microspheres were produced using emulsion-solvent evaporation method. Rat bone marrow stromal cells (BMSCs) cultured with Aggregatibacter actinomycetemcomitans in high glucose medium were chosen to mimic diabetic periodontitis. After cultivation with 25(OH)D3-loaded PLA microspheres, inflammation-related proteins in BMSCs were detected using Western blot analysis. Periodontitis was induced using silk ligatures in diabetic rats, and 25(OH)D3-loaded PLA microspheres were placed into the periodontal pockets. Periodontal tissues were examined using hematoxylin and eosin staining and western blot analysis. RESULTS: Drug release from the 25(OH)D3-loaded microspheres was relatively steady during 70 days. In a diabetic periodontitis like environment, 25(OH)D3-loaded microspheres upregulated vitamin D receptor expression, and downregulated nuclear factor-kappaB expression and signal transducer and activator of transcription 3 phosphorylation in the BMSCs. These 25(OH)D3 microspheres also attenuated periodontal inflammatory infiltrate and bone loss in diabetic rats with periodontitis. CONCLUSION: 25(OH)D3-loaded microspheres could ameliorate diabetic periodontitis by inhibiting inflammatory response, and may provide a potential therapy for patients with this disease. PMID- 25531017 TI - Stereotaxis of mandibular nerve initial point of trigeminal ganglion in rats. AB - OBJECTIVE: To acquire parameters for stereotaxis of the mandibular nerve initial point of the trigemenial ganglion (TG) and to test the accuracy of the acquired parameters for microinjection into the mandibular nerve initial point of TG in adult rats. METHODS: Sprague-Dawley rats (260-270 g) were mounted onto a stereotaxic frame. The bregma was set as an anchor point and the three dimensional parameters between the mandibular nerve initial point of the bilateral TGs and the bregma were measured in 25 rats. The accuracy of these parameters was tested using microinjection of Evans blue dye into the mandibular nerve initial point of the bilateral TGs in 30 rats and the injection sites were evaluated by dissection. RESULTS: The three-dimensional parameters of the mandibular nerve initial point of the bilateral TGs were 3.5 +/- 0.1 mm posterior and 3.6 +/- 0.2 mm lateral to the bregma, and 12.0 +/- 0.2 mm inferior to the skull surface. Accuracy for the microinjection of Evans blue dye into the mandibular nerve initial point of the bilateral TGs was 86.7% (52/60). CONCLUSION: The acquired parameters served well for stereotaxis and microinjection of reagents into the mandibular nerve initial point of TG. PMID- 25531018 TI - Involvement of bone marrow stem cells in periodontal wound healing. AB - OBJECTS: To test the hypothesis whether bone marrow stem cells (BMSCs) could migrate into the periodontium as the precursor available for the repair of tissue injury. METHODS: A chimeric mouse model was established by transplanting BMSCs derived from red fluorescent protein mouse into irradiated BALB/c mice. Subsequently, a periodontal defect was created beside the maxillary first molar and filled with ceramic bovine bone. Finally, the chimeric mice were divided into three groups and were observed 3, 14 and 28 days later respectively. The involvement of BMSCs in periodontal defects was analysed using an in vivo imaging system and immunohistochemical staining of CD45, CD105 and CD31. Cell surface marker expression in injured tissue was also compared with that in normal tissue. RESULTS: Increasing numbers of BMSCs migrated into the periodontal defect with time. The distribution was initially limited to ceramic bovine bone and then around blood vessels and near alveolar bone. Furthermore, expression of CD105 and CD31 was much higher in injured periodontal tissue than that in healthy periodontium, although CD45 was not expressed in either of these tissues. CONCLUSION: BMSCs, but not haemopoietic stem cells, were involved in periodontal defect; they entered the periodontium probably via blood vessels. PMID- 25531019 TI - Morphological analysis of apical foramen over-instrumented by three rotary NiTi systems. AB - OBJECTIVE: To evaluate morphological changes of the apical surface after root canal preparation with 1 mm beyond the apical foramen using ProTaper Universal (PTU) files, K3 files and Twisted files (TF), respectively. METHODS: Seventy teeth with a centered apical foramen and 70 teeth with a deviated apical foramen were included as group A and group B respectively. In each group, 20 teeth were randomly assigned for root canal preparation with PTU, K3 and TF files, respectively; the remaining 10 teeth were used as the control group without any preparation. The apical foramens were examined with scanning electronic microscopy. The foramen integrity damage (FID) and dentin defects (DDs) were noted and compared between different groups. RESULTS: FID and DD were significantly less in Group A. DDs was not found in the control group. Preparation with PTU, K3, and TF files caused FID in 6.67%, 10%, and 3.33% of teeth in the group A, and in 20%, 26.67%, and 10% in Group B, respectively. Preparation with PTU, K3, and TF files caused DD in 6.67%, 6.67%, and 3.33% of teeth in Group A, and in 23.33%, 26.67%, and 6.67% in Group B, respectively. PTU and K3 files produced more DDS than TF files. However, no significant difference was found between groups using PTU and K3 files. CONCLUSION: Rotary instrumentation caused less damage on the apical surface in foramencentered root canals than foramen-deviated root canals when working beyond the canal length. TF files had a tendency to produce less DDS compared with PTU or K3 files during over-instrumented root canals. PMID- 25531020 TI - Maxillary anterior teeth dimensions and proportions in a central mainland chinese population. AB - OBJECTIVES: To obtain maxillary anterior tooth dimension and proportion values for the Central Chinese population and to evaluate the existence of sexual dimorphism, any consistent relationships between the tooth ratios, and the presence of golden proportions. METHODS: Tooth dimensions and proportions of six maxillary anterior teeth were recorded on gypsum casts obtained from 147 subjects (82 women and 65 men). Of these, 115 casts were digitally photographed in a standardised manner and apparent width values for six maxillary anterior teeth were recorded for golden proportion analysis. Existence of sexual dimorphism, any consistent width/height ratio and golden proportions were statistically analysed. One-sample t-test, two-sample t-test, and paired t-test were used to analyse the data. RESULTS: There were no significant differences between measurements on the right and left side. Sexual dimorphism existed for various tooth dimensions. There was no statistically significant difference for width/height ratios between the two genders for central incisor and lateral incisor. However, canines showed a statistically significant difference. The golden proportion guideline was not applicable for this population. CONCLUSION: The maxillary anterior teeth dimensions were significantly greater for men than women; however, the mean difference was small (< 0.2 mm) and may not be clinically significant. The golden proportion, or any recurring anterior teeth proportions, was not found for the population. There was a significant difference in width/height ratio of canines between the genders, confirming its greatest gender-based morphological difference. PMID- 25531021 TI - Advanced Maternal Age and Risks for Adverse Pregnancy Outcomes: A Population Based Study in Oman. AB - To test the hypothesis that advanced maternal age (AMA) of 35 years and above is associated with increased risk of adverse pregnancy outcomes, we performed a population-based retrospective study using data from the 2000 National Health Survey in Oman. The last pregnancy outcomes of mothers aged >=35 years were compared with adult mothers aged 20-34 years using bivariate and multivariate statistical techniques. Significantly increased risks of spontaneous abortion, gestational diabetes, preeclampsia, prolonged labor, and cesarean section delivery have been observed for advanced maternal age. Our findings may contribute to cross-cultural understanding of the risks associated with AMA and will facilitate evidence-based counseling of older expectant mothers. PMID- 25531022 TI - Oxygen-rich hierarchical porous carbon derived from artemia cyst shells with superior electrochemical performance. AB - In this study, three-dimensional (3D) hierarchical porous carbon with abundant functional groups is produced through a very simple low-cost carbonization of Artemia cyst shells. The unique hierarchical porous structure of this material, combining large numbers of micropores and macropores, as well as reasonable amount of mesopores, is proven favorable to capacitive behavior. The abundant oxygen functional groups from the natural carbon precursor contribute stable pseudocapacitance. As-prepared sample exhibits high specific capacitance (369 F g(-1) in 1 M H2SO4 and 349 F g(-1) in 6 M KOH), excellent cycling stability with capacitance retention of 100% over 10 000 cycles, and promising rate performance. This work not only describes a simple way to produce high-performance carbon electrode materials for practical application, but also inspires an idea for future structure design of porous carbon. PMID- 25531023 TI - Hydrogen bond dynamics in primary alcohols: a femtosecond infrared study. AB - Hydrogen-bonded liquids are excellent solvents, in part due to the highly dynamic character of the directional interaction associated with the hydrogen bond. Here we study the vibrational and reorientational dynamics of deuterated hydroxyl groups in various primary alcohols using polarization-resolved femtosecond infrared spectroscopy. We show that the relaxation of the OD stretch vibration is similar for ethanol and its higher homologues (~0.9 ps), while it is appreciably faster for methanol (~0.75 ps). The fast relaxation for methanol is attributed to strong coupling of the OD stretch vibration to the overtone of the CH3 rocking mode. Subsequent to excited state relaxation, the dissipation of the excess energy leads to structural relaxation of the alcohol liquid structure. We show that this relaxation of the H-bonded network depends on the alkyl chain length. We find that the anisotropy of the excitation decays by both thermal diffusion from excited OD groups to nonexcited molecules and reorientational motion. The reorientation is described well by a model employing two relaxation times that increase linearly with increasing alcohol size. The short reorientation time is assigned to the partial reorientation of molecules within the alcohol cluster, while the long reorientation times can be attributed to breaking and reforming of hydrogen bonds. PMID- 25531024 TI - Electrons per atom ratio determination and Hume-Rothery electron concentration rule for P-based polar compounds studied by FLAPW-fourier calculations. AB - The extent to which reliable electrons per atom ratio, e/a, are determined and the validity of the Hume-Rothery stabilization mechanism are ensured upon increasing ionicity are studied by applying first-principles full potential linearized augmented plane wave (FLAPW)-Fourier band calculations to as many as 59 binary compounds formed by adding elements from periods 2-6 to phosphorus in group 15 of the Periodic Table. Van Arkel-Ketelaar triangle maps were constructed both by using the Allen electronegativity data and by using an energy difference between the center-of-gravity energies of FLAPW-derived s and p partial densities of states (DOSs) for the equiatomic compounds studied. The determination of e/a and the test of the interference condition, both of which play a key role in the Hume-Rothery stabilization mechanism, were reliably made for all intermetallic compounds, as long as the ionicity is less than 50%. In the A-P (A = Li, Na, K, Rb, and Cs) compounds with ionicity exceeding 50%, however, e/a determination becomes unstable, as reflected in its P concentration dependence. New Hume Rothery electron concentration rules were theoretically found in two families of polar compounds: skutterudite compounds TMP(3), TMAs(3), and TMSb(3) (TM = Co, Ni, Rh, and Ir; cI32) with e/a = 4.34 and TM(3)P (TM = Cr, Mn, Fe, and Ni; tI32) with e/a = 2.20. PMID- 25531025 TI - Biomass of algae growth on natural water medium. AB - Algae are the dominant primary producers in aquatic ecosystems. Since algae are highly varied group organisms, which have important functions in ecosystem, and their biomass is an essential biological resource. Currently, algae have been applied increasingly to diverse range of biomass applications. Therefore, this study was aimed to investigate the ecological algae features of microalgal production by natural medium, ecological function by lab scale of the symbiotic reactor which is imitated nature ecosystem, and atmospheric CO2 absorption that was related the algal growth of biomass to understand algae in natural water body better. Consequently, this study took advantages of using the unsupplemented freshwater natural medium to produce microalgae. Algal biomass by direct measurement of total suspended solids (TSS) and volatile suspended solids (VSS) resulted as 0.14g/L and 0.08g/L respectively. The biomass measurements of TSS and VSS are the sensible biomass index for algae production. The laboratory results obtained in the present study proved the production of algae by the natural water medium is potentially feasible. PMID- 25531026 TI - Chimerism and tolerance induction in kidney transplantation. AB - Chimerism is a state in which bone marrow hematopoietic stem cells from two genetically different animals coexist. To date, the approach has been used successfully to induce the state of immunologic tolerance in the animal models and is now being evaluated in clinical trials of both HLA-identical and HLA mismatched living-donor kidney transplant recipients in some transplant centers with varying degrees of success. Although the results are promising, the current conditioning regimens are not optimal and longer-term follow up and multicenter studies are needed to ensure the efficacy and safety of the procedures. PMID- 25531027 TI - Is empathy necessary to comprehend the emotional faces? The empathic effect on attentional mechanisms (eye movements), cortical correlates (N200 event-related potentials) and facial behaviour (electromyography) in face processing. AB - The present research explored the effect of social empathy on processing emotional facial expressions. Previous evidence suggested a close relationship between emotional empathy and both the ability to detect facial emotions and the attentional mechanisms involved. A multi-measure approach was adopted: we investigated the association between trait empathy (Balanced Emotional Empathy Scale) and individuals' performance (response times; RTs), attentional mechanisms (eye movements; number and duration of fixations), correlates of cortical activation (event-related potential (ERP) N200 component), and facial responsiveness (facial zygomatic and corrugator activity). Trait empathy was found to affect face detection performance (reduced RTs), attentional processes (more scanning eye movements in specific areas of interest), ERP salience effect (increased N200 amplitude), and electromyographic activity (more facial responses). A second important result was the demonstration of strong, direct correlations among these measures. We suggest that empathy may function as a social facilitator of the processes underlying the detection of facial emotion, and a general "facial response effect" is proposed to explain these results. We assumed that empathy influences cognitive and the facial responsiveness, such that empathic individuals are more skilful in processing facial emotion. PMID- 25531028 TI - Uptake and accumulation of bulk and nanosized cerium oxide particles and ionic cerium by radish (Raphanus sativus L.). AB - The potential toxicity and accumulation of engineered nanomaterials (ENMs) in agricultural crops has become an area of great concern and intense investigation. Interestingly, although below-ground vegetables are most likely to accumulate the highest concentrations of ENMs, little work has been done investigating the potential uptake and accumulation of ENMs for this plant group. The overall objective of this study was to evaluate how different forms of cerium (bulk cerium oxide, cerium oxide nanoparticles, and the cerium ion) affected the growth of radish (Raphanus sativus L.) and accumulation of cerium in radish tissues. Ionic cerium (Ce(3+)) had a negative effect on radish growth at 10 mg CeCl3/L, whereas bulk cerium oxide (CeO2) enhanced plant biomass at the same concentration. Treatment with 10 mg/L cerium oxide nanoparticles (CeO2 NPs) had no significant effect on radish growth. Exposure to all forms of cerium resulted in the accumulation of this element in radish tissues, including the edible storage root. However, the accumulation patterns and their effect on plant growth and physiological processes varied with the characteristics of cerium. This study provides a critical frame of reference on the effects of CeO2 NPs versus their bulk and ionic counterparts on radish growth. PMID- 25531029 TI - Prisoners treated for hepatitis C with protease inhibitor, New York, USA, 2012. PMID- 25531030 TI - Beryllium fluoride exchange rate accelerated by Mg2+ as discovered by 19F NMR. AB - Beryllium fluoride is widely used as a phosphoryl analogue in macromolecular studies, which are not only fluoride-sensitive but also magnesium-dependent. The beryllium fluorides are a mixture of different species including BeF3(-) and BeF4(2-) exchanging under thermodynamic equilibrium in neutral aqueous solutions. In the cases of mimicking phosphate group transfer, both beryllium fluoride and the magnesium ion are generally needed. However, the impact of magnesium on the bioactivity of beryllium fluoride is not clear. We have found by (19)F NMR spectroscopy that Mg(2+) can severely affect the chemical exchange kinetics between BeF3(-) and BeF4(2-). When the F(-) concentration is relatively low, the presence of 10.0 mM Mg(2+) can accelerate the exchange rate 3-4 fold. However, when the F(-) concentration is relatively high, the Mg(2+) effect on the chemical exchange vanishes. On the basis of these findings, we proposed a possible mechanism that BeF4(2-) and Mg(2+) form an ion pair that affects the distribution of beryllium fluoride species and thus the activity in the solution. PMID- 25531031 TI - Commentary: Promoting healthy adolescent development through comprehensive sexuality education. PMID- 25531032 TI - Monitoring water sources for environmental reservoirs of toxigenic Vibrio cholerae O1, Haiti. PMID- 25531033 TI - Angelica keiskei Koidzumi extracts improve some markers of liver function in habitual alcohol drinkers: a randomized double-blind clinical trial. AB - Alcohol induces oxidative stress and inflammatory response, which can lead to hepatitis and cirrhosis. Previous studies reported that the extracts of Angelica keiskei Koidzumi (AKE) have antioxidant and anti-inflammatory properties, suggesting that AKE could improve abnormalities associated with alcoholic liver disease. In this study, the effectiveness of AKE supplementation was assessed in 82 habitual alcohol drinkers (male: more than 14 units per week, female: more than 7 units per week) with abnormal liver biochemistry in a placebo-controlled, randomized double-blind trial over 12 weeks. Among the subjects, 65% (n=43) were heavy drinkers consuming more than 35 units per week. Among heavy drinkers, gamma glutamyl transferase levels of 19 subjects per AKE-treated group were significantly decreased (21.16+/-37.63, P=.016) with significant differences observed compared to the 24 subjects per placebo group (P=.046). However, no significant differences were observed in aspartate aminotransferase and alanine aminotransferase levels between the AKE- and placebo-treated groups. These results suggest that AKE supplementation might improve liver function in heavy drinkers. PMID- 25531034 TI - Charge Transfer Fluorescence and 34 nm Exciton Diffusion Length in Polymers with Electron Acceptor End Traps. AB - Photoexcitation of conjugated poly-2,7-(9,9-dihexylfluorene) polyfluorenes with naphthylimide (NI) and anthraquinone (AQ) electron-acceptor end traps produces excitons that form charge transfer states at the end traps. Intramolecular singlet exciton transport to end traps was examined by steady state fluorescence for polyfluorenes of 17-127 repeat units in chloroform, dimethylformamide (DMF), tetrahydrofuran (THF), and p-xylene. End traps capture excitons and form charge transfer (CT) states at all polymer lengths and in all solvents. The CT nature of the end-trapped states is confirmed by their fluorescence spectra, solvent and trap group dependence, and DFT descriptions. Quantum yields of CT fluorescence are as large as 46%. This strong CT emission is understood in terms of intensity borrowing. Energies of the CT states from onsets of the fluorescence spectra give the depths of the traps which vary with solvent polarity. For NI end traps, the trap depths are 0.06 (p-xylene), 0.13 (THF), and 0.19 eV (CHCl3). For AQ, CT fluorescence could be observed only in p-xylene where the trap depth is 0.27 eV. Quantum yields, emission energies, charge transfer energies, solvent reorganization, and vibrational energies were calculated. Fluorescence measurements on chains >100 repeat units indicate that end traps capture ~50% of the excitons, and that the exciton diffusion length is LD = 34 nm, which is much larger than diffusion lengths reported in polymer films or than previously known for diffusion along isolated chains. The efficiency of exciton capture depends on chain length but not on trap depth, solvent polarity, or which trap group is present. PMID- 25531036 TI - Electrowetting actuated microfluidic transport in surface grooves with triangular cross section. AB - Liquids show different static wetting morphologies in open triangular grooves depending upon the wedge angle (psi) of the groove and the liquid contact angle (theta) with the substrate. Switching between different morphologies can be achieved either by varying the contact angle of the liquid or by changing the wedge angle of the groove. In the present work we manipulate the apparent contact angle of a liquid by electrowetting to switch between liquid morphologies, from droplet to filament, to achieve microfluidic transport of the liquid into open triangular grooves. The static length of liquid filaments in grooves is analyzed as a function of applied voltage for different applied ac frequencies. The dynamic advancement of the filament lengths in grooves is analyzed as a function of time for different applied voltages for two different liquids: first with contact angle greater than the wedge angle and second with contact angle smaller than the wedge angle. Later an exact electrical model is derived to explain the liquid transport in triangular grooves actuated by electrowetting which includes the precise geometry of the liquid morphology. PMID- 25531035 TI - Maturation of embryonic tissues in a lymph node: a new approach for bioengineering complex organs. AB - Given our recent finding that the lymph node (LN) can serve as an in vivo factory to generate complex structures like liver, pancreas, and thymus, we investigated whether LN could also support early development and maturation from several mid embryonic (E14.5/15.5) mouse tissues including brain, thymus, lung, stomach, and intestine. Here we observed brain maturation in LN by showing the emergence of astrocytes with well-developed branching processes. Thymus maturation in LN was monitored by changes in host immune cells. Finally, newly terminally differentiated mucus-producing cells were identified in ectopic tissues generated by transplantation of lung, stomach and intestine in LN. Thus, we speculate the LN offers a unique approach to study the intrinsic and extrinsic differentiation potential of cells and tissues during early development, and provides a new site for bioengineering complex body parts. PMID- 25531037 TI - The effects of reinforcement methods on burst pressure in resected sleeve gastrectomy specimens. AB - BACKGROUND: Staple-line leak is a life-threatening complication of laparoscopic sleeve gastrectomy. Reinforcement materials have been reported to lower the risk of staple-line bleeding, but their effects on leak risk have not been elucidated. The aim of this study was to compare the effects of two supportive techniques on burst pressures in sleeved gastrectomy specimens. MATERIALS AND METHODS: Thirty patients who underwent laparoscopic sleeve gastrectomy were evaluated. The resected sleeve gastrectomy specimens were categorized into three groups. Group 1 had no extra support in the staple line, Group 2 had oversewing with continuous suture on the staple line, and Group 3 had fibrin sealant (Tisseel((r)); Baxter, Deerfield, IL) on the staple line. The end point was the first detectable leakage, at which point leak pressure and the anatomic site of leakage were recorded. RESULTS: Thirty sleeved gastrectomy specimens were included (each group included 10 specimens). There were no differences among group in terms of age, sex, and body mass index. The leak pressure was significantly higher (106+/-10.5 mm Hg) in Group 2 (P<.01). Leaks occurred significantly more frequently in the staple line than in the staple junction points (P=.014). CONCLUSIONS: Oversewing the staple line with 3-0 Vicryl((r)) (Ethicon, Somerville, NJ) suture significantly increased the strength of the staple line. Increases in intraluminal pressure are known to be one of the significant risks in leak etiology. Thus, we concluded that oversewing the staple line with 3-0 Vicryl suture can be beneficial in the prevention of leaks. However, further work is necessary in this area of research. PMID- 25531038 TI - In situ CO2-emission assisted synthesis of molybdenum carbonitride nanomaterial as hydrogen evolution electrocatalyst. AB - We reported a novel protocol to efficiently synthesize molybdenum carbonitride (MoCN) nanomaterials with dense active sites and high surface area. The key step in this protocol is the preparation of the catalyst precursor, which was obtained by polymerizing diaminopyridine in the presence of hydrogen carbonate. The abundant amino groups in the poly diaminopyridine bound numerous Mo species via coordination bonds, resulting in the formation of dense Mo active sites. The addition of hydrogen carbonate to the synthesis mixture resulted in CO2 gas evolution as the local pH decreased during polymerization. The in situ evolved CO2 bubbles mechanically broke down the precursor into MoCN nanomaterials with a high surface area. The synthesized MoCN materials were demonstrated as an electrocatalyst for hydrogen evolution reaction (HER). It exhibited an HER onset potential of -0.05 V (vs RHE) and a high hydrogen production rate (at -0.14 V vs RHE, -10 mA cm(-2)) and is therefore one of the most efficient, low-cost HER catalysts reported to date. PMID- 25531039 TI - Activity-based protein profiling of microbes. AB - Activity-based protein profiling (ABPP) in conjunction with multimodal characterization techniques has yielded impactful findings in microbiology, particularly in pathogen, bioenergy, drug discovery, and environmental research. Using small molecule chemical probes that react irreversibly with specific proteins or protein families in complex systems has provided insights in enzyme functions in central metabolic pathways, drug-protein interactions, and regulatory protein redox, for systems ranging from photoautotrophic cyanobacteria to mycobacteria, and combining live cell or cell extract ABPP with proteomics, molecular biology, modeling, and other techniques has greatly expanded our understanding of these systems. New opportunities for application of ABPP to microbial systems can enhance protein annotation, characterize protein activities in myriad environments, and reveal signal transduction and regulatory mechanisms in microbial systems. PMID- 25531040 TI - Quantification of free formaldehyde in carrageenan and processed Eucheuma seaweed using high-performance liquid chromatography. AB - In 2010 the European Commission placed a limit on the amount of free formaldehyde in carrageenan and processed Eucheuma seaweed (PES) of 5 mg kg(-1). Formaldehyde is not used in carrageenan and PES processing and accordingly one would not expect free formaldehyde to be present in carrageenan and PES. However, surprisingly high levels up to 10 mg kg(-1) have been found using the generally accepted AOAC and Hach tests. These findings are, per proposed reaction pathways, likely due to the formation of formaldehyde when sulphated galactose, the backbone of carrageenan, is hydrolysed with the strong acid used in these conventional tests. In order to minimise the risk of false-positives, which may lead to regulatory non-compliance, a new high-performance liquid chromatography (HPLC) method has been developed. Initially, carrageenan or PES is extracted with 2-propanol and subsequently reacted with 2,4-dinitrophenylhydrazine (DNPH) to form the chromophore formaldehyde-DNPH, which is finally quantified by reversed phase HPLC with ultraviolet light detection at 355 nm. This method has been found to have a limit of detection of 0.05 mg kg(-1) and a limit of quantification of 0.2 mg kg(-1). Recoveries from samples spiked with known quantities of formaldehyde were 95-107%. Using this more specific technique, 20 samples of carrageenan and PES were tested for formaldehyde. Only one sample had a detectable content of formaldehyde (0.40 mg kg(-1)), thus demonstrating that the formaldehyde content of commercial carrageenan and PES products are well below the European Commission maximum limit of 5 mg kg(-1). PMID- 25531041 TI - Relaxation of highly excited carriers in wide-gap semiconductors. AB - The electron energy relaxation in semiconductors and insulators after high-level external excitation is analysed by a semi-classical approach based on a kinetic equation of the Boltzmann type. We show that the non-equilibrium distributions of electrons and holes have a customary Fermi-like shape with some effective temperature but also possess a high-energy non-Fermian 'tail'. The latter may extend deep into the conduction and valence bands while the Fermi-like component is localized within a small energy range just above the edge of the band gap. The effective temperature, effective chemical potential, and the shape of the high energy component are governed by the process of electron-phonon interactions as well as by the rates of carrier generation and inter-band radiative recombination. PMID- 25531042 TI - What benefits could caloric restriction bring to cancer patients? PMID- 25531043 TI - Potential targets of energy restriction mimetic agents in cancer cells. PMID- 25531044 TI - Is in vitro-acquired resistance to enzalutamide a useful model? PMID- 25531045 TI - USA endometrial cancer projections to 2030: should we be concerned? AB - AIM: As the incidence of endometrial cancer (EC) increased considerably since 2007, this study aimed to project the burden of EC to the year 2030. METHODS: Multivariate linear regression was used to project EC incidence by modeling trends in EC incidence from 1990 to 2013, while accounting for temporal changes in obesity, hysterectomy and smoking. RESULTS: The best-fitting model predicting EC rates included a time effect plus effects for hysterectomy (12-year lag), severe obesity (3-year lag) and smoking (9-year lag). The best-fitting model projected an increase to 42.13 EC cases per 100,000 by the year 2030, a 55% increase over 2010 EC rates. CONCLUSION: The projected increase of EC over next 16 years indicates the need for close monitoring of EC trends. PMID- 25531046 TI - Phase I dose-escalation study of aflibercept plus docetaxel in nasopharyngeal carcinoma and other solid tumors. AB - AIM: To confirm whether the aflibercept dose, plus docetaxel, in western study TCD6120 is appropriate for Chinese patients with nasopharyngeal carcinoma (NPC) and other solid tumors. MATERIALS & METHODS: To assess dose-limiting toxicity of every 3-week 4 mg/kg or 6 mg/kg aflibercept plus 75 mg/m(2) docetaxel. RESULTS: Previously treated patients (16 with NPC and 4 with lung cancer) were enrolled. At 6 mg/kg aflibercept: one dose-limiting toxicity was seen (neutropenic infection); the most frequently reported all-grade adverse events were oropharyngeal pain, stomatitis and alopecia; the most frequently reported grade 3/4 adverse events were oropharyngeal pain, stomatitis and neutropenic infection. Eleven patients had partial response and 3 had stable disease. CONCLUSION: Preliminary efficacy data for docetaxel/aflibercept are encouraging in Chinese patients with NPC. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry ( ClinicalTrials.gov , NCT01148615). PMID- 25531047 TI - Leukemic transformation in essential thrombocythemia. AB - Essential thrombocythemia patients develop acute myeloid leukemia (AML) at a rate of 1-4% during a median follow-up of 7-10 years. The risk increases with advanced age, anemia, platelet count >= 1000 * 10(9)/l, the presence of >= 2 somatic mutations and after the first decade of diagnosis. The use of alkylating agents and (32)radiophosphorus, particularly in higher doses, but not hydroxyurea and anagrelide, increases the risk. AML in essential thrombocythemia patients is frequently associated with unfavorable cytogenetics and poor prognosis. In young and fit patients, AML-type induction chemotherapy followed by allogeneic stem cell transplantation may offer the best chance of long-term disease control. In select elderly patients with poor performance status, hypomethylating agent such as azacytidine may prolong survival. PMID- 25531048 TI - Patient-centered care in cancer treatment programs: the future of integrative oncology through psychoeducation. AB - The reciprocal relationship between the mind and body has been a neglected process for improving the psychosocial care of cancer patients. Emotions form an important link between the mind and body. They play a fundamental role in the cognitive functions of decision-making and symptom control. Recognizing this relationship is important for integrative oncology. We define psychoeducation as the teaching of self-evaluation and self-regulation of the mind-body process. A gap exists between research evidence and implementation into clinical practice. The patients' search for self-empowerment through the pursuit of complementary therapies may be a surrogate for inadequate psychoeducation. Integrative oncology programs should implement psychoeducation that helps patients to improve both emotional and cognitive intelligence, enabling them to better negotiate cancer treatment systems. PMID- 25531049 TI - Promising new therapies in advanced pancreatic adenocarcinomas. AB - Pancreatic ductal adenocarcinoma is a lethal disease due to late diagnosis, early metastasis and the lack of effective therapies. In patients with metastatic disease, 1-year survival ranges from 17 to 23% and 5-year survival is less than 5%. This necessitates an urgent need for developing more effective therapies. Targeting the neoplastic cells has been largely ineffective due to the dense stroma, which is a physical barrier for effective drug delivery and also a source for different factors that promote tumor progression and immunosuppression. In this review, we focus on understanding the complex biology of this tumor as it relates to the evaluation of previously failed molecularly targeted trials and review potential new therapies that are emerging in the treatment of metastatic pancreatic ductal adenocarcinoma. PMID- 25531050 TI - Personalized treatment is better than one treatment fits all in the management of patients with mCRC: a consensus statement. AB - The VEGF- (bevacizumab) and EGFR- (cetuximab and panitumumab) targeting monoclonal antibodies have become integral components of the first-line treatment strategies for patients with metastatic colorectal cancer (mCRC). Increasingly combination chemotherapy, with or without a targeted agent, is being used to facilitate curative liver resection and improve survival rates in patients with initially unresectable but potentially resectable mCRC. Currently, the only selective marker for the treatment of patients with mCRC is tumor RAS mutational status. BRAF status is a strong prognostic indicator. Medical and clinical oncologists from Central Asia, Russia, the Middle East, Africa and Turkey reviewed data for the use of targeted agents in the treatment of patients with mCRC and have formed recommendations for the biological of choice first-line for patients with mCRC. PMID- 25531051 TI - The hypoxic tumor microenvironment: driving the tumorigenesis of non-small-cell lung cancer. AB - Since the application of molecular biology in cancer biology, lung cancer research has classically focused on molecular drivers of disease. One such pathway, the hypoxic response pathway, is activated by reduced local oxygen concentrations at the tumor site. Hypoxia-driven gene and protein changes enhance epithelial-to-mesenchymal transition, remodel the extracellular matrix, drive drug resistance, support cancer stem cells and aid evasion from immune cells. However, it is not the tumor cells alone which drive this response to hypoxia, but rather their interaction with a complex milieu of supporting cells. This review will focus on recent advances in our understanding of how these cells contribute to the tumor response to hypoxia in non-small-cell lung cancer. PMID- 25531052 TI - The role of CT10 regulation of kinase-like in cancer. AB - V-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) is a member of CRK family. It acts as an adaptor protein in intracellular signal transduction. CRKL has been reported overexpressed in a variety of cancers affecting the aggressive and malignant behaviors of cancer cells. CRKL seems to show a tumor-promotion role in gastric cancer, glioblastoma multiforme, hepatocellular carcinoma, bladder cancer, lung cancer, colon cancer, ovarian cancer, leukemia, breast cancer, head and neck cancer, rhabdomyosarcoma and neuroblastoma. The association of CRKL with malignant tumors and its potential action mechanisms were summarized. CRKL has the potential to be used as a biomarker for the diagnosis, treatment and prognosis of certain tumors. PMID- 25531053 TI - Elevated plasma dityrosine in patients with hyperlipidemia compared to healthy individuals. AB - BACKGROUND: Dityrosine, the modification of tyrosine residues, may contribute to metabolic disorders. This study was undertaken to investigate plasma dityrosine concentrations in patients with hyperlipidemia and to examine the correlation between dityrosine and lipid profiles. METHODS: Fluorescence spectrophotometry was used to measure dityrosine in the plasma of healthy subjects (n = 203) and dyslipidemic subjects, which included patients with mild hyperlipidemia (n = 246) and hyperlipidemia (n = 179). Advanced oxidation protein products (AOPP) and malondialdehyde (MDA) were also assayed in all subjects. RESULTS: Dityrosine levels were higher by 9.3 and 22.9% in mildly hyperlipidemic and hyperlipidemic patients, respectively, compared to controls after adjustment for age, gender, and BMI. AOPP and MDA levels showed similar trends. The levels of dityrosine related positively (p < 0.05) to total cholesterol (r = 0.362), triglycerides (r = 0.449), and low-density lipoprotein cholesterol (r = 0.359). Moreover, plasma dityrosine (r = 0.408), AOPP (r = 0.488), and MDA (r = 0.181) levels were elevated with an increase in the atherosclerosis index in the subjects. CONCLUSIONS: These findings suggest that dityrosine formation may be an early event in the pathological process of hyperlipidemia. Dityrosine as a biomarker detected by fluorescence spectrophotometry might be a useful tool to evaluate the plasma redox state in hyperlipidemia. PMID- 25531054 TI - Imaging of the peritoneum evaluated by 99mTc-icodextrin scintigraphy in peritoneal dialysis patients: preliminary data. AB - AIM: In this study, we proposed a peritoneal scintigraphy with a different marker, the 99mTechnetium-Icodextrin, to evaluate the distribution of the dialysate within the peritoneal cavity in peritoneal dialysis (PD) patients. METHODS: 99mTc-Icodextrin scintigraphy was performed in 16 PD patients. 0.5 ml of 7.5% Icodextrin solution was labeled with 74 megabecquerel (MBq) of 99mTc and then added to 2,000 ml of dialysate solution (2.5% dextrose). The peritoneum scintigraphy was performed by a SPECT gamma camera with the peritoneal cavity filled and after the complete drainage of the radio compound-dialysate mixture. The images were reviewed for evidence of peritoneal leaks, hernias, loculated fluid collections, and peritoneal membrane adhesions. RESULTS: Abnormal findings were detected by 99mTc-Icodextrin scintigraphy in 4 (25%) out of 16 patients and included retroperitoneal (n = 1), diaphragmatic (n = 1) and inguinal (n = 1) leakages and peritoneal membrane adhesions (n = 1). CONCLUSIONS: Peritoneum scintigraphy with 99mTc-Icodextrin is a useful method to detect some complications occurring during peritoneal dialysis; it offers excellent imaging to assess these complications. PMID- 25531055 TI - Superconductivity and its mechanism in an ab initio model for electron-doped LaFeAsO. AB - Two families of high-temperature superconductors whose critical temperatures are higher than 50 K are known. One are the copper oxides and the other are the iron based superconductors. Comparisons of mechanisms between these two in terms of common ground as well as distinctions will greatly help in searching for higher T(c) superconductors. However, studies on mechanisms for the iron family based on first principles calculations are few. Here we first show that superconductivity emerges in the state-of-the-art numerical calculations for an ab initio multi orbital model of an electron-doped iron-based superconductor LaFeAsO, in accordance with experimental observations. Then the mechanism of the superconductivity is identified as enhanced uniform density fluctuations by one to-one correspondence with the instability towards inhomogeneity driven by first order antiferromagnetic and nematic transitions. Despite many differences, certain common features with the copper oxides are also discovered in terms of the underlying orbital-selective Mottness found in the iron family. PMID- 25531056 TI - Copper-catalyzed C-H functionalization reactions: efficient synthesis of heterocycles. PMID- 25531057 TI - Trends in inpatient mortality after ischemic and hemorrhagic strokes in the United States. PMID- 25531058 TI - Mini-laparoscopy guided liver biopsy increases diagnostic accuracy in acute liver failure. AB - BACKGROUND/AIMS: For diagnosis, prognosis, and treatment of acute liver failure (ALF), macroscopic evaluation and histological assessment of the liver are important. Due to impaired coagulation in ALF, the risk of bleeding is high after a percutaneous liver biopsy. Our aims were to assess (i) safety and benefit of mini laparoscopy (ML) in patients with ALF and (ii) the potential utility of histological markers in ALF prognosis. METHODS: ML was performed in 39 patients with ALF to assess liver surface and to obtain a liver biopsy. Serological markers of liver injury and immunohistochemical detection of cell death and proliferation were compared to a non-ALF group (n = 10). RESULTS: Liver biopsies were successfully performed in all patients with no significant complications. All patients had markedly elevated M30 and M65 levels in the serum. In the liver, M30 and Ki67 immune-reactive cells were more abundant in those with ALF. Importantly, there were significantly more Ki67-positive cells but fewer M30 positive cells in livers of ALF patients who recovered spontaneously. CONCLUSION: ML with liver biopsy in patients with ALF and severe coagulopathy is safe. Immunohistochemical detection of liver cell death and regeneration may identify individuals who would recover spontaneously or who would need a liver transplant. PMID- 25531059 TI - Feline mitochondrial DNA sampling for forensic analysis: when enough is enough! AB - Pet hair has a demonstrated value in resolving legal issues. Cat hair is chronically shed and it is difficult to leave a home with cats without some level of secondary transfer. The power of cat hair as an evidentiary resource may be underused because representative genetic databases are not available for exclusionary purposes. Mitochondrial control region databases are highly valuable for hair analyses and have been developed for the cat. In a representative worldwide data set, 83% of domestic cat mitotypes belong to one of twelve major types. Of the remaining 17%, 7.5% are unique within the published 1394 sample database. The current research evaluates the sample size necessary to establish a representative population for forensic comparison of the mitochondrial control region for the domestic cat. For most worldwide populations, randomly sampling 50 unrelated local individuals will achieve saturation at 95%. The 99% saturation is achieved by randomly sampling 60-170 cats, depending on the numbers of mitotypes available in the population at large. Likely due to the recent domestication of the cat and minimal localized population substructure, fewer cats are needed to meet mitochondria DNA control region database practical saturation than for humans or dogs. Coupled with the available worldwide feline control region database of nearly 1400 cats, minimal local sampling will be required to establish an appropriate comparative representative database and achieve significant exclusionary power. PMID- 25531060 TI - Ancestry informative markers: inference of ancestry in aged bone samples using an autosomal AIM-Indel multiplex. AB - Ancestry informative markers (AIMs) can be useful to infer ancestry proportions of the donors of forensic evidence. The probability of success typing degraded samples, such as human skeletal remains, is strongly influenced by the DNA fragment lengths that can be amplified and the presence of PCR inhibitors. Several AIM panels are available amongst the many forensic marker sets developed for genotyping degraded DNA. Using a 46 AIM Insertion Deletion (Indel) multiplex, we analyzed human skeletal remains of post mortem time ranging from 35 to 60 years from four different continents (Sub-Saharan Africa, South and Central America, East Asia and Europe) to ascertain the genetic ancestry components. Samples belonging to non-admixed individuals could be assigned to their corresponding continental group. For the remaining samples with admixed ancestry, it was possible to estimate the proportion of co-ancestry components from the four reference population groups. The 46 AIM Indel set was informative enough to efficiently estimate the proportion of ancestry even in samples yielding partial profiles, a frequent occurrence when analyzing inhibited and/or degraded DNA extracts. PMID- 25531061 TI - Linear-cyclic polymer structural transformation and its reversible control using a rational rotaxane strategy. AB - Linear-cyclic polymer structural transformation and its reversibility are demonstrated by a simple but rational strategy using the structural characteristics of crown ether-based rotaxanes. The structure of a polymer containing a [1]rotaxane unit at one end was controlled by conventional protection-deprotection reactions, giving rise to a reversible linear-cyclic polymer structural transformation. PMID- 25531062 TI - Perinatal stress and food allergy: a preliminary study on maternal reports. AB - Maternal stress in fetal and early life has been associated with the development of respiratory allergies, but no studies exist about food allergy. Stressful events and the quality of caregiving provided, as they affect the emotional and physiologic regulation of the infant, could alter the hypothalamic-pituitary adrenal and immune system, facilitating an increased allergic response. This study aimed to investigate the influence of perinatal stress, as perceived by mothers, on developing food allergy in childhood. A survey on pregnancy and the first three months after giving birth was submitted to 59 Italian mothers of at least one child suffering from severe food allergy and one completely healthy child, for a total of 118 children examined. The presence of stressful events and the quality of perinatal period for each child were assessed retrospectively. The food allergic children's data were compared to siblings' data through inferential statistics. The results showed a significantly higher number of stressful events occurred during patients' perinatal period, compared to siblings, in particular bereavements in pregnancy and parenting difficulties in postpartum. Mothers reported harder pregnancies and more stressful, harder, and, in general, worse postpartum when referring to their food-allergic children, in comparison with their siblings (p < .05). Psychological aspects are demonstrated to be involved in the development of allergic diseases. This study constitutes the first step to examine the role of early stress and perinatal psychosocial factors in the pathogenesis of food allergy; further studies are necessary to understand individual psychological impact and its relations with genetic and biological factors. PMID- 25531063 TI - Synthesis of amphiphilic copolymers containing zwitterionic sulfobetaine as pH and redox responsive drug carriers. AB - Amphiphilic poly(E-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate)-r poly(N-(3-sulfopropyl)-N-methacrylate-N,N-diethylammonium-betaine) (PCL-SS PDEASB) was designed and synthesized successfully. pH and redox dually responsive micelles were prepared based on the obtained copolymers, with zwitterionic sulfobetaines as hydrophilic shell, DEA as pH sensitive content and disulfide as redox responsive linkage. The micelle diameters were all less than 200 nm and the micelle diameter distributions were narrow. These micelles could be triggered by pH and redox condition. The drug release from the drug-loaded micelles displayed fastest under simultaneously acidic and reductive conditions. Results of in vitro cell toxicity evaluation showed that introduction of sulfobetaines could greatly decrease the toxicity of poly(E-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate) (PCL-SS-PDEA) micelles. DOX-loaded PCL-SS-PDEASB micelles showed higher efficiency to kill HeLa cells than DOX-loaded PCL-PDEASB micelles. Half inhibitory concentration (IC50) of DOX-loaded PCL-SS-PDEASB micelles decreased with the content of sulfobetaines increasing and was even closer to that of DOX.HCl. Thus, the pH and redox dually responsive biodegradable micelles generated by PCL-SS-PDEASB may be potential smart drug carriers for tumor targeted delivery. PMID- 25531064 TI - Characterization and in vitro biocompatibility of catanionic assemblies formed with oppositely charged dicetyl amphiphiles. AB - In this study, cationic dicetyldimethylammonium bromide (DCB) and anionic dicetyl phosphate (DCP) were mixed to form catanionic assemblies in water, and their colloidal morphology, size, charge characteristics, phase behavior, membrane fluidity, and in vitro biocompatibility are comprehensively investigated for the first time. Our results show that the catanionic DCB and DCP mixtures in water are capable of forming circular vesicles and this binary mixed system expresses the miscibility with deviation from the ideal mixing. Compared to the nanoscale DCB-rich vesicles, the DCP-rich vesicles have smaller size, higher negative zeta potential, higher main transition temperature, and better storage stability. The temperature and molecular cooperativity of the main transition phase for the DCP vesicles can be reduced by an addition of DCB. This work demonstrates that the head groups and the relative composition of the two considered dicetyl amphiphiles remarkably affect the phase behavior, membrane rigidity, encapsulation ability and in vitro biocompatibility of DCB/DCP vesicles. The iso stoichiometric mixed DCB/DCP vesicle, showing low cytotoxicity, long storage time, and high drug loading, is a potential candidate for the drug delivery system. PMID- 25531065 TI - Analyzing the effect of state legislation on health care utilization for children with concussion. AB - IMPORTANCE: In 2009, Washington State enacted legislation outlining the medical care of children and adolescents with concussion (ie, the Lystedt Law), with all other states and Washington, DC passing legislation by January 2014. OBJECTIVE: To evaluate the effect of concussion laws on health care utilization rates from January 1, 2006, through June 30, 2012, in states with and without legislation. DESIGN, SETTING, AND PARTICIPANTS: For commercially insured children aged 12 to 18 years from all 50 states and DC from January 1, 2006, through June 30, 2009, we examined the following: (1) prelegislation trends in concussion-related health care utilization from January 1, 2006, through June 30, 2009, (2) postlegislation trends in states without concussion legislation, and (3) the effect of state concussion laws on trends in states with concussion legislation in effect by means of negative binomial multivariable estimation with state and time fixed effects. EXPOSURES: Concussion diagnosis. MAIN OUTCOMES AND MEASURES: Emergency department and related health care utilization rates for concussion. RESULTS: Between academic school years 2008-2009 and 2011-2012, states with legislation experienced a 92% increase in concussion-related health care utilization, while states without legislation had a 75% overall increase in concussion-related health care utilization during the same period. In the multivariable fixed effects models, controlling for differences across states, rates of treated concussion in states without legislation were 7% higher in the 2009-2010 school year, 20% higher in the 2010-2011 school year, and 34% higher in the 2011-2012 school year compared with the prelegislation trends (2005-2009) (all P < .01). During the same period, states with concussion laws demonstrated a 10% higher concussion-related health care utilization rate compared with states without laws (P < .01). CONCLUSIONS AND RELEVANCE: Increased health care utilization rates among children with concussion in the United States are both directly and indirectly related to concussion legislation. A portion of the increased rates (60%) in states without legislation is attributable to an ongoing upward trend demonstrated before enactment of the first state law in 2009. The remaining 40% increase in these states is thought to have resulted from elevated awareness brought about by heightened local and national media attention. Concussion legislation has had a seemingly positive effect on health care utilization, but the overall increase can also be attributed to increased injury awareness. PMID- 25531066 TI - Editorial comment for Kozminski et al. PMID- 25531067 TI - Spatial cue reliability drives frequency tuning in the barn Owl's midbrain. AB - The robust representation of the environment from unreliable sensory cues is vital for the efficient function of the brain. However, how the neural processing captures the most reliable cues is unknown. The interaural time difference (ITD) is the primary cue to localize sound in horizontal space. ITD is encoded in the firing rate of neurons that detect interaural phase difference (IPD). Due to the filtering effect of the head, IPD for a given location varies depending on the environmental context. We found that, in barn owls, at each location there is a frequency range where the head filtering yields the most reliable IPDs across contexts. Remarkably, the frequency tuning of space-specific neurons in the owl's midbrain varies with their preferred sound location, matching the range that carries the most reliable IPD. Thus, frequency tuning in the owl's space-specific neurons reflects a higher-order feature of the code that captures cue reliability. PMID- 25531068 TI - Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy. AB - Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a 'synthetic lethal toxicity' arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity. PMID- 25531069 TI - A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity. AB - Hsp90 is a conserved chaperone that facilitates protein homeostasis. Our crystal structure of the mitochondrial Hsp90, TRAP1, revealed an extension of the N terminal beta-strand previously shown to cross between protomers in the closed state. In this study, we address the regulatory function of this extension or 'strap' and demonstrate its responsibility for an unusual temperature dependence in ATPase rates. This dependence is a consequence of a thermally sensitive kinetic barrier between the apo 'open' and ATP-bound 'closed' conformations. The strap stabilizes the closed state through trans-protomer interactions. Displacement of cis-protomer contacts from the apo state is rate-limiting for closure and ATP hydrolysis. Strap release is coupled to rotation of the N terminal domain and dynamics of the nucleotide binding pocket lid. The strap is conserved in higher eukaryotes but absent from yeast and prokaryotes suggesting its role as a thermal and kinetic regulator, adapting Hsp90s to the demands of unique cellular and organismal environments. PMID- 25531070 TI - Acceleration of aged-landfill stabilization by combining partial nitrification and leachate recirculation: a field-scale study. AB - Leachate recirculation for rapid landfill stabilization can result in the accumulation of high-strength ammonium. An on-site sequencing batch reactor (SBR) was therefore, applied to oxidize the ammonium to nitrite, which was then recirculated to the landfill for denitrification to nitrogen gas. At relatively higher ammonium levels, nitrite accumulated well in the SBR; the nitrite was denitrified stably in the landfill, despite an insufficient biodegradable carbon source in the leachate. As the leachate was recirculated, the methane and carbon dioxide contents produced from the landfill fluctuated, implying that the organic acids and hydrogen produced in the acid production phase acted as the carbon source for denitrification in the landfill. Leachate recirculation combined with ex-situ partial nitrification of the leachate may enhance the biodegradation process by: (a) removing the nitrogen that is contained with the leachate, and (b) accelerating landfill stabilization, because the biodegradation efficiency of landfill waste is increased by supplying sufficient moisture and its byproducts are used as the carbon source for denitrification. In addition, partial nitrification using an SBR has advantages for complete denitrification in the landfill, since the available carbon source is in short supply in aged landfills. PMID- 25531071 TI - Sense of belonging to specific communities and depressive symptoms among Australian gay men. AB - Sense of belonging to the general and broader gay communities has been shown to be beneficial for gay men's mental health. This research investigated the interrelations between sense of belonging to three forms of gay community (the broader gay community, gay groups, and gay friends), sense of belonging to the general community, and depressive symptoms by examining a path model. A community sample of 177 gay men, aged 18 to 79 years, completed the Sense of Belonging Instrument-Psychological subscale, the Centre for Epidemiological Studies Depression Scale, and the Sense of Belonging within Gay Communities Scale. The model provided excellent fit to the data in which sense of belonging to the general community mediated the relationships between a sense of belonging to gay groups and with gay friends and depressive symptoms. Results imply that enhancing gay men's sense of belonging to gay groups and with gay friends is likely to be associated with fewer depressive symptoms, by virtue of their enhanced sense of belonging to the general community. PMID- 25531072 TI - In Brief: Influenza in 2015. PMID- 25531073 TI - First-Trimester Screening for Gestational Diabetes Mellitus Based on Maternal Characteristics and History. AB - OBJECTIVES: To develop and validate a prediction model for gestational diabetes mellitus (GDM) at 11-13 weeks' gestation based on maternal characteristics and history and to compare its performance with the method recommended by the National Institute of Health and Care Excellence (NICE) and five other published prediction models. METHODS: A predictive logistic regression model for GDM was developed from 1,827 cases (2.4%) who developed GDM and 73,334 unaffected controls. A 5-fold cross-validation study was performed to validate this model and to compare its performance with those of the NICE guidelines and the previously published models. RESULTS: In the logistic regression model, maternal age, weight, height, racial origin, family history of diabetes, use of ovulation drugs, birth weight, and previous history of GDM were found to be significant predictors of GDM. In screening for GDM in the 5-fold cross-validation study, detection rates (DRs) were higher (p < 0.0001) for the proposed model (DR = 83.2%) than for the NICE guidelines (DR = 77.5%) for a false positive rate of approximately 40% (determined by NICE). The area under the receiver operating characteristic curve of the new model was higher (p < 0.0001) than that of the previous five models (0.823 vs. 0.688-786). CONCLUSIONS: Early effective screening for GDM can be achieved based on maternal characteristics and history. PMID- 25531074 TI - Predicting weight loss and maintenance in overweight/obese pediatric patients. AB - BACKGROUND: Pediatric lifestyle interventions have positive short-term effects on obese patients. Studies on long-term effects are still scarce in Europe. We investigated long-term weight patterns and sociodemographic predictors of a weight change in a large Central European (Germany, Austria and Switzerland) overweight pediatric cohort. METHODS: The APV (Adiposity Patients Verlaufsbeobachtung) database was retrospectively analyzed; 157 specialized childhood obesity centers contributed standardized data of 29,181 patients [body mass index (BMI) >= 90th percentile; 5-25 years old] presenting between 2000 and 2012. BMI standard deviation scores (BMI-SDS) were analyzed in a 2-year follow-up and grouped according to BMI-SDS changes. Multiple logistic regression analyses were conducted to assess associations between sociodemographic factors and weight patterns. RESULTS: 2-year follow-up data were available in 3,135 patients (54.6% female). Five distinct weight trajectories 'rapid weight loss' (n = 735, 23.4%), 'delayed success' (n = 697, 22.2%), 'cycling weight' (n = 43, 1.4%), 'initial weight loss' and 'weight rebound' (n = 383, 12.2%) and 'no weight loss throughout' (n = 1,277, 40.7%) best characterized long-term BMI-SDS changes. Younger and male patients were more likely to reduce weight and maintain weight loss. CONCLUSIONS: Our results suggest that an intervention before the onset of puberty seems promising for long-term weight maintenance in overweight children. Thus, new concepts are needed to improve long-term treatment success in patients with lower success rates. PMID- 25531075 TI - WU polyomavirus in respiratory epithelial cells from lung transplant patient with Job syndrome. AB - We detected WU polyomavirus (WUPyV) in a bronchoalveolar lavage sample from lungs transplanted into a recipient with Job syndrome by using immunoassays specific for the WUPyV viral protein 1. Co-staining for an epithelial cell marker identified most WUPyV viral protein 1-positive cells as respiratory epithelial cells. PMID- 25531076 TI - Heart Rate Recovery and Physical Conditioning. PMID- 25531077 TI - Anterior segment analysis and intraocular pressure elevation after penetrating keratoplasty and posterior lamellar endothelial keratoplasty. AB - BACKGROUND: Peripheral anterior synechiae (PAS) is a common problem after penetrating keratoplasty (PK) and leads to intraocular pressure (IOP) elevation. This study examines the risk factors for IOP elevation and post-keratoplasty glaucoma. METHODS: A retrospective analysis was performed of 47 eyes following PK and of 65 eyes following Descemet's stripping endothelial keratoplasty (DSEK) between 2009 and 2011. The assessment included preoperative history of corneal disease and glaucoma, response to treatment, IOP, and visual acuity. Irido trabecular contacts (ITC), the angle opening distance (AOD 500) and the anterior chamber angle (ACA 500) were calculated. RESULTS: The incidences of IOP elevation and post-keratoplasty glaucoma were 27-36% and 10-29%, respectively. The incidence did not differ significantly between both procedures. Pre-existing glaucoma increased the risk for developing IOP elevation and post-DSEK glaucoma. Eyes with bullous keratopathy (BK) developed significantly more IOP elevation (p = 0.01, d.f. = 1, chi(2) = 6.11) and post-keratoplasty glaucoma (p = 0.01, d.f. = 1, chi(2) = 6.22) than eyes with Fuchs' endothelial dystrophy. Eyes with ITC developed post-keratoplasty glaucoma significantly more often than eyes without ITC (p = 0.01, d.f. = 1, chi(2) = 6.63). CONCLUSION: IOP elevation and post keratoplasty glaucoma showed a high incidence. Risk factors like pre-existing glaucoma, BK and PAS elevated the rate of IOP elevation and post-keratoplasty glaucoma for both procedures. PMID- 25531078 TI - Avian influenza (H7N9) virus infection in Chinese tourist in Malaysia, 2014. AB - Of the ~400 cases of avian influenza (H7N9) diagnosed in China since 2003, the only travel-related cases have been in Hong Kong and Taiwan. Detection of a case in a Chinese tourist in Sabah, Malaysia, highlights the ease with which emerging viral respiratory infections can travel globally. PMID- 25531079 TI - Mechanisms of aging-related impairment of brown adipocyte development and function. AB - Aging is one of the primary risk factors for the development of obesity, a pathology that develops due to an imbalance of increased energy consumption over reduced expenditure. Brown adipocytes are responsible for thermogenesis and could therefore counter obesity by increasing energy expenditure. It is by now well established that humans possess thermogenesis-competent brown adipocytes throughout life, and recent findings indicate that brown fat is actively involved in metabolic control and body weight regulation in adults. Aging is accompanied by a loss of classical brown adipocytes as well as the brown-like adipocytes found in white adipose tissue, suggesting that loss of their energy-expending capacity might contribute to an obesity-prone phenotype with increased age. We here discuss the hypothesis that the age-related loss of brown adipocyte regenerative capacity is a result of dysfunctional stem/progenitor cells. The possible molecular mechanisms that lead to an age-related decline in brown adipogenic stem/progenitor cell function include cell-autonomous and external effects. General loss of mitochondrial biogenesis and function has repeatedly been linked to age-related perturbation of metabolic processes. We also discuss the possibility that alterations in neuronal control by the sympathetic nervous system may contribute to impaired regeneration and thermogenesis in aged brown adipocytes. Finally, age-related changes of endocrine signals have been proposed to exacerbate the loss of brown adipose tissue. In conclusion, age-induced impairment of brown adipogenic stem/progenitor cell function could contribute to the loss of brown adipocyte regeneration, thereby promoting the development of obesity and other metabolic disorders with age. PMID- 25531080 TI - The influence of the acyl chain on the transdermal penetration-enhancing effect of synthetic phytoceramides. AB - BACKGROUND/AIMS: The skin has become very attractive as a route for drug administration. Optimization of topical drug formulations by the addition of penetration enhancers may facilitate the passage of drugs through the stratum corneum. METHODS: In this paper, the skin penetration effect of phytosphingosine and 9 derived phytoceramides (PCERs) on 3 transdermal model drugs (i.e. caffeine, testosterone, ibuprofen) was investigated via Franz diffusion cell experiments using split-thickness human skin. Azone was included as a positive control. RESULTS: The main finding in our study was that the PCERs exerted a compound dependent penetration-enhancing effect. Some of the investigated PCERs exhibited a penetration-enhancing ratio of more than 2 (mean +/- SE): for caffeine PCER1 (2.48 +/- 0.44), PCER2 (2.75 +/- 0.74), PCER3 (2.62 +/- 0.93) and PCER6 (2.70 +/- 0.45) and for testosterone PCER1 (2.08 +/- 0.56), PCER2 (2.56 +/- 0.13), PCER3 (3.48), PCER4 (2.53), PCER5 (2.04 +/- 0.14), PCER6 (2.05 +/- 0.48) and PCER10 (4.84 +/- 0.79), but none of them had an influence on ibuprofen. CONCLUSION: The investigated PCERs exhibited a penetration-enhancing effect on caffeine and testosterone but not on ibuprofen. PMID- 25531085 TI - Observation of piezoelectricity in free-standing monolayer MoS2. AB - Piezoelectricity allows precise and robust conversion between electricity and mechanical force, and arises from the broken inversion symmetry in the atomic structure. Reducing the dimensionality of bulk materials has been suggested to enhance piezoelectricity. However, when the thickness of a material approaches a single molecular layer, the large surface energy can cause piezoelectric structures to be thermodynamically unstable. Transition-metal dichalcogenides can retain their atomic structures down to the single-layer limit without lattice reconstruction, even under ambient conditions. Recent calculations have predicted the existence of piezoelectricity in these two-dimensional crystals due to their broken inversion symmetry. Here, we report experimental evidence of piezoelectricity in a free-standing single layer of molybdenum disulphide (MoS2) and a measured piezoelectric coefficient of e11 = 2.9 * 10(-10) C m(-1). The measurement of the intrinsic piezoelectricity in such free-standing crystals is free from substrate effects such as doping and parasitic charges. We observed a finite and zero piezoelectric response in MoS2 in odd and even number of layers, respectively, in sharp contrast to bulk piezoelectric materials. This oscillation is due to the breaking and recovery of the inversion symmetry of the two dimensional crystal. Through the angular dependence of electromechanical coupling, we determined the two-dimensional crystal orientation. The piezoelectricity discovered in this single molecular membrane promises new applications in low-power logic switches for computing and ultrasensitive biological sensors scaled down to a single atomic unit cell. PMID- 25531084 TI - Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. AB - One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Abeta oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Abeta oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Abeta oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Abeta oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Abeta oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management. PMID- 25531086 TI - Piezoelectricity: Now in two dimensions. PMID- 25531087 TI - Spin transistors: Closer to an all-electric device. PMID- 25531088 TI - All-electric all-semiconductor spin field-effect transistors. AB - The spin field-effect transistor envisioned by Datta and Das opens a gateway to spin information processing. Although the coherent manipulation of electron spins in semiconductors is now possible, the realization of a functional spin field effect transistor for information processing has yet to be achieved, owing to several fundamental challenges such as the low spin-injection efficiency due to resistance mismatch, spin relaxation and the spread of spin precession angles. Alternative spin transistor designs have therefore been proposed, but these differ from the field-effect transistor concept and require the use of optical or magnetic elements, which pose difficulties for incorporation into integrated circuits. Here, we present an all-electric and all-semiconductor spin field effect transistor in which these obstacles are overcome by using two quantum point contacts as spin injectors and detectors. Distinct engineering architectures of spin-orbit coupling are exploited for the quantum point contacts and the central semiconductor channel to achieve complete control of the electron spins (spin injection, manipulation and detection) in a purely electrical manner. Such a device is compatible with large-scale integration and holds promise for future spintronic devices for information processing. PMID- 25531089 TI - Proton magnetic resonance imaging using a nitrogen-vacancy spin sensor. AB - Magnetic resonance imaging, with its ability to provide three-dimensional, elementally selective imaging without radiation damage, has had a revolutionary impact in many fields, especially medicine and the neurosciences. Although challenging, its extension to the nanometre scale could provide a powerful new tool for the nanosciences, especially if it can provide a means for non destructively visualizing the full three-dimensional morphology of complex nanostructures, including biomolecules. To achieve this potential, innovative new detection strategies are required to overcome the severe sensitivity limitations of conventional inductive detection techniques. One successful example is magnetic resonance force microscopy, which has demonstrated three-dimensional imaging of proton NMR with resolution on the order of 10 nm, but with the requirement of operating at cryogenic temperatures. Nitrogen-vacancy (NV) centres in diamond offer an alternative detection strategy for nanoscale magnetic resonance imaging that is operable at room temperature. Here, we demonstrate two dimensional imaging of (1)H NMR from a polymer test sample using a single NV centre in diamond as the sensor. The NV centre detects the oscillating magnetic field from precessing protons as the sample is scanned past the NV centre. A spatial resolution of ~12 nm is shown, limited primarily by the scan resolution. PMID- 25531091 TI - Transforming cardiovascular disease prevention in women: time for the Pygmalion construct to end. AB - The transformation of cardiovascular disease prevention for women must address that a number of nontraditional atherosclerotic cardiovascular disease risk factors are unique to or predominant in women. As well, many traditional atherosclerotic cardiovascular disease risk factors impart differential risks for women and for men. Gender-specific risk assessment and management have the potential to improve atherosclerotic cardiovascular disease outcomes in women. PMID- 25531090 TI - Genetic variants in renalase and blood pressure responses to dietary salt and potassium interventions: a family-based association study. AB - BACKGROUND/AIMS: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies indicate that common variations in the gene with RNLS are associated with hypertension. The aim of this study was to examine the association between genetic variants in RNLS and blood pressure (BP) responses to strict dietary interventions of salt and potassium intake. METHODS: A total of 334 subjects from 124 families were selected and sequentially maintained on a low salt diet for 7 days (3.0 g/day, NaCl), then a high-salt diet for 7 days (18.0 g/day, NaCl), high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). RESULTS: SNPs rs919115 and rs792205 of the RNLS gene were significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to high-salt intervention. In addition, rs12356177 was significantly associated with systolic BP (SBP) and DBP responses to low-salt diet, and SBP, DBP or MAP during the high-salt intervention. Unfortunately, no associations for the 7 RNLS SNPs with BP response to high-salt diet with potassium supplementation reached nominal statistical significance. CONCLUSIONS: This family-based study indicates that genetic variants in the RNLS gene are significantly associated with BP responses to dietary salt intake. PMID- 25531092 TI - [Recommendations for quality indicators in German S3 guidelines: a critical appraisal]. AB - BACKGROUND: Assessment of the quality of medical care plays an increasingly important role in the German healthcare system. Requirements for quality indicators include validity, reliability, responsiveness, interpretability and feasibility. Because of the high impact of guidelines, quality indicators that are recommended in such guidelines are of special relevance. METHODS: We conducted a systematic review of all German S3 guidelines (actual as of November 30(th), 2013) to investigate the proportion of guidelines recommending quality indicators, which categories to classify quality indicators were used, and whether quality indicators in German S3 guidelines were developed following evidence-based methods. RESULTS: In 34 from 87 S3 guidelines (39%) a total of 394 quality indicators were defined. The vast majority of the recommended quality indicators focused on process quality. Outcome indicators were only recommended in 9 S3 guidelines (10%). None of the guidelines analysed reported the properties of the recommended quality indicators. CONCLUSION: Despite the increasing relevance of quality assessment for all stakeholders in the German healthcare system only approximately 40% of the S3 guidelines define indicators to measure the quality of care. Recommendations to assess outcome indicators are only provided in 10% of S3 guidelines. The process of the development and recommendation of quality indicators is heterogeneous and frequently not transparently reported. The current practice for the recommendation and validation of quality indicators in German S3 guidelines does not meet the requirements of evidence-based healthcare. PMID- 25531093 TI - Reduced graphene oxide anodes for potential application in algae biophotovoltaic platforms. AB - The search for renewable energy sources has become challenging in the current era, as conventional fuel sources are of finite origins. Recent research interest has focused on various biophotovoltaic (BPV) platforms utilizing algae, which are then used to harvest solar energy and generate electrical power. The majority of BPV platforms incorporate indium tin oxide (ITO) anodes for the purpose of charge transfer due to its inherent optical and electrical properties. However, other materials such as reduced graphene oxide (RGO) could provide higher efficiency due to their intrinsic electrical properties and biological compatibility. In this work, the performance of algae biofilms grown on RGO and ITO anodes were measured and discussed. Results indicate improved peak power of 0.1481 mWm(-2) using the RGO electrode and an increase in efficiency of 119%, illustrating the potential of RGO as an anode material for applications in biofilm derived devices and systems. PMID- 25531094 TI - The long pentraxin PTX3 as a key component of humoral innate immunity and a candidate diagnostic for inflammatory diseases. AB - The innate immune system is composed of a cellular arm and a humoral arm. Components of the humoral arm include members of the complement cascade and soluble pattern recognition molecules (PRMs). These PRMs recognize pathogen associated molecular patterns and are functional ancestors of antibodies, playing a role in complement activation, opsonization and agglutination. Pentraxins consist of a set of multimeric soluble proteins and represent the prototypic components of humoral innate immunity. The prototypic long pentraxin PTX3 is highly conserved in evolution and produced by somatic and innate immune cells after proinflammatory stimuli. PTX3 interacts with a set of self, nonself and modified self ligands and exerts essential roles in innate immunity, inflammation control and matrix deposition. In addition, translational studies suggest that PTX3 may be a useful biomarker of human pathologies complementary to C-reactive protein. In this study, we will review the general functions of pentraxins in innate immunity and inflammation, focusing our attention on the prototypic long pentraxin PTX3. PMID- 25531095 TI - BaCu2Se2 based compounds as promising thermoelectric materials. AB - In the past few years, many studies have been devoted to the thermoelectric properties of copper selenides and sulfides, and several families of materials have been developed with promising performances. In this paper, we report on the synthesis and thermoelectric properties of Na-doped BaCu2Se2 from 20 K to 773 K. By Na doping at the Ba site, the electrical conductivity can be increased by 2 orders of magnitude, and the power factor can reach 8.2 MUW cm(-1) K(-2) at 773 K. Combined with a low thermal conductivity of 0.65 W m(-1) K(-1), a ZT of 1.0 has been obtained for Ba0.925Na0.075Cu2Se2 at 773 K, which is the highest value reported in this family to date. However, BaCu2Se2 volatilizes at 473 K, so a protective coating is necessary for its application. Besides, we studied the thermal expansion coefficient of BaCu2Se2 in this paper. PMID- 25531096 TI - Effects of MCP-1 inhibition by bindarit therapy in a rat model of polycystic kidney disease. AB - BACKGROUND/AIMS: Experimental and clinical evidence suggested that monocyte chemoattractant protein-1 (MCP-1/CCL2) has a role in the development of interstitial inflammation and renal failure in polycystic kidney disease (PKD). We investigated whether bindarit, an inhibitor of MCP-1/CCL2 synthesis, could influence the evolution of PKD in PCK rats. METHODS: PCK rats were treated from 5 to 15 weeks of age with vehicle or bindarit. Sprague-Dawley rats served as control. For in vitro studies, murine podocytes were exposed to albumin with or without bindarit. RESULTS: MCP-1 mRNA was upregulated in the kidney of PCK rats and reduced by bindarit. Treatment limited overexpression of MCP-1 protein by epithelial cells of dilated tubules and cysts, and interstitial inflammatory cells. Excessive renal accumulation of monocytes/macrophages was lowered by bindarit by 41%. Serum creatinine slightly increased in PCK rats on vehicle and was similar to controls after bindarit. Kidney and liver cysts were not affected by treatment. Bindarit significantly reduced progressive proteinuria of PCK rats. The antiproteinuric effect was associated with the restoration of the defective nephrin expression in podocytes of PCK rats. Bindarit limited podocyte foot process effacement and ameliorated slit diaphragm frequency. In cultured podocytes, bindarit reduced MCP-1 production in response to albumin and inhibited albumin-induced cytoskeletal remodeling and cell migration. CONCLUSION: This study showed that although bindarit did not prevent renal cyst growth, it limited interstitial inflammation and renal dysfunction and reduced proteinuria in PKD. Thus, bindarit could be considered a therapeutic intervention complementary to therapies specifically acting to block renal cyst growth. PMID- 25531097 TI - Reducing incivility in the workplace: results of a three-part educational intervention. AB - BACKGROUND: Incivility among nursing staff has a negative impact on the workplace environment. The purpose of this study was to determine whether a three-part educational intervention improved the work environment in two units of a major health sciences hospital. METHOD: Staff (N = 94) participated in assessments of the intervention at designated time points postintervention. Interviews of eight volunteer participants followed the intervention. RESULTS: Perceived acts of incivility decreased significantly for both units. Self-efficacy increased for both units, whereas collective efficacy decreased for one unit and increased for the second unit. Qualitative data supported the positive impact but identified that participants were not confident their units could effectively combat incivility without refresher sessions. CONCLUSION: A three-part educational intervention was effective in decreasing incidences of perceived incivility and increasing self-efficacy. Collective efficacy might be improved and sustained with unit refresher sessions or regular discussion. PMID- 25531098 TI - Plasmon induced self-assembly of gold nanorods in polymer films. AB - Photoactivated orientation of gold nanorods (AuNRs) incorporated into polymethylmethacrylate and SU-8 photoresist films occurs under red light activation. Excitation of the longitudinal surface plasmon resonance band leads to selective orientation of the nanostructures, revealed by a change in the absorption spectra. PMID- 25531099 TI - Patient perception of benefits and harms: the Achilles heel of high-value care. PMID- 25531100 TI - Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1. AB - BACKGROUND/AIMS: OSR1 (oxidative-stress-responsive kinase 1) participates in the regulation of renal tubular ion transport, cell volume and blood pressure. Whether OSR1 contributes to the regulation of organic solute transport remained; however, elusive. The present study thus explored the OSR1 sensitivity of the peptide transporters PEPT1 and PEPT2. METHODS: cRNA encoding PEPT1 or PEPT2 were injected into Xenopus oocytes without or with additional injection of cRNA encoding wild-type OSR1, WNK1 insensitive inactive (T185A)OSR1, constitutively active (T185E)OSR1, and catalytically inactive (D164A)OSR1. Electrogenic peptide (glycine-glycine) transport was determined by dual electrode voltage clamp, the abundance of hemagglutinin-tagged PEPT2 (PEPT2-HA) by chemiluminescence. RESULTS: In Xenopus oocytes injected with cRNA encoding PEPT1 or PEPT2, but not in oocytes injected with water, the dipeptide gly-gly (2 mM) generated an appreciable inward current (I(gly-gly)). Coexpression of OSR1 significantly decreased Igly-gly in both PEPT1 and PEPT2 expressing oocytes. The effect of OSR1 coexpression on Igly gly in PEPT1 expressing oocytes was mimicked by coexpression of (T185E)OSR1, but not of (D164A)OSR1 or (T185A)OSR1. Kinetic analysis revealed that coexpression of OSR1 decreased maximal Igly-gly. OSR1 further decreased the PEPT2-HA protein abundance in the cell membrane. CONCLUSION: OSR1 has the capacity to downregulate the peptide transporters PEPT1 and PEPT2 by decreasing the carrier protein abundance in the cell membrane. PMID- 25531101 TI - Interaction and charge transfer between isolated thylakoids and multi-walled carbon nanotubes. AB - Charge separation in photosynthetic light reactions has gained much interest in an attempt to fabricate biological photovoltaic devices through integration of photosynthetic material and conducting electrodes. Direct interaction between thylakoids, as representatives of photosynthetic materials, and multi-walled carbon nanotubes (MWCNTs) is expected to increase charge transfer. Thylakoids are isolated from spinach leaf chloroplasts and pristine MWCNTs are dispersed in Triton X-100 (TX-100) as a surfactant to retain their electronic properties through non-covalent interactions. The Raman and UV-Vis spectra suggest close interactions between the thylakoids and the MWCNTs. Stable thylakoids including the embedded protein subunits and light harvesting antennas can be detected from the non-shifted 680 nm absorbance peak. The 50% fluorescence quenching in the MWCNTs-thylakoids preparation as compared to thylakoids alone using single wavelength excitation suggests charge transfer between the thylakoids and the MWCNTs. PMID- 25531102 TI - The predictive value of the Boston Acute Stroke Imaging Scale (BASIS) in acute ischemic stroke patients among Chinese population. AB - OBJECTIVE: Evaluate the predictive value of Boston Acute Stroke Imaging Scale (BASIS) in acute ischemic stroke in Chinese population. METHODS: This was a retrospective study. 566 patients of acute ischemic stroke were classified as having a major stroke or minor stroke based on BASIS. We compared short-term outcome (death, occurrence of complications, admission to intensive care unit [ICU] or neurological intensive care unit [NICU]), long-term outcome (death, recurrence of stroke, myocardial infarction, modified Rankin scale) and economic index including in-hospital cost and length of hospitalization. Continuous variables were compared by using the Student t test or Kruskal-Wallis test. Categorical variables were tested with the Chi square test. Cox regression analysis was applied to identify whether BASIS was the independent predictive variable of death. RESULTS: During hospitalization, 9 patients (4.6%) died in major stroke group while no patients died in minor stroke group (p < 0.001), 12 patients in the major stroke group and 5 patients in minor stroke group were admitted to ICU/NICU (p = 0.001). There were more complications (cerebral hernia, pneumonia, urinary tract infection) in major stroke group than minor stroke group (p<0.05). Meanwhile, the average cost of hospitalization in major stroke group was 3,100 US$ and 1,740 US$ in minor stroke group (p<0.001); the average length of stay in major and minor stroke group was 21.3 days and 17.3 days respectively (p<0.001). Results of the follow-up showed that 52 patients (26.7%) died in major stroke group while 56 patients (15.1%) died in minor stroke group (P<0.001). 62.2% of the patients in major stroke group and 80.4% of the patients in minor stroke group were able to live independently (P = 0.002). The survival analysis showed that patients with major stroke had 80% higher of risk of death than patients with minor stroke even after adjusting traditional atherosclerotic factors and NIHSS at baseline (HR = 1.8, 95% CI: 1.1-3.1). CONCLUSION: BASIS can predict in-hospital mortality, occurrence of complication, length of stay and hospitalization cost of the acute ischemic stroke patients and can also estimate the long term outcome (death and the dependency). BASIS could and should be used as a dichotomous stroke classification system in the daily practice. PMID- 25531103 TI - Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations. AB - RATIONALE: TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as beta adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear. OBJECTIVES: We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model. METHODS AND RESULTS: Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase. CONCLUSIONS: TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity which impact heart development. PMID- 25531104 TI - An individual-based model of the evolution of pesticide resistance in heterogeneous environments: control of Meligethes aeneus population in oilseed rape crops. AB - Preventing a pest population from damaging an agricultural crop and, at the same time, preventing the development of pesticide resistance is a major challenge in crop protection. Understanding how farming practices and environmental factors interact with pest characteristics to influence the spread of resistance is a difficult and complex task. It is extremely challenging to investigate such interactions experimentally at realistic spatial and temporal scales. Mathematical modelling and computer simulation have, therefore, been used to analyse resistance evolution and to evaluate potential resistance management tactics. Of the many modelling approaches available, individual-based modelling of a pest population offers most flexibility to include and analyse numerous factors and their interactions. Here, a pollen beetle (Meligethes aeneus) population was modelled as an aggregate of individual insects inhabiting a spatially heterogeneous landscape. The development of the pest and host crop (oilseed rape) was driven by climatic variables. The agricultural land of the landscape was managed by farmers applying a specific rotation and crop protection strategy. The evolution of a single resistance allele to the pyrethroid lambda cyhalothrin was analysed for different combinations of crop management practices and for a recessive, intermediate and dominant resistance allele. While the spread of a recessive resistance allele was severely constrained, intermediate or dominant resistance alleles showed a similar response to the management regime imposed. Calendar treatments applied irrespective of pest density accelerated the development of resistance compared to ones applied in response to prescribed pest density thresholds. A greater proportion of spring-sown oilseed rape was also found to increase the speed of resistance as it increased the period of insecticide exposure. Our study demonstrates the flexibility and power of an individual-based model to simulate how farming practices affect pest population dynamics, and the consequent impact of different control strategies on the risk and speed of resistance development. PMID- 25531105 TI - Enzootic transmission of yellow fever virus, Venezuela. AB - Phylogenetic analysis of yellow fever virus (YFV) strains isolated from Venezuela strongly supports YFV maintenance in situ in Venezuela, with evidence of regionally independent evolution within the country. However, there is considerable YFV movement from Brazil to Venezuela and between Trinidad and Venezuela. PMID- 25531106 TI - DEAF1 binds unmethylated and variably spaced CpG dinucleotide motifs. AB - DEAF1 is a transcriptional regulator associated with autoimmune and neurological disorders and is known to bind TTCG motifs. To further ascertain preferred DEAF1 DNA ligands, we screened a random oligonucleotide library containing an "anchored" CpG motif. We identified a binding consensus that generally conformed to a repeated TTCGGG motif, with the two invariant CpG dinucleotides separated by 6-11 nucleotides. Alteration of the consensus surrounding the dual CpG dinucleotides, or cytosine methylation of a single CpG half-site, eliminated DEAF1 binding. A sequence within the Htr1a promoter that resembles the binding consensus but contains a single CpG motif was confirmed to have low affinity binding with DEAF1. A DEAF1 binding consensus was identified in the EIF4G3 promoter and ChIP assay showed endogenous DEAF1 was bound to the region. We conclude that DEAF1 preferentially binds variably spaced and unmethylated CpG containing half-sites when they occur within an appropriate consensus. PMID- 25531107 TI - Perception of binaural cues develops in children who are deaf through bilateral cochlear implantation. AB - There are significant challenges to restoring binaural hearing to children who have been deaf from an early age. The uncoordinated and poor temporal information available from cochlear implants distorts perception of interaural timing differences normally important for sound localization and listening in noise. Moreover, binaural development can be compromised by bilateral and unilateral auditory deprivation. Here, we studied perception of both interaural level and timing differences in 79 children/adolescents using bilateral cochlear implants and 16 peers with normal hearing. They were asked on which side of their head they heard unilaterally or bilaterally presented click- or electrical pulse- trains. Interaural level cues were identified by most participants including adolescents with long periods of unilateral cochlear implant use and little bilateral implant experience. Interaural timing cues were not detected by new bilateral adolescent users, consistent with previous evidence. Evidence of binaural timing detection was, for the first time, found in children who had much longer implant experience but it was marked by poorer than normal sensitivity and abnormally strong dependence on current level differences between implants. In addition, children with prior unilateral implant use showed a higher proportion of responses to their first implanted sides than children implanted simultaneously. These data indicate that there are functional repercussions of developing binaural hearing through bilateral cochlear implants, particularly when provided sequentially; nonetheless, children have an opportunity to use these devices to hear better in noise and gain spatial hearing. PMID- 25531108 TI - The association of longitudinal and interpersonal continuity of care with emergency department use, hospitalization, and mortality among Medicare beneficiaries. AB - BACKGROUND: Continuity of medical care is widely believed to lead to better health outcomes and service utilization patterns for patients. Most continuity studies, however, have only used administrative claims to assess longitudinal continuity with a provider. As a result, little is known about how interpersonal continuity (the patient's experience at the visit) relates to improved health outcomes and service use. METHODS: We linked claims-based longitudinal continuity and survey-based self-reported interpersonal continuity indicators for 1,219 Medicare beneficiaries who completed the National Health and Health Services Use Questionnaire. With these linked data, we prospectively evaluated the effect of both types of continuity of care indicators on emergency department use, hospitalization, and mortality over a five-year period. RESULTS: Patient-reported continuity was associated with reduced emergency department use, preventable hospitalization, and mortality. Most of the claims-based measures, including those most frequently used to assess continuity, were not associated with reduced utilization or mortality. CONCLUSION: Our results indicate that the patient- and claims-based indicators of continuity have very different effects on these important health outcomes, suggesting that reform efforts must include the patient-provider experience when evaluating health care quality. PMID- 25531109 TI - Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. AB - Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P <= 0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327691. PMID- 25531110 TI - Selective calcium sensitivity in immature glioma cancer stem cells. AB - Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca2+ signaling genes in NSCs and the more stem-like (NSC-proximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca2+ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca2+ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca2+. Conversely, a higher number of and higher expression levels of Ca2+ binding genes that may buffer Ca2+, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca2+ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca2+ drug sensitivity. The correlation between high expression of Ca2+ channels (such as GRIA1) and sensitivity to Ca2+ drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES+/FABP7+/GRIA1+ GICs were selectively sensitive to disturbances in Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells. PMID- 25531111 TI - Phosphorus-assisted biomass thermal conversion: reducing carbon loss and improving biochar stability. AB - There is often over 50% carbon loss during the thermal conversion of biomass into biochar, leading to it controversy for the biochar formation as a carbon sequestration strategy. Sometimes the biochar also seems not to be stable enough due to physical, chemical, and biological reactions in soils. In this study, three phosphorus-bearing materials, H3PO4, phosphate rock tailing (PRT), and triple superphosphate (TSP), were used as additives to wheat straw with a ratio of 1: 0.4-0.8 for biochar production at 500 degrees C, aiming to alleviate carbon loss during pyrolysis and to increase biochar-C stabilization. All these additives remarkably increased the biochar yield from 31.7% (unmodified biochar) to 46.9%-56.9% (modified biochars). Carbon loss during pyrolysis was reduced from 51.7% to 35.5%-47.7%. Thermogravimetric analysis curves showed that the additives had no effect on thermal stability of biochar but did enhance its oxidative stability. Microbial mineralization was obviously reduced in the modified biochar, especially in the TSP-BC, in which the total CO2 emission during 60-d incubation was reduced by 67.8%, compared to the unmodified biochar. Enhancement of carbon retention and biochar stability was probably due to the formation of meta-phosphate or C-O-PO3, which could either form a physical layer to hinder the contact of C with O2 and bacteria, or occupy the active sites of the C band. Our results indicate that pre-treating biomass with phosphors-bearing materials is effective for reducing carbon loss during pyrolysis and for increasing biochar stabilization, which provides a novel method by which biochar can be designed to improve the carbon sequestration capacity. PMID- 25531113 TI - Reservoir host expansion of hantavirus, China. PMID- 25531112 TI - Electrical stimulation over bilateral occipito-temporal regions reduces N170 in the right hemisphere and the composite face effect. AB - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modulate cortical excitability. Although the clinical value of tDCS has been advocated, the potential of tDCS in cognitive rehabilitation of face processing deficits is less understood. Face processing has been associated with the occipito-temporal cortex (OT). The present study investigated whether face processing in healthy adults can be modulated by applying tDCS over the OT. Experiment 1 investigated whether tDCS can affect N170, a face-sensitive ERP component, with a face orientation judgment task. The N170 in the right hemisphere was reduced in active stimulation conditions compared with the sham stimulation condition for both upright faces and inverted faces. Experiment 2 further demonstrated that tDCS can modulate the composite face effect, a type of holistic processing that reflects the obligatory attention to all parts of a face. The composite face effect was reduced in active stimulation conditions compared with the sham stimulation condition. Additionally, the current polarity did not modulate the effect of tDCS in the two experiments. The present study demonstrates that N170 can be causally manipulated by stimulating the OT with weak currents. Furthermore, our study provides evidence that obligatory attention to all parts of a face can be affected by the commonly used tDCS parameter setting. PMID- 25531114 TI - MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1alpha. AB - Hypoxia is a common feature of solid tumors and an important contributor to anti tumor drug resistance. Hypoxia inducible factor-1 (HIF-1) is one of the key mediators of the hypoxia signaling pathway, and was recently proven to be required for sorafenib resistance in hepatocarcinoma (HCC). MicroRNAs have emerged as important posttranslational regulators in HCC. It was reported that miR-338-3p levels are associated with clinical aggressiveness of HCC. However, the roles of miR-338-3p in HCC disease and resistance to its therapeutic drugs are unknown. In this study, we found that miR-338-3p was frequently down regulated in 14 HCC clinical samples and five cell lines. Overexpression of miR 338-3p inhibited HIF-1alpha 3'-UTR luciferase activity and HIF-1alpha protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1alpha overexpression rescued and HIF-1alpha knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1alpha. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1alpha. Our data indicate that miR-338-3p could be a potential candidate for HCC therapeutics. PMID- 25531115 TI - Div-BLAST: diversification of sequence search results. AB - Sequence similarity tools, such as BLAST, seek sequences most similar to a query from a database of sequences. They return results significantly similar to the query sequence and that are typically highly similar to each other. Most sequence analysis tasks in bioinformatics require an exploratory approach, where the initial results guide the user to new searches. However, diversity has not yet been considered an integral component of sequence search tools for this discipline. Some redundancy can be avoided by introducing non-redundancy during database construction, but it is not feasible to dynamically set a level of non redundancy tailored to a query sequence. We introduce the problem of diverse search and browsing in sequence databases that produce non-redundant results optimized for any given query. We define diversity measures for sequences and propose methods to obtain diverse results extracted from current sequence similarity search tools. We also propose a new measure to evaluate the diversity of a set of sequences that is returned as a result of a sequence similarity query. We evaluate the effectiveness of the proposed methods in post-processing BLAST and PSI-BLAST results. We also assess the functional diversity of the returned results based on available Gene Ontology annotations. Additionally, we include a comparison with a current redundancy elimination tool, CD-HIT. Our experiments show that the proposed methods are able to achieve more diverse yet significant result sets compared to static non-redundancy approaches. In both sequence-based and functional diversity evaluation, the proposed diversification methods significantly outperform original BLAST results and other baselines. A web based tool implementing the proposed methods, Div-BLAST, can be accessed at cedar.cs.bilkent.edu.tr/Div-BLAST. PMID- 25531116 TI - Cystic gene dosage influences kidney lesions after nephron reduction. AB - Cystic kidney disease is characterized by the progressive development of multiple fluid-filled cysts. Cysts can be acquired, or they may appear during development or in postnatal life due to specific gene defects and lead to renal failure. The most frequent form of this disease is the inherited polycystic kidney disease (PKD). Experimental models of PKD showed that an increase of cellular proliferation and apoptosis as well as defects in apico-basal and planar cell polarity or cilia play a critical role in cyst development. However, little is known about the mechanisms and the mediators involved in acquired cystic kidney diseases (ACKD). In this study, we used the nephron reduction as a model to study the mechanisms underlying cyst development in ACKD. We found that tubular dilations after nephron reduction recapitulated most of the morphological features of ACKD. The development of tubular dilations was associated with a dramatic increase of cell proliferation. In contrast, the apico-basal polarity and cilia did not seem to be affected. Interestingly, polycystin 1 and fibrocystin were markedly increased and polycystin 2 was decreased in cells lining the dilated tubules, whereas the expression of several other cystic genes did not change. More importantly, Pkd1 haploinsufficiency accelerated the development of tubular dilations after nephron reduction, a phenotype that was associated to a further increase of cell proliferation. These data were relevant to humans ACKD, as cystic genes expression and the rate of cell proliferation were also increased. In conclusion, our study suggests that the nephron reduction can be considered a suitable model to study ACKD and that dosage of genes involved in PKD is also important in ACKD. PMID- 25531117 TI - Assessment of the effects of superior canal dehiscence location and size on intracochlear sound pressures. AB - Superior canal dehiscence (SCD) is a defect in the bony covering of the superior semicircular canal. Patients with SCD present with a wide range of symptoms, including hearing loss, yet it is unknown whether hearing is affected by parameters such as the location of the SCD. Our previous human cadaveric temporal bone study, utilizing intracochlear pressure measurements, generally showed that an increase in dehiscence size caused a low-frequency monotonic decrease in the cochlear drive across the partition, consistent with increased hearing loss. This previous study was limited to SCD sizes including and smaller than 2 mm long and 0.7 mm wide. However, the effects of larger SCDs (>2 mm long) were not studied, although larger SCDs are seen in many patients. Therefore, to answer the effect of parameters that have not been studied, this present study assessed the effect of SCD location and the effect of large-sized SCDs (>2 mm long) on intracochlear pressures. We used simultaneous measurements of sound pressures in the scala vestibuli and scala tympani at the base of the cochlea to determine the sound pressure difference across the cochlear partition - a measure of the cochlear drive in a temporal bone preparation - allowing for assessment of hearing loss. We measured the cochlear drive before and after SCDs were made at different locations (e.g. closer to the ampulla of the superior semicircular canal or closer to the common crus) and for different dehiscence sizes (including larger than 2 mm long and 0.7 mm wide). Our measurements suggest the following: (1) different SCD locations result in similar cochlear drive and (2) larger SCDs produce larger decreases in cochlear drive at low frequencies. However, the effect of SCD size seems to saturate as the size increases above 2-3 mm long and 0.7 mm wide. Although the monotonic effect was generally consistent across ears, the quantitative amount of change in cochlear drive due to dehiscence size varied across ears. Additionally, the size of the dehiscence above which the effect on hearing saturated varied across ears. These findings show that the location of the SCD does not generally influence the amount of hearing loss and that SCD size can help explain some of the variability of hearing loss in patients. PMID- 25531118 TI - Phase transitions and thermal-stress-induced structural changes in a ferroelectric Pb(Zr0.80Ti0.20)O3 single crystal. AB - A single crystal of lead-zirconate-titanate, composition Pb(Zr0.80Ti0.20)O3, was studied by polarized-Raman scattering as a function of temperature. Raman spectra reveal that the local structure deviates from the average structure in both ferroelectric and paraelectric phases. We show that the crystal possesses several, inequivalent complex domain boundaries which show no sign of instability even 200 K above the ferroelectric-to-paraelectric phase transition temperature TC. Two types of boundaries are addressed. The first boundary was formed between ferroelectric domains below TC. This boundary remained stable up to the highest measurement temperatures, and stabilized the domains so that they had the same orientation after repeated heating and cooling cycles. These domains transformed normally to the cubic paraelectric phase. Another type of boundary was formed at 673 K and exhibited no signs of instability up to 923 K. The boundary formation was reversible: it formed and vanished between 573 and 673 K during heating and cooling, respectively. A model in which the crystal is divided into thin slices with different Zr/Ti ratios is proposed. The physical mechanism behind the thermal-stress-induced structural changes is related to the different thermal expansion of the slices, which forces the domain to grow similarly after each heating and cooling cycle. The results are interesting for non-volatile memory development, as it implies that the original ferroelectric state can be restored after the material has been transformed to the paraelectric phase. It also suggests that a low-symmetry structure, stable up to high temperatures, can be prepared through controlled deposition of layers with desired compositions. PMID- 25531120 TI - Validity of DSM-5 dementia criteria for population research in India. PMID- 25531119 TI - Individualization of dialysate calcium concentration according to baseline pre dialysis serum calcium. AB - BACKGROUND: A positive calcium balance may contribute to vascular calcification, while a negative balance increases iPTH. We explored the impact of different dialysate calcium concentrations on bone and mineral metabolism parameters according to pre-dialysis serum calcium levels. RESULTS: Fifty-six hemodialysis patients were dialyzed with 3.0 or 2.5 mEq/l dialysate [calcium] in a crossover study of two weeks. Bone mineral metabolites were measured prior to and following the hemodialysis session. A 3.0 mEq/l dialysate [calcium] increased more post dialysis total calcium and ionized calcium than 2.5 mEq/l dialysate [calcium]. The mildest dialysis-induced changes in calcium and PTH were observed in patients with pre-dialysis serum calcium <8.75 mg/dl dialyzed with 2.5 mEq/l dialysate [calcium] and in patients with pre-dialysis serum calcium >9.15 mg/dl dialyzed with 3.0 mEq/l calcium dialysate. CONCLUSION: In conclusion, the individualization of dialysate calcium concentration according to baseline pre dialysis serum calcium may prevent major excursions in post-dialysis serum calcium and iPTH levels. SHORT SUMMARY: High calcium dialysate may increase serum calcium in hemodialysis patients, while low dialysate calcium may increase PTH. Individualization of dialysate calcium according to predialysis serum calcium levels may prevent or decrease unwanted excursions of both serum calcium and PTH. PMID- 25531121 TI - Pediatric celiac disease patients who are lost to follow-up have a poorly controlled disease. AB - BACKGROUND: Follow-up of celiac disease (CD) patients is recommended for gluten free diet (GFD) adherence monitoring and complication detection. We recently showed that 35% of children with CD were lost to follow-up (LTFU). We aimed to characterize LTFU population, and thus identify compliance barriers to GFD and follow-up. METHODS: 50 LTFU patients were investigated using a telephone questionnaire, regarding frequency of follow-up, serology testing, and adherence to GFD (using the validated Biagi score). Fifty two regular follow-up patients served as controls. RESULTS: LTFU patients had poor adherence to GFD (average Biagi score of 2.0 +/- 1.4) compared to controls (3.0 +/- 1.0, p < 0.001). Only 22% of LTFU performed periodic celiac serology testing compared to 82% of controls (p < 0.001). LTFU had higher prevalence of positive celiac serology tests (50% compared to 25% of controls, p = 0.01). Fewer LTFU were National Celiac Association members (24%) compared with controls (44%, p = 0.05). Regression analysis showed positive relationships between LTFU and poor adherence to GFD (R(2) = 0.26737, p = 0.001), older age at diagnosis (R(2) = 0.30046, p = 0.03), and non-membership in a celiac association (R(2) = 0.18591, p = 0.0001). CONCLUSION: LTFU is associated with non-adherence to GFD and positive serology. Risk factors for LFTU should be identified and addressed in order to improve patient care. PMID- 25531122 TI - Face in profile view reduces perceived facial expression intensity: an eye tracking study. AB - Recent studies measuring the facial expressions of emotion have focused primarily on the perception of frontal face images. As we frequently encounter expressive faces from different viewing angles, having a mechanism which allows invariant expression perception would be advantageous to our social interactions. Although a couple of studies have indicated comparable expression categorization accuracy across viewpoints, it is unknown how perceived expression intensity and associated gaze behaviour change across viewing angles. Differences could arise because diagnostic cues from local facial features for decoding expressions could vary with viewpoints. Here we manipulated orientation of faces (frontal, mid profile, and profile view) displaying six common facial expressions of emotion, and measured participants' expression categorization accuracy, perceived expression intensity and associated gaze patterns. In comparison with frontal faces, profile faces slightly reduced identification rates for disgust and sad expressions, but significantly decreased perceived intensity for all tested expressions. Although quantitatively viewpoint had expression-specific influence on the proportion of fixations directed at local facial features, the qualitative gaze distribution within facial features (e.g., the eyes tended to attract the highest proportion of fixations, followed by the nose and then the mouth region) was independent of viewpoint and expression type. Our results suggest that the viewpoint-invariant facial expression processing is categorical perception, which could be linked to a viewpoint-invariant holistic gaze strategy for extracting expressive facial cues. PMID- 25531123 TI - Combined photo-fenton-SBR processes for the treatment of wastewater from the citrus processing industry. AB - In this study, the photo-Fenton process was combined with a sequencing batch reactor (SBR) for the treatment of synthetic samples of citrus wastewater (CWW). An experimental design based on the surface response methodology was applied to assess the individual and combined effects of several operating parameters (CODinitial, Fe3(+) concentration and H2O2 concentration) on the photo-Fenton treatment efficiency (DOC removal) with the aim of optimizing the process. The experimental results obtained under optimal conditions for CWW with high CODinitial (10000 mgO2/L) showed a partial degradation of organic matter of around of 61% (measured as DOC). Thereafter, the photo-Fenton effluent was neutralized and clarified before being subjected to the SBR reactor. The results show degradation yields up to 93% of the initial DOC removal without producing undesired side effects, using a hydraulic retention time (HRT) of 1.59 d. The final effluent contained a concentration of organic matter (measured as COD) of 120 mg O2/L. PMID- 25531127 TI - Polyurea microcapsules in microfluidics: surfactant control of soft membranes. AB - Interfacial polymerization techniques offer a versatile route for microcapsule synthesis. We designed a microfluidic process to synthesize monodisperse polyurea microcapsules (PUMCs); the microcapsules are formed by an interfacial polymerization of isocyanate dissolved in the oil and an amine dissolved in water. We measure the mechanical properties of the capsule as well as transport properties through the membrane using two microfluidic methods. We show that the elasticity and the permeability of the shell are controlled by surfactant additives, added during the synthesis. The control of the nanostructure of the shell by surfactants provides new means to design encapsulation systems with tailored mechanical and physicochemical properties. PMID- 25531128 TI - Expression of PRX36, PMEI6 and SBT1.7 is controlled by complex transcription factor regulatory networks for proper seed coat mucilage extrusion. AB - Mucilage secretory cells (MSC) form an intriguing cell layer important for seed germination. In Arabidopsis thaliana, several master transcription factors (TFs) and "actor" proteins have already been identified as key players for seed coat differentiation including epidermal cell formation, mucilage production and extrusion. The regulation of the genes coding for MSC cell wall "actor" proteins by TFs needs to be better established. Here, the expression and the regulation of 3 known actors (PRX36, PMEI6, SBT1.7) and 2 additional putative actors (PRX56, DIR12) have been analyzed in T-DNA mutants affected in master TFs (ap2, egl3/gl3, gl2, myb5, tt8, ttg1, ttg2 and luh1/mum1). Genes with somehow similar function are differentially regulated and conversely, genes with different functions are regulated in similar manner. PMID- 25531129 TI - Synthesis and characterization of mononuclear, pseudotetrahedral cobalt(III) compounds. AB - The preparation and characterization of two mononuclear cobalt(III) tropocoronand complexes, [Co(TC-5,5)](BF4) and [Co(TC-6,6)](BPh4), are reported. The cobalt(III) centers exist in rare pseudotetrahedral conformations, with twist angles of 65 degrees and 74 degrees for the [Co(TC-5,5](+) and [Co(TC-6,6)](+) species, respectively. Structural and electrochemical characteristics are compared with those of newly synthesized [Ga(TC-5,5)](GaCl4) and [Ga(TC 6,6)](GaCl4) analogues. The spin state of the pseudotetrahedral [Co(TC 6,6)](BPh4) compound was determined to be S = 2, a change in spin state from the value of S = 1 that occurs in the square-planar and distorted square-planar complexes, [Co(TC-3,3)](X) (X = BPh4, BAr'4) and [Co(TC-4,4)](BPh4), respectively. PMID- 25531130 TI - Donor/acceptor coupling shortcuts in electron transfer within ruthenium-modified derivatives of cytochrome b(562). AB - Quantitative theoretical studies of long-range electron transfer are still rare, and reliable computational methods to analyze these reactions are still being developed. We re-examined electron transfer reactions in ruthenium-modified cytochrome b562 derivatives focusing on accurate calculation of statistical average of electron transfer rates that are dominated by a small fraction of accessible protein conformations. We performed a series of ab initio calculations of donor/acceptor interactions over protein fragments sampled from long molecular dynamic trajectories and compared computed electron transfer rates to available experimental data. Our approach takes into account cofactor electronic structure and effects of solvation on the donor-acceptor interactions. It allows predicting absolute values of electron transfer rates in contrast to other computational methodologies that give only qualitative results. Our calculations reproduced with a good accuracy experimental electron transfer rates. We also found that electron transfer in some of the cytochrome b562 derivatives is dominated by "shortcut" conformations, where donor/acceptor interactions are mediated by nonbonded interactions of Ru ligands with protein surface groups. Several derivatives adopt long-lived conformations with the Ru complex interacting with negatively charged protein residues that are characterized by shorter Ru-Fe distances and higher ET rates. We argue that quantitative theoretical analysis is essential for detailed understanding of protein electron transfer and mechanisms of biological redox reactions. PMID- 25531131 TI - Colorimetric and plasmonic detection of lectins using core-shell gold glyconanoparticles prepared by copper-free click chemistry. AB - This study describes the simple preparation of core-shell glycosyl gold nanoparticles (AuNPs) using stepwise, copper-free click chemistry-promoted self assembly. The as-formed glyco-AuNPs can be used for the selective detection of sugar-lectin interactions, which are vital to many important physiological and pathological processes. The approach uses AuNPs as bioprobes since they produce, sensitively, changes in both color visible to the naked eye and surface plasmon resonance (SPR), on aggregation. Strain-promoted click reaction of an azido galactoside with a lipid cyclooctyne affords a galactolipid that can be embedded into polyethylene glycol (PEG)-coated AuNP via self-assembly. Subsequently, using naked-eye and plasmon resonance scattering spectroscopy, we were able to observe the colorimetric and plasmonic variations of the glyco-AuNPs, respectively, in the presence of a selective lectin over other proteins. PMID- 25531132 TI - Editorial comment for Chu et al. PMID- 25531133 TI - Concomitant laparoscopic intraperitoneal onlay mesh repair with other clean contaminated procedures-study of feasibility and safety. AB - BACKGROUND: Laparoscopic ventral hernia mesh repair has gained wide popularity with the benefits of shorter hospital stay, improved patient outcome, and fewer complications compared with traditional open procedures. It also offers the advantage of combining procedures at different quadrants of the abdomen. In this article we have retrospectively studied the safety of combining laparoscopic intraperitoneal onlay mesh (IPOM) repair with clean contaminated surgeries like cholecystectomy and hysterectomy. MATERIALS AND METHODS: The data of all patients who received concomitant laparoscopic ventral hernia repairs along with cholecystectomy and hysterectomy were collected retrospectively. The details of these surgeries and the immediate postoperative outcome parameters were analyzed. RESULTS: Between January 2006 and January 2011, 246 cases of laparoscopic IPOM in combination with clean contaminated surgeries were performed. Of these, 126 were hysterectomies, and 120 were cholecystectomies. Mean operating time for laparoscopic IPOM with cholecystectomy was 136 minutes (range, 112-172 minutes), and that for laparoscopic IPOM with hysterectomy was 224 minutes (range, 196-285 minutes). The average hospital stays were 4.3 days (range, 3-7 days) for laparoscopic IPOM with hysterectomy and 2.73 days (range, 1-5 days) for laparoscopic IPOM with cholecystectomy. Thirty-six patients (14.6%) developed seroma, for which 16 patients (6.5%) warranted aspiration. We had 0.8% mesh infection in total. The recurrence rates were 0.83% (n=1) in the cholecystectomy group and 0.8% (n=1) in the hysterectomy group. CONCLUSIONS: Laparoscopic IPOM can be performed simultaneously with selected clean contaminated surgeries with acceptable morbidity. Combining clean contaminated surgeries does not significantly alter the outcome of the procedure. PMID- 25531134 TI - Short communication: Efficiently inhibiting HIV-1 replication by a prototype foamy virus vector expressing novel H1 promoter-driven short hairpin RNAs. AB - RNA interference has shown great potential for the treatment of HIV-1. Vectors derived from prototype foamy viruses (PFVs) with a nonpathogenic nature are very promising gene transfer vehicles in anti-HIV gene therapy. In this article, three short hairpin RNAs (shRNAs) targeting the conserved regions of the HIV-1NL4-3 5' long terminal repeat (LTR) were first designed. We then constructed novel recombinant PFV vector plasmids, p?Phi-H1-shRNAs, expressing these shRNAs under the control of the H1 RNA promoter. To detect the efficacy of these ?Phi-H1 shRNAs for the inhibition of HIV-1 replication, we performed a dual-luciferase reporter assay, RT-qPCR, ELISA, western blotting, and a lactate dehydrogenase (LDH) assay by transient transfection in 293T cells. The results suggest that these novel shRNAs driven by PFV vectors inhibit HIV-1 replication efficiently without cytotoxicity, with shRNA3 being the most effective. In addition, we analyzed the shRNA target sites in the 5' LTR of HIV-1 strains other than HIV 1NL4-3 and found that these shRNAs may possibly inhibit other HIV-1 strains. PMID- 25531135 TI - Characterization of Peroxidases Expressed in Human Antigen Presenting Cells and Analysis of the Covalent Binding of Nitroso Sulfamethoxazole to Myeloperoxidase. AB - Drug hypersensitivity remains a major concern, as it causes high morbidity and mortality. Understanding the mechanistic basis of drug hypersensitivity is complicated by the multiple risk factors implicated. This study utilized sulfamethoxazole (SMX) as a model drug to (1) relate SMX metabolism in antigen presenting cells (APCs) to the activation of T-cells and (2) characterize covalent adducts of SMX and myeloperoxidase, which might represent antigenic determinants for T-cells. The SMX metabolite nitroso-SMX (SMX-NO) was found to bind irreversibly to APCs. Time- and concentration-dependent drug-protein adducts were also detected when APCs were cultured with SMX. Metabolic activation of SMX was significantly reduced by the oxygenase/peroxidase inhibitor methimazole. Similarly, SMX-NO-specific T-cells were activated by APCs pulsed with SMX, and the response was inhibited by pretreatment with methimazole or glutaraldehyde, which blocks antigen processing. Western blotting, real-time polymerase chain reaction (RT-PCR), and mass spectrometry analyses suggested the presence of low concentrations of myeloperoxidase in APCs. RT-PCR revealed mRNA expression for flavin-containing monooxygenases (FMO1-5), thyroid peroxidase, and lactoperoxidase, but the corresponding proteins were not detected. Mass spectrometric characterization of SMX-NO-modified myeloperoxidase revealed the formation of N-hydroxysulfinamide adducts on Cys309 and Cys398. These data show that SMX's metabolism in APCs generates antigenic determinants for T-cells. Peptides derived from SMX-NO-modified myeloperoxidase may represent one form of functional antigen. PMID- 25531136 TI - PPARgamma agonist-induced fluid retention depends on alphaENaC expression in connecting tubules. AB - BACKGROUND/AIMS: Thiazolidinediones (TZDs, like rosiglitazone (RGZ)) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists used to treat type 2 diabetes. Clinical limitations include TZD-induced fluid retention and body weight (BW) increase, which are inhibited by amiloride, an epithelial sodium channel (ENaC) blocker. RGZ-induced fluid retention is maintained in mice with alphaENaC knockdown in the collecting duct (CD). Since ENaC in the connecting tubule (CNT) rather than in CD appears to be critical for normal NaCl retention, we aimed to further explore the role of ENaC in CNT in RGZ-induced fluid retention. METHODS: Mice with conditional inactivation of alphaENaC in both CNT and CD were used (alphaENaC lox/lox AQP2-Cre; 'alphaENaC-CNT/CD-KO') and compared with littermate controls (alphaENaC lox/lox mice; 'WT'). BW was monitored and total body water (TBW) and extracellular fluid volume (ECF) were determined by bioelectrical impedance spectroscopy (BIS) before and after RGZ (320 mg/kg diet for 10 days). RESULTS: On regular NaCl diet, alphaENaC-CNT/CD-KO had normal BW, TBW, ECF, hematocrit, and plasma Na(+), K(+), and creatinine, associated with an increase in plasma aldosterone compared with WT. Challenging alphaENaC-CNT/CD-KO with a low NaCl diet unmasked impaired NaCl and K homeostasis, consistent with effective knockdown of alphaENaC. In WT, RGZ increased BW (+6.1%), TBW (+8.4%) and ECF (+10%), consistent with fluid retention. These changes were significantly attenuated in alphaENaC-CNT/CD-KO (+3.4, 1.3, and 4.3%). CONCLUSION: Together with the previous studies, the current results are consistent with a role of alphaENaC in CNT in RGZ-induced fluid retention, which dovetails with the physiological relevance of ENaC in this segment. PMID- 25531137 TI - Reliability and validity of the Menopausal Symptom Scale. AB - Menopausal symptom experiences differ by racial/ethnic group. Thus, health care professionals who use instruments to measure menopausal symptoms need to be aware of cultural sensitivities. The purpose of this study was to examine the psychometric properties of the Menopausal Symptom Scale among Korean women. Data from 229 Korean women between the ages of 40 and 65 years, selected by convenience sampling, were collected during 2010-2011. Psychometric properties were evaluated through content validity and item analysis, construct validity, discriminant validity, criterion-related validity, floor/ceiling effects, and internal consistency reliability. Exploratory and confirmatory factor analyses revealed four factors explaining 65% of variance in the items. Discriminant validity and the criterion-related validity were supported. No significant floor/ceiling effects were found. Cronbach's alpha values ranged from 0.90 to 0.95. The Menopausal Symptom Scale developed for Korean menopausal women appeared to be a valid and reliable instrument. It appeared that it measured psychological symptoms more comprehensively and in a culturally-specific or ethnic-specific manner in menopausal women of Asian or traditional cultures. It will be necessary to broaden the scale of research to other ethnic groups and countries to verify the psychometric properties specific to the ethnic group or country. PMID- 25531138 TI - Application of a smartphone nurse call system for nursing care. AB - BACKGROUND: Traditionally, a patient presses the nurse call button and alerts the central nursing station. This system cannot reach the primary care nurse directly. The aim of this study was to apply a new smartphone system through the cloud system and information technology that linked a smartphone and a mobile nursing station for nursing care service. MATERIALS AND METHODS: A smartphone and mobile nursing station were integrated into a smartphone nurse call system through the cloud and information technology for better nursing care. RESULTS: Waiting time for a patient to contact the most responsible nurse was reduced from 3.8 min to 6 s. The average time for pharmacists to locate the nurse for medication problem was reduced from 4.2 min to 1.8 min by the new system. CONCLUSIONS: After implementation of the smartphone nurse call system, patients received a more rapid response. This improved patients' satisfaction and reduced the number of complaints about longer waiting time due to the shortage of nurses. PMID- 25531139 TI - Mutant poisoning demonstrates a nonsequential mechanism for digestion of double stranded DNA by lambda exonuclease trimers. AB - lambda Exonuclease (lambdaexo) is a highly processive 5'-3' exonuclease that binds double-stranded DNA (dsDNA) ends and digests the 5'-strand into mononucleotides. The enzyme forms a toroidal homotrimer with a central tapered channel for tracking along the DNA. During catalysis, dsDNA enters the open end of the channel, and the 5'-strand is digested at one of the three active sites. It is currently not known if lambdaexo uses a sequential mechanism, in which the DNA moves from one active site to the next around the trimer for each round of catalysis or a nonsequential mechanism, in which the DNA locks onto a single active site for multiple rounds. To understand how lambdaexo uses its three active sites, we used a mutant poisoning approach, in which a 6xHis-tagged K131A inactive mutant of lambdaexo was mixed with untagged wild type (WT) to form hybrid trimers. Nickel-spin pull-down analysis confirmed complete subunit exchange after 1 h at 37 degrees C. Exonuclease assays revealed an approximately linear decrease in activity with increasing fraction of mutant, as expected for a nonsequential mechanism. By fitting the observed rates of digestion to a simple mathematical model, the individual rates of the two hybrid species of trimer were determined. This analysis showed that trimers containing only one or two WT subunits contribute significantly to the observed activity, in further agreement with a nonsequential mechanism. Finally, purification of hybrid trimer mixtures by Ni-spin chromatography, to remove the contribution from fully WT trimers, also resulted in significant levels of activity, again consistent with a nonsequential mechanism. PMID- 25531140 TI - Antibodies against Borrelia burgdorferi sensu lato among Adults, Germany, 2008 2011. AB - To assess Borrelia burgdorferi sensu lato (the cause of Lyme borreliosis) seropositivity in Germany, we tested serum samples from health survey (2008-2011) participants. Seroprevalence was 5.8% among women and 13.0% among men; infection risk was highest among persons >60 years of age. Public health interventions, including education about risk factors and preventive measures, are needed. PMID- 25531141 TI - Kyasanur Forest disease outbreak and vaccination strategy,Shimoga District, India, 2013-2014. AB - We investigated a Kyasanur Forest disease outbreak in Karnataka, India during December 2013-April 2014. Surveillance and retrospective study indicated low vaccine coverage, low vaccine effectiveness, and spread of disease to areas beyond those selected for vaccination and to age groups not targeted for vaccination. To control disease, vaccination strategies need to be reviewed. PMID- 25531142 TI - Trunk-rotation differences at maximal reach of the star excursion balance test in participants with chronic ankle instability. AB - CONTEXT: Functional reach on the Star Excursion Balance Test is decreased in participants with chronic ankle instability (CAI). However, comprehensive 3 dimensional kinematics associated with these deficits have not been reported. OBJECTIVE: To determine if lower extremity kinematics differed in CAI participants during anteromedial, medial, and posteromedial reach on the Star Excursion Balance Test. DESIGN: Case-control study. SETTING: Sports medicine research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty CAI participants (age = 24.15 +/- 3.84 years, height = 168.95 +/- 11.57 cm, mass = 68.95 +/- 16.29 kg) and 20 uninjured participants (age = 25.65 +/- 5.58 years, height = 170.14 +/- 8.75 cm, mass = 69.89 +/- 10.51 kg) with no history of ankle sprain. We operationally defined CAI as repeated episodes of ankle "giving way" or "rolling over" or both, regardless of neuromuscular deficits or pathologic laxity. All CAI participants scored <=26 on the Cumberland Ankle Instability Tool. INTERVENTION(S): Star Excursion Balance Test reaches in the anteromedial, medial, and posteromedial directions. The CAI participants used the unstable side as the stance leg. Control participants were sex, height, mass, and side matched to the CAI group. The 3-dimensional kinematics were assessed with a motion-capture system. MAIN OUTCOME MEASURE(S): Group differences on normalized reach distance, trunk, pelvis, and hip-, knee-, and ankle-joint angles at maximum Star Excursion Balance Test reach. RESULTS: No reach-distance differences were detected between CAI and uninjured participants in any of the 3 reach directions. With anteromedial reach, trunk rotation (t(1,38) = 3.06, P = .004), pelvic rotation (t(1,38) = 3.17, P = .003), and hip flexion (t(1,38) = 2.40, P = .002) were greater in CAI participants. With medial reach, trunk flexion (t(1,38) = 6.39, P = .05) was greater than for uninjured participants. No differences were seen with posteromedial reach. CONCLUSIONS: We did not detect reach-distance differences in any direction. However, participants with CAI rotated the trunk and pelvis more toward the stance leg than did stable-ankle participants during anteromedial and medial reach, possibly to help maintain a proximal stable posture and compensate for distal instability. These joint-angle differences with Star Excursion Balance Test performance may represent unique compensatory patterns for those with CAI. PMID- 25531143 TI - High-intensity running and plantar-flexor fatigability and plantar-pressure distribution in adolescent runners. AB - CONTEXT: Fatigue-induced alterations in foot mechanics may lead to structural overload and injury. OBJECTIVES: To investigate how a high-intensity running exercise to exhaustion modifies ankle plantar-flexor and dorsiflexor strength and fatigability, as well as plantar-pressure distribution in adolescent runners. DESIGN: Controlled laboratory study. SETTING: Academy research laboratory. PATIENTS OR OTHER PARTICIPANTS: Eleven male adolescent distance runners (age = 16.9 +/- 2.0 years, height = 170.6 +/- 10.9 cm, mass = 54.6 +/- 8.6 kg) were tested. INTERVENTION(S): All participants performed an exhausting run on a treadmill. An isokinetic plantar-flexor and dorsiflexor maximal-strength test and a fatigue test were performed before and after the exhausting run. Plantar pressure distribution was assessed at the beginning and end of the exhausting run. MAIN OUTCOME MEASURE(S): We recorded plantar-flexor and dorsiflexor peak torques and calculated the fatigue index. Plantar-pressure measurements were recorded 1 minute after the start of the run and before exhaustion. Plantar variables (ie, mean area, contact time, mean pressure, relative load) were determined for 9 selected regions. RESULTS: Isokinetic peak torques were similar before and after the run in both muscle groups, whereas the fatigue index increased in plantar flexion (28.1%; P = .01) but not in dorsiflexion. For the whole foot, mean pressure decreased from 1 minute to the end (-3.4%; P = .003); however, mean area (9.5%; P = .005) and relative load (7.2%; P = .009) increased under the medial midfoot, and contact time increased under the central forefoot (8.3%; P = .01) and the lesser toes (8.9%; P = .008). CONCLUSIONS: Fatigue resistance in the plantar flexors declined after a high-intensity running bout performed by adolescent male distance runners. This phenomenon was associated with increased loading under the medial arch in the fatigued state but without any excessive pronation. PMID- 25531144 TI - Injuries in professional male soccer players in the Netherlands: a prospective cohort study. AB - CONTEXT: Injuries are a major adverse event in a soccer player's career. Reducing injury incidence requires a thorough knowledge of the epidemiology of soccer injuries. OBJECTIVE: To investigate the incidence and characteristics of injuries in the Dutch premier soccer league. DESIGN: Cohort study. SETTING: The Dutch premier soccer league. PATIENTS OR OTHER PARTICIPANTS: During the 2009-2010 soccer season, a total of 217 professional soccer players from 8 teams were prospectively followed. MAIN OUTCOME MEASURE(S): The medical staff recorded time loss injuries, including information on injuries (ie, type, body part, duration) and exposure data for training sessions and matches. RESULTS: A total of 286 injuries were recorded, affecting 62.7% of the players. The overall injury incidence was 6.2 injuries per 1000 player-hours, 2.8 in training sessions and 32.8 in matches. Most of the recorded injuries were acute (68.5%). Eight percent of the injuries were classified as recurrent. Injuries were most likely to be located in the lower extremities (82.9%). Injury time loss ranged from 1 to 752 days, with a median of 8 days. Knee injuries had the greatest consequences in terms of days of absence from soccer play (on average, 45 days). The most common diagnosis was muscle/tendon injury of the lower extremities (32.9%). CONCLUSIONS: Injury risk in the Dutch premier soccer league is high, especially during matches. Preventive measures should focus on the most common diagnoses, namely, muscle/tendon injuries of the lower extremities. PMID- 25531145 TI - Unipedal postural stability in nonathletes with core instability after intensive abdominal drawing-in maneuver. AB - CONTEXT: The exact neuromechanical nature and relative contribution of the abdominal drawing-in maneuver (ADIM) to postural instability warrants further investigation in uninjured and injured populations. OBJECTIVE: To determine the effects of the ADIM on static core and unipedal postural stability in nonathletes with core instability. DESIGN: Controlled laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 19 nonathletes (4 women: age = 22.3 +/- 1.3 years, height = 164.0 +/- 1.7 cm, mass = 56.0 +/- 4.6 kg; 15 men: age = 24.6 +/- 2.8 years, height = 172.6 +/- 4.7 cm, mass = 66.8 +/- 7.6 kg) with core instability. INTERVENTION(S): Participants received ADIM training with visual feedback 20 minutes each day for 7 days each week over a 2 week period. MAIN OUTCOME MEASURES(S): Core instability was determined using a prone formal test and measured by a pressure biofeedback unit. Unipedal postural stability was determined by measuring the center-of-pressure sway and associated changes in the abdominal muscle-thickness ratios. Electromyographic activity was measured concurrently in the external oblique, erector spinae, gluteus medius, vastus medialis oblique, tibialis anterior, and medial gastrocnemius muscles. RESULTS: All participants initially were unable to complete the formal test. However, after the 2-week ADIM training period, all participants were able to reduce the pressure biofeedback unit by a range of 4 to 10 mm Hg from an initial 70 mm Hg and maintain it at 60 to 66 mm Hg with minimal activation of the external oblique (t(18) = 3.691, P = .002) and erector spinae (t(18) = 2.823, P = .01) muscles. Monitoring of the pressure biofeedback unit and other muscle activations confirmed that the correct muscle contraction defining the ADIM was accomplished. This core stabilization was well maintained in the unipedal-stance position, as evidenced by a decrease in the center-of-pressure sway measures (t(18) range, 3.953-5.775, P < .001), an increased muscle-thickness ratio for the transverse abdominis (t(18) = -2.327, P = .03), and a reduction in external oblique muscle activity (t(18) = 3.172, P = .005). CONCLUSIONS: We provide the first evidence to highlight the positive effects of ADIM training on core and postural stability in nonathletes with core instability. PMID- 25531146 TI - A low-salt diet increases the estimated net endogenous acid production in nondiabetic chronic kidney disease patients treated with angiotensin receptor blockade. AB - BACKGROUND/AIMS: An acid-base imbalance precedes renal disease progression in patients with chronic kidney disease (CKD). Little is known about the effects of a low-salt diet (LSD) on net endogenous acid production (NEAP) levels in CKD patients using angiotensin receptor blockade. METHODS: We enrolled a total of 202 nondiabetic CKD patients who underwent an 8-week treatment with olmesartan from the original trial [Effects of Low Sodium Intake on the Antiproteinuric Efficacy of Olmesartan in Hypertensive Patients with Albuminuria (ESPECIAL) trial: NCT01552954]. The patients were divided into good- and poor-LSD-compliance groups. RESULTS: During the interventional 8 weeks, the NEAP in the good compliance group increased compared to the control group (12.9 +/- 32.0 vs. -2.0 +/- 35.0 mmol/day, p = 0.002). NEAP was positively associated with the good-LSD compliance group in the fully adjusted analyses (r = 0.135, p = 0.016). The additional reduction of 2.39 g/day of protein intake with a reduction of 1 g/day of salt intake did not increase the NEAP under angiotensin II receptor blockade (ARB) treatment with an LSD (r = 0.546, p < 0.001). CONCLUSION: We found that an LSD may increase the NEAP in nondiabetic CKD patients using ARB, which suggests that additional acid producing-protein restriction should be required to prevent the NEAP from rising. PMID- 25531147 TI - New Developments in the Biodemography of Aging and Longevity. AB - Biodemography is a promising scientific approach based on using demographic data and methods for getting insights into biological mechanisms of observed processes. Recently, new important developments have happened in biodemographic studies of aging and longevity that call into question conventional aging theories and open up novel research directions. Recent studies found that the exponential increase of the mortality risk with age (the famous Gompertz law) continues even at extreme old ages in humans, rats, and mice, thus challenging traditional views about old-age mortality deceleration, mortality leveling-off, and late-life mortality plateaus. This new finding represents a challenge to many aging theories, including the evolutionary theory that explains senescence by a declining force of natural selection with age. Innovative ideas are needed to explain why exactly the same exponential pattern of mortality growth is observed not only at reproductive ages, but also at very-old postreproductive ages (up to 106 years), long after the force of natural selection becomes negligible (when there is no room for its further decline). Another important recent development is the discovery of long-term 'memory' for early-life experiences in longevity determination. Siblings born to young mothers have significantly higher chances to live up to 100 years, and this new finding, confirmed by two independent research groups, calls for its explanation. As recent studies found, even the place and season of birth matter for human longevity. Beneficial longevity effects of young maternal age are observed only when children of the same parents are compared, while the maternal age effect often could not be detected in across families studies, presumably being masked by between-family variation. It was also found that male gender of centenarian has a significant positive effect on the survival of adult male biological relatives (brothers and fathers) but not of female relatives. Finally, large gender differences are found in longevity determinants for males and females, suggesting a higher importance of occupation history for male centenarians as well as a higher importance of home environment history for female centenarians. PMID- 25531148 TI - Urinary incontinence: not just a mid-laugh crisis. PMID- 25531149 TI - The relationship between illness perceptions and cardiac misconceptions after Myocardial Infarction. AB - Research about cardiac misconceptions has focused on identifying the most common erroneous beliefs and understanding their impact on patients' outcomes. However, less is known about the underlying structure of cardiac misconceptions and how they relate to other belief dimensions. The aims of the present study were: (a) to characterize illness perceptions and cardiac misconceptions in a sample of Myocardial Infarction (MI) patients; (b) to analyse the structure of an experimental Portuguese version of the York Cardiac Beliefs Questionnaire (YCBQ); and (c) to examine whether illness perceptions are likely to influence cardiac misconceptions. This cross-sectional study included 127 first-MI patients from both sexes, aged up to 70 years old. Confirmatory factor analysis and structural equation modelling were performed with AMOS. The main results showed that a two dimension (stress avoidance and exercise avoidance) version of the YCBQ offered the best fit to the data. A significant impact of psychological attributions was observed on cardiac misconceptions, as well as a moderate impact of emotional response explaining 26% of the variance. Although exploratory, this study gives a significant contribution to research in this field, as clarification on the different concepts and the way they relate is needed. Our findings suggest that further investigation into the concepts of cardiac knowledge and cardiac misconceptions may have an important role in understanding health behaviours in the context of heart disease. PMID- 25531150 TI - Angiocentric and intravascular lymphomas. AB - Under the generic diagnosis of angiocentric and intravascular lymphomas are included several subtypes of lymphomas histopathologically characterized either by the predominantly endovascular-endoluminal presence of neoplastic lymphocytes of B-T or NK/T cell origin, or by a pathologic process centered around a blood vessels secondarily infiltrated and invaded by the spreading infiltrate. This group of lymphoproliferative disorders is heterogeneous regarding phenotype, but they share common features that are multiorgan involvement, worse prognosis, and, frequently Ebstein-Barr virus (EBV) genomic integration. At onset, some of these rare lymphomas, e.g. intravascular large cell lymphoma or lymphomatoid granulomatosis (Liebow dieases), are misdiagnosed as inflammatory diseases. The actual treatments of these disorders are based upon chemotherapy and/or chemotherapy plus bone marrow transplantation with variable results. Therapeutic approaches for EBV related angiocentric and intravascular lymphomas, similarly to those employed for other viral induced lymphoproliferative disease would comprise the employment of chemotherapy together with drugs able to interfere with viral infection. Such an approach has been used in rare cases of EBV-positive diffuse large B-cell lymphoma of the elderly, a lymphoproliferative disorders which development is linked to immunosuppression due to senescence. The present review will focus on intravascular and angiocentric lymphomas providing histopathologic, immunophenotypical and molecular data useful to overcome to a specific diagnosis and to differentiate them from other lymphoproliferative disorders showing a secondary vascular engulfment and infiltration and some vasculitides showing overlapping histopathologic features. PMID- 25531151 TI - Dynamics of macular hole closure in gas-filled eyes within 24 h of surgery observed with swept source optical coherence tomography. AB - BACKGROUND/AIMS: To investigate the dynamics of macular hole (MH) closure in gas filled eyes starting 20 min after vitrectomy using swept source optical coherence tomography (SS-OCT). METHODS: Twenty consecutive eyes with MH underwent vitrectomy with internal limiting membrane peeling and gas tamponade. SS-OCT imaging was performed approximately 20 min after the operation, and then once a day, until MH closure was confirmed. The correlation between the base, top and minimum hole diameters and the duration required for MH closure was investigated. RESULTS: MH closure in gas-filled eyes was confirmed in 1 eye on day 0, 10 eyes on day 1, 2 eyes on day 2, and 3 eyes on day 3, at which times face-down posturing was discontinued without MH recurrence. SS-OCT revealed a distinct closure pattern within the first 24 h postoperatively. MHs closing by day 1 had a significantly smaller minimum diameter (312.5 +/- 105.2 um) than holes closing on day 2 or later (510.8 +/- 153.5 um; p = 0.019). CONCLUSIONS: SS-OCT enables tomographic images of MH in gas-filled eyes immediately postoperatively, thus permitting early discontinuation of, or no necessity for, face-down positioning upon confirmation of MH closure. PMID- 25531152 TI - Batatins VIII-XI, glycolipid ester-type dimers from Ipomoea batatas. AB - Sweet potato (Ipomoea batatas) is native to the tropics of Central and South America, where many varieties have been consumed for more that 5000 years. In developing countries, this crop is a recognized effective food for fighting malnutrition. Purification of the minor lipophilic glicolipids found in the n hexane-soluble resin glycosides from the white-skinned variety was performed by preparative-scale recycling HPLC. Application of column overload, peak shaving, heart cutting, and recycling techniques permitted the purification of four new oligosaccharide ester-type dimer derivatives of jalapinolic acid, batatins VIII XI (1-4). The structural characterization of these complex lipo-oligosaccharides was performed through NMR spectroscopy and MS, indicating that batatins VIII-XI (1-4) possess an oligomeric structure consisting of two pentasaccharide units of the known simonic acid B. PMID- 25531153 TI - Amyloid-beta immunotherapy reduces amyloid plaques and astroglial reaction in aged domestic dogs. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by the dynamic accumulation of extracellular amyloid deposits from the interplay between amyloid-beta (Abeta) plaques, reactive astrocytes and activated microglia. Several immunotherapies against Abeta have been shown to reduce amyloid neuropathology. However, the role of the associated glia in the recovery process requires clarification. Previously, we described the safety and effectiveness in aged domestic canine with cognitive dysfunction syndrome of a new active vaccine candidate for the treatment of AD in humans. OBJECTIVE: The aim of this article is to gain a better understanding of how immunotherapy modifies the amyloid burden and its effects on astroglial and microglial reactivity in immunized dogs. METHODS: In order to achieve this, we compared and quantified amyloid plaques and astroglial and microglial reactions in the frontal cortex of unimmunized and immunized aged domestic dogs. RESULTS: We found amyloid plaques from immunized dogs to be smaller and more compact than those from unimmunized dogs. In these new plaques, the associated astrocytes were closer and less immunoreactive to the beta subunit of S100 protein (S100B). We also found no modification in the microglial reaction associated with immunization. CONCLUSION: The anti-Abeta immunotherapy developed in our laboratory modifies the equilibrium between soluble and insoluble Abeta in aged dogs in close correlation with S100B-negative astrocytosis and microglial reaction. PMID- 25531154 TI - Bone metabolism and arterial stiffness after renal transplantation. AB - BACKGROUND/AIMS: To assess the relationship between bone and vascular disease and its changes over time after renal transplantation. Metabolic bone disease (MBD) is common in chronic kidney disease (CKD) and is associated with cardiovascular (CV) disease. Following transplantation (Tx), improvement in CV disease has been reported; however, data regarding changes in bone disease remain controversial. METHODS: Bone turnover and arterial stiffness (pulse wave velocity (PWV)) were assessed in 47 Tx patients (38 (3-191) months after Tx). RESULTS: Bone alkaline phosphatase (BALP), osteocalcin (OC) and beta-crosslaps were significantly higher in Tx patients, and decreased significantly after one year. There was a negative correlation between BALP, OC and steroid administered (r = -0.35; r = -0.36 respectively). PWV increased in the Tx group (1.15 SD). In patients with a follow up of <24 months, PWV was correlated with BALP and beta-crosslaps (r=0.53; r = 0.69 respectively) while in the >=24 months group, PWV was correlated with cholesterol (r=0.38). CONCLUSIONS: Increased bone turnover and arterial stiffness are present following kidney transplantation. While bone turnover decreases with time, arterial stiffness correlates initially with bone turnover, after which the influence of cholesterol becomes significant. Non-invasive estimation of bone metabolism and arterial stiffness may help to assess CKD-MBD following renal transplantation. PMID- 25531155 TI - The role of 123I imaging in the evaluation of infants with mild congenital hypothyroidism. AB - BACKGROUND/AIMS: Controversy exists regarding the diagnosis and treatment of mild congenital hypothyroidism (MCH). We studied the value of (123)I imaging in patients with MCH. METHODS: Retrospective chart review of infants and children <4 years of age who underwent (123)I imaging: group 1 = MCH [thyroid-stimulating hormone (TSH) <25 uIU/ml, normal free T4/T3], group 2 = severe congenital hypothyroidism (TSH >=25 uIU/ml), and group 3 = MCH in infancy imaged after treatment withdrawal at age 3 years. Data collected included 4- and 24-hour (123)I uptake, TSH, free T4/total T3 at imaging, age at imaging, and levothyroxine (L-T4) dose at 1 year of. RESULTS: Thirty-six patients underwent (123)I imaging. In group 1 (n = 20, median TSH: 8.49 uIU/ml), 85% had abnormal imaging consistent with dyshormonogenesis. Two patients were referred after 1 year of age. The median age at imaging for the remaining 18 patients was 54 days. Median L-T4 dose at 1 year of age for these 18 patients was 2.8 MUg/kg, which is consistent with dyshormonogenesis. Ninety-one percent of group 2 (n = 11, median TSH: 428.03 uIU/ml) had abnormal imaging. The median age at imaging was 13 days. Four patients in group 3 had abnormal (123)I imaging and restarted treatment. CONCLUSION: (123)I imaging is a valuable tool for evaluation, diagnosis, and treatment of MCH. PMID- 25531156 TI - [In Process Citation]. AB - AIM: The influence of the demographic change and the impact on the entire health care system have been discussed by different theories (Expansion of Morbidity, Compression of Morbidity, Bimodality of Morbidity). This paper aims to project for the outpatient health care of statutory health insurance, the influence of the demographic development, the size and structure of statutory health insured and the change in morbidity based utilization on the outpatient volume of services for 2020. METHOD: Considered impact factors and their trend specifications are separately modelled and modular combined as components of scenarios. RESULTS: The compound annual growth rate of the outpatient volume of services varies between almost 0 and 2.2%. CONCLUSION: For 2020 a moderate increase of outpatient volume of services for statutory health insurance is expected, if costs of dying are taken into account, even though cross-sectional data for 2011 show a decrease in expenditure profiles with increased age. Projections with the scenario technique can support strategic decision making by estimating likely trends and effects of measures given the causal process in health care systems. PMID- 25531157 TI - [Participation in Preventive Medical Examinations for Children in Saxony-Anhalt (Germany) at the Time of School Entry Medical Examination]. AB - OBJECTIVE: The aim of this study is to present data concerning children's participation in the German preventive medical examinations for children ("U2" to "U8") in accordance with sections 26 and 92 of the German Social Code (Book V) as retrospectively recorded by the Public Health Service ("Offentlicher Gesundheitsdienst") of the German Province of Saxony-Anhalt during school entry medical examinations. Also we wanted to analyse the additional variables recorded per child in the areas of social factors, diagnostic findings and levels of therapeutic care in connection with their degree of participation in the preventive medical examinations. METHODOLOGY: The statistical analysis of 73 628 anonymised data sets from the health monitoring system of the German Province of Saxony-Anhalt that were collected by the 14 health authorities in Saxony-Anhalt during school entry medical examinations between 2008 and 2012. An analysis of the data for 20 variables per child was performed with regard to the influence of their degree of participation in the U2 to U8 medical examinations using differences in frequency in the examination groups and checking the significance of these differences by means of the chi-squared test. RESULTS: 99-96% of children in Saxony-Anhalt underwent the 5 preventive medical examinations U2-U6. As the children get older, the participation rates decrease (U2=98.7% down to U8=88.5%). By the time the school entry medical examinations are carried out (at an average age of 63 months), 83% of the children have -undergone all 7 preventive medical examinations for children, while 0.4% have not -undergone one single "U" examination. A child's gender has no influence on its parents' decision as to whether or not it should undergo the examinations. The results also reveal that children who attend day care -facilities are significantly more likely to have undergone all of the U examinations (84.8%) than children who are cared for at home (55.1%). CONCLUSION: The retrospective comprehensive collection of data concerning the children's degree of participation in preventive medical examinations using the school entry medical examination is suitable for identifying connections between participation rates and the social factors, diagnostic findings and levels of therapeutic care of the children in question. PMID- 25531158 TI - [Acceptance of the Implementation of Standardised Patient Education Programmes by the Multidisciplinary Rehabilitation Team Using the Example of a Back School - A Qualitative Study]. AB - AIM: The transfer of standardised patient education programmes into practice is a complex process with a multitude of influencing factors. Determinants relate among others to the organisation and individuals (e. g., practitioner, patient). Knowledge about individual factors regarding the trainers of patient education programmes in the German rehabilitation system is scarce. The aim of this study is to explore the acceptance of trainers concerning the implementation of a standardised back school and to derive facilitators and barriers to the implementation of patient education programmes. METHODS: Semi-structured guideline-based interviews were conducted in 10 rehabilitation clinics. The sample consisted of 46 trainers (25 women): 11 physicians, 11 psychologists, 21 physio-/exercise therapists and 3 occupational therapists with a mean age of 41. The opinions of the trainers regarding the central components of back schools in general, their opinions about the new curriculum, their expectations on its implementation, anticipated difficulties with implementation and requests to the project team were explored as indicators for acceptance. The data were analysed with a multi-step qualitative content analysis. RESULTS: 6 main categories comprising 136 subcategories were created and 729 quotations coded. Regarding the central components that should be covered by back schools, back-friendly behaviour was addressed most often. Opinions regarding the new curriculum were mostly positive. Trainers' approval of content and methods was highlighted and the similarity with existing offers in the clinics as well as the structure of the programme were rated positively. The trainers expected an increased patient orientation and personal development as well as a common, coherent language and interdisciplinarity. Difficulties were anticipated regarding time and personnel as well as therapy and appointment planning and also regarding the motivation/acceptance of patients. A wish for communication, education of trainers and feedback was directed at the project team. CONCLUSION: The study demonstrates high acceptance of programme implementation and central components of modern patient education programmes among trainers. The basis of individual facilitators and barriers has been investigated and might contribute to further development of implementation interventions. Communication and education considering those factors play a central role. PMID- 25531159 TI - [Quality Assurance in Sociomedical Evaluation by Peer Review: A Pilot Project of the German Statutory Pension Insurance]. AB - BACKGROUND: The sociomedical evaluation by the German Pension Insurance serves the purpose of determining entitlement to disability pensions. A quality assurance concept for the sociomedical evaluation was developed, which is based on a peer Review process. Peer review is an established process of external quality assurance in health care. The review is based on a hierarchically constructed manual that was evaluated in this pilot project. METHODS: The database consists of 260 medical reports for disability pension of 12 pension insurance agencies. 771 reviews from 19 peers were included in the evaluation of the inter-rater reliability. Kendall's coefficient of concordance W for more than 2 raters is used as primary measure of inter-rater reliability. RESULTS: Reliability appeared to be heterogeneous. Kendalls W varies for the particular criteria from 0.09 to 0.88 and reached for primary criterion reproducibility a value of 0.37. CONCLUSION: The reliability of the manual seemed acceptable in the context of existing research data and is in line with existing peer review research outcomes. Nevertheless, the concordance is limited and requires optimisation. Starting points for improvement can be seen in a systematic training and regular user meetings of the peers involved. PMID- 25531160 TI - Early childhood caries is associated with genetic variants in enamel formation and immune response genes. AB - Early childhood caries (ECC) is a chronic, infectious disease that affects the primary dentition of young children. It is the result of an imbalance of risk factors and protective factors that influence the disease. The aim of this study was to assess genetic and environmental factors that may contribute to ECC. Two hundred and fifty-nine unrelated children were evaluated using a cross-sectional design. Data on oral habits were obtained through a questionnaire, and caries experience data were collected by clinical examination. Twenty-three markers in 10 genes were studied. Genotyping of the selected polymorphisms was carried out by real-time PCR. Regression analyses were performed comparing individuals with and without caries experience. Of 259 subjects, 123 were caries free. The genotype TT in ALOX15 (rs7217186) was a risk factor for ECC, whereas the genotypes GG in ENAM (rs1264848), AG and GG in KLK4 (rs198968), CT in LTF (rs4547741), and GG in TUFT1 (rs3790506) were protective for EEC. In conclusion, environmental factors and gene interactions can act as protective or risk factors for ECC. These factors together contribute to the presence and severity of the disease. PMID- 25531162 TI - Design of a phase 2 clinical trial of an ASK1 inhibitor, GS-4997, in patients with diabetic kidney disease. AB - BACKGROUND: Most patients with diabetic kidney disease (DKD) experience disease progression despite receiving standard care therapy. Oxidative stress is associated with DKD severity and risk of progression, but currently approved therapies do not directly attenuate the pathologic consequences of oxidative stress. GS-4997 is a once daily, oral molecule that inhibits Apoptosis Signal regulating Kinase 1 (ASK1), which is a key mediator of the deleterious effects of oxidative stress. METHODS: We describe the rationale and design of a Phase 2 placebo-controlled clinical trial investigating the effects of GS-4997 in patients with T2DM and stage 3/4 DKD receiving standard of care therapy. Approximately, 300 subjects will be randomized in a stratified manner, based on the estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio, to one of four arms in this dose-ranging study. The primary endpoint is change in eGFR at 48 weeks, and the key secondary endpoint is change in albuminuria. CONCLUSION: Guided by the biology of oxidative stress signaling through ASK1, the biology of DKD pathogenesis, and solid statistical methods, the decisions made for this Phase 2 study regarding delineating study population, efficacy outcomes, treatment period and statistical methods represent innovative attempts to resolve challenges specific to DKD study design. PMID- 25531161 TI - Developing therapies for peanut allergy. AB - Peanut allergy is an IgE-mediated, persisting immune disorder that is of major concern worldwide. Currently, no routine immunotherapy is available to treat this often severe and sometimes fatal food allergy. Traditional subcutaneous allergen immunotherapy with crude peanut extracts has proven not feasible due to the high risk of severe systemic side effects. The allergen-specific approaches under preclinical and clinical investigation comprise subcutaneous, oral, sublingual and epicutaneous immunotherapy with whole-peanut extracts as well as applications of hypoallergenic peanut allergens or T cell epitope peptides. Allergen nonspecific approaches include monoclonal anti-IgE antibodies, TCM herbal formulations and Toll-like receptor 9-based immunotherapy. The potential of genetically engineered plants with reduced allergen levels is being explored as well as the beneficial influence of lactic acid bacteria and soybean isoflavones on peanut allergen-induced symptoms. Although the underlying mechanisms still need to be elucidated, several of these strategies hold great promise. It can be estimated that individual strategies or a combination thereof will result in a successful immunotherapy regime for peanut-allergic individuals within the next decade. PMID- 25531163 TI - Is there association between changes in eGFR value and the risk of permanent type of atrial fibrillation? Analysis of valvular and non-valvular atrial fibrillation population. AB - BACKGROUND/AIMS: There are no data concerning renal function in population with valvular and non-valvular atrial fibrillation (AF). To assess renal function in patients with AF, the association between eGFR and AF perpetuation, in-hospital mortality. METHODS: We studied 1523 patients with AF. Patients with chronic kidney disease (CKD) were compared to population with preserved renal function. RESULTS: CKD was more frequently observed in patients with valvular AF(p=0.009). In non-valvular AF patients eGFR <60 ml/min./1,73 m2 had more often permanent AF (p<0.0001). In patients with CKD CHA2DS2VASc score was 4.1+/-1.5 and HAS-BLED score was 2.1+/-1.2 and it was higher as compared to population with preserved renal function (p<0.0001 vs. p<0.0001). The odds of permanent AF in patients with non-valvular AF and CKD were increased 1.82 times (OR=1.82, p<0.0001, 95% CI:1.46 2.27). The odds of permanent AF in patients with valvular AF and CKD were not significantly increased (OR=1.46, p=0.2,95% CI:0.86-2.5). In non-valvular AF, if eGFR decrease by 10 ml/min, odds of permanent AF are increased by 10% (OR=1.1 p<0.0001, 95% CI 1.05-1.15). In multivariate logistic regression, in non-valvular AF, odds of in-hospital death were higher for patients >75 years old (OR=3.70, p=0.01, 95% CI 1.33-10.28), with CKD (OR=2.61, p=0.03, 95% CI 1.09-6.23). The type of AF had no significant influence on in-hospital mortality(OR=0.71, p=0.45,95% CI 0.30-1.70). CONCLUSIONS: CKD is more often observed in patients with valvular AF. In population with non-valvular AF decreased eGFR is associated with permanent type of AF and with higher CHA2DS2VASc and HAS-BLED score. Among valvular AF patients there are no differences in type of AF between patients with and without CKD. There is the correlation between CKD and AF perpetuation but only in non-valvular population. PMID- 25531164 TI - Quantum-dot size and thin-film dielectric constant: precision measurement and disparity with simple models. AB - We study the dielectric constant of lead sulfide quantum dot (QD) films as a function of the volume fraction of QDs by varying the QD size and keeping the ligand constant. We create a reliable QD sizing curve using small-angle X-ray scattering (SAXS), thin-film SAXS to extract a pair-distribution function for QD spacing, and a stacked-capacitor geometry to measure the capacitance of the thin film. Our data support a reduced dielectric constant in nanoparticles. PMID- 25531165 TI - Preexposure prophylaxis: a path forward. PMID- 25531166 TI - Workshop on use of intravenous immunoglobulin in hand, foot and mouth disease in Southeast Asia. AB - The South East Asia Infectious Disease Clinical Research Network convened subject matter experts at a workshop to make consensus recommendations for study design of a clinical trial for use of intravenous immunoglobulin (IVIg) in severe hand, foot and mouth disease (HFMD). HFMD is a highly contagious emerging infection among children in the region, a small proportion of whom develop neurologic and cardiopulmonary complications with high case-fatality rates. The use of IVIg for treatment of severe disease is widespread and a part of local, national, and international guidelines, but no clinical evidence warrants the use of this drug, which is expensive and has potentially serious side effects. During a 2-day workshop in March 2014, a group of HFMD experts reviewed the current evidence related to use of IVIg in HFMD and discussed potential study design, feasibility, inclusion and exclusion criteria, sample size, primary and secondary endpoints, and subsidiary studies for a randomized, placebo-controlled trial. PMID- 25531167 TI - Improving cardiopulmonary resuscitation with a CPR feedback device and refresher simulations (CPR CARES Study): a randomized clinical trial. AB - IMPORTANCE: The quality of cardiopulmonary resuscitation (CPR) affects hemodynamics, survival, and neurological outcomes following pediatric cardiopulmonary arrest (CPA). Most health care professionals fail to perform CPR within established American Heart Association guidelines. OBJECTIVE: To determine whether "just-in-time" (JIT) CPR training with visual feedback (VisF) before CPA or real-time VisF during CPA improves the quality of chest compressions (CCs) during simulated CPA. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized, 2 * 2 factorial-design trial with explicit methods (July 1, 2012, to April 15, 2014) at 10 International Network for Simulation-Based Pediatric Innovation, Research, & Education (INSPIRE) institutions running a standardized simulated CPA scenario, including 324 CPR-certified health care professionals assigned to 3 person resuscitation teams (108 teams). INTERVENTIONS: Each team was randomized to 1 of 4 permutations, including JIT training vs no JIT training before CPA and real-time VisF vs no real-time VisF during simulated CPA. MAIN OUTCOMES AND MEASURES: The proportion of CCs with depth exceeding 50 mm, the proportion of CPR time with a CC rate of 100 to 120 per minute, and CC fraction (percentage CPR time) during simulated CPA. RESULTS: The quality of CPR was poor in the control group, with 12.7% (95% CI, 5.2%-20.1%) mean depth compliance and 27.1% (95% CI, 14.2%-40.1%) mean rate compliance. JIT training compared with no JIT training improved depth compliance by 19.9% (95% CI, 11.1%-28.7%; P < .001) and rate compliance by 12.0% (95% CI, 0.8%-23.2%; P = .037). Visual feedback compared with no VisF improved depth compliance by 15.4% (95% CI, 6.6%-24.2%; P = .001) and rate compliance by 40.1% (95% CI, 28.8%-51.3%; P < .001). Neither intervention had a statistically significant effect on CC fraction, which was excellent (>89.0%) in all groups. Combining both interventions showed the highest compliance with American Heart Association guidelines but was not significantly better than either intervention in isolation. CONCLUSIONS AND RELEVANCE: The quality of CPR provided by health care professionals is poor. Using novel and practical technology, JIT training before CPA or real-time VisF during CPA, alone or in combination, improves compliance with American Heart Association guidelines for CPR that are associated with better outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02075450. PMID- 25531168 TI - Endophthalmitis outbreak associated with repackaged bevacizumab. PMID- 25531169 TI - Functional models for congenital anomalies of the kidney and urinary tract. AB - Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common developmental diseases in humans; however, the cause for most patients remains unknown. Efforts to identify novel genetic causes for CAKUT through next-generation sequencing techniques have led to the discovery of new genes and risk factors. Concomitantly, these same efforts have generated large gene candidate lists requiring individual functional characterization. Appropriate model systems are needed to assess the functionality of genes and pathogenicity of genetic variants discovered in CAKUT patients. In this review, we discuss how cellular, animal, and personal (human) models are being used to study CAKUT candidate genes and what their major advantages and disadvantages are with respect to relevance and throughput. PMID- 25531170 TI - Changes in tinnitus after cochlear implantation and its relation with psychological functioning. AB - This study retrospectively assessed the prevalence of tinnitus in cochlear implant patients and the changes after implantation in 212 patients implanted between 2000 and 2009. Patients were included at least 6 months after implantation and received 2 sets of questionnaires, one about the situation before implantation and one about the situation after implantation. Mostly standardized questionnaires assessed tinnitus handicap (Tinnitus Handicap Inventory, THI, and Tinnitus Handicap Questionnaire, THQ), tinnitus characteristics, hearing loss (Abbreviated Profile of Hearing Aid Benefit) and anxiety/depression (Hospital Anxiety and Depression Scale). Of the approached patients, 117 completed the full sets of questionnaires and 35 completed a short version. Preoperative tinnitus was reported by 51.3% of these patients, of which 55.6% reported a reduction or cessation of their tinnitus after implantation. However, 8.2% of the patients with tinnitus reported a postoperative deterioration of their tinnitus. In addition, among the patients without preoperative tinnitus, 19.6% reported the start of tinnitus after implantation. The self-reported change of tinnitus correlated with the pre- and postoperative scores on the THI and THQ. The THQ showed slightly more changes in scores after cochlear implantation compared to the THI. Overall hearing handicap and feelings of anxiety and depression decreased after implantation. In conclusion, tinnitus is reduced after cochlear implantation in an important part of the patients, but in a small part implantation has a negative effect on tinnitus. When tinnitus starts after implantation, the tinnitus handicap is mild. PMID- 25531171 TI - Spin reorientation and magnetic structure of HoCo12B6 ferrimagnetic compound. AB - The magnetic phase diagram is determined by combining magnetization measurements, ac susceptibility and neutron diffraction. The crystal and magnetic structures are also investigated. The HoCo12B6 compound exhibits ferrimagnetic behavior below TC = 147 K. Two antiferromagnetically coupled sublattices cancel out at the compensation temperature TComp = 46 K. HoCo12B6 undergoes a spin reorientation transition at TSR = 76 K; the easy magnetization axis changes from axial to basal plane upon heating. The magnitude of the magnetic moments and their orientation are described and discussed. It is revealed that HoCo12B6 compound exhibits a commensurate magnetic structure below TSR and an incommensurate one slightly above TSR. Significantly different magnetic moments have been observed on the two Co crystal sites, a very low magnetic moment of 0.14 MUB being refined on the Co 18 g position. In addition, the second order crystal electric-field parameter A2(0) at the rare-earth site is determined. This result is discussed and used to explain the observed spin reorientation transition by a competition between the Co and Ho sublattice anisotropy. PMID- 25531172 TI - High cutoff membrane to reduce systemic inflammation due to differentiation syndrome: a case report. AB - BACKGROUND: Differentiation syndrome is a life-threatening complication of therapy that is carried out with agents used for acute promyelocytic leukemia. Its physiopathology comprehends the production of inflammatory mediators by differentiating granulocytes, endothelial and alveolar cells due to stimulation by all-trans retinoic acid and leading to sustained systemic inflammation. METHODS: Treatment with high cut-off continuous veno-venous hemodialysis (HCO CVVHD) was performed to reduce the circulating mediators of systemic inflammation. RESULTS: After 52 h of treatment, an important reduction was observed in inflammatory mediators (IL-1beta: from 10 to 2 pg/ml; IL-8: from 57 to 40 pg/ml; TNF-alpha: from 200 to 105 pg/ml; IL-6: from 263 to 91 pg/ml), as well as in anti-inflammatory mediators (IL-10: from 349 to 216 pg/ml). CONCLUSIONS: HCO-CVVHD should be explored as a part of treatment in systemic inflammation states other than sepsis (e.g., differentiation syndrome). Furthermore, its immunomodulatory effects could be particularly useful in immunocompromised patient treated with corticosteroids. PMID- 25531173 TI - Local control may be the key in improving treatment outcomes of esophageal squamous cell carcinoma undergoing concurrent chemoradiation. AB - BACKGROUND/AIM: Little is known about the patterns of treatment failure following definitive chemoradiotherapy (CCRT), especially in esophageal squamous cell carcinoma (SCC). We evaluated definitive CCRT failure patterns and determined the predictive factors for treatment response in esophageal SCC. METHODS: We evaluated 136 consecutive patients with esophageal SCC treated with definitive CCRT. We evaluated the factors associated with complete remission (CR) after CCRT and analyzed the pattern of treatment failure of recurred patients and incomplete remission patients. The failures were categorized as either within (locoregional failure) or outside the radiation field (out-field failure). RESULTS: Fifty-seven patients achieved CR after CCRT. Consolidation chemotherapy was significantly associated with CR. Only 4 (7.0%) patients had CR after CCRT in patients with M1a node (Celiac or subclavian lymph nodes involvement by 6th AJCC). During follow up, 74 patients (54.4%) experienced locoregional failure, 26 (19.1%) out-field failure, and 35 (25.7%) no failure. Esophageal obstruction prior to CCRT, residual tumor according to the first follow-up endoscopy, and poor follow-up computed tomography responses were significantly associated with locoregional failure. CONCLUSION: Approximately 70% of treatment failures were local failures. Future therapeutic strategies need to focus on improving local control to increase treatment outcomes of CCRT. PMID- 25531174 TI - Effect of co-formulation of 1,3-dichloropropene and chloropicrin on evaporative emissions from soil. AB - Co-formulations of 1,3-dichloropropene (1,3-D) and chloropicrin (CP) are commonly used for preplant fumigation in the production of high-value crops. Various ratios of 1,3-D to CP are available in these co-formulations. Collation of previous field data suggested that when the two fumigants were co-applied, the emissions of CP were significantly lower than when CP was applied singly. However, none of these previous studies had a control treatment with CP applied alone, alongside a treatment where CP was co-applied with 1,3-D under the same climatic and edaphic conditions. This work aimed to address this issue by measuring emission fluxes from soil columns maintained under controlled conditions in which 1,3-D and CP were applied alone and as four commercial co formulations with various 1,3-D:CP ratios. A strong positive relationship between CP emissions and CP percentage in the formulation was observed. Furthermore, strong positive relationships between CP degradation half-life and CP percentage in the formulation and between CP degradation half-life and total column emissions suggested that the lower emissions were due to faster CP degradation when the CP percentage (and hence initial application mass) in the formulation was low. The presence of 1,3-D did not significantly affect the degradation rate of CP, and, therefore, it is hypothesized that co-application was, in itself, not a significant factor in emission losses from the columns. The findings have implications for the accurate modeling of CP because the effect of initial mass applied on CP degradation rate is not usually considered. PMID- 25531175 TI - Interaction of cholesterol in ternary lipid mixtures investigated using single molecule fluorescence. AB - Fluorescence measurements of the sterol analog 23-(dipyrrometheneboron difluoride)-24-norcholesterol (BODIPY-cholesterol) are used to compare the effects of cholesterol (Chol) in monolayers of 1,2-dipalmitoyl-sn-glycero-3 phosphatidylcholine (DPPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/Chol and chicken egg sphingomyelin (SM)/DOPC/Chol. Monolayers are formed using the Langmuir-Blodgett technique and compared at surface pressures of 8 and 30 mN/m. In particular, these ternary lipid mixtures are compared using both ensemble and single-molecule fluorescence measurements of BODIPY-cholesterol. In mixed monolayers incorporating 0.10 mol % BODIPY-cholesterol, fluorescence microscopy measurements as a function of cholesterol added reveal similar trends in monolayer phase structure for both DPPC/DOPC/Chol and SM/DOPC/Chol films. With a probe concentration reduced to ~10(-8) mol % BODIPY-cholesterol, single-molecule fluorescence measurements using defocused polarized total internal reflection microscopy are used to characterize the orientations of BODIPY-cholesterol in the monolayers. Population histograms of the BODIPY emission dipole tilt angle away from the membrane normal reveal distinct insertion geometries with a preferred angle observed near 78 degrees . The measured angles and populations are relatively insensitive to added cholesterol and changes in surface pressure for monolayers of SM/DOPC/Chol. For monolayers of DPPC/DOPC/Chol, however, the single molecule measurements reveal significant changes in the BODIPY-cholesterol insertion geometry when the surface pressure is increased to 30 mN/m. These changes are discussed in terms of a squeeze-out mechanism for BODIPY-cholesterol in these monolayers and provide insight into the partitioning and arrangement of BODIPY-cholesterol in ternary lipid mixtures. PMID- 25531176 TI - Artificial photosynthetic systems for production of hydrogen. AB - The rapid consumption of fossil fuels has caused unacceptable environmental problems such as the greenhouse effect, which may lead to disastrous climatic consequences. Because fossil fuels are the products of long-term photosynthesis, it is highly desirable to develop artificial photosynthetic systems for the production of renewable and clean energy such as hydrogen. This article summarizes recent advances on studies of artificial photosynthetic systems for photocatalytic production of hydrogen with hydrogenases and their functional mimics including hybrids of natural and artificial components. Because it is highly desired to convert gaseous H2 to an easily storable form, recent progress on storage of hydrogen as liquid or solid form has also been described in this article. PMID- 25531177 TI - Metabolic function for human renalase: oxidation of isomeric forms of beta NAD(P)H that are inhibitory to primary metabolism. AB - Renalase is a recently identified flavoprotein that has been associated with numerous physiological maladies. There remains a prevailing belief that renalase functions as a hormone, imparting an influence on vascular tone and heart rate by oxidizing circulating catecholamines, chiefly epinephrine. This activity, however, has not been convincingly demonstrated in vitro, nor has the stoichiometry of this transformation been shown. In prior work we demonstrated that renalase induced rapid oxidation of low-level contaminants of beta-NAD(P)H solutions ( Beaupre, B. A. et al. (2013) Biochemistry 52 , 8929 - 8937 ; Beaupre, B. A. et al. (2013) J. Am. Chem. Soc . 135 , 13980 - 13987 ). Slow aqueous speciation of beta-NAD(P)H resulted in the production of renalase substrate molecules whose spectrophotometric characteristics and equilibrium fractional accumulation closely matched those reported for alpha-anomers of NAD(P)H. The fleeting nature of these substrates precluded structural assignment. Here we structurally assign and identify two substrates for renalase. These molecules are 2- and 6-dihydroNAD(P), isomeric forms of beta-NAD(P)H that arise either by nonspecific reduction of beta-NAD(P)(+) or by tautomerization of beta-NAD(P)H (4 dihydroNAD(P)). The pure preparations of these molecules induce rapid reduction of the renalase flavin cofactor (230 s(-1) for 6-dihydroNAD, 850 s(-1) for 2 dihydroNAD) but bind only a few fold more tightly than beta-NADH. We also show that 2- and 6-dihydroNAD(P) are potent inhibitors of primary metabolism dehydrogenases and therefore conclude that the metabolic function of renalase is to oxidize these isomeric NAD(P)H molecules to beta-NAD(P)(+), eliminating the threat they pose to normal respiratory activity. PMID- 25531178 TI - Personalized respiratory medicine: exploring the horizon, addressing the issues. Summary of a BRN-AJRCCM workshop held in Barcelona on June 12, 2014. AB - This Pulmonary Perspective summarizes the content and main conclusions of an international workshop on personalized respiratory medicine coorganized by the Barcelona Respiratory Network ( www.brn.cat ) and the AJRCCM in June 2014. It discusses (1) its definition and historical, social, legal, and ethical aspects; (2) the view from different disciplines, including basic science, epidemiology, bioinformatics, and network/systems medicine; (3) the bottlenecks and opportunities identified by some currently ongoing projects; and (4) the implications for the individual, the healthcare system and the pharmaceutical industry. The authors hope that, although it is not a systematic review on the subject, this document can be a useful reference for researchers, clinicians, healthcare managers, policy-makers, and industry parties interested in personalized respiratory medicine. PMID- 25531179 TI - Neuroendocrine Merkel cell carcinoma is associated with mutations in key DNA repair, epigenetic and apoptosis pathways: a case-based study using targeted massively parallel sequencing. AB - INTRODUCTION: Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma with a poorly understood molecular etiology. We implemented a comprehensive deep sequencing approach to identify mutations in the tumor DNA from a cohort of patients treated at our institution over the past 15 years. Our results indicate mutations that may constitute therapeutic targets in MCC. METHODS: Five patients were treated for MCC within the study interval. Patients with adequate tissue (n = 4), positive neuroendocrine differentiation (chromogranin, synaptophysin, and cytokeratin 20), and histopathological confirmation of MCC were included in the study. DNA was extracted from archival tumor tissue samples and analyzed by massively parallel sequencing using a targeted, multiplex PCR approach followed by semiconductor sequencing. RESULTS: We demonstrate high-penetrance nonsense mutations in PDE4DIP (n = 4) as well as various missense mutations in the DNA damage response (PRKDC, AURKB, ERCC5, ATR, and ATRX) and epigenetic modulating enzymes (MLL3). CONCLUSION: We describe several mutations in potential disease relevant genes and pathways. These targets should be evaluated in a larger cohort to determine their role in the molecular pathogenesis of MCC. PMID- 25531180 TI - Coordination properties of dithiobutylamine (DTBA), a newly introduced protein disulfide reducing agent. AB - The acid-base properties and metal-binding abilities of (2S)-2-amino-1,4 dimercaptobutane, otherwise termed dithiobutylamine (DTBA), which is a newly introduced reagent useful for reducing protein and peptide disulfides, were studied in solution using potentiometry, (1)H NMR spectroscopy, spectropolarimetry, and UV-vis spectroscopy. The list of metal ions studied here includes Zn(II), Cd(II), Ni(II), Co(II), and Cu(I). We found that DTBA forms specific and very stable polynuclear and mononuclear complexes with all of these metal ions using both of its sulfur donors. DTBA forms complexes more stable than those of the commonly used disulfide reducing agent DTT, giving it more interference capacity in studies of metal binding in thiol-containing biomolecules. The ability of DTBA to strongly bind metal ions is reflected in its limited properties as a thiol protectant in their presence, which is manifested through slower disulfide reduction kinetics. We found that this effect correlated with the stabilities of the complexes. Additionally, the reducing properties of DTBA toward MMTS-modified papain (MMTS = S-methylmethanethiosulfonate) were also significantly affected by the investigated metal ions. In this case, however, electrostatic interactions and stereospecific effects, rather than metal-binding abilities, were found to be responsible for the reduced protective properties of DTBA. Despite its limitations, a high affinity toward metal ions makes DTBA an attractive agent in competition studies with metalloproteins. PMID- 25531181 TI - Frenkel to Wannier-Mott Exciton Transition: Calculation of FRET Rates for a Tubular Dye Aggregate Coupled to a CdSe Nanocrystal. AB - The coupling is investigated of Frenkel-like exciton states formed in a tubular dye aggregate (TDA) to Wannier-Mott-like excitations of a semiconductor nanocrystal (NC). A double well TDA of the cyanine dye C8S3 with a length of 63.4 nm and a diameter of 14.7 nm is considered. The TDA interacts with a spherical Cd819Te630 NC of 4.5 nm diameter. Electronic excitations of the latter are described in a tight-binding model of the electrons and holes combined with a configuration interaction scheme to consider their mutual Coulomb coupling. To achieve a proper description of TDA excitons, a recently determined structure has been used, the energy transfer coupling has been defined as a screened interaction of atomic centered transition charges, and the site energies of the dye molecules have been the subject of a polarization correction. Even if both nanoparticles are in direct contact, the energy transfer coupling between the exciton levels of the TDA and of the NC stays below 1 meV. It results in FRET type energy transfer with rates somewhat larger than 10(9)/s. They coincide rather well with recent preliminary experiments. PMID- 25531182 TI - Editorial comment for Bhattu et al. PMID- 25531183 TI - The ULT trxG factors play a role in Arabidopsis fertilization. AB - Trithorax group (trxG) and Polycomb group (PcG) proteins are epigenetic modifiers that play key roles in eukaryotic development by promoting active or repressive gene expression states, respectively. Although PcG proteins have well-defined roles in controlling developmental transitions, cell fate decisions and cellular differentiation in plants, relatively little is known about the functions of plant trxG factors. We recently determined the biological roles for the ULT1 and ULT2 trxG genes during Arabidopsis vegetative and reproductive development. Our study revealed that ULT1 and ULT2 genes have overlapping activities in regulating Arabidopsis shoot and floral stem cell activity, and that they have a redundant function in establishing the apical-basal polarity axis of the gynoecium. Here we present data that ult1 and ult1 ult2 siliques contain a significant proportion of aborted ovules, supporting an additional role for ULT1 in Arabidopsis fertility. Our results add to the number of plant developmental processes that are regulated by trxG activity. PMID- 25531184 TI - Recombinant Marburg viruses containing mutations in the IID region of VP35 prevent inhibition of Host immune responses. AB - Previous in vitro studies have demonstrated that Ebola and Marburg virus (EBOV and MARV) VP35 antagonize the host cell immune response. Moreover, specific mutations in the IFN inhibitory domain (IID) of EBOV and MARV VP35 that abrogate their interaction with virus-derived dsRNA, lack the ability to inhibit the host immune response. To investigate the role of MARV VP35 in the context of infectious virus, we used our reverse genetics system to generate two recombinant MARVs carrying specific mutations in the IID region of VP35. Our data show that wild-type and mutant viruses grow to similar titers in interferon deficient cells, but exhibit attenuated growth in interferon-competent cells. Furthermore, in contrast to wild-type virus, both MARV mutants were unable to inhibit expression of various antiviral genes. The MARV VP35 mutants exhibit similar phenotypes to those previously described for EBOV, suggesting the existence of a shared immune-modulatory strategy between filoviruses. PMID- 25531185 TI - HTLV-1 Tax protein recruitment into IKKepsilon and TBK1 kinase complexes enhances IFN-I expression. AB - The Tax protein expressed by human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in the deregulation of cellular pathways involved in the immune response, inflammation, cell survival, and cancer. Many of these effects derive from Tax multiple interactions with host factors, including the subunits of the IKK-complex that are required for NF-kappaB activation. IKKE and TBK1 are two IKK related kinases that allow the phosphorylation of interferon regulatory factors that trigger IFN type I gene expression. We observed that IKKE and TBK1 recruit Tax into cellular immunocomplexes. We also found that TRAF3, which regulates cell receptor signaling effectors, forms complexes with Tax. Transactivation analyses revealed that expression of Tax, in presence of IKKE and TBK1, enhances IFN-beta promoter activity, whereas the activation of NF-kappaB promoter is not modified. We propose that Tax may be recruited into the TBK1/IKKE complexes as a scaffolding-adaptor protein that enhances IFN-I gene expression. PMID- 25531186 TI - Foot-and-mouth disease virus serotype SAT 3 in long-horned Ankole calf, Uganda. AB - After a 16-year interval, foot-and-mouth disease virus serotype SAT 3 was isolated in 2013 from an apparently healthy long-horned Ankole calf that grazed close to buffalo in Uganda. The emergent virus strain is ~20% different in nucleotide sequence (encoding VP1 [viral protein 1]) from its closest relatives isolated previously from buffalo in Uganda. PMID- 25531187 TI - Microfluidic chips with multi-junctions: an advanced tool in recovering proteins from inclusion bodies. AB - Active recombinant proteins are used for studying the biological functions of genes and for the development of therapeutic drugs. Overexpression of recombinant proteins in bacteria often results in the formation of inclusion bodies, which are protein aggregates with non-native conformations. Protein refolding is an important process for obtaining active recombinant proteins from inclusion bodies. However, the conventional refolding method of dialysis or dilution is time-consuming and recovered active protein yields are often low, and a cumbersome trial-and-error process is required to achieve success. To circumvent these difficulties, we used controllable diffusion through laminar flow in microchannels to regulate the denaturant concentration. This method largely aims at reducing protein aggregation during the refolding procedure. This Commentary introduces the principles of the protein refolding method using microfluidic chips and the advantage of our results as a tool for rapid and efficient recovery of active recombinant proteins from inclusion bodies. PMID- 25531188 TI - Relationship between blood lead levels and hematological indices in pregnant women. AB - Several studies have revealed a negative association between blood lead levels and hematological impairment. In this cross-sectional study, we examined the relationship between blood lead levels and hematological indices in 292 pregnant women from Durango, Mexico. Apparently healthy pregnant women, aged 14-41 years and at 3-41 weeks of gestation, were recruited between June 2007 and May 2008. Blood lead and hematological indices were measured. The mean blood lead was 2.79 +/- 2.16 MUg/dL, and lead levels >= 5 MUg/dL were detected in 25 women (8.6%). Hemoglobin, hematocrit, and red blood cells count were significantly higher in pregnant women with a blood lead concentration of >= 5 MUg/dL than the group with lower blood lead levels (p < .05). Mean corpuscular volume and mean corpuscular hemoglobin were not significantly related to lead levels. Hemoglobin and hematocrit showed a non-significant positive correlation with blood lead, but the correlation between red blood cell count and blood lead levels was statistically significant (r = 0.185, p = .002). The findings suggest that a positive association between blood lead and some hematological indices may occur at relatively low blood lead concentration (mean < 5 MUg/dL). PMID- 25531189 TI - Tunable solubility parameter of poly(3-hexyl thiophene) with hydrophobic side chains to achieve rubbery conjugated films. AB - A highly pi-conjugated nanofibrillar network of poly(3-hexyl thiophene) (P3HT) embedded in polydimethylsiloxane (PDMS) elastomer films on SiO2 dielectrics was facilely developed via solution-blending of an ultrasound-assisted dilute P3HT solution with a PDMS precursor followed by spin-casting and curing. In contrast, simple blending without ultrasonication against the dilute P3HT solution yielded large agglomerates in cast films owing to a great difference in solubility parameter (delta) values (P3HT = 9.5 cal(1/2) cm(-3/2), PDMS = 7.3 cal(1/2) cm( 3/2)). In the ultrasound-assisted 0.1 vol % P3HT solutions, the pi-conjugated polymer could develop crystalline nanofibrils surrounded by nonpolar hexyl side chains with the same delta value as that of PDMS, yielding homogeneously dispersed 10 wt % loaded P3HT/PDMS blend films. Spun-cast P3HT/PDMS blend films could yield high electrical properties in organic field-effect transistor, including mobilities of up to 0.045 cm(2) V(-1) s(-1) and on/off current ratios of >5 * 10(5), as well as excellent environmental stability owing to the outer PDMS layer. PMID- 25531190 TI - Acrylamide Induces Senescence in Macrophages through a Process Involving ATF3, ROS, p38/JNK, and a Telomerase-Independent Pathway. AB - Senescence, which is irreversible cell cycle arrest, is induced by various types of DNA damage, including genotoxic stress. Senescent cells show dysregulation of tumor suppressor genes and other regulators of cellular proliferation. Activating transcription factor 3 (ATF3) plays a pleiotropic role in biological processes through genotoxic stress. In this study, we examined the effects of acrylamide (ACR), a genotoxic carcinogen, on cellular senescence and the molecular mechanisms of ATF3 function in macrophages. Treatment of macrophages with ACR at low concentrations (<1.0 mM) resulted in senescence-like morphology and an increase in senescence-associated beta-galactosidase (SA-beta-gal) activity. Exposure of macrophages to ACR led to stress-induced, telomerase-independent senescence. In addition, ACR treatment for 1, 3, or 5 days showed a concentration dependent increase in ATF3 expression and G0/G1 phase arrest. To better understand the role of ATF3 in controlling the senescence response to ACR, SA beta-gal activity was examined using ATF3 knockdown and overexpression. ACR mediated senescence was significantly decreased by knockdown of ATF3, whereas it was increased with ATF3 overexpression. We found that ATF3 regulated p53 and p21 levels. ATF3 also played an important role in regulating intracellular reactive oxygen species (ROS) production in response to ACR treatment. Moreover, phosphorylation of p38 and JNK kinases, which were activated during ATF3-mediated senescence, was observed in ACR-treated macrophages. Taken together, these results suggest that ATF3 contributes to ACR-induced senescence by enhancing ROS production, activating p38 and JNK kinases, and promoting the ATF3-dependent expression of p53, resulting in regulation of cellular senescence in macrophages. PMID- 25531191 TI - Sperm quality in men is improved by supplementation with a combination of L arginine, L-citrullin, roburins and Pycnogenol(r). AB - AIM: The aim of this study was to investigate the influence of Prelox(r)R, a combination of French maritime pine bark extract (Pycnogenol(r)), L-arginine, L citrulline and roburins, on male fertility. METHODS: Sperm quality of 50 subfertile men was tested in monthly intervals in a double-blind, randomized, placebo controlled, crossover study. Patients received 2 tablets Prelox(r)R or placebo twice daily during test periods. Following a run-in period of 1 month, patients received either Prelox(r)R or a placebo for 1 month. After a wash-out period of 1 month, patients received Prelox(r)R or a placebo in a crossover manner for 1 month. Sperm volume, concentration of spermatozoa, total count, motility, vitality and morphology were measured by standard methods of calculation of the Fertility Index (FI) in monthly intervals. Activity of e-NOS in sperm was evaluated in parallel by measuring the quantity of L-citulline produced from L-arginine. RESULTS: Supplementation with Prelox(r)R enhanced sperm volume and concentration, motility, vitality and morphology significantly versus placebo. The Fertility Index rose to normal values during treatment with Prelox(r)R. e-NOS activity in sperm was elevated by Prelox(r)R. No adverse effects were reported. CONCLUSION: Prelox(r)R offers a safe method to improve quality of human spermatozoa in subfertile men. PMID- 25531192 TI - The need for re-TUR of the bladder in non-muscle invasive bladder cancer: risk factors of tumor persistence in re-TUR specimens. AB - AIM: This study evaluated the need for re-TUR of the bladder in non-muscle invasive bladder cancer (NMIBC) with complete transurethral resection (TUR) and examined the risk factors for disease occurrence in re-TUR of the bladder. METHODS: A cohort of 211 patients diagnosed consecutively of NMIBC (July 2009 to October 2011) underwent re-TURB 4-6 weeks after the initial TURB. Association with tumor presence in re-TURB of the following parameters was analyzed: sex, primary/recurrent, number, size, stage, grade, association of carcinoma in situ, early instillation of Mitomycin C, and its classification according to the EORTC risk groups. RESULTS: Fifty-seven (27%) cases exhibited residual tumors in the re TURB and understaging was observed in 3 (1.4%) patients. The EORTC classified 151 (71.6%) patients as high risk; 124 (58.7%) patients received postoperative instillations of Mitomycin C. 31.8% of high risk patients exhibited tumors in the re-TUR compared to 14% of the low/intermediate risk (P<0.05). A total of 19.4% of patients with early instillation of Mitomycin C had tumor in re-TURB compared to 38.4% of patients without it (P<0.05). Multivariate analysis showed that high risk tumors behaved as an independent risk factor for the tumor presence in re TURB (HR=12.65, P=0.008), but early postoperative instillation of Mitomycin C was a protective factor (HR=2.16, P=0.02). The limitations of the study are the absence of randomization and its unicentric character. CONCLUSION: Patients who were at a high risk of tumor recurrence and/or progression according to the EORTC classification exhibited a higher percentage of tumors in re-TURB. Therefore, these patients are optimal candidates for re-TURB. PMID- 25531193 TI - Effects of bethanechol chloride and distigmine bromide on postvoiding residual volume in patients with underactive bladder. AB - AIM: The efficacy of cholinergic drugs for reduction of post-voiding residual volume (PVR) in patients with underactive bladder is still controversial. This study was performed to examine whether cholinergic drugs have such an effect on PVR. METHODS: Patients with underactive bladder treated for more than two months with cholinergic drugs, which were later discontinued, were extracted retrospectively based on their charts. The changes in PVR, cholinesterase activity (ChE), renal function, and voiding function before and after discontinuation of cholinergic drugs were reviewed and analyzed. RESULTS: Twenty nine patients were included in this study. In multiple linear regression analysis, the discontinuation of distigmine bromide (DB) was indicated as a significant covariate for PVR increase and ChE increase, while bethanechol chloride (BC) was not a significant covariate. The increase in ChE was significantly correlated with both PVR and voided volume after discontinuation of cholinergic drugs. CONCLUSION: DB could reduce PVR via a decrease in ChE. However, BC at doses up to 60 mg did not reduce PVR. DB may be recommended for the reduction of PVR in patients with underactive bladder. PMID- 25531194 TI - The role of stem/progenitor cells and Wnt/beta-catenin signaling pathway in the patients with prostate cancer. AB - AIM: The aim of this paper was to investigate the possible effect of cancer stem cells (CSCs) and relationship with Wnt/beta-catenin signaling pathway progressing of prostate cancer. METHODS: Thirty men with a pathological diagnosis of benign prostate hyperplasia (BPH) (group 1, N.=10), prostate cancer with a gleason score of <=6 (group 2, N.=10), and prostate cancer with a gleason score of >6 (group 3, N.=10) were included in the study. The patients' groups were compared in terms of immunoreactivity strength of prostatic stem/progenitor cell surface markers including CD133 and CD117. We also compared the immunoreactivity of Wnt7a, a part of Wnt signaling pathway which has a potential role in the progression of several cancers including prostate cancer. The immunoreactivity of Frizzled 6 (Fzd 6) which is the receptor of Wnt family was also evaluated in all groups. RESULTS: Immunohistochemical analyses demonstrated that although CD133 immunoreactivity was positive in all groups, immunoreactivity was significantly stronger in group 3 when compared to other groups. While CD117 immunoreactivity was negative in group 1 and 2, it was positive in group 3. Wnt7a immunoreactivity was weak in all groups and Fzd 6 immunoreactivity was stronger in group 1 and 3 when compared to group 2. CONCLUSION: Our findings demonstrated that CSCs and Wnt signaling pathway have a potential role in the development and progression of prostate cancer. PMID- 25531195 TI - Lung injury associated with mTOR inhibitors (sirolimus and everolimus). PMID- 25531196 TI - Iatrogenic ureteral obstruction in pediatric age: an unusual complication of ureteral stenting. PMID- 25531197 TI - Renal artery embolism: a rare cause of acute abdominal or flank pain and the significance of early diagnosis. PMID- 25531198 TI - Hospital-associated transmission of Brucella melitensis outside the laboratory. AB - Brucella melitensis was identified in an aspirate obtained from a patient's hip joint during a procedure at a hospital in Canada. We conducted an investigation into possible exposures among hospital workers; 1 worker who assisted with the procedure tested positive for B. melitensis. Aerosol-generating procedures performed outside the laboratory may facilitate transmission of this bacterium. PMID- 25531199 TI - A mechanical refractory period of chondrocytes after dynamic hydrostatic pressure. AB - PURPOSE: Mechanical stimulation, a crucial factor for maintaining the cartilaginous phenotype and promoting the chondrogenesis, has been widely used in autologous chondrocyte transplantation. This study was designed to investigate a novel concept of mechanical refractory period of chondrocytes after dynamic hydrostatic pressure (dHP). MATERIALS AND METHODS: dHP protocols (0.1 Hz, 2 MPa) were applied. The variation in type II collagen (Col II) expression induced by each dHP unit was measured. The dynamic remodeling of F-actin during the mechanical protocols was observed morphologically and mechanically by laser confocal microscopy and optical magnetic twisting cytometry (OMTC), respectively. About 20 ng/ml VEGF was used to stabilize the F-actin and restrain the mechanical refractory period. RESULTS: Compared with the remarkable increase of Col II (16 fold) induced by the initial dHP unit, the chondrocytes entered a mechanical refractory period and the second unit hardly elevated Col II expression (only 2.9 fold). This refractory period recovered partially within 2 h. The uniform, parallel, and coarse fibers of F-actin before dHP became thin, sparse, and disordered, and the cell stiffness decreased concomitantly. The variations in both the morphology and the mechanical property of F-actin were highly synchronous to the mechanical refractory period and recovered in a time-dependent manner. VEGF postponed the appearance of this refractory period and maintained the high expression of Col II by VEGF/p38/MAPKAPK-2/LIMK/cofilin pathway. CONCLUSION: A mechanical refractory period of chondrocytes has been discovered and defined in this study. The F-actin depolymerization is the putative mechanism, and this refractory period can be postponed by VEGF-induced F-actin stabilization. PMID- 25531201 TI - Summation of the year and international telemedicine. PMID- 25531202 TI - Factors that influence the acceptance of telemetry by emergency medical technicians in ambulances: an application of the extended technology acceptance model. AB - OBJECTIVE: The aim of the study was to verify the effects of patient factors perceived by emergency medical technicians (EMTs) as well as their social and organizational factors on prehospital telemetry use intention based on the technology use intention and elaboration likelihood models. MATERIALS AND METHODS: This is a retrospective empirical study. Questionnaires were developed on the basis of clinical factors of 72,907 patients assessed by prehospital telemetry from January 1, 2009 to April 30, 2012 by reviewing their prehospital medical care records and in-hospital medical records. Questionnaires regarding the social and organizational factors of EMTs were created on the basis of a literature review. To verify which factors affect the utilization of telemetry, we developed a partial least-squares route model on the basis of each characteristic. In total, 136 EMTs who had experience in using prehospital telemetry were surveyed from April 1 to April 7, 2013. Reliability, validity, hypotheses, and the model goodness of fit of the study tools were tested. RESULTS: The clinical factors of the patients (path coefficient=-0.12; t=2.38), subjective norm (path coefficient=0.18; t=2.63), and job fit (path coefficient=0.45; t=5.29) positively affected the perceived usefulness (p<0.010). Meanwhile, the clinical factors of the patients (path coefficients=-0.19; t=4.46), subjective norm (path coefficient=0.08; t=1.97), loyalty incentives (path coefficient=-0.17; t=3.83), job fit (path coefficient=-0.32; t=7.06), organizational facilitations (path coefficient=0.08; t=1.99), and technical factors (i.e., usefulness and ease of use) positively affected attitudes (path coefficient=0.10, 0.58; t=2.62, 5.81; p<0.010). Attitudes and perceived usefulness significantly positively affected use intention. CONCLUSIONS: Factors that influence the use of telemetry by EMTs in ambulances included patients' clinical factors, as well as complex organizational and environmental factors surrounding the EMTs' occupational environments. This suggests that the rapid use intention and dissemination of such systems require EMTs to be supported at both the technical and organizational levels. PMID- 25531203 TI - GPR30 Gene Polymorphisms Are Associated with Gynecomastia Risk in Adolescents. AB - AIM: The G protein-coupled receptor, GPR30, which is a third estrogen receptor, has been shown to mediate estrogenic effects on the essential features of human breast cancer cells. The aim of this study was to evaluate the association between GPR30 single nucleotide polymorphisms and gynecomastia in males. METHODS: This study included 109 male adolescents with gynecomastia and 104 controls. Follicle stimulating hormone, luteinizing hormone, total testosterone, estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and prolactin levels were measured. DNA was extracted from whole blood using a GeneJET Genomic DNA purification kit. The genotypes of the GPR30 gene (rs3808350, rs3808351 and rs11544331) were studied using a tetra-primer ARMS (amplification refractory mutation system) PCR approach. RESULTS: The median E2 (11.80 vs. 16.86 IU/l, p < 0.001) and DHEAS levels (116.8 vs. 146.5 MUg/dl, p = 0.044) were higher in the gynecomastia group. The G allele of rs3808350 and the A allele of rs3808351 were frequently observed in patients with gynecomastia. Gynecomastia was more common in patients with the GG genotype of rs3808350 and in patients with the AA genotype of rs3808351. CONCLUSIONS: Our results suggest that increased E2 levels, the G allele of rs3808350 and the A allele of rs3808351 might explain why certain adolescents are affected by gynecomastia. PMID- 25531204 TI - Fatal sulfasalazine-induced eosinophilic myocarditis in a patient with periodic fever syndrome. AB - OBJECTIVE: The aim of this paper is to report the first case of drug-induced eosinophilic myocarditis (EM) in a patient with hereditary periodic fever syndrome (PFS). CASE: A 28-year-old man with hyper-IgD syndrome, one of the PFS, developed a sulfasalazine-induced systemic hypersensitivity reaction complicated by EM. Thirteen days after sulfasalazine introduction, which had been given for arthritis, the patient developed fever, facial/neck edema, rash and cardiogenic shock, and died within 8 h. The autopsy revealed hemophagocytosis, while acute heart failure caused by necrotizing EM was established as the cause of death. CONCLUSION: This was a case of drug-induced EM in a patient with PFS that had an atypical presentation, rapid evolution and poor outcome. PMID- 25531205 TI - Easy and secure closure of petersen's defect after laparoscopic distal gastrectomy with Roux-en-Y reconstruction. AB - BACKGROUND: Previously it has reported that the incidence of internal hernia can be decreased by closing Petersen's defect, but the perfect closure method, in fact, has not been discovered yet. In this study we have developed an easy and reliable method for closing Petersen's defect in the Roux-en-Y reconstruction after a laparoscopic distal gastrectomy. MATERIALS AND METHODS: We performed intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy with antiperistaltic gastrojejunostomy. The greater omentum is placed on the cranial side of the transverse colon through the defect between the elevated jejunum and the transverse mesocolon. Anastomosis is performed of the transverse mesocolon attached to the transverse colon, the greater omentum is passed through the Petersen's defect, and the stump of the mesojejunum is attached to the elevated jejunum by an interrupted suture. Petersen's defect is spread and straightened to stabilize the visual field. The thread is inserted first at the base of the stump of the elevated mesojejunum, next to the greater omentum, which has passed through Petersen's defect, and then to the transverse mesocolon to set the starting point of continuous suture. The stitches of continuous suture are sewn toward the transverse colon. Petersen's defect is closed completely. RESULTS: We performed this technique in 37 patients. All procedures were completed without intraoperative complication or conversion to laparotomy. During the follow-up period, none of the patients developed complications related to the internal hernia, such as Petersen's hernia. CONCLUSIONS: We have indicated a novel, easy, and secure closure procedure of Petersen's defect following laparoscopic distal gastrectomy with Roux-en-Y reconstruction. PMID- 25531206 TI - A novel fluoro-chromogenic click reaction for the labelling of proteins and nanoparticles with near-IR theranostic agents. AB - Reaction of porphycene isothiocyanates with primary and secondary amines leads to the formation of thiazolo[4,5-c]porphycenes, with a substantial shift in the absorption and fluorescence spectra. The conjugates show fluorescence in the near infrared and are capable of photosensitizing the production of the cytotoxic species singlet oxygen. PMID- 25531208 TI - A novel hydroxylamine ionic liquid salt resulting from the stabilization of NH2OH by a SO3H-functionalized ionic liquid. AB - A SO3H-functionalized ionic liquid was used as an alternative to conventional inorganic acids in hydroxylamine stabilization, leading to the formation of a novel hydroxylamine ionic liquid salt that exhibits improved thermal stability and reactivity in the one-step, solvent-free synthesis of caprolactam in comparison with hydroxylamine hydrochloride and hydroxylamine sulfate. PMID- 25531207 TI - Activation of checkpoint kinase 2 is critical for herpes simplex virus type 1 replication in corneal epithelium. AB - BACKGROUND/AIMS: Herpes simplex virus (HSV) type I keratitis remains a leading cause of corneal morbidity, despite the availability of effective antiviral drugs. Improved understanding of virus-host interactions at the level of the host DNA damage response (DDR), a known factor in the development of HSV-1 keratitis, may shed light on potential new therapeutic targets. This report examines the role of checkpoint kinase 2 (Chk2), a DDR mediator protein, in corneal epithelial HSV-1 infection. METHODS: A small-molecule inhibitor of Chk2 (Chk2 inhibitor II) was applied to HSV-1-infected cultured human corneal epithelial cells (hTCEpi and HCE) as well as to explanted and organotypically cultured human and rabbit corneas. Infection levels were assessed by plaque assay and real-time PCR. RNAi mediated depletion of Chk2 was performed to confirm the effect of the inhibitor. RESULTS: Inhibition of the Chk2 kinase activity greatly suppresses the cytopathic effect, genome replication and infectious progeny production in vitro and ex vivo. CONCLUSION: This report demonstrates the critical role of Chk2 kinase in the establishment of HSV-1 corneal epithelial infection. These data contribute to our understanding of herpesvirus-host interactions and underscore the significance of DDR activation in HSV-1 keratitis. PMID- 25531209 TI - Reporter-encapsulated liposomes on graphene field effect transistors for signal enhanced detection of physiological enzymes. AB - A novel approach for enzymatic assay using reporter-encapsulated liposomes on graphene field effect transistors (FET) is proposed. This approach involves real time monitoring of drain current (Id) of reduced graphene oxide (rGO) upon rupture of reporter-encapsulated 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphatidylcholine (POPC) liposomes triggered by enzymes. For validation of the proposed approach, 2,4,6-trinitrophenol (TNP) is used as the reporter for specific detection of phospholipase A2 (PLA2), a key enzyme in various membrane related physiological processes. Experimental results revealed that Id increased with PLA2 concentration, which is attributed to the interaction between released TNP and rGO. The limit of detection (LOD) achieved by the proposed approach was 80 pM, which is superior to most assays reported previously and much lower than the cut-off level of circulating secretory PLA2 (2.07 nM). Besides the high accuracy of the electronic detection methodology, the signal enhancement effect realized by the excess concentration of TNP (approximately 1 mM) in liposomes is believed to be the main reason for the significantly enhanced sensitivity of the proposed assay, indicating great potential for further improvement in the sensitivity by increasing the concentration of TNP. In addition, the proposed approach is rapid (incubation time <= 10 min) and label-free, thus showing great potential for practical applications in the future. PMID- 25531210 TI - Multiplexed detection of two proteins by a reaction kinetics-resolved chemiluminescence immunoassay strategy. AB - A multiplexed immunoassay method was proposed for the sequential detection of two proteins in a single run based on a novel chemiluminescence (CL) reaction kinetics-resolved strategy. This method was established using acridinium ester (AE) and alkaline phosphatase (ALP) as the signal probes due to the significant difference in their CL reaction kinetics characteristics. Mouse IgG (MIgG) and mouse IgM (MIgM) were detected as the model analytes with a competitive immunoassay format. AE and ALP were used to tag goat anti-mouse IgG and rabbit anti-mouse IgM, respectively, to form two immunocomplexes. The two CL reactions with flash type and glow type kinetics characteristics were triggered simultaneously by adding the coreactants, then the CL signals from the two reactions were recorded after 0.2 s and 500 s of the reaction triggering, respectively. The multiplexed CL immunoassay provided a wide range of 0.50-200 ng mL(-1), with a low detection limit of 0.16 ng mL(-1) (S/N = 3) for both MIgG and MIgM. Additionally, no obvious signal overlap was observed in the multiplexed immunoassay. The proposed method was successfully applied for the detection of MIgG and MIgM levels in mouse serums, and the results were in good agreement with those from the reference ELISA method. We anticipate that it can be used in some other areas such as drug screening, food safety, environment monitoring and clinical diagnosis. PMID- 25531211 TI - Is home blood pressure monitoring feasible and well accepted in nephrectomized patients for renal cancer? (STAFF study). AB - AIMS: Few studies have looked at blood pressure (BP) evolution after nephrectomy, except for in living kidney donors with no clinical relevant modifications. STAFF is a pilot, open-label, observational study to evaluate the feasibility of following BP by home blood pressure monitoring (HBPM) after nephrectomy for cancer. MAJOR FINDINGS: 56 patients (66.1% previously treated for hypertension) were included between November 1, 2011, and December 31, 2012; 95.8% of the patients realized five of six primary end-points in HBPM, but the last monitoring session at 6 months was often lacking (60%) probably because of a lack of understanding. When BP was controlled before surgery, 36% of the patients underwent new hypertension or hypertension dysregulation, without any correlating factor found; 33% of the patients presented the presence of proteinuria or an increase during the follow-up. Previous hypertension or high body mass index were risk factors for proteinuria increase (p = 0.036 and 0.032) but not treatment by an renin-angiotensin system blocker. There was no statistical link between HTA control and proteinuria. CONCLUSION: Our study shows that most patients undergoing nephrectomy for cancer are able to follow HBPM. It should be encouraged for detecting high BP or proteinuria, especially if antiangiogenic therapies are envisaged because of the supplementary risk of hypertension and proteinuria induced by these treatments. PMID- 25531212 TI - An engineered genetic selection for ternary protein complexes inspired by a natural three-component hitchhiker mechanism. AB - The bacterial twin-arginine translocation (Tat) pathway is well known to translocate correctly folded monomeric and dimeric proteins across the tightly sealed cytoplasmic membrane. We identified a naturally occurring heterotrimer, the Escherichia coli aldehyde oxidoreductase PaoABC, that is co-translocated by the Tat translocase according to a ternary "hitchhiker" mechanism. Specifically, the PaoB and PaoC subunits, each devoid of export signals, are escorted to the periplasm in a piggyback fashion by the Tat signal peptide-containing subunit PaoA. Moreover, export of PaoA was blocked when either PaoB or PaoC was absent, revealing a surprising interdependence for export that is not seen for classical secretory proteins. Inspired by this observation, we created a bacterial three hybrid selection system that links the formation of ternary protein complexes with antibiotic resistance. As proof-of-concept, a bispecific antibody was employed as an adaptor that physically crosslinked one antigen fused to a Tat export signal with a second antigen fused to TEM-1 beta-lactamase (Bla). The resulting non-covalent heterotrimer was exported in a Tat-dependent manner, delivering Bla to the periplasm where it hydrolyzed beta-lactam antibiotics. Collectively, these results highlight the remarkable flexibility of the Tat system and its potential for studying and engineering ternary protein interactions in living bacteria. PMID- 25531213 TI - Symptomatic thoracic arachnoid cyst with coexisting tick paralysis: case report and review of the literature. AB - Tick paralysis is an uncommon phenomenon resulting from the release of a neurotoxin from the salivary glands of an engorged, gravid female tick about 5-7 days after attachment. The neurotoxin produces ascending weakness, mimicking other ascending paralytic processes. We present a case of a child presenting with weakness of the lower extremities and frequent falls who was found to have a compressive thoracic arachnoid cyst and a large distal syrinx. After surgical decompression, the patient made significant improvement in her leg strength, but quickly developed an ascending quadriparesis, followed by respiratory depression. Subsequent imaging and physical examination revealed an engorged tick embedded in her scalp. The tick was removed, and the patient made a rapid and complete clinical recovery. We present a unique case of concomitant tick paralysis and a symptomatic spinal intradural arachnoid cyst, and review the literature on tick paralysis. PMID- 25531214 TI - Molecular basis of the alternative recruitment of GABA(A) versus glycine receptors through gephyrin. AB - gamma-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA(A)R alpha3 complex, revealing that the N terminal region of the alpha3 peptide occupies the same binding site as the GlyR beta subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA(A)R alpha subunits, engages in unique interactions. Thermodynamic dissections of the gephyrin-receptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA(A)Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA(A)R interaction. PMID- 25531215 TI - Stimulation of Cyclooxygenase 2 Expression in Rat Peritoneal Mesothelial Cells. AB - Objective: Since peritoneal dialysis causes peritoneal fibrosis, we examined how glucose (osmotic factor), mannitol (osmotic control), and angiotensin II (AngII) regulate proinflammatory cyclooxygenase 2 (COX-2) in primary rat peritoneal mesothelial cells. Materials and Methods: For this study, we used the following material (n = 4-8 cell lines): cells, passages 1-2; 125I-AngII receptor surface binding (AT1R antagonist losartan, AT2R antagonist PD123319; both 10 uM); intracellular calcium probe calcium-5; COX-2 immunoblotting (beta-actin normalized); real-time PCR of COX-2 gene PTGS2, and NF-kappaB inhibitor Ro 1069920 (5 uM). Results: AngII surface receptors were predominantly AT1R (minimally AT2R). AngII and glucose increased COX-2 protein expression concentration dependently; mannitol also increased COX-2 expression. Maximal COX 2 protein expression was observed after 6 h (AngII) and 24 h (glucose, mannitol). The time course of increases in PTGS2 mRNA levels reflected that of COX-2 protein expression. At optimal exposure conditions (time/concentration), glucose was 5 fold more efficacious in stimulating COX-2 protein expression than AngII or mannitol. Losartan fully inhibited COX-2 protein responses to AngII and mannitol, but minimally inhibited responses to glucose. Ro-1069920 fully inhibited COX-2 protein responses to each effector. Conclusion: AngII, glucose, and osmotic stress (mannitol) activate COX-2; NF-kappaB may be an ideal site for COX-2 blockade, and COX-2 activation by osmotic stress requires AT1R, but activation by glucose is more robust and mechanistically complex. (c) 2014 S. Karger AG, Basel. PMID- 25531216 TI - Upregulation of the creatine transporter Slc6A8 by Klotho. AB - BACKGROUND/AIMS: The transmembrane Klotho protein contributes to inhibition of 1,25(OH)2D3 formation. The extracellular domain of Klotho protein could function as an enzyme with e.g. beta-glucuronidase activity, be cleaved off and be released into blood and cerebrospinal fluid. Klotho regulates several cellular transporters. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The main site of Klotho protein expression is the kidney. Klotho protein is also appreciably expressed in other tissues including chorioid plexus. The present study explored the effect of Klotho protein on the creatine transporter CreaT (Slc6A8), which participates in the maintenance of neuronal function and survival. METHODS: To this end cRNA encoding Slc6A8 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho protein. Creatine transporter CreaT (Slc6A8) activity was estimated from creatine induced current determined by two-electrode voltage-clamp. RESULTS: Coexpression of Klotho protein significantly increased creatine-induced current in Slc6A8 expressing Xenopus oocytes. Coexpression of Klotho protein delayed the decline of creatine induced current following inhibition of carrier insertion into the cell membrane by brefeldin A (5 uM). The increase of creatine induced current by coexpression of Klotho protein in Slc6A8 expressing Xenopus oocytes was reversed by beta-glucuronidase inhibitor (DSAL). Similarly, treatment of Slc6A8 expressing Xenopus oocytes with recombinant human alpha Klotho protein significantly increased creatine induced current. CONCLUSION: Klotho protein up regulates the activity of creatine transporter CreaT (Slc6A8) by stabilizing the carrier protein in the cell membrane, an effect requiring beta-glucuronidase activity of Klotho protein. PMID- 25531217 TI - Chromosome segregation: An exit for sister chromatids. PMID- 25531224 TI - Telomeres: Chaperonin' telomerase. PMID- 25531227 TI - Growth hormone treatment in patients with hypochondroplasia. PMID- 25531225 TI - Intrinsically disordered proteins in cellular signalling and regulation. AB - Intrinsically disordered proteins (IDPs) are important components of the cellular signalling machinery, allowing the same polypeptide to undertake different interactions with different consequences. IDPs are subject to combinatorial post translational modifications and alternative splicing, adding complexity to regulatory networks and providing a mechanism for tissue-specific signalling. These proteins participate in the assembly of signalling complexes and in the dynamic self-assembly of membrane-less nuclear and cytoplasmic organelles. Experimental, computational and bioinformatic analyses combine to identify and characterize disordered regions of proteins, leading to a greater appreciation of their widespread roles in biological processes. PMID- 25531228 TI - Successful replantation of 2 fingers in an 82-year-old patient: a case report. AB - We present the case of an 82-year-old patient who had successfully replanted 2 of his 4 amputated fingers in the left, non-dominant hand. Amputation was caused by a circular saw and the patient was delivered to the hospital 3 h after injury with amputated part of the hand appropriately stored. The patient's general health status was good, with no serious systemic diseases. He also did not smoke. Post-operative course was uneventful for the replanted fingers, but after his return home the patient developed left-sided pneumonia, treated successfully with i.v. antibiotics. 8 months after replantation the patient presented with slight movement in the replanted fingers (AROM 45 degrees ), a total grip strength 8 Kg and the qDASH score 24; however, he could firmly grasp objects due to having an intact, well-functioning thumb. PMID- 25531226 TI - Protein neddylation: beyond cullin-RING ligases. AB - NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) is a ubiquitin-like protein that activates the largest ubiquitin E3 ligase family, the cullin-RING ligases. Many non-cullin neddylation targets have been proposed in recent years. However, overexpression of exogenous NEDD8 can trigger NEDD8 conjugation through the ubiquitylation machinery, which makes validating potential NEDD8 targets challenging. Here, we re-evaluate studies of non-cullin targets of NEDD8 in light of the current understanding of the neddylation pathway, and suggest criteria for identifying genuine neddylation substrates under homeostatic conditions. We describe the biological processes that might be regulated by non-cullin neddylation, and the utility of neddylation inhibitors for research and as potential therapies. Understanding the biological significance of non-cullin neddylation is an exciting research prospect primed to reveal fundamental insights. PMID- 25531229 TI - Development of a mouse model for chronic cat allergen-induced asthma. AB - BACKGROUND: Allergic asthma is a chronic inflammatory airway disease caused by exposure to airborne allergens. In order to develop novel therapies for allergic asthma, models that are relevant to human disease are needed. METHODS: Female BALB/c mice were presensitised subcutaneously with alum-adsorbed recombinant cat allergen Fel d 1, followed by intranasal challenges with cat dander extract spiked with recombinant Fel d 1 for 7 weeks. For reference, mice were presensitised and challenged with ovalbumin following the same protocol. Airway hyperresponsiveness, serum antibodies, airway inflammation and cell infiltration, and cytokines in lung tissue and bronchoalveolar lavage were measured. RESULTS: Mice presensitised with recombinant Fel d 1 and challenged with cat dander extract or presensitised and challenged with ovalbumin showed airway hyperresponsiveness in response to metacholine. Mice of the cat allergen model showed influx of neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage, combined with increased levels of IL-17a and increased IL-4 mRNA expression in lung tissue. In contrast, mice sensitised and challenged with ovalbumin showed a predominant influx of eosinophils in bronchoalveolar lavage and had an increased expression of IL-5 in lung tissue. Both protocols induced features of lung tissue remodelling and allergen-specific antibody responses. CONCLUSIONS: The presented mouse model for cat allergen-induced asthma exhibits hallmarks of chronic allergic asthma, like airway hyperresponsiveness, a mixed neutrophilic/eosinophilic infiltration in bronchoalveolar lavage, expression of IL-17a and signs of remodelling in lung tissue. The model will provide a relevant platform for the development of novel treatment strategies. PMID- 25531230 TI - Diagnostic and prognostic utility of neutrophil gelatinase-associated lipocalin (NGAL) in patients with cardiovascular diseases--review. AB - NGAL (neutrophil gelatinase-associated lipocalin) is an acute phase protein, participating in antibacterial immunity. NGAL forms a complex with metalloproteinase 9 (MMP-9), thereby increasing its activity and preventing its degradation. NGAL is freely filtered through the glomerular membrane and reabsorbed by endocytosis in the proximal tubule. NGAL detected in urine is produced mainly in the distal nephron. Elevated serum and urine NGAL allows diagnosis of acute kidney injury approximately 24 hours earlier than plasma creatinine concentration. Increased levels of NGAL were detected in patients with acute myocardial infarction, heart failure or stroke and were demonstrated to be strong predictors of adverse prognosis. PMID- 25531231 TI - Mortality and treatment patterns among patients hospitalized with acute cardiovascular conditions during dates of national cardiology meetings. AB - IMPORTANCE: Thousands of physicians attend scientific meetings annually. Although hospital physician staffing and composition may be affected by meetings, patient outcomes and treatment patterns during meeting dates are unknown. OBJECTIVE: To analyze mortality and treatment differences among patients admitted with acute cardiovascular conditions during dates of national cardiology meetings compared with nonmeeting dates. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 30-day mortality among Medicare beneficiaries hospitalized with acute myocardial infarction (AMI), heart failure, or cardiac arrest from 2002 through 2011 during dates of 2 national cardiology meetings compared with identical nonmeeting days in the 3 weeks before and after conferences (AMI, 8570 hospitalizations during 82 meeting days and 57,471 during 492 nonmeeting days; heart failure, 19,282 during meeting days and 11,4591 during nonmeeting days; cardiac arrest, 1564 during meeting days and 9580 during nonmeeting days). Multivariable analyses were conducted separately for major teaching hospitals and nonteaching hospitals and for low- and high-risk patients. Differences in treatment utilization were assessed. EXPOSURES: Hospitalization during cardiology meeting dates. MAIN OUTCOMES AND MEASURES: Thirty-day mortality, procedure rates, charges, length of stay. RESULTS: Patient characteristics were similar between meeting and nonmeeting dates. In teaching hospitals, adjusted 30-day mortality was lower among high-risk patients with heart failure or cardiac arrest admitted during meeting vs nonmeeting dates (heart failure, 17.5% [95% CI, 13.7%-21.2%] vs 24.8% [95% CI, 22.9%-26.6%]; P < .001; cardiac arrest, 59.1% [95% CI, 51.4% 66.8%] vs 69.4% [95% CI, 66.2%-72.6%]; P = .01). Adjusted mortality for high-risk AMI in teaching hospitals was similar between meeting and nonmeeting dates (39.2% [95% CI, 31.8%-46.6%] vs 38.5% [95% CI, 35.0%-42.0%]; P = .86), although adjusted percutaneous coronary intervention (PCI) rates were lower during meetings (20.8% vs 28.2%; P = .02). No mortality or utilization differences existed for low-risk patients in teaching hospitals or high- or low-risk patients in nonteaching hospitals. In sensitivity analyses, cardiac mortality was not affected by hospitalization during oncology, gastroenterology, and orthopedics meetings, nor was gastrointestinal hemorrhage or hip fracture mortality affected by hospitalization during cardiology meetings. CONCLUSIONS AND RELEVANCE: High-risk patients with heart failure and cardiac arrest hospitalized in teaching hospitals had lower 30-day mortality when admitted during dates of national cardiology meetings. High-risk patients with AMI admitted to teaching hospitals during meetings were less likely to receive PCI, without any mortality effect. PMID- 25531232 TI - In vitro antimicrobial activities of 1-methoxyficifolinol, licorisoflavan A, and 6,8-diprenylgenistein against Streptococcus mutans. AB - The objective of the study was to investigate the antimicrobial effects of purified single compounds from ethanol-extracted licorice root on Streptococcus mutans. The crude licorice root extract (CLE) was obtained from Glycyrrhiza uralensis, which was subjected to column chromatography to separate compounds. Purified compounds were identified by mass spectrometry and nuclear magnetic resonance. Antimicrobial activities of purified compounds from CLE were evaluated by determining the minimum inhibitory concentration and by performing time-kill kinetics. The inhibitory effects of the compounds on biofilm development were evaluated using crystal violet assay and confocal microscopy. Cell toxicity of substances to normal human gingival fibroblast (NHGF) cells was tested using a methyl thiazolyl tetrazolium assay. Chlorhexidine digluconate (CHX) was used in the control group. Three antimicrobial flavonoids, 1-methoxyficifolinol, licorisoflavan A, and 6,8-diprenylgenistein, were isolated from the CLE. We found that the three flavonoids and CHX had bactericidal effects on S. mutans UA159 at the concentration of >=4 and >=1 ug/ml, respectively. The purified compounds completely inhibited biofilm development of S. mutans UA159 at concentrations over 4 MUg/ml, which was equivalent to 2 MUg/ml of CHX. Confocal analysis showed that biofilms were sparsely scattered in the presence of over 4 MUg/ml of the purified compounds. However, the three compounds purified from CLE showed less cytotoxic effects on NHGF cells than CHX at these biofilm-inhibitory concentrations. Our results suggest that purified flavonoids from CLE can be useful in developing oral hygiene products, such as gargling solutions and dentifrices for preventing dental caries. PMID- 25531233 TI - Relationship between fat mass measured by dual-energy X-ray absorptiometry and leptin in preterm infants between term age and 6 months' corrected age. AB - BACKGROUND/AIMS: In term subjects, fat mass (FM) is positively associated with leptin, whereas studies in preterm infants show conflicting results. However, none of these studies measured FM by dual-energy X-ray absorptiometry (DEXA). This study aims to relate FM measured by DEXA in relation to leptin and growth in preterm infants. METHODS: In 139 preterm infants, weight (kg) and length (cm) were measured at birth, term age, and 6 months' corrected age (CA). FM (kg), measured by whole-body DEXA, and leptin (ug/l) were measured at term age and 6 months' CA. RESULTS: At term age and 6 months' CA, FM was associated with leptin (beta = 1.94, 95% CI: 1.51-2.36, and beta = 0.37, 95% CI: 0.26-0.48, respectively; p < 0.001). Gain in weight standard deviation score (SDS) between term age and 6 months' CA was associated with FM and leptin at 6 months' CA (beta = 0.24, 95% CI: 0.18-0.30, and beta = 0.25, 95% CI: 0.16-0.33, respectively; p < 0.001). CONCLUSION: In preterm infants, FM measured by DEXA is associated with leptin, which indicates that leptin is a marker of body FM during the first 6 months after term age. Gain in weight SDS between term age and 6 months' CA results in higher FM and higher leptin at 6 months' CA. PMID- 25531234 TI - Women in pediatrics. PMID- 25531235 TI - Role of hemodialysis with high cut-off membranes in a patient with a non recognized leishmaniasis. AB - BACKGROUND: We report here a case of a woman affected by fever, weight loss, splenomegaly, and leucopenia associated with trombocytopenia, transferred to the intensive care unit with acute kidney injury and septic shock. METHODS: Patient was treated with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD). RESULTS: During treatment, the patient experienced a stable improvement in the hemodynamic, pulmonary function and tissue perfusion parameters. After 48 h of treatment, significant reductions in SOFA score (from 12, before starting the procedure, to 6) and in serum inflammatory mediators (as IL-6, from 599-568 pg/ml) were observed. Leishmania infection was identified as responsible of the septic condition only 48 h after removing hemodialysis. Antiprotozoal therapy was begun and the patient discharged. CONCLUSIONS: By supporting the renal function and reducing systemic inflammation, HCO-CVVHD could be a useful bridge therapy. This procedure allowed the medical team to gain sufficient time to diagnose the type of infection and begin an etiological therapy. PMID- 25531236 TI - Amniotic band syndrome: a single-institutional experience. AB - INTRODUCTION: Amniotic band syndrome (ABS) is uncommon. We review our single institutional experience to define its natural history and outcomes. MATERIALS AND METHODS: We conducted a retrospective analysis from a single, tertiary referral center of patients evaluated for and confirmed to have ABS from 1997 to 2012. RESULTS: Twenty-eight patients had confirmed ABS. The mean +/- SD maternal age was 27.9 +/- 5.9 years, and the mean gestational age at diagnosis was 20.7 +/ 3.8 months. Oligohydramnios was reported in 4 patients. Eleven patients had membrane disruption, of whom 4 had undergone a prior percutaneous intervention. Extremities were the most common site affected (n = 20), followed by the umbilical cord (n = 7), abdomen (n = 5), limb-body wall complex (n = 5), head (n = 1), and chest (n = 1). Nine patients were felt to be candidates for fetal intervention; 5 underwent fetoscopic amniotic band lysis with 4 survivors. Overall survival, excluding 3 terminations, was 74%. There were 5 fetal demises and one neonatal death. Cord involvement was higher in nonsurvivors (67%) compared to survivors (19%, p = 0.05). DISCUSSION: ABS most commonly involves the extremities. Membrane disruption is not always present. Fetoscopic lysis is appropriate for select patients, and special consideration should be given for cord involvement, which is associated with a worse outcome. PMID- 25531237 TI - Diverse Francisella tularensis strains and oropharyngeal tularemia, Turkey. PMID- 25531238 TI - Parastomal hernia: a growing problem with new solutions. AB - Parastomal hernia is one of the most common complications following stoma creation and its prevalence is only expected to increase. It often leads to a decrease in the quality of life for patients due to discomfort, pain, frequent ostomy appliance leakage, or peristomal skin irritation and can result in significantly increased healthcare costs. Surgical technique for parastomal hernia repair has evolved significantly over the past two decades with the introduction of new types of mesh and laparoscopic procedures. The use of prophylactic mesh in high-risk patients at the time of stoma creation has gained attention in lieu of several promising studies that have emerged in the recent days. This review will attempt to demonstrate the burden that parastomal hernias present to patients, surgeons, and the healthcare system and also provide an overview of the current management and surgical techniques at both preventing and treating parastomal hernias. PMID- 25531239 TI - Interlaboratory assessment of cryomilling sample preparation for residue analysis. AB - The effectiveness of the comminution approach used for bulk field samples limits the size of the subsample that must be extracted and analyzed to ensure an adequately representative and reproducible measurement. In many cases this subsample size restricts the residue method to the use of larger vessel formats, limiting downstream throughput. The introduction of a secondary fine-milling step to this process using a subsample size already known to be representative can further improve sample homogeneity and allow direct method scaling to small high throughput formats. Dramatic increases in method throughput can then be achieved through the simultaneous processing of numerous samples in parallel. This approach was evaluated across a diverse grouping of crop matrices using two substantially different pesticide types. Both fortified and field-collected samples demonstrated a high degree of precision and reproducibility across laboratories. Additional benefits of this approach include significant reductions in cost and solvent waste generation, as well as improvements in assay quality and transferability. PMID- 25531240 TI - A randomised crossover trial of clinical algorithm for oxygen saturation targeting in preterm infants with frequent desaturation episodes. AB - OBJECTIVES: Strategies for oxygen therapy for preterm infants, such as the Vermont-Oxford's 'Breathsavers' guidelines, seek to strike a balance between the potential risks of the extremes of hyperoxia and hypoxia in preterm infants. Using an algorithm based on those guidelines, we aimed to compare the proportion of time spent within the SpO2 target range during algorithm-based management of oxygen delivery compared with routine nursing care. STUDY DESIGN: In a randomised crossover trial, maintenance of SpO2 over a 4-hour period during routine care was compared with algorithm-based control (administered by a dedicated research nurse). SpO2 target (88-92%) and alarm limits (86-94%) were identical in both arms. Infants <32 weeks' gestation were eligible if having >8 desaturations episodes to <85%/4 h while receiving continuous positive airway pressure/synchronised intermittent mandatory ventilation. Data was recorded via the Powerlab system from Masimo oximeters and Babylog 8000+ ventilators. RESULTS: 16 infants with a gestation of 26.7 +/- 1.3 weeks (mean +/- SD) and birth weight 901 +/- 193 g were studied at a postmenstrual age of 30.5 +/- 2.4 weeks. The percentage of time spent within target range was 34.6 +/- 28.5% during routine care versus 38.3 +/- 29.3% during algorithm-based care (p = 0.23). Compliance with alarm limits was 58.4 +/- 21.8% during routine versus 64.7 +/- 22.1% for algorithm-based care (p = 0.091). The frequency of desaturations, episode severity or number of FiO2 adjustments did not differ between the two care strategies. CONCLUSIONS: The observation that algorithm-based control did not improve time spent within the SpO2 target and alarm limits suggests nursing care has reached an optimum in the unit studied. Our finding indicates that significant modifications to the algorithm are likely to be necessary to improve target range compliance. PMID- 25531241 TI - Computational studies of a paramagnetic planar dibenzotetraaza[14]annulene Ni(II) complex. AB - A square-planar Ni(II) dibenzotetraaza[14]annulene complex substituted with two 3,3-dimethylindolenine groups in the meso positions has recently been synthesized and characterized experimentally. In the solid-state, the Ni(II) complex forms linear pi-interacting stacks with Ni...Ni separations of 3.448(2) A. Measurements of the temperature dependence of the magnetic susceptibility revealed a drastic change in the magnetic properties at a temperature of 13 K, indicating a transition from low-to-high spin states. The molecular structures of the free base ligand, the lowest singlet, and triplet states of the monomer and the dimer of the Ni complex have been studied computationally using density functional theory (DFT) and ab initio correlation levels of theory. In calculations at the second-order Moller-Plesset (MP2) perturbation theory level, a large energy of 260 kcal mol(-1) was obtained for the singlet-triplet splitting, suggesting that an alternative explanation of the observed magnetic properties is needed. The large energy splitting between the singlet and triplet states suggests that the observed change in the magnetism at very low temperatures is due to spin-orbit coupling effects originating from weak interactions between the fine-structure states of the Ni cations in the complex. The lowest electronic excitation energies of the dibenzotetraaza[14]annulene Ni(II) complex calculated at the time dependent density functional theory (TDDFT) levels are in good agreement with values deduced from the experimental UV-vis spectrum. Calculations at the second order algebraic-diagrammatic construction (ADC(2)) level on the dimer of the meso substituted 3,3-dimethylindolenine dibenzotetraaza[14] annulene Ni(II) complex yielded Stokes shifts of 85-100 nm for the lowest excited singlet states. Calculations of the strength of the magnetically induced ring current for the free-base 3,3-dimethylindolenine-substituted dibenzotetraaza[14]annulene show that the annulene ring is very weakly antiaromatic, sustaining a paratropic ring current strength of only -1.7 nA/T. PMID- 25531243 TI - Low-melting imidazolium-based salts with the paramagnetic reineckate-analogue anion [Cr(NCS)4(bipy)]- (bipy = 2,2'-bipyridine): syntheses, properties, and structures. AB - In order to investigate the potential ionic liquid properties of Reineckate analogue materials, four new salts, consisting of the heteroleptic [Cr(NCS)(4)(bipy)](-) complex anion and imidazolium-based cations A(+) = 1-ethyl 3-methylimidazolium, 1-n-butyl-3-methylimidazolium, pentamethylimidazolium, and 1,3-dimethyl-2,4,5-triphenylimidazolium, were investigated. Their structures were established by single-crystal X-ray diffraction. The compounds are paramagnetic with effective magnetic moments in the range of those expected by the number of unpaired spins of the chromium(III) ion. All melting points are above 100 degrees C, which prevents us from calling these compounds "ionic liquids". Nevertheless, they are low for salts of this constitution and may be useful for molten salt reactions. Cyclic voltammetry measurements show no reversible electron-transfer steps. PMID- 25531242 TI - Diagnostic yield of recommendations for chest CT examination prompted by outpatient chest radiographic findings. AB - PURPOSE: To evaluate the diagnostic yield of recommended chest computed tomography (CT) prompted by abnormalities detected on outpatient chest radiographic images. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was waived. Reports of all outpatient chest radiographic examinations performed at a large academic center during 2008 (n = 29 138) were queried to identify studies that included a recommendation for a chest CT imaging. The radiology information system was queried for these patients to determine if a chest CT examination was obtained within 1 year of the index radiographic examination that contained the recommendation. For chest CT examinations obtained within 1 year of the index chest radiographic examination and that met inclusion criteria, chest CT images were reviewed to determine if there was an abnormality that corresponded to the chest radiographic finding that prompted the recommendation. All corresponding abnormalities were categorized as clinically relevant or not clinically relevant, based on whether further work-up or treatment was warranted. Groups were compared by using t test and Fisher exact test with a Bonferroni correction applied for multiple comparisons. RESULTS: There were 4.5% (1316 of 29138 [95% confidence interval {CI}: 4.3%, 4.8%]) of outpatient chest radiographic examinations that contained a recommendation for chest CT examination, and increasing patient age (P < .001) and positive smoking history (P = .001) were associated with increased likelihood of a recommendation for chest CT examination. Of patients within this subset who met inclusion criteria, 65.4% (691 of 1057 [95% CI: 62.4%, 68.2%) underwent a chest CT examination within the year after the index chest radiographic examination. Clinically relevant corresponding abnormalities were present on chest CT images in 41.4% (286 of 691 [95% CI: 37.7%, 45.2%]) of cases, nonclinically relevant corresponding abnormalities in 20.6% (142 of 691 [95% CI: 17.6%, 23.8%]) of cases, and no corresponding abnormalities in 38.1% (263 of 691 [95% CI: 34.4%, 41.8%]) of cases. Newly diagnosed, biopsy-proven malignancies were detected in 8.1% (56 of 691 [95% CI: 6.2%, 10.4%]) of cases. CONCLUSION: A radiologist recommendation for chest CT to evaluate an abnormal finding on an outpatient chest radiographic examination has a high yield of clinically relevant findings. PMID- 25531244 TI - Size-dependent energy levels of InSb quantum dots measured by scanning tunneling spectroscopy. AB - The electronic structure of single InSb quantum dots (QDs) with diameters between 3 and 7 nm was investigated using atomic force microscopy (AFM) and scanning tunneling spectroscopy (STS). In this size regime, InSb QDs show strong quantum confinement effects which lead to discrete energy levels on both valence and conduction band states. Decrease of the QD size increases the measured band gap and the spacing between energy levels. Multiplets of equally spaced resonance peaks are observed in the tunneling spectra. There, multiplets originate from degeneracy lifting induced by QD charging. The tunneling spectra of InSb QDs are qualitatively different from those observed in the STS of other III-V materials, for example, InAs QDs, with similar band gap energy. Theoretical calculations suggest the electron tunneling occurs through the states connected with L-valley of InSb QDs rather than through states of the Gamma-valley. This observation calls for better understanding of the role of indirect valleys in strongly quantum-confined III-V nanomaterials. PMID- 25531245 TI - Mannosylated polyion complexes for in vivo gene delivery into CD11c(+) dendritic cells. AB - Dendritic cells (DCs) possess unique abilities in initiating primary immune responses and thus represent prime targets for DNA-based vaccinations. Here, we describe the design and synthesis of mannosylated polyion complexes (PICs) composed of cationic polyethylenimine (PEI) and hydrophilic polyethylene glycol (PEG) segments, and bearing mono- and trivalent mannose as a ligand for targeting mannose receptor (MR/CD206)-positive DCs. Amino-terminated mannose (Man) containing ligands in mono- and trivalent presentations (Man- and Man3-, respectively) were prepared and conjugated to PEG via an N-hydroxysuccinimide (NHS)-activated terminal. Thiolated PEI was conjugated to the mannosylated PEG via the maleimide (MAL)-activated terminal. The resulting positively charged diblock copolymers bearing mannoses (Man-PEG-b-PEI and Man3-PEG-b-PEI) were self assembled with DNA to form PICs with lower surface charge than did their PEI building block and mean hydrodynamic diameters in the range of 100-450 nm, depending on the N/P ratio. Man3-PEG-b-PEI demonstrated a 3-4-fold greater transfection efficiency in MR-positive dendritic cell lines (THP-1, DC2.4), relative to Man-PEG-b-PEI, exhibited low cytotoxicity when compared with PEI, and showed low transfection efficiency in nondendritic HeLa cells. In preliminary in vivo experiments, Man-PEG-b-PEI/DNA and Man3-PEG-b-PEI/DNA demonstrated 2-3-fold higher gene delivery efficiency into CD11c(+) DCs collected from inguinal lymph nodes of C57/BL6 mice, when compared to PEI/DNA complexes, as shown by GFP expression measurements, 24 h post subcutaneous injection. The results indicate that the mannosylated PICs are a safe and effective gene delivery system, showing in vivo specificity toward CD11c(+) DCs. PMID- 25531246 TI - Fibrocytes contribute to inflammation and fibrosis in chronic hypersensitivity pneumonitis through paracrine effects. AB - RATIONALE: Hypersensitivity pneumonitis (HP) represents a lung inflammation provoked by exposure to a variety of antigens. Chronic HP may evolve to lung fibrosis. Bone marrow-derived fibrocytes migrate to injured tissues and contribute to fibrogenesis, but their role in HP is unknown. OBJECTIVES: To assess the possible participation of fibrocytes in chronic HP. METHODS: CD45(+)/CXCR4(+)/Col-I(+) circulating fibrocytes were evaluated by flow cytometry, and the presence of fibrocytes in HP and normal lungs by confocal microscopy. The concentration of CXCL12 in plasma and bronchoalveolar lavage fluids was quantified by ELISA. The effect of fibrocytes on lung fibroblasts and T lymphocytes was examined in co-cultures. MEASUREMENTS AND MAIN RESULTS: The percentage of circulating fibrocytes was significantly increased in patients with HP compared with healthy individuals (5.3 +/- 3.4% vs. 0.8 +/- 0.7%; P = 0.00004). Numerous fibrocytes were found infiltrating the HP lungs near fibroblasts and lymphocytes. Plasma CXCL12 concentration was significantly increased in patients with HP (2,303.3 +/- 813.7 vs. 1,385.6 +/- 318.5 pg/ml; P = 0.00003), and similar results were found in bronchoalveolar lavage fluids. The chemokine was primarily expressed by epithelial cells. In co-cultures, fibrocytes induced on lung fibroblasts a significant increase in the expression of alpha1 type I collagen, matrix metalloprotease-1, and platelet-derived growth factor beta. Likewise, fibrocytes induced the up-regulation of CCL2 in HP lymphocytes and fibroblasts. CONCLUSIONS: These findings demonstrate that high levels of fibrocytes are present in the peripheral blood of patients with chronic HP and that these cells infiltrate the HP lungs. Fibrocytes may participate in the pathogenesis of HP, amplifying the inflammatory and fibrotic response by paracrine signaling inducing the secretion of a variety of proinflammatory and profibrotic molecules. PMID- 25531247 TI - Effects of protein structure on iron-polypeptide vibrational dynamic coupling in cytochrome c. AB - Cytochrome c (Cyt c) has a heme covalently bound to the polypeptide via a Cys-X-X Cys-His (CXXCH) linker that is located in the interface region for protein protein interactions. To determine whether the polypeptide matrix influences iron vibrational dynamics, nuclear resonance vibrational spectroscopy (NRVS) measurements were performed on (57)Fe-labeled ferric Hydrogenobacter thermophilus cytochrome c-552, and variants M13V, M13V/K22M, and A7F, which have structural modifications that alter the composition or environment of the CXXCH pentapeptide loop. Simulations of the NRVS data indicate that the 150-325 cm(-1) region is dominated by NHis-Fe-SMet axial ligand and polypeptide motions, while the 325-400 cm(-1) region shows dominant contributions from nu(Fe-NPyr) (Pyr = pyrrole) and other heme-based modes. Diagnostic spectral signatures that directly relate to structural features of the heme active site are identified using a quantum chemistry-centered normal coordinate analysis (QCC-NCA). In particular, spectral features that directly correlate with CXXCH loop stiffness, the strength of the Fe-His interaction, and the degree of heme distortion are identified. Cumulative results from our investigation suggest that compared to the wild type (wt), variants M13V and M13V/K22M have a more rigid CXXCH pentapeptide segment, a stronger Fe-NHis interaction, and a more ruffled heme. Conversely, the A7F variant has a more planar heme and a weaker Fe-NHis bond. These results are correlated to the observed changes in reduction potential between wt protein and the variants studied here. Implications of these results for Cyt c biogenesis and electron transfer are also discussed. PMID- 25531248 TI - DNA cytosine methylation and hydroxymethylation at the borders. PMID- 25531250 TI - Epigenomics and targeted therapy in cancer. PMID- 25531249 TI - DNA methylation is a key factor in understanding differentiation phenotype in esophageal squamous cell carcinoma. PMID- 25531251 TI - Single nucleotide polymorphisms on DNA methylation microarrays: precautions against confounding. PMID- 25531252 TI - Examining peripheral DNA methylation in behavioral epigenetic and epigenetic psychiatry: opportunities and challenges. PMID- 25531253 TI - Genetic variants of methionine metabolism and DNA methylation. AB - AIM: Altered DNA methylation is associated with important and common pathologies such as cancer. The origin of altered DNA methylation is unknown. The methyl groups for DNA methylation are provided by methionine metabolism. This metabolism is characterized by a high interindividual variability, which is in part explained by genetic variants. METHODS: In a cohort of 313 individuals derived from a family-based study with index cases of cerebrovascular disease, we analyzed whether global methylation of leukocyte DNA was associated with age, gender, homocysteine plasma levels or functionally relevant genetic variants. RESULTS: We observed an association of the G-allele of the methionine synthase variant c.2756A>G (D919G) with global methylation (% methylation +/- 1 SD, AA: 41.3 +/- 14.9; AG: 36.4 +/- 18.2; GG: 30.8 +/- 16.9; F = 4.799; p = 0.009). The methionine synthase variant c.2756A>G is associated with various types of cancer. CONCLUSION: Our data suggest that an impact on DNA methylation may contribute to the clinical relevance of the methionine synthase variant. PMID- 25531254 TI - Biological and biochemical modulation of DNA methylation. AB - Epigenetic regulation is facilitated by a battery of proteins that act as 'writers' or 'erasers' to add or remove biochemical modifications to DNA and histone proteins. DNA modifications, histone modifications and long noncoding RNAs function interdependently through reciprocal crosstalk. This review will focus on DNA methylation and DNA methyltransferases with emphasis on how biological and biochemical factors such as histone modifications and noncoding RNAs might play a role in modulating DNA methylation. Other physiological and biochemical factors that can modify DNA methylation marks will also be discussed including chemical exposures and inflammation. PMID- 25531255 TI - Strategies for validation and testing of DNA methylation biomarkers. AB - DNA methylation is a stable covalent epigenetic modification of primarily CpG dinucleotides that has recently gained considerable attention for its use as a biomarker in different clinical settings, including disease diagnosis, prognosis and therapeutic response prediction. Although the advent of genome-wide DNA methylation profiling in primary disease tissue has provided a manifold resource for biomarker development, only a tiny fraction of DNA methylation-based assays have reached clinical testing. Here, we provide a critical overview of different analytical methods that are suitable for biomarker validation, including general study design considerations, which might help to streamline epigenetic marker development. Furthermore, we highlight some of the recent marker validation studies and established markers that are currently commercially available for assisting in clinical management of different cancers. PMID- 25531256 TI - Environmental challenge, epigenetic plasticity and the induction of altered phenotypes in mammals. AB - The level of transcriptional activity of a gene is regulated by epigenetic processes. There is compelling evidence that environmental challenges throughout the life course can induce phenotypic change. In this review, we summarize the current evidence, focusing specifically on the effects of nutrition and of environmental pollutants, that epigenetic processes underpin the induction by environmental change of altered phenotypic traits, emphasizing the implications for health outcomes. We also discuss whether epigenetic processes may be involved in the passage of induced traits between generations. Overall, current findings indicate that epigenetic processes may play an important role in determining disease risk, but there is a lack of studies that demonstrate causal links between epigenetic change and tissue function. PMID- 25531257 TI - Epigenetic mechanisms regulating differentiation of neural stem/precursor cells. AB - Differentiation of neural stem/precursor cells (NS/PCs) into neurons, astrocytes and oligodendrocytes during mammalian brain development is a carefully controlled and timed event. Increasing evidences suggest that epigenetic regulation is necessary to drive this. Here, we provide an overview of the epigenetic mechanisms involved in the developing mammalian embryonic forebrain. Histone methylation is a key factor but other epigenetic factors such as DNA methylation and noncoding RNAs also partake during fate determination. As numerous epigenetic modifications have been identified, future studies on timing and regional specificity of these modifications will further deepen our understanding of how intrinsic and extrinsic mechanisms participate together to precisely control brain development. PMID- 25531258 TI - Epigenetic mechanisms of breast cancer: an update of the current knowledge. AB - Epigenetic alterations are heritable changes in gene expression that occur without causing any change in DNA sequence. They are important key factors for cancer development and prognosis. Breast cancer is induced by the accumulation of altered gene regulation. Besides genetic mutations, epigenetics mechanisms have an important role in breast cancer tumorigenesis. Investigations related with aberrant epigenetic regulations in breast cancer focus on initiating molecular mechanisms in cancer development, identification of new biomarkers to predict breast cancer aggressiveness and the potential of epigenetic therapy. In this review, we will summarize the recent knowledge about the role of epigenetic alterations related with DNA methylation and histone modification in breast cancer. In addition, altered regulation of breast cancer specific genes and the potential of epigenetic therapy will be discussed according to epigenetic mechanisms. PMID- 25531260 TI - From Prader-Willi syndrome to psychosis: translating parent-of-origin effects into schizophrenia research. AB - Prader-Willi syndrome (PWS) is a relatively rare disorder that originates from paternally inherited deletions and maternal disomy (mUPD) within the 15q11-q13 region or alterations in the PWS imprinting center. Evidence is accumulating that mUPD underlies high prevalence of psychosis among PWS patients. Several genes involved in differentiation and survival of neurons as well as neurotransmission known to act in the development of PWS have been also implicated in schizophrenia. In this article, we provide an overview of genetic and epigenetic underpinnings of psychosis in PWS indicating overlapping points in the molecular background of PWS and schizophrenia. Simultaneously, we highlight the need for studies investigating genetic and epigenetic makeup of the 15q11-q13 in schizophrenia indicating promising candidate genes. PMID- 25531259 TI - The mitochondrial epigenome: a role in Alzheimer's disease? AB - Considerable evidence suggests that mitochondrial dysfunction occurs early in Alzheimer's disease, both in affected brain regions and in leukocytes, potentially precipitating neurodegeneration through increased oxidative stress. Epigenetic processes are emerging as a dynamic mechanism through which environmental signals may contribute to cellular changes, leading to neuropathology and disease. Until recently, little attention was given to the mitochondrial epigenome itself, as preliminary studies indicated an absence of DNA modifications. However, recent research has demonstrated that epigenetic changes to the mitochondrial genome do occur, potentially playing an important role in several disorders characterized by mitochondrial dysfunction. This review explores the potential role of mitochondrial epigenetic dysfunction in Alzheimer's disease etiology and discusses some technical issues pertinent to the study of these processes. PMID- 25531262 TI - Macrophage apoptosis induced by aqueous C60 aggregates changing the mitochondrial membrane potential. AB - Fullerenes have been applied to various fields in recent years for their unique physicochemical properties. C60's potential environmental and health risks are therefore being investigated. This work presents the cytotoxicity of aqueous C60 aggregates (nC60) by using the mouse peritoneal macrophage (RAW264.7) as a model biological system. Cells incubated with nC60 showed a decrease in cell viability, and the quantities of cell apoptosis increased significantly in a dose-dependent and time-dependent manner. By TEM imaging cells were observed to be asymmetric and shrunken compared to control cells. nC60 was adsorbed onto the plasma membrane and apparent phagocytosis was observed after a 24h exposure. The intracellular reactive oxygen species (ROS) were quantified with the dichlorofluorescein diacetate (DCFH-DA) detection assay kit by flow cytometry and found to increase in treated cells. Membrane damage and lipid peroxidation were not observed, since both intracellular and extracellular MDA showed no variation. Detection of the mitochondrial membrane potential (MMP) by JC-1 assay kit showed that MMP had an obvious dose-dependent loss. We speculate that the nC60 aggregates induced apoptosis of macrophage by changing the mitochondrial membrane potential. PMID- 25531263 TI - The utilisation of structural descriptors to predict metabolic constants of xenobiotics in mammals. AB - Quantitative structure-activity relationships (QSARs) were developed to predict the Michaelis-Menten constant (Km) and the maximum reaction rate (Vmax) of xenobiotics metabolised by four enzyme classes in mammalian livers: alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), flavin-containing monooxygenase (FMO), and cytochrome P450 (CYP). Metabolic constants were gathered from the literature and a genetic algorithm was employed to select at most six predictors from a pool of over 2000 potential molecular descriptors using two thirds of the xenobiotics in each enzyme class. The resulting multiple linear models were cross-validated using the remaining one-third of the compounds. The explained variances (R(2)adj) of the QSARs were between 50% and 80% and the predictive abilities (R(2)ext) between 50% and 60%, except for the Vmax QSAR of FMO with both R(2)adj and R(2)ext less than 30%. The Vmax values of FMO were independent of substrate chemical structure because the rate-limiting step of its catalytic cycle occurs before compound oxidation. For the other enzymes, Vmax was predominantly determined by functional groups or fragments and electronic properties because of the strong and chemical-specific interactions involved in the metabolic reactions. The most relevant predictors for Km were functional groups or fragments for the enzymes metabolising specific compounds (ADH, ALDH and FMO) and size and shape properties for CYP, likely because of the broad substrate specificity of CYP enzymes. The present study can be helpful to predict the Km and Vmax of four important oxidising enzymes in mammals and better understand the underlying principles of chemical transformation by liver enzymes. PMID- 25531264 TI - Dieckol as a novel anti-proliferative and anti-angiogenic agent and computational anti-angiogenic activity evaluation. AB - In the current study it was found that dieckol isolated from edible brown algae, Ecklonia cava (EC), as potent anti-proliferative and anti-angiogenic agent. Vascular endothelial growth factor (VEGF) induced EA.hy926 cell proliferation was suppressed by dieckol treatment. Further, it showed a significant inhibition of cell migration via inhibiting the protein and gene expression levels of matrix metalloproteinases, MMP-2 and -9. The signaling cascade underlying these responses was found as the dieckol induced inhibition of mitogen-activated protein kinase (MAPK) signaling pathway molecules, ERK and p38. Docking calculations were carried out on AP-N, VEGFR-1, MMP-2, MMP-9, Akt and Erk2 proteins model. Collectively, these results demonstrate the effective anti proliferative and anti-migratory activity of dieckol on VEGF induced EA.hy926 through MAPK molecular signaling pathways which could be effectively correlated to its potential as an anti-angiogenic candidate. Therefore, this study reveals the potential of dieckol to be used in the design of anti-angiogenic agents. PMID- 25531265 TI - 6-OH-BDE-47 promotes human lung cancer cells epithelial mesenchymal transition via the AKT/Snail signal pathway. AB - Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in the various human tissues. The OH-PBDEs are suggested to be stronger endocrine disrupting compounds than PBDEs, therefore the toxicological effects of OH-PBDEs had received lots of attention. However, there is no study about the carcinogenic effect of OH-PBDEs and their estrogen potencies on the tumorigenesis and development of cancer. In the present study, we found that 6-hydroxy-2,2',4',4' tetrabromodiphenyl ether (6-OH-BDE-47), the most abundant OH-PBDE congeners in human serum, promoted the in vitro migration of lung cancer A549 and H358 cells by induction of epithelial to mesenchymal transition (EMT). This was confirmed by that 6-OH-BDE-47 significantly down regulated the expression of epithelial markers E-cadherin (E-Cad) and zona occludin-1 (ZO-1) while up regulated the mesenchymal markers vimentin (Vim) and N-cadherin (N-Cad). 6-OH-BDE-47 up regulated the protein while not mRNA levels of Snail, which was the key transcription factor of EMT. Silencing of Snail by use of siRNA attenuated the 6 OH-BDE-47 induced EMT. This suggested that the stabilization of Snail was essential for 6-OH-BDE-47 induced EMT. Further, the treatment of 6-OH-BDE-47 increased the phosphorylation of AKT and ERK in A549 cells. Only PI3K/AKT inhibitor (LY294002), but not ERK inhibitor (PD98059), completely blocked the 6 OH-BDE-47 induced up regulation of Snail and down regulation of E-Cad, suggesting that PI3K/AKT pathway is important for 6-OH-BDE-47-mediated Snail stabilization and EMT in A549 cells. Generally, our results revealed for the first time that 6 OH-BDE-47 promoted the EMT of lung cancer cells via AKT/Snail signals. This suggested that more attention should be paid to the effects of OH-PBDEs on tumorigenesis and development of lung cancer. PMID- 25531266 TI - Interaction of four low dose toxic metals with essential metals in brain, liver and kidneys of mice on sub-chronic exposure. AB - This study reports on interactions between low dose toxic and essential metals. Low dose Pb (0.01mg/L), Hg (0.001mg/L), Cd (0.005mg/L) and As (0.01mg/L) were administered singly to four groups of 3-week old mice for 120 days. Pb exposure increased brain Mg and Cu by 55.5% and 266%, respectively. Increased brain Mg resulted from metabolic activity of brain to combat insults, whiles Cu overload was due to alteration and dysfunction of CTR1 and ATP7A molecules. Reduction of liver Ca by 56.0% and 31.6% (on exposure to As and Cd, respectively) resulted from inhibition of Ca-dependent ATPase in nuclei and endoplasmic reticulum through binding with thiol groups. Decreased kidney Mg, Ca and Fe was due to uptake of complexes of As and Cd with thiol groups from proximal tubular lumen. At considerably low doses, the study establishes that, toxic metals disturb the homeostasis of essential metals. PMID- 25531267 TI - A structural mechanism for calcium transporter headpiece closure. AB - To characterize the conformational dynamics of sarcoplasmic reticulum (SR) calcium pump (SERCA) we performed molecular dynamics simulations beginning with several different high-resolution structures. We quantified differences in structural disorder and dynamics for an open conformation of SERCA versus closed structures and observed that dynamic motions of SERCA cytoplasmic domains decreased with decreasing domain-domain separation distance. The results are useful for interpretation of recent intramolecular Forster resonance energy transfer (FRET) distance measurements obtained for SERCA fused to fluorescent protein tags. Those previous physical measurements revealed several discrete structural substates and suggested open conformations of SERCA are more dynamic than compact conformations. The present simulations support this hypothesis and provide additional details of SERCA molecular mechanisms. Specifically, all-atoms simulations revealed large-scale translational and rotational motions of the SERCA N-domain relative to the A- and P-domains during the transition from an open to a closed headpiece conformation over the course of a 400 ns trajectory. The open-to-closed structural transition was accompanied by a disorder-to-order transition mediated by an initial interaction of an N-domain loop (Nbeta5-beta6, residues 426-436) with residues 133-139 of the A-domain. Mutation of three negatively charged N-domain loop residues abolished the disorder-to-order transition and prevented the initial domain-domain interaction and subsequent closure of the cytoplasmic headpiece. Coarse-grained molecular dynamics simulations were in harmony with all-atoms simulations and physical measurements and revealed a close communication between fluorescent protein tags and the domain to which they were fused. The data indicate that previous intramolecular FRET distance measurements report SERCA structure changes with high fidelity and suggest a structural mechanism that facilitates the closure of the SERCA cytoplasmic headpiece. PMID- 25531268 TI - Transfer of 210Po, 210Pb and 238U from some medicinal plants to their essential oils. AB - Essential oils were extracted from 35 medicinal plants used by Syrians, organic compounds were determined in these oils and concentrations of (210)Po (210)Pb and (238)U were determined in the original plants and in the essential oils. The results showed that the highest activity concentrations of (210)Po and (210)Pb were found in leaves with large surfaces and in Sage were as high as 73.5 Bq kg( 1) and 73.2 Bq kg(-1), respectively. The activity concentration of (238)U was as high as 4.26 Bq kg(-1) in Aloe. On the other hand, activity concentrations of (210)Po ranged between 0.2 and 71.1 Bq kg(-1) in extracted essential oils for Rosemary and False yellowhead, respectively. The activity concentration of (210)Pb reached 63.7 Bq kg(-1) in Aloe oil. The activity concentrations of (238)U were very low in all extracted oils; the highest value was 0.31 Bq kg(-1) in peel of Orange oil. The transfer of (210)Po and (210)Pb from plant to its oil was the highest for Eugenia; 7.1% and 5.5% for (210)Po and (210)Pb, respectively. A linear relationship was found between the transfer factor of radionuclides from plant to its essential oil and the chemical content of this oil. PMID- 25531269 TI - Enhancing cellulose utilization for fuels and chemicals by genetic modification of plant cell wall architecture. AB - Cellulose from plant biomass can serve as a sustainable feedstock for fuels, chemicals and polymers that are currently produced from petroleum. In order to enhance economic feasibility, the efficiency of cell wall deconstruction needs to be enhanced. With the use of genetic and biotechnological approaches cell wall composition can be modified in such a way that interactions between the major cell wall polymers-cellulose, hemicellulosic polysaccharides and lignin-are altered. Some of the resulting plants are compromised in their growth and development, but this may be caused in part by the plant's overcompensation for metabolic perturbances. In other cases novel structures have been introduced in the cell wall without negative effects. The first field studies with engineered bioenergy crops look promising, while detailed structural analyses of cellulose synthase offer new opportunities to modify cellulose itself. PMID- 25531270 TI - Genomic tools to assist breeding for drought tolerance. AB - Water deficit or drought stress is a major limitation to crop production globally. Plant breeders have used a wide range of technologies to successfully breed varieties that perform well under the growth conditions for their target environments but they are always seeking new opportunities to enhance rates of genetic gain. Under drought, yield is determined by the integration of variable levels of water deficit across the developmental life of the crop. Genomics technologies were seen as a path to understand the genetic and environmental complexity of drought stress. To be relevant to breeding programs, genomic studies must consider the nature of drought stress in the target environment and use plant material and phenotyping techniques that relate to field conditions. PMID- 25531271 TI - Long-term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression. AB - Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/- mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro. PMID- 25531272 TI - Combined analysis of DNA methylation and cell cycle in cancer cells. AB - DNA methylation is a chemical modification of DNA involved in the regulation of gene expression by controlling the access to the DNA sequence. It is the most stable epigenetic mark and is widely studied for its role in major biological processes. Aberrant DNA methylation is observed in various pathologies, such as cancer. Therefore, there is a great interest in analyzing subtle changes in DNA methylation induced by biological processes or upon drug treatments. Here, we developed an improved methodology based on flow cytometry to measure variations of DNA methylation level in melanoma and leukemia cells. The accuracy of DNA methylation quantification was validated with LC-ESI mass spectrometry analysis. The new protocol was used to detect small variations of cytosine methylation occurring in individual cells during their cell cycle and those induced by the demethylating agent 5-aza-2'-deoxycytidine (5AzadC). Kinetic experiments confirmed that inheritance of DNA methylation occurs efficiently in S phase and revealed a short delay between DNA replication and completion of cytosine methylation. In addition, this study suggests that the uncoupling of 5AzadC effects on DNA demethylation and cell proliferation might be related to the duration of the DNA replication phase. PMID- 25531273 TI - Complementary metal oxide semiconductor compatible silicon nanowires-on-a-chip: fabrication and preclinical validation for the detection of a cancer prognostic protein marker in serum. AB - An integrated translational biosensing technology based on arrays of silicon nanowire field-effect transistors (SiNW FETs) is described and has been preclinically validated for the ultrasensitive detection of the cancer biomarker ALCAM in serum. High-quality SiNW arrays have been rationally designed toward their implementation as molecular biosensors. The FET sensing platform has been fabricated using a complementary metal oxide semiconductor (CMOS)-compatible process. Reliable and reproducible electrical performance has been demonstrated via electrical characterization using a custom-designed portable readout device. Using this platform, the cancer prognostic marker ALCAM could be detected in serum with a detection limit of 15.5 pg/mL. Importantly, the detection could be completed in less than 30 min and span a wide dynamic detection range (~10(5)). The SiNW-on-a-chip biosensing technology paves the way to the translational clinical application of FET in the detection of cancer protein markers. PMID- 25531274 TI - Examination of bacterial inhibition using a catalytic DNA. AB - Determination of accurate dosage of existing antibiotics and discovery of new antimicrobials or probiotics entail simple but effective methods that can conveniently track bacteria growth and inhibition. Here we explore the application of a previously reported fluorogenic E. coli-specific DNAzyme (catalytic DNA), RFD-EC1, as a molecular probe for monitoring bacterial inhibition exerted by antibiotics and for studying bacterial competition as a result of cohabitation. Because the DNAzyme method provides a convenient way to monitor the growth of E. coli, it is capable of determining the minimal inhibitory concentration (MIC) of antibiotics much faster than the conventional optical density (OD) method. In addition, since the target for RFD-EC1 is an extracellular protein molecule from E. coli, RFD-EC1 is able to identify pore forming antibiotics or compounds that can cause membrane leakage. Finally, RFD EC1 can be used to analyse the competition of cohabitating bacteria, specifically the inhibition of growth of E. coli by Bacillus subtilis. The current work represents the first exploration of a catalytic DNA for microbiological applications and showcases the utility of bacteria-sensing fluorogenic DNAzymes as simple molecular probes to facilitate antibiotic and probiotic research. PMID- 25531275 TI - Monolithic polymeric aerogels with VOCs sorbent nanoporous crystalline and water sorbent amorphous phases. AB - Monolithic syndiotactic polystyrene (s-PS) aerogels, formed by highly crystalline nanofibrils with a hydrophobic nanoporous-crystalline phase and a hydrophilic amorphous phase have been prepared and characterized. These aerogels, with a high degree of sulfonation of the amorphous phase and nearly negligible sulfonation of the crystalline phase, are obtained by treating physical gels exhibiting delta clathrate form. With respect to unsulfonated nanoporous-crystalline polymeric aerogels, these new selectively sulfonated aerogels present the great advantage of a high water diffusivity and water uptake up to 600 wt %. This water uptake increases greatly the sorption kinetics of organic pollutants by the hydrophobic nanopores of the crystalline phase. For instance, for aerogels with a sulfonation of 10%, the diffusivity of a volatile organic compound (1,2-dichloroethane, DCE) from 10 ppm aqueous solution is more than 3 orders of magnitude higher than that for the unsulfonated aerogel and is very close to the DCE diffusivity in water. PMID- 25531277 TI - Importance of being thiomethylated: formation, fate, and effects of methylated thioarsenicals. AB - Although inorganic arsenic has long been recognized as a potent toxicant and carcinogen in humans, recent evidence shows that at least some of its effects are mediated by methylated metabolites. Elucidating the conversion of inorganic arsenic to mono-, di-, and trimethylated species has provided insights into the enzymology of this pathway and identified genetic and environmental factors that influence the susceptibility of individuals to this metalloid's adverse health effects. Notably, almost all work on the formation, fate, and effects of methylated arsenicals has focused on oxoarsenicals in which arsenic is bound to one or more oxygen atoms. However, thioarsenicals are a class of arsenicals in which a sulfur atom has replaced one or more oxygens that are bound to arsenic. Thioarsenicals have been identified as urinary metabolites in humans and other animals following exposure to inorganic arsenic. Studies find that methylated thioarsenicals exhibit kinetic behavior and toxicological properties that distinguish them from methylated oxoarsenicals. This perspective considers that formation, fate, and effects of methylated thioarsenicals with an emphasis on examining the linkages between the molecular processes that underlie both methylation and thiolation reactions. Integrating this information will provide a more comprehensive view of the relationship between the metabolism of arsenic and the risk posed by chronic exposure to this environmental contaminant. PMID- 25531276 TI - Epitaxially grown collagen fibrils reveal diversity in contact guidance behavior among cancer cells. AB - Invasion of cancer cells into the surrounding tissue is an important step during cancer progression and is driven by cell migration. Cell migration can be random, but often it is directed by various cues such as aligned fibers composed of extracellular matrix (ECM), a process called contact guidance. During contact guidance, aligned fibers bias migration along the long axis of the fibers. These aligned fibers of ECM are commonly composed of type I collagen, an abundant structural protein around tumors. In this paper, we epitaxially grew several different patterns of organized type I collagen on mica and compared the morphology and contact guidance behavior of two invasive breast cancer cell lines (MDA-MB-231 and MTLn3 cells). Others have shown that these cells randomly migrate in qualitatively different ways. MDA-MB-231 cells exert large traction forces, tightly adhere to the ECM, and migrate with spindle-shaped morphology and thus adopt a mesenchymal mode of migration. MTLn3 cells exert small traction forces, loosely adhere to the ECM, and migrate with a more rounded morphology and thus adopt an amoeboid mode of migration. As the degree of alignment of type I collagen fibrils increases, cells become more elongated and engage in more directed contact guidance. MDA-MB-231 cells perceive the directional signal of highly aligned type I collagen fibrils with high fidelity, elongating to large extents and migrating directionally. Interestingly, behavior in MTLn3 cells differs. While highly aligned type I collagen fibril patterns facilitate spreading and random migration of MTLn3 cells, they do not support elongation or directed migration. Thus, different contact guidance cues bias cell migration differently and the fidelity of contact guidance is cell type dependent, suggesting that ECM alignment is a permissive cue for contact guidance, but requires a cell to have certain properties to interpret that cue. PMID- 25531279 TI - Selected antibacterial factors in the saliva of diabetic patients. AB - OBJECTIVE: Diabetes mellitus leads to many systemic complications, including changes in the morphology, function of the salivary glands, and the composition of saliva. DESIGN: The study comprised a randomly selected 156 adults, of both genders, aged from 21 to 79, out of which patients with diabetes type 1 and 2, and healthy subjects forming two control age- and gender matched to the ill subjects. In unstimulated mixed saliva, total protein, peroxidase, myeloperoxidase and immunoglobulin A were measured as well as salivary flow rate. The periodontal condition was assessed with the use of GI, mSBI and PSR index. The obtained data were analysed with the use of U Mann-Whitney's test, Spearman's rang correlation and Chi-square test at a significant level of p < 0.05 with use of Statistica 9.0 software. RESULTS: Type 1 diabetics in comparison to healthy age and gender matched control group had a lower salivary flow rate (p < 0.01), a higher content of total protein (p < 0.01), myeloperoxidase (p < 0.001) and immunoglobulin A (p < 0.001). Similarly, type 2 diabetics in comparison to control subjects had a higher level of total protein concentration (p < 0.01), myeloperoxidase (p < 0.05) and immunoglobulin A (p < 0.001). We also found worse periodontal condition. CONCLUSION: Within the limitation of the study it may be stated that diabetes type 1 and 2 can cause abnormalities in salivary glands function resulting in the diminishing of salivary flow rate and the increase in total protein content. Higher levels of myeloperoxidase and IgA in the saliva can be linked to worse periodontal condition in the diabetic patients. PMID- 25531278 TI - Polymorphisms of HLA-DRB1, -DQA1 and -DQB1 in inhabitants of Astana, the capital city of Kazakhstan. AB - BACKGROUND: Kazakhstan has been inhabited by different populations, such as the Kazakh, Kyrgyz, Uzbek and others. Here we investigate allelic and haplotypic polymorphisms of human leukocyte antigen (HLA) genes at DRB1, DQA1 and DQB1 loci in the Kazakh ethnic group, and their genetic relationship between world populations. METHODOLOGY/PRINCIPAL FINDINGS: A total of 157 unrelated Kazakh ethnic individuals from Astana were genotyped using sequence based typing (SBT Method) for HLA-DRB1, -DQA1 and -DQB1 loci. Allele frequencies, neighbor-joining method, and multidimensional scaling analysis have been obtained for comparison with other world populations. Statistical analyses were performed using Arlequin v3.11. Applying the software PAST v. 2.17 the resulting genetic distance matrix was used for a multidimensional scaling analysis (MDS). Respectively 37, 17 and 19 alleles were observed at HLA-DRB1, -DQA1 and -DQB1 loci. The most frequent alleles were HLA-DRB1*07:01 (13.1%), HLA-DQA1*03:01 (13.1%) and HLA-DQB1*03:01 (17.6%). In the observed group of Kazakhs DRB1*07:01-DQA1*02:01-DQB1*02:01 (8.0%) was the most common three loci haplotype. DRB1*10:01-DQB1*05:01 showed the strongest linkage disequilibrium. The Kazakh population shows genetic kinship with the Kazakhs from China, Uyghurs, Mongolians, Todzhinians, Tuvinians and as well as with other Siberians and Asians. CONCLUSIONS/SIGNIFICANCE: The HLA-DRB1, DQA1 and -DQB1 loci are highly polymorphic in the Kazakh population, and this population has the closest relationship with other Asian and Siberian populations. PMID- 25531280 TI - The association between occupational characteristics and hysterectomies for treating uterine fibroids in Taiwan. AB - This study examined the relationship between the occupational characteristics of women with uterine fibroids (UFs) and the decision to have a hysterectomy. Data from the Longitudinal Taiwan Health Insurance Database (LTHID) from 2000 to 2009 were analyzed to investigate the association between occupation and hysterectomies. Multivariable logistic regression analysis showed that, compared with white-collar UF patients, the odds ratio (OR) for hysterectomy surgery was 1.21 (95% confidence interval (CI) = 1.11-1.32) for blue-collar UF patients. Moreover, non-government employees with UFs also had significantly increased odds of having a hysterectomy compared to government employees with UFs (OR = 1.19, 95% CI = 1.04-1.36). This study provides information regarding the extent to which differences in occupation and decision-making processes might affect the marked variations in the use of hysterectomies for UFs. PMID- 25531281 TI - Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. AB - The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P<0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P<0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD. PMID- 25531282 TI - Minimal antileukaemic treatment followed by reduced-intensity conditioning in three consecutive children with Fanconi anaemia and AML. PMID- 25531283 TI - Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes. AB - Obesity is an important public health problem that may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic hematopoietic SCTs between 2004 and 2012. Pretransplant body mass index (BMI) was classified as underweight, normal weight, overweight or obese using the WHO classification or age-adjusted BMI percentiles for children. The study population was predominantly Caucasian, and the median age was 51 years (5 months-73 years). The cumulative 3-year incidence of nonrelapse mortality (NRM) in underweight, normal weight, overweight and obese patients was 20%, 19%, 20% and 33%, respectively. Major causes of NRM were acute and chronic GVHD. The corresponding incidence of relapse was 30%, 41%, 37% and 30%, respectively. Three-year OS was 59%, 48%, 47% and 43%, respectively. Multivariate analysis showed that obesity was associated with higher NRM (hazard ratio (HR) 1.43, P=0.04) and lower relapse (HR 0.65, P=0.002). Pretransplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese compared with normal weight patients (P=0.04 and P=0.05, respectively). The increase in NRM observed in obese patients was partially offset by a lower incidence of relapse with no difference in OS. PMID- 25531284 TI - Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage. AB - Diffuse alveolar hemorrhage (DAH) is a poorly understood complication of transplantation carrying a high mortality. Patients commonly deteriorate and require intensive care unit (ICU) admission. Treatment with high-dose steroids and aminocaproic acid (ACA) has been suggested. The current study examined 119 critically ill adult hematopoietic transplant patients treated for DAH. Patients were subdivided into low-, medium- and high-dose steroid groups with or without ACA. All groups had similar baseline characteristics and severity of illness scores. Primary objectives were 30, 60, 100 day, ICU and hospital mortality. Overall mortality (n=119) on day 100 was high at 85%. In the steroids and ACA cohort (n=82), there were no significant differences in 30, 60, 100, day, ICU and hospital mortality between the dosing groups. In the steroids only cohort (n=37), the low-dose steroid group had a lower ICU and hospital mortality (P=0.02). Adjunctive treatment with ACA did not produce differences in outcomes. In the multivariate analysis, medium- and high-dose steroids were associated with a higher ICU mortality (P=0.01) as compared with the low-dose group. Our data suggest that treatment strategies may need to be reanalyzed to avoid potentially unnecessary and potentially harmful therapies. PMID- 25531285 TI - Moderating effects of the family environment for parental mediation and pathological internet use in youths. AB - Pathological Internet use (PIU) occurs when excessive Internet use results in addictive symptoms that exert detrimental consequences on one's overall functioning and well-being. Poor family functioning has been found to be associated with youths' addictive Internet use, and parental use of active and restrictive mediation has been found to reduce online risk. The current study aims to test if parental active and restrictive mediation strategies are negatively associated with youths' PIU. Additionally, it also tests the effectiveness of these strategies as a function of the broader family environment with measures of parent-child attachment, family communication, and the youth's comfort with living at home. The data of 3,079 students in Singapore were analyzed through a series of logistic regressions. The results revealed that the family environment for students with PIU was significantly less positive. Only restrictive mediation was found to be negatively associated with PIU. This relation was stronger for higher levels of attachment, communication, and comfort at home, implying that the effectiveness of restrictive mediation varies with the degree of warmth and support in the general family environment. The implications are discussed. PMID- 25531286 TI - Hare-to-human transmission of Francisella tularensis subsp. holarctica, Germany. AB - In November 2012, a group of 7 persons who participated in a hare hunt in North Rhine-Westphalia, Germany, acquired tularemia. Two F. tularensis subsp. holarctica isolates were cultivated from human and hare biopsy material. Both isolates belonged to the FTN002-00 genetic subclade (derived for single nucleotide polymorphisms B.10 and B.18), thus indicating likely hare-to-human transmission. PMID- 25531287 TI - Heavy metals [chromium (VI) and lead (II)] removal from water using mesoporous magnetite (Fe3O4) nanospheres. AB - Magnetite nanospheres with hollow interiors were synthesized using a simple, one pot, and template free solvothermal method with ferric chloride as the iron precursor. The composition, surface properties and morphology were studied using X-ray powder diffraction (XRD), energy dispersive X-ray fluorescence (EDXRF), Fourier transform infrared spectroscopy (FTIR), surface area analysis, point of zero charge (pHpzc), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and magnetic moment determination. These mesoporous nanospheres have a SBET=11.3m(2)/g and a high saturation magnetization of 77.5emu/g. These magnetite nanospheres successfully remediated Cr(6+) and Pb(2+) from water. The optimum pHs for Cr(6+) and Pb(2+) adsorption were 4.0 and 5.0, respectively. Adsorption was carried out at 25, 35 and 45 degrees C. The sorption data were fitted using Freundlich, Langmuir, Redlich-Peterson, Sips, Koble-Corrigan, Radke and Prausnitz and Toth adsorption models. The pseudo-second order model better fitted the kinetics data. The Langmuir adsorption capacities of magnetic nanospheres were ~9 and ~19mg/g for Cr(6+) and Pb(2)(+), respectively. Magnetic collection of these magnetite nanospheres can be used to isolate and regenerate the used adsorbent. PMID- 25531288 TI - Extrasynaptic alpha6 subunit-containing GABAA receptors modulate excitability in turtle spinal motoneurons. AB - Motoneurons are furnished with a vast repertoire of ionotropic and metabotropic receptors as well as ion channels responsible for maintaining the resting membrane potential and involved in the regulation of the mechanisms underlying its membrane excitability and firing properties. Among them, the GABAA receptors, which respond to GABA binding by allowing the flow of Cl- ions across the membrane, mediate two distinct forms of inhibition in the mature nervous system, phasic and tonic, upon activation of synaptic or extrasynaptic receptors, respectively. In a previous work we showed that furosemide facilitates the monosynaptic reflex without affecting the dorsal root potential. Our data also revealed a tonic inhibition mediated by GABAA receptors activated in motoneurons by ambient GABA. These data suggested that the high affinity GABAA extrasynaptic receptors may have an important role in motor control, though the molecular nature of these receptors was not determined. By combining electrophysiological, immunofluorescence and molecular biology techniques with pharmacological tools here we show that GABAA receptors containing the alpha6 subunit are expressed in adult turtle spinal motoneurons and can function as extrasynaptic receptors responsible for tonic inhibition. These results expand our understanding of the role of GABAA receptors in motoneuron tonic inhibition. PMID- 25531289 TI - Effect of changes in food groups intake on magnesium, zinc, copper, and selenium serum levels during 2 years of dietary intervention. AB - BACKGROUND: Essential elements in serum are related to specific changes in food groups intake. OBJECTIVE: To address the effect of 2-year food intake changes in an intervention study on serum concentrations of magnesium, zinc, copper, and selenium. METHOD: Two hundred thirty-one participants, a subgroup of the Dietary Intervention Randomized Control Trial (DIRECT) study (age = 52 years; body mass index = 32.8 kg/m(2); 85% males) randomized to low-fat, Mediterranean, or low carbohydrate diets in a 2-year dietary intervention trial were followed for serum concentrations determined using inductively coupled plasma-mass spectrometry. Changes in the intake of 11 food groups were evaluated by food frequency questionnaires. RESULTS: Using multivariate regression models, adjusted for age, sex, baseline body weight (kg), and changes in intakes of 11 food groups (g/d), at 12 months, serum element elevations were observed mainly in the low carbohydrate group: selenium, by increasing consumption of fats and oils (beta = 0.415, p = 0.009) and legumes (beta = 0.183, p = 0.010) and decreasing fruit intake (beta = -0.438, p = 0.030); copper, by increasing consumption of legumes (beta = 0.453, p = 0.018) and dairy products (beta = 0.320, p = 0.039); magnesium by increasing fish consumption (beta = 0.374, p = 0.042) in the low-carbohydrate group and in the entire study population (beta = 0.237, p = 0.016); and zinc exclusively in the low-fat group by decreasing consumption of fats and oils (beta = -0.575, p = 0.022). At 24 months, serum elements were elevated mainly in the low-fat diet group, mostly by decreasing intake of snacks, sweets, and cakes: zinc (beta = -0.570, p = 0.027), copper (beta = -0.649, p = 0.012), and selenium (beta = -0.943, p < 0.001). Also in this group, magnesium levels were elevated by increasing vegetable intake (beta = 0.395, p = 0.041), copper by increasing fruit intake (beta = 0.375, p = 0.025), and selenium by increasing consumption of bread, pasta, and cereals (beta = 0.751, p = 0.011). The entire group, further adjusted to assigned diet type, increased selenium (beta = 0.294, p = 0.004) and copper (beta = 0.220, p = 0.038) by increasing consumption of bread, pasta, and cereals; selenium level was also predicted by decreasing consumption of snacks, sweets, and cakes (beta = -0.256, p = 0.014). Introducing energy expenditure, expressed in metabolic equivalents (MET = 1 kcal.kg(-1).h(-1)), as an additional variable emphasized the negative effect of sweets and cakes on increasing serum concentrations of zinc, copper, and selenium after 24 months (beta = -0.549, p = 0.021; beta = -0.669, p = 0.012; beta = -0.982, p < 0.001, respectively), especially in the low-fat diet group. No significant associations between changes in food groups intake and the 4 elements were found in the Mediterranean diet group. CONCLUSIONS: During this 2-year intervention, serum concentrations of 4 essential elements were associated with a diversity of food group intake patterns. Comprehensive predictors for elevating zinc, copper, and selenium in serum included decreasing consumption of sweets and cakes while increasing consumption of bread, cereals, and pasta. PMID- 25531290 TI - Population-referenced percentiles for waist-worn accelerometer-derived total activity counts in U.S. youth: 2003 - 2006 NHANES. AB - BACKGROUND: The total activity volume performed is an overall measure that takes into account the frequency, intensity, and duration of activities performed. The importance of considering total activity volume is shown by recent studies indicating that light physical activity (LPA) and intermittent moderate-to vigorous physical activity (MVPA) have health benefits. Accelerometer-derived total activity counts (TAC) per day from a waist-worn accelerometer can serve as a proxy for an individual's total activity volume. The purpose of this study was to develop age- and gender-specific percentiles for daily TAC, minutes of MVPA, and minutes of LPA in U.S. youth ages 6 - 19 y. METHODS: Data from the 2003 - 2006 NHANES waist-worn accelerometer component were used in this analysis. The sample was composed of youth aged 6 - 19 years with at least 4 d of >= 10 hours of accelerometer wear time (N = 3698). MVPA was defined using age specific cutpoints as the total number of minutes at >=4 metabolic equivalents (METs) for youth 6 - 17 y or minutes with >=2020 counts for youth 18 - 19 y. LPA was defined as the total number of minutes between 100 counts and the MVPA threshold. TAC/d, MVPA, and LPA were averaged across all valid days. RESULTS: For males in the 50th percentile, the median activity level was 441,431 TAC/d, with 53 min/d of MVPA and 368 min/d of LPA. The median level of activity for females was 234,322 TAC/d, with 32 min/d of MVPA and 355 min/d of LPA. CONCLUSION: Population referenced TAC/d percentiles for U.S. youth ages 6-19 y provide a novel means of characterizing the total activity volume performed by children and adolescents. PMID- 25531291 TI - Setae from larvae of the northern processionary moth (Thaumetopoea pinivora, TP) stimulate proliferation of human blood lymphocytes in vitro. AB - Larvae of the Northern pine processionary moth (Thaumetopoea pinivora, TP) carry microscopic needles (setae), which by penetrating skin and mucous membranes, may cause inflammatory/immune derived symptoms in man. In the present study the stimulatory effects of setae on human blood lymphocytes in vitro was investigated. Blood mononuclear cells were separated from venous blood or buffy coat of ten healthy individuals, six previously exposed to setae and four with no known exposure. Lymphoproliferation was measured as uptake of 3H-thymidine. Setae were prepared from TP larvae. Setae and saline setae extracts stimulated proliferation of T-lymphocytes in the presence of monocytic cells. Stimulation was pronounced in cells from persons who had been exposed to setae, and weak in cells from non-exposed donors. Chitin also induced lymphocyte proliferation in most donors, but to a lesser extent and independently of donor's previous exposure to setae. In conclusion, setae contain molecules that in the presence of monocytes activate human T-lymphocytes to proliferation. The antigenic nature of stimulatory molecules was supported by the significantly stronger lymphocyte response in persons previously exposed to setae than in non-exposed donors. The nature of such molecules remains to be defined. PMID- 25531292 TI - Usefulness and safety of a guide catheter extension system for the percutaneous treatment of complex coronary lesions by a transradial approach. AB - OBJECTIVE: The aim of this study was to describe our initial experience with the GuideLiner(r) catheter (Vascular Solutions Inc.) in the transradial treatment of complex lesions. MATERIALS AND METHODS: The clinical, angiographic and procedural data of percutaneous coronary interventions where GuideLiner was used during 2013 were collected. The transradial approach was used in all cases. The indication for its use, efficacy and periprocedural complications were determined. Sixteen consecutive procedures (in 15 patients; 12 males and 3 females) were evaluated. The indication for the use of GuideLiner was a difficulty to advance and properly position a stent through a tortuous and/or calcified artery despite using high support guide catheters or other useful techniques. RESULTS: Of the 16 angiographic procedures, 14 (87.5%) were successful (stent deployment in 13 cases and a drug-eluting balloon in 1 case). Unsuccessful cases were a chronic total occlusion and a diffusely diseased left anterior descendant artery. A type B dissection of a proximal left circumflex artery was the only periprocedural complication. CONCLUSION: Use of the GuideLiner was an effective and safe technique for the percutaneous treatment of complex coronary lesions in which the adequate progress of angioplasty devices had failed. GuideLiner was particularly helpful when using the transradial approach. Only one minor complication was recorded. PMID- 25531293 TI - Carbon-ion beam irradiation kills X-ray-resistant p53-null cancer cells by inducing mitotic catastrophe. AB - BACKGROUND AND PURPOSE: To understand the mechanisms involved in the strong killing effect of carbon-ion beam irradiation on cancer cells with TP53 tumor suppressor gene deficiencies. MATERIALS AND METHODS: DNA damage responses after carbon-ion beam or X-ray irradiation in isogenic HCT116 colorectal cancer cell lines with and without TP53 (p53+/+ and p53-/-, respectively) were analyzed as follows: cell survival by clonogenic assay, cell death modes by morphologic observation of DAPI-stained nuclei, DNA double-strand breaks (DSBs) by immunostaining of phosphorylated H2AX (gammaH2AX), and cell cycle by flow cytometry and immunostaining of Ser10-phosphorylated histone H3. RESULTS: The p53 /- cells were more resistant than the p53+/+ cells to X-ray irradiation, while the sensitivities of the p53+/+ and p53-/- cells to carbon-ion beam irradiation were comparable. X-ray and carbon-ion beam irradiations predominantly induced apoptosis of the p53+/+ cells but not the p53-/- cells. In the p53-/- cells, carbon-ion beam irradiation, but not X-ray irradiation, markedly induced mitotic catastrophe that was associated with premature mitotic entry with harboring long retained DSBs at 24 h post-irradiation. CONCLUSIONS: Efficient induction of mitotic catastrophe in apoptosis-resistant p53-deficient cells implies a strong cancer cell-killing effect of carbon-ion beam irradiation that is independent of the p53 status, suggesting its biological advantage over X-ray treatment. PMID- 25531294 TI - Effects of barbell deadlift training on submaximal motor unit firing rates for the vastus lateralis and rectus femoris. AB - Previous investigations that have studied motor unit firing rates following strength training have been limited to small muscles, isometric training, or interventions involving exercise machines. We examined the effects of ten weeks of supervised barbell deadlift training on motor unit firing rates for the vastus lateralis and rectus femoris during a 50% maximum voluntary contraction (MVC) assessment. Twenty-four previously untrained men (mean age = 24 years) were randomly assigned to training (n = 15) or control (n = 9) groups. Before and following the intervention, the subjects performed isometric testing of the right knee extensors while bipolar surface electromyographic signals were detected from the two muscles. The signals were decomposed into their constituent motor unit action potential trains, and motor units that demonstrated accuracy levels less than 92.0% were not considered for analysis. One thousand eight hundred ninety two and 2,013 motor units were examined for the vastus lateralis and rectus femoris, respectively. Regression analyses were used to determine the linear slope coefficients (pulses per second [pps]/% MVC) and y-intercepts (pps) of the mean firing rate and firing rate at recruitment versus recruitment threshold relationships. Deadlift training significantly improved knee extensor MVC force (Cohen's d = .70), but did not influence force steadiness. Training had no influence on the slopes and y-intercepts for the mean firing rate and firing rate at recruitment versus recruitment threshold relationships. In agreement with previous cross-sectional comparisons and randomized control trials, our findings do not support the notion that strength training affects the submaximal control of motor units. PMID- 25531295 TI - Changes in birth weight between 2002 and 2012 in Guangzhou, China. AB - BACKGROUND: Recent surveillance data suggest that mean birth weight has begun to decline in several developed countries. The aim of this study is to examine the changes in birth weight among singleton live births from 2002 to 2012 in Guangzhou, one of the most rapidly developed cities in China. METHODS: We used data from the Guangzhou Perinatal Health Care and Delivery Surveillance System for 34108 and 54575 singleton live births with 28-41 weeks of gestation, who were born to local mothers, in 2002 and 2012, respectively. The trends in birth weight, small (SGA) and large (LGA) for gestational age and gestational length were explored in the overall population and gestational age subgroups. RESULTS: The mean birth weight decreased from 3162 g in 2002 to 3137 g in 2012 (crude mean difference, -25 g; 95% CI, -30 to -19). The adjusted change in mean birth weight appeared to be slight (-6 g from 2002 to 2012) after controlling for maternal age, gestational age, educational level, parity, newborn's gender and delivery mode. The percentages of SGA and LGA in 2012 were 0.6% and 1.5% lower than those in 2002, respectively. The mean gestational age dropped from 39.2 weeks in 2002 to 38.9 weeks in 2012. In the stratified analysis, we observed the changes in birth weight differed among gestational age groups. The mean birth weight decreased among very preterm births (28-31 weeks), while remained relatively stable among other gestational age subcategories. CONCLUSIONS: Among local population in Guangzhou from 2002 to 2012, birth weight appeared to slightly decrease. The percentage of SGA and LGA also simultaneously dropped, indicating that newborns might gain a healthier weight for gestational age. PMID- 25531296 TI - Successful early rituximab treatment in a case of systemic lupus erythematosus with potentially fatal diffuse alveolar hemorrhage. AB - Diffuse alveolar hemorrhage (DAH) is a rare but devastating complication of systemic lupus erythematosus (SLE) with a high early mortality rate. DAH seldom occurs without active organ involvement. Recently, rituximab (RTX), a B cell targeted therapy, has been reported to be effective for life-threatening autoimmune diseases. We describe a SLE patient who presented with acute respiratory failure due to DAH without other active organ involvement. This condition was dramatically improved with RTX without cyclophosphamide. PMID- 25531297 TI - Effect of Mild Cold Exposure on Cognition in Persons with Tetraplegia. AB - Persons with a cervical spinal cord injury (SCI) have impaired thermoregulatory mechanisms secondary to interrupted of motor, sensory, and sympathetic pathways. In this study, our primary aim was to determine the effect of cool temperature exposure on core body temperature (Tcore) and cognitive performance in persons with tetraplegia. Seven men with chronic tetraplegia (C3-C7, American Spinal Injury Association Impairment Scale [AIS] A-C) and seven able-bodied controls were exposed to 27 degrees C temperature at baseline (BL) before being exposed to 18 degrees C for <=120 min (Cool Challenge). Rectal temperature (Tcore), distal skin temperatures (Tskavg), microvascular skin perfusion (LDFavg), and systolic blood pressure (SBP) were measured. Cognitive performance was assessed using Delayed Recall, Stroop Interference tests at the end of BL and Cool Challenge. After Cool Challenge, Tcore decreased -1.2+/-0.12 degrees C (p<0.0001) in tetraplegics after an average of 109+/-15.9 min with no change in controls after 120 min. Tskavg declined in both groups, but decline was less in tetraplegics than in controls (-8.6+/-5.8% vs. -31.6+/-7.9%, respectively; p<0.0001). LDFavg declined only in controls (-72+/-17.9%; p<0.001). Plasma norepinephrine levels differed after Cool Challenge (tetraplegics vs. CONTROLS: 86+/-62 pg/mL vs. 832+/ 431 pg/mL, respectively; p<0.01). SBP increased from BL to Cool Challenge only in controls (123+/-16 mm Hg to 149+/-17 mm Hg, respectively; p<0.01). Delayed Recall and Stroop Interference scores both declined in tetraplegics (-55+/-47.4%; p<0.05 and -3.9+/-3.8%; p<0.05, respectively), but not in controls. We conclude that persons with tetraplegia lack adequate thermoregulatory mechanisms to prevent downward drift in Tcore on exposure to cool temperatures. This decline in Tcore was associated with deterioration of working memory and executive function. PMID- 25531298 TI - Diversional and physical nonpharmacological interventions for behavioral and psychological symptoms of dementia. AB - This article is the last of a four-part series addressing the use of non pharmacological interventions for older adults with behavioral and psychological symptoms of dementia (BPSD). These types of interventions are used to prevent, lessen, or eliminate BPSD, thereby reducing patient reliance on psychoactive medications. These interventions are easy to use, cost-effective, and simple to implement. The Centers for Medicare & Medicaid Services' psychoactive medication reduction initiative encourages all staff to use nonpharmacological interventions to manage BPSD. As with any attempt to handle BPSD, health care professionals and staff need a tool-box of interventions, as what works one day may not work the next and what works with one older adult may not work with another. This article describes the categories of diversional and physical nonpharmalogical interventions, presents the evidence supporting their use, and provides information on effective implementation. PMID- 25531299 TI - Implementation of a heart failure quality initiative in a skilled nursing facility: lessons learned. AB - Skilled nursing facilities (SNFs) are organizations that represent complex adaptive systems, offering barriers to the implementation of quality improvement (QI) initiatives. The current article describes the authors' efforts to use the approach of reflective adaptive process to implement a new model of care (i.e., the Skilled Heart Unit Program) for effective heart failure (HF) care in one SNF. A team of stakeholders from the local hospital system and a local SNF was convened to design and implement this new model. Evaluation of the implementation processes confirmed the value of the implementation approach, which centered on team-based approaches, staff engagement, and flexibility of processes to respect the SNF's needs and culture. Interviews with facility staff and the administrator revealed their perceptions that the strategy resulted in better HF care, enhanced teamwork between staff and clinicians, and improved staff job satisfaction. This work provides a unique blueprint of strategic QI implementation for patients with HF in the SNF setting. PMID- 25531300 TI - One-step growth of well-aligned TiO2 nanorod arrays for flexible dye-sensitized solar cells. AB - We present here the feasibility of growing well-aligned TiO2 nanorod arrays by a dc reactive magnetron sputtering strategy for flexible dye-sensitized solar cells. These flexible devices yield an efficiency of 5.3% in comparison to 1.2% from traditional TiO2 nanoparticles by a low-temperature technique. PMID- 25531301 TI - Steady boundary layer slip flow along with heat and mass transfer over a flat porous plate embedded in a porous medium. AB - In this paper, a simplified model of an incompressible fluid flow along with heat and mass transfer past a porous flat plate embedded in a Darcy type porous medium is investigated. The velocity, thermal and mass slip conditions are utilized that has not been discussed in the literature before. The similarity transformations are used to transform the governing partial differential equations (PDEs) into a nonlinear ordinary differential equations (ODEs). The resulting system of ODEs is then reduced to a system of first order differential equations which was solved numerically by using Matlab bvp4c code. The effects of permeability, suction/injection parameter, velocity parameter and slip parameter on the structure of velocity, temperature and mass transfer rates are examined with the aid of several graphs. Moreover, observations based on Schmidt number and Soret number are also presented. The result shows, the increase in permeability of the porous medium increase the velocity and decrease the temperature profile. This happens due to a decrease in drag of the fluid flow. In the case of heat transfer, the increase in permeability and slip parameter causes an increase in heat transfer. However for the case of increase in thermal slip parameter there is a decrease in heat transfer. An increase in the mass slip parameter causes a decrease in the concentration field. The suction and injection parameter has similar effect on concentration profile as for the case of velocity profile. PMID- 25531302 TI - Profiling of serum and urinary microRNAs in children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin disease in children characterized by dermatitis and pruritus. MicroRNAs (miRNAs) have been shown as great potential biomarkers for disease fingerprints to predict prognostics. We aimed to identify miRNA signature from serum and urine for the prognosis of AD patient by genome-wide miRNA profiling analysis. METHODS: Serum and urine from 30 children with AD and 28 healthy children were collected and their genome-wide miRNA expression profiles were measured by TaqMan-based array and confirmed by quantitative real-time PCR. Inflammatory factors in serum were detected by Antibody Array System. RESULTS: miR-203 and miR-483-5p were significantly up-regulated in serum of children with AD compared with healthy children. The level of miR-483-5p in serum was significantly associated with other atopic conditions, such as rhinitis and/or asthma. However, miR-203 was markedly decreased in urine of children with AD compared with healthy children. Down-regulated miR-203 in urine was significant associated with abnormal level of serum IgE in AD patients. 7 inflammatory factors in serum were altered in children with AD compared with healthy children. Up-regulated miR-203 in serum was significantly associated with increased sTNFRI and sTNFRII. CONCLUSIONS: Up regulated miR-483-5p in serum may be indicative of other atopic conditions in children with AD. Down-regulated miR-203 in urine may serve as a biomarker for the severity of inflammation in children with AD. PMID- 25531303 TI - Phenotypic characteristics of nasal mast cells in a mouse model of allergic rhinitis. AB - BACKGROUND: Mast cells (MCs) in the nasal respiratory mucosa (NRM) play a triggering role in the pathogenesis of allergic rhinitis (AR). Recent research evidence in mouse models of AR suggests an underlying MC-related allergic response in mouse nasal olfactory mucosa (NOM). OBJECTIVE: We sought to investigate the phenotypic characteristics of nasal MCs in a mouse model of AR. METHODS: By MC-specific staining and immunohistochemistry, we analyzed the subset, protease and IgE-binding phenotypes of nasal MCs in ovalbumin (OVA) sensitized unchallenged and challenged mice. RESULTS: In OVA-sensitized challenged mice, increased serum OVA-specific IgE levels (p < 0.001) and eosinophil infiltration confirmed AR induction. In addition to constitutive connective tissue MCs, mucosal MCs were induced in NRM and NOM of OVA-sensitized challenged mice. Connective tissue MCs and mucosal MCs in mouse NRM and NOM were positive for mouse MC protease-1, -4, -5, -6, -7 and carboxypeptidase-A3. In line with MCs in NRM, there were increased numbers (p = 0.019) and proportions (p = 0.027) of MCs with surface-bound IgE in NOM of OVA-sensitized challenged mice. CONCLUSION: In the setting of AR, MCs in mouse NOM exhibit the same subset, protease and IgE-binding phenotypes as MCs in mouse NRM. PMID- 25531305 TI - Simultaneous total laparoscopic curative resection for synchronous gastric, cecal and rectal cancer: Report of a case. AB - INTRODUCTION: Gastric cancer (GC) and colorectal cancer (CRC) are often diagnosed simultaneously. Recent technological advances in surgical techniques and devices have enabled the use of laparoscopic approaches for GC and CRC. Laparoscopic resection is expected to increase the number of cases of synchronous gastrointestinal (GI) cancers that meet the indication for laparoscopic surgery, owing to early detection of GI cancers and extended indications for laparoscopic surgery. PRESENTATION OF CASE: We herein report a successful simultaneous total laparoscopic curative resection for synchronous early GC, early cecal cancer and advanced rectal cancer. The total time of the operation was 600min, and the estimated blood loss was 250ml. The patient was discharged on postoperative day (POD) 10 without postoperative complications. CONCLUSION: Simultaneous total laparoscopic surgery is a minimally invasive, feasible treatment option for synchronous GI cancers. PMID- 25531304 TI - Neural-specific deletion of Htra2 causes cerebellar neurodegeneration and defective processing of mitochondrial OPA1. AB - HTRA2, a serine protease in the intermembrane space, has important functions in mitochondrial stress signaling while its abnormal activity may contribute to the development of Parkinson's disease. Mice with a missense or null mutation of Htra2 fail to thrive, suffer striatal neuronal loss, and a parkinsonian phenotype that leads to death at 30-40 days of age. While informative, these mouse models cannot separate neural contributions from systemic effects due to the complex phenotypes of HTRA2 deficiency. Hence, we developed mice carrying a Htra2-floxed allele to query the consequences of tissue-specific HTRA2 deficiency. We found that mice with neural-specific deletion of Htra2 exhibited atrophy of the thymus and spleen, cessation to gain weight past postnatal (P) day 18, neurological symptoms including ataxia and complete penetrance of premature death by P40. Histologically, increased apoptosis was detected in the cerebellum, and to a lesser degree in the striatum and the entorhinal cortex, from P25. Even earlier at P20, mitochondria in the cerebella already exhibited abnormal morphology, including swelling, vesiculation, and fragmentation of the cristae. Furthermore, the onset of these structural anomalies was accompanied by defective processing of OPA1, a key molecule for mitochondrial fusion and cristae remodeling, leading to depletion of the L-isoform. Together, these findings suggest that HTRA2 is essential for maintenance of the mitochondrial integrity in neurons. Without functional HTRA2, a lifespan as short as 40 days accumulates a large quantity of dysfunctional mitochondria that contributes to the demise of mutant mice. PMID- 25531306 TI - An approach to pneumatosis intestinalis: Factors affecting your management. AB - Pneumatosis Intestinalis (PI) is defined as the presence of extra-luminal gas confined to the bowel wall. PI is an ominous condition often requiring emergent surgery. The management can be challenging in some circumstances, as the choice of surgery versus medical treatment can be difficult. In this study, we first report the case of a seventy-seven year old woman presenting to the emergency department with the presence of PI on computed tomography of the abdomen. Secondly, we review the existing literature regarding the management of PI and we suggest a treatment algorithm based on clinical, laboratory and radiological findings. PMID- 25531307 TI - Organocatalytic multicomponent synthesis of enantioenriched polycyclic 1,2,3,4 tetrahydropyridines: key substrate selection enabling regio- and stereoselectivities. AB - We have developed the first multicomponent synthesis of enantioenriched polycyclic 1,2,3,4-tetrahydropyridines bearing three contiguous stereogenic centers under iminium activation. The key to the success of this reaction was the use of polyfunctional substrates including 2-aminophenols and scarcely used beta ketoamides triggering a thermodynamically controlled regio- and diastereoselective sequence. PMID- 25531308 TI - Synthesis of highly monodisperse porous manganese oxide spheres using a butyric acid microemulsion. AB - Porous manganese oxide spheres form readily from a reaction between KMnO4 and n butanol in aqueous butyric acid under ambient conditions. Spheres have uniform size, tuneable diameters and high surface areas. The material is an active catalyst for the oxidation of isopropanol to acetone. PMID- 25531309 TI - The bacterial flagellar protein export apparatus processively transports flagellar proteins even with extremely infrequent ATP hydrolysis. AB - For self-assembly of the bacterial flagellum, a specific protein export apparatus utilizes ATP and proton motive force (PMF) as the energy source to transport component proteins to the distal growing end. The export apparatus consists of a transmembrane PMF-driven export gate and a cytoplasmic ATPase complex composed of FliH, FliI and FliJ. The FliI(6)FliJ complex is structurally similar to the alpha(3)beta(3)gamma complex of F(O)F(1)-ATPase. FliJ allows the gate to efficiently utilize PMF to drive flagellar protein export but it remains unknown how. Here, we report the role of ATP hydrolysis by the FliI(6)FliJ complex. The export apparatus processively transported flagellar proteins to grow flagella even with extremely infrequent or no ATP hydrolysis by FliI mutation (E211D and E211Q, respectively). This indicates that the rate of ATP hydrolysis is not at all coupled with the export rate. Deletion of FliI residues 401 to 410 resulted in no flagellar formation although this FliI deletion mutant retained 40% of the ATPase activity, suggesting uncoupling between ATP hydrolysis and activation of the gate. We propose that infrequent ATP hydrolysis by the FliI6FliJ ring is sufficient for gate activation, allowing processive translocation of export substrates for efficient flagellar assembly. PMID- 25531310 TI - Future time perspective: opportunities and limitations are differentially associated with subjective well-being and hair cortisol concentration. AB - BACKGROUND: Future time perspective has been associated with subjective well being, though depending on the line of research considered either an open-ended future time perspective or a limited future time perspective has been associated with high well-being. Most of this research however has conceptualized future time perspective as a one-dimensional construct, whereas recent evidence has demonstrated that there are likely at least two different underlying dimensions, a focus on opportunities and a focus on limitations. This project first seeks to replicate the two-dimensional structure of the Future Time Perspective Scale, and then examines the associations these dimensions may have with different measures of subjective well-being and a biological index of chronic stress. OBJECTIVE: To test if the two dimensions of the Future Time Perspective Scale, a focus on opportunities and a focus on limitations, differentially associate with two measures of subjective well-being and a biological indicator of chronic stress, namely hair cortisol. METHOD: Sixty-six community-dwelling participants with a mean age of 72 years (SD = 5.83) completed the Future Time Perspective Scale, Center for Epidemiologic Studies Depression Scale, and Philadelphia Geriatric Center Morale Scale. Participants also provided a 3-cm-long hair strand to index cortisol accumulation over the past 3 months. Following the results of a factor analysis, a mediation model was created for each dimension of the Future Time Perspective Scale, and significance testing was done through a bootstrapping approach to harness maximal statistical power. RESULTS: Factor analysis results replicated the two-dimensional structure of the Future Time Perspective Scale. Both dimensions were then found to have unique associations with well-being. Specifically, a high focus on opportunities was associated with fewer depressive symptoms and higher morale, whereas a low focus on limitations was associated with reduced hair cortisol, though this association was mediated by subjective well-being. CONCLUSION: RESULTS replicate and extend previous research by pointing to the multi-dimensional nature of the Future Time Perspective Scale. While an open future time perspective was overall beneficial for well-being, the exact association each dimension had with well-being differed depending on whether subjective measures of well-being or biological indices of chronic stress were considered. PMID- 25531311 TI - Dual renin-angiotensin system blockade for nephroprotection: still under scrutiny. AB - In experimental diabetic and non-diabetic chronic kidney disease (CKD), angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) combination therapy reduces proteinuria and prevents structural lesions more effectively than either drug alone. Consistently, in humans, a multidrug individually tailored antiproteinuric treatment based on combination therapy with maximum tolerated doses of ACEi and ARB (Remission Clinic protocol) reduced proteinuria and prevented end-stage renal disease (ESRD) more effectively than ACEi/ARB monotherapy, in particular in subjects with non-diabetic CKD. Fixed doses of an ACEi or renin inhibitor added to losartan failed to exert any additional renoprotective effect as compared with losartan monotherapy in patients at increased cardiovascular risk (ONTARGET study) or with type 2 diabetes and overt nephropathy (ALTITUDE study). The VA NEPHRON D study found that losartan and lisinopril combination therapy reduced by 34% the risk of predefined reductions in estimated glomerular filtration rate, ESRD or death as compared to losartan in 1,448 type 2 diabetes patients with overt nephropathy. Unfortunately, the treatment effect failed to achieve the nominal significance (p = 0.07) because of premature trial interruption. Thus, the Remission Clinic protocol is the most powerful tool to prevent progression to ESRD in non-diabetic proteinuric CKD. Results of the ongoing VALID trial will show whether this approach can be safely extended to type 2 diabetes patients. PMID- 25531312 TI - Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. AB - Epigenetic factors have been implicated in the regulation of CD4(+) T-cell differentiation. Jmjd3 plays a role in many biological processes, but its in vivo function in T-cell differentiation remains unknown. Here we report that Jmjd3 ablation promotes CD4(+) T-cell differentiation into Th2 and Th17 cells in the small intestine and colon, and inhibits T-cell differentiation into Th1 cells under different cytokine-polarizing conditions and in a Th1-dependent colitis model. Jmjd3 deficiency also restrains the plasticity of the conversion of Th2, Th17 or Treg cells to Th1 cells. The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines. H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors. Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression. PMID- 25531313 TI - Role of diet in prostate cancer: the epigenetic link. AB - Diet is hypothesized to be a critical environmentally related risk factor for prostate cancer (PCa) development, and specific diets and dietary components can also affect PCa progression; however, the mechanisms underlying these associations remain elusive. As for a maturing organism, PCa's epigenome is plastic and evolves from the pre-neoplastic to the metastatic stage. In particular, epigenetic remodeling relies on substrates or cofactors obtained from the diet. Here we review the evidence that bridges dietary modulation to alterations in the prostate epigenome. We propose that such diet-related effects offer a mechanistic link between the impact of different diets and the course of PCa development and progression. PMID- 25531314 TI - SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma. AB - Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development. PMID- 25531315 TI - FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer. AB - FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2'-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer. PMID- 25531316 TI - Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance. AB - The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma. PMID- 25531317 TI - Transforming growth factor-beta promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway. AB - Transforming growth factor-beta (TGFbeta) is enriched in the bone matrix and serves as a key factor in promoting bone metastasis in cancer. In addition, TGFbeta signaling activates mammalian target of rapamycin (mTOR) functions, which is important for the malignant progression. Here, we demonstrate that TGFbeta regulates the level of microRNA-96 (miR-96) through Smad-dependent transcription and that miR-96 promotes the bone metastasis in prostate cancer. The enhanced effects in cellular growth and invasiveness suggest that miR-96 functions as an oncomir/and metastamir. Supporting this idea, we identified a downstream target of the TGFbeta-miR-96 signaling pathway to be AKT1S1 mRNA, whose translated protein is a negative regulator of mTOR kinase. Our findings provide a novel mechanism accounting for the TGFbeta signaling and bone metastasis. PMID- 25531318 TI - LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression. AB - RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5'-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression. PMID- 25531319 TI - Caspase-2 protects against oxidative stress in vivo. AB - Caspase-2 belongs to the caspase family of cysteine proteases with established roles in apoptosis. Recently, caspase-2 has been implicated in nonapoptotic functions including maintenance of genomic stability and tumor suppression. Our previous studies demonstrated that caspase-2 also regulates cellular redox status and delays the onset of several ageing-related traits. In the current study, we tested stress tolerance ability in caspase-2-deficient (Casp2(-/-)) mice by challenging both young and old mice with a low dose of the potent reactive oxygen species (ROS) generator, PQ that primarily affects lungs. In both groups of mice, PQ induced pulmonary damage. However, the lesions in caspase-2 knockout mice were consistently and reproducibly more severe than those in wild-type (WT) mice. Furthermore, serum interleukin (IL)-1beta and IL-6 levels were higher in PQ exposed aged Casp2(-/-) mice indicating increased inflammation. Interestingly, livers from Casp2(-/-) mice displayed karyomegaly, a feature commonly associated with ageing and aneuploidy. Given that Casp2(-/-) mice show impaired antioxidant defense, we tested oxidative damage in these mice. Protein oxidation significantly increased in PQ-injected old Casp2(-/-) mice. Moreover, FoxO1, SOD2 and Nrf2 expression levels were reduced and induction of superoxide dismutase (SOD) and glutathione peroxidase activity was not observed in PQ-treated Casp2(-/ ) mice. Strong c-Jun amino-terminal kinase (JNK) activation was observed in Casp2(-/-) mice, indicative of increased stress. Together, our data strongly suggest that caspase-2 deficiency leads to increased cellular stress largely because these mice fail to respond to oxidative stress by upregulating their antioxidant defense mechanism. This makes the mice more vulnerable to exogenous challenges and may partly explain the shorter lifespan of Casp2(-/-) mice. PMID- 25531320 TI - Anoikis of colon carcinoma cells triggered by beta-catenin loss can be enhanced by tumor necrosis factor receptor 1 antagonists. AB - Detachment of non-malignant epithelial cells from the extracellular matrix causes their apoptosis, a phenomenon called anoikis. By contrast, carcinoma cells are anoikis-resistant, and this resistance is thought to be critical for tumor progression. Many oncogenes trigger not only anti- but also pr-apoptotic signals. The proapoptotic events represent an aspect of a phenomenon called oncogenic stress, which acts as a safeguard mechanism blocking tumor initiation. In cells that become malignant, oncogene-induced antiapoptotic signals outbalance the proapoptotic ones. It is now thought that treatments blocking the antiapoptotic events but preserving the proapoptotic signals can be particularly effective in killing tumor cells. Whether or not oncogenes induce any proanoikis signals that can be used for enhancing the efficiency of approaches aimed at triggering anoikis of cancer cells has never been explored. beta-Catenin is a major oncoprotein that is often activated in colorectal cancer and promotes tumor progression via mechanisms that are understood only in part. We found here that beta-catenin triggers both anti- and proanoikis signals in colon cancer cells. We observed that the antianoikis signals prevail and the cells become anoikis resistant. We further established that one proanoikis signal in these cells is triggered by beta-catenin-induced downregulation of an apoptosis inhibitor tumor necrosis factor receptor 1 (TNFR1) and subsequent reduction of the activity of a transcription factor NF-kappaB (nuclear factor-kappaB), a mediator of TNFR1 signaling. We also found that the effect of beta-catenin on TNFR1 requires the presence of transcription factor TCF1, a beta-catenin effector. We demonstrated that ablation of beta-catenin in colon cancer cells triggers their anoikis and that this anoikis is enhanced even further if low TNFR1 or NF-kappaB activity is artificially preserved in the beta-catenin-deprived cells. Thus, inhibition of TNFR1 or NF-kappaB activity can be expected to enhance the efficiency of approaches aimed at blocking beta-catenin-driven anoikis resistance of colon carcinoma cells. PMID- 25531321 TI - c-MYC is a radiosensitive locus in human breast cells. AB - Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer. PMID- 25531322 TI - Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness. AB - The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1 mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P<0.0001). Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1 deficient lung ADs. PMID- 25531323 TI - Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. AB - Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment significantly influence cancer growth and metastasis. Transforming growth factor-beta (TGF-beta) is known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN-) human breast cancer cell lines, we demonstrate that OPN induces integrin dependent MSC expression of TGF-beta1 to mediate adoption of the CAF phenotype. This OPN-TGF-beta1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1 and TGF-beta1 dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF beta1 pathway. PMID- 25531324 TI - STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer. AB - STIM1 (stromal interaction molecule 1), an endoplasmic reticulum Ca(2+) sensor that triggers the store-operated Ca(2+) entry activation, has recently been implicated in cancer progression. However, the role of STIM1 in the progression and metastasis of colorectal cancer (CRC) has not been addressed. In this study, we confirmed increased expression of STIM1 in highly invasive CRC cell lines. Enhanced expression of STIM1 promoted CRC cell metastasis in vitro and in vivo, whereas silencing of STIM1 with small interfering RNA resulted in reduced metastasis. Ectopic expression of STIM1 in CRC cells induced epithelial-to mesenchymal transition (EMT), whereas silencing of STIM1 had the opposite effect. Furthermore, STIM1 expression was markedly higher in CRC tissues than in adjacent noncancerous tissues. STIM1 overexpression correlated with poor differentiation and higher tumor node metastasis stage. CRC patients with positive STIM1 expression had poorer prognoses than those with negative STIM1 expression. Moreover, STIM1 was found to be a direct target of miR-185, a microRNA (miRNA) that has not previously been reported to be involved in EMT, in both CRC tissues and cell lines. Taken together, these findings demonstrate for the first time that STIM1 promotes metastasis and is associated with cancer progression and poor prognosis in patients with CRC. In addition, we show that expression of STIM1 is regulated by a posttranscriptional regulatory mechanism mediated by a new EMT related miRNA. This novel miR-185-STIM1 axis promotes CRC metastasis and may be a candidate biomarker for prognosis and a target for new therapies. PMID- 25531325 TI - Aberrant IDH3alpha expression promotes malignant tumor growth by inducing HIF-1 mediated metabolic reprogramming and angiogenesis. AB - Cancer cells gain a growth advantage through the so-called Warburg effect by shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis. Hypoxia-inducible factor 1 (HIF-1) has been suggested to function in metabolic reprogramming; however, the underlying mechanism has not been fully elucidated. We found that the aberrant expression of wild-type isocitrate dehydrogenase 3alpha (IDH3alpha), a subunit of the IDH3 heterotetramer, decreased alpha ketoglutarate levels and increased the stability and transactivation activity of HIF-1alpha in cancer cells. The silencing of IDH3alpha significantly delayed tumor growth by suppressing the HIF-1-mediated Warburg effect and angiogenesis. IDH3alpha expression was associated with the poor postoperative overall survival of lung and breast cancer patients. These results justify the exploitation of IDH3 as a novel target for the diagnosis and treatment of cancers. PMID- 25531326 TI - Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity. AB - Cytokines of the interleukin-1 (IL-1) family, such as IL-1alpha/beta and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL 33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose- and time dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and stat3 transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and stat3 activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast. PMID- 25531327 TI - PAX3 and ETS1 synergistically activate MET expression in melanoma cells. AB - Melanoma is a highly aggressive disease that is difficult to treat owing to rapid tumor growth, apoptotic resistance and high metastatic potential. The MET proto oncogene (MET) tyrosine kinase receptor promotes many of these cellular processes, but while MET is often overexpressed in melanoma, the mechanism driving this overexpression is unknown. As the MET gene is rarely mutated or amplified in melanoma, MET overexpression may be driven to increased activation through promoter elements. In this report, we find that transcription factors PAX3 and ETS1 directly interact to synergistically activate MET expression. Inhibition of PAX3 and ETS1 expression in melanoma cells leads to a significant reduction of MET receptor levels. The 300-bp 5' proximal MET promoter contains a PAX3 response element and two ETS1 consensus motifs. Although ETS1 can moderately activate both of these sites without cofactors, robust MET promoter activation of the first site is PAX dependent and requires the presence of PAX3, whereas the second site is PAX independent. The induction of MET by ETS1 via this second site is enhanced by hepatocyte growth factor-dependent ETS1 activation, thereby MET indirectly promotes its own expression. We further find that expression of a dominant-negative ETS1 reduces the ability of melanoma cells to grow both in culture and in vivo. Thus, we discover a pathway where ETS1 advances melanoma through the expression of MET via PAX-dependent and -independent mechanisms. PMID- 25531328 TI - Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. AB - Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten. PMID- 25531329 TI - Cytoplasmic DRAK1 overexpressed in head and neck cancers inhibits TGF-beta1 tumor suppressor activity by binding to Smad3 to interrupt its complex formation with Smad4. AB - Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive cancer with a poor prognosis and low patient survival. Because chemotherapy for advanced HNSCC is often ineffective, discovering new therapeutic targets that are important for HNSCC development and progression and elucidating their molecular mechanisms are required. In the present study, we describe the role of DRAK1 (death-associated protein kinase-related apoptosis-inducing kinase 1) as a novel negative regulator of the transforming growth factor-beta (TGF-beta) tumor suppressor signaling pathway for the first time in human HNSCC cells. DRAK1 was significantly overexpressed in primary human HNSCCs and in HNSCC cell lines. Through gain- and loss-of-function experiments, we demonstrated that the DRAK1 expression level regulated TGF-beta1-induced transcriptional activity and expression of the tumor suppressor gene p21(Waf1/Cip1). DRAK1 depletion enhanced TGF-beta1-induced growth inhibition in vitro and suppressed tumorigenicity in xenograft models in vivo. Mechanistically, DRAK1 was predominantly localized in the cytoplasm and bound to Smad3, thereby interrupting Smad3/Smad4 complex formation, which is the core process for the induction of tumor suppressor genes by TGF-beta1. Thus, our findings suggest that cytoplasmic DRAK1 increases tumorigenic potential through inhibition of TGF-beta1-mediated tumor suppressor activity in HNSCC cells and may be a potential therapeutic target for HNSCCs. PMID- 25531330 TI - SYK interaction with ITGbeta4 suppressed by Epstein-Barr virus LMP2A modulates migration and invasion of nasopharyngeal carcinoma cells. AB - Epstein-Barr virus (EBV)-encoded Latent Membrane Protein 2A (LMP2A) is an EBV latency-associated protein regularly expressed in nasopharyngeal carcinoma (NPC). In B cells, LMP2A activity resembles that of a constitutively activated antigen receptor, which recruits the Syk tyrosine kinase to activate a set of downstream signaling pathways. LMP2A also downregulates cellular Syk levels. In the present study, we demonstrate that Syk interacts with the integrin beta4 subunit (ITGbeta4) of integrin alpha6beta4 in epithelial cells and that concurrent LMP2A expression interferes with this interaction by competitive binding to Syk. We find that both Syk and LMP2A have an effect on ITGbeta4 cell surface expression. However, in LMP2A expressing cells, ITGbeta4 remains concentrated at the cellular protrusions, an expression pattern characteristic of motile cells, including NPC derived epithelial cells. This effect of LMP2A on ITGbeta4 localization is associated with a greater propensity for migration and invasion in-vitro, and may contribute to the invasive property of LMP2A-expressing NPC. PMID- 25531331 TI - MiR-873 regulates ERalpha transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells. AB - miRNAs (microRNAs) are frequently and aberrantly expressed in many cancers. MiR 873 has been revealed to be downregulated in colorectal cancer and glioblastoma. However, its function remains unclear. Here we report that miR-873 is downregulated in breast tumor compared with normal tissue. Enforced expression of miR-873 decreases the transcriptional activity of ER (estrogen receptor)-alpha but not ERbeta through the modulation of ERalpha phosphorylation in ER-positive breast cancer cells. We also found that miR-873 inhibits breast cancer cell proliferation and tumor growth in nude mice. Reporter gene assays revealed cyclin dependent kinase 3 (CDK3) as a direct target of miR-873. CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERalpha at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3. Interestingly, miR-873 was observed to be downregulated in tamoxifen-resistant MCF-7/TamR cells, while CDK3 is overexpressed in these cells. More importantly, re-expression of miR-873 reversed tamoxifen resistance in MCF 7/TamR cells. Our data demonstrate that miR-873 is a novel tumor suppressor in ER positive breast cancer and a potential therapeutic approach for treatment of tamoxifen-resistant breast cancer. PMID- 25531333 TI - Alkaline phosphatase in healthy children: reference intervals and prevalence of elevated levels. AB - BACKGROUND: Transient hyperphosphatasemia (TH) is an often unnoticed benign entity, primarily affecting children below 5 years of age. However, the prevalence among healthy children is unknown. We used data from a Swedish pediatric reference interval project to estimate the prevalence of high alkaline phosphatase (ALP) among healthy children and to calculate pediatric reference intervals. METHODS: Blood was collected from 699 subjectively healthy children aged 6 months to 18 years. After exclusion of subjects with high ALP, age- and gender-specific reference intervals were calculated. RESULTS: Six children had ALP levels >16.7 ukat/l (>1,000 U/l), including 4 females and 2 males aged 7-22 months. The prevalence in the age group from 6 months to 2 years was 6.2% (6/97). None of the older children had levels of ALP >16.7 ukat/l. The study did not include the follow-up of these apparently healthy children. Consequently, conditions others than TH explaining the elevated ALP could not be excluded. However, general chemistry analyses, such as liver enzymes, calcium, intact PTH and vitamin D, were essentially normal in these children. CONCLUSIONS: The prevalence of high ALP among subjectively healthy children was approximately 2.4% below 5 years of age and 6.2% below 2 years. Reference intervals vary with age and gender. PMID- 25531332 TI - NCOA3-mediated upregulation of mucin expression via transcriptional and post translational changes during the development of pancreatic cancer. AB - Pancreatic cancer (PC) is characterized by aberrant overexpression of mucins that contribute to its pathogenesis. Although the inflammatory cytokines contribute to mucin overexpression, the mucin profile of PC is markedly distinct from that of normal or inflamed pancreas. We postulated that de novo expression of various mucins in PC involves chromatin modifications. Analysis of chromatin modifying enzymes by PCR array identified differential expression of NCOA3 in MUC4 expressing PC cell lines. Immunohistochemistry analysis in tumor tissues from patients and spontaneous mouse models, and microarray analysis following the knockdown of NCOA3 were performed to elucidate its role in mucin regulation and overall impact on PC. Silencing of NCOA3 in PC cell lines resulted in significant downregulation of two most differentially expressed mucins in PC, MUC4 and MUC1 (P<0.01). Immunohistochemistry analysis in PC tissues and metastatic lesions established an association between NCOA3 and mucin (MUC1 and MUC4) expression. Spontaneous mouse model of PC (K-ras(G12D); Pdx-1cre) showed early expression of Ncoa3 during pre-neoplastic lesions. Mechanistically, NCOA3 knockdown abrogated retinoic acid-mediated MUC4 upregulation by restricting MUC4 promoter accessibility as demonstrated by micrococcus nuclease digestion (P<0.05) and chromatin immuno-precipitation analysis. NCOA3 also created pro-inflammatory conditions by upregulating chemokines like CXCL1, 2, 5 and CCL20 (P<0.001). AKT, ubiquitin C, ERK1/2 and NF-kappaB occupied dominant nodes in the networks significantly modulated after NCOA3 silencing. In addition, NCOA3 stabilized mucins post translationally through fucosylation by FUT8, as the knockdown of FUT8 resulted in the downregulation of MUC4 and MUC1 at protein levels. PMID- 25531334 TI - Up-regulation of intrarenal renin-agiotensin system contributes to renal damage in high-salt induced hypertension rats. AB - BACKGROUND/AIMS: To investigate the change of intrarenal renin-agiotensin system (RAS) and its role in high-salt induced hypertension. METHODS: Wistar rats were divided into normal-salt (NS), high-salt diet (HS) and high-salt diet with Losartan group (HS+L), for 6 weeks. Systolic blood pressure (SBP) was monitored. Blood and urine samples were collected every 2 weeks. Angiotensinogen (AGT) was measured by ELISA. AGT mRNA and protein were measured by real-time PCR and immunohistochemistry. Renin activity and angiotensin II (Ang II) were measured by radioimmunoassay. RESULTS: HS versus NS group, SBP increased from 2(nd) week (P<0.05), urinary protein increased at 6(th) week (P<0.05). Although plasma renin, AGT and Ang II had no significant changes (P>0.05), renal cortex renin, AGT, and Ang II increased significantly in HS (P<0.05). In HS+L, Losartan failed to reduce SBP (P>0.05) but abolished the increase of proteinuria (P<0.01), renal cortex renin, AGT, Ang II and urinary AGT reduced (P<0.05) while plasma renin, AGT and Ang II enhanced (P<0.05) when compared with HS. Urinary AGT was positively correlated with renal AGT (r=0.592, P <0.01) and Ang II (r=0.726, P <0.01). CONCLUSION: Inappropriate response of the renal RAS to a high salt diet may contribute to hypertension and renal damage, and urinary AGT could reflect intrarenal RAS activity. PMID- 25531335 TI - [Updates from RoFo]. PMID- 25531336 TI - [Pleomorphic xanthoastrocytomas]. PMID- 25531338 TI - Multivariable analysis of clinical influence factors on liver enhancement of Gd EOB-DTPA-enhanced 3T MRI. AB - PURPOSE: The purpose of this study was to identify clinical factors influencing Gd-EOB-DTPA liver uptake in patients with healthy liver parenchyma. MATERIALS AND METHODS: A total of 124 patients underwent contrast-enhanced MRI with a hepatocyte-specific contrast agent at 3 T. T1-weighted volume interpolated breath hold examination (VIBE) sequences with fat suppression were acquired before and 20 minutes after contrast injection. The relative enhancement (RE) between plain and contrast-enhanced signal intensity was calculated. Simple and multiple linear regression analyses were performed to evaluate clinical factors influencing the relative enhancement. Patients were subdivided into three groups according to their relative liver enhancement (HRE, RE >= 100 %; MRE, 100 % > RE > 50 %; NRE, RE <= 50 %) and were analyzed according to the relevant risk factors. RESULTS: Simple regression analyses revealed patient age, transaminases (AST, ALT, GGT), liver, spleen and delta-liver volume (the difference between the volumetrically measured liver volume and the estimated liver volume based on body weight) as significant factors influencing relative enhancement. In the multiple analysis the transaminase AST, spleen and delta liver volume remained significant factors influencing relative enhancement. Delta liver volume showed a significant difference between all analyzed groups. CONCLUSION: Liver enhancement in the hepatobiliary phase depends on a variety of factors. Body weight-adapted administration of Gd-EOB-DTPA may lead to inadequate liver enhancement after 20 minutes especially when the actual liver volume differs from the expected volume. KEY POINTS: * Differences between actual and expected liver volume can cause inadequate liver enhancement after 20 min. * A liver volume-adapted dose of Gd EOB-DTPA may help to improve liver enhancement. PMID- 25531339 TI - [Letter to the editor about Andresen R, Radmer S, Ludtke CW et al. balloon sacroplasty as a palliative pain treatment in patients with metastasis-induced bone destruction and pathological fractures. Fortschr Rontgenstr 2014; 186: 881 886. ]. PMID- 25531343 TI - Changes in glomerular kidney function among HIV-1-uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial. AB - IMPORTANCE: Tenofovir disoproxil fumarate (TDF) use has been associated with declines in the estimated glomerular filtration rate (eGFR) when used as part of antiretroviral treatment by persons with human immunodeficiency virus (HIV) type 1, but limited data are available for risk when used as preexposure prophylaxis (PrEP) for HIV-1 prevention. OBJECTIVE: To determine whether TDF-based PrEP causes eGFR decline in HIV-1-uninfected adults. DESIGN, SETTING, AND PARTICIPANTS: A per-protocol safety analysis of changes in eGFR in the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among heterosexual HIV-1-uninfected members of serodiscordant couples in Kenya and Uganda. The trial was conducted from 2008 to 2012. MAIN OUTCOMES AND MEASURES: Predefined outcomes of this analysis were mean eGFR change and a 25% or greater eGFR decline from baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: Of 4640 participants in the once-daily TDF (n = 1548), FTC-TDF (n = 1545), or placebo (n = 1547) groups, 63% were men. At enrollment, median age was 35 years (range, 18-64 years), and mean eGFR was 130 mL/min/1.73 m2. During a median follow-up of 18 months (interquartile range 12-27 months), mean within group eGFR change from baseline was +0.14 mL/min/1.73 m2 for TDF, -0.22 mL/min/1.73 m2 for FTC-TDF, and +1.37 mL/min/1.73 m2 for placebo, translating into average declines in eGFR attributable to PrEP vs placebo of -1.23 mL/min/1.73 m2 (95% CI, -2.06 to -0.40; P = .004) for TDF and -1.59 mL/min/1.73 m2 (95% CI, -2.44 to -0.74; P < .001) for FTC-TDF. The difference in mean eGFR between PrEP and placebo appeared by 1 month after randomization, was stable through 12 months, and then appeared to wane thereafter. The respective proportions of persons who developed a confirmed 25% or greater eGFR decline from baseline by 12 and 24 months was 1.3% and 1.8% for TDF and 1.2% and 2.5% for FTC TDF, and these frequencies were not statistically different from the confirmed decline in the placebo group (0.9% and 1.3% by 12 and 24 months, respectively). CONCLUSIONS AND RELEVANCE: In this large randomized, placebo-controlled trial among heterosexual persons, with median follow-up of 18 months and maximum follow up of 36 months, daily oral TDF-based PrEP resulted in a small but nonprogressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (>=25%) eGFR decline. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00557245. PMID- 25531345 TI - Cross-sectional evaluation of kidney function in hospitalized patients: estimated GFR versus renal scintigraphy. AB - BACKGROUND/AIMS: Accurate staging of chronic kidney disease (CKD) is very important. We tried to identify difference in GFR evaluation between CKD-EPI and Gates method with renal scintigraphy and which variables are associated with these differences. METHODS: We retrospectively reviewed the records of 341 patients who underwent dynamic renal scintigraphy in the last 5 years. Patients were categorized according to KDIGO staging I to V, using the eGFR calculated with the CKD-EPI equation. Secondarily, we stratified patients according to treatment with renin-angiotensin system (RAS) inhibitors. RESULTS: Gates method tends to underestimate GFR especially in CKD stage I (mean -22.2 ml/min) and II (mean -12.5 ml/min). The division in quartiles of ages showed an underestimation of GFR only in the first quartile of age (< 50 years old). Gates method underestimation of GFR was more pronounced in stage I patients treated with RAS inhibitors (mean -34.6 ml/min). The same occurs in stage II, even though to a lesser extent. CONCLUSION: The assessment of GFR by the Gates method must be carefully considered in the early stages of CKD, especially in younger patients. Moreover, the difference is more pronounced in patients treated with RAS inhibitors. Longitudinal studies will prove which method better predicts cardiovascular or renal events. PMID- 25531344 TI - Multiple circulating infections can mimic the early stages of viral hemorrhagic fevers and possible human exposure to filoviruses in Sierra Leone prior to the 2014 outbreak. AB - Lassa fever (LF) is a severe viral hemorrhagic fever caused by Lassa virus (LASV). The LF program at the Kenema Government Hospital (KGH) in Eastern Sierra Leone currently provides diagnostic services and clinical care for more than 500 suspected LF cases per year. Nearly two-thirds of suspected LF patients presenting to the LF Ward test negative for either LASV antigen or anti-LASV immunoglobulin M (IgM), and therefore are considered to have a non-Lassa febrile illness (NLFI). The NLFI patients in this study were generally severely ill, which accounts for their high case fatality rate of 36%. The current studies were aimed at determining possible causes of severe febrile illnesses in non-LF cases presenting to the KGH, including possible involvement of filoviruses. A seroprevalence survey employing commercial enzyme-linked immunosorbent assay tests revealed significant IgM and IgG reactivity against dengue virus, chikungunya virus, West Nile virus (WNV), Leptospira, and typhus. A polymerase chain reaction-based survey using sera from subjects with acute LF, evidence of prior LASV exposure, or NLFI revealed widespread infection with Plasmodium falciparum malaria in febrile patients. WNV RNA was detected in a subset of patients, and a 419 nt amplicon specific to filoviral L segment RNA was detected at low levels in a single patient. However, 22% of the patients presenting at the KGH between 2011 and 2014 who were included in this survey registered anti-Ebola virus (EBOV) IgG or IgM, suggesting prior exposure to this agent. The 2014 Ebola virus disease (EVD) outbreak is already the deadliest and most widely dispersed outbreak of its kind on record. Serological evidence reported here for possible human exposure to filoviruses in Sierra Leone prior to the current EVD outbreak supports genetic analysis that EBOV may have been present in West Africa for some time prior to the 2014 outbreak. PMID- 25531346 TI - Digestive Diseases. Introduction. PMID- 25531347 TI - What have we learnt about the role of the environment and natural course of IBD in the new millennium? 20-year follow-up of the IBSEN cohort. AB - The incidence and prevalence of IBD, both Crohn's disease (CD) and ulcerative colitis (UC), have increased in recent years, especially in industrialized countries. Still, the etiology of IBD remains largely unknown. Most research on IBD before the 1990s was conducted on selected patient populations. Selected patient populations are likely to introduce important bias and limit the interpretation and generalizability. The inclusion of both incident and prevalent cases or the inclusion of incident cases over long periods of time (decades) might also introduce bias due to changes in treatment regimens and socioeconomic factors over timer (time-trend bias). Consequently, the choice of a well characterized population-based inception cohort provides the best opportunity to describe the natural course of a disease. The IBSEN (Inflammatory Bowel Disease in South-Eastern Norway) study followed a large population-based cohort of newly diagnosed IBD patients for 20 years and has contributed significantly to the knowledge of the natural course of IBD. PMID- 25531348 TI - Probiotics and antibiotics in IBD. AB - The involvement of the gut microbiota in the pathogenesis of IBD is supported by many findings and is thus now commonly acknowledged. The imbalance in the composition of the microbiota (dysbiosis) observed in IBD patients is one of the strongest arguments and provides the rationale for a therapeutic manipulation of the gut microbiota. The tools available to achieve this goal include fecal microbiota transplantation, but antibiotics and probiotics have been the most used one until now. Although antibiotics have shown some efficacy in inducing remission in Crohn's disease (CD) and ulcerative colitis (UC), as well as preventing postoperative relapse in CD, they are not currently recommended for the treatment of IBD except for septic complications, notably because of long term tolerance and ecological issues. Some probiotics have been shown to be as good as 5-aminosalicylic acid to maintain remission in mild-to-moderate UC, but have been disappointing until now in CD in all tested indications. In pouchitis, antibiotics and probiotics have shown efficacy for inducing and maintaining remission, respectively. Targeting the gut microbiota in IBD is an attractive strategy. Current efforts to better understand the host-microbiota interactions in physiological as well as disease settings might lead to the development of rational-based treatments. PMID- 25531349 TI - IBD: microbiota manipulation through diet and modified bacteria. AB - BACKGROUND/AIMS: Crohn's disease (CD) and ulcerative colitis (UC) are both typified by an altered intestinal microbiota, and gene associations imply various defects in the mucosal barrier and in the innate immune response to bacteria. This review aims to assess how alterations in diet or use of modified bacteria could have therapeutic effects in CD or UC. METHODS: A MEDLINE search using the terms 'prebiotic', 'genetically modified bacteria', 'mucosal barrier in association with ulcerative colitis', 'Crohn's disease' or 'microbiota'. RESULTS: A large body of data from in vitro and animal studies shows promise for therapeutic approaches that target the microbiota. Approaches include dietary supplementation with fermentable fibres (prebiotics) and soluble fibres that block bacterial-epithelial adherence (contrabiotics), enhancement of the mucosal barrier with phosphatidylcholine, and use of genetically modified bacteria that express IL-10 or protease inhibitors. Vitamin D supplementation also shows promise, acting via enhancement of innate immunity. Clinical trials have shown benefit with enterically delivered phosphatidylcholine supplementation in UC and near-significant benefit with vitamin D supplementation in CD. CONCLUSION: Strategies that target the microbiota or the host defence against it appear to be good prospects for therapy and deserve greater investment. PMID- 25531350 TI - Mechanisms and models for intestinal fibrosis in IBD. AB - Intestinal fibrosis is a common outcome in IBD leading to significant morbidity that, to date, has no effective medical treatment. Current knowledge regarding potential mechanism(s) of intestinal fibrogenesis and stricture formation is limited, due in large part to the lack of relevant animal models. Although conventional models possess aspects that are advantageous to study specific mechanisms involved in gut fibrosis, most lack the features of a spontaneously occurring process leading to the formation of intestinal fibrotic lesions following mucosal inflammatory events and the ability to investigate the natural course of disease over time. This review aims to discuss established and novel animal models of gut fibrosis, particularly focusing on the advantages and disadvantages of each model system and the insights they bring to our understanding of the mechanisms of fibrogenesis. In fact, recent enhancements to existing models and the expansion of novel animal models of gut fibrosis is opening up multiple avenues for investigation which should stimulate progress in our mechanistic understanding of intestinal fibrogenesis and facilitate the development of effective pharmacotherapy in an area of significant unmet need. PMID- 25531351 TI - Endoscopic and medical management of fibrostenotic Crohn's disease. AB - Crohn's disease (CD) is a disease characterized by acute inflammation at diagnosis which evolves toward a more fistulizing and fibrostenotic disease phenotype over time. This leads to a high risk of bowel resections and ultimately short bowel with diarrhea and malabsorption, which represents a major part of the burden inflicted by CD. Bowel-conserving endoscopic and surgical procedures have therefore been developed. Specific antifibrotic medical therapies are currently lacking. Through-the-scope endoscopic balloon dilation has been described in several cohorts as an alternative to surgical resection or stricturoplasty in selected patients. Efficacy of endoscopic dilation is high, with an immediate success rate of 78% (between 73 and 100%), defined as the ability to pass with the scope through the stricture. However, symptomatic recurrence is frequent, with need for new dilatation in 41% and need for surgery in 42%, with a mean interval of 15 months. Adjunctive techniques such as local steroid or anti-TNF injections or stenting have not been conclusively proven to be of added benefit. We usually reserve endoscopic dilation for patients with short strictures (<5 cm) and nonpenetrating disease, preferably at the ileocolonic anastomosis. Similar to other interventions in endoscopy, endoscopic dilation has an intrinsic risk of complications which can be estimated at 2%. Balloon size and patient selection can serve to increase safety. PMID- 25531352 TI - New therapeutic avenues for treatment of fibrosis: can we learn from other diseases? AB - Crohn's disease (CD) is characterized by the frequent occurrence of complications, such as fibrotic strictures and subsequently the need for CD related surgery. Chronic or recurrent inflammation is generally regarded to be a necessary precondition for the initiation of intestinal fibrosis. In this view, fibrosis is a pathologically augmented healing response to inflammation-induced mucosal tissue destruction and injury. At present, there are no approved or effective medical therapies aimed specifically at fibrosis or stricture in IBD. Indirect benefits may occur from anti-inflammatory therapies, although there is no consensus on this. Therapy for fibrosis is complicated by the fact that a wound-healing response is essential in CD and ulcerative colitis. Several pharmaceutical companies are now working on the therapy of fibrosis in other diseases. Strategies interfering with TGF-beta expression and activation are promising. Pirfenidone has been studied in several clinical trials. Further therapeutic options are second-generation and wide-spectrum tyrosine kinase inhibitors. These inhibit growth factor receptor signaling, thus reducing fibrosis in animal models and some patients with tumor-associated fibrosis. At present, the development of antifibrotic therapies takes place in other diseases such as lung and liver fibrosis. This is partially due to a lack of experimental models for gut fibrosis and the fact that reliable readouts (MRI, serum markers) in patients are lacking. It will be important to test the above-mentioned newly available treatment strategies in IBD to profit from progress in other fibrotic diseases. PMID- 25531353 TI - Mesenchymal stromal cell therapy for Crohn's disease. AB - Current treatment approaches fail to address the underlying factors responsible for the pathogenesis of Crohn's disease (CD). Mesenchymal stromal cells (MSCs) are fibroblastic plastic adherent cells with specific surface markers, and may demonstrate trilineage differentiation ability. MSCs can be isolated from either the adipose tissue, bone marrow or umbilical cord. In refractory fistulizing CD, both autologous and allogeneic MSC therapy with repeated administrations is a feasible and safe therapeutic option with suggestion of efficacy, and several phase 3 trials are currently underway to determine its efficacy. In this review, we discuss the potential therapeutic role of MSC therapy for CD, which is predominantly related to its immunomodulatory role. The characteristics of MSCs derived from patients with CD and its pharmacological interaction are outlined. Preclinical studies using experimental models of colitis and clinical studies using MSCs for the treatment of fistulizing CD are highlighted. Finally, the current perspective and potential limitations of this novel therapy with recommendations for future studies are discussed. PMID- 25531354 TI - Immune cell therapy in IBD. AB - The therapeutic landscape of IBD has undergone a dramatic transformation since the advent of biologic therapies, especially TNF inhibitors. However, 30% of patients are primary nonresponders to biologic therapy and secondary failures are frequent. Due to substantial progress in our understanding of the biology of regulatory T cells (Tregs) and in the pathways of homing to the gastrointestinal tract, novel cell-based therapies for IBD have become possible. For example, although a reductionist view, one could envisage IBD as an imbalance between the proinflammatory effectors (such as Th17 cells) and the anti-inflammatory regulators (like Tregs). Here we focus on the development of ex vivo and in vivo approaches to enhance Tregs in the gastrointestinal tract. Specifically, herein we highlight a recently concluded phase 1/2a clinical trial that investigated the safety and efficacy of a single injection of escalating doses of autologous ovalbumin-specific Tregs in patients with active Crohn's disease refractory to conventional therapy. This therapy was well tolerated and demonstrated dose related efficacy. We also discuss the potential of directing Tregs derived through intranasal as well as epicutaneous immunization to the gastrointestinal tract by enhancing their gut homing signature and their potential to decrease gastrointestinal inflammation. Finally, the strengths and pitfalls of these new therapeutic approaches are discussed as we move forward in this largely uncharted territory. PMID- 25531355 TI - Trichuris suis ova, lecithin and other fancy molecules. AB - During the last 20 years, treatment paradigms as well as drugs used for IBD have changed significantly. However, there are still many unmet needs and a significant number of patients needing better therapy. It is obvious from this situation that many attempts have been made to implement new drugs and treatment algorithms including biologicals, new formulations of old drugs and 'fancy molecules or approaches'. For about 10 years, the application of Trichuris suis ova has been promoted and used in quite a number of patients. Two early studies suggested positive effects in ulcerative colitis as well as in Crohn's disease. These studies were based on experimental data in animal models as well as in vitro experiments. However, two large randomized controlled trials were not able to provide significant clinical effects in active Crohn's disease as compared to placebo, although a biological reaction (eosinophilia) was found. Another approach is the use of locally released phosphatidylcholine in ulcerative colitis. This approach is based on decreased phosphatidylcholine concentrations in the colonic mucus in patients, and showed positive effects in a number of monocentric trials in steroid-refractory and chronic active ulcerative colitis. A dose-finding study gave a positive signal in the highest-dose group and this approach is being tested further in controlled trials. Many other 'fancy molecules' including cannabis, vitamin D, thalidomide, hyaluronic acid, lidocaine, clonidine, chondroitin sulfate, naltrexone and melatonin have been tested in patients with claims of success. For most of those, however, controlled data in appropriate studies are lacking. Many more substances have been used in animal models and are probably applied in individual patients. Results of preliminary studies on some of the molecules mentioned are presented. PMID- 25531356 TI - New drugs on the horizon for IBD. AB - TNF antagonists have revolutionized the treatment of IBD. Nevertheless, between 30 and 45% of patients discontinue infliximab and other TNF antagonists over a 2- to 6-year period due to nonresponse, loss of response, or adverse events. Accordingly, the need for novel therapies grows each year. Recent studies have demonstrated the promise of new drugs with distinct modes of action for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). These include agents targeting leukocyte trafficking, therapies directed against IL-12/23 and Janus kinases (JAK), and antibodies against the classic inflammatory cytokine, IL 6. The anti-alpha4-integrin antibody, natalizumab, was the first effective antitrafficking agent for CD; however, its use has been greatly limited by the risk of progressive multifocal leukoencephalopathy. Therefore, second-generation antitrafficking agents have focused on restricting leukocyte blockade to the intestine through mechanisms interfering with alpha4beta7-integrin and its interaction with mucosal addressin cellular adhesion molecule 1. IL-23 is a cytokine central to the adaptive immune responses that characterize IBD. Ustekinumab, targeting the p40 subunit of IL-12 and IL-23, and the oral JAK inhibitor tofacitinib have proven to be effective in phase 2 trials in CD and UC, respectively. In addition, antibodies targeting the proinflammatory cytokine IL-6 are being studied in CD. Each of the approaches described have promise as well as limitations, so it is likely that the search for novel agents in IBD will continue. PMID- 25531357 TI - Biosimilars: are they bioequivalent? AB - Biologics have revolutionized several areas of medical therapeutics, and dozens of them are used by millions of patients. Monoclonal antibodies are only one type of biologics, but more than 900 are now in different phases of development. These drugs are complex to make and not cheap. The market is constantly increasing, and several biosimilars (copies of biologics) are being used, while many are still waiting to become available to the public. Biosimilars are more complex than generics, and regulatory agencies have very stringent criteria for approval. In the IBD field, the biosimilar infliximab (Inflectra(r), Remsima(r)) has been recently approved by the EMA, but not by Canadian authorities. The EMA has considered that 'high similarity' in preclinical studies together with clinical data from two trials in ankylosing spondylitis and rheumatoid arthritis warrant the 'extrapolation' for all approved indications for original infliximab (Remicade(r)), specifically Crohn's disease and ulcerative colitis. Canadian authorities have not accepted extrapolation, based on differences in glycosylation (fucosylation) that could be related to properties important in Crohn's disease. Most scientific societies do support the idea of asking for specific clinical trials before approval, although they acknowledge that following EMA, FDA, and WHO guidelines warrant safe products. Practical issues such as interchangeability and substitution remain unsolved, and it is very likely that there will be different solutions at the national level. Pharmacovigilance plans will be key for obtaining reliable data. Biosimilars are not better drugs, but can be clearly cheaper and may facilitate access to new treatments in many populations. PMID- 25531358 TI - Tailoring treatment to the individual patient: drug monitoring. AB - Understanding why drug concentrations vary between patients and which drug concentrations are associated with efficacy allow the development of rational treatment algorithms. Factors that affect the clearance of monoclonal antibodies include: (1) the presence of antidrug antibodies (increased clearance), (2) concomitant immunosuppression (decreased clearance), (3) increased serum CRP concentration (increased clearance), (4) decreased serum albumin concentration (increased clearance), (5) decreased body weight (increased clearance), and (6) increased fecal infliximab concentration (increased clearance). These factors can result in marked variability in drug clearance. Higher serum infliximab and adalimumab concentrations are associated with increased rates of clinical response and mucosal healing, and lower rates of colectomy. Treatment algorithms incorporate the following principles: (1) patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist, (2) patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification, and (3) patients who are negative for antidrug antibody and who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies, and if active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options. PMID- 25531359 TI - Role of immunosuppressives in special situations: perianal disease and postoperative period. AB - Complex perianal disease is associated with poor outcome and requires early effective therapy. Corticosteroids are not effective in perianal fistulising Crohn's disease, and antibiotics, immunosuppressants and anti-TNF therapy are required. It is important to consider combined medical surgical therapy after accurate imaging using an MRI scan of the pelvis. Drainage of any abscess at examination under anaesthesia and seton insertion are important before introduction of immunosuppressants and anti-TNF therapy. Long-term follow up of patients in a single centre reported responders to azathioprine having a reduced risk of perianal surgery (OR = 0.36; 95% CI: 0.27-0.46), but complex perianal fistulising Crohn's disease generally requires combination therapy with anti-TNF and azathioprine. Patients with recent perianal disease without fistulae and aged 40 years or older respond better to azathioprine monotherapy. Response to monotherapy with azathioprine is often slow and incomplete. In the recent GETAID study of early administration of azathioprine versus conventional management in patients at high risk of disabling disease, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery. In patients not responding to anti-TNF therapy, thalidomide or tacrolimus may be considered. Hyperbaric oxygen may be used as adjunctive therapy where available. The role of adipose-derived stem cell injection requires further long-term studies. In prevention of post-operative recurrence of Crohn's disease, azathioprine or 6 mercaptopurine had a favourable incremental cost-effectiveness ratio compared with no prophylactic therapy up to 1 year. In a Cochrane systematic review, azathioprine/6-mercaptopurine was associated with a significantly reduced risk of clinical recurrence [RR = 0.59, 95% CI: 0.38-0.92, number needed to treat (NNT) = 7] and severe endoscopic recurrence (RR = 0.6, 95% CI: 0.44-0.92, NNT = 4). Individual studies of prevention of post-operative recurrence using azathioprine/6-mercaptopurine have shown only modest benefit. In patients at high risk of relapse after surgical resection, anti-TNF therapy may be beneficial, but more data is required from ongoing studies. Strategies to prevent post-operative recurrence in Crohn's disease are evolving but need further refinement. PMID- 25531360 TI - Integrating omics: the future of IBD? AB - The complexity of IBD is well recognized as are the putative four major components of its pathogenesis, i.e. environment, genetic makeup, gut microbiota and mucosal immune response. Each of these components is extremely complex on its own, and at present should be more appropriately defined by the terms 'exposome', 'genome', 'microbiome' and 'immunome', respectively, based on the 'ome' suffix that refers to a totality of some sort. None of these 'omes' is apparently capable of causing IBD by itself; it is instead the intricate and reciprocal interaction among them, through the so-called 'IBD interactome', that results in the emergence of IBD, or more appropriately the 'IBD integrome'. To deal with and understand such overwhelming biological complexity, new approaches and tools are needed, and these are represented by 'omics', defined as the study of related sets of biological molecules in a comprehensive fashion, such as genomics, transcriptomics, proteomics, metabolomics, and so on. Numerous bioinformatics based tools are available to explore and take advantage of the massive amount of information that can be generated by the analysis of the various omes and their interactions, aiming at identifying the molecular interactome underlying any particular status of health and disease. These novel approaches are fully applicable to IBD and allow us to achieve the ultimate goal of developing and applying personalized medicine and far more effective therapies to individual patients with Crohn's disease and ulcerative colitis. For the practicing gastroenterologist, an omics-based delivery of healthcare may be intimidating, but it must be accepted and implemented if he or she is to provide the best possible care to IBD patients. PMID- 25531361 TI - Abdominal abscess in Crohn's disease: multidisciplinary management. AB - Crohn's disease (CD) is characterized by full-thickness inflammation of the bowel. For this reason, perforating complications such as intra-abdominal abscesses or fistulas are common. A concomitant intra-abdominal abscess with active CD of the small bowel is a challenging dilemma for gastroenterologists and surgeons. Since there is active and severe disease, this should be treated with immunosuppressive drugs. However, in the presence of an intra-abdominal abscess, immunosuppression can be dangerous. There are several treatment options for intra abdominal abscesses in CD. Nowadays, the first-line treatment is antibiotic therapy with or without percutaneous drainage. Historically, patients were treated with surgical drainage. With the development of percutaneous drainage, treatment shifted to a more nonsurgical approach. Success rates for percutaneous drainage in the literature vary from 74 to 100%, and it is considered to be a relatively safe procedure. It has been reported that surgery can be avoided after successful percutaneous drainage in a variable number of patients (14-85%). If sepsis is controlled, CD medication should be started to prevent recurrence. It is important to monitor the effect upon CD lesions to avoid further perforating complications. Finally, an undrainable or small abscess can be treated with antibiotics alone, although high recurrence rates have been described with this approach. Patients with a concomitant stenosis, an enterocutaneous fistula or refractory active disease are likely to require surgery. Percutaneous drainage in combination with delayed surgery is useful to improve the patient's condition prior to surgery and is associated with less morbidity, a lower stoma rate and more limited resection. In conclusion, when feasible, percutaneous drainage and antibiotics should be the treatment of choice in patients with an intra-abdominal abscess in CD. If surgery is inevitable, this must be delayed to reduce postoperative septic complications and high stoma rates. PMID- 25531362 TI - Refractory distal ulcerative colitis: is proctocolectomy always necessary? AB - Refractory distal ulcerative colitis (RDUC) is defined as persistence of symptoms caused by endoscopically proven colonic inflammation located at the rectum or left colon despite oral/topical steroids and 5-ASA. RDUC affects a small subset of patients and is associated with chronic disabling symptoms and increased social/medical costs. Moreover, patients with long-standing ulcerative colitis (UC) carry an elevated risk of developing colorectal cancer and colonic mucosa high-grade dysplasia. Alternative medical strategies in steroid refractory disease are unlikely to provide durable remission in all patients, carry potential severe side effects and, as immunosuppressants, the risk of other neoplasms, and may increase the short-term complication rate when surgery is finally required. Restorative proctocolectomy with ileal pouch-anal anastomosis (RP-IPAA) allows the complete removal of the diseased rectum and colon, virtually eliminating the risk of malignant transformation and reestablishing intestinal continuity with continence preservation. Since the introduction of this surgical procedure, morbidity and mortality rates have been drastically reduced. Despite the still notable rate of surgical complications, long-term quality of life assessment has shown excellent results in nearly all patients who have undergone RP-IPAA, comparing well with the general population. Furthermore, when performed for distal UC, RP-IPAA produces similar surgical outcomes with respect to pancolitis. In conclusion, RP-IPAA should always be considered in patients with RDUC, and multidisciplinary counseling should provide patients clear information about the advantages of surgery and possible complications as well as the chance to achieve disease remission with medical therapy. PMID- 25531363 TI - Previous cancer and/or lymphoma in patients with refractory IBD--pro: anti-TNF or immunosuppressive treatment. AB - Management of patients with IBD and a past or current malignancy has become more frequent in daily practice. As trends in IBD therapy are moving to more immunomodulators, administered earlier and for longer periods than ever, an increasing number of IBD patients with a prior malignancy may receive conventional immunosuppressants (IS) and/or anti-TNF. However, few data are available for managing this IBD subpopulation due to three main reasons: (1) previous cancer is usually an exclusion criterion from all clinical trials, (2) guidelines do not recommend any immunomodulator use in patients who have had a malignancy within the last 5 years, and (3) physicians are reluctant to use immunomodulators which could reactivate dormant micrometastasis. However, there is a lack of scientific evidence for avoiding immunomodulators in IBD patients with previous cancer. In a recently published cohort of patients with previous cancer, no excess incidence of incident cancer was associated with exposure to IS. Data with anti-TNF are lacking in IBD. Recently in a registry including 79 patients with refractory IBD who started an anti-TNF therapy while having had a prior malignancy within the past 5 years, survival rates without incident cancer were 96 and 72% at 1 and 5 years, respectively. Thus, evidence to not start IS and/or anti-TNF therapy in IBD patients who have had a previous cancer is weak. Pending larger studies, a case-by-case joint decision taken with the oncologist and the patient is recommended, and should take IBD and the cancer risk-benefit ratio for using immunomodulators to treat refractory disease into consideration. PMID- 25531364 TI - Previous cancer and/or lymphoma in patients with refractory IBD--con: anti-TNF or conventional immunosuppressive treatment. AB - Patients with IBD and prior cancer are at increased risk of developing recurrent or de novo cancer. Depending on the type of malignancy, risk factors include IBD itself, age, environmental factors, genetic susceptibility and exposure to immunosuppressants (IMS), namely thiopurines, methotrexate and anti-TNFalpha biologics. The procarcinogenic effect of IMS depends on the type of drug and length of exposure. Thiopurines increase the rates of nonmelanoma skin cancer and lymphomas. Methotrexate is less harmful, but data are scarce. Evidence favoring the 'safety' of anti-TNF monotherapy is weak because most patients have been exposed to combinations of IMS prior to the development of malignancy. Anti TNFalpha biologics may promote tumor proliferation and increase the risk of melanomas. Exclusion of these patients from trials with biologics, physician concerns or fear of incident cancers and medicolegal consequences, and patient concerns have led to a paucity of data regarding IMS treatment of patients with a prior malignancy. In the absence of guidelines, IMS should be avoided especially during the first 2 years after commencing cancer therapy. Depending on disease type, location and severity, 5-ASA, antibiotics, enteric nutrition, steroids alone or in combinations, seton placement, and 'curative' or 'diverting' surgery may allow for a crucial drug-holiday period before readministration of IMS. Preventive measures include smoking cessation, UV solar protection, annual skin examination and Pap test. If unavoidable, methotrexate should be the drug of first choice followed by anti-TNFalpha and then thiopurines. Patients should be managed on a case-by-case basis by a multidisciplinary team of experts. PMID- 25531368 TI - Cerebral oxygenation during intermittent hypoxemia and bradycardia in preterm infants. AB - BACKGROUND: Episodes of hypoxemia and bradycardia frequently occur with apnea of prematurity in preterm infants. Little is known about the impact of different event types on the brain. OBJECTIVES: To describe the influence of hypoxemia and bradycardia, either isolated or in combination, on cerebral oxygenation. METHODS: In 16 preterm infants with intermittent hypoxemia and/or bradycardia, cerebral tissue oxygen saturation (StO2, as measured by near-infrared spectroscopy), heart rate and pulse oximetric saturation (SpO2) were recorded simultaneously for 16 h. Events were classified as isolated bradycardia (type 1), isolated hypoxemia (type 2) or combined (simultaneous, type 3; bradycardia first, type 4; hypoxemia first, type 5). Primary outcome was a score representing the area below baseline for cerebral StO2 desaturation during an event. Secondary outcomes were duration and depth of cerebral desaturation. RESULTS: Patients had a median (range) gestational age of 25.9 (22.6-30.4) weeks and a postnatal age of 32.5 (7-58) days. The median (quartiles) number of events was 49 (34-58). Isolated hypoxemias were the most frequent events (24; 9-36) and isolated bradycardias the least common (0; 0-1). Cerebral StO2 baseline was not different between event types. Cerebral desaturation score, duration of event and depth of cerebral desaturation were smallest for isolated bradycardias and largest for combined events, especially for those starting with hypoxemia followed by bradycardia. Regardless of event type, 12/16 infants maintained cerebral StO2 >60% despite severe SpO2 desaturations. CONCLUSIONS: Isolated bradycardias had the lowest impact on cerebral desaturation, and combined events had the highest. Most infants preserved cerebral oxygenation >60% during events. PMID- 25531367 TI - Maduramicin inhibits proliferation and induces apoptosis in myoblast cells. AB - Maduramicin, a polyether ionophore antibiotic derived from the bacterium Actinomadura yumaensis, is currently used as a feed additive against coccidiosis in poultry worldwide. It has been clinically observed that maduramicin can cause skeletal muscle and heart cell damage, resulting in skeletal muscle degeneration, heart failure, and even death in animals and humans, if improperly used. However, the mechanism of its toxic action in myoblasts is not well understood. Using mouse myoblasts (C2C12) and human rhabdomyosarcoma (RD and Rh30) cells as an experimental model for myoblasts, here we found that maduramicin inhibited cell proliferation and induced cell death in a concentration-dependent manner. Further studies revealed that maduramicin induced accumulation of the cells at G0/G1 phase of the cell cycle, and induced apoptosis in the cells. Concurrently, maduramicin downregulated protein expression of cyclin D1, cyclin-dependent kinases (CDK4 and CDK6), and CDC25A, and upregulated expression of the CDK inhibitors (p21Cip1 and p27Kip1), resulting in decreased phosphorylation of Rb. Maduramicin also induced expression of BAK, BAD, DR4, TRADD and TRAIL, leading to activation of caspases 8, 9 and 3 as well as cleavage of poly ADP ribose polymerase (PARP). Taken together, our results suggest that maduramicin executes its toxicity in myoblasts at least by inhibiting cell proliferation and inducing apoptotic cell death. PMID- 25531369 TI - Comparative study of surface-active properties and antimicrobial activities of disaccharide monoesters. AB - The objective of this research was to determine the effect of sugar or fatty acid in sugar ester compounds on the surface-active properties and antimicrobial activities of these compounds. Disaccharides of medium-chain fatty acid monoesters were synthesized through transesterifications by immobilized lipase (Lipozyme TLIM) to yield nine monoesters for subsequent study. Their antimicrobial activities were investigated using three pathogenic microorganisms: Staphylococcus aureus, Escherichia coli O157:H7 and Candida albicans. Their surface-active properties including air-water surface tension, critical micelle concentration, and foaming and emulsion power and stability were also studied. The results showed that all of the tested monoesters were more effective against Staphylococcus aureus (Gram-positive bacterium) than against Escherichia coli O157:H7 (Gram-negative bacterium). The results demonstrated that the carbon chain length was the most important factor influencing the surface properties, whereas degree of esterification and hydrophilic groups showed little effect. PMID- 25531370 TI - Association of red blood cell distribution width levels with severity of coronary artery disease in patients with non-ST elevation myocardial infarction. AB - OBJECTIVES: The aim of this study was to evaluate the association of the levels of red blood cell distribution width (RDW) with the severity of atherosclerosis and to determine whether or not the RDW level on admission is an independent predictor of all-cause mortality in patients with non-ST elevation myocardial infarction (NSTEMI). MATERIALS AND METHODS: A total of 335 consecutive patients with NSTEMI were enrolled in this study. The patients were divided into high (n = 105) and low (n = 230) SYNTAX groups. The high SYNTAX group was defined as patients with a value in the third tertile (SYNTAX score, SXscore >=12), while the low SYNTAX group was defined as those with a value in the lower 2 tertiles (SXscore <12). The high RDW group (n = 152) was defined as patients with RDW >14.25% and the low RDW group (n = 183) as those with RDW <=14.25%. All-cause mortality was followed up to 38 months. RESULTS: The mean follow-up period was 18 +/- 11 months. The RDW levels of patients were significantly higher in the high SYNTAX group than in the low SYNTAX group (15.2 +/- 1.8 vs. 14.2 +/- 1.2, p < 0.001). Pearson's coefficients were used to determine the degree of association between RDW levels and SXscore and also between RDW levels and high-sensitivity C reactive protein. There was a significant correlation between RDW levels and SXscore (r = 0.460, p < 0.001). Also, there was a significant correlation between RDW levels and high-sensitivity C-reactive protein (r = 0.180, p = 0.001). All cause mortality rate was not significantly different between the high and low RDW groups (log-rank, p = 0.621). CONCLUSION: RDW levels were independently associated with high SXscore but were not associated with long-term mortality in NSTEMI patients. PMID- 25531371 TI - Increased osteopontin levels in children undergoing venom immunotherapy may serve as a marker of clinical efficacy. AB - BACKGROUND: Venom immunotherapy (VIT) has its effect by modulating various mediators resulting in immune tolerance. The aim of this study was to measure changes in plasma osteopontin (OPN) and serum basal tryptase (sBT) levels over the course of 1 year of VIT in children with venom allergy. METHODS: Children who suffered from a large local reaction (LLR) or a systemic reaction (SR) after insect stings were included along with control subjects. Measurements were performed before the initiation of VIT and 6 and 12 months after it had been started. RESULTS: A total of 58 children (24 with SR, 18 with LLR and 16 control subjects) with a median age of 9.5 years (range 6.7-12.8) were enrolled. The plasma OPN levels of patients with LLR [median 1,477 ng/ml, interquartile range (IQR) 1,123-1,772] were significantly higher than patients with SR (882 ng/ml, 579-1,086; p < 0.001) and healthy control subjects (1,015 ng/ml, 815-1,203; p = 0.002). A significant increase in plasma OPN levels in children was determined after the 1-year VIT. The sBT levels of children with SR (4.1 ng/ml, 3.6-5.8) were significantly higher than children with LLR (3.1 ng/ml, 2.5-4.0) and control subjects (3.0 ng/ml, 2.9-3.8; p = 0.001). There was no significant change in the sBT levels of the patients after the 1-year VIT. CONCLUSIONS: The results of our study showed higher baseline levels of OPN in children with LLR compared to control subjects and children with SR. In children with SR, OPN levels were increased after the 1-year VIT. Our results may suggest a possible association between OPN and successful VIT in children. PMID- 25531372 TI - Gliomas in the sellar turcica region: a retrospective study including adult cases and comparison with craniopharyngioma. AB - PURPOSE: Previous studies of sellar gliomas have been confined to pediatric optic pilocytic gliomas. The present study aimed to analyze the features of sellar gliomas involving both pediatric and adult patients with various pathologies and to compare them with craniopharyngiomas to better differentiate the diagnosis. METHODS: Twenty-seven sellar gliomas were retrospectively examined regarding their demographics, pathologies, clinical and imaging presentations, surgeries and postoperative complications. Thirty craniopharyngiomas from the same period and 880 gliomas of the most common pathologies from 2008-2014 were included for comparisons. RESULTS: In total, 55.6% of the sellar gliomas were adult cases. The pathology included pilocytic astrocytoma, ganglioglioma, diffuse astrocytoma, pilomyxoid astrocytoma, oligoastrocytoma, and glioblastoma. Compared with craniopharygiomas, sellar gliomas presented with a significantly lower ratio of visual disturbances, growth hormone deficiencies, lesion cystic changes, and calcification. Sellar gliomas had significantly greater effects on the patients' mentality and anatomical brain stem involvement. Total resections were achieved in 11 patients, which were significantly lower compared with craniopharyngiomas. CONCLUSIONS: Sellar gliomas affect both pediatric and adult patients with pathological changes extending beyond pilocytic astrocytomas. They have diverse clinical manifestations and imaging presentations. Differences exist regarding several aspects between sellar gliomas and craniopharyngiomas, which may facilitate a differential diagnosis. PMID- 25531373 TI - Burden of complicated malaria in a densely forested Bastar region of Chhattisgarh State (Central India). AB - BACKGROUND: A prospective study on severe and complicated malaria was undertaken in the tribal dominated area of Bastar division, Chhattisgarh (CG), Central India, with an objective to understand the clinical epidemiology of complicated malaria in patients attending at a referral hospital. METHODS: Blood smears, collected from the general medicine and pediatric wards of a government tertiary health care facility located in Jagdalpur, CG, were microscopically examined for malaria parasite from July 2010 to December 2013. The Plasmodium falciparum positive malaria cases who met enrollment criteria and provided written informed consent were enrolled under different malaria categories following WHO guidelines. PCR was performed to reconfirm the presence of P.falciparum mono infection among enrolled cases. Univariate and multivariate logistic regression analysis was done to identify different risk factors using STATA 11.0. RESULTS: A total of 40,924 cases were screened for malaria. The prevalence of malaria and P.falciparum associated complicated malaria (severe and cerebral both) in the hospital was 6% and 0.81%, respectively. P.falciparum malaria prevalence, severity and associated mortality in this region peaked at the age of > 4-5 years and declined with increasing age. P.falciparum malaria was significantly more prevalent in children than adults (P < 0.00001). Among adults, males had significantly more P.falciparum malaria than females (P < 0.00001). Case fatality rate due to cerebral malaria and severe malaria was, respectively, 32% and 9% among PCR confirmed mono P.falciparum cases. Coma was the only independent predictor of mortality in multivariate regression analysis. Mortality was significantly associated with multi-organ complication score (P = 0.0003). CONCLUSION: This study has revealed that the pattern of morbidity and mortality in this part of India is very different from earlier reported studies from India. We find that the peak morbidity and mortality in younger children regardless of seasonality. This suggests that this age group needs special care for control and clinical management. PMID- 25531374 TI - [Comparative study of the MELD-Na and Child-Turcotte-Pugh scores as short-term prognostic indicators of acute-on-chronic hepatitis B liver failure]. AB - OBJECTIVE: To compare the clinical values of the model for end-stage liver disease (MELD)-Na scoring system and the Child-Turcotte-Pugh (CTP) scoring system for predicting the short-term prognosis of acute-on-chronic hepatitis B liver failure. METHODS: A total of 339 patients with acute-on-chronic hepatitis B liver failure and admitted to the Eighth People's Hospital of Guangzhou and Nanfang Hospital of Southern Medical University between January 2010 and December 2012 were included in this retrospective analysis. The short-term predictive values of MELD-Na and CTP scores were compared for this patient population. RESULTS: The mean MELD-Na score in the advanced stage of liver failure was significantly higher than those in the early and middle stages, respectively (both P less than 0.01). The mean MELD-Na score in the middle stage of liver failure was also significantly higher than that in the early stage (P less than 0.01). In contrast, the mean CTP scores for the three stages of liver failure were not significantly different (all P more than 0.05). The MELD-Na score showed a stronger correlation with the stage of liver failure (rs =0.485, P less than 0.01) than did the CTP score (rs =0.306, P less than 0.01). The short-term mortality rates were significantly different for the three stages of liver failure (P less than 0.01). The mean MELD-Na score of the death group was significantly higher than that of the survival group (P less than 0.01). The CTP scores, however, were not significantly different between the death and survival groups (P more than 0.05).The short-term mortality rate of liver failure was significantly higher for patients with increased scores for the MELD-Na and CTP systems (both P less than 0.01). The areas under the curve of the MELD-Na and CTP scores were 0.813 and 0.823, respectively. The MELD-Na and CTP score have similar predictive values (P more than 0.05). CONCLUSION: The MELD-Na scoring system is slightly superior to the CTP scoring system for predicting short-term prognosis of acute-on-chronic hepatitis B liver failure.The predictive value may improve for both the MELD-Na score and the CTP score when combined with expert clinical practice and experience. PMID- 25531375 TI - [Effects of oral antiviral agents on long-term outcomes of treatment-naive patients with HBV-related decompensated cirrhosis: a retrospective cohort study]. AB - OBJECTIVE: To evaluate the efficacy of nucleos(t)ide analogues (NA) treatment and to assess the long-term outcomes, including survival, liver function improvement and virologic response, in patients with decompensated cirrhosis due to hepatitis B virus (HBV) infection. METHODS: Patients with Child-Turcotte-Pugh (CTP) scores more than or equal to 7, who had been treated with either lamivudine or other agents, but who were free of co-infection with other hepatitis virus were enrolled between January 2005 and December 2009. The study participants were subgrouped according to the antiviral drugs received or model for endstage liver disease (MELD) score for comparative analyses.Additionally, the 19 patients who were treated with NA for more than 5 years were investigated for changes in biochemical and virological indices, before and after the antiviral treatment. RESULTS: A total of 166 patients (125 males; 89 e-negative) and 52 untreated healthy patients (as control) were analyzed.The cohort of patients receiving antiviral therapy had significantly better 5-year actuarial survival than the untreated patients (74.1% vs.34.9%, P less than 0.001). For patients with MELD score more than or equal to 18, actuarial survival was not significantly different between the two groups (P=0.073). CONCLUSION: Antiviral therapy significantly increases survival and improves the clinical long-term outcome of patients with HBV-induced decompensated cirrhosis.Antiviral treatment should be initiated at an early stage to maximize benefit in the improvement of clinical status. PMID- 25531376 TI - [Proteomic analysis of peripheral blood mononuclear cells to identify potential markers of fibrosis in chronic hepatitis B]. AB - OBJECTIVE: To identify non-invasive biomarkers for diagnosis and/or prognosis of liver fibrosis in chronic hepatitis B (CHB). METHODS: Peripheral blood samples were obtained from 48 patients with CHB, including 24 with mild fibrosis (stage 1, S1) and 24 with severe fibrosis (stage 4, S4), and subjected to Ficoll density gradient centrifugation in order to obtain enriched samples of peripheral blood mononuclear cells (PBMCs).The PBMC proteomes of the two groups were assessed by first separating the total proteins by two-dimensional gel electrophoresis (2DE) and then identifying the differentially expressed proteins by liquid chromatography combined with tandem mass spectrometry (LCMS/MS). RESULTS: The enriched PBMC samples from the S1 group and the S4 group had similar amounts of platelets [(19.268+/- 6.413) * 109/L and(19.480+/- 6.538) * 109/L, respectively); however, for both, the platelet amounts were 5 to 15-fold lower than that of the normal reference (100-300 *109/L). There was no significant difference found between the platelet amounts in the S1 patients and healthy controls (P=0.930). Twelve differentially expressed proteins were identified through 2DE-LC-MS/MS, including proteins such as moesin and NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 that are involved in various biological processes like cell movement, cell adhesion, kinase signaling and transcription. CONCLUSION: s The 12 proteins with differential expression in S1 and S4 patients with CHB and liver fibrosis may represent markers related to development and/or progression of liver fibrosis. PMID- 25531377 TI - [Whole-liver perfusion imaging by multi-slice spiral computed tomography based on Couinaud segments for evaluation of the blood flow state in patients with hepatitis B cirrhosis]. AB - OBJECTIVE: To investigate the blood flow characteristics of hepatitis B cirrhosis based on Couinaud's hepatic segments and to analyze the correlation between perfusion parameters of liver cirrhosis in the hepatic segments and between the different Child-Pugh classifications by using the pattern of whole liver perfusion detected by multi-slice spiral computed tomography (MSCT). METHODS: Whole-liver perfusion enhanced CT imaging scan was performed for 51 patients with hepatitis B cirrhosis (including 24 classified as Child-Pugh A, 19 as Child-Pugh B, and 8 as Child-Pugh C) and 20 patients without any liver abnormalities (who served as the control group).The perfusion parameters of Couinaud's segments were measured in order to compare the blood perfusion differences among the Couinaud's hepatic segments in liver cirrhosis. The blood flow characteristics were analyzed for each lobe and compared between groups, and the time to peak and peak of enhancement values of the aorta and portal veins and spleen were recorded and compared between groups.The F-test was used for statistical analysis. RESULTS: The liver cirrhosis group showed higher time to peak for aorta and portal veins and spleen but lower peak of enhancement values than the control group. The hepatic arterial perfusion (HAP) was significantly higher in segment 3 than in segment 7 were (11.40+/- 5.72 vs.9.46+/-5.18 mL/min/100 mL; P less than 0.05). In addition, the differences of the portal venous perfusion (PVP) and total hepatic perfusion (THP) were significant between the liver lobes in various groups (P less than 0.05). The HAP and hepatic perfusion index (HPI) were not significantly different between the groups, but the HAP and HPI in every lobe were higher in the Child C subgroup than in either the Child A or Child B subgroups. CONCLUSION: The cirrhotic liver has different blood flow in the various Couinaud's segments. Whole-liver perfusion MSCT can reflect the hemodynamic changes of liver cirrhosis and Child-Pugh classification, and as such may be helpful for distinguishing the normal liver from the cirrhotic liver. PMID- 25531378 TI - [Relation of the plasma N-terminal pro-brain natriuretic peptide with cardiac dysfunction and liver function in patients with cirrhosis]. AB - OBJECTIVE: To determine the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and evaluate their relationships with cardiac structure and function and liver function in patients with cirrhosis. METHODS: Fifty patients with cirrhosis underwent two-dimensional Doppler echocardiography. The cirrhotic patients were divided into groups according to Child-Pugh score:Child-Pugh class A, n=15; Child-Pugh class B, n=20; Child-Pugh class C, n=15. Cardiac dimensions and left and right ventricular functions were evaluated. In addition, the plasma NT-proBNP was detected in the 50 cirrhotic patients and 11 healthy controls. RESULTS: The levels of plasma NT-proBNP was significantly higher in cirrhotic patients than in healthy controls (240.15+/-80.87 pg/mL vs.55.86+/-20.13 pg/mL, P=0.000).The Child-Pugh class A, B and C groups showed no differences for left ventricular diameter, right ventricular diameter, septal thickness, left ventricular wall thickness, E wave, A wave, aortic annulus diameter, and the value of E/A.However, the left atrial diameter was significantly lower in the A group than in the C group (29.83+/-3.76 mm vs.35.08+/-3.68 mm, P=0.015) and in the B group than in the C group (31.78+/-4.05 mm vs.35.08+/-3.68 mm, P=0.000); there was no significant difference between the A and B groups. The plasma NT proBNP was significantly lower in the A group than the C group (189.20+/-20.25 pg/mL vs.300.13+/-34.96 pg/mL, P=0.000) and in the B group than in the C group (202.34+/-31.20 pg/mL vs.300.13+/-34.96 pg/mL, P=0.000); there was no significant difference between the A and B groups (P=0.302).The NT-proBNP level was positively correlated with the left atrial diameter and the left ventricular wall thickness (r=0.540, P=0.000 andr=0.309, P=0.029 respectively).In addition, the NT proBNP showed correlation with Child-Turcotte-Pugh score (r=0.454, P=0.001), albumin level (r=-0.376, P=0.007) and total bilirubin level (r=0.283, P=0.047). CONCLUSION: s Increased levels of plasma NT-proBNP are related to disease severity in patients with cirrhosis.Furthermore, cardiac dysfunction in patients with cirrhosis may be related to increased plasma levels of NT-proBNP. PMID- 25531379 TI - [Gene expression changes of regucalcin and prohibitin in cirrhotic rat liver and the related effects of compound glutathione inosine injection intervention]. AB - OBJECTIVE: To study expression of regucalcin (RGN) and prohibitin (PHB) genes in cirrhotic rat liver and to investigate the related effects of compound glutathione inosine injection (CGII) intervention. METHODS: Forty male Wistar rats were randomly divided into a control group (n=12) and a model group (n=28).The model was established by injecting sterile porcine serum (0.5 mL) into the rat abdominal cavity, twice weekly for 8 consecutive weeks; the control group rats were treated with physiological saline injection (0.5 mL) into the abdominal cavity with the same frequency and time span. During the modeling period, four rats from the model group were randomly selected at different time points to examine changes in liver pathology. Upon pathology confirmation of liver cirrhosis, the porcine serum injection was terminated. The remaining 24 rats in the model group were randomly divided into a fibrosis group and a CGII treatment group.The CGII group received CGII (intramuscular injection of 0.018 mL 100g-1 body weight) once a day for 6 continuous weeks; the fibrosis rats were treated with the same dosage of physiological saline with the same frequency and time span.Liver tissue morphology was examined by both hematoxylin-eosin and Masson's staining. RGN and PHB expression at the mRNA and protein levels in liver tissues were detected by real time RT-PCR and immunohistochemical staining, respectively. RESULTS: Both the mRNA and protein expression levels of RGN and PHB were significantly lower in the liver tissues of the fibrosis group than in the control group.CGII intervention led to significant alleviation of the liver fibrosis severity; moreover, the mRNA and protein expression levels of RGN and PHB were significantly higher than those in the fibrosis group. CONCLUSION: Down regulation of regucalcin and prohibitin gene expression might contribute to the pathogenesis of liver cirrhosis. PMID- 25531380 TI - [Relation of polymorphisms of the XPD and GSTM1 genes with susceptibility to hepatocellular carcinoma in Qinghai Tibetans]. AB - OBJECTIVE: To explore the relationship of polymorphisms in the xeroderma pigmentosum group D (XPD) gene and the glutathione-S transferees M1 (GSTM1) gene with susceptibility to primary hepatic carcinoma (PHC) in Tibetans from the Qinghai region. METHODS: This case-control study compared equal groups (n=102 each) of patients with PHC and healthy individuals recruited from Qinghai, Tibet.PCR and denaturing high-performance liquid chromatography (DHPLC) was used to detect each participant's genotypes for the XPD and GSTM1 genes.Non conditional logistic regression modeling was used in multivariate analysis to evaluate the predictive value for PHC, to compare the risk of different genotypes for PHC, and to assess the risk of gene polymorphisms and environmental factors for PHC. RESULTS: Six factors, including smoking, carnivorous diet, alcohol consumption, hepatitis B virus (HBV) infection, immediate family members with HBV infection and immediate family members with history of PHC, were included in the logistic regression model (alpha =0.05).The XPD751C mutation genotype distribution frequencies were significantly higher in the cases than in the controls (21.6% vs. 10.8%, P=0.036). The risk of PHC increased 2.275 times (95% CI, 1.04-4.98). The frequencies of the GSTM1 genotype were remarkably higher in the cases than in the controls (60.4% vs. 39.6%, P=0.017), suggesting this as an exposure factor. Individuals with the GSTM1 genotype had 1.963 times higher risk of PHC than individuals without the GSTM1 genotype (95% CI, 1.124-3.428). With both the XPD751C mutation and the GSTM1 genotype as exposure factors, the risk incidence increased to 3.030 times (95% CI, 1.165-7.881), indicating that the combined genotypes have a synergistic effect.Application of unconditioned logistic stepwise regression analysis of the genotypes and environmental risk factors showed an interaction between the XPD751C mutation and HBV infection, alcohol consumption and immediate family members with history of PHC. In addition, an interaction between the GSTM1 genotype and HBV infection was found. CONCLUSION: Alcohol consumption, HBV infection and the presence of immediate family members with HBV infection are the main environmental risk factors of PHC in Qinghai Tibetans.Qinghai Tibetans who carry the XPD751C gene mutation and the GSTM 1 genotype are at increased risk of PHC, compared to individuals carrying only one or the other.The XPD751C mutation may increase risk of PHC when combined with the environmental factors. PMID- 25531381 TI - [The anti-apoptotic effect of cytoplasmic alpha-fetoprotein in hepatoma cells induced by all-trans retinoic acid involves activation of the PI3K/AKT signaling pathway]. AB - OBJECTIVE: To explore the effect of alpha-fetoprotein (AFP) on transduction of the PI3K/ AKT signal in hepatocellular carcinoma cells and the role played by AFP in resistance to cytotoxicity of all-trans retinoic acid (ATRA). METHODS: The effects of ATRA of human liver cancer cells was assessed using the BEL-7402 cell line with the MTT assay (to evaluate proliferation), microscopy (to evaluate morphology), flow cytometry (to evaluate apoptosis), laser confocal microscopy and coimmunoprecipitation (co-IP; to evaluate co-localization and interaction of AFP with PTEN), Western blotting (to evaluate expression of phosphorylated protein kinase B (pAKT) and Src, and RNA interference (RNAi)-mediated knockdown of AFP. Finally, application of the PI3K-specific inhibitor Ly294002 was used to monitor the influence of AFP in transduction of the PI3K signal pathway. RESULTS: The human hepatoma cell line BEL-7402 were resistant to ATRA cytotoxicity. PTEN and AFP co-localized in the cytoplasm, and co-IP indicated that AFP interacts with PTEN in BEL-7402 cells.RNAi knockdown of AFP expression led to reduced growth of BEL-7402 cells.BEL-7402 cells transfected with AFP-short interfering (si)RNA vectors showed enhanced sensitivity to ATRA and reduced expression of pAKT(Ser473) and Src; Ly294002 reduced the role of AFP in stimulating expression of pAKT(Ser473) and Src. CONCLUSION: AFP can activate transduction of the PI3K/AKT signal, and expression of AFP in hepatoma cells is a pivotal event for resisting ATRA-induced apoptosis. PMID- 25531382 TI - [Single-chain human anti-EGFR antibody/truncated protamine fusion protein carrying Hsp47 siRNA can induce apoptosis of human hepatic stellate cells]. AB - OBJECTIVE: To construct a single-chain human anti-EGFR antibody (scFv) and truncated protamine (tP) fusion protein, ScFv/tP, carrying small interfering (si)RNA directed against the heat shock protein Hsp47, a collagen-binding glycoprotein, in order to evaluate the role Hsp47 in apoptosis of hepatic stellate cells. METHODS: A single chain of the human variable fragment was obtained by phage display and fused with the tP gene and with or without (negative control) the Hsp47 siRNA sequences. Following expression and purification of the scFv/tP fusion protein and the scFv/tPHsp47 siRNA fusion protein, internalization capabilities were tested in isolated human hepatic stellate cells and the QSG-7701 human hepatocyte cells with visualization by immunofluorescent staining. The DNA binding ability of the fusion proteins were verified by gel shift assay.Following ScFv/tP-Hsp47 siRNA fusion protein transfection into the human hepatic stellate cells, the levels of Hsp47 mRNA and protein expression were tested by RT-PCR and Western blotting; in addition, effects of siRNA-mediated silencing of Hsp47 on cell proliferation and apoptosis were analyzed by the cell counting kit (CCK)-8, flow cytometry and Western blot detection of the apoptosis marker poly (ADP-ribose) polymerase (PARP). RESULTS: Indirect immunofluorescence revealed that the ScFv/tP fusion proteins were internalized into human hepatic stellate cells but not into the QSG-7701 cells.The ScFv/tP-Hsp47 siRNA fusion protein caused reduced expression of Hsp47 mRNA and protein expression in the human hepatic stellate cells, as well as increased the cells' apoptosis remarkably. CONCLUSION: The ScFv/tP fusion protein can be used as a transfection reagent to deliver Hsp47 siRNA into hepatic stellate cells and to mediate apoptosis via blockade of Hsp47 expression. PMID- 25531383 TI - [Liraglutide protects against nonalcoholic fatty liver disease in ApoE knockout mice with high-fat diet and silenced Acrp30 by increasing AMPK]. AB - OBJECTIVE: To investigate the mechanism of liraglutide-mediated protection against nonalcoholic fatty liver disease (NAFLD) using aApoE knockout (KO) mouse with high-fat diet (HFD) and Acrp30 knockdown. METHODS: Fifty-six male ApoE KO mice were divided into the following six modeling and experimental groups:regular chow fed (ApoE KO, n=10), HFD fed (HF, n=10), HFD+Adenovirus (Ad)-small hairpin (sh) Acrp30 (Ad-shAcrp30, n=10), HFD+Ad-shGreen Fluorescent Protein (GFP) (Ad shGFP, n=6), HFD+Ad-shAcrp30+liraglutide (liraglutide, n=10), and HFD+Ad shAcrp30+saline (saline, n=10). Weight-matched C57BL/6 mice on the regular chow diet were used as the control group (WT control, n=10).All mice were fed their assigned diet for 16 weeks.The Ad-shGFP or Ad-shAcrp30 was injected by tail vein at the end of 14 and 15 weeks.Mice in the liraglutide group received 1 mg/kg of the drug, twice daily, intraperitoneally for a total of 8 weeks (from the 9th to 16th week).Fasting blood samples were collected for testing levels of fasting plasma glucose (FPG), triglycerides (TGs), total cholesterol (TC), free fatty acid (FFA), alanine aminotransferase (ALT), Acrp30 and insulin.Liver tissue was procured for histological examination.Expression of mRNA was detected by real time RT-PC and of protein was detected by western blot analysis. RESULTS: The Ad shAcrp30 treated mice had reduced expression of Acrp30 at both the mRNA and protein levels in adipose tissues and plasma, as compared with the AdshGFP treated mice (all P < 0.01).Compared to the WT and ApoE KO groups, the HF group showed higher levels of FPG, FFA, TGs and TC (all P < 0.01); furthermore, the Ad shAcrp30 treatment compounded these changes.The Ad-shAcrp30 treated group had markedly higher hepatic TC and TGs than the HF group (P < 0.01 and P < 0.05).Oil Red O staining showed that there was more lipid droplets in the liver tissue of the Ad-shAcrp30 treated group than in that of the HF group (P < 0.01), and hematoxylin-eosin staining confirmed these results.Liraglutide treatment prevented the increase in body weight, FPG, FFA, TGs, TC and ALT levels, as compared to the saline controls (all P < 0.01), but the plasma Acrp30 levels and the Acrp30 mRNA and protein expression in adipose tissues were elevated (all P < 0.01).Oil-Red O staining indicated that the liraglutide group had a significantly lower hepatic lipid content than the saline group, and total hepatic TG and TC were reduced in the former group (P < 0.01 and P < 0.05).The liraglutide treatment significantly attenuated the mRNA expression of ACC and FAS (both P < 0.01) but increased AMPK phosphorylation (P < 0.01). CONCLUSION: Administration of liraglutide prevented the development of HFD-and hypoadiponectinemia-induced metabolic disturbance and accumulation of hepatic lipids in this mouse model system of NAFLD. PMID- 25531384 TI - [Role of miR-21 in rat hepatic oval cell proliferation and activation]. AB - OBJECTIVE: To investigate the possible mechanisms of miR-21-mediated regulation of proliferation and activation of hepatic oval cells. METHODS: The 2 acetamidofluorene/partial hepatectomy (2-AAF/PH) method was applied to generate hepatic oval cell activation model in male Sprague-Dawley rats; after the 7 days of 2-AAF/PH or PH alone (control), the rats were sacrificed at 0 h, 6 h, 12 h, 24 h, 72 h and 168 h. Expression of miR-21 was detected by real-time PCR and differences between groups were evaluated using the two-sample t-test. Differential transcription of miR-21 target genes was assessed bioinformatically, and with western blotting to detect changes in protein expression of the target gene. RESULTS: The rat hepatic oval cell activation model was successfully established.The 2-AAF/PH rats showed miR-21 expression beginning to increase at 12 h, peaking at 24 h, and decreasing thereafter until an increase at 168 h.For the control group, the miR-21 expression began to increase at 6 h, until 24 h when expression began steadily declining to reach the original level.Compared to the control group, the experimental group showed expression of miR-21 that was significantly less at 6 h (P=0.039, t =3.029) and significantly more at 24 h and 168 h (P=0.026, t =-3.433 and P=0.007, t =-5.105). Among the predicted target genes of miR-21 were WW domain containing E3 ubiquitin protein ligase 1 (WWD), Smad family member 7 (Smad7), and polybromo-1 (Pbrm1).Smad7 protein expression began to decrease at 6 h in the control group, until reaching its minimum at 24 h when it increased; in the experimental group, SMAD7 expression increased at 6 h, then began to decrease with the minimum detected at 168 hour.In the control group, the Smad7 mRNA expression decreased slightly at 6 h, then began to increase, reaching its peak at 24 h when the expression fell to the original level. In the experimental group, the Smad7 mRNA expression began to increase at 6 h and reached its peak at 24 h when it decreased; the expression was little more than its original level at 168 h.Smad7 protein expression was negatively correlated with miR-21, and Smad7 mRNA expression was positively correlated with miR-21 but negatively correlated with Smad7 protein expression. CONCLUSION: miR 21 may play a vital role in the activation and proliferation of hepatic oval cells.As a target gene of miR-21, Smad7 might be involved in the process. PMID- 25531385 TI - Nature of the chemical bond and origin of the inverted dipole moment in boron fluoride: a generalized valence bond approach. AB - The generalized product function energy partitioning (GPF-EP) method has been applied to investigate the nature of the chemical bond and the origin of the inverted dipole moment of the BF molecule. The calculations were carried out with GPF wave functions treating all of the core electrons as a single Hartree-Fock group and the valence electrons at the generalized valence bond perfect-pairing (GVB-PP) or full GVB levels, with the cc-pVTZ basis set. The results show that the chemical structure of both X (1)Sigma(+) and a (3)Pi states is composed of a single bond. The lower dissociation energy of the excited state is attributed to a stabilizing intraatomic singlet coupling involving the B 2sp-like lobe orbitals after bond dissociation. An increase of electron density on the B atom caused by the reorientation of the boron 2sp-like lobe orbitals is identified as the main responsible effect for the electric dipole inversion in the ground state of BF. Finally, it is shown that pi back-bonding from fluorine to boron plays a minor role in the electron density displacement to the bonding region in both states. Moreover, this effect is associated with changes in the quasi-classical component of the electron density only and does not contribute to covalency in either of the states. Therefore, at least for the case of the BF molecule, the term back bonding is misleading, since it does not contribute to the bond formation. PMID- 25531386 TI - A new decaoxidooctaborate(2-) anion, [B8O10(OH)6](2-): synthesis and characterization of [Co(en)3][B5O6(OH)4][B8O10(OH)6)].5H2O (en = 1,2 diaminoethane). AB - The synthesis and X-ray diffraction structure of [Co(en)3][B5O6(OH)4][B8O10(OH)6].5H2O (1) are reported. Compound 1 arises through a selective-templating process from a Dynamic Combinatorial Library of polyborate anions. Compound 1 contains two different polyborate species, with [B8O10(OH)6](2 ) being particularly novel. It is comprised of fused tetraborate and pentaborate anions with a 4-coordinate B atom and a 3-coordinate O atom in common. PMID- 25531387 TI - Identifying Staging Markers for Hepatocellular Carcinoma before Transarterial Chemoembolization: Comparison of Three-dimensional Quantitative versus Non-three dimensional Imaging Markers. AB - Purpose To test and compare the association between radiologic measurements of lesion diameter, volume, and enhancement on baseline magnetic resonance (MR) images with overall survival and tumor response in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Materials and Methods This HIPAA-compliant retrospective, single institution analysis was approved by the institutional review board, with waiver of informed consent. It included 79 patients with unresectable HCC who were treated with TACE. Baseline arterial phase contrast material-enhanced (CE) MR imaging was used to measure the overall and enhancing tumor diameters. A segmentation-based three-dimensional quantification of the overall and enhancing tumor volumes was performed in each patient. Numeric cutoff values (5 cm for diameters and 65 cm(3) for volumes) were used to stratify the patient cohort in two groups. Tumor response rates according to Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) guidelines were recorded for all groups. Survival was evaluated by using Kaplan-Meier analysis and was compared by using Cox proportional hazard ratios (HRs) after univariate and multivariate analysis. Results Stratification according to overall and enhancing tumor diameters did not result in a significant separation of survival curves (HR, 1.4; 95% confidence interval [CI]: 0.7, 2.5; P = .234; and HR, 1.6; 95% CI: 0.9, 2.8; P = .08, respectively). The stratification according to overall and enhancing tumor volume achieved significance (HR, 1.8; 95% CI: 0.9, 3.4; P = .022; and HR, 1.8; 95% CI: 1.1, 3.1; P = .017, respectively). As for tumor response, higher response rates were observed in smaller lesions compared with larger lesions, when the 5-cm threshold (27% vs 15% for mRECIST and 45% vs 24% for EASL) was used. Conclusion As opposed to anatomic tumor diameter as the most commonly used staging marker, volumetric assessment of lesion size and enhancement on baseline CE MR images is strongly associated with survival of patients with HCC who were treated with TACE. PMID- 25531388 TI - Prediction of vertebral failure load by using x-ray vector radiographic imaging. AB - PURPOSE: To examine whether x-ray vector radiographic (XVR) parameters could predict the biomechanically determined vertebral failure load. MATERIALS AND METHODS: Local institutional review boards approved the study and donors provided written informed consent before death. Twelve thoracic vertebral bodies were removed from three human cadavers and embedded in resin. XVR measurements were performed by using a Talbot-Lau grating interferometer with the beam direction in anterior-posterior and lateral direction. The mean anisotropy and the mean local average scattering power were calculated for a region of interest within each vertebra. Trabecular bone mineral density (BMD) was determined in each vertebra by using a clinical multidetector computed tomographic scanner. Failure load of the vertebral bodies was determined from destructive biomechanical tests. Statistical analyses were performed with statistical software with a two-sided Pvalue of .05 to calculate Pearson correlation coefficients and multiple regression model. RESULTS: Statistically significant correlations (P < .05) for failure load with XVR parameters in the lateral direction (r = -0.84 and 0.68 for anisotropy and local average scattering power, respectively) and for failure load and anisotropy in anteroposterior direction (r = -0.65) were found. A multiple regression model showed that the combination of the local average scattering power in lateral direction and BMD predicted failure load significantly better than BMD alone (adjusted R = 0.88 compared with 0.78, respectively; P < .001). CONCLUSION: The study results imply that XVR can improve the prediction of osteoporosis. PMID- 25531389 TI - Multiple locations of peptides in the hydrocarbon core of gel-phase membranes revealed by peptide (13)C to lipid (2)H rotational-echo double-resonance solid state nuclear magnetic resonance. AB - Membrane locations of peptides and proteins are often critical to their functions. Solid-state rotational-echo double-resonance (REDOR) nuclear magnetic resonance is applied to probe the locations of two peptides via peptide (13)CO to lipid (2)H distance measurements. The peptides are KALP, an alpha-helical membrane-spanning peptide, and HFP, the beta-sheet N-terminal fusion peptide of the HIV gp41 fusion protein that plays an important role in HIV-host cell membrane fusion. Both peptides are shown to have at least two distinct locations within the hydrocarbon core of gel-phase membranes. The multiple locations are attributed to snorkeling of lysine side chains for KALP and to the distribution of antiparallel beta-sheet registries for HFP. The relative population of each location is also quantitated. To the best of our knowledge, this is the first clear experimental support of multiple peptide locations within the membrane hydrocarbon core. These data are for gel-phase membranes, but the approach should work for liquid-ordered membranes containing cholesterol and may be applicable to liquid-disordered membranes with appropriate additional analysis to take into account protein and lipid motion. This paper also describes the methodological development of (13)CO-(2)H REDOR using the lyophilized I4 peptide that is alpha helical and (13)CO-labeled at A9 and (2)Halpha-labeled at A8. The I4 spins are well-approximated as an ensemble of isolated (13)CO-(2)H spin pairs each separated by 5.0 A with a 37 Hz dipolar coupling. A pulse sequence with rectangular 100 kHz (2)H pi pulses results in rapid and extensive buildup of REDOR (DeltaS/S0) with a dephasing time (tau). The buildup is well-fit by a simple exponential function with a rate of 24 Hz and an extent close to 1. These parameter values reflect nonradiative transitions between the (2)H spin states during the dephasing period. Each spin pair spends approximately two-thirds of its time in the (13)CO-(2)H (m = +/-1) states and approximately one-third of its time in the (13)CO-(2)H (m = 0) state and contributes to the DeltaS/S0 buildup during the former but not the latter time segments. PMID- 25531390 TI - Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease. AB - High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively. PMID- 25531391 TI - Clinical utility of multimodality imaging with dynamic contrast-enhanced MRI, diffusion-weighted MRI, and 18F-FDG PET/CT for the prediction of neck control in oropharyngeal or hypopharyngeal squamous cell carcinoma treated with chemoradiation. AB - The clinical usefulness of pretreatment imaging techniques for predicting neck control in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) treated with chemoradiation remains unclear. In this prospective study, we investigated the role of pretreatment dynamic contrast-enhanced perfusion MR imaging (DCE-PWI), diffusion-weighted MR imaging (DWI), and [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG PET)/CT derived imaging markers for the prediction of neck control in OHSCC patients treated with chemoradiation. Patients with untreated OHSCC scheduled for chemoradiation between August, 2010 and July, 2012 were eligible for the study. Clinical variables and the following imaging parameters of metastatic neck lymph nodes were examined in relation to neck control: transfer constant, volume of blood plasma, and volume of extracellular extravascular space (Ve) on DCE-PWI; apparent diffusion coefficient (ADC) on DWI; maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis on 18F-FDG PET/CT. There were 69 patients (37 with oropharynx SCC and 32 with hypopharynx SCC) with successful pretreatment DCE-PWI and DWI available for analysis. After a median follow-up of 31 months, 25 (36.2%) participants had neck failure. Multivariate analysis identified hemoglobin level <14.3 g/dL (P = 0.019), Ve <0.23 (P = 0.040), and ADC >1.14*10-3 mm2/s (P = 0.003) as independent prognostic factors for 3-year neck control. A prognostic scoring system was formulated by summing up the three significant predictors of neck control. Patients with scores of 2-3 had significantly poorer neck control and overall survival rates than patients with scores of 0-1. We conclude that hemoglobin levels, Ve, and ADC are independent pretreatment prognostic factors for neck control in OHSCC treated with chemoradiation. Their combination may identify a subgroup of patients at high risk of developing neck failure. PMID- 25531392 TI - Hepatitis C virus core protein triggers expansion and activation of CD4(+)CD25(+) regulatory T cells in chronic hepatitis C patients. AB - CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus (HCV)-specific T-cell responses and viral persistence in HCV infected individuals. We postulated that HCV core protein (HCVc) directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells (PBMCs) and sera were collected from 87 treatment-naive chronic HCV infected patients, CD4(+)CD25(+) Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. CD4(+), CD8(+), CD4(+)CD25(+) and CD4(+)CD25(-) T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor (TLR) ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4(+)CD25(+) Tregs. Mechanistic studies showed that HCVc, together with anti CD3 antibody, augmented CD4(+)CD25(+) Treg proliferation, but inhibited CD4(+)CD25(-) T-cell proliferation and IFN-gamma production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand (poly I:C) and the TLR4 ligand (lipopolysaccharide, LPS), the TLR2 ligand (lipoteichoic acid, LTA) and HCVc both inhibited TCR-induced CD4(+) T-cell proliferation and IFN-gamma secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4(+)CD25(+) Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV infected patients. PMID- 25531393 TI - Kruppel-like factor 4 negatively regulates cellular antiviral immune response. AB - Viral infection triggers activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce the expression of type I interferons (IFNs) and elicit innate antiviral response. In this report, we identified Kruppel-like factor 4 (KLF4) as a negative regulator of virus-triggered signaling. Overexpression of KLF4 inhibited virus-induced activation of ISRE and IFN-beta promoter in various types of cells, while knockdown of KLF4 potentiated viral infection-triggered induction of IFNB1 and downstream genes and attenuated viral replication. In addition, KLF4 was found to be localized in the cytosol and nucleus, and viral infection promoted the translocation of KLF4 from cytosol to nucleus. Upon virus infection, KLF4 was bound to the promoter of IFNB gene and inhibited the recruitment of IRF3 to the IFNB promoter. Our study thus suggests that KLF4 negatively regulates cellular antiviral response. PMID- 25531394 TI - The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis. PMID- 25531395 TI - Dengue virus serotype 3 infection in traveler returning from West Africa to Germany. PMID- 25531396 TI - Comparison of T stage, N stage, multifocality, and bilaterality in papillary thyroid carcinoma patients according to the presence of coexisting lymphocytic thyroiditis. AB - PURPOSE: This study aimed to assess the relationship between coexisting lymphocytic thyroiditis and T-N stages of papillary thyroid carcinoma (PTC) by histopathological analysis. MATERIALS AND METHODS: The study included 653 patients who underwent thyroid surgery for PTC at our hospital. Each case was classified as either Hashimoto's thyroiditis (HT), non-Hashimoto type of lymphocytic thyroiditis (NHLT), or normal according to the histopathology of thyroid parenchyma. Patient age, gender, surgical modality, location, T stage, N stage, multifocality and bilaterality were compared according to the histopathology. RESULTS: The prevalence of coexisting lymphocytic thyroiditis was 25.8% (169/653); HT (7.5%, 49/653) and NHLT (18.3%, 120/653). There were no significant differences in T stage, N stage, multifocality and bilaterality with regard to coexisting lymphocytic thyroiditis, regardless of whether HT and NHLT were considered collectively or discretely. Primary tumor size (p < 0.0001), location (p = 0.0011), N stage (p < 0.0001), multifocality (p < 0.0001) and bilaterality (p < 0.0001) differed significantly according to T stage, and gender (p = 0.0193), primary tumor size (p < 0.0001), T stage (p < 0.0001), multifocality (p < 0.0001) and bilaterality (p < 0.0001) differed significantly according to N stage. CONCLUSIONS: PTC patients with coexisting lymphocytic thyroiditis did not differ from those with normal parenchyma in terms of T stage, N stage, multifocality and bilaterality. PMID- 25531397 TI - Force-induced dynamical properties of multiple cytoskeletal filaments are distinct from that of single filaments. AB - How cytoskeletal filaments collectively undergo growth and shrinkage is an intriguing question. Collective properties of multiple bio-filaments (actin or microtubules) undergoing hydrolysis have not been studied extensively earlier within simple theoretical frameworks. In this paper, we study the collective dynamical properties of multiple filaments under force, and demonstrate the distinct properties of a multi-filament system in comparison to a single filament. Comparing stochastic simulation results with recent experimental data, we show that multi-filament collective catastrophes are slower than catastrophes of single filaments. Our study also shows further distinctions as follows: (i) force-dependence of the cap-size distribution of multiple filaments are quantitatively different from that of single filaments, (ii) the diffusion constant associated with the system length fluctuations is distinct for multiple filaments, and (iii) switching dynamics of multiple filaments between capped and uncapped states and the fluctuations therein are also distinct. We build a unified picture by establishing interconnections among all these collective phenomena. Additionally, we show that the collapse times during catastrophes can be sharp indicators of collective stall forces exceeding the additive contributions of single filaments. PMID- 25531398 TI - Characteristics and long-term outcome of patients with systemic immunoglobulin light-chain amyloidosis. AB - BACKGROUND/AIMS: Immunoglobulin light-chain (AL) amyloidosis is a systemic disorder that causes progressive organ dysfunction. The optimal treatment strategy requires accurate patient stratification with an emphasis on the extent of cardiac involvement. Reports on its prognosis are sparse and predominantly originate from highly selected centers. We aimed to evaluate patient characteristics and outcomes in a cohort treated at a single center. METHODS: This is a single-center retrospective study of 63 consecutive patients diagnosed with AL amyloidosis between January 2000 and December 2012. Patients were evaluated by treatment strategy and cardiac involvement. RESULTS: The mean age at diagnosis was 61.4 years (+/-8.9), and 39 patients (62%) were male. Thirty-two (51%) patients presented with cardiac amyloid involvement (CA) and the remaining 31 (49%) had noncardiac amyloidosis (NCA). The median follow-up time was 12.7 months (0.3-90.8), and 38 (60%) patients died during follow-up. The median overall survival (OS) was 29 months (95% CI 12.1-57.2) and the OS was not significantly lower for patients with CA compared to NCA (log-rank = 0.21). CONCLUSION: The prognosis in AL amyloidosis is grave, but the outcome with treatment in the current series was comparable to those in series from larger centers. CA did not significantly predict the OS. PMID- 25531399 TI - Rapid urbanization of red foxes in Estonia: distribution, behaviour, attacks on domestic animals, and health-risks related to zoonotic diseases. AB - Urban areas are becoming increasingly important for wildlife as diminishing natural habitats no longer represent a suitable environment for many species. Red foxes (Vulpes vulpes) are nowadays common in many cities worldwide, and in recent years they have colonized urban areas in Estonia. We used a public web-based questionnaire approach to evaluate the distribution and behaviour of Estonian urban foxes, to detect related problems and to assess health risks to humans and domestic animals. In total, 1205 responses were collected throughout the country. Foxes have colonized the majority of Estonian towns (33 out of 47) in a relatively short period of time, and have already established breeding dens in several towns. Despite their recent arrival, the behaviour of Estonian urban foxes is similar to that reported in longer-established urban fox populations: they are mostly active during night-time, often visit city centres and some also have dens in such locations. Certain characteristics of urban foxes serve as a basis for conflict with humans: foxes have entered houses and attacked domestic animals, killing cats and poultry. About 8% of reported foxes exhibited symptoms of sarcoptic mange, a disease that also infects domestic animals, especially dogs. The proportion of mange-infected foxes was higher in large urban areas. In addition to mange, a substantial fraction of red foxes in Estonia are known to be infected with the life-threatening tapeworm Echinococcus multilocularis, the causative agent of alveolar echinococcosis. Therefore, urban foxes may represent a source of serious infectious disease for pets and humans. PMID- 25531400 TI - Diagnostic and predictive accuracy of blood pressure screening methods with consideration of rescreening intervals: a systematic review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Elevated blood pressure (BP) is the largest contributing risk factor to all-cause and cardiovascular mortality. PURPOSE: To update a systematic review on the benefits and harms of screening for high BP in adults and to summarize evidence on rescreening intervals and diagnostic and predictive accuracy of different BP methods for cardiovascular events. DATA SOURCES: Selected databases searched through 24 February 2014. STUDY SELECTION: Fair- and good-quality trials and diagnostic accuracy and cohort studies conducted in adults and published in English. DATA EXTRACTION: One investigator abstracted data, and a second checked for accuracy. Study quality was dual-reviewed. DATA SYNTHESIS: Ambulatory BP monitoring (ABPM) predicted long-term cardiovascular outcomes independently of office BP (hazard ratio range, 1.28 to 1.40, in 11 studies). Across 27 studies, 35% to 95% of persons with an elevated BP at screening remained hypertensive after nonoffice confirmatory testing. Cardiovascular outcomes in persons who were normotensive after confirmatory testing (isolated clinic hypertension) were similar to outcomes in those who were normotensive at screening. In 40 studies, hypertension incidence after rescreening varied considerably at each yearly interval up to 6 years. Intrastudy comparisons showed at least 2-fold higher incidence in older adults, those with high-normal BP, overweight and obese persons, and African Americans. LIMITATION: Few diagnostic accuracy studies of office BP methods and protocols in untreated adults. CONCLUSION: Evidence supports ABPM as the reference standard for confirming elevated office BP screening results to avoid misdiagnosis and overtreatment of persons with isolated clinic hypertension. Persons with BP in the high-normal range, older persons, those with an above-normal body mass index, and African Americans are at higher risk for hypertension on rescreening within 6 years than are persons without these risk factors. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 25531401 TI - Stochastic fluctuations and distributed control of gene expression impact cellular memory. AB - Despite the stochastic noise that characterizes all cellular processes the cells are able to maintain and transmit to their daughter cells the stable level of gene expression. In order to better understand this phenomenon, we investigated the temporal dynamics of gene expression variation using a double reporter gene model. We compared cell clones with transgenes coding for highly stable mRNA and fluorescent proteins with clones expressing destabilized mRNA-s and proteins. Both types of clones displayed strong heterogeneity of reporter gene expression levels. However, cells expressing stable gene products produced daughter cells with similar level of reporter proteins, while in cell clones with short mRNA and protein half-lives the epigenetic memory of the gene expression level was completely suppressed. Computer simulations also confirmed the role of mRNA and protein stability in the conservation of constant gene expression levels over several cell generations. These data indicate that the conservation of a stable phenotype in a cellular lineage may largely depend on the slow turnover of mRNA-s and proteins. PMID- 25531402 TI - A new cecal slurry preparation protocol with improved long-term reproducibility for animal models of sepsis. AB - Sepsis, a life-threatening systemic inflammatory response syndrome induced by infection, is widely studied using laboratory animal models. While cecal-ligation and puncture (CLP) is considered the gold standard model for sepsis research, it may not be preferable for experiments comparing animals of different size or under different dietary regimens. By comparing cecum size, shape, and cecal content characteristics in mice under different experimental conditions (aging, diabetes, pancreatitis), we show that cecum variability could be problematic for some CLP experiments. The cecal slurry (CS) injection model, in which the cecal contents of a laboratory animal are injected intraperitoneally to other animals, is an alternative method for inducing polymicrobial sepsis; however, the CS must be freshly prepared under conventional protocols, which is a major disadvantage with respect to reproducibility and convenience. The objective of this study was to develop an improved CS preparation protocol that allows for long-term storage of CS with reproducible results. Using our new CS preparation protocol we found that bacterial viability is maintained for at least 6 months when the CS is prepared in 15% glycerol-PBS and stored at -80 degrees C. To test sepsis-inducing efficacy of stored CS stocks, various amounts of CS were injected to young (4-6 months old), middle-aged (12-14 months old), and aged (24-26 months old) male C57BL/6 mice. Dose- and age-dependent mortality was observed with high reproducibility. Circulating bacteria levels strongly correlated with mortality suggesting an infection-mediated death. Further, injection with heat-inactivated CS resulted in acute hypothermia without mortality, indicating that CS-mediated death is not due to endotoxic shock. This new CS preparation protocol results in CS stocks which are durable for freezing preservation without loss of bacterial viability, allowing experiments to be performed more conveniently and with higher reproducibility than before. PMID- 25531403 TI - Increased outbreaks associated with nonpasteurized milk, United States, 2007 2012. AB - The number of US outbreaks caused by nonpasteurized milk increased from 30 during 2007-2009 to 51 during 2010-2012. Most outbreaks were caused by Campylobacter spp. (77%) and by nonpasteurized milk purchased from states in which nonpasteurized milk sale was legal (81%). Regulations to prevent distribution of nonpasteurized milk should be enforced. PMID- 25531404 TI - New 15-membered tetraaza (N4) macrocyclic ligand and its transition metal complexes: spectral, magnetic, thermal and anticancer activity. AB - Novel tetraamidemacrocyclic 15-membered ligand [L] i.e. naphthyl dibenzo[1,5,9,12]tetraazacyclopentadecine-6,10,11,15-tetraoneand its transition metal complexes with Fe(II), Co(II), Ni(II), Cu(II), Ru(III) and Pd(II) have been synthesized and characterized by elemental analysis, spectral, thermal as well as magnetic and molar conductivity measurements. On the basis of analytical, spectral (IR, MS, UV-Vis, (1)H NMR and EPR) and thermal studies distorted octahedral or square planar geometry has been proposed for the complexes. The antitumor activity of the synthesized ligand and some complexes against human breast cancer cell lines (MCF-7) and human hepatocarcinoma cell lines (HepG2) has been studied. The complexes (IC50=2.27-2.7, 8.33-31.1MUg/mL, respectively) showed potent antitumor activity, towards the former cell lines comparable with their ligand (IC50=13, 26MUg/mL, respectively). The results show that the activity of the ligand towards breast cancer cell line becomes more pronounced and significant when coordinated to the metal ion. PMID- 25531405 TI - Synthesis, characterization and photocatalytic applications of N-, S-, and C doped SnO2 nanoparticles under ultraviolet (UV) light illumination. AB - N-, S-, and C-doped SnO2 nanoparticles were synthesized via a precipitation method and were characterized by X-ray diffractometer (XRD), X-ray photoelectron spectra (XPS), scanning electron microscopy (SEM), Transmission Electron Microscope (TEM), UV-vis diffuse reflectance spectral (UV-vis DRS) and Brunauer Emmett-Teller (BET) techniques. The photocatalytic activities of these SnO2 samples were investigated with methyl orange as the organic pollutant under UV light illumination. UV-vis spectroscopy demonstrated that dopants N,S,C-species can shift the absorption edge to the near UV and visible light region. N,S,C-SnO2 nanoparticles achieved the best photocatalytic efficiency and the most optimal doping ratio was 3 (T/S). The degradation of methyl orange by N,S,C-SnO2 nanoparticles fitted well with the Langmuir-Hinshelwood kinetics model. The results of subsequent experiments indicate that enhanced adsorption ability of light and high separation rate of photo induced charge carriers all play an major role in promotion of photocatalytic activity of N,S,C-SnO2 nanoparticles. PMID- 25531406 TI - Disparity in disinfection byproducts concentration between hot and cold tap water. AB - The quality of water entering a distribution system may differ substantially from the quality at the point of exposure to the consumer. This study investigated temporal variations in the levels of regulated and non-regulated disinfection byproducts (DBPs) in cold and hot tap water in a home on a medium-sized municipal water system. In addition, samples were collected directly from the water plant with some being held in accordance with a simulated distribution system (SDS) test protocol. The location for this work was a system in western Massachusetts, USA that uses free chlorine as a final disinfectant. Very little short term variability of DBPs at the point of entry (POE) was observed. The concentration of DBPs in the time-variable SDS test was similar to concentrations in the cold water tap. For most DBPs, the concentrations continued to increase as the cold water tap sample was held for the time-variable SDS incubation period. However, the impact of heating on DBP levels was compound specific. For example, the concentrations of trihalomethanes (THMs), dichloroacetic acid (DCAA) and chloropicrin (CP) were substantially higher in the hot water tap than in the cold water time-variable SDS samples. In contrast, the concentration of trichloroacetic acid (TCAA) was lower in the heated hot tap water, but about equal to that observed in the cold tap water. The situation was more pronounced for dichloroacetonitrile (DCAN), bromodichloroacetic acid (BDCAA), bromochloroacetic acid (BCAA) and 1,1,1-trichloropropanone (TCP), which all showed lower concentrations in the hot water then in either of the cold water samples (instantaneous or time-variable SDS). The latter was viewed as a clear indication of thermally-induced decomposition. The ratio of unknown total organic halide (UTOX) to TOX was substantially lower in the hot tap water as the THM to TOX ratio became correspondingly larger. The results of this study show that DBP exposure in the home is not well represented by concentrations measured in cold water taps where most compliance monitoring is done. PMID- 25531408 TI - How to measure metabolic fluxes: a taxonomic guide for (13)C fluxomics. AB - Metabolic reaction rates (fluxes) contribute fundamentally to our understanding of metabolic phenotypes and mechanisms of cellular regulation. Stable isotope based fluxomics integrates experimental data with biochemical networks and mathematical modeling to 'measure' the in vivo fluxes within an organism that are not directly observable. In recent years, (13)C fluxomics has evolved into a technology with great experimental, analytical, and mathematical diversity. This review aims at establishing a unified taxonomy by means of which the various fluxomics methods can be compared to each other. By linking the developed modeling approaches to recent studies, their challenges and opportunities are put into perspective. The proposed classification serves as a guide for scientific 'travelers' who are striving to resolve research questions with the currently available (13)C fluxomics toolset. PMID- 25531407 TI - mRNP granules. Assembly, function, and connections with disease. AB - Messenger ribonucleoprotein (mRNP) granules are dynamic, self-assembling structures that harbor non-translating mRNAs bound by various proteins that regulate mRNA translation, localization, and turnover. Their importance in gene expression regulation is far reaching, ranging from precise spatial-temporal control of mRNAs that drive developmental programs in oocytes and embryos, to similarly exquisite control of mRNAs in neurons that underpin synaptic plasticity, and thus, memory formation. Analysis of mRNP granules in their various contexts has revealed common themes of assembly, disassembly, and modes of mRNA regulation, yet new studies continue to reveal unexpected and important findings, such as links between aberrant mRNP granule assembly and neurodegenerative disease. Continued study of these enigmatic structures thus promises fascinating new insights into cellular function, and may also suggest novel therapeutic strategies in various disease states. PMID- 25531409 TI - Smart polymeric nanoparticles for cancer gene delivery. AB - The massive amount of human genetic information already available has accelerated the identification of target genes, making gene and nucleic acid therapy the next generation of medicine. Nanoparticle (NP)-based anticancer gene therapy treatment has received significant interest in this evolving field. Recent advances in vector technology have improved gene transfection efficiencies of nonviral vectors to a level similar to viruses. This review serves as an introduction to surface modifications of NPs based on polymeric structural improvements and target moieties. A discussion regarding the future perspective of multifunctional NPs in cancer therapy is also included. PMID- 25531410 TI - Did androgen-binding protein paralogs undergo neo- and/or Subfunctionalization as the Abp gene region expanded in the mouse genome? AB - The Androgen-binding protein (Abp) region of the mouse genome contains 30 Abpa genes encoding alpha subunits and 34 Abpbg genes encoding betagamma subunits, their products forming dimers composed of an alpha and a betagamma subunit. We endeavored to determine how many Abp genes are expressed as proteins in tears and saliva, and as transcripts in the exocrine glands producing them. Using standard PCR, we amplified Abp transcripts from cDNA libraries of C57BL/6 mice and found fifteen Abp gene transcripts in the lacrimal gland and five in the submandibular gland. Proteomic analyses identified proteins corresponding to eleven of the lacrimal gland transcripts, all of them different from the three salivary ABPs reported previously. Our qPCR results showed that five of the six transcripts that lacked corresponding proteins are expressed at very low levels compared to those transcripts with proteins. We found 1) no overlap in the repertoires of expressed Abp paralogs in lacrimal gland/tears and salivary glands/saliva; 2) substantial sex-limited expression of lacrimal gland/tear expressed-paralogs in males but no sex-limited expression in females; and 3) that the lacrimal gland/tear expressed-paralogs are found exclusively in ancestral clades 1, 2 and 3 of the five clades described previously while the salivary glands/saliva expressed-paralogs are found only in clade 5. The number of instances of extremely low levels of transcription without corresponding protein production in paralogs specific to tears and saliva suggested the role of subfunctionalization, a derived condition wherein genes that may have been expressed highly in both glands ancestrally were down-regulated subsequent to duplication. Thus, evidence for subfunctionalization can be seen in our data and we argue that the partitioning of paralog expression between lacrimal and salivary glands that we report here occurred as the result of adaptive evolution. PMID- 25531411 TI - The perception of naturalness correlates with low-level visual features of environmental scenes. AB - Previous research has shown that interacting with natural environments vs. more urban or built environments can have salubrious psychological effects, such as improvements in attention and memory. Even viewing pictures of nature vs. pictures of built environments can produce similar effects. A major question is: What is it about natural environments that produces these benefits? Problematically, there are many differing qualities between natural and urban environments, making it difficult to narrow down the dimensions of nature that may lead to these benefits. In this study, we set out to uncover visual features that related to individuals' perceptions of naturalness in images. We quantified naturalness in two ways: first, implicitly using a multidimensional scaling analysis and second, explicitly with direct naturalness ratings. Features that seemed most related to perceptions of naturalness were related to the density of contrast changes in the scene, the density of straight lines in the scene, the average color saturation in the scene and the average hue diversity in the scene. We then trained a machine-learning algorithm to predict whether a scene was perceived as being natural or not based on these low-level visual features and we could do so with 81% accuracy. As such we were able to reliably predict subjective perceptions of naturalness with objective low-level visual features. Our results can be used in future studies to determine if these features, which are related to naturalness, may also lead to the benefits attained from interacting with nature. PMID- 25531412 TI - Chemical composition and biological activity of four salvia essential oils and individual compounds against two species of mosquitoes. AB - The chemical compositions of essential oils obtained from four species of genus Salvia were analyzed by gas chromatography with a flame ionization detector (GC FID) and gas chromatography-mass spectrometry (GC-MS). The main compounds identified from Salvia species essential oils were as follows: 1,8-cineole (71.7%), alpha-pinene (5.1%), camphor (4.4%), and beta-pinene (3.8%) in Salvia apiana; borneol (17.4%), beta-eudesmol (10.4%), bornyl acetate (5%), and guaiol (4.8%) in Salvia elegans; bornyl acetate (11.4%), beta-caryophyllene (6.5%), caryophyllene oxide (13.5%), and spathulenol (7.0%) in Salvia leucantha; alpha thujene (25.8%), viridiflorol (20.4%), beta-thujene (5.7%), and camphor (6.4%) in Salvia officinalis. In biting-deterrent bioassays, essential oils of S. leucantha and S. elegans at 10 MUg/cm(2) showed activity similar to that of DEET (97%, N, N diethyl-m-toluamide) in two species of mosquitoes, whereas the activities of S. officinalis and S. apiana essential oils were lower than those of the other oils or DEET. Pure compounds beta-eudesmol and guaiol showed biting-deterrent activity similar to DEET at 25 nmol/cm(2), whereas the activity of 13-epi-manool, caryophyllene oxide, borneol, bornyl acetate, and beta-caryophyllene was significantly lower than that of beta-eudesmol, guaiol, or DEET. All essential oils showed larvicidal activity except that of S. apiana, which was inactive at the highest dose of 125 ppm against both mosquito species. On the basis of 95% CIs, all of the essential oils showed higher toxicity in Anopheles quadrimaculatus than in Aedes aegypti. The essential oil of S. leucantha with an LC50 value of 6.2 ppm showed highest toxicity in An. quadrimaculatus. PMID- 25531413 TI - In vitro fertilization outcome following embryo transfer with or without preinstillation of human chorionic gonadotropin into the uterine cavity: a randomized controlled trial. AB - BACKGROUND: Intrauterine injection of human chorionic gonadotropin (hCG) at embryo transfer (ET) has been shown to improve the outcome of assisted reproductive techniques. The aim of this study was to confirm previous findings. METHODS: In this randomized controlled trial, 483 infertile women who were candidates for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) for the first time were randomly assigned to receive an intrauterine injection of 500 IU hCG or placebo (tissue culture media) before ET. The main outcome measures were implantation and clinical pregnancy rates. RESULTS: Both the hCG-treated group (n = 240) and control group (n = 243) were similar at baseline in terms of demographic and obstetrical characteristics. There were significant differences between the two groups regarding the implantation rate (23.6 vs. 12.2%, p < 0.001), pregnancy rate (54.6 vs. 35.8%, p < 0.001), clinical pregnancy rate (50 vs. 32.1%, p < 0.001), ongoing pregnancy rate (15.3 vs. 9.2%, p < 0.001) and live delivery rate (14.3 vs. 8.4%, p < 0.001). The rate of fertilization and abortion rates were not statistically different. CONCLUSION: Intrauterine injection of hCG before ET improves implantation and pregnancy rates and may be considered an adjuvant in IVF/ICSI. PMID- 25531414 TI - A multifunctional drug combination shows highly potent therapeutic efficacy against human cancer xenografts in athymic mice. AB - The tumor microenvironment plays a crucial role during tumor development. Integrated combination of drugs that target tumor microenvironment is a promising approach to anticancer therapy. Here, we report a multifunctional combination of low-cytotoxic drugs composed of dipyridamole, bestatin and dexamethasone (DBDx) which mainly acts on the tumor microenvironment shows highly potent antitumor efficacy in vivo. In mouse hepatoma H22 model, the triple drug combination showed synergistic and highly potent antitumor efficacy. The combination indices of various combinations of the triple drugs were between 0.2 and 0.5. DBDx inhibited the growth of a panel of human tumor xenografts and showed no obvious systemic toxicity. At tolerated doses, DBDx suppressed the growth of human hepatocellular carcinoma BEL-7402, HepG2, and lung adenocarcinoma A549 xenografts by 94.5%, 93.7% and 96.9%, respectively. Clonogenic assay demonstrated that DBDx showed weak cytotoxicity. Western blot showed that Flk1 and Nos3 were down-regulated in the DBDx-treated group. Proteomic analysis showed that DBDx mainly affected the metabolic process and immune system process; in addition, the angiogenesis and VEGF signaling pathway were also affected. Conclusively, DBDx, a multifunctional drug combination of three low-cytotoxic drugs, shows synergistic and highly potent antitumor efficacy evidently mediated by the modulation of tumor microenvironment. Based on its low-cytotoxic attributes and its broad-spectrum antitumor therapeutic efficacy, this multifunctional combination might be useful in the treatment of cancers, especially those refractory to conventional chemotherapeutics. PMID- 25531415 TI - Influence of the metal precursor on the catalytic behavior of Pt/ceria catalysts in the preferential oxidation of CO in the presence of H2 (PROX). AB - The effect of the metal precursor (presence or absence of chlorine) on the preferential oxidation of CO in the presence of H2 over Pt/CeO2 catalysts has been studied. The catalysts are prepared using (Pt(NH3)4)(NO3)2 and H2PtCl6, as precursors, in order to ascertain the effect of the chlorine species on the chemical properties of the support and on the catalytic behavior of these systems in the PROX reaction. The results show that chloride species exert an important effect on the redox properties of the oxide support due to surface chlorination. Consequently, the chlorinated catalyst exhibits a poorer catalytic activity at low temperatures compared with the chlorine-free catalyst, and this is accompanied by a higher selectivity to CO2 even at high reaction temperatures. It is proposed that the CO oxidation mechanism follows different pathways on each catalyst. PMID- 25531416 TI - Antimicrobial properties of nano-silver: a cautionary approach to ionic interference. AB - HYPOTHESIS: Metallic nanoparticles such as nano-silver have found many applications as alternative antimicrobials in recent years. However methods for determining their proposed antimicrobial activity have received little attention to date. The disk diffusion assay is commonly used as a demonstration of antimicrobial properties and is a regular feature in synthetic nanoparticle papers. The aim of this study was to assess its effectiveness in demonstrating the "nanoparticle specific" antimicrobial properties in the absence of ionic contributions from unreacted reducing agents and or impurities. EXPERIMENTS: The disk diffusion assay was carried out on a range of silver nanoparticles, both in house synthesised and commercially available, using Escherichia coli ATCC 25922 as a model organism. RESULTS: Capped and purified nanoparticles show no antimicrobial activity despite claims to the contrary for this assay. Results will be discussed in terms of the need for researchers without a background in microbiology to understand the mechanism of antimicrobial action before choosing an assay. Also discussed is the importance understanding the physiochemical characteristics of when interpreting results. Finally the relevance of the results in terms establishing protocols for method development for 'nanoparticle specific' antimicrobial properties will also be considered. PMID- 25531417 TI - Effective removal of zinc (II) from aqueous solutions by tricalcium aluminate (C3A). AB - Recently, studies have identified high zinc levels in various environmental resources, and excessive intake of zinc has long been considered to be harmful to human health. The aim of this research was to investigate the effectiveness of tricalcium aluminate (C3A) as a removal agent of zinc from aqueous solution. Inductively coupled plasma-atomic emission spectrometer (ICP-AES), X-ray diffraction (XRD) and scanning electron microscopy (SEM) have been used to characterize such removal behavior. The effects of various factors such as pH influence, temperature and contact time were investigated. The adsorption capacity of C3A for Zn(2+) was computed to be up to 13.73 mmol g(-1), and the highest zinc removal capacity was obtained when the initial pH of Zn(NO3)2 solution was between 6.0 and 7.0, with temperature around 308 K. The XRD analysis showed that the resultant products were ZnAl-LDHs. Combined with the analysis of solution component, it was proved the existence of both precipitation and cation exchange in the removal process. From the experimental results, it was clear that C3A could be potentially used as a cost-effective material for the removal of zinc in aqueous environment. PMID- 25531418 TI - Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status. AB - Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P value = 1.7 * 10(-6)), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies. PMID- 25531419 TI - Manganese-Enhanced Magnetic Resonance Imaging of Traumatic Brain Injury. AB - Calcium dysfunction is involved in secondary traumatic brain injury (TBI). Manganese-enhanced MRI (MEMRI), in which the manganese ion acts as a calcium analog and a MRI contrast agent, was used to study rats subjected to a controlled cortical impact. Comparisons were made with conventional T2 MRI, sensorimotor behavior, and immunohistology. The major findings were: (1) Low-dose manganese (29 mg/kg) yielded excellent contrast with no negative effects on behavior scores relative to vehicle; (2) T1-weighted MEMRI was hyperintense in the impact area at 1-3 h, hypointense on day 2, and markedly hypointense with a hyperintense area surrounding the core on days 7 and/or 14, in contrast to the vehicle group, which did not show a biphasic profile; (3) in the hyperacute phase, the area of hyperintense T1-weighted MEMRI was larger than that of T2 MRI; (4) glial fibrillary acidic protein staining revealed that the MEMRI signal void in the impact core and the hyperintense area surrounding the core on day 7 and/or 14 corresponded to tissue cavitation and reactive gliosis, respectively; (5) T2 MRI showed little contrast in the impact core at 2 h, hyperintense on day 2 (indicative of vasogenic edema), hyperintense in some animals but pseudonormalized in others on day 7 and/or 14; (6) behavioral deficit peaked on day 2. We concluded that MEMRI detected early excitotoxic injury in the hyperacute phase, preceding vasogenic edema. In the subacute phase, MEMRI detected contrast consistent with tissue cavitation and reactive gliosis. MEMRI offers novel contrasts of biological processes that complement conventional MRI in TBI. PMID- 25531420 TI - Dentoskeletal changes following mini-implant molar intrusion in anterior open bite patients. AB - OBJECTIVE: To evaluate skeletal and dental changes after intrusion of the maxillary molars in subjects with anterior open bite. MATERIALS AND METHODS: This retrospective cephalometric study evaluated skeletal and dental changes resulting from the use of maxillary orthodontic mini-implants in 31 consecutively treated patients. Radiographs were taken at the start and end of maxillary molar intrusion to evaluate the associated changes. Statistical analysis was performed using a one-sample t-test. RESULTS: The mean treatment observation time was 1.31 years (SD = 2.03). The maxillary first molars (P = 0.0026) and second molars (P = 0.039) were intruded. However, the mandibular first molars (P = 0.0004) and second molars (P = 0.003) erupted in adolescent patients. Both the maxillary and mandibular first molars inclined distally (P = 0.025 and P = 0.044, respectively). The mandibular plane angle decreased (P = 0.036), lower facial height decreased (P = 0.002), and the occlusal plane angle increased (P = 0.009). The overbite increased (P < .0001). The ANB angle decreased (P < .0001). Mandibular dental and skeletal changes were more apparent in adolescents, while adults tended toward maxillary changes. CONCLUSIONS: Vertical traction from orthodontic mini-implants reduces the maxillary posterior dentoalveolar height, thereby assisting orthodontic closure of anterior open bite. However, simultaneous eruption or extrusion of the mandibular molars should be controlled. Adolescent patients tend to demonstrate more favorable effects of mandibular autorotation than do adults. PMID- 25531421 TI - Impact of malocclusion on oral health-related quality of life in young adults. AB - OBJECTIVE: To assess oral health-related quality of life (OHRQoL) in young adult patients with malocclusion and to measure the association between orthodontic treatment need and OHRQoL. MATERIALS AND METHODS: The study sample comprised 190 young adults aged 18 to 25 years who were attending orthodontic clinics at the Faculty of Dentistry. The Index of Orthodontic Treatment Need-Dental Health Component was used to measure orthodontic treatment need. Each participant was assessed for OHRQoL before and after treatment by using the Oral Health Impact Profile, Chinese version (OHIP-14). RESULTS: Patients who had little or no, borderline, and actual need for orthodontic treatment represented 21.6%, 50.5%, and 27.9% of the total sample, respectively. OHRQoL (total OHIP-14 score and score for each domain) improved after treatment (P < .05). Significant differences in summary OHIP-14 scores were apparent with respect to orthodontic treatment need. Participants with high treatment need reported a significantly greater negative impact on the overall OHRQoL score. The greatest impact was seen in the psychological discomfort domain and the psychological disability domain. CONCLUSION: Malocclusion has a significant negative impact on OHRQoL. This is greatest for the psychological discomfort and psychological disability domains. The orthodontic treatment of malocclusion improves OHRQoL of patients. PMID- 25531422 TI - Epidemiology and genetics of hypodontia and microdontia: a study of twin families. AB - OBJECTIVE: To identify genetic and environmental factors contributing to hypodontia and microdontia by using Korean twin family data. MATERIALS AND METHODS: A total of 1267 individuals (525 men and 742 women; 180 monozygotic twins [MZ] and 43 dizygotic twins [DZ] from 282 families) underwent an oral examination as part of the Healthy Twin Study in Korea. Dental anomalies classified as hypodontia or microdontia were diagnosed using radiographs and clinical examinations. In order to estimate genetic contributions to dental anomalies, we estimated the pairwise concordance rate (PCR), recurrence risk ratio (RRR), and heritability (h2). RESULTS: The prevalence of hypodontia and microdontia was 3.55% and 3.00%, respectively. MZ had the highest PCR and RRR (13.0-15.3). The PCR and RRR values for both anomalies were much higher for DZ (5.0-11.9) than for siblings (1.4-2.6), despite the fact that DZ pairs and sibling pairs share 50% genetic identity. Further genetic analysis revealed both an additive genetic effect (0.38 when hypodontia and microdontia were pooled) and a strong "twin effect" (0.52 when hypodontia and microdontia were pooled). CONCLUSIONS: This twin-based study revealed that the formation of dental anomalies is affected by both genetic and environmental factors, and that the impact of these factors varies according to the specific dental anomaly. PMID- 25531423 TI - Towards a better understanding of caregiver distress in early psychosis: a systematic review of the psychological factors involved. AB - OBJECTIVES: We sought to review empirical studies of psychological factors accounting for distress in caregivers of young people with early psychosis. METHOD: Following the PRISMA guidelines, we included studies that empirically tested psychological models of caregiver distress in early psychosis by searching the following databases up until March 2014: PsycINFO, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL). This was followed by additional manual searches of reference lists and relevant journals. RESULTS: The search identified 15 papers describing 13 studies together comprising 1056 caregivers of persons with early psychosis. The mean age of caregivers was 47.2years (SD=9.8), of whom 71.5% were female and 74.4% were parents. Nine different psychological variables were examined in the included studies, which were categorised in the following non-mutually exclusive groups: coping, appraisal/attribution and interpersonal response. There was considerable data to support the link between distress and psychological factors such as avoidant coping, appraisal and emotional over-involvement. However, the possibilities of drawing conclusions were limited by a number of methodological issues, including cross-sectional data, small sample sizes, confounding variables not being accounted for, and a wide variation in outcome measures. DISCUSSION: The strengths of the review were the systematic approach, the exclusion of non-empirical papers and the rating of methodological quality by two independent raters. Limitations were that we excluded studies published in languages other than English, that data extraction forms were developed for this study and hence not tested for validity, and that there was a potential publication bias in favour of significant findings. CONCLUSION AND IMPLICATIONS: A better grasp of the psychological factors accounting for caregiver distress early in the course of illness may help us understand the trajectory of distress. This is an important step in preventing long-term distress in caregivers and supporting recovery in the whole family. PMID- 25531424 TI - Streptococcus equi subsp. zooepidemicus infections associated with guinea pigs. AB - Streptococcus equi subsp. zooepidemicus is a known zoonotic pathogen. In this public health investigation conducted in Virginia, USA, in 2013, we identified a probable family cluster of S. zooepidemicus cases linked epidemiologically and genetically to infected guinea pigs. S. zooepidemicus infections should be considered in patients who have severe clinical illness and report guinea pig exposure. PMID- 25531425 TI - Structural and dynamic basis of acid amido synthetase GH3.1: an investigation of substrate selectivity and major active site access channels. AB - Auxin/IAA (Indole-3-acetic acid) plays critical roles in many aspects of plant growth and development. Gretchen Hagen 3.1 (GH3.1) enzyme from grapevine (Vitis vinifera) catalyzes the ATP-dependent conjugation of aspartate to IAA suggesting a significant way to modulate levels of cellular auxins/IAA. It is reported that VvGH3.1 prefers IAA as the substrate than 1-naphthaleneacetic acid (NAA) and benzothiazole-2-oxyacetic acid (BTOA), whereas the detailed interaction mechanism of these substrates remains unclear. In this study, based on the recently reported crystal structure of VvGH3.1 and AtGH3.12, the open form of VvGH3.1 was built. Then combined computational techniques including molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics Generalized Born Surface Area and Poisson-Boltzmann Surface Area (MM-GB/PBSA) methods and active site access channel analysis were utilized to investigate the binding mechanism of three substrates, IAA, NAA and BTOA, and dynamic behaviors of GH3.1 induced by substrate binding. The predicted binding free energy is in agreement with the experimental work with an order of IAA < NAA < BTOA. Key residues interacting with three substrates and residues specifically binding to one of them were identified. The strong hydrogen bond interaction formed between IAA and Ser108, Ser339, Gln560 makes it the best substrate over NAA and BTOA. The dynamic behaviors, especially in the dominant access channels of IAA and NAA bound GH3.1, were found to be different from those in the BTOA-GH3.1 system with larger bottleneck radius and shorter length. This study provided novel insight to understand the substrate selectivity mechanism of GH3.1 and also for the rational design of novel auxin-based herbicides and growth regulators. PMID- 25531426 TI - Development of a nanobody-alkaline phosphatase fusion protein and its application in a highly sensitive direct competitive fluorescence enzyme immunoassay for detection of ochratoxin A in cereal. AB - A rapid and sensitive direct competitive fluorescence enzyme immunoassay (dc FEIA) for ochratoxin A (OTA) based on a nanobody (Nb)-alkaline phosphatase (AP) fusion protein was developed. The VHH (variable domain of heavy chain antibody) gene of Nb28 was subcloned into the expression vector pecan45 containing the AP double-mutant gene. The Nb28-AP construct was transformed into Escherichia coli BL21(DE3)plysS, and soluble expression in bacteria was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot. Both the Nb properties and AP enzymatic activity were validated by colorimetric and fluorometric analysis. The 50% inhibitory concentration and the detection limit of the dc-FEIA were 0.13 and 0.04 ng/mL, respectively, with a linear range of 0.06-0.43 ng/mL. This assay was compared with LC-MS/MS, and the results indicated the reliability of Nb-AP fusion protein-based dc-FEIA for monitoring OTA contamination in cereal. PMID- 25531427 TI - Circadian variability of insulin sensitivity: physiological input for in silico artificial pancreas. AB - BACKGROUND: Closed-loop control clinical research trials have been considerably accelerated by in silico trials using the Food and Drug Administration-accepted type 1 diabetes mellitus (T1DM) simulator. We have recently demonstrated that postprandial insulin sensitivity (SI) in T1DM subjects was lower at breakfast (B) than lunch (L) and dinner (D), but not significantly, because of the small population size. The goal of this study was therefore to incorporate this novel information into the University of Virginia/Padova T1DM simulator and to reproduce in silico the observed circadian variability. SUBJECTS AND METHODS: Twenty T1DM subjects received an identical mixed meal at B, L, and D. SI was calculated for each meal using the oral glucose minimal model. Seven SI daily patterns were identified, and their probabilities were estimated. Each in silico subject was linked to a time-varying SI profile, while random deviations of up to 40% were allowed. RESULTS: Simulations were compared with experimental data. The integrated area above the basal glucose curve values were 2.60 +/- 0.91 (B), 1.38 +/- 0.91 (L), and 1.44 +/- 1.07 (D) 10(4) min . mg/dL in silico versus 2.87 +/- 1.65 (B), 1.98 +/- 1.56 (L), and 2.16 +/- 2.00 (D) 10(4) min . mg/dL in vivo. Incremental peak glucose values were 109 +/- 33 (B), 80 +/- 29 (L), and 81 +/- 30 (D) mg/dL in silico versus 136 +/- 39 (B), 126 +/- 37 (L), and 125 +/- 48 (D) mg/dL in vivo. CONCLUSIONS: The incorporation of a time-varying SI into the simulator makes this technology suitable for running multiple-meal scenarios, thus enabling a more robust design of artificial pancreas algorithms. PMID- 25531428 TI - Biologic treatment in glomerular disease. PMID- 25531429 TI - Establishing the thematic framework for a diabetes-specific health-related quality of life item bank for use in an english-speaking asian population. AB - AIMS: To establish a thematic framework for a Diabetes Mellitus (DM)-specific health-related quality of life (HRQoL) item bank by identifying important HRQoL themes and content gaps in existing DM-specific HRQoL measures and determining whether Patient-Reported Outcomes Measurement Information System (PROMIS) item banks are useful as a starting point. METHODOLOGY: English-speaking Type 2 DM patients were recruited from an outpatient specialist clinic in Singapore. Thematic analysis was performed through open coding and axial coding. Items from four existing DM-specific measures and PROMIS Version 1.0 and 2.0 item banks were compared with identified themes and sub-themes. RESULTS: 42 patients participated (25 men and 17 women; 28 Chinese, 4 Malay, 8 Indians, 2 other ethnicities). Median age was 53.70 years (IQR45.82-56.97) and the median disease duration was 11.13 (SD9.77) years. 10 subthemes (neutral emotions, coping emotions, empowered to help others, support from family, spend more time with family, relationships, financial burden on family, improved relationship, social support and religion/spirituality) were not covered by existing DM-specific measures. PROMIS covered 5 of 6 themes, 15 of 30 subthemes and 19 of 35 codes identified. Emotional distress (frustration, fear and anxiety) was most frequently mentioned (200 times). CONCLUSIONS: We had developed a thematic framework for assessing DM specific HRQoL in a multi-ethnic Asian population, identified new items that needed to be written and confirmed that PROMIS was a useful starting point. We hope that better understanding and measurement of HRQoL of Asian DM patients will translate to better quality of care for them. PMID- 25531430 TI - Regulation of CDX4 gene transcription by HoxA9, HoxA10, the Mll-Ell oncogene and Shp2 during leukemogenesis. AB - Cdx and Hox proteins are homeodomain transcription factors that regulate hematopoiesis. Transcription of the HOX and CDX genes decreases during normal myelopoiesis, but is aberrantly sustained in leukemias with translocation or partial tandem duplication of the MLL1 gene. Cdx4 activates transcription of the HOXA9 and HOXA10 genes, and HoxA10 activates CDX4 transcription. The events that break this feedback loop, permitting a decreased Cdx4 expression during normal myelopoiesis, were previously undefined. In the current study, we find that HoxA9 represses CDX4 transcription in differentiating myeloid cells, antagonizing activation by HoxA10. We determine that tyrosine phosphorylation of HoxA10 impairs transcriptional activation of CDX4, but tyrosine phosphorylation of HoxA9 facilitates repression of this gene. As HoxA9 and HoxA10 are phosphorylated during myelopoiesis, this provides a mechanism for differentiation stage-specific Cdx4 expression. HoxA9 and HoxA10 are increased in cells expressing Mll-Ell, a leukemia-associated MLL1 fusion protein. We find that Mll-Ell induces a HoxA10 dependent increase in Cdx4 expression in myeloid progenitor cells. However, Cdx4 decreases in a HoxA9-dependent manner on exposure of Mll-Ell-expressing cells to differentiating cytokines. Leukemia-associated, constitutively active mutants of Shp2 block cytokine-induced tyrosine phosphorylation of HoxA9 and HoxA10. In comparison with myeloid progenitor cells that are expressing Mll-Ell alone, we find increased CDX4 transcription and Cdx4 expression in cells co-expressing Mll Ell plus constitutively active Shp2. Increased Cdx4 expression is sustained on exposure of these cells to differentiating cytokines. Our results identify a mechanism for increased and sustained CDX4 transcription in leukemias co overexpressing HoxA9 and HoxA10 in combination with constitutive activation of Shp2. This is clinically relevant, because MLL1 translocations and constitutive Shp2 activation co-exist in human myeloid leukemias. PMID- 25531431 TI - Different effect of dietborne and waterborne Zn exposure on lipid deposition and metabolism in juvenile yellow catfish Pelteobagrus fulvidraco. AB - Juvenile yellow catfish Pelteobagrus fulvidraco were exposed to 0.04 or 0.35 mg l(-1) waterborne Zn, 27.25 or 213.84 mg kg(-1) dietary Zn, singly or in combination for 42 days. Growth and lipid metabolism in juvenile yellow catfish were investigated. Growth and survival were significantly inhibited by single waterborne Zn exposure but not by dietary Zn exposure. Dietary Zn addition reduced but waterborne Zn exposure increased hepatic lipid content. In contrast, muscle lipid content was reduced by waterborne Zn exposure but not by dietborne Zn exposure. The single exposure also affected several lipogenic enzymatic activities and expression of genes (in this article gene expression is taken synonymous to mRNA expression) related to lipogenesis and lipolysis. Pearson correlations among lipid content, enzymatic activities and mRNA expression levels were also observed, suggesting that changes at molecular and enzymatic levels may underlie the patterns of lipid metabolism and accordingly affect lipid deposition. For the first time, our study demonstrates the differential effect of different Zn exposure pathways on lipid metabolism at the molecular level in fish, indicating that the exposure route is critical to lipid deposition and metabolism. PMID- 25531432 TI - Chronic sublethal exposure to silver nanoparticles disrupts thyroid hormone signaling during Xenopus laevis metamorphosis. AB - Nanoparticles (NPs) are engineered in the nanoscale (<100 nm) to have unique physico-chemical properties from their bulk counterparts. Nanosilver particles (AgNPs) are the most prevalent NPs in consumer products due to their strong antimicrobial action. While AgNP toxicity at high concentrations has been thoroughly investigated, the sublethal effects at or below regulatory guidelines are relatively unknown. Amphibian metamorphosis is mediated by thyroid hormone (TH), and initial studies with bullfrogs (Rana catesbeiana) indicate that low concentrations of AgNPs disrupt TH-dependent responses in premetamorphic tadpole tailfin tissue. The present study examined the effects of low, non-lethal, environmentally-relevant AgNP concentrations (0.018, 0.18 or 1.8 MUg/L Ag; ~10 nm particle size) on naturally metamorphosing Xenopus laevis tadpoles in two-28 day chronic exposures beginning with either pre- or prometamorphic developmental stages. Asymmetric flow field flow fractionation with online inductively coupled plasma mass spectrometry and nanoparticle tracking analysis indicated a mixture of single AgNPs with homo-agglomerates in the exposure water with a significant portion (~30-40%) found as dissolved Ag. Tadpoles bioaccumulated AgNPs and displayed transient alterations in snout/vent and hindlimb length with AgNP exposure. Using MAGEX microarray and quantitative real time polymerase chain reaction transcript analyses, AgNP-induced disruption of five TH-responsive targets was observed. The increased mRNA abundance of two peroxidase genes by AgNP exposure suggests the presence of reactive oxygen species even at low, environmentally-relevant concentrations. Furthermore, differential responsiveness to AgNPs was observed at each developmental stage. Therefore, low concentrations of AgNPs had developmental stage-specific endocrine disrupting effects during TH dependent metamorphosis. PMID- 25531433 TI - Incremental evaluation of coupled cluster dipole polarizabilities. AB - In this work we present the first implementation of the incremental scheme for coupled cluster linear-response frequency-dependent dipole polarizabilities. The implementation is fully automated and makes use of the domain-specific basis set approach. The accuracy of the approach is determined on the basis of a test suite of 47 molecules and small clusters. The local approximation in the coupled cluster singles and doubles polarizability exhibits a mean error of 0.02% and a standard deviation of 0.32% when using a third-order incremental expansion. With the proposed approach, it is possible to compute polarizabilities with larger basis sets compared to the canonical implementation and thus it is possible to obtain higher total accuracy. The incremental scheme yields the smallest errors for weakly-bound and quasi-linear systems, while two- and three-dimensional (cage like) structures exhibit somewhat larger errors as compared to the full test set. PMID- 25531435 TI - A rootstock provides water conservation for a grafted commercial tomato (Solanum lycopersicum L.) line in response to mild-drought conditions: a focus on vegetative growth and photosynthetic parameters. AB - The development of water stress resistant lines of commercial tomato by breeding or genetic engineering is possible, but will take considerable time before commercial varieties are available for production. However, grafting commercial tomato lines on drought resistant rootstock may produce drought tolerant commercial tomato lines much more rapidly. Due to changing climates and the need for commercial production of vegetables in low quality fields there is an urgent need for stress tolerant commercial lines of vegetables such as tomato. In previous observations we identified a scion root stock combination ('BHN 602' scion grafted onto 'Jjak Kkung' rootstock hereafter identified as 602/Jjak) that had a qualitative drought-tolerance phenotype when compared to the non-grafted line. Based on this initial observation, we studied photosynthesis and vegetative above-ground growth during mild-drought for the 602/Jjak compared with another scion-rootstock combination ('BHN 602' scion grafted onto 'Cheong Gang' rootstock hereafter identified as 602/Cheong) and a non-grafted control. Overall above ground vegetative growth was significantly lower for 602/Jjak in comparison to the other plant lines. Moreover, water potential reduction in response to mild drought was significantly less for 602/Jjak, yet stomatal conductance of all plant-lines were equally inhibited by mild-drought. Light saturated photosynthesis of 602/Jjak was less affected by low water potential than the other two lines as was the % reduction in mesophyll conductance. Therefore, the Jjak Kkung rootstock caused aboveground growth reduction, water conservation and increased photosynthetic tolerance of mild drought. These data show that different rootstocks can change the photosynthetic responses to drought of a high yielding, commercial tomato line. Also, this rapid discovery of one scion rootstock combination that provided mild-drought tolerance suggests that screening more scion-rootstock combination for stress tolerance may rapidly yield commercially viable, stress tolerant lines of tomato. PMID- 25531436 TI - Distinguishing patients with Parkinson's disease subtypes from normal controls based on functional network regional efficiencies. AB - Many studies have demonstrated that the pathophysiology and clinical symptoms of Parkinson's disease (PD) are inhomogeneous. However, the symptom-specific intrinsic neural activities underlying the PD subtypes are still not well understood. Here, 15 tremor-dominant PD patients, 10 non-tremor-dominant PD patients, and 20 matched normal controls (NCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). Functional brain networks were constructed based on randomly generated anatomical templates with and without the cerebellum. The regional network efficiencies (i.e., the local and global efficiencies) were further measured and used to distinguish subgroups of PD patients (i.e., with tremor-dominant PD and non-tremor-dominant PD) from the NCs using linear discriminant analysis. The results demonstrate that the subtype-specific functional networks were small-world-organized and that the network regional efficiency could discriminate among the individual PD subgroups and the NCs. Brain regions involved in distinguishing between the study groups included the basal ganglia (i.e., the caudate and putamen), limbic regions (i.e., the hippocampus and thalamus), the cerebellum, and other cerebral regions (e.g., the insula, cingulum, and calcarine sulcus). In particular, the performances of the regional local efficiency in the functional network were better than those of the global efficiency, and the performances of global efficiency were dependent on the inclusion of the cerebellum in the analysis. These findings provide new evidence for the neurological basis of differences between PD subtypes and suggest that the cerebellum may play different roles in the pathologies of different PD subtypes. The present study demonstrated the power of the combination of graph-based network analysis and discrimination analysis in elucidating the neural basis of different PD subtypes. PMID- 25531438 TI - Evolution of self-assembled ZnTe magic-sized nanoclusters. AB - Three families of ZnTe magic-sized nanoclusters (MSNCs) were obtained exclusively using polytellurides as a tellurium precursor in a one-pot reaction by simply varying the reaction temperature and time only. Different ZnTe MSNCs exhibit different self-assembling or aggregation behavior, owing to their different structure, cluster size, and dipole-dipole interactions. The smallest family of ZnTe MSNCs (F323) does not reveal a crystalline structure and as a result assembles into lamellar triangle plates. Continuous heating of as synthesized ZnTe F323 assemblies resulted in the formation of ZnTe F398 MSNCs with wurzite structure and concomitant transformation into lamellar rectangle assemblies with the organization of nanoclusters along the ?002? direction. Further annealing of ZnTe F398 assembled lamellar rectangles leads to full organization of MSNCs in all directions and formation of larger ZnTe F444 NCs that spontaneously form ultrathin nanowires following an oriented attachment mechanism. The key step in control over the size distribution of ZnTe ultrathin nanowires is, in fact, the growth mechanism of ZnTe F398 MSNCs; namely, the step growth mechanism enables formation of more uniform nanowires compared to those obtained by continuous growth mechanism. High yield of ZnTe nanowires is achieved as a result of the wurzite structure of F398 precursor. Transient absorption (TA) measurements show that all three families possess ultrafast dynamics of photogenerated electrons, despite their different crystalline structures. PMID- 25531437 TI - The grafting of universal T-helper epitopes enhances immunogenicity of HIV-1 Tat concurrently improving its safety profile. AB - Extracellular Tat (eTat) plays an important role in HIV-1 pathogenesis. The presence of anti-Tat antibodies is negatively correlated with disease progression, hence making Tat a potential vaccine candidate. The cytotoxicity and moderate immunogenicity of Tat however remain impediments for developing Tat based vaccines. Here, we report a novel strategy to concurrently enhance the immunogenicity and safety profile of Tat. The grafting of universal helper T lymphocyte (HTL) epitopes, Pan DR Epitope (PADRE) and Pol711 into the cysteine rich domain (CRD) and the basic domain (BD) abolished the transactivation potential of the Tat protein. The HTL-Tat proteins elicited a significantly higher titer of antibodies as compared to the wild-type Tat in BALB/c mice. While the N-terminal epitope remained immunodominant in HTL-Tat immunizations, an additional epitope in exon-2 was recognized with comparable magnitude suggesting a broader immune recognition. Additionally, the HTL-Tat proteins induced cross reactive antibodies of high avidity that efficiently neutralized exogenous Tat, thus blocking the activation of a Tat-defective provirus. With advantages such as presentation of multiple B-cell epitopes, enhanced antibody response and importantly, transactivation-deficient Tat protein, this approach has potential application for the generation of Tat-based HIV/AIDS vaccines. PMID- 25531439 TI - High-resolution melting of 12S rRNA and cytochrome b DNA sequences for discrimination of species within distinct European animal families. AB - The cheap and easy identification of species is necessary within multiple fields of molecular biology. The use of high-resolution melting (HRM) of DNA provides a fast closed-tube method for analysis of the sequence composition of the mitochondrial genes 12S rRNA and cytochrome b. We investigated the potential use of HRM for species identification within eleven different animal groups commonly found in Europe by animal-group-specific DNA amplification followed by DNA melting. Influence factors as DNA amount, additional single base alterations, and the existence of mixed samples were taken into consideration. Visual inspection combined with mathematical evaluation of the curve shapes did resolve nearly all species within an animal group. The assay can therefore not only be used for identification of animal groups and mixture analysis but also for species identification within the respective groups. The use of a universal 12S rRNA system additionally revealed a possible approach for species discrimination, mostly by exclusion. The use of the HRM assay showed to be a reliable, fast, and cheap method for species discrimination within a broad range of different animal species and can be used in a flexible "modular" manner depending on the question to be solved. PMID- 25531440 TI - Associations of two common genetic variants with breast cancer risk in a chinese population: a stratified interaction analysis. AB - Recent genome-wide association studies (GWAS) have identified a series of new genetic susceptibility loci for breast cancer (BC). However, the correlations between these variants and breast cancer are still not clear. In order to explore the role of breast cancer susceptibility variants in a Southeast Chinese population, we genotyped two common SNPs at chromosome 6q25 (rs2046210) and in TOX3 (rs4784227) in a case-control study with a total of 702 breast cancer cases and 794 healthy-controls. In addition, we also evaluated the multiple interactions among genetic variants, risk factors, and tumor subtypes. Associations of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (95% CI). The results indicated that both polymorphisms were significantly associated with the risk of breast cancer, with per allele OR = 1.35, (95%CI = 1.17-1.57) for rs2046210 and per allele OR = 1.24 (95%CI = 1.06 1.45) for rs4784227. Furthermore, in subgroup stratified analyses, we observed that the T allele of rs4784227 was significantly associated with elevated OR among postmenopausal populations (OR = 1.44, 95%CI 1.11-1.87) but not in premenopausal populations, with the heterogeneity P value of P = 0.064. These findings suggest that the genetic variants at chromosome 6q25 and in the TOX3 gene may play important roles in breast cancer development in a Chinese population and the underlying biological mechanisms need to be further elucidated. PMID- 25531442 TI - Small molecular neutral microcrystalline iridium(III) complexes as promising molecular oxygen sensors. AB - Small molecular neutral Ir(III) complexes have been demonstrated to be promising self-inclusive microcrystalline thin-film oxygen sensors with relatively high sensitivity (Ksv = 6.41), good stability, and linear Stern-Volmer behavior (R(2) = 0.9979). PMID- 25531441 TI - Deficiency in either 4E-BP1 or 4E-BP2 augments innate antiviral immune responses. AB - Genetic deletion of both 4E-BP1 and 4E-BP2 was found to protect cells against viral infections. Here we demonstrate that the individual loss of either 4E-BP1 or 4E-BP2 in mouse embryonic fibroblasts (MEFs) is sufficient to confer viral resistance. shRNA-mediated silencing of 4E-BP1 or 4E-BP2 renders MEFs resistant to viruses, and compared to wild type cells, MEFs knockout for either 4E-BP1 or 4E-BP2 exhibit enhanced translation of Irf-7 and consequently increased innate immune response to viruses. Accordingly, the replication of vesicular stomatitis virus, encephalomyocarditis virus, influenza virus and Sindbis virus is markedly suppressed in these cells. Importantly, expression of either 4E-BP1 or 4E-BP2 in double knockout or respective single knockout cells diminishes their resistance to viral infection. Our data show that loss of 4E-BP1 or 4E-BP2 potentiates innate antiviral immunity. These results provide further evidence for translational control of innate immunity and support targeting translational effectors as an antiviral strategy. PMID- 25531443 TI - Vitamin C effect on mitoxantrone-induced cytotoxicity in human breast cancer cell lines. AB - In recent years the use of natural dietary antioxidants to minimize the cytotoxicity and the damage induced in normal tissues by antitumor agents is gaining consideration. In literature, it is reported that vitamin C exhibits some degree of antineoplastic activity whereas Mitoxantrone (MTZ) is a synthetic anti cancer drug with significant clinical effectiveness in the treatment of human malignancies but with severe side effects. Therefore, we have investigated the effect of vitamin C alone or combined with MTZ on MDA-MB231 and MCF7 human breast cancer cell lines to analyze their dose-effect on the tumor cellular growth, cellular death, cell cycle and cell signaling. Our results have evidenced that there is a dose-dependence on the inhibition of the breast carcinoma cell lines, MCF7 and MDA-MB231, treated with vitamin C and MTZ. Moreover, their combination induces: i) a cytotoxic effect by apoptotic death, ii) a mild G2/M elongation and iii) H2AX and mild PI3K activation. Hence, the formulation of vitamin C with MTZ induces a higher cytotoxicity level on tumor cells compared to a disjointed treatment. We have also found that the vitamin C enhances the MTZ effect allowing the utilization of lower chemotherapic concentrations in comparison to the single treatments. PMID- 25531444 TI - As easy to move as a feather: perception of lightness as ease to move. AB - When perception by touch is couched in terms of movement, perception of heaviness can be understood as perception of difficulty to move. This experiment further investigated this proposal as well as the corollary proposal that perception of lightness may be understood as perception of ease to move. Blindfolded participants wielded weighted objects and rated how heavy or light each object felt and how difficult or easy each object was to move. Ratings of heaviness and difficulty to move were analogously constrained by movement-relevant variables. Ratings of lightness and ease-to-move were also analogously constrained by such variables, but in the opposite manner. Conventional descriptors such as heaviness or lightness may be inappropriate for a principled understanding of perception by touch. PMID- 25531445 TI - Dual sgRNA-directed gene knockout using CRISPR/Cas9 technology in Caenorhabditis elegans. AB - The CRISPR RNA-guided Cas9 nuclease gene-targeting system has been successfully used for genome editing in a variety of organisms. Here, we report the use of dual sgRNA-guided Cas9 nuclease to generate knockout mutants of protein coding genes, noncoding genes, and repetitive sequences in C. elegans. Co-injection of C. elegans with dual sgRNAs results in the removal of the interval between two sgRNAs and the loss-of-function phenotype of targeted genes. We sought to determine how large an interval can be eliminated and found that at least a 24 kb chromosome segment can be deleted using this dual sgRNA/Cas9 strategy. The deletion of large chromosome segments facilitates mutant screening by PCR and agarose electrophoresis. Thus, the use of the CRISPR/Cas9 system in combination with dual sgRNAs provides a powerful platform with which to easily generate gene knockout mutants in C. elegans. Our data also suggest that encoding multiple sgRNA sequences into a single CRISPR array to simultaneously edit several sites within the genome may cause the off-target deletion of chromosome sequences. PMID- 25531446 TI - Innovation in hepatic alveolar echinococcosis imaging: best use of old tools, and necessary evaluation of new ones. AB - Hepatic Alveolar Echinococcosis (HAE), caused by larvae of Echinococcus multilocularis, is a rare but potentially lethal parasitic disease. The first diagnostic suspicion is usually based on hepatic ultrasound exam performed because of abdominal symptoms or in the context of a general checkup; HAE diagnosis may thus also be an incidental finding on imaging. The next step should be Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). They play an important role in the initial assessment of the disease; with chest and brain imaging, they are necessary to assess the PNM stage (parasite lesion, neighboring organ invasion, metastases) of a patient with AE. Performed at least yearly, they also represent key exams for long-term follow-up after therapeutic interventions. Familiarity of radiologists with HAE imaging findings, especially in the endemic regions, will enable earlier diagnosis and more effective treatment. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is currently considered to be the only noninvasive, albeit indirect, tool for the detection of metabolic activity in AE. Delayed acquisition of images (3 hrs after FDG injection) enhances its sensitivity for the assessment of lesion metabolism and its reliability for the continuation/withdrawal of anti-parasite treatment. However, sophisticated equipment and high cost widely limit PET/CT use for routine evaluation. Preliminary studies show that new techniques, such as contrast enhanced ultrasound (US), Dual Energy CT or Spectral CT, and Diffusion-Weighted MRI, might also be useful in detecting the blood supply and metabolism of lesions. However, they cannot be recommended before further evaluation of their reliability in a larger number of patients with a variety of locations and stages of AE lesions. PMID- 25531447 TI - A double built-in containment strategy for production of recombinant proteins in transgenic rice. AB - Using transgenic rice as a bioreactor for mass production of pharmaceutical proteins could potentially reduce the cost of production significantly. However, a major concern over the bioreactor transgenic rice is the risk of its unintended spreading into environment and into food or feed supplies. Here we report a mitigating method to prevent unwanted transgenic rice spreading by a double built in containment strategy, which sets a selectively termination method and a visual tag technology in the T-DNA for transformation. We created transgenic rice with an inserted T-DNA that harbors a human proinsulin gene fused with the far-red fluorescent protein gene mKate_S158A, an RNAi cassette suppressing the expression of the rice bentazon detoxification enzyme CYP81A6, and an EPSPS gene as the selection marker for transformation. Herbicide spray tests indicated that such transgenic rice plants can be killed selectively by a spray of bentazon at regular field application dosage for rice weed control. Moreover, the transgenic rice seeds were bright red in color due to the fused far-red fluorescent protein, and could be easily visualized under daylight by naked eyes. Thus, the transgenic rice plants reported in this study could be selectively killed by a commonly used herbicide during their growth stage, and their seeds may be detected visually during processing and consumption after harvest. This double built-in containment strategy may greatly enhance the confinement of the transgenic rice. PMID- 25531448 TI - PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. AB - BACKGROUND: Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. METHODS: The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. RESULTS: The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. CONCLUSIONS: PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID- 25531449 TI - Is schizophrenia a neurodegenerative disease? Evidence from age-related decline of brain-derived neurotrophic factor in the brains of schizophrenia patients and matched nonpsychiatric controls. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) protein levels decline in the brain during senescence and are also shown to be reduced in schizophrenia patients. BDNF is present in both the gray and white matters of the brain. It is unclear whether BDNF abnormalities in schizophrenia are specific to gray and/or white matter. OBJECTIVE: We hypothesized that the age-related BDNF decline is abnormal and contributes to the reduced BDNF in schizophrenia. METHODS: We tested this hypothesis by measuring BDNF protein levels in postmortem gray and white matter, using the prefrontal cortex (PFC) and the genu of the corpus callosum as regions of interests, from 20 schizophrenia patients and 20 matched nonpsychiatric controls. Samples were selected across the adult lifespan--from 20 to 80 years of age. RESULTS: PFC gray matter BDNF protein levels were significantly lower in older age in both nonpsychiatric comparisons and patients, while BDNF in white matter did not decrease significantly with age in either group. PFC BDNF was linearly lower from 20 to 80 years of age in nonpsychiatric comparisons. In schizophrenia, the age effect was similarly linear in younger patients but a decline did not occur in older patients. CONCLUSION: PFC BDNF does not follow a normative linear age effect in schizophrenia patients as they grow older, which may represent a 'floor effect' due to earlier decline or a survivor cohort of older patient donors who are less susceptible to a schizophrenia related pathological aging process. PMID- 25531451 TI - Patients' expectations of the benefits and harms of treatments, screening, and tests: a systematic review. AB - IMPORTANCE: Unrealistic patient expectations of the benefits and harms of interventions can influence decision making and may be contributing to increasing intervention uptake and health care costs. OBJECTIVE: To systematically review all studies that have quantitatively assessed patients' expectations of the benefits and/or harms of any treatment, test, or screening test. EVIDENCE REVIEW: A comprehensive search strategy was used in 4 databases (MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO) up to June 2013, with no language or study type restriction. We also ran cited reference searches of included studies and contacted experts and study authors. Two researchers independently evaluated methodological quality and extracted participants' estimates of benefit and harms and authors' contemporaneous estimates. FINDINGS: Of the 15,343 records screened, 36 articles (from 35 studies) involving a total of 27,323 patients were eligible. Fourteen studies focused on a screen, 15 on treatment, 3 a test, and 3 on treatment and screening. More studies assessed only benefit expectations (22 [63%]) than benefit and harm expectations (10 [29%]) or only harm (3 [8%]). Fifty-four outcomes (across 32 studies) assessed benefit expectations: of the 34 outcomes with overestimation data available, the majority of participants overestimated benefit for 22 (65%) of them. For 17 benefit expectation outcomes, we could not calculate the proportion of participants who overestimated or underestimated, although for 15 (88%) of these, study authors concluded that participants overestimated benefits. Expectations of harm were assessed by 27 outcomes (across 13 studies): underestimation data were available for 15 outcomes and the majority of participants underestimated harm for 10 (67%) of these. A correct estimation by at least 50% of participants only occurred for 2 outcomes about benefit expectations and 2 outcomes about harm expectations. CONCLUSIONS AND RELEVANCE: The majority of participants overestimated intervention benefit and underestimated harm. Clinicians should discuss accurate and balanced information about intervention benefits and harms with patients, providing the opportunity to develop realistic expectations and make informed decisions. PMID- 25531450 TI - A minimal dose of electrically induced muscle activity regulates distinct gene signaling pathways in humans with spinal cord injury. AB - Paralysis after a spinal cord injury (SCI) induces physiological adaptations that compromise the musculoskeletal and metabolic systems. Unlike non-SCI individuals, people with spinal cord injury experience minimal muscle activity which compromises optimal glucose utilization and metabolic control. Acute or chronic muscle activity, induced through electrical stimulation, may regulate key genes that enhance oxidative metabolism in paralyzed muscle. We investigated the short and long term effects of electrically induced exercise on mRNA expression of human paralyzed muscle. We developed an exercise dose that activated the muscle for only 0.6% of the day. The short term effects were assessed 3 hours after a single dose of exercise, while the long term effects were assessed after training 5 days per week for at least one year (adherence 81%). We found a single dose of exercise regulated 117 biological pathways as compared to 35 pathways after one year of training. A single dose of electrical stimulation increased the mRNA expression of transcriptional, translational, and enzyme regulators of metabolism important to shift muscle toward an oxidative phenotype (PGC-1alpha, NR4A3, IFRD1, ABRA, PDK4). However, chronic training increased the mRNA expression of specific metabolic pathway genes (BRP44, BRP44L, SDHB, ACADVL), mitochondrial fission and fusion genes (MFF, MFN1, MFN2), and slow muscle fiber genes (MYH6, MYH7, MYL3, MYL2). These findings support that a dose of electrical stimulation (~10 minutes/day) regulates metabolic gene signaling pathways in human paralyzed muscle. Regulating these pathways early after SCI may contribute to reducing diabetes in people with longstanding paralysis from SCI. PMID- 25531452 TI - Borane as an efficient directing group. Stereoselective 1,2-addition of organometallic reagents to borane P-stereogenic N-phosphanylimines. AB - In non-coordinating solvents, borane was shown to be an efficient directing group for the stereoselective 1,2-addition of organolithium reagents to P-stereogenic N phosphanylimines. Selectivity was reversed in coordinating solvents. This process can lead to novel ligand scaffolds for asymmetric catalysis. PMID- 25531454 TI - Monitoring clinical levels of heparin in human blood samples with an indicator displacement assay. AB - We report that a "tree-like" polymer of lysine is able to form a multi-ligand complex with a fluorescently labelled peptide, leading to the almost complete extinction of the optical signal that can be restored upon the introduction of heparin. This simple system allows, for the first time, the turn-ON fluorescent sensing of the anticoagulant in human blood at clinically relevant levels. PMID- 25531453 TI - Invariant Natural Killer T Cells Promote T Cell Immunity by Modulating the Function of Lung Dendritic Cells during Chlamydia pneumoniae Infection. AB - In this study, we examined the effect of invariant natural killer T (iNKT) cells on the function of lung dendritic cells (LDCs) in eliciting protective immunity against Chlamydia pneumoniae (Cpn) lung infection. We employed a combination of approaches including the use of iNKT cell-deficient, Jalpha18-knockout (KO) mice and LDC adoptive transfer. We found that iNKT cells significantly altered the number, phenotype and cytokine profile of LDCs following infection. Furthermore, coculture of T cells with LDCs from Cpn-infected wild-type (WT) and KO mice induced type-1 and type-2 responses, respectively. More importantly, upon adoptive transfer, LDCs from Cpn-infected WT mice (WT-LDCs) conferred protective immunity, whereas LDCs from KO mice (KO-LDCs) increased the severity of disease after challenge infection. Further cytokine analyses of the lung tissues and lung draining lymph node cells showed that KO-LDC-recipient mice exhibited a type-2 cytokine production pattern, while WT-LDC recipients exhibited a type-1 cytokine profile. Taken together, our results provide in vivo evidence that iNKT cells play a critical role in modulating LDC function to generate protective T-cell immunity, particularly in a clinically relevant intracellular bacterial infection. PMID- 25531455 TI - Predicting acute mountain sickness. PMID- 25531458 TI - Pro: pulse oximetry is useful in predicting acute mountain sickness. PMID- 25531459 TI - Con: pulse oximetry is useful in predicting acute mountain sickness. PMID- 25531460 TI - Rebuttal to the con statement. PMID- 25531461 TI - Rebuttal to the pro statement. PMID- 25531462 TI - The effect of hypoxia preconditioning on DNA methyltransferase and PP1gamma in hippocampus of hypoxia preconditioned mice. AB - It is well known that hypoxia preconditioning can increase hypoxic tolerance by changing the expressions of some genes in the brain. DNA methylation is important for regulating gene expression and is catalyzed by DNA methyltransferase (DNMT), an enzyme that is abundant in the brain. However, the impact of hypoxia preconditioning on DNA methylation remains unknown. In the current study, mice were randomly divided into three groups: blank control group with no exposure to hypoxia (H0), the hypoxia control group exposed to hypoxia once (H1), and the hypoxia preconditioning group exposed to 4 runs of hypoxia (H4). The mRNA and protein levels of three kinds of DNMTs and the activity of total DMNT were measured. Protein phosphatase 1(PP1)gamma, which critically regulates neuroprotective pathways in brain, was measured in mRNA and protein activity and promoter methylation. DNMT1 was unchanged in H1 and H4, while DNMT3A and DNMT3B were decreased in H4. The mRNA and protein levels of PP1gamma were decreased in H4. However, there was no detectable change in the level of DNA methylation of the promoter of PP1gamma (-321 bp to 95 bp). These findings suggest that DNA methylation may have a role in hypoxia neuroprotection, and the change of PP1gamma, which did not depend on the change of its promoter (-321 bp to 95bp) DNA methylation, may be involved in neuroprotection. PMID- 25531463 TI - Is extracorporeal rewarming indicated in avalanche victims with unwitnessed hypothermic cardiorespiratory arrest? AB - International guidelines recommend using extracorporeal rewarming in all hypothermic avalanche victims with prolonged cardiac arrest if they have patent airways and a plasma potassium level<=12 mmol/L. The aim of this study was to evaluate outcome data to determine if available experience with extracorporeal rewarming of avalanche victims supports this recommendation. At Innsbruck Medical University Hospital, 28 patients with hypothermic cardiac arrest following an avalanche accident were resuscitated using extracorporeal circulation. Of these patients, 25 were extricated from the snow masses with no vital signs and did not survive to hospital discharge. Three patients had witnessed cardiac arrest after extrication and a core temperature of 21.7 degrees C, 22 degrees C, and 24.0 degrees C, two of whom survived long-term with full neurological recovery. A search of the literature revealed only one asystolic avalanche victim with unwitnessed hypothermic cardiac arrest (core temperature 19 degrees C) surviving long-term. All other avalanche victims in the medical literature surviving prolonged hypothermic cardiac arrest suffered witnessed arrest after extrication with a core temperature below 24 degrees C. Our results suggest that prognosis of hypothermic avalanche victims with unwitnessed asystolic cardiac arrest and a core temperature>24 degrees C is extremely poor. Available outcome data do not support the use of extracorporeal rewarming in these patients. PMID- 25531464 TI - Prevalence of high altitude pulmonary hypertension among the natives of Spiti Valley--a high altitude region in Himachal Pradesh, India. AB - The study aimed to determine the prevalence of high altitude pulmonary hypertension (HAPH) and its predisposing factors among natives of Spiti Valley. A cross-sectional survey study was done on the permanent natives of Spiti Valley residing at an altitude of 3000 m to 4200 m. Demographic characteristics, health behavior, anthropometrics, and blood pressure were recorded. Investigations included recording of 12 lead electrocardiogram (ECG), SaO2 with pulse oximeter, spirometry and echocardiography study, and measurement of Hb levels using the cynmethhemoglobin method. HAPH was diagnosed using criteria; tricuspid regurgitation (TR) gradient of >=46 mmHg. ECG evidence of RV overload on 12 lead ECG was documented based on presence of 2 out of 3 criteria; R>S in V1, right axis deviation or RV strain, T wave inversion in V1 and V2. Data of 1087 subjects were analyzed who were free of cardiorespiratory diseases to determine the prevalence of HAPH and its predisposing factors. HAPH was recorded in 3.23% (95% C.I. of 0.9-8.1%) and ECG evidence of right ventricular (RV) overload was 1.5% in the study population. Prevalence of HAPH was not different in men and women 2.63% vs. 3.54% p<0.2. Age (Z statistics of 3.4 p<0.0006), hypoxemia (Z statistics of 2.9 p<0.002), and erythrocythemia (Z statistics of 4.7 p<0.003) were independently associated with HAPH. Altitude of residence was not found to be significantly associated with HAPH, although there was a trend of increasing prevalence with increasing altitude. It can be concluded that HAPH is prevalent in 3.23% of natives of Spiti Valley. Increasing age, erythrocythemia and hypoxemia are independent predisposing factors. PMID- 25531465 TI - Outcome and safety of the Montgomery T-tube for laryngotracheal stenosis: a single-center retrospective analysis of 546 cases. AB - OBJECTIVE: We retrospectively analyzed the surgical outcome and safety of the Montgomery T-tube for laryngotracheal stenosis. METHODS: The patients with laryngotracheal stenosis who had undergone T-tube placement between 1996 and 2010 were reviewed. The severity of the stenosis was evaluated using the Cotton-Myer staging method. The primary endpoint was the rate of successful extubation and the secondary endpoint was safety. RESULTS: 546 patients were eligible. T-tubes were successfully extubated in 342 patients 6-24 months following intubation. The initial extubation success rate was 62.3%. Laryngotracheal restenosis following extubation occurred in 192 patients, necessitating T-tube placement for a second time. The success rate for the second attempt was 58.9%. The overall success rate was 83.3%. Hemoptysis was reported in 8 patients, postoperative infection in 6 patients, wound dehiscence in 3 patients, laryngeal obstruction in 13 patients, aspiration in 12 patients, and postoperative tracheoesophageal fistula in 2 patients. CONCLUSION: This large clinical series demonstrated the safety and effectiveness of the T-tube for grade 1 and 2 stenosis with stenosed segments of <6 cm. For those being >6 cm, tracheal end-to-end anastomosis is not appropriate and long-term placement of a T-tube is recommended. Our findings provide useful guidance for preoperatively selecting patients with laryngotracheal stenosis of various causes and differing severity. PMID- 25531466 TI - Modification of PCR conditions and design of exon-specific primers for the efficient molecular diagnosis of PKD1 mutations. AB - BACKGROUND/AIMS: Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by mutations in the PKD1 and PKD2 genes. Currently, long-range PCR followed by nested PCR and sequencing (LRNS) is the gold standard approach for PKD1 testing. However, LRNS is complicated by the high structural and sequence complexity of PKD1, which makes the procedure for amplification and analysis of PKD1 difficult. METHODS: Here in, we modified the PCR conditions and designed primers for efficient and specific amplification of both the long-range and individual exons of PKD1. RESULTS: Using the modified system, seven long-range fragments were specifically amplified using two distinct sets of conditions, and all individual exon PCR assays were easily performed using a touch-down PCR method. Seven pathogenic or likely pathogenic variants, including two novel truncated frameshift indels and two novel likely pathogenic missense mutations, were identified in eight unrelated patients with or without histories of ADPKD disease (one variant was observed in two unrelated patients). Using combined bioinformatics tools, two indeterminate missense variants were identified in two sporadic patients. CONCLUSION: Four novel PKD1 variants were identified in this study. We demonstrated that the modified LRNS method achieves high sensitivity and specificity for detecting pathogenic variants of ADPKD. PMID- 25531468 TI - Cumulative association of obstructive sleep apnea severity and short sleep duration with the risk for hypertension. AB - Obstructive sleep apnea (OSA) and short sleep duration are individually associated with an increased risk for hypertension (HTN). The aim of this multicenter cross-sectional study was to test the hypothesis of a cumulative association of OSA severity and short sleep duration with the risk for prevalent HTN. Among 1,499 patients undergoing polysomnography for suspected OSA, 410 (27.3%) previously diagnosed as hypertensive and taking antihypertensive medication were considered as having HTN. Patients with total sleep time (TST) <6 h were considered to be short sleepers. Logistic regression procedures were performed to determine the independent association of HTN with OSA and sleep duration. Considering normal sleepers (TST >=6 h) without OSA as the reference group, the odds ratio (OR) (95% confidence intervals) for having HTN was 2.51 (1.35-4.68) in normal sleepers with OSA and 4.37 (2.18-8.78) in short sleepers with OSA after adjustment for age, gender, obesity, diabetes, depression, current smoking, use of thyroid hormones, daytime sleepiness, poor sleep complaint, time in bed, sleep architecture and fragmentation, and study site. The risk for HTN appeared to present a cumulative association with OSA severity and short sleep duration (p<0.0001 for linear trend). The higher risk for HTN was observed in short sleepers with severe OSA (AHI >=30) (OR, 4.29 [2.03-9.07]). In patients investigated for suspected OSA, sleep-disordered breathing severity and short sleep duration have a cumulative association with the risk for prevalent HTN. Further studies are required to determine whether interventions to optimize sleep may contribute to lower BP in patients with OSA. PMID- 25531467 TI - Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. AB - Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyse 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations. In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations. PMID- 25531469 TI - Science to practice: can decreased lymph node MR imaging signal intensity be used as a biomarker for the efficacy of cancer vaccination? AB - Summary In the study of Zhang et al (1), tumor-bearing mice were vaccinated with magnetically labeled, tumor antigen-primed dendritic cells (DCs). After homing of these antigen-presenting cells to the draining lymph node (LN), it was shown that the iron oxide-induced decrease in LN magnetic resonance (MR) imaging signal intensity correlated with the observed tumor growth delay, suggesting that the degree of hypointensity can serve as a surrogate marker for the efficacy of tumor vaccination. PMID- 25531470 TI - Introducing the "golden oldies" of radiology. AB - Online supplemental material is available for this article. PMID- 25531474 TI - Ronald L. Arenson, MD, president, Radiological Society of North America, 2015. PMID- 25531475 TI - Visual search and lung nodule detection on CT scans. PMID- 25531476 TI - Reflections on the Press Service for RSNA 1961-1969. PMID- 25531477 TI - Radiology's legacy: rummaging through the attic. PMID- 25531478 TI - Pediatric MR enterography: technique and approach to interpretation-how we do it. AB - Magnetic resonance (MR) enterography is an increasingly important pediatric imaging modality that is most often used to evaluate inflammatory bowel disease ( IBD inflammatory bowel disease ), while sparing children and adolescents from potential risks of ionizing radiation exposure. MR enterography allows for evaluation of the bowel lumen and wall, adjacent mesentery and soft tissues, as well as a variety of extraintestinal abdominopelvic IBD inflammatory bowel disease manifestations. While MR enterography can be used to initially confirm the diagnosis of IBD inflammatory bowel disease , particularly small bowel Crohn disease, it has also proven useful in assessing the degree inflammatory activity over time, serving as a radiologic biomarker for response to medical therapy, and identifying a variety of disease-related complications, including strictures, fistulae, and abscesses. The purpose of this review article is to provide radiologists with a systematic approach for MR enterography review and interpretation in children and adolescents with known or suspected of having IBD inflammatory bowel disease and to illustrate both common and infrequent but important imaging findings. Additionally, the authors will present their well established and clinically successful pediatric MR enterography protocol, up-to date clinical indications for MR enterography, and briefly mention the role of MR enterography in assessing non- IBD inflammatory bowel disease abnormalities affecting the bowel. Online supplemental material is available for this article . PMID- 25531479 TI - Diffusion-weighted MR imaging of the pancreas: current status and recommendations. AB - Advances in image quality over the past few years, mainly due to refinements in hardware and coil systems, have made diffusion-weighted ( DW diffusion weighted ) magnetic resonance (MR) imaging a promising technique for the detection and characterization of pancreatic conditions. DW diffusion weighted MR imaging can be routinely implemented in clinical protocols, as it can be performed relatively quickly, does not require administration of gadolinium-based contrast agents, and enables qualitative and quantitative assessment of tissue diffusivity (diffusion coefficients). In this review, acquisition parameters, postprocessing, and quantification methods applied to pancreatic DW diffusion weighted MR imaging will be discussed. The current common clinical uses of DW diffusion weighted MR imaging (ie, pancreatic lesion detection and characterization) and the less common applications of DW diffusion weighted MR imaging used for the diagnosis of pancreatic parenchymal diseases will be reviewed. Also, the limitations of the technique, mainly image quality and reproducibility of diffusion parameters, as well as future directions for pancreatic DW diffusion weighted MR imaging will be discussed. The utility of apparent diffusion coefficient ( ADC apparent diffusion coefficient ) measurement for the characterization of pancreatic lesions is now well accepted but there are a number of limitations. Future well-designed, multicenter studies are needed to better determine the most appropriate use of ADC apparent diffusion coefficient in the area of pancreatic disease. PMID- 25531483 TI - Case 213: primary splenic angiosarcoma. AB - History A 75-year-old woman with a medical history of gastroesophageal reflux disease and type II diabetes presented to the hospital with a 3-month history of gradually worsening headaches, vague upper abdominal pain, and lower back pain. The patient denied fevers, night sweats, contact with sick individuals, occupational exposure to infection, bleeding, immunodeficiency, intravenous drug use, alcohol or tobacco abuse, history of malignancy, family history of genetic disorders, and international travel. Physical examination revealed a skin-colored mass protruding from the right side of her forehead, but there were no other notable abnormalities. Her diabetes was managed with diet, and the only prescription medication she was taking was esomeprazole. She was not taking anticoagulants. Initial laboratory work-up revealed anemia and profound thrombocytopenia (hemoglobin level, 9.4 g/dL; platelet count, 16 * 10(9)/L); these were refractory to aggressive treatment, including plasmapheresis, immunosuppression with prednisolone, and numerous transfusions. Contrast material enhanced magnetic resonance (MR) imaging of the head was performed at admission to further evaluate the patient's headache and the mass on the patient's forehead. Ultrasonography (US) of the abdomen was performed to evaluate the cause of abdominal pain. The discovery of liver lesions at US led us to perform contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis. Contrast-enhanced MR imaging of the abdomen was performed to narrow the diagnostic considerations for the lesions identified at CT. Bone marrow biopsy revealed no evidence of infectious or neoplastic processes. Endoscopy and colonoscopy were performed; however, they revealed no abnormalities. Further laboratory work-up included extensive testing for parasites, fungi, bacteria, and viruses, including the human immunodeficiency virus (HIV). All of the results were negative. On the 17th day of admission, the patient became acutely unresponsive, her condition deteriorated rapidly, and she died. Unenhanced head CT was performed at the time of the patient's acute decompensation. PMID- 25531484 TI - Hybrid SPECT/US. PMID- 25531486 TI - Predictive value of coronary CT angiography for side-branch occlusion. PMID- 25531485 TI - Use of radiation-based techniques for a study: to perform or not to perform. PMID- 25531488 TI - Louis A. Gilula, MD. PMID- 25531490 TI - Method for automatically identifying spectra of different wood cell wall layers in Raman imaging data set. AB - The technique of Raman spectroscopic imaging is finding ever-increasing applications in the field of wood science for its ability to provide spatial and spectral information about the sample. On the basis of the acquired Raman imaging data set, it is possible to determine the distribution of chemical components in various wood cell wall layers. However, the Raman imaging data set often contains thousands of spectra measured at hundreds or even thousands of individual frequencies, which results in difficulties accurately and quickly extracting all of the spectra within a specific morphological region of wood cell walls. To address this issue, the authors propose a new method to automatically identify Raman spectra of different cell wall layers on the basis of principal component analysis (PCA) and cluster analysis. A Raman imaging data set collected from a 55.5 MUm * 47.5 MUm cross-section of poplar tension wood was analyzed. Several thousand spectra were successfully classified into five groups in accordance with different morphological regions, namely, cell corner (CC), compound middle lamella (CML), secondary wall (SW), gelatinous layer (G-layer), and cell lumen. Their corresponding average spectra were also calculated. In addition, the relationship between different characteristic peaks in the obtained Raman spectra was estimated and it was found that the peak at 1331 cm(-1) is more related to lignin rather than cellulose. Not only can this novel method provide a convenient and accurate procedure for identifying the spectra of different cell wall layers in a Raman imaging data set, but it also can bring new insights into studying the morphology and topochemistry in wood cell walls. PMID- 25531491 TI - Preneoplastic conditions in the stomach: always a point of no return? AB - Gastric atrophy (GA) and intestinal metaplasia are defined preneoplastic conditions of the stomach, whereas Helicobacter pylori gastritis by itself represents a risk condition for gastric cancer (GC) development. After H. pylori eradication, an overall reduction of GC incidence has been shown. However, this effect is lost once H. pylori gastritis has evolved to severe GA. On the other hand, only up to 5% of patients with severe GA may develop intestinal-type GC, and therefore the so-called 'point of no return' may not be appropriate to define the condition of all patients carrying preneoplastic changes in the gastric mucosa. Patients with the highest risk for GC are those who have already had GC that was cured by endoscopic resection. Prospective trials on the effect of H. pylori eradication in this high-risk group of patients showed inconsistent results, probably because of the inclusion of patients with and without baseline severe GA. Severe fundic GA determined by means of histology or serology represents the condition with the highest risk for metachronous neoplastic lesions in the stomach. In the present review, we focus on the effects of H. pylori eradication in patients with severe atrophy in terms of GC prevention. PMID- 25531492 TI - Management of gastric mucosa-associated lymphoid tissue lymphoma. AB - Extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) type represent 7-8% of all B cell lymphomas and up to 50% of primary gastric lymphomas and can arise at any extranodal site. The most common manifestation is the stomach, which is almost invariably associated with a chronic Helicobacter pylori infection. The diagnosis is based on the histopathological evaluation of multiple gastric biopsies in accordance with the current WHO classification. The mainstay of therapy is H. pylori eradication, which must be delivered to all gastric MALT lymphoma patients, independent of stage. In patients who do not achieve lymphoma regression following antibiotic therapy, irradiation and/or systemic oncological therapies should be applied, depending on the stage of the disease. Radiotherapy might be the preferred option for localized stage. However, in the presence of disseminated or advanced disease, chemotherapy and/or immunotherapy with the anti-CD 20 antibody rituximab is the treatment of choice, but no standard chemotherapy has been defined so far. Gastric MALT lymphomas have a limited tendency to distant spreading and to histological transformation and thus MALT lymphoma usually has a favorable outcome, with an overall survival rate at 5 years of more than 85%. PMID- 25531493 TI - How can screening colonoscopy be optimized? AB - Since the implementation of screening programmes, both the incidence and mortality of colorectal cancer have been decreasing. The choice of the preferred screening tool, however, is divergent and the adherence to screening programmes in most countries is still low. Cancer detection tests such as the guaiac faecal occult blood test (gFOBT) and the immunohistochemical FOBT (iFOBT) achieve higher acceptance than endoscopy. The sensitivity and specificity of iFOBT are higher than those of gFOBT, but gFOBT is cheaper and easier to perform. Endoscopic screening, which represents cancer prevention tests, has higher sensitivity for premalignant lesions than gFOBT and iFOBT and enables diagnosis and therapy in one single procedure. Since screening colonoscopy and sigmoidoscopy are invasive procedures with potentially severe adverse events, the highest possible quality must be provided. High-tech equipment, experience, training, quality control programmes, excellent bowel preparation and low adverse event rates are pivotal. Alternative screening tools such as CT colonography, barium enema CT and multitarget stool DNA tests have not been established as routine screening tools to date. PMID- 25531494 TI - Serrated and non-serrated precursor lesions of colorectal cancer. AB - Although often viewed as a single disease, colorectal cancer more accurately represents a family of diseases with different precursor lesions. Conventional (tubular, tubulovillous and villous) adenomas are the most common neoplastic lesions occurring in the large intestine. They have adenomatous polyposis coli (APC) mutations and arise from dysplastic aberrant crypt foci, initially as polyclonal lesions. In sporadic tumours, neoplastic progression follows the traditional pathway (chromosomal instability pathway), resulting in CpG island methylator phenotype (CIMP)-negative, microsatellite-stable (MSS), BRAF and KRAS wild-type cancers. Germline mutations in the APC gene lead to familial adenomatous polyposis. Conventional adenomas are also the precursors of Lynch syndrome-associated microsatellite-instable (MSI-high) cancers. Sessile serrated adenoma/polyp (SSA/P) is the principal precursor lesion of the serrated pathway, in which BRAF mutation can lead to colorectal cancer with MSI-high CIMP-high or MSS CIMP-high phenotype. SSA/Ps have been associated with synchronous and metachronous invasive adenocarcinomas as well as so-called interval carcinomas. Serrated polyposis is rare but most likely underdiagnosed. Affected individuals bear an increased but unspecified risk for the development of colorectal cancer; close endoscopic surveillance is warranted. Traditional serrated adenomas (TSAs) are much less common than the other serrated lesions. Cancers originating from TSAs may show KRAS mutation with a CIMP-high MSS phenotype. PMID- 25531495 TI - Small colorectal polyps. AB - Small (<10 mm) and diminutive (<6 mm) polyps harbour high-grade dysplasia or cancer in 0.3-5% of cases. The potential to grow and develop advanced histology is low. Traditional guidelines still recommend the removal of all polyps. Visual characterisation with modern endoscopic technology could enable us to leave diminutive hyperplastic polyps in situ and remove but discard small polyps. In expert hands, high-definition white-light endoscopy and virtual chromoendoscopy can reach an accuracy of more than 90% in distinguishing between hyperplastic and adenomatous pathology. For less experienced endoscopists the values are lower and therefore the concept is not yet fit for routine use. Polyps can be removed completely with snares but not with forceps. The cold snaring technique in particular has proved safe and effective for small polyps. With more experience in the future a 'cut and discard' strategy for small polyps and a 'do not resect' strategy for diminutive polyps will save money and time to deal with more advanced lesions. PMID- 25531496 TI - Small bowel Crohn's disease: an emerging disease phenotype? AB - An increasing understanding of the pathogenesis of Crohn's disease (CD), coupled with improvements in therapeutic options, has promoted the concept of stratifying patients with CD into distinct disease phenotypes according to risk. Small bowel CD, due to the numerous non-specific potential symptoms and the anatomical location of the disease, is a particularly difficult phenotype to identify. The fact that the majority of de novo strictures occur in the ileum/ileo-colonic region ensures that recognition of small bowel involvement is essential. Certainly, it is becoming increasingly recognised due to improvements in imaging and endoscopic techniques. Both CT and MR enterography appear capable of accurately diagnosing small bowel CD. Furthermore, the development of capsule endoscopy and balloon-assisted enteroscopy allow direct visualisation of the small bowel. Limited data to date would suggest that small bowel CD is a difficult entity to treat even in the current era of the ever-expanding field of biological therapies. Further long-term follow-up studies are necessary using both small bowel capsule endoscopy and cross-sectional imaging to truly assess, firstly, whether small bowel CD is more resistant to treatment and, secondly, whether it has an effect over time in terms of complications. In the future, serological and genetic tests, coupled with the aforementioned investigations, will permit early diagnosis and early treatment of small bowel CD. PMID- 25531497 TI - Colorectal cancer in patients with inflammatory bowel disease: the true impact of the risk. AB - Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). The association between IBD and CRC is well supported, but reported risk estimates vary widely. Although recent evidence from population-based studies reports a decline in risk, CRC accounts for 10-15% of all deaths in IBD. The potential causes of recent epidemiological trends and the real magnitude of risk of CRC in IBD are subjects of debate. The molecular pathway leading to CRC differs from the classic adenoma-to-CRC sequence. Chronic inflammation contributes to the development of low- and high-grade dysplasia which may further convert into CRC. Patients with a young age at onset, long standing and extensive colitis with severe inflammatory burden, a family history of sporadic CRC, and concomitant primary sclerosing cholangitis are at greatest risk. The CRC risk in patients with colonic Crohn's disease is similar to that of ulcerative colitis. IBD-associated CRC can frequently be detected at late stages and at a younger age. The long-term prognosis of CRC may be poorer in patients with IBD than in those with sporadic CRC. Regular surveillance colonoscopies may permit earlier detection of CRC, with a corresponding improved prognosis. The interval between surveillance colonoscopies is dependent on each patient's personal risk profile. PMID- 25531498 TI - Chemoprevention of colorectal cancer. AB - Colorectal cancer has become one of the most prevalent malignant diseases for both men and women. Patients with inflammatory bowel diseases or certain inherited cancer syndromes are at high risk of developing colorectal cancer and have naturally the highest need for cancer prevention. In familial adenomatous polyposis (FAP) and Lynch syndrome, most of the underlying germline mutations can be detected by DNA sequencing, and medical counselling of affected individuals involves both surveillance tests and chemopreventive measures. However, as the mechanisms leading to colorectal cancer differ in these high-risk groups, the molecular action of chemopreventive drugs needs to be adjusted to the certain pathway of carcinogenesis. In the last decades, a number of drugs have been tested, including sulindac, aspirin, celecoxib, and mesalazine, but some of them are still controversially discussed. This review summarizes the advances and current standards of colorectal cancer prevention in patients with inflammatory bowel disease, FAP and Lynch syndrome. PMID- 25531499 TI - Development and validation of an endoscopic classification of diverticular disease of the colon: the DICA classification. AB - BACKGROUND: A validated endoscopic classification of diverticular disease (DD) of the colon is lacking at present. Our aim was to develop a simple endoscopic score of DD: the Diverticular Inflammation and Complication Assessment (DICA) score. METHODS: The DICA score for DD resulted in the sum of the scores for the extension of diverticulosis, the number of diverticula per region, the presence and type of inflammation, and the presence and type of complications: DICA 1 (<= 3), DICA 2 (4-7) and DICA 3 (>7). A comparison with abdominal pain and inflammatory marker expression was also performed. A total of 50 videos of DD patients were reassessed in order to investigate the predictive role of DICA on the outcome of the disease. RESULTS: Overall agreement in using DICA was 0.847 (95% confidence interval, CI, 0.812-0.893): 0.878 (95% CI 0.832-0.895) for DICA 1, 0.765 (95% CI 0.735-0.786) for DICA 2 and 0.891 (95% CI 0.845-0.7923) for DICA 3. Intra-observer agreement (kappa) was 0.91 (95% CI 0.886-0.947). A significant correlation was found between the DICA score and C-reactive protein values (p = 0.0001), as well as between the median pain score and the DICA score (p = 0.0001). With respect to the 50 patients retrospectively reassessed, occurrence/recurrence of disease complications was recorded in 29 patients (58%): 10 (34.5%) were classified as DICA 1 and 19 (65.5%) as DICA 2 (p = 0.036). CONCLUSIONS: The DICA score is a simple, reproducible, validated and easy-to-use endoscopic scoring system for DD of the colon. PMID- 25531500 TI - Risk assessment in early colorectal cancer: histological and molecular markers. AB - The pathological examination of early colorectal cancer specimens, in particular 'malignant polyps', provides important prognostic information. The depth of invasion into the submucosal layer assessed according to the Haggitt (for pedunculated lesions) or Kikuchi (for nonpolypoid lesions) classification systems or by direct measurement has been associated with the risk of lymph node metastasis. Angioinvasion, in particular lymphatic invasion, budding, tumor differentiation or grade, and resection margin status have been identified as further risk factors. The combination of these parameters allows the stratification of affected individuals into low- and high-risk categories, which is pivotal for clinical management. For low-risk cancers, defined as a completely excised Haggitt level 1-3/Kikuchi sm1 tumor with no evidence of poor differentiation or angioinvasion, local excision is generally regarded as adequate treatment. Oncological surgical resection is, however, indicated for high-risk cancers, which show at least one of the following features: Haggitt level 4/Kikuchi sm3 invasion, the presence of lymphatic (or vascular) invasion, poor differentiation, or positive resection margin. The inclusion of molecular markers such as tumor suppressor genes and their products, markers involved in tumor vascularization, and markers related to tumor cell adhesion and invasion may help to refine risk stratification, but data on molecular markers are still limited in this regard. PMID- 25531501 TI - Immunoglobulin G4, autoimmune pancreatitis and pancreatic cancer. AB - BACKGROUND: Immunoglobulin G4 (IgG4)-related diseases are a group of diseases characterized by enlargement of the affected organs, elevation of serum IgG4, massive infiltration of affected organs with lymphocytes and plasma cells with IgG4 positivity and tissue fibrosis. Type I autoimmune pancreatitis is one form of IgG4-related disease. For IgG4-related diseases, various localizations are described for up to 10% of malignancies. The aim of our study was to examine IgG4 serum levels and pancreatic tissue with respect to the simultaneous presence of autoimmune pancreatitis in patients with pancreatic cancer. METHODS: IgG4 serum levels were examined In 106 patients with histologically confirmed pancreatic cancer. The level of 135 mg/dl was considered as the normal value. Pancreatic tissue was histologically examined with respect to the presence of markers of autoimmune pancreatitis. RESULTS: A higher IgG4 level than the cut-off value of 135 mg/dl was proven in 11 patients with pancreatic cancer. Of these 11 patients, 7 had levels twice the normal limit (65.6%). Autoimmune pancreatitis was diagnosed in these individuals. In the case of 1 patient, it was basically an unexpected finding; another patient was initially diagnosed with autoimmune pancreatitis. Repeated biopsy of the pancreas at the time of diagnosis did not confirm the presence of tumour structures, therefore steroid therapy was started. At a check-up 6 months after starting steroid therapy, the condition of the patient improved subjectively and IgG4 levels decreased. However, endosonographically, malignancy was suspected, which was subsequently confirmed histologically. This patient also demonstrated an IgG4 level twice the normal limit. CONCLUSION: IgG4-related diseases can be accompanied by the simultaneous occurrence of malignancies, which also applies to autoimmune pancreatitis. Chronic pancreatitis is considered a risk factor for pancreatic cancer. It cannot be reliably confirmed whether this also applies to autoimmune pancreatitis. In accordance with other works, however, it is evident that, despite the described high sensitivity and specificity for IgG4 elevation in the case of autoimmune pancreatitis, even levels twice the normal limit are demonstrable in some individuals with pancreatic cancer, without the presence of autoimmune pancreatitis. We believe that patients with IgG4-related disease, including autoimmune pancreatitis, must be systematically monitored with respect to the potential presence of malignancy. PMID- 25531502 TI - Radiological evaluation of focal pancreatic lesions. AB - The early and accurate characterization of pancreatic masses remains a challenge in diagnostic radiology, while the continuously evolving diagnostic possibilities give rise to an ever-increasing number of incidentally found pancreatic masses. This article discusses the relevance and role of ultrasound, endoscopic ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) in the diagnosis of pancreatic lesions. Specific protocols such as MR cholangiopancreatography and multiphase CT allow for a close characterization. While CT and MRI deliver information to further evaluate pancreatic disease, PET/CT has shown potential for staging purposes and in the clinical follow-up of pancreatic cancer patients. Common differential diagnoses regarding pancreatic cancer are discussed, and typical imaging features of anatomical variations, cystic lesions and pancreatitis are illustrated, together with clinical signs of pancreatic disease. The use of cross-sectional imaging in correlation with clinical features allows for an accurate and early detection of pancreatic masses and assists in differentiating benign from malignant disease. PMID- 25531503 TI - Pancreatic intraductal papillary mucinous neoplasm--where is the challenge? AB - Cystic lesions of the pancreas are increasingly recognized due to the widespread use of modern abdominal imaging technologies. The majority of these lesions display pseudocysts and mucinous cystic neoplasms. In contrast to pseudocysts, it is well established that mucinous cystic neoplasms of the pancreas exhibit a significant potential for malignant transformation over time. Among mucinous cystic tumors, the most frequently observed entity is pancreatic intraductal papillary mucinous neoplasm (IPMN). IPMNs are characterized by cystic dilation of pancreatic ducts and the production of mucus and by an adenoma-carcinoma sequence eventually culminating in invasive carcinoma in some patients. Due to the high risk of harboring malignancy, there is international consensus that IPMNs with involvement of the main pancreatic duct should be recommended for surgical resection. To date, the indication for surgery of branch-duct IPMNs is controversially discussed because of the overall lower risk of malignant transformation compared to main-duct IPMNs. Particularly for small and asymptomatic side-branch IPMNs, the indication for surgical resection remains challenging. In addition to the international consensus guidelines, a number of potential preoperative features predicting malignant transformation have been discussed recently. Moreover, novel surgical pancreatic parenchyma-sparing techniques such as enucleations or segmental pancreatic resections have been reported in order to treat IPMNs. The present article aims to demonstrate the current scientific knowledge in this field and to highlight the current controversy. PMID- 25531505 TI - Clearance approach in hyperinsulinemic-euglycemic clamp evaluation in lean and obese subjects. AB - PURPOSE/AIM: The main aim of this study was to propose a method to express whole body insulin sensitivity as estimated by a hyperinsulinemic-euglycemic clamp (HEC) as a dimensionless parameter. MATERIALS AND METHODS: Two groups of subjects were examined: The first group was comprised of seven healthy lean volunteers with BMI <25 kg/m(2) and a second group comprised of four obese subjects with BMI >=30 kg/m(2). The dependence between the M/I index expressing the whole body insulin sensitivity, and the dimensionless whole human body effect E as a ratio of the clearance of glucose and the clearance of insulin after their exogenous administration during the last 40 min of the HEC test, was expressed by regression analysis. Unlike an expression of insulin sensitivity/resistance as a function of M taking into account the space corrections or the M/I index, our whole human body effect represents the insulin sensitivity/resistance as a dimensionless number. RESULTS: A linear dependence between the M/I index and the dimensionless effect E with zero intercept and slope at 2.2623 +/- 0.157, r = 0.914, and between the M/I index and the effect E recalculated per kg of human body weight with zero intercept and slope at 0.03164 +/- 0.00127, r = 0.978, were observed. CONCLUSIONS: The high correlation between the M/I index and new effect E in lean and obese volunteers confirms our proposal that the HEC test could be evaluated by a dimensionless parameter which eliminates potential unit mismatches in the expression of clamp results. PMID- 25531506 TI - Cyclometalated Fe(II) complexes as sensitizers in dye-sensitized solar cells. AB - Dye-sensitized solar cells (DSSCs) often utilize transition metal-based chromophores for light absorption and semiconductor sensitization. Ru(II)-based dyes are among the most commonly used sensitizers in DSSCs. As ruthenium is both expensive and rare, complexes based on cheaper and more abundant iron could serve as a good alternative. In this study, we investigate Fe(II)-bis(terpyridine) and its cyclometalated analogues, in which pyridine ligands are systematically replaced by aryl groups, as potential photosensitizers in DSSCs. We employ density functional theory at the B3LYP/6-31G*,SDD level to obtain the ground state electronic structure of these complexes. Quantum dynamics simulations are utilized to study interfacial electron transfer between the Fe(II) photosensitizers and a titanium dioxide semiconductor. We find that cyclometalation stabilizes the singlet ground state of these complexes by 8-19 kcal/mol but reduces the electron density on the carboxylic acid attached to the aryl ring. The results suggest that cyclometalation provides a feasible route to increasing the efficiency of Fe(II) photosensitizers but that care should be taken in choosing the substitution position for the semiconductor anchoring group. PMID- 25531508 TI - Key chemical factors of arginine finger catalysis of F1-ATPase clarified by an unnatural amino acid mutation. AB - A catalytically important arginine, called Arg finger, is employed in many enzymes to regulate their functions through enzymatic hydrolysis of nucleotide triphosphates. F1-ATPase (F1), a rotary motor protein, possesses Arg fingers which catalyze hydrolysis of adenosine triphosphate (ATP) for efficient chemomechanical energy conversion. In this study, we examined the Arg finger catalysis by single-molecule measurements for a mutant of F1 in which the Arg finger is substituted with an unnatural amino acid of a lysine analogue, 2,7 diaminoheptanoic acid (Lyk). The use of Lyk, of which the side chain is elongated by one CH2 unit so that its chain length to the terminal nitrogen of amine is set to be equal to that of arginine, allowed us to resolve key chemical factors in the Arg finger catalysis, i.e., chain length matching and chemical properties of the terminal groups. Rate measurements by single-molecule observations showed that the chain length matching of the side-chain length is not a sole requirement for the Arg finger to catalyze the ATP hydrolysis reaction step, indicating the crucial importance of chemical properties of the terminal guanidinium group in the Arg finger catalysis. On the other hand, the Lyk mutation prevented severe formation of an ADP inhibited state observed for a lysine mutant and even improved the avoidance of inhibition compared with the wild-type F1. The present study demonstrated that incorporation of unnatural amino acids can widely extend with its high "chemical" resolution biochemical approaches for elucidation of the molecular mechanism of protein functions and furnishing novel characteristics. PMID- 25531507 TI - Is prehospital treatment of acute stroke too expensive? An economic evaluation based on the first trial. AB - BACKGROUND: Recently, a strategy for treating stroke directly at the emergency site was developed. It was based on the use of an ambulance equipped with a scanner, a point-of-care laboratory, and telemedicine capabilities (Mobile Stroke Unit). Despite demonstrating a marked reduction in the delay to thrombolysis, this strategy is criticized because of potentially unacceptable costs. METHODS: We related the incremental direct costs of prehospital stroke treatment based on data of the first trial on this concept to one year direct cost savings taken from published research results. Key parameters were configuration of emergency medical service personnel, operating distance, and population density. Model parameters were varied to cover 5 different relevant emergency medical service scenarios. Additionally, the effects of operating distance and population density on benefit-cost ratios were analyzed. RESULTS: Benefits of the concept of prehospital stroke treatment outweighed its costs with a benefit-cost ratio of 1.96 in the baseline experimental setting. The benefit-cost ratio markedly increased with the reduction of the staff and with higher population density. Maximum benefit-cost ratios between 2.16 and 6.85 were identified at optimum operating distances in a range between 43.01 and 64.88 km (26.88 and 40.55 miles). Our model implies that in different scenarios the Mobile Stroke Unit strategy is cost-efficient starting from an operating distance of 15.98 km (9.99 miles) or from a population density of 79 inhabitants per km2 (202 inhabitants per square mile). CONCLUSION: This study indicates that based on a one-year benefit-cost analysis that prehospital treatment of acute stroke is highly cost effective across a wide range of possible scenarios. It is the highest when the staff size of the Mobile Stroke Unit can be reduced, for example, by the use of telemedical support from hospital experts. Although efficiency is positively related to population density, benefit-cost ratios can be greater than 1 even in rural settings. PMID- 25531509 TI - An experimental study on the effectiveness of disclosing stressful life events and support messages: when cognitive reappraisal support decreases emotional distress, and emotional support is like saying nothing at all. AB - How can we best support others in difficult times? Studies testing the effects of supportive communication revealed mixed findings. The current study focuses on the effects of supportive communication following different disclosure styles, and includes outcome measures to assess emotional well-being. Hypotheses were tested in a 2 (disclosure style: cognitive reappraisal disclosure vs. emotional disclosure) * 3 (support message: cognitive reappraisal response vs. socio affective response vs. no response) between subjects factorial design. Receiving a cognitive reappraisal response, rather than a socio-affective response or no response, decreased emotional distress in the emotional disclosure group. Support messages showed no effects in the cognitive reappraisal disclosure group. Although socio-affective responses were positively evaluated, cognitive reappraisal responses may be more effective during emotional upheaval because they provide a positive way out of negative emotions. PMID- 25531512 TI - [Squatting cast for biomechanical treatment of decentred hip joints]. AB - The so-called "congenital" luxation of the hip joint is endemic in Central Europe and occurs in about 1% of all newborn infants. By the means of ultrasonographic diagnosis according to the Graf method an early detection instantly after birth has become a good clinical routine in the German-speaking countries. Sonography based conservative treatment has become the gold standard. The cast in squatting ("human") position is a standard procedure in order to retain the originally decentred or unstable hip joints in the reduced position: 100 degrees flexion and 50 degrees abduction are necessary to fix the hip joint in the reduced position without the risk of avascular necrosis. After the fixation in a squatting-cast, a period of functional bracing in flexed position enhances bony maturation. This two-phase functional conservative treatment can avoid later osteotomies or even early total hip replacement. PMID- 25531513 TI - [Journal impact factor: unsuited for scientific quality evaluation ]. PMID- 25531510 TI - Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease, yet its etiology and pathogenesis are poorly understood. PD is characterized by selective dopaminergic (DAergic) degeneration and progressive hypokinetic motor impairment. Mutations in dj-1 cause autosomal recessive early-onset PD. DJ-1 is thought to protect DAergic neurons via an antioxidant mechanism, but the precise basis of this protection has not yet been resolved. Aging and manganese (Mn) exposure are significant non-genetic risk factors for PD. Caenorhabditis elegans (C. elegans) is an optimal model for PD and aging studies because of its simple nervous system, conserved DAergic machinery, and short 20-day lifespan. Here we tested the hypothesis that C. elegans DJ-1 homologues were protective against Mn induced DAergic toxicity in an age-dependent manner. We showed that the deletion of C. elegans DJ-1 related (djr) genes, djr-1.2, decreased survival after Mn exposure. djr-1.2, the DJ-1 homologue was expressed in DAergic neurons and its deletion decreased lifespan and dopamine (DA)-dependent dauer movement behavior after Mn exposure. We also tested the role of DAF-16 as a regulator of dj-1.2 interaction with Mn toxicity. Lifespan defects resulting from djr-1.2 deletion could be restored to normal by overexpression of either DJR-1.2 or DAF-16. Furthermore, dauer movement alterations after djr-1.2 deletion were abolished by constitutive activation of DAF-16 through mutation of its inhibitor, DAF-2 insulin receptor. Taken together, our results reveal PD-relevant interactions between aging, the PD environmental risk factor manganese, and homologues of the established PD genetic risk factor DJ-1. Our data demonstrate a novel role for the DJ-1 homologue, djr-1.2, in mitigating Mn-dependent lifespan reduction and DA signaling alterations, involving DAF-2/DAF-16 signaling. PMID- 25531514 TI - [Is the standard retention of syndesmotic positioning screws after ankle fracture fixation safe and feasible? A retrospective cohort study in 140 consecutive patients at a North American trauma centre]. AB - BACKGROUND: Unstable ankle injuries with associated disruption of the distal fibular syndesmosis are typically managed by adjunctive placement of temporary syndesmotic positioning screws. The widespread notion that positioning screws must be removed by default after healing of the syndesmosis remains a topic of debate which lacks scientific support. The present study was designed to test the hypothesis that syndesmotic positioning screws are safely retained per protocol in asymptomatic patients. PATIENTS AND METHODS: A retrospective analysis of an institutional prospective database was performed during a 5-year time-window at an academic level 1 trauma centre in the United States. All ankle fractures requiring surgical fixation were included in the analysis. The primary outcome parameter consisted of the rate of elective hardware removal for syndesmotic positioning screws within 6 months after surgical fixation. RESULTS: A total of 496 consecutive patients with 496 isolated ankle fractures managed by surgical fixation were included in this study. Of these, 140 injuries were managed by placement of syndesmotic positioning screws. Within 6 months follow-up, 17.1% of all syndesmotic screws were found to be radiographically broken, and 13.6% of syndesmotic screws revealed radiographic signs of loosening. Only 2 patients (1.4%) required the elective removal of symptomatic positioning screws within 6 months of surgical fracture fixation. CONCLUSION: Despite the high rate of radiographic complications related to breaking or loosening of syndesmotic screws in almost one third of all cases, more than 98% of all patients remain asymptomatic and do not require a scheduled hardware removal. The routine removal of syndesmotic positioning screws does not appear to be justified from a patient safety perspective. PMID- 25531515 TI - [Influence of disc degeneration on the development of disc prolapse]. AB - PURPOSE: The present clinical-radiological study examines retrospectively the relation between lumbar disc prolapse and degenerations like chondrosis and spondylosis. METHOD: Firstly the relation between disc prolapse and chondrosis was examined. 44 patients with disc prolapse and chondrosis in actual MRI scans in the same segment were recruited in our clinic. By regarding older MRI scans, we could find out which finding was first to occur. Concerning the second question, we followed patients with spondylosis to see if they could progress to a disc prolapse. RESULTS: In 67% of our cases with disc prolapse and chondrosis, a chondrosis was seen before the disc prolapse. More than a half had had a spondylosis and a chondrosis in the same segment before the herniation. Only 33% of our cases showed a prolapse before chondrosis. CONCLUSION: Concerning patients with disc prolapse and chondrosis in the same segment, chondrosis was seen before the herniation in most cases. Also patients with spondylosis progress to a herniation. A causal relation between both radiological findings is not possible. In a future study it must be analysed with statistical tests whether these results are generally valid. PMID- 25531516 TI - [The non-vascularised fibular transfer - indications and limits in infancy and adulthood]. AB - BACKGROUND: The non-vascularised fibular transfer is an established surgical procedure whose indication limits are verified and discussed. PATIENTS/MATERIAL AND METHODS: 12 patients with an average age of 17.9 years have been treated with a non-vascularised fibula transfer. The results are evaluated critically in comparison with those in the relevant literature. RESULTS: In ten cases a bone tumour and in two cases a chronic osteomyelitis have been treated. 11/12 patients showed a complete osseous integration. In one case a rigid pseudarthrosis of the ankle joint was observed. Clinical results were evaluated by the MSTS score (results 83.3-100). CONCLUSION: The non-vascularised fibula transfer is a reliable method to span bony defects of up to 25 cm in length. Unlike the autologous spongiosa graft it ensures a mechanical support because of the high cortical proportion. A temporarily occurring absorption of the transplant can be solved by a vascularised transfer, also the indication can be extended for covering combined osseous-soft tissue-defects or for reconstruction of the growth plate through epiphyseal transplantation. Indeed a strikingly increased extraction morbidity by resection of the peroneal artery and an essential elevated surgical effort are associated with these procedures. In consideration of the excellent results, the indication limits of the non-vascularised fibula transfer need to be defined. It can be successfully applied, especially in infancy, under the following conditions: unstable osseous defects with vital soft tissues, appropriate shape of the fibula for reconstruction as well as appropriate osseous requirements for a stable incorporation or osteosynthesis. PMID- 25531517 TI - [100th anniversary of the Oskar-Helene-Heim - an obituary]. AB - The Oskar-Helene-Heim is one of the birthplaces of German orthopaedic clinics. The clinic was demolished in winter 2013/2014. Almost all of the historic buildings of the traditional specialist hospital in south-west Berlin were torn down in in the preparation for a housing project. The history of this facility is briefly described in this article. PMID- 25531518 TI - [Current treatment strategies for spondylodiscitis in surgical clinics in Germany]. AB - BACKGROUND: Spondylodiscitis is a rare disease which is associated with high mortality. No guidelines for treatment exist and the available studies are not homogeneous. Attempts have been made in recent years to structure therapy using algorithms. Early recognition of the disease is above all important for its later outcome. Therapy takes place in not only orthopaedic/trauma surgery clinics but also in neurosurgical clinics. MATERIAL AND METHOD: We sent an online survey on this subject to orthopaedic clinics, trauma surgery and neurosurgery clinics in Germany. The aim was to ascertain current care strategies in Germany. A further objective was to elicit differences between the specialist fields. RESULTS: A total of 164 clinics responded to the survey. The response rate was 16% of the orthopaedic/trauma surgery clinics and 32% of the neurosurgical clinics. Differences between the two specialist fields can be found particularly in the use of systemic and local antibiotics, in the choice of surgical access to the thoracic spine and the lumbar spine and in post-operative imaging. In both specialist fields, patients with neurological dysfunctions are treated primarily in clinics with high case numbers. In terms of surgery, 2/3 of the responding clinics choose a one-stage operative treatment. Minimally invasive procedures and the use of cages are widespread. The participants estimate that, on the whole, a better outcome and higher patient satisfaction tend to exist after operative treatment. CONCLUSIONS: The lack of homogeneity regarding treatment strategies which is indicated here clearly shows the need for therapy guidelines as an aid to orientation. This will be a challenge for the future due to the low incidence and the situation regarding currently available studies. PMID- 25531519 TI - [Pertrochanteric fracture - operation for beginners?]. AB - BACKGROUND: In patients over 65 years, pertrochanteric proximal femur fractures are very common, with an incidence of 966/100,000. Treatment of choice is nailing or dynamic hip screws. The operative approaches are standardised and easy to learn. QUESTION: Is nail fixation a good procedure for surgical training? PATIENTS: From 1 January 2012 until 31 December 2013, 210 patients with an average age of 80.7 years and pertrochanteric fractures underwent treatment. 139 patients (66%) were treated by surgical trainees, 55 (26%) by staff surgeons, and 16 by the head of the department (8%). RESULTS: Preoperative delay averaged one day. Skin to skin operative time averaged 48 minutes for all patients. For trainees, the procedure averaged 45 minutes, while the more complex cases treated by staff surgeons (multi-fragment, markedly displaced) averaged 67 minutes and thus took significantly longer (p < 0.1). There was no difference in complications. There were 6 misplaced implants and cutouts (2.8%), one infection (0.5%), and 6 operative revisions because of hematoma or seroma (2.8%). Four patients (1.9%) died of cardiovascular failure with ASA 3 and 4 during the inpatient stay (2 in each group). CONCLUSION: Internal fixation with nailing in pertrochanteric femur fractures is a standard operative approach. It is suitable as a "beginner's" procedure, that is quickly and easily performed. Only complex, multifragmented or markedly displaced or long-segment fractures need to be treated by staff physicians. Mortality is not affected by the surgeon's experience, but rather by comorbidity and from the preoperative duration. PMID- 25531520 TI - [Intramedullary stabilisation of displaced midshaft clavicular fractures: does the fracture pattern (simple vs. complex) influence the anatomic and functional result]. AB - BACKGROUND: Displaced midshaft clavicular fractures are often treated operatively. The most common way of treatment is plating. Elastic stable intramedullary nailing (ESIN) is an alternative, but seldom used. Studies showed comparable or even better results for intramedullary nailing than for plating in simple 2- or 3-fragment midshaft fractures. The indication of ESIN for multifragmentary clavicular fractures is discussed critically in the literature because of reduced primary stability and danger of secondary shortening. Until now only few studies report functional results after fracture healing depending on the fracture type. To the best of our knowledge there is no study showing significantly worse functional scores for ESIN in complex displaced midshaft fractures. The objective of this study was to examine anatomic and functional results of simple (2 or 3 fragments, OTA type 15B1 and 15B2) and complex (multifragmentary, OTA type 15B3) displaced midshaft clavicula fractures after internal fixation. PATIENTS AND METHODS: Between 2009 and 2012, 40 patients (female/male 10/30; mean age 33 [16-60] years) with closed displaced midshaft clavicular fractures were treated by open reduction and ESIN (Titanium Elastic Nail [TEN], Synthes, Umkirch, Germany). Thirty-seven patients were retrospectively analysed after a mean of 27 (12-43) months. Twenty patients (group A) had simple fractures (OTA type 15B1 and 15B2), 17 patients (group B) had complex fractures (OTA type 15B3). All shoulder joints were postoperatively treated functionally for six weeks without weight limited to 90 degrees abduction/flexion. Both groups were comparable in gender, age, body mass index, months until metal removal, number of physiotherapy sessions and time until follow-up examination. Joint function (neutral zero method) and strength (standing patient with arm in 90 degrees abduction, holding 1-12 kg for 5 sec) in both shoulders were documented. The distance between the centre of the jugulum and the lateral acromial border was measured for both sides. The DASH, Constant Murley, Oxford shoulder and clavicular scores (Jubel) were calculated. Patients documented contentedness of outcome by VAS between 0 (absolute discontented) and 10 (very contented). Complications were recorded. RESULTS: Operatively treated displaced midshaft clavicular fractures. in comparison to the healthy side in group A had an average shortening of 5 (0-20) mm and in group B of 10 (3-25) mm, with a statistical significance between both groups. Patients of both groups were very contented with the results (VAS group A: 9.6; B: 9.5). DASH score (group A: 28; B: 3.1), Constant-Murley score (group A: 95.0; B: 93.8), Oxford shoulder score (group A: 46.2; B: 45.9) and the clavicula score (Jubel) (group A: 1.2; B: 2.1) were comparable between both groups without significance. In 4 patients (11%) complications occurred. Once (group B) an infection was seen, three times (group B) the ESIN had to be shortened on the medial side because of telescoping. CONCLUSION: Open ESIN of simple and complex displaced midshaft clavicular fractures leads after an average of 27 months to good or even excellent results. Healing of the clavicle in a modestly shortened position does not impair the patient. PMID- 25531521 TI - [High bone consolidation rates after humeral head-preserving revision surgery in non-unions of the proximal humerus]. AB - BACKGROUND: Fractures of the subcapital and proximal humerus shaft region are common fractures of the human skeleton. Their treatment should provide an early functional after-care of the shoulder joint, that is prone to arthrofibrosis. Although the upper extremity is not weight-bearing the occurrence of proximal humerus non-unions leads to severe impairment with inability to work and restrictions of activity of daily life. The aim of this study was to investigate whether an operative revision of proximal humerus non-unions with reosteosynthesis and application of distant autologous bone grafts can lead to sufficient bone healing. The second aim was to find out whether patients achieved an acceptable functional outcome, as alternatively patients could be treated by reconstruction with a shoulder prosthesis. PATIENTS AND METHODS: 27 patients (female = 15, male = 12) with reosteosynthesis of the proximal humerus and proximal humeral shaft due to non-union after initially operative fracture treatment were included between 2008 and 2014. Average age of patients was 56 years (23-87), 48% had no comorbidities, while 52% of the patients had at least 1 comorbidity such as diabetes, hypertension or nicotine abusus. The mean number of prior surgical intervention was 1.2 (1-3). The mean time between initial surgery and re-osteosynthesis was 12.3 months. Patients with signs of infection pseudarthrosis were excluded. The initial type of osteosynthesis was with plates (n = 16; thereof PHILOS Plate n = 14), and intramedullary nails (T2, Targon Nail, PHN, Seidel Nail; n = 11). Revision surgery was done with plate osteosynthesis (n = 26; thereof PHILOS Plate n = 4; LC Plate n = 10; angle plate n = 12). In 23 patients (89%) a distant bone transplantation was done from the iliac crest, and 1 patient received allogenous bone. Three patients (11%) received bone morphogenetic protein 7 (BMP 7) in combination with distant bone graft. Intraoperative swabs from the pseudarthrosis area showed no bacterial pathogen after 14 days of incubation. DASH score and Constant score were used to evaluate the functional outcome after revision surgery. Bone healing was determined by standard X-rays and evaluated by a modified radiological score. RESULTS: 89% of the patients could be followed for an average of 28 months and the radiological follow-up was at 9 months. The radiological score showed very good (50%), or good results, and a sufficient bone healing was shown in 25 of 27 patients (93%). The pseudarthrosis revision surgery failed in two cases (n = 1 persisting non-union; n = 1 humeral head necrosis after re-operation with angle plate). DASH scores provided a mean of 40 +/- 28.8 with a range from 0-97 points, and the results from the Constant score provided 45 +/- 25.4. The analysis with variation of age showed a trend for better results in female patients < 60 years of age. As complications after bone graft 3 patients had persistent local dysesthesia (11%), in one case fracture of the iliac bone occurred that healed with conservative treatment. CONCLUSION: The pseudarthrosis revision surgery with humeral head preserving re-osteosynthesis with bone transplantation is an effective treatment for non-unions of the proximal humerus and the proximal humeral shaft and the current results showed high bone consolidation rates. As the functional results remained limited after revision an individual treatment decision should be made concerning the most appropriate therapy. While a shoulder prosthesis may be considered in the aged patient, a revision strategy with reosteosynthesis should be considered particularly in younger patients. PMID- 25531523 TI - [Perthes disease]. AB - Morbus Perthes today still poses a challenge for the orthopaedic surgeon because of the unclear aetiology as well as the controversial discussion about the role and kind of multiple treatment principles. The prognosis depends upon clinical (e.g. age at onset, reduction of range of motion, gender) and radiological (extent of necrosis, containment) parameters. Of these, only the reduced range of motion and a loss of containment can be adressed therapeutically, be it in a conservative and/or operative concept. Pelvic osteotomies have the advantage of a high potential of correction without the biomechanic disadvantages which are associated with intertrochanteric varus osteotomies. Nowadays, the use of orthoses is considered to be obsolete. Non-containment is targeted mainly on the symptomatic treatment and the correction of residual deformities. Based on the outcome after the final stage there is a risk of premature osteoarthritis with the need of early total hip replacement. PMID- 25531522 TI - [Evaluation of biomechanical models for therapy planning of total hip arthroplasty - direct comparison of computational results with in vivo measurements]. AB - A consideration of the patient-specific biomechanical situation in the context of the surgical planning of total hip arthroplasty is highly recommended and may have a positive impact on the therapeutic outcome. In current clinical practice, surgical planning is based on the status of the individual hip and its radiographic appearance. Several authors proposed different biomechanical modeling approaches for the calculation of the resultant hip force R on the basis of parameters gathered from plain radiography. The comparative study presented in this paper shows that the biomechanical models by Pauwels, Debrunner, Blumentritt and Iglic provide a good approximation of the magnitude of R when compared to the in vivo data from instrumented prostheses. In contrast, the Blumentritt model resulted in abnormally high values. However, the computational results for the orientation of R show a high variability of all modeling approaches and seem to depend more on the model used than on patient-specific parameters. PMID- 25531524 TI - Xenopus Nkx6.3 is a neural plate border specifier required for neural crest development. AB - In vertebrates, the neural plate border (NPB) is established by a group of transcription factors including Dlx3, Msx1 and Zic1. The crosstalk between these NPB specifiers governs the separation of the NPB region into placode and neural crest (NC) territories and also their further differentiation. Understanding the mechanisms of NPB formation and NC development is critical for our knowledge of related human diseases. Here we identified Nkx6.3, a transcription factor of the Nkx family, as a new NPB specifier required for neural crest development in Xenopus embryos. XNkx6.3 is expressed in the ectoderm of the neural plate border region at neurula stages, covering the epidermis, placode and neural crest territories, but not the neural plate. Inhibition of Nkx6.3 by dominant negative construct or specific morpholino leads to neural crest defects, while overexpression of Nkx6.3 induces ectopic neural crest in the anterior neural fold. In animal caps, Nkx6.3 alone is able to initiate the whole neural crest regulatory network and induces neural crest fate robustly. We showed that overexpression of Nkx6.3 affects multiple signaling pathways, creating a high Wnt, low-BMP environment required for neural crest development. Gain- and loss-of function of Nkx6.3 have compound effects on the expression of known NPB genes, which is largely opposite to that of Dlx3. Overexpression of Dlx3 blocks the NC inducing activity of Nkx6.3. The crosstalk between Nkx6.3, Dlx3 and Msx1 is likely crucial for proper NPB formation and neural crest development in Xenopus. PMID- 25531525 TI - Clonidine treatment delays postnatal motor development and blocks short-term memory in young mice. AB - During the development of the nervous system, the perinatal period is particularly sensitive as neuronal connections are still forming in the brain of the neonate. Alpha2-adrenergic receptors are overexpressed temporarily in proliferative zones in the developing brain, reaching a peak during the first postnatal week of life. Both stimulation and blocking of these receptors during this period alter the development of neural circuits, affecting synaptic connectivity and neuronal responses. They even affect motor and cognitive skills later on in the adult. It's especially important to look for the early neurological consequences resulting from such modifications, because they may go unnoticed. The main objective of the present study has been to reaffirm the importance of the maturation of alpha-adrenergic system in mice, by carrying out a comprehensive examination of motor, behavioral and cognitive effects in neonates, during early postnatal development, following chronic administration of the drug Clonidine, an alpha2 adrenergic system agonist. Our study shows that mice treated postnatally with clonidine present a temporal delay in the appearance of developmental markers, a slow execution of vestibular reflexes during first postnatal week of life and a blockade of the short term memory in the novel object recognition task. Shortly after the treatment the startle response is hyperreactive. PMID- 25531526 TI - Long-lasting responses under treatment with ipilimumab: an argument against maintenance therapy? AB - Ipilimumab, a monoclonal CTLA-4 antibody, was the first drug improving overall survival in patients with metastatic melanoma. However, there are still unanswered questions concerning therapeutic regimes, e.g. if maintenance therapy is needed to achieve long-term response. We present three patients with metastatic melanoma who received ipilimumab after progression under chemotherapy. In all of these patients ipilimumab led to a long-term tumor control of at least 32 months. Interestingly, all of them developed severe autoimmune toxicity and ipilimumab treatment was discontinued after 1 respectively 2 cycles. The present cases demonstrate that a long-term response to ipilimumab can be achieved without maintenance therapy. PMID- 25531527 TI - Enzymes from fungal and plant origin required for chemical diversification of insecticidal loline alkaloids in grass-Epichloe symbiota. AB - The lolines are a class of bioprotective alkaloids that are produced by Epichloe species, fungal endophytes of grasses. These alkaloids are saturated 1 aminopyrrolizidines with a C2 to C7 ether bridge, and are structurally differentiated by the various modifications of the 1-amino group: -NH2 (norloline), -NHCH3 (loline), -N(CH3)2 (N-methylloline), -N(CH3)Ac (N acetylloline), -NHAc (N-acetylnorloline), and -N(CH3)CHO (N-formylloline). Other than the LolP cytochrome P450, which is required for conversion of N-methylloline to N-formylloline, the enzymatic steps for loline diversification have not yet been established. Through isotopic labeling, we determined that N-acetylnorloline is the first fully cyclized loline alkaloid, implying that deacetylation, methylation, and acetylation steps are all involved in loline alkaloid diversification. Two genes of the loline alkaloid biosynthesis (LOL) gene cluster, lolN and lolM, were predicted to encode an N-acetamidase (deacetylase) and a methyltransferase, respectively. A knockout strain lacking both lolN and lolM stopped the biosynthesis at N-acetylnorloline, and complementation with the two wild-type genes restored production of N-formylloline and N-acetylloline. These results indicated that lolN and lolM are required in the steps from N acetylnorloline to other lolines. The function of LolM as an N-methyltransferase was confirmed by its heterologous expression in yeast resulting in conversion of norloline to loline, and of loline to N-methylloline. One of the more abundant lolines, N-acetylloline, was observed in some but not all plants with symbiotic Epichloe siegelii, and when provided with exogenous loline, asymbiotic meadow fescue (Lolium pratense) plants produced N-acetylloline, suggesting that a plant acetyltransferase catalyzes N-acetylloline formation. We conclude that although most loline alkaloid biosynthesis reactions are catalyzed by fungal enzymes, both fungal and plant enzymes are responsible for the chemical diversification steps in symbio. PMID- 25531528 TI - Flagellin as carrier and adjuvant in cocaine vaccine development. AB - Cocaine abuse is problematic, directly and indirectly impacting the lives of millions, and yet existing therapies are inadequate and usually ineffective. A cocaine vaccine would be a promising alternative therapeutic option, but efficacy is hampered by variable production of anticocaine antibodies. Thus, new tactics and strategies for boosting cocaine vaccine immunogenicity must be explored. Flagellin is a bacterial protein that stimulates the innate immune response via binding to extracellular Toll-like receptor 5 (TLR5) and also via interaction with intracellular NOD-like receptor C4 (NLRC4), leading to production of pro inflammatory cytokines. Reasoning that flagellin could serve as both carrier and adjuvant, we modified recombinant flagellin protein to display a cocaine hapten termed GNE. The resulting conjugates exhibited dose-dependent stimulation of anti GNE antibody production. Moreover, when adjuvanted with alum, but not with liposomal MPLA, GNE-FliC was found to be better than our benchmark GNE-KLH. This work represents a new avenue for exploration in the use of hapten-flagellin conjugates to elicit antihapten immune responses. PMID- 25531529 TI - Cancer immunotherapy employing an innovative strategy to enhance CD4+ T cell help in the tumor microenvironment. AB - Chemotherapy and/or radiation therapy are widely used as cancer treatments, but the antitumor effects they produce can be enhanced when combined with immunotherapies. Chemotherapy kills tumor cells, but it also releases tumor antigen and allows the cross-presentation of the tumor antigen to trigger antigen specific cell-mediated immune responses. Promoting CD4+ T helper cell immune responses can be used to enhance the cross-presentation of the tumor antigen following chemotherapy. The pan HLA-DR binding epitope (PADRE peptide) is capable of generating antigen-specific CD4+ T cells that bind various MHC class II molecules with high affinity and has been widely used in conjunction with vaccines to improve their potency by enhancing CD4+ T cell responses. Here, we investigated whether intratumoral injection of PADRE and the adjuvant CpG into HPV16 E7-expressing TC-1 tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and PADRE was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and PADRE also enhanced the generation of PADRE-specific CD4+ T cells and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci. The treatment regimen presented here represents a universal approach to cancer control. PMID- 25531531 TI - SynPAnal: software for rapid quantification of the density and intensity of protein puncta from fluorescence microscopy images of neurons. AB - Continuous modification of the protein composition at synapses is a driving force for the plastic changes of synaptic strength, and provides the fundamental molecular mechanism of synaptic plasticity and information storage in the brain. Studying synaptic protein turnover is not only important for understanding learning and memory, but also has direct implication for understanding pathological conditions like aging, neurodegenerative diseases, and psychiatric disorders. Proteins involved in synaptic transmission and synaptic plasticity are typically concentrated at synapses of neurons and thus appear as puncta (clusters) in immunofluorescence microscopy images. Quantitative measurement of the changes in puncta density, intensity, and sizes of specific proteins provide valuable information on their function in synaptic transmission, circuit development, synaptic plasticity, and synaptopathy. Unfortunately, puncta quantification is very labor intensive and time consuming. In this article, we describe a software tool designed for the rapid semi-automatic detection and quantification of synaptic protein puncta from 2D immunofluorescence images generated by confocal laser scanning microscopy. The software, dubbed as SynPAnal (for Synaptic Puncta Analysis), streamlines data quantification for puncta density and average intensity, thereby increases data analysis throughput compared to a manual method. SynPAnal is stand-alone software written using the JAVA programming language, and thus is portable and platform-free. PMID- 25531530 TI - How the context matters. Literal and figurative meaning in the embodied language paradigm. AB - The involvement of the sensorimotor system in language understanding has been widely demonstrated. However, the role of context in these studies has only recently started to be addressed. Though words are bearers of a semantic potential, meaning is the product of a pragmatic process. It needs to be situated in a context to be disambiguated. The aim of this study was to test the hypothesis that embodied simulation occurring during linguistic processing is contextually modulated to the extent that the same sentence, depending on the context of utterance, leads to the activation of different effector-specific brain motor areas. In order to test this hypothesis, we asked subjects to give a motor response with the hand or the foot to the presentation of ambiguous idioms containing action-related words when these are preceded by context sentences. The results directly support our hypothesis only in relation to the comprehension of hand-related action sentences. PMID- 25531532 TI - Cryptococcus neoformans induces antimicrobial responses and behaves as a facultative intracellular pathogen in the non mammalian model Galleria mellonella. AB - Cryptococcus neoformans is an encapsulated opportunistic fungal pathogen that is found in multiple niches in the environment and that can cause fatal meningoencephalitis in susceptible patients, mainly HIV+ individuals. Cryptococcus also infects environmental hosts such as nematodes, insects and plants. In particular, C. neoformans can kill the lepidopteran Galleria mellonella, which offers a useful tool to study microbial virulence and drug efficacy. Galleria mellonella immunity relies on innate responses based on melanization, accumulation of antimicrobial peptides, and cellular responses as phagocytosis or multicellular encapsulation. In this work we have investigated the immune response of G. mellonella during cryptococcal infection. We found that G. mellonella infected with C. neoformans had a high lytic activity in their hemolymph. This response was temperature- and capsule-dependent. During interaction with phagocytic cells, C. neoformans behaved as an intracellular pathogen since it could replicate within hemocytes. Non-lytic events were also observed. In contrast to Candida species, C. neoformans did not induce melanization of G. mellonella after infection. Finally, passage of C. neoformans through G. mellonella resulted in changes in capsule structure as it has been also reported during infection in mammals. Our results highlight that G. mellonella is an optimal model to investigate innate immune responses against C. neoformans. PMID- 25531533 TI - A simple and feasible method to determine absolute blood volume in hemodialysis patients in clinical practice. AB - BACKGROUND: We developed a simple method to determine the absolute blood volume (V) during hemodialysis in everyday clinical practice and examined its relationship with volume overload, clinical relevance, and accuracy. METHODS: The increase in relative blood volume (RBVpost - RBVpre) measured before and after infusion of 240 ml of ultra-pure dialysate using the bolus function of a commercial online hemodiafiltration machine incorporating a relative blood volume monitor was applied to determine absolute blood volume. The specific blood volume (Vs, blood volume per kg body mass at dry weight, in ml/kg) was compared to volume status as assessed by bioimpedance analysis and clinical criteria. RESULTS: The blood volume measured in 30 stable hemodialysis patients was 6.51 +/ 1.70 l at the beginning, corresponding to a specific blood volume of 80.1 +/- 12.8 ml/kg, and dropped to 5.84 +/- 1.61 l or 72.0 +/- 12.1 ml/kg at the end of the dialysis session, respectively. Specific blood volume correlated with volume status assessed both clinically and by bioimpedance analysis. Intradialytic morbid events occurred only in treatments where specific blood volume fell below 65 ml/kg. The reproducibility of the technique was better than 4% and the in vitro accuracy corresponds to a resolution in Vs of better than 1 ml/kg. CONCLUSION: Absolute blood volume can be easily measured at the beginning of the dialysis session using the current dialysis technology. Information about V and Vs could be a promising tool to avoid intradialytic morbid events. This technique could be completely automated without altering the hardware of currently available online dialysis devices. Therefore, it is recommended that this technique be integrated into all hemodiafiltration machines. PMID- 25531534 TI - A new pediatric protocol for rapid desensitization to monoclonal antibodies. AB - Monoclonal antibodies are important therapeutic tools, but their usefulness may be limited when patients experience acute hypersensitivity reactions. Patients reporting a history of adverse allergic reaction are likely to discontinue their therapeutic protocol or be switched to an alternative drug, which is sometimes less effective than that originally prescribed. Drug desensitization has proven to be a highly effective strategy to readminister a drug in a patient who has experienced a hypersensitivity reaction. It involves forcing the patient's immune system to accept and tolerate the allergen. Nevertheless, such a procedure is still empiric for monoclonal antibodies and not common in the pediatric population. The aim of our study is to demonstrate the clinical success of a new protocol of rapid desensitization to infliximab in a pediatric patient affected by ulcerative colitis, who developed an anaphylaxis to the drug. We used a protocol of rapid desensitization consisting of 13 steps, with the first being 1/1,000,000 of the cumulative and total dose. Such a protocol has proven to be able to induce a temporary tolerance to infliximab, allowing the patient to achieve complete control of his disease. PMID- 25531535 TI - Intermittent hypoxemia/bradycardia and the developing brain: how much is too much? Commentary on M.B. Schmid et al.: Cerebral oxygenation during intermittent hypoxemia and bradycardia in preterm infants (Neonatology 2015;107:137-146). PMID- 25531537 TI - Unexpected magnetic properties of gas-stabilized platinum nanostructures in the tunneling regime. AB - Nanostructured materials often have properties widely different from bulk, imposed by quantum limits to a physical property of the material. This includes, for example, superparamagnetism and quantized conductance, but original properties such as magnetoresistance in nonmagnetic molecular structures may also emerge. In this Letter, we report on the atomic manipulation of platinum nanocontacts in order to induce magnetoresistance. Platinum is a paramagnetic 5d metal, but atomic chains of this material have been predicted to be magnetically ordered with a large anisotropy. Remarkably, we find that a gas flow stabilizes Pt atomic structures in a break junction experiment, where we observe extraordinary resistance changes over 30,000% in a temperature range up to 77 K. Simulations indicate that this behavior may stem from a previously unknown magnetically ordered, low-energy state in platinum oxide atomic chains. This is supported by measurements in Pt/PtOx superlattices revealing the presence of a ferromagnetic moment. These properties open new paths of research for atomic scale "dirty" magnetic sensors and quantum devices. PMID- 25531536 TI - Intolerance for withdrawal discomfort and motivation predict voucher-based smoking treatment outcomes for smokers with substance use disorders. AB - Identifying predictors of abstinence with voucher-based treatment is important for improving its efficacy. Smokers with substance use disorders have very low smoking cessation rates so identifying predictors of smoking treatment response is particularly important for these difficult-to-treat smokers. Intolerance for Smoking Abstinence Discomfort (IDQ-S), motivation to quit smoking, nicotine dependence severity (FTND), and cigarettes per day were examined as predictors of smoking abstinence during and after voucher-based smoking treatment with motivational counseling. We also investigated the relationship between IDQ-S and motivation to quit smoking. Smokers in residential substance treatment (n=184) were provided 14days of vouchers for complete smoking abstinence (CV) after a 5 day smoking reduction lead-in period or vouchers not contingent on abstinence. Carbon monoxide readings indicated about 25% of days abstinent during the 14days of vouchers for abstinence in the CV group; only 3-4% of all participants were abstinent at follow-ups. The IDQ-S Withdrawal Intolerance scale and FTND each significantly predicted fewer abstinent days during voucher treatment; FTND was nonsignificant when controlling for variance shared with withdrawal intolerance. The one significant predictor of 1-month abstinence was pretreatment motivation to quit smoking, becoming marginal (p<.06) when controlling for FTND. Lower withdrawal intolerance significantly predicted 3month abstinence when controlling for FTND. Higher withdrawal intolerance pretreatment correlated with less motivation to quit smoking. Implications for voucher-based treatment include the importance of focusing on reducing these expectancies of anticipated smoking withdrawal discomfort, increasing tolerance for abstinence discomfort, and increasing motivation. PMID- 25531538 TI - Molecular phylogenetic study and expression analysis of ATP-binding cassette transporter gene family in Oryza sativa in response to salt stress. AB - ATP-binding cassette (ABC) transporter is a large gene superfamily that utilizes the energy released from ATP hydrolysis for transporting myriad of substrates across the biological membranes. Although many investigations have been done on the structural and functional analysis of the ABC transporters in Oryza sativa, much less is known about molecular phylogenetic and global expression pattern of the complete ABC family in rice. In this study, we have carried out a comprehensive phylogenetic analysis constructing neighbor-joining and maximum likelihood trees based on various statistical methods of different ABC protein subfamily of five plant lineages including Chlamydomonas reinhardtii (green algae), Physcomitrella patens (moss), Selaginella moellendorffii (lycophyte), Arabidopsis thaliana (dicot) and O. sativa (monocot) to explore the origin and evolutionary patterns of these ABC genes. We have identified several conserved motifs in nucleotide binding domain (NBD) of ABC proteins among all plant lineages during evolution. Amongst the different ABC protein subfamilies, 'ABCE' has not yet been identified in lower plant genomes (algae, moss and lycophytes). The result indicated that gene duplication and diversification process acted upon these genes as a major operative force creating new groups and subgroups and functional divergence during evolution. We have demonstrated that rice ABCI subfamily consists of only half size transporters that represented highly dynamic members showing maximum sequence variations among the other rice ABC subfamilies. The evolutionary and the expression analysis contribute to a deep insight into the evolution and diversity of rice ABC proteins and their roles in response to salt stress that facilitate our further understanding on rice ABC transporters. PMID- 25531539 TI - Joining forces for better care. PMID- 25531542 TI - Estimation of sampling uncertainty of pesticide residues based on supervised residue trial data. AB - Typical sampling uncertainties were calculated as the average of relative standard deviations (CV) of residues measured in individual crops tested in supervised residue trials and from their pooled variance for crop groups. The relative confidence intervals of the sampling uncertainty for different crops were estimated from the random duplicate composite samples generated with computer modeling from residues in 182 independent primary sample sets, each consisting of 100-320 residue data. The relative 95% confidence intervals were found to be independent from the CV of primary residue data populations; therefore, the calculated values are generally applicable. In view of the potentially serious consequences of underestimated sampling uncertainties, their upper confidence limits are recommended for practical use to verify the compliance of products and for planning statistically based sampling programs. Sampling uncertainties are reported for 24 crop groups and 106 individual crops. PMID- 25531541 TI - Sub1 and Maf1, two effectors of RNA polymerase III, are involved in the yeast quiescence cycle. AB - Sub1 and Maf1 exert an opposite effect on RNA polymerase III transcription interfering with different steps of the transcription cycle. In this study, we present evidence that Sub1 and Maf1 also exhibit an opposite role on yeast chronological life span. First, cells lacking Sub1 need more time than wild type to exit from resting and this lag in re-proliferation is correlated with a delay in transcriptional reactivation. Second, our data show that the capacity of the cells to properly establish a quiescent state is impaired in the absence of Sub1 resulting in a premature death that is dependent on the Ras/PKA and Tor1/Sch9 signalling pathways. On the other hand, we show that maf1Delta cells are long lived mutant suggesting a connection between Pol III transcription and yeast longevity. PMID- 25531543 TI - A slot blot immunoassay for quantitative detection of Plasmodium falciparum circumsporozoite protein in mosquito midgut oocyst. AB - There is still a need for sensitive and reproducible immunoassays for quantitative detection of malarial antigens in preclinical and clinical phases of vaccine development and in epidemiology and surveillance studies, particularly in the vector host. Here we report the results of sensitivity and reproducibility studies for a research-grade, quantitative enhanced chemiluminescent-based slot blot assay (ECL-SB) for detection of both recombinant Plasmodium falciparum circumsporozoite protein (rPfCSP) and native PfCSP from Oocysts (Pf Oocyst) developing in the midguts of Anopheles stephensi mosquitoes. The ECL-SB detects as little as 1.25 pg of rPfCSP (linear range of quantitation 2.5-20 pg; R2 = 0.9505). We also find the earliest detectable expression of native PfCSP in Pf Oocyst by ECL-SB occurs on day 7 post feeding with infected blood meal. The ECL SB was able to detect approximately as few as 0.5 day 8 Pf Oocysts (linear quantitation range 1-4, R2 = 0.9795) and determined that one Pf Oocyst expressed approximately 2.0 pg (0.5-3 pg) of native PfCSP, suggesting a similar range of detection for recombinant and native forms of Pf CSP. The ECL-SB is highly reproducible; the Coefficient of Variation (CV) for inter-assay variability for rPf CSP and native PfCSP were 1.74% and 1.32%, respectively. The CVs for intra assay variability performed on three days for rPf CSP were 2.41%, 0.82% and 2% and for native Pf CSP 1.52%, 0.57%, and 1.86%, respectively. In addition, the ECL SB was comparable to microscopy in determining the P. falciparum prevalence in mosquito populations that distinctly contained either high and low midgut Pf Oocyst burden. In whole mosquito samples, estimations of positivity for P. falciparum in the high and low burden groups were 83.3% and 23.3% by ECL-SB and 85.7% and 27.6% by microscopy. Based on its performance characteristics, ECL-SB could be valuable in vaccine development and to measure the parasite prevalence in mosquitoes and transmission-blocking interventions in endemic areas. PMID- 25531545 TI - The new Editor-in-Chief of Ophthalmologica. PMID- 25531544 TI - Secondary antifungal prophylaxis in hematological malignancy patients with previous invasive fungal disease: a retrospective analysis. AB - BACKGROUND: Invasive fungal disease (IFD) causes morbidity and mortality in patients with hematological malignancy. Recurrence of IFD after chemotherapy or hematopoietic stem cell transplantation (HSCT) is associated with poor prognosis. The present study aimed to investigate the efficacy of different strategies of secondary antifungal prophylaxis (SAP) for IFD and choose an appropriate SAP regimen. METHODS: Clinical data of patients with previous IFD who underwent chemotherapy or HSCT between Jan 2008 and Jun 2013 were retrospectively reviewed and followed up to 180 days post-chemotherapy or HSCT. The clinical characteristics and diagnosis were analyzed according to the diagnostic criteria for IFD. The efficacy of different strategies for SAP and risk factors influencing the failure of SAP were evaluated. RESULTS: Of the 164 patients enrolled, 121 patients received SAP regimen (73.78%), and IFD recurred in 40 patients: 16.5% (20/121) in SAP group and 46.5% (20/43) in non-SAP group. In SAP group, 58 received SAP agents which were proven effective for their previous IFD, while other 63 patients received other broad-spectrum antifungal agents. There was no significant difference in the recurrence rates between these two subgroups (13.8% (8/58) vs 19.0% (12/63), P = 0.437). The IFD recurrence rates were statistically significant between patients with allogeneic HSCT and chemotherapy or autologous HSCT (25% vs 8.2%, P = 0.013). Multivariate analysis indicated that allogeneic HSCT was the independent risk factor of IFD recurrence after SAP. CONCLUSIONS: Secondary antifungal prophylaxis is necessary to prevent IFD recurrence in patients with hematological malignancy, especially for patients in the setting of allogeneic HSCT. PMID- 25531546 TI - The compression anastomotic ring-locking procedure: a novel technique for creating a sutureless colonic anastomosis. AB - BACKGROUND/AIM: Compression anastomoses might represent an improvement over traditional hand-sewn or stapled techniques. Herein, we describe a novel concept of sutureless colonic anastomosis named compression anastomotic ring-locking procedure (CARP). MATERIALS AND METHODS: The surgical device consists of two anastomotic rings and their associated helping tools, facilitating the placement of the rings into the intestinal ends. Furthermore, four catheters are connected to the surgical device, allowing the evaluation of the anastomosis during and after surgery. A total of 31 pigs underwent a low colocolic anastomosis using the anastomotic rings. The compression pressure was measured perioperatively and up to 96 h after surgery. Anastomotic integrity and morphology were analyzed by use of radiology and histology, respectively. A long-term follow-up was conducted in a subgroup of pigs up to 108 days after surgery when the bursting pressure and stricture formation were examined. RESULTS: All animals recovered uneventfully, and macroscopic examination revealed intact anastomoses without signs of pathological inflammation or adhesions. The perioperative compression pressure was inversely proportional to the gap size between the anastomotic rings. For example, an anastomotic gap of 1.5 mm created a colonic anastomosis with a perioperative compression pressure of 91 mbar, which remained constant for up to 48 h and resulted in a markedly increased compression pressure. Contrast infusion via the catheters effectively visualized the anastomoses, and no leakage was detected within the study. The surgical device was spontaneously evacuated from the intestines within 6 days after surgery. Histology showed collagen bridging of the anastomoses already 72 h after surgery. Long-term follow-up (54-108 days) revealed no stricture formation in the anastomoses, and the bursting pressure ranged from 120 to 235 mbar. The majority of bursts (10/12) occurred distant from the anastomoses. CONCLUSION: We conclude that the surgical device associated to CARP is safe and efficient for creating colonic anastomoses. Further studies in patients undergoing colorectal surgery are warranted. PMID- 25531547 TI - Association of melioidosis incidence with rainfall and humidity, Singapore, 2003 2012. AB - Soil has been considered the natural reservoir for the bacterium Burkholderia pseudomallei, which causes melioidosis. We examined 550 melioidosis cases that occurred during a 10-year period in the highly urbanized city of Singapore, where soil exposure is rare, and found that rainfall and humidity levels were associated with disease incidence. PMID- 25531548 TI - Partial trisomy of the pericentromeric region of chromosome 5 in a girl with binder phenotype. AB - The patient reported here displayed most characteristic features of Binder syndrome (OMIM: 155050), a rare maxillonasal malformation with unknown etiology. She was sent for genetic evaluation at the age of 10 years because of facial dysmorphism and borderline intellectual disability. Cytogenetic analyses showed a de novo supernumerary small ring chromosome with a pericentromeric region of chromosome 5 in all lymphocytes. Array painting revealed that the marker contains a 20,950-kb genomic region comprising cytogenetic band 5p14.1q11.1. Additionally, 7 reports have been published in the literature with partial trisomy of chromosome 5 overlapping with our case. These 8 cases were analyzed for phenotype/genotype correlation which suggested that the maxillonasal anomalies of Binder phenotype and trisomy of the pericentromeric region of chromosome 5 may be in causal relationship. Future functional annotation studies of genes localized in this genomic region should take this into consideration. To the best of our knowledge, this is the first report on a patient with association of a chromosome abnormality and clinical characteristics of Binder phenotype. PMID- 25531549 TI - Genetic diversity of enterovirus A71, India. AB - We have identified circulation of 3 genogroups of enterovirus (EV) A71 in India. A new genogroup (proposed designation G) was discovered during this study. We isolated genogroups D and G in wide geographic areas but detected subgenogroup C1 only in 1 focus in western India. A systematic nationwide search for EV-A71 is warranted. PMID- 25531550 TI - Constrained choices? Linking employees' and spouses' work time to health behaviors. AB - There are extensive literatures on work conditions and health and on family contexts and health, but less research asking how a spouse or partners' work conditions may affect health behaviors. Drawing on the constrained choices framework, we theorized health behaviors as a product of one's own time and spouses' work time as well as gender expectations. We examined fast food consumption and exercise behaviors using survey data from 429 employees in an Information Technology (IT) division of a U.S. Fortune 500 firm and from their spouses. We found fast food consumption is affected by men's work hours-both male employees' own work hours and the hours worked by husbands of women respondents in a nonlinear way. The groups most likely to eat fast food are men working 50 h/week and women whose husbands work 45-50 h/week. Second, exercise is better explained if work time is conceptualized at the couple, rather than individual, level. In particular, neo-traditional arrangements (where husbands work longer than their wives) constrain women's ability to engage in exercise but increase odds of men exercising. Women in couples where both partners are working long hours have the highest odds of exercise. In addition, women working long hours with high schedule control are more apt to exercise and men working long hours whose wives have high schedule flexibility are as well. Our findings suggest different health behaviors may have distinct antecedents but gendered work-family expectations shape time allocations in ways that promote men's and constrain women's health behaviors. They also suggest the need to expand the constrained choices framework to recognize that long hours may encourage exercise if both partners are looking to sustain long work hours and that work resources, specifically schedule control, of one partner may expand the choices of the other. PMID- 25531551 TI - Post-mortem tissue biopsies obtained at minimally invasive autopsy: an RNA quality analysis. AB - INTRODUCTION: Bereaved relatives often refuse to give consent for post-mortem investigation of deceased cancer patients, mainly because of the mutilation due to conventional autopsy (CA). Minimally invasive autopsy (MIA) may be a more acceptable alternative and, if implemented in clinical practice, creates an opportunity to more often obtain post-mortem tissue samples of (recurred) primary tumors and metastases for molecular research. As a measure for tissue quality for molecular studies, we hereby present a feasibility study, comparing the RNA quality of MIA and CA samples, and fresh frozen samples as reference. MATERIALS AND METHODS: Tissue samples of heart, liver and kidney were prospectively collected from 24 MIAs followed by CA, and compared to corresponding archival fresh frozen tissue. After RNA isolation and RT-qPCR, RNA integrity numbers (RIN) and GAPDH expression (six amplicon sizes ranging from 71 to 530 base pairs) were measured. RIN values and GAPDH Cq values were analyzed and compared between all sample groups and post-mortem intervals (PMI). RESULTS: RIN values in MIA samples were significantly higher than those in CA samples. GAPDH was expressed significantly higher in MIA samples than in CA samples and 530 bp PCR products could be measured in all cases. GAPDH expression was significantly lower in samples with PMI >15 hours. As expected, the samples of the fresh frozen reference standard performed best in all analyses. CONCLUSION: MIA samples showed better RNA quality than CA samples, probably due to shorter PMI. Both had lower RNA quality and expression levels than fresh frozen tissue, however, remaining GAPDH RNA was still sufficiently intact. Therefore, other highly expressed genes are most likely also detectable. Gene array analysis should be performed to gain insight into the quality of entire post-mortem genomes. Reducing PMI will further improve the feasibility of demanding molecular research on post-mortem tissues, this is most likely more feasible with MIA than CA. PMID- 25531552 TI - Effects of blood pressure reduction in mild hypertension: a systematic review and meta-analysis. AB - BACKGROUND: Effects of blood pressure reduction in persons with grade 1 hypertension are unclear. PURPOSE: To investigate whether pharmacologic blood pressure reduction prevents cardiovascular events and deaths in persons with grade 1 hypertension. DATA SOURCES: Trials included in the BPLTTC (Blood Pressure Lowering Treatment Trialists' Collaboration) and trials identified from a previous review and electronic database searches. STUDY SELECTION: Patients without cardiovascular disease with blood pressures in the grade 1 hypertension range (140 to 159/90 to 99 mm Hg) who were randomly assigned to an active (antihypertensive drug or more intensive regimen) or control (placebo or less intensive regimen) blood pressure-lowering regimen. DATA EXTRACTION: Individual patient data from BPLTTC trials and aggregate data from other trials were extracted. Risk of bias was assessed for all trials. DATA SYNTHESIS: Individual patient data involved 10 comparisons from trials where most patients had diabetes, and aggregate data involved 3 comparisons from trials of patients without diabetes. The average blood pressure reduction was about 3.6/2.4 mm Hg. Over 5 years, odds ratios were 0.86 (95% CI, 0.74 to 1.01) for total cardiovascular events, 0.72 (CI, 0.55 to 0.94) for strokes, 0.91 (CI, 0.74 to 1.12) for coronary events, 0.80 (CI, 0.57 to 1.12) for heart failure, 0.75 (CI, 0.57 to 0.98) for cardiovascular deaths, and 0.78 (CI, 0.67 to 0.92) for total deaths. Results were similar in secondary analyses. Withdrawal from treatment due to adverse effects was more common in the active groups. LIMITATION: Blood pressure reductions and numbers of events were small. CONCLUSION: Blood pressure lowering therapy is likely to prevent stroke and death in patients with uncomplicated grade 1 hypertension. PRIMARY FUNDING SOURCE: Swedish Heart-Lung Foundation, Swedish Research Council, Australian Research Council, and National Health and Medical Research Council of Australia. PMID- 25531553 TI - Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice. AB - Alterations in the composition of the commensal microbiota (dysbiosis) seem to be a pathogenic component of functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and might participate in the secretomotor and sensory alterations observed in these patients.We determined if a state antibiotics induced intestinal dysbiosis is able to modify colonic pain-related and motor responses and characterized the neuro-immune mechanisms implicated in mice. A 2 week antibiotics treatment induced a colonic dysbiosis (increments in Bacteroides spp, Clostridium coccoides and Lactobacillus spp and reduction in Bifidobacterium spp). Bacterial adherence was not affected. Dysbiosis was associated with increased levels of secretory-IgA, up-regulation of the antimicrobial lectin RegIIIgamma, and toll-like receptors (TLR) 4 and 7 and down-regulation of the antimicrobial-peptide Resistin-Like Molecule-beta and TLR5. Dysbiotic mice showed less goblet cells, without changes in the thickness of the mucus layer. Neither macroscopical nor microscopical signs of inflammation were observed. In dysbiotic mice, expression of the cannabinoid receptor 2 was up-regulated, while the cannabinoid 1 and the mu-opioid receptors were down-regulated. In antibiotic treated mice, visceral pain-related responses elicited by intraperitoneal acetic acid or intracolonic capsaicin were significantly attenuated. Colonic contractility was enhanced during dysbiosis. Intestinal dysbiosis induce changes in the innate intestinal immune system and modulate the expression of pain related sensory systems, an effect associated with a reduction in visceral pain related responses. Commensal microbiota modulates gut neuro-immune sensory systems, leading to functional changes, at least as it relates to viscerosensitivity. Similar mechanisms might explain the beneficial effects of antibiotics or certain probiotics in the treatment of IBS. PMID- 25531554 TI - Epidermal growth factor receptor inhibitor protects against abdominal aortic aneurysm in a mouse model. AB - Angiotensin II (Ang II) has been implicated in the development of abdominal aortic aneurysm (AAA). In vascular smooth muscle cells (VSMC), Ang II activates epidermal growth factor receptor (EGFR) mediating growth promotion. We hypothesized that inhibition of EGFR prevents Ang II-dependent AAA. C57BL/6 mice were co-treated with Ang II and beta-aminopropionitrile (BAPN) to induce AAA with or without treatment with EGFR inhibitor, erlotinib. Without erlotinib, 64.3% of mice were dead due to aortic rupture. All surviving mice had AAA associated with EGFR activation. Erlotinib-treated mice did not die and developed far fewer AAA. The maximum diameters of abdominal aortas were significantly shorter with erlotinib treatment. In contrast, both erlotinib-treated and non-treated mice developed hypertension. The erlotinib treatment of abdominal aorta was associated with lack of EGFR activation, endoplasmic reticulum (ER) stress, oxidative stress, interleukin-6 induction and matrix deposition. EGFR activation in AAA was also observed in humans. In conclusion, EGFR inhibition appears to protect mice from AAA formation induced by Ang II plus BAPN. The mechanism seems to involve suppression of vascular EGFR and ER stress. PMID- 25531555 TI - Impact of health literacy level on aspects of medication nonadherence reported by underserved patients with type 2 diabetes. AB - BACKGROUND: Medication adherence can be affected by many factors, including health literacy. The purpose of this study is to determine (1) if a relationship exists between health literacy and self-reported or objectively measured medication adherence and (2) which aspect or aspects of medication nonadherence are most associated with health literacy. SUBJECTS AND METHODS: This is a multicenter, cross-sectional survey study of adult patients with type 2 diabetes mellitus (T2DM), taking one or more antidiabetes medication for >=6 months with a hemoglobin A1c (HbA1c) measure on record. Data collected included patient demographics (age, gender, race, language, highest level of education, injectable diabetes medication use, last HbA1c, and diabetes medication refill history) and two survey instruments (the Morisky eight-item Medication Adherence Scale [MMAS 8] and the short-form Test of Functional Health Literacy in Adults [s-TOFHLA]). Descriptive statistics and bivariate correlations were assessed, along with linear and logistic regression. RESULTS: One hundred ninety-two patients with an average HbA1c level of 8.1% were included. Of these subjects, 32.8% had limited health literacy as measured by the s-TOFHLA, 58.9% had low adherence as measured by MMAS-8, and 65.1% were nonadherent based on cumulative medication gap (CMG) analysis. Age was associated with s-TOFHLA (-0.411; P<0.01) and MMAS-8 (0.157; P<0.05) scores. HbA1c was associated with MMAS-8 (-0.209; P<0.01) and CMG (0.152; P<0.05) scores. There was no significant association between s-TOFHLA and MMAS-8 or CMG. However, s-TOFHLA was positively related to MMAS-8 question 8, assessing difficulty remembering to take medications (P=0.017). CONCLUSIONS: Health literacy level is not associated with self-reported or objectively measured medication adherence in underserved patients with T2DM. Lower health literacy scores are associated with a patient experiencing difficulty remembering to take medications. PMID- 25531556 TI - Correction: In situ study of the catalytic mechanism for the oxygen reduction reaction on a polypyrrole modified carbon supported cobalt hydroxide cathode in direct borohydride fuel cells. AB - Correction for 'In situ study of the catalytic mechanism for the oxygen reduction reaction on a polypyrrole modified carbon supported cobalt hydroxide cathode in direct borohydride fuel cells' by Haiying Qin et al., Phys. Chem. Chem. Phys., 2013, 15, 9070-9074. PMID- 25531557 TI - Rethinking aromaticity in H-bonded systems. Caveats for transition structures involving hydrogen transfer and pi-delocalization. AB - Monoaza- and diaza-derivatives of malondialdehydes, in short aminoacroleins and vinamidines, are prototypical examples of open-chain structures prone to pi electron delocalization, for which intramolecular hydrogen bonding enhances (or diminishes) their pseudoaromaticity depending on the substitution pattern. This interplay is illustrated herein by DFT-based calculations of aromaticity indices in the gas phase and polar solvents. Elucidation of transition structures involved in tautomeric conversions helps to solve how the intramolecular hydrogen transfer occurs. While TSs exhibit a high degree of aromaticity, the dichotomy between forward and backward pathways points to a complex trajectory. Addition of thermal corrections to the electronic energy decreases both the enthalpy and free energy leading to negative DeltaH(?) and DeltaG(?) values. This variational effect accounts for the otherwise elusive distinction between transition structures and saddle points (usually overlooked for high electronic barriers). Also, this rationale fits well within the framework of Marcus' theory. PMID- 25531558 TI - Occupational accidents in the Netherlands: incidence, mental harm, and their relationship with psychosocial factors at work. AB - This study investigated the incidence of mental harm due to occupational accidents and the relation between psychosocial factors at work and the occurrence of occupational accidents in the Netherlands for the construction industry and health and welfare sector. Analyses revealed that occupational accidents in the construction industry more often involved physical harm, whereas accidents in the health and welfare sector relatively more often resulted in mental harm, in comparison to other sectors. Results showed that psychosocial factors were associated with occupational accidents in both sectors. For the construction industry, high time pressure and exposure to violence and harassment by colleagues or supervisors were associated with occupational accidents. For the health and welfare sector, low autonomy and exposure to violence and harassment by colleagues or supervisors or by people outside the organization were associated with occupational accidents. The present paper stresses the importance of also taking psychological consequences and psychosocial factors at work into account in assessing the occurrence of occupational accidents. PMID- 25531559 TI - Photobiocatalytic decarboxylation for olefin synthesis. AB - Here, we describe the combination of OleTJE with a light-driven in situ H2O2 generation system for the selective and quantitative conversion of fatty acids into terminal alkenes. The photobiocatalytic system shows clear advantages regarding enzyme activity and yield, resulting in a simple and efficient system for fatty acid decarboxylation. PMID- 25531560 TI - Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models. PMID- 25531561 TI - One- and two-photon absorption of a spiropyran-merocyanine system: experimental and theoretical studies. AB - We report on the nonlinear optical properties measurements and quantum-chemical calculations of a well-known photochromic system consisting of spiropyran and the merocyanine photoproduct. The study of nonlinear absorption and refraction properties of the molecules dissolved in chloroform were performed with the Z scan technique, using femtosecond pulses in a wide range of wavelengths. Maxima in the two-photon absorption spectrum at 700 and 1050 nm were found for the merocyanine form, and the corresponding two-photon absorption cross section is 80 GM and 20 GM, respectively. The latter feature does not vanish completely in the nonlinear spectrum of the spiropyran form, possibly because of the existence of some photoconversion caused by the laser beam during the measurements. A nonlinear absorption peak at 900 nm is found in the spiropyran form with an effective cross section of about 20 GM; it is likely due to three-photon absorption or to absorption by some intermediate species. The experimental data are supported by calculations performed with the use of a hybrid quantum mechanics-molecular mechanics approach. PMID- 25531562 TI - Community-acquired invasive GAS disease among Native Americans, Arizona, USA, Winter 2013. PMID- 25531563 TI - Remodeling of epithelial cells and basement membranes in a corneal deficiency model with long-term follow-up. AB - The ocular surface consists of the cornea, conjunctiva, and the limbus that is located in the transitional zone between the cornea and conjunctiva. The corneal epithelial cells are generated through the mitosis of corneal epithelial stem cells in the limbus. This study investigated a rabbit corneal deficiency model prepared by the surgical removal of the corneal and limbal epithelia, which express cytokeratin 12 (K12). After the surgery, K13-expressing conjunctival epithelium migrated onto the corneal surface and completely covered the surface, leading to neovascularization and corneal opacification. However, at 24 and 48 weeks after the surgery, K12-expressing cornea-like cells reappeared on the model ocular surface. These cells formed an island surrounded by invaded conjunctiva and were isolated from the limbus. Interestingly, in the 24-week model surface, alpha1(IV) and alpha2(IV) collagen chains, which are normally found in the basement membrane of the native limbus and conjunctiva, and not in the cornea, were continuously deposited throughout the entire basement membrane, including the basement membrane under cornea-like cells. By contrast, in the 48-week model surface, alpha1(IV) and alpha2(IV) collagen chains were absent from the basement membrane beneath the central part of cornea-like cells and were localized below the invaded conjunctiva and the transitional zone between cornea-like cells and the invaded conjunctiva, which had similar distribution to the native ocular basement membrane. Moreover, K12, K14, p63, vimentin, and alpha1(IV) and alpha2(IV) collagen chains, which are colocalized in the native limbus, were all present at the transitional zone of the 48-week model surface. Therefore, a limbus-like structure appeared to be reconstructed on the surface of the 48-week model as a stem cell niche. This study should aid in the understanding of human corneal deficiency, the correlation between the epithelial cell phenotype and the composition of the basement membrane, and the epithelial stem cell niche. PMID- 25531564 TI - Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman's capsule in diabetes. AB - The metabolic and hemodynamic alterations in diabetes activate podocytes to increase extracellular matrix (ECM) production, leading to thickening of the glomerular basement membrane (GBM). We hypothesized that diabetes would activate parietal epithelial cells (PECs) in a similar manner and cause thickening of Bowman's capsules. Periodic acid Schiff staining of human kidney biopsies of 30 patients with diabetic nephropathy (DN) revealed a significantly thicker Bowman's capsule as compared with 20 non-diabetic controls. The average thickness was 4.55+/-0.21 MUm in the group of patients with DN compared with 2.92+/-0.21 MUm in the group of non-diabetic controls (P<0.001). Transmission electron microscopy confirmed this finding. In vitro, short-term exposure of human PECs to hyperglycemic conditions (30 mM glucose) advanced glycation end products (100 MUg/ml) or transforming growth factor-beta1 (TGF-beta1; 5 ng/ml) increased the mRNA expression of collagen type I alpha-1, collagen type IV (all six alpha chains), bamacan, nidogen 1, laminin alpha-1, and perlecan. Western blot and colorimetric collagen assays confirmed these results for collagen type IV at the protein level. The production and secretion of TGF-beta1 as a possible positive feedback loop was excluded as a mechanism for the autocrine activation of human PECs. To validate these findings in vivo, activation of the PECs was assessed by immunohistochemical staining for CD44 of 12 human biopsy cases with DN. Thickening of the Bowman's capsule showed strong association with CD44-positive PECs. In summary, metabolic alterations in diabetes activate PECs to increase the expression and secretion of Bowman's capsule proteins. This process may contribute to the thickening of the Bowman's capsule, similar to the thickening of the GBM that is driven by activated podocytes. These data may also imply that activated PECs contribute to ECM production once they migrate to the glomerular tuft, a process resulting in glomerular scaring, for example, in diabetic glomerulosclerosis. PMID- 25531565 TI - Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice. AB - Recent studies have indicated that perinatal infection with cytomegalovirus (CMV) may promote bile duct damage in biliary atresia (BA) and that the decreased regulatory T cell (Treg) percentage associated with BA may further amplify the bile duct damage. Although a majority of BA patients have had previous CMV infections and lower percentages of Tregs, it is unknown whether an initial exposure to a low dose of CMV could induce exaggerated and progressive biliary injury. A Treg-depleted neonatal mouse was infected with low-dose CMV (LD-CMV) as a model to study BA patients. LD-CMV infection in Treg-depleted mice induced extensive inflammation in both the intrahepatic and extrahepatic bile ducts, accompanied with injury to and atresia of intrahepatic bile ducts and partial obstruction of the extrahepatic bile ducts. Serum total and direct bilirubin amounts were also elevated. Evidence for the involvement of cellular and humoral autoimmune responses in LD-CMV-infection of Treg-depleted mice was also obtained through detection of increased percentages of CD3 and CD8 mononuclear cells and serum autoantibodies reactive to bile duct epithelial proteins, one of which was identified as alpha-enolase. Depletion of Tregs that can lead to the decreased inhibition of aberrantly activated hepatic T-lymphocytes and generation of autoantibodies may lead to further injury. Increased hepatic expression of Th1 related genes (TNF-alpha), IFN-gamma-activated genes (STAT-1) and Th1 cytokines (TNF-alpha, lymphotactin, IL-12p40 and MIP -1gamma) were also identified. In conclusion, autoimmune-mediated and inflammatory responses induced by LD-CMV infection in Treg-depleted mice results in increased intrahepatic and extrahepatic bile duct injury and contributed to disease progression. PMID- 25531566 TI - Gammaherpesvirus infection modulates the temporal and spatial expression of SCGB1A1 (CCSP) and BPIFA1 (SPLUNC1) in the respiratory tract. AB - Murine gamma-herpesvirus 68 (MHV-68) infection of Mus musculus-derived strains of mice is an established model of gamma-herpesvirus infection. We have previously developed an alternative system using a natural host, the wood mouse (Apodemus sylvaticus), and shown that the MHV-68 M3 chemokine-binding protein contributes significantly to MHV-68 pathogenesis. Here we demonstrate in A. sylvaticus using high-density micro-arrays that M3 influences the expression of genes involved in the host response including Scgb1a1 and Bpifa1 that encode potential innate defense proteins secreted into the respiratory tract. Further analysis of MHV-68 infected animals showed that the levels of both protein and RNA for SCGB1A1 and BPIFA1 were decreased at day 7 post infection (p.i.) but increased at day 14 p.i. as compared with M3-deficient and mock-infected animals. The modulation of expression was most pronounced in bronchioles but was also present in the bronchi and trachea. Double staining using RNA in situ hybridization and immunohistology demonstrated that much of the BPIFA1 expression occurs in club cells along with SCGB1A1 and that BPIFA1 is stored within granules in these cells. The increase in SCGB1A1 and BPIFA1 expression at day 14 p.i. was associated with the differentiation of club cells into mucus-secreting cells. Our data highlight the role of club cells and the potential of SCGB1A1 and BPIFA1 as innate defense mediators during respiratory virus infection. PMID- 25531567 TI - Serum amyloid A and inflammation in diabetic kidney disease and podocytes. AB - Inflammatory pathways are central mechanisms in diabetic kidney disease (DKD). Serum amyloid A (SAA) is increased by chronic inflammation, but SAA has not been previously evaluated as a potential DKD mediator. The aims of this study were to determine whether SAA is increased in human DKD and corresponding mouse models and to assess effects of SAA on podocyte inflammatory responses. SAA was increased in the plasma of people with DKD characterized by overt proteinuria and inversely correlated with estimated glomerular filtration rate (creatinine-based CKD-EPI). SAA was also elevated in plasma of diabetic mouse models including type 1 diabetes (streptozotocin/C57BL/6) and type 2 diabetes (BTBR-ob/ob). SAA mRNA (Nephromine) was increased in human DKD compared with non-diabetic and/or glomerular disease controls (glomerular fold change 1.5, P=0.017; tubulointerstitium fold change 1.4, P=0.021). The kidneys of both diabetic mouse models also demonstrated increased SAA mRNA (quantitative real-time PCR) expression compared with non-diabetic controls (type 1 diabetes fold change 2.9; type 2 diabetes fold change 42.5, P=0.009; interaction by model P=0.57). Humans with DKD and the diabetic mouse models exhibited extensive SAA protein deposition in the glomeruli and tubulointerstitium in similar patterns by immunohistochemistry. SAA localized within podocytes of diabetic mice. Podocytes exposed to advanced glycation end products, metabolic mediators of inflammation in diabetes, increased expression of SAA mRNA (fold change 15.3, P=0.004) and protein (fold change 38.4, P=0.014). Podocytes exposed to exogenous SAA increased NF-kappaB activity, and pathway array analysis revealed upregulation of mRNA for NF-kappaB-dependent targets comprising numerous inflammatory mediators, including SAA itself (fold change 17.0, P=0.006). Inhibition of NF-kappaB reduced these pro inflammatory responses. In conclusion, SAA is increased in the blood and produced in the kidneys of people with DKD and corresponding diabetic mouse models. Podocytes are likely to be key responder cells to SAA-induced inflammation in the diabetic kidney. SAA is a compelling candidate for DKD therapeutic and biomarker discovery. PMID- 25531568 TI - TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency. AB - Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Cirrhotic patients show low expression of GNMT that is absent in hepatocellular carcinoma (HCC) samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis, and HCC. Lack of GNMT triggers NK cell activation in GNMT(-/-) mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL(-/-)/GNMT(-/-) mice in which we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT(-/-) and TRAIL(-/-)/GNMT(-/-) mice. In GNMT(-/-) mice, exacerbated fibrogenic response after BDL concurred with NK1.1(+) cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT(-/-) mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL(-/-)/GNMT(-/-) mice showed significantly less fibrosis after BDL than GNMT(-/-) mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT(-/-) mice. Finally, in vivo silencing of DR5 efficiently protected GNMT(-/-) mice from BDL liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease. PMID- 25531569 TI - Genotype to phenotype relationships in autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and nontruncating de novo mutations contribute to autism, with a bias against truncating mutations in early embryonic development. We find that functional mutations are preferentially observed in genes likely to be haploinsufficient. Multiple cell types and brain areas are affected, but the impact of ASD mutations appears to be strongest in cortical interneurons, pyramidal neurons and the medium spiny neurons of the striatum, implicating cortical and corticostriatal brain circuits. In females, truncating ASD mutations on average affect genes with 50-100% higher brain expression than in males. Our results also suggest that truncating de novo mutations play a smaller role in the etiology of high-functioning ASD cases. Overall, we find that stronger functional insults usually lead to more severe intellectual, social and behavioral ASD phenotypes. PMID- 25531570 TI - NeuroGrid: recording action potentials from the surface of the brain. AB - Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material-based, ultraconformable, biocompatible and scalable neural interface array (the 'NeuroGrid') that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 week's duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders. PMID- 25531571 TI - Theta sequences are essential for internally generated hippocampal firing fields. AB - Sensory cue inputs and memory-related internal brain activities govern the firing of hippocampal neurons, but which specific firing patterns are induced by either of the two processes remains unclear. We found that sensory cues guided the firing of neurons in rats on a timescale of seconds and supported the formation of spatial firing fields. Independently of the sensory inputs, the memory-related network activity coordinated the firing of neurons not only on a second-long timescale, but also on a millisecond-long timescale, and was dependent on medial septum inputs. We propose a network mechanism that might coordinate this internally generated firing. Overall, we suggest that two independent mechanisms support the formation of spatial firing fields in hippocampus, but only the internally organized system supports short-timescale sequential firing and episodic memory. PMID- 25531572 TI - Calcium dynamics in astrocyte processes during neurovascular coupling. AB - Enhanced neuronal activity in the brain triggers a local increase in blood flow, termed functional hyperemia, via several mechanisms, including calcium (Ca(2+)) signaling in astrocytes. However, recent in vivo studies have questioned the role of astrocytes in functional hyperemia because of the slow and sparse dynamics of their somatic Ca(2+) signals and the absence of glutamate metabotropic receptor 5 in adults. Here, we reexamined their role in neurovascular coupling by selectively expressing a genetically encoded Ca(2+) sensor in astrocytes of the olfactory bulb. We show that in anesthetized mice, the physiological activation of olfactory sensory neuron (OSN) terminals reliably triggers Ca(2+) increases in astrocyte processes but not in somata. These Ca(2+) increases systematically precede the onset of functional hyperemia by 1-2 s, reestablishing astrocytes as potential regulators of neurovascular coupling. PMID- 25531574 TI - Neptunyl(VI) centred visible LMCT emission directly observable in the presence of uranyl(VI). AB - Room temperature detection of neptunyl(VI) LMCT emission in a coordination compound and in the presence of uranyl(VI) is reported for the first time. Differences in the excitation profiles of the complexes enable spectral editing so either exclusively neptunyl(VI) or uranyl(VI) emission is observed or a sum of the two. PMID- 25531573 TI - Fear generalization in the primate amygdala. AB - Broad generalization of negative memories is a potential etiology for anxiety disorders, yet the underlying mechanisms remain unknown. We developed a non-human primate model that replicates behavioral observations in humans and identifies specific changes in tuning properties of amygdala neurons: the width of auditory tuning increases with the distance of its center from the conditioned stimulus. This center-width relationship can account for better detection and at the same time explain the wide stimulus generalization. PMID- 25531575 TI - Characterization of upper airway obstruction by fiber-optic nasolaryngoscopy and MRI in preoperative OSAHS patients. AB - OBJECTIVE: To investigate changes in the upper airway and its surrounding soft tissue and to characterize the extent and severity of upper airway obstruction in 136 obstructive sleep apnea/hypopnea syndrome (OSAHS) patients who were awake. METHODS: OSAHS patients and healthy controls were evaluated by fiber-optic nasolaryngoscopy and MRI. The cross-sectional area and pharyngeal wall thickness of the retropalatal, retroglossal and epiglottic region were determined. RESULTS: Ninety-five percent of the mild OSAHS subjects had single-plane obstruction (vs. severe OSAHS, p < 0.05), 5.0% of the mild OSAHS subjects had two-plane obstruction (p < 0.05) and none of them had three-plane obstruction (p < 0.05). The cross-sectional area of the retropalatal, retroglossal and epiglottic region progressively declined as the severity of OSAHS increased (severe OSAHS vs. controls, p < 0.05). The lateral pharyngeal wall was significantly thicker in OSAHS subjects than in healthy controls (p < 0.05). The cross-sectional area of the soft palate in moderate and severe OSAHS subjects was markedly larger than that of the healthy controls (p < 0.05) and positively correlated with the apnea/hypopnea index (p < 0.05). CONCLUSION: Moderate and severe OSAHS patients exhibit multi-plane obstruction of the upper airway, particularly in the retropalatal and retroglossal region. The severity of OSAHS negatively correlates with the thickness, length and cross-sectional area size of the soft palate. PMID- 25531576 TI - Regiocontrol in catalytic reductive couplings through alterations of silane rate dependence. AB - Combinations of ligand, reducing agent, and reaction conditions have been identified that allow alteration in the rate- and regioselectivity-determining step of nickel-catalyzed aldehyde-alkyne reductive couplings. Whereas previously developed protocols involve metallacycle-forming oxidative cyclization as the rate-determining step, this study illustrates that the combination of large ligands, large silanes, and elevated reaction temperature alters the rate- and regiochemistry-determining step for one of the two possible product regioisomers. These modifications render metallacycle formation reversible for the minor isomer pathway, and sigma-bond metathesis of the metallacycle Ni-O bond with the silane reductant becomes rate limiting. The ability to tune regiocontrol via this alteration in reversibility of a key step allows highly regioselective outcomes that were not possible using previously developed methods. PMID- 25531577 TI - Prolactin protects cardiomyocytes against intermittent hypoxia-induced cell damage by the modulation of signaling pathways related to cardiac hypertrophy and proliferation. AB - OBJECTIVES: Prolactin (PRL) is a multifunctional hormone that influences multiple physiological processes. It has been shown to have a protective effect on the cardiovascular system; however, the mechanisms of this effect are poorly understood. The purpose of the study was to elucidate the role of PRL in intermittent hypoxia (IH)-induced apoptosis in the cardiovascular system. METHOD AND RESULTS: We established a hyperprolactinemic rat model by implanting two anterior pituitary (AP) glands into the renal capsule of male Sprague-Dawley rats. The rats were kept under normoxic conditions for 4weeks after implantation in order to reach the expression plateau of PRL in the plasma, and then treated with IH for 7 or 14days. Their hearts were then removed for histological and protein expression analyses. Cerebral cortex (CX)-grafted control rats challenged with IH displayed unique phenotypes such as a thicker heart wall, an abnormal myocardial architecture and an increased interstitial space of the left ventricle. They exhibited reduced expressions of p-JAK2, p-STAT5, cell cycle dependent proteins (cyclin D1, cyclin E and cyclin A), IGF-IRalpha, PI3Kalpha, p AKT and p-ERK1/2 in cardiomyocytes at 7days. CONCLUSIONS: Our comprehensive analysis suggested that high plasma PRL can protect rat cardiomyocytes against IH through (1) the p-JAK2 and p-STAT5 pathways for transient cell proliferation, (2) the PI3Kalpha/AKT and MAPK survival pathways through IGF-I, and (3) the downregulation of IGF-II and ERK5, which inhibit cell hypertrophy. PMID- 25531578 TI - Methionine sulfoxide reductase A, B1 and B2 are likely to be involved in the protection against oxidative stress in the inner ear. AB - The methionine sulfoxide reductase (Msr) family of proteins is a class of repair enzymes that reduce methionine-S (MsrA) or methionine-R (MsrB) sulfoxide to methionine. Recent studies have reported that mutations in the MSRB3 gene cause autosomal recessive hearing loss in humans, and in mice MsrB3 deficiency leads to profound hearing loss due to hair cell apoptosis and stereocilia degeneration. However, apart from MsrB3, studies on Msr proteins in the inner ear have not yet been reported. In this study, we identified and characterized Msr expression in the cochlea and vestibule. First, we confirmed RNA expression levels of Msr family members in the cochlea and vestibule using reverse transcription PCR and detected Msr family members in both tissues. We also conducted immunohistochemical staining to localize Msr family members within the cochlea and vestibule. In the cochlea, MsrA was detected in supporting cells, spiral ligament, spiral limbus, Reissner's membrane and the spiral ganglion. MsrB1 was specifically expressed in hair cells and the spiral ganglion. MsrB2 was noted in the spiral ganglion, tectorial membrane and stria vascularis. In the vestibule, MsrA and MsrB1 were detected in hair cells and the vestibular ganglion, while MsrB2 was restricted to the vestibular ganglion. In this study, we identified distinct distributions of Msr family members in the organ of Corti and hypothesized that MsrA, MsrB1 and MsrB2 protect proteins in the organ of Corti from oxidative stress. PMID- 25531579 TI - The Relevance of Sociodemographic and Health Variables on MMSE Normative Data. AB - The Mini Mental State Examination (MMSE) is the most broadly used cognitive screening instrument in clinical and research contexts. The MMSE was administered to a community-based sample of cognitively healthy adults (n = 850), stratified according to several sociodemographic variables, with a distribution similar to that observed in the Portuguese population. This study aimed to analyze the influence of sociodemographic (age, gender, education level, marital and employment status, geographic region, geographic localization, and residence area) and health variables (subjective memory complaints of the participant and evaluated by the informant, depressive symptoms, and family history of dementia) on the participants' performance on the MMSE and to establish normative data for the Portuguese population. Education level and age significantly contributed to the prediction of the MMSE scores and explained 26% of its variance. Regarding health variables, only the subjective memory complaints of the participant showed a small contribution (4%) to the variance of the MMSE scores. According to these results, age and education were considered in the development of the normative data of the MMSE for the Portuguese population. PMID- 25531580 TI - The facile surface chemical modification of a single glass nanopore and its use in the nonenzymatic detection of uric acid. AB - A conical glass nanopore was first modified with ultrathin gold nanofilm via a simple and innovative chemical reduction of HAuCl4 on a surface-attached poly(L histidine) monolayer in the presence of a mild reductant, NH2OH.HCl, followed by surface functionalization with 2-thiouracil, and exploited for the selective nonenzymatic detection of uric acid and especially for serum sample detection. PMID- 25531581 TI - Echinococcus multilocularis in North America: the great unknown. AB - Over the last decade, studies have begun to shed light on the distribution and genetic characterization of Echinococcus multilocularis, the causative agent of alveolar echinococcosis (AE), in North America. Recent findings indicate that the parasite is likely expanding its range in the central region of the United States and Canada and that invasions of European strains might have occurred. In our review, we present the available data on E. multilocularis infections in wild and domestic animals and humans in North America and emphasize the lack of knowledge on the distribution of the parasite in wild and domestic hosts. Furthermore, we stress the need to better understand the complexity of host communities and their roles in shaping the transmission and distribution of the parasite. We hypothesize that a lack of knowledge about AE by North American physicians might result in the misdiagnosis of cases and an underestimation of disease incidence. The endemic presence of the parasite in urban areas and a recent human case in Alberta, Canada, suggest that the scientific community may need to reconsider the local public health risks, re-assess past cases that might have been overlooked and increase surveillance efforts to identify new cases of human AE. PMID- 25531583 TI - Role of endogenous neural stem cells in spinal cord injury and repair. AB - Spinal cord injury is followed by glial scar formation, which has positive and negative effects on recovery from the lesion. More than half of the astrocytes in the glial scar are generated by ependymal cells, the neural stem cells in the spinal cord. We recently demonstrated that the neural stem cell-derived scar component has several beneficial functions, including restricting tissue damage and neural loss after spinal cord injury. This finding identifies endogenous neural stem cells as a potential therapeutic target for treatment of spinal cord injury. PMID- 25531582 TI - A novel role for RhoA GTPase in the regulation of airway smooth muscle contraction. AB - Recent studies have demonstrated a novel molecular mechanism for the regulation of airway smooth muscle (ASM) contraction by RhoA GTPase. In ASM tissues, both myosin light chain (MLC) phosphorylation and actin polymerization are required for active tension generation. RhoA inactivation dramatically suppresses agonist induced tension development and completely inhibits agonist-induced actin polymerization, but only slightly reduces MLC phosphorylation. The inhibition of MLC phosphatase does not reverse the effects of RhoA inactivation on contraction or actin polymerization. Thus, RhoA regulates ASM contraction through its effects on actin polymerization rather than MLC phosphorylation. Contractile stimulation of ASM induces the recruitment and assembly of paxillin, vinculin, and focal adhesion kinase (FAK) into membrane adhesion complexes (adhesomes) that regulate actin polymerization by catalyzing the activation of cdc42 GTPase by the G protein-coupled receptor kinase-interacting target (GIT) - p21-activated kinase (PAK) - PAK-interacting exchange factor (PIX) complex. Cdc42 is a necessary and specific activator of the actin filament nucleation activator, N-WASp. The recruitment and activation of paxillin, vinculin, and FAK is prevented by RhoA inactivation, thus preventing cdc42 and N-WASp activation. We conclude that RhoA regulates ASM contraction by catalyzing the assembly and activation of membrane adhesome signaling modules that regulate actin polymerization, and that the RhoA mediated assembly of adhesome complexes is a fundamental step in the signal transduction process in response to a contractile agonist. PMID- 25531584 TI - Does forgiveness mediate the impact of school bullying on adolescent mental health? AB - OBJECTIVE: The link between both bullying and victimisation and psychopathology has been well established. Forgiveness has been associated with better mental health. However, few studies have examined the relationship between adolescent forgiveness, psychopathology and bullying/victimisation. This study investigated forgiveness as a mediator of the adverse mental health problems experienced by bullies and victims of bullying. METHOD: Participants were 355 Year 10 or Year 11 pupils (age = 14.9 years) from two British secondary schools in 2007, who completed self-administered measures on bullying and victimisation, mental health, forgiveness of self and others, and forgivingness. The mediating influence of forgiveness on the impact of bullying/victimisation on mental health was tested with a structural equation model. RESULTS: Data from 55.6% of the 639 eligible pupils were analysed. Results confirmed an association between bullying/victimisation, forgiveness and psychopathology. Forgiveness scores were found to play a mediating role between bullying/victimisation and psychopathology. CONCLUSIONS: Victimised adolescents who were better able to forgive themselves were more likely to report lower levels of psychopathology, while bullying adolescents who were unable to forgive others were more likely to report higher levels of psychopathology. This suggests a greater role for forgiveness within future research, intervention and policy on bullying. Forgiveness can form a valuable part of preventative and educational anti bullying programmes. PMID- 25531585 TI - Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. AB - BACKGROUND/AIMS: Transport regulation involves several kinases including SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether SPAK and/or OSR1 participate in the regulation of the creatine transporter CreaT (SLC6A8), which accomplishes Na+ coupled cellular uptake of creatine in several tissues including kidney, intestine, heart, skeletal muscle and brain. METHODS: cRNA encoding SLC6A8 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild type SPAK, constitutively active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, wild-type OSR1, constitutively active (T185E)OSR1, WNK insensitive (T185A)OSR1 and catalytically inactive (D164A)OSR1. Transporter activity was determined from creatine (1 mM) induced current utilizing dual electrode voltage clamp. RESULTS: Coexpression of wild-type SPAK and of (T233E)SPAK, but not of (T233A)SPAK or of (D212A)SPAK was followed by a significant decrease of creatine induced current in SLC6A8 expressing oocytes. Coexpression of SPAK significantly decreased maximal transport rate. Coexpression of wild-type OSR1, (T185E)OSR1 and (T185A)OSR1 but not of (D164A)OSR1 significantly negatively regulated SLC6A8 activity. OSR1 again decreased significantly maximal transport rate. CONCLUSIONS: Both, SPAK and OSR1, are negative regulators of the creatine transporter SLC6A8. PMID- 25531586 TI - Unexpected off-targets and paradoxical pathway activation by kinase inhibitors. AB - Protein kinase inhibitors are an increasingly important class of targeted anticancer therapeutics. More than two dozen new drugs of this class have entered routine clinical use over the past decade. This review article focuses on how the development of methods to study the kinome- and proteome-wide selectivity of kinase inhibitors, in conjunction with advances in the structural understanding of kinase inhibitor binding modes, has resulted in a better appreciation of the mechanism of action of clinical kinase inhibitors. I provide examples of how this has led to the discovery of unexpected off-target effects, intriguing cases in which kinase inhibitors may cause pathway activation, and new mechanisms responsible for resistance to kinase inhibitors. Finally, I illustrate that although certain kinase targets may be pharmacologically easily tractable, a better understanding of the regulation and biology of the targets is required to generate drugs that are efficacious in cancer patients. PMID- 25531587 TI - Complete low-intensity endurance training programme in haemodialysis patients: improving the care of renal patients. AB - BACKGROUND: Patients on haemodialysis (HD) have a decreased physical and functional capacity. Several studies have reported the beneficial effects of exercise on the physical, functional and psychological functioning of HD patients. Despite these results, exercise programmes on HD are not commonplace. OBJECTIVE: To analyse the effect of an intradialysis endurance training programme on muscular strength and functional capacity in our HD patients. MATERIAL AND METHODS: A 6-month single-centre prospective study. HD patients were non-randomly assigned to an exercise group (group E) or a control group (group C). Exercise training included complete endurance training using balls, weights and elastic bands in the first 2 h of an HD session; group C received standard HD care. Analysed data: (1) biochemical parameters; (2) biceps and quadriceps muscle tone, maximum quadriceps length strength (MQLS) and dominant hand grip (HG); (3) functional capacity tests: sit-to-stand-to-sit (STS10) and 6-min walking test (6MWT). RESULTS: Forty patients were included, 55% were men; their mean age was 68.4 years; the patients were 61.6 months on HD; 16 patients were in group E and 24 in group C. In group E, muscular strength showed a significant improvement in MQLS (15.6 +/- 10.7 vs. 17.7 +/- 12.5 kg, p < 0.05) and HG (22.1 +/- 13.2 vs. 24.1 +/- 15.8 kg, p < 0.05) at the end of the programme, while a global decrease was reported in group C (MQLS 20.9 +/- 9.3 vs. 16.2 +/- 8.4 kg, p < 0.05; HG 25.1 +/- 10.3 vs. 24.1 +/- 11.1 kg). 6MWT significantly improved in group E (20%, 293.1 vs. 368 m, p < 0.001) and decreased in group C (10%, 350 vs. 315 m, p < 0.004). At the end of the programme, STS10 time was reduced in group E (2.1 +/- 18.5 vs. 28.7 +/- 20.6 s), while it rose in group C (31.5 +/- 17.9 vs. 36.4 +/- 19.8 s), though significant differences were not found. CONCLUSIONS: (1) The intradialysis training programme improved muscular strength and functional capacity in our HD patients. (2) These results support the benefits of exercise training for HD patients. (3) Nephrologists should consider exercise training as a standard practice for the care of HD patients. PMID- 25531589 TI - Occurrence, bioaccumulation and risk assessment of lipophilic pharmaceutically active compounds in the downstream rivers of sewage treatment plants. AB - The occurrence, bioaccumulation and risk assessment of lipophilic pharmaceutically active compounds (LPhACs), such as antibiotics (roxithromycin, erythromycin and ketoconazole), anti-inflammatories (ibuprofen and diclofenac), beta-blockers (propranolol), antiepileptics (carbamazepine) and steroid hormones (17alpha-ethinylestradiol), were investigated in the downstream rivers of sewage treatment plants in Nanjing, China. The results indicate that these LPhACs were widely detected in the surface water and fish samples, with the mean concentrations of the total LPhACs (SigmaLPhACs) being in the range of 15.4 and 384.5 ng/L and 3.0 and 128.4 ng/g (wet weight), respectively. The bioaccumulation of the SigmaLPhACs in wild fish tissues was generally in the order the liver>brain>gill>muscle. Among the target LPhACs, however, an interspecies difference in tissue distribution was evident for erythromycin. The bioaccumulation factors of LPhACs in the liver and brain, the two major targeted storage sites for toxicants, exhibited an obvious negative correlation with the aquatic concentrations (P<0.05). Finally, risk quotients posed by pharmaceuticals were assessed by comprehensive and comparative methods for different aquatic organisms (algae, daphnids and fish). The overall relative order of susceptibility was estimated to be algae>daphnids>fish. However, the results indicate that diclofenac, ibuprofen and 17alpha-ethinylestradiol each posed chronic risks for high trophic level organisms (fish). In all of the risk assessments, erythromycin was found to be the most harmful for the most sensitive algae group. In this work, however, the total BAF and toxicological interactions of pharmaceuticals were not performed due to the lack of metabolite information and combined toxicity data, which represents a major hindrance to the effective risk assessment of pharmaceuticals. PMID- 25531588 TI - Uncovering surface-exposed antigens of Lactobacillus rhamnosus by cell shaving proteomics and two-dimensional immunoblotting. AB - The present study reports the identification and comparison of all expressed cell surface exposed proteins from the well-known probiotic L. rhamnosus GG and a related dairy strain, Lc705. To obtain this information, the cell-surface bound proteins were released from intact cells by trypsin shaving under hypertonic conditions with and without DTT. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of the purified peptides identified a total of 102 and 198 individual proteins from GG and Lc705, respectively. Comparison of both data sets suggested that the Msp-type antigens (Msp1, Msp2) and the serine protease HtrA were uniquely exposed at the cell surface of GG, whereas the Lc705-specific proteins included lactocepin and a wider range of different moonlighting proteins. ImmunoEM analyses with the GG and Lc705 antibodies suggested that the whole-cell immunization yielded antibodies toward surface-bound proteins and proteins that were secreted or released from the cell-surface. One of the detected antigens was a pilus-like structure on the surface of GG cells, which was not detected with Lc705 antibodies. Further 2-DE immunoblotting analysis of GG proteins with both L. rhamnosus antisera revealed that majority of the detected antigens were moonlighting proteins with potential roles in adhesion, pathogen exclusion or immune stimulation. The present study provides the first catalog of surface-exposed proteins from lactobacilli and highlights the importance of the specifically exposed moonlighting proteins for adaptation and probiotic functions of L. rhamnosus. PMID- 25531590 TI - Sorption behaviour of perfluoroalkyl substances in soils. AB - The sorption behaviour of three perfluoroalkyl substances (PFASs), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorobutane sulfonic acid (PFBS), was studied in six soils with contrasting characteristics, especially in the organic carbon content. Sorption isotherms were obtained by equilibrating the soil samples with 0.01 mol L(-1) CaCl2 solutions spiked with increasing concentrations of the target PFAS. The sorption reversibility of PFASs was also tested for some of the samples. Liquid chromatography coupled to tandem mass spectrometry was used to quantify the target PFASs in the solutions. Both the Freundlich and linear models were appropriate to describe the sorption behaviour of PFASs in soils, and enabled us to derive solid-liquid distribution coefficients (Kd) for each compound in each soil. Kd values increased from 19 to 295 mL g(-1) for PFOS, from 2.2 to 38 mL g( 1) for PFOA and from 0.4 to 6.8 mL g(-1) for PFBS, and were positively correlated with the organic carbon content of the soil. KOC values obtained from the correlations were 710, 96 and 17 mL g(-1) for PFOS, PFOA and PFBS, respectively. Whereas Kd values decreased in the sequence PFOS>PFOA>PFBS, desorption yields were lower than 13% for PFOS, from 24 to 58% for PFOA, and from 32 to 60% for PFBS. This shows that the physicochemical characteristics of PFASs, basically their hydrophobicity, controlled their sorption behaviour in soils, with PFOS being the most irreversibly sorbed PFAS. PMID- 25531591 TI - Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins and dibenzofurans in street dust of North Rhine-Westphalia, Germany. AB - In this study the occurrence of polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins and polychlorinated dibenzofurans (PCDDs/PCDFs) in street dust samples was investigated using pressurized liquid extraction and gas chromatography coupled to mass spectrometry. Street dust samples were taken from rural, urban, industrial and industrially influenced urban areas. PCB6 concentrations ranged from 5090+/-2200 MUg/kg (average+/-standard error of mean) in dusts from industrial premises to 29+/-8.7 MUg/kg in rural areas. Concentration ranges were for dioxin-like PCB toxicity equivalents (dl-PCB TEQ) from 362+/-164 ng/kg (industrial premises) to 6.5+/-1.8 ng/kg (rural areas), and for PCDD/PCDF TEQ from 503+/-448 ng/kg to 2.4+/-0.13 ng/kg, respectively. Area concentrations of PCB6 (0.040 MUg/m2-22 MUg/m2), dl-PCB TEQ (0.0038 ng/m2-2.6 ng/m2) and PCDD/PCDF TEQs (14 pg/m2-1980 pg/m2) were estimated. Furthermore, particle size related concentrations of PCBs and PCDD/PCDFs in street dusts were analysed showing throughout almost all samples a distinctive trend of increasing concentrations with decreasing particle sizes. Characterization of homologue patterns of PCBs and PCDDs/PCDFs in street dusts was performed showing a dependence of homologue patterns on different area types, especially for PCBs. It could be demonstrated that the analysis of concentrations in combination with specific homologue patterns of PCBs and PCDDs/PCDFs in street dust samples enables allocation of potential emission sources. PMID- 25531593 TI - Graphene plasmon propagation on corrugated silicon substrates. AB - The scheme of graphene on a silicon substrate is potentially compatible to the microelectronic technology. But the maintained plasmons have considerable ohmic loss because of silicon's large permittivity. We introduce air grooves in the silicon surface to reduce the optical thickness of substrate and hence decrease the propagation loss. The properties of graphene plasmons on the corrugated substrates are numerically investigated, in terms of the photon frequency and the geometrical parameters of the corrugated layer, considering both ohmic loss and scattering loss. The plasmons propagation lengths for the corrugated substrates can exceed twice of those for flat silicon in a broadband in mid-infrared. This study may be useful for designing of compact mid-infrared waveguides based on graphene for future photonic integrated circuits. PMID- 25531592 TI - Exposure to TCDD from base perimeter application of Agent Orange in Vietnam. AB - Using recognized methods routinely employed by pesticide regulatory agencies, the exposures of military personnel that were mixer/loader/applicators (M/L/A) of Agent Orange (AO) for perimeter foliage at bases during the Vietnam War were estimated. From the fraction of TCDD in AO, absorbed dosage of the manufacturing contaminant was estimated. Dermal exposure estimated from spray drift to residents of the bases was calculated using internationally recognized software that accounted for proximity, foliar density of application site, droplet size and wind speed among other factors, and produced estimates of deposition. Those that directly handled AO generally had much higher exposures than those further from the areas of use. The differences in exposure potential varied by M/L/A activity, but were typically orders of magnitude greater than bystanders. However, even the most-exposed M/L/A involved in perimeter application had lifetime exposures comparable to persons living in the U.S. at the time, i.e., ~1.3 to 5 pg TCDD/kg bodyweight. PMID- 25531594 TI - Optical super-resolution imaging by high-index microspheres embedded in elastomers. AB - We demonstrated feasibility of super-resolution imaging through high-index microspheres embedded in transparent elastomers. We performed imaging, with resolution improvement by a factor of two, by using implanted barium titanate glass microspheres (diameters ~30-150 MUm and refractive index ~1.9-2.1) in a thin film of polydimethylsiloxane elastomer placed over the specimen. Microsphere assisted imaging technique is a promising candidate for applications in cancer research. As a proof-of-principle, we used microsphere-assisted imaging technique for the observation of radiation-induced gamma-H2AX foci formation in U87 human glioblastoma cells irradiated by clinical proton beams. PMID- 25531595 TI - Tm-based fiber-laser system with more than 200 MW peak power. AB - Tm-based fiber-laser systems are an attractive concept for the development of high-performance laser sources in the spectral region around 2 MUm wavelength. Here we present a system delivering a pulse-peak power higher than 200 MW in combination with 24 W average power and 120 MUJ pulse energy. Key components enabling this performance level are a Tm-doped large-pitch fiber with a mode field diameter of 65 MUm, highly efficient dielectric gratings, and a Tm-based fiber oscillator operating in the stretched-pulse regime. PMID- 25531596 TI - Nonlinear diffraction from high-order Hermite-Gauss beams. AB - We investigate experimentally and theoretically the nonlinearly diffracted second harmonic light from the first-order Hermite-Gauss beam. We investigate the cases of loosely and tightly focused beams in a periodically poled lithium niobate crystal in the temperature range near the birefringent phase matching. Unlike the case of fundamental Gaussian beam, the nonlinear diffracted beam is spatially structured. Its shape depends on the focusing conditions and on the crystal temperature. Furthermore, for the case of tight focusing, the diffracted beam structure depends on the beam's position with respect to the domain wall. PMID- 25531597 TI - Effect of ambient air on femtosecond laser ablation of highly oriented pyrolytic graphite. AB - Highly oriented pyrolytic graphite is ablated by femtosecond laser in air and vacuum, respectively. The morphologies and material components of the ablated target surface are examined by scanning electron microscopy and micro-Raman spectroscopy. For laser fluence no less than 0.5 J/cm(2), the laser-induced periodic surface grooves formed in air are found to be much less clearer than those formed in vacuum; beneath the amorphous carbon debris, the surface ablated in air is composed of nanocrystalline graphite, but in vacuum it retains the ordered graphite structure. The thermal relaxation of the ablated target induced by air-assisted heat transfer is considered to be the main reason for the differences. The transportation of air molecules along the surface, the classical size effect of heat conduction and high solid-air heat transfer coefficient in nanoscale enhance the air-assisted heat transfer. PMID- 25531598 TI - Core-shell nanostructures of covalently grafted polyaniline multi-walled carbon nanotube hybrids for improved optical limiting. AB - Polyaniline multi-walled carbon nanotube (MWCNT) hybrids are synthesized by the in situ polymerization of aniline in the presence of phenylenediamine functionalized MWCNTs. Along with the aniline monomer, the aniline moiety on the surface of phenylenediamine-functionalized MWCNTs also participates in the polymerization and acts as a covalent bridge between the polyaniline and the MWCNT. The photoluminescence quenching in the hybrid, due to the electron transfer between the polyaniline and the MWCNT, and the resulting improvement in optical limiting are also discussed. The large nonlinear absorption coefficient with the low-limiting threshold of the hybrids compared to polyaniline is attributed to the combined nonlinear optical (NLO) mechanisms and the photo induced electron transfer interactions. PMID- 25531599 TI - Flat grating lens utilizing widely variable transmission-phase via guided-modes. AB - We experimentally demonstrate a polarization-independent flat grating lens in the near-infrared region. The grating lens consists of ridges in the square lattice arrangement, and the ridge dimensions are gradually changed to distribute a phase map with focusing ability. It is well known that guided modes in gratings offer unity-reflection at a resonance, and therefore the transmission phase is widely varied around the resonance. We employ such transmission phase behavior and show that high transmittance is obtained in each unit cell for wide variation range of the transmission phase at the operation wavelength by sharpening the resonance. This enables us to accomplish a highly efficient transmissive grating lens. PMID- 25531600 TI - Investigating the frequency-dependent amplification of a tapered amplifier in atom interferometers. AB - We present the investigation on the frequency-dependent amplification (FDA) of a tapered amplifier (TA) and the corresponding influence on Raman-type atom interferometers. In our interferometer, the output of two phase-locked diode lasers is injected into a TA to generate Raman beams. The frequency of one laser is chirped during the interfering process, which induces a variance of the Raman lasers power as a result of the FDA of the TA. The corresponding power ratio variation of the Raman lasers is measured by beat note method, which shows a linear dependence with a slope of -0.087(4)/GHz when the laser frequency changes over 2 GHz at 780 nm. The corresponding error related to AC Stark effect due to this frequency-dependent variation is estimated for our atom interferometer. The investigation presented here may provide hints for other experiments involving TAs. PMID- 25531601 TI - All-periodically poled, high-power, continuous-wave, single-frequency tunable UV source. AB - We report on experimental demonstration of an all-periodically poled, continuous wave (CW), high-power, single-frequency, ultra-violet (UV) source. Based on internal second-harmonic-generation (SHG) of a CW singly resonant optical parametric oscillator (OPO) pumped in the green, the UV source provides tunable radiation across 398.94-417.08 nm. The compact source comprising of a 25-mm-long MgO-doped periodically poled stoichiometric lithium tantalate (MgO:sPPLT) crystal of period Lambda(SLT)=8.5 MUm for OPO and a 5-mm-long, multi-grating (Lambda(KTP)=3.3, 3.4, 3.6 and 3.8 MUm), periodically poled potassium titanium phosphate (PPKTP) for intra-cavity SHG, provides as much as 336 mW of UV power at 398.94 nm, corresponding to a green-to-UV conversion efficiency of ~6.7%. In addition, the singly resonant OPO (SRO) provides 840 mW of idler at 1541.61 nm and substantial signal power of 108 mW at 812.33 nm transmitted through the high reflective cavity mirrors. UV source provides single-frequency radiation with instantaneous line-width of ~18.3 MHz and power >100 mW in Gaussian beam profile (ellipticity >92%) across the entire tuning range. Access to lower UV wavelengths requires smaller grating periods to compensate high phase-mismatch resulting from high material dispersion in the UV wavelength range. Additionally, we have measured the normalized temperature and spectral acceptance bandwidth of PPKTP crystal in the UV wavelength range to be ~2.25 degrees C.cm and ~0.15 nm.cm, respectively. PMID- 25531602 TI - Frequency comb-based multiple-access ultrastable frequency dissemination with 7 * 10(-17) instability. AB - In this letter, we demonstrate frequency-comb-based multiple-access ultrastable frequency dissemination over a 10-km single-mode fiber link. First, we synchronize optical pulse trains from an Er-fiber frequency comb to the remote site by using a simple and robust phase-conjugate stabilization method. The fractional frequency-transfer instability at the remote site is 2.6*10(-14) and 4.9*10(-17) for averaging times of 1 and 10,000 s, respectively. Then, we reproduce the harmonic of the repetition rate from the disseminated optical pulse trains at an arbitrary point along the fiber link to test comb-based multiple access performance, and demonstrate frequency instability of 4*10(-14) and 7*10( 17) at 1 and 10,000 s averaging time, respectively. The proposed comb-based multiple-access frequency dissemination can easily achieve highly stable wideband microwave extraction along the whole link. PMID- 25531603 TI - THz-bandwidth photonic Hilbert transformers based on fiber Bragg gratings in transmission. AB - THz-bandwidth photonic Hilbert transformers (PHTs) are implemented for the first time, to the best of our knowledge, based on fiber Bragg grating (FBG) technology. To increase the practical bandwidth limitation of FBGs (typically <200 GHz), a superstructure based on two superimposed linearly-chirped FBGs operating in transmission has been employed. The use of a transmission FBG involves first a conversion of the non-minimum phase response of the PHT into a minimum-phase response by adding an anticipated instantaneous component to the desired system temporal impulse response. Using this methodology, a 3-THz bandwidth integer PHT and a fractional (order 0.81) PHT are designed, fabricated, and successfully characterized. PMID- 25531604 TI - Demonstration of type-II superlattice MWIR minority carrier unipolar imager for high operation temperature application. AB - An InAs/GaSb type-II superlattice-based mid-wavelength infrared (MWIR) 320*256 unipolar focal plane array (FPA) using pMp architecture exhibited excellent infrared image from 81 to 150 K and ~98% operability, which illustrated the possibility for high operation temperature application. At 150 K and -50 mV operation bias, the 27 MUm pixels exhibited dark current density to be 1.2*10(-5) A/cm(2), with 50% cutoff wavelength of 4.9 MUm, quantum efficiency of 67% at peak responsivity (4.6 MUm), and specific detectivity of 1.2*10(12) Jones. At 90 K and below, the 27 MUm pixels exhibited system limited dark current density, which is below 1*10(-9) A/cm(2), and specific detectivity of 1.5*10(14) Jones. From 81 to 100 K, the FPA showed ~11 mK NEDT by using F/2.3 optics and a 9.69 ms integration time. PMID- 25531605 TI - High-speed tunable microwave photonic notch filter based on phase modulator incorporated Lyot filter. AB - A high-speed tunable microwave photonic notch filter with ultrahigh rejection ratio is presented, which is achieved by semiconductor optical amplifier (SOA) based single-sideband modulation and optical spectral filtering with a phase modulator-incorporated Lyot (PM-Lyot) filter. By varying the birefringence of the phase modulator through electro-optic effect, electrically tuning of the microwave photonic notch filter is experimentally achieved at tens of gigahertz speed. The use of SOA-polarizer based single-sideband modulation scheme provides good sideband suppression over a wide frequency range, resulting in an ultrahigh rejection ratio of the microwave photonic notch filter. Stable filter spectrum with bandstop rejection ratio over 60 dB is observed over a frequency tuning range from 1.8 to 10 GHz. Compare with standard interferometric notch filter, narrower bandwidth and sharper notch profile are achieved with the unique PM-Lyot filter, resulting in better filter selectivity. Moreover, bandwidth tuning is also achieved through polarization adjustment inside the PM-Lyot filter, that the 10-dB filter bandwidth is tuned from 0.81 to 1.85 GHz. PMID- 25531606 TI - Recovering three-dimensional shape through a small hole using three laser scatterings. AB - An approach was proposed and developed to recover the 3D shape concealed in a shelter with a small hole only using three laser scatterings. This approach extends reconstruction of concealed 3D shape from "around a corner" to "through a small hole". Based on principle of rectilinear propagation of light, a simple geometric mapping tentative theoretical frame independent of scene was proposed to extract 3D information of concealed objects. Experimental setup mainly consists of a nanosecond laser and a single-photon APD, both of which are commercially available. The 3D reconstructions of three hidden objects were acquired with a resolution of centimeters. PMID- 25531607 TI - Dual-bandgap hollow-core photonic crystal fibers for third harmonic generation. AB - We present two novel hybrid photonic structures made of silica that possess two well-separated frequency bandgaps. The addition of interstitial air holes in a precise location and size allows these bandgaps to open with a ratio of ~3 between their central frequencies at the air line ck(z)/w=1, thus fulfilling the basic guidance condition for third harmonic generation in hollow-core fibers. In addition, these designs may serve for high-power laser delivery of two well separated wavelengths, such as visible and near infrared. PMID- 25531608 TI - DC-field-assisted grating formation and nonlinear diffractions in methyl-red dye doped blue phase liquid crystals. AB - We report the observation of enhanced nonlinear optical responses of methyl-red doped blue-phase liquid crystals by application of a DC field. We have observed strong multi-order nonlinear grating diffractions characterized by a nonlinear index coefficient n(2)~0.5 cm(2)/W using unfocused CW laser power of ~1 mW and a DC field of a few V/MUm. The underlying mechanisms are crystalline lattice and director axis reorientations by torques exerted by the DC field and photo-excited dye molecules. PMID- 25531609 TI - Ultrafast carrier dynamics and coherent acoustic phonons in bulk CdSe. AB - The femtosecond pump-probe technique is used to study the dynamics of photoexcited carriers and coherent acoustic phonons in bulk CdSe semiconductor. A turning point from fast to slow decay is observed, whose amplitude decreases with pump fluences and eventually flips the sign of differential reflectivity. The maximum change of differential reflectivity shows a saturation at high pump fluences, which is attributed to the optical energy gap dependent on carrier density. Long-lasting coherent oscillations of acoustic phonons have also been detected, and their amplitude and lifetime have a strong dependence on pump fluences. Our results can facilitate the understanding of ultrafast carrier and phonon dynamics in CdSe nanocrystals. PMID- 25531610 TI - Silicon single-crystal cryogenic optical resonator: erratum. AB - We correct fit formulas from a previous paper [Opt. Lett.39, 3242 (2014)10.1364/OL39.005896OPLEDP0146-9592] for the coefficient of thermal expansion alphareson(T). PMID- 25531611 TI - Ground-state lasing in high-power InAs/GaAs quantum dots-in-a-well laser using active multimode interference structure. AB - We have designed and demonstrated InAs/GaAs quantum dots-in-a-well laser diodes for short cavities with transverse fundamental mode operation by using an active multimode interferometer (MMI) structure for the first time to the best of our knowledge. Room-temperature continuous-wave ground-state lasing at 1280 nm has been achieved with an output power of 116 mW per facet, which is 2.4 times higher than that of the conventional ridge laser diodes. By using the MMI structures, the excited-state (ES) lasing is effectively suppressed with no ES lasing, even at a high injection current of 400 mA. This device has great potential for high power single-mode laser emission with low electric power consumption and simple fabrication processes. PMID- 25531612 TI - Continuous-wave anti-Stokes Raman laser based on phase-matched nondegenerate four wave mixing. AB - We demonstrate phase-matched nondegenerate four-wave mixing (FWM) in a high finesse optical cavity using a gaseous Raman-active medium pumped by two independent continuous-wave lasers. Efficient upconversion is achieved for pump beams at different wavelengths under phase-matched conditions by optimizing the total dispersion of the hydrogen-filled optical cavity. The independent control of the pump-beam polarizations leads to further enhancement of the upconversion efficiency arising from a larger Raman gain than that in degenerate FWM. This approach offers a promising alternative for a narrow-linewidth tunable light source for highly precise laser spectroscopy. PMID- 25531613 TI - Monolithically integrated 2.5 GHz extended cavity mode-locked ring laser with intracavity phase modulators. AB - A mode-locked extended cavity quantum well ring laser at 1.58 MUm with a repetition rate of 2.5 GHz in the form of a photonic integrated circuit is presented. The device is realized using InP-based active-passive integration technology. The 33 mm long cavity contains gain, saturable absorption, and passive waveguide sections as well as phase shifter sections to enable fine tuning of the spectral position of the lasing modes. Passive and hybrid mode locked operation, along with the wavelength tuning of the laser modes, are experimentally demonstrated. In the passive mode-locking regime, a beat signal at the fundamental round trip frequency with a 3 dB bandwidth of 6.1 kHz is produced on a fast photo diode. PMID- 25531614 TI - All-fiber DFB laser operating at 2.8 MUm. AB - Single-frequency laser emission from a distributed feedback all-fiber laser operating in the vicinity of 3 MUm is demonstrated. The laser cavity was made of a 30 mm long pi-phase-shifted fiber Bragg grating inscribed in a heavily erbium doped fluoride fiber using infrared femtosecond pulses and the dithering phase mask technique. A maximum CW output power of 12 mW was obtained at 2794.4 nm by using a multimode pumping scheme. The narrow linewidth was characterized to be lower than 20 kHz using a heterodyne technique. This achievement represents a significant step toward the development of active frequency references operating in the mid-infrared. PMID- 25531616 TI - High-energy chirped- and divided-pulse Sagnac femtosecond fiber amplifier. AB - We report on the generation of 1.1-mJ, 300-fs pulses at 50 kHz by implementing an amplifier architecture whereby four stretched pulse replicas are created in the temporal and spatial domains, allowing pulse energy scaling by the same factor. The whole spatiotemporal coherent combining geometry is passive, avoiding the need for active electronic stabilization loop systems. The combining efficiency remains above 90% at all power levels. PMID- 25531615 TI - Calibration-free sinusoidal rectification and uniform retinal irradiance in scanning light ophthalmoscopy. AB - Sinusoidal rectification (i.e., desinusoiding) is necessary for scanning imaging systems and is typically achieved by calculating a rectification transform from a calibration image such as a regular grid. This approach is susceptible to error due to electronic or mechanical instability that can alter the phase of the imaging window with respect to the calibration transform. Here, we show a calibration-free rectification method implemented from live video of a scanning light ophthalmoscope (SLO) with or without adaptive optics (AO). This approach, which capitalizes on positional differences in the images obtained in the forward and backward scan directions, dynamically keeps the imaging window in phase with the motion of the sinusoidal resonant scanner, preventing errors from signal drift over time. A benefit of this approach is that it allows the light power across the field-of-view (FOV) to be modulated inversely to achieve uniform irradiance on the retina, a feature desirable for functional imaging methods and light safety in SLOs. PMID- 25531617 TI - Experimental demonstration of sharp Fano resonance within binary gold nanodisk array through lattice coupling effects. AB - Fano resonance originating from the interaction of anti-phased and in-phased lattice collective resonances supported by a binary gold nanodisk array is investigated both numerically and experimentally. As the magnitude of particle radii in the two arrays approaches gradually, the Q factor of such resonance increases while the spectral contrast reduces. In the experiment, a high spectral contrast of 0.7 and a large Q factor of 14 could be achieved at the same time due to the excitation of the pure dipole resonance of each particle resulting from the weak near-field coupling. Optimal calculation gives rise to a higher Q factor of up to 85 and a corresponding spectral contrast of 0.86, which is very promising in refractive sensors. The sensitivity and the figure of merit are 337 nm/RIU and 116, respectively. PMID- 25531618 TI - Precise evaluation of the Helmholtz equation for optical propagation. AB - A precise computational integration of the Helmholtz equation was performed for laser propagation of an electromagnetic wave with no approximations or linearization. This computation integration was performed using 64-bit processors. This is illustrated for a uniform monochromatic beam from a circular aperture that has a uniform intensity. It predicts many Arago spots and near field intensity fluctuations for a large ratio of aperture size to wavelength and converges to the usual Airy pattern in the far field. PMID- 25531619 TI - High-power diode lasers at 1178 nm with high beam quality and narrow spectra. AB - High-power distributed Bragg reflector tapered diode lasers (DBR-TPLs) at 1180 nm were developed based on highly strained InGaAs quantum wells. The lasers emit a nearly diffraction-limited beam with more than two watts with a narrow spectral width. These features are believed to make this type of diode laser a key component for the manufacturing of miniaturized laser modules in the yellow and orange spectral range by second-harmonic generation to cover a spectral region currently not accessible with direct emitting diode lasers. Future applications might be the laser-cooling of sodium, high-resolution glucose-content measurements, as well as spectroscopy on rare earth elements. PMID- 25531620 TI - Controlling thermo-optic response in microresonators using bimaterial cantilevers. AB - We demonstrate a novel platform to control the thermo-optic sensitivity in nanophotonic devices by evanescent coupling of light with bimaterial cantilevers. The cantilever can be designed to provide a negative thermal feedback to passively compensate for the positive thermo-optic effect in the waveguide core. We demonstrate athermal operation over 14 deg in cantilever coupled Silicon ring resonators, limited only by fabrication tolerances. We also show how the same platform can provide positive thermal feedback and overcome the material thermo optic limit for increasing sensitivity of resonant detectors and thermal imagers. PMID- 25531621 TI - Wavelength conversion in modulated coupled-resonator systems and their design via an equivalent linear filter representation. AB - We propose wavelength converters based on modulated coupled resonators that achieve conversion by matching the modulation frequency to the frequency splitting of the supermodes of the unmodulated system. Using temporal coupled mode theory, we show that these time-variant systems have an equivalent linear, time-invariant filter representation that simplifies the optimal engineering of design parameters for realistic systems. Applying our model to carrier plasma dispersion modulators as an example implementation, we calculate conversion efficiencies between -5.4 and -1.7 dB for intrinsic quality factors of 10(4) 10(6). We show that the ratio of the resonance shift to the total linewidth is the most important parameter when determining conversion efficiency. Finally, we discuss how this model can be used to design devices such as frequency shifters, widely tunable radio frequency oscillators, and frequency combs. PMID- 25531622 TI - Enhancing optical isolator performance in nonreciprocal waveguide arrays. AB - We investigate the operation of optical isolators based on magneto-optics waveguide arrays beyond the coupled mode analysis. Semi-vectorial beam propagation simulations demonstrate that evanescent tail coupling and the effects of radiation are responsible for degrading the device's performance. Our analysis suggests that these effects can be mitigated when the array size is scaled up. In addition, we propose the use of radiation blockers in order to offset some of these effects, and we show that they provide a dramatic improvement in performance. Finally, we also study the robustness of the system with respect to fabrication tolerances using the coupled mode theory. We show that small, random variations in the system's parameters tend to average out as the number of optical guiding channels increases. PMID- 25531623 TI - Concatenation of surface plasmon resonance sensors in a single optical fiber using tilted fiber Bragg gratings. AB - An inline multichannel surface plasmon resonance (SPR) sensor scheme excited with tilted fiber Bragg gratings (TFBG) in a chromium- and gold-coated fiber is demonstrated. The channels have different operating wavelengths, different TFBG tilt angles, and hence different refractive index operating ranges. The polarization state of each channel based on the TFBG orientation can be used to switch each SPR sensor on or off as required. This system provides an operating range of 1.40-1.44 RIU and a sensitivity of around 500 nm/RIU. The multiplexing in a single optical fiber of a number of TFBG-SPR sensors is demonstrated for the first time. PMID- 25531624 TI - In situ non-perturbative temperature measurement in a Cs alkali laser. AB - The two-dimensional (2D) temperature profiles of an active-gain medium in a Cs + methane diode pumped alkali laser (DPAL) have been experimentally measured. This nonperturbative technique uses a Mach-Zehnder interferometer, which is longitudinally coupled into the cavity of an operating alkali laser to probe the distortion of the optical path length in the gain medium due to heating. The resulting interferograms are analyzed using the commercial program QuickFringe to quickly and accurately measure the distortion through which the temperature profile can be determined. For a 9 W Cs + methane DPAL being pumped with 20 W of resonant D2 light, a maximum temperature rise of 58 degrees C is observed. PMID- 25531625 TI - Coherent supercontinuum generation in a silicon photonic wire in the telecommunication wavelength range. AB - We demonstrate a fully coherent supercontinuum spectrum spanning 500 nm from a silicon-on-insulator photonic wire waveguide pumped at 1575 nm wavelength. An excellent agreement with numerical simulations is reported. The simulations also show that a high level of two-photon absorption can essentially enforce the coherence of the spectral broadening process irrespective of the pump pulse duration. PMID- 25531626 TI - Temporal phase conjugation based on time-domain holography. AB - A novel, simple method for wavelength-preserving temporal phase conjugation (TPC) of complex optical waveforms is proposed and experimentally validated. The method is based on the concept of time-domain holography; it requires direct photo detection of the original waveform mixed with a CW light beam (temporal hologram recording), followed by intensity-only modulation of a second CW light source with the photo-detected interference-like pattern. The conjugated signal is directly obtained from the modulated light through an optical bandpass filtering process, without requiring any further processing on the detected interferogram. The proposed scheme is successfully demonstrated by conjugating a train of arbitrarily chirped Gaussian-like pulses and a 3 Gbps 16-QAM data stream. PMID- 25531627 TI - Mass spectrometric detection of short-lived drug metabolites generated in an electrochemical microfluidic chip. AB - The costs of drug development have been rising exponentially over the last six decades, making it essential to select drug candidates in the early drug discovery phases before proceeding to expensive clinical trials. Here, we present novel screening methods using an electrochemical chip coupled online to mass spectrometry (MS) or liquid chromatography (LC) and MS, to generate phase I and phase II drug metabolites and to demonstrate protein modification by reactive metabolites. The short transit time (~4.5 s) between electrochemical oxidation and mass spectrometric detection, enabled by an integrated electrospray emitter, allows us to detect a short-lived radical metabolite of chlorpromazine which is too unstable to be detected using established test routines. In addition, a fast way to screen candidate drugs is established by recording real-time mass voltammograms, which allows one to identify the drug metabolites that are expected to be formed upon oxidation by applying a linear potential sweep and simultaneously detect oxidation products. Furthermore, detoxification of electrochemically generated reactive metabolites of paracetamol was mimicked by their adduct formation with the antioxidant glutathione. Finally, the potential toxicity of reactive metabolites can be investigated by the modification of proteins, which was demonstrated by modification of carbonic anhydrase I with electrochemically generated reactive metabolites of paracetamol. With this series of experiments, we demonstrate the potential of this electrochemical chip as a complementary tool for a variety of drug metabolism studies in the early stages of drug discovery. PMID- 25531629 TI - Correction to h2 evolution and molecular electrocatalysts: determination of overpotentials and effect of homoconjugation. PMID- 25531628 TI - Interactions between traumatic brain injury and frontotemporal degeneration. AB - BACKGROUND/AIMS: Prior work in smaller cohorts suggests that traumatic brain injury (TBI) may be a risk factor for frontotemporal degeneration (FTD). We sought to confirm and extend these results using the National Alzheimer's Coordinating Center Uniform Data Set. METHODS: We compared the TBI prevalence between FTD subjects and matched normal controls. Indices of cognitive, behavioral, functional, and global dementia severity were compared between FTD subjects with and without prior TBI. RESULTS: Remote TBI with extended loss of consciousness (TBI-ext) was more common in individuals with FTD than in controls (OR: 1.67; 95% CI: 1.004-2.778). With TBI-ext, less functional and global impairment was seen in the behavioral variant of FTD, but more behavioral pathology was seen in the semantic variant. CONCLUSION: TBI may increase the FTD risk and influence clinical symptomatology and severity in FTD subtypes. PMID- 25531630 TI - [Lichtenstein's hernia repair]. AB - AIM: Lichtenstein's hernia repair (LHR) is presented as a technically feasible procedure for inguinal hernia. INDICATION: LHR is a standard procedure for open mesh techniques with very good postoperative results. METHOD: We demonstrate an LHR step by step with preservation of the iliohypogastricus and ilioinguinalis nerves. CONCLUSION: LHR is a technically feasible and safe procedure which should have a firm place in a general surgical education. PMID- 25531631 TI - [Editorial Zentralblatt fur Chirurgie "topic paediatric surgery"]. PMID- 25531632 TI - [Strategies for paediatric spleen and liver injuries]. AB - Traumatic injuries of the spleen and liver are typically caused by age-related falls or sports and traffic accidents. Today, the non-operative management for isolated injuries is established and evidence-based guidelines are available. The intact abdominal wall and the limited space within the peritoneum produce a compression which is the pathophysiological explanation for the limitation of the haemorrhage. Precondition for the non-operative therapy is the radiology-based classification of the injury (organ injury scale) and a haemodynamically stable patient. Haemodynamic stability is, if necessary maintained with blood transfusion, volume substitutes and the administration of catecholamines. In cases of hilar vascular injury and devascularisation or haemodynamic instability of the patient, despite utilisation of the measures mentioned above, urgent operative therapy needs to be performed. Organ sparing surgery is the therapy of choice for both liver and spleen. The spleen is required for the development of a competent immune system in the growing organism. Liver injuries can be further complicated by injury to the bile system, which might require operative reconstruction. If a patient suffers from multiple injuries and spleen or liver are involved, the decision on the management needs to be taken individually, no guidelines exist but the rate for operative therapy increases. Independent of the dimensions of injury, an experienced paediatric surgeon with his multidisciplinary team, considering the anatomic and age specific characteristics of a child, achieves the best therapeutic results. PMID- 25531633 TI - [The significance of minimally invasive surgery in the treatment of inguinal hernia and hypertrophic pyloric stenosis]. AB - BACKGROUND: Inguinal hernia repair and pyloromyotomy are among the most common operations performed on children. In the last two decades minimally invasive surgery has been employed for an increasing number of these procedures. This review describes the development of the techniques involved, and their current role in therapy. MATERIAL AND METHODS: A systematic review of the paediatric surgical literature since 1990 was performed on laparoscopic inguinal hernia repair and pyloromyotomy. Relevant publications were summarised. RESULTS: The first laparoscopic pyloromyotomy was described in 1991, the first laparoscopic inguinal hernia repair in children was published in 1998. The learning curve for both procedures is initially steep and reaches a plateau only after about 20 to 30 cases. Both randomised controlled trials and meta-analyses are available comparing the laparoscopic and open techniques for both procedures. The advantages of laparoscopic versus open pyloromyotomy include faster recovery and shorter hospital stay, at similar complication rates. The operation times of laparoscopic inguinal hernia repair are shorter in bilateral cases, while the complication rate again is similar. However, the incidence of metachronous contralateral inguinal hernia is lower after laparoscopic repair. CONCLUSION: Laparoscopic pyloromyotomy and paediatric inguinal hernia repair require special skills. As a minimum, a surgeon's first 20 cases should therefore be performed under competent supervision. Besides resulting in smaller scars, both procedures have concrete advantages and the same complication rates compared to the open techniques. Therefore, both operations can be regarded as the current gold standard. PMID- 25531634 TI - [Cytoreductive surgery and HIPEC for peritoneal malignancies in children]. AB - Peritoneal tumour dissemination represents an advanced tumour stage and survival rates are usually low. In the past, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been established in adults leading to increased survival rates in comparison to chemotherapy alone. CRS and HIPEC are indicated in primary peritoneal tumours such as mesothelioma and pseudomyxoma peritonei, and in peritoneal metastases from gastrointestinal and ovarian cancers in adults. The incidence of peritoneal surface malignancies in children seems to be lower than in adults, but the incidence is unknown. Nevertheless, peritoneal carcinomatosis/sarcomatosis may occur in patients suffering from desmoplastic small round cell tumour (DSRCT), soft tissue sarcoma (rhabdomyosarcoma, leiomyosarcoma, GIST or liposarcoma), as well as in patients with gastrointestinal cancers. CRS and HIPEC have been established as a novel treatment option in children suffering from peritoneal carcinomatosis/sarcomatosis in very few centres worldwide. This paper reviews the indications, treatment regimens, and pitfalls of this approach in children. PMID- 25531635 TI - [Strategies in the treatment of supracondylar fractures of the humerus in children - proven and controversial]. AB - Elbow fractures are the 2nd most frequent fractures in children. Their therapy needs high expertise. Particularly an adequate analgesic therapy as well as an efficient and differentiated non-surgical or surgical therapy depending on the fracture type needs to be chosen. Secondary damage, especially growth disturbances, has to be prevented. Type I fractures can be managed conservatively with a cast. The crossed percutaneous pin fixation after open or closed reduction is the typical and most frequent surgical treatment option in supracondylar humeral fractures in children. Another good treatment option for supracondylar fractures type II to IV after closed reduction is the elastic-stable intramedullar nailing (ESIN). It is a minimally invasive treatment away from the fracture zone, which allows immediate free movement of the extremity. An immobilisation in a cast is therefore not necessary. That are the most possible effects (opinion of the authors) of the ESIN method, but discussed controversial in the literature. Especially neurovascular concomitant injuries require a differentiated treatment strategy to prevent long-term damage and should only be carried out in a specialised paediatric surgery unit. Long-term complications of supracondylar fractures are limitations in range of motion, nerval palsies, disturbances of growth, as well as cubitus varus (30 %) and valgus (3-7 %). These last ones often result from an insufficient initial anatomic reduction. The aim of the therapy should in any case be a patient-orientated treatment with the expected quickest recovery time and lowest long-term complications. Therefore supracondylar fractures should be treated only by a specialised paediatric trauma team, which can provide all non-surgical and surgical treatments. The spontaneous correcture is only seen in the sagittal view in young children between 6-7 years of age. PMID- 25531636 TI - [Teamwork in the operating theatre: the German Observational Teamwork Assessment for Surgery (OTAS-D) and its first application in Germany]. AB - BACKGROUND: The quality of surgical teamwork contributes to performance of the operating theatre team, service quality and patient safety in surgery. Observational tools are a feasible and reliable way to capture and evaluate teamwork in the operating theatre (OT). We introduce the German version of the Observational Teamwork Assessment for Surgery (OTAS-D) and present the first observational results from German OTs. METHODS: Quality of surgical teamwork was assessed with observational teamwork assessment for surgery (OTAS-D). It evaluates five dimensions of OT teamwork: communication, coordination, cooperation/backup behaviour, leadership, and team monitoring/situation awareness. Each dimension is evaluated for each profession (surgical, nursing, and anaesthesia team) as well for each phase of the procedure (pre-, intra-, and post-operative). We observed n = 63 procedures, mainly in abdominal/general and orthopaedic surgery. Additionally, all OT team members scored their individual evaluation of the intra-operative teamwork (standardised 1-item questions). RESULTS: The OTAS-D evaluations showed meaningful results and differences for the OT professions as well as across the different phases of the procedures. Overall, a medium to good level of the OT teamwork was observed. There were no differences in regard to type of surgery (minimally invasive vs. open) or surgical specialties. With an increased coordination of the surgical team we observed a significantly increased cooperation of the nursing team (r = 0.36, p = 0.004). Concerning the OT staffs self-reports, the surgical and nursing teams reported higher scores for quality of surgical teamwork during the procedure than their anaesthesia team members. No significant relationships between observed quality of OT teamwork and self-reports were found. CONCLUSIONS: The German version of OTAS-D is a psychometrically robust method to capture the quality of teamwork in operating theatres. It enables the analyses of teamwork between the surgical, nursing and anaesthesia professions in acute surgical care. Limitations of the first application results are considered. Finally, potential applications for surgical teaching, research and quality management are discussed. PMID- 25531637 TI - [Requirements for final year medical studies in the era of generation Y - implementation for general and visceral surgery at the Ludwig Maximilians University of Munich]. AB - The revision of the medical licensing regulations in 2012 has changed the underlying conditions for the practical year (PY), especially in the sense of markedly more flexibility for the medical students. The driving force for these and future changes, however, is not the legislature but rather the students themselves who are explicitly demanding that their training be adapted to their requirements and wishes. Time for the realisation of personal aims, planning of leisure time activities, for the family and social contacts as well as an altogether balanced work-life balance have replaced the wish for professional advancement as premise for the lifestyle of generation Y. Many hospitals, especially the privately-supported, attract students with special offers - university hospitals are called upon to defend their position in the competition for newly qualified students. The present article describes the changes of 2012 as part of a programme for a sustainable increase in the attractivity of the surgical PY at the Ludwig-Maximilian University (LMU) in Munich. PMID- 25531638 TI - Triallelic digenic mutation in the prokineticin 2 and GNRH receptor genes in two brothers with normosmic congenital hypogonadotropic hypogonadism. AB - Purpose/aim of the study: To date, different genes have been identified as responsible for the presence of normosmic congenital hypogonadotropic hypogonadism (nCHH). Herein, we report the molecular findings regarding the analysis of PROK2, in two brothers with nCHH. SUBJECTS AND METHODS: Two siblings with nCHH, in whom mutations in GNRHR, PROKR2 and FGFR1 had been investigated previously, as well as their family were studied. DNA was amplified by PCR and sequenced for the PROK2 gene. Controls were analyzed by restriction fragment length polymorphism. The structure of PROK2 and its mutant protein were compared using a protein molecular model. RESULTS: Both affected siblings exhibited a heterozygous p.R117W mutation in PROK2, while their mother was a heterozygous carrier and their father, an unaffected brother and their sister were homozygous wild type. Besides, both patients presented a homozygous p.E90K mutation in GNRHR that had been previously reported. CONCLUSIONS: We found a novel mutation in PROK2 in two siblings in whom a mutation in the GNRHR gene had been previously reported. PMID- 25531639 TI - Naphthopyranones--isolation, bioactivity, biosynthesis and synthesis. AB - The 1H-naphtho[2,3-c]pyran-1-one (naphthopyranone) moiety forms the structural framework of a group of secondary metabolites that have been isolated from a range of organisms including fungi, bacteria, lichen and plants. This review documents the known naturally occurring naphthopyranones - their isolation, biosynthesis and biological activity. A survey of methods reported for the synthesis of naphthopyranone natural products is presented. PMID- 25531640 TI - Deciphering the prokaryotic community and metabolisms in South African deep-mine biofilms through antibody microarrays and graph theory. AB - In the South African deep mines, a variety of biofilms growing in mine corridor walls as water seeps from intersections or from fractures represents excellent proxies for deep-subsurface environments. However, they may be greatly affected by the oxygen inputs through the galleries of mining activities. As a consequence, the interaction between the anaerobic water coming out from the walls with the oxygen inputs creates new conditions that support rich microbial communities. The inherent difficulties for sampling these delicate habitats, together with transport and storage conditions may alter the community features and composition. Therefore, the development of in situ monitoring methods would be desirable for quick evaluation of the microbial community. In this work, we report the usefulness of an antibody-microarray (EMChip66) immunoassay for a quick check of the microbial diversity of biofilms located at 1.3 km below surface within the Beatrix deep gold mine (South Africa). In addition, a deconvolution method, previously described and used for environmental monitoring, based on graph theory and applied on antibody cross-reactivity was used to interpret the immunoassay results. The results were corroborated and further expanded by 16S rRNA gene sequencing analysis. Both culture-independent techniques coincided in detecting features related to aerobic sulfur-oxidizers, aerobic chemoorganotrophic Alphaproteobacteria and metanotrophic Gammaproteobacteria. 16S rRNA gene sequencing detected phylotypes related to nitrate-reducers and anaerobic sulfur-oxidizers, whereas the EMChip66 detected immunological features from methanogens and sulfate-reducers. The results reveal a diverse microbial community with syntrophic metabolisms both anaerobic (fermentation, methanogenesis, sulphate and nitrate reduction) and aerobic (methanotrophy, sulphur oxidation). The presence of oxygen-scavenging microbes might indicate that the system is modified by the artificial oxygen inputs from the mine galleries. PMID- 25531641 TI - Hypoxia inducible factor-1 alpha promotes mesangial cell proliferation in lupus nephritis. AB - BACKGROUND: Evidence has accumulated that hypoxia plays a significant role in the pathogenesis and progression of both acute renal injury and chronic renal disease. However, little was known about the effects of hypoxia on lupus nephritis (LN). In the current study, we investigated the expression of hypoxia inducible factor-1 alpha (HIF-1alpha) in LN. METHODS: Renal biopsies from 22 LN patients and 20 patients with renal carcinoma were obtained. In situ HIF-1alpha expression was examined by immunohistochemical staining, and the relationship between HIF-1alpha and clinical/pathological features was analyzed. HIF-1alpha expression in kidney from both MRL/lpr and C57BL/6 mice was detected by immunohistochemical technology. Dimethyloxaloylglycine (DMOG), an inhibitor of HIF-degrading prolylhydroxylases, was utilized to prevent HIF-1alpha degradation in mouse mesangial cells (MCs). After DMOG treatment, the proliferation and apoptosis rates of mouse MCs were determined. RESULTS: LN patients showed larger amounts of HIF-1alpha in both glomerular and tubulointerstitial areas. The levels of intraglomerular HIF-1alpha were closely associated with renal pathology activity index and clinical manifestations in LN patients. In MRL/lpr mice, intraglomerular HIF-1alpha-positive cells were also significantly increased. Interestingly, the levels of HIF-1alpha positively correlated with cell density in glomerulus in both LN patients and MRL/lpr mice. Upon treatment with DMOG, the proliferation of MCs was upregulated, and apoptosis was downregulated. CONCLUSION: HIF-1alpha is highly expressed in both glomerular and tubulointerstitial tissues in LN, especially in proliferative LN. HIF-1alpha may promote MCs growth through the induction of proliferation and inhibition of apoptosis, and hence plays an important role in the pathogenesis of LN. PMID- 25531642 TI - Enhancing allosteric inhibition in Thermus thermophilus Phosphofructokinase. AB - The coupling between the binding of the substrate Fru-6-P and the inhibitor phospho(enol)pyruvate (PEP) in phosphofructokinase (PFK) from the extreme thermophile Thermus thermophilus is much weaker than that seen in a PFK from Bacillus stearothermophilus. From the crystal structures of Bacillus stearothermophilus PFK (BsPFK) the residues at positions 59, 158, and 215 in BsPFK are located on the path leading from the allosteric site to the nearest active site and are part of the intricate hydrogen-bonding network connecting the two sites. Substituting the corresponding residues in Thermus thermophilus PFK (TtPFK) with the amino acids found at these positions in BsPFK allowed us to enhance the allosteric inhibition by PEP by nearly 3 kcal mol(-1) (50-fold) to a value greater than or equal to the coupling observed in BsPFK. Interestingly, each single variant N59D, A158T, and S215H produced a roughly 1 kcal mol(-1) increase in coupling free energy of inhibition. The effects of these variants were essentially additive in the three combinations of double variants N59D/A158T, N59D/S215H, and A158T/S215H as well as in the triple variant N59D/A158T/S215H. Consequently, while the hydrogen-bonding network identified is likely involved in the inhibitory allosteric communication, a model requiring a linked chain of interactions connecting the sites is not supported by these data. Despite the fact that the allosteric activator of the bacterial PFK, MgADP, binds at the same allosteric site, the substitutions at positions 59, 158, and 215 do not have an equally dramatic effect on the binding affinity and the allosteric activation by MgADP. The effect of the S215H and N59D/A158T/S215H substitutions on the activation by MgADP could not be determined because of a dramatic drop in MgADP binding affinity that resulted from the S215H substitution. The single variants N59D and A158T supported binding but showed little change in the free energy of activation by MgADP compared to the wild type TtPFK. These results support previous suggestions that heterotropic inhibition and activation occur by different pathways prokaryotic PFK. PMID- 25531643 TI - Complete Occlusion of a Subcutaneous Pyelovesical Bypass Graft (Detour(r) System) Caused by Uric Acid Stone Formation. AB - Subcutaneous pyelovesical bypass graft (SPBG) is a urinary diversion treatment option for ureteral obstruction. Initially its use was limited to palliative care patients. However, the indication profile has been extended to selected patients with benign conditions causing ureteral obstruction and hydronephrosis. Occlusion of SPBGs is rarely reported and mostly related to infections. We describe the clinical case of a patient with SPBG after iatrogenic ureteral stricture who was not suitable for other reconstructive treatment forms due to distinct retroperitoneal scarring after multiple previous surgeries. Several months after the SPBG insertion, the patient developed complete occlusion of the system with uric acid stone material. Sufficient endoscopic intervention was not feasible. After forced chemolitholysis, the stone mass could be completely dissolved. Since then the patient has remained symptom-free. PMID- 25531644 TI - Initial results of endoscopic gastrocutaneous fistula closure in children using an over-the-scope clip. AB - Gastrocutaneous fistula (GCF) occurs commonly in pediatric patients after removal of long-term gastrostomy tubes. Although open repair is generally successful, endoscopic approaches may offer benefits in terms of incisional complications, postoperative pain, and procedure time. In addition, endoscopic approaches may offer particular benefit in patients with varied degrees of skin irritation or erosion surrounding a GCF, making surgical repair difficult, or patients with significant comorbidities, making minimal intervention and anesthesia time preferable. Over-the-scope (OSC) clips are a new technology that enables endoscopic closure of intestinal fistulas up to 2 cm in diameter. Six pediatric patients underwent endoscopic GCF closure using OSC clips under Institutional Review Board approval. The procedure was technically successful in 5 of 6 cases with an average operating time of 29 minutes. The technical failure required an open revision, whereas all other patients reported full healing of the GCF site at 1 month. All successful cases were performed as outpatients without postoperative narcotics. In addition, all patients reported high satisfaction with the procedure and cosmetic results. Endoscopic GCF closure using an OSC clip is technically feasible in the pediatric population. Based on limited cases with a 1-month follow-up, the functional and cosmetic results of technically successful cases are excellent. Endoscopic GCF closure is a potential alternative to standard surgical closure in patients with skin irritation or erosion and/or significant comorbidities. PMID- 25531645 TI - Osteoinductive fibrous scaffolds of biopolymer/mesoporous bioactive glass nanocarriers with excellent bioactivity and long-term delivery of osteogenic drug. AB - Designing scaffolds with bioactive composition and long-term drug delivery capacity is a promising method to improve the therapeutic efficacy in bone regeneration. Herein, electrospun fibrous scaffolds of polycaprolactone-gelatin incorporating mesoporous bioactive glass nanoparticles (mBGn) were proposed to be excellent matrix platforms for bone tissue engineering. In particular, the mBGn were loaded with osteogenic drug Dexamethasone (DEX) to elicit additional therapeutic potential. The mBGn-added fiber scaffolds demonstrated excellent properties, including improved mechanical tensile strength, elasticity, and hydrophilicity compared to pure biopolymer matrix. The scaffolds could release substantial amounts of calcium and silicate ions. The loading of DEX onto mBGn was as high as 63%, that is, 0.63 mg DEX loaded per 1 mg of mBGn, demonstrating an effective nanodepot role of the mBGn. The release of DEX from the mBGn-added fiber scaffolds was highly sustainable, profiling an almost linear release kinetics up to the test period of 28 days, after a rapid initial release of ~30% within 24 h. The proliferation and osteogenic differentiation of stem cells derived from periodontal ligament were significantly improved by the mBGn incorporation and synergistically stimulated with DEX loading, as confirmed by both direct and indirect cultures. The effects on bone regeneration in vivo, as analyzed by microcomputed tomography and histological stains in a rat calvarium model over 6 weeks, were substantial with the mBGn incorporation and even better with DEX loading, evidencing the osteogenic effects of the drug-eluting nanocomposite fiber scaffolds in bone formation. The current scaffolds with bone bioactive composition and drug delivery capacity may be potentially useful for bone regeneration as novel osteogenic matrices. PMID- 25531647 TI - Correlation of lower concentrations of hydrogen sulfide with atherosclerosis in chronic hemodialysis patients with diabetic nephropathy. AB - BACKGROUND/AIMS: To explore the relationship between hydrogen sulfide (H2S) and uremic accelerated atherosclerosis (UAAS) in chronic hemodialysis patients with diabetic nephropathy (CHD/DN). METHODS: A total of 36 CHD/DN and 32 chronic hemodialyzed non-diabetic patients with chronic glomerulonephritis (CHD/non-DN) were studied. Plasma H2S was measured with a sulfide sensitive electrode. RESULTS: Plasma H2S in CHD/DN was significantly lower than that in CHD/non-DN patients. Plasma H2S was positively correlated with plasma TGF-beta1, and negatively correlated with MMP-12 in CHD/DN patients. CHD/DN patients exhibited higher CCA-IMT, hsCRP, and lower H2S levels than in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was negatively correlated with plasma H2S, and positively correlated with hsCRP and LDL. On multiple regression analysis, H2S levels exhibited independent association with IMT in CHD/DN patients. CONCLUSIONS: These findings suggest possible linkage between H2S metabolism and TGF-beta/Smad signaling pathway modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients. PMID- 25531648 TI - Noninvasive estimation of oxygen consumption in human calf muscle through combined NMR measurements of ASL perfusion and T2 oxymetry. AB - The objective of this work was to demonstrate the feasibility of measuring muscle O2 consumption (VO2) noninvasively with a combination of functional nuclear magnetic resonance (NMR) imaging methods, and to verify that changes in muscle VO2 can be detected with a temporal resolution compatible with physiological investigation and patient ease. T2-based oxymetry of arterial and venous blood was combined with the arterial-spin labeling (ASL)-based determination of muscle perfusion. These measurements were performed on 8 healthy volunteers under normoxic and hypoxic conditions in order to assess the sensitivity of measurements over a range of saturation values. Blood samples were drawn simultaneously and used to titrate blood T2 measurements versus hemoglobin O2 saturation (%HbO2) in vitro. The in vitro calibration curve of blood T2 fitted very well with the %HbO2 (r(2): 0.95). The in vivo venous T2 measurements agreed well with the in vitro measurements (intraclass correlation coefficient 0.82, 95% confidence interval 0.61-0.91). Oxygen extraction at rest decreased in the calf muscles subjected to hypoxia (p = 0.031). The combination of unaltered muscle perfusion and pinched arteriovenous O2 difference (p = 0.038) pointed towards a reduced calf muscle VO2 during transient hypoxia (p = 0.018). The results of this pilot study confirmed that muscle O2 extraction and VO2 can be estimated noninvasively using a combination of functional NMR techniques. Further studies are needed to confirm the usefulness in a larger sample of volunteers and patients. PMID- 25531649 TI - Long-term quiescent fibroblast cells transit into senescence. AB - Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen conditions. Both, long-term quiescent and senescent fibroblasts almost completely fail to undergo apoptosis. The transition of long term quiescent fibroblasts into senescence is also independent of HES1 which protects short-term quiescent cells from becoming senescent. Most significantly, DNA damage accumulates during senescence as well as during long-term quiescence at physiological oxygen levels. We suggest that telomere-independent, potentially maintenance driven gradual induction of cellular senescence during quiescence is a counterbalance to tumor development. PMID- 25531650 TI - Olmesartan decreased levels of IL-1beta and TNF-alpha, down-regulated MMP-2, MMP 9, COX-2, RANK/RANKL and up-regulated SOCs-1 in an intestinal mucositis model. AB - Methotrexate (MTX) is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukaemia and other malignancies. The efficacy of methotrexate is often limited by mucositis and intestinal injury, which are major causes of morbidity in children and adults. The aim of this study was to evaluate the effect of olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pre-treated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX. Small intestinal homogenates were assayed for levels of the IL-1beta, IL-10 and TNF-alpha cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX + OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and haemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1beta (p<0.001) and TNF-a (p<0.01), and increase anti-inflammatory cytocine IL-10 (p<0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP 9, COX-2, RANK and RANKL(p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signalling in an IMM. We also suggest that the beneficial effect of olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytocines. PMID- 25531651 TI - Chronic exercise increases plasma brain-derived neurotrophic factor levels, pancreatic islet size, and insulin tolerance in a TrkB-dependent manner. AB - BACKGROUND: Physical exercise improves glucose metabolism and insulin sensitivity. Brain-derived neurotrophic factor (BDNF) enhances insulin activity in diabetic rodents. Because physical exercise modifies BDNF production, this study aimed to investigate the effects of chronic exercise on plasma BDNF levels and the possible effects on insulin tolerance modification in healthy rats. METHODS: Wistar rats were divided into five groups: control (sedentary, C); moderate- intensity training (MIT); MIT plus K252A TrkB blocker (MITK); high intensity training (HIT); and HIT plus K252a (HITK). Training comprised 8 weeks of treadmill running. Plasma BDNF levels (ELISA assay), glucose tolerance, insulin tolerance, and immunohistochemistry for insulin and the pancreatic islet area were evaluated in all groups. In addition, Bdnf mRNA expression in the skeletal muscle was measured. PRINCIPAL FINDINGS: Chronic treadmill exercise significantly increased plasma BDNF levels and insulin tolerance, and both effects were attenuated by TrkB blocking. In the MIT and HIT groups, a significant TrkB-dependent pancreatic islet enlargement was observed. MIT rats exhibited increased liver glycogen levels following insulin administration in a TrkB-independent manner. CONCLUSIONS/SIGNIFICANCE: Chronic physical exercise exerted remarkable effects on insulin regulation by inducing significant increases in the pancreatic islet size and insulin sensitivity in a TrkB dependent manner. A threshold for the induction of BNDF in response to physical exercise exists in certain muscle groups. To the best of our knowledge, these are the first results to reveal a role for TrkB in the chronic exercise-mediated insulin regulation in healthy rats. PMID- 25531652 TI - Live cell interferometry quantifies dynamics of biomass partitioning during cytokinesis. AB - The equal partitioning of cell mass between daughters is the usual and expected outcome of cytokinesis for self-renewing cells. However, most studies of partitioning during cell division have focused on daughter cell shape symmetry or segregation of chromosomes. Here, we use live cell interferometry (LCI) to quantify the partitioning of daughter cell mass during and following cytokinesis. We use adherent and non-adherent mouse fibroblast and mouse and human lymphocyte cell lines as models and show that, on average, mass asymmetries present at the time of cleavage furrow formation persist through cytokinesis. The addition of multiple cytoskeleton-disrupting agents leads to increased asymmetry in mass partitioning which suggests the absence of active mass partitioning mechanisms after cleavage furrow positioning. PMID- 25531653 TI - Realizing the full potential of insertion anodes for Mg-ion batteries through the nanostructuring of Sn. AB - Magnesium is of great interest as a replacement for lithium in next-generation ion-transfer batteries but Mg-metal anodes currently face critical challenges related to the formation of passivating layers during Mg-plating/stripping and anode-electrolyte-cathode incompatibilities. Alternative anode materials have the potential to greatly extend the spectrum of suitable electrolyte chemistries but must be systematically tailored for effective Mg(2+) storage. Using analytical (scanning) transmission electron microscopy ((S)TEM) and ab initio modeling, we have investigated Mg(2+) insertion and extraction mechanisms and transformation processes in beta-SnSb nanoparticles (NPs), a promising Mg-alloying anode material. During the first several charge-discharge cycles (conditioning), the beta-SnSb particles irreversibly transform into a porous network of pure-Sn and Sb-rich subparticles, as Mg ions replace Sn atoms in the SnSb lattice. After electrochemical conditioning, small Sn particles/grains (<33 +/- 20 nm) exhibit highly reversible Mg-storage, while the Sb-rich domains suffer substantial Mg trapping and contribute little to the system performance. This result strongly indicates that pure Sn can act as a high-capacity Mg-insertion anode as theoretically predicted, but that its performance is strongly size-dependent, and stable nanoscale Sn morphologies (<40 nm) are needed for superior, reversible Mg storage and fast system kinetics. PMID- 25531654 TI - Confirmatory factor analysis of the WHO Violence Against Women instrument in pregnant women: results from the BRISA prenatal cohort. AB - BACKGROUND: Screening for violence during pregnancy is one of the strategies for the prevention of abuse against women. Since violence is difficult to measure, it is necessary to validate questionnaires that can provide a good measure of the phenomenon. The present study analyzed the psychometric properties of the World Health Organization Violence Against Women (WHO VAW) instrument for the measurement of violence against pregnant women. METHODS: Data from the Brazilian Ribeirao Preto and Sao Luis birth cohort studies (BRISA) were used. The sample consisted of 1,446 pregnant women from Sao Luis and 1,378 from Ribeirao Preto, interviewed in 2010 and 2011. Thirteen variables were selected from a self applied questionnaire. Confirmatory factor analysis was used to investigate whether violence is a uni-or-multidimensional construct consisting of psychological, physical and sexual dimensions. The mean-and-variance-adjusted weighted least squares estimator was used. Models were fitted separately for each city and a third model combining data from the two settings was also tested. Models suggested from modification indices were tested to determine whether changes in the WHO VAW model would produce a better fit. RESULTS: The unidimensional model did not show good fit (Root mean square error of approximation [RMSEA] = 0.060, p < 0.001 for the combined model). The multidimensional WHO VAW model showed good fit (RMSEA = 0.036, p = 0.999 for the combined model) and standardized factor loadings higher than 0.70, except for the sexual dimension for SL (0.65). The models suggested by the modification indices with cross loadings measuring simultaneously physical and psychological violence showed a significantly better fit compared to the original WHO model (p < 0.001 for the difference between the model chi-squares). CONCLUSIONS: Violence is a multidimensional second-order construct consisting of psychological, physical and sexual dimensions. The WHO VAW model and the modified models are suitable for measuring violence against pregnant women. PMID- 25531655 TI - The effect of metformin on cardiac fibrosis via differentiation of cardiac fibroblasts. PMID- 25531657 TI - Cytological findings for the diagnosis of primary thyroid mucosa-associated lymphoid tissue lymphoma by fine needle aspiration. AB - OBJECTIVE: We examined cytological findings for the diagnosis of primary thyroid mucosa-associated lymphoid tissue (MALT) lymphoma by fine needle aspiration. STUDY DESIGN: During the study period of 4 years, a total of 101 cases including 51 MALT lymphomas, 20 Hashimoto's thyroiditis (HT), and 30 diffuse large-cell B cell lymphomas were cytologically examined. MALT lymphomas were divided into 44 common MALT and 7 MALT lymphomas with extreme plasmacytic differentiation (MALT EPCD). RESULTS: (1) Small- to medium-sized cells displaying irregularly shaped nuclei with prominent nucleoli (ISN-PN) were neoplastic cells. (2) In the case of a frequency of plasma cells (PC) below 15%, the accuracy rate for distinguishing common MALT from HT was 97% for ISN-PN cell frequencies above 20% in combination with the presence of lymphoepithelial lesion clusters (LELC) and mountain range like clusters (MRLC). The frequency of large-sized cells was below 15% in common MALT. (3) In the case of a frequency of PC above 15%, cases with a sum of PC and ISN-PN cells above 30% were MALT-EPCD. (4) MRLC were cell clusters derived from regions of follicular colonization, and LELC were cell clusters from lymphoepithelial lesions of MALT lymphomas. CONCLUSION: Useful cytological criteria for the diagnosis of thyroid primary MALT lymphoma, such as neoplastic cells and cell clusters, were defined. PMID- 25531656 TI - Lamina cribrosa defects and optic disc morphology in primary open angle glaucoma with high myopia. AB - PURPOSE: To investigate whether lamina cribrosa (LC) defects are associated with optic disc morphology in primary open angle glaucoma (POAG) eyes with high myopia. METHODS: A total of 129 POAG patients and 55 age-matched control subjects with high myopia were evaluated. Three-dimensional scan images obtained by swept source optical coherence tomography were used to detect LC defects. Radial B scans and infrared images obtained by spectral domain optical coherence tomography were used to measure beta-peripapillary atrophy (PPA) lengths with and without Bruch's membrane (BM) (temporal, nasal, superior, and inferior), tilt angle (vertical and horizontal), and disc diameter (transverse and longitudinal). Peripapillary intrachoroidal cavitations (PICCs), disc area, ovality index, and cyclotorsion of the optic disc were analyzed as well. RESULTS: LC defects were found in 70 of 129 (54.2%) POAG eyes and 1 of 55 (1.8%) control eyes (P < 0.001). Age, sex, spherical equivalent, axial length, intraocular pressure, and central corneal thickness were not significantly different among POAG eyes with LC defects, POAG eyes without LC defects, and control eyes. Temporal PPA lengths without BM in all three groups correlated significantly with vertical and horizontal tilt angles, although no PPA length with BM correlated significantly with any tilt angle. PICCs were detected more frequently in POAG eyes with LC defects than those without LC defects (P = 0.01) and control eyes (P = 0.02). POAG eyes with LC defects showed a smaller ovality index (P = 0.004), longer temporal PPA without BM (P < 0.001), and larger vertical/horizontal tilt angles (vertical, P < 0.001; horizontal, P = 0.01), and transverse diameter (P = 0.01). In multivariate analysis for the presence of LC defects, presence of POAG (P < 0.001) and vertical tilt angle (P < 0.001) were identified as significant. CONCLUSIONS: The presence of LC defects was associated with myopic optic disc morphology in POAG eyes with high myopia. PMID- 25531658 TI - Principles of cerebral ultrasound contrast imaging. AB - Ultrasound contrast is gaining acceptance worldwide as an adjunct to conventional ultrasound imaging. It has clinical applications as diverse as liver disease detection and characterization, myocardial perfusion and wall motion studies, and imaging of cerebral vascularity and perfusion. This paper will focus on imaging techniques used for transcranial ultrasound contrast imaging. The interaction of ultrasound with the microbubbles in the contrast agent is complex and nonlinear. This has led to the development of a variety of imaging modes to improve contrast detection compared with non-contrast optimized modes. This article presents several of these imaging methods in such a way as to help users of ultrasound contrast in the clinic and in research to understand this rapidly developing field. PMID- 25531659 TI - Physical principles of microbubbles for ultrasound imaging and therapy. AB - Microbubble ultrasound contrast agents have been in clinical use for more than two decades, during which time their range of applications has increased to encompass echocardiography, Doppler enhancement, perfusion studies and molecular imaging, as well as a number of therapeutic applications, including drug delivery, gene therapy, high-intensity focused ultrasound treatments and sonothrombolysis. The aim of this article is to review the different types of microbubble agents, their physical behaviours and the mechanisms underlying their effectiveness in imaging and therapeutic applications. PMID- 25531660 TI - Ultrasound bio-effects and safety considerations. AB - The responsibility for safe ultrasound applications has been devolved to the user with the introduction of displayed safety indices on the scanner screen. It is therefore essential that the mechanisms of interaction of the ultrasound beam with the tissue being interrogated are properly understood and that the potential biological effects are determined. PMID- 25531661 TI - Intima-media thickness of carotid arteries. AB - Carotid intima-media thickness (CIMT) is a validated predictive marker of increased plaque occurrence and the incidence of major cardiovascular events. However, due to technical issues associated with the measurement of CIMT, a well trained and certified sonographer is needed to overcome causes of variability due to the patient, device, sonographer, and quantification tool. The recently updated Mannheim consensus defined and described how to differentiate CIMT from plaques. These definitions allow for the better analysis and quantification of early atherosclerosis. Indications for CIMT measurements largely include the detection of coronary heart disease risk among intermediate-risk patients. CIMT is frequently used in clinical trials, and recent technical recommendations have been provided to improve the quality of the procedures. The final choice of a CIMT protocol depends on the purpose of the measurement, the research question at hand, the cost effectiveness, the quality of the data and the added value provided by the additional information. PMID- 25531662 TI - Functional TCD: regulation of cerebral hemodynamics--cerebral autoregulation, vasomotor reactivity, and neurovascular coupling. AB - Three main mechanisms influence cerebral hemodynamics, with the aim of adapting the cerebral blood flow to the metabolic demand of the brain. Cerebral autoregulation ensures stable perfusion of the brain, independent of the systemic blood pressure. Vasomotor reactivity reflects the hemodynamic responses to modifications of the arterial pCO2/pH of the brain tissue. Neurovascular coupling adapts the perfusion to increased metabolic demand as a consequence of enhanced brain activity to permit reasonable functioning of cells. Different methods using transcranial Doppler sonography have been developed to characterize these mechanisms in healthy subjects and under pathologic conditions. The most established applications in clinical settings are described, and the results of specific research studies are briefly reported. PMID- 25531663 TI - Intracranial perfusion imaging with ultrasound. AB - In the last several years, great progress has been made in ultrasound perfusion imaging of the brain. Different approaches have been assessed and shown to be capable of the early detection of cerebral perfusion deficits in stroke patients. Real-time low-mechanical index imaging simplifies the acquisition of perfusion parameters and alleviates many of the previous imaging problems related to shadowing, uniplanar analysis, and temporal resolution. With the advent of this new, highly sensitive contrast-specific imaging technique, new possibilities of the real-time visualization of brain infarctions and cerebral hemorrhages have emerged. This review will detail the methodology of ultrasound perfusion imaging, discuss aspects of its safety and present the emerging clinical applications of brain perfusion assessment with ultrasound in acute stroke patients. PMID- 25531664 TI - Parenchymal imaging in movement disorders. AB - The use of B-mode sonography in neurological diagnosis was once considered of limited importance due to the barrier of the skull. However, modern ultrasound systems allow visualization of the brain parenchyma with a high degree of accuracy. Transcranial sonography (TCS) can offer unique information on brain tissue pathology, as it uses different physical principles for imaging acquisition than do other neuroimaging techniques. The method is harmless, is quick to perform at low cost and demands no sedation. The main limitations of this technique are dependence on the quality of the individual bone window and on proper operator training. A huge body of research has shown that patients with Parkinson's disease (PD) display an enlarged hyperechogenic substantia nigra by TCS with a positive predictive value of 92.9%. Healthy individuals (8-15%) may show the same marker, in some cases correlating with decreased striatal dopamine uptake, motor slowing and prodromal markers of PD, indicating that this ultrasound sign may constitute a risk marker for PD. Other movement disorder diagnoses, although less extensively studied for TCS, may benefit from using this method as a supplementary diagnostic tool. This review provides a summary of the typical TCS findings and their value in the differential diagnosis of some movement disorders. PMID- 25531665 TI - Sonothrombolysis. AB - Ultrasound (US) applied as an adjunct to thrombolytic therapy improves the recanalization of occluded vessels, and microbubbles can amplify this effect. New data suggests that the combination of US and microbubbles without tissue plasminogen activator may achieve recanalization with a lower risk of hemorrhage. Further possibilities include specific targeting of thrombus with immunobubbles as well as local drug delivery with US-sensitive liposomes. Clinical studies support the use of US for ischemic stroke therapy, and the first trials of enhancing sonothrombolysis with microbubbles have been encouraging. One emerging clinical application is sonothrombolysis of intracranial hemorrhages for clot evacuation. Microcirculation, irrespective of recanalization, may also be improved by US and microbubbles, and this effect may open new opportunities for the application of sonothrombolysis in acute ischemic stroke. Understanding the mechanisms of therapeutic action and relating this knowledge to issues of efficacy and safety are important objectives of ongoing research. This review will discuss the translational capacities of in vitro studies and preclinical research and will assess the first clinical studies of this promising therapeutic strategy. PMID- 25531666 TI - Non-invasive transcranial brain ablation with high-intensity focused ultrasound. AB - The idea to ablate brain tissue with high-intensity focused ultrasound (HIFU) in a highly precise and localized manner is relatively old. For HIFU tissue ablation, ultrasound (US) waves are concentrated to a focal point. Due to US absorption, the focal area will be heated and consequently thermally destroyed. The spatial accuracy of the non-invasive procedure and the sharp delineation of the induced tissue lesions have led to the term 'focused ultrasound surgery' (FUS). The major obstacle for HIFU ablation in the brain is the skull bone, which absorbs most of the US energy and disturbs the focused US field. The development of large-sized phased array US transducers and adaptive focusing techniques based on computed tomography images have allowed these difficulties to be overcome. With the combination of FUS and MR-imaging and MR-thermometry (MR-guided Focused Ultrasound Surgery, MRgFUS), real-time therapy guidance and control has been established. The safety, feasibility and effectiveness of transcranial MRgFUS were investigated in four initial clinical studies including 4 to 15 patients each. In the first study, which dealt with the treatment of inoperable recurrent glioblastoma, MR was used to monitor localized tissue heating, but no tissue ablation was possible due to technical restrictions of the treatment setup. With improved equipment, the precise induction of thermal lesions in the target area was achieved in studies on neuropathic pain and essential tremor. An instantaneous and persistent significant improvement of disease symptoms was observed in most patients. However, there were serious adverse effects in two cases, where intracranial hemorrhages appeared due to the induction of cavitation. Based on these encouraging clinical results, more extensive clinical studies have been initiated. Transcranial MRgFUS is a fast-growing field of neurological research with high clinical potential. PMID- 25531667 TI - Ultrasound-induced blood-brain barrier opening for drug delivery. AB - Treatment of central nervous system (CNS) diseases is highly limited due to the presence of the blood-brain barrier (BBB), which prevents the entry of approximately 99% of potential therapeutic agents into the CNS. Focused ultrasound (FUS) in combination with microbubbles can lead to a transient and focal opening of the BBB, thus enabling the passage of therapeutic agents across the BBB. Mechanical ultrasound effects, such as stable and inertial cavitation, contribute to BBB opening, possibly via transient disintegration of tight junctions. Facilitation of transcellular passage through vesicle transport may also be influenced. FUS-induced BBB opening can be performed without tissue damage, given an optimal set of ultrasound parameters. However, the risk of parenchymal damage or microhaemorrhage increases with increasing acoustic energy. To date, several therapeutic substances, such as chemotherapeutics, antibodies, plasmids and viral vectors, have successfully been delivered to the CNS by FUS induced BBB opening in animal models, including non-human primates. Translation to a clinical application is pending. PMID- 25531668 TI - Noninvasive detection of Echinococcus multilocularis tapeworm in urban area, Estonia. PMID- 25531669 TI - Multi-mycotoxin Analysis of Finished Grain and Nut Products Using Ultrahigh Performance Liquid Chromatography and Positive Electrospray Ionization-Quadrupole Orbital Ion Trap High-Resolution Mass Spectrometry. AB - Ultrahigh-performance liquid chromatography using positive electrospray ionization and quadrupole orbital ion trap high-resolution mass spectrometry was evaluated for analyzing mycotoxins in finished cereal and nut products. Optimizing the orbital ion trap mass analyzer in full-scan mode using mycotoxin fortified matrix extracts gave mass accuracies, deltaM, of < +/- 2.0 ppm at 70,000 full width at half maximum (FWHM) mass resolution (RFWHM). The limits of quantitation were matrix- and mycotoxin-dependent, ranging from 0.02 to 11.6 MUg/kg. Mean recoveries and standard deviations for mycotoxins from acetonitrile/water extraction at their relevant fortification levels were 91 +/- 10, 94 +/- 10, 98 +/- 12, 91 +/- 13, 99 +/- 15, and 93 +/- 17% for corn, rice, wheat, almond, peanut, and pistachio, respectively. Nineteen mycotoxins with concentrations ranging from 0.3 (aflatoxin B1 in peanut and almond) to 1175 MUg/kg (fumonisin B1 in corn flour) were found in 35 of the 70 commercial grain and nut samples surveyed. Mycotoxins could be identified at deltaM < +/- 5 ppm by identifying the precursor and product ions in full-scan MS and data-dependent MS/MS modes. This method demonstrates a new analytical approach for monitoring mycotoxins in finished grain and nut products. PMID- 25531670 TI - Differences between older and younger adults in residential treatment for co occurring disorders. AB - OBJECTIVE: The purpose of this study was to examine differences between older and younger adults who received integrated treatment for co-occurring substance use and mental disorders, including differences on demographic and baseline characteristics (e.g., substance use, readiness for change, mental health symptoms, and severity of problems associated with substance use), as well as predictors of retention in treatment. METHODS: This study included 1400 adults who received integrated substance abuse and mental health treatment services at one of two private residential facilities offering residential and outpatient services. Initial analyses consisted of basic descriptive and bivariate analyses to examine differences between older (>= 50 years old) and younger (< 50 years old) adults on baseline variables. Next, three ordinary least squares regression models were employed to examine the influence of baseline characteristics on length of stay. RESULTS: Three main findings emerged. First, older adults differed from younger adults on pre-treatment characteristics. Older adults used more alcohol and experienced greater problem severity in the medical and alcohol domains, while younger adults used more illicit drugs (e.g., heroin, marijuana, and cocaine) and experienced problems in the drug, legal, and family/social domains. Second, while readiness to change did not differ between groups at baseline, older adults remained enrolled in treatment for a shorter period of time (nearly four days on average) than younger adults. Third, the pattern of variables that influenced length of stay in treatment for older adults differed from that of younger adults. Treatment retention for older adults was most influenced by internal factors, like psychological symptoms and problems, while younger adults seemed influenced primarily by external factors, like drug use, employment difficulties, and readiness for change. CONCLUSIONS: The results of this study add to the limited knowledge base regarding older adults receiving integrated treatment for co-occurring substance use and mental health disorders by documenting that age-based differences exist in general and in the factors that are associated with the length of stay in residential treatment. PMID- 25531671 TI - The effect of recombinant human growth hormone and insulin-like growth factor-1 on the mitochondrial function and viability of peripheral blood mononuclear cells in vitro. AB - This study investigated whether the putative physiological benefits induced by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are countered at supra-physiological concentrations because of an augmentation in the production of mitochondrial-derived free radicals with a subsequent increase in oxidative damage, compromising mitochondrial function. To test this hypothesis, peripheral blood mononuclear cells were incubated for 4 h with either recombinant human GH (rhGH) (range = 0.25-100 MUg/L) or recombinant IGF-1 (rIGF-1) (range = 100-600 MUg/L) and along with control samples were subsequently analyzed by flow cytometry for the determination of cellular viability, mitochondrial membrane potential (Deltapsim), mitochondrial superoxide (O2(-)) generation, and mitochondrial permeability transition pore (mtPTP) activity. Results showed levels of mitochondrial O2(-) generation to be significantly reduced compared with control samples (lymphocytes: 21.5 +/- 1.6 AU; monocytes: 230.2 +/- 9.8 AU) following rhGH treatment at both concentrations of 5 MUg/L (13.5 +/- 1.3 AU, P <= 0.05) and 10 MUg/L (12.3 +/- 1.5 AU, P <= 0.05) in lymphocytes and at 10 MUg/L (153.4 +/- 11.4 AU, P <= 0.05) in monocytes. However, no significant effect was found at either higher rhGH concentrations or following treatment with any concentration of rIGF-1. In addition, neither of the 2 hormones had any significant effect on Deltapsim, mtPTP activity, or on cellular viability. In conclusion, physiological concentrations of rhGH elicited a protective cellular effect through the reduction of oxidative free radicals within mitochondria. This antioxidant effect was diminished at supra-physiological concentrations but not to a level that would elicit disruption of mitochondrial function. PMID- 25531672 TI - Use of Treponema pallidum PCR in testing of ulcers for diagnosis of primary syphilis. AB - Treponema pallidum PCR (Tp-PCR) has been noted as a valid method for diagnosing syphilis. We compared Tp-PCR to a combination of darkfield microscopy (DFM), the reference method, and serologic testing in a cohort of 273 patients from France and Switzerland and found the diagnostic accuracy of Tp-PCR was higher than that for DFM. PMID- 25531673 TI - Uremic toxins and their effects on multiple organ systems. AB - Nearly all body organs and systems are affected by the toxicity of uremic compounds retained in the course of renal dysfunction. Knowledge about the origin, chemical structure and composition of the retained endogenous substances responsible for these symptoms is far from complete. Organic retention solutes present a great variety of properties which makes their accurate classification extremely difficult. Their potential toxicity remains to be elucidated with meticulous observation of clearly formulated rules guiding the process. Toxicity assessment is a complex process because not just one but several retained compounds may be simultaneously involved in the same biological and metabolic processes. The search for new uremic compounds and combining them into panels of substances involved in the same pathophysiological processes seems to offer a novel approach to identifying and explaining any so far unexplored specific effects of endogenous compounds on the body organs and systems. PMID- 25531675 TI - Special relativity at the quantum scale. AB - It has been suggested that the space-time structure as described by the theory of special relativity is a macroscopic manifestation of a more fundamental quantum structure (pre-geometry). Efforts to quantify this idea have come mainly from the area of abstract quantum logic theory. Here we present a preliminary attempt to develop a quantum formulation of special relativity based on a model that retains some geometric attributes. Our model is Feynman's "checker-board" trajectory for a 1-D relativistic free particle. We use this model to guide us in identifying (1) the quantum version of the postulates of special relativity and (2) the appropriate quantum "coordinates". This model possesses a useful feature that it admits an interpretation both in terms of paths in space-time and in terms of quantum states. Based on the quantum version of the postulates, we derive a transformation rule for velocity. This rule reduces to the Einstein's velocity addition formula in the macroscopic limit and reveals an interesting aspect of time. The 3-D case, time-dilation effect, and invariant interval are also discussed in term of this new formulation. This is a preliminary investigation; some results are derived, while others are interesting observations at this point. PMID- 25531674 TI - CD4+CD25hiFOXP3+ cells in cord blood of neonates born from filaria infected mother are negatively associated with CD4+Tbet+ and CD4+RORgammat+ T cells. AB - BACKGROUND: Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses. METHODOLOGY: Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORgammat, and FOXP3. RESULTS: No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORgammat+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORgammat+ T cells in the infected group only (B = -0.242, P = 0.002; B = 0.178, P = 0.013 respectively). CONCLUSION: Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check. PMID- 25531676 TI - Obstacle optimization for panic flow--reducing the tangential momentum increases the escape speed. AB - A disastrous form of pedestrian behavior is a stampede occurring in an event involving a large crowd in a panic situation. To deal with such stampedes, the possibility to increase the outflow by suitably placing a pillar or some other shaped obstacles in front of the exit has been demonstrated. We present a social force based genetic algorithm to optimize the best design of architectural entities to deal with large crowds. Unlike existing literature, our simulation results indicate that appropriately placing two pillars on both sides but not in front of the door can maximize the escape efficiency. Human experiments using 80 participants correspond well with the simulations. We observed a peculiar property named tangential momentum, the escape speed and the tangential momentum are found to be negatively correlated. The idea to reduce the tangential momentum has practical implications in crowd architectural design. PMID- 25531677 TI - Evaluation of the long-term durability and glycemic control of fasting plasma glucose and glycosylated hemoglobin for pioglitazone in Japanese patients with type 2 diabetes. AB - BACKGROUND: This study applied a pharmacodynamic model-based approach to evaluate the long-term durability and glycemic control of pioglitazone in comparison with other oral glucose-lowering drugs in Japanese type 2 diabetes mellitus (T2DM) patients. SUBJECTS AND METHODS: Japanese T2DM patients were enrolled in a prospective, randomized, open-label, blinded-end point study and received pioglitazone with or without other oral glucose-lowering drugs (excluding another thiazolidinedione [TZD]) (n=293) or oral glucose-lowering drugs excluding TZD (n=294). Treatment was adjusted to achieve glycosylated hemoglobin (HbA1c) <6.9%, and samples for fasting plasma glucose (FPG) and HbA1c were collected over 2.5-4 years. A simultaneous cascading indirect response model structure was applied to describe the time course of FPG and HbA1c. HbA1c levels were described using both an FPG-dependent and an FPG-independent function. To account for titration, drug effects for both treatment groups were implemented using a time-dependent Emax model. RESULTS: Pioglitazone was superior in both time to maximum effect and the magnitude of reduction achieved in FPG and HbA1c. A greater reduction in median FPG (-21 mg/dL vs. -9 mg/dL) was observed with pioglitazone (P<0.05). Maximum drug effect for FPG was predicted to occur earlier (11 months) for pioglitazone than for the control group (14 months). The simulated additional reduction in FPG and HbA1c achieved with pioglitazone was predicted to be maintained beyond the currently observed study duration. CONCLUSIONS: Pioglitazone was found to result in improved glycemic control and durability compared with control treatment. This model-based approach enabled the quantification of differences in FPG and HbA1c for both treatment groups and simulation to evaluate longer-term durability on FPG and HbA1c. PMID- 25531678 TI - Alteration of the fecal microbiota and serum metabolite profiles in dogs with idiopathic inflammatory bowel disease. AB - Idiopathic inflammatory bowel disease (IBD) is a common cause of chronic gastrointestinal (GI) disease in dogs. The combination of an underlying host genetic susceptibility, an intestinal dysbiosis, and dietary/environmental factors are suspected as main contributing factors in the pathogenesis of canine IBD. However, actual mechanisms of the host-microbe interactions remain elusive. The aim of this study was to compare the fecal microbiota and serum metabolite profiles between healthy dogs (n = 10) and dogs with IBD before and after 3 weeks of medical therapy (n = 12). Fecal microbiota and metabolite profiles were characterized by 454-pyrosequencing of 16 S rRNA genes and by an untargeted metabolomics approach, respectively. Significantly lower bacterial diversity and distinct microbial communities were observed in dogs with IBD compared to the healthy control dogs. While Gammaproteobacteria were overrepresented, Erysipelotrichia, Clostridia, and Bacteroidia were underrepresented in dogs with IBD. The functional gene content was predicted from the 16 S rRNA gene data using PICRUSt, and revealed overrepresented bacterial secretion system and transcription factors, and underrepresented amino acid metabolism in dogs with IBD. The serum metabolites 3-hydroxybutyrate, hexuronic acid, ribose, and gluconic acid lactone were significantly more abundant in dogs with IBD. Although a clinical improvement was observed after medical therapy in all dogs with IBD, this was not accompanied by significant changes in the fecal microbiota or in serum metabolite profiles. These results suggest the presence of oxidative stress and a functional alteration of the GI microbiota in dogs with IBD, which persisted even in the face of a clinical response to medical therapy. PMID- 25531679 TI - Sinapic acid prevents hypertension and cardiovascular remodeling in pharmacological model of nitric oxide inhibited rats. AB - OBJECTIVES: Hypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling. METHODS: An experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA) was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.). Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells. RESULTS: Rats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO) metabolites level, elevated markers of oxidative stress (TBARS, LOOH), ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH), aberrant expression of TGF-beta, beta-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner. CONCLUSIONS: Taken together, these results suggest that SA may have beneficial role in the treatment of hypertensive heart disease by attenuating fibrosis and oxidative stress through its antioxidant potential. PMID- 25531680 TI - Synergism between polyurethane and polydopamine in the synthesis of Ni-Fe alloy monoliths. AB - Herein, we report the first synthesis of a light-weight macroporous 3-D alloy monolith of Ni-Fe/C using synergism between polydopamine (pDA) and polyurethane (pU); in situ formed polyurethane (pU) enables efficient mixing of pDA (carbon source) and Ni-FeOx resulting in Ni-Fe alloy monoliths at a temperature as low as ~600 degrees C. The monolithic Ni-Fe/C exhibits enhanced oxygen evolution activity. PMID- 25531681 TI - The benefits of detecting and treating mild hypertension: what we know, and what we need to learn. PMID- 25531682 TI - Remediation of pharmaceuticals and personal care products using an aerobic granular sludge sequencing bioreactor and microbial community profiling using Solexa sequencing technology analysis. AB - Recently, a new type of organic pollution derived from pharmaceuticals and personal care products (PPCPs) is gradually on the rise. Wastewater treatment to remove PPCPs was investigated using an aerobic granular sludge sequencing bioreactor (GSBR). After optimization of influent organic load, hydraulic shear stress, sludge settling time, etc., aerobic granular sludge was analyzed for its physiological and biochemical characteristics and tested for its efficacy to remove PPCPs wastewater. The granular sludge effectively removed some but not all of the PPCPs tested; removal correlated with the microbial profiles in the granules, as assessed using Solexa sequencing technology. Sequencing revealed the presence of five phylogenetic groups: Proteobacteria, Bacteroidetes, Betaproteobacteria, an unclassified genus, and Zoogloea. The results demonstrated changes in the microbial profiles with time in response to the presence of PPCPs. The effects of PPCPs on microbial communities in granular sludge process are discussed. PMID- 25531683 TI - Kinetics of the pyrolysis of arundo, sawdust, corn stover and switch grass biomass by thermogravimetric analysis using a multi-stage model. AB - A new multi-stage kinetic model has been developed for TGA pyrolysis of arundo, corn stover, sawdust and switch grass that accounts for the initial biomass weight (W0). The biomass were decomposed in a nitrogen atmosphere from 23 degrees C to 900 degrees C in a TGA at a single 20 degrees C/min ramp rate in contrast with the isoconversion technique. The decomposition was divided into multiple stages based on the absolute local minimum values of conversion derivative, (dx/dT), obtained from DTG curves. This resulted in three decomposition stages for arundo, corn stover and sawdust and four stages for switch grass. A linearized multi-stage model was applied to the TGA data for each stage to determine the pre-exponential factor, activation energy, and reaction order. The activation energies ranged from 54.7 to 60.9 kJ/mol, 62.9 to 108.7 kJ/mol, and 18.4 to 257.9 kJ/mol for the first, second and the third decomposition stages respectively. PMID- 25531684 TI - New tools for the evaluation of patients with neurodegenerative diseases. PMID- 25531685 TI - MObility ImproVEment with spasticity in multiple sclerosis in Europe: the MOVE 1 EU study. AB - AIM: using a protocol similar to that of the MOVE 1 study in Germany, the multicenter, observational MOVE 1 EU study examined the burden of multiple sclerosis (MS)-related spasticity in other EU countries (Belgium, Finland, France, Ireland, Norway, Poland and Portugal). MATERIALS & METHODS: A 12-month retrospective chart documentation was combined with questionnaires for physicians and patients at the time of enrollment. A total of 281 patients from neurology departments and MS units formed the per protocol population. RESULTS: in most patients, MS spasticity frequently restricted daily activities and caused some/moderate problems in EQ-5D subdomains of mobility, usual activities and pain/discomfort. Overall, 48% of physicians and 34% of patients were at least partly dissatisfied with the effectiveness of available pharmacotherapy options for MS spasticity. CONCLUSION: Results of the MOVE 1 Germany and MOVE 1 EU studies are aligned and highlight the need to optimize the therapeutic management of patients with MS spasticity across Europe so as to improve their overall well being and quality of life. PMID- 25531688 TI - Collaborative transdisciplinary team approach for dementia care. AB - Alzheimer's disease (AD) has high economic impact and places significant burden on patients, caregivers, providers and healthcare delivery systems, fostering the need for an evaluation of alternative approaches to healthcare delivery for dementia. Collaborative care models are team-based, multicomponent interventions that provide a pragmatic strategy to deliver integrated healthcare to patients and families across a wide range of populations and clinical settings. Healthcare reform and national plans for AD goals to integrate quality care, health promotion and preventive services, and reduce the impact of disease on patients and families reinforcing the need for a system-level evaluation of how to best meet the needs of patients and families. We review collaborative care models for AD and offer evidence for improved patient- and family-centered outcomes, quality indicators of care and potential cost savings. PMID- 25531689 TI - Pathogenesis and treatment of vascular cognitive impairment. AB - Vascular cognitive impairment (VCI) defines a continuum of disorders ranging from mild cognitive impairment to full-blown dementia, attributable to cerebrovascular causes. Major morphological types - multi-infarct encephalopathy, strategic infarct type, subcortical arteriosclerotic leukoencephalopathy, multilacunar state, postischemic encephalopathy - result from systemic, cardiac and local large or small vessel disease. Cognitive decline is commonly caused by widespread small cerebrovascular lesions (CVLs) affecting regions/networks essential for cognition, memory and behavior. CVLs often coexist with Alzheimer-type and other pathologies, which interact in promoting dementia, but in many nondemented elderly individuals, mixed brain pathologies are also present. Due to the high variability of CVLs, no validated clinical and neuropathological criteria for VCI are available. Cholinesterase inhibitors and memantine produce small cognitive improvement but without essential effect. Antihypertensive treatment, cardiovascular control and lifestyle modifications reducing vascular risk factors are essential. Given its growing health, social and economic burden, prevention and treatment of VCI are a major challenge of neuroscience. PMID- 25531686 TI - Aberrant RNA homeostasis in amyotrophic lateral sclerosis: potential for new therapeutic targets? AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. The disease pathogenesis is multifaceted in that multiple cellular and molecular pathways have been identified as contributors to the disease progression. Consequently, numerous therapeutic targets have been pursued for clinical development, unfortunately with little success. The recent discovery of mutations in RNA modulating genes such as TARDBP/TDP-43, FUS/TLS or C9ORF72 changed our understanding of neurodegenerative mechanisms in ALS and introduced the role of dysfunctional RNA processing as a significant contributor to disease pathogenesis. This article discusses the latest findings on such RNA toxicity pathways in ALS and potential novel therapeutic approaches. PMID- 25531687 TI - Frontotemporal dementia: diagnosis, deficits and management. AB - Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome, neuropsychiatric symptoms and language difficulties are common in FTD, but the diversity of presentation raises unique diagnostic challenges that can significantly impact patient care and counsel for caregivers regarding clinical status and prognosis. While neuropsychiatric symptom measures are helpful, more sensitive assessments delineating the specific behavioral and linguistic deficits accompanying FTD are needed. Comprehensive clinical assessment in combination with evaluation of language, socio-emotional functioning, cognition and neuroimaging aid in accurate and early diagnosis and treatment planning. In what follows, we review each of the FTD syndromes, highlight current research investigating the cognitive, behavioral and socio-emotional deficits observed with this disease, address common diagnostic challenges and summarize best practices associated with management of FTD. PMID- 25531690 TI - Neurological disability and its association with walking impairment in multiple sclerosis: brief review. AB - Neurological disability and walking impairment are two common, co-varying consequences of multiple sclerosis (MS) that can result in substantial patient burden for daily activities and quality of life. Indeed, neurological disability and walking impairment are driven by pathological changes in the central nervous system, and measurement of walking function is a common method of monitoring the progression of disease and neurological disability. The existing data indicate that the presence of walking impairments range from performance through real world outcomes based on comparison of MS versus healthy controls, and walking impairments become worse with increasing severity of neurological disability (i.e., progression). Accordingly, researchers and clinicians have considered both pharmaceutical and rehabilitation approaches for managing walking impairment in MS. Both approaches yield beneficial effects on walking outcomes, although the majority of research has focused on exercise training rather than pharmaceutical interventions. Overall, this underscores the importance of continued efforts toward identifying approaches for preventing, forestalling and restoring walking function in persons with MS across the spectrum of neurological disability and its progression. PMID- 25531692 TI - Structural and spectroscopic properties of methanediol in aqueous solutions from quantum chemistry calculations and ab initio molecular dynamics simulations. AB - The structural, electronic, and spectroscopic properties of methanediol in aqueous solutions have been studied by a combined approach based on Car Parrinello molecular dynamics simulations and ab initio calculations. The hydrogen bond interactions between the solute and water have been characterized, showing the important role of the solvent in the stabilization of the methanediol conformers in solution. First insights on the experimental vibrational spectra have been obtained by the analysis of the simulation results, with particular regard to the most prominent band at 1050 cm(-1) that has been attributed to both the symmetric and antisymmetric CO stretching modes. The assignment has been completed adopting both electric and mechanical anharmonic calculations considering the interactions with the solvent using a polarizable continuum model. PMID- 25531691 TI - Soft fluorescent nanomaterials for biological and biomedical imaging. AB - Soft fluorescent nanomaterials have attracted recent attention as imaging agents for biological applications, because they provide the advantages of good biocompatibility, high brightness, and easy biofunctionalization. Here, we provide a survey of recent developments in fluorescent soft nano-sized biological imaging agents. Various soft fluorescent nanoparticles (NPs) (including dye-doped polymer NPs, semiconducting polymer NPs, small-molecule organic NPs, nanogels, micelles, vesicles, and biomaterial-based NPs) are summarized from the perspectives of preparation methods, structure, optical properties, and surface functionalization. Based on both optical and functional properties of the nano sized imaging agents, their applications are then reviewed in terms of in vitro imaging, in vivo imaging, and cellular-process imaging, by means of specific or nonspecific targeting. PMID- 25531693 TI - Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. AB - Pexa-Vec (pexastimogene devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia virus designed to destroy cancer cells through viral lysis and induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) driven tumor-specific immunity. Pexa-Vec has undergone phase 1 and 2 testing alone and in combination with other therapies in adult patients, via both intratumoral and intravenous administration routes. We sought to determine the safety of intratumoral administration in pediatric patients. In a dose-escalation study using either 10(6) or 10(7) plaque-forming units per kilogram, we performed one-time injections in up to three tumor sites in five pediatric patients and two injections in one patient. Ages at study entry ranged from 4 to 21 years, and their cancer diagnoses included neuroblastoma, hepatocellular carcinoma, and Ewing sarcoma. All toxicities were <= grade 3. The most common side effects were sinus fever and sinus tachycardia. All three patients at the higher dose developed asymptomatic grade 1 treatment-related skin pustules that resolved within 3-4 weeks. One patient showed imaging evidence suggestive of antitumor biological activity. The two patients tested for cellular immunoreactivity to vaccinia antigens showed strong responses. Overall, our study suggests Pexa-Vec is safe to administer to pediatric patients by intratumoral administration and could be studied further in this patient population. PMID- 25531696 TI - Molecular and structural characterization of hybrid poly(ethylene oxide) polyhedral oligomeric silesquioxanes star-shaped macromolecules. AB - Octafunctionalized spherosilsesquioxanes (Q8M8(H)), decorated with Si-H functions, could be used to design, by coupling via hydrosilylation with alpha methoxy-omega-undecenyl poly(ethylene oxide)s (PEOs), organic-inorganic nanocomposite structures. (1)H, (13)C, and (29)Si NMR; size exclusion chromatography; and Fourier transfrom infrared spectroscopy were used to follow the grafting reaction and determine the molar mass and the functionality of the different species. Hybrid star-shaped poly(ethylene oxide)s of precise molar mass and functionality could be isolated by fractional precipitation of the raw reaction product. Absolute molar masses of the purified star-shaped PEOs, calculated with the assumption of a functionality of 8, were comparable when measured by light scattering in methanol and by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Small-angle X-ray scattering was employed to determine their molecular and structural characteristics, representing the versatility and innovative aspect to this study. Both differential scanning calorimetry and optical microscopy were utilized to elaborate and analyze the thermal properties and crystallization, respectively, of the hybrid stars. Further ongoing work is being carried out currently to investigate and foresee the use of longer PEO branches onto the core. PMID- 25531694 TI - Synthetic consensus HIV-1 DNA induces potent cellular immune responses and synthesis of granzyme B, perforin in HIV infected individuals. AB - This study evaluated the safety and immunogenicity of PENNVAX-B in 12 HIV infected individuals. PENNVAX-B is a combination of three optimized synthetic plasmids encoding for multiclade HIV Gag and Pol and a consensus CladeB Env delivered by electroporation. HIV infected individuals whose virus was effectively suppressed using highly active antiretroviral therapy (HAART) received PENNVAX-B DNA followed by electroporation with CELLECTRA-5P at study weeks 0, 4, 8, and 16. Local administration site and systemic reactions to PENNVAX-B were recorded after each treatment along with any adverse events. Pain of the treatment procedure was assessed using a Visual Analog Scale. Whole PBMCs were isolated for use in IFN ELISpot and Flow Cytometric assays. PENNVAX-B was generally safe and well tolerated. Overall, the four dose regimen was not associated with any serious adverse events or severe local or systemic reactions. A rise in antigen-specific SFU was detected in the INFgamma ELISpot assay in all 12 participants. T cells from 8/12 participants loaded with both granzyme B and perforin in response to HIV antigen, an immune finding characteristic of long term nonprogressors (LTNPs) and elite controllers (ECs). Thus administration of PENNVAX-B may prove useful adjunctive therapy to ART for treatment and control of HIV infection. PMID- 25531695 TI - HDAC inhibitors target HDAC5, upregulate microRNA-125a-5p, and induce apoptosis in breast cancer cells. AB - Histone deacetylase inhibitors (HDACi) are novel clinical anticancer drugs that inhibit HDAC gene expression and induce cell apoptosis in human cancers. Nevertheless, the detailed mechanism or the downstream HDAC targets by which HDACi mediates apoptosis in human breast cancer cells remains unclear. Here, we show that HDACi reduce tumorigenesis and induce intrinsic apoptosis of human breast cancer cells through the microRNA miR-125a-5p in vivo and in vitro. Intrinsic apoptosis was activated by the caspase 9/3 signaling pathway. In addition, HDACi mediated the expression of miR-125a-5p by activating RUNX3/p300/HDAC5 complex. Subsequently, miR-125a-5p silenced HDAC5 post transcriptionally in the cells treated with HDACi. Thus, a regulatory loop may exist in human breast cancer cells involving miR-125a-5p and HDAC5 that is controlled by RUNX3 signaling. Silencing of miR-125a-5p and RUNX3 inhibited cancer progression and activated apoptosis, but silencing of HDAC5 had a converse effect. In conclusion, we demonstrate a possible new mechanism by which HDACi influence tumorigenesis and apoptosis via downregulation of miR-125a-5p expression. This study provides clinical implications in cancer chemotherapy using HDACi. PMID- 25531697 TI - Eight-Day Temporal Stability of the Automated Neuropsychological Assessment Metric (ANAM) in a Deployment Environment. AB - Automated neurocognitive tests are commonly used by military providers for making clinical decisions about the recovery of postconcussive cognitive sequelae. This practice often utilizes baseline assessments that precede the concussive injury. As such, investigating and establishing the psychometrics of an instrument is necessary to minimize confounds for interpreting assessment scores. Test-retest reliability (TRR) values for an 8.3 +/- 2-day retest window for the Automated Neuropsychological Assessment Metrics-Version 4 (ANAM) were calculated in 86 healthy U.S. Army soldiers deployed to Iraq. After removal of outliers, all but 1 subtest, Simple Reaction Time, had adequate or greater TRR values (intraclass correlation coefficient = 0.72-0.86). The findings suggest that overall, the ANAM has good temporal stability when the retesting intertrial interval is less than 11 days while in a deployed environment. PMID- 25531698 TI - [Daratumumab--breakthrough drug in multiple myeloma therapy]. AB - Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM. PMID- 25531699 TI - [Single nucleotide polymorphisms in lung cancer patients and cisplatin treatment]. AB - Lung cancer is a major cause of mortality worldwide and non-small cell lung cancer (NSCLC) accounts for over 80% of all cases of lung cancer. Despite efforts to develop and improve early screening methods, the majority of tumors are detected at advanced stages. For over 30 years, cisplatin (CDDP), or any of its analogues, has been used in the treatment of many types of tumors, including lung cancer. The use of platinum-based chemotherapeutics is limited by their toxicity and later on by the development of chemoresistance by tumor cells. The molecular mechanisms of CDDP resistance are not fully resolved. Genetic variants of DNA repair proteins, as well as proteins involved in drug accumulation or detoxification, play a crucial role in determining the cell's response to platinum-based chemotherapy. The identification of selected gene polymorphisms could improve the prognosis of a patient's response to therapy and overall survival. In this review we will focus on the gene polymorphisms involved in CDDP resistance, in particular in lung tumors, and discuss their potential as prognosis and survival markers. PMID- 25531700 TI - [Associations between basic indicators of inflammation and metabolic disturbances]. AB - BACKGROUND: Inflammation is involved in initiation and progression of diabetic complications related to cell damage of tissues, especially endothelial cells, and deepening of metabolic disturbances. This study was conducted in order to assess potential associations between basic laboratory parameters of inflammation and common metabolic factors such as glycated hemoglobin and C-reactive protein. MATERIALS AND METHODS: The studied group consisted of 95 patients with diabetes mellitus type 2 and 77 subjects without signs of disturbances in glucose metabolism, aged between 40 and 74 years. Fasting plasma glucose, glycated hemoglobin, complete blood count and high-sensitivity C-reactive protein concentration in blood were determined. Also blood pressure as well as weight and height measurements were taken to calculate BMI. RESULTS: Fasting plasma glucose and glycated hemoglobin concentrations, total leukocyte count and granulocytes were significantly higher in diabetics. Significant correlations between both glycated hemoglobin and BMI and C-reactive protein concentration were noted. However, after adjusting for age and gender, leucocyte count was independently related to BMI and glycated hemoglobin, while C-reactive protein concentration was dependent on gender and BMI. CONCLUSION: Glycated hemoglobin as a marker of long-term glycemic control and BMI as an indicator of adipose tissue accumulation are significantly related to white blood cell count and C-reactive protein concentration, even when values of these parameters are in the normal range. This is consistent with the hypothesis that chronic activation of the immune system plays a role in the pathogenesis and progression of type 2 diabetes. PMID- 25531701 TI - [DNA methylation in obesity]. AB - The number of overweight and obese people is increasing at an alarming rate, especially in the developed and developing countries. Obesity is a major risk factor for diabetes, cardiovascular disease, and cancer, and in consequence for premature death. The development of obesity results from the interplay of both genetic and environmental factors, which include sedentary life style and abnormal eating habits. In the past few years a number of events accompanying obesity, affecting expression of genes which are not directly connected with the DNA base sequence (e.g. epigenetic changes), have been described. Epigenetic processes include DNA methylation, histone modifications such as acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, as well as non coding micro-RNA (miRNA) synthesis. In this review, the known changes in the profile of DNA methylation as a factor affecting obesity and its complications are described. PMID- 25531702 TI - Comparison of microbiological and physicochemical methods for enumeration of microorganisms. AB - Determination of the number of cultured bacteria is essential for scientific and industrial practice. A spread plate technique is the most common and accurate method for counting of microorganisms. However, time consuming incubation does not allow for a quick estimation of the number of bacteria in a growing culture. In the present study, the results of photometric measurements: direct optical density method (OD at 585 nm), UV absorbance at 260 and/or 280 nm of separated and lysed bacteria by sodium hydroxide and surfactant with the spread plate technique were compared. The linear regression model for bacterial strains Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli was used to compare these three methods. The UV measurement method enabled determination of the number of bacteria with similar precision. The procedure for solubilized bacteria UV measurement is robust, and is not influenced by dispersions in the original culture medium. PMID- 25531703 TI - Rheological properties of erythrocytes in patients infected with Clostridium difficile. AB - INTRODUCTION: Clostridium difficile infection (CDI) is a bacterial infection of the digestive tract. Acute infections are accompanied by increased risk for venous thromboembolism (VTE). To date, there have been no studies of the rheological properties of blood during the course of digestive tract infections. The aim of our study was to examine the effects of CDI on red blood cell (RBC) rheology, specifically RBC deformability, RBC aggregation, and plasma viscosity. In addition, the activity of glucose 6 phosphate dehydrogenase (G6PD) and acetylcholinesterase (AChE) in RBC was studied. MATERIALS AND METHODS: Our study group included 20 patients with CDI, 20 healthy persons comprised the control group. We examined the effects of CDI on the rheology of RBCs, their deformability and aggregation, using a Laser-assisted Optical Rotational Cell Analyzer (LORCA). Plasma viscosity was determined using a capillary tube plasma viscosymeter. Moreover, we estimated the activity of AChE and G6PD in RBC using spectrophotometric method. RESULTS: A statistically significant increase was found in the aggregation index, viscosity and activity of G6PD whereas the amount of time to reach half of maximum aggregation (t1/2) and the amplitude of aggregation (AMP) both showed statistically significantly decreases among patients with CDI compared to the control group. We also observed that the Elongation Index (EI) was decreased when shear stress values were low, between 0.3 Pa and 0.58 Pa, whereas EI was increased for shear stress in the range of 1.13-59.97 Pa. These observations were statistically significant. CONCLUSIONS: We report for the first time that acute infection of the gastrointestinal tract with Clostridium difficile is associated with abnormalities in rheological properties of blood, increased serum viscosity as well as increased aggregation of RBCs, which correlated with severity of inflammation. These abnormalities may be an additional mechanism causing increased incidence of VTE in CDI. PMID- 25531704 TI - A game of survival: herpesvirus strategies of autophagy manipulation. AB - Viruses are a very "clever" group of pathogens and well known for disrupting multiple processes in host cells. One of them is autophagy, a conserved mechanism that relies on degradation of intracellular structures in lysosomes. Autophagy can be triggered in response to viral infections and its aim is to digest viral particles, thereby limiting virus replication and spread. Induction of autophagy during viral infections is mediated by different regulatory pathways, but the biggest participation belongs to PKR and eIF2alpha. In this review we focused on the herpesvirus interactions with autophagic machinery. The Herpesviridae family presents various strategies to manipulate autophagy induction or suppression of that process may depend on cell type and stage of infection. Research carried out in the past 10 years has demonstrated the impact of herpesviruses on autophagy not only during productive infections, but in latency infections also. PMID- 25531705 TI - Oculomotor disturbances in HIV-positive individuals treated with methadone. AB - INTRODUCTION: Methadone substitution is claimed to be the most effective way of pharmacological management of human immunodeficiency virus (HIV) positive patients addicted to opioids. Possible and clinically the most relevant drug interactions are those between methadone and antiretroviral agents [13,18,25,32]. HIV causes cognitive impairment by infiltrating the central nervous system (CNS) in the initial phase of infection. The consequence of this is damage to the hippocampus, caudate nucleus, and basal ganglia [2,26]. METHODS: Eighty-six patients from the substitution program group were examined. The trial was conducted twice: before and about 1.5 hours after the administration of a therapeutic dose of methadone. The antisaccades task (AT) and latency task (LT) were performed using a saccadometer diagnostic system. RESULTS: The statistical analysis showed that the mean duration of latency measured by AT in HIV(-) and HIV(+) subjects after the administration of a therapeutic dose of methadone was significantly increased (p=0.03 HIV(-); p=0.04 HIV(+)). There was a statistically significant increase in the mean latency after the administration of methadone in HIV(+) subjects when compared to the control group measured by LT (p=0.03). CONCLUSION: The statistical analysis confirms the change in the saccadic refixation parameters in patients addicted to opioids. Methadone influences saccadic dynamic parameters less in HIV(+) than in HIV(-) drug users. Oculomotor disturbances are probably related to the neurotropic effects of HIV leading to damage of the striatum, which plays an important role in psychomotor functions. PMID- 25531706 TI - [Characterization and biological role of extracellular vesicles]. AB - Extracellular vesicles (EV) form a heterogeneous population of mostly spherical membrane structures released by almost all cells, including tumour cells, both in vivo and in vitro. Their size varies from 30 nm to 1 MUm, and size is one of the main criteria of the selection of two categories of EV: small (30-100 nm), more homogeneous exosomes and larger fragments (0.1-1 MUm) called membrane microvesicles or ectosomes. The presence of EV has already been detected in many human body fluids: blood, urine, saliva, semen and amniotic fluid. Formation of EV is tightly controlled, and their function and biochemical composition depend on the cell type they originate from. EV are the "vehicles" of bioactive molecules, such as proteins, mRNA and microRNA, and may play an important role in intercellular communication and modulation of e.g. immune system cell activity. In addition, on the surface of tumour-derived microvesicles (TMV), called oncosomes, several markers specific for cancer cells were identified, which indicates a role of TMV in tumour growth and cancer development. On the other hand, TMV may be an important source of tumour-associated antigens (TAA) which can be potentially useful as biomarkers with prognostic value, as well as in development of new forms of targeted immunotherapy of cancer. PMID- 25531707 TI - Cytotoxic and apoptosis-inducing effects of bendamustine used alone and in combination with rituximab on chronic lymphocytic leukemia cells in vitro. AB - AIM: The aim of our study was to compare the cytotoxic effects of bendamustine (BENDA) and rituximab (RIT) used either alone or in combination and to evaluate the influence of the above mentioned drugs on apoptosis measured as changes in mitochondrial transmembrane potential (Deltapsim), expression of caspases and selected apoptosis-regulating proteins in freshly isolated peripheral blood mononuclear cells of chronic lymphocytic leukemia (CLL) patients. MATERIALS/METHODS: Cytotoxic effect of tested drugs, as well as induction of apoptosis, drop in Deltapsim and expression of selected proteins involved in regulation of apoptosis were assessed in 48 hour cultures containing autologous serum (AS) using flow cytometry. BENDA was used at the concentration of 40 MUg/ml and RIT at the concentration of 10 MUg/ml. Control cultures were incubated without drugs. RESULTS: BENDA used either alone or in combination with RIT strongly induced apoptosis as well as enhanced expression of selected apoptotic proteins, especially those involved in the intrinsic apoptotic pathway: P53, PUMA and BAX, which cause mitochondrial transmembrane potential changes leading to activation of caspase-9 and -3. CONCLUSIONS: Our results indicate that both BENDA and RIT participate in the induction of apoptosis of CLL lymphocytes in vitro in the presence of AS in the culture medium. The drug-induced apoptosis occurs mainly via intrinsic pathway and activation of P53 and PUMA proteins, however the extrinsic pathway is likely to be involved as well. We also found that the combination of these drugs induces the expression of P53, caspase-8 and -9 more potently than either of them used separately. PMID- 25531708 TI - Blocking of alpha1beta1 and alpha2beta1 adhesion molecules inhibits eosinophil migration through human lung microvascular endothelial cell monolayer. AB - INTRODUCTION: In cell trafficking to the airways in asthma, among integrins the most important are those containing alpha4 and beta2 subunits. We have previously shown that also blocking of collagen receptors, alpha1beta1 and alpha2beta1 integrins, inhibits transmigration of eosinophils of asthmatic subjects through a monolayer of skin microvascular endothelial cells seeded on collagen IV coated inserts. However, it was not clear whether this observation was limited to asthma or depended on the type of microvascular cell and collagen IV used as a base. MATERIALS & METHODS: In the current study we performed a transmigration assay using human lung microvascular endothelial cells seeded directly on a plastic surface as a base and blood cells isolated from 12 representatives of each of two groups, asthmatics and healthy donors, by gradient centrifugation, followed by immunomagnetic negative separation of eosinophils. Isolated eosinophils and peripheral blood mononuclear cells (PBMC) were inhibited by snake venom-derived integrin antagonists including viperistatin and VP12, as inhibitors of alpha1beta1 and alpha2beta1 integrin, respectively, and VLO5 and VLO4, as inhibitors of alpha4beta1 and alpha5beta1 integrin, respectively. RESULTS: All snake venom-derived anti-adhesive proteins were effective in inhibiting eosinophil transmigration, whilst only VLO5 and VLO4 reduced PBMC mobility in this assay. This observation was similar in both groups of subjects studied. DISCUSSION: alpha1beta1 and alpha2beta1 integrins could be involved in transmigration of eosinophil to the inflammatory site. Migratory inhibition was observed in asthma subjects as well as in healthy donors, and did not depend on origin of endothelial cells or the extracellular matrix component used as a base. PMID- 25531709 TI - [Archaeons--still unknown microorganisms]. AB - Archaea is a group of microorganisms described by Carl Woese in 1977. Although Archaea have a similar cellular organization to bacteria, their cell wall and cell membrane are quite unique. Archaeal cell wall lacks peptidoglican and cell membrane is composed of ether-lipids which are far more stable than bacteria specific esther-lipids. Besides, Archaea have some specific external structures, like: archaella, pili, hami and cannulae but their exact functions are still unclear. Most of Archaea obtain energy via anaerobic processes of simple inorganic or organic compounds, however some of these organisms are also able to generate methane in the process known as methanogesis. They reproduce by cell division or budding-like process and some studies demonstrated the mechanisms of genetic transfer such as conjugation, transduction and natural transformation for the Archaea. They are capable of forming biofilms also in interaction with bacteria. Some archaeons, such as Haloferax mediterranei and Sulfolobus islandicus can synthesize antimicrobial agents which are called archaeocins. In recent years huge progress has been made in understanding of Archaea but many aspects of their biology remain still unknown. In this review, we present recent advances in Archaea biology focusing mainly on archaeal morphology, metabolism and reproduction. PMID- 25531710 TI - [Characteristic of innate lymphoid cells (ILC)]. AB - Innate lymphoid cells (ILC) is a newly described family of immune cells that are part of the natural immunity which is important not only during infections caused by microorganisms, but also in the formation of lymphoid tissue, tissue remodeling after damage due to injury and homeostasis tissue stromal cells. Family ILC cells form NK cells (natural killer) and lymphoid tissue inducer T cells (LTi), which, although they have different functions, are evolutionarily related. NK cells are producing mainly IFN-gamma, whereas LTi cells as NKR+LTi like, IL-17 and/or IL-22, which suggests that the last two cells, can also represent the innate versions of helper T cell--TH17 and TH22. Third population of ILC is formed by cells with characteristics such as NK cells and LTi (ILC22)- which are named NK22 cells, natural cytotoxicity receptor 22 (NCR22) cells or NK receptor-positive (LTi NKR+) LTi cells. Fourth population of ILC cells are ILC17- producing IL-17, while the fifth is formed by natural helper type 2 T cells (nTH2), nuocyte, innate type 2 helper cells (IH2) and multi-potent progenitor type 2 cells (MPPtype2). Cells of the last population synthesize IL-5 and IL-13. It is assumed that an extraordinary functional diversity of ILC family, resembles T cells, probably because they are under the control of the corresponding transcription factors - as direct regulation factors, such as the family of lymphocytes T. PMID- 25531711 TI - [Pro-angiogenic cytokines in systemic sclerosis]. AB - Systemic sclerosis (SSc) is a multifactorial connective tissue disease characterized by excessive and progressive fibrosis along with microvasculopathy due to poor vascular formation and repair. Despite a general increase in many potent angiogenic factors, the vasculopathy compensatory angiogenesis and vasculogenesis are impaired. In this review, we discuss the role of proangiogenic factors--VEGF, PlGF, endoglin, PDGF, endothelin-1, angiopoietins, SDF-1, uPAR- and the paradoxical paucity of an inadequate angiogenic response in SSc. PMID- 25531712 TI - [The correlations between aging of the human body, oxidative stress and reduced efficiency of repair systems]. AB - The article presents an current knowledge overview about the importance of oxidative stress and reduced efficiency of repair processes during the aging process of the human body. Oxidative damage to cellular macromolecules (proteins, lipids, nucleic acids), are formed under the influence of reactive oxygen species (ROS). They are the part of important mechanism which is responsible for the process of aging and the development of many diseases. The most important effects result from DNA damage, due to the mutations formation, which can lead to the development of tumors. However, a well-functioning repair systems (i.a. homologous recombination) remove the damage and prevent harmful changes in the cells. Lipid peroxidation products also cause oxidative modification of nucleic acids (and proteins). Proteins and fats also have repair systems, but much simpler than those responsible for the repair of nucleic acids. Unfortunately, with increasing age, they are more weakened, which contributes to increase numbers of cell damage, and consequently development of diseases specific to old age: cancer, neurodegenerative diseases or atherosclerosis. PMID- 25531713 TI - Arsenic trioxide preferentially induces nonapoptotic cell deaths as well as actin cytoskeleton rearrangement in the CHO AA8 cell line. AB - INTRODUCTION: The therapeutic effect of arsenic trioxide (ATO, As2O3) has been investigated for many years. However, the precise molecular mechanisms underlying the antitumor activity of ATO are still not fully understood, but seem to depend on cell types, dosage, and duration of exposure. The purpose of this study was to assess the actin cytoskeleton rearrangement during the cell death process induced by arsenic trioxide in the CHO AA8 cells. A better understanding the mechanisms of ATO-action is likely to lead to more rational use of this drug either as monotherapies or in combination with other anticancer agents. MATERIAL AND METHODS: The effect of ATO on actin cytoskeleton was studied in Chinese Hamster Ovary AA8 cell line. Actin was visualized by fluorescence microscopy and phalloidin conjugated to Alexa Fluor(r) 488. Morphological and ultrastructural alterations in the CHO AA8 cells were evaluated by using light and electron microscope, respectively. For quantitative measurement of cell death, Annexin V Alexa Fluor(r) 488 and Propidium Iodide assay was performed. The vital staining of CHO AA8 cells with acridine orange was applied to detect the development of acidic vesicular organelles (AVOs). RESULTS: The performed experiments revealed a dose-dependent decrease in the cell survival. The morphological and ultrastructural features acquired by the cells after ATO-treatment were considered as typical for autophagy and mitotic cell death. As was shown by acridine orange staining, arsenic trioxide treatment increased red fluorescence signals in dose-dependent manner, indicating the development of AVOs, a hallmark of autophagy. Low level of apoptosis was induced in the ATO-treated CHO AA8 cells. Furthermore, the rearrangement of actin filaments associated with cell death process was also detected. CONCLUSIONS: The obtained results suggest that arsenic trioxide preferentially induces nonapoptotic cell deaths, autophagy and mitotic cell death, in p53-deficient CHO AA8 cells. Furthermore, the distinctive patterns of F-actin remodeling after As2O3 treatment were associated with different modes of cell death, confirming that cytoskeleton is a dynamic structure actively involved in the cell death process. PMID- 25531714 TI - [Lysozyme--occurrence in nature, biological properties and possible applications]. AB - Lysozyme (LZ, muramidase, N-acetylmuramylhydrolase) is a protein occuring in animals, plants, bacteria and viruses. It can be found e.g. in granules of neutrophils, macrophages and in serum, saliva, milk, honey and hen egg white. The enzyme hydrolyzes the beta-1,4 glycosidic bonds between N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) of cell wall peptidoglycan (PG) in Gram positive and Gram-negative bacteria. In the animal kingdom, three muramidase types have been identified: the c-type (chicken type), the g-type (goose-type) and the i-type (invertebrates). The c-type LZ from hen egg white is a model for the study of protein structure and function. Muramidase shows bactericidal activity mainly against Gram-positive bacteria. Cytolytic activity against cells of Gram-negative bacteria has not been proved. Bacterial cells have developed defense mechanisms that allow them to avoid the action of LZ. They are based e.g. on the production of enzyme inhibitors or modification of the PG. LZ is one of the most studied enzymes and yet not all aspects characterizing this protein are fully understood. One of the most important unresolved issues concerning the biological function of LZ is the role of muramidase in the bactericidal action of serum against Gram-negative bacteria. In order to clarify the function of LZ, the enzyme is e.g. removed from the serum by adsorption onto bentonite (montmorillonite, MMT). By using X-ray diffraction techniques it has been shown that MMT after contact with the serum is delaminated. The problems associated with folding of muramidase and LZ participation in the development of amyloidoses also await explanation. PMID- 25531715 TI - Usefulness of estimation of blood procalcitonin concentration versus C-reactive protein concentration and white blood cell count for therapeutic monitoring of sepsis in neonates. AB - AIM: This study was intended to assess the clinical usefulness of blood procalcitonin (PCT) concentrations for the diagnosis and therapeutic monitoring of nosocomial neonatal sepsis. MATERIAL/METHODS: The enrolment criterion was sepsis clinically manifesting after three days of life. PCT concentrations were measured in venous blood from 52 infected and 88 uninfected neonates. The results were interpreted against C-reactive protein (CRP) concentrations and white blood cell counts (WBC). RESULTS: Differences between the two groups in PCT and CRP concentrations were highly significant. No significant differences between the groups were noted for WBC. The threshold value on the receiver operator characteristic curve was 2.06 ng/mL for PCT (SE 75%; SP 80.68%; PPV 62.22%; NPV 88.75%; AUC 0.805), 5.0 mg/L for CRP (SE 67.44%; SP 73.68%; PPV 42.02%; NPV 88.89%; AUC 0.801), and 11.9 x109/L for WBC (SE 51.16%; SP 50.68%; PPV 23.16%; NPV 78.13%; AUC 0.484). Procalcitonin concentrations decreased 24 hours after initiation of antibiotic therapy and reverted to the control level after 5-7 days. C-reactive protein concentrations began to decline after two days of antibiotic therapy but were still higher than in the control group after 5-7 days of treatment. No significant changes in WBC during the treatment were observed. CONCLUSIONS: Procalcitonin concentrations in blood appear to be of use for the diagnosis and therapeutic monitoring of nosocomial infections in neonates as this parameter demonstrates greater sensitivity and specificity than C-reactive protein. White blood cell counts appear to be of little diagnostic value in the early phase of infection or for therapeutic monitoring. PMID- 25531716 TI - Antiangiogenic agents combined with chemotherapy in the first-line treatment of advanced non-small-cell lung cancer: overall and histology subgroup-specific meta analysis. AB - AIM: This study investigated the overall and histology subtype-specific results of antiangiogenic agents combined with chemotherapy versus chemotherapy alone for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). METHODS: Literature retrieval, trial selection, data collection, and statistical analysis were performed according to the Cochrane Handbook. The outcome measures were tumor response rate, progression-free survival (PFS), overall survival (OS), and adverse effects. RESULTS: 13 randomized controlled trials comprising 5,451 patients were included. The meta-analysis showed a higher response rate (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.53-0.74) and a significantly prolonged PFS (hazard ratio (HR) 0.75, 95% CI 0.66-0.85) and OS (HR 0.92, 95% CI 0.86-0.98) in the groups combining antiangiogenic agents with chemotherapy versus the chemotherapy alone groups. In the histology subgroup analysis, treatment with antiangiogenic agents plus chemotherapy significantly improved the RR, PFS, and OS as compared with the chemotherapy groups in patients with nonsquamous NSCLC, but not in those with squamous NSCLC. The risk of grade 3/4 thrombocytopenia, hypertension, bleeding, proteinuria, rash, diarrhea, fatigue, headache, anorexia, and febrile neutropenia was significantly increased in the antiangiogenic agent combination groups as compared with the chemotherapy groups. CONCLUSION: The use of antiangiogenic agents in addition to chemotherapy is a valid option for the first-line treatment of advanced NSCLC. The benefit is restricted to patients with nonsquamous-cell tumors. PMID- 25531717 TI - Pattern of variation in the mono- and dinucleotide repeat microsatellites associated with lynch syndrome in an Indian population. AB - BACKGROUND: Microsatellite instability (MSI) is associated with Lynch syndrome and hence is a surrogate marker for defective mismatch repair genes. The aim of this study was to investigate the degree of instability associated with each of the 5 microsatellite (MS) loci recommended by the National Cancer Institute (NCI), USA within an Indian population of mixed ethnicity and suffering from Lynch syndrome. METHODS: DNA from clinical samples originating from the study population (n = 130) were subjected to automated fragment analysis for all 5 MS loci, and data generated were analyzed to determine the frequency of variation of each of the MS in the resource population. RESULTS: Out of 130, 116 samples responded to polymerase chain reaction (PCR) for all 5 MS loci. 21 (16.15%) were MSI-high (MSI-H) while 27 (20.76%) and 68 (52.30%) were MSI-low (MSI-L) and microsatellite stable (MSS), respectively. D5S346 exhibited the highest instability (27 out of a total of 82 cases of instability recorded for all 5 MS in all 116 patients tested) followed by D2S123 (23/82), BAT26 (14/82), BAT25 (11/82), and D17S250 (7/82). CONCLUSION: MS D17S250 and BAT25 of the 5 MS panel recommended by the NCI are not informative enough and hence should be avoided for diagnosing Lynch syndrome in the Indian population. PMID- 25531718 TI - Supraclavicular lymphadenopathy: should it be perceived as the virchow's node of head and neck tumors? AB - BACKGROUND: In this study, we aimed to determine the correlation between supraclavicular lymph node involvement (SLNI) and metastatic potential, frequency, and metastases predilection sites in patients diagnosed with various head and neck tumors (HNT) and staged via positron emission tomography/computed tomography (PET/CT) imaging. We also investigated the impact of different variables on SLNI. PATIENTS AND METHODS: 270 patients diagnosed with HNT were enrolled in the study (194 males and 96 females, mean age 54.9 +/- 14.7 years (range 18-89 years)). RESULTS: Nasopharyngeal carcinoma demonstrated significant SLNI (p < 0.01); however, other subtypes of HNT did not. In all HNT studied, no apparent metastatic predilection tendency for the supraclavicular region was observed, as opposed to the well-described Virchow's node. Age, gender, tumor size, and systemic metastases were not identified as statistically significant variables contributing to SLNI. Multivariate regression analysis revealed an increased cervical (p < 0.01) and thoracic (p = 0.001) lymph node involvement in patients with SLNI. CONCLUSION: SLNI with the possibility of metastasis was more frequently observed in nasopharyngeal carcinoma, advancing the nodal status without significantly influencing the T and M stages. A careful evaluation of this very small region is of critical importance for proper nodal staging in nasopharyngeal cancer patients. PMID- 25531719 TI - Overexpression of tumor-associated trypsin inhibitor (SPINK1/TATI) in hepatitis C associated hepatocellular carcinoma: potential implications for viral hepatocarcinogenesis. AB - BACKGROUND: The molecular pathomechanisms leading to hepatitis C virus (HCV) induced hepatocarcinogenesis remain unclear. This study investigated the molecular pathways and key genes underlying HCV-positive hepatocellular carcinoma (HCC) using gene expression profiling. METHODS: Oligonucleotide arrays (Affymetrix HU133A) were used to determine and compare the tissue-specific gene expression profiles in 39 cases of HCV-positive or -negative HCC and non malignant liver tissue. The expression values of the most overexpressed genes were validated by real-time polymerase chain reaction (RT-PCR). RESULTS: 837 genes or expressed sequence tags (ESTs) were significantly differently expressed in HCV-positive HCC versus healthy tissue: 414 were upregulated and 423 were downregulated (p < 0.05; > 2-fold change in >= 70% of the samples). A specific gene expression profile for HCV-positive HCC was obtained using 2-dimensional cluster analysis and was confirmed using supervised neuronal network modeling. The most consistently overexpressed gene coded for serine protease inhibitor Kazal-type 1 (SPINK1)/tumor-associated trypsin inhibitor (TATI) (median fold change, 19.7; significantly overexpressed in 90% of the samples). SPINK1/TATI was coregulated with matrix metalloproteinases (MMPs) and their natural inhibitors (tissue inhibitors of metalloproteinases (TIMPs)). CONCLUSIONS: Gene expression profiling identified specific dysregulated molecular pathways and SPINK1/TATI as the most overexpressed gene in HCV-positive HCC. These data highlight the importance of SPINK1/TATI as a tumor marker for HCV-induced HCC and may lead to a better understanding of HCV-induced hepatocarcinogenesis. PMID- 25531720 TI - Analysis of the discriminative methods for diagnosis of benign and malignant solitary pulmonary nodules based on serum markers. AB - BACKGROUND: Screening indexes of tumor serum markers for benign and malignant solitary pulmonary nodules (SPNs) were analyzed to find the optimum method for diagnosis. METHODS: Enzyme-linked immunosorbent assays, an automatic immune analyzer and radioimmunoassay methods were used to examine the levels of 8 serum markers in 164 SPN patients, and the sensitivity for differential diagnosis of malignant or benign SPN was compared for detection using a single plasma marker or a combination of markers. The results for serological indicators that closely relate to benign and malignant SPNs were screened using the Fisher discriminant analysis and a non-conditional logistic regression analysis method, respectively. The results were then verified by the k-means clustering analysis method. RESULTS: The sensitivity when using a combination of serum markers to detect SPN was higher than that using a single marker. By Fisher discriminant analysis, cytokeratin 19 fragments (CYFRA21-1), carbohydrate antigen 125 (CA125), squamous cell carcinoma antigen (SCC) and breast cancer antigen (CA153), which relate to the benign and malignant SPNs, were screened. Through non-conditional logistic regression analysis, CYFRA21-1, SCC and CA153 were obtained. Using the k-means clustering analysis, the cophenetic correlation coefficient (0.940) obtained by the Fisher discriminant analysis was higher than that obtained with logistic regression analysis (0.875). CONCLUSION: This study indicated that the Fisher discriminant analysis functioned better in screening out serum markers to recognize the benign and malignant SPN. The combined detection of CYFRA21-1, CA125, SCC and CA153 is an effective way to distinguish benign and malignant SPN, and will find an important clinical application in the early diagnosis of SPN. PMID- 25531721 TI - Quality of life under capecitabine (Xeloda(r)) in patients with metastatic breast cancer: data from a german non-interventional surveillance study. AB - AIM: This non-interventional surveillance study (NIS) collected data on the quality of life (QoL) of patients treated with capecitabine as mono- or combination chemotherapy in an outpatient setting. METHODS: Capecitabine was administered orally for 14 days of each 21-day cycle. The main parameters of interest were QoL, compliance, patient and physician satisfaction, handling of hand-foot syndrome (HFS), and efficacy. The statistics were descriptive; some differences were compared using confidence intervals (CIs). RESULTS: 735 patients from 161 centers received at least 1 dose of capecitabine. The median duration of observation was 5.5 months overall. The QoL global score was 53% (mean from the entire study population at all times), without any correlation to HFS. The overall response rate (ORR) was 35.1%, and the disease control rate (DCR) 64.4%. The median progression-free survival (PFS) was overall 6.81 months (95% CI 6.32 7.63 months) and it was significantly higher in patients with HFS (8.4 months, 95% CI 7.5-9.2 months, hazard ratio (HR) 0.60; p < 0.0001). The safety and tolerability of capecitabine were considered acceptable. The HFS incidence (all grades) was 27.1%. CONCLUSIONS: Capecitabine had a favorable risk-benefit relation in outpatient therapy. The QoL remained stable over the course of the investigation, indicating good compliance. HFS was a strong predictor of longer PFS and had no negative impact on the global QoL. PMID- 25531722 TI - Late-onset paraplegia after complete response to two cycles of ipilimumab for metastatic melanoma. AB - BACKGROUND: Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune related side effects usually involve the skin or gastrointestinal tract. Neurologic events occur less frequently but are well described. CASE REPORT: We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation. He developed a colitis post cycle 2 and ipilimumab was discontinued. Imaging, however, documented a radiological CR. 8 weeks later, he developed paraplegia and a myelitis despite an ongoing radiological CR. Steroid use resulted in some improvement radiologically, without clinical improvement. CONCLUSION: We report myelitis with consequent paraplegia as a potential neurological immune-related side effect of ipilimumab. We further describe a patient with a CR after 2 cycles of ipilimumab in the setting of radiation. PMID- 25531723 TI - Management of von hippel-lindau disease: an interdisciplinary review. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumour predisposition syndrome with an incidence of 1:36,000 newborns, the estimated prevalence in Europe is about 1-9/100,000. It is associated with an increased risk of developing various benign and malignant tumours, thus affecting multiple organs at different time points in the life of a patient. Disease severity and diversity as well as age at first symptoms vary considerably, and diagnostic delay due to failure of recognition is a relevant issue. The identification of a disease-causing VHL germline mutation subsequently allows family members at risk to undergo predictive genetic testing after genetic counselling. Clinical management of patients and families should optimally be offered as an interdisciplinary approach. Prophylactic screening programs are a cornerstone of care, and have markedly improved median overall survival of affected patients. The aim of this review is to give an overview of the heterogeneous manifestations of the VHL syndrome and to highlight the diagnostic and therapeutic challenges characteristic for this orphan disease. A comprehensive update of the underlying genetic and molecular principles is additionally provided. We also describe how the St. Gallen VHL multidisciplinary group is organised as an example of interdisciplinary cooperation in a tertiary hospital in Switzerland. PMID- 25531724 TI - Prognostic impact of C-reactive protein in metastatic prostate cancer: a systematic review and meta-analysis. AB - BACKGROUND: Serum C-reactive protein (CRP) demonstrates a prognostic impact in small studies of metastatic prostate cancer (MPC). METHODS: A systematic review was conducted to identify publications and presentations exploring the association of serum CRP and overall survival (OS) in MPC, both castration sensitive and castration-resistant. Heterogeneity among trials was assessed using Cochrane's Q statistic, and the I(2) statistic was used to quantify inconsistency. The assumption of homogeneity was considered invalid if p < 0.1. All statistical tests were 2-sided, and p < 0.05 was considered significant. RESULTS: 6 studies were eligible, totaling 659 evaluable patients. 2 studies evaluated castration-sensitive men receiving androgen deprivation, while the remaining 4 studies evaluated castration-resistant men receiving docetaxel-based chemotherapy. Men with higher CRP had significantly worse OS than those with lower CRP (hazard ratio (HR) = 1.42, p < 0.001, 95% confidence interval (CI) 1.17 1.73). In trials of castration-sensitive men, high CRP yielded a HR = 1.92 (p = 0.005, 95% CI 1.22-3.03; I(2) = 0). In castration-resistant men, high CRP yielded HR = 1.35 (p = 0.003, 95% CI 1.11-1.65; I(2) = 78.6%). CONCLUSION: This meta analysis suggests a detrimental impact for CRP on OS in MPC. Prospective validation is justified to enhance prognostication and trial design, given the affordability, ready availability, and large dynamic range of CRP. PMID- 25531725 TI - Automatic detection of epileptic seizures in long-term EEG records. AB - Epilepsy is a neurological disorder which affects nearly 1.5% of the world's total population. Trained physicians and neurologists visually scan the long-term electroencephalographic (EEG) records to identify epileptic seizures. It generally requires many hours to interpret the data. Therefore, tools for quick detection of seizures in long-term EEG records are very useful. This study proposes an algorithm to help detect seizures in long-term iEEG based on low computational costs methods using Spectral Power and Wavelet analysis. The detector was tested on 21 invasive intracranial EEG (iEEG) records. A sensitivity of 85.39% was achieved. The results indicate that the proposed method detects epileptic seizures in long-term iEEG records successfully. Moreover, the algorithm does not require long processing time due to its simplicity. This feature will allow significant time reduction of the visual inspection of iEEG records performed by the specialists. PMID- 25531726 TI - Multidrug-resistant tuberculosis outbreak in gaming centers, Singapore, 2012. PMID- 25531727 TI - Inherent directionality explains the lack of feedback loops in empirical networks. AB - We explore the hypothesis that the relative abundance of feedback loops in many empirical complex networks is severely reduced owing to the presence of an inherent global directionality. Aimed at quantifying this idea, we propose a simple probabilistic model in which a free parameter gamma controls the degree of inherent directionality. Upon strengthening such directionality, the model predicts a drastic reduction in the fraction of loops which are also feedback loops. To test this prediction, we extensively enumerated loops and feedback loops in many empirical biological, ecological and socio-technological directed networks. We show that, in almost all cases, empirical networks have a much smaller fraction of feedback loops than network randomizations. Quite remarkably, this empirical finding is quantitatively reproduced, for all loop lengths, by our model by fitting its only parameter gamma. Moreover, the fitted value of gamma correlates quite well with another direct measurement of network directionality, performed by means of a novel algorithm. We conclude that the existence of an inherent network directionality provides a parsimonious quantitative explanation for the observed lack of feedback loops in empirical networks. PMID- 25531728 TI - Palladium-catalyzed oxidative carbonylation of hydrazides: synthesis of 1,3,4 oxadiazol-2(3H)-ones. AB - A novel palladium-catalyzed oxidative carbonylation reaction was developed via the carbon monoxide insertions between the amine group and the carbonyl group to realize the intramolecular cyclization, which provides efficient access to 1,3,4 oxadiazol-2(3H)-ones with a wide range of substrates under mild conditions, resulting in good to excellent yields. PMID- 25531729 TI - Ethylaluminum as an ethylene source for the Mizoroki-Heck-type reaction. Rhodium catalyzed preparation of stilbene derivatives. AB - Treatment of an organoaluminum reagent bearing aryl and ethyl groups furnishes 1,2-diarylethene derivatives in good to excellent yields by the catalysis of a rhodium complex, in which the ethyl group of the aluminum reagent serves as an ethylene source in the product formation. PMID- 25531730 TI - Non-surgical and non-chemical attempts to treat echinococcosis: do they work? AB - Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are chronic, complex and neglected diseases. Their treatment depends on a number of factors related to the lesion, setting and patient. We performed a literature review of curative or palliative non-surgical, non-chemical interventions in CE and AE. In CE, some of these techniques, like radiofrequency thermal ablation (RFA), were shelved after initial attempts, while others, such as High-Intensity Focused Ultrasound, appear promising but are still in a pre-clinical phase. In AE, RFA has never been tested, however, radiotherapy or heavy-ion therapies have been attempted in experimental models. Still, application to humans is questionable. In CE, although prospective clinical studies are still lacking, therapeutic, non surgical drainage techniques, such as PAIR (puncture, aspiration, injection, re aspiration) and its derivatives, are now considered a useful option in selected cases. Finally, palliative, non-surgical drainage techniques such as US- or CT guided percutaneous biliary drainage, centro-parasitic abscesses drainage, or vascular stenting were performed successfully. Recently, endoscopic retrograde cholangiopancreatography (ERCP)-associated techniques have become increasingly used to manage biliary fistulas in CE and biliary obstructions in AE. Development of pre-clinical animal models would allow testing for AE techniques developed for other indications, e.g. cancer. Prospective trials are required to determine the best use of PAIR, and associated procedures, and the indications and techniques of palliative drainage. PMID- 25531731 TI - Nasopharyngeal Airway Volume for Different GOSLON Scores in Patients With Unilateral Cleft Lip and Palate. AB - OBJECTIVE: The aim of this study is to evaluate the nasopharyngeal airway volumes of patients with unilateral cleft lip and palate (UCLP) with different GOSLON scores. METHODS: The study sample consisted of 34 patients with UCLP and 20 controls with no cleft history. In the UCLP group, three experienced examiners used the GOSLON Yardstick to rate dental arch relationships, and the sample was divided into three groups as GOSLON 2 (G2) (n = 13), GOSLON 3 (G3) (n = 10), and GOSLON 4 (G4) (n = 11). Airway volumes were constructed using three-dimensional computed tomography data and divided into four compartments named the nasal airway, and superior, middle, and inferior pharyngeal airways. RESULTS: No statistically significant difference was detected among G2, G3, and G4 between the constitutive airway departments of the nasopharyngeal region. However, nasal airway volumes were significantly higher in the control group when compared with the UCLP group. DISCUSSION: Although there was no correlation among the investigated parameters, it is also a fact that airway capacities display a great variability among patients when investigated three dimensionally. CONCLUSION: Although the severity of GOSLON scores might predetermine the extent of which the airways are affected from the cleft, a larger sample size is needed in future studies. PMID- 25531732 TI - Use of the On-Q Pain Pump in Alveolar Bone Grafting: Effect on Hospital Length of Stay. AB - OBJECTIVE: Alveolar bone grafting (ABG) with iliac crest bone graft can be associated with significant pain at the donor site. The On-Q pain pump has been shown to be efficacious in treating postsurgical pain. The aim of this study was to compare the length of postoperative hospital stay in patients undergoing ABG who received the On-Q pain pump at the iliac crest donor site (On-Q+) with that of patients who did not receive the On-Q pain pump (On-Q-). DESIGN: A retrospective, cohort study, approved by institutional review board, was performed. Thirty-one consecutive patients in the On-Q- group were compared with 38 consecutive patients in the On-Q+ group. The two cohorts were assessed for length of stay. Statistical analysis was performed using the Fisher exact probability test. SETTING: Tertiary care academic medical center. PATIENTS: Sixty nine patients with cleft lip and/or cleft palate (CL/P) undergoing secondary ABG with iliac crest bone graft were operated on between May 1993 and January 2014. MAIN OUTCOME MEASURE: Length of postoperative hospital stay. RESULTS: Mean length of stay in the On-Q- patients was 0.52 days versus 0.37 days for the On-Q+ patients. This difference between the two cohorts was not statistically significant (P = .234). CONCLUSION: Although there is a trend toward a shorter length of stay in our patients who received the On-Q pump, this finding was not statistically significant. Given the expense and additional burden of care associated with the device, we have become more selective in its utilization. PMID- 25531733 TI - Evaluation of the Efficacy of Tranexamic Acid on the Surgical Field in Primary Cleft Palate Surgery on Children-A Prospective, Randomized Clinical Study. AB - OBJECTIVE: To assess the effect of tranexamic acid on the quality of the surgical field. DESIGN: Prospective, randomized, double-blind study. SETTING: Institutional, tertiary referral hospital. PARTICIPANTS: American Society of Anesthesiologists physical status class I patients, aged 8 to 60 months with Group II or III (Balakrishnan's classification) clefts scheduled for cleft palate repair. INTERVENTIONS: Children were randomized into two groups. The control group received saline, and the tranexamic acid group received tranexamic acid 10 mg/kg as a bolus, 15 minutes before incision. MAIN OUTCOME MEASURES: Grade of surgical field on a 10-point scale, surgeon satisfaction, and primary hemorrhage. RESULTS: Significant improvements were noted in surgeon satisfaction and median grade of assessment of the surgical field (4 [interquartile range, 4 to 6] in the control group vs. 3 [interquartile range, 2 to 4] in the test group; P = .003) in the tranexamic acid group compared to the control group. CONCLUSION: Preincision administration of 10 mg/kg of tranexamic acid significantly improved the surgical field during cleft palate repair. PMID- 25531734 TI - Maxillary Expansion and Midline Correction by Asymmetric Transverse Distraction Osteogenesis in a Patient With Unilateral Cleft Lip/Palate: A Case Report. AB - This case report presents the management of a female patient with unilateral cleft lip and palate presenting with skeletal Class III malocclusion and a narrow upper dental arch with a midline deviation. The treatment plan involved asymmetric transverse distraction osteogenesis of the maxilla to make the upper dental midline coincident with the facial midline. After the treatment, a good facial profile and a close intercuspation of teeth were achieved. Occlusion remained stable with normal overjet and overbite after 2-year retention. PMID- 25531735 TI - Parent, dentist, and orthodontist satisfaction following alveolar cleft repair using recombinant human bone morphogenic protein. AB - OBJECTIVE: Our aim was to evaluate dental/orthodontic outcomes for patients who underwent recombinant human bone morphogenic protein (rhBMP-2) alveolar cleft repair and to examine parental satisfaction following the procedure. Design Retrospective review. Setting Tertiary children's hospital. Participants Parents, dentists, and orthodontists completed satisfaction questionnaires. Main Outcome Measures Parent, dentist, and orthodontist satisfaction with the use of rhBMP-2 in alveolar cleft repair. Results Parent response rate was 71.4% (30/42). The dentist response rate was 60% (18/30). The orthodontist response rate was 53.3% (16/30). Parent and patient satisfaction was 93.3% and 83.3%, respectively. Of dentist respondents, 55.6% reported that the bone quality and alveolar ridge mucosal repair allowed for dental treatment. Of orthodontist respondents, 87.5% reported the graft enabled treatment, and 73.3% felt the graft prevented tooth root exposure and resorption. Conclusions Parents, dentists, and orthodontists are satisfied with outcomes when rhBMP-2 is used for alveolar cleft repair. The bone formed was reported as adequate to support dental and orthodontic treatment in most cases with few complications. Because of safety concerns over the use of this product in an off-label manner, further controlled studies are warranted. PMID- 25531736 TI - Two Cases of Cleft Lip and Other Congenital Anomalies in Wild Chimpanzees Living in Kibale National Park, Uganda. AB - DESIGN: Observations of wild chimpanzees ( Pan troglodytes schweinfurthii) were conducted in Kibale National Park, Uganda, at the sites of Sebitoli and Ngogo. RESULTS: We report the first two cases of cleft lip in wild chimpanzees. Additionally, some other chimpanzees in the Sebitoli community show facial dysplasia and congenital anomalies, such as patches of depigmented hairs and limb defects. CONCLUSIONS: Cleft lip has been documented in several species of nonhuman primates, but much remains unknown about the occurrence of cleft lip and cleft palate in great apes, probably because such malformations are rare, wild apes are difficult to monitor and observe, and severe cases associated with cleft palates render suckling impossible and lead to early death of infants. The genetic basis of such defects in great apes warrants investigation, as does the possibility that environmental toxins contribute to their etiology in Kibale in ways that could affect humans as well. PMID- 25531737 TI - Heart Failure in an Infant With Pierre Robin Sequence: Is There a Diagnostic Test to Aid in Treatment Planning and Monitoring? AB - This case report describes an infant with Pierre Robin sequence who was managed conservatively until he presented at 4 months of age with right-sided heart failure. This rare clinical presentation displays the physiologic response to chronic respiratory obstruction and the acid-base disturbances, which become evident on metabolic panel and blood gas. We suggest that these tests can be added to the workup, especially in conservatively managed infants, to help predict which infants may fail conservative treatment and to avoid the rare complication of heart failure in infants with Pierre Robin sequence. PMID- 25531739 TI - Evaluation of the Reproducibility of Nonverbal Facial Expressions Using a 3D Motion Capture System. AB - OBJECTIVE: To evaluate the reproducibility of three nonverbal facial expressions using a three-dimensional motion capture system. DESIGN: Prospective, cross sectional, controlled study. SETTING: Glasgow Dental Hospital and School, University of Glasgow, United Kingdom. PATIENTS AND PARTICIPANTS: Thirty-two subjects, 16 males and 16 females. METHODS: With a three-dimensional video passive stereophotogrammetry imaging system, maximal smile, cheek puff, and lip purse were captured for each subject. Anatomical facial landmarks were digitized on the first frame and then tracked automatically. The same facial expressions were captured 15 minutes later. MAIN OUTCOME MEASURES: The magnitude of each expression and speed of landmark displacement were calculated. The landmark motion curves were spatially and temporally aligned to calculate the similarity of the dynamic movements of the same landmarks between the captures. RESULTS: There were no significant differences between individuals for magnitude (P = .892) or for speed (P = .456). There were significant differences in landmark movement similarity (P = .011); similarity was more reproducible for maximal smile. There was no significant gender effect on the difference in magnitude. There was a significant gender effect on speed to reach maximal smile (P = .044) and a pursed-lip expression (P = .038). There was a significant gender effect on landmark movement similarities (P = .031) for cheek puff expression. CONCLUSIONS: There were no differences in magnitude and speed for maximal smile, cheek puff, and lip purse between the two captures for all participants. For individual expressions, maximal smile expression had the highest similarity value for individual landmarks. PMID- 25531738 TI - The Americleft Speech Project: A Training and Reliability Study. AB - OBJECTIVE: To describe the results of two reliability studies and to assess the effect of training on interrater reliability scores. DESIGN: The first study (1) examined interrater and intrarater reliability scores (weighted and unweighted kappas) and (2) compared interrater reliability scores before and after training on the use of the Cleft Audit Protocol for Speech-Augmented (CAPS-A) with British English-speaking children. The second study examined interrater and intrarater reliability on a modified version of the CAPS-A (CAPS-A Americleft Modification) with American and Canadian English-speaking children. Finally, comparisons were made between the interrater and intrarater reliability scores obtained for Study 1 and Study 2. PARTICIPANTS: The participants were speech-language pathologists from the Americleft Speech Project. RESULTS: In Study 1, interrater reliability scores improved for 6 of the 13 parameters following training on the CAPS-A protocol. Comparison of the reliability results for the two studies indicated lower scores for Study 2 compared with Study 1. However, this appeared to be an artifact of the kappa statistic that occurred due to insufficient variability in the reliability samples for Study 2. When percent agreement scores were also calculated, the ratings appeared similar across Study 1 and Study 2. CONCLUSION: The findings of this study suggested that improvements in interrater reliability could be obtained following a program of systematic training. However, improvements were not uniform across all parameters. Acceptable levels of reliability were achieved for those parameters most important for evaluation of velopharyngeal function. PMID- 25531740 TI - Orthognathic Surgeries in Patients With Congenital Craniofacial Anomalies: Profile and Hospitalization Outcomes. AB - OBJECTIVE: To examine the occurrence of complications in patients with congenital facial anomalies who underwent orthognathic surgeries and to identify the role of patient-related factors in occurrence of complications. DESIGN: Retrospective analysis of hospital discharge database. SETTING: Nationwide inpatient sample for the years 2004 to 2010. All patients with a diagnosis of cleft lip and/or palate or congenital craniofacial anomalies and who had an orthognathic surgery were selected. INTERVENTIONS: Orthognathic surgery. MAIN OUTCOME MEASURES: Occurrence of complications. RESULTS: During the study period, a total of 8340 patients with congenital craniofacial anomalies underwent orthognathic surgeries. The overall complication rate was 9.1%. Six different complications (bacterial infections, hemorrhage, postoperative pneumonia, iatrogenic-induced complications such as accidental punctures/lacerations or pneumothorax, other infections, and respiratory complications) occurred in at least 1% of all patients having orthognathic surgeries. Ninety-five percent of patients were discharged routinely after surgery. Patients with high comorbid burden are at a higher risk for developing complications (P < .05). CONCLUSIONS: The current study findings indicate that orthognathic surgeries can be safely performed in patients with congenital craniofacial anomalies. The present study results reflect the practice patterns and hospitalization outcomes across the country and could serve as benchmarks for future well-designed prospective controlled studies to examine risk factors associated with complications for not only orthognathic surgeries but also for a wider range of surgical procedures. PMID- 25531741 TI - Two-phase orthodontic treatment in a patient with turner syndrome: an unusual case of deep bite. AB - Turner syndrome is caused by complete or partial absence of one X chromosome. These patients usually have a delay in growth and altered body proportions, causing sexual infantilism, short stature, delayed bone maturation, and variations in craniofacial morphology, among other systemic complications. The skeletal features associated with this syndrome include maxillary growth reduction with midface hypoplasia; mandibular micrognathia; high, narrow palate; V-shaped maxillary arch; and open bite. This case report shows a two-phase orthodontic treatment in a patient with Turner syndrome with a Class II malocclusion and severe deep bite, which is an unusual feature in patients with this disease. A conventional orthodontic treatment was performed, and after 20 months in retention the patient remains stable. PMID- 25531742 TI - Is no evidence of disease activity a realistic goal for patients with multiple sclerosis? PMID- 25531744 TI - Acute ischaemic heart block in hypoplastic left heart syndrome. AB - In hypoplastic left heart syndrome, thrombosis of the native ascending aorta is rare and often fatal; there are no previously reported cases presenting with acute heart block. We review a case of native ascending aorta thrombosis in a 2 year-old boy with hypoplastic left heart syndrome, presenting with acute heart block. This case highlights the benefit of multi-modality imaging in complex cases. PMID- 25531743 TI - Mucosal Immunosenescence in the Gastrointestinal Tract: A Mini-Review. AB - It has been shown that pathogen-specific secretory IgA (SIgA) antibody (Ab) is the major player at mucosal surfaces for host defense. However, alterations in the mucosal immune system occur in advanced aging, which results in a failure of induction of SIgA Abs for the protection from infectious diseases. Signs of mucosal senescence first appear in the gut immune system. Further, changes in the intestinal microbiota most likely influence mucosal immunity. To overcome the immunological aging decline in mucosal immunity, several adjuvant systems including mucosal dendritic cell targeting have been shown to be attractive and effective immunological strategies. Similarly, microfold (M) cells involved in the antigen (Ag) uptake are ideal targets for facilitating Ag-specific mucosal immune responses. However, the numbers of M cells are reduced in aged mice. In this regard, Spi-B, an essential transcription factor for the functional and structural differentiation of M cells, could be a potent strategy for the induction of effective mucosal immunity in aging. PMID- 25531745 TI - Use of counselling services by school-attending adolescent girls in Nigeria. AB - PURPOSE: The purpose of this study was to examine the predictors and barriers to the use of school counselling services by school attending adolescent girls in south-east Nigeria. METHOD: The study used a cross-sectional survey of 3065 adolescent girls, using a self-report counselling utilisation scale. Data were analysed using both descriptive and inferential statistics. RESULTS: About 80% of the participants had school counsellors and nearly half of the participants utilised the service. Regression results showed that father's level of education, availability of a counselling laboratory/room, contentment with the counselling services rendered predicted the use of the counselling service. Some of the barriers for non-use of school counselling services were shyness, fear and lack of confidentiality. CONCLUSION: School authorities will encourage uptake of counselling services by adolescents when adequate counselling consulting rooms are provided. This will increase confidence in adolescent clients and reduce fear attached to use of these services. This will improve their mental health and their academic performance. PMID- 25531747 TI - Rationally designed cooperatively enhanced receptors to magnify host-guest binding in water. AB - When disengaged interactions within a receptor are turned on by its guest, these intrahost interactions will contribute to the overall binding energy. Although such receptors are common in biology, their synthetic mimics are rare and difficult to design. By engineering conflictory requirements between intrareceptor electrostatic and hydrophobic interactions, we enabled complementary guests to eliminate the "electrostatic frustration" within the host and turn on the intrahost interactions. The result was a binding constant of Ka >10(5) M(-1) from ammonium-carboxylate salt bridges that typically function poorly in water. These cooperatively enhanced receptors displayed excellent selectivity in binding, despite a large degree of conformational flexibility in the structure. PMID- 25531746 TI - Quantitative imaging of glutathione in live cells using a reversible reaction based ratiometric fluorescent probe. AB - Glutathione (GSH) plays an important role in maintaining redox homeostasis inside cells. Currently, there are no methods available to quantitatively assess the GSH concentration in live cells. Live cell fluorescence imaging revolutionized the field of cell biology and has become an indispensable tool in current biological studies. In order to minimize the disturbance to the biological system in live cell imaging, the probe concentration needs to be significantly lower than the analyte concentration. Because of this, any irreversible reaction-based GSH probe can only provide qualitative results within a short reaction time and will exhibit maximum response regardless of the GSH concentration if the reaction is completed. A reversible reaction-based probe with an appropriate equilibrium constant allows measurement of an analyte at much higher concentrations and, thus, is a prerequisite for GSH quantification inside cells. In this contribution, we report the first fluorescent probe-ThiolQuant Green (TQ Green) for quantitative imaging of GSH in live cells. Due to the reversible nature of the reaction between the probe and GSH, we are able to quantify mM concentrations of GSH with TQ Green concentrations as low as 20 nM. Furthermore, the GSH concentrations measured using TQ Green in 3T3-L1, HeLa, HepG2, PANC-1, and PANC 28 cells are reproducible and well correlated with the values obtained from cell lysates. TQ Green imaging can also resolve the changes in GSH concentration in PANC-1 cells upon diethylmaleate (DEM) treatment. In addition, TQ Green can be conveniently applied in fluorescence activated cell sorting (FACS) to measure GSH level changes. Through this study, we not only demonstrate the importance of reaction reversibility in designing quantitative reaction-based fluorescent probes but also provide a practical tool to facilitate redox biology studies. PMID- 25531748 TI - Head-up tilt testing for detecting orthostatic hypotension: how long do we need to wait? AB - BACKGROUND: Orthostatic hypotension (OH) is a common underdiagnosed condition characterized by a fall in systolic or diastolic blood pressure (BP). There is some uncertainty about the minimum duration needed to detect OH beyond 3 min (delayed OH). We aimed to define a minimum time range for measurement of delayed OH in subjects referred to as tilt testing. METHODS: A repeated measurements study Tel-Aviv Medical Center, on 692 subjects who underwent prolonged (40 min, vertical position) drug-free tilt testing. Survival curves were used to study time to an OH event; logistic regression to study factors associated with delayed OH and mixed models to study the pattern of repeated BP measures. RESULTS: In our sample, 17% had OH within 3 min, 35% within 30 min, and 40% within 40 min. Among the 270 OH patients, 43 and 91% were identified within 3 and 30 min, respectively. Delayed OH was associated with female gender (OR = 1.95, 1.16-3.27) and age <65 years (OR = 2.17, 1.24-3.80). Older patients differed significantly from younger patients in BP pattern changes and had a higher rate of a fall in systolic BP. CONCLUSION: Tilt testing for 30 min identifies most cases of delayed OH in older patients, while those younger than 65 years need 10 min longer. PMID- 25531749 TI - Willingness to pay for public health policies to treat illnesses. AB - As the US pursues health care reform, it is important to understand the patterns in demand for, and opposition to, public provision of medical treatments. Using data from a nationally representative survey, we develop and estimate a utility theoretic choice model to quantify demand for publicly provided medical treatment policies. We find diminishing marginal utility for increased recoveries and avoided premature deaths. We also show how the utility associated with different types of treatment policies varies with the socio-demographic group that would benefit (e.g. men, women, children, and seniors) and the program's duration and scope. Our model further permits utility, and hence willingness to pay, to vary with each respondent's own gender, age, race, income, community ethnic fractionalization and immigrant composition, as well as the respondent's expected private benefits from the policy and attitude toward government interventions and overall health care funding allocations. Self-interest is a prevailing finding. PMID- 25531750 TI - IgA nephropathy in Czech patients--are we able reliably predict the outcome? AB - BACKGROUND/AIMS: The aim of our study was to retrospectively analyse data of 520 Czech patients with IgA nephropathy (IgAN) and to specify the risk factors affecting renal survival of IgAN patients. METHODS: Cox proportional hazards regression model was used to evaluate the effects of different variables on renal survival during a median follow up of six years. McNemar's test was used to analyse the progression of renal function according to Bartosik's formula. RESULTS: In our retrospective analysis of 520 Czech IgAN patients Cox proportional hazards regression model with five variables [hypertension, sex, GFR, proteinuria, age] was used. Significant regression coefficient was found for GFR, hypertension and proteinuria. Using stepwise algorithm GFR (OR = 3.09), hypertension (OR = 2.09) and proteinuria (OR = 1.97) were found as the most important factors for renal survival in our group of IgAN patients. Among patients with CKD 3 we found significantly better renal survival in patients with proteinuria < 1g/day compared to patients with higher proteinuria. We did not find the significant difference between predicted progression of renal function due to Bartosik's formula and real progression of renal parametres assessed by GFR at the end of the follow up in our group of IgAN patients. CONCLUSION: Our retrospective study of 520 Czech IgAN patients confirmed GFR, hypertension and proteinuria as the most important factors affecting the prognosis of IgAN patients. We validated Toronto Bartosik's formula to predict prognosis of IgAN patients. PMID- 25531751 TI - A maize wall-associated kinase confers quantitative resistance to head smut. AB - Head smut is a systemic disease in maize caused by the soil-borne fungus Sporisorium reilianum that poses a grave threat to maize production worldwide. A major head smut quantitative resistance locus, qHSR1, has been detected on maize chromosome bin2.09. Here we report the map-based cloning of qHSR1 and the molecular mechanism of qHSR1-mediated resistance. Sequential fine mapping and transgenic complementation demonstrated that ZmWAK is the gene within qHSR1 conferring quantitative resistance to maize head smut. ZmWAK spans the plasma membrane, potentially serving as a receptor-like kinase to perceive and transduce extracellular signals. ZmWAK was highly expressed in the mesocotyl of seedlings where it arrested biotrophic growth of the endophytic S. reilianum. Impaired expression in the mesocotyl compromised ZmWAK-mediated resistance. Deletion of the ZmWAK locus appears to have occurred after domestication and spread among maize germplasm, and the ZmWAK kinase domain underwent functional constraints during maize evolution. PMID- 25531752 TI - Safety and effectiveness of a 2009 H1N1 vaccine in chronic kidney disease children. AB - BACKGROUND/AIMS: Influenza vaccination is the most effective method for preventing influenza infection and its complications. The risk groups are children with chronic kidney diseases (CKDs) such as children on peritoneal dialysis (PD) and hemodialysis (HD), predialysis CKD (pCKD) and renal transplant (RTx) patients and immunosuppressed children. The aim of the present study was to assess the safety and immunogenicity of a single administration of a monovalent inactivated pandemic (H1N1) 2009 vaccine in children with CKD. METHODS: Patients were given a single intramuscular injection of 0.5 ml of monovalent inactivated vaccine. RESULTS: Totally, there were 25 pediatric patients with a diagnosis of CKD (16 PD, 2 HD, 3 pCKD and 4 RTx). Seroconversion was observed in 15 of the 16 patients with PD. Seroconversion occurred in all patients undergoing pCKD and HD. However, 3 of the RTx patients were seronegative. CONCLUSION: This study demonstrated a high level of immunogenicity and safety of an (H1N1) 2009 influenza vaccine in children with CKD. PMID- 25531753 TI - Insights into substrate binding to the oxygen-evolving complex of photosystem II from ammonia inhibition studies. AB - Water oxidation in Photosystem II occurs at the oxygen-evolving complex (OEC), which cycles through distinct intermediates, S0-S4. The inhibitor ammonia selectively binds to the S2 state at an unresolved site that is not competitive with substrate water. By monitoring the yields of flash-induced oxygen production, we show that ammonia decreases the net efficiency of OEC turnover and slows the decay kinetics of S2 to S1. The temperature dependence of biphasic S2 decay kinetics provides activation energies that do not vary in control and ammonia conditions. We interpret our data in the broader context of previous studies by introducing a kinetic model for both the formation and decay of ammonia-bound S2. The model predicts ammonia binds to S2 rapidly (t1/2 = 1 ms) with a large equilibrium constant. This finding implies that ammonia decreases the reduction potential of S2 by at least 2.7 kcal mol(-1) (>120 mV), which is not consistent with ammonia substitution of a terminal water ligand of Mn(IV). Instead, these data support the proposal that ammonia binds as a bridging ligand between two Mn atoms. Implications for the mechanism of O-O bond formation are discussed. PMID- 25531755 TI - Synthesis of enantiopure glycidol derivatives via a one-pot two-step enzymatic cascade. AB - Styrene monooxygenase (SMO) can catalyze the kinetic resolution of secondary allylic alcohols to provide enantiopure glycidol derivatives. To overcome the low theoretical yield of kinetic resolution, we designed a one-pot two-step enzymatic cascade using prochiral alpha,beta-unsaturated ketones as the substrates. An S specific ketoreductase ChKRED03 was screened for the efficient bioreduction of the substrates to provide (S)-allylic alcohols, which underwent SMO-catalyzed epoxidation to achieve glycidol derivatives with contiguous stereogenic centers. Excellent enantioselectivity (ee > 99%) and diastereoselectivity (de > 99%) were achieved for the majority of the substrates, and product yields reached up to >99%. PMID- 25531756 TI - One-step biosynthesis of alpha-keto-gamma-methylthiobutyric acid from L methionine by an Escherichia coli whole-cell biocatalyst expressing an engineered L-amino acid deaminase from Proteus vulgaris. AB - alpha-Keto-gamma-methylthiobutyric acid (KMTB), a keto derivative of l methionine, has great potential for use as an alternative to l-methionine in the poultry industry and as an anti-cancer drug. This study developed an environment friendly process for KMTB production from l-methionine by an Escherichia coli whole-cell biocatalyst expressing an engineered l-amino acid deaminase (l-AAD) from Proteus vulgaris. We first overexpressed the P. vulgaris l-AAD in E. coli BL21 (DE3) and further optimized the whole-cell transformation process. The maximal molar conversion ratio of l-methionine to KMTB was 71.2% (mol/mol) under the optimal conditions (70 g/L l-methionine, 20 g/L whole-cell biocatalyst, 5 mM CaCl2, 40 degrees C, 50 mM Tris-HCl [pH 8.0]). Then, error-prone polymerase chain reaction was used to construct P. vulgaris l-AAD mutant libraries. Among approximately 104 mutants, two mutants bearing lysine 104 to arginine and alanine 337 to serine substitutions showed 82.2% and 80.8% molar conversion ratios, respectively. Furthermore, the combination of these mutations enhanced the catalytic activity and molar conversion ratio by 1.3-fold and up to 91.4% with a KMTB concentration of 63.6 g/L. Finally, the effect of immobilization on whole cell transformation was examined, and the immobilized whole-cell biocatalyst with Ca2+ alginate increased reusability by 41.3% compared to that of free cell production. Compared with the traditional multi-step chemical synthesis, our one step biocatalytic production of KMTB has an advantage in terms of environmental pollution and thus has great potential for industrial KMTB production. PMID- 25531754 TI - Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll like receptor 2 (sTLR2) production. AB - Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders. PMID- 25531758 TI - Simulation of biomass yield and soil organic carbon under bioenergy sorghum production. AB - Developing sustainable management practices including appropriate residue removal and nitrogen (N) fertilization for bioenergy sorghum is critical. However, the effects of residue removal and N fertilization associated with bioenergy sorghum production on soil organic carbon (SOC) are less studied compared to other crops. The objective of our research was to assess the impacts of residue removal and N fertilization on biomass yield and SOC under biomass sorghum production. Field measurements were used to calibrate the DNDC model, then verified the model by comparing simulated results with measured results using the field management practices as agronomic inputs. Both residue removal and N fertilization affected bioenergy sorghum yields in some years. The average measured SOC at 0-50 cm across the treatments and the time-frame ranged from 47.5 to 78.7 Mg C ha-1, while the simulated SOC was from 56.3 to 67.3 Mg C ha-1. The high correlation coefficients (0.65 to 0.99) and low root mean square error (3 to 18) between measured and simulated values indicate the DNDC model accurately simulated the effects of residue removal with N fertilization on bioenergy sorghum production and SOC. The model predictions revealed that there is, in the long term, a trend for higher SOC under bioenergy sorghum production regardless of residue management. PMID- 25531759 TI - Renal function in hepatosplenic schistosomiasis--an assessment of renal tubular disorders. AB - BACKGROUND: Renal involvement in Schistosoma mansoni infection is not well studied. The aim of this study is to investigate the occurrence of renal abnormalities in patients with hepatosplenic schistosomiasis (HSS), especially renal tubular disorders. METHODS: This is a cross-sectional study with 20 consecutive patients with HSS followed in a medical center in Maceio, Alagoas, Brazil. Urinary acidification and concentration tests were performed using calcium chloride (CaCl2) after a 12-h period of water and food deprivation. The biomarker monocyte chemoattractant protein 1 (MCP-1) was quantified in urine. Fractional excretion of sodium (FENa+), transtubular potassium gradient (TTKG) and solute-free water reabsorption (TcH2O) were calculated. The HSS group was compared to a group of 17 healthy volunteers. RESULTS: Patients' mean age and gender were similar to controls. Urinary acidification deficit was found in 45% of HSS patients. Urinary osmolality was significantly lower in HSS patients (588 +/- 112 vs. 764 +/- 165 mOsm/kg, p = 0,001) after a 12-h period of water deprivation. TcH2O was lower in HSS patients (0.72 +/- 0.5 vs. 1.1 +/- 0.3, p = 0.04). Urinary concentration deficit was found in 85% of HSS patients. The values of MCP-1 were higher in HSS group than in control group (122 +/- 134 vs. 40 +/- 28 pg/mg-Cr, p = 0.01) and positively correlated with the values of microalbuminuria and proteinuria. CONCLUSIONS: HSS is associated with important kidney dysfunction. The main abnormalities found were urinary concentrating ability and incomplete distal acidification defect, demonstrating the occurrence of tubular dysfunction. There was also an increase in urinary MCP-1, which appears to be a more sensitive marker of renal damage than urinary albumin excretion rate. PMID- 25531760 TI - Tubulocystic carcinoma of the kidney with fatal outcome in an adolescent male. AB - Non-clear cell renal cell carcinoma accounts for about 20% of all kidney cancers. Tubulocystic carcinoma of the kidney (TCK) is a newly described entity with distinct molecular, genetic and clinical features. In 2013, it was one of five new renal tumors to be recognized by the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. We describe here a case of TCK with a rare genetic signature, unusual metastases and limited response to an anti-vascular endothelial growth factor inhibitor in what we believe is the youngest patient on record to date. PMID- 25531762 TI - Drinking pattern and risk of chronic kidney disease: the kansai healthcare study. AB - BACKGROUND/AIMS: The association between alcohol consumption and the risk of chronic kidney disease (CKD) has been reported. What is not known is whether drinking pattern combined with the weekly frequency of alcohol consumption and the quantity per drinking day is associated with the risk of CKD. METHODS: We enrolled 9,112 Japanese nondiabetic men aged 40 to 55 years with absence of proteinuria, an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m(2) or higher, and not on antihypertensive medications at baseline. CKD was defined if eGFR was <60 ml/min/1.73 m(2). The weekly frequency classification was nondrinkers, 1-3 drinking days/week, or 4-7 drinking days/week. The quantity consumed per drinking day was classified as 0.1-23.0 g ethanol/drinking day, 23.1 46.0 g ethanol/drinking day, 46.1-69.0 g ethanol/drinking day, and >=69.1 g ethanol/drinking day. RESULTS: During the 79,099 person-years, 1,253 subjects developed CKD. Compared to nondrinkers, those who consumed 23.1-46.0 or 46.1-69.0 g ethanol/drinking day on 4-7 drinking days/week had a decreased risk of CKD (multiple-adjusted hazard ratio (HR) 0.62 (0.52-0.74) and 0.76 (0.59-0.97), respectively). The association between the quantity per drinking day and the incidence of CKD was U-shaped among each category of the weekly frequency. HRs within similar categories of quantity per drinking day were lower in the 4-7 drinking days/week group than in the 1-3 drinking days/week group. CONCLUSION: Among middle-aged Japanese men, the people who drank middle-range quantity, specifically who drank 4-7 days/week, had lower risk of CKD than nondrinkers. PMID- 25531761 TI - Anterior lamina cribrosa insertion in primary open-angle glaucoma patients and healthy subjects. AB - PURPOSE: To determine using swept-source optical coherence tomography (SS-OCT) whether there are differences in the location of the anterior lamina cribrosa insertion (ALI) in primary open-angle glaucoma (POAG) patients and healthy subjects. METHODS: Fifty three eyes from 53 patients with POAG, and 53 eyes from 53 age-matched healthy subjects were included prospectively in Seoul National University Bundang Hospital. Twelve radial line B-scans centered on the optic disc in every half-clock-hour meridian were acquired using SS-OCT. The ALI position was assessed by measuring two parameters: (1) ALI distance (ALID)--the distance from the anterior scleral canal opening (ASCO) to the ALI; and (2) marginal anterior lamina cribrosa surface depth (mALCSD)--the perpendicular distance from the ASCO plane to the anterior lamina cribrosa surface. These parameters were compared between the two groups for each meridian. RESULTS: Both ALID (256 +/- 54 vs. 209 +/- 37 um, mean +/- SD, p < 0.001) and mALCSD (232 +/- 63 vs. 187 +/- 40 um, p < 0.001) were significantly greater in the POAG group than in the normal group. The largest difference was observed at the 6.5 o'clock and 11.5 o'clock meridians for both ALID and mALCSD. Multiple regression analysis revealed a negative correlation between age and both ALID and mALCSD in the control group, and a negative correlation between mean deviation of the visual field test and both ALID and mALCSD in the POAG group. CONCLUSIONS: The ALI was displaced posteriorly in eyes with POAG compared to those of healthy controls. This finding suggests that the posteriorly located lamina cribrosa insertion is an important component of glaucomatous optic nerve excavation. PMID- 25531763 TI - Complications of long-standing foreign body in the airway and their outcomes after endoscopic management: an experience of 20 cases. AB - AIM: To study the outcomes after endoscopic treatment of chronic foreign bodies (FBs) in the airway. MATERIALS AND METHODS: A retrospective study (2008-2013) of 20 cases with chronic airway FBs (>2 weeks) was done with emphasis on endoscopic management. All cases were initially evaluated by the pediatric pulmonologist. Flexible and rigid bronchoscopy was done for diagnosis and retrieval, respectively. The techniques of FB retrieval, problems encountered, and their solutions were analyzed. Follow-up flexible bronchoscopy was done in symptomatic cases. Outcomes were assessed in terms of successful removal of the FB, clinical recovery, lung expansion, and need for further procedures. RESULTS: Twenty cases (16 boys, 4 girls) with a mean age of 7 years had a chronic airway FB diagnosed on chest X-ray (n=6) and flexible bronchoscopy (n=14). Six cases had computed tomography evaluation. On rigid bronchoscopy, the FB was successfully retrieved in 16 cases. Two cases required open surgery for FB-induced tracheoesophageal fistula. One case required pneumonectomy because of a battery eroding into the lung parenchyma. One patient died. Of the 16 who had successful retrieval, 11 recovered with full lung expansion. Four recovered after additional bronchoscopic procedures (cauterization of granulation [n=2] and balloon dilatation of bronchial stenoses [n=2]). One case required pneumonectomy for persistent collapse despite multiple dilatations. CONCLUSIONS: An airway FB producing chronic respiratory symptoms may be missed because of lack of definite history of an inhaled FB. Clinical suspicion and flexible bronchoscopy are instrumental in diagnosis. Treatment is challenging because of chronicity-related complications and requires innovative ideas to make best use of the available urologic and bronchoscopic equipment. Addition of tracheotomy provides safety in difficult cases. Bronchoscopic removal leads to clinical and radiological recovery in most cases. PMID- 25531764 TI - Association between red blood cell distribution width and polycystic ovary syndrome. AB - AIMS: The red blood cell distribution width (RDW) is being recognized as a marker of chronic inflammation and routinely reported as part of a complete blood count (CBC) without any additional costs. High levels of RDW associate with oxidative stress and cardiovascular disease risk. We aimed to investigate the relation between the level of RDW and high-sensitive C-reactive protein (hs-CRP), HOMA-IR, BMI and body fat percentage in women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Cross-sectional and observational studies were conducted in 90 subjects with PCOS and 87 age- and BMI-matched controls. Body fat percentage, CBC, fasting serum glucose, serum insulin, hs-CRP, lipids, and total and free-testosterone levels were measured. RESULTS: RDW levels were significantly higher in the PCOS group compared with the control group (12.98 +/- 0.92% versus 12.59 +/- 0.84%, p = 0.004). RDW levels were positively correlated with hs-CRP, HOMA-IR and BMI. Multivariate analysis showed that high-RDW levels were associated with PCOS. Subjects with the highest quartile RDW levels were nearly 2.8 times more likely to develop PCOS compared with subjects with the lowest quartile RDW. ROC curve analysis showed that RDW levels were useful as a diagnostic marker for PCOS. The optimal cut-off value for detecting PCOS was >=12.54% (sensitivity 67% and specificity 70%). CONCLUSIONS: RDW levels were higher in women with PCOS, and high-RDW levels were independently associated with PCOS. This link in between RDW and PCOS may be due to an underlying chronic inflammation in subjects with PCOS. PMID- 25531765 TI - Elevated uptake of plasma macromolecules by regions of arterial wall predisposed to plaque instability in a mouse model. AB - Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E /- mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TCFA type develop. Computational simulations and effects of reversing the cuff orientation indicated a role for solid as well as fluid mechanical stresses. Inhibiting NO synthesis abolished the difference in uptake between the upstream and downstream sites. The data support the hypothesis that excessively elevated wall uptake of plasma macromolecules initiates the development of the TCFA, suggest that such uptake can result from solid and fluid mechanical stresses, and are consistent with a role for NO synthesis. Modification of wall transport properties might form the basis of novel methods for reducing plaque rupture. PMID- 25531766 TI - Parenteral medication prescriptions, dispensing and administration habits in Mongolia. AB - High levels of injection prescribing were reported in Mongolia. Understanding the factors influencing the injection prescribing is essential to reduce their inappropriate use. The study evaluated the views, experiences and attitudes of community members associated with the prescribing of injections in Mongolia. A structured questionnaire focusing on respondents' characteristics, experiences and views about injections was developed and administered face-to-face to community members in Ulaanbaatar, Mongolia. Standard descriptive statistics were used to summarize demographic data and responses to the questionnaires. Dependent variables were compared using Kruskal-Wallis Tests for independence. Statistical analyses were performed using SPSS Version 21.0. Six hundred participants were approached and the response rate was 79% (n = 474). Almost half of the respondents were aged between 31 and 50 (n = 228, 48.1%) and 40.9% of respondents were male (n = 194). Most respondents were from Ulaanbaatar city (n = 407, 85.7%). All respondents had received injections in the past and 268 (56.5%) had received injection in the past year. The most common reason for having an injection in the past year was reported as treatment of a disease (n = 163, 60.8%), or for administration of vitamins (n = 70, 26.1%). Injections were prescribed by a doctor (n = 353, 74.9%), dispensed by a pharmacist (n = 283, 59.7%) and administered by a nurse (n = 277, 54.9%). Only 16% of all respondents had the expectation of receiving injections when they visited a doctor (n = 77). An important perception regarding injections was that they hastened the recovery process (n = 269, 56.8%). When asked their opinion about therapeutic injections, 40% of all respondents agreed that injections were a better medicine (n = 190) than oral medications, with older respondents strongly agreeing (p<0.001). Based on this total sample, approximately 1891 injections per 1000 patients were administered. The excessive injection use seems to be promoted by inappropriate prescribing, dispensing and administration of medication by doctors and others. PMID- 25531767 TI - Osteogenic differentiation of late-outgrowth CD45-negative endothelial progenitor cells. AB - BACKGROUND/AIMS: Late-outgrowth CD45-negative endothelial colony-forming cells are implicated to be circulating endothelial progenitor cells (EPCs), as they express endothelial cell markers and can directly form blood vessels. As these cells share characteristics of other progenitor cell phenotypes, late-outgrowth EPCs were assayed for both multilineage differentiation capability and for markers of pluripotency. METHODS: Clonal single-colony late-outgrowth EPCs were derived from human cord blood and assayed both for multilineage differentiation capability in vitro and for markers of pluripotency by qPCR. RESULTS: Under osteogenic growth conditions, these EPCs expressed the osteogenic markers RUNX2, COL1A1, ALPL, and osteocalcin and demonstrated calcium deposition and bone mineralization. Endothelial colony-forming cells expressed markers associated with induced pluripotent stem cells, including SOX2, POU5F1, c-MYC, and KLF4. CONCLUSIONS: Late-outgrowth EPCs express markers associated with pluripotency and can directly express an osteogenic phenotype under bone differentiation conditions in vitro. PMID- 25531768 TI - Thymoquinone inhibits murine leukemia WEHI-3 cells in vivo and in vitro. AB - BACKGROUND: Thymoquinone is an active ingredient isolated from Nigella sativa (Black Seed). This study aimed to evaluate the in vitro and in vivo anti-leukemic effects of thymoquinone on WEHI-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of thymoquinone was assessed using an MTT assay, while the inhibitory effect of thymoquinone on murine WEHI-3 cell growth was due to the induction of apoptosis, as evidenced by chromatin condensation dye, Hoechst 33342 and acridine orange/propidium iodide fluorescent staining. In addition, Annexin V staining for early apoptosis was performed using flowcytometric analysis. Apoptosis was found to be associated with the cell cycle arrest at the S phase. Expression of Bax, Bcl2 and HSP 70 proteins were observed by western blotting. The effects of thymoquinone on BALB/c mice injected with WEHI-3 cells were indicated by the decrease in the body, spleen and liver weights of the animal, as compared to the control. CONCLUSION: Thymoquinone promoted natural killer cell activities. This compound showed high toxicity against WEHI-3 cell line which was confirmed by an increase of the early apoptosis, followed by up-regulation of the anti-apoptotic protein, Bcl2, and down-regulation of the apoptotic protein, Bax. On the other hand, high reduction of the spleen and liver weight, and significant histopathology study of spleen and liver confirmed that thymoquinone inhibited WEHI-3 growth in the BALB/c mice. Results from this study highlight the potential of thymoquinone to be developed as an anti-leukemic agent. PMID- 25531769 TI - Poor lower extremity function was associated with pre-diabetes and diabetes in older chinese people. AB - OBJECTIVE: To determine whether a relationship exists between performance-based physical assessments and pre-diabetes/diabetes in an older Chinese population. METHODS: Our study population comprised 976 subjects (mean +/- SD age: 67.6+/-6.0 years; 44.5% men) from the Hangu area of Tianjin, China. Diabetes was defined by self-reporting of a physician's diagnosis, or a fasting plasma glucose level >=126 mg/dL; and pre-diabetes was defined as a fasting plasma glucose level >=100 mg/dL and <126 mg/dL. RESULTS: When all other variables were adjusted for, men needing longer to finish a Timed Up and Go Test and a decreased usual walking speed had higher odds of pre-diabetes (P for trend = 0.007 and 0.008, respectively) and diabetes (P for trend = 0.012 and 0.014, respectively). However, women needing longer to finish the test and a decreased usual walking speed had a higher odds of diabetes (P for trend = 0.020 and 0.034, respectively) but not of pre-diabetes. There was no apparent association between grip strength and pre-diabetes/diabetes in both sexes. CONCLUSIONS: In this study, poor lower extremity function was associated with pre-diabetes/diabetes in older people. PMID- 25531770 TI - Characterization of structure and function of ZS-9, a K+ selective ion trap. AB - Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ~ 3 A (~ diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2 0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS 9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options. PMID- 25531771 TI - Reconceptualizing the HIV epidemiology and prevention needs of Female Sex Workers (FSW) in Swaziland. AB - BACKGROUND: HIV is hyperendemic in Swaziland with a prevalence of over 25% among those between the ages of 15 and 49 years old. The HIV response in Swaziland has traditionally focused on decreasing HIV acquisition and transmission risks in the general population through interventions such as male circumcision, increasing treatment uptake and adherence, and risk-reduction counseling. There is emerging data from Southern Africa that key populations such as female sex workers (FSW) carry a disproportionate burden of HIV even in generalized epidemics such as Swaziland. The burden of HIV and prevention needs among FSW remains unstudied in Swaziland. METHODS: A respondent-driven-sampling survey was completed between August-October, 2011 of 328 FSW in Swaziland. Each participant completed a structured survey instrument and biological HIV and syphilis testing according to Swazi Guidelines. RESULTS: Unadjusted HIV prevalence was 70.3% (n = 223/317) among a sample of women predominantly from Swaziland (95.2%, n = 300/316) with a mean age of 21(median 25) which was significantly higher than the general population of women. Approximately one-half of the FSW(53.4%, n = 167/313) had received HIV prevention information related to sex work in the previous year, and about one-in-ten had been part of a previous research project(n = 38/313). Rape was common with nearly 40% (n = 123/314) reporting at least one rape; 17.4% (n = 23/314)reported being raped 6 or more times. Reporting blackmail (34.8%, n = 113/314) and torture(53.2%, n = 173/314) was prevalent. CONCLUSIONS: While Swaziland has a highly generalized HIV epidemic, reconceptualizing the needs of key populations such as FSW suggests that these women represent a distinct population with specific vulnerabilities and a high burden of HIV compared to other women. These women are understudied and underserved resulting in a limited characterization of their HIV prevention, treatment, and care needs and only sparse specific and competent programming. FSW are an important population for further investigation and rapid scale-up of combination HIV prevention including biomedical, behavioral, and structural interventions. PMID- 25531772 TI - Trimethoprim and sulfamethoxazole transmembrane clearance during modeled continuous renal replacement therapy. AB - BACKGROUND/AIMS: There is limited data regarding trimethoprim (TMP)/sulfamethoxazole (SMX) continuous renal replacement therapy (CRRT) dosing. We aimed to estimate TMP/SMX transmembrane clearance (CLtm) during continuous hemofiltration (CH) and continuous hemodialysis (CD) to guide dosing. METHODS: Using an in vitro model, TMP/SMX sieving coefficients (SC) and saturation coefficients (SA) were determined with high-flux polyarylethersulfone and polyacrylonitrile-sodium methallyl sulfonate copolymer hemodiafilters at ultrafiltration/dialysate rates of 1, 2, 3, and 6 l/h. TMP/SMX CLtm was calculated using measured SC and SA. TMP/SMX CRRT doses were modeled using CLtm and published TMP/SMX pharmacokinetic parameters. RESULTS: TMP SC/SA during CH/CD were significantly higher than SMX SC/SA. During modeling, TMP 10 mg/kg/day and its corresponding SMX dose, 50 mg/kg/day, resulted in steady state TMP/SMX peak concentrations associated with efficacy against Pneumocystis jirovecii. CONCLUSIONS: CRRT resulted in greater TMP CLtm than SMX. TMP 10 mg/kg/day divided q12h may be an appropriate initial dose to consider in patients undergoing CRRT. PMID- 25531773 TI - Including pathogen risk in life cycle assessment of wastewater management. Implications for selecting the functional unit. PMID- 25531774 TI - Response to the paper by Unlu et al. entitled 'The effect of metformin on cardiac fibrosis via differentiation of cardiac fibroblasts'. PMID- 25531775 TI - Cheap carbon black-based high-performance electrocatalysts for oxygen reduction reaction. AB - A family of cheap carbon black based Fe-Nx/C electrocatalysts with superhigh performance for oxygen reduction reaction (ORR) were synthesized. The one with Fe 10 wt% and N 1.57 wt% shows the best performance. The activity order of different active sites for ORR was revealed firstly: Fe-N4/2-C > Fe4-N-C > N-C ? Fe4-C ~ C. PMID- 25531776 TI - Covalent entrapment of cobalt-iron sulfides in N-doped mesoporous carbon: extraordinary bifunctional electrocatalysts for oxygen reduction and evolution reactions. AB - To alleviate the kinetic barriers associated with ORR (oxygen reduction reaction) and OER (oxygen evolution reaction) in electrochemical systems, efficient nonprecious electrocatalysts are urgently required. Here we report a facile soft template mediated approach for fabrication of nanostructured cobalt-iron double sulfides that are covalently entrapped in nitrogen-doped mesoporous graphitic carbon (Co0.5Fe0.5S@N-MC). Notably, with a positive half-wave potential (0.808 V) and a high diffusion-limiting current density, the composite material delivers unprecedentedly striking ORR electrocatalytic activity among recently reported nonprecious late transition metal chalcogenide materials in alkaline medium. Various characterization techniques, including X-ray absorption spectroscopy, X ray photoelectron spectroscopy, and X-ray diffraction, are conducted to elucidate the correlation between structural features and catalytic activities of the composite. Moderate substitution and well-dispersion of iron in bimetallic sulfide composites are believed to have positive effect on the adsorption and activation of oxygen-containing species, thus leading to conspicuous ORR and OER catalytic enhancement compared to their monometallic counterparts. Besides, the covalent bridge between active sulfide particles and mesoporous carbon shells provides facile pathways for electron and mass transport. Beneficially, the intimate coupling interaction renders prolonged electrocatalytic performances to the composite. Our results may possibly lend a new impetus to the rational design of bi- or multimetallic sulfides encapsulated in porous carbon with improved performance for electrocatalysis and energy storage applications. PMID- 25531777 TI - The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras MAPK signalling. AB - We identified the Rho GTPase Rnd1 as a candidate metastasis suppressor in basal like and triple-negative breast cancer through bioinformatics analysis. Depletion of Rnd1 disrupted epithelial adhesion and polarity, induced epithelial-to mesenchymal transition, and cooperated with deregulated expression of c-Myc or loss of p53 to cause neoplastic conversion. Mechanistic studies revealed that Rnd1 suppresses Ras signalling by activating the GAP domain of Plexin B1, which inhibits Rap1. Rap1 inhibition in turn led to derepression of p120 Ras-GAP, which was able to inhibit Ras. Inactivation of Rnd1 in mammary epithelial cells induced highly undifferentiated and invasive tumours in mice. Conversely, Rnd1 expression inhibited spontaneous and experimental lung colonization in mouse models of metastasis. Genomic studies indicated that gene deletion in combination with epigenetic silencing or, more rarely, point mutation inactivates RND1 in human breast cancer. These results reveal a previously unappreciated mechanism through which Rnd1 restrains activation of Ras-MAPK signalling and breast tumour initiation and progression. PMID- 25531778 TI - Dual role of YAP and TAZ in renewal of the intestinal epithelium. AB - The rapidly self-renewing intestinal epithelium represents an exquisite model for stem cell biology. So far, genetic studies in mice have uncovered crucial roles for several signalling pathways in the tissue. Here we show, by using intestine specific gene transfer (iGT), that Hippo signalling effectors, YAP and TAZ, promote both the proliferation of intestinal stem/progenitor cells and their differentiation into goblet cells. These functions of YAP/TAZ are regulated by the upstream Hippo pathway kinases MST1/2 and LATS1/2. Moreover, we identify TEADs and Klf4 as partner transcription factors of YAP/TAZ in the proliferation and differentiation processes, respectively. These results indicate that Hippo signalling plays a dual role in renewal of the intestinal epithelium through the regulation of two different processes, stem/progenitor cell proliferation and differentiation into goblet cells, using two different types of transcription factor. Moreover, iGT should provide a robust platform to elucidate molecular mechanisms of intestinal epithelium self-renewal. PMID- 25531779 TI - STRIPAK components determine mode of cancer cell migration and metastasis. AB - The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3 and MST4 kinases, which promote the co-localization of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we demonstrate that co-localization of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours migration in confined environments similar to those observed in vivo. We further show that FAM40B mutations found in human tumours uncouple it from PP2A and enable it to drive a contractile phenotype, which may underlie its role in human cancer. PMID- 25531781 TI - Therapeutic drug monitoring of atypical antipsychotic drugs. AB - Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM) of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results. PMID- 25531780 TI - Glycolytic switch in response to betulinic acid in non-cancer cells. AB - The naturally occurring triterpenoid betulinic acid (BA) shows pronounced polypharmacology ranging from anti-inflammatory to anti-lipogenic activities. Recent evidence suggests that rather diverse cellular signaling events may be attributed to the same common upstream switch in cellular metabolism. In this study we therefore examined the metabolic changes induced by BA (10 uM) administration, with focus on cellular glucose metabolism. We demonstrate that BA elevates the rates of cellular glucose uptake and aerobic glycolysis in mouse embryonic fibroblasts with concomitant reduction of glucose oxidation. Without eliciting signs of obvious cell death BA leads to compromised mitochondrial function, increased expression of mitochondrial uncoupling proteins (UCP) 1 and 2, and liver kinase B1 (LKB1)-dependent activation AMP-activated protein kinase. AMPK activation accounts for the increased glucose uptake and glycolysis which in turn are indispensable for cell viability upon BA treatment. Overall, we show for the first time a significant impact of BA on cellular bioenergetics which may be a central mediator of the pleiotropic actions of BA. PMID- 25531782 TI - Influence of different formulations and process parameters during the preparation of drug-loaded PLGA microspheres evaluated by multivariate data analysis. AB - The main objective of this study was to evaluate the influence of the formulation and process parameters on PLGA microparticles containing a practically insoluble model drug (ibuprofen) prepared by the o/w solvent evaporation method. Multivariate data analysis was used. The effects of altered stirring speed of a mechanical stirrer (600, 1000 rpm), emulsifier concentrations (PVA concentration 0.1 %, 1 %) and solvent selection (dichloromethane, ethyl acetate) on microparticle characteristics (encapsulation efficiency, drug loading, burst effect) were observed. It was found that with increased stirring speed, the PVA concentration or the use of ethyl acetate had a significantly negative effect on encapsulation efficiency. In addition, ethyl acetate had an adverse effect on the burst effect, while increased stirring speed had the opposite effect. Drug load was not affected by any particular variable, but rather by the interactions of evaluated variables. PMID- 25531783 TI - Novel thiophene derivatives with sulfonamide, isoxazole, benzothiazole, quinoline and anthracene moieties as potential anticancer agents. AB - A novel series of thiophenes having biologically active sulfonamide 2-11, 3 methylisoxazole 12, 4-methoxybenzo[d] thiazole 13, quinoline 14, 15, benzoylphenylamino 16, and anthracene-9,10-dione 17 moieties were prepared. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. All newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed cytotoxic activities compared to doxorubicin as a positive control. Compounds 6, 7, 9 and 13 (IC50 values 10.25, 9.70, 9.55 and 9.39 MUmol L-1) revealed higher cytotoxic activities than that of doxorubicin (IC50 = 32.00 MUmol L-1). Also, compounds 5, 8 and 10 were found nearly as active as doxorubicin (IC50 28.85, 23.48 and 27.51 MUmol L-1). PMID- 25531784 TI - High-performance liquid chromatography and derivative spectrophotometry for simultaneous determination of pravastatin and fenofibrate in the dosage form. AB - High performance liquid chromatography (HPLC) and second-order derivative spectrophotometry have been used for simultaneous determination of pravastatin (PS) and fenofibrate (FF) in pharmaceutical formulations. HPLC separation was performed on a phenyl HYPERSIL C18 column (125 mm * 4.6 mm i.d., 5 MUm particle diameter) in the isocratic mode using a mobile phase acetonitrile/0.1 % diethyl amine (50:50, V/V, pH 4.5) pumped at a flow rate of 1.0 mL min-1. Measurement was made at 240 nm. Both drugs were well resolved on the stationary phase, with retention times of 2.15 and 5.79 min for PS and FF, respectively. Calibration curves were linear (R = 0.999 for PS and 0.996 for FF) in the concentration range of 5-50 and 20-200 ug mL-1 for PS and FF, respectively. Pravastatin and fenofibrate were quantitated in combined preparations also using the second-order derivative response at 237.6 and 295.1 nm for PS and FF, respectively. Calibration curves were linear, with the correlation coefficient R = 0.999 for pravastatin and fenofibrate, in the concentration range of 5-20 and 3-20 ug mL-1 for PS and FF, respectively. Both methods were fully validated and compared, the results confirmed that they were highly suitable for their intended purpose. PMID- 25531785 TI - Attitudes of physicians, nurses and pharmacists concerning the development of clinical pharmacy activities in a university hospital. AB - It is essential to identify the expectations of physicians and nurses regarding clinical pharmacy (CP) services before its introduction in a hospital, because it is known that their expectations can substantially differ from the pharmacists' point of view. Agreement of leading physicians, nurses and clinical pharmacists about the importance of CP activities in the hospital was evaluated using five point Likert scale questionnaire. Two groups of CP activities were set; the activities related to the hospital system (first group) and the activities connected with an individual patient (second group). Total mean score of agreement of physicians with the first and second group of CP activities is 4.28 and 3.73, respectively, while these scores are lower for nurses (3.87 and 3.38 for the first and second group, respectively). Pharmacists' total mean scores are highest, 4.57 and 4.23 for the first and second group, respectively. PMID- 25531786 TI - Use of compounded dispersing media for extemporaneous pediatric syrups with candesartan cilexetil and valsartan. AB - Available tablets or capsules for adults are often used to prepare extemporaneously formulated medicines appropriate for children. The most acceptable drug forms in pediatric population are oral liquids and pharmacists use commercial dispersing media to compound syrups from an active substance or from tablets available on the market. In many countries ready-to-use dispersing media are not available or refunded, but pharmacists can use other compounded media, providing their compatibility and stability are proven. The aim of this study was to formulate and evaluate the stability of syrups with candesartan cilexetil (1 mg mL-1) and valsartan (4 mg mL-1) extemporaneously prepared using commercial tablets (Diovan(r) and Atacand(r)). The following three different suspending media, which could be easily made in a pharmacy, were investigated: V1 - with xanthan gum (0.5 %), V2 - the USP/NF vehicle for oral solution and V3 - the medium based on a simple sucrose syrup. The stability of preparations was studied during 35 days of storage in a dark place at controlled temperature of 25 and 4 degrees C. During the study, microscopic observation was carried out and pH, viscosity, and concentration of candesartan cilexetil and valsartan were analyzed. Syrups with valsartan prepared with V2 and V3 media were stable for 3 or 4 weeks when stored at 25 degrees C, while syrups with candesartan were stable for as long as 35 days. For syrups prepared using V1 medium, the 14-day expiry date was not achieved because of microbial deterioration. PMID- 25531787 TI - Evaluation of anti-Bothrops asper venom activity of ethanolic extract of Brownea rosademonte leaves. AB - Significant inhibition of the coagulant and hemorrhagic effects of Bothrops asper venom was demonstrated by ethanolic extract prepared from the leaves of Brownea rosademonte. In vitro experiments preincubating 5.5 mg of extract kg-1 b.m. for 30 min with a minimum hemorrhagic dose of venom (273.8 +/- 16.1 MUg of venom kg-1 b.m.) lowered the hemorrhagic activity of the venom alone in CD-1 mice by 51.5 +/ 2.6 %. Additionally, 1.7 mg extract L-1 plasma prolonged 5.1 times the plasma coagulation time. Fractionation of the extract led to the isolation of two compounds: ononitol (1) and quercetrin (2). The structure of compounds 1 and 2 was established by spectroscopic analyses, including APCI-HRMS and NMR (1H, 13C, HSQC, HMBC and COSY). A quercetrin concentration of 0.11 MUmol L-1 prolonged the plasma coagulation time 2.6 times demonstrating that this compound was one of the active constituents of the Brownea rosademonte extract. PMID- 25531788 TI - Preparation and in vitro characterization of non-effervescent floating drug delivery system of poorly soluble drug, carvedilol phosphate. AB - The objective of the study was to enhance the solubility of carvedilol phosphate and to formulate it into non-effervescent floating tablets using swellable polymers. Solid dispersions (SD) of carvedilol were prepared with hydrophilic carriers such as polyvinylpyrrolidone and poloxamer to enhance solubility. Non effervescent floating tablets were prepared with a combination of optimized solid dispersions and release retarding polymers/swellable polymers such as xanthan gum and polyethylene oxide. Tablets were evaluated for physicochemical properties such as hardness, thickness and buoyancy. SD prepared with the drug to poloxamer ratio of 1:4 by melt granulation showed a higher dissolution rate than all other dispersions. Formulations containing 40 mg of polyethylene oxide (C-P40) and 50 mg xanthan gum (C-X50) were found to be best, with the drug retardation up to 12 hours. Optimized formulations were characterized using FTIR and DSC and no drug and excipient interactions were detected. PMID- 25531789 TI - Seasonal phytochemical study and antimicrobial potential of Vetiveria zizanioides roots. AB - This paper describes the seasonal phytochemical variation and the antimicrobial potential of V. zizanioides roots collected in Brazil. Considering the high levels of chemical constituents and their biological activity in dichloromethane fraction, the plants were grown in different seasons and the respective dichloromethane fractions were analyzed by gas chromatography-mass spectrometry. The antimicrobial activity was evaluated against several pathogenic microorganisms by determining the minimum inhibitory concentration (MIC) using the agar dilution method. Yields of dichloromethane fractions from plants collected in the autumn and spring occurred in a higher proportion than in other seasons. Khusimol (2) was isolated by column chromatography and identified by NMR and CG-MS, along with other sesquiterpenes, including beta-vetivenene (1), vetiselinenol (3), isovalencenol (4), vetivenic acid (5), alpha-vetivone (6) and beta-vetivone (7). Some extracts showed promising antimicrobial effects, with MICs ranging from 31.25 to 500 MUg mL-1. Kushimol was slightly active against the tested microorganisms. PMID- 25531790 TI - TLC densitometric method for screening of lycopsamine in comfrey root (Symphytum officinale L.) extracts using retrorsine as a reference compound. AB - Due to severe toxicity of pyrrolizidine alkaloids, their quantification in medicinal products is very important. The idea of this research was to use retrorsine as a surrogate reference compound instead of lycopsamine reference or lycopsamine isolated from comfrey. A method for the analysis of lycopsamine in extracts of comfrey roots was developed and validated, employing thin layer chromatography, derivatisation with Dann-Mattocks reagent followed by densitometric analysis. The new method showed linearity within 0.70 to 7.0 MUg of lycopsamine per application of 10 MUL of a solution. It has also been proven to be specific and precise (repeatability RSD 2-4 % within the plate). The method was successfully employed for quantification of lycopsamine in comfrey root and comfrey root medicinal products such as ointments. PMID- 25531791 TI - A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep. AB - BACKGROUND: Idiopathic Pulmonary fibrosis (IPF) is a fatal respiratory disease, characterized by a progressive fibrosis and worsening lung function. While the outcomes of recent clinical trials have resulted in therapies to slow the progression of the disease, there is still a need to develop alternative therapies, which are able to prevent fibrosis. AIM: This study uses a segmental lung infusion of bleomycin (BLM) to investigate pulmonary fibrosis in a physiologically relevant large animal species. METHODS: Two separate lung segments in eight sheep received two fortnightly challenges of either 3U or 30U BLM per segment, and a third segment received saline (control). Lung function was assessed using a wedged-bronchoscope procedure. Bronchoalveolar lavage fluid and lung tissue were assessed for inflammation, fibrosis and collagen content two weeks after the final dose of BLM. RESULTS: Instillation of both BLM doses resulted in prominent fibrosis in the treated lobes. More diffuse fibrosis and loss of alveolar airspace was observed in high-dose BLM-treated segments, while multifocal fibrosis was seen in low-dose BLM-treated segments. Extensive and disorganised collagen deposition occurred in the BLM-treated lobes, compared to controls. Significant loss of lung compliance was also observed in the BLM treated lobes, which did not occur in controls. CONCLUSIONS: Fibrosis comparable to IPF was induced into isolated lung segments, without compromising the respiratory functioning of the animal. This model may have potential for investigating novel therapies for IPF by allowing direct comparison of multiple treatments with internal controls, and sampling and drug delivery that are clinically relevant. PMID- 25531792 TI - Discovery of multitarget-directed ligands against Alzheimer's disease through systematic prediction of chemical-protein interactions. AB - To determine chemical-protein interactions (CPI) is costly, time-consuming, and labor-intensive. In silico prediction of CPI can facilitate the target identification and drug discovery. Although many in silico target prediction tools have been developed, few of them could predict active molecules against multitarget for a single disease. In this investigation, naive Bayesian (NB) and recursive partitioning (RP) algorithms were applied to construct classifiers for predicting the active molecules against 25 key targets toward Alzheimer's disease (AD) using the multitarget-quantitative structure-activity relationships (mt QSAR) method. Each molecule was initially represented with two kinds of fingerprint descriptors (ECFP6 and MACCS). One hundred classifiers were constructed, and their performance was evaluated and verified with internally 5 fold cross-validation and external test set validation. The range of the area under the receiver operating characteristic curve (ROC) for the test sets was from 0.741 to 1.0, with an average of 0.965. In addition, the important fragments for multitarget against AD given by NB classifiers were also analyzed. Finally, the validated models were employed to systematically predict the potential targets for six approved anti-AD drugs and 19 known active compounds related to AD. The prediction results were confirmed by reported bioactivity data and our in vitro experimental validation, resulting in several multitarget-directed ligands (MTDLs) against AD, including seven acetylcholinesterase (AChE) inhibitors ranging from 0.442 to 72.26 MUM and four histamine receptor 3 (H3R) antagonists ranging from 0.308 to 58.6 MUM. To be exciting, the best MTDL DL0410 was identified as an dual cholinesterase inhibitor with IC50 values of 0.442 MUM (AChE) and 3.57 MUM (BuChE) as well as a H3R antagonist with an IC50 of 0.308 MUM. This investigation is the first report using mt-QASR approach to predict chemical-protein interaction for a single disease and discovering highly potent MTDLs. This protocol may be useful for in silico multitarget prediction of other diseases. PMID- 25531793 TI - Reply to "Comment on 'Structural properties of POPC monolayers under lateral compression: computer simulations analysis'". PMID- 25531795 TI - Computational and experimental study of the behavior of cyano-based ionic liquids in aqueous solution. AB - The solvation of cyano- (CN-) based ionic liquids (ILs) and their capacity to establish hydrogen bonds (H-bonds) with water was studied by means of experimental and computational approaches. Experimentally, water activity data were measured for aqueous solutions of ILs based on 1-butyl-3-methylimidazolium ([BMIM](+)) cation combined with one of the following anions: thiocyanate ([SCN]( )), dicyanamide ([DCA](-)), or tricyanomethanide ([TCM](-)), and of 1-ethyl-3 methylimidazolium tetracyanoborate ([EMIM][TCB]). From the latter data, water activity coefficients were estimated showing that [BMIM][SCN] and [BMIM][DCA], unlike [BMIM][TCM] and [EMIM][TCB], are able to establish favorable interactions with water. Computationally, the conductor like screening model for real solvents (COSMO-RS) was used to estimate the water activity coefficients which compare well with the experimental ones. From the COSMO-RS results, it is suggested that the polarity of each ion composing the ILs has a strong effect on the solvation phenomena. Furthermore, classical molecular dynamics (MD) simulations were performed for obtaining an atomic level picture of the local molecular neighborhood of the different species. From the experimental and computational data it is showed that increasing the number of CN groups in the ILs' anions does not enhance their ability to establish H-bonds with water but decreases their polarities, being [BMIM][DCA] and [BMIM][SCN] the ones presenting higher propensity to interact. PMID- 25531794 TI - Simulations reveal adverse hemodynamics in patients with multiple systemic to pulmonary shunts. AB - For newborns diagnosed with pulmonary atresia or severe pulmonary stenosis leading to insufficient pulmonary blood flow, cyanosis can be mitigated with placement of a modified Blalock-Taussig shunt (MBTS) between the innominate and pulmonary arteries. In some clinical scenarios, patients receive two systemic-to pulmonary connections, either by leaving the patent ductus arteriosus (PDA) open or by adding an additional central shunt (CS) in conjunction with the MBTS. This practice has been motivated by the thinking that an additional source of pulmonary blood flow could beneficially increase pulmonary flow and provide the security of an alternate pathway in case of thrombosis. However, there have been clinical reports of premature shunt occlusion when more than one shunt is employed, leading to speculation that multiple shunts may in fact lead to unfavorable hemodynamics and increased mortality. In this study, we hypothesize that multiple shunts may lead to undesirable flow competition, resulting in increased residence time (RT) and elevated risk of thrombosis, as well as pulmonary overcirculation. Computational fluid dynamics-based multiscale simulations were performed to compare a range of shunt configurations and systematically quantify flow competition, pulmonary circulation, and other clinically relevant parameters. In total, 23 cases were evaluated by systematically changing the PDA/CS diameter, pulmonary vascular resistance (PVR), and MBTS position and compared by quantifying oxygen delivery (OD) to the systemic and coronary beds, wall shear stress (WSS), oscillatory shear index (OSI), WSS gradient (WSSG), and RT in the pulmonary artery (PA), and MBTS. Results showed that smaller PDA/CS diameters can lead to flow conditions consistent with increased thrombus formation due to flow competition in the PA, and larger PDA/CS diameters can lead to insufficient OD due to pulmonary hyperfusion. In the worst case scenario, it was found that multiple shunts can lead to a 160% increase in RT and a 10% decrease in OD. Based on the simulation results presented in this study, clinical outcomes for patients receiving multiple shunts should be critically investigated, as this practice appears to provide no benefit in terms of OD and may actually increase thrombotic risk. PMID- 25531796 TI - A prospective longitudinal study of growth and pubertal progress in adolescents with inflammatory bowel disease. AB - BACKGROUND: Puberty and growth may be affected in inflammatory bowel disease (IBD) but the extent is unclear. METHODS: We performed a prospective study over 12 months in 63 adolescents (Crohn's disease, CD, n = 45; ulcerative colitis/IBD unclassified, UC, n = 18) with a median age of 13.4 years (range 10-16.6). Assessment included anthropometry, biochemical markers of growth and puberty and an assessment of quality of life by IMPACT-III. RESULTS: Compared to the normal population, boys with CD were shorter, with a median height SDS (HtSDS) of -0.13 (-2.52 to 1.58; p < 0.05). In addition, the study cohort had a lower median IGF-1 SDS of -0.29 (-4.53 to 2.96; p = 0.008) and a higher median IGFBP3 SDS of 0.45 ( 3.15 to 2.55; p = 0.002). Over the study period, the median Ht velocity (HV) was 5 cm/year (0.2-8.7) and the change in HtSDS was 0.06 (-0.48 to 0.57). The median difference between the chronological and bone age was 0.3 years (-2.5 to 3.0) and pubertal examination was not delayed. In the whole group, the erythrocyte sedimentation rate (ESR) showed an inverse association with HV (r = -0.29; p = 0.025) and IGF-1:IGFBP3 (r = -0.34; p = 0.016). The score in the body image domain, IMPACT-III, was inversely associated with HtSDS (r = -0.31; p = 0.03). CONCLUSION: Despite no evidence of pubertal delay, adolescents with IBD display growth retardation which may be associated with raised ESR, adverse quality of life measures and an abnormality of IGF-1 bioavailability. PMID- 25531798 TI - Graphene quantum dots coated VO2 arrays for highly durable electrodes for Li and Na ion batteries. AB - Nanoscale surface engineering is playing important role in enhancing the performance of battery electrode. VO2 is one of high-capacity but less-stable materials and has been used mostly in the form of powders for Li-ion battery cathode with mediocre performance. In this work, we design a new type of binder free cathode by bottom-up growth of biface VO2 arrays directly on a graphene network for both high-performance Li-ion and Na-ion battery cathodes. More importantly, graphene quantum dots (GQDs) are coated onto the VO2 surfaces as a highly efficient surface "sensitizer" and protection to further boost the electrochemical properties. The integrated electrodes deliver a Na storage capacity of 306 mAh/g at 100 mA/g, and a capacity of more than 110 mAh/g after 1500 cycles at 18 A/g. Our result on Na-ion battery may pave the way to next generation postlithium batteries. PMID- 25531797 TI - In vivo visualization of prostate brachytherapy seeds with photoacoustic imaging. AB - We conducted a canine study to investigate the in vivo feasibility of photoacoustic imaging for intraoperative updates to brachytherapy treatment plans. A fiber coupled to a 1064-nm Nd:YAG laser was inserted into high-dose-rate brachytherapy needles, which diffused light spherically. These needles were inserted through the perineum into the prostate for interstitial light delivery and the resulting acoustic waves were detected with a transrectal ultrasound probe. Postoperative computed tomography images and ex vivo photoacoustic images confirmed seed locations. Limitations with insufficient light delivery were mitigated with short-lag spatial coherence (SLSC) beamforming, providing a 10-20 dB contrast improvement over delay-and-sum (DAS) beamforming for pulse energies ranging from 6.8 to 10.5 mJ with a fiber-seed distance as large as 9.5 mm. For the same distance and the same range of energy densities, signal-to-noise ratios (SNRs) were similar while the contrast-to-noise ratio (CNR) was higher in SLSC compared to DAS images. Challenges included visualization of signals associated with the interstitial fiber tip and acoustic reverberations between seeds separated by <= 2 mm. Results provide insights into the potential for clinical translation to humans. PMID- 25531799 TI - Effects of interaction experiences and undergraduate coursework on attitudes toward gay and lesbian issues. AB - College experiences can expand knowledge, decrease negative stereotypes, and increase acceptance toward diversity, especially regarding gay and lesbian issues. This study found that the more interaction undergraduate students have with gay and lesbian people on campus, the more accepting their attitudes are regarding (1) same-sex, consensual sex, (2) same-sex relations between adults is not unnatural, (3) vote for a gay presidential candidate, (4) friends with a feminine man, (5) friends with a masculine woman, (6) knowledge of GL issues important for future career, and (7) comfortable with GL roommate. Furthermore, the more undergraduate students are exposed to coursework addressing gay and lesbian issues, the more positive their attitudes are regarding the importance of knowledge of gay/lesbian issues for future career and comfort with a gay/lesbian roommate. Discussion explores possible long-term implications of systematic interaction experiences and coursework at all levels within the educational system to prevent negative attitude formation. PMID- 25531800 TI - Severe delayed hemolysis associated with regulated parenteral antimalarial drug. PMID- 25531801 TI - North American ginseng protects against muscle damage and reduces neutrophil infiltration after an acute bout of downhill running in rats. AB - Eccentric muscle contractions such as those experienced during downhill running are associated with inflammation, delayed-onset of muscle soreness, myofiber damage, and various functional deficits. North American ginseng (Panax quinquefolius L.) has been reported to possess anti-inflammatory properties and thus may offset some of this exercise-induced damage. Hence, we tested the hypothesis that intervention with North American ginseng would reduce eccentric exercise-induced muscle damage and inflammation. Male Wistar rats were fed (300 mg/(kg.day)(-1)) of either an alcohol (AL) or aqueous (AQ) extract of North American ginseng for 14 days before a single bout of downhill running and were compared with matching nonexercised (C) groups. Plasma creatine kinase levels were significantly reduced in both ginseng treated groups compared with the C group that received a water placebo (p < 0.002). Further, the AQ but not AL group also showed attenuated morphological signs of damage (hemotoxylin and eosin) as well as reduced levels of infiltrating neutrophils (HIS48) in the soleus muscle (p < 0.001). In summary, supplementation with an AQ but not AL extract of North American ginseng was able to reduce eccentric exercise-induced muscle damage and inflammation. PMID- 25531802 TI - Nickel(II) complexes with a flexible piperazinyl moiety: studies on DNA and protein binding and catecholase like properties. AB - Four new mononuclear Ni(ii) complexes [Ni(L(1))]ClO4 (), [Ni(L(2))]ClO4(), [Ni(SCN)3(CH3OH)(aminoethylpiperazineH)] (), and [Ni(DMSO)4(aminoethylpiperazineH)](ClO4)3()have been synthesized from two Schiff base ligands [L(1) = 1-phenyl-3-((2-(piperidin-4-yl)ethyl)imino)but-1-en-1-ol and L(2) = 4-((2-(piperazin-1-yl)ethyl)imino)pent-2-en-2-ol] by exploiting the flexibility of the piperazinyl moiety. Structural analysis reveals that and are square planar complexes with piperazine rings in boat conformations whereas hydrolysis of Schiff bases (L(1) and L(2)) occurs during formation of octahedral complexes ( and ) with piperazine rings in chair conformations. Screening tests were conducted to quantify the binding ability of complexes (, and ) towards DNA, BSA and HSA and it was found that square planar complexes ( and ) showed more effective binding properties over octahedral complex (). Furthermore, enzyme kinetic studies reflect that square planar complexes ( and ) are also effective in mimicking catecholase like activities over octahedral complex (). Among all the complexes, was found to be the most promising molecule among the series due to its large binding affinity towards different bio-macromolecules and higher T.O.N in the catechol oxidation reaction. PMID- 25531803 TI - Two-dimensional nuclear magnetic resonance: exploiting spin echoes to maximize information content by suppression of diagonal peaks in homonuclear experiments. AB - Two-dimensional nuclear magnetic resonance (2D NMR) correlation spectra help visualize inter- or intra-molecular spin connectivity through space or through bonds. This is accomplished by magnetization transfer between interacting ("connected") spins located at different sites in molecules. In homonuclear 2D experiments, cross peaks which demonstrate spin connectivity and result from magnetization transfer between sites are unfortunately invariably accompanied by other peaks that result from magnetization that has not undergone any transfer, viz., diagonal peaks. The latter can often mask close-lying cross peaks. We report here the general principles that constitute a design strategy for diagonal suppression, relying on echo formation. Next, a novel experiment that effects diagonal suppression in the high-resolution mode is demonstrated. Pure phase capability is also introduced. Examples from both 2D exchange and high-resolution 2D correlation spectroscopy are included, and the proposed method is compared with other established as well as recent attempts to accomplish diagonal suppression. PMID- 25531804 TI - Fatal legionellosis after water birth, Texas, USA, 2014. AB - In 2014, a fatal infection with Legionella pneumophila serogroup 1 occurred in a neonate after a water birth. The death highlighted the need for infection control education, client awareness, and standardization of cleaning procedures in Texas midwife facilities. PMID- 25531805 TI - Carbohydrate receptors combining both a macrocyclic building block and flexible side arms as recognition units: design, syntheses, and binding studies. AB - Carbohydrate receptors combining a macrocyclic building block and two flexible side arms were designed on the base of the analysis of the binding motifs found in the crystal structures of the complexes formed between artificial receptors and monosaccharides, reported previously by our group. Binding studies in two phase systems, such as extractions of sugars from water into organic phase, as well as in homogeneous organic media, using (1)H NMR and fluorescence spectroscopic titrations, confirmed the suitability of the designed compounds to act as highly effective and selective carbohydrate receptors. Depending on the nature of the bridges and side arms used as the building blocks, various receptors with different binding properties could be developed. The obtained results confirmed the validity of the receptor design and revealed that crystalline receptor-sugar complexes are particularly a valuable basis for the design of new effective receptor systems. PMID- 25531806 TI - The core self-evaluation scale: psychometric properties of the german version in a representative sample. AB - The Core Self-Evaluation Scale (CSES) is an economical self-reporting instrument that assesses fundamental evaluations of self-worthiness and capabilities. The broad aims of this study were to test the CSES's psychometric properties. The study is based on a representative survey of the German general population. Confirmatory factor analyses were conducted for different models with 1, 2, and 4 latent factors. The CSES was found to be reliable and valid, as it correlated as expected with measures of depression, anxiety, quality of life, self-report health status, and pain. A 2-factor model with 2 related factors (r = -.62) showed the best model fit. Furthermore, the CSES was measurement invariant across gender and age. In general, males had higher values of positive self-evaluations and lower negative self-evaluations than females. It is concluded that the CSES is a useful tool for assessing resource-oriented personality constructs. PMID- 25531807 TI - In-vivo RGB marking and multicolour single-cell tracking in the adult brain. AB - In neuroscience it is a technical challenge to identify and follow the temporal and spatial distribution of cells as they differentiate. We hypothesised that RGB marking, the tagging of individual cells with unique hues resulting from simultaneous expression of the three basic colours red, green and blue, provides a convenient toolbox for the study of the CNS anatomy at the single-cell level. Using gamma-retroviral and lentiviral vector sets we describe for the first time the in-vivo multicolour RGB marking of neurons in the adult brain. RGB marking also enabled us to track the spatial and temporal fate of neural stem cells in the adult brain. The application of different viral envelopes and promoters provided a useful approach to track the generation of neurons vs. glial cells at the neurogenic niche, allowing the identification of the prominent generation of new astrocytes to the striatum. Multicolour RGB marking could serve as a universal and reproducible method to study and manipulate the CNS at the single cell level, in both health and disease. PMID- 25531808 TI - Assessment of acceptability and usability of new delivery prototype device for intradermal vaccination in healthy subjects. AB - The objectives of this study were to assess the acceptability and usability of a newly developed intradermal prototype device, VAX-IDTM, in healthy subjects. In April 2012 an investigational study was conducted in healthy subjects aged 18 to 65 y. To compare injection site and route of administration, subjects were allocated to 4 subgroups, either receiving subsequently 2 intradermal (ID) injections (one in the forearm and one in the deltoid) or an ID (forearm) and an intramuscular (IM) (deltoid) injection. All injections contained saline solution. Acceptability was assessed with a subjects' questionnaire and a daily electronic diary for 5 d. Usability was assessed with a vaccinators' questionnaire and an expert panel. A 10-point Visual Analog Scale was used to score several statements on usability and acceptability. A total of 102 healthy subjects were enrolled in the study (age: 19-63). No statistically significant differences were seen in demographic characteristics between the ID and IM groups. Anxiety before injection, pain during injection and duration of injection were rated significantly lower for ID compared to IM. One day after the injections, redness was reported more often after ID injection in the forearm versus ID in the deltoid; pain at injection site was reported significantly more often after IM vs. ID injection. The new VAX-ID prototype device was found easy to handle, easy to use and safe. The new VAX-ID prototype device was shown to have a high degree of acceptability as well as usability. Further studies with VAX-ID will be conducted using vaccine antigen allowing assessment of immunogenicity and safety. Additionally, these studies will help to further improve VAX-ID in terms of accuracy of delivered dose and feedback to the vaccinator. (NCT01963338). PMID- 25531809 TI - Charge gradient-induced on-surface growth of ultralarge single-crystalline Ag nanomembranes for long surface plasmon propagation. AB - A facile strategy for the fabrication of ultralarge (edge length >50 MUm), single crystalline Ag nanomembranes is reported in this work. The Ag nanomembrane with an atomically smooth surface demonstrates a much longer surface plasmonic propagation length as compared to vacuum-deposited polycrystalline Ag film, representing superior plasmonic properties. PMID- 25531810 TI - Diastereoselective synthesis of propargylic N-hydroxylamines via NHC-copper(I) halide-catalyzed reaction of terminal alkynes with chiral nitrones on water. AB - The first NHC-copper(I)-halide catalyzed addition of terminal alkynes to enantiomerically pure nitrones on water is described. This reaction provides a straightforward access to propargylic N-hydroxylamines in excellent yield and with excellent stereoselectivity (up to 97%). The presented methodology was applied as a key step in the formal synthesis of (-)-lentiginosine. PMID- 25531811 TI - Altered inhibitory function of the E-type prostanoid receptor 4 in eosinophils and monocytes from aspirin-intolerant patients. AB - Prostaglandin (PG) E2 has been implicated in the pathogenesis of aspirin exacerbated respiratory disease (AERD). E-type prostanoid (EP) receptor 4 is known to confer inhibitory signals to eosinophils and monocytes, amongst others. In this study, we investigated whether the responsiveness of eosinophils and monocytes to PGE2 and EP4 receptor activation is altered in AERD patients. While the expression of the EP4 receptor in eosinophils was unaltered in AERD patients, inhibition of eosinophil chemotaxis by PGE2 or the EP4 agonist CAY10598 was less pronounced in AERD patients as compared to healthy control subjects. In monocytes, we found no changes in basal or lipopolysaccharide (LPS)-stimulated PGE2 synthesis, but the response to EP4 receptor activation with respect to inhibition of LPS-induced tumor necrosis factor-alpha release was reduced in AERD patients, especially in the presence of aspirin (acetylsalicylic acid). Our data point towards a decreased sensitivity of inhibitory EP4 receptor that may play a role in AERD. PMID- 25531813 TI - Mitochondrial Aging: Focus on Mitochondrial DNA Damage in Atherosclerosis - A Mini-Review. AB - Atherosclerosis is a complex disease which can be described as an excessive fibrofatty, proliferative, inflammatory response to damage to the artery wall involving several cell types such as smooth muscle cells, monocyte-derived macrophages, lymphocytes, dendritic cells and platelets. On the other hand, atherosclerosis is a typical age-related degenerative pathology, which is characterized by signs of cell senescence in the arterial wall including reduced cell proliferation, irreversible growth arrest and apoptosis, increased DNA damage, the presence of epigenetic modifications, shortening of telomere length and mitochondrial dysfunction. The most prominent characteristics of mitochondrial aging are their structural alterations and mitochondrial DNA damage. The mechanisms of mitochondrial genome damage in the development of chronic age-related diseases such as atherosclerosis are not yet well understood. This review focuses on the latest findings from studies of those mutations of the mitochondrial genome which may play an important role in the development of atherosclerosis and which are, at the same time, also markers of mitochondrial aging and cell senescence. PMID- 25531815 TI - Quantile regression in environmental health: Early life lead exposure and end-of grade exams. AB - Conditional means regression, including ordinary least squares (OLS), provides an incomplete picture of exposure-response relationships particularly if the primary interest resides in the tail ends of the distribution of the outcome. Quantile regression (QR) offers an alternative methodological approach in which the influence of independent covariates on the outcome can be specified at any location along the distribution of the outcome. We implemented QR to examine heterogeneity in the influence of early childhood lead exposure on reading and math standardized fourth grade tests. In children from two urban school districts (n=1,076), lead exposure was associated with an 18.00 point decrease (95% CI: 48.72, -3.32) at the 10th quantile of reading scores, and a 7.50 point decrease (95% CI: -15.58, 2.07) at the 90th quantile. Wald tests indicated significant heterogeneity of the coefficients across the distribution of quantiles. Math scores did not show heterogeneity of coefficients, but there was a significant difference in the lead effect at the 10th (beta=-17.00, 95% CI: -32.13, -3.27) versus 90th (beta=-4.50, 95% CI: -10.55, 4.50) quantiles. Our results indicate that lead exposure has a greater effect for children in the lower tail of exam scores, a result that is masked by conditional means approaches. PMID- 25531814 TI - Bisphenol A, benzophenone-type ultraviolet filters, and phthalates in relation to uterine leiomyoma. AB - Bisphenol A, benzophenone-type UV filters, and phthalates are chemicals in high production and use including in a range of personal care products. Exposure of humans to these chemicals has been shown to affect endocrine function. Although short-lived, widespread exposure may lead to continual opportunity for these chemicals to elicit health effects in humans. The association of these chemicals with incident uterine leiomyoma, an estrogen sensitive disease, is not known. Urinary concentrations of bisphenol A (BPA), five benzophenone-type UV filters (2 hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH BP), 2,2'-dihydroxybenzophenone (2,2'OH-4MeO-BP), 2,2'4,4' tetrahydroxybenzophenone (2,2'4,4'OH-BP), and 4-hydroxybenzophenone (4OH-BP), and 14 phthalate monoesters were quantified in 495 women who later underwent laparoscopy/laparotomy at 14 clinical sites for the diagnosis of fibroids. Significantly higher geometric mean creatinine-corrected concentrations of BPA, 2,4OH-BP, and 2OH-4MeO-BP were observed in women with than without fibroids [BPA: 2.09ug/g vs. 1.46ug/g p=0.004; 2,4OH-BP:11.10ug/g vs. 6.71ug/g p=0.01; 2OH-4MeO BP: 11.31ug/g vs. 6.10ug/g p=0.01]. Mono-methyl phthalate levels were significantly lower in women with than without fibroids (1.78ug/g vs. 2.40ug/g). However, none of the exposures were associated with a significant odds ratio even when adjusting for relevant covariates. There was a lack of an association between select nonpersistent chemicals and the odds of a fibroid diagnosis. PMID- 25531816 TI - Urinary levels of endocrine-disrupting chemicals, including bisphenols, bisphenol A diglycidyl ethers, benzophenones, parabens, and triclosan in obese and non obese Indian children. AB - Obesity has been recognized as a major global public health concern. In particular, childhood obesity is a major risk factor for other health issues, such as type 2 diabetes, in later stages of life. A few earlier studies have associated exposure to endocrine-disrupting chemicals (EDCs) with childhood obesity. There is limited information, however, on exposure to EDCs and childhood obesity in India. In this study, urinary levels of 26 EDCs were determined in 49 obese and 27 non-obese Indian children. Eleven EDCs, including 2,2-bis(4 hydroxyphenyl)propane (BPA), 4,4'-sulfonyldiphenol (BPS), methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), 4-hydroxybenzoic acid (4-HB), 3,4 dihydroxybenzoic acid (3,4-DHB), triclosan (TCS), benzophenone-3 (BP3), bisphenol A diglycidyl ether (BADGE), and bisphenol A bis(2,3-dihydroxypropyl) glycidyl ether (BADGE.2H2O) were found in >70% of urine samples. No significant associations were found between childhood obesity and most target chemicals studied, except for 3,4-DHB, which showed a significant positive association. Urinary concentrations of 3,4-DHB were higher in obese children than in non-obese children, independent of age, sex, family income, parent education, physical activity, and urinary creatinine. Urinary concentrations of several EDCs were higher in Indian children than the concentrations reported for children in the USA and China. To our knowledge, this is the first study to report urinary concentrations of several EDCs in Indian children. PMID- 25531817 TI - An investigation into porch dust lead levels. AB - Lead in porch dust can expose children through direct contact or track-in to the home, but has not been adequately evaluated. At homes undergoing lead hazard control in Rochester, NY, we sampled settled dust lead on exterior porch floors at baseline, immediately post-lead hazard control and one-year post-work (n=79 homes with complete data) via wipe sampling and collected housing, neighborhood and soil data. Baseline GM porch floor dust lead loading (PbPD) was 68 ug/ft(2), almost four times more than baseline GM interior floor dust lead (18 ug/ft(2)). Immediate post-work PbPD declined 55% after porch floor replacement and 53% after porch floor paint stabilization (p=0.009 and p=0.041, respectively). When no porch floor work was conducted but lead hazard control was conducted elsewhere, immediate post-work PbPD increased 97% (p=0.008). At one-year, GM PbPD continued to decline for porch replacement (77% below baseline) and paint stabilization (72% below baseline), but where no porch floor work was done, GM PbPD was not significantly different than baseline (p<0.001, p=0.028 and p=0.504, respectively). Modeling determined that porch floor replacement had significantly lower one-year PbPD than stabilization when baseline PbPD levels were higher than 148 ug/ft(2) (the 77th percentile) but not at lower levels. Treatment of porches with lead paint results in substantial declines in PbPD levels. It is of concern that PbPD levels increased significantly at immediate post-work when lead hazard control was not conducted on the porch but was conducted elsewhere. Standards for porch lead dust should be adopted to protect children from inadequate clean-up after lead hazard control. PMID- 25531812 TI - Rarity of the Alzheimer disease-protective APP A673T variant in the United States. AB - IMPORTANCE: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS: Case control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. CONCLUSIONS AND RELEVANCE: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations. PMID- 25531818 TI - Health impact assessment of traffic noise in Madrid (Spain). AB - The relationship between environmental noise and health has been examined in depth. In view of the sheer number of persons exposed, attention should be focused on road traffic noise. The city of Madrid (Spain) is a densely populated metropolitan area in which 80% of all environmental noise exposure is attributed to traffic. The aim of this study was to quantify avoidable deaths resulting from reducing the impact of equivalent diurnal noise levels (LeqD) on daily cardiovascular and respiratory mortality among people aged >=65 years in Madrid. A health impact assessment of (average 24h) LeqD and PM2.5 levels was conducted by using previously reported risk estimates of mortality rates for the period 2003-2005: For cardiovascular causes: LeqD 1.048 (1.005, 1.092) and PM2.5 1.041(1.020, 1.062) and for respiratory causes: LeqD 1.060 (1.000, 1.123) and PM2.5 1.030 (1.000, 1.062). The association found between LeqD exposure and mortality for both causes suggests an important health effect. A reduction of 1dB(A) in LeqD implies an avoidable annual mortality of 284 (31, 523) cardiovascular- and 184 (0, 190) respiratory-related deaths in the study population. The magnitude of the health impact is similar to reducing average PM2.5 levels by 10ug/m(3). Regardless of air pollution, exposure to traffic noise should be considered an important environmental factor having a significant impact on health. PMID- 25531819 TI - Urban air and tobacco smoke as conditions that increase the risk of oxidative stress and respiratory response in youth. AB - BACKGROUND: Air pollution and tobacco smoke can induce negative effects on the human health and often leads to the formation of oxidative stress. OBJECTIVE: The purpose of this study was to clarify the role of the urbanization degree and of passive exposure to tobacco smoke in the formation of oxidative stress. Thus, a group of non-smoking adolescents was recruited among those who live and attend school in areas with three different population densities. To each subject a spot of urine was collected to quantify 15-F2t isoprostane as a marker of oxidative stress and cotinine as a marker of passive exposure to tobacco smoke. Furthermore, respiratory functionality was also measured. RESULTS: Multiple linear regression analysis results showed a direct correlation (p<0.0001) of 15 F2t isoprostane with both the urbanization and passive smoke. Lung function parameters proved significantly lower for the subjects living in the most populous city of Torino. CONCLUSION: This remarks the negative effect that urbanization has on the respiratory conditions. Lastly, lung functionality presented a low inverse correlation with 15-F2t isoprostane, suggesting an independent mechanism than that of the urban factor. PMID- 25531820 TI - Serologic assessment of possibility for MERS-CoV infection in equids. PMID- 25531821 TI - Health-related quality of life after solid organ transplantation: the role of sport activity. AB - The aim of the study was to investigate the effects of sport activity on health related quality of life (HRQoL) of solid organ transplant recipients participating in sports competitions. A group of 168 sportive transplanted patients (STP), a group of 97 nonsportive transplanted patients (NSTP), and a group of 152 sportive healthy controls (SHC) were compared on the eight scales of the SF-36 questionnaire. STP and NSTP reported significantly lower scores than SHC on the physical functioning scale. STP did not differ from SHC in the Role Physical, General Health, and Vitality scales, while NSTP reported significantly lower scores. STP obtained higher scores than NSTP and SHC on Mental Health. Among STP, the effect of quantity of sport activity was significant on General Health and Role Emotional, with more sport activity associated with higher HRQoL. Organ failure and post-transplant therapies may have negative consequences on HRQoL. Sports activities and participation in sports competitions can reduce this impact, improving general and psychological functioning of solid organ transplant recipients. PMID- 25531822 TI - Structural effects of the dispersing agent polysorbate 80 on liquid crystalline nanoparticles of soy phosphatidylcholine and glycerol dioleate. AB - Well-defined, stable and highly structured I2 (Fd3m) liquid crystalline nanoparticles (LCNP) of 50/50 (wt/wt) soy phosphatidylcholine (SPC)/glycerol dioleate (GDO), can be formed by using a low fraction (5-10 wt%) of the dispersing polymeric surfactant polyoxyethylene (20) sorbitan monooleate (polysorbate 80 or P80). In the present study we used small angle neutron scattering (SANS) and deuterated P80 (d-P80) to determine the location and concentration of P80 within the LCNP and small angle X-ray scattering (SAXS) to reveal the internal structure. SANS data suggests that some d-P80 already penetrates the particle core at 5%. However, the content of d-P80 is still low enough not to significantly change the internal Fd3m structure of the LCNP. At higher fractions of P80 a phase separation occurs, in which a SPC and P80 rich phase is formed at the particle surface. The surface layer becomes gradually richer in both solvent and d-P80 when the surfactant concentration is increased from 5 to 15%, while the core of the particle is enriched by GDO, resulting in loss of internal structure and reduced hydration. We have used neutron reflectometry to reveal the location of the stabiliser within the adsorbed layer on an anionic silica and cationic (aminopropyltriethoxysilane (APTES) silanized) surface. d-P80 is enriched closest to the supporting surface and slightly more so for the cationic APTES surface. The results are relevant not only for the capability of LCNPs as drug delivery vehicles but also as means of preparing functional surface coatings. PMID- 25531823 TI - Keeping the secret: how HIV-positive children in Iringa, Tanzania, respond to the perceived need for silence and secrecy. AB - Children who live with HIV may experience two aspects of disclosure: receiving disclosure and disclosing their status to others. The objective of this paper is to explore how HIV-positive children respond to: (1) the disclosure process; and (2) the perceived need for secrecy and silence concerning living with HIV. Thirteen HIV-positive children between the ages of 10 and 15 years were recruited through a HIV treatment centre in Iringa, Tanzania. Data were collected through in-depth interviews with the children and staff members. The children received disclosure about their status from healthcare workers rather than caregivers. Several children were asked by their caregivers to keep their status secret, some chose to do so themselves, largely to avoid experienced or perceived stigma from the community. Secrecy had an impact on potentially supportive relationships. Children tend to mimic adult responses, including partial disclosure and lying to others. PMID- 25531825 TI - Excess mortality, mental illness and global burden of disease. PMID- 25531826 TI - Synthesis and characterization of 1,2,3,4,5-pentafluoroferrocene. AB - Starting from ferrocene, pentafluoroferrocene [Fe(C5F5)(C5H5)] can be prepared in five steps via a one-pot lithiation-electrophilic fluorination strategy. Pentafluoroferrocene was characterized by multinuclear NMR and IR spectroscopy, by cyclovoltammetry as well as X-ray (solid) and electron diffraction (gas) and the experimental results compared with DFT calculations. PMID- 25531824 TI - Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML associated mutants. AB - Nucleophosmin (NPM1) is a multifunctional phosphoprotein localized predominantly within the nucleoli of eukaryotic cells. Mutations within its C-terminal domain are frequently observed in patients with acute myeloid leukemia (AML), are thought to play a key role in the initiation of the disease, and result in aberrant, cytoplasmic localization of the mutant protein. We have previously shown that the electrophilic antiproliferative natural product (+) avrainvillamide (1) binds to proteins, including nucleophosmin, by S-alkylation of cysteine residues. Here, we report that avrainvillamide restores nucleolar localization of certain AML-associated mutant forms of NPM1 and provide evidence that this relocalization is mediated by interactions of avrainvillamide with mutant NPM1 and exportin-1 (Crm1). Immunofluorescence and mass spectrometric experiments employing a series of different NPM1 constructs suggest that a specific interaction between avrainvillamide and Cys275 of certain NPM1 mutants mediates the relocalization of these proteins to the nucleolus. Avrainvillamide treatment is also shown to inhibit nuclear export of Crm1 cargo proteins, including AML-associated NPM1 mutants. We also observe that avrainvillamide treatment displaces Thr199-phosphorylated NPM1 from duplicated centrosomes, leads to an accumulation of supernumerary centrosomes, and inhibits dephosphorylation of Thr199-phosphorylated NPM1 by protein phosphatase 1. Avrainvillamide is the first small molecule reported to relocalize specific cytoplasmic AML-associated NPM1 mutants to the nucleolus, providing an important demonstration of principle that small molecule induction of a wild-type NPM1 localization phenotype is feasible in certain human cancer cells. PMID- 25531827 TI - Estimation of background incidence rates of Guillain-Barre syndrome in Germany - a retrospective cohort study with electronic healthcare data. AB - BACKGROUND: The Guillain-Barre syndrome (GBS) occurs after infections and as an adverse reaction to vaccines. No detailed information on incidence rates (IRs) in Germany is available. METHODS: This retrospective cohort study estimated age- and sex-specific IRs of GBS in Germany in the years 2007-2009 based on electronic healthcare data from the German Pharmacoepidemiological Research Database (GePaRD). Two case definitions were applied. GBS cases had a main discharge diagnosis of GBS. GBS_PROCEDURE cases in addition had codes for relevant diagnostic procedures. Crude and standardized IRs (SIRs) with 95% confidence intervals were stratified by year, age group, sex, region and season. IR ratios (IRRs) for each stratification factor were calculated by multivariable Poisson regression. RESULTS: Among 13,297,678 persons, 889 (693) incident GBS (GBS_PROCEDURE) cases were identified. Overall SIRs per 100,000 person years were 2.4 (2.2-2.5) for GBS and 1.8 (1.7-2.0) for GBS_PROCEDURE. (S)IRs increased with age, peaking in the age group 70-79 years (IR GBS: 5.5 (4.7-6.5)) and were higher in males than in females (e.g., IR GBS: IRR = 1.5 (1.3-1.7)) and in February April, as compared to the rest of the year. No regional pattern was observed. CONCLUSION: (S)IRs of GBS in Germany differed by age, sex and season and were comparable to those found in other studies. RESULTS might be used as a comparator in vaccine safety monitoring. PMID- 25531828 TI - Mortality prediction using modern peptide biomarkers in hemodialysis patients--a comparative analysis. AB - BACKGROUND/AIMS: Determination of peptide biomarkers such as troponins, natriuretic peptides or the recently reported FGF23 can be useful to identify hemodialysis patients with a high risk of mortality. However, it is desirable to focus on few robust parameters to warrant their routine application. METHODS: In a prospective cohort study with 239 prevalent hemodialysis patients we studied the prognostic significance of 10 simultaneously determined modern peptide biomarkers (high sensitive troponin I and T, NT-pro-BNP, BNP, MR-pro-ANP, MR-pro ADM, CT-pro-ET1, copeptin, FGF23 and a-Klotho) and compared them with parameters traditionally associated with mortality (PTH, Ca, Pi, albumin, CRP, cholesterol, AP). RESULTS: After a follow-up of 4 years, plasma concentration of troponins, natriuretic peptides, MR-pro-ADM, FGF23 as well as PTH, CRP, AP were significantly higher in deceased patients (n=95). Hazard ratios from cox regression on a continuous scale (doubling of plasma concentration) or relative in tertiles were highest for high sensitive troponins, followed by natriuretic peptides and MR-pro-ADM (1.6-2.0 and 2.3-5.5, resp.). C-indices were also highest for troponins (0.708-0.746), followed by natriuretic peptides (0.706-0.731). Traditional parameters had low c-indices (0.598-0.655). Stepwise cox regression revealed that among all parameters troponin I, NT-pro-BNP, PTH and CRP remained independent predictors of mortality and a composite score had the highest c-index (0.799 [0.740-0.849]). CONCLUSIONS: Among peptide biomarkers high sensitive troponins and to a lesser extent natriuretic peptides are strong predictors of mortality in asymptomatic hemodialysis patients, followed by markers of mineral bone disease and inflammation. PMID- 25531829 TI - The effects of kidney transplantation on sleep, melatonin, circadian rhythm and quality of life in kidney transplant recipients and living donors. AB - BACKGROUND: Sleep disturbance is an important medical problem in patients with end-stage renal disease. It might be related to the disruption of the body's circadian clock since nocturnal levels of its key biomarker melatonin are markedly reduced. We aimed at investigating whether a change in renal function due to kidney transplantation or donation would modify sleep, melatonin levels, circadian rhythmicity, and quality of life in kidney transplant recipients (KTR) and living donors (LD). METHODS: In KTR, we assessed saliva melatonin concentrations, sleep quality and daytime sleepiness prior to and at 2 weeks and 3 months after transplantation. In LD, we assessed these parameters prior to and at 3 months after donation. We additionally assessed 24-hour core body temperature (cBT), 24-hour blood pressure profile, and quality of life (QoL) prior to and 3 months after transplantation. RESULTS: Twenty-three KTR and 23 LD completed the study. Regarding sleep, the amount of nighttime awake minutes tended to be reduced in recipients after transplantation (p = 0.05). Nocturnal melatonin concentrations did not change with transplantation or donation. Blood pressure dipping profile and the two circadian markers dim-light melatonin onset and time of core body temperature minimum did not change. Nevertheless, KTR reported that daytime sleepiness and QoL had improved. CONCLUSION: Objectively nocturnal sleep quality marginally improved after transplantation. Subjectively patients reported improved QoL and daytime sleepiness scores. Changes in renal function were not associated with modified melatonin secretion or circadian rhythmicity. PMID- 25531830 TI - IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential 'inflammatory' type 2 innate lymphoid cells. AB - Innate lymphoid cells (ILCs) are lymphocyte-like cells that lack T cell or B cell antigen receptors and mediate protective and repair functions through cytokine secretion. Among these, type 2 ILCs (ILC2 cells) are able to produce type 2 cytokines. We report the existence of an inflammatory ILC2 (iILC2) population responsive to interleukin 25 (IL-25) that complemented IL-33-responsive natural ILC2 (nILC2) cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo and contributed to the expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing ability and provided partial protection against Candida albicans. We propose that iILC2 cells are transient progenitors of ILCs mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi. PMID- 25531832 TI - DNA damage in haemocytes and midgut gland cells of Steatoda grossa (Theridiidae) spiders exposed to food contaminated with cadmium. AB - The aim of this study was to assess the genotoxic effects of Cd on haemocytes and midgut gland cells of web-building spiders, Steatoda grossa (Theridiidae), exposed to the metal under laboratory conditions. Analyzes were conducted on adult females and males, fed for four weeks with cadmium-contaminated Drosophila hydei flies, grown on a medium suplemented with 0.25 mM CdCl2. The comet assay, providing a quantitative measure of DNA strand breaks, was used to evaluate the DNA damage caused by the metal. Cadmium content was measured in whole spider bodies by the AAS method. Metal body burden was significantly lower in females (0.25 ugg(-1) dry weight) than in males (3.03 ugg(-1) dry weight), suggesting that females may have more effective mechanisms controlling the uptake of metal, via the digestive tract, or its elimination from the body. Irrespectively of sex, spiders fed prey contaminated with cadmium showed significantly higher values of comet parameters: tail DNA (TDNA), tail length (TL) and olive tail moment (OTM), in comparison with the control. In midgut gland cells, the level of DNA damage was higher for males than females, while in haemocytes the genotoxic effect of cadmium was greater in females. The obtained results indicate that in spiders cadmium displays strong genotoxic effects and may cause DNA damage even at low concentrations, however the severity of damage seems to be sex- and internal organ-dependent. The comet assay can be considered a sensitive tool for measuring the deleterious effect of cadmium on DNA integrity in spiders. PMID- 25531833 TI - Developmental toxicity of cigarette butts - An underdeveloped issue. AB - Cigarette butts (CBs) littering is not just an unsightly nuisance but also a public health problem, because chemicals contained in cigarettes can leach into aquatic environments and pose a risk to the health of humans and wildlife. However, this risk is largely unrecognized or ignored by the public, and toxicological evidence of CBs is scarce. Therefore, we used medaka embryos (Oryzias latipes) to explore developmental toxicity of CBs. The embryos were exposed to various concentrations of leachates from smoked and unsmoked cigarette tobacco (ST and UST) and filters (SF and USF), and observed from 1 to 3 days post fertilization. The images were recorded and several developmental endpoints analyzed. The values from these endpoints were then used to calculate the Integrated Biomarker Response and evaluate overall effects of the leachates. Some of the embryos were allowed to hatch, and the hatchlings were tested for anxiety like behavior. Our results showed that low concentrations of the leachates from ST, UST, and SF raised the heart rate, accelerated development, and changed behavior, while high concentrations lowered the heart rate, suppressed development, and increased mortality. The lowest observed effect concentration for the leachates was <=0.2piece (pc)/L. The USF leachate had no effect at the concentration of 20pc/L. Developmental toxicity of the leachates was ranked as: ST>UST>SF>USF. This study has demonstrated for the first time that CB leachates affect fish development, and provided toxicological evidence to better assess ecological impacts of CBs. PMID- 25531831 TI - Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. AB - Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (Treg) cells. The TH2 transcriptional activator GATA-3 and the Treg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis. PMID- 25531834 TI - Sublethal copper toxicity impairs chemical orientation in the crayfish, Orconectes rusticus. AB - Before reaching concentrations that are high enough to cause mortality, elevated levels of chemical pollution can significantly alter a keystone indicator species' ability to extract sensory information. To organisms that rely on chemical signals to make crucial ecological decisions, increased amounts of a pollutant may impact chemoreceptive abilities by altering the perception of the sensory landscape or impairing the functioning of sensory organs. Heavy metal pollutants entering an aquatic ecosystem are of increasing concern due to discernible effects on chemoreception in many ecologically and economically important species. In order to determine the effects of sublethal copper toxicity on chemically mediated behavior, male and female rusty crayfish, Orconectes rusticus, were exposed to ecologically relevant concentrations of copper (4.5, 45, and 450 ug/l) for 120 h. Following exposure, crayfish were allowed to orient toward a food odor stimulus. During orientation trials, select crayfish oriented under a point or nonpoint source copper background pollutant at the same concentration as the exposure period. Orientation trials were videotaped and analyzed using EthoVision XT 8.5 (Noldus Information Technology, The Netherlands) for differences in overall success in locating the food source and orienting parameters. Significant differences were found in the overall orientation ability of O. rusticus to locate an odor source when previously exposed to copper in combination with a source of pollution in the background of orientation trials. Crayfish exposed to copper in any capacity during the experiment (regardless of concentration or background during trials) showed slower walking speeds toward the source, decreased turning angles, increased heading angles toward the source, and decreased upstream heading angles. Results from this experiment support that copper impairs the ability of crayfish to detect, process, and/or respond appropriately to chemosensory information in order to successfully localize a food odor source. PMID- 25531835 TI - The effect of 900 and 1800 MHz GSM-like radiofrequency irradiation and nicotine sulfate administration on the embryonic development of Xenopus laevis. AB - The aim of this study was to investigate the effects of GSM-like radiofrequency electromagnetic radiation (RF EMR) and nicotine sulfate (NS) exposure on Xenopus embryonic development.The developmental effects of GSM-like RF-EMR (900-1800 MHz, at a SAR value of 1W/kg and NS on Xenopus laevis embryos were investigated). Following the application of radiofrequency radiation and/or NS administration, the embryos were closely examined in order to determine their possible teratogenic effects. Xenopus frogs obtained from the Department of Physiology of the Cukurova University, in accordance described by the Standard Guide of the American Society for Testing and Materials (ASTM). Following the exposure of Xenopus embryos to RF-EMR at 900 and 1800 MHz (1.0W/kg) for 4, 6 and 8h; the whole body specific energy absorption rate (SAR) of the embryos was calculated. With the exception of irradiation at 1800 MHz no dramatic developmental anomalies were observed in the Xenopus embryos in association with RF-EMR applications. Combined RF-EMR and NS applications resulted in dramatic abnormalities and death among the Xenopus embryos. The study results indicated that GSM-like RF-EMR (e.g. radiation from cell phones) was not as harmful to Xenopus embryos as might have been expected. However, the combined effects of GSM-like RF-EMR and NS on Xenopus embryos were more severe than the effect of RF-EMR or NS alone. In conclusion, the study results appear to suggest that the combined use of nicotine and cell phones might result in more pronounced detrimental effects on the health of smokers. PMID- 25531837 TI - Listening to music during transrectal ultrasound-guided prostate biopsy decreases anxiety, pain and dissatisfaction in patients: a pilot randomized controlled trial. AB - OBJECTIVE: To determine whether listening to music during transrectal ultrasound (TRUS)-guided 12-core needle prostate biopsy decreases anxiety, pain and dissatisfaction among patients and results in a more comfortable and better tolerated procedure. PATIENTS AND METHODS: 76 male patients who underwent TRUS guided prostate biopsy between March 2013 and June 2014 were randomized into the following groups: no music (group I, n = 38) or classical music (group II, n = 38) during the procedure. Before TRUS-guided prostate biopsy, lidocaine gel was instilled into the rectum. Patient anxiety levels were quantified using the State Trait Anxiety Inventory. A visual analog scale (0-10) was used for self assessment of satisfaction, discomfort and willingness among patients to have a repeat TRUS-guided prostate biopsy. RESULTS: Demographic characteristics, mean age, procedure duration and procedure indications did not differ statistically between the two groups. The mean anxiety level and mean pain score of group II were significantly lower than those of group I (p = 0.001 and p = 0.003, respectively). Group II also had a significantly higher mean satisfaction score than group I (p = 0.007). Before the procedure, heart rate and systolic blood pressure were similar in groups I and II; however, after the procedure, levels were lower in group II than in group I (heart rate, p = 0.014; systolic blood pressure, p = 0.011). CONCLUSION: Listening to music during TRUS-guided prostate biopsy significantly reduced patients' feelings of pain, discomfort and dissatisfaction. Music can serve as a simple, inexpensive and effective adjunct to sedation during TRUS-guided prostate biopsy. We recommend playing music during TRUS-guided prostate biopsy. PMID- 25531838 TI - Understanding the regulation of pharmaceutical drug promotion [Editorial]. PMID- 25531836 TI - Mutational analysis of the ability of resveratrol to inhibit amyloid formation by islet amyloid polypeptide: critical evaluation of the importance of aromatic inhibitor and histidine-inhibitor interactions. AB - The process of amyloid formation by the normally soluble hormone islet amyloid polypeptide (IAPP) contributes to beta-cell death in type 2 diabetes and in islet transplants. There are no clinically approved inhibitors of islet amyloidosis, and the mode of action of existing inhibitors is not well-understood. Resveratrol, a natural polyphenol, has been reported to inhibit amyloid formation by IAPP and by the Alzheimer's disease Abeta peptide. The mechanism of action of this compound is not known, nor is its mode of interaction with IAPP. In this study, we use a series of IAPP variants to examine possible interactions between resveratrol and IAPP. Fluorescence assays, transmission electron microscopy, and mass spectrometry demonstrate that resveratrol is much less effective as an inhibitor of IAPP amyloid formation than the polyphenol (-)-epigallocatechin 3 gallate (EGCG) and, unlike EGCG, does not significantly disaggregate preformed IAPP amyloid fibrils. Resveratrol is also shown to interfere with thioflavin-T assays. His-18 mutants, a truncation mutant, mutants of each of the aromatic residues, and mutants of Arg-11 of IAPP were examined. Mutation of His to Gln or Leu weakens the ability of resveratrol to inhibit amyloid formation by IAPP, as do mutations of Arg-11, Phe-15, or Tyr-37 to Leu, and truncation to form the variant Ac 8-37-IAPP, which removes the first seven residues to eliminate Lys-1 and the N-terminal amino group. In contrast, replacement of Phe-23 with Leu has a smaller effect. The data highlight Phe-15, His-18, and Tyr-37 as being important for IAPP-resveratrol interactions and are consistent with a potential role of the N-terminus and Arg-11 in polypeptide-resveratrol interactions. PMID- 25531839 TI - Amyotrophic lateral sclerosis presenting as bilateral abductor paralysis. PMID- 25531840 TI - Sinus transillumination, then and now. PMID- 25531841 TI - Calcific tendinitis of the longus colli muscle. PMID- 25531842 TI - Temporal bone chondrosarcoma: Presentation of 4 cases and review of the literature. AB - We describe 4 cases of chondrosarcoma of the temporal bone, which occurred in a 66-year-old man and in 3 women aged 34, 37, and 47 years. One of these patients was originally diagnosed with an epithelial cyst and another with a middle ear neoplasm. Three patients underwent surgical removal of their tumor, while the other patient declined (a craniotomy for biopsy was performed in this case). An accurate diagnosis in all 4 cases was not made until histopathologic examination was performed. None of the patients received postoperative radiotherapy for various reasons. However, the male patient experienced a tumor recurrence, which necessitated a second surgery, and he did receive radiotherapy after the second operation. All 3 operated patients were doing well at the most recent follow-up, and the other patient was soon lost to follow-up. Because of its rarity and potential for severe complications, temporal bone chondrosarcoma remains a difficult disease to diagnose and manage. PMID- 25531843 TI - Iatrogenic fracture of the superomedial orbital rim during frontal trephine irrigation. AB - Frontal sinus trephination (FST) has numerous applications in the treatment of acute and chronic sinus disease. This procedure involves making an incision at the medial aspect of the supraorbital rim and then drilling the sinus's anterior table. Placement of a frontal trephine allows for irrigation of the frontal recess in order to evacuate the frontal sinus in a minimally invasive manner. Orbital injury is a rare complication of FST. We present a case of previously unreported orbital compartment syndrome secondary to iatrogenic fracture of the superomedial orbital rim as a complication of frontal trephine irrigation. We also review the literature on the applications of FST and its associated complications, and we discuss orbital compartment syndrome as a complication of sinus surgery. PMID- 25531844 TI - Simultaneous non-Hodgkin lymphoma of the external auditory canal and thyroid gland: A case report. AB - Approximately 25% of all cases of extranodal non-Hodgkin lymphoma (NHL) occur in the head and neck region; NHL of the external auditory canal (EAC) and thyroid gland are rare. Specific immunohistochemical staining of the excised tissue is required to confirm the final pathologic diagnosis. We report the case of a 53 year-old woman with underlying systemic lupus erythematosus and autoimmune hemolytic anemia that were in remission. She presented with chronic left ear pain, a mass in the left EAC, and rapid growth of an anterior neck swelling that had led to left vocal fold palsy. High-resolution computed tomography (CT) of the temporal bone and CT of the neck detected a mass lateral to the left tympanic membrane and another mass in the anterior neck that had infiltrated the thyroid gland. The patient was diagnosed with simultaneous B-cell lymphoma of the left EAC and thyroid gland. She was treated with chemotherapy. She responded well to treatment and was lost to follow-up after 1 year. To the best of our knowledge, the simultaneous occurrence of a lymphoma in the EAC and the thyroid has not been previously described in the literature. PMID- 25531845 TI - Cutaneous malignant melanoma metastatic to the sphenoid sinus. AB - While metastases to the paranasal sinuses are unusual, metastases to the sphenoid sinus are exceedingly rare, especially metastases of a cutaneous melanoma to the mucosa. We report the case of a 38-year-old man who presented with a solitary sphenoid sinus metastasis that had spread from a cutaneous malignant melanoma. The metastasis was removed via a wide, endoscopically assisted sphenoidotomy. The patient was further treated with external radiotherapy, and at 8 months of follow up he was free of disease. However, he experienced a recurrence at 3 years that proved to be fatal. We review the pathogenesis and histopathology of sinus metastases, and we discuss the imaging features that characterize melanoma metastatic to the upper respiratory tract. While complete cure of patients with a sphenoid sinus metastasis has not been reported, significant palliation with radiation therapy is possible in many patients. Therefore, patients with sphenoid sinus symptoms suggestive of a sphenoid sinus malignancy should be vigorously evaluated for the possibility of a primary malignancy as well as a metastasis to the sinus. PMID- 25531846 TI - Laryngeal inflammatory myofibroblastic tumor. AB - Inflammatory myofibroblastic tumor seldom involves the larynx, as only about 50 to 60 cases have been described in the literature. Even though these tumors are often not aggressive, they have the potential for invasion and local recurrence. We describe the case of a 27-year-old man who was admitted to an emergency department with signs of upper airway obstruction secondary to an obstructive mass. Histology identified the mass as an inflammatory myofibroblastic tumor of the subglottis. The patient underwent an emergency tracheotomy followed by a partial laryngectomy. During 14 months of follow-up, he remained free of active disease. PMID- 25531847 TI - Adult presentation of laryngeal cleft: Utility of the modified barium swallow study in diagnosis and management. AB - We present a case of laryngeal cleft in a 41-year-old man to illustrate the co occurrence of laryngeal cleft and tracheoesophageal fistula. We advocate the use of the modified barium swallow study in the diagnosis of laryngeal cleft. We also review the advantages and limitations of the various diagnostic methods, as well as the potential for known tracheoesophageal fistula to mask laryngeal cleft. Finally, we discuss the importance of early identification of laryngeal cleft in the context of its potentially serious health implications. PMID- 25531848 TI - Acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma of the thyroid: A complicated case. AB - The fibrous variant of Hashimoto thyroiditis is uncommon, accounting for approximately 10% of all cases of Hashimoto thyroiditis. We report a case of this variant that behaved like a malignant neoplasm. The patient was a 69-year-old man who presented with a right-sided anterior neck mass that had been rapidly growing for 2 weeks. Fine-needle aspiration cytology revealed clusters of large multinucleated cells suggestive of an anaplastic carcinoma. A week after presentation, we ruled out that possibility when the mass had shrunk slightly. Instead, we diagnosed the patient with an acute exacerbation of Hashimoto thyroiditis on the basis of laboratory findings. We performed a right thyroid lobectomy, including removal of the isthmus, to clarify the pathology and alleviate pressure symptoms. The final diagnosis was the fibrous variant of Hashimoto thyroiditis, with no evidence of malignant changes. Physicians should keep in mind that on rare occasions, Hashimoto thyroiditis mimics a malignant neoplasm. PMID- 25531849 TI - Fusobacterium necrophorum in a pediatric retropharyngeal abscess: A case report and review of the literature. AB - We present the case of a 17-year-old boy who developed a deep space neck infection following cervical trauma. He was initially managed conservatively with broad-spectrum antibiotics, but when he failed to improve clinically, he required surgical drainage. Wound cultures grew Fusobacterium necrophorum, an uncommon pathogen that can cause pediatric deep neck space infections, especially when it is not associated with Lemierre syndrome. The prognosis for this infection is favorable when it is identified early. Treatment with culture-directed antibiotics and surgical drainage as indicated is appropriate. When treating a pediatric deep neck space infection empirically, physicians should avoid treatment with a macrolide antibiotic, since Fusobacterium spp may be involved and they are often resistant to this class of drugs. PMID- 25531850 TI - Necrotizing sialometaplasia of the nasopharynx with parapharyngeal extension: Case report and brief review of the literature. AB - We report a rare case of necrotizing sialometaplasia of the right lateral nasopharynx with extension into the right parapharyngeal space in a 39-year-old man. Since this is a self-limiting condition, the patient began to improve spontaneously over the next few weeks, and he experienced a complete recovery. Necrotizing sialometaplasia is an uncommon condition that is known to involve the palate; nasopharyngeal involvement is very rare, and to the best of our knowledge, extension into the parapharyngeal area has not been previously reported in the English-language literature. This condition poses a diagnostic dilemma because it closely mimics a malignancy, and failure to recognize it can result in unnecessary investigations and extensive surgery. We also review the literature on necrotizing sialometaplasia of the oropharyngeal area. PMID- 25531851 TI - Solitary peritoneal lymph node metastasis of head and neck cancer diagnosed with FDG-PET/CT imaging. AB - Distant metastasis of head and neck squamous cell carcinoma (SCC) to the infraclavicular lymph nodes-with the exception of the upper mediastinal lymph nodes-is rare. We report the case of a 44-year-old man who was treated with surgery and radiotherapy for SCC of the floor of the mouth. During regular follow up 6 months after the cessation of radiotherapy, F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) detected a hypermetabolic lesion in the left lobe of the liver that was diagnosed as a metastasis of the head and neck SCC; no locoregional recurrence was found. The metastasis was surgically removed and more radiotherapy was administered, but the SCC recurred at the same site and the patient died of disseminated disease 12 months after the appearance of the first metastasis. To the best of our knowledge, this is the first reported case of a solitary peritoneal lymph node metastasis from an SCC of the floor of the mouth. We believe that regular FDG-PET/CT follow-up scans are useful for the detection of unusual distant metastases of head and neck cancers. PMID- 25531852 TI - Cervical presentation of peripheral T-cell lymphoma not otherwise specified. AB - Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is an uncommon type of lymphoma with a clinically aggressive course and a relatively poor prognosis. Many affected patients present with nodal involvement, and there is also potential for extranodal involvement of the liver, gastrointestinal tract, bone marrow, and/or skin. We describe the case of a 68-year-old woman who presented with a 6-week history of an intermittently tender left-sided neck mass. Findings on imaging and fine-needle aspiration biopsy were inconclusive. Pathologic studies of excisional biopsy specimens ultimately revealed the diagnosis of PTCL NOS. Of the lymphomas, neither PTCL nor the PTCL-NOS subtype is frequently discussed or studied in prospective trials. However, these cases should be identified because of their substantial clinical management implications. PMID- 25531853 TI - Retropharyngeal masses in neurofibromatosis type 1: Imaging findings in 2 cases. AB - Neurofibromatosis type 1 (NF-1) affects mesenchymal development via multisystemic manifestations. We present 2 cases of NF-1 that manifested as a retropharyngeal mass-1 as a lateral cervical meningocele in a 60-year-old man and the other as a focal neurofibroma in a 37-year-old man. Contrast-enhanced magnetic resonance imaging (MRI) was invaluable in identifying the exact nature of the 2 lesions; no contrast enhancement was seen in the case of the meningocele, and enhancement was seen in the case of the neurofibroma. These 2 cases illustrate the importance of the history and contrast-enhanced MRI in managing NF-1 patients with a retropharyngeal mass. PMID- 25531854 TI - Superior omohyoid muscle flap repair of cervical esophageal perforation induced by spinal hardware. AB - Cervical esophageal perforation is a rare and life-threatening condition. Its prompt diagnosis and treatment require a high index of suspicion. Cervical spine hardware is an uncommon cause of posterior esophageal perforation. Management has included a variety of musculofascial flaps for surgical repair. We present 2 cases of cervical esophageal perforation induced by spinal hardware that were repaired with a superior omohyoid muscle (SOM) flap for closure and/or primary closure reinforcement. Advantages and techniques of the SOM flap are discussed. PMID- 25531855 TI - Clival fibrous dysplasia: Case series and review of the literature. AB - Slightly more than 30 cases of fibrous dysplasia involving the clivus have been reported in the international literature, primarily in the neurosurgery and radiology literature. In this article we present a series of 4 cases involving patients with clival fibrous dysplasia. In a retrospective chart review, 4 patients presenting to tertiary care centers from January 1, 2006, to January 31, 2008, were identified and their presenting symptoms and radiologic findings reviewed. Based on our literature review, we describe the presenting symptoms of patients with clival fibrous dysplasia and characterize the findings of imaging studies associated with this disorder. All patients in this series had a presenting complaint of headache or cranial nerve deficits, which is consistent with previous reports found in our literature review. Additional presenting symptoms that have been reported include dysphagia and a nontender occipital mass; there was also an incidental asymptomatic finding. Magnetic resonance imaging findings are consistent with those associated with fibrous dysplasia at other sites of the body. We conclude that clival involvement in monostotic fibrous dysplasia may not be as rare as previously perceived. PMID- 25531856 TI - Cerebrospinal fluid leaks following septoplasty. AB - We conducted a retrospective review to identify the characteristics of cerebrospinal fluid (CSF) leak in patients who had undergone septoplasty and in selected patients who had experienced a spontaneous CSF leak. CSF leak is a known but infrequently reported complication of septoplasty; to the best of our knowledge, only 4 cases have been previously published in the literature. A review of our institution's database revealed 3 cases of postseptoplasty CSF leak. We reviewed all the available data to look for any commonalities among these 7 cases. In addition, we reviewed 6 cases of spontaneous CSF leak selected from our database for the same purpose. For all patients, we noted the side of the cribriform plate defect, its size and, for the postseptoplasty cases, the interval between the septoplasty and the leak repair. Overall, we found that leaks were much more common on the right side than on the left. The sizes of the leaks in the 2 postseptoplasty groups were comparable (mean: 14.0 * 6.4 mm). The interval between septoplasty and leak repair ranged from 2.5 to 20 years in our cases and from 3 days to 22 weeks in the previously published cases. All 3 of the postseptoplasty patients in our database presented with clear rhinorrhea. Two of the 3 patients had meningitis; 1 of these 2 also had pneumocephalus. Of the 6 cases of spontaneous CSF leaks, 4 occurred on the right and 2 on the left; the average size of the defect was 5.8 mm in the greatest dimension. The finding that cribriform plate defects after septoplasty were typically right-sided likely reflects the prevalence of left-sided surgical approaches. Also, the fact that the defects were larger in the postseptoplasty cases than in the spontaneous cases is likely attributable to the torque effect toward the thin skull base that occurs when the perpendicular plate is twisted during septoplasty. PMID- 25531857 TI - Painful rash of the auricle: Herpes zoster oticus. PMID- 25531859 TI - The small bowel in its hammock: how to avoid irradiation thanks to the sigmoid. AB - BACKGROUND: High-dose irradiation is the cornerstone treatment of bone cancers of the pelvic rim. To protect the small bowel from irradiation and following consequences, we described the laparoscopic use of the sigmoid to perform a hammock. MATERIALS AND METHODS: Three patients were diagnosed with metastatic Ewing's sarcoma, localized malignant peripheral nerve sheath tumor, and localized BCOR-CCNB3 (Ewing-like) sarcoma of the pelvic rim at 13.1, 5.7, and 12.9 years, respectively. After neoadjuvant chemotherapy, the 2 female patients underwent a hemisacrectomy under S2 only by the posterior approach, whereas no orthopedic surgery was required for the male patient because of excellent local response to chemotherapy. A 54-Gy intensity-modulated radiotherapy of the posterior part of the pelvis was intended for all patients. RESULTS: The laparoscopic procedure consisted in the fixation of the sigmoid loop to the anterior parietal wall on a transverse line just below the umbilicus, associated with a colostomy in the right iliac fossa. The anterior transposition of the two ovaries, uterus, and rectum and the dissection of left iliac vessels to move them anteriorly were added in female patients. Stomas were closed around 6 months after completion of the radiotherapy course, associated with the repositioning of the uterus, ovaries, and colon. With a mean follow-up of 22 months, all patients are alive without any recurrences or radiation-related symptoms. CONCLUSIONS: The laparoscopic "hammock technique" both protects the small bowel from irradiation and secures the orthopedic procedure by displacing the abdominal organs forward. PMID- 25531860 TI - Magnetic resonance-visible polypropylene mesh for pelvic organ prolapse repair. AB - AIM: To develop a magnetic resonance (MR)-visible mesh using iron oxides and prove visibility. METHODS: In a phantom study, a suitable iron oxide, Fe3O4 [iron(II,III) oxide] and FeOOH [iron(III) oxide-hydroxide], concentration was determined using relaxometric MR measurements of the transverse relaxation rates R2 and R2*. Next, a nonabsorbable mesh was designed from the MR-visible threads woven into a polypropylene mesh. The mesh was implanted into a fresh female cadaver via the transobturator route, and MR visibility was assessed with various MR pulse sequences in a clinical 3-tesla system. RESULTS: Optimal contrast was achieved with Fe3O4 at 0.2 weight-% in all imaging sequences, and the optimal contrast was achieved in a 3D spoiled gradient-echo (fast low-angle shot) acquisition. In this concentration range the apparent transverse relaxation rate R2* is below 10 ms. The mesh was visible in the cadaver on T1-weighted 3D spoiled gradient-echo images and T1-weighted fast spin-echo images. CONCLUSION: Mesh materials can be manufactured to be visible on MR with a negative contrast. Fe3O4 meshes could simplify follow-up examinations and help diagnose origins of postsurgical lesions after urogynecological procedures with mesh material. PMID- 25531861 TI - Free triiodothyronine levels are positively associated with non-alcoholic fatty liver disease in euthyroid middle-aged subjects. AB - BACKGROUND: Studies on the relationship between thyroid function and non alcoholic fatty liver disease (NAFLD) among euthyroid subjects have produced conflicting results. OBJECTIVES: The aim of this study was to investigate the association between thyroid function and the presence of NAFLD in a large-sample middle-aged euthyroid subjects. METHODS: A total of 2576 euthyroid subjects who underwent health check-up were included. NAFLD was diagnosed by hepatic ultrasonography. Conventional risk factors for NAFLD were assessed as well as serum levels of TSH, FT3 and FT4. RESULTS: Levels of FT3 were significantly higher in NAFLD group (5.12 +/- 0.58 versus 4.84 +/- 0.58 pmol/L, adjusted p = 0.000) than non-NAFLD group, while levels of TSH and FT4 were comparable between NAFLD and non-NAFLD groups (TSH: 2.13 +/- 0.90 versus 2.20 +/- 0.93 mIU/L, adjusted p = 0.190; FT4: 16.41 +/- 2.04 versus 16.18 +/- 2.06 pmol/L, adjusted p = 0.146, respectively). Levels of FT3 were positively correlated with components of metabolic syndrome. Multivariate logistic regression analysis revealed that high level of FT3 was an independent predictor for NAFLD (odds ratio: 1.253, p = 0.040). The relationship between FT4 and NAFLD in women was different according to menopausal status, with negative association in pre-menopausal women (OR: 0.777, 95% CI: 0.617-0.979, p = 0.032) and null association in post-menopausal women (OR: 1.037, 95% CI: 0.841-1.277, p = 0.736). CONCLUSIONS: Our findings suggested that high levels of FT3 were significantly associated with NAFLD among middle-aged euthyroid subjects independently of known metabolic risk factors. A negative correlation of serum FT4 level with NAFLD was only observed in pre menopausal women. PMID- 25531862 TI - Core data necessary for reporting clinical trials on nutrition in infancy. AB - This paper presents an updated and revised summary of the 'core data set' that has been proposed to be recorded and reported in all clinical trials on infant nutrition by the recently formed Consensus Group on Outcome Measures Made in Paediatric Enteral Nutrition Clinical Trials (COMMENT). This core data set was developed based on a previous proposal by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition in 2003. It comprises confidential data to identify subjects and facilitate contact for further follow-up, data to characterize the cohort studied and data on withdrawals from the study, and some additional core data for all nutrition studies on preterm infants. We recommend that all studies on nutrition in infancy should collect and report this core data set to facilitate interpretation and comparison of results from clinical studies, and of systematic data evaluation and meta-analyses. Editors of journals publishing such reports are encouraged to require the reporting of the minimum data set described here either in the main body of the publication or as supplementary online material. PMID- 25531863 TI - Metabolic control of microvascular networks: oxygen sensing and beyond. AB - The metabolic regulation of blood flow is central to guaranteeing an adequate supply of blood to the tissues and microvascular network stability. It is assumed that vascular reactions to local oxygenation match blood supply to tissue demand via negative-feedback regulation. Low oxygen (O2) levels evoke vasodilatation, and thus an increase of blood flow and oxygen supply, by increasing (decreasing) the release of vasodilatory (vasoconstricting) metabolic signal substances with decreasing partial pressure of O2. This review analyses the principles of metabolic vascular control with a focus on the prevailing feedback regulations. We propose the following hypotheses with respect to vessel diameter adaptation. (1) In addition to O2-dependent signaling, metabolic vascular regulation can be effected by signal substances produced independently of local oxygenation (reflecting the presence of cells) due to the dilution effect. (2) Control of resting vessel tone, and thus perfusion reserve, could be explained by a vascular activity/hypoxia memory. (3) Vasodilator but not vasoconstrictor signaling can prevent shunt perfusion via signal conduction upstream to feeding arterioles. (4) For low perfusion heterogeneity in the steady state, metabolic signaling from the vessel wall or a perivascular tissue sleeve is optimal. (5) For amplification of perfusion during transient increases of tissue demand, red blood cell-derived vasodilators or vasoconstrictors diluted in flowing blood may be relevant. PMID- 25531864 TI - An LC-MS/MS method for the determination of five erectile dysfunction drugs and their selected metabolites in hair. AB - The abuse of sildenafil and its analogous, accelerated by their inappropriate or illegal distribution, is a serious social issue globally. However, no studies have been conducted to monitor these drugs simultaneously in hair, which can provide valuable information on chronic drug use. In the present study, an LC MS/MS method was developed for the simultaneous determination in hair of five erectile dysfunction drugs having a high risk for abuse (mirodenafil, sildenafil, tadalafil, udenafil and vardenafil) and their selected metabolites (SK3541, desmethylsildenafil, DA8164 and desethylvardenafil). The novel method was fully validated after optimizing matrix effects and extraction efficiency. The optimized sample preparation included acidic methanol extraction followed by solid phase extraction using C18 mixed mode strong cation exchange polymeric cartridges. The prepared samples were analyzed by LC-MS/MS with electrospray ion source in the positive ionization mode. The validation results proved the method to be selective, sensitive, accurate and precise, with acceptable linearity within calibration ranges. LODs ranged from 0.05 (DA8164) to 1 ng/10 mg hair (tadalafil). LOQs were 1 ng/10 mg hair except for DA8164 and vardenafil, of which they were 2.5 ng/10 mg hair. No significant variations were observed by different sources of matrices in both human and rat hair, except for tadalafil, for which a stable isotope-labeled internal standard was effective. The animal study suggested hair pigmentation was a major factor for the incorporation of the drugs and metabolites into hair. However, a wide variation of the sildenafil-to desmethylsildenafil ratios was observed in human hair samples. The developed method will be very useful for monitoring the abuse of erectile dysfunction drugs for both legal and public health aspects. PMID- 25531865 TI - Quantification of 5,7-dimethoxyflavone in mouse plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to a pharmacokinetic study. AB - 5,7-Dimethoxyflavone (5,7-DMF), a natural flavonoid abundant in many plants, has been reported to have many beneficial pharmacological effects, including strong chemopreventive and chemosensitizing properties, anti-oxidant, cardiovascular protectant, and anti-inflammatory activities. However, to date 5,7-DMF was evaluated mainly in vitro and its pharmacokinetics (PK) in vivo remains largely unknown. In addition, current available quantification methods of 5,7-DMF all lack sufficient sensitivity (lower limit of quantification >800 ng/mL). The purposes of our study are to establish a sensitive quantification method of 5,7 DMF using LC-MS/MS and evaluate the PK profile of 5,7-DMF in mouse. Our method was fully validated and all of the fundamental parameters in method validation, including accuracy, precision, sensitivity, selectivity, recovery and stability were evaluated thoroughly in mouse plasma. The calibration curve covered 2-1000 ng/mL with the lower limit of quantification (LLOQ) of 2 ng/mL. The inter-run and intra-run precision and accuracy were less than 15% of nominal concentrations. The matrix effect and recovery yield were within +/-15% of nominal concentrations. In the PK study, 5,7-DMF was detectable in mouse plasma up to 21 h, with a terminal half-life of 11.5h. The clearance of 5,7-DMF (CL/F) is 22.3 L/h/kg and area under the curve (AUCinf) is 449 h ng/mL. In conclusion, a fast, accurate, sensitive and selective quantification method of 5,7-DMF was established and the developed method was successfully applied to a PK study of 5,7-DMF following oral administration of 5,7-DMF in mice. PMID- 25531866 TI - Determination of urinary cortisol, cortisone and 6-sulfatoxymelatonin using dilute and shoot ultra-high pressure liquid chromatography-tandem mass spectrometry. AB - Human sleep is a natural part of every individual's life. Clear relationship between sleep and endocrine system has been already established. In particular, melatonin and cortisol are known to affect and regulate sleep/wake patterns. Here we report the development of an ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous measurement of 6 sulfatoxymelatonin (MT6s), cortisol and cortisone in urine. A separate method was developed for measurement of creatinine in urine. These levels were used to normalise the levels of analytes. First void morning urine samples were collected from 24 healthy volunteers. Samples were diluted 1:1 in water prior to injection onto reversed-phase C18 column and analysed using UHPLC-MS/MS method. Linear calibrations were obtained for all analytes with correlation coefficient in the range 0.998-0.999. The observed concentration was found to be in the range 92 105% for cortisol, 92-107% for cortisone and between 93 and 120% for MT6s of the reference levels. The total run time of 6 min with all peaks of interest eluting within 3 min was obtained. This demonstrates the feasibility of utilising the method for large multi-scale studies, where high throughput is required for studying the circadian rhythm of melatonin and cortisol secretion. These hormones play significant role in circadian rhythm and sleep/wake cycle; therefore it is important to monitor the levels of these endocrine markers in individuals suffering from sleep disorders. It is also beneficial with clinical applications to analyse melatonin and cortisol simultaneously in order to assess their interrelationships of these substances, such as their effect on diurnal rhythm and sleep. PMID- 25531867 TI - Ultra-high performance liquid chromatography-tandem mass spectrometry for the quantification of icaritin in mouse bone. AB - Icaritin (ICT), a bioactive metabolite of prenylflavonoids from genus Epimedium, has displayed potential benefits for the treatment of osteoporosis, prostate cancer, liver cancer, renal cancer and breast cancer. To investigate the quantity of ICT in bones in vivo, a simple and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed. After a rapid one-step liquid-liquid extraction using ethyl acetate with recovery more than 87.2% at four levels (0.1, 0.2, 8 and 15 ng/mL), ICT and internal standard coumestrol were analyzed on a C18 column using a gradient elution of acetonitrile and water containing ammonium formate and formic acid at a flow rate of 0.3 mL/min. Quantification was performed using selected reaction monitoring mode to monitor precursor-product ion transitions of m/z 367.1->297.1 for ICT and of 267.0->211.1 for coumestrol in the negative ionization mode. A calibration curve with good linearity (r>0.99) within the concentration range of 0.1-20 ng/mL for ICT was obtained with the lower limit of quantification of 0.1 ng/mL. Matrix effect did not interfere with ICT analysis and ICT was stable under three freeze thaw cycles, short-term temperature, post-preparative and long-term temperature conditions. The method was successfully applied to a dynamic distribution of ICT in mouse bone after a single intraperitoneal administration to ICT to mice. PMID- 25531868 TI - Highly sensitive analysis of nucleic acids using capillary gel electrophoresis with ultraviolet detection based on the combination of matrix field-amplified and head-column field-amplified stacking injection. AB - To develop a highly sensitive method for analyzing nucleic acids using capillary gel electrophoresis with ultraviolet detection (CGE-UV), we combined matrix field amplified with head-column field-amplified stacking injection (C-FASI) to employ the advantages of two methods. Without diminishing the resolution, a limit of detection of 0.13 ng/ml (signal/noise=3) in a 300,000-fold diluted sample was obtained, the sensitivity is 102,308 times higher than that achieved with normal pressure injection, 3077 times that with normal electrokinetic injection, 154 times that with pressure field-amplified sample stacking injection, and 31 times that with matrix field-amplified stacking injection. After establishing the method, we tested the detection of a phiX174-Hae III digest DNA product without purification and with a high ionic strength. At the lowest dilution of 5000-fold, sample at a concentration of 10 ng/ml was enriched and detected. The relative standard deviations for migration time and peak area (n=3) were 0.03-1.15 and 0.72-6.42, respectively. To further validate C-FASI was applicable for real sample, a 400 bp PCR product without purification was directly detected with a limit of detection at the concentration of 6000-fold dilution (signal/noise=3), The relative standard deviations for migration time and peak area (n=6) were 0.44 and 4.8, respectively. These results indicated that C-FASI had good qualitative and quantitative detection abilities and CGE-UV based on C-FASI is easy to perform, practical, highly-sensitive and robust for nucleic acid detection, which makes it a highly valuable tool for genetic diagnostics based on nucleic acid analysis. PMID- 25531869 TI - Simultaneous determination of ten active constituents of Yankening Capsule in rat plasma by ultra high performance liquid chromatography with tandem mass spectrometry. AB - An ultra high performance liquid chromatography with tandem mass spectrometry (U HPLC-MS/MS) method was developed for simultaneous determination and pharmacokinetic study of ten active constituents, phellodendrine, coptisine, jatrorrhizine, berberine, palmatine, baicalin, wogonoside, baicalein, wogonin and emodin in rat plasma after oral administration of Yankening Capsule. After mixing with two internal standards tetrahydropalmatine and rutin, plasma samples were pretreated by protein precipitation with anhydrous ethanol-acetonitrile (9:1, v/v). The U-HPLC separation was carried on a ZORBAX RRHD Eclipse Plus C18 column (2.1 mm * 50 mm, 1.8 MUm) with gradient elution using a mobile phase composed of methanol and water (containing 0.3% formic acid) at a flow rate of 0.3 mL min( 1). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring via electrospray ionization source with positive negative ionization mode. The calibration curves of ten analytes showed good linearity (r>0.9979). The lower limits of quantification of phellodendrine, coptisine, jatrorrhizine, berberine, palmatine, baicalin, wogonoside, baicalein, wogonin and emodin were 0.50, 0.50, 0.30, 0.30, 0.30, 10, 3.0, 8.0, 1.0, 8.0 MUg L(-1), respectively. The relative standard deviation of intra-day precision and inter-day precision were in the range from 1.13% to 5.96% and from 0.65% to 8.85%, respectively. The matrix effects of all analytes were found to be within the acceptable range with a range of 89.99-109.3%. The method is reliable and rapid and has been applied successfully to pharmacokinetic study of the ten active constituents in rat plasma after oral administration of Yankening Capsule. PMID- 25531870 TI - Simultaneous determination of six flavonoids from Paulownia tomentosa flower extract in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. AB - A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for simultaneous determination of six components including apigenin, quercetin, apigenin-7-O-beta-D-glucoside, quercetin-3-O-beta-D-glucoside, 3'-methoxyluteolin-7-O-beta-D-glucoside, and tricin-7-O-beta-D-glucopyranoside in rat plasma using formononetin as the internal standard (IS). The plasma samples were pretreated by a one-step liquid liquid extraction with dichloromethane. The chromatographic separation was carried out on a ZORBAX SB-Aq column with a gradient mobile phase consisting of acetonitrile and 2mM aqueous ammonium acetate. All analytes and IS were quantitated through electrospray ionization in negative ion multiple reaction monitoring mode. The mass transitions were as follows: m/z 269.1->117.2 for apigenin, m/z 301.2->151.2 for quercetin, m/z 431.3->311.2 for apigenin-7-O-beta D-glucoside, m/z 463.2->300.2 for quercetin-3-O-beta-D-glucoside, m/z 461.3 >283.1 for 3'-methoxyluteolin-7-O-beta-D-glucoside, m/z 491.3->313.1 for tricin-7 O-beta-D-glucopyranoside, and m/z 267.2->252.2 for IS, respectively. All calibration curves exhibited good linearity with correlation coefficient (r)>0.995. The intra-day and inter-day precisions (RSD) at three QC levels were both less than 14.0% and the accuracies ranged from 89.8% to 113.8%. The extraction recoveries of six compounds ranged from 82.3% to 92.5%. The validated method was successfully applied to pharmacokinetic study of the six components in male rat plasma after oral administration of Paulownia tomentosa flower extract. PMID- 25531871 TI - The analysis of linear and monomethylalkanes in exhaled breath samples by GC*GC FID and GC-MS/MS. AB - A new arrangement of the INCAT (inside needle capillary adsorption trap) device with Carbopack X and Carboxen 1000 as sorbent materials was applied for sampling, preconcentration and injection of C6C19n-alkanes and their monomethyl analogs in exhaled breath samples. For the analysis both GC-MS/MS and GC*GC-FID techniques were used. Identification of the analytes was based on standards, measured retention indices and selective SRM transitions of the individual isomers. The GC MS/MS detection limits were in the range from 2.1 pg for n-tetradecane to 86 pg for 5-methyloctadecane. The GC*GC-FID detection limits ranged from 19 pg for n dodecane to 110 pg for 3-methyloctane. PMID- 25531872 TI - A validated method for quantifying hypoglycin A in whole blood by UHPLC-HRMS/MS. AB - Hypoglycin A (HGA) is the toxic principle in ackee (Blighia sapida Koenig), a nutritious and readily available fruit which is a staple of the Jamaican working class and rural population. The aril of the unripe fruit has high concentrations of HGA, the cause of Jamaican vomiting sickness, which is very often fatal. HGA is also present in the samara of several species of maple (Acer spp.) which are suspected to cause seasonal pasture myopathy in North America and equine atypical myopathy in Europe, often fatal for horses. The aim of this study was to develop a method for quantifying HGA in blood that would be sensitive enough to provide toxicological evidence of ackee or maple poisoning. Analysis was carried out using solid-phase extraction (HILIC cartridges), dansyl derivatization and UHPLC HRMS/MS detection. The method was validated in whole blood with a detection limit of 0.35 MUg/L (range: 0.8-500 MUg/L). This is the first method applicable in forensic toxicology for quantifying HGA in whole blood. HGA was quantified in two serum samples from horses suffering from atypical myopathy. The concentrations were 446.9 and 87.8 MUg/L. HGA was also quantified in dried arils of unripe ackee fruit (Suriname) and seeds of sycamore maple (Acer pseudoplatanus L.) (France). The concentrations were 7.2 and 0.74 mg/g respectively. PMID- 25531873 TI - Rapid determination of fenoldopam in human plasma by UPLC-MS/MS for pharmacokinetic analysis in patients. AB - We developed and validated a rapid, selective, and sensitive ultra-performance liquid-chromatography mass-spectrometry (UPLC-MS/MS) method for quantifying fenoldopam in human plasma for pharmacokinetic studies. Fenoldopam and the internal-standard (IS), oxazepam, were isolated from human plasma by liquid liquid extraction using ethyl acetate after alkalization, and were separated on a 2.1*100 mm Acquity UPLC HSS T3 C18 column (inside diameter, 1.8 MUm) using a mobile phase of water (0.05% formic acid) and acetonitrile gradient elution. The fenoldopam and IS were eluted at 1.07 and 2.32 min, respectively. Quantification was performed using positive-ion electrospray-ionization (ESI), and the fenoldopam and IS responses were optimized at the m/z 306.16->107.10 and m/z 287.1->241.01 transitions, respectively. The assay was validated over the linear range of 0.1-40 ng/mL fenoldopam with intra- and interassay precision <13.21%. The matrix effect of normal and hemolyzed plasma was 94.9-101.6%. Fenoldopam was stable for >=34 days at -70 degrees C in normal and hemolyzed plasma containing ascorbic acid as a stabilizer. This method can be successfully applied in pharmacokinetic studies of fenoldopam in hypertensive patients. PMID- 25531874 TI - LC-MS analysis of the plasma metabolome--a novel sample preparation strategy. AB - Blood plasma is a well-known body fluid often analyzed in studies on the effects of toxic compounds as physiological or chemical induced changes in the mammalian body are reflected in the plasma metabolome. Sample preparation prior to LC-MS based analysis of the plasma metabolome is a challenge as plasma contains compounds with very different properties. Besides, proteins, which usually are precipitated with organic solvent, phospholipids, are known to cause ion suppression in electrospray mass spectrometry. We have compared two different sample preparation techniques prior to LC-qTOF analysis of plasma samples: the first is protein precipitation; the second is protein precipitation followed by solid phase extraction with sub-fractionation into three sub-samples: a phospholipid, a lipid and a polar sub-fraction. Molecular feature extraction of the data files from LC-qTOF analysis of the samples revealed 1792 molecular features from the protein precipitation procedure. The protein precipitation followed by solid phase extraction procedure with three sub-samples gave a total of 4234 molecular features. This suggests that sub-sampling into polar, lipid and phospholipid fractions enables extraction of more metabolomic information as compared to protein precipitation alone. Chromatography showed good separation of the metabolites with little retention time drift (<1s) and a mass accuracy below 3 ppm was observed. The performance of the method was investigated using plasma samples from rats administered the environmental pollutant perfluorononanoic acid. PMID- 25531875 TI - Ultrafast quantification of beta-lactam antibiotics in human plasma using UPLC MS/MS. AB - There is an increasing interest in monitoring plasma concentrations of beta lactam antibiotics. The objective of this work was to develop and validate a fast ultra-performance liquid chromatographic method with tandem mass spectrometric detection (UPLC-MS/MS) for simultaneous quantification of amoxicillin, cefuroxime, ceftazidime, meropenem and piperacillin with minimal turn around time. Sample clean-up included protein precipitation with acetonitrile containing 5 deuterated internal standards, and subsequent dilution of the supernatant with water after centrifugation. Runtime was only 2.5 min. Chromatographic separation was performed on a Waters Acquity UPLC system using a BEH C18 column (1.7 MUm, 100 mm * 2.1 mm) applying a binary gradient elution of water and methanol both containing 0.1% formic acid and 2 mmol/L ammonium acetate on a Water TQD instrument in MRM mode. All compounds were detected in electrospray positive ion mode and could be quantified between 1 and 100 mg/L for amoxicillin and cefuroxime, between 0.5 and 80 mg/L for meropenem and ceftazidime, and between 1 and 150 mg/L for piperacillin. The method was validated in terms of precision, accuracy, linearity, matrix effect and recovery and has been compared to a previously published UPLC-MS/MS method. PMID- 25531876 TI - Comprehensive polar lipid identification and quantification in milk by liquid chromatography-mass spectrometry. AB - Polar lipids (PLs) are a significant functional component of milk that are difficult to quantitate. A simple method for comprehensive identification and quantitative analysis of all essential PL species using bovine milk is described. The lipid fraction was extracted by a mix of chloroform and methanol and the extract was directly used for PL identification and quantification. PLs were separated by hydrophilic interaction liquid chromatography (HILIC) and detected by an Orbitrap mass analyser in positive mode. The structure of PLs was established or confirmed by tandem MS in both positive and negative modes. The method is sensitive (with a LOD for all PL classes <=0.1 ng) and reproducible, enabling simultaneous quantification of 70 PL species within a run of 45 min. Application of this method to the quantification of PLs in 32 bovine milk samples revealed the relative abundance of different PL classes, significant variation of PL content between individual samples and the correlation between the major PL classes. The method provides a tool for investigating the variation and metabolism of important PL components in bovine and human milk and in diverse mammalian species. PMID- 25531877 TI - Multi-residues determination of antimicrobials in fish tissues by HPLC-ESI-MS/MS method. AB - A rapid, simple, sensitive and specific LC-MS/MS method was developed and validated for the simultaneous quantification of four antimicrobials commonly used in aquaculture, namely ciprofloxacin (CPX), trimethoprim (TMP), sulphadimethoxine (SDM) and florphenicol (FLOR) in fish tissues. The LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Sample preparation involves simple liquid extraction step followed by post-extraction clean-up step with n-hexane. The purified extracts were chromatographed on Agilent Poroshell 120 EC, C18 (50 mm * 3 mm, 2.7 MUm) column by pumping an isocratic mobile phase consisting of 0.1% formic acid in water:0.1% formic acid in methanol (20:80, by volume) at a flow rate of 0.4 mL/min. A detailed validation of the method was performed as per FDA guidelines and the standard curves were found to be linear in the range of 1-100 ng/g for both CPX and TMP, 0.5-100 ng/g for SDM and 1-50 ng/g for FLOR. The intra-day and inter-day precision and accuracy of the results were within the acceptable limits. A run time of 1.5 min for each sample made it possible to analyze multiple fish tissue samples per day. The developed assay method was successfully applied for the detection of antimicrobials in real fish tissue samples obtained from different fish farms. PMID- 25531878 TI - Nonparametric hemodynamic deconvolution of FMRI using homomorphic filtering. AB - Functional magnetic resonance imaging (fMRI) is an indirect measure of neural activity which is modeled as a convolution of the latent neuronal response and the hemodynamic response function (HRF). Since the sources of HRF variability can be nonneural in nature, the measured fMRI signal does not faithfully represent underlying neural activity. Therefore, it is advantageous to deconvolve the HRF from the fMRI signal. However, since both latent neural activity and the voxel specific HRF is unknown, the deconvolution must be blind. Existing blind deconvolution approaches employ highly parameterized models, and it is unclear whether these models have an over fitting problem. In order to address these issues, we 1) present a nonparametric deconvolution method based on homomorphic filtering to obtain the latent neuronal response from the fMRI signal and, 2) compare our approach to the best performing existing parametric model based on the estimation of the biophysical hemodynamic model using the Cubature Kalman Filter/Smoother. We hypothesized that if the results from nonparametric deconvolution closely resembled that obtained from parametric deconvolution, then the problem of over fitting during estimation in highly parameterized deconvolution models of fMRI could possibly be over stated. Both simulations and experimental results demonstrate support for our hypothesis since the estimated latent neural response from both parametric and nonparametric methods were highly correlated in the visual cortex. Further, simulations showed that both methods were effective in recovering the simulated ground truth of the latent neural response. PMID- 25531879 TI - Effects of ultrapure hemodialysis and low molecular weight heparin on the endothelial surface layer. AB - BACKGROUND: Chronic kidney disease patients show changes in the endothelial surface layer (ESL). Whether hemodialysis (HD) itself or low molecular weight heparins (LMWH) induce ESL alterations is unknown. METHODS: We studied the ESL in 20 HD patients with Sidestream Dark Field Imaging [measuring perfused boundary region (PBR)] and measurement of ESL constituents in plasma during HD in 2 studies. LMWH was administered at the start of HD in study A, and 120 min after the start of HD in study B. Mean platelet volume (MPV) and platelet large cell ratio (P-LCR) were also measured. RESULTS: Syndecan-1 increased significantly 30 min after LMWH administration. sP-Selectin increased 120 min after HD start, and MPV and P-LCR decreased significantly during HD. No significant changes of PBR, sE-Selectin, sICAM-1, or sVCAM-1 were perceived. CONCLUSIONS: HD caused a significant increase in Syndecan-1 without a change in PBR. The administration of LMWH appeared to precede the rise in Syndecan-1. PMID- 25531880 TI - mTORC2 is required for rit-mediated oxidative stress resistance. AB - Rit, a member of the Ras family of GTPases, has been shown to promote cell survival in response to oxidative stress, in part by directing an evolutionarily conserved p38 MAPK-Akt survival cascade. Aberrant Rit signaling has recently been implicated as a driver mutation in human cancer, adding importance to the characterization of critical Rit effector pathways. However, the mechanism by which Rit-p38 signaling regulated Akt activity was unknown. Here, we identify mTORC2 as a critical downstream mediator of Rit-dependent survival signaling in response to reactive oxygen species (ROS) stress. Rit interacts with Sin1 (MAPKAP1), and Rit loss compromises ROS-dependent mTORC2 complex activation, blunting mTORC2-mediated phosphorylation of Akt kinase. Taken together, our findings demonstrate that the p38/mTORC2/Akt signaling cascade mediates Rit dependent oxidative stress survival. Inhibition of this previously unrecognized cascade should be explored as a potential therapy of Rit-dependent malignancies. PMID- 25531882 TI - General regression and representation model for classification. AB - Recently, the regularized coding-based classification methods (e.g. SRC and CRC) show a great potential for pattern classification. However, most existing coding methods assume that the representation residuals are uncorrelated. In real-world applications, this assumption does not hold. In this paper, we take account of the correlations of the representation residuals and develop a general regression and representation model (GRR) for classification. GRR not only has advantages of CRC, but also takes full use of the prior information (e.g. the correlations between representation residuals and representation coefficients) and the specific information (weight matrix of image pixels) to enhance the classification performance. GRR uses the generalized Tikhonov regularization and K Nearest Neighbors to learn the prior information from the training data. Meanwhile, the specific information is obtained by using an iterative algorithm to update the feature (or image pixel) weights of the test sample. With the proposed model as a platform, we design two classifiers: basic general regression and representation classifier (B-GRR) and robust general regression and representation classifier (R-GRR). The experimental results demonstrate the performance advantages of proposed methods over state-of-the-art algorithms. PMID- 25531883 TI - A computational study of stimulus driven epileptic seizure abatement. AB - Active brain stimulation to abate epileptic seizures has shown mixed success. In spike-wave (SW) seizures, where the seizure and background state were proposed to coexist, single-pulse stimulations have been suggested to be able to terminate the seizure prematurely. However, several factors can impact success in such a bistable setting. The factors contributing to this have not been fully investigated on a theoretical and mechanistic basis. Our aim is to elucidate mechanisms that influence the success of single-pulse stimulation in noise induced SW seizures. In this work, we study a neural population model of SW seizures that allows the reconstruction of the basin of attraction of the background activity as a four dimensional geometric object. For the deterministic (noise-free) case, we show how the success of response to stimuli depends on the amplitude and phase of the SW cycle, in addition to the direction of the stimulus in state space. In the case of spontaneous noise-induced seizures, the basin becomes probabilistic introducing some degree of uncertainty to the stimulation outcome while maintaining qualitative features of the noise-free case. Additionally, due to the different time scales involved in SW generation, there is substantial variation between SW cycles, implying that there may not be a fixed set of optimal stimulation parameters for SW seizures. In contrast, the model suggests an adaptive approach to find optimal stimulation parameters patient-specifically, based on real-time estimation of the position in state space. We discuss how the modelling work can be exploited to rationally design a successful stimulation protocol for the abatement of SW seizures using real-time SW detection. PMID- 25531884 TI - Systematic Omics Analysis Review (SOAR) tool to support risk assessment. AB - Environmental health risk assessors are challenged to understand and incorporate new data streams as the field of toxicology continues to adopt new molecular and systems biology technologies. Systematic screening reviews can help risk assessors and assessment teams determine which studies to consider for inclusion in a human health assessment. A tool for systematic reviews should be standardized and transparent in order to consistently determine which studies meet minimum quality criteria prior to performing in-depth analyses of the data. The Systematic Omics Analysis Review (SOAR) tool is focused on assisting risk assessment support teams in performing systematic reviews of transcriptomic studies. SOAR is a spreadsheet tool of 35 objective questions developed by domain experts, focused on transcriptomic microarray studies, and including four main topics: test system, test substance, experimental design, and microarray data. The tool will be used as a guide to identify studies that meet basic published quality criteria, such as those defined by the Minimum Information About a Microarray Experiment standard and the Toxicological Data Reliability Assessment Tool. Seven scientists were recruited to test the tool by using it to independently rate 15 published manuscripts that study chemical exposures with microarrays. Using their feedback, questions were weighted based on importance of the information and a suitability cutoff was set for each of the four topic sections. The final validation resulted in 100% agreement between the users on four separate manuscripts, showing that the SOAR tool may be used to facilitate the standardized and transparent screening of microarray literature for environmental human health risk assessment. PMID- 25531886 TI - [Au(dien)(N-heterocycle)](3+): reactivity with biomolecules and zinc finger peptides. AB - The reaction of [Au(dien)(N-heterocycle)](3+) (AuN4) coordination compounds with simple amino acids and zinc finger proteins is reported. Compared to [AuCl(dien)](2+), NMR studies show that the presence of a more substitution-inert N-donor as the putative leaving group slows the reaction with the sulfur containing amino acids N-acetylmethionine (NAcMet) and N-acetylcysteine (NAcCys). Lack of ligand dissociation upon reaction with NAcCys indicates, to our knowledge, the first long-lived N-heterocycle-Au-S species in solution. Reactions with zinc finger proteins show a higher reactivity with the Cys3His zinc finger than with Cys2His2, likely due to the presence of fewer aurophilic cysteines in the latter. Of the Au(III) compounds studied, [Au(dien)(DMAP)](3+) (DMAP = 4 dimethylaminopyridine) appears to be the least reactive, with ESI-MS studies showing the presence of intact zinc fingers at initial reaction times. These results, in combination with previously reported characterization and pH dependency studies, will further aid in optimizing the structure of these AuN4 species to obtain a substitution-reactive yet selective compound for targeting zinc finger proteins. PMID- 25531885 TI - SNP typing for germplasm identification of Amomum villosum Lour. Based on DNA barcoding markers. AB - Amomum villosum Lour., produced from Yangchun, Guangdong Province, China, is a Daodi medicinal material of Amomi Fructus in traditional Chinese medicine. This herb germplasm should be accurately identified and collected to ensure its quality and safety in medication. In the present study, single nucleotide polymorphism typing method was evaluated on the basis of DNA barcoding markers to identify the germplasm of Amomi Fructus. Genomic DNA was extracted from the leaves of 29 landraces representing three Amomum species (A. villosum Lour., A. xanthioides Wall. ex Baker and A. longiligulare T. L. Wu) by using the CTAB method. Six barcoding markers (ITS, ITS2, LSU D1-D3, matK, rbcL and trnH-psbA) were PCR amplified and sequenced; SNP typing and phylogenetic analysis were performed to differentiate the landraces. Results showed that high-quality bidirectional sequences were acquired for five candidate regions (ITS, ITS2, LSU D1-D3, matK, and rbcL) except trnH-psbA. Three ribosomal regions, namely, ITS, ITS2, and LSU D1-D3, contained more SNP genotypes (STs) than the plastid genes rbcL and matK. In the 29 specimens, 19 STs were detected from the combination of four regions (ITS, LSU D1-D3, rbcL, and matK). Phylogenetic analysis results further revealed two clades. Minimum-spanning tree demonstrated the existence of two main groups: group I was consisting of 9 STs (ST1-8 and ST11) of A. villosum Lour., and group II was composed of 3 STs (ST16-18) of A. longiligulare T.L. Wu. Our results suggested that ITS and LSU D1-D3 should be incorporated with the core barcodes rbcL and matK. The four combined regions could be used as a multiregional DNA barcode to precisely differentiate the Amomi Fructus landraces in different producing areas. PMID- 25531887 TI - High-k gate stacks on low bandgap tensile strained Ge and GeSn alloys for field effect transistors. AB - We present the epitaxial growth of Ge and Ge0.94Sn0.06 layers with 1.4% and 0.4% tensile strain, respectively, by reduced pressure chemical vapor deposition on relaxed GeSn buffers and the formation of high-k/metal gate stacks thereon. Annealing experiments reveal that process temperatures are limited to 350 degrees C to avoid Sn diffusion. Particular emphasis is placed on the electrical characterization of various high-k dielectrics, as 5 nm Al2O3, 5 nm HfO2, or 1 nmAl2O3/4 nm HfO2, on strained Ge and strained Ge0.94Sn0.06. Experimental capacitance-voltage characteristics are presented and the effect of the small bandgap, like strong response of minority carriers at applied field, are discussed via simulations. PMID- 25531888 TI - Oxidized low-density lipoprotein promotes osteoblastic differentiation of valvular interstitial cells through RAGE/MAPK. AB - OBJECTIVES: We have previously shown that oxidized low-density lipoprotein (oxLDL) promotes the osteogenic differentiation of valvular interstitial cells (VICs) by inducing endoplasmic reticulum (ER) stress. We also demonstrated the detrimental role of the receptor for advanced glycation end products (RAGE) activation and signaling in the development and progression of aortic valve (AV) calcification. Here, we test the hypothesis that oxLDL may induce the osteoblastic differentiation of VICs via RAGE. METHODS: Cultured porcine aortic VICs were used in an in vitro model. The VICs were incubated with oxLDL for analysis, with and without RAGE siRNA. RESULTS: We found that oxLDL markedly increased the expression of RAGE, induced high levels of proinflammatory cytokine production and promoted the osteoblastic differentiation and calcification of VICs. oxLDL also induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) MAPK. However, these effects were found to be markedly suppressed by siRNA silencing of RAGE. CONCLUSIONS: Our data provide evidence that RAGE mediates oxLDL-induced activation of p38 and JNK MAPK and the osteogenic differentiation of VICs. PMID- 25531889 TI - Expression patterns of HvCKX genes indicate their role in growth and reproductive development of barley. AB - Cytokinin oxidase/dehydrogenase proteins (CKX) are encoded by a multigene family of CKX genes with a varying number of members depending on species. For some of the genes, spectacular effects on grain production in selected cereals have been observed. Despite the fact that partial or full length sequences of most HvCKX genes in barley (Hordeum vulgare) have already been published, in most cases their specific biological functions have not been reported. Detailed expression patterns for five HvCKX genes in different organs/tissues of developing barley plants coupled with analysis of RNAi silent for two genes are presented to test the hypothesis that these expression profiles might indicate their function. Elevated expression for four of them - HvCKX1, HvCKX9, HvCKX4, and HvCKX11 - was found in developing kernels of wild-type plants compared to other tissues. HvCKX5 was mainly expressed in leaf tissue. Lower expression was noted for HvCKX1 in seedling roots and for HvCKX9 in leaves. The documented effect of RNAi silencing of HvCKX1 and a trend for HvCKX9 was higher plant productivity, and the trait was inherited through four generations. Higher plant yield was determined by higher numbers of seeds and spikes. Increased productivity was significantly greater in HvCKX1 silenced plants showing higher relative expression of HvCKX1 in developing kernels of wild-type plants compared to the expression of HvCKX9. Both HvCKX1 silenced T1 seedlings of cv. Golden Promise and the newly transformed breeding line STH7308 showed greater root mass, but this trait was not inherited in the next generation. Similarly HvCKX9 silenced T1 seedlings exhibited greater plant height without inheritance in the next generation. It is suggested that these effects were not inherited because of compensation by other genes co-ordinately regulating reproductive development. One line with untypically changed, inherited phenotype, which was selected from several dozen silenced lines showing stable and common phenotypes is presented. PMID- 25531890 TI - miR-CLIP capture of a miRNA targetome uncovers a lincRNA H19-miR-106a interaction. AB - Identifying the interaction partners of noncoding RNAs is essential for elucidating their functions. We have developed an approach, termed microRNA crosslinking and immunoprecipitation (miR-CLIP), using pre-miRNAs modified with psoralen and biotin to capture their targets in cells. Photo-crosslinking and Argonaute 2 immunopurification followed by streptavidin affinity purification of probe-linked RNAs provided selectivity in the capture of targets, which were identified by deep sequencing. miR-CLIP with pre-miR-106a, a miR-17-5p family member, identified hundreds of putative targets in HeLa cells, many carrying conserved sequences complementary to the miRNA seed but also many that were not predicted computationally. miR-106a overexpression experiments confirmed that miR CLIP captured functional targets, including H19, a long noncoding RNA that is expressed during skeletal muscle cell differentiation. We showed that miR-17-5p family members bind H19 in HeLa cells and myoblasts. During myoblast differentiation, levels of H19, miR-17-5p family members and mRNA targets changed in a manner suggesting that H19 acts as a 'sponge' for these miRNAs. PMID- 25531892 TI - Biosynthesis: a terminal triple bond toolbox. PMID- 25531891 TI - De novo biosynthesis of terminal alkyne-labeled natural products. AB - The terminal alkyne is a functionality widely used in organic synthesis, pharmaceutical science, material science and bioorthogonal chemistry. This functionality is also found in acetylenic natural products, but the underlying biosynthetic pathways for its formation are not well understood. Here we report the characterization of what is to our knowledge the first carrier protein dependent terminal alkyne biosynthetic machinery in microbes. We further demonstrate that this enzymatic machinery can be exploited for the in situ generation and incorporation of terminal alkynes into two natural product scaffolds in Escherichia coli. These results highlight the prospect for tagging major classes of natural products, including polyketides and polyketide/nonribosomal peptide hybrids, using biosynthetic pathway engineering. PMID- 25531893 TI - Personalized adapted physical activity before liver transplantation: acceptability and results. AB - BACKGROUND: Altered aerobic capacity and muscular strength among patients suffering from cirrhosis are poor prognosis factors of the overall survival after liver transplantation (LT). A program of adapted physical activity (APA) is recommended in patients awaiting solid organ transplantation. However, there is no standard program in LT, and therefore none is applied. METHODS: Prospective pilot study to evaluate the acceptability of a 12-week personalized APA and its impact on aerobic capacity, muscle strength, and quality of life before LT. RESULTS: Thirteen patients (six men, seven women) were included. Five patients interrupted the program: two for personal convenience, two were transplanted before the end of the program, and one for deterioration of the general condition. Eight patients (mean age, 51 +/- 12 years; mean Child Pugh, 7 +/- 3; and mean model for end-stage liver disease score, 13 +/- 6) completed the program. The mean VO2 peak values increased from 21.5 +/- 5.9 mL/kg per min at baseline to 23.2 +/- 5.9 mL/kg per min after 12 weeks of training (P<0.008). The maximum power (P=0.02), the 6-min walk distance (P<0.02), the strength testing of knee extensor muscles (P=0.008), and the ventilatory threshold power (P=0.02) were also significantly increased. Quality of life scale showed a global trend to improvement. No adverse event was observed. CONCLUSION: A personalized and standardized APA is acceptable, effective and safe in patients awaiting LT. It positively influences the index of fitness and quality of life. Its promising impact on the posttransplantation period, duration of hospitalization, and 6 month survival needs to be prospectively evaluated in a large randomized study. PMID- 25531895 TI - Quantifying prognostic impact of prescription opioid use before kidney transplantation through linked registry and pharmaceutical claims data. AB - BACKGROUND: Limited data are available on the outcome implications of prescription narcotic use before kidney transplantation. METHODS: We examined a novel database wherein national transplant registry identifiers for kidney transplant recipients were linked to records from a large U.S. pharmaceutical claims clearinghouse (2005-2010). We selected recipients with 1 year of captured pretransplant pharmaceutical fill records (N=31,197). Opioid analgesic fills in the year before transplantation were normalized to morphine equivalents (ME) and expressed as mg/kg exposures. Adjusted associations of ME level with posttransplant graft and patient survival (adjusted hazards ratio, aHR) were quantified by multivariate Cox regression. RESULTS: Among the 29% of the sample who filled opioid prescriptions in the year before transplantation, the 25th, 50th, and 75th percentiles of annual ME were 1.8, 5.5, and 23.7 mg/kg, respectively. Three-year graft survival was 88.0% and 84.4% in live donor recipients with upper quartiles of ME use, compared with 92.0% among those who did not receive prescription narcotics (P<0.0001). Adjusted risks of posttransplant death and all-cause graft loss in live donor recipients with the highest quartile of narcotic use were 2.3 times (aHR, 2.27; 95% confidence interval, 1.66-3.10) and 1.8 times (aHR, 1.75; 95% confidence interval, 1.37 2.26), respectively, that of narcotic nonusers. Graded associations of pretransplant opioid exposure level with death and graft loss after deceased donor transplantation were also observed. CONCLUSIONS: Although associations may in part reflect underlying conditions or behaviors, high levels of prescription opioid use before kidney transplantation predict increased risk of posttransplant death and graft loss. PMID- 25531894 TI - Antithymocyte globulin facilitates alloreactive T-cell apoptosis by means of caspase-3: potential implications for monitoring rejection-free outcomes. AB - BACKGROUND: Alloreactive T-cell apoptosis may explain reduced immunosuppression requirements with proapoptotic immunosuppression and among rejection-free recipients. This possibility remains unproven. METHODS: Apoptotic (caspase-3+, cathepsin B+) and inflammatory (CD154+) T-cell subsets were evaluated before and after adding rabbit antithymocyte globulin (rATG) to mixed lymphocyte co-cultures between human leukocyte antigen-mismatched peripheral blood lymphocytes from healthy adults. In random samples from children with liver (LTx-20) and intestine (ITx-13) transplantation, apoptotic T cells were evaluated for association with rejection-free outcomes using the caspase-3 substrate, phiphilux. RESULTS: In mixed lymphocyte co-cultures between normal human peripheral blood lymphocytes, (1) frequencies of memory (M) and naive (N) Th and Tc, which expressed activated caspase-3, were enhanced most by the combination of allostimulation and rATG, than either stimulus alone. These findings were confirmed with antibody to activated caspase-3, phiphilux, and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay; (2) frequencies of Th subsets, which expressed activated cathepsin B, were similarly increased with combined stimulation. Tc seemed resistant to cathepsin B activation; (3) with increasing rATG concentrations, proportionately more allospecific CD154+T-cytotoxic memory cells (TcM) survived than TcM, resulting in relative enrichment of allospecific CD154+TcM. In random blood samples, phiphilux+T-cell subset frequencies were higher among 14 rejection-free LTx and ITx recipients and demonstrated a greater increase with ex vivo rATG pretreatment than 19 rejectors. In logistic regression analysis, phiphilux+TcM associated best with rejection-free outcomes with a sensitivity of 57% and a specificity of 89%. CONCLUSION: Rabbit antithymocyte globulin facilitates apoptosis of alloreactive T cells by means of caspase-3 activation, which may explain its steroid-sparing effect in pediatric liver and intestine recipients. Apoptotic susceptibility of T-cytotoxic memory cells, which resist cathepsin B activation, may distinguish rejection-free and rejection-prone liver recipients. PMID- 25531897 TI - SERS optrode as a "fishing rod" to direct pre-concentrate analytes from superhydrophobic surfaces. AB - SERS optrodes were used to "fish" aqueous drops from superhydrophobic surfaces. The technique led to an improvement of 2-3 orders of magnitude in the lowest detectable amount of the Raman probe nile blue A, reaching 25 fg (34 attomoles). Further tests run on samples containing pesticide revealed that 20 pg of triazophos could be clearly detected from a single drop. PMID- 25531896 TI - Disparities in completion rates of the medical prerenal transplant evaluation by race or ethnicity and gender. AB - BACKGROUND: A significant number of potential kidney transplant candidates do not complete the required medical evaluation after referral to a transplant program. METHODS: Factors associated with rate of completion of the renal transplant evaluation were analyzed using a retrospective chart review of patients first seen between October 1, 2009, and September 30, 2010 (n=256). The primary endpoint was completion in 12 months. Independent variables included socioeconomic, demographic, and medical factors. RESULTS: Mean age was 50.7 years; 49.6% were black, 28.5% Hispanic, and 21.9% white and other; 26.3% did not require dialysis. During follow-up, 23.4% did not complete the evaluation. Multivariable analysis indicated that slower rates of completion were associated with needing a greater number of medical tests (compared to 0-2: 3-5 tests, hazard ratio [HR]=0.65, P=0.02; >= 6 tests, HR=0.47, P=0.0005) and requiring more than one hospitalization (compared to none: HR=0.37, P=0.0008). A significant interaction between race or ethnicity and gender on completion was found: compared to black men, Hispanic men (HR=2.75, P<0.0001), Hispanic women (HR=1.96, P=0.006), and white men (HR=1.99, P=0.005) showed a more rapid completion. In comparison, black and white women (HR=1.38, P=0.16; HR=0.94, P=0.83, respectively) were not significantly different from black men in rates of completion. Differences by race or ethnicity and gender were not confounded by socioeconomic variables or social support. CONCLUSION: To lessen barriers and facilitate renal transplantation, black men and women, white women, and patients needing multiple medical tests and requiring several hospitalizations may benefit from additional assistance during the medical evaluation process. PMID- 25531899 TI - Systemic testing on Bradley-Terry model against nonlinear ranking hierarchy. AB - We take a system point of view toward constructing any power or ranking hierarchy onto a society of human or animal players. The most common hierarchy is the linear ranking, which is habitually used in nearly all real-world problems. A stronger version of linear ranking via increasing and unvarying winning potentials, known as Bradley-Terry model, is particularly popular. Only recently non-linear ranking hierarchy is discussed and developed through recognition of dominance information contents beyond direct dyadic win-and-loss. We take this development further by rigorously arguing for the necessity of accommodating system's global pattern information contents, and then introducing a systemic testing on Bradley-Terry model. Our test statistic with an ensemble based empirical distribution favorably compares with the Deviance test equipped with a Chi-squared asymptotic approximation. Several simulated and real data sets are analyzed throughout our development. PMID- 25531898 TI - Identification and molecular characterization of microneme 5 of Eimeria acervulina. AB - In the present study, the microneme 5 gene of Eimeria acervulina (E. acervulina) (EaMIC5) was cloned and characterized. Specific primers for the rapid amplification of cDNA ends (RACE) were designed based on the expressed sequence tag (EST, GenBank Accession No. EH386430.1) to amplify the 3'- and 5'-ends of EaMIC5. The full length cDNA of this gene was obtained by overlapping the sequences of 3'- and 5'-extremities and amplification by reverse transcription PCR. Sequence analysis revealed that the open reading frame (ORF) of EaMIC5 was 336 bp and encoded a protein of 111 amino acids with 12.18 kDa. The ORF was inserted into pET-32a (+) to produce recombinant EaMIC5. Using western blotting assay, the recombinant protein was successfully recognized by the sera of chicks experimentally infected with E. acervulina, while the native protein in the somatic extract of sporozoites was as well detected by sera from rats immunized with the recombinant protein of EaMIC5. Immunofluorescence analysis using antibody against recombinant protein EaMIC5 indicated that this protein was expressed in the sporozoites and merozoites stages of E. acervulina. Animal challenge experiments demonstrated that the recombinant protein of EaMIC5 could significantly increase the average body weight gains, decrease the mean lesion scores and the oocyst outputs of the immunized chickens, and presented anti coccidial index (ACI) more than 160. All the above results suggested that the EaMIC5 was a novel E. acervulina antigen and could be an effective candidate for the development of a new vaccine against this parasite. PMID- 25531900 TI - Long-term sickness absence due to mental disorders is associated with individual features and psychosocial work conditions. AB - AIMS: Sickness absence is a socioeconomic global burden. In Brazil, mental disorders are the third leading cause of social security benefits payments. The aim of the present study was to compare factors associated with long-term sickness absence between workers who claimed social benefits due to mental disorders or by other causes. We investigated individual features and occupational characteristics. In addition, we evaluated psychosocial factors at work assessed by the Demand-Control-Support (DCS) and Effort-Reward Imbalance (ERI) models, and whether they were associated with long-term sickness absence due to mental disorders (LTSA-MD). METHODS: The present case-control study was conducted in Sao Paulo, Brazil. The sample (n = 385) included workers on sick leave for more than 15 days. Cases were the participants with disabling psychiatric illnesses, and controls were the ones with other disabling diseases. Interviews were conducted to assess individual features (sociodemographic data, health habits/lifestyle, health conditions) and occupational characteristics. The participants' perception of exposure to dimensions of the DCS and ERI models was also recorded. Multiple logistic regressions were performed to evaluate the association between independent variables and LTSA-MD. RESULTS: All the regression analyses showed that LTSA-MD was associated with female sex, self reported white skin color, higher education level, high tobacco consumption, high alcohol intake, two or more comorbidities, exposure to violence at work, high job strain and low social support at work, effort-reward imbalance and high overcommitment to work. LTSA-MD was associated with separate and combined DCS and ERI stress models. CONCLUSIONS: Individual features and work conditions were associated with LTSA-MD. Combined analysis of stress models showed that psychosocial factors at work were significantly associated with LTSA-MD. Resourceful use of this information may contribute to the implementation of preventive actions and strategies to facilitate return to work targeting the populations most susceptible to mental disorders. PMID- 25531901 TI - Predictors of viral pneumonia in patients with community-acquired pneumonia. AB - BACKGROUND: Viruses are increasingly recognized as major causes of community acquired pneumonia (CAP). Few studies have investigated the clinical predictors of viral pneumonia, and the results have been inconsistent. In this study, the clinical predictors of viral pneumonia were investigated in terms of their utility as indicators for viral pneumonia in patients with CAP. METHODS: Adult patients (>= 18 years old) with CAP, tested by polymerase chain reaction (PCR) for respiratory virus, at two teaching hospitals between October 2010 and May 2013, were identified retrospectively. Demographic and clinical data were collected by reviewing the hospital electronic medical records. RESULTS: During the study period, 456 patients with CAP were identified who met the definition, and 327 (72%) patients were tested using the respiratory virus PCR detection test. Viral pneumonia (n = 60) was associated with rhinorrhea, a higher lymphocyte fraction in the white blood cells, lower serum creatinine and ground glass opacity (GGO) in radiology results, compared to non-viral pneumonia (n = 250) (p < 0.05, each). In a multivariate analysis, rhinorrhea (Odd ratio (OR) 3.52; 95% Confidence interval (CI), 1.58-7.87) and GGO (OR 4.68; 95% CI, 2.48 8.89) were revealed as independent risk factors for viral pneumonia in patients with CAP. The sensitivity, specificity, positive- and negative-predictive values (PPV and NPV) of rhinorrhea were 22, 91, 36 and 83%: the sensitivity, specificity, PPV and NPV of GGO were and 43, 84, 40 and 86%, respectively. CONCLUSION: Symptom of rhinorrhea and GGO predicted viral pneumonia in patients with CAP. The high specificity of rhinorrhea and GGO suggested that these could be useful indicators for empirical antiviral therapy. PMID- 25531903 TI - Contribution of temperature to deformation of adsorbed vesicles studied by nanoplasmonic biosensing. AB - With increasing temperature, biological macromolecules and nanometer-sized aggregates typically undergo complex and poorly understood reconfigurations, especially in the adsorbed state. Herein, we demonstrate the strong potential of using localized surface plasmon resonance (LSPR) sensors to address challenging questions related to this topic. By employing an LSPR-based gold nanodisk array platform, we have studied the adsorption of sub-100-nm diameter 1,2-dipalmitoyl sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid vesicles on titanium oxide at two temperatures, 23 and 50 degrees C. Inside this temperature range, DPPC lipid vesicles undergo the gel-to-fluid phase transition accompanied by membrane area expansion, while DOPC lipid vesicles remain in the fluid-phase state. To interpret the corresponding measurement results, we have derived general equations describing the effect of deformation of adsorbed vesicles on the LSPR signal. At the two temperatures, the shape of adsorbed DPPC lipid vesicles on titanium oxide remains nearly equivalent, while DOPC lipid vesicles become less deformed at higher temperature. Adsorption and rupture of DPPC lipid vesicles on silicon oxide were also studied for comparison. In contrast to the results obtained on titanium oxide, adsorbed vesicles on silicon oxide become more deformed at higher temperature. Collectively, the findings demonstrate that increasing temperature may ultimately promote, hinder, or have negligible effect on the deformation of adsorbed vesicles. The physics behind these observations is discussed, and helps to clarify the interplay of various, often hidden, factors involved in adsorption of biological macromolecules at interfaces. PMID- 25531902 TI - Medication reconciliation in patients hospitalized in a cardiology unit. AB - OBJECTIVES: To compare drugs prescribed on hospital admission with the list of drugs taken prior to admission for adult patients admitted to a cardiology unit and to identify the role of a pharmacist in identifying and resolving medication discrepancies. METHOD: This study was conducted in a 300 bed university hospital in Brazil. Clinical pharmacists taking medication histories and reconciling medications prescribed on admission with a list of drugs used prior to admission. Discrepancies were classified as justified (e.g., based on the pharmacotherapeutic guidelines of the hospital studied) or unintentional. Treatments were reviewed within 48 hours following hospitalization. Unintentional discrepancies were further classified according to the categorization of medication error severity. Pharmacists verbally contacted the prescriber to recommend actions to resolve the discrepancies. RESULTS: A total of 181 discrepancies were found in 50 patients (86%). Of these discrepancies, 149 (82.3%) were justified changes to the patient's home medication regimen; however, 32 (17.7%) discrepancies found in 24 patients were unintentional. Pharmacists made 31 interventions and 23 (74.2%) were accepted. Among unintentional discrepancies, the most common was a different medication dose on admission (42%). Of the unintentional discrepancies 13 (40.6%) were classified as error without harm, 11 (34.4%) were classified as error without harm but which could affect the patient and require monitoring, 3 (9.4%) as errors could have resulted in harm and 5 (15.6%) were classified as circumstances or events that have the capacity to cause harm. CONCLUSION: The results revealed a high number of unintentional discrepancies and the pharmacist can play an important role by intervening and correcting medication errors at a hospital cardiology unit. PMID- 25531904 TI - Comparison of bond strength of self-etch adhesive to pulp chamber dentin after placement of calcium hydroxide and various antibiotic pastes. AB - OBJECTIVE: The aim of this study was to evaluate the effect of calcium hydroxide, double antibiotic paste (DAP) and triple antibiotic paste (TAP) with minocycline, cefaclor and amoxicillin on the micro tensile bond strength (uTBS) of self-etch adhesive to pulp chamber dentin. MATERIALS AND METHODS: Sixty mandibular first molars were cut horizontally and randomly divided into a control group and five experimental groups, which received an intra-canal dressing, as follows: calcium hydroxide, DAP, TAP with minocycline, TAP with cefaclor and TAP with amoxicillin. After storing the specimens for 4 weeks, the medicaments were removed by irrigation with 10 mL each of the following solution: 2.5% NaOCl, 17% EDTA and distilled water. A self-etch adhesive (Clearfil S3 Bond, Okayama, Japan) was applied and composite resin (Clearfil Majesty Posterior, Kuraray Medical Inc., Japan) was placed into the cavity. A uTBS test was performed on each specimen using a universal test machine. RESULTS: The DAP reduced the uTBS of self-etch adhesive compared to the control group, calcium hydroxide and TAP with minocycline and with cefaclor (p < 0.05). However, the other medicaments did not result in a decreased uTBS of self-etch adhesive to pulp chamber dentin as compared to the control group (p > 0.05). CONCLUSIONS: The use of DAP resulted in a reduced uTBS of self-etch adhesive to pulp chamber dentin. PMID- 25531906 TI - Occupational injuries prone to infectious risks amongst healthcare personnel in Kuwait: a retrospective study. AB - OBJECTIVE: The study aimed at determining the prevalence of incident occupational exposure to blood and other potentially infectious materials (OPIM) among healthcare personnel (HCP) during 2010 and at evaluating the factors associated with these incidents. SUBJECTS AND METHODS: An epidemiological, retrospective, record-based study was conducted. All self-reported incidents of occupational exposure to blood and OPIM among HCP from all healthcare settings of the Kuwait Ministry of Health during 2010 were included. RESULTS: The total number of the exposed HCP was 249. The prevalence of incident exposure was 0.7% of the HCP at risk. Their mean age was 32.31 +/- 6.98 years. The majority were nurses: 166 (66.7%), followed by doctors: 35 (14.1%), technicians: 26 (10.4%) and housekeeping personnel: 22 (8.8%). Needle stick injury was the most common type of exposure, in 189 (75.9%), followed by sharp-object injury, mucous-membrane exposure and contact with nonintact skin. The majority of needle stick exposures, i.e. 177 (93.7%), were caused by hollow-bore needles. Exposure to blood represented 96.8%, mostly during drawing blood and the insertion or removal of needles from patients [88 (35.4%)] and when performing surgical interventions [56 (22.6%)]. Easily preventable exposures such as injuries related to 2-handed recapping of needles [24 (9.6%)] and garbage collection [21 (8.4%)] were reported. Exposures mainly occurred in the inpatient wards [75 (30.1%)] and operating theaters [56 (22.6%)]. Among the exposed HCP, 130 (52.2%) had been fully vaccinated against hepatitis B virus (HBV). CONCLUSION: Needle stick injuries are the most common exposure among HCP in Kuwait, and nurses are the most frequently involved HCP category. A good proportion of exposures could be easily prevented. HBV vaccination coverage is incomplete. PMID- 25531907 TI - Heteroatom-bridged benzothiazolyls for organic solar cells: a theoretical study. AB - On the basis of a typical organic photovoltaic (OPV) building block of 4,7 di(thiophen-2-yl)benzo[c][1,2,5]thiadiazole (DTBT), a series of novel DTBT derivatives were designed following a heteroatom-bridging strategy to take advantage of the diversified interactions between heteroatoms and pi-conjugated systems. These heteroatom-bridged DTBTs, whose outer electron-rich thiophene moieties are covalently fastened to the central electron-deficient benzothiadiazole with additional heteroatom bridges, exhibit promising features for OPV applications with rigid molecular structures, properly lain frontier molecular orbitals (FMOs), broad and intense absorption spectra, and adequate charge transport properties, as revealed by systematic theoretical calculations on molecular geometries, FMOs, absorption spectra, and relaxation and reorganization energies. The structure-property relationship investigations show that the mono-/di-heteroatom bridging is effective not only in tuning the rigidity of the molecular geometries but also in adjusting the optoelectronic properties of the resulting materials. Among the studied heteroatoms, the C and Si were found to be the most efficient in designing novel molecules for OPV applications. These theoretical insights may provide a solid basis for experimental synthesis and device investigations of the proposed heteroatom bridged DTBTs as potential high-performance building blocks for bulk heterojunction OPV molecules. PMID- 25531905 TI - Collagen structure and mechanical properties of the human sclera: analysis for the effects of age. AB - The objective of this study was to measure the collagen fiber structure and estimate the material properties of 7 human donor scleras, from age 53 to 91. The specimens were subjected to inflation testing, and the full-field displacement maps were measured by digital image correlation. After testing, the collagen fiber structure was mapped using wide-angle X-ray scattering. A specimen-specific inverse finite element method was applied to calculate the material properties of the collagen fibers and interfiber matrix by minimizing the difference between the experimental displacements and model predictions. Age effects on the fiber structure and material properties were estimated using multivariate models accounting for spatial autocorrelation. Older age was associated with a larger matrix stiffness (p = 0.001), a lower degree of fiber alignment in the peripapillary sclera (p = 0.01), and a lower mechanical anisotropy in the peripapillary sclera (p = 0.03). PMID- 25531908 TI - The tumor suppressor miR-124 inhibits cell proliferation by targeting STAT3 and functions as a prognostic marker for postoperative NSCLC patients. AB - The aim of the present study was to investigate the role of miR-124 in lung cancer and identify the potential predictive value of miR-124 in postoperative non-small cell lung cancer (NSCLC) patients. We detected miR-124 expression in A549, NCL-H460 and normal lung epithelial BEAS-2E cells and showed a significantly lower expression level of miR-124 in NSCLC cells than in BEAS-2E cells. Upregulation of miR-124 expression levels in both A549 and NCL-H460 cells by transfection with miR-124 mimics suppressed cell proliferation and induced apoptosis. Further investigation revealed that miR-124 bound directly to the 3' UTR region of STAT3, thereby inhibiting STAT3 expression. In addition, miR-124 levels detected in NSCLC tissues were lower than those in adjacent normal lung tissues, while the opposite was observed for STAT3. In NSCLC, the expression levels of miR-124 and STAT3 correlated significantly with the tumor node metastases (TNM) stage, differentiation grade and lymph node metastasis, while the levels of these molecules did not differ significantly by gender, age, location, smoking index, pleural invasion or pathological type. The expression level of miR-124 was significantly associated with disease-free survival (DFS) in both positive and negative lymph node groups. Furthermore, patients with low miR 124 or high STAT3 expression generally received a worse prognosis in terms of both overall survival (OS) and DFS. In conclusion, our findings suggest that miR 124 functions as a tumor suppressor by targeting STAT3, and that miR-124 may potentially serve as a useful biomarker for the prognosis of NSCLC patients. PMID- 25531910 TI - A second-generation phosphohistidine analog for production of phosphohistidine antibodies. AB - Protein histidine phosphorylation plays a crucial role in cell signaling and central metabolism. However, its detailed functions remain elusive due to technical challenges in detecting and isolating proteins bearing phosphohistidine (pHis), a labile posttranslational modification (PTM). To address this issue, we previously developed the first pHis-specific antibodies using stable, synthetic triazole-based pHis analogs. A second-generation, pyrazole-based pHis analog that enabled the development of a pan-pHis antibody with much improved pHis specificity is now reported. PMID- 25531909 TI - Effects of hyperbaric oxygen at 1.25 atmospheres absolute with normal air on macrophage number and infiltration during rat skeletal muscle regeneration. AB - Use of mild hyperbaric oxygen less than 2 atmospheres absolute (2026.54 hPa) with normal air is emerging as a common complementary treatment for severe muscle injury. Although hyperbaric oxygen at over 2 atmospheres absolute with 100% O2 promotes healing of skeletal muscle injury, it is not clear whether mild hyperbaric oxygen is equally effective. The purpose of the present study was to investigate the impact of hyperbaric oxygen at 1.25 atmospheres absolute (1266.59 hPa) with normal air on muscle regeneration. The tibialis anterior muscle of male Wistar rats was injured by injection of bupivacaine hydrochloride, and rats were randomly assigned to a hyperbaric oxygen experimental group or to a non hyperbaric oxygen control group. Immediately after the injection, rats were exposed to hyperbaric oxygen, and the treatment was continued for 28 days. The cross-sectional area of centrally nucleated muscle fibers was significantly larger in rats exposed to hyperbaric oxygen than in controls 5 and 7 days after injury. The number of CD68- or CD68- and CD206-positive cells was significantly higher in rats exposed to hyperbaric oxygen than in controls 24 h after injury. Additionally, tumor necrosis factor-alpha and interleukin-10 mRNA expression levels were significantly higher in rats exposed to hyperbaric oxygen than in controls 24 h after injury. The number of Pax7- and MyoD- or MyoD- and myogenin positive nuclei per mm2 and the expression levels of these proteins were significantly higher in rats exposed to hyperbaric oxygen than in controls 5 days after injury. These results suggest that mild hyperbaric oxygen promotes skeletal muscle regeneration in the early phase after injury, possibly due to reduced hypoxic conditions leading to accelerated macrophage infiltration and phenotype transition. In conclusion, mild hyperbaric oxygen less than 2 atmospheres absolute with normal air is an appropriate support therapy for severe muscle injuries. PMID- 25531912 TI - Burkholderia pseudomallei sequence type 562 in China and Australia. PMID- 25531913 TI - High-yielding, automated production of 3'-deoxy-3'-[(18)F]fluorothymidine using a modified Bioscan Coincidence FDG reaction module. AB - INTRODUCTION: High-yielding, automated production of a PET tracer that reflects proliferation, 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), is reported using a modified Bioscan Coincidence FDG reaction module. METHODS: Production of [(18)F]FLT was implemented through: (1) modification of an original FDG manifold; (2) application of an alternate time sequence; and (3) altered solid-phase extraction (SPE) purification. Quality control testing, including standard radiochemical figures of merit and preclinical positron emission tomography (PET) imaging, was carried out. RESULTS: High decay-corrected yields of [(18)F]FLT (16 39%) were reproducibly obtained. The product exhibited very high specific activity (4586.9TBq/mmol; 123,969Ci/mmol) and radiochemical purity (>99%). Overall, the [(18)F]FLT produced in this manner was superior to typical productions that utilized a GE TRACERlab FXF-N reaction module. Additionally, purification with SPE cartridges, followed by manual elution, accelerated overall run time and resulted in a two-fold increase in [(18)F]FLT concentration. PET imaging showed the [(18)F]FLT produced by this method was highly suitable for non invasive tumor imaging in mice. CONCLUSIONS: The Bioscan Coincidence GE FDG Reaction Module was readily adapted to reproducibly provide [(18)F]FLT in high yield, specific activity, and radiochemical purity. The approach was suitable to provide sufficient amounts of material for preclinical studies. PMID- 25531914 TI - RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward? AB - BACKGROUND: There is no established systemic treatment option for unresectable osteosarcoma progressing after standard chemotherapy. A recently published clinical trial has demonstrated some activity of sorafenib in this situation. Preclinical research suggests a role for the inhibition of the receptor activator of nuclear factor-KB ligand (RANKL), but no clinical data have been reported so far. CASE REPORT: A 37-year-old man was diagnosed with unresectable osteoblastic, osteoblastoma-like osteosarcoma in the C7/Th1 vertebra. The tumour progressed locally despite two lines of chemotherapy and stereotactic radiotherapy. On treatment with sorafenib and denosumab, a complete metabolic remission was achieved and is ongoing for over 18 months. Immunohistochemistry revealed an overexpression of RANK and RANKL in the patient's primary tumour. DISCUSSION: This is the first report of activity achieved by the combination of the tyrosine kinase inhibitor sorafenib and the RANKL inhibitor denosumab in a patient with osteosarcoma. It confirms preclinical data on RANK/RANKL inhibition in osteosarcoma and could serve as a hypothesis-generating approach for clinical trials in this patient population. PMID- 25531916 TI - Motion of Br2 molecules in clathrate cages. A computational study of the dynamic effects on its spectroscopic behavior. AB - This work looks into the spectroscopic behavior of bromine molecules trapped in clathrate cages combining different methodologies. We developed a semiempirical quantum mechanical model to incorporate through molecular dynamics trajectories, the effect movement of bromine molecules in clathrate cages has on its absorption spectra. A simple electrostatic model simulating the cage environment around bromine predicts a blue shift in the spectra, in good agreement with the experimental evidence. PMID- 25531915 TI - Evidence of an Association between Age-Related Functional Modifications and Pathophysiological Changes in Zebrafish Heart. AB - BACKGROUND: Zebrafish have become a valuable model for the study of developmental biology and human disease, such as cardiovascular disease. It is difficult to discriminate between disease-related and age-related alterations. OBJECTIVE: This study was aimed to investigate the effects and potential mechanisms of age related cardiac modifications in an older zebrafish population. METHODS: In this study, we calculated the survival rate and measured the spinal curvature through the aging process. A swimming challenge test was performed and showed that swimming capacity and endurance dramatically dropped in older fish groups. RESULTS: To find out the effect of stress on zebrafish during the aging process, we recorded electrocardiograms on zebrafish and showed that during stress, aging not only led to a significant reduction in heart rate, but also caused other age related impairments, such as arrhythmias and ST-T depression. Echocardiography showed a marked increase in end-diastolic ventricular dimensions and in isovolumic relaxation time and a notably slower mean and peak velocity of the bulboventricular valve in older zebrafish, but stroke volume and cardiac output were not different in young and old zebrafish. Both nppa and nppb (cardiac fetal genes for natriuretic factor) expression detected by real-time polymerase chain reaction analysis increased in older fish compared to the younger group. Histological staining revealed fibrosis within cardiomyocytes and an increase in ventricular myocardial density and a decrease in epicardial vessel dimensions in older fish hearts that may correlate with a deterioration of cardiac function and exercise capacity. CONCLUSION: These data suggest that cardiac functional modifications in zebrafish are comparable to those in humans and may partly be due to changes in the cardiovascular system including cardiac fetal gene reprogramming, myocardial density, and epicardial vessel dimensions. PMID- 25531917 TI - Sputtering-deposition of Ru nanoparticles onto Al2O3 modified with imidazolium ionic liquids: synthesis, characterisation and catalysis. AB - Well-distributed Ru nanoparticles (Ru-NPs) were produced over Al(2)O(3) supports modified with covalently anchored imidazolium ionic liquids (ILs) containing different anions and cation lateral alkyl chain lengths by simple sputtering from a Ru foil. These Ru-NPs were active catalysts for the hydrogenation of benzene. Furthermore, depending on the nature of the IL used to modify the support (hydrophilic or hydrophobic), different catalytic behaviours were observed. Turnover numbers (TON) as high as 27 000 with a turnover frequency (TOF) of 2.73 s(-1) were achieved with Ru-NPs of 6.4 nm supported in Al(2)O(3) modified with an IL containing the N(SO(2)CF(3))2(-) anion, whereas higher initial cyclohexene selectivities (ca. 20% at 1% benzene conversion) were attained for Ru-NPs of 6.6 nm in the case where Cl(-) and BF(4)(-) anions were used. Such observations strongly suggest that thin layers of ILs surround the NP surface, modifying the reactivity of these catalytic systems. These findings open a new window of opportunity in the development of size-controlled Ru-NPs with tuneable reactivity. PMID- 25531918 TI - Fly ash-TiO2 nanocomposite material for multi-pollutants wastewater treatment. AB - This paper reports on the synthesis, characterization and adsorption properties of a novel nano-composite obtained using the hydrothermal method applied to a fly ash-TiO2 slurry and hexadecyltrimethyl-ammonium bromide, as surface controlling agent. The new adsorbent was investigated in terms of crystallinity (XRD), surface properties (AFM, SEM, and porosity and BET surface) and surface chemistry (EDX, FTIR). The nanocomposite's properties were sequentially tested in adsorption and photocatalysis processes applied to multi-pollutant synthetic wastewaters loaded with copper cations and two industrial dyes: the acid dye Bemacid Blau and the reactive dye Bemacid Rot; the nano-composite substrate allowed reaching high removal efficiencies, above 90%, both in adsorption and in photodegradation experiments, in optimised conditions. PMID- 25531919 TI - Tularemia among free-ranging mice without infection of exposed humans, Switzerland, 2012. AB - The animals primarily infected by Francisella tularensis are rapidly consumed by scavengers, hindering ecologic investigation of the bacterium. We describe a 2012 natural tularemia epizootic among house mice in Switzerland and the assessment of infection of exposed humans. The humans were not infected, but the epizootic coincided with increased reports of human cases in the area. PMID- 25531920 TI - Metal-catalyzed thermal reactions of cyclic beta-dicarbonyl phenyliodonium ylide with styrenes. AB - A cyclic beta-dicarbonyl phenyliodonium ylide reacted with various substituted styrenes under Rh2(OAc)4 catalysis to give cyclopropanes and dihydrofurans in a highly regioselective fashion. When styrenes with electron-donating substituents or disubstituted were employed, only dihydrofurans were isolated instead. A mechanism involving two competing pathways rationalizes the results. PMID- 25531921 TI - British Fertility Society Policy and Practice Committee: adjuvants in IVF: evidence for good clinical practice. AB - Optimisation of the environment favourable for satisfactory ovarian response to stimulation and successful embryo implantation remains at the core of assisted conception programmes. The evidence base for the routine use of different adjuvants, alone or in combination, for women undergoing their first in vitro fertilisation (IVF) treatment cycle and for those with poor prognosis is inadequate. The aim of this document is to update the last review of the available literature carried out by the British Fertility Society Policy and Practice Committee (BFS P&P) published in 2009 and to provide fertility professionals with evidence-based guidance and recommendations regarding the use of immunotherapy, vasodilators, uterine relaxants, aspirin, heparin, growth hormone, dehydroepiandrosterone, oestrogen and metformin as adjuvants in IVF. Unfortunately despite the lapse of 5 years since the last publication, there is still a lack of robust evidence for most of the adjuvants searched and large well designed randomised controlled trials are still needed. One possible exception is metformin, which seems to have a positive effect in women with polycystic ovary syndrome undergoing IVF. Patients who are given other adjuvants on an empirical basis should always be informed of the lack of evidence and the potential side effects. PMID- 25531923 TI - Towards enantioselective adsorption in surface-confined nanoporous systems. AB - The adsorption of chiral molecules in surface-confined chiral porous networks shows pronounced selectivity, as a result of complementary host-guest interactions. PMID- 25531922 TI - Prognostic value of physical function tests: hand grip strength and six-minute walking test in elderly hospitalized patients. AB - To discern if physical function test are better mortality predictors than muscle mass in elderly hospitalized patients, we analyzed the prognostic value of muscle mass malnutrition and compared it with physical muscle function tests, including the six-minute walking test (6 MWT) and hand grip strength. We included the ankle brachial index (ABI) to assess arterial disease, related to muscle atrophy due to hypoperfusion. We also analyzed the relationship of ABI with malnutrition, physical function tests and survival. We studied 310 hospitalized patients older than 60 years. To assess nutritional status, we determined BMI, triceps skinfold and mid-arm muscle area; we performed a subjective nutritional assessment; and evaluated the degree of inflammatory stress. We assessed physical function by hand grip strength and 6 MWT. We evaluated arterial disease by ABI. Forty-one patients died during hospitalization; 269 were discharged and followed for a mean 808 days, reaching a mortality of 49%. Muscle malnutrition was frequent and was related to mortality, but the best predictors were physical function tests: inability to perform the 6 MWT and low handgrip strength. Function tests were closely related to each other and correlated with nutritional data. Reduced ABI was related to impaired nutritional status, physical function tests and mortality. PMID- 25531924 TI - Carbon nanoscroll from C4H/C4F-type graphene superlattice: MD and MM simulation insights. AB - Morphology manipulation opens up a new avenue for controlling and tailoring the functional properties of graphene, enabling the exploration of graphene-based nanomaterials. Through mixing single-side-hydrogenated graphene (C4H) with fluorinated graphene (C4F) on one single sheet, the C4H/C4F-type graphene superlattices can self-scroll at room temperature. We demonstrate using molecular dynamic (MD) simulations that different proportions, sizes, directions of hydrogenation and fluorination, and geometry of graphene have a great influence on the self-scrolling of superlattices into a variety of well-defined carbon nanoscrolls (CNSs), thus providing a controllable approach to tune their structures. Based on molecular mechanics (MM) simulations, the CNSs bear more than eight times the radial pressure than that of their multiwalled carbon nanotube (MWNT) counterparts, and an excellent radial elasticity of CNSs is also shown. Compared with conventional CNSs, these novel CNSs are endowed with more ample and flexible heterogeneous structures due to the on-demand hydrogenation and fluorination. Besides, this work provides a feasible route to achieve the necessary electronic and optical changes to be applied in graphene device applications. PMID- 25531926 TI - Biomaterial-based local drug delivery to brain tumors. PMID- 25531925 TI - The nitric oxide/soluble cyclic guanylase/cyclic guanosine monophosphate pathway is involved in the cardiovascular effects of a novel alpha1- and beta adrenoceptor antagonist. AB - The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2 methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for alpha1- and beta-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel alpha1- and beta-adrenoceptor antagonist (MH 78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both alpha1- and beta-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to alpha1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nomega-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to alpha1-adrenoceptors. Our results demonstrated that MH-78 possesses alpha1- and beta-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to alpha1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway. PMID- 25531927 TI - Polylactide-co-glycolide nanoparticles of antitubercular drugs: formulation, characterization and biodistribution studies. AB - BACKGROUND: The present study was designed to prepare and characterize poly lactide-co-glycolide nanoparticles of antitubercular drugs (ATDs) for delivery through oral route to alveolar macrophages. METHODS: Nanoparticles were prepared by double emulsification solvent evaporation method. Ex vivo and in vivo drug accumulation studies were performed in alveolar macrophages, harvested by broncheoalveolar lavaging. Internalization of nanoparticles was studied by confocal laser scanning microscopy. gamma-scintigraphy imaging using technetium 99m was done to study the biodistribution pattern of nanoparticles. RESULTS: High intracellular concentrations of ATDs were observed in macrophages within 30 min of administration of nanoparticles. Intense radioactivity recorded in liver, spleen and lungs revealed uptake of nanoparticles in macrophages, abundantly present in mononuclear phagocyte system present in these organs. CONCLUSION: Targeted delivery of ATDs will help reduce dose and associated side effects including hepatotoxicity of ATDs. Further studies are required to assess the potential therapeutic advantages for treatment of TB. PMID- 25531928 TI - Opportunities in respiratory drug delivery. AB - A wide range of asthma and chronic obstructive pulmonary disease products are soon to be released onto the inhaled therapies market and differentiation between these devices will help them to gain market share over their competitors. Current legislation is directing healthcare towards being more efficient and cost effective in order to continually provide quality care despite the challenges of aging populations and fewer resources. Devices and drugs that can be differentiated by producing improved patient outcomes would, therefore, be likely to win market share. In this perspective article, the current and potential opportunities for the successful delivery and differentiation of new inhaled drug products are discussed. PMID- 25531929 TI - Gene therapy and imaging in preclinical and clinical oncology: recent developments in therapy and theranostics. AB - In the case of disseminated cancer, current treatment options reach their limit. Gene theranostics emerge as an innovative route in the treatment and diagnosis of cancer and might pave the way towards development of an efficacious treatment of currently incurable cancer. Various gene vectors have been developed to realize tumor-specific nucleic acid delivery and are considered crucial for the successful application of cancer gene therapy. By adding reporter genes and imaging agents, these systems gain an additional diagnostic function, thereby advancing the theranostic paradigm into cancer gene therapy. Numerous preclinical studies have demonstrated the feasibility of combined tumor gene therapy and diagnostic imaging, and clinical trials in human and veterinary oncology have been executed with partly encouraging results. PMID- 25531930 TI - Advances in ophthalmic drug delivery. AB - Various strategies for ocular drug delivery are considered; from basic formulation techniques for improving availability of drugs; viscosity enhancers and mucoadhesives aid drug retention and penetration enhancers promote drug transport into the eye. The use of drug-loaded contact lenses and ocular inserts allows drugs to be better placed where they are needed for more direct delivery. Developments in ocular implants gives a means to overcome the physical barriers that traditionally prevented effective treatment. Implant technologies are under development allowing long-term drug delivery from a single procedure, these devices allow posterior chamber diseases to be effectively treated. Future developments could bring artificial corneas to eliminate the need for donor tissue and one-off implantable drug depots lasting the patient's lifetime. PMID- 25531931 TI - Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. AB - IMPORTANCE: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown. OBJECTIVE: To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset). MAIN OUTCOMES AND MEASURES: NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes. RESULTS: A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change <=0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years. CONCLUSIONS AND RELEVANCE: NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA. PMID- 25531932 TI - Capillaria plectropomi n. sp. (Nematoda: Capillariidae), a new intestinal parasite of the leopard coral grouper Plectropomus leopardus (Serranidae) off New Caledonia. AB - A new nematode species, Capillaria plectropomi n. sp. (Capillariidae), is described from the intestine of the leopard coral grouper Plectropomus leopardus (Lacepede) from coral reefs off New Caledonia. The new species, belonging to the subgenus Neocapillaria Moravec, 1987, differs from other congeneric species of this subgenus from marine fishes mainly in the length (168-186 MUm), shape and structure of the spicule. It is characterized, in the male, by the presence of two well-developed dorsolateral caudal lobes, a pair of lateral papillae, a heavily sclerotized spicule with many rough transverse grooves in the middle part, a spinose spicular sheath, and in the female, by eggs measuring 60-66 * 27 MUm without protruding polar plugs. The buccal cavity contains a small finger shaped stylet. Capillaria plectropomi n. sp. is the first known species of this genus parasitizing fishes of the perciform family Serranidae. PMID- 25531933 TI - Polyuria in Hantavirus Infection Reflects Disease Severity and Is Associated with Prolonged Hospital Stay: A Systematic Analysis of 335 Patients from Southern Germany. AB - Background/Aims: Puumala virus (PUUV) infection leads to nephropathia epidemica (NE), especially in endemic areas in Central Europe. The clinical course of NE is characterized by acute kidney injury (AKI) with thrombocytopenia followed by polyuria to a different degree. The prevalence of polyuria and its associated risk factors have not been reported in a large cohort of NE patients. Methods: Clinical and laboratory data during the acute phase of the disease were obtained from the medical reports and files of 335 patients who received in-hospital treatment during acute hantavirus infection. Comprehensive statistical models were developed to estimate the probability of polyuria. Results: The median age at diagnosis was 47 years (interquartile range, IQR 40-59) and 48% of the patients developed polyuria with a urinary output of 5,100 ml/day (IQR 4,200 7,300). The hospital stay was significantly longer in the polyuric group compared to the nonpolyuric group [8 days (IQR 6-10) vs. 6 days (IQR 5-8); p = 0.04]. Using logistic regression analysis, male gender (odds ratio, OR = 1.6; 95% confidence interval, CI 1.05-2.58; p = 0.03), oliguria/anuria during NE (OR = 2.56; 95% CI 1.65-4.01; p < 0.001), severe AKI (OR = 1.87; 95% CI 1.22-2.9; p < 0.001), and hematuria (OR = 1.78; 95% CI 1.02-3.15; p = 0.04) were significantly associated with the development of polyuria. In a multivariate model, the probability of polyuria was 0.19 (SEM +/- 0.05) in female patients presenting with mild/moderate AKI without anuria/oliguria. Conclusions: Almost 50% of hospitalized NE patients developed polyuria, which was associated with a prolonged hospital stay. The probability of the development of polyuria was lowest in female patients with mild/moderate, non-oliguric/anuric AKI. (c) 2014 S. Karger AG, Basel. PMID- 25531934 TI - Autochthonous dengue fever imported to England from Japan, 2014. PMID- 25531936 TI - Nano-scale surface wrinkling in chiral liquid crystals and plant-based plywoods. AB - We present theoretical scaling and computational analysis of nanostructured free surfaces formed in chiral liquid crystals (LC) and plant-based twisted plywoods. A nemato-capillary model is used to derive a generalized equation that governs the shape of cholesteric free surfaces. It is shown that the shape equation includes three distinct contributions to the capillary pressure: area dilation, area rotation, and director curvature. To analyse the origin of periodic reliefs in plywood surfaces, these three pressure contributions and corresponding surface energies are systematically investigated. It is found that for weak homeotropic surface anchoring, the nano-wrinkling is driven by the director curvature pressure mechanism. Consequently, the model predicts that for a planar surface with a uniform tangential helix vector, no surface nano-scale wrinkling can be observed because the director curvature pressure is zero. Scaling is used to derive the explicit relation between the wrinkling's amplitude to the wavelength ratio as a function of the anisotropic surface tension, which is then validated with experimental values. These new findings can be used to characterize plant based twisted plywoods, as well as to inspire the design of biomimetic chiro optical devices. PMID- 25531937 TI - Sonogashira cross-coupling and homocoupling on a silver surface: chlorobenzene and phenylacetylene on Ag(100). AB - Scanning tunneling microscopy, temperature-programmed reaction, near-edge X-ray absorption fine structure spectroscopy, and density functional theory calculations were used to study the adsorption and reactions of phenylacetylene and chlorobenzene on Ag(100). In the absence of solvent molecules and additives, these molecules underwent homocoupling and Sonogashira cross-coupling in an unambiguously heterogeneous mode. Of particular interest is the use of silver, previously unexplored, and chlorobenzene-normally regarded as relatively inert in such reactions. Both molecules adopt an essentially flat-lying conformation for which the observed and calculated adsorption energies are in reasonable agreement. Their magnitudes indicate that in both cases adsorption is predominantly due to dispersion forces for which interaction nevertheless leads to chemical activation and reaction. Both adsorbates exhibited pronounced island formation, thought to limit chemical activity under the conditions used and posited to occur at island boundaries, as was indeed observed in the case of phenylacetylene. The implications of these findings for the development of practical catalytic systems are considered. PMID- 25531935 TI - Patients with diabetes respond well to contingency management treatment targeting alcohol and substance use. AB - Alcohol and drug use contribute to the pathogenesis of diabetes and are associated with adverse health outcomes, but little research exists on treatments for substance use disorders (SUDs) in patients with diabetes. The aim of this study was to evaluate contingency management (CM) treatments targeting substance use in patients with diabetes. A secondary analysis evaluated the main and interactive effects of diabetes status and treatment condition on outcomes of 681 substance abusers. All participants were enrolled in randomized clinical trials comparing CM to standard care (SC). Overall, CM treatment improved outcomes. There was also a significant treatment condition X diabetes status interaction effect in terms of duration of abstinence achieved and proportion of negative samples submitted; patients with diabetes responded even more favorably than their counterparts without diabetes when receiving CM. Analyses of post-treatment effects revealed that patients with diabetes, regardless of the type of SUD treatment to which they were earlier assigned, were more likely than those without diabetes to be abstinent at the nine-month follow-up. The findings suggest CM may be an effective treatment for this vulnerable subgroup of substance-abusing patients. PMID- 25531938 TI - The drug prescription network: a system-level view of drug co-prescription in community-dwelling elderly people. AB - Networks are well suited to display and analyze complex systems that consist of numerous and interlinked elements. This study aimed at: (1) generating a series of drug prescription networks (DPNs) displaying co-prescription in community dwelling elderly people; (2) analyzing DPN structure and organization; and (3) comparing various DPNs to unveil possible differences in drug co-prescription patterns across time and space. Data were extracted from the administrative prescription database of the Lombardy Region in northern Italy in 2000 and 2010. DPNs were generated, in which each node represents a drug chemical subclass, whereas each edge linking two nodes represents the co-prescription of the corresponding drugs to the same patient. At a global level, the DPN was a very dense and highly clustered network, whereas at the local level it was organized into anatomically homogeneous modules. In addition, the DPN was assortative by class, because similar nodes (representing drugs with the same anatomic, therapeutic, and pharmacologic annotation) connected to each other more frequently than expected, indicating that similar drugs are often co-prescribed. Finally, temporal changes in the co-prescription of specific drug sub-groups (for instance, proton pump inhibitors) translated into topological changes of the DPN and its modules. In conclusion, complementing more traditional pharmaco epidemiology methods, the DPN-based method allows appreciatiation (and representation) of general trends in the co-prescription of a specific drug (e.g., its emergence as a heavily co-prescribed hub) in comparison with other drugs. PMID- 25531940 TI - Effects of spironolactone in combination with angiotensin-converting enzyme inhibitors or Angiotensin receptor blockers in patients with proteinuria. AB - BACKGROUND/AIMS: This study aimed to investigate the potential beneficial anti proteinuric effect of an add-on aldosterone blockade and the impact of the aldosterone escape phenomenon. METHODS: We retrospectively analyzed data of 304 patients with persistent proteinuria, who were administered spironolactone (25 mg/day) after treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) for >3 months. Patients were divided according to their aldosterone levels during ACEI/ARB treatment into an escape group (plasma aldosterone >80 pg/mL, N=95, 31.5%) and a non-escape group (plasma aldosterone <=80 pg/mL, N=209, 68.5%) and according to their urine albumin-to creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). RESULTS: After 12 months, the UACR decreased significantly in patients with 1<=UACR<3.5 g/g Cr, UACR >=3.5 g/g Cr, and eGFR >=60 mL/min/1.73 m2, and in the non-escape group. Severe hyperkalemia (K>=7.0 mEq/L) developed in 9 of 137 patients with eGFR<60 mL/min/1.73 m2 (6.5%) and in none of the 167 patients with eGFR >=60 mL/min/1.73 m2. CONCLUSIONS: Proteinuria decreased significantly after add-on spironolactone treatment in patients with 1<=UACR<3.5 g/g Cr, UACR >=3.5 g/g Cr, and eGFR >=60 mL/min/1.73 m2, and in the non-escape group. The anti-proteinuric effect of spironolactone may vary according to the degree of albuminuria, impaired eGFR, and aldosterone escape. PMID- 25531939 TI - Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain. AB - Antibacterial agents that exploit new targets will be required to combat the perpetual rise of bacterial resistance to current antibiotics. We are exploring the inhibition of histidine kinases, constituents of two-component systems. Two component systems are the primary signaling pathways that bacteria utilize to respond to their environment. They are ubiquitous in bacteria and trigger various pathogenic mechanisms. To attenuate these signaling pathways, we sought to broadly target the histidine kinase family by focusing on their highly conserved ATP-binding domain. Development of a fluorescence polarization displacement assay facilitated high-throughput screening of ~53 000 diverse small molecules for binding to the ATP-binding pocket. Of these compounds, nine inhibited the catalytic activity of two or more histidine kinases. These scaffolds could provide valuable starting points for the design of broadly effective HK inhibitors, global reduction of bacterial signaling, and ultimately, a class of antibiotics that function by a new mechanism of action. PMID- 25531941 TI - Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria. AB - In Fabry disease, globotriaocylceramid (GL3) starts to accumulate in kidney cells in utero, and continues to accumulate throughout childhood and adulthood with progressive tissue damage, which may lead to renal failure. MATERIAL AND METHODS: Eight children with classical Fabry disease, median age 12 (range 4-16 years) had a renal biopsy performed before the initiation of enzyme replacement therapy (ERT). All patients were normalbuminuric and had normal GFR. Three patients were re-biopsied after three or five years. RESULTS: In all patients, significant GL3 accumulation was found in several types of kidney cells with high amounts of GL3 in the podocytes. Segmental podocyte foot process effacement was shown in all but two patients; no effacement was seen neither in the youngest male patient at 4 years of age nor in a male aged 12. A 12-year-old female patient had normal podocyte foot processes before the start of ERT, but de novo foot process flattening and unchanged high score of podocyte GL3 accumulation were seen in the re-biopsy after three years of ERT (agalsidase alpha 0.2 mg/kg/every other week). Two boys showed worsening of podocyte effacement in kidney biopsy after five years of agalsidase alpha 0.2 mg/kg/eow. CONCLUSIONS: Podocyte foot process effacement was found in the majority of eight young classical Fabry patients of both genders after the age of 11 years, without clinical signs of Fabry nephropathy. Kidney biopsies are essential in the early diagnosis of nephropathy and in the evaluation of the response to enzyme replacement therapy of early Fabry nephropathy. PMID- 25531943 TI - Vitamin E intake is not associated with glioma risk: evidence from a meta analysis. AB - BACKGROUND: Epidemiological studies evaluating the association between vitamin E intake and glioma risk have produced inconsistent results. Thus, we conducted a meta-analysis to summarize the evidence from epidemiological studies of vitamin E intake with the risk of glioma. METHODS: Pertinent studies were identified by a search in pubmed and web of knowledge up to August 2014. The random-effect model was used to combine the results. Publication bias was estimated using the Egger's regression asymmetry test. RESULTS: Twelve studies including 3180 glioma cases about vitamin E intake with the risk of glioma were included in this meta analysis. The combined relative risk (RR) of glioma associated with vitamin E intake was 0.88 (95% CI = 0.69-1.12). The association was significant neither in the case-control studies nor in the cohort studies. No publication biases were found. CONCLUSIONS: Our analysis indicated that vitamin E intake is not associated with the risk of glioma. PMID- 25531942 TI - High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. AB - Tumor-specific neo-antigens that arise as a consequence of mutations are thought to be important for the therapeutic efficacy of cancer immunotherapies. Accumulating evidence suggests that neo-antigens may be commonly recognized by intratumoral CD8+ T cells, but it is unclear whether neo-antigen-specific CD4+ T cells also frequently reside within human tumors. In view of the accepted role of tumor-specific CD4+ T-cell responses in tumor control, we addressed whether neo antigen-specific CD4+ T-cell reactivity is a common property in human melanoma. PMID- 25531944 TI - Suprasegmental information affects processing of talking faces at birth. AB - From birth, newborns show a preference for faces talking a native language compared to silent faces. The present study addresses two questions that remained unanswered by previous research: (a) Does the familiarity with the language play a role in this process and (b) Are all the linguistic and paralinguistic cues necessary in this case? Experiment 1 extended newborns' preference for native speakers to non-native ones. Given that fetuses and newborns are sensitive to the prosodic characteristics of speech, Experiments 2 and 3 presented faces talking native and nonnative languages with the speech stream being low-pass filtered. Results showed that newborns preferred looking at a person who talked to them even when only the prosodic cues were provided for both languages. Nonetheless, a familiarity preference for the previously talking face is observed in the "normal speech" condition (i.e., Experiment 1) and a novelty preference in the "filtered speech" condition (Experiments 2 and 3). This asymmetry reveals that newborns process these two types of stimuli differently and that they may already be sensitive to a mismatch between the articulatory movements of the face and the corresponding speech sounds. PMID- 25531945 TI - Particle placement and sheet topological control in the fabrication of Ag hexaniobate nanocomposites. AB - Synthetic methods are demonstrated that allow for the fabrication of Ag hexaniobate nanocomposites with directed nanoparticle (NP) placement and nanosheet morphological control. The solvothermal treatment of exfoliated nanosheets (NSs) in the presence of Ag NPs leads to a high yield of Ag nanocomposites. This approach is quite flexible and, with control of time and temperature, can be used to produce nanocomposites with specific architectures; Ag NPs can be attached to nanosheets, attached to the surfaces of nanoscrolls, or at higher temperatures, captured within nanoscrolls to form nanopeapod (NPP) structures. The decorated nanosheets and nanoscrolls show surface plasmon resonance (SPR) maxima similar to that of free Ag NPs, while the Ag NPPs exhibit a red shift of about 10 nm. PMID- 25531946 TI - Electrostatically self-assembled biodegradable microparticles from pseudoproteins and polysaccharide: fabrication, characterization, and biological properties. AB - Electrostatically self-assembling hybrid microparticles derived from novel cationic unsaturated arginine-based poly(ester amide) polymers (UArg-PEA) and anionic hyaluronic acid (HA) were fabricated into sub-micron-sized particles in aqueous medium with subsequent UV crosslinking treatment to stabilize the structure. These hybrid microparticles were characterized for size, charge, viscosity, chemical structure, morphology, and biological properties. Depending on the feed ratio of cationic UArg-PEA to anionic HA, the crosslinked microparticles formed spherical structures of 0.772-22.08 MUm in diameter, whereas the uncrosslinked microparticles formed a core with an outer petal-like structure of 2.49-15 MUm in diameter. It was discovered that the morphological structure of the self-assembled microparticles had a profound influence on their biological properties. At a 1:1 feed ratio of UArg-PEA to HA, the uncrosslinked microparticles showed no cytotoxicity toward NIH 3T3 fibroblasts at concentrations up to 20 MUg/mL, and the crosslinked particles exhibited no cytotoxicity at concentrations up to 10 MUg/mL. The UArg-PEA/HA hybrid microparticles exhibited a significantly lower macrophage-induced proinflammatory response (via TNF-alpha) than that from a pure hyaluronic acid control while retaining the beneficial anti-inflammatory IL-10 production by HA. The UArg PEA/HA microparticles also stimulated size-dependent induction of arginase activity. Therefore, self-assembling these two types of biomaterials in a favorable nontoxic aqueous environment, having complementary biological properties like those of the currently reported UArg-PEA/HA hybrid microparticles, may provide a new class of biomaterials to improve the overall tissue microenvironment for promoting wound healing. PMID- 25531947 TI - Morphology, Crystal Structure and Charge Transport in Donor-Acceptor Block Copolymer Thin Films. AB - We studied structure and charge transport properties of thin films of donor acceptor block copolymers, poly(3-hexylthiophene-block-perylene bisimide acrylate), using a combination of X-ray scattering, AFM and vertical charge transport measurements in diode devices. Block copolymer self-assembly and crystallization of the individual components are interrelated and different structural states of the films could be prepared by varying preparation conditions and thermal history. Generally the well-defined microphase structures found previously in bulk could also be prepared in thin films, in addition alignment induced by interfacial interactions was observed. Microphase separated block copolymers sustain ambipolar charge transport, but the exact values of electron and hole mobilities depend strongly on orientation and connectivity of the microdomains as well as the molecular order within the domains. PMID- 25531948 TI - Smoothed low rank and sparse matrix recovery by iteratively reweighted least squares minimization. AB - This paper presents a general framework for solving the low-rank and/or sparse matrix minimization problems, which may involve multiple nonsmooth terms. The iteratively reweighted least squares (IRLSs) method is a fast solver, which smooths the objective function and minimizes it by alternately updating the variables and their weights. However, the traditional IRLS can only solve a sparse only or low rank only minimization problem with squared loss or an affine constraint. This paper generalizes IRLS to solve joint/mixed low-rank and sparse minimization problems, which are essential formulations for many tasks. As a concrete example, we solve the Schatten-p norm and l2,q-norm regularized low-rank representation problem by IRLS, and theoretically prove that the derived solution is a stationary point (globally optimal if p,q >= 1). Our convergence proof of IRLS is more general than previous one that depends on the special properties of the Schatten-p norm and l2,q-norm. Extensive experiments on both synthetic and real data sets demonstrate that our IRLS is much more efficient. PMID- 25531949 TI - Saliency-guided color-to-gray conversion using region-based optimization. AB - Image decolorization is a fundamental problem for many real-world applications, including monochrome printing and photograph rendering. In this paper, we propose a new color-to-gray conversion method that is based on a region-based saliency model. First, we construct a parametric color-to-gray mapping function based on global color information as well as local contrast. Second, we propose a region based saliency model that computes visual contrast among pixel regions. Third, we minimize the salience difference between the original color image and the output grayscale image in order to preserve contrast discrimination. To evaluate the performance of the proposed method in preserving contrast in complex scenarios, we have constructed a new decolorization data set with 22 images, each of which contains abundant colors and patterns. Extensive experimental evaluations on the existing and the new data sets show that the proposed method outperforms the state-of-the-art methods quantitatively and qualitatively. PMID- 25531950 TI - A novel SURE-based criterion for parametric PSF estimation. AB - We propose an unbiased estimate of a filtered version of the mean squared error- the blur-SURE (Stein's unbiased risk estimate)--as a novel criterion for estimating an unknown point spread function (PSF) from the degraded image only. The PSF is obtained by minimizing this new objective functional over a family of Wiener processings. Based on this estimated blur kernel, we then perform nonblind deconvolution using our recently developed algorithm. The SURE-based framework is exemplified with a number of parametric PSF, involving a scaling factor that controls the blur size. A typical example of such parametrization is the Gaussian kernel. The experimental results demonstrate that minimizing the blur-SURE yields highly accurate estimates of the PSF parameters, which also result in a restoration quality that is very similar to the one obtained with the exact PSF, when plugged into our recent multi-Wiener SURE-LET deconvolution algorithm. The highly competitive results obtained outline the great potential of developing more powerful blind deconvolution algorithms based on SURE-like estimates. PMID- 25531951 TI - Fusing inertial sensor data in an extended Kalman filter for 3D camera tracking. AB - In a setup where camera measurements are used to estimate 3D egomotion in an extended Kalman filter (EKF) framework, it is well-known that inertial sensors (i.e., accelerometers and gyroscopes) are especially useful when the camera undergoes fast motion. Inertial sensor data can be fused at the EKF with the camera measurements in either the correction stage (as measurement inputs) or the prediction stage (as control inputs). In general, only one type of inertial sensor is employed in the EKF in the literature, or when both are employed they are both fused in the same stage. In this paper, we provide an extensive performance comparison of every possible combination of fusing accelerometer and gyroscope data as control or measurement inputs using the same data set collected at different motion speeds. In particular, we compare the performances of different approaches based on 3D pose errors, in addition to camera reprojection errors commonly found in the literature, which provides further insight into the strengths and weaknesses of different approaches. We show using both simulated and real data that it is always better to fuse both sensors in the measurement stage and that in particular, accelerometer helps more with the 3D position tracking accuracy, whereas gyroscope helps more with the 3D orientation tracking accuracy. We also propose a simulated data generation method, which is beneficial for the design and validation of tracking algorithms involving both camera and inertial measurement unit measurements in general. PMID- 25531952 TI - Background fluorescence estimation and vesicle segmentation in live cell imaging with conditional random fields. AB - Image analysis applied to fluorescence live cell microscopy has become a key tool in molecular biology since it enables to characterize biological processes in space and time at the subcellular level. In fluorescence microscopy imaging, the moving tagged structures of interest, such as vesicles, appear as bright spots over a static or nonstatic background. In this paper, we consider the problem of vesicle segmentation and time-varying background estimation at the cellular scale. The main idea is to formulate the joint segmentation-estimation problem in the general conditional random field framework. Furthermore, segmentation of vesicles and background estimation are alternatively performed by energy minimization using a min cut-max flow algorithm. The proposed approach relies on a detection measure computed from intensity contrasts between neighboring blocks in fluorescence microscopy images. This approach permits analysis of either 2D + time or 3D + time data. We demonstrate the performance of the so-called C-CRAFT through an experimental comparison with the state-of-the-art methods in fluorescence video-microscopy. We also use this method to characterize the spatial and temporal distribution of Rab6 transport carriers at the cell periphery for two different specific adhesion geometries. PMID- 25531953 TI - The evolution of Helicobacter pylori antibiotics resistance over 10 years in Greece. AB - BACKGROUND: Increasingly, over time, antibiotic resistance is considered a problem for the efficacy of H. pylori eradication treatment. The aim of our study was to evaluate the changes in clarithromycin and levofloxacin resistance of H. pylori strains in Greek patients in two different time periods (in 2000 and in 2010). METHODS: Gastric biopsies of consecutive H. pylori-positive patients were investigated retrospectively. Mutations in H. pylori 23S rRNA and gyrA genes associated with resistance to clarithromycin and quinolones, respectively, were determined by allelic specific polymerase chain reaction. RESULTS: In the first time period (2000), H. pylori resistance patterns were evaluated in 50 and in the second period (2010) in 57 patients. During the first time period 30 and 0% of patients were infected with clarithromycin- or quinolone-resistant strains, respectively. In the second time period (2010), the percentage of patients infected with clarythromycin or quinolone resistance strains increased to 42 and 5.3%, respectively. CONCLUSIONS: Our study showed an increase in the prevalence of both clarithromycin and quinolones resistance of H. pylori. Although the resistance rate to quinolones increased over the years, it is relatively low justifying its use for the eradication of H. pylori infections. PMID- 25531954 TI - Associated Da Vinci and magellan robotic systems for successful treatment of nutcracker syndrome. AB - Here, we report the case of a 26-year-old woman suffering from nutcracker syndrome with concurrent disabling pelvic congestion syndrome. She was given the minimally invasive treatment of left renal vein transposition with the Da Vinci((r)) robotic system (Intuitive Surgical, Sunnyvale, CA), followed the next day by a gonadal vein and pelvic varicose embolization using a robotic intraluminal navigation with the MagellanTM robotic system (Hansen Medical, Mountain View, CA). The procedure was uneventful, and the patient had good results at 6 months of follow-up, including a patent left renal vein and complete relief of symptoms. PMID- 25531955 TI - Beliefs and attitudes about opioid prescribing and chronic pain management: survey of primary care providers. AB - OBJECTIVE: There is growing concern of medication misuse and noncompliance among patients with chronic pain prescribed opioids for pain. The aim of this survey was to obtain information from primary care providers (PCPs) about their perception of prescribing opioids for patients with chronic pain. METHODS: PCPs were invited to complete a packet of questionnaires about attitudes and concerns about opioids for chronic pain. These questionnaires included 1) General Health Questionnaire, 2) Test of Opioid Knowledge (TOK), 3) Opioid Therapy Provider Survey, and 4) Concerns About Analgesic Prescription Questionnaire. RESULTS: Fifty-six (N = 56) PCPs from eight centers participated in this study. In general, the PCPs showed adequate opioid knowledge on the KOT and their general health was unrelated to prescription attitudes. Most expressed concern about medication misuse (89 percent) and felt that managing patients with chronic pain was stressful (84 percent). Most were worried about addiction (82 percent) and less than half felt that they were sufficiently trained in prescribing opioids (46 percent). Younger providers felt more reluctant to prescribe opioids, experienced more stress in managing patients with pain, had less overall confidence in managing patients with pain, and worried more about opioid dependence than older providers (p < 0.05). Younger providers were also less knowledgeable about opioids, but opioid knowledge was not found to be related to concerns about analgesic prescriptions. CONCLUSION: This study indicates a general concern and reluctance of primary care physicians to manage the prescribing of opioids among their patients with chronic pain and younger providers expressed more concern about opioids than older providers. PMID- 25531956 TI - Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia. AB - Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies. PMID- 25531957 TI - Effectiveness of opioid rotation in the control of cancer pain: the ROTODOL study. AB - OBJECTIVE: To assess the effectiveness of opioid rotation (OR) to manage cancer pain. To describe the adverse events (AEs) associated with OR. SETTING: Thirty nine tertiary hospital services. PATIENTS: Sixty-seven oncological patients with cancer-related pain treated at outpatient clinics. INTERVENTION: Prospective multicenter study. Pain intensity was scored using a Numerical Rating Scale (NRS) of 0-10. Average pain (AP) intensity in the last 24 hours, breakthrough pain (BTP), and the number of episodes of BTP on the days before and 1 week after OR were assessed. The pre-OR and post-OR opioid were recorded. The presence and intensity of any AEs occurring after OR were also recorded. RESULTS: In the 67 patients evaluated, 75 ORs were recorded. In all cases, the main reason for OR was poor pain control. Pain intensity decreased by >=2 points after OR in 75.4 percent and 57.8 percent of cases for AP and BTP, respectively. If the initial NRS score was >=4, a decrease below <4 accounted for 50.9 percent and 32.3 percent of cases for AP and BTP, respectively. The number of episodes of BTP also decreased significantly (p<0.001). A total of 107 AEs were reported, most of which were mild in intensity, with gastrointestinal symptoms predominating. CONCLUSIONS: Opioid rotation appears to be both safe and effective in the management of basal and breakthrough cancer pain. PMID- 25531958 TI - Demographic characteristics and clinical predictors of patients discharged from university hospital-affiliated pain clinic due to breach in narcotic use contract. AB - OBJECTIVE: The current retrospective study was completed with the aim to identify demographic characteristics and clinical predictors (if any) of the patients discharged from our pain clinic due to breach in narcotic use contract (BNUC). DESIGN: Retrospective patient charts' review and data audit. SETTING: University hospital-affiliated pain clinic in the United States. PARTICIPANTS: All patient charts in our pain clinic for a 2-year period (2011-2012). INTERVENTIONS: The patients with BNUC were delineated from the patients who had not been discharged from our pain clinic. MAIN OUTCOME MEASURES: Pain characteristics, pain management, and substance abuse status were compared in each patient with BNUC between the time of admission and the time of discharge. RESULTS: The patients with BNUC discharges showed significant variability for the discharging factors among the pain physicians within a single pain clinic model with this variability being dependent on their years of experience and their proactive interventional pain management. The patients with BNUC in our pain clinic setting were primarily middle-aged, obese, unmarried males with nondocumented stable occupational history who were receiving only noninterventional pain management. Substance abuse, doctor shopping, and potential diversion were the top three documented reasons for BNUC discharges. CONCLUSION: In 2011-2012, our pain clinic discharged 1-in-16 patients due to breach in narcotic use contract. PMID- 25531959 TI - Activity-based cost analysis of opioid-related nausea and vomiting among inpatients. AB - OBJECTIVE: Nausea and/or vomiting (N/V) are frequent side effects of opioid drugs. These are of major concerns to patients and caregivers and only few studies have focused on their economical costs. DESIGN: This is a prospective, nonproduct-related, activity-based evaluation of personnel and material costs of opioid-related N/V among inpatients. SETTING: Data were obtained from surgical, general medicine, and palliative care wards at 16 German hospitals of different size, healthcare mandate, and ownership. PATIENTS, PARTICIPANTS: According to predefined criteria, of 462 documented N/V events, 340 were diagnosed as opioid related. INTERVENTIONS: Elicited activities and pharmacological interventions for N/V episodes followed local standards. MAIN OUTCOME MEASURE: Both materials used and the time engaged to treat patients with N/V were documented on an "ad hoc" activity recording form. The total cost of an opioid-related N/V episode was calculated based on standard wages of the involved personnel and standard costs of the inherent materials used. RESULTS: Mean staff tenure time for handling an episode of N/V was 26.2 +/- 19.8 minutes (nausea 16.9 +/- 28.7 minutes; nausea + vomiting: 33.4 +/- 26.8 minutes). In the German context, this corresponds to average personnel costs of ?18.06 +/- 13.64. Material cost contributes to another ?13.49 +/-13.38 of costs mainly depending on acquisition costs of antiemetic drugs. CONCLUSIONS: N/V showed to have impact on workload of nurses and (to lesser extent) physicians and economic burden of ?31 +/- 22 for each N/V episode. In view of these results, the potential costs of strategies to minimize the incidence of N/V (use of antiemetics and/or the use of new analgesics) should be outweighed against the incurred costs of N/V. PMID- 25531961 TI - Perioperative substance use disorder, opioid diversion, and opioid misuse by a medical professional undergoing orthopedic surgery. AB - Patients with substance use disorders can present challenges for effective perioperative pain management. Healthcare professionals with substance abuse disorders requiring medical treatment and pain management represent a unique subpopulation. The authors present a case of a nurse undergoing an orthopedic surgical procedure who was found with two large, organized tackle boxes of opioid medication in her hospital room. Although the incidence of substance use disorders in healthcare professionals is thought to be equivalent to the general population, the presentation, substances of choice, and inciting factors are unique. Further, treatment options available to such individuals have been established and proven successful. PMID- 25531960 TI - A multicenter, 12-month, open-label, single-arm safety study of oxycodone hydrochloride/naltrexone-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain. AB - OBJECTIVE: To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. DESIGN: Open-label, single-arm safety study. SETTING: Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). PATIENTS: Three hundred ninety-five adults (opioid experienced and opioid naive) with moderate-to-severe chronic noncancer pain (CNCP). INTERVENTIONS: Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. MAIN OUTCOME MEASURES: Number and type of adverse events (AEs) and drugrelated AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). RESULTS: A total of 193 (48.9 percent) patients received ALO-02 for >=181 days and 105 (26.6 percent) patients for >=361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. CONCLUSIONS: Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naive patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed. PMID- 25531962 TI - Depression: discrete or continuous? AB - Elucidating the true structure of depression is necessary if we are to advance our understanding and treatment options. Central to the issue of structure is whether depression represents discrete types or occurs on a continuum. Nature almost universally operates on the basis of continuums, whereas human perception favors discrete categories. This reality might be formalized into a 'continuum principle': natural phenomena tend to occur on a continuum, and any instance of hypothesized discreteness requires unassailable proof. Research evidence for discrete types falls far short of this standard, with most evidence supporting a continuum. However, quantitative variation can yield qualitative differences as an emergent property, fostering the appearance of discreteness. Depression as a continuum is best characterized by duration and severity dimensions, with the latter understood in terms of depressive inhibition. In the absence of some degree of cognitive, emotional, social, and physical inhibition, depression should not be diagnosed. Combining the dimensions of duration and severity provides an optimal way to characterize the quantitative and related qualitative aspects of depression and to describe the overall degree of dysfunction. The presence of other symptom types occurs when anxiety, hypomanic/manic, psychotic, and personality continuums interface with the depression continuum. PMID- 25531963 TI - What is the potential of structure-based target prediction methods? PMID- 25531964 TI - Phthalocyanine-based photosensitizers: more efficient photodynamic therapy? PMID- 25531965 TI - Practical permeability-based hepatic clearance classification system (HepCCS) in drug discovery. AB - BACKGROUND: The use of liver microsomes and hepatocytes to predict total in vivo clearance is standard practice in the pharmaceutical industry; however, metabolic stability data alone cannot always predict in vivo clearance accurately. RESULTS: Apparent permeability generated from Mardin-Darby canine kidney cells and rat hepatocyte uptake for 33 discovery compounds were obtained. CONCLUSION: When there is underprediction of in vivo clearance, compounds with low apparent permeability (less than 3 * 10(-6) cm/s) all exhibited hepatic uptake. A systematic approach in the form of a classification system (hepatic clearance classification system) and decision tree that will help drug discovery scientists understand in vitro-in vivo clearance prediction disconnect early is proposed. PMID- 25531966 TI - Chemoinformatics for medicinal chemistry: in silico model to enable the discovery of potent and safer anti-cocci agents. AB - BACKGROUND: Gram-positive cocci are increasingly antibiotic-resistant bacteria responsible for causing serious diseases. Chemoinformatics can help to rationalize the discovery of more potent and safer antibacterial drugs. We have developed a chemoinformatic model for simultaneous prediction of anti-cocci activities, and profiles involving absorption, distribution, metabolism, elimination and toxicity (ADMET). RESULTS: A dataset containing 48,874 cases from many different chemicals assayed under dissimilar experimental conditions was created. The best model displayed accuracies around 93% in both training and prediction (test) sets. Quantitative contributions of several fragments to the biological effects were calculated and analyzed. Multiple biological effects of the investigational drug JNJ-Q2 were correctly predicted. CONCLUSION: Our chemoinformatic model can be used as powerful tool for virtual screening of promising anti-cocci agents. PMID- 25531967 TI - Extending in silico mechanism-of-action analysis by annotating targets with pathways: application to cellular cytotoxicity readouts. AB - BACKGROUND: An in silico mechanism-of-action analysis protocol was developed, comprising molecule bioactivity profiling, annotation of predicted targets with pathways and calculation of enrichment factors to highlight targets and pathways more likely to be implicated in the studied phenotype. RESULTS: The method was applied to a cytotoxicity phenotypic endpoint, with enriched targets/pathways found to be statistically significant when compared with 100 random datasets. Application on a smaller apoptotic set (10 molecules) did not allowed to obtain statistically relevant results, suggesting that the protocol requires modification such as analysis of the most frequently predicted targets/annotated pathways. CONCLUSION: Pathway annotations improved the mechanism-of-action information gained by target prediction alone, allowing a better interpretation of the predictions and providing better mapping of targets onto pathways. PMID- 25531968 TI - Composing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity? AB - AIMS: In order to identify new scaffolds for drug discovery, surface plasmon resonance is frequently used to screen structurally diverse libraries. Usually, hit rates are low and identification processes are time consuming. Hence, approaches which improve hit rates and, thus, reduce the library size are required. METHODS: In this work, we studied three often used strategies for their applicability to identify inhibitors of PqsD. In two of them, target-specific aspects like inhibition of a homologous protein or predicted binding determined by virtual screening were used for compound preselection. Finally, a fragment library, covering a large chemical space, was screened and served as comparison. RESULTS & CONCLUSION: Indeed, higher hit rates were observed for methods employing preselected libraries indicating that target-oriented compound selection provides a time-effective alternative. PMID- 25531969 TI - Library construction, selection and modification strategies to generate therapeutic peptide-based modulators of protein-protein interactions. AB - In the modern age of proteomics, vast numbers of protein-protein interactions (PPIs) are being identified as causative agents in pathogenesis, and are thus attractive therapeutic targets for intervention. Although traditionally regarded unfavorably as druggable agents relative to small molecules, peptides in recent years have gained considerable attention. Their previous dismissal had been largely due to the susceptibility of unmodified peptides to the barriers and pressures exerted by the circulation, immune system, proteases, membranes and other stresses. However, recent advances in high-throughput peptide isolation techniques, as well as a huge variety of direct modification options and approaches to allow targeted delivery, mean that peptides and their mimetics can now be designed to circumvent many of these traditional barriers. As a result, an increasing number of peptide-based drugs are reaching clinical trials and patients beyond. PMID- 25531970 TI - Cyclic endomorphin analogs in targeting opioid receptors to achieve pain relief. AB - Endomorphins, the endogenous ligands of the u-opioid receptor, are attractive candidates for opioid-based pain-relieving agents. These tetrapeptides, with their remarkable affinity for the u-opioid receptor, display favorable antinociceptive activity when injected directly into the brain of experimental animals. However, the application of endomorphins as clinical analgesics has been impeded by their instability in body fluids and inability to reach the brain after systemic administration. Among numerous modifications of the endomorphin structure aimed at improving their pharmacological properties, cyclization can be viewed as an interesting option. Here, we have summarized recent advances in obtaining endomorphin-based cyclic peptide analogs. PMID- 25531971 TI - The use of high-throughput screening in identifying chemotherapeutic agents for gastric cancer. AB - Gastric cancer claims many lives around the world, particularly in Asia. Although diagnosis and treatment has improved, long-term survival of patients is still poor and there is an urgent need to develop more effective treatments for this disease. This review outlines some of the more innovative high-throughput screening-based approaches and strategies that may be used to identify compounds that have new or novel mechanisms of action and could be developed further as possible gastric cancer treatments in the future. PMID- 25531972 TI - Biophysical characterization of lectin-glycan interactions for therapeutics, vaccines and targeted drug-delivery. AB - Lectin-glycan interactions play a role in biological processes, host-pathogen interactions and in disease. A more detailed understanding of these interactions is not only useful for the elucidation of their biological function but can also be applied in immunology, drug development and delivery and diagnostics. We review some commonly used biophysical techniques for studying lectin-glycan interactions; namely: frontal affinity chromatography, glycan/lectin microarray, surface plasmon resonance, electrochemical impedance spectroscopy, isothermal titration calorimetry, fluorescent assays, enzyme linked lectin sorbent assay and saturation transfer difference nuclear magnetic resonance spectroscopy. Each method is evaluated on efficiency, cost and throughput. We also consider the advantages and limitations of each technique and provide examples of their application in biology, drug discovery and delivery, immunology, glycoprofiling and biosensing. PMID- 25531976 TI - Composition of dietary macronutrient intake is not associated with prevalence of coronary artery calcification in healthy Korean adults. AB - BACKGROUND AND AIMS: There is little information supporting the relationships between macronutrients and pre-clinical atherosclerosis. The aim of this study was to identify whether dietary macronutrient content is related with CAC. METHODS: 10,793 healthy Korean adults in a cohort were enrolled. Subjects were divided into CAC (CAC score >0) or non-CAC group (CAC score = 0). Intake of energy, carbohydrate (CHO), protein and fat were obtained using food frequency questionnaire (FFQ). Macronutrient composition was expressed as the ratio of energy from each macronutrient to total energy. Subjects were classified into three groups according to tertiles of intake for each macronutrient. To investigate the association between macronutrient intake and CAC, multiple regression analysis was conducted according to tertile groups of each macronutrient. RESULTS: The prevalence of CAC significantly differed among tertile groups of CHO and fat intake in men (p < 0.001, p < 0.01) and women (p < 0.05, p < 0.01). However, multiple logistic regression analysis revealed that the odds ratios (ORs) for CAC were not significantly different among tertile groups of each macronutrient intake after adjustment in men (CHO: OR = 0.965 [95% CI = 0.826-1.129]; protein: OR = 1.029 [95% CI = 0.881-1.201]; fat: OR = 1.015 [95% CI = 0.868-1.188]) and women (CHO: OR = 1.158 [95% CI = 0.550-2.438]; protein: OR = 1.261 [95% CI = 0.629-2.528]; fat: OR = 0.625 [95% CI = 0.286-1.365]). CONCLUSIONS: The prevalence of CAC may not be associated with composition of dietary macronutrient intake in in healthy Korean adults. PMID- 25531977 TI - Crocetin, a carotenoid derived from saffron (Crocus sativus L.), improves acetylcholine-induced vascular relaxation in hypertension. AB - BACKGROUND: Hypertension is associated with endothelial dysfunction characterized by decreased vasorelaxation. Crocetin, a bioactive compound of saffron, exhibits favorable cardiovascular properties. We analyze the vasomodulatory effects of crocetin in hypertension. METHODS: Myographical experiments were performed to compare the relaxation induced by acetylcholine (ACH) on aortic rings from normotensive (Wistar) and hypertensive (SHR) rats, incubated with or without crocetin or saffron extract and L-NAME or indomethacin. Extracts were also assayed in deendothelialized rings. UV-vis spectrophotometry and HPLC-DAD were used to characterize and quantify the saffron used. RESULTS: Crocetin enhanced the ACH relaxations in aorta from hypertensive (strongly) and normotensive rats (weakly). Saffron extract did not modify this. Crocetin plus L-NAME abolished the relaxant response in SHR but not in Wistar aorta. Crocetin plus indomethacin did not modify the indomethacin response in either SHR or Wistar aorta. Crocetin in rubbed segments did not modify the ACH responses. In contrast, saffron increased this response in rubbed segments from SHR but not Wistar rats. CONCLUSION: Crocetin exerts healthy vasomodulatory effects in hypertension, strongly improving endothelium-dependent ACH relaxations via endothelial nitric oxide but not the cyclooxygenase pathway. This work proposes that crocetin supplements are a possible complement in the therapy of hypertension. PMID- 25531978 TI - Continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a preliminary report. AB - BACKGROUND/AIM: We investigated the clinical efficacy of continuous hemodiafiltration (CHDF) with AN69ST hemofilter (AN69ST-CHDF) in patients with septic shock. MATERIALS AND METHODS: A prospective, multicenter, single-arm study was conducted. Patients with sepsis and shock defined by hyperlactemia were enrolled. The patients were treated with CHDF and in accordance with the Surviving Sepsis Campaign guidelines (SSCG). RESULTS: Thirty-four patients were enrolled. On ICU admission, the mean blood IL-6 level was 44,800 +/- 77,700 pg/ml, and the mean blood lactate level was 69.0 +/- 49.4 mg/dl. Both the mean blood IL-6 and lactate levels had significantly decreased to normal ranges after 72 h of AN69ST-CHDF. Though the mean APACHE II score was 32.7 +/- 9.8, 28-day survival was 73.5%. CONCLUSION: The current study suggested that adding AN69ST CHDF to the treatments outlined in the SSCG might lead to good outcomes for patients with septic shock, probably via the removal of cytokines from the bloodstream. PMID- 25531979 TI - Syntheses, structures, and antimicrobial activity of new remarkably light-stable and water-soluble tris(pyrazolyl)methanesulfonate silver(I) derivatives of N methyl-1,3,5-triaza-7-phosphaadamantane salt - [mPTA]BF4. AB - Two new silver(I) complexes of formula [Ag(mPTA)4](Tpms)4(BF4) (1) and [Ag(Tpms)(mPTA)](BF4) (2) (mPTA = N-methyl-1,3,5-triaza-7-phosphaadamantane cation, Tpms = tris(pyrazol-1-yl)methanesulfonate anion) have been synthesized and fully characterized by elemental analyses, (1)H and (31)P{(1)H} NMR, ESI-MS, and IR spectroscopic techniques. The single-crystal X-ray diffraction study of 1 discloses a noncoordinated nature of the Tpms species, existing as counterions around the highly charged metal center [Ag(mPTA)](5+), 1 being the first reported coordination compound bearing a kappa(0)-Tpms. 1 features high solubility and stability in water (S25 degrees C ~ 30 mg.mL(-1)). The two complexes interact with calf thymus DNA via intercalation mode, binding to the BSA with decrease of its tryptophan fluorescence with a static quenching mechanism. The two new silver complexes exhibit significant antibacterial and antifungal activities screened in vitro against the standard strains of Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. PMID- 25531980 TI - Asphalt-derived high surface area activated porous carbons for carbon dioxide capture. AB - Research activity toward the development of new sorbents for carbon dioxide (CO2) capture have been increasing quickly. Despite the variety of existing materials with high surface areas and high CO2 uptake performances, the cost of the materials remains a dominant factor in slowing their industrial applications. Here we report preparation and CO2 uptake performance of microporous carbon materials synthesized from asphalt, a very inexpensive carbon source. Carbonization of asphalt with potassium hydroxide (KOH) at high temperatures (>600 degrees C) yields porous carbon materials (A-PC) with high surface areas of up to 2780 m(2) g(-1) and high CO2 uptake performance of 21 mmol g(-1) or 93 wt % at 30 bar and 25 degrees C. Furthermore, nitrogen doping and reduction with hydrogen yields active N-doped materials (A-NPC and A-rNPC) containing up to 9.3% nitrogen, making them nucleophilic porous carbons with further increase in the Brunauer-Emmett-Teller (BET) surface areas up to 2860 m(2) g(-1) for A-NPC and CO2 uptake to 26 mmol g(-1) or 114 wt % at 30 bar and 25 degrees C for A-rNPC. This is the highest reported CO2 uptake among the family of the activated porous carbonaceous materials. Thus, the porous carbon materials from asphalt have excellent properties for reversibly capturing CO2 at the well-head during the extraction of natural gas, a naturally occurring high pressure source of CO2. Through a pressure swing sorption process, when the asphalt-derived material is returned to 1 bar, the CO2 is released, thereby rendering a reversible capture medium that is highly efficient yet very inexpensive. PMID- 25531981 TI - Corals concentrate dissolved inorganic carbon to facilitate calcification. AB - The sources of dissolved inorganic carbon (DIC) used to produce scleractinian coral skeletons are not understood. Yet this knowledge is essential for understanding coral biomineralization and assessing the potential impacts of ocean acidification on coral reefs. Here we use skeletal boron geochemistry to reconstruct the DIC chemistry of the fluid used for coral calcification. We show that corals concentrate DIC at the calcification site substantially above seawater values and that bicarbonate contributes a significant amount of the DIC pool used to build the skeleton. Corals actively increase the pH of the calcification fluid, decreasing the proportion of DIC present as CO2 and creating a diffusion gradient favouring the transport of molecular CO2 from the overlying coral tissue into the calcification site. Coupling the increases in calcification fluid pH and [DIC] yields high calcification fluid [CO3(2-)] and induces high aragonite saturation states, favourable to the precipitation of the skeleton. PMID- 25531982 TI - High-dose weekly liposomal amphotericin b antifungal prophylaxis in patients undergoing liver transplantation: a prospective phase II trial. AB - BACKGROUND: To assess the safety and tolerability of high-dose weekly (10 mg/kg) liposomal amphotericin B (LamB) for antifungal prophylaxis in liver transplantation (LT) recipients with predefined risk factors for invasive fungal infection (IFI), a prospective phase II noncomparative trial was performed at our center over a 4-year period. METHODS: In the selected LT recipients, LamB was administered weekly until hospital discharge after LT for minimum 2 weeks. Criteria for early discontinuing prophylaxis were: (i) any adverse event (AE); (ii) suspicion of IFI. Safety and tolerability were assessed according to the incidence of grades 3 to 4 AEs based on Common Toxicity Criteria (CTC) classification. Post-LT follow-up was of 180 days. RESULTS: Overall, 76 patients were included. Liposomal amphotericin B was started within a median of 1 (interquartile range, 1-4) day after LT. Overall, 66 of 76 (86.8%) patients completed the prophylaxis, 10 discontinued the study protocol: 6 for infusion related AE, 4 for suspected IFI. Adverse events consisted of five cases of lumbar pain and one case of thoracic pain which occurred after a median of 1.5 (interquartile range, 1-2) LamB infusions. None of the patients reported CTC grades 3 to 4 hypokalemia, three reported CTC grade 3 acute renal injury, none of which were deemed directly attributable to LamB. No drug-drug interactions with immunosuppressive drugs were reported, and no episode of rejection occurred during the prophylaxis. In only two of the four patients with suspected IFI was the diagnosis of invasive candidiasis confirmed. CONCLUSION: Our results suggest high-dose weekly LamB may be a safe prophylactic strategy for high-risk LT recipients. PMID- 25531983 TI - A new strategy for synthesis of porous magnetic supraparticles with excellent biodegradability. AB - Porous magnetic supraparticles (p-MSPs) with surface area up to 285.4 m(2) g(-1) have been fabricated by a one-step etching method, which is 4 times greater than the unetched counterpart. They exhibit significantly better biodegradability than their counterpart in both mimicked physiological buffer solution and the cellular environment of HeLa cells. PMID- 25531984 TI - Conductivity and magnetoresistance of La0.7Ce0.3MnO(3-delta) thin films under photoexcitation. AB - La0.7Ce0.3MnO3 thin films of different thicknesses, degrees of CeO2-phase segregation and oxygen deficiency, grown on SrTiO3 single crystal substrates, were comparatively investigated with respect to both their spectral and temperature-dependent photoconductivity (PC) and their magnetoresistance (MR) behaviour under photoexcitation. While as-grown films were insensitive to optical excitation, oxygen reduction appeared to be an effective way to decrease the film resistance, but the film thickness was found to play a minor role. However, from the evaluation of the spectral behaviour of the PC and the comparison of the MR of the LCeMO/substrate-samples with a bare substrate under illumination we find that the photoconductivity data reflects not only contributions from (i) photogenerated charge carriers in the film and (ii) carriers injected from the photoconductive substrate (as concluded from earlier works), but also (iii) a decisive parallel photoconduction in the SrTiO3 substrate. Furthermore--also by analyzing the MR characteristics--the unexpected occurence of a strong electroresistive effect in the sample with the highest degree of CeO2 segregation and oxygen deficiency could be attributed to the electroresistance of the SrTiO3 substrate as well. The results suggest a critical reconsideration and possibly a reinterpretation of several previous photoconductivity and electroresistance investigations of manganite thin films on SrTiO3. PMID- 25531985 TI - Sex-specific urinary biomarkers for diagnosing bipolar disorder. AB - Sex-based differences are prominent in affective disorders, but there are no biomarkers available to support sex-specific, laboratory-based diagnostics for male and female bipolar disorder (BD) patients. Here, a NMR-based metabonomic approach was used to preliminarily identify sex-specific urinary metabolite biomarkers for diagnosing male and female BD patients. A male-specific biomarker panel consisting of four metabolites (alpha-hydroxybutyrate, choline, formate, and N-methylnicotinamide) effectively discriminated between male BD and healthy controls (HC) subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.942. A female-specific biomarkers panel consisting of four metabolites (alpha-hydroxybutyrate, oxalacetate, acetone, and N-methylnicotinamide) effectively discriminated between female BD and HC subjects, achieving an AUC of 0.909. The male-specific biomarker panel displayed low discriminatory power in the female group, and the female-specific biomarker panel displayed low discriminatory power in the male group. Moreover, several other metabolites showed different trends between male and female BD subjects. These findings suggest that male and female BD patients have distinct biomarker fingerprints and that these two sex-specific biomarker panels may serve as effective diagnostic tools in distinguishing male and female BD patients from their healthy counterparts. Our work may provide a window into the mechanisms underlying the pathoetiology of BD in both men and women. PMID- 25531986 TI - Retrograde Intrarenal Surgery Versus Percutaneous Nephrolithotomy Versus Extracorporeal Shockwave Lithotripsy for Treatment of Lower Pole Renal Stones: A Meta-Analysis and Systematic Review. AB - BACKGROUND AND PURPOSE: The optimal treatment of patients with lower pole renal stones continues to be a dilemma for urologists. Retrograde intrarenal surgery (RIRS), percutaneous nephrolithotomy (PCNL), and extracorporeal shockwave lithotripsy (SWL) all constitute viable therapeutic options in selected patients. The aim of this study was to assess the efficacy and safety of RIRS, PCNL, and SWL in management of lower pole renal stones. METHODS: A literature search was performed in July 2014 using PubMed, Embase, and Web of Science databases. Literature reviewed included meta-analysis and randomized and nonrandomized controlled studies to identify relevant studies for the meta-analysis. RESULTS: Six randomized and eight nonrandomized studies were identified for analysis. PCNL provided a significantly higher stone-free rate (SFR) compared with RIRS and SWL. Furthermore, no statistical significant difference was found when PCNL was compared with RIRS and SWL for complication rate. Compared with the other two treatments, RIRS had a longer operative time and PCNL had a longer hospital stay. SWL was associated with significantly higher re-treatment rate compared with RIRS and PCNL, whereas there were no significant differences in auxiliary procedure rates among the three treatment techniques. CONCLUSION: RIRS offers a relative higher SFR while it has a longer operative time. PCNL is associated with the highest SFR at the expense of the longest hospital stay. SWL is performed as an outpatient procedure with a relative shorter operative time; however, it has lower a SFR and higher re-treatment rate. The categories of complications vary while the overall complication rates are comparable among the three treatment techniques. PMID- 25531987 TI - A dictionary learning approach with overlap for the low dose computed tomography reconstruction and its vectorial application to differential phase tomography. AB - X-ray based Phase-Contrast Imaging (PCI) techniques have been demonstrated to enhance the visualization of soft tissues in comparison to conventional imaging methods. Nevertheless the delivered dose as reported in the literature of biomedical PCI applications often equals or exceeds the limits prescribed in clinical diagnostics. The optimization of new computed tomography strategies which include the development and implementation of advanced image reconstruction procedures is thus a key aspect. In this scenario, we implemented a dictionary learning method with a new form of convex functional. This functional contains in addition to the usual sparsity inducing and fidelity terms, a new term which forces similarity between overlapping patches in the superimposed regions. The functional depends on two free regularization parameters: a coefficient multiplying the sparsity-inducing L1 norm of the patch basis functions coefficients, and a coefficient multiplying the L2 norm of the differences between patches in the overlapping regions. The solution is found by applying the iterative proximal gradient descent method with FISTA acceleration. The gradient is computed by calculating projection of the solution and its error backprojection at each iterative step. We study the quality of the solution, as a function of the regularization parameters and noise, on synthetic data for which the solution is a-priori known. We apply the method on experimental data in the case of Differential Phase Tomography. For this case we use an original approach which consists in using vectorial patches, each patch having two components: one per each gradient component. The resulting algorithm, implemented in the European Synchrotron Radiation Facility tomography reconstruction code PyHST, has proven to be efficient and well-adapted to strongly reduce the required dose and the number of projections in medical tomography. PMID- 25531988 TI - Gastric cat scratch--an upper endoscopy finding? PMID- 25531989 TI - Ileum adenocarcinoma, a missed cause of anemia. PMID- 25531990 TI - Esophagitis dissecans superficialis associated with severe clindamycin toxicity. PMID- 25531991 TI - Computed tomography view of Menetrier's disease. PMID- 25531992 TI - TIMP-1: a strong player in colorectal cancer. PMID- 25531993 TI - Quadruple rescue therapy after first and second line failure for Helicobacter pylori treatment: comparison between two tetracycline-based regimens. AB - BACKGROUND AND AIMS: Antibiotic resistance is the main reason for failure of Helicobacter pylori (H. pylori) treatment. Currently, guidelines recommend a treatment guided by antimicrobial susceptibility testing after two failures. However, microbial culture is not feasible everywhere, and the limited number of effective antibiotics against the bacterium narrows the options; thus a rescue therapy combining antibiotics with a low resistance may be fitting. METHODS: Patients who have failed a first-line treatment (either prolonged triple or sequential regimens) and, successively, a levofloxacin-based triple therapy were considered for the study. Subjects underwent urea breath test (UBT), stool antigen test (ST) and endoscopy/histology to confirm the diagnosis. Cytopenia and impaired liver and kidney function were exclusion criteria. Fifty-four subjects were randomized 1:1 to two regimens: RMB Rabeprazole/Rifabutin/Minocycline/Bismuth sub-citrate or MTB Rabeprazole/Tinidazole/Minocycline/Bismuth sub-citrate both for 10 days. The results were checked 6 weeks after the end of therapy with ST/UBT plus endoscopy when indicated. RESULTS: RMB eradicated the bacterium in 21 patients. Two subjects dropped out. The eradication rate was 77.7% (CI 62.0-93.4%) at intention to-treat and 84.0% (CI 69.6-98.4%) at per-protocol analysis. MTB was successful in 14 patients (51.9%, CI 33.1-70.7%). No patient withdrew from the treatment for adverse events. Drug-related side effects were reported only in 3 subjects, but in all cases the treatment was carried on. CONCLUSIONS: The association minocycline/rifabutin seems to have a synergic effect and a good therapeutic outcome in patients who have failed at least two previous regimens, although a trial on a large population is needed. PMID- 25531994 TI - Health-related quality of life and utilities in gastric premalignant conditions and malignant lesions: a multicentre study in a high prevalence country. AB - BACKGROUND AND AIMS: A recent review of economic studies relating to gastric cancer revealed that authors use different tests to estimate utilities in patients with and without gastric cancer. Our aim was to determine the utilities of gastric premalignant conditions and adenocarcinoma with a single standardized health measure instrument. METHODS: Cross-sectional nationwide study of patients undergoing upper endoscopy (n=1,434) using the EQ-5D-5L quality of life (QoL) questionnaire. RESULTS: According to EQ-5D-5L, utilities in individuals without gastric lesions were 0.78 (95% confidence interval: 0.76-0.80), with gastric premalignant conditions 0.79 (0.77-0.81), previously treated for gastric cancer 0.77 (0.73-0.81) and with present cancer 0.68 (0.55-0.81). Self-reported QoL according to the visual analogue scale (VAS) for the same groups were 0.67 (0.66 0.69), 0.67 (0.66-0.69), 0.62 (0.59-0.65) and 0.62 (0.54-0.70) respectively. Utilities were consistently lower in women versus men (no lesions 0.71 vs. 0.78; premalignant conditions 0.70 vs. 0.82; treated for cancer 0.72 vs. 0.78 and present cancer 0.66 vs. 0.70). CONCLUSION: The health-related QoL utilities of patients with premalignant conditions are similar to those without gastric diseases whereas patients with present cancer show decreased utilities. Moreover, women had consistently lower utilities than men. These results confirm that the use of a single standardized instrument such as the EQ-5D-5L for all stages of the gastric carcinogenesis cascade is feasible and that it captures differences between conditions and gender dissimilarities, being relevant information for authors pretending to conduct further cost-utility analysis. PMID- 25531995 TI - Acute colonic diverticulitis: diagnostic evidence, demographic and clinical features in three practice settings. AB - BACKGROUND AND AIMS: Diverticulitis is often diagnosed in outpatients, yet little evidence exists on diagnostic evidence and demographic/clinical features in various practice settings. We assessed variation in clinical characteristics and diagnostic evidence in inpatients, outpatients, and emergency department cases and effects of demographic and clinical variables on presentation features. METHODS: In a retrospective cohort study of 1749 patients in an integrated health care system, we compared presenting features and computed tomography findings by practice setting and assessed independent effects of demographic and clinical factors on presenting features. RESULTS: Inpatients were older and more often underweight/normal weight and lacked a diverticulitis past history and had more comorbidities than other patients. Outpatients were most often Hispanic/Latino. The classical triad (abdominal pain, fever, leukocytosis) occurred in 78 (38.6%) inpatients, 29 (5.2%) outpatients and 34 (10.7%) emergency department cases. Computed tomography was performed on 196 (94.4%) inpatients, 110 (9.2%) outpatients and 296 (87.6%) emergency department cases and was diagnostic in 153 (78.6%) inpatients, 62 (56.4%) outpatients and 243 (82.1%) emergency department cases. Multiple variables affected presenting features. Notably, female sex had lower odds for the presence of the triad features (odds ratio [95% CI], 0.65 [0.45-0.94], P<0.05) and increased odds of vomiting (1.78 [1.26-2.53], P<0.01). Patients in age group 56 to 65 and 66 or older had decreased odds of fever (0.67 [0.46-0.98], P<0.05) and 0.46 [0.26-0.81], P<0.01), respectively, while > / =1 co morbidity increased the odds of observing the triad (1.88 [1.26-2.81], P<0.01). CONCLUSION: There was little objective evidence for physician-diagnosed diverticulitis in most outpatients. Demographic and clinical characteristics vary among settings and independently affect presenting features. PMID- 25531996 TI - The effect of Lactobacillus reuteri supplementation in adults with chronic functional constipation: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND AND AIMS: There is a growing interest for the use of probiotics for chronic constipation. A recent randomized controlled trial (RCT) showed a positive effect of Lactobacillus reuteri (L. reuteri) on bowel movement frequency in infants with chronic constipation. The aim of the present study was to evaluate the effects of L. reuteri in adult patients with functional constipation. METHODS: A double-blind, placebo RCT was conducted in 40 adults (18M/22F, 35+/-15 years) affected by functional constipation according to the Rome III criteria. Patients were randomly assigned to receive a supplementation of L. reuteri (DSM 17938), or matching placebo for 4 weeks. The increase of bowel movements/week was the primary outcome, while the improvement of stool consistency was the secondary outcome. RESULTS: At week 4, the mean increase in bowel movements/week was 2.6 (SD +/-1.14, 95% CI:1.6-3.6) in the L. reuteri group and 1.0 (SD+/-1. 95% CI:0.12-1.88) in the placebo group (p=0.046). At the end of the treatment, the mean bowel movements/week was 5.28+/-1.93 in the L. reuteri group and 3.89+/-1.79 in the placebo group. There was a not significant difference in the stool consistency between the two groups. CONCLUSIONS: L. reuteri is more effective than the placebo in improving bowel movement frequency in adult patients with functional constipation as previously demonstrated in children, even if it seems to have no effect on stool consistency. PMID- 25531997 TI - Clinical usefulness of HCV core antigen assay for the management of patients with chronic hepatitis C. AB - AIM: The study aimed to evaluate the clinical utility of the chemiluminescent HCV core Ag test compared to viral load assessment in the management of patients with chronic hepatitis C. METHODS: A retrospective study was performed at a tertiary care infectious diseases hospital on samples collected from anti-HCV positive patients. Seventy-six samples were tested with the Architect HCV core Antigen kit and Cobas AmpliPrep/Cobas Taqman HCV kit. The HCV Ag test accuracy was estimated using data from all the HCV RNA tested samples received between January 2011 and December 2012. RESULTS: The HCV Ag test showed a good correlation between the logarithmic values of HCV RNA and HCV Ag (R=0.98), with a 100% specificity and PPV, but with reduced sensitivity for viral loads lower than 1,000 UI/mL. In a model using data from 2,478 HCV RNA tested samples and a cut-off of the Ag assay corresponding to 1,000 UI/mL HCV RNA, the Ag test would have a sensitivity of 82.4%, a NPV of 80.9% and a high specificity and PPV (100%) compared to the viral load. The sensitivity would be higher for baseline evaluation compared to on treatment samples (98.5 vs. 50%). The highest NPV (98%) would be obtained at 48 and 72 weeks after the initiation of treatment, with a sensitivity of 88.2% and 96.1%, respectively. CONCLUSION: The Architect HCV core Ag assay might be an alternative for the diagnosis of active HCV infection if molecular tests are not available, and a useful method for the evaluation of sustained virological response in treated patients. PMID- 25531998 TI - The metabolic syndrome is not correlated with the short-term risk of decompensation in patients with cirrhosis. AB - BACKGROUND AND AIMS: Obesity proved to favor clinical decompensation in patients with cirrhosis. Our aim was to investigate if metabolic syndrome (MS) in cirrhotic patients represents a risk factor for decompensation. METHODS: 704 cirrhotics, included in a MS prevalence study were considered for evaluation; 121 patients were excluded because they did not complete the follow-up and 303 because they were decompensated at the start of the study. The remaining 280 were followed-up for a median period of 28.1+/-18 months. Patients were censored at the end of follow-up or at occurrence of a liver related event (LRE). Liver related events were considered the following: decompensation (ascites, variceal bleeding, hepatorenal syndrome, jaundice, encephalopathy), hepatocellular carcinoma, portal vein thrombosis and infections. RESULTS: All MS criteria except the abdominal circumference were significantly different between decompensated and compensated patients. HDL-cholesterol levels were lower in decompensated patients. Among the 280 patients who completed the follow-up, 85 (30%) presented LREs. Ascites was the most frequent event. In the univariate analysis of the MS criteria we found a trend to significance of an inverse correlation between MS and LREs. There was no significant difference between patients with or without MS regarding survival free of LREs, 76.7% and 66.5%, respectively. None of the MS criteria reached the level of significance in discriminating patients with and without LREs. CONCLUSIONS: In short term, presence of MS was not a risk factor for LREs. In short term, liver function and lower nutritional status influenced the prognosis. In decompensated patients, the MS defining criteria are not applicable. PMID- 25531999 TI - Clinical usefulness of endoscopic ultrasound-guided fine needle aspiration for gastric subepithelial lesions smaller than 2 cm. AB - BACKGROUND AND AIMS: There is no evidence of postoperative metastasis of gastric gastrointestinal stromal tumors (GISTs) smaller than 2 cm. The aim of this study was to evaluate the clinical usefulness of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) for gastric subepithelial lesions (SELs) smaller than 2 cm. PATIENTS AND METHODS: Using a prospectively maintained EUS-FNA database, 90 consecutive EUS-FNAs of gastric hypoechoic solid SELs smaller than 2 cm diagnosed by EUS were evaluated retrospectively. The reference standards for the final diagnosis were surgery (n=44) and/or clinical follow-up (n=46) using esophagogastroduodenoscopy (EGD), CT, and/or ultrasonography (US). Additionally, immunophenotyping of specimens obtained by EUS-FNA and surgical resection specimens were compared. RESULTS: The diagnostic rate of EUS-FNA for gastric hypoechoic solid SELs smaller than 2 cm was 73% (66/90). Histological diagnosis of EUS-FNA showed 47 (52%) malignant SELs (44 GISTs, 1 glomus tumor, 1 SEL like cancer, and 1 malignant lymphoma), 19 (21%) benign SELs (14 leiomyomas, 4 ectopic pancreas, and 1 neurinoma), and 24 (27%) indeterminate SELs. In 44 surgically resected cases, the diagnostic accuracy of EUS-FNA using immunohistochemical analysis was 98% (43/44). There were no complications. Appropriate management was performed in 65 out of 66 SELs (98%) diagnosed by definitive EUS-FNA. After surgery, there was no recurrence of malignant SELs. CONCLUSIONS: EUS-FNA is an accurate and safe method in the pre-therapeutic diagnosis of gastric SELs smaller than 2 cm. EUS-FNA for gastric SELs smaller than 2 cm is a promising way to permit early management of patients with gastric SELs including GIST. PMID- 25532000 TI - TIMP-1 expression in human colorectal cancer is associated with SMAD3 gene expression levels: a pilot study. AB - BACKGROUND AND AIMS: The prognosis of colorectal cancer (CRC) varies considerably, and there is a compelling need to identify novel biomarkers with prognostic significance. The aim of the present study was to evaluate the prognostic value of a panel of six genes (CDH1, SMAD3, TGFbeta1, ICAM-1, TIMP-1 and MUC12) in CRC patients. METHODS. We evaluated these genes by qRT-PCR in normal and CRC tumor tissue, and correlated the relative gene expression values with clinical, pathological aspects and other biological factors. RESULTS. RNA expression levels of CDH1, SMAD3, TGFbeta1, ICAM-1, TIMP-1 and MUC12 were measured by qRT-PCR in a set of 39 tumor samples and non-cancer tissue. Statistically significant increases in expression levels were found for ICAM-1 and TIMP-1 when comparing tumor samples to the non-tumor group. CONCLUSIONS. Among the genes which displayed differential expressions between tumor tissue and adjoining normal tissue, the ones that presented statistically significant correlations were TIMP-1 and SMAD3, possibly with prognostic significance. PMID- 25532001 TI - A comparison of three chromogranin A assays in patients with neuroendocrine tumours. AB - BACKGROUND AND AIMS: Chromogranin A (CgA) is the most important general tumour marker used in the diagnosis and follow-up of patients with neuroendocrine tumours (NET). Chromogranin A assays may have different sensitivities, which is of importance for the clinical diagnosis and handling of NET patients. The aim of this study was to compare the clinical sensitivities of three different CgA assays in NET patients. METHODS: We measured CgA level in 42 NET patients (male/female: 23/19, median age: 63 years, range 29-85 years). Twenty-five patients had liver metastases, eight had local disease, and nine were disease free after surgery. We studied an in-house RIA: RH RIA assay (Rigshospitalet, Copenhagen, Denmark); NEOLISATM (Euro Diagnostica, Malmo, Sweden) and EURIA CgA RIA (Euro Diagnostica, Malmo, Sweden). RESULTS: The RH RIA assay showed a clinical sensitivity of 97%, while the NEOLISA and EURIA assays both showed similar clinical sensitivities of 79%. Patients with liver metastases had significantly higher CgA levels compared to disease free patients by all three assays (P<0.001), but only the RH RIA assay was able to discriminate between patients with liver metastases and with regional disease (P<0.01). CONCLUSION: Chromogranin A measurements are significantly assay-dependent and caution should be applied in the interpretation of CgA measurement for assessment of NET status. The in-house RH RIA assay was better at predicting NET status than the NEOLISA and EURIA assays. PMID- 25532002 TI - Non-invasive biomarkers in non-alcoholic steatohepatitis-induced hepatocellular carcinoma. AB - Non-alcoholic fatty liver disease (NAFLD) is by far the most common form of chronic liver disease worldwide, affecting adults as well as children. Under the term of NAFLD there is a wide spectrum of diseases ranging from simple steatosis to the non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC). Several mechanisms have been described to influence the progression of the disease from the benign NAFL to the aggressive NASH. The imbalance between pro- and anti-oxidant mechanisms and between pro- and anti-inflammatory cytokines is thought to play a pivotal role in the pathogenesis of NAFLD and disease progression toward NASH and fibrosis. The present review intends to look at some of the mechanistic biomarkers to be employed in establishing an early diagnosis in HCC derived from NASH. PMID- 25532003 TI - The use of mebeverine in irritable bowel syndrome. A Position paper of the Romanian Society of Neurogastroenterology based on evidence. PMID- 25532004 TI - Primary hepatic amyloidosis presenting as nodular masses on the background of diffuse infiltration and extreme liver stiffness on MR elastography. AB - Amyloidosis is characterized by the deposition of extracellular protein material, amyloid, in various organs. The clinical and imaging features of the disease are often nonspecific and a tissue biopsy is often required. We present the case of a 64-year-old man with biopsy proven amyloidosis of the liver. The patient presented with non-specific clinical symptoms. Routine imaging showed hepatomegaly with heterogeneous enhancement, and several large nodular space occupying lesions, mimicking neoplasm. MR elastography revealed an extremely stiff liver. Amyloidosis presenting as multiple nodular masses on the background of diffuse infiltrative pattern or demonstration of extreme stiffness in hepatic amyloidosis on MR elastography have not been described previously. PMID- 25532005 TI - Hepatic cyst infection following aspiration sclerotherapy: a case series. AB - Mass-related symptoms caused by hepatic cysts are effectively treated by aspiration sclerotherapy (AS). This minimal-invasive intervention is regarded as a safe procedure. Hence, occurrence of complications is low. Transient fever is commonly reported as a side effect. However, documentation on a post-procedural hepatic cyst infection as a complication of AS is limited. We present five cases in which a tentative diagnosis of post-procedural hepatic cyst infection was made. Patients typically presented with abdominal pain and fever, had to be admitted to our hospital, and were treated with long term antibiotics. Ultimately, the cyst infection successfully resolved with ciprofloxacin in all cases. PMID- 25532006 TI - Malignant familial adenomatous polyposis treated by laparoscopic colectomy and ileal pouch anal anastomosis: a case report. AB - The mean age of colorectal cancer in untreated familial adenomatous polyposis (FAP) is 39 years. We present the case of a 21-year-old patient with FAP and colorectal cancer. The patient was detected with significant family history: her mother died at age 45 with colon cancer; two uncles were diagnosed with colon cancer at the age of 40 and 43 and one aunt at the age of 45 with colon cancer and gastric cancer. The treatment was laparoscopic restorative proctocolectomy with total excision of the mesorectum and ileal pouch anal anastomosis completed with endoanal excision of inferior rectal polyps. The histopathological report described a well differentiated rectal adenocarcinoma T1N1aMx developed on a tubulo-villous adenoma located on the rectosigmoid jonction, the rest of the polyps with benign histology. PMID- 25532007 TI - Disappearance of an advanced adenomatous colon polyp after intratumoural injection with Viscum album (European mistletoe) extract: a case report. AB - BACKGROUND AND AIM: Extracts of Viscum album (European mistletoe) have immune stimulatory and cytotoxic effects, with trials showing a well-established effect on the quality of life and prolonged survival in patients with advanced pancreatic cancer. Regression of tumours following intratumoural injection with Viscum album extract has been documented in individual cases. However, its influence on colon polyps has not been investigated. CASE PRESENTATION: We present the case of a 78-year-old Caucasian male who had undergone hemi-colectomy for a stage IIIC colon cancer but who refused adjuvant chemotherapy. Five years later a newly detected high-grade dysplasia colon adenoma was discovered; however, the adenoma could not be resected endoscopically and the patient did not consent to surgery. Intratumoural injections with Viscum album L extract (Quercus; Iscador(r)Qu) were administered twice in an attempt to limit tumour growth. Eight months after the second intratumoural injection the adenoma had disappeared and biopsy revealed no intraepithelial dysplasia or adenoma. CONCLUSIONS: This is the first report showing complete regression of a colon adenoma after intratumoural injection with Viscum album extract. Prospective studies should evaluate if the treatment effect is reproducible and if this approach could be a useful pre-operative measure for colon adenomas too large for endoscopic resection. PMID- 25532008 TI - The deleterious effects of non-selective beta-blockers on cirrhotic patients: the confused clinician! PMID- 25532009 TI - Reply. When to stop non-selective beta-blockers: the window hypothesis in clinical practice. PMID- 25532010 TI - Epidemiology and predictors of recurrence of Clostridium difficile infection in a North Italian tertiary care hospital. PMID- 25532011 TI - An extremely rare primary gallbladder myxoid liposarcoma associated with amplification of DDIT3 gene. PMID- 25532012 TI - Increased rate of spontaneous clearance of hepatitis C virus in patients infected with HIV. PMID- 25532013 TI - Assessment of active mucosal inflammation in IBD patients in clinical remission. PMID- 25532014 TI - Reply: To PMID 25267955. PMID- 25532015 TI - Use of echocardiography reveals reestablishment of ventricular pumping efficiency and partial ventricular wall motion recovery upon ventricular cryoinjury in the zebrafish. AB - AIMS: While zebrafish embryos are amenable to in vivo imaging, allowing the study of morphogenetic processes during development, intravital imaging of adults is hampered by their small size and loss of transparency. The use of adult zebrafish as a vertebrate model of cardiac disease and regeneration is increasing at high speed. It is therefore of great importance to establish appropriate and robust methods to measure cardiac function parameters. METHODS AND RESULTS: Here we describe the use of 2D-echocardiography to study the fractional volume shortening and segmental wall motion of the ventricle. Our data show that 2D echocardiography can be used to evaluate cardiac injury and also to study recovery of cardiac function. Interestingly, our results show that while global systolic function recovered following cardiac cryoinjury, ventricular wall motion was only partially restored. CONCLUSION: Cryoinjury leads to long-lasting impairment of cardiac contraction, partially mimicking the consequences of myocardial infarction in humans. Functional assessment of heart regeneration by echocardiography allows a deeper understanding of the mechanisms of cardiac regeneration and has the advantage of being easily transferable to other cardiovascular zebrafish disease models. PMID- 25532017 TI - Epigenetics: novel therapeutics targeting epigenetics. PMID- 25532016 TI - Normocaloric low cholesterol diet modulates Th17/Treg balance in patients with chronic hepatitis C virus infection. AB - Hepatitis C virus (HCV) infection is associated with hepatic and extrahepatic manifestations, including immunological disorders. Chronic Hepatitis C (CHC) is often characterized by cholesterol and lipid metabolism alterations, leading to hepatic steatosis. Cholesterol metabolism, in fact, is crucial for the viral life cycle. Recent works described that a higher dietary cholesterol intake is associated with the progression of HCV-related liver disease. CHC patients have increased levels of T helper 17 (Th17)-cells, a lymphocytic population involved in the pathogenesis of liver inflammation and autoimmune hepatitis. The balance between Th17 and regulatory T (Treg) cells is crucial for chronic inflammation and autoimmunity. Th17-cell differentiation is deeply influenced by the activation LXRs, nuclear receptors modulating cholesterol homeostasis. Moreover, HCV may affect these nuclear receptors, and cholesterol metabolism, through both direct and indirect mechanisms. On these bases, we hypothesized that modulation of cholesterol levels through Normocaloric Low Cholesterol Diet (NLCD) may represent an innovative strategy to reduce the progression of HCV infection, through the modulation of peripheral Th17/Treg balance. To this end, we performed a pilot study to investigate whether a Normocaloric Low Cholesterol Diet may be able to modulate Th17/Treg balance in patients affected by chronic HCV infection. After 30 days of NLCD CHC patients showed a significant reduction in Th17 cells frequency, which correlated with strong reduction of IL-17 and IL-22 serum levels. At the same time, we appreciated an increase in the percentage of Treg cells, thus improving Treg/Th17 balance. Moreover, we observed an increased expression of LXRs and their target genes: SREBP-1c and ABCA-1. In conclusion, NLCD finely regulates Th17/Treg balance, improving immune system response in CHC patients. This study could pave the way for new treatments of CHC patients, suggesting that change in lifestyle could support the management of these patients, promoting well-being and possibly hindering disease progression. TRIAL REGISTRATION: ClinicalTrials.gov NCT02038387. PMID- 25532018 TI - Spatial complementarity and the coexistence of species. AB - Coexistence of apparently similar species remains an enduring paradox in ecology. Spatial structure has been predicted to enable coexistence even when population level models predict competitive exclusion if it causes each species to limit its own population more than that of its competitor. Nevertheless, existing hypotheses conflict with regard to whether clustering favours or precludes coexistence. The spatial segregation hypothesis predicts that in clustered populations the frequency of intra-specific interactions will be increased, causing each species to be self-limiting. Alternatively, individuals of the same species might compete over greater distances, known as heteromyopia, breaking down clusters and opening space for a second species to invade. In this study we create an individual-based model in homogeneous two-dimensional space for two putative sessile species differing only in their demographic rates and the range and strength of their competitive interactions. We fully characterise the parameter space within which coexistence occurs beyond population-level predictions, thereby revealing a region of coexistence generated by a previously unrecognised process which we term the triadic mechanism. Here coexistence occurs due to the ability of a second generation of offspring of the rarer species to escape competition from their ancestors. We diagnose the conditions under which each of three spatial coexistence mechanisms operates and their characteristic spatial signatures. Deriving insights from a novel metric - ecological pressure - we demonstrate that coexistence is not solely determined by features of the numerically-dominant species. This results in a common framework for predicting, given any pair of species and knowledge of the relevant parameters, whether they will coexist, the mechanism by which they will do so, and the resultant spatial pattern of the community. Spatial coexistence arises from complementary combinations of traits in each species rather than solely through self limitation. PMID- 25532019 TI - Multiscale approach to investigate self-assembly of telodendrimer based nanocarriers for anticancer drug delivery. AB - Delivery of poorly soluble anticancer drugs can be achieved by employing polymeric drug delivery systems, capable of forming stable self-assembled nanocarriers with drug encapsulated within their hydrophobic cores. Computational investigations can aid the design of efficient drug-delivery platforms; however, simulations of nanocarrier self-assembly process are challenging due to high computational cost associated with the large system sizes (millions of atoms) and long time scales required for equilibration. In this work, we overcome this challenge by employing a multiscale computational approach in conjunction with experiments to analyze the role of the individual building blocks in the self assembly of a highly tunable linear poly(ethylene glycol)-b-dendritic oligo(cholic acid) block copolymer called telodendrimer. The multiscale approach involved developing a coarse grained description of the telodendrimer, performing simulations over several microseconds to capture the self-assembly process, followed by reverse mapping of the coarse grained system to atomistic representation for structural analysis. Overcoming the computational bottleneck allowed us to run multiple self-assembly simulations and determine average size, drug-telodendrimer micellar stoichiometry, optimal drug loading capacity, and atomistic details such hydrogen-bonding and solvent accessible area of the nanocarrier. Computed results are in agreement with the experimental data, highlighting the success of the multiscale approach applied here. PMID- 25532021 TI - Trait anxiety and impaired control of reflective attention in working memory. AB - The present study investigated whether the control of reflective attention in working memory (WM) is impaired in high trait anxiety individuals. We focused on the consequences of refreshing-a simple reflective process of thinking briefly about a just-activated representation in mind-on the subsequent processing of verbal stimuli. Participants performed a selective refreshing task, in which they initially refreshed or read one word from a three-word set, and then refreshed a non-selected item from the initial phrase or read aloud a new word. High trait anxiety individuals exhibited greater latencies when refreshing a word after experiencing the refreshing of a word from the same list of semantic associates. The same pattern was observed for reading a new word after prior refreshing. These findings suggest that high trait anxiety individuals have difficulty resolving interference from active distractors when directing reflective attention towards contents in WM or processing a visually presented word. PMID- 25532020 TI - Decreased elastic energy storage, not increased material stiffness, characterizes central artery dysfunction in fibulin-5 deficiency independent of sex. AB - Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries-the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery-from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function. PMID- 25532022 TI - From breathing to respiration. AB - The purpose of breathing remained an enigma for a long time. The Hippocratic school described breathing patterns but did not associate breathing with the lungs. Empedocles and Plato postulated that breathing was linked to the passage of air through pores of the skin. This was refuted by Aristotle who believed that the role of breathing was to cool the heart. In Alexandria, breakthroughs were accomplished in the anatomy and physiology of the respiratory system. Later, Galen proposed an accurate description of the respiratory muscles and the mechanics of breathing. However, his heart-lung model was hampered by the traditional view of two non-communicating vascular systems - veins and arteries. After a period of stagnation in the Middle Ages, knowledge progressed with the discovery of pulmonary circulation. The comprehension of the purpose of breathing progressed by steps thanks to Boyle and Mayow among others, and culminated with the contribution of Priestley and the discovery of oxygen by Lavoisier. Only then was breathing recognized as fulfilling the purpose of respiration, or gas exchange. A century later, a controversy emerged concerning the active or passive transfer of oxygen from alveoli to the blood. August and Marie Krogh settled the dispute, showing that passive diffusion was sufficient to meet the oxygen needs. PMID- 25532024 TI - Predicting the Rate Constant of Electron Tunneling Reactions at the CdSe-TiO2 Interface. AB - Current interest in quantum dot solar cells (QDSCs) motivates an understanding of the electron transfer dynamics at the quantum dot (QD)-metal oxide (MO) interface. Employing transient absorption spectroscopy, we have monitored the electron transfer rate (ket) at this interface as a function of the bridge molecules that link QDs to TiO2. Using mercaptoacetic acid, 3-mercaptopropionic acid, 8-mercaptooctanoic acid, and 16-mercaptohexadecanoic acid, we observe an exponential attenuation of ket with increasing linker length, and attribute this to the tunneling of the electron through the insulating linker molecule. We model the electron transfer reaction using both rectangular and trapezoidal barrier models that have been discussed in the literature. The one-electron reduction potential (equivalent to the lowest unoccupied molecular orbital) of each molecule as determined by cyclic voltammetry (CV) was used to estimate the effective barrier height presented by each ligand at the CdSe-TiO2 interface. The electron transfer rate (ket) calculated for each CdSe-ligand-TiO2 interface using both models showed the results in agreement with the experimentally determined trend. This demonstrates that electron transfer between CdSe and TiO2 can be viewed as electron tunneling through a layer of linking molecules and provides a useful method for predicting electron transfer rate constants. PMID- 25532023 TI - Electromyographic permutation entropy quantifies diaphragmatic denervation and reinnervation. AB - Spontaneous reinnervation after diaphragmatic paralysis due to trauma, surgery, tumors and spinal cord injuries is frequently observed. A possible explanation could be collateral reinnervation, since the diaphragm is commonly double innervated by the (accessory) phrenic nerve. Permutation entropy (PeEn), a complexity measure for time series, may reflect a functional state of neuromuscular transmission by quantifying the complexity of interactions across neural and muscular networks. In an established rat model, electromyographic signals of the diaphragm after phrenicotomy were analyzed using PeEn quantifying denervation and reinnervation. Thirty-three anesthetized rats were unilaterally phrenicotomized. After 1, 3, 9, 27 and 81 days, diaphragmatic electromyographic PeEn was analyzed in vivo from sternal, mid-costal and crural areas of both hemidiaphragms. After euthanasia of the animals, both hemidiaphragms were dissected for fiber type evaluation. The electromyographic incidence of an accessory phrenic nerve was 76%. At day 1 after phrenicotomy, PeEn (normalized values) was significantly diminished in the sternal (median: 0.69; interquartile range: 0.66-0.75) and mid-costal area (0.68; 0.66-0.72) compared to the non denervated side (0.84; 0.78-0.90) at threshold p<0.05. In the crural area, innervated by the accessory phrenic nerve, PeEn remained unchanged (0.79; 0.72 0.86). During reinnervation over 81 days, PeEn normalized in the mid-costal area (0.84; 0.77-0.86), whereas it remained reduced in the sternal area (0.77; 0.70 0.81). Fiber type grouping, a histological sign for reinnervation, was found in the mid-costal area in 20% after 27 days and in 80% after 81 days. Collateral reinnervation can restore diaphragm activity after phrenicotomy. Electromyographic PeEn represents a new, distinctive assessment characterizing intramuscular function following denervation and reinnervation. PMID- 25532025 TI - Anonymity versus privacy in the dictator game: revealing donor decisions to recipients does not substantially impact donor behavior. AB - Anonymity is often offered in economic experiments in order to eliminate observer effects and induce behavior that would be exhibited under private circumstances. However, anonymity differs from privacy in that interactants are only unaware of each others' identities, while having full knowledge of each others' actions. Such situations are rare outside the laboratory and anonymity might not meet the requirements of some participants to psychologically engage as if their actions were private. In order to explore the impact of a lack of privacy on prosocial behaviors, I expand on a study reported in Dana et al. (2006) in which recipients were left unaware of the Dictator Game and given donations as "bonuses" to their show-up fees for other tasks. In the current study, I explore whether differences between a private Dictator Game (sensu Dana et al. (2006)) and a standard anonymous one are due to a desire by dictators to avoid shame or to pursue prestige. Participants of a Dictator Game were randomly assigned to one of four categories-one in which the recipient knew of (1) any donation by an anonymous donor (including zero donations), (2) nothing at all, (3) only zero donations, and (4) and only non-zero donations. The results suggest that a lack of privacy increases the shame that selfish-acting participants experience, but that removing such a cost has only minimal effects on actual behavior. PMID- 25532026 TI - Nutritional deficiencies and overweight prevalence among children with autism spectrum disorder. AB - Children with autism spectrum disorder (ASD) are at risk of developing nutritional deviations. Three to six year old children with ASD were compared to their typically developing siblings and to a typically developing age and gender matched control group, in order to evaluate their intake and body mass index. Nutrient intake was compared to the Dietary Reference Intake using three-day diet diaries completed by the parents. The sum percentage of nutritional deficiencies in the ASD group compared to the typical development group was 342.5% (+/-122.9%) vs. 275.9% (+/-106.8%), respectively (P=0.026). A trend toward higher deficiency in the ASD group was observed as compared to the sibling group 363% (+/-122.9%) vs. 283.2% (+/-94.7%) (P=0.071). A higher body mass index was found in the ASD group compared to their counterparts, despite their nutritional deficiencies. In conclusion, children with ASD are more likely to suffer from nutritional deficiencies despite higher body mass index. PMID- 25532027 TI - A peptide antigen derived from EGFR T790M is immunogenic in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, have demonstrated marked clinical activity against non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. However, in most cases, patients develop acquired resistance to EGFR TKI therapy. The threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation is the most common acquired resistance mutation, and is present in ~50% cases of TKI resistance. New treatment strategies for NSCLC patients harboring the EGFR T790M mutation are required. We evaluated the immunogenicity of an antigen derived from EGFR with the T790M mutation. Using BIMAS we selected several EGFR T790M-derived peptides bound to human leukocyte antigen (HLA) A*02:01. T790M-A peptide (789-797) (IMQLMPFGC)-specific cytotoxic T lymphocytes (CTLs) were induced from peripheral blood mononuclear cells (PBMCs) of HLA-A2+ healthy donors. An established T790M-A-specific CTL line showed reactivity against the NCSLC cell line, H1975-A2 (HLA-A2+, T790M+), but not H1975 (HLA-A2-, T790M+), and the corresponding wild-type peptide (ITQLMPFGC)-pulsed T2 cells using an interferon-gamma (IFN-gamma) enzyme-linked immuno spot (ELISPOT) assay. This CTL line also demonstrated peptide-specific cytotoxicity against H1975-A2 cells. This finding suggests that the EGFR T790M mutation-derived antigen could be a new target for cancer immunotherapy. PMID- 25532029 TI - Elucidating the cyclization cascades in xiamycin biosynthesis by substrate synthesis and enzyme characterizations. AB - Indolosesquiterpene xiamycin A features a pentacyclic core structure. The chemical synthesis of two key precursors, 3-farnesylindole and 3-(epoxyfarnesyl) indole, allowed elucidation of the enzymatic cascades forming the pentacyclic ring system of xiamycin A by XiaO-catalyzed epoxidation and the membrane protein XiaH-catalyzed terpene cyclization. The substrate flexibility of XiaI, an indole oxygenase for assembly of the central ring, was also demonstrated. PMID- 25532028 TI - Subsets of memory CD4+ T cell and bactericidal antibody response to Neisseria meningitidis serogroup C after immunization of HIV-infected children and adolescents. AB - Meningococcal disease is endemic in Brazil, with periodic outbreaks and case fatality rates reach as high as 18 to 20% of cases. Conjugate vaccines against meningococci are immunogenic in healthy children. However, we have previously shown a poor bactericidal antibody response to a Men C conjugate vaccine in Brazilian HIV-infected children and adolescents after a single vaccine administration. The goal of the present work was to investigate associations between bactericidal antibody response induced by MenC vaccine and the frequency and activation profile (expression of CD38, HLA-DR and CCR5 molecules) of total CD4+ memory T cell sub-populations in HIV-1-infected children and adolescents. Responders to vaccination against MenC had a predominance (about 44%) of CD4+ TINTERMEDIATE subset followed by TTRANSITIONAL memory subset (23 to 26%). Importantly, CD4+ TINT frequency was positively associated with bactericidal antibody response induced by vaccination. The positive correlation persisted despite the observation that the frequency TINT CD38+HLA-DR+ was higher in responders. In contrast, CD4+ TCENTRAL MEMORY (TCM) subset negatively correlated with bactericidal antibodies. In conclusion, these data indicate that less differentiated CD+ T cells, like TCM may be constantly differentiating into intermediate and later differentiated CD4+ T cell subsets. These include CD4 TINT subset which showed a positive association with bactericidal antibodies. PMID- 25532030 TI - Hemolytic uremic syndrome associated with Escherichia coli O8:H19 and Shiga toxin 2f gene. PMID- 25532031 TI - Ambivalent spaces--the emergence of a new gay male norm situated between notions of the commercial and the political in the Swedish gay press, 1969-1986. AB - Within sexual geographies, sexual struggles over urban public spaces are frequently explored. Less common is research on sexual struggles within sexually shared spaces and gay spaces. The aim of the article is to examine discursive struggles of meanings of gay male identity enacted in discussions of commodification/capitalism, disclosure, and space in Swedish gay press during 1969-1986. We trace the ambivalent feelings or the emergence of a new gay male norm situated between commercialism and non-commercialism within the Swedish gay press back to the 1970s. In the article we show how a monosexualization process was taking place in both the Swedish gay press as well as within sexual spaces. We explore rhetorical struggles between two competing discursive meanings of (ideal homonormative) male homosexuality, gay culture, and space: one wider (inclusive) and one narrower (exclusive). PMID- 25532032 TI - Evidence of significant central fatigue in patients with cancer-related fatigue during repetitive elbow flexions till perceived exhaustion. AB - OBJECTIVE: To investigate whether fatigue induced by an intermittent motor task in patients with cancer-related fatigue (CRF) is more central or peripheral. METHODS: Ten patients with CRF who were off chemo and radiation therapies and 14 age-matched healthy controls were enrolled. Participants completed a Brief Fatigue Inventory (BFI) and performed a fatigue task consisting of intermittent elbow-flexion contractions at submaximal (40% maximal voluntary contraction) intensity till self-perceived exhaustion. Twitch force was elicited by an electrical stimulation applied to the biceps brachii muscle. The relative degree of peripheral (muscle) vs. central contribution to fatigue induced by the intermittent motor task (IMT) was assessed using twitch force ratio (TF ratio) defined as post IMT twitch force to pre IMT twitch force. The total number of trials (intermittent contractions) and total duration of all trials performed by each subject were also quantified. RESULTS: BFI scores were higher (p < 0.001) in CRF than controls, indicating greater feeling of fatigue in CRF patients than controls. A significantly smaller number of trials and shorter total duration of the trials (p < 0.05) were observed in CRF than control participants. The TF ratio (0.81 +/- 0.05) in CRF was higher (p < 0.05) compared with that of controls (0.62 +/- 0.05), suggesting CRF patients experienced a significantly lower degree of muscle (peripheral) fatigue at the time of perceived exhaustion. CONCLUSION: Consistent with prior findings for fatigue under submaximal sustained contraction, our results indicate that motor fatigue in CRF is more of central than peripheral origin during IMT. Significant central fatigue in CRF patients limits their ability to prolong motor performance. PMID- 25532033 TI - Characterization of the Inflammatory Properties of Actively Released HMGB1 in Juvenile Idiopathic Arthritis. AB - AIMS: Pathogenic effects of the endogenous inflammatory mediator high mobility group box protein 1 (HMGB1) have been described in several inflammatory diseases. Recent reports have underlined the importance of post-translational modifications (PTMs) in determination of HMGB1 function and release mechanisms. We investigated the occurrence of PTMs of HMGB1 obtained from synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients. RESULTS: Analyses of 17 JIA patients confirmed high HMGB1 levels in SF. Liquid chromatography tandem mass-spectrometry (LC-MS/MS) analyses of PTMs revealed that total HMGB1 levels were not associated with increased lactate dehydrogenase activity but strongly correlated with nuclear location sequence 2 (NLS2) hyperacetylation, indicating active release of HMGB1. The correlation between total HMGB1 levels and NLS2 hypoacetylation suggests additional, acetylation-independent release mechanisms. Monomethylation of lysine 43 (K43), a proposed neutrophil-specific PTM, was strongly associated with high HMGB1 levels, implying that neutrophils are a source of released HMGB1. Analysis of cysteine redox isoforms, fully reduced HMGB1, disulfide HMGB1, and oxidized HMGB1, revealed that HMGB1 acts as both a chemotactic and a cytokine inducing mediator. These properties were associated with actively released HMGB1. INNOVATION: This is the first report that characterizes HMGB1-specific PTMs during a chronic inflammatory condition. CONCLUSION: HMGB1 in SF from JIA patients is actively released through both acetylation-dependent and nondependent manners. The presence of various functional HMGB1 redox isoforms confirms the complexity of their pathogenic role during chronic inflammation. Defining HMGB1 release pathways and redox isoforms is critical for the understanding of the contribution of HMGB1 during inflammatory processes. PMID- 25532035 TI - The impact of roads on the demography of grizzly bears in Alberta. AB - One of the principal factors that have reduced grizzly bear populations has been the creation of human access into grizzly bear habitat by roads built for resource extraction. Past studies have documented mortality and distributional changes of bears relative to roads but none have attempted to estimate the direct demographic impact of roads in terms of both survival rates, reproductive rates, and the interaction of reproductive state of female bears with survival rate. We applied a combination of survival and reproductive models to estimate demographic parameters for threatened grizzly bear populations in Alberta. Instead of attempting to estimate mean trend we explored factors which caused biological and spatial variation in population trend. We found that sex and age class survival was related to road density with subadult bears being most vulnerable to road based mortality. A multi-state reproduction model found that females accompanied by cubs of the year and/or yearling cubs had lower survival rates compared to females with two year olds or no cubs. A demographic model found strong spatial gradients in population trend based upon road density. Threshold road densities needed to ensure population stability were estimated to further refine targets for population recovery of grizzly bears in Alberta. Models that considered lowered survival of females with dependant offspring resulted in lower road density thresholds to ensure stable bear populations. Our results demonstrate likely spatial variation in population trend and provide an example how demographic analysis can be used to refine and direct conservation measures for threatened species. PMID- 25532036 TI - Use of continuous glucose monitoring to identify glucose dysregulation in growth hormone insensitivity syndrome. AB - BACKGROUND/AIMS: Monogenic forms of growth hormone insensitivity (GHI) and its treatment with recombinant insulin-like growth factor-1 (rIGF-1) are both associated with glucose dysregulation. We used the information provided by continuous glucose monitoring systems (CGMS) for the clinical management of two children with monogenic GHI prior to the commencement of therapy as well as during the years when they received rIGF-1 treatment and continued to do so after the cessation of therapy. METHODS: We evaluated the extent of hyper- and hypoglycaemia with CGMS. RESULTS: In one patient, before treatment CGMS identified self-limiting nocturnal hypoglycaemia. Initiation of rIGF-1 treatment resulted in severe and persistent hypoglycaemia with an absence of spontaneous recovery. Corrective dietary measures were instituted. In a second patient, who had a poor growth response to rIGF-1 therapy, CGMS identified significant fluctuations in daytime glucose levels whilst on treatment with evidence of postprandial hyperglycaemia and both rebound and nocturnal hypoglycaemia. Given the lack of improved growth and the documented glucose dysregulation, treatment was stopped and repeat measurements with CGMS 1 month afterwards showed complete resolution. CONCLUSIONS: We have demonstrated that CGMS is an effective tool to assess glucose dysregulation in patients with GHI and alters clinical management. PMID- 25532034 TI - Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention. AB - The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 uM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 uM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 uM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 uM promoted endothelial tube formation (118% of the control), whereas at 10-20 uM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint. PMID- 25532037 TI - Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. AB - Xanthines like theophylline have long been recognised as being effective drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They are of interest as they possess both anti-inflammatory and bronchodilator activity in the same molecule. Since the discovery of phosphodiesterases (PDEs) in the late 1950s, it has been suggested that xanthines work, in part, by acting as non-selective PDE inhibitors. However, it has also been suggested that the ability of xanthines to non-selectively inhibit PDEs contributes to their many unwanted side effects, thus limiting their use since the arrival of inhaled drugs with more favourable safety profiles. As our understanding of PDEs has improved over the last 30 years, and with the recognition that the distribution of different PDEs varies across different cell types, this family of enzymes has been widely investigated as targets for novel drugs. In particular, PDE3 in airway smooth muscle and PDE4 and PDE7 in inflammatory cells have been targeted to provide new bronchodilators and anti-inflammatory agents, respectively. This review discusses the progress made in this field over the last decade in the development of selective PDE inhibitors to treat COPD and asthma. PMID- 25532038 TI - Circulating miR-192 and miR-193b are markers of prediabetes and are modulated by an exercise intervention. AB - CONTEXT: Diabetes is frequently diagnosed late, when the development of complications is almost inevitable, decreasing the quality of life of patients. However, early detection of affected individuals would allow the implementation of timely and effective therapies. OBJECTIVE: Here we set to describe the profile of circulating microRNAs (miRNAs) in prediabetic patients with the intention of identifying novel diagnostic and therapeutic tools. DESIGN: We used real-time RT PCR to measure the abundance of 176 miRNAs in serum of a cohort of 92 control and prediabetic individuals with either impaired fasting glucose or impaired glucose tolerance, as well as newly diagnosed diabetic patients. We validated the results in a second cohort of control and prediabetic subjects undergoing a therapeutic exercise intervention, as well as in a mouse model of glucose intolerance. RESULTS: We identified two miRNAs, miR-192 and miR-193b, whose abundance is significantly increased in the prediabetic state but not in diabetic patients. Strikingly, these miRNAs are also increased in plasma of glucose-intolerant mice. Moreover, circulating levels of miR-192 and miR-193b return to baseline in both prediabetic humans and glucose-intolerant mice undergoing a therapeutic intervention consisting in chronic exercise, which succeeded in normalizing metabolic parameters. CONCLUSIONS: Our data show that the pattern of circulating miRNAs is modified by defects in glucose metabolism in a similar manner in mice and humans. This circulating miRNA signature for prediabetes could be used as a new diagnostic tool, as well as to monitor response to intervention. PMID- 25532039 TI - Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. AB - CONTEXT: Klinefelter syndrome (KS) is the most common chromosome disorder in men (47,XXY), exhibiting a phenotype with marked variation and increased morbidity. The pathophysiological link between the supernumerary X chromosome and the clinical phenotype remains unknown. OBJECTIVE: To elucidate whether differential gene expression patterns can be detected in KS patients and whether these are related to inherent clinical features. DESIGN, SETTING, PARTICIPANTS: EXAKT (Epigenetics, X-chromosomal Features and Clinical Applications in Klinefelter Syndrome Trial) is a Munster-based prospective project involving 132 Klinefelter men and their parents. A range of cardiovascular, inflammatory, and metabolic factors, in comparison to age-matched male (n = 50)/female controls (n = 50) and in relation to genetic features, is assessed. MAIN OUTCOMES AND MEASURES: Our predefined hypothesis was that differential gene expression patterns in blood cells exist in KS patients vs male controls and are related to the clinical phenotype. RESULTS: Differential expression of 36 X-chromosomal and autosomal genes put KS patients into a unique genetic setting vs male and female controls. The KS cohort exhibited increased insulin resistance, enhanced inflammatory and procoagulatory status, higher waist circumference, dyslipidemia, and a markedly shorter 12-lead electrocardiogram QTc interval (partly located within the pathological range) vs male controls (all P < .001). Clinical dyshomeostasis was associated with expression patterns of dysregulated genes (all P < .01). Parental origin of the supernumerary X chromosome was a confounder regarding insulin resistance and cardiac phenotype (P < .05). Results are considered preliminary because gene expression was measured in blood cells. CONCLUSIONS: The supernumerary X chromosome contributes to a number of pathologies in KS. The pattern of gene expression is altered in KS, and the degree of differential gene expression is associated with the clinical phenotype. PMID- 25532040 TI - Residual beta-cell function and the insulin-like growth factor system in Danish children and adolescents with type 1 diabetes. AB - CONTEXT: C-peptide-positive adults with type 1 diabetes (T1D) have higher circulating total and free IGF-1 and lower IGF binding protein 1 (IGFBP-1) than C peptide-negative patients. Whether this is also the case in children remains unknown. OBJECTIVE: The objective of the study was to examine the IGF system in children/adolescents with and without residual beta-cell function (RBF). DESIGN AND PATIENTS: This was a cross-sectional study containing 136 prepubertal (hereof 15 RBF positive) and 206 pubertal (hereof 42 RBF positive) children/adolescents with T1D for 3-6 years as well as 40 prepubertal and 30 pubertal healthy controls. RBF was evaluated by meal-stimulated C-peptide. MAIN OUTCOME MEASURES: Fasting serum levels of bioactive IGF (ie, the ability of serum to activate the IGF-1 receptor in vitro), total IGF-1, total IGF-2, and IGFBP-1 and -3. RESULTS: Irrespective of pubertal status, patients with T1D showed lower bioactive IGF and total IGF-1, but higher IGFBP-1 as compared with controls (P < .05). When stratified according to RBF status, a positive RBF was associated with normalization of all IGF-related peptides but IGFBP-1 in prepubertal children (P < .05), whereas none of the IGF components were normalized in prepubertal, RBF negative children. In pubertal children, total IGF-1 and bioactive IGF remained subnormal and IGFBP-1 supranormal, irrespective of RBF status (P < .05). CONCLUSION: Independent of pubertal status, T1D was associated with an abnormal IGF system. However, a positive RBF status appeared important but only in prepubertal children, in whom all IGF components but IGFBP-1 were normalized. We speculate that the pubertal GH surge induces insulin resistance, which overrides the stimulatory effect that an RBF may exert on the liver-derived IGF system. PMID- 25532041 TI - Continuous glucose monitoring and its relationship to hemoglobin A1c and oral glucose tolerance testing in obese and prediabetic youth. AB - CONTEXT: The optimal screening test for diabetes and prediabetes in obese youth is controversial. OBJECTIVE: We examined whether glycosylated hemoglobin (HbA1c) or the oral glucose tolerance test (OGTT) is a better predictor of free-living glycemia as measured by continuous glucose monitoring (CGM). DESIGN: This was a cross-sectional study of youth 10-18 years old, body mass index (BMI) 85th percentile or greater, with diabetes risk factors. SETTING AND PARTICIPANTS: Participants (n = 118) with BMI 85th percentile or greater, not on medications for glucose management, were recruited from primary care and pediatric endocrinology clinics around Denver, Colorado. INTERVENTION: HbA1c, fasting plasma glucose, and 2-hour glucose were collected and all participants wore a blinded CGM for 72 hours. MAIN OUTCOME MEASURES: CGM outcomes were determined and descriptive statistics calculated. Performance characteristics at current American Diabetes Association cutpoints were compared with CGM outcomes. RESULTS: CGM data were successfully collected on 98 obese youth. Those with prediabetes had significantly higher average glucose, area under the curve (AUC), peak glucose, and time greater than 120 and greater than 140 mg/dL (P < .01) on CGM than youth with normal HbA1c or OGTT. HbA1c had a greater magnitude of correlation to CGM average glucose, AUC, and minimum glucose; 2-hour glucose had a greater magnitude of correlation to CGM SD, peak glucose, and time greater than 140 and greater than 200 mg/dL. However, there were no overall differences in the strength comparisons between 2-hour glucose and HbA1c correlations to CGM outcomes. CONCLUSIONS: In obese youth, HbA1c and 2-hour glucose performed equally well at predicting free-living glycemia on CGM, suggesting that both are valid tests for dysglycemia screening. PMID- 25532043 TI - Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients. AB - BACKGROUND: Pituitary adenomas are rare in children and adolescents. The response of macroprolactinomas to dopamine agonists (DA) in this age group has been less extensively studied than in adults. OBJECTIVE: We retrospectively analyzed data on a large cohort of young patients with macroprolactinomas. PATIENTS AND METHODS: Patients aged younger than 20 years at macroprolactinoma diagnosis and seen in three tertiary referral centers between 1983 and 2013 were studied by analyzing their clinical and genetic (AIP and MEN1) characteristics. Hormonal and tumoral responses to DA were analyzed, and the patients' status at their last visit, after a mean (+/-SD) follow-up of 8.2 +/- 5.8 years, was assessed. RESULTS: The cohort comprised 77 patients (26 males, 51 females). Mean age at diagnosis was 16.1 +/- 2.5 years (range, 4.5-20 y). In both sexes, the most frequent revealing symptom was a pubertal disorder (49%), followed by visual problems (24%) and growth retardation (24%). Basal prolactin (PRL) levels and maximal tumor diameter were significantly higher in boys than in girls (7168 ng/mL, 202-40 168 vs 1433 ng/mL, 115-20 000, P = .002; and 33 +/- 14 mm, 15-64 vs 19 +/- 9 mm; 10-50, P < .001, respectively). PRL levels normalized in 74% of the patients treated with DA. A mutation of AIP or MEN1 was found in 14% of the patients. Factors associated with resistance to DA were young age, higher PRL levels, larger volume, and the presence of a MEN1 (but not an AIP) mutation. CONCLUSION: Macroprolactinomas are rare below the age of 20 years, mainly occurring in girls and during adolescence. Like adults, young patients are very sensitive to DA, which should therefore be considered the first-line treatment. DA resistance is associated with a higher PRL level and larger tumor size, both parameters being closely linked together. About 14% of these young patients have an AIP or MEN1 mutation, this latter being an independent predictor of DA resistance. PMID- 25532042 TI - Expression pattern of 12-lipoxygenase in human islets with type 1 diabetes and type 2 diabetes. AB - CONTEXT: Inflammation in the pancreas can cause beta-cell stress, leading to diabetes development. Access to human pancreas tissues via the Network for Pancreatic Organ Donors with Diabetes (nPOD) has allowed characterization of pathways leading to this inflammation. OBJECTIVE: 12-Lipoxygenase (12-LO) induces inflammation and has been implicated in diabetes development. Our goal was to determine expression of 12-LO in human islets from control, autoantibody positive, type 1 diabetic, and type 2 diabetic nPOD pancreas donors. DESIGN: Pancreas tissues from nPOD donors were examined by immunohistochemistry and immunofluorescence for islet expression of 12-LO in different subsets of islet cells. PARTICIPANTS: Donor pancreas samples were obtained from nPOD based on disease status (control, n = 7; autoantibody-positive, n = 8; type 1 diabetic, n = 17; or type 2 diabetic donors, n = 15). MAIN OUTCOME MEASURE: Determination of 12-LO expression within human islets served as the main outcome measure, including distinguishing which types of islet cells expressed 12-LO. RESULTS: Islets from control participants (nondiabetic) lacked islet expression of 12-LO. Of donors in the other groups, 25% to 37% expressed islet 12-LO with a clear inverse relation between the numbers of beta-cells and 12-LO(+) cells within islets of 12-LO(+) cases. 12-LO expression was not seen within macrophages, endothelial cells, alpha-cells, or beta-cells, but only within cells expressing low levels of pancreatic polypeptide (PP) and increased levels of vimentin. CONCLUSIONS: 12-LO expression colocalizes within a specific type of islet PP(+) cell under prediabetic and diabetic conditions. The costaining of PP and vimentin suggests that 12-LO participates in the process leading to beta-cell dedifferentiation in the islet. PMID- 25532044 TI - The role of leptin and other hormones related to bone metabolism and appetite regulation as determinants of gain in body fat and fat-free mass in 8-11-year-old children. AB - BACKGROUND: Regulation of body composition during childhood is complex. Numerous hormones are potentially involved. Leptin has been proposed to restrain weight gain, but results are inconsistent. OBJECTIVE: We examined whether baseline fasting levels of ghrelin, adiponectin, leptin, insulin, IGF-I, osteocalcin, and intact parathyroid hormone (iPTH) were associated with body composition cross sectionally and longitudinally in 633 8-11-year-olds. DESIGN: Data on hormones and body composition by dual-energy x-ray absorptiometry from the OPUS School Meal Study were used. We looked at baseline hormones as predictors of baseline fat mass index (FMI) or fat-free mass index (FFMI), and also subsequent changes (3 and 6 months) in FMI or FFMI using models with hormones individually or combined. RESULTS: Cross-sectionally, baseline leptin was positively associated with FMI in girls (0.211 kg/m(2) pr. MUg/mL; 97.5% confidence interval [CI],0.186 0.236; P < .001) and boys (0.231 kg/m(2) pr. MUg/mL; 97.5% CI, 0.200-0.261; P < .001). IGF-I in both sexes and iPTH in boys were positively associated with FMI. An inverse association between adiponectin and FFMI in boys and a positive association between IGF-I and FFMI were found in girls. In longitudinal models, baseline leptin was inversely associated with subsequent changes in FMI (-0.018 kg/m(2) pr. MUg/mL; 97.5% CI, -0.034 - -0.002; P = .028) and FFMI (-0.014 kg/m(2) pr. MUg/mL; 97.5% CI, -0.024 - -0.003; P = .006) in girls. CONCLUSIONS: Cross sectional findings support that leptin is produced in proportion to body fat mass, but the longitudinal observations support that leptin inhibits gains in FMI and FFMI in girls, a finding that may reflect preserved leptin sensitivity in this predominantly normal weight population. PMID- 25532045 TI - The potential implications of a PCOS diagnosis on a woman's long-term health using data linkage. AB - CONTEXT: The polycystic ovary syndrome (PCOS) is the commonest endocrine abnormality in women of reproductive age. OBJECTIVE: To determine the rate of hospital admissions for women with PCOS in Western Australian population in comparison to women without PCOS. DESIGN: A population-based retrospective cohort study using data linkage in a statewide hospital morbidity database system. SETTING: All hospitals within Western Australia. PARTICIPANTS: A total of 2566 women with PCOS hospitalized from 1997-2011 and 25 660 randomly selected age matched women without a PCOS diagnosis derived from the electoral roll. MAIN OUTCOME MEASURES: Hospitalizations by ICD-10-M diagnoses from 15 years were compared. RESULTS: Hospitalizations were followed until a median age of 35.8 years (interquartile range, 31.0-39.9). PCOS was associated with more nonobstetric and non-injury-related hospital admissions (median, 5 vs 2; P < .001), a diagnosis of adult-onset diabetes (12.5 vs 3.8%), obesity (16.0 vs 3.7%), hypertensive disorder (3.8 vs 0.7%), ischemic heart disease (0.8 vs 0.2%), cerebrovascular disease (0.6 vs 0.2%), arterial and venous disease (0.5 vs 0.2% and 10.4 vs 5.6%, respectively), asthma (10.6 vs 4.5%), stress/anxiety (14.0 vs 5.9%), depression (9.8 vs 4.3%), licit/illicit drug-related admissions (8.8 vs 4.5%), self-harm (7.2 vs 2.9%), land transport accidents (5.2 vs 3.8%), and mortality (0.7 vs 0.4%) (all P < .001). Women with PCOS had a higher rate of admissions for menorrhagia (14.1 vs 3.6%), treatment of infertility (40.9 vs 4.6%), and miscarriage (11.1 vs 6.1%) and were more likely to require in vitro fertilization (17.2 vs 2.0%). CONCLUSION: PCOS has profound medical implications for the health of women, and health care resources should be directed accordingly. PMID- 25532046 TI - Self-assembly of channel type beta-CD dimers induced by dodecane. AB - Cyclodextrins (CDs) can hardly self-assemble into well-defined structures. Here we report if they preassemble into channel type dimers assisted by dodecane, well defined vesicles and bricks can be formed. Unlike the traditional self-assembly of amphiphilic molecules driven by hydrophobic effect, the self-assembly of the channel type dodecane@2beta-CD supramolecular building block is predoninantly driven by hydrogen-bonds. More water molecules are found in the lyophilized vesicles than in the bricks, suggesting water molecules play an important role in the self-assembly of the channel-type dimers of beta-CD. The amount of structural water in the self-assembly is closely related to the curvature of the final self assembled structures. Our work reveals that the channel-type dimer of beta-CD may represent a new sort of building block for advanced structures. PMID- 25532047 TI - NMR study of CHN hydrogen bond and proton transfer in 1,1-dinitroethane complex with 2,4,6-trimethylpyridine. AB - The intermolecular complex with a CHN hydrogen bond formed by 1,1-dinitroethane (DNE) and 2,4,6-trimethylpyridine (collidine) dissolved in CD2Cl2 was studied experimentally by (1)H NMR spectroscopy at 180-300 K. Equilibrium between the molecular CH...N form and the zwitterionic C(-)/HN(+) form was detected in the slow exchange regime in the NMR time scale. No sign of a direct C(-)...HN(+) bond was observed; the ion pair is likely to be held by Coulomb interactions. Moreover, there are indications that the protonated base is involved in the formation of homoconjugated (NHN)(+) collidine-collidinium hydrogen bonded complexes. The reaction pathway of proton transfer in the DNE-pyiridine complex in a vacuum was studied computationally at the B3LYP/6-31++G(d,p) level of theory. NMR chemical shifts and coupling constants were calculated for a series of snapshots along the proton transfer coordinate. While the central carbon atom has a pyramidal (sp(3)) configuration in DNE, it is flat (sp(2)) in the DNE carbanion. As a result, the most indicative computed NMR parameter reflecting hybridization of a carbon atom appeared to be (1)JCC, which starts to change rapidly as soon as a structure with a quasi-symmetric C..H..N bond is reached. Couplings within the hydrogen bridge, (1)JCH, (1h)JHN, and (2)JCN, can serve as good indicators of the degree of proton transfer. PMID- 25532048 TI - Ionothermal synthesis and crystal structures of novel aluminum phosphates with in situ generated templates. AB - Protic ionic liquids (PILs) are a subgroup of ionic liquids and easily formed by proton transfer from a Bronsted acid to a Bronsted base. Two new crystalline aluminophosphates, [C5H16N2][Al(PO4)(HPO4)] (AlPO-PIL1) and [C5H16N2][Al2(OH)2 (PO4)2] (AlPO-PIL2), are successfully prepared for the first time from a protic ionic liquid, 3-dimethylaminopropylamine acetate. Their structures were determined from single-crystal X-ray diffraction data. It was found that HF in the reaction mixture is crucial in determining the selectivity of the phase. In the absence of HF, AlPO-PIL1 with a one-dimensional chain structure was synthesized by templating the protonated 3-dimethylaminopropylamine cation of the PIL. Upon addition of HF to the initial reaction mixture, AlPO-PIL2 was obtained by templating the protonated N,N'-dimethyl-1,3-propanediamine, which was in situ generated from the protonated 3-dimethylaminopropylamine through migration of methyl groups during the crystallization. AlPO-PIL2 has a novel layered structure with a 3-connected 4.8.8 two-dimensional network which has never been found in the previously reported layered aluminophosphates. PMID- 25532049 TI - Targeted synthesis of a large triazine-based [4+6] organic molecular cage: structure, porosity and gas separation. AB - Herein, we report the targeted synthesis and solid state assembly of a novel triazine-based [4+6] organic molecular cage. The tetrahedral cage features a large cavity (~2070 A(3)), and after desolvation, the resultant material exhibits a high Brunauer-Emmett-Teller surface area of 1181 m(2) g(-1) and also features selective adsorption of CO2 over N2. PMID- 25532051 TI - A direct Fe-O coordination at the FePc/MoO(x) interface investigated by XPS and NEXAFS spectroscopies. AB - Molecule-substrate interaction plays a vital role in determining the electronic structures and charge transfer properties in organic-transition metal oxides (TMOs) hybridized devices. In this work, the interactions at the FePc/MoO3 interface has been investigated in detail by using synchrotron radiation photoemission spectroscopy (SRPES) and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. Compared with the annealing of the bare MoO3 film, the FePc adsorption is found to promote the thermal reduction of the underlying MoO3 film. XPS and NEXAFS experimental results unanimously demonstrate a strong electronic coupling between FePc molecules and the MoOx (x < 3) substrate. A direct Fe-O coordination at the interface as well as an electron transfer from the molecules toward the substrate is proposed. This strong coupling is compatible with a facile electron transfer from FePc molecules toward electrode through a MoOx interlayer. The understanding of the molecule-substrate interaction at the atomic level is of significance in engineering functionalized surfaces with potential applications in nanoscience, molecular electronics and photonics. PMID- 25532054 TI - Workplace slip, trip and fall injuries and obesity. AB - The objective of this study was to examine the relationship between slip, trip and fall injuries and obesity in a population of workers at the Idaho National Laboratory (INL) in Idaho Falls, Idaho. INL is an applied engineering facility dedicated to supporting the US Department of Energy's mission. An analysis was performed on injuries reported to the INL Medical Clinic to determine whether obesity was related to an increase in slip, trip and fall injuries. Records were analysed that spanned a 6-year period (2005-2010), and included 8581 employees (mean age, 47 +/- 11 years and body mass index [BMI], 29 +/- 5 kg/m(2); 34% obesity rate). Of the 189 people who reported slip, trip and fall injuries (mean age, 48 +/- 11 years), 51% were obese (P < 0.001 compared with uninjured employees), and their mean BMI was 31 +/- 6 kg/m(2) (P < 0.001). Obesity in this population was associated with a greater rate of slip, trip and fall injuries. PMID- 25532050 TI - Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013-14. AB - We report characteristics of oseltamivir-resistant influenza A(H1N1)pdm09 viruses and patients infected with these viruses in the United States. During 2013-14, fifty-nine (1.2%) of 4,968 analyzed US influenza A(H1N1)pdm09 viruses had the H275Y oseltamivir resistance-conferring neuraminidase substitution. Our results emphasize the need for local surveillance for neuraminidase inhibitor susceptibility among circulating influenza viruses. PMID- 25532055 TI - Design and synthesis of alpha-carboxy nucleoside phosphonate analogues and evaluation as HIV-1 reverse transcriptase-targeting agents. AB - The synthesis of the first series of a new class of nucleoside phosphonate analogues is described. Addition of a carboxyl group at the alpha position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, alpha-carboxy nucleoside phosphonates (alpha-CNPs). Key steps in the synthesis of the compounds are Rh-catalyzed O-H insertion and Pd-catalyzed allylation reactions. In cell-free assays, the final products are markedly inhibitory against HIV RT and do not require phosphorylation to exhibit anti-RT activity, which indicates that the alpha carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates. PMID- 25532056 TI - Latest approaches on green chemistry preconcentration methods for trace metal determination in seawater--a review. AB - Evaluation of trace metal levels in seawater samples is undertaken regularly by research groups all over the world, leading to a growing demand for techniques involving fewer toxic reagents, less time-consuming protocols and lower limits of detection. This review focuses on providing a brief but concise description of the latest methodologies developed to this end, outlining the advantages and disadvantages of the various protocols, chelating and dispersive agents and instruments used. Conclusions are drawn on the basis of the articles reviewed, highlighting improvements introduced in order to enhance the performance of the protocols. PMID- 25532057 TI - Evaluation of stormwater micropollutant source control and end-of-pipe control strategies using an uncertainty-calibrated integrated dynamic simulation model. AB - The estimation of micropollutant (MP) fluxes in stormwater systems is a fundamental prerequisite when preparing strategies to reduce stormwater MP discharges to natural waters. Dynamic integrated models can be important tools in this step, as they can be used to integrate the limited data provided by monitoring campaigns and to evaluate the performance of different strategies based on model simulation results. This study presents an example where six different control strategies, including both source-control and end-of-pipe treatment, were compared. The comparison focused on fluxes of heavy metals (copper, zinc) and organic compounds (fluoranthene). MP fluxes were estimated by using an integrated dynamic model, in combination with stormwater quality measurements. MP sources were identified by using GIS land usage data, runoff quality was simulated by using a conceptual accumulation/washoff model, and a stormwater retention pond was simulated by using a dynamic treatment model based on MP inherent properties. Uncertainty in the results was estimated with a pseudo Bayesian method. Despite the great uncertainty in the MP fluxes estimated by the runoff quality model, it was possible to compare the six scenarios in terms of discharged MP fluxes, compliance with water quality criteria, and sediment accumulation. Source-control strategies obtained better results in terms of reduction of MP emissions, but all the simulated strategies failed in fulfilling the criteria based on emission limit values. The results presented in this study shows how the efficiency of MP pollution control strategies can be quantified by combining advanced modeling tools (integrated stormwater quality model, uncertainty calibration). PMID- 25532058 TI - Functional and taxonomic plant diversity for riverbank protection works: bioengineering techniques close to natural banks and beyond hard engineering. AB - Erosion control is a major issue in the Prealps region since piedmont is subject to both intense flood hazards and anthropic pressure. Riverbank protections may have major impacts on local ecosystem functioning and ecological corridor continuity. This study aimed to estimate the effects of the types of riverbank protection technique (from pure riprap to pure bioengineering) on the taxonomic and ecological composition of plant communities in comparison with unmanaged riverbanks as the referential system. Thirty-eight embankments were sampled in the foothills of the French and Swiss Alps. Four distinct riverbank techniques were analyzed and natural young willow stands were chosen as the referential system. At each site, vegetation was sampled along three transects from the waterline to the top of the riverbank. Plant communities were characterized using biological group composition (growth forms and life history, life strategies and distribution in space and time) and functional diversity indices (MFAD, FDc and wFDc). We identified 177 distinct plant species on 38 sites. Higher species richness levels were observed on bioengineered banks (from an average of 12 species recorded on ripraps to 27 species recorded on bioengineered banks) strongly dominated by Salicaceae species, especially for fascine and cribwall banks. Functional analyses of plant communities highlighted significant differences among bank types (p-value: 0.001) for all selected biological groups. Competitive - ruderal strategy, rooting shoots, stems or leaves that lie down or break off, and unisexual - dioecious, as well as pioneer plants and low shrubs (<4 m tall) distinguished bioengineered bank types. Functional diversity indices confirmed these differences among bank types (MFAD: p-value: 0.002; FDc: p-value: 0.003; wFDc: p-value: 0.005). Riprap always showed the lowest levels on functional diversity indices, fascine and cribwall banks were at the medium level and finally mixed and natural banks the highest level. These results confirm the low ecological potential of purely hard engineering techniques and highlight the similarity of bioengineered techniques and unmanaged riverbanks. PMID- 25532059 TI - High-value, cost-conscious medical education. PMID- 25532060 TI - Prediction of the time course of callus stiffness as a function of mechanical parameters in experimental rat fracture healing studies--a numerical study. AB - Numerous experimental fracture healing studies are performed on rats, in which different experimental, mechanical parameters are applied, thereby prohibiting direct comparison between each other. Numerical fracture healing simulation models are able to predict courses of fracture healing and offer support for pre planning animal experiments and for post-hoc comparison between outcomes of different in vivo studies. The aims of this study are to adapt a pre-existing fracture healing simulation algorithm for sheep and humans to the rat, to corroborate it using the data of numerous different rat experiments, and to provide healing predictions for future rat experiments. First, material properties of different tissue types involved were adjusted by comparing experimentally measured callus stiffness to respective simulated values obtained in three finite element (FE) models. This yielded values for Young's moduli of cortical bone, woven bone, cartilage, and connective tissue of 15,750 MPa, 1,000 MPa, 5 MPa, and 1 MPa, respectively. Next, thresholds in the underlying mechanoregulatory tissue differentiation rules were calibrated by modifying model parameters so that predicted fracture callus stiffness matched experimental data from a study that used rigid and flexible fixators. This resulted in strain thresholds at higher magnitudes than in models for sheep and humans. The resulting numerical model was then used to simulate numerous fracture healing scenarios from literature, showing a considerable mismatch in only 6 of 21 cases. Based on this corroborated model, a fit curve function was derived which predicts the increase of callus stiffness dependent on bodyweight, fixation stiffness, and fracture gap size. By mathematically predicting the time course of the healing process prior to the animal studies, the data presented in this work provides support for planning new fracture healing experiments in rats. Furthermore, it allows one to transfer and compare new in vivo findings to previously performed studies with differing mechanical parameters. PMID- 25532061 TI - DataSHIELD: an ethically robust solution to multiple-site individual-level data analysis. AB - BACKGROUND: DataSHIELD (Data Aggregation Through Anonymous Summary-statistics from Harmonised Individual levEL Databases) has been proposed to facilitate the co-analysis of individual-level data from multiple studies without physically sharing the data. In a previous paper, we investigated whether DataSHIELD could protect participant confidentiality in accordance with UK law. In this follow-up paper, we investigate whether DataSHIELD addresses a broader range of ethics related data-sharing concerns. METHODS: Ethics-related data-sharing concerns of Institutional Review Boards, ethics experts, international research consortia and research participants were identified through a literature search and systematically examined at a multidisciplinary workshop to determine whether DataSHIELD proposes mechanisms which can address these concerns. RESULTS: DataSHIELD addresses several ethics-related data-sharing concerns related to privacy, confidentiality, and the protection of the research participant's rights while sharing data and after the data have been shared. The data remain entirely under the direct management of the study that collected them. Data processing commands are strictly supervised, and the data are queried in a protected environment. Issues related to the return of individual research results when data are shared are eliminated; the responsibility for return remains at the study of origin. CONCLUSION: DataSHIELD can provide an innovative and robust solution for addressing commonly encountered ethics-related data-sharing concerns. PMID- 25532062 TI - Genome sequence of enterovirus D68 from St. Louis, Missouri, USA. PMID- 25532064 TI - Combined collapse by bridging and self-adhesion in a prototypical polymer model inspired by the bacterial nucleoid. AB - Recent experimental results suggest that the E. coli chromosome feels a self attracting interaction of osmotic origin, and is condensed in foci by bridging interactions. Motivated by these findings, we explore a generic modeling framework combining solely these two ingredients, in order to characterize their joint effects. Specifically, we study a simple polymer physics computational model with weak ubiquitous short-ranged self attraction and stronger sparse bridging interactions. Combining theoretical arguments and simulations, we study the general phenomenology of polymer collapse induced by these dual contributions, in the case of regularly spaced bridging. Our results distinguish a regime of classical Flory-like coil-globule collapse dictated by the interplay of excluded volume and attractive energy and a switch-like collapse where bridging interactions compete with entropy loss terms from the looped arms of a star-like rosette. Additionally, we show that bridging can induce stable compartmentalized domains. In these configurations, different "cores" of bridging proteins are kept separated by star-like polymer loops in an entropically favorable multi-domain configuration, with a mechanism that parallels micellar polysoaps. Such compartmentalized domains are stable, and do not need any intra specific interactions driving their segregation. Domains can be stable also in the presence of uniform attraction, as long as the uniform collapse is above its theta point. PMID- 25532063 TI - Explanatory style differences in health literacy: a survey among young adults in Taiwan. AB - Explanatory styles are related to individuals' positive health management. Everyone interprets and thinks about issues differently; therefore, medical information is understood in different ways. This study explored the relationship of optimistic and positive views on health literacy. A survey method was used to collect information from 342 university students. This study used PLS2.0 and SPSS 18.0 for data analysis. The results indicated that optimists had more accurate self-reported health status and medication-taking and nutritional knowledge than pessimists did. Females had higher scores on health knowledge and medication taking and nutritional knowledge than males. In addition, female optimists had better performance on self-reported health status and health and medication taking knowledge than female pessimists did. The major contribution of this study is the confirmation of the effect of explanatory style on health literacy. PMID- 25532065 TI - Complementary medicine as a path toward empowerment of Arab-Palestinian women in Israel. AB - Arab-Palestinians in Israel compose a traditional minority population that previously relied on traditional folk medicine and religious healing. Today some among this minority population are adopting imported complementary medicine. We interviewed Arab-Palestinians of the first generation of complementary medicine practitioners. Their decision to study complementary medicine constitutes a path toward empowerment, providing healers with an aura of modernity, enabling integration into the predominantly Jewish Israeli medical establishment to gain professional recognition as experts, and to acquire a sense of belonging. Practicing complementary medicine provides financial independence, liberation, and self-fulfillment and an opportunity to help female patients break through constraining barriers. PMID- 25532066 TI - Phase diagram of (Li(1-x)Fe(x))OHFeSe: a bridge between iron selenide and arsenide superconductors. AB - Previous experimental results have shown important differences between iron selenide and arsenide superconductors which seem to suggest that the high temperature superconductivity in these two subgroups of iron-based families may arise from different electronic ground states. Here we report the complete phase diagram of a newly synthesized superconducting (SC) system, (Li1-xFex)OHFeSe, with a structure similar to that of FeAs-based superconductors. In the non-SC samples, an antiferromagnetic (AFM) spin-density-wave (SDW) transition occurs at ~127 K. This is the first example to demonstrate such an SDW phase in an FeSe based superconductor system. Transmission electron microscopy shows that a well known ?5*?5 iron vacancy ordered state, resulting in an AFM order at ~500 K in AyFe2-xSe2 (A = metal ions) superconductor systems, is absent in both non-SC and SC samples, but a unique superstructure with a modulation wave vector q = (1)/2(1,1,0), identical to that seen in the SC phase of KyFe2-xSe2, is dominant in the optimal SC sample (with an SC transition temperature Tc = 40 K). Hence, we conclude that the high-Tc superconductivity in (Li1-xFex)OHFeSe stems from the similarly weak AFM fluctuations as FeAs-based superconductors, suggesting a universal physical picture for both iron selenide and arsenide superconductors. PMID- 25532067 TI - Effects of paricalcitol and aliskiren combination therapy on experimental diabetic nephropathy model in rats. AB - BACKGROUND/AIMS: The aim of the present study was to investigate the effect of combination of aliskiren with paricalcitol on experimental diabetic nephropathy (DN) model in rats. METHODS: Forty male Sprague Dawley rats were divided into 5 groups of 8 rats each, namely the control (Group C), diabetes (Group D), aliskiren (Group A), paricalcitol (Group P), and aliskiren plus paricalcitol (Group A+P) groups. Aliskiren was given by oral-gavage at a dose of 50 mg/kg/day once daily for 12 weeks. Paricalcitol was given by intraperitoneally at a dose of 0,4 ug/kg/three day of week for 12 weeks. Renal function parameters, oxidative stress biomarkers, mRNA expression of renin-angiotensin system parameters and kidney histology were determined. RESULTS: Group A+P had lower mean albumin-to creatinine ratio (ACR) (p=0.004) as well as higher creatinine clearance (CCr) (p<0.005) than the diabetic rats (Group D). Combination therapy significantly increased CCr (Group A+P vs. Group A, p<0.005; Group A+P vs. Group P, p=0.022) and reduced ACR (Group A+P vs. Group A, p=0.018; Group A+P vs. Group P, p<0.005) when compared to monotherapy. Serum malondialdehyde levels were significantly lower (p=0.004); glutathion levels (p=0.003), glutathion peroxidase (p=0.004) and superoxide dismutase (p<0.005) activities were significantly higher in group A+P than in group D. The mean scores of mRNA expression of renin (p<0.005), angiotensin II (p=0.012) and angiotensin type 1 receptor (p=0.018) in group A+P were significantly lower. Although combination therapy showed no additional effect on oxidative system, renin-angiotensin system and renal histology, aliskiren plus paricalcitol significantly decreased interstitial fibrosis volume when compared to monotherapy (Group A+P vs. Group A, p<0.005; Group A+P vs. Group P, p=0.002). CONCLUSION: Our data seem to suggest a potential role of aliskiren plus paricalcitol acting synergystically for reducing the progression of diabetic nephropathy in an experimental rat model. PMID- 25532068 TI - Pyridoxamine dihydrochloride in diabetic nephropathy (PIONEER-CSG-17): lessons learned from a pilot study. AB - BACKGROUND/AIMS: Pyridoxamine dihydrochloride (PyridorinTM) blocks pathogenic oxidative pathways in the progression of diabetic nephropathy. The pyridoxamine pilot study was designed to test entry criteria and outcomes. Subjects had SCr 1.3-3.5 mg/dl, protein-to-creatinine >=1,200 mg/g and used a surrogate outcome of DeltaSCr over 52 weeks. Subjects had to be on a maximally tolerated dose of ACE/ARB for 3 months; stable other antihypertensive doses for 2 months; stable diuretic dose for 2 weeks, and BP <=160/90 mm Hg; or enter a Pharmaco Stabilization Phase (PSP). This pilot failed to detect an effect on DeltaSCr in intent-to-treat analysis. METHODS: We queried the locked clinical trial database for subgroups in which there was a treatment effect. RESULTS: Subjects not requiring PSP and those with entry SCr <2.0 mg/dl had a treatment effect. Subjects entering PSP required more changes in antihypertensive medications and experienced larger DeltaSCr over 52 weeks. PSP subjects with BP >140/90 mm Hg had no treatment effect, but those <=140/90 mm Hg did. CONCLUSION: Time required for acute effects of ACE/ARB to stabilize is unknown, but these data suggest >3 months. Thus, subjects in the pivotal trial must be on ACE/ARB for 6 months. Frequent antihypertensive adjustment could engender SCr changes unrelated to CKD progression. Thus, we will require subjects to have BP <=150/90 mm Hg and on stable antihypertensives for 26 weeks, or <=140/90 mm Hg and on stable antihypertensives for 13 weeks. Since DeltaSCr over 52 weeks is limited as a surrogate outcome, the pivotal trial uses a time-to-event analysis of baseline SCr to at least a 50% increase in SCr or ESRD as the primary outcome. This substantial DeltaSCr is protected from noise and is clinically relevant. The pyridoxamine pilot provided critical information to inform the design of PIONEER CSG-17, which we conducted under the SPA agreement with FDA. PMID- 25532069 TI - Velocity Selective Neural Signal Recording Using a Space-Time Electrode Array. AB - Extracting the activity of a particular neural fiber from the extracellular recording of a peripheral nerve is quite important from different clinical perspectives. While traditional neural recording methods are unable to provide such granularity, new signal recording and processing techniques have offered promising solutions recently. A multi-electrode cuff in conjunction with a delay and sum beamforming structure has been used to detect the activity of different fibers in a nerve based on the propagation velocity of action potentials. However, as it is shown in this paper, simple delay and sum beamforming method encounters severe selectivity problem and signal distortion especially at higher velocities. In addition to scrutinizing the performance of the delay and sum beamformer and its inherent problems, here we propose a new beamforming method, based on broadband sensor array signal processing techniques, which exhibits much better selectivity with uniform frequency-velocity response. Our simulation results show how the new method can faithfully extract individual neural fiber activities and explore potential applications which could emerge from using such technique. PMID- 25532070 TI - Eliminating degradation in solid oxide electrochemical cells by reversible operation. AB - One promising energy storage technology is the solid oxide electrochemical cell (SOC), which can both store electricity as chemical fuels (electrolysis mode) and convert fuels to electricity (fuel-cell mode). The widespread use of SOCs has been hindered by insufficient long-term stability, in particular at high current densities. Here we demonstrate that severe electrolysis-induced degradation, which was previously believed to be irreversible, can be completely eliminated by reversibly cycling between electrolysis and fuel-cell modes, similar to a rechargeable battery. Performing steam electrolysis continuously at high current density (1 A cm(-2)), initially at 1.33 V (97% energy efficiency), led to severe microstructure deterioration near the oxygen-electrode/electrolyte interface and a corresponding large increase in ohmic resistance. After 4,000 h of reversible cycling, however, no microstructural damage was observed and the ohmic resistance even slightly improved. The results demonstrate the viability of applying SOCs for renewable electricity storage at previously unattainable reaction rates, and have implications for our fundamental understanding of degradation mechanisms that are usually assumed to be irreversible. PMID- 25532071 TI - Impact of mesoscale order on open-circuit voltage in organic solar cells. AB - Structural order in organic solar cells is paramount: it reduces energetic disorder, boosts charge and exciton mobilities, and assists exciton splitting. Owing to spatial localization of electronic states, microscopic descriptions of photovoltaic processes tend to overlook the influence of structural features at the mesoscale. Long-range electrostatic interactions nevertheless probe this ordering, making local properties depend on the mesoscopic order. Using a technique developed to address spatially aperiodic excitations in thin films and in bulk, we show how inclusion of mesoscale order resolves the controversy between experimental and theoretical results for the energy-level profile and alignment in a variety of photovoltaic systems, with direct experimental validation. Optimal use of long-range ordering also rationalizes the acceptor donor-acceptor paradigm for molecular design of donor dyes. We predict open circuit voltages of planar heterojunction solar cells in excellent agreement with experimental data, based only on crystal structures and interfacial orientation. PMID- 25532072 TI - Layered oxygen-deficient double perovskite as an efficient and stable anode for direct hydrocarbon solid oxide fuel cells. AB - Different layered perovskite-related oxides are known to exhibit important electronic, magnetic and electrochemical properties. Owing to their excellent mixed-ionic and electronic conductivity and fast oxygen kinetics, cation layered double perovskite oxides such as PrBaCo2O5 in particular have exhibited excellent properties as solid oxide fuel cell oxygen electrodes. Here, we show for the first time that related layered materials can be used as high-performance fuel electrodes. Good redox stability with tolerance to coking and sulphur contamination from hydrocarbon fuels is demonstrated for the layered perovskite anode PrBaMn2O5+delta (PBMO). The PBMO anode is fabricated by in situ annealing of Pr0.5Ba0.5MnO3-delta in fuel conditions and actual fuel cell operation is demonstrated. At 800 degrees C, layered PBMO shows high electrical conductivity of 8.16 S cm(-1) in 5% H2 and demonstrates peak power densities of 1.7 and 1.3 W cm(-2) at 850 degrees C using humidified hydrogen and propane fuels, respectively. PMID- 25532073 TI - Highly confined low-loss plasmons in graphene-boron nitride heterostructures. AB - Graphene plasmons were predicted to possess simultaneous ultrastrong field confinement and very low damping, enabling new classes of devices for deep subwavelength metamaterials, single-photon nonlinearities, extraordinarily strong light-matter interactions and nano-optoelectronic switches. Although all of these great prospects require low damping, thus far strong plasmon damping has been observed, with both impurity scattering and many-body effects in graphene proposed as possible explanations. With the advent of van der Waals heterostructures, new methods have been developed to integrate graphene with other atomically flat materials. In this Article we exploit near-field microscopy to image propagating plasmons in high-quality graphene encapsulated between two films of hexagonal boron nitride (h-BN). We determine the dispersion and plasmon damping in real space. We find unprecedentedly low plasmon damping combined with strong field confinement and confirm the high uniformity of this plasmonic medium. The main damping channels are attributed to intrinsic thermal phonons in the graphene and dielectric losses in the h-BN. The observation and in-depth understanding of low plasmon damping is the key to the development of graphene nanophotonic and nano-optoelectronic devices. PMID- 25532074 TI - The role of graphene for electrochemical energy storage. AB - Since its first isolation in 2004, graphene has become one of the hottest topics in the field of materials science, and its highly appealing properties have led to a plethora of scientific papers. Among the many affected areas of materials science, this 'graphene fever' has influenced particularly the world of electrochemical energy-storage devices. Despite widespread enthusiasm, it is not yet clear whether graphene could really lead to progress in the field. Here we discuss the most recent applications of graphene - both as an active material and as an inactive component - from lithium-ion batteries and electrochemical capacitors to emerging technologies such as metal-air and magnesium-ion batteries. By critically analysing state-of-the-art technologies, we aim to address the benefits and issues of graphene-based materials, as well as outline the most promising results and applications so far. PMID- 25532075 TI - Prevalence of muscular dystrophies: a systematic literature review. AB - BACKGROUND: Determining the prevalence of neuromuscular disorders for the general population is important to identify the scope of burden on society and enable comparisons with other health conditions. This systematic review aims to identify and collate the findings of studies published between 1960 and 2013 on the prevalence of all types of muscular dystrophies. SUMMARY: Relevant articles were identified through electronic database searches and manual searches of reference lists. There were 38 articles from across 19 countries that met the inclusion criteria. The total combined prevalence for all muscular dystrophies for studies classified as having a low risk of bias ranged between 19.8 and 25.1 per 100,000 person-years. Myotonic dystrophy (0.5-18.1 per 100,000), Duchenne muscular dystrophy (1.7-4.2) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000) were found to be the most common types of disorder. There was wide variation in study methodology, case ascertainment, and verification procedures and populations studied, all of which may contribute to the wide prevalence range, in addition to the likely variation in prevalence by country. Key Messages: Greater consistency in the conduct and reporting of neuroepidemiological studies is urgently needed to enable comparisons to be made between studies, countries, and over time. PMID- 25532076 TI - Cariprazine in the treatment of acute mania in bipolar I disorder: a double blind, placebo-controlled, phase III trial. AB - BACKGROUND: This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. METHODS: Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3-12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. RESULTS: Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3-12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (>=50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score<=12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (>=10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. LIMITATIONS: Lack of active comparator arm; short duration of study. CONCLUSION: In this study, cariprazine 3-12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder. PMID- 25532077 TI - Gender differences in the treatment of patients with bipolar disorder: a study of 7354 patients. AB - BACKGROUND: Gender differences in treatment that are not supported by empirical evidence have been reported in several areas of medicine. Here, the aim was to evaluate potential gender differences in the treatment for bipolar disorder. METHODS: Data was collected from the Swedish National Quality Assurance Register for bipolar disorder (BipolaR). Baseline registrations from the period 2004-2011 of 7354 patients were analyzed. Multiple logistic regression analysis was used to study the impact of gender on interventions. RESULTS: Women were more often treated with antidepressants, lamotrigine, electroconvulsive therapy, benzodiazepines, and psychotherapy. Men were more often treated with lithium. There were no gender differences in treatment with mood stabilizers as a group, neuroleptics, or valproate. Subgroup analyses revealed that ECT was more common in women only in the bipolar I subgroup. Contrariwise, lamotrigine was more common in women only in the bipolar II subgroup. LIMITATIONS: As BipolaR contains data on outpatient treatment of persons with bipolar disorder in Sweden, it is unclear if these findings translate to inpatient care and to outpatient treatment in other countries. CONCLUSIONS: Men and women with bipolar disorder receive different treatments in routine clinical settings in Sweden. Gender differences in level of functioning, bipolar subtype, or severity of bipolar disorder could not explain the higher prevalence of pharmacological treatment, electroconvulsive therapy, and psychotherapy in women. Our results suggest that clinicians' treatment decisions are to some extent unduly influenced by patients' gender. PMID- 25532078 TI - Physical activity and energy expenditure during depressive episodes of major depression. AB - BACKGROUND: Recent data suggest a substantial association between physical activity and depressive symptoms, but there is a lack of research evaluating the physical activity levels in patients suffering from unipolar depression across different stages of disease in an objective way. The aim of the present pilot study was to objectively examine physical activity levels of this patient group compared to healthy controls. METHODS: Physical activity performance of 19 patients with major depressive episode and 19 healthy controls was assessed at three different time points using a multisensory armband device (SenseWear(r) Pro3 Armband) and was reported as total energy expenditure (TEE), active energy expenditure (EE), metabolic equivalents (METs), physical activity (PA) and time of lying down (LD), in each case over 24h. RESULTS: Over all measurements, depressive patients presented a significantly lower mean TEE and EE over 24h. Moreover, the patient group showed significantly shorter duration of PA and lower average MET over 24h. When depressive symptoms abated, physical activity parameters significantly increased in the patient group. Correlation analyses demonstrated a significant relation between depressive status/anhedonia and parameters of physical activity, especially in healthy subjects. LIMITATIONS: Results represented valid data for inpatients only. CONCLUSION: Acute unipolar depression was associated with a significantly lower level of physical activity and showed a significant increase in parallel to clinical improvement. Electronic monitoring of physical activity may be an additional tool for evaluating and controlling therapeutic effects. PMID- 25532079 TI - Impairment and reorganization of the phosphoinositide-specific phospholipase C enzymes in suicide brains. AB - A number of studies suggested that suicide may be associated with specific neurobiological abnormalities. Neurobiology studies focused upon abnormalities of signalling mechanisms with special regard to the serotonin system and the related Phosphoinositide (PI) signalling system. Previous data suggested the involvement of the PI-specific phospholipase C (PLC) family in neuropsychiatric disorders. By using PCR and morphological microscopy observation we examined the whole panel of expression of PLC isoforms in the brains of 28 individuals who committed suicide and in normal controls in order to evaluate the involvement of specific PLC isoforms. The overall PLC expression was reduced and a complex reorganization of the isoforms was observed. The knowledge of the complex network of neurobiological molecules and interconnected signal transduction pathways in the brain of suicide victims might be helpful to understand the natural history and the pathogenesis of the suicidal behavior. That might lead to obtain prognostic suggestions in order to prevent suicide and to new therapeutic agents targeting specific sites in this signalling cascade. PMID- 25532080 TI - Endoscopic mucosal resection for middle and large colorectal polyps with a double loop snare. AB - BACKGROUND/AIMS: This study aimed to analyze the endoscopic mucosal resection (EMR) with a novel uniquely shaped, double-loop snare (Dualoop, Medico's Hirata Inc., Tokyo, Japan) for colorectal polyps. METHODS: This was a clinical trial conducted in two referral centers, Kyoto Prefectural University of Medicine and National Cancer Center Hospital in Japan. First, the firmness of various snares including 'Dualoop' was experimentally analyzed with a pressure gauge. Five hundred and eighty nine consecutive polyps that underwent EMR with 'Dualoop' were compared to 339 polyps with the standard round snare. Lesion characteristics, en bloc resection, and complications were analyzed. RESULTS: 'Dualoop' had the most firmness among the various snares. The average tumor size was 9.3 mm (5-30), and en bloc resection was achieved in 95.4%. The rate of en bloc resection for middle polyps 15-19 mm in diameter was significantly higher with the 'Dualoop' than that with the round snare (97.9 vs. 80.0%, p < 0.05). The rate of en bloc resection was 64.7% for large polyps >=20 mm in diameter using 'Dualoop'. Higher age, larger tumor size, and superficial polyps were associated with the failure of en bloc resection. CONCLUSION: EMR with 'Dualoop' was effective for resecting both middle and large polyps en-bloc. PMID- 25532081 TI - Prophylactic manual rotation for fetal malposition to reduce operative delivery. AB - BACKGROUND: Manual rotation is commonly performed to increase the chances of normal vaginal delivery and is perceived to be safe. Manual rotation has the potential to prevent operative delivery and caesarean section, and reduce obstetric and neonatal complications. OBJECTIVES: To assess the effect of prophylactic manual rotation for women with malposition in labour on mode of delivery, and maternal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014), the Australian and New Zealand Clinical Trials Registry (ANZCTR), ClinicalTrials.gov, Current Controlled Trials and the WHO International Clinical Trials Registry Platform (ICTRP) (all searched 23 February 2014), previous reviews and, references of retrieved studies. SELECTION CRITERIA: Randomised, quasi-randomised or cluster-randomised clinical trials comparing prophylactic manual rotation in labour for fetal malposition versus expectant management, augmentation of labour or operative delivery. We defined prophylactic manual rotation as rotation performed without immediate assisted delivery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and quality, and extracted data. MAIN RESULTS: We included only one small pilot study (involving 30 women). The study, which we considered to be at low risk of bias, was conducted in a tertiary referral hospital in Australia, and involved women with cephalic, singleton pregnancies. The primary outcome was operative delivery (instrumental delivery or caesarean section).In the manual rotation group, 13/15 women went on to have an instrumental delivery or caesarean section, whereas in the control group, 12/15 women had an operative delivery. The estimated risk ratio was 1.08 (95% confidence interval 0.79 to 1.49). There were no maternal or fetal mortalities in either groupThere were no clear differences for any of the secondary maternal or neonatal outcomes reported (e.g. perineal trauma, analgesia use duration of labour).In terms of adverse events, there were no reported cases of umbilical cord prolapse or cervical laceration and a single case of a non reassuring or pathological cardiotocograph during the procedure. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to determine the efficacy of prophylactic manual rotation early in the second stage of labour for prevention of operative delivery. One additional study is ongoing. Further appropriately designed trials are required to determine the efficacy of manual rotation. PMID- 25532082 TI - Hemodynamic behavior during hemodialysis: effects of dialysate concentrations of bicarbonate and potassium. AB - BACKGROUND/AIMS: Ultrafiltration that occurs during hemodialysis (HD) promotes profound alterations in a relatively short period of time. The dialysate content of bicarbonate (DBic) and potassium (DK) may have impact over intradialytic hemodynamics, which goes beyond ultrafiltration, and its impact was evaluated in a prospective cohort. METHODS: 30 patients under HD were submitted to hemodynamic assessment (HA) at the beginning and at the end of HD sessions, through a non invasive method. Serum minus dialysate potassium concentration was expressed as K Gap. Cardiac index (CI) and peripheral arterial resistance (PAR) variation (post HD minus pre-HD) were expressed as DeltaCI and DeltaPAR. Dialysate content of sodium and calcium were expressed as DNa and DCa, respectively. RESULTS: Mean DNa, DK and DBic were, respectively, 136.4 +/- 1.1, 2.1 +/- 0.6 and 38.2 +/- 2.1 mEq/L. In 15 patients, DCa was >1.5 mmol/L and in the other 15 patients <= 1.5 mmol/L. The K-Gap ranged from 1.4 to 5.1 mEq/l (median 3.0 mEq/L). There was a reduction in post-HD CI and systolic blood pressure (DeltaCI = -0.72l/min/m(2) and -11.3+/-15.1mmHg, respectively, p<0.001 for both). Conversely, PAR increased (DeltaPAR = 272dyn.s/cm(5), p<0.001). Lower post-HD CI was was associated to higher DBic (p=0.0013) and lower K-Gap (p=0.026). In multivariate analysis, DeltaCI was dependent on DBic and K-Gap, whereas DeltaPAR was dependent on dialysate calcium during HD. CONCLUSION: We confirmed that Na and Ca dialysate content exerts and important role on hemodynamic during HD. In addition, our findings pointed out that higher dialysate concentrations of bicarbonate and potassium promote lower cardiac performance at the end of hemodialysis session. PMID- 25532083 TI - Symptomatic epileptogenic lesions. AB - BACKGROUND AND OBJECTIVES: The main aim of this study is to prove the association of seizure types with the MRI findings of the brain (etiological factor). Also, to prove which type of lesion is mostly represented in which age-group, and with which type of seizure. METHODS: A total of 100 patients with symptomatic epilepsy, aged from 16 to 80 years, were hospitalized at the Neurology Clinic or in its Outpatient Unit, in the period from 2009 to 2012. They were neurologically examined and the seizure type registered. All patients underwent MRI of the brain. RESULTS: (56%) men and 44 (44%) women were examined. The represented type of epileptic seizures were 41.0% with SPC + CPC, followed by 15.0% GTCC, and 14.0% CPC with secondary generalization, 12,0% CPC, 10,0% SPC and 8.0% with absences. The epileptic lesions of 25.0% were hippocampal sclerosis, 20.0% post traumatic injuries, 19.0%, post-vascular and brain tumours, and the lowest percentage of 17.0% with post-infectious lesions. CONCLUSIONS: Post-traumatic lesions occur more frequently in the elderly population with the accent on the male, while hippocampal sclerosis occurs in the adolescent and younger population with higher frequency in the female. PMID- 25532084 TI - Depression in ophthalmological patients. AB - INTRODUCTION: Vision is the most important sensorial part of the human information system. Visual loss leads to reduced ability to perform routine activities of daily living and can be a risk for stable mental health. AIM: The aim of this cross-sectional study is to assess the incidence of depression in patients treated in an ophthalmological outpatient clinic. To our knowledge this is the first study of its kind in our country. SUBJECTS AND METHOD: The number of evaluated patients was a hundred; mean age 41.6 +/- 15.9 years, with different educational levels and common ophthalmological disorders. For the assessment of the level of depression the Beck Depression Inventory was used. Patients were divided into two groups: serious ophthalmological diagnoses where we expected psychological problems (N = 65) and the simplest ones (N = 35) as a control. RESULTS: Obtained results show that the levels of depression correlate with the diagnoses. Patients in the first group (serious ophthalmological diagnoses) showed moderate depression in 12% and severe in 13% of patients. It was shown that the most depressed were the patients suffering from age-related macular degeneration and proliferative diabetic retinopathy, as well as glaucoma and cataract. The second group showed BDI scores of normal values. The level of depression is positively correlated with age and the level of education (p < 0.05). CONCLUSION: Depression is an important mental problem in ophthalmological practice. It is usually unrecognized and untreated. Depression could be the risk factor for treatment and prognosis of eyes diseases. Some measures for mitigation of psychological problems are proposed. PMID- 25532085 TI - Emotional intelligence and big-five personality factors in female student sample. AB - The aim of this study is to figure out possible connectedness between emotional intelligence and five big personality factors in female students selected from social sciences faculties. The evaluated sample comprised 66 healthy students, of Macedonian nationality, mean age 18.9 +/- 0.63 years. As psychometric instruments, we used the EI-test and NEO-PI-R, both with eligible metric characteristic and already used in the Republic of Macedonia. Statistical analysis was performed using Sta17, both descriptive and inferential statistics including medians, standard deviations, and two-tailed Pearson's correlation. The obtained results for emotional intelligence showed an average anxiety level (M = 77.35), extraversion (M = 50.91) and a realistic outlook on life (M = 81.64), high self-confidence (M = 44.44) and generally satisfactory empathy (M = 85.39). Personality characteristics obtained with NEO-PI-R showed high extroversion (M = 123. 70), low agreeableness (M = 105.82) and consciousness (M = 104.67), as well as mild neuroticism (M = 91.33) and openness (M = 117.45). The results confirmed a high positive correlation between anxiety, optimism, and empathy; and between self-confidence and empathy within the EI test. Within NEO-PR-R there was a positive correlation between factors Extroversion and Openness to Experience and a negative correlation between the factors Extroversion and Agreeableness. However, just one negative correlation is noted, between Extroversion from EI and Openness to experience from NEO-PR-R (-0,25; p < 0.05). We concluded that similar facets measured with different psychometric instruments have different basic concepts. The obtained results, although they figure out some support from other research, also differ from other studies. It is important for us to follow the obtained results and to provoke further research on a bigger and more diverse sample. PMID- 25532086 TI - The prevalence of high anxiety and substance use in university students in the Republic of Macedonia. AB - AIM: The aim of the study was to determine the prevalence of high anxiety and substance use among university students in the Republic of Macedonia. MATERIAL AND METHODS: The sample comprised 742 students, aged 18-22 years, who attended the first (188 students) and second year studies at the Medical Faculty (257), Faculty of Dentistry (242), and Faculty of Law (55) within Ss. Cyril and Methodius University in Skopje. As a psychometric test the Beck Anxiety Inventory (BAI) was used. It is a self-rating questionnaire used for measuring the severity of anxiety. A psychiatric interview was performed with students with BAI scores > 25. A self-administered questionnaire consisted of questions on the habits of substance (alcohol, nicotine, sedative-hypnotics, and illicit drugs) use and abuse was also used. For statistical evaluation Statistica 7 software was used. RESULTS: The highest mean BAI scores were obtained by first year medical students (16.8 +/- 9.8). Fifteen percent of all students and 20% of first year medical students showed high levels of anxiety. Law students showed the highest prevalence of substance use and abuse. CONCLUSION: High anxiety and substance use as maladaptive behaviours among university students are not systematically investigated in our country. The study showed that students show these types of unhealthy reactions, regardless of the curriculum of education. More attention should be paid to students in the early stages of their education. A student counselling service which offers mental health assistance needs to be established within University facilities in R. Macedonia alongside the existing services in our health system. PMID- 25532087 TI - Continuous versus patient-controlled epidural analgesia for labour analgesia and their effects on maternal motor function and ambulation. AB - BACKGROUND AND OBJECTIVES: The advantages of patient-controlled epidural analgesia (PCEA) for delivery compared with continuous epidural analgesia (CEA) have been a point of interest in research obstetric anaesthesia for more than two decades. The aim of this single blind randomized controlled study was to evaluate the incidence of motor block and ability to perform partial knee flexion in women who received CEA or PCEA. METHOD: Fifty-one healthy nulliparous women were included in this study. After an initial dose and established sensory block at Th 10, parturients were randomized into two groups: group CEA (10 ml/h), and group PCEA (bolus - 5 ml, lockout interval - 15 minutes, basal rate - 0 ml) with bupivacaine 0.08% and fentanyl 2 ug/ml. The motor function of the lower limbs was evaluated by modified Bromage scale at regular hourly intervals until full cervical dilatation. The quality of analgesia was assessed using a visual analogue pain scale (VAPS) and maternal satisfaction. Mode of delivery, the total number of additional rescue boluses, foetal and neonatal outcomes were recorded. RESULTS: Motor block was significantly lower in the third (33.3% vs. 4.35%; p = 0.008), fourth (57.9% vs. 6.3%; p = 0.003) and fifth hour (75.0% vs. 18.2%; p = 0.001) in the PCEA group. Ambulation occurred in 18% in the CEA and 46% in the PCEA group (p = 0.036). VAPS was with borderline significance in the second (p = 0.076) and significantly lower in the fourth hour (p = 0.034). CONCLUSION: Compared with CEA, PCEA provided less motor block and better first-stage analgesia, which leads to the conclusion that patient-controlled analgesia techniques are the preferred model in obstetric anesthesia. PMID- 25532088 TI - Continuous femoral nerve block versus fascia iliaca compartment block as postoperative analgesia in patients with hip fracture. AB - INTRODUCTION: Systemic postoperative analgesia is inefficient in most patients with hip fracture, which is the reason for pain, especially during leg movement. Peripheral and plexus nerve blocks are an efficient option for postoperative pain relief. The aim of this study was to compare the effect and duration of continuous FNB versus a single FIC block as a postoperative analgesia in patients with hip fracture. METHODS: Sixty patients with hip fracture were included and were randomly assigned to two groups of 30 patients: FNB group - patients with continuous femoral nerve block; and FIC group -patients with a single fascia iliaca compartment block. In all patients, pain intensity was measured at rest and in passive leg movement by using VDS (0-4) at several intervals: 1, 2, 12, 24, 36 and 48 hours after intervention. The amount of supplemental analgesia was measured, together with the time when the patient needed it for the first time, as well as the side effects. RESULTS: The values of VDS were significantly lower in patients with FNB block versus patients with FIC block in rest and movement at the 24-hour intervals (46.67% vs 0% felt moderate pain), after 36 hours (43.33% vs 0% felt moderate pain) and 48 hours after intervention (46.67% vs 3.33% felt moderate to severe pain) for p < 0.05. Patients with FNB block received a significantly lower amount of supplemental analgesia, 23.3% of the FNB group vs 50% of the FIC group (p < 0.05). Registered side effects were were nausea, dizziness and sedation, and they were statistically significantly more frequent in the FIC group (p < 0.05). CONCLUSION: Pain relief in the postoperative period was superior in the FNB group versus the FIC group at rest and in movement in patients with hip fracture. PMID- 25532089 TI - Influence of hysteroscopic metroplasty on reproductive outcome in patients with infertility and recurrent pregnancy loss. AB - INTRODUCTION: Patients with congenital uterine anomalies (CUA) have decreased reproductive potential and an unfavourable reproductive outcome compared to the population with normal uterine cavity. Patients with untreated CUA have a higher abortion rate, higher foetal loss rate and decreased live birth rate. Hysteroscopic metroplasty is a standard, safe and minimally invasive method for the treatment of correctible types of congenital uterine anomalies. The aim of the study was to analyse the reproductive outcome in certain groups of patients with CUA and infertility, before and after hysteroscopic metroplasty. MATERIAL AND METHODS: We analyzed 115 patients on whom 129 hysteroscopic metroplasty interventions were performed at the University Clinic of Obstetrics and Gynaecology in Skopje over a oneyear period, between 01.01.2011 and 31.12.2011. Patients and their reproductive outcome were monitored over a two-year period and the same group served as a control group, taking into account their previous reproductive history before and after metroplasty. Statistical analysis was performed using the Chi-square test and p < 0.05 was considered to be statistically significant. RESULTS: The most common CUA were types 5b and 6, represented by 83.3%. In a follow-up period of two years, there were 55 patients with previous foetal loss treated by hysteroscopic metroplasty, and 31 of them had pregnancies. There was a statistically significant decrease of abortion rate from 88.5% to 19.3%, and a significant increase in term delivery rate from 2.3% to 71%. CONCLUSION: Hysteroscopic metroplasty significantly improves the reproductive outcome in patients with previous foetal loss. PMID- 25532090 TI - Minimally invasive surgery for stress urinary incontinence - mesh complications. AB - Currently, the most commonly performed surgeries for stress urinary incontinence (SUI) are mesh midurethral slings (MUS). They are minimally invasive outpatient procedures, and they are as effective as traditional suburethral slings, open retropubic colposuspension (Burch, Marshall-Marchetti), and laparoscopic retropubic colposuspension. They have a short operative time and fewer postoperative complications. In the paper we present results from a prospective study of 214 patients with SUI who underwent midurethral sling placement: 68 patients with retropubic slings (TVT) and 146 patients with transobturator slings (TVT-O) followed over 12 months. The operations were performed at the Department of Obstetrics and Gynaecology at the Medical Faculty, Skopje, R. Macedonia and at the Department of Obstetrics and Gynaecology, General Hospital, Sibenik, Croatia. All MUS placements (TVT and TVT-O) were performed by one surgeon (urogynaecologist) using the standard surgical technique and operative and postoperative protocol for those procedures. TVT and TVT-O meshes are polypropylene macroporous meshes produced by "Ethicon" We evaluated mesh complications related to the procedure (Table 1) and complications specific to the mesh (Table 2). In the article are presented the data from up-to-date literature related to the evaluated topic parallel to our results. We can conclude that all our findings on the evaluated groups are comparable with the data from competent literature. Instead of a conclusion we would like to suggest continuous follow-up of all minimally invasive procedures with midurethral slings placement for collecting experience of side-effects and complications and improving those procedures which are gold standard today in the treatment of SUI. PMID- 25532091 TI - Analysis of the results of implantation of total hip endoprothesis in severe dysplastic coxarthrosis. AB - BACKGROUND: The aim of this study is to affirm the importance of operative treatment of severe dysplastic coxarthrosis through analysis of the results of implantation of total cementless endoprothesis in patients with DDH Crowe types III and IV. PATIENTS AND METHODS: This retrospective study involved 28 patients (30 hips) with dysplastic coxarthrosis, in whom an implantation of cementless total hip endoprothesis was performed at the University Clinic for Orthopaedic Surgery in Skopje. In 26 of the patients the involvement was unilateral and in two patients it was bilateral. The inclusion criterion was radiographically proved severe hip dysplasia Crowe types III and IV. Twenty-one of the patients were female and 7 male, and age distribution was in an interval from 30 to 65 years. The ingrowth of the implant was evaluated using the clinical method, native radiographs and radioisotopic examination with Tc99m. The follow-up period lasted 5 years, and the results were evaluated using the Harris hip score system. RESULTS: 19 of the patients presented an excellent result of the operative treatment, there were 8 good results with persistent local pain 6 months postoperatively, in one case a surgical revision and reimplantation of the acetabular cup was performed, while one patient underwent a surgical revision and reimplantation of the femoral stem and in another patient there was nonunion at the place of the subtrochanteric osteotomy. Full weight-bearing without the use of crutches was achieved 3 months postoperatively, and no serious early postoperative complications were registered in our patients. DISCUSSION AND CONCLUSIONS: In the majority of cases in whom a total hip replacement with cementless endoprothesis is performed because of dysplastic coxarthrosis, a sufficient primary fixation both of the acetabular and the femoral component is achieved, unless one-third of the acetabular cup is left uncovered with bone stock. The problems of decreased muscle strength and limping are usually solved by means of physical therapy in a time period of 45 months. PMID- 25532092 TI - Partial caecal necrosis - a rare cause of right-sided inferior abdominal pain and tenderness. AB - INTRODUCTION: Non-occlusive caecal infarction is a rare condition that has been described in association with a variety of clinical entities, generally due to a low-flow state, and has been reported to occur in association with chronic heart disease, open-heart surgery, certain drugs, and haemodialysis. The aim of this article is to describe the presentation, diagnosis and management of this unusual clinical problem. CASE PRESENTATION: We report on an 84-year-old female with known chronic heart disease presenting with right lower abdominal quadrant pain, tenderness and leukocytosis. Although initial clinical findings were highly suggestive of acute appendicitis, CT revealed marked circumferential wall thickening of the caecum. Intraoperatively, caecal necrosis was confirmed, while the appendix and the remainder of the intestine appeared normal. There was no evidence of major vascular occlusion or embolization. The right hemicolectomy was performed with ileo-transverse anastomosis. Histopathologic analysis demonstrated isolated transmural caecal necrosis with marked infiltration of the caecal wall by numerous bacteria and neutrophils as a consequence of nonocclusive ischaemic colitis. The patient recovered completely and was discharged from the hospital on the tenth postoperative day without any surgical complications. CONCLUSION: Partial caecal necrosis should be included in the differential diagnosis of acute right lower quadrant pain, especially in elderly patients with chronic heart disease. PMID- 25532093 TI - Congenital hydronephrosis: disease or condition? AB - The aim of this paper is to address the dilemmas of the paediatric surgeon when facing an isolated, unilateral, congenital hydronephrosis and discuss the strategic options for the management of this condition. Congenital hydronephrosis, the most commonly diagnosed uropathy in children, is usually a benign and self-resolving condition. Nonobstructive hydronephrosis does not require operative treatment, while timely treatment is imperative for obstructive hydronephrosis before significant renal damage ensues. Managing congenital hydronephrosis is a challenging task. Thirty-two children with unilateral, isolated hydronephrosis and nonobstructed renography curves were followed up for 3 years. On the initial evaluation according to the grade of hydronephrosis: 22.6% were grade I, 54.8% grade II and 22.6% grade III. After 12 months of follow up: 30% were grade I, 51 .5% grade II and 18.5% grade III, respectively. After the three-year follow-up, there were no hydroneproses greater than grade II. The mean value of the separate GFR of the affected kidney at initial evaluation was 42.83%, and 40.33% after three years. In three children the treatment was converted from conservative to surgical. Nonobstructive, congenital hydronephrosis is a benign condition not requiring any medical treatment, but aggressive observation is indicated. PMID- 25532094 TI - Effect of lipid parameters on foetal growth in gestational diabetes mellitus pregnancies. AB - INTRODUCTION: Women with gestational diabetes mellitus (GDM) often deliver newborns large for their gestational age (LGA). The aim of the study was to evaluate the effect of lipid parameters in the second half of pregnancy on foetal growth in GDM pregnancies. MATERIAL AND METHODS: In two hundred consecutive women with GDM the age, body mass index before pregnancy, body mass index before delivery, gestational week of GDM diagnosis, lipid parameters after 24 weeks of pregnancy, fasting glycaemia, HbA1c in the second and third trimester of pregnancy, gestational age at delivery, mode of delivery, and baby birth weight were analyzed. RESULTS: Of the 200 GDM pregnancies, 50 (25%) women delivered LGA newborns, 135 (67.5%) women delivered newborns appropriate for gestational age (AGA), and 15 (7.5%) women delivered newborns small for gestational age (SGA). Maternal triglyceride levels and HbA1c in the second trimester were higher, and HDL-C was significantly lower, in the LGA group than in the AGA group (3.8 +/- 1.8 vs. 3.1 +/- 1.1 mmol/L, 6.1 +/- 1.1 vs. 5.5 +/- 0.8%, and 1.3 +/- 0.4 vs. 1.6 +/- 0.4 mmol/L, p < 0.05). Also, maternal triglyceride levels and HbA1c in the second trimester were significantly higher in the SGA group than in the AGA group (3.8 +/- 1.9 vs. 3.1 +/- 1.1 mmol/L and 6.8 +/- 0.8 vs. 5.5 +/- 0.8%, p < 0.05). Maternal triglycerides were independent predictors for delivering LGA newborns in GDM women. CONCLUSION: In GDM pregnancies, maternal triglycerides in the second half of pregnancy may indentify women who will deliver LGA newborns. Thus, with good regulation of lipid profile, we can avoid macrosomia from GDM pregnancies. PMID- 25532095 TI - Echocardiographic predictors of chronotropic incompetence to exercise in patients with heart failure with preserved ejection fraction. AB - OBJECTIVE: Exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) is most often attributed to diastolic dysfunction (DD); however, chronotropic incompetence (CI) could also play an important role. We intended to examine whether there are predictive echocardiographic parameters of DD for impaired chronotropic response to exercise. METHODS AND RESULTS: Patients (n = 143) with unexplained dyspnea and/or exercise intolerance who fulfilled clinical and echocardiographic criteria of HFpEF presence underwent a symptom limited exercise test using a treadmill (ETT) according to the Bruce protocol. CI was defined as an achieved heart rate reserve (HRR) of <= 80%. Comparison of the groups with (n = 98) and without CI (n = 45) did not show any statistically significant difference regarding demographic and clinical characterristics except for use of beta blockers (BB) that were more frequently present (p = 0.012) in patients with CI in comparison with those without. Patients with CI had a higher mean E-wave velocity, E/A ratio, increased E/E' septal, lateral as well as average ratio and abnormal IVRT/TE-e' index all consistent with elevated LV filling pressures. E/E' average ratio > 15 was statistically insignificantly more frequently present in patients with CI. In addition, by multivariate stepwise regression analysis value of E' septal (beta = 3.697, 95%CI 0.921-6.473, p = 0.009) along with use of BB, current smoking and basal heart rate appeared as statistically significant independent predictors of lower HRR %. CONCLUSION: Patients with HFpEF frequently have chronotropic incompetence to graded exercise which may partly be predicted with echocardiographic parameters that are consistent with elevated LV filling pressures. PMID- 25532096 TI - Anthropometric parameters in national footballers in the Republic of Macedonia. AB - OBJECTIVES: The focus of this study is on anthropometric characteristics of footballers in the Republic of Macedonia, and the aim is to provide normative data for selected anthropometric parameters for adult male footballers in our country. MATERIAL AND METHOD: The study included eight hundred (800) adult male footballers, aged 24.06 +/- 4.8y (age range 18-35y), who have undertaken routine sport medical examinations over a ten-year period. The football players were divided into six age - specific subgroups ("up to 20"; "up to 22"; "up to 24"; "up to 26"; "up to 28" and "over 28" years). Anthropometric measurements were made by Matiegka's protocols and body composition components were determined. RESULTS: Average values of body height (178.8 +/- 6.7 cm), body weight (77.72 +/- 7.9 kg), lean body mass (66.21 +/- 6.36 kg), body components ( MM% = 53.04; BM% = 17.15; FM% = 14.7%) and a large series of anthropometric measurements which define the footballers' anthropometric dimensions were obtained. The distribution of the adipose tissue regarding the body and limbs showed that the skinfolds were thickest on the lower limbs and thinnest on the arms. CONCLUSIONS: The adult football players in Republic of Macedonia were insignificantly variable in height and body mass from their counter parts from European and American teams. The football players up to 20 year, who played in the senior national football league were lighter and smaller than their older colleagues. The football players aged from 20 to 35 years were insignificantly variable in height, body mass, and anthropometric dimensions of limbs and trunk. PMID- 25532097 TI - T-scan III system diagnostic tool for digital occlusal analysis in orthodontics - a modern approach. AB - INTRODUCTION: This systematic literature review was performed to establish the mechanism, methodology, characteristics, clinical application and opportunities of the T-Scan III System as a diagnostic tool for digital occlusal analysis in different fields of dentistry, precisely in orthodontics. METHODS: Searching of electronic databases, using MEDLINE and PubMed, hand searching of relevant key journals, and screening of reference lists of included studies with no language restriction was performed. Publications providing statistically examined data were included for systematic review. RESULTS: Twenty potentially relevant Randomized Controlled Trials (RCTs) were identified. Only ten met the inclusion criteria. The literature demonstrates that using digital occlusal analysis with T Scan III System in orthodontics has significant advantage with regard to the capability of measuring occlusal parameters in static positions and during dynamic of the mandible. CONCLUSION: Within the scope of this systematic review, there is evidence to support that T-Scan system is rapid and accurate in identifying the distribution of the tooth contacts and it shows great promise as a clinical diagnostic screening device for occlusion and for improving the occlusion after various dental treatments. Additional clinical studies are required to advance the indication filed of this system. Importance of using digital occlusal T-Scan analysis in orthodontics deserves further investigation. PMID- 25532098 TI - White spot lesions: prevention and management during the orthodontic treatment. AB - The formation of white spot lesions, or enamel demineralization, around fixed orthodontic attachments is a common complication during and following fixed orthodontic treatment, which marks the result of a successfully completed case. This article is a contemporary review of the risk factors and preventive methods of these orthodontics scars. Preventive programmes must be emphasized to all orthodontic patients. The responsibility of an orthodontist is to minimize the risk of the patient having decalcification as a consequence of orthodontic treatment by educating and motivating the patients for excellent oral hygiene practice. Prophylaxis with topical fluoride application should be implemented: high-fluoride toothpastes, fluoride mouthwashes, gels and varnishes during and after the orthodontic treatment, especially for patients at high risk of caries. PMID- 25532099 TI - The influence of etiological factors in the occurence of diastema mediana. AB - Even from the distant past the aesthetic perception in an individual was diminished by the presence of gap between the central incisors. This condition is found under the term "dents du bonheur" or "lucky teeth" and is encountered even among world famous figures including Brigitte Bardot, Eliah Wood, Madonna, Zac Efron, Amy Winehouse and Elton John. The teeth gaps are still considered main reasons for dissatisfaction of the dental patients and reasons for the requirement of aesthetic treatment. The purpose of this study is to exhibit the influence of the etiological factors in the occurrence of diastema mediana classified according to the dominance of their occurrence expressed in percentage values. Materials of this investigation were 100 patients with diastema mediana from the following factors: inheritance, disproportion in the dental arches, inborn or acquired missing teeth, harmful oral habits, high insertion of the labial frenulum as well as mesiodens. After the diagnosis and evaluation of the etiological factor for diastema mediana was performed, a decision regarding the course of treatment was made in direction of the removal of the etiological factor at an early age and orthodontic treatment. The end of the orthodontic treatment in a group of the patients was the beginning of prosthodontic reconstruction. From our clinical investigation we came to the realization that in 49 patients (49%) the hereditary influence was a dominant factor, next followed disproportions and discrepancies in the dental arch in 14 (14%), inborn or acquired missing teeth in 11 patients (11%), harmful oral habits in 10 (10%), high frenulum insertion in 4 (4%), and pathological objects between central incisors, mesiodens, iatrogenic factors and periodontal disease, in 3 of the clinical cases (3%) each. We concluded that the occurrence of diastema mediana is multi-causal. The dominant place is occupied by the hereditary factors. With regard to the mutual relationship between the multitudes of factors in the occurrence of diastema mediana, the diagnosis should be made conciliary and the clinical treatment should be interdisciplinary including a prosthodontist, orthodontist and oral surgeon. PMID- 25532100 TI - Nickel catalyzed dealkoxylative C(sp2)-C(sp3) cross coupling reactions- stereospecific synthesis of allylsilanes from enol ethers. AB - The application of cyclic and acyclic enol ethers as electrophiles in cross coupling reactions offers new possibilities for the preparation of functional compounds. A novel nickel catalyzed dealkoxylative cross coupling reaction allows access to structurally diverse allylsilanes and alcohol derivatives with high stereospecificity and in good yields under mild reaction conditions directly from the corresponding enol ethers. PMID- 25532101 TI - Neighbourhood social fragmentation and the mental health of children in poverty. AB - Using data from 7,776 Millennium Cohort Study children in England, we examined the role of neighbourhood social fragmentation in trajectories of emotional/behavioural problems at ages three, five and seven, and in moderating the association of children's emotional/behavioural problems with neighbourhood poverty, family poverty and adverse family events. Allowing for key background characteristics, social fragmentation generally added little to explain child outcomes, but there were fewer conduct problems among children in poor neighbourhoods with less fragmentation. Surprisingly, in less fragmented neighbourhoods poor families tended to feel less safe and more distressed, which was associated with children's conduct problems. PMID- 25532102 TI - The 2014 Ebola outbreak and mental health: current status and recommended response. PMID- 25532103 TI - Establishing a standard for assessing the appropriateness of trauma team activation: a retrospective evaluation of two outcome measures. AB - BACKGROUND: Trauma team activation (TTA) is a well-recognised standard of care to provide rapid stabilisation of patients with time-critical, life-threatening injuries. TTA is associated with a substantial use of valuable hospital resources that may adversely impact upon the care of other patients if not carefully balanced. This study aimed to determine which of the two outcome measures would be a better standard for assessing the appropriateness of TTA at a paediatric centre: retrospective major trauma classification as defined within our state, and the use of emergency department high-level resources as recently published by Falcone et al (Falcone Interventions; FI). METHODS: Trauma registry data and patients' charts between February 2011 and June 2013 were reviewed. Over-triage and under-triage rates for TTA, using both major trauma and FIs as outcome measures, were compared. RESULTS: Totally, 280 patients received TTA, 243 met major trauma definition and 102 received one or more FIs. The rates of over triage and under-triage were 39.7% (95% CI 35.0 to 44.6%) and 30.5% (95% CI 26.2 to 35.2%), when the major trauma definition was used as the outcome measure, and 67.5% (95% CI 62.2 to 72.5%) and 10.8% (95% CI 7.9 to 14.8%) when FI was used. Only 17.1% (95% CI 11.4% to 24.7%) of the under-triaged patients using the major trauma definition received one or more FIs. CONCLUSIONS: Assessment of TTA appropriateness varied significantly based on the outcome measure used. FIs better reflected the use of acute-care TTA-related resources compared with the major trauma definition, and it should be used as the gold standard to prospectively assess and refine TTA criteria. PMID- 25532104 TI - Age before acuity: the drivers of demand for emergency department services in the Greater Sydney Area. AB - OBJECTIVE: To contrast long-term population-based trends in general practice (GP) presentations and acute inpatient admissions from the emergency department (ED) in the elderly population within the Greater Sydney Area. METHODS: This was a retrospective analysis of population-based ED presentation data over 11 years, between January 2001 and December 2011, conducted within the Greater Sydney Area in Australia. De-identified data were obtained from the New South Wales Emergency Department Data Collection database on all patients presenting to 30 public hospital EDs located within the Greater Sydney Area. The outcomes of interest were GP presentations to ED (triage category 4 or 5, self-referred and discharged from ED) and of acute inpatient admissions from ED per 1000 population. RESULTS: Over 11 million presentations were identified. Around 40% of presentations were classified as a GP presentation and 23% were classified as acute inpatient admissions. There was a 2.9% per annum increase in acute inpatient admissions per 1000 population in those >=80 years of age and no appreciable change in other age groups. Rates of GP presentations were higher in those <65 years of age. GP presentations increased 1.9% per annum in those aged <65 years of age. CONCLUSIONS: The increase in ED demand appears to be driven by the elderly presenting with acute problems requiring inpatient admission. There has been a modest increase in the rate of GP presentations to ED. PMID- 25532105 TI - Carbon disulfide mediates socially-acquired nicotine self-administration. AB - The social environment plays a critical role in smoking initiation as well as relapse. We previously reported that rats acquired nicotine self-administration with an olfactogustatory cue only when another rat consuming the same cue was present during self-administration. Because carbon disulfide (CS2) mediates social learning of food preference in rodents, we hypothesized that socially acquired nicotine self-administration is also mediated by CS2. We tested this hypothesis by placing female adolescent Sprague-Dawley rats in operant chambers equipped with two lickometers. Licking on the active spout meeting a fixed-ratio 10 schedule triggered the concurrent delivery of an i.v. infusion (saline, or 30 ug/kg nicotine, free base) and an appetitive olfactogustatory cue containing CS2 (0-500 ppm). Rats that self-administered nicotine with the olfactogustatory cue alone licked less on the active spout than on the inactive spout. Adding CS2 to the olfactogustatory cue reversed the preference for the spouts. The group that received 500 ppm CS2 and the olfactogustatory cue obtained a significantly greater number of nicotine infusions than other groups. After extinction training, the original self-administration context reinstated nicotine-seeking behavior in all nicotine groups. In addition, in rats that received the olfactogustatory cue and 500 ppm CS2 during SA, a social environment where the nicotine-associated olfactory cue is present, induced much stronger drug-seeking behavior compared to a social environment lacking the olfactogustatory cue. These data established that CS2 is a critical signal that mediates social learning of nicotine self-administration with olfactogustatory cues in rodents. Additionally, these data showed that the social context can further enhance the drug-seeking behavior induced by the drug-taking environment. PMID- 25532106 TI - MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2Delta16 mediated breast tumorigenesis and reverse trastuzumab resistance. AB - The oncogenic isoform of HER2, HER2Delta16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Delta16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Delta16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Delta16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2Delta16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2Delta16 cells, we found that expression of HER2Delta16 significantly altered expression of 16 microRNAs by 2-fold or more including a 4.8 fold suppression of the miR-7 tumor suppressor. Reestablished expression of miR-7 in the MCF-7/HER2Delta16 cell line caused a G1 cell cycle arrest and reduced both colony formation and cell migration activity to levels of parental MCF-7 cells. Suppression of miR-7 in the MCF-7 cell line resulted in enhanced colony formation activity but not cell migration, indicating that miR-7 suppression is sufficient to drive tumor cell proliferation but not migration. MiR-7 inhibited MCF-7/HER2Delta16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2Delta16 cell proliferation involved a pathway where miR-7 expression resulted in the inactivation of Src kinase independent of suppressed EGFR expression. Also independent of EGFR suppression, reestablished miR-7 expression sensitized refractory MCF-7/HER2Delta16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2Delta16 induced cell proliferation and migration while sensitizing HER2Delta16 expressing cells to trastuzumab therapy. We propose that miR-7 regulated pathways, including EGFR and Src kinase, represent targets for the therapeutic intervention of refractory and metastatic HER2Delta16 driven breast cancer. PMID- 25532109 TI - Novel diagnostic approach to pancreatic cysts: is confocal laser endomicroscopy bridging the gap? PMID- 25532110 TI - Nonsteroidal anti-inflammatory drugs for preventing post-ERCP pancreatitis: why rectal and not intramuscular? PMID- 25532107 TI - Transcriptional analyses of natural leaf senescence in maize. AB - Leaf senescence is an important biological process that contributes to grain yield in crops. To study the molecular mechanisms underlying natural leaf senescence, we harvested three different developmental ear leaves of maize, mature leaves (ML), early senescent leaves (ESL), and later senescent leaves (LSL), and analyzed transcriptional changes using RNA-sequencing. Three sets of data, ESL vs. ML, LSL vs. ML, and LSL vs. ESL, were compared, respectively. In total, 4,552 genes were identified as differentially expressed. Functional classification placed these genes into 18 categories including protein metabolism, transporters, and signal transduction. At the early stage of leaf senescence, genes involved in aromatic amino acids (AAAs) biosynthetic process and transport, cellular polysaccharide biosynthetic process, and the cell wall macromolecule catabolic process, were up-regulated. Whereas, genes involved in amino acid metabolism, transport, apoptosis, and response to stimulus were up regulated at the late stage of leaf senescence. Further analyses reveals that the transport-related genes at the early stage of leaf senescence potentially take part in enzyme and amino acid transport and the genes upregulated at the late stage are involved in sugar transport, indicating nutrient recycling mainly takes place at the late stage of leaf senescence. Comparison between the data of natural leaf senescence in this study and previously reported data for Arabidopsis implies that the mechanisms of leaf senescence in maize are basically similar to those in Arabidopsis. A comparison of natural and induced leaf senescence in maize was performed. Athough many basic biological processes involved in senescence occur in both types of leaf senescence, 78.07% of differentially expressed genes in natural leaf senescence were not identifiable in induced leaf senescence, suggesting that differences in gene regulatory network may exist between these two leaf senescence programs. Thus, this study provides important information for understanding the mechanism of leaf senescence in maize. PMID- 25532111 TI - Are endoscopists definitely stepping into the arena of weight-loss therapy? PMID- 25532112 TI - Morbidity and mortality after minor bile duct injury following laparoscopic cholecystectomy. AB - BACKGROUND AND STUDY AIMS: Cystic duct and Luschka duct leakage after laparoscopic cholecystectomy are often classified as minor injuries because the outcome of endoscopic stenting and percutaneous drainage is generally reported to be good. However, the potential associated early mortality and risk factors for mortality are scarcely reported. The aim of this study was to describe the outcome, mortality, and risk factors for poor survival of patients with type A bile duct injury (BDI) referred to a tertiary center. PATIENTS AND METHODS: Between January 1990 and January 2012, 800 patients were referred for BDI treatment and included in a prospective database. RESULTS: Type A BDI, according to the Amsterdam and Strasberg classifications, was diagnosed in 216 patients. Treatment after referral was mainly endoscopic (n = 192 [88.9 %]) and radiologic (n = 14 [6.5 %]). Complications related to endoscopic retrograde cholangiopancreatography (ERCP) occurred in 14 patients (6.5 %). Other complications were sepsis (n = 34 [15.7 %]), cardiopulmonary (n = 22 [10.2 %]), and abscess formation (n = 15 [6.9 %]). BDI-related mortality was 4.2 % (9/216). Multivariate analysis showed age (hazard ratio [HR] = 1.04, 95 % confidence interval [CI] 1.00 - 1.07) and American Society of Anesthesiologists class 3 or 4 (HR = 5.64, 95 %CI 2.31 - 13.77) to be independent factors significantly associated with mortality. CONCLUSIONS: Type A "minor" BDI after laparoscopic cholecystectomy is associated with considerable short-term mortality related to the patient's condition at referral. Older patients and patients with ASA 3 or 4 have a significantly higher risk of mortality. PMID- 25532113 TI - Postpolypectomy surveillance in patients with adenomas and serrated lesions: a proposal for risk stratification in the context of organized colorectal cancer screening programs. PMID- 25532114 TI - Reply to Castells et al. PMID- 25532115 TI - Polyps in Lynch syndrome. Differences in quality of colonoscopy between Western and Eastern endoscopists. PMID- 25532118 TI - Measurement of physician-patient communication--a systematic review. AB - BACKGROUND: Effective communication with health care providers has been found as relevant for physical and psychological health outcomes as well as the patients' adherence. However, the validity of the findings depends on the quality of the applied measures. This study aimed to provide an overview of measures of physician-patient communication and to evaluate the methodological quality of psychometric studies and the quality of psychometric properties of the identified measures. METHODS: A systematic review was performed to identify psychometrically tested instruments which measure physician-patient communication. The search strategy included three databases (EMBASE, PsycINFO, PubMed), reference and citation tracking and personal knowledge. Studies that report the psychometric properties of physician-patient communication measures were included. Two independent raters assessed the methodological quality of the selected studies with the COSMIN (COnsensus based Standards for the selection of health status Measurement INtruments) checklist. The quality of psychometric properties was evaluated with the quality criteria of Terwee and colleagues. RESULTS: Data of 25 studies on 20 measures of physician-patient communication were extracted, mainly from primary care samples in Europe and the USA. Included studies reported a median of 3 out of the nine COSMIN criteria. Scores for internal consistency and content validity were mainly fair or poor. Reliability and structural validity were rated mainly of fair quality. Hypothesis testing scored mostly poor. The quality of psychometric properties of measures evaluated with Terwee et al.'s criteria was rated mainly intermediate or positive. DISCUSSION: This systematic review identified a number of measures of physician-patient communication. However, further psychometric evaluation of the measures is strongly recommended. The application of quality criteria like the COSMIN checklist could improve the methodological quality of psychometric property studies as well as the comparability of the studies' results. PMID- 25532120 TI - Growth, physiological adaptation, and gene expression analysis of two Egyptian rice cultivars under salt stress. AB - Abiotic stressors, such as high salinity, greatly affect plant growth. In an attempt to explore the mechanisms underlying salinity tolerance, physiological parameters of two local Egyptian rice (Oryza sativa L.) cultivars, Sakha 102 and Egyptian Yasmine, were examined under 50 mM NaCl stress for 14 days. The results indicate that Egyptian Yasmine is relatively salt tolerant compared to Sakha 102, and this was evident in its higher dry mass production, lower leaf Na(+) levels, and enhanced water conservation under salt stress conditions. Moreover, Egyptian Yasmine exhibited lower Na(+)/K(+) ratios in all tissues examined under salinity stress. The ability to maintain such traits seemed to differ in the leaves and roots of Egyptian Yasmine, and the root K(+) content was much higher in Egyptian Yasmine than in Sakha 102. In order to understand the basis for these differences, we studied transcript levels of genes encoding Na(+) and K(+) transport proteins in different tissues. In response to salinity stress, Egyptian Yasmine showed induction of expression of some membrane transporter/channel genes that may contribute to Na(+) exclusion from the shoots (OsHKT1;5), limiting excess Na(+) entry into the roots (OsLti6b), K(+) uptake (OsAKT1), and reduced expression of a Na(+) transporter gene (OsHKT2;1). Therefore, the active regulation of genes related to Na(+) transport at the transcription level may be involved in salt tolerance mechanisms of Egyptian Yasmine, and these mechanisms offer the promise of improved salinity stress tolerance in local Egyptian rice genotypes. PMID- 25532119 TI - Regulated expression of PTPRJ by COX-2/PGE2 axis in endothelial cells. AB - BACKGROUND: This study was designed to examine a novel role of COX-2/PGE2 signaling as a regulator of PTPRJ expression in endothelial cells. METHODS: A bioinformatics analysis of a whole genome array was carried out to search for regulators of PTPRJ expression in endothelial cells. PTPRJ expression was also measured in endothelial cells derived from a balloon injury-induced neointimal hyperplasia model in male New Zealand Rabbits. Changes in PTPRJ expression in HUVEC cells was examined by RT-PCR and western blotting after transfection of COX 2 plasmids or treatment with varying concentrations of a COX-2 inhibitor. RESULTS: A significant correlation was identified between COX-2 and PTPRJ in GSE39264 (Pearson correlation coefficient = -0.87; n = 22; P < 0.01, two tailed). PTPRJ expression was reduced during the progression of neointimal hyperplasia after balloon injury, which correlated with an increase in COX-2 expression. In HUVECs, after transfection with 1 ug/ml, 0.5 ug/ml, or 0.25 ug/ml COX-2 plasmids, PTPRJ protein expression was reduced to 0.60- (+/- 0.08), 0.75- (+/- 0.09), and 0.88- (+/- 0.04) fold, respectively, while mRNA expression was reduced to 0.15- (+/- 0.03), 0.26- (+/- 0.05), and 0.47- (+/- 0.09) fold, respectively. After treatment of HUVECs with 10 umol/L or 20 umol/L celecoxib, the reduction in PTPRJ expression induced by COX-2 over-expression was not only rescued but in fact increased by 2.05-fold (+/- 0.28) and 3.34-fold (+/- 0.37), respectively, compared with control. CONCLUSIONS: Our results suggest that COX 2/PGE2 signaling may function as a negative regulator of PTPRJ expression in endothelial cells both in vivo and vitro. PMID- 25532121 TI - Euphorbia characias latex: micromorphology of rubber particles and rubber transferase activity. AB - We have recently characterized a natural rubber in the latex of Euphorbia characias. Following that study, we here investigated the rubber particles and rubber transferase in that Mediterranean shrub. Rubber particles, observed by scanning electron microscopy, are spherical in shape with diameter ranging from 0.02 to 1.2 MUm. Washed rubber particles exhibit rubber transferase activity with a rate of radiolabeled [(14)C]IPP incorporation of 4.5 pmol min(-1)mg(-1). Denaturing electrophoresis profile of washed rubber particles reveals a single protein band of 37 kDa that is recognized in western blot analysis by antibodies raised against the synthetic peptide whose sequence, DVVIRTSGETRLSNF, is included in one of the five regions conserved among cis-prenyl chain elongation enzymes. The cDNA nucleotide sequence of E. characias rubber transferase (GenBank JX564541) and the deduced amino acid sequence appear to be highly homologous to the sequence of several plant cis-prenyltransferases. PMID- 25532122 TI - Molecular identification and characterization of the pyruvate decarboxylase gene family associated with latex regeneration and stress response in rubber tree. AB - In plants, ethanolic fermentation occurs not only under anaerobic conditions but also under aerobic conditions, and involves carbohydrate and energy metabolism. Pyruvate decarboxylase (PDC) is the first and the key enzyme of ethanolic fermentation, which branches off the main glycolytic pathway at pyruvate. Here, four PDC genes were isolated and identified in a rubber tree, and the protein sequences they encode are very similar. The expression patterns of HbPDC4 correlated well with tapping-simulated rubber productivity in virgin rubber trees, indicating it plays an important role in regulating glycometabolism during latex regeneration. HbPDC1, HbPDC2 and HbPDC3 had striking expressional responses in leaves and bark to drought, low temperature and high temperature stresses, indicating that the HbPDC genes are involve in self-protection and defense in response to various abiotic and biotic stresses during rubber tree growth and development. To understand ethanolic fermentation in rubber trees, it will be necessary to perform an in-depth study of the regulatory pathways controlling the HbPDCs in the future. PMID- 25532123 TI - Atomic scale dynamics of a solid state chemical reaction directly determined by annular dark-field electron microscopy. AB - Dynamic processes, such as solid-state chemical reactions and phase changes, are ubiquitous in materials science, and developing a capability to observe the mechanisms of such processes on the atomic scale can offer new insights across a wide range of materials systems. Aberration correction in scanning transmission electron microscopy (STEM) has enabled atomic resolution imaging at significantly reduced beam energies and electron doses. It has also made possible the quantitative determination of the composition and occupancy of atomic columns using the atomic number (Z)-contrast annular dark-field (ADF) imaging available in STEM. Here we combine these benefits to record the motions and quantitative changes in the occupancy of individual atomic columns during a solid-state chemical reaction in manganese oxides. These oxides are of great interest for energy-storage applications such as for electrode materials in pseudocapacitors. We employ rapid scanning in STEM to both drive and directly observe the atomic scale dynamics behind the transformation of Mn3O4 into MnO. The results demonstrate we now have the experimental capability to understand the complex atomic mechanisms involved in phase changes and solid state chemical reactions. PMID- 25532124 TI - Direct splash dispersal prevails over indirect and subsequent spread during rains in Colletotrichum gloeosporioides infecting yams. AB - Plant pathogens have evolved many dispersal mechanisms, using biotic or abiotic vectors or a combination of the two. Rain splash dispersal is known from a variety of fungi, and can be an efficient driver of crop epidemics, with infectious strains propagating rapidly among often genetically homogenous neighboring plants. Splashing is nevertheless a local dispersal process and spores taking the droplet ride seldom move farther than a few decimeters. In this study, we assessed rain splash dispersal of conidia of the yam anthracnose agent, Colletotrichum gloeosporioides, in an experimental setting using a rain simulator, with emphasis on the impact of soil contamination (i.e., effect of re splashing events). Spores dispersed up to 50 cm from yam leaf inoculum sources, though with an exponential decrease with increasing distance. While few spores were dispersed via re-splash from spore-contaminated soil, the proportion deposited via this mechanism increased with increasing distance from the initial source. We found no soil contamination carryover from previous rains, suggesting that contamination via re-splashing from contaminated soils mainly occurred within single rains. We conclude that most dispersal occurs from direct splashing, with a weaker contribution of indirect dispersal via re-splash. PMID- 25532125 TI - Sol-gel syntheses, luminescence, and energy transfer properties of alpha GdB5O9:Ce(3+)/Tb(3+) phosphors. AB - Sol-gel method was applied to prepare homogenous and highly crystalline phosphors with the formulas alpha-GdB5O9:xTb(3+) (0 <= x <= 1), alpha-Gd1-xCexB5O9 (0 <= x <= 0.40), alpha-GdB5O9:xCe(3+), 0.30Tb(3+) (0 <= x <= 0.15) and alpha GdB5O9:0.20Ce(3+), xTb(3+) (0 <= x <= 0.10). The success of the syntheses was proved by the linear shrinkage or expansion of the cell volumes against the substitution contents. In alpha-GdB5O9:xTb(3+), an efficient energy transfer from Gd(3+) to Tb(3+) was observed and there was no luminescence quenching. The exceptionally high efficiency of the f-f excitations of Tb(3+) implies that these phosphors may be good green-emitting UV-LED phosphors. For alpha-Gd1-xCexB5O9, Ce(3+) absorbs the majority of the energy and transfers it to Gd(3+). Therefore, the co-doping of Ce(3+) and Tb(3+) leads to a significant enhancement in the green emission of Tb(3+). Our current results together with the study on alpha GdB5O9:xEu(3+) in the literature indicate that alpha-GdB5O9 is a good phosphor host with advantages including controllable preparation, diverse cationic doping, the absence of concentration quenching, and effective energy transfer. PMID- 25532127 TI - Direct fabrication of nanoporous graphene from graphene oxide by adding a gasification agent to a magnesiothermic reaction. AB - CaCO3 acts as a gasification agent during magnesiothermic reduction of graphene oxide, thus preventing the newly formed graphene from restacking. The surface area of the obtained graphene increases from 66 m(2) g(-1) to 603 m(2) g(-1) by adding CaCO3 with a high yield of ~70% based on the carbon content in graphene oxide. PMID- 25532126 TI - Age-related mitochondrial DNA depletion and the impact on pancreatic Beta cell function. AB - Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes. PMID- 25532129 TI - Radiolysis of crown ether-ionic liquid systems: identification of radiolytic products and their effect on the removal of Sr(2+) from nitric acid. AB - The quantitative analysis and identification of the radiolytic products of dicyclohexano-18-crown-6 (DCH18C6), 4',4''(5'')-di-tert-butyldicyclohexano-18 crown-6 (DtBuCH18C6) and benzo-18-crown-6 (B18C6) in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide ([C4mim][NTf2]) ionic liquid after irradiation were performed for the first time. It was found that the yield for radiolytic destruction of DCH18C6 and DtBuCH18C6 was less than that for B18C6. The main radiolytic products were identified as substituted crown ethers formed between crown ether and active radicals such as methyl, trifluoromethyl, butyl, and [C4mim] radicals generated during the irradiation of the crown ether [C4mim][NTf2] system. The radiation effect on the Sr(2+) partitioning of the crown ether-[C4mim][NTf2] system shows further that DCH18C6-[C4mim][NTf2] and DtBuCH18C6-[C4mim][NTf2] still have good extractability for Sr(2+) after irradiation. The extraction ability of DCH18C6-[C4mim][NTf2] and DtBuCH18C6 [C4mim][NTf2] system for Sr(2+) decreased by 14.4% and 18.2% even at 500 kGy, respectively. PMID- 25532128 TI - Epidemiological, clinical and histological characteristics of HBV/HDV co infection: a retrospective cross-sectional study in Guangdong, China. AB - BACKGROUND: The epidemiology of hepatitis D virus (HDV) in China is fairly unknown. The mechanisms whereby HDV leads to accelerated liver disease in hepatitis B virus (HBV)/HDV co-infected patients and the histological characteristics of chronic hepatitis D (CHD) patients need further investigation. METHODS: The prevalence of HDV was retrospectively evaluated in all consecutive hospitalized patients with chronic HBV infection from May 2005 to October 2011. HBV/HDV co-infected patients and HBV mono-infected patients were compared clinically and histologically. Significant histological abnormality was defined as significant necroinflammation (grade >=A2) and/or significant fibrosis (stage >= F2). RESULTS: 6.5% of patients (426/6604) tested positive for IgM anti-HDV. HDV was more common in patients over 50 years old than those under 50 (11.7% vs. 5.1%, P<0.001). HBV/HDV co-infected patients had higher frequencies of end-stage liver disease (ESLD) than HBV mono-infected patients, and HDV co-infection was an independent risk factor for ESLD (OR: 1.428, 95%CI: 1.116-1.827; P = 0.005). The HBV DNA levels in the HBV/HDV group were significantly lower than the HBV group in chronic hepatitis patients (median: 6.50 log10copies/mL vs 6.80 log10copies/mL, P = 0.003), but higher than the HBV group in ESLD patients (median: 5.73 log10copies/mL vs 5.16 log10copies/mL, P<0.001). When stratified by alanine aminotransferase (ALT) level, 46.7%, 56.5% and 80.5% of CHD patients had significant necroinflammation and 86.7%, 87.0% and 90.3% had significant fibrosis with ALT 1-2*upper limit normal (ULN), 2-5*ULN and>5*ULN respectively. CONCLUSION: The prevalence of HDV is not low in patients with chronic HBV infection. HDV may contribute to progression to ESLD through late-phase HBV DNA reactivation. PMID- 25532130 TI - Why is seed production so variable among individuals? A ten-year study with oaks reveals the importance of soil environment. AB - Mast-seeding species exhibit not only a large inter-annual variability in seed production but also considerable variability among individuals within the same year. However, very little is known about the causes and consequences for population dynamics of this potentially large between-individual variability. Here, we quantified seed production over ten consecutive years in two Mediterranean oak species - the deciduous Quercus canariensis and the evergreen Q. suber - that coexist in forests of southern Spain. First, we calibrated likelihood models to identify which abiotic and biotic variables best explain the magnitude (hereafter seed productivity) and temporal variation of seed production at the individual level (hereafter CVi), and infer whether reproductive effort results from the available soil resources for the plant or is primarily determined by selectively favoured strategies. Second, we explored the contribution of between-individual variability in seed production as a potential mechanism of satiation for predispersal seed predators. We found that Q. canariensis trees inhabiting moister and more fertile soils were more productive than those growing in more resource-limited sites. Regarding temporal variation, individuals of the two studied oak species inhabiting these resource-rich environments also exhibited larger values of CVi. Interestingly, we detected a satiating effect on granivorous insects at the tree level in Q. suber, which was evident in those years where between-individual variability in acorn production was higher. These findings suggest that individual seed production (both in terms of seed productivity and inter-annual variability) is strongly dependent on soil resource heterogeneity (at least for one of the two studied oak species) with potential repercussions for recruitment and population dynamics. However, other external factors (such as soil heterogeneity in pathogen abundance) or certain inherent characteristics of the tree might be also involved in this process. PMID- 25532131 TI - Thermophysical properties of lignocellulose: a cell-scale study down to 41 K. AB - Thermal energy transport is of great importance in lignocellulose pyrolysis for biofuels. The thermophysical properties of lignocellulose significantly affect the overall properties of bio-composites and the related thermal transport. In this work, cell-scale lignocellulose (mono-layer plant cells) is prepared to characterize their thermal properties from room temperature down to ~ 40 K. The thermal conductivities of cell-scale lignocellulose along different directions show a little anisotropy due to the cell structure anisotropy. It is found that with temperature going down, the volumetric specific heat of the lignocellulose shows a slower decreasing trend against temperature than microcrystalline cellulose, and its value is always higher than that of microcrystalline cellulose. The thermal conductivity of lignocellulose decreases with temperature from 243 K to 317 K due to increasing phonon-phonon scatterings. From 41 K to 243 K, the thermal conductivity rises with temperature and its change mainly depends on the heat capacity's change. PMID- 25532133 TI - Simulating sharp geometric features in six degrees-of-freedom haptic rendering. AB - It is a challenging problem to achieve six degree-of-freedom (DoF) haptic simulation of subtle force feelings caused by contacts at sharp geometric features in multi-region contact scenarios. We design a novel sphere-tree model for objects with sharp features and use a configuration-based optimization method to compute feedback force and torque. Given a triangle mesh of an object, a sphere-tree model is created based on dihedral angles between pairs of adjacent triangles. The model consists of a hierarchical sphere-tree for global shape and a linked-list of spheres for local areas with sharp features. In each local area with a sharp edge, we first identify those spheres with radii greater than an upper limit determined by the dihedral angle of the edge. Those spheres are further divided into a linear list of smaller spheres by a splitting method. The experiment results from a cylinder-cube interaction validate that the proposed method can simulate subtle force direction changes when an object slides across sharp edges. Perception-based experiments and a haptic-to-vision shape matching task are also used to compare the performance between our proposed method and other rendering methods. The comparison results show that our method is more effective in simulating sharp features both in terms of measured force signals and human subjective evaluation. Non-penetration among objects is maintained for multi-region contact scenarios. The haptic rendering rate is about 1 kHz, and the subtle force feeling of sliding along sharp features can be stably simulated. PMID- 25532132 TI - Investigating the neural correlates of voice versus speech-sound directed information in pre-school children. AB - Studies in sleeping newborns and infants propose that the superior temporal sulcus is involved in speech processing soon after birth. Speech processing also implicitly requires the analysis of the human voice, which conveys both linguistic and extra-linguistic information. However, due to technical and practical challenges when neuroimaging young children, evidence of neural correlates of speech and/or voice processing in toddlers and young children remains scarce. In the current study, we used functional magnetic resonance imaging (fMRI) in 20 typically developing preschool children (average age = 5.8 y; range 5.2-6.8 y) to investigate brain activation during judgments about vocal identity versus the initial speech sound of spoken object words. FMRI results reveal common brain regions responsible for voice-specific and speech-sound specific processing of spoken object words including bilateral primary and secondary language areas of the brain. Contrasting voice-specific with speech sound specific processing predominantly activates the anterior part of the right hemispheric superior temporal sulcus. Furthermore, the right STS is functionally correlated with left-hemispheric temporal and right-hemispheric prefrontal regions. This finding underlines the importance of the right superior temporal sulcus as a temporal voice area and indicates that this brain region is specialized, and functions similarly to adults by the age of five. We thus extend previous knowledge of voice-specific regions and their functional connections to the young brain which may further our understanding of the neuronal mechanism of speech-specific processing in children with developmental disorders, such as autism or specific language impairments. PMID- 25532134 TI - Comparison of seeding methods for visualization of the corticospinal tracts using single tensor tractography. AB - OBJECTIVES: To compare five different seeding methods to delineate hand, foot, and lip components of the corticospinal tract (CST) using single tensor tractography. METHODS: We studied five healthy subjects and 10 brain tumor patients. For each subject, we used five different seeding methods, from (1) cerebral peduncle (CP), (2) posterior limb of the internal capsule (PLIC), (3) white matter subjacent to functional MRI activations (fMRI), (4) whole brain and then selecting the fibers that pass through both fMRI and CP (WBF-CP), and (5) whole brain and then selecting the fibers that pass through both fMRI and PLIC (WBF-PLIC). Two blinded neuroradiologists rated delineations as anatomically successful or unsuccessful tractography. The proportions of successful trials from different methods were compared by Fisher's exact test. RESULTS: To delineate hand motor tract, seeding through fMRI activation areas was more effective than through CP (p<0.01), but not significantly different from PLIC (p>0.1). WBF-CP delineated hand motor tracts in a larger proportion of trials than CP alone (p<0.05). Similarly, WBF-PLIC depicted hand motor tracts in a larger proportion of trials than PLIC alone (p<0.01). Foot motor tracts were delineated in all trials by either PLIC or whole brain seeding (WBF-CP and WBF PLIC). Seeding from CP or fMRI activation resulted in foot motor tract visualization in 87% of the trials (95% confidence interval: 60-98%). The lip motor tracts were delineated only by WBF-PLIC and in 36% of trials (95% confidence interval: 11-69%). CONCLUSIONS: Whole brain seeding and then selecting the tracts that pass through two anatomically relevant ROIs can delineate more plausible hand and lip motor tracts than seeding from a single ROI. Foot motor tracts can be successfully delineated regardless of the seeding method used. PMID- 25532135 TI - Baclofen dosage after traumatic spinal cord injury: a multi-decade retrospective analysis. AB - OBJECTIVES: To perform an analysis of oral baclofen dosage in patients with traumatic spinal cord injuries over time and to ascertain the clinical determinants of long-term baclofen dosage trends. STUDY DESIGN: Retrospective cohort study of patient records from the PM&R units at the Johns Hopkins Bayview Medical Center and the Johns Hopkins Hospital. SUBJECTS: A total of 115 PM&R patients suffering spinal cord injury due to trauma leading to either complete or incomplete paralysis. The modes of injury included were motor vehicle accidents (MVA) (n=39), gunshot wounds (GSW) (n=55), falls (n=17), diving (n=2), workplace (n=1) and swimming (n=1) accidents. The location of injury in the spinal cord was categorized into either cervical (n=52), thoracic (n=59), lumbar (n=2), or unspecified (n=2). RESULTS: From time of injury, an aggregate of all dosage assignments for each patient demonstrated a significant yearly increase in baclofen dosage (1.26 mg/year, p<0.01). Baclofen dosage for MVA cases were seen to rise at 4.99 mg/year (p<0.0001). Kaplan-Meier analysis revealed that GSW patients received their first baclofen dosage earlier than MVA patients (log-rank p<0.05, unadjusted). CONCLUSIONS: We observed a marginal increase in baclofen dosage over nearly 25 years in a single provider's patient database and observed different timings of first dose between two causes of traumatic SCI. These results provide an estimate of baclofen dosage trends over time after spinal cord injury and may be useful for patient counseling or as a method to assess costs of providing SCI patient care. PMID- 25532136 TI - Macromolecular X-ray structure determination using weak, single-wavelength anomalous data. AB - We describe a likelihood-based method for determining the substructure of anomalously scattering atoms in macromolecular crystals that allows successful structure determination by single-wavelength anomalous diffraction (SAD) X-ray analysis with weak anomalous signal. With the use of partial models and electron density maps in searches for anomalously scattering atoms, testing of alternative values of parameters and parallelized automated model-building, this method has the potential to extend the applicability of the SAD method in challenging cases. PMID- 25532139 TI - Modulation of electronic and self-assembly properties of a donor-acceptor-donor based molecular materials via atomistic approach. AB - The performance of molecular materials in optoelectronic devices critically depends upon their electronic properties and solid-state structure. In this report, we have synthesized sulfur and selenium based (T4BT and T4BSe) donor acceptor-donor (D-A-D) organic derivatives in order to understand the structure property correlation in organic semiconductors by selectively tuning the chalcogen atom. The photophysical properties exhibit a significant alteration upon varying a single atom in the molecular structure. A joint theoretical and experimental investigation suggests that replacing sulfur with selenium significantly reduces the band gap and molar absorption coefficient because of lower electronegativity and ionization potential of selenium. Single-crystal X ray diffraction analysis showed differences in their solid-state packing and intermolecular interactions. Subsequently, difference in the solid-state packing results variation in self-assembly. Micorstructural changes within these materials are correlated to their electrical resistance variation, investigated by conducting probe atomic force microscopy (CP-AFM) measurements. These results provide useful guidelines to understand the fundamental properties of D-A-D materials prepared by atomistic modulation. PMID- 25532137 TI - Selecting causal genes from genome-wide association studies via functionally coherent subnetworks. AB - Genome-wide association (GWA) studies have linked thousands of loci to human diseases, but the causal genes and variants at these loci generally remain unknown. Although investigators typically focus on genes closest to the associated polymorphisms, the causal gene is often more distal. Reliance on published work to prioritize candidates is biased toward well-characterized genes. We describe a 'prix fixe' strategy and software that uses genome-scale shared-function networks to identify sets of mutually functionally related genes spanning multiple GWA loci. Using associations from ~100 GWA studies covering ten cancer types, our approach outperformed the common alternative strategy in ranking known cancer genes. As more GWA loci are discovered, the strategy will have increased power to elucidate the causes of human disease. PMID- 25532138 TI - Simultaneous all-optical manipulation and recording of neural circuit activity with cellular resolution in vivo. AB - We describe an all-optical strategy for simultaneously manipulating and recording the activity of multiple neurons with cellular resolution in vivo. We performed simultaneous two-photon optogenetic activation and calcium imaging by coexpression of a red-shifted opsin and a genetically encoded calcium indicator. A spatial light modulator allows tens of user-selected neurons to be targeted for spatiotemporally precise concurrent optogenetic activation, while simultaneous fast calcium imaging provides high-resolution network-wide readout of the manipulation with negligible optical cross-talk. Proof-of-principle experiments in mouse barrel cortex demonstrate interrogation of the same neuronal population during different behavioral states and targeting of neuronal ensembles based on their functional signature. This approach extends the optogenetic toolkit beyond the specificity obtained with genetic or viral approaches, enabling high throughput, flexible and long-term optical interrogation of functionally defined neural circuits with single-cell and single-spike resolution in the mouse brain in vivo. PMID- 25532140 TI - Cardiac patient outcomes during national cardiology meetings. PMID- 25532142 TI - Comparison of Three Different Types of Wrist Pulse Signals by Their Physical Meanings and Diagnosis Performance. AB - Increasing interest has been focused on computational pulse diagnosis where sensors are developed to acquire pulse signals, and machine learning techniques are exploited to analyze health conditions based on the acquired pulse signals. By far, a number of sensors have been employed for pulse signal acquisition, which can be grouped into three major categories, i.e., pressure, photoelectric, and ultrasonic sensors. To guide the sensor selection for computational pulse diagnosis, in this paper, we analyze the physical meanings and sensitivities of signals acquired by these three types of sensors. The dependence and complementarity of the different sensors are discussed from both the perspective of cardiovascular fluid dynamics and comparative experiments by evaluating disease classification performance. Experimental results indicate that each sensor is more appropriate for the diagnosis of some specific disease that the changes of physiological factors can be effectively reflected by the sensor, e.g., ultrasonic sensor for diabetes and pressure sensor for arteriosclerosis, and improved diagnosis performance can be obtained by combining three types of signals. PMID- 25532143 TI - A Hybrid Memetic Framework for Coverage Optimization in Wireless Sensor Networks. AB - One of the critical concerns in wireless sensor networks (WSNs) is the continuous maintenance of sensing coverage. Many particular applications, such as battlefield intrusion detection and object tracking, require a full-coverage at any time, which is typically resolved by adding redundant sensor nodes. With abundant energy, previous studies suggested that the network lifetime can be maximized while maintaining full coverage through organizing sensor nodes into a maximum number of disjoint sets and alternately turning them on. Since the power of sensor nodes is unevenly consumed over time, and early failure of sensor nodes leads to coverage loss, WSNs require dynamic coverage maintenance. Thus, the task of permanently sustaining full coverage is particularly formulated as a hybrid of disjoint set covers and dynamic-coverage-maintenance problems, and both have been proven to be nondeterministic polynomial-complete. In this paper, a hybrid memetic framework for coverage optimization (Hy-MFCO) is presented to cope with the hybrid problem using two major components: 1) a memetic algorithm (MA)-based scheduling strategy and 2) a heuristic recursive algorithm (HRA). First, the MA based scheduling strategy adopts a dynamic chromosome structure to create disjoint sets, and then the HRA is utilized to compensate the loss of coverage by awaking some of the hibernated nodes in local regions when a disjoint set fails to maintain full coverage. The results obtained from real-world experiments using a WSN test-bed and computer simulations indicate that the proposed Hy-MFCO is able to maximize sensing coverage while achieving energy efficiency at the same time. Moreover, the results also show that the Hy-MFCO significantly outperforms the existing methods with respect to coverage preservation and energy efficiency. PMID- 25532144 TI - Online Signature Verification Based on DCT and Sparse Representation. AB - In this paper, a novel online signature verification technique based on discrete cosine transform (DCT) and sparse representation is proposed. We find a new property of DCT, which can be used to obtain a compact representation of an online signature using a fixed number of coefficients, leading to simple matching procedures and providing an effective alternative to deal with time series of different lengths. The property is also used to extract energy features. Furthermore, a new attempt to apply sparse representation to online signature verification is made, and a novel task-specific method for building overcomplete dictionaries is proposed, then sparsity features are extracted. Finally, energy features and sparsity features are concatenated to form a feature vector. Experiments are conducted on the Sabanci University's Signature Database (SUSIG) Visual and SVC2004 databases, and the results show that our proposed method authenticates persons very reliably with a verification performance which is better than those of state-of-the-art methods on the same databases. PMID- 25532145 TI - Prototype-Based Discriminative Feature Learning for Kinship Verification. AB - In this paper, we propose a new prototype-based discriminative feature learning (PDFL) method for kinship verification. Unlike most previous kinship verification methods which employ low-level hand-crafted descriptors such as local binary pattern and Gabor features for face representation, this paper aims to learn discriminative mid-level features to better characterize the kin relation of face images for kinship verification. To achieve this, we construct a set of face samples with unlabeled kin relation from the labeled face in the wild dataset as the reference set. Then, each sample in the training face kinship dataset is represented as a mid-level feature vector, where each entry is the corresponding decision value from one support vector machine hyperplane. Subsequently, we formulate an optimization function by minimizing the intraclass samples (with a kin relation) and maximizing the neighboring interclass samples (without a kin relation) with the mid-level features. To better use multiple low-level features for mid-level feature learning, we further propose a multiview PDFL method to learn multiple mid-level features to improve the verification performance. Experimental results on four publicly available kinship datasets show the superior performance of the proposed methods over both the state-of-the-art kinship verification methods and human ability in our kinship verification task. PMID- 25532147 TI - Analysis of hand contact areas and interaction capabilities during manipulation and exploration. AB - Manual human-computer interfaces for virtual reality are designed to allow an operator interacting with a computer simulation as naturally as possible. Dexterous haptic interfaces are the best suited for this goal. They give intuitive and efficient control on the environment with haptic and tactile feedback. This paper is aimed at helping in the choice of the interaction areas to be taken into account in the design of such interfaces. The literature dealing with hand interactions is first reviewed in order to point out the contact areas involved in exploration and manipulation tasks. Their frequencies of use are then extracted from existing recordings. The results are gathered in an original graphical interaction map allowing for a simple visualization of the way the hand is used, and compared with a map of mechanoreceptors densities. Then an interaction tree, mapping the relative amount of actions made available through the use of a given contact area, is built and correlated with the losses of hand function induced by amputations. A rating of some existing haptic interfaces and guidelines for their design are finally achieved to illustrate a possible use of the developed graphical tools. PMID- 25532148 TI - Analysis of human grasping behavior: correlating tasks, objects and grasps. AB - This paper is the second in a two-part series analyzing human grasping behavior during a wide range of unstructured tasks. It investigates the tasks performed during the daily work of two housekeepers and two machinists and correlates grasp type and object properties with the attributes of the tasks being performed. The task or activity is classified according to the force required, the degrees of freedom, and the functional task type. We found that 46 percent of tasks are constrained, where the manipulated object is not allowed to move in a full six degrees of freedom. Analyzing the interrelationships between the grasp, object, and task data show that the best predictors of the grasp type are object size, task constraints, and object mass. Using these attributes, the grasp type can be predicted with 47 percent accuracy. Those parameters likely make useful heuristics for grasp planning systems. The results further suggest the common sub categorization of grasps into power, intermediate, and precision categories may not be appropriate, indicating that grasps are generally more multi-functional than previously thought. We find large and heavy objects are grasped with a power grasp, but small and lightweight objects are not necessarily grasped with precision grasps-even with grasped object size less than 2 cm and mass less than 20 g, precision grasps are only used 61 percent of the time. These results have important implications for robotic hand design and grasp planners, since it appears while power grasps are frequently used for heavy objects, they can still be quite practical for small, lightweight objects. PMID- 25532146 TI - Evaluation of the "steal" phenomenon on the efficacy of hypoxia activated prodrug TH-302 in pancreatic cancer. AB - Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the "steal" phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a "steal" effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia. PMID- 25532149 TI - Haptic tumor augmentation: exploring multi-point interaction. AB - We currently explore the application of haptic augmentation in the context of palpation training systems. The key idea is to modify real touch sensations with computed haptic feedback. In earlier work, we have introduced an algorithmic framework for determining appropriate augmentation forces during interaction at one contact point. In this paper, we present an extension of the approach to deal with manipulations at more than one contact location. At the heart of our method is the data-driven estimation of Hunt-Crossley model parameters in a pre computation step. Feeding the parameters into a contact dynamics model allows us to approximate the feedback behavior of various physical tissue mock-ups. Further, we combine the parameter estimation with the tracking of the position of a stiffer inclusion in the mock-up. These data are employed to create a model of movement due to external forces. The combination of these models then allows us to represent and render the mutual effects at multiple contact points. Several experiments have been carried out on a setup with two haptic devices. Comparisons of recorded with simulated interaction data demonstrate the performance and potential of our method. PMID- 25532150 TI - Human-robot formation control via visual and vibrotactile haptic feedback. AB - In this paper we present a new visuo-haptic interaction mechanism for human-robot formation control. The formation setup consists of a human leader and multiple follower robots. The mobile robots are equipped only with RGB-D cameras, and they should maintain a desired distance and orientation to the leader at all times. Mechanical limitations common to all the robots limit the possible trajectories that the human can take. In this regard, vibrotactile feedback provided by a haptic bracelet guides the human along trajectories that are feasible for the team by warning her/him when the formation constraints are being violated. Psychophysical tests on the bracelet together with real-world experiments conducted with a team of Pioneer robots show the effectiveness of the proposed visuo-haptic paradigm for the coordination of mixed human-robot teams. PMID- 25532151 TI - Incrementally learning objects by touch: online discriminative and generative models for tactile-based recognition. AB - Human beings not only possess the remarkable ability to distinguish objects through tactile feedback but are further able to improve upon recognition competence through experience. In this work, we explore tactile-based object recognition with learners capable of incremental learning. Using the sparse online infinite Echo-State Gaussian process (OIESGP), we propose and compare two novel discriminative and generative tactile learners that produce probability distributions over objects during object grasping/palpation. To enable iterative improvement, our online methods incorporate training samples as they become available. We also describe incremental unsupervised learning mechanisms, based on novelty scores and extreme value theory, when teacher labels are not available. We present experimental results for both supervised and unsupervised learning tasks using the iCub humanoid, with tactile sensors on its five-fingered anthropomorphic hand, and 10 different object classes. Our classifiers perform comparably to state-of-the-art methods (C4.5 and SVM classifiers) and findings indicate that tactile signals are highly relevant for making accurate object classifications. We also show that accurate "early" classifications are possible using only 20-30 percent of the grasp sequence. For unsupervised learning, our methods generate high quality clusterings relative to the widely-used sequential k-means and self-organising map (SOM), and we present analyses into the differences between the approaches. PMID- 25532152 TI - Robotically enhanced rubber hand illusion. AB - The rubber hand illusion is a well-known multisensory illusion. In brief, watching a rubber hand being stroked by a paintbrush while one's own unseen hand is synchronously stroked causes the rubber hand to be attributed to one's own body and to "feel like it's my hand." The rubber hand illusion is thought to be triggered by the synchronized tactile stimulation of both the subject's hand and the fake hand. To extend the conventional rubber hand illusion, we introduce robotic technology in the form of a master-slave telemanipulator. The developed one degree-of-freedom master-slave system consists of an exoskeleton master equipped with an optical encoder that is worn on the subject's index finger and a motor-actuated index finger on the rubber hand, which allows the subject to perform unilateral telemanipulation. The moving rubber hand illusion has been studied by several researchers in the past with mechanically connected rigs between the subject's body and the fake limb. The robotic instruments let us investigate the moving rubber hand illusion with less constraints, thus behaving closer to the classic rubber hand illusion. In addition, the temporal delay between the body and the fake limb can be precisely manipulated. The experimental results revealed that the robotic instruments significantly enhance the rubber hand illusion. The time delay is significantly correlated with the effect of the multisensory illusion, and the effect significantly decreased at time delays over 100 ms. These findings can potentially contribute to the investigations of neural mechanisms in the field of neuroscience and of master-slave systems in the field of robotics. PMID- 25532153 TI - Search efficiency for tactile features rendered by surface haptic displays. AB - Haptic interfaces controlled by a single fingertip or hand-held probe tend to display surface features individually, requiring serial search for multiple features. Novel surface haptic devices, however, have the potential to provide displays to multiple fingertips simultaneously, affording the possibility of parallel search. Using variable-friction surface haptic devices, we investigated the ability of participants to detect a target feature among a set of distractors in parallel across the fingers. We found that searches for a material property (slipperiness) and an illusory shape (virtual hole) were significantly impaired by distractors, while search for an abrupt discontinuity (virtual edge) was not. The efficiency of search for edges rendered by surface haptics suggests that they engage primitive detectors in the haptic perceptual system. PMID- 25532154 TI - Feature selection using a neural framework with controlled redundancy. AB - We first present a feature selection method based on a multilayer perceptron (MLP) neural network, called feature selection MLP (FSMLP). We explain how FSMLP can select essential features and discard derogatory and indifferent features. Such a method may pick up some useful but dependent (say correlated) features, all of which may not be needed. We then propose a general scheme for dealing with feature selection with "controlled redundancy" (CoR). The proposed scheme, named as FSMLP-CoR, can select features with a controlled redundancy both for classification and function approximation/prediction type problems. We have also proposed a new more effective training scheme named mFSMLP-CoR. The idea is general in nature and can be used with other learning schemes also. We demonstrate the effectiveness of the algorithms using several data sets including a synthetic data set. We also show that the selected features are adequate to solve the problem at hand. Here, we have considered a measure of linear dependency to control the redundancy. The use of nonlinear measures of dependency, such as mutual information, is straightforward. Here, there are some advantages of the proposed schemes. They do not require explicit evaluation of the feature subsets. Here, feature selection is integrated into designing of the decision-making system. Hence, it can look at all features together and pick up whatever is necessary. Our methods can account for possible nonlinear subtle interactions between features, as well as that between features, tools, and the problem being solved. They can also control the level of redundancy in the selected features. Of the two learning schemes, mFSMLP-CoR, not only improves the performance of the system, but also significantly reduces the dependency of the network's behavior on the initialization of connection weights. PMID- 25532155 TI - Pareto-path multitask multiple kernel learning. AB - A traditional and intuitively appealing Multitask Multiple Kernel Learning (MT MKL) method is to optimize the sum (thus, the average) of objective functions with (partially) shared kernel function, which allows information sharing among the tasks. We point out that the obtained solution corresponds to a single point on the Pareto Front (PF) of a multiobjective optimization problem, which considers the concurrent optimization of all task objectives involved in the Multitask Learning (MTL) problem. Motivated by this last observation and arguing that the former approach is heuristic, we propose a novel support vector machine MT-MKL framework that considers an implicitly defined set of conic combinations of task objectives. We show that solving our framework produces solutions along a path on the aforementioned PF and that it subsumes the optimization of the average of objective functions as a special case. Using the algorithms we derived, we demonstrate through a series of experimental results that the framework is capable of achieving a better classification performance, when compared with other similar MTL approaches. PMID- 25532156 TI - Learning understandable neural networks with nonnegative weight constraints. AB - People can understand complex structures if they relate to more isolated yet understandable concepts. Despite this fact, popular pattern recognition tools, such as decision tree or production rule learners, produce only flat models which do not build intermediate data representations. On the other hand, neural networks typically learn hierarchical but opaque models. We show how constraining neurons' weights to be nonnegative improves the interpretability of a network's operation. We analyze the proposed method on large data sets: the MNIST digit recognition data and the Reuters text categorization data. The patterns learned by traditional and constrained network are contrasted to those learned with principal component analysis and nonnegative matrix factorization. PMID- 25532157 TI - A latent manifold Markovian dynamics Gaussian process. AB - In this paper, we propose a Gaussian process (GP) model for analysis of nonlinear time series. Formulation of our model is based on the consideration that the observed data are functions of latent variables, with the associated mapping between observations and latent representations modeled through GP priors. In addition, to capture the temporal dynamics in the modeled data, we assume that subsequent latent representations depend on each other on the basis of a hidden Markov prior imposed over them. Derivation of our model is performed by marginalizing out the model parameters in closed form using GP priors for observation mappings, and appropriate stick-breaking priors for the latent variable (Markovian) dynamics. This way, we eventually obtain a nonparametric Bayesian model for dynamical systems that accounts for uncertainty in the modeled data. We provide efficient inference algorithms for our model on the basis of a truncated variational Bayesian approximation. We demonstrate the efficacy of our approach considering a number of applications dealing with real-world data, and compare it with the related state-of-the-art approaches. PMID- 25532158 TI - Existence and uniform stability analysis of fractional-order complex-valued neural networks with time delays. AB - This paper deals with the problem of existence and uniform stability analysis of fractional-order complex-valued neural networks with constant time delays. Complex-valued recurrent neural networks is an extension of real-valued recurrent neural networks that includes complex-valued states, connection weights, or activation functions. This paper explains sufficient condition for the existence and uniform stability analysis of such networks. Three numerical simulations are delineated to substantiate the effectiveness of the theoretical results. PMID- 25532159 TI - Identification of the dynamic operating envelope of HCCI engines using class imbalance learning. AB - Homogeneous charge compression ignition (HCCI) is a futuristic automotive engine technology that can significantly improve fuel economy and reduce emissions. HCCI engine operation is constrained by combustion instabilities, such as knock, ringing, misfires, high-variability combustion, and so on, and it becomes important to identify the operating envelope defined by these constraints for use in engine diagnostics and controller design. HCCI combustion is dominated by complex nonlinear dynamics, and a first-principle-based dynamic modeling of the operating envelope becomes intractable. In this paper, a machine learning approach is presented to identify the stable operating envelope of HCCI combustion, by learning directly from the experimental data. Stability is defined using thresholds on combustion features obtained from engine in-cylinder pressure measurements. This paper considers instabilities arising from engine misfire and high-variability combustion. A gasoline HCCI engine is used for generating stable and unstable data observations. Owing to an imbalance in class proportions in the data set, the models are developed both based on resampling the data set (by undersampling and oversampling) and based on a cost-sensitive learning method (by overweighting the minority class relative to the majority class observations). Support vector machines (SVMs) and recently developed extreme learning machines (ELM) are utilized for developing dynamic classifiers. The results compared against linear classification methods show that cost-sensitive nonlinear ELM and SVM classification algorithms are well suited for the problem. However, the SVM envelope model requires about 80% more parameters for an accuracy improvement of 3% compared with the ELM envelope model indicating that ELM models may be computationally suitable for the engine application. The proposed modeling approach shows that HCCI engine misfires and high-variability combustion can be predicted ahead of time, given the present values of available sensor measurements, making the models suitable for engine diagnostics and control applications. PMID- 25532160 TI - Synchronization of nonlinear coupled networks via aperiodically intermittent pinning control. AB - In this paper, pinning synchronization problem for nonlinear coupled networks is investigated, which can be recurrently connected neural networks, cellular neural networks, Hodgkin-Huxley models, Lorenz chaotic oscillators, and so on. Nodes in the network are assumed to be identical and nodes' dynamical behaviors are described by continuous-time equations. The network topology is undirected and static. At first, the scope of accepted nonlinear coupling functions is defined, and the effect of nonlinear coupling functions on synchronization is carefully discussed. Then, the pinning control technique is used for synchronization, especially the control type is aperiodically intermittent. Some sufficient conditions to guarantee global synchronization are presented. Furthermore, the adaptive approach is also applied on the pinning control, and a centralized adaptive algorithm is designed and its validity is also proved. Finally, several numerical simulations are given to verify the obtained theoretical results. PMID- 25532161 TI - Digital implementation of a biological astrocyte model and its application. AB - This paper presents a modified astrocyte model that allows a convenient digital implementation. This model is aimed at reproducing relevant biological astrocyte behaviors, which provide appropriate feedback control in regulating neuronal activities in the central nervous system. Accordingly, we investigate the feasibility of a digital implementation for a single astrocyte and a biological neuronal network model constructed by connecting two limit-cycle Hopf oscillators to an implementation of the proposed astrocyte model using oscillator-astrocyte interactions with weak coupling. Hardware synthesis, physical implementation on field-programmable gate array, and theoretical analysis confirm that the proposed astrocyte model, with considerably low hardware overhead, can mimic biological astrocyte model behaviors, resulting in desynchronization of the two coupled limit-cycle oscillators. PMID- 25532162 TI - Off-policy reinforcement learning for Hinfinity control design. AB - The Hinfinity control design problem is considered for nonlinear systems with unknown internal system model. It is known that the nonlinear Hinfinity control problem can be transformed into solving the so-called Hamilton-Jacobi-Isaacs (HJI) equation, which is a nonlinear partial differential equation that is generally impossible to be solved analytically. Even worse, model-based approaches cannot be used for approximately solving HJI equation, when the accurate system model is unavailable or costly to obtain in practice. To overcome these difficulties, an off-policy reinforcement leaning (RL) method is introduced to learn the solution of HJI equation from real system data instead of mathematical system model, and its convergence is proved. In the off-policy RL method, the system data can be generated with arbitrary policies rather than the evaluating policy, which is extremely important and promising for practical systems. For implementation purpose, a neural network (NN)-based actor-critic structure is employed and a least-square NN weight update algorithm is derived based on the method of weighted residuals. Finally, the developed NN-based off policy RL method is tested on a linear F16 aircraft plant, and further applied to a rotational/translational actuator system. PMID- 25532165 TI - Wavelet-based regularization for robust microwave imaging in medical applications. AB - Microwave imaging (MWI) is an emerging tool for medical diagnostics, potentially offering unique advantages such as the capability of providing quantitative images of the inspected tissues. This involves, however, solving a challenging nonlinear and ill-posed electromagnetic inverse scattering problem. This paper presents a robust method for quantitative MWI in medical applications where very little, if any, a priori information on the imaging scenario is available. This is accomplished by employing a distorted Born iterative method and a regularization by projection technique, which reconstructs the tissue parameters using a wavelet basis expansion to represent the unknown contrast. This approach is suited for any microwave medical imaging application where the requirement for increased resolution dictates the use of higher frequency data and, consequently, a robust regularization strategy. To demonstrate the robustness of the proposed approach, this paper presents reconstructions of highly heterogeneous anatomically realistic numerical breast phantoms in a canonical 2-D configuration. PMID- 25532164 TI - Wavelet augmented cough analysis for rapid childhood pneumonia diagnosis. AB - Pneumonia is the cause of death for over a million children each year around the world, largely in resource poor regions such as sub-Saharan Africa and remote Asia. One of the biggest challenges faced by pneumonia endemic countries is the absence of a field deployable diagnostic tool that is rapid, low-cost and accurate. In this paper, we address this issue and propose a method to screen pneumonia based on the mathematical analysis of cough sounds. In particular, we propose a novel cough feature inspired by wavelet-based crackle detection work in lung sound analysis. These features are then combined with other mathematical features to develop an automated machine classifier, which can separate pneumonia from a range of other respiratory diseases. Both cough and crackles are symptoms of pneumonia, but their existence alone is not a specific enough marker of the disease. In this paper, we hypothesize that the mathematical analysis of cough sounds allows us to diagnose pneumonia with sufficient sensitivity and specificity. Using a bedside microphone, we collected 815 cough sounds from 91 patients with respiratory illnesses such as pneumonia, asthma, and bronchitis. We extracted wavelet features from cough sounds and combined them with other features such as Mel Cepstral coefficients and non-Gaussianity index. We then trained a logistic regression classifier to separate pneumonia from other diseases. As the reference standard, we used the diagnosis by physicians aided with laboratory and radiological results as deemed necessary for a clinical decision. The methods proposed in this paper achieved a sensitivity and specificity of 94% and 63%, respectively, in separating pneumonia patients from non-pneumonia patients based on wavelet features alone. Combining the wavelets with features from our previous work improves the performance further to 94% and 88% sensitivity and specificity. The performance far surpasses that of the WHO criteria currently in common use in resource-limited settings. PMID- 25532163 TI - Ultrasound elasticity imaging for determining the mechanical properties of human posterior tibial tendon: a cadaveric study. AB - Posterior tibial tendon dysfunction (PTTD) is a common degenerative condition leading to a severe impairment of gait. There is currently no effective method to determine whether a patient with advanced PTTD would benefit from several months of bracing and physical therapy or ultimately require surgery. Tendon degeneration is closely associated with irreversible degradation of its collagen structure, leading to changes to its mechanical properties. If these properties could be monitored in vivo, they could be used to quantify the severity of tendonosis and help determine the appropriate treatment. The goal of this cadaveric study was, therefore, to develop and validate ultrasound elasticity imaging (UEI) as a potentially noninvasive technique for quantifying tendon mechanical properties. Five human cadaver feet were mounted in a materials testing system (MTS), while the posterior tibial tendon (PTT) was attached to a force actuator. A portable ultrasound scanner collected 2-D data during loading cycles. Young's modulus was calculated from the strain, loading force, and cross sectional area of the PTT. Average Young's modulus for the five tendons was (0.45 +/- 0.16 GPa) using UEI, which was consistent with simultaneous measurements made by the MTS across the whole tendon (0.52 +/- 0.18 GPa). We also calculated the scaling factor (0.12 +/- 0.01) between the load on the PTT and the inversion force at the forefoot, a measurable quantity in vivo. This study suggests that UEI could be a reliable in vivo technique for estimating the mechanical properties of the PTT, and as a clinical tool, help guide treatment decisions for advanced PTTD and other tendinopathies. PMID- 25532166 TI - Magneto-Acousto-Electrical Tomography With Magnetic Induction for Conductivity Reconstruction. AB - Magneto-acousto-electrical tomography (MAET) is an imaging modality proposed to conduct noninvasive electrical conductivity imaging of biological tissue with high spatial resolution. In this study, we present a method of MAET in coil detection mode, which is named as magneto-acousto-electrical tomography with magnetic induction (MAET-MI). Based on the analysis of the mechanism of MAET-MI, we derive a reciprocal theorem and give an integral equation for computing the induced voltage of the coil. The forward problem of MAET-MI can be solved by this integral equation. In the inverse problem of MAET-MI, two steps are taken to reconstruct the conductivity. The first step is to reconstruct the curl of the eddy current density in the reciprocal process by the compression sensing method. And then the conductivity is recovered by the iterative methods such as the Levenberg-Marquardt algorithm. Both the mechanism of MAET-MI and the reconstruction of conductivity are verified by computer simulations. We have also conducted the phantom experiments. The reconstructed images are approximately consistent with the phantom's conductivity. The imaging results prove the ability and the reliability of our proposed methods. It is shown that the relative conductivity distribution can be reconstructed with our proposed reciprocal theorem in MAET-MI modality. Comparing with the traditional MAET, The MAET-MI modality would benefit from the noncontact measurement and be convenient for clinical application. PMID- 25532168 TI - Detecting statistically significant differences in quantitative MRI experiments, applied to diffusion tensor imaging. AB - In this work we present a framework for reliably detecting significant differences in quantitative magnetic resonance imaging and evaluate it with diffusion tensor imaging (DTI) experiments. As part of this framework we propose a new spatially regularized maximum likelihood estimator that simultaneously estimates the quantitative parameters and the spatially-smoothly-varying noise level from the acquisitions. The noise level estimation method does not require repeated acquisitions. We show that the amount of regularization in this method can be set a priori to achieve a desired coefficient of variation of the estimated noise level. The noise level estimate allows the construction of a Cramer-Rao-lower-bound based test statistic that reliably assesses the significance of differences between voxels within a scan or across different scans. We show that the regularized noise level estimate improves upon existing methods and results in a substantially increased precision of the uncertainty estimates of the DTI parameters. It enables correct specification of the null distribution of the test statistic and with it the test statistic obtains the highest sensitivity and specificity. The source code of the estimation framework, test statistic and experiment scripts are made available to the community. PMID- 25532167 TI - Simultaneous multi-scale diffusion estimation and tractography guided by entropy spectrum pathways. AB - We have developed a method for the simultaneous estimation of local diffusion and the global fiber tracts based upon the information entropy flow that computes the maximum entropy trajectories between locations and depends upon the global structure of the multi-dimensional and multi-modal diffusion field. Computation of the entropy spectrum pathways requires only solving a simple eigenvector problem for the probability distribution for which efficient numerical routines exist, and a straight forward integration of the probability conservation through ray tracing of the convective modes guided by a global structure of the entropy spectrum coupled with a small scale local diffusion. The intervoxel diffusion is sampled by multi b-shell multi q-angle diffusion weighted imaging data expanded in spherical waves. This novel approach to fiber tracking incorporates global information about multiple fiber crossings in every individual voxel and ranks it in the most scientifically rigorous way. This method has potential significance for a wide range of applications, including studies of brain connectivity. PMID- 25532169 TI - Geodesic Atlas-Based Labeling of Anatomical Trees: Application and Evaluation on Airways Extracted From CT. AB - We present a fast and robust atlas-based algorithm for labeling airway trees, using geodesic distances in a geometric tree-space. Possible branch label configurations for an unlabeled airway tree are evaluated using distances to a training set of labeled airway trees. In tree-space, airway tree topology and geometry change continuously, giving a natural automatic handling of anatomical differences and noise. A hierarchical approach makes the algorithm efficient, assigning labels from the trachea and downwards. Only the airway centerline tree is used, which is relatively unaffected by pathology. The algorithm is evaluated on 80 segmented airway trees from 40 subjects at two time points, labeled by three medical experts each, testing accuracy, reproducibility and robustness in patients with chronic obstructive pulmonary disease (COPD). The accuracy of the algorithm is statistically similar to that of the experts and not significantly correlated with COPD severity. The reproducibility of the algorithm is significantly better than that of the experts, and negatively correlated with COPD severity. Evaluation of the algorithm on a longitudinal set of 8724 trees from a lung cancer screening trial shows that the algorithm can be used in large scale studies with high reproducibility, and that the negative correlation of reproducibility with COPD severity can be explained by missing branches, for instance due to segmentation problems in COPD patients. We conclude that the algorithm is robust to COPD severity given equally complete airway trees, and comparable in performance to that of experts in pulmonary medicine, emphasizing the suitability of the labeling algorithm for clinical use. PMID- 25532170 TI - Sparse-view spectral CT reconstruction using spectral patch-based low-rank penalty. AB - Spectral computed tomography (CT) is a promising technique with the potential for improving lesion detection, tissue characterization, and material decomposition. In this paper, we are interested in kVp switching-based spectral CT that alternates distinct kVp X-ray transmissions during gantry rotation. This system can acquire multiple X-ray energy transmissions without additional radiation dose. However, only sparse views are generated for each spectral measurement; and the spectra themselves are limited in number. To address these limitations, we propose a penalized maximum likelihood method using spectral patch-based low-rank penalty, which exploits the self-similarity of patches that are collected at the same position in spectral images. The main advantage is that the relatively small number of materials within each patch allows us to employ the low-rank penalty that is less sensitive to intensity changes while preserving edge directions. In our optimization formulation, the cost function consists of the Poisson log likelihood for X-ray transmission and the nonconvex patch-based low-rank penalty. Since the original cost function is difficult to minimize directly, we propose an optimization method using separable quadratic surrogate and concave convex procedure algorithms for the log-likelihood and penalty terms, which results in an alternating minimization that provides a computational advantage because each subproblem can be solved independently. We performed computer simulations and a real experiment using a kVp switching-based spectral CT with sparse-view measurements, and compared the proposed method with conventional algorithms. We confirmed that the proposed method improves spectral images both qualitatively and quantitatively. Furthermore, our GPU implementation significantly reduces the computational cost. PMID- 25532171 TI - Temporal Hierarchical Adaptive Texture CRF for Automatic Detection of Gadolinium Enhancing Multiple Sclerosis Lesions in Brain MRI. AB - We propose a conditional random field (CRF) based classifier for segmentation of small enhanced pathologies. Specifically, we develop a temporal hierarchical adaptive texture CRF (THAT-CRF) and apply it to the challenging problem of gad enhancing lesion segmentation in brain MRI of patients with multiple sclerosis. In this context, the presence of many nonlesion enhancements (such as blood vessels) renders the problem more difficult. In addition to voxel-wise features, the framework exploits multiple higher order textures to discriminate the true lesional enhancements from the pool of other enhancements. Since lesional enhancements show more variation over time as compared to the nonlesional ones, we incorporate temporal texture analysis in order to study the textures of enhanced candidates over time. The parameters of the THAT-CRF model are learned based on 2380 scans from a multi-center clinical trial. The effect of different components of the model is extensively evaluated on 120 scans from a separate multi-center clinical trial. The incorporation of the temporal textures results in a general decrease of the false discovery rate. Specifically, THAT-CRF achieves overall sensitivity of 95% along with false discovery rate of 20% and average false positive count of 0.5 lesions per scan. The sensitivity of the temporal method to the trained time interval is further investigated on five different intervals of 69 patients. Moreover, superior performance is achieved by the reviewed labelings of our model compared to the fully manual labeling when applied to the context of separating different treatment arms in a real clinical trial. PMID- 25532172 TI - A Small Surrogate for the Golden Angle in Time-Resolved Radial MRI Based on Generalized Fibonacci Sequences. AB - In golden angle radial magnetic resonance imaging a constant azimuthal radial profile spacing of 111.246...( degrees ) guarantees a nearly uniform azimuthal profile distribution in k-space for an arbitrary number of radial profiles. Even though this profile order is advantageous for various real-time imaging methods, in combination with balanced steady-state free precession (SSFP) sequences the large azimuthal angle increment may lead to strong image artifacts, due to the varying eddy currents introduced by the rapidly switching gradient scheme. Based on a generalized Fibonacci sequence, a new sequence of smaller irrational angles is introduced ( 49.750...( degrees ), 32.039...( degrees ), 27.198...( degrees ), 23.628...( degrees ), ... ). The subsequent profile orders guarantee the same sampling efficiency as the golden angle if at least a minimum number of radial profiles is used for reconstruction. The suggested angular increments are applied for dynamic imaging of the heart and the temporomandibular joint. It is shown that for balanced SSFP sequences, trajectories using the smaller golden angle surrogates strongly reduce the image artifacts, while the free retrospective choice of the reconstruction window width is maintained. PMID- 25532173 TI - Hippocampal Shape Modeling Based on a Progressive Template Surface Deformation and its Verification. AB - Accurately recovering the hippocampal shapes against rough and noisy segmentations is as challenging as achieving good anatomical correspondence between the individual shapes. To address these issues, we propose a mesh-to volume registration approach, characterized by a progressive model deformation. Our model implements flexible weighting scheme for model rigidity under a multi level neighborhood for vertex connectivity. This method induces a large-to-small scale deformation of a template surface to build the pairwise correspondence by minimizing geometric distortion while robustly restoring the individuals' shape characteristics. We evaluated the proposed method's (1) accuracy and robustness in smooth surface reconstruction, (2) sensitivity in detecting significant shape differences between healthy control and disease groups (mild cognitive impairment and Alzheimer's disease), (3) robustness in constructing the anatomical correspondence between individual shape models, and (4) applicability in identifying subtle shape changes in relation to cognitive abilities in a healthy population. We compared the performance of the proposed method with other well known methods--SPHARM-PDM, ShapeWorks and LDDMM volume registration with template injection--using various metrics of shape similarity, surface roughness, volume, and shape deformity. The experimental results showed that the proposed method generated smooth surfaces with less volume differences and better shape similarity to input volumes than others. The statistical analyses with clinical variables also showed that it was sensitive in detecting subtle shape changes of hippocampus. PMID- 25532174 TI - Combining left and right palmprint images for more accurate personal identification. AB - Multibiometrics can provide higher identification accuracy than single biometrics, so it is more suitable for some real-world personal identification applications that need high-standard security. Among various biometrics technologies, palmprint identification has received much attention because of its good performance. Combining the left and right palmprint images to perform multibiometrics is easy to implement and can obtain better results. However, previous studies did not explore this issue in depth. In this paper, we proposed a novel framework to perform multibiometrics by comprehensively combining the left and right palmprint images. This framework integrated three kinds of scores generated from the left and right palmprint images to perform matching score level fusion. The first two kinds of scores were, respectively, generated from the left and right palmprint images and can be obtained by any palmprint identification method, whereas the third kind of score was obtained using a specialized algorithm proposed in this paper. As the proposed algorithm carefully takes the nature of the left and right palmprint images into account, it can properly exploit the similarity of the left and right palmprints of the same subject. Moreover, the proposed weighted fusion scheme allowed perfect identification performance to be obtained in comparison with previous palmprint identification methods. PMID- 25532175 TI - Generalized assorted camera arrays: robust cross-channel registration and applications. AB - One popular technique for multimodal imaging is generalized assorted pixels (GAP), where an assorted pixel array on the image sensor allows for multimodal capture. Unfortunately, GAP is limited in its applicability because of the need for multimodal filters that are amenable with semiconductor fabrication processes and results in a fixed multimodal imaging configuration. In this paper, we advocate for generalized assorted camera (GAC) arrays for multimodal imaging- i.e., a camera array with filters of different characteristics placed in front of each camera aperture. The GAC provides us with three distinct advantages over GAP: ease of implementation, flexible application-dependent imaging since filters are external and can be changed and depth information that can be used for enabling novel applications (e.g., postcapture refocusing). The primary challenge in GAC arrays is that since the different modalities are obtained from different viewpoints, there is a need for accurate and efficient cross-channel registration. Traditional approaches such as sum-of-squared differences, sum-of absolute differences, and mutual information all result in multimodal registration errors. Here, we propose a robust cross-channel matching cost function, based on aligning normalized gradients, which allows us to compute cross-channel subpixel correspondences for scenes exhibiting nontrivial geometry. We highlight the promise of GAC arrays with our cross-channel normalized gradient cost for several applications such as low-light imaging, postcapture refocusing, skin perfusion imaging using color + near infrared, and hyperspectral imaging. PMID- 25532176 TI - Symmetric smoothing filters from global consistency constraints. AB - Many patch-based image denoising methods can be viewed as data-dependent smoothing filters that carry out a weighted averaging of similar pixels. It has recently been argued that these averaging filters can be improved using their doubly stochastic approximation, which are symmetric and stable smoothing operators. In this paper, we introduce a simple principle of consistency that argues that the relative similarities between pixels as imputed by the averaging matrix should be preserved in the filtered output. The resultant consistency filter has the theoretically desirable properties of being symmetric and stable, and is a generalized doubly stochastic matrix. In addition, we can also interpret our consistency filter as a specific form of Laplacian regularization. Thus, our approach unifies two strands of image denoising methods, i.e., symmetric smoothing filters and spectral graph theory. Our consistency filter provides high quality image denoising and significantly outperforms the doubly stochastic version. We present a thorough analysis of the properties of our proposed consistency filter and compare its performance with that of other significant methods for image denoising in the literature. PMID- 25532177 TI - Exploiting information geometry to improve the convergence of nonparametric active contours. AB - This paper presents a fast converging Riemannian steepest descent method for nonparametric statistical active contour models, with application to image segmentation. Unlike other fast algorithms, the proposed method is general and can be applied to any statistical active contour model from the exponential family, which comprises most of the models considered in the literature. This is achieved by first identifying the intrinsic statistical manifold associated with this class of active contours, and then constructing a steepest descent on that manifold. A key contribution of this paper is to derive a general and tractable closed-form analytic expression for the manifold's Riemannian metric tensor, which allows computing discrete gradient flows efficiently. The proposed methodology is demonstrated empirically and compared with other state of the art approaches on several standard test images, a phantom positron-emission tomography scan and a B-mode echography of in-vivo human dermis. PMID- 25532178 TI - What is a salient object? A dataset and a baseline model for salient object detection. AB - Salient object detection or salient region detection models, diverging from fixation prediction models, have traditionally been dealing with locating and segmenting the most salient object or region in a scene. While the notion of most salient object is sensible when multiple objects exist in a scene, current datasets for evaluation of saliency detection approaches often have scenes with only one single object. We introduce three main contributions in this paper. First, we take an in-depth look at the problem of salient object detection by studying the relationship between where people look in scenes and what they choose as the most salient object when they are explicitly asked. Based on the agreement between fixations and saliency judgments, we then suggest that the most salient object is the one that attracts the highest fraction of fixations. Second, we provide two new less biased benchmark data sets containing scenes with multiple objects that challenge existing saliency models. Indeed, we observed a severe drop in performance of eight state-of-the-art models on our data sets (40% 70%). Third, we propose a very simple yet powerful model based on superpixels to be used as a baseline for model evaluation and comparison. While on par with the best models on MSRA-5 K data set, our model wins over other models on our data highlighting a serious drawback of existing models, which is convoluting the processes of locating the most salient object and its segmentation. We also provide a review and statistical analysis of some labeled scene data sets that can be used for evaluating salient object detection models. We believe that our work can greatly help remedy the over-fitting of models to existing biased data sets and opens new venues for future research in this fast-evolving field. PMID- 25532179 TI - Efficient variational Bayesian approximation method based on subspace optimization. AB - Variational Bayesian approximations have been widely used in fully Bayesian inference for approximating an intractable posterior distribution by a separable one. Nevertheless, the classical variational Bayesian approximation (VBA) method suffers from slow convergence to the approximate solution when tackling large dimensional problems. To address this problem, we propose in this paper a more efficient VBA method. Actually, variational Bayesian issue can be seen as a functional optimization problem. The proposed method is based on the adaptation of subspace optimization methods in Hilbert spaces to the involved function space, in order to solve this optimization problem in an iterative way. The aim is to determine an optimal direction at each iteration in order to get a more efficient method. We highlight the efficiency of our new VBA method and demonstrate its application to image processing by considering an ill-posed linear inverse problem using a total variation prior. Comparisons with state of the art variational Bayesian methods through a numerical example show a notable improvement in computation time. PMID- 25532180 TI - Color-direction patch-sparsity-based image inpainting using multidirection features. AB - This paper proposes a color-direction patch sparsity-based image in painting method to better maintain structure coherence, texture clarity, and neighborhood consistence of the in painted region of an image. The method uses super-wavelet transform to estimate the multi-direction features of a degraded image, and combines with color information to construct the weighted color-direction distance (WCDD) to measure the difference between two patches. Based on the WCDD, the color-direction structure sparsity is defined to obtain a more robust filling order and more suitable multiple candidate patches are searched. Then, the target patches are sparsely represented by the multiple candidate patches under neighborhood consistency constraints in both the color and the multi-direction spaces. Experimental results are presented to demonstrate the effectiveness of the proposed approach on tasks such as scratch removal, text removal, block removal, and object removal. The effects of super-wavelet transforms and direction features are also investigated. PMID- 25532181 TI - The segmentation of 3D images using the random walking technique on a randomly created image adjacency graph. AB - This paper considers the problem of image segmentation using the random walker algorithm. In the case of 3D images, the method uses an extreme amount of memory and time resources. These are required in order to represent the corresponding enormous image graph and to solve the resulting sparse linear system. Having in mind these limitations, this paper proposes techniques for the optimization of the random walker approach. The optimization is obtained by processing supervoxels representing homogeneous image regions rather than single voxels. A fast and efficient method for supervoxel determination is introduced. A method for the creation of an image adjacency graph from an irregular grid of supervoxels is also proposed. The results of applying the introduced approach to segmentation of 3D CT data sets are presented and compared with the results of the original random walker approach and other state-of-the-art methods. The accuracy and the computational overhead is regarded in the comparison. The analysis of results shows that the modified method can be successfully applied for the segmentation of volumetric images and provides results in a reasonable time without a significant loss in the image segmentation accuracy. It also outperforms the state-of-the-art methods considered in the comparison. PMID- 25532182 TI - An efficient DCT-based image compression system based on laplacian transparent composite model. AB - Recently, a new probability model dubbed the Laplacian transparent composite model (LPTCM) was developed for DCT coefficients, which could identify outlier coefficients in addition to providing superior modeling accuracy. In this paper, we aim at exploring its applications to image compression. To this end, we propose an efficient nonpredictive image compression system, where quantization (including both hard-decision quantization (HDQ) and soft-decision quantization (SDQ)) and entropy coding are completely redesigned based on the LPTCM. When tested over standard test images, the proposed system achieves overall coding results that are among the best and similar to those of H.264 or HEVC intra (predictive) coding, in terms of rate versus visual quality. On the other hand, in terms of rate versus objective quality, it significantly outperforms baseline JPEG by more than 4.3 dB in PSNR on average, with a moderate increase on complexity, and ECEB, the state-of-the-art nonpredictive image coding, by 0.75 dB when SDQ is OFF (i.e., HDQ case), with the same level of computational complexity, and by 1 dB when SDQ is ON, at the cost of slight increase in complexity. In comparison with H.264 intracoding, our system provides an overall 0.4-dB gain or so, with dramatically reduced computational complexity; in comparison with HEVC intracoding, it offers comparable coding performance in the high-rate region or for complicated images, but with only less than 5% of the HEVC intracoding complexity. In addition, our proposed system also offers multiresolution capability, which, together with its comparatively high coding efficiency and low complexity, makes it a good alternative for real-time image processing applications. PMID- 25532183 TI - Fine-tuning regression forests votes for object alignment in the wild. AB - In this paper, we propose a object alignment method that detects the landmarks of an object in 2D images. In the regression forests (RFs) framework, observations (patches) that are extracted at several image locations cast votes for the localization of several landmarks. We propose to refine the votes before accumulating them into the Hough space, by sieving and/or aggregating. In order to filter out false positive votes, we pass them through several sieves, each associated with a discrete or continuous latent variable. The sieves filter out votes that are not consistent with the latent variable in question, something that implicitly enforces global constraints. In order to aggregate the votes when necessary, we adjusts on-the-fly a proximity threshold by applying a classifier on middle-level features extracted from voting maps for the object landmark in question. Moreover, our method is able to predict the unreliability of an individual object landmark. This information can be useful for subsequent object analysis like object recognition. Our contributions are validated for two object alignment tasks, face alignment and car alignment, on data sets with challenging images collected in the wild, i.e., the Labeled Face in the Wild, the Annotated Facial Landmarks in the Wild, and the street scene car data set. We show that with the proposed approach, and without explicitly introducing shape models, we obtain performance superior or close to the state of the art for both tasks. PMID- 25532184 TI - A probabilistic approach to online eye gaze tracking without explicit personal calibration. AB - Existing eye gaze tracking systems typically require an explicit personal calibration process in order to estimate certain person-specific eye parameters. For natural human computer interaction, such a personal calibration is often inconvenient and unnatural. In this paper, we propose a new probabilistic eye gaze tracking system without explicit personal calibration. Unlike the conventional eye gaze tracking methods, which estimate the eye parameter deterministically using known gaze points, our approach estimates the probability distributions of the eye parameter and eye gaze. Using an incremental learning framework, the subject does not need personal calibration before using the system. His/her eye parameter estimation and gaze estimation can be improved gradually when he/she is naturally interacting with the system. The experimental result shows that the proposed system can achieve <3 degrees accuracy for different people without explicit personal calibration. PMID- 25532185 TI - 3D visual discomfort predictor: analysis of horizontal disparity and neural activity statistics. AB - Being able to predict the degree of visual discomfort that is felt when viewing stereoscopic 3D (S3D) images is an important goal toward ameliorating causative factors, such as excessive horizontal disparity, misalignments or mismatches between the left and right views of stereo pairs, or conflicts between different depth cues. Ideally, such a model should account for such factors as capture and viewing geometries, the distribution of disparities, and the responses of visual neurons. When viewing modern 3D displays, visual discomfort is caused primarily by changes in binocular vergence while accommodation in held fixed at the viewing distance to a flat 3D screen. This results in unnatural mismatches between ocular fixations and ocular focus that does not occur in normal direct 3D viewing. This accommodation vergence conflict can cause adverse effects, such as headaches, fatigue, eye strain, and reduced visual ability. Binocular vision is ultimately realized by means of neural mechanisms that subserve the sensorimotor control of eye movements. Realizing that the neuronal responses are directly implicated in both the control and experience of 3D perception, we have developed a model-based neuronal and statistical framework called the 3D visual discomfort predictor (3D VDP)that automatically predicts the level of visual discomfort that is experienced when viewing S3D images. 3D-VDP extracts two types of features: 1) coarse features derived from the statistics of binocular disparities and 2) fine features derived by estimating the neural activity associated with the processing of horizontal disparities. In particular, we deploy a model of horizontal disparity processing in the extrastriate middle temporal region of occipital lobe. We compare the performance of 3D-VDP with other recent discomfort prediction algorithms with respect to correlation against recorded subjective visual discomfort scores,and show that 3D-VDP is statistically superior to the other methods. PMID- 25532186 TI - Analysis and Prediction of the Freezing of Gait Using EEG Brain Dynamics. AB - Freezing of Gait (FOG) is a common symptom in the advanced stages of Parkinson's disease (PD), which significantly affects patients' quality of life. Treatment options offer limited benefit and there are currently no mechanisms able to effectively detect FOG before it occurs, allowing time for a sufferer to avert a freezing episode. Electroencephalography (EEG) offers a novel technique that may be able to address this problem. In this paper, we investigated the univariate and multivariate EEG features determined by both Fourier and wavelet analysis in the confirmation and prediction of FOG. The EEG power measures and network properties from 16 patients with PD and FOG were extracted and analyzed. It was found that both power spectral density and wavelet energy could potentially act as biomarkers during FOG. Information in the frequency domain of the EEG was found to provide better discrimination of EEG signals during transition to freezing than information coded in the time domain. The performance of the FOG prediction systems improved when the information from both domains was used. This combination resulted in a sensitivity of 86.0%, specificity of 74.4%, and accuracy of 80.2% when predicting episodes of freezing, outperforming current accelerometry-based tools for the prediction of FOG. PMID- 25532187 TI - Spatial Map of Synthesized Criteria for the Redundancy Resolution of Human Arm Movements. AB - The kinematic redundancy of the human arm enables the elbow position to rotate about the axis going through the shoulder and wrist, which results in infinite possible arm postures when the arm reaches to a target in a 3-D workspace. To infer the control strategy the human motor system uses to resolve redundancy in reaching movements, this paper compares five redundancy resolution criteria and evaluates their arm posture prediction performance using data on healthy human motion. Two synthesized criteria are developed to provide better real-time arm posture prediction than the five individual criteria. Of these two, the criterion synthesized using an exponential method predicts the arm posture more accurately than that using a least squares approach, and therefore is preferable for inferring the contributions of the individual criteria to motor control during reaching movements. As a methodology contribution, this paper proposes a framework to compare and evaluate redundancy resolution criteria for arm motion control. A cluster analysis which associates criterion contributions with regions of the workspace provides a guideline for designing a real-time motion control system applicable to upper-limb exoskeletons for stroke rehabilitation. PMID- 25532188 TI - Robust Automated Step Extraction From Time-Series Contact Force Data Using the PDShoe. AB - This paper presents a method of stride identification, extraction, and analysis of data sets of time-series contact force data for ambulating subjects both with and without Parkinson's disease (PD). This method has been made robust with the use of seeded K-Means clustering, fast Fourier transformation (FFT) spectral analysis, and minimum window size rejection. These methods combine to produce well selected strides of active walking data. We are able to calculate quality of walking measures of stride duration, stance duration (as percent of gait cycle - %GC), swing duration (%GC), time to maximum heel force (%GC), time to maximum toe force (%GC), time spent in heel contact (%GC), and time spent in toe contact (%GC). PMID- 25532189 TI - Low-Power CMOS Laser Doppler Imaging Using Non-CDS Pixel Readout and 13.6-bit SAR ADC. AB - Laser Doppler imaging (LDI) measures particle flows such as blood perfusion by sensing their Doppler shift. This paper is the first of its kind in analyzing the effect of circuit noise on LDI precision which is distinctively different from conventional imaging. Based on this result, it presents a non-correlated-double sampling (non-CDS) pixel readout scheme along with a high-resolution successive approximation-register (SAR) analog-to-digital-converter (ADC) with 13.6b effective resolution (ER). Measurement results from the prototype chip in 0.18 MUm technology confirm the theoretical analysis and show that the two techniques improve LDI sensing precision by 6.9 dB and 4.4 dB (compared to a 10b ADC) respectively without analog pre-amplification. The sensor's ADC occupies 518 MUm*84 MUm and is suitable for fast column parallel readout. Its differential non linearity (DNL), integral non-linearity (INL), and input referred noise are +3.0/ 2.8 LSB, +24/-17 LSB, and 110 MUVrms respectively, leading to a Figure-of-Merit (FoM) of 23 fJ/state which makes it one of the most energy efficient image sensor ADCs and an order of magnitude better than the best reported LDI system using commercial high-speed image sensors. PMID- 25532190 TI - A kinesthetic washout filter for force-feedback rendering. AB - Today haptic feedback can be designed and associated to audiovisual content (haptic-audiovisuals or HAV). Although there are multiple means to create individual haptic effects, the issue of how to properly adapt such effects on force-feedback devices has not been addressed and is mostly a manual endeavor. We propose a new approach for the haptic rendering of HAV, based on a washout filter for force-feedback devices. A body model and an inverse kinematics algorithm simulate the user's kinesthetic perception. Then, the haptic rendering is adapted in order to handle transitions between haptic effects and to optimize the amplitude of effects regarding the device capabilities. Results of a user study show that this new haptic rendering can successfully improve the HAV experience. PMID- 25532191 TI - Incorporating Wind Power Forecast Uncertainties Into Stochastic Unit Commitment Using Neural Network-Based Prediction Intervals. AB - Penetration of renewable energy resources, such as wind and solar power, into power systems significantly increases the uncertainties on system operation, stability, and reliability in smart grids. In this paper, the nonparametric neural network-based prediction intervals (PIs) are implemented for forecast uncertainty quantification. Instead of a single level PI, wind power forecast uncertainties are represented in a list of PIs. These PIs are then decomposed into quantiles of wind power. A new scenario generation method is proposed to handle wind power forecast uncertainties. For each hour, an empirical cumulative distribution function (ECDF) is fitted to these quantile points. The Monte Carlo simulation method is used to generate scenarios from the ECDF. Then the wind power scenarios are incorporated into a stochastic security-constrained unit commitment (SCUC) model. The heuristic genetic algorithm is utilized to solve the stochastic SCUC problem. Five deterministic and four stochastic case studies incorporated with interval forecasts of wind power are implemented. The results of these cases are presented and discussed together. Generation costs, and the scheduled and real-time economic dispatch reserves of different unit commitment strategies are compared. The experimental results show that the stochastic model is more robust than deterministic ones and, thus, decreases the risk in system operations of smart grids. PMID- 25532192 TI - Fick's Law Assisted Propagation for Semisupervised Learning. AB - How to propagate the label information from labeled examples to unlabeled examples is a critical problem for graph-based semisupervised learning. Many label propagation algorithms have been developed in recent years and have obtained promising performance on various applications. However, the eigenvalues of iteration matrices in these algorithms are usually distributed irregularly, which slow down the convergence rate and impair the learning performance. This paper proposes a novel label propagation method called Fick's law assisted propagation (FLAP). Unlike the existing algorithms that are directly derived from statistical learning, FLAP is deduced on the basis of the theory of Fick's First Law of Diffusion, which is widely known as the fundamental theory in fluid spreading. We prove that FLAP will converge with linear rate and show that FLAP makes eigenvalues of the iteration matrix distributed regularly. Comprehensive experimental evaluations on synthetic and practical datasets reveal that FLAP obtains encouraging results in terms of both accuracy and efficiency. PMID- 25532193 TI - Group Factor Analysis. AB - Factor analysis (FA) provides linear factors that describe the relationships between individual variables of a data set. We extend this classical formulation into linear factors that describe the relationships between groups of variables, where each group represents either a set of related variables or a data set. The model also naturally extends canonical correlation analysis to more than two sets, in a way that is more flexible than previous extensions. Our solution is formulated as a variational inference of a latent variable model with structural sparsity, and it consists of two hierarchical levels: 1) the higher level models the relationships between the groups and 2) the lower models the observed variables given the higher level. We show that the resulting solution solves the group factor analysis (GFA) problem accurately, outperforming alternative FA based solutions as well as more straightforward implementations of GFA. The method is demonstrated on two life science data sets, one on brain activation and the other on systems biology, illustrating its applicability to the analysis of different types of high-dimensional data sources. PMID- 25532194 TI - A Distributed Approach Toward Discriminative Distance Metric Learning. AB - Distance metric learning (DML) is successful in discovering intrinsic relations in data. However, most algorithms are computationally demanding when the problem size becomes large. In this paper, we propose a discriminative metric learning algorithm, develop a distributed scheme learning metrics on moderate-sized subsets of data, and aggregate the results into a global solution. The technique leverages the power of parallel computation. The algorithm of the aggregated DML (ADML) scales well with the data size and can be controlled by the partition. We theoretically analyze and provide bounds for the error induced by the distributed treatment. We have conducted experimental evaluation of the ADML, both on specially designed tests and on practical image annotation tasks. Those tests have shown that the ADML achieves the state-of-the-art performance at only a fraction of the cost incurred by most existing methods. PMID- 25532195 TI - Comparison of l1-Norm SVR and Sparse Coding Algorithms for Linear Regression. AB - Support vector regression (SVR) is a popular function estimation technique based on Vapnik's concept of support vector machine. Among many variants, the l1-norm SVR is known to be good at selecting useful features when the features are redundant. Sparse coding (SC) is a technique widely used in many areas and a number of efficient algorithms are available. Both l1-norm SVR and SC can be used for linear regression. In this brief, the close connection between the l1-norm SVR and SC is revealed and some typical algorithms are compared for linear regression. The results show that the SC algorithms outperform the Newton linear programming algorithm, an efficient l1-norm SVR algorithm, in efficiency. The algorithms are then used to design the radial basis function (RBF) neural networks. Experiments on some benchmark data sets demonstrate the high efficiency of the SC algorithms. In particular, one of the SC algorithms, the orthogonal matching pursuit is two orders of magnitude faster than a well-known RBF network designing algorithm, the orthogonal least squares algorithm. PMID- 25532196 TI - Reduced Daily Recalibration of Myoelectric Prosthesis Classifiers Based on Domain Adaptation. AB - Control scheme design based on surface electromyography (sEMG) pattern recognition has been the focus of much research on a myoelectric prosthesis (MP) technology. Due to inherent nonstationarity in sEMG signals, prosthesis systems may need to be recalibrated day after day in daily use applications; thereby, hindering MP usability. In order to reduce the recalibration time in the subsequent days following the initial training, we propose a domain adaptation (DA) framework, which automatically reuses the models trained in earlier days as input for two baseline classifiers: a polynomial classifier (PC) and a linear discriminant analysis (LDA). Two novel algorithms of DA are introduced, one for PC and the other one for LDA. Five intact-limbed subjects and two transradial amputee subjects participated in an experiment lasting ten days, to simulate the application of a MP over multiple days. The experiment results of four methods were compared: PC-DA (PC with DA), PC-BL (baseline PC), LDA-DA (LDA with DA), and LDA-BL (baseline LDA). In a new day, the DA methods reuse nine pretrained models, which were calibrated by 40 s training data per class in nine previous days. We show that the proposed DA methods significantly outperform nonadaptive baseline methods. The improvement in classification accuracy ranges from 5.49% to 28.48%, when the recording time per class is 2 s. For example, the average classification rates of PC-BL and PC-DA are 83.70% and 92.99%, respectively, for intact-limbed subjects with a nine-motions classification task. These results indicate that DA has the potential to improve the usability of MPs based on pattern recognition, by reducing the calibration time. PMID- 25532198 TI - Exploiting Semantic Web Technologies to Develop OWL-Based Clinical Practice Guideline Execution Engines. AB - Computerizing paper-based CPG and then executing them can provide evidence informed decision support to physicians at the point of care. Semantic web technologies especially web ontology language (OWL) ontologies have been profusely used to represent computerized CPG. Using semantic web reasoning capabilities to execute OWL-based computerized CPG unties them from a specific custom-built CPG execution engine and increases their shareability as any OWL reasoner and triple store can be utilized for CPG execution. However, existing semantic web reasoning-based CPG execution engines suffer from lack of ability to execute CPG with high levels of expressivity, high cognitive load of computerization of paper-based CPG and updating their computerized versions. In order to address these limitations, we have developed three CPG execution engines based on OWL 1 DL, OWL 2 DL and OWL 2 DL + semantic web rule language (SWRL). OWL 1 DL serves as the base execution engine capable of executing a wide range of CPG constructs, however for executing highly complex CPG the OWL 2 DL and OWL 2 DL + SWRL offer additional executional capabilities. We evaluated the technical performance and medical correctness of our execution engines using a range of CPG. Technical evaluations show the efficiency of our CPG execution engines in terms of CPU time and validity of the generated recommendation in comparison to existing CPG execution engines. Medical evaluations by domain experts show the validity of the CPG-mediated therapy plans in terms of relevance, safety, and ordering for a wide range of patient scenarios. PMID- 25532197 TI - A Virtual Reality System for PTCD Simulation Using Direct Visuo-Haptic Rendering of Partially Segmented Image Data. AB - This study presents a new visuo-haptic virtual reality (VR) training and planning system for percutaneous transhepatic cholangio-drainage (PTCD) based on partially segmented virtual patient models. We only use partially segmented image data instead of a full segmentation and circumvent the necessity of surface or volume mesh models. Haptic interaction with the virtual patient during virtual palpation, ultrasound probing and needle insertion is provided. Furthermore, the VR simulator includes X-ray and ultrasound simulation for image-guided training. The visualization techniques are GPU-accelerated by implementation in Cuda and include real-time volume deformations computed on the grid of the image data. Computation on the image grid enables straightforward integration of the deformed image data into the visualization components. To provide shorter rendering times, the performance of the volume deformation algorithm is improved by a multigrid approach. To evaluate the VR training system, a user evaluation has been performed and deformation algorithms are analyzed in terms of convergence speed with respect to a fully converged solution. The user evaluation shows positive results with increased user confidence after a training session. It is shown that using partially segmented patient data and direct volume rendering is suitable for the simulation of needle insertion procedures such as PTCD. PMID- 25532199 TI - Intelligent deflection routing in buffer-less networks. AB - Deflection routing is employed to ameliorate packet loss caused by contention in buffer-less architectures such as optical burst-switched networks. The main goal of deflection routing is to successfully deflect a packet based only on a limited knowledge that network nodes possess about their environment. In this paper, we present a framework that introduces intelligence to deflection routing (iDef). iDef decouples the design of the signaling infrastructure from the underlying learning algorithm. It consists of a signaling and a decision-making module. Signaling module implements a feedback management protocol while the decision making module implements a reinforcement learning algorithm. We also propose several learning-based deflection routing protocols, implement them in iDef using the ns-3 network simulator, and compare their performance. PMID- 25532200 TI - Node Topology Effect on Target Tracking Based on UWSNs Using Quantized Measurements. AB - On one hand, due to the energy and bandwidth constraint of underwater wireless sensor networks (UWSNs), local data quantization/compression is not only a necessity, but also an integral part of the design of UWSNs; on the other hand, since underwater nodes provide measurements for target tracking based on UWSNs, node topology, which is made up of the underwater nodes, may affect the performance of target tracking. This paper studies the effect of node topology on the target tracking in UWSNs using quantized measurements. Firstly, by using the knowledge of geometry, the effects of four typical topologies on target tracking using quantized measurements are analyzed qualitatively. The four typical topologies include two nodes are close to each other, three nodes are close to each other, three nodes are co-linear, and three nodes form a regular triangle. Secondly, under the condition of quantized measurements, the relationship between the posterior Cramer-Rao lower bound (PCRLB) and node's position is derived to evaluate the arbitrary topology. Thirdly, our target tracking scheme consisting of the optimal topology selection scheme by minimizing PCRLB, the optimal fusion center selection scheme by minimizing energy consumption, and the multisensor particle filter with quantized measurements is designed. Last, simulation results show the effectiveness of the proposed scheme. PMID- 25532201 TI - Multilayer Joint Gait-Pose Manifolds for Human Gait Motion Modeling. AB - We present new multilayer joint gait-pose manifolds (multilayer JGPMs) for complex human gait motion modeling, where three latent variables are defined jointly in a low-dimensional manifold to represent a variety of body configurations. Specifically, the pose variable (along the pose manifold) denotes a specific stage in a walking cycle; the gait variable (along the gait manifold) represents different walking styles; and the linear scale variable characterizes the maximum stride in a walking cycle. We discuss two kinds of topological priors for coupling the pose and gait manifolds, i.e., cylindrical and toroidal, to examine their effectiveness and suitability for motion modeling. We resort to a topologically-constrained Gaussian process (GP) latent variable model to learn the multilayer JGPMs where two new techniques are introduced to facilitate model learning under limited training data. First is training data diversification that creates a set of simulated motion data with different strides. Second is the topology-aware local learning to speed up model learning by taking advantage of the local topological structure. The experimental results on the Carnegie Mellon University motion capture data demonstrate the advantages of our proposed multilayer models over several existing GP-based motion models in terms of the overall performance of human gait motion modeling. PMID- 25532202 TI - Energy Efficient Execution of POMDP Policies. AB - Recent advances in planning techniques for partially observable Markov decision processes (POMDPs) have focused on online search techniques and offline point based value iteration. While these techniques allow practitioners to obtain policies for fairly large problems, they assume that a nonnegligible amount of computation can be done between each decision point. In contrast, the recent proliferation of mobile and embedded devices has lead to a surge of applications that could benefit from state-of-the-art planning techniques if they can operate under severe constraints on computational resources. To that effect, we describe two techniques to compile policies into controllers that can be executed by a mere table lookup at each decision point. The first approach compiles policies induced by a set of alpha vectors (such as those obtained by point-based techniques) into approximately equivalent controllers, while the second approach performs a simulation to compile arbitrary policies into approximately equivalent controllers. We also describe an approach to compress controllers by removing redundant and dominated nodes, often yielding smaller and yet better controllers. Further compression and higher value can sometimes be obtained by considering stochastic controllers. The compilation and compression techniques are demonstrated on benchmark problems as well as a mobile application to help persons with Alzheimer's to way-find. The battery consumption of several POMDP policies is compared against finite-state controllers learned using methods introduced in this paper. Experiments performed on the Nexus 4 phone show that finite-state controllers are the least battery consuming POMDP policies. PMID- 25532203 TI - A Unified Semi-Supervised Community Detection Framework Using Latent Space Graph Regularization. AB - Community structure is one of the most important properties of complex networks and is a foundational concept in exploring and understanding networks. In real world, topology information alone is often inadequate to accurately find community structure due to its sparsity and noises. However, potential useful prior information can be obtained from domain knowledge in many applications. Thus, how to improve the community detection performance by combining network topology with prior information becomes an interesting and challenging problem. Previous efforts on utilizing such priors are either dedicated or insufficient. In this paper, we firstly present a unified interpretation to a group of existing community detection methods. And then based on this interpretation, we propose a unified semi-supervised framework to integrate network topology with prior information for community detection. If the prior information indicates that some nodes belong to the same community, we encode it by adding a graph regularization term to penalize the latent space dissimilarity of these nodes. This framework can be applied to many widely-used matrix-based community detection methods satisfying our interpretation, such as nonnegative matrix factorization, spectral clustering, and their variants. Extensive experiments on both synthetic and real networks show that the proposed framework significantly improves the accuracy of community detection, especially on networks with unclear structures. PMID- 25532204 TI - Biologically Inspired Visual Model With Preliminary Cognition and Active Attention Adjustment. AB - Recently, many computational models have been proposed to simulate visual cognition process. For example, the hierarchical Max-Pooling (HMAX) model was proposed according to the hierarchical and bottom-up structure of V1 to V4 in the ventral pathway of primate visual cortex, which could achieve position- and scale tolerant recognition. In our previous work, we have introduced memory and association into the HMAX model to simulate visual cognition process. In this paper, we improve our theoretical framework by mimicking a more elaborate structure and function of the primate visual cortex. We will mainly focus on the new formation of memory and association in visual processing under different circumstances as well as preliminary cognition and active adjustment in the inferior temporal cortex, which are absent in the HMAX model. The main contributions of this paper are: 1) in the memory and association part, we apply deep convolutional neural networks to extract various episodic features of the objects since people use different features for object recognition. Moreover, to achieve a fast and robust recognition in the retrieval and association process, different types of features are stored in separated clusters and the feature binding of the same object is stimulated in a loop discharge manner and 2) in the preliminary cognition and active adjustment part, we introduce preliminary cognition to classify different types of objects since distinct neural circuits in a human brain are used for identification of various types of objects. Furthermore, active cognition adjustment of occlusion and orientation is implemented to the model to mimic the top-down effect in human cognition process. Finally, our model is evaluated on two face databases CAS-PEAL-R1 and AR. The results demonstrate that our model exhibits its efficiency on visual recognition process with much lower memory storage requirement and a better performance compared with the traditional purely computational methods. PMID- 25532205 TI - Multi-Center MRI Carotid Plaque Component Segmentation Using Feature Normalization and Transfer Learning. AB - Automated segmentation of plaque components in carotid artery magnetic resonance imaging (MRI) is important to enable large studies on plaque vulnerability, and for incorporating plaque composition as an imaging biomarker in clinical practice. Especially supervised classification techniques, which learn from labeled examples, have shown good performance. However, a disadvantage of supervised methods is their reduced performance on data different from the training data, for example on images acquired with different scanners. Reducing the amount of manual annotations required for each new dataset will facilitate widespread implementation of supervised methods. In this paper we segment carotid plaque components of clinical interest (fibrous tissue, lipid tissue, calcification and intraplaque hemorrhage) in a multi-center MRI study. We perform voxelwise tissue classification by traditional same-center training, and compare results with two approaches that use little or no annotated same-center data. These approaches additionally use an annotated set of different-center data. We evaluate 1) a nonlinear feature normalization approach, and 2) two transfer learning algorithms that use same and different-center data with different weights. Results showed that the best results were obtained for a combination of feature normalization and transfer learning. While for the other approaches significant differences in voxelwise or mean volume errors were found compared with the reference same-center training, the proposed approach did not yield significant differences from that reference. We conclude that both extensive feature normalization and transfer learning can be valuable for the development of supervised methods that perform well on different types of datasets. PMID- 25532206 TI - Modeling the subjective quality of highly contrasted videos displayed on LCD with local backlight dimming. AB - Local backlight dimming is a technology aiming at both saving energy and improving visual quality on television sets. As the rendition of the image is specified locally, the numerical signal corresponding to the displayed image needs to be computed through a model of the display. This simulated signal can then be used as input to objective quality metrics. The focus of this paper is on determining which characteristics of locally backlit displays influence quality assessment. A subjective experiment assessing the quality of highly contrasted videos displayed with various local backlight-dimming algorithms is set up. Subjective results are then compared with both objective measures and objective quality metrics using different display models. The first analysis indicates that the most significant objective features are temporal variations, power consumption (probably representing leakage), and a contrast measure. The second analysis shows that modeling of leakage is necessary for objective quality assessment of sequences displayed with local backlight dimming. PMID- 25532207 TI - A methodology for visually lossless JPEG2000 compression of monochrome stereo images. AB - A methodology for visually lossless compression of monochrome stereoscopic 3D images is proposed. Visibility thresholds are measured for quantization distortion in JPEG2000. These thresholds are found to be functions of not only spatial frequency, but also of wavelet coefficient variance, as well as the gray level in both the left and right images. To avoid a daunting number of measurements during subjective experiments, a model for visibility thresholds is developed. The left image and right image of a stereo pair are then compressed jointly using the visibility thresholds obtained from the proposed model to ensure that quantization errors in each image are imperceptible to both eyes. This methodology is then demonstrated via a particular 3D stereoscopic display system with an associated viewing condition. The resulting images are visually lossless when displayed individually as 2D images, and also when displayed in stereoscopic 3D mode. PMID- 25532208 TI - A Nonlinear Model for Mouse Pointing Task Movement Time Analysis Based on Both System and Human Effects. AB - This paper provides a detailed model for analyzing movement time performance during rapid goal-directed point- and-click motions with a computer mouse. Twelve typically developed individuals and eleven youths with cerebral palsy conducted point and click computer tasks from which the model was developed. The proposed model is nonlinear and based on both system (target width and movement amplitude) and human effects (erroneous clicks, number of submovements, number of slip-offs, curvature index, and average speed). To ensure successful targeting by youths with cerebral palsy, the index of difficulty was limited to a range of 1.58 - 3.0 bits. For consistency, the same range was used with both groups. The most significant contributing human effect to movement time was found to be the curvature index for both typically developed individuals and individuals with cerebral palsy. This model will assist in algorithm development to improve cursor speed and accuracy for youths with cerebral palsy. PMID- 25532209 TI - An analog-digital hybrid RX beamformer chip with non-uniform sampling for ultrasound medical imaging with 2D CMUT array. AB - To reduce the memory area, a two-stage RX beamformer (BF) chip with 64 channels is proposed for the ultrasound medical imaging with a 2D CMUT array. The chip retrieved successfully two B-mode phantom images with a steering angle from -45 ( degrees ) to +45 ( degrees ), the maximum delay range of 8 MUs, and the delay resolution of 6.25 ns. An analog-digital hybrid BF (HBF) is chosen for the proposed chip to utilize the easy beamforming operation in the digital domain and also to reduce chip area by minimizing the number of ADCs. The chip consists of eight analog beamformers (ABF) for the 1st-stage and a digital beamformer (DBF) for the 2nd-stage. The two-stage architecture reduces the memory area of both ABF and DBF by around four times. The DBF circuit is divided into three steps to further reduce the digital FIFO memory area by around twice. Coupled with the non uniform sampling scheme, the proposed two-stage HBF chip reduces the total memory area by around 40 times compared to the uniform-sampling single-stage BF chip. The chip fabricated in a 0.13- MUm CMOS process occupies the area of 19.4 mm(2), and dissipates 1.14 W with the analog supply of 3.3 V and the digital supply of 1.2 V. PMID- 25532210 TI - Recognition of haptic interaction patterns in dyadic joint object manipulation. AB - The development of robots that can physically cooperate with humans has attained interest in the last decades. Obviously, this effort requires a deep understanding of the intrinsic properties of interaction. Up to now, many researchers have focused on inferring human intents in terms of intermediate or terminal goals in physical tasks. On the other hand, working side by side with people, an autonomous robot additionally needs to come up with in-depth information about underlying haptic interaction patterns that are typically encountered during human-human cooperation. However, to our knowledge, no study has yet focused on characterizing such detailed information. In this sense, this work is pioneering as an effort to gain deeper understanding of interaction patterns involving two or more humans in a physical task. We present a labeled human-human-interaction dataset, which captures the interaction of two humans, who collaboratively transport an object in an haptics-enabled virtual environment. In the light of information gained by studying this dataset, we propose that the actions of cooperating partners can be examined under three interaction types: In any cooperative task, the interacting humans either 1) work in harmony, 2) cope with conflicts, or 3) remain passive during interaction. In line with this conception, we present a taxonomy of human interaction patterns; then propose five different feature sets, comprising force-, velocity-and power related information, for the classification of these patterns. Our evaluation shows that using a multi-class support vector machine (SVM) classifier, we can accomplish a correct classification rate of 86 percent for the identification of interaction patterns, an accuracy obtained by fusing a selected set of most informative features by Minimum Redundancy Maximum Relevance (mRMR) feature selection method. PMID- 25532211 TI - Application of Reinforcement Learning Algorithms for the Adaptive Computation of the Smoothing Parameter for Probabilistic Neural Network. AB - In this paper, we propose new methods for the choice and adaptation of the smoothing parameter of the probabilistic neural network (PNN). These methods are based on three reinforcement learning algorithms: Q(0)-learning, Q(lambda) learning, and stateless Q-learning. We regard three types of PNN classifiers: the model that uses single smoothing parameter for the whole network, the model that utilizes single smoothing parameter for each data attribute, and the model that possesses the matrix of smoothing parameters different for each data variable and data class. Reinforcement learning is applied as the method of finding such a value of the smoothing parameter, which ensures the maximization of the prediction ability. PNN models with smoothing parameters computed according to the proposed algorithms are tested on eight databases by calculating the test error with the use of the cross validation procedure. The results are compared with state-of-the-art methods for PNN training published in the literature up to date and, additionally, with PNN whose sigma is determined by means of the conjugate gradient approach. The results demonstrate that the proposed approaches can be used as alternative PNN training procedures. PMID- 25532212 TI - Robust Novelty Detection via Worst Case CVaR Minimization. AB - Novelty detection models aim to find the minimum volume set covering a given probability mass. This paper proposes a robust single-class support vector machine (SSVM) for novelty detection, which is mainly based on the worst case conditional value-at-risk minimization. By assuming that every input is subject to an uncertainty with a specified symmetric support, this robust formulation results in a maximization term that is similar to the regularization term in the classical SSVM. When the uncertainty set is l1 -norm, linfinity -norm or box, its training can be reformulated to a linear program; while the uncertainty set is l2 -norm or ellipsoidal, its training is a tractable second-order cone program. The proposed method has a nice consistent statistical property. As the training size goes to infinity, the estimated normal region converges to the true provided that the magnitude of the uncertainty set decreases in a systematic way. The experimental results on three data sets clearly demonstrate its superiority over three benchmark models. PMID- 25532213 TI - Adaptive control of uncertain nonaffine nonlinear systems with input saturation using neural networks. AB - This paper presents a tracking control methodology for a class of uncertain nonlinear systems subject to input saturation constraint and external disturbances. Unlike most previous approaches on saturated systems, which assumed affine nonlinear systems, in this paper, tracking control problem is solved for uncertain nonaffine nonlinear systems with input saturation. To deal with the saturation constraint, an auxiliary system is constructed and a modified tracking error is defined. Then, by employing implicit function theorem, mean value theorem, and modified tracking error, updating rules are derived based on the well-known back-propagation (BP) algorithm, which has been proven to be the most relevant updating rule to control problems. However, most of the previous approaches on BP algorithm suffer from lack of stability analysis. By injecting a damping term to the standard BP algorithm, uniformly ultimately boundedness of all the signals of the closed-loop system is ensured via Lyapunov's direct method. Furthermore, the presented approach employs nonlinear in parameter neural networks. Hence, the proposed scheme is applicable to systems with higher degrees of nonlinearity. Using a high-gain observer to reconstruct the states of the system, an output feedback controller is also presented. Finally, the simulation results performed on a Duffing-Holmes chaotic system, a generalized pendulum-type system, and a numerical system are presented to demonstrate the effectiveness of the suggested state and output feedback control schemes. PMID- 25532214 TI - Stitching and Surface Reconstruction From Endoscopic Image Sequences: A Review of Applications and Methods. AB - Endoscopic procedures form part of routine clinical practice for minimally invasive examinations and interventions. While they are beneficial for the patient, reducing surgical trauma and making convalescence times shorter, they make orientation and manipulation more challenging for the physician, due to the limited field of view through the endoscope. However, this drawback can be reduced by means of medical image processing and computer vision, using image stitching and surface reconstruction methods to expand the field of view. This paper provides a comprehensive overview of the current state of the art in endoscopic image stitching and surface reconstruction. The literature in the relevant fields of application and algorithmic approaches is surveyed. The technological maturity of the methods and current challenges and trends are analyzed. PMID- 25532215 TI - General Dimensional Multiple-Output Support Vector Regressions and Their Multiple Kernel Learning. AB - Support vector regression has been considered as one of the most important regression or function approximation methodologies in a variety of fields. In this paper, two new general dimensional multiple output support vector regressions (MSVRs) named SOCPL1 and SOCPL2 are proposed. The proposed methods are formulated in the dual space and their relationship with the previous works is clearly investigated. Further, the proposed MSVRs are extended into the multiple kernel learning and their training is implemented by the off-the-shelf convex optimization tools. The proposed MSVRs are applied to benchmark problems and their performances are compared with those of the previous methods in the experimental section. PMID- 25532216 TI - Retaining critical therapeutic elements of behavioral interventions translated for delivery via the Internet: recommendations and an example using pain coping skills training. AB - Evidence supporting the efficacy of behavioral interventions based on principles of cognitive behavioral therapies has spurred interest in translating these interventions for delivery via the Internet. However, the benefits of this dissemination method cannot be realized unless the translated interventions are as effective as possible. We describe a challenge that must be overcome to ensure this occurs--Internet interventions must retain therapeutic components and processes underlying the success of face-to-face interventions on which they are based. These components and processes vary in the ease with which they can be translated to the online environment. Moreover, some are subtle and may be overlooked, despite being recognized as essential to the success of face-to-face interventions. We provide preliminary guidance for retaining critical therapeutic components and processes in the translation process, using Pain Coping Skills Training for osteoarthritis pain to illustrate methods. Directions for future research are also discussed. PMID- 25532217 TI - Consumer participation in quality improvements for chronic disease care: development and evaluation of an interactive patient-centered survey to identify preferred service initiatives. AB - BACKGROUND: With increasing attention given to the quality of chronic disease care, a measurement approach that empowers consumers to participate in improving quality of care and enables health services to systematically introduce patient centered initiatives is needed. A Web-based survey with complex adaptive questioning and interactive survey items would allow consumers to easily identify and prioritize detailed service initiatives. OBJECTIVE: The aim was to develop and test a Web-based survey capable of identifying and prioritizing patient centered initiatives in chronic disease outpatient services. Testing included (1) test-retest reliability, (2) patient-perceived acceptability of the survey content and delivery mode, and (3) average completion time, completion rates, and Flesch-Kincaid reading score. METHODS: In Phase I, the Web-based Consumer Preferences Survey was developed based on a structured literature review and iterative feedback from expert groups of service providers and consumers. The touchscreen survey contained 23 general initiatives, 110 specific initiatives available through adaptive questioning, and a relative prioritization exercise. In Phase II, a pilot study was conducted within 4 outpatient clinics to evaluate the reliability properties, patient-perceived acceptability, and feasibility of the survey. Eligible participants were approached to complete the survey while waiting for an appointment or receiving intravenous therapy. The age and gender of nonconsenters was estimated to ascertain consent bias. Participants with a subsequent appointment within 14 days were asked to complete the survey for a second time. RESULTS: A total of 741 of 1042 individuals consented to participate (71.11% consent), 529 of 741 completed all survey content (78.9% completion), and 39 of 68 completed the test-retest component. Substantial or moderate reliability (Cohen's kappa>0.4) was reported for 16 of 20 general initiatives with observed percentage agreement ranging from 82.1%-100.0%. The majority of participants indicated the Web-based survey was easy to complete (97.9%, 531/543) and comprehensive (93.1%, 505/543). Participants also reported the interactive relative prioritization exercise was easy to complete (97.0%, 189/195) and helped them to decide which initiatives were of most importance (84.6%, 165/195). Average completion time was 8.54 minutes (SD 3.91) and the Flesch-Kincaid reading level was 6.8. Overall, 84.6% (447/529) of participants indicated a willingness to complete a similar survey again. CONCLUSIONS: The Web-based Consumer Preferences Survey is sufficiently reliable and highly acceptable to patients. Based on completion times and reading level, this tool could be integrated in routine clinical practice and allows consumers to easily participate in quality evaluation. Results provide a comprehensive list of patient-prioritized initiatives for patients with major chronic conditions and delivers practice ready evidence to guide improvements in patient-centered care. PMID- 25532218 TI - Development and validation of a personalized, web-based decision aid for lung cancer screening using mixed methods: a study protocol. AB - BACKGROUND: The National Lung Screening Trial demonstrated that low-dose computed tomography (LDCT) screening could be an effective way to reduce lung cancer mortality. Informed decision-making in the context of lung cancer screening requires that potential screening subjects accurately recognize their own lung cancer risk, as well as the harms and benefits associated with screening, while taking into account their personal values and preferences. OBJECTIVE: Our objective is to develop a Web-based decision aid in accordance with the qualifying and certification criteria in the International Patient Decision Aid Standards instrument version 4.0 that will assist patients in making informed decisions with regard to lung cancer screening. METHODS: In "alpha" testing, a prototype of the decision aid was tested for usability with 10 potential screening participants in focus groups. Feedback was also sought from public health and health risk communication experts external to the study. Following that, improvements to the prototype were made accordingly, and "beta" testing was done in the form of a quasi-experimental design-a before-after study-with a group of 60 participants. Outcomes tested were knowledge, risk perception of lung cancer and lung cancer screening, decisional conflict, and acceptability of the decision aid as determined by means of a self-administered electronic survey. Focus groups of a subsample of survey participants will be conducted to gain further insight into usability issues. RESULTS: Alpha testing is completed. Beta testing is currently being carried out. As of 2014 December 7, 60 participants had completed the before-after study. We expect to have results by 2015 January 31. Qualitative data collection and analysis are expected to be completed by 2015 May 31. CONCLUSIONS: We hypothesize that this Web-based, interactive decision aid containing personalized, graphical, and contextual information on the benefits and harms of LDCT screening will increase knowledge, reduce decisional conflict, and improve concordance between patient preferences and the current US Preventive Services Task Force's screening guidelines. PMID- 25532220 TI - Streptomycin hydrazone derivatives: synthesis and molecular recognition in aqueous solution. AB - Five hydrazone derivatives of streptomycin were synthetized (D0h, D1ph, D2bt, D3dctf, D4ag) and characterized by IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. Protonation constants were determined by potentiometry for all derivatives. D1ph and D2bt derivatives were investigated as receptors of dicarboxylates and adenine nucleotides in aqueous solution by potentiometric and 1H NMR titrations. D1ph and D2bt derivatives have the highest affinity with AMP and ATP, respectively, which shows that electrostatic forces are not always the dominant factor in binding of streptomycin derivatives with nucleotides, but the conformational fit between them. Calculated structures at the DFT level of the D1ph derivative bonded with either AMP or ADP showed that the complexes are stabilized by the formation of multiple interactions with the receptors. The antibiotic activity of the derivatives was explored and compared with native streptomycin. PMID- 25532219 TI - The RNA-binding protein Arrest (Bruno) regulates alternative splicing to enable myofibril maturation in Drosophila flight muscle. AB - In Drosophila, fibrillar flight muscles (IFMs) enable flight, while tubular muscles mediate other body movements. Here, we use RNA-sequencing and isoform specific reporters to show that spalt major (salm) determines fibrillar muscle physiology by regulating transcription and alternative splicing of a large set of sarcomeric proteins. We identify the RNA-binding protein Arrest (Aret, Bruno) as downstream of salm. Aret shuttles between the cytoplasm and nuclei and is essential for myofibril maturation and sarcomere growth of IFMs. Molecularly, Aret regulates IFM-specific splicing of various salm-dependent sarcomeric targets, including Stretchin and wupA (TnI), and thus maintains muscle fiber integrity. As Aret and its sarcomeric targets are evolutionarily conserved, similar principles may regulate mammalian muscle morphogenesis. PMID- 25532221 TI - Response from Mr. Viola. PMID- 25532223 TI - Findings of research misconduct. PMID- 25532222 TI - Findings of research misconduct. PMID- 25532226 TI - Gender and psychiatry. PMID- 25532227 TI - [Process of improvement in X-ray TV image quality at Keio University]]. PMID- 25532228 TI - [Basis of the flat panel detector and its technological usefulness]. PMID- 25532229 TI - [New possibilities brought to gastrointestinal radiography by the use of X-ray flat panel detector]. PMID- 25532230 TI - [Technological description of FPD and future objectives]. PMID- 25532231 TI - [Radiographic examination of the gastrointestinal system using an equipment with FPD: expectation and utilization of imaging systems. A discussion]. PMID- 25532232 TI - Why a national high-risk insurance pool is not a workable alternative to the marketplace. AB - The Pre-Existing Condition Insurance Plan (PCIP) was a national high-risk pool established under the Affordable Care Act (ACA) to provide coverage for individuals with preexisting conditions who had been uninsured for at least six months. It was intended to be a temporary program: PCIPs opened in 2010 and closed in April 2014. At that point, those with preexisting conditions could shop for health insurance in the marketplaces, where plans are prevented from using applicants' health status to deny coverage or charge more. This issue brief draws on the PCIP experience to outline why national high-risk pools, which continue to be proposed as policy alternatives to ACA coverage expansions, are expensive to enrollees as well as their administrators and ultimately unsustainable. The key lesson--and the principle on which the ACA is built--is that insurance works best when risk is evenly spread across a broad population. PMID- 25532233 TI - [Historical background of smoking and smoking cessation]. PMID- 25532234 TI - [Fundamental knowledge on tobacco smoke]. PMID- 25532235 TI - [Effects of smoking throughout the body]. PMID- 25532236 TI - [Systemic effects of smoking]. PMID- 25532238 TI - [Effects of smoking on the respiratory system (overall effects)]. PMID- 25532237 TI - National trends in the cost of employer health insurance coverage, 2003-2013. AB - Looking at trends in private employer-based health insurance from 2003 to 2013, this issue brief finds that premiums for family coverage increased 73 percent over the past decade--faster than median family income. Employees' contributions to their premiums climbed by 93 percent over that time frame. At the same time, deductibles more than doubled in both large and small firms. Workers are thus paying more but getting less protective benefits. However, the study also finds that while premiums continued to rise through 2013, the rate of growth slowed between 2010 and 2013, following implementation of the Affordable Care Act. While families experienced slower growth in premium contributions and deductibles over this period, sluggish growth in median family income means families are paying more in premiums and deductibles as a share of their income than ever before. PMID- 25532239 TI - [Effects of smoking on the respiratory organs (specific processes)]. PMID- 25532240 TI - [The basis of guidelines for smoking cessation]. PMID- 25532241 TI - [Smoking cessation on an ambulatory basis]. PMID- 25532242 TI - [Smoking cessation for ambulatory patients at the department of general respiratory diseases]. PMID- 25532243 TI - [Smoking cessation by in-patients]. PMID- 25532244 TI - Clostridium difficile infection and inflammatory bowel disease: what gastroenterologists and surgeons should know. AB - Over the past two decades there has been a dramatic increase worldwide in both incidence and severity of Clostridium difficile infection (CDI). Paralleling the rising incidence of CDI in the general population, there has been an even higher increase in the incidence of CDI among patients with inflammatory bowel disease (IBD). CDI may mimic a flare of IBD as symptoms and laboratory parameters are often similar, and therefore, screening for CDI is recommended at every flare in such patients. Enzyme immunoassay to detect Clostridium difficile toxin A and B in stool is still the most widely used test for CDI diagnosis despite its low sensitivity. Metronidazole for mild/moderate CDI,and vancomycin for severe CDI are the preferred agents for the treatment of infection. CDI has a negative impact both on short- and long- term IBD outcomes, increasing the need for surgery, as well as the mortality rate and healthcare costs. All gastroenterologists and surgeons should have a high index of suspicion for CDI when evaluating a patient with IBD flare, as prompt diagnosis and adequate treatment of infection improve outcomes. Measures must be taken to prevent spreading of infection in gastroenterology /surgery settings. PMID- 25532245 TI - Obituary. Prof. Dr. Nicolae Angelescu is no longer among us... PMID- 25532246 TI - Summertime and the research is easy. PMID- 25532247 TI - The end of the first year. PMID- 25532248 TI - [Voluntary pregnancy termination: a law and a right]. PMID- 25532249 TI - ["A right of women to manage their bodies is not negotiable nor amendable"]. PMID- 25532250 TI - [Reconsidering the vaccination policy for the general population]. PMID- 25532251 TI - [Registered nurses authorized to perform the preliminary interview at blood donation]. PMID- 25532252 TI - [Mixed results for protocols of cooperation between health professionals]. PMID- 25532253 TI - [CCNE formulates general observations to the State Council]. PMID- 25532254 TI - [Monitoring for suicidal acts]. PMID- 25532255 TI - [Users and operation of institutions and services]. PMID- 25532256 TI - [Sanofi Diabetes supports Machu Picchu Challenge]. PMID- 25532257 TI - [A blog and a theater play for living with Alzheimer disease]. PMID- 25532258 TI - [Women victims of violence and health]. PMID- 25532259 TI - [Violence against women: an involvement of all players]. AB - Every year in France, 201,000 women are victims of physical and/or sexual violence perpetrated by their partner or ex-partner. At the same time, 83,000 are victims of rape or attempted rape, by a known or unknown aggressor. The impact of this violence on the health and overall quality of life of female victims is considerable. Faced with the extent of these violences, initiatives are being set up, instigated by the government and numerous players in the field. PMID- 25532260 TI - [Adapting the law to offer better protection to female victims of violence]. AB - As society has become more aware of the seriousness and the extent of domestic violence, the law has been adapted in order to offer female victims better protection. These legislative changes are recent and still meet with some resistance. The act of the 9th of July 2010 modified penal and civil laws to take better account of the specificities of the mechanisms of domestic abuse and create appropriate tools. The law about real equality between women and men, approved by the National Assembly on the 23rd of July 2014, is in line with this same objective. PMID- 25532261 TI - ["Health professionals all have a role to play in identifying violence."]. AB - The national coordinator of the "Violence against women" programme of the Interministerial mission for the protection of female victims of violence and the fight against human trafficking (Miprof), Ernestine Ronai is also the co president of the "gender-based violence" commission at the French High Council for Equality between Women and Men (HCEfh). In this interview, she shares with us her expert insight with regard to the issue of violence against women and the help available to them. PMID- 25532262 TI - [The general practitioner's role in identifying and supporting female victims of violence]. AB - Violence has a major impact on the health of victims and can be masked by various psychological and somatic pathologies. Systematic questioning by general practitioners gives women the opportunity to be finally heard and enables doctors to make the connection with the violence to which they are being subjected. Identifying this abuse is essential in order to be able to help and orient the women towards the appropriate support. PMID- 25532263 TI - [Psychological consequences and treatment of female victims of violence]. AB - Domestic violence often just reproduces the repeated violence suffered as a child. The treatment of a female victim depends a lot on her traumatic past, and the care is designed in coordination with various partners. By improving the identification and care of children who are so-called witnesses to family violence, but who are really co-victims, in other words abused, it is possible to avoid violence in all its forms being reproduced across the generations. PMID- 25532264 TI - [Systematic screening for domestic violence in the accident and emergency department]. AB - The accident and emergency department is a place where female victims of domestic abuse may arrive with various symptoms. The systematic screening of female victims was studied and implemented by an A&E team in the Paris region and has now been extended to all the hospital's departments where female victims may arrive for treatment. PMID- 25532265 TI - [Treating female victims of violence in a medical-judicial unit]. AB - Receiving and treating victims of violence is one of the missions of the medical judicial unit. The nurse is present when the victims arrive and works with the medical examiner during the consultation. Having a nurse's perspective within this unit has helped to improve the global care of the people seen here. PMID- 25532266 TI - [Nurse expertise and coordination of care pathways]. AB - Interested, since she first qualified as a nurse, in the complex care of people with chronic diseases, Marina Vignot has focused on the coordination of care pathways throughout her career. She now shares her expertise by teaching the follow-up of patients with cardio-metabolic diseases. PMID- 25532267 TI - [The nurse faced with sudden cardiac arrest]. AB - The nursing intervention in a sudden cardiac arrest only comes as a continuation of the resuscitation procedures undertaken by the first person on the scene. Hence the importance of raising the awareness of and training the general public. In a healthcare facility, experts recommend putting in place an emergency procedure, a standard crash trolley and a dedicated life-threatening emergency response team. PMID- 25532268 TI - [Belgium: an innovation in the training and assessment of student nurses]. AB - The pedagogical team of the Haute Ecole Robert Schuman in Libramont, Belgium, has introduced an original form of clinical assessment. Called "structured objective clinical assessment", this approach is based on simulated scenarios carried out in the training institution. An integrated active pedagogical method which ensures the optimal preparation of students for their future profession and the continuation of university studies. PMID- 25532269 TI - [Imbalance in diabetes and acute complications: hypo- or hyperglycemia]. PMID- 25532270 TI - [The nurse faced with a pregnancy]. PMID- 25532271 TI - Talking about contraception with a teenager. PMID- 25532272 TI - [Setting up a preparatory course for the entrance examination in Ifsi]. PMID- 25532273 TI - [Performing a evacuation enema]. PMID- 25532274 TI - Sesinoside, a new iridoid glucoside from sesame (Sesamum indicum) seedlings. AB - A new iridoid glucoside, sesinoside (1), was isolated from the seedlings of Sesamum indicum. The structure of 1 was elucidated by spectroscopic analyses and by methanolysis of 1, which produced the known compounds, phlorigidosides C (2) and (6Z)-foliamenthic acid methyl ester (3). This is the first report of an iridoid glucoside with 3. PMID- 25532275 TI - A new sesquiterpene lactone and other constituents of Moquiniastrum polymorphum subsp. floccosum (Asteraceae). AB - A new guaianolide, 1S, 3S, 5R, 6S, 7S, 11R-l-hydroxy-11alpha,13-dihydrozaluzanin C (1), was isolated from Moquiniastrum polymorphum subsp. floccosum trunk bark, together with fifteen known compounds, which were identified as 11alpha,13 dihydroglucozaluzanin C (2), 8alpha-hydroxy-11alpha,13-dihydrozaluzanin C (3), zaluzanin C (4), gochnatiolide B (5), ethyl caffeate (6), methyl chlorogenate (7), ethyl chlorogenate (8), methyl 3,5-dicaffeoyl quinate (9), ethyl 3,5 dicaffeoyl quinate (10), methyl 4,5-dicaffeoyl quinate (11), ethyl 4,5-dicaffeoyl quinate (12), ethyl 3,4-dicaffeoyl quinate (13), 3,5-dicaffeoyl quinic acid (14), 4,5-dicaffeoyl quinic acid (15), and 3,4-dicaffeoyl quinic acid (16). With the exception of 5, all known compounds are being reported for the first time in M. polymorphum. PMID- 25532276 TI - Further degraded diterpenoids from the stems of Trigonostemon lii. AB - Two degraded diterpenoids, thrigonosomones D and E, were isolated from the stems of Trigonostemon lii. Their structures were established by spectroscopic methods, including extensive 1D- and 2D-NMR experiments. PMID- 25532277 TI - Antitumor screening of Pterodon pubescens terpenic fraction indicates high sensitivity for lymphocytic leukemia cells. AB - Cancer is the second leading cause of human mortality worldwide. Therefore, the search for new drugs or alternative therapy strategies has been required. Anticancer agents have been developed from plants since the 1950s and natural products still represent an important source of new and promising bioactive molecules. This work describes the cytotoxic effects of SF5 on tumor cells of high prevalence in the world and investigated some mechanisms of its antitumor action. The antitumor screening was performed with human lung carcinoma (A549), human breast (MCF-7) and prostate (PC-3) adenocarcinoma and chronic myeloid and acute lymphocytic leukemia cell lines. The acute lymphocytic leukemia Jurkat cells presented high sensitivity to the cytotoxic effects of SF5 (inhibition of 85-90%), compared with either the chronic myeloid leukemia K562 or solid tumor cell lines (lung, breast and prostate). SF5 arrested the cell cycle in G1 phase, which may be related with the observed downregulation of mRNA expression of c-Myc transcription factor at 24 h and 36 h. SF5 treatment induced cytochrome c release from mitochondria to cytosol, leading the Jurkat cells into apoptosis, which was evidenced by the internucleosomal fragmented DNA and increased number of annexin V-FITC positive cells. The SF5 showed high cytotoxicity for lymphocytic leukemia cells and low or none for solid tumor cells, without toxicity for peripheral mononuclear cells of healthy humans. SF5 altered gene expression, arrested the cell cycle and induced apoptosis via the mitochondrial pathway, similar to traditional antineoplastic chemotherapeutic drugs. PMID- 25532278 TI - Dammarane terpenoids from the fruits of Dysoxylum mollissimum. AB - Two new dammaranes, dysomollisol (1) and dysomollisone (2), along with seven known compounds (3-9) were isolated and identified from the fruits of Dysoxylum mollissimum. The structures of these compounds were determined on the basis of spectroscopic analyses, including 1D and 2D NMR, UV, IR and mass spectrometry. The antibacterial activity and cytotoxicity against epidermoid carcinoma of oral cavity (KB) cell line of compounds 1-9 were evaluated. PMID- 25532279 TI - Anti-tumor activities of triterpenes from Syzygium kusukusense. AB - In this study, we report the isolation from the stem of Syzygium kusukusense of five triterpenes, 2alpha-hydroxybetulinic acid (1), betulinic acid (2), platanic acid (3), ursolic acid (4), and hyptatic acid A (5). All were identified for the first time from this indigenous plant of Taiwan. Assessment of the cytotoxic activities of these compounds against a panel of human tumor cell lines, including MCF-7 breast, PC-3 prostate, and SCC2095 oral squamous cell cancers, revealed the high potency of compounds 1 (IC50, 5.7 - 7.6 MUM) and, especially, 4 (IC50, 1.7 - 3.7 MUM) in suppressing cell viability, which warrants further mechanistic investigations. PMID- 25532280 TI - Non-competitive inhibition of acetylcholinesterase by bromotyrosine alkaloids. AB - Fifteen bromotyrosine-derived alkaloids were isolated from the sponge Pseudoceratina cf. purpurea. The acetylcholinesterase-inhibiting activity of all the isolated compounds were examined; to purealidin Q, isoanomoian A, aplyzanzine A, and aplysamine 2 were active with IC50 values of 1.2, 70, 104, and 1.3 MUM, respectively. On the other hand, antiproliferative activity against MCF-7 cells of aerophobin 1 gave an IC50 value of 0.8 MUM. The Michaelis-Menten plots of the active alkaloids indicated that all the four compounds inhibited acetylcholinesterase in a non-competitive manner. The structures of the active compounds suggested that the N,N-dimethylaminopropyloxydibromotyramine moiety may play an important role in the enzyme-inhibiting activity, presumably on the anionic and hydrophobic binding sites. PMID- 25532281 TI - Facile, protection-free, one-pot synthesis of aureusidin. AB - A new, reliable, and convenient protection-free one-pot method for the synthesis of aureusidin (1) is described. The present synthetic approach involves the condensation of 4,6-dihydroxybenzofuranone with 3,4-dihydroxybenzaldehyde in the presence of concentrated HCl to afford aureusidin (1) in good yield with high purity. This procedure offers a short and simple route for the preparation of aureusidin (1), a bioactive natural product from several vegetal species, as well as for synthesis of other aurones. PMID- 25532282 TI - Profiling of flavonols in seeds and sprouts of Luffa cylindrical. AB - Seeds of Luffa cylindrica (Luffa) have been considered as agricultural wastes. However, we hypothesized that the seeds and its sprouts may provide bioactive components that could provide health benefits for humans. The current study profiled the bioactive components in both seeds and sprouts of Luffa by using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MSn). Apigenin was identified as a major component in the seeds of Luffa, with a concentration of 2.89 mg from 1 g fresh weight. The bioactive components in the sprouts were myricetin, luteolin, and quercetin, with concentrations of 32.4, 12.5, and 32.5 MUg from 1 g fresh weight, respectively. Apigenin metabolites, such as apigenin glucuronic acid and apigenin-acetyl glucuronic acid, were also identified in the sprouts. This implied that apigenin in the seeds, when sprouting, was changed to other flavonols having a flavone backbone. Results from the current study suggest that both seeds and sprouts of Luffa could be a bio-resource for health-promoting food materials. PMID- 25532283 TI - Direct identification and characterization of phenolic compounds from crude extracts of buds and internodes of grapevine (Vitis vinifera cv Merlot). AB - The crude methanol extracts of latent buds and internodes Vitis vinifera L. cv. Merlot were used for the determination of phenolic compounds by a combination of reverse phase HPLC with diode array detection (HPLC-DAD) and mass spectrometry (LC-MS). This method allowed the identification of 9 phenolic compounds without purification or fractionation. These 9 compounds were divided into three groups: procyanidins, flavonols and stilbenes. Detection by HPLC-DAD at different wave lengths of 280 nm to 320 nm, allowed the estimation of concentrations of those compounds. This method permitted, for the first time, both characterization and quantification of polyphenolic compounds in buds of grapevine. Comparison with the results obtained in internodes showed that quercetin, resveratrol tetramer and epsilon-viniferin had similar levels in buds and internodes while six other compounds identified had higher levels in buds. PMID- 25532284 TI - Phytochemical analysis, antioxidant and anti-inflammatory activity of calyces from Physalis peruviana. AB - Physalis peruviana calyces are used extensively in folk medicine. The crude ethanolic extract and some fractions of calyces were evaluated in order to explore antioxidant and anti-inflammatory activities. The anti-inflammatory activity was evaluated by the TPA-induced ear edema model. The antioxidant in vitro activity was measured by means of the superoxide and nitric oxide scavenging activity of the extracts and fractions. The butanolic fraction was found to be promising due to its anti-inflammatory and antioxidant activities. Therefore, a bio-assay guided approach was employed to isolate and identify rutin (1) and nicotoflorin (2) from their NMR spectroscopic and MS data. The identification of rutin in calyces of P. peruviana supports the possible use of this waste material for phytotherapeutic, nutraceutical and cosmetic preparations. PMID- 25532285 TI - Phenolic derivatives from Radix Astragali and their anti-inflammatory activities. AB - Two new (3, 4) and two known phenolic derivatives (1, 2) were isolated from Radix Astragali. The structures of 1-4 were elucidated by extensive spectroscopic analysis. The anti-inflammatory activities of the isolated compounds were evaluated in LPS-induced mouse peritoneal macrophages. All four compounds exhibited potent inhibitory effects on TNF-alpha production and TNF-alpha, COX-2, IL-1beta, IL-6 and iNOS mRNA expression at 50 MUM. PMID- 25532286 TI - Isolation of hydroxyoctaprenyl-1',4'-hydroquinone, a new octaprenylhydroquinone from the marine sponge Sarcotragus spinosulus and evaluation of its pharmacological activity on acetylcholine and glutamate release in the rat central nervous system. AB - Three polyprenyl-1',4'-hydroquinone derivatives, heptaprenyl-1',4'-hydroquinone (1), octaprenyl-1',4'-hydroquinone (2), and hydroxyoctaprenyl-1',4'- hydroquinone (3) were isolated from the marine sponge Sarcotragus spinosulus collected at Baia di Porto Conte, Alghero (Italy). Our findings indicate that the compounds isolated from S. spinosulus can significantly modulate the release of glutamate and acetylcholine in the rat hippocampus and cortex and might, therefore, represent the prototype of a new class of drugs regulating glutamatergic and cholinergic transmission in the mammalian central nervous system. PMID- 25532288 TI - Anti-inflammatory and anti-oxidative activities of polyacetylene from Dendropanax dentiger. AB - Dendropanax dentiger has been used as a folk medicine since ancient times. In our current study, we observed that D. dentiger exhibited a significant anti inflammatory activity, which could efficiently inhibit nitric oxide (NO) production in the lipopolysaccharide (LPS)-induced macrophage inflammation assay. (9Z,16S)-16-Hydroxy-9,17-octadecadiene-12,14-diynoic acid (HODA) was isolated from the leaves of D. dentiger following a bioactivity guided fractionation protocol. Our data indicated that HODA significantly inhibited the NO production in LPS-induced RAW 264.7 murine macrophage cells (IC50 = 4.28 MUM). Consistent with these observations, the mRNA and protein expression levels of iNOS were also inhibited by HODA in a dose-dependent manner. HODA also reduced the translocation of NF-kappaB into nuclear fractions. Meanwhile, HODA enhanced Nrf-2 activation and its downstream antioxidant gene HO-1. We concluded that HODA possessed significant anti-inflammatory and anti-oxidative activity; the compound may have a potential for development as a chemoprevention agent. PMID- 25532287 TI - PTP1B inhibitory effect of alkyl p-coumarates from Calystegia soldanella. AB - In this report, the PTP1B inhibitory effect of Calystegia soldanella was investigated. Bioassay-guided fractionation of the crude extracts revealed that the n-hexane fraction had the strongest PTP1B inhibitory effect. Nine known alkyl p-coumarates were isolated from the n-hexane fraction, and each compound was evaluated for its effect on PTP1B. All compounds effectively inhibited PTP1B activity. The IC50 values of the compounds were 3 (10.8 MUg/mL) > 2 (15.5 MUg/mL) > 7 (26.6 MUg/mL) > 1 (37.0 MUg/mL) > 8 (41.2 MUg/mL) > 9 (43.4 MUg/mL) > 5 (44.7 MUg/mL) > 4 (> 50 MUg/mL) > 6 (> 50 MUg/mL). PMID- 25532289 TI - Identification of the country of growth of Sophora flavescens using direct analysis in real time mass spectrometry (DART-MS). AB - In order to identify the country of growth of Sophora flavescens by chemical fingerprinting, extracts of plants grown in China and Japan were analyzed using direct analysis in real time mass spectrometry (DART)-MS. The peaks characteristic of each country of growth were statistically analyzed using a volcano plot to summarize the relationship between the p-values of a statistical test and the magnitude of the difference in the peak intensities of the samples in the groups. Peaks with ap value < 0.05 in the t-test and a >= 2 absolute difference were defined as characteristic. Peaks characteristic of Chinese S. flavescens were found at m/z 439 and 440. In contrast, peaks characteristic of Japanese S. flavescens were found at m/z 313, 423, 437 and 441. The intensity of the selected peaks was similar in Japanese samples, whereas the m/z 439 peak had a significantly higher intensity than the other peaks in Chinese samples. Therefore, differences in selected peak patterns may allow identification of the country of growth of S. flavescens. PMID- 25532290 TI - Physicochemical properties of honey from Marche, Central Italy: classification of unifloral and multifloral honeys by multivariate analysis. AB - The purpose of this study was the physicochemical characterization and classification of Italian honey from Marche Region with a chemometric approach. A total of 135 honeys of different botanical origins [acacia (Robinia pseudoacacia L.), chestnut (Castanea sativa), coriander (Coriandrum sativum L.), lime (Tilia spp.), sunflower (Helianthus annuus L.), Metcalfa honeydew and multifloral honey] were considered. The average results of electrical conductivity (0.14-1.45 mS cm( 1)), pH (3.89-5.42), free acidity (10.9-39.0 meq(NaOH) kg(-1)), lactones (2.4-4.5 meq(NaOH) kg(-1)), total acidity (14.5-40.9 meq(NaOH) kg(-1)), proline (229-665 mg kg(-1)) and 5-(hydroxy-methyl)-2-furaldehyde (0.6-3.9 mg kg(-1)) content show wide variability among the analysed honey types, with statistically significant differences between the different honey types. Pattern recognition methods such as principal component analysis and discriminant analysis were performed in order to find a relationship between variables and types of honey and to classify honey on the basis of its physicochemical properties. The variables of electrical conductivity, acidity (free, lactones), pH and proline content exhibited higher discriminant power and provided enough information for the classification and distinction of unifloral honey types, but not for the classification of multifloral honey (100% and 85% of samples correctly classified, respectively). PMID- 25532291 TI - Antifungal activity of plant extracts against Aspergillus niger and Rhizopus stolonifer. AB - Despite recent advances in antifungal development, fungi remain a devastating threat to human health and compromise viability of the food supply. Plant based antimicrobials represent a vast untapped source with tremendous potential. Herein we present the antifungal properties of more than 50 plant extracts against two important human and agricultural pathogens, Aspergillus niger and Rhizopus stolonifer. Multiple extracts exhibit promising MIC values of less than 100 MUg/mL and are reported for both fungal species. PMID- 25532292 TI - GC/MS analysis of the essential oil of Leucas indica from India. AB - The aim of the present study was to investigate and identify the essential oil constituents of Leucas indica (L.) R.Br. (Lamiaceae). The chemical composition of the hydro-distilled essential oil was obtained from the flowering aerial parts of L. indica for the first time. The oil was analyzed by gas chromatography equipped with flame ionization detector (GC-FID) and gas chromatography coupled with mass spectrometry (GC/MS). Fifty-six compounds were identified, representing 99.1% of the total oil. The main constituents were beta-caryophyllene (51.1%) and alpha caryophyllene (10.2%). The oil was found to be rich in sesquiterpene hydrocarbons (71.8%). PMID- 25532293 TI - Composition of headspace volatiles and essential oils of three Thymus species. AB - Analysis of head space volatiles (HSV) and hydrodistilled essential oils (EO) of the above-ground parts of Thymus glabrescens Willd., T. praecox Opiz subsp. jankae (Celak.) Jalas (from two localities) and T. pulegoides L. was made by GC FID and GC-MS. This is the first report on the headspace volatiles composition of T. glabrescens and T. pulegoides. The most abundant compound of T. glabrescens HSV was p-cymene (27.8%) followed by gamma-terpinene (18.4%), while thymol (55.4%) and geraniol (10.5%) were the most abundant in the corresponding EO. T. praecox subsp. jankae EO from Serbia was characterized by (E)-caryophyllene (14.6%) and thymol (10.7%), which is substantially different from that of Bulgarian T. praecox subsp. jankae, which contained a-terpinyl acetate (20.1%) and linalool (17.7%) as its main components. The dominating components of the Serbian and Bulgarian T. praecox subsp. jankae HSV were alpha-pinene (29.4% and 18.6%, respectively), myrcene (12.1% and 23.2%, respectively), limonene (7.5% and 17.8%, respectively) and beta-pinene (11.7% and 7.6%, respectively). Linalyl acetate predominated in T. pulegoides EO and HSV, representing 40.0% and 42.4% (respectively) of the total peak area. The chemical composition of the essential oils of the examined Thymus species could not be attributed to any particular recorded chemotype of T. glabrescens, T. praecox and T. pulegoides. PMID- 25532294 TI - Constituents of essential oils from the leaf and flower of Plumeria alba grown in Nigeria. AB - This paper reports on the compounds identified in the leaf and flower essential oils obtained by hydrodistillation of Plumeria alba L. (Apocynaceae) grown in Nigeria. The chemical analysis of the essential oils was achieved by means of gas chromatography (GC) and gas chromatography coupled with mass spectrometry (GC MS). Linalool (13.2%), n-nonanal (9.6%), phenyl acetaldehyde (8.5%), neryl acetone (5.3%) and n-decanal (5.1%) were the main constituents of the leaf oil. On the other hand, the flower oil comprised mainly of limonene (9.1%), linalool (7.9%), alpha-cedrene (8.0%), caryophyllene oxide (7.9%) and (E, E)-alpha farnesene (6.6%). This is the first report on the essential oil constituents of P. alba. PMID- 25532295 TI - Anticonvulsant activity of Citrus aurantium blossom essential oil (neroli): involvment of the GABAergic system. AB - Citrus aurantium L. blossoms are an important medicinal plant part in Iran and some other countries. It is used in traditional medicine as an antiseizure and anticonvulsant natural agent. Early in vitro research of the anticonvulsant activity of the blossom extracts were done but there has been no investigation focused on the blossom essential oil and its anticonvulsant activity. The anticonvulsant activity of the essential oil of C. aurantium blossoms (neroli) was investigated. The anticonvulsant activity of neroli was assessed in pentylenetetrazole (PTZ)-induced convulsion by i.v. and i.p. methods and maximal electroshock (MES) in mice, with diazepam as the standard drug. While mechanistic studies were conducted using flumazenil, a GABA A-benzodiazepine receptor complex site antagonist. Neroli produced protection against clonic by i.v adminiatration of PTZ at 20 and 40 mg/kg, compared with protection with benzodiazepine. The mean onset and percentage protection against convulsion in neroli-treated mice were reduced by flumazenil. Intraperitonaeal PTZ also decreased the latency of clonic seizure in the neroli (40 mg/kg) treated group. We also showed that neroli (20 and 40 mg/kg), exhibited inhibition of the tonic convulsion induced by MES and decreased the mortality rate. Neroli was analyzed by GC and GC-MS and twenty three constituents, representing 91.0 % of the chromatographical oil were identified. The major components of neroli were characterized as linalool (28.5%), linalyl acetate (19.6%), nerolidol (9.1%) E,E-farnesol (9.1%), alpha terpineol (4.9%) and limonene (4.6%) which might be responsible for the anticonvulsant activity. The results suggest that neroli possesses biologically active constituent(s) that have anticonvulsant activity which supports the ethnomedicinal claims of the use of the plant in the management of seizure. PMID- 25532296 TI - Skin regeneration effect and chemical composition of essential oil from Artemisia Montana. AB - Artemisia montana Pampan (Compositae) (AMP) contains various compounds, including phenolic acids, alkaloids, and essential oil. It has been widely used in oriental medicine due to a variety of biological effects. However, the biological activity of the essential oil from AMP (AMPEO) on skin has not been investigated. In the present study, AMPEO was evaluated for its composition and its effect on cellular events (migration and proliferation) related to skin regeneration using normal human keratinocytes (HaCats). AMPEO, which was extracted by steam distillation, contained 42 components. AMPEO increased proliferation in HaCats in a dose dependent manner (EC 50, 8.5 ng/mL) and did not affect migration. AMPEO also enhanced the phosphorylation of Akt and ERK 1/2 and induced the synthesis of type IV collagen, but not type I collagen in HaCats. In addition, AMPEO promoted wound closure in the dorsal side skin of rat tail. These results demonstrated that AMPEO extracted by steam distillation induced proliferation and synthesis of type IV collagen in human skin keratinocytes, and may thereby exert positive effects on skin regeneration and wound healing in human skin. PMID- 25532297 TI - Chemical composition and antimicrobial activity of the essential oils of Pinus peuce (Pinaceae) growing wild in R. Macedonia. AB - The chemical composition and antimicrobial activity of the essential oils isolated from twigs with needles (T+N) and from twigs without needles (T-N) from wild Pinus peuce Griseb. (Pinaceae), from three different locations in R. Macedonia, were investigated. Essential oil yields of T+N ranged from 7.5 mL/kg to 12.5 mL/kg and for T-N from 13.8 mL/kg to 17.3 mL/kg. GC/FID/MS analysis of the essential oils revealed eighty-four components, representing 93.7-95.7% and 91.2-92.0% of the T+N and T-N oils, respectively. The major components in T+N and T-N oils were monoterpenes: alpha-pinene (23.8-39.9%, 21.2-23.3%), camphene (2.2 5.5%, 0.7-2.0%), beta-pinene (10.1-17.1%, 8.2-16.4%), myrcene (1.2-1.41%, 1.6 2.5%), limonene+beta-phellandrene (6.8-14.0%, 8.8-23.6%) and bornyl acetate (2.3 6.9%, 1.1-3.4%), followed by the sesquiterpenes: trans-(E)-caryophyllene (3.6 4.3%, 3.2-7.3%), germacrene D (7.1-9.5%, 5.0-10.3%) and delta-cadinene (2.1-3.1%, 3.3-4.2%, respectively). Antimicrobial screening of the essential oils was made by disk diffusion and broth dilution methods against 13 bacterial isolates of Gram-positive and Gram-negative bacteria and one strain of Candida albicans. T-N essential oils showed antimicrobial activity toward Streptococcus pneumoniae, Staphylococcus aureus, S. epidermidis and Candida albicans as well as Streptococcus agalactiae, Acinetobacter spp. and Haemophilus influenzae. The antimicrobial activity of T+N essential oils was greater, especially against Streptococcus agalactiae, S. pyogenes, Enterococcus and Candida albicans, followed by Haemophilus influenzae, Acinetobacter spp., Escherichia coli, Salmonella enteritidis, Staphylococcus aureus and S. epidermidis. Minimal inhibitory concentrations (MICs) of all tested essential oils ranged from 15-125 MUL/mL. Summarizing the obtained results, the antimicrobial activity of Pinus peuce T+N and T-N essential oils collected from different localities in R. Macedonia varied considerably. These alterations in the antimicrobial activity can be attributed to the differences in the quantitative composition and percentage amounts of the components present in the respective essential oils, although it was evident that there were no differences in the qualitative composition of the essential oils, regardless of the locality of collection, or the type of plant material (T+N or T-N). PMID- 25532298 TI - An in vitro antibacterial study of savory essential oil and geraniol in combination with standard antimicrobials. AB - The chemical composition and antibacterial activity of Satureja kitaibelii Wierzb. ex Heuff. (savory) essential oil were examined, as well as the association between it and standard antimicrobials: tetracycline and chloramphenicol. The antibacterial activities of geraniol, the main constituent of S. kitaibelii oil, individually and in combination with standard antimicrobials were also determined. The interactions of the essential oil and geraniol with antimicrobials toward five selected strains were evaluated using the microdilution checkerboard assay in combination with chemometric methods. Oxygenated monoterpenes were the most abundant compound class in the oil (59.7%), with geraniol (50.4%) as the major compound. The essential oil exhibited in vitro antibacterial activity against all tested bacterial strains, but the activities were lower than those of the standard antimicrobials. The combinations savory oil chloramphenicol, savory oil-tetracycline and geraniol-chloramphenicol produced predominantly synergistic interactions (FIC indices in the range 0.21-0.87) and substantial reductions in the MIC values of antimicrobials against Gram-negative bacteria, the pharmacological treatment of which is very difficult nowadays. In the PCA and HCA analyses these combinations form a separate group. PMID- 25532299 TI - Chemical composition and biological activity of Pulicaria vulgaris essential oil from Iran. AB - The present study investigated the chemical composition of the essential oil (EO) from aerial parts (flowering stage) of Pulicaria vulgaris Gaertn. by GC-MS. Also, the antimicrobial activity of the EO against Gram-positive bacteria (Bacillus cereus and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungi (Aspergillus niger and Candida albicans) was tested. In total, 23 compounds were recognized, accounting for 98.08% of the EO. The main compounds in the EO were thymol (50.22%), p-menth-6-en-2-one (carvotanacetone, 20.2%), thymol isobutyrate (16.88%), menthan-2-one (4.31%), 1 methyl-1,2-propanedione (4.13%), 2,5-dimethoxy-p-cymene (4.01%), myrtenol (1.22%), linalool (1.1%), and beta-myrcene (1.9%). Results of antibacterial test of P. vulgaris essential oil showed that all assayed concentrations significantly inhibited the growth of B. cereus, S. aureus, E. coli, and P. aeruginosa at P < 0.05. MIC for B. cereus, S. aureus, E. coli, P. aeruginosa was 17.5, 25.2, 19.4 and 33.2 MUg/mL respectively; antifungal screening of the essential oil of P. vulgaris showed that the oil significantly inhibited the growth of A. niger and C. albicans (MIC = 15.5 and 9.9 MUg/mL, respectively). Results of cytotoxicity assay showed that the essential oil exhibited a significant cytotoxic activity against both cell lines. In case of MCF-7 and Hep-G2 cell lines, IC50 of the essential oil were 5.36 and 7.16 MUg/ml, respectively. The potent antimicrobial and cytotoxic activities of the EO may be attributed to its high contents of thymol, carvotanacetone and thymol isobutyrate. Antimicrobial and antitumor chemotherapies are showing diminishing effectiveness because of emergence of drug resistance. Hence, using efficient natural chemotherapeutic agents such as Pulicaria vulgaris essential oil with fewer side effects is an encouraging approach to fight cancer and infectious diseases in medicine, agriculture, food science and related fields. PMID- 25532300 TI - Activity against microorganisms affecting cellulosic objects of the volatile constituents of Leonotis nepetaefolia from Nicaragua. AB - The chemical composition of the essential oil from aerial parts of L. nepetaefolia (L.) R. Br. collected in Nicaragua was evaluated by GC and GC-MS. The main components were (Z)-phytol (22.8%), caryophyllene oxide (18.9%) and hexahydrofarnesylacetone (9.0%). The antibacterial activity against several Gram + and Gram - bacteria, including Bacillus cereus and B. subtilis, both infesting historical cellulosic material, was also determined. B. cereus, B. subtilis and Staphylococcus epidermis were the most affected by the action of the oil. PMID- 25532301 TI - Nutrigenomics of essential oils and their potential domestic use for improving health. AB - The use of essential oils as industrial food additives is notorious, like their medicinal properties. However, their use in household food spicing is for now limited. In this work, we have made a review to reveal the nutrigenomic actions exerted by their bioactive components, to promote awareness of their modulating gene expression ability and the potential that this implies. Also considered is how essential oils can be used as flavoring and seasoning after cooking and before consumption, such as diet components which can improve human health. Genetic mechanisms involved in the medicinal properties of essential oils for food use are identified from literature. These genetic mechanisms reveal nutrigenomic actions. Reviews on the medicinal properties of essential oils have been particularly considered. A wide diversity of nutrigenomic effects from essential oils useful potentially for food spicing is reviewed. General ideas are discussed about essential oils and their properties, such as anti-inflammatory, analgesic, immunomodulatory, anticancer, hepatoprotective, hypolipidemic, anti diabetic, antioxidant, bone-reparation, anti-depressant and mitigatory for Alzheimer's disease. The essential oils for food use are potentially promoting health agents, and, therefore, worth using as flavoring and condiments. Becoming aware of the modulating gene expression actions from essential oils is important for understanding their potential for use in household dishes as spices to improve health. PMID- 25532302 TI - Biotechnological valorization of pectinolytics and their industrial applications: a review. AB - In the last several years, in serious consideration of the worldwide economic and environmental issues there has been an increasing research interest in the value of naturally occurring bio-sourced materials. Agro-industrial based biomass comprised of pectin is an inexpensive, renewable, abundant natural resource that could be utilized for large-scale and cost-effective production of natural products i.e., pectinolytics. Pectinolytics are one of the most widely distributed enzymes in bacteria, fungi and plants. From ancient times to date, many methods have been introduced to improve the optimization of pectinolytics to obtain high yields of maximal purity. To expand the range of natural bio resources the rapidly evolving tools of biotechnology can lower the conversion costs and also enhance target yield of the product of interest. This green biotechnology presents a promising approach to convert most of the agricultural materials into a value-added product with multiple applications. Major advances have already been achieved in recent years in order to obtain high levels of purity with optimal yields. The present review begins with an overview of pectinolytics and their physico-chemical features, and their specific role with classification based on pectic materials. Information is also given on the culture influences and potential sources of pectinolytics, followed by a brief summary of various industrial and biotechnological applications and future considerations. PMID- 25532303 TI - Anticancer agents from diverse natural sources. AB - This review attempts to portray the discovery and development of anticancer agents/drugs from diverse natural sources. Natural molecules from these natural sources including plants, microbes and marine organisms have been the basis of treatment of human diseases since the ancient times. Compounds derived from nature have been important sources of new drugs and also serve as templates for synthetic modification. Many successful anti-cancer drugs currently in use are naturally derived or their analogues and many more are under clinical trials. This review aims to highlight the invaluable role that natural products have played, and continue to play, in the discovery of anticancer agents. PMID- 25532304 TI - [Methodological basis for modern stage of medical examination of the state aviation air crew]. AB - The main methodological framework to improve the system of medical examination of flight crews is the concept of occupational health. One of the important areas is the study of the epidemiology of professionally caused disadaptation functional disorders and subclinical disease in aircrew, their preclinical diagnosis and classification. Pointed to the need to improve organizational and practical principle of comprehensive and regular inspection of the body of the pilot, not only for diagnostic purposes, but also for the smooth conduct medical and rehabilitation measures. Proved the ways to achieve these goals. PMID- 25532305 TI - [The experience of creation and deployment of mobile medical units of EMERCOM of Russia]. AB - The experience of the creation and deployment of mobile medical units of EMERCOM of Russia: medical service of specialized fire department on large-scale fire suppression of the Main Directorate of the Russian Emergency Ministry of the Republic of Karelia and the field mobile medical unit of the Southern regional search and rescue team of EMERCOM of Russia. Medical service of specialized fire department on large-scale fire suppression of the Main Directorate of EMERCOM of the Republic of Karelia during the period from 2010 to 2012 provided medical assistance to 636 wounded, including 486 road traffic accident victims and 140 fire victims. Field mobile medical unit of the Southern Regional search and rescue team of EMERCOM of Russia during the humanitarian operation in the Republic of South Ossetia (August - September 2008) registered 635 calls for medical aid: 435 primary and 200--repeated; performed 10 operations. The characteristic structure of traumatic diseases and injuries is presented. Coverage of fluorography for students, teachers and schools staff in three districts of South Ossetia was 1041 (81.1%) patients, 6 (0.57%) cases of pulmonary tuberculosis were revealed among them. PMID- 25532306 TI - [Clinical picture, diagnostics and prophylaxis of a syndrome in conditions of the Far North]. AB - The analysis of a clinical picture barometeosensitivity in a seaside zone of the Far North is carried out in the article. A diagnostic test included the following laboratory assessments: complete blood count, complete urinary analysis, biomedical measurement assessment, immunology blood research and functional renal test; analysis of the level of an electrolyte in the blood and hormone receptor status; and the following instrumental diagnostics: The auscultatory Korotkov's method of determining blood pressure, electrocardiography, variational pulsometry, chest X-ray, mechanocardiography, echocardiography and abdominal ultrasound; and also consultation of ophthalmologist and neuropathologist. Every patient should keep a diary "weather - health" before and after the treatment. Peculiarities of cardiovascular system, vegetative systems and neuroendocrine system of servicemen, coming to the Far North and mechanisms of development of barometeosensivity were revealed. It has been established that atmospheric pressure variation affects systolic and diastolic blood pressure, heart rate, systolic discharge, Kerdo index, effectiveness of myocardial function, end diastolic and end-systolic volume, level of cholesterol, triglycerides, kalium, adrenalin, triiodothyronine, blood plasma and plasma renin activity in barometeosensetiv servicemen. The criteria of diagnostics of barometeosensivity in conditions of the Far North are suggested. The influence of baromemteosensivity on the combat capability of serviceman is researched. PMID- 25532307 TI - [Surgical peculiarities of gunshot injuries to arteries of the extremities caused by modern small arms and light weapons]. AB - The aim of the given study was development of surgical tactics in case of femoral artery injury, caused by medium-calibre bullet, on the basis acute experiment on large biological objects. Experimental animals were shot into mid third of the femora by a rifle cartridge in 7,62-mm calibre (AK-47 made in 1943). The analysis of microstructure, made in 5 cross-sections performed every 1-centimetre way from the wound canal, showed that there were no any damages of arterial wall. Authors came to conclusion that the surgical debridement of the gunshot wound, made by a rifle cartridge in 7,62-mm calibre of AK-47, should consist of exsection of devitalized section of artery. PMID- 25532308 TI - [Ballistocardiography as a part of cardiac function research]. AB - Provided an overview of materials on the history of the formation method ballistocardiography for diagnosis of cardiovascular disease, an assessment of its current status and prospects for further development. Investigation of the physiological changes in the myocardium by recording ballistocardiogram acquires greater relevance since the existing knowledge in the field of cardiac diagnosis were obtained using instruments that do not meet modern requirements. Although the results of previous studies and define the basic characteristics ballistocardiography nonetheless update and clarification of details in relation to the data obtained by the use of modern methods of measuring contractility of the myocardium, it is useful. The resumption of work on the development of reliable devices for ballistocardiography is an urgent task. Method ballistocardiography under military medicine may be used for the integrated assessment of the functional state of the cardiovascular system during clinical examination of servicemen during mass examinations of recruits, the selection of students in military schools, as well as in monitoring the hemodynamic status in a hospital. PMID- 25532309 TI - [Modern ideas about pain syndrome in Parkinson's disease]. AB - The analysis of the literature dedicated to modern ideas and achievements in the study of the pathogenesis, the incidence and characteristics of the clinical manifestations of pain syndromes in Parkinson's disease. It is shown that the disease is characterized by a variety of painful phenomena, combining features of the central and peripheral pain. Peripheral mechanisms of pain are realized as a consequence of mixed neuropathy (predominantly axonopathy) sensory and motor fibers. When electroneuromyographic study found a reduction of the amplitude sensory capacity, latency increase and decrease the speed of the pulse. PMID- 25532310 TI - [Pathogenic variants of brain injuries and pharmalogic cerebroprotection performed on the model of brain condition during cardiovascular bypass surgery]. AB - Developed and approved a pathogenic grounded experimental model of brain condition during cardiovascular bypass surgery. Undertaken in Wistar rats research allowed to evaluate in detail effectiveness and safety of protracted cerebroprotective treatment. Advantages of this model are researches in laboratory animals with the aim to research condition of nerve tissue, not intensive procedures and consequently high reproducibility and possibility of complex evaluation of changes at every stage of research. Results of neurons, neuroglia and activation of neurotrophic mechanisms prove that simulation of brain condition during cardiovascular bypass surgery is accompanied with acute and delayed brain injuries. Use of Cytoflavin under pharmalogic cerebroprotection had prolonged multimodal and neuroprotactive effect, leading to improvement of neurotrophic protection from the first days. PMID- 25532311 TI - [C-peptide level as an early diagnostic marker of metabolic syndrome and predictor of cardiovascular disease in patients with diabetes mellitus type 2]. AB - The aim of the present study was to investigate the relationship of C-peptide levels with insulin, resistance; components of metabolic syndrome and cardiovascular disease in patients with diabetes mellitus type 2. The study included 98 patients with diabetes mellitus type 2, who were divided into two groups by the level of C-peptide. The first group consisted of 54 patients with elevated levels of C-peptide; the second group consisted of 44 patients with normal levels of C-peptide. Our study has shown a positive correlation between C peptide levels and a body mass index (BMI), triglyceride levels and the triglyceride/high-density lipoprotein ratio. Correlation analysis also allowed identifying a statistically significant association of the HOMA-2-IR-C-peptide with a BMI, triglycerides and the triglyceride/high-density lipoprotein ratio. In the group of patients with elevated levels of C-peptide found in practically all components of metabolic syndrome, as well as a high incidence of arterial hypertension and ischemic heart disease. The study shows that the detection of the C-peptide level is preferred in comparison with insulin for assessment of insulin resistance, presence of metabolic syndrome and can be used in type 2 diabetic patients for early detection of cardiovascular risk. PMID- 25532312 TI - [Molecular genetic methods of identification of infectious bacterial agents]. AB - The paper presents an overview of modern molecular genetic methods for identification of pathogenic bacteria. One of the main current methods is the polymerase chain reaction and its modifications. Agarose gel electrophoresis is used for PCR analysis. The authors presented the advantages of the real-time fluorescent tag on this stage (quantitative PCR, Quantitative PCR, Q-PCR, Real Time PCR) and Flash PCR. Real-Time PCR permits quantitative analysis of a test sample and reduces analysis time. Simplified version of the PCR detection of the fluorescent signal is Flash PCR. In addition to PCR, there are other methods based on the amplification of DNA, in particular, the ligase chain reaction. Considered sophisticated methods of identification of pathogenic bacteria- multilocus sequence typing, the analysis of variable nucleotide tandem repeats. One of the most convenient methods for the complete identification of pathogenic bacteria can be sequenced bacterial genome. PMID- 25532313 TI - [Suppositions for development of preventive military air medicine]. AB - It is shown that on the basis of scientific concepts for regenerative medicine and organizational principles of prevention as a result of the research were revealed fundamental laws of life of the organism in an unusual environment. It is concluded that the need to integrate the methodology of research and testing aircraft and medical equipment on a single scientific basis. This will enable more productive use of research results in the field of ergonomics, ecology, and computer science in order to preserve the life and health of military personnel and maintain their combat capability. PMID- 25532314 TI - [The current state and prospectives of military endocrinology]. AB - The article is dedicated to the current state and prospectives of military endocrinology demonstrated on the examples of the endocrinology services of armed forces of Serbia, Poland, France, and USA. It is shown that this branch of military healthcare receives much attention abroad. The prospectives of military endocrinology are demonstrated in the context of two nosological forms which dominate in this section of military medicine, namely, primary hypothyroidism an diabetes mellitus. PMID- 25532315 TI - [Efim Ivanovich Smirnov--an outstanding founder of the military medicine and civil health care (to the 110th anniversary of birth)]. AB - In October 2014 we celebrate the 110th anniversary of the birth of Chief of the Main Military Medical Administration of the People's Commissariat of Defense, Minister of Health of the USSR, Hero of Socialist Labor, Member of the Academy of Medical Sciences of the USSR, Colonel-General of the Medical Service Efim Smirnov (1904-1989). The article highlights biographical information about him. PMID- 25532316 TI - [S.S. Yudin during the First World War]. AB - The article is devoted to famous Russian surgeon Sergei Sergeevich Yudin (1891 1954) and his life during 1914-1916. The article is based on a great collection of documents stored in Manuscripts Department of the Russian State Library. PMID- 25532317 TI - The spectroscopic and electronic properties of dimethylpyrazole and its derivatives using the experimental and computational methods. AB - In this paper the spectroscopic and the geometric properties of four ligands with pyrazole unit are studied at both experimental and computational levels. The computational results are perfectly in good agreement with the experimental results especially in terms of the IR, H-NMR and 13C-NMR shifts. The spectroscopic features as well as the computed properties help to establish the successful synthesis of ligands bdmpzm and bdmpza. The theoretical and the experimental IR and Raman significantly help in distinguishing the four ligands. The results show that the Raman spectral is better applicable in characterising the CH3 deformation, the C-H, CNN and CCNNout of the ligands but vibrations like N-H in dmpz and O-H, C=O in bdmpza are observed to be Raman inactive. A significant variations are observed among the two available * N atoms characterising the bidentate features of bdmpzm, bdmpza and bdcpzm which indicates a possible different affinities for metal coordination: Also the result suggest that bdmpza will be the best starting material for NLO application than other while bdcpzm is predicted to have potential of been a poor coordinating ligand. The computed variations in the properties of * N atoms that are the characteristic features of their power of coordination can be of immense help since these type of ligands have a wide application in transition metal coordination. PMID- 25532318 TI - Polymer crystallization dynamics investigated by synchronous scanning spectrum. AB - There is a cosine function between the reflected light intensity of a solid surface and its refractive index. And the mean squared fluctuation of refractive index is related to fluctuation of density and concentration. So some internal structures changes of materials can be reflected by changes in reflected light. Based on this theory, the synchronous scanning spectrum (SSS) technique was successfully applied to monitor melting and nonisothermal melt-crystallization of poly(epsilon-caprolactone) (PCL) film on a copper substrate. SSS can be implemented on a spectrofluorimeter by simultaneously scanning the excitation and emission monochromators (i. e, Deltalambda = lambdaex-lambdaem = 0 nm). In SSS of PCL films, two dominant peaks correlated to the light source spectrum of the spectrofluorimeter (at 467 and 473 nm) were used to characterize the macromolecular structure evolution during the melting and nonisothermal melt crystallization processes. Detailed thermodynamic and crystallization kinetics parameters obtained by SSS method. The Avrami exponent n obtained by SSS method is in the range of 2.8-3.2 with an average of 3.13, illustrating a heterogeneous nucleation process followed by a three-dimensional spherulitic crystal growth mechanism. The crystallization activation energy is -158.2 kJ . mol(-1). These results are in agreement with values determined from differential scanning calorimetry (DSC) method. It indicates that SSS technique is a simple, effective in situ method for measuring the dynamic melting and crystallization process of polymers. Moreover, the SSS method is a universal spectroscopic technique based on a spectrofluorimeter for monitoring both luminescent and non-luminous solid polymers. PMID- 25532319 TI - [Spectral characteristics of novel accelerometer based on optical microring resonator]. AB - A structure of an optical accelerometer based on an optical single ring resonator located onto the cantilever is proposed to meet the requirements of microminiaturization and economical applications in the present paper. The spectra of out port are obtained using transfer matrix method and theory of coupled modes. According to the measurement of intensity of drop port at the same wavelength, the influences of different structure parameters on the sensitivity of the whole acceleration sensor are analyzed. The results show that the cantilever length and thickness and the ring resonator position are all key factors which can influence the sensing property of acceleration sensor. Hence the sensitivity can be effectively improved by adjusting the factors mentioned above. The sensitivity reaches up to 2.112 g(-1) and the limit of detection can achieve 1.421 x 10(-3) at 1.515 MUm with a cantilever of 180 MUm in length and 3 in thickness for a 30 dB signal-noise system. Such structure has great potential to develop low-cost and easy made high sensitive acceleration meter. PMID- 25532320 TI - [Study of the termination of two acrylonitrile radicals and infrared spectrum]. AB - By using the density functional theory, the study of reaction termination mechanism of two (CH3)2 (CN)C--CH2-- (CN)CH was carried out at the B3LYP/6-31G(d) level. The initiator AIBN was used. Reactants, coupled intermediates, transition states and disproportionation products were optimized at the B3LYP/6-31G(d) level. Then the total energies corrected by zero-point energy, vibrational frequencies and electronic structures were calculated, the transition states structure was also verified. The results show that it forms the energy-rich adducts a through the coupling termination. Then, the disproportionation product P[p1 (CH3)2 (CN) C-CH=CHCN + p2 (CH3)2 (CN)C-CH2-CH2CN] formed via hydrogen shift and dissociation. The reactions of coupling termination and disproportionation termination are all exothermic reactions, and the coupled product has lower energy. The rate constant of step a->TS->P k(298.15 K) = 2.71 x 10(-59) at the normal atmospheric temperature. Disproportionation termination occurs more easily with the reaction temperature rising, so the proportion of disproportionation products is increasing. Also, the analysis of infrared spectrogram of each species in reaction process shows chemical change of free radicals in the whole termination reaction. The authors give the HOMO-LUMO in this paper to verify the accuracy of biradical coupling termination and structures. It has important guiding significance to controlling the free radicals termination methods of acrylonitrile monomer. PMID- 25532321 TI - [Study of self-absorption effect on laser-induced metal plasma]. AB - In order to reduce the effect of the spectral line self-absorption on the analysis result in the laser induced plasma and enhance the qualities of spectrum, the spectral information was recorded by the spectral analysis system consisting of a modular multifunctional grating spectrometer and a CCD detector etc., and the electron temperature and electron density of the plasma were measured with the spectroscopic methods. A plane mirror device was used to constraint the laser plasma, and a reasonable explanation was got through comparing the linear evolution under different experimental conditions and measuring the temperature, electronic density and sample evaporation. The result shows that when an appropriate plane mirror device was used to constraint the laser plasma, the axial temperature of the plasma increased and the radial distribution of the plasma becomes uniform; the electron density increased dramatically; however, obviously sample evaporation decreased, which may be the reasons for being able to effectively reduce the level of self-absorption spectral lines. Therefore, the plane mirror device could reduce the self absorption effect in the laser-induced plasma. This makes it possible to choose a sensitive line that acts as analysis line in the quantitative analysis of the major elements. In other words, this promotes the measurement precision in the laser-induced break-down spectroscopy. PMID- 25532322 TI - [Research on locking of the output power of pulsed laser in laser-induced breakdown spectroscopy]. AB - Laser-induced breakdown spectroscopy (LIBS) as a rapid spectral analysis technology shows the outstanding application foreground and research value in coal quality on-line monitoring. In the practical application of this technology, the pulsed laser power fluctuation leads to the worse performance of long term stability, so a closed-loop feedback pulsed laser power locking device is set up, using laser power feedback signal to control and lock Nd:YAG laser output power. The laser power locking experiments are investigated in the same pre-set value with different splitting ratios, the different laser output power with the same proportion and the long time running modes. The results show that the beam split ration has little impact to the stability of the laser power, and the smaller split ration leads to the faster stabilization. This device can keep the output power of the pulsed laser being locked in the pre-set range for a long-term running, RSD values decrease from 2.4% of free-running to 1.1%. PMID- 25532323 TI - [Studies on carbonization of saccharides by using aqueous solution of various acids]. AB - The authors tried to establish an approach to use acids to convert biomass into a fuel with higher carbon content and lower oxygen content in a zero-energy consumption fashion. Considering that biomass is composed of monosaccharide, we used aqueous solutions of variation acids including hydrochloric acid, sulfuric acid and perchloric acid to treat 2-deoxy-ribose and fructose at ambient temperature and pressure. Black substances were produced after a period of time when 2-deoxy-ribose and fructose were mixed with aqueous solutions containing 8 mol . L(-1) acids. The black substance was collected and characterized by using elemental analysis, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Elemental analysis results indicate that the contents of carbon increases significantly in the black substances in comparison with 2-deoxy-ribose and fructose. Moreover, XPS results indicate that the content of oxygen in the black substance undergoes a significant decrease compared with pure 2-deoxy-ribose and fructose. In the XPS spectra, the is peaks of 2-deoxy ribose, strong sub peak at 286. 05 eV, which is assigned to carbon linked to oxygen directly, dominate in the C is peak envelop. After treatment by HClO4, the peak decreased dramatically. This result also supports the conclusion that the content of oxygen in mono-saccharide is significantly reduced after treatment by acids. In the FTIR spectra of the black substances, strong peaks can be observed around 1 600 cm(-1), indicating that C==C bond is formed in the product. The above results suggest that treatments with acids may be developed as a new zero energy-consumption approach to convert biomass in a new fuel with improved energy output efficiency. PMID- 25532324 TI - [Research on night visibility inversion algorithm based on the dual light sources image and curve evolution theory]. AB - In the present paper, we propose a novel night visibility inversion algorithm. The key idea is based on the curve evolution theory in the context of dual light sources. First, we describe the features of the dual light sources night visibility inversion method, and explain the relationship between fluctuation of light source intensity and curve evolution with the special characters. Then, level set method is introduced ito define the light source intensity and establish the model with visibility inversion, and the algorithm formula is detailed. Experiments results show that, the algorithm is characterized with a strong robustness and compared with the standard visibility, the correlation of visibility result reaches up to 0.98 in the range of 2,000 meter to 12,000 me- ter, which can be used in the visibility monitoring with a large range, high precision and strong robustness. PMID- 25532325 TI - [Preparation of MgxZn1-xO/Au/MgxZn1-xO multilayer transparent conductive film and studies of its photoelectric properties]. AB - In the present paper, MgxZn1-xO and MgxZn1-xO/Au/MgxZn1-xO multilayer structures of transparent conductive film were prepared by the simple operation of sol-gel and RF magnetron sputtering method on quartz substrate respectively and then they were annealed. The surface, electrical, crystal and optical properties of the films at different annealing temperature were determined by UV-Vis spectrophotometer, X-ray diffraction, photoluminescence and Hall effect, respectively. The influence of annealing temperature on the films was also investigated. The testing results indicated that the films with good c-axis orientation presented hexagonal wurtzite structure. With increasing Mg components, the optical band gap of ZnO thin film increased gradually. There was an obvious blue shift phenomenon in PL spectrum and absorption spectrum line. But the electrical properties of the films declined. In MgxZn1-xO/Au/MgxZn1-xO multilayer structure of thin film samples, the existence of Au interlining led to the poor optical properties of thin film, and the light transmittance in the ultraviolet region was 60%. Compared with MgxZn1-xO film, the electrical properties of MgxZn1-xO/Au/MgxZn1-xO multilayer structure of transparent conductive film were improved, the resistivity and migration rate were significantly increased. In addition, high temperature annealing treatment could effectively improve the crystal quality of thin film and further improve the electrical characteristics of the samples. After the annealing treatment at 500 degrees C, migration rate of the film reached to 40.9 cm2 . 1 Vs(-1) while the resistivity was 0.0057 Omega . cm. Due to the rising of temperature, the crystal size increased from 25.1 to 32.4 nm to reduce the mobility of the film. Therefore, MgxZn1-xO/Au/MgxZn1-xO multilayer structure of transparent conductive film played an important role in promoting the ZnO transparent conductive film application in deep ultraviolet devices. PMID- 25532326 TI - [Highly efficient, color-stable white top-emitting organic light-emitting diodes]. AB - Top-emitting white organic light-emitting diodes (WOLEDs) have potential applications in lighting and full color dis- plays due to the potential realization of a large aperture ratio and a high resolution when recombining top emitting WOLEDs with active-matrix driving circuits. In the present paper, the authors fabricated top-emitting WOLEDs based on the red/blue dual-phosphorescent emitting layers and improved luminous efficiency and color stability in WOLEDs through inserting an tris(pheny-pyrazole)iridium (Ir(ppz)3) thin film as an electron-blocking layer between the red layer and the blue one. The insertion of an Ir(ppz)3 thin film can easily generate white emission through the enhancement of doping concentration of the red dopant, thus reducing the serious requirements of manufacture technology and improving the reproducibility of process technology. In addition, the authors analyzed the mechanism of color stability, optimized the concentrations of the red and blue phosphorescent dopants, and realized a luminous efficiency of as high as 7.9 cd . A(-1) in the authors' top emitting WOLED. The white emission lies in the warm-white region with a very small chromaticity change of (0.006, 0.01) under a wide brightness range of 87 2,403 cd . m(-2). PMID- 25532327 TI - [Research progress in the application of biosensors by using metamaterial in terahertz wave]. AB - In the present paper, the recent progress in terahertz metamaterials-based sensing is reviewed with the principle of metamaterial biosensor,metamaterial substrate, and structure design, respectively. The paper introduces the principle in detail, analyzes the sensitivity of the biosensor with the material and the thickness of the substrate and the structure of metamaterial. The analysis shows that we can enhance the sensitivity and resolution of biosensor by designing specific metamaterial structure, using low dielectric constant and low loss thin substrate, especially many materials have a specific response in the terahertz frequency. So, there is a large potential application for label-free sensing by using the terahertz metamaterials. This paper also presents the future development of THz metamaterial sensors. PMID- 25532328 TI - [Determination of degree of polymerization of natural cellulose pulp using near infrared diffuse reflectance spectroscopy]. AB - A new method of near-infrared (NIR) diffuse reflectance spectroscopy is proposed to rapidly determine the degree of polymerization (DP) of natural cellulose (cotton and wood) pulp produced by a new clean pulping process. One hundred and ninety five samples were collected and their DP data were determined by standard method GB/T 9107-1999. The spectroscopy measurement method of the samples was studied and their near-infrared diffuse reflectance spectra were collected. The quantitative DP calibration models of one mixed cotton & wood and two separate cotton and wood pulps were established by partial least squares (PLS). The optimum models were developed using the spectra pretreated by derivative, autoscaling and mean-centering, and their performance is as follows: correlation coefficient of 0.980, 0.993 and 0.886, and RMSEP of 147, 143 and 53, respectively. The accuracy of NIR method was also studied. The results show that the accuracy of the two separate models of cotton and wood is better than that of the mixed model, and the precision of the two separate models is better than that of GB/T9107-1999. The identification model of cotton and wood was also established using principal component analysis (PCA). The result shows that the spectra of cotton and wood pulp have obvious difference, and the model can identify successfully the two kinds of pulp. The result indicates that the new NIR method is feasible to realize the on-line analysis of polymerization degree of natural cellulose pulp with its advantage of rapidness and easy operation. PMID- 25532330 TI - [Application of visible/near-infrared spectroscopy to the determination of catalase and peroxidase content in barley leaves]. AB - Visible/near-infrared spectroscopy was applied to determine the content of catalase (CAT) and peroxidase (POD) in barley leaves under the herbicide stress of propyl 4-(2-(4, 6-dimethoxypyrimidin-2-yloxy) benzylamino) benzoate (ZJ0273). The spectral data of the barley leaves in the range of 500-900 nm were preprocessed by moving average with 11 points. Seven outlier samples for CAT and 8 outlier samples for POD were detected and removed by Monte Carlo-partial least squares (MCPLS). PLS, least-squares support vector machine (LS-SVM) and extreme learning machine (ELM) models were built for both CAT and POD. ELM model obtained best results for CAT, with correlation coefficient of calibration (Rc) of 0.916 and correlation co-efficient of prediction (Rp) of 0.786. PLS model obtained best prediction results for POD, with Rc of 0.984 and Rp of 0.876. Successive projections algorithm (SPA) was applied to select 8 and 19 effective wavelengths for CAT and POD, respectively. PLS, LS-SVM and ELM models were built using the selected effective wavelengths of CAT and POD. ELM model performed best for CAT and POD prediction, with Rc of 0.928 and Rp of 0.790 for CAT and Rp of 0.965 and Rp of 0.941 for POD. The prediction results using the full spectral data and the effective wavelengths were quite close, and the prediction performance for POD was much better than the prediction performance for CAT, and the studies should be further explored to build more precise and more robust models for CAT and POD determination. The overall results indicated that it was feasible to use visible/near-infrared spectroscopy for CAT and POD content determination in barley leaves under the stress of ZJ0273. PMID- 25532329 TI - [Research progress and application prospect of near-infrared spectroscopy in analysis of food amino acid]. AB - To investigate the progress and application of near infrared spectroscopy (NIR) used to detect amino acids in the growth of crops and food processing process. With online searching databases including ISI (Web of Knowledge), CNKI (China Knowledge Network), summarize the detection of chemical value using high performance liquid chromatography (HPLC) and chemometric methods involved in the application of NIR used to analyze amino acids in food, meanwhile summarize the data, materials and main topics in relevant original literature. Overview the methods of chemical value detection using HPLC and chemometric analysis, their applications in detecting the quality of crops, determining the content of water, amino acids and polyphenol in green tea, detecting the quality of feed and determining the content of amino acids in cheese, ham and meat products, We forecasted the application of NIR in determining the content of amino acids in food and analyzed its merits and drawbacks. The development of NIR's application in amino acids detection should be based on the HPLC detection, and the problem of model transfer mainly restricts its large-scale promotion currently. Online analysis can monitor the entire reaction and change process from raw materials to products and thus meets the needs of real-time monitoring food quality from production to sales, and it will be an important direction for future. PMID- 25532331 TI - [The effect of MSC spectral pretreatment regions on near infrared spectroscopy calibration results]. AB - In the present paper, 60 whole wheat flour samples were prepared and corresponding NIR spectra were collected. After the determinations of calibration range, several spectral sub-regions containing calibration range and prepared for the correction using multiple scattering correction (MSC) were obtained in the whole spectral region firstly, and MSC correction based on different spectral sub region followed subsequently. Corresponding spectral data were obtained from the fixed calibration range of the spectra corrected based on different regions. Several partial least squares regression (PLSR) calibration models for analyzing protein content of whole wheat flour were established based on corresponding spectral data, and according to the performance about the calibration coefficient and the root mean square error of cross validation (RMSEV) of every calibration, the effects of MSC pretreatment spectral region on PLSR calibration results were investigated and the pretreatment spectral regions were optimized by comparing theperformance of more calibration models. For the optimized calibration, the calibration coefficient and the RMSECV improved compared with the calibration established based on the spectral data corrected using MSC in the fixed region of calibration. The correlation coefficient can be raised from 0.96 to 0.98 and RMSECV can be decreased from 0.37% to 0.32%. The results show that the capability of MSC on correcting the spectral interference information of non-chemical absorption can be influenced by preprocessing spectral regions, the performance of calibration model can be improved by optimizing the MSC pretreatment spectral region, and the appropriate pretreatment spectral region is prerequisite to obtain the best calibration results while using MSC for near-infrared spectra analysis. PMID- 25532332 TI - [Rapid assessment of critical quality attributes of Chinese materia medica (II): strategy of NIR assignment]. AB - The present paper firstly reviewed the research progress and main methods of NIR spectral assignment coupled with our research results. Principal component analysis was focused on characteristic signal extraction to reflect spectral differences. Partial least squares method was concerned with variable selection to discover characteristic absorption band. Two-dimensional correlation spectroscopy was mainly adopted for spectral assignment. Autocorrelation peaks were obtained from spectral changes, which were disturbed by external factors, such as concentration, temperature and pressure. Density functional theory was used to calculate energy from substance structure to establish the relationship between molecular energy and spectra change. Based on the above reviewed method, taking a NIR spectral assignment of chlorogenic acid as example, a reliable spectral assignment for critical quality attributes of Chinese materia medica (CMM) was established using deuterium technology and spectral variable selection. The result demonstrated the assignment consistency according to spectral features of different concentrations of chlorogenic acid and variable selection region of online NIR model in extract process. Although spectral assignment was initial using an active pharmaceutical ingredient, it is meaningful to look forward to the futurity of the complex components in CMM. Therefore, it provided methodology for NIR spectral assignment of critical quality attributes in CMM. PMID- 25532333 TI - [Myanmar jadeitite low-temperature metamorphic water-rock reaction: eveidence from microscopic fourier transform infrared spectroscopy]. AB - Weathering & transporting and depositing processes may improve the quality of some natural low-quality jadeite through reaction with surrounding water fluids. But the mechanism of such water-rock reaction has not been known clearly to date. Applying microscopic Fourier transform infrared spectroscopy (Micro-FTIR), this paper carried out comparatively in-situ research of jadeites' mineral composition before and after water-rock reaction. The results show that water-rock reaction cannot impact jadeites in their major and minor element composition, but greatly change their water content. Jadeites became richer, with even several times increase, in water content, after experiencing water-rock reaction, and hence show a shift of absorption peak at 3 550 cm(-1) to higher frequency. The mineral crystals of these jadeites showed reglar variation in water content from core to edge, and these jadeites have more water in marginal area than in center area, being opposite to the change in water content in jadeite during high temperature and pressure metamorphic process, hence implying that there are different mechanism and shift direction for H+/OH of jadeite between high pressure metamorphic process and low temperature water-rock reaction. We think that this finding may contribute to understanding the behavior of water in jadeite during metamorphic process and the mechanism of jadeite quality improvement. PMID- 25532334 TI - [Study on brand traceability of vinegar based on near infrared spectroscopy technology]. AB - In the present paper, 152 vinegar samples with four different brands were chosen as research targets, and their near infrared spectra were collected by diffusion reflection mode and transmission mode, respectively. Furthermore, the brand traceability models for edible vinegar were constructed. The effects of the collection mode and pretreatment methods of spectrum on the precision of traceability models were investigated intensively. The models constructed by PLS1 DA modeling method using spectrum data of 114 training samples were applied to predict 38 test samples, and R2, RMSEC and RMSEP of the model based on transmission mode data were 0.92, 0.113 and 0.127, respectively, with recognition rate of 76.32%, and those based on diffusion reflection mode data were 0.97, 0.102 and 0.119, with recognition rate of 86.84%. The results demonstrated that the near infrared spectrum combined with PLS1-DA can be used to establish the brand traceability models for edible vinegar, and diffuse reflection mode is more beneficial for predictive ability of the model. PMID- 25532335 TI - [Influence of silver/silicon dioxide on infrared absorption spectroscopy of sodium nitrate]. AB - Quickly detecting of ocean nutrient was one important task in marine pollution monitoring. We discovered the application of surface-enhanced infrared absorption spectroscopy in the detection of ocean nutrient through researching the evaporation of sodium nitrate solution. The silicon dioxide (SiO2) with highly dispersion was prepared by Stober method, The silver/silica (Ag/SiO2) composite materials were prepared by mixing ammonia solution and silicon dioxide aqueous solution. Three kinds of composite materials with different surface morphology were fabricated through optimizing the experimental parameter and changing the experimental process. The surface morphology, crystal orientation and surface plasmon resonance were investigated by means of the scanning electronic microscope (SEM), X-ray diffraction (XRD), UV-Visible absorption spectrum and infrared ab- sorption spectroscopy. The SEM images showed that the sample A was purified SiO2, sample B and sample C were mixture of silver nanoparticle and silicon dioxide, while sample D was completed nanoshell structure. The absorption spectroscopy showed that there was surface plasmon resonance in the UV-visible region, while there was possibility of surface plasmon resonance in the Infrared absorption region. The effect of Ag/SiO2 composite material on the infrared absorption spectra of sodium nitrite solution was investigated through systematically analyzing the infrared absorption spectroscopy of sodium nitrate solution during its evaporation, i. e. the peak integration area of nitrate and the peak integration area of water molecule. The experimental results show that the integration area of nitrate was enhanced greatly during the evaporation process while the integration area of water molecule decreased continuously. The integration area of nitrate comes from the anti-symmetric stretch vibration and the enhancement of the vibration is attributed to the interface effect of Ag/SiO2 which is consistent with Jensen T.R's result. PMID- 25532336 TI - [Analysis on the impact of composting with different proportions of corn stalks and pig manure on humic acid fractions and IR spectral feature]. AB - Using pig manure and corn straw as raw materials for high-temperature composting, setting three different treat- ments: C/N 15, C/N 25, and C/N 35. Composting period is 120 days, which contains 30 days for ventilation cycle by forced continuous ventilation. Sampled on 0, 22, 30, 60, 90, 120th days, they were analyzed by elemental analysis and IR spectroscopy to study effect of different lignin content on compost humic acid (HA) composition and molecular structure. The results showed that the change in composting humic acid C focused on the first 30 days, while after composting, the O/C of compost HA increased, H/C decreased, and N content increased. Low C/N (15) and higher C/N ratio (35) had higher degree of oxidation than the C/N 25 in compost HA. FTIR indicated that the infrared spectrum shapes with different lignin content treatment are similar during the composting process, but the peak intensity is obviously different. Research results proved that the composting stage is more conducive to enhanced aromatic in compost HA. After composting, C/N 15 had less polysaccharide and fat ingredients and more aromatic structural components in compost HA, compared with C/N 25 and 35. In addition, compost HA of C/N 15 had higher degree of humification and its structure was more stable. PMID- 25532337 TI - [Identification of some Piper crude drugs based on Fourier transform infrared spectrometry]. AB - The common peak ratio and variant peak ratio were calculated by FTIR spectroscopy of seven medicinal plants of Piper. The dual index sequence of common peak ratio and variant peak ratio was established, which showed the sibship of the medicinal plants. The common peak ratio of Piper kadsura (Choisy) Ohwi, Piper wallichii (Miq.) Hand.-Mazz. Piper laetispicum (C. DC.) was greater than 77%, and the variant peak ratio was less than 30%. The results showed the near sibship between the three drugs. The common peak ratio of Piper kadsura (Choisy) Ohwi, Piper nigrum L. and Piper boehmeriae folium Wall (Miq.) C. DC. Var. tonkinense (C. DC.) was about 61% which showed the farther sibship. The common peak ratio of Piper kadsura (Choisy) Ohwi and Piper betle (Linn.) was only 44%, which showed the farthest sibship. Piper kadsura (choisy) Ohwi and its adulterants, such as Piper wallichii (Miq.) Hand. -Mazz., Piper boehmeriaefolium Wall (Miq.) C. DC. Var. tonkinense C. DC. , Piper laetispicum C. DC., Piper nigrum L., could be identified by comparing their second order derivative IR spectrum of the samples. FTIR technique is a non-destructive analysis method which provides information of functional group, type and hydrogen bond without complex pretreatment procedures such as extraction and separatioin. FTIR method has some characteristics such as rapid and simple analysis procedure, good reproducibility, non-destructive testing, few amount of required sample and low cost and is environment-friendly. The method solved the problems of limit in resource of Piper kadsura (Choisy) Ohwi, many fakes and difficulties in identification, and brought the security for the clinical medication. FTIR provides a new method for identification of Piper kadsura (choisy) Ohwi and its fakes and meets the requirement for comprehensive analy sis and global analysis of traditional Chinese medicine. PMID- 25532338 TI - [Identification of pearl powder using microscopic infrared reflectance spectroscopy]. AB - Pearl is a precious ornament and traditional Chinese medicine, which application history in China is more than 2000 years. It is well known that the chemical ingredients of shell and pearl are very similar, which all of them including calcium carbonate and various amino acids. Generally, shell powders also can be used as medicine; however, its medicinal value is much lower than that of pearl powders. Due to the feature similarity between pearl powders and shell powders, the distinguishment of them by detecting chemical composition and morphology is very difficult. It should be noted that shell powders have been often posing as pearl powders in markets, which seriously infringes the interests of consumers. Identification of pearl powder was investigated by microscopic infrared reflectance spectroscopy, and pearl powder as well as shell powder was calcined at different temperatures for different time before infrared reflectance spectroscopy analysis. The experimental results indicated that when calcined at 400 degrees C for 30 minutes under atmospheric pressure, aragonite in pearl powder partly transformed into calcite, while aragonite in shell powder completely transformed into calcite. At the same time, the difference in phase transition between the pearl powders 'and shell powders can be easily detected by using the microscopic infrared reflectance spectroscopy. Therefore, based on the difference in their phase transition process, infrared reflectance spectroscopy can be used to identify phase transformation differences between pearl powder and shell powder. It's more meaningfully that the proposed infrared reflectance spec- troscopy method was also investigated for the applicability to other common counterfeits, such as oyster shell powders and abalone shell powders, and the results show that the method can be a simple, efficiently and accurately method for identification of pearl powder. PMID- 25532339 TI - [Analysis and identification of Semen Glycines Nigrae and Semen Pharbitidis by infrared spectroscopy]. AB - Semen Glycines Nigrae and Semen Pharbitidis containing a large amount of fats and proteins are commonly used in Chinese herbal medicine. Tri-step infrared spectroscopy was applied to fast analyze and identify the two samples. In the conventional infrared spectroscopy, the samples both have obvious characteristic absorption peaks at 1,745 cm(-1) assigned to the stretching mode of C==O in esters. Furthermore, the two kinds of herbs have the peaks at 1,656 and 1,547 cm( 1) assigned to the amide I and II bands of protein. Obviously, the infrared spectra of herbs demonstrate that protein and fat is the major component in two kinds of herbs, and the relative intensity of the peaks assigned to fat and protein indicate their relative content is different. And the result is consistent with the reported. In the second derivative spectra, Semen Pharbitidis has a peak at 1,712 cm(-1) assigned to the organic acid, however, Semen Glycines Nigrae has not this absorption peak. In addition, in the second derivative spectra, appeared more differences between the two samples in shape and intensity of the peaks. In two-dimensional correlation infrared spectra, the two samples were visually distinguished due to their significant differences in auto-peak position and intensity. In the region of 1,500-1,700 cm(-1), Semen Glycines Nigrae has two autopeaks and Semen Pharbitidis has three autopeaks. In the region of 2,800-3,000 cm(-1), the samples both have two autopeaks, but the position of the strongest autopeak is different. It was demonstrated that the Tri-step infrared spectroscopy were successfully applied to fast analyze and identify the two kinds of samples containing the same major component, and made sure the foundation for future researches. PMID- 25532340 TI - [The analyses and identification of Flos rhododendri mollis and Flos chrysanthemi indici via infrared spectroscopy]. AB - In this study, major chemical components of Flos rhododendri mollis and Flos chrysanthemi indici were characterized using Fourier transform infrared spectroscopy (FTIR). For Flos rhododendri mollis, the bands at 1,648 and 1,543 cm(-1) were attributed to amide I and amide II , respectively, indicating that it contained proteins probably resulting in immunization. In case of Flos chrysanthemi indici, stretching vibration of C==O function group was responsible for the bands at 1,734 and 1,515 cm(-1), as a result of essential oils, lipids, etc. Since FTIR spectra of Flos rhododendri mollis and Flos chrysanthemi indici are almost identical and it is difficult to discriminate them, two-step identification was investigated via secondary derivative of the FTIR spectra. The bands at 1,656 and 1,515 cm(-1) corresponds to flavonoides in Flos rhododendri mollis and Flos chrysanthemi indici. In the secondary derivative of the FTIR spectrum of Flos chrysanthemi indici, characteristic bands of inulin were present at 1,163, 1,077, 1,026, 986 and 869 cm(-1), and therefore Flos chrysanthemi indici contained inulin as well. Tri-step identification was carried out for Flos rhododendri mollis and Flos chrysanthemi indici by means of comparing their 2D-IR correlation spectra in different wave number range. In the characteristic range of flavonoides (1,700-1,400 cm(-1)), Flos rhododendri mollis exhibited 3 obvious autopeaks, while 10 autopeaks were visualized in the 2D-IR correlation spectrum of Flos chrysanthemi indici Moreover, in the characteristic range of glucoside (1,250-900 cm(-1)), 10 and 9 autopeaks were present in the 2D-IR correlation spectra of Flos rhododendri mollis and Flos chrysanthemi indici, respectively. Therefore, the tri-step identification of FTIR is a time-saving; accurate, cost saving and convenient method to effectively distinguish traditional Chinese medicines. PMID- 25532341 TI - Micro-Raman spectral characteristics and implication of FeS2 from Augen granites in west of Guangdong. AB - Some FeS2 samples among Augen granite from Guanshanzhang mass in the west of Guangdong Province were retrieved to characterize the spectral signature of Raman. The results show that three distinct scattering modes active of Fe-[S2]2- Liberational Motion (Eg), Fe-[S2]2- Stretching Motion (Ag) and S--S Stretching Motion (Tg) are observed from all samples. Detailed analyses indicate that Raman shift (Deltaupsilon), Modes intensity (I) and full width at half maximum (FWHM) are different between each type pyrite. The spectra show that there are three peaks respectively about 318 cm(-1) (Deltaupsilon1), 381 cm(-1) (Deltaupsilon1) and 440 cm(-1) (Deltaupsilon1) in Banded pyrite and three peaks in others samples about 344 cm(-1) (Deltaupsilon1), 379 cm(-1) (Deltaupsilon1) and 430 cm(-1) (Deltaupsilon1). Under compression to Alterated pyrite, all modes (Eg, Ag and Tg) shift continuously to higher frequencies from Deformed samples to Euhedral type. Eg mode is much intenser than Ag mode as well as the latter is intenser than Tg mode too in Banded samples (I(Eg) >> I(Ag) >> I(Tg)), the intensity of Ag mode is higher than Eg mode, and the latter is much higher than Tg mode in other samples (I(Ag) > ?I(Eg) >> I(Tg)). Compared with Alterated pyrite, all modes of Eg, Ag and Tg intense continuously to higher frequencies from Euhedral samples to Deformed type. Those spectral characteristics above evidence that, the Raman shift and intensity of Banded samples is similar to marcasite, while those of others show characteristics of the pyrite. The crystallization temperature of Euhedral pyrite is higher than Deformed as well as Euhedral is higher than Alterated too. The formation pressure of Euhedral samples is higher than Alterated pyrite the same as Deformed pyrite hingher than Euhedral one too. Thus, The authors' studies suggest that the forming conditions of FeS2 in Guanshanzhang mass experienced marcasite period-->high-pressure pyrite period--> high temperature pyrite period-->Alterated pyrite period. PMID- 25532342 TI - [Three-dimensional vertically aligned CNTs coated by Ag nanoparticles for surface enhanced Raman scattering]. AB - In order to make surface-enhanced Raman scattering (SERS) substrates contained more "hot spots" in a three-dimensional (3D) focal volume, and can be adsorbed more probe molecules and metal nanoparticles, to obtain stronger Raman spectral signal, a new structure based on vertically aligned carbon nanotubes (CNTs) coated by Ag nanoparticles for surface Raman enhancement is presented. The vertically aligned CNTs are synthesized by chemical vapor deposition (CVD). A silver film is first deposited on the vertically aligned CNTs by magnetron sputtering. The samples are then annealed at different temperature to cause the different size silver nanoparticles to coat on the surface and sidewalls of vertically aligned CNTs. The result of scanning electron microscopy(SEM) shows that Ag nanoparticles are attached onto the sidewalls and tips of the vertically aligned CNTs, as the annealing temperature is different , pitch size, morphology and space between the silver nanoparticles is vary. Rhodamine 6G is served as the probe analyte. Raman spectrum measurement indicates that: the higher the concentration of R6G, the stronger the Raman intensity, but R6G concentration increase with the enhanced Raman intensity varies nonlinearly; when annealing temperature is 450 degrees C, the average size of silver nanoparticles is about 100 to 120 nm, while annealing temperature is 400 degrees C, the average size is about 70 nm, and the Raman intensity of 450 degrees C is superior to the annealing temperature that of 400 degrees C and 350 degrees C. PMID- 25532343 TI - [Study of volatile organic compounds of fresh allium species using headspace combined with surface-enhanced Raman scattering]. AB - In order to identify volatile organic compounds of fresh plants at room temperature and avoid sample pretreatment and extractions which can be labor intensive, garlic, Chinese chives and scallion were chopped into pieces. Then some of them were placed in the headspace vial and sealed. The gases were drawn from the vial with a syringe and were injected very slowly into Ag colloids for test using R-3000 portable Raman spectrometer. The spectra of volatile organic compounds of allium species, fresh garlic, Chinese chive and shallot plants were successfully.recorded for the first time. For garlic high intensity bands are present at 307, 399, 569, 711, 1,182, 1,287, 1,397 and 1,622 cm(-1). For Chinese chives the high intensity band is present at 672 cm(-1). Low intensity bands are present at 274, 412, 575, 1,185, 1,289, 1,396, 1,618 cm(-1). For shallot high intensity bands are present at 693 cm(-1). Lower intensity bands are present at 372, 888, 1,023 cm(-1). Low intensity bands are present at 1,088, 1,211 and 1,322 cm(-1). The SERS of diallyl disulfide, allyl methyl sulfide and 1-propanethiol in liquid state and gas state were also obtained. The main volatile organic compound of fresh garlic, Chinese chive and shallot are diallyl disulfide, allyl methyl sulfide and 1-propanethiol respectively, and the volatile organic compound of fresh onion, scallion, shallot and chive are all 1-propanethiol. The presented results illustrate that combining headspace and SERS is a powerful tool for volatile organic compound analysis in fresh plants. The volatile organic compound can be detected in fresh plant samples directly and quickly without extraction. PMID- 25532344 TI - [Theoretical investigation on the structure and vibration spectrum of D luciferin]. AB - In the present study, the geometry of D-Luciferin was fully optimized by the density functional theory at the B3LYP/6-311++G** and B3PW91/6-311++G** level, and the Cartesian coordinate force constant was calculated at the same level. The scaled quantum mechanism force field (SQM) method was performed to analyze the vibration spectrum. The local internal symmetry coordinates were defined using the method given by Pulay. The theoretical force field matrix, which was obtained through molecular vibration calculation programs, was transformed from Cartesian coordinates into the local internal coordinates. A normal coordinate analysis was carried out using GF matrix method developed by Wilson to give the scaled vibration frequencies and the potential energy distributions (PEDs). In order to make the vibration frequencies in good agreement with the experimental values, we empirically scale the theoretical force fields. According to PEDs, all vibration modes were assigned reliably to certain vibration frequencies. The calculated results show that the D-Luciferin molecule belongs to the point group C1 and involves 66 free degrees of vibration. All vibration modes are infrared and Raman activity. In the Infrared spectrum, the vibration frequency of the strongest absorption peak is 1,780 cm(-1), and the absorption intensity is 507 KM . mol( 1), which is mainly contributed by the stretching vibration mode of the C21==O22, double bond with the PEDs of 93%. In the Raman spectrum, the vibration frequency in the range of 1,200-1.700 cm(-1) presented strong Raman activity, the frequency of the strongest absorption peak is 1,573 cm(-1), and the absorpiton intensity is 297 KM . mol, which is mainly contributed by the stretching vibration made of the C21==N22 double bond in the five-membered ring. The results are helpful to further studying the structure and the luminescence activity of Luciferin derivatives in experiment and theory. PMID- 25532345 TI - [Study on quantitative mechanism and the interference of the UV spectrum of HABS reduced by beta-Cyclodextrin]. AB - A novel ultraviolet absorption spectrometry method was developed for the quantitative determination of HABS by adding beta-cyclodextrin with the molar ratio of 1:1 in strong interference aqueous solution. The results indicated that the effect of several common interfering flooding agents (SAS, OP-10, HPAM) on the determination of HABS could be greatly reduced in beta- cyclodextrin aqueous solution. Thus, the determination errors of the determined HABS were less than 2.0% under strong inter- ference, and the detection limit (S/N==3) of the method could be also as high was 8.3-9.1 x 10(-4) mg . L(-1). Various characterization results including 1H-NMR, TG-DSC and FTIR showed the interaction between beta cyclodextrin and HABS. The results of H-NMR analysis showed that HABS molecule could enter into the interior of the cavity of beta-cyclodextrin molecule. TG-DSC analysis exhibited that the stable inclusion of beta-cyclodextrin and HABS could be automatically formed. The interactions between the functional groups of beta cyclodextrin and HABS were showed by FTIR analysis, which also exhibited that the stable inclusion could be formed by HABS entering from the narrow or the broad mouth of the beta-cyclodextrin. The interference of the UV spectrum of HABS could be reduced by beta-cyclodextrin since the interaction between beta-cyclodextrin due to the interaction between beta-cyclodextrin and HABS in the inclusion complex. PMID- 25532346 TI - [Analysis of fluorescence spectrum of petroleum-polluted water]. AB - In four ratio experiments, natural waters, sampled from the mountain reservoir and the sea water around Dalian city, were mixed with the sewage from petroleum refinery and petroleum exploitation plants. The fluorescence spectra of water samples containing only chromophoric dissolved organic matters(CDOM), samples containing only petroleum, and samples containing a mixture of petroleum and CDOM were analyzed, respectively. The purpose of this analysis is to provide a basis for determining the contribution of petroleum substances and CDOM to the total absorption coefficient of the petroleum-contaminated water by using fluorescence technique. The results showed that firstly, CDOM in seawater had three main fluorescence peaks at Ex: 225-230 nm/Em: 320-330 nm, Ex: 280 nm/Em: 340 nm and Ex: 225-240 nm/Em: 430-470 nm, respectively, and these may arise from the oceanic chlorophyll. CDOM in natural reservoir water had two main fluorescence peaks at EX: 240- 260 nm/Em: 420-450 nm and Ex: 310~350 nm/Em: 420--440 nm, respectively, and these may arise from the terrestrial sources; secondly, the water samples containing only petroleum extracted with n-hexane had one to three fluorescence spectral peaksat Ex: 220-240 nm/Em: 320-340 nm, Ex: 270-290 nm/Em: 310-340 nm and Ex: 220-235 nm/Em: 280-310 nm, respectively, caused by their hydrocarbon component; finally, the water samples containing both petroleum and CDOM showed a very strong fluorescence peak at Ex: 230-250 nm/Em: 320-370 nm, caused by the combined effect of CDOM and petroleum hydrocarbons. PMID- 25532347 TI - [Study of the air plasma expansion dynamics by fluorescence method]. AB - The expansion dynamics of air plasma induced by 1,064 nm nanosecond laser pulse was studied by plasma fluorescence method. The time evolution images of air plasma expansion were acquired using the ICCD camera at different laser pulse energy, and the expansion velocity of air plasma was deduced based on the air plasma frontier expansion wave front distance at 150 mJ. The experimental results show that the plasma fluorescence was mainly distributed in the plasma expansion region, the plasma fluorescence intensity firstly increased then became weaker and the expansion area increased gradually with time evolution. The biggest expansion distance was 3. 76 mm with 300 mi at 20 ns. The plasma expansion speed was the order of magnitude of 10s m . s(-1) at the early stage of expansion process. The expansion speed of air plasma decayed rapidly within 16ns, then changed slowly with time. The time of air breakdown was close to the rising phase of laser pulse when the greater laser pulse energy was radiated. PMID- 25532348 TI - [The field radiometric calibration and validation of ZY-3 multispectral sensor]. AB - A field calibration campaign of ZY-3 multispectral sensor (MUS) was performed by the China Center for Resources Satellite Data and Application at the Dunhuang site. The reflectance-based method with two-point sites was used to obtain MUS absolute calibration coefficients in 2013. Compared to the calibration results in 2012, the calibration coefficients in 2013 changed by about 1%-8.5% in different bands. The results were also validated by intercalibration method using the Landsat 8 Operational Land Imager (OLI) data. It shows largely good consistency between field calibration and intercalibration. It was concluded that the absolute calibration coefficients were highly reliable. PMID- 25532349 TI - [Resonance Rayleigh scattering determination of trace tobramycin using aptamer modified nanogold as probe ]. AB - Nanogold (NG) was prepared using NaBH4 reduction of HAuCl4. The NG was modified by the tobramycin-aptamer to obtain a stable Apt-NG probe for tobramycin. The three aptamers containing 15, 21 and 27 bases were examined, and results showed that the aptamer with 21 bases was best and was chosen for use. In pH 6. 8 PBS buffer solution and in the presence of NaCl, the Apt-GN probes were not aggregated. When tobramycin was added, it reacted with the Apt of Apt-NG probe to form a very stable Apt-Tbc complex and released NGs that were aggregated into big particles under the action of NaCl with three resonance Rayleigh scattering peaks at 285, 368 and 525 nm respectively. The resonance Rayleigh scattering peak increased at 368 nm due to the formation of big NG particles from the probe. The effect of pH buffer solution, its volume, and Apt-GN probe concentration on the DeltaI value was considered. A 200 MUL pH 6. 8 PBS buffer solution and 19. 1 nmol . L(-3) Apt-GN, giving max DeltaI value, were chosen for use. Under the chosen conditions, the increased resonance Rayleigh scattering intensity DeltaI368 nm was linear with Tbc concentration in the range of 1.9-58.3 ng mL(-3), with a regress equation of DeltaI = 35.3c-23 and a detection limit of 0.8 ng . mL(-3) Tbc. A 10.0, 20.0 and 30.0 ng mL-3 Tbc was determined five times respectively, and the relative standard deviations were 6.8%, 5.0% and 4.4%. The influence of some foreign substances was examined on the determination of 38.9 ng . mL(-3) Tbc, within +/-10% related error. Results showed that a 80 times of Zn2+, 40 times of L-glutamic acid, Cu2+, Mg2+ and Ca2+, 20 times of glucose and terramycin, 10 times of L-phenylalanine and glycin, 2 times of L-aspartic acid, and 6 times of bovine serum albumin (BSA) and human serum albumin (HSA) do not interfere with the RRS determination of Tbc. The results showed that this aptamer nanogold RRS method is of good selectivity. Tbc in real sample was analyzed, and the analytical result was in agreement with that of reference results, with a relative standard deviation of 6.5%-7.6% and a recovery of 95.0%-107%. PMID- 25532350 TI - [Models for estimating foliar Fe and Mn Concentration of Armeniaca vulgaris cv. Luntaibaixing using spectral reflectance]. AB - Aimed at providing technology for a rapid nutrition diagnosis system of micronutrients in Armeniaca vulgaris cv. Luntaibaixing, we established an element concentration estimation model for its foliar ferrum (Fe) and manganese (Mn) concentration based on spectrum analysis. The foliar spectrum reflectance at various phenological periods of fruit development under different soil fertility conditions was measured by Unispec-SC spectrometer. By analyzing the correlation of foliar Fe, Mn concentration at various phenological periods of fruit development, the spectrum reflectance Rlambda and its first-order differential f' (Rlambda), we filtered out its sensitive bands. And we established an element concentration estimation model for its foliar Fe and Mn at various phenological periods of fruit development with the linear regression model. The results showed that the spectral sensitive bands of foliar Fe in fruit setting period were 873 and 874 nm, 375 and 437 nm in fruit core-hardening period, 836 and 837 nm in maturity period and 325 and 1 054 nm in post-harvest period. However, the spectral sensitive bands of Mn were 913 and 1 129 nm, 425 and 970 nm, 390 and 466 nm, 423 and 424 nm, respectively. The Fe and Mn concentration of A. vulgaris cv. Luntaibaixing leaves were the most relevant to the first-order differential f' (RD) of its spectrum reflectance, whose linear spectrum estimation model fitting degree was the highest and reached to a significant or highly significant level. It showed that the spectral sensitive bands of Fe and Mn element varied with different phenological periods of fruit development. The spectrum estimation models for its foliar Fe and Mn concentration could be established with linear model according to its first-order differential f' (Rlambda). PMID- 25532351 TI - [Response of winter wheat (Triticum aestivum L. ) hyperspectral characteristics to low temperature stress]. AB - The simple winter wheat variety was conducted under the low temperature treatment at -2, -4, and -6 degrees C, the canopy reflectance was measured and the red edge parameters were extracted to study the winter wheat canopy spectral characteristics effected by the low temperature stress and the hyperspectral response to the low temperature stress of winter wheat at jointing stage. The results showed that the canopy reflectance decreased in visible region and increases at near infrared band with the high intensively low temperature stress, and "green peak" was weakened and "red well" was not distinctive. Moreover, the derivate spectrum had the trend of shift to short wavelength direction with the strengthening of low temperature stress and the red edge presented the blue shift. The area of red edge and red edge amplitude exhibit increase. It indicated that the canopy spectrum of winter wheat is sensitive to the low temperature stress, and the hyperspectral technology can be used to monitor the low temperature stress of winter wheat at jointing stage. PMID- 25532352 TI - [Analysis of related factors of slope plant hyperspectral remote sensing]. AB - In the present paper, the slope gradient, aspect, detection zenith angle and plant types were analyzed. In order to strengthen the theoretical discussion, the research was under laboratory condition, and modeled uniform slope for slope plant. Through experiments we found that these factors indeed have influence on plant hyperspectral remote sensing. When choosing slope gradient as the variate, the blade reflection first increases and then decreases as the slope gradient changes from 0 degrees to 36 degrees ; When keeping other factors constant, and only detection zenith angle increasing from 0 degrees to 60 degrees , the spectral characteristic of slope plants do not change significantly in visible light band, but decreases gradually in near infrared band; With only slope aspect changing, when the dome meets the light direction, the blade reflectance gets maximum, and when the dome meets the backlit direction, the blade reflectance gets minimum, furthermore, setting the line of vertical intersection of incidence plane and the dome as an axis, the reflectance on the axis's both sides shows symmetric distribution; In addition, spectral curves of different plant types have a lot differences between each other, which means that the plant types also affect hyperspectral remote sensing results of slope plants. This research breaks through the limitations of the traditional vertical remote sensing data collection and uses the multi-angle and hyperspectral information to analyze spectral characteristics of slope plants. So this research has theoretical significance to the development of quantitative remote sensing, and has application value to the plant remote sensing monitoring. PMID- 25532353 TI - [Study on the polarized reflectance-hyperspectral information fusion technology of tomato leaves nutrient diagnoses]. AB - With 25%, 50%, 75%, 100% and 150%, five levels of, nitrogen (N), phosphorus (P) and potassium (K) nutrition stress samples cultivated in Venlo type greenhouse soilless cultivation mode as the research object, polarized reflectance spectra and hyperspectral images of different nutrient deficiency greenhouse tomato leaves were acquired by using polarized reflectance spectroscopy system developed by our own research group and hyperspectral imaging system respectively. The relationship between a certain number of changes in the bump and texture of non smooth surface of the nutrient stress leaf and the level of polarization reflected radiation was clarified by scanning electron microscopy (SEM). On the one hand, the polarization spectrum was converted into the degree of polarization through Stokes equation, and the four polarization characteristics between the polarization spectroscopy and reference measurement values of N, P and K respectively were extracted. On the other hand, the four characteristic wavelengths of N, P, K hyperspectral image data were determined respectively through the principal component analysis, followed by eight hyperspectral texture features extracted corresponding to the four characteristic wavelengths through correlation analysis. Polarization characteristics and hyperspectral texture features combined with each characteristics of N, P, K were extracted. These 12 characteristic variables were normalized by maximum-minimum value method. N, P, K nutrient levels quantitative diagnostic models were established by SVR. Results of models are as follows: the correlation coefficient of nitrogen r = 0.961 8, root mean square error RMSE= 0.451; correlation coefficient of phosphorus r = 0.916 3, root mean square error RMSE = 0.620; correlation coefficient of potassium r = 0.940 6, root mean square error RMSE = 0.494. The results show that high precision tomato leaves nutrition prediction model could be built by using polarized reflectance spectroscopy combined with high spectral information fusion technology and achieve good diagnoses effect. It has a great significance for the improvement of model accuracy and the development of special instruments. The research provides a new idea for the rapid detection of tomato nutrient content. PMID- 25532354 TI - [Determination of photosynthetic pigments in citrus leaves based on hyperspectral images datas]. AB - The effective region was segmented from the hyperspectral image of citrus leaf by threshold method with the average spectrum extracted and used to describe the corresponding leaf. Based on the different spectral pre-processing methods, the prediction models of three photosynthetic pigments (i. e., chlorophyll a, chlorophyll b, and carotenoid) were calibrated by partial least squares (PLS), BP neural network (BPNN) and least square support vector machine (LS-SVM). The LS SVM model for chlorophyll a was established based on multiplicative scatter correction (MSC), and the correlation coefficient (Rp) and the root mean square error of prediction (RMSEP) were 0.898 3 and 0.140 4, respectively. The LS-SVM model for chlorophyll b with Rp = 0.912 3 and RMSEP = 0.042 6, was established based on standard normal variable (SNV). The PLS model for carotenoid was established with Rp = 0.712 8 and RMSEP = 0.062 4 based on moving average smoothing (MAS), but the result was no better than the other two. The results illustrated that these three photosynthetic pigments could be nondestructively and real time estimated by hyperspectral image. PMID- 25532355 TI - [Rapid detection of nitrogen content and distribution in oilseed rape leaves based on hyperspectral imaging]. AB - Visible and near infrared (Vis-NIR) hyperspectral imaging system was carried out to rapidly determinate the content and estimate the distribution of nitrogen (N) in oilseed rape leaves. Hyperspectral images of 420 leaf samples were acquired at seedling, flowering and pod stages. The spectral data of rape leaves were extracted from the region of interest (ROI) in the wave- length range of 380 1,030 nm. Different spectra preprocessing including Savitzky-Golay smoothing (SG), standard normal variate (SNV), multiplicative scatter correction (MSC), first and second derivatives were applied to improve the signal to noise ratio. Among 471 wavelengths, only twelve wavelengths (467, 557, 665, 686, 706, 752, 874, 879, 886, 900, 978 and 995 nm) were selected by successive projections algorithm(SPA) as the effective wavelengths for N prediction. Based on these effective wavelengths, partial least squares(PLS) and least-squares support vector machines (LS-SVM) calibration models were established for the determination of N content. Reasonable estimation accuracy was obtained, with Rp of 0.807 and RMSEP of 0.387 by PLS and Rp of 0.836 and RMSEP of 0.358 by LS-SVM, respectively. Considering the simple structure and satisfying results of PLS model, SPA-PLS model was used to generate the distribution maps of N content in rape leaves. The concentrations of N were calculated at each pixel of hyperspectral images at the selected effective wavelengths by inputting its correspond- ing spectrum into the established SPA-PLS model. Different colour represented the change in N content in the rape leaves under different fertilizer treatments. By including all pixels within the selected ROI, the average N status can be displayed in more detail and visualised. The visualization of N distribution could be helpful to understanding the change in N content in rape leaves during rape growth period and facilitate discovering the difference of N content within one sample as well as among the samples from different fertilising plots. The overall results revealed that hyperspectral imaging is a promising technique to detect N content and distribution within oilseed rape leaves rapidly and nondestructively. PMID- 25532356 TI - [Variety recognition of Chinese cabbage seeds by hyperspectral imaging combined with machine learning]. AB - The variety of Chinese cabbage seeds were recognized using hyperspectral imaging with 256 bands from 874 to 1,734 nm in the present paper. A total of 239 Chinese cabbage seed samples including 8 varieties were acquired by hyperspectral image system, 158 for calibration and the rest 81 for validation. A region of 15 pixel x 15 pixel was selected as region of interest (ROI) and the average spectral information of ROI was obtained as sample spectral information. Multiplicative scatter correction was selected as pretreatment method to reduce the noise of spectrum. The performance of four classification algorithms including Ada-boost algorithm, extreme learning machine (ELM), random forest (RF) and support vector machine (SVM) were examined in this study. In order to simplify the input variables, 10 effective wavelengths (EMS) including 1,002, 1,005, 1,015, 1,019, 1,022, 1,103, 1,106, 1,167, 1,237 and 1,409 nm were selected by analysis of variable load distribution in PLS model. The reflectance of effective wavelengths was taken as the input variables to build effective wavelengths based models. The results indicated that the classification accuracy of the four models based on full-spectral were over 90%, the optimal models were extreme learning machine and random forest, and the classification accuracy achieved 100%. The classification accuracy of effective wavelengths based models declined slightly but the input variables compressed greatly, the efficiency of data processing was improved, and the classification accuracy of EW-ELM model achieved 100%. ELM performed well both in full-spectral model and in effective wavelength based model in this study, it was proven to be a useful tool for spectral analysis. So rapid and nondestructive recognition of Chinese cabbage seeds by hyperspectral imaging combined with machine learning is feasible, and it provides a new method for on line batch variety recognition of Chinese cabbage seeds. PMID- 25532357 TI - [Research on algorithm for self-absorption correction based on multi-particles LIBS spectra]. AB - In order to overcome the influence of self-absorption on quantitative analysis, the optimizing process of very fast simulated annealing algorithm was studied. According to basic theory of plasma emission spectrum, a new algorithm for self absorpton correction based on multi-particles spectra was proposed, and the algorithm flowchart was given. With the self-absorption correction algorithm mentioned above, the spectra of refining slag and blast furnace slag were corrected. The effect of self-ab sorption correction on the quantitative analysis results was analyzed based on calibration free method. Comparison of Boltzmann plots before and after self-absorption correction indicated that the plasma temperatures calculated with spectra after self-absorption correction tended to be uniform, and remained stable around 11,600 K. The Boltzmann plots constructed with plasma spectra of the same particle after self-absorption correction indicated that the intercepts were almost the same except for one group data. With calibration free method and spectra after self-absorption correction, the contents of components in slag were analyzed. For refining slag, quantitative analysis precision of MgO was low. If ignoring the existence of MgO, the relative errors of quantitative analysis results of CaO, Al2 O3 and SiOs were much smaller. For blast furnace slag in which the content of MgO was 8.49%, the relative error of quantitative analysis result of Al2 O3 was 2.38%, which was the smallest. And the relative error of quantitative analysis result of MgO was 28.27%, which was still the biggest. PMID- 25532358 TI - [Effects of temperature and heating time on armco iron spectral emissivity in atmospheric environment]. AB - The spectral emissivity of pure iron at 1.55 MUm was investigated systematically by using our self-designed reflective experimental apparatus based on the Kirchhoff's law, and the influences of temperature and heating time on the spectral emissivity of pure iron were also discussed. The experimental data showed that the spectral emissivity of pure iron increased with temperature rising and its peak value and valley value appeared at certain temperatures. By analyzing the emissivity model of metal with oxidation layer, the variation of the spectral emissivity of pure iron was illustrated. The influence of heating time on the spectral emissivity was different at different temperature. The research results will further enrich pure iron spectral emissivity data, and provide the experimental basis for its application in atmospheric environment. PMID- 25532359 TI - [Determination of trace element silver in animal serum, tissues and organs by microwave digestion-ICP-MS]. AB - Nowadays, the silver is widely used in the biological field and its biological safety catches great attention. It is important to know the distribution of silver ions within the biological organism and the toxic threshold concentration in the tissue. Therefore, a highly sensitive method for measurement of trace amount of silver ion in the medical biological samples is needed. With its high sensitivity for detection of metal ions, inductively coupled plasma mass spectrometry (ICP-MS) method is well suited for quantification of trace amount of silver ion in such samples, but method development is still in its infancy. Consequently, a simple and convenient method for determination of trace amount of silver in the animal serum, tissues or organs was developed, in which the samples were subjected to the microwave digestion, followed by the ICP-MS analysis. To begin with, the samples of serum, muscle, bone marrow, bone, heart, liver, spleen, and kidney were sequently processed in 5 mL of HNO3 and 2 mL of H2O2 solution. Then the samples were completely digested by microwave with the power of 2 000 watts. The temperature was raised gradually by 3-step program. Moreover, the data achieved were reproducible and the method was time saving and especially for large amounts of sample processing. Then the digested solutions were diluted to constant volume. Finally, the concentration of 107Ag in the samples was analyzed by the method of ICP-MS under the optimized conditions. Element yttrium (Y) was used as the internal standard to compensate for matrix suppression effect and improve the accuracy of measurement. For one thing, the analytical results showed that the detection limit of the trace element 107Ag was 0.98 MUg . kg(-1), and furthermore, the correlation coefficient of standard curve was 0.999 9. For another thing, the recovery rate of the silver element ranged from 98% to 107%, which was calculated according to measured quantity before adding standard, adding standard and measured quantity after adding standard. At the same time, the relative standard deviation (RSD) of the method was in the range of 2.0% 4.3%. The concentrations of element silver in animal serum, tissues and organs were determined by the aboved method. The obtained results showed that silver ions were mainly accumulated in the liver after they were intaken into the body. The results suggested that the microwave digestion-ICP-MS method could accurately determine the trace element Ag in the body. The method developed has good feasibility and is suitable for the determination of trace element Ag in various types of medical and biological samples, especially for large quantities of biological samples. The process has the advantages of easysample processing and it is simple and convenient. In addition, the accurate results could be obtained in a short time with high sensitivity. Last but not least, the method provides the guidance for the determination of trace elements in other biological samples. PMID- 25532360 TI - [Principal component analysis of mineral elements and fatty acids composition in flaxseed from ten different regions]. AB - Flaxseed is a kind of biomass with high edible and medical value. It is rich in many kinds of nutrients and mineral elements. China is one of the important producing places of flaxseed. In order to explore the main characteristic constituents of mineral elements and fatty acids in flaxseed, the study of analyzing the mineral elements and fatty acid composition from 10 different regions was carried out. The contents of seventeen kinds of mineral elements in flaxseed were determined by inductively coupled plasma mass spectrometry (ICP MS). The contents of fatty acids of the flaxseed oil obtained under the same conditions were determined by gas chromatography-mass spectrometer (GC-MS). The principal component analysis (PCA) method was applied to the study of analyzing the mineral elements and fatty acid compositions in flaxseeds. The difference in mineral elements and fatty acids of flaxseed from different regions were discussed. The main characteristic constituents of mineral elements and fatty acids were analyzed. The results showed that K, Sr, Mg, Ni, Co, Cr, Cd, Se, Zn and Cu were the main characteristic constituents of the mineral elements. At the same time, C16:0, C18:0, C18: 2, C18:3, C20:0 and C20:1 were the main characteristic constituents of the fatty acids. The combination of ICP-MS, GS-MS and PCA can reveal the characteristics and difference of mineral elements and fatty acids from different regions. The results would provide important theoretical basis for the reasonable and effective utilization of flaxseed. PMID- 25532361 TI - Characteristics of trace elements in freshwater and seawater cultured pearls. AB - Trace elements in pearls have characteristic disciplines and functions. The previous work had paid attention to different characteristics of trace elements in freshwater and seawater cultured pearls, but only limited species of trace elements have been detected by former testing techniques and analysis methods, and the test results have not been further analyzed. With the advantages of detection in good capability and high speed, inductively coupled plasma mass spectrometer (ICP-MS) can concurrently test various trace and ultra-trace elements. In the present paper, trace elements of cultured pearls in freshwater and seawater were measured by ICP-MS, and analyzed compared by a method of data processing. The results show that: (1) The kinds of higher content of trace elements (Sr, Zn, Ni, Ba, Mn, Cr, Cu, Pb, Ti, Co, Ce, Zr, La, Rb) in cultured pearls are approximately the same, but the total amount of trace elements in freshwater cultured pearls is significantly less than that of seawater cultured pearls. (2) The content of trace elements (Sr, Mn, Ba, Ni, Cr, Pb) in freshwater cultured pearls is more regular, and has a relatively fixed sequence from high to low, namely Sr > Mn > Ba > Ni > Cr > Pb. The content of trace elements in seawater cultured pearls is quite different. Sr is enriched in all samples. There is no a stable order of contents for the other trace elements. (3) There is a significant correlation among some trace elements in cultured pearls. The conclusion is instructive to indicate cultured environment, cultured technology, identification, comprehensive development and utilization of cultured pearls. PMID- 25532362 TI - Determination of elements by atomic absorption spectrometry in medicinal plants employed to alleviate common cold symptoms. AB - Eleven important medicinal plants generally used by the people of Turkey for the treatment of common cold have been studied for their mineral contents. Eleven minor and major elements (essential, non-essential and toxic) were identified in the Asplenium adiantum-nigrum L. , Althaea officinalis L. , Verbascum phlomoides L., Euphorbia chamaesyce L., Zizyphus jujube Miller, Peganum harmala L., Arum dioscoridis Sm., Sambucus nigra L., Piperlongum L., Tussilago farfara L. and Elettaria cardamomum Maton by employing flame atomic absorption and emission spectrometry and electro-thermal atomic absorption spectrometry. Microwave digestion procedure for total concentration was applied under optimized conditions for dissolution of medicinal plants. Plant based biological certified reference materials (CRMs) served as standards for quantification. These elements are found to be present in varying concentrations in the studied plants. The baseline data presented in this work can be used in understanding the role of essential, non-essential and toxic elements in nutritive, preventive and therapeutic properties of medicinal plants. PMID- 25532363 TI - Measuring the content of 17 elements in the flesh of Prunus cerasifera and its cultivars by ICP-MS. AB - The present study compared the contents of inorganic elements in the pulp of purple, red, and yellow Prunus cerasifera with its cultivars. A method was established for the analysis of 17 kinds of trace elements (K, Ca, Mg, Na, Fe, Mn, Cu, Zn, Be, Li, Se, Sr, Cr, Pb, Cd, As and Hg) in the flesh of Prunus cerasifera by microwave digestion-ICP-MS. The detection method is simple and quick, yet shoes high precision and high sensitivity. The recovery rate of 17 elements ranged, from 93.5% to 110.4%. The analysis results showed that the contents of 17 elements in the flesh of purple, red, and yellow Prunus cerasifera and its cultivars are similar, containing extremely rich K elements (as high as 1 per thousand) and higher contents of Ca, Mg, Na, Fe and Mn. The contents of Cu, Zn, Li, Se, Sr and Cr are also present. The contents of Pb, Cd, As, Hg and other harmful element are either very low or not detectable. The experimental results for the study of trace elements in pulp of Prunus cerasifera and its cultivars provide empirical data for. future research in this area. PMID- 25532364 TI - Excitation-emission matrix spectroscopy and parallel factor analysis for micro content petroleum pollutant. AB - In order to solve the identification problem of oil pollutants containing micro content, the fluorescence characteristics of oil samples were studied using fluorescence excitation emission matrix spectra (EEMs) combined with parallel factor (PARAFAC) analysis. According to the conventional standard of oil content in water, simulated the component of oil pollution in I-V water was simulated by preparing samples of CCL4 with oil content. Firstly, measured the EEMs of 97# gasoline, 0# diesel, kerosene and CCL4 were measured individually, then the EEMs of 97# gasoline, 0# diesel, and kerosene in CCL4 were measured, and finally, the EEMs of the composite sample with all three oil contents in CCL4 were measured. The EEMs of the composite sample were superimposed by the EEMs of all its different components. It is therefore difficult to analyze the fluorescence component by chemical separation or simple fluorescence analysis. Since the EEMs of each oil component are already measured, we used the PARAFAC analysis to decompose the EEMs of the composite sample, and then extract the concentration ratio of each component. In this work, we solved the problem of identifying and quantifying the main micro-content petroleum pollutant in composite oil samples using EEMs and PARAFAC analysis. PMID- 25532365 TI - [Simultaneous determination of four flavone C-glycosides in Phyllostachys edulis leaves by high-performance liquid chromatography with ultraviolet spectrometry]. AB - High-performance liquid chromatography with ultraviolet spectrometer (HPLC-UV) was used to simultaneously detect the four flavone C-glycosides, i. e. orientin, isoorientin, vitexin and isovitexin. Analytes were separated with Waters XTerra MS C18 column (250 mm x 4.6 mm, 5 MUm) using acetonitrile and 0.5% (phi) formic acid as mobile phase. The flow rate was set at 1.0 mL . min(-1) with the column temperature at 30 degrees C, and the detection wavelength was 360 nm. The calibration curve was linear over the concentration range of 0.1-10.0 mg . L(-1) for the mixed standard solution. Analytes were separated in 22 minutes, and the relative standard deviation values were all above 0.999. LOD values of standards were found to be between 0.03 and 0.07 mg . L(-1), and LOQ values were in the range of 0.04-0.08 mg . L(-1). After comparing the spectra (240-400 nm) of four flavone C-glycosides in mixed standards and the final product purified by macroporous resin, respectively, the curve shape and characteristic ultraviolet absorption wavelength of each flavone C-glycoside including orientin, isoorientin, vitexin and isovitexin were fitted well. The bamboo leaves sample was extracted by ethanol under reflux, and then partitioned with water and petroleum ether. The aqueous phase was added onto macroporous resin (AB-8), and the fraction of ethanol-water (40%, phi) was concentrated. It was found that the contents of orientin, isoorientin, vitexin and isovitexin relative to the fraction of ethanol- water were 13.73, 49.68, 7.85 and 30.70 mg . g(-1), respectively. In addition, the average recovery of the four flavone C-glycosides ranged from 34.90% to 87.64% with RSD values from 0.41% to 10.83%. The results showed that bamboo leaves sample had good stability and repeatability. The new method was used to analyze the four flavone C-glycosides quickly and provide quality control for commercial products. PMID- 25532366 TI - Sandmeier model based topographic correction to lunar spectral profiler (SP) data from KAGUYA satellite. AB - The Moon may be considered as the frontier base for the deep space exploration. The spectral analysis is one of the key techniques to determine the lunar surface rock and mineral compositions. But the lunar topographic relief is more remarkable than that of the Earth. It is necessary to conduct the topographic correction for lunar spectral data before they are used to retrieve the compositions. In the present paper, a lunar Sandmeier model was proposed by considering the radiance effect from the macro and ambient topographic relief. And the reflectance correction model was also reduced based on the Sandmeier model. The Spectral Profile (SP) data from KAGUYA satellite in the Sinus Iridum quadrangle was taken as an example. And the digital elevation data from Lunar Orbiter Laser Altimeter are used to calculate the slope, aspect, incidence and emergence angles, and terrain-viewing factor for the topographic correction Thus, the lunar surface reflectance from the SP data was corrected by the proposed model after the direct component of irradiance on a horizontal surface was derived. As a result, the high spectral reflectance facing the sun is decreased and low spectral reflectance back to the sun is compensated. The statistical histogram of reflectance-corrected pixel numbers presents Gaussian distribution Therefore, the model is robust to correct lunar topographic effect and estimate lunar surface reflectance. PMID- 25532367 TI - [Thermal effect on optical properties of spatial heterodyne spectroscopy]. AB - To study the thermal effort on optical properties of spatial heterodyne spectroscopy (SHS), the relation between the change in temperature and the degradation of optical properties was analyzed, including collimator lens, imaging lens and interferometer unit. The theoretical model was verified and corrected by simulation and thermal-optical test, which was established to describe the relation between spectral-line shift and groove density change of gratings. The results show that spectrum measurements are not affected by small temperature changes in the instrument since the primary effects. are a slight defocus of the focal plane array in collimating lens and re-imaging lens under the temperature from 15 to 25 degrees C. Spectral-line shift obtained by the thermal optical analysis is well coincident with the ones calculated by thermal optical experiment because of the temperature chan- ges of interferometer unit. The Littrow wavelength accuracy is better than 2.3 nm unless the temperature change is less than 2.5 degrees C under the interferometer unit by use of the material BK7. PMID- 25532368 TI - [Passive ranging of infrared target using oxygen A-band and Elsasser model]. AB - Passive ranging method of short range and single band was developed based on target radiation and attenuation characteristic of oxygen spectrum absorption. The relation between transmittance of oxygen A band and range of measured target was analyzed. Radiation strength distribution of measured target can be obtained according to the distribution law of absorption coefficient with environmental parameters. Passive ranging mathematical model of short ranges was established using Elsasser model with Lorentz line shape based on the computational methods of band average transmittance and high-temperature gas radiation narrowband model. The range of measured object was obtained using transmittance fitting with test data calculation and theoretical model. Besides, ranging precision was corrected considering the influence of oxygen absorption with enviromental parameter. The ranging experiment platform was established. The source was a 10 watt black body, and a grating spectrometer with 17 cm(-1) resolution was used. In order to improve the light receiving efficiency, light input was collected with 23 mm calibre telescope. The test data was processed for different range in 200 m. The results show that the transmittance accuracy was better than 2.18% in short range compared to the test data with predicted value in the same conditions. PMID- 25532369 TI - [Development and application of six-channel fiber optic sensing drug dissolution monitor]. AB - The drug dissolution test is an important examination of drug testing, which plays a very important role in the drug quality assessment. Automation and proceduring monitoring of drug dissolution can be implemented by the optical fiber sensing technology. Two modes of detection of UV-Vis absorption and fluorescence quenching were established by software implementation, with xenon lamp, deuterium lamp or halogen tungsten lamp as fluorescence, UV and visible light source, branch Y type optical fiber as light path transmission medium, UV Vis probe and fluorescence molecular probe as light response devices, and CCD as detector. Optical fiber sensing drug dissolution monitor not only solves the current problems of time-consuming, and sampling of off-line analysis, but also provides real-time information of drug dissolution process. Thus, our study may provide a better evaluation method for the drug quality control. PMID- 25532370 TI - [Taking evaluation of post-marketing as point of cut-in to promote systematic research of traditional Chinese medicine]. AB - Research on post-marketing Chinese medicine should be the systematic study from application to mechanism. Clinical evaluation is the basis of mechanism study, we can find the clue from clinical evaluation, then make a mechanism study to find the reason, then apply the results to clinic. So it is a virtuous circle. In order to achieve it, we cannot be limited to traditional Chinese medicine, we should form multi-disciplinary team under the direction of grand science thinking, try hard to put industry-university-research institute collaboration association to use, and if necessary, explore the new model of the whole nation system. An appropriate operation mechanism is very important. PMID- 25532371 TI - [Exploration and demonstration study on drug combination from clinical real world]. AB - Drug combination is extensive in the clinical real world,which is an important part and the inherent requirements of the post-marketing evaluation of traditional Chinese medicine (TCM). The key issues and technology include multi domain and multi-disciplinary such as the rationality, efficacy and safety evaluation of combination drug starting from clinical real world, study on component in vivo and mechanism of combination drug, the risk/benefit assessment and cost-benefit evaluation of combination drug and so on. The topic has been studied as clinical demonstration on combination therapy of variety of diseases such as coronary heart disease, stroke, insomnia, depression, hepatitis, herpes zoster, psoriasis and ectopic pregnancy. Meanwhile, multi-disciplinary dynamic innovation alliance of clinical drug combination has been presented, which can promote the academic development and improving service ability and level of TCM. PMID- 25532372 TI - [Opportunity and challenge of post-marketing evaluation of traditional Chinese medicine]. AB - Post-marketing evaluation is a process which evaluate the risks and benefits of drug clinical application comprehensively and systematically, scientific and systematic results of post-marketing evaluation not only can provide data support for clinical application of traditional Chinese medicine, but also can be a reliable basis for the supervision department to develop risk control measures. With the increasing demands for treatment and prevention of disease, traditional Chinese medicine has been widely used, and security issues are also exposed. How to find risk signal of traditional Chinese medicine in the early stages, carry out targeted evaluation work and control risk timely have become challenges in the development of traditional Chinese medicine industry. PMID- 25532373 TI - [Explore ideal of establishing ischemic stroke drugs group modules based on electronic medical records]. AB - Ischemic stroke is a kind of common and frequently-occurring disease in clinic. It has high morbidity and high mortality and high morbidity characteristics. It was treated may also use a variety of Chinese and western medicine in the acute phase in the large general hospital in clinical practice. According to the "modularity theory" from biology, different patients using different drugs, and with combination of drugs for the treatment of this disease may have a variety of topological structure characteristics. This study proposed in the national 15 large general hospital electronic medical records of database, the complex network constructed by acute ischemic stroke disease using drugs, adopting to the complex network analysis and data mining methods to build for different ischemic stroke patients who are many of Chinese and western medicine group modules. These modules can be explained structure and function characteristics, and to explore the appropriate crowd and evaluate drug group module efficacy and safety in use in clinic. It provide direction to optimize the clinical treatment for ischemic stroke, provide new method for the research on combination, also provide the basis for drug combination of Chinese and western solution into the guide. PMID- 25532374 TI - [Study on medical pattern of traditional Chinese medicine and western medicine diagnosis and treatment of hypertension patients in 30 034 cases in real world]. AB - Select patients diagnosed of hypertension in the first place in 16 hospitals and the patients were described by association rules analysis and distribution for the analysis in the study,in order to understand the information of diagnosis and treatment in hypertension patients in real world. The information include age, gender, admission condition, inpatient department, hospitalization expenses, western medicine comorbidities, the traditional Chinese medicine (TCM) syndrome and the medicine. The average age of patients was 64 years in the study. The proportion of men to women about 1. 10: 1. Admission condition is critical for about 10.12% of the total and more concentrated in the cardiovascular department. Hospital stay ranged from 8 to 14 d. Inpatients with medical insurance is 62.93%. Total hospitalization cost distribution most is the 5 000-10 000 RMB. Hypertension complicated with coronary heart disease, blood lipoprotein disorder disease; phlegm and blood stasis and Yin deficiency of liver and kidney are the most in TCM syndrome type. Promoting blood circulation and removing blood stasis is the major in Chinese medicine treatment. Western medicine treatment basically conforms to the guidelines. The most antihypertensive drugs is calcium antagonistst, accounting for about 81.2% of the total number. Class ACEI, class ARB, beta blockers, diuretics class are accounted for 43.0%, 43.4%, 42.4%, 42.4%, fixed compound is only 2 393, accounting for about 8%. the total frequency of five classes of antihypertensive drugs is 78 206 times. The principal conclusions of this analysis are as follows: the elderly people is the most in hypertension, more men than women; medical insurance is the majority type in hospitalization cost; nearly half of the population is combined with coronary heart disease; phlegm and blood stasis and yin deficiency of liver and kidney are the most in TCM syndrome type; western medicine treatment basically conforms to the guidelines. Combination therapy is more, less fixed compound preparation in western medicine. Chinese medicine is mainly to promoting blood circulation. Suggesting that the clinical treatment in strict blood pressure and at the same time, pay attention to combination therapy and the use of fixed compound preparation,it's useful to control the blood pressure better. Combined with traditional Chinese medicine and resolving phlegm and removing blood stasis, reduce the target organ damage, reduce complications, the prevention and control work of hypertension in China still faces enormous challenges at present. The result provides reference information for clinical medicine and medical research. PMID- 25532375 TI - [Clinical characteristics and combined use of medicine analysis of 2 991 hospitalized patients with psoriasis based on real world database]. AB - To analyze the clinical characteristics and combined use of chemical and traditional Chinese medicine (TCM) medicine of hospitalized patients with psoriasis base on real world database, 2 991 cases of hospitalized patients with psoriasis in hospital information system (HIS) database from 16 hospitals in China were analyzed for general hospitalization information, combined diseases and combined use of drugs et al. The results showed that half of inpatients aged 18-45 years old. The most common syndrome of TCM was intrinsic blood heat. More than 1/3 inpatients' hospitalization time was 18-25 days, and the average expense of hospitalization was 6 989. 20 RMB. The top five combined diseases were hypertension, non-alcoholic fatty liver disease, diabetes, upper respiratory tract infection and lipoprotein disorders. Medicine information analysis showed 599 chemical medicines and 341 TCMs were used and combined use of drugs was common in clinical practice. Licorice extract medicine was the most common combined TCM with western medicine; in the next two places were compound Qingdai capsule and tripterygium glycosides. The most common combined use of chemical medicines were Vitamin C, calcium gluconate, ketotifen, cetirizine, retinoic acid and external use glucocorticoid. Anti-inflammatory and liver protection, clearing heat and toxic materials, activating blood and dissolving stasis were the most common combined TCM medicine with western medicine, while the most common combined chemical medicine with TCM were anti-allergic, anti-infection, glucocorticoid and retinoic acid. In conclusion, half of hospitalized patients of psoriasis were young adults. The main type of combined diseases was metabolic disorders and upper respiratory infections. Combined use of chemical medicine and TCM was common in clinical practice. Licorice extract medicine was the most common combined TCM with western medicine. PMID- 25532376 TI - [Study of clinical character and medicinal therapy of viral hepatitis in hospital based on real world]. AB - Viral hepatitis was the most common infectious disease in china. But the diagnosis and treatment were varied because the viral hepatitis patients were hospitalized in different kinds of hospital such as infectious disease hospital, general hospital and Chinese medical hospital. It was necessary to know clinical characters and information of viral hepatitis patients in different hospitals. The general information, subtype distribution, prognosis, complication, medication and relations of onset with solar term from 41 180 viral hepatitis patients based on HIS data were analyzed. It was found that the age of patients between 18 to 59 years old was most; most patients were males. The national basic medical insurance was the most type of payment. The outcome of viral hepatitis in the youth and female were better than that in the old and male. Acute hepatitis was easer to restore than chronic hepatitis. Liver cirrhosis and hepatocellular carcinoma were the two most complications. The peak of onset was during summer solstice, slight heat and great heat. The most common Chinese medicine was Diammonium glycyrrhizinate and the most common western medicine was reduced glutathione. The combination of D. glycyrrhizinate with reduced glutathione, polyene phosphatidylcholine and thymosin was the main pattern. But It was not knew if the combination of western and Chinese medicine was the most effective therapy to protect liver function. It was necessary to take deeply research of the relationship between the combination therapy and their effectiveness. PMID- 25532377 TI - [HIS-based analysis of comorbid characteristics and combined treatment of Chinese and western medicine in patients with depressive disorder]. AB - OBJECTIVE: To understand the comorbid characteristics and distribution of combined treatment of Chinese and Western medicine in depressive patients. METHOD: The descriptive statistic method and association rule were used to analyze the data from 19 general hospitals with 3-A level in China. RESULT: Among the depressive disorder, the most frequent co-morbid physical diseases included hypertension (24.67%), coronary heart disease (16.10%) and cerebral infarction (12.89%), and the proportion of comorbid changes with the increasing age, from 6.51% to 12.55%, 16.33% and 12.47% for hypertension; from 2.79% to 5.69%, 10.17% and 14.22% for coronary heart disease; from 3.72%, 6.27%, 7.70% and 12.25% for cerebral infarction. The use frequency of the antidepressants is 77.18%, and the use frequency of flupentixol & melitracen is 20.95%. The use frequency of Huoxue Huayu Tongluo of traditional Chinese medicine is 59.97%, with that of 27.91% for Ginkgo biloba extract The combined use frequency of Huoxue Huayu Tongluo of TCM and the antidepressants is the highest, especially for the combined use of Shuxuening injection and fluoxetine. CONCLUSION: The most frequent comorbid diseases of depression include three kinds of diseases, such as hypertension, coronary heart disease and cerebral infarction, and its proportion gradually increased with the growth of age. The single use frequency of flupentixol & melitracen and G. biloba extract is the highest, while the combined use of Shuxuening injection and fluoxetine is the highest. PMID- 25532378 TI - [Analysis of traditional Chinese medicine syndrome, traditional Chinese medicine and western medicine in 84 697 patients with coronary heart disease based on big data]. AB - In order to understand the clinical characteristics of patients with coronary heart disease (CHD) in real world and provide reference for clinical prevention and treatment, this study analyzed informations of patient with CHD in hospital information system. Data from 17 national hospitals were collected. Select patients with coronaryheart disease in diagnosis of the first place in 17 hospitals, general informations and traditional Chinese medicine (TCM) syndrome, complications, medicine were analyzed using frequency method and association rules. This study included 84 697 patients with CHD, the majority of men and in the elderly. The average age of patients was 71 years. The proportion of men to women was about 1. 45: 1. Hospital stay time ranged from 8 to 14 d. The most common total hospitalization cost distribution was 5 000-20 000 RMB. Young patients have a rising trend year by year. The death of patients increased with increasing age. Common complications were hypertension, diabetes, cerebral infarction and hyperlipidemia, 57.24 percent of the CHD patient complicated with hypertension, 21.94 percent patients complicated with diabetes. Among TCM syndrome types, Qi-Yin deficiency and qi deficiency blood stasis were the most common syndromes. Blood stasis was the highest syndrome elements, accounted for 79.97%, followed by Qi deficiency, phlegm, Yin deficiency, and so on. The most common western medicine was aspirin, followed with isosorbide dinitrate, clopidogrel. The most common used traditional Chinese medicine was danhong injection, followed by shuxuetong injection. Combined with removing blood stasis drugs has been more common at present clinical treatment, there were 43.46 percent of patients combined with anti-platelet western drug and injection of removing blood stasis. PMID- 25532379 TI - [Analysis on clinical features and treatment of herpes zoster patients hospitalized in real world]. AB - From the hospital information system (HIS) of 20 national grade III-A general hospitals, 2 960 cases of herpes zoster as the research object, analyzes the relations between the general information, syndrome of traditional Chinese medicine (TCM), western medicine combined diseases, the relationship between the solar term and the incidence of herpes zoster, and the combined use of Chinese and western medicine. Among the patients with 46-65 year old has the highest percentage of diseased; admission to general outpatient clinic is the most; the most common medical payment is medicare; combined disease such as hypertension, diabetes and coronary heart disease is more common; early treatment effect of herpes zoster is better than the sequelae; summer and autumn solar term patients is hospitalized more, TCM syndrome is damp heat of liver fire; about drugs, western medicine is the most commonly used vitamin B1 and mecobalamin, traditional Chinese medicine is the most frequently used Danhong injection, combination therapy with promoting blood circulation drugs and neurotrophic drugs. Thus, herpes zoster, more common in elderly patients, with no obvious relationship between solar term, should be early diagnosis and early treatment, often with combination of Chinese traditional and western medicine treatment. PMID- 25532380 TI - [Preliminary study on integration of traditional Chinese medicine and western medicine in patients with coronary heart disease in real world]. AB - OBJECTIVE: Observe and analyze the informations of western medicine and traditional Chinese medicine in patients with coronary heart disease (CHD), in order to provide reference for clinical treatment. METHOD: Select patients with CHD in diagnosis of the first place in 17 hospitals, drug informations of these patients were analyzed using frequency method and association rules. RESULT: In 84 697 patients,there were 47 564 males and 32 882 females. The median age was 71 years old, 76 172 patients have medicine records, including 278 kinds of western medicine and 331 kinds of traditional Chinese medicine. Aspirin was the most common used western medicine (51 132 patients, 67.08%), followed by isosorbide dinitrate, clopidogrel etc. The most common used traditional Chinese medicine was danhong injection, followed by shuxuetong injection. After classified the drugs, at the forefront of western medicine were antiplatelet drugs, nitrates drugs, statins, beta blockers, calcium antagonists, ACEI; the most used in traditional Chinese medicine was injection of blood-activating and stasis-resolving, followed by oral preparations of blood-activating and stasis-resolving medicine, Fuzheng class oral medicine, purgation medicine etc. After association rules, combination therapy among western medicine was the most common, combination of western medicine with blood-activating and stasis-resolving was very commonly, especially antiplatelet drugs and nitrates drugs. CONCLUSION: Western medicine in the treatment of patients with CHD was in accordance with the guidelines recommend, but with the lower utilization rate. Traditional Chinese medicine has become an important method for the treatment of CHD, promoting blood circulation and removing blood stasis is an important part of traditional Chinese medicine treatment in patients with CHD. PMID- 25532381 TI - [Analysis about characteristics of drug used in clinical for ischemic stroke patients based on hospital electronic medical database]. AB - There are many different kinds of drugs which can treat ischemic stroke. This study aims to analyze the clinical treatment of ischemic stroke using Chinese and western medicines and their combination scheme. Data abstracted from 15 national 3a grad hospitals' hospital information system (HIS) databases were collected, then were used frequencies to find the common used drug and type, and were used association rules to anylizs the common combined medication scheme of Chinese and western medicines. It was found that the Shuxuetong (9 015 cases, 22.66%), Danhong (7 369 cases,18.53%) and Xueshuaitong (5 302 cases,13.33%) injections were the most frequently used drugs, and blood-activating and stasis-dissolving prescription (30 384 cases, 76.39%), resuscitative prescription (6 850 cases,17.22%) and tonic prescription (5 997 cases,15.08%) were the most commonly used types of Chinese medicine. The oral dose of aspirin (20 924 cases, 52.60%), Guangxi pp injection (10 771 cases, 27.08%) and insulin injection (10 599 cases, 26.65%) were frequently used. And the types of antiplatelet agents (23 049 cases, 57.95%), vasodilator (19 608 cases, 59.29%) and antihypertensive drug (15 475 cases, 39.90%) were commonly used. The drug combination of aspirin, twenty five pearl pill, Danhong and Xueshuaitong injection were the most frequently used group and its confidence coefficient is 97.5%. The type combination of blood activating and stasis-dissolving prescription, thrombolytic drug, insulin and vasodilator was the most commonly used group and its confidence coefficient is 97.424%. This study concludes that the drug combination of aspirin, twenty five pearl pill, Danhong and Xueshuaitong injection and the type combination of blood activating and stasis-dissolving prescription, thrombolytic drug, insulin and vasodilator were commonly used in clinical. PMID- 25532382 TI - [Correlation analysis of clinical medication of ectopic pregnancy based on hospital information system data]. AB - To analyze the reality of ectopic pregnancy patients' clinical medication, find out the association rules of chemical medicine and traditional Chinese medicine, HIS data from 15 grade III-A general hospitals were collected, descriptive statistic methods and association rules were used in analysis of the data. The results showed that the most commonly used western medicine types were antibiotics,hemostatic medicine and killing embryo medicine. The most commonly used traditional Chinese medicine types were heat clearing and detoxicating drugs, promoting blood circulation and removing blood stasis drugs, tonifying Qi and blood drugs. The common combinations of western medicine and Chinese medicine were heat clearing and detoxicating drug add antibiotics, heat clearing and detoxicating drug add hemostatic medicine, promoting blood circulation and removing blood stasis drug add antibiotics, tonifying Qi and blood drug add antibiotics. In conclusion, the medicine types of ectopic pregnancy were concentrated. For conbined treatment of traditional Chinese medicine and western medicine, heat clearing and detoxicating, tonic righting, promoting blood circulation and removing blood stasis treatment were often used on the basis of anti-inflammatory, killing embryo and hemostasis. PMID- 25532383 TI - [Clinical and medicine characteristics of patients with Parkinson's syndrome]. AB - This study analyze the characteristics and clinical medicine in 17 hospitals all over China, based on hospital information system diagnostic information database, including 4 497 cases of hospitalized patients with Parkinson's syndrome. Results indicate, the most common comorbidities are infarction, hypertension, coronary heart disease, diabetes and lung infections, including cerebral infarction, the combined incidence of hypertension in men reached 33.46% and 30.05%, respectively, it is slightly lower in the females. Men with coronary heart disease are more than women, women with diabetes and bone disease are more than men. Combined incidence of the disease increases with age, vascular factors occupy an important position. The most common combined diseases in patients with 90 years of age or older are coronary heart disease, lung infection, and often accompanied by metabolic disorders and nutritional emergency, critical care. Constipation, depression, anxiety, sleep disorders, cognitive impairment are common non-motor symptoms. The drug categories associated with Parkinson's core symptoms treatment are about 20% to 30% of clinical medicine, the others are associated with the treatment of combined disease, clinical medicine and disease spectrum consistent. Blood circulation topped Chinese agents applied frequency, reaching 44.52%; laxative drugs accounted for 11.66%; detoxification agent representing 9.46%. The first twenty Chinese medicine of the applying frequency reached 56.07% of the total utilization, including 12 kinds of traditional Chinese medicine injections, accounting for 60%. Therefore, in the diagnosis and treatment of Parkinsons syndrome, the treatment of comorbidities is very important, more attentions should be paid to vascular factors of the disease, Chinese medicine should be more concerned to improve the non-motor symptoms, give full play to the pharmaceutical multi-target, the overall regulation of advantages, integrative medicine, and improve the quality of life of patients. PMID- 25532384 TI - [Analysis of clinical use of shuxuening injection in treatment of cerebral infarction based on real world]. AB - To know the characteristics of Shuxuening injection used on cerebral infarction patients in clinical practice, 6 053 cases of Hospital information system (HIS) data from 20 hospitals were analyzed. Using the basic description method and association rules to analysis the data. By analysis the data we found that the average age of cerebral infarction patients who used Shuxuening injection is 67.96, 83.94% of patients were aged 46-80. The injection is administered intravenously,with most patients receiving a dosage of 15-20 mL per dose for between 1 and 14 days. It is always combined with aspirin (48.508%), cinepazide maleate injection (22.073%), atorvastatin calcium tablets (18.873%) in clinical practice. When it comes to two drug combinations, it always combined with cinepazide maleate injection and aspirin (8.178%), nicergoline capsules and aspirin (7.63%). Therefore, based on existing data, we give the conclusion that for the treatment of cerebral infarction Shuxuening injection is mainly used for older patients, and is often combination with similar pharmacological effects chemical drugs, which is complied with the guidelines. However, the wrong dose is still exist, doctors should realize the hiding risk. PMID- 25532385 TI - [Analysis of characteristics of using traditional Chinese and western medicine on type 1 diabetes adult patients based on electronic medical records]. AB - To understand the kinds and the characteristics of combination of traditional Chinese medicines and western medicines using on adults with type 1 diabetes in general hospitals,This research brings into 4 602 hospitalized adult patients with type 1 diabetes from hospital information system (HIS) of 13 third class A hospitals. These research objects were hospitalized in December 2003-July 2011. The research analyzes the operating frequency and associated usage of western medicines and traditional Chinese medicines by the method of frequency statistics and association rules. Through the analysis, the research says that in the clinical treatment of adult patients with type 1 diabetes, the western medicine used most frequently is insulin, a total of 1 539 cases, accounted for 8.47%; the traditional Chinese medicine used most frequently is oral agents of pseudo ginseng, a total of 183 cases, accounting for 6.25%; the combinations of Chinese and western medicines commonly used include Huoxue Huayu Tongmai Shuluo decoction + vasodilator, support degree is 45.93%, followed by Huoxue Huayu Tongmai Shuluo decoction + vasodilator + hypoglycemic drugs, support degree is 45.50%; Huoxue Huayu Tongmai Shuluo decoction + vasodilator + nutritional agent, support degree is 36.29%. PMID- 25532386 TI - [Clinical characteristics research of shenmai injection treating tumor based on hospital information system in real world]. AB - The study was to research the clinical characteristics of Shenmai injection treating tumor based on hospital information system, including the characteristics of the age, the sex, the dosage, the course of the treatment and the combination drugs. The data of tumor patients injected with Shenmai injection was analyzed. The information was collected from the hospital information system (HIS) in twenty hospitals of grade III-A. The method of frequencies and association rules was used in this reaearch. The patients over 45 years old were up to 3 338, about 79.36% of the whole. The ratio of male and female was 1.73: 1. The hospitalization day between 15 and 28 was most. The complications of the hypertension and coronary heart disease happened most. The support was 5.939% and 5.099% respectively. Fifty-five patients had the traditional Chinese medicine (TCM) syndrome of Qi-Yin deficiency, about 14.78% of the whole. There were 8 491 patients treated with the single dose of 81 to 100 mL, about 48.70% of the whole. The main combination drugs were dexamethasone, tropisetron and maxolon. The confidence was 44.63%, 31.22% and 20.53% respectively. The information from HIS showed that tumor patients used Shenmai injection were most quinquagenarian with smooth condition. The dose of the Shenmai injection sometimes was higher than that of the drug use instructions in clinical. Shenmai injection was most often combined with glucocorticoid, antemetic and nutritional support medicine when treating tumor in clinical. PMID- 25532387 TI - [Characteristics and drug analysis associated with vertigo disease in real world]. AB - To explore the characteristics and influenced factors associated with the onset of vertigo disease, analysis of 3 719 cases of hospitalized patients with vertigo disease from the real world. Analysis the date of patients diagnosed with vertigo disease from the hospital information system of 19 grade-III class-A hospital from 2004 to 2011, include general information, the doctor's advice, other diseases combined, diagnostic information and the relationship with the onset of 24 solar terms, and the treatment drugs. The median age of hospitalized patients with vertigo disease was 59, the number of women (65.91%) was more than men (34.09%), manual workers (85.32%) were the majority career, most patients (81.63%) condition were general by the time they were hospital admission, patients more like admitted to neurologist (70.34%) when they first time to outpatient serves, hospitalization days were in 8-14 days (46.65%), 46.04% of the patients in the hospital total cost is in 5 000 RMB to 10 000 RMB, 73.86% of patients paid by National Health Medical Insurance. Hypertension (20.79%) was the most common underlying health problems, The most common syndromes was deficiency of liver-Yin and kidney-Yin(44. 21%) , followed by hyperactivity of liver-yang, disease of phlegm turbidity in mongolia and deficiency of Qi and blood. There were more deficiency syndrome and less excess syndrome. The highest rate of hospital admission solar terms in 2009 was the insects awaken throttle (5.21%), In 2010, the highest rate solar terms of hospital admission was the rain throttle (6.14%). The most frequently used traditional Chinese medicine was gastrodine injection (20.55%), the most frequently used western medicine for betahistine (10.19%), gastrodine injection was the most traditional Chinese medicine that combination with other western medicine. Hypertension was the most underlying health problems in the patients with vertigo disease in the real world, although the mental factors should also be attention. Liver was the most closely internal organs with vertigo, and solar terms in spring was the highest-frequency time. Gastrodine injection was the most commonly used traditional Chinese medicin in clinical to treat vertigo diserse, the therapeutic regimen combining with traditional Chinese and western medicine has more advantages. We should pay more attention to the guidance of Chinese medicine "syncretism between heaven and man", to keep up with the rhythm of change, adapt to the changes in the human body growth and decline of the Yin and Yang, by adopting the method of syndrome differentiation in traditional Chinese medicine to prevention and treatment vertigo disease. PMID- 25532388 TI - [Real-world analysis of concurrent diseases and medicine use among patients with insomnia]. AB - This study aims to explore and analyze the condition of concurrent diseases and medicine use of traditional Chinese medicine (TCM) and western medicine among the patients with insomnia. One thousand and sxity seven cases of data from 20 national hospitals' hospital information system (HIS) databases were collected. The frequent concurrent diseases included hypertension (26.9%), brain blood supply insufficiency (24.93%), cerebral infarction (19.49%), blood lipoprotein disturbance (15.28%), coronary heart disease (14.15%), headache (10.68%), chronic gastritis (8.81%), type 2 diabetes mellitus (7.87%), depressive disorder (7.4%) and anxiety disorder (6.65%). The 10 most frequently-used western drugs included alprazolam (35.99%), aspirin (25.4%), olanzapine (24.18%), cinepazide (23.06%), flupentixol & melitracen (18.74%), zolpidem (18.37%), oxiracetam (15.65%), estazolam (15%), aniracetam (13.4%) and piracetam (13.31%). The 10 most frequently-used TCM included Shuxuening injection (16.4%), Shuxuetong injection (15.18%), extract of ginkgo biloba leaf (14.71%), gastrodin (12.46%), Dengzanxixin injection (11.34%), Xueshuantong (8.53%), Danhong injection (6.37%), compound liquorice tablet (5.81%), Sanqi Tongshu capsule (5.72%) and sowthistle leaf ixeridium injection (5.34%). Among all combined uses, the most frequent western drug use was alprazolam and olanzapine, while combined use of hypnotic drug and Huoxuehuayu formula is the most frequent. This study concludes that the concurrent diseases mainly include cardio-cerebrovascular diseases, metabolic disorders and anxiety-depression disorders, with increasing tendency of diseases types by ages, especially for cardio-cerebrovascular diseases. The most frequently-used hypnotic is alprazolam in the insomnia patients, and it is worth being concerned about the off-label use of olanzapine as an antipsychotic for the treatment of insomnia However, due to the fact that all cases data are from the inpatients, these findings have some limitations. PMID- 25532389 TI - [Clinical analysis on combined medication in patients of acute pancreatitis in real world]. AB - OBJECTIVE: To study the characteristics and regular pattern of the medicine in common use and combined medication in patients of acute pancreatitis in real world. METHOD: Collect the information of 5 433 acute pancreatitis patients in 19 grade IIIA general hospitals in China, analysis by descriptive statistics and association rule. RESULT: In the 5 433 patients of acute pancreatitis, the glycyrrhizic acid injection and somatostatin are the frequency top used Chinese traditional and western medication. Glycyrrhizic acid injection, somatostatin and insulin are the frequency top used drug combination pattern. CONCLUSION: The Chinese and western integrative medicine drug use pattern are accord with the clinical guideline of acute panceatitis. The hepatic and renal function, blood routine and coagulation function should be monitored when the medicines are used. PMID- 25532390 TI - [Analysis of characteristics of traditional Chinese medicine and western medicine clinical use in patients with viral hepatitis based on real world hospital information system data]. AB - Viral hepatitis is clinical multiple strong infectious disease, to know characteristics of traditional Chinese medicine and western medicine clinical use in patients with viral hepatitis, the research object of this study is 41 180 cases of hospitalized patients with viral hepatitis in hospital information system from 17 grade A hospitals, using frequency statistics and association rules method to analyze the traditional Chinese medicine and western medicine clinical use information, the drug kinds analysis results: western medicine of reduced glutathione tablets use frequency is highest, 14 079 cases (34.61%), traditional Chinese medicine of diammonium glycyrrhizinateuse frequency is highest, 14 058 cases (34.56%); traditional Chinese medicine and western medicine drug combination in diammonium glycyrrhizinate combined with reduced glutathione tabletsuse frequency is highest, 8 607 cases (25.09%). The mechanism of drug classification results :both traditional Chinese medicine and western medicine are the sort of educed enzyme medicine that has the highest percentage of drug use, traditional Chinese medicine 10 983 cases (27.01%), western medicine, 9 595 cases (23.59%); traditional Chinese medicine and western medicine combination in a kind of medicine to clear heat and promote diuresis combined with educed enzyme drug use frequency is highest, 5 621 cases (13.82%). Through the analysis above, combine traditional Chinese and western medicine therapy for the treatment of viral hepatitis should be given priority. Traditional Chinese medicine to clear heat and promote diuresis combined with western medicine of educed enzyme drug is the most commonly appear in clinical two drug combination scheme, traditional Chinese medicine to clear heat and promote diuresis combined with western medicine of educed enzyme drug and nucleustide analogsis the most commonly appear in clinical three drug combination scheme. PMID- 25532391 TI - [Clinical research on effectiveness of 2 110 patients with Henoch Schonlein purpura from 19 comprehensive hospitals in real world]. AB - Nineteen comprehensive hospital information system (HIS) data are collected. Cleaning up the database, then analysis the patients' information. Using the basic description method and association rules to analysis the data. Analysis the data come from HIS database, we found that in 2 110 patients, main five complications are Henoch Schonlein purpura nephritis, upper respiratory tract infections, renal insufficiency, virus infection and glomerulonephritis (chronic), treatment of chemical drugs with sugar cortical hormone and anti infection drugs, such as intravenous input cephalosporin drugs. Traditional Chinese medicine with blood-activating and stasis-resolving medicine, heat clearing and detoxifying medicine. Combination scheme with blood-activating and stasis-resolving medicine joint glucocorticoid, followed by blood-activating and stasis-resolving medicine combined antiallergic drugs, heat-clearing and detoxifying medicine combined antiallergic drugs. Promoting blood circulation and removing blood stasis is an important part of traditional Chinese medicine treatment in patients with Henoch Schonlein purpura. PMID- 25532392 TI - [Real world clinical research of common complications and characteristics of traditional Chinese and western treatment in gastric malignant tumor inpatients]. AB - OBJECTIVE: To Understand the characteristics of the common complications in the gastric malignant tumor inpatients in our country, the related traditional Chinese and western medicine combined usage. METHOD: By using the method of frequency analysis and correlation, analysis the diagnostic and Prescribing information in HIS database of 20 national first-class ternary general hospital inpatients. RESULT: The most common coexistent disease are malignant tumor in other parts, benign tumor. The most common complications are serous cavity effusion, lung infection, abnormal liver function. In other parts malignant tumor, more than 50% with advanced gastric malignancy; in other parts benign tumor, 86.00% located in the digestive and Urinary system, in the complications, digestive system diseases accounted for 23.80%; further according to the association rules of data mining, and calculate the combination scheme of the most commonly used for acid suppression drugs in combination with the centralizer and eliminate pathogenic traditional Chinese medicine (TCM). CONCLUSION: In the real world, most of the gastric malignant tumor disorder crowd is in the advanced stage, with lymph nodes and other parts of the transfer; and at the same time to incorporate the spleen and kidney disease in TCM zang-fu organs dialectical, should notice the reach mark early intervention, achieve the purpose of cure not ill; acid suppression hemostatic drugs combined the centralizer and eliminate pathogenic the three medicine combined treatment of Chinese traditional medicine is relevant. PMID- 25532393 TI - [Real world study of Dengzhan xixin injection in treatment of cerebral infarction with medication]. AB - To analysis of Dengzhan Xixin injection (DZI) in treatment of cerebral infarction (EBHM) in the real world population characteristics and concomitant medication. By selecting the 20 hospital information system (HIS) used in the database of DZI and primary diagnosis of 2 484 cases of cerebral infarction patients information, use the Apriori algorithm to construct the model, using Clementine 12.0 analysis, cerebral infarction complicating diseases, commonly used drug combination analysis of DZI. The results showed that patients with more males than females (1.63: 1); age > 46 in older persons, treatment 7-14 days accounted for the majority of patients with hypertension, cerebral infarction, diabetes, coronary heart disease and other diseases; common drug combination can be divided into seven categories: medicine of antiplatelet therapy (aspirin, clopidogrel hydrogen), hypolipidemic drugs (atorvastatin, probucol), calcium channel blockers (cinepazide), cerebral protection drugs (laci staw), to improve cerebral circulation drugs (alprostadil), other traditional Chinese medicine injection (Shuxuetong injection, Xueshuantong), treatment with underlying disease: nifedipine, metoprolol, isosorbide dinitrate etc. The clinical cure rate and improvement rate of 97.60%. The next step needs to be combined with clinical practice, carry out analysis of effectiveness and safety of the combination scheme, and provide reference for clinical rational drug use. PMID- 25532394 TI - [Shuxuetong injection-based on nested case-control study of blood through injection suspect allergic reaction influencing factors]. AB - OBJECTIVE: To understand the real world Shuxuetong injection suspicious allergic factors. METHOD: National 18 hospitals of the hospital information system using Shuxuetong data, using design methods retrospective nested case-control, and contrast using Shuxuetong after the occurrence of allergic reactions in patients with non-allergic patients differences in age, gender, admission illness, allergies, etc. RESULT: Based on available data, indicate suspicious allergies affect Shuxuetong factors may be hospitalized illness, solvent, single dose, concomitant medications. CONCLUSION: When using Shuxuetong for critically ill patients should use caution and pay attention to solvents, dose, combination therapy of choice clinically. Conclusions of this study need further study to be verified. PMID- 25532395 TI - [Analysis of questionable allergic factors to kudiezi injection--nested case control study using hospital information system data]. AB - This study aims to assess if adverse drug reactions (ADRs) to Kudiezi injection are allergic in origin. Hospital information system (HIS) data from 18 hospitals in China were used to carry out a nested case control design study. Included were patients who received dexamethasone for suspected allergic reactions after receiving Kudiezi injection. These were compared with non-allergic reaction people. Single factor logistic regression and multiple factor logistic regression were used to analyze data. Condition on admission, allergic history, dosage, disease status and drug combinations were taken into account in cases of suspected allergic reactions. After analysis in two subgroups we found that the condition on solvents had a significant effect, P values were 0.005 5 and < 0.000 1 on suspected cases of allergic reactions. For the first subgroup analysis, we found using other eight injections at the same time as Kudiezi injection could be risk factors in suspected cases of allergic reactions. For the second subgroup analysis combining using mannitol or fructose could increase risks. Based on this current research, condition on admission as well as the concomitant use of some other drugs may be the risk factors in suspected cases of allergic reactions. However, further research for verification is required. This study can provide guidance for safe clinical practice in using Kudiezi injection. PMID- 25532396 TI - [Analysis suspected allergic factors to shenqi fuzheng injection based on prescription sequence analysis and nested case control study]. AB - This study based on twenty 3A grade hospital information system (HIS) database in China, adopt toprescription sequence analysis (PSA) with nested case control study (NCCS) to analysis mainly suspected allergy factor of Shenqi Fuzheng injection (Shenqi Fuzheng). Study design according to start to stop using Shenqi Fuzheng whether using dexamethasone injection will crowd divided into cases group and control group, each case matched 4 controls were selected, two groups according to the ratio of the age and sex matched well. Square test, Fisher exact test, single factor and multiple factor logistic regression were used to analyze data Condition on admission, allergic history, dosage and drug combinations were taken into account in cases of suspected allergic reactions. After analysis in two subgroups we found that the single dose (P = 0.000 2) and the combined use of matrine (P < 0.000 1, OR = 14.312, confidence interval [8.184, 25.029]) had significant effects on the suspected allergic reaction. Study on the existing HIS data and the study method based on screening suspected risk factors for allergic reaction. This study can provide guidance for Shenqi Fuzheng injection safety using in clinical practice, and it can also provides new method for the clinical safety reevaluation of post-marketing Chinese medicine injection. PMID- 25532397 TI - [Demonstration of nested case-control study design in mechanisms research of allergic reaction of tanreqing injection]. AB - The paper is focused on the clinical applications of Tanreqing injection after listing, detecting and analyzing the related blood indicators of patients with allergic reactions based on prospective, multi-center, large sample, registration type clinical safety monitoring nested case-control study (NCCS) to explore the possible mechanisms of allergic reaction of Tanreqing injection, 3 006 patients cases used with Tanreqing injection were monitored, including 3 cases of adverse reactions and 2 cases of allergic reactions. Each patient of allergic reactions, according to the ratio of 1:4 matches four cases of not adverse reactions as a control group of patients, while 5 healthy and 5 cases of volunteers into the healthy group. We examined the correlation detection of cases of allergic reactions among groups such as T-IgE, IgA, IgG, C3, C4, IFN-g, IL-2, IL-4, IL-6, IL-10. Allergic reactions of Tanreqing injection may be mediated by IgE as type I based on existing research data. This results and conclusions will promote the justifiability and safety of clinical applications. PMID- 25532398 TI - [Registration study on analysis of adaptation syndromes and medication characteristics of tanreqing injection]. AB - Tanreqing injection is suitable for early pneumonia, acute bronchitis, acute exacerbations of chronic, and upper respiratory tract infection which are classified with phlegm-heat obstructing lung syndrome of traditional Chinese medicine. To understand the clinical adaptation syndromes and medication characteristics of the post-market Tanreqing injection, the research team of the paper monitored the patients who are used with Tanreqing injection from September 2012 to October 2013 in four leader hospitals based on the method--prospective, multi-center, large sample, registration-type hospital centralized monitoring,and analyzes the general information, diagnostic information and medication characteristics of patients, in order to produce evidence for clinical practice and medication decisions and to establish the foundation of rational drug use. PMID- 25532399 TI - [Analysis of questionable allergic factors to parenterally administered salvianolate--a nested case control study using hospital information system data]. AB - This study aims to assess if adverse drug reactions (ADRs) to parenterally administered salvianolate are allergic in origin. Hospital information system (HIS) data from 20 hospitals in China were used to carry out a retrospective nested case control design study. Included were patients who received dexamethasone for suspected allergic reactions after receiving parenterally administered salvianolate. These were compared with non-allergic reaction people. Single factor logistic regression and multiple factor logistic regression were used to analyze data. Condition on admission, allergic history, dosage, disease status and drug combinations were taken into account in cases of suspected allergic reactions. After analysis in two subgroups we found that the condition on admission had a significant effect, P values was < 0.000 1 on suspected cases of allergic reactions in the first subgroup analysis. For the second subgroup analysis, we found condition on solvents had a significant effects, P values was 0.005 1 on suspected cases of allergic reactions. We also found that using other four injections at the same time as parenterally administered salvianolate could be risky factors in suspected cases of allergic reactions. For the second subgroup analysis combining using three injections could increase risks. However, further research for verification is required. This study can provide guidance for safe clinical practice in using parenterally administered salvianolate. PMID- 25532400 TI - [Analysis of real-world use different treatment shuxuetong injection effects on liver and kidney function]. AB - OBJECTIVE: To understand the real world, the use of ultra- treatment Shuxuetong injection on liver and kidney functions are affected. METHOD: The 18 hospitals of the country's HIS data sources from which to choose to use Shuxuetong injection, between the ages of 18 to 80 years, using Shuxuetong and the first seven days after discontinuation of at least 7 days has once aspartate aminotransferase or alanine aminotransferase, or creatinine or blood urea nitrogen were measured value as a research object, the number of days of medication is based on more than 14 days, divided into treatment group and the normal course of super-group to reach the normal range of physical and chemical indicators 200% of the upper limit is defined as abnormal. Using the propensity score method, balance the known confounding factors, differences in the occurrence of abnormal renal function and compared between the two groups. RESULT: The treatment group and the normal course of super-group, resulting in alanine aminotransferase, aspartate aminotransferase, creatinine, urea nitrogen equally likely targets abnormal changes, no statistically significant difference. CONCLUSION: Based on the available data did not find "super treatment using Shuxuetong damage the liver and kidney function" the situation, but the clinical disease lasts insist on the principle can not be arbitrarily extended treatment to prevent long-term medication. PMID- 25532401 TI - [Analysis of kudiezi injection different dosage impact on patient's liver and kidney function based on hospital information system]. AB - This study aims to explore the impact on patient's liver and kidney function by different dosage of Kudiezi injection. This study retrospectively analyzed 15 228 patients' records from 18 nationwide general hospital information system (HIS). All patients were treated with Kudiezi injection, 1 956 patients that were given doses of > 40 mL, which is above the recommended dose, acted as the observation group. Fifty-five patients receiving the recommended dose of < 40 mL were the control group. Data about alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr) and blood urea nitrogen (BUN) were collected before and after using Kudiezi injection, changes after treatment were outcomes. Also recorded were: age, costs, length of hospitalization and the patients' condition on admission. Propensity score method was used to balance 71 confounding variables such as gender, age, mortality, and costs. There were no significant difference on the four indexes between the two groups. It is hard to conclude that the use of Kudiezi injection over the recommended dose could influence the four indexes of liver and kidney from this data analysis. More conclusive evidence should be collected by further prospective study. PMID- 25532402 TI - [Data analysis of electronic medical recored clinical changes in indexs of liver and kidney function when salvianolate injection is parenterally administered over extended period]. AB - To understand the impact of salvianolate injection treatment of liver and kidney function using different from the hospital information system nationwide 18 large three hospitals (hospital information system, HIS) to extract using salvianolate age 18-80 years-old patient, a total of 10 470 cases, depending on the treatment used to have two times before and after treatment 7 d aspartate aminotransferase (AST), alanine aminotransferase patients (ALT), serum creatinine (Cr) and blood urea nitrogen (BUN) measurement indicators grouped according salvianolate continuous use different treatment patients were divided into two groups, continuous medication time > 14 d were defined as the observation group, <= 14 d were defined as the control group, continuous medication longer than 31 d were not included in the analysis. Each index number of the observation group and the control group were: ALT (268/1 465), AST (270/1 585), Cr (278/1 582), BUN (278/1 611). After using propensity score methods to balance two groups of covariates, based on unweighted logistic regression logistic regression propensity score weighting combined with propensity score weighting to adjust for covariates logistic regression of liver and kidney function in the two groups were analyzed. The results showed: three logistic regression analysis showed no likelihood of ALT, AST, Cr targets two groups of patients with abnormal statistically significant difference, continuous medication time > 14 d may increase the risk of abnormal BUN indicators, comprehensive analysis still can not explain use different treatment of patients salvianolate cause liver and kidney toxicity damage, still large prospective randomized controlled trials further study. PMID- 25532403 TI - [Analysis of clinical effects of shuxuening injectionon renal function based on hospital information system data]. AB - The safety of drugs has been the important issue that has caught the mutual attention of clinicians and patients. Kidney is one of the important organs in drug metabolism. The study is based on hospital information system (HIS) data from 20 nationwide general hospitals, indicated by Scr and BUN. Generalized boosted models (GBM) based on propensity score method were used to balance confounding factors. The study contrasts changes on renal function between used Shuxuening injection patients and the unused to explore whether Shuxuening injection affects renal function in clinical. The results showed that Shuxuening injection is likely to affect Scr in logistic regression (P value is 0.035); after the logistic regression based on propensity score method (P value became 0.513, 0.590), no differences were found between the two groups; before and after the logistic regression based on propensity score method (P value was less than 0.05), Shuxuening injection possibly affects BUN. Nevertheless, this study is a retrospective analysis. Logistic regression based on propensity score method can control the known confounding factors very well, while there may be the unknown ones. Therefore, the further exploration is required to monitor whether Shuxuening injection affects really BUN, which will provide clinical guidance for Shuxuening injection safe application. PMID- 25532404 TI - [Impact analysis of shenqi fuzheng injection of course on liver function based on hospital information system data]. AB - OBJECTIVE: Use propensity score methods to explore the effect of Shenqi Fuzheng injection (SQFZ) on ALT and AST lever of real worlds. METHOD: HIS data from 18 hospitals was analyzed. Patients ranging from 18 to 80 years, it were divided into the cases group was used Shenqi Fuzheng injection > 21 days under the instruction, and control group used SQFZ <= 21 days. A large number of confounding biases are taken into account through the generalized boosted models (GBM) and multiple logistic regression model to estimate the treatment effects of SQFZ on abnormal changes in ALT and AST index and to explore possible influencing factors. RESULT: Sventy and one confounding factors had been counterpoised, stratified analysis showed that the abnormal changes of cases group lower than control group, but not statistically significant. CONCLUSION: Analysis of HIS database showed that significant effects of SQFZ on abnormal changes in ALT and AST have not been found. The results of this study form the retrospective data, for the purpose of validating its clinical safety should be have a prospective clinical study of large sample. PMID- 25532405 TI - [Analysis effects of shuxuening injection on patient's liver function based on electronic medical data]. AB - To assess whether the Shuxuening injection influences liver function, this paper analyzes the hospital information system (HIS) data from 20 national hospitals. The patients were divided two groups: patients (5 353 cases) using Shuxuening injection acted as the exposed group, then the patients (4 863 cases) not using Shuxuening injection acted as the unexposed group. Take the abnormal changes of alanine aminotransferase and aspartate aminotransferase indexes as the result. Control confounding factors by stratification analysis, classic logistic regression analysis, before logistic regression based on propensity score weighting method and logistic regression based on generalized boosted models (GBM) of propensity score weighted combination of covariate adjustment. Then, the study analyzes the effects of Shuxuening injection on liver function by observing the changes of the indexes. Analysis of the impact of parenterally administered Shuxuening on ALT shows that, before logistic regression based on propensity score, then the regression is -0.232 (P value is 0.017). However, after logistic regression based on propensity score method the regression became -0.150 (P value is 0.370). Whereas, analysis of the impact of parenterally administered Shuxuening on AST shows that, before logistic regression based on propensity score, then the regression is -0.034 (P value is 0.767). However, after logistic regression based on propensity score method the regression became -0.091(P value is 0.538). Thus, propensity score method can control a large number of confounding factors, making the results more close to the clinic. Hence, based on existing electronic medical data, this study didn't find that parenterally administered Shuexuening influences ALT and AST. PMID- 25532406 TI - [Apply association rules to analysis adverse drug reactions of shuxuening injection based on spontaneous reporting system data]. AB - This research based on the analysis of spontaneous reporting system (SRS) data which the 9 601 case reports of Shuxuening injection adverse drug reactions (ADR) in national adverse drug reaction monitoring center during 2005-2012. Apply to the association rules to analysis of the relationship between Shuxuening injection's ADR and the characteristics of ADR reports were. We found that ADR commonly combination were "nausea + breath + chills + vomiting", "nausea + chills + vomiting + palpitations", and their confidence level were 100%. The ADR and the case reports information commonly combination were "itching, and glucose and sodium chloride Injection, and generally ADR report, and normal dosage", "palpitation, and glucose and sodium chloride injection, and normal dosage, and new report", "chills, and generally ADR report, and normal dosage, and 0.9% sodium chloride injection", and their confidence level were 100% too. The results showed that patients using Shuxuening injection occurred most of ADRs were systemic damage, skin and its accessories damage, digestive system damage, etc. And most of cases were generally and new reports, and patients with normal dosage. The ADR's occurred had little related with solvent. It is showed that the Shuxuening injection occurred of ADR mainly related to drug composition. So Shuxuening injection used in clinical need to closely observation, and focus on the ADR reaction, and to do a good job of drug risk management. PMID- 25532407 TI - [Study on path of transforming traditional Chinese medicine research achievement into guideline]. AB - At present, a number of scientific research achievements has been formed. Scientific achievement is the crystallization of great efforts from scientific workers, and it's also the valuable treasure of human civilization. Standardization is an important way to promote the international communication of Chinese medicine, and it's significant in boosting China's scientific and technological progress, improving market competitiveness and promoting international trade. Transformation of scientific research to the guideline is not only beneficial to improving the technology content of the standard, but also to the conversion from scientific research achievements into productivity. Therefore, only by absorbing the advanced scientific and technological achievements, reproducing the theory of traditional Chinese medicine (TCM) and medical technology in standard form, can make TCM keep pace with the times. This study preliminarily explores for the method to transform scientific research achievements into guideline, in order to provide reference for the future technical specifications, thus to further the development of TCM. PMID- 25532408 TI - [Systematic report on re-evaluating kudiezi injection]. AB - There are few articles or reports collecting evidence about Kudiezi injection from premarketing and postmarketing research or studies systematically. This article is an exact miniature of a systematical report about Kudiezi injection. We analyzed information from four aspects, such as quality control reports, non clinical premarketing safety experiments, postmarketing research (efficacy studies, hospital information system data and national spontaneous reporting system data), and literature analysis. All the four aspects build an evidence body for Kudiezi injection in order to inform its safety use in clinical practice and further study. PMID- 25532409 TI - [Building safety evidence body of shuxuetong injection]. AB - Evidence body is defined as an evidence complex incorporating the evidence obtained from various research methods and various resources. As one of common parenterally administered Chinese medicines, Shuxuetong's safety drew high concern from doctors. However, we only have grasped several but less systematic evidence on the safety of Shuxuetong. To build a safety evidence body of Shuxuetong injection. Review and evaluate the evidence related to the safety of Shuxuetong injection after accumulating, searching and classfying related literature. Accoeding to levels of evidence from high to low, the evidence related to the safety of Shuxuetong injection was classified as following: the evidence from a long-term, prospective, large-sample-size and intensive hospital monitoring study was the strongest; the evidence of hospital information system (HIS) data analysis; the evidence of spontaneous reporting system (SRS) data analysis; the evidence of adverse drugreactions (ADRs)/adverse drug events (ADEs) reported in systematic evaluation, ADRs case report, toxicological tests, pharmacological tests were weakest. Based on the evidence body, Shuxuetong Injection was proved to be safe, and its ADRs were mainly allergic reactions, and more often happened among the old patients. PMID- 25532410 TI - [Study of post marketing safety reevaluation of shenqi fuzheng injection]. AB - In order to promote the Shenqifuzheng injection (SQFZ) clinical medication safety, this study reevaluate on SQFZ post marketing safety study systematically. Including multi center large sample registration type safety monitoring research, the analysis based on national spontaneous reporting system data, the analysis based on the 20 national hospital information system data and literature research. Above the analysis, it suggests that SQFZ has good security. The more adverse drug reaction (ADR) as allergic reactions, mainly involved in the damage of skin, appendages and its systemic damage, serious person can appear allergic shock. ADR/E is more common in the elderly, may be related to medication (tumor) populations. Early warning analysis based on SRS data and literature research are of the view that "phlebitis" has a strong association with SQFZ used. PMID- 25532411 TI - [Literature review on premarketing and postmarketing evidence of xiyanping injection]. AB - This article systematically summarizes the non-clinical safety studies, pharmacological studies and postmarketing safety studies of Xiyanping injection based on literature. These studies include acute toxicity test, long-term toxicity test, reproductive toxicity test, active and passive anaphylaxis test, curative mechanism study, clinical trials of effectiveness, active surveillance, security analysis of passive monitoring data, the real world analysis of hospital information system (HIS) data, literature analysis, etcetera This article also analysis the relationship of the different evidence, summarizes the strategy of the researches, in order to make it to be a reference for making a systemic research program of traditional Chinese medicine injection. PMID- 25532412 TI - [Research and practice about risk control of shenfu injection]. AB - Shenfu injection is developed by improving dosage form of ancient prescription "Shenfu Tang" and is mainly derived from extracts of both traditional Chinese medicine red ginseng and prepared lateral root of monkshood with polysorbate 80 as auxiliary material. Shenfu injection may be administered through intramuscular injection, intravenous drip or intravenous injection. It produces good effects in restoring Yang and rescuing patients from collapse, tonifying Qi and preventing exhaustion. It is mainly used to treat not only syncope and prostration resulting from sudden Yang collapse (infectious, hemorrhagic and water depletion shock etc), but also pavor, palpitation, dyspnea with cough, stomachache, diarrhea and arthralgia etc caused by deficiency of Yang (deficiency of vital energy). Research group has audited the monitored hospitals and has carried out postmarketing study of Shenfu solution from many aspects including literature review, spontaneous reporting system (SRS) and hospital information system (HIS) data analysis etc. A summary is shown below. PMID- 25532413 TI - [Systematic report on re-evaluating parenterally administered salvianolate]. AB - There are few articles or reports collecting evidence about parenterally administered salvianolate from premarketing and postmarketing research or studies systematically. This article is an exact miniature of a systematical report about parenterally administered salvianolate. We analyzed information from four aspects, such as quality control reports, non-clinical premarketing safety experiments, postmarketing research (efficacy studies, hospital information system data and national spontaneous reporting system data) and literature analysis. All the four aspects build an evidence body for Kudiezi Solution in order to inform its safety use in clinical practice and further study. PMID- 25532414 TI - [Systematic review of efficacy and safety of shenmai injection for chronic heart failure]. AB - The paper is to evaluate the efficacy and safety of Shenmai injection for chronic heart failure, retrieving the Pubmed, CBM, CNKI, Wanfang database and VIP database to comprehensively collect all types research report of Shenmai injection for chronic heart failure (CHF). Particularly wishing to point out, randomized controlled trials are include for the evaluation of effectiveness, which are statistically analyzed and evaluated by Rev-Man 5. 2. The current studies show that the improvement rate of NYHA classification of cardiac function of CHF patients and their related indexes figure such as LVEF, SV, CO, BNP, 6 min walking test value are all improved by the combination of Shenmai injection and foundation treatment. However, HR is almost no improvement. Meanwhile, serious ADR/AE of Shenmai injection for CHF isn't appear. PMID- 25532415 TI - Rotationally Inelastic Scattering of Quantum-State-Selected ND3 with Ar. AB - Rotationally inelastic scattering of ND3 with Ar is studied at mean collision energies of 410 and 310 cm(-1). In the experimental component of the study, ND3 molecules are prepared by supersonic expansion and subsequent hexapole state selection in the ground electronic and vibrational levels and in the jk(+/-) = 1(1) rotational level. A beam of state-selected ND3 molecules is crossed with a beam of Ar, and scattered ND3 molecules are detected in single final j'k'(+/-) quantum states using resonance enhanced multiphoton ionization spectroscopy. State-to-state differential cross sections for rotational-level changing collisions are obtained by velocity map imaging. The experimental measurements are compared with close-coupling quantum-mechanical scattering calculations performed using an ab initio potential energy surface. The computed DCSs agree well with the experimental measurements, confirming the high quality of the potential energy surface. The angular distributions are dominated by forward scattering for all measured final rotational and vibrational inversion symmetry states. This outcome is in contrast to our recent results for inelastic scattering of ND3 with He, where we observed significant amount of sideways and backward scattering for some final rotational levels of ND3. The differences between He and Ar collision partners are explained by differences in the potential energy surfaces that govern the scattering dynamics. PMID- 25532416 TI - Australian Liver Association (ALA) expert consensus recommendations for the use of transient elastography in chronic viral hepatitis. AB - Since the introduction of Transient Elastography (TE) into Australia in 2008, non invasive liver fibrosis assessments have integrated themselves into clinical hepatology. The Australian Liver Association (ALA) recognizes these technologies perform an important role in the assessment of chronic viral hepatitis B and C. However, in the setting of viral hepatitis and many other chronic liver diseases, there remains no consensus or guidelines regarding the performance, utility or reporting of TE. Accordingly, the ALA sought to produce an expert consensus statement for the use of TE in chronic viral hepatitis. The recommendations incorporated in this document are based upon a thorough literature review and draw on extensive clinical experience using TE. The initial draft was presented at Australian Gastroenterology Week (AGW) 2013. Through a collaborative process and expert external review a finalized document was presented at AGW 2014. PMID- 25532417 TI - Insulin resistance and depressive symptoms in older men: the health in men study. AB - OBJECTIVE: A positive association between depression and diabetes has been reported, but the direction and nature of this association is unclear. Insulin resistance is a state of reduced responsiveness of target tissues to normal circulating levels of insulin and predisposes to diabetes in the presence of beta cell dysfunction. METHODS: We conducted this cross-sectional and prospective study in a community representative sample of 3,140 older men free of diabetes to determine if insulin resistance was associated with prevalent and incident depressive symptoms. RESULTS: Men with insulin resistance had increased odds of depression cross-sectionally (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.08-2.40), although this was not significant after adjustment for possible confounding (OR: 1.32; 95% CI: 0.85-2.03). In the longitudinal analysis, men with insulin resistance were more likely to develop clinically significant depressive symptoms (adjusted risk ratio [RR]: 2.33; 95% CI: 1.17-4.62), and this risk was greatest for men in the highest quartile of insulin resistance compared with those in the lowest quartile (adjusted RR: 2.54; 95% CI: 1.04-6.18). CONCLUSION: Older men with clinically significant depressive symptoms were more likely to have higher markers of insulin resistance. Additionally, the odds of depression increased with increasing levels of insulin resistance, and insulin resistance increased the risk of developing depression over 5 years later. Because depression is now a leading cause of disability worldwide, addressing the rising challenge of insulin resistance may prove important in improving the future health of our communities. PMID- 25532419 TI - Single symptomatic colonic metastasis as first presentation of a pulmonary mucoepidermoid carcinoma. AB - Metastatic lesions in the large bowel are rare. A case of single symptomatic colonic metastasis as first presentation of pulmonary mucoepidermoid carcinoma (MEC) is described. A 62-year-old male was admitted with constipation and rectal bleeding. Colonoscopy revealed extrinsic compression at sigmoid colon, and microscopy suggested a secondary origin. Subsequent chest computed tomography confirmed a right perihilar mass invading posterior mediastinum, carina and esophagus, and also a second consolidation on right lower lobe and ipsilateral mediastinal and subcarinal lymph nodes. After pathologic evaluation of a transthoracic biopsy specimen, the diagnosis of pulmonary high-grade MEC, stage IV (T4, N3, M1b - 7th ed. TNM), was established. Chemotherapy with carboplatin and paclitaxel was initiated, and disease progression occurred after two cycles with increasing colonic mass. Palliative surgery was rejected because of advanced stage, and the patient was submitted to palliative pelvic radiotherapy. Second line chemotherapy with gemcitabine was initiated, but clinical status worsened and the patient died because of severe lung failure. Clinical, pathological and therapeutic aspects of this uncommon site of extrathoracic metastatic disease are discussed, emphasizing the important contribution of special stains and immunohistochemistry to the diagnosis. PMID- 25532420 TI - The mosquito Anopheles (Cellia) oreios sp. n., formerly species 6 of the Australasian Anopheles farauti complex, and a critical review of its biology and relation to disease. AB - Species 6 of the Australasian Anopheles farauti sibling species complex (Diptera: Culicidae) is described and formally named Anopheles oreios Bangs & Harbach, sp. n. Adult, pupal and fourth-instar larval specimens collected in the Baliem Valley, Papua Province, Indonesia, are characterized and compared with those of Anopheles farauti, Anopheles hinesorum, Anopheles irenicus and Anopheles torresiensis (formerly informally denoted as species 1, 2, 7 and 3, respectively). The variable wings of adult females, the male genitalia, the pupa and the fourth-instar larva of An. oreios are illustrated and DNA sequence data are included for regions coding for sections of the mitochondrial COI and COII genes. The biology of An. oreios and its relation to malaria transmission are discussed in detail and contrasted with the biology and disease relations of some members of the An. farauti and Anopheles punctulatus sibling species complexes. PMID- 25532418 TI - Proteomics of muscle chronological ageing in post-menopausal women. AB - BACKGROUND: Muscle ageing contributes to both loss of functional autonomy and increased morbidity. Muscle atrophy accelerates after 50 years of age, but the mechanisms involved are complex and likely result from the alteration of a variety of interrelated functions. In order to better understand the molecular mechanisms underlying muscle chronological ageing in human, we have undertaken a top-down differential proteomic approach to identify novel biomarkers after the fifth decade of age. RESULTS: Muscle samples were compared between adult (56 years) and old (78 years) post-menopausal women. In addition to total muscle extracts, low-ionic strength extracts were investigated to remove high abundance myofibrillar proteins and improve the detection of low abundance proteins. Two dimensional gel electrophoreses with overlapping IPGs were used to improve the separation of muscle proteins. Overall, 1919 protein spots were matched between all individuals, 95 were differentially expressed and identified by mass spectrometry, and they corresponded to 67 different proteins. Our results suggested important modifications in cytosolic, mitochondrial and lipid energy metabolism, which may relate to dysfunctions in old muscle force generation. A fraction of the differentially expressed proteins were linked to the sarcomere and cytoskeleton (myosin light-chains, troponin T, ankyrin repeat domain containing protein-2, vinculin, four and a half LIM domain protein-3), which may account for alterations in contractile properties. In line with muscle contraction, we also identified proteins related to calcium signal transduction (calsequestrin-1, sarcalumenin, myozenin-1, annexins). Muscle ageing was further characterized by the differential regulation of several proteins implicated in cytoprotection (catalase, peroxiredoxins), ion homeostasis (carbonic anhydrases, selenium-binding protein 1) and detoxification (aldo-keto reductases, aldehyde dehydrogenases). Notably, many of the differentially expressed proteins were central for proteostasis, including heat shock proteins and proteins involved in proteolysis (valosin-containing protein, proteasome subunit beta type-4, mitochondrial elongation factor-Tu). CONCLUSIONS: This study describes the most extensive proteomic analysis of muscle ageing in humans, and identified 34 new potential biomarkers. None of them were previously recognized as differentially expressed in old muscles, and each may represent a novel starting point to elucidate the mechanisms of muscle chronological ageing in humans. PMID- 25532423 TI - Optic nerve involvement in retinal migraine. PMID- 25532424 TI - Cognitive problems after traumatic brain injury. PMID- 25532422 TI - Clinical significance of inactivated glycogen synthase kinase 3beta in HPV associated cervical cancer: Relationship with Wnt/beta-catenin pathway activation. AB - PROBLEM: To determine the role of inactivated GSK3beta with respect to Wnt/beta catenin pathway activation in HPV-16/18-associated cervical cancer. METHOD OF STUDY: The expression of active (pGSK3beta-Try(216)), inactive (pGSK3beta Ser(9)), and c-Myc as well as HPV-16/18 infection was analyzed in cervical intra epithelial neoplasia (CIN), squamous cell carcinoma (SCCs) and normal by immunohistochemistry and multiplex PCR. The proteins level was also compared with beta-catenin and APC expression. RESULTS: The dramatic decrease of pGSK3beta Try(216) expression but ectopic overexpression of pGSK3beta-Ser(9) and c-Myc was observed both in CIN and SCCs samples compared to normal tissues. 57/67 CIN and 132/153 SCCs showed HPV-16 infection, while 3/67 CIN and 4/153 SCCs were harbored with HPV-18 infection. Both the proteins were significantly upregulated in HPV-16 infected cases (P = 0.0001; P = 0.001) and also positively correlated with nuclear beta-catenin (P = 0.0001; P = 0.0001). CONCLUSION: The process of generation of HPV-16-associated cervical tumorigenesis is synergized with GSK3beta inactivation and overactivation of Wnt/beta-catenin pathway. PMID- 25532421 TI - The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. AB - The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides discussion on the management recommendations on 3 focused areas: (1) anemia; (2) biomarkers, especially natriuretic peptides; and (3) clinical trials that might change practice in the management of patients with heart failure. First, all patients with heart failure and anemia should be investigated for reversible causes of anemia. Second, patients with chronic stable heart failure should undergo natriuretic peptide testing. Third, considerations should be given to treat selected patients with heart failure and preserved systolic function with a mineralocorticoid receptor antagonist and to treat patients with heart failure and reduced ejection fraction with an angiotensin receptor/neprilysin inhibitor, when the drug is approved. As with updates in previous years, the topics were chosen in response to stakeholder feedback. The 2014 Update includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers to best manage patients with heart failure. PMID- 25532425 TI - Phenotypic and functional comparison of mobilized peripheral blood versus umbilical cord blood megakaryocyte populations. AB - BACKGROUND AIMS: Hematopoietic stem cell transplantation of mobilized peripheral blood progenitor cell (PBPC) products results in rapid platelet engraftment, whereas the use of cord blood (CB) shows significant delays. The difference in the quality and number of megakaryocyte (MK) progenitors that may be responsible for the delay in platelet engraftment has not been fully defined. The objective of this study was to quantify the cells of the MK lineage in PBPC and CB products to determine whether potential differences exist. METHODS: We examined PBPC or CB for differences in surface markers and subpopulations as well as polyploidization status within the MK lineage. Colony-forming assays were used to determine whether differences exist in the clonogenic MK progenitor cell. Finally, we transplanted PBPC and CB mononuclear cells into NOD/SCID/IL2Rgamma-/- (NSG) mice to study platelet engraftment rates. RESULTS: Equivalent MK populations and polyploidization was observed in PBPCs and CB. MK progenitors were present only in CD34+ cells and had little difference in colony growth between PBPC and CB. Additionally, MK subpopulations were similar in either product with a slightly more progenitor-enriched phenotype in CB. Finally, when PBPC or CB was transplanted at similar doses, equivalent platelet engraftment rates were observed. CONCLUSIONS: PBPC and CB contain similar frequencies of MK populations, and, when transplanted in comparable doses, CB is as effective as PBPCs in producing platelet engraftment in vivo. Understanding the differences in MK populations between PBPC and CB could help generate protocols to improve platelet engraftment after CB transplantation. PMID- 25532426 TI - Bone mineral density and fractures after risk-reducing salpingo-oophorectomy in women at increased risk for breast and ovarian cancer. AB - AIM: Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA mutation carriers. RRSO is assumed to decrease bone mineral density (BMD) and increase fracture risk more than natural menopause. We aimed to compare BMD and fracture incidence after premenopausal RRSO to general population data and identify risk factors for low BMD and fractures after RRSO. METHODS: In 212 women with RRSO at premenopausal age, BMD was measured by dual energy X-ray absorptiometry. Fractures and risk factors were assessed by self-administered questionnaire. Fracture incidence after RRSO was compared to general practitioner data by using standardised incidence ratios (SIRs). Risk factors for low standardised BMD-scores and fractures were identified by regression analyses. RESULTS: Median age at RRSO was 42years (range 35-65) and duration of follow-up 5years (2-8). Standardised lumbar spine (Z=0.01, p=0.870) and femoral neck BMD (Z=0.15, p=0.019) were not lower than population BMD. Higher age at time of RRSO and use of hormonal replacement therapy were associated with higher, and current smoking with lower standardised BMD-scores. Sixteen women reported 22 fractures. Fracture incidence was not higher than expected from the general population (all fractures: 25-44years: SIR 2.12 [95% confidence interval (CI) 0.85-4.37]; 45 64years: SIR 1.65 [95% CI 0.92-2.72]). CONCLUSION: Five years after RRSO, BMD and fracture incidence were not different than expected from the general population. Based on these data it appears safe not to intensively screen for osteoporosis within five years after RRSO, although prospective research on the long-term effects of RRSO on bone is warranted. PMID- 25532427 TI - The phage tail tape measure protein, an inner membrane protein and a periplasmic chaperone play connected roles in the genome injection process of E. coli phage HK97. AB - Phages play critical roles in the spread of virulence factors and control of bacterial populations through their predation of bacteria. An essential step in the phage lifecycle is genome entry, where the infecting phage must productively interact with the components of the bacterial cell envelope in order to transmit its genome out of the viral particle and into the host cell cytoplasm. In this study, we characterize this process for the Escherichia coli phage HK97. We have discovered that HK97 genome injection requires the activities of the inner membrane glucose transporter protein, PtsG, and the periplasmic chaperone, FkpA. The requirements for PtsG and FkpA are determined by the sequence of the phage tape measure protein (TMP). We also identify a region of the TMP that mediates inhibition of phage genome injection by the HK97 superinfection exclusion protein, gp15. This region of the TMP also determines the PtsG requirement, and we show that gp15-mediated inhibition requires PtsG. Based on these data, we present a model for the in vivo genome injection process of phage HK97 and postulate a mechanism by which the inhibitory action of gp15 is reliant upon PtsG. PMID- 25532428 TI - Selecting medical students: An unresolved challenge. AB - Despite the abundant supply of academically outstanding applicants to medical schools in most countries the regularly recurring debate in the academic literature, and indeed sometimes in the popular media, implies that admissions committees are still getting it wrong in a significant number of instances. How can this be so when our procedures are directed unashamedly at selecting the most highly academically and intellectually qualified students in the expectation that they will make the best doctors? Perhaps it is time for a radical change in emphasis. Instead of endeavouring to differentiate among the top ranks of a pool of outstandingly qualified applicants, the selection effort might be better focused on identifying those potentially unsuitable in terms of their non academic personal qualities to ensure they do not gain entry. The account that follows is an analysis of the problems of medical student selection and offers a potential solution - a solution that was first suggested in the medical literature 70 years ago, but not adopted. It is the present author's contention that the cycle of debate will continue to recur unless such an approach is pursued. PMID- 25532429 TI - Targeting the MET pathway for potential treatment of NSCLC. AB - INTRODUCTION: The mesenchymal-epithelial transition (MET) protein is the only known receptor for hepatocyte growth factor and has recently been identified as a novel promising target in several human cancers, including NSCLC. Activation of the MET signaling pathway can occur via different mechanisms. A number of compounds targeting MET have been evaluated in clinical trials, and recent clinical data have begun to afford some insight into the tumor types and patient populations that might benefit from treatment with MET pathway inhibitors. AREAS COVERED: We review recent publications and information disclosed at public conferences and summarize the epidemiology of dysregulation of MET signaling, and the associations thereof with other driver genes and therapeutic inhibitors useful to treat NSCLC. EXPERT OPINION: The MET pathway is emerging as a target for advanced NSCLC that is either resistant to EGFR tyrosine kinase inhibitors or that arises de novo. MET inhibitors currently being evaluated in clinical trials have yielded compelling evidence of clinical activities when used to treat various solid tumors, especially NSCLC. Remaining challenges are the identification of patient populations who might benefit from the use of MET inhibitors, and the most effective diagnostic methods for such patients. PMID- 25532430 TI - Acute effects of extended interval training on countermovement jump and handgrip strength performance in endurance athletes: postactivation potentiation. AB - The purpose of this study was to analyze multiple effects of an extended interval training (EIT) protocol on countermovement jump (CMJ) and handgrip strength in endurance athletes and to determine the relationship between fatigue and potentiation. Thirty experienced sub-elite male long-distance runners (age = 28.26 +/- 8.27 years, body mass index = 22.24 +/- 2.50 kg.m, and (Equation is included in full-text article.)= 58.7 +/- 4.50 ml.kg.min) participated voluntarily in this study. Subjects performed the protocol on an outdoor running track, which consisted of 12 runs of 400 m, grouped into 4 sets of 3 runs, with a passive recovery of 1 minute between runs and 3 minutes between sets (4 * 3 * 400 m). During protocol, fatigue parameters (lactate, heart rate, and rate of perceived exertion) and performance parameters (CMJ, handgrip strength, and time spent in each 400-m run) were controlled. Analysis of variance revealed a significant improvement in CMJ (p < 0.001) throughout the protocol. Cluster analysis grouped according to whether potentiation was experienced (responders group, n = 17) or not (nonresponders group, n = 13) in relation to CMJ change from rest to fatigued condition at the end of activity. Responders group significantly improved (p <= 0.05) the performance in CMJ, handgrip strength and time spent in each 400-m run. Results suggest that despite induced fatigue for EIT, trained subjects can maintain their strength and power levels and their work capacity. This fact would support the rationale that improvements in performance may be due not only to metabolic adaptations but also to specific neuromuscular adaptations. Therefore, the evaluation of power should be considered simultaneously with running performance when monitoring endurance athletes. PMID- 25532431 TI - Two percent hypohydration does not impair self-selected high-intensity intermittent exercise performance. AB - The level of hypohydration at which power output during intermittent exercise performance starts to decrease is not fully understood. The purpose of this study was to investigate the effects of 2% hypohydration without hyperthermia on intermittent exercise performance. Eight collegiate amateur boxers completed 2 exercise tests. On day 1, subjects hypohydrated by 2% of body mass by exercising in a hot environment, and on day 2, subjects performed intermittent exercise (4 * 2 minute per round [R] separated by 1-minute recovery) under a randomly assigned condition of with (HYP) or without (EUH) hypohydration. Each bout consisted of 8 * 5 seconds of maximal cycling exercise (0.05 kp * body mass) separated by 10 seconds of passive recovery. Mean power output per kilogram (MPO), total power output per kilogram (TPO), energy system relative contribution, and core rectal temperature (Tre) were measured. Changes in body mass before the exercise tests were -2.25 +/- 0.18% (HYP) and -0.17 +/- 0.19% (EUH) (p < 0.001). Mean power output, TPO, and each energy contribution ratio were not significantly different between the trials, and pre- and postexercise test Tre did not differ significantly between trials. Results demonstrated that approximately 2% hypohydration lies below the point at which power output during intermittent exercise starts to decline. PMID- 25532432 TI - Core temperature changes and sprint performance of elite female soccer players after a 15-minute warm-up in a hot-humid environment. AB - Warm-up session should be modified according to the environmental conditions. However, there is limited evidence regarding the proper soccer warm-up time for female players in the heat. The purpose of this study was to examine the rise in core body temperature and the sprint performance after a 15-minute warm-up in a hot-humid environment using female soccer players during the different phases of their menstrual cycle. Thirteen eumenorrheic national female soccer players (aged 18.8 +/- 1.3 years, (Equation is included in full-text article.)53.05 +/- 6.66 ml.kg.min) performed a 15-minute warm-up protocol at an ambient temperature of 32.5 +/- 1.6 degrees C with a relative humidity of 53.6 +/- 10.2% during their early follicular and midluteal phases of their cycle. The warm-up protocol is composed of jogging, skipping by moving the legs in various directions, and sprinting alternated with jogging, followed by a 45-minute recovery period. Rectal temperatures were recorded during the rest period and every 5 minutes throughout the warm-up and recovery phases of the study. Heart rate was monitored at rest and every 5 minutes during the warm-up. Forty-yard sprint time was assessed immediately after the completion of warm-up, which was later compared with the time at baseline. The value for the baseline was obtained at least 2 days before the experiment. During the early follicular and midluteal phases, the rectal temperatures obtained at the end of the warm-up period were significantly (p < 0.05) higher by 1.26 degrees C (95% confidence interval [CI] = +0.46 to +2.06 degrees C) and 1.18 degrees C (95% CI = +0.53 to +1.83 degrees C), whereas the heart rates increased to 153.67 +/- 20.34 and 158.38 +/- 15.19 b.min, respectively. After 20 minutes of the recovery period, the rectal temperature decreased by approximately 50%. The sprint times were significantly (p < 0.05) faster post-warm-up during both the early follicular (5.52 seconds; 95% CI = 5.43 5.60 seconds) and midluteal phases (5.51 seconds; 95% CI = 5.41-5.60 seconds) compared with the baseline time (5.66 seconds; 95% CI = 5.58-5.74 seconds). There were no significant differences in any parameters assessed after warm-up between the 2 phases. In conclusion, a 15-minute warm-up increased the core temperature by approximately 1 degrees C and improved the 40-yd sprint time for elite female soccer players in a hot environment regardless of menstrual phase. PMID- 25532433 TI - Modified versus standard D2 lymphadenectomy in total gastrectomy for nonjunctional gastric carcinoma with lymph node metastasis. AB - BACKGROUND: Although D2 lymphadenectomy has been shown to improve outcomes in gastric cancer, it may increase postoperative morbidity, mainly owing to splenopancreatic complications. In addition, the effects of nodal dissection along the proper hepatic artery have not been extensively elucidated. We hypothesized that modified D2 (ie, D1+) lymphadenectomy may decrease surgical risks without impairing oncologic adequacy. METHODS: Patients with node-positive gastric cancer undergoing curative total gastrectomy were intraoperatively randomized to D1+ (group 1, 36 patients) or standard D2 lymphadenectomy (group 2, 37 patients), the latter including splenectomy and nodal group 12a. The index of estimated benefit was used to assess the efficacy of dissection of each nodal station. The primary endpoint for oncologic adequacy was the disease-free survival (DFS) rate. RESULTS: Surgical complications were significantly more common in group 2, which also included 2 postoperative deaths. Overall, 35 patients (49%) experienced tumor recurrence. The primary site of tumor relapse and the 5-year DFS rate were not different between the 2 groups. Involvement of the second nodal level was associated with a worse DFS rate; however, patients undergoing more extensive lymphadenectomy did not show a better DFS rate. The incidence of involvement of nodal stations 10, 11d, and 12a was 5%, and the 5 year DFS rate was zero. Consequently, the benefit to dissect such lymph nodes was null. CONCLUSION: These findings suggest that modified D2 lymphadenectomy confers the same oncologic adequacy as standard D2 lymphadenectomy, with a significant reduction of postoperative morbidity. PMID- 25532434 TI - Mediastinal lymph node metastasis and recurrence in adenocarcinoma of the esophagogastric junction. AB - BACKGROUND: Whether thorough mediastinal dissection is indicated in patients with Siewert type II adenocarcinoma of the esophagogastric junction (EGJ) remains controversial. We conducted a multicenter study to find a preoperative indicator of mediastinal node metastasis. METHODS: We retrospectively collected data on 315 patients with pT2-T4 Siewert type II tumors who underwent R0 or R1 resection. The rates of metastasis or recurrence were investigated for the upper, middle, and lower mediastinal lymph nodes. Multivariate logistic analysis was used to identify significant indicators of metastasis or recurrence in the mediastinal nodes. RESULTS: The overall rates of metastasis or recurrence in the upper, middle, and lower mediastinal lymph nodes were 4%, 7%, and 11%, respectively. Rates were significantly higher when the distance from the EGJ to the proximal edge of primary tumor was >3 cm for the upper and middle mediastinal nodes and >2 cm for the lower mediastinal nodes. Multivariate analysis revealed that this distance was the only factor significantly associated with metastasis or recurrence in any mediastinal region. The 5-year overall survival rate in the 12 patients with metastasis in the upper or middle mediastinal lymph nodes was 17%. CONCLUSION: The distance from the EGJ to the proximal edge of primary tumor may be a significant indicator of metastasis or recurrence in the mediastinal lymph nodes in patients with Siewert type II tumors. Thorough mediastinal lymph node dissection via a transthoracic approach may provide a therapeutic benefit when the distance is >3 cm. PMID- 25532435 TI - Postoperative hypoparathyroidism after thyroidectomy: efficient and cost effective diagnosis and treatment. AB - BACKGROUND: To describe a standardized, efficient, and cost-effective protocol for the diagnosis of temporary/persisting postoperative hypoparathyroidism after (total) thyroidectomy. METHODS: We included 237 consecutive patients who underwent (total) thyroidectomy without central neck dissection for various indications. Serum calcium (sCa) and intact parathyroid hormone (iPTH) levels were measured prospectively on the morning of postoperative day 1 to predict the long-term parathyroid metabolism. On the morning of postoperative day 2, measurements were repeated. Follow-up was performed at 1 and 6 months postoperatively. RESULTS: On the morning of postoperative day 1, patients with iPTH >= 15 pg/mL (178/237; 75%) and sCa > 2.0 mmol/L were normocalcemic, and "normal" parathyroid metabolism was predicted. iPTH levels of <10 pg/mL and sCa levels of <=2.0 mmol/L were present in 33 of the 237 patients ("disturbed" parathyroid metabolism; 14%). A "gray zone" included patients with "uncertain" parathyroid metabolism demonstrating iPTH levels between 10 and 15 pg/mL (26/237; 11%). Patients with "disturbed" and "uncertain" parathyroid metabolism were given oral calcium and vitamin D. On the morning of the second postoperative day, iPTH turned to "normal" in 10 of those 26 (38%) patients, and no further calcium or vitamin D was given. During follow-up, supplemental calcium and vitamin D was able to be stopped in all but 2 patients ("permanent" hypoparathyroidism; 2/237; 0.8%). CONCLUSION: Measurement of iPTH on the morning after operation allows accurate prediction of postoperative parathyroid function in >=99% of cases. This simple recommendation is practicable in all surgical units, and is an efficient and cost-effective way to recognize patients who require calcium and vitamin D supplementation. PMID- 25532436 TI - Distal pancreatectomy, splenectomy, and celiac axis resection (DPS-CAR): common hepatic arterial stump pressure should determine the need for arterial reconstruction. AB - BACKGROUND: Tumors arising in the neck and body of the pancreas often invade the common hepatic artery and celiac axis (CA), necessitating distal pancreatectomy, splenectomy, and celiac axis resection (DPS-CAR). In these patients, the need for revascularization of the common hepatic artery (CHA) can be avoided on the basis of the pressure change in the CHA after clamping of the CA. METHODS: All patients presenting to North Shore Hospital Campus of University of Sydney with advanced pancreatic malignancy of the neck and body between 2007 and 2014 were included in the study. The pressure in the CHA was measured pre- and postclamping of the CA; a decrease of more than 25% in the mean arterial pressure necessitated vascular reconstruction of the CHA. RESULTS: Seven patients underwent a DPS-CAR between 2007 and 2014. Arterial reconstruction was required in 2 patients based on a decrease of >25% mean arterial pressure in the CHA after clamping the CA. There was no in hospital or 90-day mortality, and no patients developed ischemic hepatitis. CONCLUSION: A single-stage DPS-CAR with selective arterial reconstruction based on the CHA pressure change after clamping the CA is a safe approach. PMID- 25532437 TI - Developing and implementing an accreditation system for health promoting schools in Northern India: a cross-sectional study. AB - BACKGROUND: The "Health Promoting School" (HPS) is a holistic and comprehensive approach to integrating health promotion within the community. At the time of conducting this study, there was no organized accreditation system for HPS in India. We therefore developed an accreditation system for HPSs using support from key stakeholders and implemented this system in HPS in Chandigarh territory, India. METHODS: A desk review was undertaken to review HPS accreditation processes used in other countries. An HPS accreditation manual was drafted after discussions with key stakeholders. Seventeen schools (eight government and nine private) were included in the study. A workshop was held with school principals and teachers and other key stakeholders, during which parameters, domains and an accreditation checklist were discussed and finalized. The process of accreditation of these 17 schools was initiated in 2011 according to the accreditation manual. HPSs were encouraged to undertake activities to increase their accreditation grade and were reassessed in 2013 to monitor progress. Each school was graded on the basis of the accreditation scores obtained. RESULTS: The accreditation manual featured an accreditation checklist, with parameters, scores and domains. It categorized accreditation into four levels: bronze, silver, gold and platinum (each level having its own specific criteria and mandate). In 2011, more than half (52.9%) of the schools belonged to the bronze level and only 23.5% were at the gold level. Improvements were observed upon reassessment after 2 years (2013), with 76.4% of schools at the gold level and only 11.8% at bronze. CONCLUSIONS: The HPS accreditation system is feasible in school settings and was well implemented in the schools of Chandigarh. Improvements in accreditation scores between 2011 and 2013 suggest that the system may be effective in increasing levels of health promotion in communities. PMID- 25532438 TI - Lanthanum aluminum oxide thin-film dielectrics from aqueous solution. AB - Amorphous LaAlO3 dielectric thin films were fabricated via solution processing from inorganic nitrate precursors. Precursor solutions contained soluble oligomeric metal-hydroxyl and/or -oxo species as evidenced by dynamic light scattering (DLS) and Raman spectroscopy. Thin-film formation was characterized as a function of annealing temperature using Fourier transform infrared (FTIR), X ray diffraction (XRD), X-ray reflectivity (XRR), scanning electron microscopy (SEM), and an array of electrical measurements. Annealing temperatures >=500 degrees C result in thin films with low leakage-current densities (~1 * 10(-8) A.cm(-2)) and dielectric constants ranging from 11.0 to 11.5. When incorporated as the gate dielectric layer in a-IGZO thin-film transistors (TFTs), LaAlO3 thin films annealed at 600 degrees C in air yielded TFTs with relatively low average mobilities (~4.5 cm(2).V(-1).s(-1)) and high turn-on voltages (~26 V). Interestingly, reannealing the LaAlO3 in 5%H2/95%N2 at 300 degrees C before deposition of a-IGZO channel layers resulted in TFTs with increased average mobilities (11.1 cm(2).V(-1).s(-1)) and lower turn-on voltages (~6 V). PMID- 25532439 TI - Insights into the pathogenesis of GvHD: what mice can teach us about man. AB - Acute graft-vs-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). Most of the knowledge about the biology of GvHD is derived from mouse models of this disease and therefore a critical analysis of potential advantages and disadvantages of the murine GvHD models is important to classify and understand the findings made in these models. The central events leading up to GvHD were characterized in three phases which includes the tissue damage-phase, the T cell priming-phase and the effector-phase, when the disease becomes clinically overt. The role of individual cytokines, chemokines, transcription factor or receptors was studied in these models by using gene deficient or transgenic mice in the donor or recipient compartments. Besides, numerous studies have been performed in these models to prevent or treat GvHD. Several recent clinical trials were all based on previously reported findings from the mouse model of GvHD such as the trials on CCR5-blockade, donor statin treatment, vorinostat treatment or adoptive transfer of regulatory T cells for GvHD prevention. The different mouse models for GvHD and graft-vs-leukemia effects are critically reviewed and their impact on current clinical practice is discussed. PMID- 25532440 TI - Hemolysis in patients with antibody deficiencies on immunoglobulin replacement treatment. AB - BACKGROUND: Immunoglobulin (Ig)G replacement with intravenous or subcutaneous immunoglobulins is a lifelong substitutive therapy in patients with primary antibody deficiencies (PADs). Hemolysis after immunoglobulin therapy was described in patients receiving high immunoglobulin dosages. The issue of hemolysis after immunoglobulin administration at replacement doses has been considered of little clinical significance. STUDY DESIGN AND METHODS: This was a single-center observational study over a 2-year period on immunoglobulin-induced hemolysis in a cohort of 162 patients with PADs treated with immunoglobulin administered at replacement dosages. RESULTS: Six patients had signs and symptoms of immunoglobulin-induced hemolysis. Two additional asymptomatic patients were identified by a short-term study run on 16 randomly selected asymptomatic patients. Alloantibodies eluted from patients' red blood cells (RBCs) had anti-A and Rh specificities (anti-D and anti-C). The immunoglobulins contained alloantibodies with the same specificities of the antibodies eluted from patients' RBCs. CONCLUSION: Hemolysis occurred in patients receiving immunoglobulin at replacement dosages. Polyvalent immunoglobulin preparations contained multiple clinically significant antibodies that could have unexpected hemolytic consequences, as anti-C whose research and titration are not required by the European Pharmacopoeia. The issue of hemolysis in long-term recipients of immunoglobulin treatment administered at replacement dosages should be more widely recognized. PMID- 25532441 TI - Benefits, limits and danger of ephedrine and pseudoephedrine as nasal decongestants. AB - Due to their vasoconstrictive action on the nasal mucosa, ephedrine and pseudoephedrine are highly efficient amines for relief of nasal congestion. As with any vasoconstrictor and as underscored by the French Society of Otorhinolaryngology in its 2011 guideline, these molecules should not be used in patients under the age of 15. Furthermore, due to unpredictable severe cardiovascular and neurological adverse events that may occur even at low dose and in the absence of any pre-existing pathology, they should not be prescribed for the common cold, and ENT physicians must carefully weigh the risk/benefit ratio in patients with allergic rhinitis. Distribution should be regulated and over-the-counter sales banned. PMID- 25532442 TI - Nanoemulsions produced by rotor-stator high speed stirring. AB - Nanoemulsions were produced by high speed stirring using an ART MICCRA D27 rotor stator system. Nanoemulsions with a droplet size of 135 nm and a narrow size distribution were obtained. The emulsions are physically stable for at least three months. Optimized production parameters are a stirring speed of 36,000 rpm (maximum speed) and a production time of 5 min. A further reduction in processing time might be possible with a rotor with ultrafine slit size, i.e., 0.5 mm. The droplet size of the emulsion produced by high speed stirring is slightly larger than droplet sizes obtained by high pressure homogenization. However, the differences in size can be expected to have no influence on the in vivo efficacy of the emulsions. Thus, high speed stirring was found to be a highly effective method for the production of nanoemulsions. The process is fast, cost-effective and can be used for large scale production. PMID- 25532443 TI - Neural activation during response inhibition is associated with adolescents' frequency of risky sex and substance use. AB - OBJECTIVE: INTRODUCTION: While many have identified the important role of the developing brain in youth risk behavior, few have examined the relationship between salient cognitive factors (response inhibition) and different types of real-world adolescent health risk behaviors such as substance use and risky sex, within the same sample of youth. METHODS: We therefore sought to examine these relationships with 95 high-risk youth (ages 14-18; M age = 16.29 years). We examined blood oxygen level dependent (BOLD) response to an fMRI-based cognitive task designed to assess response inhibition (Go/NoGo) and past month risk behavior (number of substance use days; number of unprotected sex days). RESULTS: For this sample of youth, we found significant negative correlations between past month substance use and response inhibition within the left inferior frontal gyrus (IFG) and right insula (uncorrected p < .001; extent threshold >= 10 voxels). In addition, in the same contrast, we found significant positive correlations between past month risky sex and activation within the right IFG and left middle occipital gyrus (uncorrected p < .001; extent threshold >= 10 voxels). CONCLUSIONS: These results suggest the particular relevance of these regions in this compelling, albeit slightly different, pattern of response for adolescent risky behaviors. PMID- 25532444 TI - Decision making about alcohol use: the case for scientific convergence. AB - Research on cognitive processes related to the decision to drink alcohol has yielded assessment tools that predict drinking as well or better than any other predictor. Although largely overlapping in content, some of these tools have been issued from different theoretical perspectives and consequently have been named to reflect separate cognitive constructs. This article describes a single theme that may be shared by what now appear to be separate constructs: anticipatory information processing. These anticipatory processes are reviewed at multiple levels of analysis, from neurobiology, to learning and memory, and finally to behavioral choice. Evidence supporting anticipatory processing as a causal influence on drinking also is reviewed, along with evidence that these ideas may be usefully applied to prevention/treatment efforts. PMID- 25532445 TI - SNPs in APOBEC3 cytosine deaminases and their association with Visna/Maedi disease progression. AB - The Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3) genes are able to inhibit the replication of a wide range of exogenous retroviruses, as well as endogenous retroviruses and retrotransposons. Three APOBEC3 genes, named APOBEC3Z1, APOBEC3Z2 and APOBEC3Z3, have been described in sheep. In this work the three genes have been screened in order to identify polymorphisms. No polymorphism was detected for the A3Z2 and A3Z3 genes but 16 SNPs and a 3-bp deletion were found in the A3Z1 gene. A thermoestability prediction analysis was applied to the detected amino acidic SNPs by three different programs. This analysis revealed a number of polymorphisms that could affect the protein stability. The SNPs of the 3'UTR were tested to detect alterations on the predicted microRNA target sites. Two new microRNA target sites were discovered for one of the alleles. Two SNPs were selected for association studies in relation with the retroviral disease Visna/Maedi in Latxa and Assaf sheep breeds. Although association analyses resulted unconclusive, probably due to the unsuitability of the SNP allele frequency distribution of the selected polymorphisms in the analyzed breeds, these genes remain good candidates for association studies. PMID- 25532446 TI - Combining serum and urine biomarkers in the early diagnosis of mild cognitive impairment that evolves into Alzheimer's disease in patients with the apolipoprotein E epsilon4 genotype. AB - Possession of the apolipoprotein E (APOE) epsilon4 genotype is a major predictor of progression to Alzheimer's disease (AD), particularly in patients with mild cognitive impairment (MCI). However, the use of APOE genotyping in the diagnosis of MCI is limited due to its low sensitivity and specificity, which often results in a high false-positive rate. In this study, we found that there was a significant decrease in serum BDNF and notable increase in urine AD7c-NTP in MCI patients who harbored the APOE epsilon4 allele. Both serum BDNF and urine AD7c NTP had higher positive predictive values and were more sensitive biomarkers of MCI. Additionally, a testing strategy employing serum BDNF and urine AD7c-NTP revealed increases in sensitivity, positive and negative predictive values, and predictive ability compared with the use of either biomarker alone, suggested that combinatorial detection might have great potential for translation to the clinic. PMID- 25532447 TI - Anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion: a case report. AB - INTRODUCTION: Anaplastic transformation of well-differentiated papillary thyroid carcinoma at distant metastasis sites is rare. To the best of our knowledge, this is the first report of an autopsy case of anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion. CASE PRESENTATION: We report an autopsy case of a 61-year-old Japanese man with anaplastic transformation of papillary thyroid carcinoma with multiple lung metastases presenting with a malignant pleural effusion, which was difficult to diagnose by cytological examination before the autopsy. He presented with a 1 month history of progressive dyspnea, and examination of the left pleural effusion revealed a bloody exudate with an increase in thyroglobulin; however, malignant cells in the pleural fluid were negative for thyroglobulin. CONCLUSION: It is important to be aware that anaplastic transformation of differentiated thyroid carcinoma could develop in lung metastases and could be a cause of a malignant pleural effusion. PMID- 25532448 TI - Are Moroccan cannabis growers able to adapt to recent European market trend? PMID- 25532450 TI - Healthy vs. osteoarthritic hips: a comparison of hip, pelvis and femoral parameters and relationships using the EOS(r) system. AB - BACKGROUND: Osteoarthritis is a debilitating disease, for which the development path is unknown. Hip, pelvis and femoral morphological and positional parameters relate either to individual differences or to changes in the disease state, both of which should be taken into account when diagnosing and treating patients. These have not yet been comprehensively quantified. Previous imaging studies have been limited by a number of factors: supine rather than standing measurements; high radiation dose; a limited field of view; and 2D rather than 3D measurements. EOS(r), a new radiographic imaging modality that acquires simultaneous frontal and lateral (sagittal) X-ray images of the full body, allows 3D reconstruction of the hip, pelvis and lower limb. The aim of the study was to explore similarities and differences between healthy and osteoarthritis groups. METHODS: Two groups of subjects, 30 healthy and 30 with hip osteoarthritis, were assessed and compared for pelvic, acetabular and femoral parameters in the standing position. FINDINGS: There were not only significant differences between groups but also considerable overlap amongst the individuals. Sacral slope, acetabular angle of Idelberger and Frank, femoral mechanical angle and femoral head eccentricity as well as right left asymmetries in centre-edge acetabular angle and femoral head diameter were higher on average in osteoarthritic patients compared to healthy subjects, whereas acetabular abduction was lower in the osteoarthritic group (P<0.05). Correlations were identified between key parameters in both groups. INTERPRETATION: Differences between the groups suggest either degenerative changes over time or inherent differences between individuals that may contribute to the disease progression. These data provide a basis for longitudinal and post surgery studies. Due to the considerable variability amongst individuals and the considerable overlap between groups, patients should be evaluated individually and at multiple joints when planning hip, knee and spine surgery. PMID- 25532449 TI - High prevalence of non-fatal overdose among people who inject drugs in Malaysia: Correlates of overdose and implications for overdose prevention from a cross sectional study. AB - BACKGROUND: Overdose is the leading cause of death among opioid users, but no data are available on overdose among people who inject drugs in Malaysia. We present the first estimates of the prevalence and correlates of recent non-fatal overdose among people who inject drugs in Malaysia. METHODS: In 2010, 460 people who inject drugs were recruited using respondent-driven sampling (RDS) in Klang Valley to assess health outcomes associated with injection drug use. Self reported history of non-fatal overdose in the previous 6 months was the primary outcome. Sociodemographic, behavioral and structural correlates of non-fatal overdose were assessed using multivariable logistic regression. RESULTS: All 460 participants used opioids and nearly all (99.1%) met criteria for opioid dependence. Most injected daily (91.3%) and were male (96.3%) and ethnically Malay (90.4%). Overall, 20% of participants had overdosed in the prior 6 months, and 43.3% had ever overdosed. The RDS-adjusted estimate of the 6-month period prevalence of overdose was 12.3% (95% confidence interval [CI] 7.9-16.6%). Having injected for more years was associated with lower odds of overdose (adjusted odds ratio [AOR] 0.6 per 5 years of injection, CI: 0.5-0.7). Rushing an injection from fear of the police nearly doubled the odds of overdose (AOR 1.9, CI: 1.9-3.6). Alcohol use was associated with recent non-fatal overdose (AOR 2.1, CI: 1.1-4.2), as was methamphetamine use (AOR 2.3, CI: 1.3-4.6). When adjusting for past-month drug use, intermittent but not daily methadone use was associated with overdose (AOR 2.8, CI: 1.5-5.9). CONCLUSION: This study reveals a large, previously undocumented burden of non-fatal overdose among people who inject drugs in Malaysia and highlights the need for interventions that might reduce the risk of overdose, such as continuous opioid substitution therapy, provision of naloxone to prevent fatal overdose, treatment of polysubstance use, and working with police to improve the risk environment. PMID- 25532452 TI - The year of light for enlightening photonics and cytometry- start of new year's note. PMID- 25532451 TI - The use of an acetoacetyl-CoA synthase in place of a beta-ketothiolase enhances poly-3-hydroxybutyrate production in sugarcane mesophyll cells. AB - Engineering the production of polyhydroxyalkanoates (PHAs) into high biomass bioenergy crops has the potential to provide a sustainable supply of bioplastics and energy from a single plant feedstock. One of the major challenges in engineering C4 plants for the production of poly[(R)-3-hydroxybutyrate] (PHB) is the significantly lower level of polymer produced in the chloroplasts of mesophyll (M) cells compared to bundle sheath (BS) cells, thereby limiting the full PHB yield-potential of the plant. In this study, we provide evidence that the access to substrate for PHB synthesis may limit polymer production in M chloroplasts. Production of PHB in M cells of sugarcane is significantly increased by replacing beta-ketothiolase, the first enzyme in the bacterial PHA pathway, with acetoacetyl-CoA synthase. This novel pathway enabled the production of PHB reaching an average of 6.3% of the dry weight of total leaf biomass, with levels ranging from 3.6 to 11.8% of the dry weight (DW) of individual leaves. These yields are more than twice the level reported in PHB-producing sugarcane containing the beta-ketothiolase and illustrate the importance of producing polymer in mesophyll plastids to maximize yield. The molecular weight of the polymer produced was greater than 2 * 10(6) Da. These results are a major step forward in engineering a high biomass C4 grass for the commercial production of PHB. PMID- 25532453 TI - Improving flow cytometric methodology for blood cell functional analysis. PMID- 25532459 TI - A one-step rectification of sperm cell targeting ensures the success of double fertilization. AB - Successful fertilization in animals depends on competition among millions of sperm cells, whereas double fertilization in flowering plants usually involves just one pollen tube releasing two immobile sperm cells. It is largely a mystery how the plant sperm cells fuse efficiently with their female targets within an embryo sac. We show that the initial positioning of sperm cells upon discharge from the pollen tube is usually inopportune for gamete fusions and that adjustment of sperm cell targeting occurs through release and re-adhesion of one sperm cell, while the other connected sperm cell remains in stagnation. This enables proper adhesion of each sperm cell to a female gamete and coordinates the gamete fusions. Our findings reveal inner embryo sac dynamics that ensure the reproductive success of flowering plants and suggest a requirement for sperm cell differentiation as the basis of double fertilization. PMID- 25532458 TI - Computer-aided molecular pathology interpretation in exploring prospective markers for oral submucous fibrosis progression. AB - BACKGROUND: Evaluation of molecular pathology markers using a computer-aided quantitative assessment framework would help to assess the altered states of cellular proliferation, hypoxia, and neoangiogenesis in oral submucous fibrosis and could improve diagnostic interpretation in gauging its malignant potentiality. METHODS: Immunohistochemical (IHC) expression of c-Myc, hypoxia inducible factor-1-alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), VEGFRII, and CD105 were evaluated in 58 biopsies of oral submucous fibrosis using computer-aided quantification. After digital stain separation of original chromogenic IHC images, quantification of the diaminobenzidine (DAB) reaction pattern was performed based on intensity and extent of cytoplasmic, nuclear, and stromal expression. RESULTS: Assessment of molecular expression proposed that c Myc and HIF-1alpha may be used as strong screening markers, VEGF for risk stratification and VEGFRII and CD105 for prognosis of precancer into oral cancer. CONCLUSION: Our analysis indicated that the proposed method can help in establishing IHC as an effective quantitative immunoassay for molecular pathology and alleviate diagnostic ambiguities in the clinical decision process. PMID- 25532460 TI - Cognitive-behavioural therapy for patients with schizophrenia: a multicentre randomized controlled trial in Beijing, China. AB - BACKGROUND: Meta-analyses support the efficacy of cognitive-behavioural therapy (CBT) for schizophrenia in western cultures. This study aimed to compare the efficacy of CBT and supportive therapy (ST) for patients with schizophrenia in China. METHOD: A multicentre randomized controlled, single-blinded, parallel group trial enrolled a sample of 192 patients with schizophrenia. All patients were offered 15 sessions of either CBT or ST over 24 weeks and followed up for an additional 60 weeks. All measures used were standardized instruments with good reliability and validity. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptoms of schizophrenia. The Schedule for Assessing Insight (SAI) was used to assess patients' insight and the Personal and Social Performance Scale (PSP) was used to assess their social functioning. RESULTS: Effect-size analysis showed that patients made rapid improvements in all symptoms, insight and social functioning as measured by the PANSS, SAI and PSP at 12 and 24 weeks and maintained these improvements over the course of the study to 84 weeks. Patients in the CBT group showed significantly greater and more durable improvement in PANSS total score (p = 0.045, between-group d = 0.48), positive symptoms (p = 0.018, between-group d = 0.42) and social functioning (p = 0.037, between-group d = 0.64), with significant differences emerging after completion of therapy. CONCLUSIONS: Both CBT and ST combined with medication had benefits on psychopathology, insight and social functioning of patients with schizophrenia. CBT was significantly more effective than ST on overall, positive symptoms and social functioning of patients with schizophrenia in the long term. PMID- 25532461 TI - Intraperitoneal sertraline and fluvoxamine increase contextual fear conditioning but are without effect on overshadowing between cues. AB - Treatment with selective serotonin reuptake inhibitors (SSRIs) can reduce contextual conditioning. Since contexts comprise a variety of potentially competing cues, impaired overshadowing may provide an account of such effects. The present study therefore compared the effects of two SSRIs on overshadowing and contextual conditioning, testing suppression of an ongoing behavioral response (licking) by cues previously paired with foot shock. Conditioning to a 5 s light stimulus was reduced when it was presented in compound with a 5 s noise, thus overshadowing was demonstrated. In two experiments, this overshadowing was unaffected by treatment with either sertraline or fluvoxamine. However, unconditioned suppression to the noise (tested in a control group previously conditioned to the light alone) was reduced after sertraline (10 mg/kg, i.p.). The successful demonstration of overshadowing required the use of a second conditioning session or an additional conditioning trial within the same conditioning session. Neither weak nor strong overshadowing (of the light by the tone) was affected by any drug treatment. Moreover, counter to prediction, conditioning to contextual cues was increased rather than impaired by treatment with sertraline (10 mg/kg, i.p.) and fluvoxamine (30 mg/kg, i.p.). PMID- 25532462 TI - CO2 hydrate nucleation kinetics enhanced by an organo-mineral complex formed at the montmorillonite-water interface. AB - In this study, we investigated experimentally and computationally the effect of organo-mineral complexes on the nucleation kinetics of CO2 hydrate. These complexes formed via adsorption of zwitter-ionic glycine (Gly-zw) onto the surface of sodium montmorillonite (Na-MMT). The electrostatic attraction between the -NH3(+) group of Gly-zw, and the negatively charged Na-MMT surface, provides the thermodynamic driving force for the organo-mineral complexation. We suggest that the complexation of Gly-zw on the Na-MMT surface accelerates CO2 hydrate nucleation kinetics by increasing the mineral-water interfacial area (thus increasing the number of effective hydrate-nucleation sites), and also by suppressing the thermal fluctuation of solvated Na(+) (a well-known hydrate formation inhibitor) in the vicinity of the mineral surface by coordinating with the -COO(-) groups of Gly-zw. We further confirmed that the local density of hydrate-forming molecules (i.e., reactants of CO2 and water) at the mineral surface (regardless of the presence of Gly-zw) becomes greater than that of bulk phase. This is expected to promote the hydrate nucleation kinetics at the surface. Our study sheds new light on CO2 hydrate nucleation kinetics in heterogeneous marine environments, and could provide knowledge fundamental to successful CO2 sequestration under seabed sediments. PMID- 25532463 TI - Characteristics of nonbalding scalp zones of androgenetic alopecia in East Asians. AB - BACKGROUND: Hair is known to persist on the occipital and part of the temporal scalp in patients with androgenetic alopecia (AGA), but no quantified data about the follicular changes in such areas exist. AIM: To evaluate the hair characteristics in nonbalding scalp areas in East Asian patients with AGA. METHODS: In total, 265 participants [211 patients with AGA and 50 healthy controls (HCs)] were enrolled. The patients were divided by the Basic and Specific (BASP) classification [four basic types (L, M, C, and U) and two special types (V and F)], and the hair in the occipital region and two sites of the temporal region were analysed by computer-assisted phototrichography. Hair density, hair width, number of each follicular unit, ratio of single to compound hairs and ratio of terminal to vellus hairs were examined. RESULTS: In the temporal region, a statistically significant (P < 0.05) decrease in hair density was observed in patients with C, U or F subtypes, and a significant (P < 0.05) decrease in hair thickness was observed in patients with the U subtype compared with HCs. In the mastoid and occipital areas, both hair density and hair thickness was significantly (P < 0.05) decreased in patients with the U subtype compared with HCs. Within each classification, hairs became generally thinner as the hair loss progressed. CONCLUSIONS: Hair density and hair thickness of known nonbalding scalp regions showed some differences depending on the severity and the BASP subtypes in East Asian people with male pattern baldness. PMID- 25532464 TI - [Surgical site infections]. AB - Surgical site infections (SSIs) are recognized as a common surgical complication, occurring in about 2-5% of all surgical procedures. SSIs represent the third most frequent nosocomial infection, accounting for 14-16% of all infections observed in hospitalized patients and up to 38% of those observed among surgical patients. Knowledge of incidence, epidemiology, classification, process of wound healing, and pathogenesis of surgical site infection is of great importance. Given the high economic burden that infections provoke, beyond the increased morbidity and mortality, it appears mandatory to improve our tools in order to reduce their incidence, as a reduction of only 0.1% can result in a considerable saving of economic resources to be allocated to other activities, such as screening and prevention programs. PMID- 25532465 TI - Sexually transmitted diseases: epidemiological and clinical aspects in adults. AB - Sexually transmitted diseases (STDs) are the first 10 causes of unpleased diseases in young adult women in the world. The concept of STDs includes a series of syndromes caused by pathogens that can be acquired by sexual intercourse or sexual activity.Adolescents and young adults are responsible for only 25% of the sexually active population and they represent almost 50% of all newly acquired STDs.In this way, we evaluated the epidemiological and clinical aspects of most relevant pathogens as Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Haemophilus Ducreyi, Trichomonas vaginalis, herpes simplex virus, human papilloma virus (HPV) with the exception of hepatitis, and HIV infections for which we suggest specific guidelines.To attain this objective, we analyzed the results of epidemiological and clinical aspects of STDs through a review of the literature using MEDLINE and PubMed database for original articles published using the terms "sexual transmitted disease, epidemiology, diagnosis and therapy" from 2005 to 2014. PMID- 25532466 TI - [Antibiotic prophylaxis in urology]. AB - INTRODUCTION: Antibiotic prophylaxis (AP) is used to minimize infectious complications resulting from interventions. Due to high rates of development of bacterial resistance and side effects, the use of antibiotics must be weighed on the basis of high levels of evidence. The main endpoints of urology AP are the prevention of symptomatic urogenital infections, urosepsis and wound infections. The purpose of this review is to bring objectives, principles and recommendations on urology AP according to the latest scientific evidence. METHODS: We carried out a systematic search of MEDLINE, EMBASE and the Cochrane Library using keywords such as AP, prophylaxis, antibiotics, urological surgery, urogenital surgery and the names of the urologic procedures. The results of studies on the AP for each procedure were classified according to the levels of evidence and grades of recommendation from the European Association of Urology. RESULTS: There are a number of good quality studies on AP about endoscopic resection of the prostate (TURP), urodynamic studies and transrectal prostate biopsies (trPB). The majority of the studies about other procedures have several limitations (sample size, consistency of definitions, statistics and trial design). Lack of consistency in the definitions of infectious complications does not allow comparison between different studies. CONCLUSIONS: The AP is evidence-based is indicated only for TURP and trPB. It is desirable to perform randomized, prospective and controlled trials in order to rationalize the use of antibiotics, improve the cost/benefit ratio and reduce bacterial antibiotic resistances. PMID- 25532467 TI - [Antibiotic prophylaxis and prostate biopsy]. AB - OBJECTIVES: Perioperative antibiotic prophylaxis is considered a safe and valid option from the urologist to prevent infective complications after prostate biopsy procedure. The transrectal approach is the most experienced by European urologists and the prevalence of infective complications from this procedure is increasing. Aim of this mini-review article is to improve the urologist knowledge on the prevention of infective complications after prostate transrectal biopsy. METHODS: Recent publications from Medline and Cochrane Library have been collected. Data from the abstracts presented at the EAU and AUA Congresses during the last 5 years have also been analysed. RESULTS: Fluorquinolone and other antibiotics-resistant bacteria prevalence is normally very high. Other strategies of infective complication prevention such as the use of rectal swab microbiological analysis and relative antibiotics/sensitivity test or the rectal enema with antiseptic solutions or the combined use of different antibiotics are thus justified. The number of biopsy cores reduction and the perineal approach still remain valid alternative indirect options. CONCLUSIONS: Different innovative prevention strategies can be easily used in daily clinical practice to reduce the risk of infectious complications after transrectal prostate biopsy, although a specific policy should be adequately introduced to obtain optimal effects from the current use of antibiotic prophylaxis strategies, thus reducing the risk of developing life-threatening situations for the patient and antibiotic resistance phenomena. PMID- 25532468 TI - Cyclic generalized projection MRI. AB - Progress in the development of portable MRI hinges on the ability to use lightweight magnets that have non-uniform magnetic fields. An image encoding method and mathematical procedure for recovering the image from the NMR signal from non-uniform magnets with closed isomagnetic contours is given. Individual frequencies in an NMR signal from an object in a non-uniform magnetic field give rise to integrals of the object along contours of constant magnetic field: generalized projections. With closed isomagnetic field contours a simple, cyclic, direct reconstruction of the image from the generalized projections is possible when the magnet and RF transmit coil are held fixed relative to the imaged object while the RF receive coil moves. Numerical simulations, using the Shepp and Logan mathematical phantom, were completed to show that the mathematical method works and to illustrate numerical limitations. The method is numerically verified and exact reconstruction demonstrated for discrete mathematical image phantoms. Correct knowledge of the RF receive field is necessary or severe image distortions will result. The cyclic mathematical reconstruction method presented here will be useful for portable MRI schemes that use non-uniform magnets with closed isomagnetic contours along with mechanically or electronically moving the RF receive coils. PMID- 25532470 TI - Comparison of the in vitro and in vivo degradations of silk fibroin scaffolds from mulberry and nonmulberry silkworms. AB - Degradation behavior is very important in the field of silk-based biomaterials. Mulberry and nonmulberry silk fibroins are structurally and functionally distinguishable; however, no studies have examined the differences in the degradation behaviors of silk materials from various silkworm species. In this study, Ca(NO3)2 was used as a uniform solvent to obtain regenerated mulberry and nonmulberry (Antheraea pernyi and Antheraea yamamai) silk fibroin (SF) solutions, and the degradation behaviors of various SF scaffolds were examined. In vitro and in vivo results demonstrated that regenerated mulberry SF scaffolds exhibited significantly higher mass loss and free amino acid content release than did nonmulberry SF scaffolds. The differences in the primary structures and condensed structures between mulberry and nonmulberry SF contributed to the significant difference in degradation rates, in which the characteristic (-Ala-)n repeats, compact crystal structure and high alpha-helix and beta-sheet contents make nonmulberry SF more resistant than mulberry SF to enzymatic degradation. Moreover, the Antheraea pernyi and Antheraea yamamai SFs possess similar primary structures and condensed structures, although a slight difference in degradation was observed; this difference might depend on the differences in molecular weight following the regeneration process. The results indicate that the original sources of SF significantly influence the degradation rates of SF-based materials; therefore, the original sources of SF should be fully considered for preparing tissue engineering scaffolds with matched degradation rates. PMID- 25532469 TI - A phenomenological particle-based platelet model for simulating filopodia formation during early activation. AB - We developed a phenomenological three-dimensional platelet model to characterize the filopodia formation observed during early stage platelet activation. Departing from continuum mechanics based approaches, this coarse-grained molecular dynamics (CGMD) particle-based model can deform to emulate the complex shape change and filopodia formation that platelets undergo during activation. The platelet peripheral zone is modeled with a two-layer homogeneous elastic structure represented by spring-connected particles. The structural zone is represented by a cytoskeletal assembly comprising of a filamentous core and filament bundles supporting the platelet's discoid shape, also modeled by spring connected particles. The interior organelle zone is modeled by homogeneous cytoplasm particles that facilitate the platelet deformation. Nonbonded interactions among the discrete particles of the membrane, the cytoskeletal assembly, and the cytoplasm are described using the Lennard-Jones potential with empirical constants. By exploring the parameter space of this CGMD model, we have successfully simulated the dynamics of varied filopodia formations. Comparative analyses of length and thickness of filopodia show that our numerical simulations are in agreement with experimental measurements of flow-induced activated platelets. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25532471 TI - Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. AB - OBJECTIVE: To determine whether presurgical sunitinib reduces primary renal cell carcinoma (RCC) size and facilitates partial nephrectomy (PN). METHODS: Data from potential candidates for PN treated with sunitinib with primary RCC in situ were reviewed retrospectively. Primary outcome was reduction in tumor bidirectional area. RESULTS: Included were 72 potential candidates for PN who received sunitinib before definitive renal surgery on 78 kidneys. Median primary tumor size was 7.2 cm (interquartile range [IQR]: 5.3-8.7 cm) before and 5.3 cm (IQR: 4.1-7.5 cm) after sunitinib treatment (P<0.0001), resulting in 32% reduction in tumor bidirectional area (IQR: 14%-46%). Downsizing occurred in 65 tumors (83%), with 15 partial responses (19%). Tumor complexity per R.E.N.A.L. score was reduced in 59%, with median posttreatment score of 9 (IQR: 8-10). Predictors of lesser tumor downsizing included clinical evidence of lymph node metastases (P<0.0001), non-clear cell histology (P = 0.0017), and higher nuclear grade (P = 0.023). Surgery was performed for 68 tumors (87%) and was not delayed in any patient owing to sunitinib toxicity. Grade >= 3 surgical complications occurred in 5 patients (7%). PN was performed for 49 kidneys (63%) after sunitinib, including 76% of patients without and 41% with metastatic disease (P = 0.0026). PN was completed in 100%, 86%, 65%, and 60% of localized cT1a, cT1b, cT2, and cT3 tumors, respectively. CONCLUSION: Presurgical sunitinib leads to modest tumor reduction in most primary RCC, and many patients can be subsequently treated with PN with acceptable morbidity and preserved renal function. A randomized trial is required to definitively determine whether presurgical therapy enhances feasibility of PN. PMID- 25532472 TI - Autocrine production of IGF-I increases stem cell-mediated neuroprotection. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron (MN) loss. There are currently no effective therapies; however, cellular therapies using neural progenitor cells protect MNs and attenuate disease progression in G93A-SOD1 ALS rats. Recently, we completed a phase I clinical trial examining intraspinal human spinal stem cell (HSSC) transplantation in ALS patients which demonstrated our approach was safe and feasible, supporting the phase II trial currently in progress. In parallel, efforts focused on understanding the mechanisms underlying the preclinical benefit of HSSCs in vitro and in animal models of ALS led us to investigate how insulin-like growth factor-I (IGF-I) production contributes to cellular therapy neuroprotection. IGF-I is a potent growth factor with proven efficacy in preclinical ALS studies, and we contend that autocrine IGF-I production may enhance the salutary effects of HSSCs. By comparing the biological properties of HSSCs to HSSCs expressing sixfold higher levels of IGF-I, we demonstrate that IGF I production augments the production of glial-derived neurotrophic factor and accelerates neurite outgrowth without adversely affecting HSSC proliferation or terminal differentiation. Furthermore, we demonstrate that increased IGF-I induces more potent MN protection from excitotoxicity via both indirect and direct mechanisms, as demonstrated using hanging inserts with primary MNs or by culturing with organotypic spinal cord slices, respectively. These findings support our theory that combining autocrine growth factor production with HSSC transplantation may offer a novel means to achieve additive neuroprotection in ALS. PMID- 25532473 TI - The chemistry and biological activity of heterocycle-fused quinolinone derivatives: A review. AB - Among all heterocycles, the heterocycle-fused quinolinone scaffold is one of the privileged structures in drug discovery as heterocycle-fused quinolinone derivatives exhibit various biological activities allowing them to act as anti inflammatory, anticancer, antidiabetic, and antipsychotic agents. This wide spectrum of biological activity has attracted a great deal of attention in the field of medicinal chemistry. In this review, we provide a comprehensive description of the biological and pharmacological properties of various heterocycle-fused quinolinone scaffolds and discuss the synthetic methods of some of their derivatives. PMID- 25532474 TI - A comparison of magnetic resonance arthrography and arthroscopic findings in the assessment of anterior shoulder dislocations. AB - OBJECTIVE: The aim of this study is to establish the sensitivity and specificity of MRA in the investigation of patients with traumatic anterior shoulder dislocations. MATERIALS AND METHODS: A retrospective analysis of consecutive patients undergoing both magnetic resonance arthrography and arthroscopic assessment after a traumatic anterior shoulder dislocation between January 2011 and 2014 was performed. Demographic data were collected from electronic records. Images were interpreted by 8 musculoskeletal radiologists and patients were treated by 8 consultant orthopaedic surgeons. Arthroscopic findings were obtained from surgical notes and these findings were used as a reference for MRA. The sensitivity, specificity, and positive predictive value were calculated for the different injuries. RESULTS: Sixty-nine patients underwent both an MRA and shoulder arthroscopy during the study period; however, clinical notes were unavailable in 9 patients. Fifty-three patients (88 %) were male, the mean age was 28 years (range 18 to 50) and 16 subjects (27 %) had suffered a primary dislocation. The overall sensitivity and specificity of MRA to all associated injuries was 0.9 (CI 0.83-0.95) and 0.94 (CI 0.9-0.96) retrospectively. The lowest sensitivity was seen in osseous Bankart 0.8 (CI 0.44-0.96) and superior labral tear (SLAP) lesions 0.5 (CI 0.14-0.86). The overall positive predictive value was 0.88 (CI 0.76-0.91) with the lowest values found in rotator cuff 0.4 (CI 0.07-0.83) and glenohumeral ligament (GHL) lesions 0.29 (CI 0.05-0.7). CONCLUSION: Magnetic resonance angiography has a high sensitivity when used to identify associated injuries in shoulder dislocation, although in 8 patients (13 %) arthroscopy identified an additional injury. The overall agreement between MRA and arthroscopic findings was good, but the identification of GHL and rotator cuff injuries was poor. PMID- 25532475 TI - Pycnogenol(r) and its fractions influence the function of isolated heart in rats with experimental diabetes mellitus. AB - The aim of this study was to test the effect of Pycnogenol((r)) (PYC) mixture and its three fractions (buthanolic, water, ethyl acetate) on heart function in rats with experimental diabetes mellitus (DM) and compare their effects to the diabetic group. Their antioxidant activity "in vitro" was also determined. DM rats (streptozotocin over 3 consecutive days at a dose of 25 mg/kg of body weight) had increased systolic blood pressure, thicker left ventriculi wall (LV) and weaker myocardial contraction, prolonged QT interval in comparison to controls rats. In comparison to the diabetic group, PYC (20 mg/kg b.w./day) suppressed the influence of DM on the LV, improved contraction, increased coronary flow and displayed negative effect on electrical activity of hearts. The most effective of PYC's fractions was the water fraction. It improved biometric parameters and hemodynamic function of the DM hearts, enhanced shortening the QT interval, reduced the amount of dysrhythmias of the DM hearts and had the strongest antioxidant activity. In conclusion, DM damaged isolated rat heart function. Only the water fraction improved the function of the diabetic heart. The different results of three fractions and PYC on myocardial function may be caused by a various lipo- and hydro-philic action of the PYC components. PMID- 25532476 TI - Rebuttal comments on "a potential biomarker for objective diagnosis of overactive bladder: urinary nerve growth factor". PMID- 25532477 TI - Morphology and function of the female reproductive system of Ebalia tumefacta (Decapoda, Brachyura, Leucosiidae). AB - In this article, the morphology and function of the female reproductive organs of Ebalia tumefacta were investigated using histological methods. While the vagina conforms to the concave type, the study reveals a new orientation of seminal receptacle compartments. The seminal receptacle consists of two chambers, which are oriented in anterior-posterior direction. This is in contrast to the dorso ventral orientation of seminal receptacle chambers in all other known brachyuran crabs. The anterior chamber is lined by cuticle, whereas the posterior chamber is covered with a holocrine glandular epithelium. The oviduct connection is located ventrally, close to the opening of the vagina. The oviduct orifice is characterized by a transition of the epithelium lining of the oviduct to the seminal receptacle holocrine glandular epithelium. Special features are muscle fibers, which are attached to the oviduct orifice and to the sternal cuticle as well. The muscle fibers can be found exactly at that point where the oviduct opens into the seminal receptacle and are secondly attached to the sternum beneath. This musculature is newly described for Eubrachyuran crabs. This musculature can be interpreted as an important feature in the fertilization and egg-laying process in relation to supporting and controling the inflow of eggs into the seminal receptacle lumen. These new discoveries were compared to the known pattern of an Eubrachyuran seminal receptacle. PMID- 25532478 TI - Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: mouse strain disparities and synergic effect with zoledronic acid. AB - High doses of bone resorption inhibitors are currently under evaluation in pediatric oncology. Previous works have evidenced transient arrest in long bone and skull bone growth and tooth eruption blockage when mice were treated with zoledronic acid (ZOL). The question of potential similar effects with a RANKL blocking antibody (IK22.5) was raised. Sensitivity disparities in these inhibitors between mouse strains and synergic effects of zoledronic acid and a RANKL-blocking antibody were subsidiary questions. In order to answer these questions, newborn C57BL/6J and CD1 mice were injected every two or three days (4 injections in total so 7 or 10 days of treatment length) with high doses of a RANKL-blocking antibody. The consequences on the tibia, craniofacial bones and teeth were analyzed by MUCT and histology at the end of the treatment and one, two and three months later. The results obtained showed that RANKL-blocking antibody injections induced a transient arrest of tibia and skull bone growth and an irreversible blockage of tooth eruption in C57BL/6J mice. In CD1 mice, tooth eruption defects were also present but only at much higher doses. Similar mouse strain differences were obtained with zoledronic acid. Finally, a synergic effect of the two inhibitors was evidenced. In conclusion as previously observed for bisphosphonates (ZOL), a RANKL-blocking antibody induced a transient arrest in long bone and skull bone growth and a blockage of tooth eruption with however disparities between mouse strains with regard to this last effect. A synergic effect of both bone resorption inhibitors was also demonstrated. PMID- 25532479 TI - Bone quality and biomechanical function: a lesson from human ossicles. AB - In humans, the middle ear contains a chain of three ossicles with a major highly specific mechanical property (transmission of vibrations) and modeling that stops rapidly after birth. Their bone quality has been rarely studied either in noninflammatory ossicles or in those from ears with chronic inflammation. Our primary goal was to assess bone microarchitecture, morphology and variables reflecting bone quality from incuses, in comparison with those from human femoral cortical bone as controls. Secondly, the impact of chronic inflammation on quality of ossicles was documented. The study was performed on 15 noninflammatory incuses from 15 patients (35+/-32 years, range: 2-91). Comparisons were performed with 13 inflammatory incuses from 13 patients (55+/-20 years, range: 1-79) with chronic inflammation of the middle ear, essentially cholesteatoma. Microarchitecture and bone mineral density (BMD) were assessed by microcomputed tomography. Microhardness was measured by microindentation. Mineral and organic characteristics were investigated by Fourier transform infrared microspectroscopy. Noninflammatory incuses were composed of a compact, well mineralized bone without bone marrow and with sparse vessels. Remodeling activity was rarely observed. Woven or lamellar textures and numerous osteocytes were observed. In inflammatory incuses, architecture was degraded, organic tissue was abundant and bone cavities contained fibrocellular tissue and adipocytes. BMD of noninflammatory incuses was significantly higher than BMD from both control bones (4 embedded cortical femoral bone samples; age: 72+/-15 years, range: 50-85) and inflammatory incuses. Noninflammatory incuses were less hard than both control bone (8 cortical femoral bone samples; age: 49+/-18 years, range: 24-74) and inflammatory incuses. All incuses were more mineralized and less mature than controls. In conclusion, bone quality of incuses (dense, well mineralized, hard) is well adapted to their function of sound transmission. In inflammatory condition, incuses were degraded, thus explaining the decline of hearing. Moreover, microhardness was found higher than in noninflammatory incuses. Compared to bone with remodeling, the mineralization index in incuses does not explain variation of microhardness. Interestingly, a linear multiple regression model indicated that a combination of two variables, i.e., crystallinity index (crystal size/perfection) and carbonation (incorporation of carbonate ions in apatite) explains 26% of the increase in microhardness variability. Because the low remodeling level of ossicles could not prevent the reversibility of their degradation which impacts audition quality, an early management of ear inflammation in chronic otitis is recommended. PMID- 25532480 TI - Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice. AB - Endoplasmic reticulum (ER) stress is associated with increased reactive oxygen species (ROS), results from accumulation of misfolded/unfolded proteins, and can trigger apoptosis. ER stress is alleviated by phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha), which inhibits protein translation allowing the ER to recover, thus promoting cell viability. We investigated whether osteoblastic cell apoptosis induced by glucocorticoids (GCs) is due to induction of ROS/ER stress and whether inhibition of eIF2alpha dephosphorylation promotes survival opposing the deleterious effects of GC in vitro and in vivo. Apoptosis of osteocytic MLO-Y4 and osteoblastic OB-6 cells induced by dexamethasone was abolished by ROS inhibitors. Like GC, the ER stress inducing agents brefeldin A and tunicamycin induced osteoblastic cell apoptosis. Salubrinal or guanabenz, specific inhibitors of eIF2alpha dephosphorylation, blocked apoptosis induced by either GC or ER stress inducers. Moreover, GC markedly decreased mineralization in OB-6 cells or primary osteoblasts; and salubrinal or guanabenz increased mineralization and prevented the inhibitory effect of GC. Furthermore, salubrinal (1 mg/kg/day) abolished osteoblast and osteocyte apoptosis in cancellous and cortical bone and partially prevented the loss of BMD at all sites and the decreased vertebral cancellous bone formation induced by treatment with prednisolone for 28 days (1.4 mg/kg/day). We conclude that part of the pro-apoptotic actions of GC on osteoblastic cells is mediated through ER stress, and that inhibition of eIF2alpha dephosphorylation protects from GC-induced apoptosis of osteoblasts and osteocytes in vitro and in vivo and from the deleterious effects of GC on the skeleton. PMID- 25532482 TI - Thymosin alpha1 based immunomodulatory therapy for sepsis: a systematic review and meta-analysis. AB - OBJECTIVES: Thymosin alpha1 (Talpha1) is considered a promising immunomodulatory drug. However, it is still unclear whether Talpha1 should be recommended for the management of sepsis. Here we conducted a systematic review and meta-analysis to assess the efficacy of Talpha1 based immunomodulatory therapy on the clinical outcomes of septic patients. METHODS: We searched for relevant clinical trials published before Dec. 12, 2014 through electronic databases. All articles about Talpha1 based immunomodulatory therapy for sepsis were included regardless of language. Two authors independently selected studies, extracted data and assessed the quality of each included study. We polled the data related to all-cause mortality with Review Manager 5.1. RESULTS: Twelve controlled trials were evaluated in all. Talpha1 based immunomodulatory therapy had a significant trend toward lower all-cause mortality among patients with sepsis (pooled risk ratio 0.68, 95%CI 0.59-0.78, p<0.00001, 12 trials, n=1480). CONCLUSIONS: Talpha1 based immunomodulatory therapy was associated with a lower mortality in septic patients. Nevertheless, these findings should be interpreted cautiously because of the poor quality and small number of participants of the included trials. More well-designed worldwide multicenter clinical trials are needed to provide a conclusive guideline for clinical practice. PMID- 25532481 TI - Risk of maternal alloimmunization in Southern Pakistan - a study in a cohort of 1000 pregnant women. AB - BACKGROUND: Haemolytic disease of the fetus and the newborn [HDFN] is caused by incompatibility of maternal and fetal erythrocytes. Red blood cell alloimmunization is a well-known cause of HDFN. Due to heterogeneity of populations, the spectrum of alloimmunization varies around the world. This study aimed to determine the frequency of alloimmunization in pregnant women and to determine the risk of HDFN in our population. STUDY DESIGN AND METHODS: This was a descriptive study conducted at Aga Khan University Hospital Karachi. Blood type and red cell antibody screening was determined on every pregnant woman at her first antenatal visit. Red cell antibody identification was performed on positive screening results. RESULTS: A total of 1000 pregnant females including 633 (63.3%) multigravida were studied. Blood type B was predominant (n = 374 or 37.4%) and D negative was observed in 136 women (13.6%). No red cell antibody was detected in 982 females (98.2%). 20 red cell antibodies were detected in 18 women (1.8%). The incidence of non-anti-D was 16/1000 [1.6%] in all pregnant females. The non-anti-D alloantibodies included anti-M (n = 3; 15%), anti-Lewis(a) (n = 3; 15%), anti C ( n = 1; 5%), anti-E (n = 1; 5%), anti-e (n = 1; 5%), anti-Lewis(b) (n = 1; 5%) and nonspecific antibodies (n = 6; 30%). The incidence of anti-D was 4/136 or 2.9% in D negative blood type. After excluding prior sensitization due to blood transfusions, risk remained was 2.2%. Antibodies of clinical significance were identified in 9 (0.9%) females. CONCLUSIONS: In our cohort, frequency of red cell alloimmunization during pregnancy was 1. 8% out of which 0.9% were clinically significant antibodies posing a risk for HDFN. Despite prenatal and post natal prophylaxis, risk of sensitization with D antigen in D negative women was high at 2.2%. We recommend that all pregnant women should be screened for irregular antibodies irrespective of the rhesus type. PMID- 25532483 TI - A new case of Mycoplasma hominis mediastinitis and sternal osteitis after cardiac surgery. AB - We report a case of nosocomial mediastinitis and sternal osteitis due to M. hominis after open-heart surgery in an immuno-competent patient. This infection has been diagnosed by incubating the culture media for an extended period of time, and sequencing 16S rDNA directly from the clinical samples. PMID- 25532484 TI - All trans retinoic acid modulates peripheral nerve fibroblasts viability and apoptosis. AB - OBJECTIVE: Following peripheral nerve injury, residing fibroblasts start to proliferate and accumulate at the injury site and may participate in neuroma tissue evolution. Retinoic acid has been shown to regulate many cellular processes and to display anti-proliferative and anti-fibrotic properties. The aim of this study was to investigate the impact of all trans retinoic acid (ATRA) on rat peripheral nerve fibroblasts. MATERIALS AND METHODS: Peripheral nerve fibroblasts and C166 cells were treated with increasing doses of ATRA (0.05 nM to 1 MUM). The viability of cells was determined with 3-(4,5-dimethlthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the number of peripheral nerve fibroblasts was counted after two days of ATRA treatment and alternatively up to the end of next week. Acridine orange/ethidium bromide double staining was implemented to morphologically visualize the possible mechanism of cell death. For apoptosis, caspase 3/7 activity was measured using Caspase-Glo 3/7 assay kit. RESULTS: MTT assay revealed that 0.05-1 nM of ATRA reduces fibroblasts viabilities. Then, almost a plateau state was observed from 1 nM to 1 MUM of ATRA exposure. Additionally, a deceleration in peripheral nerve fibroblasts growth was confirmed via cell counting. Quantification of acridine orange/ethidium bromide staining displayed highly increased number of early apoptotic cells following ATRA administration. Amplified activation of caspase 3/7 was in favor of apoptosis in ATRA treated peripheral nerve fibroblasts. CONCLUSION: The data from the present study demonstrate that ATRA could interfere in peripheral nerve fibroblasts viabilities and induce apoptosis. Although more investigations are needed to be implemented, our in vitro results indicate that retinoic acid can probably help the regeneration of injured axon via reducing of fibroblasts growth. PMID- 25532485 TI - GAL3ST2 from mammary gland epithelial cells affects differentiation of 3T3-L1 preadipocytes. AB - INTRODUCTION: In the mammary gland, the involution that occurs when lactation ends is an important period for cancer development. We have previously demonstrated stromal-epithelium interactions evaluating conditioned medium of adipose tissue on breast epithelial metalloproteases activity (Creydt et al., Clin Transl Oncol 15:124-131, 2013). Here, we evaluated the effects of conditioned medium of breast epithelial mammary cells on stromal cells. MATERIALS AND METHODS: Conditioned medium from normal murine mammary gland cell line (NMuMG) and conditioned medium proteins were obtained. Then, they were evaluated on modulation of adipocyte differentiation, using 3T3-L1 cell line. RESULTS: We described, for the first time, that breast epithelial mammary cells could produce the enzyme galactose 3-O-sulfotransferase 2 (GAL3ST2). Importantly, GAL3ST2 is present in NMMuMG and two human breast cancer cell lines, and it is more strongly expressed in more metastatic tumors. When 3T3-L1 preadipocyte differentiation was triggered in the presence of conditioned medium from NMuMG or GAL3ST2, triglyceride accumulation was decreased by 40 % and C/EBPbeta expression by 80 % in adipocytes. In addition, the expression of FABP4 (aP2), another marker of adipocyte differentiation, was inhibited by 40 % in GAL3ST2-treated cells. CONCLUSIONS: Taken together, these results suggest that GAL3ST2 would interfere with normal differentiation of 3T3-L1 preadipocytes; raising the possibility that it may affect normal differentiation of stromal preadipocytes and be a link to tumor metastatic capacity. PMID- 25532486 TI - Serodiagnosis of sparganosis by ELISA using recombinant cysteine protease of Spirometra erinaceieuropaei spargana. AB - The Spirometra erinaceieuropaei cysteine protease (SeCP) gene encoding a 36 kDa protein was expressed in Escherichia coli, and the potential of recombinant SeCP protein (rSeCP) as an antigen for the serodiagnosis of sparganosis was investigated by ELISA and compared with those of ELISA with sparganum excretory secretory (ES) antigens. The sensitivity of rSeCP-ELISA and ES-ELISA was 96.67 % (29/30) and 100 % (30/30) respectively, for the detection of anti-sparganum IgG antibodies in sera of the experimentally infected mice (P > 0.05), and the specificities of both ELISA were 100 % (77/77). In heavily, moderately, and lightly infected mice (five, three, and one larvae per mouse), anti-sparganum antibodies were firstly detected by rSeCP-ELISA at 10-12 days post-infection (dpi), respectively, and then continued to increase with a detection rate of 100 % at 14-22 dpi. In three groups of infected mice, the anti-sparganum antibody levels at different times after infection were statistically different (P < 0.05). The results showed that the rSeCP might be a potential candidate antigen for early and specific serodiagnosis of sparganosis. But, it needs to be further evaluated with sera of the patients with sparganosis and other helminthiasis. PMID- 25532487 TI - A simplified method to recover urinary vesicles for clinical applications, and sample banking. AB - Urinary extracellular vesicles provide a novel source for valuable biomarkers for kidney and urogenital diseases: Current isolation protocols include laborious, sequential centrifugation steps which hampers their widespread research and clinical use. Furthermore, large individual urine sample volumes or sizable target cohorts are to be processed (e.g. for biobanking), the storage capacity is an additional problem. Thus, alternative methods are necessary to overcome such limitations. We have developed a practical vesicle isolation technique to yield easily manageable sample volumes in an exceptionally cost efficient way to facilitate their full utilization in less privileged environments and maximize the benefit of biobanking. Urinary vesicles were isolated by hydrostatic dialysis with minimal interference of soluble proteins or vesicle loss. Large volumes of urine were concentrated up to 1/100 of original volume and the dialysis step allowed equalization of urine physico-chemical characteristics. Vesicle fractions were found suitable to any applications, including RNA analysis. In the yield, our hydrostatic filtration dialysis system outperforms the conventional ultracentrifugation-based methods and the labour intensive and potentially hazardous step of ultracentrifugations are eliminated. Likewise, the need for trained laboratory personnel and heavy initial investment is avoided. Thus, our method qualifies as a method for laboratories working with urinary vesicles and biobanking. PMID- 25532488 TI - Quercetin protects human peripheral blood mononuclear cells from OTA-induced oxidative stress, genotoxicity, and inflammation. AB - Ochratoxin A (OTA) is one of the most abundant food-contaminating mycotoxins world wide, and is detrimental to human and animal health. This study evaluated the protective effect of quercetin against OTA-induced cytotoxicity, genotoxicity, and inflammatory response in lymphocytes. Cytotoxicity determined by MTT assay revealed IC20 value of OTA to be 20 uM, which was restored to near control values by pretreatment with quercetin. Oxidative stress parameters such as antioxidant enzymes, LPO and PCC levels indicated that quercetin exerted a protective effect on OTA-induced oxidative stress. Quercetin exerted an antigenotoxic effect on OTA-induced genotoxicity, by significantly reducing the number of structural aberrations in chromosomes and comet parameters like, % olive tail moment from 2.76 +/- 0.02 to 0.56 +/- 0.02 and % tail DNA from 56.23 +/- 2.56 to 12.36 +/- 0.56 as determined by comet assay. OTA-induced NO, TNF alpha, IL-6, and IL-8 were significantly reduced in the quercetin pretreated samples indicating its anti-inflammatory role. Our results demonstrate for the first time that quercetin exerts a cytoprotective effect against OTA-induced oxidative stress, genotoxicity, and inflammation in lymphocytes. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 855-865, 2016. PMID- 25532489 TI - Quantification of planning target volume margin when using a robotic radiosurgery system to treat lung tumors with spine tracking. AB - PURPOSE: The use of fiducial markers or direct tumor visualization allows for tumor tracking and ultimately smaller planning target volume (PTV) margins in the treatment of lung tumors, yet many patients are either not amenable to fiducial marker placement or their tumors are unable to be visualized on orthogonal-axis x ray images. Spine tracking is an alternative method for tumor localization but is limited by the assumption that the location of the lung tumor relative to the spine is constant. The purpose of this study was to quantify the additional PTV margin needed when spine tracking is used to ensure the internal target volume (ITV) receives the prescription dose during treatment. METHODS AND MATERIALS: Daily cone beam computed tomography images, registered based on tumor position, from 63 patients with lung cancer treated with stereotactic body radiation therapy were collected and analyzed. Rigid registrations were reperformed so that the position of the spine on the cone beam computed tomography image was aligned to its position on the planning computed tomography. Shifts from the treatment position to the new position were recorded, and per-patient mean shifts and standard deviations were calculated, as well as group systematic and random standard deviations. These data were used with van Herk's margin recipe to determine the additional margin required to adequately treat the patient population if spine tracking were used instead of direct daily tumor imaging. A retrospective dosimetric analysis was also performed on 6 patients with lung cancer previously treated by CyberKnife using spine tracking to determine the potential decrease in target coverage attributable to insufficient margin on the ITV. This analysis was performed by shifting the PTV volume relative to the CyberKnife treatment geometry to simulate a setup error caused by tracking the spine as opposed to the tumor. RESULTS: The additional margins calculated by van Herk's margin recipe to adequately cover the ITV with the 95% isodose surface for 90% of the entire patient population in the vertical, longitudinal, and lateral directions were 6.4, 6.0, and 4.5 mm, respectively. The retrospective analysis showed a decrease in PTV coverage from 95.6% to 93.1% and an increase in new conformity index by 2.7% when the average shift data were used to simulate setup error. When the maximum shift data were used to simulate the worst possible outcome, PTV coverage decreased to 73.4% and the new conformity index increased by 26.8%. CONCLUSIONS: Standard margins of 5 mm on the ITV for patients with lung cancer being treated with stereotactic body radiation therapy are insufficient and may result in geographic misses of the tumor when spine tracking is used to locate the position of the tumor in the lung. Therefore, we recommend the addition of 5-mm margins in all directions for a total of 10 mm to take into account the change in position of the tumor relative to the spine from the time of simulation to treatment. PMID- 25532490 TI - Radiation recall precipitated by iodinated nonionic contrast. PMID- 25532491 TI - Extended field intensity modulated radiation therapy for gynecologic cancers: Is the risk of duodenal toxicity high? AB - PURPOSE: There have been conflicting reports regarding the incidence of duodenal toxicity in patients receiving intensity modulated radiation therapy (IMRT) with an extended field covering the para-aortic (PA) lymph nodes for gynecologic cancers. We reviewed our experiences and rates of duodenal toxicity in patients treated with extended field IMRT. METHODS AND MATERIALS: Patients with either cervical or endometrial cancer who were treated with IMRT to the PA nodes for involved lymph nodes or for prophylactic intent between 2005 and 2013 were included. For prophylactic intent, the radiation dose to the PA nodes was 45 Gy in 25 fractions. For involved lymph nodes, a boost was delivered to the gross disease with a 0.7-cm expansion, with editing for critical structures. The entire duodenum was retrospectively contoured on all patients from the gastric outlet to the jejunal transition. RESULTS: We identified 76 eligible patients with endometrial and cervical cancer. The PA region was treated prophylactically in 46.1% (n = 35) and for involved PA lymph nodes in 53.9% (n = 41). The duodenum was contoured on all patients with a median volume of 83.2 cm(3) (range, 21.2 174.9 cm(3)). The mean volume of duodenum receiving 55 Gy (V55) for those treated prophylactically and for involved PA nodes was 0 cm(3) and 0.8 cm(3) (range, 0 10.6 cm(3)), respectively (P = .014). Specifically, no patient had a V55 >15 cm(3). The mean V40 was 28.3 cm(3) (range, 0-77.3 cm(3)) and 41.4 (range, 0-90.0 cm(3)), respectively (P = .016). The mean dose delivered to 2 cm(3) of the duodenum was 34.9 Gy (range, 0-52.3 Gy) and 50.1 Gy (range, 31.3 - 58.3 Gy), respectively. Grade 3 acute gastrointestinal toxicity was recorded in 3.9% (n = 3) of patients. CONCLUSIONS: In our experience, the treatment of PA lymph nodes using an IMRT technique is associated with a low duodenal toxicity profile and there has been no high-grade late duodenal toxicity. PMID- 25532492 TI - Short Hospitalization system: a new way of interpreting day surgery care. AB - Today's poorer income on the one hand and the more and more unbearable costs on the other, call for solutions to maintain public health through proper and collective care. We need to think of a new dimension of health, to found a modern and innovative approach, which can combine the respect of healthcare rights with the optimization of resources. Worldwide, franchises serving millions of people every year succeed in limiting operating costs and still offer a service and a quality equal to single businesses. Let's imagine every single Day Surgery Unit (DSU), within its own hospital, as a single trade: starting a process of centralized management and subsequent affiliation with other DSUs, they would increase their healthcare offer by means of solid organization, efficiency and foresight that with a strong focus on innovation and continuous updating, thus increasing its range of consumers and containing management costs. The Short Hospitalization System (SHS) is the proposed project, which is not only a type of hospitalization which is different from the ordinary, but also an innovative clinical-organizational model, with an important economic impact, where the management and maximization of the different hospital flows (care, professional, logistical, information), as well as the ability to implement strategies to anticipate them are crucial. The expected benefits are both clinically and socially relevant. Among them: 1) best practice build up; 2) lower impact on daily habits and increased patient satisfaction; 3) reduction of social and health expenditure. PMID- 25532493 TI - Minimum alveolar concentration threshold of sevoflurane for postoperative dream recall. AB - BACKGROUND: Many factors affect postoperative dream recall, including patient characteristics, type of anesthesia, timing of postoperative interview and stress hormone secretion. Aims of the study were to determine whether Bispectral Index (BIS)-guided anesthesia might decrease sevoflurane minimum alveolar concentration (MAC) when compared with hemodynamically-guided anesthesia, and to search for a MAC threshold useful for preventing arousal, dream recall and implicit memory. METHODS: One hundred thirty patients undergoing elective thyroidectomy were enrolled. Anesthesia was induced with propofol 2 mg kg(-1), fentanyl 3 mcg kg(-1) and cis-atracurium 0.15 mg kg(-1). For anesthesia maintenance, patients were randomly assigned to one of two groups: a BIS-guided group in which sevoflurane MAC was adjusted on the basis of BIS values, and a hemodynamic parameters (HP) guided group in which MAC was adjusted based on HP. An auditory recording was presented to patients during anesthesia maintenance. Dream recall and explicit/implicit memory were investigated upon awakening and approximately after 24 h. RESULTS: Mean sevoflurane MAC during auditory presentation was similar in the two groups (0.85 +/- 0.16 and 0.87 +/- 0.17 [P = 0.53] in BIS-guided and HP guided groups, respectively). Frequency of dream recall was similar in the two groups: 27% (N. = 17) in BIS-guided group, 18% (N. = 12) in HP-guided group, P = 0.37. In both groups, dream recall was less probable in patients anesthetized with MAC values >= 0.9 (area under ROC curve = 0.83, sensitivity = 90%, and specificity = 49%). CONCLUSION: BIS-guided anesthesia was not able to generate different MAC values compared to HP-guided anesthesia. Independent of the guide used for anesthesia, a sevoflurane MAC over 0.9 was required to prevent postoperative dream recall. PMID- 25532494 TI - TMT predator odor activated neural circuit in C57BL/6J mice indicates TMT-stress as a suitable model for uncontrollable intense stress. AB - Intense stressful events can result in chronic disorders such as posttraumatic stress disorder (PTSD). In vulnerable individuals, a single aversive experience can be sufficient to cause long-lasting behavioral changes. Candidate brain regions implicated in stress-related psychopathology are the amygdala, the bed nucleus of the stria terminalis (BNST), and the hypothalamic pituitary adrenal (HPA) axis. In rodents exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), an ethologically relevant stressor, has been shown to induce intense stress and innate anxiety responses. To study dispositions for the development of maladaptive stress responses, mice models are required. Therefore C57BL/6J mice were exposed to TMT and Fos expression was studied in key brain regions implicated in stress responses and anxiety-like behavior. Our results show TMT induced activation of a distinct neural circuit involving the BNST, the lateral septum (LS), the paraventricular nucleus of the hypothalamus (PVN), the periaqueductal gray (PAG) and the locus coeruleus (LC). Anatomical interconnection of the BNST with all these regions could point to an important modulatory role of this nucleus. Since, the BNST gets direct input from the olfactory bulbs and projects to the PVN and PAG and is therefore well positioned to modulate behavioral and endocrine stress responses to TMT. Hence, we suggest that TMT exposure is suitable to investigate uncontrollable stress responses in mice which exhibit similarities to maladaptive stress responses underlying PTSD in humans. PMID- 25532496 TI - Infrared detection based on localized modification of Morpho butterfly wings. AB - Inspired by butterflies an advanced detection and sensing system is developed. The hierarchical nanoarchitecture of Morpho butterfly wings is shown to facilitate the selective modification of such a structure, which results in a sensitive infrared response. These findings offer a new path both for detecting infrared photons and for generating nanostructured bimaterial systems for high performance sensing platforms. PMID- 25532495 TI - Asymmetric parental genome engineering by Cas9 during mouse meiotic exit. AB - Mammalian genomes can be edited by injecting pronuclear embryos with Cas9 cRNA and guide RNA (gRNA) but it is unknown whether editing can also occur during the onset of embryonic development, prior to pronuclear embryogenesis. We here report Cas9-mediated editing during sperm-induced meiotic exit and the initiation of development. Injection of unfertilized, mouse metaphase II (mII) oocytes with Cas9 cRNA, gRNA and sperm enabled efficient editing of transgenic and native alleles. Pre-loading oocytes with Cas9 increased sensitivity to gRNA ~100-fold. Paternal allelic editing occurred as an early event: single embryo genome analysis revealed editing within 3 h of sperm injection, coinciding with sperm chromatin decondensation during the gamete-to-embryo transition but prior to pronucleus formation. Maternal alleles underwent editing after the first round of DNA replication, resulting in mosaicism. Asymmetric editing of maternal and paternal alleles suggests a novel strategy for discriminatory targeting of parental genomes. PMID- 25532497 TI - Copper isotope effect in serum of cancer patients. A pilot study. AB - The isotope effect describes mass-dependent variations of natural isotope abundances for a particular element. In this pilot study, we measured the (65)Cu/(63)Cu ratios in the serums of 20 breast and 8 colorectal cancer patients, which correspond to, respectively, 90 and 49 samples taken at different times with molecular biomarker documentation. Copper isotope compositions were determined by multiple-collector inductively coupled plasma mass spectrometry (MC ICP-MS). When compared with the literature data from a control group of 50 healthy blood donors, abundances of Cu isotopes predict mortality in the colorectal cancer group with a probability p = 0.018. For the breast cancer patients and the group of control women the probability goes down to p = 0.0006 and the AUC under the ROC curve is 0.75. Most patients considered in this preliminary study and with serum delta(65)Cu lower than the threshold value of 0.350/00 (per mil) did not survive. As a marker, a drop in delta(65)Cu precedes molecular biomarkers by several months. The observed decrease of delta(65)Cu in the serum of cancer patients is assigned to the extensive oxidative chelation of copper by cytosolic lactate. The potential of Cu isotope variability as a new diagnostic tool for breast and colorectal cancer seems strong. Shifts in Cu isotope compositions fingerprint cytosolic Cu chelation by lactate mono- and bidentates. This simple scheme provides a straightforward explanation for isotopically light Cu in the serum and isotopically heavy Cu in cancer cells: Cu(+) escaping chelation by lactate and excreted into the blood stream is isotopically light. Low delta(65)Cu values in serum therefore reveal the strength of lactate production by the Warburg effect. PMID- 25532498 TI - Lack of familial aggregation in chronic constipation excluding irritable bowel syndrome: a population-based study. AB - BACKGROUND: Despite strong evidence supporting a genetic and gene-environment interaction in the irritable bowel syndrome (IBS), the role of genes and early life in another common functional bowel disorder, chronic constipation (CC), have been little studied. AIM: To determine whether familial aggregation occurs in CC and whether risk factors differed in those with family members. METHODS: A randomly selected population-based cohort from Olmsted County, MN, was surveyed (n = 8,006); 3,831 completed questionnaires (response rate 48 %). Cases were identified based upon their responses to a validated questionnaire and meeting Rome criteria for CC. Controls were matched one to one by age and gender. IBS (by Rome II criteria) was excluded. Recruitment of case and control probands occurred in 2010-2011 by mailing a family information form; then, first-degree relatives (FDR) were mailed a questionnaire. All potential proband participants were not informed of CC status. RESULTS: Overall 1,185 cases who met criteria for CC without symptoms of IBS and 1,185 controls were surveyed; 309 case and 336 control probands provided data. The proportion of family members having CC was not associated with case status, and the constipation status of FDR was not significantly associated with case-controls status of the respective probands. Symptom burden in FDR was associated with gender and SSC score, but not age or proband status. CONCLUSIONS: No evidence of familial aggregation was observed in adults from the community with CC (excluding IBS). Our data suggest environmental factors in later life more likely account for adult CC. PMID- 25532499 TI - Association of Serotonin Transporter Promoter Polymorphism (5-HTTLPR) with Microscopic Colitis and Ulcerative Colitis. AB - BACKGROUND: Serotonin (5-HT) release and serotonin reuptake transporter (5-HTT) expression have been reported to be decreased in experimental colitis, in interleukin-10 knockout-associated colitis, and in patients with ulcerative colitis. Serotonin is known to play an important role in the pathogenesis of colitis, but individual genetic variants of 5-HTT gene in microscopic colitis and ulcerative colitis are not known. AIM: This study aimed to evaluate the association between the serotonin transporter gene promoter polymorphism (5 HTTLPR) and 5-HT concentration in microscopic colitis (MC) and ulcerative colitis (UC) patients. METHOD: This prospective case-control study included 41 patients with microscopic colitis (age 19-82 years, mean 35 +/- 13.6), 75 patients with ulcerative colitis (age 16-65 years, mean 38.5 +/- 11.6), and 100 controls (age 20-64 years, mean 38 +/- 11). 5-HTTLPR gene polymorphism was studied by polymerase chain reaction-based assay. 5-HT levels were measured by ELISA. RESULTS: The frequency of the 5-HTTLPR (SS) genotype was significantly lower in MC (12 %) patients compared to controls (30 %) (p < 0.05). When the L/L and L/S genotypes were combined into one group, the frequencies of the non-S genotype were significantly higher than those of S/S genotype between the MC patients and the controls (p < 0.05). 5-HT levels were significantly higher in UC and MC patients compared to healthy controls (p < 0.01). CONCLUSIONS: A significant association was observed between LL genotype of 5-HTTLPR polymorphism and microscopic colitis, suggesting that 5-HTTLPR is a potential candidate gene involved in the pathogenesis of microscopic colitis. Serotonin levels were significantly higher in microscopic colitis and ulcerative colitis patients compared to healthy controls. PMID- 25532500 TI - A Treat-to-Target Concept to Guide the Medical Management of Hepatorenal Syndrome. AB - BACKGROUND: The principle of treating-to-target has been successfully applied to many diseases with significant improvement in patient care and as a useful guidance for healthcare providers. Appreciation of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin in patients with HRS. An appropriate target to guide such therapy, however, has not yet been established. AIMS: The purpose of the current study was to identify a suitable target that can predict clinical outcome and guide the medical management of type 1 HRS, a condition associated with very poor prognosis. METHODS: A total of 85 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled. A potential therapeutic target was identified by univariate and multivariate logistic regression analyses. The treat-to-target concept to guide the management of HRS was then tested via a retrospective cohort study. RESULTS: A change in mean arterial pressure (MAP) during treatment was identified as a sole independent predictor for patient survival. Compared with mild or no increase in MAP, achievement in a marked increase in MAP of more than 10 mmHg in these patients was associated with better overall survival and transplant-free survival. Increased MAP to higher than 15 mmHg did not result in further improvement in clinical outcome. CONCLUSIONS: A treat-to-target concept by the use of a specific goal of MAP is feasible and may potentially guide the medical management of type 1 HRS. PMID- 25532501 TI - Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. AB - BACKGROUND: Long-term tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) is associated with sustained viral suppression and regression of fibrosis and cirrhosis at year 5 (240 weeks) and no TDF resistance through 6 years (288 weeks). AIM: We assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients. METHODS: Patients who completed 1 year (48 weeks) of randomized treatment with TDF or adefovir dipivoxil were eligible to receive open-label TDF for a total duration of 8 years (384 weeks). RESULTS: Of 641 patients initially randomized, 585 (91.3 %) entered the open-label phase; 437/585 (74.7 %) remained on study at year 7. For patients on treatment at year 7, 99.3 % maintained viral suppression (HBV DNA < 69 IU/mL), 80.0 % achieved serum alanine aminotransferase normalization, and in HBeAg-positive patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved HBeAg and HBsAg loss, respectively. One/375 (0.3 %) HBeAg-negative patients achieved HBsAg loss. No resistance to TDF was detected through 7 years. During the open-label phase, grade 3/4 drug-related adverse events were uncommon (1.0 %); ten (1.7 %) patients had elevation of serum creatinine >= 0.5 mg/dL above baseline. No significant change in bone mineral density was observed from year 4 to year 7 (week 192 to week 336). CONCLUSIONS: Long-term TDF treatment was associated with sustained virologic, biochemical, and serologic responses, without resistance. TDF treatment was well tolerated, with a low incidence of renal and bone events. These data confirm the safety and efficacy of long-term TDF for CHB. PMID- 25532503 TI - Efficacy of Lafutidine Versus Famotidine in Patients with Reflux Esophagitis: A Multi-Center, Randomized, Double-Blind, Non-inferiority Phase III Trial. AB - BACKGROUND: There has been no study on the efficacy of lafutidine for patients with reflux esophagitis in Korea. AIM: To evaluate the efficacy of a new generation histamine-2 receptor antagonist, lafutidine, in comparison with famotidine in patients with reflux esophagitis. METHODS: This was a randomized, double-blind, non-inferiority trial enrolling patients with erosive esophagitis. The efficacy and safety of 20 mg lafutidine (treatment group) were compared with those of 40 mg famotidine (control group) and 20 mg omeprazole (reference group). The primary endpoint was the complete healing rates of reflux esophagitis on endoscopy after 8 weeks of treatment. The non-inferiority margin was assumed to be -15 %. RESULTS: The healing rates of reflux esophagitis on endoscopy after 8 weeks of treatment were 70.14 % (101/144) in the lafutidine, 63.45 % (92/145) in the famotidine, and 85.71 % (126/147) in the omeprazole group. The difference in healing rates between the lafutidine and famotidine groups was 6.69 % (95 % confidence interval = [-4.14 to 17.52]). In addition, lafutidine was superior to famotidine in clinical improvement (53.73 % vs. 39.55 %, P = 0.0200). CONCLUSIONS: Lafutidine was non-inferior to famotidine in healing of reflux esophagitis. Lafutidine, however, was superior to famotidine in terms of symptom relief of reflux esophagitis. PMID- 25532502 TI - Curcumin targets multiple pathways to halt hepatic stellate cell activation: updated mechanisms in vitro and in vivo. AB - Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease, which is often accompanied by obese and/or type II diabetes mellitus. Approximately one-third of NASH patients develop hepatic fibrosis. Hepatic stellate cells are the major effector cells during liver fibrogenesis. Advanced liver fibrosis usually proceeds to cirrhosis and even hepatocellular carcinoma, leading to liver failure, portal hypertension and even death. Currently, there are no approved agents for treatment and prevention of liver fibrosis in human beings. Curcumin, the principal curcuminoid of turmeric, has been reported to show antitumor, antioxidant, and anti-inflammatory properties both in in vitro and in vivo systems. Accumulating data shows that curcumin plays a critical role in combating liver fibrogenesis. This review will discuss the inhibitory roles of curcumin and update the underlying mechanisms by which curcumin targets in inhibiting hepatic stellate cell activation. PMID- 25532504 TI - Low yield and utilization of confirmatory testing in a cohort of patients with liver disease assessed for alpha-1 antitrypsin deficiency. AB - BACKGROUND: Alpha-1 antitrypsin (AAT) deficiency is often evaluated in patients with liver disease of unknown etiology. AIMS: We aimed to describe the practice and yield of AAT testing at a large clinical laboratory. METHODS: This is the retrospective cohort study of all patients with AAT measurements at one major clinical laboratory between 2003 and 2012. RESULTS: AAT was measured in 4,985 patients by more than 339 physicians. Eight (0.16 %) patients were found to have AAT deficiency disease. Low AAT levels were associated with two clinical factors. Aspartate aminotransferase (>40 IU/L) was inversely related, odds ratio (OR) 0.53, 95 % CI (0.32-0.88), while comorbid pulmonary disease was positively correlated, OR 4.00, 95 % CI (1.37-9.30). Non-directed testing was common. More than 90 % of patients with ALT > 40 were simultaneously assessed for AAT deficiency, hepatitis B or C, hemochromatosis, and autoimmune hepatitis. Rates of phenotype utilization were low for patients with low AAT (23, 31.5 %). Phenotype utilization was inversely related to the practice of simultaneous testing for simultaneous autoimmune hepatitis [OR 0.34 (95 % CI 0.13-0.88)], hepatitis B [OR 0.32 (95 % CI 0.11-0.89)], hepatitis C [OR 0.36 (95 % CI 0.13-1.00)], and Wilson disease evaluation [OR 0.35 (95 % CI 0.14-0.92)]. CONCLUSION: The yield of AAT testing for patients with elevated liver enzymes is low. Utilization of phenotype testing is low and related to non-directed liver testing patterns. These data suggest a role for guidelines and laboratory protocols to encourage directed testing and phenotype utilization. PMID- 25532505 TI - Efficacy of concomitant elemental diet therapy in scheduled infliximab therapy in patients with Crohn's disease to prevent loss of response. AB - BACKGROUND: Loss of response (LOR) to infliximab (IFX) has become an important clinical issue for patients with Crohn's disease (CD). Elemental diet (ED) therapy has been established as a nutrition therapy for CD in Japan. ED therapy can reduce antigen exposure and is both efficacious and safe. AIM: To evaluate the efficacy of concomitant ED therapy in maintaining regular IFX infusion in patients with CD. METHODS: We retrospectively studied 125 patients with luminal CD treated with scheduled IFX maintenance therapy with a regular dosage. Patients were classified into two groups: the ED group with intake >= 900 kcal/day and the non-ED group with intake <900 kcal/day. When clinical LOR was detected on the basis of disease activity, laboratory parameters, or endoscopic findings, the physician discontinued the infusion schedule of IFX. We investigated the efficacy of ED therapy for sustaining the scheduled IFX maintenance therapy. RESULTS: With the exception of ED intake, no significant differences were found in patient characteristics between the ED group and the non-ED group. The ED group was significantly superior to the non-ED group (p = 0.049) in sustaining scheduled IFX maintenance therapy. It is well known that ED therapy is more effective for small bowel lesions than colonic lesions in CD. When comparing ileitis and ileocolitis patients with CD, the ED group was significantly superior to the non ED group (p = 0.015). CONCLUSIONS: Concomitant ED therapy is effective in maintaining scheduled IFX maintenance therapy in patients with luminal CD in order to prevent LOR. PMID- 25532506 TI - Faecal carriage of carbapenemase-producing Gram-negative bacilli in hospital settings in southern France. AB - The emergence of carbapenemase-producing Gram-negative bacilli is a worldwide problem. To date, no study has evaluated the prevalence of faecal carriage of carbapenemase-producing and carbapenem-resistant Gram-negative bacilli (CR GNB) in France. From 1 February to 30 April 2012, we conducted a prospective, multicentre study in three University Hospitals and four General Hospitals in the south of France. The carriage of carbapenemase-producing Enterobacteriaceae (CPE) and other CR GNB was screened by both cultivation on chromID(r) CARBA and chromID(r) OXA-48 media (bioMerieux) and molecular tools [multiplex polymerase chain reaction (PCR) and NucliSENS EasyQ(r) KPC (bioMerieux)]. The genetic relationship between isolates was assessed by rep-PCR (DiversiLab, bioMerieux) or multilocus sequence typing (MLST). The prevalences of CR GNB and carbapenemase producing bacteria were 2.4 % (27/1,135) and 0.4 % (n = 5), respectively. Two strains corresponded to OXA-23-producing Acinetobacter baumannii and belonged to the widespread sequence type (ST) 2/international clone II, whereas one strain was an ST15 OXA-48-producing Klebsiella pneumoniae. Two OXA-48-producers were detected exclusively by PCR. This first French study revealed the very low dissemination of carbapenemase-producing bacteria in patients attending hospitals in southern France during a non-outbreak situation. However, the increasing description of epidemic cases in this area must reinforce the use of hygiene procedures to prevent diffusion of these multidrug-resistant microorganisms. PMID- 25532507 TI - Staphylococcus pseudintermedius can be misdiagnosed as Staphylococcus aureus in humans with dog bite wounds. AB - The purpose of this study was to investigate whether S. pseudintermedius is misdiagnosed as S. aureus by clinical laboratories when isolated from humans with dog bite wounds. In addition, we attempted to determine whether S. pseudintermedius isolates related to dog bite wounds share phenotypic and genotypic traits. S. pseudintermedius was identified by PCR targeting the nuc gene. Isolates were tested for antibiotic susceptibility using VetMIC GP-mo microdilution panels. The occurrence of genes encoding leukocidins, exfoliatins, pyrogenic toxin superantigens and enterotoxins was determined by PCR. The relatedness of S. pseudintermedius isolates was investigated using Multi Locus Sequence Typing (MLST). Out of 101 isolates defined as S. aureus by human clinical microbiology laboratories, 13 isolates were re-identified as S. pseudintermedius and one isolate was confirmed to carry the mecA gene, i.e. methicillin-resistant (MRSP). The MRSP isolate was also defined as multi resistant. Two methicillin-susceptible S. pseudintermedius isolates were also multi-resistant and five were susceptible to all antibiotics tested. With the exception of three S. pseudintermedius isolates belonging to multi locus sequence type (MLST) 158, all the isolates belonged to unique STs. All isolates contained lukS/F-I, siet and se-int, and expA were identified in two isolates and expB and sec canine-sel in one isolate respectively. S. pseudintermedius is frequently misdiagnosed as S. aureus from humans with dog bite wounds showing that it can act as an opportunistic pathogen in humans. No common phenotypic and genotypic traits shared by the S. pseudintermedius isolates could be identified. PMID- 25532508 TI - COP1 E3 ligase protects HYL1 to retain microRNA biogenesis. AB - Constitutive photomorphogenic 1 (COP1) is a RING-finger E3 ligase that plays a central role in photomorphogenesis by destabilizing many light-regulated transcription factors and photoreceptors. Here, we reveal a novel function for COP1 E3 ligase in controlling global miRNA biogenesis in Arabidopsis thaliana. In cop1 mutants, the level of miRNAs is dramatically reduced because of the diminution of HYPONASTIC LEAVES 1 (HYL1), an RNA-binding protein required for precise miRNA processing. HYL1 is destabilized by an unidentified protease, which we tentatively call protease X, that specifically cleaves the N-terminal region from HYL1, thus neutralizing its function. Our results further show that the cytoplasmic partitioning of COP1 under light is essential to protect HYL1 against protease X. Taken together, we suggest a novel regulatory network involving HYL1, protease X, COP1 and light signalling that is indispensable for miRNA biogenesis in Arabidopsis thaliana. PMID- 25532509 TI - Durotomy is associated with pseudoarthrosis following lumbar fusion. AB - Pseudoarthrosis is a known complication following lumbar fusion, and although several risk factors have been established, the association of durotomy and pseudoarthrosis has not been studied to our knowledge. A retrospective review was performed to identify all adult patients who underwent lumbar posterolateral fusion (without interbody fusion) for degenerative spine disease over a 20 year period at a single institution. Patients were divided into durotomy and no durotomy cohorts. Patients were included if they had at least 1 year of follow up. The main outcome variable was development of pseudoarthrosis. A total of 327 patients were identified, of whom 17 (5.19%) had a durotomy. Pseudoarthrosis rates were significantly higher in the durotomy group (35.29%) when compared to the no durotomy group (13.87%), with the difference being statistically significant (p=0.016). Univariate analysis revealed that durotomy (p=0.003) and the number of levels fused (p=0.015) were the only two significant risk factors for pseudoarthrosis. After controlling for the number of levels fused, the adjusted relative risk (RR) revealed that patients with a durotomy were 2.23 times more likely to develop pseudoarthrosis (RR 2.23; 95% confidence interval 1.05-4.75) when compared to patients without durotomy. The findings in the present study suggest an association between durotomy and pseudoarthrosis development. Patients with a durotomy were 2.2 times more likely to develop pseudoarthrosis compared to patients without a durotomy. Future and larger studies are required to corroborate our findings. PMID- 25532510 TI - Automated localization of breast cancer in DCE-MRI. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly being used for the detection and diagnosis of breast cancer. Compared to mammography, DCE-MRI provides higher sensitivity, however its specificity is variable. Moreover, DCE-MRI data analysis is time consuming and depends on reader expertise. The aim of this work is to propose a novel automated breast cancer localization system for DCE-MRI. Such a system can be used to support radiologists in DCE-MRI analysis by marking suspicious areas. The proposed method initially corrects for motion artifacts and segments the breast. Subsequently, blob and relative enhancement voxel features are used to locate lesion candidates. Finally, a malignancy score for each lesion candidate is obtained using region-based morphological and kinetic features computed on the segmented lesion candidate. We performed experiments to compare the use of different classifiers in the region classification stage and to study the effect of motion correction in the presented system. The performance of the algorithm was assessed using free-response operating characteristic (FROC) analysis. For this purpose, a dataset of 209 DCE-MRI studies was collected. It is composed of 95 DCE-MRI studies with 105 breast cancers (55 mass-like and 50 non-mass-like malignant lesions) and 114 DCE-MRI studies from women participating in a screening program which were diagnosed to be normal. At 4 false positives per normal case, 89% of the breast cancers (91% and 86% for mass-like and non-mass-like malignant lesions, respectively) were correctly detected. PMID- 25532511 TI - Insulin therapy refusal among type II diabetes mellitus patients in Kubang Pasu district, the state of Kedah, Malaysia. AB - INTRODUCTION: Diabetes mellitus is a rising non-communicable disease in Malaysia. Insulin therapy refusal is a great challenge for healthcare providers, as it results in delayed insulin initiation. This study was conducted to determine the prevalence of insulin therapy refusal and its associated factors. METHODS: This cross sectional study was conducted at seven public health clinics in Kubang Pasu district, Malaysia, from March to October 2012. A newly developed and validated questionnaire was used and participants were selected via systematic random sampling. Only patients diagnosed with type II diabetes mellitus (T2DM) and under the public health clinic care in Kubang Pasu were included in the study. Multiple logistic regressions were used to study the association between insulin therapy refusal and its associated factors. RESULTS: There were 461 respondents and the response rate was 100%. Among these 461 patients with T2DM, 74.2% refused insulin therapy. The most common reason given for refusal was a lack of confidence in insulin injection (85.4%). Multiple logistic regression revealed that respondents who had secondary education were 55.0% less likely to refuse insulin therapy than those who had primary or no formal education (p = 0.009, adjusted odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.25-0.82). There was also a significant inverse association between glycated haemoglobin (HbA1c) and insulin therapy refusal (p = 0.047, adjusted OR = 0.87, 95% CI = 0.76-1.00). CONCLUSION: Insulin therapy refusal is common in Kubang Pasu. Education status and HbA1c should be taken into consideration when counselling patients on insulin therapy initiation. PMID- 25532512 TI - The prevalence of fatigue and associated health and safety risk factors among taxi drivers in Singapore. AB - INTRODUCTION: Driver fatigue is one of the biggest health and safety concerns within the road transport sector. This study aimed to find out the prevalence of fatigue among taxi drivers in Singapore, to better understand the general working and health conditions of this group of people and to determine the risk factors associated with fatigued driving. METHODS: A total of 340 taxi drivers were randomly selected for participation in this self-administered questionnaire survey, with height and weight measurements. The response rate was 68.2%. The survey consisted of four main categories: personal particulars; social habits; work patterns and sleep profile; and Epworth Sleepiness Scale, which was used to estimate the level of daytime sleepiness and fatigue. Multiple logistic regression analysis was used to estimate the adjusted odd ratios and 95% confidence intervals associated with the risk factors related to fatigue among the taxi drivers. RESULTS: A high proportion of the taxi drivers were obese and had self-reported hypertension, diabetes mellitus and high cholesterol. Driver fatigue was associated with very poor/poor self-rating of the quality of sleep, having an additional part-time job, drinking three or more caffeinated drinks daily, and driving more than 10 hours a day. CONCLUSION: We hope that the findings of the present study will improve the awareness regarding the work and health conditions of taxi drivers, and contribute toward the effort to achieve a healthier workforce. A lower prevalence of fatigued driving will lead to lower risks of road traffic accidents, decreased economic loss, increased productivity, and safer roads for all. PMID- 25532513 TI - Frequent nasopharyngeal suctioning as a risk factor associated with neonatal coagulase-negative staphylococcal colonisation and sepsis. AB - INTRODUCTION: This case-control study aimed to determine whether catheter use was significantly associated with coagulase-negative staphylococci (CoNS) colonisation and/or sepsis in neonates. METHODS: Weekly swabs of the nose, umbilicus, rectum, wounds, eye discharge and intravenous catheter tips (after removal) of infants admitted to the neonatal intensive care unit of Universiti Kebangsaan Malaysia Medical Centre, Malaysia, were cultured. CoNS sepsis was diagnosed if pure growth of CoNS was cultured from the peripheral blood specimen of symptomatic infants. For each infant with CoNS colonisation or sepsis, a control infant was retrospectively and randomly selected from unaffected infants in the ward. Multivariate analyses were performed to determine whether catheter use was a significant risk factor. RESULTS: CoNS colonisation was detected in 113 (8.7%) infants. CoNS sepsis was found in 12 (10.6%) infants with CoNS colonisation and 7 (0.6%) infants without CoNS colonisation. Multivariate analysis showed that the following were significantly associated with CoNS colonisation: conjunctivitis (adjusted odds ratio [OR] 8.2, 95% confidence interval [CI] 1.9-34.8, p = 0.005); central venous catheters (adjusted OR 5.8, 95% CI 1.9-17.8, p = 0.002); and nasopharyngeal and/or oral suctioning more than twice in the 48 hours before positive culture (adjusted OR 7.3, 95% CI 3.3-16.2, p < 0.001). Exposure to frequent nasopharyngeal and/or oral suctioning (adjusted OR 20.8, 95% CI 3.5-125.3, p = 0.001) was the only significant factor associated with CoNS sepsis. CONCLUSION: Infants requiring more than two nasopharyngeal and/or oral suctions in the previous 48 hours were found to have a higher risk of developing CoNS colonisation and sepsis. PMID- 25532514 TI - Development and validation of algorithms for heart failure patient care: a Delphi study. AB - INTRODUCTION: Although heart failure (HF) management is available at primary and secondary care facilities in Malaysia, the optimisation of drug therapy is still suboptimal. Although pharmacists can help bridge the gap in optimising HF therapy, pharmacists in Malaysia currently do not manage and titrate HF pharmacotherapy. The aim of this study was to develop treatment algorithms and monitoring protocols for angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers and spironolactone based on extensive literature review for validation and utilization by pharmacists involved in HF management. METHODS: A Delphi survey involving 32 panellists, from private and government hospitals that provide cardiac services in Malaysia, was conducted to obtain a consensus opinion on the treatment protocols. The panellists completed two rounds of self-administered questionnaires to determine their level of agreement with all the components in the protocols. RESULTS: Consensus agreement was achieved for most of the sections of the protocols for the four classes of drugs. Panellists' opinions were taken into consideration when amending the components of the protocols that did not achieve consensus opinion. Full consensus agreement was achieved with the second survey conducted, enabling the finalisation of the drug titration protocols. CONCLUSION: The resulting validated HF titration protocols can be used as a guide for pharmacists when recommending the initiation and titration of HF drug therapy in daily clinical practice. Recommendations should be made in collaboration with the patient's treating physician, with concomitant monitoring of patient's response to the drugs. PMID- 25532515 TI - Effect of GnRH antagonists on clinical pregnancy rates in ovulation induction protocols with gonadotropins and intrauterine insemination. AB - INTRODUCTION: Intrauterine insemination (IUI) after controlled ovarian hyperstimulation (COH) was applied to selected infertile patients to determine the effect of gonadotropin-releasing hormone (GnRH) antagonists in IUI cycles, in which recombinant follicle-stimulating hormone (rFSH) had been used for COH. METHODS: This study was conducted between April 1, 2009 and June 10, 2009, and involved a total of 108 patients. These patients had primary or secondary infertility, which resulted in an indication for IUI, and they each received two cycles of ovarian stimulation treatment with clomiphene citrate. The patients were randomised into two groups--patients in group A received rFSH + GnRH antagonist (n = 45), while those in group B received only rFSH (n = 63). RESULTS: The mean age of the patients was 31.84 +/- 3.73 years and the mean body mass index (BMI) was 24.40 +/- 1.88 kg/m(2). The mean age and BMI of the patients in groups A and B were not significantly different. There was no significant difference in the mean total rFSH dose administered (988.33 IU in group A and 871.83 IU in group B). When compared to group B, the mean number of follicles that were > 16 mm on the human chorionic gonadotropin (HCG) trigger day was significantly higher in group A (1.58 and 1.86, respectively; p < 0.05). When the two groups were compared, there were no statistically significant differences in the number of cancelled cycles due to premature luteinisation (none in group A vs. two in group B) and the rate of clinical pregnancy (8.9% in group A vs. 7.9% in group B). CONCLUSION: No significant improvement in the clinical pregnancy rates was observed when GnRH antagonists were used in COH + IUI cycles, despite the significant increase in the number of follicles that were > 16 mm on HCG trigger day. PMID- 25532516 TI - Adverse effects of young maternal age on neonatal outcomes. AB - INTRODUCTION: Teenage pregnancy is associated with poor neonatal outcomes, which may burden the young mothers and their families. The aim of this study was to determine the effect young maternal age and single motherhood has on neonatal outcomes. METHODS: We conducted a retrospective cohort study of 267 infants born to mothers aged <= 21 years in National University Hospital, Singapore, from January 2011 to December 2012. We compared the maternal demographics and neonatal outcomes of single mothers with those of married mothers. The neonatal outcomes of our study cohort were also compared to the hospital's birth cohort during the same period. RESULTS: Unsatisfactory antenatal care was more prevalent among the young single mothers than among the young married mothers (odds ratio [OR] 2.90, 95% confidence interval [CI] 1.71-4.92, p < 0.01). The infants of the young single mothers had a lower mean birth weight (p = 0.01), with a significant proportion weighing < 2.5 kg (OR 2.91, 95% CI 1.35-6.37, p < 0.01). Young maternal age was linked to a higher incidence of prematurity (OR 1.70, 95% CI 1.18-2.43, p < 0.01), major congenital defects (OR 4.68, 95% CI 2.10-10.13, p < 0.01), and a perinatal mortality of 18.7 per 1,000 births (OR 3.76, 95% CI 1.26 10.32, p = 0.02). CONCLUSION: Young single mothers were more likely to have unsatisfactory antenatal care and lighter infants. Young maternal age was associated with a higher risk of prematurity, major congenital malformations and perinatal mortality. More studies are needed to ascertain the cause of these adverse outcomes. PMID- 25532517 TI - Surveillance of childhood blood lead levels in Chengdu, China in 2010-2011. AB - INTRODUCTION: Lead poisoning has been receiving great attention around the world. The Child Hygiene Cooperation Center of the World Health Organization in China has been conducting investigations to monitor blood lead levels (BLLs) from as early as 2004. However, only several lead poisoning studies have been conducted in China since August 2009. The aim of the present study was to investigate the BLLs in children aged < 7 years and to analyse the risk factors of high BLLs in Chengdu, China. METHODS: Questionnaires were distributed to children in Chengdu from 2010 to 2011. A total of 2,271 children were included in this study - 1,157 received BLL tests in 2010 and the remaining received the tests in 2011. BLL was measured using a tungsten atomiser absorption spectrophotometer. RESULTS: The mean BLL of the 2,271 children was 6.2 ug/dL and 2.03% of the children had BLLs >= 10 ug/dL. Mean BLL seemed to increase with age. Unhygienic habits (e.g. not washing hands frequently, biting of toys and pencils), history of pica, use of coal and residence in an industrial zone were found to be the main risk factors contributing to high BLL (p < 0.05). Children with high BLLs have a higher risk of manifesting anorexia and/or abdominal pain as compared to those with low BLLs (p < 0.05). CONCLUSION: The mean BLL of children in Chengdu (i.e. 6.2 ug/dL) was found to be higher than that of children in developed countries. Childhood lead poisoning remains a public health problem. PMID- 25532518 TI - Production of a fragment of glycoprotein G of herpes simplex virus type 2 and evaluation of its diagnostic potential. AB - INTRODUCTION: Herpes simplex virus type 2 (HSV-2) is the most common cause of genital herpes. Glycoprotein G (gG) is a prototype antigen for type-specific serodiagnosis distinguishing between HSV type 1 (HSV-1) and HSV-2 infections. As immunological diagnosis kits for accurate differentiation between HSV-1 and HSV-2 antibodies can be expensive, there is a need to develop a convenient, sensitive, specific and cost-effective serodiagnostic kit. METHODS: We successfully expressed a fragment of gG comprising residues 321-580 of HSV-2 with histidine tag (gG(321-580His)) in a Bac-to-Bac baculovirus expression system, which had an antigenicity similar to its native counterpart. An indirect enzyme-linked immunosorbent assay (ELISA) was developed using gG(321-580His) as the diagnostic antigen and evaluated by comparison with a commercial HerpeSelect 2 ELISA immunoglobulin G kit as reference. RESULTS: In testing 318 field serum samples, the diagnostic relative sensitivity and specificity of the developed gG(321 580His)-ELISA test in qualitative comparison with the commercial kit were 93.81% and 96.74%, respectively, and the accuracy was 94.65%. CONCLUSION: The study indicates that gG(321-580His) has a high diagnostic potential for HSV-2 virus serodiagnosis in humans. PMID- 25532519 TI - One size fits all? Challenges faced by physicians during shift handovers in a hospital with high sender/recipient ratio. AB - INTRODUCTION: The aim of the present study was to investigate the challenges faced by physicians during shift handovers in a university hospital that has a high handover sender/recipient ratio. METHODS: A multifaceted approach was adopted, comprising recording and analysis of handover information, rating of handover quality, and shadowing of handover recipients. Data was collected at the general medical ward of a university hospital in Singapore for a period of three months. Handover information transfer (i.e. senders' and recipients' verbal communication, and recipients' handwritten notes) and handover environmental factors were analysed. The relationship between 'to-do' tasks, and information transfer, handover quality and handover duration, were examined using analysis of variance. RESULTS: Verbal handovers for 152 patients were observed; handwritten notes on 102 (67.1%) patients and handover quality ratings for the handovers of 98 (64.5%) patients were collected. Although there was good task prioritisation (information transfer: p < 0.005, handover duration: p < 0.01), incomplete information transfer and poor implementation of nonmodifiable identifiers were observed. The high sender/recipient ratio of the hospital made face-to-face and/or bedside handover difficult to implement. Although the current handover method (i.e. use of telephone communication), allowed interactive communication, it resulted in systemic information loss due to the lack of written information. The handover environment was chaotic in the high sender/recipient ratio setting, and the physicians had no designated handover time or location. CONCLUSION: Handovers in high sender/recipient ratio settings are challenging. Efforts should be made to improve the handover processes in such situations, so that patient care is not compromised. PMID- 25532520 TI - Spatio-temporal imaging correlation to measure tissue impedance in the neonatal brain. PMID- 25532521 TI - Integrating phosphoproteome and transcriptome reveals new determinants of macrophage multinucleation. AB - Macrophage multinucleation (MM) is essential for various biological processes such as osteoclast-mediated bone resorption and multinucleated giant cell associated inflammatory reactions. Here we study the molecular pathways underlying multinucleation in the rat through an integrative approach combining MS-based quantitative phosphoproteomics (LC-MS/MS) and transcriptome (high throughput RNA-sequencing) to identify new regulators of MM. We show that a strong metabolic shift toward HIF1-mediated glycolysis occurs at transcriptomic level during MM, together with modifications in phosphorylation of over 50 proteins including several ARF GTPase activators and polyphosphate inositol phosphatases. We use shortest-path analysis to link differential phosphorylation with the transcriptomic reprogramming of macrophages and identify LRRFIP1, SMARCA4, and DNMT1 as novel regulators of MM. We experimentally validate these predictions by showing that knock-down of these latter reduce macrophage multinucleation. These results provide a new framework for the combined analysis of transcriptional and post-translational changes during macrophage multinucleation, prioritizing essential genes, and revealing the sequential events leading to the multinucleation of macrophages. PMID- 25532522 TI - Fine mapping of Rcr1 and analyses of its effect on transcriptome patterns during infection by Plasmodiophora brassicae. AB - BACKGROUND: The protist Plasmodiophora brassicae is a biotrophic soil-borne pathogen that causes clubroot on Brassica crops worldwide. Clubroot disease is a serious threat to the 8 M ha of canola (Brassica napus) grown annually in western Canada. While host resistance is the key to clubroot management, sources of resistance are limited. RESULTS: To identify new sources of clubroot resistance (CR), we fine mapped a CR gene (Rcr1) from B. rapa ssp. chinensis to the region between 24.26 Mb and 24.50 Mb on the linkage group A03, with several closely linked markers identified. Transcriptome analysis was conducted using RNA sequencing on a segregating F1 population inoculated with P. brassicae, with 2,212 differentially expressed genes (DEGs) identified between plants carrying and not carrying Rcr1. Functional annotation of these DEGs showed that several defense-related biological processes, including signaling and metabolism of jasmonate and ethylene, defensive deposition of callose and biosynthesis of indole-containing compounds, were up-regulated significantly in plants carrying Rcr1 while genes involved in salicylic acid metabolic and signaling pathways were generally not elevated. Several DEGs involved in metabolism potentially related to clubroot symptom development, including auxin biosynthesis and cell growth/development, showed significantly lower expression in plants carrying Rcr1. CONCLUSION: The CR gene Rcr1 and closely linked markers will be highly useful for breeding new resistant canola cultivars. The identification of DEGs between inoculated plants carrying and not carrying Rcr1 is an important step towards understanding of specific metabolic/signaling pathways in clubroot resistance mediated by Rcr1. This information may help judicious use of CR genes with complementary resistance mechanisms for durable clubroot resistance. PMID- 25532523 TI - Supporting health promotion practitioners to undertake evaluation for program development. AB - BACKGROUND: The vital role of evaluation as integral to program planning and program development is well supported in the literature, yet we find little evidence of this in health promotion practice. Evaluation is often a requirement for organisations supported by public funds, and is duly undertaken, however the quality, comprehensiveness and use of evaluation findings are lacking. Practitioner peer-reviewed publications presenting evaluation work are also limited. There are few published examples where evaluation is conducted as part of a comprehensive program planning process or where evaluation findings are used for program development in order to improve health promotion practice. DISCUSSION: For even the smallest of programs, there is a diverse array of evaluation that is possible before, during and after program implementation. Some types of evaluation are less prevalent than others. Data that are easy to collect or that are required for compliance purposes are common. Data related to how and why programs work which could be used to refine and improve programs are less commonly collected. This finding is evident despite numerous resources and frameworks for practitioners on how to conduct effective evaluation and increasing pressure from funders to provide evidence of program effectiveness. We identify several organisational, evaluation capacity and knowledge translation factors which contribute to the limited collection of some types of data. In addition, we offer strategies for improving health promotion program evaluation and we identify collaboration of a range of stakeholders as a critical enabler for improved program evaluation. SUMMARY: Evaluation of health promotion programs does occur and resources for how to conduct evaluation are readily available to practitioners. For the purposes of program development, multi-level strategies involving multiple stakeholders are required to address the organisational, capacity and translational factors that affect practitioners' ability to undertake adequate evaluation. PMID- 25532524 TI - Kernel-based logistic regression model for protein sequence without vectorialization. AB - Protein sequence data arise more and more often in vaccine and infectious disease research. These types of data are discrete, high-dimensional, and complex. We propose to study the impact of protein sequences on binary outcomes using a kernel-based logistic regression model, which models the effect of protein through a random effect whose variance-covariance matrix is mostly determined by a kernel function. We propose a novel, biologically motivated, profile hidden Markov model (HMM)-based mutual information (MI) kernel. Hypothesis testing can be carried out using the maximum of the score statistics and a parametric bootstrap procedure. To improve the power of testing, we propose intuitive modifications to the test statistic. We show through simulation studies that the profile HMM-based MI kernel can be substantially more powerful than competing kernels, and that the modified test statistics bring incremental gains in power. We use these proposed methods to investigate two problems from HIV-1 vaccine research: (1) identifying segments of HIV-1 envelope (Env) protein that confer resistance to neutralizing antibody and (2) identifying segments of Env that are associated with attenuation of protective vaccine effect by antibodies of isotype A in the RV144 vaccine trial. PMID- 25532526 TI - Engineering a Blood Vessel Network Module for Body-on-a-Chip Applications. AB - The blood circulatory system links all organs from one to another to support and maintain each organ's functions consistently. Therefore, blood vessels have been considered as a vital unit. Engineering perfusable functional blood vessels in vitro has been challenging due to difficulties in designing the connection between rigid macroscale tubes and fragile microscale ones. Here, we propose a generalizable method to engineer a "long" perfusable blood vessel network. To form millimeter-scale vessels, fibroblasts were co-cultured with human umbilical vein endothelial cells (HUVECs) in close proximity. In contrast to previous works, in which all cells were permanently placed within the device, we developed a novel method to culture paracrine factor secreting fibroblasts on an O-ring shaped guide that can be transferred in and out. This approach affords flexibility in co-culture, where the effects of secreted factors can be decoupled. Using this, blood vessels with length up to 2 mm were successfully produced in a reproducible manner (>90%). Because the vessels form a perfusable network within the channel, simple links to inlets and outlets of the device allowed connections to the outside world. The robust and reproducible formation of in vitro engineered vessels can be used as a module to link various organ components as parts of future body-on-a-chip applications. PMID- 25532525 TI - Bayesian kernel machine regression for estimating the health effects of multi pollutant mixtures. AB - Because humans are invariably exposed to complex chemical mixtures, estimating the health effects of multi-pollutant exposures is of critical concern in environmental epidemiology, and to regulatory agencies such as the U.S. Environmental Protection Agency. However, most health effects studies focus on single agents or consider simple two-way interaction models, in part because we lack the statistical methodology to more realistically capture the complexity of mixed exposures. We introduce Bayesian kernel machine regression (BKMR) as a new approach to study mixtures, in which the health outcome is regressed on a flexible function of the mixture (e.g. air pollution or toxic waste) components that is specified using a kernel function. In high-dimensional settings, a novel hierarchical variable selection approach is incorporated to identify important mixture components and account for the correlated structure of the mixture. Simulation studies demonstrate the success of BKMR in estimating the exposure response function and in identifying the individual components of the mixture responsible for health effects. We demonstrate the features of the method through epidemiology and toxicology applications. PMID- 25532527 TI - New easy-to-use hybrid system for extracellular potential and impedance recordings. AB - The need for predictive, in vitro cardiac safety screening drives further development of automated, high-throughput-compatible drug evaluation based on cardiac cell preparations. Recently, pluripotent stem cells are evaluated as a new, more predictive model for cardiovascular risk assessment pertaining to in vitro assays. We present a new screening platform, the CardioExcyte 96, a hybrid instrument that combines impedance (cell contractility) with extracellular field potential (EFP) recordings. The electrophysiological measurements are noninvasive, label free and have a temporal resolution of 1 ms. This hybrid technology addresses the lack of easy-to-use high-throughput screening for in vitro assays and permits the reliable investigation of short- and long-term pharmacological effects. Several models of cardiomyocyte preparations were successfully validated for use with the CardioExcyte96. Furthermore, the pharmacological effects of a number of reference compounds were evaluated. Compound effects on cell monolayers of human-induced pluripotent stem cell derived cardiomyocytes are evaluated using a quasi-simultaneous hybrid recording mode that combines impedance and EFP readouts. A specialized software package for rapid data handling and real-time analysis was developed, which allows for comprehensive investigation of the cellular beat signal. Combining impedance readouts of cell contractility and EFP (microelectrode array-like) recordings, the system opens up new possibilities in the field of in vitro cardiac safety assessment. PMID- 25532528 TI - Sympathetic nerve stimulation, not circulating norepinephrine, modulates T-peak to T-end interval by increasing global dispersion of repolarization. AB - BACKGROUND: T-peak to T-end interval (Tp-e) is an independent marker of sudden cardiac death. Modulation of Tp-e by sympathetic nerve activation and circulating norepinephrine is not well understood. The purpose of this study was to characterize endocardial and epicardial dispersion of repolarization (DOR) and its effects on Tp-e with sympathetic activation. METHODS AND RESULTS: In Yorkshire pigs (n=13), a sternotomy was performed and the heart and bilateral stellate ganglia were exposed. A 56-electrode sock and 64-electrode basket catheter were placed around the epicardium and in the left ventricle (LV), respectively. Activation recovery interval, DOR, defined as variance in repolarization time, and Tp-e were assessed before and after left, right, and bilateral stellate ganglia stimulation and norepinephrine infusion. LV endocardial and epicardial activation recovery intervals significantly decreased, and LV endocardial and epicardial DOR increased during sympathetic nerve stimulation. There were no LV epicardial versus endocardial differences in activation recovery interval during sympathetic stimulation, and regional endocardial activation recovery interval patterns were similar to the epicardium. Tp-e prolonged during left (from 40.4+/-2.2 ms to 92.4+/-12.4 ms; P<0.01), right (from 47.7+/-2.6 ms to 80.7+/-11.5 ms; P<0.01), and bilateral (from 47.5+/-2.8 ms to 78.1+/-9.8 ms; P<0.01) stellate stimulation and strongly correlated with whole heart DOR during stimulation (P<0.001, R=0.86). Of note, norepinephrine infusion did not increase DOR or Tp-e. CONCLUSIONS: Regional patterns of LV endocardial sympathetic innervation are similar to that of LV epicardium. Tp-e correlated with whole heart DOR during sympathetic nerve activation. Circulating norepinephrine did not affect DOR or Tp-e. PMID- 25532529 TI - Spatial and time-course thermodynamics during pulmonary vein isolation using the second-generation cryoballoon in a canine in vivo model. AB - BACKGROUND: Thermodynamics in the left atrium-pulmonary vein (PV) junction, phrenic nerve, and esophagus during PV isolation (PVI) using the second generation cryoballoon are not known. METHODS AND RESULTS: Twenty dogs underwent PVI using second-generation cryoballoon. Ablations were performed for <=2 deliveries based on PVI without a bonus freeze. Inner balloon, balloon surface, and tissue temperatures were monitored during cryoablation. The tissue thermocouples were placed on the epicardial surface of the left atrium-PV junction, as well as on the phrenic nerve and within the esophagus. A total of 259 cryoballoon and 229 tissue tissue thermocouples profiles during 53 cryoablations of 40 PVs were analyzed. Acutely, PVI was achieved in 36 of 40 PVs (90%). Conductive tissue cooling spread radially from the balloon-left atrium-PV contact point. The lowest tissue temperatures were dependent on the distance of the tissue thermocouples to the balloon surface (r=0.85; P<0.001). In addition, blood flow leaks around the balloon had a warming effect on the balloon and tissue temperature profiles. Chronic isolation (mean, 48+/-16 days) was achieved in 27 of 36 PVs (75%). In 8 of 9 acutely isolated but with chronic reconnection PVs, the blood flow leak location was concordant with chronic reconnection gap. Although only 1 esophageal ulcerated lesion was observed, neither phrenic nerve palsy nor severe PV stenosis was seen in any dogs. CONCLUSIONS: Variance in tissue thermodynamics during cryothermal ablation depends on the distance from balloon and peri-balloon blood flow leaks. This information may be useful for successful PVI without severe complications. PMID- 25532530 TI - The place of RNA in the origin and early evolution of the genetic machinery. AB - The extant genetic machinery revolves around three interrelated polymers: RNA, DNA and proteins. Two evolutionary views approach this vital connection from opposite perspectives. The RNA World theory posits that life began in a cold prebiotic broth of monomers with the de novo emergence of replicating RNA as functionally self-contained polymer and that subsequent evolution is characterized by RNA -> DNA memory takeover and ribozyme -> enzyme catalyst takeover. The FeS World theory posits that life began as an autotrophic metabolism in hot volcanic-hydrothermal fluids and evolved with organic products turning into ligands for transition metal catalysts thereby eliciting feedback and feed-forward effects. In this latter context it is posited that the three polymers of the genetic machinery essentially coevolved from monomers through oligomers to polymers, operating functionally first as ligands for ligand accelerated transition metal catalysis with later addition of base stacking and base pairing, whereby the functional dichotomy between hereditary DNA with stability on geologic time scales and transient, catalytic RNA with stability on metabolic time scales existed since the dawn of the genetic machinery. Both approaches are assessed comparatively for chemical soundness. PMID- 25532532 TI - Intrapartum anti-disseminated intravascular coagulation therapy leading to successful vaginal delivery following intrauterine fetal death caused by placental abruption: a case report. AB - INTRODUCTION: Disseminated intravascular coagulation due to placental abruption with intrauterine fetal death is not uncommon. It can result in increased maternal mortality rates and the need for hysterectomy or greater transfusion volumes if the delivery is not completed within six to eight hours. However, consensus is lacking regarding the delivery approach for cases in which delivery is prolonged. CASE PRESENTATION: A 37-year-old Japanese woman was transported to our tertiary center two and a half hours after the onset of labor because of a diagnosis of placental abruption with intrauterine fetal death at 40 weeks and three days' gestation. On arrival, although severe hypofibrinogenemia was observed, there was no external hemorrhage. Because her cervical canal dilation was good (Bishop score, 7), labor was induced using oxytocin. Anti-disseminated intravascular coagulation therapy was simultaneously started via transfusion. After her hypofibrinogenemia resolved, delivery progressed rapidly, and the fetus was delivered approximately 10 hours after the onset. To reduce postpartum hemorrhage, 6g of fibrinogen concentrate and tranexamic acid, an antifibrinolytic agent, were administered immediately before extraction of the dead fetus and placenta. Although the amount of intrapartum hemorrhage was 1824g, there was no abnormal bleeding after delivery, and our patient was discharged three days later. CONCLUSION: In cases of placental abruption complicated with disseminated intravascular coagulation, intrapartum administration of coagulation factors can simultaneously promote effective labor and correct hypofibrinogenemia, enabling minimally invasive vaginal delivery. PMID- 25532533 TI - Assisted reproductive technology: an overview of Cochrane reviews. AB - BACKGROUND: As many as one in six couples will encounter problems with fertility, defined as failure to achieve a clinical pregnancy after regular intercourse for 12 months. Increasingly, couples are turning to assisted reproductive technology (ART) for help with conceiving and ultimately giving birth to a healthy live baby of their own. Fertility treatments are complex, and each ART cycle consists of several steps. If one of the steps is incorrectly applied, the stakes are high as conception may not occur. With this in mind, it is important that each step of the ART cycle is supported by good evidence from well-designed studies. OBJECTIVES: To summarise the evidence from Cochrane systematic reviews on procedures and treatment options available to couples with subfertility undergoing assisted reproductive technology (ART). METHODS: Published Cochrane systematic reviews of couples undergoing ART (in vitro fertilisation or intracytoplasmic sperm injection) were eligible for inclusion in the overview. We also identified Cochrane reviews in preparation, for future inclusion.The outcomes of the overview were live birth (primary outcome), clinical pregnancy, multiple pregnancy, miscarriage and ovarian hyperstimulation syndrome (secondary outcomes). Studies of intrauterine insemination and ovulation induction were excluded.Selection of systematic reviews, data extraction and quality assessment were undertaken in duplicate. Review quality was assessed by using the AMSTAR tool. Reviews were organised by their relevance to specific stages in the ART cycle. Their findings were summarised in the text and data for each outcome were reported in 'Additional tables'. MAIN RESULTS: Fifty-eight systematic reviews published in The Cochrane Library were included. All were high quality. Thirty two reviews identified interventions that were effective (n = 19) or promising (n = 13), 14 reviews identified interventions that were either ineffective (n = 3) or possibly ineffective (n=11), and 12 reviews were unable to draw conclusions due to lack of evidence.An additional 11 protocols and one title were identified for future inclusion in this overview. AUTHORS' CONCLUSIONS: This overview provides the most up to date evidence on ART cycles from systematic reviews of randomised controlled trials. Fertility treatments are costly and the stakes are high. Using the best available evidence to optimise outcomes is best practice. The evidence from this overview could be used to develop clinical practice guidelines and protocols for use in daily clinical practice, in order to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation and ovarian hyperstimulation syndrome. PMID- 25532534 TI - A bioengineered murine model using CD24+CD44+ pancreatic cancer stem cells for chemotherapy study. AB - In this work we first developed a murine pancreatic tumor model using CD24(+)CD44(+) pancreatic cancer stem cells (CSC) supported by an electrospun scaffold. Unlike conventional models, the use of CSC and the scaffold, which were biologically and chemically defined, afforded scientists a reliable platform to evaluate novel chemotherapy regimens. CD24(+)CD44(+) CSC successfully initiated tumorigenesis in vitro on the scaffold without suffering apoptosis, evidencing the lack of cytotoxicity of scaffolding materials. Also, the scaffold contributed to the acceleration of in vivo tumorigenesis and increased the likelihood of tumor formation. Using this model, we set out to explore the effectiveness of irinotecan/gemcitabine (IRIN-GEM), a chemotherapy regimen, for pancreatic cancer. Our study showed that IRIN-GEM induced a tumor regression whereas gemcitabine alone could only arrest the tumor growth. Further study suggested that the superior performance of IRIN-GEM could be attributed to its capacity to demolish the CD24(+)CD44(+) CSC sub-population by inducing a large-scale apoptosis. The use of highly proliferative yet homogenous CD24(+)CD44(+) CSC along with a chemically defined scaffold accelerated the tumor formation and significantly reduced the variability associated with conventional murine models. Armed with this new model, we discovered that IRIN-GEM would be a promising chemotherapy candidate for patients with advanced pancreatic cancer. PMID- 25532531 TI - Synthetic Biology: A Bridge between Artificial and Natural Cells. AB - Artificial cells are simple cell-like entities that possess certain properties of natural cells. In general, artificial cells are constructed using three parts: (1) biological membranes that serve as protective barriers, while allowing communication between the cells and the environment; (2) transcription and translation machinery that synthesize proteins based on genetic sequences; and (3) genetic modules that control the dynamics of the whole cell. Artificial cells are minimal and well-defined systems that can be more easily engineered and controlled when compared to natural cells. Artificial cells can be used as biomimetic systems to study and understand natural dynamics of cells with minimal interference from cellular complexity. However, there remain significant gaps between artificial and natural cells. How much information can we encode into artificial cells? What is the minimal number of factors that are necessary to achieve robust functioning of artificial cells? Can artificial cells communicate with their environments efficiently? Can artificial cells replicate, divide or even evolve? Here, we review synthetic biological methods that could shrink the gaps between artificial and natural cells. The closure of these gaps will lead to advancement in synthetic biology, cellular biology and biomedical applications. PMID- 25532535 TI - Effect of crotamine, a cell-penetrating peptide, on blastocyst production and gene expression of in vitro fertilized bovine embryos. AB - The present study investigated the effects of crotamine, a cell-penetrating peptide from rattlesnake venom, at different exposure times and concentrations, on both developmental competence and gene expression (ATP1A1, AQP3, GLUT1 and GLUT3) of in vitro fertilized (IVF) bovine embryos. In Experiment 1, presumptive zygotes were exposed to 0.1 MUM crotamine for 6, 12 or 24 h and control groups (vehicle and IVF) were included. In Experiment 2, presumptive zygotes were exposed to 0 (vehicle), 0.1, 1 and 10 MUM crotamine for 24 h. Additionally, to visualize crotamine uptake, embryos were exposed to rhodamine B-labelled crotamine and subjected to confocal microscopy. In Experiment 1, no difference (P > 0.05) was observed among different exposure times and control groups for cleavage and blastocyst rates and total cells number per blastocyst. Within each exposure time, mRNA levels were similar (P > 0.05) in embryos cultured with or without crotamine. In Experiment 2, concentrations as high as 10 MUM crotamine did not affect (P > 0.05) the blastocyst rate. Crotamine at 0.1 and 10 MUM did not alter mRNA levels when compared with the control (P > 0.05). Remarkably, only 1 MUM crotamine decreased both ATP1A1 and AQP3 expression levels relative to the control group (P < 0.05). Also, it was possible to visualize the intracellular localization of crotamine. These results indicate that crotamine can translocate intact IVF bovine embryos and its application in the culture medium is possible at concentrations from 0.1-10 MUM for 6-24 h. PMID- 25532537 TI - Review of experimental and clinical studies of autoimmune sensorineural hearing loss. AB - The purpose of this review was to analyze recent studies, both clinical and experimental, on diagnosis and treatment of autoimmune sensorineural hearing loss (ASNHL). Relevant studies were identified by searching Chinese Biomedical Literature Database and China Academic Journals Full-text Database for articles published nationally during the period of 1993-2013. The manuscripts were analyzed for the following aspects: selection of patients, sample size, presence of control group, experimental methods, study outcomes including audiological evaluation results, and efficacy of treatment. Forty-one manuscripts were identified including 12 reviews, 2 case reports, 20 experimental studies, and 7 clinical studies. The patient numbers in clinical studies ranged from 14 to 71 patients. Five clinical studies included control group of healthy individuals, while further two studies had no control group. Patients with ASNHL were treated with corticosteroids (prednisone or dexamethasone) in all seven clinical studies. However, statistical analyses of therapeutic efficacy were not carried out. Animal models were developed by immunization with allogeneic inner ear antigen, and some pathological changes were not specific to the disease. Experimental animals also had various degrees of changes in auditory brainstem response. Treatment guidelines need to be developed, while specific criteria of treatment efficacy need to be established. Further research is needed to demonstrate that experimental ASNHL resembles pathophysiologically the clinical situation. PMID- 25532536 TI - Early changes of the kinetics of monocyte trem-1 reflect final outcome in human sepsis. AB - BACKGROUND: TREM-1 (triggering receptor expressed on myeloid cells), a receptor expressed on neutrophils and monocytes, is upregulated in sepsis and seems to tune the inflammatory response. We explored the expression of TREM-1 at the gene level and on cell membranes of monocytes and association with clinical outcome. METHODS: Peripheral venous blood was sampled from 75 septic patients (39 patients with sepsis, 25 with severe sepsis and 11 with septic shock) on sepsis days 1, 3 and 7. TREM-1 on monocytes was measured by flow cytometry; gene expression of TREM-1 in circulating mononuclear cells was assessed by real-time PCR. sTREM-1 was measured in serum by an enzyme immunoassay. RESULTS: Although surface TREM-1, sTREM-1 and TREM-1 gene expression did not differ between sepsis, severe sepsis and septic shock on day 1, survivors had greater expression of surface TREM-1 on days 3 and 7 compared to non-survivors. sTREM-1 on non-survivors decreased on day 3 compared to baseline. Patients with increase of monocyte gene expression of TREM-1 from day 1 to day 3 had prolonged survival compared to patients with decrease of gene expression of TREM-1 from day 1 to day 3 (p: 0.031). CONCLUSIONS: Early decrease of gene expression of TREM-1 in monocytes is associated with poor outcome. A reciprocal decrease of the pro-inflammatory surface receptor TREM-1 linked with sepsis-induced immunosuppression may be part of the explanation. PMID- 25532538 TI - Metformin: the past, presence, and future. AB - The authors trace the history of metformin and its clinical use to the present day. Recent insights into its mode of action and latest data from experimental and clinical medicine have unraveled novel properties of metformin, which may be particularly useful in the treatment of conditions other than diabetes. Results of ongoing clinical trials will show whether or not the hypoglycemic effect of metformin will become only one of the many to be employed in clinical practice. PMID- 25532539 TI - Interface structure in Cu/Ta2O5/Pt resistance switch: a first-principles study. AB - The interface structures of a Cu/Ta2O5/Pt resistance switch under various oxidation conditions have been examined from first-principles. The O-rich Cu/Ta2O5 interface is found to be stable within a wide range of O chemical potentials. In this interface structure, a considerable number of interface Cu atoms tend to migrate to the amorphous Ta2O5 (a-Ta2O5) layer, which causes the formation of the Cu2O layer. The interface Cu atoms become more ionized with an increase in the interface O concentration and/or temperature. These ionized Cu(+) ions could function as one of the main sources for the formation of conduction filaments in the Cu/a-Ta2O5/Pt resistance switch. In contrast, the ionization of the interface Cu atoms is not observed in the Cu/crystal-Ta2O5 interface primarily due to the much lower Cu ionic conductivity in crystal-Ta2O5 than that in amorphous state. In addition, the Pt electrode could not be ionized, irrespective of the interface O concentration and temperature. The formation of interface O vacancies in Pt/Ta2O5 is always energetically more stable than that in Cu/Ta2O5, which may be partly responsible for the cone shape of conduction filament formed in the Cu/a-Ta2O5/Pt resistance switch, where the base of the cone lies on the Pt/Ta2O5 interface. PMID- 25532540 TI - Pretransplant replacement of donor liver grafts with recipient Kupffer cells attenuates liver graft rejection in rats. AB - BACKGROUND AND AIM: Rejection of liver grafts is a difficult issue that has not been resolved. Preoperative replacement of liver cells in the graft with cells from the intended recipient may attenuate rejection. We investigated whether preoperative transplant of recipient bone marrow cells (BMCs) to the donor replaced liver allograft cells and attenuated rejection. METHODS: We used a rat model of allogeneic liver transplant (LT) from Dark Agouti (DA) to Lewis (LEW) rats. In BMC group, DA rats received BMC transplants from LacZ-transgenic LEW rats at 1 week before LT. In the control group, DA rats received no preoperative treatment. We evaluated graft damage at 7 days after LT and the survival of the recipient rats. RESULTS: Rats in the BMC group experienced prolonged survival that was abrogated by the administration of gadolinium chloride to donors at 24 h before LT. Serum concentrations of total bilirubin and hyaluronic acid on day 7 were significantly lower in the BMC group, and histopathological analyses revealed that rejection of the liver graft was attenuated. X-gal staining and immunohistostaining of the liver graft revealed that BMCs engrafted in the sinusoidal space differentiated into Kupffer cells. CONCLUSIONS: Preoperative transplant of recipient BMCs to LT donors replaced donor Kupffer cells and attenuated post-LT rejection, indicating that this strategy may increase the success of LT. PMID- 25532541 TI - Radiological dose rates to marine fish from the Fukushima Daiichi accident: the first three years across the North Pacific. AB - A more complete record is emerging of radionuclide measurements in fish tissue, sediment, and seawater samples from near the Fukushima Daiichi Nuclear Power Plant (FDNPP) and across the Pacific Ocean. Our analysis of publicly available data indicates the dose rates to the most impacted fish species near the FDNPP (median 1.1 mGy d(-1), 2012-2014 data) have remained above benchmark levels for potential dose effects at least three years longer than was indicated by previous, data-limited evaluations. Dose rates from (134,137)Cs were highest in demersal species with sediment-associated food chains and feeding behaviors. In addition to (134,137)Cs, the radionuclide (90)Sr was estimated to contribute up to approximately one-half of the total 2013 dose rate to fish near the FDNPP. Mesopelagic fish 100-200 km east of the FDNPP, coastal fish in the Aleutian Islands (3300 km), and trans-Pacific migratory species all had increased dose rates as a consequence of the FDNPP accident, but their total dose rates remained dominated by background radionuclides. A hypothetical human consumer of 50 kg of fish, gathered 3 km from the FDNPP in 2013, would have received a total committed effective dose of approximately 0.95 mSv a(-1) from combined FDNPP and ambient radionuclides, of which 0.13 mSv a(-1) (14%) was solely from the FDNPP radionuclides and below the 1 mSv a(-1) benchmark for public exposure. PMID- 25532542 TI - Ophthalmic & Physiological Optics, 90 years young. PMID- 25532543 TI - Hypermetropia or hyperopia? PMID- 25532544 TI - Modelling the effects of secondary spherical aberration on refractive error, image quality and depth of focus. AB - PURPOSE: To examine the role of Zernike secondary spherical aberration and its component terms on refraction, image quality and depth of focus. METHODS: Computational methods were used to define wavefronts with controlled levels of r(6) , r(4) and r(2) terms, and image quality associated with these terms for a range of target vergences. Target vergences that generated maximum image quality were used as an objective measures of refractive error. RESULTS: Unlike primary Zernike spherical aberration, which generates peak image quality with a near paraxial focus, in the absence of other higher order aberrations, peak image quality with secondary spherical aberration is achieved with a near marginal focus. When alone, positive primary and secondary spherical aberration induce small hyperopic shifts in refraction, but in the presence of other higher order aberrations, secondary spherical aberration can induce significant myopic shifts in refractive error, as predicted by the combined lower order r(4) & r(2) component of Z60. The predicted expansion in depth of focus associated with increased primary or secondary spherical aberration is mostly absent if a strict image quality criterion is applied. The expansion of depth of focus observed with a low image quality criterion when opposite sign Z40 and Z60 are combined is primarily due to the elevated r(4) term. CONCLUSIONS: Secondary Zernike spherical aberration can have a significant impact on refractive error, image quality and depth of focus, but mostly due to the lower order components within this polynomial. Our analysis shows that the r(6) term that defines secondary spherical aberration actually narrows rather than expands depth of focus, when in the presence of the r(4) term within Z60. Therefore, a multifocal lens generated with exclusively primary spherical aberration is likely to be more effective than one that includes opposite sign of primary and secondary spherical aberration. PMID- 25532545 TI - Peripheral nasal-temporal corneal asymmetry in relation to corneal thickness: a Scheimpflug imaging study. AB - PURPOSE: To investigate the asymmetry of the peripheral cornea up to 5 mm nasally and temporally from the centre and to assess correlations with regional peripheral corneal thickness. METHODS: Central and peripheral corneal thickness was measured by Scheimpflug imaging (Pentacam) in 113 eyes of 113 healthy, pre presbyopic Caucasian subjects. Absolute and relative corneal thickness were analysed in 1 mm steps up to 5 mm to the nasal and temporal sides with the corneal apex as the central reference point. Nasal-temporal asymmetry was calculated as the thickness ratio between corresponding off-centre thickness measurements. RESULTS: The mean (+/-SD) central corneal thickness was 552 +/- 36 MUm. CT increased by 22% at 4 mm temporally to 672 +/- 44 MUm, and 32% at 4 mm nasally to 731 +/- 45 MUm. The nasal-temporal asymmetry became greater with increasing distance from the corneal centre, with a mean difference of 59 +/- 22 MUm at 4 mm from the apex. The nasal-temporal thickness ratio, based on this difference, was significantly related to the relative temporal (r = -0.41, p < 0.001, simple linear regression) and nasal corneal thickness (r = 0.61, p < 0.001). CONCLUSIONS: A substantial and progressively increasing nasal-temporal asymmetry in corneal thickness has been confirmed by Scheimpflug imaging, which is related to the magnitude of corneal thickness at peripheral locations. Pachymetry output data and models, including volume calculations, that assume symmetry to the corneal thickness profile may not provide optimum metrics for planning and predicting the outcome of corneal refractive surgery procedures. PMID- 25532546 TI - Refractive indices used by the Haag-Streit Lenstar to calculate axial biometric dimensions. AB - PURPOSE: To estimate refractive indices used by the Lenstar biometer to translate measured optical path lengths into geometrical path lengths within the eye. METHODS: Axial lengths of model eyes were determined using the IOLMaster and Lenstar biometers; comparing those lengths gave an overall eye refractive index estimate for the Lenstar. Using the Lenstar Graphical User Interface, we noticed that boundaries between media could be manipulated and opposite changes in optical path lengths on either side of the boundary could be introduced. Those ratios were combined with the overall eye refractive index to estimate separate refractive indices. Furthermore, Haag-Streit provided us with a template to obtain 'air thicknesses' to compare with geometrical distances. RESULTS: The axial length estimates obtained using the IOLMaster and the Lenstar agreed to within 0.01 mm. Estimates of group refractive indices used in the Lenstar were 1.340, 1.341, 1.415, and 1.354 for cornea, aqueous, lens, and overall eye, respectively. Those refractive indices did not match those of schematic eyes, but were close in the cases of aqueous and lens. Linear equations relating air thicknesses to geometrical thicknesses were consistent with our findings. CONCLUSION: The Lenstar uses different refractive indices for different ocular media. Some of the refractive indices, such as that for the cornea, are not physiological; therefore, it is likely that the calibrations in the instrument correspond to instrument-specific corrections and are not the real optical path lengths. PMID- 25532547 TI - Multivariate methods to visualise colour-space and colour discrimination data. AB - PURPOSE: Despite most modern colour spaces treating colour as three-dimensional (3-D), colour data is usually not visualised in 3-D (and two-dimensional (2-D) projection-plane segments and multiple 2-D perspective views are used instead). The objectives of this article are firstly, to introduce a truly 3-D percept of colour space using stereo-pairs, secondly to view colour discrimination data using that platform, and thirdly to apply formal statistics and multivariate methods to analyse the data in 3-D. This is the first demonstration of the software that generated stereo-pairs of RGB colour space, as well as of a new computerised procedure that investigated colour discrimination by measuring colour just noticeable differences (JND). METHODS: An initial pilot study and thorough investigation of instrument repeatability were performed. Thereafter, to demonstrate the capabilities of the software, five colour-normal and one colour deficient subject were examined using the JND procedure and multivariate methods of data analysis. RESULTS: Scatter plots of responses were meaningfully examined in 3-D and were useful in evaluating multivariate normality as well as identifying outliers. The extent and direction of the difference between each JND response and the stimulus colour point was calculated and appreciated in 3-D. Ellipsoidal surfaces of constant probability density (distribution ellipsoids) were fitted to response data; the volumes of these ellipsoids appeared useful in differentiating the colour-deficient subject from the colour-normals. Hypothesis tests of variances and covariances showed many statistically significant differences between the results of the colour-deficient subject and those of the colour-normals, while far fewer differences were found when comparing within colour-normals. CONCLUSIONS: The 3-D visualisation of colour data using stereo pairs, as well as the statistics and multivariate methods of analysis employed, were found to be unique and useful tools in the representation and study of colour. Many additional studies using these methods along with the JND and other procedures have been identified and will be reported in future publications. PMID- 25532548 TI - Understanding visual impairment in UK Biobank. PMID- 25532549 TI - Author's reply: To PMID 24888710. PMID- 25532552 TI - Butalbital and pediatric headache: stay off the downward path. AB - Despite limited evidence from the literature surrounding safety or efficacy, butalbital-containing medicines (BCMs) have maintained their rank as "go-to" prescribed migraine and headache relief drugs in the United States, despite bans on these barbiturates in Germany and other European countries. Providers at the Pediatric Headache Program at Boston Children's Hospital recommend that clinicians prescribe triptan-based medications instead of BCMs, given the known negative side effects of BCMs on the general population, and the uncertain longitudinal trajectory of BCMs on developing brains. PMID- 25532553 TI - Patterns of health risk behaviors among job-seekers: a latent class analysis. AB - OBJECTIVES: To examine the patterning of four behavior-related health risk factors (tobacco smoking, risky alcohol drinking, overweight, and physical inactivity) among job-seekers and to investigate socio-demographic and health related predictors of patterning. METHODS: The sample of 3,684 female and 4,221 male job-seekers was proactively recruited at three job agencies in northeastern Germany in 2008/09. Participants provided data on socio-demographics, substance use, body mass index, physical activity and self-rated health. Latent class analyses (LCA) and multinomial logistic regression analyses were applied to identify health risk patterns and possible predictors of patterning, respectively. RESULTS: Forty-three percent of the female and 58% of the male participants had two or more health risk factors. LCA revealed three similar patterns for women and men: Substance use (tobacco smoking, risky drinking), Non exercising overweight (physical inactivity, overweight/obesity) and Health conscious (non-smoking, low-risk drinking, under-/normal weight, physical activity). Age, education, marital status, life-time unemployment and self-rated health were significantly associated with patterning in both genders. CONCLUSIONS: Our results may help to define target populations for improving health behaviors among job-seekers. PMID- 25532554 TI - Perceived problems with computer gaming and Internet use are associated with poorer social relations in adolescence. AB - OBJECTIVES: Young people's engagement in electronic gaming and Internet communication have caused concerns about potential harmful effects on their social relations, but the literature is inconclusive. The aim of this paper was to examine whether perceived problems with computer gaming and Internet communication are associated with young people's social relations. METHODS: Cross sectional questionnaire survey in 13 schools in the city of Aarhus, Denmark, in 2009. Response rate 89%, n = 2,100 students in grades 5, 7, and 9. Independent variables were perceived problems related to computer gaming and Internet use, respectively. Outcomes were measures of structural (number of days/week with friends, number of friends) and functional (confidence in others, being bullied, bullying others) dimensions of student's social relations. RESULTS: Perception of problems related to computer gaming were associated with almost all aspects of poor social relations among boys. Among girls, an association was only seen for bullying. For both boys and girls, perceived problems related to Internet use were associated with bullying only. CONCLUSIONS: Although the study is cross sectional, the findings suggest that computer gaming and Internet use may be harmful to young people's social relations. PMID- 25532555 TI - Excessive internet use in European adolescents: what determines differences in severity? AB - OBJECTIVES: This study investigated the differences between non-excessive, moderately excessive, and highly excessive internet use among adolescents. These differences were explored in terms of personal characteristics, psychological difficulties, environmental factors, and manner of internet use. METHODS: A representative sample was investigated, consisting of 18,709 adolescents aged 11 16 and their parents, from 25 European countries. Excessive internet use was measured using a five item scale covering following factors: salience, conflict, tolerance, withdrawal symptoms, and relapse and reinstatement. The main data analysis utilised multinomial and binary logistic regression models. RESULTS: The vast majority of respondents reported no signs of excessive internet use. Moderately excessive users (4.4%) reported higher emotional and behavioural difficulties, but also more sophisticated digital skills and a broader range of online activities. The highly excessive users (1.4%) differed from the non excessive and moderately excessive users in their preference for online games and in having more difficulties with self-control. CONCLUSIONS: Adolescents who struggle with attention and self-control and who are inclined toward online gaming may be especially vulnerable to the otherwise uncommon phenomenon of excessive internet use. PMID- 25532556 TI - Comparative analysis of undernutrition screening and diagnostic tools as predictors of hospitalisation costs. AB - BACKGROUND: Undernutrition is associated with higher hospitalisation costs. The present study aims (i) to explore whether undernutrition status at hospital admission, as evaluated by different screening and diagnostic tools, can predict patient's hospitalisation costs and (ii) to provide an updated economic analysis of undernutrition burden. METHODS: A prospective study was conducted in a university hospital. Participants' (n = 637) nutritional risk was evaluated within 72 h of admission using the Nutritional Risk Screening (NRS-2002) and the Malnutrition Universal Screening Tool ('MUST'). Undernutrition status was determined by Academy of Nutrition and Dietetics (AND) and American Society for Parenteral and Enteral Nutrition (ASPEN) recommended clinical characteristics and by the Patient Generated Subjective Global Assessment (PG-SGA). The hospitalisation cost was calculated for each inpatient using the diagnosis related group system. Multivariable linear regression analysis was conducted to identify predictors of hospitalisation costs via percentage deviation from the mean cost, after adjustment for patients' characteristics and comorbidities. RESULTS: Undernutrition risk according to NRS-2002 and high undernutrition risk according to 'MUST' increased patient's costs, respectively, by 21.1% [95% confidence interval (CI) = 9.0-33.2%] and 28.8% (95% CI = 13.7-39.9%). Severe undernutrition by AND-ASPEN recommended clinical characteristics and by PG-SGA was also associated with higher hospitalisation costs, respectively 19.4% (95% CI = 7.3-31.5%) and 27.5% (95% CI = 14.0-41.1%). The cost of a nutritionally-at-risk or undernourished patient is between ?416 (95% CI = ?156-675) and ?617 (95% CI = ?293-855) higher than the average of the respective diagnosis-related group. CONCLUSIONS: Undernutrition is a predictor of hospitalisation costs, increasing costs by between 19% and 29%. Undernutrition screening tools have an ability for predicting hospitalisation costs similar to that of diagnostic tools. An updated analysis of undernutrition associated costs was provided, highlighting the economic burden of undernutrition. PMID- 25532557 TI - Pre-operative baroreflex sensitivity and efferent cardiac parasympathetic activity are correlated with post-operative pain. AB - BACKGROUND: A maladaptation of the autonomic nervous system may been seen in patients with chronic pain that includes persistent changes in the autonomic tone, increased heart rate, and reduced heart rate variability and baroreflex sensitivity. Baroreflex sensitivity and acute pain intensity have been reported to be inversely correlated. However, it is unknown whether the same correlation applies with regard to post-operative pain. In the present study, autonomic function was measured in patients scheduled for minor hand surgery and correlated with early and persistent pain after the procedure. Thus, the cause (autonomic imbalance) was present before the effect (post-operative pain). Our primary hypothesis was that a lower level of pre-operative baroreflex sensitivity is correlated with increased early post-operative pain. METHODS: There were 30 patients included and scheduled for open carpal tunnel surgery. Baroreflex sensitivity and heart rate variability were measured before surgery. Efferent cardiac parasympathetic activity was estimated by power spectral analysis of heart rate variability. Post-operative pain was recorded daily for 6 weeks (early post-operative pain) and for 1 week 1 year after surgery (persistent post operative pain). RESULTS: Pre-operative baroreflex sensitivity correlated negatively with early (P=0.05) and persistent (P=0.04) post-operative pain. Efferent cardiac parasympathetic activity correlated negatively with early (P=0.03) but not persistent post-operative pain (P=0.12). CONCLUSIONS: The findings suggest that a low pre-operative level of baroreflex sensitivity is associated with higher post-operative pain intensity. To our knowledge, this is the first study to show the correlation between baroreflex sensitivity and post operative pain. PMID- 25532558 TI - Right-lateralized alpha desynchronization during regularity discrimination: hemispheric specialization or directed spatial attention? AB - When actively classifying abstract patterns according to their regularity, alpha desynchronization (ERD) becomes right lateralized over posterior brain areas. This could reflect temporary enhancement of contralateral visual inputs and specifically a shift of attention to the left, or right hemisphere specialization for regularity discrimination. This study tested these competing hypotheses. Twenty-four participants discriminated between dot patterns containing a reflection or a translation. The direction of the transformation, which matched one half onto the other half, was either vertical or horizontal. The strategy of shifting attention to one side of the patterns would not produce lateralized ERD in the horizontal condition. However, right-lateralized ERD was found in all conditions, regardless of orientation. We conclude that right hemisphere networks that incorporate the early posterior regions are specialized for regularity discrimination. PMID- 25532560 TI - MicroRNA156 as a promising tool for alfalfa improvement. AB - A precursor of miR156 (MsmiR156d) was cloned and overexpressed in alfalfa (Medicago sativa L.) as a means to enhance alfalfa biomass yield. Of the five predicted SPL genes encoded by the alfalfa genome, three (SPL6, SPL12 and SPL13) contain miR156 cleavage sites and their expression was down-regulated in transgenic alfalfa plants overexpressing miR156. These transgenic plants had reduced internode length and stem thickness, enhanced shoot branching, increased trichome density, a delay in flowering time and elevated biomass production. Minor effects on sugar, starch, lignin and cellulose contents were also observed. Moreover, transgenic alfalfa plants had increased root length, while nodulation was maintained. The multitude of traits affected by miR156 may be due to the network of genes regulated by the three target SPLs. Our results show that the miR156/SPL system has strong potential as a tool to substantially improve quality and yield traits in alfalfa. PMID- 25532559 TI - Proteome changes underpin improved meat quality and yield of chickens (Gallus gallus) fed the probiotic Enterococcus faecium. AB - BACKGROUND: Supplementation of broiler chicken diets with probiotics may improve carcass characteristics and meat quality. However, the underlying molecular mechanism remains unclear. In the present study, 2D-DIGE-based proteomics was employed to investigate the proteome changes associated with improved carcass traits and meat quality of Arbor Acres broilers (Gallus gallus) fed the probiotic Enterococcus faecium. RESULTS: The probiotic significantly increased meat colour, water holding capacity and pH of pectoral muscle but decreased abdominal fat content. These meat quality changes were related to the altered abundance of 22 proteins in the pectoral muscle following E. faecium feeding. Of these, 17 proteins have central roles in regulating meat quality due to their biological interaction network. Altered cytoskeletal and chaperon protein expression also contribute to improved water holding capacity and colour of meat, which suggests that upregulation of chaperon proteins maintains cell integrity and prevents moisture loss by enhancing folding and recovery of the membrane and cytoskeletal proteins. The down-regulation of beta-enolase and pyruvate kinase muscle isozymes suggests roles in increasing the pH of meat by decreasing the production of lactic acid. The validity of the proteomics results was further confirmed by qPCR. CONCLUSIONS: This study reveals that improved meat quality of broilers fed probiotics is triggered by proteome alterations (especially the glycolytic proteins), and provides a new insight into the mechanism by which probiotics improve poultry production. PMID- 25532561 TI - Detection and fine-mapping of SC7 resistance genes via linkage and association analysis in soybean. AB - Soybean mosaic virus (SMV) disease is one of the most serious and broadly distributed soybean (Glycine max (L.) Merr.) diseases. Here, we combine the advantages of association and linkage analysis to identify and fine-map the soybean genes associated with resistance to SMV strain SC7. A set of 191 soybean accessions from different geographic origins and 184 recombinant inbred lines (RILs) derived from Kefeng No.1 (resistant) * Nannong 1138-2 (susceptible) were used in this study. The SC7 resistance genes were previously mapped to a 2.65 Mb region on chromosome 2 and a 380 kb region on chromosome 13. Among 19 single nucleotide polymorphisms (SNPs) detected via association analysis in the study, the SNP BARC-021625-04157 was located in the 2.65 Mb region, and the SNP BARC 041671-08065 was located near the 380 kb region; three genes harboring the SNPs were probably related to SC7 resistance. The resistance gene associated with BARC 021625-04157 was then fine-mapped to a region of approximately 158 kb on chromosome 2 using 184 RILs. Among the 15 genes within this region, one NBS-LRR type gene, one HSP40 gene and one serine carboxypeptidase-type gene might be candidate SC7 resistance genes. These results will be useful for map-based cloning and marker-assisted selection in soybean breeding programs. PMID- 25532562 TI - Online health information - what the newspapers tell their readers: a systematic content analysis. AB - BACKGROUND: This study investigated the nature of newspaper reporting about online health information in the UK and US. Internet users frequently search for health information online, although the accuracy of the information retrieved varies greatly and can be misleading. Newspapers have the potential to influence public health behaviours, but information has been lacking in relation to how newspapers portray online health information to their readers. METHODS: The newspaper database Nexis(r)UK was searched for articles published from 2003 - 2012 relating to online health information. Systematic content analysis of articles published in the highest circulation newspapers in the UK and US was performed. A second researcher coded a 10% sample to establish inter-rater reliability of coding. RESULTS: In total, 161 newspaper articles were included in the analysis. Publication was most frequent in 2003, 2008 and 2009, which coincided with global threats to public health. UK broadsheet newspapers were significantly more likely to cover online health information than UK tabloid newspapers (p = 0.04) and only one article was identified in US tabloid newspapers. Articles most frequently appeared in health sections. Among the 79 articles that linked online health information to specific diseases or health topics, diabetes was the most frequently mentioned disease, cancer the commonest group of diseases and sexual health the most frequent health topic. Articles portrayed benefits of obtaining online health information more frequently than risks. Quotations from health professionals portrayed mixed opinions regarding public access to online health information. 108 (67.1%) articles directed readers to specific health-related web sites. 135 (83.9%) articles were rated as having balanced judgement and 76 (47.2%) were judged as having excellent quality reporting. No difference was found in the quality of reporting between UK and US articles. CONCLUSIONS: Newspaper coverage of online health information was low during the 10-year period 2003 to 2012. Journalists tended to emphasise the benefits and understate the risks of online health information and the quality of reporting varied considerably. Newspapers directed readers to sources of online health information during global epidemics although, as most articles appeared in the health sections of broadsheet newspapers, coverage was limited to a relatively small readership. PMID- 25532563 TI - Aaptamine derivatives with antifungal and anti-HIV-1 activities from the South China Sea sponge Aaptos aaptos. AB - Five new alkaloids of aaptamine family, compounds (1-5) and three known derivatives (6-8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1-2 are characterized with triazapyrene lactam skeleton, whereas compounds 4-5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 MUg/mL. Compounds 7-8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 MUM. PMID- 25532564 TI - An update on 2,5-diketopiperazines from marine organisms. AB - 2,5-Diketopiperazines (2,5-DKPs) are an important category of structurally diverse cyclic dipeptides with prominent biological properties. These 2,5-DKPs have been obtained from a variety of natural resources, including marine organisms. Because of the increasing numbers and biological importance of these compounds, this review covers 90 marine originated 2,5-DKPs that were reported from 2009 to the first half-year of 2014. The review will focus on the structure characterizations, biological properties and proposed biosynthetic processes of these compounds. PMID- 25532565 TI - Design of chitosan and its water soluble derivatives-based drug carriers with polyelectrolyte complexes. AB - Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail. PMID- 25532566 TI - Multiple beneficial lipids including lecithin detected in the edible invasive mollusk Crepidula fornicata from the French Northeastern Atlantic coast. AB - The invasive mollusk Crepidula fornicata, occurring in large amounts in bays along the French Northeastern Atlantic coasts, may have huge environmental effects in highly productive ecosystems where shellfish are exploited. The present study aims at determining the potential economic value of this marine species in terms of exploitable substances with high added value. Lipid content and phospholipid (PL) composition of this mollusk collected on the Bourgneuf Bay were studied through four seasons. Winter specimens contained the highest lipid levels (5.3% dry weight), including 69% of PLs. Phosphatidylcholine (PC) was the major PL class all year, accounting for 63.9% to 88.9% of total PLs. Consequently, the winter specimens were then investigated for PL fatty acids (FAs), and free sterols. Dimethylacetals (DMAs) were present (10.7% of PL FA + DMA mixture) revealing the occurrence of plasmalogens. More than forty FAs were identified, including 20:5n-3 (9.4%) and 22:6n-3 (7.3%) acids. Fourteen free sterols were present, including cholesterol at 31.3% of the sterol mixture and about 40% of phytosterols. These data on lipids of C. fornicata demonstrate their positive attributes for human nutrition and health. The PL mixture, rich in PC and polyunsaturated FAs, offers an interesting alternative source of high value added marine lecithin. PMID- 25532567 TI - Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis. AB - INTRODUCTION: The safety of arterial hyperoxia is under increasing scrutiny. We performed a systematic review of the literature to determine whether any association exists between arterial hyperoxia and mortality in critically ill patient subsets. METHODS: Medline, Thomson Reuters Web of Science and Scopus databases were searched from inception to June 2014. Observational or interventional studies evaluating the relationship between hyperoxia (defined as a supranormal arterial O2 tension) and mortality in adult intensive care unit (ICU) patients were included. Studies primarily involving patients with exacerbations of chronic pulmonary disease, acute lung injury and perioperative administration were excluded. Adjusted odds ratio (OR) of patients exposed versus those not exposed to hyperoxia were extracted, if available. Alternatively, unadjusted outcome data were recorded. Data on patients, study characteristics and the criteria used for defining hyperoxia exposure were also extracted. Random effects models were used for quantitative synthesis of the data, with a primary outcome of hospital mortality. RESULTS: In total 17 studies (16 observational, 1 prospective before-after) were identified in different patient categories: mechanically ventilated ICU (number of studies (k) = 4, number of participants (n) = 189,143), post-cardiac arrest (k = 6, n = 19,144), stroke (k = 2, n = 5,537), and traumatic brain injury (k = 5, n = 7,488). Different criteria were used to define hyperoxia in terms of PaO2 value (first, highest, worst, mean), time of assessment and predetermined cutoffs. Data from studies on ICU patients were not pooled because of extreme heterogeneity (inconsistency (I(2)) 96.73%). Hyperoxia was associated with increased mortality in post-cardiac arrest patients (OR = 1.42 (1.04 to 1.92) I(2) 67.73%) stroke (OR = 1.23 (1.06 to 1.43) I(2) 0%) and traumatic brain injury (OR = 1.41 (1.03 to 1.94) I(2) 64.54%). However, these results are limited by significant heterogeneity between studies. CONCLUSIONS: Hyperoxia may be associated with increased mortality in patients with stroke, traumatic brain injury and those resuscitated from cardiac arrest. However, these results are limited by the high heterogeneity of the included studies. PMID- 25532568 TI - Adult-onset Still's disease with disseminated intravascular coagulation and hemophagocytic syndrome: a case report. AB - BACKGROUND: Adult-onset Still's disease is a rare inflammatory condition of unknown origin characterized by high spiking fever, arthralgia, arthritis, myalgia, salmon-colored evanescent rash, and hepatosplenomegaly. The diagnosis of adult-onset Still's disease requires the exclusion of other possible disorders because it lacks specific clinical and histopathological findings. Adult-onset Still's disease rarely become fatal due to visceral involvements such as disseminated intravascular coagulation. CASE PRESENTATION: A 22-year-old Chinese female presented to our medical center with high spiking fever for one week, myalgia for two weeks, and arthralgia and pink maculopapular rash for four weeks. She developed disseminated intravascular coagulation on the fourth day after admission. There was no other explanation for the fever and rash, including infection, malignancy, and collagenosis. Together, the high spiking fever, salmon colored rash, splenomegaly, and excess hepatic enzyme, indicated adult-onset Still's disease based on the Yamaguchi criteria. Therefore, prednisolone therapy was initiated. The combination of nafamostat mesilate and prednisolone therapies caused a rapid reduction in the fever and rash. The inflammatory markers decreased immediately, and disseminated intravascular coagulation improved. Her symptoms resolved with low-dose prednisolone treatment, and she was monitored thereafter at our outpatient clinic. CONCLUSION: The previous use of nonsteroidal anti-inflammatory drugs could have caused disseminated intravascular coagulation in this patient with adult-onset Still's disease. We propose that physicians should consider the possibility of disseminated intravascular coagulation as a complication during the course of adult-onset Still's disease and suggest that prednisolone therapy should be initiated in the early stages of adult-onset Still's disease. PMID- 25532569 TI - Effect of SMAD7 gene overexpression on TGF-beta1-induced profibrotic responses in fibroblasts derived from Peyronie's plaque. AB - Transforming growth factor-beta1 (TGF-beta1) has been identified as one of the most important fibrogenic cytokines associated with Peyronie's disease (PD). The mothers against decapentaplegic homolog 7 (SMAD7) is an inhibitory Smad protein that blocks TGF-beta signaling pathway. The aim of this study was to examine the anti-fibrotic effect of the SMAD7 gene in primary fibroblasts derived from human PD plaques. PD fibroblasts were pretreated with the SMAD7 gene and then stimulated with TGF-beta1. Treated fibroblasts were used for Western blotting, fluorescent immunocytochemistry, hydroxyproline determination, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. Overexpression of the SMAD7 gene inhibited TGF-beta1-induced phosphorylation and nuclear translocation of SMAD2 and SMAD3, transdifferentiation of fibroblasts into myofibroblasts, and quashed TGF-beta1 induced production of extracellular matrix protein and hydroxyproline. Overexpression of the SMAD7 gene decreased the expression of cyclin D1 (a positive cell cycle regulator) and induced the expression of poly (ADP-ribose) polymerase 1, which is known to terminate Smad-mediated transcription, in PD fibroblasts. These findings suggest that the blocking of the TGF-beta pathway by use of SMAD7 may be a promising therapeutic strategy for the treatment of PD. PMID- 25532570 TI - Serum 25-hydroxyvitamin D levels and testosterone deficiency in middle-aged Korean men: a cross-sectional study. AB - Previous studies have demonstrated that male hypogonadism is associated with a low level of vitamin D. However, no reports have investigated the effects of vitamin D on testosterone levels in Korean men. Our aim was to investigate whether testosterone levels are associated with serum vitamin D levels and whether seasonal variation exists. This cross-sectional study analyzed serum 25 hydroxyvitamin D [25(OH)D], total testosterone (TT), and free testosterone (FT) in 652 Korean men over 40 years of age who had undergone a comprehensive medical examination. The average age of the subjects was 56.7 +/- 7.9 years, and the mean serum 25(OH)D, TT and FT levels were 21.23 +/- 7.9 ng ml-1 , 4.70 +/- 1.6 ng ml-1 , and 8.12 +/- 3.3 pg ml-1 , respectively. In the multiple linear regression model, 25(OH)D showed positive association with TT (beta =0.137, P< 0.001) and FT (beta =0.103, P= 0.008). 25(OH)D and FT showed similar seasonal or monthly variation after adjustment for age. A vitamin D deficiency [25(OH)D < 20 ng ml-1 ] was associated with an increased risk of deficiencies of TT (<2.30 ng ml-1 ) (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.21-5.78, P= 0.014) and FT (<6.50 pg ml-1 ) (OR: 1.44; 95% CI: 1.01-2.06 P= 0.048) after adjusting for age, season, body mass index, body composition, chronic disease, smoking, and alcohol use. In conclusion, we demonstrated a positive correlation between 25(OH)D and testosterone, which showed similar seasonal variation in Korean men. PMID- 25532572 TI - Extended lymph node dissection for intermediate and high-risk prostate cancer: do we have all the evidence? PMID- 25532571 TI - Survey of knowledge, attitude, and practice regarding reproductive health among urban men in China: a descriptive study. AB - There has been little focus on men's reproductive health (RH) in China. This descriptive study conducted in Yiling District, Yichang, China, surveyed male knowledge of sexual physiology and RH to assess levels of knowledge, attitudes and practices (KAPs) regarding prevention of sexually transmitted diseases (STDs). A total of 3933 men, aged 18-59 years (mean, 40.3 years), were recruited by cluster random sampling. They completed a questionnaire in the presence of an interviewer, with items related to subject characteristics, RH knowledge, and subjective symptoms of the reproductive system. Physical examination and reproductive system disease diagnosis were performed. Participants' occupations were predominantly skilled labor (80.5%). Nearly four-fifths (78.5%) respondents had at least one reproductive disease. Over half of respondents were aware of and declared a positive attitude about sexual physiology and safe sex, and 70% of them selected to visit a doctor when they had a reproductive disorder. However, only 41.9% believed human immunodeficiency virus/acquired immunodeficiency syndrome could be transmitted through breastfeeding, and 64.6% incorrectly thought they could avoid contracting STDs by cleaning their genitals after intercourse. In addition, 45% discriminated against and were unwilling to be friends with infected persons. Nearly 45% of those with a reproductive system disorder refused to discuss it with friends or family members. These results indicate that this cohort of Chinese men had a certain degree of KAP about RH, whereas some aspects require further public health education in the general population. It is necessary to disseminate accurate knowledge of STD risk in China based on sociodemographic characteristics. PMID- 25532573 TI - Prostate cancer screening: and yet it moves! AB - The debate of prostate cancer (PCa) screening has been shaped over decades. There is a plethora of articles in the literature supporting as well as declining prostate-specific antigen (PSA) screening. Does screening decrease PCa mortality? With the long-term results of the European Randomized Study of Screening for Prostate (ERSPC) the answer is clearly YES. It moves! However, in medicine there are no benefits without any harm and thus, screening has to be performed in targeted and smart way-or in other words-in a risk-adapted fashion when compared with the way it was done in the past. Here, we discuss the main findings of the ERSPC trials and provide insights on how the future screening strategies should be implemented. PMID- 25532574 TI - The relationship between erectile function and complex panurethral stricture: a preliminary investigative and descriptive study. AB - The aim of this study was to evaluate erectile function in patients with panurethral stricture after urethral reconstruction. Totally, 65 patients were enrolled. Different urethral reconstructions were performed according to the details of urethral strictures. The erectile function was evaluated before and after surgery. The length and location of stricture and duration from initial diagnosis to operation were recorded. The International Index of Erectile Function-5 (IIEF-5) scores, the quality of life (QoL) scores and the maximal flow rate were obtained before and 3, 6, and 12 months after surgery. A significant improvement in QoL and maximal flow rate was observed 3, 6, and 12 months after surgery compared with those observed before surgery (P < 0.05). An impairment of erectile function was observed in patients with multi-site stricture 3 months after surgery (P < 0.05). Subsequently, these patients recovered 6 and 12 months after surgery. Three months after surgery, the IIEF-5 scores in patients with anterior urethral stricture were higher than those with multi-site stricture. Similar results were observed 6 and 12 months after surgery. No significant difference in age or duration from initial diagnosis to final operation was observed between patients with erectile dysfunction after surgery and patients with normal erectile function. However, a linear regressive relationship was detected between IIEF-5 scores and location of urethral stricture. Surgical reconstruction for treating panurethral strictures has limited effects on erectile function. The location of the stricture, particularly when extended to posterior urethra, was found to be associated with erectile function after surgery. PMID- 25532576 TI - Association of polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) with idiopathic azoospermia or oligospermia in Sichuan, China. AB - The reported effects of the glutathione S-transferase (GSTs) genes (GSTM1, GSTT1, and GSTP1) on male factor infertility have been inconsistent and even contradictory. Here, we conducted a case-control study to investigate the association between functionally important polymorphisms in GST genes and idiopathic male infertility. The study group consisted of 361 men with idiopathic azoospermia, 118 men with idiopathic oligospermia, and 234 age-matched healthy fertile male controls. Genomic DNA was extracted from the peripheral blood, and analyzed by polymerase chain reaction and restriction fragment length polymorphism analysis. There was a significant association between the GSTP1 variant genotype (Ile/Val + Val/Val) with idiopathic infertility risk (odds ratio [OR]: 1.53; 95% confidence interval [CI]: 1.11-2.11; P = 0.009). Similarly, a higher risk of infertility was noted in individuals carrying a genotype combination of GSTT1-null and GSTP1 (Ile/Val + Val/Val) (OR: 2.17; 95% CI: 1.43 3.31; P = 0.0002). These results suggest an increased risk of the GSTP1 variant genotype (Ile/Val + Val/Val) for developing male factor infertility. Our findings also underrate the significance of the effect of GSTM1 and/or GSTT1 (especially the former) in modulating the risk of male infertility in males from Sichuan, Southwest China. PMID- 25532575 TI - Diagnosis and management of testosterone deficiency. AB - Testosterone supplementation therapy (TST) use has dramatically increased over the past decade, due to the availability of newer agents, aggressive marketing, and an increasing incidence of testosterone deficiency (TD). Despite the increase in TST, a degree of ambiguity remains as to the exact diagnostic criteria of TD, and administration and monitoring of TST. One explanation for this phenomenon is the complex role testosterone plays in multiple physiologic pathways. Numerous medical co-morbidities and medications can alter testosterone levels resulting in a wide range of nonspecific clinical signs and symptoms of TD. The diagnosis is also challenging due to the lack of a definitive serum total testosterone level that reliably correlates with symptoms. This observation is particularly true in the aging male and is exacerbated by inconsistencies between different laboratory assays. Several prominent medical societies have developed guideline statements to clarify the diagnosis, but they differ from each other and with expert opinion in several ways. Aside from diagnostic dilemmas, there are numerous subtle advantages and disadvantages of the various testosterone agents to appreciate. The available TST agents have changed significantly over the past decade similar to the trends in the diagnosis of TD. Therefore, as the usage of TST increases, clinicians will be challenged to maintain an up-to-date understanding of TD and TST. The purpose of this review is to provide a clear description of the current strategies for diagnosis and management of TD. PMID- 25532578 TI - An infertile man with gynecomastia caused by a novel mutation of the androgen receptor gene. PMID- 25532577 TI - Plasticity of male germline stem cells and their applications in reproductive and regenerative medicine. AB - Spermatogonial stem cells (SSCs), also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies. PMID- 25532579 TI - Transcriptome sequencing in prostate cancer identifies inter-tumor heterogeneity. AB - Given the dearth of gene mutations in prostate cancer, [1] ,[2] it is likely that genomic rearrangements play a significant role in the evolution of prostate cancer. However, in the search for recurrent genomic alterations, "private alterations" have received less attention. Such alterations may provide insights into the evolution, behavior, and clinical outcome of an individual tumor. In a recent report in "Genome Biology" Wyatt et al. [3] defines unique alterations in a cohort of high-risk prostate cancer patient with a lethal phenotype. Utilizing a transcriptome sequencing approach they observe high inter-tumor heterogeneity; however, the genes altered distill into three distinct cancer-relevant pathways. Their analysis reveals the presence of several non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. PMID- 25532580 TI - Endovascular treatment of vasculogenic erectile dysfunction. AB - The treatment of erectile dysfunction (ED) has been a fascination involving multiple medical specialities over the past century with urologic, cardiac and surgical experts all contributing knowledge toward this multifactorial disease. With the well-described association between ED and cardiovascular disease, angiography has been utilized to identify vasculogenic impotence. Given the success of endovascular drug-eluting stent (DES) placement for the treatment of coronary artery disease, there has been interest in using this same technology for the treatment of vasculogenic ED. For men with inflow stenosis, DES placement to bypass arterial lesions has recently been reported with a high technical success rate. Comparatively, endovascular embolization as an approach to correct veno-occlusive dysfunction has produced astonishing procedural success rates as well. However, after a thorough literature review, arterial intervention is only recommended for younger patients with isolated vascular injuries, typically from previous traumatic experiences. Short-term functional outcomes are less than optimal with long-term results yet to be determined. In conclusion, the hope for a minimally invasive approach to ED persists but additional investigation is required prior to universal endorsement. PMID- 25532581 TI - Cardiovascular disease and male sexual dysfunction. AB - Erectile dysfunction (ED) is a form of sexual dysfunction that is estimated to affect > 30% of men between the ages of 40 and 70. As a result of an improved understanding about the pathophysiology of ED and improved treatment options, an increasing number of men are presenting for evaluation than several decades ago. In fact, many of these men are visiting their health care professional for the first time with ED as their primary complaint. Most of these men are unaware of the link between ED and cardiovascular disease (CVD). PMID- 25532582 TI - Commentary on "Disposable circumcision suture device: clinical effect and patient satisfaction". PMID- 25532583 TI - Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer. AB - The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7), in circulating tumor cells (CTCs) from metastatic castrate-resistant prostate cancer (mCRPC) patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA) responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival. PMID- 25532584 TI - Progressive motility - a potential predictive parameter for semen fertilization capacity in bovines. AB - We examined the association between progressive motility of spermatozoa and in vitro fertilization (IVF) competence of bovine ejaculates. Fresh semen was evaluated using a computerized sperm quality analyzer for bulls using progressive motility as the primary parameter. Ejaculates with high progressive motility (HPM; >81%) were compared with those with low progressive motility (LPM; 0.05). Examination of sperm morphology revealed a higher proportion of spermatozoa with abnormal morphology (P < 0.01) in LPM versus HPM ejaculates, the predominant abnormal feature being a bent tail (P < 0.05). Sperm viability, acrosome integrity and DNA fragmentation did not differ between HPM and LPM samples. Mitochondrial membrane potential was higher (P < 0.01) in HPM versus LPM semen. Zinc concentrations in the seminal plasma correlated with progressive motility (R2 = 0.463, P = 0.03). In addition, representative ejaculates from HPM and LPM groups were cryopreserved in straws and used for IVF. The proportions of embryos cleaved to 2- and 4-cell stages (88.1 +/- 1.1 versus 80.5 +/- 1.7, P = 0.001) and developed to blastocysts (33.5 +/- 1.6 versus 23.5 +/- 2.2, P = 0.026) were higher for HPM than LPM semen. The total cell number of embryos and blastocyst apoptotic index did not differ between groups. Although sperm progressive motility is associated with IVF competence, further examination is required to determine whether progressive motility can serve as a predictor of semen fertilization capacity in vivo. PMID- 25532585 TI - Highly thermostable GH39 beta-xylosidase from a Geobacillus sp. strain WSUCF1. AB - BACKGROUND: Complete enzymatic hydrolysis of xylan to xylose requires the action of endoxylanase and beta-xylosidase. beta-xylosidases play an important part in hydrolyzing xylo-oligosaccharides to xylose. Thermostable beta-xylosidases have been a focus of attention as industrially important enzymes due to their long shelf life and role in the relief of end-product inhibition of xylanases caused by xylo-oligosaccharides. Therefore, a highly thermostable beta-xylosidase with high specific activity has significant potential in lignocellulose bioconversion. RESULTS: A gene encoding a highly thermostable GH39 beta-xylosidase was cloned from Geobacillus sp. strain WSUCF1 and expressed in Escherichia coli. Recombinant beta-xylosidase was active over a wide range of temperatures and pH with optimum temperature of 70 degrees C and pH 6.5. It exhibited very high thermostability, retaining 50% activity at 70 degrees C after 9 days. WSUCF1 beta-xylosidase is more thermostable than beta-xylosidases reported from other thermophiles (growth temperature <= 70 degrees C). Specific activity was 133 U/mg when incubated with p-nitrophenyl xylopyranoside, with Km and Vmax values of 2.38 mM and 147 U/mg, respectively. SDS-PAGE analysis indicated that the recombinant enzyme had a mass of 58 kDa, but omitting heating prior to electrophoresis increased the apparent mass to 230 kDa, suggesting the enzyme exists as a tetramer. Enzyme exhibited high tolerance to xylose, retained approximately 70% of relative activity at 210 mM xylose concentration. Thin layer chromatography showed that the enzyme had potential to convert xylo-oligomers (xylobiose, triose, tetraose, and pentaose) into fermentable xylose. WSUCF1 beta-xylosidase along with WSUCF1 endo-xylanase synergistically converted the xylan into fermentable xylose with more than 90% conversion. CONCLUSIONS: Properties of the WSUCF1 beta-xylosidase i.e. high tolerance to elevated temperatures, high specific activity, conversion of xylo oligomers to xylose, and resistance to inhibition from xylose, make this enzyme potentially suitable for various biotechnological applications. PMID- 25532586 TI - Efficacy of the low-dose Saccharum iron treatment of idiopathic restless legs syndrome. AB - AIM: The aim of the study was to determine the efficacy of low-dose and high-dose Saccharum iron injected intravenously in patients with idiopathic restless legs syndrome (RLS) by detecting levels of serum ferritin (SF) and international RLS Severity Scale. METHODS: For this purpose, 38 patients with idiopathic RLS were randomly divided into the following two groups: low-dose group (18 cases) and high-dose group (20 cases). Low-dose group received Saccharum iron intravenously (200 mg/dose); once a week for 5 weeks with a total dose of 1000 mg. High-dose group received Saccharum iron intravenously (500 mg/dose); once every two weeks for 4 weeks with a total dose of 1000 mg. The pre- and post-treatment (at 2, 4, and 6 weeks) level of SF and RLS scores were determined and the differences were compared between two groups. RESULTS: Post-therapeutic SF levels increased significantly in both groups as compared with before treatment (P<0.05). At 6 week post-therapy, SF levels in low-dose group were significantly higher than those in high-dose group (P<0.05). The clinical symptoms were improved and RLS scores were lower than pretreatment ratings in both groups (P<0.05). After 6 weeks of treatment, RLS scores of low-dose group were lower than those of high dose group (P<0.05). CONCLUSION: Both the low-dose and high-dose Saccharum iron treatments increased the SF levels and improved clinical symptoms in patients with idiopathic RLS; however, the low-dose iron treatment was found to be more effective and had fewer side effects. PMID- 25532587 TI - A pH-responsive molecular switch with tricolor luminescence. AB - We developed a new ratiometric pH sensor based on poly(N-phenylmaleimide) (PPMI) containing block copolymer that emits three different fluorescent colors depending on the pH. The strong solvatochromism and tautomerism of the PPMI derivatives enabled precise pH sensing for almost the entire range of the pH scale. Theoretical calculations have predicted largely dissimilar band gaps for the keto, enol, and enolate tautomers of PPMI owing to low-dimensional conjugation effects. The tunable emission wavelength and intensity of our sensors, as well as the reversible color switching with high-luminescent contrast, were achieved using rational molecular design of PPMI analogues as an innovative platform for accurate H(+) detection. The self-assembly of block copolymers on the nanometer length scale was particularly highlighted as a novel prospective means of regulating fluorescence properties while avoiding the self quenching phenomenon, and this system can be used as a fast responsive pH sensor in versatile device forms. PMID- 25532588 TI - Combining age and HBsAg level predicts post-treatment durability of nucleos(t)ide analogue-induced HBeAg seroconversion. AB - BACKGROUND AND AIMS: Previous studies have indicated that lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion may not be durable in the Asian population. We investigated the useful predictors of post-treatment hepatitis B virus (HBV) relapse in patients with nucleos(t)ide analogue (NA)-induced HBeAg loss/seroconversion. METHODS: A total of 157 non-cirrhotic patients with NA induced HBeAg loss/seroconversion (78, lamivudine; 68, entecavir; 11, telbivudine) were retrospectively analyzed. All patients had at least 12 months of post-treatment follow-up and consolidation therapy duration. RESULTS: The cumulative rate of post-treatment HBV relapse at 5 years was 57.1%. Multivariate analysis revealed that age and baseline hepatitis B surface antigen (HBsAg) levels independently predicted post-treatment HBV relapse. The post-treatment HBV relapse rate was significantly higher in patients aged > 40 years than in those < 40 years (P < 0.001). A baseline HBsAg level of 2000 IU/mL was the optimal cut off value for predicting post-treatment HBV relapse (P = 0.002). The post treatment HBV relapse risk further increased with the presence of both risk factors (age >= 40 years and baseline HBsAg level >= 2000 IU/mL; P < 0.001). A prolonged consolidation therapy period of >= 18 or 24 months had no positive effect on sustained viral suppression. There was no significant difference in post-treatment HBV relapse rates between patients with lamivudine- and entecavir induced HBeAg loss/seroconversion during the off-treatment follow-up (P = 0.31). CONCLUSION: The combination of an age of 40 years and a baseline HBsAg level of 2000 IU/mL was a useful marker for predicting post-treatment HBV relapse in patients with NA-induced HBeAg loss/seroconversion. PMID- 25532589 TI - Varying the electronic structure of surface-bound ruthenium(II) polypyridyl complexes. AB - In the design of light-harvesting chromophores for use in dye-sensitized photoelectrosynthesis cells (DSPECs), surface binding to metal oxides in aqueous solutions is often inhibited by synthetic difficulties. We report here a systematic synthesis approach for preparing a family of Ru(II) polypyridyl complexes of the type [Ru(4,4'-R2-bpy)2(4,4'-(PO3H2)2-bpy)](2+) (4,4'(PO3H2)2-bpy = [2,2'-bipyridine]-4,4'-diylbis(phosphonic acid); 4,4'-R2-bpy = 4,4'-R2-2,2' bipyridine; and R = OCH3, CH3, H, or Br). In this series, the nature of the 4,4' R2-bpy ligand is modified through the incorporation of electron-donating (R = OCH3 or CH3) or electron-withdrawing (R = Br) functionalities to tune redox potentials and excited-state energies. Electrochemical measurements show that the ground-state potentials, E(o')(Ru(3+/2+)), vary from 1.08 to 1.45 V (vs NHE) when the complexes are immobilized on TiO2 electrodes in aqueous HClO4 (0.1 M) as a result of increased Ru dpi-pi* back-bonding caused by the lowering of the pi* orbitals on the 4,4'-R2-bpy ligand. The same ligand variations cause a negligible shift in the metal-to-ligand charge-transfer absorption energies. Emission energies decrease from lambdamax = 644 to 708 nm across the series. Excited-state redox potentials are derived from single-mode Franck-Condon analyses of room temperature emission spectra and are discussed in the context of DSPEC applications. PMID- 25532590 TI - Identification of blue staining vaccine-derived material in inflammatory lesions using cultured canine macrophages. AB - BACKGROUND: Vaccine reactions are described in cytology textbooks as having eosinophilic to magenta colored globules within and admixed with inflammatory cells. Recently, we have seen increased numbers of inflammatory lesions containing blue to blue-gray globular material, with historical information suggesting an association with rabies vaccination. OBJECTIVES: The purpose of the study was to confirm the blue-gray and the eosinophilic material observed microscopically in some inflammatory lesions as being vaccine-derived. METHODS: Three different vaccines were cytocentrifuged and Wright stained. Vaccine aliquots were also added to the culture media of canine-derived macrophages for 24 hours and the cells subsequently harvested, cytocentrifuged, and Wright stained. The globular material present in both preparations was compared to that observed in vaccine-induced inflammatory lesions. Morin staining was used to identify metal within vaccine material in both in vitro- and in vivo-derived cytology samples. RESULTS: Vaccine-derived material has a characteristic color and appearance. Appearance of the material was consistent in cytologic samples, in cells incubated with the vaccine, and in cytocentrifuged preparations of the vaccine vial contents. The blue-gray globules stained positively for Morin stain, while the eosinophilic material did not stain. CONCLUSIONS: Vaccine-induced inflammatory lesions may contain blue to blue-gray or magenta stained globular material. Blue-gray material was associated with administration of rabies vaccine Imrab 3 TF and the observed material may be metal-containing adjuvant. Magenta material was associated with other vaccines and negative for Morin stain, suggesting a metal-free adjuvant. PMID- 25532591 TI - Facial pain radiating upwards: could the pain of epicrania fugax start in the lower face? AB - BACKGROUND: Epicrania fugax (EF) is characterized by painful paroxysms starting in a particular area of the head, and rapidly radiating forwards or backwards through the territories of different nerves. In former clinical descriptions, the pain moved between the posterior scalp (C2) and the frontal or periorbital area (V1), either in forward or backward direction. METHODS: We report 5 patients with a paroxysmal EF-type pain starting in the lower face (V2 or V3) and radiating upwards. RESULTS: In each patient, the pain stemmed from the cheek (n = 1), the upper lip (n = 2) or the chin and mandibular area (n = 2), and then moved up to the forehead or the scalp with linear trajectory. Pain intensity was moderate (n = 1) or severe (n = 4), and pain quality was stabbing (n = 2) or electric (n = 3). The duration of attacks was very brief, lasting 1 to a few seconds. Three patients had ocular or nasal autonomic accompaniments, and 3 had triggers. CONCLUSIONS: There seems to be a facial variant of EF. These observations could not only expand the clinical spectrum of EF but also enlarge the differential diagnosis of facial pain. PMID- 25532592 TI - Effects of kynurenine on CD3+ and macrophages in wound healing. AB - As prolongation of the inflammation phase in a healing process frequently leads to wound impairment, here we queried whether kynurenine (Kyn) could modulate this phase of wound healing. To address this, a protein microarray, quantitative polymerase chain reaction (qPCR), flow cytometry for immune cells and immune cell proliferation in the presence and absence of Kyn were conducted and compared. The result of a protein microarray revealed that the expression of 12 pro inflammatory cytokines and chemokines was modulated in Kyn-treated mouse splenocytes as compared with those of control. These findings were then evaluated by conducting a qPCR for the gene expression of these factors and showed a significant reduction in the gene expression of majority of these cytokines and chemokines (interleukin [IL]-2, IL-17, C-X-C motif chemokine ligand [CXCL] 10, CXCL1, C-C motif ligand [CCL] 12, CXCL9, CCL4, CXCL2, and CCL5) in response to Kyn treatment. To test the anti-inflammatory effect of Kyn in an animal model, dorsal surface wounds were generated in a mouse model and wounds received daily topical application of either nothing (control), dermal cream (second control), or Kyn cream using uninjured skin tissue as another control. The wounded tissues were harvested on days 3, 6, and 10 postwounding. As anticipated, the results of fluorescence-activated cell sorting analysis revealed that upon wounding, the number of total infiltrated CD3+ cells and macrophages (CD11b+) significantly increased on day 3, peaked on day 6, and reduced on day 10 post-wounding. Interestingly, as compared with those of uninjured and dermal cream alone-treated wounds, Kyn treatment significantly reduced the number of infiltrated CD3+ cells, but not CD11b+ cells, at different time intervals examined. These findings collectively suggest that Kyn, as a small molecule, can potentially be used to overcome the difficulties associated with persistency of inflammation in healing wounds. PMID- 25532594 TI - Effects of a startle stimulus on response speed and inhibition in a go/no-go task. AB - Two studies examined the interaction of an acoustic startle stimulus and visual go/no-go task stimuli on startle reactivity and task performance. In the first study, an acoustic stimulus (50 ms, 100 dB noise) was presented alone or with a green (go) or red (no-go) circle; in the second study, a prepulse (50 ms, 75 dB noise) was presented alone or 120 ms before the startle stimulus or circle. The startle stimulus speeded responses to the go stimuli and increased the covert false alarm rate in the no-go condition (measured by EMG activity in the hand), although very few overt errors were made in the no-go condition. Startle response magnitude was increased by a circle but decreased by a prepulse. The speeding of go responses caused by a startle stimulus was attenuated by the occurrence of a startle response, suggesting that an intense accessory stimulus can facilitate responding to an imperative stimulus, and that the startle response to that intense stimulus can interfere with that facilitation. PMID- 25532595 TI - The Student Curriculum Review Team: How we catalyze curricular changes through a student-centered approach. AB - Student feedback is a valuable asset in curriculum evaluation and improvement, but many institutions have faced challenges implementing it in a meaningful way. In this article, we report the rationale, process and impact of the Student Curriculum Review Team (SCRT), a student-led and faculty-supported organization at the Johns Hopkins University School of Medicine. SCRT's evaluation of each pre clinical course is composed of a comprehensive three-step process: a review of course evaluation data, a Town Hall Meeting and online survey to generate and assess potential solutions, and a thoughtful discussion with course directors. Over the past two years, SCRT has demonstrated the strength of its approach by playing a substantial role in improving medical education, as reported by students and faculty. Furthermore, SCRT's uniquely student-centered, collaborative model has strengthened relationships between students and faculty and is one that could be readily adapted to other medical schools or academic institutions. PMID- 25532596 TI - Non-nutritive sweeteners and obesity. AB - Non-nutritive sweeteners (NNSs) provide sweetness to foods and beverages without adding calories. They have thus been found useful in minimizing the dietary sugar content of diabetics and the dietary energy content of individuals attempting to lose or maintain body weight. Their usefulness in weight reduction has recently been questioned, however, based on the notion that they can actually increase hunger and food intake and thereby promote weight gain. The evidence offered in support of this idea comes principally from the fields of taste physiology, metabolic endocrinology, human behavior, and epidemiology. This review evaluates this evidence and does not find it compelling. Indeed, the most straightforward findings to the contrary derive from several intervention studies in both children and adults showing that the chronic, covert replacement of dietary sugar with NNSs does not increase, and can in fact reduce, energy intake and body weight. PMID- 25532597 TI - Genetic mechanisms of prebiotic oligosaccharide metabolism in probiotic microbes. AB - Recent insights into the relationship between the human gut and its resident microbiota have revolutionized our appreciation of this symbiosis and its impact on health and disease development. Accumulating evidence on probiotic and prebiotic interventions has demonstrated promising effects on promoting gastrointestinal health by modulating the microbiota toward the enrichment of beneficial microorganisms. However, the precise mechanisms of how prebiotic nondigestible oligosaccharides are metabolized by these beneficial microbes in vivo remain largely unknown. Genome sequencing of probiotic lactobacilli and bifidobacteria has revealed versatile carbohydrate metabolic gene repertoires dedicated to the catabolism of various oligosaccharides. In this review, we highlight recent findings on the genetic mechanisms involved in the utilization of prebiotic fructooligosaccharides, beta-galactooligosaccharides, human milk oligosaccharides, and other prebiotic candidates by these probiotic microbes. PMID- 25532598 TI - Cardiac autonomic changes in middle-aged women: identification based on principal component analysis. AB - The purpose of this study was to investigate the application of the principal component analysis (PCA) technique on power spectral density function (PSD) of consecutive normal RR intervals (iRR) aiming at assessing its ability to discriminate healthy women according to age groups: young group (20-25 year-old) and middle-aged group (40-60 year-old). Thirty healthy and non-smoking female volunteers were investigated (13 young [mean +/- SD (median): 22.8 +/- 0.9 years (23.0)] and 17 Middle-aged [51.7 +/- 5.3 years (50.0)]). The iRR sequence was collected during ten minutes, breathing spontaneously, in supine position and in the morning, using a heart rate monitor. After selecting an iRR segment (5 min) with the smallest variance, an auto regressive model was used to estimate the PSD. Five principal component coefficients, extracted from PSD signals, were retained for analysis according to the Mahalanobis distance classifier. A threshold established by logistic regression allowed the separation of the groups with 100% specificity, 83.2% sensitivity and 93.3% total accuracy. The PCA appropriately classified two groups of women in relation to age (young and Middle aged) based on PSD analysis of consecutive normal RR intervals. PMID- 25532599 TI - p21, p53, TP53BP1 and p73 polymorphisms and the risk of gastric cardia adenocarcinoma in a Chinese population. AB - Gastric cardia adenocarcinoma (GCA) is one of the most common malignant tumors and among the leading causes of cancer-related death. Genetic factors might play an important role in GCA carcinogenesis. Here, we performed a hospital-based case control study to evaluate the effect of functional p21, p53, TP53BP1 and p73 single nucleotide polymorphisms (SNPs) on the risk of GCA. The study included 330 GCA cases and 608 controls. Genotypes were determined using the ligation detection reaction (LDR) method. The p21 rs1059234 TT, p21 rs3176352 GC/CC, p21 rs762623 GA and TP53BP1 rs560191 CC genotypes were associated with the risk of GCA, and a genotype combination effect was observed. After Bonferroni correction, the association remained significant for TP53BP1 rs560191 G > C, whereas the remaining four SNPs showed no association between the polymorphisms and GCA risk in all comparison models. Further large replication studies are needed to confirm the present findings. PMID- 25532600 TI - The effectiveness of an oral health care program for preventing ventilator associated pneumonia. AB - AIMS AND OBJECTIVES: To determine the effectiveness of an oral health care program for preventing ventilator-associated pneumonia (VAP). BACKGROUND: Research has shown a significant correlation between oral bacteria and VAP, indicating that an oral health care program plays a very important role in VAP prevention. DESIGN AND METHODS: A quasi-experimental study was used and conducted in the intensive care unit in a medical centre. A total of 199 mechanically ventilated patients were enrolled and divided into two groups: the experimental group (n=99) and control group (n=100). The experimental group was cared for using an evidence-based oral health care program, and the control group was cared for using routine nursing care procedures. Each group received the assigned treatment for four consecutive days. RESULTS: The incidence of VAP in the experimental group (4%, 4/95) was significantly lower than that in the control group (21%, 18/82). The oral assessment guide (OAG) mean score (9.16 +/- 2.07) of the experimental group was significantly different (P<0.05) from that of the control group (10.07 +/- 1.79). The general estimated equation further showed that there was a significant difference between groups (P<0.01) for the third post-test data and no significant difference for the pre-test or the first and second post-test data between groups, indicating that an increased duration of intervention resulted in significant decreases in the OAG scores in the experimental group compared with the control group. CONCLUSIONS: The evidence based oral health care program effectively improved oral mucosal health and statistically reduced the incidence of VAP in this study. RELEVANCE TO CLINICAL PRACTICE: The study findings may be useful as an empirical reference for health care professionals performing an oral health care program in the future. Additionally, it may serve as a reference for long-term care policies aimed at reducing the ventilation duration, days of hospitalization and mortality rate to enhance patient safety and the quality of medical care. PMID- 25532601 TI - NextGen sequencing reveals short double crossovers contribute disproportionately to genetic diversity in Toxoplasma gondii. AB - BACKGROUND: Toxoplasma gondii is a widespread protozoan parasite of animals that causes zoonotic disease in humans. Three clonal variants predominate in North America and Europe, while South American strains are genetically diverse, and undergo more frequent recombination. All three northern clonal variants share a monomorphic version of chromosome Ia (ChrIa), which is also found in unrelated, but successful southern lineages. Although this pattern could reflect a selective advantage, it might also arise from non-Mendelian segregation during meiosis. To understand the inheritance of ChrIa, we performed a genetic cross between the northern clonal type 2 ME49 strain and a divergent southern type 10 strain called VAND, which harbors a divergent ChrIa. RESULTS: NextGen sequencing of haploid F1 progeny was used to generate a genetic map revealing a low level of conventional recombination, with an unexpectedly high frequency of short, double crossovers. Notably, both the monomorphic and divergent versions of ChrIa were isolated with equal frequency. As well, ChrIa showed no evidence of being a sex chromosome, of harboring an inversion, or distorting patterns of segregation. Although VAND was unable to self fertilize in the cat, it underwent successful out-crossing with ME49 and hybrid survival was strongly associated with inheritance of ChrIII from ME49 and ChrIb from VAND. CONCLUSIONS: Our findings suggest that the successful spread of the monomorphic ChrIa in the wild has not been driven by meiotic drive or related processes, but rather is due to a fitness advantage. As well, the high frequency of short double crossovers is expected to greatly increase genetic diversity among progeny from genetic crosses, thereby providing an unexpected and likely important source of diversity. PMID- 25532603 TI - Prospective Clinical and Radiographic Results of Activ L Total Disk Replacement at 1- to 3-Year Follow-up. AB - STUDY DESIGN: A prospective clinical study. OBJECTIVE: To assess the clinical and radiographic results of activ L total disk replacement (TDR) on degenerative disk diseases. SUMMARY OF BACKGROUND DATA: There are few reports on Activ L TDR, and this is the first in China. MATERIALS AND METHODS: From March 2009 to March 2012, 32 patients with degenerative disk disease underwent either monosegmental or bisegmental lumbar TDR, which was documented in a prospective observational mode. Clinical success was defined as disability [Oswestry Disability Index (ODI)] improvement of at least 15 points versus baseline, no device failure, no major complications, no neurological deterioration. Additional clinical parameters as Visual Analogue Scale and Oswestry Disability Index (ODI) were evaluated preoperatively and postoperatively (1, 2, and 3 y). Radiographic parameters as range of motion (ROM) and intervertebral disk height (IDH) of the index and adjacent segments were also carried out. Prosthesis subsidence and heterotopic ossification were observed during the follow-up period. Work status was tracked for all patients. RESULTS: Overall, 30 patients (93.7%) were available for a mean follow-up of 28.8 months (12-46 mo) and had complete radiographic data. Their mean age was 45.1 years (32-58 y). At 3 years postoperatively, the success rate was 86.7% (26/30). After surgery, clinical parameters as Visual Analogue Scale score for back and leg pain, and ODI score showed statistically significant improvement (P<0.001), and the situation was well maintained during the follow-up time points. At 3 years postoperatively, the mean IDH at the index segment and upper and lower adjacent segments were 12.87, 12.61, and 11.62 mm, respectively, showing no significant difference compared with preoperative data (P1=0.0597, P2=0.6669, P3=0.9813). The ROM of the index and upper adjacent segment showed a slight but significant increase at the 3-year follow-up compared with baseline (P1=0.0128, P2=0.0007). The changes of ROM at the lower adjacent segment were not significant (P=0.6637). Tears of the iliac vein were observed in 2 patients. Prosthesis subsidence was observed in 3 patients (1 at 12 mo postoperatively, 1 at 24 mo postoperatively, and 1 at 32 mo postoperatively). Heterotopic ossification was observed in 1 patient at 36 mo postoperatively. At the 3-year follow-up, only 8 patients went back to their original work, and 15 patients changed jobs, whereas the last 7 patients stopped working. CONCLUSIONS: The 1- to 3-year follow-up of this cohort of patients showed satisfactory clinical outcomes. The IDHs at index and adjacent segments were well maintained after the surgery. The ROM at the lower adjacent segment remained unchanged, but the ROM at the index and upper adjacent segments showed a slight increase. The long-term results of activ L TDR was to be investigated. PMID- 25532602 TI - The longitudinal relationship of changes of adiposity to changes in pulmonary function and risk of asthma in a general adult population. AB - BACKGROUND: Adiposity has been linked to both higher risk of asthma and reduced lung function. The effects of adiposity on asthma may depend on both atopic status and gender, while the relationship is less clear with respect to lung function. This study aimed to explore longitudinal weight changes to changes in forced expiratory volume in first second (FEV1) and forced vital capacity (FVC), as well as to incident cases of asthma and wheezing, according to atopy and gender. METHODS: A general population sample aged 19-72 years was examined with the same methodology five years apart. Longitudinal changes in weight, body mass index, waist circumference, and fat percentage (bio-impedance) were analyzed with respect to changes of FEV1 and FVC (spirometry), and incidence of asthma and wheezing (questionnaire). Gender, atopy (serum specific IgE-positivity to inhalant allergens) and adipose tissue mass prior to adiposity changes were examined as potential effect modifiers. RESULTS: A total of 2,308 persons participated in both baseline and five-year follow-up examinations. Over the entire span of adiposity changes, adiposity gain was associated with decreasing levels of lung function, whereas adiposity loss was associated with increasing levels of lung function. All associations were dependent on gender (p interactions < 0.0001). For one standard deviation weight gain or weight loss, FEV1 changed with (+/-)72 ml (66-78 ml) and FVC with (+/-)103 ml (94-112 ml) in males. In females FEV1 changed with (+/-) 27 ml (22-32 ml) and FVC with (+/-) 36 ml (28-44 ml). There were no changes in the FEV1/FVC-ratio. The effect of adiposity changes increased with the level of adipose tissue mass at the start of the study (baseline), thus, indicating an aggregate effect of the total adipose tissue mass. Atopy did not modify these associations. There were no statistically significant associations between changes in adiposity measures and risk of incident asthma or wheeze. CONCLUSIONS: Over a five-year period, increasing adiposity was associated with decreasing lung function, whereas decreasing adiposity was associated with increasing lung function. This effect was significantly greater in males than in females and increased with pre-existing adiposity, but was independent of atopy. PMID- 25532604 TI - Single incision device (TVT Secur) versus retropubic tension-free vaginal tape device (TVT) for the management of stress urinary incontinence in women: a randomized clinical trial. AB - BACKGROUND: In 2006, Ethicon Inc. introduced a new minimally invasive single incision sling device for the surgical treatment of stress urinary incontinence, the Gynecare TVT Secur(r). For device licensing, no new evidence of TVT Secur efficacy and safety was needed: rather evidence was provided of the long-term follow-up of patients who had a procedure using a predecate retropubic tension free vaginal tape device. Before adopting TVT Secur into our routine clinical practice, we decided to evaluate it. The objective of our Canadian multi-centre pragmatic randomized controlled trial was to compare the effectiveness of the new single-incision device, TVT Secur, to the established TVT device, in terms of objective cure of stress urinary incontinence (SUI) at 12 months postoperatively. Other outcomes included: complications, symptoms, and incontinence-related quality of life. RESULTS: The sample size estimate for our trial was 300, but the trial stopped early because of poor recruitment. 74 women participated (40 allocated to TVT Secur, 34 to TVT). At 12 months postoperatively, 27/33(82%) of TVT Secur group were cured, compared with 25/28(89%) of the TVT group (relative risk 0.92, 95% confidence interval 0.75 to 1.13, p=0.49). Most women reported little or no SUI symptoms (35/37(95%) vs 29/30(97%), >0.999). Quality of life improved significantly from baseline for both groups (IIQ-7 mean change -25 for both groups) but did not differ between groups (p=0.880). CONCLUSION: Our small randomized trial did not find statistically significant differences in outcomes between women allocated to the TVT Secur device versus those allocated to the TVT device for stress urinary incontinence. Despite the discontinuation of TVT Secur in March 2013 for commercial reasons, the importance of our study lies in making evidence available for the many women who had a TVT Secur device implanted and their physicians who may be considering alternative treatments. Our experience illustrates the difficulty of undertaking research on new licensed devices in a rapidly changing surgical specialty, and further highlights the need for research before licensing if surgeons and their patients are to be confident in the effectiveness and safety of new surgical devices. TRIAL REGISTRATION: ClinicalTrials.gov NCT00685217, 22 May 2008. PMID- 25532605 TI - An infant with out-of-hospital cardiac arrest secondary to enteroviral myocarditis surviving up to cardiac transplantation. AB - We report the case of a 13-day-old infant with enteroviral myocarditis surviving an out-of-hospital cardiac arrest. She underwent orthotopic cardiac transplantation three months later. A year after the transplantation, she is alive and well. Enteroviral infection is common in neonates with high mortality in cases of enteroviral myocarditis. Cardiac transplantation is a treatment option for infants who fail to recover and remain dependent on inotropic support. This is the first report of an infant with out-of-hospital cardiac arrest secondary to enteroviral myocarditis surviving up to cardiac transplantation. PMID- 25532607 TI - Correlation between chronotropic incompetence and metabolic equivalents in patients with type 2 diabetes mellitus and concomitant metabolic syndrome. AB - AIM: The aim of the study was to examine the relationship between chronotropic incompetence and motor ability in patient with type 2 diabetes mellitus and concomitant metabolic syndrome (MS) in order to facilitate exercise prescriptions for these patients. METHODS: A total of 120 patients with type 2 diabetes mellitus were randomly enrolled and divided into study groups with (N.=64) or without MS (N.=56). All patients completed the electrocardiographic exercise testing, after which ratio of heart rate (rHR) and heart rate reserve (HRR) were calculating to assess chronotropic incompetence. In addition, maximum metabolic equivalents (maxMETs) were calculated to assess the motor ability. RESULTS: The MS group had significantly higher indicators of chronotropic incompetence (rHR and HRR) as well as maxMETs than patients without MS (all P<0.05). Further, maxMETs significantly correlated with rHR (r=0.81, P=0.003) and HRR (r=0.78, P<0.001). CONCLUSION: Patients with type 2 diabetes mellitus and concomitant MS have higher chronotropic incompetence and maxMETs compared with those without MS. METs or perceived level of exertion can be used in patients in whom heart rate is not available during the exercise. PMID- 25532606 TI - Comparison of mcl-Poly(3-hydroxyalkanoates) synthesis by different Pseudomonas putida strains from crude glycerol: citrate accumulates at high titer under PHA producing conditions. AB - BACKGROUND: Achieving a sustainable society requires, among other things, the use of renewable feedstocks to replace chemicals obtained from petroleum-derived compounds. Crude glycerol synthesized inexpensively as a byproduct of biodiesel production is currently considered a waste product, which can potentially be converted into value-added compounds by bacterial fermentation. This study aimed at evaluating several characterized P. putida strains to produce medium-chain length poly(3-hydroxyalkanoates) (mcl-PHA) using raw glycerol as the only carbon/energy source. RESULTS: Among all tested strains, P. putida KT2440 most efficiently synthesized mcl-PHA under nitrogen-limiting conditions, amassing more than 34% of its cell dry weight as PHA. Disruption of the PHA depolymerase gene (phaZ) in P. putida KT2440 enhanced the biopolymer titer up to 47% PHA (%wt/wt). The low biomass and PHA titer found in the mutant strain and the wild-type strain KT2440 seems to be triggered by the high production of the side-product citrate during the fermentation process which shows a high yield of 0.6 g/g. CONCLUSIONS: Overall, this work demonstrates the importance of choosing an appropriate microbe for the synthesis of mcl-PHA from waste materials, and a close inspection of the cell metabolism in order to identify undesired compounds that diminish the availability of precursors in the synthesis of biopolymers such as polyhydroxyalkanoates. Future metabolic engineering works should focus on reducing the production of citrate in order to modulate resource allocation in the cell's metabolism of P. putida, and finally increase the biopolymer production. PMID- 25532608 TI - Show me your neighbours and I will tell you how you are. PMID- 25532609 TI - Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. PMID- 25532610 TI - Hepatitis B reverse seroconversion in a patient with well controlled HIV infection: a case report and a review of the literature. PMID- 25532611 TI - Experiences and expectations of participants completing an HIV cure focused clinical trial. PMID- 25532612 TI - Introduction of a mediator for enhancing photocatalytic performance via post synthetic metal exchange in metal-organic frameworks (MOFs). AB - Ti-substituted NH2-Uio-66(Zr/Ti) prepared by using a post-synthetic exchange (PSE) method showed enhanced photocatalytic performance for both CO2 reduction and hydrogen evolution under visible light. Density functional theory (DFT) calculations and electron spin resonance (ESR) results reveal that the introduced Ti substituent acts as a mediator to facilitate electron transfer, which results in enhanced performance. PMID- 25532613 TI - Potential stagnation in the splanchnic hemodynamics demonstrated by the dynamic microbubbles in chronic liver disease. AB - BACKGROUND AND AIM: Impaired splanchnic hemodynamics are well-documented phenomena in cirrhosis. However, comprehensive hemodynamic features from the superior mesenteric artery (SMA) to the superior mesenteric vein (SMV) via intestinal capillaries have not been studied. The aim was to examine splanchnic hemodynamics and their relationship with clinical presentations. METHODS: Contrast-enhanced ultrasound was performed for both the SMA and SMV under fasting conditions and postprandially following ingestion of a liquid diet. The microbubble traveling time (MTT) was determined as the difference between the contrast onset in the SMA and SMV, indicating the time required for microbubble transit through the splanchnic circulation. RESULTS: There were 192 subjects for fasting conditions (81 cirrhosis, 72 chronic hepatitis, 39 healthy controls), and 74/192 for postprandial conditions (44 cirrhosis, 11 chronic hepatitis, 19 healthy controls). The MTT (fasting; postprandial) was significantly longer in cirrhosis (7.7 +/- 2.9 s; 7.0 +/- 0.3 s) than in controls (5.4 +/- 2.3 s, P < 0.001; 3.9 +/- 0.9 s, P<0.001) and chronic hepatitis (6.3 +/- 2.5 s, P=0.007; 5.1 +/- 1.4 s, P=0.013). The MTT ratio (postprandial/fasting) showed disease-related changes: 0.75 +/- 0.20 in controls, 0.78 +/- 0.15 in chronic hepatitis, and 1.00 +/- 0.28 in cirrhosis (P=0.003, vs controls; P=0.036, vs chronic hepatitis). CONCLUSIONS: The real-time observation of traveling microbubble on the sonogram revealed a prolonged transit with a weak postprandial response in the intestinal circulation, suggesting better understanding of underlying pathophysiology of splanchnic hemodynamics in chronic liver disease. PMID- 25532614 TI - Metal- and ligand-assisted CO2 insertion into Ru-C, Ru-N, and Ru-O bonds of ruthenium(II) phosphine complexes: a density functional theory study. AB - The CO2 insertion reactions of [L4Ru(eta(2)-CH2C6H4)] (1), [L4Ru(eta(2)-OC6H3Me)] (2), and [L4Ru(eta(2)-NHC6H4)] (3), where L = PH3 and PMe3, are modeled using density functional theory methods. In 1 and 2, the metal-assisted CO2 insertion occurs because of the favorable initial axial phosphine dissociation mechanism, whereas in 3, the ligand (NHC6H4)-assisted mechanism operates (DeltaG(?) = +19.0 kcal/mol), wherein the nucleophilic affinity of the -NHC6H4 moiety aids the CO2 insertion process. The modeled mechanisms are consistent with the experimental findings by Hartwig et al. (J. Am. Chem. Soc, 1991, 113, 6499), in which the rate of the reactions of 1 and 2 depends on the added phosphine concentration, whereas the rate of the reaction of 3 is independent of the added phosphine concentration. In 1 and 2, CO2 is preferably inserted into the Ru-Caryl bond rather than the competitive Ru-CH2 and Ru-O bonds, respectively. In 1, the pi type orbital interaction of the aryl ring with the metal center is found to stabilize the transition state for Ru-Caryl bond insertion (DeltaG(?) = +25.7 kcal/mol). In 2, the Ru-Caryl insertion (DeltaG(?) = +23.0 kcal/mol) is thermodynamically preferred, while the kinetically preferred Ru-O bond insertion (DeltaG(?) = +17.4 kcal/mol) is highly reversible. The more electron-donating and sterically bulky PMe3 facilitates the CO2 insertion of 1 and 2 because the initial dissociation of axial PMe3 is easier than that of PH3 by ca. +11.0 kcal/mol, whereas in the case of 3, the effect of PMe3 slightly increases the DeltaG(?) value of 3. The increase in the nucleophilic affinity of amido nitrogen in 3 and the increase in the polarity of the solvent decrease the DeltaG(?) value of 3 by 48%. The inclusion of the chelating dimethylphosphinoethane ligand in 3 along with the electron-donating substituent at the -NHC6H4 moiety and the polar solvent further reduces the DeltaG(?) value of 3 by 62%, which demonstrates the role of the chelating ligand, electron-donating substituent, and polar solvent in the ligand-assisted CO2 insertion reactions. PMID- 25532615 TI - Lanthanide-doped luminescent nano-bioprobes for the detection of tumor markers. AB - Sensitive and specific biodetection of tumor markers is essential for early-stage cancer diagnosis and therapy, and will ultimately increase the patient survival rate. As a new generation of luminescent bioprobes, lanthanide (Ln(3+))-doped inorganic luminescent nanoparticles have attracted considerable interest for a variety of biomedical applications due to their superior physicochemical properties. In this feature article, we provide a brief overview of the most recent advances in the development of Ln(3+)-doped luminescent nano-bioprobes and their promising applications for in vitro detection of tumor markers with an emphasis on the establishment of state-of-the-art assay techniques, such as heterogeneous time-resolved (TR) luminescent bioassay, dissolution-enhanced luminescent bioassay, upconversion (UC) luminescent bioassay, homogeneous TR Forster resonance energy transfer (TR-FRET) and UC-FRET bioassays. Some future prospects and efforts towards this emerging field are also envisioned. PMID- 25532616 TI - A Longitudinal Study of State Strategies and Policies to Accelerate Evidence Based Practices in the Context of Systems Transformation. AB - OBJECTIVE: To profile state agency efforts to promote implementation of three evidence-based practices (EBPs): screening and brief intervention (SBIRT), psychosocial interventions, and medication-assisted treatment (MAT). DATA SOURCES/STUDY SETTING: Primary data collected from representatives of 50 states and the District of Columbia's Single State Authorities from 2007 to 2009. STUDY DESIGN/DATA COLLECTION: The study used mixed methods, in-depth, semistructured interviews and quantitative surveys. Interviews assessed state and provider strategies to accelerate implementation of EBPs. PRINCIPAL FINDINGS: Statewide implementation of psychosocial interventions and MAT increased significantly over 3 years. In the first two assessments, states that contracted directly with providers were more likely to link use of EBPs to reimbursement, and states with indirect contract, through counties and other entities, increased recommendations, and some requirements for provision of specific EBPs. The number of states using legislation as a policy lever to promote EBPs was unchanged. CONCLUSIONS: Health care reform and implementation of parity in coverage increases access to treatment for alcohol and drug use. Science-based substance abuse treatment will become even more crucial as payers seek consistent quality of care. This study provides baseline data on service delivery, contracting, and financing as state agencies and treatment providers prepare for implementation of the Affordable Care Act. PMID- 25532617 TI - Surgical wound misclassification: a multicenter evaluation. AB - BACKGROUND: Surgical wound classification (SWC) is used by hospitals, quality collaboratives, and Centers for Medicare and Medicaid to stratify patients for their risk for surgical site infection. Although these data can be used to compare centers, the validity and reliability of SWC as currently practiced has not been well studied. Our objective was to assess the reliability of SWC in a multicenter fashion. We hypothesized that the concordance rates between SWC in the electronic medical record and SWC determined from the operative note review is low and varies by institution and operation. STUDY DESIGN: Surgical wound classification concordance was assessed at 11 participating institutions between SWC from the electronic medical record and SWC from operative note review for 8 common pediatric surgical operations. Cases with concurrent procedures were excluded. A maximum of 25 consecutive cases were selected per operation from each institution. A designated surgeon reviewed the included operative notes from his/her own institution to determine SWC based on a predetermined algorithm. RESULTS: In all, 2,034 cases were reviewed. Overall SWC concordance was 56%, ranging from 47% to 66% across institutions. Inguinal hernia repair had the highest overall median concordance (92%) and appendectomy had the lowest (12%). Electronic medical records and reviewer SWC differed by up to 3 classes for certain cases. CONCLUSIONS: Surgical site infection risk stratification by SWC, as currently practiced, is an unreliable methodology to compare patients and institutions. Surgical wound classification should not be used for quality benchmarking. If SWC continues to be used, individual institutions should evaluate their process of assigning SWC to ensure its accuracy and reliability. PMID- 25532618 TI - Very low birth weight is an independent risk factor for emergency surgery in premature infants with inguinal hernia. AB - BACKGROUND: Common surgical knowledge is that inguinal hernia repair in premature infants should be postponed until they reach a certain weight or age. Optimal management, however, is still under debate. The objective of this study was to collect evidence for the optimal management of inguinal hernia repair in premature infants. STUDY DESIGN: In the period between 2010 and 2013, data for all premature infants with inguinal hernia who underwent hernia correction within 3 months after birth in the Erasmus MC-Sophia Children's Hospital, Rotterdam were analyzed. Primary outcomes measures were the incidences of incarceration and subsequent emergency surgery. In a multivariate analysis, Cox proportional hazards model served to identify independent risk factors for incarceration requiring an emergency procedure. RESULTS: A total of 142 premature infants were included in the analysis. Median follow-up was 28 months (range 15 to 39 months). Seventy-nine premature infants (55.6%) presented with a symptomatic inguinal hernia; emergency surgery was performed in 55.7%. Complications occurred in 27.3% of emergency operations vs 10.2% after elective repair; recurrences occurred in 13.6% vs 2.0%, respectively. Very low birth weight (<=1,500 g) was an independent risk factor for emergency surgery, with a hazard ratio of 2.7 in the Cox proportional hazards model. CONCLUSIONS: More than half of premature infants with an inguinal hernia have incarceration. Those with very low birth weight have a 3 fold greater risk of requiring an emergency procedure than heavier premature infants. Emergency repair results in higher recurrence rates and more complications. Elective hernia repair is recommended, particularly in very low birth weight premature infants. PMID- 25532619 TI - Hyperbaric oxygen therapy activates hypoxia-inducible factor 1 (HIF-1), which contributes to improved wound healing in diabetic mice. AB - Hyperbaric oxygen (HBO) therapy has been used as an adjunctive therapy for diabetic foot ulcers, although its mechanism of action is not completely understood. Recently, it has been shown that HBO mobilizes the endothelial progenitor cells (EPCs) from bone marrow that eventually will aggregate in the wound. However, the gathering of the EPCs in diabetic wounds is impaired because of the decreased levels of local stromal-derived factor-1alpha (SDF-1alpha). Therefore, we investigated the influence of HBO on hypoxia-inducible factor 1 (HIF-1), which is a central regulator of SDF-1alpha and is down-regulated in diabetic wounds. The effects of HBO on HIF-1alpha function were studied in human dermal fibroblasts, SKRC7 cells, and HIF-1alpha knock-out and wild-type mouse embryonic fibroblasts using appropriate techniques (Western blot, quantitative polymerase chain reaction, and luciferase hypoxia-responsive element reporter assay). Cellular proliferation was assessed using H(3) -thymidine incorporation assay. The effect of HIF in combination with HBOT was tested by inoculating stable HIF-1alpha-expressing adenovirus (Adv-HIF) into experimental wounds in db/db mice exposed to HBO. HBO activates HIF-1alpha at several levels by increasing both HIF-1alpha stability (by a non-canonical mechanism) and activity (as shown both by induction of relevant target genes and by a specific reporter assay). HIF-1alpha induction has important biological relevance because the induction of fibroblast proliferation in HBO disappears when HIF-1alpha is knocked down. Moreover, the local transfer of stable HIF-1alpha-expressing adenovirus (Adv-HIF) into experimental wounds in diabetic (db/db mice) animals has an additive effect on HBO-mediated improvements in wound healing. In conclusion, HBO stabilizes and activates HIF-1, which contributes to increased cellular proliferation. In diabetic animals, the local transfer of active HIF further improves the effects of HBO on wound healing. PMID- 25532620 TI - Assessment of the Healthy Eating Index-2005 as a predictor of early childhood caries. AB - BACKGROUND: Early childhood caries (ECC) is a multifactorial disease resulting mainly from a time-specific interaction of micro-organisms with sugars on a tooth surface. AIM: The purpose of this study was to assess the relationship of dietary intake, as measured by the Healthy Eating Index-2005 (HEI-2005) to ECC. DESIGN: Cross-sectional analytical study. METHODS: Sixty preschool children were equally divided into three groups according to their caries experience [Group 1: caries free children, group 2: children with ECC, group 3: children with severe early childhood caries (S-ECC)]. The decayed (non-cavitated or cavitated), missing (due to caries) and filled tooth surfaces (dmfs) score was determined through visual dental examination for each child. Questionnaires were collected recording the demographic characteristics of the families as well as 24-h food recall forms capturing the dietary intake of the children during the previous day. Accordingly, the HEI-2005 score was calculated for each child. RESULTS: The caries experience of the children in this study was significantly associated with their age. Caries-free children showed significantly higher 'Whole fruit', 'Milk', 'Sodium' and total HEI-2005 scores. CONCLUSIONS: The study findings illustrate the prominent protective role played by healthful dietary practices against dental caries in preschool children. PMID- 25532621 TI - Limited dissection and early primary closure of the tracheostomy stoma in head and neck oncology operations: a retrospective study of 158 cases. AB - Tracheostomy is an efficient and widely used method to secure a patent airway in patients undergoing major oral and maxillofacial oncology operations. The inferiorly based Bjork flap technique, through a limited incision, followed by early primary skin closure, has been the preferred method in our unit. Patients who underwent tracheostomy for major oral and maxillofacial oncology operations during the period June 2005 to December 2012 were reviewed. Age, gender, preoperative diagnosis, duration the tracheostomy tube was in situ, tracheostomy associated complications, and long-term sequelae were evaluated. A total 158 tracheostomies were performed using the same surgical approach in patients aged 18-84 years (median 59, mean 58.2, standard deviation 14.24 years). The time the tracheostomy tube was in situ ranged from 3 to 40 days (median 7, mean 9.0, standard deviation 6.52 days). The complication rate was 5.06% (8/158 patients). A major concern highlighted in previous publications is the risk of surgical emphysema with early closure. In this study, no patients developed surgical emphysema, tracheal fistula, clinical tracheal stenosis, or cosmetically unacceptable scarring of the neck. No patient died of a tracheostomy-related cause. In summary, the Bjork flap with early primary closure of the skin by simple sutures provides a safe and easily managed approach, causing minimal postoperative morbidity. PMID- 25532622 TI - Cement augmentation of the acetabulum for revision total hip arthroplasty for infection. AB - Antibiotic-loaded cement spacers in first-stage revision hip arthroplasty for infection are associated with a high dislocation and fracture rate. This technical note describes a novel surgical technique, utilizing screws and cement, improving acetabular coverage and reducing the risk of mechanical failure. Fifteen infected hip prostheses underwent removal, cement acetabular augmentation and insertion of a femoral cement spacer. Eleven hips had successful infection eradication and subsequently underwent a second stage revision procedure a mean duration of 15 weeks (9-48) after the first stage. No dislocations or fractures of the cement spacers were observed. This technique affords the potential to reduce the duration of time cement spacers remaining in situ, provides enhanced mechanical stability and improved antibiotic elution through cement-on-cement articulation. PMID- 25532623 TI - 2014 San Antonio Breast Cancer Symposium. PMID- 25532624 TI - Ovarian suppression and breast cancer. PMID- 25532625 TI - FDA approves new upgraded Gardasil 9. PMID- 25532626 TI - Lumpectomy margins: everything old is new again? PMID- 25532627 TI - A photoCORM nanocarrier for CO release using NIR light. AB - A water-soluble nanocarrier for a photo-activated CO releasing moiety (photoCORM) that can be triggered with NIR excitation is described. This has an upconversion nanoparticle core encapsulated by an amphiphilic polymer imparting both water solubility and a hydrophobic interior containing the photoCORM trans Mn(bpy)(PPh3)2(CO)2. Such an ensemble offers a unique strategy for CO delivery to biological targets. PMID- 25532628 TI - Reeling in the years. PMID- 25532629 TI - Intrastromal lamellar keratoplasty in patients with pellucid marginal degeneration. AB - We describe a new method (intrastromal lamellar keratoplasty) to treat patients with pellucid marginal degeneration (PMD). After a pocket is created along the marked margins of the thinned inferior cornea with Melles dissectors, a crescent of the same size is marked on the donor cornea. The epithelial and endothelial layers are removed, and the donor tissue is cut in a crescentic shape in the size of the marked corneal pocket. The donor crescentic stroma is then inserted into the stromal pocket. The technique was performed in 10 eyes of 10 patients with PMD. The uncorrected and corrected distance visual acuities had significantly improved after 6 months. The cylinder was significantly reduced after 1 month and this was maintained up to 3 months of follow-up. Intrastromal lamellar keratoplasty appeared to be effective in the treatment of PMD. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532630 TI - Cystotome-assisted prechop technique. AB - We describe a manual prechop technique to divide the nucleus using a cystotome. In the cystotome-assisted prechop technique, after the capsulorhexis, the surgeon bent cystotome is inserted into the lens while the Nagahara chopper is set around the lens equator. The cystotome and the chopper are then brought together in the center to create a bisecting crack in the nucleus, dividing it cleanly into 2 hemispheres. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532631 TI - Simple technique to treat pupillary capture after transscleral fixation of intraocular lens. AB - We describe a simple surgical technique to manage pupillary capture after previous transscleral fixation of an intraocular lens. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 25532632 TI - Surgical technique for explantation of cosmetic anterior chamber iris implants. AB - The Newcoloriris is a silicone implant for cosmetic alteration of iris color. Implantation is associated with significant ocular complications of decreased vision, glaucoma, and corneal edema. Although removal of the implant also entails risks, it is ultimately necessary to preserve vision. We describe a technique for removing the implant that may also reduce intraoperative complications. The implant is explanted using a bimanual technique with small incisions in 3 sections via a "slicing-the-pie" technique using iris microforceps, microscissors, and microinstrumentation. Our patient required removal 5 years after implantation, which is the longest reported interval in the literature. This suggests that as long as these implants are present, ocular structures are at risk. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532633 TI - Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. AB - PURPOSE: To analyze the 10-year results of corneal collagen crosslinking (CXL) for keratoconus. SETTING: Department of Ophthalmology, University Hospital, Dresden, Germany. DESIGN: Retrospective interventional case series. METHODS: The study included eyes treated for progressive keratoconus from 2000 to 2004. Corneal collagen crosslinking was performed by applying riboflavin and ultraviolet-A. The corrected distance visual acuity (CDVA), corneal topography, and endothelial cell count (ECC) were recorded preoperatively and 10 years postoperatively. RESULTS: The study enrolled 24 patients (34 eyes). The mean age of the 18 men and 6 women was 28.4 years +/- 7.3 (SD) and the mean follow-up, 131.9 +/- 20.1 months. The mean apical keratometry (K) value was 61.5 diopters (D) preoperatively and 55.3 D 10 years postoperatively; the decrease was statistically significant (P<.001). The mean values for maximum K (53.2 D and 49.56 D, respectively) and minimum K (47.5 D and 45.5 D, respectively) were also significantly lower (P<.001). The preoperative and postoperative CDVA were statistically significantly different (P=.002). The mean CDVA improved by 0.14 logMAR over preoperatively; the change was statistically significant (P=.002). The ECC was unchanged. CONCLUSIONS: Corneal CXL was effective in treating progressive keratoconus, achieving long-term stabilization of the condition. It was easy to perform, had a good safety profile, and reduced the need for corneal transplantation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532634 TI - Incidence of postoperative endophthalmitis from 1990 to 2009 using povidone iodine but no intracameral antibiotics at a single academic institution. AB - PURPOSE: To correlate the incidence of postoperative endophthalmitis with changes in the preoperative prophylaxis over a 20-year period. SETTING: Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany. DESIGN: Retrospective chart review. METHODS: Patients diagnosed with postoperative endophthalmitis from 1990 to 2009 after intraocular surgery performed at the same institution were included. Because of changes in the preoperative prophylaxis during the study period, 3 groups were formed for data analysis: Period 1 (1990 to 1992), no standardized prophylaxis regimen; period 2 (1993 to 1998), preoperative topical medication, povidone-iodine 10.0% periorbitally, and 1 drop of povidone-iodine 1.0% in the conjunctiva sac; and period 3 (1999 to 2009), similar to period 2 except with irrigation of the conjunctival sac with 10 mL of povidone-iodine 1.0%. RESULTS: The overall rate of postoperative endophthalmitis was 0.113% (77/68,323) for all intraocular surgeries. It decreased significantly from 0.291% (16/5505) in period 1 to 0.170% (33/19,413) in period 2 to 0.065% (28/43,405) in period 3 (P < .001). In cataract surgery, the overall rate of postoperative endophthalmitis was 0.125% (30/24,034). It decreased in each subsequent period, from 0.338% (9/2662) in period 1 to 0.224% (15/6696) in period 2 to 0.041% (6/14,676) in period 3 (P < .001). Coagulase-negative Staphylococcus was the most commonly isolated organism (47.4%). CONCLUSIONS: The rate of postoperative endophthalmitis decreased over a 20-year period at a single academic institution. Although multiple factors might have contributed to this decline, implementation of a preoperative prophylaxis protocol using copious povidone-iodine might have been the most important contributor. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532635 TI - Comparison of vault after implantation of posterior chamber phakic intraocular lens with and without a central hole. AB - PURPOSE: To compare the vault after implantation of a posterior chamber phakic intraocular lens (pIOL) (Visian Implantable Collamer Lens) with and without a central artificial hole for moderate to high ametropia. SETTING: Department of Ophthalmology, Kitasato University, Kanagawa, Japan. DESIGN: Retrospective comparative study. METHODS: The study comprised eyes of patients who had central hole pIOL implantation in 1 eye and conventional pIOL implantation in the fellow eye. The time course of the postoperative pIOL vault was quantitatively assessed using a rotating Scheimpflug camera (Pentacam HR). RESULTS: Twenty-three patients (46 eyes) (mean age 31.3 years +/- 7.4 [SD]) were enrolled in the study. The amount of vault with the central hole pIOL was 603 +/- 276 MUm, 552 +/- 261 MUm, 539 +/- 258 MUm, 520 +/- 240 MUm, and 482 +/- 245 MUm, at 1 week, 1 month, 3 months, 6 months, and 1 year postoperatively, respectively. The amount with the conventional pIOL vault was 585 +/- 252 MUm, 550 +/- 269 MUm, 514 +/- 253 MUm, 485 +/- 233 MUm, and 459 +/- 239 MUm, respectively. There was no significant association between the pIOL vault and the refractive accuracy 1 year postoperatively (Spearman correlation coefficient r = 0.18, P = 0.41 for central hole pIOL and r = 0.07, P = .76 for conventional pIOL). CONCLUSIONS: The vault of the new central hole pIOL appeared to be essentially equivalent to the vault of the conventional pIOL, suggesting that the presence of the central hole did not significantly affect the vault or the refractive accuracy. FINANCIAL DISCLOSURE: Dr. Shimizu is a consultant to Staar Surgical Co. and has assisted with the development of patented technologies. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25532636 TI - Effect of posterior corneal astigmatism on refractive outcomes after toric intraocular lens implantation. AB - PURPOSE: To compare the prediction error after toric intraocular lens (IOL) (Acrysof IQ) implantation using corneal astigmatism measurements obtained with an IOLMaster automated keratometer and a Galilei dual rotating camera Scheimpflug Placido tomographer. SETTING: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: The predicted residual astigmatism after toric IOL implantation was calculated using preoperative astigmatism values from an automated keratometer and the total corneal power (TCP) determined by ray tracing through the measured anterior and posterior corneal surfaces using dual Scheimpflug-Placido tomography. The prediction error was calculated as the difference between the predicted astigmatism and the manifest astigmatism at least 1 month postoperatively. The calculations included vector analysis. RESULTS: The study evaluated 35 eyes (35 patients). The preoperative corneal posterior astigmatism mean magnitude was 0.33 diopter (D) +/- 0.16 (SD) (vector mean 0.23 * 176). Twenty-six eyes (74.3%) had with-the-rule (WTR) posterior astigmatism. The postoperative manifest refractive astigmatism mean magnitude was 0.38 +/- 0.18 D (vector mean 0.26 * 171). There was no statistically significant difference in the mean magnitude prediction error between the automated keratometer and TCP techniques. However, the automated keratometer method tended to overcorrect WTR astigmatism and undercorrect against-the-rule (ATR) astigmatism. The TCP technique lacked these biases. CONCLUSIONS: The automated keratometer and TCP methods for estimating the magnitude of corneal astigmatism gave similar results. However, the automated keratometer method tended to overcorrect WTR astigmatism and undercorrect ATR astigmatism. FINANCIAL DISCLOSURE: Dr. Hamilton has received honoraria for educational lectures from Ziemer Ophthalmic Systems. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25532637 TI - Collagen copolymer posterior chamber phakic intraocular lens supported by the ciliary sulcus to treat myopia: one-year follow-up. AB - PURPOSE: To evaluate the predictability, stability, safety, and efficacy of Visian V4b Implantable Collamer Lens phakic intraocular lens (pIOL) implantation to treat varying degrees of myopia. SETTING: Fernandez-Vega Ophthalmological Institute, Oviedo, Spain. DESIGN: Prospective nonrandomized clinical study. METHODS: The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction, pIOL vault, and adverse effects were evaluated 12 months postoperatively. RESULTS: The study enrolled 121 eyes (68 patients). The mean spherical equivalent decreased from -8.61 diopters (D) +/- 3.41 (SD) (range 18.75 to -2.25 D) preoperatively to -0.18 +/- 0.29 D (range -1.25 to 0.50 D) 12 months postoperatively; 97 eyes (80.2%) were within +/-0.25 D of the target refraction and 114 eyes (94.2%) were within +/-0.50 D (r(2) = 0.99). The mean Snellen decimal UDVA and CDVA were 0.91 +/- 0.17 and 0.97 +/- 0.09, respectively. Postoperatively, the UDVA was 20/20 or better in 80 eyes (66.1%) and 20/40 or better in 115 eyes (95.0%). The mean efficacy index was 0.96 +/- 0.14. The CDVA was 20/20 or better in 103 eyes (85.1%) and 20/40 or better in all eyes. No eye lost lines of CDVA, and 22 eyes (18.2%) gained 1 or more lines of CDVA. The mean safety index was 1.04 +/- 0.10. There were no intraoperative complications. CONCLUSIONS: The predictability, safety, and effectiveness of the pIOL were good throughout the 12-month follow-up and comparable to outcomes reported for previous pIOL models. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532638 TI - Results and complications of surgeons-in-training learning bimanual microincision cataract surgery. AB - PURPOSE: To evaluate visual outcomes and complications of bimanual microincision cataract surgery performed by surgeons in training. SETTING: Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy. DESIGN: Prospective case series. METHODS: The corrected distance visual acuity (CDVA), astigmatism, corneal pachymetry, and endothelial cell count were evaluated before and 7 and 30 days after bimanual MICS performed by surgeons in training. Intraoperative and postoperative complications were also recorded. RESULTS: Three surgeons in training performed bimanual MICS in 150 eyes of 131 patients. There were 18 intraoperative complications (12.0%) (10 iris traumas [6.6%]; 4 capsule ruptures without vitreous loss [2.7%]; 3 capsule ruptures with vitreous loss [2.0%]; 1 intraocular lens [IOL] implantation in the sulcus due to zonular laxity [0.7%]). There were 5 postoperative complications (3.3%) (2 iris prolapses [1.3%]; 1 IOL loop malposition [0.7%]; 1 narrowing of anterior chamber [0.7%]; 1 capsulorhexis phimosis [0.7%]). Thirty days postoperatively, the mean CDVA improvement was 0.53 +/- 0.20 (Snellen decimal) (P < .05), the mean decrease in astigmatism was 0.09 +/- 0.54 diopter (P = .29), and the mean increase in corneal pachymetry was 7.42 +/- 22.01 MUm (P = .12). There was statistically significant endothelial cell loss (mean 496.50 +/- 469.66 cells/mm(2)) (P < .05). CONCLUSIONS: Bimanual MICS performed by surgeons in training was safe and effective. Visual outcomes and complication rates were similar to those reported for coaxial cataract surgery performed by surgeons in training. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532639 TI - Documenting the subjective patient experience of first versus second cataract surgery. AB - PURPOSE: To examine the subjective patient experience after cataract surgery. SETTING: Single multisurgeon cataract facility. DESIGN: Prospective intraindividual observational study. METHODS: Patients completed a questionnaire immediately after cataract extraction performed in their second eye. All patients had second-eye surgery within 6 months of first-eye surgery. Cases longer than 30 minutes were excluded. RESULTS: Of the 292 patients who completed the questionnaire, 12 were excluded based on surgical time. The response rate varied per question. The surgery was rated as taking longer or being more painful in the second eye by 127 patients (45.4%) and in the first eye by 38 patients (13.5%) (P < .05); 115 patients (41.1%) reported no difference. Patients (47.83%) who rated the second eye as the generally more negative experience thought their vision would be better and 3.48% worse (P < .05); 48.70% thought it would be the same. No difference was noted in length of surgery (P = .3) or sedation used (P = .96). CONCLUSIONS: Of 125 patients who rated second-eye surgery as the generally more unpleasant procedure, 90 (72.0%) were similarly or more relaxed during the second procedure. Second-eye cataract surgery was perceived as being a longer and/or more painful procedure by a significant number of patients (45.4%), and only 3.48% thought that vision in the second eye would be worse. These results can help surgeons when counseling patients regarding expectations for second surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532640 TI - In vitro antimicrobial analysis of aqueous humor after topical application of moxifloxacin hydrochloride 0.5%. AB - PURPOSE: To evaluate the in vitro antimicrobial activity of aqueous humor in patients who had preoperative topical application of moxifloxacin hydrochloride 0.5%. SETTING: Department of Ophthalmology, Santa Casa de Misericordia de Sao Paulo, Brazil. DESIGN: Comparative case series. METHODS: Twenty-nine eyes from 29 cataract surgery patients were included in this study. In the study group (n = 15 eyes), 3 topical applications of moxifloxacin hydrochloride 0.5% were administered preoperatively; in the control group (n = 14 eyes), no topical applications were administered. Aqueous humor samples were collected and stored in sterile microtubes at -80 degrees C until analysis. Antimicrobial analysis was performed using standard strains with standard sterile filter paper disks. Inhibition halos were measured in millimeters, and both bactericidal and bacteriostatic effects were analyzed. RESULTS: Inhibition halos were observed on most of the study group plates except those with Streptococcus pneumoniae: Escherichia coli (13.93 mm +/- 0.64 [SD]), Klebsiella pneumoniae (10.63 +/- 0.61 mm), Staphylococcus aureus (7.47 +/- 0.68 mm), and S epidermidis (4.20 +/- 3.33 mm) The differences between the mean inhibition halo diameters were statistically significant (P < .0001) in all samples. No bactericidal effect was observed against any of the microorganisms studied. CONCLUSIONS: After topical application of moxifloxacin 0.5%, aqueous humor showed bacteriostatic effect against E coli, K pneumoniae, S aureus, and S epidermidis. No bactericidal effect was observed against any of the microorganisms evaluated. No antimicrobial effect against S pneumoniae was observed. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532641 TI - Intraocular lens opacification after corneal endothelial keratoplasty: electron microscopy and x-ray element spectroscopy analysis. AB - PURPOSE: To assess a newly recognized long-term complication of Descemet stripping automated endothelial keratoplasty (DSAEK). SETTING: Plymouth Royal Eye Infirmary and Plymouth Electron Microscope Centre, Plymouth, United Kingdom. DESIGN: Retrospective case series. METHODS: This study evaluated cases of intraocular lens (IOL) opacification that developed after uneventful DSAEK. None of the IOLs was previously known to opacify. In 1 case, the opacified IOL was explanted and analyzed using detailed light microscopy, scanning electron microscopic (SEM) analysis, and element x-ray spectroscopy. RESULTS: In all 5 cases, the IOL was hydrophilic acrylic and the eye developed IOL anterior surface opacification 4 to 12 months after DSAEK. In 1 eye, the opacification was symptomatic; thus, an IOL exchange was performed. Light microscopy and SEM analysis of the explanted IOL confirmed opacification on the anterior surface and subsurface areas. X-ray element spectroscopy showed the granules were composed of calcium and phosphorous. CONCLUSIONS: These cases indicate that IOL opacification after DSAEK is a late, although newly recognized, complication of endothelial keratoplasty. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532642 TI - One-year results of simultaneous laser in situ keratomileusis and small-aperture corneal inlay implantation for hyperopic presbyopia: comparison by age. AB - PURPOSE: To compare by age the safety, efficacy, and patient satisfaction after simultaneous laser in situ keratomileusis (LASIK) and small-aperture corneal inlay implantation (Kamra) for hyperopic presbyopia. SETTING: Shinagawa LASIK Center, Tokyo, Japan. DESIGN: Retrospective comparative cohort study. METHODS: Simultaneous LASIK and small-aperture corneal inlay implantation were performed in the nondominant eye of hyperopic presbyopic patients with astigmatism. Patients were divided into groups by age as follows: Group 1 (40 to 49 years), Group 2 (50 to 59 years), and Group 3 (60 to 65 years). The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, uncorrected near visual acuity (UNVA), and patient questionnaire results were compared. RESULTS: The study evaluated 277 eyes of 277 patients. All groups achieved a mean UDVA of 20/20, with Group 1, Group 2, and Group 3 gaining 1 line, 2 lines, and 3 lines, respectively. The mean UNVA was J2 with 4 lines gained in Group 1 and J3 with 5 lines gained in Group 2 and Group 3. The mean CDVA and corrected near visual acuity remained the same as at baseline. CONCLUSIONS: Simultaneous LASIK and small-aperture corneal inlay implantation for hyperopic presbyopia was a safe and effective treatment option. Although the outcomes were comparable between groups, Group 3 had the largest gain in UDVA and UNVA and the highest patient satisfaction, despite having the lowest reduction in dependence on reading glasses. Taking age into account might help achieve optimum postoperative outcomes and improved patient satisfaction. FINANCIAL DISCLOSURE: Dr. Tomita is a consultant to Ziemer Ophthalmic Systems AG, Acufocus, Inc., and Schwind eye-tech solutions GmbH and Co. KG. Dr. Waring is a consultant to Acufocus, Inc. PMID- 25532643 TI - Repeatability and reproducibility of a new optical biometer in normal and keratoconic eyes. AB - PURPOSE: To evaluate the repeatability and reproducibility of measurements obtained by a new optical biometer (Nidek AL-Scan) in normal eyes and keratoconic eyes. SETTING: Department of Ophthalmology, Turgut Ozal University, Medical School, Ankara, Turkey. DESIGN: Evaluation of diagnostic technology. METHODS: To assess the repeatability and reproducibility of the optical biometer, 2 independent examiners performed 3 consecutive measurements. The following parameters were evaluated: central corneal thickness (CCT), anterior chamber depth, axial length (AL), corneal dioptric power in the flattest meridian (flat keratometry [K]) and in the steepest meridian (steep K), and white-to-white (WTW) distance. Repeatability was assessed using the within-subject standard deviation (S(w)), repeatability, and precision. Reproducibility was evaluated using the 95% limits of agreement proposed by Bland and Altman. RESULTS: Thirty healthy subjects and 27 patients with keratoconus were evaluated. Both examiners achieved high repeatability for all parameters in each group except for the steep K measurement in keratoconic eyes performed by examiner 2 (S(w) = 3.341). The WTW in normal eyes and the CCT and steep K in keratoconic eyes showed less repeatability. In both groups, the smallest range of agreement was in AL measurements whereas the largest was in CCT measurements. In keratoconic eyes, the range of agreement for steep K was also greater (3.766). CONCLUSIONS: The precision of the measurements obtained by the new optical biometer was high. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532644 TI - Thermal characterization of phacoemulsification probes operated in axial and torsional modes. AB - PURPOSE: To analyze temperature increases and identify potential sources of heat generated when sleeved and sleeveless phacoemulsification probes were operated in axial and torsional modes using the Infiniti Vision System with the Ozil torsional handpiece. SETTING: Phacodynamics Laboratory, Pasteur Ophthalmic Clinic, Santiago, Chile. DESIGN: Experimental study. METHODS: Two computer controlled thermal transfer systems were developed to evaluate the contribution of internal metal stress and tip-to-sleeve friction on heat generation during phacoemulsification using axial and torsional ultrasound modalities. Both systems incorporated infrared thermal imaging and used a black-body film to accurately capture temperature measurements. RESULTS: Axial mode was consistently associated with greater temperature increases than torsional mode whether tips were operated with or without sleeves. In tests involving bare tips, axial mode and torsional mode peaked at 51.7 degrees C and 34.2 degrees C, respectively. In an example using sleeved tips in which a 30.0 g load was applied for 1 second, temperatures for axial mode reached 45 degrees C and for torsional mode, 38 degrees C. Friction between the sleeved probe and the incisional wall contributed more significantly to the temperature increase than internal metal stress regardless of the mode used. CONCLUSIONS: In all experiments, the temperature increase observed with axial mode was greater than that observed with torsional mode, even when conditions such as power or amplitude and flow rate were varied. Tip-to sleeve friction was a more dominant source of phaco probe heating than internal metal stress. The temperature increase due to internal metal stress was greater with axial mode than with torsional mode. FINANCIAL DISCLOSURE: Dr. Zacharias received research funding from Alcon Laboratories, Inc., to conduct this study. He has no financial or proprietary interest in any material or method mentioned. PMID- 25532645 TI - Confidence of ophthalmology residents in obtaining informed consent. AB - Ophthalmology residents often obtain informed consent for common procedures. In this study, we set out to determine the confidence levels among ophthalmology residents who obtain informed consent. An anonymous online survey was distributed to United States ophthalmology residents across the country. Ninety-five residents participated, evenly distributed geographically and by postgraduate year (PGY). Residents were frequently obtaining consent for procedures despite not being comfortable doing so. Only 18% of residents reported that they always felt comfortable with the informed consent process. Comfort level increased significantly with PGY (P < .001) and prior training in informed consent (P = .032). Of the residents surveyed, 76% indicated a desire for more formal training in the consent process. Most residents would welcome an informed-consent formal training curriculum, which would address 5 of the 6 Accreditation Council for Graduate Medical Education core competencies and meet resident milestones in the Next Accreditation System. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532646 TI - Diagnosis and management of opacified silicone intraocular lenses in patients with asteroid hyalosis. AB - We analyzed 3 calcified silicone IOLs from 2 patients with a history of asteroid hyalosis. In both cases, posterior capsule opacification had been diagnosed and a laser capsulotomy performed before referral. Subsequently, both IOLs were exchanged with hydrophobic acrylic IOLs that were placed in the sulcus. The IOL exchange was challenging due to the open capsule. Light microscopy demonstrated that the white deposits on the explanted IOLs formed an almost confluent crust in some areas, interspersed with clear areas on the posterior optic surfaces. The findings in our cases and in other reported cases may affect the choice of IOL in the presence of asteroid hyalosis. Also, ophthalmologists may consider deferring laser posterior capsulotomy treatment in a calcified silicone IOL to facilitate an IOL exchange procedure. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532647 TI - Iris atrophy and erosion caused by an anterior-chamber angle-supported phakic intraocular lens. AB - We report a case in which an angle-supported phakic IOL was implanted to correct high myopia. Subsequently, the patient experienced photophobia, glare, halo, and loss of visual acuity and became concerned about the cosmetically deforming aspect of her eye. Findings included endothelial cell loss, cataract, pupil ovalization, and severe iris atrophy. The pIOL was removed and cataract surgery was performed, followed by implantation of a bag-in-the-lens IOL, but successful surgical repair of the iris was not possible because of severe iris atrophy. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532648 TI - Unusual case of Scedosporium apiospermum keratitis following phacoemulsification in a systemically well patient. AB - We report the case of a 65-year-old immunocompetent woman who developed Scedosporium apiospermum keratitis after clear-corneal phacoemulsification. A 3.5 mm by 2.7 mm full-thickness stromal infiltrate, corresponding to the superior 2.75 mm clear-corneal incision, was observed 44 days postoperatively. Treatment included preservative-free voriconazole 1.0% hourly, ofloxacin 0.3% 6 times a day, oral voriconazole 200 mg once daily, natamycin 5.0% hourly, dexamethasone 0.1% 4 times a day, and ocular cyclosporine 4 times a day. After 4 months of treatment, the new vessels had regressed, the infiltrate had disappeared, and residual deep scarring remained; the uncorrected distance visual acuity was 0.8 logMAR. To our knowledge, this is the first case of S apiospermum keratitis following clear-corneal phacoemulsification. Another unusual feature is that there were no risk factors for fungal keratitis, specifically no history of trauma, systemic illness, immunosuppression, or contact lens wear. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25532649 TI - Reviewing the reviewers: appraisal of the United States Veterans Health Administration report on femtosecond laser-assisted cataract surgery. PMID- 25532650 TI - December consultation #2. PMID- 25532651 TI - Glaucoma surgical problem: December consultation #1. PMID- 25532652 TI - December consultation #4. PMID- 25532653 TI - December consultation #3. PMID- 25532654 TI - December consultation #5. PMID- 25532655 TI - December consultation #6. PMID- 25532656 TI - December consultation #7. PMID- 25532657 TI - December consultation #9. PMID- 25532658 TI - December consultation #8. PMID- 25532659 TI - December consultation #10. PMID- 25532660 TI - Canaloplasty: its role in glaucoma management. PMID- 25532661 TI - Reply: To PMID 25088621. PMID- 25532662 TI - Minimum stromal thickness for corneal collagen crosslinking. PMID- 25532663 TI - Preventing toric intraocular lens rotation. PMID- 25532664 TI - Reply: To PMID 25135534. PMID- 25532665 TI - Reply: To PMID 25149554. PMID- 25532666 TI - Corneal stromal demarcation line after high-intensity (accelerated) collagen crosslinking. PMID- 25532668 TI - Why are more highly educated people with dementia less likely to be prescribed antipsychotics? PMID- 25532670 TI - Ovariectomy-associated changes in interradicular septum and in tibia metaphysis in different observation periods in rats. AB - In order to standardize an experimental model to study the effects of absence of ovarian hormones in maxillary bones compared with long bones, the aim of this research was to analyze the influence of ovariectomy (OVX) on rat alveolar bone and tibiae, in different observation periods. Thirty-six female rats were ovariectomized or sham operated. After 60, 90 or 120 days, the animals were sacrificed and their hemimandibles, maxillae and tibiae were removed and routinely prepared for hematoxylin and eosin staining. The percentage of bone matrix area in bone septum in the first molar furcation region, and in tibial metaphysis was calculated, and data were submitted to statistical analysis (p<0.05). As regards the histomorphometrical analysis in jaw bones, there was no statistical difference between groups, while the effects of ovariectomy on tibiae were seen as early as 60 days. According to the methods used, there was no significant influence of absence of ovarian hormones on interradicular septum of mandibular or maxillary first molars in the periods studied, despite the reduction in bone matrix area in tibia metaphysis as early as 60 days. PMID- 25532669 TI - Case study: Possible differences in phthalates exposure among the Czech, Hungarian, and Slovak populations identified based on the DEMOCOPHES pilot study results. AB - OBJECTIVE: Phthalates and their metabolites are classified as endocrine modulators. They affect the hormonal balance in both children and adults. The aim of this publication was to compare the urinary levels of phthalate metabolites in selected populations of the Czech Republic (CZ), Slovakia (SK), and Hungary (HU) in relation to the sources of phthalate exposure identified by means of questionnaire (personal care products, floor and wall coverings, plastic toys, and some kinds of foods). METHODS: Data were obtained through the twin projects COPHES (COnsortium to Perform Human biomonitoring on a European Scale) and DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) from 2009 to 2012. The target groups were children aged 6-11 years old and their mothers up to 45 years of age. The metabolites of phthalates (monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), mono-cyclohexyl phthalate (MCHP), mono-(2 ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), and mono-(2-ethyl-5-oxohexyl) phthalate (5OXO-MEHP)) were analysed in first morning urine samples. After enzymatic glucuronide cleavage, the urine sample analyses were performed using ultra-high-performance liquid chromatography electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) in one laboratory that qualified in the External Quality Assessment exercises organised by COPHES. RESULTS: Significant differences in phthalate exposure between countries were revealed for children only but not for mothers. The concentrations of 5-OH-MEHP (P<0.001), 5OXO-MEHP (P<0.001), and their sum (P<0.001) were the highest in SK compared to CZ and HU. The health based guidance values for the sum of DEHP metabolites 5-OH MEHP and 5OXO-MEHP established by the German Commission for biomonitoring of 300 ug/L and 500 ug/L for women adults and children, respectively, were only exceeded in one mother and three boys. A significant difference was also found for MEP (P=0.0149), with the highest concentrations detected in HU. In all countries, the increasing frequency of using personal care products significantly elevated the concentrations of MEP. CONCLUSION: Some differences were observed between countries in the concentrations of individual urinary phthalate metabolites in children. However, the questionnaire results give no direct explanation for the differences between the countries except the variation in using personal care products. PMID- 25532672 TI - Enhanced diesel fuel fraction from waste high-density polyethylene and heavy gas oil pyrolysis using factorial design methodology. AB - Factorial Design Methodology (FDM) was developed to enhance diesel fuel fraction (C9-C23) from waste high-density polyethylene (HDPE) and Heavy Gas Oil (HGO) through co-pyrolysis. FDM was used for optimization of the following reaction parameters: temperature, catalyst and HDPE amounts. The HGO amount was constant (2.00 g) in all experiments. The model optimum conditions were determined to be temperature of 550 degrees C, HDPE = 0.20 g and no FCC catalyst. Under such conditions, 94% of pyrolytic oil was recovered, of which diesel fuel fraction was 93% (87% diesel fuel fraction yield), no residue was produced and 6% of noncondensable gaseous/volatile fraction was obtained. Seeking to reduce the cost due to high process temperatures, the impact of using higher catalyst content (25%) with a lower temperature (500 degrees C) was investigated. Under these conditions, 88% of pyrolytic oil was recovered (diesel fuel fraction yield was also 87%) as well as 12% of the noncondensable gaseous/volatile fraction. No waste was produced in these conditions, being an environmentally friendly approach for recycling the waste plastic. This paper demonstrated the usefulness of using FDM to predict and to optimize diesel fuel fraction yield with a great reduction in the number of experiments. PMID- 25532671 TI - Long-range Fourier domain optical coherence tomography of the pediatric subglottis. AB - BACKGROUND: Acquired subglottic stenosis (SGS) most commonly results from prolonged endotracheal intubation and is a diagnostic challenge in the intubated child. At present, no imaging modality allows for in vivo characterization of subglottic microanatomy to identify early signs of acquired SGS while the child remains intubated. Fourier domain optical coherence tomography (FD-OCT) is a minimally invasive, light-based imaging modality which provides high resolution, three dimensional (3D) cross-sectional images of biological tissue. We used long range FD-OCT to image the subglottis in intubated pediatric patients undergoing minor head and neck surgical procedures in the operating room. METHODS: A long range FD-OCT system and rotary optical probes (1.2mm and 0.7mm outer diameters) were constructed. Forty-six pediatric patients (ages 2-16 years) undergoing minor upper airway surgery (e.g., tonsillectomy and adenoidectomy) were selected for intraoperative, trans-endotracheal tube FD-OCT of the subglottis. Images were analyzed for anatomical landmarks and subepithelial histology. Volumetric image sets were rendered into virtual 3D airway models in Mimics software. RESULTS: FD OCT was performed on 46 patients (ages 2-16 years) with no complications. Gross airway contour was visible on all 46 data sets. Twenty (43%) high-quality data sets clearly demonstrated airway anatomy (e.g., tracheal rings, cricoid and vocal folds) and layered microanatomy of the mucosa (e.g., epithelium, basement membrane and lamina propria). The remaining 26 data sets were discarded due to artifact, high signal-to-noise ratio or missing data. 3D airway models were allowed for user-controlled manipulation and multiplanar airway slicing (e.g., sagittal, coronal) for visualization of OCT data at multiple anatomic levels simultaneously. CONCLUSIONS: Long-range FD-OCT produces high-resolution, 3D volumetric images of the pediatric subglottis. This technology offers a safe and practical means for in vivo evaluation of lower airway microanatomy in intubated pediatric patients. Ultimately, FD-OCT may be applied to serial monitoring of the neonatal subglottis in long-term intubated infants at risk for acquired SGS. PMID- 25532673 TI - Co-gasification of sewage sludge and woody biomass in a fixed-bed downdraft gasifier: toxicity assessment of solid residues. AB - As the demand for fossil fuels and biofuels increases, the volume of ash generated will correspondingly increase. Even though ash disposal is now strictly regulated in many countries, the increasing volume of ash puts pressure on landfill sites with regard to cost, capacity and maintenance. In addition, the probability of environmental pollution from leakage of bottom ash leachate also increases. The main aim of this research is to investigate the toxicity of bottom ash, which is an unavoidable solid residue arising from biomass gasification, on human cells in vitro. Two human cell lines i.e. HepG2 (liver cell) and MRC-5 (lung fibroblast) were used to study the toxicity of the bottom ash as the toxins in the bottom ash may enter blood circulation by drinking the contaminated water or eating the food grown in bottom ash-contaminated water/soil and the toxic compounds may be carried all over the human body including to important organs such as lung, liver, kidney, and heart. It was found that the bottom ash extract has a high basicity (pH = 9.8-12.2) and a high ionic strength, due to the presence of alkali and alkaline earth metals e.g. K, Na, Ca and Mg. Moreover, it also contains concentrations of heavy metals (e.g. Zn, Co, Cu, Fe, Mn, Ni and Mo) and non-toxic organic compounds. Although human beings require these trace elements, excessive levels can be damaging to the body. From the analyses of cell viability (using MTS assay) and morphology (using fluorescence microscope), the high toxicity of the gasification bottom ash extract could be related to effects of high ionic strength, heavy metals or a combination of these two effects. Therefore, our results suggest that the improper disposal of the bottom ash wastes arising from gasification can create potential risks to human health and, thus, it has become a matter of urgency to find alternative options for the disposal of bottom ash wastes. PMID- 25532674 TI - Mass balance of dioxins over a cement kiln in China. AB - The cement production process may be a potential source of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, "dioxins"), due to the widespread distribution of dioxins and potential precursors in raw materials and to conditions favorable to de novo formation in the heat exchangers. The emission, gas/particle distribution, and mass balance of PCDD/Fs were investigated at a typical state-of-the-art Chinese cement kiln. Input and output inventories were established for three campaigns, including two in normal operation and one while co-processing refuse derived fuel (RDF). Sample analysis from stack gas, cement kiln dust, raw meal, fly dust and clinker for the analysis of PCDD/Fs were reported in this study. Dioxins were also analyzed at various positions in the pre-heater, presenting an adsorption-desorption circulation process of PCDD/Fs. The over-all dioxin mass balance was negative, indicating that this cement kiln is not a source but a sink process of dioxins. PMID- 25532675 TI - Randomization to plant-based dietary approaches leads to larger short-term improvements in Dietary Inflammatory Index scores and macronutrient intake compared with diets that contain meat. AB - Studies have examined nutrient differences among people following different plant based diets. However, all of these studies have been observational. The aim of the present study was to examine differences in nutrient intake and Dietary Inflammatory Index (DII) scores among overweight and obese (body mass index 25.0 49.9 kg/m(2)) adults randomized to receive dietary instruction on a vegan (n = 12), vegetarian (n = 13), pescovegetarian (n = 13), semivegetarian (n = 13), or omnivorous (n = 12) diet during a 6-month randomized controlled trial. Nutrient intake, nutrient adequacy, and DII score were assessed via two 24-hour dietary recalls (Automated Self-Administered 24-Hour Dietary Recall) at baseline and at 2 and 6 months. Differences in nutrient intake and the DII were examined using general linear models with follow-up tests at each time point. We hypothesized that individuals randomized to the vegan diet would have lower DII scores and greater improvements in fiber, carbohydrate, fat, saturated fat, and cholesterol at both 2 and 6 months as compared with the other 4 diets. Participants randomized to the vegan diet had significantly greater changes in most macronutrients at both time points, including fat and saturated fat, as well as cholesterol and, at 2 months, fiber, as compared with most of the other diet groups (Ps < .05). Vegan, vegetarian, and pescovegetarian participants all saw significant improvements in the DII score as compared with semivegetarian participants at 2 months (Ps < .05) with no differences at 6 months. Given the greater impact on macronutrients and the DII during the short term, finding ways to provide support for adoption and maintenance of plant-based dietary approaches, such as vegan and vegetarian diets, should be given consideration. PMID- 25532676 TI - Precarious employment and the risk of suicidal ideation and suicide attempts. AB - OBJECTIVE: Although the effect of occupation or employment status on suicide risk is notable, there are few studies on the effect of precarious employment on suicide. We compared suicidal ideation and suicide attempts in precarious workers and their non-precarious counterparts using a representative sample from South Korea. METHOD: The 2008 Korean Community Health Survey data were used for this study. Information was obtained on 52,161 participants (41,063 employees with non precarious work and 11,098 employees with precarious work). The outcome of the logistic regression model was the presence of suicidal thoughts and attempts, and the independent variables were the demographics, socioeconomic status, and health status. RESULTS: Employees with precarious work were more likely to exhibit suicidal ideation (OR=1.41; 95% CI, 1.28-1.55) and suicide attempts (OR=1.52; 95% CI, 1.02-2.27) than employees with non-precarious work. After controlling for income and education (Model 2) depressive feelings (Model 6), compared with unadjusted model, remained significant but the odds ratio was largely attenuated, indicating a strong association between suicidal risk and socioeconomic and feelings of depression. CONCLUSION: Precarious workers had a higher risk of suicidal ideation and suicide attempts than non-precarious workers. Our study suggests that precarious employment is an important risk for suicide. PMID- 25532677 TI - Greater frequency of nut consumption is associated with lower prevalence of peripheral arterial disease. AB - Nut consumption has been associated with lower risk of coronary heart disease and all-cause mortality. The association between nut intake and peripheral arterial disease (PAD) is uncertain. OBJECTIVE: We sought to investigate the association between nut consumption and presence of prevalent PAD in a large cross-sectional sample. METHODS: Self-referred participants at >20,000 US sites who completed a medical and lifestyle questionnaire were evaluated by screening ankle brachial indices for PAD. Multivariable logistic regression analysis was used to estimate odds of PAD in different nut consumption categories. RESULTS: Among 3,312,403 individuals, mean age was 63.6 +/- 10.6 years and 62.8% were female. There were 219,527 cases of PAD. After multivariable adjustment there was an inverse association of nut intake with PAD. Compared to subjects with consumption of nuts=15 g/4184 kJ and alcohol intake <=20 g/day - and diabetes incidence over 10 years. RESULTS: Median interquartile range (IQR) follow-up time was 9.9 (0.3) years; 2211 individuals (7%) developed diabetes. Only 4.4% of participants met all 6 goals (n=1245) and compared to these individuals, participants meeting 0/1 goals had a 3.74 times higher diabetes incidence (95% confidence interval (CI)=2.50 to 5.59), adjusting for sex, age, calendar period, education, family history of diabetes, history of myocardial infarction and long-term illness. If everyone achieved at least four behavioural goals, 14.1% (95% CI: 11.7 to 16.5%) of incident diabetes cases might be avoided. CONCLUSION: Interventions promoting the achievement of behavioural goals in the general population could significantly reduce diabetes incidence. PMID- 25532679 TI - Photo-biotechnology as a tool to improve agronomic traits in crops. AB - Phytochromes are photosensory phosphoproteins with crucial roles in plant developmental responses to light. Functional studies of individual phytochromes have revealed their distinct roles in the plant's life cycle. Given the importance of phytochromes in key plant developmental processes, genetically manipulating phytochrome expression offers a promising approach to crop improvement. Photo-biotechnology refers to the transgenic expression of phytochrome transgenes or variants of such transgenes. Several studies have indicated that crop cultivars can be improved by modulating the expression of phytochrome genes. The improved traits include enhanced yield, improved grass quality, shade-tolerance, and stress resistance. In this review, we discuss the transgenic expression of phytochrome A and its hyperactive mutant (Ser599Ala PhyA) in selected crops, such as Zoysia japonica (Japanese lawn grass), Agrostis stolonifera (creeping bentgrass), Oryza sativa (rice), Solanum tuberosum (potato), and Ipomea batatas (sweet potato). The transgenic expression of PhyA and its mutant in various plant species imparts biotechnologically useful traits. Here, we highlight recent advances in the field of photo-biotechnology and review the results of studies in which phytochromes or variants of phytochromes were transgenically expressed in various plant species. We conclude that photo biotechnology offers an excellent platform for developing crops with improved properties. PMID- 25532680 TI - Real-world treatment patterns and costs in a US Medicare population with metastatic squamous non-small cell lung cancer. AB - OBJECTIVES: Despite advances in the treatment of nonsquamous non-small cell lung cancer (NSCLC), therapeutic choices and overall disease course for squamous NSCLC have remained relatively unchanged over the past several years. We provide a detailed account of current treatment patterns, healthcare use, and survival in real-world clinical settings for metastatic squamous NSCLC. MATERIALS AND METHODS: Patients aged >=65 years with metastatic squamous NSCLC diagnosed 2001 2009 were identified and followed through 2010 using the Surveillance, Epidemiology and End Results-Medicare database. Treatment patterns were descriptively analyzed. Multivariate logistic regressions were estimated to identify predictors of treatment pattern events; generalized linear models were estimated for total all-cause and NSCLC-related costs to assess cost drivers. RESULTS: Of 17,133 patients, 72% received cancer-directed therapy (surgery, radiation, chemotherapy, or biologic therapy), whereas 28% received only supportive care. Median survival was significantly longer in patients receiving cancer-directed therapy (8 months) than in patients receiving supportive care only (2 months) (P<0.0001). An agent-specific first-line chemotherapy regimen was identified for 91% of the 7700 patients who received chemotherapy. Among these, the most common first-line regimen was carboplatin-paclitaxel combination therapy (46%). Common second-line regimens were gemcitabine monotherapy (16%) and pemetrexed monotherapy (11%). Factors associated with decreased odds of receiving cancer-directed treatment were black versus white race (OR, 0.72; 95% CI, 0.64 0.82), residence in the West versus South (OR, 0.73; 95% CI, 0.66-0.81), and metastatic disease at initial diagnosis versus progression to metastatic disease (OR, 0.77; 95% CI, 0.70-0.84). CONCLUSIONS: Our study shows that prognosis remains poor for patients with metastatic squamous NSCLC, even among those receiving treatment, but particularly for patients limited to supportive care only, highlighting the continuing unmet medical need in this population. Additionally, our analysis indicates that selections for second-line and third line chemotherapies are not necessarily consistent with National Comprehensive Cancer Network guidelines. PMID- 25532681 TI - Normal Vulvovaginal Health in Adolescents. AB - As adolescence is often the first time a woman will see a gynecologist, it is important for health care providers to understand and be capable of explaining the changes that occur to a young woman during these years. Many adolescents and their caretakers who seek gynecologic care for what they consider vulvovaginal abnormalities may be misinterpreting completely normal changes; education and reassurance are the best treatment in these cases. Most medical literature on vulvovaginal health focuses on abnormalities and there is a paucity of information on what is considered "normal." This goal of this review is to describe normal anatomic and physiologic vulvovaginal changes that occur during the adolescent years, as well as to offer advice on how to educate and reassure young women during this vulnerable time. PMID- 25532682 TI - Incidental gonadal tumors at the time of gonadectomy in women with Swyer syndrome: a case series. AB - BACKGROUND: Swyer syndrome (46XY complete gonadal dysgenesis) is an uncommonly encountered condition in our population. Gonadectomy is recommended upon diagnosis due to a significant risk of malignant transformation of the dysgenetic gonads, typically to dysgerminoma. CASES: We present 3 cases of women who underwent gonadectomy following a diagnosis of Swyer syndrome. Two of these patients had dysgerminoma confirmed on histopathology. In particular we discuss the macroscopic appearance of the affected gonads and the further management of each case. SUMMARY AND CONCLUSION: Individuals with Swyer syndrome require gonadectomy upon diagnosis of their condition, as part of their multidisciplinary management. For treatment of early stage dysgerminoma, surgical resection of the involved gonad and fallopian tube is curative, again highlighting the need for early intervention. PMID- 25532683 TI - HPV and Cervical Dysplasia in Adolescents: A Progressive March Toward Prevention. AB - Cervical cancer caused by infection with the human papillomavirus is the second most common malignancy among women worldwide. Over the course of the past century our understanding of the virus and the disease has expanded exponentially through landmark studies and pioneers of academic medicine. It has all led to the current evidence-based guidelines for prevention of cervical dysplasia and invasive carcinoma in adolescent females that will significantly lessen morbidity and mortality and may eradicate the disease completely. Unfortunately, the greatest challenge to this may be overcoming common misunderstandings and other barriers to compliance with these guidelines among practitioners, patients, and the general public. PMID- 25532684 TI - [Fourth edition of WHO classification tumours of soft tissue]. AB - The new World Health Organization (WHO) classification of soft tissue tumours was published in 2013, 11years after the previous edition. This new classification includes several changes: newly included sections (gastrointestinal stromal tumors...), newly recognized entities (pseudomiogenic haemangioendothelioma, haemosiderotic fibrolipomatous tumour...), and new genetic and molecular data leading to better understanding and definition of tumours, and are useful as diagnostic tools. This brief review summarizes changes in this new edition of the WHO classification of tumours of soft tissue. PMID- 25532685 TI - [Immunohistochemistry in the diagnosis of sarcomas]. AB - Immunohistochemistry (IHC) is essential in the diagnosis of soft tissue tumor and must rely on good quality technic. Among useful antibodies, it is important to distinguish those with a poor specificity required in order to establish the broad lineage, from those with high specificity, which may lead straightforward towards the entity. Diagnostically useful antibodies such as myogenin, ALK1 and DOG1 have been recently completed by MUC4 and STAT6 which show good sensitivity and specificity in the diagnosis of low-grade fibromyxoid sarcoma and solitary fibrous tumor respectively. ERG is also an interesting antibody. However, it is not completely specific of vascular tumors. Moreover, available material is often limited because of the increase of microbiopsy specimens. Therefore, it is mandatory to optimize this precious tissue by using these new antibodies, especially because molecular technics are increasingly performed in addition to IHC. PMID- 25532686 TI - A randomized trial of the disabilities of the arm, shoulder, and hand administration: tablet computer versus paper and pencil. AB - PURPOSE: To compare the Disabilities of the Arm, Shoulder, and Hand (DASH) patient-reported outcome measure as administered by tablet computer to the traditional paper format. METHODS: In a prospective, randomized study design, 223 consecutive adult patients who presented to the clinic of a single hand surgeon at a tertiary medical center were randomized by visit time to receive the DASH by either paper or tablet computer. Test completeness, time to completion, DASH score, and diagnostic and demographic data were collected and compared between the two cohorts. In total, 120 participants took the DASH using the tablet and 103 using paper. RESULTS: 43% of the paper surveys had at least one question that was omitted, compared with 13% in the tablet group; 14% of the paper surveys were not scoreable (< 27 questions answered) compared with 4% of the tablet surveys. The mean time to complete was 3.1 minutes for the paper version of the DASH and 4.3 minutes for the tablet version. Among our study population, there was no influence of age, sex, or diagnosis category on the time required to complete either version of the test. The mean DASH score was 45 for the paper version and 32 for the tablet version. CONCLUSIONS: The use of digital data entry methods in the arena of health care outcomes research is increasing. Administration of the DASH via a tablet computer resulted in more complete data, slightly increased responder burden, and a lower DASH score. This finding may have important implications for the use of this metric in an electronic format in future research endeavors. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 25532687 TI - Head and neck cancer: from research to therapy and cure. AB - Cumulative findings from many research groups have identified new signaling mechanisms associated with head and neck cancers. We summarize these findings, including discussion of aberrant NOTCH, PI3K, STAT3, immune recognition, oxidative pathway, and regulation of cell cycle and cell death. The genomic landscape of head and neck cancers has been shown to differ depending on human papillomavirus (HPV) status. We discuss studies examining the integration of HPV into genomic regions, as well as the epigenetic alterations that occur in response to HPV infection, and how these may help reveal new biomarker and treatment predictors. The characterization of premalignant lesions is also highlighted, as is evidence indicating that the surgical removal of these lesions is associated with better clinical outcomes. Current surgical methods are also discussed, including several less aggressive approaches such as minimal invasive robotic surgery. While much remains to be done in the fight against head and neck cancer, continued integration of basic research with new treatment options will likely lead to more effective therapeutic strategies directed against this disease. PMID- 25532688 TI - [Professional risk factors associated with the cancer of the ovary. Literature review]. AB - The aim of this work was to review the available literature on occupational risk factors associated with ovarian cancer. A PubMed search was performed using an algorithm with the following search terms: ovary, ovarian, exposure, work, occupation. Relevant articles were selected through assessment of titles and abstracts as well as through the reference lists of related articles. A total of 54 studies were selected for this review, including 17 studies on asbestos exposure and risk of ovarian cancer and, 16 studies on other occupational factors (5 cohort studies and 11 case control studies). An increased risk of ovarian cancer has been reported for several occupations (teachers, administration employees, nurses, religious workers) and various industrial sectors (biomedical research, telephony industry, hairdresser and beautician, printing factories) with inconsistent results. Moreover, in many of these studies, individual risk factors of ovarian cancers were not considered. Despite methodological limitations of published studies, a significantly increased risk for ovarian cancer associated with asbestos exposure have been consistently reported. PMID- 25532689 TI - [FRalpha: a target for prophylactic photodynamic therapy of ovarian peritoneal metastasis?]. AB - Partly due to delays in its diagnosis, ovarian cancer's prognosis remains dire after primary therapy. Treatment consists in complete cytoreductive surgery and platinum-based chemotherapy. Recurrence rates are disappointingly high, as 60% of women with advanced epithelial ovarian cancer considered in remission will develop recurrent disease within five years. Special attention to undetected peritoneal metastasis and residual tumorous cells during surgery is necessary as they are the main predictors of recurrences. Targeted therapies aim to bring chemotherapy, radiotherapy and selective tumor photosensitizer (PS) agents to the targeted cell and its tumoral microenvironment. Folate receptor alpha (FRalpha) shows promising prospects in targeting ovarian cancerous cells. Indeed, with good specificity and frequent overexpression in ovarian cancer, FRalpha is a recurrent topic in recent publications. The aim of this review is to present FRalpha and the reasons that make it an ideal targeting ligand for ovarian carcinoma therapy. Prophylactic photodynamic therapy (PPDT) using new generation FRalpha-coupled agents combined with complete cytoreductive surgery could allow for a significant decrease in recurrence rates. Preclinical trials are being run in order to allow for human clinical applications. PMID- 25532690 TI - [Pertuzumab and solid tumors: perspectives]. AB - Over the past decade, trastuzumab was the only available monoclonal anti-HER2 antibody for the treatment of HER2 positive breast and gastric cancer. Recently, pertuzumab added to docetaxel and trastuzumab showed dramatic overall survival improvement in first line treatment of HER2 positive metastatic breast cancer. Pertuzumab is the first approved monoclonal antibody in a new class of drugs called dimerization inhibitors. This agent was also approved in association with trastuzumab for neoadjuvant HER2-positive breast cancer treatment. However, pertuzumab development was not confined to breast cancer and in the present review, we will focus on biological rational, preclinical data and clinical trial results of pertuzumab in solid tumors excluding breast cancer. PMID- 25532691 TI - Experiences of pain: a longitudinal, qualitative study of patients with head and neck cancer recently treated with radiotherapy. AB - It is not unusual for patients with head and neck cancer (HNC) to suffer from both tumor- and treatment-related pain that is difficult to alleviate despite individualized pain management. The aim of this qualitative study was to describe how HNC patients experience pain and how pain influences those who are treated with radiotherapy (RT). Qualitative semistructured interviews were performed 1 and 6 months after patients completed RT. The interviews addressed symptoms, moods, and suffering. The study included 26 patients with HNC who had recently completed RT. The interviews were analyzed using manifest content analysis. The main category was: HNC patients did not report that their severe physical pain influenced their psychological suffering, but it did influence their social lives. Furthermore, four categories were revealed: pain in the head and neck region, overwhelming fatigue, altered mood and preoccupied mind, and decreased participation and changed relationships. Physical pain, psychological distress, and social withdrawal were prominent at both interviews and consequently their situation can be considered as chronic. Remarkably, patients did not express a clear relationship between pain and psychological load. This may imply a biomedical view of pain or may reflect the difficult situation patients were in (i.e., facing a possibly life-threatening cancer). Thus, their situation might require a prioritization and might negatively affect the possibility of identifying the interaction between the different pain dimensions. The biopsychosocial model of chronic pain aims to understand the interaction between pain and psychosocial factors. Interventions aiming to teach patients with HNC how to internalize the biopsychosocial model framework to manage pain could be useful and should be evaluated in future research. PMID- 25532692 TI - Evidence of cognitive decline in older adults after remote traumatic brain injury: an exploratory study. AB - Separate bodies of literature indicate that a history of a traumatic brain injury (TBI) and natural aging may result in overlapping cognitive profiles, yet little is known about their combined effect. We predicted that a remote TBI would compound normal age-related cognitive decline, particularly affecting executive function. Neuropsychological task performance was compared between a group of older adults who sustained a TBI in their distant past (N = 9) and a group of older adults with no history of head injury (N = 15). While all participants scored in the normal range on the Mini-Mental State Examination, the TBI group scored lower than the non-TBI group. Also, in line with predictions, the TBI group made more errors on measures of executive functioning compared to the non TBI group (the Trail Making B test and the incongruent condition of the Stroop Test), but performed similarly on all tasks with little executive requirements. Findings from this exploratory study indicate that a past TBI may put older adults at a higher risk for exacerbated age-related cognitive decline compared to older adults with no history of TBI. PMID- 25532693 TI - Plasmacytoid dendritic cell bactericidal activity against Burkholderia pseudomallei. AB - Melioidosis sepsis, caused by Burkholderia pseudomallei, is associated with high mortality due to an overwhelming inflammatory response. Plasmacytoid dendritic cells (pDC) are potent producers of type I interferons (IFN). This study investigated whether pDC and type I IFN play a role during the early stages of B. pseudomallei infection. Human and murine pDC internalised and killed B. pseudomallei as efficiently as murine conventional DC (cDC). pDC derived from B. pseudomallei-susceptible (BALB/c) mice demonstrated poor intracellular killing and increased IFN-alpha compared to pDC derived from B. pseudomallei-resistant (C57BL/6) mice. This is the first evidence of pDC bactericidal activity against B. pseudomallei infection. PMID- 25532694 TI - The spectrum of changes in adults with multifocal pulmonary neuroendocrine proliferations: what is the minimum set of pathologic criteria to diagnose DIPNECH? AB - Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) can be difficult to diagnose in resections for lung tumors and other conditions, as variable diagnostic criteria and definitions of "diffuse" and/or "idiopathic" have been used in the literature. We reviewed 70 consecutive lung wedge biopsies and resection specimens with multifocal neuroendocrine cell proliferations (NEP) including neuroendocrine cell hyperplasia (NECH) and/or carcinoid tumorlets to identify pathologic findings significantly associated with neuroendocrine neoplasms. The presence of pathologic changes other than NEP (eg, interstitial fibrosis, bronchiectasis, others) and the number of tumorlets were recorded to identify "idiopathic NEP." Cases were classified into 4 groups: A: NECH only, B: >1 tumorlet without NECH, C: NECH + 2 tumorlets, and D: NECH + >2 tumorlets. Proportions of neuroendocrine neoplasms and presence/absence of pathologic changes other than NEP were compared by group with chi(2) statistics. Carcinoids were seen in 8 (22.8%) of 35 and in 21 (72.4%) of 29 groups B and D cases, respectively. Of the 21 group D carcinoids, 18 (85.7%) lacked other associated pathologic changes, and the incidence of these tumors in this group was significantly higher (P < .001) than in group B. Three high-grade neuroendocrine carcinomas were seen, 1 each in groups A to C. Because group D cases had a significantly higher proportion of carcinoid tumors and a significant lack of association with conditions that could result in secondary NECH, the presence of multifocal NECH combined with 3 or more carcinoid tumorlets is proposed as minimum pathologic criteria for the diagnosis of DIPNECH. PMID- 25532695 TI - Prognostic factors of a satisfactory functional result in patients with unilateral amputations of the upper limb above the wrist that use an upper limb prosthesis. AB - PURPOSE: The purpose of this study is to determine the prognostic factors of a satisfactory functional outcome in patients using upper extremity prosthetics with a proximal third forearm stump, and above, level of amputation. MATERIALS AND METHODS: All patients with longitudinal deficiencies and traumatic amputations of upper extremity with a level of amputation of proximal third forearm and above were included. A total of 49 patients with unilateral upper extremity amputations that had used the prosthetic for a minimum of 2 years were included in the protocol. The Disability arm shoulder hand (DASH) scale was used to determine a good result with a cut-off of less than 40%. The independent variables were the level of amputation, the etiology for its use, initial age of use and number of hours/day using the prosthesis. RESULTS: It was found that patients with a congenital etiology and those that started using the prosthetic before 6 years of age had better functional results. DISCUSSION: It was found that when adapting a patient with an upper extremity prosthetic, which has a high rejection rate of up to 49%, better functional outcomes are found in those who started using it before 6 years of age, and preferably because of a congenital etiology. It was also found that the number of hours/day strongly correlates with a favorable functional outcome. PMID- 25532696 TI - Periprosthetic femoral fractures after hemiarthroplasty. An analysis of 17 cases. AB - PURPOSE: To describe the characteristics of patients with periprosthetic femoral fractures after hemiarthroplasty and analyze their treatment. MATERIAL AND METHOD: An observational, longitudinal, retrospective study was conducted on a series of 17 patients with periprosthetic femoral fractures after hip hemiarthroplasty. Fourteen fractures were treated surgically. The characteristics of patients, fractures and treatment outcomes in terms of complications, mortality and functionality were analyzed. RESULTS: The large majority (82%) of patients were women, the mean age was 86 years and with an ASA index of 3 or 4 in 15 patients. Ten fractures were type B. There were 8 general complications, one deep infection, one mobilization of a non-exchanged hemiarthroplasty, and 2 non unions. There were 85% consolidated fractures, and only 5 patients recovered the same function prior to the injury. At the time of the study 9 patients had died (53%). DISCUSSION: Periprosthetic femoral fractures after hemiarthroplasty will increase in the coming years and their treatment is difficult. CONCLUSION: Periprosthetic femoral fractures after hemiarthroplasty are more common in women around 90 years-old, and usually occur in patients with significant morbidity. Although the Vancouver classification is reliable, simple and reproducible, it is only a guide to decide on the best treatment in a patient often fragile. The preoperative planning is essential when deciding a surgical treatment. PMID- 25532697 TI - Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10. AB - Aldose reductase (AR, AKR1B1) and AKR1B10 are enzymes implicated in important pathologies (diabetes and cancer) and therefore they have been proposed as suitable targets for drug development. Sulindac is the metabolic precursor of the potent non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide, which suppresses prostaglandin production by inhibition of cyclooxygenases (COX). In addition, sulindac has been found to be one of the NSAIDs with higher antitumoral activity, presumably through COX inhibition. However, sulindac anticancer activity could be partially mediated through COX-independent mechanisms, including the participation of AR and AKR1B10. Previously, it had been shown that sulindac and sulindac sulfone were good AR inhibitors and the structure of the ternary complex with NADP(+) and sulindac was described (PDB ID 3U2C). In this work, we determined the three-dimensional structure of AKR1B10 with sulindac and established structure-activity relationships (SAR) of sulindac and their derivatives with AR and AKR1B10. The difference in the IC50 values for sulindac between AR (0.36 MUM) and AKR1B10 (2.7 MUM) might be explained by the different positioning and stacking interaction given by Phe122/Phe123, and by the presence of two buried and ordered water molecules in AKR1B10 but not in AR. Moreover, SAR analysis shows that the substitution of the sulfinyl group is structurally allowed in sulindac derivatives. Hence, sulindac and its derivatives emerge as lead compounds for the design of more potent and selective AR and AKR1B10 inhibitors. PMID- 25532698 TI - Educational handouts for Latino youth who are obese. AB - Although obesity is a significant problem for many children in the United States, youth who are ethnic minorities, especially Latinos, are at an even great risk than their White counterparts. This ethnic disparity suggests that it is important to target Latino youth with prevention and intervention efforts if there is to be a meaningful decline in pediatric obesity rates. Unfortunately, children, including Latino youth, often do not receive specific recommendations at their primary care visits regarding proper nutrition and exercise. With this in mind, we summarized literature related to pediatric obesity in Latino youth and translated four educational handouts that were previously published in English. The handouts are designed to be used by a variety of different professionals who work in pediatric obesity clinics and are an efficient way to share detailed information with patients. PMID- 25532699 TI - Advance practice nurse fellowships: creating awareness, creating opportunities. PMID- 25532701 TI - Dual serotonergic signals: a key to understanding paradoxical effects? AB - Neuroscientists have been puzzled by the fact that acute administration of a selective serotonin reuptake inhibitor (SSRI) produces results that are, at times, compatible with either decreases or increases in serotonergic neurotransmission. Furthermore, the underlying cause of the delayed onset of antidepressant effects of SSRI treatment has remained obscure. It has recently been reported that serotonergic raphe neurons co-release glutamate and that serotonergic and glutamatergic components constitute a dual signal with behaviorally distinct effects. We discuss the consequences of these novel findings and propose a framework for understanding the controversial effects of acute SSRI administration. Furthermore, we suggest that the delayed remedial onset of SSRI treatment could be explained by an initial reduction of the glutamatergic component of the dual serotonergic signal. PMID- 25532700 TI - PET imaging detection of macrophages with a formyl peptide receptor antagonist. AB - Macrophages are a major inflammatory cell type involved in the development and progression of many important chronic inflammatory diseases. We previously found that apolipoprotein E-deficient (Apoe(-/-)) mice with the C57BL/6 (B6) background develop type 2 diabetes mellitus (T2DM) and accelerated atherosclerosis when fed a Western diet and that there are increased macrophage infiltrations in pancreatic islets and aorta. The formyl peptide receptor 1 (FPR1) is abundantly expressed on the surface of macrophages. The purpose of this study was to evaluate the applicability of cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF), a natural FPR1 antagonist, to detection of macrophages in the pancreatic islets and aorta. (64)Cu labeled cFLFLF and (18)F-fluorodeoxyglucose (FDG) were administered to mice with or without T2DM. Diabetic mice showed an increased (18)FDG uptake in the subcutaneous fat compared with control mice, but pancreatic uptake was minimal for either group. In contrast, diabetic mice exhibited visually noticeable more cFLFLF-(64)Cu retention in pancreas and liver than control mice. The heart and pancreas isolated from diabetic mice contained more macrophages and showed stronger PET signals than those of control mice. Flow cytometry analysis revealed the presence of macrophages but not neutrophils in pancreatic islets. Real-time PCR analysis revealed much higher FPR1 expression in pancreatic islets of diabetic over control mice. Autoradiography and immunohistochemical analysis confirmed abundant FPR1 expression in atherosclerotic lesions. Thus, (64)Cu labeled cFLFLF peptide is a more effective PET agent for detecting macrophages compared to FDG. PMID- 25532702 TI - The publication and reproducibility challenges of shared data. AB - The amount of shared data available for re-analysis has greatly increased in the last few years. Here we discuss some of the challenges raised by the analysis of these shared datasets and propose some strategies to address these issues. PMID- 25532703 TI - Overview on major lipid peroxidation bioactive factor 4-hydroxynonenal as pluripotent growth-regulating factor. AB - The reactive aldehyde 4-hydroxynonenal (HNE) is major bioactive marker of lipid peroxidation generated under oxidative stress from polyunsaturated fatty acids. Biomedical significance of HNE was first revealed in pathogenesis of various degenerative and malignant diseases. Thus, HNE was considered for decades only as cytotoxic molecule, "second toxic messenger of free radicals" responsible for numerous undesirable consequences of oxidative stress. However, the increase of knowledge on physiology of redox signaling revealed also desirable, physiological roles of HNE, especially in the field of cellular signaling pathways regulating proliferation, differentiation, and apoptosis. These pluripotent effects of HNE can be explained by its concentration-dependent interactions with the cytokine networks and complex cellular antioxidant systems also showing cell and tissue specificities. Therefore, this paper gives a comprehensive, yet short overview on HNE as pluripotent growth-regulating factor. PMID- 25532704 TI - Social support exchanges in a social media community for people living with HIV/AIDS in China. AB - In recent years, social media has become an important source of social support. People living with HIV/AIDS in China created an online support group (the HIV/AIDS Weibo Group) on Weibo, the Chinese version of Twitter, in January 2011. The current study examined how social support transmitted in this social media community. First, messages over five successive weeks (2 May 2011 to 13 June 2011) were randomly selected from the HIV/AIDS Weibo Group on Weibo. Next, we employed social network analysis to map the HIV/AIDS Weibo Group's structure and to measure the study variables. After that, a multivariate analysis of variance was applied to examine the influence of frequency of contact and reciprocity on informational and emotional social support exchanged in each dyad. The results revealed that pairs with a high level of contact frequency or reciprocity exchanged more informational support than do pairs with a low level of contact frequency or reciprocity. Moreover, dyadic partners with high frequency of contact exchanged a larger amount of emotional support than those with a low level frequency of contact; but strongly reciprocal dyads did not exchange significantly more emotional social support than their counterparts with a low level of reciprocity. PMID- 25532705 TI - Cardiac function assessed by exercise echocardiography on the first morning after coronary artery bypass grafting. AB - Cardiac surgery patients are urged to resume light physical activity on the first postoperative day, even if cardiac function may not have recovered fully after the operation. To elucidate the postoperative recovery process, we examined cardiac surgery patients with exercise echocardiography before and on the first day after the operation. Patients undergoing on-pump coronary artery bypass grafting were examined with echocardiography during semirecumbent cycle exercise. Patients exercised for five minutes at 10 W intensity and five minutes at 30 W intensity in bed with the upper body supported to approximately 30 degrees . Fourteen patients were studied. Mitral annulus excursion and pulsed wave Doppler from the left ventricular outflow tract indicated postoperatively reduced cardiac stroke volume. Early diastolic tissue velocities of the mitral annulus were reduced, and early trans-mitral flow velocity was increased. The ratio between early mitral flow velocity and early diastolic mitral tissue velocity was increased postoperatively, indicating impaired left ventricular relaxation and increased left atrial pressure. Postoperative systolic mitral annulus tissue velocities were similar to preoperative velocities, indicating maintained systolic function. Postoperative exercise was associated with improvements in myocardial function indices and cardiac stroke volume similar to preoperative improvements. There were no signs of further deterioration in myocardial function during 30 W exercise. In summary, reduced left ventricular diastolic function after surgery resulted in reduced cardiac stroke volume, increased left atrial pressure and a higher rate of perceived exertion on the first postoperative day. PMID- 25532706 TI - Effectiveness of tranexamic acid in reducing blood loss in spinal surgery: a meta analysis. AB - BACKGROUND: The aim of present meta-analysis was to evaluate the effectiveness of tranexamic acid (TXA) use in reducing blood loss and the related thrombotic complications in spinal surgery. METHODS: Three databases (MEDLINE, EMBASE, and the Cochrane Library) were searched through October 2012 to identify the relevant randomized controlled trials (RCTs) regarding the TXA effective in spinal surgery. Mean differences (MDs) of blood loss, blood transfusions, and postoperative partial thromboplastic time (PTT), odds ratios (ORs) of blood transfusion and thrombotic complication in TXA-treated group compared to placebo group were extracted and combined using random-effect meta-analysis. RESULTS: A total of 6 RCTs comprising 411 patients were included in the meta-analysis according to the pre-defined selection criteria. TXA-treated group had significantly less amount of blood loss and blood transfusions per patient, and had smaller proportion of patients who required a blood transfusion compared with the placebo group. The use of TXA can significantly reduce the postoperative PTT with weighted MD of -1.59 [(95% confidence interval (CI):-3.07, -0.10] There is a null association between thrombosis complications and the use of TXA. CONCLUSION: We conclude that the use of TXA in patients undergoing spinal surgery appears to be effective in reducing the amount of blood loss, the volume of blood transfusion, the transfusion rate, and the postoperative PTT. However, data were too limited for any conclusions regarding safety. More high-quality RCTs are required before recommending the administered of TXA in spinal surgery. PMID- 25532707 TI - Ultrafast fluorescence upconversion technique and its applications to proteins. AB - The basic principles and main characteristics of the ultrafast time-resolved fluorescence upconversion technique (conventional and space-resolved), including requirements for nonlinear crystals, mixing spectral bandwidth, acceptance angle, etc., are presented. Applications to flavoproteins [wild-type (WT) FMN-binding protein and its W32Y, W32A, E13R, E13K, E13Q and E13T mutants] and photoresponsive proteins [WT photoactive yellow protein and its R52Q mutant in solution and as single crystals] are demonstrated. For flavoproteins, investigations elucidating the effects of ionic charges on ultrafast electron transfer (ET) dynamics are summarized. It is shown that replacement of the ionic amino acid Glu13 and the resulting modification of the electrostatic charge distribution in the protein chromphore-binding pocket substantially alters the ultrafast fluorescence quenching dynamics and ET rate in FMN-binding protein. It is concluded that, together with donor-acceptor distances, electrostatic interactions between ionic photoproducts and other ionic groups in the proteins are important factors influencing the ET rates. In WT photoactive yellow protein and the R52Q mutant, ultrafast photoisomerization dynamics of the chromophore (deprotonated trans-p-coumaric acid) in liquid and crystal phases are investigated. It is shown that the primary dynamics in solution and single crystal phases are quite similar; hence, the photocycle dynamics and structural differences observed at longer time scales arise mostly from the structural restraints imposed by the crystal lattice rigidity versus the flexibility in solution. PMID- 25532708 TI - Panstrongylus geniculatus and four other species of triatomine bug involved in the Trypanosoma cruzi enzootic cycle: high risk factors for Chagas' disease transmission in the Metropolitan District of Caracas, Venezuela. AB - BACKGROUND: Chagas' disease is caused by the protozoan Trypanosoma cruzi and is autochthonous to the Americas. Its distribution depends on triatomine bugs that are responsible for the transmission of the disease. In 2005, we reported the presence of Panstrongylus geniculatus as a risk for Chagas' disease transmission in Caracas and neighboring areas. Three massive oral outbreaks occurred in the following years. Here we report the results of a 7-year study on triatomine species found in the Metropolitan District of Caracas (MDC), Venezuela. METHODS: Triatomine species collected by inhabitants of Caracas during 7 years were analyzed for parasite infection and blood meal. Triatomines were found in 31 of the 32 parishes surveyed. Traitomines were examined for the presence of blood and parasites in the digestive tract. Molecular techniques were used for the typing of parasites. RESULTS: A total of 3551 triatomines were captured from 31 of the 32 parishes surveyed. The vast majority of these were identified as P. geniculatus (98.96%), followed by Triatoma nigromaculata (0.59%), Triatoma maculata (0.39%) and Rhodnius prolixus (0.06%). Triatomines were always most abundant between April and June, and 2010 showed the highest number. We found that 54% of the specimens were females, 42.5% males and 3.5% nymphs. Overall, 75.2% of the insects were naturally infected with T. cruzi and 48.7% had fed on blood. Analysis of the adult forms showed that 60% of the females and 31.9 % of the males had blood in their stomachs, and 77.5% of the females and 73.3% of the males were naturally infected with T. cruzi. Nearly all, 99.6% of the T. cruzi isolates analyzed belonged to the TcI genotype. CONCLUSIONS: Blood-fed triatomine bugs infected with T. cruzi were distributed throughout Caracas. Four different species of triatomines were identified of which P. geniculatus was by far the most predominant. Our previous report of Eratyrus mucronatus raises the number of triatomine species in the MDC to 5. Dramatic modifications to the surrounding natural habitats have led to the establishment of a T. cruzi urban enzootic cycle, resulting in a high risk for Chagas' disease transmission in this capital city. PMID- 25532709 TI - Evaluation of Bio-VOC Sampler for Analysis of Volatile Organic Compounds in Exhaled Breath. AB - Monitoring volatile organic compounds (VOCs) from exhaled breath has been used to determine exposures of humans to chemicals. Prior to analysis of VOCs, breath samples are often collected with canisters or bags and concentrated. The Bio-VOC breath sampler, a commercial sampling device, has been recently introduced to the market with growing use. The main advantage for this sampler is to collect the last portion of exhaled breath, which is more likely to represent the air deep in the lungs. However, information about the Bio-VOC sampler is somewhat limited. Therefore, we have thoroughly evaluated the sampler here. We determined the volume of the breath air collected in the sampler was approximately 88 mL. When sampling was repeated multiple times, with the succeeding exhalations applied to a single sorbent tube, we observed linear relationships between the normalized peak intensity and the number of repeated collections with the sampler in many of the breath VOCs detected. No moisture effect was observed on the Tenax sorbent tubes used. However, due to the limitation in the collection volume, the use of the Bio-VOC sampler is recommended only for detection of VOCs present at high concentrations unless repeated collections of breath samples on the sampler are conducted. PMID- 25532710 TI - Towards the fecal metabolome derived from moderate red wine intake. AB - Dietary polyphenols, including red wine phenolic compounds, are extensively metabolized during their passage through the gastrointestinal tract; and their biological effects at the gut level (i.e., anti-inflammatory activity, microbiota modulation, interaction with cells, among others) seem to be due more to their microbial-derived metabolites rather than to the original forms found in food. In an effort to improve our understanding of the biological effects that phenolic compounds exert at the gut level, this paper summarizes the changes observed in the human fecal metabolome after an intervention study consisting of a daily consumption of 250 mL of wine during four weeks by healthy volunteers (n = 33). It assembles data from two analytical approaches: (1) UPLC-ESI-MS/MS analysis of phenolic metabolites in fecal solutions (targeted analysis); and (2) UHPLC-TOF MS analysis of the fecal solutions (non-targeted analysis). Both approaches revealed statistically-significant changes in the concentration of several metabolites as a consequence of the wine intake. Similarity and complementarity between targeted and non-targeted approaches in the analysis of the fecal metabolome are discussed. Both strategies allowed the definition of a complex metabolic profile derived from wine intake. Likewise, the identification of endogenous markers could lead to new hypotheses to unravel the relationship between moderate wine consumption and the metabolic functionality of gut microbiota. PMID- 25532711 TI - The current state of welfare, housing and husbandry of the English pet rabbit population. AB - BACKGROUND: The welfare of pet rabbits is an area of growing interest in Europe and the UK. This study analyses questionnaire results from a diverse population of 1254 rabbit owners from three different geographical areas in England with the aim of providing an accurate representation of how pet rabbits are currently housed and cared for and key aspects of their health and welfare. RESULTS: Rabbits were kept in a variety of different housing types, the most common being a traditional hutch/cage (59%). Although the majority had additional exercise areas, access was often unpredictable, or ill-timed, which may compromise welfare. Only 41.9% of owners kept their rabbit with conspecifics, limiting their ability to engage in social behaviour. Of those rabbits housed with a companion, although many were reported to be amicable and to engage in positive interactions, over a quarter were reported to fight at least occasionally (25.3%), whilst 22.7% guarded resources and 27.1% avoided one another. Whilst low levels of some of these behaviours may be a normal part of social interaction, the relatively high levels reported here suggest that not all cohabiting pairs of rabbits are compatible, which is potentially a significant welfare issue.Although the vast majority of owners fed hay for over 10% this was less than daily. Pelleted foods were very popular (71.4% at least daily) compared to commercial muesli mixes (32.6%). As in previous studies, dental problems were commonly reported (12.2% of rabbits); however, so were eye problems (12.9%), digestive problems (11.5%) and parasites (11.3%). A large proportion of rabbits (58%) were thought to be fearful of loud noises, and 61% were not reported as calm when handled by their owner, which may be a significant concern for this species. CONCLUSION: This study has confirmed and expanded on previous findings: many pet rabbits were found to be in good health, had compatible companions and were provided with enriched living areas. However, it also found numerous welfare issues that affect large numbers of pet rabbits. We suggest further studies are required exploring the accuracy of owner reports (which possibly under-report many problems) and prioritising the issues raised here. PMID- 25532712 TI - Computed tomography screening for lung cancer: preliminary results in a diverse urban population. AB - PURPOSE: The purpose of this study was to describe the baseline characteristics and results of the initial 18 months of our clinical computed tomography (CT) lung cancer screening program in an ethnically diverse, poor, predominantly overweight, and obese population, which differs dramatically from the National Lung Screening Trial population. MATERIALS AND METHODS: All patients had a physician referral for CT lung cancer screening and met National Lung Screening Trial eligibility criteria. Infrastructure developed for the program included a standardized results report [Bronx score of 1 to 5 (modeled on BI-RADS)] for the electronic medical record and a dedicated bilingual screening coordinator. If the patient's insurance did not cover CT screening, a fee of $75 was charged. RESULTS: A total of 320 patients [54% (174) men, mean age 64 y] underwent initial CT lung cancer screening from December 18, 2012 to July 3, 2014. The median pack years was 47, and 68% (218) were current smokers. Twenty-six percent (84) were white, and 70% (223) were overweight (101) or obese (122). The lung cancer prevalence was 2.2% (7/320). Seventy-eight percent (7/9) of patients with CT findings positive for lung cancer (score 5a, 5b) had proven lung cancer; 1 had stage 1 (1B) disease, and 6 had stage IIA or higher disease. The false-positive rate for a Bronx score >=3 was 19% (60). Medicare and Medicaid insure 80% of the institution's overall population but only 38% (121) of the CT screening patients. CONCLUSIONS: CT screening is feasible in a diverse inner-city population with the support of a robust infrastructure. Further study is needed to determine whether CT screening will confer a mortality benefit in this population. PMID- 25532713 TI - Predicting feed digestibility from NIRS analysis of pig faeces. AB - Digestibility is a key parameter in the evaluation of feeds; however, the measurements on animals require heavy experimental trials, which are hardly feasible when large numbers of determinations are required - for example, in genetic studies. This experiment aimed at investigating the possibility to predict digestibility from NIRS spectra measured on faeces. A total of 196 samples were available from a digestibility experiment investigating the effects of age and genetic background of Large White pigs fed the same diet, rich in fibre (NDF=21.4% DM). Digestibility of dry matter (dDM), organic matter (dOM), nitrogen content (dN), energy (dE) and apparent digestible energy content (ADE) were calculated, as well as total N content of faeces (N). The faeces samples were submitted to reflectance NIRS analysis after freeze-drying and grinding. Calibration errors and validation errors were, respectively, 0.08 and 0.13% DM for total N in faeces, 0.97% and 1.08% for dDM, 0.79% and 1.04% for dOM, 1.04% and 1.47% for dN, 0.87% and 1.12% for dE and 167 and 213 kJ/kg DM for ADE. These results indicate that NIRS can account for digestibility differences due to animal factors, with an acceptable accuracy. NIRS appears to be a promising tool for large-scale evaluations of digestibility. It could also be used for the study of digestibility of different feeds, after appropriate calibration based on a wide range of feed types. PMID- 25532714 TI - Indicators for Universal Health Coverage: can Kenya comply with the proposed post 2015 monitoring recommendations? AB - INTRODUCTION: Universal Health Coverage (UHC), referring to access to healthcare without financial burden, has received renewed attention in global health spheres. UHC is a potential goal in the post-2015 development agenda. Monitoring of progress towards achieving UHC is thus critical at both country and global level, and a monitoring framework for UHC was proposed by a joint WHO/World Bank discussion paper in December 2013. The aim of this study was to determine the feasibility of the framework proposed by WHO/World Bank for global UHC monitoring framework in Kenya. METHODS: The study utilised three documents--the joint WHO/World Bank UHC monitoring framework and its update, and the Bellagio meeting report sponsored by WHO and the Rockefeller Foundation--to conduct the research. These documents informed the list of potential indicators that were used to determine the feasibility of the framework. A purposive literature search was undertaken to identify key government policy documents and relevant scholarly articles. A desk review of the literature was undertaken to answer the research objectives of this study. RESULTS: Kenya has yet to establish an official policy on UHC that provides a clear mandate on the goals, targets and monitoring and evaluation of performance. However, a significant majority of Kenyans continue to have limited access to health services as well as limited financial risk protection. The country has the capacity to reasonably report on five out of the seven proposed UHC indicators. However, there was very limited capacity to report on the two service coverage indicators for the chronic condition and injuries (CCIs) interventions. Out of the potential tracer indicators (n = 27) for aggregate CCI-related measures, four tracer indicators were available. Moreover the country experiences some wider challenges that may impact on the implementation and feasibility of the WHO/World Bank framework. CONCLUSION: The proposed global framework for monitoring UHC will only be feasible in Kenya if systemic challenges are addressed. While the infrastructure for reporting the MDG related indicators is in place, Kenya will require continued international investment to extend its capacity to meet the data requirements of the proposed UHC monitoring framework, particularly for the CCI-related indicators. PMID- 25532715 TI - COMT gene haplotypes are closely associated with postoperative fentanyl dose in patients. AB - BACKGROUND: Fentanyl's analgesic efficacy varies widely among individuals. The single-nucleotide polymorphisms (SNPs) of catechol-O-methyltransferase (COMT) modulate sensitivity to pain. It remains unclear, however, whether COMT genetic variability affects postoperative fentanyl analgesia in patients undergoing radical gastrectomy. METHODS: One hundred fifteen patients, ASA physical status I III, who were scheduled for radical gastrectomy under general anesthesia, were enrolled in this study. Patient-controlled IV analgesia with fentanyl was administered during the first 48 hours after surgery. Visual analog scale score for patients' pain was maintained at <=30 mm. The amount of fentanyl consumed and side effects were recorded for the first 24 and 48 hours postoperatively. The SNPs of COMT (rs6269, rs4633, rs4818, and rs4680) of all patients were screened by DNA sequence analysis of polymerase chain reaction-amplified DNA or polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There were no significant differences in the doses of fentanyl used among patients possessing different SNPs of COMT rs6269, rs4633, rs4818, and rs4680 at 24 (all P > 0.207) and 48 (all P > 0.148) hours after surgery. COMT gene haplotypes combined by COMT rs6269, rs4633, rs4818, and rs4680, however, significantly affected fentanyl consumption at 24 (P = 0.029) and 48 (P = 0.032) hours after surgery. Among the haplotypes of COMT gene, patients with haplotype ACCG consumed more fentanyl than GCGG and ATCA haplotypes during the first 24 and 48 hours (all P < 0.042) after surgery. No significant differences were found in the incidence of nausea, vomiting, and dizziness among the 4 SNPs of COMT gene (all P > 0.079) and their haplotypes (all P > 0.482). CONCLUSIONS: COMT gene haplotype constructed by rs6269, rs4633, rs4818, and rs4680 contributes to the individual variation of postoperative analgesia with fentanyl. Patients carrying the COMT gene haplotype ACCG consumed the most drug during the first 24 and 48 hours postoperatively. PMID- 25532716 TI - Highly lithium-ion conductive battery separators from thermally rearranged polybenzoxazole. AB - High power density lithium ion battery (HLIB) separators were fabricated for the first time from thermally rearranged poly(benzoxazole-co-imide) (TR-PBOI) nanofibrous membranes coated with TR-PBOI nanoparticles, which show distinct thermal and dimensional stabilities as well as excellent cycle retention and rate capability. PMID- 25532720 TI - A multicenter prospective study on the prevalence of Helicobacter pylori-negative and nonsteroidal anti-inflammatory drugs-negative idiopathic peptic ulcers in Japan. AB - BACKGROUND AND AIM: The prevalence of Helicobacter pylori-negative and nonsteroidal anti-inflammatory drug-negative peptic ulcers, commonly known as idiopathic peptic ulcers (IPUs), has been reported to be very low (0.9-2.6%) in Japan based on data from the 1990s. However, recent trends have yet to be been reported. Herein, we present a multicenter prospective analysis between 2012 and 2013 investigating current trends in the prevalence and characteristics of IPUs in Japan. METHODS: Clinical data of all peptic ulcer subjects detected via endoscopy at four participating hospitals were prospectively collected between April 2012 and March 2013. Enrolled subjects were classified according to H. pylori infection status and intake of nonsteroidal anti-inflammatory drugs. Multiple logistic regression analyses were used to determine the risk factors for IPUs. RESULTS: Of 382 enrolled patients with peptic ulcers, 46 (12%) were judged to have IPUs. Compared with those with simple H. pylori-positive ulcers, patients with IPUs were significantly older (P < 0.02) and more often had underlying comorbidities such as hypertension (P < 0.02) and hyperlipidemia (P < 0.05). Multivariate regression analysis indicated that the presence of multiple underlying diseases was the only significant risk factor for IPUs, with an odds ratio of 3.8 (95% confidence interval, 1.3-11.1). CONCLUSIONS: This study revealed that the prevalence of IPUs in patients with peptic ulcers in Japan is 12%, much higher than previously reported. Presence of multiple underlying comorbid diseases, rather than aging itself, is an important risk factor for IPUs. PMID- 25532721 TI - Evaluation of Escherichia coli viability by flow cytometry: A method for determining bacterial responses to antibiotic exposure. AB - BACKGROUND: In this study, we check for the presence of specific resistance genes by polymerase chain reaction (PCR) and then we used flow cytometry (FCM) to evaluate antibiotic-induced effects in different strains of Escherichia coli (E. coli). METHODS: The presence of resistance genes was investigated by PCR in 10 strains of E. coli isolated from Foglia River. Bacterial responses to different antibiotics were also tested with FCM techniques by evaluating both the degree of decrease in viability and the light scatter changes in all of the strains. RESULTS: PCR revealed that only one strain exhibits the presence of one resistance gene. Despite this, analyses of strains using FCM evidenced the presence of viable subpopulations after antibiotic treatment. Furthermore, analyses of scatter signals revealed profound changes in the Forward Scatter and Side Scatter of the bacterial populations as a consequence of antibiotic exposure, confirming the viability and membrane potential data. The riverine strains were in general less sensitive to antibiotics than the reference strain (ATCC 25922). CONCLUSIONS: Antibiotic resistance is a widespread phenomena. The multiparametric approach based on FCM used in this study, providing results about different aspects (cell viability, membrane potential, light scatter changes), may overcome the limitation of PCR and could represent an adequate method for the evaluation of bacteria responses to antibiotic exposure. PMID- 25532722 TI - Halide binding and inhibition of laccase copper clusters: the role of reorganization energy. AB - Laccase-like proteins are multicopper oxidases involved in several biological and industrial processes. Their application is commonly limited due to inhibition by fluoride and chloride, and as-isolated proteins are often substantially activated by heat, suggesting that multiple redox states can complicate characterization. Understanding these processes at the molecular level is thus desirable but theoretically unexplored. This paper reports systematic calculations of geometries, reorganization energies, and ionization energies for all partly oxidized states of the trinuclear copper clusters in realistic models with ~200 atoms. Corrections for scalar-relativistic effects, dispersion, and thermal effects were estimated. Fluoride, chloride, hydroxide, or water was bound to the T2 copper site of the oxidized resting state, and the peroxo intermediate was also computed for reference. Antiferromagnetic coupling, assigned oxidation states, and general structures were consistent with known spectroscopic data. The computations show that (i) ligands bound to the T2 site substantially increase the reorganization energy of the second reduction of the resting state and reduce the redox potentials, providing a possible mechanism for inhibition; (ii) the reorganization energy is particularly large for F(-) but also high for Cl(-), consistent with the experimental tendency of inhibition; (iii) reduction leads to release of Cl(-) from the T2 site, suggesting a mechanism for heat/reduction activation of laccases by dissociation of inhibiting halides or hydroxide from T2. PMID- 25532723 TI - Risk factors for late dysphagia after (chemo)radiotherapy for head and neck cancer: A systematic methodological review. AB - BACKGROUND: The purpose of this systematic review was to identify the risk factors for late dysphagia in patients with head and neck cancer after (chemo)radiotherapy. METHODS: The review was performed using search strategies, including PubMed, the Cochrane Library, and Embase databases. The effects of studies were combined with the study quality score using a best-evidence synthesis model. RESULTS: Twenty observational studies were evaluated. According to the best-evidence synthesis criteria, there were 2 strong-evidence risk factors for late dysphagia, including the use of chemoradiotherapy (CRT) and the presence of hypopharyngeal carcinoma. We also identified 8 moderate-evidence, 17 limited-evidence, and 1 conflicting-evidence risk factors. CONCLUSION: Although there is no conclusive evidence for dysphagia in patients with head and neck cancer after (chemo)radiotherapy, these data provide evidence to guide clinicians in patients who will have late dysphagia and to choose an optimal prophylactic strategy. PMID- 25532724 TI - Comparison of chemiluminescence and toluidine blue in the diagnosis of dysplasia in leukoplakia: a cross-sectional study. AB - AIMS: The early diagnosis and treatment of oral cancer at a potentially-malignant stage would reduce morbidity and improve the survival rates and quality of life of patients. Leukoplakia is the most common potentially-malignant disorder. Clinical examination alone cannot differentiate between dysplastic and non dysplastic leukoplakia. Chemiluminescence and toluidine blue are adjuncts to conventional examination for the early detection of dysplasia. The present study was conducted to compare the efficacies of chemiluminescence and toluidine blue for the diagnosis of dysplasia in leukoplakia. METHODS: One hundred patients with leukoplakia were subjected to conventional oral examination, chemiluminescent examination with ViziLite and toluidine blue test, followed by histopathological confirmation of dysplasia. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of chemiluminescence was 84.84%, 41.17%, 73.68%, 58.33%, and 70%, respectively. For toluidine blue it was 42.4%, 88.23%, 87.50%, 44.11%, and 58% respectively. CONCLUSIONS: Both the techniques have adjunctive utility in the diagnosis of dysplasia in leukoplakia, but toluidine blue was more effective in identifying the more severe grades of dysplasia, and thus it effectively discriminated high-risk from low-risk lesions. PMID- 25532726 TI - How can two soft bodied animals be precisely connected? a miniature quick-connect system in the slugs, Arion lusitanicus and Arion rufus. AB - Among stylommatophoran gastropods, many species have simplified or reduced their copulatory organs, for example, within the Arionidae, many species lack penes. In this study, I ask two questions 1) How are soft bodied slugs which do not possess a penis connected during copulation? and 2) Is there a mechanical isolating barrier between related sympatric slug species? Observations on the mating behavior and the functional morphology of the distal genital apparatus were made in a mixed population of Arion lusitanicus and Arion rufus. The investigated Arion species exhibit an elaborate copulation process with a quick genital coupling. Prior to full eversion of the distal genitalia, the genital coupling proceeds inside the atrium cavity of one of the partners. This is in contrast to the symmetrical mutual eversion in penis-bearing species. The donor-recipient channels are tightly connected to one after another and fit precisely. During copulation, the jelly-coated spermatophore of the donor is pressed out into the connected channel of the partner, where it is implanted only with its frontal part. In the field, successful interspecific matings in terms of spermatophore transfer were rarely observed. The observations presented indicate a mechanical barrier which may profoundly influence the intraspecific and interspecific mating success. PMID- 25532725 TI - Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo. AB - The use of bone marrow-derived mesenchymal stromal cells (BMSC) in the treatment of alloimmune and autoimmune conditions has generated much interest, yet an understanding of the therapeutic mechanism remains elusive. We therefore explored immune modulation by a clinical-grade BMSC product in a model of human-into-mouse xenogeneic graft-versus-host disease (x-GVHD) mediated by human CD4(+) Th1 cells. BMSC reversed established, lethal x-GVHD through marked inhibition of Th1 cell effector function. Gene marking studies indicated BMSC engraftment was limited to the lung; furthermore, there was no increase in regulatory T cells, thereby suggesting a paracrine mechanism of BMSC action. BMSC recipients had increased serum CD73 expressing exosomes that promoted adenosine accumulation ex vivo. Importantly, immune modulation mediated by BMSC was fully abrogated by pharmacologic therapy with an adenosine A2A receptor antagonist. To investigate the potential clinical relevance of these mechanistic findings, patient serum samples collected pre- and post-BMSC treatment were studied for exosome content: CD73 expressing exosomes promoting adenosine accumulation were detected in post BMSC samples. In conclusion, BMSC effectively modulate experimental GVHD through a paracrine mechanism that promotes adenosine-based immune suppression. PMID- 25532727 TI - Fe3 O4 nanoparticle redox system modulation via cell-cycle progression and gene expression in human mesenchymal stem cells. AB - The use of engineered nanoparticles (NPs) across multiple fields and applications has rapidly increased over the last decade owing to their unusual properties. However, there is an increased need in understanding their toxicological effect on human health. Particularly, iron oxide (Fe3 O4 ) have been used in various sectors, including biomedical, food, and agriculture, but the current understanding of their impact on human health is inadequate. In this investigation, we assessed the toxic effect of Fe3 O4 NPs on human mesenchymal stem cells (hMSCs) adopting cell viability, cellular morphological changes, mitochondrial transmembrane potential, and cell-cycle progression assessment methodologies. Furthermore, the expression of oxidative stress, cell death, and cell-cycle regulatory genes was assessed using quantitative polymerase chain reaction. The Fe3 O4 NPs induced cytotoxicity and nuclear morphological changes in hMSCs by dose and time exposure. Cell-cycle analysis indicated that Fe3 O4 NPs altered the cell-cycle progression through a decrease in the proportion of cells in the G0 -G1 phase. The hMSC mitochondrial membrane potential loss increased with an increase in the concentration of Fe3 O4 NPs exposure. The observed expression levels of the CYP1A, TNF3, TNFSF10, E2F1, and CCNC genes were significantly upregulated in hMSCs in response to Fe3 O4 NPs exposure. Our findings suggest that Fe3 O4 NPs caused metabolic stress through altered cell cycle, oxidative stress, and cell death regulatory gene expression in hMSCs. The results of this investigation revealed that Fe3 O4 NPs exhibited moderate toxicity on hMSCs and that Fe3 O4 NPs may have biomedical applications at low concentrations. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 901-912, 2016. PMID- 25532728 TI - Stimuli-responsive electrodes detect oxidative stress and liver injury. AB - A digital point-of-care biosensor for measuring reactive oxygen species is presented based on novel reactive oxygen species responsive polymer-based electrodes. The biosensor is able to detect a drug-induced liver injury by monitoring the oxidative stress in the blood. PMID- 25532730 TI - Atomically precise metal nanoclusters: stable sizes and optical properties. AB - Controlling nanoparticles with atomic precision has long been a major dream of nanochemists. Breakthroughs have been made in the case of gold nanoparticles, at least for nanoparticles smaller than ~3 nm in diameter. Such ultrasmall gold nanoparticles indeed exhibit fundamentally different properties from those of the plasmonic counterparts owing to the quantum size effects as well as the extremely high surface-to-volume ratio. These unique nanoparticles are often called nanoclusters to distinguish them from conventional plasmonic nanoparticles. Intense work carried out in the last few years has generated a library of stable sizes (or stable stoichiometries) of atomically precise gold nanoclusters, which are opening up new exciting opportunities for both fundamental research and technological applications. In this review, we have summarized the recent progress in the research of thiolate (SR)-protected gold nanoclusters with a focus on the reported stable sizes and their optical absorption spectra. The crystallization of nanoclusters still remains challenging; nevertheless, a few more structures have been achieved since the earlier successes in Au102(SR)44, Au25(SR)18 and Au38(SR)24 nanoclusters, and the newly reported structures include Au20(SR)16, Au24(SR)20, Au28(SR)20, Au30S(SR)18, and Au36(SR)24. Phosphine protected gold and thiolate-protected silver nanoclusters are also briefly discussed in this review. The reported gold nanocluster sizes serve as the basis for investigating their size dependent properties as well as the development of applications in catalysis, sensing, biological labelling, optics, etc. Future efforts will continue to address what stable sizes are existent, and more importantly, what factors determine their stability. Structural determination and theoretical simulations will help to gain deep insight into the structure property relationships. PMID- 25532729 TI - Intraoperative local anaesthesia for reduction of postoperative pain following general anaesthesia for dental treatment in children and adolescents. AB - BACKGROUND: Whilst carrying out dental procedures under general anaesthesia (GA), practitioners routinely give local anaesthetics (LA) intraoperatively to children. Local anaesthetics are used to help manage postoperative pain and reduce bleeding and the physiological response to procedures. Studies of effectiveness of intraoperative LA to date have reported contradictory results. OBJECTIVES: To assess the effects of intraoperative local anaesthesia for reducing postoperative pain following general anaesthesia for dental treatment in children and young people aged 17 years or younger. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 12), MEDLINE via OVID (1946 to 02 January 2014), EMBASE via OVID (1980 to 02 January 2014) and Web of Science Conference Proceedings (1990 to 02 January 2014). We searched for ongoing trials in the US National Institutes of Health Register, the metaRegister of Controlled Trials (mRCT) and the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical Trials Portal. We did not place any restrictions on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials in which local anaesthetic was given intraoperatively under general anaesthesia for dental treatment of children and young people aged 17 years or younger. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We performed data extraction and assessment of risk of bias independently and in duplicate. We contacted authors to clarify omissions in trial reports. In the 'Summary of findings' tables, we elected to report the outcomes pain, distress, postoperative bleeding, and physiological parameters related to the general anaesthetic, as we considered these to be the outcomes of greatest importance to readers of the review. MAIN RESULTS: We included 14 trials in this review, with 1152 randomised participants. The studies were published between 1990 and 2009 and were conducted in the United Kingdom, Egypt, Saudi Arabia, and the United States. The age of participants ranged from 2 to 40 years. Three studies were at an overall high risk of bias, seven studies were at an unclear risk of bias, and we judged four studies to be at low risk of bias. The clinical heterogeneity of the included studies precluded pooling of studies in terms of method of administration of LA (e.g., intraligamental injection, infiltration injection, or topical delivery) and variation in the use of supplementary analgesics and follow up time.Of the seven studies where administration of LA was by infiltration injection, six studies (very low-quality body of evidence, 542 participants analysed, 1 study had overall high risk of bias, 4 studies had overall unclear risk of bias, 1 study had overall low risk of bias) measured postoperative pain. The results were equivocal. There was a decrease in bleeding and increase in soft tissue damage in the LA groups, but we did not judge this to be clinically significant.In the 2 studies where administration of LA was by intraligamental injection, there was no difference in mean pain scores, and they did not report any soft tissue damage (very low-quality body of evidence, 115 participants analysed, 1 study had overall high risk of bias, 1 study had overall unclear risk of bias).One 3-armed study (very low-quality body of evidence, 54 participants analysed, overall high risk of bias) compared the effects of intraligamental and infiltration LA injection with no treatment. There was no evidence of a mean difference in pain, distress, or postoperative anxiety among the three groups.Four studies (very low-quality body of evidence, 343 participants analysed, 2 studies had overall low risk of bias, 2 studies had overall unclear risk of bias) evaluated the effects of topical LA compared with no treatment or placebo. One study (overall unclear risk of bias) with a no-treatment comparator reported lower mean pain in the LA group; all other studies reported no difference in mean pain scores. Two studies reported on bleeding (overall unclear risk of bias): One study reported a clinically insignificant increase in bleeding with no treatment; the other reported no difference.None of the studies reported on participant or child satisfaction. AUTHORS' CONCLUSIONS: In this review, it was difficult to reach firm conclusions as to the benefit of using local anaesthetic for dental treatment under general anaesthesia. The information reported in the included studies was comprehensive and applicable to the review question, but ultimately it was not sufficient to address the objective of the review. We were unable to pool the included studies in a meta-analysis because of substantial variation in outcome measures, interventions, and treatment types. The use of supplementary analgesia further obscured the effect of local anaesthetics.Based on the literature review and the results of this review, we recommend further randomised controlled trials that minimise bias through adequate allocation concealment and blinding of participants and assessors, and assess the effect of intraoperative local anaesthetic on the volume and type of anaesthetic used and on the cardiovascular system in participants receiving supplementary analgesics as well. Researchers should give consideration to the impact of any changes on the health and well-being of the participant and report baseline measures of pain or distress, or both, and preoperative anxiety. PMID- 25532732 TI - Letter from Buenos Aires ('here and now'). PMID- 25532733 TI - How and why unconscious phantasy and transference are the defining features of psychoanalytic practice. PMID- 25532734 TI - Comments on Lucy LaFarge's paper How and why unconscious phantasy and transference are the defining features of psychoanalytic practice. PMID- 25532735 TI - A response to LaFarge. PMID- 25532736 TI - LaFarge's rejoinder to Michael Feldman and Donnel B. Stern. PMID- 25532737 TI - Responsiveness to timothy grass pollen in individuals without known natural exposure in an allergen challenge chamber. AB - BACKGROUND: The responsiveness to a nonendemic grass species is unknown and cannot be research without an allergen challenge chamber. OBJECTIVE: To determine the clinical responsiveness to timothy grass pollen (TGP) in participants without known natural exposure in an allergen challenge chamber (ACC). METHODS: Of the 26 screened participants, 22 met screening criteria and completed the 2 chamber exposures. The study consisted of an initial screening visit that included a blood draw for serum specific IgE (ssIGE) to Bermuda grass pollen and TGP followed by a 41/2-day run-in phase and two 3-hour ACC exposure visits. This study was performed early in the first week of December 2013, when no seasonal pollens were detected in San Antonio, Texas. Symptom scores were recorded at baseline and every 30 minutes. RESULTS: Of the 26 screened participants, 22 met the screening criteria and completed the 2 chamber exposures. Thirteen participants had always lived in South Texas without natural exposure, and 9 had previously lived in areas with TGP exposure. All participants tested positive to TGP and Bermuda grass pollen. Twelve and 13 of 22 had positive ssIgE test results to Timothy and Bermuda allergens, respectively, with 11 having positive results for both allergens. There were strong correlations among skin prick test size, a positive ssIgE test result, and high symptoms from TGP exposure. There was little difference in symptoms between those who had lived their entire lives in South Texas and those who had lived elsewhere. CONCLUSION: In Texas, where exposure to TGP is minimal, strongly positive SPT and ssIgE test results were predictors of high symptoms to TGP exposure. Never exposed participants in South Texas reacted to TGP similar to those who had previous natural exposure, suggesting that in vivo cross-reactivity may be higher than predicted by prior in vitro data and may allow the use in clinical trials of allergens not endemic to the locale of an ACC. PMID- 25532740 TI - Underserved groups and barriers to cancer care. PMID- 25532738 TI - Relationship between prenatal antibiotic use and asthma in at-risk children. AB - BACKGROUND: Asthma prevalence has doubled in developed countries during the past 30 years. Pre- and perinatal events are essential in shaping the development of the immune system and systemic antibiotic use during this time could alter the maternal or placental microbiome, leading to an increase in the child's risk of developing asthma. OBJECTIVE: To determine whether prenatal antibiotic use is associated with asthma and wheezing in children at risk for asthma. METHODS: Using data from a randomized education intervention of families at risk for asthma from 1998 followed through 2009 in urban Chicago, asthma was defined as ever having a physician asthma diagnosis by year 3 and wheezing in the third year. Logistic regression models controlling for confounders investigated the effect of antibiotic use during pregnancy on these outcomes. RESULTS: After adjustment, prenatal antibiotic use was a risk factor for asthma (odds ratio 3.1, 95% confidence interval 1.4-6.8) but was only weakly associated with wheezing (odds ratio 1.8, 95% confidence interval 0.9-3.3). Analyses of the effects of timing of prenatal antibiotic use on asthma and wheezing showed the relation remained consistent for antibiotic use later in pregnancy, but the outcomes were not associated with antibiotic use in the first trimester. CONCLUSION: This study suggests prenatal antibiotic use might be associated with the development of asthma in children at risk for asthma. Although the relation with prenatal antibiotics does not hold for wheezing in this study, there might be a trend that could be delineated further within a larger cohort study. PMID- 25532741 TI - Determination of in vitro synergy for dual antimicrobial therapy against resistant Neisseria gonorrhoeae using Etest and agar dilution. AB - In response to antimicrobial resistance of Neisseria gonorrhoeae to last-resort extended-spectrum cephalosporins, combination therapy of azithromycin+ceftriaxone is now recommended. Dual therapy can be effective to treat monoresistant strains as well as multidrug-resistant strains, preferably employing the effect of in vitro synergy. As reports on in vitro synergy of azithromycin+ceftriaxone in N. gonorrhoeae are conflicting, in this study an evaluation of this combination was performed using a cross-wise Etest method and agar dilution. Synergy was defined as a fractional inhibitory concentration index (FICI) of <=0.5. To identify other dual treatment options for gonorrhoea, in vitro synergy was evaluated for 65 dual antimicrobial combinations using Etest. Azithromycin, cefixime, ceftriaxone, colistin, ertapenem, fosfomycin, gentamicin, minocycline, moxifloxacin, rifampicin, spectinomycin and tigecycline were screened for synergy in all possible combinations. No synergy or antagonism was found for any of the 65 combinations. The geometric mean FICI ranged from 0.82 to 2.00. The mean FICI of azithromycin+ceftriaxone was 1.18 (Etest) and 0.55 (agar dilution). The difference between both methods did not result in a difference in interpretation of synergy. Ceftriaxone-resistant strain F89 was tested in all combinations and no synergy was found for any of them. Most importantly, the ceftriaxone minimum inhibitory concentration of F89 was not decreased below the breakpoint with any concentration of azithromycin. PMID- 25532742 TI - Complexity of antimicrobial peptide regulation during pathogen-host interactions. AB - Antimicrobial peptides (AMPs) are a key component of the immune system and are expressed by a large variety of organisms. AMPs are capable of eliminating a broad range of micro-organisms, illustrated by murine models where lack of AMP expression resulted in enhanced susceptibility to infection. Despite the importance of AMPs in immune defences, it is not clear whether a change in AMP expression is pathogen-specific or reflects a general response to groups of pathogens. Furthermore, it is unclear how the evoked change in AMP expression affects the host. To fully exploit the therapeutic potential of AMPs - by direct application of peptides or by using AMP-inducers - it is crucial to gain an insight into the complexity involved in pathogen-mediated regulation of AMP expression. This review summarises current knowledge on how AMP expression is affected by pathogens. In addition, the relevance and specificity of these changes in AMPs during infection will be discussed. PMID- 25532743 TI - IncA/C plasmids harboured in serious multidrug-resistant Vibrio cholerae serogroup O139 strains in China. AB - Vibrio cholerae serogroup O139 emerged in 1992 and is one of two major serogroups to have caused cholera epidemics. After 1998, serious multidrug-resistant (MDR) O139 strains quickly became common in China, showing a multidrug resistance profile to eight antibiotics. It is a great threat to public health, and elucidation of its mechanisms of resistance will provide a helpful guide for the clinical treatment and prevention of cholera. In this study, mega-plasmids from MDR V. cholerae O139 strains were identified by pulsed-field gel electrophoresis (PFGE) without enzyme digestion. One plasmid was isolated and sequenced, belonging to the IncA/C family. Ten antibiotic resistance genes were found in the MDR regions, including a blaTEM-20 gene, and these genes endowed the host with resistance to seven antibiotics. This kind of plasmid was positive in 71.2% (198/278) of toxigenic O139 strains, and the rate of plasmid positivity was consistent with the yearly change in MDR rates of these strains. This study reveals an important role of the IncA/C family plasmid in the spread of multiple antibiotic resistance of epidemic V. cholerae serogroup O139 strains, which has recombined with plasmids from different bacterial species and transferred among V. cholerae strains. PMID- 25532744 TI - Central element in liver masses, helpful, or pitfall? AB - A central element was first described in focal nodular hyperplasia (FNH) as a so called "central scar," and is normally associated with this entity. However, many other liver masses may present with a central element. Depending on its appearance, and the lesion itself, central elements can be essential, helpful, or confusing for diagnosis. Indeed, nodules that develop on liver vascular disorders, fibrolamellar hepatocellular carcinoma, large hemangioma, peripheral cholangiocarcinoma, or epithelioid hemangioenthelioma often present with a central element, thus increasing the level of diagnostic confidence when present. On the other hand, central elements are rare or atypical in liver metastases, hepatocellular adenoma, or hepatocellular carcinoma. In this setting, the presence of a central element can lead to a misdiagnosis. The description and details of the imaging features of these different central elements, especially on MRI, as well as a thorough evaluation of the entire lesion, can improve the diagnostic performance in these cases. PMID- 25532745 TI - Biodegradation of hexachlorobenzene by a constructed microbial consortium. AB - A consortium comprised of an engineered Escherichia coli DH5alpha and a natural pentachlorophenol (PCP) degrader, Sphingobium chlorophenolicum ATCC 39723, was assembled for degradation of hexachlorobenzene (HCB), a persistent organic pollutant. The engineered E. coli strain, harbouring a gene cassette (camA (+) camB (+) camC) that encodes the F87W/Y96F/L244A/V247L mutant of cytochrome P 450cam (CYP101), oxidised HCB to PCP. The resulting PCP was then further completely degraded by ATCC 39723. The results showed that almost 40 % of 4 MUM HCB was degraded by the consortium at a rate of 0.033 nmol/mg (dry weight)/h over 24 h, accompanied by transient accumulation and immediate consumption of the intermediate PCP, detected by gas chromatography. In contrast, in the consortium comprised of Pseudomonas putida PaW340 harbouring camA (+) camB (+) camC and ATCC 39723, PCP accumulated in PaW340 cells but could not be further degraded, which may be due to a permeability barrier of Pseudomonas PaW340 for PCP transportation. The strategy of bacterial co-culture may provide an alternative approach for the bioremediation of HCB contamination. PMID- 25532746 TI - Management of patent ductus arteriosus in premature infants. AB - Patency of the ductus arteriosus is required for fetal survival in utero. In infants born prematurely, ductus fails to close and shunt reverses from left to right. Incidence of patent ductus arteriosus (PDA) is inversely proportional to the gestational age. A large PDA (>1.5 mm diameter) with left to right shunt in very low birth weight infants can cause pulmonary edema, congestive heart failure, pulmonary hemorrhage and increase the risk for bronchopulmonary dysplasia. Attempts to prevent or close the duct by pharmacological or surgical methods have not changed the morbidity or the long term outcome. Pharmacological treatment with indomethacin or ibuprofen is successful in 75 to 80 % of infants but its use also exposes these infants to undesirable side effects like gastrointestinal bleeding, perforation and necrotizing enterocolitis. Prophylactic therapy with indomethacin or ibuprofen to prevent PDA has not altered the morbidity or long term outcome. Currently, there is a dilemma as to how to treat, when to treat and whom to treat. Recent literature suggests a trial of conservative management during the first week followed by selective use of anti-inflammatory drugs. Surgical ligation is reserved for infants who fail medical therapy and still remain symptomatic. Spontaneous closure of the PDA has been reported in up to 40-67 % of very low birth weight (VLBW) infants by 7 d. In this review authors discuss these controversies and propose a more rational approach. PMID- 25532747 TI - Lipid profile in neonates and its relation with birth weight and gestational age. AB - This study was undertaken to compare lipid profile of small for gestational age (SGA) and appropriate for gestational age (AGA) neonates. A total of 103 neonates were included; of which 63 were AGA and 40 SGA. Venous blood (2 ml) was obtained 2 h after the previous feed between 8 and 10 am on Day 3 or Day 4 of life and lipid profile was done. In AGA neonates, mean TC (total cholesterol), LDL (low density lipoprotein cholesterol), HDL (high density lipoprotein cholesterol) and triglycerides were 103.92 +/- 47.79, 51.70 +/- 23.03, 23.35 +/- 11.41 and 187.62 +/- 144.44 mg/dl respectively. AGA neonates had more TC and LDL than SGA neonates (P < 0.05). There was no significant difference in mean lipid profile between preterm and term neonates. Thus, normal lipid profiles in neonates in the index study are higher than that of the neonates from other parts of the world. The authors recommend further studies in India to outline normal values of lipid profile across various gestations and birth weights. PMID- 25532748 TI - Clinico-radiological and genetic features of a common neuro-ichthyotic syndrome. PMID- 25532749 TI - Editorial: Advances in neonatology--III. PMID- 25532750 TI - Chromosomal locations of a gene underlying heat-accelerated brown spot formation and its suppressor genes in rice. AB - Brown spots on mature leaves from the heading to ripening stages in rice are considered to be lesions induced by heat stress. However, there are few studies of lesions that are induced by heat stress rather than by pathogen infections. To understand the genetic background underlying such lesions, we used the chromosome segment substitution line (CSSL) SL518, derived from a distant cross between rice cultivars Koshihikari (japonica) and Nona Bokra (indica). We observed brown spots on mature leaf blades of the CSSL, although the parents barely showed any spots. Spot formation in SL518 was accelerated by high temperature, suggesting that the candidate gene for spot formation is related to heat stress response. Using progeny derived from a cross between SL518 and Koshihikari, we mapped the causative gene, BROWN-SPOTTED LEAF 1 (BSPL1), on chromosome 5. We speculated that one or more Nona Bokra genes suppress spot formation caused by BSPL1 and identified candidate genomic regions on chromosomes 2 and 9 using a cross between a near-isogenic line for BSPL1 and other CSSLs possessing Nona Bokra segments in the Koshihikari genetic background. In conclusion, our data support the concept that multiple genes are complementarily involved in brown spot formation induced by heat stress and will be useful for cloning of the novel gene(s) related to the spot formation. PMID- 25532751 TI - Low genetic diversity and high differentiation among relict populations of the neotropical gymnosperm Podocarpus sellowii (Klotz.) in the Atlantic Forest. AB - Podocarpus sellowii (Podocarpaceae) is one of only a few gymnosperms native to Brazil and the sole species of the genus found in the northeastern region of that country. It has a very restricted distribution in this region, with only three known populations in highland forests (called Brejos de Altitude), which apparently have been isolated from each other since the Pleistocene. Due to this long-term isolation and the fact that these populations have few adult individuals and suffer great anthropogenic pressure, low genetic variability is expected, compromising their long-term viability. The present work assessed the genetic variability and structure of northeastern populations of P. sellowii to investigate the role of Pleistocene glaciations on the genetic relationships between them and to propose strategies for their conservation by analyzing the SSR and ISSR markers of adult and juvenile individuals. Low genetic diversity was found with both markers, associated with a high differentiation of the Brejo de Baturite population in relation to the others-suggesting their isolation at different points in time, probably during the Pleistocene. Actions directed towards increasing the genetic diversity of these populations will be needed, such as planting seedlings with high genetic variability-but the high degrees of differentiation observed between the populations must be taken into account. PMID- 25532753 TI - [Management of postoperative hemorrhage following thyroid surgery]. AB - The incidence of postoperative hemorrhage following thyroid surgery stands at 1% 2 %. This low incidence contrasts with the significant potential complications of postoperative hemorrhage. Influencing factors and measures mentioned in the literature and own studies are discussed. Although an improvement in the postoperative hemorrhage rate was to be expected indirectly due to the increasing use of coagulation-relevant medication, there has been neither an increase in incidence nor a reduction in resultant complications, including primarily recurrent vocal cord paresis, tracheotomy and mortality. Factors that influence surgical success include a meticulous technique and caution, as well as ensuring intensive and qualified postoperative monitoring for a minimum of 4-6 h, thereby permitting immediate revision surgery at any time. PMID- 25532754 TI - Coming soon: probiotics-based malaria vaccines. AB - The beneficial health effect of gut probiotics has been known since its discovery by Elie Metchnikoff. A new study has linked the microbiome of the human gut with immunity against malaria infections. Gut probiotics represent innovative tools for malaria prevention and lead the way to novel types of vaccination strategies. PMID- 25532755 TI - Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor. AB - Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor. PMID- 25532756 TI - The role of reaction conditions in the polymorphic control of Eu3+ doped YInO3: structure and size sensitive luminescence. AB - With the aim of exploring the effect of particle size and different polymorphic structures on the luminescence behaviour of Eu(3+) ions, all in a single compound, the YInO(3):Eu(3+) system was synthesized. Metastable C-type modification could be obtained in YInO(3) nanopowders synthesized by gel combustion. The broadening in Raman modes has been related to both the particle size and the strain in the metastable C-type modification. The hexagonal polymorph of YInO(3), with a layered structure, quite unlike the C-type modification, could be obtained by heating nanopowders to 1175 degrees C. Such a change in the structure, leading to different site symmetries for Eu(3+) ions exhibited a tremendous bearing on its luminescence behaviour. Detailed steady state and time resolved luminescence studies revealed a highly distorted local site symmetry for the Y(3+) ion in hexagonal YInO(3). The nano C-type YInO(3) exhibited greater asymmetry and a shorter lifetime as compared to the bulk C-type YInO(3), attributable to more surface defects in the case of the former. The Judd Ofelt parameters (Omega(2) and Omega(4)) were determined which established a much higher asymmetry in the hexagonal modification. Along with higher lifetime, the hexagonal polymorph also possessed superior quantum yield values. In addition to providing a significant insight into the structure-luminescence correlation in this study, we propose an efficient red phosphor with a high red color purity. PMID- 25532757 TI - An error-resilient non-volatile magneto-elastic universal logic gate with ultralow energy-delay product. AB - A long-standing goal of computer technology is to process and store digital information with the same device in order to implement new architectures. One way to accomplish this is to use nanomagnetic logic gates that can perform Boolean operations and then store the output data in the magnetization states of nanomagnets, thereby doubling as both logic and memory. Unfortunately, many of these nanomagnetic devices do not possess the seven essential characteristics of a Boolean logic gate : concatenability, non-linearity, isolation between input and output, gain, universal logic implementation, scalability and error resilience. More importantly, their energy-delay products and error rates tend to vastly exceed that of conventional transistor-based logic gates, which is unacceptable. Here, we propose a non-volatile voltage-controlled nanomagnetic logic gate that possesses all the necessary characteristics of a logic gate and whose energy-delay product is two orders of magnitude less than that of other nanomagnetic (non-volatile) logic gates. The error rate is also superior. PMID- 25532758 TI - FKBP5 variation is associated with the acute and chronic effects of nicotine. AB - Stress and hormones released in response to stress influence the effects of nicotine and the severity of nicotine withdrawal. Here, we systematically examine the contribution of a stress response gene, FKBP5, to the acute and chronic behavioral effects of nicotine in smokers. Subjects were European- and African American (EA and AA) heavy smokers who participated in an intravenous (IV) nicotine administration study (total n=169). FKBP5 rs3800373 genotype was analyzed for association to several outcomes, including nicotine withdrawal and the acute subjective, heart rate (HR), blood pressure and plasma cortisol responses to IV nicotine. Nicotine withdrawal was also examined in relation to rs3800373 allele frequencies in an independent cohort of EA and AA current smokers (n=3821). For a subset of laboratory subjects FKBP5 mRNA (n=48) expression was explored for an association to the same outcomes. The rs3800373 minor allele was associated with less severe nicotine withdrawal in laboratory subjects and the independent cohort of smokers. The rs3800373 minor allele was also associated with lower subjective ratings of negative drug effects in response to IV nicotine. Low FKBP5 mRNA expression was associated lower cortisol levels, lower subjective ratings of negative drug effects and a blunted HR response to nicotine. Stress hormone regulation via FKBP5 warrants further investigation as a potential contributor to the effects of nicotine withdrawal, which occurs commonly, and has an important role in the maintenance of smoking behavior and relapse following a quit attempt. PMID- 25532760 TI - DNA barcoding reveals diverse growth kinetics of human breast tumour subclones in serially passaged xenografts. AB - Genomic and phenotypic analyses indicate extensive intra- as well as intertumoral heterogeneity in primary human malignant cell populations despite their clonal origin. Cellular DNA barcoding offers a powerful and unbiased alternative to track the number and size of multiple subclones within a single human tumour xenograft and their response to continued in vivo passaging. Using this approach we find clone-initiating cell frequencies that vary from ~1/10 to ~1/10,000 cells transplanted for two human breast cancer cell lines and breast cancer xenografts derived from three different patients. For the cell lines, these frequencies are negatively affected in transplants of more than 20,000 cells. Serial transplants reveal five clonal growth patterns (unchanging, expanding, diminishing, fluctuating or of delayed onset), whose predominance is highly variable both between and within original samples. This study thus demonstrates the high growth potential and diverse growth properties of xenografted human breast cancer cells. PMID- 25532759 TI - Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy. AB - Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location has an impact on the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the messenger RNA (mRNA) expression of proteins involved in major signaling pathways, including tumor growth (epidermal growth factor receptor (EGFR)), angiogenesis (vascular endothelial growth factor receptor 2 (VEGFR2)), DNA repair (excision repair cross complement group 1 (ERCC1)) and fluoropyrimidine metabolism (thymidylate synthase (TS)). Formalin fixed paraffin-embedded tumor specimens from 431 advanced CRC patients were analyzed. The presence of seven different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by reverse transcriptase-PCR. BRAF mutations were significantly more common in the proximal colon (P<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared with distal and proximal colon tumors (P=0.001), and increased TS levels compared with distal colon cancers (P=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms. PMID- 25532761 TI - Zinc finger protein genes from Cucurbita pepo are promising tools for conferring non-Cucurbitaceae plants with ability to accumulate persistent organic pollutants. AB - Some cultivars of cucumbers, melons, pumpkins, and zucchini, which are members of the Cucurbitaceae family, are uniquely subject to contamination by hydrophobic pollutants such as the organohalogen insecticides DDT. However, the molecular mechanisms for the accumulation of these pollutants in cucurbits have not been determined. Here, cDNA subtraction analysis of Cucurbita pepo cultivars that are low and high accumulators of hydrophobic contaminants revealed that a gene for zinc finger proteins (ZFPs) are preferentially expressed in high accumulators. The cloned CpZFP genes were classified into 2 types: (1) the PBG type, which were expressed in C. pepo cultivars Patty Green, Black Beauty, and Gold Rush, and (2) the BG type, which were expressed in Black Beauty and Gold Rush. Expression of these CpZFP genes in transgenic tobacco plants carrying an aryl hydrocarbon receptor-based inducible gene expression system significantly induced beta glucuronidase activity when the plants were treated with a polychlorinated biphenyl (PCB) compound, indicating that highly hydrophobic PCBs accumulated in the plants. In transgenic tobacco plants carrying CpZFPs, accumulation of dioxins and dioxin-like compounds increased in their aerial parts when they were cultivated in the dioxin-contaminated soil. In summary, we propose that addition of CpZFP genes is a promising tool for conferring noncucurbits with the ability to accumulate hydrophobic contaminants. PMID- 25532762 TI - Exposure assessment of organophosphorus and organobromine flame retardants via indoor dust from elementary schools and domestic houses. AB - To assess the exposure of flame retardants (FRs) for school-children, organophosphorus flame retardants and plasticizers (PFRs) and organobromine flame retardants (BFRs) were determined in the indoor dust samples collected from elementary schools and domestic houses in Japan in 2009 and 2010. PFRs were detected in all the dust samples analyzed and the highest concentration of total PFRs was thousand-fold higher than that of BFRs. Among the PFRs, tris(butoxyethyl)phosphate (TBOEP) showed the highest concentration with a median (med.) of 270,000 ng g(-1) dry weight (3700-5,500,000 ng g(-1) dry weight), followed by tris(methylphenyl)phosphate (TMPPs)>triphenyl phosphate (TPHP)=tris(1,3-dichloro-2-propyl)phosphate (TDCIPP)=tris(2 chloroisopropyl)phosphate (TCIPP)=tris(2chloroethyl)phosphate (TCEP)>ethylhexyl diphenyl phosphate (EHDPP). Significantly higher concentrations of TBOEP, tri-n butyl phosphate (TNBP), TPHP, TMPPs, and total-PFRs were found in dust samples from elementary schools than from domestic houses. It might be due to that higher concentrations of TBOEP (as leveling agent) were detected from the floor polisher/wax products collected in those elementary schools. On the other hand, significantly higher concentrations of TCEP, TCIPPs, and total chloroalkyl-PFRs were found in domestic houses than in elementary schools. Exposure assessments of PFRs via indoor dust from elementary schools and domestic houses were conducted by calculating the hazard quotient (HQ). Among PFRs, HQs for TBOEP exceeded 1 (higher than reference dose: RfD) and its highest value was 1.9. To reduce the intake of TBOEP by school-children, it is recommended that the use of floor polisher/wax containing TBOEP be reduced in schools. PMID- 25532763 TI - Simultaneous removal of nanosilver and fullerene in sequencing batch reactors for biological wastewater treatment. AB - Increasing use of engineered nanomaterials (ENMs) inevitably leads to their potential release to the sewer system. The co-removal of nano fullerenes (nC60) and nanosilver as well as their impact on COD removal were studied in biological sequencing batch reactors (SBR) for a year. When dosing nC60 at 0.07-2mgL(-1), the SBR removed greater than 95% of nC60 except for short-term interruptions occurred (i.e., dysfunction of bioreactor by nanosilver addition) when nC60 and nanosilver were dosed simultaneously. During repeated 30-d periods of adding both 2 mg L(-1) nC60 and 2 mg L(-1) nanosilver, short-term interruption of SBRs for 4d was observed and accompanied by (1) reduced total suspended solids in the reactor, (2) poor COD removal rate as low as 22%, and (3) decreased nC60 removal to 0%. After the short-term interruption, COD removal gradually returned to normal within one solids retention time. Except for during these "short-term interruptions", the silver removal rate was above 90%. A series of bottle-point batch experiments was conducted to determine the distribution coefficients of nC60 between liquid and biomass phases. A linear distribution model on nC60 combined with a mass balance equation simulated well its removal rate at a range of 0.07-0.76 mg L(-1) in SBRs. This paper illustrates the effect of "pulse" inputs (i.e., addition for a short period of time) of ENMs into biological reactors, demonstrates long-term capability of SBRs to remove ENMs and COD, and provides an example to predict the removal of ENMs in SBRs upon batch experiments. PMID- 25532764 TI - Contamination of fish in UK fresh water systems: risk assessment for human consumption. AB - There is growing evidence that more people in the UK are consuming fish taken from inland waterways. This may be partly due to the increased numbers of migrants from Eastern Europe where this is part of traditional culture and partly because of a desire to try new foods encouraged by celebrity chefs. Fish can bioaccumulate environmental contaminants and so could contribute a significant amount to dietary exposure to these chemicals. This study examined the changing habits of anglers and consumers and characterised a range of existing and emerging contaminants in freshwater fish species with a view to determining current levels of occurrence and possible risk from consumption. The project was conducted in two stages. The first stage included (a) a study that identified freshwater systems that are contaminated either by anthropogenic activity or as a result of the geology of the area; and (b) socioeconomic research to assess the consumption habits of the public, particularly anglers, with respect to fish and shellfish from unmanaged inland waterways. Based on the outcome from the first stage, specific rivers and other inland waterways were chosen for investigation, along with the range of contaminants to be included in the analytical programme. Predicted contamination levels and prevalence of anglers were among the factors taken into consideration. The second stage of the project involved sampling and analysis of fish taken from selected locations on the chosen waterways. A range of fish species from a variety of inland water habitats were obtained. These were analysed for the following contaminants: heavy metals, chlorinated dioxins (PCDD/Fs), polybrominated biphenyls (PBBs), polychlorinated biphenyls (PCBs), brominated dioxins (PBDD/Fs), polychlorinated naphthalenes (PCNs), polybrominated diphenylethers (PBDEs), OC pesticides, organotin compounds and organo-fluorine compounds. Legal limits for contaminants apply only to food traded commercially, but some samples were in excess of the regulatory limits for PCDD/Fs and PCBs in such fish. The maximum detected WHO-TEQ (1998) for PCDD/Fs plus PCBs was over 32ngkg(-1) on a whole weight basis for a sample of barbel from the River Don, and 6 other samples were also above the 8ngkg(-1) limit. PMID- 25532765 TI - Removal and fate of trace organic compounds in microbial fuel cells. AB - This study focused on understanding and characterizing the removal of trace organic compounds (TOrCs) in microbial fuel cells (MFC). 26 TOrCs with broad physicochemical properties were spiked in synthetic wastewater. Single-chamber air-cathode MFC (SMFC) and double-chamber air-cathode MFC (DMFC) were constructed to provide combined or separated oxidation/reduction environments for TOrCs removal. The study showed that TOrCs removal processes involved both sorption and biodegradation. For neutral TOrCs, the removal efficiency was affected primarily by the biodegradability probability and hydrophobicity of the compounds, while electrostatic interactions played an additional role in the MFCs as the removal of positively charged TOrCs was generally higher than negatively charged TOrCs. The presence of TOrCs showed negligible impact on MFC power generation, likewise the operation of MFCs had marginal effect on TOrCs removal, except longer residence time in MFCs improved biological removal performance. PMID- 25532766 TI - The effects of Na/K additives and flyash on NO reduction in a SNCR process. AB - An experimental study of Na/K additives and flyash on NO reduction during the selective non-catalytic reduction (SNCR) process were carried out in an entrained flow reactor (EFR). The effects of reaction temperature (Tr), water vapor, Na/K additives (NaCl, KCl, Na2CO3) and flyash characteristics on NO reduction were analyzed. The results indicated that NO removal efficiency shows a pattern of increasing first and decreasing later with the increase of the temperature at Tr=850-1150 degrees C. Water vapor can improve the performance of NO reduction, and the NO reduction of 70.5% was obtained while the flue gas containing 4% water vapor at 950 degrees C. Na/K additives have a significant promoting effect on NO reduction and widen the SNCR temperature window, the promoting effect of the test additives is ordered as Na2CO3>KCl>NaCl. NO removal efficiency with 125ppm Na2CO3 and 4% water vapor can reach up to 84.9% at the optimal reaction temperature. The additive concentration has no significant effects on NO reduction while its concentration is above 50ppm. Addition of circulating fluidized combustion (CFB) flyash deteriorates NO reduction significantly. However, CFB flyash and Na/K additives will get a coupling effect on NO reduction during the SNCR process, and the best NO reduction can reach 72.3% while feeding Na2CO3-impregnated CFB flyash at 125ppm Na2CO3 and Tr=950 degrees C. PMID- 25532767 TI - Reactive solute transport in physically and chemically heterogeneous porous media with multimodal reactive mineral facies: the Lagrangian approach. AB - Physical and chemical heterogeneities have a large impact on reactive transport in porous media. Examples of heterogeneous attributes affecting reactive mass transport are the hydraulic conductivity (K), and the equilibrium sorption distribution coefficient (Kd). This paper uses the Deng et al. (2013) conceptual model for multimodal reactive mineral facies and a Lagrangian-based stochastic theory in order to analyze the reactive solute dispersion in three-dimensional anisotropic heterogeneous porous media with hierarchical organization of reactive minerals. An example based on real field data is used to illustrate the time evolution trends of reactive solute dispersion. The results show that the correlation between the hydraulic conductivity and the equilibrium sorption distribution coefficient does have a significant effect on reactive solute dispersion. The anisotropy ratio does not have a significant effect on reactive solute dispersion. Furthermore, through a sensitivity analysis we investigate the impact of changing the mean, variance, and integral scale of K and Kd on reactive solute dispersion. PMID- 25532768 TI - Increasing the bioaccessibility of polycyclic aromatic hydrocarbons in sediment using ultrasound. AB - In this study, the effect of sonication on the distribution of polycyclic aromatic hydrocarbons (PAHs) in the bioaccessible and less bioaccessible fractions of three contaminated sediments (Little Scioto River, OH-LS; Gary, IN GI; Eagle Harbor, WA-EH) was examined. After 60min sonication, the fractions of naphthalene, phenanthrene and pyrene remaining in the LS sediment were 0.76+/ 0.18, 0.83+/-0.04 and 0.76+/-0.05, respectively, indicating ultrasonic degradation of PAHs in the sediment. In addition, there was a significant decrease in PAH concentration (i.e., up to 91.4%) in the less bioaccessible fractions for all three sediments with sonication. The bioaccessible fraction of phenanthrene and pyrene in LS and pyrene in EH increased by 12.9%, 48.3% and 27.8%, respectively, followed by a slight decrease due to degradation. The initial increase suggests that ultrasonic irradiation of sediment either transfers the PAHs from the less bioaccessible sites to the bioaccessible sites for treatment or transforms less bioaccessible sites into bioaccessible sites. A comparatively smaller reduction (i.e., 20.2%) in the less bioaccessible fraction in GI sediment is attributed to the larger fraction of black carbon in the organic carbon content of the sediment hindering the ability of ultrasound to switch the PAHs from the less to the more bioaccessible sites. Overall ultrasonic irradiation of contaminated sediments is a technique to enhance contaminant remediation by reducing the fraction of contaminants in less bioaccessible sites. PMID- 25532769 TI - Distribution of sedimentary mercury off Svalbard, European Arctic. AB - The European Arctic, including the Svalbard archipelago, receives mercury loads due to long range atmospheric transport, local contamination, melting of glaciers and as a result of bedrock weathering. Few studies have been devoted to the contamination history and sources of sedimentary mercury in the Svalbard area. This knowledge gap is addressed in this study. Concentrations of total mercury (10-80ng/g), fractions of mercury differing with affinity to the sediment matrix (88-97% refractory, 3-12% mobile), organic and methyl mercury (100-500pg/g) were measured in surface and subsurface sediments in the Spitsbergen fjords and in the Barents Sea off Svalbard. The atmospheric mercury signal can be observed in the Barents Sea, while in the Svalbard fjords it is strongly modified by supply of mercury from natural sources that may include weathering of rocks and glaciers melting, all modified by organic matter supply. Sedimentary methyl mercury concentrations seem to be dependent on environmental factors affecting mercury methylation rather than on location of sampling stations. PMID- 25532770 TI - Removing selected steroid hormones, biocides and pharmaceuticals from water by means of biogenic manganese oxide nanoparticles in situ at ppb levels. AB - The oxidation of organic micro-pollutants by biogenic manganese oxide nanoparticles (BioMnOx) has been studied with respect to possible implementation of BioMnOx in wastewater treatment. For this it would be prerequisite that microbial Mn(2+) oxidation and BioMnOx-driven pollutant removal can occur in situ, i.e. in the same reactor as the removal. Here we present the in situ reactivity of BioMnOx produced by Pseudomonas putida towards a range of micro pollutants at environmentally relevant concentrations (10 MUg L(-1)). We found that in situ formed BioMnOx completely removed the steroid hormones estrone and 17-alpha ethinylestradiol, while only 26% removal of diclofenac was achieved. Ibuprofen, tebuconazole, carbamazepine, carbendazim, and terbutryn were not removed under in situ conditions. PMID- 25532771 TI - Effects of aspect ratio (AR) and specific surface area (SSA) on cytotoxicity and phototoxicity of ZnO nanomaterials. AB - With growing interests in the applications of high aspect ratio (AR) ZnO nanomaterials (NMs), their potential toxicity to human health and nature environment remains a critical concern because these NMs have extremely large specific surface area (SSA) that could dramatically enhance interactions between NMs and surrounding molecules. In addition, originated to their intrinsic photocatalytical activity, ZnO NMs may induce phototoxicity under environmentally UV exposure. In this paper, ZnO spheres, grains, rods and needles with increasing AR (from 1.1 to 17.8) and various SSA (from 2.0 m(2) g(-1) to 27.4 m(2) g(-1)) were used to study the influence of AR and SSA on viabilities of WIL2-NS human lymphoblastoid cells in both dark and UV conditions. In dark, SSA was the main influencing factor for toxicity of NMs with low AR (spheres, grains and rods) and smaller SSA leads to higher cell viability. However, ZnO needles with the smallest SSA did not further enhance cell viability which may be possibly attributed to its high AR. Cell viability measured under UV irradiation did not show evident relationship with SSA or AR, but indicated that lower photocatalytic activity could mitigate phototoxicity. PMID- 25532772 TI - In silico prediction of chemical toxicity on avian species using chemical category approaches. AB - Avian species are sensitive to pesticides and industrial chemicals, and hence used as model species in evaluation of chemical toxicity. In present study, we assessed the toxicity of more than 663 diverse chemicals on 17 avian species. All the chemicals were classified into three categories, i.e. highly toxic, slightly toxic and non-toxic, based on the toxicity classification criteria of the United States Environmental Protection Agency (EPA). To evaluate these chemicals, the toxicity prediction models were built using chemical category approaches with molecular descriptors and five commonly used fingerprints, in which five machine learning methods were performed on two standard test species: aquatic bird mallard duck and terrestrial bird northern bobwhite quail. The support vector machine (SVM) method with Pubchem fingerprint performed best as revealed by 5 fold cross-validation and the external validation set on Japanese quail. No species difference existed in our database despite several chemicals with different toxicity on some avian species. The best model had an overall accuracy at 0.851 for the prediction of toxicity on avian species, which outperformed the work of Mazzatorta et al. Furthermore, several representative substructures for characterizing avian toxicity were identified via information gain (IG) method. This study would provide a new tool for chemical safety assessment. PMID- 25532773 TI - Use of epidermis for the monitoring of tissular trace elements in Mediterranean striped dolphins (Stenella coeruleoalba). AB - Trace elements accumulate in epidermis, liver, kidney and muscle tissues in cetaceans. However, contrarily to internal tissues, epidermis can be sampled using minimally-invasive techniques. We investigate the patterns of trace element tissue concentrations in relation to individual sex and length and the degree of inter-tissue equilibrium between epidermis and the main internal organs of the Mediterranean striped dolphin. With it, we aim to test whether epidermis is a suitable tissue to predict trace element concentrations of internal tissues in cetaceans. We focused on trace elements with high potential toxicity (mercury and cadmium) or biological significance (zinc, copper and selenium). In contrast to what was found for Cu and Zn, the concentrations of Hg, Cd and Se in epidermis were positively correlated with the levels found in the internal tissues sampled probably due to their capacity to bioaccumulate. Thus, we conclude that sampling and analysing epidermis is appropriate to monitor and predict the concentrations of Hg, Cd and Se in internal tissues but not for Cu and Zn. PMID- 25532774 TI - Educational disparities in antipsychotic drug use among older people with and without dementia in Sweden. AB - OBJECTIVE: Antipsychotic drugs are commonly used to treat behavioural and psychological symptoms of dementia. The aim was to investigate if socioeconomic position was associated with antipsychotic drug treatment among older adults with and without dementia. METHOD: By record linkage of the Swedish Prescribed Drug Register, Patient Register, and Educational Register, we obtained information on antipsychotics, dementia status, and educational level for 641,566 persons aged 75-89 year old in Sweden 2005. RESULTS: Among persons diagnosed with dementia (n = 32 092), 21% used antipsychotics compared with 4% in the total sample (n = 641,566). Lower education was associated with a higher probability of antipsychotic use in the total sample (adjusted odds ratio [OR] low vs. high education: 1.56; 95% confidence interval [CI]: 1.48-1.64). In the dementia subpopulation, lower education was also associated with a higher likelihood of use of antipsychotics (adjusted OR(low vs. high) 1.43; 95% CI: 1.28-1.59). CONCLUSION: People with dementia were five times more likely to use antipsychotic drugs than the general population of older adults. Also, lower education was associated with a higher use of antipsychotics, both in the general population and in the subgroup of persons with dementia. This finding highlights the importance of investigating healthcare inequalities also among cognitively impaired older adults. PMID- 25532775 TI - Stroke in children with cardiac disease: report from the International Pediatric Stroke Study Group Symposium. AB - BACKGROUND: Cardiac disease is a leading cause of stroke in children, yet limited data support the current stroke prevention and treatment recommendations. A multidisciplinary panel of clinicians was convened in February 2014 by the International Pediatric Stroke Study group to identify knowledge gaps and prioritize clinical research efforts for children with cardiac disease and stroke. RESULTS: Significant knowledge gaps exist, including a lack of data on stroke incidence, predictors, primary and secondary stroke prevention, hyperacute treatment, and outcome in children with cardiac disease. Commonly used diagnostic techniques including brain computed tomography and ultrasound have low rates of stroke detection, and diagnosis is frequently delayed. The challenges of research studies in this population include epidemiologic barriers to research such as small patient numbers, heterogeneity of cardiac disease, and coexistence of multiple risk factors. Based on stroke burden and study feasibility, studies involving mechanical circulatory support, single ventricle patients, early stroke detection strategies, and understanding secondary stroke risk factors and prevention are the highest research priorities over the next 5-10 years. The development of large-scale multicenter and multispecialty collaborative research is a critical next step. The designation of centers of expertise will assist in clinical care and research. CONCLUSIONS: There is an urgent need for additional research to improve the quality of evidence in guideline recommendations for cardiogenic stroke in children. Although significant barriers to clinical research exist, multicenter and multispecialty collaboration is an important step toward advancing clinical care and research for children with cardiac disease and stroke. PMID- 25532776 TI - Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. AB - BACKGROUND: Tuberous sclerosis complex is a multisystem genetic disorder with a range of physical manifestations that require evaluation, surveillance, and management. Individuals with tuberous sclerosis complex also have a range of behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial difficulties. These may represent the greatest burden of the disease. Around 90% of individuals with tuberous sclerosis complex will have some of these difficulties during their lifetime, yet only about 20% ever receive evaluation and treatment. The Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference expressed concern about the significant "treatment gap" and about confusion regarding terminology relating to the biopsychosocial difficulties associated with tuberous sclerosis complex. METHODS: The Tuberous Sclerosis Complex Neuropsychiatry Panel coined the term TAND-tuberous sclerosis complex-associated neuropsychiatric disorders-to bring together these multidimensional manifestations of the disorder, and recommended annual screening for TAND. In addition, the Panel agreed to develop a TAND Checklist as a guide for screening. RESULTS: Here, we present an outline of the conceptualization of TAND, rationale for the structure of the TAND Checklist, and include the full US English version of the TAND Checklist. CONCLUSION: We hope that the unified term TAND and the TAND Checklist will raise awareness of the importance of tuberous sclerosis complex-associated neuropsychiatric disorders and of the major burden of disease associated with it, provide a shared language and a simple tool to describe and evaluate the different levels of TAND, alert clinical teams and families or individuals of the importance of screening, assessment, and treatment of TAND, and provide a shared framework for future studies of tuberous sclerosis complex-associated neuropsychiatric disorders. PMID- 25532777 TI - Susceptibility-weighted imaging helps to discriminate pediatric multiple sclerosis from acute disseminated encephalomyelitis. AB - BACKGROUND: Susceptibility-weighted imaging is a relatively new magnetic resonance imaging sequence that can identify lesions of multiple sclerosis in adults. This study was designed to determine if susceptibility-weighted imaging is a useful discriminator between children who develop multiple sclerosis and children with monophasic acute disseminated encephalomyelitis. METHODS: Eighteen children who presented with acute central nervous system demyelination and had a brain magnetic resonance imaging study including susceptibility-weighted imaging within 6 months of the first clinical attack were studied. Final diagnosis was based on international consensus definitions. Brain lesions detected on the fluid attenuated inversion recovery sequence were assessed for abnormal signal on susceptibility-weighted imaging. The burden of susceptibility abnormalities was then analyzed for differences between the multiple sclerosis and acute disseminated encephalomyelitis groups. RESULTS: Eight patients had a final diagnosis of acute disseminated encephalomyelitis and ten had multiple sclerosis. Twenty-two percent of fluid-attenuated inversion recovery lesions were identified on susceptibility-weighted imaging. The percentage of fluid-attenuated inversion recovery lesions identified on susceptibility-weighted imaging differed between the multiple sclerosis and acute disseminated encephalomyelitis groups (P = 0.04). The median percentage (minimum-maximum) of lesions identified on susceptibility-weighted imaging in the multiple sclerosis group was 0.22 (0-0.68) and in the acute disseminated encephalomyelitis group was 0.0 (0-0.17). CONCLUSION: Susceptibility-weighted imaging may be a useful technique in differentiating acute disseminated encephalomyelitis from multiple sclerosis at initial presentation. PMID- 25532778 TI - Geriatrics education is associated with positive attitudes toward older people in internal medicine residents: a multicenter study. AB - OBJECTIVE: The number of older people is growing fast in Turkey. In this context, internal medicine residents and specialists contact older people more frequently. Thus, healthcare providers' knowledge and attitudes toward older people is becoming more important. Studies that specifically investigate internal medicine residents' attitudes toward the elderly are scarce. We aimed to investigate the attitudes of internal medicine residents toward older people. METHODS: This cross sectional multicenter study was undertaken in the internal medicine clinics of six university state hospitals that provide education in geriatric care. All internal medicine residents working in these hospitals were invited to participate in this questionnaire study between March 2013 and December 2013. We recorded the participants' age, sex, duration of internal medicine residency, existence of relatives older than 65 years, history of geriatrics course in medical school, geriatrics rotation in internal medicine residency, and nursing home visits. RESULTS: A total of 274 (82.3%) of the residents participated in this study, and 83.6% of them had positive attitudes toward older people. A geriatrics rotation during internal medicine residency was the only independent factor associated with positive attitudes toward the elderly in this multivariate analysis. A geriatrics course during medical school was associated with positive attitudes in the univariate analysis, but only tended to be so in the multivariate analysis. CONCLUSION: Geriatrics rotation during internal medicine residency was independently associated with positive attitudes toward older people. Generalization of geriatrics education in developing countries may translate into a better understanding and improved care for older patients. PMID- 25532779 TI - Assessment of immunogenicity and protective efficacy of Microsporum canis secreted components coupled to monophosphoryl lipid-A adjuvant in a vaccine study using guinea pigs. AB - Microsporum canis is the most common dermatophyte in pets and is of zoonotic importance but currently there is no effective vaccine available to prevent dermatophytosis. The aim of this work was to assess the immunogenicity and protective efficacy of secreted components (SC) from M. canis adjuvanted with the monophosphoryl lipid-A (MPLA), in a vaccine study using the guinea pig as an experimental model. Animals were vaccinated with either the SC adjuvanted with the MPLA, the MPLA adjuvant alone or PBS three times at two-week intervals, until 42 days prior to M. canis infection. A blind evaluation of dermatophytosis symptoms development and fungal persistence in skin was monitored weekly. The antibody response towards the SC and the levels of Interferon (IFN)gamma and Interleukin-4 expressed in peripheral blood mononuclear cells were assessed along or at the end of the study period respectively. The animals that received MPLA had a significantly lower clinical score than those inoculated with PBS. However, no significant difference was observed between the guinea pigs vaccinated with the SC adjuvanted with the MPLA and those having received MPLA alone. The results also showed that vaccination induced a strong antibody response towards the SC and an increase in IFNgamma mRNA level. Our results show that the MPLA adjuvant used in this vaccine study can induce per se a partial protection against a M. canis infection. Although they induce a delayed-type hypersensitivity reaction in guinea pigs, the SC do not confer a protection under the present experimental conditions. PMID- 25532781 TI - C3 glomerulonephritis associated with complement factor B mutation. PMID- 25532780 TI - Pestiviruses infections at the wild and domestic ruminants interface in the French Southern Alps. AB - In alpine pasture, interspecies transmission has recently been incriminated in the epidemiology of pestivirus infection. The aim of this study was to investigate pestivirus infections in wild and domestic ruminants sharing pastures in the French Southern Alps. Animal sera were screened for pestivirus antibodies against the pestivirus NS3 protein by a commercial blocking enzyme linked immunosorbent assay (ELISA). All 38 domestic herds tested were positive for pestivirus-specific antibodies. Individual sero-prevalence reached 76.5% (95% confidence interval [95% CI]: [74.2-78.8%]) of the 1383 sheep tested. For wild ruminants, 38.7% (95% CI: [33.8-43.9%]) of the 369 chamois tested, 28.7% (95% CI: [17.4-38.1%]) of the 72 roe deer, and 22.2% (95% CI: [6.5-37.9%]) of the 27 mouflons were seropositive. Virus screening was carried out on spleen samples from hunted wild animals (n=160) and from 15 domestic ruminants (clinically suspected to be persistently infected animals), by a conventional reverse transcription-polymerase chain reaction (RT-PCR). Three pestivirus strains were isolated from the sheep samples positive by RT-PCR. The viruses were classified in the BDV-3, BDV-Tunisian and BDV-6 genotypes. For the first time, one strain (RUPI-05 strain) was isolated from an alpine chamois and clustered in the BDV-6 genotype, showing in the 5'-UTR region 92% of identity with the ovine isolate from the same area. Thus, an active circulation of pestiviruses was demonstrated in both wild and domestic ungulates from the French Southern Alps. The results suggest that interspecies transmission between sheep and chamois probably occur. PMID- 25532782 TI - Characterization and bioactivities of an exopolysaccharide produced by Lactobacillus plantarum YW32. AB - The exopolysaccharide (EPS) produced by Lactobacillus plantarum YW32 was purified and characterized, and the in vitro bioactivities of the purified EPS were also evaluated. The EPS had a molecular weight of 1.03*10(5) Da, and it consisted of mannose, fructose, galactose and glucose in an approximate molar ratio of 8.2:1:4.1:4.2. Microstructural studies of the EPS demonstrated a web-like structure composed of compact ropes, and presence of many homogeneous rod-shaped lumps. The EPS also showed high thermal stability with a degradation temperature of 283.5 degrees C. Furthermore, the EPS at a dose of 5mg/ml had strong scavenging abilities toward hydroxyl (77.5%) and superoxide radicals (66.5%). The EPS exhibited a concentration-dependent inhibitory effect on the formation of biofilms by several pathogenic bacteria, including Escherichia coli O157, Shigella flexneri CMCC (B), Staphylococcus aureus AC1 and Salmonella typhimurium S50333. In vitro antitumor assay of the EPS showed that it had good inhibitory activity against colon cancer HT-29 cells. These characteristics and bioactivities of the EPS would make it a promising candidate for use as a potential food adjunct in foods with healthy properties. PMID- 25532783 TI - Therapy with radio-attenuated vaccine in experimental murine visceral leishmaniasis showed enhanced T cell and inducible nitric oxide synthase levels, suppressed tumor growth factor-beta production with higher expression of some signaling molecules. AB - BACKGROUND: Visceral leishmaniasis (VL) or Kala-Azar (KA) is one of the most deadly forms of disease among all neglected tropical diseases. There are no satisfactory drugs or vaccine candidates available for this dreaded disease. Our previous studies showed promising therapeutic and prophylactic efficacy of the live, radio-attenuated parasites through intramuscular (I.M.) and intraperitoneal (I.P.) route in BALB/c mice model. METHODS: The T-cell proliferation level, the mRNA expression level of inducible nitric oxide synthase (iNOS) and tumor growth factor-beta (TGF-beta) genes and finally the phosphorylation levels of phosphoinositide dependent kinase 1 (PDK1), phosphoinositide 3 kinase (PI3K) and p38 mitogen activated protein kinase (p38MAPK) molecules were checked in BALB/c mice model immunized with radio-attenuated Leishmania donovani parasites through I.M. route. RESULTS: Higher T-cell proliferation, increased iNOS level, and suppressed TGF-beta level were found in treated infected animal groups (100 and 150Gy) in relation to untreated infected animals. Likewise, phosphorylation levels of PDK1, PI3K and p38MAPK of these two groups were increased when compared to untreated infected controls. CONCLUSION: The clearance of the parasites from treated infected groups of animals may be mediated by the restoration of T-cell due to therapy with radio-attenuated L. donovani parasites. The killing of parasites was mediated by increase in nitric oxide release through PDK1, PI3K and p38MAPK signaling pathways. A lower TGF-beta expression has augmented the restored Th1 ambience in the 100 and 150Gy treated animal groups proving further the efficacy of the candidate vaccine. PMID- 25532784 TI - Prolonged REM sleep restriction induces metabolic syndrome-related changes: Mediation by pro-inflammatory cytokines. AB - Chronic sleep restriction in human beings results in metabolic abnormalities, including changes in the control of glucose homeostasis, increased body mass and risk of cardiovascular disease. In rats, 96h of REM sleep deprivation increases caloric intake, but retards body weight gain. Moreover, this procedure increases the expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), which may be involved with the molecular mechanism proposed to mediate insulin resistance. The goal of the present study was to assess the effects of a chronic protocol of sleep restriction on parameters of energy balance (food intake and body weight), leptin plasma levels and its hypothalamic receptors and mediators of the immune system in the retroperitoneal adipose tissue (RPAT). Thirty-four Wistar rats were distributed in control (CTL) and sleep restriction groups; the latter was kept onto individual narrow platforms immersed in water for 18h/day (from 16:00h to 10:00h), for 21days (SR21). Food intake was assessed daily, after each sleep restriction period and body weight was measured daily, after the animals were taken from the sleep deprivation chambers. At the end of the 21day of sleep restriction, rats were decapitated and RPAT was obtained for morphological and immune functional assays and expression of insulin receptor substrate 1 (IRS-1) was assessed in skeletal muscle. Another subset of animals was used to evaluate blood glucose clearance. The results replicated previous findings on energy balance, e.g., increased food intake and reduced body weight gain. There was a significant reduction of RPAT mass (p<0.001), of leptin plasma levels and hypothalamic leptin receptors. Conversely, increased levels of TNF-alpha and IL-6 and expression of phosphorylated NFkappa-beta in the RPAT of SR21 compared to CTL rats (p<0.01, for all parameters). SR21 rats also displayed reduced glucose clearance and IRS-1 expression than CTL rats (p<0.01). The present results indicated that 21days of sleep restriction by the platform method induced metabolic syndrome-related alterations that may be mediated by inflammation of the RPAT. PMID- 25532785 TI - The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep. AB - When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). PGE2 is the principal mediator of fever, and both PGE2 and PGD2 regulate sleep-wake behavior. The extent to which PGE2 and PGD2 are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE2 receptors type EP3 or EP4, in mice with total body KO of microsomal PGE synthase-1 or the PGD2 receptor type DP, and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP4 receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP3 receptors or in the presence of a COX inhibitor. PMID- 25532786 TI - Effects of insomnia disorder and knee osteoarthritis on resting and pain-evoked inflammatory markers. AB - Osteoarthritis is the most prevalent arthritic condition. Systemic inflammatory cytokines appear to have an important role in the onset and maintenance of the disease. Sleep disturbances are prevalent in osteoarthritis and associated with alterations in systemic inflammatory cytokines, suggesting a common pathophysiology across these conditions. A comparative investigation of the effects of insomnia disorder and osteoarthritis on pain-evoked cytokine responses has yet to be undertaken. We examined the influence of symptomatic knee osteoarthritis and insomnia disorder on resting C-reactive protein (CRP), interleukin (IL)-6, and IL-10 levels, and pain-evoked IL-6 and IL-10 responses. Participants were N=117 older adults (mean age=59.7years; 61.8% women) rigorously evaluated for knee osteoarthritis and insomnia disorder using established diagnostic guidelines. Results revealed no association of osteoarthritis or insomnia disorder with CRP. Resting IL-6 was greater in osteoarthritis participants versus those without osteoarthritis, although this association was largely attributable to BMI. IL-10 was highest among participants with osteoarthritis or insomnia disorder. Growth curve modeling revealed that participants with insomnia disorder had greater pain-evoked IL-6 responses than participants without insomnia disorder or osteoarthritis. These findings highlight the utility of laboratory pain testing methods for understanding individual differences in inflammatory cytokines. Moreover, our findings provide evidence for amplified pain-evoked pro-inflammatory cytokine reactivity among older adults with clinically diagnosed insomnia disorder, even after controlling for individual differences in BMI and age. Additional research will be required determine whether an amplified pain-related cytokine response contributes to OA, and possibly other age-related disease, associated with insomnia disorder. PMID- 25532793 TI - Regulatory cells induced by acute toxoplasmosis prevent the development of allergic lung inflammation. AB - The increased prevalence of allergies in developed countries has been attributed to a reduction of some infections. Supporting epidemiological studies, we previously showed that both acute and chronic Toxoplasma gondii infection can diminish allergic airway inflammation in BALB/c mice. The mechanisms involved when sensitization occurs during acute phase would be related to the strong Th1 response induced by the parasite. Here, we further investigated the mechanisms involved in T. gondii allergy protection in mice sensitized during acute T. gondii infection. Adoptive transference assays and ex vivo co-cultures experiments showed that not only thoracic lymph node cells from infected and sensitized mice but also from non-sensitized infected animals diminished both allergic lung inflammation and the proliferation of effector T cells from allergic mice. This ability was found to be contact-independent and correlated with high levels of CD4(+)FoxP3(+) cells. IL-10 would not be involved in allergy suppression since IL-10-deficient mice behaved similar to wild type mice. Our results extend earlier work and show that, in addition to immune deviation, acute T. gondii infection can suppress allergic airway inflammation through immune suppression. PMID- 25532787 TI - Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat? AB - All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well-being. This is no less true for psychiatric well-being than for physical well-being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis. PMID- 25532794 TI - Synergy between TLR-2 and TLR-3 signaling in primary human nasal epithelial cells. AB - INTRODUCTION: Although we have a detailed understanding of how single microbial derived triggers activate specialized Toll-like receptors (TLR) on airway epithelial cells, we know little of how these receptors react in a more complex environment. In everyday life, nasal epithelial cells are exposed to multiple TLR agonists, therefore we explored whether exposure to one trigger could affect the responsiveness to another TLR trigger. METHODS: Primary nasal epithelium from healthy individuals and the bronchial epithelium cell line NCI-H292 were exposed in vitro to different TLR specific agonists. The effect on the expression of different TLRs was determined using the q-PCR. We also evaluated the effect of TLR-3 stimulation on TLR-2, functionally using ELISA to determine levels of secreted mediators. RESULTS: Stimulation of airway epithelial cells with a specific TLR agonist affects gene expression of other TLRs. In primary nasal epithelium, poly(I:C) challenge results in an up-regulation of the TLR-1, TLR-2, and TLR-3 genes and reduction of expression of TLR-5. Poly(I:C) induced activation of TLR-2 contributes to stronger cell responses to a TLR-2 agonist and regulation of these synergistic responses may take place at the mRNA level of IL 6 and IL-8. The effect of TLR-3 stimulation on TLR-2 functionality and most of the effects on the expression of other TLRs could be replicated in NCI-H292. Poly(I:C) failed to up-regulate TLR-1 and showed an additional up-regulation of TLR-4. CONCLUSION: Our data suggest that to better understand TLR mediated innate responses we need to consider the impact of the presence of multiple triggers. PMID- 25532795 TI - Evaluation of assays for troponin I in healthy horses and horses with cardiac disease. AB - Cardiac troponin I (cTnI) is a marker for detection of myocardial damage in horses. Many cTnI assays exist and medical studies have shown that the clinical performance of assays differs. The aim of this study was to compare two different cTnI assays in horses. Serum samples were taken from 23 healthy horses (group 1) and 72 horses with cardiac disease (group 2). Cardiac troponin I was determined using assay 1 in laboratory A (limit of detection, LOD, 0.03 ng/mL) and assay 2 in laboratories B and C (LOD 0.01 ng/mL). In group 1, a median cTnI concentration of <0.03 (<0.03-0.04) ng/mL and <0.01 (<0.01-0.15) ng/mL was found with assays 1 and 2, respectively. A higher median value was demonstrated in group 2 for both assays (assay 1: 0.11 ng/mL, range 0.03-58.27 ng/mL, P < 0.001; assay 2: 0.02 ng/mL, range 0.01-22.87 ng/mL, P = 0.044). Although a significant correlation between assays existed, large mean differences that could be important for clinical interpretation of test results were found. A small mean difference was found between laboratories B and C. A significant optimal (P < 0.001) cut-off value for detection of cardiac disease could only be determined for assay 1 (0.035 ng/mL, sensitivity 70%, specificity 91%). Assay 1 performed better for detection of cardiac disease in horses in this study. PMID- 25532797 TI - Measuring cognitive effects: cognition in drug development and repositioning. PMID- 25532798 TI - Small molecule inhibitors of ebola virus infection. AB - Ebola viruses are extremely virulent and highly transmissible. They are responsible for sporadic outbreaks of severe hemorrhagic fevers with human mortality rates of up to 90%. No prophylactic or therapeutic treatments in the form of vaccine, biologicals or small molecule, currently exist. Yet, a wealth of antiviral research on ebola virus is being generated and potential inhibitors have been identified in biological screening and medicinal chemistry programs. Here, we detail the state-of-the-art in small molecule inhibitors of ebola virus infection, with >60 examples, including approved drugs, compounds currently in clinical trials, and more exploratory leads, and summarize the associated in vitro and in vivo evidence for their effectiveness. PMID- 25532799 TI - SUDEP and emotional leveraging: why not? PMID- 25532796 TI - The mechanisms of calcium cycling and action potential dynamics in cardiac alternans. AB - RATIONALE: Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans manifests as beat-to-beat alternations in contraction, action potential duration (APD), and magnitude of the Ca(2+) transient (CaT). Electromechanical and CaT alternans are highly correlated, however, it has remained controversial whether the primary cause of alternans is a disturbance of cellular Ca(2+) signaling or electrical membrane properties. OBJECTIVE: To determine whether a primary failure of intracellular Ca(2+) regulation or disturbances in membrane potential and AP regulation are responsible for the occurrence of alternans in atrial myocytes. METHODS AND RESULTS: Pacing-induced APD and CaT alternans were studied in single rabbit atrial and ventricular myocytes using combined [Ca(2+)]i and electrophysiological measurements. In current-clamp experiments, APD and CaT alternans strongly correlated in time and magnitude. CaT alternans was observed without alternation in L-type Ca(2+) current, however, elimination of intracellular Ca(2+) release abolished APD alternans, indicating that [Ca(2+)]i dynamics have a profound effect on the occurrence of CaT alternans. Trains of 2 distinctive voltage commands in form of APs recorded during large and small alternans CaTs were applied to voltage-clamped cells. CaT alternans was observed with and without alternation in the voltage command shape. During alternans AP-clamp large CaTs coincided with both long and short AP waveforms, indicating that CaT alternans develop irrespective of AP dynamics. CONCLUSIONS: The primary mechanism underlying alternans in atrial cells, similarly to ventricular cells, resides in a disturbance of Ca(2+) signaling, whereas APD alternans are a secondary consequence, mediated by Ca(2+)-dependent AP modulation. PMID- 25532800 TI - Major transitions in human evolution revisited: a tribute to ancient DNA. AB - The origin and diversification of modern humans have been characterized by major evolutionary transitions and demographic changes. Patterns of genetic variation within modern populations can help with reconstructing this ~200 thousand year long population history. However, by combining this information with genomic data from ancient remains, one can now directly access our evolutionary past and reveal our population history in much greater detail. This review outlines the main recent achievements in ancient DNA research and illustrates how the field recently moved from the polymerase chain reaction (PCR) amplification of short mitochondrial fragments to whole-genome sequencing and thereby revisited our own history. Ancient DNA research has revealed the routes that our ancestors took when colonizing the planet, whom they admixed with, how they domesticated plant and animal species, how they genetically responded to changes in lifestyle, and also, which pathogens decimated their populations. These approaches promise to soon solve many pending controversies about our own origins that are indecipherable from modern patterns of genetic variation alone, and therefore provide an extremely powerful toolkit for a new generation of molecular anthropologists. PMID- 25532802 TI - Ancient pathogen genomics: insights into timing and adaptation. AB - Disease is a major cause of natural selection affecting human evolution, whether through a sudden pandemic or persistent morbidity and mortality. Recent contributions in the field of ancient pathogen genomics have advanced our understanding of the antiquity and nature of human-pathogen interactions through time. Technical advancements have facilitated the recovery, enrichment, and high throughput sequencing of pathogen and parasite DNA from archived and archaeological remains. These time-stamped genomes are crucial for calibrating molecular clocks to infer the timing of evolutionary events, while providing finer-grain resolution to phylogenetic reconstructions and complex biogeographical patterns. Additionally, genome scale data allow better identification of substitutions linked to adaptations of the pathogen to their human hosts. As methodology continues to improve, ancient genomes of humans and their diverse microbiomes from a range of eras and archaeological contexts will enable population-level ancient analyses in the near future and a better understanding of their co-evolutionary history. PMID- 25532801 TI - The use of museum specimens with high-throughput DNA sequencers. AB - Natural history collections have long been used by morphologists, anatomists, and taxonomists to probe the evolutionary process and describe biological diversity. These biological archives also offer great opportunities for genetic research in taxonomy, conservation, systematics, and population biology. They allow assays of past populations, including those of extinct species, giving context to present patterns of genetic variation and direct measures of evolutionary processes. Despite this potential, museum specimens are difficult to work with because natural postmortem processes and preservation methods fragment and damage DNA. These problems have restricted geneticists' ability to use natural history collections primarily by limiting how much of the genome can be surveyed. Recent advances in DNA sequencing technology, however, have radically changed this, making truly genomic studies from museum specimens possible. We review the opportunities and drawbacks of the use of museum specimens, and suggest how to best execute projects when incorporating such samples. Several high-throughput (HT) sequencing methodologies, including whole genome shotgun sequencing, sequence capture, and restriction digests (demonstrated here), can be used with archived biomaterials. PMID- 25532803 TI - DNA analysis of ancient dogs of the Americas: identifying possible founding haplotypes and reconstructing population histories. AB - As dogs have traveled with humans to every continent, they can potentially serve as an excellent proxy when studying human migration history. Past genetic studies into the origins of Native American dogs have used portions of the hypervariable region (HVR) of mitochondrial DNA (mtDNA) to indicate that prior to European contact the dogs of Native Americans originated in Eurasia. In this study, we summarize past DNA studies of both humans and dogs to discuss their population histories in the Americas. We then sequenced a portion of the mtDNA HVR of 42 pre Columbian dogs from three sites located in Illinois, coastal British Columbia, and Colorado, and identify four novel dog mtDNA haplotypes. Next, we analyzed a dataset comprised of all available ancient dog sequences from the Americas to infer the pre-Columbian population history of dogs in the Americas. Interestingly, we found low levels of genetic diversity for some populations consistent with the possibility of deliberate breeding practices. Furthermore, we identified multiple putative founding haplotypes in addition to dog haplotypes that closely resemble those of wolves, suggesting admixture with North American wolves or perhaps a second domestication of canids in the Americas. Notably, initial effective population size estimates suggest at least 1000 female dogs likely existed in the Americas at the time of the first known canid burial, and that population size increased gradually over time before stabilizing roughly 1200 years before present. PMID- 25532804 TI - Diet dominates host genotype in shaping the murine gut microbiota. AB - Mammals exhibit marked interindividual variations in their gut microbiota, but it remains unclear if this is primarily driven by host genetics or by extrinsic factors like dietary intake. To address this, we examined the effect of dietary perturbations on the gut microbiota of five inbred mouse strains, mice deficient for genes relevant to host-microbial interactions (MyD88(-/-), NOD2(-/-), ob/ob, and Rag1(-/-)), and >200 outbred mice. In each experiment, consumption of a high fat, high-sugar diet reproducibly altered the gut microbiota despite differences in host genotype. The gut microbiota exhibited a linear dose response to dietary perturbations, taking an average of 3.5 days for each diet-responsive bacterial group to reach a new steady state. Repeated dietary shifts demonstrated that most changes to the gut microbiota are reversible, while also uncovering bacteria whose abundance depends on prior consumption. These results emphasize the dominant role that diet plays in shaping interindividual variations in host associated microbial communities. PMID- 25532806 TI - Reply: To PMID 24704526. PMID- 25532805 TI - Cyclin L2 is a critical HIV dependency factor in macrophages that controls SAMHD1 abundance. AB - The restriction factor SAMHD1 limits HIV-1 replication in noncycling cells. SIV and HIV-2 overcome this restriction via the accessory protein Vpx, which targets SAMHD1 for degradation through interactions with the host ubiquitin ligase adaptor DCAF1. However, the factors used by HIV-1 to replicate in macrophages, despite the presence of the restriction factor SAMHD1, are unknown. Using a yeast two-hybrid screen, we identified cyclin L2 as a DCAF1-interacting protein required for HIV-1 replication in macrophages. Knockdown of cyclin L2 results in severe attenuation of HIV-1 replication in macrophages but not cycling cells, and this effect is lost in the absence of SAMHD1. Cyclin L2 and SAMHD1 form a molecular complex that is partially dependent on the presence of DCAF1 and results in SAMHD1 degradation in a proteasome- and DCAF1-dependent manner. Therefore, cyclin L2-mediated control of SAMHD1 levels in macrophages supports HIV-1 replication. PMID- 25532807 TI - Use of Hy's Law, R criteria, and nR criteria to predict acute liver failure or transplantation in patients with drug-induced liver injury. PMID- 25532808 TI - A symptomatic anorectal polyp. PMID- 25532810 TI - Endoscopic sphincterotomy for sphincter of oddi dysfunction: inefficacious therapy for a fictitious disease. PMID- 25532811 TI - What are these yellow deposits in the duodenum? PMID- 25532812 TI - Optimizing rapid solvent exchange preparation of multilamellar vesicles. AB - We have enhanced the rapid solvent exchange (RSE) apparatus by adding controls in temperature, evacuation speed and vortex velocity. Following published protocols yielded vesicles of diverse size and lamellarity as detected by differential scanning calorimetry, photon correlation spectroscopy and X-ray experiments. To optimize the net production of multilamellar vesicles (MLVs) we varied in addition to vortex and evacuation speed lipid and organic solvent concentration, as well as composition of the aqueous medium. Reducing vortexing frequencies and speed of degassing were most beneficial for the yield in MLVs. Additionally also high lipid concentrations and organic solvent/buffer ratios supported MLV formation. To explain our findings we hypothesize on the role of microscopic instabilities on the aqueous phase, which may act as molds for vesicle formation. PMID- 25532813 TI - Discriminating simulated vocal tremor source using amplitude modulation spectra. AB - OBJECTIVES/HYPOTHESIS: Sources of vocal tremor are difficult to categorize perceptually and acoustically. This article describes a preliminary attempt to discriminate vocal tremor sources through the use of spectral measures of the amplitude envelope. The hypothesis is that different vocal tremor sources are associated with distinct patterns of acoustic amplitude modulations. STUDY DESIGN: Statistical categorization methods (discriminant function analysis) were used to discriminate signals from simulated vocal tremor with different sources using only acoustic measures derived from the amplitude envelopes. METHODS: Simulations of vocal tremor were created by modulating parameters of a vocal fold model corresponding to oscillations of respiratory driving pressure (respiratory tremor), degree of vocal fold adduction (adductory tremor), and fundamental frequency of vocal fold vibration (F0 tremor). The acoustic measures were based on spectral analyses of the amplitude envelope computed across the entire signal and within select frequency bands. RESULTS: The signals could be categorized (with accuracy well above chance) in terms of the simulated tremor source using only measures of the amplitude envelope spectrum even when multiple sources of tremor were included. CONCLUSIONS: These results supply initial support for an amplitude-envelope-based approach to identify the source of vocal tremor and provide further evidence for the rich information about talker characteristics present in the temporal structure of the amplitude envelope. PMID- 25532816 TI - Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. AB - Despite recent advances in novel therapies, the prognosis for patients with squamous cell carcinoma of the head and neck (SCCHN) remains poor. Progress in understanding the biology of cancer has led to the development of personalized therapy targeted at blocking defective signaling pathways of cancer cells. These drugs aim to act selectively to reduce the adverse effects associated with systemic therapy. Cetuximab (Erbitux(r)), an anti-epidermal growth factor receptor gene (EGFR)-targeted agent, is the only approved targeted therapy for patients with SCCHN. However, resistance to EGFR therapy remains a major obstacle to achieving a positive clinical outcome with cetuximab. Other therapies that offer better clinical outcomes in patients with advanced SCCHN are urgently needed. The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway, which is downstream of EGFR, has also been implicated in SCCHN development and progression, and therefore, targeting this pathway offers another rational treatment approach. This review discusses the potential role of PI3K pathway inhibitors in the treatment of patients with advanced SCCHN, both alone and in combination with other therapies. PMID- 25532814 TI - Recent coselection in human populations revealed by protein-protein interaction network. AB - Genome-wide scans for signals of natural selection in human populations have identified a large number of candidate loci that underlie local adaptations. This is surprising given the relatively short evolutionary time since the divergence of the human population. One hypothesis that has not been formally examined is whether and how the recent human evolution may have been shaped by coselection in the context of complex molecular interactome. In this study, genome-wide signals of selection were scanned in East Asians, Europeans, and Africans using 1000 Genome data, and subsequently mapped onto the protein-protein interaction (PPI) network. We found that the candidate genes of recent positive selection localized significantly closer to each other on the PPI network than expected, revealing substantial clustering of selected genes. Furthermore, gene pairs of shorter PPI network distances showed higher similarities of their recent evolutionary paths than those further apart. Last, subnetworks enriched with recent coselection signals were identified, which are substantially overrepresented in biological pathways related to signal transduction, neurogenesis, and immune function. These results provide the first genome-wide evidence for association of recent selection signals with the PPI network, shedding light on the potential mechanisms of recent coselection in the human genome. PMID- 25532815 TI - Evolutionary dynamics of hAT DNA transposon families in Saccharomycetaceae. AB - Transposable elements (TEs) are widespread in eukaryotes but uncommon in yeasts of the Saccharomycotina subphylum, in terms of both host species and genome fraction. The class II elements are especially scarce, but the hAT element Rover is a noteworthy exception that deserves further investigation. Here, we conducted a genome-wide analysis of hAT elements in 40 ascomycota. A novel family, Roamer, was found in three species, whereas Rover was detected in 15 preduplicated species from Kluyveromyces, Eremothecium, and Lachancea genera, with up to 41 copies per genome. Rover acquisition seems to have occurred by horizontal transfer in a common ancestor of these genera. The detection of remote Rover copies in Naumovozyma dairenensis and in the sole Saccharomyces cerevisiae strain AWRI1631, without synteny, suggests that two additional independent horizontal transfers took place toward these genomes. Such patchy distribution of elements prevents any anticipation of TE presence in incoming sequenced genomes, even closely related ones. The presence of both putative autonomous and defective Rover copies, as well as their diversification into five families, indicate particular dynamics of Rover elements in the Lachancea genus. Especially, we discovered the first miniature inverted-repeat transposable elements (MITEs) to be described in yeasts, together with their parental autonomous copies. Evidence of MITE insertion polymorphism among Lachancea waltii strains suggests their recent activity. Moreover, 40% of Rover copies appeared to be involved in chromosome rearrangements, showing the large structural impact of TEs on yeast genome and opening the door to further investigations to understand their functional and evolutionary consequences. PMID- 25532817 TI - Upregulation of osteoprotegerin expression correlates with bone invasion and predicts poor clinical outcome in oral cancer. AB - OBJECTIVES: We aimed to determine the prognostic significance of receptor activator of nuclear factor kappa-B ligand (RANKL), RANK and osteoprotegerin (OPG) in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The protein expression of RANKL, RANK and OPG was assessed by immunohistochemistry on pretreatment biopsies of 93 patients with locally advanced OSCC who received preoperative chemoradiotherapy (CRT). The primary endpoint was cancer-specific survival. Secondary endpoints were correlation of biomarkers with bone invasion and pathological tumor response. Kaplan-Meier curves and Cox regression models were used for survival analyses. RESULTS: A significantly higher OPG expression was demonstrated in patients with malignant bone invasion and non-responders to CRT as compared to patients without bone invasion and responders (p=0.032 and p=0.033, respectively). Multivariate analysis revealed that higher OPG expression was independently associated with shorter cancer-specific survival (p=0.04). The expression status of RANKL and RANK was not significantly related to clinicopathological characteristics and had no impact on survival of OSCC patients. CONCLUSION: Upregulation of OPG expression is associated with bone invasion, poor pathological tumor regression to neoadjuvant CRT, and worse long-term cancer-specific survival in patients with locally advanced OSCC. Our results indicate that OPG may be a novel prognostic biomarker in oral cancer. PMID- 25532819 TI - Strain and strain rate imaging using speckle tracking in acute allograft rejection in children with heart transplantation. AB - Acute allograft rejection is a major cause of morbidity and mortality following heart transplantation. There is no reliable noninvasive test to diagnose rejection. We aimed to investigate the accuracy of strain by speckle tracking echocardiography in the detection of acute rejection. We identified acute rejection episodes in patients followed at a single transplant center. Data were collected at baseline, during rejection and two follow-up points. Peak systolic radial and circumferential strain at the level of papillary muscles and peak systolic longitudinal strain from apical four-chamber view were analyzed offline. ANOVA was used for comparison between groups. p value <=0.05 was considered significant. Fifteen rejection episodes were identified. There were no differences in the fractional shortening, LV posterior wall thickness, E/A, septal E/E', septal S', lateral E/E', lateral S', or MPI during rejection, compared to baseline. There was a significant increase in the LV mass during a rejection episode (47.5 vs. 34.4 g/ht(2.7) [p = 0.03]). The peak systolic radial strain (18.3 vs. 26.5; p = 0.03), longitudinal strain (-11.7 vs. -14.6; p = 0.05), and circumferential strain (-14.4 vs. -21.7; p = 0.05) declined significantly during rejection. In conclusion, peak systolic radial, longitudinal and circumferential strain decline and LV mass increases during an episode of rejection. PMID- 25532821 TI - The impact of short duration, high intensity exercise on cardiac troponin release. AB - The aim of this study was to assess the appearance of cardiac troponins (cTnI and/or cTnT) after a short bout (30 s) of 'all-out' intense exercise and to determine the stability of any exercise-related cTnI release in response to repeated bouts of high intensity exercise separated by 7 days recovery. Eighteen apparently healthy, physically active, male university students completed two all out 30 s cycle sprint, separated by 7 days. cTnI, blood lactate and catecholamine concentrations were measured before, immediately after and 24 h after each bout. Cycle performance, heart rate and blood pressure responses to exercise were also recorded. Cycle performance was modestly elevated in the second trial [6.5% increase in peak power output (PPO)]; there was no difference in the cardiovascular, lactate or catecholamine response to the two cycle trials. cTnI was not significantly elevated from baseline through recovery (Trial 1: 0.06 +/- 0.04 ng ml(-1) , 0.05 +/- 0.04 ng ml(-1) , 0.03 +/- 0.02 ng ml(-1) ; Trial 2: 0.02 +/- 0.04 ng ml(-1) , 0.04 +/- 0.03 ng ml(-1) , 0.05 +/- 0.06 ng ml(-1) ) in either trial. Very small within subject changes were not significantly correlated between the two trials (r = 0.06; P>0.05). Subsequently, short duration, high intensity exercise does not elicit a clinically relevant response in cTnI and any small alterations likely reflect the underlying biological variability of cTnI measurement within the participants. PMID- 25532820 TI - Modern modelling techniques are data hungry: a simulation study for predicting dichotomous endpoints. AB - BACKGROUND: Modern modelling techniques may potentially provide more accurate predictions of binary outcomes than classical techniques. We aimed to study the predictive performance of different modelling techniques in relation to the effective sample size ("data hungriness"). METHODS: We performed simulation studies based on three clinical cohorts: 1282 patients with head and neck cancer (with 46.9% 5 year survival), 1731 patients with traumatic brain injury (22.3% 6 month mortality) and 3181 patients with minor head injury (7.6% with CT scan abnormalities). We compared three relatively modern modelling techniques: support vector machines (SVM), neural nets (NN), and random forests (RF) and two classical techniques: logistic regression (LR) and classification and regression trees (CART). We created three large artificial databases with 20 fold, 10 fold and 6 fold replication of subjects, where we generated dichotomous outcomes according to different underlying models. We applied each modelling technique to increasingly larger development parts (100 repetitions). The area under the ROC curve (AUC) indicated the performance of each model in the development part and in an independent validation part. Data hungriness was defined by plateauing of AUC and small optimism (difference between the mean apparent AUC and the mean validated AUC <0.01). RESULTS: We found that a stable AUC was reached by LR at approximately 20 to 50 events per variable, followed by CART, SVM, NN and RF models. Optimism decreased with increasing sample sizes and the same ranking of techniques. The RF, SVM and NN models showed instability and a high optimism even with >200 events per variable. CONCLUSIONS: Modern modelling techniques such as SVM, NN and RF may need over 10 times as many events per variable to achieve a stable AUC and a small optimism than classical modelling techniques such as LR. This implies that such modern techniques should only be used in medical prediction problems if very large data sets are available. PMID- 25532825 TI - Stories of MDM: from a conversation to a career of making less data more useful. PMID- 25532824 TI - Decision Regret following Treatment for Localized Breast Cancer: Is Regret Stable Over Time? AB - BACKGROUND: While studies suggest most women have little regret regarding their breast cancer treatment decisions immediately following treatment, no studies to date have evaluated how regret may change over time. OBJECTIVE: To measure the stability of posttreatment decision regret over time among women with breast cancer. METHODS: Women diagnosed with breast cancer between August 2005 and May 2007 reported to the Detroit, Michigan, or Los Angeles County Surveillance, Epidemiology, and End Results (SEER) registry and completed surveys at 9 months following diagnosis (time 1) and again approximately 4 years later (time 2). A decision regret scale consisting of 5 items was summed to create 2 decision regret scores at both time 1 and time 2 (range, 0-20). Multivariable linear regression was used to examine change in regret from 9 months to 4 years. Independent variables included surgery type, receipt of reconstruction, and recurrence status at follow-up. The model controlled for demographic and clinical factors. RESULTS: The analytic sample included 1536 women. Mean regret in the overall sample was 4.9 at time 1 and 5.4 at time 2 (P < 0.001). In the multivariable linear model, we found no difference in change in decision regret over time by surgery type. Reporting a new diagnosis of breast cancer at time 2 was associated with a 2.6-point increase in regret over time compared with women without an additional diagnosis (P = 0.003). Receipt of reconstruction was not associated with change in decision regret over time. CONCLUSIONS: Decision regret following treatment was low and relatively stable over time for most women. Those facing an additional diagnosis of breast cancer following treatment may be at risk for elevated regret-related distress. PMID- 25532826 TI - US-Based Drug Cost Parameter Estimation for Economic Evaluations. AB - INTRODUCTION: In the United States, more than 10% of national health expenditures are for prescription drugs. Assessing drug costs in US economic evaluation studies is not consistent, as the true acquisition cost of a drug is not known by decision modelers. Current US practice focuses on identifying one reasonable drug cost and imposing some distributional assumption to assess uncertainty. METHODS: We propose a set of Rules based on current pharmacy practice that account for the heterogeneity of drug product costs. The set of products derived from our Rules, and their associated costs, form an empirical distribution that can be used for more realistic sensitivity analyses and create transparency in drug cost parameter computation. The Rules specify an algorithmic process to select clinically equivalent drug products that reduce pill burden, use an appropriate package size, and assume uniform weighting of substitutable products. Three diverse examples show derived empirical distributions and are compared with previously reported cost estimates. RESULTS: The shapes of the empirical distributions among the 3 drugs differ dramatically, including multiple modes and different variation. Previously published estimates differed from the means of the empirical distributions. Published ranges for sensitivity analyses did not cover the ranges of the empirical distributions. In one example using lisinopril, the empirical mean cost of substitutable products was $444 (range = $23-$953) as compared with a published estimate of $305 (range = $51-$523). CONCLUSIONS: Our Rules create a simple and transparent approach to creating cost estimates of drug products and assessing their variability. The approach is easily modified to include a subset of, or different weighting for, substitutable products. The derived empirical distribution is easily incorporated into 1-way or probabilistic sensitivity analyses. PMID- 25532827 TI - Discontinuation of antiviral prophylaxis correlates with high prevalence of hepatitis B virus (HBV) reactivation in rheumatoid arthritis patients with HBV carrier state: a real-world clinical practice. AB - BACKGROUND: To investigate the risk of hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients with HBV carrier state during treatment of disease-modifying antirheumatic drugs (DMARDs) and the use of antiviral prophylaxis in real-world clinical practice. METHODS: Consecutive RA patients with HBV carrier state were included. Clinical data including liver evaluation, HBV infection evaluation and the use of antiviral prophylaxis were recorded. RESULTS: Fifty-three RA patients with HBV carrier state were screened and 36 patients were qualified for analysis. Thirty-six percentage of patients developed HBV reactivation and 17% developed HBV hepatitis together with reactivation, one of which developed decompensate cirrhosis. Only 50% of patients accepted lamivudine although all patients were recommended antiviral prophylaxis with entecavir or tenofovir and only 31% continued during DMARDs therapy. Seventy-one percentage of patients who discontinued antiviral prophylaxis developed HBV reactivation 3 ~ 21 months after discontinuation. Logistic regression analyses showed discontinuation of antiviral prophylaxis (OR: 66, p = 0.027), leflunomide (OR: 64, p = 0.011) and past history of hepatitis (OR: 56, p = 0.013) were risk factors of HBV reactivation. Past history of hepatitis (OR: 10, p = 0.021) was also risk factor of HBV hepatitis together with reactivation. CONCLUSION: Our results suggest poor patient acceptance and discontinuation of antiviral prophylaxis should not be ignored for Chinese RA patients with HBV carrier state in real-world clinical practice. Discontinuation of antiviral prophylaxis, past history of hepatitis and LEF might increase risk of HBV reactivation for RA patients with HBV carrier state during DMARDs therapy. PMID- 25532828 TI - The burden and spatial distribution of bovine African trypanosomes in small holder crop-livestock production systems in Tororo District, south-eastern Uganda. AB - BACKGROUND: African animal trypanosomiasis (AAT) is considered to be one of the greatest constraints to livestock production and livestock-crop integration in most African countries. South-eastern Uganda has suffered for more than two decades from outbreaks of zoonotic Human African Trypanosomiasis (HAT), adding to the burden faced by communities from AAT. There is insufficient AAT and HAT data available (in the animal reservoir) to guide and prioritize AAT control programs that has been generated using contemporary, sensitive and specific molecular techniques. This study was undertaken to evaluate the burden that AAT presents to the small-scale cattle production systems in south-eastern Uganda. METHODS: Randomised cluster sampling was used to select 14% (57/401) of all cattle containing villages across Tororo District. Blood samples were taken from all cattle in the selected villages between September-December 2011; preserved on FTA cards and analysed for different trypanosomes using a suite of molecular techniques. Generalized estimating equation and Rogen-Gladen estimator models were used to calculate apparent and true prevalences of different trypanosomes while intra cluster correlations were estimated using a 1-way mixed effect analysis of variance (ANOVA) in R statistical software version 3.0.2. RESULTS: The prevalence of all trypanosome species in cattle was 15.3% (95% CI; 12.2-19.1) while herd level trypanosome species prevalence varied greatly between 0-43%. Trypanosoma vivax (17.4%, 95% CI; 10.6-16.8) and Trypanosoma brucei rhodesiense (0.03%) were respectively, the most, and least prevalent trypanosome species identified. CONCLUSIONS: The prevalence of bovine trypanosomes in this study indicates that AAT remains a significant constraint to livestock health and livestock production. There is need to implement tsetse and trypanosomiasis control efforts across Tororo District by employing effective, cheap and sustainable tsetse and trypanosomiasis control methods that could be integrated in the control of other endemic vector borne diseases like tick-borne diseases. PMID- 25532829 TI - Improving the accuracy of recombinant protein production through integration of bioinformatics, statistical and mass spectrometry methodologies. AB - Heterologous protein production is a key technology for biotechnological, health sciences and many other research fields. Various approaches have been developed for its optimization, but the research emphasis has been on optimization of protein yield rather than protein quality. In this study, we have established a workflow for synthetic gene optimization for heterologous protein expression that combines bioinformatics, laboratory experiments, mass spectrometry and statistical analysis. Two gene primary structure analysis platforms, Anaconda and EuGene, and multivariate optimization methods were employed to re-design the Plasmodium falciparum lysyl-tRNA synthetase gene for optimal expression in Escherichia coli. Synthetic genes were expressed from common vectors, and amino acid mis-incorporations in the expressed proteins were detected and quantified using mass spectrometry. The association between the identified amino acid mis incorporations and 23 gene variables was then analysed. The synthetic genes yielded significantly higher levels of protein relative to the wild-type gene, but 71 amino acid mis-incorporation sites were observed along the whole protein and across the synthetic genes that were statistically associated with specific codons and protein secondary structures. The optimization method that led to production of the most accurate protein was based on a multivariate approach that combined variables that are known to influence mRNA translation. PMID- 25532830 TI - Surgical management of metastatic melanoma in the era of targeted systemic therapies. AB - Treatment strategies for metastatic melanoma have changed markedly in recent times due to the advent of targeted systemic therapies. In addition to these developments, surgery remains a useful adjunct that can confer survival benefits in selected patients. In this review, we examine the current literature to highlight the role of surgical intervention in metastatic melanoma in the era of targeted systemic therapies. PMID- 25532831 TI - Annotated bibliography on participatory consultations to help aid the inclusion of marginalized perspectives in setting policy agendas. AB - The purpose of this bibliography is to present studies from peer-reviewed and grey literature that used consultations and other participatory strategies to capture a community's perspective of their health priorities, and of techniques used to elevate participation from the implementation phase to a more upstream phase of prioritization, policymaking and agenda setting. The focus here is of those studies that worked with marginalized populations or sub-populations. This bibliography contains four areas of research. It begins by first offering some philosophical and conceptual frameworks that link participatory interventions with inclusive policy making or agenda setting, and a rationale for prioritizing marginalized populations in such an undertaking. After situating ourselves in this manner, the second section looks at various participatory instruments for participatory consultations, for reaching out to marginalized populations, and for communicating the results to policymakers. Two sets of distinctions are made here: one between external (non-invitation) and internal (stifling of opinions) exclusion, and between mere participation and from active inclusion within consultations and within the policies. In the third section, examples of consultations that created or changed policy in various jurisdictions are shared, followed by a final section on a reflective and evaluative look at the recruitment, instruments and examples. An earlier iteration of this bibliography was created to assist a multi-country research project by the author to inform the UN Post-2015 development framework of the views of several diverse and highly marginalized populations around the world on their health-related priorities. PMID- 25532832 TI - Is patient confidentiality compromised with the electronic health record?: a position paper. AB - In order for electronic health records to fulfill their expected benefits, protection of privacy of patient information is key. Lack of trust in confidentiality can lead to reluctance in disclosing all relevant information, which could have grave consequences. This position paper contemplates whether patient confidentiality is compromised by electronic health records. The position that confidentiality is compromised was supported by the four bioethical principles and argued that despite laws and various safeguards to protect patients' confidentiality, numerous data breaches have occurred. The position that confidentiality is not compromised was supported by virtue ethics and a utilitarian viewpoint and argued that safeguards keep information confidential and the public feels relatively safe with the electronic health record. The article concludes with an ethically superior position that confidentiality is compromised with the electronic health record. Although organizational and governmental ways of enhancing the confidentiality of patient information within the electronic health record facilitate confidentiality, the ultimate responsibility of maintaining confidentiality rests with the individual end-users and their ethical code of conduct. The American Nurses Association Code of Ethics for nurses calls for nurses to be watchful with data security in electronic communications. PMID- 25532833 TI - Resveratrol trimers from seed cake of Paeonia rockii. AB - In the course of screening natural products for antibacterial activities, a total acetone extract of the seed cake of Paeonia rockii showed significant effects against bacterial strains. Bioactivity-guided fractionation of the EtOAc-soluble fraction of the total acetone extract resulted in the isolation and identification of five resveratrol trimers, including rockiiol C (1), gnetin H (2), suffruticosol A (3), suffruticosol B (4) and suffruticosol C (5). The relative configuration of these compounds was elucidated mainly by comprehensive 1D and 2D-NMR experiments. Compound 1 was a new compound. All isolated compounds exhibited strong antibacterial activities against Gram-positive bacteria. PMID- 25532834 TI - A review on visible light active perovskite-based photocatalysts. AB - Perovskite-based photocatalysts are of significant interest in the field of photocatalysis. To date, several perovskite material systems have been developed and their applications in visible light photocatalysis studied. This article provides a review of the visible light (lambda > 400 nm) active perovskite-based photocatalyst systems. The materials systems are classified by the B site cations and their crystal structure, optical properties, electronic structure, and photocatalytic performance are reviewed in detail. Titanates, tantalates, niobates, vanadates, and ferrites form important photocatalysts which show promise in visible light-driven photoreactions. Along with simple perovskite (ABO3) structures, development of double/complex perovskites that are active under visible light is also reviewed. Various strategies employed for enhancing the photocatalytic performance have been discussed, emphasizing the specific advantages and challenges offered by perovskite-based photocatalysts. This review provides a broad overview of the perovskite photocatalysts, summarizing the current state of the work and offering useful insights for their future development. PMID- 25532835 TI - Is development of high-grade gliomas sulfur-dependent? AB - We characterized gamma-cystathionase, rhodanese and 3-mercaptopyruvate sulfurtransferase activities in various regions of human brain (the cortex, thalamus, hypothalamus, hippocampus, cerebellum and subcortical nuclei) and human gliomas with II to IV grade of malignancy (according to the WHO classification). The human brain regions, as compared to human liver, showed low gamma cystathionase activity. The activity of rhodanese was also much lower and it did not vary significantly between the investigated brain regions. The activity of 3 mercaptopyruvate sulfurtransferase was the highest in the thalamus, hypothalamus and subcortical nuclei and essentially the same level of sulfane sulfur was found in all the investigated brain regions. The investigations demonstrated that the level of sulfane sulfur in gliomas with the highest grades was high in comparison to various human brain regions, and was correlated with a decreased activity of gamma-cystathionase, 3-mercaptopyruvate sulfurtransferase and rhodanese. This can suggest sulfane sulfur accumulation and points to its importance for malignant cell proliferation and tumor growth. In gliomas with the highest grades of malignancy, despite decreased levels of total free cysteine and total free glutathione, a high ratio of GSH/GSSG was maintained, which is important for the process of malignant cells proliferation. A high level of sulfane sulfur and high GSH/GSSG ratio could result in the elevated hydrogen sulfide levels. Because of the disappearance of gamma-cystathionase activity in high-grade gliomas, it seems to be possible that 3-mercaptopyruvate sulfurtransferase could participate in hydrogen sulfide production. The results confirm sulfur dependence of malignant brain tumors. PMID- 25532836 TI - One new and nine known flavonoids from Choerospondias axillaries and their in vitro antitumor, anti-hypoxia and antibacterial activities. AB - In the present study, a new flavanoid 1, together with nine known ones 2-10 were isolated from the stem bark of Choerospondias axillaries, the fruit of which was used mainly for treatment of cardiovascular diseases in China. The structure of 1 was established on the basis of its extensive spectral data, and the absolute structures of 1 and 10 were determined by their CD data. The absolute structure of 10 was established for the first time. Among the obtained compounds, 5-8 inhibited the proliferation of K562 cells with inhibition rates of 26.6%, 65.7%, 40.4% and 45.6% at 100 ug/mL; 1 and 4-10 showed significant protective effects on anoxia-induced injury in cultured ECV304 or PC12 cells at 50 ug/mL; 8 and 9 showed antibacterial effects on Staphylococcus aureus ATCC6538 at the tested concentration of 150 ug/8 mm paper disc. Compounds 2 and 4-10 were isolated for the first time from this genus. The proliferation inhibiting activities of 7 and 8, the anti-hypoxia activities of 1 and 4-10, and the antibacterial effect of 8 and 9 on Staphylococcus aureus ATCC6538 are reported here for the first time. PMID- 25532837 TI - New and Cytotoxic Components from Antrodia camphorata. AB - The solid-state cultured products of Antrodia camphorata as health foods has been blooming for the past few decades in Taiwan. In continuing our studies on the chemical constituents of the solid-state cultured products of this fungus, 6 methoxy-4-methyl-2,3-(methylenedioxy)phenol (1) and 4,4'-(ethane-1,2 diyl)bis(2,3,6-trimethoxyphenol)(2) together with 2,3,6-trimethoxy-4-methylphenol (3), 1(10->6)abeo-ergosta-5,7,9,22-tetraen-3alpha-ol (4), citreoanthrasteroid B (5) and dankasterones A (6) and B (7) were purified by a series of column chromatography. Their structures were elucidated by spectral data analysis. For bioactivity assay, compounds 4-7 showed significant cytotoxicity toward murine colorectal CT26 and human leukemia K562 cancer cell lines with IC50 values ranging from 6.7 to 15.3 uM and from 12.5 to 23.1 uM, respectively. PMID- 25532838 TI - Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. AB - Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown 6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (alpha) of 1.25 and resolution (RS) of 1.55 when a mobile phase consisting of methanol-acetonitrile-trifluoroacetic acid-triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition. PMID- 25532839 TI - A new solid phase extraction for the determination of anthocyanins in grapes. AB - A method for the concentration and cleaning of red grape extracts prior to the determination of anthocyanins by UPLC-DAD has been developed. This method is of special interest in the determination of phenolic maturity as it allows the analysis of the anthocyanins present in grapes. Several different SPE cartridges were assessed, including both C-18- and vinylbenzene-based cartridges. C-18-based cartridges presented a very low retention for the glucosylated anthocyanidins while vinylbenzene-based cartridges showed excellent retention for these compounds. The optimized method involves the initial conditioning of the cartridge using 10 mL of methanol and 10 mL of water, followed by loading of up to 100 mL of red grape extract. Ten mL of water was used in the washing step and anthocyanins were subsequently eluted using 1.5 mL of acidified methanol at pH 2. This method simplifies the determination of individual anthocyanins as, on the one hand, it cleans the sample of interference and, on the other hand, it increases the concentration to up to 25:1.5. The developed method has been validated with a range of different grapes and it has also been tested as a means of determining the different anthocyanins in grapes with different levels of maturity. PMID- 25532840 TI - Effects of platycodin D on proliferation, apoptosis and PI3K/Akt signal pathway of human glioma U251 cells. AB - Effects of platycodin D (PD) on the proliferation, apoptosis and PI3K/Akt signaling pathway of human glioma U251 cells were investigated. Glioma U251 cells were treated with PD at final concentrations of 0, 16.3, 40.8, 81.6, 163.2 MUM, and inhibition rate, early and late apoptotic rate, apoptotic index, expression of apoptosis-related proteins and phosphorylation of the PI3K/Akt signaling pathway were evaluated. The results showed that compared with the control group, PD could increase the proliferation inhibition rate of U251 cells in a dose- and time -dependent manner; PD could also elevate the early and late apoptotic rate, apoptotic index and the level of pro-apoptotic proteins of glioma U251 cells, such as Bax and cleaved caspase-3, but lower the level of apoptosis inhibitory protein, such as Bcl-2; PD could increase the ratio of G0/G1 phase U251 cells, and lower the proportion of Sphase U251 cells and the ratio of G2/M phase U251 cells; PD could reduce the ratio of p-Akt/Akt. The results indicate that PD can inhibit the proliferation, induce the apoptosis and cause the cell cycle arrest in human glioma U251 cells, which may be related to the inhibition of PD on the activation of PI3K/Akt signaling pathway. PMID- 25532841 TI - Photocatalytic oxidation of diethyl sulfide vapor over TiO2-based composite photocatalysts. AB - Composite TiO2/activated carbon (TiO2/AC) and TiO2/SiO2 photocatalysts with TiO2 contents in the 10 to 80 wt. % range were synthesized by the TiOSO4 thermal hydrolysis method and characterized by AES, BET, X-ray diffraction and FT-IR ATR methods. All TiO2 samples were in the anatase form, with a primary crystallite size of about 11 nm. The photocatalytic activities of the TiO2/AC and TiO2/SiO2 samples were tested in the gas-phase photocatalytic oxidation (PCO) reaction of diethyl sulfide (DES) vapor in a static reactor by the FT-IR in situ method. Acetaldehyde, formic acid, ethylene and SO2 were registered as the intermediate products which finally were completely oxidized to the final oxidation products - H2O, CO2, CO and SO42- ions. The influence of the support on the kinetics of DES PCO and on the TiO2/AC and TiO2/SiO2 samples' stability during three long-term DES PCO cycles was investigated. The highest PCO rate was observed for TiO2/SiO2 photocatalysts. To evaluate the activity of photocatalysts the turnover frequency values (TOF) were calculated for three photocatalysts (TiO2, TiO2/AC and TiO2/SiO2) for the same amount of mineralized DES. It was demonstrated that the TOF value for composite TiO2/SiO2 photocatalysts was 3.5 times higher than for pure TiO2. PMID- 25532842 TI - Anti-depressant-like effect of kaempferitrin isolated from Justicia spicigera Schltdl (Acanthaceae) in two behavior models in mice: evidence for the involvement of the serotonergic system. AB - We evaluated the antidepressant-like effect of kaempferitrin (Km) isolated from the plant Justicia spicigera (Asteraceae), which is used in traditional medicine for relieving emotional disorders, such as "la tristeza" (sadness or dysthymia) and "el humor" (mood changes). The actions of Km were evaluated in a forced swimming test (FST) and a suspension tail test (TST) in mice. We explored the involvement of the serotonergic system and the hypothalamic-hypophysis-adrenal axis (HPA) in the antidepressant-like effect of Km. To evaluate nonspecific effects of Km on general activity, the open field test (OFT) was performed. Km at 5, 10, and 20 mg/kg induced an antidepressant-like effect. Sub-effective dose of Km (1 mg/kg) produced a synergistic effect with imipramine (6.25 mg/kg) and fluoxetine (10 mg/kg) but not with desipramine (3.12 mg/kg). Pretreatment with p chlorophenylalanine methyl ester (PCPA), a serotonin synthesis inhibitor, N-{2-(4 (2-methoxyphenyl)-1-piperazinyl}-N-(2-pyridinyl)cyclohexecarboxamide (WAY 100635), a selective 5-HT1A receptor antagonist, and 8OH-DPAT, a selective 5-HT1A agonist, but not pindolol (10 mg/kg) blocked the anti- immobility effect induced by Km. Taken together, these results indicate that the antidepressant-like effect of Km is related to the serotonergic system, principally 5-HT1A. This effect was not related to changes in locomotor activity. PMID- 25532843 TI - 1-[2-(2-Methoxyphenylamino)ethylamino]-3-(naphthalene-1- yloxy)propan-2-ol may be a promising anticancer drug. AB - We have originally synthesized the naftopidil analogue 1-[2-(2 methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol (HUHS 1015) as a new anticancer drug. HUHS1015 induces cell death in a wide variety of human cancer cell lines originated from malignant pleural mesothelioma, lung cancer, hepatoma, gastric cancer, colorectal cancer, bladder cancer, prostate cancer, and renal cancer. HUHS1015-induced cell death includes necrosis (necroptosis) and apoptosis, and the underlying mechanism differs depending upon cancer cell types. HUHS1015 effectively suppresses tumor growth in mice inoculated with NCI-H2052, MKN45, or CW2 cells, with a potential similar to or higher than that of currently used anticancer drugs. Here we show how HUHS1015 might offer brilliant hope for cancer therapy. PMID- 25532844 TI - Design and synthesis of chalcone derivatives as inhibitors of the ferredoxin - ferredoxin-NADP+ reductase interaction of Plasmodium falciparum: pursuing new antimalarial agents. AB - Some chalcones have been designed and synthesized using Claisen-Schmidt reactions as inhibitors of the ferredoxin and ferredoxin-NADP+ reductase interaction to pursue a new selective antimalaria agent. The synthesized compounds exhibited inhibition interactions between PfFd-PfFNR in the range of 10.94%-50%. The three strongest inhibition activities were shown by (E)-1-(4-aminophenyl)-3-(4 methoxyphenyl)prop-2-en-1-one (50%), (E)-1-(4-aminophenyl)-3-(2,4 dimethoxyphenyl)prop-2-en-1-one (38.16%), and (E)-1-(4-aminophenyl)-3-(2,3 dimethoxyphenyl)prop-2-en-1-one (31.58%). From the docking experiments we established that the amino group of the methoxyamino chlacone derivatives plays an important role in the inhibition activity by electrostatic interaction through salt bridges and that it forms more stable and better affinity complexes with FNR than with Fd. PMID- 25532845 TI - Transfer hydrogenation in open-shell nucleotides - a theoretical survey. AB - The potential of a larger number of sugar models to act as dihydrogen donors in transfer hydrogenation reactions has been quantified through the calculation of hydrogenation energies of the respective oxidized products. Comparison of the calculated energies to hydrogenation energies of nucleobases shows that many sugar fragment radicals can reduce pyrimidine bases such as uracil in a strongly exothermic fashion. The most potent reducing agent is the C3' ribosyl radical. The energetics of intramolecular transfer hydrogenation processes has also been calculated for a number of uridinyl radicals. The largest driving force for such a process is found for the uridin-C3'-yl radical, whose rearrangement to the C2' oxidized derivative carrying a dihydrouracil is predicted to be exothermic by 61.1 kJ/mol in the gas phase. PMID- 25532846 TI - Bio and nanomaterials based on Fe3O4. AB - During the past few years, nanoparticles have been used for various applications including, but not limited to, protein immobilization, bioseparation, environmental treatment, biomedical and bioengineering usage, and food analysis. Among all types of nanoparticles, superparamagnetic iron oxide nanoparticles, especially Fe3O4, have attracted a great deal of attention due to their unique magnetic properties and the ability of being easily chemical modified for improved biocompatibility, dispersibility. This review covers recent advances in the fabrication of functional materials based on Fe3O4 nanoparticles together with their possibilities and limitations for application in different fields. PMID- 25532847 TI - Design and optimisation of bioactive cyclic peptides: generation of a down regulator of TNF secretion. AB - Although strong binding interactions between protein receptor and ligand do not require the participation of a large number of amino acids in either site, short peptide chains are generally poor at recreating the types of protein-protein interactions which take place during cell recognition and signalling process, probably because their flexible backbones prevent the side chains from forming sufficiently rigid and stable epitopes, which can take part in binding with the desired strength and specificity. In a recently-reported study, it was shown that a proto-epitope containing F, R and S amino acids has the ability to down regulate TNF secretion by macrophages. This paper extends these findings, putting those amino acids into a short cyclic peptide scaffold, and determining the optimal configuration required to overcome the problems of conformational instability, and give rise to molecules which have potential as therapeutic agents in human disease, such as rheumatoid arthritis. PMID- 25532848 TI - Molecular insights into the genetic diversity of Hemarthria compressa germplasm collections native to southwest China. AB - Start codon targeted polymorphism (SCoT) analysis was employed to distinguish 37 whipgrass (Hemarthria compressa L.) clones and assess the genetic diversity and population structure among these genotypes. The informativeness of markers was also estimated using various parameters. Using 25 highly reproducible primer sets, 368 discernible fragments were generated. Of these, 282 (77.21%) were polymorphic. The number of alleles per locus ranged from five to 21, and the genetic variation indices varied. The polymorphism information content (PIC) was 0.358, the Shannon diversity index (H) was 0.534, the marker index (MI) was 4.040, the resolving power (RP) was 6.108, and the genotype index (GI) was 0.782. Genetic similarity coefficients (GS) between the accessions ranged from 0.563 to 0.872, with a mean of 0.685. Their patterns observed in a dendrogram constructed using the unweighted pair group method with arithmetic mean analysis (UPGMA) based on GS largely confirmed the results of principal coordinate analysis (PCoA). PCoA was further confirmed by Bayesian model-based STRUCTURE analysis, which revealed no direct association between genetic relationship and geographical origins as validated by Mantel's test (r = 0.2268, p = 0.9999). In addition, high-level genetic variation within geographical groups was significantly greater than that between groups, as determined by Shannon diversity analysis, analysis of molecular variance (AMOVA) and Bayesian analysis. Overall, SCoT analysis is a simple, effective and reliable technique for characterizing and maintaining germplasm collections of whipgrass and related species. PMID- 25532849 TI - Determination and pharmacokinetic study of gentiopicroside, geniposide, baicalin, and swertiamarin in Chinese herbal formulae after oral administration in rats by LC-MS/MS. AB - A sensitive and efficient liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed for the simultaneous determination of gentiopicroside, geniposide, baicalin, and swertiamarin in rat plasma. To avoid the stress caused by restraint or anesthesia, a freely moving rat model was used to investigate the pharmacokinetics of herbal medicine after the administration of a traditional Chinese herbal prescription of Long-Dan-Xie-Gan-Tang (10 g/kg, p.o.). Analytes were separated by a C18 column with a gradient system of methanol water containing 1 mM ammonium acetate with 0.1% formic acid. The linear ranges were 10-500 ng/mL for gentiopicroside, geniposide, and baicalin, and 5-250 ng/mL for swertiamarin in biological samples. The intra- and inter-day precision (relative standard deviation) ranged from 0.9% to 11.4% and 0.3% to 14.4%, respectively. The accuracy (relative error) was from -6.3% to 10.1% at all quality control levels. The analytical system provided adequate matrix effect and recovery with good precision and accuracy. The pharmacokinetic data demonstrated that the area under concentration-time curve (AUC) values of gentiopicroside, geniposide, baicalin, and swertiamarin were 1417 +/- 83.8, 302 +/- 25.8, 753 +/- 86.2, and 2.5 +/- 0.1 min ug/mL. The pharmacokinetic profiles provide constructive information for the dosage regimen of herbal medicine and also contribute to elucidate the absorption mechanism in herbal applications and pharmacological experiments. PMID- 25532850 TI - Non-innocent ligands. PMID- 25532851 TI - Management of transcatheter aortic valve embolization into the left ventricle. AB - Embolization of transcatheter aortic valve replacement (TAVR) prostheses is a rare and serious procedural complication. While embolization into the aorta can sometimes be managed by transcatheter techniques, embolization into the left ventricle (LV) often requires immediate open heart surgery. We report three TAVR cases complicated by LV embolization. In each case, successful implantation of a second transcatheter prosthesis was accomplished, followed by surgical removal of the first embolized device. PMID- 25532853 TI - All-solid-state cable-type flexible zinc-air battery. AB - A cable-type flexible Zn-air battery with a spiral zinc anode, gel polymer electrolyte (GPE), and air cathode coated on a nonprecious metal catalyst is designed in order to extend its application area toward wearable electronic devices. PMID- 25532852 TI - Physicomechanical and antibacterial properties of experimental resin-based dental sealants modified with nylon-6 and chitosan nanofibers. AB - This study aimed to develop and evaluate resin-based experimental dental sealants containing electrospun nylon-6 (N6) and chitosan (CH) fibers in an attempt to improve the physicomechanical properties and provide an antibacterial protective effect, respectively. Electrospun N6 and CH mats were immersed into a resin mixture, light-cured, and then cryomilled to obtain micron-sized resin-modified fiber particles. Different levels of the novel cryomilled particles (i.e. 1, 2.5, and 5% relative to the resin mixture, % by weight) were used to prepare the N6- and CH-containing sealants. A commercial sealant and the experimental resin mixture (unfilled) were used as controls. Flexural strength (FS), Vickers microhardness (VH), and agar diffusion tests were performed. The data were analyzed at the 5% significance level. No significant difference in fiber diameter of N6 (503 +/- 31 nm) and CH (595 +/- 38 nm) was observed. Upon cryomilling, the resin-modified CH and N6 mats led to the formation of irregularly-shaped particles, with an average diameter of 14.24 um and 15.87 um, respectively. CH-5% had significantly higher FS (115.3 +/- 1.3 MPa) than all the other groups. CH-1% had significantly higher hardness values (38.3 +/- 0.3 VHN) than all the other groups. Collectively, the results indicated that CH-containing sealants presented the highest FS and hardness; however, none of the CH containing sealants displayed antimicrobial properties. PMID- 25532854 TI - Phenylthiocarbamide taste sensitivity is associated with sinonasal symptoms in healthy adults. AB - BACKGROUND: The bitter taste receptor T2R38, expressed in the tongue and nasal epithelium, has been shown to trigger sinonasal innate immunity contributing to the prevention of gram-negative upper airway bacterial infections. Common polymorphisms of the T2R38 gene, correlating with bitter taste sensitivity to phenylthiocarbamide (PTC), have been linked to differences in sinonasal innate immune response, with specific genotypes significantly more common in medically recalcitrant chronic rhinosinusitis patients. The purpose of this study was to examine this association between T2R38 function and sinonasal infection or symptoms in a healthy population. METHODS: A survey of the frequency of sinus infections, as well as other nasal symptoms such as colds, allergies, and overall nasal quality of life (nQOL), was administered to healthy adult participants. nQOL was measured using a 0 to 3 scale of worsening symptoms. A PTC compound taste strip was administered with T2R38 taste sensitivity classified as extremely, somewhat, or not sensitive. RESULTS: Among 217 participants (55% female, 70% Caucasian, 42% age 21 to 25 years), 30% did not detect bitterness (nontasters), 34% were moderate tasters, and 36% were "supertasters," experiencing a strong, unpalatable bitterness. Supertasters were associated with less frequent sinus infections (p = 0.04), and PTC sensitivity was predictive of nasal symptoms: Supertasters had the best nQOL scores, followed by moderate tasters and nontasters (means: 0.65, 0.81, 1.00, respectively; p = 0.014 for trend). There were no significant associations with other variables. CONCLUSION: This study provides evidence that T2R38 functionality in the tongue correlates with nasal symptoms in healthy individuals. PMID- 25532855 TI - MicroRNA expression as predictor of local recurrence risk in oral squamous cell carcinoma. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide with a high rate of recurrence. MicroRNAs (miRNAs) are gene regulators playing an important role in oral carcinogenesis. The purpose of this study was for us to identify and functionally characterize miRNAs that predict recurrence in OSCC. METHODS: We collected 92 OSCC with their normal tissue counterparts and we performed miRNAs expression profiling on 74 OSCC and 38 normal tissues. The association between the expression of miRNAs and clinical outcome was evaluated in the follow-up of 69 patients. RESULTS: Four of the miRNAs deregulated between OSCC and normal tissues are prognostic for recurrence either when considered individually or as a group. Depletion of the expression of prognostic miRNAs inhibit the proliferation of OSCC cells CONCLUSION: MiRNAs are differentially expressed in OSCC versus normal samples. The expression of 4 prognostic miRNA signatures is able to predict recurrence risk independently from other clinical factors in OSCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E189-E197, 2016. PMID- 25532856 TI - MicroRNA-155 targets cyb561d2 in zebrafish in response to fipronil exposure. AB - MicroRNAs (miRNAs), which are a class of small noncoding RNAs, can modulate the expression of many protein-coding genes when an organism is exposed to an environmental chemical. We previously demonstrated that miR-155 was significantly downregulated in adult zebrafish (Danio rerio) in response to fipronil (5-amino-1 [2,6-dichloro-4-(trifluoromethyl) phenyl]-4-[(trifluoromethyl) sulphinyl]-1H pyrazole-3-carbonitrile) exposure. However, the regulation of this miRNA's predicted target gene cyb561d2, which is a member of the cytochrome b561 (cyt b561) family involved in electron transfer, cell defence, and chemical stress, has not been experimentally validated to date. In this study, we evaluated the effects of fipronil on miR-155 and cyb561d2 in zebrafish. The expression of miR 155 was downregulated, whereas cyb561d2 was upregulated in both mRNA and protein level in a dose-dependent manner upon stimulation of fipronil. The dual luciferase report assay demonstrated that miR-155 interacted with cyb561d2 3' untranslated regions (3'-UTR). The expression of cyb561d2 was reduced in both mRNA and protein levels when ZF4 cells were transfected with an miR-155 mimic, whereas its expression levels of both mRNA and protein were increased when endogenous miR-155 was inhibited by transfection with an miR-155 inhibitor. The results improved our understanding of molecular mechanism of toxicity upon fipronil exposure, and presents miR-155 as a potential novel toxicological biomarker for chemical exposure. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 877-886, 2016. PMID- 25532860 TI - Comment on Madelaine et al.: Results and complications of single-stage total knee arthroplasty and high tibial osteotomy. PMID- 25532859 TI - When should clinicians search for GLUT1 deficiency syndrome in childhood generalized epilepsies? AB - GLUT1 deficiency (GLUT1D) has recently been identified as an important cause of generalized epilepsies in childhood. As it is a treatable condition, it is crucial to determine which patients should be investigated. METHODS: We analyzed SLC2A1 for mutations in a group of 93 unrelated children with generalized epilepsies. Fasting lumbar puncture was performed following the identification of a mutation. We compared our results with a systematic review of 7 publications of series of patients with generalized epilepsies screened for SLC2A1 mutations. RESULTS: We found 2/93 (2.1%) patients with a SLC2A1 mutation. One, carrying a novel de novo deletion had epilepsy with myoclonic-atonic seizures (MAE), mild slowing of head growth, choreiform movements and developmental delay. The other, with a paternally inherited missense mutation, had childhood absence epilepsy with atypical EEG features and paroxysmal exercise-induced dyskinesia (PED) initially misdiagnosed as myoclonic seizures. Out of a total of 1110 screened patients with generalized epilepsies from 7 studies, 2.4% (29/1110) had GLUT1D. This rate was higher (5.6%) among 303 patients with early onset absence epilepsy (EOAE) from 4 studies. About 50% of GLUT1D patients had abnormal movements and 41% a family history of seizures, abnormal movements or both. CONCLUSION: GLUT1D is most likely to be found in MAE and in EOAE. The probability of finding GLUT1D in the classical idiopathic generalized epilepsies is very low. Pointers to GLUT1D include an increase in seizures before meals, cognitive impairment, or PED which can easily be overlooked. PMID- 25532861 TI - Full weight bearing and dynamisation with Limmed(r) locked plate fixation accelerates bone regeneration in the volume of opening wedge high tibial osteotomy. AB - PURPOSE: The efficacy of immediate full weight bearing in accelerating bone regeneration after medial opening wedge high tibial osteotomy (HTO) was evaluated in patients operated with the Limmed system (locked plate fixation) that allows dynamisation of the site of the osteotomy. METHODS: A case series of 50 consecutive osteotomies performed with Limmed locked plate fixation for medial opening wedge HTO had full weight bearing immediately after the HTO; they were compared to a case-matched control series of 50 HTOs (50 patients) performed using the same implant without locked screws. Radiographs were observed at 30 days and two, three, four, five and six months after surgery. The osteotomy gap was only partially filled by a medial bone substitute leaving the lateral part unfilled. Bone surface areas of osteotomy planes were quantified and opening volumes were determined applying wedge heights. End points for evaluation included radiographic evidence of bone regeneration in the volume created by the opening of the osteotomy. RESULTS: Statistically significant differences were seen between the groups in terms of radiographic union and radiographic stability between the two groups. Patients of the Limmed group reported a shorter time for union (average four weeks difference) without loss of correction during healing. At the radiographic evaluation, there was a significant increase in osseointegration in the group with weight bearing compared to the control group without weight bearing with increased rate of speed to fill the void volume of the osteotomy. The computed tomography scan of the grafted area at four months after surgery showed no significant difference in the quality of the newly formed bone between the two groups. CONCLUSIONS: The Limmed medial opening wedge HTO system with immediate full weight bearing accelerates bone graft substitute osseointegration and bone healing as compared with controls without full weight bearing. PMID- 25532862 TI - Long-term survival of the glenoid components in total shoulder replacement for arthritis. AB - PURPOSE: Aseptic glenoid component loosening remains a common problem in total shoulder arthroplasty (TSA). This study presents long-term prospective follow-up after implantation of a glenoid component using the "cancellous compaction technique" and its effect on clinical outcome and presence and progression of radiolucent lines (RLLs). METHOD: Thirty-nine TSAs were performed for primary osteoarthritis by one surgeon using the same technique. For the glenoid side, a keeled, polyethylene, convex-backed component was implanted using the "cancellous compaction technique" consisting of minimal reaming, compaction bone grafting of the glenoid and minimal addition of cement. Postoperative clinical outcome was analysed using Constant scores and patient's subjective evaluation. Independent observers evaluated postoperative X-rays for radiolucent lines (RLL) around the base plate and keel. RESULTS: At an average follow-up of 8.5 years (range 4.7 12.5), the Constant score improved from 33.5 to 73.0 points (P < 0.0001). Active anterior elevation improved from an average 95 degrees to 140 degrees (P < 0.0001), and active external rotation improved from 20 degrees to 45 degrees (P < 0.0001). Pain score improved from 3.1 to 13.6 (P < 0.0001). Radiologically, the RLL score increased from 1.09 (range, 0-3) postoperative to 5.7 (range, 0-18) (P < 0.0001) at final follow-up. The occurrence of definite radiological glenoid loosening was 15.5 %. Constant scores deteriorated with the progression of RLLs (P = 0.006). The rate of revision surgery for glenoid loosening was 2.5 %. CONCLUSIONS: This study showed highly satisfactory clinical outcomes and low rates of revision for glenoid loosening using a bone-saving compaction technique for implantation of an all-polyethylene glenoid component. PMID- 25532863 TI - A development of Freudian metapsychology for schizophrenia. AB - The author states that psychoanalysis has much to contribute to schizophrenia. Beginning with a development of Freudian metapsychology, he addresses the in depth psychopathological study of a session (the first on the couch) with a schizophrenic patient who hears voices and feels that he is being watched. Since the symptoms appear at the level of the heard word and the visual image - key to Freudian metapsychology - he delineates a circuit for the word and one for the image, describing a blockage in both and the consequences of these. Furthermore, with regard to the patient's progress, he demonstrates first a quantitative improvement in symptoms, and later qualitative changes in his functioning. He shows how, over a time, functioning is improved in a once-a-week on-the-couch setting after two years of face-to-face treatment. PMID- 25532864 TI - The D3 dopamine receptor: From structural interactions to function. AB - Novel structural and functional aspects of the dopamine (DA) D3 receptors (D3R) have been recently described. D3R expressed in dopaminergic neurons have been classically considered to play the role of autoreceptors inhibiting, as the D2R, DA release. However, evidence for D3R-mediated neurotrophic and neuroprotective effects on DA neurons suggests their involvement in preventing pathological alterations leading to neurodegeneration. On the other hand, given its localization and functional role at postsynaptic striatal levels, the D3R may also be involved in the pathogenesis of movement disorders and psychiatric diseases. Functional interactions of D3R with other receptor systems are crucial for the modulation of several physiological events. On this line, the discovery that the D3R can form heteromers with other receptors has opened the possibility of uncover novel molecular mechanisms of brain functions and dysfunctions. This paper summarizes the functional and physical interactions of D3R with other receptors both at pre-synaptic sites, where it is co-expressed with the D2R and nicotinic receptors, and at post-synaptic sites where it interacts with the DA D1 receptors (D1R). The biochemical and functional properties of the D1R-D3R heteromer will be especially discussed. Both D1R and D3R have been in fact implicated in several disorders, including schizophrenia and motor dysfunctions. Therefore, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases. PMID- 25532865 TI - Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis. AB - Cannabis use can induce acute psychotic symptoms and increase the risk of schizophrenia. Impairments in inhibitory control and processing are known to occur both under the influence of cannabis and in schizophrenia. Whether cannabis induced impairment in inhibitory processing is related to the acute induction of psychotic symptoms under its influence is unclear. We investigated the effects of acute oral administration of 10mg of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on inhibitory control and regional brain activation during inhibitory processing in humans and examined whether these effects are related to the induction of psychotic symptoms under its influence using a repeated-measures, placebo-controlled, double-blind, within subject design. We studied thirty-six healthy, English-speaking, right-handed men with minimal previous exposure to cannabis and other illicit drugs twice using functional magnetic resonance imaging (fMRI) while they performed a response inhibition (Go/No-Go) task. Relative to placebo, delta-9-THC caused transient psychotic symptoms, anxiety, intoxication and sedation, inhibition errors and impaired inhibition efficiency. Severity of psychotic symptoms was directly correlated with inhibition error frequency and inversely with inhibition efficiency under the influence of delta-9-THC. Delta-9-THC attenuated left inferior frontal activation which was inversely correlated with the frequency of inhibition errors and severity of psychotic symptoms and positively with inhibition efficiency under its influence. These results provide experimental evidence that impairments in cognitive processes involved in the inhibitory control of thoughts and actions and inferior frontal function under the influence of cannabis may have a role in the emergence of transient psychotic symptoms under its influence. PMID- 25532866 TI - Epiphyseal fusion in Pan troglodytes relative to dental age. AB - Previous studies on different aspects of chimpanzee growth and development have documented dental eruption and development, long bone and somatic growth, and to a lesser extent, skeletal fusion. Such data are useful in comparative and evolutionary studies of growth and some aspects of life history evolution in apes and early hominids. However, few studies have integrated dental development and other aspects of skeletal development, and none of these have been able to incorporate a large study sample. This study documents dental mineralization and skeletal epiphyseal fusion in a mixed-sex sample of 155 Pan troglodytes skeletons, and aims to: a) document the pattern of dental and skeletal developmental in chimpanzees; b) compare male and female developmental patterns in chimpanzees; and c) compare these chimpanzee developmental patterns to general patterns of dental and skeletal development in published human studies. The analysis of both dental and skeletal development in this sample demonstrates clearly that dental development is complete before the fusion of the many skeletal epiphyses, in contrast to the pattern observed in humans. Age estimates for individuals were calculated using previously published regression equations for dental development and used to estimate fusion ages. These appear to be accurate in that our estimates are similar to published ranges. These data improve our understanding about chimpanzee dental and skeletal development and provide a basis for further comparison between extant apes and humans, as well as those extinct species represented by fossil partial skeletons. PMID- 25532867 TI - The Park Grass Experiment and next-generation approaches: local adaptation of sweet vernal grass revisited. AB - Long-term ecological experiments provide unique opportunities to observe the effects of natural selection. The Park Grass Experiment at Rothamsted Experiment Station in Hertfordshire, UK, is the longest running ecological experiment that incorporates fertilization treatments and has been ongoing since 1856. In the 1970s, local adaptation was observed in the grass Anthoxanthum odoratum to the elevated soil aluminium levels of the fertilized plots. Gould et al. (2014) have utilized this system to reevaluate the extent of local adaptation, first documented nearly 45 years ago (Snaydon), and to use emerging molecular approaches to identify candidate genes for the adaptation. From their work, they identify several plausible candidate loci for aluminium tolerance. This work shows the power of long-term field-based trials in a scientific age concentrated on rapidly emerging molecular techniques often utilized in short, narrowly focused laboratory or controlled environment experiments. The current study clearly illustrates the benefits gained by combining these molecular approaches within long-term monitoring experiments that can be regularly revisited in a changing world and used to address questions on evolutionary scales. PMID- 25532868 TI - Masterpiece of epigenetic engineering - how Toxoplasma gondii reprogrammes host brains to change fear to sexual attraction. AB - The protozoan parasite Toxoplasma gondii is known to induce specific behavioural changes in its intermediate hosts, including humans, that are believed to increase the chance of its successful transmission to the definitive host, the cat. The most conspicuous change is the so-called fatal attraction phenomenon, the switch from the mice's and rats' natural fear of the smell of cats toward an attraction to this smell. The mechanism of this manipulation activity is unknown; however, many indices suggest that changes in the concentrations of dopamine and testosterone are involved. In this issue of Molecular Ecology, Hari Dass & Vyas (2014) present results of a study showing that, by hypomethylation of certain regulatory elements of key gene, Toxoplasma is able to reprogramme the brain's genetic machinery in such a way that cat odour activates and changes the wiring of the medial amygdala circuits responsible for sexual behaviour. This study delivers the first clear evidence of a parasite's ability to use sophisticated epigenetic engineering techniques for the manipulation of the phenotype of its infected host. PMID- 25532869 TI - One-step functionalization of zwitterionic poly[(3 (methacryloylamino)propyl)dimethyl(3-sulfopropyl)ammonium hydroxide] surfaces by metal-polyphenol coating. AB - The non-biofouling properties of a zwitterionic sulfobetaine polymer surface were easily made attractive to bioentities (e.g., proteins and cells) by metal polyphenol coating, and spatio-selective functionalization of the zwitterionic polymer surface was achieved by using a soft lithographic technique. PMID- 25532871 TI - Chemical fertilizers as a source of (238)U, (40)K, (226)Ra, (222)Rn, and trace metal pollutant of the environment in Saudi Arabia. AB - The specific activities of (238)U, (226)Ra, (40)K, and (222)Rn in chemical fertilizers were measured using gamma ray spectrometer and Cr-39 detector. In this study, 21 chemical fertilizers were collected from Eastern Saudi Arabian markets. The specific activities of (238)U ranged from 23 +/- 0.5 to 3900 +/- 195 Bq kg(-1); (226)Ra ranged from 5.60 +/- 2.80 to 392 +/- 18 Bq kg(-1); and (40)K ranged from 18.4 +/- 3 to 16,476 +/- 820 Bq kg(-1). The radon concentrations and the radon exhalation rates were found to vary from 3.20 +/- 1.20 to 1532 +/- 160 Bq m(-3) and from 1.60 to 774 mBq m(-2) h(-1), respectively. Radium equivalent activities (Raeq) were calculated for the analyzed samples to assess the radiation hazards arising due to the use of these chemical fertilizers in the agriculture soil. The Raeq for six local samples (nitrogen, phosphorous, and potassium (NPK) and single superphosphate (SSP)) and one imported sample (Sulfate of Potash (SOP)) were greater than the acceptable value 370 Bq kg(-1). The total air absorbed doses rates in air 1 m above the ground (D) were calculated for all samples. All samples, except one imported granule sample diammonium phosphate (DAP), were higher than the estimated average global terrestrial radiation of 55 nGy h(-1). The highest annual effective dose was in triple super phosphate (TSP) fertilizers (2.1 mSv y(-1)). The results show that the local TSP, imported SOP, and local NPK (sample 13) fertilizers were unacceptable for use as fertilizers in agricultural soil. Furthermore, the toxic elements and trace metals (Pb, Cd, Cr, Co, Ni, Hg, and As) were determined using atomic absorption spectrometer. The concentrations of chromium in chemical fertilizers were higher than the global values. PMID- 25532872 TI - Nuclear lamina remodelling and its implications for human disease. AB - The intermediate filament A- and B-type lamins are key architectural components of the nuclear lamina, a proteinaceous meshwork that lies underneath the inner nuclear membrane. In the past decade, many different monogenic human diseases have been linked to mutations in various components of the nuclear lamina. Mutations in LMNA (encoding lamin A and C) cause a variety of human diseases, collectively called laminopathies. These include cardiomyopathies, muscular dystrophies, lipodystrophies and progeroid syndromes. In addition, elevated levels of lamin B1, attributable to genomic duplications of the LMNB1 locus, cause adult-onset autosomal dominant leukodystrophy. The molecular mechanism(s) enabling the mutations and perturbations of the nuclear lamina to give rise to such a wide variety of diseases that affect various tissues remains unclear. The composition of the nuclear lamina changes dynamically during development, between cell types and even within the same cell during differentiation and ageing. Here, we discuss the functional and cellular aspects of lamina remodelling and their implications for the tissue-specific nature of laminopathies. PMID- 25532870 TI - Zebrafish cardiotoxicity: the effects of CYP1A inhibition and AHR2 knockdown following exposure to weak aryl hydrocarbon receptor agonists. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates many of the toxic effects of dioxin-like compounds (DLCs) and some polycyclic aromatic hydrocarbons (PAHs). Strong AHR agonists, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, such as benzo[a]pyrene and beta-naphthoflavone, have been shown to cause similar cardiotoxic effects when coupled with a cytochrome P450 1A (CYP1A) inhibitor, such as fluoranthene (FL). We sought to determine if weak AHR agonists, when combined with a CYP1A inhibitor (FL) or CYP1A morpholino gene knockdown, are capable of causing cardiac deformities similar to moderately strong AHR agonists (Wassenberg and Di Giulio Environ Health Perspect 112(17):1658-1664, 2004a; Wassenberg and Di Giulio Res 58(2-5):163-168, 2004b; Billiard et al. Toxicol Sci 92(2):526-536, 2006; Van Tiem and Di Giulio Toxicol Appl Pharmacol 254(3):280 287, 2011). The weak AHR agonists included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. Danio rerio (zebrafish) embryos were first exposed to weak AHR agonists at equimolar concentrations. The agonists were assessed for their relative potency as inducers of CYP1 enzyme activity, measured by the ethoxyresorufin-O-deethylase (EROD) assay, and cardiac deformities. Carbaryl, 2-methylindole, and 3-methylindole induced the highest CYP1A activity in zebrafish. Experiments were then conducted to determine the individual cardiotoxicity of each compound. Next, zebrafish were coexposed to each agonist (at concentrations below those determined to be cardiotoxic) and FL in combination to assess if CYP1A inhibition could induce cardiac deformities. Carbaryl, 2-methylindole, 3-methylindole, and phenanthrene significantly increased pericardial edema relative to controls when combined with FL. To further evaluate the interaction of the weak AHR agonists and CYP1A inhibition, a morpholino was used to knockdown CYP1A expression, and embryos were then exposed to each agonist individually. In embryos exposed to 2-methylindole, CYP1A knockdown caused a similar level of pericardial edema to that caused by exposure to 2-methylindole and FL. The results showed a complex pattern of cardiotoxic response to weak agonist inhibitor exposure and morpholino-knockdown. However, CYP1A knockdown in phenanthrene and 3-methylindole only moderately increased pericardial edema relative to coexposure to FL. AHR2 expression was also knocked down using a morpholino to determine its role in mediating the observed cardiac teratogenesis. Knockdown of AHR2 did not rescue the pericardial edema as previously observed with strong AHR agonists. While some of the cardiotoxicity observed may be attributed to the combination of weak AHR agonism and CYP1A inhibition, other weak AHR agonists appear to be causing cardiotoxicity through an AHR2-independent mechanism. The data show that CYP1A is protective of the cardiac toxicity associated with weak AHR agonists and that knockdown can generate pericardial edema, but these findings are also suggestive of differing mechanisms of cardiac toxicity among known AHR agonists. PMID- 25532873 TI - During development intense Sox2 expression marks not only Prox1-expressing taste bud cell but also perigemmal cell lineages. AB - Sox2 is proposed to regulate the differentiation of bipotential progenitor cells into taste bud cells. However, detailed expression of Sox2 remains unclear. In this report, Sox2 expression during taste bud development in the fungiform (FF), circumvallate (CV) and soft palate (SP) areas is examined together with Prox1. First, we immunohistochemically checked Prox1 expression in adults and found that almost all taste bud cells are Prox1-positive. During FF development, intense Sox2 expression was restricted to taste bud primordia expressing Prox1 at E12.5. However, at E14.5, Sox2 was intensely expressed outside the developing taste buds resolving to perigemmal Sox2 expression in adults. In the SP, at E14.5, taste bud primordia emerged as Prox1-expressing cell clusters. However, intense Sox2 expression was not restricted to taste bud primordia but was detected widely in the epithelium. During development, Sox2 expression outside developing taste buds was generally down-regulated but was retained in the perigemmal region similarly to that in the FF. In the CV, the initial stage of taste bud development remained unclear because of the lack of taste bud primordia comparable to that in the FF and SP. Here, we show that Prox1-expressing cells appear in the apical epithelium at E12.5, in the inner trench wall at E17.5 and in the outer trench wall at E18.5. Sox2 was again not restricted to developing taste bud cells expressing Prox1 during CV development. The expression patterns support that Sox2 does not serve as a cell fate selector between taste bud cells and surrounding keratinocytes but rather may contribute to them both. PMID- 25532874 TI - Applications for single cell trajectory analysis in inner ear development and regeneration. AB - Single cell trajectory analysis is a computational approach that orders cells along a pseudotime axis. This temporal modeling approach allows the characterization of transitional processes such as lineage development, response to insult, and tissue regeneration. The concept can also be applied to resolve spatial organization of cells within the originating tissue. Known as temporal and spatial transcriptomics, respectively, these methods belong to the most powerful analytical techniques for quantitative gene expression data currently available. Here, we discuss three different approaches: principal component analysis, the 'Monocle' algorithm, and self-organizing maps. We use a previously published qRT-PCR dataset of single neuroblast cells isolated from the developing mouse inner ear to highlight the basic features of the three methods and their individual limitations, as well as the distinct advantages that make them useful for research on the inner ear. The complex developmental morphogenesis of the inner ear and its specific challenges such as the paucity of cells as well as important open questions such as sensory hair cell regeneration render this organ a prime target for single cell trajectory analysis strategies. PMID- 25532876 TI - Greatness and quiet determination: tribute to Professor Alan Pearson. PMID- 25532875 TI - Effects of high heel wear and increased weight on the knee during walking. AB - Knee osteoarthritis (OA), a leading cause of disability, is more prevalent in women than men. Wearing high heeled shoes has been implicated as a potential contributing factor for the higher lifetime risk of osteoarthritis in women. This study tests the hypotheses that changes to knee kinematics and kinetics observed during high heeled walking increase in magnitude with increasing heel height and are accentuated by a 20% increase in weight. Fourteen healthy females were tested using marker-based gait analysis in combinations of footwear (flat athletic shoe, 3.8 cm and 8.3 cm heeled shoes) and weight (with and without 20% bodyweight vest). At preferred walking speed, knee flexion angle at heel-strike and midstance increased with increasing heel height and weight. Maximum knee extension moment during loading response decreased with added weight; maximum knee extension moment during terminal stance decreased with heel height; maximum adduction moments increased with heel height. Many of the changes observed with increasing heel height and weight were similar to those seen with aging and OA progression. This suggests that high heel use, especially in combination with additional weight, may contribute to increased OA risk in women. PMID- 25532877 TI - Reflections on Professor Pearson, AM, Founding Chair of the Cochrane Nursing Care Field. PMID- 25532878 TI - Professor Alan Pearson, Founder of the Joanna Briggs Institute. PMID- 25532879 TI - The Nursing Care Field AGM in Singapore this November. PMID- 25532880 TI - Nursing by numbers. PMID- 25532882 TI - CNCF podcast: postoperative tamoxifen in women with ductal carcinoma in situ. PMID- 25532883 TI - CNCF podcast: music interventions for preoperative anxiety. PMID- 25532884 TI - CNCF podcast: exercise interventions on health-related quality of life for patients with cancer during active treatment. PMID- 25532885 TI - Epidemiology, methodological and reporting characteristics of systematic reviews of nursing interventions published in China. AB - The importance of systematic reviews (SRs) of nursing interventions' impact on practice makes their methodological quality and reporting characteristics especially important as it directly influence their utility for clinicians, patients and policy makers.The study aims to assess the methodological quality and reporting characteristics of SRs of nursing interventions in Chinese nursing journals. Three Chinese databases were searched for SRs of nursing interventions from inception to October 2011. The assessment of multiple systematic reviews (AMSTAR) and Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statements were used to assess methodological quality and reporting characteristics. Seventy-four SRs were included. The proportion of SRs complying with AMSTAR checklist items ranged from 0% to 82.4%. No SRs reported an 'a priori' design or conflict of interest. Only four items were found to be reported in more than 50% of the SRs: a list of included and excluded studies, the scientific quality of included studies, the appropriate use of methods to combine findings, and formulating conclusions appropriately. The majority of SRs of nursing interventions in China had major methodological and reporting flaws that limited their value to guide decisions. Chinese authors and journals should adopt and keep up with the AMSTAR and PRISMA statements to improve the quality of SRs in this field. PMID- 25532886 TI - Interventions for the treatment of trachoma: an overview of Cochrane systematic reviews. AB - Trachoma is an infectious disease caused by the bacterium Chlamydia trachomatis. Infection with C. trachomatis produces characteristic changes to the inner surface of the eyelids, resulting in sequela that when left untreated, leads to vision impairment and blindness. Repeated trachoma infections can cause severe scarring of the inside of the eyelid and can cause the eyelashes to scratch the cornea (trichiasis). The objective of this overview was to synthesize the evidence from Cochrane systematic reviews regarding the treatment of trachoma, and to provide a brief and user-friendly front end for health professionals, researchers and policy makers. Face washing plus topical tetracycline eye ointment gave no additional protective benefit against active trachoma when compared with topical tetracycline eye ointment alone. Nor was any benefit conferred in the presence of severe trachoma. Primary health-care education was found to be effective in reducing the odds of active trachoma. Evidence of benefit from insecticide spray or provision of latrines away from living areas was inconclusive for active trachoma. Surgical interventions that involve full thickness incision with tarsal rotation are more effective than alternate surgical procedures. PMID- 25532887 TI - Probing short-range protein Brownian motion in the cytoplasm of living cells. AB - The translational motion of molecules in cells deviates from what is observed in dilute solutions. Theoretical models provide explanations for this effect but with predictions that drastically depend on the nanoscale organization assumed for macromolecular crowding agents. A conclusive test of the nature of the translational motion in cells is missing owing to the lack of techniques capable of probing crowding with the required temporal and spatial resolution. Here we show that fluorescence-fluctuation analysis of raster scans at variable timescales can provide this information. By using green fluorescent proteins in cells, we measure protein motion at the unprecedented timescale of 1 MUs, unveiling unobstructed Brownian motion from 25 to 100 nm, and partially suppressed diffusion above 100 nm. Furthermore, experiments on model systems attribute this effect to the presence of relatively immobile structures rather than to diffusing crowding agents. We discuss the implications of these results for intracellular processes. PMID- 25532888 TI - The exercise heart rate profile in master athletes compared to healthy controls. AB - Endurance exercise protects the heart via effects on autonomic control of heart rate (HR); however, its effects on HR indices in healthy middle-aged men are unclear. This study compared HR profiles, including resting HR, increase in HR during exercise and HR recovery after exercise, in middle-aged athletes and controls. Fifty endurance-trained athletes and 50 controls (all male; mean age, 48.7 +/- 5.8 years) performed an incremental symptom-limited exercise treadmill test. The electrocardiographic findings and HR profiles were evaluated. Maximal O2 uptake (52.6 +/- 7.0 versus 34.8 +/- 4.5 ml kg(-1) min(-1) ; P<0.001) and the metabolic equivalent of task (15.4 +/- 1.6 versus 12.2 +/- 1.5; P<0.001) were significantly higher in athletes than in controls. Resting HR was significantly lower in athletes than in controls (62.8 +/- 6.7 versus 74.0 +/- 10.4 beats per minute (bpm), respectively; P<0.001). Athletes showed a greater increase in HR during exercise than controls (110.1 +/- 11.0 versus 88.1 +/- 15.4 bpm; P<0.001); however, there was no significant between-group difference in HR recovery at 1 min after cessation of exercise (22.9 +/- 5.6 versus 21.3 +/- 6.7 bpm; P = 0.20). Additionally, athletes showed a lower incidence of premature ventricular contractions (PVCs) during exercise (0.0% versus 24.0%; P<0.001). Healthy middle aged men participating in regular endurance exercise showed more favourable exercise HR profiles and a lower incidence of PVCs during exercise than sedentary men. These results reflect the beneficial effect of endurance training on autonomic control of the heart. PMID- 25532889 TI - The impact of multiuser virtual environments on student engagement. AB - The purpose of this pilot study was to test the hypothesis that web-based synchronous instruction utilizing Multi-user Virtual World Environments (MUVEs) increases student engagement compared to traditional asynchronous learning methods. In a quasi-experimental two group posttest only study, a sample of Family Nurse Practitioner students (n = 21) received instruction using either a synchronous (n = 10) or asynchronous (n = 11) learning method. Engagement was measured using the Community of Inquiry survey. Results indicated that engagement scores were significantly higher for the synchronous learning platform (mean = 3.61, SD = 1.13) compared to the asynchronous learning platform (mean = 3.49, SD = 1.08, t(1766) = -2.21, p < 0.05). Increased student engagement with synchronous MUVE platforms have the potential to improve learning outcomes and offer nursing students a multitude of educational opportunities to practice new skills and behaviors in real life scenarios, all within the safety of a controlled environment. PMID- 25532890 TI - Genealogical correspondence of mushroom bodies across invertebrate phyla. AB - Except in species that have undergone evolved loss, paired lobed centers referred to as "mushroom bodies" occur across invertebrate phyla. Unresolved is the question of whether these centers, which support learning and memory in insects, correspond genealogically or whether their neuronal organization suggests convergent evolution. Here, anatomical and immunohistological observations demonstrate that across phyla, mushroom body-like centers share a neuroanatomical ground pattern and proteins required for memory formation. Paired lobed or dome like neuropils characterize the first brain segment (protocerebrum) of mandibulate and chelicerate arthropods and the nonganglionic brains of polychaete annelids, polyclad planarians, and nemerteans. Structural and cladistic analyses resolve an ancestral ground pattern common to all investigated taxa: chemosensory afferents supplying thousands of intrinsic neurons, the parallel processes of which establish orthogonal networks with feedback loops, modulatory inputs, and efferents. Shared ground patterns and their selective labeling with antisera against proteins required for normal mushroom body function in Drosophila are indicative of genealogical correspondence and thus an ancestral presence predating arthropod and lophotrochozoan origins. Implications of this are considered in the context of mushroom body function and early ecologies of ancestral bilaterians. PMID- 25532891 TI - Transient membrane localization of SPV-1 drives cyclical actomyosin contractions in the C. elegans spermatheca. AB - BACKGROUND: Actomyosin contractility is the major cellular force driving changes in cell and tissue shape. A principal regulator of contractility is the small GTPase RhoA. External mechanical forces have been shown to impact RhoA activity and cellular contractility. However, the mechanotransduction pathway from external forces to actomyosin contractility is poorly understood. RESULTS: Here, we show that actomyosin contractility in the C. elegans spermatheca is under control of RHO-1/RhoA, which, in turn, is regulated by the F-BAR and RhoGAP protein SPV-1. In the relaxed spermatheca, SPV-1 localizes through its F-BAR domain to the apical membrane, where it inhibits RHO-1/RhoA activity through its RhoGAP domain. Oocyte entry forces the spermatheca cells to stretch, and subsequently SPV-1 detaches from the membrane, permitting RHO-1 activity to increase. The increase in RHO-1 activity facilitates spermatheca contraction and expulsion of the newly fertilized embryo into the uterus, leading to relaxation of the spermatheca, SPV-1 membrane localization, and initiation of a new cycle. CONCLUSIONS: Our results demonstrate how transient membrane localization of a novel F-BAR domain, likely via specific binding to curved membranes, coupled to a RhoGAP domain, can provide feedback between a mechanical signal (membrane stretching) and actomyosin contractility. We anticipate this to be a widely utilized feedback mechanism used to balance actomyosin forces in the face of externally applied forces, as well as intrinsic processes involving cell deformation, from single-cell migration to tissue morphogenesis. PMID- 25532892 TI - The neuroscience of implicit moral evaluation and its relation to generosity in early childhood. AB - Despite cultural and individual variation, humans are a judgmental bunch. There is accumulating evidence for early social and moral evaluation as shown by research with infants and children documenting the notion that some behaviors are perceived as right and others are perceived as wrong. Moreover, social interactions are governed by a concern for fairness and others' well-being. However, although generosity increases between infancy and late childhood, it is less clear what mechanisms guide this change. Early predispositions toward prosociality are thought to arise in concert with the social and cultural environment, developing into adult morality, a complex incorporation of emotional, motivational, and cognitive processes. Using EEG combined with eye tracking and behavioral sharing, we investigated, for the first time, the temporal neurodynamics of implicit moral evaluation in 3- to 5-year-old children. Results show distinct early automatic attentional (EPN) and later cognitively controlled (N2, LPP) patterns of neural response while viewing characters engaging in helping and harming behaviors. Importantly, later (LPP), but not early (EPN), waveforms predicted actual generosity. These results shed light on theories of moral development by documenting the respective contribution of automatic and cognitive neural processes underpinning social evaluation and directly link these neural computations to prosocial behavior in children. PMID- 25532894 TI - Crows spontaneously exhibit analogical reasoning. AB - Analogical reasoning is vital to advanced cognition and behavioral adaptation. Many theorists deem analogical thinking to be uniquely human and to be foundational to categorization, creative problem solving, and scientific discovery. Comparative psychologists have long been interested in the species generality of analogical reasoning, but they initially found it difficult to obtain empirical support for such thinking in nonhuman animals (for pioneering efforts, see [2, 3]). Researchers have since mustered considerable evidence and argument that relational matching-to-sample (RMTS) effectively captures the essence of analogy, in which the relevant logical arguments are presented visually. In RMTS, choice of test pair BB would be correct if the sample pair were AA, whereas choice of test pair EF would be correct if the sample pair were CD. Critically, no items in the correct test pair physically match items in the sample pair, thus demanding that only relational sameness or differentness is available to support accurate choice responding. Initial evidence suggested that only humans and apes can successfully learn RMTS with pairs of sample and test items; however, monkeys have subsequently done so. Here, we report that crows too exhibit relational matching behavior. Even more importantly, crows spontaneously display relational responding without ever having been trained on RMTS; they had only been trained on identity matching-to-sample (IMTS). Such robust and uninstructed relational matching behavior represents the most convincing evidence yet of analogical reasoning in a nonprimate species, as apes alone have spontaneously exhibited RMTS behavior after only IMTS training. PMID- 25532893 TI - Redox metabolites signal polymicrobial biofilm development via the NapA oxidative stress cascade in Aspergillus. AB - BACKGROUND: Filamentous fungi and bacteria form mixed-species biofilms in nature and diverse clinical contexts. They secrete a wealth of redox-active small molecule secondary metabolites, which are traditionally viewed as toxins that inhibit growth of competing microbes. RESULTS: Here, we report that these "toxins" can act as interspecies signals, affecting filamentous fungal development via oxidative stress regulation. Specifically, in coculture biofilms, Pseudomonas aeruginosa phenazine-derived metabolites differentially modulated Aspergillus fumigatus development, shifting from weak vegetative growth to induced asexual sporulation (conidiation) along a decreasing phenazine gradient. The A. fumigatus morphological shift correlated with the production of phenazine radicals and concomitant reactive oxygen species (ROS) production generated by phenazine redox cycling. Phenazine conidiation signaling was conserved in the genetic model A. nidulans and mediated by NapA, a homolog of AP-1-like bZIP transcription factor, which is essential for the response to oxidative stress in humans, yeast, and filamentous fungi. Expression profiling showed phenazine treatment induced a NapA-dependent response of the global oxidative stress metabolome, including the thioredoxin, glutathione, and NADPH-oxidase systems. Conidiation induction in A. nidulans by another microbial redox-active secondary metabolite, gliotoxin, also required NapA. CONCLUSIONS: This work highlights that microbial redox metabolites are key signals for sporulation in filamentous fungi, which are communicated through an evolutionarily conserved eukaryotic stress response pathway. It provides a foundation for interspecies signaling in environmental and clinical biofilms involving bacteria and filamentous fungi. PMID- 25532895 TI - Detecting regular sound changes in linguistics as events of concerted evolution. AB - BACKGROUND: Concerted evolution is normally used to describe parallel changes at different sites in a genome, but it is also observed in languages where a specific phoneme changes to the same other phoneme in many words in the lexicon-a phenomenon known as regular sound change. We develop a general statistical model that can detect concerted changes in aligned sequence data and apply it to study regular sound changes in the Turkic language family. RESULTS: Linguistic evolution, unlike the genetic substitutional process, is dominated by events of concerted evolutionary change. Our model identified more than 70 historical events of regular sound change that occurred throughout the evolution of the Turkic language family, while simultaneously inferring a dated phylogenetic tree. Including regular sound changes yielded an approximately 4-fold improvement in the characterization of linguistic change over a simpler model of sporadic change, improved phylogenetic inference, and returned more reliable and plausible dates for events on the phylogenies. The historical timings of the concerted changes closely follow a Poisson process model, and the sound transition networks derived from our model mirror linguistic expectations. CONCLUSIONS: We demonstrate that a model with no prior knowledge of complex concerted or regular changes can nevertheless infer the historical timings and genealogical placements of events of concerted change from the signals left in contemporary data. Our model can be applied wherever discrete elements-such as genes, words, cultural trends, technologies, or morphological traits-can change in parallel within an organism or other evolving group. PMID- 25532896 TI - Microtubule nucleation in mitosis by a RanGTP-dependent protein complex. AB - BACKGROUND: The gamma-tubulin ring complex (gammaTuRC) is a multisubunit complex responsible for microtubule (MT) nucleation in eukaryotic cells. During mitosis, its spatial and temporal regulation promotes MT nucleation through different pathways. One of them is triggered around the chromosomes by RanGTP. Chromosomal MTs are essential for functional spindle assembly, but the mechanism by which RanGTP activates MT nucleation has not yet been resolved. RESULTS: We used a combination of Xenopus egg extracts and in vitro experiments to dissect the mechanism by which RanGTP triggers MT nucleation. In egg extracts, NEDD1-coated beads promote MT nucleation only in the presence of RanGTP. We show that RanGTP promotes a direct interaction between one of its targets, TPX2, and XRHAMM that defines a specific gammaTuRC subcomplex. Through depletion/add-back experiments using mutant forms of TPX2 and NEDD1, we show that the activation of MT nucleation by RanGTP requires both NEDD1 phosphorylation on S405 by the TPX2 activated Aurora A and the recruitment of the complex through a TPX2-dependent mechanism. CONCLUSIONS: The XRHAMM-gammaTuRC complex is the target for activation by RanGTP that promotes an interaction between TPX2 and XRHAMM. The resulting TPX2-RHAMM-gammaTuRC supracomplex fulfills the two essential requirements for the activation of MT nucleation by RanGTP: NEDD1 phosphorylation on S405 by the TPX2 activated Aurora A and the recruitment of the complex onto a TPX2-dependent scaffold. Our data identify TPX2 as the only direct RanGTP target and NEDD1 as the only Aurora A substrate essential for the activation of the RanGTP-dependent MT nucleation pathway. PMID- 25532897 TI - Tornadic storm avoidance behavior in breeding songbirds. AB - Migration is a common behavior used by animals of many taxa to occupy different habitats during different periods. Migrant birds are categorized as either facultative (i.e., those that are forced to migrate by some proximal cue, often weather) or obligate (i.e., those that migrate on a regular cycle). During migration, obligate migrants can curtail or delay flights in response to inclement weather or until favorable winds prevail, and they can temporarily reorient or reverse direction when ecological or meteorological obstacles are encountered. However, it is not known whether obligate migrants undertake facultative migrations and make large-scale movements in response to proximal cues outside of their regular migration periods. Here, we present the first documentation of obligate long-distance migrant birds undertaking a facultative migration, wherein breeding golden-winged warblers (Vermivora chrysoptera) carrying light-level geolocators performed a >1,500 km 5-day circumvention of a severe tornadic storm. The birds evacuated their breeding territories >24 hr before the arrival of the storm and atmospheric variation associated with it. The probable cue, radiating >1,000 km from tornadic storms, perceived by birds and influencing bird behavior and movements, is infrasound (i.e., sound below the range of human hearing). With the predicted increase in severity and frequency of similar storms as anthropogenic climate change progresses, understanding large scale behavioral responses of animals to such events will be an important objective of future research. PMID- 25532898 TI - A goal direction signal in the human entorhinal/subicular region. AB - Navigating to a safe place, such as a home or nest, is a fundamental behavior for all complex animals. Determining the direction to such goals is a crucial first step in navigation. Surprisingly, little is known about how or where in the brain this "goal direction signal" is represented. In mammals, "head-direction cells" are thought to support this process, but despite 30 years of research, no evidence for a goal direction representation has been reported. Here, we used fMRI to record neural activity while participants made goal direction judgments based on a previously learned virtual environment. We applied multivoxel pattern analysis to these data and found that the human entorhinal/subicular region contains a neural representation of intended goal direction. Furthermore, the neural pattern expressed for a given goal direction matched the pattern expressed when simply facing that same direction. This suggests the existence of a shared neural representation of both goal and facing direction. We argue that this reflects a mechanism based on head-direction populations that simulate future goal directions during route planning. Our data further revealed that the strength of direction information predicts performance. Finally, we found a dissociation between this geocentric information in the entorhinal/subicular region and egocentric direction information in the precuneus. PMID- 25532899 TI - If a little bit is wrong, how much is alright? Interpreting the significance of small numerators in clinical trials. PMID- 25532901 TI - [The pharmacist Dr. Gerd Wolf]. PMID- 25532900 TI - [Adaptive immune response and associated trigger factors in atopic dermatitis]. AB - Due to a broad variety of extrinsic trigger factors, patients with atopic dermatitis (AD) are characterized by complex response mechanisms of the adaptive immune system. Notably, skin colonization with Staphylococcus aureus seems to be of particular interest since not only exotoxins, but also other proteins of S. aureus can induce specific humoral and cellular immune responses which partially also correlate with the severity of AD. In a subgroup of AD patients Malassezia species induce specific IgE- and T cell-responses which has been demonstrated by atopy patch tests. Moreover, Mala s 13 is characterized by high cross-reactivity to the human corresponding protein (thioredoxin). Induction of a potential autoallergy due to molecular mimicry seems therefore to be relevant for Malassezia-sensitized AD patients. In addition, sensitization mechanisms to autoallergens aside from cross-reactivity are under current investigation. Regarding inhalant allergens, research projects are in progress with the aim to elucidate allergen-specific immune response mechanisms in more depth. For grass pollen allergens a flare-up of AD following controlled exposure has been observed while for house dust mite-allergens a polarization towards Th2 and Th2/Th17 T cell phenotypes can be observed. These and further findings might finally contribute to the development of specific and effective treatments for aeroallergen-sensitized AD patients. PMID- 25532902 TI - [Allergic diseases in the genital area]. AB - BACKGROUND: The genital area has a high exposure to various allergens that are not always obvious. Out of shame patients may not complain about symptoms in this area. Moreover, diagnosis and therapy are often not primarily conducted by a dermatologist and allergologist. Therefore, many cases of allergic diseases in the genital area remain undetected. OBJECTIVES: Which type I and type IV allergies occur in the genital area? Which allergens are currently of importance? Which are the characteristics of allergic diseases in the genital area? What are the symptoms and differential diagnoses? What to focus on when taking medical history and in clinical diagnostics? MATERIALS AND METHODS: The current medical literature regarding allergic diseases in the genital area is discussed. RESULTS: In the genital area type IV allergies such as contact dermatitis exceed type I allergies in number. Contact urticaria can occur due to seminal plasma allergy, latex allergy and a transfer of type I allergens via semen. Contact allergens are found in sex products such as condoms, but also in topical products. Methylisothiazolinone has become a new and important contact allergen for the genital area in recent years. Also, fixed drug eruption occurs preferentially in the genital area. As a delayed type IV allergy due to systemically administered drugs it has to be considered in the differential diagnosis. CONCLUSION: Presumably, there are a high number of unreported cases of allergic diseases in the genital area. Interdisciplinary collaboration between gynecologists, urologists and dermatologist should be increased. The use of methylisothiazolinone in rinse-off and leave-on products should be discussed. PMID- 25532904 TI - Osteoprotective effect of geraniin against ovariectomy-induced bone loss in rats. AB - In the present study, we investigated the antiosteoporotic effect of geraniin on osteoporosis induced by OVX in rats. The analysis of biochemical parameters showed that geraniin could significantly increase serum calcium, estradiol and calcitonin levels, and decrease serum ALP, tartrate-resistant acid phosphatase, serum crosslinked C-terminal telopeptide of type I collagen, and urinary deoxypyridinoline/creatinine ratio levels, respectively. Geraniin was also found to prevent OVX-induced bone loss in bone mineral density and bone mineral content, to elevate femur weight and bone calcium content, and to enhance the bone mechanical properties as compared with OVX group. In addition, geraniin was demonstrated to improve the histomorphological parameters of OVX-induced bone loss, including bone trabecular number, thickness, and separation. These results indicated that geraniin have a protective effect against OVX-induced rat osteoporosis. PMID- 25532905 TI - Potent and selective MAO-B inhibitory activity: amino- versus nitro-3 arylcoumarin derivatives. AB - In this study we synthesized and evaluated a new series of amino and nitro 3 arylcoumarins as hMAO-A and hMAO-B inhibitors. Compounds 2, 3, 5 and 6 presented a better activity and selectivity profile against the hMAO-B isoform (IC50 values between 2 and 6nM) than selegiline. In general, the amino derivatives (4-6) proved to be more selective against MAO-B than the nitro derivatives (1-3). Additionally, a theoretical study of some physicochemical properties, PAMPA and reversibility assays for the most potent derivative, and molecular docking simulations were carried out to further explain the pharmacological results, and to identify the hypothetical binding mode for the compounds inside the hMAO-B. PMID- 25532906 TI - Three dimensional nano-assemblies of noble metal nanoparticle-infinite coordination polymers as specific oxidase mimetics for degradation of methylene blue without adding any cosubstrate. AB - Novel three-dimensional (3D) nano-assemblies of noble metal nanoparticle (NP) infinite coordination polymers (ICPs) are conveniently fabricated through the infiltration of HAuCl4 into hollow Au@Ag@ICPs core-shell nanostructures and its replacement reaction with Au@Ag NPs. The present 3D nano-assemblies exhibit highly efficient and specific intrinsic oxidase-like activity even without adding any cosubstrate. PMID- 25532907 TI - Passive breath gating equipment for cone beam CT-guided RapidArc gastric cancer treatments. AB - BACKGROUND AND PURPOSE: To report preliminary results of passive breath gating (PBG) equipment for cone-beam CT image-guided gated RapidArc gastric cancer treatments. MATERIAL AND METHODS: Home-developed PBG equipment integrated with the real-time position management system (RPM) for passive patient breath hold was used in CT simulation, online partial breath hold (PBH) CBCT acquisition, and breath-hold gating (BHG) RapidArc delivery. The treatment was discontinuously delivered with beam on during BH and beam off for free breathing (FB). Pretreatment verification PBH CBCT was obtained with the PBG-RPM system. Additionally, the reproducibility of the gating accuracy was evaluated. RESULTS: A total of 375 fractions of breath-hold gating RapidArc treatments were successfully delivered and 233 PBH CBCTs were available for analysis. The PBH CBCT images were acquired with 2-3 breath holds and 1-2 FB breaks. The imaging time was the same for PBH CBCT and conventional FB CBCT (60s). Compared to FB CBCT, the motion artifacts seen in PBH CBCT images were remarkably reduced. The average BHG RapidArc delivery time was 103 s for one 270-degree arc and 269 s for two full arcs. CONCLUSIONS: The PBG-RPM based PBH CBCT verification and BHG RapidArc delivery was successfully implemented clinically. The BHG RapidArc treatment was accomplished using a conventional RapidArc machine with high delivery efficiency. PMID- 25532908 TI - Radiofrequency thermal ablation of osteoid osteomas of the proximal femur. Usefulness of ultrasound guidance in selected cases. AB - PURPOSE: To review symptoms and imaging findings of proximal femoral osteoid osteomas (OO); to analyse the results of a thermal ablation technique for radiofrequency of the nidus in this location; and to describe usefulness of ultrasound guidance in selected cases. MATERIAL AND METHOD: Descriptive and retrospective study consisting of 8 patients with OO in the proximal epiphysis of the femur, which were treated by thermal ablation of the nidus with radiofrequency waves from 1998 to 2004. RESULTS: The mean pain period until the performance of the thermal ablation was 11.5 months (range 5-18 months). There were no complications, and all patients stated that the pain was gone by the day following the procedure, with some discomfort during the first week, except for one where it lasted more than one month due to technique difficulties. At present, with a mean follow up of 6 years and 2 months (range 6-190 months), all patients remain asymptomatic and live a rigorous normal life. DISCUSSION: Thermal ablation with CT-guided radiofrequency waves is a safe, effective and efficient procedure. CONCLUSION: Normal appearance of a proximal femoral OO does not differ significantly from other location osteomas and its diagnosis is easier with previous knowledge. Thermal ablation of the nidus with radiofrequency waves, that may be performed using ultrasound guidance, appears to be the elective treatment of choice due to its efficiency and minimum morbidity. PMID- 25532909 TI - Correlative electron and X-ray microscopy: probing chemistry and bonding with high spatial resolution. AB - Two powerful and complementary techniques for chemical characterisation of nanoscale systems are electron energy-loss spectroscopy in the scanning transmission electron microscope, and X-ray absorption spectroscopy in the scanning transmission X-ray microscope. A correlative approach to spectro microscopy may not only bridge the gaps in spatial and spectral resolution which exist between the two instruments, but also offer unique opportunities for nanoscale characterisation. This review will discuss the similarities of the two spectroscopy techniques and the state of the art for each microscope. Case studies have been selected to illustrate the benefits and limitations of correlative electron and X-ray microscopy techniques. In situ techniques and radiation damage are also discussed. PMID- 25532910 TI - RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells. AB - BACKGROUND: ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo. METHODS: Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot. RESULTS: ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b. CONCLUSION: ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer. PMID- 25532912 TI - Action observation and motor imagery in performance of complex movements: evidence from EEG and kinematics analysis. AB - Motor imagery (MI) and action observation (AO) are considered effective cognitive tools for motor learning, but little work directly compared their cortical activation correlate in relation with subsequent performance. We compared AO and MI in promoting early learning of a complex four-limb, hand-foot coordination task, using electroencephalographic (EEG) and kinematic analysis. Thirty healthy subjects were randomly assigned into three groups to perform a training period in which AO watched a video of the task, MI had to imagine it, and Control (C) was involved in a distracting computation task. Subjects were then asked to actually perform the motor task with kinematic measurement of error time with respect to the correct motor performance. EEG was recorded during baseline, training and task execution, with task-related power (TRPow) calculation for sensorimotor (alpha and beta) rhythms reactive with respect to rest. During training, the AO group had a stronger alpha desynchronization than the MI and C over frontocentral and bilateral parietal areas. However, during task execution, AO group had greater beta synchronization over bilateral parietal regions than MI and C groups. This beta synchrony furthermore demonstrated the strongest association with kinematic errors, which was also significantly lower in AO than in MI. These data suggest that sensorimotor activation elicited by action observation enhanced motor learning according to motor performance, corresponding to a more efficient activation of cortical resources during task execution. Action observation may be more effective than motor imagery in promoting early learning of a new complex coordination task. PMID- 25532911 TI - G protein-coupled estrogen receptor protects from atherosclerosis. AB - Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity. PMID- 25532913 TI - Altered perirhinal cortex activity patterns during taste neophobia and their habituation in aged rats. AB - Perirhinal cortex (PRh) pathology and chemosensory identification dysfunction are early signs of Alzheimer's disease. We have assessed the impact of normal aging on PRh activity during flavor recognition memory using c-Fos immunoreactivity as a marker for neuronal activity. Adult (5-month-old) and aged (24-month-old) Wistar male rats were exposed to a vinegar solution on a daily basis for a period of six days. Behavioral assessment indicated similar performance in both age groups but suggested slower attenuation of neophobia in aged rats. Regarding c Fos immunoreactivity, an opposite pattern of PRh activity was found in adult and aged groups drinking the flavor solution during the first (Novel), second (Familiar I) or sixth (Familiar II) exposure as the flavor became familiar. While adult rats exhibited a higher number of PRh c-Fos-positive neurons during the presentation of the novel flavor than during the second and sixth presentation, in aged rats the number of PRh c-Fos-positive neurons was higher during the presentation of the familiar flavor in the last session than in the first and second. The results suggest that the role of the PRh changes during aging and can help to dissociate PRh dysfuntions induced by neurodegenerative diseases and normal aging. PMID- 25532914 TI - Novel object exploration in the C58/J mouse model of autistic-like behavior. AB - Mouse models of autistic like behaviors are a valuable tool to use when studying the causes, symptoms, and potential treatments for autism. The inbred C58/J strain is a strain of interest for this model and has previously been shown to possess face validity for some of the core traits of autism, including low social behavior and elevated motor stereotypies. Higher order repetitive behaviors have not been extensively studied in this strain, or in mice in general. In this study, we looked for evidence of higher-order repetitive behaviors in the C58/J strain using a novel object assay. This assay utilized a mouse's natural exploratory behavior among unfamiliar objects to identify potential sequencing patterns in motor activity. The motor stereotypies displayed by the C58/J strain during testing were consistent with past studies. The C58/J strain also displayed a high preference for a single object in the round arena assays and the females demonstrating elevated sequencing patterns in the round arena. Although the C58/J strain did not show pervasive evidence of higher-order repetitive behaviors across all measures, there was evidence of higher order repetitive behaviors in certain situations. This study further demonstrates the potential of the C58/J mouse strains as a model for lower-order and potentially, higher-order repetitive behaviors. This study also demonstrates that the shape of the novel object arena can change the behavior displayed by the test animals. Further studies utilizing the C58/J strain and further validation of the novel object assay are warranted. PMID- 25532915 TI - Effects of clinically relevant doses of methyphenidate on spatial memory, behavioral sensitization and open field habituation: a time related study. AB - The psychostimulant methylphenidate (MPD) is a first-line drug for the treatment of attention deficit hyperactivity disorder (ADHD). Despite acceptable therapeutic efficacy, there is limited data regarding the long-term consequences of MPD exposure over extended periods. The present study concerns effects of clinically relevant doses of MPD, administered orally to rats for an extended period, on spatial memory, behavioral sensitization and habituation to an open field. Water maze test was used to monitor memory acquisition (2 h after training), retention (day next to training), extinction (1 week after training) and reconsolidation (weekly for 4 weeks). Administration of MPD at doses of 0.25 1.0 mg/kg improved memory acquisition, retention, reconsolidation and impaired memory extinction. Treatment with 0.25 and 0.5 mg/kg MPD for 6 weeks produced a sustained increase in motor activity but higher dose (1.0 mg/kg) elicited behavioral sensitization. High as well as low doses MPD impaired open field habituation. We conclude that clinically relevant doses of MPD enhance memory even if used for extended period. It is suggested that higher (1.0 mg/kg) clinically relevant doses of MPD, if used for extended period, may exacerbate hyperactivity and impulsivity associated with the disease. PMID- 25532917 TI - Complications after arthroscopic labral repair for shoulder instability. AB - Arthroscopic labral repair is a widely performed and safe technique for anterior or posterior shoulder instability; however, complications have been reported in the literature. Postoperative injection of local anesthetic via an intra articular pain pump should be avoided to prevent chondrolysis of the glenohumeral joint. Postoperative stiffness of the shoulder can be treated with physiotherapy, and a surgical treatment is indicated in shoulders that failed a conservative treatment. Although nerve injury is relatively rare, the axillary nerve should be given careful attention. Recurrent shoulder instability is the most common complication after labral repair, but most reported rates of recurrent instability after arthroscopic Bankart repair are less than 10 %. Augmentations, such as rotator interval closure and Hill-Sachs remplissage, have a potential to reduce the rate of recurrence. A better understanding of these possible complications, including their pathology and treatment, is essential for optimization of outcomes after arthroscopic labral repair. PMID- 25532920 TI - [Clinical practice guidelines as opportunity-duty for research]. PMID- 25532916 TI - Management of complications after rotator cuff surgery. AB - Rotator cuff repair (RCR) is a common procedure performed by orthopedic surgeons via arthroscopic, open, or mini-open techniques. While this surgery is considered to be of low morbidity, several potential complications can arise either intraoperatively or during the postoperative time period. Some of these complications are related to the surgical approach (arthroscopic or open), while others are patient dependent. Many of these complications can be managed through nonoperative means; however, early recognition and timely treatment is essential in limiting the long-term sequela and improving patient outcome. There are several different ways to classify complications after RCR repair: timing, severity, preventability, whether or not the pathology is intra- or extra articular, and the type of treatment necessary. It is essential that the surgeon is cognizant of the etiology contributing to the failed RCR surgery in order to provide timely and proper management. PMID- 25532921 TI - [Critical issues and limits in the production and implementation of clinical practice guidelines]. AB - The introduction of clinical practice guidelines, initially welcomed as the solution for improving the quality of care, left space to a rising debate on the problems and pitfalls of guidelines production and implementation. In this contribute some of the main criticisms (the quality of the guidelines, their real implementation in practice, the misconceptions that they should be rigidly implemented, that should limit the variability of practices...) are addressed and discussed. PMID- 25532922 TI - [Readability and comprehension of guidelines for hand hygiene: a comparison between WHO (2009) and CDC (2002) guidelines]. AB - INTRODUCTION: Updating clinical practice guidelines (CPGs) is a crucial process for maintaining the validity of recommendations. However, the updating process should be explicit and changes made highlighted in the updated text. AIM: To confront and compare two CPGs on hand hygiene (World Health Organization, WHO, 2009 and Centres for Disease Control, CDC 2002), to identify discrepancies and changes made. RESULTS: Although mostly comparable, CDC and WHO guidelines use a different terminology on hand hygiene which could be onfounding: in the former handwashing includes the use of plain soap in the latter also the use of an antimicrobial soap. The lack of a glossary may render tricky the interpretation. Some problems in retrieving the evidence base of a recommendation are highlighted. CONCLUSIONS: Great attention should be paid before implementing an updated guideline. The need of essential and easy to consult guidelines, where in the updated version the news and modifications are highlighted are stressed. PMID- 25532923 TI - [The implementation of recommendations in daily practice: the experience of the nurses of the Oncology institute of Southern Switzerland]. AB - INTRODUCTION: In spite of the wide spread and availability of the clinical practice guidelines, several problems limit and influence their implementation. Several studies explored how a protocol based care may influence nurses' decision making processes, while only few studies explored how it is used in everyday practice. AIM: This paper explores how the nurses of the Oncology Institute of Southern Switzerland implement the care protocols and problems encountered. METHODS: Information on the frequency of use of protocols in the previous month, the need and reasons for modifications were collected with a semistructured questionnaire. Nurses were asked to briefly describe the situations that required a change of the protocol. The nurses'perceptions on the use of protocols in clinical practice were further explored with a focus group. RESULTS: Of the 47 questionnaires distributed 38 were returned and 18 cases briefly described. In general, the protocols were widely used but at the same time, frequently adapted mainly by expert nurses (although 19/39 nursed declared that protocols were never modified). Reasons for modifications were mainly related to the clinical situation of the patient, to his/her values and preferences. CONCLUSIONS: Instruments that standardize patients' care are frequently modified to account for patients preferences and characteristics. The nurses acknowledged the need of flexible instruments (and not hard rules) to guide their professional practice. PMID- 25532924 TI - [Critical issues in clinical practice guidelines for geriatric care]. AB - Behavioral and psychological symptoms of dementia(BPSD) are one of the most disturbing issues in the management of patients, both for caregivers and health care personnel. Aim of this paper is to critically appraise the available guidelines on the non pharmacological management of BPSD. Some effective interventions such as person centred care, communication skills e dementia care mapping are not mentioned while interventions of dubious efficacy (aromatherapy, per therapy, light therapy or music therapy) are proposed. The variability in the expression of behavioral disorders and the different causes suggest an accurate tailoring of the interventions, based on the assessment of the patient, the organization and the environment. Further studies are necessary to improve the implementation of the non drug strategies for the management of BPSDs. PMID- 25532926 TI - [Clinical practice guidelines: juridical and medico legal issues in health care malpractice liability]. AB - Clinical Practice Guidelines are clinical tools addressed to medical and health professionals and are normally employed to improve quality and safety of diagnostic and therapeutical procedures but may sometimes limit the autonomy of medical and other health care professionals. The adherence to Clinical Practice Guidelines should not be an exclusive step to evaluate the liability and respect of standards of care in case of medico-legal investigations being each clinical case very specific. Medical liability and respect of standards of care should be evaluated with the support of Clinical Practice Guidelines and the extensive examination of all specific features, professional background and experience requested to treat each single patient. PMID- 25532925 TI - [Protocol based care and organizations: strengths and limits]. AB - A protocol based care may impact on the organization under several aspects. In this contribution, starting from real life experiences, the impact on the implementation of guidelines and recommendations on the use of resources and costs is explored, underlying strengths and weaknesses. A judicious and tailored implementation of these instruments is warranted. However, the transformation of some guidelines in laws and decrees may limit their local adaptation. PMID- 25532927 TI - [Clinical practice guidelines: what they are and how are developed]. AB - Guidelines are designed to support the decision-making processes in patient care. The content of a guideline is based on a systematic review of clinical evidence - the main source for evidence-based care. The guidelines may be consensus or evidence based; for each statement the level of evidence and strength of the recommendation are defined. The grading of the recommendations may vary across Agencies and Scientific societies. PMID- 25532928 TI - [The GRADE system]. AB - The Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE Working Group) has developed a system for grading the quality of evidence. Over 20 organizations including the World Health Organization (WHO) have adopted it. The quality of a body of evidence involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias, and the system considers the assessment of the quality of a body of evidence for each individual outcome. The GRADE approach specifies four levels of quality. Randomized trials, usually the highest grade of evidence, can be downgraded depending on the presence of the methodological problems. A brief overview of the grade system is presented. PMID- 25532929 TI - [Where and how to retreive clinical practice guidelines]. AB - Indications on how to retrieve clinical practice guidelines are offered, presenting the main agencies that produce guidelines and the trip database. A google search with the key word nursing guidelines, after a selection of agencies with multiprofessional groups, with an explicit process of bibliographic search and a grading of recommendations produced the selection of 4 agencies. PMID- 25532930 TI - [The local adaptation of clinical practice guidelines]. AB - The ADAPTE process is a systematic approach to adapting guidelines produced in one setting for use in a different cultural and organizational context. It ensures that the guideline addresses specific health questions relevant to the context, accounting for the needs, priorities, legislation, policies, and resources in the targeted setting. The ADAPTE process was developed to meet the needs of different user groups, including guideline developers, health care providers, and policy makers at the local, national, and international level. The process is flexible; the transparent and explicit reporting enhances the quality and validity of the adapted guideline. The ADAPTE process is briefly described. PMID- 25532931 TI - [Proposal for a nursing research on and from clinical practice guidelines]. AB - A research agenda for nurses, to render more visible and active their contribution to the development and implementation of clinical practice guidelines is proposed. The areas for development of multicenter research project are the epidemiology of the [non] applicability of the guidelines; a critical appraisal of existing guidelines to identify the missing recommendations relevant for nursing care; the problems orphan of recommendations. Nurses should suggest how uncertainty should be made explicit in the recommendations and promote research on nurses' decision making in protocol based care. PMID- 25532932 TI - The Varian story. AB - This Perspective offers a personal view of the story of Varian NMR, a courageous initiative that began in the 1950s but came to an abrupt end some 60 years later. Without doubt, Varian leaves behind a priceless legacy, particularly in the field of structural chemistry. The highlights are set out in four main sections, named after the four seasons, but not necessarily in strict chronology. How did the accepted business practices influence the evolution, growth, and eventual demise of this exciting venture? How well did management handle an unconventional group of young scientific entrepreneurs? What does it all mean for the future of magnetic resonance? The subject can be viewed on two different levels, the Varian story itself, and the larger picture - the Silicon Valley phenomenon as a whole, with Varian considered as an interesting microcosm. PMID- 25532933 TI - Ferritin-stimulated lipid peroxidation, lysosomal leak, and macroautophagy promote lysosomal "metastability" in primary hepatocytes determining in vitro cell survival. AB - Several pathologies are associated with elevated levels of serum ferritin, for which growth inhibitory properties have been reported; however, the underlying mechanisms are still poorly defined. Previously we have described cytotoxic properties of isoferritins released from primary hepatocytes in vitro, which induce apoptosis in an iron and oxidative stress-dependent mode. Here we show that this ferritin species stimulates endosome clustering and giant endosome formation in primary hepatocytes accompanied by enhanced lysosomal membrane permeability (LMP). In parallel, protein modification by lipid peroxidation derived 4-hydroxynonenal (HNE) is strongly promoted by ferritin, the HNE-modified proteins (HNE-P) showing remarkable aggregation. Emphasizing the prooxidant context, GSH is rapidly depleted and the GSH/GSSG ratio is substantially declining in ferritin-treated cells. Furthermore, ferritin triggers a transient upregulation of macroautophagy which is abolished by iron chelation and apparently supports HNE-P clearance. Macroautophagy inhibition by 3-methyladenine strongly amplifies ferritin cytotoxicity in a time- and concentration-dependent mode, suggesting an important role of macroautophagy on cellular responses to ferritin endocytosis. Moreover, pointing at an involvement of lysosomal proteolysis, ferritin cytotoxicity and lysosome fragility are aggravated by the protease inhibitor leupeptin. In contrast, EGF which suppresses ferritin-induced cell death attenuates ferritin-mediated LMP. In conclusion, we propose that HNE-P accumulation, lysosome dysfunction, and macroautophagy stimulated by ferritin endocytosis provoke lysosomal "metastability" in primary hepatocytes which permits cell survival as long as in- and extrinsic determinants (e.g., antioxidant availability, damage repair, EGF signaling) keep the degree of lysosomal destabilization below cell death-inducing thresholds. PMID- 25532935 TI - A low cost instrumentation system to analyze different types of milk adulteration. AB - In this paper, the design of a complete instrumentation system to detect different types of milk adulteration has been reported. A simple to use indicator type readout device is reported which can be used by milk community people. A low cost microcontroller based automatic sensing system is also reported to detect 'synthetic milk', which has been reconstructed after adulterating the milk with 'liquid-whey'. PMID- 25532936 TI - Frequency domain stability analysis of nonlinear active disturbance rejection control system. AB - This paper applies three methods (i.e., root locus analysis, describing function method and extended circle criterion) to approach the frequency domain stability analysis of the fast tool servo system using nonlinear active disturbance rejection control (ADRC) algorithm. Root locus qualitative analysis shows that limit cycle is generated because the gain of the nonlinear function used in ADRC varies with its input. The parameters in the nonlinear function are adjustable to suppress limit cycle. In the process of root locus analysis, the nonlinear function is transformed based on the concept of equivalent gain. Then, frequency domain description of the nonlinear function via describing function is presented and limit cycle quantitative analysis including estimating prediction error is presented, which virtually and theoretically demonstrates that the describing function method cannot guarantee enough precision in this case. Furthermore, absolute stability analysis based on extended circle criterion is investigated as a complement. PMID- 25532937 TI - Trajectory-Shaping Guidance with final speed and load factor constraints. AB - This paper describes the design of a guidance law used for guiding a hypersonic gliding vehicle against a ground target from a near-vertical orientation with a specified final speed and a near-zero final load factor. The guidance law consists of two terms: one is Trajectory-Shaping Guidance (TSG) used for steering the vehicle to the target from the specified orientation; the other is Final Speed-Control Scheme (FSCS) used for controlling the vehicle to perform lateral maneuver to adjust the final speed. Further, the generalized closed form solutions of TSG are obtained from a more general linearized engagement model, where the speed of the vehicle can be an arbitrary positive function of time. By analyzing these solutions, the stability domain of the guidance coefficients is obtained such that the final load factor is zero. This domain is not affected by the change rate of the speed. Thus, according to this analysis, the proposed guidance law can achieve a near zero final load factor by properly selecting the guidance coefficients in the stability domain. PMID- 25532938 TI - Investigation of diethylthiourea and ethyl isothiocyanate as potent skin allergens in chloroprene rubber. AB - BACKGROUND: Exposure to chloroprene rubber has resulted in numerous cases of allergic contact dermatitis, attributed to organic thiourea compounds used as vulcanization accelerators. However, thiourea compounds are not considered to be strong haptens. OBJECTIVES: To analyse common commercial chloroprene materials for their contents of diethylthiourea (DETU), dibutylthiourea (DBTU), diphenylthiourea (DPTU), and their degradation products, isothiocyanates; and to investigate the sensitization potencies of possible degradation products of the mentioned thiourea compounds. METHODS: Liquid chromatography/mass spectrometry (MS) was used for quantification of organic thiourea compounds in chloroprene products, such as medical, sports and diving gear; isothiocyanates were measured by solid-phase microextraction/gas chromatography/MS. Sensitization potencies were determined with the murine local lymph node assay (LLNA). RESULTS: DETU was identified at concentrations of 2.7-9.4 ug/cm(2) in all samples, whereas neither DBTU nor DPTU was detected. At 37 degrees C, degradation of DETU in the materials to ethyl isothiocyanate (EITC) was detected. EITC and ethyl isocyanate showed extreme and strong sensitization potencies, respectively, in the LLNA. CONCLUSIONS: DETU can act as a prehapten, being degraded to EITC when subjected to body temperature upon skin contact. EITC could thus be the culprit behind allergic contact dermatitis caused by chloroprene rubber. PMID- 25532939 TI - Pediatric low-grade fibromyxoid sarcoma mimicking ossifying fibromyxoid tumor: adding to the diagnostic spectrum of soft tissue tumors with a bony shell. AB - We describe a case of superficial low-grade fibromyxoid sarcoma (LGFMS) in a 12 year-old boy, confirmed by the detection of FUS-CREB3L2 fusion transcripts by reverse-transcription polymerase chain reaction and FUS rearrangement with fluorescence in situ hybridization, which had morphological features similar to ossifying fibromyxoid tumor (OFMT), including an almost complete rim of mature, metaplastic bone. LGFMS and OFMT can appear morphologically similar, with bland ovoid cells within a fibrous to myxoid matrix. Both can occur superficially; and whereas MUC4 immunoreactivity is characteristic of LGFMS, this can also be seen in some OFMTs. As the morphological spectrum of LGFMS is wide, we highlight the potential for diagnostic confusion with OFMT, which is clinically pertinent as most OFMTs behave in a benign manner whereas LGFMS is a malignant neoplasm with a propensity for local recurrence and a significant metastatic rate. PMID- 25532940 TI - Disseminated infection with Lacazia loboi and immunopathology of the lesional spectrum. AB - The pathogenesis of lacaziosis continues to be obscure, and works have investigated the blood systemic immune response or the dermal immune response in restricted lesions in different body regions. Some authors describe that the inflammatory infiltrate in lacaziosis lesions showed a predominance of macrophages followed by CD45RO(+), CD4(+), and CD8(+) T cells; CD57(+) natural killer cells; S-100(+) cells; and CD20(+) B lymphocytes. A 54-year-old man and living in the State of Para, Amazon region, Brazil, was seen with a lesion on the left lower limb, which had started as a small nodular area 18 years ago. The lesion showed progressive growth and disseminated to other parts of the body. Our findings showed that dermal immune response differs depending on the type of lesions and clinical presentation, with presence of CD1a(+), FXIIIa(+), CD45(+), CD4(+), CD8(+), and S-100(+) cells and cytokine profile with expression of interleukin 1 beta, tumor necrosis factor alpha, transforming growth factor beta, IL-10, and interferon gamma. PMID- 25532941 TI - Dysregulated microRNA-224/apelin axis associated with aggressive progression and poor prognosis in patients with prostate cancer. AB - Our previous study revealed that microRNA (miR)-224 down-regulation could promote tumor progression of prostate cancer (PCa) and might be associated with poor biochemical recurrence-free survival of patients with this malignancy. However, the underlying mechanisms of miR-224 have not been fully elucidated. In the current study, apelin (APLN) was identified as a target gene of miR-224. Forced expression of miR-224 inhibited PCa cell invasion and migration by suppressing the expression of APLN. In addition, the down-regulation of miR-224 was negatively correlated with the up-regulation of APLN mRNA in PCa tissues. Moreover, miR-224 down-regulation was significantly associated with advanced clinical stage (P = .027) and metastasis (P = .001), whereas APLN up-regulation more frequently occurred in PCa tissues with advanced pathologic stage (P = .003), metastasis (P < .001), and prostate-specific antigen failure (P = .001). Furthermore, patients with PCa in the miR-224-low/APLN-high group more frequently had shorter biochemical recurrence-free survival than those in groups with other expression patterns of the 2 molecules. Taken together, our data strongly confirmed for the first time that the dysregulated miR-224/APLN axis may be associated with tumorigenesis and aggressive progression of PCa. More importantly, miR-224 down-regulation and APLN up-regulation may synergistically predict biochemical recurrence-free survival in patients with PCa. PMID- 25532942 TI - Activating mutations in the RAS/mitogen-activated protein kinase signaling pathway in sporadic trichoblastoma and syringocystadenoma papilliferum. AB - Trichoblastoma (TB) and syringocystadenoma papilliferum (SCAP) are both rare adnexal skin lesions occurring either sporadically or as secondary neoplasms in sebaceous nevi. TB and SCAP associated with sebaceous nevi have been shown to carry the same HRAS mutation as the underlying nevus. However, the genetic background of sporadic TB and SCAP has remained unknown. Therefore, we screened 18 sporadic TBs and 23 sporadic syringocystadenoma papillifera from 41 patients for the presence of activating mutations in RAS genes and other oncogenes. Using a RAS SNaPshot assay, HRAS mutations were detected in 2 (11%) of 18 sporadic TB and 6 (26%) of 23 sporadic syringocystadenoma papillifera. A KRAS mutation was identified in 1 sporadic SCAP. High-throughput oncogene mutation profiling furthermore identified BRAF V600E mutations in sporadic syringocystadenoma papillifera, which could be validated in 12 (52%) of 23 lesions using a BRAF SNaPshot assay. BRAF and RAS mutations were mutually exclusive in sporadic syringocystadenoma papillifera. No BRAF mutation could be detected in 3 syringocystadenoma papillifera secondarily arisen from a sebaceous nevus as well as in sporadic TB. In 14 lesions carrying an oncogenic mutation, nonlesional control tissue from the epidermal margin revealed a wild-type sequence, thus proving the somatic character of the mutation. Our results indicate that activation of the RAS-mitogen-activated protein kinase pathway by BRAF and RAS mutations contributes significantly to the tumorigenesis of sporadic SCAP and, less frequently, of sporadic TB. PMID- 25532934 TI - Tumor mechanics and metabolic dysfunction. AB - Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation. PMID- 25532943 TI - Catechol-O-methyltransferase inhibits colorectal cancer cell proliferation and invasion. AB - BACKGROUND AND AIMS: Catechol-O-methyltransferase (COMT) has been reported as an important molecule in various types of cancers. The biological function of COMT in colorectal cancer (CRC) has not yet been fully investigated. METHODS: We constructed a transient transfection of a CRC cell lines to up- and downregulate COMT expression level and tested the proliferative, invasion ability in vitro. We also constructed a stable transduced CRC cell line and conducted tumor-forming capacity experiment in mouse xenograft model in vivo. RESULTS: In vitro experiment showed that COMT inhibited the cell proliferation by regulating p-Akt, PTEN and inhibited G1 to S phase transition by regulating p53, p27, and cyclinD1. COMT inhibited invasion by regulating E-cadherin. In vivo experiment showed decreased tumor growth in COMT overexpressing cell line. CONCLUSIONS: COMT has tumor-suppressive functions for CRC cell lines in vitro and in vivo experiments. PMID- 25532944 TI - Two sites of action for PLD2 inhibitors: The enzyme catalytic center and an allosteric, phosphoinositide biding pocket. AB - Phospholipase D (PLD) has been implicated in many physiological functions, such as chemotaxis and phagocytosis, as well as pathological functions, such as cancer cell invasion and metastasis. New inhibitors have been described that hamper the role of PLD in those pathologies but their site of action is not known. We have characterized the biochemical and biological behavior of the PLD1/2 dual inhibitor 5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), and the specific PLD2 inhibitor, N-[2-[1-(3-Fluorophenyl)-4-oxo-1,3,-8-triazaspiro[4.5]dec-8-yl]ethyl] 2-naphthalenecarboxamide (NFOT), and found that both FIPI and NFOT are mixed kinetics inhibitors. Mutagenesis studies indicate that FIPI binds at S757 of PLD2, which is within the HKD2 catalytic site of the enzyme, whereas NFOT binds to PLD2 at two different sites, one being at S757/S648 and another to an allosteric site that is a natural site occupied by PIP2 (R210/R212). This latter site, along with F244/L245/L246, forms a hydrophobic pocket in the PH domain. The mechanism of action of FIPI is a direct effect on the catalytic site (and as such inhibits both PLD1 and PLD2 isoforms), whereas PLD2 affects both the catalytic site (orthosteric) and blocks PIP2 binding to PLD2 (allosteric), which negates the natural enhancing role of PIP2. Moreover, NFOT prevents cell invasion of cancer cells, which does not occur in cells overexpressing PLD2 F244A/L245A/L246A, or PLD2-R210A/R212A, or PLD2-S757/S648 mutants. This study provides new specific knowledge of enzyme regulation and mechanisms of activation and inhibition of PLD2 that are necessary to understand its role in cell signaling and to develop new inhibitors for cancer cell invasion and metastasis. PMID- 25532945 TI - The burden of non-radiographic axial spondyloarthritis. AB - OBJECTIVES: To identify patients earlier, new classification criteria have been introduced for axial spondyloarthritis (axSpA). Patients who satisfy the clinical or imaging criteria for axSpA in the absence of definite sacroiliac joint changes on pelvic x-rays are classified as having non-radiographic axSpA. Although the burden associated with radiographic axSpA (i.e., ankylosing spondylitis) has been extensively studied, the impact of non-radiographic disease is not well understood. The purpose of this review is to provide an overview of the burden of illness in non-radiographic axSpA, including epidemiology and effects on patients' functioning and health-related quality of life (HR-QoL). METHODS: A PubMed search was performed using relevant key words (e.g., "spondyloarthritis," "ankylosing spondylitis," "epidemiology," and "quality of life") to examine literature published from 2003 to 2013. RESULTS: Studies conducted to date suggest that radiographic progression is detected in approximately 10% of patients with non-radiographic axSpA over 2 years. Differences between patients with non-radiographic and radiographic axSpA were found in age, symptom duration, and gender distribution. Although less inflammation (i.e., lower C-reactive protein levels and less spinal inflammation on MRI) and less impairment in spinal mobility are observed in non-radiographic than in radiographic axSpA, the 2 conditions pose a similar burden in terms of disease activity, physical function, HR-QoL impairment. CONCLUSIONS: Patients with non-radiographic axSpA are more frequently female. Although patients with non-radiographic axSpA have shorter disease duration and lack radiological changes, they demonstrate a substantial burden of illness, with self-reported disease activity and functional impairments comparable to those found in patients with radiographic disease. PMID- 25532946 TI - Safety of disease-modifying antirheumatic drugs and biologic agents for rheumatoid arthritis patients in real-life conditions. AB - OBJECTIVE: The aim of this study was to describe the incidence rate (IR) of adverse drug reactions (ADRs) in daily clinical practice, related to disease modifying antirheumatic drugs (DMARDs) and biologic agents (BA) in rheumatoid arthritis (RA) patients, and to analyze factors causing discontinuation due to ADRs. METHODS: This was a prospective observational study (October 2010 to October 2011). RA patients who were attended in our hospital taking DMARDs or BA during the study period were included. ADRs were injuries related to these drugs and registered with a software system in routine visits. ADRs could be mild (lowering dosage), moderate (drug discontinuation), or severe (hospital admission). The IR of ADR per 100 patient-years was estimated using survival techniques. Cox regression models (HR; 95% confidence interval) were used to explore factors associated with discontinuation due to ADRs. RESULTS: In total, 1202 patients were analyzed, with 158 ADRs (IR = 15.2). Of all ADRs, 80.4% required drug discontinuation (IR = 12.2). Age, less disease and therapy duration, taking corticoids, and combined therapy versus monotherapy (HR = 3; 95% CI: 2.0-4.4) were the factors independently associated to discontinuation due to ADRs. We did not find statistical differences between the different monotherapy regimens. Regarding combinations, Methotrexate + BA had the lowest risk of discontinuation compared to the rest (HR = 0.24; 95% CI: 0.09-0.6). CONCLUSIONS: We have estimated the incidence of ADRs related to DMARDs/BA in real-life conditions. We confirm the role of combined therapy in the development of discontinuations due to ADRs, except for BA + MTX, which did not show an increase of toxicity compared to monotherapy. This combination seems to be safer than others. PMID- 25532948 TI - Genotyping of wild-type cytochrome P450 2A6 and whole-gene deletion using human blood samples and a multiplex real-time polymerase chain reaction method with dual-labeled probes. AB - BACKGROUND: Genetic polymorphisms of human cytochrome P450 2A6 (CYP2A6) are one of the determinants of smoking behavior and/or tobacco-related lung cancer risk in male Japanese smokers. To help identify those at high risk, we developed a multiplex real-time polymerase chain reaction (PCR)-based genotyping method with dual-labeled probes to detect wild-type and whole-gene deletion of CYP2A6 directly from blood samples without DNA isolation. METHODS: We validated the new real-time PCR method that uses dual-labeled probes by utilizing 116 genomic DNA samples that had been genotyped previously and 33 blood samples. RESULTS: The new method could discriminate CYP2A6 from highly homologous CYP2A7 and CYP2A13 genes and could also determine CYP2A6*1 (wild type) and CYP2A6*4 (whole-gene deletion) alleles in perfect accordance with previous analysis data. Amplification curve profiles were obtained by multiplex real-time PCR assay with CYP2A6*1 and CYP2A6*4 primer sets and dual-labeled probes using one-drop blood samples previously genotyped for CYP2A6*1/*1, CYP2A6*1/*4, and CYP2A6*4/*4. CONCLUSIONS: A real-time multiplex PCR assay for genotyping wild-type CYP2A6 and whole-gene deletion was developed with dual-labeled probes. The new method achieved 100% agreement with data from the conventional PCR method for 116 genomic DNA samples and samples from 33 volunteers, thereby establishing its validity. PMID- 25532949 TI - Contact precautions and hand hygiene in veterinary clinics. AB - Hand hygiene, contact precautions, and other basic infection control measures are crucial in veterinary clinics, because these facilities can be community mixing pots of animals and people with a wide range of health and disease-carrier states. Veterinary staff must be knowledgeable and well trained regarding when and how to apply situation-appropriate contact precautions and to properly perform hand hygiene. The limited information on the use of contact precautions and hand hygiene practices among veterinary staff suggests that compliance is low. Improving the infection control culture in clinics and in veterinary medicine is critical to achieving better compliance with these practices. PMID- 25532947 TI - Plaque array method and proteomics-based identification of biomarkers from Alzheimer's disease serum. AB - BACKGROUND: Progressive accumulation of amyloid plaques in the regions of brain, carotid and cerebral arteries is the leading cause of Alzheimer's disease (AD) and related dementia in affected patients. The early identification of individuals with AD remains a challenging task relying on symptomatic events and thus the development of a biomarker-based approach will significantly aid in the diagnosis of AD. METHODS: Here we describe a flow cytometer-based serum biomarker identification method using plaque particles, and applying mass spectrometry based proteomic analysis of the isolated plaque particles for the identification of serum proteins present in the plaque particles. RESULTS: We identified 195 serum proteins that participate in the process of plaque particle formation. Among the 195 proteins identified, 68.2% of them overlapped in abeta-42, cholesterol, tau-275 and alpha-synuclein plaque particles. Significantly, 22.5% of the proteins identified as bound to abeta-42 plaque particles generated in AD serum were unique when compared with cholesterol, alpha-synuclein and tau plaque particles. In age-matched control experiments, 15% of them showed in vitro insoluble abeta-42 particle formation and 59% of the identified plaque particle constituents from AD serum were also present in the insoluble plaque particles derived from control. CONCLUSIONS: We have developed an in vitro method for plaque particle detection and identified serum protein markers that are associated with AD-related plaque particle formation. With further clinical validation, this assay may provide a novel, non-invasive means for the early detection of AD. PMID- 25532950 TI - Cold and controlled molecular beams: production and applications. AB - The field of cold molecules has become an important source of new insight in fundamental chemistry and molecular physics. High-resolution spectroscopy benefits from translationally and internally cold molecules by increased interaction times and reduced spectral congestion. Completely new effects in scattering dynamics become accessible with cold and controlled molecules. Many of these experiments use molecular beams as a starting point for the generation of molecular samples. This review gives an overview of methods to produce beams of cold molecules, starting from supersonic expansions or effusive sources, and provides examples of applications in spectroscopy and molecular dynamics studies. PMID- 25532952 TI - The role of gut hormones in appetite regulation (review). AB - Eating process is an aggregate of complex and different forms of behavior. Its regulation is based on energy homeostasis and appetite control which includes two components: the homeostatic and the hedonistic control. Important signals in appetite regulation are gut-derived hormones. They are produced by enteroendocrine cells in response to nutrient and energy intake, and achieve their effects by influencing brain structures involved in food intake regulation. The key brain structure involved in this process is the hypothalamus. Gut hormones reach the hypothalamus from the circulation or by the vagal nerve via the nucleus of the solitary tract. Among gut peptides, ghrelin is the only orexigenic hormone, leading to an increase in food intake and body weight. All others, such as cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine or pancreatic polypeptide, are anorexigenic, leading to decrease in food intake. Also, gut-derived endocannabinoids exert orexigenic effect on appetite. Keeping in mind the growing problem of obesity, the crucial issue when considering gut derived peptides is to understand their mechanisms of acting because of potential role in clinical therapy, and discovering long lasting gut peptides or their analogues, with no or minimal side effects. PMID- 25532953 TI - Streptozotocin-nicotinamide-induced rat model of type 2 diabetes (review). AB - Diabetes is one of the five leading causes of death in the world, with type 2 diabetes occurring more frequently than type 1. Management of diabetes without side effects is still a challenge and therefore new strategies need to be examined. Because of difficulties in human research, animal models of diabetes are useful research tools for this purpose and rodent models of type 2 diabetes are the first choice. The aim of this study is an overview on one of the most frequently used models of type 2 diabetes in rat, induced by streptozotocin and nicotinamide, considering its advantages and disadvantages for diabetes research in humans. PMID- 25532954 TI - Orally given gastroprotective capsaicin does not modify aspirin-induced platelet aggregation in healthy male volunteers (human phase I examination). AB - Capsaicin is a well-known component of red pepper. Recent studies have shown that capsaicin could prevent gastric ulcer provoked by various NSAID-s like acetylsalicylic acid (ASA). Primary objective of this human clinical phase I trial was to investigate whether two different doses of capsaicin co-administered with ASA could alter the inhibitory effect of ASA on platelet aggregation. 15 healthy male subjects were involved in the study and treated orally with 400 MUg capsaicin, 800 MUg capsaicin, 500 mg ASA, 400 MUg capsaicin+500 mg ASA and 800 MUg capsaicin+500 mg ASA. Blood was drawn before and 1, 2, 6 and 24 hours after the drug administration. After that epinephrine induced platelet aggregation was measured by optical aggregometry. Between treatments, volunteers had a 6-day wash out period. Our results showed that capsaicin had no effect on platelet aggregation, while as expected, ASA monotherapy resulted in a significant and clinically effective platelet aggregation inhibition (p <= 0.001). The combined ASA-capsaicin therapies reached equivalent effectiveness in platelet aggregation inhibition as ASA monotherapy. Our investigation proved that capsaicin did not influence the inhibitory effect of ASA on platelet aggregation, thus the capsaicin-ASA treatment would combine the antiplatelet effect of ASA with the possible gastroprotection of capsaicin. PMID- 25532955 TI - Protective effect of ghrelin in a rat model of celiac disease. AB - Ghrelin is a gut hormone shown to have protective effects throughout the gastrointestinal tract. This study aims to investigate its protective effect in celiac disease induced in rats. Twenty-four rat pups were divided into 4 groups as follows: control, disease (1.5 mg/g intragastric gliadin), co-treatment (50 ng/g intraperitoneal ghrelin after gliadin gavage) and pretreatment (50 ng/g intraperitoneal ghrelin before gliadin gavage). Animals' weight gain was charted. Histological features assessed include villus length, villus width, crypt depth and number of intraepithelial lymphocytes. Tissue interferon-gamma was quantified by ELISA. ANOVA was used to compare results statistically. Results showed that villi were shortened in the diseased group, but were as long as the control in pretreatment and co-treatment groups. Crypt depth had increased in disease group, but turned to normal in co-treatment group. Number of intraepithelial lymphocytes was significantly higher in disease group than the control, while no difference was observed between co-treatment and control groups. Disease and control animals weighed equally at the end of the experiment, but ghrelin-treated animals had significantly gained more weight than these two. Interferon-gamma measurement revealed no significant difference among groups. We concluded administration of ghrelin led to histological improvement of celiac disease which was more obvious if administered after exposure to gliadin. PMID- 25532951 TI - Mechanisms of virus assembly. AB - Viruses are nanoscale entities containing a nucleic acid genome encased in a protein shell called a capsid and in some cases are surrounded by a lipid bilayer membrane. This review summarizes the physics that govern the processes by which capsids assemble within their host cells and in vitro. We describe the thermodynamics and kinetics for the assembly of protein subunits into icosahedral capsid shells and how these are modified in cases in which the capsid assembles around a nucleic acid or on a lipid bilayer. We present experimental and theoretical techniques used to characterize capsid assembly, and we highlight aspects of virus assembly that are likely to receive significant attention in the near future. PMID- 25532956 TI - The analysis of transduction mechanisms associated with an acute action of homocysteine on isolated rat femoral artery. AB - The present study was undertaken in order to examine transduction mechanism involved in the single application of 100 MUM homocysteine (Hcy) on isolated rat femoral artery (RFA) rings equilibrated on the basal tone; to establish if a single application of 100 MUM Hcy alters contractile effect of phenylephrine (Phe), or oppositely the relaxant effect of acetylcholine (ACh) or bradykinin (BK) after 60-min-long incubation of 100 MUM Hcy; and finally to identify morphological changes on the vascular wall after a 24-h-long incubation of 100 MUM Hcy. Hcy produced contractile response of intact RFA, which was increased after endothelial denudation, while decreased by urapidil (an alpha1 receptor blocker), nifedipine (a voltage-gated L-type Ca++ channel blocker) or indomethacin (a cyclooxygenase inhibitor). The initial RFA contraction evoked by Phe was further increased by the single addition of Hcy, which was not the case when ouabain (an inhibitor of Na+/K+-ATPase) was preincubated. After 60-min-long incubation of Hcy relaxant actions of ACh and BK were unaltered, equieffective and equipotent. A 24-h-long incubation of RFA rings with Hcy produced an impairment of vascular endothelium, expressed as a minor or more pronounced interruption of endothelial cells. PMID- 25532957 TI - Dose dependent effects of serotonergic agents on anxiety. AB - The role of serotonin in depression and anxiety is still highly controversial. In this experiment the effect of two substances upon anxiety was studied in rats. METHODS: Forty adult (45-55 weeks old) male Wistar rats were used to study the following behavioral parameters on elevated plus maze test: open arm and closed arm entries; open arm, closed arm and central square activity duration, open arm preference and total distance traveled. RESULTS: A single injected dose of the antidepressant fluoxetine had no significant effect on animals' activity in the open-arm test, neither in a small dosage (5 mg/kgbw) nor in a higher one (10 mg/kgbw), whereas a single high dose of buspirone significantly impeded the open arm activity of the rats. None of the substances influenced the general locomotor activity significantly, but the higher doses of buspirone mainly blocked the closed-arm entries and they even decreased the total distance traveled. CONCLUSION: Acute fluoxetine and buspirone administration influenced the rats' behavior in the elevated plus-maze test in a dose dependent manner. Anxiolytic effects occur after small doses but anxiogenic-like effects were noticed in rodents when higher doses were used. PMID- 25532958 TI - The combined effect of cycling cadence and crank resistance on hamstrings and quadriceps muscle activities during cycling. AB - The effect of cycling cadence and crank resistance on the activity of hamstrings and quadriceps muscles was investigated during cycling movements of able-bodied subjects on a stationary bike with slow and fast speed against different resistance conditions. The ratio of average EMG amplitudes obtained in the two speed conditions (fast/slow) was computed in each resistance condition. This ratio is higher for both muscles if cycling against higher resistance. This shows that in higher resistance condition muscle activities are not only increased but the change of muscle activities with respect to cadence change varied according to resistance condition. Average EMG amplitudes increased at a higher rate with respect to change of cadence when cycling was performed in higher resistance condition. Besides, when cycling faster, hamstrings activity increased generally at a higher rate than that of quadriceps. The correlation between cadence and EMG amplitudes were also investigated. Considering hamstrings, this correlation was low and decreased as resistance increased. The correlation between the time required to drive one cycle and EMG amplitude is negative but in absolute value it is larger than the correlation of cadence and EMG amplitude. PMID- 25532959 TI - The slope of the VO2 slow component is associated with exercise intolerance during severe-intensity exercise. AB - The aim of this study was to analyze the relationship between the slope of the VO2 slow component (VO2sc) and exercise tolerance (tlim) during constant-work rate (CWR) exercise performed within the severe intensity domain. Fifteen active subjects (VO2max = 41.2 +/- 5.1 ml.kg-1.min-1) performed the following tests: 1) an incremental test to determine the VO2max and the work rate associated with the VO2max (IVO2max) and; 2) two CWR transitions at 95% of the IVO2max to determine the slope of the VO2 slow component and the tlim. Three tlims were obtained: tlim1 = CWR1; tlim2 = CWR2; and tlim1+2 = (CWR1 + CWR2) / 2. There was no significant difference between the VO2max (3271.7 +/- 410.7 mL.min-1) and VO2peak obtained during the CWR tests (CWR1 = 3356.3 +/- 448.8 mL.min-1, CWR2 = 3362.2 +/ 393.4 mL.min-1, p > 0.05). Significant correlations (p < 0.05) were found among the VO2sc kinetics and tlim1 (r = -0.53), tlim2 (r = -0.49) and tlim1+2 (r = 0.55). Thus, exercise tolerance during CWR performed within the severe intensity domain is partially explained by the slope of the VO2 slow component. PMID- 25532961 TI - Levels of feline infectious peritonitis virus in blood, effusions, and various tissues and the role of lymphopenia in disease outcome following experimental infection. AB - Twenty specific pathogen free cats were experimentally infected with a virulent cat-passaged type I field strain of FIPV. Eighteen cats succumbed within 2-4 weeks to effusive abdominal FIP, one survived for 6 weeks, and one seroconverted without outward signs of disease. A profound drop in the absolute count of blood lymphocytes occurred around 2 weeks post-infection (p.i.) in cats with rapid disease, while the decrease was delayed in the one cat that survived for 6 weeks. The absolute lymphocyte count of the surviving cat remained within normal range. Serum antibodies as measured by indirect immunofluorescence appeared after 2 weeks p.i. and correlated with the onset of disease signs. Viral genomic RNA was either not detectable by reverse transcription quantitative real-time PCR (RT qPCR) or detectable only at very low levels in terminal tissues not involved directly in the infection, including hepatic and renal parenchyma, cardiac muscle, lung or popliteal lymph node. High tissue virus loads were measured in severely affected tissues such as the omentum, mesenteric lymph nodes and spleen. High levels of viral genomic RNA were also detected in whole ascitic fluid, with the cellular fraction containing 10-1000 times more viral RNA than the supernatant. Replicating virus was strongly associated with macrophages by immunohistochemistry. Virus was usually detected at relatively low levels in feces and there was no evidence of enterocyte infection. Viral genomic RNA was not detected at the level of test sensitivity in whole blood, plasma, or the white cell fraction in terminal samples from the 19 cats that succumbed or in the single survivor. These studies reconfirmed the effect of lymphopenia on disease outcome. FIPV genomic RNA was also found to be highly macrophage associated within diseased tissues and effusions as determined by RT-qPCR and immunohistochemistry but was not present in blood. PMID- 25532962 TI - Genomic investigation of etiologic heterogeneity: methodologic challenges. AB - BACKGROUND: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. METHODS: We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. RESULTS: The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. CONCLUSIONS: Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub types, paving the way for a more refined understanding of cancer etiology. PMID- 25532963 TI - Correlation of dosimetric and clinical factors with the development of esophagitis and radiation pneumonitis in patients with limited-stage small-cell lung carcinoma. AB - BACKGROUND: The purpose of the study was to correlate clinical and dosimetric factors with the development of esophagitis and radiation pneumonitis in patients with limited-stage small-cell lung carcinoma (LS SCLC). PATIENTS AND METHODS: One hundred eighteen patients who received curative intent chemoradiotherapy for LS SCLC and had electronically archived radiation treatment plans were included. The medical charts were reviewed for clinical data. The treatment plan was reviewed for critical structure delineation and dose delivered. Treatment planning data were analyzed using Computational Environment for Radiotherapy Research (V3.3). Dosimetric parameters were correlated with the risk of toxicity using Spearman rank correlation. RESULTS: Radiotherapy dose was 40 Gy in 15 fractions (fx) (n = 80) and 45 Gy in 30 fractions twice per day (n = 38). The 6-month cumulative incidence of Grade >= 2 radiation pneumonitis was 6.5% and 7.9% for the 40 Gy/15 fx and 45 Gy/30 fx groups, respectively (P = .40). The 3-month cumulative incidence of Grade 3 esophagitis was 7.5% and 13.2% for the 40 Gy/15 fx and 45 Gy/30 fx groups, respectively (P = .31). Grade >= 3 pneumonitis was correlated with volume of lung receiving 20 Gy (V20) and mean lung dose. Grade >= 3 esophagitis was correlated with mean esophagus dose and minimum dose to the hottest 45% of the esophagus (D45). CONCLUSION: Mean lung dose and V20 were significant predictors of radiation pneumonitis in LS SCLC. Mean esophageal dose and D45 were significant predictors of esophagitis. These 2 treatment schedules have similar toxicity profiles. PMID- 25532964 TI - Cytotoxic compounds from the marine-derived fungus Aspergillus sp. recovered from the sediments of the Brazilian coast. AB - A fungal strain of Aspergillus sp. (BRF 030) was isolated from the sediments collected in the northeast coast of Brazil, and the cytotoxic activity of its secondary metabolites was investigated against HCT-116 tumour cell line. The cytotoxicity-guided fractionation of the extracts from this fungus cultured in potato-dextrose-sea water for 14 days at room temperature yielded the hetero spirocyclic gamma-lactams pseurotin A (1), pseurotin D (2) and pseurotin FD-838 (7), the alkaloids fumitremorgin C (5), 12,13-dihydroxy fumitremorgin C (6), methylsulochrin (4) and bis(dethio)bis(methylthio)gliotoxin (3). Among them, fumitremorgin C (5) and 12,13-dihydroxy fumitremorgin C (6) were the most active. The cytotoxic activities of the extracts from Aspergillus sp. grown from 7 to 28 days were investigated, and they were associated with the kinetic production of the compounds. The most active extracts (14 and 21 days) were those with the highest relative concentrations of the compounds fumitremorgin C (5) and 12,13 dihydroxy fumitremorgin C (6). PMID- 25532966 TI - Wide-bladed mandibular channel retractor efficiently secures surgical manoeuvres during ramus osteotomy. PMID- 25532965 TI - Absence of genetic structure in Baylisascaris schroederi populations, a giant panda parasite, determined by mitochondrial sequencing. AB - BACKGROUND: Infection with the parasitic nematode, Baylisascaris schroederi (Ascaridida: Nematoda), is one of the most important causes of death in giant pandas, and was responsible for half of deaths between 2001 and 2005. Mitochondrial (mt) DNA sequences of parasites can unveil their genetic diversity and depict their likely dynamic evolution and therefore may provide insights into parasite survival and responses to host changes, as well as parasite control. METHODS: Based on previous studies, the present study further annotated the genetic variability and structure of B. schroederi populations by combining two different mtDNA markers, ATPase subunit 6 (atp6) and cytochrome c oxidase subunit I (cox1). Both sequences were completely amplified and genetically analyzed among 57 B. schroederi isolates, which were individually collected from ten geographical regions located in three important giant panda habitats in China (Minshan, Qionglai and Qinling mountain ranges). RESULTS: For the DNA dataset, we identified 20 haplotypes of atp6, 24 haplotypes of cox1, and 39 haplotypes of atp6 + cox1. Further haplotype network and phylogenetic analyses demonstrated that B. schroederi populations were predominantly driven by three common haplotypes, atp6 A1, cox1 C10, and atp6 + cox1 H11. However, due to low rates of gene differentiation between the three populations, both the atp6 and cox1 genes appeared not to be significantly associated with geographical divisions. In addition, high gene flow was detected among the B. schroederi populations, consistent with previous studies, suggesting that this parasite may be essentially homogenous across endemic areas. Finally, neutrality tests and mismatch analysis indicated that B. schroederi had undergone earlier demographic expansion. CONCLUSIONS: These results confirmed that B. schroederi populations do not follow a pattern of isolation by distance, further revealing the possible existence of physical connections before geographic separation. This study should also contribute to an improved understanding of the population genetics and evolutionary biology of B. schroederi and assist in the control of baylisascariasis in giant pandas. PMID- 25532967 TI - Effect of preoperative continuous positive airway pressure duration on outcomes after maxillofacial surgery for obstructive sleep apnoea. AB - Continuous positive airway pressure (CPAP) remains the first-line treatment for obstructive sleep apnoea (OSA), and is known to result in various physiological changes. The objective of this study was to evaluate the association between duration of preoperative CPAP therapy and outcome after maxillomandibular advancement (MMA) for OSA. We retrospectively analysed consecutive patients treated at our institution, and divided them into 2 groups based on duration of treatment with CPAP: short-term (up to 12 months) and long-term use (12 months or more). We controlled for baseline demographic and clinical characteristics. We compared postoperative scores for the apnoea/hypopnoea index (AHI) and the Epworth sleepiness scale (ESS), and lowest recorded oxygen saturation between groups. In 43 patients data were available on the preoperative use of CPAP, and in 37 of them preoperative and postoperative polysomnographic data were also available for inclusion. Most had bimaxillary advancement with genioplasty. Differences between the groups in mean reduction in the AHI and lowest oxygen saturation were not significant, and operative success rates were comparable. After operation, the reduction in ESS scores was significantly greater in the long-term group than in the short-term group (mean (SD) 8(3) compared with 2 (2), respectively, p<0.001). Our results suggest that the duration of use of CPAP preoperatively does not significantly influence objective outcome measures. The reduction in AHI scores after MMA was equivalent in both groups. The long-term group seemed to fare better than the short-term group on subjective outcome measures. PMID- 25532968 TI - Unusual complication of repair of fractured mandibular angle. AB - Internal fixation with miniplates remains an accepted and reliable approach to the management of mandibular fractures, and erosion through the oral mucosa is a well-recognised long-term complication. We report a case of erosion of a miniplate through the skin 5 years after internal fixation of a fracture of the left mandibular angle. PMID- 25532969 TI - Relationship between cognitive impairment and echocardiographic parameters: a review. AB - With >24 million people affected worldwide, dementia is one of the main public health challenges modern medicine has to face. The path leading to dementia is often long, with a wide spectrum of clinical presentations, and preceded by a long preclinical phase. Previous studies have demonstrated that clinical strokes and covert vascular lesions of the brain contribute to the risk for developing dementia. Although it is not yet known whether preventing such lesions reduces the risk for dementia, it is likely that starting preventive measures early in the course of the disease may be beneficial. Echocardiography is a widely available, relatively inexpensive, noninvasive imaging modality whereby morphologically or hemodynamically derived parameters may be integrated easily into a risk assessment model for dementia. The aim of this review is to analyze the information that has accumulated over the past two decades on the prognostic value of echocardiographic factors in cognitive impairment. The associations between cognitive impairment and echocardiographic parameters, including left ventricular systolic and diastolic indices, left atrial morphologic parameters, cardiac output, left ventricular mass, and aortic root diameter, have previously been reported. In the light of these studies, it appears that echocardiography may help further improve currently used risk assessment models by allowing detection of subclinical cardiac abnormalities associated with future cognitive impairment. However, many limitations, including methodologic heterogeneity and the observational designs of these studies, restrict the scope of these results. Further prospective studies are required before integrating echocardiography into a preventive strategy. PMID- 25532970 TI - Atrial fibrillation may affect the success of mitral balloon valvuloplasty. PMID- 25532971 TI - Typology of patients with fibromyalgia: cluster analysis of duloxetine study patients. AB - BACKGROUND: To identify distinct groups of patients with fibromyalgia (FM) with respect to multiple outcome measures. METHODS: Data from 631 duloxetine-treated women in 4 randomized, placebo-controlled trials were included in a cluster analysis based on outcomes after up to 12 weeks of treatment. Corresponding classification rules were constructed using a classification tree method. Probabilities for transitioning from baseline to Week 12 category were estimated for placebo and duloxetine patients (Ntotal = 1188) using logistic regression. RESULTS: Five clusters were identified, from "worst" (high pain levels and severe mental/physical impairment) to "best" (low pain levels and nearly normal mental/physical function). For patients with moderate overall severity, mental and physical symptoms were less correlated, resulting in 2 distinct clusters based on these 2 symptom domains. Three key variables with threshold values were identified for classification of patients: Brief Pain Inventory (BPI) pain interference overall scores of <3.29 and <7.14, respectively, a Fibromyalgia Impact Questionnaire (FIQ) interference with work score of <2, and an FIQ depression score of >=5. Patient characteristics and frequencies per baseline category were similar between treatments; >80% of patients were in the 3 worst categories. Duloxetine patients were significantly more likely to improve after 12 weeks than placebo patients. A sustained effect was seen with continued duloxetine treatment. CONCLUSIONS: FM patients are heterogeneous and can be classified into distinct subgroups by simple descriptive rules derived from only 3 variables, which may guide individual patient management. Duloxetine showed higher improvement rates than placebo and had a sustained effect beyond 12 weeks. PMID- 25532973 TI - Protocol for metagenomic virus detection in clinical specimens. AB - Sixty percent of emerging viruses have a zoonotic origin, making transmission from animals a major threat to public health. Prompt identification and analysis of these pathogens are indispensable to taking action toward prevention and protection of the affected population. We quantifiably compared classical and modern approaches of virus purification and enrichment in theory and experiments. Eventually, we established an unbiased protocol for detection of known and novel emerging viruses from organ tissues (tissue-based universal virus detection for viral metagenomics [TUViD-VM]). The final TUViD-VM protocol was extensively validated by using real-time PCR and next-generation sequencing. We could increase the amount of detectable virus nucleic acids and improved the detection of viruses <75,000-fold compared with other tested approaches. This TUViD-VM protocol can be used in metagenomic and virome studies to increase the likelihood of detecting viruses from any biological source. PMID- 25532974 TI - Trust a nurse's intuition. PMID- 25532972 TI - Age-associated alterations in corpus callosum white matter integrity in bipolar disorder assessed using probabilistic tractography. AB - OBJECTIVES: Atypical age-associated changes in white matter integrity may play a role in the neurobiology of bipolar disorder, but no studies have examined the major white matter tracts using nonlinear statistical modeling across a wide age range in this disorder. The goal of this study was to identify possible deviations in the typical pattern of age-associated changes in white matter integrity in patients with bipolar disorder across the age range of 9-62 years. METHODS: Diffusion tensor imaging was performed in 57 (20 male and 37 female) patients with a diagnosis of bipolar disorder and 57 (20 male and 37 female) age- and sex-matched healthy volunteers. Mean diffusivity and fractional anisotropy were computed for the genu and splenium of the corpus callosum, two projection tracts, and five association tracts using probabilistic tractography. RESULTS: Overall, patients had lower fractional anisotropy and higher mean diffusivity compared to healthy volunteers across all tracts (while controlling for the effects of age and age(2) ). In addition, there were greater age-associated increases in mean diffusivity in patients compared to healthy volunteers within the genu and splenium of the corpus callosum beginning in the second and third decades of life. CONCLUSIONS: Our findings provide evidence for alterations in the typical pattern of white matter development in patients with bipolar disorder compared to healthy volunteers. Changes in white matter development within the corpus callosum may lead to altered inter-hemispheric communication that is considered integral to the neurobiology of the disorder. PMID- 25532978 TI - Ebola among us. PMID- 25532976 TI - Managing scorpion envenomation in children. PMID- 25532979 TI - CAUTI awakenings. PMID- 25532980 TI - Transitioning from staff nurse to clinical faculty, part 3. PMID- 25532984 TI - Drug therapy 101. PMID- 25532985 TI - Why should you attend a conference this year? PMID- 25532986 TI - Patient education: what worries the patient most? PMID- 25532987 TI - Safety alert: protecting yourself and others from violence. PMID- 25532988 TI - Screening nurses for tuberculosis. PMID- 25532989 TI - Looking into hyperthermic intraperitoneal chemotherapy. PMID- 25532990 TI - Are nurses prepared to care for Black American patients in pain? PMID- 25532992 TI - Author's reply to "comments on HPV and lung cancer risk: a meta-analysis" [J. Clin. Virol. (in press)]. PMID- 25532993 TI - The association between vasomotor symptoms and metabolic health in peri- and postmenopausal women: a systematic review. AB - The objective of this study was to systematically review studies describing the association between vasomotor symptoms and metabolic syndrome, type 2 diabetes and insulin resistance in peri- and postmenopausal women. A systematic search of studies was performed in EMBASE, MEDLINE, Web-of-science, Scopus, PubMed publisher, Cochrane Library, Google scholar. To identify studies eligible for inclusion, the following criteria were defined: randomised trials, cohort, case control, and cross-sectional studies investigating the association between vasomotor symptoms and metabolic syndrome, type 2 diabetes and insulin resistance in peri- and postmenopausal women with natural menopause. Methodological quality was assessed using a modified NewCastle Ottawa Assessment Scale. After screening 2660 titles and abstracts, four studies, of which two cohort studies met the criteria of high methodological quality, were included in the review. Because of the heterogeneity and the limited number of studies, there is no sufficient evidence on the potential role of vasomotor symptoms in metabolic health. However, both high-quality cohort studies, with large study populations and adjustment for multiple confounding variables showed positive associations between vasomotor symptoms and insulin resistance and type 2 diabetes mellitus. These findings suggest that there is an association between vasomotor symptoms and metabolic health outcomes. To confirm this and to strengthen the evidence, more high quality longitudinal research on this topic is needed. PMID- 25532995 TI - Topographic hot spot before descemet stripping automated endothelial keratoplasty is associated with postoperative hyperopic shift. AB - PURPOSE: The aim of this study was to investigate topographic "hot spots" on the anterior corneal surface before Descemet stripping automated endothelial keratoplasty (DSAEK) and their effects on postoperative visual acuity and hyperopic shift. METHODS: Twenty-seven eyes of 27 patients with bullous keratopathy, who underwent DSAEK were studied. We defined a hot spot as a focal area with relatively high refractive power on the anterior corneal surface in eyes with bullous keratopathy. Refractive spherical equivalent, keratometric value, and corneal topography were retrospectively evaluated using anterior segment optical coherence tomography (AS-OCT). RESULTS: Hot spots were identified in 11 eyes (42.3%) before DSAEK and disappeared in 9 eyes of these eyes (81.8%) at 6 months after DSAEK. AS-OCT revealed focal epithelial thickening in the same areas as the hot spots. There was no significant difference in the postoperative visual acuity between eyes with and without hot spots (P > 0.05). The keratometric value of the anterior corneal surface significantly flattened from 45.7 +/- 2.7 diopters (D) before DSAEK to 44.2 +/- 2.7 D 1 month after DSAEK in eyes with hot spots (P = 0.01), whereas in eyes without hot spots, there were no significant differences in the keratometric values before and after DSAEK. At 6 months, the refractive change was +1.1 +/- 1.3 D in eyes with hot spots and -0.2 +/- 0.6 D in eyes without hot spots (P = 0.034). CONCLUSIONS: In eyes with focal epithelial thickening, topographic hot spots on the anterior corneal surface were observed using AS-OCT. The hot spots disappeared after DSAEK and had no influence on the postoperative visual acuity. PMID- 25532996 TI - A prospective study of the clinical characteristics of patients with herpes simplex and varicella zoster keratitis, presenting to a New Zealand emergency eye clinic. AB - PURPOSE: To identify the demographic and clinical associations of patients presenting with herpetic keratitis in New Zealand compared with presentations of presumed microbial keratitis. METHODS: A prospective, 6-month, observational case series of presumed microbial keratitis (including marginal keratitis), specifically identifying all cases of herpes simplex and varicella zoster keratitis attending an emergency eye clinic was conducted. Main outcome measures included demographics, presenting signs and symptoms, and medical, ocular, and drug history. RESULTS: A total of 140 cases of herpetic keratitis were identified, which comprised 125 cases of herpes simplex virus (89%) and 15 cases of varicella zoster virus (11%). Herpes simplex keratitis was associated with a history of keratitis (n = 58, phi = 0.24, P < 0.0001), Maori ethnicity (n = 27, phi = 0.26, P < 0.0001), respiratory disease (n = 18, phi = 0.14, P = 0.009), corticosteroid use (n = 23, phi = 0.22, P < 0.0001), and cardiovascular disease (CVD) (n = 10, phi = 0.11, P = 0.03). Inverse association was observed between herpes simplex keratitis and ocular surface disease (n = 8, phi = -0.16, P < 0.002) and Asian ethnicity (n = 4, phi = -0.11, P = 0.04). Varicella zoster keratitis was associated with CVD (n = 3, phi = 0.15, P = 0.03). CONCLUSIONS: Patients with asthma, CVD, on long-term corticosteroid inhalers or creams, or of Maori ethnicity need particular assessment to investigate herpes simplex as a possible cause of keratitis. Clinicians prescribing inhaled corticosteroids or topical corticosteroid creams should be aware of possible association with herpes simplex keratitis. PMID- 25532997 TI - Optical coherence tomography findings in recurrent corneal erosion syndrome. AB - PURPOSE: To report the findings of optical coherence tomography (OCT) in the corneas of patients with recurrent corneal erosion syndrome (RCES). METHODS: Ten normal subjects and 25 patients with RCES were recruited for the study. Ten patients with RCES suffered from an acute episode of pain and 15 patients complained of typical chronic symptoms of RCES. All eyes were scanned with the anterior segment 5 line raster acquisition protocol of the Cirrus HD-OCT platform (Zeiss). The etiology of RCES was investigated and treatment was provided following a standard clinical protocol. Scans were obtained at different stages of the pathology and each patient was followed-up after treatment. RESULTS: Tear film, epithelium, basement membrane, Bowman layer, stroma, and Descemet endothelium complex were identified by OCT in all normal corneas. The same structures were identified in nonaffected areas of RCES corneas. The findings on OCT from patients suffering from acute RCES were as follows: anterior stromal hyper-reflectivity (100%), epithelial edema (100%), and irregular breaks in the epithelium (90%). Undetected epithelial basement membrane (100%), intraepithelial basement membrane (60%), intraepithelial inclusions (60%), and anterior stromal hyper-reflectivity (40%) were seen in patients with chronic RCES. These findings correlated well with the clinical symptoms and with previously described histological reports of RCES. CONCLUSIONS: Corneal OCT can be useful to study and manage RCES. Specific OCT findings may clarify etiology, confirm a suspected diagnosis, and give advice on the decision to treat patients. PMID- 25532994 TI - A comparative analysis of predictors for 1-year recurrent acute coronary syndromes events, by age group: the Greek observational study of ACS (GREECS). AB - OBJECTIVES: To evaluate the potential differences in risk factors' profile for in hospital mortality and up to 1-year prognosis, between younger and older patients with first acute coronary syndromes (ACS). METHODS: From October 2003 to September 2004, 1323 patients with first ACS event from 6 urban and rural Greek hospitals were enrolled into the study, classified as those < 65 years and >= 65 years old. Multiple logistic regression analysis was used to evaluate the association between socio-demographic, lifestyle, clinical characteristics and the disease prognosis for one year after discharge. RESULTS: The men-to-women ratio was 8.5-to-1.5 for those < 65 years, whereas, it was 6.6-to-3.4 for those above 65 years (p < 0.001). In-hospital deaths and recurrent event within 30-days was higher among older patients (p < 0.001). After the period of 6-months, the event-rate was higher among the younger patients (p < 0.001). Current smoking was associated with increased risk of 1-month recurrent events, in patients < 65 years (p < 0.05). Myocardial infarction and history of diabetes were associated with increased risk in older patients (p < 0.1). CONCLUSION: Age-specific identification of the risk factors for recurrent events may have important clinical and public health implications and lead to the development of more effective risk reduction strategies. PMID- 25532998 TI - Effects of androgen on ultrastructure of corneal epithelium and function of the tear film in BALB/c mice. AB - PURPOSE: The aim of this study was to investigate the effects of androgen on the ultrastructure of corneal epithelium and function of the tear film in a mouse model. METHODS: Healthy adult male BALB/c mice were randomly apportioned to normal control, sham-operated, or orchiectomy groups. In the orchiectomy group, 4 subgroups with treatment [blank group, dihydrotestosterone (DHT) eye drop group, DHT injection group, and dimethyl sulfoxide (DMSO) eye drop group] were further established at 3 weeks after orchiectomy. Tear production, tear break-up time, and corneal fluorescein staining were evaluated in all groups at multiple time points. Serum androgen concentrations were measured by competitive radioimmunoassay, and ultrastructure of corneal epithelial cells was examined by transmission electron microscopy. RESULTS: Before orchiectomy, the mean serum concentration of androgen was 43.4 ng/MUL, which decreased to approximately 0 ng/MUL at 1 week after orchiectomy. Significantly less tear production, shorter tear break-up time, higher corneal fluorescein staining score, shorter and flattened corneal epithelial microvilli, and looser intercellular desmosomes were observed in mice after orchiectomy. DHT supplements increased serum androgen levels, and some of the tear film functions and morphological features of microvilli and desmosomes were gradually close to those at baseline in the DHT injection group. CONCLUSIONS: Persistent corneal staining, decreased tear production, short break-up time, and unhealthy corneal ultrastructure were observed in mice that received orchiectomy for at least 8 weeks. A mouse that received orchiectomy could be used as a dry eye model. Exogenous DHT supplement improved corneal epithelial ultrastructure and tear film function in this model. PMID- 25533000 TI - Microsporidial stromal keratitis masquerading as acute graft rejection. AB - PURPOSE: To describe the clinical features, disease course, management, and visual outcome of stromal microsporidial keratitis involving the corneal graft in an immunocompetent patient. METHODS: Case report. RESULTS: We report the case of a 21-year-old immunocompetent woman, who underwent penetrating keratoplasty for advanced keratoconus in her right eye and presented with features of acute graft rejection after 15 months. Standard treatment using topical and systemic steroids failed to reverse the graft rejection. A regraft was performed in that eye. Histopathology of the donor corneal button revealed microsporidiosis involving the deep stroma. CONCLUSIONS: Microsporidiosis is rarely encountered in a corneal graft and masquerades as acute graft rejection. Histopathology could help in making a final diagnosis. PMID- 25532999 TI - Long-term clinical outcomes of conjunctival flap surgery for calcified scleromalacia after periocular surgery. AB - PURPOSE: The aim of this study was to investigate long-term clinical outcomes of conjunctival flap surgery for calcified scleromalacia after periocular surgery. METHODS: We examined 73 surgical sites (nasal and/or temporal area) in 60 eyes from 43 patients who underwent conjunctival flap surgery for calcified scleromalacia arising from cosmetic wide conjunctivectomy or pterygium excision. Clinical outcomes, including the need for reoperation and development of complications, were evaluated over a long-term follow-up period. Morphological evaluations of the surgical area at final follow-up were performed using a total score for injection severity, ocular surface smoothness, and choroid visibility, and patients subjectively evaluated their cosmetic outcome using a scale of 0 (very poor) to 4 (excellent). RESULTS: The mean follow-up duration after final conjunctival flap surgery was 26.5 +/- 6.8 months (range, 15-52 months). There were no cases of progressive scleral thinning or serious complications such as flap necrosis or scleral perforation. Only 3 surgical areas with an inferior flap required additional flap placement because of avascular sclera exposure. Minor complications such as conjunctival cyst, edematous flap, vessel engorgement, and flap hypertrophy were easily treated or spontaneously improved. Mean morphological score was 2.2 and cosmetic outcome score was 2.9, indicating almost "good" outcomes. CONCLUSIONS: Based on our long-term experience, we propose that conjunctival flap surgery may be a safe and satisfactory treatment for complicated calcified scleromalacia after periocular surgery. PMID- 25533001 TI - Computational modeling suggests dimerization of equine infectious anemia virus Rev is required for RNA binding. AB - BACKGROUND: The lentiviral Rev protein mediates nuclear export of intron containing viral RNAs that encode structural proteins or serve as the viral genome. Following translation, HIV-1 Rev localizes to the nucleus and binds its cognate sequence, termed the Rev-responsive element (RRE), in incompletely spliced viral RNA. Rev subsequently multimerizes along the viral RNA and associates with the cellular Crm1 export machinery to translocate the RNA-protein complex to the cytoplasm. Equine infectious anemia virus (EIAV) Rev is functionally homologous to HIV-1 Rev, but shares very little sequence similarity and differs in domain organization. EIAV Rev also contains a bipartite RNA binding domain comprising two short arginine-rich motifs (designated ARM-1 and ARM-2) spaced 79 residues apart in the amino acid sequence. To gain insight into the topology of the bipartite RNA binding domain, a computational approach was used to model the tertiary structure of EIAV Rev. RESULTS: The tertiary structure of EIAV Rev was modeled using several protein structure prediction and model quality assessment servers. Two types of structures were predicted: an elongated structure with an extended central alpha helix, and a globular structure with a central bundle of helices. Assessment of models on the basis of biophysical properties indicated they were of average quality. In almost all models, ARM-1 and ARM-2 were spatially separated by >15 A, suggesting that they do not form a single RNA binding interface on the monomer. A highly conserved canonical coiled coil motif was identified in the central region of EIAV Rev, suggesting that an RNA binding interface could be formed through dimerization of Rev and juxtaposition of ARM-1 and ARM-2. In support of this, purified Rev protein migrated as a dimer in Blue native gels, and mutation of a residue predicted to form a key coiled-coil contact disrupted dimerization and abrogated RNA binding. In contrast, mutation of residues outside the predicted coiled-coil interface had no effect on dimerization or RNA binding. CONCLUSIONS: Our results suggest that EIAV Rev binding to the RRE requires dimerization via a coiled-coil motif to juxtapose two RNA binding motifs, ARM-1 and ARM-2. PMID- 25533002 TI - Epidemiology, pathophysiology, and classification of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) workshop. AB - In August 2013, the National Institutes of Health sponsored a conference to address major gaps in our understanding of the epidemiology, pathophysiology, and management of fecal incontinence (FI) and to identify topics for future clinical research. This article is the first of a two-part summary of those proceedings. FI is a common symptom, with a prevalence that ranges from 7 to 15% in community dwelling men and women, but it is often underreported, as providers seldom screen for FI and patients do not volunteer the symptom, even though the symptoms can have a devastating impact on the quality of life. Rough estimates suggest that FI is associated with a substantial economic burden, particularly in patients who require surgical therapy. Bowel disturbances, particularly diarrhea, the symptom of rectal urgency, and burden of chronic illness are the strongest independent risk factors for FI in the community. Smoking, obesity, and inappropriate cholecystectomy are emerging, potentially modifiable risk factors. Other risk factors for FI include advanced age, female gender, disease burden (comorbidity count, diabetes), anal sphincter trauma (obstetrical injury, prior surgery), and decreased physical activity. Neurological disorders, inflammatory bowel disease, and pelvic floor anatomical disturbances (rectal prolapse) are also associated with FI. The pathophysiological mechanisms responsible for FI include diarrhea, anal and pelvic floor weakness, reduced rectal compliance, and reduced or increased rectal sensation; many patients have multifaceted anorectal dysfunctions. The type (urge, passive or combined), etiology (anorectal disturbance, bowel symptoms, or both), and severity of FI provide the basis for classifying FI; these domains can be integrated to comprehensively characterize the symptom. Several validated scales for classifying symptom severity and its impact on the quality of life are available. Symptom severity scales should incorporate the frequency, volume, consistency, and nature (urge or passive) of stool leakage. Despite the basic understanding of FI, there are still major knowledge gaps in disease epidemiology and pathogenesis, necessitating future clinical research in FI. PMID- 25533003 TI - Metabolic phenotyping for enhanced mechanistic stratification of chronic hepatitis C-induced liver fibrosis. AB - OBJECTIVES: The invasive nature of biopsy alongside issues with categorical staging and sampling error has driven research into noninvasive biomarkers for the assessment of liver fibrosis in order to stratify and personalize treatment of patients with liver disease. Here, we sought to determine whether a metabonomic approach could be used to identify signatures reflective of the dynamic, pathological metabolic perturbations associated with fibrosis in chronic hepatitis C (CHC) patients. METHODS: Plasma nuclear magnetic resonance (NMR) spectral profiles were generated for two independent cohorts of CHC patients and healthy controls (n=50 original and n=63 validation). Spectral data were analyzed and significant discriminant biomarkers associated with fibrosis (as graded by enhanced liver fibrosis (ELF) and METAVIR scores) identified using orthogonal projection to latent structures (O-PLS). RESULTS: Increased severity of fibrosis was associated with higher tyrosine, phenylalanine, methionine, citrate and, very low-density lipoprotein (vLDL) and lower creatine, low-density lipoprotein (LDL), phosphatidylcholine, and N-Acetyl-alpha1-acid-glycoprotein. Although area under the receiver operator characteristic curve analysis revealed a high predictive performance for classification based on METAVIR-derived models, <40% of identified biomarkers were validated in the second cohort. In the ELF-derived models, however, over 80% of the biomarkers were validated. CONCLUSIONS: Our findings suggest that modeling against a continuous ELF-derived score of fibrosis provides a more robust assessment of the metabolic changes associated with fibrosis than modeling against the categorical METAVIR score. Plasma metabolic phenotypes reflective of CHC-induced fibrosis primarily define alterations in amino-acid and lipid metabolism, and hence identify mechanistically relevant pathways for further investigation as therapeutic targets. PMID- 25533005 TI - The impact of anemia on child mortality: an updated review. AB - Iron deficiency anemia and child mortality are public health problems requiring urgent attention. However, the degree to which iron deficiency anemia contributes to child mortality is unknown. Here, we utilized an exhaustive article search and screening process to identify articles containing both anemia and mortality data for children aged 28 days to 12 years. We then estimated the reduction in risk of mortality associated with a 1-g/dL increase in hemoglobin (Hb). Our meta-analysis of nearly 12,000 children from six African countries revealed a combined odds ratio of 0.76 (0.62-0.93), indicating that for each 1-g/dL increase in Hb, the risk of death falls by 24%. The feasibility of a 1-g/dL increase in Hb has been demonstrated via simple iron supplementation strategies. Our finding suggests that ~1.8 million deaths in children aged 28 days to five years could be avoided each year by increasing Hb in these children by 1 g/dL. PMID- 25533004 TI - Does vitamin C deficiency promote fatty liver disease development? AB - Obesity and the subsequent reprogramming of the white adipose tissue are linked to human disease-complexes including metabolic syndrome and concurrent non alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The dietary imposed dyslipidemia promotes redox imbalance by the generation of excess levels of reactive oxygen species and induces adipocyte dysfunction and reprogramming, leading to a low grade systemic inflammation and ectopic lipid deposition, e.g., in the liver, hereby promoting a vicious circle in which dietary factors initiate a metabolic change that further exacerbates the negative consequences of an adverse life-style. Large epidemiological studies and findings from controlled in vivo animal studies have provided evidence supporting an association between poor vitamin C (VitC) status and propagation of life-style associated diseases. In addition, overweight per se has been shown to result in reduced plasma VitC, and the distribution of body fat in obesity has been shown to have an inverse relationship with VitC plasma levels. Recently, a number of epidemiological studies have indicated a VitC intake below the recommended daily allowance (RDA) in NAFLD-patients, suggesting an association between dietary habits, disease and VitC deficiency. In the general population, VitC deficiency (defined as a plasma concentration below 23 MUM) affects around 10% of adults, however, this prevalence is increased by an adverse life-style, deficiency potentially playing a broader role in disease progression in specific subgroups. This review discusses the currently available data from human surveys and experimental models in search of a putative role of VitC deficiency in the development of NAFLD and NASH. PMID- 25533007 TI - Sugar intake, obesity, and diabetes in India. AB - Sugar and sweet consumption have been popular and intrinsic to Indian culture, traditions, and religion from ancient times. In this article, we review the data showing increasing sugar consumption in India, including traditional sources (jaggery and khandsari) and from sugar-sweetened beverages (SSBs). Along with decreasing physical activity, this increasing trend of per capita sugar consumption assumes significance in view of the high tendency for Indians to develop insulin resistance, abdominal adiposity, and hepatic steatosis, and the increasing "epidemic" of type 2 diabetes (T2DM) and cardiovascular diseases. Importantly, there are preliminary data to show that incidence of obesity and T2DM could be decreased by increasing taxation on SSBs. Other prevention strategies, encompassing multiple stakeholders (government, industry, and consumers), should target on decreasing sugar consumption in the Indian population. In this context, dietary guidelines for Indians show that sugar consumption should be less than 10% of total daily energy intake, but it is suggested that this limit be decreased. PMID- 25533006 TI - Simple sugar intake and hepatocellular carcinoma: epidemiological and mechanistic insight. AB - Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved. PMID- 25533008 TI - Anemia and feeding practices among infants in rural Shaanxi Province in China. AB - Anemia is one of the most prevalent public health problems among infants and iron deficiency anemia has been related to many adverse consequences. The overall goal of this study is to examine the prevalence of anemia among infants in poor rural China and to identify correlates of anemia. In April 2013, we randomly sampled 948 infants aged 6-11 months living in 351 villages across 174 townships in nationally-designated poverty counties in rural areas of southern Shaanxi Province, China. Infants were administered a finger prick blood test for hemoglobin (Hb). Anthropometric measurement and household survey of demographic characteristics and feeding practices were conducted in the survey. We found that 54.3% of 6-11 month old infants in poor rural China are anemic, and 24.3% of sample infants suffer from moderate or severe anemia. We find that children still breastfed over 6 months of age had lower Hb concentrations and higher anemia prevalence than their non-breastfeeding counterparts (p < 0.01), and that children who had ever been formula-fed had significantly higher Hb concentrations and lower anemia prevalence than their non-formula-fed counterparts (p < 0.01). The results suggest the importance of iron supplementation or home fortification while breastfeeding. PMID- 25533009 TI - Effects of levocarnitine on brachial-ankle pulse wave velocity in hemodialysis patients: a randomized controlled trial. AB - BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is the most common cause of mortality in patients with end-stage kidney disease. Chronic kidney disease patients often exhibit a deficiency in L-carnitine due to loss during hemodialysis (HD). We studied the effects of L-carnitine supplementation on brachial-ankle pulse wave velocity (baPWV), a marker of atherosclerosis, in HD patients. METHODS: This was a prospective, open-label, randomized, parallel controlled, multi-center trial testing the anti-atherosclerotic efficacy of oral L-carnitine administration (20 mg/kg/day). HD patients (n = 176, mean age, 67.2 +/- 10.3 years old; mean duration of HD, 54 +/- 51 months) with plasma free L carnitine deficiency (<40 MUmol/L) were randomly assigned to the oral L-carnitine group (n = 88) or control group (n = 88) and monitored during 12 months of treatment. RESULTS: There were no significant differences in baseline clinical variables between the L-carnitine and control groups. L-carnitine supplementation for 12 months significantly increased total, free, and acyl carnitine levels, and reduced the acyl/free carnitine ratio. The baPWV value decreased from 2085 +/- 478 cm/s at baseline to 1972 +/- 440 cm/s after six months (p < 0.05) to 1933 +/- 363 cm/s after 12 months (p < 0.001) of L-carnitine administration, while no significant changes in baPWV were observed in the control group. Baseline baPWV was the only factor significantly correlated with the decrease in baPWV. CONCLUSIONS: L-carnitine supplementation significantly reduced baPWV in HD patients. L-carnitine may be a novel therapeutic strategy for preventing the progression of atherosclerotic cardiovascular disease. PMID- 25533010 TI - Dietary magnesium intake and metabolic syndrome in the adult population: dose response meta-analysis and meta-regression. AB - ncreasing evidence has suggested an association between dietary magnesium intake and metabolic syndrome. However, previous research examining dietary magnesium intake and metabolic syndrome has produced mixed results. Our objective was to determine the relationship between dietary magnesium intake and metabolic syndrome in the adult population using a dose-response meta-analysis. We searched the PubMed, Embase and the Cochrane Library databases from August, 1965, to May, 2014. Observational studies reporting risk ratios with 95% confidence intervals (CIs) for metabolic syndrome in >= 3 categories of dietary magnesium intake levels were selected. The data extraction was performed independently by two authors, and the quality of the studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). Based on eight cross sectional studies and two prospective cohort studies, the pooled relative risks of metabolic syndrome per 150 mg/day increment in magnesium intake was 0.88 (95% CI, 0.84-0.93; I(2) = 36.3%). The meta-regression model showed a generally linear, inverse relationship between magnesium intake (mg/day) and metabolic syndrome. This dose-response meta-analysis indicates that dietary magnesium intake is significantly and inversely associated with the risk of metabolic syndrome. However, randomized clinical trials will be necessary to address the issue of causality and to determine whether magnesium supplementation is effective for the prevention of metabolic syndrome. PMID- 25533012 TI - Neurochemical effects of chronic administration of calcitriol in rats. AB - Despite accumulating data showing the various neurological actions of vitamin D (VD), its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25 dihydroxyvitamin D) administration (50 ng/kg/day or 100 ng/kg/day). Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated gamma-aminobutyric acid (GABA) status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD) 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS) expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA) expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function. PMID- 25533013 TI - Intake of seafood in the US varies by age, income, and education level but not by race-ethnicity. AB - Current US federal dietary guidance recommends regular consumption of seafood (fish + shellfish) to promote health; however, little is known about how well Americans meet the guideline, particularly population subgroups that may be at risk for inadequate intake. The purposes of this study were to describe the prevalence of seafood consumption and, among consumers, the amounts of seafood eaten by sex, age group, income and education level, and race-ethnicity. Data from 15,407 adults aged 19+ participating in the 2005-2010 National Health and Nutrition Examination Surveys were analyzed using methods to account for sporadic intake of seafood. Over 80% of Americans reported consuming any seafood over the past 30 days, 74% reported consuming fish, and 54% reported eating shellfish. The percentages varied by socio-demographic group. Younger age and lower income and education levels were associated with lower odds of being a seafood consumer (p < 0.0001). Among those who reported eating seafood, the average amount eaten of any seafood was 158.2 +/- 5.6 g/week. Among seafood consumers, women and individuals of lower age and education levels consumed less seafood. Approximately 80%-90% of seafood consumers did not meet seafood recommendations when needs were estimated by energy requirements. A great deal of work remains to move Americans toward seafood consumption at current recommended levels. PMID- 25533011 TI - Resources and biological activities of natural polyphenols. AB - The oxidative stress imposed by reactive oxygen species (ROS) plays an important role in many chronic and degenerative diseases. As an important category of phytochemicals, phenolic compounds universally exist in plants, and have been considered to have high antioxidant ability and free radical scavenging capacity, with the mechanism of inhibiting the enzymes responsible for ROS production and reducing highly oxidized ROS. Therefore, phenolic compounds have attracted increasing attention as potential agents for preventing and treating many oxidative stress-related diseases, such as cardiovascular diseases, cancer, ageing, diabetes mellitus and neurodegenerative diseases. This review summarizes current knowledge of natural polyphenols, including resource, bioactivities, bioavailability and potential toxicity. PMID- 25533014 TI - Selected nutrients and their implications for health and disease across the lifespan: a roadmap. AB - Worldwide approximately two billion people have a diet insufficient in micronutrients. Even in the developed world, an increasing number of people consume nutrient-poor food on a regular basis. Recent surveys in Western countries consistently indicate inadequate intake of nutrients such as vitamins and minerals, compared to recommendations. The International Osteoporosis Foundation's (IOF) latest figures show that globally about 88% of the population does not have an optimal vitamin D status. The Lancet's "Global Burden of Disease Study 2010" demonstrates a continued growth in life expectancy for populations around the world; however, the last decade of life is often disabled by the burden of partly preventable health issues. Compelling evidence suggests that improving nutrition protects health, prevents disability, boosts economic productivity and saves lives. Investments to improve nutrition make a positive contribution to long-term national and global health, economic productivity and stability, and societal resilience. PMID- 25533017 TI - Cardiac paraganglioma. AB - Cardiac paragangliomas are rare tumors arising from chromaffin cells. Two patients with cardiac paragangliomas underwent surgical resection with no evidence of recurrence three and 13 years following surgery. This report describes these two patients with cardiac paragangliomas and discusses their management. PMID- 25533016 TI - Enantioconvergent synthesis of functionalized gamma-butyrolactones via (3 + 2) annulation. AB - A dynamic kinetic resolution of beta-halo alpha-keto esters in an asymmetric homoenolate reaction is described. A chiral N-hetereocyclic carbene catalyzes the a(3) -> d(3)-umpolung addition of alpha,beta-enals to racemic alpha-keto esters, forming gamma-butyrolactones with three contiguous stereocenters. The addition occurs with high regio-, diastereo-, and enantiocontrol. This methodology constitutes an intermolecular DKR process to set three stereocenters during the key bond forming event. PMID- 25533015 TI - The role of dietary fat throughout the prostate cancer trajectory. AB - Prostate cancer is the second most common cancer diagnosed world-wide; however, patients demonstrate exceptionally high survival rates. Many lifestyle factors, including obesity and diet, are considered risk factors for advanced prostate cancer. Dietary fat is a fundamental contributor to obesity and may be specifically important for prostate cancer patients. Prostate cancer treatment can result in changes in body composition, affecting quality of life for survivors by increasing the risk of co-morbidities, like cardiovascular disease and diabetes. We aim to examine dietary fat throughout the prostate cancer treatment trajectory, including risk, cancer development and survivorship. Focusing on one specific nutrient throughout the prostate cancer trajectory provides a unique perspective of dietary fat in prostate cancer and the mechanisms that may exacerbate prostate cancer risk, progression and recurrence. Through this approach, we noted that high intake of dietary fat, especially, high intake of animal and saturated fats, may be associated with increased prostate cancer risk. In contrast, a low-fat diet, specifically low in saturated fat, may be beneficial for prostate cancer survivors by reducing tumor angiogenesis and cancer recurrence. The insulin-like growth factor (IGF)/Akt signaling pathway appears to be the key pathway moderating dietary fat intake and prostate cancer development and progression. PMID- 25533019 TI - Metamaterials enable chiral-selective enhancement of two-photon luminescence from quantum emitters. AB - The amplification of chirally modified, non-linear signals from quantum emitters is demonstrated by manipulating the geometric chirality of resonant plasmonic nanostructures. The chiral center of the metamaterial is opened and emitters occupy this light-confining and chirally sensitive region. Non-linear emission signals are enhanced by 40* that of the emitters not embedded in the metamaterial and display a 3* contrast for the opposite circular polarization. PMID- 25533018 TI - Nanostructured Ti-Zr-Pd-Si-(Nb) bulk metallic composites: Novel biocompatible materials with superior mechanical strength and elastic recovery. AB - The microstructure, mechanical behaviour, and biocompatibility (cell culture, morphology, and cell adhesion) of nanostructured Ti45 Zr15 Pd35- x Si5 Nbx with x = 0, 5 (at. %) alloys, synthesized by arc melting and subsequent Cu mould suction casting, in the form of rods with 3 mm in diameter, are investigated. Both Ti-Zr Pd-Si-(Nb) materials show a multi-phase (composite-like) microstructure. The main phase is cubic beta-Ti phase (Im3m) but hexagonal alpha-Ti (P63/mmc), cubic TiPd (Pm3m), cubic PdZr (Fm3m), and hexagonal (Ti, Zr)5 Si3 (P63/mmc) phases are also present. Nanoindentation experiments show that the Ti45 Zr15 Pd30 Si5 Nb5 sample exhibits lower Young's modulus than Ti45 Zr15 Pd35 Si5 . Conversely, Ti45 Zr15 Pd35 Si5 is mechanically harder. Actually, both alloys exhibit larger values of hardness when compared with commercial Ti-40Nb, (HTi-Zr-Pd-Si ~ 14 GPa, HTi-Zr-Pd Si-Nb ~ 10 GPa and HTi-40Nb ~ 2.7 GPa). Concerning the biological behaviour, preliminary results of cell viability performed on several Ti-Zr-Pd-Si-(Nb) discs indicate that the number of live cells is superior to 94% in both cases. The studied Ti-Zr-Pd-Si-(Nb) bulk metallic system is thus interesting for biomedical applications because of the outstanding mechanical properties (relatively low Young's modulus combined with large hardness), together with the excellent biocompatibility. PMID- 25533020 TI - Autophagy is deficient in nasal polyps: implications for the pathogenesis of the disease. AB - BACKGROUND: Nasal polyposis is characterized by persistent inflammation but the pathogenesis is complex and still debatable. Autophagy has been associated with many human health problems including chronic inflammatory airway diseases. Whether autophagy plays a role in nasal polyps and could be a therapeutic target is completely unknown. METHODS: We studied light chain 3 (LC3) protein expression, a common indication of autophagy, in fresh tissue specimens of 5 nasal polyps and 6 normal nasal mucosa by Western blot analysis. The results were also confirmed by immunohistochemistry (IHC) using additional 25 paraffin embedded nasal tissue sections. Finally the autophagic activity was validated in nasal polyp-derived fibroblasts by evaluating the number of green fluorescent protein (GFP)-labeled LC3 puncta. RESULTS: The expression of LC3 was dramatically decreased in all 5 nasal polyp tissues. In contrast, protein kinase B-mechanistic target of rapamycin (Akt-mTOR) signaling, an established negative regulator of autophagy, was significantly activated in these tissues. Immunohistochemical results further demonstrated a negative correlation between autophagy and nasal polyps (p < 0.05). GFP-LC3 puncta formation, an alternative indicator of autophagy, was also diminished in nasal polyp-derived fibroblasts (p < 0.01). CONCLUSION: Autophagy is deficient presumably due to suppression by high Akt-mTOR activity in nasal polyps, which may provide a molecular basis for future mechanistic study of the disease. PMID- 25533021 TI - Normalcy of food intake in patients with head and neck cancer supported by combined dietary counseling and swallowing therapy: A randomized clinical trial. AB - BACKGROUND: Dysphagia resulting in altered food intake is common among patients with head and neck cancer. This randomized trial investigated the effect of combined individual dietary counseling with individualized swallowing therapy (intervention) compared to individual dietary counseling (control) on normalcy of food intake (NFI). METHODS: Patients with stage II to IV head and neck cancer treated with postoperative (chemo)radiation were randomly assigned to this study. NFI, dysphagia severity, social eating, and nutritional status were measured at the start of treatment and in weeks 6, 10, 18, and 30. RESULTS: One hundred twenty patients, 60 in each group, were recruited. No overall estimated difference was detected for NFI, dysphagia severity, social eating, or nutritional status. At week 10, the intervention group slightly improved dysphagia recovery 0.6 (95% confidence interval [CI] = 0.1-1.1). This difference diminished by week 30. CONCLUSION: Adding individualized swallowing therapy to individual dietary counseling did not improve NFI but slightly accelerate swallowing recovery. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E198-E206, 2016. PMID- 25533022 TI - Social capital: theory, evidence, and implications for oral health. AB - In the last two decades, there has been increasing application of the concept of social capital in various fields of public health, including oral health. However, social capital is a contested concept with debates on its definition, measurement, and application. This study provides an overview of the concept of social capital, highlights the various pathways linking social capital to health, and discusses the potential implication of this concept for health policy. An extensive and diverse international literature has examined the relationship between social capital and a range of general health outcomes across the life course. A more limited but expanding literature has also demonstrated the potential influence of social capital on oral health. Much of the evidence in relation to oral health is limited by methodological shortcomings mainly related to the measurement of social capital, cross-sectional study designs, and inadequate controls for confounding factors. Further research using stronger methodological designs should explore the role of social capital in oral health and assess its potential application in the development of oral health improvement interventions. PMID- 25533023 TI - Regulations of essential amino acids and proteomics of bacterial endophytes Sphingomonas sp. Lk11 during cadmium uptake. AB - Endophytic bacteria have been recently known for their potential to bioaccumulate metal from contaminated mediums. However, little is known about the physiological responses of phytohormone producing (gibberellins and auxins) endophytes during metal stressed environment. Endophytic bacteria Sphingomonas sp. LK11 was assessed for metals bioaccumulation and its physiological responses towards metal stress. The endophyte was grown in cadmium (Cd), zinc (Zn), aluminum (Al), manganese (Mn), and copper (Cu) contaminated mediums. The results revealed significantly higher endophytic growth potentials in Cd, Cu and Zn contaminations; however, the bio-accumulation rate of Cd was more prolific as compared to Zn and Cu. Interestingly, the SDS-PAGE profile showed increased expressions of proteins in Zn and Cu than in Cd. A similar attenuate response of amino acids was also observed for Cd than in case of Zn and Cu. Only asparagine, glutamate and proline showed significant impact in Cd while Cu and Zn had significantly higher responses of almost all amino acids. Detailed protein profile showed the activation of chaperone, antioxidative and detoxification proteins. Increased regulations of oxidoreductases, superoxide dismutase, thioredoxin, malate dehydrogenase, 2-oxoisovalerate dehydrogenase, 2 oxoisovalerate dehydrogenase, and dihydrolipoyl dehydrogenase were observed. The cellular defense-related protein responses were potent against Cd stress. The results conclude that Sphingomonas sp. LK11 reprogram its amino acids and proteomic expressions and maintain a steady growth during Cd stress. Using such phytohromones producing endophytic bacterium can be ideal approach to increase the phytoextraction potential of metal remediating plants. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 887-896, 2016. PMID- 25533024 TI - A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria. AB - Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced. PMID- 25533025 TI - Experimental and computational study of the catalytic asymmetric 4pi electrocyclization of N-heterocycles. AB - The first asymmetric metal-catalyzed Nazarov cyclization of N-heterocycles has been developed. The use of a chiral catalyst allows the enantioselective electrocyclization of N-heterocycles under mild conditions and the corresponding products are obtained in good yields with excellent enantio- and diastereoselectivity. The reaction mechanism and the absolute configuration of the obtained products are explained by means of computational studies. PMID- 25533026 TI - Anatomical basis of female pelvic cavity for nerve sparing radical hysterectomy. AB - PURPOSE: The separation and sparing of the vesical branch of the inferior hypogastric plexus (IHP), to preserve the pelvic autonomic nerve, is critical and difficult in nerve sparing radical hysterectomy. Pelvic local anatomy was performed to provide the necessary anatomical information. METHODS: Precise pelvic anatomy was performed in 15 adult corpses, and immunohistochemical analysis was carried out on the parametrial tissues of three fresh cadavers to analyze the nerve fiber type and content of the vesical branch of the IHP. RESULTS: The deep uterine vein is located in the upper region of the cardinal ligament (CL), with three to six multiple branches and anatomical variation, including one or two cervical branches, and two to four vesical branches. Three branches were found to be most common (63.3 %). The major distribution of the vesical branch of the IHP is dorsomedial to the middle and inferior vesical veins, with less ventral and lateral distribution. There are more sympathetic fibers than parasympathetic fibers in the vesical branch. There is a region rare of vasculature and nerve between the vaginal lateral margin and the vesical branch. CONCLUSION: The deep uterine vein is suggested as an anatomical landmark during surgery, to process the CL and preserve the pelvic splanchnic nerves. The middle and inferior vesical veins can be used as the landmark to preserve the vesical branch of the IHP. PMID- 25533027 TI - Influence of enzymatic extrusion liquefaction pretreatment for Chinese rice wine on the volatiles generated from extruded rice. AB - Volatile compounds in enzymatic extruded rice, produced under different conditions of varying barrel temperature (BT), alpha-amylase concentration (AC) and moisture content (MC), were extracted and identified by headspace solid phase microextraction (HS-SPME) and gas chromatography-linked mass spectrometry (GC MS). Statistical analyses reflected that the Maillard reaction could be inhibited both by the mild extrusion conditions and the enhanced hydrolysis caused by thermostable alpha-amylase. Relative amounts of total volatiles in enzymatic extruded rice were far less than those in severe processed extruded rice. Reverse phase high-performance liquid chromatography (RP-HPLC) showed that the amino acids (AAs) involved in Maillrad reaction were utmostly preserved in extruded rice with highest amylase concentration by comparison of total AA content of different extrudates. These results suggest that enzymatic extrusion liquefaction is an effective way to control the generation of volatiles from extruded rice for Chinese rice wine production. PMID- 25533028 TI - The relationship of brain structure to age and executive functioning in adolescent disruptive behavior disorder. AB - Characterizing brain maturation in adolescents with disruptive behavior disorders (DBDs) may provide insight into the progression of their behavioral deficits. Therefore, this study examined how age and executive functioning were related to structural neural characteristics in DBD. Thirty-three individuals (aged 13-17) with a DBD, along with a matched control sample, completed neuropsychological testing and underwent magnetic resonance imaging (MRI) to measure gray matter volume and microstructural white matter properties. Voxel-based morphometry quantified gray matter volume, and diffusion tensor imaging measured fractional anisotropy (FA) in white matter tracts. In the anterior cingulate, gray matter volume decreased with age in healthy controls but showed no such change in the DBD sample. In the corpus callosum and superior longitudinal fasciculus (SLF), FA increased with age in the control sample significantly more than in the DBD sample. Executive functioning, particularly working memory, was associated with SLF FA bilaterally. However, the relationship of SLF FA to working memory performance was weaker in the DBD sample. These data suggest that youth with DBD have altered brain development compared with typically developing youth. The abnormal maturation of the anterior cingulate and frontoparietal tracts during adolescence may contribute to the persistence of behavioral deficits in teens with a DBD. PMID- 25533032 TI - Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia. AB - Early transcranial Doppler (TCD) screening of the Creteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Creteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18 8.70; P = .023) are significant and independent risk factors for SCI. PMID- 25533033 TI - Jun-regulated genes promote interaction of diffuse large B-cell lymphoma with the microenvironment. AB - Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with a high proliferation rate. However, the molecular and genetic features that drive the aggressive clinical behavior of DLBCL are not fully defined. Here, we have demonstrated that activated Jun signaling is a frequent event in DLBCL that promotes dissemination of malignant cells. Downregulation of Jun dramatically reduces lymphoma cell adhesion to extracellular matrix proteins, subcutaneous tumor size in nude mice, and invasive behavior, including bone marrow infiltration and interaction with bone marrow stromal cells. Furthermore, using a combination of RNA interference and gene expression profiling, we identified Jun target genes that are associated with disseminated lymphoma. Among them, ITGAV, FoxC1, and CX3CR1 are significantly enriched in patients with 2 or more extranodal sites. Our results point to activated Jun signaling as a major driver of the aggressive phenotype of DLBCL. PMID- 25533036 TI - How I treat incidental pulmonary embolism. AB - The identification of pulmonary embolism (PE) on computed tomography scans performed for indications other than identification of thromboembolism is a growing clinical problem that has not been adequately addressed by prospective treatment trials. The prevalence of incidentally detected PE ranges from 1% to 4% in unselected populations, with higher rates among hospital inpatients and patients with cancer. Current guidelines recommend using the same approach to type and duration of anticoagulation as is used for patients with suspected PE. Available data regarding the significance of symptomatic subsegmental PE (SSPE) are conflicting, making it difficult to draw conclusions about the appropriate treatment of incidentally detected SSPE, for which the data are sparse. Among cancer patients, the bulk of available data suggest that incidental SSPE is associated with recurrent venous thromboembolism and, when symptomatic, may adversely impact survival. Here, the topic is reviewed utilizing 3 clinical cases, each of which is followed by a discussion of salient features and then by treatment recommendations. PMID- 25533035 TI - Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. AB - We present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N = 102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission (CR) on brentuximab vedotin, with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively, in this group (medians not reached). Of the 34 patients who obtained CR, 16 (47%) remain progression-free after a median of 53.3 months (range, 29.0 to 56.2 months) of observation; 12 patients remain progression-free without a consolidative allogeneic stem cell transplant. Younger age, good performance status, and lower disease burden at baseline were characteristic of patients who achieved a CR and were favorable prognostic factors for overall survival. These results suggest that a significant proportion of patients who respond to brentuximab vedotin can achieve prolonged disease control. The trial was registered at www.clinicaltrials.gov as #NCT00848926. PMID- 25533031 TI - Characterizing a hybrid zone between a cryptic species pair of freshwater snails. AB - Characterizing hybrid zones and their dynamics is a central goal in evolutionary biology, but this is particularly challenging for morphologically cryptic species. The lack of conspicuous divergence between parental types means intermediate hybrid forms often go undetected. We aimed to detect and characterize a suspected hybrid zone between a pair of morphologically cryptic lineages of the freshwater snail, Radix. We sampled Radix from across a contact zone between two mitochondrial lineages (Radix balthica and an undescribed lineage termed 'MOTU3') and detected admixture between two nuclear genotype clusters, which were significantly but not categorically associated with the mitochondrial lineages. Using a model selection approach, we show that the admixture cline is best explained by an interaction between precipitation and temperature gradients over the area, rather than geographic distance. We thus hypothesize that the correlation with climatic gradients suggests environmental selection has played a role in maintaining the hybrid zone. In a 2050 climate change scenario, we furthermore predict an expansion of one of the nuclear clusters and a widening of the hybrid zone as the climate warms and dries. PMID- 25533037 TI - Through the lens of the clinician: autopsy services and utilization in a large teaching hospital in Ghana. AB - BACKGROUND: Declining hospital autopsy rates in many countries have generated considerable concern. The survey determined challenges of the autopsy service in a large Teaching Hospital in Ghana, from the perspective of clinicians. METHODS: This was a cross-sectional study of doctors at the Korle-Bu Teaching Hospital (KBTH) over in 2012. The data was collected using a 69 item self-administered structured questionnaire. In all a total of 215 questionnaires were sent out and 119 doctors responded. Data was collected on the challenges of the autopsy services and barriers to autopsy request from the perspectives of clinicians. Survey data were analyzed by simple descriptive statistics (i.e. proportions, ratios and percentages. Data from survey was analyzed with SPSS version 21. RESULTS: The most common reasons for requesting autopsies were to answer clinical questions, 55 (46.2%) and in cases of uncertain diagnosis, 54 (45.4%). Main demand side barriers to the use of autopsy services by clinicians were reluctance of family to give consent for autopsy 100 (84%), due to cultural and religious objections 89 (74.8%), extra funeral cost to family53 (44.5%) and increased duration of stay of body in the morgue 19 (16%). Health system barriers included delayed feedback from autopsy service 54 (45.4%), difficulties following up the autopsy process 40 (33.6%) due to uncertainties in the timing of particular events in the autopsy process, and long waiting time for autopsy reports 81 (68.1%). More than a third of clinicians 43 (36.2%), received full autopsy report beyond three weeks and 75 (63.1%) clinicians had concerns with the validity of reports issued by the autopsy service (i.e. reports lack specificity or at variance with clinical diagnosis, no toxicological, histological or tissue diagnoses are performed). CONCLUSION: The autopsy service should restructure itself efficiently and management should support the provision of histological and toxicological services. Strengthening internal and external quality improvement and control of autopsies in the Hospital are essential. PMID- 25533039 TI - Filamentous bacteria existence in aerobic granular reactors. AB - Filamentous bacteria are associated to biomass settling problems in wastewater treatment plants. In systems based on aerobic granular biomass they have been proposed to contribute to the initial biomass aggregation process. However, their development on mature aerobic granular systems has not been sufficiently studied. In the present research work, filamentous bacteria were studied for the first time after long-term operation (up to 300 days) of aerobic granular systems. Chloroflexi and Sphaerotilus natans have been observed in a reactor fed with synthetic wastewater. These filamentous bacteria could only come from the inoculated sludge. Thiothrix and Chloroflexi bacteria were observed in aerobic granular biomass treating wastewater from a fish canning industry. Meganema perideroedes was detected in a reactor treating wastewater from a plant processing marine products. As a conclusion, the source of filamentous bacteria in these mature aerobic granular systems fed with industrial effluents was the incoming wastewater. PMID- 25533034 TI - MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome. AB - Children with Down syndrome (DS) are at increased risk for acute myeloid leukemias (ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The chromosome 21 microRNA (miR)-125b cluster has been previously shown to cooperate with GATA1s in transformation of fetal hematopoietic progenitors. In this study, we report that the expression of miR-486-5p is increased in ML-DS compared with non-DS acute megakaryocytic leukemias (AMKLs). miR-486-5p is regulated by GATA1 and GATA1s that bind to the promoter of its host gene ANK1. miR-486-5p is highly expressed in mouse erythroid precursors and knockdown (KD) in ML-DS cells reduced their erythroid phenotype. Ectopic expression and KD of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR 486-5p cooperates with Gata1s to enhance their self renewal. Consistent with its activation of AKT, overexpression and KD experiments showed its importance for growth and survival of human leukemic cells. Thus, miR-486-5p cooperates with GATA1s in supporting the growth and survival, and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS. PMID- 25533038 TI - Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. AB - KEY POINTS: The voltage-gated Ca(2+) channels (VGCCs) that catalyse striatal dopamine transmission are critical to dopamine function and might prime subpopulations of neurons for parkinsonian degeneration. However, the VGCCs that operate on mesostriatal axons are incompletely defined; previous studies encompassed channels on striatal cholinergic interneurons that strongly influence dopamine transmission. We define that multiple types of axonal VGCCs operate that extend beyond classic presynaptic N/P/Q channels to include T- and L-types. We reveal differences in VGCC function between mouse axon types that in humans are vulnerable versus resistant to Parkinson's disease. We show for the first time that this is underpinned by different sensitivity of dopamine transmission to extracellular Ca(2+) and by different spatiotemporal intracellular Ca(2+) microdomains. These data define key principles of how Ca(2+) and VGCCs govern dopamine transmission in the healthy brain and reveal differences between neuron types that might contribute to vulnerability in disease. ABSTRACT: The axonal voltage-gated Ca(2+) channels (VGCCs) that catalyse dopamine (DA) transmission are incompletely defined. Yet, they are critical to DA function and might prime subpopulations of DA neurons for parkinsonian degeneration. Previous studies of VGCCs will have encompassed those on striatal cholinergic interneurons, which strongly influence DA transmission. We identify which VGCCs on DA axons govern DA transmission, we determine their dynamic properties and reveal an underlying basis for differences between the caudate putamen (CPu) and nucleus accumbens (NAc). We detected DA release evoked electrically during nicotinic receptor blockade or optogenetically by light activation of channel rhodopsin-expressing DA axons in mouse striatal slices. Subtype-specific VGCC blockers indicated that N-, Q-, T- and L-VGCCs govern DA release in CPu, but in NAc, T and L-channels are relatively silent. The roles of the most dominant channels were inversely frequency-dependent, due to low-pass filtering of DA release by Ca(2+)-dependent relationships between initial release probability and short-term plasticity. Ca(2+) concentration-response curves revealed that differences between CPu and NAc were due to greater underlying Ca(2+) sensitivity of DA transmission from CPu axons. Functions for 'silent' L- and T-channels in NAc could be unmasked by elevating extracellular [Ca(2+)]. Furthermore, we identified a greater coupling between BAPTA-sensitive, fast Ca(2+) transients and DA transmission in CPu axons, and evidence for endogenous fast buffering of Ca(2+) in NAc. These data reveal that a range of VGCCs operate dynamically on DA axons, depending on local driving forces. Furthermore, they reveal dramatic differences in Ca(2+) handling between axonal subpopulations that show different vulnerability to parkinsonian degeneration. PMID- 25533040 TI - UV photolysis for relieved inhibition of sulfadiazine (SD) to biomass growth. AB - UV photolysis was used to relieve inhibition of biomass growth by sulfadiazine (SD), a broad-spectrum anti-microbial. To investigate the effects of SD on biomass growth, three substrates-glucose alone (G), glucose plus sulfadiazine (G+SD), and glucose plus photolyzed SD (G+PSD)-were used to culture the bacteria acclimated to glucose. The biomass was strongly inhibited when SD was added into the glucose solution, but inhibition was relieved to a significant degree when the SD was treated with UV irradiation as a pretreatment. The biomass growth kinetics were described well by the Monod model when glucose was used as a substrate alone, but the kinetics followed a hybrid Aiba model for non competitive inhibition when SD was added to the solution. When photolyzed SD was added to glucose solution to replace original SD, the growth still followed Aiba inhibition, but inhibition was significantly relieved: the maximum specific growth rate (MU max) increased by 17 %, and the Aiba inhibition concentration increased by 60 %. Aniline, a major product of UV photolysis, supported the growth of the glucose-biodegrading bacteria. Thus, UV photolysis of SD significantly relieved inhibition by lowering the SD concentration and by generating a biodegradable product. PMID- 25533041 TI - Production of thermo-alkali-stable laccase and xylanase by co-culturing of Bacillus sp. and B. halodurans for biobleaching of kraft pulp and deinking of waste paper. AB - To reduce pollution and cost of treatment for fresh and recycled paper, co production of xylanase and laccase was carried out in the same production medium using two compatible species of Bacillus. These co-produced enzymes were used for deinking of old newsprint (ONP) and biobleaching of eucalyptus Kraft pulp. Solid state co-cultivation of Bacillus sp. and B. halodurans FNP135 was optimized statistically by response surface methodology for the co-production of xylanase (X) and laccase (L). A significant increase in production of xylanase (2.1-fold, 1,685 IU/g) and laccase (2.04-fold, 2,270 nkat/g) was observed under optimized conditions viz. pH (10.5), inoculum size (10 + 10 %) and moisture:substrate ratio (0.8:1). Both the enzymes showed identical temperature and pH optima of 70 degrees C and 9, respectively, and were used for deinking of ONP pulp and biobleaching of kraft pulp. In case of ONP pulp deinking, the XL treatment increased brightness (11.8 %), freeness (17.8 %), breaking length (34.8 %), burst factor (2.77 %) and tear factor (2.4 %). In case of kraft pulp biobleaching, XL treatment showed a significant increase in brightness (13 %), whiteness (106.15 %) breaking length (49 %), burst factor (6.9 %), tear factor (23 %), and viscosity (11.68 %) and reduction in kappa number (15 %) after alkali extraction and peroxide stage. This enhancement of pulp properties revealed a synergistic effect of xylanase and laccase produced in one setup. PMID- 25533043 TI - Correlation between umbilical cord hemoglobin and rate of jaundice requiring phototherapy in healthy newborns. AB - BACKGROUND: Delay of umbilical cord clamping by at least 1 min is recommended for newborns not requiring resuscitation in the International Liaison Committee On Resuscitation-Consensus on Science with Treatment Recommendations (ILCOR-CoSTR) 2010 guidelines. The delay in clamping improves iron status through early infancy but may increase the likelihood of jaundice requiring phototherapy. The present study investigated the relationship between umbilical cord hemoglobin and the rate of jaundice requiring phototherapy in healthy Japanese newborns. METHODS: Cord hemoglobin was measured in healthy newborns and the rate of infants receiving phototherapy for jaundice and other data were obtained from medical records. RESULTS: Jaundice requiring phototherapy mostly occurred in association with high cord blood hemoglobin, which is increased by delayed cord clamping. CONCLUSIONS: Higher cord hemoglobin may increase neonatal jaundice in newborns in Japan, therefore the present results support the Japan Resuscitation Council guideline 2010, which does not recommend delay of umbilical cord clamping by at least 1 min, in contrast to the ILCOR guidelines. PMID- 25533042 TI - Overproduction of laccase from a newly isolated Ganoderma lucidum using the municipal food waste as main carbon and nitrogen supplement. AB - A strain of Ganoderma lucidum was separated and identified according to its morphological characteristics and phylogenetic data. The fungus is a laccase producer and it can secrete laccase using the municipal food waste (FW) as carbon and nitrogen supplement. After the statistic optimization, a laccase activity of 42,000 +/- 600 U/l was obtained at 500 ml flask level and the activity is 12,000 U/l higher than that obtained by fermenting glucose and peptone, indicating that the use of FW to produce laccase not only reduces production cost, but also improves laccase activity. In 15 l bioreactor, FW is also suitable for laccase production and the maximum laccase activity reached 54,000 U/l. Moreover, some details of laccase overproduction using FW were investigated. The G. lucidum consumes FW by secreting a series of hydrolases and proteases and the improvement of laccase activity is because FW induces over-expression of three isoenzymes by polyacrylamide gel electrophoresis analysis. PMID- 25533044 TI - Tunable ferroelectric polarization and its interplay with spin-orbit coupling in tin iodide perovskites. AB - Ferroelectricity is a potentially crucial issue in halide perovskites, breakthrough materials in photovoltaic research. Using density functional theory simulations and symmetry analysis, we show that the lead-free perovskite iodide (FA)SnI3, containing the planar formamidinium cation FA, (NH2CHNH2)(+), is ferroelectric. In fact, the perpendicular arrangement of FA planes, leading to a 'weak' polarization, is energetically more stable than parallel arrangements of FA planes, being either antiferroelectric or 'strong' ferroelectric. Moreover, we show that the 'weak' and 'strong' ferroelectric states with the polar axis along different crystallographic directions are energetically competing. Therefore, at least at low temperatures, an electric field could stabilize different states with the polarization rotated by pi/4, resulting in a highly tunable ferroelectricity appealing for multistate logic. Intriguingly, the relatively strong spin-orbit coupling in noncentrosymmetric (FA)SnI3 gives rise to a co existence of Rashba and Dresselhaus effects and to a spin texture that can be induced, tuned and switched by an electric field controlling the ferroelectric state. PMID- 25533045 TI - Localization and expression profile of Group I and II Activators of G-protein Signaling in the kidney. AB - Activators of G-protein Signaling (AGS) are a family of accessory proteins that were discovered as modulators of heterotrimeric G-protein subunits. The primary aim of the present study was to localize Group I and II AGS proteins and determine the renal expression profile using immunohistochemistry and quantitative RT-PCR, respectively, during normal and injured states of the kidney. Group I AGS1 was found to be predominantly localized to the proximal tubule, Group II AGS3 and AGS5 were exclusively localized to the distal tubular segments, and Group II AGS6 was ubiquitously expressed in every nephron segment of the rodent kidney. In rat kidneys following ischemia-reperfusion injury (IRI), Group I AGS1 mRNA was dramatically increased after 24 h by fivefold (P < 0.05), whereas Group II AGS3 and AGS4 mRNA was significantly decreased at the same time point (P < 0.05). No significant change in the transcript levels were detected at other time points for any of the AGS genes between control and IRI groups. In polycystic diseased kidneys, mRNA levels for AGS3, AGS4 and AGS6 was significantly increased (P < 0.05) by 75-80 % in PCK rat kidneys. The identification of Group I and II AGS mRNA and protein in the kidney may provide insight into the potential mechanism of action during normal and varying states of renal disease or injury. PMID- 25533047 TI - Screening for thyroid dysfunction and diabetes in patients with carpal tunnel syndrome. AB - BACKGROUND: Current literature demonstrates that patients with carpal tunnel syndrome (CTS) have a higher prevalence of hypothyroidism and diabetes. The British Society for Surgery of the Hand (BSSH) advises screening CTS patients for thyroid and glucose dysfunction before surgery. This study aimed to analyze the current departmental practice for patients listed for carpal tunnel decompression (CTD) with respect to preoperative assessment of diabetic and thyroid status. METHOD: A retrospective review of all patients who underwent surgery for CTS under one team over a 3 year period (2009-2011) in a UK teaching hospital was performed. Patients' medical records and pathology results were reviewed. RESULTS: A total of 103 procedures were performed in 100 patients. Preoperative thyroid function was checked in 63/100 patients with an abnormal result in 3/63 patients. Two of these patients were subsequently diagnosed with hypothyroidism. Similarly blood glucose was checked in 67/100 patients. This resulted in the new diagnosis of three patients with diabetes. CONCLUSION: The results are consistent with the view that CTS is associated with thyroid dysfunction and diabetes and screening helps in diagnosing new cases of these conditions in this select group. The cost of diagnosing new cases of hypothyroidism and diabetes can be considered as money well spent. PMID- 25533046 TI - An intrahepatic transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B. AB - BACKGROUND & AIMS: Differences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B (CHB) patients. METHODS: We employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48 weeks, and compared expression patterns of combined responders (HBeAg loss, HBV-DNA <2000 IU/ml, alanine aminotransferase normalization after 1 year of treatment-free follow-up) with non-responders. Genes identified by transcriptome analysis in 15 biopsies were confirmed in 25 additional biopsies by RT-qPCR. RESULTS: Transcriptome analysis demonstrated significant differences in expression of 41 genes between responders and non responders. In responders, pathway analysis showed specific upregulation of genes related to the immune response, including chemotaxis and antigen processing and presentation. Genes upregulated in responders exhibited strongest similarity with a set of genes induced in livers of chimpanzees with acute Hepatitis B infection. Differential expression was confirmed for eight selected genes. A 2-gene subset (HLA-DPB1, SERPIN-E1) was found to predict response most accurately. Incorporation of these genes in a multivariable model with HBeAg status, HBV genotype and baseline HBsAg level correctly classified 90% of all patients, in which HLA-DPB1 and SERPIN-E1 were independent predictors of response. CONCLUSION: We identified an intrahepatic transcriptional signature associated with enhanced immune activation which predicts therapy response. These novel associations could lead to better understanding of responsiveness to peginterferon in CHB patients, and may assist in selecting possible responders to interferon-based treatment. PMID- 25533048 TI - [Cardiogenic syncope]. AB - BACKGROUND: Cardiogenic syncope is a serious clinical event and the cause has to be clarified as rapidly and definitively as possible. DIAGNOSTICS: With knowledge of the pathophysiological background the reason for syncope can mostly be clarified by taking a thorough medical history. In most cases a physical examination, electrocardiogram (ECG) and echocardiography can provide sufficient evidence for most of the causes. Rhythmogenic syncope, however, often tends to be extremely difficult to diagnose which is why many different instruments have been developed for the detection of changes in heart rhythm. Several drugs can induce syncope by different modes of action and is the reason why particular attention should always be paid to this aspect. PMID- 25533049 TI - Which type of cane is the most efficient, based on oxygen consumption and balance capacity, in chronic stroke patients? AB - Canes are widely prescribed as walking aids, but little is known about the effects of canes on the physiological cost of walking. The purpose of this study was to investigate the differences in oxygen consumption associated with the gaits of hemiplegic patients in terms of balance capacity according to the type of cane used. Twenty-nine patients with chronic stroke were divided into poor balance (n=15) and relatively-better-balance groups (n=14) based on a cutoff score of 49 on the Berg balance scale (BBS). Each patient completed three consecutive days of walking with a randomly assigned singlepoint cane, quad cane, or hemi-walker. We measured the oxygen expenditure and oxygen cost using a portable gas analyzer and heart rate during a 6-min walk test (6MWT) and a 10-m walk test (10MWT). The oxygen expenditure, gait endurance, and gait velocity were higher with the single-point cane (p<0.01) than with any of the other cane types, and the oxygen costs were lower (p<0.01) with the single-point cane among the patients with relatively better balance. The oxygen cost for the quad cane was lower (p<0.01) than that found for any the other cane types among the patients with relatively poor balance. Our study revealed that single-point canes require less oxygen use at a given speed and permits greater speed at the same oxygen consumption for hemiplegic patients with good balance. Walking aids with a greater base support may be more suitable than those with a smaller base support for patients with relatively poor balance. However, our conclusions are only preliminary because of the small sample size (KCT0001076). PMID- 25533050 TI - A simple method to choose the most representative stride and detect outliers. AB - Kinematic data for gait analysis consists of joint angle curves plotted against percentages of the gait cycle. A typical gait analysis entails repeated measurement of the kinematic data. We present an automatic and computationally inexpensive method to choose the most representative curve and detect outliers amongst repeated curves. The method is based on the notion of depth, where the deepest curve is the equivalent to the median for univariate data. The method applies to single kinematic variable or multi-kinematic variables such as the gait profile. It is sensitive to both shape and position of the curves. A comparison with an existing statistical method is presented as well as an example on one patient's data. PMID- 25533051 TI - Anterior cervical discectomy with arthroplasty versus anterior cervical discectomy and fusion for cervical spondylosis. AB - This meta-analysis aims to estimate the benefits and drawbacks associated with anterior cervical discectomy with arthroplasty (ACDA) versus anterior cervical discectomy and fusion (ACDF) for cervical spondylosis. Of 3651 identified citations, 10 randomised controlled studies involving 2380 participants were included. Moderate quality evidence supports that patients in the ACDA group had: (1) a higher Neck Disability Index (NDI) success rate at 3 month (relative risk [RR]=0.85, 95% confidence interval [CI] 0.78 to 0.93, p=0.0002) and 2 year follow up (RR=0.95, 95%CI 0.91 to 1.00, p=0.04); (2) greater neurological success at 2 year follow-up (RR=0.95, 95%CI 0.92 to 0.98); and (3) were more likely to be employed within 6 weeks after surgery (RR=0.80 95%CI 0.66 to 0.96). In summary, the current evidence indicates that ACDA is associated with a higher NDI success rate in the short and long-term as well as a higher neurological success rate. Patients who undergo ACDA may also have a greater likelihood of being employed in the short-term. However, all of the evidence reviewed is of moderate or low quality and the clinical significance often marginal or unclear. Additional data are needed to compare the benefits and limitations of ACDA and ACDF. PMID- 25533052 TI - Leptomeningeal rheumatoid nodules: diagnosis and failed therapeutics. AB - A 67-year-old woman presented with recurrent transient ischaemic attack-like episodes over a 2 year period. Nodular enhancing leptomeningeal changes were detected on MRI and were consistent with meningeal rheumatoid nodules on biopsy. The patient's nodular disease continued to progress and regress clinically and radiologically irrespective of disease modifying agents and peripheral and serological rheumatoid arthritis control. This patient's unique presentation and diagnostic work-up is discussed alongside the dilemma of therapeutic management of meningeal rheumatoid nodules. PMID- 25533053 TI - Radiosurgery for brain metastases and cerebral edema. AB - The objective of this study was to assess reduction in cerebral edema following linear accelerator radiosurgery (LINAC) as first line therapy for brain metastasis. We reviewed the medical records of all patients who underwent LINAC radiosurgery for brain metastasis at our institution during 2010-2012, and who had not previously undergone either surgery or whole brain radiotherapy. Data were analyzed for 55 brain metastases from 46 patients (24 males), mean age 59.9 years. During the 2 months following LINAC radiosurgery, the mean steroid dose decreased from 4.8 to 2.6 mg/day, the mean metastasis volume decreased from 3.79+/-4.12 cc to 2.8+/-4.48 cc (p=0.001), and the mean edema volume decreased from 16.91+/-30.15 cc to 12.85+/-24.47 cc (p=0.23). The 17 patients with reductions of more than 50% in brain edema volume had single metastases. Edema volume in the nine patients with two brain metastases remained stable in five patients (volume change <10%, 0-2 cc) and increased in four patients (by >10%, 2 14 cc). In a subanalysis of eight metastases with baseline edema volume greater than 40 cc, edema volume decreased from 77.27+/-37.21 cc to 24.84+/-35.6 cc (p=0.034). Reductions in brain edema were greater in metastases for which non small-cell lung carcinoma and breast cancers were the primary diseases. Overall, symptoms improved in most patients. No patients who were without symptoms or who had no signs of increased intracranial pressure at baseline developed signs of intracranial pressure following LINAC radiosurgery. In this series, LINAC stereotactic radiosurgery for metastatic brain lesions resulted in early reduction in brain edema volume in single metastasis patients and those with large edema volumes, and reduced the need for steroids. PMID- 25533054 TI - Mitochondrial potential (DeltaPsim) changes in single rat hepatocytes: the effect of orthovanadate nanoparticles doped with rare-earth elements. AB - Rare-earth-based nanoparticles (NPs) are widely used as fluorescent probes for imaging in vitro and in vivo. One of the challenges that restrain NPs applications in biomedical research is their effect on subcellular structures. In this paper, the ability of lanthanide NPs to affect the cellular oxidative balance and alter the mitochondrial function was analyzed. Since size and shape mutually affect the cellular internalization and intracellular distribution of NPs, the investigations were performed with NPs of spherical (GdYVO4:Eu(3+), spindle-(GdVO4: Eu(3+) and rod-like (LaVO4: Eu(3+) shapes. Quantitative microfluorimetry with JC-1 (5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolocarbocyanine iodide) as a mitochondrial probe was used for monitoring of the mitochondrial transmembrane potential (DeltaPsi m) in single living cells. Changes in the ratio of the JC-1 probe fluorescence were used to analyze the NPs effect on DeltaPsi(m). The fastest suppressive effect (within 1 hour) was found for spherical NPs. Gradual lowering of DeltaPsi(m) was observed at the exposure of cells within 24 hours for all types of NPs. Exogenous thiols were required for DeltaPsi(m) protection. The protective role of exogenous glutathione (GSH) proves that the increase of reactive oxygen species (ROS) formation with depletion of GSH can mediate NPs toxicity. The dynamics of the shape-dependent effect can be explained by the features of NPs transportation into cells. PMID- 25533055 TI - Setting the stage for the AJO-DO: the haphazard times before orthodontic specialty journals. AB - The professional distinction of "surgeon-dentist," created in France in the 18th century, stimulated dentistry's early advance as a learned profession. By 1841, Pierre-Joachim Lefoulon coined the term "orthodontosie," which was the root of "orthodontics and dentofacial orthopedics" as a distinct academic field and a specialty. In 1907, the American Orthodontist became the first scientific journal in the world completely devoted to orthodontics. Its failure after 5 years of publication prompted former editor Martin Dewey to find a new publisher for an orthodontic specialty journal. In 1915, the International Journal of Orthodontia was created with Dewey as editor. After some years, its name was changed to the American Journal of Orthodontics, which later became the American Journal of Orthodontics and Dentofacial Orthopedics, or AJO-DO. Today, the AJO-DO at 100 years is a mainstay of scientific advancement in orthodontics. PMID- 25533056 TI - January 1, 1915, revisited. PMID- 25533057 TI - Orthodontics-a vocation I love! PMID- 25533058 TI - Prediction of 3-dimensional pharyngeal airway changes after orthognathic surgery: a methodological issue. PMID- 25533059 TI - Authors' response. PMID- 25533060 TI - Treatment effectiveness of the Frankel function regulator on Class III malocclusion. PMID- 25533061 TI - Authors' response. PMID- 25533063 TI - Author's response. PMID- 25533062 TI - CBCT volumetric analyses have no value in assessing functional airway. PMID- 25533064 TI - Authors' response. PMID- 25533065 TI - Perceptions of midline deviations among different facial types. PMID- 25533066 TI - A case for collaboration. PMID- 25533068 TI - Late adult skeletofacial growth after adolescent Herbst therapy: a 32-year longitudinal follow-up study. AB - INTRODUCTION: The aim of this longitudinal 32-year follow-up investigation was to analyze the very long-term effects of Herbst treatment on the dentoskeletal structures. We followed 14 patients from a sample of 22 with Class II Division 1 malocclusions who were consecutively treated with the banded Herbst appliance at ages 12 to 14 years. The subjects were reexamined after therapy at the ages of 20 years (when the radius epiphysis/diaphysis plate was closed) and 46 years. METHODS: Lateral head films were analyzed from before (T1) and after (T2) treatment, and at 6 years (T3) and 32 years (T4) after treatment. RESULTS: (1) In the standard analysis (angular measurements) during the T2 to T3 period of 6 years, significant skeletal changes were the following: increase of the SNB (1.0 degrees ; P <0.01), decrease of the ANB (0.9 degrees ; P <0.01), and decrease of the ML/NSL (2.5 degrees ; P <0.001). During the T3 to T4 period of 24 years, no further significant angular changes occurred. (2) In the analysis of the sagittal changes in the occlusion (linear measurements) during the T2 to T3 period of 6 years, the mandible (6.1 mm; P <0.001) and the maxilla (3.0 mm; P <0.01) grew forward. During the T3 to T4 period of 24 years, the mandible (2.8 mm; P <0.01) and the maxilla (3.1 mm; P <0.01) continued to grow forward. Thus, during the total posttreatment (T2-T4) period of 32 years, there was continuous forward growth of the mandible (8.9 mm; P <0.001) and the maxilla (6.1 mm; P <0.001). (3) The analysis of superimposed lateral head films showed in all 14 subjects large amounts of sagittal and vertical skeletofacial growth during T3 to T4. CONCLUSIONS: In all 14 subjects, large amounts of sagittal and vertical skeletofacial growth occurred after the age of 20 years. However, the question of when, during the period from 20 to 46 years, growth had come to an end remains open. Closure of the radius epiphysis/diaphysis plate is not useful as an indicator for completed skeletofacial growth. Our findings indicate the importance of considering late adult skeletofacial growth in dentofacial orthopedics, orthognathic surgery, and tooth implantology with respect to treatment timing, posttreatment retention, and relapse. PMID- 25533069 TI - Bisphenol A release from orthodontic adhesives and its correlation with the degree of conversion. AB - INTRODUCTION: Our objective was to quantitatively assess and compare the bisphenol A (BPA) released from an orthodontic adhesive using a light-emitting diode device (LED) or a halogen light-curing unit (HLC) at 3 tip-to-bracket distances (0, 5, and 10 mm) and varying curing times using high-performance liquid chromatography. BPA release with self-etching and moisture-insensitive primers with light-cured and chemically cured composites was also evaluated. BPA release was correlated to the corresponding degree of conversion. METHODS: Our sample consisted of 598 stainless steel first premolar brackets. Of these, 520 were used for assessing BPA release and divided into 13 groups of 40 each. In groups I, II, and III, the composite was cured with the LED for 20 seconds at distances of 0, 5, and 10 mm, respectively. Groups IV, V, and VI were cured with the HLC for 40 seconds at the same 3 distances. Groups VII and VIII were cured for 5 and 10 seconds with the LED, and groups IX and X were cured for 10 and 20 seconds with the HLC at 0-mm distance. Groups XI, XII, and XIII consisted of brackets bonded with a self-etching primer and Transbond (3M Unitek, Monrovia, Calif), with a moisture-insensitive primer and Transbond, and with a chemically cured composite. The remaining 78 brackets were also divided into 13 groups and used for assessing the degree of conversion. RESULTS: The LED devices demonstrated significantly less BPA release and greater degrees of conversion (P <0.05). For both units, BPA release increased and the degree of conversion decreased as the tip distance increased and curing time decreased. The chemically cured group showed significantly less BPA release (P <0.05). Among the light cured composites, those cured according to the manufacturers' recommendations (40 seconds and 0-mm distance for the HLC unit) released less BPA than did the self etching primer and the moisture-insensitive primer. The degree of conversion was greatest for the chemically cured composite, whereas it was similar for the conventional, self-etching primer, and moisture-insensitive primer groups. However, correlations ranged from strongly negative to weakly positive between BPA release and degree of conversion. CONCLUSIONS: Clinicians should consider using LEDs in clinical practice and should keep the light-cure tip as close to the bracket as clinically possible. Curing time should be according to the manufacturer's recommendations. These steps will ensure less BPA release and a greater degree of conversion. Since chemically cured composites had less BPA release and a greater degree of conversion, they can be considered superior to light-cured composites in this aspect. PMID- 25533070 TI - Relationship between mandibular dental and basal bone arch forms for severe skeletal Class III patients. AB - INTRODUCTION: The purpose of this study was to analyze the relationship between the mandibular dental and basal bone arch forms for severe skeletal Class III patients by using 3-dimensional digital models. METHODS: Thirty-three virtual pretreatment mandibular models were created with a laser scanning system. The most prominent part of the center of the clinical crown where an orthodontic bracket would be placed (FA) and the most prominent point on the soft-tissue ridge at the mucogingival junction (WALA) were used to represent the dental and basal arch forms, respectively. RESULTS: A moderate-to-high correlation between the FA and WALA curves was found, especially in the canine (r = 0.61) and molar (r = 0.91) areas. The WALA curve's radius of curvature in the anterior teeth areas was greater than that of the FA curve (WALA, 22.47; FA, 18.18). In the canine and molar areas, the coefficients of variation of FA (6.70%, 6.01%, 15.30%, and 9.97%) were greater than those of WALA (5.42%, 3.88%, 8.53%, and 7.22%). For the FA and WALA points, the coefficients of variation of the canine area were greater than those of the molar area. CONCLUSIONS: Both curves were individualized. A moderate-to-high correlation was found between the dental and basal bone arch forms. Compared with the WALA points, the FA points are located more lingually. The individual differences were found to be significantly greater in the canine region. PMID- 25533071 TI - Influence of bone architecture on the primary stability of different mini-implant designs. AB - INTRODUCTION: Mechanical interlocking between a mini-implant (MI) and the bone substrate reflects directly on the primary stability achieved. The purposes of this study were to evaluate MI design performance in distinct bone substrates and correlate geometric characteristics with insertion site quality. METHODS: Two types of self-drilling MIs (1.6 * 8 mm) were allocated to 2 groups according to their geometric designs: Tomas system (Dentaurum, Ispringen, Germany) and Dual Top (Rocky Mountain Orthodontics, Denver, Colo). Forty sections (8 * 10 mm) were taken from bovine pelvic ilium and pubic bone. Geometric design characteristics were evaluated using scanning electron microscope imaging and Image-Pro Insight software (Media Cybernetics, Rockville, Md). Bone quality parameters were assessed with a microcomputed tomography system, and primary stability was evaluated by insertion torque and pull-out strength. Intergroup comparisons were performed with analysis of variance and Tukey tests, and the Pearson correlation test was carried out (P <0.05). RESULTS: No significant difference was observed in the comparisons of the groups (Tomas: insertion torque, 12.87 N.cm; pull-out strength, 181 N; and Dual-Top: insertion torque, 9.95 N.cm; pull-out strength, 172.5 N) in the ilium. However, the Tomas group had a marked increase in insertion torque (25.08 N.cm; P <0.05) in the pubic bone. CONCLUSIONS: MI mechanical performance differed according to bone quality parameters, indicating that certain geometric parameters may be set depending on the insertion substrate. PMID- 25533072 TI - Predisposing factors for severe incisor root resorption associated with impacted maxillary canines. AB - INTRODUCTION: Severe incisor root resorption (SIRR) associated with impacted maxillary canines is rare but has important implications. Early diagnosis and treatment are imperative. In this investigation, we aimed to identify predisposing factors for impacted canine-linked SIRR. METHODS: Clinical and radiographic data of 55 consecutive patients (77 canines) with SIRR of 96 incisors were compared with data from 57 consecutive control subjects (72 canines). The studied variables were age, sex, position of the impacted canine, size of the dental follicle, and incidence of anomalous lateral incisors. RESULTS: Lateral incisors were more often affected than central incisors, and bilateral SIRR was common. When each variable was examined separately, SIRR was significantly associated with female sex, severely mesiodistally displaced and vertically positioned canines in the middle third of the adjacent incisor root, dental follicles wider than 2 mm, and normal lateral incisors. The multivariate statistical analysis showed that the risk for SIRR was significantly higher in female subjects (4.2 times) with enlarged dental follicles (8.3 times) and normal lateral incisors (5.8 times). CONCLUSIONS: SIRR should be carefully screened in female patients with enlarged dental follicles and normal lateral incisors. A greater degree of canine displacement might also be associated with SIRR. PMID- 25533073 TI - Cone-beam computed tomography evaluation of dentoskeletal changes after asymmetric rapid maxillary expansion. AB - INTRODUCTION: The aims of this study were to quantitatively evaluate the changes in arch widths and buccolingual inclinations of the posterior teeth after asymmetric rapid maxillary expansion (ARME) and to compare the measurements between the crossbite and the noncrossbite sides with cone-beam computed tomography (CBCT). METHODS: From our clinic archives, we selected the CBCT records of 30 patients with unilateral skeletal crossbite (13 boys, 14.2 +/- 1.3 years old; 17 girls, 13.8 +/- 1.3 years old) who underwent ARME treatment. A modified acrylic bonded rapid maxillary expansion appliance including an occlusal locking mechanism was used in all patients. CBCT records had been taken before ARME treatment and after a 3-month retention period. Fourteen angular and 80 linear measurements were taken for the maxilla and the mandible. Frontally clipped CBCT images were used for the evaluation. Paired sample and independent sample t tests were used for statistical comparisons. RESULTS: Comparisons of the before-treatment and after-retention measurements showed that the arch widths and buccolingual inclinations of the posterior teeth increased significantly on the crossbite side of the maxilla and on the noncrossbite side of the mandible (P <0.05). Comparison of the 2 sides showed statistically significant differences in both the maxilla and the mandible (P <0.05). CONCLUSIONS: After ARME treatment, the crossbite side of the maxilla and the noncrossbite side of the mandible were more affected than were the opposite sides. PMID- 25533074 TI - Influence of temporomandibular joint disc displacement on craniocervical posture and hyoid bone position. AB - INTRODUCTION: The purpose of this study was to evaluate craniocervical posture and hyoid bone position in orthodontic patients with temporomandibular joint (TMJ) disc displacement. METHODS: The subjects consisted of 170 female orthodontic patients who consented to bilateral magnetic resonance imaging of their TMJs. They were divided into 3 groups based on the results of magnetic resonance imaging of their TMJs: bilateral normal disc position, bilateral disc displacement with reduction, and bilateral disc displacement without reduction. Twenty-five variables from lateral cephalograms were analyzed with 1-way analysis of variance to investigate differences in craniocervical posture and hyoid bone position with respect to TMJ disc displacement status. Pearson correlation coefficients were calculated to analyze the relationships between craniofacial morphology and craniocervical posture or hyoid bone position. RESULTS: Subjects with TMJ disc displacement were more likely to have an extended craniocervical posture with Class II hyperdivergent patterns. The most significant differences were found between patients with bilateral normal disc position and bilateral disc displacement without reduction. However, hyoid bone position in relation to craniofacial references was not significantly different among the TMJ disc displacement groups, except for variables related to the mandible. Pearson correlation coefficients indicated that extended craniocervical posture was significantly correlated with backward positioning and clockwise rotation of the mandible. CONCLUSIONS: This suggests that craniocervical posture is significantly influenced by TMJ disc displacement, which may be associated with hyperdivergent skeletal patterns with a retrognathic mandible. PMID- 25533075 TI - Impact of local steroid or statin treatment of experimental temporomandibular joint arthritis on bone growth in young rats. AB - INTRODUCTION: Juvenile idiopathic arthritis in temporomandibular joints (TMJs) is often treated with intra-articular steroid injections, which can inhibit condylar growth. The purpose of this study was to compare simvastatin (a cholesterol lowering drug that reduces TMJ inflammation) with the steroid triamcinolone hexacetonide in experimental TMJ arthritis. METHODS: Joint inflammation was induced by injecting complete Freund's adjuvant (CFA) into the TMJs of 40 growing Sprague Dawley rats; 4 other rats were left untreated. In the same intra articular injection, one of the following was applied: (1) 0.5 mg of simvastatin in ethanol carrier, (2) ethanol carrier alone, (3) 0.15 mg of triamcinolone hexacetonide, (4) 0.5 mg of simvastatin and 0.15 mg of triamcinolone hexacetonide, or (5) nothing additional to the CFA. The animals were killed 28 days later, and their mandibles were evaluated morphometrically and with microcomputed tomography. RESULTS: The analysis showed that the TMJs subjected to CFA alone had decreased ramus height compared with those with no treatment (P <0.05). Groups that had injections containing the steroid overall had decreases in weight, ramus height, and bone surface density when compared with the CFA alone group (P <0.0001). Groups that had injections containing simvastatin, however, had overall increases in weight (P <0.0001), ramus height (P <0.0001), condylar width (P <0.05), condylar bone surface density (P <0.05), and bone volume (P <0.0001) compared with the groups receiving the steroid injections, and they were not different from the healthy (no treatment) group. CONCLUSIONS: Treatment of experimentally induced arthritis in TMJs with intra-articular simvastatin preserved normal condylar bone growth. PMID- 25533076 TI - Internet discussion forums, an information and support resource for orthognathic patients. AB - INTRODUCTION: Orthognathic patients appear to be increasingly using the Internet to obtain information about their proposed treatment. The aim of this study was to investigate the information that orthognathic patients share and discuss with peers away from the clinical environment to improve the provision of information for orthognathic patients. METHODS: Posts made by persons in a large publicly accessible online orthognathic discussion forum were analyzed; 1912 randomly selected forum posts were evaluated using a qualitative analysis technique known as "thematic analysis" that involves coding the posts and collating them into meaningful and distinct themes. RESULTS: The main themes identified were (1) reasons for undergoing orthognathic treatment, (2) presurgery and postsurgery treatment stages including orthodontics, (3) surgery including postsurgical complications and difficulties, (4) expected and actual end of treatment changes, and (5) seeking and sharing information. CONCLUSIONS: This study demonstrates that orthognathic patients look to the Internet to supplement information regarding their proposed treatment. This may suggest a possible gap in the provision of information by health care professionals. However, it is clear that patients use Internet forums to seek additional information, support, and reassurance from peers undergoing similar treatment. Therefore, there is a need for clinicians to ensure that patients have access and are guided to appropriate and relevant Internet resources. PMID- 25533077 TI - Bimaxillary protrusion with an atrophic alveolar defect: orthodontics, autogenous chin-block graft, soft tissue augmentation, and an implant. AB - Bimaxillary protrusion in a 28-year-old woman was complicated by multiple missing, restoratively compromised, or hopeless teeth. The maxillary right central incisor had a history of avulsion and replantation that subsequently evolved into generalized external root resorption with Class III mobility and severe loss of the supporting periodontium. This complex malocclusion had a discrepancy index of 21, and 8 additional points were scored for the atrophic dental implant site (maxillary right central incisor). The comprehensive treatment plan included extraction of 4 teeth (both maxillary first premolars, the maxillary right central incisor, and the mandibular right first molar), orthodontic closure of all spaces except for the future implant site (maxillary right central incisor), augmentation of the alveolar defect with an autogenous chin-block graft, enhancement of the gingival biotype with a connective tissue graft, and an implant-supported prosthesis. Orthodontists must understand the limitations of bone grafts. Augmented alveolar defects are slow to completely turn over to living bone, so they are usually good sites for implants but respond poorly to orthodontic space closure. However, postsurgical orthodontic treatment is often indicated to optimally finish the esthetic zone before placing the final prosthesis. The latter was effectively performed for this patient, resulting in a total treatment time of about 36 months for comprehensive interdisciplinary care. An excellent functional and esthetic result was achieved. PMID- 25533078 TI - Comprehensive treatment approach for bilateral cleft lip and palate in an adult with premaxillary osteotomy, tooth autotransplantation, and 2-jaw surgery. AB - We report the successful treatment of a woman aged 25 years 3 months with bilateral cleft lip and palate. She had a protruded premaxilla, collapsed posterior segments, wide alveolar defects with oronasal fistulae, a congenital missing tooth, and severe facial asymmetry with a transverse occlusal cant. The comprehensive treatment approach included (1) premaxillary osteotomy combined with alveolar bone grafting to reposition the premaxilla and minimize the wide alveolar defects, (2) autotransplantation of a tooth with complete root formation to the grafted bone region to restore the missing tooth without a prosthesis such as a dental implant or bridge, and (3) 2-jaw surgery to improve facial asymmetry. The premaxillary osteotomy was managed orthodontically, in combination with bone grafting. The results suggest that surgical orthodontic treatment with tooth autotransplantation might be useful to improve the occlusion and facial esthetics without prosthetics. PMID- 25533079 TI - Incidental findings of skull-base abnormalities in cone-beam computed tomography scans with consultation by maxillofacial radiologists. AB - INTRODUCTION: Cone-beam computed tomography (CBCT) gives orthodontists and other dental clinicians 3-dimensional information for planning treatment in the craniofacial region. Often overlooked are incidental findings outside the treatment region of interest. METHODS: Two patients with incidental findings of skull-base abnormalities are presented. The orthodontic patient was tentatively diagnosed with a notochordal remnant in the clivus; the implant patient exhibited an empty sella turcica. RESULTS: For the clivus lesion in the orthodontic patient, an artifact was ruled out after a second CBCT image and further distinguished from a fat-containing tumor after magnetic resonance imaging. The impression after magnetic resonance imaging was a notochordal remnant, although chordoma was also included in the differential, warranting a 6-month follow-up magnetic resonance image to confirm the diagnosis. The CBCT study for the implant patient demonstrated an enlarged sella turcica. The impression after the magnetic resonance imaging was an enlarged and partially empty sella with no evidence of a pituitary mass. CONCLUSIONS: Orthodontists and implant surgeons may come across incidental findings outside their area of expertise on CBCT scans, highlighting the importance of appropriate consultation with maxillofacial radiologists. Notochordal remnants may present as nonexpansile intraosseous low-density areas. The challenge in distinguishing these lesions radiographically with chordomas warrants follow-up to confirm a diagnosis. An empty sella is a noteworthy finding because of its potential for endocrine and neuro-ophthalmological disorders despite an asymptomatic presentation. PMID- 25533081 TI - Litigation and legislation. You secretly did what? PMID- 25533080 TI - Three-dimensional monitoring of root movement during orthodontic treatment. AB - INTRODUCTION: A significant objective of orthodontic treatment is to achieve proper and stable tooth positions that involve not only the crowns, but also their roots. However, the current methods of clinically monitoring root alignment are unreliable and inaccurate. Therefore, the purpose of this study was to develop a methodology that can accurately identify root position in a clinical situation. METHODS: Pretreatment and posttreatment cone-beam computed tomography (CBCT) and extraoral laser scans of study models of a patient were obtained. Threshold segmentation of the CBCT scans was performed, resulting in 3 dimensional surface models. The pretreatment CBCT teeth were isolated from their respective arches for individual tooth manipulation. These isolated pretreatment CBCT teeth were superimposed onto the posttreatment surface scan depicting the expected root position setup. To validate the accuracy of the expected root position setup, it was compared with the true root position represented by the posttreatment CBCT scan. Color displacement maps were generated to measure any differences between the expected and true root positions. RESULTS: Color map analysis through crown superimposition showed displacement differences of 0.148 +/- 0.411 mm for the maxillary roots and 0.065 +/- 0.364 mm for the mandibular roots. CONCLUSIONS: This methodology has been demonstrated to be an accurate and reliable approach to visualize the 3-dimensional positions of all teeth, including the roots, with no additional radiation applied. PMID- 25533082 TI - Sample-size calculation for repeated-measures and longitudinal studies. PMID- 25533083 TI - Iron-sulfur proteins responsible for RNA modifications. AB - RNA molecules are decorated with various chemical modifications, which are introduced post-transcriptionally by RNA-modifying enzymes. These modifications are required for proper RNA function. Among more than 100 known species of RNA modifications, several modified bases in tRNAs and rRNAs are introduced by RNA modifying enzymes containing iron-sulfur (Fe/S) clusters. Most Fe/S-containing RNA-modifying enzymes contain radical SAM domains that catalyze a variety of chemical reactions, including methylation, methylthiolation, carboxymethylation, tricyclic purine formation, and deazaguanine formation. Lack of these modifications can cause pathological consequences. Here, we review recent studies on the biogenesis and function of RNA modifications mediated by Fe/S proteins. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25533084 TI - Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner. AB - Onconase(r) (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinical trials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yet been fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreatic adenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates a strong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggers Beclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrial uncoupling protein 2 (UCP2) and of manganese dependent superoxide dismutase (MnSOD) triggering mitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagic stimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediated cytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells to the standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used in combination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our results shed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and support its potential use to develop new anticancer strategies. PMID- 25533086 TI - In-situ and tunable nitrogen-doping of MoS2 nanosheets. AB - Molybdenum disulfide (MoS2) nanosheets have unique physical and chemical properties, which make it a perfect candidate for next generation electronic and energy storage applications. Herein, we show the successful synthesis of nitrogen doped MoS2 nanosheets by a simple, effective and large-scale approach. MoS2 nanosheets synthesised by this method show a porous structure formed by curled and overlapped nanosheets with well-defined edges. Analysis of the nanosheets shows that they have an enlarged interlayer distance and high specific surface area. X-ray photoelectron spectroscopy analysis shows the nanosheets have Mo-N bond indicating successful nitrogen doping. The nitrogen content of the product can be modulated by adjusting the ratio of starting materials easily within the range from ca. 5.8 to 7.6 at%. PMID- 25533085 TI - Coarse particulate matter and emergency ambulance dispatches in Fukuoka, Japan: a time-stratified case-crossover study. AB - OBJECTIVES: There is no conclusive evidence of adverse health effects caused by short-term exposure to coarse particulate matter, so in this case-crossover study we looked for an association between exposure and emergency ambulance dispatches (as a proxy of acute health outcomes). METHODS: We used data on emergency ambulance dispatches in Fukuoka City, Japan between 2005 and 2010. After excluding ambulance dispatches related to external injuries and pregnancy/childbirth, we analyzed data on 176,123 dispatches. Citywide daily mean concentrations of suspended particulate matter (SPM) and fine particulate matter (PM2.5) were calculated from ambient monitoring data, and the differences between concentrations of SPM and PM2.5 were used as an exposure surrogate of coarse particulate matter. Using a conditional logistic regression model, we estimated the ambient temperature and relative humidity adjusted odds ratios (ORs) per 10 MUg/m(3) increase in coarse particulate matter. RESULTS: The average daily concentration of coarse particulate matter over the study period was 9.9 MUg/m(3), representing 33% of the total concentration of SPM. Elevated concentrations of coarse particulate matter were associated with an increase in respiratory disease-related emergency ambulance dispatches for adults aged 65 years or older (9,716 dispatches, OR for lag0-1 = 1.065, 95% confidence interval = 1.023-1.109). After additional adjustment for exposure to PM2.5, we observed a statistically non-significant increased risk (OR = 1.035, 0.986-1.086). CONCLUSIONS: We found weak evidence of adverse effects of short-term exposure to coarse particulate matter on human health. PMID- 25533087 TI - Cell adhesion century: culture breakthrough. PMID- 25533090 TI - The functional significance of density and distribution of outgrowths on co-opted contact pairs in biological arresting systems. AB - Microstructures responsible for temporary arresting of contacting surfaces are widely distributed on surfaces in different organisms. Recent morphological studies show that these structures have different density of outgrowths and not ideal distribution pattern on both complementary parts of the contact. One can suggest that this difference is optimized by natural selection to get stronger mechanical arrest within the system. In this paper, we simulate such a system numerically, both in the frames of continuous contact and discrete dynamical models to prove this hypothesis and elucidate other aspects of optimization of such mechanical adhesive systems. PMID- 25533089 TI - Force fluctuations in three-dimensional suspended fibroblasts. AB - Cells are sensitive to mechanical cues from their environment and at the same time generate and transmit forces to their surroundings. To test quantitatively forces generated by cells not attached to a substrate, we used a dual optical trap to suspend 3T3 fibroblasts between two fibronectin-coated beads. In this simple geometry, we measured both the cells' elastic properties and the force fluctuations they generate with high bandwidth. Cell stiffness decreased substantially with both myosin inhibition by blebbistatin and serum-starvation, but not with microtubule depolymerization by nocodazole. We show that cortical forces generated by non-muscle myosin II deform the cell from its rounded shape in the frequency regime from 0.1 to 10 Hz. The amplitudes of these forces were strongly reduced by blebbistatin and serum starvation, but were unaffected by depolymerization of microtubules. Force fluctuations show a spectrum that is characteristic for an elastic network activated by random sustained stresses with abrupt transitions. PMID- 25533088 TI - Scaling and biomechanics of surface attachment in climbing animals. AB - Attachment devices are essential adaptations for climbing animals and valuable models for synthetic adhesives. A major unresolved question for both natural and bioinspired attachment systems is how attachment performance depends on size. Here, we discuss how contact geometry and mode of detachment influence the scaling of attachment forces for claws and adhesive pads, and how allometric data on biological systems can yield insights into their mechanism of attachment. Larger animals are expected to attach less well to surfaces, due to their smaller surface-to-volume ratio, and because it becomes increasingly difficult to distribute load uniformly across large contact areas. In order to compensate for this decrease of weight-specific adhesion, large animals could evolve overproportionally large pads, or adaptations that increase attachment efficiency (adhesion or friction per unit contact area). Available data suggest that attachment pad area scales close to isometry within clades, but pad efficiency in some animals increases with size so that attachment performance is approximately size-independent. The mechanisms underlying this biologically important variation in pad efficiency are still unclear. We suggest that switching between stress concentration (easy detachment) and uniform load distribution (strong attachment) via shear forces is one of the key mechanisms enabling the dynamic control of adhesion during locomotion. PMID- 25533091 TI - The frequency and duration of Salmonella-macrophage adhesion events determines infection efficiency. AB - Salmonella enterica causes a range of important diseases in humans and a in a variety of animal species. The ability of bacteria to adhere to, invade and survive within host cells plays an important role in the pathogenesis of Salmonella infections. In systemic salmonellosis, macrophages constitute a niche for the proliferation of bacteria within the host organism. Salmonella enterica serovar Typhimurium is flagellated and the frequency with which this bacterium collides with a cell is important for infection efficiency. We investigated how bacterial motility affects infection efficiency, using a combination of population-level macrophage infection experiments and direct imaging of single cell infection events, comparing wild-type and motility mutants. Non-motile and aflagellate bacterial strains, in contrast to wild-type bacteria, collide less frequently with macrophages, are in contact with the cell for less time and infect less frequently. Run-biased Salmonella also collide less frequently with macrophages but maintain contact with macrophages for a longer period of time than wild-type strains and infect the cells more readily. Our results suggest that uptake of S. Typhimurium by macrophages is dependent upon the duration of contact time of the bacterium with the cell, in addition to the frequency with which the bacteria collide with the cell. PMID- 25533092 TI - Antiviral adhesion molecular mechanisms for influenza: W. G. Laver's lifetime obsession. AB - Infection by the influenza virus depends firstly on cell adhesion via the sialic acid-binding viral surface protein, haemagglutinin, and secondly on the successful escape of progeny viruses from the host cell to enable the virus to spread to other cells. To achieve the latter, influenza uses another glycoprotein, the enzyme neuraminidase (NA), to cleave the sialic acid receptors from the surface of the original host cell. This paper traces the development of anti-influenza drugs, from the initial suggestion by MacFarlane Burnet in 1948 that an effective 'competitive poison' of the virus' NA might be useful in controlling infection by the virus, through to the determination of the structure of NA by X-ray crystallography and the realization of Burnet's idea with the design of NA inhibitors. A focus is the contribution of the late William Graeme Laver, FRS, to this research. PMID- 25533093 TI - The role of cellular adhesion molecules in virus attachment and entry. AB - As obligate intracellular parasites, viruses must traverse the host-cell plasma membrane to initiate infection. This presents a formidable barrier, which they have evolved diverse strategies to overcome. Common to all entry pathways, however, is a mechanism of specific attachment to cell-surface macromolecules or 'receptors'. Receptor usage frequently defines viral tropism, and consequently, the evolutionary changes in receptor specificity can lead to emergence of new strains exhibiting altered pathogenicity or host range. Several classes of molecules are exploited as receptors by diverse groups of viruses, including, for example, sialic acid moieties and integrins. In particular, many cell-adhesion molecules that belong to the immunoglobulin-like superfamily of proteins (IgSF CAMs) have been identified as viral receptors. Structural analysis of the interactions between viruses and IgSF CAM receptors has not shown binding to specific features, implying that the Ig-like fold may not be key. Both proteinaceous and enveloped viruses exploit these proteins, however, suggesting convergent evolution of this trait. Their use is surprising given the usually occluded position of CAMs on the cell surface, such as at tight junctions. Nonetheless, the reason for their widespread involvement in virus entry most probably originates in their functional rather than structural characteristics. PMID- 25533094 TI - Study of interactions between polymer nanoparticles and cell membranes at atomistic levels. AB - Knowledge of how the structure of nanoparticles and the interactions with biological cell membranes is important not only for understanding nanotoxicological effects on human, animal health and the environment, but also for better understanding of nanoparticle fabrication for biomedical applications. In this work, we use molecular modelling techniques, namely molecular dynamics (MD) simulations, to explore how polymer nanoparticles interact with 1-palmitoyl 2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid cell membranes. Two different polymers have been considered: 100 monomer units of polyethylene (approx. 2.83 kDa) and polystyrene (approx. 10.4 kDa), both of which have wide industrial applications. We found that, despite the polar lipid head groups acting as an effective barrier to prevent the nanoparticles from interacting with the membrane surface, irreversible adhesion can be initiated by insertion of dangling chain ends from the polymer into the hydrophobic interior of the membrane. In addition, alignment of chain segments from the polymers with that of hydrocarbon chains in the interior of the membrane facilitates the complete immersion of the nanoparticles into the cell membrane. These findings highlight the importance of the surface and the topological structures of the polymer particles that dictate the absorption behaviour into the membrane and, subsequently, induce the possible translocation into the cell. PMID- 25533095 TI - Adsorption of surfactant protein D from human respiratory secretions by carbon nanotubes and polystyrene nanoparticles depends on nanomaterial surface modification and size. AB - The alveolar respiratory unit constitutes one of the main targets of inhaled nanoparticles; the effect of engineered nanomaterials (NMs) on human health is largely unknown. Surfactant protein D (SP-D) is synthesized by alveolar type II epithelial cells and released into respiratory secretions; its main function is in immune defence, notably against inhaled microbes. SP-D also plays an important role in modulating an appropriate inflammatory response in the lung, and reduced SP-D is associated with a number of inflammatory lung diseases. Adsorption of SP D to inhaled NMs may facilitate their removal via macrophage phagocytosis. This study addresses the hypothesis that the chemistry, size and surface modification of engineered NMs will impact on their interaction with, and adsorption of, SP-D. To this purpose, we have examined the interactions between SP-D in human lung lavage and two NMs, carbon nanotubes and polystyrene nanoparticles, with different surface functionalization. We have demonstrated that particle size, functionalization and concentration affect the adsorption of SP-D from human lung lavage. Functionalization with negatively charged groups enhanced the amount of SP-D binding. While SP-D binding would be expected to enhance macrophage phagocytosis, these results suggest that the degree of binding is markedly affected by the physicochemistry of the NM and that deposition of high levels of some nanoparticles within the alveolar unit might deplete SP-D levels and affect alveolar immune defence mechanisms. PMID- 25533096 TI - N-cadherin antagonists as oncology therapeutics. AB - The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N cadherin antagonists as anti-cancer drugs. PMID- 25533098 TI - Unique database study linking gingival inflammation and smoking in carcinogenesis. AB - We investigated statistical association between gingival inflammation and cancer in a group of patients followed up for 26 years with the hypothesis that gingival inflammation affects carcinogenesis. Altogether, 1676 30- to 40-year-old subjects from Stockholm were clinically examined in 1985. In 2011, we compared the baseline oral examination and follow-up data with cancer diagnoses sourced from the Swedish national hospital register databases. Of 1676 individuals, 89 (55 women, 34 men) had got cancer by the year 2011. Women were found to be at higher risk for cancer than men. Smoking (expressed in pack-years) had been more prevalent in the cancer group than in those with no cancer diagnosis. Gingival index, marker of gingival inflammation, was higher in the cancer group than in subjects with no cancer. There were no significant differences between the groups regarding age, education, dental plaque and calculus index scores, or in the number of missing teeth. In multiple logistic regression analysis with cancer as the dependent variable and several independent variables, pack-years of smoking appeared to be a principal independent predictor with odds ratio (OR) 1.32 while gingival inflammation showed OR 1.29. Hence, our present findings showed that together with smoking, gingival inflammation indeed associated with the incidence of cancer in this cohort. PMID- 25533097 TI - Advances in cell culture: anchorage dependence. AB - Anchorage-dependent cells are of great interest for various biotechnological applications. (i) They represent a formidable production means of viruses for vaccination purposes at very large scales (in 1000-6000 l reactors) using microcarriers, and in the last decade many more novel viral vaccines have been developed using this production technology. (ii) With the advent of stem cells and their use/potential use in clinics for cell therapy and regenerative medicine purposes, the development of novel culture devices and technologies for adherent cells has accelerated greatly with a view to the large-scale expansion of these cells. Presently, the really scalable systems--microcarrier/microcarrier-clump cultures using stirred-tank reactors--for the expansion of stem cells are still in their infancy. Only laboratory scale reactors of maximally 2.5 l working volume have been evaluated because thorough knowledge and basic understanding of critical issues with respect to cell expansion while retaining pluripotency and differentiation potential, and the impact of the culture environment on stem cell fate, etc., are still lacking and require further studies. This article gives an overview on critical issues common to all cell culture systems for adherent cells as well as specifics for different types of stem cells in view of small- and large-scale cell expansion and production processes. PMID- 25533101 TI - van der Waals forces influencing adhesion of cells. AB - Adhesion molecules, often thought to be acting by a 'lock and key' mechanism, have been thought to control the adhesion of cells. While there is no doubt that a coating of adhesion molecules such as fibronectin on a surface affects cell adhesion, this paper aims to show that such surface contamination is only one factor in the equation. Starting from the baseline idea that van der Waals force is a ubiquitous attraction between all molecules, and thereby must contribute to cell adhesion, it is clear that effects from geometry, elasticity and surface molecules must all add on to the basic cell attractive force. These effects of geometry, elasticity and surface molecules are analysed. The adhesion force measured between macroscopic polymer spheres was found to be strongest when the surfaces were absolutely smooth and clean, with no projecting protruberances. Values of the measured surface energy were then about 35 mJ m(-2), as expected for van der Waals attractions between the non-polar molecules. Surface projections such as abrasion roughness or dust reduced the molecular adhesion substantially. Water cut the measured surface energy to 3.4 mJ m(-2). Surface active molecules lowered the adhesion still further to less than 0.3 mJ m(-2). These observations do not support the lock and key concept. PMID- 25533100 TI - Nanoparticles modulate surfactant protein A and D mediated protection against influenza A infection in vitro. AB - Numerous epidemiological and toxicological studies have indicated that respiratory infections are exacerbated following enhanced exposure to airborne particulates. Surfactant protein A (SP-A) and SP-D form an important part of the innate immune response in the lung and can interact with nanoparticles to modulate the cellular uptake of these particles. We hypothesize that this interaction will also affect the ability of these proteins to combat infections. TT1, A549 and differentiated THP-1 cells, representing the predominant cell types found in the alveolus namely alveolar type I (ATI) epithelial cells, ATII cells and macrophages, were used to examine the effect of two model nanoparticles, 100 nm amine modified (A-PS) and unmodified polystyrene (U-PS), on the ability of SP A and SP-D to neutralize influenza A infections in vitro. Pre-incubation of low concentrations of U-PS with SP-A resulted in a reduction of SP-A anti-influenza activity in A549 cells, whereas at higher concentrations there was an increase in SP-A antiviral activity. This differential pattern of U-PS concentration on surfactant protein mediated protection against IAV was also shown with SP-D in TT1 cells. On the other hand, low concentrations of A-PS particles resulted in a reduction of SP-A activity in TT1 cells and a reduction in SP-D activity in A549 cells. These results indicate that nanoparticles can modulate the ability of SP-A and SP-D to combat viral challenges. Furthermore, the nanoparticle concentration, surface chemistry and cell type under investigation are important factors in determining the extent of these modulations. PMID- 25533099 TI - Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena. AB - Cadherins are mediators of cell-cell adhesion in epithelial tissues. E-cadherin is a known tumour suppressor and plays a central role in suppressing the invasive phenotype of cancer cells. However, the abnormal expression of N- and P-cadherin ('cadherin switching', CS) has been shown to promote a more invasive and malignant phenotype of cancer, with P-cadherin possibly acting as a key mediator of invasion and metastasis in bladder cancer. Cadherins are also implicated in numerous signalling events related to embryonic development, tissue morphogenesis and homeostasis. It is these wide ranging effects and the serious implications of CS that make the cadherin cell adhesion molecules and their related pathways strong candidate targets for the inhibition of cancer progression, including bladder cancer. This review focuses on CS in the context of bladder cancer and in particular the switch to P-cadherin expression, and discusses other related molecules and phenomena, including EpCAM and the development of the cancer stem cell phenotype. PMID- 25533102 TI - Nanoparticle growth and surface chemistry changes in cell-conditioned culture medium. AB - When biomolecules attach to engineered nanoparticle (ENP) surfaces, they confer the particles with a new biological identity. Physical format may also radically alter, changing ENP stability and agglomeration state within seconds. In order to measure which biomolecules are associated with early ENP growth, we studied ENPs in conditioned medium from A549 cell culture, using dynamic light scattering (DLS) and linear trap quadrupole electron transfer dissociation mass spectrometry. Two types of 100 nm polystyrene particles (one uncoated and one with an amine functionalized surface) were used to measure the influence of surface type. In identically prepared conditioned medium, agglomeration was visible in all samples after 1 h, but was variable, indicating inter-sample variability in secretion rates and extracellular medium conditions. In samples conditioned for 1 h or more, ENP agglomeration rates varied significantly. Agglomerate size measured by DLS was well correlated with surface sequestered peptide number for uncoated but not for amine coated polystyrene ENPs. Amine coated ENPs grew much faster and into larger agglomerates associated with fewer sequestered peptides, but including significant sequestered lactose dehydrogenase. We conclude that interference with extracellular peptide balance and oxidoreductase activity via sequestration is worthy of further study, as increased oxidative stress via this new mechanism may be important for cell toxicity. PMID- 25533103 TI - Cross-species fertilization: the hamster egg receptor, Juno, binds the human sperm ligand, Izumo1. AB - Fertilization is the culminating event in sexual reproduction and requires the recognition and fusion of the haploid sperm and egg to form a new diploid organism. Specificity in these recognition events is one reason why sperm and eggs from different species are not normally compatible. One notable exception is the unusual ability of zona-free eggs from the Syrian golden hamster (Mesocricetus auratus) to recognize and fuse with human sperm, a phenomenon that has been exploited to assess sperm quality in assisted fertility treatments. Following our recent finding that the interaction between the sperm and egg recognition receptors Izumo1 and Juno is essential for fertilization, we now demonstrate concordance between the ability of Izumo1 and Juno from different species to interact, and the ability of their isolated gametes to cross-fertilize each other in vitro. In particular, we show that Juno from the golden hamster can directly interact with human Izumo1. These data suggest that the interaction between Izumo1 and Juno plays an important role in cross-species gamete recognition, and may inform the development of improved prognostic tests that do not require the use of animals to guide the most appropriate fertility treatment for infertile couples. PMID- 25533104 TI - 'Bio-nano interactions: new tools, insights and impacts': summary of the Royal Society discussion meeting. AB - Bio-nano interactions can be defined as the study of interactions between nanoscale entities and biological systems such as, but not limited to, peptides, proteins, lipids, DNA and other biomolecules, cells and cellular receptors and organisms including humans. Studying bio-nano interactions is particularly useful for understanding engineered materials that have at least one dimension in the nanoscale. Such materials may consist of discrete particles or nanostructured surfaces. Much of biology functions at the nanoscale; therefore, our ability to manipulate materials such that they are taken up at the nanoscale, and engage biological machinery in a designed and purposeful manner, opens new vistas for more efficient diagnostics, therapeutics (treatments) and tissue regeneration, so called nanomedicine. Additionally, this ability of nanomaterials to interact with and be taken up by cells allows nanomaterials to be used as probes and tools to advance our understanding of cellular functioning. Yet, as a new technology, assessment of the safety of nanomaterials, and the applicability of existing regulatory frameworks for nanomaterials must be investigated in parallel with development of novel applications. The Royal Society meeting 'Bio-nano interactions: new tools, insights and impacts' provided an important platform for open dialogue on the current state of knowledge on these issues, bringing together scientists, industry, regulatory and legal experts to concretize existing discourse in science law and policy. This paper summarizes these discussions and the insights that emerged. PMID- 25533105 TI - On the interplay between working memory consolidation and attentional selection in controlling conscious access: parallel processing at a cost--a comment on 'The interplay of attention and consciousness in visual search, attentional blink and working memory consolidation'. PMID- 25533106 TI - Exploiting cell-mediated contraction and adhesion to structure tissues in vitro. AB - Progress in tissue engineering is now impacting beyond the field of regenerative medicine. Engineered tissues are now used as tools to evaluate the toxicity of compounds or even to enable the modelling of disease. While many of the materials that are used to facilitate tissue growth are designed to enable cell attachment, many researchers consider that the contraction and modification of these matrices by attached cells is not desirable and take measures to prevent this from occurring. Where substantial alignment of the molecules within tissues, however, is a feature of structure the process of contraction can be exploited to guide new matrix deposition. In this paper, we will demonstrate how we have used the cell contraction process to generate tissues with high levels of organization. The tissues that have been grown in the laboratory have been characterized using a suite of analytical techniques to demonstrate significant levels of matrix organization and mechanical behaviour analogous to natural tissues. This paper provides an overview of research that has been undertaken to determine how tissues have been grown in vitro with structuring from the molecular, right through to the macroscopic level. PMID- 25533107 TI - Rapid switching and complementary evidence accumulation enable flexibility of an all-or-none global workspace for control of attentional and conscious processing: a reply to Wyble et al. PMID- 25533108 TI - Correction to: 'Developmental plasticity, cell fate specification and morphogenesis in the early mouse embryo'. PMID- 25533109 TI - Comparison of the renal hyperemic effects of papaverine and dopamine in patients with renal artery stenosis. AB - The purpose of this study was to assess the hyperemic effects of papaverine and dopamine in the renal microcirculation of hypertensive patients with renal artery stenosis (RAS). Although a poor correlation between angiographic lesion assessment and its hemodynamic significance is known, angiography is a major criterion for the decision of renal artery stenting. Assessment of the hyperemic translesional pressure gradient was recently shown to be conducive in identifying patients who may benefit from renal revascularization. The study included 14 patients (mean age, 66 +/- 11.2 years) with resistant hypertension and moderate RAS. Using a pressure-sensing catheter, systolic, diastolic, and mean translesional pressure gradients, and the distal pressure (Pd):aortic pressure (Pa) ratio (Pd/Pa) were analyzed at baseline and after administration of 40 mg papaverine and 50 MUg/kg dopamine. We did not observe significant changes in DG. Dopamine administration resulted in significant changes in systolic and mean translesional pressure gradients and Pd/Pa when compared with baseline (P < .05 for all). Changes in these parameters were caused by a decrease in systolic Pd in comparison with baseline conditions (119 +/- 34 mm Hg vs. 101 mm Hg; P < .05). Systolic Pd pressure after papaverine (104 mm Hg) did not change significantly. Systolic and diastolic Pa values did not differ from baseline after either dopamine or papaverine bolus administration.This study indicates that, compared with papaverine, the intrarenal bolus of dopamine in hypertensive patients with RAS remains a more powerful hyperemic agent. PMID- 25533110 TI - In situ synthesis of a NiS/Ni3S2 nanorod composite array on Ni foil as a FTO-free counter electrode for dye-sensitized solar cells. AB - A NiS/Ni3S2 nanorod composite array that directly grows on Ni foil has been used as a counter electrode for dye-sensitized solar cells; these nickel sulfide nanorods exhibit excellent photo-electrical conversion efficiency when compared with conventional noble-metal Pt electrodes. PMID- 25533112 TI - Intravenous injection of AAVrh10-GALC after the neonatal period in twitcher mice results in significant expression in the central and peripheral nervous systems and improvement of clinical features. AB - Globoid cell leukodystrophy (GLD) or Krabbe disease is an autosomal recessive disorder resulting from the defective lysosomal enzyme galactocerebrosidase (GALC). The lack of GALC enzyme leads to severe neurological symptoms. While most human patients are infants who do not survive beyond 2 years of age, older patients are also diagnosed. In addition to human patients, several naturally occurring animal models, including dog, mouse, and monkey, have also been identified. The mouse model of Krabbe disease, twitcher (twi) mouse has been used for many treatment trials including gene therapy. Using the combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of the adeno-associated virus serotype rh10 (AAVrh10) expressing mouse GALC in neonate twi mice we previously have demonstrated a significantly extended normal life and exhibition of normal behavior in treated mice. In spite of the prolonged healthy life of these treated mice and improved myelination, it is unlikely that using multiple injection sites for viral administration will be approved for treatment of human patients. In this study, we have explored the outcome of the single iv injection of viral vector at post-natal day 10 (PND10). This has resulted in increased GALC activity in the central nervous system (CNS) and high GALC activity in the peripheral nervous system (PNS). As we have shown previously, an iv injection of AAVrh10 at PND2 results in a small extension of life beyond the typical lifespan of the untreated twi mice (~40 days). In this study, we report that mice receiving a single iv injection at PND10 had no tremor and continued to gain weight until a few weeks before they died. On average, they lived 20-25 days longer than untreated mice. We anticipate that this strategy in combination with other therapeutic options may be beneficial and applicable to treatment of human patients. PMID- 25533113 TI - [The PARADIGM-HF study]. PMID- 25533114 TI - [The ATLANTIC study]. PMID- 25533111 TI - Targeting novel signaling pathways for resistant acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a hematologic malignancy that is the most common type of acute leukemia diagnosed in adults and the second most common type in children. The overall survival is poor and treatment is associated with significant complications and even death. In addition, a significant number of patients will not respond to therapy or relapse. In this review, several new signaling proteins aberrantly regulated in AML are described, including CREB, Triad1, Bcl-2 family members, Stat3, and mTOR/MEK. Identifying more effective and less toxic agents will provide novel approaches to treat AML. PMID- 25533115 TI - [Role of secreted and lipoprotein-associated phospholipase A2 in cardiovascular risk]. AB - Phospholipase A(2) (PLA(2)) are enzymes that hydrolyze the ester bond of glycerophospholipids releasing free fatty acids and lysophospholipids, including the arachidonic acid, the precursor of the eicosanoids and the inflammatory cascades. PLA(2) are present in the atherosclerotic plaques and their direct involvement in the proatherogenic inflammatory response is well documented. Epidemiological and genetic studies have demonstrated the correlation of the PLA(2) mass and enzymatic activity with the incidence of cardiovascular diseases. The potential pro-atherogenic role of PLA(2) led to the development of two small molecules, varespladib, a reversible sPLA(2) inhibitor, and darapladib, a selective Lp-PLA(2) inhibitor. Both molecules have demonstrated antiatherosclerotic properties in animal models, and positive effects on atherosclerotic plaque composition evaluated in phase 2 clinical trials. On these grounds, the results of three phase 3 studies have recently been published: the VISTA-16 study with varespladib in patients with acute coronary syndrome, and the STABILITY and SOLID-TIMI 52 studies with darapladib in patients with stable coronary heart disease and acute coronary syndrome, respectively. Unexpectedly, both studies did not demonstrate an additional protective action of PLA 2 inhibitors over the standard of care treatment with statins, antiplatelet drugs, and coronary revascularization. In the present article, the enzymatic properties and the involvement of sPLA(2) and Lp-PLA(2) in atherogenesis are reviewed, with a focus on the results of experimental studies and clinical studies with both varespladib and darapladib inhibitors. PMID- 25533116 TI - [Role of standard resting ECG in the assessment of sudden cardiac death risk]. AB - Today the ECG is still, over 100 years after its invention (Willem Einthoven 1903), the most commonly used diagnostic procedure in clinical cardiology. In recent years, we have accumulated knowledge that has significantly expanded the diagnostic possibilities of ECG, through the recognition of patterns associated with a number of primary electrical diseases of the myocardium, the so-called inherited arrhythmogenic diseases. These clinical entities are caused by gene mutations that determine a substrate leading to the onset of life-threatening rhythm disturbances. The study of ECG abnormalities in these diseases showed characteristic phenotypic traits, which in combination with information derived from molecular genetics, have allowed using the ECG as a prognostic tool as well as a diagnostic test. The assessment of genotype-phenotype correlations in inherited arrhythmogenic diseases has allowed to advance the idea of the ECG as an inheritable trait. Such heritable quantitative traits are potentially related to the risk of sudden death in the general population, which is known to have a familial predisposition. This article summarizes the pathophysiology and phenotypic manifestation of the main arrhythmogenic diseases. Also shown are current possibilities and limitations of the use of a simple and low-cost technology, not only as a tool for diagnosis but also as a tool to identify prognostic markers. We will show how, rather surprisingly, the ECG often allows extracting the most important information for appropriate risk classification and clinical management. PMID- 25533117 TI - [Treatment of arrhythmias in children without heart disease]. AB - In children, arrhythmias have an etiology, evolution and treatment strategy that often differs from that of adults. Ectopic beats are very common, but rarely need to be treated. Macroreentrant supraventricular tachycardia is the arrhythmia that usually requires a treatment intervention. Adenosine for tachycardia interruption and 1C anti-arrhythmic drugs for prevention of recurrences are the first-line treatment. Automatic supraventricular tachycardias are infrequent but are typical of the pediatric age; treatment should be targeted at rate control in addition to tachycardia interruption. Beta-blockers and calcium antagonists are the most useful drugs for tachycardia control. Ventricular tachycardia is a very uncommon arrhythmia in children usually related to channelopathies; in this setting beta blockers are often the first-choice treatment, but in many selected patients implantation of a cardioverter-defibrillator is required. Other types of ventricular tachycardia include fascicular and infundibular tachycardias that are usually well controlled by medical and/or ablation therapy. Ablation procedures are very effective in curing many tachyarrhythmias also in the pediatric age; the main indication for ablation is the need for continuing medical therapy after the age of 10-12 years. Hypokinetic arrhythmias are very rare and usually require pacemaker implantation. PMID- 25533118 TI - [Current role of echocardiography in patients with pulmonary disease]. AB - Pulmonary embolism is a major health problem. Clinical presentation may vary from cardiovascular emergency with high mortality risk to mild or atypical illness, and the diagnosis is not always easy. However, the timeliness of diagnosis and prognostic stratification are crucial because immediate treatment and thromboembolic prophylaxis are highly effective. Echocardiography can play a key role in pulmonary embolism regarding different aspects: diagnosis, risk stratification, and follow-up but sometimes it is not properly used. Therefore, it is important for a physician to know exactly how to utilize echocardiography in pulmonary embolism. The purpose of this paper is to review the role of echocardiography as part of the diagnosis, management and follow-up of acute pulmonary embolism in the light of current literature. PMID- 25533119 TI - [Surgical indication and timing in infective endocarditis]. AB - Infective endocarditis is a complex disease to treat. Despite considerable improvements in diagnostic and therapeutic management, mortality in infective endocarditis remains high. Recent data converge in giving a central role to surgery that, within a multidisciplinary approach and with earlier timing, primarily aims to eradicate the infection rather than to treat its acute or chronic complications. In this paper, we sought to review and comment on current available data and last recommendations for the management of patients with infective endocarditis. PMID- 25533120 TI - [Diagnosis and therapy of pulmonary arterial hypertension in Italy: results of the INCIPIT2 survey]. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare clinical condition characterized by increased pulmonary vascular resistance and premature death. It is necessary to activate a pathway from the screening of pulmonary hypertension to the diagnosis of PAH, so as to use the drugs able to improve the outcome. Nowadays, in Italy, there are no data about the management of PAH in peripheral centers and about the integration of peripheral centers with those of excellence. METHODS: In order to have a map of the actual Italian pathway for diagnosis and therapy of PAH, on behalf of the ANMCO Pulmonary Circulation Area, 923 Italian cardiology departments were asked to reply, on a special electronic file, to a few simple questions about their organization, from December 2012 to May 2013. RESULTS: 101/923 centers (48 in the North, 18 in the Middle, 35 in the South) answered correctly. 32% has no organization for PAH, 68% has a pathway for PAH diagnosis and management, and two thirds of them collaborate with excellence centers. 36 centers perform right heart catheterization with vascular reactivity (21 with nitric oxide, 8 with adenosine, 5 with epoprostenol, 2 with nitric oxide or epoprostenol). 61/101 are prescriber centers: 33 perform right heart catheterization with vascular reactivity test, 23 send their patients to the reference center for right heart catheterization, 5 perform no right heart catheterization before the prescription of specific drugs for PAH, and only 14 prescribe intravenous prostanoids. In 2011, the participating centers followed 561 patients with PAH, of whom 126 (23%) were in independent centers. With regard to the network organization of the groups, the participating centers are partly independent of the diagnostic pathway, partly refer to outside regions; in others there is a structured regional network and there are 3 Italian regions with Hub & Spoke networks that receive patients coming from other regions. CONCLUSIONS: Our results show the interest of Italian Cardiology to find a pathway for the diagnosis of PAH and a heterogeneity suggesting the need for a shareable pathway, thus improving the collaboration between peripheral cardiology departments and the excellence centers for PAH in a functional Hub & Spoke network. PMID- 25533121 TI - [Mutation of the lamin A/C gene associated with left ventricular apical hypoplasia: a new phenotype for laminopathies?]. AB - Isolated left ventricular (LV) apical hypoplasia is a rare anomaly characterized by a dysfunctioning, spherical left ventricle and elongated right ventricle wrapping around the deficient LV apex. The etiology is unknown; it is presumed to be a rare congenital developmental defect during partitioning of the ventricles, caused by an in-utero infection. We describe for the first time a case of isolated LV apical hypoplasia associated with lamin A/C gene mutation. Echocardiography showed a mildly dilated left ventricle with spherical configuration and impaired systolic function, and an elongated right ventricle wrapping around the deficient LV apex. Magnetic resonance imaging also identified fatty replacement of the LV apical myocardium. Late gadolinium enhancement imaging showed mid-wall fibrosis in the interventricular septum. Family screening by ECG and echocardiography failed to identify heart disease in the patient's family; however, the proband's father and daughter were found to carry the same mutation. This case report highlights the difficulties of a correct interpretation of genetic mutations in a single patient with cardiomyopathy. Indeed, the causative role of a mutation needs to be confirmed by co-segregation analysis. Although the etiology of LV apical hypoplasia remains unknown, the first hypothesis is an acquired process interfering with the early development of the heart, the new one is a genetic defect. PMID- 25533122 TI - [Pediatric ECG: chance, limits and necessity]. PMID- 25533124 TI - Steatogenesis in adult-onset type II citrullinemia is associated with down regulation of PPARalpha. AB - SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1alpha, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial beta-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor alpha (PPARalpha), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARalpha expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARalpha. Collectively, down-regulation of PPARalpha is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARalpha. PMID- 25533126 TI - Understanding and meeting information needs following unintentional injury: comparing the accounts of patients, carers and service providers. AB - OBJECTIVE: To explore information needs of unintentional injury patients and their carers over time, across services, and how such needs are met from the perspectives of patients, carers and service providers. METHODS: Qualitative nested study within a multi-centre longitudinal study quantifying psycho-social, physical, occupational outcomes and service use and costs following a range of unintentional injuries. Semi-structured interviews conducted with 45 patients during the first year post injury, 18 of their carers and 40 providers of services. RESULTS: Patients and carers needed information about the nature and severity of injury, prognosis, self-management and further services. Information needs changed over time with the biggest difficulties being during transfer from primary to secondary care. Barriers to information provision included service providers' time limitations and uncertainty around information provision, and patients' reluctance to ask for information or inability to process it. Suggested improvements included provision of reassurance as well as factual information, information about further services, earlier follow-up, increased appointment times and greater involvement of families where appropriate. CONCLUSIONS: The information needs of patients and carers post injury change with time and there are a number of ways to remove gaps and barriers in current provision to meet such needs. PRACTICE IMPLICATIONS: Providing information on injury management, prognosis and available services and reassurance at each stage of the recovery process in secondary care and when transferring to primary care would be helpful for patients and carers. A follow-up contact soon after discharge and the opportunity to ask questions could be beneficial. Better information about the patient's needs and ways they can help could help carers fulfil their caring role. PMID- 25533125 TI - SUMOylation occurs in acute kidney injury and plays a cytoprotective role. AB - SUMOylation is a form of post-translational modification where small ubiquitin like modifiers (SUMO) are covalently attached to target proteins to regulate their properties. SUMOylation has been demonstrated during cell stress and implicated in cellular stress response. However, it is largely unclear if SUMOylation contributes to the pathogenesis of kidney diseases, such as acute kidney injury (AKI). Here we have demonstrated a dynamic change of protein SUMOylation in ischemic and cisplatin nephrotoxic AKI in mice. In rat kidney proximal tubular cells (RPTC), cisplatin-induced SUMOylation was diminished by two antioxidants (N-acetylcysteine and dimethylurea), supporting a role of oxidative stress in the activation of SUMOylation. In addition, SUMOylation by SUMO-2/3, but not SUMO-1, was partially suppressed by pifithrin-alpha (a pharmacological inhibitor of p53), supporting a role of p53 in SUMOylation by SUMO-2/3. We further examined the role of SUMOylation during cisplatin treatment of RPTC by using ginkgolic acid (GA), a pharmacological inhibitor of SUMOylation. Pretreatment with GA suppressed SUMOylation and importantly, GA enhanced apoptosis during cisplatin incubation. Taken together, the results demonstrate the first evidence of SUMOylation in AKI and suggest that SUMOylation may play a cytoprotective role in kidney tubular cells. PMID- 25533128 TI - The sperm of Matsucoccus feytaudi (Insecta, Coccoidea): Can the microtubular bundle be considered as a true flagellum? AB - In the present work the spermiogenesis and sperm structure of Matsucoccus feytaudi, a primary pest of the maritime pine in southern eastern Europe, is studied. In addition to the already known characteristics of coccid sperm, such as the absence of the acrosome and mitochondria, and the presence of a bundle of microtubules responsible for sperm motility, a peculiar structure from which the microtubule bundle takes origin is described. Such a structure--a short cylinder provided with a central hub surrounded by several microtubules with a dense wall- is regarded as a Microtubule Organizing Centre (MTOC). During spermiogenesis, quartets of fused spermatids are formed; from each spermatid, a bundle of microtubules, generated by the MTOC, projects from the cell surface. Each cell has two centrioles, suggesting the lack of a meiotic process and the occurrence of parthenogenesis. At the end of the spermiogenesis, when the cysts containing bundles of sperm are formed, part of the nuclear material together with the MTOC structure is eliminated. Based on the origin of the microtubular bundle from the MTOC, the nature of the bundle as a flagellum is discussed. PMID- 25533127 TI - BMP-7 induces TF expression in human monocytes by increasing F3 transcriptional activity. AB - BACKGROUND: Bone morphogenetic protein (BMP)-7, a major regulator of bone metabolism, inhibits ectopic calcification in atherosclerotic plaques. We have recently reported that BMP-7 is also a potent inducer of tissue factor (TF) in human mononuclear cells (MNCs). While nuclear factor kappa beta (NF-kB) and activation protein-1 (AP-1) are the transcription factors essential for inducible expression of human TF gene (F3), the mechanisms responsible for TF induction by BMP-7 are not known. OBJECTIVE: To elucidate the molecular mechanisms governing BMP-7-triggered TF expression in human MNCs. METHODS: Human blood monocytes were stimulated with BMP-7 and western blotting, qRT-PCR, and flow cytometry studies were carried out to assess F3 expression; promoter studies were also performed using a panel of reporter constructs. Procoagulant TF activity was measured using a validated FXa generation assay. The significance of NF-kB transcriptional activity was verified via pharmacological inhibition. RESULTS: BMP-7 increased TF protein levels, procoagulant activity, surface presentation, and TF mRNA expression. This increase was accompanied by activation of NF-kB as evidenced by reduced IkB-alpha levels and elevated transcriptional activity of an NF-kB sensitive reporter in transfected MNCs. Although treatment with BMP-7 also led to a strong phosphorylation of c-Jun, activation of AP-1 alone was not sufficient to induce TF expression: JSH-23, a potent and specific NF-kB inhibitor, completely blocked BMP-7-induced TF expression. CONCLUSIONS: We report that BMP-7-dependent activation of TF in human MNCs is mediated via increased activity of NF-kB, leading to enhanced F3 transcription in human MNCs. PMID- 25533129 TI - Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients. AB - Venous thromboembolism (VTE) is a common complication and a major cause of morbidity and mortality in patients with cancer. In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Platelet/lymphocyte ratio (PLR), which can be easily calculated from the differential blood count, have been proposed as novel markers predictive of thrombotic events. The aim of this study was to determine whether PLR levels might represent significant prognostic indices in cancer patients with VTE. We retrospectively analyzed the clinical characteristics and laboratory parameters in 76 cancer patients with VTE, among 173 patients pathologically confirmed for cancer between June 2008 and December 2013.Receiving surgical procedure (51.3 VS 33.0%, p=0.015), chemotherapy (51.3 VS 40.2%, p=0.013) and the PLR >260 (32.9 VS 14.4%, p=0.004) were significantly different between the cancer patients with VTE and without VTE. Multiple logistic regression analysis showed that receiving surgical procedure (OR=1.537, 95%CI=1.241-1.984, p=0.021), chemotherapy (OR=1.969, 95%CI=1.321-2.225, p=0.013) and the PLR >260 (OR=2.757, 95%CI=1.655 3.862, p=0.025) were independent predictors of a VTE episode in patients with cancer. The results demonstrate that the PLR at the time of cancer diagnosis could be a useful clinically important, independent risk predictor for VTE in cancer patients. PMID- 25533130 TI - Annexin A2 autoantibodies in thrombosis and autoimmune diseases. AB - Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial, venous or small-vessel thrombotic events, and recurrent miscarriages or fetal loss. APS diagnosis is based on the repeated detection of anti-phospholipid (PL) antibodies (Ab), typically associated with anti-beta2 glycoprotein I (beta2GPI)-Ab. Recent studies suggest that anti-beta2GPI Ab activity involves a protein complex including beta2GPI and annexin A2 (ANXA2). Anti-ANXA2 Ab recognizes this complex, and these Ab can effectively promote thrombosis by inhibiting plasmin generation, and by activating endothelial cells. Therefore, anti-ANXA2 Ab represent a new biomarker, which can be detected in up to 25% of APS patients. Moreover, anti-ANXA2 Ab have been detected, in thrombotic associated diseases including pre-eclampsia, in other autoimmune diseases, and in cancer. PMID- 25533131 TI - Tolerance induction and reversal of diabetes in mice transplanted with human embryonic stem cell-derived pancreatic endoderm. AB - Type 1 diabetes (T1D) is an autoimmune disease caused by T cell-mediated destruction of insulin-producing beta cells in the islets of Langerhans. In most cases, reversal of disease would require strategies combining islet cell replacement with immunotherapy that are currently available only for the most severely affected patients. Here, we demonstrate that immunotherapies that target T cell costimulatory pathways block the rejection of xenogeneic human embryonic stem-cell-derived pancreatic endoderm (hESC-PE) in mice. The therapy allowed for long-term development of hESC-PE into islet-like structures capable of producing human insulin and maintaining normoglycemia. Moreover, short-term costimulation blockade led to robust immune tolerance that could be transferred independently of regulatory T cells. Importantly, costimulation blockade prevented the rejection of allogeneic hESC-PE by human PBMCs in a humanized model in vivo. These results support the clinical development of hESC-derived therapy, combined with tolerogenic treatments, as a sustainable alternative strategy for patients with T1D. PMID- 25533132 TI - Comparison of two different methods in the cryopreservation of Eurasian perch (Perca fluviatilis) sperm. AB - Two different cryopreservation methods were compared and an optimal dilution ratio for the use of controlled-rate freezer (CRF) was established for Eurasian perch (Perca fluviatilis) sperm. Progressive motility (72 +/- 15%) and curvilinear velocity (VCL, 146 +/- 11 MUm/s) of sperm cryopreserved with CRF did not reduce significantly compared to fresh sperm [progressive motility (90 +/- 4%), VCL (173 +/- 24 MUm/s)]. On the other hand, progressive motility (62 +/- 15%) and VCL (120 +/- 21 MUm/s) of sperm cryopreserved with the conventional floating frame technique were significantly lower when compared to the fresh control. Sperm in both cryopreserved groups showed significantly higher straightness [STR, CRF (84 +/- 4%), frame (84 +/- 2%)] than in the fresh control group (68 +/- 4%). Perch sperm cryopreserved with CRF at a dilution ratio of 1:20 showed significantly higher progressive motility (49 +/- 6%) than at a ratio of 1:5 (39 +/- 6%) and showed significantly higher VCL (129 +/- 11 MUm/s) than at dilution ratios of 1:10 (112 +/- 17 MUm/s) and 1:5 (115 +/- 9 MUm/s). PMID- 25533133 TI - A clinical reasoning model focused on clients' behaviour change with reference to physiotherapists: its multiphase development and validation. AB - BACKGROUND AND PURPOSE: A biopsychosocial approach and behaviour change strategies have long been proposed to serve as a basis for addressing current multifaceted health problems. This emphasis has implications for clinical reasoning of health professionals. This study's aim was to develop and validate a conceptual model to guide physiotherapists' clinical reasoning focused on clients' behaviour change. METHODS: Phase 1 consisted of the exploration of existing research and the research team's experiences and knowledge. Phases 2a and 2b consisted of validation and refinement of the model based on input from physiotherapy students in two focus groups (n = 5 per group) and from experts in behavioural medicine (n = 9). RESULTS: Phase 1 generated theoretical and evidence bases for the first version of a model. Phases 2a and 2b established the validity and value of the model. The final model described clinical reasoning focused on clients' behaviour change as a cognitive, reflective, collaborative and iterative process with multiple interrelated levels that included input from the client and physiotherapist, a functional behavioural analysis of the activity-related target behaviour and the selection of strategies for behaviour change. CONCLUSIONS: This unique model, theory- and evidence-informed, has been developed to help physiotherapists to apply clinical reasoning systematically in the process of behaviour change with their clients. PMID- 25533137 TI - Letters to the editor. PMID- 25533138 TI - 2014 reviewers for endocrine practice. PMID- 25533139 TI - Managing intimate partner violence in the emergency department. PMID- 25533140 TI - Techniques, success, and adverse events of emergency department adult intubations. AB - STUDY OBJECTIVE: We describe the operators, techniques, success, and adverse event rates of adult emergency department (ED) intubation through multicenter prospective surveillance. METHODS: Eighteen EDs in the United States, Canada, and Australia recorded intubation data onto a Web-based data collection tool, with a greater than or equal to 90% reporting compliance requirement. We report proportions with binomial 95% confidence intervals (CIs) and regression, with year as the dependent variable, to model change over time. RESULTS: Of 18 participating centers, 5 were excluded for failing to meet compliance standards. From the remaining 13 centers, we report data on 17,583 emergency intubations of patients aged 15 years or older from 2002 to 2012. Indications were medical in 65% of patients and trauma in 31%. Rapid sequence intubation was the first method attempted in 85% of encounters. Emergency physicians managed 95% of intubations and most (79%) were physician trainees. Direct laryngoscopy was used in 84% of first attempts. Video laryngoscopy use increased from less than 1% in the first 3 years to 27% in the last 3 years (risk difference 27%; 95% CI 25% to 28%; mean odds ratio increase per year [ie, slope] 1.7; 95% CI 1.6 to 1.8). Etomidate was used in 91% and succinylcholine in 75% of rapid sequence intubations. Among rapid sequence intubations, rocuronium use increased from 8.2% in the first 3 years to 42% in the last 3 years (mean odds ratio increase per year 1.3; 95% CI 1.3 to 1.3). The first-attempt intubation success rate was 83% (95% CI 83% to 84%) and was higher in the last 3 years than in the first 3 (86% versus 80%; risk difference 6.2%; 95% CI 4.2% to 7.8%). The airway was successfully secured in 99.4% of encounters (95% CI 99.3% to 99.6%). CONCLUSION: In the EDs we studied, emergency intubation has a high and increasing success rate. Both drug and device selection evolved significantly during the study period. PMID- 25533141 TI - Comparative efficiency research (COMER): meta-analysis of cost-effectiveness studies. AB - BACKGROUND: The aim of this study was to create a new meta-analysis method for cost-effectiveness studies using comparative efficiency research (COMER). METHODS: We built a new score named total incremental net benefit (TINB), with inverse variance weighting of incremental net benefits (INB). This permits determination of whether an alternative is cost-effective, given a specific threshold (TINB > 0 test). Before validation of the model, the structure of dependence between costs and quality-adjusted life years (QoL) was analysed using copula distributions. The goodness-of-fit of a Spanish prospective observational study (n = 498) was analysed using the Independent, Gaussian, T, Gumbel, Clayton, Frank and Placket copulas. Validation was carried out by simulating a copula distribution with log-normal distribution for costs and gamma distribution for disutilities. Hypothetical cohorts were created by varying the sample size (n: 15 500) and assuming three scenarios (1-cost-effective; 2-non-cost-effective; 3 dominant). The COMER result was compared to the theoretical result according to the incremental cost-effectiveness ratio (ICER) and the INB, assuming a margin of error of 2,000 and 500 monetary units, respectively. RESULTS: The Frank copula with positive dependence (-0.4279) showed a goodness-of-fit sufficient to represent costs and QoL (p-values 0.524 and 0.808). The theoretical INB was within the 95% confidence interval of the TINB, based on 15 individuals with a probability > 80% for scenarios 1 and 2, and > 90% for scenario 3. The TINB > 0 test with 15 individuals showed p-values of 0.0105 (SD: 0.0411) for scenario 1, 0.613 (SD: 0.265) for scenario 2 and < 0.0001 for scenario 3. CONCLUSIONS: COMER is a valid tool for combining cost-effectiveness studies and may be of use to health decision makers. PMID- 25533142 TI - Resistance and mutations of non-specificity in the field of anxiety-depressive disorders in Canadian medical journals, 1950-1990. AB - Pharmaceuticalisation is a complex phenomenon, co-constitutive of what scholars identify as a pharmaceutical regime, comprised of networks of actors, institutions and artefacts as well as cognitive structures that underlie the production, promotion and use of medications. The aim of this paper is to explore the linkages between different components of this pharmaceutical regime through the analysis of psychotropic drug advertising in Canadian medical journals between 1950 and 1990. Advertisements stand at the nexus of macro-level processes related to the development, regulation and marketing of new drug treatments and of micro-level processes related to the use of these drug treatments, both by clinicians and lay persons. We thus examine advertisements from the angle of the mental and classificatory universes to which doctors were exposed through direct to-prescriber advertisement strategies implemented during this period. Furthermore, we explore to what extent the rationale behind advertisements was permeated by both scientific/professional and popular narratives of mind-body connections. This paper demonstrates that, although this period was marked by paradigm shifts in the classification of mental diseases, the development of modern psychopharmacology, and the questioning of the scientific legitimacy of psychiatry, advertisements unveil a remarkable continuity: that of the mass management of anxiety-depressive disorders by primary care physicians through psychotropic drugs. Also, despite the effective resistance to specificity as shown by the constant redefinitions of diagnostic categories and therapeutic indications, our analysis suggests that the language of specificity used in the promotion of new drugs and in the various narratives of mind-body connection may have been appealing to general practitioners. Finally, our study of the classes of psychoactive medications that have been in use for over half a century reveals a complex, non-linear dynamic of pharmaceuticalisation and de pharmaceuticalisation. PMID- 25533143 TI - Causal inferences: identical twins help and clarity about necessary assumptions is critical. PMID- 25533144 TI - Nature of the antimicrobial activity of Lactobacillus casei, Bifidobacterium bifidum and Bifidobacterium animalis against foodborne pathogenic and spoilage microorganisms. AB - The antimicrobial activities as well as the nature of the inhibitory compounds obtained from Lactobacillus casei, Bifidobacterium bifidum and Bifidobacterium animalis strains were assayed on foodborne pathogenic - Staphyloccoccus aureus subsp. aureus (CCUG ATCC(r) 25926TM) and Escherichia coli (ATCC(r) 25922TM) - and spoilage microorganisms - Pseudomonas aeruginosa (ATCC(r) 27853TM). Test producer strains showed inhibitory effect on all indicator microorganisms in diffusion of cell-free concentrated supernatant by agar in well methods (10.0-22.5 mm) in periods of 24, 48 and 72 h. Inhibitory compounds showed no sensitivity to the action of proteolytic enzyme trypsin and were completely inactivated by adjusting the pH of the cell-free 20 * concentrated supernatant to 7.0. The results demonstrated that antimicrobial substances do not have proteinaceous nature and are caused by the action of organic acids with decreasing medium pH. PMID- 25533145 TI - Osteosarcopenic obesity and fall prevention strategies. AB - Sarcopenia, obesity, and osteoporosis are three interrelated entities which may share common pathophysiological factors. In the last decades, overall survival has drastically increased. Postmenopausal women, due to their estrogen depletion, are at higher risk of developing any of these three conditions or the three, which is termed osteosarcopenic obesity. One of the most common health problems among these patients is the elevated risk of falls and fractures. Falls and fall related injuries are one of the major causes of mortality and morbidity in older adults, and have a significant impact on social, economical and health-related costs. Several extrinsic and intrinsic risk factors have been described that play a role in the etiology of falls. A therapeutic approach to osteosarcopenic obesity aimed at the prevention of falls must include several factors, and act on those risk elements which can be effectively modified. An adequate weight-loss diet and a good nutritional intake, with an appropriate amount of vitamin D and the right protein/carbohydrates ratio, may contribute to the prevention of falls. The recommendation of physical exercise, both traditional (resistance or aerobic training) and more recent varieties (Tai Chi, Pilates, body vibration), can improve balance and positively contribute to fall prevention, whether by itself or in combination with other therapeutic strategies. Finally, a pharmacological approach, especially one focused on hormone therapy, has shown to have a positive effect on postmenopausal women's balance, leading to a decreased risk of falls. PMID- 25533146 TI - Twenty-four-year demographic trends of a Brazilian long-term care institution for the aged. AB - OBJECTIVES: The objectives of this study were to assess demographic trends of a long-term care institution (LTCI) for the aged throughout 24 years and to discuss the results considering regulations and demographic, socioeconomic, and epidemiological changes in Brazil during this period. METHODS: We assessed administrative data of 394 residents of a Brazilian LTCI between January 1, 1990, and December 31, 2013. We calculated age at admission, age at death, length of stay (LOS), and median age of the residents on December 31 for each year from 1990 to 2013. Annual mortality index and total number of admissions and discharges also were analyzed. We used the Jonckheere-Terpstra trend test and 1 way ANOVA for statistical analysis. RESULTS: We observed a significant statistical increased trend of the mean age at admission, of the median age of the residents, and of the median LOS throughout the period. There was no increased or decreased trend of the median age at death. CONCLUSIONS: The increased trend of the mean age at admission and the median age of the residents may reflect improvements in health, socioeconomic status, life expectancy, and the development of protective regulations for older adults in Brazil. The increased trend of the median LOS may reflect the aforementioned improvements, but we expect a future inversion of this trend due to the admission of older, sicker, and more functionally dependent elderly individuals. PMID- 25533149 TI - Rates and risk factors for Coccidioidomycosis among prison inmates, California, USA, 2011. AB - In California, coccidioidomycosis is a disease acquired by inhaling spores of Coccidioides immitis, a fungus found in certain arid regions, including the San Joaquin Valley, California, USA, where 8 state prisons are located. During 2011, we reviewed coccidioidomycosis rates at 2 of the prisons that consistently report >80% of California's inmate cases and determined inmate risk factors for primary, severe (defined as pulmonary coccidioidomycosis requiring >10 hospital days), and disseminated coccidioidomycosis (defined by hospital discharge International Classification of Disease, Ninth Revision code). Inmates of African American ethnicity who were >40 years of age were at significantly higher risk for primary coccidioidomycosis than their white counterparts (odds ratio = 2.0, 95% CI 1.5 2.8). Diabetes was a risk factor for severe pulmonary coccidioidomycosis, and black race a risk factor for disseminated disease. These findings contributed to a court decision mandating exclusion of black inmates and inmates with diabetes from the 2 California prisons with the highest rates of coccidioidomycosis. PMID- 25533147 TI - The characteristics of diabetic residents in European nursing homes: results from the SHELTER study. AB - OBJECTIVES: The objectives of this study were to describe the prevalence of diabetes mellitus (DM) in European nursing homes (NHs), and the health and functional characteristics of diabetic residents (DMR) aged 60 years and older. DESIGN: Between 2009 and 2011, the Services and Health for Elderly in Long TERm care (SHELTER) project, a 12-month prospective cohort study, was conducted to assess NH residents across different health care systems in 7 European countries and Israel. METHODS: The study included 59 NHs in 8 countries with a total of 4037 residents living in or admitted to a NH during the 3-month enrollment period. The multidimensional InterRAI instrument for Long-Term Care Facilities (InterRAI-LTCF) was used to assess health and functional status among residents. Descriptive statistics and linear, ordinal, and logistic regression were used to perform the analyses. RESULTS: We found a 21.8% prevalence of DM among NH residents. Residents with DM (DMRs) were significantly younger compared with non DMRs (82.3, SD +/- 7.7; 84.6, SD +/- 8.4; P < .001). DMRs were more frequently overweight or obese, and presented more often with ischemic heart disease, congestive heart failure, hypertension, and stroke than residents without DM. DMRs also took more drugs, had pressure ulcers (PU) or other wounds more often, and more frequently had urinary incontinence (UI); they also reported worse self perceived health. DM independently of other factors increased risk of PU occurrence (odds ratio 1.38; 95% confidence interval [CI] 1.02-1.86; P = .036) and decreased probability of higher pain scores (B = -0.28; 95% CI -0.41 to 0.14; P < .001). DM was not associated with ADL dependency, cognitive impairment, and depression in NH residents. CONCLUSION: Prevalence of DM in European NH residents is comparable to US national NH surveys, and to UK and German NH data based on glucose-level testing. DMRs compared with non-DMRs have more comorbid conditions, and a particularly higher incidence of cardiovascular diseases and obesity, PU, and severe UI. DMRs should be regarded as a specific group of residents who require an interdisciplinary approach in medical and nursing care. PMID- 25533150 TI - Navigating the self in maternity care: how Chinese midwives work on their professional identity in hospital setting. AB - OBJECTIVE: to explore the strategies Chinese midwives employed to work on their professional identity in hospital setting and the consequence of such identity work. DESIGN AND METHODS: this paper draws upon findings from a Constructivist Grounded Theory study that explored the professional identity construction of 15 Chinese midwives with a mixture of midwifery experiences, practising in three different types of hospital settings in a capital city in Southeast China. The accounts from participants in the form of in-depth individual interviews were collected. Work journals voluntarily provided by three participants were also included. FINDINGS: in everyday practice, hospital midwives in China were working on their professional identity in relation to two definitions of the midwife: the external definition ('obstetric nurse'), bound up in the idea of risk management under the medical model of their work organisations; and the internal definition ('professional midwife'), associated with the philosophy of normal birth advocacy in the professional discourse. Six strategies for identity work were identified and grouped into two principle categories: 'compromise' and 'engagement'. The adoption of each strategy involved a constant negotiation between the external and internal definitions of the midwife, being influenced by midwifery experiences, relationships with women, opportunities for professional development and the definition of the situation. A 'hybrid identity', which demonstrated the dynamic nature of midwifery professional identity, was constructed as a result. KEY CONCLUSIONS AND IMPLICATIONS: this paper explored the dynamic nature of midwifery professional identity. This exploration contributes to the body of knowledge regarding understanding the professional identity of hospital midwives in China, while also extending the current theoretical knowledge of identity work by elaborating on the various strategies individuals use to work on their professional identity in the workplace. PMID- 25533148 TI - Prevalence of Rickettsiales in ticks removed from the skin of outdoor workers in North Carolina. AB - BACKGROUND: Tick-transmitted rickettsial diseases, such as ehrlichiosis and spotted fever rickettsiosis, are significant sources of morbidity and mortality in the southern United States. Because of their exposure in tick-infested woodlands, outdoor workers experience an increased risk of infection with tick borne pathogens. As part of a double blind randomized-controlled field trial of the effectiveness of permethrin-treated clothing in preventing tick bites, we identified tick species removed from the skin of outdoor workers in North Carolina and tested the ticks for Rickettsiales pathogens. METHODS: Ticks submitted by study participants from April-September 2011 and 2012 were identified to species and life stage, and preliminarily screened for the genus Rickettsia by nested PCR targeting the 17-kDa protein gene. Rickettsia were further identified to species by PCR amplification of 23S-5S intergenic spacer (IGS) fragments combined with reverse line blot hybridization with species specific probes and through cloning and nucleotide sequence analysis of 23S-5S amplicons. Ticks were examined for Ehrlichia and Anaplasma by nested PCR directed at the gltA, antigen-expressing gene containing a variable number of tandem repeats, 16S rRNA, and groESL genes. RESULTS: The lone star tick (Amblyomma americanum) accounted for 95.0 and 92.9% of ticks submitted in 2011 (n = 423) and 2012 (n = 451), respectively. Specimens of American dog tick (Dermacentor variabilis), Gulf Coast tick (Amblyomma maculatum) and black-legged tick (Ixodes scapularis) were also identified. In both years of our study, 60.9% of ticks tested positive for 17-kDa. "Candidatus Rickettsia amblyommii", identified in all four tick species, accounted for 90.2% (416/461) of the 23S-5S-positive samples and 52.9% (416/787) of all samples tested. Nucleotide sequence analysis of Rickettsia-specific 23S-5S IGS, ompA and gltA gene fragments indicated that ticks, principally A. americanum, contained novel species of Rickettsia. Other Rickettsiales, including Ehrlichia ewingii, E. chaffeensis, Ehrlichia sp. (Panola Mountain), and Anaplasma phagocytophilum, were infrequently identified, principally in A. americanum. CONCLUSIONS: We conclude that in North Carolina, the most common rickettsial exposure is to R. amblyommii carried by A. americanum. Other Rickettsiales bacteria, including novel species of Rickettsia, were less frequently detected in A. americanum but are relevant to public health nevertheless. PMID- 25533152 TI - Copresentation of relative and absolute effects is essential to promote optimal interpretability of treatment effects. PMID- 25533151 TI - Discordances originated by multiple meta-analyses on interventions for myocardial infarction: a systematic review. AB - OBJECTIVES: To clarify the impact of multiple (covering the same population, intervention, control, and outcomes) systematic reviews (SRs) on interventions for myocardial infarction (MI). STUDY DESIGN AND SETTING: Clinical Evidence (BMJ Group) sections and related search strategies regarding MI were used to identify multiple SRs published between 1997 and 2007. Multiple SRs were classified as discordant if they featured conflicting results or interpretation of them. RESULTS: Thirty-six SRs (23.5% of 153 on the treatment or prevention of MI) were classified as multiple and grouped in 16 clusters [ie, at least two SRs with the same PICO (population, condition/disease, intervention, control) and at least one common outcome] exploring angioplasty, angiotensin-converting enzyme inhibitors, anticoagulants, antiplatelets, beta-blockers, and stents. Complete agreement on statistically significant differences between interventions was found in 7 of 10 clusters with a shared composite outcome. Agreement was reduced when single outcomes were considered. Despite substantial variation and limited agreement in reporting of major outcomes, SRs agreed in their conclusions on the superiority of either the intervention or control in 14 of 16 clusters. Sources of minor discrepancies were found in terms of study and outcome selection, subgroup analyses, and interpretation of findings. CONCLUSION: Multiple SRs agreed in their qualitative conclusions but not on reporting and on analyses of hard outcomes. Discordance on significance of treatment effects was due to a combination of variation in design with inclusion of different studies and lack of precision for single hard outcomes compared with a composite outcome. Such inconsistencies among SRs could potentially slow the translation of SRs' results to clinical and public health decision making and suggest the need for a broader methodological and clinical agreement on their design. PMID- 25533153 TI - Quality improvement practices used by teaching versus non-teaching trauma centres: analysis of a multinational survey of adult trauma centres in the United States, Canada, Australia, and New Zealand. AB - BACKGROUND: Although studies have suggested that a relationship exists between hospital teaching status and quality improvement activities, it is unknown whether this relationship exists for trauma centres. METHODS: We surveyed 249 adult trauma centres in the United States, Canada, Australia, and New Zealand (76% response rate) regarding their quality improvement programs. Trauma centres were stratified into two groups (teaching [academic-based or -affiliated] versus non-teaching) and their quality improvement programs were compared. RESULTS: All participating trauma centres reported using a trauma registry and measuring quality of care. Teaching centres were more likely than non-teaching centres to use indicators whose content evaluated treatment (18% vs. 14%, p < 0.001) as well as the Institute of Medicine aim of timeliness of care (23% vs. 20%, p < 0.001). Non-teaching centres were more likely to use indicators whose content evaluated triage and patient flow (15% vs. 18%, p < 0.001) as well as the Institute of Medicine aim of efficiency of care (25% vs. 30%, p < 0.001). While over 80% of teaching centres used time to laparotomy, pulmonary complications, in hospital mortality, and appropriate admission physician/service as quality indicators, only two of these (in hospital mortality and appropriate admission physician/service) were used by over half of non-teaching trauma centres. The majority of centres reported using morbidity and mortality conferences (96% vs. 97%, p = 0.61) and quality of care audits (94% vs. 88%, p = 0.08) while approximately half used report cards (51% vs. 43%, p = 0.22). CONCLUSIONS: Teaching and non-teaching centres reported being engaged in quality improvement and exhibited largely similar quality improvement activities. However, differences exist in the type and frequency of quality indicators utilized among teaching versus non-teaching trauma centres. PMID- 25533155 TI - Suicide risk among 1.3 million veterans who were on active duty during the Iraq and Afghanistan wars. AB - PURPOSE: We conducted a retrospective cohort mortality study to determine the postservice suicide risk of recent wartime veterans comparing them with the US general population as well as comparing deployed veterans to nondeployed veterans. METHODS: Veterans were identified from the Defense Manpower Data Center records, and deployment to Iraq or Afghanistan war zone was determined from the Contingency Tracking System. Vital status of 317,581 deployed and 964,493 nondeployed veterans was followed from the time of discharge to December 31, 2009. Underlying causes of death were obtained from the National Death Index Plus. RESULTS: Based on 9353 deaths (deployed, 1650; nondeployed, 7703), of which 1868 were suicide deaths (351; 1517), both veteran cohorts had 24% to 25% lower mortality risk from all causes combined but had 41% to 61% higher risk of suicide relative to the US general population. However, the suicide risk was not associated with a history of deployment to the war zone. After controlling for age, sex, race, marital status, branch of service, and rank, deployed veterans showed a lower risk of suicide compared with nondeployed veterans (hazard ratio, 0.84; 95% confidence interval, 0.75-0.95). Multiple deployments were not associated with the excess suicide risk among deployed veterans (hazard ratio, 1.00; 95% confidence interval, 0.79-1.28). CONCLUSIONS: Veterans exhibit significantly higher suicide risk compared with the US general population. However, deployment to the Iraq or Afghanistan war, by itself, was not associated with the excess suicide risk. PMID- 25533156 TI - Helping children survive sepsis. PMID- 25533154 TI - Does territoriality modify the relationship between perceived neighborhood challenges and physical activity? A multilevel analysis. AB - PURPOSE: Individuals who perceive more neighborhood challenges are less physically active. Territoriality, an observable positive marker of social presence and defensible space in the neighborhood, may influence the association between neighborhood challenges and physical activity (PA). We hypothesized that greater territoriality would reduce the negative effects of neighborhood challenges on PA levels. METHODS: Data were collected by the Healthy Environments Partnership in an urban Midwestern city. Multilevel regressions were used to test associations in a sample of 696 white, black, and Hispanic adults older than 25 years. RESULTS: Territoriality moderated associations between residents' perceptions of neighborhood challenges and PA. Contrary to our hypothesis, individuals who perceived more neighborhood challenges and lived in areas with more territoriality markers (e.g., buildings with decorations, buildings with security signage, and neighborhood watch signs) were less physically active than other respondents (b = -2.41, standard error = 0.84, P < .01). CONCLUSIONS: Our findings suggest that associations between perceived neighborhood challenges and PA are shaped by the context in which the individual lives. Our study provides empirical evidence that individual perceptions and observed neighborhood characteristics are joint contributors to PA and suggest the need for continued research to characterize the complexity of individual and contextual factors that contribute to PA. PMID- 25533157 TI - Efficacy and safety of 532-nm and 1,064-nm Q-switched Nd:YAG laser treatment of frictional dermal melanosis over bony prominences (Lifa disease). AB - BACKGROUND: Frictional dermal melanosis over bony prominences (Lifa disease) is a common pigmentary skin disorder in Iraqi patients. Q-switched lasers are the gold standard treatment of correcting pigmentation; among them are the 532-nm and 1,064-nm lasers. OBJECTIVE: To evaluate the efficacy of these lasers in the treatment of hyperpigmentation due to Lifa disease. PATIENTS AND METHODS: A prospective, comparative, controlled, split-lesion clinical trial study was designed. Nineteen female patients with clinical diagnosis of Lifa disease were enrolled. Each patient was treated for 3 sessions at 2-week intervals. A 532-nm Q switched Nd:YAG laser was used on the left side and 1,064-nm on the right side of each lesion. Both objective and subjective parameters were assessed 1 and 3 months after the last treatment session. Darkness score, photographic assessment and patient satisfaction, and improvement of itch were recorded, respectively. RESULTS: Seventeen patients completed the study. The color score changes of both sides demonstrated that although both lasers were effective in reducing the pigmentation, the 1,064-nm wavelength had a more significant response. Similar results were obtained for the photographic evaluations and patient satisfaction scores. These changes were sustained throughout the 3 month follow-up. CONCLUSION: Both lasers were effective in the treatment of pigmentation abnormalities caused by Lifa disease. However, the efficacy was greater with the 1,064-nm wavelength. PMID- 25533158 TI - Intralesional bleomycin sclerotherapy of lymphangioma: partial response to treatment. PMID- 25533159 TI - Foam sclerotherapy for reticular veins of the chest: a retrospective review of efficacy and safety. AB - BACKGROUND: No study has evaluated the use of foam sclerotherapy in treating clinically conspicuous reticular chest veins. OBJECTIVE: This retrospective study evaluates patient-rated efficacy, safety, and satisfaction after foam sclerotherapy for reticular veins of the chest. MATERIALS AND METHODS: A telephone-based questionnaire was used for patient self-assessment of overall improvement, satisfaction, and adverse events. All patients had been treated with 0.25% to 0.50% sodium tetradecyl sulfate (STS) foam using room air (1:4 ratio). The mean length of follow-up was 3.7 years. RESULTS: Twelve of 23 patients were successfully contacted, with a total of 14 treatment sessions. Overall, patients reported scores of 2.4 +/- 0.8 for overall improvement (0 = none, 1 = mild, 2 = moderate, and 3 = complete resolution) and 1.75 +/- 0.6 for satisfaction with results (0 = not satisfied at all, 1 = mildly satisfied, and 2 = very satisfied), with minor treatment-related adverse events. CONCLUSION: Foam sclerotherapy with STS is effective for management of reticular veins of the chest with an excellent safety profile and high long-term patient satisfaction. PMID- 25533160 TI - Patient perception on the usage of smartphones for medical photography and for reference in dermatology. AB - BACKGROUND: With increasing use of smartphones in the practice and delivery of dermatologic care, little is known on patient perceptions regarding its applications in the clinical setting. OBJECTIVE: To survey patient viewpoints regarding medical photography and the usage of smartphone applications during a medical encounter. MATERIALS AND METHODS: Cross-sectional survey of adult patients in urban academic and private practice clinics. Patients responded to questionnaires tailored to identify respondent characteristics, preferences of photographing procedure and smartphone uses, and concerns regarding smartphone camera use. RESULTS: Of the 300 patients surveyed, the majority preferred a hospital-owned camera (97.7%) over the use of personal photographing equipment including a physician's digital camera (27.5%) or a physician's smartphone camera (27.2%). The majority found personal smartphones to be an acceptable reference tool (69.7%) and means to provide information to the patient (75.3%). CONCLUSION: Patients appear to have clear preferences in the equipment used for medical photography and acceptable applications of smartphones, highlighting the importance of feedback in shaping patient-physician interactions. In light of patient opinions on camera preferences, it may be prudent to make a conscientious effort to refrain from using smartphones as a camera in the clinical setting until patient concerns regarding its use can be addressed. PMID- 25533161 TI - A novel closure method for surgical defects in atrophic skin using cyanoacrylate adhesive and suture. PMID- 25533162 TI - Repair of an unwanted navel piercing. PMID- 25533163 TI - Aneurysmal dermatofibroma successfully treated with Mohs micrographic surgery. PMID- 25533164 TI - Eruptive keratoacanthomas as a complication of fractionated CO2 laser resurfacing and combination therapy with imiquimod and intralesional methotrexate. PMID- 25533165 TI - Commentary on Melanoma diagnosed following excision of "dysplastic nevi". PMID- 25533167 TI - Transport of ions in mesoporous carbon electrodes during capacitive deionization of high-salinity solutions. AB - Desalination of high-salinity solutions has been studied using a novel experimental technique and a theoretical model. Neutron imaging has been employed to visualize lithium ions in mesoporous carbon materials, which are used as electrodes in capacitive deionization (CDI) for water desalination. Experiments were conducted with a flow-through CDI cell designed for neutron imaging and with lithium-6 chloride ((6)LiCl) as the electrolyte. Sequences of neutron images have been obtained at a relatively high concentration of (6)LiCl solution to provide information on the transport of ions within the electrodes. A new model that computes the individual ionic concentration profiles inside mesoporous carbon electrodes has been used to simulate the CDI process. Modifications have also been introduced into the simulation model to calculate results at high electrolyte concentrations. Experimental data and simulation results provide insight into why CDI is not effective for desalination of high ionic-strength solutions. The combination of experimental information, obtained through neutron imaging, with the theoretical model will help in the design of CDI devices, which can improve the process for high ionic-strength solutions. PMID- 25533166 TI - Cross-clade simultaneous HIV drug resistance genotyping for reverse transcriptase, protease, and integrase inhibitor mutations by Illumina MiSeq. AB - BACKGROUND: Viral resistance to antiretroviral therapy threatens our best methods to control and prevent HIV infection. Current drug resistance genotyping methods are costly, optimized for subtype B virus, and primarily detect resistance mutations to protease and reverse transcriptase inhibitors. With the increasing use of integrase inhibitors in first-line therapies, monitoring for integrase inhibitor drug resistance mutations is a priority. We designed a universal primer pair to PCR amplify all major group M HIV-1 viruses for genotyping using Illumina MiSeq to simultaneously detect drug resistance mutations associated with protease, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, and integrase inhibitors. RESULTS: A universal primer pair targeting the HIV pol gene was used to successfully PCR amplify HIV isolates representing subtypes A, B, C, D, CRF01_AE and CRF02_AG. The universal primers were then tested on 62 samples from a US cohort of injection drug users failing treatment after release from prison. 94% of the samples were successfully genotyped for known drug resistance mutations in the protease, reverse transcriptase and integrase gene products. Control experiments demonstrate that mutations present at >= 2% frequency are reliably detected and above the threshold of error for this method. New drug resistance mutations not found in the baseline sample were identified in 54% of the patient samples after treatment failure. 86% of patients with major drug resistance mutations had 1 or more mutations associated with drug resistance to the treatment regimen at the time point of treatment failure. 59% of the emerging mutations were found at frequencies between 2% and 20% of the total sequences generated, below the estimated limit of detection of current FDA approved genotyping techniques. Primary plasma samples with viral loads as low as 799 copies/ml were successfully genotyped using this method. CONCLUSIONS: Here we present an Illumina MiSeq-based HIV drug resistance genotyping assay. Our data suggests that this universal assay works across all major group M HIV-1 subtypes and identifies all drug resistance mutations in the pol gene known to confer resistance to protease, reverse transcriptase and integrase inhibitors. This high throughput and sensitive assay could significantly improve access to drug resistance genotyping worldwide. PMID- 25533168 TI - Germline acquisition of Cas9/RNA-mediated gene modifications in monkeys. PMID- 25533169 TI - A year for nanoscience. PMID- 25533171 TI - Enhanced diffusion, chemotaxis, and pumping by active enzymes: progress toward an organizing principle of molecular machines. AB - Active enzymes diffuse more rapidly than inactive enzymes. This phenomenon may be due to catalysis-driven conformational changes that result in "swimming" through the aqueous solution. Recent additional work has demonstrated that active enzymes can undergo chemotaxis toward regions of high substrate concentration, whereas inactive enzymes do not, and, further, that active enzymes immobilized at surfaces can directionally pump liquids. In this Perspective, I will discuss these phenomena in light of Purcell's work on directed motion at low Reynold's number and in the context of microscopic reversibility. The conclusions suggest that a deep understanding of catalytically driven enhanced diffusion of enzymes and related phenomena can lead toward a general organizing principle for the design, characterization, and operation of molecular machines. PMID- 25533172 TI - Extended Klein edges in graphene. AB - Graphene has three experimentally confirmed periodic edge terminations, zigzag, reconstructed 5-7, and arm-chair. Theory predicts a fourth periodic edge of graphene called the extended Klein (EK) edge, which consists of a series of single C atoms protruding from a zigzag edge. Here, we confirm the existence of EK edges in both graphene nanoribbons and on the edge of bulk graphene using atomic resolution imaging by aberration-corrected transmission electron microscopy. The formation of the EK edge stems from sputtering and reconstruction of the zigzag edge. Density functional theory reveals minimal energy for EK edge reconstruction and bond distortion both in and out of plane, supporting our TEM observations. The EK edge can now be included as the fourth member of observed periodic edge structures in graphene. PMID- 25533173 TI - Vertical bone augmentation induced by ultrathin hydroxyapatite sputtered coated mini titanium implants in a rabbit calvaria model. AB - BACKGROUND: The purpose of this study was to evaluate the vertical new bone formation induced by sputtered HA-coated titanium implants (HA-coated) compared with sandblasted acid-etched titanium implants (noncoated) in a rabbit calvarial model. MATERIALS AND METHOD: Twenty HA-coated and 20 noncoated titanium implants were divided equally into four groups as HA-coated implant (HA); noncoated implant (NC); HA-coated implant with membrane (HA/M); noncoated implant with membrane (NC/M). All implants were placed 5 mm above the original bone (OB). Collagen membranes were placed over the implants in HA/M and NC/M groups. The animals were sacrificed at 4 weeks (n = 5) and 8 weeks (n = 5). Vertical bone height above OB (VBH, mm) and augmented bone area (ABA, mm(2) ) were analyzed histologically and radiographically. RESULTS: At 4 weeks, VBH reached significantly higher level in HA/M group compared with other three groups (p < 0.05). At 8 weeks, significant difference was detected between HA/M and NC groups (p < 0.05). At 4 and 8 weeks, ABA in HA/M group was significantly larger compared with other three groups (p < 0.05). CONCLUSION: The present results indicated that sputtered HA-coated titanium implant together with collagen membrane could be a novel and effective approach for vertical bone augmentation. PMID- 25533174 TI - A series of pi-extended thiadiazoles fused with electron-donating heteroaromatic moieties: synthesis, properties, and polymorphic crystals. AB - pi-Extended thiadiazoles 4-8 fused with various electron-donating heteroaromatic moieties have been designed and synthesized. Just like thiadiazoles 1-3 synthesized previously, 4-8 exhibit intramolecular charge-transfer (CT) interactions, moderate-to-good fluorescence quantum yields of up to 0.78, and electrochemical amphoterism. In comparison with 1-3, the benzannulation in thiadiazoles 4-7 moderately extends the pi conjugation and significantly increases the stability of the cationic species formed upon electrochemical oxidation. The fluorescence quantum yields increase remarkably from 3 to 6 and 7 due to the efficient suppression of nonradiative intersystem crossing resulting from the benzannulation. The properties of 4-8 strongly reflect the different species annulated to the pyrrole rings, namely benzothiophene, naphthalene, and benzofuran. Eleven crystals, including poly- and pseudopolymorphic crystals of 1 (1-Crys.(Y) and 1-Crys.(G)), 2 (2-Crys.(O) and 2-Crys.(G)), 4 (4-Crys.(O) and 4 Crys.(G)), and 6 (6-Crys.(O) and 6-Crys.(G)), were obtained and characterized by X-ray crystallography. The fluorescence colors and efficiencies are distinct for each poly- and pseudopolymorph of 1, 2, 4, and 6. It has been suggested that both the extent of the electronic interactions in the pi-stacked dimers and the presence of excitonic interactions originating in the 1D face-to-face slipped columns affect the fluorescence wavelengths of the poly- and pseudopolymorphs. PMID- 25533175 TI - Update on endoscopic endonasal resection of skull base meningiomas. AB - BACKGROUND: The objective of this work was to report success rates as well as potential obstacles in transnasal endoscopic resection of anterior skull base meningiomas. METHODS: The study design was a case series with chart review at tertiary referral centers in South Australia and New Zealand. The patients were 37 consecutive patients who underwent endoscopic resection of skull-base meningiomas between 2004 and 2013. Review of patient charts and operative details were performed. Outcomes including complications are reported. RESULTS: Eighty four percent of patients were women. There were 28 primary and 9 revision cases. Tumor locations were as follows: 14 olfactory groove/subfrontal; 12 planum/jugum sphenoidale; 7 tuberculum sellae; 3 clinoidal; and 1 clival. Vision change was the most common presenting symptom. Mean tumor volume was 33.68 cm(3) , mean diameter was 2.78 cm. Average operating times decreased with an initial learning curve and then plateaued. Primary tumors larger than 60 cm(3) took an average of 10 hours to resect. Gross total removal was achieved in 29 patients. There were no perioperative deaths. Two deaths occurred within 1 year of surgery. Postoperative cerebrospinal fluid (CSF) leaks occurred in 13 patients. Seventy five percent of patients presenting with visual loss reported visual improvement. Of the 29 patients considered to have had complete resection at surgery, one was found to have residual disease on a postoperative magnetic resonance imaging (MRI) and another one later developed radiological evidence of recurrence. CONCLUSION: Using a 2-team approach, meningiomas of the skull base were successfully removed via an intranasal endoscopic technique. Although complete resection is typically possible even with large tumors, the lengthy resection required time for tumors larger than 60 cm(3) (diameter >=4 cm) may obviate some of the advantages of this approach. The rate of postoperative CSF leak decreases when a synthetic dural substitute is added but does not approach zero. PMID- 25533176 TI - Genome-wide methylation analysis in vestibular schwannomas shows putative mechanisms of gene expression modulation and global hypomethylation at the HOX gene cluster. AB - Schwannomas are tumors that develop from Schwann cells in the peripheral nerves and commonly arise from the vestibular nerve. Vestibular schwannomas can present unilaterally and sporadically or bilaterally when the tumor is associated with neurofibromatosis Type 2 (NF2) syndrome. The molecular hallmark of the disease is biallelic inactivation of the NF2 gene. The epigenetic signature of schwannomas remains poorly understood and is mostly limited to DNA methylation of the NF2 gene, whose altered expression due to epigenetic factors in this tumor is controversial. In this study, we tested the genomewide DNA methylation pattern of schwannomas to shed light on this epigenetic alteration in these particular tumors. The methodology used includes Infinium Human Methylation 450K BeadChip microarrays in a series of 36 vestibular schwannomas, 4 nonvestibular schwannomas, and 5 healthy nerves. Our results show a trend toward hypomethylation in schwannomas. Furthermore, homeobox (HOX) genes, located at four clusters in the genome, displayed hypomethylation in several CpG sites in the vestibular schwannomas but not in the nonvestibular schwannomas. Several microRNA (miRNA) and protein-coding genes were also found to be hypomethylated at promoter regions and were confirmed as upregulated by expression analysis; including miRNA-21, Met Proto-Oncogene (MET), and PMEPA1. We also detected methylation patterns that might be involved in alternative transcripts of several genes such as NRXN1 or MBP, which would increase the complexity of the methylation and expression patterns. Overall, our results show specific epigenetic signatures in several coding genes and miRNAs that could potentially be used as therapeutic targets. PMID- 25533177 TI - Conventional versus minimally invasive aortic valve replacement: pooled analysis of propensity-matched data. AB - BACKGROUND: Minimally invasive aortic valve replacement (mAVR) is increasingly preferred over conventional AVR (cAVR). However, data comparing these procedures present conflicting results. Hence, we conducted a systematic review and meta analysis comparing clinical results in these cohorts. METHOD: Only randomized controlled trials (RCT) and propensity-matched observational studies (POS) (1998 2013) comparing clinical outcome of patients subjected to mAVR or cAVR were pooled. Continuous data was compared using mean/standardized mean difference (MD/SMD) while categorical results were pooled to obtain an odds ratio (OR) with a 95% confidence interval. RESULTS: A total of 18 studies (6 RCT and 12 POS) (1973 mAVR patients; 2697 cAVR patients) were analyzed. The mean ischemic time was significantly longer with mAVR (MD 9.42 minutes [4.25-14.59]; p < 0.01). However, early mortality (mAVR [1.8%] and cAVR [3%]) was comparable (OR 0.70 [0.46-1.06]; p = 0.09). Postoperative ventilation time was slightly shorter after mAVR (7.5 vs 11.1 hours; p = 0.07), and hospital discharge was earlier after mAVR (MD -1.05 [-1.64 to -0.46]; p < 0.01). However, mAVR failed to reduce transfusion requirement (OR 0.77 [0.51-1.14]; p = 0.19) or pain scores (SMD -0.25 [-0.65 to 0.13]; p = 0.20). Postoperative atrial fibrillation (p = 0.67) and stroke (p = 0.79) rates were comparable. Pooled rate of conversion to full sternotomy was 2.5%. Cosmetic satisfaction could not be pooled due to reporting heterogeneity. CONCLUSION: Minimally invasive aortic valve replacement can be performed safely despite the longer ischemic time. While minimally invasive surgery does demonstrate some advantages in postoperative recovery, we failed to find any other substantial improvement in outcome over conventional aortic valve replacement. PMID- 25533178 TI - Colloid versus crystalloid fluid therapy in surgical patients. PMID- 25533179 TI - Changes in the profile of volatiles of canned coconut milk during storage. AB - The alteration of the profile of volatiles of canned coconut milk was monitored during storage at ambient temperature. Canned coconut milk was thermally processed (121 degrees C for 5 min), and then stored at ambient temperature (32 to 35 degrees C) for 6 mo. Volatile compounds were assessed monthly using direct solvent extraction (diethyl ether), followed by high-vacuum distillation and gas chromatography-mass spectrometry analysis. Six groups of compounds consisting of alcohols, aldehydes, ketones, acids, esters, lactones, and others were identified. Two stages of major changes in profile of volatiles were observed. The 1st occurred after 2 mo as indicated by a high abundance of alcohols, acids, and lactones. The 2nd was observed after 5 mo and corresponded to a large increase in lactones, short-chain free fatty acids, 3-methyl-2(5H)-furanone, and phenol. Acetic and butyric acids observed after 5 mo could contribute to the potential of off-odor development in the product as indicated by their high odor activity values. Lactones increased approximately 10-fold. Identification of 3 methyl-2(5H)-furanone indicated that Maillard reaction had occurred in conjunction with the development of a coconut, toffee-like, and caramel odor. PMID- 25533180 TI - Co-occurrence of Dystonic and Dyskinetic Tongue Movements with Oral Apraxia in Post-regression Dysphagia in Classical Rett Syndrome Years of Life 1 Through 5. AB - We do not know the natural history of dysphagia in classical Rett syndrome (RTT) by stage or age. This study investigated swallowing physiology in 23 females ages 1:7 to 5:8 (years, months) with classical Rett syndrome to determine common and distinguishing features of dysphagia in post-regression early Pseudostationary Stage III. In-depth analysis of videofluoroscopic swallowing studies (VFSS) found dysmotility of oral stage events across subjects implicating oral apraxia. Impaired motility was further compromised by recurrent dystonic and dyskinetic movements that co-occurred with oral apraxia during oral ingestion in 78 % (n = 18) of the subjects with RTT. Of this group, 44 % displayed rocking and/or rolling lingual pattern, 56 % had recurrent oral tongue retroflexions, and/or elevated posturing of the tongue tip, and, 72 % displayed multi-wave oropharyngeal transfer pattern. The proportion of subjects whose swallowing motility was disrupted by aberrant involuntary tongue movements did not differ significantly between bolus types (liquid, puree, and solid) trialed. Liquid ingestion was significantly more efficient in subjects using bottles with nipples than their counterparts who used spouted or straw cups. Dystonic and dyskinetic tongue movements disrupted liquid ingestion in subjects using cups with spouts or straws significantly more than those using bottles. Analysis of food ingestion revealed that significantly more subjects were able to orally form, transport, and transfer a puree bolus into the pharynx than they were a solid bolus. A significantly larger number of subjects aspirated and penetrated liquid than they did puree or solid. No significant relationship was found between subjects with airway contamination and those with dystonic and dyskinetic tongue movements. Subjects' rocking and rolling lingual patterns were consistent with those evidenced in adults with Parkinson's disease. Subjects' tongue retroflexions were classified as provisionally unique to RTT. VFSS pre-planning, fluoroscopic procedures, and therapeutic strategies specific to this specialty population were derived. PMID- 25533181 TI - Swallowing problems at the end of the palliative phase: incidence and severity in 164 unsedated patients. AB - Swallowing problems are reported to be a common finding in patients who receive palliative care. In existing literature, the incidence of swallowing problems is mostly described in small numbers of patients at the start of the palliative phase. As we hypothesized that the incidence of dysphagia might increase as the palliative phase progresses, this study describes the incidence of swallowing problems and related problems in 164 unsedated patients at the end of the palliative phase, defined by the last 72 h before their death. To determine the incidence of swallowing problems and related problems, questionnaires were completed bereaved by relatives and nursing staff. Our data shows that in the palliative phase the incidence of swallowing problems can be as high as 79 %. A significant correlation was found between swallowing problems and reduced psycho social quality of life as assessed by nursing staff (rho = -.284). Overall the nursing staff rated the incidence and severity of swallowing problems (and related problems like frequent coughing, loss of appetite, and problems with oral secretions) lower than the relatives. This study suggests that incidence of swallowing problems at the end of the palliative phase is high and that these difficulties may not only result in discomfort for patients, but also can raise concern for caregivers. More information and education on management of swallowing problems in palliative settings might be needed for both relatives and nursing staff. However, the data also suggest that any intervention should be proportional to the level of distress caused by the intervention. PMID- 25533182 TI - Turner syndrome--issues to consider for transition to adulthood. AB - BACKGROUND: Turner syndrome (TS) is associated with a spectrum of health problems across the age span, which requires particular attention during the transition period in these adolescents. AREAS OF AGREEMENT: The majority of girls with TS require oestrogen replacement from puberty onwards, which is important for adequate feminization, uterine development and maintenance of bone health. There is a lifetime increased risk from autoimmune conditions like hypothyroidism, coeliac disease, hearing loss and aortic dilatation with the potential to lead to aortic dissection. A systematic and holistic approach to provision of health care in TS is needed. AREAS OF CONTROVERSY: Several unanswered questions remain, including the choice of hormone replacement therapy in the young person with TS and in adulthood; the optimal mode of cardiovascular assessment; the best management and assessment prior to and during pregnancy. AREAS TIMELY FOR DEVELOPING RESEARCH: The optimal model of care and transition to adult services in TS requires attention. Further research is needed in relation to cardiovascular risk assessment, pregnancy management and hormone replacement therapy in TS. PMID- 25533183 TI - Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats. AB - The present study was aimed to investigate the mechanistic aspect of Aroclor 1260 induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016. PMID- 25533184 TI - Impact of pazopanib on docetaxel exposure: results of a phase I combination study with two different docetaxel schedules. AB - PURPOSE: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. METHODS: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. RESULTS: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m(2), while for D1w MTD, it was 20 mg/m(2). In the D3w schedule, the administration of pazopanib led to a 33% lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m(2); P = 0.019) and >50% increase in AUC(0-infinity) (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. CONCLUSIONS: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition. PMID- 25533185 TI - Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. AB - SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Noncovalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA interstrand crosslinks (ICLs), yet how SLX4 is targeted to other functional contexts remains unclear. Here, we show that SLX4 binds SUMO-2/3 chains via SUMO-interacting motifs (SIMs). The SIMs of SLX4 are dispensable for ICL repair but important for processing CPT-induced replication intermediates, suppressing fragile site instability, and localizing SLX4 to ALT telomeres. The localization of SLX4 to laser-induced DNA damage also requires the SIMs, as well as DNA end resection, UBC9, and MDC1. Furthermore, the SUMO binding of SLX4 enhances its interaction with specific DNA-damage sensors or telomere-binding proteins, including RPA, MRE11-RAD50-NBS1, and TRF2. Thus, the interactions of SLX4 with SUMO and ubiquitin increase its affinity for factors recognizing different DNA lesions or telomeres, helping to direct the SLX4 complex in distinct functional contexts. PMID- 25533186 TI - Yeast PP4 interacts with ATR homolog Ddc2-Mec1 and regulates checkpoint signaling. AB - Mec1-Ddc2 (ATR-ATRIP) controls the DNA damage checkpoint and shows differential cell-cycle regulation in yeast. To find regulators of Mec1-Ddc2, we exploited a mec1 mutant that retains catalytic activity in G2 and recruitment to stalled replication forks, but which is compromised for the intra-S phase checkpoint. Two screens, one for spontaneous survivors and an E-MAP screen for synthetic growth effects, identified loss of PP4 phosphatase, pph3Delta and psy2Delta, as the strongest suppressors of mec1-100 lethality on HU. Restored Rad53 phosphorylation accounts for part, but not all, of the pph3Delta-mediated survival. Phosphoproteomic analysis confirmed that 94% of the mec1-100-compromised targets on HU are PP4 regulated, including a phosphoacceptor site within Mec1 itself, mutation of which confers damage sensitivity. Physical interaction between Pph3 and Mec1, mediated by cofactors Psy2 and Ddc2, is shown biochemically and through FRET in subnuclear repair foci. This establishes a physical and functional Mec1 PP4 unit for regulating the checkpoint response. PMID- 25533187 TI - mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. AB - mTORC1 plays a key role in autophagy as a negative regulator. The currently known targets of mTORC1 in the autophagy pathway mainly function at early stages of autophagosome formation. Here, we identify that mTORC1 inhibits later stages of autophagy by phosphorylating UVRAG. Under nutrient-enriched conditions, mTORC1 binds and phosphorylates UVRAG. The phosphorylation positively regulates the association of UVRAG with RUBICON, thereby enhancing the antagonizing effect of RUBICON on UVRAG-mediated autophagosome maturation. Upon dephosphorylation, UVRAG is released from RUBICON to interact with the HOPS complex, a component for the late endosome and lysosome fusion machinery, and enhances autophagosome and endosome maturation. Consequently, the dephosphorylation of UVRAG facilitates the lysosomal degradation of epidermal growth factor receptor (EGFR), reduces EGFR signaling, and suppresses cancer cell proliferation and tumor growth. These results demonstrate that mTORC1 engages in late stages of autophagy and endosome maturation, defining a broader range of mTORC1 functions in the membrane associated processes. PMID- 25533188 TI - The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. AB - The SLX4 Fanconi anemia protein is a tumor suppressor that may act as a key regulator that engages the cell into specific genome maintenance pathways. Here, we show that the SLX4 complex is a SUMO E3 ligase that SUMOylates SLX4 itself and the XPF subunit of the DNA repair/recombination XPF-ERCC1 endonuclease. This SLX4 dependent activity is mediated by a remarkably specific interaction between SLX4 and the SUMO-charged E2 conjugating enzyme UBC9 and relies not only on newly identified SUMO-interacting motifs (SIMs) in SLX4 but also on its BTB domain. In contrast to its ubiquitin-binding UBZ4 motifs, SLX4 SIMs are dispensable for its DNA interstrand crosslink repair functions. Instead, while detrimental in response to global replication stress, the SUMO E3 ligase activity of the SLX4 complex is critical to prevent mitotic catastrophe following common fragile site expression. PMID- 25533189 TI - Monitoring and targeting the initial dimerization stage of amyloid self-assembly. AB - Amyloid deposits are pathological hallmark of a large group of human degenerative disorders of unrelated etiologies. While accumulating evidence suggests that early oligomers may account for tissue degeneration, most detection tools do not allow the monitoring of early association events. Here we exploit bimolecular fluorescence complementation analysis to detect and quantify the dimerization of three major amyloidogenic polypeptides; islet amyloid polypeptide, beta-amyloid and alpha-synuclein. The constructed systems provided direct visualization of protein-protein interactions in which only assembled dimers display strong fluorescent signal. Potential inhibitors that interfere with the initial intermolecular interactions of islet amyloid polypeptide were further identified using this system. Moreover, the identified compounds were able to inhibit the aggregation and cytotoxicity of islet amyloid polypeptide, demonstrating the importance of targeting amyloid dimer formation for future drug development. PMID- 25533190 TI - Biomimetic glycopolymers tethered gold nanoparticles: preparation, self-assembly and lectin recognition properties. AB - Biomimetic glycopolymers poly(gluconamidoethylmethacrylate)-b-poly(E caprolactone)-b-poly(gluconamidoethylmethacrylate) with degradable disulfide groups in the backbone (PGAMA-PCL-SS-PCL-PGAMA) were synthesized by the combination of ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The internal disulfide bonds were cleaved by reduction with dl-dithiothreitol to yield the corresponding thiol terminated glycopolymers. The thiol terminated glycopolymers were effectively anchored on the surface of gold nanoparticles to prepare the biomimetic glycopolymers modified gold nanoparticles (Gly@Au NPs). Moreover, the properties of the Gly@Au NPs in aqueous solution were investigated. Transmission electron microscopy (TEM) analysis revealed that the self-assembly morphology of the Gly@Au NPs can be fine-tuned, from irregular clusters to spherical aggregates, by changing the weight fraction of the hydrophobic PCL block. Furthermore, the Gly@Au NPs had specific recognition with Concanavalin A (Con A). PMID- 25533191 TI - Diet strongly influences the gut microbiota of surgeonfishes. AB - Intestinal tracts are among the most densely populated microbial ecosystems. Gut microbiota and their influence on the host have been well characterized in terrestrial vertebrates but much less so in fish. This is especially true for coral reef fishes, which are among the most abundant groups of vertebrates on earth. Surgeonfishes (family: Acanthuridae) are part of a large and diverse family of reef fish that display a wide range of feeding behaviours, which in turn has a strong impact on the reef ecology. Here, we studied the composition of the gut microbiota of nine surgeonfish and three nonsurgeonfish species from the Red Sea. High-throughput pyrosequencing results showed that members of the phylum Firmicutes, especially of the genus Epulopiscium, were dominant in the gut microbiota of seven surgeonfishes. Even so, there were large inter- and intraspecies differences in the diversity of surgeonfish microbiota. Replicates of the same host species shared only a small number of operational taxonomic units (OTUs), although these accounted for most of the sequences. There was a statistically significant correlation between the phylogeny of the host and their gut microbiota, but the two were not completely congruent. Notably, the gut microbiota of three nonsurgeonfish species clustered with some surgeonfish species. The microbiota of the macro- and microalgavores was distinct, while the microbiota of the others (carnivores, omnivores and detritivores) seemed to be transient and dynamic. Despite some anomalies, both host phylogeny and diet were important drivers for the intestinal microbial community structure of surgeonfishes from the Red Sea. PMID- 25533192 TI - Calculation of pediatric left ventricular mass: validation and reference values using real-time three-dimensional echocardiography. AB - BACKGROUND: Reference values for left ventricular mass (LVM) are important echocardiographic tools for the follow-up of pediatric patients with cardiac disease. Cardiac magnetic resonance (CMR) imaging is currently regarded as the gold standard. The aims of this study were to validate LVM calculated using real time three-dimensional echocardiography (RT3DE) and to establish pediatric reference values. METHODS: For validation, 40 subjects (20 patients) consecutively underwent CMR (3-T TX Achieva, 25 cardiac phases/slice) and RT3DE (iE33 or Vivid E9, four subvolumes) in a single-center approach. The quantification of CMR data by the disk summation method as standard (mean LVM, 84.2 +/- 53 g; range, 17.7-231.7 g) was compared with RT3DE. In a multicenter prospective design, 434 healthy children were investigated using standard software (LV-Analysis version 3.1). RESULTS: In comparison with CMR, RT3DE provided a slight overestimation of LVM of only 2.5 +/- 11.3% (r = 0.990, intraclass correlation coefficient = 0.995), and there was low intraobserver (mean, 0.9 +/- 7.1%; scatter, 13.2% to -15.0%; r = 0.996; intraclass correlation coefficient = 0.998) and interobserver (mean, 1.5 +/- 9.3%; scatter, 17.2% to 20.1%; r = 0.993; intraclass correlation coefficient = 0.996) variability. Feasibility of the multicenter approach was 76%, resulting in 332 healthy children (median age, 10.0 years; range, 0-18 years; group I range, 0-6 years; group II range, 7-18 years) with data sets providing adequate image quality. LVM was correlated with sex (group II), age (r = 0.901), height (r = 0.881), weight (r = 0.876), and body surface area (r = 0.898). Unisex percentiles for 0 to 6 years of age and separated according to gender from 7 to 18 years of age were established. Mean calculation time for RT3DE was <3 min. CONCLUSIONS: In children, LVM calculation presuming excellent real-time three-dimensional echocardiographic data sets is accurate, quick, and reproducible. The percentiles provided are based on a large sample size and may be useful for clinical practice. PMID- 25533193 TI - Evolution of left ventricular function in the preterm infant. AB - BACKGROUND: The aim of this study was to evaluate left ventricular function in preterm infants from 28 days to near term using echocardiography. METHODS: Thirty clinically stable preterm infants delivered at <30 weeks' gestational age were prospectively enrolled. At 28 days, conventional, tissue Doppler, and speckle tracking echocardiography evaluations of left ventricular function were performed, with comparison made to findings in 30 healthy term infants of similar postnatal age. Sixteen preterm infants underwent repeat examinations near term. RESULTS: Compared with controls, preterm infants at 28 days had decreased peak mitral valve (MV) E-wave velocities (P < .01), E/A ratios (P < .0001), annular e' velocities (P < .0001), and e'/a' ratios (P < .0001); increased MV E/e' ratios (P < .01); and lower basal circumferential early diastolic and higher late diastolic strain rates. No significant differences were found in fractional shortening, ejection fraction, and longitudinal or circumferential strain and strain rate between preterm infants and controls. Although preterm infants at 28 days had higher heart rates compared with controls (161 +/- 15 vs 142 +/- 16 beats/min), no significant correlations existed between heart rate and MV E, E/A ratio, e', e'/a' ratio, and E/e' ratio. Near term, the differences in diastolic function persisted, including decreased MV e'/a' ratio (P < .05), increased E/e' ratio (P < .01), and increased late diastolic strain rate. CONCLUSIONS: Clinically stable preterm infants have normal left ventricular systolic function but altered diastolic function, with greater dependence on atrial contraction, the latter of which persists despite nearing term. These findings may be relevant to the management of preterm infants and may relate to the longer term myocardial dysfunction observed in affected adults. PMID- 25533195 TI - Timing in response-initiated fixed intervals. AB - Different events can serve as time markers that initiate intervals in schedules of reinforcement. Pigeons were exposed to fixed-interval (FI) schedules in which the onset of the interval was signaled by the illumination of a key light or initiated by a peck to a lighted key. Food was delivered following the first response after the interval elapsed. In Experiment 1, three pigeons were exposed to a multiple schedule. One component was a standard FI schedule: Key light illumination signaled the onset of the interval. The other component was a response-initiated fixed-interval (RIFI) schedule: The first key-peck response determined the onset of the interval. In Experiment 2, three pigeons were exposed to a multiple FI-RIFI schedule of reinforcement and on occasional trials food was not delivered (i.e. "no-food" or "peak trials"). A yoking procedure equated reinforcement rates between the schedule types in both experiments. Absolute response rates early in the intervals were higher in the RIFI schedules of both experiments. Normalized response-rate gradients, ogive fits of normalized response gradients, and breakpoints were not systematically different for the schedule types in Experiment 1, indicating similar patterns of responding between interval onset and food delivery. However, during peak trials in Experiment 2 the duration of responding at a high rate was longer for RIFI schedules than FI schedules. This suggests that timing precision was reduced in the RIFI schedules and that relative "distinctiveness" of a time marker may determine its efficacy. PMID- 25533194 TI - How do physicians and trainers experience outcome-based education in "Rational prescribing"? AB - BACKGROUND: Continuing medical education (CME) is compulsory in Iran, but has shown limitations in terms of educational style and format. Outcome-based education (OBE) has been proposed internationally to create links to physicians' actual practices. We designed an outcome-based educational intervention for general physicians in primary care (GPs). Positive outcomes on GPs' knowledge, skills and performance in the field of rational prescribing were found and have been reported.The specific purpose of this study was to explore the perceptions of the GPs and trainers, who participated in the outcome-based education on rational prescribing. METHODS: All nine trainers in the educational programme and 12 general physicians (out of 58) were invited to individual interviews four months after participation in the CME program. Semi-structured open-ended interviews were carried out. Qualitative content analysis was used to explore the text and to interpret meaning and intention. RESULTS: There was a widespread agreement that the programme improved the participants' knowledge and skills to a higher extent than previously attended programmes. Trainers emphasized the effect of outcome-based education on their educational planning, teaching and assessment methods, while the general physicians' challenges were how to adapt their learning in the real work environment considering social and economical barriers. Self-described attitudes and reported practice changed towards more rational prescribing. CONCLUSIONS: Outcome-based CME seems attractive and additionally useful for general physicians in Iran and could be an effective approach when creating CME programmes to improve general physicians' performance. Similar approaches could be considered in other contexts both regionally and globally. PMID- 25533196 TI - A comparison of axial versus coronal image viewing in computer-aided detection of lung nodules on CT. AB - PURPOSE: To compare primarily viewing axial images (Axial mode) versus coronal reconstruction images (Coronal mode) in computer-aided detection (CAD) of lung nodules on multidetector computed tomography (CT) in terms of detection performance and reading time. MATERIALS AND METHODS: Sixty CT data sets from two institutions were collected prospectively. Ten observers (6 radiologists, 4 pulmonologists) with varying degrees of experience interpreted the data sets using CAD as a second reader (performing nodule detection first without then with aid). The data sets were interpreted twice, once each for Axial and Coronal modes, in two sessions held 4 weeks apart. Jackknife free-response receiver operating characteristic analysis was used to compare detection performances in the two modes. RESULTS: Mean figure-of-merit values with and without aid were 0.717 and 0.684 in Axial mode and 0.702 and 0.671 in Coronal mode; use of CAD significantly increased the performance of observers in both modes (P < 0.01). Mean reading times for radiologists did not significantly differ between Axial (156 +/- 74 s) and Coronal mode (164 +/- 69 s; P = 0.08). Mean reading times for pulmonologists were significantly lower in Coronal (112 +/- 53 s) than in Axial mode (130 +/- 80 s; P < 0.01). CONCLUSION: There was no statistically significant difference between Axial and Coronal modes for lung nodule detection with CAD. PMID- 25533197 TI - Ketone body production is differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans. AB - BACKGROUND & AIMS: Levels of ketone bodies have been reported to be both increased and decreased in individuals with non-alcoholic fatty liver disease. We investigated whether the metabolism of ketone bodies is different in simple steatosis and in non-alcoholic steatohepatitis (NASH). METHODS: Serum low molecular weight molecules including ketone bodies were measured using high throughput proton (1H) nuclear magnetic resonance in 116 (76 categorized unequivocally to those with normal liver, simple steatosis or NASH) morbidly obese individuals [age 47.3 +/- 8.7 (mean +/- SD) years, body mass index 45.1 +/- 6.1 kg/m(2) , 39 men and 77 women] with histological assessment of NASH and analysis of gene expression in the liver. Finally, we correlated beta hydroxybutyrate (beta-OHB) levels with NASH predicting score in Metabolic Syndrome in Men Study (METSIM) population study (n = 8749 non-diabetic men). RESULTS: Levels of ketone bodies were lower in individuals with NASH compared to individuals with simple steatosis (P = 0.004 and P = 0.018 for beta-OHB and acetoacetate respectively). Lower levels of beta-OHB were associated with the NASH predicting score in the METSIM study (P = 0.001). Liver inflammation correlated with mRNA expression of genes regulating ketolysis in the liver (Spearman correlation 0.379-0.388, P < 0.0006 for ACAT1, ACSS2 and BDH1). CONCLUSION: Lower levels of ketone bodies in individuals with NASH compared to individuals with simple steatosis suggest a decrease in ketone body metabolism in NASH. PMID- 25533198 TI - STEAM-MiTiS: An MR spectroscopy method for the detection of scalar-coupled metabolites and its application to glutamate at 7 T. AB - PURPOSE: We herein present a spectroscopic technique for the detection of scalar coupled metabolites based on stimulated echo acquisition mode (STEAM). The method is based on the time evolution of scalar-coupled metabolites at different mixing times and a constant echo time. The technique is optimized for targeting the metabolite glutamate at 7T. METHODS: Numerical simulations were used to optimize the parameters to maximize the chosen metabolite signal. The maximum detection efficiency and metabolite signal as a function of echo time were used to identify the optimal parameters. In vitro and in vivo validations of the method were also performed. RESULTS: This method canceled all the strong singlet lines and signals from macromolecules and preserved signals originating from the scalar-coupled metabolites. The subtracted spectrum was strongly simplified, but the complete spectral information of the traditional STEAM acquisition was retained in the sum spectrum. CONCLUSIONS: The simulations performed in this study were in agreement with the experimental results, and a clear detection of the metabolite of interest was obtained. The applicability in vivo was also demonstrated, with the selective detection of glutamate in human brain. This technique is simple, suitable for standard MR systems without sequence programming and could be used to detect other metabolites. PMID- 25533201 TI - Differences in serum protein 2D gel electrophoresis patterns of Przewalski's (Mongolian wild horse) and thoroughbred horses. AB - The objective of this study was to assess differences in serum protein expression profiles of Przewalski's (Mongolian wild horse) and thoroughbred horses using proteome analysis. The serum proteins were separated by two-dimensional electrophoresis (2-DE) and five different gene products were identified. Proteins represented by the five spots were identified by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry (MS)/MS technology. The identities of all proteins were deduced based on their similarity to proteins in the human plasma protein database. Three proteins (a haptoglobin-2 alpha glycoprotein and two haptoglobin-2beta glycoproteins with different accession numbers) were downregulated in Przewalski's horse sera compared to thoroughbred horse sera. Moreover, two proteins (tetraspanin-18 and pM5) were upregulated in Przewalski's horses compared to thoroughbred horses. Haptoglobin-2 alpha and haptoglobin-2beta may serve as candidate molecules in future studies of inflammation, coagulation, immune modulation and pro-oxidant and antioxidant activity with consequential effects on the entire metabolism of the horse. PMID- 25533200 TI - The DNMT1 intrinsically disordered domain regulates genomic methylation during development. AB - The DNMT1 cytosine methyltransferase enzyme contains a large ~300-aa intrinsically disordered domain (IDD) that we previously showed regulated DNA methylation patterns in mouse ES cells. Here we generated seven mouse lines with different mutations in the IDD. Homozygous mutant mice of five lines developed normally, with normal levels of methylation on both imprinted and nonimprinted DNA sequences. The other two lines, however, had alterations in imprinted and/or nonimprinted (global) DNA methylation appearing during embryonic development. Embryos of one line expressing a DNMT1 variant containing a 6-aa rat orthologous sequence in the IDD maintained imprinted methylation, showed very reduced levels of global methylation and occasionally completed fetal development. These in vivo studies demonstrate that at least two DNMT1-dependent methylation processes can be distinguished during fetal development. One process maintains the bulk of genomic methylation on nonimprinted sequences. The other process maintains methylation on a much smaller class of sequences including but not limited to gametic differentially methylated domains (gDMDs) that transmit essential imprinted parent-specific methylation for embryonic development. PMID- 25533199 TI - Mitotic accumulation of dimethylated lysine 79 of histone H3 is important for maintaining genome integrity during mitosis in human cells. AB - The loss of genome stability is an early event that drives the development and progression of virtually all tumor types. Recent studies have revealed that certain histone post-translational modifications exhibit dynamic and global increases in abundance that coincide with mitosis and exhibit essential roles in maintaining genomic stability. Histone H2B ubiquitination at lysine 120 (H2Bub1) is regulated by RNF20, an E3 ubiquitin ligase that is altered in many tumor types. Through an evolutionarily conserved trans-histone pathway, H2Bub1 is an essential prerequisite for subsequent downstream dimethylation events at lysines 4 (H3K4me2) and 79 (H3K79me2) of histone H3. Although the role that RNF20 plays in tumorigenesis has garnered much attention, the downstream components of the trans-histone pathway, H3K4me2 and H3K79me2, and their potential contributions to genome stability remain largely overlooked. In this study, we employ single-cell imaging and biochemical approaches to investigate the spatial and temporal patterning of RNF20, H2Bub1, H3K4me2, and H3K79me2 throughout the cell cycle, with a particular focus on mitosis. We show that H2Bub1, H3K4me2, and H3K79me2 exhibit distinct temporal progression patterns throughout the cell cycle. Most notably, we demonstrate that H3K79me2 is a highly dynamic histone post translational modification that reaches maximal abundance during mitosis in an H2Bub1-independent manner. Using RNAi and chemical genetic approaches, we identify DOT1L as a histone methyltransferase required for the mitotic-associated increases in H3K79me2. We also demonstrate that the loss of mitotic H3K79me2 levels correlates with increases in chromosome numbers and increases in mitotic defects. Collectively, these data suggest that H3K79me2 dynamics during mitosis are normally required to maintain genome stability and further implicate the loss of H3K79me2 during mitosis as a pathogenic event that contributes to the development and progression of tumors. PMID- 25533202 TI - The HLA-DRbeta1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations. AB - Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRbeta1 (P=2.48 * 10(-17)) and its proxy position 11 (P=4.15 * 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 * 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope binding groove of HLA-DRbeta1 that are responsible for most of the association between SLE and MHC. PMID- 25533203 TI - Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. AB - INTRODUCTION: Synaptic dysfunction is an early event in Alzheimer's disease (AD) pathogenesis and directly related to cognitive impairment. Consequently, synaptic biomarkers may be valuable tools for both early diagnosis and disease stage. Neurogranin (Ng) is a postsynaptic protein involved in memory consolidation. METHODS: We developed three monoclonal anti-Ng antibodies. Mass spectrometry and a novel enzyme-linked immunosorbent assay were used to analyze cerebrospinal fluid (CSF) Ng in three independent clinical cohorts including patients with AD dementia (n = 100 in total), mild cognitive impairment patients (MCI), (n = 40) and controls (n = 80 in total). RESULTS: We show in three independent clinical cohorts a marked increase in CSF Ng levels in AD dementia (P < .001 in all studies). In addition, high CSF Ng levels at the MCI stage predicted progression to dementia due to AD with a hazard ratio of 12.8 (95% confidence interval 1.6 103.0, P = .02). In amyloid-positive MCI patients, high CSF Ng correlated with a more rapid change in cognition during clinical follow-up (P = .03). DISCUSSION: These results suggest that CSF Ng is a novel AD biomarker that may be used to monitor synaptic degeneration, and correlates with the rate of cognitive decline in prodromal AD. PMID- 25533205 TI - Microwave assisted formation of monoreactive perfluoroalkylsilane-based self assembled monolayers. AB - We demonstrate the use of microwave radiation as a tool to accelerate the formation of perfluoroalkylsilane based self-assembled monolayers (SAMs) on silicon oxide surfaces. Surface coverage of these SAMs of monoreactive perfluoroalkylsilanes increased in proportion to the duration over which the solutions were heated by microwave radiation. PMID- 25533208 TI - The effect of real-time auditory feedback on learning new characters. AB - The present study investigated the effect of handwriting sonification on graphomotor learning. Thirty-two adults, distributed in two groups, learned four new characters with their non-dominant hand. The experimental design included a pre-test, a training session, and two post-tests, one just after the training sessions and another 24h later. Two characters were learned with and two without real-time auditory feedback (FB). The first group first learned the two non sonified characters and then the two sonified characters whereas the reverse order was adopted for the second group. Results revealed that auditory FB improved the speed and fluency of handwriting movements but reduced, in the short term only, the spatial accuracy of the trace. Transforming kinematic variables into sounds allows the writer to perceive his/her movement in addition to the written trace and this might facilitate handwriting learning. However, there were no differential effects of auditory FB, neither long-term nor short-term for the subjects who first learned the characters with auditory FB. We hypothesize that the positive effect on the handwriting kinematics was transferred to characters learned without FB. This transfer effect of the auditory FB is discussed in light of the Theory of Event Coding. PMID- 25533207 TI - The Pallbearer E3 ligase promotes actin remodeling via RAC in efferocytosis by degrading the ribosomal protein S6. AB - Clearance of apoptotic cells (efferocytosis) is achieved through phagocytosis by professional or amateur phagocytes. It is critical for tissue homeostasis and remodeling in all animals. Failure in this process can contribute to the development of inflammatory autoimmune or neurodegenerative diseases. We found previously that the PALL-SCF E3-ubiquitin ligase complex promotes apoptotic cell clearance, but it remained unclear how it did so. Here we show that the F-box protein PALL interacts with phosphorylated ribosomal protein S6 (RpS6) to promote its ubiquitylation and proteasomal degradation. This leads to RAC2 GTPase upregulation and activation and F-actin remodeling that promotes efferocytosis. We further show that the specific role of PALL in efferocytosis is driven by its apoptotic cell-induced nuclear export. Finding a role for RpS6 in the negative regulation of efferocytosis provides the opportunity to develop new strategies to regulate this process. PMID- 25533206 TI - Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish. AB - The widespread availability of programmable site-specific nucleases now enables targeted gene disruption in the zebrafish. In this study, we applied site specific nucleases to generate zebrafish lines bearing individual mutations in more than 20 genes. We found that mutations in only a small proportion of genes caused defects in embryogenesis. Moreover, mutants for ten different genes failed to recapitulate published Morpholino-induced phenotypes (morphants). The absence of phenotypes in mutant embryos was not likely due to maternal effects or failure to eliminate gene function. Consistently, a comparison of published morphant defects with the Sanger Zebrafish Mutation Project revealed that approximately 80% of morphant phenotypes were not observed in mutant embryos, similar to our mutant collection. Based on these results, we suggest that mutant phenotypes become the standard metric to define gene function in zebrafish, after which Morpholinos that recapitulate respective phenotypes could be reliably applied for ancillary analyses. PMID- 25533210 TI - Knee arthroplasty with a medial rotating total knee replacement. Midterm clinical findings: a district general experience of 38 cases. AB - BACKGROUND: The Medial Rotating Knee replacement (MRK) was first used in 1994, reporting high rates of satisfaction. It is designed to replicate natural knee kinematics and improve stability and function. There are limited studies on the mid-term clinical outcomes, in particular in a district general hospital (DGH) environment. This is the first study that we are aware of that evaluates the learning curve of the implementation of this knee system in this environment. PATIENTS/METHOD: Between 2007 and 2009 we performed 38 consecutive MRK replacements (MAT ORTHO, UK) in 36 patients. The mean follow-up was four years. Patients were evaluated clinically, using OKS and patient questionnaire and radiographically (good/acceptable/poor) to assess outcome. RESULTS: Mean age was 73.0 years. Mean pre-operative OKS was 17.7 (range 8-29), which rose to 38.1 (range 23-48) at latest follow up (p<0.005). Overall 71% of the patients were either satisfied (29%) or very satisfied (42%). 81% felt an improvement of the ability to go up or down stairs and 92% felt stable. All poor radiographic and the majority of acceptable outcomes were experienced in the first 50% of cases. CONCLUSION: The MRK can be successfully implanted in a DGH environment. It improves pain and function comparably to standard TKRs, however, subjective improvement may be higher. Radiographic evaluation shows an acceptable learning curve. LEVEL OF EVIDENCE: Level IV case series. PMID- 25533209 TI - Molecular characterization of a new powdery mildew resistance gene Pm54 in soft red winter wheat. AB - KEY MESSAGE: A new powdery mildew resistance gene Pm54 was identified on chromosome 6BL in soft red winter wheat. Powdery mildew is causing increasing damage to wheat production in the southeastern USA. To combat the disease, a continuing need exists to discover new genes for powdery mildew resistance and to incorporate those genes into breeding programs. Pioneer((r)) variety 26R61 (shortened as 26R61) and AGS 2000 have been used as checks in the Uniform Southern Soft Red Winter Wheat Nursery for a decade, and both have provided good resistance across regions during that time. In the present study, a genetic analysis of mildew resistance was conducted on a RIL population developed from a cross of 26R61 and AGS 2000. Phenotypic evaluation was conducted in the field at Plains, GA, and Raleigh, NC, in 2012 and 2013, a total of four environments. Three quantitative trait loci (QTL) with major effect were consistently detected on wheat chromosomes 2BL, 4A and 6BL. The 2BL QTL contributed by 26R61 was different from Pm6, a widely used gene in the southeastern USA. The other two QTL were identified from AGS 2000. The 6BL QTL was subsequently characterized as a simple Mendelian factor when the population was inoculated with a single Blumeria graminis f. sp. tritici (Bgt) isolate in controlled environments. Since there is no known powdery mildew resistance gene (Pm) on this particular location of common wheat, the gene was designated Pm54. The closely linked marker Xbarc134 was highly polymorphic in a set of mildew differentials, indicating that the marker should be useful for pyramiding Pm54 with other Pm genes by marker assisted selection. PMID- 25533211 TI - Clinical impact of molecular biomarkers in gliomas. AB - The World Health Organization (WHO) classification system for glial tumors provides guidance as to the predicted course of the disease and choice of treatment. However, histologically identical tumors may have a very different outcome and response to treatment. Molecular markers that carry both diagnostic and prognostic information add valuable tools by redefining tumor subtypes within each WHO category. Therefore, molecular biomarkers have become an integral part of tumor assessment in modern neuro-oncology and biomarker status now guides clinical decisions in some subtypes of gliomas, including anaplastic oligodendroglioma and glioblastoma in the elderly. This review discusses the prognostic and predictive impact of molecular markers that have undergone extensive study in recent years. The clinical relevance of contemporary molecular classification of gliomas using the routine assessment of IDH mutations, promoter methylation of MGMT, chromosomal deletion of 1p/19q, mutations of EGFR and ATRX genes, and BRAF fusion or point mutation is highlighted. The potential of molecular biomarker-based classification to guide future therapeutic approach is discussed and accentuated. PMID- 25533212 TI - Development of venous thromboembolism (VTE) in patients undergoing surgery for brain tumors: results from a single center over a 10 year period. AB - Patients who undergo craniotomy for brain neoplasms have a high risk of developing venous thromboembolism (VTE), including deep vein thromboses (DVT) and pulmonary emboli (PE). The reasons for this correlation are not fully understood. This retrospective, single-center review aimed to determine the risk factors for VTE in patients who underwent neurosurgical resection of brain tumors at Northwestern University from 1999 to 2010. Our cohort included 1148 patients, 158 (13.7%) of whom were diagnosed with DVT and 38 (3.3%) of whom were diagnosed with PE. A variety of clinical factors were studied to determine predictors of VTE, including sex, ethnicity, medical co-morbidities, surgical positioning, length of hospital stay, tumor location, and tumor histology. Use of post-operative anticoagulants and hemorrhagic complications were also investigated. A prior history of VTE was found to be highly predictive of post-operative DVT (odds ratio [OR]=7.6, p=0.01), as was the patient's sex (OR=14.2, p<0.001), ethnicity (OR=0.5, p=0.04), post-operative intensive care unit days (OR=0.2, p=0.003), and tumor histology (OR=-0.16, p=0.01). Contrary to reports in the literature, the data collected did not indicate that the administration of post-operative medical prophylaxis for VTE was significant in preventing their formation (OR=-0.14, p=0.76). Hemorrhagic complications were low (2.2%) and resultant neurologic deficit was lower still (0.7%). The study indicates that patients with high-grade primary brain tumors and metastatic lesions should receive aggressive preventative measures in the post-operative period. PMID- 25533214 TI - New challenges with the Journal of Plant Research. PMID- 25533213 TI - Mean hemoglobin concentration after acute subarachnoid hemorrhage and the relation to outcome, mortality, vasospasm, and brain infarction. AB - Lower mean hemoglobin (HGB) levels are associated with unfavorable outcome after spontaneous subarachnoid hemorrhage (SAH). Currently, there is no cutoff level for mean HGB levels associated with unfavorable outcome. This study was conducted to evaluate a threshold for mean HGB concentrations after SAH, and to observe the relation to outcome. The medical records of 702 patients with spontaneous SAH were reviewed. Predictors of outcome were proved by univariate analysis. Predictors with p<0.1 were included in a multivariate binary logistic regression model. Cutoff points for mean HGB levels were calculated by receiver operating characteristic curve analysis. Mean HGB was 11.9 g/dl (+/-standard deviation [SD] 1.7 g/dl) in patients with favorable outcome compared to 10.8 g/dl (+/-SD 1.1g/dl) in patients with unfavorable outcome (p<0.001). The highest Youden's index value was found for a HGB cutoff at 11.1 g/dl. In a binary logistic regression model, predictors of unfavorable outcome were identified as an initially high Hunt-Hess grade (odds ratio [OR]: 7.7; 95% confidence interval [CI]: 4.4-13.4; p<0.001), cerebral infarction on a CT scan during hospital stay (OR: 3.8; 95% CI: 2.0-7.3; p<0.001), rebleeding during the hospital stay (OR: 3.5; 95% CI: 1.6-8.0; p=0.002), mean HGB concentration <11.1g/dl (OR: 3.3; 95% CI: 2.0-5.3; p<0.001), and hydrocephalus (OR: 2.3; 95% CI: 1.4-3.7; p=0.001). In conclusion, a mean HGB concentration <11.1 g/dl during the hospital stay was associated with unfavorable outcome after acute SAH. PMID- 25533204 TI - Convergent genetic and expression data implicate immunity in Alzheimer's disease. AB - BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 * 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 * 10(-11)), cholesterol transport (P = 2.96 * 10(-9)), and proteasome-ubiquitin activity (P = 1.34 * 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics. PMID- 25533216 TI - Chemical fixation methods for Raman spectroscopy-based analysis of bacteria. AB - Preservation of biological samples for downstream analysis is important for analytical methods that measure the biochemical composition of a sample. One such method, Raman microspectroscopy, is commonly used as a rapid phenotypic technique to measure biomolecular composition for the purposes of identification and discrimination of species and strains of bacteria, as well as investigating physiological responses to external stressors and the uptake of stable isotope labelled substrates in single cells. This study examines the influence of a number of common chemical fixation and inactivation methods on the Raman spectrum of six species of bacteria. Modifications to the Raman-phenotype caused by fixation were compared to unfixed control samples using difference spectra and Principal Components Analysis (PCA). Additionally, the effect of fixation on the ability to accurately classify bacterial species using their Raman phenotype was determined. The results showed that common fixatives such as glutaraldehyde and ethanol cause significant changes to the Raman spectra of bacteria, whereas formaldehyde and sodium azide were better at preserving spectral features. PMID- 25533215 TI - Label-free, non-invasive light scattering sensor for rapid screening of Bacillus colonies. AB - Bacillus species are widely distributed in nature and have great significance both as industrially beneficial microbes and as public health burdens. We employed a novel light-scattering sensor, BARDOT (bacterial rapid detection using optical scattering technology) for instant screening of colonies of Bacillus species on agar plates. A total of 265 Bacillus and non-Bacillus isolates from our collection were used to develop and verify scatter image libraries including isolates from food, environmental and clinical samples. All Bacillus species (n=118) were detected with a high positive predictive value, PPV (>=90%) while non-Bacillus spp. had very low PPV (<5%) when compared with scatter images from the library. Among all media tested for culturing, Bacillus colonies on phenol red mannitol (PRM) generated the highest differential scatter patterns and were used in subsequent studies. Surface plot analysis of scatter patterns confirmed differences for Bacillus and non-Bacillus isolates. BARDOT successfully detected Bacillus from inoculated baby formula, cheese, and naturally contaminated bovine unpasteurized milk in 7-16h. Ten of 129 colonies (isolates) from seven milk samples were Bacillus and remainders were non-Bacillus spp. BARDOT results were confirmed by PCR and 16S rDNA sequencing. This study demonstrates that BARDOT could be used as a screening tool to identify relevant Bacillus colonies from a community prior to genome sequencing. PMID- 25533217 TI - Performance evaluation of a DNA chip assay in the identification of major genitourinary pathogens. AB - BACKGROUND: To prevent the recurrence of genitourinary infections and to reduce the risks of their complications, accurate and rapid diagnosis are required. STDetect(r) Chip is a DNA chip which allows for the simultaneous detection of 13 major genitourinary pathogens in a single vaginal swab or urine specimen. We evaluated the analytical performance of the STDetect(r) Chip for detecting target pathogens that commonly cause genitourinary infections. METHODS: The target pathogens of the STDetect(r) Chip are Chlamydia trachomatis, Candida albicans, Enterococcus faecalis, Gardnerella vaginalis, Mycoplasma hominis, Neisseria gonorrhoeae, Mycoplasma genitalium, Ureaplasma urealyticum, Staphylococcus aureus, Klebsiella pneumoniae, Trichomonas vaginalis, and Herpes simplex virus types 1 and 2. Performance of the STDetect(r) Chip for the detection of target pathogens was evaluated comparing with the result of direct sequencing and conventional multiplex PCR assay. And precision tests for STDetect(r) Chip were performed with quality control materials. RESULTS: The STDetect(r) Chip showed high sensitivities (95.1%-100%), specificities (93.4% to 100%), concordance rates (95.0%-100%), positive predictive values (69.8%-100%), and negative predictive values (93.1%-100%) in its identification of 13 target pathogens. The STDetect(r) Chip had a particularly excellent concordance rate (96.5%) for the 4 major pathogens, C. albicans, G. vaginalis, M. hominis, and U. urealyticum, compared with direct sequencing. Comparing to multiplex PCR assay, STDetect(r) Chip showed better sensitivity for detecting M. hominis (97.0% vs. 54.5%) and U. urealyticum (93.2% vs. 65.9%). In precision tests, coefficients of variations for signal intensities were ranged from 11.2% to 26.2%. CONCLUSION: The STDetect(r) Chip showed excellent analytical performance, and its result was in good agreement with that obtained by direct sequencing. PMID- 25533218 TI - Three-dimensional characterization of bacterial microcolonies on solid agar-based culture media. AB - For the last century, in vitro diagnostic process in microbiology has mainly relied on the growth of bacteria on the surface of a solid agar medium. Nevertheless, few studies focused in the past on the dynamics of microcolonies growth on agar surface before 8 to 10h of incubation. In this article, chromatic confocal microscopy has been applied to characterize the early development of a bacterial colony. This technology relies on a differential focusing depth of the white light. It allows one to fully measure the tridimensional shape of microcolonies more quickly than classical confocal microscopy but with the same spatial resolution. Placing the device in an incubator, the method was able to individually track colonies growing on an agar plate, and to follow the evolution of their surface or volume. Using an appropriate statistical modeling framework, for a given microorganism, the doubling time has been estimated for each individual colony, as well as its variability between colonies, both within and between agar plates. A proof of concept led on four bacterial strains of four distinct species demonstrated the feasibility and the interest of the approach. It showed in particular that doubling times derived from early tri-dimensional measurements on microcolonies differed from classical measurements in micro dilutions based on optical diffusion. Such a precise characterization of the tri dimensional shape of microcolonies in their late-lag to early-exponential phase could be beneficial in terms of in vitro diagnostics. Indeed, real-time monitoring of the biomass available in a colony could allow to run well established microbial identification workflows like, for instance, MALDI-TOF mass spectrometry, as soon as a sufficient quantity of material is available, thereby reducing the time needed to provide a diagnostic. Moreover, as done for pre identification of macro-colonies, morphological indicators such as three dimensional growth profiles derived from microcolonies could be used to perform a first pre-identification step, but in a shorten time. PMID- 25533219 TI - Real-time fluorescence Loop-Mediated Isothermal Amplification (LAMP) for rapid and reliable diagnosis of pulmonary tuberculosis. AB - A reliable, simple and rapid diagnostic method that can be helpful in pulmonary tuberculosis diagnosis is urgently needed. Loop-mediated Isothermal Amplification (LAMP) allows DNA to be amplified rapidly at a constant temperature. In this study, real-time fluorescence LAMP was evaluated to rapidly detect Mycobacterium tuberculosis in sputum and was compared to the performance of real-time fluorescence quantitative PCR (Q-PCR). All the standard MTB strains were successfully detected and limit of detection (LOD) was 10(2)CFU/mL by real-time fluorescence LAMP within 20min. In light of MTB in sputum, the real-time fluorescence LAMP method yielded a sensitivity of 98.0% and a specificity of 78.3%, compared to Q-PCR assay, which yielded a sensitivity of 96.0% and a specificity of 82.6% for PTB diagnosis. There was an excellent overall agreement between LAMP and Q-PCR for PTB (kappa=0.315) and non-PTB (kappa=0.862). Therefore, the real-time fluorescence LAMP assay is a rapid, sensitive, and specific method to detect pulmonary tuberculosis. PMID- 25533220 TI - Cardiac endothelial cell-derived exosomes induce specific regulatory B cells. AB - The mechanism of immune tolerance is to be further understood. The present study aims to investigate the role of the Cardiac endothelial cell (CEC)-derived exosomes in the induction of regulatory B cells. In this study, CECs were isolated from the mouse heart. Exosomes were purified from the culture supernatant of the primary endothelial cells. The suppressor functions of the regulatory B cells were determined by flow cytometry. The results showed that the CEC-derived exosomes carried integrin alphavbeta6. Exposure to lipopolysaccharide (LPS) induced B cells to express the latent transforming growth factor (TGF) beta, the latter was converted to the active form, TGF-beta, by the exosome derived alphavbeta6. The B cells released TGF-beta in response to re-exposure to the exosomes in the culture, which suppressed the effector T cell proliferation. We conclude that CEC-derived exosomes have the capacity to induce B cells with immune suppressor functions. PMID- 25533222 TI - Manual, semiautomated, and fully automated measurement of the aortic annulus for planning of transcatheter aortic valve replacement (TAVR/TAVI): analysis of interchangeability. AB - BACKGROUND: Preprocedural 3-dimensional CT imaging of the aortic annular plane plays a critical role for transcatheter aortic valve replacement (TAVR) planning; however, manual reconstructions are complex. Automated analysis software may improve reproducibility and agreement between readers but is incompletely validated. METHODS: In 110 TAVR patients (mean age, 81 years; 37% female) undergoing preprocedural multidetector CT, automated reconstruction of the aortic annular plane and planimetry of the annulus was performed with a prototype of now commercially available software (syngo.CT Cardiac Function-Valve Pilot; Siemens Healthcare, Erlangen, Germany). Fully automated, semiautomated, and manual annulus measurements were compared. Intrareader and inter-reader agreement, intermodality agreement, and interchangeability were analyzed. Finally, the impact of these measurements on recommended valve size was evaluated. RESULTS: Semiautomated analysis required major correction in 5 patients (4.5%). In the remaining 95.5%, only minor correction was performed. Mean manual annulus area was significantly smaller than fully automated results (P < .001 for both readers) but similar to semiautomated measurements (5.0 vs 5.4 vs 4.9 cm(2), respectively). The frequency of concordant recommendations for valve size increased if manual analysis was replaced with the semiautomated method (60% agreement was improved to 82.4%; 95% confidence interval for the difference [69.1%-83.4%]). CONCLUSIONS: Semiautomated aortic annulus analysis, with minor correction by the user, provides reliable results in the context of TAVR annulus evaluation. PMID- 25533221 TI - Harnessing biomaterials to engineer the lymph node microenvironment for immunity or tolerance. AB - Nanoparticles, microparticles, and other biomaterials are advantageous in vaccination because these materials provide opportunities to modulate specific characteristics of immune responses. This idea of "tuning" immune responses has recently been used to combat infectious diseases and cancer, and to induce tolerance during organ transplants or autoimmune disease. Lymph nodes and other secondary lymphoid organs such as the spleen play crucial roles in determining if and how these responses develop following vaccination or immunotherapy. Thus, by manipulating the local microenvironments within these immunological command centers, the nature of systemic immune response can be controlled. This review provides recent examples that harness the interactions between biomaterials and lymph nodes or other secondary lymphoid organs to generate immunity or promote tolerance. These strategies draw on mechanical properties, surface chemistry, stability, and targeting to alter the interactions of cells, signals, and vaccine components in lymph nodes. While there are still many unanswered questions surrounding how best to design biomaterial-based vaccines to promote specific structures or functions in lymph nodes, features such as controlled release and targeting will help pave the way for the next generation of vaccines and immunotherapies that generate immune responses tuned for specific applications. PMID- 25533224 TI - Use of cardiac CT angiography to assist in the diagnosis and treatment of aortic prosthetic paravalvular leak: a practical guide. AB - Percutaneous repair of aortic paravalvular regurgitation can help avoid the need for repeat valve surgery. Although the initial diagnosis of paravalvular regurgitation is usually made with echocardiography, cardiac CT angiography helps to determine the site and morphology of these leaks. The utility of CT is highly dependent on the quality of the data. Herein, we describe a systematic approach to image acquisition and interpretation of cardiac CT angiography in patients with aortic paravalvular regurgitation, which integrates findings from echocardiography. This approach can be used to minimize inaccuracies in the diagnosis and enhance the procedural success for percutaneous repair of aortic paravalvular regurgitation. PMID- 25533223 TI - Quantification of coronary artery calcium in nongated CT to predict cardiovascular events in male lung cancer screening participants: results of the NELSON study. AB - OBJECTIVE: To evaluate the incremental prognostic value of the number and maximum volume of coronary artery calcifications over modified Agatston score strata, age, pack-years, and smoking status for predicting cardiovascular events. METHODS: A total of 3559 male current and former smokers received a CT examination for lung cancer screening. Smoking characteristics, patient demographics, and physician-diagnosed cardiovascular events were collected. Images were acquired without electrocardiography gating on 16-slice CT scanners. The association between the presence of both fatal and nonfatal cardiovascular events and the predictors was quantified using Cox proportional hazard analysis. RESULTS: Median follow-up period was 2.9 years. Incident cardiovascular events occurred in 186 participants. Adjusted hazard ratios for modified Agatston score strata of 1 to 10, 11 to 100, 101 to 400, and >400 were 3.39 (95% confidence interval [CI], 1.20-9.59), 6.52 (95% CI, 2.73-15.60), 6.58 (95% CI, 2.75-15.78), and 12.58 (95% CI, 5.42-29.16), respectively. Moreover, comparing the models with and without modified Agatston score strata to the model with age, pack-years, and smoking status yielded a significantly better net reclassification improvement (NRI; 27.3%; P < .0001). Adding the number of calcifications to the model with age, pack-years, smoking status, and modified Agatston score strata resulted in a slightly better NRI (1.68%; P = .0490) with a hazard ratio of 1.13 (95% CI, 1.05 1.21) per 10 calcifications. The incremental prognostic information contained in the volume of the largest calcification was not statistically significant (NRI, 0.14%; P = .3458). CONCLUSION: Cardiovascular event rate increased with higher numbers of calcified lesions. The number but not maximum volume of calcifications has independent, although minimal, prognostic value over age, pack-years, smoking status, and modified Agatston score strata in our population. PMID- 25533226 TI - beta-ketothioamides: efficient reagents in the synthesis of heterocycles. AB - beta-Ketothioamides (KTAs) are versatile building blocks for the rapid construction of various heterocyclic compounds. In the past decade, a number of successful reactions based on KTAs have been developed for the construction of heterocyclic skeletons under mild conditions. This minireview focuses on the annulation reactions of KTAs with dielectrophilic or dinucleophilic reagents. Multicomponent reactions using KTAs to construct various heterocycles are also the major contents in this review. PMID- 25533225 TI - Cardiac CT imaging in the context of left atrial appendage occlusion. AB - Left atrial occlusion devices are a recognized treatment option in patients with difficult to treat atrial fibrillation or intolerance to warfarin therapy. There are an increasing number of devices on the market, and good quality preoperative imaging is crucial to assess the feasibility of the procedure and help plan the occlusion. Electrocardiography-gated cardiac CT is ideal for this purpose as the high spatial and temporal resolution allow accurate measurements and reformats in multiple planes. As the imaging specialist reporting the CT may not necessarily be the interventionalist performing the implantation, this review will illustrate the important points in reporting the preimplant CT. The expected postoperative appearances and potential complications will also be described. PMID- 25533229 TI - [Are medical students influenced by the promotion of the pharmaceutical industry?]. AB - The pharmaceutical and medical devices industry provides one of the main sources of scientific information for physicians. The impact of this kind of information on physicians' prescribing behavior has been extensively studied. Available evidence consistently shows that prescription habits are affected by industry driven scientific research data. This questionable influence has an impact also on medical students, residents, and doctors in training. Recent studies have shown that a frequent contact with industry representatives is inversely related to the knowledge of the foundations of evidence-based medicine and directly related to a higher use of brand-name prescription drugs. Several American universities decided to prohibit any relationships between students and industry representatives. It would be desirable that such policies be adopted by other institutions. In addition, the practical guide published by the World Health Organization "Understanding and Responding to Pharmaceutical Promotion" should be better known and used. PMID- 25533230 TI - [Placebo and pediatric cough: the constant reinvention of the wheel]. AB - The placebo effect has been studied and discussed in depth in recent years but, despite the extensive literature on the subject, the evidence of its impact in the clinic still arouses surprise. A study published in a major international journal of Pediatrics has compared blue agave pasteurized nectar, placebo and no treatment. The results demonstrate the greater effectiveness of both blue agave nectar and placebo versus the no-therapy option. Nothing new under the sun, except for a forced reflection on the real need of clinical research on the subject. PMID- 25533231 TI - [Long-term health effects of air pollution: results of the European project ESCAPE]. AB - Air pollution has been recently classified among the top ten risk factors for mortality worldwide. The evidence on the long-term effects of air pollutants is mounting, mostly from multi-centre American studies or longitudinal studies conducted in single European cohorts. Recently, the EU-funded project ESCAPE (European Study of Cohorts for Air Pollution Effects) involved more than 30 cohort studies with the aim of producing pooled estimates of the long-term health effects of ambient air pollution at European level. The project developed a standardized and flexible methodology to estimate chronic exposure to several air pollutants, applied such estimates to existing cohorts in Europe, and analyzed the exposure-response relationships with different health endpoints, including adverse pregnancy outcomes, respiratory diseases among children, cardio respiratory diseases among adults, cause-specific mortality and lung cancer incidence. One of the most important results has been the detection of relevant health effects of particulate matter at concentrations below the current air quality limit values in Europe. PMID- 25533232 TI - [Obesity and cardiovascular risk in children]. AB - Prevalence of overweight and obesity in childhood has substantially increased worldwide in recent decades with children becoming obese at progressively younger ages. Obesity in children carries a wide range of serious complications, and contributes to an increased prevalence of cardiovascular risk factors such as hypertension, hypertrygliceridema, low high-density lipoprotein cholesterol (HDL), impaired glucose metabolism and early atherosclerotic changes not only in adulthood but since in very early pediatric age. In the ORIGIN study (Outcome Reduction with an Initial Glargine Intervention), cardiometabolic risk factors including fatty liver were already detectable in preschoolers at the onset of overweight/obesity despite short-term exposure to excess weight and fairly reduced insulin sensitivity. These facts together with the evidence that early cardiometabolic impairment reverts with lifestyle intervention in pediatric age, emphasize the need to start prevention of childhood obesity and screening of cardiometabolic co-morbities at the earliest stage with multidisciplinary strategies. PMID- 25533233 TI - [The heart between the risk of sudden death and chronic life]. AB - In recent years, medical and surgical therapy has progressed such that even children with the most complex cardiac disease may reach adulthood with an acceptable quality of life. However, apart from this minority, pediatricians and cardiologists deal with diseases such as cardiomyopathies, arrhythmias, channelopathies and other acquired heart diseases. The majority of patients can be problematic 'cause of a cardiac murmur or in obtaining a certificate of sports eligibility. Following recent regulations, in Italy the electrocardiogram (ECG) must be performed also in 6-year-old children who want to practice sport. Although the ECG is a simple and inexpensive tool with good diagnostic accuracy, there remains the issue of false positives that results in additional costs and alarms. The modern era is facing a pandemic, that is, the spread of digital lifestyle and obesity. The only vaccine against this plague is exercise. Denying sport to children for a false positive test may expose them to obesity, hypertension, diabetes and other bad habits. For some, it may be preferable to accept the infinitesimal risk of sudden death rather than being condemned to a chronic life. Like all therapies, sports can have side effects and overdoses. If this happens in the most dramatic way - cardiac arrest - there is the antidote (i.e., the automated external defibrillator). More than 100 years since its birth, the ECG retains a sustainable and irreplaceable lightness. Nevertheless, the ECG seems to suffer from a sort of collective dyslexia. As cardiologists, we should learn to read pediatric ECG and minimize the false positive rate to prevent a healthy child from having a worse quality of life than cardiac patients saved from modern cardiac surgery. PMID- 25533234 TI - [Simplification of antiretroviral therapy: proposal for a score for the evaluation of patients with suppressed viremia]. AB - Simplification of a suppressive triple antiretroviral therapy to a dual or monotherapy has demonstrated safety and efficacy in a high proportion of stable patients. The key rationales behind regimen simplification are to improve the patient's quality of life and to maintain long-term compliance, without enhancing the risk of virological failure. A simplified startegy offers the potential advantages of a decreased risk of toxicities associated with the use of nucleoside analogue reverse transcriptase inhibitors. Moreover, the use of high genetic barrier antiretroviral drugs (basically, PIs/r) in dual regimen or in monotherapy regimen minimises the selection of drug-resistant HIV variants. The aim of this paper is to present a score that taking into account all the data in the literature relating to the simplification studies to monotherapy with PI/r allows the clinician to have more information to choose with less chance of error by the patient simplify. PMID- 25533235 TI - [Cardiac auscultation in children]. AB - Cardiac auscultation permits to distinguish between the innocent heart murmurs and pathologic murmurs; characteristics of pathologic murmurs include a holosystolic or diastolic murmur, maximal murmur intensity at the upper left sternal border and increased intensity when the patient stands. Murmurs should be described by their timing in the cardiac cycle, intensity, shape, pitch, location, radiation, and response to dynamic maneuvers. When the medical history and physical examination support the diagnosis of innocent heart murmur, neither further investigation nor referal is indicated. On the contrary, echocardiography is recommended for patients with any other abnormal physical examination findings that increase the likelihood of structural heart disease. In this review we discuss the definition and classification of murmurs, how to evaluate it. PMID- 25533236 TI - [Environmental factors and clinical course of inflammatory bowel disease: which evidences?]. AB - Identify environmental factors that can influence the course of inflammatory bowel disease (IBD) is of great interest since managing on these factors might improve the prognosis of patients. No environmental factor has been shown to have a linear cause-and-effect link with the relapse of the disease, but many environmental factors (smoking, diet, medications, stress, etc.) seem to play a plausible role in influencing the clinical course of IBD. The aim of this review is to describe the current evidence of the impact of different environmental factors on the long-term course of IBD and to give practical indications that can help doctors and patients in the management of IBD. PMID- 25533238 TI - [Cinema and medicine]. PMID- 25533237 TI - [Communication and interpersonal skills in medicine: an educational intervention in hospital]. AB - The present paper is aimed to describe methods and results of an educational intervention on doctor-patient communication. The intervention was addressed to 26 hospital physicians and lasted 20 hours, and it was formulated according to patient-centred model. At the end of the intervention, participants referred satisfaction for the course, and the proportion of doctors with patient-centred style was higher compared to the one of the initial assessment (Z Wilcoxon=2,236; p=.02). No associations were found between communicative-relational style and sociodemographic variables. For hospital physicians, three main topics seems require future interventions: the communication of bad news, the management of own emotions, the influence of context's factors on doctor-patient relationship. PMID- 25533239 TI - [Nursing service certification. Norm UNE-EN-ISO 9001-2008]. AB - OBJECTIVE: To certify the nursing services using a quality management system, taking an international standard as a reference, and based on a continuous improvement process. MATERIAL AND METHOD: The standard was revised, and the Quality Management System documentation was updated, consisting of a Quality Manual and 7 control procedures. All the existing procedures were coded in accordance with the documentation control process. Each operational procedure was associated with a set of indicators which permitted to know the results obtained, analyze the deviations and to implement further improvements. RESULTS: The system was implemented successfully. Twenty-eight care procedures and eleven procedures concerning techniques were incorporated into the management system. Thirty indicators were established that allowed the whole process to be monitored. All patients were assigned to a nurse in their clinical notes and all of them had a personalized Care Plan according to planning methodology using North American Nursing Diagnosis Association (NANDA), Nursing Interventions Classification (NIC) and Nursing Outcomes Classification (NOC) international rankings. The incidence of falls, as well as the incidence of chronic skin wounds, was low, taking into account the characteristics of the patient and the duration of the stay (mean=35.87 days). The safety indicators had a high level of compliance, with 90% of patients clearly identified and 100% with hygiene protocol. The confidence rating given to the nurses was 91%. CONCLUSION: The certification enabled the quality of the service to be improved using a structured process, analyzing the results, dealing with non-conformities and introducing improvements. PMID- 25533240 TI - Combination of retinyl palmitate and UV-filters: phototoxic risk assessment based on photostability and in vitro and in vivo phototoxicity assays. AB - This study aimed to assess the phototoxic potential of combined UV-filters and retinyl palmitate (RP) in the presence or not of bemotrizinol (BMTZ), employing photostability and in vitro and in vivo phototoxicity assays. The formulations tested contained octocrylene (OCT), octyl methoxycinnamate (OMC), benzophenone-3 (BZP-3) and RP (photostable) or octocrylene (OCT), octyl methoxycinnamate (OMC), avobenzone (AVO) and RP (less photostable). Both formulations were supplemented with bemotrizinol. Photostability was evaluated by exposing, or not, formulations spread on a glass plate to UVA/UVB irradiation. The resulting products were quantified by HPLC analysis. In vitro phototoxicity of UV-filters and combinations were evaluated using 3T3 viable monolayer fibroblast cultures submitted, or not, to irradiation according to OECD TG 432. In vivo photoallergy and photoxicity were assessed by clinical studies (photopatch test). Photostability assays showed that UV-filter bemotrizinol was a better photostabilizer for RP/benzophenone-3 than for RP/avobenzone. The in vitro phototoxicity of the combination RP/avobenzone was reduced by bemotrizinol. Clinical studies did not indicate phototoxic or photoallergenic potentials in all formulations tested. It is concluded that the 3T3 NRU phototoxicity test may be considered a supplementary assay in formulation developments, since it can detect chemically unstable and potentially phototoxic combinations. However, extrapolation of in vitro positive results to human photopatch tests may be performed only to a limited extent. PMID- 25533241 TI - Pristane primed rat T cells enhance TLR3 expression of fibroblast-like synoviocytes via TNF-alpha initiated p38 MAPK and NF-kappaB pathways. AB - Based on pristane-induced arthritis (PIA), we found that T cells mediate TLR3 overexpression in fibroblast-like synoviocytes (FLS). The aim of this study is to determine key factors by which T cells induce TLR3 expression. Rat FLS were co cultured with pristane primed T cell conditioned medium (PPT medium), and TLR3 expression of FLS was significantly induced. TNF-alpha, IFN-gamma and IL-17 were dominantly expressed in PIA T cells. The overexpression of TLR3 and its related genes in FLS co-cultured with PPT medium could be reduced through blocking TNF alpha pathway. CD4(+) T cells from spleen of PIA rats showed increase of TNF alpha secretion. P38 MAPK and NF-kappaB were activated in FLS by PPT medium, and their inhibitors decreased TLR3 upregulation significantly. Finally, TNF-alpha induced TLR3 expression was confirmed in human synovial cells. Summarily, TNF alpha derived from pristane primed T cells induced TLR3 expression of FLS through activating p38 MAPK and NF-kappaB pathways. PMID- 25533242 TI - JMJD2B as a potential diagnostic immunohistochemical marker for hepatocellular carcinoma: a tissue microarray-based study. AB - The purpose of this study was to examine JMJD2B expression in human hepatocellular carcinoma (HCC) and elucidate relationships between various expression patterns and clinicopathological parameters of HCC patients. Immunohistochemical techniques were performed to detect JMJD2B expression in a tissue microarray from patients with breast, cerebrum, colon, esophagus, kidney, liver, lung, prostate, stomach, and uterus cancers. We performed immunohistochemical staining of a multiple tissue array to examine the expression profile of JMJD2B. Our results demonstrate that JMJD2B protein levels were upregulated in malignant human tumors, including breast, colon, liver, and lung. Immunohistochemistry staining examination of liver tumor tissue microarray revealed that the expression of JMJD2B is significant according to the histological grade and TNM stage of liver tumor. Moreover, JMJD2B was also correlated with Ki-67 expression in HCC samples. These results reveal that JMJD2B is dramatically upregulated in HCC, making it a potential diagnostic marker for the further development of HCC treatment therapies. PMID- 25533244 TI - An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. AB - BACKGROUND: This study examined the potential feasibility and utility of trigeminal nerve stimulation (TNS) for attention-deficit/hyperactivity disorder (ADHD) in youth. METHODS: Twenty-four participants ages 7-14 with ADHD enrolled in an 8-week open trial of TNS administered nightly during sleep, and were assessed weekly with parent- and physician-completed measures of ADHD symptoms and executive functioning as well as measures of treatment compliance, adverse events, and side effects. Computerized tests of cognitive functioning were administered at baseline and weeks 4 and 8. RESULTS: Significant improvements were seen on the ADHD-IV Rating Scale (P < .0001) and parent-completed Conners Global Index (P < .0001), as well as the majority of scales on the parent completed Behavior Rating Inventory of Executive Functioning (BRIEF). Improvements were also noted on the computerized Attention Network Task (ANT) Incongruent Reaction Time (P = .006), suggesting that TNS has positive effects on response inhibition. CONCLUSIONS: TNS therapy for youth with ADHD appears to be both feasible and without significant risk. Subjective improvements on rating scales and laboratory measures of cognition suggest a potential role for TNS in treating ADHD that merits further investigation. Future research in anticipation of designing definitive controlled efficacy trials should evaluate time to onset of TNS response and durability of treatment effects following TNS discontinuation, as well as validate an effective active sham comparator suitable for blinded studies. PMID- 25533246 TI - [Minor emergencies]. PMID- 25533243 TI - TMS enhances retention of a motor skill in Parkinson's disease. AB - BACKGROUND: In Parkinson's disease (PD), skill retention is poor, even when acquisition rate is generally preserved. Recent work in normal subjects suggests that 5 Hz-repetitive transcranial magnetic stimulation (5Hz-rTMS) may induce phenomena of long-term potentiation at the cortical level. OBJECTIVE/HYPOTHESIS: We thus verified whether, in PD, 5Hz-rTMS enhances retention of a visuo-motor skill that involves the activity of the right posterior parietal cortex. METHODS: A group of patients with PD was tested in two two-day sessions, separated by one week (treatment and placebo sessions). The first day of each session, they learned to adapt their movements to a step-wise 60 degrees visual rotation. Immediately after the task, either real 5Hz-rTMS (treatment) or sham (placebo) stimulation was applied over the right posterior parietal cortex (P6). Retention of this motor skill was tested the following day. RESULTS: In patients with PD, adaptation achieved at the end of training was comparable in the treatment and placebo sessions and was similar to that of a group of age-matched controls. However, retention indices tested on the following day were significantly lower in the placebo compared to the treatment session in which retention indices were restored to the level of the controls. Importantly, reaction and movement time as well as other kinematic measures were the same in the treatment and placebo sessions. CONCLUSION: These results suggest that rTMS applied after the acquisition of a motor skill over specific areas involved in this process might enhance skill retention in PD. PMID- 25533245 TI - A diffusible signal derived from hematopoietic cells supports the survival and proliferation of regenerative cells during zebrafish fin fold regeneration. AB - Multicellular organisms maintain body integrity by constantly regenerating tissues throughout their lives; however, the overall mechanism for regulating regeneration remains an open question. Studies of limb and fin regeneration in teleost fish and urodeles have shown the involvement of a number of locally activated signals at the wounded site during regeneration. Here, we demonstrate that a diffusible signal from a distance also play an essential role for regeneration. Among a number of zebrafish mutants, we found that the zebrafish cloche (clo) and tal1 mutants, which lack most hematopoietic tissues, displayed a unique regeneration defect accompanying apoptosis in primed regenerative tissue. Our analyses of the mutants showed that the cells in the primed regenerative tissue are susceptible to apoptosis, but their survival is normally supported by the presence of hematopoietic tissues, mainly the myeloid cells. We further showed that a diffusible factor in the wild-type body fluid mediates this signal. Thus, our study revealed a novel mechanism that the hematopoietic tissues regulate tissue regeneration through a diffusible signal. PMID- 25533247 TI - [Minor emergency cases in big hospitals]. AB - Our hospitals are suffering from an increasing run of "minor emergency cases". Those are simple medical or surgical ailments that could be taken care of by a general practitioner's office in a competent and cost efficient way. Because of the ever growing problem of a shortage of general practitioners, those patients are directly going to the emergency room of our hospitals, where they are usually seen by a young and yet unexperienced doctor, who is ordering an expensive battery of tests even for minor troubles of his or her wellbeing. It was shown that emergency room crowding has a negative impact on the quality of patient care. The establishment of an office run by a general practitioner within the hospital emergency room may result in a certain relief of the situation. PMID- 25533248 TI - [Emergency telephone cosultations]. AB - Telephone consultations are part of GP's daily routine. The patients appreciate the quick and uncomplicated access to consultations via phone and therefore the demand for telephone consultations is increasing steadily. Nevertheless, telephone consultations pose a challenge to healthcare professionals. Safety is improved by adhering to recommendations. The required skills are learnable. PMID- 25533249 TI - [Management of fever in children]. AB - Fever is one of the most common reasons for encounter in pediatrics. This article gives information on how to judge the condition of a feverish child or infant correctly: Special emphasis should be put on the general condition of the patient and the clinical course of symptoms over time. With a few skills and tools severe pitfalls can be avoided. General practitioners administer antibiotics in febrile children more often than pediatricians do. The decision of giving antibiotics in an ambulatory setting should not exclusively be based on elevated inflammatory markers in the blood without a sufficient clinical proof of bacterial infection. Also normal lab results can be misleading and are no proof of absence of severe infection. Rapid deterioration in the child's condition without a proper response to NSAID or acetaminophen is a primary warning sign and parents should always be encouraged to have their child rejudged immediately in that case. This applies especially to young children. The option of a follow up encounter should always be offered to parents when dismissing them. PMID- 25533250 TI - [Ophthalmic emergencies for the general practitioner]. AB - This article point out guidelines for the general practitioner when he can manage himself ophthalmic emergencies, which patients an ophthamologist should see on the same day and when an immediate intervention by an ophthalmologist is necessary. PMID- 25533251 TI - [Rheumatology emergencies in general practice]. AB - In rheumatology there may occur emergencies especially in the field of inflammable diseases, the sudden occlusion of the central retinal artery in temporal arteritis as an example. Such incidents are rare. The general practitioner is more often confronted with not necessarily threatening, but very painful and function obstructing acute cases. In this paper four typical problems are represented which can be seen in everyday practice, sometimes misleading to wrong actions and therefore needing to be recognized in time and treated correctly: acute low back pain, periarthropathy of the shoulder joint, crystal arthritis and ruptured Baker's cyst. PMID- 25533252 TI - [What you can do when dealing with emergencies in the dementia setting]. AB - Frequent emergencies in patients with dementia include aggressiveness, screaming, day/night reversal, other behavioral disorders, and falls. They are often caused by delirium, especially if there has been a rapid change in the patient's state of health. Hypoactive delirium in particular is difficult to recognize in the dementia setting. Acute somatic diseases bear a different meaning in dementia than in non-dementia patients, and priorities must be given to the impaired cerebral performance. In addition to medical decisions, ethical ones need to be made. Special attention should be paid to the resources of the caregiver network. This article describes both non-pharmacological and pharmacological treatment modalities when dealing with emergencies in dementia patients. PMID- 25533253 TI - [Difficulties in diagnosis and treatment of heart failure]. AB - Heart failure is a frequent diagnosis in both in- and outpatients. Despite advances in therapy during the past two decades, prognosis is still serious with a mortality rate of 30 % in the first year after diagnosis. Echocardiography is the important investigation when clinical findings suggest heart failure. Pharmacotherapy is well established and evidence-based in HF-REF. A multidisciplinary approach including counsellers, rehabilitation therapists and heart failure specalists may optimize the patients treatment. In daily practice doctors are confronted with multiborbid patients, where adequate therapy is challenging. Side effects and contraindications of drugs must be considered. However, most patients can achieve a satisfying quality of life with appropriate treatment. PMID- 25533254 TI - [Acute urinary retention: a few simple rules for a successful catheterization]. AB - Acute urinary retention is a common emergency condition in elderly men. Transurethral and suprapubic catheterization are easy and safe procedures provided that a few simple rules are followed. Primarily, a transurethral catheter is placed if there is no urethral injury or stricture. Local anaesthesia of the urethra up to the sphincter region and a well-stretched penis warrant an atraumatic insertion of the catheter into the bladder. The use of a thick catheter with a round tip or of a catheter with a bended tip under rectal guidance facilitate the insertion of the catheter in difficult conditions. Alternatively, a suprapubic catheterization can be performed provided that no contraindication such as history or suspicion of transitional cell carcinoma is present. Optimal interventional conditions using ultrasound-guidance are mandatory in patients after abdominal surgery and with hemorrhagic diathesis in view of a safe and straight-forward placement of the suprapubic catheterization. In case of persistent bleeding after insertion of a suprapubic catheter, the suprapubic catheter should be replaced by one with a balloon blocked and kept under tension for several minutes. PMID- 25533255 TI - [Urgent care: psychiatry]. AB - This text gives advice on how to take a history of present illness, do a mental status examination and come to a correct diagnosis in psychiatric emergencies. Certain syndromes are described that form the most common energency situations: suicidal ideations, agitation, danger to others, confusion, delirium, intoxications and substance withdrawal and stupor. Each situation is described in detail, its prevalance is noted and recommendations are made for appropriate interventions. PMID- 25533256 TI - [Competent treatment also in "surgical peanuts"!]. AB - Ankle sprains, burns, cuts and lacerated wounds, ingrowing toenail - topics, that are common in the general practitioner's office. Just peanuts? If they are correctly treated, yes, maybe. But if poorly diagnosed and badly treated they turn out to be troublesome for the patient and the doctor - a real "pain in the neck"! Therefore competent treatment is mandatory, also for these "peanuts"! PMID- 25533257 TI - [Shoulder dislocations in and outside of the doctor's surgery]. AB - In over 95 % of shoulder dislocations, the humerus is displaced anteriorly, a trauma regularly seen in skiing- and mountainresorts. All physicians should be trained to diagnose and relocate a dislocated shoulder. A variety of techniques exist, but some are preferred due to fewer complications or easier execution. In the Bernese Alps, the self-relocation technique "Davos" (Boss-Holzach-Matter) and the "Baumann" technique are well established and well approved over the years - in the outdoors as well as in the surgeries. PMID- 25533258 TI - [Management of frostbite in and outside of the doctor's surgery]. AB - Frostbite is most likely to happen in combination with accidents, intoxications or psychiatric emergencies and typically affects smaller, more exposed areas of the body, such as fingers, toes, nose, ears, cheeks and chin. The preclinical treatment consists of rapid rewarming of the injured tissue in a water-bath that is held between 38 - 42 degrees C (hand-hot) in a stable, warm environment. A new clssification allows a faster assessment of the outcome. New retrospective studies suggest the efficacy of thrombolysis or prostacyclin analogues against spasm and thrombosis for a better outcome. PMID- 25533259 TI - [Treatment of subungual hematoma in office and outdoor conditions]. AB - Treptising with an glowing spike or paperclip can be performed everywhere without local anesthesia and even by non-professionals. Evacuation of hematoma with a Insulin-Syringe/Needle in small nails (children, toe 2 - 5) is an interesting alternative. PMID- 25533260 TI - [Dog bites]. AB - In Switzerland 10'000 people are bitten by a dog annualy. Dog bites are notifiable incidents. Defensive and offensive aggression of dogs (why does a dog bite?), history, signs, treatment and prevention are discussed. Finally a short psychogram of dog owner and victim emphasizes the role of avoiding any escalation. PMID- 25533261 TI - [Chest pain]. AB - Chest pain in ambulatory setting is predominantly not heart-associated. Most patients suffer from muskuloskeletal or functional (psychogenic) chest pain. Differential diagnosis covers aortic dissection, rib-fracture, shingles, GERD, Tietze-Syndrome, pulmonary embolism, pleuritis, pneumothorax, pleurodynia and metastatic disease. In most cases history, symptoms and signs allow a clinical diagnosis of high pretest-probability. PMID- 25533262 TI - [Falls in the elderly: a practical approach]. AB - Fractures, especially in elder persons after falls, get more frequent and lead to immens costs. Facts about risks at home and in public areas as well as caused by illness and medicaments are discussed. Some ideas and hints for prevention by family physician and public services and organisations are mentioned. PMID- 25533263 TI - The epidemiology of firearm violence in the twenty-first century United States. AB - This brief review summarizes the basic epidemiology of firearm violence, a large and costly public health problem in the United States for which the mortality rate has remained unchanged for more than a decade. It presents findings for the present in light of recent trends. Risk for firearm violence varies substantially across demographic subsets of the population and between states in patterns that are quite different for suicide and homicide. Suicide is far more common than homicide and its rate is increasing; the homicide rate is decreasing. As with other important health problems, most cases of fatal firearm violence arise from large but low-risk subsets of the population; risk and burden of illness are not distributed symmetrically. Compared with other industrialized nations, the United States has uniquely high mortality rates from firearm violence. PMID- 25533264 TI - Facial nerve hemangiomas at geniculate ganglion: preservation of nerve integrity is correlated with duration of facial palsy. AB - OBJECTIVE: To study preservation of nerve integrity in 16 cases with facial nerve hemangiomas at geniculate ganglion (GG). METHODS: 16 cases with facial nerve hemangiomas at GG, who presented with facial palsy, were included in the study. Preservation of nerve integrity was attempted by the same surgeon during surgical removal, and those who failed to preserve nerve integrity underwent nerve grafting. The patients were divided into longer duration group (>12months) and shorter duration group (<=12months) according to duration of facial palsy, and preservation of nerve integrity in the couple of groups was compared. RESULTS: Nerve integrity was preserved in 2 of 10 cases (20%) among longer duration group, while it was preserved in 5 of 6 cases (83.3%) among shorter duration group (p<0.05). All the cases with nerve integrity preserved recovered to grade III or better, among which 3 cases recovered to grade I or grade II, while only 3 of 9 cases (33.3%) with nerve grafting recovered to grade III at the best. CONCLUSIONS: Preservation of nerve integrity was correlated with duration of facial palsy in cases with hemangiomas at GG. Patients with nerve integrity preserved showed better outcomes of facial nerve. PMID- 25533265 TI - Indirect comparisons of ranibizumab and dexamethasone in macular oedema secondary to retinal vein occlusion. AB - BACKGROUND: Two treatments, ranibizumab and dexamethasone implant, for visual impairment due to macular oedema (ME) secondary to retinal vein occlusion (RVO) have recently been studied in clinical trials. There have been no head to head comparisons of the two treatments, and improvement measured as gain in Best Corrected Visual Acuity (BCVA) was reported using different outcomes thresholds between trials. To overcome these limitations, and inform an economic model, we developed a combination of a multinomial model and an indirect Bayesian comparison model for multinomial outcomes. METHODS: Outcomes of change from baseline in BCVA for dexamethasone compatible with those available for ranibizumab, reported by 4 randomised controlled trials, were estimated by fitting a multinomial distribution model to the probability of a patient achieving outcomes in a range of changes from baseline in BCVA (numbers of letters) at month 1. A Bayesian indirect comparison multinomial model was then developed to compare treatments in the Branch RVO (BRVO) and Central RVO (CRVO) populations. RESULTS: The multinomial model had excellent fit to the observed results. With the Bayesian indirect comparison, the probabilities of achieving >=20 letters, with 95% credible intervals, at month 1 in patients with BRVO were 0.191 (0.130, 0.261) with ranibizumab and 0.093 (0.027, 0.213) with dexamethasone. In patients with CRVO, probabilities were 0.133 (0.082, 0.195) (ranibizumab) and 0.063 (0.016, 0.153) (dexamethasone). Probabilities of a gain in >=10 letters in BRVO patients were 0.500 (0.365, 0.650) v 0.459 (0.248, 0.724) and in CRVO patients 0.459 (0.332, 0.602) v 0.498 (0.263, 0.791) for ranibizumab and dexamethasone treatments respectively. The comparisons also favoured ranibizumab at month 6 although changes to therapies after month 3 may have introduced bias. CONCLUSION: The newly developed combination of multinomial and indirect Bayesian comparison models indicated a trend for ranibizumab association with a greater percentage of ME patients achieving visual gains than dexamethasone at months 1 and 6 in a common clinical context, although results were not classically significant. The method was a useful tool for comparisons of probability distributions between clinical trials that reported events on different categorical scales and estimates can be used to inform economic models. PMID- 25533266 TI - Antioxidant activities and quali-quantitative analysis of different Smallanthus sonchifolius [(Poepp. and Endl.) H. Robinson] landrace extracts. AB - Five landraces of Smallanthus sonchifolius [(Poepp. and Endl.) H. Robinson], known as yacon, were investigated in total phenolic content, antioxidant activity and chemical composition of ethanol extracts (EEs) and decoction extracts (DEs). The results demonstrated that DEs are rich in phenolic acids as caffeic acid, while the EEs show an higher amount of flavonoids, as luteolin 3',7-O-diglucoside and luteolin 7-O-glucoside. These flavonoid glycosides were identified for the first time in yacon extracts, together with apigenin and luteolin. The phytochemical profile explains the different antioxidant activities shown in our study. The landraces PER6-DE and PER4-DE showed the highest radical-scavenging activity and reducing power related to their polyphenolic contents. Results also show that yacon can be considered an important source of bioactive compounds with significant differences among the analysed landraces. PMID- 25533267 TI - Intestinal schistosomiasis and geohelminths of Ukara Island, North-Western Tanzania: prevalence, intensity of infection and associated risk factors among school children. AB - BACKGROUND: Schistosoma mansoni and soil-transmitted helminths (STH) are among the most prevalent and highly neglected tropical diseases in Tanzania. However, little is known on the distribution of these infections in rural settings, especially in the island areas on Lake Victoria. Identifying the local risk factors of S. mansoni and soil-transmitted helminths is one step towards understanding their transmission patterns and will facilitate the design of cost effective intervention measures. The present study was therefore conducted to determine the prevalence, intensity of infection and risk factors associated with S. mansoni and soil-transmitted helminth infections among school children in Ukara Island. METHODS: This was a cross sectional study which enrolled 774 school children aged 4-15 years in 5 primary schools in Ukara Island, North-Western Tanzania. Single stool samples were collected, processed using the Kato Katz technique and examined for eggs of S. mansoni and geohelminths under a light microscope. A pre-tested questionnaire was used to collect socio-demographic information. RESULTS: Overall, 494/773 (63.91%, 95% CI; 45.19-90.36) of the study participants were infected with S. mansoni and the overall geometrical mean eggs per gram (GM-epg) of feaces were 323.41epg (95% CI: 281.09-372.11). The overall prevalence of soil-transmitted helminth (STH) was 6.73% (n = 52/773, 95% CI = 4.39-10.32) with the most prevalent species being hookworms, 5.69% (n = 44/773, 95% CI; 3.68-8.79). Location of school in the study villages (P < 0.0001), parent occupation, fishing (P < 0.03) and reported involvement in fishing activities (P < 0.048) remained significantly associated with the prevalence and intensity of S.mansoni infection. CONCLUSION: Schistosoma mansoni infection is highly prevalent in the islands whereas the prevalence of soil-transmitted helminths is low. The risk of infection with S. mansoni and the intensity of infection increased along the shorelines of Lake Victoria. These findings call for the need to urgently implement integrated control interventions, starting with targeted mass drug administration. PMID- 25533268 TI - Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany. AB - Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7 35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection. PMID- 25533269 TI - The Kraepelinian dichotomy viewed by neuroimaging. AB - The Kraepelinian dichotomy between schizophrenia (SZ) and bipolar disorder (BD) is being challenged by recent epidemiological and biological studies. We performed a comparative review of neuroimaging features in both conditions at several scales: whole-brain and regional volumes, brain activity, connectivity, and networks. Structural volumetric neuroimaging studies suggest a common pattern of volume decreases, but networks studies reveal a clearer distinction between BD and SZ with an altered connectivity generalized to all brain networks in SZ and restricted to limbic, paralimbic, and interhemispheric networks in BD. PMID- 25533271 TI - Suprapectoral biceps tenodesis: a biomechanical comparison of a new "soft anchor" tenodesis technique versus interference screw biceps tendon fixation. AB - BACKGROUND: The interference screw technique is commonly used in tenodesis of the long head of the biceps for its well-documented robust fixation strength. Some complications may occur after tenodesis with interference screw such as persistent pain, bone fracture and cyst formation. A new technique using a small "soft anchor" has been proposed to avoid the risk of occurrence of the above mentioned complications associated with the use of the interference screw. However, the proposed technique must provide adequate fixation strength. This study investigated the mechanical performance of the new technique and compared it with interference screw fixation. METHODS: Fourteen human humeri and proximal biceps were tested after tenodesis using the two techniques. The fixation constructs were cycled 500 times between 20N and 100N at 1Hz to simulate some level of post-operative physical activity. Then, a tensile test to failure was performed to determine the strength of the two tenodesis constructs. FINDINGS: The ultimate strength was 238N (SD 96N) and 172N (SD 58N) for the "soft anchor" and the interference screw, respectively (P=0.14). In two out of seven repetitions in both groups, failure occurred at low load level due to inaccuracies in performing tenodesis. Considering these cases as outliers, the strength values increased up to 290N (SD 40N) and 202N (SD 32N) for the "soft anchor" and the interference screw, respectively (P=0.02). INTERPRETATION: The "soft anchor" technique provides a fixation strength comparable with the interference screw, but without using a screw. It could be considered as an alternative for suprapectoral biceps tenodesis. PMID- 25533270 TI - Neurobiological changes of schizotypy: evidence from both volume-based morphometric analysis and resting-state functional connectivity. AB - The current study sought to examine the underlying brain changes in individuals with high schizotypy by integrating networks derived from brain structural and functional imaging. Individuals with high schizotypy (n = 35) and low schizotypy (n = 34) controls were screened using the Schizotypal Personality Questionnaire and underwent brain structural and resting-state functional magnetic resonance imaging on a 3T scanner. Voxel-based morphometric analysis and graph theory-based functional network analysis were conducted. Individuals with high schizotypy showed reduced gray matter (GM) density in the insula and the dorsolateral prefrontal gyrus. The graph theoretical analysis showed that individuals with high schizotypy showed similar global properties in their functional networks as low schizotypy individuals. Several hubs of the functional network were identified in both groups, including the insula, the lingual gyrus, the postcentral gyrus, and the rolandic operculum. More hubs in the frontal lobe and fewer hubs in the occipital lobe were identified in individuals with high schizotypy. By comparing the functional connectivity between clusters with abnormal GM density and the whole brain, individuals with high schizotypy showed weaker functional connectivity between the left insula and the putamen, but stronger connectivity between the cerebellum and the medial frontal gyrus. Taken together, our findings suggest that individuals with high schizotypy present changes in terms of GM and resting-state functional connectivity, especially in the frontal lobe. PMID- 25533272 TI - Development of a scoliotic spine model for biomechanical in vitro studies. AB - BACKGROUND: In vitro experiments are important to compare surgical treatments. Especially new implants need preclinical evaluation. However, in vitro experiments with scoliotic specimens are impossible because they are not available. The purpose of this study was to develop an in vitro scoliosis model with cadaveric calf spine specimens, which may serve as a surrogate for human scoliotic spines. METHODS: Six cadaveric calf spine specimens (T8-L6) were modified in three different steps to create a thoracolumbar scoliosis, convex to the right. First, all intervertebral discs received a nucleotomy. In the second step the cavity was filled with silicone. The silicone hardened in a bend position to obtain an asymmetrical nucleus. Finally, a wedge profile of the vertebral bodies was achieved by unilateral horizontal cuts (T9-L5), followed by spreading and fixation. Flexibility tests in a spine tester were performed in all motion planes with the original spine and after the different steps during the creation of the model. FINDINGS: A Cobb angle >40 degrees in the frontal plane could be achieved. Additionally, the vertebrae showed an axial rotation to the convex side. The range of motion increased due to the nucleotomy, decreased slightly after replacement with silicone, and decreased below the values of the intact spine after producing the wedge shape of the vertebrae. In each loading direction there was no significant asymmetry in the motion behavior. INTERPRETATION: This study suggests a method to modify a straight spine specimen into a scoliotic one, which can be used for biomechanical in vitro experiments. PMID- 25533274 TI - Compressive Optic Neuropathy and Repeat Orbital Decompression: A Case Series. AB - PURPOSE: To characterize the presenting characteristics, preoperative clinical activity score (CAS), surgical approach, and visual outcomes in patients with thyroid eye disease undergoing repeat orbital decompression for recurrent or recalcitrant compressive optic neuropathy (CON). METHODS: The medical records of patients with recurrent or recalcitrant CON undergoing repeat orbital decompressions were retrospectively reviewed. The primary outcome measures included pre- and postoperative Humphrey visual field mean deviation, visual acuity (VA) measured in logarithm of the minimal angle of resolution, color vision measured by Ishihara plates, and presence of relative afferent pupillary defect. Details of the surgical procedure and each patient's CAS at presentation were also recorded. RESULTS: Six patients, 9 orbits, with a mean preoperative CAS of 3.8 were included in this review. The mean time between initial decompression and presentation to our center for recurrent or persistent CON symptoms was 8.6 years (range, 1 to 15 years). At presentation, the average Humphrey visual field mean deviation was -16.5 (standard deviation: 8.8), improving to -3.8 (2.4) postoperatively with a mean of 9.3 months follow up (mean improvement of 75%). Preoperative VA was 0.34 (0.23) LogMAR, improving to 0.05 (0.10) LogMAR with a mean follow up of 10.4 months. Pre- to postoperative comparisons of clinical measures all showed statistically significant improvement (p < 0.05). Eight eyes presented with decreased VA (any VA < 20/20), 4 with decreased color vision (any color vision < 11), and 1 with a relative afferent pupillary defect, and all these patients demonstrated improvement following repeat orbital decompression. CONCLUSIONS: In patients with thyroid eye disease, symptoms of recurrent CON occurred up to 15 years following initial orbital decompression underscoring the smoldering, progressive nature of the disease. Repeat decompression that focused on the orbital apex resulted in visual improvement in all 6 patients. Despite clinical evidence of CON, the mean CAS of these patients at presentation was only 3.8, highlighting the importance of close monitoring of patients with thyroid eye disease following decompression regardless of the external manifestations of disease activity. PMID- 25533275 TI - Jaw tremor as a physiological biomarker of bruxism. AB - OBJECTIVE: To determine if sleep bruxism is associated with abnormal physiological tremor of the jaw during a visually-guided bite force control task. METHODS: Healthy participants and patients with sleep bruxism were given visual feedback of their bite force and asked to trace triangular target trajectories (duration=20s, peak force <35% maximum voluntary force). Bite force control was quantified in terms of the power spectra of force fluctuations, masseter EMG activity, and force-to-EMG coherence. RESULTS: Patients had greater jaw force tremor at ~8 Hz relative to controls, along with increased masseter EMG activity and force-to-EMG coherence in the same frequency range. Patients also showed lower force-to-EMG coherence at low frequencies (<3 Hz), but greater coherence at high frequencies (20-40 Hz). Finally, patients had greater 6-10 Hz force tremor during periods of descending vs. ascending force, while controls showed no difference in tremor with respect to force dynamics. CONCLUSION: Patients with bruxism have abnormal jaw tremor when engaged in a visually-guided bite force task. SIGNIFICANCE: Measurement of jaw tremor may aid in the detection/evaluation of bruxism. In light of previous literature, our results also suggest that bruxism is marked by abnormal or mishandled peripheral feedback from the teeth. PMID- 25533277 TI - Emergency medicine in Europe: looking forward to 2015. PMID- 25533276 TI - Inter-session reliability of electrical impedance myography in children in a clinical trial setting. AB - OBJECTIVE: High reliability is a prerequisite for any test to be useful as a biomarker in a clinical trial. Here we assessed the reproducibility of electrical impedance myography (EIM) in children by comparing data obtained by different evaluators on separate days. METHODS: Healthy boys and boys with Duchenne muscular dystrophy (DMD) aged 2-14 years underwent EIM of multiple muscles performed by two evaluators on two visits separated by 3-7 days. Single and multifrequency data were analyzed. Reliability was assessed via calculation of the percent relative standard deviation (% RSD), Bland-Altman analysis, and the intraclass correlation coefficient (ICC). RESULTS: For both individual muscle data and data averaged across muscles, intra-evaluator measurements showed high repeatability for both 50 kHz phase and 50/200 kHz phase ratio values, with ICCs generally above 0.90 and % RSD below 10%. Inter-evaluator results showed very similar ICC and % RSD values as those obtained by the same evaluator. CONCLUSIONS: Both the 50 kHz phase and 50/200 kHz phase ratio are reliable measures both across time and evaluators and in both health and disease. SIGNIFICANCE: These results support the concept that EIM can serve as a reliable measure in clinical therapeutic trials in a pediatric population. PMID- 25533278 TI - Failure of noninvasive mechanical ventilation: could we assess determining factors in emergency department? PMID- 25533279 TI - Intubation after noninvasive ventilation failure in chronic obstructive pulmonary disease: is it properly evaluated? PMID- 25533281 TI - Effect of rescuer's sex on the quality of chest compression during cardiopulmonary resuscitation on manikins. PMID- 25533280 TI - Intubation after noninvasive ventilation failure in chronic obstructive pulmonary disease: associated factors at emergency department presentation. PMID- 25533282 TI - Rescuer's gender-effect on the quality of chest compression during cardiopulmonary resuscitation on manikins. PMID- 25533284 TI - Giant axonal disease: Report of eight cases. AB - BACKGROUND: Giant axonal neuropathy (GAN) is an autosomal recessive inherited progressive motor and sensory neuropathy with typical onset in early childhood. The disease is caused by GAN gene mutations on chromosome 16q24.1. To determine clinical and genetic results in Turkish patients with GAN. METHODS: Eight children with GAN were retrospectively analyzed. Five (62.5%) were girls and 3 (37.5%) were boys with the mean age on admission 10.13+/-3.8 years (range: 5-15 years). RESULTS: Parental consanguinity was found in all the families. The patients had the classical clinical phenotype characterized by a severe axonal neuropathy with kinky hair. Two patients had contractures of extremities, and not walking. One patient was walking with aid. The other patients were walking without aid. Mutation analysis was performed in two patients and IVS9 (+1G>T) (homozygous) mutation was detected. CONCLUSION: The classical clinical findings allowed considering the GAN diagnosis, but, in atypical cases and milder phenotypes, the presence of giant axons in nerve biopsy was helpful to specify molecular analysis. PMID- 25533283 TI - Human oral cells' response to different endodontic restorative materials: an in vitro study. AB - INTRODUCTION: The aim of this study was to compare the biological interaction of human osteoblasts and cells of the human periodontal ligament (PDL) with different endodontic restorative material as Mineral Trioxide Aggregate (MTA), Biodentine, amalgam and composite over a time period of 20 days. MATERIALS AND METHODS: Human PDL cells and osteoblasts were harvested, cultured and according to standardized protocols. The cell populations were characterized with the corresponding surface markers following standardized procedures. The specimens were produced with special regard to constant dimensions and volume in the different groups. Cell attachment and proliferation were evaluated morphologically after Richardson staining and cell count was performed after 1d, 8d, 13d and 20d. All experiments were performed in triplets. The results were statistically analyzed using the ANOVA- and Tukey-test (p < 0.05). RESULTS: Morphological analysis proved good proliferation and cell attachment in both cements. A remarkable result was the organized spreading and parallel alignment of the PDL cells in contact with MTA and especially Biodentine (cells maturing in a second cell layer crossway to the first one). From 8d onward Biodentine showed the highest quantity of PDL cells (p < 0.05). Biodentine and MTA resulted in a significantly higher cell density in osteoblast and PDL cell culture. The other groups showed a lower PDL cell density from 8d and a lower osteoblast cell density from 13d when compared to control and cement samples (p < 0.05). CONCLUSIONS: MTA and Biodentine showed a good biocompatibility in contact with the human osteoblasts and cells of the periodontal ligament. Regarding cell survival and proliferation particularly of PDL cells Biodentine showed good results and can be considered as a well-tolerated bioactive endodontic material. PMID- 25533285 TI - Stability of proteins on hydrophilic surfaces. AB - The physical and chemical properties of solid substrates or surfaces critically influence the stability and activity of immobilized proteins such as enzymes. Reports of increased stability and activity of enzymes near/on surfaces as compared with those in solution abound; however, a mechanistic understanding is wanting. Simulations and experiments are used here to provide details toward such a mechanistic understanding. Experiments demonstrate increased activity of alcohol dehydrogenase (ADH) inside moderate hydrophilic mesopourous silica (SBA 15) pores but drastically decreased activity inside very hydrophilic NH2-SBA-15 surfaces as compared with that in solution. Also, the temperature stability of ADH was increased over that in solution when immobilized in a cavity with a mildly hydrophilic surface. Simulations confirm these experimental findings. Simulations calculated in the framework of a hydrophobic-polar (H-P) lattice model show increased thermal stability of a model 64-mer peptide on positive and zero curvature surfaces over that in solution. Peptides immobilized inside negative curvature cavities (concave) with hydrophilic surfaces exhibit increased stability only inside pores that are only 3-4 nm larger than the hydrodynamic radius of the peptide. Peptides are destabilized, however, when the surface hydrophilic character inside very small cavities/pores becomes large. PMID- 25533287 TI - Toxoplasma gondii-infected natural killer cells display a hypermotility phenotype in vivo. AB - Toxoplasma gondii is a highly prevalent intracellular protozoan parasite that causes severe disease in congenitally infected or immunocompromised hosts. T. gondii is capable of invading immune cells and it has been suggested that the parasite harnesses the migratory pathways of these cells to spread through the body. Although in vitro evidence suggests that the parasite further enhances its spread by inducing a hypermotility phenotype in parasitized immune cells, in vivo evidence for this phenomenon is scarce. Here we use a physiologically relevant oral model of T. gondii infection, in conjunction with two-photon laser scanning microscopy, to address this issue. We found that a small proportion of natural killer (NK) cells in mesenteric lymph nodes contained parasites. Compared with uninfected 'bystander' NK cells, these infected NK cells showed faster, more directed and more persistent migratory behavior. Consistent with this, infected NK cells showed impaired spreading and clustering of the integrin, LFA-1, when exposed to plated ligands. Our results provide the first evidence for a hypermigratory phenotype in T. gondii-infected NK cells in vivo, providing an anatomical context for understanding how the parasite manipulates immune cell motility to spread through the host. PMID- 25533286 TI - IRF5 is a novel regulator of CXCL13 expression in breast cancer that regulates CXCR5(+) B- and T-cell trafficking to tumor-conditioned media. AB - Clinical studies using prognostic and predictive signatures have shown that an immune signal emanating from whole tumors reflects the level of immune cell infiltration--a high immune signal linked to improved outcome. Factors regulating immune cell trafficking to the tumor, however, are not known. Previous work has shown that expression of interferon regulatory factor 5 (IRF5), a critical immune regulator, is lost in ~80% of invasive ductal carcinomas examined. We postulated that IRF5-positive and -negative breast tumors would differentially regulate immune cell trafficking to the tumor. Using a focused tumor inflammatory array, differences in cytokine and chemokine expression were examined between IRF5 positive and -negative MDA-MB-231 cells grown in three-dimensional culture. A number of cytokines/chemokines were found to be dysregulated between cultures. CXCL13 was identified as a direct target of IRF5 resulting in the enhanced recruitment of B and T cells to IRF5-positive tumor-conditioned media. The ability of IRF5 to regulate mediators of cell migration was confirmed by enzyme linked immunosorbent assay, chromatin immunoprecipitation assay, small interfering RNA knockdown and immunofluorescence staining of human breast tumor tissues. Analysis of primary immune cell subsets revealed that IRF5 specifically recruits CXCR5(+) B and T cells to the tumor; CXCR5 is the receptor for CXCL13. Analysis of primary breast tumor tissues revealed a significant correlation between IRF5 and CXCL13 expression providing clinical relevance to the study. Together, these data support that IRF5 directly regulates a network of genes that shapes a tumor immune response and may, in combination with CXCL13, serve as a novel prognostic marker for antitumor immunity. PMID- 25533288 TI - Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3+ and Foxp3- T cells. AB - Costimulatory signals by CD28 are critical for thymic regulatory T-cell (Treg) development. To determine the functional relevance of CD28 for peripheral Treg post thymic selection, we crossed the widely used Forkhead box protein 3 (Foxp3) CreYFP mice to mice bearing a conditional Cd28 allele. Treg-specific CD28 deficiency provoked a severe autoimmune syndrome as a result of a strong disadvantage in competitive fitness and proliferation of CD28-deficient Tregs. By contrast, Treg survival and lineage integrity were not affected by the lack of CD28. This data demonstrate that, even after the initial induction requirement, Treg maintain a higher dependency on CD28 signalling than conventional T cells for homeostasis. In addition, we found the Foxp3-CreYFP allele to be a hypomorph, with reduced Foxp3 protein levels. Furthermore, we report here the stochastic activity of the Foxp3-CreYFP allele in non-Tregs, sufficient to recombine some conditional alleles (including Cd28) but not others (including R26-RFP). This hypomorphism and 'leaky' expression of the Foxp3-CreYFP allele should be considered when analysing the conditionally mutated Treg. PMID- 25533289 TI - A microRNA expression atlas of mouse dendritic cell development. AB - Dendritic cells (DCs) are sentinel cells of the immune system and are essential for inducing a proper immune response. The mechanisms driving the development of DCs are not fully understood. Although the roles of cytokines and transcription factors have been a major focus, there is now substantial interest in the role of microRNAs (miRNAs). miRNAs are small RNAs that regulate gene expression by targeting messenger RNAs for translational repression and ultimately degradation. By means of deep sequencing, we have assembled a comprehensive and quantitative resource of miRNA expression during DC development. We show that mature DCs and their hematopoietic progenitors can be distinguished based on miRNA expression profiles. On the other hand, we show that functionally distinct conventional and plasmacytoid DC subsets are indistinguishable based on miRNA profile. In addition, we identify differences between ex vivo purified conventional DCs and their in vitro Flt3L-generated counterparts. This miRNA expression atlas will provide a valuable resource for the study of miRNAs in DC development and function. PMID- 25533291 TI - Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice. AB - BACKGROUND: For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS. OBJECTIVE: To investigate the influence of female puberty on central nervous system (CNS) autoimmunity. METHODS: We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident 'acquired demyelinating syndromes' (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004-2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status. RESULTS: In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of >=1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age matched, pre-pubertal mice. CONCLUSION: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice. PMID- 25533292 TI - Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis. AB - We correlated the weighted genetic risk score measured using 107 established susceptibility variants for multiple sclerosis (MS) with the age at onset in bout onset (BOMS, n=906) and progressive-onset MS Italian patients (PrMS) (n=544). We observed an opposite relationship in the two disease courses: a higher weighted genetic risk score was associated with an earlier age at onset in BOMS (rho= 0.1; p=5 * 10(-3)) and a later age at onset in PrMS cases (rho=0.07; p=0.15) (p of difference of regression=1.4 * 10(-2)). These findings suggest that established MS risk variants anticipate the onset of the inflammatory phase, while they have no impact on, or even delay, the onset of the progressive phase. PMID- 25533290 TI - Epigenetic roots of immunologic disease and new methods for examining chromatin regulatory pathways. AB - The ability to accurately quantitate and experimentally examine epigenetic modifications across the human genome has exploded in the past decade. This has given rise to a wealth of new information concerning the contributions of epigenetic regulatory networks to the pathogenesis of human disease. In particular, immunological disorders have strong developmental roots in chromatin regulatory pathways. In this review, we focus on the epigenetic signatures and new discoveries revealing the epigenetic compositions of specific immunological cancers and autoimmune diseases. We also comment on the conserved epigenetic roots among diverse immunological disorders and suggest inhibition strategies that may be relevant for future treatment. Finally, we highlight emerging experimental tools with the capability to examine the mechanisms of chromatin regulatory enzymes with a high level of temporal control. The knowledge of genetic and epigenetic defects in immunological disease combined with new experimental approaches will elucidate the contribution of individual enzymes in complex epigenetic regulatory networks. This could lead to new diagnostic and therapeutic approaches for some very diverse and difficult to treat human diseases. PMID- 25533293 TI - Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) frequently affects women of childbearing age. While short-term effects of pregnancy on MS course are well-known, whether pregnancy may influence long-term disability progression is debated. METHODS: A two-centre retrospective study to investigate long-term effect of pregnancy on disability was performed in a population of MS women. Survival analyses and multivariate Cox proportional regression models (including early predictors of MS severity and exposure to disease-modifying treatments) were performed to compare time to reach well-established disability milestones in nulliparous women and in those with pregnancies after MS onset ('parous'). Women with pregnancies before MS onset were excluded from analyses as they represent a heterogeneous group. RESULTS: Data about 445 women (261 nulliparous, 184 'parous') were analysed. A longer time to reach Expanded Disability Status Scale (EDSS) 4.0 and 6.0 was observed in parous women; Cox regression models revealed a lower risk for 'parous' than nulliparous women in reaching EDSS 4.0 and 6.0 (HR = 0.552, p = 0.008 and HR = 0.422, p = 0.012 respectively). CONCLUSION: Our findings suggest that pregnancy after MS onset is associated with a slower long-term disability progression. Whether this represents a biological/immunological effect, or reflects a higher propensity toward childbearing in women with milder disease, it remains uncertain deserving further investigations. PMID- 25533294 TI - Structural 'connectomic' alterations in the limbic system of multiple sclerosis patients with major depression. AB - BACKGROUND: Major depression (MD) is a common psychiatric disorder in multiple sclerosis (MS). Despite the negative impact of MD on the quality of life of MS patients, little is known about its underlying brain mechanisms. OBJECTIVE: We studied the whole-brain connectivity patterns that were associated with MD in MS. Alterations were mainly expected within limbic circuits. METHODS: Diffusion tensor imaging data were collected in 20 MS patients with MD, 22 non-depressed MS patients and 16 healthy controls. We used deterministic tractography and graph analysis to study the white-matter connectivity patterns that characterized MS patients with MD. RESULTS: We found that MD in MS was associated with increased local path length in the right hippocampus and right amygdala. Further analyses revealed that these effects were driven by an increased shortest distance between both the right hippocampus and right amygdala and a series of regions including the dorsolateral and ventrolateral prefrontal cortex, orbitofrontal cortex, sensory-motor cortices and supplementary motor area. CONCLUSION: Our data provide strong support for neurobiological accounts positing that MD in MS is mediated by abnormal 'communications' within limbic circuits. We also found evidence that MD in MS may be linked with connectivity alterations at the limbic-motor interface, a group of regions that translates emotions into survival-oriented behaviors. PMID- 25533295 TI - Genetic and environmental determinants of 25-hydroxyvitamin D levels in multiple sclerosis. AB - BACKGROUND: Evidence is accumulating supporting a beneficial effect of vitamin D in multiple sclerosis (MS). Genome-wide association studies (GWAS) have shown significant associations between 25-hydroxyvitamin D (25(OH)D) and single nucleotide polymorphisms (SNPs) in key genes in the vitamin D metabolism. OBJECTIVE: To examine the association between 25(OH)D and six GWAS SNPs and environmental factors in 1497 MS patients. METHODS: Blood samples and lifestyle questionnaires were collected between 2009 and 2012. Genotyping of GC-, CYP2R1- and NADSYN1-SNPs was performed by TaqMan allelic discrimination (Life Technologies). RESULTS: We found significant associations between 25(OH)D and SNPs in GC (rs7041, p = 0.01 and rs2282679, p = 0.03) and CYP2R1 (rs10741657, p =1.8 * 10(-4)). Season of blood sampling (p = 2.8 * 10(-31)), sex (p = 1.9 * 10( 5)), BMI (p = 2.3 * 10(-5)), vitamin supplements (p = 7.0 * 10(-22)), and fish intake (p = 0.02) also had significant effects on 25(OH)D. CONCLUSION: In this cross-sectional study, we found significant effects of environmental factors and SNPs in GC and CYP2R1 on 25(OH)D in MS patients. Since 25(OH)D might have protective effects in MS, and vitamin D supply is a modifiable factor, it may be important to include this in the MS treatment regimen. PMID- 25533297 TI - Is there a cognitive signature for multiple sclerosis-related fatigue? PMID- 25533296 TI - The use of gaming technology for rehabilitation in people with multiple sclerosis. AB - Gaming technology - exergaming - is a novel tool to facilitate exercise, improve balance, and encourage rehabilitation training. This review will describe some of the key exergame research to promote physical activity and its use in rehabilitation in other diseases or clinical populations. We will then describe the current state of research in exergaming in people with multiple sclerosis and describe the theories for the mechanism behind some of the improvements in outcomes seen after using exergaming. Lastly, we will identify gaps in the literature and provide directions for future work in this growing area. The current work is contradictory and there is no consensus with regards to training duration/intensity and the outcomes used to assess the clinical effectiveness. This in part is due to the off-the-shelf nature of the games used. A more satisfactory approach would be the development of bespoke games which match a clinical need. Exergames are seen as enjoyable and could be effective in enhancing adherence to rehabilitation. However, the definitive RCT has yet to be carried out comparing exergaming to traditional exercise. PMID- 25533298 TI - Impact of neurological impairment, depression, cognitive function and coping on quality of life of people with multiple sclerosis: A relative importance analysis. AB - BACKGROUND: Determining the relative importance of factors that predict quality of life (QoL) in people with multiple sclerosis (MS) must be addressed through multiple regression metrics, e.g. relative weights, which are designed to solve colinearity problems. OBJECTIVE: We aimed to compare disease variables, Expanded Disability Status Scale (EDSS), depressive symptomatology (BDI-FS), cognitive performance and coping in predicting MS patients' QoL, using relative weights. METHODS: We assessed 97 patients with MS, using the Functional Assessment of MS (FAMS) as the criterion. RESULTS: EDSS predicted global and physical QoL domains, whereas BDI-FS predicted general contentment and global QoL. CONCLUSION: EDSS and BDI-FS are relevant determinants of QoL in people with MS. PMID- 25533299 TI - A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. AB - BACKGROUND: As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS). OBJECTIVE: The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS. METHODS: The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies. RESULTS: Sixty one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid. CONCLUSION: Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide. PMID- 25533300 TI - A systematic review of the incidence and prevalence of cardiac, cerebrovascular, and peripheral vascular disease in multiple sclerosis. AB - BACKGROUND: Findings regarding the prevalence of vascular comorbidities in multiple sclerosis (MS) are conflicting. OBJECTIVE: The objective of this review is to estimate the incidence and prevalence of vascular comorbidities and predisposing comorbidities in persons with MS and to assess the quality of the included studies. METHODS: The PubMed, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched. One reviewer abstracted data using a standardized data collection form, while the second reviewer verified the abstraction. Included studies were assessed qualitatively. Quantitatively, we assessed studies using the I2 statistic, and conducted meta-analyses for population-based studies only. RESULTS: The prevalence of hypertension and hyperlipidemia exceeded 10% in the MS population and increased with age. While the prevalence of ischemic heart disease, congestive heart failure, and stroke were less than 5% overall, the prevalence of these conditions exceeded expectations when compared to the general population. Cardiac valvular disease, however, affected the MS population less often than expected. Problems with study quality were common. CONCLUSION: Despite the relatively high prevalence of some vascular comorbidities in the MS population, important gaps exist in our understanding of their epidemiology. Most of our knowledge is based on studies conducted in a small number of regions. PMID- 25533303 TI - We can compare the relative efficacy multiple sclerosis medications by examining the results of independent clinical trials: commentary. PMID- 25533301 TI - A systematic review of the incidence and prevalence of sleep disorders and seizure disorders in multiple sclerosis. AB - BACKGROUND: Several studies have suggested that comorbid neurologic disorders are more common than expected in multiple sclerosis (MS). OBJECTIVE: To estimate the incidence and prevalence of comorbid seizure disorders and sleep disorders in persons with MS and to evaluate the quality of studies included. METHODS: The PUBMED, EMBASE, Web of Knowledge, and SCOPUS databases, conference proceedings, and reference lists of retrieved articles were searched. Two reviewers independently screened abstracts to identify relevant articles, followed by full text review of selected articles. We assessed included studies qualitatively and quantitatively (I2 statistic), and conducted meta-analyses among population-based studies. RESULTS: We reviewed 32 studies regarding seizure disorders. Among population-based studies the incidence of seizure disorders was 2.28% (95% CI: 1.11-3.44%), while the prevalence was 3.09% (95% CI: 2.01-4.16%). For sleep disorders we evaluated 18 studies; none were population-based. The prevalence ranged from 0-1.6% for narcolepsy, 14.4-57.5% for restless legs syndrome, 2.22 3.2% for REM behavior disorder, and 7.14-58.1% for obstructive sleep apnea. CONCLUSION: This review suggests that seizure disorders and sleep disorders are common in MS, but highlights gaps in the epidemiological knowledge of these conditions in MS worldwide. Other than central-western Europe and North America, most regions are understudied. PMID- 25533302 TI - A systematic review of the incidence and prevalence of cancer in multiple sclerosis. AB - BACKGROUND: Studies of cancer incidence and prevalence in multiple sclerosis (MS) have produced conflicting results. OBJECTIVE: To estimate the incidence and prevalence of cancer in persons with MS and review the quality of included studies. METHODS: We searched the PUBMED, SCOPUS, Web of Knowledge, and EMBASE databases, conference proceedings, and reference lists of all articles retrieved. Abstracts were screened for relevance by two reviewers. Data from included articles were captured using a standardized form, and the abstraction was verified by a second reviewer. We assessed quality of the included studies. We quantitatively assessed studies using the I (2) statistic, and conducted meta analyses for population-based studies. RESULTS: We identified 38 studies. Estimates for incidence and prevalence varied substantially for most cancers. In population-based studies, cervical, breast, and digestive cancers had the highest incidence. The risk of meningiomas and urinary system cancers appeared higher than expected, while the risks of pancreatic, ovarian, prostate and testicular cancer were lower than expected. CONCLUSION: The complexity of understanding cancer risk in MS is augmented by inconsistencies in study design, and the relative paucity of age, sex and ethnicity-specific risk estimates from which the strong impact of age on the incidence of cancers can be assessed. PMID- 25533304 TI - Effect of the preparation methods on architecture, crystallinity, hydrolytic degradation, bioactivity, and biocompatibility of PCL/bioglass composite scaffolds. AB - In this study, two different composition gel derived silica-rich (S2) or calcium rich (A2) bioactive glasses (SBG) from a basic CaO-P2 O5 -SiO2 system were incorporated into poly(epsilon-caprolactone) (PCL) matrix to obtain novel bioactive composite scaffolds for bone tissue engineering applications. The composites were fabricated in the form of highly porous 3D scaffolds using following preparation methods: solvent casting particulate leaching (SCPL), solid liquid phase separation, phase inversion (PI). Scaffolds containing 21% vol. of each bioactive glass were characterized for architecture, crystallinity, hydrolytic degradation, surface bioactivity, and cellular response. Results indicated that the use of different preparation methods leads to obtain highly porous (60-90%) materials with differentiated morphology: pore shape, size, and distributions. Thermal analysis (DSC) showed that the preparation method of materials and addition of bioactive glass particles into polymer matrix induced the changes of PCL crystallinity. Composites obtained by SCPL and PI method containing A2 SBG rapidly formed a hydroxyapatite calcium phosphate surface layer after incubation in SBF. Bioactive glasses used as filler in composite scaffolds could neutralize the released acidic by-products of the polymer degradation. Preliminary in vitro biological studies of the composites in contact with osteoblastic cells showed good biocompatibility of the obtained materials. Addition of bioactive glass into the PCL matrix promotes mineralization estimated on the basis of the ALP activity. These results suggest that through a process of selection appropriate methods of preparation and bioglass composition it is possible to design and obtain porous materials with suitable properties for regeneration of bone tissue. PMID- 25533305 TI - First 11 genomic medicine centres are named by NHS England. PMID- 25533306 TI - Accessing Data Resources in the Mouse Phenome Database for Genetic Analysis of Murine Life Span and Health Span. AB - Understanding the source of genetic variation in aging and using this variation to define the molecular mechanisms of healthy aging require deep and broad quantification of a host of physiological, morphological, and behavioral endpoints. The murine model is a powerful system in which to understand the relations across age-related phenotypes and to identify research models with variation in life span and health span. The Jackson Laboratory Nathan Shock Center of Excellence in the Basic Biology of Aging has performed broad characterization of aging in genetically diverse laboratory mice and has placed these data, along with data from several other major aging initiatives, into the interactive Mouse Phenome Database. The data may be accessed and analyzed by researchers interested in finding mouse models for specific aging processes, age related health and disease states, and for genetic analysis of aging variation and trait covariation. We expect that by placing these data in the hands of the aging community that there will be (a) accelerated genetic analyses of aging processes, (b) discovery of genetic loci regulating life span, (c) identification of compelling correlations between life span and susceptibility for age-related disorders, and (d) discovery of concordant genomic loci influencing life span and aging phenotypes between mouse and humans. PMID- 25533308 TI - Drug stability analysis by Raman spectroscopy. AB - Pharmaceutical drugs are available to astronauts to help them overcome the deleterious effects of weightlessness, sickness and injuries. Unfortunately, recent studies have shown that some of the drugs currently used may degrade more rapidly in space, losing their potency before their expiration dates. To complicate matters, the degradation products of some drugs can be toxic. Here, we present a preliminary investigation of the ability of Raman spectroscopy to quantify mixtures of four drugs; acetaminophen, azithromycin, epinephrine, and lidocaine, with their primary degradation products. The Raman spectra for the mixtures were replicated by adding the pure spectra of the drug and its degradant to determine the relative percent contributions using classical least squares. This multivariate approach allowed determining concentrations in ~10 min with a limit of detection of ~4% of the degradant. These results suggest that a Raman analyzer could be used to assess drug potency, nondestructively, at the time of use to ensure crewmember safety. PMID- 25533309 TI - Iontophoretic and microneedle mediated transdermal delivery of glycopyrrolate. AB - PURPOSE: The objective of this study was to investigate the use of iontophoresis, soluble microneedles and their combination for the transdermal delivery of glycopyrrolate. METHODS: In vitro permeation was tested using full thickness porcine ear skin mounted onto Franz diffusion cells. Iontophoresis (0.5 mA/cm2) was done for 4 h using Ag/AgCl electrodes. For microneedles, three line array (27 needles/line) of maltose microneedles were used to microporate the skin prior to mounting. Pore uniformity was determined by taking fluorescent images of distribution of calcein into pores and processing the images using an image analysis tool, which measured the fluorescent intensity in and around each pore to provide a pore permeability index (PPI). The donor chamber contained 500 uL of a 1 mg/mL solution of glycopyrrolate, and the receptor chamber contained 5 mL of 50 mM NaCl in deionized water. Samples were collected at predetermined time points over a period of 24 h and analyzed by HPLC. Skin irritation testing was performed with a 3D cell culture kit of human skin. MTT assay determined cell viability; viability less than 50% was considered irritant. RESULTS: A control experiment which investigated passive permeation of glycopyrrolate delivered an average cumulative amount of 24.92 +/- 1.77 ug/cm2 at 24 h, while microneedle pretreatment increased permeability to 46.54 +/- 6.9 ug/cm2. Both iontophoresis (158.53 +/- 17.50 ug/cm2) and a combination of iontophoresis and microneedles (182.43 +/- 20.06 ug/ cm2) significantly increased delivery compared to passive and microneedles alone. Glycopyrrolate solution was found to be nonirritant with cell viability of 70.4% +/- 5.03%. CONCLUSION: Iontophoresis and a combination of iontophoresis with microneedle pretreatment can be effectively used to enhance the transdermal delivery of glycopyrrolate. Glycopyrrolate was found to be non irritant to skin. PMID- 25533307 TI - Short-term morbidity and quality of life from a randomized clinical trial of close rectal dissection and total mesorectal excision in ileal pouch-anal anastomosis. AB - BACKGROUND: Posterior rectal dissection during ileal pouch-anal anastomosis (IPAA) can be performed in the total mesorectal excision (TME) or close rectal dissection (CRD) plane. The aim of this study was to compare morbidity and quality of life (QoL) in patients having TME or CRD during proctectomy followed by IPAA for benign disease. METHODS: In this randomized clinical trial, patients undergoing IPAA were allocated to TME or CRD. Thirty-day morbidity was determined and QoL assessed using Short Form 36, GIQLI (GastroIntestinal Quality of Life Index) and COREFO (COloREctal Functional Outcome) questionnaires. The primary outcome (pouch compliance) of the trial is to be reported separately. RESULTS: Fifty-nine patients were included, 28 in the CRD and 31 in the TME group. Baseline data were similar, except for more previous abdominal surgery in the TME group. Operating time was longer for patients having CRD (195 min versus 166 min for TME; P = 0.008). More patients in the TME group had a primary defunctioning ileostomy (7 of 31 versus 1 of 28 for CRD; P = 0.055). Severe complications occurred more frequently in the TME group (10 of 31 versus 2 of 28 for CRD). QoL was better in the CRD group for several subscales of the questionnaires measured at 1, 3 and 6 months after surgery. At 12 months, QoL was similar in the two groups for all subscales. CONCLUSION: CRD led to a lower severe complication rate and better short-term QoL than wide TME. PMID- 25533310 TI - Brain-controlled applications using dynamic P300 speller matrices. AB - OBJECTIVES: Access to the world wide web and multimedia content is an important aspect of life. We present a web browser and a multimedia user interface adapted for control with a brain-computer interface (BCI) which can be used by severely motor impaired persons. METHODS: The web browser dynamically determines the most efficient P300 BCI matrix size to select the links on the current website. This enables control of the web browser with fewer commands and smaller matrices. The multimedia player was based on an existing software. Both applications were evaluated with a sample of ten healthy participants and three end-users. All participants used a visual P300 BCI with face-stimuli for control. RESULTS: The healthy participants completed the multimedia player task with 90% accuracy and the web browsing task with 85% accuracy. The end-users completed the tasks with 62% and 58% accuracy. All healthy participants and two out of three end-users reported that they felt to be in control of the system. CONCLUSIONS: In this study we presented a multimedia application and an efficient web browser implemented for control with a BCI. SIGNIFICANCE: Both applications provide access to important areas of modern information retrieval and entertainment. PMID- 25533311 TI - Behind the color switching in gasochromic VO2. AB - Gasochromic VO2 thin films were fabricated by the sol-gel spin-coating technique. The results of X-ray absorption spectroscopy and resonant inelastic X-ray scattering spectroscopy reveal that the origin of gasochromic coloration in VO2 is strongly related to the modulation of its structure and the electron-electron correlation. Upon gasochromic coloration, not only does the valence state change with the incorporation of hydrogen, but also the film undergoes the modification of the local atomic structure. The structural distortion varies the strength of hybridization of the O 2p-V 3d states and the bond distance of V-O and V-O varies. In the hydric process, the local atomic structure of VO2 changes from that of an un-symmetric to that of a symmetric V-O framework. The incorporated hydrogen adds electrons into the V 3d t2g orbital, enhancing the electron electron correlation by reducing the V-V distance. This work presents a new physical insight in which the modulation of the electron-electron correlation is exploited to control the bleached and colored states, giving rise to the gasochromic phenomenon. The strong correlation among atomic spatial rearrangement, electronic structures, and transmittance supports a cooperative mechanism of the VO2 gasochromic transition. These results reveal a clear correlation between the dynamics of the lattice structure and the electronic properties and suggest a possible pathway to gasochromism and elucidation of its mechanism. PMID- 25533312 TI - Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury. AB - AIMS: Many traumatic brain injury (TBI) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI induced long-term brain damage. Ethyl pyruvate (EP) has shown neuroprotection in several models of acute brain injury. The present study therefore investigated the potential beneficial effect of EP on long-term outcomes after TBI and the underlying mechanisms. METHODS: Male adult rats were subjected to unilateral controlled cortical impact injury. EP was injected intraperitoneally 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Neurological deficits, blood brain barrier (BBB) integrity, and neuroinflammation were assessed. RESULTS: Ethyl pyruvate improved sensorimotor and cognitive functions and ameliorated brain tissue damage up to 28 day post-TBI. BBB breach and brain edema were attenuated by EP at 48 h after TBI. EP suppressed matrix metalloproteinase (MMP) 9 production from peripheral neutrophils and reduced the number of MMP-9 overproducing neutrophils in the spleen, and therefore mitigated MMP-9-mediated BBB breakdown. Moreover, EP exerted potent antiinflammatory effects in cultured microglia and inhibited the elevation of inflammatory mediators in the brain after TBI. CONCLUSION: Ethyl pyruvate confers long-term neuroprotection against TBI, possibly through breaking the vicious cycle among MMP-9-mediated BBB disruption, neuroinflammation, and long-lasting brain damage. PMID- 25533313 TI - Comparison of the diagnostic accuracy of 99 m-Tc-MDP bone scintigraphy and 18 F FDG PET/CT for the detection of skeletal metastases. AB - BACKGROUND: Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is commonly performed for cancer staging, as it can detect metastatic disease in multiple organ systems. However, there has been some controversy in the scientific literature when comparing FDG PET/CT and technetium 99 m-bone scintigraphy (bone scan) for the detection of skeletal metastases. PURPOSE: To compare the accuracy of FDG PET/CT with bone scan for the detection of skeletal metastases. MATERIAL AND METHODS: The study group comprised 202 adult cancer patients who underwent both FDG PET/CT and bone scan within 31 days for staging. Bone scans and FDG PET/CT were evaluated by two musculoskeletal radiologists for the presence and location of skeletal metastatic disease. Confirmation of the final diagnosis was based on the CT or magnetic resonance imaging (MRI) appearance, follow-up imaging, or histology. RESULTS: The sensitivity, specificity, and accuracy for detecting skeletal metastatic disease of FDG PET/CT were 97%, 98%, and 98%, respectively, and of bone scan were 83%, 98%, and 93%, respectively. The lesions that bone scan most commonly missed were located in the pelvis, spine, and sacrum. FDG PET/CT missed mostly lesions that were outside of the field of view, but in all of these cases the patient had additional sites of skeletal metastatic disease. Bone scan falsely identified six metastatic lesions and FDG PET/CT falsely identified three metastatic lesions. CONCLUSION: FDG PET/CT is an accurate technique for detection of skeletal metastases, and is superior to bone scan, especially in the spine and pelvis. PMID- 25533314 TI - A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. AB - Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m(2) ) in combination with YM155 (5 mg/m(2) per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m(2) and 56 patients received 75 mg/m(2) of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3-48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5-43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate >=20%) was not achieved. PMID- 25533315 TI - Vertical distribution of the soil microbiota along a successional gradient in a glacier forefield. AB - Spatial patterns of microbial communities have been extensively surveyed in well developed soils, but few studies investigated the vertical distribution of micro organisms in newly developed soils after glacier retreat. We used 454 pyrosequencing to assess whether bacterial and fungal community structures differed between stages of soil development (SSD) characterized by an increasing vegetation cover from barren (vegetation cover: 0%/age: 10 years), sparsely vegetated (13%/60 years), transient (60%/80 years) to vegetated (95%/110 years) and depths (surface, 5 and 20 cm) along the Damma glacier forefield (Switzerland). The SSD significantly influenced the bacterial and fungal communities. Based on indicator species analyses, metabolically versatile bacteria (e.g. Geobacter) and psychrophilic yeasts (e.g. Mrakia) characterized the barren soils. Vegetated soils with higher C, N and root biomass consisted of bacteria able to degrade complex organic compounds (e.g. Candidatus Solibacter), lignocellulolytic Ascomycota (e.g. Geoglossum) and ectomycorrhizal Basidiomycota (e.g. Laccaria). Soil depth only influenced bacterial and fungal communities in barren and sparsely vegetated soils. These changes were partly due to more silt and higher soil moisture in the surface. In both soil ages, the surface was characterized by OTUs affiliated to Phormidium and Sphingobacteriales. In lower depths, however, bacterial and fungal communities differed between SSD. Lower depths of sparsely vegetated soils consisted of OTUs affiliated to Acidobacteria and Geoglossum, whereas depths of barren soils were characterized by OTUs related to Gemmatimonadetes. Overall, plant establishment drives the soil microbiota along the successional gradient but does not influence the vertical distribution of microbiota in recently deglaciated soils. PMID- 25533316 TI - More than half of UK prescriptions for antipsychotics are for non-severe mental illnesses. PMID- 25533318 TI - Functionalization of hydride-terminated photoluminescent silicon nanocrystals with organolithium reagents. AB - Hydride-terminated photoluminescent silicon nanocrystals (SiNCs) were functionalized with organolithium compounds. The reaction is proposed to proceed through cleavage of Si - Si bonds and formation of a Si - Li surface species. The method yields colloidally stabilized SiNCs at room temperature with short reaction times. SiNCs with mixed surface functionalities can be prepared in an easy two-step reaction by this method by quenching of the Si - Li group with electrophiles or by addressing free Si - H groups on the surface with a hydrosilylation reaction. PMID- 25533317 TI - How Did Medicare Part D Affect Racial and Ethnic Disparities in Drug Coverage? AB - OBJECTIVE: To examine the effect of Medicare Part D on racial/ethnic disparities in having any drug coverage and in sources of payment for drug expenditure. METHODS: We used nationally representative data on whites, African-Americans, and Hispanics aged 55 and older from the 2002-2009 Medical Expenditure Panel Survey to analyze disparities in having any drug coverage and in sources of coverage for individuals aged 65 and older as compared with those for adults aged 55-63 without Medicare. RESULTS: There was no disparity in the probability of drug coverage for African-American or Hispanic compared to white Medicare beneficiaries, before or after 2006. There were, however, differences in the sources of coverage. African-Americans and Hispanics over the age of 65 had lower rates of private coverage than whites. This disparity in private coverage was completely offset by minorities' higher rates of drug coverage through Medicaid before 2006 and through Part D since 2006. In contrast, among individuals aged 55 63, there are large and persistent disparities in the probability of having drug coverage throughout the period. DISCUSSION: Pronounced racial/ethnic disparities in drug coverage in the years just before Medicare eligibility are eliminated by access to public coverage at age 65. This was true even before the introduction of Part D. PMID- 25533319 TI - Ligand transformations and efficient proton/water reduction with cobalt catalysts based on pentadentate pyridine-rich environments. AB - A series of cobalt complexes with pentadentate pyridine-rich ligands is studied. An initial Co(II) amine complex 1 is prone to aerial oxidation yielding a Co(III) imine complex 2 that is further converted into an amide complex 4 in presence of adventitious water. Introduction of an N-methyl protecting group to the ligand inhibits this oxidation and gives rise to the Co(II) species 5. Both the Co(III) 4 and Co(II) 5 show electrocatalytic H2 generation in weakly acidic media as well as in water. Mechanisms of catalysis seem to involve the protonation of a Co(II) H species generated in situ. PMID- 25533320 TI - [Professional satisfaction for doctors of the Mobile Emergency Team and the Emergency Coordinator Office 061. Region of Murcia]. AB - OBJECTIVE: The objective was to analyze the phenomenon of work satisfaction of doctors of the Mobile Emergency Team and the Emergency Coordinator Office 061 of the Region of Murcia. MATERIAL AND METHOD: A observational, analytical and cross sectional study of development carried out with the medical staff of the Casualty and Emergency Operations Department 061 of the Region of Murcia. Data collection was carried out in December 2013 and January 2014. NTP 394 was used. Work satisfaction: general satisfaction scale. DATA ANALYSIS: nonparametric tests for 2 samples or k samples depending on type of comparison. RESULTS: A participation rate of 88.2% was obtained, in relation to the general job satisfaction, the average of the participants was 69.55 (SD = 14.4). Of the 15 items that make up the questionnaire, " work colleagues " is the factor with which doctors are more satisfied with, indicating that up to an 87%, show a positive assessment on this point. Being the second aspect most respondents valued their " job stability " with a percentage of positive ratings of 76.7%. CONCLUSIONS: The main findings clearly demonstrate the importance of inter-professional relations and human potential as the cornerstone in the exercise of the activity of healthcare professionals. PMID- 25533321 TI - Memories of falling in elderly patients with dementia: response concordance rate and reproducibility. AB - BACKGROUND: Although demented elderly patients have impaired memory, memories of falling are not uncommon. We aim to clarify reliability of memories of falling in such patients. METHODS: Subjects included 62 patients (18 men, 44 women) diagnosed with dementia who resided in long-term care facilities. Mean age was 82.9 +/- 7.8 years, mean Mini-Mental State Examination score was 16.4 +/- 4.7 points, and mean Functional Independence Measure score was 67.9 +/- 18.4 points. Subjects were asked a closed question about whether they were aware of having fallen (i.e. memories of falling) over the past year. Fear of falling was quantified using the visual analogue scale and FACES Pain Rating Scale. Scores were re-measured during retest approximately 10 days later to examine reproducibility of memories and fear of falling. Subjects whom staff had witnessed suffering a fall between baseline and retest session were excluded. RESULTS: Fall memory concordance rate was 0.84, visual analogue scale reproducibility (correlation coefficient) was 0.98, and FACES Pain Rating Scale was 0.86. No differences in Mini-Mental State Examination scores were noted between groups for whom memories of falling were or were not reproducible. No correlation was observed among Mini-Mental State Examination, Functional Independence Measure scores, and intensity of fear of falling. CONCLUSIONS: There was a high concordance rate for patients' memories of falling, which suggests that falls were retained as memories. No relationship was observed between memories of falling and degree of cognitive impairment, and severe dementia did not necessarily imply memories of falling were unreliable. The reproducibility of fear of falling suggested the intensity of fear of falling was not easily altered. It was possible memories of falling and fear of falling mutually interacted to reinforce and fixate with each other, leading to the observed phenomenon. Therefore, it appeared memories of falling were retained by patients; this fact can be used in fall prevention and vital function maintenance. PMID- 25533322 TI - Multimorbidity measures were poor predictors of adverse events in patients aged >=80 years: a prospective cohort study. AB - OBJECTIVES: To assess and compare the ability of two measures of multimorbidity and a simple disease count (DC) to predict health outcomes in a population of patients aged >=80 years. STUDY DESIGN AND SETTING: A prospective, observational, and population-based cohort study including 567 individuals [3.0 years (standard deviation +/- 0.25) follow-up]. RESULTS: Of the patients, 37.6% were reported with five or more diseases. Multimorbidity was measured by means of a modified Charlson comorbidity index [mCCI; median score, 5 (range, 4-15)], Cumulative Illness Rating Scale [CIRS; median score, 4 (range, 1-11)], and a simple DC of 22 selected chronic conditions [median score, 4 (range, 0-13)]. All measures were independently related to mortality [adjusted hazard ratio (HR) mCCI, 2.5 (confidence interval {CI}: 1.5, 4.1); CIRS, 2.1 (CI: 1.4, 3.2); DC, 2.1 (CI: 1.4, 3.2)] and hospitalization [adjusted HR DC, 2.3 (CI: 1.7, 3.1); mCCI, 2.1 (CI: 1.5, 3.0), CIRS, 1.9 (CI: 1.5, 2.6)] but not to functional decline. Areas under the curve for mortality and hospitalization were all below 0.70. Net reclassification improvements did not indicate that any one measure provided a significant benefit over the others. CONCLUSION: In this population, the mCCI, CIRS, and unweighted DC predicted mortality and hospitalization but not functional decline. There is no clear advantage of using one measure over another. PMID- 25533323 TI - Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties. AB - A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not only to improve passive permeability, but also to balance permeability with other physicochemical properties with the goal of understanding and applying the knowledge to develop active cyclic peptides into drug candidates. Evaluation of the methods herein suggest that increasing passive permeability often occurs at the expense of solubility and lipophilicity. Computational methods can be useful when attempting to predict and design features to balance these properties, though limitations were observed. PMID- 25533324 TI - [Chances and risks of blood-based molecular pathological analysis of circulating tumor cells (CTC) and cell-free DNA (cfDNA) in personalized cancer therapy: positional paper from the study group on liquid biopsy of the working group for molecular pathology in the German Society of Pathology (DGP)]. PMID- 25533325 TI - Incidental midgut malrotation detected during second laparotomy: Case report and literature review. AB - INTRODUCTION: Intestinal malrotation is defined as intestinal nonrotation or incomplete rotation around superior mesenteric artery (SMA), involving anomalies of intestinal fixation as well. The patients may be recognized incidentally during other surgical procedures or at autopsy. Here in, we present a case of midgut malrotation which was diagnosed incidentally during hepaticojejunostomy procedure for benign biliary stricture. PRESENTATION OF CASE: A 46 years old male patient was referred to our clinic with failed surgery for biliary stricture due to extensive adhesions. Prior to our surgery, intestinal malrotation was not reported and noticed by the diagnostic tools. When the patient underwent relaparotomy, midgut malrotation was observed. DISCUSSION: Distruption in the normal embryological development of bowel is the cause of intestinal malrotation. Various anatomic configurations and anomalies resulting from rotation anomalies of midgut. Adult patients are usually asymptomatic and the anomaly is discovered only at autopsy or incidentally at surgery. The role of additional surgery especially in patients with asymptomatic disease related to malrotation is debated. CONCLUSION: Performing loop hepaticojejunostomy with Braun enteroenterostomy is feasible and acceptable option rather than Roux-N-Y hepaticojejunostomy in case of intestinal malrotation. PMID- 25533326 TI - Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine. AB - The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of Burkholderia thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ~1*10(4) CFU B. mallei produced mortality in 50% of naive animals (n=2/4), 2-3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p=0.42), serum LPS-specific IgG titers were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies. PMID- 25533327 TI - Determining rubella immunity in pregnant Alberta women 2009-2012. AB - Rubella IgG levels for 157,763 pregnant women residing in Alberta between 2009 and 2012 were analyzed. As there have been no reported cases of indigenous rubella infection in Canada since 2005, there has been a lack of naturally acquired immunity, and the current prenatal population depends almost entirely on vaccine induced immunity for protection. Rubella antibody levels are significantly lower in younger maternal cohorts with 16.8% of those born prior to universal vaccination programs (1971-1980), and 33.8% of those born after (1981 1990) having IgG levels that are not considered protective (<15 IU/mL). Analysis across pregnancies showed only 35.0% of women responded with a 4-fold increase in antibody levels following post-natal vaccination. Additionally, 41.2% of women with antibody levels <15 IU/mL had previously received 2 doses of rubella containing vaccine. These discordant interpretations generate a great deal of confusion for laboratorians and physicians alike, and result in significant patient follow-up by Public Health teams. To assess the current antibody levels in the prenatal population, latent class modeling was employed to generate a two class fit model representing women with an antibody response to rubella, and women without an antibody response. The declining level of vaccine-induced antibodies in our population is disconcerting, and a combined approach from the laboratory and Public Health may be required to provide appropriate follow up for women who are truly susceptible to rubella infection. PMID- 25533328 TI - Conceptual frameworks and key dimensions to support coverage decisions for vaccines. AB - BACKGROUND: Health policy makers often have to face decisions on whether and how to incorporate new vaccines into immunisation plans. This study aims to review and catalogue the relevant current frameworks and taxonomies on vaccines and connect these to the DECIDE Evidence to Decision framework (EtD), a general framework based on evidence-based criteria to guide decision-making on intervention adoption. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library and funding agency websites from 1990 to 2013. We included systematic reviews and primary studies presenting decision-making tools for community vaccine adoption. We qualitatively summarised the reports by purpose, targeted country, principal results, and decisional models. We then extracted and compared the dimensions adopted by vaccine frameworks across studies. RESULTS: Fourteen studies (five systematic reviews and nine primary studies) were included. Several factors frequently influenced decision-makers' views on vaccines: the most frequent political-context factors considered were Importance of illness or problem, Vaccine characteristics, Resource use, and Feasibility. Others such as Values and preferences and Acceptability were less consistently reported. We did not find evidence on the reasons why a framework for vaccine adoption differs from that for decisions on the adoption of an intervention in general, such as the EtD. There are limited data on how dimensions are explained in practical factors and directly linked to coverage decisions. CONCLUSIONS: This review summarises conceptual models and taxonomy of a heterogeneous and evolving area in health policy decisions. A shared and comprehensive framework on vaccine coverage remains to be achieved with its single dimensions (epidemiologic, effectiveness, economic, and social) valued differently across studies. A generic tool such as the EtD conceptualises all relevant dimensions, and might reduce inconsistencies. PMID- 25533329 TI - In vitro susceptibility of amphotericin-B, voriconazole and caspofungin against Candida guilliermondii biofilms, isolated from dentals units water pipes, under different growth phases. AB - OBJECTIVE: The dental units water pipes are a favorable medium for biofilms formation because of the small diameter of the pipe and the duration of water stagnation, but the question which arises is the nature of the biofilms which are formed inside? This article gives a progress report on the nature of this microbial contamination and precisely the fungal biofilms formation by examining their susceptibility to antifungal agents under different growth phases. METHODS: Sixteen samples of dental units water pipes were taken from public dental clinic and from stomatology unit at the university hospital of Tlemcen (Algeria). The isolated strains were identified by the conventional mycological methods and were analyzed to determine their minimal concentrations inhibiting their growth (planktonic and sessile forms) using three antifungal agents. RESULTS: Five strains type Candida guilliermondii were identified and analyzed for their resistance to antifungal agents. Antifungal susceptibility testing demonstrated the sensitivity of all planktonic Candida guilliermondii cells against amphotericin-B, voriconzole and caspofungin but the sessile cells of these strains revealed a less susceptibility to antifungal agents and even a resistance when the biofilm made mature. CONCLUSION: Several types of yeast contaminated the dental units water pipes and especially Candida guilliermondii that was the most founded. This specie was susceptible to antifungal agents under planctonic forms and resistance where the biofilm made mature. PMID- 25533331 TI - Baicalein protects against polymicrobial sepsis-induced liver injury via inhibition of inflammation and apoptosis in mice. AB - Liver dysfunction has been known to occur frequently in cases of sepsis. Baicalein, the main active ingredient of the Scutellaria root, exerts anti inflammatory and anti-apoptotic properties in endotoxic shock. However, the role of baicalein in polymicrobial sepsis-induced liver injury and its regulatory mechanisms remain unclear. In this study, we aimed to investigate the protective effects of baicalein on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were treated with baicalein (100mg/kg, i.p) at 1h, 6h and 12h following CLP. Baicalein significantly improved the survival of septic mice. Treatment with baicalein ameliorated the CLP-induced liver injury, as indicated by the lower serum aminotransferase levels and the fewer histopathologic abnormalities. Baicalein reduced the neutrophil infiltration and the hepatic inflammatory cytokine expression and release. It also decreased the hepatic and the serum high-mobility group box 1 and macrophage migration inhibitory factor levels in septic mice. Moreover, baicalein significantly inhibited the mitogen-activated protein kinases (MAPKs) activation and suppressed the transcriptional activity of nuclear factor-kappa B (NF-kappaB). In conclusion, these results suggest that baicalein treatment could protect against the sepsis-induced liver injury, and improve the survival of mice with polymicrobial sepsis. The mechanism of the protective action of baicalein seems to involve its ability to reduce inflammatory response, to inhibit hepatic apoptosis, and to suppress MAPKs and NF-kappaB activation. PMID- 25533330 TI - Topical application of delphinidin reduces psoriasiform lesions in the flaky skin mouse model by inducing epidermal differentiation and inhibiting inflammation. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and aberrant keratinocyte differentiation. We have shown that treatment of reconstituted human skin with delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, increased the expression and processing of caspase-14, which is involved in cornification. Delphinidin also increases the expression of epidermal differentiation marker proteins. OBJECTIVES: To determine whether topical application of delphinidin can modulate pathological markers of psoriasiform lesions in flaky skin mice and if this is associated with increased epidermal differentiation and a reduction in proliferation and inflammation. METHODS: Five-week-old female homozygous flaky skin mice (fsn/fsn) were treated topically with delphinidin (0.5 mg cm(-2) and 1 mg cm(-2) skin areas, respectively), five times a week, up to 14 weeks of age. RESULTS: Treatment of flaky skin mice with delphinidin resulted in a reduction in (i) pathological markers of psoriasiform lesions; (ii) infiltration of inflammatory cells; and (iii) mRNA and protein expression of inflammatory cytokines. Delphinidin treatment also increased the expression and processing of caspase-14, and expression of filaggrin, loricrin, keratin-1 and keratin-10. Furthermore, there was a decrease in the expression of markers for cell proliferation (proliferating cell nuclear antigen and keratin-14) and modulation of tight junction proteins (occludin and claudin-1). In addition, delphinidin treatment increased the expression of activator protein-1 transcription factor proteins (JunB, JunD, Fra1 and Fra2). CONCLUSIONS: Delphinidin could be a promising agent for treatment of psoriasis and other hyperproliferative skin disorders. PMID- 25533333 TI - Anogenital distance as a measure of human male fertility. AB - PURPOSE: In humans, recent studies have correlated anogenital distance (AGD) in adult men to testicular function. While studies of a group of men suggest an association, the utility of AGD in an infertility evaluation remains uncertain. We sought to determine the utility of AGD to predict male fertility. METHODS: Between 2010 and 2011, men were recruited at a urology clinic to participate. AGD was measured using digital calipers in men being evaluated at a urology clinic. ANOVA and ROC analyses were used to determine correlations between AGD, fatherhood status, and semen parameters. RESULTS: In all, 473 men were included in the analysis with a mean age of 43 +/- 13 years. Anogenital distance was significantly longer in men with higher sperm concentration, total sperm count, and total motile sperm count. In order to evaluate the discriminating ability of AGD, ROC curves were created comparing AGD and total testis volume. The area under the curve (AUC) was significantly larger for total testis volume compared to AGD when evaluating fertility (0.71 vs 0.63, p = 0.02). Similarly, there was a trend towards a higher AUC for testis volume compared to AGD for sperm concentration and total sperm count. Stratification of men with long/short AGD and large/small testes also did not improve the predictive value of AGD. CONCLUSIONS: While AGD is associated with sperm production on a population level, at the individual level the distinction based AGD alone cannot accurately estimate the efficiency of spermatogenesis. PMID- 25533332 TI - The role of Wnt signaling members in the uterus and embryo during pre implantation and implantation. AB - Wnt family members are best known for their roles in cell fate determination, differentiation, proliferation and apoptosis during embryonic development. Wnt signaling becomes effective during these cellular processes through the proper interaction between its ligands, receptors, effectors and inhibitors. Here we review Wnt signaling in terms of embryonic development to the blastocyst stage implantation with emphasis on endometrial changes that are critical for receptivity in the uterus. The relationship between Wnt signaling and implantation clearly reveals that, Wnt family members are critical for both early embryonic development and changing of the endometrium before implantation. Specific Wnt signaling pathway members are demonstrated to be critical for endometrial events such as decidualization and endometrial gland formation in addition to cyclic changes in the endometrium controlled by reproductive hormones. In conclusion, specific roles of Wnt members and associated factors for both uterine function and embryonic development should be further investigated with respect to the efficiency of human ARTs. PMID- 25533334 TI - Validation of miRNA genes suitable as reference genes in qPCR analyses of miRNA gene expression in Atlantic salmon (Salmo salar). AB - BACKGROUND: MicroRNAs (miRNAs) are an abundant class of endogenous small RNA molecules that downregulate gene expression at the post-transcriptional level. They play important roles by regulating genes that control multiple biological processes, and recent years there has been an increased interest in studying miRNA genes and miRNA gene expression. The most common method applied to study gene expression of single genes is quantitative PCR (qPCR). However, before expression of mature miRNAs can be studied robust qPCR methods (miRNA-qPCR) must be developed. This includes identification and validation of suitable reference genes. We are particularly interested in Atlantic salmon (Salmo salar). This is an economically important aquaculture species, but no reference genes dedicated for use in miRNA-qPCR methods has been validated for this species. Our aim was, therefore, to identify suitable reference genes for miRNA-qPCR methods in Salmo salar. RESULTS: We used a systematic approach where we utilized similar studies in other species, some biological criteria, results from deep sequencing of small RNAs and, finally, experimental validation of candidate reference genes by qPCR to identify the most suitable reference genes. Ssa-miR-25-3p was identified as most suitable single reference gene. The best combinations of two reference genes were ssa-miR-25-3p and ssa-miR-455-5p. These two genes were constitutively and stably expressed across many different tissues. Furthermore, infectious salmon anaemia did not seem to affect their expression levels. These genes were amplified with high specificity, good efficiency and the qPCR assays showed a good linearity when applying a simple cybergreen miRNA-PCR method using miRNA gene specific forward primers. CONCLUSIONS: We have identified suitable reference genes for miRNA-qPCR in Atlantic salmon. These results will greatly facilitate further studies on miRNA genes in this species. The reference genes identified are conserved genes that are identical in their mature sequence in many aquaculture species. Therefore, they may also be suitable as reference genes in other teleosts. Finally, the systematic approach used in our study successfully identified suitable reference genes, suggesting that this may be a useful strategy to apply in similar validation studies in other aquaculture species. PMID- 25533335 TI - Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. AB - We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. PMID- 25533336 TI - Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. AB - The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause gammadelta lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5 unresponsive tumor-bearing mice but only accelerates malignant progression in IL 6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5 responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism. PMID- 25533337 TI - Contrast enhancement by combining T1- and T2-weighted structural brain MR Images. AB - PURPOSE: In order to more precisely differentiate cerebral structures in neuroimaging studies, a novel technique for enhancing the tissue contrast based on a combination of T1-weighted (T1w) and T2-weighted (T2w) MRI images was developed. METHODS: The combined image (CI) was calculated as CI = (T1w - sT2w)/(T1w + sT2w), where sT2w is the scaled T2-weighted image. The scaling factor was calculated to adjust the gray- matter (GM) voxel intensities in the T2w image so that their median value equaled that of the GM voxel intensities in the T1w image. The image intensity homogeneity within a tissue and the discriminability between tissues in the CI versus the separate T1w and T2w images were evaluated using the segmentation by the FMRIB Software Library (FSL) and FreeSurfer (Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston, MA) software. RESULTS: The combined image significantly improved homogeneity in the white matter (WM) and GM compared to the T1w images alone. The discriminability between WM and GM also improved significantly by applying the CI approach. Significant enhancements to the homogeneity and discriminability also were achieved in most subcortical nuclei tested, with the exception of the amygdala and the thalamus. CONCLUSION: The tissue discriminability enhancement offered by the CI potentially enables more accurate neuromorphometric analyses of brain structures. PMID- 25533339 TI - The DET1-COP1-HY5 pathway constitutes a multipurpose signaling module regulating plant photomorphogenesis and thermomorphogenesis. AB - Developmental plasticity enables plants to respond to elevated ambient temperatures by adapting their shoot architecture. On the cellular level, the basic-helix-loop-helix (bHLH) transcription factor phytochrome interacting factor 4 (PIF4) coordinates this response by activating hormonal modules that in turn regulate growth. In addition to an unknown temperature-sensing mechanism, it is currently not understood how temperature regulates PIF4 activity. Using a forward genetic approach in Arabidopsis thaliana, we present extensive genetic evidence demonstrating that the de-etiolated 1 (DET1)-constitutive photomorphogenic 1 (COP1)-elongated hypocotyl 5 (HY5)-dependent photomorphogenesis pathway transcriptionally regulates PIF4 to coordinate seedling growth in response to elevated temperature. Our findings demonstrate that two of the most prevalent environmental cues, light and temperature, share a much larger set of signaling components than previously assumed. Similar to the toolbox concept in animal embryonic patterning, multipurpose signaling modules might have evolved in plants to translate various environmental stimuli into adaptational growth processes. PMID- 25533338 TI - Reducing occupational stress with a B-vitamin focussed intervention: a randomized clinical trial: study protocol. AB - BACKGROUND: Workplace stress in Australia and other western countries has been steadily increasing over the past decade. It can be observed not only in terms of increased compensation claims but also costs due to absenteeism, loss of productivity at work and reduced psychological and physiological health and well being. Given the cost and pervasive effects of stress in the modern workforce, time efficient and cost-effective interventions capable of reducing occupational stress (or strain) and burnout are urgently required for the improved well-being of stressed employees. One intervention gaining scientific traction is supplementation with nutritional interventions, particularly the B group vitamins. METHODS: This study was developed to examine the effects of B group vitamins on workplace stress and mood variables with a sample of full-time employed older adults who subjectively report feeling stressed. The study is a randomized, double-blind, placebo-controlled, parallel-groups clinical trial where 200 (N = 100/group) participants will be randomized to receive Blackmores(r) Executive B Stress Formula or placebo daily for a period of 6 months. Participants will be tested at baseline and 6 months post-randomization on workplace stress, cognitive, personality and mood measures, cardiovascular (brachial and aortic systolic and diastolic blood pressures as well as arterial stiffness), biochemical (assays to measure inflammation and safety) as well as genetic assessments (to assess stress processing) and neuroimaging measures (to investigate in vivo mechanisms of action of B vitamins). In addition to this pre- and post- supplementation testing, participants will also complete a battery of self-report questionnaires online to assess their stress and mood once a month for the duration of the study. The primary aim of the study is to investigate the effects of B vitamin supplementation on work related stress. The secondary aims are to explore the mechanisms underpinning any changes in mood or workplace stress due to the B vitamin intervention by examining relationships between cognitive, biological, neuroimaging and cardiovascular variables over 6 months. A subset of 40 participants (N = 20/group) will undergo neuroimaging at baseline and at 6 months using functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) in order to further explore in vivo mechanisms of action of B vitamins. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR):ACTRN12613000294752. PMID- 25533340 TI - Cdk1 restrains NHEJ through phosphorylation of XRCC4-like factor Xlf1. AB - Eukaryotic cells use two principal mechanisms for repairing DNA double-strand breaks (DSBs): homologous recombination (HR) and nonhomologous end-joining (NHEJ). DSB repair pathway choice is strongly regulated during the cell cycle. Cyclin-dependent kinase 1 (Cdk1) activates HR by phosphorylation of key recombination factors. However, a mechanism for regulating the NHEJ pathway has not been established. Here, we report that Xlf1, a fission yeast XLF ortholog, is a key regulator of NHEJ activity in the cell cycle. We show that Cdk1 phosphorylates residues in the C terminus of Xlf1 over the course of the cell cycle. Mutation of these residues leads to the loss of Cdk1 phosphorylation, resulting in elevated levels of NHEJ repair in vivo. Together, these data establish that Xlf1 phosphorylation by Cdc2(Cdk1) provides a molecular mechanism for downregulation of NHEJ in fission yeast and indicates that XLF is a key regulator of end-joining processes in eukaryotic organisms. PMID- 25533341 TI - A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. AB - Adhesion G protein-coupled receptors (aGPCRs) comprise the second largest yet least studied class of the GPCR superfamily. aGPCRs are involved in many developmental processes and immune and synaptic functions, but the mode of their signal transduction is unclear. Here, we show that a short peptide sequence (termed the Stachel sequence) within the ectodomain of two aGPCRs (GPR126 and GPR133) functions as a tethered agonist. Upon structural changes within the receptor ectodomain, this intramolecular agonist is exposed to the seven transmembrane helix domain, which triggers G protein activation. Our studies show high specificity of a given Stachel sequence for its receptor. Finally, the function of Gpr126 is abrogated in zebrafish with a mutated Stachel sequence, and signaling is restored in hypomorphic gpr126 zebrafish mutants upon exogenous Stachel peptide application. These findings illuminate a mode of aGPCR activation and may prompt the development of specific ligands for this currently untargeted GPCR family. PMID- 25533342 TI - Localization and function of budding yeast CENP-A depends upon kinetochore protein interactions and is independent of canonical centromere sequence. AB - In many eukaryotes, the centromere is epigenetically specified and not strictly defined by sequence. In contrast, budding yeast has a specific 125 bp sequence required for kinetochore function. Despite the difference in centromere specification, budding yeast and multicellular eukaryotic centromeres contain a highly conserved histone H3 variant, CENP-A. The localization of budding yeast CENP-A, Cse4, requires the centromere DNA binding components, which are not conserved in multicellular eukaryotes. Here, we report that Cse4 localizes and functions at a synthetic kinetochore assembly site that lacks centromere sequence. The outer kinetochore Dam1-DASH and inner kinetochore CBF3 complexes are required for Cse4 localization to that site. Furthermore, the natural kinetochore also requires the outer kinetochore proteins for full Cse4 localization. Our results suggest that Cse4 localization at a functional kinetochore does not require the recognition of a specific DNA sequence by the CBF3 complex; rather, its localization depends on stable interactions among kinetochore proteins. PMID- 25533344 TI - Integrins regulate apical constriction via microtubule stabilization in the Drosophila eye disc epithelium. AB - During morphogenesis, extracellular signals trigger actomyosin contractility in subpopulations of cells to coordinate changes in cell shape. To illuminate the link between signaling-mediated tissue patterning and cytoskeletal remodeling, we study the progression of the morphogenetic furrow (MF), the wave of apical constriction that traverses the Drosophila eye imaginal disc preceding photoreceptor neurogenesis. Apical constriction depends on actomyosin contractility downstream of the Hedgehog (Hh) and bone morphogenetic protein (BMP) pathways. We identify a role for integrin adhesion receptors in MF progression. We show that Hh and BMP regulate integrin expression, the loss of which disrupts apical constriction and slows furrow progression; conversely, elevated integrins accelerate furrow progression. We present evidence that integrins regulate MF progression by promoting microtubule stabilization, since reducing microtubule stability rescues integrin-mediated furrow acceleration. Thus, integrins act as a genetic link between tissue-level signaling events and morphological change at the cellular level, leading to morphogenesis and neurogenesis in the eye. PMID- 25533343 TI - Conversion of fibroblasts to neural cells by p53 depletion. AB - Conversion from fibroblasts to neurons has recently been successfully induced. However, the underlying mechanisms are poorly understood. Here, we find that depletion of p53 alone converts fibroblasts into all three major neural lineages. The induced neuronal cells express multiple neuron-specific proteins and generate action potentials and transmitter-receptor-mediated currents. Surprisingly, depletion does not affect the well-known tumorigenic p53 target, p21. Instead, knockdown of p53 upregulates neurogenic transcription factors, which in turn boosts fibroblast-neuron conversion. p53 binds the promoter of the neurogenic transcription factor Neurod2 and regulates its expression during fibroblast neuron conversion. Furthermore, our method provides a high efficiency of conversion in late-passage fibroblasts. Genome-wide transcriptional analysis shows that the p53-deficiency-induced neurons exhibit an expression profile different from parental fibroblasts and similar to control-induced neurons. The results may help to understand and improve neural conversion mechanisms to develop robust neuron-replacement therapy strategies. PMID- 25533345 TI - Erk signaling suppresses embryonic stem cell self-renewal to specify endoderm. AB - Fgf signaling via Erk activation has been associated with both neural induction and the generation of a primed state for the differentiation of embryonic stem cells (ESCs) to all somatic lineages. To dissect the role of Erk in both ESC self renewal and lineage specification, we explored the requirements for this pathway in various in vitro differentiation settings. A combination of pharmacological inhibition of Erk signaling and genetic loss of function reveal a role for Erk signaling in endodermal, but not neural differentiation. Neural differentiation occurs normally despite a complete block to Erk phosphorylation. In support of this, Erk activation in ESCs derepresses primitive endoderm (PrE) gene expression as a consequence of inhibiting the pluripotent/epiblast network. The early response to Erk activation correlates with functional PrE priming, whereas sustained Erk activity results in PrE differentiation. Taken together, our results suggest that Erk signaling suppresses pluripotent gene expression to enable endodermal differentiation. PMID- 25533347 TI - Cytoskeletal regulation by AUTS2 in neuronal migration and neuritogenesis. AB - Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations. PMID- 25533346 TI - p62 is required for stem cell/progenitor retention through inhibition of IKK/NF kappaB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche. AB - In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MPhis), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-kappaB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1-binding partner Nbr1. A functional "MPhi-Ob niche" is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-kappaB signaling repression, osteogenesis, and BM progenitor retention. PMID- 25533349 TI - Mapping gene regulatory networks in Drosophila eye development by large-scale transcriptome perturbations and motif inference. AB - Genome control is operated by transcription factors (TFs) controlling their target genes by binding to promoters and enhancers. Conceptually, the interactions between TFs, their binding sites, and their functional targets are represented by gene regulatory networks (GRNs). Deciphering in vivo GRNs underlying organ development in an unbiased genome-wide setting involves identifying both functional TF-gene interactions and physical TF-DNA interactions. To reverse engineer the GRNs of eye development in Drosophila, we performed RNA-seq across 72 genetic perturbations and sorted cell types and inferred a coexpression network. Next, we derived direct TF-DNA interactions using computational motif inference, ultimately connecting 241 TFs to 5,632 direct target genes through 24,926 enhancers. Using this network, we found network motifs, cis-regulatory codes, and regulators of eye development. We validate the predicted target regions of Grainyhead by ChIP-seq and identify this factor as a general cofactor in the eye network, being bound to thousands of nucleosome-free regions. PMID- 25533348 TI - Tolerance of deregulated G1/S transcription depends on critical G1/S regulon genes to prevent catastrophic genome instability. AB - Expression of a G1/S regulon of genes that are required for DNA replication is a ubiquitous mechanism for controlling cell proliferation; moreover, the pathological deregulated expression of E2F-regulated G1/S genes is found in every type of cancer. Cellular tolerance of deregulated G1/S transcription is surprising because this regulon includes many dosage-sensitive proteins. Here, we used the fission yeast Schizosaccharomyces pombe to investigate this issue. We report that deregulating the MBF G1/S regulon by eliminating the Nrm1 corepressor increases replication errors. Homology-directed repair proteins, including MBF regulated Ctp1(CtIP), are essential to prevent catastrophic genome instability. Surprisingly, the normally inconsequential MBF-regulated S-phase cyclin Cig2 also becomes essential in the absence of Nrm1. This requirement was traced to cyclin dependent kinase inhibition of the MBF-regulated Cdc18(Cdc6) replication origin licensing factor. Collectively, these results establish that, although deregulation of G1/S transcription is well tolerated by cells, nonessential G1/S target genes become crucial for preventing catastrophic genome instability. PMID- 25533350 TI - Channelrhodopsin-assisted patching: in vivo recording of genetically and morphologically identified neurons throughout the brain. AB - Brain networks contain a large diversity of functionally distinct neuronal elements, each with unique properties, enabling computational capacities and supporting brain functions. Understanding their functional implications for behavior requires the precise identification of the cell types of a network and in vivo monitoring of their activity profiles. Here, we developed a channelrhodopsin-assisted patching method allowing the efficient in vivo targeted recording of neurons identified by their molecular, electrophysiological, and morphological features. The method has a high yield, does not require visual guidance, and thus can be applied at any depth in the brain. This approach overcomes limitations of present technologies. We validate this strategy with in vivo recordings of identified subtypes of GABAergic and glutamatergic neurons in deep cortical layers, subcortical cholinergic neurons, and neurons in the thalamic reticular nucleus in anesthetized and awake mice. We propose this method as an important complement to existing technologies to relate specific cell-type activity to brain circuitry, function, and behavior. PMID- 25533352 TI - Application of autochthonous mixed starter for controlled Kedong sufu fermentation in pilot plant tests. AB - Traditional sufu is fermented by back-slopping and back-slopping has many defects. The objective of this study was to apply autochthonous mixed starter to control Kedong sufu fermentation. Sufu was manufactured using back-slopping (batch A) and autochthonous mixed starter (batch B) with Kocuria kristinae F7, Micrococcus luteus KDF1, and Staphylococcus carnosus KDFR1676. Considering physicochemical properties of sufu, 150-day sufu samples from batch A and 90-day sufu samples from batch B met the standard requirements, respectively. Considering sensory characteristics of sufu, 150-day sufu samples from batch A and 90-day sufu samples from batch B showed no significant differences (P > 0.05). The maturation period of sufu was shortened by 60 d. Profiles of free amino acids and peptides partly revealed the mechanism of typical sensory quality and shorter ripening time of sufu manufactured by autochthonous mixed starter. In final products, content of total biogenic amines was reduced by 48%. Autochthonous mixed starter performed better than back-slopping. Fermentation had a positive influence on the quality, safety, and sensory properties of sufu. The application of autochthonous mixed starter does not change the sensory characteristics of traditional fermented sufu. In addition, it reduces maturation period and improves their homogeneity and safety. It is possible to substitute autochthonous mixed starter for back-slopping in the manufacture of sufu. PMID- 25533353 TI - Information flow through neural circuits for pheromone orientation. AB - Moths use a sophisticated olfactory navigation strategy for resource localization. Here we investigate the neuronal circuits involved in sensory processing to generate locomotor commands for pheromone-source orientation in the moth. We identify a candidate pathway for pheromone processing in the protocerebrum using a mass-staining technique. Our intracellular recordings of pheromone responsiveness detect four major circuits, including a newly identified unstructured neuropil, the superior medial protocerebrum, which supplies output to the lateral accessory lobe (LAL), the premotor centre for walking commands. Interneurons innervating the lower division of the LAL elicited longer responses than those innervating the upper division. Descending interneurons innervating the lower division of the LAL showed a state-dependent flip-flop response. In contrast, input from other visual areas in the protocerebrum mostly converge onto the upper division of the LAL. These results reveal the basic organization of the LAL: the upper division is identified as a protocerebral hub that receives inputs from various areas, while the lower division generates long-lasting activity for locomotor command. PMID- 25533351 TI - ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages. AB - Posttranscriptional gene regulation by miRNAs and RNA binding proteins (RBP) is important in development, physiology, and disease. To examine the interplay between miRNAs and the RBP ELAVL1 (HuR), we mapped miRNA binding sites at the transcriptome-wide scale in wild-type and Elavl1 knockout murine bone-marrow derived macrophages. Proximity of ELAVL1 binding sites attenuated miRNA binding to transcripts and promoted gene expression. Transcripts that regulate angiogenesis and macrophage/endothelial crosstalk were preferentially targeted by miRNAs, suggesting that ELAVL1 promotes angiogenesis, at least in part by antagonism of miRNA function. We found that ELAVL1 antagonized binding of miR-27 to the 3' UTR of Zfp36 mRNA and alleviated miR-27-mediated suppression of the RBP ZFP36 (Tristetraprolin). Thus, the miR-27-regulated mechanism synchronizes the expression of ELAVL1 and ZFP36. This study provides a resource for systems-level interrogation of posttranscriptional gene regulation in macrophages, a key cell type in inflammation, angiogenesis, and tissue homeostasis. PMID- 25533355 TI - Immunophenotypic analysis reveals heterogeneity and common biologic aspects in monoclonal B-cell lymphocytosis. AB - Monoclonal B-cell lymphocytosis (MBL) is the presence of small B-cell clones in the peripheral blood of healthy subjects. Most MBL have the characteristic phenotype of chronic lymphocyte leukemia (chronic lymphocytic leukemia (CLL)-like MBL), and depending on the number of monoclonal B-cells, may characterize a preclinical stage of the CLL. However, there are also MBL with an atypical (CD5(+) CD20(+/bright) CD23(dim/-) ) or a CD5(neg) phenotype, which remain largely unexplored. We performed an extended immunophenotypic, cytogenetic, and hematologic analysis in 75 CLL-like, 39 atypical, 50 CD5(neg) , and 7 biphenotypic MBL cases to detect differences or similarities among the MBL subsets. The phenotypic analysis showed expression variations in many surface markers and a wide spectrum of disease-specific phenotypes within each MBL subtype. Interphase fluorescent in situ hybridization analysis showed a different panel of aberrations according to the phenotype. Overall, del(13q14) and +12 were the most common abnormalities (39%), whereas del(11q13), del(17p13), and del(6q23) were detected only in 3, 1, and 0 cases, respectively. A comparison of MBL with overt chronic lymphoproliferations revealed common aspects in the preclinical state, regarding both the kind of cytogenetic aberrations detected and the lymphocyte composition. Our findings highlight not only the heterogeneity among MBL subsets but also indicate common biologic features which differentiate MBL from clinical disease. PMID- 25533356 TI - Use of extracellular matrix patches in cardiac surgery. AB - A noncellular xenogeneic extracellular matrix derived from the porcine small intestinal submucosa can be used as a new patch material with potential advantages. We review the literature on the use of this material in cardiac surgery. PMID- 25533354 TI - Pro-inflammatory response and oxidative stress induced by specific components in ambient particulate matter in human bronchial epithelial cells. AB - Previous studies have shown that biological effect of particulate matter (PM2.5) is involved in including chemical composition and mass concentration, but the precise components and biological action on human bronchial epithelial cell line (BEAS-2B) are still unclear. The aim of this study was to evaluate the in vitro toxicity of PM2.5 collected at six urban sites in China, and to investigate how particle composition affects cytotoxicity. We used human bronchial epithelial (BEAS-2B) cell lines as model in vitro to expose to PM2.5 from different source, and then reactive oxygen species (ROS), superoxide dismutase activity and total antioxidant capacity were analyzed. Furthermore, we estimated the polycyclic aromatic hydrocarbon (PAH) and transition metal and the endotoxin contents. The mRNA expression of IL-1beta and IL-10 following exposure to PM2.5 was measured by QRT-PCR. We also observed the mitochondrial membrane potential (MMP) using JC-1 staining, and apoptosis of BEAS-2B using flow cytometry. In addition, double stranded DNA breaks (DSBs) were assessed using gamma-H2AX immunofluorescence. Our results show that high concentrations of PAHs and elemental Ni were strongly associated with high apoptosis rates and high expression of IL-1beta, in addition, Fe element was associated with the ROS level, furthermore, Fe and Cr element were associated with DNA damage in BEAS-2B cells. The cytotoxic effects of urban PM2.5 derived from six different cities in China appear dependent on the specific components in each. Our results indicate that air quality standards based on PM2.5 components may be more relevant than concentration-response functions (CRF). (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 923-936, 2016. PMID- 25533358 TI - [Future toxicology-quantum toxicology]. PMID- 25533359 TI - [Effects of trichloroethylene toxicity on normal human liver cells and hepatocytes with CYP2E1 gene overexpression]. AB - OBJECTIVE: To investigate the effects of trichloroethylene (TCE) toxicity on the normal human liver cells (L02 cells) and hepatocytes with CYP2E1 gene overexpression which was constructed through molecular cloning technology in our laboratory, then to explore the roles of CYP2E1 gene in TCE toxicity. METHODS: L02 cells and hepatocytes with CYP2E1 overexpression were treated with various doses of TCE (0,0.25, 0.5, 1.0, 2.0, 4.0 mmol/L) for 12h, the expression of apoptosis genes (Bcl-2, Caspase-3, Caspase-8, Caspase-9) and oncogenes (c-fos, c myc, k-ras, p53) were determined by real-time fluorescent PCR. RESULTS: Bcl-2 mRNA expression levels increased significantly in normal liver cells and CYP2E1 overexpressing cells after TCE treatment, Bcl-2 levels were 20%~50%higher in CYP2E1-overexpressing cells than in L02 liver cells at doses of 0.25~2.0 mmol/L TCE. Caspase-3, Caspase-8 and caspase-9 mRNA expression increased by 30%~600% in CYP2E1-overexpressing cells at doses of 0.5~4.0 mmol/L TCE when compared with L02 cells (P < 0.01). Additionally, c-fos, k-ras and c-myc mRNA expression levels were 25%~120% higher in CYP2E1-overexpressing cells than in L02 cells (P < 0.01), p53 mRNA expression levels were lower 10%~50% in CYP2E1-overexpressing cells than in L02 cells (P < 0.05 or P < 0.01). CONCLUSIONS: There were significant differences for apoptosis gene and oncogene expression levels between normal liver cells and CYP2E1-overexpressing cells after they were treated with TCE, these findings indicated that CYP2E1 might play an important role in TCE metabolism in vivo. PMID- 25533360 TI - [Investigation on psychological stress of mine emergency rescue personnel]. AB - OBJECTIVE: To investigate psychological stress and influence factors on the mine emergency rescue personnel. METHOD: 564 mine emergency rescue personnel from a rescue group were select as subjects, and 60 designers from a steel design institute were as controls. Self-made questionnaire and general job stress questionnaire were used to investigate the basic information, rescue history, psychosomatic symptoms, depression symptoms, daily job stress and negative emotions of emergency rescue personnel. SPSS17.0 software was used to analysis the psychological stress on the mine rescue personnel and its influence factors. RESULTS: The detection rate (41.94%) of depression symptoms in rescue team was higher than that of controls (24.90%). The score of daily job stress was higher than that of logistical support. The older age group with higher negative emotional and daily job stress than the younger. The highest negative emotion was in age group of more than 40 years old. The highest score of daily job stress was in <=30 years old. The score of depression and psychosomatic symptoms were higher than those of the college and the above. The scores of depression in group of duration of rescue <10 years was higher than that of duration>=10 years. The score of daily job stress is the lowest in rescue for 1 to 2 times per year and the highest in group of simulation training once a week. The score of daily job stress and depressive symptoms were getting higher with the extension of combat duty time. Age, hours of combat duty, training times a week, education and life events were the main affecting fectors on mental health of mine rescuers. CONCLUSIONS: Mine rescuers have more psychological stress than generic population. The psychological stress of the mine crew is related to age, education, life events, training and combat readiness duty time. PMID- 25533357 TI - Effects of gatifloxaine content in gatifloxacine-loaded PLGA and beta-tricalcium phosphate composites on efficacy in treating osteomyelitis. AB - Composites of gatifloxacin (GFLX)-loaded poly (lactic-co-glycolic) acid (PLGA) and beta-tricalcium phosphate (betaTCP) containing 0, 1, and 10 wt % GFLX (0, 1, and 10 wt % GFLX composites), and GFLX-loaded PLGA containing 1, 5, and 10 wt % GFLX (1, 5, and 10wt % GFLX-PLGA) as controls were fabricated and characterized in vitro and in vivo. On in vitro evaluation, the 10 wt % GFLX composite released GFLX over at least 28 days in Hanks' balanced solution and exhibited clinically sufficient bactericidal activities against Streptococcus milleri and Bacteroides fragilis from 1 h to 10 days. The 0, 1, and 10 wt % GFLX composites and 10 wt % GFLX-PLGA were implanted in bone defects created by debridement of osteomyelitis lesions induced by S. milleri and B. fragilis in the mandible of rabbits (n = 5). Four weeks after implantation of the 10 wt % GFLX composite, inflammation in the debrided area disappeared in all the rabbits, while inflammation remained in all the rabbits after implantation of the 0 wt % GFLX composite and 10 wt % GFLX PLGA, and in three rabbits after implantation of the 1 wt % GFLX composite. Bone formation appears to be less intense for the 10 wt % GFLX composite than for the 1 wt % GFLX composite probably owing to the rapid degradation of the 10 wt % GFLX composite. These findings show that the GFLX composite is effective for the local treatment of osteomyelitis. PMID- 25533362 TI - [The serumproteomics research of vinyl chloride workers]. AB - OBJECTIVE: To screen out serum differential proteins between vinyl chloride monomer (VCM)-exposed workers and healthy controls by proteomics and analyze the functions of differential proteins, and to provide a basis for elucidating the pathogenesis of diseases caused by VCM exposure and searching for the protein biomarkers. METHODS: Fasting venous blood was collected from 125 VCM-exposed workers and 40 healthy controls according to accumulated exposure doses. Proteins were precipitated by acetone precipitation. These proteins were identified by 2D nano LC-ESI-TOF/MS and quantified by isobaric tags for relative and absolute quantitation. The functions of differential proteins were analyzed by gene ontology. RESULTS: A total of 596 proteins were identified, including 194 quantified proteins. There were 21 differential proteins according to the screening criteria (19 upregulated proteins and 2 downregulated proteins), including complement, apolipoprotein, and glycoprotein. The functions of these differential proteins were binding, enzyme regulator activity, catalytic activity, and transporter activity, and they were involved in the biological processes including immune system process and response to stimulus. CONCLUSION: The complement, apolipoprotein, and glycoprotein identified in the proteomics may be related to liver injury caused by VCM exposure, and they could be used as candidate protein biomarkers of diseases caused by VCM exposure. PMID- 25533363 TI - [A study on prevalence of functional gastrointestinal disease in 375 nurses]. PMID- 25533361 TI - [Study on willingness to participate and willingness to pay for hypothetical industrial injury insurance scheme]. AB - OBJECTIVE: To investigate workers' willingness to participate and wiliness to pay for a hypothetical industrial injury insurance scheme, to analyze the influential factors, and to provide information for policy making of the government. METHODS: Multistage cluster sampling was used to select subjects: In the first stage, 9 small, medium, orlarge enterprises were selected fromthree cities (counties) in Zhejiang province, China, according to the level of economic development, transportation convenience, and cooperation of government agencies; in the second stage, several workshops were randomly selected from each of the 9 enterprises. Face-to-face interviews among all workers in the workshops were conducted by trained interviewers using a pre-designed questionnaire. RESULTS: It was found that 73.87% (2095) of all workers were willing to participate in the hypothetical work injury insurance scheme and to pay 2.21% of monthly wage (51.77 yuan) on average, and more than half of the workers were willing to pay less than 1%of monthly wage (35 yuan). Of the 741 workers who were not willing to participate, 327 thought that the premium should be borne by the state or enterprises, instead of individuals, and others were not willing to participate because of low income, unstable job, or poor understanding of the hypothetical industrial injury insurance scheme. Logistic regression analysis showed that workers with higher education levels, longer length of services, longer weekly working time, or more knowledge of occupational diseases showed higher willingness to participate in the scheme; workers who were exposed to physical hazards, had health records, or had participated in the existing medical insurance or industrial injury insurance were more willing to participate. Multiple linear regression analysis showed that with increasing average monthly wage, weekly working time, and self?health evaluation, the proportion of workers with willingness to pay increased; however, with increasing work intensity and awareness of occupational disease, the proportion of workers with willingness to pay decreased. The workers who were not covered by the industrial injury insurance paid more than those covered by the industrial injury insurance. CONCLUSION: The hypothetical industrial injury insurance scheme increased the applicability and advantage of independent third party running and lifetime insurance, which significantly increased the workers' willingness to participate in or to pay for the insurance scheme. Therefore, the industrial injury insurance can be improved in these aspects to promote workers' willingness to participate in and to pay for the insurance scheme. This conclusion provided a reference for the solution of delayed or shirking corporate responsibility for paying the premium. PMID- 25533364 TI - [A study on occupational risk factor investigation of sanitation workers]. PMID- 25533365 TI - [Prevalence study on pneumoconiosis in 1367 dust exposed workers]. PMID- 25533366 TI - [A study on effects on accoucheuses' job burnout by their professional identity and professional benefits]. PMID- 25533367 TI - [The Influence of risk factors on visual performance in of phototoxic maculopathy in occupational welders]. AB - OBJECTIVE: To investigate the Influence of risk factors that cause the phototoxic maculopathy by welding arc in occupational welders. METHODS: We examined randomly a group of 86 male occupational welders 172 eyes from some local metal manufacturing enterprise from August 2010 to December 2013. The ophthalmologic examination which the participants underwent thorough including the best visual acuity, fundus examination by the supplementary lens, fundus photography, and the high definition optical coherence tomography (OCT) scan. All participants of this study underwent thorough the medicine examined by a specialist of occupational who prior to the OCT. All the subjects were divided into groups according to age, protection degrees , length of service, operating time . The incidences of phototoxic maculopathy were compared within groups. The subjects was divided randomly into the lutein group and the placebo group. The examination including the best visual acuity, serum lutein concentrations, macular pigmentoptical density (MPOD), Contrast and glare Sensitivity. RESULTS: (1) The total incidence of phototoxic maculopathy is 32.0%. (2) The incidences of phototoxic maculopathy in the strict protection group, the randomed protective group and the nonprofessional protection group were respectively 21.4%, 36.7%, 53.6%. The incidence in the strict protection group was lower than the other two groups, the incidence was the highest in the nonprofessional protection group, and the difference was statistically significant. (3) The longer length of service, and operating time , the more incidence of phototoxic maculopathy develop. (4) The lutein group prior to the placebo group at the best visual acuity, serum lutein concentrations, macular pigmentoptical density (MPOD), Contrast and glare Sensitivity. CONCLUSION: The risk factors of phototoxic maculopathy in male occupational welders are the length of service, operating time, protection degrees and the lutein assistantly. The incidence of phototoxic maculopathy occurs regardless of age. PMID- 25533368 TI - [The ameliorate effect of anthocyanin onMouse testis damage]. AB - OBJECTIVE: To study the effect of Anthocyanin (Ay) on Cadmium-Induced Mouse testis Damage. METHODS: Mouse testis damage model were constructed and testis malonaldehyde (MDA) and protein carbonxyl content (PCO), as well as catalase (CAT) and superoxide dismutase (SOD) were determined. RESULTS: The intoxication of cadmium can cause the increase of MDA and PCO content in mouse testis (P < 0.05), however, the activities of SOD and CAT were altered (P < 0.01). CONCLUSION: Ay have the strong potent to scavenge free radicals, owing to its special chemical structures, and act as a protector to inhibit the oxidative stress induced by cadmium. PMID- 25533369 TI - [Serumcell adhesion factor and cytokine levels of toxic patients induced by paraquat]. PMID- 25533371 TI - [Correlation between diffusion tensor imaging and cognitive dysfunction in patients with delayed encephalopathy after acute carbon monoxide poisoning]. AB - OBJECTIVE: To explore the diagnostic value of magnetic resonance (MR) diffusion tensor imaging (DTI) in detecting brain white matter (WM) damage of patients with delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) and evaluating their cognitive dysfunction. METHODS: Thirteen patients with DEACMP and thirteen age- and sex-matched volunteers underwent DTI using 1.5T MR scanner. FA and ADC values of 16 WM regions of interests (ROIs) were measured on DTI by two experienced radiologists independently with double blind methods, cognitive functions were evaluated by another experienced neurologist blinded to patient's medical history using the Montreal cognitive assessment (MoCA). ADC and FA values in DEACMP patients, and their correlations with cognitive dysfunction were analyzed. RESULTS: ADC values of DEACMP patients increased significantly in all ROIs (P < 0.05) in comparison with the corresponding ROIs of healthy controls, whereas FA values were significantly decreased in all ROIs (P < 0.05) in comparison with that in controls except the bilateral optic radiations, anterior and posterior internal capsules. MoCA scores were positively correlated with FA values of bilateral lower frontal (r(L) = 0.736, P = 0.011; r(R) = 0.762, P = 0.003) lobe, temporal lobe (r(L) = 0.605, P = 0.016; r(R) = 0.559, P = 0.021) and total average WM (r(A) = 0.688, P = 0.001), however it inversely correlated with ADC values of bilateral lower frontal WM (r(L) = -0.674, P = 0.007; r(R) = 0.681, P = 0.019). CONCLUSION: DTI can quantitatively reveal WM microstructure damage of DEACMP patients, indicate the severity of cognitive dysfunctions, and provide important information for pathogenesis and pathological study for DEACMP. PMID- 25533370 TI - [Clinical analysis of using hyperbaric oxygen comprehensive therapy for the treatment of 110 cases noise induced deafness]. AB - OBJECTIVE: To observe the clinical effects of using hyperbaric oxygen comprehensive therapy for the treatment of noise induced deafness. METHODS: From May 2009 to April 2012 in our hospital 220 cases of noise induced deafness patients were chosen and they were all construction workers; According to different treatments all patients were divided into the control group (110 cases) only having hyperbaric oxygen treatment and the treatment group (110 cases) using hyperbaric oxygen comprehensive therapy, including control group simply by. Hearing improvements of the two groups were recorded and compared. RESULTS: The cure rate of the comprehensive therapy group was 53.6%which was higher than that of the control group 38.2% (chi(2) = 5.290, P < 5.290), while the total effective rate of the comprehensive therapy group was 79.1%which was also significantly higher than that of the control group 67.3% (chi(2) = 3.914, P < 0.05). After two courses of comprehensive treatment the cure rate and total effective rate were 47.3%and 73.6%respectively, while after four courses of comprehensive treatment group the cure rate and total effective rate turned to be 60.9% and 84.5% respectively, which had significant difference (chi(2) values were 4.118 and 3.958, P < 0.05). CONCLUSIONS: The cure rate and total effective rate of the comprehensive therapy group are higher than the simple hyperbaric oxygen treatment group, which is worthy of clinical application and promotion in the future. PMID- 25533372 TI - [Determination of methyl propyl ketone in air of workplace by capillary gas chromatography]. AB - OBJECTIVE: To establish a gas chromatography method for determination of methyl propyl ketone in the air of workplace. METHODS: Methyl propyl ketone in the air of workplace was collected with activated carbon tubes and desorbed with carbon disulfide before sample loading. The target toxicant was separated with the capillary column and detected with a hydrogen flame ionization detector, identified by retention time, and quantified by peak area. RESULTS: The linear range of methyl propyl ketone in the air of workplace was 202.5~4 860.0 ug/ml, with a correlation coefficient of 0.999 98. The limit of detection was 1.5 ug/ml. The lower limit of quantification was 5.0 ug/ml. The minimum detectable concentration was 1.0 mg/m(3) under 1.5 L sampling volume and 1.0 ml desorption solution volume. The relative standard deviation of different methyl propyl ketone concentrations was 1.42%~1.65%, and the recovery rate was 94.9%~ 97.9%. CONCLUSION: This method has high sensitivity, precision, and accuracy, and it is applicable for determination of methyl propyl ketone in the air of workplace. PMID- 25533373 TI - [Determination a variety of acidic gas in air of workplace by Ion Chromatography]. AB - OBJECTIVE: To establish a method for determination of a variety of acid gas in the workplace air by Ion Chromatography. (hydrofluoric acid, hydrogen chloride or hydrochloric acid, sulfur anhydride or sulfuric acid, phosphoric acid, oxalic acid). METHOD: The sample in workplace air was collected by the porous glass plate absorption tube containing 5 ml leacheate. (Sulfuric acid fog, phosphoric acid aerosol microporous membrane after collection, eluted with 5 ml of eluent.) To separated by AS14+AG14 chromatography column, by carbonate (2.0+1.0) mmol/L (Na(2)CO(3)-NaHCO(3)) as eluent, flow rate of 1 ml/min, then analyzed by electrical conductivity detector. The retain time was used for qualitative and the peak area was used for quantitation. RESULTS: The each ion of a variety of acid gas in the air of workplace were excellent in carbonate eluent separation. The linear range of working curve of 0~20 mg/L. The correlation coefficient r>0.999; lower detection limit of 3.6~115 ug/L; quantitative limit of 0.012~0.53 mg/L; acquisition of 15L air were measured, the minimum detection concentration is 0.004 0~0.13 mg/m(3). The recovery rate is 99.7%~101.1%. In the sample without mutual interference ions. Samples stored at room temperature for 7 days. CONCLUSION: The same analysis method, the detection of various acidic gases in the air of workplace, simple operation, good separation effect, high sensitivity, high detection efficiency, easy popularization and application. PMID- 25533375 TI - [Tracing evaluation of the application of occupational health surveillance technical specification]. PMID- 25533374 TI - [A study on determination of trace antimony in urine by sequential injection atomic fluorescence spectrometry]. PMID- 25533376 TI - [The overview of the role of ceramides in biological effects induced by ultraviolet exposure]. PMID- 25533377 TI - [Clinical research progress of heart rate variability in pneumoconiosis patients]. PMID- 25533378 TI - [Revision overview of occupational disease classification and list in China]. PMID- 25533379 TI - A metabolomic study in oats (Avena sativa) highlights a drought tolerance mechanism based upon salicylate signalling pathways and the modulation of carbon, antioxidant and photo-oxidative metabolism. AB - Although a wealth of information is available on the induction of one or several drought-related responses in different species, little is known of how their timing, modulation and crucially integration influence drought tolerance. Based upon metabolomic changes in oat (Avena sativa L.), we have defined key processes involved in drought tolerance. During a time course of increasing water deficit, metabolites from leaf samples were profiled using direct infusion-electrospray mass spectroscopy (DI-ESI-MS) and high-performance liquid chromatography (HPLC) ESI-MS/MS and analysed using principal component analysis (PCA) and discriminant function analysis (DFA). The involvement of metabolite pathways was confirmed through targeted assays of key metabolites and physiological experiments. We demonstrate an early accumulation of salicylic acid (SA) influencing stomatal opening, photorespiration and antioxidant defences before any change in the relative water content. These changes are likely to maintain plant water status, with any photoinhibitory effect being counteracted by an efficient antioxidant capacity, thereby representing an integrated mechanism of drought tolerance in oats. We also discuss these changes in relation to those engaged at later points, consequence of the different water status in susceptible and resistant genotypes. PMID- 25533380 TI - Characterization of water-soluble dark-brown pigment from Antarctic bacterium, Lysobacter oligotrophicus. AB - Lysobacter oligotrophicus strain 107-E2(T) isolated from Antarctica produces dark brown colored water-soluble pigment, in addition to hydrolases and lytic enzymes. The production of pigment is a common characteristic among members of the genus Lysobacter, but the identity of the pigments has been unknown. In this study, we identified the pigment from L. oligotrophicus as melanin pigment (Lo-melanin) by chemical and spectroscopic analyses. Although melanin is generally insoluble in both aqueous and organic solvents, the results in this study revealed that Lo melanin shows water-solubility by means of the added polysaccharide chain. Lo melanin production of L. oligotrophicus was increased by ultraviolet (UV) exposure, and survival rate of Escherichia coli under UV-irradiated condition was increased by the addition of Lo-melanin to the medium. PMID- 25533383 TI - Erratum: Concomitant Takayasu arteritis and Cushing syndrome in a child undergoing open adrenalectomy: An anaesthetic challenge: Corrigendum. AB - [This corrects the article on p. 467 in vol. 58, PMID: 25197120.]. PMID- 25533382 TI - The awareness, perceptions and experiences of primary open angle glaucoma patients in Lagos Nigeria. AB - The awareness, perceptions and experiences of Nigerian Primary Open Angle Glaucoma (POAG) patients were assessed using a hospital based cross-sectional study design. One hundred and twenty POAG patients attending a glaucoma clinic in Lagos Nigeria were recruited consecutively. They underwent face-to-face interviews with trained interviewers using a semi-structured questionnaire and an interview guide consisting of open-ended questions. A comprehensive ocular examination which included static automated perimetry, gonioscopy, stereoscopic optic nerve head assessment and contrast sensitivity was carried out for all participants. Twenty per cent (n = 24) of the respondents did not know they were being managed for a disease called Glaucoma. Age, gender, religion, ethnicity, marital status and occupation did not significantly affect the awareness of glaucoma diagnosis (p > 0.05). Positive family history of glaucoma, educational status and duration of disease were the most significant factors associated with awareness of glaucoma diagnosis (p < 0.05). POAG patients in Nigeria lack the depth of perception that can equip them to educate and motivate their family members to screen for glaucoma. There is an urgent need to develop continuous eye health education programmes to improve their perception and outlook; thereby increasing the uptake of glaucoma screening by first degree relatives of glaucoma patients. PMID- 25533381 TI - Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis. AB - INTRODUCTION: Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model. METHODS: OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40 degrees C to 50 degrees C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed. RESULTS: Behavioural hypersensitivity ipsilateral to knee injury was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind limb weight-bearing asymmetry in MIA-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Abeta- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight-bearing asymmetry was not corrected. CONCLUSIONS: Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA dependent. This suggests that, if used in OA patients, LCM may allow physiological transmission but suppress secondary hyperalgesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation. PMID- 25533385 TI - Dienogest, a synthetic progestin, down-regulates expression of CYP19A1 and inflammatory and neuroangiogenesis factors through progesterone receptor isoforms A and B in endometriotic cells. AB - Dienogest (DNG) is a selective progesterone receptor (PR) agonist and oral administration of DNG is used for the treatment of endometriosis. DNG is considered to act on PR to down-regulate pathophysiological factors associated with endometriosis. PR exists as two major isoforms, PR-A and PR-B, and their physiological functions are mostly distinct. It was suggested that PR isoform expression patterns are altered in endometriosis, but it is unknown whether the pharmacological effects of DNG are exerted through PR-A, PR-B or both. In the present study, we investigated the pharmacological effects of DNG through these PR isoforms on the expression of CYP19A1 which encodes aromatase and inflammatory and neuroangiogenesis factors associated with the pain and progression of endometriosis. We used immortalized human endometriotic epithelial cell lines that specifically express PR-A or PR-B in a spheroid cell culture system, and treated them with DNG. We evaluated messenger RNA (mRNA) expression of CYP19A1, prostaglandin (PG)E2 synthase (cyclooxygenase (COX)-2 and microsomal PGE2 synthase (mPGES)-1), inflammatory cytokines (interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1) and neuroangiogenesis factors (vascular endothelial growth factor (VEGF) and nerve growth factor (NGF)) using real-time polymerase chain reaction. In addition, PGE2 production was measured by enzyme immunoassay. We found that DNG down-regulated mRNA expression of CYP19A1, COX-2, mPGES-1, IL-6, IL-8, MCP-1, NGF and VEGF, and PGE2 production in human endometriotic epithelial cell lines that specifically express either PR-A or PR B. These results demonstrate that DNG activates both PR-A and PR-B and down regulates the expression of pathophysiological factors associated with pain and progression of endometriosis. Our results suggest that DNG exerts therapeutic efficacy against the pain and progression of endometriosis regardless of PR isoform expression patterns. PMID- 25533384 TI - Tuberous sclerosis complex: the past and the future. AB - Renal lesions represent the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC). Recent advances in the understanding of the pathophysiology of TSC have led to the exploration of new potential therapeutic targets. Clinical trials with mammalian target of rapamycin (mTOR) inhibitors have demonstrated promising results for several indications, such as renal angiomyolipoma, subependymal giant cell astrocytoma, lymphangioleiomyomatosis and facial angiofibromas. Currently, there is a scarcity of natural history data and randomized, placebo-controlled clinical trials on TSC. Recently, however, recommendations for the diagnostic criteria, surveillance, and management of TSC patients have been updated. This review focuses on these novel recommendations and highlights the need for multidisciplinary follow-up of this multi-systemic disease. PMID- 25533386 TI - Could vitamin D sufficiency improve the survival of colorectal cancer patients? AB - PURPOSE: To determine whether a higher serum 25-hydroxyvitamin D [25(OH)D] concentration at diagnosis is associated with longer survival of colorectal cancer patients. METHODS: A meta-analysis was performed of studies of the relationship between 25(OH)D and mortality of patients with colorectal cancer. A random-effects model was used to calculate a pooled hazards ratio. Homogeneity was evaluated through a DerSimonian-Laird test. RESULTS: Higher serum concentrations of 25(OH)D were associated with lower mortality in patients with colorectal cancer. Patients in the highest quintile of 25(OH)D had 37% lower mortality from colorectal cancer compared to those in the lowest quintile of 25(OH)D (pooled odds ratio=0.63, p<0.0001). Dose-response curves showed lower hazard ratios for mortality with higher serum 25(OH)D through at least 40ng/ml. There were no exceptions. CONCLUSIONS: Higher serum 25(OH)D was associated with lower mortality of patients with colorectal cancer. These results suggest that colorectal cancer patients with deficient levels of serum 25(OH)D should have their levels restored to a normal range (30-80ng/ml). This could be done with regular testing of serum 25(OH)D to be confident that an adequate serum level is being maintained. Additional studies would be worthwhile to evaluate confounding or the possibility of reverse causation. PMID- 25533387 TI - Plasma isoflavone concentration is associated with decreased risk of type 2 diabetes in Korean women but not men: results from the Korean Genome and Epidemiology Study. AB - AIMS/HYPOTHESIS: To examine the association between soybean products and risk of type 2 diabetes, we measured four isoflavone biological markers--genistein, daidzein, glycitein and equol--in a nested case-control study. METHODS: The study population was composed of 693 cases (316 women and 377 men) and 698 matched controls (317 women and 381 men) within the Korean Genome and Epidemiology Study. The concentrations of isoflavone biomarkers were measured using HPLC-MS/MS on plasma samples that were collected at baseline. A stratified analysis was undertaken to examine the association between plasma isoflavone concentrations and risk of type 2 diabetes according to sex and equol production. Logistic regression models were used to compute ORs and 95% CIs adjusted for confounders. RESULTS: In women, compared with the lowest quartile of plasma concentration of genistein, the highest quartile exhibited a significantly decreased risk of diabetes (OR 0.58, 95% CI 0.35, 0.95). When stratified by equol-producing status in women, the OR for diabetes in the highest vs the lowest quartile of genistein concentration was 0.31 (95% CI 0.16, 0.60) in equol producers, but genistein concentration was not associated with risk of diabetes in equol non-producers (p for interaction = 0.013). In men, isoflavone concentrations were not associated with risk of diabetes, regardless of equol-producing status. CONCLUSIONS/INTERPRETATION: High plasma concentrations of genistein were associated with a decreased risk of type 2 diabetes in women. This inverse association was prominent in equol-producing participants. These results suggest a beneficial effect of a high intake of soybean products on risk of type 2 diabetes in women. PMID- 25533388 TI - ABO and Rhesus blood groups and risk of type 2 diabetes: evidence from the large E3N cohort study. AB - AIMS/HYPOTHESIS: The objective of this study was to evaluate the relationship of ABO blood type (A, B, AB and O), Rhesus factor (positive or negative) and a combination of the two (ABO * Rhesus) with type 2 diabetes mellitus risk. METHODS: In total, 82,104 women from the large prospective E3N cohort were followed between 1990 and 2008. Multivariate Cox regression models were used to estimate HRs and 95% CIs. RESULTS: Those with either the A (HR 1.10 [95% CI 1.02, 1.18]) or B (HR 1.21 [95% CI 1.07, 1.36]) group were at increased risk of type 2 diabetes mellitus compared with those with the O group. The association with the AB group did not reach statistical significance (HR 1.17 [95% CI 0.99, 1.39]). There was no difference in type 2 diabetes mellitus risk between Rhesus positive and negative groups (HR 0.96 [95% CI 0.88, 1.05]). When the universal donors (O( )) were taken as the reference category, we observed an increased risk for both A(+) (HR 1.17 [95% CI 1.02, 1.35]) and A(-) (HR 1.22 [95% CI 1.03, 1.45]) individuals. The greatest increase in risk was seen for those with the B(+) blood group (HR 1.35 [95% CI 1.13, 1.60]). We also observed a greater type 2 diabetes mellitus risk for those with the AB(+) group (HR 1.26 [95% CI 1.02, 1.57]). Adjustment for fasting plasma glucose and lipid concentrations in a case-control subsample did not alter the associations. CONCLUSIONS/INTERPRETATION: This study suggests that people with the O blood type have a lower risk of developing type 2 diabetes mellitus. Therefore, blood group should be investigated in future clinical and epidemiological studies on diabetes, and further pathophysiological research is needed to determine why individuals with blood type O have a lower risk of type 2 diabetes mellitus. PMID- 25533389 TI - Capsule commentary on Tannenbaum et al., nudging physician prescription decisions by partitioning the order set: results of a vignette-based study. PMID- 25533390 TI - Capsule commentary on Bassett et al., Gender, race, and variations in the evaluation of microscopic hematuria among Medicare beneficiaries. PMID- 25533391 TI - Capsule commentary on Zuchowski et al., challenges in referral communication between VHA primary care and specialty care. PMID- 25533393 TI - Change in delay discounting and substance reward value following a brief alcohol and drug use intervention. AB - The present study examined (1) the impact of a brief substance use intervention on delay discounting and indices of substance reward value (RV), and (2) whether baseline values and posttreatment change in these behavioral economic variables predict substance use outcomes. Participants were 97 heavy drinking college students (58.8% female, 41.2% male) who completed a brief motivational intervention (BMI) and then were randomized to one of two conditions: a supplemental behavioral economic intervention that attempted to increase engagement in substance-free activities associated with delayed rewards (SFAS) or an Education control (EDU). Demand intensity, and Omax, decreased and elasticity significantly increased after treatment, but there was no effect for condition. Both baseline values and change in RV, but not discounting, predicted substance use outcomes at 6-month follow-up. Students with high RV who used marijuana were more likely to reduce their use after the SFAS intervention. These results suggest that brief interventions may reduce substance reward value, and that changes in reward value are associated with subsequent drinking and drug use reductions. High RV marijuana users may benefit from intervention elements that enhance future time orientation and substance-free activity participation. PMID- 25533392 TI - National patterns in diabetes screening: data from the National Health and Nutrition Examination Survey (NHANES) 2005-2012. AB - BACKGROUND: There are few current population-based estimates of the patterns of diabetes screening in the United States. The American Diabetes Association (ADA) recommends universal screening of adults >= 45 years, and high-risk adults < 45 years, but there is no current assessment of ADA guideline performance in detecting diabetes and prediabetes. Furthermore, data on racial/ethnic patterns of screening are limited. OBJECTIVE: Our aim was to estimate diabetes screening prevalence for the US adult population and specifically for those who meet ADA criteria; to report the prevalence of prediabetes and diabetes among these groups; and to determine if high-risk race/ethnicity was associated with reported screening. DESIGN: This was a Cross-sectional survey. PARTICIPANTS: Non-pregnant adults (>= 21 years) without diabetes or prediabetes who participated in the National Health and Nutrition Examination Survey (NHANES) in 2005-2012 (n = 17,572) were included in the study. "Screening-recommended" participants, classified by ADA criteria, included (1) adults >= 45 years and (2) "high-risk" adults < 45 years. "Screening-not-recommended" participants were adults < 45 years who did not meet criteria. MAIN MEASURES: Diabetes screening status was obtained by self-report. We used calibrated HbA1c and/or fasting glucose levels to define undiagnosed diabetes and prediabetes. KEY RESULTS: Seventy-six percent of the study population (approximately 136 million US adults) met ADA criteria. Among them, less than half (46.2%) reported screening; undiagnosed diabetes affected 3.7% (5 million individuals), and undiagnosed prediabetes affected 36.3% (49 million people.) African Americans were more likely to report screening, both among adults >= 45 years and among "high risk" younger adults (OR 1.27 and 1.36, respectively.) Hispanic participants were also more likely to report screening (OR 1.31 for older adults, 1.42 for younger adults.) The screening rate among "screening-not-recommended" adults was 29.6%; the prevalence of diabetes and prediabetes were 0.4 and 10.2%, respectively. CONCLUSIONS: In a nationally representative sample, 76% of adults met ADA screening criteria, of whom fewer than half reported screening. Limitations include cross-sectional design and screening self-report. PMID- 25533395 TI - Validation of a gas chromatography-triple quadrupole mass spectrometry method for confirmatory analysis of dioxins and dioxin-like polychlorobiphenyls in feed following new EU Regulation 709/2014. AB - The European Regulations laying down methods of sampling and analysis for the EU official control of levels of polychlorodibenzo-p-dioxins (PCDDs), polychloro dibenzofurans (PCDFs), dioxin-like (DL) and non dioxin-like (NDL) PCBs in food and feed have been recently amended by EU Regulation Nos. 589/2014 and 709/2014. A major update is the recognition of gas chromatography (GC) triple quadrupole mass spectrometry (GC-QQQMS/MS) as a confirmatory tool for checking compliance with maximum levels (ML). These revisions have been initiated since this technology now exhibits similar performances to GC (magnetic sector) high resolution mass spectrometry (GC-HRMS). In this paper, we show a fully validated method for PCDD/Fs and DL-PCBs analysis in feed material of plant origin (vegetable oil) using GC-QQQMS/MS following the dedicated EU Regulation 709/2014. We show that individual analytical criteria (selectivity, linearity, quant/qual MRM transitions, accuracy around ML of 1.50ng WHO2005TEQ/kg, within-lab reproducibility, robustness, and background subtraction) meet the strict requirements set by the EU Regulation. We also propose a clear interpretation of instrumental limit of quantitation (iLOQ) as a 'performance-LOQ', defined in a specific way for GC-QQQMS/MS, and method limit of quantitation (mLOQ) as 'real LOQ' that is used to report bound results. Eventually, the evaluation of measurement uncertainty, following a top-down approach and data produced with our method, demonstrates similar results than with GC-HRMS, thus offering a reliable alternative to the standard method for vegetable oil. PMID- 25533394 TI - Stir fabric phase sorptive extraction for the determination of triazine herbicides in environmental waters by liquid chromatography. AB - Stir fabric phase sorptive extraction (SFPSE), which integrates sol-gel hybrid organic-inorganic coated fabric phase sorptive extraction media with a magnetic stirring mechanism, is presented for the first time. Two flexible fabric substrates, cellulose and polyester were used as the host matrix for three different sorbents e.g., sol-gel poly(tetrahydrofuran), sol-gel poly(ethylene glycol), and sol-gel poly(dimethyldiphenylsiloxane). The new microextraction device has been analytically evaluated using triazine herbicides as model compounds. The factors affecting the extraction efficiency of SFPSE have been investigated and the optimal extraction conditions have been determined. Under these optimum conditions, the limits of quantification (LOQs) for sol-gel poly(ethylene glycol) coated SFPSE device in combination with UPLC-DAD for the analysis of the seven triazine herbicides were in the range of 0. 26-1.50MUg/L with precision (relative standard deviation) at 2MUg/L concentration ranging from 1.4-4.8% (intra-day, n=5) and 6.8-11.8% (inter-day, n=3). Enrichment factors were found between 444 and 1411 (compared to 2000 theoretical maximum). Absolute extraction recoveries were in the range of 22.2-70.5%. The developed method was applied for the determination of selected triazine herbicides from three river water samples. Relative recoveries of the target analytes, in the range from 75 to 126%, were found to be satisfactory. The combination of SFPSE with LC-MS/MS allows the improvement of the method sensitivity to the range from 0.015MUg/L to 0.026MUg/L with precision better than 10.8% expressed as relative standard deviation (RSD). PMID- 25533396 TI - Structural characterization of telechelic polyisobutylene diol. AB - The chemical homogeneity of telechelic polyisobutylene diol (PIB-diol), prepared by hydroboration-oxidation of allyl telechelic PIB obtained by reacting living PIB with allyltrimethylsilane, was investigated by liquid chromatography at critical conditions (LCCC) and HPLC coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). A normal phase gradient HPLC method was developed that was able to separate the as synthesized PIB-diol into three components; PIB-diol, PIB-monool and PIB without any OH functionality. These were analyzed by MALDI-TOF MS, which suggested that the reaction of living PIB with allyltrimethylsilane was incomplete. LCCC using refractive index (RI) detector as a concentration detector allowed separation and quantification of PIB species according to their chemical heterogeneity (PIB diol=95.3%, PIB-monool=3.3%, non-functional PIB=1.4%). The calculated number average functionality (Fn) of PIB-diol=1.94 suggests high quality of PIB-diol suitable for high molecular weight polyurethane synthesis. PMID- 25533397 TI - Pharmacokinetics screening for multi-components absorbed in the rat plasma after oral administration of traditional Chinese medicine Flos Lonicerae Japonicae Fructus Forsythiae herb couple by sequential negative and positive ionization ultra-high-performance liquid chromatography/tandem triple quadrupole mass spectrometric detection. AB - The current study aims to investigate the pharmacokinetics of multi-components (caffeic acid, quinic acid, genistein, luteolin, quercetin, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, arctigenin, genistin, luteoloside, astragalin, hyperoside, isoquercitrin, 3,5-dicaffeoylquinic acid, 3,4 dicaffeoylquinic acid, rutin, loganin, pinoresinol-beta-d-glucoside, phillyrin, isoforsythoside, forsythoside A and forsythoside B) following oral administration of Flos Lonicerae Japonicae-Fructus Forsythiae herb couple in rats. A rapid and sensitive UPLC-ESI-MS/MS with sequential positive and negative ionization modes was developed to determine the 23 absorbed ingredients using one sample preparation combined with three chromatographic conditions in rat plasma. After mixing with internal standard (IS) (tinidazole and chloramphenicol), samples were pretreated by liquid-liquid extraction (LLE) with n-butyl alcohol/ethyl acetate (1:1, v/v). The separations for pinoresinol-beta-d-glucoside, phillyrin, isoforsythoside, forsythoside A and forsythoside B were performed on an ACQUITY UPLC BEH C18 column (100mm*2.1mm, 1.7MUm) with acetonitrile/methanol (4:1, v/v) water as mobile phase. For analyzing quinic acid, an ACQUITY UPLC HSS T3 column (100mm*2.1mm, 1.8MUm) was applied with acetonitrile/methanol (4:1, v/v)-0.01% formic acid as mobile phase after dilution up to 25-fold. The same column was applied to the other components with acetonitrile/methanol (4:1, v/v)-0.4% formic acid as mobile phase. The method validation results demonstrated that the proposed method was sensitive, specific and reliable, which was successfully applied to the pharmacokinetic study of the multi-components after oral administration of Flos Lonicerae Japonicae-Fructus Forsythiae herb couple. PMID- 25533398 TI - Stability of single copy transgene expression in CHOK1 cells is affected by histone modifications but not by DNA methylation. AB - Intraclonal heterogeneity of genetically modified mammalian cells has been observed as a phenomenon that has a strong impact on overall transgene expression levels and that limits the predictability of transgene expression in genetically modified cells, thereby hampering single cell based screening approaches. The underlying mechanism(s) leading to this variance are poorly understood. To study the dynamics and mechanisms of heterogeneity of early stage silencing we analyzed the expression in more than 100 independent clones of CHOK1 cells that harbour genetically stable integrates of single copy reporter cassettes driven by EF1alpha and CMV promoters. Single cell analysis showed intraclonal variability with heterogeneity in expression in genetically uniform populations. DNA methylation is a well known mechanism responsible for silencing of gene expression. Interestingly, loss of expression was not associated with DNA methylation of the CMV promoter. However, in most of the clonal populations expression could be increased by inhibitors of the histone deacetylases (HDACi) suggesting that heterogeneity of transgene expression is crucially governed by histone modifications. Further, to determine if the epigenetic status of transgene expression is governed by the chromosomal integration locus we targeted heterologous expression cassettes into two chromosomal sites using recombinase mediated cassette exchange (RMCE). The expression status of a particular clone was faithfully re-established when the same promoter used. In this way the problem of early stage cell clone instability can be bypassed. However, upon introduction of an unrelated promoter methylation-independent silencing was observed. Together, these results suggest that histone modifications are the relevant mechanisms by which epigenetic modulation of transgene expression cassettes is governed in the early phase of clone generation. PMID- 25533399 TI - Complete genome sequence of the probiotic Lactobacillus fermentum F-6 isolated from raw milk. AB - Lactobacillus fermentum F-6 was isolated from raw milk in Inner Mongolia of China with desirable probiotic properties. The genome contains a circular 2.06Mb chromosome and has no plasmid. Further in silico analysis revealed its genetic basis for adhesion, exopolysaccharides production and citrate fermentation, which makes it a strain of high industrial potential. PMID- 25533400 TI - Effect of introducing a disulphide bond between the A and C domains on the activity and stability of Saccharomycopsis fibuligera R64 alpha-amylase. AB - Native enzyme and a mutant containing an extra disulphide bridge of recombinant Saccharomycopsis fibuligera R64 alpha-amylase, designated as Sfamy01 and Sfamy02, respectively, have successfully been overexpressed in the yeast Pichia pastoris KM71H. The purified alpha-amylase variants demonstrated starch hydrolysis resulting in a mixture of maltose, maltotriose, and glucose, similar to the wild type enzyme. Introduction of the disulphide bridge shifted the melting temperature (TM) from 54.5 to 56 degrees C and nearly tripled the enzyme half life time at 65 degrees C. The two variants have similar kcat/KM values. Similarly, inhibition by acarbose was only slightly affected, with the IC50 of Sfamy02 for acarbose being 40 +/- 3.4 MUM, while that of Sfamy01 was 31 +/- 3.9 MUM. On the other hand, the IC50 of Sfamy02 for EDTA was 0.45 mM, nearly two times lower than that of Sfamy01 at 0.77 mM. These results show that the introduction of a disulphide bridge had little effect on the enzyme activity, but made the enzyme more susceptible to calcium ion extraction. Altogether, the new disulphide bridge improved the enzyme stability without affecting its activity, although minor changes in the active site environment cannot be excluded. PMID- 25533401 TI - Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE). AB - Through the fine tuning of the activity-sensitive aminoalkoxy moiety of 4,6 bisphenyl-2-(3-alkoxyanilino)pyrimidine as a novel inhibitor of the receptor for advanced glycation end products (RAGE), the tertiary amine was elucidated as an essential part associated with RAGE inhibition. On the basis of this finding, a 3 (N,N-dimethylamino)pyrrolidine analog 12o was identified as a therapeutically useful RAGE inhibitor with improved activity and solubility. Molecular modeling studies predicted that the improved inhibitory activity is induced by additional hydrogen bonds between the nitrogen atom of the pyrrolidine ring and Arg48 and by an interaction between the dimethylamino-substituent of the pyrrolidine moiety and a relatively hydrophobic groove in the RAGE binding site. PMID- 25533402 TI - Sulfonamide inhibition studies of the eta-class carbonic anhydrase from the malaria pathogen Plasmodium falciparum. AB - The eta-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the eta-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with KIs of 131-132 nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (KIs of 153-198 nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with KIs ranging from 217 to 308 nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for eta-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known eta-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors. PMID- 25533403 TI - Mechanistic insights into landscape genetic structure of two tropical amphibians using field-derived resistance surfaces. AB - Conversion of forests to agriculture often fragments distributions of forest species and can disrupt gene flow. We examined effects of prevalent land uses on genetic connectivity of two amphibian species in northeastern Costa Rica. We incorporated data from field surveys and experiments to develop resistance surfaces that represent local mechanisms hypothesized to modify dispersal success of amphibians, such as habitat-specific predation and desiccation risk. Because time lags can exist between forest conversion and genetic responses, we evaluated landscape effects using land-cover data from different time periods. Populations of both species were structured at similar spatial scales but exhibited differing responses to landscape features. Litter frog population differentiation was significantly related to landscape resistances estimated from abundance and experiment data. Model support was highest for experiment-derived surfaces that represented responses to microclimate variation. Litter frog genetic variation was best explained by contemporary landscape configuration, indicating rapid population response to land-use change. Poison frog genetic structure was strongly associated with geographic isolation, which explained up to 45% of genetic variation, and long-standing barriers, such as rivers and mountains. However, there was also partial support for abundance- and microclimate response derived resistances. Differences in species responses to landscape features may be explained by overriding effects of population size on patterns of differentiation for poison frogs, but not litter frogs. In addition, pastures are likely semi-permeable to poison frog gene flow because the species is known to use pastures when remnant vegetation is present, but litter frogs do not. Ongoing reforestation efforts will probably increase connectivity in the region by increasing tree cover and reducing area of pastures. PMID- 25533404 TI - Identifying community risk factors for HIV among South African adolescents with mental health problems: a qualitative study of parental perceptions. AB - High risk sexual behaviour, alcohol and drug use, and mental health problems combine to yield high levels of HIV-risk behaviour among adolescents with mental health problems. In South Africa, little research has been conducted on parental perspectives of HIV-risk among this population. We conducted a series of focus group discussions with 28 mothers of adolescents receiving services at two mental health clinics in South Africa to identify, from their perspectives, the key community problems facing their children. Participants indicated that HIV remained a serious threat to their adolescent children's well-being, in addition to substance abuse, early sexual debut, and teenage pregnancy. These social problems were mentioned as external to their household dynamics, and thus seemingly beyond the purview of the parent-adolescent relationship. These data have implications for the design of family-based interventions to ameliorate the factors associated with HIV-risk among youth receiving mental health services. PMID- 25533405 TI - South African adolescents with cystic fibrosis: a qualitative exploration of their bio-psychosocial fields. AB - OBJECTIVE: This qualitative case study explored risk factors and protective factors in the bio-psychosocial fields of adolescents living with cystic fibrosis (CF). METHOD: Semi-structured interviews were conducted with adolescents in the middle and late adolescent years (15-22 years) who had the defining characteristics of CF and were living in Gauteng province. FINDINGS: Themes emerged from individual interviews. The fundamental human need to be understood and to understand was negatively affected as the illness affected socialisation and learning. Participants experienced an array of emotions including loss and bereavement linked to their illness and when friends with CF died. Constructive internal dialogue and positive thinking emerged as protective variables. Participants generally showed awareness of how they regulated their contact with the illness and how they self-regulate. Despite the severity of their symptoms and the taxing demands of managing CF, participants expressed hope for the future and could find some meaning in the illness. CONCLUSION: Adolescents with CF who participated in this study indicated that they felt different from their peers. Apart from the general developmental tasks typical to adolescence they faced the challenge of managing a severe chronic and potentially terminal illness. PMID- 25533406 TI - Eating attitudes, body image satisfaction and self-esteem of South African Black and White male adolescents and their perception of female body silhouettes. AB - This cross-sectional study of urban high schools in Johannesburg, South Africa, sought to examine eating attitudes, body image and self-esteem among male adolescents (n = 391). Anthropometric measurements, Eating Attitudes Test-26 (EAT 26), Rosenberg self-esteem, body image satisfaction and perception of females were collected at age 13, 15 and 17 years. Descriptive analysis was done to describe the sample, and non-parametric Wilcoxon Mann-Whitney test was used to test for significant differences between data that were not normally distributed (EAT-26). Spearman's rank correlation coefficient analyses were conducted to test for associations between self-esteem scores and eating attitudes, body mass indices and body image satisfaction scores. To assess the differences between groups that were normally distributed chi-square tests were carried out. Ethnic differences significantly affected adolescent boys' body mass index (BMI), eating attitudes and self-esteem; White boys had higher self-esteem, BMI and normal eating attitudes than the Black boys did. BMI was positively associated with self esteem (p = 0.01, r = 0.134) and negatively with dieting behaviour in White boys (p = 0.004, r = -0.257), and with lower EAT-26 bulimic and oral control scores in Black boys. In conclusion, the findings highlight ethnic differences and a need to better understand cultural differences that influence adolescent attitudes and behaviour. PMID- 25533407 TI - The impact of a mental health teaching programme on rural and urban secondary school students' perceptions of mental illness in southwest Nigeria. AB - OBJECTIVE: Available evidence suggests that children hold negative views about mental illness. Studies show that it is possible for schools and mental health services to jointly undertake child and adolescent mental health promotion. This study aimed to assess the impact of a school based mental health awareness programme aimed at increasing mental health literacy and reducing negative views about persons with mental illness. METHODS: A total of 154 secondary school students in Ibadan, southwest Nigeria, were allocated into an intervention and a control group. Students in the intervention group received a three-hour mental health awareness session. All students completed a pre-, immediate post, and six month post-intervention questionnaire on their views about mental health and illness. RESULTS: There was a significant difference in the mean knowledge scores between the intervention and the control group post-intervention, but no significant differences in attitude and social distance scores. CONCLUSION: Brief training workshops appear able to produce small but positive changes in the mental health knowledge of young Nigerians. PMID- 25533408 TI - Improving mental health and wellbeing for young men in the building and construction industry. AB - Statistics on causes of death gathered by the Australian Bureau of Statistics (2010) report that suicide was the leading cause amongst young men in Australia between the ages of 15-24. The figures have been similarly high for over a decade. In Australia these alarming statistics have led to the funding of a range of programmes tackling youth suicide and more recently programmes that are aimed at improving help-seeking behaviours of young men. The programme reported in this paper is one such programme that is working with young men in the building and construction industry who are regarded at even greater risk of poor mental health outcomes. The research that was undertaken uncovered some of the impact of a universal programme on improving the protective factors of young men in this industry. Young men can present themselves in a very positive light as robust and resilient human beings, contrary to much of the research that has been undertaken with a focus on young men in building and construction and living in rural and remote communities. This paper discusses the data and uses the material to consider how resilient young men in this industry can become key informants and informal peer mentors. PMID- 25533409 TI - Feasibility of the Strengths and Difficulties Questionnaire in assessing children's mental health in primary care: Finnish parents', teachers' and public health nurses' experiences with the SDQ. AB - BACKGROUND: The aim of the study was to evaluate the feasibility of the Strengths and Difficulties Questionnaire (SDQ). METHOD: Following the administration of the SDQ in medical check-ups of 4-9 year-old children (n = 2 682) the involved parents, teachers and public health nurses were asked to complete a feedback questionnaire of the SDQ. RESULTS: Parents took a maximum of 10-15 minutes to complete the SDQ, and only the public health nurses reported that its use was rather burdensome. The SDQ was an age-appropriate method and it was helpful in increasing information and agreement about the child's mental health and need for support. Using the SDQ was a positive experience for parents, but they expected more dialogue with the professionals about the child's situation. The respondents criticised the questionnaire somewhat for being difficult to interpret and complete. CONCLUSIONS: The SDQ was found to be a feasible method for screening children's mental health in primary health care together with parents, teachers and public health nurses. Using the SDQ was a positive experience for parents. However, they reminded the professionals of the importance of sensitive dialogue when assessing the mental health of the child. PMID- 25533410 TI - Resilience and post-traumatic stress disorder in the acute aftermath of rape: a comparative analysis of adolescents versus adults. AB - BACKGROUND: Rape trauma contributes significantly to the mental burden of disease, affecting resilience and vulnerabilities at every developmental life stage. Appropriate resilience-promoting strategies could potentially buffer or protect trauma-exposed individuals from psychopathology. AIM: This study aimed to assess and compare (using validated measuring instruments) resilience, post traumatic stress disorder (PTSD) and other variables in the acute aftermath of rape, between adolescent and adult females and to assess associations with these variables. METHOD: We conducted a comparative analysis of resilience, PTSD, prior trauma, demographic variables and psychiatric morbidity in 41 adolescent and 47 adult female rape survivors six weeks post-rape. We assessed the relationship of resilience to PTSD, demographic variables and prior trauma and investigated if resilience levels predicted PTSD after adjusting for prior trauma. RESULTS: We found no significant differences in resilience levels between the groups, but the adolescent PTSD rate (40%) was double that in adults (20%). In adults, a significant negative correlation was evident between resilience and PTSD symptoms scores. CONCLUSION: More knowledge of resilience versus stress susceptibility for PTSD throughout the lifespan is needed and can inform the development of more effective clinical assessment and resilience-promoting strategies. PMID- 25533411 TI - Attachment, parenting styles and bullying during pubertal years. AB - Research that focuses on combining attachment, parenting styles, bullying and the reciprocal nature thereof in the parent-adolescent and peer relationships is limited. The bio-psychosocial changes that adolescents experience open up broader social realities and are perceived differently by parents and adolescents. Attachment processes and parenting styles may elicit dissimilar perceptions. These processes are also associated with the multifaceted dynamics of bullying. The aim of the article is to advocate for research on the possible link between the implications of attachment, parenting styles and bullying. Exploring the association between attachment, parenting styles and bullying can deepen the understanding of the developmental challenges within the parent-adolescent relationship, add insight to the different perceptions of adolescents and parents, and complement intervention programmes accordingly. Firstly, this article outlines bio-psychosocial changes in the pubertal years as related to the social realities of the adolescent. Secondly, a discussion on the concepts 'attachment', 'parenting styles', 'bullying', and the potential link between these concepts will follow. Thirdly, an outline of the clinical implications of the apparent association between these concepts is given. The article concludes with recommendations that researchers can consider while exploring the relationship between attachment, parenting styles, and bullying and the delineation thereof in the parent-adolescent relationship. PMID- 25533414 TI - Titanium implant impairment and surrounding muscle cell death following neuro myoelectrostimulation: An in vivo study. AB - Electrical currents have deleterious effects on biomedical metallic implants. However, following arthroplasty, neuro-myoelectrostimulation (NMES) is often used in patient rehabilitation. Such a rehabilitation technique could compromise patient recovery through deleterious effects on metallic alloys and biological tissues. The purpose of our study was to assess the effects of NMES on a Ti6Al4V implant placed in a rat tibial crest and the surrounding muscle tissues. This in vivo study allowed to bring to the fore the prosthesis behavior under mechanical and electromagnetic loads induced by NEMS stimulation. After 3 weeks, implant-to bone adhesion significantly decreased in stimulated animals compared with nonstimulated animals. Surface mapping indicated titanium implant degradation after NMES. Furthermore, NMES alone did not induce muscle damage contrary to that found in implanted animals. The muscle damage rate was significantly higher in implanted and stimulated animals compared with implanted-only animals. It seems obvious that rehabilitation programs using the NMES technique could induce early deterioration of biomaterial employed for surgical implants. Clinicians should reconsider the use of NMES as a rehabilitation technique for patients with titanium prostheses. PMID- 25533415 TI - Heterogeneous dose calculations for Collaborative Ocular Melanoma Study eye plaques using actual seed configurations and Task Group Report 43 formalism. AB - PURPOSE: Collaborative Ocular Melanoma Study (COMS) eye plaques (EPs) contain silastic and Modulay materials that introduce 15-30% dose differences compared with all-water dosimetry. A Task Group Report 43 (TG43) dose rate calculation method is presented that includes silastic and Modulay heterogeneous effects, uses the actual plaque seed configuration, is not restricted to a particular commercial treatment planning system, and does not require purchase of additional software. METHODS AND MATERIALS: Dose rate is calculated using TG43 formalism: Dose(EP)(r,theta)=S(K)Lambda(G(L)(r,theta)/G(L)(r0,theta0))g(EP)(r)F(EP)(r,theta) with revised radial dose, g(EP)(r), and anisotropy, F(EP)(r,theta), functions specific to (125)I or (103)Pd seeds in COMS EPs. The EP signifies that the functions are specific to COMS EPs. The g(EP)(r) is obtained from Monte Carlo (MC) data for EPs that contain just a single center seed. The F(EP)(r,theta) is obtained by performing a Nelder-Mead Simplex routine to find a least squares solution that minimizes differences between MC dose rate and DoseEP(r,theta). RESULTS: The TG43 formalism calculations agree with MC results, for 10-22-mm (125)I and (103)Pd EPs, to within 2% along and near the plaque central axis and within 4% in the penumbra region for depths of 1 mm or greater. Methods and data are provided for COMS plaque calculations using seed models other than (125)I Model 6711 and (103)Pd Model 200. Because actual seed configurations are used in dose rate calculations, this formalism may also be used to estimate dosimetry for nonstandard seed loadings. CONCLUSION: This manuscript enables the clinical user to perform accurate heterogeneity-corrected dose rate calculations for COMS EPs using TG43 formalism in a spreadsheet or commercial treatment planning system that has a TG43 line source geometry function calculation capabilities. PMID- 25533416 TI - Bladder wall recurrence of prostate cancer after high-dose-rate brachytherapy. AB - PURPOSE: Prostate cancer seeding after needle biopsy has been reported in the perineum, rectal wall, and periprostatic soft tissue. In this article, we report the results of a localized prostate cancer recurrence in the bladder following protrusion of a single high-dose-rate brachytherapy catheter through the bladder wall at the ultimate site of failure. METHOD AND MATERIALS: A 62-year-old man with high-risk prostate adenocarcinoma was treated with long-term androgen deprivation therapy, intensity-modulated radiation, and high-dose-rate brachytherapy boost. He developed biochemical recurrence 4 years after treatment, and a CT scan of the pelvis revealed a nodule in the posterior, inferior bladder wall. RESULTS: Surgical pathology following transurethral resection of tumor within the bladder was consistent with high-grade prostate adenocarcinoma. The patient's prostate-specific antigen level fell to the range of normal postoperatively, and whole body imaging, including a multi-parametric MRI of the prostate with diffusion and spectroscopy, failed to reveal any other sites of disease. Review of the CT scan obtained for dosimetry at the time of brachytherapy demonstrated a lone catheter protruding through the bladder wall at the site of eventual recurrence. The tumor recurred in the bladder 12 months later, once more without evidence of disease within the prostate itself or distantly, and the patient was started on salvage androgen deprivation therapy. CONCLUSIONS: This case is the first report of prostate cancer recurrence in the bladder wall after brachytherapy and raises questions about prostate cancer biology, brachytherapy technique, and the timing of brachytherapy boost relative to whole pelvic radiotherapy for prostate cancer. PMID- 25533419 TI - Quality of life after primary treatment for localized prostate cancer: long-term considerations. PMID- 25533418 TI - A national multicenter phase 2 study of prostate-specific antigen (PSA) pox virus vaccine with sequential androgen ablation therapy in patients with PSA progression: ECOG 9802. AB - BACKGROUND: E9802 was a phase 2 multi-institution study conducted to evaluate the safety and effectiveness of vaccinia and fowlpox prostate-specific antigen (PSA) vaccine (step 1) followed by combination with androgen ablation therapy (step 2) in patients with PSA progression without visible metastasis. OBJECTIVE: To test the hypothesis that vaccine therapy in this early disease setting will be safe and have a biochemical effect that would support future studies of immunotherapy in patients with minimal disease burden. DESIGN, SETTING, AND PARTICIPANTS: Patients who had PSA progression following local therapy were treated with PROSTVAC-V (vaccinia)/TRICOM on cycle 1 followed by PROSTVAC-F (fowlpox)/TRICOM for subsequent cycles in combination with granulocyte-macrophage colony stimulating factor (step 1). Androgen ablation was added on progression (step 2). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Step 1 primary end points included progression at 6 mo and characterization of change in PSA velocity pretreatment to post-treatment. Step 2 end points included PSA response with combined vaccine and androgen ablation. RESULTS AND LIMITATIONS: In step 1, 25 of 40 eligible patients (63%) were progression free at 6 mo after registration (90% confidence interval [CI], 48-75). The median pretreatment PSA velocity was 0.13 log(PSA)/mo, in contrast to median postregistration velocity of 0.09 log(PSA)/mo (p=0.02), which is an increase in median PSA doubling time from 5.3 mo to 7.7 mo. No grade >=4 treatment-related toxicity was observed. In the 27 patients eligible and treated for step 2, 20 patients achieved a complete response (CR) at 7 mo (CR rate: 74%; 90% CI, 57-87). Although supportive of larger studies in the cooperative group setting, this study is limited by the small number of patients and the absence of a control group as in a phase 3 study. CONCLUSIONS: A viral PSA vaccine can be administered safely in the multi-institutional cooperative group setting to patients with minimal disease volume alone and combined with androgen ablation, supporting the feasibility of future phase 3 studies in this population. PATIENT SUMMARY: These data support consideration of vaccine therapy earlier in the course of prostate cancer progression with minimal disease burden in future studies of vaccine approaches in earlier stages of disease. PMID- 25533417 TI - Health economic changes as a result of implementation of targeted therapy for metastatic renal cell carcinoma: national results from DARENCA study 2. AB - BACKGROUND: Limited data exist on the economic consequences of implementing targeted therapy (TT) for metastatic renal cell carcinoma (RCC) in a real-world setting. OBJECTIVE: To analyze health care and productivity costs for TT implementation in a national cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: Costs were measured per patient per year during a 2-yr follow-up during 2002-2005 (immunotherapy only) and 2006-2009 (TT implementation). All Danish patients with a diagnosis code for RCC and a procedure code for TT or immunotherapy were linked to the Danish National Patient Registry (contains information on all contacts with primary and secondary health sector). Health care and productivity costs were retrieved from the Danish case-mix system and Coherent Social Statistics, respectively. Drug costs were calculated separately from procedure codes and retail prices. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Generalized linear models were used to analyze costs adjusted for age, gender, and civil status. RESULTS AND LIMITATIONS: A total of 439 patients were included for 2006-2009 and 192 for 2002-2005. Comparison of the health care cost per patient per year between 2006-2009 and 2002-2005 revealed lower inpatient costs (?11 899 vs ?19 944, adjusted relative risk [RR] 0.64), higher outpatient costs (?14 308 vs ?6209, RR 2.39), lower radiotherapy costs (?194 vs ?633, RR 0.31), higher radiology costs (?676 vs ?191, RR 3.73), and higher separately calculated drug costs (?12 040 vs ?3103, RR 3.82, all p<0.001) for the former. Total health care costs per patient per year did not significantly differ (?27 676 vs ?27 856, RR 1.05, p=0.5) between the two periods. Income from employment did not significantly differ between 2006-2009 and 2002-2005 (RR 1.11, p=0.11) and costs associated with loss of productivity were ?7852 and ?8265, respectively. CONCLUSIONS: A different pattern of health care costs were observed but total health care costs per patient per year did not significantly differ after implementation of TT for patients with mRCC. PATIENT SUMMARY: In this nationwide study, we found changes in the pattern of health care costs for patients with metastatic kidney cancer after implementation of targeted therapy compared to an immunotherapy control period; however, total health care costs and income from employment were without significant changes. PMID- 25533420 TI - Effect of pretransplant diabetes on short-term outcomes after liver transplantation: a national cohort study. AB - BACKGROUND & AIMS: We sought to analyse the effect of pretransplant diabetes on post-operative outcomes and resource utilization following liver transplantation. METHODS: A retrospective cohort study was designed using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases. We identified 12 442 patients who underwent liver transplantation at 63 centres from 2007-2011 and separated cohorts of patients with diabetes (n = 2971; 24%) and without (n = 9471; 76%) at the time of transplant. We analysed transplant related outcomes and short-term survival. RESULTS: Diabetic recipients were more likely to be male (70% vs 67%), non-white (32% vs 26%), older (age >=60; 41% vs 28%), and have a higher BMI (29 vs 27; P < 0.001). More diabetic patients were on haemodialysis (10% vs 7%), had cirrhosis caused by NASH (24% vs 9%; P < 0.001), and received liver allografts from older donors (>= 60 years; 19% vs 15%) with a higher donor risk index (>1.49; 46% vs 42%; P < 0.001). Post-transplant, diabetic recipients had longer hospital length of stay (10 vs 9 days), higher peri-transplant mortality (5% vs 4%) and 30-day readmission rates (41% vs 37%), were less often discharged to home (83% vs 87%; P < 0.05), and had inferior graft and patient survival. Liver transplant was more expensive for type 1 vs type 2 diabetics ($105 078 vs $100 624, P < 0.001). Poorly controlled diabetic recipients were less likely discharged home following transplant (75% vs 82%, P < 0.01). CONCLUSIONS: This national study indicates that pretransplant diabetes is associated with inferior post-operative outcomes and increased resource utilization after liver transplantation. PMID- 25533421 TI - Distal pancreatectomy for pancreatic carcinoma in the era of multimodal treatment. AB - BACKGROUND: Recent publications have suggested improvements in the outcome of distal pancreatectomy (DP) for cancer, but the series were small and heterogeneous. The aim of the present study was to assess perioperative and long term outcomes of DP for pancreatic adenocarcinoma in the era of multimodal treatment in a major European country. METHODS: This was a nationwide study of all patients undergoing DP for pancreatic adenocarcinoma between 2004 and 2009 in 28 centres in France. Postoperative and long-term outcomes were assessed retrospectively and outcome predictors were explored by multivariable analysis. RESULTS: A total of 278 patients were enrolled. Multivisceral resections were performed in 58 patients (20.9 per cent), venous resections in 33 (11.9 per cent) and arterial resections in 11 (4.0 per cent). Neoadjuvant chemoradiotherapy was used in 20 patients. Postoperative complications occurred in 96 patients (34.5 per cent) and pancreatic fistulas developed in 76 (27.3 per cent). The postoperative 90-day mortality rate was 5.0 per cent. In univariable analysis, multivisceral resection was the only factor associated with postoperative morbidity (P = 0.048). Age 65 years or less, body mass index of at least 30 kg/m(2) and absence of preoperative chemoradiotherapy were associated with an increased risk of pancreatic fistula in multivariable analysis. Overall survival rates at 3 and 5 years were 44.9 and 29.5 per cent respectively. In multivariable analysis, only the presence of lymph node metastases was associated with poorer overall survival. CONCLUSION: Postoperative morbidity and mortality associated with pancreatic fistula remain considerable after DP, but both short- and long term survival have improved markedly. PMID- 25533422 TI - Chemical composition of the essential oil of Jacobaea maritima (L.) Pelser & Meijden and Jacobaea maritima subsp. bicolor (Willd.) B. Nord. & Greuter (Asteraceae) collected wild in Croatia and Sicily, respectively. AB - In this study, the chemical compositions of the essential oils from aerial parts (JmA) and radices (JmR) of Jacobaea maritima (L.) Pelser & Meijden, collected in Croatia, and of Jacobaea maritima subsp. bicolor (Willd.) B. Nord. & Greuter, collected in Sicily, were evaluated by using gas chromatography and gas chromatography-mass spectrometry. The main components of the essential oil from J. maritima, both in JmA and JmR, were pentacosane (15.7%), heptacosane (13.1%) and nonacosane (8.1%) whereas the essential oil from J. maritima subsp. bicolor was characterised by the presence of hexadecanoic acid (14.6%), caryophyllene oxide (9.3%) and hexahydrofarnesylacetone (6.5%). The comparison of the essential oil with other studied oils of the genus Jacobaea is discussed. PMID- 25533423 TI - Association between hyperglycemia at admission and microvascular obstruction in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Blood glucose level at admission in ST-segment elevation myocardial infarction (STEMI) is a predictor of heart failure and mortality. A previous study showed the association between hyperglycemia and microvascular dysfunction using myocardial contrast echocardiography. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) can demonstrate microvascular obstruction (MVO) as the area with hypointense core within LGE. This study was performed to investigate the association between hyperglycemia at admission and MVO using CMR in patients with STEMI. METHODS: Ninety-three patients with first STEMI who were treated by percutaneous coronary intervention (PCI) were included. CMR was performed within 7 days after PCI. Venous blood was collected routinely immediately after admission for plasma glucose determination before intravenous injection of some medications. Samples were analyzed in the hospital's central laboratory. We performed LGE-CMR to assess the presence of MVO. RESULTS: MVO was found in 34 (37%) of all 93 patients; their glucose level at admission was significantly higher than that of patients who did not exhibit MVO [204 (153 267)mg/dl vs. 157 (127-200)mg/dl, p=0.002]. There were no differences in glycosylated hemoglobin and incidence of diabetes mellitus between the two groups. A multivariable logistic regression analysis showed that glucose level at admission was an independent predictor of MVO (odds ratio, 1.014; 95% confidence interval, 1.004 to 1.023; p=0.006). The glucose level at admission 190mg/dl was the best threshold value for identifying MVO. The occurrence of MVO was significantly higher in the patients with glucose level at admission ?190mg/dl compared with the patients with glucose level <190mg/dl [18 (53%) vs. 16 (27%), p=0.023]. CONCLUSIONS: Hyperglycemia at admission in STEMI patients who were treated by PCI was associated with the presence of MVO assessed by LGE-CMR. PMID- 25533424 TI - Influence of exercise-induced pulmonary hypertension on exercise capacity in asymptomatic degenerative mitral regurgitation. AB - BACKGROUND: Exercise capacity is helpful in the management of patients with mitral regurgitation (MR). However, the determinants of exercise capacity reduction in MR have remained unclear. This study was designed to objectively assess exercise capacity, identify the echocardiographic predictors of exercise capacity, and investigate its impact on development of symptoms in asymptomatic degenerative MR. METHODS: A total of 49 consecutive asymptomatic patients (age, 58.9+/-13.1 years; 82% males) with at least moderate degenerative MR (effective regurgitant orifice area=0.40+/-0.14cm(2); regurgitant volume=60.9+/-19.6mL) underwent the symptom-limited cardiopulmonary exercise testing for assessing exercise capacity (peak oxygen uptake, peak VO2; the minute ventilation/carbon dioxide production, VE/VCO2 slope). All patients also underwent exercise stress echocardiography for detecting exercise-induced pulmonary hypertension (EIPH) defined by systolic pulmonary arterial pressure (SPAP) >=60mmHg. RESULTS: The mean peak VO2 was 22.6+/-5.1mL/kg/min (86.7+/-14.1% of age, gender-predicted); peak VO2 widely varied (48-121% of predicted), and was markedly reduced (<80.4% of predicted) in 24% of the study patients. The patients with EIPH had lower 2 year symptom-free survival than those without EIPH (p=0.003). The multivariable analysis demonstrated that EIPH was an independent echocardiographic determinant of peak VO2 (p=0.001) and VE/VCO2 slope (p=0.021). Furthermore, the area under curve of age- and gender-adjusted exercise SPAP was 0.88 (95% confidence interval: 0.78-0.97) for reduced exercise capacity. CONCLUSIONS: In asymptomatic moderate to severe degenerative MR, EIPH was independently associated with exercise capacity and predicted the occurrence of symptoms. Exercise stress echocardiography is an important tool in managing patients with asymptomatic degenerative MR. PMID- 25533425 TI - Differential profile in inflammatory and mineral metabolism biomarkers in patients with ischemic heart disease without classical coronary risk factors. AB - BACKGROUND: Patients with coronary heart disease (CHD) without classical cardiovascular risk factors (CRFs) are uncommon, and their profile has not been thoroughly studied. In CHD patients, we have assessed the differences in several biomarkers between those with and without CRF. METHODS: We studied 704 patients with CHD, analyzing plasma levels of biomarkers related to inflammation, thrombosis, renal damage, and heart failure: high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1), galectin-3, N-terminal fragment of brain natriuretic peptide (NT-pro-BNP), calcidiol (vitamin D metabolite), fibroblast growth factor-23 (FGF-23), parathormone, and phosphate. RESULTS: Twenty patients (2.8%) exhibited no CRFs. Clinical variables were well balanced in both groups, with the logical exceptions of no use of antidiabetic drugs, lower triglyceride and glucose, and higher high-density lipoprotein cholesterol in no-CRF patients. No-CRF patients showed lower hs-CRP (2.574+/ 3.120 vs. 4.554+/-9.786mg/L; p=0.018), MCP-1 (114.75+/-36.29 vs. 143.56+/ 65.37pg/ml; p=0.003), and FGF-23 (79.28+/-40.22 vs. 105.17+/-156.61RU/ml; p=0.024), and higher calcidiol (23.66+/-9.12 vs. 19.49+/-8.18ng/ml; p=0.025) levels. At follow-up, 10.0% vs. 11.0% patients experienced acute ischemic event, heart failure, or death in the non-CRF and CRF groups, respectively (p=0.815, log rank test). The limited number of non-CRF patients may have influenced this finding. A Cox regression analysis in the whole population showed that high calcidiol, and low MCP-1 and FGF-23 plasma levels are associated with a better prognosis. CONCLUSIONS: CHD patients without CRFs show a favorable biomarker profile in terms of inflammation and mineral metabolism. Further studies are needed to investigate whether this difference translates into a better prognosis. PMID- 25533427 TI - The local environment of the molecules in water-DMSO mixtures, as seen from computer simulations and Voronoi polyhedra analysis. AB - Molecular dynamics simulations of water-DMSO mixtures, containing 10, 20, 30, 40, 50, 60, 70, 80, and 90 mol% DMSO, respectively, have been performed on the isothermal-isobaric (N,p,T) ensemble at T = 298 K and at the pressure equal to the experimental vapor pressure at each mixture composition. In addition, simulations of the two neat systems have also been performed for reference. The potential models used in the simulations are known to excellently reproduce the mixing properties of these compounds. The simulation results have been analyzed in detail by means of the Voronoi polyhedra (VP) of the molecules. Distributions of the VP volume and the asphericity parameter as well as that of the radius of the spherical intermolecular voids have been calculated. Detailed analyses of these distributions have revealed that both molecules prefer to be in an environment consisting of both types of molecules, but the affinity of DMSO for mixing with water is clearly stronger than that of water for mixing with DMSO. As a consequence, the dilution of the two neat liquids by the other component has been found to follow different mechanisms: when DMSO is added to neat water small domains of neat-like water persist up to the equimolar composition, whereas no such domains are found when neat DMSO is diluted by water. The observed behaviour is also in line with the fact that the main thermodynamic driving force behind the full miscibility of water and DMSO is the energy change accompanying their mixing, and that the entropy change accompanying this mixing is negative in systems of low and positive in systems of high DMSO mole fractions. Finally, we have found a direct evidence for the existence of strong hydrogen bonded complexes formed by one DMSO and two water molecules, but it has also been shown that these complexes are in equilibrium with single (monomeric) water and DMSO molecules in the mixed systems. PMID- 25533428 TI - Alternative bibliometrics from impact factor improved the esteem of a journal in a 2-year-ahead annual-citation calculation: multivariate analysis of gastroenterology and hepatology journals. AB - INTRODUCTION: A deeper understanding of supplementary bibliometrics beyond the impact factor might provide researchers with a better understanding of the citation process. This study presents a multivariate analysis of gastroenterology and hepatology journals to evaluate the predictive ability of seven bibliometrics in the Web of Science to calculate total cites over a 2-year period. METHODS: Coincidentally, bibliometrics appearing during 2008, 2009, and 2010, with their corresponding cites in 2010, 2011, and 2012, were recorded from the Journal Citation Reports Science Edition. A linear mixed-effects design using random slopes and intercepts was performed on 51 out of 74 journals in the Gastroenterology and Hepatology category. RESULT: There was a significant global effect size (R(2) = 0.992; P < 0.001), which yielded a total variance of 99.2%. The strongest predictors in the model were the Eigenfactor Score and Cited Half life (P < 0.001), followed by the Number of Articles (P = 0.011) and the Immediacy Index (P = 0.021). The impact factor was not a significant predictor. CONCLUSION: The Eigenfactor Score and Cited Half-life predictors might be the new standards to assess the influence and importance of scientific journals; this approach may help researchers select journals in which to publish their work. PMID- 25533426 TI - Commentary: is Alzheimer's disease uniquely human? AB - That Alzheimer's disease (AD) might be a human-specific disease was hypothesized by Rapoport in 1989. Apes and humans share an identical amyloid beta (Abeta) peptide amino acid sequence and accumulate considerable Abeta deposits after age 40 years, an age when amyloid plaques are uncommon in humans. Despite their early Abeta buildup, ape brains have not shown evidence dystrophic neurites near plaques. Aging great ape brains also have few neurofibrillary tangles, with one exception of 1 obese chimpanzee euthanized after a stroke who displayed abundant neurofibrillary tangles, but without the typical AD distribution. We discuss the need for more exacting evaluation of neuron density with age, and note husbandry issues that may allow great apes to live to greater ages. We remain reserved about expectations for fully developed AD-like pathology in the great apes of advanced ages and cautiously support Rapoport's hypothesis. PMID- 25533430 TI - Assessment of p21, p53 expression, and Ki-67 proliferative activities in the gastric mucosa of children with Helicobacter pylori gastritis. AB - BACKGROUND: Helicobacter pylori that is generally acquired in childhood and infects the gastric mucosa is considered to be responsible for many pathobiological changes that are linked to the pathogenesis of gastric cancer. Although the majority of studies on the subject have been carried out in adults, there are a limited number of studies on children that reflect the early period of infection and may be of greater significance. AIM: We aimed to determine the role of H. pylori infection and/or gastritis in several histopathological changes, p53, p21, and cell proliferation-associated Ki-67 antigen expression in the gastric mucosa. MATERIALS AND METHODS: We studied 60 patients with a mean age of 7.5 +/- 4.5 years at referral. On the basis of endoscopic appearance and the evaluation of the gastric antral specimens, the patients were divided into three groups: patients without gastritis, patients with H. pylori-positive gastritis, and patients with H. pylori-negative gastritis. To determine the expression of p53, Ki-67, and p21 in gastric biopsy specimens, immunohistochemical stains were performed. RESULTS: The incidence of neutrophil activity, which was one of our histopathologic parameters, was significantly higher in the H. pylori-positive gastritis group than the other two groups. The presence of lymphoid aggregate was more frequent in H. pylori +/- gastritis groups than the nongastritis group. p53 expression was found to be significantly higher in the H. pylori-positive gastritis group than the nongastritis group. Ki-67 and p21 expressions were significantly more frequent in the H. pylori-positive gastritis group than the other two groups. When we evaluated the density of H. pylori, as the density of bacteria increases, we found that the expressions of p53, p21, and Ki-67 increased significantly. CONCLUSION: Expression of the studied precancerous markers in significant amounts indicates the importance of childhood H. pylori infection in the constitution of gastric cancer in adulthood. PMID- 25533429 TI - Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease that is increasingly being associated with cardiovascular disease. Ursodeoxycholic acid (UDCA) may have antioxidant and anti-inflammatory activities, and may reduce liver injury in NASH. To date, no studies have assessed the efficacy of UDCA in carotid intima media thickness (CIMT), serum lipids, apolipoprotein A1 (apo A), apolipoprotein B (apo B), and apolipoprotein B/A1 (apo B/A1) ratios in patients with NASH. PATIENTS AND METHODS: In this prospective study, 30 patients with biopsy-proven NASH and 25 healthy adults as a control group were evaluated. None of the participants had diabetes, hypertension, or hyperlipidemia. Patients with NASH received UDCA 15 mg/kg/day for 6 months. BMI, waist circumference, homeostasis model assessment, lipids, apo A1, apo B, apo B/A1 ratios, and CIMT were analyzed before and after the treatment period. RESULTS: At the end of the study, there were no statistically significant changes in BMI or waist circumference. Liver enzymes decreased gradually. The homeostasis model assessment decreased from 3.4 +/- 1.89 to 2.06 +/- 1.68 (P < 0.001). No significant changes in the mean triglyceride, total cholesterol, low-density lipoprotein, or apo B levels were observed. The mean high-density lipoprotein (42.9 +/- 7.1 vs. 45.5 +/- 9.8; P = 0.037) and apo A1 (127.6 +/- 17.7 vs. 135.9 +/- 22.2; P = 0.02) increased significantly. Apo B/A1 ratios tended to decrease, but this decrease was not statistically significant. The mean CIMT decreased significantly (0.56 +/- 0.15 vs. 0.47 +/- 0.12; P = 0.001). CONCLUSION: UDCA treatment in NASH patients resulted in statistically significant reductions in the mean CIMT over a 6-month period. We believe that this benefit of UDCA may have resulted from decreased insulin resistance and increased serum high-density lipoprotein-apo A1 levels. However, larger, longer-term studies are needed to confirm this effect of UDCA in NASH. PMID- 25533431 TI - Which diagnostic tool for the prediction of intermediate liver fibrosis stages? PMID- 25533432 TI - Helicobacter pylori and cirrhosis: any missing data in the meta-analysis? PMID- 25533433 TI - Association between cirrhosis and Helicobacter pylori-related brain pathologies. PMID- 25533434 TI - Benefit of antibiotic prophylaxis in cirrhotic patients with gastrointestinal bleeding in real life. PMID- 25533435 TI - Assessment of the neutrophil to lymphocyte ratio in inactive hepatitis B carriers. PMID- 25533438 TI - Survey study assessing attitudes and experiences of pediatric registered dietitians regarding blended food by gastrostomy tube feeding. AB - BACKGROUND: Families of children requiring nutrition support may be interested in providing blenderized food by gastrostomy tube (BFGT). Some registered dietitians (RDs) recommend partial or full BFGT for children with tube feeding intolerance who are unresponsive to standard interventions. There is little published information on the safety and efficacy of BFGT feeding. The purpose of this survey was to elicit experiences of pediatric RDs with BFGT in clinical practices. METHODS: A survey instrument was distributed to members of the Pediatric Nutrition Practice Group to report experiences of BFGT in clinical practice. RESULTS: Response rate was 9.9% of total members (N = 2,448). Over half (58%) of the 244 respondents use and recommend BFGT. Reasons for use included parent request (70.2%), tube feeding intolerance (22.9%), and inability to obtain commercial formula (6.1%). Seventy-nine percent reported an overall positive outcome with BFGT. Older RDs were more familiar with BFGT but less likely to use it compared with younger RDs who use BFGT or wanted more information (P = .007). Twelve percent did not use or recommend BFGT due to concerns about bacterial contamination, unknown nutrient composition, inability to provide follow-up, and/or facility policy violations. Twenty-eight percent were familiar with BFGT but wanted more information. CONCLUSIONS: Interest in BFGT is largely parent driven or explored as an option for children with tube feeding intolerance. Almost 80% of RDs using this feeding substrate report overall positive outcomes, but 28% indicate they want more information on using BFGT in clinical practice. PMID- 25533439 TI - Acid-base disorders: learning the basics. AB - Nutrition support practitioners should be confident in their ability to recognize and treat various metabolic and respiratory disorders encountered in daily practice. A clinician's comprehension of the underlying physiologic processes and/or exogenous causes that occur during acid-base disorders is essential when making therapeutic decisions regarding fluids, parenteral nutrition, and electrolyte management. This invited review will discuss basic metabolic and respiratory disorders while briefly addressing mixed acid-base disorders. PMID- 25533437 TI - Sparse modeling of spatial environmental variables associated with asthma. AB - Geographically distributed environmental factors influence the burden of diseases such as asthma. Our objective was to identify sparse environmental variables associated with asthma diagnosis gathered from a large electronic health record (EHR) dataset while controlling for spatial variation. An EHR dataset from the University of Wisconsin's Family Medicine, Internal Medicine and Pediatrics Departments was obtained for 199,220 patients aged 5-50years over a three-year period. Each patient's home address was geocoded to one of 3456 geographic census block groups. Over one thousand block group variables were obtained from a commercial database. We developed a Sparse Spatial Environmental Analysis (SASEA). Using this method, the environmental variables were first dimensionally reduced with sparse principal component analysis. Logistic thin plate regression spline modeling was then used to identify block group variables associated with asthma from sparse principal components. The addresses of patients from the EHR dataset were distributed throughout the majority of Wisconsin's geography. Logistic thin plate regression spline modeling captured spatial variation of asthma. Four sparse principal components identified via model selection consisted of food at home, dog ownership, household size, and disposable income variables. In rural areas, dog ownership and renter occupied housing units from significant sparse principal components were associated with asthma. Our main contribution is the incorporation of sparsity in spatial modeling. SASEA sequentially added sparse principal components to Logistic thin plate regression spline modeling. This method allowed association of geographically distributed environmental factors with asthma using EHR and environmental datasets. SASEA can be applied to other diseases with environmental risk factors. PMID- 25533440 TI - A review of uric acid, crystal deposition disease, and gout. AB - There has been increased interest in gout in both academic and clinical practice settings. Several reasons may explain this. The prevalence of both hyperuricemia and gout has risen in the last decades in developed countries and therefore the burden of gout has increased. The association of hyperuricemia and gout with cardiovascular outcomes and the opportunity of further benefits of intervention on hyperuricemia have been recently highlighted in the literature. Imaging techniques have proven to be useful for detection of urate deposition, even prior to the first clinical symptoms, enabling the evaluation of the extent of deposition and providing objective measurement of crystal depletion during urate lowering treatment. Treating to target is increasingly used as the approach to treatment of diverse diseases. Therefore, different targets have been recommended for different stages of the burden of disease and for different stages of treatment. The final strategic target, to which any effort should be taken into consideration, is to completely dissolve urate crystals in tissues and therefore avoid further symptoms and structural damage of involved musculoskeletal structures. In summary, evidence suggest that an early approach to the treatment of gout and associated comorbidities is advisable, that new imaging techniques may help to evaluate both the burden of deposition and response to urate-lowering treatment in selected patients, and finally that the final strategic objective of healthcare for patients with gout is to completely resolve urate crystal deposits. PMID- 25533441 TI - Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder. AB - Previously, using the single-prolonged stress (SPS) rat model of posttraumatic stress disorder, we reported that moderate treadmill exercise, via modulation of oxidative stress-related mechanisms, rescued anxiety- and depression-like behaviors and reversed SPS-induced memory impairment. In this study using the SPS model (2-hour restrain, 20-minute forced swimming, 15-minute rest, and 1-2-minute diethyl ether exposure), we hypothesized that antioxidant rich grape powder (GP) prevents SPS-induced behavioral and memory impairment in rats. Male Sprague Dawley rats were randomly assigned into control (CON) (provided tap water), SPS (provided tap water), GP-SPS (provided 15 g/L GP in tap water for 3 weeks followed by SPS), or GP-CON (3 weeks of GP followed by CON exposure). Anxiety- and depression-like behaviors were significantly greater in SPS rats, when compared with CON- or GP-treated rats, and GP reversed these behavioral deficits. Single-prolonged stress rats made significantly more errors in both short- and long-term memory tests compared with CON- or GP-treated rats, which were prevented in GP-SPS rats. Grape powder prevented SPS-induced increase in plasma corticosterone level. Furthermore, brain-derived neurotrophic factor levels were significantly decreased in amygdala of SPS rats but not in GP-SPS rats compared with CON or (GP-CON) rats. In addition, GP significantly increased acetylated histone 3 and histone deacetylase 5 in hippocampus and amygdala of SPS rats as compared with CON or GP-CON rats. In conclusion, we suggest protective role of GP in SPS-induced behavioral, cognitive, and biochemical impairments in rats. Perhaps, epigenetic regulation of brain-derived neurotrophic factor enables GP mediated prevention of SPS-induced deficits in rats. PMID- 25533442 TI - Effect of pelvic floor muscle training compared with watchful waiting in older women with symptomatic mild pelvic organ prolapse: randomised controlled trial in primary care. AB - OBJECTIVE: To compare the effects of pelvic floor muscle training and watchful waiting on pelvic floor symptoms in a primary care population of women aged 55 years and over with symptomatic mild pelvic organ prolapse. DESIGN: Randomised controlled trial. SETTING: Dutch primary care. PARTICIPANTS: Women aged 55 years or over with symptomatic mild prolapse (leading edge above the hymen) were identified by screening. Exclusion criteria were current prolapse treatment or treatment in the previous year, malignancy of pelvic organs, current treatment for another gynaecological disorder, severe/terminal illness, impaired mobility, cognitive impairment, and insufficient command of the Dutch language. INTERVENTIONS: Pelvic floor muscle training versus watchful waiting. MAIN OUTCOME MEASURES: The primary outcome was change in bladder, bowel, and pelvic floor symptoms measured with the Pelvic Floor Distress Inventory-20 (PFDI-20), three months after the start of treatment. Secondary outcomes were changes in condition specific and general quality of life, sexual function, degree of prolapse, pelvic floor muscle function, and patients' perceived change in symptoms. RESULTS: Of the 287 women who were randomised to pelvic floor muscle training (n=145) or watchful waiting (n=142), 250 (87%) completed follow-up. Participants in the intervention group improved by (on average) 9.1 (95% confidence interval 2.8 to 15.4) points more on the PFDI-20 than did participants in the watchful waiting group (P=0.005). Of women in the pelvic floor muscle training group, 57% (82/145) reported an improvement in overall symptoms from the start of the study compared with 13% (18/142) in the watchful waiting group (P<0.001). Other secondary outcomes showed no significant difference between the groups. CONCLUSIONS: Although pelvic floor muscle training led to a significantly greater improvement in PFDI-20 score, the difference between the groups was below the presumed level of clinical relevance (15 points). Nevertheless, 57% of the participants in the intervention group reported an improvement of overall symptoms. More studies are needed to identify factors related to success of pelvic floor muscle training and to investigate long term effects.Trial registration Dutch Trial Register (www.trialregister.nl) identifier: NTR2047. PMID- 25533443 TI - Chondroitin sulfate cluster of epiphycan from salmon nasal cartilage defines binding specificity to collagens. AB - Epiphycan (EPY) from salmon nasal cartilage has a glycosaminoglycan (GAG) domain that is heavily modified by chondroitin 4-sulfate and chondroitin 6-sulfate. The functional role of the GAG domain has not been investigated. The interaction of EPY with collagen was examined in vitro using surface plasmon resonance analysis. EPY was found to bind to type I collagen via clustered chondroitin sulfate (CS), while a single chain of CS was unable to bind. Types I, III, VII, VIII and X collagen showed high binding affinity with EPY, whereas types II, IV, V, VI and IX showed low binding affinities. Chemical modification of lysine residues in collagen decreased the affinity with the clustered CS. These results suggest that lysine residues of collagen are involved in the interaction with the clustered CS, and the difference in lysine modification defines the binding affinity to EPY. The clustered CS was also involved in an inter-saccharide interaction, and formed self-associated EPY. CS of EPY promoted fibril formation of type I collagen. PMID- 25533444 TI - Staphylococcus aureus-induced clotting of plasma is an immune evasion mechanism for persistence within the fibrin network. AB - Recent work has shown that coagulation and innate immunity are tightly interwoven host responses that help eradicate an invading pathogen. Some bacterial species, including Staphylococcus aureus, secrete pro-coagulant factors that, in turn, can modulate these immune reactions. Such mechanisms may not only protect the micro organism from a lethal attack, but also promote bacterial proliferation and the establishment of infection. Our data showed that coagulase-positive S. aureus bacteria promoted clotting of plasma which was not seen when a coagulase deficient mutant strain was used. Furthermore, in vitro studies showed that this ability constituted a mechanism that supported the aggregation, survival and persistence of the micro-organism within the fibrin network. These findings were also confirmed when agglutination and persistence of coagulase-positive S. aureus bacteria at the local focus of infection were studied in a subcutaneous murine infection model. In contrast, the coagulase-deficient S. aureus strain which was not able to induce clotting failed to aggregate and to persist in vivo. In conclusion, our data suggested that coagulase-positive S. aureus have evolved mechanisms that prevent their elimination within a fibrin clot. PMID- 25533445 TI - Dynamics and diversity of the 'Atopobium cluster' in the human faecal microbiota, and phenotypic characterization of 'Atopobium cluster' isolates. AB - This study monitored the dynamics and diversity of the human faecal 'Atopobium cluster' over a 3-month period using a polyphasic approach. Fresh faecal samples were collected fortnightly from 13 healthy donors (six males and seven females) aged between 26 and 61 years. FISH was used to enumerate total (EUB338mix) and 'Atopobium cluster' (ATO291) bacteria, with counts ranging between 1.12*10(11) and 9.95*10(11), and 1.03*10(9) and 1.16*10(11) cells (g dry weight faeces)(-1), respectively. The 'Atopobium cluster' population represented 0.2-22 % of the total bacteria, with proportions donor-dependent. Denaturing gradient gel electrophoresis (DGGE) using 'Atopobium cluster'-specific primers demonstrated faecal populations of these bacteria were relatively stable, with bands identified as Collinsella aerofaciens, Collinsella intestinalis/Collinsella stercoris, Collinsella tanakaei, Coriobacteriaceae sp. PEAV3-3, Eggerthella lenta, Gordonibacter pamelaeae, Olsenella profusa, Olsenella uli and Paraeggerthella hongkongensis in the DGGE profiles of individuals. Colony PCR was used to identify 'Atopobium cluster' bacteria isolated from faeces (n = 224 isolates). 16S rRNA gene sequence analysis of isolates demonstrated Collinsella aerofaciens represented the predominant (88 % of isolates) member of the 'Atopobium cluster' found in human faeces, being found in nine individuals. Eggerthella lenta was identified in three individuals (3.6 % of isolates). Isolates of Collinsella tanakaei, an 'Enorma' sp. and representatives of novel species belonging to the 'Atopobium cluster' were also identified in the study. Phenotypic characterization of the isolates demonstrated their highly saccharolytic nature and heterogeneous phenotypic profiles, and 97 % of the isolates displayed lipase activity. PMID- 25533448 TI - [Research on therapeutic compliance]. PMID- 25533446 TI - LPS modification promotes maintenance of Yersinia pestis in fleas. AB - Yersinia pestis, the causative agent of plague, can be transmitted by fleas by two different mechanisms: by early-phase transmission (EPT), which occurs shortly after flea infection, or by blocked fleas following long-term infection. Efficient flea-borne transmission is predicated upon the ability of Y. pestis to be maintained within the flea. Signature-tagged mutagenesis (STM) was used to identify genes required for Y. pestis maintenance in a genuine plague vector, Xenopsylla cheopis. The STM screen identified seven mutants that displayed markedly reduced fitness in fleas after 4 days, the time during which EPT occurs. Two of the mutants contained insertions in genes encoding glucose 1-phosphate uridylyltransferase (galU) and UDP-4-amino-4-deoxy-l-arabinose-oxoglutarate aminotransferase (arnB), which are involved in the modification of lipid A with 4 amino-4-deoxy-l-arabinose (Ara4N) and resistance to cationic antimicrobial peptides (CAMPs). These Y. pestis mutants were more susceptible to the CAMPs cecropin A and polymyxin B, and produced lipid A lacking Ara4N modifications. Surprisingly, an in-frame deletion of arnB retained modest levels of CAMP resistance and Ara4N modification, indicating the presence of compensatory factors. It was determined that WecE, an aminotransferase involved in biosynthesis of enterobacterial common antigen, plays a novel role in Y. pestis Ara4N modification by partially offsetting the loss of arnB. These results indicated that mechanisms of Ara4N modification of lipid A are more complex than previously thought, and these modifications, as well as several factors yet to be elucidated, play an important role in early survival and transmission of Y. pestis in the flea vector. PMID- 25533447 TI - Efficacy of triplet regimen antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in bone and soft tissue sarcoma patients receiving highly emetogenic chemotherapy, and an efficacy comparison of single-shot palonosetron and consecutive-day granisetron for CINV in a randomized, single-blinded crossover study. AB - The first aim of this study was to evaluate combination antiemetic therapy consisting of 5-HT3 receptor antagonists, neurokinin-1 receptor antagonists (NK 1RAs), and dexamethasone for multiple high emetogenic risk (HER) anticancer agents in bone and soft tissue sarcoma. The second aim was to compare the effectiveness of single-shot palonosetron and consecutive-day granisetron in a randomized, single-blinded crossover study. A single randomization method was used to assign eligible patients to the palonosetron or granisetron arm. Patients in the palonosetron arm received a palonosetron regimen during the first and third chemotherapy courses and a granisetron regimen during the second and fourth courses. All patients received NK-1RA and dexamethasone. Patients receiving the palonosetron regimen were administered 0.75 mg palonosetron on day 1, and patients receiving the granisetron regimen were administered 3 mg granisetron twice daily on days 1 through 5. All 24 patients in this study received at least 4 chemotherapy courses. A total of 96 courses of antiemetic therapy were evaluated. Overall, the complete response CR rate (no emetic episodes and no rescue medication use) was 34%, while the total control rate (a CR plus no nausea) was 7%. No significant differences were observed between single-shot palonosetron and consecutive-day granisetron. Antiemetic therapy with a 3-drug combination was not sufficient to control chemotherapy-induced nausea and vomiting (CINV) during chemotherapy with multiple HER agents for bone and soft tissue sarcoma. This study also demonstrated that consecutive-day granisetron was not inferior to single-shot palonosetron for treating CINV. PMID- 25533450 TI - The percutaneous cecostomy tube in the management of fecal incontinence in children. AB - PURPOSE: To retrospectively evaluate experience with percutaneous cecostomies and their long-term outcomes. MATERIALS AND METHODS: Between June 1994 and March 2009, 290 patients (mean age, 10.1 y) with fecal incontinence underwent percutaneous cecostomy tube placement and subsequent tube management. Technical success, procedural complications, and long-term follow-up until March 2012 were evaluated. RESULTS: A cecostomy was successfully placed in 284 patients (98%), and 257 of 280 patients (92%) underwent a successful exchange to a low-profile tube. A total of 1,431 routine exchanges to low-profile tubes were reviewed in 258 patients (mean, 1.6 +/- 1.3 routine tube changes per 1,000 days). Eighty-five patients (29%) experienced one or more early problems after cecostomy, and 10 (3%) had major complications. In the total 463,507 tube-days, 938 late problems were noted: 917 (98%) minor and 22 (2%) major. Forty patients had the cecostomy catheter removed and 141 "graduated" to an adult health care facility. CONCLUSIONS: The percutaneous cecostomy procedure provides a safe management option for fecal incontinence in the pediatric population. PMID- 25533449 TI - [Consensus document on the treatment of dyslipidemia in diabetes]. AB - People with type 2 diabetes mellitus have a 2 to 4 times higher risk of developing cardiovascular diseases when compared to general population of similar age and sex. This risk remains after adjustment of other traditional cardiovascular risk factors. The dyslipidemia associated with type 2 diabetes mellitus is present in up to 60% of people with diabetes and contributes greatly to increased cardiovascular, morbidity and mortality risk in these patients. Diabetic dyslipidemia is a disorder of lipid metabolism characterized by an excess of triglycerides, a decrease in HDL-cholesterol and altered lipoprotein composition, consisting mainly in an excess of small, dense LDL particles. Multiple clinical trials have demonstrated the benefits of drug treatment of dyslipidemia (mainly statins) to prevent cardiovascular events and mortality in people with diabetes, both in primary and secondary prevention. This consensus document, developed by general practitioners, members of the Diabetes Group of the Spanish Society of Primary Care Physicians (SEMERGEN), aims to assist in the management of patients with diabetes and dyslipidemia in accordance with the most recent recommendations. PMID- 25533451 TI - Feasibility and safety of prophylactic uterine artery catheterization and embolization in the management of placenta accreta. AB - PURPOSE: To evaluate the feasibility and safety of prophylactic uterine artery catheterization and embolization in the management of placenta accreta (PA). MATERIALS AND METHODS: Retrospective chart review was performed of 95 consecutive patients with prenatal suspicion of PA managed in a 10-year period with a strategy that included prophylactic bilateral uterine artery catheterization, delivery of the baby, uterine artery embolization if indicated, and subsequent surgery. Feasibility was defined as catheterization being possible to perform, technical success as embolization being possible when indicated and complete stasis of the vessels achieved, and clinical success as no maternal death or major blood loss. Median gestational age at delivery was 36 weeks (interquartile range, 24-39 wk). RESULTS: PA was confirmed in 79 patients (83%). Feasibility was 97% (92 of 95); in three cases (3%), acute early massive hemorrhage forced emergency delivery without catheterization. Embolization was performed in 83 of 92 patients (87%) to the extent of complete stasis; in the remaining nine, it was unnecessary because spontaneous placental detachment was visualized after fetal delivery (technical success rate, 100%). There were several complications, including bleeding requiring blood transfusion (49%) and bladder surgery (37%), but there were no major complications attributable to the endovascular procedures. There was one minor complication presumably related to embolization (transient paresthesia and decreased temperature of lower limb), with uneventful follow-up. Clinical success rate was 86%, with no maternal deaths, but 14% of patients received large-volume blood transfusion. CONCLUSIONS: Prophylactic uterine artery catheterization and embolization in the management of PA appeared to be feasible and safe in this consecutive series of patients. PMID- 25533452 TI - Risk of bleeding after native renal biopsy as a function of preprocedural systolic and diastolic blood pressure. AB - PURPOSE: To determine the risk of bleeding complications after native renal biopsy as a function of preprocedural blood pressure (BP). MATERIALS AND METHODS: A total of 293 patients (163 men; mean age, 59.1 y) who underwent ultrasound guided native kidney biopsy at a single institution over a 10-year period were retrospectively identified. Demographic and clinical data were collected, including systolic BP (SBP) and diastolic BP (DBP) at the time of the biopsy and presence and severity of complications. Differences in clinical and demographic data among patients with and without complications were analyzed. RESULTS: Of 293 patients, nine (3.1%) experienced major complications (required transfusion or intervention) and 10 (3.4%) experienced minor complications (pain, hematoma, or hematuria). Patients with SBP greater than 140 mm Hg or DBP greater than 90 mm Hg were 10 times more likely to experience major complications (P < .02) than patients without high BP (odds ratio [OR], 10.6; 95% confidence interval [CI], 1.3-86.0). The odds of complications were particularly increased in patients with SBP greater than 170 mm Hg (OR, 23.3; 95% CI, 2.3-234.4) and were modestly increased in patients with SBP between 141 and 170 mm Hg (OR, 7.11; 95% CI, 0.8 61.7). For DBP, the odds of complications increased with DBP greater than 90 mm Hg (OR, 7.2; 95% CI, 1.9-27.9). CONCLUSIONS: Patients undergoing native renal biopsy who have an SBP greater than 140 mm Hg or DBP greater than 90 mm Hg are at higher risk for bleeding complications. Further research is needed to determine whether medically lowering these patients' BP before kidney biopsy decreases complications. PMID- 25533454 TI - Insulating or metallic: coexistence of different electronic phases in zinc clusters. AB - How many of the several attributes of the bulk metallic state persist in a nanoparticle containing a finite number of atoms of a metallic element? Do all those attributes emerge suddenly at a well-defined cluster size or do they rather evolve at different rates and in a broad size range? These fundamental questions have been addressed through a conjoint experimental/theoretical investigation of zinc clusters. We report the observation of novel coexistence phenomena involving different electronic phases: for some sizes, metallic and insulating electronic states coexist within a single, Janus-like, nanoparticle; for the rest of sizes, we report the coexistence of two weakly interacting metallic phases with different dimensionalities, localized at the shell and the core of the nanoparticle. These fascinating features are due to an anomalously long core shell separation that equips the shell and core regions with largely independent structural, vibrational, and thermal properties. PMID- 25533453 TI - Therapeutic affordances of social media: emergent themes from a global online survey of people with chronic pain. AB - BACKGROUND: Research continues to present tenuous suggestions that social media is well suited to enhance management of chronic disease and improve health outcomes. Various studies have presented qualitative reports of health outcomes from social media use and have examined discourse and communication themes occurring through different social media. However, there is an absence of published studies examining and unpacking the underlying therapeutic mechanisms driving social media's effects. OBJECTIVE: This paper presents a qualitative analysis thoroughly describing what social media therapeutically affords people living with chronic pain who are self-managing their condition. From this therapeutic affordance perspective, we aim to formulate a preliminary conceptual model aimed at better understanding "how" social media can influence patient outcomes. METHODS: In total, 218 people with chronic pain (PWCP) completed an online survey, investigating patient-reported outcomes (PROs) from social media use. Supplementary to quantitative data collected, participants were also given the opportunity to provide further open commentary regarding their use of social media as part of chronic pain management; 68/218 unique users (31.2%) chose to provide these free-text responses. Through thematic content analysis, 117 free text responses regarding 10 types of social media were coded. Quotes were extracted and tabulated based on therapeutic affordances that we had previously identified. Inductive analysis was then performed to code defining language and emergent themes central to describing each affordance. Three investigators examined the responses, developed the coding scheme, and applied the coding to the data. RESULTS: We extracted 155 quotes from 117 free-text responses. The largest source of quotes came from social network site users (78/155, 50.3%). Analysis of component language used to describe the aforementioned affordances and emergent themes resulted in a final revision and renaming of therapeutic affordances: "exploration" (52/155, 33.5% of quotes), "connection" (50/155, 32.3% of quotes), "narration" (33/155, 21.3% of quotes), "adaptation" (13/155, 8.4% of quotes), and "self-presentation" (7/155, 4.5% of quotes). Of the most described affordances, "exploration" was based on a propensity for participants to explain their social media use for information seeking purposes. "Connection" placed greater emphasis on interaction, highlighting themes of "exchanging information" and "mitigating isolation". Responses regarding "narration" highlighted the value of shared experiences and the emotionally cathartic role this plays. CONCLUSIONS: Much of the efficacy of social media may be explicable via a closer examination of therapeutic affordances. Particular areas that warrant attention include social media's ability to filter and guide people to useful information, connect individuals, and share experiences. Further research into a variety of chronic conditions is warranted. Coupled with the results of the present study, a greater theoretical basis detailing how social media may foster health outcomes may lead to an improved evidence base for conducting research and may inform recommendations for social media use in chronic disease management. PMID- 25533455 TI - N-acetylglucosaminidases from CAZy family GH3 are really glycoside phosphorylases, thereby explaining their use of histidine as an acid/base catalyst in place of glutamic acid. AB - CAZy glycoside hydrolase family GH3 consists primarily of stereochemistry retaining beta-glucosidases but also contains a subfamily of beta-N acetylglucosaminidases. Enzymes from this subfamily were recently shown to use a histidine residue within a His-Asp dyad contained in a signature sequence as their catalytic acid/base residue. Reasons for their use of His rather than the Glu or Asp found in other glycosidases were not apparent. Through studies on a representative member, the Nag3 beta-N-acetylglucosaminidase from Cellulomonas fimi, we now show that these enzymes act preferentially as glycoside phosphorylases. Their need to accommodate an anionic nucleophile within the enzyme active site explains why histidine is used as an acid/base catalyst in place of the anionic glutamate seen in other GH3 family members. Kinetic and mechanistic studies reveal that these enzymes also employ a double-displacement mechanism involving a covalent glycosyl-enzyme intermediate, which was directly detected by mass spectrometry. Phosphate has no effect on the rates of formation of the glycosyl-enzyme intermediate, but it accelerates turnover of the N acetylglucosaminyl-enzyme intermediate ~3-fold, while accelerating turnover of the glucosyl-enzyme intermediate several hundredfold. These represent the first reported examples of retaining beta-glycoside phosphorylases, and the first instance of free beta-GlcNAc-1-phosphate in a biological context. PMID- 25533456 TI - Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI alpha2(VI) chain. AB - Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD) sit at opposite ends of a clinical spectrum caused by mutations in the extracellular matrix protein collagen VI. Bethlem myopathy is relatively mild, and patients remain ambulant in adulthood while many UCMD patients lose ambulation by their teenage years and require respiratory interventions. Dominant and recessive mutations are found across the entire clinical spectrum; however, recessive Bethlem myopathy is rare, and our understanding of the molecular pathology is limited. We studied a patient with Bethlem myopathy. Electron microscopy of his muscle biopsy revealed abnormal mitochondria. We identified a homozygous COL6A2 p.D871N amino acid substitution in the C-terminal C2 A-domain. Mutant alpha2(VI) chains are unable to associate with alpha1(VI) and alpha3(VI) and are degraded by the proteasomal pathway. Some collagen VI is assembled, albeit more slowly than normal, and is secreted. These molecules contain the minor alpha2(VI) C2a splice form that has an alternative C terminus that does include the mutation. Collagen VI tetramers containing the alpha2(VI) C2a chain do not assemble efficiently into microfibrils and there is a severe collagen VI deficiency in the extracellular matrix. We expressed wild-type and mutant alpha2(VI) C2 domains in mammalian cells and showed that while wild-type C2 domains are efficiently secreted, the mutant p.D871N domain is retained in the cell. These studies shed new light on the protein domains important for intracellular and extracellular collagen VI assembly and emphasize the importance of molecular investigations for families with collagen VI disorders to ensure accurate diagnosis and genetic counseling. PMID- 25533457 TI - STIM1 and STIM2 proteins differently regulate endogenous store-operated channels in HEK293 cells. AB - The endoplasmic reticulum calcium sensors stromal interaction molecules 1 and 2 (STIM1 and STIM2) are key modulators of store-operated calcium entry. Both these sensors play a major role in physiological functions in normal tissue and in pathology, but available data on native STIM2-regulated plasma membrane channels are scarce. Only a few studies have recorded STIM2-induced CRAC (calcium release activated calcium) currents. On the other hand, many cell types display store operated currents different from CRAC. The STIM1 protein regulates not only CRAC but also transient receptor potential canonical (TRPC) channels, but it has remained unclear whether STIM2 is capable of regulating store-operated non-CRAC channels. Here we present for the first time experimental evidence for the existence of endogenous non-CRAC STIM2-regulated channels. As shown in single channel patch clamp experiments on HEK293 cells, selective activation of native STIM2 proteins or STIM2 overexpression results in store-operated activation of Imin channels, whereas STIM1 activation blocks this process. Changes in the ratio between active STIM2 and STIM1 proteins can switch the regulation of Imin channels between store-operated and store-independent modes. We have previously characterized electrophysiological properties of different Ca(2+) influx channels coexisting in HEK293 cells. The results of this study show that STIM1 and STIM2 differ in the ability to activate these store-operated channels; Imin channels are regulated by STIM2, TRPC3-containing INS channels are induced by STIM1, and TRPC1-composed Imax channels are activated by both STIM1 and STIM2. These new data about cross-talk between STIM1 and STIM2 and their different roles in store operated channel activation are indicative of an additional level in the regulation of store-operated calcium entry pathways. PMID- 25533458 TI - A love affair with Bacillus subtilis. AB - My career in science was launched when I was an undergraduate at Princeton University and reinforced by graduate training at the Massachusetts Institute of Technology. However, it was only after I moved to Harvard University as a junior fellow that my affections were captured by a seemingly mundane soil bacterium. What Bacillus subtilis offered was endless fascinating biological problems (alternative sigma factors, sporulation, swarming, biofilm formation, stochastic cell fate switching) embedded in a uniquely powerful genetic system. Along the way, my career in science became inseparably interwoven with teaching and mentoring, which proved to be as rewarding as the thrill of discovery. PMID- 25533459 TI - Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis. AB - Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system. PMID- 25533460 TI - Direct interaction of CaVbeta with actin up-regulates L-type calcium currents in HL-1 cardiomyocytes. AB - Expression of the beta-subunit (CaVbeta) is required for normal function of cardiac L-type calcium channels, and its up-regulation is associated with heart failure. CaVbeta binds to the alpha1 pore-forming subunit of L-type channels and augments calcium current density by facilitating channel opening and increasing the number of channels in the plasma membrane, by a poorly understood mechanism. Actin, a key component of the intracellular trafficking machinery, interacts with Src homology 3 domains in different proteins. Although CaVbeta encompasses a highly conserved Src homology 3 domain, association with actin has not yet been explored. Here, using co-sedimentation assays and FRET experiments, we uncover a direct interaction between CaVbeta and actin filaments. Consistently, single molecule localization analysis reveals streaklike structures composed by CaVbeta2 that distribute over several micrometers along actin filaments in HL-1 cardiomyocytes. Overexpression of CaVbeta2-N3 in HL-1 cells induces an increase in L-type current without altering voltage-dependent activation, thus reflecting an increased number of channels in the plasma membrane. CaVbeta mediated L-type up-regulation, and CaVbeta-actin association is prevented by disruption of the actin cytoskeleton with cytochalasin D. Our study reveals for the first time an interacting partner of CaVbeta that is directly involved in vesicular trafficking. We propose a model in which CaVbeta promotes anterograde trafficking of the L-type channels by anchoring them to actin filaments in their itinerary to the plasma membrane. PMID- 25533461 TI - K+ congeners that do not compromise Na+ activation of the Na+,K+-ATPase: hydration of the ion binding cavity likely controls ion selectivity. AB - The Na(+),K(+)-ATPase is essential for ionic homeostasis in animal cells. The dephosphoenzyme contains Na(+) selective inward facing sites, whereas the phosphoenzyme contains K(+) selective outward facing sites. Under normal physiological conditions, K(+) inhibits cytoplasmic Na(+) activation of the enzyme. Acetamidinium (Acet(+)) and formamidinium (Form(+)) have been shown to permeate the pump through the outward facing sites. Here, we show that these cations, unlike K(+), are unable to enter the inward facing sites in the dephosphorylated enzyme. Consistently, the organic cations exhibited little to no antagonism to cytoplasmic Na(+) activation. Na(+),K(+)-ATPase structures revealed a previously undescribed rotamer transition of the hydroxymethyl side chain of the absolutely conserved Thr(772) of the alpha-subunit. The side chain contributes its hydroxyl to Na(+) in site I in the E1 form and rotates to contribute its methyl group toward K(+) in the E2 form. Molecular dynamics simulations to the E1.AlF4 (-).ADP.3Na(+) structure indicated that 1) bound organic cations differentially distorted the ion binding sites, 2) the hydroxymethyl of Thr(772) rotates to stabilize bound Form(+) through water molecules, and 3) the rotamer transition is mediated by water traffic into the ion binding cavity. Accordingly, dehydration induced by osmotic stress enhanced the interaction of the congeners with the outward facing sites and profoundly modified the organization of membrane domains of the alpha-subunit. These results assign a catalytic role for water in pump function, and shed light on a backbone independent but a conformation-dependent switch between H-bond and dispersion contact as part of the catalytic mechanism of the Na(+),K(+)-ATPase. PMID- 25533462 TI - A direct role for ATP1A1 in unconventional secretion of fibroblast growth factor 2. AB - Previous studies proposed a role for the Na/K-ATPase in unconventional secretion of fibroblast growth factor 2 (FGF2). This conclusion was based upon pharmacological inhibition of FGF2 secretion in the presence of ouabain. However, neither independent experimental evidence nor a potential mechanism was provided. Based upon an unbiased RNAi screen, we now report the identification of ATP1A1, the alpha1-chain of the Na/K-ATPase, as a factor required for efficient secretion of FGF2. As opposed to ATP1A1, down-regulation of the beta1- and beta3-chains (ATP1B1 and ATP1B3) of the Na/K-ATPase did not affect FGF2 secretion, suggesting that they are dispensable for this process. These findings indicate that it is not the membrane potential-generating function of the Na/K-ATPase complex but rather a so far unidentified role of potentially unassembled alpha1-chains that is critical for unconventional secretion of FGF2. Consistently, in the absence of beta-chains, we found a direct interaction between the cytoplasmic domain of ATP1A1 and FGF2 with submicromolar affinity. Based upon these observations, we propose that ATP1A1 is a recruitment factor for FGF2 at the inner leaflet of plasma membranes that may control phosphatidylinositol 4,5-bisphosphate-dependent membrane translocation as part of the unconventional secretory pathway of FGF2. PMID- 25533463 TI - Stimulation, inhibition, or stabilization of Na,K-ATPase caused by specific lipid interactions at distinct sites. AB - The activity of membrane proteins such as Na,K-ATPase depends strongly on the surrounding lipid environment. Interactions can be annular, depending on the physical properties of the membrane, or specific with lipids bound in pockets between transmembrane domains. This paper describes three specific lipid-protein interactions using purified recombinant Na,K-ATPase. (a) Thermal stability of the Na,K-ATPase depends crucially on a specific interaction with 18:0/18:1 phosphatidylserine (1-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine; SOPS) and cholesterol, which strongly amplifies stabilization. We show here that cholesterol associates with SOPS, FXYD1, and the alpha subunit between trans membrane segments alphaTM8 and -10 to stabilize the protein. (b) Polyunsaturated neutral lipids stimulate Na,K-ATPase turnover by >60%. A screen of the lipid specificity showed that 18:0/20:4 and 18:0/22:6 phosphatidylethanolamine (PE) are the optimal phospholipids for this effect. (c) Saturated phosphatidylcholine and sphingomyelin, but not saturated phosphatidylserine or PE, inhibit Na,K-ATPase activity by 70-80%. This effect depends strongly on the presence of cholesterol. Analysis of the Na,K-ATPase activity and E1-E2 conformational transitions reveals the kinetic mechanisms of these effects. Both stimulatory and inhibitory lipids poise the conformational equilibrium toward E2, but their detailed mechanisms of action are different. PE accelerates the rate of E1 -> E2P but does not affect E2(2K)ATP -> E13NaATP, whereas sphingomyelin inhibits the rate of E2(2K)ATP -> E13NaATP, with very little effect on E1 -> E2P. We discuss these lipid effects in relation to recent crystal structures of Na,K-ATPase and propose that there are three separate sites for the specific lipid interactions, with potential physiological roles to regulate activity and stability of the pump. PMID- 25533464 TI - Structural and kinetic basis of steroid 17alpha,20-lyase activity in teleost fish cytochrome P450 17A1 and its absence in cytochrome P450 17A2. AB - Cytochrome P450 (P450) 17A enzymes play a critical role in the oxidation of the steroids progesterone (Prog) and pregnenolone (Preg) to glucocorticoids and androgens. In mammals, a single enzyme, P450 17A1, catalyzes both 17alpha hydroxylation and a subsequent 17alpha,20-lyase reaction with both Prog and Preg. Teleost fish contain two 17A P450s; zebrafish P450 17A1 catalyzes both 17alpha hydroxylation and lyase reactions with Prog and Preg, and P450 17A2 is more efficient in pregnenolone 17alpha-hydroxylation but does not catalyze the lyase reaction, even in the presence of cytochrome b5. P450 17A2 binds all substrates and products, although more loosely than P450 17A1. Pulse-chase and kinetic spectral experiments and modeling established that the two-step P450 17A1 Prog oxidation is more distributive than the Preg reaction, i.e. 17alpha-OH product dissociates more prior to the lyase step. The drug orteronel selectively blocked the lyase reaction of P450 17A1 but only in the case of Prog. X-ray crystal structures of zebrafish P450 17A1 and 17A2 were obtained with the ligand abiraterone and with Prog for P450 17A2. Comparison of the two fish P450 17A abiraterone structures with human P450 17A1 (DeVore, N. M., and Scott, E. E. (2013) Nature 482, 116-119) showed only a few differences near the active site, despite only ~50% identity among the three proteins. The P450 17A2 structure differed in four residues near the heme periphery. These residues may allow the proposed alternative ferric peroxide mechanism for the lyase reaction, or residues removed from the active site may allow conformations that lead to the lyase activity. PMID- 25533465 TI - In vitro reassembly of the ribose ATP-binding cassette transporter reveals a distinct set of transport complexes. AB - Bacterial ATP-binding cassette (ABC) importers are primary active transporters that are critical for nutrient uptake. Based on structural and functional studies, ABC importers can be divided into two distinct classes, type I and type II. Type I importers follow a strict alternating access mechanism that is driven by the presence of the substrate. Type II importers accept substrates in a nucleotide-free state, with hydrolysis driving an inward facing conformation. The ribose transporter in Escherichia coli is a tripartite complex consisting of a cytoplasmic ATP-binding cassette protein, RbsA, with fused nucleotide binding domains; a transmembrane domain homodimer, RbsC2; and a periplasmic substrate binding protein, RbsB. To investigate the transport mechanism of the complex RbsABC2, we probed intersubunit interactions by varying the presence of the substrate ribose and the hydrolysis cofactors, ATP/ADP and Mg(2+). We were able to purify a full complex, RbsABC2, in the presence of stable, transition state mimics (ATP, Mg(2+), and VO4); a RbsAC complex in the presence of ADP and Mg(2+); and a heretofore unobserved RbsBC complex in the absence of cofactors. The presence of excess ribose also destabilized complex formation between RbsB and RbsC. These observations suggest that RbsABC2 shares functional traits with both type I and type II importers, as well as possessing unique features, and employs a distinct mechanism relative to other ABC transporters. PMID- 25533466 TI - The FBXL10/KDM2B scaffolding protein associates with novel polycomb repressive complex-1 to regulate adipogenesis. AB - Polycomb repressive complex 1 (PRC1) plays an essential role in the epigenetic repression of gene expression during development and cellular differentiation via multiple effector mechanisms, including ubiquitination of H2A and chromatin compaction. However, whether it regulates the stepwise progression of adipogenesis is unknown. Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. Knockdown of either RING1B or SKP1 prevented FBXL10-mediated repression of 3T3-L1 preadipocyte differentiation indicating that PRC1 formation mediates the inhibitory effect of FBXL10 on adipogenesis. Using ChIP-seq, we show that FBXL10 recruits RING1B to key specific genomic loci surrounding the key cell cycle and the adipogenic genes Cdk1, Uhrf1, Pparg1, and Pparg2 to repress adipogenesis. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage. PMID- 25533467 TI - A mutation within the extended X loop abolished substrate-induced ATPase activity of the human liver ATP-binding cassette (ABC) transporter MDR3. AB - The human multidrug resistance protein 3 (MDR3/ABCB4) belongs to the ubiquitous family of ATP-binding cassette (ABC) transporters and is located in the canalicular membrane of hepatocytes. There it flops the phospholipids of the phosphatidylcholine (PC) family from the inner to the outer leaflet. Here, we report the characterization of wild type MDR3 and the Q1174E mutant, which was identified previously in a patient with progressive familial intrahepatic cholestasis type 3 (PFIC-3). We expressed different variants of MDR3 in the yeast Pichia pastoris, purified the proteins via tandem affinity chromatography, and determined MDR3-specific ATPase activity in the presence or absence of phospholipids. The ATPase activity of wild type MDR3 was stimulated 2-fold by liver PC or 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine lipids. Furthermore, the cross-linking of MDR3 with a thiol-reactive fluorophore blocked ATP hydrolysis and exhibited no PC stimulation. Similarly, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin lipids did not induce an increase of wild type MDR3 ATPase activity. The phosphate analogues beryllium fluoride and aluminum fluoride led to complete inhibition of ATPase activity, whereas orthovanadate inhibited exclusively the PC-stimulated ATPase activity of MDR3. The Q1174E mutation is located in the nucleotide-binding domain in direct proximity of the leucine of the ABC signature motif and extended the X loop, which is found in ABC exporters. Our data on the Q1174E mutant demonstrated basal ATPase activity, but PC lipids were incapable of stimulating ATPase activity highlighting the role of the extended X loop in the cross-talk of the nucleotide-binding domain and the transmembrane domain. PMID- 25533468 TI - Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases. AB - synGAP is a neuron-specific Ras and Rap GTPase-activating protein (GAP) found in high concentrations in the postsynaptic density (PSD) fraction from the mammalian forebrain. We have previously shown that, in situ in the PSD fraction or in recombinant form in Sf9 cell membranes, synGAP is phosphorylated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), another prominent component of the PSD. Here, we show that recombinant synGAP (r-synGAP), lacking 102 residues at the N terminus, can be purified in soluble form and is phosphorylated by cyclin-dependent kinase 5 (CDK5) as well as by CaMKII. Phosphorylation of r-synGAP by CaMKII increases its HRas GAP activity by 25% and its Rap1 GAP activity by 76%. Conversely, phosphorylation by CDK5 increases r synGAP's HRas GAP activity by 98% and its Rap1 GAP activity by 20%. Thus, phosphorylation by both kinases increases synGAP activity; CaMKII shifts the relative GAP activity toward inactivation of Rap1, and CDK5 shifts the relative activity toward inactivation of HRas. GAP activity toward Rap2 is not altered by phosphorylation by either kinase. CDK5 phosphorylates synGAP primarily at two sites, Ser-773 and Ser-802. Phosphorylation at Ser-773 inhibits r-synGAP activity, and phosphorylation at Ser-802 increases it. However, the net effect of concurrent phosphorylation of both sites, Ser-773 and Ser-802, is an increase in GAP activity. synGAP is phosphorylated at Ser-773 and Ser-802 in the PSD fraction, and its phosphorylation by CDK5 and CaMKII is differentially regulated by activation of NMDA-type glutamate receptors in cultured neurons. PMID- 25533469 TI - Interactions among cytochromes P450 in microsomal membranes: oligomerization of cytochromes P450 3A4, 3A5, and 2E1 and its functional consequences. AB - The body of evidence of physiologically relevant P450-P450 interactions in microsomal membranes continues to grow. Here we probe oligomerization of human CYP3A4, CYP3A5, and CYP2E1 in microsomal membranes. Using a technique based on luminescence resonance energy transfer, we demonstrate that all three proteins are subject to a concentration-dependent equilibrium between the monomeric and oligomeric states. We also observed the formation of mixed oligomers in CYP3A4/CYP3A5, CYP3A4/CYP2E1, and CYP3A5/CYP2E1 pairs and demonstrated that the association of either CYP3A4 or CYP3A5 with CYP2E1 causes activation of the latter enzyme. Earlier we hypothesized that the intersubunit interface in CYP3A4 oligomers is similar to that observed in the crystallographic dimers of some microsomal drug-metabolizing cytochromes P450 (Davydov, D. R., Davydova, N. Y., Sineva, E. V., Kufareva, I., and Halpert, J. R. (2013) Pivotal role of P450-P450 interactions in CYP3A4 allostery: the case of alpha-naphthoflavone. Biochem. J. 453, 219-230). Here we report the results of intermolecular cross-linking of CYP3A4 oligomers with thiol-reactive bifunctional reagents as well as the luminescence resonance energy transfer measurements of interprobe distances in the oligomers of labeled CYP3A4 single-cysteine mutants. The results provide compelling support for the physiological relevance of the dimer-specific peripheral ligand-binding site observed in certain CYP3A4 structures. According to our interpretation, these results reveal an important general mechanism that regulates the activity and substrate specificity of the cytochrome P450 ensemble through interactions between multiple P450 species. As a result of P450-P450 cross-talk, the catalytic properties of the cytochrome P450 ensemble cannot be predicted by simple summation of the properties of the individual P450 species. PMID- 25533470 TI - Loss of apoptosis regulator through modulating IAP expression (ARIA) protects blood vessels from atherosclerosis. AB - Atherosclerosis is the primary cause for cardiovascular disease. Here we identified a novel mechanism underlying atherosclerosis, which is provided by ARIA (apoptosis regulator through modulating IAP expression), the transmembrane protein that we recently identified. ARIA is expressed in macrophages present in human atherosclerotic plaque as well as in mouse peritoneal macrophages. When challenged with acetylated LDL, peritoneal macrophages isolated from ARIA deficient mice showed substantially reduced foam cell formation, whereas the uptake did not differ from that in wild-type macrophages. Mechanistically, loss of ARIA enhanced PI3K/Akt signaling and consequently reduced the expression of acyl coenzyme A:cholesterol acyltransferase-1 (ACAT-1), an enzyme that esterifies cholesterol and promotes its storage, in macrophages. Inhibition of PI3K abolished the reduction in ACAT-1 expression and foam cell formation in ARIA deficient macrophages. In contrast, overexpression of ARIA reduced Akt activity and enhanced foam cell formation in RAW264.7 macrophages, which was abrogated by treatment with ACAT inhibitor. Of note, genetic deletion of ARIA significantly reduced the atherosclerosis in ApoE-deficient mice. Oil red-O-positive lipid-rich lesion was reduced, which was accompanied by an increase of collagen fiber and decrease of necrotic core lesion in atherosclerotic plaque in ARIA/ApoE double deficient mice. Analysis of bone marrow chimeric mice revealed that loss of ARIA in bone marrow cells was sufficient to reduce the atherosclerogenesis in ApoE deficient mice. Together, we identified a unique role of ARIA in the pathogenesis of atherosclerosis at least partly by modulating macrophage foam cell formation. Our results indicate that ARIA could serve as a novel pharmacotherapeutic target for the treatment of atherosclerotic diseases. PMID- 25533471 TI - Mouse insulin cells expressing an inducible RIPCre transgene are functionally impaired. AB - We used cre-lox technology to test whether the inducible expression of Cre minimize the deleterious effect of the enzyme on beta cell function. We studied mice in which Cre is linked to a modified estrogen receptor (ER), and its expression is controlled by the rat insulin promoter (RIP). Following the injection of tamoxifen (TM), CreER- migrates to the nucleus and promotes the appearance of a reporter protein, enhanced yellow fluorescent protein (EYFP), in cells. Immunocytochemical analysis indicated that 46.6 +/- 2.1% insulin cells of adult RIPCreER- EYFP expressed EYFP. RIPCreER-EYFP (+TM) mice were normoglycemic throughout the study, and their glucose tolerance test results were similar to control CD-1 mice. However, an extended exposure to reagents that stimulate insulin synthesis was detrimental to the survival of IN+EYFP+cells. The administration of an inhibitor of the enzyme dipeptidyl-peptidase (DPP4i), which prevents the cleavage of glucagon-like peptide (GLP-1), to adult RIPCreER-EYFP mice lead to a decrease in the percentage of IN+EYFP+ to 17.5 +/- 1.73 and a significant increase in apoptotic cells in islets. Similarly, a 2-week administration of the GLP-1 analog exendin 4 (ex-4) induced an almost complete ablation of IN+ expressing a different reporter protein and a significant decrease in the beta cell mass and rate of beta cell proliferation. Since normal beta cells do not die when induced to increase insulin synthesis, our observations indicate that insulin cells expressing an inducible RIPCre transgene are functionally deficient. Studies employing these mice should carefully consider the pitfalls of the Cre-Lox technique. PMID- 25533473 TI - Polo-like kinase 1-mediated phosphorylation of Forkhead box protein M1b antagonizes its SUMOylation and facilitates its mitotic function. AB - Transcription factor Forkhead box protein M1b (FoxM1b) plays an important role during mitotic entry and progression. Our previous studies identified polo-like kinase 1 (PLK1) as a major regulator of FoxM1b. During G2/M transition, PLK1 directly interacts with and phosphorylates FoxM1b, resulting in full activation of the transactivation capacity of FoxM1b. Such a vital regulatory mechanism is essential for timely mitotic entry and progression. However, the molecular mechanism by which PLK1-mediated phosphorylation enhances the transcriptional activity of FoxM1b remains to be determined. We demonstrate that FoxM1b can be SUMOylated in vitro and in vivo, preferentially by SUMO-1. SUMOylation of FoxM1b was found to occur at multiple sites, leading to suppression of FoxM1b transcriptional activity. Such a posttranslational modification of FoxM1b was antagonized by PLK1-mediated phosphorylation. By immunofluorescence staining and subcellular fractionation, we demonstrate that SUMO conjugation promotes cytosolic translocation of FoxM1b. Moreover, SUMO modification of FoxM1b facilitates the ubiquitin-mediated proteasomal degradation of FoxM1b. PLK1 mediated phosphorylation of FoxM1b abrogates the inhibitory effect on FoxM1b by SUMO modification, thereby promoting its nuclear translocation and preventing its proteolytic degradation in the cytoplasm. Such an antagonistic regulatory mechanism is essential for the mitotic function of FoxM1b, ensuring timely mitotic entry and progression. Taken together, our studies have revealed a working mechanism by which PLK1 positively regulates the activity and level of FoxM1b, which would greatly facilitate therapeutic interventions that focus on targeting the PLK1-mediated and/or FoxM1-mediated signaling network. PMID- 25533472 TI - Insulin regulates nitric oxide production in the kidney collecting duct cells. AB - The kidney is an important organ for arterial blood pressure (BP) maintenance. Reduced NO generation in the kidney is associated with hypertension in insulin resistance. NO is a critical regulator of vascular tone; however, whether insulin regulates NO production in the renal inner medullary collecting duct (IMCD), the segment with the greatest enzymatic activity for NO production in kidney, is not clear. Using an NO-sensitive 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF FM) fluorescent dye, we found that insulin increased NO production in mouse IMCD cells (mIMCD) in a time- and dose-dependent manner. A concomitant dose-dependent increase in the NO metabolite (NOx) was also observed in the medium from insulin stimulated cells. NO production peaked in mIMCD cells at a dose of 100 nm insulin with simultaneously increased NOx levels in the medium. At this dose, insulin significantly increased p-eNOS(Ser1177) levels in mIMCD cells. Pretreatment of cells with a PI 3-kinase inhibitor or insulin receptor silencing with RNA interference abolished these effects of insulin, whereas insulin-like growth factor-1 receptor (IGF-1R) silencing had no effect. We also showed that chronic insulin infusion to normal C57BL/6J mice resulted in increased endothelial NOS (eNOS) protein levels and NO production in the inner medulla. However, insulin infused IRKO mice, with targeted deletion of insulin receptor from tubule epithelial cells of the kidney, had ~50% reduced eNOS protein levels in their inner medulla along with a significant rise in BP relative to WT littermates. We have previously reported increased baseline BP and reduced urine NOx in IRKO mice. Thus, reduced insulin receptor signaling in IMCD could contribute to hypertension in the insulin-resistant state. PMID- 25533475 TI - Conformational dependence of through-space tellurium-tellurium spin-spin coupling in peri-substituted bis(tellurides). AB - Three related series of peri-substituted bis(tellurides) bearing naphthalene, acenaphthene and acenaphthylene backbones (Nap/Acenap/Aceyl(TeY)2 (Nap = naphthalene-1,8-diyl N; Acenap = acenaphthene-5,6-diyl A; Aceyl = acenaphthylene 5,6-diyl Ay; Y = Ph 1; Fp 2; Tol 3; An-p- 4; An-o- 5; Tp 6; Mes 7; Tip 8) have been synthesised and their solid-state structures determined by X-ray crystallography. Molecular conformations were classified as a function of the two C9-C-Te-C(Y) dihedral angles (theta); in the solid all members adopt AB or CCt configurations, with larger Te(aryl) moieties exclusively imposing the CCt variant. Exceptionally large J((125)Te,(125)Te) spin-spin coupling constants between 3289-3848 Hz were obtained for compounds substituted by bulky Te(aryl) groups, implying these species are locked in a CCt-type conformation. In contrast, compounds incorporating smaller Te(aryl) moieties are predicted to be rather dynamic in solution and afford much smaller J values (2050-2676 Hz), characteristic of greater populations of AB conformers with lower couplings. This conformational dependence of through-space coupling is supported by DFT calculations. PMID- 25533474 TI - RDH13L, an enzyme responsible for the aldehyde-alcohol redox coupling reaction (AL-OL coupling reaction) to supply 11-cis retinal in the carp cone retinoid cycle. AB - Cone photoreceptors require effective pigment regeneration mechanisms to maintain their sensitivity in the light. Our previous studies in carp cones suggested the presence of an unconventional and very effective mechanism to produce 11-cis retinal, the necessary component in pigment regeneration. In this reaction (aldehyde-alcohol redox coupling reaction, AL-OL coupling reaction), formation of 11-cis retinal, i.e. oxidation of 11-cis retinol is coupled to reduction of an aldehyde at a 1:1 molar ratio without exogenous NADP(H) which is usually required in this kind of reaction. Here, we identified carp retinol dehydrogenase 13-like (RDH13L) as an enzyme catalyzing the AL-OL coupling reaction. RDH13L was partially purified from purified carp cones, identified as a candidate protein, and its AL-OL coupling activity was confirmed using recombinant RDH13L. We further examined the substrate specificity, subcellular localization, and expression level of RDH13L. Based on these results, we concluded that RDH13L contributes to a significant part, but not all, of the AL-OL coupling activity in carp cones. RDH13L contained tightly bound NADP(+) which presumably functions as a cofactor in the reaction. Mouse RDH14, a mouse homolog of carp RDH13L, also showed the AL-OL coupling activity. Interestingly, although carp cone membranes, carp RDH13L and mouse RDH14 all showed the coupling activity at 15-37 degrees C, they also showed a conventional NADP(+)-dependent 11-cis retinol oxidation activity above 25 degrees C without addition of aldehydes. This dual mechanism of 11-cis retinal synthesis attained by carp RDH13L and mouse RDH14 probably contribute to effective pigment regeneration in cones that function in the light. PMID- 25533476 TI - Accuracy of electronic apex locators to detect root canal perforations with inserted metallic posts: an ex vivo study. AB - INTRODUCTION: The detection of possible root canal perforations caused during a metal post placement is frequently difficult to diagnose. The aim of this study was to investigate the accuracy of apex locators to diagnose such perforations. MATERIALS AND METHODS: Thirty mesiolingual root canals of extracted mandibular molars were instrumented (30/.04) and a post space was prepared. A root canal perforation was intentionally made at the bi-furcation (n = 15). Metal posts were cemented in 15 perforated and 15 non-perforated root canals. The teeth roots were embedded in an agar-agar solution. The resulting measurements ("short" or "beyond" the apex) disclosed if a perforation could be identified with five different apex locators (ProPex II, Elements Apex Locator, Apex NRG, Raypex 5 and Raypex 6). The sensitivity and specificity (95% interval confidence) were calculated. RESULTS: All devices excluded the absence of perforations (100% with 95% confidence interval [78%; 100%] specificity). The Apex NRG and Raypex 6 detected all perforations (100% with 95% confidence interval [78%; 100%] sensitivity). The ProPex II, Elements Apex Locator, and Raypex 5 detected 14 out of 15 perforations (93% with 95% confidence interval [68%; 100%] sensitivity). CONCLUSIONS: All devices determined root canal perforations, due to metallic posts, within clinical acceptable ranges. PMID- 25533477 TI - Comparisons of clinical symptoms in biomarker-confirmed Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia patients in a local memory clinic. AB - BACKGROUND: There has been no previous Chinese study that differentiated the clinical symptoms among biomarker-confirmed Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). The objective of this study was to compare the cognitive, behavioural, and neuropsychiatric symptoms in biomarker-confirmed AD, DLB, and FTD patients. METHODS: We recruited 30 patients (14 AD, 7 DLB, 9 FTD) who presented to the memory clinic at Queen Mary Hospital from 1 January 2007 to 31 December 2013. AD was diagnosed according to the National Institution of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria with cerebrospinal fluid biomarkers (tau, phosphorylated tau, and amyloid beta-42) fulfilling locally determined cut-off values for AD. DLB was diagnosed based on the McKeith diagnostic criteria. The behavioural variant of FTD was diagnosed based on the revised diagnostic criteria proposed by the International bvFTD Criteria Consortium, and language variant FTD was diagnosed based on the latest published criteria. In addition, patients with DLB and FTD had typical imaging features on single-photon emission computed tomography or (18) fludeoxyglucose positron emission tomography, either with or without Pittsburgh Compound B imaging, which supported their diagnoses. Data on patient characteristics including demographics, presenting clinical features, Mini-Mental State Examination, clinical dementia ratings, and neuropsychiatry inventory scores were collected. RESULTS: There were no differences in age, education level, dementia severity, and duration of symptoms before presentation among the three subgroups of patients. All patients had amnesia symptoms, which were not statistically significant. Apraxia was most common in AD. While 83% of the patients were affected by behavioural and neuropsychiatric symptoms of dementia, behavioural disinhibition and decline in executive function were most common in FTD patients. Recurrent hallucinations, fluctuation of consciousness, parkinsonism, and rapid eye movement sleep behaviour disorder were most common in DLB. CONCLUSION: Memory impairment and apathy are not useful discriminative symptoms in diagnosing AD, DLB, and FTD. Apraxia favours AD. Hallucinations, particularly well-formed visual hallucinations, favour DLB. Overall, behavioural and neuropsychiatric symptoms of dementia symptoms are common among the three groups of dementia patients. PMID- 25533478 TI - The AtLRK10L1.2, Arabidopsis ortholog of wheat LRK10, is involved in ABA-mediated signaling and drought resistance. AB - KEY MESSAGE: The loss-of-function mutants of the Arabidopsis orthologue of the wheat LRK10 gene shows ABA-insensitive and drought stress-sensitive phenotypes, suggesting that LRK10L1.2 is positively involved in ABA signaling. A subset of receptor-like kinases (RLKs) superfamily proteins play a key role in sensing internal and external signals. A gene encoding Arabidopsis thaliana Leaf rust 10 disease-resistance locus receptor-like protein kinase 1 (AtLRK10L1), most closely related to wheat LRK10, expresses two different transcripts, LRK10L1.1 and LRK10L1.2, using alternative promoters. The T-DNA insertion mutant, lrk10l1-2, that specifically shuts down LRK10L1.2 transcription displayed an abscisic acid (ABA)-insensitive phenotype in seed germination and seedling growth. However, the lrk10l1.2 mutant exhibited reduced tolerance to drought stress, compared with wild type, which is accompanied by alteration of stomatal apertures. The transgenic plants overexpressing full-length LRK10L1.2, which localizes to the plasma membrane (PM) complemented the phenotypes of lrk10l1-2 mutant background, while those expressing LRK10L1.2 Nu1, which switched its localization to the endoplasmic reticulum (ER) by skipping of a mini-exon, showed even higher ABA insensitivity and drought sensitivity than its mutant background. Our results suggest that ABA signaling involves the PM-localized LRK10L1.2. PMID- 25533480 TI - Factors affecting the use of single-fraction radiotherapy for the palliation of bone metastases in Australia. AB - AIMS: Palliative radiotherapy for bone metastases remains an important treatment in patients with metastatic malignancy. Previous studies have indicated a reluctance to adopt single-fraction treatment despite considerable evidence. This study aims to describe the factors determining the use of palliative radiotherapy in patients with bone metastases and assess whether fractionation patterns have changed over time with emerging evidence. MATERIALS AND METHODS: A retrospective review of radiotherapy databases at Liverpool/Macarthur Cancer Therapy Centre and the Royal Brisbane and Women's Hospital was conducted for the period 1997-2009. Patients receiving palliative radiotherapy for bony metastases were identified and treatment sites were grouped into 'spine', 'limb', 'multiple' or 'other'. Treatment courses were divided into single- or multiple-fraction treatments. The effects of socioeconomic and geographical factors on radiotherapy utilisation and fractionation were assessed. RESULTS: In total, 5683 patients were identified in the cohort; they received a total of 8211 bone treatments. The overall proportion of single-fraction radiotherapy was 29%, with significant variation over the study period (P < 0.001). Age under 70 years and spine or multiple treatment sites were all associated with lower usage of single-fraction radiotherapy on multivariate analysis. Prostate and lung primary sites were associated with higher usage of single-fraction treatment. The proportion of single-fraction treatment remained low (35%), even for patients who survived less than 22 days from their last treatment. Socioeconomic and geographical factors had little effect on the number of fractions used. CONCLUSIONS: The rate of single-fraction radiotherapy for bone metastases has remained low in two large Australian institutions, despite considerable evidence that single-fraction treatment provides equivalent pain relief to fractionated therapy. This trend towards fractionated treatment was largely maintained, even in patients with limited life expectancy. Further measures to increase the rate of single-fraction therapy are needed. PMID- 25533479 TI - Diet-induced unresolved ER stress hinders KRAS-driven lung tumorigenesis. AB - Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, we present surprising evidence for anti-proliferative action of high-calorie-diet (HCD) feeding on KRAS-driven lung tumors. Tumors of mice that commenced HCD feeding before tumor onset displayed defective unfolded protein response (UPR) and unresolved endoplasmic reticulum (ER) stress. Unresolved ER stress and reduced proliferation are reversed by chemical chaperone treatment. Whole-genome transcriptional analyses revealed FKBP10 as one of the most downregulated chaperones in tumors of the HCD-pre-tumor-onset group. FKBP10 downregulation dampens tumor growth in vitro and in vivo. Providing translational value to these results, we report that FKBP10 is expressed in human KRAS-positive and -negative lung cancers, but not in healthy parenchyma. Collectively, our data shed light on an unexpected anti-tumor action of HCD imposed before tumor onset and identify FKBP10 as a putative therapeutic target to selectively hinder lung cancer. PMID- 25533481 TI - Stoichiometry and phosphoisotypes of hippocampal AMPA-type glutamate receptor phosphorylation. AB - It has been proposed that the AMPAR phosphorylation regulates trafficking and channel activity, thereby playing an important role in synaptic plasticity. However, the actual stoichiometry of phosphorylation, information critical to understand the role of phosphorylation, is not known because of the lack of appropriate techniques for measurement. Here, using Phos-tag SDS-PAGE, we estimated the proportion of phosphorylated AMPAR subunit GluA1. The level of phosphorylated GluA1 at S831 and S845, two major sites implicated in AMPAR regulation, is almost negligible. Less than 1% of GluA1 is phosphorylated at S831 and less than 0.1% at S845. Considering the number of AMPAR at each synapse, the majority of synapses do not contain any phosphorylated AMPAR. Also, we did not see evidence of GluA1 dually phosphorylated at S831 and S845. Neuronal stimulation and learning increased phosphorylation, but the proportion was still low. Our results impel us to reconsider the mechanisms underlying synaptic plasticity. PMID- 25533482 TI - NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. AB - Abnormal NFkappaB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFkappaB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFkappaB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Abeta activates astroglial NFkappaB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFkappaB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial. PMID- 25533483 TI - Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on alpha-synuclein. AB - Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and alpha-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation. VIDEO ABSTRACT: PMID- 25533484 TI - Nanoscale distribution of presynaptic Ca(2+) channels and its impact on vesicular release during development. AB - Synaptic efficacy and precision are influenced by the coupling of voltage-gated Ca(2+) channels (VGCCs) to vesicles. But because the topography of VGCCs and their proximity to vesicles is unknown, a quantitative understanding of the determinants of vesicular release at nanometer scale is lacking. To investigate this, we combined freeze-fracture replica immunogold labeling of Cav2.1 channels, local [Ca(2+)] imaging, and patch pipette perfusion of EGTA at the calyx of Held. Between postnatal day 7 and 21, VGCCs formed variable sized clusters and vesicular release became less sensitive to EGTA, whereas fixed Ca(2+) buffer properties remained constant. Experimentally constrained reaction-diffusion simulations suggest that Ca(2+) sensors for vesicular release are located at the perimeter of VGCC clusters (<30 nm) and predict that VGCC number per cluster determines vesicular release probability without altering release time course. This "perimeter release model" provides a unifying framework accounting for developmental changes in both synaptic efficacy and time course. PMID- 25533485 TI - Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells. AB - Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (4-week-old) GCs can efficiently drive distal CA3 targets but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition toward maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus. PMID- 25533488 TI - Discovery of substrates for a SET domain lysine methyltransferase predicted by multistate computational protein design. AB - Characterization of lysine methylation has proven challenging despite its importance in biological processes such as gene transcription, protein turnover, and cytoskeletal organization. In contrast to other key posttranslational modifications, current proteomics techniques have thus far shown limited success at characterizing methyl-lysine residues across the cellular landscape. To complement current biochemical characterization methods, we developed a multistate computational protein design procedure to probe the substrate specificity of the protein lysine methyltransferase SMYD2. Modeling of substrate bound SMYD2 identified residues important for substrate recognition and predicted amino acids necessary for methylation. Peptide- and protein- based substrate libraries confirmed that SMYD2 activity is dictated by the motif [LFM]-1-K(*) [AFYMSHRK]+1-[LYK]+2 around the target lysine K(*). Comprehensive motif-based searches and mutational analysis further established four additional substrates of SMYD2. Our methodology paves the way to systematically predict and validate posttranslational modification sites while simultaneously pairing them with their associated enzymes. PMID- 25533486 TI - Near-atomic resolution for one state of F-actin. AB - Actin functions as a helical polymer, F-actin, but attempts to build an atomic model for this filament have been hampered by the fact that the filament cannot be crystallized and by structural heterogeneity. We have used a direct electron detector, cryo-electron microscopy, and the forces imposed on actin filaments in thin films to reconstruct one state of the filament at 4.7 A resolution, which allows for building a reliable pseudo-atomic model of F-actin. We also report a different state of the filament where actin protomers adopt a conformation observed in the crystal structure of the G-actin-profilin complex with an open ATP-binding cleft. Comparison of the two structural states provides insights into ATP-hydrolysis and filament dynamics. The atomic model provides a framework for understanding why every buried residue in actin has been under intense selective pressure. PMID- 25533487 TI - Structural biochemistry of a fungal LOV domain photoreceptor reveals an evolutionarily conserved pathway integrating light and oxidative stress. AB - Fungal LOV proteins facilitate photoadaptation via blue light regulation of dimer formation. Despite considerable homology of these proteins in closely related fungi, deviations in signaling exist. Here we report the crystal structure of ENVOY (ENV1), a homolog of N. crassa VVD in the fungus T. reesei, a model organism for plant cell wall degradation. Structural studies contradict a model of reversible competitive dimerization. Rather, evolutionary pressures have facilitated a two-residue shift in the position of a key Cys residue (Cys96) that enables the integration of environmental stress and light responses. A Cys96Thr variant abolishes adaptive responses to light and oxidative stress in a carbon source-dependent manner in vivo. Phylogenetic analysis verifies an evolutionary relevance of the Cys residue shift in different orders within Sordariomycetes. In this manner, we identified a widespread oxidative stress signaling mechanism that couples metabolic sensing and blue light responses not previously identified in LOV proteins. PMID- 25533489 TI - Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC. AB - Binding of the chromatin remodeling complex NoRC to RNA complementary to the rDNA promoter mediates transcriptional repression. TIP5, the largest subunit of NoRC, is involved in recruitment to rDNA by interactions with promoter-bound TTF-I, pRNA, and acetylation of H4K16. TIP5 domains that recognize posttranslational modifications on histones are essential for recruitment of NoRC to chromatin, but how these reader modules recognize site-specific histone tails has remained elusive. Here, we report crystal structures of PHD zinc finger and bromodomains from human TIP5 and BAZ2B in free form and bound to H3 and/or H4 histones. PHD finger functions as an independent structural module in recognizing unmodified H3 histone tails, and the bromodomain prefers H3 and H4 acetylation marks followed by a key basic residue, KacXXR. Further low-resolution analyses of PHD bromodomain modules provide molecular insights into their trans histone tail recognition, required for nucleosome recruitment and transcriptional repression of the NoRC complex. PMID- 25533490 TI - The modular structure of the inner-membrane ring component PrgK facilitates assembly of the type III secretion system basal body. AB - The type III secretion system (T3SS) is a large macromolecular assembly found at the surface of many pathogenic Gram-negative bacteria. Its role is to inject toxic "effector" proteins into the cells of infected organisms. The molecular details of the assembly of this large, multimembrane-spanning complex remain poorly understood. Here, we report structural, biochemical, and functional analyses of PrgK, an inner-membrane component of the prototypical Salmonella typhimurium T3SS. We have obtained the atomic structures of the two ring building globular domains and show that the C-terminal transmembrane helix is not essential for assembly and secretion. We also demonstrate that structural rearrangement of the two PrgK globular domains, driven by an interconnecting linker region, may promote oligomerization into ring structures. Finally, we used electron microscopy-guided symmetry modeling to propose a structural model for the intimately associated PrgH-PrgK ring interaction within the assembled basal body. PMID- 25533492 TI - Host genetics shapes adult sepsis survival. PMID- 25533493 TI - Evaluating the Referring Physician's Clinical History and Indication as a Means for Communicating Chronic Conditions That Are Pertinent at the Point of Radiologic Interpretation. AB - The clinical history and indication (CHI) provided with a radiological examination are critical components of a quality interpretation by the radiologist. A patient's chronic conditions offer the context in which acute symptoms and findings can be interpreted more accurately. Seven pertinent (potentially diagnosis altering) chronic conditions, which are fairly prevalent at our institution, were selected. We analyze if and how in 140 CHIs there was mention of a patient's previously reported chronic condition and if and how the condition was subsequently described in the radiology report using a four-item scheme (Mention/Specialization, Generalization, Common comorbidity, No mention). In 40.7% of CHIs, the condition was rated Mention/Specialization. Therefore, we reject our first hypothesis that the CHI is a reliable source for obtaining pertinent chronic conditions (>= 90.0%). Non-oncological conditions were significantly more likely rated No mention in the CHI than oncological conditions (58.7 versus 8.3%, P < 0.0001). Stat cases were significantly more frequently No mention than non-stat cases (60.0 versus 31.3%, P = 0.0134). We accept our second hypothesis that the condition's rating in the CHI is significantly correlated with its rating of the final radiology report (chi(2) test, P < 0.00001). Our study demonstrates an alarming lack of communication of pertinent medical information to the radiologist, which may negatively impact interpretation quality. Presenting automatically aggregated patient information to the radiologist may be a potential avenue for improving interpretation and adding value of the radiology department to the care chain. PMID- 25533491 TI - Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. AB - BACKGROUND: Sepsis continues to be a major cause of death, disability, and health care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9.7 * 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5.6 * 10(-8) (odds ratio 0.56, 95% CI 0.45 0.69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0.56, 95% CI 0.45-0.69; likelihood ratio test p=3.4 * 10(-9), after adjustment for age and stratification by cohort). Mortality was 9.5% in patients carrying the CC genotype, 15.2% in those carrying the TC genotype, and 25.3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust. PMID- 25533494 TI - Unsupervised Segmentation of Head Tissues from Multi-modal MR Images for EEG Source Localization. AB - In this paper, we present and evaluate an automatic unsupervised segmentation method, hierarchical segmentation approach (HSA)-Bayesian-based adaptive mean shift (BAMS), for use in the construction of a patient-specific head conductivity model for electroencephalography (EEG) source localization. It is based on a HSA and BAMS for segmenting the tissues from multi-modal magnetic resonance (MR) head images. The evaluation of the proposed method was done both directly in terms of segmentation accuracy and indirectly in terms of source localization accuracy. The direct evaluation was performed relative to a commonly used reference method brain extraction tool (BET)-FMRIB's automated segmentation tool (FAST) and four variants of the HSA using both synthetic data and real data from ten subjects. The synthetic data includes multiple realizations of four different noise levels and several realizations of typical noise with a 20% bias field level. The Dice index and Hausdorff distance were used to measure the segmentation accuracy. The indirect evaluation was performed relative to the reference method BET-FAST using synthetic two-dimensional (2D) multimodal magnetic resonance (MR) data with 3% noise and synthetic EEG (generated for a prescribed source). The source localization accuracy was determined in terms of localization error and relative error of potential. The experimental results demonstrate the efficacy of HSA BAMS, its robustness to noise and the bias field, and that it provides better segmentation accuracy than the reference method and variants of the HSA. They also show that it leads to a more accurate localization accuracy than the commonly used reference method and suggest that it has potential as a surrogate for expert manual segmentation for the EEG source localization problem. PMID- 25533495 TI - Percutaneous cryoablation for a symptomatic non-ossifying fibroma. A case report. PMID- 25533496 TI - Liver iron overload assessment by MRI R2* relaxometry in highly transfused pediatric patients: an agreement and reproducibility study. AB - AIMS: Perform an agreement and reproducibility study of the estimation of iron overload in highly transfused pediatric patients comparing R2* relaxometry (R2*=1000/T2*) to the reference technique liver/muscle signal intensity ratio (SIR). PATIENTS AND METHODS: Ninety-two MRI were performed in 68 children who were mainly transfused for sickle cell disease, mean age 9.9 years old. The examination included six sequences for the SIR protocol and a single multiecho T2* sequence. R2* relaxometry was measured by two radiologists independently, either by a region of interest (ROI) in the right liver, or an outline of the whole liver. Hepatic iron load was determined by the Wood formula (Fe mg/g=R2**0.0254+0.202). The validity of R2* relaxometry compared to SIR was evaluated by the coefficient of variation and the quadratic weighted Kappa value. RESULTS: The correlation between R2* relaxometry and SIR was very good with a Pearson coefficient of 0.89 and a coefficient of variation of 17.3%. The inter- and intraobserver reproducibility of the measurement of R2* relaxometry by ROI and whole liver mapping was excellent. However, we observed a common positive variation of one class between SIR and R2* relaxometry, with higher hepatic iron content values with SIR than with R2* relaxometry. CONCLUSION: Hepatic iron content can be rapidly and precisely estimated on MRI by multiecho gradient-echo sequences. PMID- 25533497 TI - A spindle cell sarcoma of liver supplied by internal mammary artery. PMID- 25533498 TI - "Bones in Silenz": A new T1-weighted SILENZ sequence evaluating the bone in MRI. PMID- 25533499 TI - Aggressive angiomyxoma of the pelvis with inferior vena cava involvement: MR imaging features. PMID- 25533500 TI - Relationship between certain T helper cytokines and ANA staining: who is the helper? AB - OBJECTIVE: This study investigated some T helper cytokines' association with different ANA positive sera. METHODS: Sera of 53 ANA-positive subjects (11 were stained of homogeneous pattern, 12 of speckled particle pattern, 9 of nucleolar pattern, 15 of centromere pattern, and 6 of the peripheral nuclear type) were collected and analyzed by ELISA for related cytokines and concentrations were compared with each other and 16 healthy donors. RESULTS: Investigated cytokines including IL-12(p70) and IFN-gamma varied differently in the ANA sera. CONCLUSION: This study demonstrated that some T helper cytokines varied with different ANA-positive sera, suggesting that they may play different roles in related autoimmune diseases. PMID- 25533501 TI - The comparison of BLyS-binding peptides from phage display library and computer aided design on BLyS-TACI interaction. AB - BLyS antagonists have become the therapeutic reagents in the treatment of autoimmune disorders. BLyS binding peptides and their Fc fusion proteins may be alternative BLyS antagonists in such application. In this study, the activity of BLyS binding peptide 814 obtained from phage display library and peptide TA designed by computer-aided modeling on the interaction of BLyS-TACI was compared. In addition, to maintain the spatial conformation and stability of the peptides, human IgG1 Fc fragment was fused to peptides 814 and TA to form peptide-Fc fusion proteins, steady and innovative peptibodies. The prokaryotic expression plasmids pET30a-814-Fc and pET30a-TA-Fc for these peptibodies were acquired by genetic engineering, and confirmed by DNA sequencing. After the right plasmids were transformed into Escherichia coli BL21 (DE3), the fusion proteins were expressed and purified by protein A affinity column. As a result of competitive ELISA, peptides 814 and TA at 100MUg/ml displayed 52.2% and 28.6% inhibition on the interaction of TACI-Fc with BLyS respectively. Moreover, 814-Fc and TA-Fc fusion proteins could bind to BLyS in a dosage-dependent manner as TACI-Fc did, and displayed 54.7% and 26.1% inhibition on the interaction of TACI-Fc-Myc with BLyS at 100MUg/ml respectively. So 814-Fc and TA-Fc proteins had the similar bioactivity as the peptides did. Furthermore, compared with TA-Fc, 814-Fc showed two-fold inhibition effect on BLyS binding to TACI, suggesting that 814-Fc could inhibit BLyS bioactivity significantly and might serve as a potential antagonist to treat autoimmune diseases associated with BLyS overexpression. PMID- 25533502 TI - Butein suppresses ICAM-1 expression through the inhibition of IkappaBalpha and c Jun phosphorylation in TNF-alpha- and PMA-treated HUVECs. AB - Butein (3,4,2',4'-tetrahydroxychalcone), a flavonoid derivative, has been reported to show several biological actions, including anti-inflammatory and anti cancer. However, the possible molecular mechanisms involved are poorly understood. Treatment of human umbilical vein endothelial cells (HUVECs) with butein significantly inhibited cell surface intercellular adhesion molecule-1 (ICAM-1) expression, ICAM-1 protein synthesis, and mRNA expression induced by tumor necrotic factor-alpha (TNF-alpha) and/or phorbol 12-myristate 13-acetate (PMA). Electrophoretic mobility shift assay revealed that butein blocked activation of transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), induced by TNF-alpha and PMA. Moreover, butein abolished TNF-alpha- and PMA-induced IkappaBalpha phosphorylation, which participates in NF-kappaB activation, and PMA-induced phosphorylation of c-Jun, a subunit composed of AP-1. In vitro, butein inhibited the phosphorylation of c Jun, binding to GST beads, mediated by JNK isolated from PMA-treated cells. The inhibitory action of butein on the JNK-mediated in vitro c-Jun phosphorylation was abrogated in the presence of ATP. These results indicate that in HUVECs, butein suppresses the expression of ICAM-1 mRNA and protein through the inhibition of the activation of NF-kappaB and AP-1 induced by TNF-alpha and PMA, that the inhibitory action of butein on NF-kappaB activation results from the inhibition of IkappaBalpha phosphorylation by IkappaB kinase (IKK), and that the inactivation of PMA-activated AP-1 by butein is due to the blocking of JNK mediated c-Jun phosphorylation through the inhibition of ATP binding. PMID- 25533503 TI - Carbocisteine attenuates hydrogen peroxide-induced inflammatory injury in A549 cells via NF-kappaB and ERK1/2 MAPK pathways. AB - Carbocisteine is a mucolytic drug with anti-oxidative effect, we had previously proved that carbocisteine remarkably reduced the rate of acute exacerbations and improved the quality of life in patients with chronic obstructive pulmonary disease (COPD), however, very little is known about its mechanisms. In this study, we aimed to investigate the anti-inflammatory effects of carbocisteine against hydrogen peroxide (H2O2). A549 cells were cultured in vitro and treated with H2O2 as damaged cell models, carbocisteine was administered 24h prior to or after H2O2 exposure, and the protective effects of carbocisteine were determined by MTT, qRT-PCR, ELISA, western blot and immunofluorescence assays. The results showed that carbocisteine could increase cell viability and decrease LDH, IL-6 and IL-8 levels in the supernatant. Additionally, carbocisteine decreased IL-6, IL-8, TNF-alpha, IP-10 and MIP-1beta mRNA in a dose-dependent manner. Moreover, carbocisteine could attenuate phosphorylation of NF-kappaB p65 and ERK1/2 and inhibit the nuclear translocation of pNF-kappaB p65 induced by H2O2. In conclusion, carbocisteine inhibited H2O2-induced inflammatory injury in A549 cells, NF-kappaB and ERK1/2 MAPK were the target pathways. PMID- 25533504 TI - A novel pentapeptide originated from calf thymus named TIPP shows an inhibitory effect on lung allergic inflammation. AB - Thymic immunosuppressive pentapeptide (TIPP) is a novel pentapeptide originally obtained from calf thymic immunosuppressive extract. In this study we aimed to investigate the anti-inflammatory effect and mechanisms of TIPP in vivo with an ovalbumin-induced mouse allergic asthma model. We investigated the effects of TIPP on the infiltration of inflammation cells, immune cell subtypes, Th2 cytokines in BALF and IgE in serum, mRNA levels of IL-4, IL-10, TNF-alpha and eotaxin-1, expression of MCP-1, VCAM-1 and COX-2, and activation of MAP kinases and NF-kappaB. Our results showed that TIPP significantly inhibited the increase in Th2 cytokines and OVA-specific IgE production, mRNA levels of IL-4, TNF-alpha and eotaxin-1 and the expression of MCP-1, VCAM-1 and COX-2 in lung tissues, as well effectively resisting the balance changes of cells in BALF. In addition, it was found that the administration of TIPP attenuated the activation of MAP kinases and NF-kappaB in the lung tissues of the allergic mice. Our data suggest that TIPP effectively suppresses the allergic and inflammatory responses in allergic mice via blocking MAP kinases/NF-kappaB signalling pathway. The investigation indicated that TIPP may become an anti-allergic and anti inflammatory drug. PMID- 25533505 TI - Protective effects of Acanthopanax vs. Ulinastatin against severe acute pancreatitis-induced brain injury in rats. AB - OBJECTIVES: To observe the protecting effects of Acanthopanax and Ulinastatin against severe acute pancreatitis (SAP)-induced brain injury in rats. METHODS: SAP-modeled rats were equally randomized into three groups: model group, Acanthopanax-treated group and Ulinastatin-treated group. A sham-operation group was used as negative control. Serum tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 levels were assayed by enzyme linked immunosorbent assay (ELISA). Nuclear factor kappa B p65 (NF-kappaB p65) activity in the brain tissue was determined by immunohistochemistry. The mortality, pathological changes of the pancreas and brain, and expression of TNF-alpha mRNA, IL-6 mRNA and IL-10 mRNA in the brain tissue were observed at 6, 12 and 24h after operations in all groups. RESULTS: The mortality of the model group was significantly higher than that of both treatment groups at 24h (P<0.01). Serum levels of TNF-alpha and IL-6, activity of NF-kappaB p65, expression levels of TNF alpha and IL-6 mRNA in the brain tissue, and the pathological scores of the pancreas and brain in the two treatment groups were lower than those in the model group at 12 and 24h after operation (P<0.01), while serum IL-10 and IL-10 mRNA expression levels of the brain tissue in the two treatment groups were higher. There was no significant difference in all indexes between Acanthopanax and Ulinastatin groups at all designated time points (P>0.05). CONCLUSIONS: Acanthopanax and Ulinastatin have similar protecting effects against SAP-induced brain injury in rats. PMID- 25533506 TI - Imaging Optimization of Temporal Bones With Cochlear Implant Using a High resolution Cone Beam CT and the Corresponding Effective Dose. AB - OBJECTIVE: To evaluate the impact of tube voltage, tube current, pulse number, and magnification factor on the image quality of a novel experimental set-up and the corresponding radiation. MATERIALS AND METHODS: Six human temporal bones with cochlear implant were imaged using various tube voltages, tube currents, pulse numbers, and magnification. The effect of radiation was evaluated using a metaloxide semiconductor field-effect transistor (MOSFET) dosimeter device on an anthropomorphic RANDO RAN102 male head phantom. A copper and aluminum combination filter was used for hardware filtration. RESULTS: Overall, 900 frames, 11 mA, and 88 kV provided the best image quality. In temporal bones imaged with the optimized parameters, the cochlea, osseous spiral lamina, modiolus, stapes, round window niche, and oval window landmarks were demonstrated with anatomic structures still fully assessable in all parts and acceptable image quality. The most dominant contributor to the effective dose was bone marrow (36%-37 %) followed by brain (34%-36%), remainder tissues (12%), extra-thoracic airways (7%), and oral mucosa (5%). CONCLUSIONS: By increasing the number of frames, the image quality of the inner ear details obtained using the novel cone-beam computed tomography improved. PMID- 25533507 TI - Safety of outpatient airway dilation for adult laryngotracheal stenosis. AB - OBJECTIVES: To evaluate the safety of outpatient airway dilation for adult patients with subglottic or tracheal stenosis. METHODS: The records of patients treated with airway dilation between October 2003 and September 2013 were reviewed. Outcomes of patients who underwent dilation as inpatients versus outpatients were compared. Emergency room visits, readmissions, and 3 or more primary care physician visits within 30 days postoperatively were specifically evaluated. Postoperative hemorrhage, airway edema, recurrent laryngeal nerve paralysis, reintubation, tracheostomy, tracheal rupture, pneumomediastinum, pneumothorax, acute respiratory distress, or death were also reviewed. RESULTS: One hundred fourteen dilations performed in 53 patients with airway stenosis were included. Outpatient dilation was performed in 93 (82%); 21 (18%) underwent the procedure in the inpatient setting. Complications were low among both inpatient and outpatient groups (10% vs 1%, P=.09). No complications occurred during the overnight stay of the inpatient group. CONCLUSIONS: Outpatient airway dilation is a safe and feasible procedure. It can be routinely performed on an ambulatory basis. PMID- 25533508 TI - Healing septal perforations by secondary intention using acellular dermis as a bioscaffold. AB - OBJECTIVE: Several techniques are described in the literature for nasal septal perforation repair. Most of these involve interposition grafts in conjunction with local pedicled mucosal flaps. The following article describes our experience using acellular dermis as a bioscaffold to support the regrowth of nasal septal mucosa by secondary intention. METHODS: Retrospective chart review of all patients who underwent repair of nasal septal perforations by the senior author using acellular dermis placed between the 2 sides of the perforation and covered with silastic splints to allow for mucosalization. RESULTS: Thirteen patients underwent nasal septal perforation repair using this technique. All perforations repaired were under 2 cm in greatest dimension. Two-thirds of patients had complete closure of the perforation upon initial use of bioscaffolding technique. The remaining third achieved near-total closure with bioscaffolding technique and were able to be completely closed with a single additional procedure. CONCLUSIONS: Acellular dermis offers an alternative to most currently described complex flaps. The method can be used in patients with defects less than 2 cm, but initial data suggest caution when using in those with wound healing impediments. This technique is also an excellent choice for patients with multiple small septal perforations. PMID- 25533509 TI - Clinical characteristics of patients with abnormal ocular/cervical vestibular evoked myogenic potentials in the presence of normal caloric responses. AB - OBJECTIVE: To investigate the clinical features and vestibular symptoms of patients with abnormal ocular vestibular evoked myogenic potentials (oVEMPs) and/or cervical VEMPs (cVEMPs) in the presence of normal caloric responses. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. METHODS: One thousand five hundred twenty-one consecutive patients with balance problems who underwent the caloric, cVEMP, and oVEMP tests were included, and patients who showed abnormal oVEMPs and/or cVEMPs in the presence of normal caloric responses were selected. Clinical characteristics, diagnoses, and vestibular symptoms of the patients were analyzed. RESULTS: Of the 1521 patients, 227 (15%) were found to have abnormal oVEMPs and/or cVEMP responses with normal caloric responses. Benign paroxysmal positional vertigo (BBPV), Meniere's disease, and vestibular migraine were the common diagnoses of these patients. Eighty-one patients (36%) could not be diagnosed with a recognizable disease. Multiple episodes of spinning vertigo with a duration of seconds to hours were their most common vestibular symptoms. CONCLUSION: BPPV, Meniere's disease, and vestibular migraine are the most frequent diagnoses showing abnormal oVEMP and/or cVEMPs without canal paresis. Apart from these clinical entities, a portion of undiagnosed patients with multiple episodes of vertigo might have a disease that involves the otolith organs only. PMID- 25533510 TI - Introduction to the special issue of the journal of bioenergetics and biomembranes: "mitochondrial lipids: essential roles in physiology and disease.". PMID- 25533512 TI - Distribution characteristics of meridian sinew (jingjin) syndrome in 313 cases of whiplash-associated disorders. AB - OBJECTIVE: To investigate and analyze the characteristics of Meridian Sinew (Jingjin) syndrome in patients with whiplash-associated disorders (WAD). METHODS: From August 2010 to September 2011, 313 WAD cases from New York and California states were collected. The survey mostly collects the information of "Sinew Knotted Points" and symptoms of four types of Meridian Sinew differentiation Taiyang, Shaoyin, Shaoyang and Yangming. RESULTS: Among the cases which are on the average of medium injury level, the higher frequency of "Sinew Knotted Points" tenderness were found on Jianwaishu (SI 14), Jianzhongshu (SI 15), Tianchuang (SI 16), C3-6 Spinous Process, Dazhui (GV 14), Fengchi (GB 20), Tianliao (SJ 15) and Tianding (LI 17). The most commonly presented symptoms were widespread spasm and tenderness in the neck (Taiyang), difficulty in lateral flexion (Shaoyang), problems of extension and flexion (Taiyang), and stiffness and pain during neck movement (Yangming). Among the cases, 237 cases (75.72%) were related to Taiyang Meridian Sinew syndrome, 82 cases (26.20%) to Shaoyin syndrome and 175 (55.91%) and 176 (56.23%) cases to Shaoyang and Yangming syndrome respectively. The most of cases presented in a combination format. The syndrome distribution under Grade I, II and III reflected that more combination of the Meridian Sinew syndromes in the whiplash injury patients which is resulted from more severity of injury. CONCLUSION: It is practical to identify the location of abnormality through Meridian Sinew differentiation, considering both "Sinew Knotted Points" tenderness and corresponding symptoms, for the local neck symptoms of WAD. PMID- 25533511 TI - Pro-angiogenic activity of notoginsenoside R1 in human umbilical vein endothelial cells in vitro and in a chemical-induced blood vessel loss model of zebrafish in vivo. AB - OBJECTIVE: This study aimed at investigating whether notoginsenoside R1 (R1), a unique saponin found in Panax notoginseng could promote angiogenic activity on human umbilical vein endothelial cells (HUVECs) and elucidate their potential molecular mechanisms. In addition, vascular restorative activities of R1 was assessed in a chemically-induced blood vessel loss model in zebrafish. METHODS: The in vitro angiogenic effect of R1 was compared with other previously reported angiogenic saponins Rg1 and Re. The HUVECs proliferation in the presence of R1 was determined by cell proliferation kit II (XTT) assay. R1, Rg1 and Re-induced HUVECs invasion across polycarbonate membrane was stained with Hoechst-33342 and quantified microscopically. Tube formation assay using matrigelcoated wells was performed to evaluate the pro-angiogenic actions of R1. In order to understand the mechanism underlying the pro-angiogenic effect, various pathway inhibitors such as SU5416, wortmannin (wort) or L-Nomega-nitro- L-arginine methyl ester hydrochloride (L-NAME), SH-6 were used to probe the possible involvement of signaling pathway in the R1 mediated HUVECs proliferation. In in vivo assays, zebrafish embryos at 21 hpf were pre-treated with vascular endothelial growth factor (VEGF) receptor kinase inhibitor II (VRI) for 3 h only and subsequently post-treated with R1 for 48 h, respectively. The intersegmental vessels (ISVs) in zebrafish were assessed for the restorative effect of R1 on defective blood vessels. RESULTS: R1 could stimulate the proliferation of HUVECs. In the chemoinvasion assay, R1 significantly increased the number of cross-membrane HUVECs. In addition, R1 markedly enhanced the tube formation ability of HUVECs. The proliferative effects of these saponins on HUVECs were effectively blocked by the addition of SU5416 (a VEGF-KDR/Flk-1 inhibitor). Similarly, pre-treatment with wort [a phosphatidylinositol 3-kinase (PI3K)-kinase inhibitor], L-NAME [an endothelial nitric oxide synthase (eNOS) inhibitor] or SH-6 (an Akt pathway inhibitor) significantly abrogated the R1 induced proliferation of HUVECs. In chemicallyinduced blood vessel loss model in zebrafish, R1 significantly rescue the damaged ISVs. CONCLUSION: R1, similar to Rg1 and Re, had been showed pro angiogenic action, possibly via the activation of the VEGF-KDR/Flk-1 and PI3K-Akt eNOS signaling pathways. Our findings also shed light on intriguing pro angiogenic effect of R1 under deficient angiogenesis condition in a pharmacologic induced blood vessels loss model in zebrafish. The present study in vivo and in vitro provided scientific evidence to explain the ethnomedical use of Panax notoginseng in the treatment of cardiovascular diseases, traumatic injuries and wound healing. PMID- 25533513 TI - Genome-wide association study on susceptibility genes associated with yang deficiency constitution: A small sample case-control study. AB - OBJECTIVE: To explore susceptibility genes associated with yang-deficiency constitution using single nucleotide polymorphism (SNP) genotyping. METHODS: Based on an epidemiological survey, 30 volunteers with yang-deficiency constitution and 30 volunteers with a balanced constitution were included according to the Classification and Determination Standards of Constitutions in Traditional Chinese Medicine. Peripheral blood was collected and DNA was extracted from white blood cells. A genome-wide association study (GWAS) was conducted by SNP 6.0 genotyping at the Beijing CapitalBio Corporation Ltd. A minimum association P-value (Fisher's exact value) of less than 10(-4) in the allele, genotype, dominant, and recessive models served as the standard for significant association of SNP with yang-deficiency constitution. RESULTS: Among the four genetic models, a total of 42 SNPs were significantly associated with yang-deficiency constitution (Fisher's exact P-values P<10(-4)). These SNPs were adjacent to more than 20 genes, including RGS6, mGluR5, GAPDHL19, and IKZF1. CONCLUSION: Yang-deficiency constitution exhibits the characteristics of polygenic inheritance. This pilot study suggests that the polymorphisms in RGS6, mGluR5, GAPDHL19, and IKZF1 are associated with changes in cyclic adenosine monophosphate and cyclic guanosine monophosphate levels, memory, metabolic energy status, and immune function, respectively in people with yang-deficiency constitution. PMID- 25533515 TI - Feasibility and reproducibility of measurement of whole muscle blood flow, oxygen extraction, and VO2 with dynamic exercise using MRI. AB - PURPOSE: Develop an MRI method to estimate skeletal muscle oxygen consumption (VO2 ) with dynamic exercise using simultaneous measurement of venous blood flow (VBF) and venous oxygen saturation (SvO2 ). METHODS: Real-time imaging of femoral VBF using a complex-difference method was interleaved with imaging of venous hemoglobin oxygen saturation (SvO2 ) using magnetic susceptometry to estimate muscle VO2 (Fick principle). Nine healthy subjects performed repeated 5-watt knee extension (quadriceps) exercise within the bore of a 1.5 Tesla MRI scanner, for test/re-test comparison. VBF, SvO2 , and derived VO2 were estimated at baseline and immediately (<1 s) postexercise and every 2.4 s for 4 min. RESULTS: Quadriceps muscle mass was 2.43 +/- 0.31 kg. Mean baseline values were VBF = 0.13 +/- 0.06 L/min/kg, SvO2 = 69.4 +/- 10.1%, and VO2 = 6.8 +/- 4.1 mL/min/kg. VBF, SvO2 , and VO2 values from peak exercise had good agreement between trials (VBF = 0.9 +/- 0.1 versus 1.0 +/- 0.1 L/min/kg, R(2) = 0.83, CV = 7.6%; SvO2 = 43.2 +/- 13.5 versus 40.9 +/- 13.1%, R(2) = 0.88, CV = 15.6%; VO2 = 95.7 +/- 18.0 versus 108.9 +/- 17.3 mL/min/kg, R(2) = 0.88, CV = 12.3%), as did the VO2 recovery time constant (26.1 +/- 3.5 versus 26.0 +/- 4.0 s, R(2) = 0.85, CV = 6.0%). CV = coefficient of variation. CONCLUSION: Rapid imaging of VBF and SvO2 for the estimation of whole muscle VO2 is compatible with dynamic exercise for the estimation of peak values and recovery dynamics following exercise with good reproducibility. PMID- 25533516 TI - Electro-optical detection of single lambda-DNA. AB - Single lambda-DNA molecules are detected on a nanopore-gated optofluidic chip electrically and optically. Statistical variations in the single particle trajectories are used to predict the intensity distribution of the fluorescence signals. PMID- 25533517 TI - Protective effect of two yeast based feed additives on pigs chronically exposed to deoxynivalenol and zearalenone. AB - To evaluate the effects of the mycotoxins deoxynivalenol (DON) and zearalenone (ZEA) on pigs and the benefits of two mycotoxin mitigation strategies, gilts (n = 84, 9.1 +/- 0.1 kg) were allotted to four treatments: CON (control); MT (4.8 mg/kg feed DON and 0.3 mg/kg feed ZEA); MT-YC (MT + 2 g/kg of yeast cell wall product); and MT-YF (MT + 2 g/kg of yeast fermentation product). After 42 days of feeding, pigs fed MT had reduced (p < 0.05) growth performance compared with pigs fed CON. Pigs fed MT-YF had greater (p < 0.05) average daily gain and tended to have greater (p = 0.080) average daily feed intake than MT, whereas pigs fed MT YC did not differ from MT. Oxidative DNA damage increased (p < 0.05) in MT, whereas pigs fed MT-YF tended to have lower (p = 0.067) oxidative stress. Liver hydropic degeneration was increased (p < 0.05) in MT in contrast to CON and MT YF, and tended to be greater (p = 0.079) than MT-YC. Collectively, feeding diets contaminated with mycotoxins significantly reduced growth performance and impacted pig health. The yeast additives had varied ability to reduce mycotoxin effects on pig growth and health, but may still play a beneficial role in reducing the overall impacts of a mycotoxin challenge on pigs. PMID- 25533519 TI - Staphylococcal enterotoxin H induced apoptosis of bovine mammary epithelial cells in vitro. AB - Staphylococcal enterotoxins (SEs) are powerful superantigenic toxins produced by Staphylococcus aureus (S. aureus). They can cause food poisoning and toxic shock. However, their impact on bovine mammary epithelial cells (bMECs) is still unknown. In this study, the distribution of SE genes was evaluated in 116 S. aureus isolates from bovine mastitis, and the most prevalent genes were seh (36.2%), followed by sei (12.1%), seg (11.2%), ser (4.3%), sec (3.4%), sea (2.6%) and sed (1.7%). To better understand the effect of staphylococcal enterotoxin H (SEH) on bMECs, the seh gene was cloned and inserted into the prokaryotic expression vector, pET28a, and transformed into Escherichia coli BL21 (DE3). The recombinant staphylococcal enterotoxin H (rSEH) was expressed and purified as soluble protein. Bioactivity analysis showed that rSEH possessed the activity of stimulating lymphocytes proliferation. The XTT assay showed that 100 MUg/mL of rSEH produced the cytotoxic effect on bMECs, and fluorescence microscopy and flow cytometry analysis revealed that a certain dose of rSEH is effective at inducing bMECs apoptosis in vitro. This indicates that SEs can directly lead to cellular apoptosis of bMECs in bovine mastitis associated with S. aureus. PMID- 25533520 TI - Indole alkaloids from Fischerella inhibit vertebrate development in the zebrafish (Danio rerio) embryo model. AB - Cyanobacteria are recognized producers of toxic or otherwise bioactive metabolite associated, in particular, with so-called "harmful algal blooms" (HABs) and eutrophication of freshwater systems. In the present study, two apparently teratogenic indole alkaloids from a freshwater strain of the widespread cyanobacterial genus, Fischerella (Stigonemataceae), were isolated by bioassay guided fractionation, specifically using the zebrafish (Danio rerio) embryo, as a model of vertebrate development. The two alkaloids include the previously known 12-epi-hapalindole H isonitrile (1), and a new nitrile-containing variant, 12-epi ambiguine B nitrile (2). Although both compounds were toxic to developing embryos, the former compound was shown to be relatively more potent, and to correlate best with the observed embryo toxicity. Related indole alkaloids from Fischerella, and other genera in the Stigonemataceae, have been widely reported as antimicrobial compounds, specifically in association with apparent allelopathy. However, this is the first report of their vertebrate toxicity, and the observed teratogenicity of these alkaloids supports a possible contribution to the toxicity of this widespread cyanobacterial family, particularly in relation to freshwater HABs and eutrophication. PMID- 25533518 TI - Quo vadis venomics? A roadmap to neglected venomous invertebrates. AB - Venomics research is being revolutionized by the increased use of sensitive omics techniques to identify venom toxins and their transcripts in both well studied and neglected venomous taxa. The study of neglected venomous taxa is necessary both for understanding the full diversity of venom systems that have evolved in the animal kingdom, and to robustly answer fundamental questions about the biology and evolution of venoms without the distorting effect that can result from the current bias introduced by some heavily studied taxa. In this review we draw the outlines of a roadmap into the diversity of poorly studied and understood venomous and putatively venomous invertebrates, which together represent tens of thousands of unique venoms. The main groups we discuss are crustaceans, flies, centipedes, non-spider and non-scorpion arachnids, annelids, molluscs, platyhelminths, nemerteans, and echinoderms. We review what is known about the morphology of the venom systems in these groups, the composition of their venoms, and the bioactivities of the venoms to provide researchers with an entry into a large and scattered literature. We conclude with a short discussion of some important methodological aspects that have come to light with the recent use of new -omics techniques in the study of venoms. PMID- 25533521 TI - Fossilized venom: the unusually conserved venom profiles of Heloderma species (beaded lizards and gila monsters). AB - Research into snake venoms has revealed extensive variation at all taxonomic levels. Lizard venoms, however, have received scant research attention in general, and no studies of intraclade variation in lizard venom composition have been attempted to date. Despite their iconic status and proven usefulness in drug design and discovery, highly venomous helodermatid lizards (gila monsters and beaded lizards) have remained neglected by toxinological research. Proteomic comparisons of venoms of three helodermatid lizards in this study has unravelled an unusual similarity in venom-composition, despite the long evolutionary time (~30 million years) separating H. suspectum from the other two species included in this study (H. exasperatum and H. horridum). Moreover, several genes encoding the major helodermatid toxins appeared to be extremely well-conserved under the influence of negative selection (but with these results regarded as preliminary due to the scarcity of available sequences). While the feeding ecologies of all species of helodermatid lizard are broadly similar, there are significant morphological differences between species, which impact upon relative niche occupation. PMID- 25533524 TI - Asthma outcomes in children and adolescents with multiple morbidities: Findings from the National Health Interview Survey. AB - BACKGROUND: More Americans are managing multiple chronic conditions (MCCs), and trends are particularly alarming in youth. OBJECTIVE: The purpose of this study was to examine the prevalence and distribution of 9 chronic conditions in children and adolescents with and without asthma, and adverse asthma outcomes associated with having MCCs. METHODS: Cross-sectional interview data from the National Health Interview Survey were analyzed (N = 66,790) between 2007 and 2012 in youth 0 to 17 years of age. Bivariate analysis methods and multivariate generalized linear regression were used to examine associations. RESULTS: Five percent of children with asthma had 1 or more coexisting health conditions. The prevalence of 1 or more comorbidities was greater among those with asthma than those without (5.07% [95% CI: 4.5-5.6] vs. 2.73% [95% CI: 2.6-2.9]). Those with asthma were twice as likely to have co-occurring hypertension (prevalence ratio [PR] = 2.2 [95% CI: 1.5-3.2]) and arthritis (PR = 2.7 [95% CI: 1.8-4.0]) compared with those without asthma. Every additional chronic condition with asthma was associated with a greater likelihood of an asthma attack (PR = 1.1 [95% CI: 1.0 1.2]), all-cause emergency department visits (PR = 1.3 [95% CI: 1.1-1.5]), and missed school days (PR = 2.3 [95% CI: 1.7-3.2]). CONCLUSIONS: Children and adolescents with asthma in the US who suffer from MCCs have increased asthma symptoms, missed school days, and all-cause emergency department visits. Further research on optimal management strategies for this group is needed. PMID- 25533523 TI - Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway. AB - A major hallmark feature of Alzheimer's disease is the accumulation of amyloid beta (Abeta), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as gamma-secretase activating protein, or GSAP). Because GSAP interacts with the gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Abeta therapy. GSAP derives from a C-terminal fragment of a larger precursor protein of 98 kDa via a caspase 3 mediated cleavage. However, the mechanism(s) involved in its degradation remain unknown. In this study, we show that GSAP has a short half-life of approximately 5 h. Neuronal cells treated with proteasome inhibitors markedly prevented GSAP protein degradation, which was associated with a significant increment in Abeta levels and gamma-secretase cleavage products. In contrast, treatment with calpain blocker and lysosome inhibitors had no effect. In addition, we provide experimental evidence that GSAP is ubiquitinated. Taken together, our findings reveal that GSAP is degraded through the ubiquitin-proteasome system. Modulation of the GSAP degradation pathway may be implemented as a viable target for a safer anti-Abeta therapeutic approach in Alzheimer's disease. The GSAP derives from a precursor via a caspase 3-mediated cleavage, is up-regulated in Alzheimer's disease brains and facilitates Abeta production by interacting directly with the gamma-secretase complex. Here, we demonstrate that GSAP is ubiquitinated and then selectively degraded via the proteasome system but not the calpains or lysosome pathways. These findings provide further evidence for the involvement of the proteasome system in the regulation of amyloid beta (Abeta) precursor protein metabolism and Abeta formation. AICD, APP intracellular domain; APP, amyloid precursor protein; ATP, adenosine triphosphate; CTF-alpha, alpha-C-terminal fragment; CTF-beta, beta-C-terminal fragment; GSAP, gamma-secretase activating protein; Ub, ubiquitin. PMID- 25533522 TI - Triggering of programmed erythrocyte death by alantolactone. AB - The sesquiterpene alantolactone counteracts malignancy, an effect at least in part due to stimulation of suicidal death or apoptosis of tumor cells. Signaling of alantolactone induced apoptosis involves altered gene expression and mitochondrial depolarization. Erythrocytes lack mitochondria and nuclei but may enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Cellular mechanisms involved in triggering of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i) and oxidative stress. The present study explored, whether alantolactone stimulates eryptosis. To this end, erythrocyte volume was estimated from forward scatter, phosphatidylserine-exposure at the erythrocyte surface from FITC-annexin-V-binding, [Ca2+]i from Fluo3-fluorescence, ceramide abundance from binding of fluorescent antibodies, and oxidative stress from 2',7'-dichlorodihydrofluorescein-diacetate (DCFDA) fluorescence. As a result, a 48 h exposure of human erythrocytes to alantolactone (>=20 MUM) significantly decreased erythrocyte forward scatter and increased the percentage of annexin-V-binding cells. Alantolactone significantly increased Fluo3 fluorescence (60 MUM), ceramide abundance (60 MUM) and DCFDA fluorescence (>=40 MUM). The effect of alantolactone (60 MUM) on annexin-V-binding was not significantly modified by removal of extracellular Ca2+. In conclusion, alantolactone stimulates suicidal erythrocyte death or eryptosis, an effect paralleled by increase of [Ca2+]i, ceramide abundance and oxidative stress. PMID- 25533525 TI - Ebola in the United States. AB - The ongoing epidemic of Ebola virus in West Africa and attendant cases described in other parts of the world has focused attention on this heretofore rare disease. In this brief opinion article, we provide a short primer on the epidemiology, pathogenesis, clinical manifestations, US-based hospital preparedness, vaccine and therapy development, and control of Ebola virus disease for noninfectious disease physicians. PMID- 25533527 TI - A helix-coil transition induced by the metal ion interaction with a grafted iron binding site of the CyaY protein family. AB - Iron-protein interactions are involved in electron transfer reactions. Alterations of these processes are present in a number of human pathologies; among them, in Friedreich's ataxia, in which a deficiency of functional frataxin, an iron-binding protein, leads to progressive neuromuscular degenerative disease. The putative iron-binding motif of acidic residues EExxED was selected from the first alpha-helical stretch of the frataxin protein family and grafted onto a foreign peptide scaffold corresponding to the C-terminal alpha-helix from E. coli thioredoxin. The resulting grafted peptide named GRAP was studied by applying experimental (circular dichroism, isothermal titration calorimetry, capillary zone electrophoresis, thermal denaturation, NMR) and computational approaches (docking, molecular dynamics simulations). Although isolated GRAP lacks a stable secondary structure in solution, when iron is added, the peptide acquires an alpha-helical structure. Here we have shown that the designed peptide is able to specifically bind Fe(3+) with a moderate affinity (KD = 1.9 +/- 0.2 MUM) and a 1 : 1 stoichiometry. Remarkably, the GRAP/Fe(3+) interaction is entropically driven (DeltaH degrees = -1.53 +/- 0.03 kcal mol(-1) and TDeltaS degrees = 6.26 kcal mol(-1)). Experiments and simulations indicate that Fe(3+) interacts with the peptide through three acidic side chains, inducing an alpha-helical conformation of the grafted motif. In addition, the acidic side chains involved undergo significant conformational rearrangements upon binding, as judged by the analysis of MDs. Altogether, these results contribute to an understanding of the iron binding mechanisms in proteins and, in particular, in the case of human frataxin. PMID- 25533526 TI - Staphylococcus aureus colonization is associated with wheeze and asthma among US children and young adults. PMID- 25533528 TI - The effect of response rate on reward value in a self-control task. AB - To understand how effort, defined by number of responses required to obtain a reward, affects reward value, five pigeons were exposed to a self-control task. They chose between two alternatives, 2 s of access to food after a delay of 10 s, and 6 s of access to food after an adjusting delay. The adjusting delay increased or decreased depending on the pigeons' choices. The delay at which the two alternatives were equally chosen defined the indifference point. To determine whether requiring responses during the delay led to more impulsive (smaller sooner rewards) or self-controlled (larger-later rewards) choices, we varied the number of required pecks during the 10-s delay to the 2-s reinforcer, and assessed how the requirement affected the indifference points. In the High Rate Phase, they had to peck at least 10 times during the delay; in the Low Rate Phase, they could peck at most 5 times during the delay. For four pigeons the indifference point increased with the response requirement; for one pigeon it decreased. The results suggest that, in general, reward value varies inversely with effort. PMID- 25533530 TI - In situ intramolecular catalytic 1,2-addition of allenoates to cyclic ketones towards polycyclic allenoates. AB - Sequential deprotonation, isomerization of 3-alkynoates and subsequent 1,2 addition led to bicyclic allenoate in the presence of a catalytic amount of Cs2CO3. Cyclization proceeds in a totally stereoselective manner in the case of the two-carbon linker chain. A one-pot reaction starting from alkynyl ketones afforded tricyclic fused ring systems with good yields. PMID- 25533529 TI - Effects of single N-glycosylation site knockout on folding and defibrinogenating activities of acutobin recombinants from HEK293T. AB - Acutobin, the alpha-fibrinogenase from Deinagkistrodon acutus venom, contains four N-glycosylation sites with disialylated complex-typed glycans. Here, we explore the functional roles of each of the N-glycan by site-directed mutagenesis. The wild-type (ATB-wt) and single glycan-knockout mutants of recombinant acutobin were prepared from HEK293T, demonstrating that mutations at Asn(77), Asn(81) and Asn(100) impaired the folding while the S79A mutant and various Asn(229)-deglycosylated mutants were correctly folded. Based on homology modeling of acutobin and multiple sequence alignment with various venom thrombin like enzymes, the importance of a hydrophilic environment at each glycosylation site to the enzyme folding could be rationalized. Remarkably, all the mutants showed similar catalytic activities for the chromogenic substrate and similar thermal stabilities as ATB-wt, suggesting that the glycan knockout did not affect the gross conformation and stability of the active sites. Although SDS-PAGE analyses revealed that ATB-wt and the D229-mutant degraded all human fibrinogen subunits faster but less specifically in vitro as compared with other mutants that cleaved only the alpha-subunit, ATB-wt and D229-mutant were not able to release fibrinogen-peptide A and thus coagulated human plasma slower than the other mutants did. In the mice model, the defibrinogenating effect of ATB-wt was stronger and lasting-longer than those of all the mutants. Taken together, all the glycans contribute to the pharmacokinetics of acutobin and ATB-wt in vivo, and the microenvironment around the Asn(229)-glycan appears to regulate the fibrinogen-chain specificity of acutobin while the N-glycans at positions 77, 81 and 100 are crucial for its folding. PMID- 25533531 TI - Identification of the interaction between vimentin and nucleocapsid protein of transmissible gastroenteritis virus. AB - Nucleocapsid (N) protein of transmissible gastroenteritis virus (TGEV) packages viral RNA genome to form a ribonucleoprotein complex. In addition to its function as a structural protein, N protein is involved in cell apoptosis or cell-cycle regulation. N protein possibly interacts with host factors to modulate cellular functions. To identify cellular proteins that interacted with N protein of TGEV, methods of GST pull-down and Co-IP were utilized to precipitate cellular proteins of swine testicular (ST). Bound cellular proteins were resolved by SDS-PAGE. Analysis of interacting proteins by mass spectrometry allowed identification of 15 cellular protein bands representative of 12 cellular proteins including vimentin that bound to N protein. Furthermore, the function of vimentin cytoskeleton in ST cells during TGEV infection was examined. Vimentin cytoskeleton was required for virus replication. The present study thus provides protein-related information about interaction of TGEV N protein with host cell that should be useful for understanding host cell response to coronavirus pathogenesis infection and the underlying mechanism of coronavirus replication. PMID- 25533532 TI - The role of Moloney leukemia virus 10 in hepatitis B virus expression in hepatoma cells. AB - Recent studies have shown that the Moloney leukemia virus 10 (Mov10), a putative RNA helicase, has very broad and potent antiretroviral activities. Hepatitis B virus (HBV) has a reverse transcription process, but the potential role of Mov10 in HBV replication remains unknown. In this study, Mov10 was demonstrated to affect HBV expression in HepG2 and HepG2.2.15 cell lines. The data showed that the over-expression of exogenous Mov10 resulted in an increase of the HBsAg and HBeAg levels in the culture supernatant and HBV mRNA level in transfected cells at a low dose and resulted in a decrease at a high dose, but HBV DNA in culture supernatant was not affected. The knockdown of endogenous Mov10 expression through siRNA treatment could suppress levels of HBsAg, HBeAg and HBV mRNA, but had no effect on HBV DNA. Above results indicate that an appropriate level of exogenous Mov10 is responsible for HBV replication, that any perturbation in the level of Mov10 could affect HBV replication, while the endogenous Mov10 could promote HBV replication in vitro. The precise mechanisms that underlie the action of Mov10 on HBV still need further investigation. PMID- 25533533 TI - Systemic AA amyloidosis as a prion-like disorder. AB - Amyloidosis is a collective term for a group of disorders that induce functional impairment of organs and occurs through the accumulation of amyloid, or misfolded protein in beta-sheets. AA amyloidosis is a lethal systemic amyloidosis with SAA as the precursor protein, and is observed in various animal species, including humans. AA amyloidosis can be induced artificially by continuously administering inflammatory stimuli in experimental animal models. In this process of experimental induction, the administration of AA amyloids from either the same or different species is known to markedly expedite AA amyloidosis development, and this is also termed transmission of AA amyloidosis. Similarly to prion disease, AA amyloidosis is considered to be transmitted via a "seeding-nucleation" process. In this manuscript, we reviewed the pathology and transmissibility of AA amyloidosis in animals. PMID- 25533535 TI - GC/MS-based metabolomic studies reveal key roles of glycine in regulating silk synthesis in silkworm, Bombyx mori. AB - Metabolic profiling of silkworm, especially the factors that affect silk synthesis at the metabolic level, is little known. Herein, metabolomic method based on gas chromatography-mass spectrometry was applied to identify key metabolic changes in silk synthesis deficient silkworms. Forty-six differential metabolites were identified in Nd group with the defect of silk synthesis. Significant changes in the levels of glycine and uric acid (up-regulation), carbohydrates and free fatty acids (down-regulation) were observed. The further metabolomics of silk synthesis deficient silkworms by decreasing silk proteins synthesis using knocking out fibroin heavy chain gene or extirpating silk glands operation showed that the changes of the metabolites were almost consistent with those of the Nd group. Furthermore, the increased silk yields by supplying more glycine or its related metabolite confirmed that glycine is a key metabolite to regulate silk synthesis. These findings provide important insights into the regulation between metabolic profiling and silk synthesis. PMID- 25533534 TI - The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus. AB - The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell. PMID- 25533537 TI - Modeling depletion mediated colloidal assembly on topographical patterns. AB - This work reports a model and Monte Carlo simulations of excluded volume mediated interactions between colloids and topographically patterned substrates in the presence of thermosensitive depletants. The model is matched to experiments to yield density, free energy, and potential energy landscapes that quantitatively capture particle microstructures varying from immobilized non-close packed configurations to random fluid states. A numerical model of local excluded volume affects is developed to enable computation of local depletion attraction in the presence of arbitrary geometries. Our findings demonstrate a quantitative modeling method to interpret and predict how surface patterns mediate local depletion interactions, which enables the design of colloidal based materials and devices. PMID- 25533536 TI - Magnetocubosomes for the delivery and controlled release of therapeutics. AB - The design of nanostructured drug delivery systems (DDS) that improve the efficacy of therapeutic principles by enhancing their biocompatibility, bioavailability and targeting, has been the focus of extensive research over the past years. Of particular relevance in this field is the development of multifunctional architectures that can deliver different therapeutics or diagnostic agents and release them in a controlled way. In this study we report on the design, preparation and characterization of a DDS where hydrophobic Fe3O4 magnetic nanoparticles (NPs) are included in the bilayer of bicontinuous cubic lipid nanoparticles of Glyceryl Monooleate (GMO). The "magnetocubosomes" are characterized and investigated in terms of their ability to encapsulate and release both hydrophilic and hydrophobic model drugs. For the first time Fluorescence Correlation Spectroscopy (FCS) is used to study the diffusion of encapsulated molecules inside the bicontinuous cubic phase and to monitor their release from the matrix towards the aqueous phase. In addition, we show with the same technique that magnetocubosomes are responsive to a low frequency alternating magnetic field (LF-AMF), which acts as an external trigger to boost the release of model drugs confined in the cubic phase. Magnetocubosomes, reported for the first time in this paper, represent a novel biocompatible, multifunctional and responsive DDS. PMID- 25533538 TI - Colloidosomes: synthesis, properties and applications. AB - Colloidosomes represent a rapidly expanding field with various applications in microencapsulation, including the triggered release of cargoes. With self assembled shells comprising colloidal particles, they offer significant flexibility with respect to microcapsule functionality. This review explores the various types of particles and techniques that have been employed to prepare colloidosomes. The relative advantages and disadvantages of these routes are highlighted and their potential as microcapsules for both small molecule and macromolecular actives is evaluated. PMID- 25533539 TI - A 12-week open-label, multicenter study evaluating the safety and patient reported efficacy of sodium oxybate in patients with narcolepsy and cataplexy. AB - OBJECTIVE: This study aimed to evaluate safety and efficacy of sodium oxybate (SXB) titrated to effect. METHODS: SXB-naive patients who had participated in a randomized SXB clinical trial and had not been titrated to adequate clinical effect were initiated on open-label SXB at 4.5 g/night and titrated in 1.5-g increments to 6, 7.5, or 9 g/night or down to 3 g/night, based on individual clinical response. Treatment was 12 weeks; safety was the primary outcome. Efficacy was evaluated using the Narcolepsy Symptom Assessment Questionnaire (NSAQ), a five-point scale ("much improved" to "much worse") that assessed changes from baseline in specific symptoms. Response was defined as "much improved" or "somewhat improved" overall at weeks 6 and 12. RESULTS: Of 202 patients, 171 (85%) completed treatment; final doses were 3 g (n = 5), 4.5 g (n = 29), 6 g (n = 80), 7.5 g (n = 66), and 9 g (n = 22). Adverse events (AEs) were reported in 114 patients (56%), serious AEs in five (2%). The most common AEs were nausea (10%), headache (7%), and dizziness (5%). Response rate was 92% at week 6 and 90% at week 12; most patients reported improvements in all individual symptoms. Overall, 60% of patients rated their symptoms at 12 weeks as "much improved," and this improvement was dose dependent. CONCLUSIONS: The SXB safety profile was consistent with parent trials. Ninety percent of patients reported improvements as measured by the NSAQ. PMID- 25533541 TI - Sleep and chronic stress: new directions for allostatic load research. PMID- 25533540 TI - Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study. AB - BACKGROUND: Restless legs syndrome (RLS) often responds to agents that enhance dopamine neurotransmission. The present 12-week study aimed to evaluate the efficacy and adverse events of pramipexole (PPX) for the treatment of adult, Chinese people with primary RLS. METHODS: A total of 204 Chinese people with RLS were randomly assigned to receive either the placebo or PPX (flexibly titrated from 0.25 mg to 0.75 mg), 2 h to 3 h before bedtime for 12 weeks. The primary measuring outcomes were the International RLS Study Group Rating Scale (IRLS) and the Clinical Global Impressions-Improvement (CGI-I) scale. The secondary outcome was adverse events. RESULTS: One hundred and ninety participants completed the study. At 12 weeks, the adjusted mean (SE) change from baseline was greater for PPX (vs placebo) for the IRLS score (-13.2 +/- 0.7 vs -9.4 +/- 0.6; p <0.01), and (-12.1 +/- 0.6 vs -8.3 +/- 0.6; p <0.01) at the end of one month follow-up after treatment. The CGI-I rating of "very much improved" or "much improved" in the percentage of participants (61.8% vs 34.3%; p <0.01), and (51.0% vs 26.5%; p <0.01) after week 12, and one month follow-up of treatment, respectively. The proportion of adverse events was 60.8% in the PPX group and 45.1% in the placebo group. No deaths related to PPX treatment were recorded. CONCLUSIONS: In summary, the present study showed that PPX is efficacious and well tolerated in Chinese people with primary RLS. PMID- 25533542 TI - Sante De Sanctis (1862-1935), a forerunner of the 20th century research on sleep and dreaming. AB - This article aims to reconstruct the elements of continuity and/or discontinuity in Sante De Sanctis' (1862-1935) contributions in the scientific understanding of sleep and dreaming as compared to the scientific research of his time. An Italian psychologist and psychiatrist, De Sanctis, in his work conducted between the 19th and 20th centuries, has framed the study of dreams using multi-methodology. In addition, De Sanctis experimentally established the correspondence between the deep and desynchronization phases of sleep with respect to dreaming. In this context, De Sanctis' subjects described the periodicity of sleep and consciousness, influencing the explanations of the themes that modern sleep research has, after decades, systematically studied. We demonstrate that De Sanctis' work has been underestimated, and in our opinion, deserves to be reconsidered as a source of the psychophysiological explanation of dreams and sleep. Finally, we present a graphical representation of De Sanctis' psycho- and neurophysiological model of dreaming. PMID- 25533543 TI - Crosstalk between sleep disturbances and cancer survival. PMID- 25533544 TI - Vacuolar protein sorting 4B regulates apoptosis of intestinal epithelial cells via p38 MAPK in Crohn's disease. AB - Vacuolar protein sorting 4B (VPS4B), a member of ATPase family proteins, reportedly possesses multiple biological functions, such as regulating the development of breast cancer and non-small-cell lung cancer, participating in Parkinson's disease, and modulating neuronal apoptosis after cerebral ischemia. However, its expression and potential functions in Crohn's disease (CD) has not been understood. In this study, we reported for the first time that VPS4B was over-expressed in intestinal epithelial cell (IECs) of patients with CD. In TNBS induced mouse colitis models, we observed the up-regulation of VPS4B was accompanied with the elevated levels of IEC apoptotic markers (active caspase-3 and cleaved PARP) and phosphorylated p38 in colitis IECs. Co-localization of VPS4B and active caspase-3 in IECs of the TNBS group further indicated the possible involvement of VPS4B in IEC apoptosis. Employing the TNF-alpha-treated HT29 cells as an in vitro IEC apoptosis model, we confirmed the positive correlation of VPS4B with caspase-dependent cellular apoptosis. Knocking VPS4B down by siRNA significantly alleviated TNF-alpha-induced p38 phosphorylation and cellular apoptosis in HT29 cells. Taken together, our findings suggested that VPS4B may facilitate the IEC apoptosis in CD via p38 MAPK signaling pathway. PMID- 25533545 TI - Evaluation of the effects of preconditioning regimens on hepatic veno-occlusive disease in mice after hematopoietic stem cell transplantation. AB - Pre-conditioning regimens before hematopoietic stem cell transplantation (HSCT), such as total body irradiation (TBI) or busulfan/cyclophosphamide (BU/CY), are associated with hepatic veno-occlusive disease (HVOD). However, the mechanism of these regimens on hepatic veno-occlusive disease remains unclear. The aim of this study is to evaluate the effect of TBI or BU/CY on HVOD in mice after HSCT. Mice received TBI or BU/CY followed by HSCT. Analysis of liver pathology and function, and platelet aggregation were performed. Both these regimens caused damage to liver sinusoid endothelial cells, leading to loss of normal structural integrity of liver sinusoid, abnormal liver function, fibrin deposition, inflammatory cells infiltration and platelet aggregation. No differences of liver function in these regimens were observed. Increased hepatic lipid droplets, mitochondrial swelling and higher incidence of HVOD were observed in BU/CY. In conclusion, both TBI and BU/CY caused damage to liver sinusoid endothelial cells and occurrence of HVOD with higher incidence for BU/CY. Meanwhile, inflammation and platelet activation was also observed, suggesting targeting them maybe beneficial in the prophylaxis of HVOD. PMID- 25533546 TI - The importance of the interaction between hepatocyte and hepatic stellate cells in fibrogenesis induced by fatty accumulation. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease is characterized by an initial accumulation of triglycerides that can progress to non-alcoholic steatohepatitis, which can ultimately evolve to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells play a key role in liver fibrogenesis by an increased activation and an altered profile of genes involved in the turnover of extracellular matrix components. To reproduce in-vitro the functional cell connections observed in vivo it is essential to consider cell-to-cell proximity and interaction. The aim of this study was to determine the response to free fatty acids in a simultaneous co-culture model of hepatocytes and hepatic stellate cells. METHODS: Simultaneous co-culture model and monoculture of each cell type (control) were exposed to FFA for 24 up to 144 h. Quantification of steatosis; stellate cell activation; assessment of fibrogenic response; expression and activity of metalloproteinases as well as collagen biosynthesis were evaluated. RESULTS: Free fatty acids induced comparable steatosis in simultaneous co-culture and monoculture. However, the activation of the stellate cells assessed by alpha-smooth muscle actin expression is greater when cells were in close contact. Furthermore, a time-dependent increment of tissue inhibitor metalloproteinase-2 protein was observed, which was inversely correlated with protein expression and activity of matrix-metalloproteinases, suggesting enhanced collagen biosynthesis. This behavior was absent in cell monoculture. CONCLUSIONS: These data indicate that cell-to-cell proximity between hepatocytes and stellate cells is necessary for the initiation of the fibrotic process. PMID- 25533548 TI - How can a country learn from the experience of another? Expanding nurses' scope of practice in Portugal: lessons from England. AB - INTRODUCTION: The composition of the Portuguese health workforce suggests an inefficient combination of nurses and physicians. Evidence indicates that, under specific circumstances, nurses can provide equivalent care to that delivered by physicians. England has a broader experience in developing policy-led initiatives in this field from which Portugal can learn. The study explores this issue, aiming to assist in informing policy formulation. METHODS: The study analysed English policies which led to the enhancement of nurses' roles between 2000 and 2010. A literature review and interviews with selected informants were carried out. RESULTS: In 2000, the British government adopted a new policy for the health sector. A "working differently" strategy was subsequently developed. An increase in demand as well as the failure to improve access, efficiency and quality of service were the drivers for change. The strategy was fostered by the idea of building roles around patients and several tools were developed in order to trigger change, in which different stakeholders performed a central role. In spite of the registered progress, by the end of 2010, some issues remained unresolved, namely the lack of a specific framework to regulate nurses' expanded functions. CONCLUSION: This study provides Portuguese policy-makers with useful knowledge for defining a strategy to expand nurses' scope of practice, by proposing a general framework of key aspects to be taken into account. PMID- 25533547 TI - Prediction of common epitopes on hemagglutinin of the influenza A virus (H1 subtype). AB - Influenza A virus infection is a persistent threat to public health worldwide due to hemagglutinin (HA) variation. Current vaccines against influenza A virus provide immunity to viral isolates similar to vaccine strains. Antibodies against common epitopes provide immunity to diverse influenza virus strains and protect against future pandemic influenza. Therefore, it is vital to analyze common HA antigenic epitopes of influenza virus. In this study, 14 strains of monoclonal antibodies with high sensitivity to common epitopes of influenza virus antigens identified in our previous study were selected as the tool to predict common HA epitopes. The common HA antigenic epitopes were divided into four categories by ELISA blocking experiments, and separately, into three categories according to the preliminary results of computer simulation. Comparison between the results of computer simulations and ELISA blocking experiments indicated that at least two classes of common epitopes are present in influenza virus HA. This study provides experimental data for improving the prediction of HA epitopes of influenza virus (H1 subtype) and the development of a potential universal vaccine as well as a novel approach for the prediction of epitopes on other pathogenic microorganisms. PMID- 25533549 TI - Medicine price awareness in chronic patients in Belgium. AB - INTRODUCTION: Under increasing pressure to contain health expenditures governments across Europe have implemented policies to increase responsible medicine use, e.g. by increasing co-insurance paid for by patients. In times of austerity, how do chronic disease patients perceive the medicine price they have to pay? METHOD: We used a mixed methods research design. First, we distributed a close-ended questionnaire among 983 chronic disease patients in 30 Flemish pharmacies. Second, we performed semi-structured interviews with 15 of these patients. We surveyed for knowledge on the prescription medicine they bought, as well as for their needs for information and their therapeutic compliance. RESULTS: Although patients express a lack (and a need) of information on prices during the consultation with the general practitioner (GP), (s)he hardly addresses medicine prices. Patients often only know the medicine price when they are at the pharmacy and patients need to decide to buy the medicine or not. This often results in patients taking the medicine when considered affordable within their social and financial context. CONCLUSION: It seems essential that patients are better informed about medicine prices as well as the constraints on physicians to prescribe cost-effectively. Therefore, medicine prices should be discussed more often during physician consults. PMID- 25533550 TI - The impact of New Public Management on efficiency: an analysis of Madrid's hospitals. AB - Madrid has recently become the site of one of the most controversial cases of public healthcare reform in the European Union. Despite the fact that the introduction of New Public Management (NPM) into Madrid hospitals has been vigorous, little scholarship has been done to test whether NPM actually led to technical efficiency. This paper is one of the first attempts to do so. We deploy a bootstrapped data envelopment analysis to compare efficiency scores in traditionally managed hospitals and those operating with new management formulas. We do not find evidence that NPM hospitals are more efficient than traditionally managed ones. Moreover, our results suggest that what actually matters may be the management itself, rather than the management model. PMID- 25533551 TI - The effect of equipment scaling on children's sport performance: the case for tennis. AB - The influence of scaling court-size and net height on children's tennis performance was examined. Sixteen boys (9.7 +/- 0.5 years) had to perform a 30 min match in four different conditions, where court-size and/or net height were scaled by using a scaling ratio based on the differences in temporal demands between the children and the adult game. These 30-min matches were analysed using Tennis Analyst (FairPlay Ltd., Jindalee, QLD, Australia) software to determine typical tennis match performance characteristics. Children hit more winners, more forced errors, played more volleys, struck more shots from a comfortable height and played in a more forward court position when the net was scaled. Scaling both the court and net lead to a faster children's game, more closely approximating what is typical of the adult game. The differences between the typical tennis performance variables recorded suggested that scaling the net led to a more aggressive way of playing. Further, children enjoyed playing on the standard court-scaled net condition more than standard adult conditions. It is suggested that optimising the scaling of net height may be as critical as other task constraints, such as racquet length or court-size, as it leads to a more engaging learning environment for experienced children. PMID- 25533552 TI - Erratum: Anatomical model broncho-trainer: A new training device: Corrigendum. AB - [This corrects the article on p. 481 in vol. 58, PMID: 25197126.]. PMID- 25533554 TI - [Strengthen Chinese translational medicine research in ocular surface]. AB - Translational medicine emphasizes the application of the results of basic research to clinical practice and the solution of clinical issues through basic research. It is very important for the development direction of the medical field. Over the past decade, the translational medicine research in ocular surface disease has drawn international attention and developed rapidly. This field in China has made great progress, but overall there are still some gaps with the international advanced level. We need to establish the concept and the platform of translational research, explore scientific and effective methods, and create a whole chain to enhance our ocular research. It also requires research institutions and government departments to give full support. Finally, we need to explore a suitable way for the development of Chinese translational medical research. PMID- 25533553 TI - [The status quo and expectation of corneal research in China]. AB - In China, corneal disease is currently the second leading cause of blindness. Severe donor shortage, insufficient technique supports and promotion, and the lack of corneal disease specialists due to poor systematic training are all urgent problems to be resolved. The last 5 years have witnessed a considerable progress in basic and clinical researches of corneal disease. Investigations on the pathogenesis and treatment of fungal keratitis have won an international reputation. Results from the study of corneal reconstruction with tissue engineered and acellular matrix corneas have been tested in clinical trials with good preliminary performance. Moreover, the clinical researches of corneal refractive surgery have kept pace with the latest international progresses. However, Descemet's membrane endothelial keratoplasty needs further promotion, and the development and application of keratoprosthesis remains a blank. Although keratoprosthesis and corneal collagen cross-linking have been widely applied in Europe with satisfactory clinical efficacy, they are still under assessment by China Food and Drug Administration for approval of use. PMID- 25533555 TI - [Rethinking clinical significance of tear osmolarity measurement for dry eye diagnosis and therapeutic efficacy evaluation]. AB - Increased tear osmolarity is one of the core mechanisms of dry eye and has been considered as an important diagnostic criterion, if not"gold standard", of dry eye. However, recent studies showed the limitations of tear osmolarity measurement not only in the diagnosis, but also in the therapeutic efficacy evaluation of dry eye. The clinical significance of tear osmolarity measurement has become a hot topic of argument. Herein, we review the publications on this topic and try to find the underlying causes of such argument. PMID- 25533556 TI - [Corneal thickness distribution and its relationship with corneal topography in ametropic population]. AB - OBJECTIVE: To explore the distribution of relational corneal thickness parameters including central corneal thickness (CCT), thinnest pachymetry (TP), cornea thickness spatial profile (CTSP), percentage thickness increase (PTI), pachymetric progression index (PPI) and Ambrosio's relational thickness (ART) in the normal population, and their relationships with corneal astigmatism and curvature. METHODS: A total of 1 203 eyes from 1 203 normal outpatients were enrolled in this cross-sectional study. The data information of CCT, TP, CTSP, PTI, PPI-max, PPI-min, PPI-ave, axes of PPI-max and PPI-min, ART-max and ART-ave was collected from Pentacam HR for the subsequent analysis of their distribution. Astigmatism, astigmatism axis (AA), and keratometry (K) including Km and Kmax were also collected to explore their relationships with relational thickness parameters. RESULTS: The mean values for CCT and TP were (547.20 +/- 31.441) um and (543.26 +/- 31.271) um, respectively. The mean values for CTSP-2, CTSP-4, CTSP-6 and CTSP-8 were (552.11 +/- 31.654) um, (580.72 +/- 32.919) um, (632.11 +/ 34.738) um and (711.80 +/- 37.880) um, respectively. PTI-2, PTI-4, PTI-6 and PTI 8 were (1.67 +/- 0.471)%, (6.89 +/- 0.945)%, (16.37 +/- 1.996)% and (31.10 +/- 3.652)%. PPI-max, PPI-min and PPI-ave were 1.222 +/- 0.175, 0.733 +/- 0.138 and 0.994 +/- 0.123. The axes of PPI-max and PPI-min were 230.74 +/- 104.862 and 159.81 +/- 62.292. ART-max and ART-ave were (454.940 +/- 78.506)um and (556.140 +/- 86.492)um. CCT, TP, PPI and ART were found to have a weak but significant correlation with Kmax-front, Km-front and Km-back. PPI and ART were also found to weakly correlate with Astig-back. The converted astigmatism axis was found to correlate with the axes of PPI-max (rs = -0.125, P = 0.000) and PPI-min (rs = 0.613, P = 0.000). CONCLUSIONS: The front and back curvatures and the back astigmatism correlate with the distribution of corneal thickness, while the front astigmatism does not correlate with it. The front astigmatism axis tends to distribute coincidently with PPI-min axis. PMID- 25533558 TI - [Two millimeter micro incision lenticule extraction surgery with minimal invasion: a preliminary clinical report]. AB - OBJECTIVE: To report the clinical results of micro incision lenticule extraction (MILE) to correct myopia or myopia with astigmatism, and enlighten its viability and mechanism. METHODS: Prospective case-control study. All patients enrolled were treated by the VisuMax femtosecond laser system to correct refractive errors. Sixty-one patients underwent MILE with an incision of 2 mm. Another 53 patients underwent small incision lenticule extraction (SMILE) with a 3-5 mm incision as the control group. All patients took measurements of uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), refractive power and intraocular pressure, slit-lamp microscopy, and corneal topography preoperatively and at 1 day, 1 week, 1 month, 6 months postoperatively. The visual acuity was presented as median. To compare the visual acuity and astigmatism between the MILE group and the SMILE group, as well as before surgery and at each time point after surgery, non-parametric tests were applied in this study. The repeated measures analysis of variance was used to compare the differences between these two surgeries and between pre- and post-operation in diopters and morphological parameters. The paired-sample t test was used to compare the diopters and morphological parameters at each time point postoperatively and preoperatively. The independent-sample t test was applied to compare the basic characteristics preoperatively and the diopters, morphological parameters at each time point between these two groups. RESULTS: Forty-one eyes (24 patients) in the MILE group and fifty-one eyes (29 patients) in the SMILE group had complete follow-up data. Before surgery and at 1 day, 1 week, 1 month, 6 months after surgery, the spherical diopters in the MILE group were (-5.09 +/- 1.04), (0.12 +/- 0.32), (0.11 +/- 0.29), (0.02 +/- 0.33) and (0.02 +/- 0.23) D; the cylinder diopters were (-0.90 +/- 0.83), (-0.25 +/- 0.27), (-0.23 +/- 0.30), (-0.20 +/- 0.25) and ( 0.16 +/- 0.21) D. In the SMILE group, the spherical diopters were (-5.37 +/- 1.26), (-0.04 +/- 0.49), (0.12 +/- 0.38), (0.10 +/- 0.34) and (0.02 +/- 0.33) D; the cylinder diopters were (-0.76 +/- 0.65), (-0.22 +/- 0.26), (-0.25 +/- 0.30), (-0.26 +/- 0.29) and (-0.21 +/- 0.28) D. No significant difference was found between the two groups (F = 1.042, 0.941, 0.018; P = 0.310, 0.335, 0.894). In the vector analysis of astigmatism, at 1 month and 6 months after surgery, the values on Y axis were -0.06 +/- 0.11 and -0.04 +/- 0.10 in the MILE group, smaller than 0.14 +/- 0.18 and -0.11 +/- 0.16 in the SMILE group (Z = -2.076, -2.149; P = 0.038, 0.032). All full-correction patients had UCVA of 20/20 or better, and no BCVA decreased after 6 month follow-up postoperatively. Refractive stability was achieved within 1 month postoperatively, and less volatility appeared in the MILE group than the SMILE group. Before surgery and at 1 day, 1 week, 1 month, 6 months after surgery, no significant difference in the index of surface variance (ISV) and the index of vertical asymmetry (IVA) was found between the MILE group and the SMILE group (F = 0.902, 0.744; P = 0.345, 0.391), whereas the values of ISV and IVA were smaller in the MILE group than the SMILE group at each time point after surgery, and the D-value between the two groups increased with time. Six cases (9 eyes) had an opaque bubble layer while femtosecond laser passed in the procedure, 2 eyes had a small tear at the incision edge, 1 eye had local diffuse inflammatory exudates at 1 day postoperatively, and no eye had transient light-sensitivity syndrome, decrease of corneal transparency or infection. CONCLUSIONS: MILE surgery (1.5-2.0 mm) is safe, predictable, effective and stable to treat refractive errors. It can reduce astigmatism values on oblique axis and maintain the integrality and stability of the structure of the cornea. PMID- 25533559 TI - [The clinical study of corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas]. AB - OBJECTIVE: To evaluate the clinical results of keratoconic eyes with thin corneas that were treated by using corneal collagen cross-linking with hypo-osmolar riboflavin solution. METHODS: Retrospective, nonrandomized study. Fifteen eyes of 15 patients with progressive keratoconus and corneal thickness of less than 400 um (without the epithelium) were included in this study. Application of hypo osmolar riboflavin solution to the cornea for 30 minutes after its de epithelialization was followed by ultraviolet A collagen cross-linking. Corneal thickness was measured with anterior segment OCT before surgery, after epithelial removal, and after hypotonic riboflavin solution application. Before the ultraviolet A application was started, we must be sure that the thinnest cornea was equal to or greater than 400 um. Examinations comprised an evaluation of uncorrected distance visual acuity and best corrected visual acuity, slit-lamp microscopy, corneal topography, and endothelial cell counting after the procedure. RESULTS: Before surgery, the mean corneal thickness (with the epithelium) was (399.27 +/- 17.87) um, and after the removal of epithelium, the thickness of the cornea was reduced to (354.00 +/- 18.57) um. After the application of the hypo-osmolar riboflavin solution, this value increased to (477.73 +/- 20.87) um. The improvements in visual acuity and keratometry readings occurred during the follow-up. No statistically signiflcant differences were found between preoperative and postoperative endothelial cell counts. No complications such as scarring lesions in the stroma and corneal endothelial damage were observed throughout the study period. CONCLUSIONS: The results of our study, using hypo-osmolar riboflavin solution in a cross-linking procedure in thin corneas, show a stability of keratoconus 12 months after cross-linking. PMID- 25533557 TI - [The study of corneal epithelial change in keratoconic eyes with Fourier-domain optical coherence tomographic pachymetry]. AB - OBJECTIVE: To compare the corneal epithelial thickness profile in keratoconic and normal eyes with advanced Fourier-domain optical coherence tomography (OCT) and to evaluate the diagnostic efficiency of pachymetry parameters. METHODS: Cross sectional observational study. Twenty-five consecutive keratoconus patients (34 eyes) and 41 normal volunteers (41 eyes) in Eye & ENT Hospital of Fudan University between June 1 and July 31, 2013 were enrolled.Observations of corneal epithelial thickness and corneal thickness profiles were taken from all subjects. The epithelial pachymetry parameters were superior, inferior, inferior-superior (I-S), minimum (Min), maximum (Max), Min-Max, and central. The corneal pachymetry parameters were inferotemporal-superonasal (IT-SN), I-S, Min, Min-median, Min Max, and central.Statistical analysis methods included Chi-square test, independent two-sample t-test, and Wilcoxon rank sum test. The diagnostic efficiency of all parameters were analyzed by receiver operating characteristic (ROC) curves and Youden index. RESULTS: The inferior, I-S, Min, Min-Max, and central epithelial thickness averages were (50.5 +/- 4.8) um, (-2.7 +/- 7.5) um, (35.9 +/- 10.7) um, (-33.6 +/- 18.9) um, and (50.1 +/- 6.8) um in keratoconic eyes.In normal eyes, they were (54.8 +/- 2.5) um, (0.9 +/- 1.3) um, (51.4 +/- 2.6) um, (-5.7 +/- 1.8) um, and (54.7 +/- 2.2) um. Among the epithelial pachymetry parameters, Min-Max and Min showed high diagnostic efficiency for keratoconus (AUC = 0.967, 0.968; Youden index = 0.882, 0.829); inferior, I-S, and central parameters showed moderate efficiency (AUC = 0.794, 0.728, 0.715; Youden index = 0.461, 0.564, 0.565). The IT-SN, I-S, Min, Min-median, Min-Max, and central corneal thickness averages were (-82.8 +/- 65.2) um, (-72.5 +/- 55.6) um, (401.2 +/- 83.8) um, (-83.4 +/- 48.2) um, (-169.7 +/- 99.4) um, and (453.4 +/- 58.6) um in keratoconic eyes.In normal eyes, these parameters were respectively ( 23.7 +/- 18.5) um, (-20.5 +/- 19.8) um, (525.4 +/- 28.1) um, (-23.1 +/- 4.8) um, (-59.2 +/- 23.3) um, and (533.4 +/- 28.8) um. Min, Min-median, and Min-Max had preferable diagnostic efficiency (AUC = 0.952, 0.938, 0.924; Youden index = 0.784, 0.829, 0.721); central, IT-SN, and I-S parameters showed moderate efficiency (AUC = 0.891, 0.877, 0.862; Youden index = 0.643, 0.707, 0.580). CONCLUSIONS: In observation with Fourier-domain OCT, keratoconus was characterized by central and inferior epithelial thinning, increased epithelial thickness variation, central cornea thinning, increase in asymmetry, and gaps between corneal IT-SN and I-S thickness.Fourier-domain OCT was confirmed to have high speed, high resolution, and noninvasion. The pachymetry parameters showed specific strengths in diagnosis of keratoconus, especially epithelial pachymetry parameters of Min and Min-Max, and corneal pachymetry parameters of Min, Min median and Min-Max. PMID- 25533560 TI - [The clinical comparison of conjunctival resection with conjunctival resection and sclera fixation in the treatment of conjunctivochalasis]. AB - OBJECTIVE: To evaluate the efficacy of two surgical treatments for conjunctivochalasis. METHODS: Prospective randomized control study. Thirty-three conjunctivochalasis patients (33 eyes) were randomly divided into two groups:simple resection group, and resection and fixation group. The former received simple conjunctival resection, and the latter received conjunctival resection and scleral fixation. Postoperative conjunctiva relaxation, BUT and ocular surface disease index (OSDI) points were compared to evaluate the efficacy of the two kinds of surgical methods. RESULTS: The recurrence rate of conjunctivochalasis was 6/16 in the simple resection group and 1/17 in the resection and fixation group on month 6 after operation, and there was significant difference (P = 0.039). In 1 month, 3 months and 6 months postoperatively, the proportion of normal BUT increased respectively in both groups (simple resection group:8/16, 9/16, 10/16; resection and fixation group:8/17, 10/17, 11/17) compared with that before operation (simple resection group:3/16; resection and fixation group:4/17). The difference was statistically significant 6 months after operation compared with that before operation (simple resection group:P = 0.029; resection and fixation group:P = 0.037), but there was no statistical significance between the two groups at each time point postoperatively (P = 1.00). OSDI scores were significantly decreased in 6 months after operation in both groups (simple resection group:7.76 +/- 2.42; resection and fixation group:7.21 +/- 2.39) compared with those before operation (simple resection group:22.35 +/- 14.68; resection and fixation group:21.83 +/- 15.73). Both of the differences were statistically significant (simple resection group:t = 6.598, P < 0.01; resection and fixation group:t = 6.603, P < 0.01), but there was no statistically significant difference between the two groups on month 6 postoperatively (t = 0.647, P = 0.537). CONCLUSIONS: Both conjunctival resection and conjunctival resection with sclera fixation can effectively improve symptoms, but the latter has a lower recurrence rate. PMID- 25533561 TI - [Conjunctival Fas-FasL expression in chronic Stevens-Johnson syndrome]. AB - OBJECTIVE: To investigate the expression level of Fas-FasL in conjunctiva tissue of chronic Stevens-Johnson syndrome (SJS) patients and to analyze the role of Fas FasL pathway in the mechanism of ocular damage related to SJS. METHODS: Conjunctiva tissue was obtained during symblepharon release operation and cryostat sectioned at 5 um. The tissue morphology was observed by electron microscopy. The expression of Fas-FasL (CD95/CD178) in conjunctiva was detected by immunohistochemistry (direct immunofluorescence). The conjunctiva tissue of normal people was also observed and tested as contrast group. RESULTS: The pathogenic changes included incrassation of epithelium and cavity of mucous glands in the sub-epithelium. The expression of Fas in SJS patients focusing in the basal layer of epithelium appeared a lower level compared to that in normal human conjunctiva, which distributed equally in all layers of epithelium. The expressions of FasL in SJS patients and normal people were both weak. CONCLUSIONS: The low level expression of Fas-FasL in conjunctiva of SJS patients has certain effect on the chronic ocular damage. PMID- 25533562 TI - [Ten most progression of corneal and ocular surface disease research in China]. AB - Ten researches that may represent the most advanced cornea and ocular surface disease (OSD) related studies in China were voted by specialists from Chinese Cornea Group of Ophthalmology Society. These researches were concentrated in the following fields: Clinical and basic research in infectious keratitis; clinical application of modern corneal surgeries and technology; tissue engineering corneal material development; prevention and treatment of immune rejection after corneal transplantation, et al. These studies represented the level of our national cornea and ocular surface specialists in the international cornea and OSD field and have become the landmark study of our specialists. PMID- 25533563 TI - [Characteristics of filamentous fungal biofilms and their roles in ophthalmology]. AB - A filamentous fungal biofilm is a collection of hyphae and spores encased in a matrix, which has distinct developmental phases governed by complex molecular events. Resistance to antifungal drugs and components of the innate immune system remain the greatest threats to patients with filamentous fungal biofilms. There is increasing evidence that filamentous fungal biofilms play a role in a variety of ocular infections. Filamentous fungal biofilms may participate in ocular infections by allowing filamentous fungi to persist on abiotic surfaces that come in contact with the eye, and by direct biofilm formation on biotic surfaces of the eye. This review discusses the current understanding of the basic biology and clinical implications associated with filamentous fungal biofilms in ophthalmology. PMID- 25533564 TI - [Diagnosis and treatment of cytomegalovirus endotheliitis]. AB - Cytomegalovirus endotheliitis is an inflammation of the corneal endothelium caused by cytomegaloviruses. It may represent a newly identified clinical entity that has drawn increasing attention since cytomegalovirus DNA was detected from the aqueous humor of a patient with corneal endotheliitis. Its pathogenesis is still unclear, and it typically presents as corneal edema, coin-shaped/linear keratic precipitates, mild anterior chamber inflammation and with or without raised intraocular pressure in an otherwise healthy individual. In order to make an accurate diagnosis, the patient's medical history, clinical manifestations and ocular signs should all be considered, and further detection of pathogens by PCR from the ocular tissue should be done. However, misdiagnoses may occur because cytomegalovirus endotheliitis can mimic other clinical diagnoses. Patients with cytomegalovirus endotheliitis respond to systemic and topical ganciclovir with the use of topical steroids. Therefore, making an accurate early diagnosis is crucial in preventing loss of corneal endothelial cells. Moreover, if left undiagnosed, these eyes often receive increasing amounts of immunosuppressants in attempts to control the inflammation, which may worsen the ocular infection, thus compromising their visual outcomes. PMID- 25533565 TI - Dual-hormone treatment with insulin and glucagon in patients with type 1 diabetes. AB - Intensive insulin treatment in type 1 diabetes reduces the incidence and slows the progression of microvascular and macrovascular complications; however, it is associated with an increased risk of hypoglycaemia and weight gain. In this review, we propose dual-hormone treatment with insulin and glucagon as a method for achieving near normalization of blood glucose levels without increasing hypoglycaemia frequency and weight gain. We briefly summarize glucagon pathophysiology in type 1 diabetes as well as the current applications of glucagon for the treatment of hypoglycaemia. Until now, the use of glucagon has been limited by the need for reconstitution immediately before use, because of instability of the available compounds; however, stabile compounds are soon to be launched and will render long-term intensive dual-hormone treatment in type 1 diabetes possible. PMID- 25533566 TI - Assessing atrazine-induced toxicities in Bufo bufo gargarizans Cantor. AB - Atrazine (AZ), a widely used herbicide has drawn attentions for its potential impacts on amphibians. This study aims to investigate the toxicity of AZ in Bufo bufo gargarizans Cantor (B. bufo gargarizans), a species of toad commonly found in China and countries in East Asia. We treated tadpoles with 0.1, 1, 10 and 100 MUg/L AZ for 85 days and examined related parameters. The results showed that the mortality of the toads in the treatment group increased dramatically in a U shaped dose-response relationship. The hindlimb extension and metamorphosis rate of the toads were significantly inhibited by AZ at 10 and 100 MUg/L. Under the same condition, there were significant progressive changes in the testicular structures. Moreover, we found that AZ has no significant effects on growth, sex ratios, gonadal morphology, forelimb emergence and histology in the ovaries. Our results support the idea that environmental contaminants including AZ may be relevant to global amphibian decline. PMID- 25533567 TI - The heterologous expression of the Iris lactea var. chinensis type 2 metallothionein IlMT2b gene enhances copper tolerance in Arabidopsis thaliana. AB - Iris lactea var. chinensis (I. lactea var. chinensis) is a widely adapted perennial species with a high level of copper tolerance. To evaluate the role of metallothioneins (MTs) in copper tolerance in I. lactea var. chinensis, a full length cDNA homologue of MT2, designated IlMT2b (GenBank accession No. AB907788), was cloned using the RACE-PCR method. The expression level of IlMT2b in the leaves and roots of I. lactea var. chinensis was induced in response to copper (Cu) treatment. Ectopic expression of IlMT2b in Arabidopsis thaliana increased the Cu concentration and reduced H2O2 production in the transgenic plants. After treatment with 50 and 100 MUM Cu, the root length of two transgenic seedlings was respectively about 1.5- and 3-fold longer than that of the wild-type. Together, these results suggested that IlMT2b may represent a useful target gene for the phytoremediation of Cu-polluted soil. PMID- 25533568 TI - Contribution to the sustainable management of resources by novel combination of industrial solid residues into red ceramics. AB - Limited amounts of industrial residues are recycled while the remaining huge quantities are stockpiled or disposed of, thus frequently leading to soil contamination. The utilization of industrial residues as valuable secondary resources into ceramics can contribute to efficient waste management and substitution for massive amounts of natural resources (clayey minerals) demanded for ceramic production. The low cost of these residues and even possible energy savings during mixture firing may also be beneficial. In the present study, the innovative combination of lignite fly ash with steel-making dust into clay-based red ceramics is undertaken, to contribute both to sustainable use of resources and prevention of soil contamination. Brick specimens were shaped by extrusion and fired, their microstructure was examined and the effect of the mixture composition and firing temperature on physico-mechanical properties was determined. Ceramic microstructures were successfully obtained by a suitable combination of fly ash with steel dust (5 + 5 wt%) into clays. Properties can be predicted and tailored to meet the needs for specific applications by appropriately adjusting the mixture composition and sintering temperature. PMID- 25533569 TI - The colour of the human skin: fruitful science, unsuitable wordings. AB - A review of the various facets of the colour of human skin is proposed. It aims first at illustrating the paradoxical association of the remarkable recent scientific advances that characterize changes in the skin colour, with some totally inappropriate or outdated phrasings used in its communication. As a second objective, it aims at proposing an alternative to these wordings. The latter would combine six shade types, defined by Individual Type Angle (ITA) values, a coloured reference chart and associated colour adjectives, highly corresponding to the six Phototypes previously defined by Fitzpatrick. Such alternative would overcome most references to both ethnic- and ethical-related issues. PMID- 25533570 TI - Trauma history as a resilience factor for patients recovering from total knee replacement surgery. AB - Research concerning the impact of trauma history on individuals' ability to cope with subsequent events is mixed. While many studies find that trauma history increases vulnerability for conditions such as post-traumatic stress disorder and chronic pain, others reveal that there are benefits associated with moderate levels of stress (e.g. development of coping skills). OBJECTIVE: The present study investigated whether the experience of prior traumatic stressors would serve as a risk or resilience factor based on physical and emotional outcomes among patients recovering from total knee replacement surgery (TKR). DESIGN: 110 patients undergoing unilateral, TKR completed surveys before surgery, as well as one and three months following the procedure. RESULTS: Contrary to hypotheses, patients who reported more prior traumas experienced less severe pain and functional limitations at one- (beta = -.259, p = .006) and three-month follow-up assessments (beta = -.187, p = .04). A similar pattern emerged when specific types of traumas (e.g. interpersonal) were examined in relation to physical recovery. Further, patients' trauma history was negatively related to symptoms of post-traumatic stress three-months following surgery (e.g. Avoidance: beta = .200, p = .037). CONCLUSION: Trauma history represents a source of resilience, rather than vulnerability, within the context of arthroplastic surgery. PMID- 25533572 TI - Evaluation of the treatment modalities for neurosensory disturbances of the inferior alveolar nerve following retromolar bone harvesting for bone augmentation. AB - SUBJECTS: The purpose of this study was to evaluate the treatment modalities for neurosensory disturbances (NSDs) of the inferior alveolar nerve occurring after retromolar bone harvesting for bone augmentation procedures before implant placement. METHODS: One hundred four patients, of which 49 and 55 exhibited vertical or horizontal alveolar ridge defects in the mandible and maxilla, respectively, were enrolled. Nineteen patients underwent block bone grafting, 38 underwent guided bone generation or autogenous bone grafting combined with titanium mesh reconstruction, and 47 underwent sinus floor augmentation. Using a visual analog scale, we examined subjective symptoms and discomfort related to sensory alteration within the area of the NSDs in these patients. NSDs were clinically investigated using a two-point discrimination test with blunt-tipped calipers. In addition, neurometry was used for evaluation of trigeminal nerve injury. We tested three treatment modalities for NSDs: follow-up observation (no treatment), medication, and stellate ganglion block (SGB). RESULTS: A week after surgery, 26 patients (25.0%) experienced NSDs. Five patients received no treatment, 10 patients received medication, and 11 patients received SGB. Three months after surgery, patients in the medication and SGB group achieved complete recovery. Current perception threshold values recovered to near-baseline values at 3 months: recovery was much earlier in this group than in the other two groups. SGB can accelerate recovery from NSDs. CONCLUSIONS: Our results justify SGB as a reasonable treatment modality for NSDs occurring after the harvesting of retromolar bone grafts. PMID- 25533571 TI - Insulin-producing cells from embryonic stem cells rescues hyperglycemia via intra spleen migration. AB - Implantation of embryonic stem cells (ESC)-derived insulin-producing cells has been extensively investigated for treatment of diabetes in animal models. However, the in vivo behavior and migration of transplanted cells in diabetic models remains unclear. Here we investigated the location and migration of insulin-producing cells labeled with superparamagnetic iron oxide (SPIO) using a dynamic MRI tracking method. SPIO labeled cells showed hypointense signal under the kidney subcapsules of diabetic mice on MRI, and faded gradually over the visiting time. However, new hypointense signal appeared in the spleen 1 week after transplantation, and became obvious with the time prolongation. Further histological examination proved the immigrated cells were insulin and C-peptide positive cells which were evenly distributed throughout the spleen. These intra spleen insulin-producing cells maintained their protective effects against hyperglycemia in vivo, and these effects were reversed upon spleen removal. Transplantation of insulin-producing cells through spleen acquired an earlier blood glucose control as compared with that through kidney subcapsules. In summary, our data demonstrate that insulin-producing cells transplanted through kidney subcapsules were not located in situ but migrated into spleen, and rescues hyperglycemia in diabetic models. MRI may provide a novel tracking method for preclinical cell transplantation therapy of diabetes continuously and non invasively. PMID- 25533573 TI - Perceptions, experiences and needs of patients with idiopathic pulmonary fibrosis. AB - AIMS: To understand the perceptions, needs and experiences of patients with Idiopathic Pulmonary Fibrosis. BACKGROUND: Idiopathic pulmonary fibrosis is a progressive interstitial lung disease, with a mean life expectancy similar to some forms of cancer of 2-4 years from diagnosis. Unlike the cancer literature, which is rich with studies exploring the needs of their disease group, few publications exist on patient needs with this severe fibrotic lung disease. DESIGN: A Qualitative study which took place between 2007-2012. METHODS: Seventeen patients with a multidisciplinary team confirmed diagnosis of Idiopathic Pulmonary Fibrosis, with moderate to advanced disease severity and six of their informal carers were interviewed. An interview topic guide was developed by the researchers and service user group. The interviews were audio-recorded, semi-structured and took place at a regional respiratory and lung transplant centre in North West England. Interviews were transcribed verbatim and data analysed using Framework Analysis. FINDINGS: Three main themes were identified: 'Struggling to get a diagnosis'; 'Loss of the life I previously had'; and 'Living with Idiopathic Pulmonary Fibrosis'. Patients reported struggling to get a diagnosis and coping with a life-limiting, rapidly progressive illness with no good treatment and few support structures. CONCLUSIONS: There is an urgent need for a better understanding of the difficulties faced by people with Idiopathic Pulmonary Fibrosis and their carers. This can be used to develop better supportive care in the United Kingdom and ultimately improve the quality of life of these patients. PMID- 25533574 TI - A randomized controlled trial: preoperative home-based combined Tai Chi and Strength Training (TCST) to improve balance and aerobic capacity in patients with total hip arthroplasty (THA). AB - OBJECTIVES: To investigate the effect of a 12-week balance training program, combined TCST, on balance activity and aerobic capacity in patients with hip osteoarthritis. METHODS: Single-blind randomized grouping cohort study was conducted at our hospital from December 2008 to December 2011. A total of 81 patients aged from 60 to 69 years old diagnosed with end-stage hip osteoarthritis were recruited. They were randomly divided into two groups: training group (TG) and control group (CG). Participants in TG should do the TCST program under family's supervision for 12 weeks. Parameters including WOMAC score, 6 min walk test, stand up, walk test, situation of the hip mobility were compared between TG and CG by one-way ANOVA. RESULTS: There was no significant difference of baseline characteristics between these two groups (P>0.05). Participants in TG could complete 87.1% of movements of TCST. After training, the distance of 6-min walk was obviously increased from 409.59+/-51.31 m to 478.10+/-52.46 m (P<0.01), and the time for up and go was significantly shorten from 18.53+/-3.90 s to 14.61+/ 2.60 s (P<0.01), and self-reported functional status scores evaluated by WOMAC was improved from 40.97+/-5.65 to 36.28+/-5.11 (P<0.01). However, there were no significant changes in pain WOMAC and side hip motion. CONCLUSION: The 12-week TCST program have good adherence, and can effectively improve balance and aerobic capacity status in patients with end-stage osteoarthritis, while this training can not effectively alleviate the pain and improve hip motion of patients. Hence, further THA is necessary to solve the problems. PRACTICE: Patients with osteoarthritis can do this training program under family's supervision. IMPLICATIONS: Providing a good advice on rehabilitation for patients preparing to do THA. PMID- 25533575 TI - Forensic entomology of decomposing humans and their decomposing pets. AB - Domestic pets are commonly found in the homes of decedents whose deaths are investigated by a medical examiner or coroner. When these pets become trapped with a decomposing decedent they may resort to feeding on the body or succumb to starvation and/or dehydration and begin to decompose as well. In this case report photographic documentation of cases involving pets and decedents were examined from 2009 through the beginning of 2014. This photo review indicated that in many cases the pets were cats and dogs that were trapped with the decedent, died and were discovered in a moderate (bloat to active decay) state of decomposition. In addition three cases involving decomposing humans and their decomposing pets are described as they were processed for time of insect colonization by forensic entomological approach. Differences in timing and species colonizing the human and animal bodies were noted as was the potential for the human or animal derived specimens to contaminate one another at the scene. PMID- 25533576 TI - Pirfenidone gel in patients with localized scleroderma: a phase II study. AB - INTRODUCTION: Localized scleroderma is an inflammatory disease in its first stages and a fibrotic process in later stages, principally mediated by the transforming growth factor beta. To date, there is no standard treatment. The objective of this study was to determine the effectiveness and safety of 8% pirfenidone gel in patients with localized scleroderma. METHODS: This was an open phase II clinical trial that included 12 patients. Treatment with pirfenidone was indicated, three times daily for 6 months. Patients were evaluated clinically with the modified Localized Scleroderma Skin Severity Index (mLoSSI), as well with a durometer and histologically using hematoxylin and eosin stain and Masson's trichrome stain. RESULTS: The baseline mLoSSI average scores were 5.83 +/- 4.80 vs. 0.83 +/- 1.75 (P = 0.002) at 6 months. The initial durometer induration of the scleroderma plaques was 35.79 +/- 9.10 vs. 32.47 +/- 8.97 at 6 months (P = 0.05). We observed histopathological improvement with respect to epidermal atrophy, inflammation, dermal or adipose tissue fibrosis and annex atrophy from 12.25 +/- 3.25 to 9.75 +/- 4.35 (P = 0.032). The 8% pirfenidone gel application was well tolerated, and no side effects were detected. CONCLUSIONS: This is the first study on the therapeutic use of pirfenidone gel in localized scleroderma. It acts on both the inflammatory and the fibrotic phases. Considering its effectiveness, good safety profile and the advantage of topical application, pirfenidone is a treatment option in this condition. PMID- 25533577 TI - Percutaneous thrombectomy of AVF: immediate success and long-term patency rates. AB - The purpose of this study was to report the results obtained in a cohort of 520 cases of thrombosed arteriovenous fistulas (AVF) treated by percutaneous intervention over a period of 8 years. The methods used varied according to the individual characteristics of the case. A clinical success rate of 91.1% was obtained with no significant difference being noted among radial-cephalic, brachial-cephalic, and brachial-basilic AVFs. The mean primary patency for this group was 227.3 +/- 14.6 days, and the mean assisted primary patency was 677.2 +/ 44.6 days. The lower arm AVFs had both a primary patency and an assisted primary patency that were significantly better than the upper arm cases (p = 0.006 and 0.002, respectively). The primary patency for radial-cephalic AVFs was significantly better than that for brachial-cephalic AVFs (p = 0.021), but not for brachial-basilic cases (p = 0.122). Assisted primary patency for radial cephalic cases was significantly superior to the values for either patients with a brachial cephalic (p = 0.046) or a brachial-basilic (p = 0.004). Complications occurred in seven cases (1.3%), all of which were venous ruptures. Blood flow was affected in four cases. Only one of these was salvaged with angioplasty balloon tamponade. In the remaining three cases, the AVF was lost. PMID- 25533578 TI - Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents. AB - Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease. PMID- 25533579 TI - Fatigue scores in patients receiving palliative radiotherapy for painful bone metastases. AB - INTRODUCTION: The purpose of this study was to examine changes in fatigue scores for patients receiving radiation therapy for bone metastases and its impact on quality of life (QOL). METHODS: Fatigue and QOL scores were prospectively collected in patients for up to 3 months following radiation therapy for bone metastases using three questionnaires: group 1, Edmonton Symptom Assessment System (ESAS) (0-10); group 2, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30); and Core 15 Palliative (EORTC QLQ-C15-PAL) (1-4). RESULTS: Average fatigue score in group 1 (399 patients) was 4.72 at baseline, 5.08 at month 1, 5.01 at month 2, and 4.95 at month 3, and was 2.40, 2.39, 2.56, and 2.70 in group 2 (482 patients), respectively. Thirty-five percent of patients in group 1 had fatigue score increase >=2 points at month 1, 36% at month 2, and 36% at month 3. Twenty-one percent of patients in group 2 had fatigue score increase >=1 at month 1, 27% at month 2, and 40% at month 3. There was a statistically significant increase in fatigue score from baseline to all 3 months in group 1 only. In both groups, there was a highly significant negative correlation between fatigue and overall QOL scores at baseline and any follow-up month. CONCLUSIONS: There was a statistically significant worsening in fatigue in group 1 only. Up to one third had increased fatigue of clinical significance. Patients with less fatigue symptoms reported better overall QOL. PMID- 25533580 TI - Cancer-related fatigue: results from patient experience surveys undertaken in a UK regional cancer centre. AB - PURPOSE: Cancer-related fatigue (CRF) is a common but under reported symptom significantly impacting on cancer patients' quality of life. The purpose of these surveys was to drive improvements in the provision of support of patients with CRF. METHOD: Two surveys were conducted to determine the incidence and impact of cancer-related fatigue (CRF) amongst patients attending a Cancer Centre (CC) for radiotherapy and/or systemic anti-cancer therapy. RESULTS: Survey 1: retrospective examination of 68 patients' clinical notes. Survey 2: a questionnaire distributed prospectively to 148 patients whilst attending for treatment. Survey 1 identified 29 patients' notes recording the patient experiencing fatigue, but only two were given any advice to manage symptoms. In survey 2, the majority of patients (86%) were advised about the risk of CRF before treatment, but only 67% were assessed and advised about CRF during treatment. Physical fatigue (57%) was more common than emotional (37%) or cognitive fatigue (29%). CONCLUSIONS: Many patients are not being given advice to manage their CRF symptoms. Reasons for this include a lack of awareness regarding the occurrence of CRF and its impact and a misunderstanding by Health Care Professionals (HCPs) about the advice patients should be given. Recommendations include the continued need to improve education of HCPs to ensure patients receive the appropriate advice they need to manage their CRF. PMID- 25533581 TI - Management of fever and neutropenia in children with cancer. AB - PURPOSE: Febrile neutropenia remains a common, life-threatening complication of chemotherapy in paediatric oncology. Delays in institution of empiric antibiotics have been identified at tertiary and regional centres caring for these patients and associated with decreased survival. Our objective was to reduce the time to administration of empiric antibiotics to less than 60 min from the time of presentation to hospital. METHODS: A retrospective study of the records of oncology patients presenting to the emergency department of a tertiary hospital over a 3-month period was performed and time to first antibiotic administration recorded. Potential causes of delay in commencement of antibiotics were identified and an algorithm-based approach to the management of fever in immunocompromised children developed and implemented. Follow-up evaluation data were collected at 12 and 60 months post-intervention. Causes of delay in commencement of antibiotics at regional hospitals that share care with the tertiary hospital were identified through questionnaires, interviews and focus groups, involving patients and medical and nursing staff. The impact of the introduction of the algorithm at one peripheral hospital was evaluated. RESULTS: The mean time to empiric antibiotics was reduced from 148 min (95% confidence interval (CI) 81-216) at baseline to 76 min (95% CI 50-101) at 12 months post intervention and sustained at 65 min (95% CI 52-77) 5 years after the intervention. At the peripheral hospital, mean time to antibiotic delivery was reduced from 221 min (95% CI 114-328) to 65 min (95% CI 42-87) at 12 months after the intervention. CONCLUSION: The introduction of the guideline, with teaching and support for staff and parents, resulted in an improvement in practice, meeting international guidelines and achieving sustained results at 5 years after introduction at a tertiary hospital. The guideline has been shown to be feasible and effective at a regional hospital. PMID- 25533582 TI - Low-level vagosympathetic trunk stimulation inhibits atrial fibrillation in a rabbit model of obstructive sleep apnea. AB - BACKGROUND: Atrial fibrillation (AF) is highly associated with obstructive sleep apnea (OSA) in which AF is triggered by hyperactivity of the cardiac autonomic nervous system. Previous studies showed that low-level vagosympathetic trunk stimulation (LLVS), at voltages not slowing sinus rate or AV conduction, inhibits AF by suppressing the cardiac autonomic nervous system. OBJECTIVE: The purpose of this study was to investigate whether LLVS delivered at the right vagosympathetic trunk suppresses AF in a rabbit model of OSA. METHODS: Eleven rabbits received a tracheostomy under general anesthesia. The endotracheal tube was clamped at end expiration for 1 minute to simulate OSA. Over a period of 4 hours, OSA was delivered every 6 minutes. Effective refractory period (ERP), blood pressure, intraesophageal pressure, and blood gases (O2, CO2, pH) were measured before and after each episode of OSA. AF duration and ERP were measured by programmed stimulation. Group 1 rabbits (n = 6) received LLVS (50% below that which slowed the sinus rate) in the first 3 hours. Group 2 rabbits (n = 5) only received OSA. RESULTS: Group 1 ERP began to lengthen progressively from the second hour compared to group 2. AF duration increased in the first hour for both groups but began to shorten progressively after the first hour in group 1 rabbits. Blood pH, O2 or CO2 level, intraesophageal pressure, and hypertensive response during OSA were not different between the 2 groups. CONCLUSION: LLVS is capable of suppressing ERP shortening and AF induced by OSA. LLVS may serve as a new therapeutic approach to treat OSA-induced AF. PMID- 25533583 TI - Pseudo-tamponade during transvenous lead extraction. PMID- 25533584 TI - Morphology of right atrial appendage for permanent atrial pacing and risk of iatrogenic perforation of the aorta by active fixation lead. AB - BACKGROUND: Permanent atrial pacing usually involves lead placement in the right atrial appendage (RAA). Anatomical studies addressing features predisposing to complications are scanty. OBJECTIVE: To assess the morphology of RAA in the perspective of pacing, including the morphology of tenia sagittalis (TS) and the spatial relationship with the aorta. METHODS: The gross anatomy of the RAA has been analyzed in a consecutive series of 100 hearts following a case of iatrogenic perforation of the aorta by active fixation lead located in the RAA. Transmural RAA sections were taken from 40 hearts to assess the wall thickness at the level of pectinate muscles (PMs) and of inter-PMs spaces and the distance between adjacent PMs. RESULTS: The TS was present in 90% of cases (single trunk, 76%; double trunk, 13%; and triple trunk, 1%), demarcating the proximal antral RAA region (facing the adjacent aorta) from the distal saccular RAA region (facing the pulmonary infundibulum). The RAA free wall in the inter-PMs spaces is usually paper-thin and translucent. Histomorphometric analysis reveals that the RAA wall mean thickness was 1.38 +/- 0.05 mm (range 0.64-4.25 mm) at the level of PMs and 0.39 +/- 0.23 mm (range 0.09-1.05 mm) at the level of inter-PMs spaces. The mean distance between adjacent PMs was 0.88 +/- 0.99 mm (range 0.04-4.12 mm). CONCLUSION: In 90% of hearts, a well-defined TS separates the distal saccular from the proximal antral RAA, the latter being closely adjacent to the ascending aorta. The paper-thin wall between PMs is potentially at risk of perforation, and aortic injury could occur when active fixation leads are anchored in the antral RAA, as demonstrated in an iatrogenic fatal case. PMID- 25533585 TI - Myocardial tissue characterization by cardiac magnetic resonance imaging using T1 mapping predicts ventricular arrhythmia in ischemic and non-ischemic cardiomyopathy patients with implantable cardioverter-defibrillators. AB - BACKGROUND: Diffuse myocardial fibrosis may provide a substrate for the initiation and maintenance of ventricular arrhythmia. T1 mapping overcomes the limitations of the conventional delayed contrast-enhanced cardiac magnetic resonance (CE-CMR) imaging technique by allowing quantification of diffuse fibrosis. OBJECTIVE: The purpose of this study was to assess whether myocardial tissue characterization using T1 mapping would predict ventricular arrhythmia in ischemic and non-ischemic cardiomyopathies. METHODS: This was a prospective longitudinal study of consecutive patients receiving implantable cardioverter defibrillators in a tertiary cardiac center. Participants underwent CMR myocardial tissue characterization using T1 mapping and conventional CE-CMR scar assessment before device implantation. The primary end point was an appropriate implantable cardioverter-defibrillator therapy or documented sustained ventricular arrhythmia. RESULTS: One hundred thirty patients (71 ischemic and 59 non-ischemic) were included with a mean follow-up period of 430 +/- 185 days (median 425 days; interquartile range 293 days). At follow-up, 23 patients (18%) experienced the primary end point. In multivariable-adjusted analyses, the following factors showed a significant association with the primary end point: secondary prevention (hazard ratio [HR] 1.70; 95% confidence interval [95% CI] 1.01-1.91), noncontrast T1(_native) for every 10-ms increment in value (HR 1.10; CI 1.04-1.16; 90-ms difference between the end point-positive and end point negative groups), and Grayzone(_2sd-3sd) for every 1% left ventricular increment in value (HR 1.36; CI 1.15-1.61; 4% difference between the end point-positive and end point-negative groups). Other CE-CMR indices including Scar(_2sd), Scar(_FWHM), and Grayzone(_2sd-FWHM) were also significantly, even though less strongly, associated with the primary end point as compared with Grayzone(_2sd 3sd). CONCLUSION: Quantitative myocardial tissue assessment using T1 mapping is an independent predictor of ventricular arrhythmia in both ischemic and non ischemic cardiomyopathies. PMID- 25533587 TI - Performance of a novel left ventricular lead with short bipolar spacing for cardiac resynchronization therapy: primary results of the Attain Performa quadripolar left ventricular lead study. AB - BACKGROUND: The Medtronic Attain Performa quadripolar leads provide 16 pacing vectors with steroid on every electrode. This includes a short bipolar configuration between the middle 2 electrodes. OBJECTIVE: A prospective clinical study was conducted to investigate the safety and effectiveness of these new leads in 27 countries. METHODS: Cardiac resynchronization therapy with defibrillator candidates were enrolled (mean age 68 years; 71% men). All implanted subjects were followed at 1, 3, and 6 months postimplant. Pacing capture threshold (PCT) values were measured at each visit. Adverse events were reported upon occurrence. RESULTS: Of 1124 subjects in whom a left ventricular (LV) lead was attempted, 1097 (97.6%) were successfully implanted with an Attain Performa lead. Thirty-six LV lead-related complications were reported (the 6 month LV lead-related complication-free survival rate was 96.9%). Phrenic nerve stimulation (PNS) occurred in 81 subjects (7.2%), with only 3 (0.3%) requiring surgical intervention. At 6 months, the mean PCT at the programmed vector was (1.1 +/- 0.8) V and 94.4% of subjects had a PCT of <=2.5 V. All 16 programming polarities were used in at least 1 patient, and short bipolar configurations were used in 17% of subjects. CONCLUSION: This large multicenter study demonstrated a high success rate for the implantation of Attain Performa quadripolar LV leads with a low complication rate. The PCT was low and stable over time. A low rate of postimplantation PNS was observed, and cases of PNS were readily resolved with reprogramming. Nonstandard vectors were often used for LV pacing. PMID- 25533588 TI - The use of low-level electromagnetic fields to suppress atrial fibrillation. AB - BACKGROUND: Extremely low-level electromagnetic fields have been proposed to cause significant changes in neural networks. OBJECTIVE: We sought to investigate whether low-level electromagnetic fields can suppress atrial fibrillation (AF). METHODS: In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the placement of multielectrode catheters in both atria and at all pulmonary veins. AF was induced by rapid atrial pacing (RAP) or programmed atrial extrastimulation. At baseline and end of each hour of RAP, during sinus rhythm, atrial programmed stimulation gave both the effective refractory period (ERP) and the width of the window of vulnerability. The latter was a measure of AF inducibility. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural firing. Helmholtz coils were powered by a function generator inducing an electromagnetic field (EMF; 0.034 MUG, 0.952 Hz). The study sample was divided into 2 groups: group 1 (n = 7)-application of EMF to both cervical vagal trunks; group 2 (n = 10)-application of EMF across the chest so that the heart was located in the center of the coil. RESULTS: In group 1, EMF induced a progressive increase in AF threshold at all pulmonary vein and atrial sites (all P < .05). In group 2, the atrial ERP progressively shortened and ERP dispersion and window of vulnerability progressively increased (P < .05 compared to baseline values) during 3 hours of RAP and then returned to baseline values during 3 hours of combined application of RAP and EMF (P < .05 compared to the end of the third hour of RAP). The frequency and amplitude of the neural activity recorded from the anterior right ganglionated plexi were markedly suppressed by EMF in both groups. CONCLUSION: Pulsed EMF applied to the vagal trunks or noninvasively across the chest can significantly reverse AF inducibility. PMID- 25533589 TI - Asymmetric block copolymers for supramolecular templating of inorganic nanospace materials. AB - This review focuses on polymeric micelles consisting of asymmetric block copolymers as designed templates for several inorganic nanospace materials with a wide variety of compositions. The presence of chemically distinct domains of asymmetric triblock and diblock copolymers provide self-assemblies with more diverse morphological and functional features than those constructed by EOn POm EOn type symmetric triblock copolymers, thereby affording well-designed nanospace materials. This strategy can produce unprecedented nanospace materials, which are very difficult to prepare through other conventional organic templating approaches. Here, the recent development on the synthesis of inorganic nanospace materials are mainly focused on, such as hollow spheres, tubes, and porous oxides, using asymmetric triblock copolymers. PMID- 25533590 TI - Interaction of alcohols with the calcite surface. AB - A clearer understanding of calcite interactions with organic molecules would contribute to a range of fields including harnessing the secrets of biomineralisation where organisms produce hard parts, increasing oil production from spent reservoirs, remediating contaminated soils and drinking water aquifers and improving manufacturing methods for industrial products such as pigments, soft abrasives, building materials and optical devices. Biomineralisation by some species of blue green algae produces beautifully elaborate platelets of calcite where the individual crystals are of nanometer scale. Controlling their growth requires complex polysaccharides. Polysaccharide activity depends on the functionality of OH groups, so to simplify the system in order to get closer to a molecular level understanding, we investigated the interaction of OH from a suite of alcohols with clean, freshly cleaved calcite surfaces. X-ray photoelectron spectroscopy (XPS) provided binding energies and revealed the extent of surface coverage. Molecular dynamics (MD) simulations supplemented with information about molecule ordering, orientation and packing density. The results show that all alcohols studied bond with the calcite surface through the OH group, with their carbon chains sticking away in a standing-up orientation. Alcohol molecules are closely packed and form a well-ordered monolayer on the surface. PMID- 25533586 TI - Comparison of preexisting and ablation-induced late gadolinium enhancement on left atrial magnetic resonance imaging. AB - BACKGROUND: Postablation atrial fibrillation recurrence is positively associated with the extent of preexisting left atrial (LA) late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI), but negatively associated with the extent of postablation LGE regardless of proximity to the pulmonary vein antra. The characteristics of pre- vs postablation LA LGE may provide insight into this seeming paradox and inform future strategies for ablation. OBJECTIVE: The purpose of this study was to define the characteristics of preexisting vs ablation induced LA LGE. METHODS: LGE-MRI was prospectively performed before and >=3 months after initial ablation in 20 patients. The intracardiac locations of ablation points were coregistered with the corresponding sites on axial planes of postablation LGE-MRI. The image intensity ratio (IIR), defined as the LA myocardial MRI signal intensity divided by the mean LA blood pool intensity, and LA myocardial wall thickness were calculated on pre- and postablation images. RESULTS: Imaging data from 409 pairs of pre- and postablation axial LGE-MRI planes and 6961 pairs of pre- and postablation image sectors were analyzed. Ablation-induced LGE revealed a higher IIR, suggesting greater contrast uptake and denser fibrosis, than did preexisting LGE (1.25 +/- 0.25 vs 1.14 +/- 0.15; P < .001). In addition, ablation-induced LGE regions had thinner LA myocardium (2.10 +/- 0.67 mm vs 2.37 +/- 0.74 mm; P < .001). CONCLUSION: Regions with ablation-induced LGE exhibit increased contrast uptake, likely signifying higher scar density, and thinner myocardium as compared with regions with preexisting LGE. Future studies examining the association of postablation LGE intensity and nonuniformity with ablation success are warranted and may inform strategies to optimize ablation outcome. PMID- 25533591 TI - Effects of 8 weeks of CPAP on lipid-based oxidative markers in obstructive sleep apnea: a randomized trial. AB - Dyslipidaemia and increased oxidative stress have been reported in severe obstructive sleep apnea, and both may be related to the development of cardiovascular disease. We have previously shown in a randomized crossover study in patients with moderate to severe obstructive sleep apnea that therapeutic continuous positive airway pressure treatment for 8 weeks improved postprandial triglycerides and total cholesterol when compared with sham continuous positive airway pressure. From this study we have now compared the effect of 8 weeks of therapeutic continuous positive airway pressure and sham continuous positive airway pressure on oxidative lipid damage and plasma lipophilic antioxidant levels. Unesterified cholesterol, esterified unsaturated fatty acids (cholesteryl linoleate: C18:2; and cholesteryl arachidonate: C20:4; the major unsaturated and oxidizable lipids in low-density lipoproteins), their corresponding oxidized products [cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE O(O)H)] and antioxidant vitamin E were assessed at 20:30 hours before sleep, and at 06:00 and 08:30 hours after sleep. Amongst the 29 patients completing the study, three had incomplete or missing [CE-O(O)H] data. The mean apnea -hypopnoea index, age and body mass index were 38 per hour, 49 years and 32 kg m(-2) , respectively. No differences in lipid-based oxidative markers or lipophilic antioxidant levels were observed between the continuous positive airway pressure and sham continuous positive airway pressure arms at any of the three time-points [unesterified cholesterol 0.01 mm, P > 0.05; cholesteryl linoleate: C18:2 0.05 mm, P > 0.05; cholesteryl arachidonate: C20:4 0.02 mm, P = 0.05; CE-O(O)H 2.5 nm, P > 0.05; and lipid-soluble antioxidant vitamin E 0.03 MUm, P > 0.05]. In this study, accumulating CE-O(O)H, a marker of lipid oxidation, does not appear to play a role in oxidative stress in obstructive sleep apnea. PMID- 25533592 TI - Insight in inpatients with schizophrenia: relationship to symptoms and neuropsychological functioning. AB - OBJECTIVE: Lack of insight into illness has long been recognized as a central characteristic of schizophrenia. Although recent theories have emphasized neurocognitive dysfunction as a central impairment in schizophrenia it remains unclear whether the lack of insight in schizophrenia is more strongly associated with measures of symptom severity or neuropsychological dysfunction. METHODS: Seventy-four consecutive inpatients with chronic schizophrenia were enrolled in a cross-sectional study. All subjects were assessed with the Positive and Negative Syndrome Scale (PANSS, five-factor model), the Insight and Treatment Attitudes Questionnaire (ITAQ), and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). Bivariate association and multiple linear regression analyses were used to investigate the relationship between insight and both symptoms and neurocognition. RESULTS: On bivariate correlation, the positive, negative, disorganized and excited factors of the PANSS showed a negative correlation with insight but there was no significant association between the MCCB total score or any component subscale and insight. Multiple regression analysis showed that positive symptoms, disorganized/concrete symptoms and excited symptoms contributed to awareness of mental illness; positive and disorganized/concrete symptoms were significant contributors to awareness of the need for treatment; but there were no significant associations with the MCCB. CONCLUSIONS: Insight in this sample of patients with chronic schizophrenia is significantly associated with clinical symptoms but not with neuropsychological functioning. PMID- 25533593 TI - Persistence of effectiveness of cognitive remediation interventions in schizophrenia: a 1-year follow-up study. AB - OBJECTIVES: Cognitive remediation interventions are effective in patients with schizophrenia, but the durability of their effects is still under debate. This study aimed to investigate the 1-year persistence of the effectiveness of cognitive remediation. METHODS: Patients with schizophrenia treated with cognitive remediation or usual rehabilitation were reassessed with clinical, neuropsychological and functional measures 1year after cognitive remediation. RESULTS: At the 1-year follow-up, the advantages of cognitive remediation remained significant for clinical variables and specific cognitive domains. Functional measures showed increasing improvement at follow-up. CONCLUSIONS: The study suggests that the effectiveness of cognitive remediation in schizophrenia persists after 1year. PMID- 25533594 TI - 'What is more familiar than I? Self, other and familiarity in schizophrenia. AB - BACKGROUND: Familiarity disorders (FDs) critically impact social cognition in persons with schizophrenia. FDs can affect both relationships with people familiar to the patient and the patient's relationship with himself, in the case of a self-disorder. Skin conductance response (SCR) studies have shown that familiar and unknown faces elicit the same emotional response in persons with schizophrenia with FD. Moreover, in control subjects, one's own face and familiar faces have been shown to activate strongly overlapping neural networks, suggesting common processing. The aim of the present study was to determine whether the mechanisms involved in processing one's own and familiar faces are similarly impaired in persons with schizophrenia, suggesting a link between them. METHOD: Twenty-eight persons with schizophrenia were compared with twenty control subjects. Three face conditions were used: specific familiar, self and unknown. The task was to indicate the gender of the faces presented randomly on a screen during SCR recording. Face recognition was evaluated afterwards. RESULTS: Control subjects exhibited similar SCRs for the familiar and self-conditions, which were higher than the responses elicited by the unknown condition, whereas persons with schizophrenia exhibited no significant differences between the three conditions. CONCLUSION: Persons with schizophrenia have a core defect of both self and familiarity that is emphasised by the lack of an increased SCR upon presentation with either self or familiar stimuli. Familiarity with specific familiar faces and one's own face may be driven by the same mechanism. This perturbation may predispose persons with schizophrenia to delusions and, in particular, to general familiarity disorder. PMID- 25533596 TI - Special issue: Basic mechanisms of pediatric epilepsy. PMID- 25533595 TI - Emotion recognition in unaffected first-degree relatives of individuals with first-episode schizophrenia. AB - OBJECTIVE: Impairments in recognising negative emotions are found in individuals with first-episode and chronic schizophrenia and also in those at ultra-high risk for the illness. Whether these impairments are an endophenotype for schizophrenia is unclear. To examine the heritability of emotion recognition, the aim of this study was to examine whether facial and prosody emotion recognition deficits, particularly for negative emotions, are also present in unaffected first-degree relatives of people with schizophrenia. METHODS: Face and prosody emotion recognition (ER) were examined in individuals with first-episode schizophrenia (n=30), their unaffected first-degree relatives (n=27) and healthy controls (n=30). Measures of psychopathology and IQ were also administered. RESULTS: On the face ER task, first-episode schizophrenia participants performed significantly more poorly in recognising anger (p=.017), disgust (p=.033) and fear (p=.040) and first-degree relatives were significantly poorer at recognising fear (p=.003) than healthy controls. On the prosody ER task, first-episode schizophrenia participants made significantly more errors in recognising anger (p=.001) and surprise (p=.003) and first-degree relatives were significantly poorer at recognising anger (p=.005) than healthy controls. Effect sizes were medium to large. After controlling for age, IQ and symptoms, both unaffected first-degree relatives and first-episode schizophrenia patients displayed a significant deficit in facial fear recognition relative to healthy controls (p=.040 and p=.048, respectively). This deficit was not associated with current psychiatric symptoms. CONCLUSIONS: These findings bolster evidence for emotion recognition (particularly for fear) as a heritable characteristic of schizophrenia. However, the diagnostic specificity of this finding requires further investigation. PMID- 25533597 TI - Preparation of Ge nanotube arrays from an ionic liquid for lithium ion battery anodes with improved cycling stability. AB - Ge nanotube array anodes are prepared by template-assisted electrodeposition from an ionic liquid to obtain superior cycling performance. They show remarkable cycling ability at 0.2 C, with a very high initial discharge capacity of 1641 mA h g(-1) and a charge capacity of 1260 mA h g(-1). After 250 cycles the capacity retention is 98% relative to that at the 50th cycle. PMID- 25533598 TI - Alterations in microRNA expression in a murine model of diet-induced vasculogenic erectile dysfunction. AB - INTRODUCTION: MicroRNAs (miRs) are noncoding, endogenous RNA molecules that regulate gene expression and play roles in response to vascular injury. AIM: The aim of this study was to identify miRs expressed in corporal tissue (CT) and to determine whether miRs demonstrate differential expression in a mouse model of diet-induced erectile dysfunction (ED). METHODS: RNA was isolated from the CT from control mice and mice with diet-induced ED. A quantifiable miR profiling technique (NanoString) was used to determine the expression of over 600 miRs. MAIN OUTCOME MEASURES: Differential expression analysis was performed using a negative binomial regression model for count-based data. Mean expression levels, fold change, and false discovery-corrected P values were determined. Candidate miRs were validated via quantitative polymerase chain reaction (Q-PCR). RESULTS: In control mice, NanoString analysis revealed that 181 miRs were expressed above background levels and 5 miRs were expressed at high levels. Diet-induced ED resulted in the up-regulation of 6 miRs and the down-regulation of 65 miRs in the CT compared with mice on control diet. Focusing on the upregulated miRs, we chose five for Q-PCR validation. Of these five, two (miR-151-5p and miR-1937c) demonstrated significance via Q-PCR, whereas the other three (miR-720, miR-1937a, miR-205) trended in the correct direction. CONCLUSIONS: MiRs may play a significant role in mRNA regulation in CT and specific miRs may be involved in diet-induced vasculogenic ED. Future studies are aimed at determining the mRNA targets of these miRs. PMID- 25533599 TI - Changing incidence and outcomes following dialysis-requiring acute kidney injury among critically ill adults: a population-based cohort study. AB - BACKGROUND: Dialysis-requiring acute kidney injury (AKI) is common among critically ill patients, but little is known about trends in the incidence and outcomes of this condition over time. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: All adult patients admitted to an intensive care unit in Ontario, Canada, 1996 to 2010. PREDICTOR: Year and era (1996-2000, 2001 2005, and 2006-2010) of cohort entry. OUTCOMES: Mortality and dialysis dependence, each evaluated at 90 and 365 days after initiation of dialysis therapy for AKI. MEASUREMENTS: The annual incidence proportion of dialysis requiring AKI was evaluated and patients with this condition were characterized by era. Associations between era and the outcomes of interest were evaluated with Cox proportional hazards (for time to death) and logistic regression (for dialysis dependence), with adjustment for relevant demographic and clinical variables. RESULTS: The annual incidence of dialysis-requiring AKI among critically ill patients increased from 0.8% in 1996 to 3.0% in 2010 (P for trend < 0.001). 90-day mortality declined from 50% in 1996 to 2000 to 45% in 2006 to 2010 (adjusted HR, 0.83 [95% CI, 0.79-0.87] compared to 1996-2000). Dialysis dependence among surviving patients at 90 days was marginally lower in 2006 to 2010 (25.1%) compared to 1996 to 2000 (27.2%), but after adjustment for confounding factors, was not significantly different (adjusted OR, 0.91; 95% CI, 0.80-1.03). LIMITATIONS: Unmeasured confounding by factors that may have changed in patients with dialysis-requiring AKI during the different eras; data set does not allow for mechanistic explanation for the findings; and lack of access to laboratory investigations after hospital discharge. CONCLUSIONS: The incidence proportion of dialysis-requiring AKI among critically ill patients increased by almost 4-fold between 1996 and 2010. This was accompanied by a significant decline in mortality, but the risk of long-term dialysis dependence continues to affect a substantial minority of surviving patients with no clear evidence of improvement over time. PMID- 25533600 TI - Distal renal tubular acidosis with multiorgan autoimmunity: a case report. AB - A 61-year-old woman with a history of pernicious anemia presented with progressive muscle weakness and dysarthria. Hypokalemic paralysis (serum potassium, 1.4 mEq/L) due to distal renal tubular acidosis (dRTA) was diagnosed. After excluding several possible causes, dRTA was considered autoimmune. However, the patient did not meet criteria for any of the autoimmune disorders classically associated with dRTA. She had very high antibody titers against parietal cells, intrinsic factor, and thyroid peroxidase (despite normal thyroid function). The patient consented to a kidney biopsy, and acid-base transporters, anion exchanger type 1 (AE1), and pendrin were undetectable by immunofluorescence. Indirect immunofluorescence detected diminished abundance of AE1- and pendrin-expressing intercalated cells in the kidney, as well as staining by the patient's serum of normal human intercalated cells and parietal cells expressing the adenosine triphosphatase hydrogen/potassium pump (H(+)/K(+)-ATPase) in normal human gastric mucosa. The dRTA likely is caused by circulating autoantibodies against intercalated cells, with possible cross-reactivity against structures containing gastric H(+)/K(+)-ATPase. This case demonstrates that in patients with dRTA without a classic autoimmune disorder, autoimmunity may still be the underlying cause. The mechanisms involved in autoantibody development and how dRTA can be caused by highly specific autoantibodies against intercalated cells have yet to be determined. PMID- 25533602 TI - Parent-mediated reading interventions with children up to four years old: a systematic review. AB - Research demonstrates that literacy and academic achievement are predicated on the emergent literacy knowledge and skills children acquire from birth up to 4 years of age. Parents are children's first and most important language and literacy teachers, yet not all parents have the capacity to establish an adequate early literacy foundation. Efforts to address this situation have resulted in numerous programs aimed at fostering emergent literacy development. This systematic review evaluates evidence on the effectiveness of parent-mediated interventions that increase the time parents spend reading with young children up to 4 years old. Four studies met inclusion criteria, reporting outcomes for 664 children. Three provided data for meta-analysis of effects on reading duration. The standardized mean difference in reading duration was 1.61 (95% CI, 1.03, 2.19 fixed-effect), favoring intervention over control. Results indicate that interventions aimed at increasing the amount of time parents spend reading interactively with their children yield positive results. Findings also demonstrate that pediatric primary care providers are well positioned to deliver reading promotion programs to parents and preschoolers. PMID- 25533601 TI - Progressive Resistance Exercise Training in CKD: A Feasibility Study. AB - BACKGROUND: Skeletal muscle wasting in chronic kidney disease (CKD) is associated with morbidity and mortality. Resistance exercise results in muscle hypertrophy in the healthy population, but is underinvestigated in CKD. We aimed to determine the feasibility of delivering a supervised progressive resistance exercise program in CKD, with secondary aims to investigate effects on muscle size, strength, and physical functioning. STUDY DESIGN: Parallel randomized controlled feasibility study. SETTING & PARTICIPANTS: Patients with CKD stages 3b to 4 were randomly assigned to the exercise (n=20; 11 men; median age, 63 [IQR, 57-65] years; median estimated glomerular filtration rate, 28.5 [IQR, 19.0-32.0] mL/min/1.73 m(2)) or nonexercise control (n=18; 14 men; median age, 66 [IQR, 45 79] years; estimated glomerular filtration rate, 20.5 [IQR, 16.0-26.0] mL/min/1.73 m(2)) group. INTERVENTION: Patients in the exercise group undertook an 8-week progressive resistance exercise program consisting of 3 sets of 10 to 12 leg extensions at 70% of estimated 1-repetition maximum thrice weekly. Patients in the control group continued with usual physical activity. OUTCOMES: Primary outcomes were related to study feasibility: eligibility, recruitment, retention, and adherence rates. Secondary outcomes were muscle anatomical cross sectional area, muscle volume, pennation angle, knee extensor strength, and exercise capacity. MEASUREMENTS: Two- and 3-dimensional ultrasonography of skeletal muscle, dynamometry, and shuttle walk tests at baseline and 8 weeks. RESULTS: Of 2,349 patients screened, 403 were identified as eligible and 38 enrolled in the study. 33 (87%) completed the study, and those in the exercise group attended 92% of training sessions. No changes were seen in controls for any parameter. Progressive resistance exercise increased muscle anatomical cross sectional area, muscle volume, knee extensor strength, and exercise capacity. LIMITATIONS: No blinded assessors, magnetic resonance imaging not used to assess muscle mass, lack of a healthy control group. CONCLUSIONS: This type of exercise is well tolerated by patients with CKD and confers important clinical benefits; however, low recruitment rates suggest that a supervised outpatient-based program is not the most practical implementation strategy. PMID- 25533603 TI - Data driven processes for assessing children's hospitals and units: professor Alan Glasper discusses how children's nurses can enhance care delivery using pertinent data. PMID- 25533605 TI - Competition H(D) kinetic isotope effects in the autoxidation of hydrocarbons. AB - Hydrogen atom transfer is central to many important radical chain sequences. We report here a method for determination of both the primary and secondary isotope effects for symmetrical substrates by the use of NMR. Intramolecular competition reactions were carried out on substrates having an increasing number of deuterium atoms at symmetry-related sites. Products that arise from peroxyl radical abstraction at each position of the various substrates reflect the competition rates for H(D) abstraction. The primary KIE for autoxidation of tetralin was determined to be 15.9 +/- 1.4, a value that exceeds the maximum predicted by differences in H(D) zero-point energies (~7) and strongly suggests that H atom abstraction by the peroxyl radical occurs with substantial quantum mechanical tunneling. PMID- 25533606 TI - Retreatment with rituximab offers a similar survival benefit as maintenance therapy in patients with low tumor burden follicular lymphoma. PMID- 25533608 TI - Reply: To PMID 23928675. PMID- 25533609 TI - Reply: To PMID 24362413. PMID- 25533610 TI - A comparative study on morphological versus molecular identification of dermatophyte isolates. AB - OBJECTIVE: Dermatophytes are taxonomically classified in the genera Trichophyton, Microsporum, and Epidermophyton. Pleomorphism, cultural variability, slow growth and sporulation, and the need for additional physiological tests make dermatophytes notoriously difficult to identify. The present study aimed to compare the results of morphological and molecular identification of certain groups of clinical isolates of dermatophytes with a view to evaluating the accuracy of molecular methods. PATIENTS AND METHODS: For each sample, the ITS1 5.8S-ITS2 rDNA region was amplified using the primers ITS1 and ITS4. PCR products were subjected to restriction fragment length polymorphism (RFLP) analysis using the enzyme MvaI and isolate identification was performed by comparing the electrophoretic RFLP patterns with reference profiles obtained previously. Finally, paired comparative analyses of molecular and conventional methods were performed. RESULTS: While morphology results from routine daily reports of the laboratories indicated that 18 (6.8%) and 136 (52.10%) of the isolates were T. rubrum and T. interdigitale, respectively, PCR-RFLP results suggested that T. rubrum was the most common etiological agent of ringworm accounting for 94 (36.01%), followed by T. interdigitale accounting for 71 (27.20%). Interestingly, 80.8% out of the 94 isolates identified as T. rubrum by molecular testing had been identified by morphological examination as belonging to different species, such as T. interdigitale (75.5%), E. floccosum (2.1%) and M. canis, T. verrucosum, and T. tonsurans (each 1.06%). Ten strains out of 261 (T. interdigitale, n=8; E. floccosum, n=2) had been defined as unknown species by morphological tests. CONCLUSION: An unexpected high percent of isolates identified as T. interdigitale by conventional methods were in effect T. rubrum shown by PCR-RFLP, and regarding the necessity of correct identification of dermatophytes recovered from different clinical forms of the infection, we highly recommend ITS-sequencing or ITS-RFLP of the isolates, particularly for epidemiological research studies. PMID- 25533611 TI - Sex differences in bladder cancer pathology and survival: analysis of a population-based cancer registry. AB - Sex differences in bladder cancer pathology and epidemiology have been the focus of recent research. We investigated the epidemiological characteristics and compared bladder cancer pathology and survival between men and women in Japan. A total of 13,184 patients with primary bladder cancer diagnosed from 1954 to 2010 were identified in a large-scale cancer registry database in Kanagawa Prefecture. Using this database, we compared the odds ratios (ORs) for nonurothelial carcinoma (non-UC) using a multiple logistic regression model adjusted for age and diagnosis periods. We also compared hazard ratios (HRs) for overall death and cancer-specific death using a Cox proportional hazards model adjusted for non-UC, age, and diagnosis period. The proportion of non-UC was significantly higher in female compared with male patients (OR = 2.14, 95% confidence interval [CI]: 1.81 2.52). Furthermore, survival was significantly poorer in female patients than in male patients after adjusting for UC or non-UC (HR for overall death = 1.15, 95% CI: 1.06-1.23; HR for cancer-specific death = 1.39, 95% CI: 1.28-1.52). Sex differences exist in the epidemiological characteristics of bladder cancer in Japan, with female patients having less favorable pathology and poorer survival compared with male patients. PMID- 25533613 TI - Molecular analysis and antimicrobial susceptibility of enterotoxigenic Escherichia coli from diarrheal patients. AB - A total of 123 enterotoxigenic Escherichia coli (ETEC) isolates from diarrheal patients from June to December 2012 in Shanghai, China, were examined to determine their genetic relatedness using multilocus sequence typing and pulsed field gel electrophoresis (PFGE) and for the presence of virulence genes and antimicrobial susceptibility. Twenty-nine sequence types (STs) and 63 PFGE patterns were identified, and results from the 2 subtyping methods correlated well. The 12 isolates of PFGE cluster B all belonged to ST-2332 and were associated with nosocomial neonatal diarrhea. Isolates of a cluster usually had the same set of virulence factors, whereas isolates of different PFGE clusters carried diverse combinations of virulence determinants. Isolates belonging to ST 2332 and ST-182 (n=9) were resistant to at least 6 antimicrobials. Our findings highlighted the need of active surveillance programs for infectious diseases collecting data at both epidemiological and genetic levels that can detect high risk lineages of pathogens in order to rapidly identify disease outbreaks. PMID- 25533615 TI - Matrix-assisted laser desorption ionization time of flight mass spectrometry and diagnostic testing for prosthetic joint infection in the clinical microbiology laboratory. AB - Identification of pathogen(s) associated with prosthetic joint infection (PJI) is critical for patient management. Historically, many laboratories have not routinely identified organisms such as coagulase-negative staphylococci to the species level. The advent of matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) has enhanced clinical laboratory capacity for accurate species-level identification. The aim of this study was to describe the species-level identification of microorganisms isolated from periprosthetic tissue and fluid specimens using MALDI-TOF MS alongside other rapid identification tests in a clinical microbiology laboratory. Results of rapid identification of bacteria isolated from periprosthetic joint fluid and/or tissue specimens were correlated with clinical findings at Mayo Clinic, Rochester, Minnesota, between May 2012 and May 2013. There were 178 PJI and 82 aseptic failure (AF) cases analyzed, yielding 770 organisms (median, 3/subject; range, 1 19/subject). MALDI-TOF MS was employed for the identification of 455 organisms (59%) in 197 subjects (123 PJIs and 74 AFs), with 89% identified to the species level using this technique. Gram-positive bacteria accounted for 68% and 93% of isolates in PJI and AF, respectively. However, the profile of species associated with infection compared to specimen contamination differed. Staphylococcus aureus and Staphylococcus caprae were always associated with infection, Staphylococcus epidermidis and Staphylococcus lugdunensis were equally likely to be a pathogen or a contaminant, whereas the other coagulase-negative staphylococci were more frequently contaminants. Most streptococcal and Corynebacterium isolates were pathogens. The likelihood that an organism was a pathogen or contaminant differed with the prosthetic joint location, particularly in the case of Propionibacterium acnes. MALDI-TOF MS is a valuable tool for the identification of bacteria isolated from patients with prosthetic joints, providing species-level identification that may inform culture interpretation of pathogens versus contaminants. PMID- 25533614 TI - Improved serotype-specific dengue virus detection in Trinidad and Tobago using a multiplex, real-time RT-PCR. AB - Dengue virus (DENV) transmission occurs throughout the Caribbean, though laboratory confirmation and epidemiologic surveillance are limited by the availability of serotype-specific molecular diagnostics. In this study, we show that a serotype-specific DENV multiplex, real-time reverse transcriptase-PCR (RT PCR) detected DENV RNA in significantly more samples (82/182) than a reference hemi-nested RT-PCR (57/182; P=0.01). PMID- 25533616 TI - Accuracy of different methods for susceptibility testing of gentamicin with KPC carbapenemase-producing Klebsiella pneumoniae. AB - Performance of Vitek2, Etest, and TREK broth microdilution (BMD) panels was evaluated versus reference CLSI BMD for gentamicin susceptibility testing with 57 bloodstream isolates of KPC-producing Klebsiella pneumoniae. Compared with reference BMD, the Essential Agreement and Categorical Agreement for TREK panels, Vitek2, and Etest were 91.2%, 31.6%, and 61.4%, respectively, and 86%, 21%, and 52.6%, respectively. Four very major discrepancies occurred with Vitek2. In these 4 strains, gentamicin resistance was associated with the presence of an armA aminoglycoside resistance determinant. PMID- 25533617 TI - Regiodivergent addition of phenols to allylic oxides: control of 1,2- and 1,4 additions for cyclitol synthesis. AB - Control of 1,2- and 1,4-addition of substituted phenols to allylic oxides is achieved by intercepting palladium pi-allyl complexes. The interconversion of palladium complexes results in the total synthesis of MK 7607, cyathiformine B type, streptol, and a new cyclitol. PMID- 25533618 TI - Quantum size effects in the size-temperature phase diagram of gallium: structural characterization of shape-shifting clusters. AB - Finite temperature analysis of cluster structures is used to identify signatures of the low-temperature polymorphs of gallium, based on the results of first principle Born-Oppenheimer molecular dynamics simulations. Pre-melting structural transitions proceed from either the beta- and/or the delta-phase to the gamma- or delta-phase, with a size- dependent phase progression. We relate the stability of each isomer to the electronic structures of the different phases, giving new insight into the origin of polymorphism in this complicated element. PMID- 25533619 TI - Ethical issues in using Twitter for public health surveillance and research: developing a taxonomy of ethical concepts from the research literature. AB - BACKGROUND: The rise of social media and microblogging platforms in recent years, in conjunction with the development of techniques for the processing and analysis of "big data", has provided significant opportunities for public health surveillance using user-generated content. However, relatively little attention has been focused on developing ethically appropriate approaches to working with these new data sources. OBJECTIVE: Based on a review of the literature, this study seeks to develop a taxonomy of public health surveillance-related ethical concepts that emerge when using Twitter data, with a view to: (1) explicitly identifying a set of potential ethical issues and concerns that may arise when researchers work with Twitter data, and (2) providing a starting point for the formation of a set of best practices for public health surveillance through the development of an empirically derived taxonomy of ethical concepts. METHODS: We searched Medline, Compendex, PsycINFO, and the Philosopher's Index using a set of keywords selected to identify Twitter-related research papers that reference ethical concepts. Our initial set of queries identified 342 references across the four bibliographic databases. We screened titles and abstracts of these references using our inclusion/exclusion criteria, eliminating duplicates and unavailable papers, until 49 references remained. We then read the full text of these 49 articles and discarded 36, resulting in a final inclusion set of 13 articles. Ethical concepts were then identified in each of these 13 articles. Finally, based on a close reading of the text, a taxonomy of ethical concepts was constructed based on ethical concepts discovered in the papers. RESULTS: From these 13 articles, we iteratively generated a taxonomy of ethical concepts consisting of 10 top level categories: privacy, informed consent, ethical theory, institutional review board (IRB)/regulation, traditional research vs Twitter research, geographical information, researcher lurking, economic value of personal information, medical exceptionalism, and benefit of identifying socially harmful medical conditions. CONCLUSIONS: In summary, based on a review of the literature, we present a provisional taxonomy of public health surveillance related ethical concepts that emerge when using Twitter data. PMID- 25533620 TI - Managing mild, symptomatic pelvic organ prolapse. PMID- 25533621 TI - Experience of non-breastfeeding mothers: Norms and ethically responsible risk communication. AB - BACKGROUND: Breastfeeding is currently strongly recommended by midwives and paediatricians, and the recommendations are based on documents provided by the World Health Organization and public health authorities worldwide. RESEARCH QUESTION: The underlying question is, how are non-breastfeeding mothers affected emotionally when informed that breastfeeding is the safest and healthiest option? RESEARCH DESIGN: The method used is an anonymous web-based qualitative survey exploring the narratives of non-breastfeeding mothers, published on Thesistools.com. The aim is to achieve qualitative knowledge about the emotions of non-breastfeeding mothers. PARTICIPANTS AND RESEARCH CONTEXT: Participants were based in Sweden, the United Kingdom and the Netherlands and were selected through a purposeful sample. ETHICAL CONSIDERATIONS: The online survey anonymizes responses automatically, and all respondents had to tick a box agreeing to be quoted anonymously in scientific articles. The study conforms to research ethics guidelines. FINDINGS: Respondents describe how they were affected, and the following themes emerged in studying their descriptions: depression, anxiety and pain, feeling failed as a mother and woman, loss of freedom/feeling trapped, relief and guilt. DISCUSSION: The themes are discussed against the background of the ethics of care and a theory of ethically responsible risk communication. CONCLUSION: Three conclusions are made. First, the message should become more empathetic. Second, information should be given in an attentive dialogue. Third, information providers should evaluate effects in a more inclusive way. PMID- 25533622 TI - Radiation promotes malignant phenotypes through SRC in breast cancer cells. AB - Despite the fact that ionizing radiation (IR) is widely used as a standard treatment for breast cancer, much evidence suggests that IR paradoxically promotes cancer malignancy. However, the molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that irradiation activates SRC signaling among SRC family kinase proteins, thereby promoting malignant phenotypes such as invasiveness, expansion of the cancer stem like cell population, and resistance to anticancer agents in breast cancer cells. Importantly, radiation-activated SRC induced SLUG expression and caused epithelial-mesenchymal cell transition through phosphatidylinositol 3 kinase/protein kinase B and p38 MAPK signaling. In agreement, either inhibition of SRC or downstream signaling of p38 MAPK or protein kinase B effectively attenuated radiation-induced epithelial-mesenchymal cell transition along with an increase in the cancer stem-like cell population. In addition, downregulation of SRC also abolished radiation-acquired resistance of breast cancer cells to anticancer agents such as cisplatin, etoposide, paclitaxel, and IR. Taken together, our findings suggest that combining radiotherapy with targeting of SRC might attenuate the harmful effects of radiation and enhance the efficacy of breast cancer treatment. PMID- 25533624 TI - Novel high dose rate lip brachytherapy technique to improve dose homogeneity and reduce toxicity by customized mold. AB - PURPOSE/OBJECTIVES: The purpose of this study is to describe a novel brachytherapy technique for lip Squamous Cell Carcinoma, utilizing a customized mold with embedded brachytherapy sleeves, which separates the lip from the mandible, and improves dose homogeneity. MATERIALS AND METHODS: Seven patients with T2 lip cancer treated with a "sandwich" technique of High Dose Rate (HDR) brachytherapy to the lip, consisting of interstitial catheters and a customized mold with embedded catheters, were reviewed for dosimetry and outcome using 3D planning. Dosimetric comparison was made between the "sandwich" technique to "classic" - interstitial catheters only plan. We compared dose volume histograms for Clinical Tumor Volume (CTV), normal tissue "hot spots" and mandible dose. We are reporting according to the ICRU 58 and calculated the Conformal Index (COIN) to show the advantage of our technique. RESULTS: The seven patients (ages 36-81 years, male) had median follow-up of 47 months. Four patients received Brachytherapy and External Beam Radiation Therapy, 3 patients received brachytherapy alone. All achieved local control, with excellent esthetic and functional results. All patients are disease free. The Customized Mold Sandwich technique (CMS) reduced the high dose region receiving 150% (V150) by an average of 20% (range 1-47%), The low dose region (les then 90% of the prescribed dose) improved by 73% in average by using the CMS technique. The COIN value for the CMS was in average 0.92 as opposed to 0.88 for the interstitial catheter only. All differences (excluding the low dose region) were statistically significant. CONCLUSION: The CMS technique significantly reduces the high dose volume and increases treatment homogeneity. This may reduce the potential toxicity to the lip and adjacent mandible, and results in excellent tumor control, cosmetic and functionality. PMID- 25533623 TI - Therapeutic vaccine using a monoclonal antibody against a 70-kDa glycoprotein in mice infected with highly virulent Sporothrix schenckii and Sporothrix brasiliensis. AB - Sporotrichosis is a chronic granulomatous mycosis caused by the dimorphic fungi that comprise the Sporothrix complex. The latter are widely distributed in nature, developing a saprophytic mycelial form on plant debris and soil. Formerly, the S. schenckii species was thought to be the only species capable of causing sporotrichosis. However, in recent years, the existence of a group of highly genotypically and phenotypically variable species has been reported as etiologic agents of this mycosis. Recently, it has become important to study aspects such as virulence and the immune response against key members of the Sporothrix complex and to observe the presence of glycoprotein (gp) 70 and efficacy of the P6E7 monoclonal antibody against more virulent strains. The data presented here demonstrate that the strain isolated from a case of feline sporotrichosis, that is, strain 5110 (American Type Culture Collection MYA-4823) is the most virulent and the only one able to secrete gp70. This glycoprotein is apparently an important factor in the virulence of Sporothrix spp. because treatment with MAb P6E7 resulted in the reduction of fungal burden in the analyzed organs. Additional studies of the role of gp70 in modulating the immune response of the host are needed to understand the pathology of sporotrichosis. PMID- 25533626 TI - Enhancing the radiation dose detection sensitivity of optical fibres. AB - A method for improving the thermoluminescence (TL) yield of silica-based optical fibres is demonstrated. Using silica obtained from a single manufacturer, three forms of pure (undoped) fibre (capillary-, flat-, and photonic crystal fibre (PCF)) and two forms of Ge-doped fibre (capillary- and flat-fibre) were fabricated. The pure fibre samples were exposed to 6 and 21MeV electrons, the doped fibres to 6MV photons. The consistent observation of large TL yield enhancement is strongly suggestive of surface-strain defects generation. For 6MeV irradiations of flat-fibre and PCF, respective TL yields per unit mass of about 12.0 and 17.5 times that of the undoped capillary-fibre have been observed. Similarly, by making a Ge-doped capillary-fibre into flat-fibre, the TL response is found to increase by some 6.0 times. Thus, in addition to TL from the presence of a dopant, the increase in fused surface areas of flat-fibres and PCF is seen to be a further important source of TL. The glow-curves of the undoped fibres have been analysed by computational deconvolution. Trap centre energies have been estimated and compared for the various fibre samples. Two trap centre types observed in capillary-fibre are also observed in flat-fibre and PCF. An additional trap centre in flat-fibre and one further trap centre in PCF are observed when compared to capillary fibre. These elevated-energy trap centres are linked with strain-generated defects in the collapsed regions of the flat fibre and PCF. PMID- 25533625 TI - Comment on: Secondary surgery after sleeve gastrectomy: Roux-en-Y gastric bypass or biliopancreatic diversion with duodenal switch. PMID- 25533627 TI - The urothelium: anatomy, review of the literature, perspectives for veterinary medicine. AB - Over time, much knowledge has been accumulated about the active role of the urothelium, principally in rodents and human. Far from being a mere passive barrier, this specialized epithelium can alter the ion and protein composition of the urine, is able to sense and respond to mechanical stimuli such as pressure, and react to mechanical stimuli by epithelial cell communication with the nervous system. Most of the specialized functions of the urothelium are linked to a number of morpho-physiologic properties exhibited by the superficial umbrella cells, including specialized membrane lipids, asymmetric unit membrane particles and a plasmalemma with stiff plaques which function as a barrier to most substances found in urine, thus protecting the underlying tissues. Moreover, the entire mucosa lining the low urinary tract, composed of urothelium and sub urothelium, forms a functional transduction unit, able to respond to eso- and endogenous physical and chemical stimuli in a manner assuring an adequate functional response. This review will summarize the available information on each area of inquiry from a morpho-functional point of view. Possible considerations pertaining to species of veterinary interest are reviewed as well. The review was prepared consulting the electronic databases PubMed and Cab Abstracts and retrieving all pertinent reports and the relative reference lists, in order to identify any potential additional studies that could be included. Full-length research articles and thematic reviews were considered. Information on the urothelium of some domestic animal species was also included. PMID- 25533628 TI - CD30 ligand is a new therapeutic target for central nervous system autoimmunity. AB - The CD30 ligand (CD30L)/CD30 axis plays a critical role in Th1 and Th17 cell differentiation. However, the role in the pathogenesis of central nervous system autoimmunity remains unknown. Here we show the resistance for experimental autoimmune encephalomyelitis (EAE) with markedly reduced induction of antigen specific Th1 and Th17 cells in CD30L knockout mice. Bone marrow chimera experiments indicated that CD30L on bone marrow-derived cells were critical for the development of EAE and that CD30L reverse signaling in CD4 T cells was dispensable for the pathogenic Th17 cell differentiation at the induction phase. Adoptive transfer experiment revealed an additional role for CD30L in the environment at the effector phase. In vivo neutralization of CD30L by soluble murine CD30-Immunoglobulin fusion protein before disease onset or even after disease onset significantly ameliorated the clinical symptoms. These results indicate that CD30L/CD30 signaling is critically involved in antigen-specific CD4 T cell responses at both the induction and effector phase, thus could be a new target molecule for the treatment of central nervous system autoimmunity. PMID- 25533629 TI - Preclinical studies of the potent and selective nicotinic alpha4beta2 receptor ligand VMY-2-95. AB - The discovery and development of small molecules that antagonize neuronal nicotinic acetylcholine receptors may provide new ligands for evaluation in models of depression or addiction. We discovered a small molecule, VMY-2-95, a nAChR ligand with picomolar affinity and high selectivity for alpha4beta2 receptors. In this study, we investigated its preclinical profile in regards to solubility, lipophilicity, metabolic stability, intestinal permeability, bioavailability, and drug delivery to the rat brain. Metabolic stability of VMY-2 95.2HCl was monitored on human liver microsomes, and specific activity of VMY-2 95.2HCl on substrate metabolism by CYP1A2, 2C9, 2C19, 2D6, and 3A4 was tested in a high-throughput manner. The intestinal transport of VMY-2-95.2HCl was studied through Caco-2 cell monolayer permeability. VMY-2-95.2HCl was soluble in water and chemically stable, and the apparent partition coefficient was 0.682. VMY-2 95.2HCl showed significant inhibition of CYP2C9 and 2C19, but weak or no effect on 1A2, 2D6, and 3A4. The Caco-2 cell model studies revealed that VMY-2-95.2HCl was highly permeable with efflux ratio of 1.11. VMY-2-95.2HCl achieved a maximum serum concentration of 0.56 mg/mL at 0.9 h and was orally available with a half life of ~9 h. Furthermore, VMY-2-95.2HCl was detected in the rat brain after 3 mg/kg oral administration and achieved a maximal brain tissue concentration of 2.3 MUg/g within 60 min. Overall, the results demonstrate that VMY-2-95.2HCl has good drug like properties and can penetrate the blood-brain barrier with oral administration. PMID- 25533630 TI - Intravoxel water diffusion heterogeneity MR imaging of nasopharyngeal carcinoma using stretched exponential diffusion model. AB - PURPOSE: To determine the utility of stretched exponential diffusion model in characterisation of the water diffusion heterogeneity in different tumour stages of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Fifty patients with newly diagnosed NPC were prospectively recruited. Diffusion-weighted MR imaging was performed using five b values (0-2,500 s/mm(2)). Respective stretched exponential parameters (DDC, distributed diffusion coefficient; and alpha (alpha), water heterogeneity) were calculated. Patients were stratified into low and high tumour stage groups based on the American Joint Committee on Cancer (AJCC) staging for determination of the predictive powers of DDC and alpha using t test and ROC curve analyses. RESULTS: The mean +/- standard deviation values were DDC = 0.692 +/- 0.199 (*10(-3) mm(2)/s) for low stage group vs 0.794 +/- 0.253 (*10(-3) mm(2)/s) for high stage group; alpha = 0.792 +/- 0.145 for low stage group vs 0.698 +/- 0.155 for high stage group. alpha was significantly lower in the high stage group while DDC was negatively correlated. DDC and alpha were both reliable independent predictors (p < 0.001), with alpha being more powerful. Optimal cut-off values were (sensitivity, specificity, positive likelihood ratio, negative likelihood ratio) DDC = 0.692 * 10(-3) mm(2)/s (94.4 %, 64.3 %, 2.64, 0.09), alpha = 0.720 (72.2 %, 100 %, -, 0.28). CONCLUSION: The heterogeneity index alpha is robust and can potentially help in staging and grading prediction in NPC. KEY POINTS: * Stretched exponential diffusion models can help in tissue characterisation in nasopharyngeal carcinoma * alpha and distributed diffusion coefficient (DDC) are negatively correlated * alpha is a robust heterogeneity index marker * alpha can potentially help in staging and grading prediction. PMID- 25533631 TI - Low-dose biplanar radiography can be used in children and adolescents to accurately assess femoral and tibial torsion and greatly reduce irradiation. AB - PURPOSE: To evaluate in children the agreement between femoral and tibial torsion measurements obtained with low-dose biplanar radiography (LDBR) and CT, and to study dose reduction ratio between these two techniques both in vitro and in vivo. MATERIALS AND METHODS: Thirty children with lower limb torsion abnormalities were included in a prospective study. Biplanar radiographs and CTs were performed for measurements of lower limb torsion on each patient. Values were compared using Bland-Altman plots. Interreader and intrareader agreements were evaluated by intraclass correlation coefficients. Comparative dosimetric study was performed using an ionization chamber in a tissue-equivalent phantom, and with thermoluminescent dosimeters in 5 patients. RESULTS: Average differences between CT and LDBR measurements were -0.1 degrees +/-1.1 for femoral torsion and -0.7 degrees +/-1.4 for tibial torsion. Interreader agreement for LDBR measurements was very good for both femoral torsion (FT) (0.81) and tibial torsion (TT) (0.87). Intrareader agreement was excellent for FT (0.97) and TT (0.89). The ratio between CT scan dose and LDBR dose was 22 in vitro (absorbed dose) and 32 in vivo (skin dose). CONCLUSION: Lower limb torsion measurements obtained with LDBR are comparable to CT measurements in children and adolescents, with a considerably reduced radiation dose. KEY POINTS: * LDBR and CT lower-limb torsion measurements are comparable in children and adolescents. * LDBR considerably reduced radiation dose necessary for lower-limb torsion measurements. * LDBR can be used for evaluation of lower limb-torsion in orthopaediatric patients. PMID- 25533632 TI - Antibacterial activity of a cell wall hydrolase from Lactobacillus paracasei NRRL B-50314 produced by recombinant Bacillus megaterium. AB - The cell-free supernatant (CFS) from Lactobacillus paracasei NRRL B-50314 culture has been previously reported as containing antibacterial activity against a wide variety of Gram-positive bacteria. The CFS protein gel slice corresponding to antibacterial activities was subjected to trypsin digestion and ion trap MASS (Gel/LC-MS/MS) analysis. BlastP search of the resulted IQAVISIAEQQIGKP sequence led to a hypothetical cell-wall associated hydrolase (designated as CWH here) from Lactobacillus paracasei ATCC 25302. Further analyses of CWH revealed that the IQAVISIAEQQIGKP belongs to a highly conserved region of the NlpC/P60 superfamily. The L. paracasei NRRL B-50314 CWH gene, cloned in pStrepHIS1525CWH477, was introduced into Bacillus megaterium MS 941. The production of CWH477 protein was induced by xylose. The CWH477 protein was purified by using NiNTA column, and elution fraction E2 showed highest antibacterial activity. This study and bioinformatics analyses suggested that the antibacterial activity of CWH could originate from its cell wall degrading enzymatic function. PMID- 25533633 TI - Metabolic engineering of Escherichia coli to produce zeaxanthin. AB - Zeaxanthin is a high-value carotenoid that is used in nutraceuticals, cosmetics, food, and animal feed industries. Zeaxanthin is chemically synthesized or purified from microorganisms as a natural product; however, increasing demand requires development of alternative sources such as heterologous biosynthesis by recombinant bacteria. For this purpose, we molecularly engineered Escherichia coli to optimize the synthesis of zeaxanthin from lycopene using fusion protein mediated substrate channeling as well as by the introduction of tunable intergenic regions. The tunable intergenic regions approach was more efficient compared with protein fusion for coordinating expression of lycopene beta-cyclase gene crtY and beta-carotene 3-hydroxylase gene crtZ. The influence of the substrate channeling effect suggests that the reaction catalyzed by CrtZ is the rate-limiting step in zeaxanthin biosynthesis. Then Pantoea ananatis, Pantoea agglomerans and Haematococcus pluvialis crtZ were compared. Because P. ananatis crtZ is superior to that of P. agglomerans or H. pluvialis for zeaxanthin production, we used it to generate a recombinant strain of E. coli BETA-1 containing pZSPBA-2(P37-crtZPAN) that produced higher amounts of zeaxanthin (11.95 +/- 0.21 mg/g dry cell weight) than other engineered E. coli strains described in the literature. PMID- 25533634 TI - Construction and validation of a mCherry protein vector for promoter analysis in Lactobacillus acidophilus. AB - Lactobacilli are widespread in natural environments and are increasingly being investigated as potential health modulators. In this study, we have adapted the broad-host-range vector pNZ8048 to express the mCherry protein (pRCR) to expand the usage of the mCherry protein for analysis of gene expression in Lactobacillus. This vector is also able to replicate in Streptococcus pneumoniae and Escherichia coli. The usage of pRCR as a promoter probe was validated in Lactobacillus acidophilus by characterizing the regulation of lactacin B expression. The results show that the regulation is exerted at the transcriptional level, with lbaB gene expression being specifically induced by co culture of the L. acidophilus bacteriocin producer and the S. thermophilus STY-31 inducer bacterium. PMID- 25533635 TI - Lime application for the efficient production of nutraceutical glucooligosaccharides from Leuconostoc mesenteroides NRRL B-742 (ATCC13146). AB - We have previously demonstrated the production of glucooligosaccharides via a fermentation of sucrose with Leuconostoc mesenteroides NRRL B-742 using sodium hydroxide (NaOH) to control the pH. Because NaOH is expensive, we sought to minimize the cost of our process by substituting hydrated lime and saccharate of lime (lime sucrate) in its place. The yield of glucooligosaccharides using either 5 % lime (41.4 +/- 0.5 g/100 g) or 5 % lime sucrate (40.0 +/- 1.4 g/100 g) were both similar to the NaOH control (42.4 +/- 1.5 g/100 g). Based on this, it appears that the cost associated with pH control in our process can be reduced by a factor of approximately 2.4 using lime instead of NaOH. Because our chromatographic stage is based on a Ca(2+)-form resin to separate glucooligosaccharides, the use of lime not only negates the need for costly de salting via ion-exchange (elimination of two ion-exchange sections) prior to separation, but also greatly reduces the resin regeneration cost. PMID- 25533636 TI - SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. AB - When pluripotency factors are removed, embryonic stem cells (ESCs) undergo spontaneous differentiation, which, among other lineages, also gives rise to cardiac sublineages, including chamber cardiomyocytes and pacemaker cells. Such heterogeneity complicates the use of ESC-derived heart cells in therapeutic and diagnostic applications. We sought to direct ESCs to differentiate specifically into cardiac pacemaker cells by overexpressing a transcription factor critical for embryonic patterning of the native cardiac pacemaker (the sinoatrial node). Overexpression of SHOX2 during ESC differentiation upregulated the pacemaker gene program, resulting in enhanced automaticity in vitro and induced biological pacing upon transplantation in vivo. The accentuated automaticity is accompanied by temporally evolving changes in the effectors and regulators of Wnt signaling. Our findings provide a strategy for enriching the cardiac pacemaker cell population from ESCs. PMID- 25533638 TI - [Toxicity of nanoparticles on reproduction]. AB - Nanoparticles (NPs) are sized between 1 and 100nm. Their size allows new nanoscale properties of particular interest for industrial and scientific purpose. Over the past twenty years, nanotechnology conquered many areas of use (electronic, cosmetic, textile...). While, human is exposed to an increasing number of nanoparticles sources, health impacts and, particularly on reproductive function, remains poorly evaluated. Indeed, traceability of nanoparticles use is lacking and nanotoxicology follows different rules than classical toxicology. This review focuses on the impact of NPs on health and particularly on fertility and addresses potential risks of chronic exposure to NPs on human fertility. PMID- 25533637 TI - Genetic and functional diversity of propagating cells in glioblastoma. AB - Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo. PMID- 25533639 TI - Congenital hemidysplasia with ichthyosiform naevus and limb defects (CHILD) syndrome without hemidysplasia. PMID- 25533640 TI - Planned Bone Resections Using an MRI-Based Custom Cutting Guide System Versus 3 Dimensional, Weight-Bearing Images in Total Knee Arthroplasty. AB - Potential sources of alignment variability not yet investigated with the use of custom cutting guides (CCG) in total knee arthroplasty (TKA) are weight-bearing and lower extremity rotation. This study compared the preoperative planned bone resections created using an MRI-based CCG system to those from 3-dimensional, weight-bearing, full-length lower extremity images in 53 patients undergoing TKA. The angular difference between the proposed resections of the two systems was greater than 2 degrees in 30.2% of patients for the distal femur, and 52.8% for the proximal tibia. An increased preoperative varus alignment had a slight association with an increased angular difference for the tibial resection (r=0.4). This study demonstrates weight-bearing and lower extremity rotation to be potential sources of alignment variability when using MRI-based CCGs. PMID- 25533641 TI - Synergistic effects of food insecurity and drug use on medication adherence among people living with HIV infection. AB - Food insecurity and drug use are closely connected in the context of poverty, and both have been suggested to interfere with HIV medication adherence among people living with HIV/AIDS (PLWH). Yet the potential interaction between the two factors on adherence has not been examined. For this study we collected longitudinal data on HIV medication adherence among PLWH in Atlanta, GA, to assess a possible synergistic effect between the two factors on HIV medication adherence. People informed about the study came to the research site and completed an audio computer-assisted self-interview and instructions for pill counting. Over the next 5 weeks participants received three unscheduled follow-up phone assessments conducted 2 weeks apart to collect pill counts of their HIV medication. The prevalence of food insecurity was 60 % (488) and that of drug use was 33 % (274) in the sample of 809 participants. Among 770 participants who completed follow-up phone assessments, both food insecurity and drug use were associated with HIV medication adherence after adjusting for socio-demographic characteristics. The negative association between drug use and adherence persisted after further adjusting for health-related characteristics. Moreover, drug use appeared to moderate the effect of food insufficiency on adherence, with drug users who were food insufficient being the least likely to achieve 85 % adherence. Results from the current study demonstrate a synergism between food insecurity and drug use that may impede adherence among PLWH. The findings imply that the disruptive effects of food insecurity and drug use on adherence are likely to be intensified with the presence of each other, and encourage interventions to address the problem of HIV medication adherence from a multi faceted perspective that takes into account detrimental combination of problem factors. PMID- 25533642 TI - Genetic counseling content: How does it impact health behavior? AB - Women with hereditary breast-ovarian cancer face decisions about screening (transvaginal ultrasound, CA125, mammography, breast exams) and proactive (before cancer) or reactive (after cancer) surgery (oophorectomy, mastectomy). The content of genetic counseling and its relation to these key health behaviors is largely unexamined. Ashkenazi Jewish women (n = 78) were surveyed through the process of genetic testing and had audiorecorded counseling sessions available for Linguistic Inquiry and Word Count analysis. Proportions for participant and counselor cognitive and affective content during sessions were used as primary predictor variables in linear mixed models for change in intentions for screening and treatment and in self-reported screening. Cognitive and affective content were important predictors of behavior. Counselor cognitive content was associated with ovarian screening. An interaction effect also emerged for CA-125, such that counselor cognitive content plus participant cognitive content or counselor affective content were associated with more screening. Teasing out the factors in risk communication that impact decision-making are critical, and affect from a risk communicator can spur action, such as cancer screening. PMID- 25533643 TI - Depressive symptoms and spiritual wellbeing in asymptomatic heart failure patients. AB - Depression adversely predicts prognosis in individuals with symptomatic heart failure. In some clinical populations, spiritual wellness is considered to be a protective factor against depressive symptoms. This study examined associations among depressive symptoms, spiritual wellbeing, sleep, fatigue, functional capacity, and inflammatory biomarkers in 132 men and women with asymptomatic stage B heart failure (age 66.5 years +/- 10.5). Approximately 32 % of the patients scored >=10 on the Beck Depression Inventory, indicating potentially clinically relevant depressive symptoms. Multiple regression analysis predicting fewer depressive symptoms included the following significant variables: a lower inflammatory score comprised of disease-relevant biomarkers (p < 0.02), less fatigue (p < 0.001), better sleep (p < 0.04), and more spiritual wellbeing (p < 0.01) (overall model F = 26.6, p < 0.001, adjusted R square = 0.629). Further analyses indicated that the meaning (p < 0.01) and peace (p < 0.01) subscales, but not the faith (p = 0.332) subscale, of spiritual wellbeing were independently associated with fewer depressive symptoms. Interventions aimed at increasing spiritual wellbeing in patients lives, and specifically meaning and peace, may be a potential treatment target for depressive symptoms asymptomatic heart failure. PMID- 25533644 TI - Perfluoroalkyl substances and time to pregnancy in couples from Greenland, Poland and Ukraine. AB - BACKGROUND: Perfluoroalkyl substances (PFAS) are suggested to affect human fecundity through longer time to pregnancy (TTP). We studied the relationship between four abundant PFAS and TTP in pregnant women from Greenland, Poland and Ukraine representing varying PFAS exposures and pregnancy planning behaviors. METHODS: We measured serum levels of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) in 938 women from Greenland (448 women), Poland (203 women) and Ukraine (287 women). PFAS exposure was assessed on a continuous logarithm transformed scale and in country-specific tertiles. We used Cox discrete-time models and logistic regression to estimate fecundability ratios (FRs) and infertility (TTP >13 months) odds ratios (ORs), respectively, and 95% confidence intervals (CI) according to PFAS levels. Adjusted analyses of the association between PFAS and TTP were done for each study population and in a pooled sample. RESULTS: Higher PFNA levels were associated with longer TTP in the pooled sample (log-scale FR = 0.80; 95% CI 0.69-0.94) and specifically in women from Greenland (log-scale FR = 0.72; 95% CI 0.58-0.89). ORs for infertility were also increased in the pooled sample (log-scale OR = 1.53; 95% CI 1.08-2.15) and in women from Greenland (log-scale OR = 1.97; 95% CI 1.22-3.19). However, in a sensitivity analysis of primiparous women these associations could not be replicated. Associations with PFNA were weaker for women from Poland and Ukraine. PFOS, PFOA and PFHxS were not consistently associated with TTP. CONCLUSIONS: Findings do not provide consistent evidence that environmental exposure to PFAS is impairing female fecundity by delaying time taken to conceive. PMID- 25533645 TI - A three-plane architectonic atlas of the rat hippocampal region. AB - The hippocampal region, comprising the hippocampal formation and the parahippocampal region, has been one of the most intensively studied parts of the brain for decades. Better understanding of its functional diversity and complexity has led to an increased demand for specificity in experimental procedures and manipulations. In view of the complex 3D structure of the hippocampal region, precisely positioned experimental approaches require a fine grained architectural description that is available and readable to experimentalists lacking detailed anatomical experience. In this paper, we provide the first cyto- and chemoarchitectural description of the hippocampal formation and parahippocampal region in the rat at high resolution and in the three standard sectional planes: coronal, horizontal and sagittal. The atlas uses a series of adjacent sections stained for neurons and for a number of chemical marker substances, particularly parvalbumin and calbindin. All the borders defined in one plane have been cross-checked against their counterparts in the other two planes. The entire dataset will be made available as a web-based interactive application through the Rodent Brain WorkBench (http://www.rbwb.org) which, together with this paper, provides a unique atlas resource. PMID- 25533647 TI - Recurrent cholangitis in a 65-year-old man. Biliary papillomatosis. PMID- 25533648 TI - A survivor: the eosinophil as a regulator in asthma. PMID- 25533646 TI - Randomised controlled trial of mesalazine in IBS. AB - OBJECTIVE: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. DESIGN: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. RESULTS: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. CONCLUSIONS: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. TRIAL REGISTRATION NUMBER: ClincialTrials.gov number, NCT00626288. PMID- 25533649 TI - Immune factors in breast milk related to infant milk allergy are independent of maternal atopy. PMID- 25533650 TI - Potential herb-drug interaction in the prevention of cardiovascular diseases during integrated traditional and Western medicine treatment. AB - The combination of herbs and drugs is one of the most important approaches in the prevention and treatment of diseases in the integrated traditional and Western medicine (ITWM). While most medical practices have proved that the combination of herbs and drugs led to a clinical efficacy that was often superior to merely using only one of them; results from some studies have triggered adverse reactions to such an approach. Since few herb-drug interaction studies were carried out during treatments combining herbs and drugs, it really restricts the development of treatment and treatment theory of the combination of herbs and drugs. Given that herb-drug interactions may occur through the main pathway of cytochrome P450 enzymes and transporters; then to exhaustively study the role and impact of herbs in drug metabolism, as well as to establish a corresponding database, is of great significance for guiding the rational combination of herbs and drugs. When the herb-drug interaction information platform is implemented, we would get at ease a reasonable herb-drug prescription to achieve a better outcome, reduce dosage of some expensive drugs preserving the same efficacy, or even reduce some side effects of particular drugs; which might also promote the dynamic combination of Chinese and Western medicine, and accelerate the theory development of ITWM. PMID- 25533652 TI - Traditional Tibetan medicine in China: an overview of current status and prospects. AB - OBJECTIVE: To introduce and explore the current status and prospects of traditional Tibetan medicine (TTM) in China. METHODS: Government websites, national statistics, and authoritative papers from journal and government daily were fully searched. Further data were gathered by related experts. RESULTS: With the implementation of policies on growing TTM, there have been improvements in TTM's health care, scientific research, education, and pharmacy industry. TTM hospitals contribute to the health service system in Tibet Autonomous Region and other four Tibetan regions; TTM education has been incorporated into national education system in China; the number of scientific researches on TTM funded by the government is increasing year by year; Tibetan medicines become available to more people with the development of TTM pharmacy industry. CONCLUSION: TTM is well preserved and developed in China, and more efforts should be taken to promote its spread and development. PMID- 25533651 TI - Chinese medicine herbal treatment based on syndrome differentiation improves the overall survival of patients with unresectable hepatocellular carcinoma. AB - OBJECTIVE: To investigate the effects of Chinese medicine (CM) herbal treatment based on syndrome differentiation on patients with unresectable hepatocellular carcinoma (HCC). METHODS: A total of 94 patients with unresectable HCC were reviewed between June 2008 and June 2011. Survival analysis was performed between patients who received CM with/without non-curative antitumor treatments of Western medicine (WM) (CM group, 30 cases) and patients who were not treated with CM but with non-curative antitumor treatments of WM or supportive treatment alone (non-CM group, 64 cases). Then, survival analysis was performed between patients treated with CM combined with non-curative antitumor treatments of WM (combination therapy group, 25 cases) and patients with non-curative antitumor treatments of WM alone (non-curative antitumor treatments group of WM, 52 cases). The survival analysis was performed by Kaplan-Meier method and prognostic factors for overall survival (OS) were assessed by the Cox proportional hazards regression model. RESULTS: The median survival time (MST), 1- and 2-year survival rates of the CM group and the non-CM group were 36 months, 76.7%, 56.1% and 12 months, 48.4%, 26.6%, respectively. The Log-rank test revealed significant difference between the two groups in OS (P<0.01). Cox proportional multivariate analysis revealed that CM was an independent favorable prognostic factor for OS. The MST, 1- and 2-year survival rates of combination therapy group and non curative antitumor treatments group of WM were 36 months, 76.0%, 55.5% and 13 months, 55.8%, 30.8%, respectively. There was significant difference in OS between the two groups (P=0.004). CONCLUSIONS: CM herbs based on syndrome differentiation have positive effects on survival of patients with unresectable HCC. Furthermore, combination therapy of CM and WM are recommended in HCC treatment. PMID- 25533653 TI - Concentric rings K-space trajectory for hyperpolarized (13)C MR spectroscopic imaging. AB - PURPOSE: To develop a robust and rapid imaging technique for hyperpolarized (13)C MR Spectroscopic Imaging and investigate its performance. METHODS: A concentric rings readout trajectory with constant angular velocity is proposed for hyperpolarized (13)C spectroscopic imaging and its properties are analyzed. Quantitative analyses of design tradeoffs are presented for several imaging scenarios. The first application of concentric rings on (13)C phantoms and in vivo animal hyperpolarized (13)C MR Spectroscopic Imaging studies were performed to demonstrate the feasibility of the proposed method. Finally, a parallel imaging accelerated concentric rings study is presented. RESULTS: The concentric rings MR Spectroscopic Imaging trajectory has the advantages of acquisition timesaving compared to echo-planar spectroscopic imaging. It provides sufficient spectral bandwidth with relatively high efficiency compared to echo-planar spectroscopic imaging and spiral techniques. Phantom and in vivo animal studies showed good image quality with half the scan time and reduced pulsatile flow artifacts compared to echo-planar spectroscopic imaging. Parallel imaging accelerated concentric rings showed advantages over Cartesian sampling in g factor simulations and demonstrated aliasing-free image quality in a hyperpolarized (13)C in vivo study. CONCLUSION: The concentric rings trajectory is a robust and rapid imaging technique that fits very well with the speed, bandwidth, and resolution requirements of hyperpolarized (13)C MR Spectroscopic Imaging. PMID- 25533654 TI - The role of cytosolic phospholipase A2 alpha in amyloid precursor protein induction by amyloid beta1-42 : implication for neurodegeneration. AB - Amyloid-beta peptides generated by proteolysis of the beta-amyloid precursor protein (APP) play an important role in the pathogenesis of Alzheimer's disease. The present study aimed to determine whether cytosolic phospholipase A2 alpha (cPLA2 alpha) plays a role in elevated APP protein expression induced by aggregated amyloid-beta1-42 (Abeta) in cortical neurons and to elucidate its specific role in signal events leading to APP induction. Elevated cPLA2 alpha and its activity determined by phosphorylation on serine 505 as well as elevated APP protein expression, were detected in primary rat cortical neuronal cultures exposed to Abeta for 24 h and in cortical neuron of human amyloid-beta1-42 brain infused mice. Prevention of cPLA2 alpha up-regulation and its activity by oligonucleotide antisense against cPLA2 alpha (AS) prevented the elevation of APP protein in cortical neuronal cultures and in mouse neuronal cortex. To determine the role of cPLA2 alpha in the signals leading to APP induction, increased cPLA2 alpha expression and activity induced by Abeta was prevented by means of AS in neuronal cortical cultures. Under these conditions, the elevated cyclooxygenase-2 and the production of prostaglandin E2 (PGE2 ) were prevented. Addition of PGE2 or cyclic AMP analogue (dbcAMP) to neuronal cultures significantly increased the expression of APP protein, while the presence protein kinase A inhibitor (H-89) attenuated the elevation of APP induced by Abeta. Inhibition of elevated cPLA2 alpha by AS prevented the activation of cAMP response element binding protein (CREB) as detected by its phosphorylated form, its translocation to the nucleus and its DNA binding induced by Abeta which coincided with cPLA2 alpha dependent activation of CREB in the cortex of Abeta brain infused mice. Our results show that accumulation of Abeta induced elevation of APP protein expression mediated by cPLA2 alpha, PGE2 release, and CREB activation via protein kinase A pathway. PMID- 25533655 TI - Glaucoma treatment: by the highest level of evidence. PMID- 25533657 TI - Genomic sequencing and biological characteristics of a novel Escherichia coli bacteriophage 9g, a putative representative of a new Siphoviridae genus. AB - Bacteriophage 9 g was isolated from horse feces using Escherichia coli C600 as a host strain. Phage 9 g has a slightly elongated capsid 62 * 76 nm in diameter and a non-contractile tail about 185 nm long. The complete genome sequence of this bacteriophage consists of 56,703 bp encoding 70 predicted open reading frames. The closest relative of phage 9 g is phage PhiJL001 infecting marine alpha proteobacterium associated with Ircinia strobilina sponge, sharing with phage 9 g 51% of amino acid identity in the main capsid protein sequence. The DNA of 9 g is resistant to most restriction endonucleases tested, indicating the presence of hypermodified bases. The gene cluster encoding a biosynthesis pathway similar to biosynthesis of the unusual nucleoside queuosine was detected in the phage 9 g genome. The genomic map organization is somewhat similar to the typical temperate phage gene layout but no integrase gene was detected. Phage 9 g efficiently forms stable associations with its host that continues to produce the phage over multiple passages, but the phage can be easily eliminated via viricide treatment indicating that no true lysogens are formed. Since the sequence, genomic organization and biological properties of bacteriophage 9 g are clearly distinct from other known Enterobacteriaceae phages, we propose to consider it as the representative of a novel genus of the Siphoviridae family. PMID- 25533656 TI - Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo controlled trial. AB - BACKGROUND: Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. METHODS: In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0.005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. FINDINGS: We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19.6 mm Hg (SD 4.6) in 258 patients in the latanoprost group and 20.1 mm Hg (4.8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3.8 mm Hg (4.0) in 231 patients assessed in the latanoprost group and 0.9 mm Hg (3.8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0.44 (95% CI 0.28 0.69; p=0.0003). We noted 18 serious adverse events, none attributable to the study drug. INTERPRETATION: This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. FUNDING: Pfizer, UK National Institute for Health Research Biomedical Research Centre. PMID- 25533659 TI - Progressive adaptation of a CpGV isolate to codling moth populations resistant to CpGV-M. AB - The NPP-R1 isolate of CpGV is able to replicate on CpGV-M-resistant codling moths. However, its efficacy is not sufficient to provide acceptable levels of control in natural (orchard) conditions. A laboratory colony derived from resistant codling moths was established, which exhibited a homogeneous genetic background and a resistance level more than 7000 fold. By successive cycles of replication of NPP-R1 in this colony, we observed a progressive increase in efficacy. After 16 cycles (isolate 2016-r16), the efficacy of the virus isolate was equivalent to that of CpGV-M on susceptible insects. This isolate was able to control both CpGV-M-susceptible and CpGV-M-resistant insects with similar efficacy. No reduction in the levels of occlusion body production in susceptible larvae was observed for 2016-r16 compared to CpGV-M. PMID- 25533661 TI - Heparan sulfate proteoglycan: an arbovirus attachment factor integral to mosquito salivary gland ducts. AB - Variants of the prototype Alphavirus, Sindbis (SINV), were used in per os infections of adult female mosquitoes to investigate arbovirus interaction with the salivary gland (SG). Infection of Aedine mosquitoes with AR339, a heparan sulfate proteoglycan (HSPG)-dependent variant, resulted in gross pathology in the SG lateral lobes while infection with TR339, a HSPG-independent variant, resulted in minimal SG pathology. HSPG was detected in the internal ducts of the SG lateral lobes by immunolabeling but not in the median lobe, or beyond the triad structure and external ducts. Reports that human lactoferrin interacts with HSPG, suggested an interference with virus attachment to receptors on vertebrate cells. Pre-incubation of Aedes albopictus cultured C7-10 cells with bovine lactoferrin (bLF) followed by adsorption of SINV resulted in earlier and greater intensity of cytopathic response to TR339 compared with AR339. Following pre-treatment of C7 10 cells with bLF, plaques from tissue culture-adapted high-titer SINVTaV-GFP-TC were observed at 48 h post-infection (p.i.), while plaques from low-titer SINVTaV GFP-TC were not observed until 120 h p.i. Confocal optics detected this reporter virus at 30 days p.i. in the SG proximal lateral lobe, a region of HSPG immunolocalization. Altogether these data suggest an association between SINV and HSPG in the host mosquito. PMID- 25533662 TI - Intertrial interval duration and impulsive choice. AB - Discrete-trial intertemporal choice procedures assess impulsive choice or preference for a smaller, immediate reinforcer over a larger, delayed one. The effect of the delay associated with the larger reinforcer has been the focus of much research. It, however, is not the only delay in the context of discrete trial procedures. Often separating each choice trial is an intertrial interval (ITI) that maintains equal trial spacing of the two alternatives. The removal of this ITI has been shown to increase impulsive choice, perhaps because choosing the small alternative results in another choice trial immediately following reinforcer delivery. Impulsive choice has not been affected when the ITI duration is manipulated in conditions that equate the trial presentation rate across the two alternatives. These null results could have been due to floor effects and/or an inadequate range of ITI durations. To address these possibilities, three experiments were conducted to determine how changes in ITI duration affected impulsive choice in rats and pigeons. All three experiments found that preference for the large delayed alternative decreased (i.e., impulsive choice increased) when the ITI was shortened. Satiation was not a likely explanation since preference for the large alternative at the 0-s delay was not affected by ITI duration. Trial spacing, like other temporal properties of choice situations, is an important variable underlying the occurrence of impulsive choice. PMID- 25533664 TI - Catechin as a new improving agent for a photo-Fenton-like system at near-neutral pH for the removal of inderal. AB - Photodegradation of inderal in a photo-Fenton like system at near-neutral pH modified with catechin, a natural catecholate siderophore, was investigated under simulated sunlight. The main factors influencing the process, such as Fe(iii) catechin complexes, pH, and catechin concentration were examined. Photodegradation of inderal was strongly dependent on pH, following the order pH 3.0 < 5.0 < 7.0 < 6.0. Formation of the Fe(iii)-catechin complex resulted in the stabilization of ferric iron and generation of OH under irradiation at near neutral pH values. The removal of inderal was about 75% under optimal conditions (50 MUmol L(-1) Fe(iii) and 200 MUmol L(-1) catechin at pH 6.0). The photodegradation products of inderal were identified by LC-ESI-MS and GC-MS, and the photodegradation pathway was proposed. Iron in the Fe(iii)-catechin system was reused by simple addition of catechin to the reaction mixture. Results of this study suggest that the Fe(iii)-catechin complex may be used in the photo Fenton like process, an advanced approach to the removal of organic pollutants at near-neutral pH. PMID- 25533663 TI - Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP 2/HNF-4alpha/CYP7A1 axis. AB - BACKGROUND & AIMS: Bile acids (BAs) play a crucial role in dietary fat digestion and in the regulation of lipid, glucose, and energy metabolism. Thyroid stimulating hormone (TSH) is a hormone produced by the anterior pituitary gland that directly regulates several metabolic pathways. However, the impact of TSH on BA homeostasis remains largely unknown. METHODS: We analyzed serum BA and TSH levels in healthy volunteers under strict control of caloric intake. Thyroidectomized rats were administered thyroxine and injected with different doses of TSH. Tshr(-/-) mice were supplemented with thyroxine, and C57BL/6 mice were injected with Tshr-siRNA via the tail vein. The serum BA levels, BA pool size, and fecal BA excretion rate were measured. The regulation of SREBP-2, HNF 4alpha, and CYP7A1 by TSH were analyzed using luciferase reporter, RNAi, EMSA, and CHIP assays. RESULTS: A negative correlation was observed between the serum levels of TSH and the serum BA levels in healthy volunteers. TSH administration led to a decrease in BA content and CYP7A1 activity in thyroidectomized rats supplemented with thyroxine. When Tshr was silenced in mice, the BA pool size, fecal BA excretion rate, and serum BA levels all increased. Additionally, we found that HNF-4alpha acts as a critical molecule through which TSH represses CYP7A1 activity. We further confirmed that the accumulation of mature SREBP-2 protein could impair the capacity of nuclear HNF-4alpha to bind to the CYP7A1 promoter, a mechanism that appears to mediate the effects of TSH. CONCLUSIONS: TSH represses hepatic BA synthesis via a SREBP-2/HNF-4alpha/CYP7A1 signaling pathway. This finding strongly supports the notion that TSH is an important pathophysiological regulator of liver BA homeostasis independently of thyroid hormones. PMID- 25533665 TI - Epigenetics: Histone methylation: it's in the numbers. PMID- 25533660 TI - Cetacean morbillivirus: current knowledge and future directions. AB - We review the molecular and epidemiological characteristics of cetacean morbillivirus (CeMV) and the diagnosis and pathogenesis of associated disease, with six different strains detected in cetaceans worldwide. CeMV has caused epidemics with high mortality in odontocetes in Europe, the USA and Australia. It represents a distinct species within the Morbillivirus genus. Although most CeMV strains are phylogenetically closely related, recent data indicate that morbilliviruses recovered from Indo-Pacific bottlenose dolphins (Tursiops aduncus), from Western Australia, and a Guiana dolphin (Sotalia guianensis), from Brazil, are divergent. The signaling lymphocyte activation molecule (SLAM) cell receptor for CeMV has been characterized in cetaceans. It shares higher amino acid identity with the ruminant SLAM than with the receptors of carnivores or humans, reflecting the evolutionary history of these mammalian taxa. In Delphinidae, three amino acid substitutions may result in a higher affinity for the virus. Infection is diagnosed by histology, immunohistochemistry, virus isolation, RT-PCR, and serology. Classical CeMV-associated lesions include bronchointerstitial pneumonia, encephalitis, syncytia, and lymphoid depletion associated with immunosuppression. Cetaceans that survive the acute disease may develop fatal secondary infections and chronic encephalitis. Endemically infected, gregarious odontocetes probably serve as reservoirs and vectors. Transmission likely occurs through the inhalation of aerosolized virus but mother to fetus transmission was also reported. PMID- 25533666 TI - Therapeutics: Winning combination. PMID- 25533658 TI - Phocine distemper virus: current knowledge and future directions. AB - Phocine distemper virus (PDV) was first recognized in 1988 following a massive epidemic in harbor and grey seals in north-western Europe. Since then, the epidemiology of infection in North Atlantic and Arctic pinnipeds has been investigated. In the western North Atlantic endemic infection in harp and grey seals predates the European epidemic, with relatively small, localized mortality events occurring primarily in harbor seals. By contrast, PDV seems not to have become established in European harbor seals following the 1988 epidemic and a second event of similar magnitude and extent occurred in 2002. PDV is a distinct species within the Morbillivirus genus with minor sequence variation between outbreaks over time. There is now mounting evidence of PDV-like viruses in the North Pacific/Western Arctic with serological and molecular evidence of infection in pinnipeds and sea otters. However, despite the absence of associated mortality in the region, there is concern that the virus may infect the large Pacific harbor seal and northern elephant seal populations or the endangered Hawaiian monk seals. Here, we review the current state of knowledge on PDV with particular focus on developments in diagnostics, pathogenesis, immune response, vaccine development, phylogenetics and modeling over the past 20 years. PMID- 25533673 TI - PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. AB - Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most common events in human cancers. In this Review, we discuss recent advances in our knowledge of the roles of specific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can be upregulated, and the current state and future potential of targeting this pathway in the clinic. PMID- 25533674 TI - Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. AB - Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. Low-grade non muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle-invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy. PMID- 25533677 TI - Cardioprotective Effect of Hydrogen-rich Saline on Isoproterenol-induced Myocardial Infarction in Rats. AB - BACKGROUND: Infusion with hydrogen gas-saturated saline has recently been reported to exert antioxidant and anti-inflammatory activity that may protect against organ damage induced by oxidative stress. Therefore because oxidative stress plays a significant role in the pathophysiology of myocardial infarction (MI), the aim of our study was to investigate whether hydrogen-rich saline has cardioprotective effects against isoproterenol-induced MI in rats. METHODS: An acute MI model was induced in male Wistar rats by subcutaneous injection of isoproterenol. Different doses of hydrogen-rich saline (5, 7.5, and 10 mL/kg body weight i.p.) or Vitamin C (250 mg/kg body weight i.g.) were administered to the rats. Oxidative stress indices including levels of myocardial marker enzymes, inflammatory cytokines, membrane-bound myocardial enzymes and histopathological changes were measured. RESULTS: Compared with those in isoproterenol-MI group, hydrogen-rich saline decreased malondialdehyde and 8-hydroxy-desoxyguanosine concentrations, enhanced superoxide dismutase and Na(+)-K(+)-ATPase activity, lowered Ca(2+)-ATPase activity and decreased interleukin-6 and tumour necrosis factor-alpha levels in the serum and/or cardiac tissue of rats. Hydrogen-rich saline pretreatment also diminished infarct size, improved left heart function, and ameliorated pathological changes of the left heart. CONCLUSION: From these results, hydrogen-rich saline exerts cardiovascular protective effects against isoproterenol-induced MI at least in part via interactions which evoke antioxidant and anti-inflammatory activities. PMID- 25533678 TI - The use of skill tests to predict status in junior Australian football. AB - This study examined whether skill tests were predictive of status in junior Australian football. Players were recruited from the 2013 under 18 (U18) West Australian Football League competition and classified into two groups: elite (state U18 squad representative; n = 25; 17.9 +/- 0.5 years) and subelite (nonstate U18 squad representative; n = 25; 17.3 +/- 0.6 years). Both groups completed the Australian football kicking (AFK) and Australian football handballing (AFHB) tests, assessing kicking accuracy/ball speed and handballing accuracy on dominant and nondominant sides. A multivariate analysis of variance (MANOVA) modelled the main effect of "status", whilst logistic regression models were built for the predictive analysis using the same test parameters. Between group differences were noted across all parameters, with the combination of kicking accuracy and ball speed on the dominant and nondominant sides being the best predictor of status for the AFK test (wi = 0.25, AUC = 89.4%) and the combination of accuracy on the dominant and nondominant sides being the best predictor of status for the AFHB test (wi = 0.80, AUC = 88.4%). The AFK and AFHB tests are predictive of status, suggesting that their use is warranted as a means of talent identification in junior Australian football. PMID- 25533675 TI - Modelling bladder cancer in mice: opportunities and challenges. AB - The prognosis and treatment of bladder cancer have improved little in the past 20 years. Bladder cancer remains a debilitating and often fatal disease, and is among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as to affect its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described, and in particular, few that develop invasive cancer phenotypes. This Review focuses on opportunities for improving the landscape of mouse models of bladder cancer. PMID- 25533679 TI - Intracellular pathways following uptake of bevacizumab in RPE cells. AB - The anti-VEGF antibody bevacizumab is widely used off-label for the treatment of various ocular diseases, most commonly in age-related macular degeneration and diabetic macular edema. Bevacizumab is able to penetrate the retina and is found in the choroid after intravitreal injection in a time dependent manner. It has previously been shown to be taken up by the retinal pigment epithelium (RPE). In this study, we have investigated the intracellular pathway following uptake of bevacizumab in RPE cells, tested both in primary porcine RPE cells and in the human cell line ARPE19. Bevacizumab displays a characteristic, time-dependent pattern of intracellular distribution, as detected by immunofluorescence and pulse chase experiments. In both primary cells and the cell line, intracellular bevacizumab can be found after seven days, as detected by immunofluorescence and Western blotting. Immediately after application, bevacizumab partially colocalizes with Rab5, indicating some uptake in early endosomes. Intracellularly, bevacizumab is detected in the cytoskeletal fraction, aligning with actin filaments, as revealed by subcellular fractioning and immunofluorescence. Bevacizumab seems to travel along actin filaments by myosin7a, as determined by triple staining immunofluorescence. Interestingly, over a period of seven days, bevacizumab seems to accumulate in certain storage areas, as observed by immunofluorescence. Furthermore, results obtained with immunocytochemistry, Western blotting and flow cytometry indicate that bevacizumab may be released from the RPE cells via exosomes. In conclusion, bevacizumab is taken up by and transported in the retinal pigment epithelial cells in a characteristic, time-dependent manner, where it seems to move along actin filaments by myosin7a and seem to be partially released from the cells via exosomes. PMID- 25533680 TI - Seasonal effects of the UCP3 and the RPTOR gene polymorphisms on obesity traits in Japanese adults. AB - BACKGROUND: Non-shivering thermogenesis (NST) involves a substantial amount of energy expenditure in humans and, thus, contributes to reducing the risk for obesity. Molecular evolutionary studies have reported that SNPs in/near the uncoupling protein 3 gene (UCP3) and the regulatory associated protein of mTOR complex 1 gene (RPTOR) might influence NST and confer adaptive advantages for modern human dispersal into cold environments. In the present study, the impact of these SNPs on obesity-related traits was investigated. METHODS: Study subjects consisted of 2,834 Japanese adults (percentage of female: 46%, mean age: 51.5). Associations of the UCP3-55C/T and the RPTOR-26934C/T - the 2 potential genetic variations involved in cold adaptation and thermogenic mechanisms in mammals, with quantitative obesity-related traits including body mass index (BMI), waist circumference, visceral fat area (VFA), VFA adjusted for BMI, and selected blood parameters - were tested using multiple linear regression models. Sliding windowsampling analysis was applied to depict seasonal effects of the SNPs on the obesity-related phenotypes. RESULTS: UCP3-55C/T and the RPTOR-26934C/T did not show any association with obesity traits and blood chemical parameters in multiple linear regression models consisting of the whole subjects. Moreover, sliding window sampling-based association analyses involving seasonality also failed to find associations between these two SNPs and obesity-related traits. CONCLUSIONS: UCP3-55C/T and the RPTOR-26934C/T may only have subtle effects on the development of obesity-related traits in the present humans. These two SNPs might be irrelevant to inter-individual variations in energy metabolism and efficiency of NST. PMID- 25533676 TI - VHL, the story of a tumour suppressor gene. AB - Since the Von Hippel-Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC. PMID- 25533682 TI - Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an accepted treatment for motor symptoms in a subset of Parkinson's disease (PD) patients. The mechanisms why DBS is effective are incompletely understood, but previous studies show that DBS targeted in brain structures other than the STN may modify the microvasculature. However, this has not been studied in PD subjects who have received STN-DBS. Here we investigated the extent and nature of microvascular changes in post-mortem STN samples from STN-DBS PD patients, compared to aged controls and PD patients who had not been treated with STN-DBS. We used immunohistochemical and immunofluorescent methods to assess serial STN containing brain sections from PD and STN-DBS PD cases, compared to similar age controls using specific antibodies to detect capillaries, an adherens junction and tight junction-associated proteins as well as activated microglia. Cellular features in stained sections were quantified by confocal fluorescence microscopy and stereological methods in conjunction with in vitro imaging tools. We found significant upregulation of microvessel endothelial cell thickness, length and density but lowered activated microglia density and striking upregulation of all analysed adherens junction and tight junction-associated proteins in STN-DBS PD patients compared to non-DBS PD patients and controls. Moreover, in STN-DBS PD samples, expression of an angiogenic factor, vascular endothelial growth factor (VEGF), was significantly upregulated compared to the other groups. Our findings suggest that overexpressed VEGF and downregulation of inflammatory processes may be critical mechanisms underlying the DBS-induced microvascular changes. PMID- 25533684 TI - [Further discussion of the treatment of idiopathic pulmonary fibrosis]. PMID- 25533681 TI - Metabolic responses differentiate between interictal, ictal and persistent epileptiform activity in intact, immature hippocampus in vitro. AB - Interictal spikes, ictal responses, and status epilepticus are characteristic of abnormal neuronal activity in epilepsy. Since these events may involve different energy requirements, we evaluated metabolic function (assessed by simultaneous NADH and FAD+ imaging and tissue O2 recordings) in the immature, intact mouse hippocampus (P5-P7, in vitro) during spontaneous interictal spikes and ictal-like events (ILEs), induced by increased neuronal network excitability with either low Mg2+ media or decreased inhibition with bicuculline. In low Mg2+ medium NADH fluorescence showed a small decrease both during the interictal build-up leading to an ictal event and before ILE occurrences, but a large positive response during and after ILEs (up to 10% net change). Tissue O2 recordings (pO2) showed an oxygen dip (indicating oxygen consumption) coincident with each ILE at P5 and P7, closely matching an NADH fluorescence increase, indicating a large surge in oxidative metabolism. The ILE O2 dip was significantly larger at P7 as compared to P5 suggesting a higher metabolic response at P7. After several ILEs at P7, continuous, low voltage activity (late recurrent discharges: LRDs) occurred. During LRDs, whilst the epileptiform activity was relatively small (low voltage synchronous activity) oxygen levels remained low and NADH fluorescence elevated, indicating persistent oxygen utilization and maintained high metabolic demand. In bicuculline, NADH fluorescence levels decreased prior to the onset of epileptiform activity, followed by a slow positive phase, which persisted during interictal responses. Metabolic responses can thus differentiate between interictal, ictal-like and persistent epileptiform activity resembling status epilepticus, and confirm that spreading depression did not occur. These results demonstrate clear translational value to the understanding of metabolic requirements during epileptic conditions. PMID- 25533685 TI - [The definition and classification of the evolution of idiopathic interstitial pneumonia]. PMID- 25533686 TI - [The diagnosis and treatment of idiopathic pulmonary fibrosis]. PMID- 25533683 TI - Clinical and pathological predictors of estimated GFR decline in patients with type 2 diabetes and overt proteinuric diabetic nephropathy. AB - BACKGROUND: The effect of clinical and pathological parameters on the estimated glomerular filtration rate (eGFR) decline has not been investigated in patients with type 2 diabetes and overt proteinuric biopsy-proven diabetic nephropathy. METHODS: Among 198 patients with type 2 diabetes who underwent renal biopsy and were confirmed to have pure diabetic nephropathy according to the recent classification, 128 patients with overt proteinuria were enrolled. Receiver operating characteristic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were performed using models adjusted for various clinical and pathological covariates to determine the best predictors of rapid eGFR decline [defined as >14.9%/year (median eGFR decline)]. RESULTS: A model that incorporated proteinuria showed the largest area under the curve (AUC) among clinical models, which suggested that proteinuria was the best clinical predictor. Although a model incorporating interstitial fibrosis and tubular atrophy (IFTA) score did not display a significantly larger AUC than the model with proteinuria (0.843 vs 0.812, respectively, p = 0.47), a model with both IFTA score and proteinuria had a significantly larger AUC than the model with proteinuria alone (0.875 vs 0.812, respectively, p = 0.014). Similarly, the addition of IFTA score resulted in a significantly greater net reclassification improvement and integrated discrimination improvement than the model with proteinuria alone [NRI: 0.78 (95% CI: 0.43-1.13; p < 0.001), IDI: 0.13 (95% CI: 0.07-0.19; p < 0.001)]. CONCLUSIONS: Our results suggest that not only proteinuria but also tubulointerstitial lesions should be assessed to predict rapid eGFR decline in patients with type 2 diabetes who have overt proteinuria and biopsy-proven diabetic nephropathy. PMID- 25533687 TI - [Surgical lung biopsy for the management of diffuse interstitial lung disease]. AB - OBJECTIVE: To evaluate the role of surgical lung biopsy (SLB) in the management of diffuse interstitial lung disease (DILD) with no specific diagnosis. METHODS: We conducted a retrospective analysis of 179 cases with DILD of non-specific diagnosis after non-invasive methods and minimally invasive processes, including bronchoscopy and CT-guided lung biopsy, were performed SLB at Peking Union Medical College Hospital between 2006 and 2012. Patient demographics, surgical approach, number and site of biopsies, post-operative complications and postoperative pathological diagnosis and treatment were analyzed. RESULTS: Of 179 cases, there were 91 males (50.8%) and 88 females (49.2%), with a median age of 47.3 years (range 16-76). There were 6 cases(3.4%) who were younger than 20 years and 25 cases(14%) older than 60 years. From 2006 to 2012, every year there were 16 case (8.9%), 17 cases(9.5%), 19 cases (10.6%), 44 cases (24.6%), 33 cases(18.4%), 31 cases (17.3%) and 19 cases (10.6%) respectively. The total median hospital stay was 33.4 days (range 6-76) and the mean postoperative stay was 18.6 days (range 2-56). The mean duration for chest drainage was 3.2 days (range 2-18). Among them, 150 cases were arranged with video-assisted thoracoscopy surgery (VATS) and 29 cases were arranged with minithoracotomy. The number of biopsies taken was ranged from one to four and there were 126 cases (70.4%) had more than one biopsy. The biopsy was performed in left lingular lobe (54 cases/30.2%), left natural upper lobe (16 cases/8.9%), left inferior basal segments (56 cases/31.3%), right upper lobe (30 cases/16.7%), right meddle lobe (40case/22.3%) and right inferior basal segments (56 case/31.3%) respectively. Definitive pathological diagnosis was reached in 103 cases (57.5%), diagnosis was reached after combination of pathological, clinical and radiological manifestations in 32 cases (17.9%) and there were 44 cases (24.6%) could not achieved diagnosis even after the SLB. Chronic extrinsic allergic alveolitis was the most common diagnosis (33/24.4%), following nonspecific interstitial pneumonia (27/20%) for the 135 cases with a definite diagnosis. Among 179 cases, there were 114 cases had a change in their treatment following the results of SLB. There were 16 cases had a fever after surgery and antibiotics were administrated for eleven of them. Other complication were included delayed wound healing (>10 days after surgery, 6 cases), thoracic hemorrhage (5 cases), chest tube re-indwelling because of pneumothorax (4 cases), delayed weaning of ventilator (>3 days after surgery, 4 cases), respiratory failure (3 cases), and thoracic infection (2 cases). There were two cases died within 30 days following surgery because of respiratory failure. CONCLUSIONS: Most of the DILD patients who were arranged with SLB were young and middle-aged cases. The left lingular lobe, right meddle lobe and both inferior lobes were the preferred biopsy sites. The results of biopsy surgery could provides a diagnosis for most of the DILD patients and could modulate the treatment for more than half of them. Fever and delayed wound healing were the major complications. The SLB related mortality was low. SLB was suggested to the undiagnosed DILD patients. PMID- 25533689 TI - [Effects of fasudil on bleomycin-induced pulmonary fibrosis in mice and on the biological behaviors in NIH3T3 mouse fibroblast cell line]. AB - OBJECTIVE: To determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice and to determine the effects and mechanisms of fasudil on the biological behaviors in NIH3T3 mouse fibroblast cell line. METHODS: The BPF model was induced by a single dosage of 2.5 mg/kg bleomycin intratracheal injection in mice and fasudil intraperitoneal injection was given to the mice. The fibrosis degree was determined pathologically by using the Ashcroft scoring method and biochemically by hydroxyproline assay in lung tissue. NIH3T3 mouse fibroblast cell line was cultured in vitro and fasudil was given to the cell. The proliferation activity in NIH3T3 cells were detected by MTT assay and flat colony forming experiment. The migration activity in NIH3T3 cells were detected by scratch test and transwell chamber experiment. The expression of CyclinD1, MMP2 and TIMP1 mRNA in NIH3T3 cells was detected by RT-PCR. The expression of CyclinD1, MMP2 and TIMP1 protein and the level of MYPT1 phosphorylation in NIH3T3 cells was detected by Western blot. RESULTS: Compare to the mice administrated by bleomycin, the Ashcroft score and hydroxyproline content were significantly decreased in the mice administered fasudil. Administration of fasudil can reduce the ability of proliferation and migration in a dose-dependent manner in NIH3T3 cells. The effect of fasudil was possibly related to increase the production of TIMP1 and decrease the production of CyclinD1 and MMP2. CONCLUSIONS: Administration of fasudil can attenuate pulmonary fibrosis both in vivo and in vitro. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis. PMID- 25533688 TI - [The expressions and meanings of BMP-7 and TGF-beta in idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonia]. AB - OBJECTIVE: To investigate the expressions of cytokines in idiopathic pulmonary fibrosis (IPF) and in idiopathic nonspecific interstitial pneumonia (INSIP); To discuss expressions and meanings of bone morphogenetic protein 7 (BMP-7) and transforming growth factor beta (TGF-beta) in IPF and IPF. METHODS: Selected 47 cases of idiopathic interstitial pneumonia (IIP), which were diagnosed by clinical-radiologic-pathologic (CRP), and classified into two groups which were group IPF (25 IPF) and group INSIP (22 INSIP, including 6 cellular pattern and 16 fibrosing pattern). The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of BMP-7 and TGF-beta in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. RESULTS: According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,BMP-7 expressed decreasingly in IPF and INSIP groups (t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001). The expression of IPF were lower than INSIP (t = 5.387, P < 0.05); In INSIP group, patients of cellular pattern expressed BMP-7 more than fibrosing pattern's (t = 5.341, P < 0.001). There were dramatically increasing expressions of TGF-beta in IPF and INSIP, when compared with the control group (t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001) and it presented negative correlation with BMP-7(group IPF: r = -0.771, P < 0.001; group INSIP: r = -0.729, P < 0.001). (3) Clinical follow-up data showed, the stability(improvement), deterioration and death rates of the group IPF and the group INSIP were, respectively, 0(0%), 2 (8%), 23 (92%) and 15 (68.1%), 3 (13.6%), 4 (18.2%). The results were statistically significant (all P < 0.05). The median survival time of the part with higher BMP-7 expression and the part with relatively lower BMP-7 expression, in the group IPF, were 110.8 and 66.4 months (t = -2.686, P < 0.05); In the group INSIP, were 146.4 and 74.9 months (t = -3.037, P < 0.05). CONCLUSIONS: Cellular cytokines presented different expression profiles in IPF and INSIP patients. Differently with highly activated TGF-beta, BMP-7 was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. BMP-7 would be expected to be a novel target for IIP pathogenesis and prognostic research. PMID- 25533690 TI - [Mixed types of pulmonary aspergillosis]. AB - OBJECTIVE: To describe the clinical features of mixed types of pulmonary aspergillosis (MTPA), and therefore to improve the diagnosis and treatment of MTPA. METHODS: This study retrospectively analyzed 3 patients with MTPA in Peking University First Hospital from November 2010 to 2012. "Invasive pulmonary aspergillosis (IPA), pulmonary aspergilloma, allergic bronchopulmonary aspergillosis (ABPA)" were used as the Chinese and English keywords, to search the literatures from Wanfang database and Pubmed database until to May 2014. RESULTS: There were 3 patients with MTPA, respectively with aspergilloma and IPA (patient 1), ABPA and IPA (patient 2), aspergilloma and IPA (patient 3). The cultures of respiratory secretions of the patients all yielded A.fumigatus. Patient 1 was treated by amphotericin B; Patient 2 was treated by intravenous itraconazole and glucocorticoid; Patient 3 was treated by oral voriconazole and inhaled corticosteroid, and the aspergilloma was surgically removed at the same time. Eventually, patients 1 and 2 died, while the symptoms of patient 3 were significantly improved. Drug sensitivity test of A. fumigatus showed resistance to amphotericin B or itraconazole. By far there was no concept of MTPA in the literatures and there were only 3 relevant case reports. CONCLUSION: MTPA is a new subtype of pulmonary aspergillosis, which is more complicated and severe, and perhaps with drug resistance. MTPA should be treated by comprehensive therapies on the basis of sensitive and effective antifungal drugs. PMID- 25533693 TI - [Familial pulmonary fibrosis]. PMID- 25533692 TI - [The clinical and CT two-phase imaging features of bronchial-pulmonary arterial fistula]. AB - OBJECTIVE: To study the clinical features of bronchial-pulmonary arterial fistula, and to analyze its imaging features. METHODS: In continuous five months, 502 patients for pulmonary angiography were analyzed by pulmonary/aortic arterial two-phase scanning. The 128-slice MSCT (Siemens Definition AS 128) was used with the following parameters: the speed of 0.5 s/weeks, the collimator width of 64 * 0.6 mm, the pitch of 0.9, the tube voltage of 120 kV, the contrast agent of 300 mg/ml (1.2 ml/kg) , and the flow rate of 4.3 ml/s. Automatic trigger technology was used, while the threshold of the main pulmonary artery trunk was set to 80 HU. After 4 s delay, the pulmonary-arterial phase was scanned for 3-5 s. Then, the aortic-arterial phase was taken after 12 s. Finally, the clinical features and CTA two-phase images were analyzed by two radiologists, respectively. The diagnozied criteria of CTA images for bronchial-pulmonary arterial fistula were as following.In pulmonary/aortic arterial two-phase scanning, pulmonary artery or aortic artery could be displayed, respectively. The filling defect of fistula's pulmonary artery was observed in pulmonary arterial phase. However, the filling defect of fistula's pulmonary artery had significant filling in aortic arterial phase, with the similar density intensity of aortic artery.In addition, the thicken bronchial artery were observed in the fistula area. RESULTS: CLINICAL FEATURES: In all 502 patients, 65 positive cases of the bronchial-pulmonary arterial fistula included 37 male cases and 28 female cases with ages from 45 to 83 years (69 +/- 11). The clinical symptoms included hemoptysis (32%), anhelation (69%), hypoxia (66%), the raise of D2 dimer (70%), and pulmonary hypertension (64%). CTA two-phase images features: In the pulmonary-arterial phase, the intensity difference of pulmonary/aortic was [322 +/- 122 (100-751)] HU. The local filling defect in the proximal pulmonary artery (12%) and the filling defect in the whole pulmonary artery (88%) were observed in 65 positive cases.In the aortic-arterial phase, the intensity difference of pulmonary/aortic was [251 +/- 89 (85-428)] HU. The local enhancement in the proximal pulmonary artery (24%) and the enhancement in the whole pulmonary artery (76%) were observed in 58 positive cases. The visible thicken bronchial artery were observed in the fistula area of all cases.In 65 cases of bronchial-pulmonary arterial fistula, the fistula lesions contained 56 cases of lung lesions (including 35 cases of honeycomb lung, 16 cases of atelectasis, and 3 cases of chronic mass-like pneumonia) and 9 cases of vascular lesions (including 4 cases of chronic pulmonary artery embolism, 3 cases of congenital vascular malformation, 1 case of pulmonary arthritis, and 1 case of pulmonary artery aneurysm). 437 cases of non bronchial-pulmonary arterial fistula had 4 cases of of vascular lesions and 76 cases of lung lesions. There were significant statistic difference between the fistula and vascular lesions or lung lesions (the value of chi(2): 37.51 or 165.11, all values of P < 0.001). CONCLUSION: The disease of bronchial-pulmonary arterial fistula usually occurred in the chronic pneumonia and the pulmonary vascular lesions. The CT pulmonary/aortic arterial two-phase scanning could detect the homodynamic changes to diagnosis this disease correctly. The pulmonary embolism need be differentiated. PMID- 25533691 TI - [Distribution of influenza A (H5N1) virus and pathological lesions in major organ tissues of experimentally infected rhesus macaques]. AB - OBJECTIVE: To investigate the pathological changes and viral invasion in the main organs of rhesus macaques after experimental infection with H5N1 virus. METHODS: The rhesus macaques were infected with H5N1 virus (AF148678/ACGoose/Guangdong/11961H5N1) by nasal inoculation under anesthesia. One rhesus macaque was killed respectively at 1, 3, 6, 14 days after infection. The pathologic changes of the main organs were observed using HE staining and the characteristics of the viral invasion in the body were analyzed using viral isolation, RT-PCR andimmunohistochemistry. RESULTS: The influenza virus replicated only in the lung tissues characterized by diffuse alveolar damage in the infected rhesus macaques, mainly involving alveolar epithelial cells and pulmonary macrophages. The pathological changes showed 3 phases including exudative inflammation, hyperplasia and fibrosis. Extra-pulmonary organs also showed different degree of pathological changes such as degeneration and necrosis, but virus was not isolated in the corresponding organs. CONCLUSIONS: Acute diffuse lung injury was a central part of the pathogenesis in H5N1 avian influenza virus infection. The lung was the main target organ in H5N1 viral infection, and H5N1 virus cannot replicate in other organs, which may be one of the obstacles to H5N1 viral transmission from person to person. PMID- 25533694 TI - [Research progress on the treatment options of pulmonary alveolar proteinosis]. PMID- 25533695 TI - [Research progress on the treatment options of pulmonary alveolar proteinosis]. PMID- 25533696 TI - [Clinical status of right heart thrombus with pulmonary embolism]. PMID- 25533697 TI - Erratum to "Usefulness of Ultrasound for Detecting Suspected Peripheral Nerve Lesions in Diagnosis of Peripheral Neuropathy : Case Report and Brief Review of the Literature" by Jung JH, et al. (J Korean Neurosurg Soc 53 : 132-135, 2013). AB - [This corrects the article on p. 132 in vol. 53, PMID: 23560182.]. PMID- 25533698 TI - Predictors of flexion using the rotating concave-convex total knee arthroplasty: preoperative range of motion is not the only determinant. AB - PURPOSE: The range of motion achieved after a total knee arthroplasty (TKA) affects many daily activities and overall patients' satisfaction. This study aims to define the determinants affecting post-operative midterm active flexion according to a specific cruciate-sacrificing prosthesis, the rotating concave convex (ROCC((r))) TKA. METHOD: Four hundred and eighty-four consecutive patients (584 TKAs) were prospectively followed. After baseline patient demographics and anatomical characteristics, clinical and radiological post-operative assessments were periodically recorded. The rotational alignment of the femoral component was additionally reported for 120 patients. Eligibility for final inclusion was a minimum of 5-year follow-up. Univariate analyses followed by a multivariate model were fitted to determine the independent predictors of midterm active knee flexion. RESULTS: Thirty-four TKA (5.8%) were excluded for a secondary surgery before their 50 years, 69 patients died (11.8%), and 21 (3.6%) were lost to follow-up. Overall, 460 TKAs were included. The post-operative mean knee flexion angle was measured at 127.7 degrees +/- 9.3 degrees . Significant factors affecting final flexion under univariate analyses were the patient height and body mass index, the absence of previous surgery, a depressive state, the preoperative flexion angle, a preoperative flexion contracture, a patellar residual subluxation, the reconstructed patellar height, and the rotation of the femoral component. The multivariate model confirmed the patient's height, a depression, the preoperative flexion angle, a patellar residual subluxation, and the patellar height as statistically significant determinants. CONCLUSION: Aside from the preoperative flexion angle, numerous predictors of flexion, both patient and procedure-related were identified. Surgeons should take these into account both when adequately informing their patient before surgery and when performing the arthroplasty itself. LEVEL OF EVIDENCE: Prognostic, Level II. PMID- 25533699 TI - Microfracture for chondral defects: assessment of the variability of surgical technique in cadavers. AB - PURPOSE: The purpose of this study was to assess the variability of the microfracture technique when performed by experienced knee arthroscopy surgeons. METHOD: Four surgeons were each asked to perform microfracture on six preformed cartilage defects in fresh human cadaveric knees. Surgeons were instructed on penetration depth, inter-hole distance, and to place the holes perpendicular to the subchondral surface. Micro-computed tomography was used to calculate depth error, inter-hole distance error, and deviation of penetration angles from the perpendicular. RESULTS: All surgeons misjudged depth and inter-hole distance, tending to make microfracture holes too deep (depth error 1.1 mm +/- 1.9) and too close together (inter-hole distance error: -0.8 mm +/- 0.4). Fifty-one per cent of holes were angled more than 10 degrees from the perpendicular (range 2.6 degrees -19.8 degrees ). Both depth and distance errors were significantly lower in the trochlear groove than on the femoral condyle (p < 0.05). Surface shearing was associated with both penetration depth >4 mm and angles >20 degrees . Inter hole infraction occurred in holes closer than 2.5 mm to each other. CONCLUSION: Even experienced knee arthroscopy surgeons demonstrate inconsistency in surgical technique when performing microfracture. While further research will be required to demonstrate that these variations in surgical technique are associated with poorer clinical outcomes after microfracture, surgeons should attempt to minimizing such variations in order to prevent surface shearing and inter-hole infraction. PMID- 25533700 TI - Biomechanical differences of the anterior and posterior bands of the ulnar collateral ligament of the elbow. AB - PURPOSE: The main purpose of this study was to examine the functional characteristics of the anterior and posterior bands of the anterior bundle of the ulnar collateral ligament (UCL). METHODS: Six cadaveric elbows were tested using a digital tracking system to measure the strain in the anterior band and posterior band of the anterior bundle of the UCL throughout a flexion/extension arc. The specimens were then placed in an Instron materials testing machine and loaded to failure to determine yield load and ultimate load of the UCL. RESULTS: The posterior band showed a linear increase in strain with increasing degrees of elbow flexion while the anterior band showed minimal change in strain throughout. The bands showed similar strain at yield load and ultimate load, demonstrating similar intrinsic properties. CONCLUSION: The anterior band of the anterior bundle of the UCL shows an isometric strain pattern through elbow range of motion, while the posterior band shows an increasing strain pattern in higher degrees of elbow flexion. Both bands show similar strain in a load to failure model, indicating insertion point, not intrinsic differences, of the bands determine the function of the anterior bundle of the UCL. This demonstrates a biomechanical rationale for UCL reconstructions using single point anatomical insertion points. PMID- 25533701 TI - Magnetic structure and magnetic transport properties of graphene nanoribbons with sawtooth zigzag edges. AB - The magnetic structure and magnetic transport properties of hydrogen-passivated sawtooth zigzag-edge graphene nanoribbons (STGNRs) are investigated theoretically. It is found that all-sized ground-state STGNRs are ferromagnetic and always feature magnetic semiconductor properties, whose spin splitting energy gap E(g) changes periodically with the width of STGNRs. More importantly, for the STGNR based device, the dual spin-filtering effect with the perfect (100%) spin polarization and high-performance dual spin diode effect with a rectification ratio about 10(10) can be predicted. Particularly, a highly effective spin-valve device is likely to be realized, which displays a giant magnetoresistace (MR) approaching 10(10)%, which is three orders magnitude higher than the value predicted based on the zigzag graphene nanoribbons and six orders magnitude higher than previously reported experimental values for the MgO tunnel junction. Our findings suggest that STGNRs might hold a significant promise for developing spintronic devices. PMID- 25533703 TI - Assessment of repeatability of composition of perfumed waters by high-performance liquid chromatography combined with numerical data analysis based on cluster analysis (HPLC UV/VIS - CA). AB - High-performance liquid chromatography (HPLC) with UV/VIS spectrophotometric detection combined with the chemometric method of cluster analysis (CA) was used for the assessment of repeatability of composition of nine types of perfumed waters. In addition, the chromatographic method of separating components of the perfume waters under analysis was subjected to an optimization procedure. The chromatograms thus obtained were used as sources of data for the chemometric method of cluster analysis (CA). The result was a classification of a set comprising 39 perfumed water samples with a similar composition at a specified level of probability (level of agglomeration). A comparison of the classification with the manufacturer's declarations reveals a good degree of consistency and demonstrates similarity between samples in different classes. A combination of the chromatographic method with cluster analysis (HPLC UV/VIS - CA) makes it possible to quickly assess the repeatability of composition of perfumed waters at selected levels of probability. PMID- 25533702 TI - Immunity to helminths: resistance, regulation, and susceptibility to gastrointestinal nematodes. AB - Helminth parasites are a highly successful group of pathogens that challenge the immune system in a manner distinct from rapidly replicating infectious agents. Of this group, roundworms (nematodes) that dwell in the intestines of humans and other animals are prevalent worldwide. Currently, more than one billion people are infected by at least one species, often for extended periods of time. Thus, host-protective immunity is rarely complete. The reasons for this are complex, but laboratory investigation of tractable model systems in which protective immunity is effective has provided a mechanistic understanding of resistance that is characterized almost universally by a type 2/T helper 2 response. Greater understanding of the mechanisms of susceptibility has also provided the basis for defining host immunoregulation and parasite-evasion strategies, helping place in context the changing patterns of immunological disease observed worldwide. PMID- 25533704 TI - Home birth: moving toward shared goals. PMID- 25533705 TI - Evidence-based practice for intrapartum care: the Pearls of Midwifery. AB - Care for women in labor in the United States is in a period of significant transition. Many intrapartum care practices that are standard policies in hospitals today were instituted in the 20th century without strong evidence for their effect on the laboring woman, labor progress, or newborn outcomes. Contemporary research has shown that many common practices, such as routine intravenous fluids, electronic fetal monitoring, and routine episiotomies, do more harm than good. In 2010, the American College of Nurse-Midwives released a PowerPoint presentation titled Evidence-Based Practice: Pearls of Midwifery. This presentation reviews 13 intrapartum-care strategies that promote normal physiologic vaginal birth and are associated with a lower cesarean rate. They are also practices long associated with midwifery care. This article reviews the history of intrapartum practices that are now changing, the evidence that supports these changes, and the practical applications for the 13 Pearls of Midwifery. PMID- 25533706 TI - A systematic review of maternal confidence for physiologic birth: characteristics of prenatal care and confidence measurement. AB - INTRODUCTION: Because a focus on physiologic labor and birth has reemerged in recent years, care providers have the opportunity in the prenatal period to help women increase confidence in their ability to give birth without unnecessary interventions. However, most research has only examined support for women during labor. The purpose of this systematic review was to examine the research literature for information about prenatal care approaches that increase women's confidence for physiologic labor and birth and tools to measure that confidence. METHODS: Studies were reviewed that explored any element of a pregnant woman's interaction with her prenatal care provider that helped build confidence in her ability to labor and give birth. Timing of interaction with pregnant women included during pregnancy, labor and birth, and the postpartum period. In addition, we looked for studies that developed a measure of women's confidence related to labor and birth. Outcome measures included confidence or similar concepts, descriptions of components of prenatal care contributing to maternal confidence for birth, and reliability and validity of tools measuring confidence. RESULTS: The search of MEDLINE, CINAHL, PsycINFO, and Scopus databases provided a total of 893 citations. After removing duplicates and articles that did not meet inclusion criteria, 6 articles were included in the review. Three relate to women's confidence for labor during the prenatal period, and 3 describe tools to measure women's confidence for birth. DISCUSSION: Research about enhancing women's confidence for labor and birth was limited to qualitative studies. Results suggest that women desire information during pregnancy and want to use that information to participate in care decisions in a relationship with a trusted provider. Further research is needed to develop interventions to help midwives and physicians enhance women's confidence in their ability to give birth and to develop a tool to measure confidence for use during prenatal care. PMID- 25533707 TI - Induction of labor: update and review. AB - Rates of labor induction in the United States have more than doubled in the past 2 decades. Trends of indications and risk factors related to induction of labor are also increasing. Professional organizations such as the American College of Obstetricians and Gynecologists and The Joint Commission have taken steps to discourage elective induction of labor prior to 39 weeks' gestation and have created new definitions of early-term, full-term, late-term, and postterm gestation to guide clinicians in the timing of birth for specified indications. Induction of labor is associated with potential risks to both the woman and her fetus. The cost associated with induction of labor and the impact on the health care system is of growing concern. Education of women and the process of shared decision making when obtaining informed consent are key factors in reducing early elective births. Use of tools such as scheduling forms, hard stop methods, induction of labor indication tools, and informed consents may aid the provider in reducing overdiagnosis, overtreatment, and disease creep. This article provides a review of the trends of induction of labor, medical indications and criteria, associated risks, cost and health system impact, and initiatives to lower the incidence of induction of labor. PMID- 25533709 TI - Current resources for evidence-based practice, November/December 2014. PMID- 25533708 TI - Transfer from planned home birth to hospital: improving interprofessional collaboration. AB - Women's heightened interest in choice of birthplace and increased rates of planned home birth in the United States have been well documented, yet there remains significant public and professional debate about the ethics of planned home birth in jurisdictions where care is not clearly integrated across birth settings. Simultaneously, the quality of interprofessional interactions is recognized as a predictor of health outcomes during obstetric events. When care is transferred across birth settings, confusion and conflict among providers with respect to roles and responsibilities can adversely affect both outcomes and the experience of care for women and newborns. This article reviews findings of recent North American studies that examine provider attitudes toward planned home birth, differing concepts of safety of birthplace as reported by women and providers, and sources of conflict among maternity care providers during transfer from home to hospital. Emerging evidence and clinical exemplars can inform the development of systems for seamless transfer of women and newborns from planned home births to hospital and improve experience and perceptions of safety among families and providers. Three successful models in the United States that have enhanced multidisciplinary cooperation and coordination of care across birth settings are described. Finally, best practice guidelines for roles, communication, and mutual accommodation among all participating providers when transfer occurs are introduced. Research, health professional education, and policy recommendations for incorporation of key components into existing health care systems in the United States are included. PMID- 25533711 TI - [Share with women. Vaccines for adults]. PMID- 25533712 TI - [Share with women. Vaccines during pregnancy]. PMID- 25533713 TI - Concept clarification of grief in mothers of children with an addiction. AB - AIM: To report an analysis of the concept of grief in mothers of children with an addiction. BACKGROUND: The concept of grief in this context is poorly understood and often synonymously used with concepts depression, loss and chronic sorrow. In the US, the core concept grief has been recently revised by both NANDA and the DSM-V in efforts to better understand and characterize the concept. The plethora of literature on grief worldwide often characterizes grief as a response to a death. DESIGN: Concept analysis. DATA SOURCES: Search terms 'parental grief' and 'substance abuse' yielded 30 articles. A second review using terms 'grief' and 'substance abuse' yielded 323 articles, in PsychInfo, CINAHL, PubMed databases from 1980-2013. Limits for articles in English and for the terms 'death' and 'child' yielded 13 usable articles. METHODS: The hybrid model of concept analysis, using a theoretical phase, an empirical phase and a final phase when a clarified definition of grief emerged. RESULTS: Definitions in the literature and defining characteristics of grief outline bio-psycho-social aspects of the concept. For one mother grief was accompanied by recurring feelings of sadness across time, while for the other mother grief was seen as coping, after having passed through a variety of stages of grief. For both, grief was seen to fall on a continuum. CONCLUSIONS: Grief is a universal concept and has a trajectory. Case study data have been essential in clarifying understandings of grief as experienced by mothers of addicted children and will provide direction for meaningful and tailored interventions. PMID- 25533714 TI - Markers of endothelial function in migraine patients: Results from a bi-center prospective study. AB - BACKGROUND: Numerous studies suggest an increased vascular risk in patients with migraine, in particular in those with aura. A possible link between both conditions might be a dysfunction of the vascular endothelium. This observational study analyzed the endothelial markers angiopoietin-1, angiopoietin-2, Tie-2, sFlt-1 and NT-proBNP for the first time in migraineurs, patients with other primary headache disorders and healthy controls. METHODS: Patients with episodic migraine with and without aura, episodic cluster headache, tension-type headache and healthy controls were included. Blood samples were obtained during migraine attacks and headache-free periods in migraineurs, in and out of bout in cluster headache and during headache-free periods in tension-type headache and healthy individuals to analyze markers of endothelial function. RESULTS: No significant difference in endothelial markers between migraine, other headache disorders and healthy controls was detected. There was no significant difference between migraine attacks and headache-free intervals. Additionally, no distinction could be found between migraine with and without aura. DISCUSSION: The endothelial markers analyzed do not display a characteristic pattern in different headache disorders especially migraine compared to healthy controls. The novel findings of our study indicate that factors other than endothelial dysfunction seem to be responsible for the at least statistical association of migraine with vascular disease. PMID- 25533715 TI - An evidence-based review of oral magnesium supplementation in the preventive treatment of migraine. AB - BACKGROUND: Migraine is an incompletely understood, debilitating disorder that lacks a universally effective treatment. Magnesium participates in a variety of biochemical processes related to migraine pathophysiology, and a deficiency could contribute to migraine development. METHODS: A review of the literature from 1990 to the present on magnesium and migraine was conducted. REVIEW: The authors identified 16 studies aimed at magnesium status assessment in migraine, and four intervention trials assessing the efficacy of oral magnesium supplementation, independent of other therapies, in the prevention of migraine. CONCLUSION: The strength of evidence supporting oral magnesium supplementation is limited at this time. With such limited evidence, a more advantageous alternative to magnesium supplementation, in patients willing to make lifestyle changes, may be to focus on increasing dietary magnesium intake. PMID- 25533716 TI - MRI in diagnosis of pathological complete response in breast cancer patients after neoadjuvant chemotherapy. AB - OBJECTIVE: To select effective indicators for diagnosis of pathological complete response (pCR) by MRI and to establish an appropriate diagnostic program to maximize the accuracy of pCR detection by MRI. MATERIALS AND METHODS: Twenty-one pCR patients and 22 non-pCR randomly selected patients receiving neoadjuvant chemotherapy (NAC) and subsequent surgery were recruited for the study. All patients underwent breast MRIs both before and after chemotherapy. Changes in diameter, area and dynamic variables between the first and final MRI were compared between the two groups. Logistic and ROC analysis were performed to select effective indicators for predicting pCR on MRI. RESULTS: Eleven out of 43 patients had no residual enhanced areas on MRI, and the sensitivity and specificity for predicting pCR on MRI under the current criterion was 52.38% and 100%, respectively. Logistic regression analysis revealed that changes in diameter, SIpeak and area were effective in predicting pCR by MRI. The latter two parameters had a greater impact on diagnosis than the diameter change. Two new independent criteria were established to predict pCR on MRI: (1) a reduction of >=78% in area; and (2) a combination of a reduction of >=27% in SIpeak and of >=78% in area on MRI. Both had diagnostic accuracy of 88.37% and criterion 1 had higher sensitivity of 90.48%. However, criterion 2 had perfect specificity of 100%. CONCLUSION: MRI is an effective means for detecting pCR from non-pCR patients. Changes in area and SIpeak can be used to establish two new independent criteria which perform better in diagnosing pCR on MRI than the current criterion. PMID- 25533717 TI - MR imaging of transient osteoporosis of the hip: an update on 155 hip joints. AB - PURPOSE: Transient osteoporosis of the hip (TOH) presents with acute onset pain and bone marrow edema (BMe) on MR imaging. The purpose of this study is to revise the MR imaging characteristics of TOH by analyzing the data derived from 155 hip examinations. We also sought to explore the relationship between the duration of symptoms and the presence of sparing and subchondral fractures. MATERIALS AND METHODS: MR images of 155 hips (141 TOH patients) were retrospectively evaluated for the presence of insufficiency fractures and the morphology of BMe. Sparing of the medial bone marrow of the femoral head was recorded together with demographic and clinical data. Progression to regional migratory osteoporosis (RMO) and postpartum cases were also recorded. RESULTS: Our population consisted of 76.4% male and 23.6% female patients. RMO progression was recorded in 19.4% and 4 postpartum cases displayed bilateral disease. Sparing of the medial bone marrow was present at 87.7% of patients and disappeared as the disease progressed (P=0.005). BMe was restricted within the femoral head in 11.0%, extended to the femoral neck in 40% and to the femoral shaft in 49% of the cases studied. Subchondral fractures were present at 48.7% of the hips. CONCLUSION: This study describes TOH patient characteristics, the MR imaging findings (BMe pattern, microfractures), their association with symptom duration and the chance of progressing to RMO. PMID- 25533718 TI - The early predictive value of a decrease of metabolic tumor volume in repeated (18)F-FDG PET/CT for recurrence of locally advanced non-small cell lung cancer with concurrent radiochemotherapy. AB - PURPOSE: The aim of this study is to investigate the value of [(18)F] fluorodeoxyglucose positron emission tomography/computed tomography ((18)F FDG PET/CT) to predict recurrence of patients with locally advanced non-small cell lung cancer (NSCLC) during the early stage of concurrent chemoradiotherapy (CCRT). METHODS: A total of 53 stage III NSCLC patients without diabetics or undergoing surgery were enrolled in the prospective study. Those patients were evaluated by FDG PET before and following 40Gy radiotherapy (RT) with a concurrent cisplatin-based heterogeneous chemotherapy regimen. Semiquantitative assessment was used to determine maximum and mean SUVs (SUVmax/SUVmean) and metabolic tumor volume (MTV) of the primary tumor. The prognostic significance of PET/CT parameters and other clinical variables was assessed using Cox regression analyses. The cutoffs of PET/CT parameters which have been determined by the previous study were used to separate the groups with Kaplan-Meier curves. RESULTS: Recurrence rates at 1- and 2-years were 18.9% (10/53) and 50.9% (27/53) for all patients, respectively. Cox regression analysis showed that the only prognostic factor for recurrence was a decrease of MTV. Using the cutoff of 29.7%, a decrease of MTV can separate the patients into 2 groups with Kaplan Meier curve successfully. CONCLUSION: The prospective study has reinforced the early predictive value of MTV in repeated (18)F-FDG PET/CT for recurrence in a subgroup of locally advanced NSCLC who underwent CCRT. A decrease of MTV in (18)F FDG uptake by the primary tumor correlates with higher LRFS. PMID- 25533720 TI - Shear wave elastography of thyroid nodules for the prediction of malignancy in a large scale study. AB - OBJECTIVES: The purpose of this study is to validate the usefulness of shear wave elastography (SWE) in predicting thyroid malignancy with a large-scale quantitative SWE data. METHODS: This restrospective study included 476 thyroid nodules in 453 patients who underwent gray-scale US and SWE before US-guided fine needle aspiration biopsy (US-FNA) or surgical excision were included. Gray-scale findings and SWE elasticity indices (EIs) were retrospectively reviewed and compared between benign and malignant thyroid nodules. The optimal cut-off values of EIs for predicting malignancy were determined. The diagnostic performances of gray-scale US and SWE for predicting malignancy were analyzed. The diagnostic performance was compared between the gray-scale US findings only and the combined use of gray-scale US findings with SWEs. RESULTS: All EIs of malignant thyroid nodules were significantly higher than those of benign nodules (p<=.001). The optimal cut-off value of each EI for predicting malignancy was 85.2kPa of Emean, 94.0kPa of Emax, 54.0kPa of Emin. Emean (OR 3.071, p=.005) and Emax (OR 3.015, p=.003) were the independent predictors of thyroid malignancy. Combined use of gray-scale US findings and each EI showed elevated sensitivity (95.0-95.5% vs 92.9%, p<=.005) and AUC (0.820-0.834 vs 0.769, p<=.005) for predicting malignancy, compared with the use of only gray-scale US findings. CONCLUSIONS: Quantitative parameters of SWE were the independent predictors of thyroid malignancy and SWE evaluation combined with gray-scale US was adjunctive to the diagnostic performance of gray-scale US for predicting thyroid malignancy. PMID- 25533719 TI - Diagnostic accuracy of post mortem MRI for abdominal abnormalities in foetuses and children. AB - BACKGROUND: To compare the diagnostic accuracy of post-mortem magnetic resonance imaging (PMMR) specifically for abdominal pathology in foetuses and children, compared to conventional autopsy. METHODS: Institutional ethics approval and parental consent was obtained. 400 unselected foetuses and children underwent PMMR using a 1.5T Siemens Avanto MR scanner before conventional autopsy. PMMR images and autopsy findings were reported blinded to the other data respectively. RESULTS: Abdominal abnormalities were found in 70/400 (12%) autopsies. Overall sensitivity and specificity (95% confidence interval) of PMMR for abdominal pathology was 72.5% (61.0, 81.6) and 90.8% (87.0, 93.6), with positive (PPV) and negative predictive values (NPV) of 64.1% (53.0, 73.9) and 93.6% (90.2, 95.8) respectively. PMMR was good at detecting renal abnormalities (sensitivity 80%), particularly in foetuses, and relatively poor at detecting intestinal abnormalities (sensitivity 50%). Overall accuracy was 87.4% (83.6, 90.4). CONCLUSIONS: PMMR has high overall accuracy for abdominal pathology in foetuses, newborns and children. PMMR is particularly good at detecting renal abnormalities, and relatively poor at detecting intestinal abnormalities. In clinical practice, PMMR may be a useful alternative or adjunct to conventional autopsy in foetuses and children for detecting abdominal abnormalities. PMID- 25533721 TI - Role of spinal ultrasound in diagnosis of meningitis in infants younger than 6 months. AB - BACKGROUND: Spinal ultrasound (US) can detect changes in CSF echogenicity and decreased cord pulsations which reflect the inflammatory changes in meningitis. Till date, there is no published data about the prospective accuracy of spinal US in meningitis. OBJECTIVE: To assess accuracy of spinal US in diagnosis of meningitis in infants younger than 6 months. METHODS: This was an institute ethics committee approved prospective study carried out in infants less than 6 months of age with clinical suspicion of meningitis who presented to pediatric emergency unit. 60 infants each in study and control group were enrolled. US of thoraco-lumbar spine were performed prior to lumbar puncture in all cases. We looked for the presence of echogenicity or trabeculations in posterior subarachnoid space and for presence or absence of spinal cord and nerve root pulsations on real time ultrasound. The results of spinal US were evaluated in correlation with cerebrospinal fluid analysis. Follow up ultrasounds were done in infants who showed abnormal findings after the initiation of treatment and findings compared with initial results. RESULTS: The study group comprised of 40 boys and 20 girls with mean age of 47.85 days. The control group comprised of 36 boys and 24 girls with a mean age of 60.53 days. 34/60 cases in study group had CSF findings suggestive of meningitis. Based on imaging parameters, spinal US had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 67.16%, 92.3%, 93.1% and 74.64%, respectively. Chi square test showed a statistically significant association between infants with meningitis and positive US findings (p<0.05). CONCLUSION: Spinal US findings of CSF debris, septations and decreased spinal cord pulsations can be seen in infants with meningitis. PMID- 25533723 TI - The number of FoxP3+ cells in transbronchial lung allograft biopsies does not predict bronchiolitis obliterans syndrome within the first five years after transplantation. AB - BACKGROUND: An important limitation to the success of lung transplantation is the development of bronchiolitis obliterans syndrome (BOS). It has been hypothesized that regulatory T lymphocytes (Tregs) are related to the risk of BOS. We aim to evaluate whether the number of forkhead box P3 (FoxP3+) cells/mm(2) in lung allograft biopsies is a predictor of long-term outcome. MATERIALS AND METHODS: A total of 58 consecutive lung transplant patients were included in the study. For 233 routine surveillance biopsy samples, the numbers of FoxP3+ cells/mm(2) were assessed by immunohistochemical staining with antibodies against FoxP3. BOS scores were calculated for the first five yr after transplantation. RESULTS: We determined that acute rejection was related to the time elapsed from transplantation to BOS with hazard ratios of 3.18 (p = 0.02) and 3.73 (p = 0.04) when comparing the levels of acute rejection grade 1 and grade 2/3, respectively, to no rejection. According to a Cox regression analysis, the number of FoxP3+ cells/mm(2) was not predictive of time to BOS. DISCUSSION AND CONCLUSIONS: Our data indicate that the number of FoxP3+ cells in the lung allograft did not correlate with BOS-free survival time. Previous studies have been contradictory and included different time points. Our findings emphasize the importance of including a time factor. PMID- 25533722 TI - Modulation of peripheral T-cell function by interleukin-7 in rheumatoid arthritis. AB - INTRODUCTION: Interleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity. We previously demonstrated reduced levels of circulating IL-7 in rheumatoid arthritis (RA), although high amounts are expressed in joints, suggesting differences between systemic and synovial effects. We observed healthy levels of IL-7 in 48% of RA patients in clinical remission (CR) and aimed to investigate the consequences of IL-7 deficiency on T-cell responses. METHODS: We used RA patients with active disease and in CR presenting various levels of IL-7, to investigate its modulatory effects on T cells by analysing responses to phyto haemagglutinin (PHA), expression of polarization or survival factors, or suppression by regulatory T cells (Tregs). RESULTS: IL-7 levels were normal (>10 pg/ml) in 48% of RA patients in CR. Amongst 63 CR patients followed up for 18 months, lack of IL-7 recovery was observed in 13 out of 15 (86%) patients experiencing relapse but only 11 out of 48 (23%) of those who did not (P = 0.0002). Binary regressions showed high significance for below normal IL-7 levels for self-reported maternal family history of arthritis (odds ratio (OR): 7.66, P = 0.006) and a trend for smoking (OR: 3.33, P = 0.068) with no further demographic or clinical associations. Serum IL-7 correlated with restored CD4+T cell response to PHA (rho = 0.879); this was not related to an increase in T-cell proliferation capacity or expression of survival factors B-cell lymphoma 2 (BCL2) and BCL2-associated protein X (BAX). Expression of Th1 polarization factor (TBET) was also dependent on exposure to IL-7 in vivo (rho = 0.600). In contrast CD25highTregs' response to PHA was not affected by in vivo IL-7, but their suppression capabilities were related to circulating IL-7 (rho = 0.589). Co stimulation with IL-7 (mimicking the joint environment) increased responsiveness of CD4+T-cells to PHA, lowering the ability of CD25highTregs to suppress them. CONCLUSIONS: Our data demonstrate that IL-7 has a critical role in modulating T cell function in vivo, possibly explaining opposing effects observed systemically and in the joint. Lack of IL-7 recovery in CR by maintaining a suppressed immune system may be a determinant factor in the occurrence of relapse. PMID- 25533725 TI - Investigation of the chick embryo as a potential alternative to the mouse for evaluation of radiopharmaceuticals. AB - INTRODUCTION: The chick embryo is an emerging in vivo model in several areas of pre-clinical research including radiopharmaceutical sciences. Herein, it was evaluated as a potential test system for assessing the biodistribution and in vivo stability of radiopharmaceuticals. For this purpose, a number of radiopharmaceuticals labeled with (18)F, (125)I, (99m)Tc, and (177)Lu were investigated in the chick embryo and compared with the data obtained in mice. METHODS: Chick embryos were cultivated ex ovo for 17-19 days before application of the radiopharmaceutical directly into the peritoneum or intravenously using a vein of the chorioallantoic membrane (CAM). At a defined time point after application of radioactivity, the embryos were euthanized by shock-freezing using liquid nitrogen. Afterwards they were separated from residual egg components for post mortem imaging purposes using positron emission tomography (PET) or single photon emission computed tomography (SPECT). RESULTS: SPECT images revealed uptake of [(99m)Tc]pertechnetate and [(125)I]iodide in the thyroid of chick embryos and mice, whereas [(177)Lu]lutetium, [(18)F]fluoride and [(99m)Tc] methylene diphosphonate ([(99m)Tc]-MDP) were accumulated in the bones. [(99m)Tc] dimercaptosuccinic acid ((99m)Tc-DMSA) and the somatostatin analog [(177)Lu] DOTATOC, as well as the folic acid derivative [(177)Lu]-DOTA-folate showed accumulation in the renal tissue whereas [(99m)Tc]-mebrofenin accumulated in the gall bladder and intestine of both species. In vivo dehalogenation of [(18)F]fallypride and of the folic acid derivative [(125)I]iodo-tyrosine-folate was observed in both species. In contrast, the 3'-aza-2'-[(18)F]fluorofolic acid ([(18)F]-AzaFol) was stable in the chick embryo as well as in the mouse. CONCLUSIONS: Our results revealed the same tissue distribution profile and in vivo stability of radiopharmaceuticals in the chick embryo and the mouse. This observation is promising with regard to a potential use of the chick embryo as an inexpensive and simple test model for preclinical screening of novel radiopharmaceuticals. PMID- 25533724 TI - Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging. AB - We sought to develop a practical, reproducible and clinically translatable method of radiolabeling serum albumins with fluorine-18 for use as a PET blood pool imaging agent in animals and man. Fluorine-18 radiolabeled fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester, [(18)F]F-Py-TFP was prepared first by the reaction of its quaternary ammonium triflate precursor with [(18)F]tetrabutylammonium fluoride ([(18)F]TBAF) according to a previously published method for peptides, with minor modifications. The incubation of [(18)F]F-Py-TFP with rat serum albumin (RSA) in phosphate buffer (pH9) for 15 min at 37-40 degrees C produced fluorine-18-radiolabeled RSA and the product was purified using a mini-PD MiniTrap G-25 column. The overall radiochemical yield of the reaction was 18-35% (n=30, uncorrected) in a 90-min synthesis. This procedure, repeated with human serum albumin (HSA), yielded similar results. Fluorine-18-radiolabeled RSA demonstrated prolonged blood retention (biological half-life of 4.8 hours) in healthy awake rats. The distribution of major organ radioactivity remained relatively unchanged during the 4 hour observation periods either by direct tissue counting or by dynamic PET whole-body imaging except for a gradual accumulation of labeled metabolic products in the bladder. This manual method for synthesizing radiolabeled serum albumins uses fluorine-18, a widely available PET radionuclide, and natural protein available in both pure and recombinant forms which could be scaled up for widespread clinical applications. These preclinical biodistribution and PET imaging results indicate that [(18)F]RSA is an effective blood pool imaging agent in rats and might, as [(18)F]HSA, prove similarly useful as a clinical imaging agent. PMID- 25533726 TI - Sevoflurane attenuates stress-enhanced fear learning by regulating hippocampal BDNF expression and Akt/GSK-3beta signaling pathway in a rat model of post traumatic stress disorder. AB - PURPOSE: Post-traumatic stress disorder (PTSD) is a psychiatric disease that may occur after intense psychological trauma or physiological stress. Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) and the serine/threonine kinase (Akt)/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway are critically involved in brain plasticity, including hippocampal-dependent learning and memory, while sevoflurane impairs memory processing. Thus, we hypothesized that sevoflurane can suppress fear learning by regulating the expression of BDNF and the Akt/GSK-3beta signaling pathway in a rat model of PTSD. METHOD: Rats were exposed to sevoflurane during or after a 15 foot-shock stressor. Thereafter, rats were subjected to a single foot-shock in a totally different environment. The fear response was recorded in response to the 15 foot-shock and the single foot-shock environments. In another set of experiments, the brain tissue was harvested and subjected to biochemistry studies. RESULTS: Our data suggested that increasing sevoflurane concentrations decreased stress-enhanced fear learning (SEFL) when given during but not after the stressor. Furthermore, administration of lithium chloride (100 mg/kg, intraperitoneally) 30 min before the contextual fear conditioning reversed the inhibitory effect of 0.8 % sevoflurane on SEFL as well as phosphorylated (p)-Akt, p-GSK-3beta and BDNF expressions. CONCLUSION: Our data suggested that increasing sevoflurane administration during but not after the stressor can impair SEFL in a rat model of PTSD, which may be due, at least in part, to the regulation of hippocampal BDNF expression and the Akt/GSK-3beta signaling pathway. PMID- 25533727 TI - The Tracking Study: description of a randomized controlled trial of variations on weight tracking frequency in a behavioral weight loss program. AB - BACKGROUND: Observational evidence from behavioral weight control trials and community studies suggests that greater frequency of weighing oneself, or tracking weight, is associated with better weight outcomes. Conversely, it has also been suggested that frequent weight tracking may have a negative impact on mental health and outcomes during weight loss, but there are minimal experimental data that address this concern in the context of an active weight loss program. To achieve the long-term goal of strengthening behavioral weight loss programs, the purpose of this randomized controlled trial (the Tracking Study) is to test variations on frequency of self-weighing during a behavioral weight loss program, and to examine psychosocial and mental health correlates of weight tracking and weight loss outcomes. This paper describes the study design, intervention features, recruitment, and baseline characteristics of participants enrolled in the Tracking Study. METHODS/DESIGN: Three hundred thirty-nine overweight and obese adults were recruited and randomized to one of three variations on weight tracking frequency during a 12-month weight loss program with a 12-month follow up: daily weight tracking, weekly weight tracking, or no weight tracking. The primary outcome is weight in kilograms at 24 months. The weight loss program integrates each weight tracking instruction with standard behavioral weight loss techniques (goal setting, self-monitoring, stimulus control, dietary and physical activity enhancements, lifestyle modifications); participants in weight tracking conditions were provided with wireless Internet technology (wi-fi-enabled digital scales and touchscreen personal devices) to facilitate weight tracking during the study. CONCLUSION: This study was successful in recruiting adult male and female participants and is positioned to enhance the standard of care with regard to weight tracking recommendations. PMID- 25533728 TI - Design and implementation of a physical activity intervention to enhance children's use of the built environment (the CUBE study). AB - BACKGROUND: Adequate physical activity promotes physical and mental health and decreases obesity risk. However, most adolescents do not attain recommended physical activity levels and effective interventions are lacking. Physical activity trials rarely incorporate built environment use patterns. PURPOSE: This paper describes the design and rationale of the Children's Use of the Built Environment (CUBE) Study, an office-based intervention designed to teach youth how to use their surrounding built environment to increase physical activity. METHODS: CUBE is a 6-month intervention trial among 60 overweight and obese 10-16 year old adolescents from a community health center in Massachusetts. The study began in the winter of 2013. Patients are sequentially assigned to either the intervention or control group. Baseline physical activity by accelerometry and location by GPS, along with measured height, weight, and blood pressure are collected. Control subjects receive standard of care lifestyle counseling. Intervention subjects receive tailored recommendations on how to increase their physical activity based on their accelerometer and GPS data. Data collections are repeated at end-of-treatment, and again 3 months later. CONCLUSION: The findings from this study should help guide future efforts to design interventions aimed at increasing adolescent physical activity as well as to inform design professionals and government officials charged with creating outdoor spaces where adolescents spend time. PMID- 25533730 TI - Validity of participant-reported diagnoses in an online patient registry: a report from the NF1 Patient Registry Initiative. AB - BACKGROUND: With increased internet accessibility worldwide, it is now possible to assemble individuals with rare diseases through web-based patient registries. However, the validity of participant-reported medical diagnoses is unknown. The objective of this study was to evaluate the accuracy of participant-reported Neurofibromatosis Type 1 (NF1) diagnoses among participants in the NF1 Patient Registry Initiative (NPRI). METHODS: Subjects enrolled in the NPRI from 5/17/2011 to 7/7/2014 were included. Medical records (MRs) were obtained for participants who returned medical record release forms (MRRFs) during the study period. Participants were classified as having definite, probable, suspected, or no NF1 diagnosis based on MR information. To assess whether a returned MRRF served as a reliable marker of MR-documented NF1, we calculated the positive predictive value (PPV) as the proportion of individuals with MR-documented NF1 among those from whom MRs were obtained. We further examined whether a returned MRRF predicted the number of reported NF1 clinical signs in multivariable linear regression analyses. RESULTS: A total of 1456 individuals were included in the analyses. Of 416 individuals who returned MRRFs, 205 MRs were reviewed within the study period. The PPV ranged from 72.0 to 98.5% when including definite or definite/probable/suspected cases, respectively. The mean number of reported NF1 clinical signs was similar between those who returned (mean=3.3 +/- 1.2) and did not return (mean=3.2 +/- 1.3) their MRRFs. MRRF return was not a significant predictor of the number of NF1 clinical signs after adjusting for covariates. CONCLUSION: These data strongly suggest that individuals enrolling in the NPRI accurately report their NF1 diagnosis. PMID- 25533731 TI - It is time for radiologists to stop using the word "clinician". PMID- 25533732 TI - Health Care Delivery Meets Hospitality: A Pilot Study in Radiology. AB - The patient experience has moved to the forefront of health care-delivery research. The University of Texas MD Anderson Cancer Center Department of Diagnostic Radiology began collaborating in 2011 with the University of Houston Conrad N. Hilton College of Hotel and Restaurant Management, and in 2013 with the University of Nevada, Las Vegas, William F. Harrah College of Hotel Administration, to explore the application of service science to improving the patient experience. A collaborative pilot study was undertaken by these 3 institutions to identify and rank the specific needs and expectations of patients undergoing imaging procedures in the MD Anderson Department of Diagnostic Radiology. We first conducted interviews with patients, providers, and staff to identify factors perceived to affect the patient experience. Next, to confirm these factors and determine their relative importance, we surveyed more than 6,000 patients by e-mail. All factors considered important in the interviews were confirmed as important in the surveys. The surveys showed that the most important factors were acknowledgment of the patient's concerns, being treated with respect, and being treated like a person, not a "number"; these factors were more important than privacy, short waiting times, being able to meet with a radiologist, and being approached by a staff member versus having one's name called out in the waiting room. Our work shows that it is possible to identify and rank factors affecting patient satisfaction using techniques employed by the hospitality industry. Such factors can be used to measure and improve the patient experience. PMID- 25533729 TI - Brain function predictors and outcome of weight loss and weight loss maintenance. AB - Obesity rates are associated with public health consequences and rising health care costs. Weight loss interventions, while effective, do not work for everyone, and weight regain is a significant problem. Eating behavior is influenced by a convergence of processes in the brain, including homeostatic factors and motivational processing that are important contributors to overeating. Initial neuroimaging studies have identified brain regions that respond differently to visual food cues in obese and healthy weight individuals that are positively correlated with reports of hunger in obese participants. While these findings provide mechanisms of overeating, many important questions remain. It is not known whether brain activation patterns change after weight loss, or if they change differentially based on amount of weight lost. Also, little is understood regarding biological processes that contribute to long-term weight maintenance. This study will use neuroimaging in participants while viewing food and non-food images. Functional Magnetic Resonance Imaging will take place before and after completion of a twelve-week weight loss intervention. Obese participants will be followed though a 6-month maintenance period. The study will address three aims: 1. Characterize brain activation underlying food motivation and impulsive behaviors in obese individuals. 2. Identify brain activation changes and predictors of weight loss. 3. Identify brain activation predictors of weight loss maintenance. Findings from this study will have implications for understanding mechanisms of obesity, weight loss, and weight maintenance. Results will be significant to public health and could lead to a better understanding of how differences in brain activation relate to obesity. PMID- 25533734 TI - The future of radiology: lessons from the stoics. PMID- 25533733 TI - Contrast Is the New Penicillin, and Possibly Worse. PMID- 25533735 TI - Fine motor and self-care milestones for individuals with Down syndrome using a Retrospective Chart Review. AB - BACKGROUND: Developmental milestone markers for fine motor and self-care skills among children with Down syndrome (DS) are either minimal, anecdotal or out-of date. Our goal was to produce normative expectations for the development of fine motor and self-care milestones specific to children with DS. METHOD: A cross sectional retrospective chart review was completed on 274 children with DS seen at a specialty clinic that ranged in age from 4 months to 18 years. Specific skills were assessed at occupational therapy assessments as either present or absent, including fine motor, handwriting, scissor usage, self-feeding and clothing management. RESULTS: Fine motor milestones describing when 10-30% ('early achievers') and 75-95% ('representative achievement') of children with DS had mastered each skill were developed based upon descriptive review. As the fine motor and self-care skills advanced in complexity, the range of ages for documented skill acquisition was observed to increase. CONCLUSIONS: Age ranges for the mastery of fine motor developmental milestones for early and representative achievement were developed based upon descriptive analysis of cross-sectional retrospective clinical chart reviews. That the age range for mastering fine motor and self-care skills broadens as children with DS get older is in agreement with what is identified in the DS behavioural phenotype with regard to variable motor skills overall. These fine motor and self-care developmental milestone markers contribute to the field by informing parents, caregivers and healthcare providers of potential fine motor and self-care outcomes and describing normative development for children with DS. PMID- 25533736 TI - Diagnostic and therapeutic ionizing radiation and the risk of a first and second primary breast cancer, with special attention for BRCA1 and BRCA2 mutation carriers: a critical review of the literature. AB - Occurrence of breast cancer is a well-known long-term side effect of ionizing radiation (both diagnostic and therapeutic). The radiation-induced breast cancer risk increases with longer follow-up, higher radiation dose and younger age of exposure. The risk for breast cancer following irradiation for lymphomas is well known. Although data regarding the carcinogenic risk of adjuvant radiotherapy for a primary breast cancer are sparse, an increased risk is suggested with longer follow-up mainly when exposed at younger age. Particularly, patients with a BRCA1/2 mutation might be more sensitive for the deleterious effects of ionizing radiation due to an impaired capacity of repairing double strand DNA breaks. This might have consequences for the use of mammography in breast cancer screening, as well as the choice between breast conserving therapy including radiotherapy and mastectomy at primary breast cancer diagnosis in young BRCA1/2 mutation carriers. Good data regarding this topic, however, are scarce, mainly due to constraints in the design of performed studies. In this review, we will discuss the current literature on the association between ionizing radiation and developing breast cancer, with particular attention to patients with a BRCA1/2 mutation. PMID- 25533738 TI - Magnetic resonance sialography of the parotid glands in chronic hepatitis C virus patients with and without vasculitis. AB - AIM: Hepatitis C virus (HCV) is sialotropic. The pathogenesis of sicca manifestations in patients with chronic HCV infection is not fully understood. We aimed to detect changes in magnetic resonance sialography (MRS) of HCV patients with and without vasculitis. METHOD: We studied 32 HCV patients (19 female, mean age 48.8 +/- 10.3 years) and 20 age- and gender-matched healthy controls. Half of the patients had vasculitis. Demographic, clinical and serological data were prospectively evaluated. In patients with vasculitis, the disease activity was assessed by the Birmingham Vasculitis Activity Score (BVAS). MRS was performed on all patients and controls. RESULTS: Abnormal MRS was found in 25% of patients, (6/16 and 2/16 in patients with and without vasculitis, respectively). Among patients with vasculitis, those with abnormal MRS had longer disease duration, higher leukocytic and lymphocytic counts and more frequent cryoglobulinemia (P < 0.01, P < 0.001, P < 0.001 and P < 0.008, respectively), while BVAS scores were not significantly different. CONCLUSION: Among HCV patients with vasculitis, longer disease duration and cryoglobulinemia were associated with abnormal findings on MRS. To confirm our results, we propose larger-scale, multicentre studies with longer evaluation periods. PMID- 25533739 TI - Association of heart rate with albuminuria in a general adult population: the 2011 Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Albuminuria is associated with increased risk of multiple adverse health outcomes, such as progressive renal failure, cardiovascular disease and death. However, in the general population, it is uncertain whether albuminuria is associated with elevated heart rate, which is an independent and powerful risk factor for cardiovascular disease. AIM: To investigate whether an elevated heart rate is an independent factor associated with albuminuria in the general adult population of Korea. METHODS: A cross-sectional analysis was carried out on 5198 Korean adults aged 19 years or older who participated in the fifth (2011) Korea National Health and Nutrition Examination Survey (KNHANES V-2). RESULTS: The prevalence of albuminuria showed an increasing trend throughout the whole range of heart rate, even after adjusting for confounders (P = 0.002). The increment was most profound at the heart rate of 70-75 and >76 beats per minute (b.p.m.; P = 0.011). In multiple logistic regression analysis, age (P < 0.001), hypertension (P < 0.001), diabetes (P < 0.001), hypertriglyceridaemia (P = 0.025), estimated glomerular filtration rate (P = 0.028) and heart rate (P = 0.023) were independently associated with the presence of albuminuria in Korean adults. Compared with participants with heart rate <= 64 b.p.m., the odds ratio (95% CI) for albuminuria was 1.50 (1.15-1.96) for those with heart rate >= 76 b.p.m. CONCLUSIONS: The prevalence of albuminuria is independently associated with heart rate in the general adult population of Korea. PMID- 25533740 TI - Metabolic phenotyping applied to pre-clinical and clinical studies of acetaminophen metabolism and hepatotoxicity. AB - Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF. PMID- 25533737 TI - Optimising translational oncology in clinical practice: strategies to accelerate progress in drug development. AB - Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer. PMID- 25533741 TI - [Septic arthritis of a lumbar facet joint with epidural and paraspinal abscess: Report of a case]. PMID- 25533742 TI - High prevalence of antibodies against hepatitis E virus in HIV-infected patients with unexplained liver disease. AB - OBJECTIVE: To look for evidence of hepatitis E virus (HEV) exposure in HIV infected patients with unexplained elevations of liver stiffness (LS). METHODS: Case-control study conducted in 31 HIV-infected patients with unexplained elevations of LS and in 31 HIV-controls with normal LS, matched by age, sex and CD4 cell-counts. Serum HEV antibodies were tested by two ELISA procedures and by Immunoblot. We defined exposure to HEV as the detection of serum HEV antibodies by at least one of the two ELISA assays, provided that it was confirmed by Immunoblot. A real-time PCR RNA assay was conducted in all plasma samples to identify subjects with active HEV infection. RESULTS: Exposure to HEV was demonstrated, according to the criteria used in this study, in 9 (29%) of the cases, whereas it was shown in 5 (16%) of the controls (p=.3). Serum HEV RNA was detected in none of the controls and in only in one case. This patient had a documented chronic hepatitis E with progression to cirrhosis. CONCLUSIONS: HEV antibodies are frequently found in HIV-infected patients with unexplained liver disease. PMID- 25533743 TI - 52-year-old man with recurrent urinary tract infection, Munchausen's syndrome. PMID- 25533745 TI - [Clostridium difficile infections in Internal Medicine Departments. Addendum]. PMID- 25533744 TI - [Chlamydia trachomaatis DNA in leukocytes of peripheral blood from neonates]. AB - INTRODUCTION: Diagnosis of Chlamydia trachomatis infection in newborns is difficult; however, this diagnosis is performed by cell culture or by detection of IgM antibodies against C. trachomatis. Detection of C. trachomatis DNA in peripheral blood leukocytes using polymer chain reaction (PCR) may be a better tool for the diagnosis of infection by this pathogen. MATERIAL AND METHODS: A total of 44 premature newborns, all weighing less than 2500g, were included in the study. A blood sample and nasopharyngeal lavages were obtained from each newborn. Leukocyte DNA was obtained by phenol-chloroform extraction technique. Detection of C. trachomatis was performed by amplifying the ompA gene using the PCR endpoint. Cell culture tests and the detection of IgM antibodies against C. trachomatis by microimmunofluorescence assay were also performed. RESULTS: Twenty newborns were PCR-positive (45.5%), with this test being significantly associated with the presence of pneumonia (RR=2.28; 95%CI: 1.01 to 5.17; P=.035). The cell culture of nasopharyngeal lavage was positive in only 7 samples and no significant association was observed with any clinical or laboratory data. The titer of IgM antibodies against C. trachomatis associated with PCR-positive was 1:32 (RR=2.74; 95%CI: 1.21 to 6.23; P=.008), however this titer was not associated with the presence of pneumonia. CONCLUSION: DNA detection in peripheral blood leukocytes could be useful for diagnosis of C. trachomatis infection. PMID- 25533746 TI - The most reactive amide as a transition-state mimic for cis-trans interconversion. AB - 1-Azatricyclo[3.3.1.1(3,7)]decan-2-one (3), the parent compound of a rare class of 90 degrees -twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed cis-trans rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making 3 by some way the most reactive known "amide". PMID- 25533747 TI - The contrast-to-noise ratio for image quality evaluation in scanning electron microscopy. AB - The contrast-to-noise ratio (CNR) is presented and characterized as a tool for quantitative noise measurement of scanning electron microscope (SEM) images. Analogies as well as differences between the CNR and the widely used signal-to noise ratio (SNR) are analytically and experimentally investigated. With respect to practical SEM image evaluation using the contrast-to-noise ratio, a standard specimen and an evaluation program are presented. PMID- 25533748 TI - Screening mammography after autologous breast reconstruction is not beneficial. PMID- 25533749 TI - New technique of extracorporeal hepatic inflow control for pure laparoscopic liver resection. AB - We have developed a new technique of the Pringle maneuver by clamping outside the abdominal wall for pure laparoscopic liver resection (pure Lap). Our technique successfully controls bleeding and enables pure Lap to be completed without any events, even for a large tumor. Between 2008 and 2010, we compared consecutive patients who received pure Lap with (n=11) and without (n=7) this Pringle maneuver. Although tumor size in the Pringle group was significantly larger than in the no-Pringle group (3.35+/-1.64 vs. 1.11+/-0.29 cm, respectively), intraoperative bleeding was not significantly different (165.5+/-188.5 vs. 177.9+/-364.4 mL, respectively). In contrast, operation time in the Pringle group was significantly longer than in the no-Pringle group (343.1+/-99.5 vs. 199.6+/ 63.2 min, respectively). Pure Lap for large tumors is feasible when employing a new Pringle maneuver outside the abdominal wall. PMID- 25533751 TI - Antecedents to workplace injury in the health care industry: A synthesis of the literature. AB - BACKGROUND: The U.S. Department of Labor has identified the health care industry as a major source of all U.S. workplace injuries. Studies have shown that injury within the health care workforce is related to high turnover rates, burnout, poor job satisfaction, and leaving the health care workforce permanently, thus contributing to the existing health care workforce shortages. PURPOSE: The purpose of this synthesis of the literature was twofold. The first was to conduct a comprehensive evaluation of the occupational health and safety literature to determine the key antecedents to health care provider injury. The second was to utilize the National Institute for Occupational Safety and Health (NIOSH) framework to organize the findings. METHODOLOGY: Empirical studies published between 1985 and 2013 examining work-related injuries sustained by nurses and nurses' aides were systematically reviewed and evaluated for inclusion in the synthesis of the literature. Thirty-six studies met the criteria for inclusion. Using the NIOSH framework, antecedent variables to workplace injury were identified and then grouped into three broad categories that were highlighted during the synthesis: organization of work, job characteristics, and safety programs and training. A fourth category, individual characteristics, was added based on its use by many studies. FINDINGS: Over half of the studies (n = 20) included factors within the organization of work category. Over two thirds of the studies (n = 26) included job characteristics such as task and demand. Nine studies contained information related to safety programs and training, whereas 17 studies included information on individual factors. The findings suggest that the NIOSH framework, with the addition of individual characteristics, provide a foundation for conceptually organizing occupational health and safety studies. PRACTICE IMPLICATIONS: Health care administrators and leaders should be aware and understand the antecedents to workplace injury that will assist their organizations in developing training programs to reduce the current excessive rates of health care provider injury. PMID- 25533750 TI - Brief Report: Methotrexate Prevents Wear Particle-Induced Inflammatory Osteolysis in Mice Via Activation of Adenosine A2A Receptor. AB - OBJECTIVE: Adenosine, acting at the A2A receptor, mediates the antiinflammatory effects of methotrexate (MTX) in models of inflammation. We previously reported that A2A receptor ligation diminishes wear particle-driven osteolysis. The aim of this study was to investigate whether MTX treatment could prevent bone resorption caused by inflammatory osteolysis. METHODS: C57BL/6 mice (6-8 weeks old) received intraperitoneal injections of 1 mg/kg MTX (n = 20) or 0.9% saline (n = 10), starting 2 weeks prior to surgical implantation of 3 mg of wear particles (ultrahigh molecular weight polyethylene [UHMWPE] particles). The MTX-treated mice received daily injections of vehicle or ZM241385 at the surgical site until they were killed, 14 days later. XenoLight RediJect Bone Probe 680 was injected intravenously, and fluorescence analysis of the calvaria using an IVIS imaging system was performed to assess bone formation. Micro-computed tomography (micro CT) and immunostaining for osteoclast and osteoblast markers were performed. RESULTS: Implantation of wear particles induced bone pitting and thinning, as shown by micro-CT. MTX treatment markedly reduced osteolysis, and this effect was abrogated by treatment with the A2A receptor antagonist ZM241385. Implantation of UHMWPE reduced new bone formation, and MTX treatment restored new bone formation, an effect that was completely reversed by treatment with ZM241385. Histologic examination of particle-exposed calvariae demonstrated that MTX prevented accumulation of an inflammatory infiltrate at the site of particle implantation, increased the number of osteoblasts, and reduced the number of osteoclasts at the site of inflammation, an effect that was reversed by treatment with ZM241385. CONCLUSION: MTX reduces inflammatory osteolysis indirectly via stimulation of A2A receptor and may represent a novel approach to enhance orthopedic implant survival, delaying or eliminating the need for revision arthroplasty surgery. PMID- 25533752 TI - Measuring Patient Satisfaction's Relationship to Hospital Cost Efficiency: Can Administrators Make a Difference? AB - OBJECTIVE: The aim of this study was to assess the ability and means by which hospital administrators can influence patient satisfaction and its impact on costs. DATA SOURCES: Data are drawn from the American Hospital Association's Annual Survey of Hospitals, federally collected Hospital Cost Reports, and Medicare's Hospital Compare. STUDY DESIGN: Stochastic frontier analyses (SFA) are used to test the hypothesis that the patient satisfaction-hospital cost relationship is primarily a latent "management effect." The null hypothesis is that patient satisfaction measures are main effects under the control of care providers rather than administrators. PRINCIPLE FINDINGS: Both SFA models were superior to the standard regression analysis when measuring patient satisfaction's relationship to hospitals' cost efficiency. The SFA model with patient satisfaction measures treated as main effects, rather than "latent, management effects," was significantly better comparing the log-likelihood statistics. Higher patient satisfaction scores on the environmental quality and provider communication dimensions were related to lower facility costs. Higher facility costs were positively associated with patients' overall impressions (willingness to recommend and overall satisfaction), assessments of medication and discharge instructions, and ratings of caregiver responsiveness (pain control and help when called). CONCLUSIONS: In the short term, managers have a limited ability to influence patient satisfaction scores, and it appears that working through frontline providers (doctors and nurses) is critical to success. In addition, results indicate that not all patient satisfaction gains are cost neutral and there may be added costs to some forms of quality. Therefore, quality is not costless as is often argued. PMID- 25533753 TI - Public concerns regarding the storage and secondary uses of residual newborn bloodspots: an analysis of print media, legal cases, and public engagement activities. AB - Recently, public concerns have been expressed regarding the non-consented storage and secondary research uses of residual newborn bloodspot (RBS) samples. The purpose of this paper is to examine public responses to the storage and secondary uses of RBS that can be identified through analysis of media, legal cases, and documented public engagement activities. Coverage in the examined print media confirmed the importance of RBS to journalists and those people who expressed their concerns to these journalists. Several lawsuits, brought by parents concerned about the storage of newborn bloodspots, placed the practice of storing NBS into the spotlight. This resulted in controversial debates and the mandatory destruction of millions of samples. Analysis of public engagement activities across several jurisdictions indicated that across (inter)national boundaries there are common elements to what is perceived as inappropriate governance of RBS. Public concerns were grouped into five main themes: trust, transparency, confidentiality, ownership, and stigmatization/discrimination. The results of our analysis help to make a compelling case for placing citizens at the center of the debate and developing policy about the storage and secondary uses of newborn bloodspots. PMID- 25533754 TI - Exercise limitation associated with asymptomatic left ventricular impairment: analogy with stage B heart failure. AB - BACKGROUND: Stage B heart failure (SBHF) describes asymptomatic ventricular disease that may presage the development of heart failure (HF) symptoms. This entity has been largely defined by structural changes; the roles of sensitive indicators of nonischemic left ventricular (LV) dysfunction, such as LV strain, are undefined. OBJECTIVES: This study sought to define the association of exercise capacity with left ventricular hypertrophy (LVH) and systolic/diastolic dysfunction in asymptomatic patients with HF risk factors. METHODS: We used echocardiography to study 510 asymptomatic patients (age 58 +/- 12 years) with type 2 diabetes mellitus, hypertension, or obesity. The results of cardiopulmonary exercise testing in patients with structural evidence of SBHF were compared with those in patients with subclinical dysfunction, defined by reduced LV strain (>-18%) or increased LV filling pressure (E/e' >13). RESULTS: Compared with healthy subjects, groups with LV abnormalities differed in terms of oxygen uptake (peak VO2): 25.5 +/- 8.2 versus 21.0 +/- 8.2 for strain >-18% (p < 0.001); 26.4 +/- 8.0 versus 19.0 +/- 7.2 for E/e' >13 (p < 0.0001); and 26.0 +/- 7.7 versus 15.9 +/- 6.9 ml/kg/min for LVH (p < 0.0001). SBHF, defined as >=1 imaging variable present, was associated with lower peak VO2 (beta = -0.20; p < 0.0001) and metabolic equivalents (beta = -0.21; p < 0.0001), independent of higher body mass index and insulin resistance, older age, male sex, and treatment with beta-blockers. CONCLUSIONS: LVH, elevated LV filling pressure, and abnormal myocardial deformation were independently associated with impaired exercise capacity. Including functional markers may improve identification of SBHF in nonischemic heart disease. PMID- 25533755 TI - Stage B heart failure: is it more common than we think? PMID- 25533756 TI - Chirality-assisted ring-like aggregation of abeta(1-40) at liquid-solid interfaces: a stereoselective two-step assembly process. AB - Molecular chirality is introduced at liquid-solid interfaces. A ring-like aggregation of amyloid Abeta(1-40) on N-isobutyryl-L-cysteine (L-NIBC)-modified gold substrate occurs at low Abeta(1-40) concentration, while D-NIBC modification only results in rod-like aggregation. Utilizing atomic force microscope controlled tip-enhanced Raman scattering, we directly observe the secondary structure information for Abeta(1-40) assembly in situ at the nanoscale. D- or L NIBC on the surface can guide parallel or nonparallel alignment of beta-hairpins through a two-step process based on electrostatic-interaction-enhanced adsorption and subsequent stereoselective recognition. Possible electrostatic interaction sites (R5 and K16) and a chiral recognition site (H14) of Abeta(1-40) are proposed, which may provide insight into the understanding of this effect. PMID- 25533757 TI - Rational molecular design towards Vis/NIR absorption and fluorescence by using pyrrolopyrrole aza-BODIPY and its highly conjugated structures for organic photovoltaics. AB - Pyrrolopyrrole aza-BODIPY (PPAB) developed in our recent study from diketopyrrolopyrrole by titanium tetrachloride-mediated Schiff-base formation reaction with heteroaromatic amines is a highly potential chromophore due to its intense absorption and fluorescence in the visible region and high fluorescence quantum yield, which is greater than 0.8. To control the absorption and fluorescence of PPAB, particularly in the near-infrared (NIR) region, further molecular design was performed using DFT calculations. This results in the postulation that the HOMO-LUMO gap of PPAB is perturbed by the heteroaromatic moieties and the aryl-substituents. Based on this molecular design, a series of new PPAB molecules was synthesized, in which the largest redshifts of the absorption and fluorescence maxima up to 803 and 850 nm, respectively, were achieved for a PPAB consisting of benzothiazole rings and terthienyl substituents. In contrast to the sharp absorption of PPAB, a PPAB dimer, which was prepared by a cross-coupling reaction of PPAB monomers, exhibited panchromatic absorption across the UV/Vis/NIR regions. With this series of PPAB chromophores in hand, a potential application of PPAB as an optoelectronic material was investigated. After identifying a suitable PPAB molecule for application in organic photovoltaic cells based on evaluation using time-resolved microwave conductivity measurements, a maximized power conversion efficiency of 1.27 % was achieved. PMID- 25533758 TI - Predicting daily use of the affected upper extremity 1 year after stroke. AB - BACKGROUND: The ultimate goal of upper extremity (UE) stroke rehabilitation is for the individual with stroke to return using their arms and hands during daily activities in their own environment. No studies have monitored arm use as individuals with stroke transition from rehabilitation to the home setting. This longitudinal study compared the functional ability and daily use of the affected UE of individuals with stroke between discharge to home and 12 months after stroke and predicted the UE daily use 12 months after stroke. METHODS: Participants were assessed on discharge to home from rehabilitation and at 12 months after stroke. UE daily use was measured by wrist accelerometers and self report by the Motor Activity Log (MAL). Multivariate logistic regression models were used to predict UE daily use 12 months after stroke. RESULTS: The UE functional ability improved significantly from discharge to 12 months after stroke. The amount of self-report UE daily use significantly improved (z = -2.9, P = .004), but accelerometer activity counts did not (z = -0.15, P = .88), and the daily use of the nonaffected UE was 3 times more than the affected UE. After controlling for age and accelerometer daily use on discharge, UE variables of movement, function, dexterity, and strength accounted for an additional 10.9% 13.6% of the variance for accelerometer readings. After controlling for gender and MAL daily use on discharge, UE variables accounted for an additional 7%-12% of the variance for the MAL. CONCLUSIONS: UE daily use 12 months after stroke is very limited despite the motor and functional improvement. Enhanced motor and functional ability at discharge predicts more UE daily use at 12 months after stroke. Interventions that monitor and encourage these individuals to use their UE are required to ensure that functional gains translate to daily use. PMID- 25533759 TI - Atrial ectopic activity in cryptogenic ischemic stroke and TIA: a risk factor for recurrence. AB - BACKGROUND: To characterize atrial ectopic activity in patients with cryptogenic ischemic stroke (CIS) or transient ischemic attack (TIA) and determine its prognostic significance. METHODS: Retrospective cohort study, in which 184 patients with CIS or TIA who had performed 24-hour Holter electrocardiogram were included. The median follow-up was 27.5 months. Baseline clinical and imagiologic characteristics, etiologic investigation results, and ischemic stroke and TIA recurrences information were collected. Number of atrial premature complexes (APCs) per hour was categorized as less than 10 APCs/hour, 10-30 APCs/hour, and more than 30 APCs/hour. RESULTS: Most of the patients had less than 10 APCs/hour (82.6%), 8.2% had 10-30 APCs/hour, and 9.2% had more than 30 APCs/hour. Patients with more than 30 APCs/hour had a greater median left atrium diameter than patients with 30 APCs/hour or less (42 mm vs. 38 mm; 95% confidence interval [CI], .50-7.00; P = .003). Annual recurrence rate of CIS or TIA was 2.9% in patients with less than 10 APCs/hour, 11.0% in 10-30 APCs/hour, and 22.6% in more than 30 APCs/hour (P = .001). More than 30 APCs/hour were independently associated with recurrence risk in multivariate survival analysis (hazard ratio, 3.40; 95% CI, 1.12-10.32; P = .030). CONCLUSIONS: In patients with CIS or TIA, frequent atrial ectopic activity (>30 APCs/h) was independently associated with increased risk of stroke or TIA recurrence. Further studies need to validate frequent atrial ectopic activity as a risk factor for recurrence in cryptogenic stroke and confirm its role as a predictor of occult atrial fibrillation. PMID- 25533760 TI - Toward the development of a lupus interactive navigator to facilitate patients and their health care providers in the management of lupus: results of web-based surveys. AB - BACKGROUND: Systemic lupus erythematosus is an inflammatory autoimmune disease associated with high morbidity and unacceptable mortality. Information and management tools are needed to help persons with lupus cope with their illness and facilitate health care providers in the delivery of care. OBJECTIVE: The objective of the study was to assess the needs and find solutions to support persons with lupus and their health care providers. METHODS: Web-based surveys were distributed across Canada to persons with lupus and their relatives (n=3119), rheumatologists (n=517), and arthritis health professionals (AHPs) (n=226) by Lupus Canada, the Canadian Rheumatology Association, and the Arthritis Health Professions Association, respectively. RESULTS: The survey sample comprised 665 (21.3%) persons with lupus, 98 (19.0%) rheumatologists, and 74 (32.7%) AHPs. Among the participants with lupus, 92.4% were female, the average age was 46.8 (SD 12.7) years, 79.2% were Caucasian, and 58.8% were employed. All Canadian provinces and territories were represented. The majority (43.3%) of respondents were from Ontario. Mean disease duration was 10.2 (SD 9.5) years, and 41.9% rated their global assessment as fair or poor. There was high agreement between lupus participants and health care providers regarding disease-specific information topics. All groups rated topics related to lupus, fatigue, medications, and stress as most important. Ratings differed among lupus participants and their health care providers regarding perceived helpfulness of some of the patient tools, such as the option to view test results. Needs differed for persons with lupus based on age, sex, depression, stress, and disease activity. Differences in health care provider needs were based on amount of experience in treating lupus. CONCLUSIONS: Information and support tools needed for persons with lupus and their health care providers were identified. These results will help guide us in the development of a Web-based Lupus Interactive Navigator as an intervention tool to help persons with lupus self manage their disease and to facilitate heath care providers in clinical management. PMID- 25533761 TI - Comparison of Acuros (AXB) and Anisotropic Analytical Algorithm (AAA) for dose calculation in treatment of oesophageal cancer: effects on modelling tumour control probability. AB - AIM: To investigate systematic changes in dose arising when treatment plans optimised using the Anisotropic Analytical Algorithm (AAA) are recalculated using Acuros XB (AXB) in patients treated with definitive chemoradiotherapy (dCRT) for locally advanced oesophageal cancers. BACKGROUND: We have compared treatment plans created using AAA with those recalculated using AXB. Although the Anisotropic Analytical Algorithm (AAA) is currently more widely used in clinical routine, Acuros XB (AXB) has been shown to more accurately calculate the dose distribution, particularly in heterogeneous regions. Studies to predict clinical outcome should be based on modelling the dose delivered to the patient as accurately as possible. METHODS: CT datasets from ten patients were selected for this retrospective study. VMAT (Volumetric modulated arc therapy) plans with 2 arcs, collimator rotation +/- 5-10 degrees and dose prescription 50 Gy / 25 fractions were created using Varian Eclipse (v10.0). The initial dose calculation was performed with AAA, and AXB plans were created by re-calculating the dose distribution using the same number of monitor units (MU) and multileaf collimator (MLC) files as the original plan. The difference in calculated dose to organs at risk (OAR) was compared using dose-volume histogram (DVH) statistics and p values were calculated using the Wilcoxon signed rank test. The potential clinical effect of dosimetric differences in the gross tumour volume (GTV) was evaluated using three different TCP models from the literature. RESULTS: PTV Median dose was apparently 0.9 Gy lower (range: 0.5 Gy - 1.3 Gy; p < 0.05) for VMAT AAA plans re-calculated with AXB and GTV mean dose was reduced by on average 1.0 Gy (0.3 Gy -1.5 Gy; p < 0.05). An apparent difference in TCP of between 1.2% and 3.1% was found depending on the choice of TCP model. OAR mean dose was lower in the AXB recalculated plan than the AAA plan (on average, dose reduction: lung 1.7%, heart 2.4%). Similar trends were seen for CRT plans. CONCLUSIONS: Differences in dose distribution are observed with VMAT and CRT plans recalculated with AXB particularly within soft tissue at the tumour/lung interface, where AXB has been shown to more accurately represent the true dose distribution. AAA apparently overestimates dose, particularly the PTV median dose and GTV mean dose, which could result in a difference in TCP model parameters that reaches clinical significance. PMID- 25533762 TI - Identification of Staphylococcus aureus infection by aptamers directly radiolabeled with technetium-99m. AB - INTRODUCTION: Aptamers are oligonucleotides that have high affinity and specificity for their molecular targets which are emerging as a new class of molecules for radiopharmaceuticals development. In this study, aptamers selected to Staphylococcus aureus were evaluated for bacterial infection identification. METHODS: Anti S. aureus aptamers were labeled with (99m)Tc by the direct method. The radiolabel yield and complex stability were assessed by thin-layer chromatography (TLC). Three groups of Swiss mice containing 6 animals each were used. The first group was infected intramuscularly in the right thigh with S. aureus. The second group was infected in the same way with C. albicans and the third group was injected with zymosan to induce aseptic inflammation. After 24 h, radiolabeled aptamers (22.2 MBq) were injected by the tail vein. The mice were euthanized 4 h post injection and tissue sample activities measured in a gamma counter. RESULTS: The (99m)Tc labeled aptamers were stable in saline, plasma and cystein excess. Radiolabeled aptamers showed increased uptake in the kidneys for all groups indicating a main renal excretion, which is consistent with the hydrophilic nature and small size of aptamers. The radiopharmaceutical showed rapid blood clearance indicated by a reduced dose (% ID/g) in the blood. The biodistribution showed that aptamers were able to identify the infection foci caused by S. aureus displaying a target/non-target ratio of 4.0+/-0.5. This ratio for mice infected with C. albicans was 2.0+/-0.4 while for mice with aseptic inflammation was 1.2+/-0.2. Histology confirmed the presence of infection in groups 1 and 2, and inflammation in group 3. CONCLUSIONS: The biodistibution study demonstrated a statistically higher uptake in the S. aureus foci relative to inflammation and C. albicans infected areas. These results highlight the potential of aptamers labeled directly with (99m)Tc for bacterial infection diagnosis by scintigraphy. PMID- 25533763 TI - PEG modification on (111)In-labeled phosphatidyl serine liposomes for imaging of atherosclerotic plaques. AB - INTRODUCTION: Previously, we reported a probe for imaging of atherosclerotic plaques: (111)In-labeled liposomes. Liposomes were modified with phosphatidylserine (PS) because macrophages recognize PS and phagocytize apoptotic cells in plaques. PS modification was successful and we could visualize atherosclerotic plaques by single-photon emission computed tomography (SPECT). However, too-rapid blood clearance reduced accumulation of PS-liposomes in plaques in vivo. Therefore, in the present study, PS-liposomes were modified with polyethylene glycol (PEG) to retard the rate of blood clearance. METHODS: PS liposomes (size, 100 nm or 200 nm) were PEGylated with PEG2000 or PEG5000 at 1 or 5 mol%, and radiolabeled with (111)In. For the study of uptake in vitro, liposomes were incubated with mouse peritoneal macrophages. Biodistribution studies in vivo were carried out in ddY mice. En face autoradiograms were obtained with apoE(-/-) mice upon intravenous injection of (111)In-liposomes. RESULTS: Uptake was decreased significantly at 5 mol% PEGylation in 100-nm PS liposomes (*P<0.05 vs. 0 mol%). All the PEGylated liposomes tested showed significantly lower uptake than the non-PEGylated control in 200-nm liposomes. In vivo results showed slower blood clearance in PEGylated liposomes. Autoradiograms in apoE(-/-) mice were well matched with Oil Red O staining. Additionally, 200-nm PS-liposomes modified with 5%PEG2000 ([(111)In]5%PEG2000PS200) showed the highest uptake to the region in vivo. CONCLUSIONS: As expected, PEGylation retarded the rate of blood clearance. In addition, it affected liposome uptake by macrophages in vitro. These results suggest that the balance between the rate of blood clearance and macrophage recognition is important, and [(111)In]5%PEG2000PS200 showed the best results in our investigation. PMID- 25533765 TI - Eight-choice sound localization by manatees: performance abilities and head related transfer functions. AB - Two experiments investigated the ability and means by which two male Florida manatees (Trichechus manatus latirostris) may determine the direction of a sound source. An eight-choice discrimination paradigm was used to determine the subjects' sound localization abilities of five signal conditions covering a range of frequencies, durations, and levels. Subjects performed above the 12.5% chance level for all broadband frequencies and were able to localize sounds over a large level range. Errors were typically located to either side of the signal source location when presented in the front 180 degrees but were more dispersed when presented from locations behind the subject. Front-to-back confusions were few and accuracy was greater when signals originated from the front 180 degrees . Head-related transfer functions were measured to determine if frequencies were filtered by the manatee body to create frequency-specific interaural level differences (ILDs). ILDs were found for all frequencies as a function of source location, although they were largest with frequencies above 18 kHz and when signals originated to either side of the subjects. Larger ILDs were found when the signals originated behind the subjects. A shadowing-effect produced by the body may explain the relatively low occurrence of front-back confusions in the localization study. PMID- 25533764 TI - Detection of breast cancer microcalcification using (99m)Tc-MDP SPECT or Osteosense 750EX FMT imaging. AB - BACKGROUND: In previous work, we demonstrated the presence of hydroxyapetite (type II microcalcification), HAP, in triple negative MDA-MB-231 breast cancer cells. We used (18)F-NaF to detect these types of cancers in mouse models as the free fluorine, (18)F(-), binds to HAP similar to bone uptake. In this work, we investigate other bone targeting agents and techniques including (99m)Tc-MDP SPECT and Osteosense 750EX FMT imaging as alternatives for breast cancer diagnosis via targeting HAP within the tumor microenvironment. METHODS: Thirteen mice were injected subcutaneously in the right flank with 10(6) MDA-MB-231 cells. When the tumor size reached ~0.6 cm(3), mice (n=9) were injected with ~37 MBq of (99m)Tc-MDP intravenously and then imaged one hour later in a NanoSPECT/CT or injected intravenously with 4 nmol/g of Osetosense 750EX and imaged 24 hours later in an FMT (n=4). The imaging probe concentration in the tumor was compared to that of muscle. Following SPECT imaging, the tumors were harvested, sectioned into 10 MUm slices, and underwent autoradiography or von Kossa staining to correlate (99m)Tc-MDP binding with HAP distribution within the tumor. The SPECT images were normalized to the injected dose and regions-of-interest (ROIs) were drawn around bone, tumor, and muscle to obtain the radiotracer concentration in these regions in units of percent injected dose per unit volume. ROIs were drawn around bone and tumor in the FMT images as no FMT signal was observed in normal muscle. RESULTS: Uptake of (99m)Tc-MDP was observed in the bone and tumor with little or no uptake in the muscle with concentrations of 11.34+/-1.46 (mean+/ SD), 2.22+/-0.95, and 0.05+/-0.04%ID/cc, respectively. Uptake of Osteosense 750EX was also observed in the bone and tumor with concentrations of 0.35+/-0.07 (mean+/-SD) and 0.04+/-0.01picomoles, respectively. No FMT signal was observed in the normal muscle. There was no significant difference in the bone-to-tumor ratio between the two modalities (5.1+/-2.3 for SPECT and 8.8+/-2.2 for FMT) indicating that there is little difference in tumor uptake between these two agents. CONCLUSION: This study provides evidence of the accessibility of HAP within the breast tumor microenvironment as an in vivo imaging target for bone-seeking agents. SPECT imaging using (99m)Tc-MDP can be rapidly translated to the clinic. FMT imaging using Osteosense 750EX is not currently approved for clinical use and is limited to animal research. PMID- 25533766 TI - Instant live-cell super-resolution imaging of cellular structures by nanoinjection of fluorescent probes. AB - Labeling internal structures within living cells with standard fluorescent probes is a challenging problem. Here, we introduce a novel intracellular staining method that enables us to carefully control the labeling process and provides instant access to the inner structures of living cells. Using a hollow glass capillary with a diameter of <100 nm, we deliver functionalized fluorescent probes directly into the cells by (di)electrophoretic forces. The label density can be adjusted and traced directly during the staining process by fluorescence microscopy. We demonstrate the potential of this technique by delivering and imaging a range of commercially available cell-permeable and nonpermeable fluorescent probes to cells. PMID- 25533767 TI - Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury. AB - This preliminary study investigated whether direct measurement of head rotation improves prediction of mild traumatic brain injury (mTBI). Although many studies have implicated rotation as a primary cause of mTBI, regulatory safety standards use 3 degree-of-freedom (3DOF) translation-only kinematic criteria to predict injury. Direct 6DOF measurements of human head rotation (3DOF) and translation (3DOF) have not been previously available to examine whether additional DOFs improve injury prediction. We measured head impacts in American football, boxing, and mixed martial arts using 6DOF instrumented mouthguards, and predicted clinician-diagnosed injury using 12 existing kinematic criteria and 6 existing brain finite element (FE) criteria. Among 513 measured impacts were the first two 6DOF measurements of clinically diagnosed mTBI. For this dataset, 6DOF criteria were the most predictive of injury, more than 3DOF translation-only and 3DOF rotation-only criteria. Peak principal strain in the corpus callosum, a 6DOF FE criteria, was the strongest predictor, followed by two criteria that included rotation measurements, peak rotational acceleration magnitude and Head Impact Power (HIP). These results suggest head rotation measurements may improve injury prediction. However, more 6DOF data is needed to confirm this evaluation of existing injury criteria, and to develop new criteria that considers directional sensitivity to injury. PMID- 25533769 TI - Vibrating Frequency Thresholds in Mice and Rats: Implications for the Effects of Vibrations on Animal Health. AB - Vibrations in research facilities can cause complex animal behavioral and physiological responses that can affect animal health and research outcomes. The goal of this study was to determine the range of frequency values, where animals are unable to attenuate vibrations, and therefore may be most susceptible to their effects. Anesthetized and euthanized adult rats and mice were exposed to vibration frequencies over a wide range (0-600 Hz) and at a constant magnitude of 0.3 m/s(2). Euthanized animals were additionally exposed to vibrations at an acceleration of 1 m/s(2). The data showed that at most frequencies rodents were able to attenuate vibration magnitudes, with values for the back-mounted accelerometer being substantially less than that of the table. At frequencies of 41-60 Hz mice did not attenuate vibration magnitude, but instead the magnitude of the table and animal were equal or amplified. Rats experienced the same pattern of non-attenuation between 31 and 50 Hz. Once euthanized, the mice vibrated at a slightly more elevated frequency (up to 100 Hz). Based on these results, it may be prudent that in laboratory settings, vibrations in the ranges reported here should be accounted for as possible contributors to animal stress and/or biomechanical changes. PMID- 25533768 TI - MRI-based Protocol to Characterize the Relationship Between Bicuspid Aortic Valve Morphology and Hemodynamics. AB - Bicuspid aortic valve (BAV) is the most common congenital heart defect and can lead to severe complications. Many studies have been conducted to evaluate the potential of geometric and hemodynamic biomarkers to predict BAV-related aortopathy. This work proposes a novel semi-automatic protocol to characterize geometry and hemodynamics of aorta and aortic valve based on 2D cine and 4D flow MRI data. The protocol was applied to 12 BAV and 12 control subjects. Statistical differences between the groups were identified and linear regression models were investigated to elucidate the potential of this protocol to investigate the risk of disease progression. Statistical differences between the groups were found for orifice eccentricity, aorta diameter, velocity, jet angle and flow displacement. Key findings of the regression analysis include the association in the proximal ascending aorta between aorta diameter and mean velocity (negative), jet angle (positive) and flow displacement (positive), in the combined cohort. Positive association between flow displacement in the proximal aorta and orifice jet angle in TAV subjects was found. This study represents a pilot application of a protocol for standardized assessment of aortic geometry and hemodynamics associated with BAV disease. Its limited need for user input is advantageous for large cohort studies. PMID- 25533770 TI - A review of the role of the partial pressure of carbon dioxide in mechanically loaded tissues: the canary in the cage singing in tune with the pressure ulcer mantra. AB - Pressure ulcers (PUs) can occur in any situations where people are subjected to non-uniform distribution of pressure over a prolonged period. They can have devastating effects on the patients' well-being and in extreme conditions can prove fatal. In addition to traditional wisdom implicating mechanically induced ischaemia, there is strong evidence that other mechanisms play a role in the cascade of events which can initiate the PU damage process at the cellular level. Some of these refer to a metabolic imbalance with compromised delivery of nutrients and accumulation of waste products in the local environment of the cells. The approach of much research has focused on the measure of oxygen in compressed tissues as a means of predicting early damage. However, the present review adopting a hierarchical approach, using length scales ranging from cells through to human models, has revealed compelling evidence which highlights the importance of carbon dioxide levels and associated concentration of other metabolites, such as lactate and purines. The temporal profiles of these metabolites have been monitored in the various models subjected to periods of mechanical-induced loading where the localized cells have converted to anaerobic metabolism. They reveal threshold levels of carbon dioxide which might be indicative of early tissue damage during both mechanical-induced ischaemia and subsequent reperfusion and an appropriate sensor could be used in a similar manner to the long-standing "canary in a cage" method to detect toxic gasses in enclosed mines. PMID- 25533771 TI - Setting a standard for the initiation of steroid therapy in refractory or severe Mycoplasma pneumoniae pneumonia in adolescents and adults. AB - Serum interleukin (IL)-18 level was thought to be a useful as a predictor of refractory or severe Mycoplasma pneumoniae pneumonia, and steroid administration is reported to be effective in this situation. The serum levels of IL-18 correlated significantly with those of lactate dehydrogenase (LDH). The purpose of this study was to set a standard for the initiation of steroid therapy in M. pneumoniae pneumonia using a simple serum marker. We analyzed 41 adolescent and adult patients with refractory or severe M. pneumoniae pneumonia who received steroid therapy, and compared them with 108 patients with M. pneumoniae pneumonia who responded to treatment promptly (control group). Serum LDH levels were significantly higher in the refractory and severe group than in the control group at the initiation of steroid therapy (723 vs 210 IU/L, respectively; p < 0.0001). From receiver operating characteristic curve analysis, we calculated serum LDH cut-off levels of 364 IU/L at initiation of steroid therapy and 302 IU/L at 1-3 days before the initiation of steroid therapy. The administration of steroids to patients in the refractory and severe group resulted in the rapid improvement of symptoms and a decrease in serum LDH levels in all patients. Serum LDH level can be used as a useful parameter to determine the initiation of steroid therapy in refractory or severe M. pneumoniae pneumonia. A serum LDH level of 302-364 IU/L seems to be an appropriate criterion for the initiation of steroid therapy. PMID- 25533773 TI - Can RAS inhibitors affect the course of hypertrophic cardiomyopathy? PMID- 25533772 TI - Asthma in patients with psoriasis. PMID- 25533774 TI - Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo controlled trial. AB - BACKGROUND: No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. METHODS: In this single-centre, randomised, double blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654. FINDINGS: Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0.60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0.0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1%) patient had angioedema, one (1%) had deterioration of renal function, and one (1%) had hyperkalaemia. Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline. INTERPRETATION: Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other indications in patients with hypertrophic cardiomyopathy, irrespective of obstructive physiology. Additional studies are needed to assess the effect of angiotensin II receptor blockers in preclinical hypertrophic cardiomyopathy-eg, in genotype-positive but phenotype-negative individuals. PMID- 25533775 TI - Identification of the sex pheromone of the diurnal hawk moth, Hemaris affinis. AB - Sex pheromones of nocturnal hawk moths have been identified previously, but not those of diurnal hawk moths. Here, we report laboratory analyses and field testing of the sex pheromone of the diurnal hawk moth, Hemaris affinis (Bremer 1861) (Lepidoptera: Sphingidae). Sex pheromone glands were removed and extracted in hexane during peak calling activity of virgin female moths. Analysis of gland extracts by gas chromatography (GC) with electroantennographic detection revealed three components that elicited responses from male moth antennae. These components were identified, based on their mass spectra and retention indices on two GC columns, as (Z)-11-hexadecenal and (10E, 12Z)- and (10E,12E)-10,12 hexadecadienals with a ratio of 45:20:35. In a field experiment, traps baited with the three-component synthetic blend, but none of the single- or two component blends, caught male moths. All three pheromone components have been identified previously in pheromones of other Lepidoptera, including Sphingid moths, and thus the ternary blend is probably responsible for the species specificity of the pheromone of this moth. PMID- 25533776 TI - Female sex pheromones of two Japanese saturniid species, Rhodinia fugax and Loepa sakaei: identification, synthesis, and field evaluation. AB - While 11 species in the family Saturniidae are found in Japan, no sex pheromones of the native species had been investigated previously. We collected larvae of Rhodinia fugax in Nagano and Tottori Prefecture, and of Loepa sakaei in Okinawa Prefecture, and extracted sex pheromones of these two species from virgin female moths. In gas chromatography-electroantennogram detection (GC-EAD) analyses, male antennae of each species responded to one component in the respective pheromone extracts of conspecific females. Chemical analyses of the extracts by GC/mass spectrometry revealed that the EAD-active compounds of R. fugax and L. sakaei were a hexadecadienal and a tetradecadienyl acetate, respectively. The two species belong to the subfamily Saturniinae, and the mass spectra of both were similar to that of the 6,11-hexadecadienyl acetate identified from Antheraea polyphemus, classified in the same subfamily, suggesting the same 6,11-dienyl structure for the C16 aldehyde and a 4,9-dienyl structure for the C14 acetate. Based on this assumption, four geometrical isomers of each dienyl compound were stereoselectively synthesized via acetylene intermediates, compared to the natural products, and tested in the field. Male catches confirmed the pheromone structures of the two Japanese saturniid species as (6E,11Z)-6,11-hexadecadienal for R. fugax and (4E,9Z)-4,9-tetradecadienyl acetate for L. sakaei. The compounds have a characteristic 1,6-dienyl motif common to the pheromones of Saturniinae species. PMID- 25533777 TI - Economic stress or random variation? Revisiting German reunification as a natural experiment to investigate the effect of economic contraction on sex ratios at birth. AB - BACKGROUND: The economic stress hypothesis (ESH) predicts decreases in the sex ratio at birth (SRB) following economic decline. However, as many factors influence the SRB, this hypothesis is difficult to test empirically. Thus, researchers make use of quasi-experiments such as German reunification: The economy in East, but not in West Germany, underwent a rapid decline in 1991. A co occurrence of a decline in the East German SRB in 1991 has been interpreted by some as support for the ESH. However, another explanation might be that the low SRB in 1991 stems from increased random variation in the East German SRB due to a drastically reduced number of births during the crisis. We look into this alternative random variation hypothesis (RVH) by re-examining the German case with more detailed data. METHODS: Our analysis has two parts. First, using aggregate-level birth register data for all births in the period between 1946 and 2011, we plot the quantum and variance of the SRB and the number of births and unemployment rates, separately for East and West Germany, and conduct a time series analysis on the East German SRB over time. Second, we model the odds for a male birth at the individual level in a multiple logistic regression (1991-2010, ~13.9 million births). Explanatory variables are related to the level of the individual birth, the mother of the child born, and the regional economic context. RESULTS: The aggregate-level analysis reveals a higher degree of variation of the SRB in East Germany. Deviations from the time trend occur in several years, seemingly unrelated to economic development, and the deviation in 1991 is not statistically significant. The individual-level analysis confirms that the 1991-drop in the East German SRB cannot directly be attributed to economic development and that there is no statistically significant effect of economic development on sex determination in East or West Germany. CONCLUSION: Outcomes support the RVH but not the ESH. Furthermore, our results speak against a statistically significant effect of the reunification event itself on the East German SRB. We discuss the relative importance of behavioral and physiological responses to macro-level stressors, a distinction that may help integrate previously mixed findings. PMID- 25533778 TI - Future Costs, Fixed Healthcare Budgets, and the Decision Rules of Cost Effectiveness Analysis. AB - Life-saving medical technologies result in additional demand for health care due to increased life expectancy. However, most economic evaluations do not include all medical costs that may result from this additional demand in health care and include only future costs of related illnesses. Although there has been much debate regarding the question to which extent future costs should be included from a societal perspective, the appropriate role of future medical costs in the widely adopted but more narrow healthcare perspective has been neglected. Using a theoretical model, we demonstrate that optimal decision rules for cost effectiveness analyses assuming fixed healthcare budgets dictate that future costs of both related and unrelated medical care should be included. Practical relevance of including the costs of future unrelated medical care is illustrated using the example of transcatheter aortic valve implantation. Our findings suggest that guidelines should prescribe inclusion of these costs. PMID- 25533779 TI - Public trust in the healthcare system in a developing country. AB - Broadly defined, trust in the healthcare system is concerned with how the public perceives the system and the actors therein as it pertains to their ability to both deliver services and seek the best interests of their clientele. Trust is important because it impacts upon a range of health behaviors including compliance and ultimately affects the ability of the healthcare system to meet its goals. While several studies exist on public trust within the developed world, few studies have explored this issue in developing countries. This paper therefore assesses public trust in the healthcare system of a developing small island nation, Trinidad and Tobago. A cross-sectional survey of adults was conducted using a questionnaire that has been successfully used across Europe. We report that trust levels in the healthcare system in Trinidad and Tobago are relatively low with less than 50% of persons indicating fair trust in the healthcare system. In addition, individual health professionals also did not score highly with lowest scores found for nurses and complementary therapists. Results on four out of five dimensions of trust also demonstrated scores significantly lower than those reported in more developed nations. Open-ended comments supported these findings with the majority of persons indicating a lack of confidence in the healthcare system. These results may reflect the reality in the wider developing world, and we suggest that bolstering trust is a needed area of focus in the delivery of healthcare services throughout the nation. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25533780 TI - Relationship between receptive vocabulary and the neural substrates for story processing in preschoolers. AB - A left-lateralized fronto-temporo-parietal language network has been well characterized in adults; however, the neural basis of this fundamental network has hardly been explored in the preschool years, despite this being a time for rapid language development and vocabulary growth. We examined the functional imaging correlates associated with vocabulary ability and narrative comprehension in 30 preschool children ages 3 to 5. Bilateral auditory cortex and superior temporal activation as well as left angular and supramarginal gyrus activation were observed during a passive listening-to-stories task. Boys showed greater activation than girls in the right anterior cingulate and right superior frontal gyrus (SFG). Finally, children with higher vocabulary scores showed increased grey matter left-lateralization and greater activation in bilateral thalamus, hippocampus, and left angular gyrus. This study is novel in its approach to relate left-hemisphere language regions and vocabulary scores in preschool-aged children using fMRI. PMID- 25533781 TI - GMC urges national support service for doctors' health concerns. PMID- 25533782 TI - Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficient neurosurgical treatment for advanced Parkinson's disease. Non-invasive metabolic neuroimaging during the course of DBS in animal models may contribute to our understanding of its action mechanisms. Here, DBS was adapted to in vivo proton magnetic resonance spectroscopy at 11.7 T in the rat to follow metabolic changes in main basal ganglia structures, the striatum, and the substantia nigra pars reticulata (SNr). Measurements were repeated OFF and ON acute and subchronic (7 days) STN-DBS in control and parkinsonian (6-hydroxydopamine lesion) conditions. Acute DBS reversed the increases in glutamate, glutamine, and GABA levels induced by the dopamine lesion in the striatum but not in the SNr. Subchronic DBS normalized GABA in both the striatum and SNr, and glutamate in the striatum. Taurine levels were markedly decreased under subchronic DBS in the striatum and SNr in both lesioned and unlesioned rats. Microdialysis in the striatum further showed that extracellular taurine was increased. These data reveal that STN-DBS has duration-dependent metabolic effects in the basal ganglia, consistent with development of adaptive mechanisms. In addition to counteracting defects induced by the dopamine lesion, prolonged DBS has proper effects independent of the pathological condition. Non-invasive metabolic neuroimaging might be useful to understand the physiological mechanisms of deep brain stimulation (DBS). Here, we demonstrate the feasibility of repeated high-field proton magnetic resonance spectroscopy of basal ganglia structures under subthalamic nucleus DBS in control and parkinsonian rats. Results show that DBS has both rapid and delayed effects either dependent or independent of disease state. PMID- 25533783 TI - Product binding enforces the genomic specificity of a yeast polycomb repressive complex. AB - We characterize the Polycomb system that assembles repressive subtelomeric domains of H3K27 methylation (H3K27me) in the yeast Cryptococcus neoformans. Purification of this PRC2-like protein complex reveals orthologs of animal PRC2 components as well as a chromodomain-containing subunit, Ccc1, which recognizes H3K27me. Whereas removal of either the EZH or EED ortholog eliminates H3K27me, disruption of mark recognition by Ccc1 causes H3K27me to redistribute. Strikingly, the resulting pattern of H3K27me coincides with domains of heterochromatin marked by H3K9me. Indeed, additional removal of the C. neoformans H3K9 methyltransferase Clr4 results in loss of both H3K9me and the redistributed H3K27me marks. These findings indicate that the anchoring of a chromatin modifying complex to its product suppresses its attraction to a different chromatin type, explaining how enzymes that act on histones, which often harbor product recognition modules, may deposit distinct chromatin domains despite sharing a highly abundant and largely identical substrate-the nucleosome. PMID- 25533784 TI - Reservoir host immune responses to emerging zoonotic viruses. AB - Zoonotic viruses, such as HIV, Ebola virus, coronaviruses, influenza A viruses, hantaviruses, or henipaviruses, can result in profound pathology in humans. In contrast, populations of the reservoir hosts of zoonotic pathogens often appear to tolerate these infections with little evidence of disease. Why are viruses more dangerous in one species than another? Immunological studies investigating quantitative and qualitative differences in the host-virus equilibrium in animal reservoirs will be key to answering this question, informing new approaches for treating and preventing zoonotic diseases. Integrating an understanding of host immune responses with epidemiological, ecological, and evolutionary insights into viral emergence will shed light on mechanisms that minimize fitness costs associated with viral infection, facilitate transmission to other hosts, and underlie the association of specific reservoir hosts with multiple emerging viruses. Reservoir host studies provide a rich opportunity for elucidating fundamental immunological processes and their underlying genetic basis, in the context of distinct physiological and metabolic constraints that contribute to host resistance and disease tolerance. PMID- 25533785 TI - Long-term culture of genome-stable bipotent stem cells from adult human liver. AB - Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from alpha1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy. PMID- 25533786 TI - Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. AB - Eukaryotic cells execute complex transcriptional programs in which specific loci throughout the genome are regulated in distinct ways by targeted regulatory assemblies. We have applied this principle to generate synthetic CRISPR-based transcriptional programs in yeast and human cells. By extending guide RNAs to include effector protein recruitment sites, we construct modular scaffold RNAs that encode both target locus and regulatory action. Sets of scaffold RNAs can be used to generate synthetic multigene transcriptional programs in which some genes are activated and others are repressed. We apply this approach to flexibly redirect flux through a complex branched metabolic pathway in yeast. Moreover, these programs can be executed by inducing expression of the dCas9 protein, which acts as a single master regulatory control point. CRISPR-associated RNA scaffolds provide a powerful way to construct synthetic gene expression programs for a wide range of applications, including rewiring cell fates or engineering metabolic pathways. PMID- 25533787 TI - Site for bone-anchored hearing system for children younger than 5 years. AB - OBJECTIVE: To describe in children younger than the present US FDA-approved 5 years of age the thickest part of the temporal bone available for placement of a bone-anchored hearing system. Children with unilateral hearing loss, as with aural atresia, have deficits in at least language comprehension and oral expression. The early provision of hearing to the atretic ear may minimize the potential for auditory deprivation. STUDY DESIGN: Point prevalence descriptive study. SETTING: Tertiary referral pediatric hospital. SUBJECTS AND METHODS: Thirty-eight patients less than 6 years old with congenital aural atresia had undergone temporal bone computed tomography (CT). Bone thickness lateral (ie, superficial) to the sinodural angle, in the topmost axial CT slice that included any adjacent petrous ridge, was measured. RESULTS: The mean bone thicknesses lateral to the sinodural angles of the atretic ears were 5.1, 5.0, 5.9, 5.2, 5.2, and 4.8 mm for the <1, 1-, 2-, 3-, 4-, 5-year-olds, respectively; of the non atretic ears, thicknesses were 4.1, 4.9, 5.5, 6.7, 4.3, and 4.7 mm. CONCLUSION: Based on this small case series, bone thickness lateral (ie, superficial) to the sinodural angle is sufficient for many children suffering from aural atresia to have bone-anchored hearing devices implanted younger than age 5 years. Use of the sinodural site would require a magnetic bone-anchored hearing system, which could be repositioned posteriorly at age 5 years when pinna construction and atresiaplasty endeavors typically begin. PMID- 25533790 TI - Functional diversity and evolutionary dynamics of thermoTRP channels. AB - Animals have evolved sophisticated physiological systems for sensing ambient temperature since changes in environmental temperatures affect various biological processes. Thermosensitive transient receptor potential (thermoTRP) channels serve as thermal sensors in diverse animal species. They are multimodal receptors that are activated by temperature as well as other physical and chemical stimuli. Since thermoTRP channels are calcium permeable non-selective cation channels, their activation leads to an influx of calcium and sodium ions into the cell and triggers downstream signal transduction. ThermoTRP channels have been characterized in diverse animal species over the past several years, illuminating the diversification of thermoTRP channels in the course of evolution. The gene repertoires of thermoTRP channels differ among animal species. Additionally, in some cases, the temperature and chemical sensitivities among orthologous thermoTRP channels vary among species. The evolutionary flexibility of thermoTRP channels enabled them to contribute to unique physiological systems such as infrared sensation in snakes and bats and seasonal adaptation in silk moth. On the other hand, the functional differences of thermoTRP channels among species have been utilized for understanding the molecular basis for their activation (or inhibition) mechanisms, and amino acid residues (or domains) responsible for the respective channel properties have been identified in various thermoTRP channels. Here we summarize the current understanding of the functional diversity and evolutionary dynamics of thermoTRP channels. PMID- 25533789 TI - Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy. AB - The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca(2+) uptake (Fulop et al., 2011). Therefore we studied mitochondrial Ca(2+) metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell-inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca(2+) signals. The present data indicate that enhanced mitochondrial Ca(2+) uptake is a pathogenetic factor in the progress of ADOA. PMID- 25533791 TI - Ephrins and Ephs in cochlear innervation and implications for advancing cochlear implant function. AB - OBJECTIVES/HYPOTHESIS: Determine if the neuronal pathfinding cues resulting from Eph/ephrin interaction in the inner ear play a role in establishing the tonotopic innervation of the cochlea. STUDY DESIGN: Protein expression of Ephs and ephrins was evaluated in the inner ear of mice and chicks. Subsequently, in vitro, in vivo, and functional electrophysiologic studies were performed to indicate that Ephs and ephrins play a role regulating the normal innervation patterns in the mouse inner ear. METHODS: Eph and ephrin protein expression was identified in the inner ear by western blotting and localized by fluorescence immunohistochemistry and X-gal staining. Eph/ephrin effects on neurite outgrowth was assessed via co culture with EphB2 expressing COS-1 cells. Anatomic effects of disrupting Eph/ephrin signaling on cochlear innervation were determined with lipophilic dye tracing and functional effects with auditory brainstem response (ABR). RESULTS: Expression of several different Ephs and ephrins were found in the inner ear of chicks and mice. The changes in ephrin-A2 immunoreactivity after gentamicin ototoxicity coincide with the spatio-temporal pattern of hair cell loss and regeneration in the chick cochlea. EphB2 inhibited outgrowth of spiral ganglion cell neurites. Knockout mice with null function of EphB1, EphB2, and EphB3 demonstrated abnormal inner ear innervation and elevated ABR thresholds, indicating hearing loss. CONCLUSIONS: Ephrin-A2 may be involved in the guidance of ganglion cells to hair cells in the chick. Disruption of Eph/ephrin signaling results in abnormal innervation and hearing loss, suggesting that these proteins play a role in establishing normal innervation patterns in the mouse cochlea. LEVEL OF EVIDENCE: NA PMID- 25533792 TI - A 90-day study of three bruchid-resistant mung bean cultivars in Sprague-Dawley rats. AB - Mung bean has been traditionally and widely used as an edible and medicinal plant in the South and Southeast Asia. Bruchid resistance mung bean has more potential in commercial use, but scarcely been evaluated for safety through standard in vivo toxicological studies. In the present study, subchronic oral toxicity studies of bruchid-resistant mung bean were designed and conducted in Sprague Dawley (SD) rats for 90 days. During the subchronic oral toxicity study, no mortality and toxicologically significant changes in clinical signs, food consumption, opthalmoscopic examination, hematology, clinical biochemistry, macroscopic findings, organ weights and histopathological examination were noted in animal administered diet containing bruchid-resistant mung bean. These results demonstrated that bruchid resistant mung bean is as safe as conventional mung bean. PMID- 25533793 TI - The furofuran-ring selectivity, hydrogen peroxide-production and low Km value are the three elements for highly effective detoxification of aflatoxin oxidase. AB - AFO (aflatoxin oxidase), an enzyme from Armillariella tabescens previously named aflatoxin detoxifizyme, exhibits oxidative detoxification activity toward aflatoxin B1 and sterigmatocystin. Bioinformatics reveals that AFO is a newly discovered oxidase because AFO does not share any significant similarities with any known oxidase. It is critically important to understand how AFO acts on aflatoxin B1. In this study, in addition to aflatoxin B1 (AFB1) and sterigmatocystin (ST), five other chemicals that have furan or pyran structures were investigated. The results indicated that in addition to AFB1 and ST, AFO is also able to act on versicolorin A, 3,4-dihydro-2H-pyran and furan. These results suggested that 8,9-unsaturated carboncarbon bond of aflatoxin B1 is the potential reactive site for AFO. Further findings indicated that the action of AFO is oxygen-dependent and hydrogen peroxide-producing. The simultaneously produced hydrogen peroxide possibly plays the essential role in detoxification of AFO. In addition, the extremely low Km value of 0.33 umol/l for AFO-AFB1 and 0.11 umol/l for AFO-ST signifies that AFO is highly selective for AFB1 as well as ST. PMID- 25533794 TI - Metabolic characterization of meso-dihydroguaiaretic acid in liver microsomes and in mice. AB - meso-Dihydroguaiaretic acid (MDGA) is a major component of Myristica fragrans and Machilus thunbergii that is traditionally used as a spice and for medicinal purposes. Despite reports of various biological activities exerted by MDGA, there is no information regarding its metabolic properties. The purpose of this study was to determine the metabolic stability and cytochrome P450 (CYP) inhibitory potential of MDGA, using pooled human liver microsomes (HLMs) to characterize its metabolic properties. In addition, pharmacokinetic analysis was performed in mice treated intravenously (5 mg/kg) or orally (20 mg/kg) with MDGA for comparison with our in vitro results. The half-life of MDGA in HLMs and mouse liver microsomes incubated with NADPH, UDPGA or NADPH plus UDPGA was 25.41 and 22.74, 0.39 and 0.20 or 0.28 and 0.22 min, respectively. In our pharmacokinetic study, MDGA rapidly declined in plasma and had low bioavailability, which was attributable to extensive metabolism by UDP-glucuronosyltransferases and CYPs. Among CYP isoforms, CYP2E1 activity was selectively inhibited by MDGA through a competitive inhibitory mode, with an inhibitory constant (Ki) value of 13.1 uM. These results suggest that MDGA can be used as a selective CYP2E1 inhibitor in vitro, which warrants evaluation of the pharmacological significance of MDGA induced CYP2E1 inhibition. PMID- 25533795 TI - Toxicogenomic markers for corticosteroid treatment in beef cattle: integrated analysis of transcriptomic data. AB - In the present work, an integrated analysis was performed on DNA-microarray data of bovine muscle samples belonging to controls, animals treated with various growth promoters (GPs) and unknown commercial samples. The aim was identify a robust gene expression signature of corticosteroid treatment for the classification of commercial samples, despite the effects of biological variation and other confounding factors. DNA-Microarray data from 5 different batches of bovine skeletal muscle samples were analyzed (146 samples). After preprocessing, expression data from animals treated with corticosteroids and controls from the different batches (89 samples) were used to train a Support Vector Machines (SVMs) classifier. The optimal number of gene probes chosen by our classification framework was 73. The SVMs with linear kernel built on these 73 biomarker genes was predicted to perform on novel samples with a high classification accuracy (Matthew's correlation coefficient equal to 0.77) and an average percentage of false positive and false negative equal to 5% and 6%, respectively. Concluding, a relatively small set of genes was able to discriminate between controls and corticosteroid-treated animals, despite different breeds, animal ages, and combination of GPs. The results are extremely promising, suggesting that integrated analysis provides robust transcriptomic signatures for GP abuse. PMID- 25533797 TI - Antiarrhythmic therapy in 2014: Contemporary approaches to treating arrhythmias. PMID- 25533798 TI - Gene therapy: Targeting apoc-III to lower triglycerides. PMID- 25533796 TI - Cardiorheumatology: cardiac involvement in systemic rheumatic disease. AB - Autoimmune rheumatic diseases can affect the cardiac vasculature, valves, myocardium, pericardium, and conduction system, leading to a plethora of cardiovascular manifestations that can remain clinically silent or lead to substantial cardiovascular morbidity and mortality. Although the high risk of cardiovascular pathology in patients with autoimmune inflammatory rheumatological diseases is not owing to atherosclerosis alone, this particular condition contributes substantially to cardiovascular morbidity and mortality-the degree of coronary atherosclerosis observed in patients with rheumatic diseases can be as accelerated, diffuse, and extensive as in patients with diabetes mellitus. The high risk of atherosclerosis is not solely attributable to traditional cardiovascular risk factors: dysfunctional immune responses, a hallmark of patients with rheumatic disorders, are thought to cause chronic tissue destructive inflammation. Prompt recognition of cardiovascular abnormalities is needed for timely and appropriate management, and aggressive control of traditional risk factors remains imperative in patients with rheumatic diseases. Moreover, therapies directed towards inflammatory process are crucial to reduce cardiovascular disease morbidity and mortality. In this Review, we examine the multiple cardiovascular manifestations in patients with rheumatological disorders, their underlying pathophysiology, and available management strategies, with particular emphasis on the vascular aspects of the emerging field of 'cardiorheumatology'. PMID- 25533799 TI - Genetics: Mutations in APOA5 or LDLR increase risk of myocardial infarction. PMID- 25533800 TI - Anticoagulation therapy: Reducing factor XI with antisense oligonucleotides superior to endoxaparin for postoperative venous thromboembolism. PMID- 25533802 TI - CVD prevention in 2014: Advances in the prevention of cardiovascular disease. PMID- 25533801 TI - Treatment of degenerative mitral regurgitation in elderly patients. AB - Advanced age is a common contraindication for cardiac surgery, particularly in high-risk patients with comorbidities, such as pulmonary and renal impairment, associated coronary artery disease, and neurological disorders. In elderly patients with degenerative mitral regurgitation who are not eligible for conventional surgical valve repair or replacement, percutaneous valve repair is emerging as a viable alternative therapeutic option. Nonsurgical and minimally invasive therapies for degenerative mitral regurgitation are of particular value in this subset of patients, because these interventions are associated with reduced perioperative mortality, clinical improvement, and faster recovery than is possible with surgical procedures. However, given that surgery remains the gold-standard treatment and should still be considered an option regardless of a patient's age, transcatheter mitral valve repair should be performed only in candidates who will gain the most benefit from it. The balance between the risks and benefits, and the value versus the futility of procedures to treat degenerative mitral regurgitation in elderly patients should be assessed by a specialized multidisciplinary care team. In this Review, we discuss the treatment options and indications for degenerative mitral regurgitation in elderly patients. PMID- 25533803 TI - Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion. AB - Cultures of human CD34(pos) cells stimulated with erythroid growth factors plus dexamethasone, a model for stress erythropoiesis, generate numerous erythroid cells plus a few macrophages (approx. 3%; 3:1 positive and negative for CD169). Interactions occurring between erythroblasts and macrophages in these cultures and the biological effects associated with these interactions were documented by live phase-contrast videomicroscopy. Macrophages expressed high motility interacting with hundreds/thousands of erythroblasts per hour. CD169(pos) macrophages established multiple rapid 'loose' interactions with proerythroblasts leading to formation of transient erythroblastic island-like structures. By contrast, CD169(neg) macrophages established 'tight' interactions with mature erythroblasts and phagocytosed these cells. 'Loose' interactions of CD169(pos) macrophages were associated with proerythroblast cytokinesis (the M phase of the cell cycle) suggesting that these interactions may promote proerythroblast duplication. This hypothesis was tested by experiments that showed that as few as 103 macrophages significantly increased levels of 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide incorporation frequency in S/G2/M and cytokinesis expressed by proerythroblasts over 24 h of culture. These effects were observed also when macrophages were co-cultured with dexamethasone directly conjugated to a macrophage-specific CD163 antibody. In conclusion, in addition to promoting proerythroblast proliferation directly, dexamethasone stimulates expansion of these cells indirectly by stimulating maturation and cytokinesis supporting activity of macrophages. PMID- 25533805 TI - Living through pelvic radiotherapy:A mixed method study of self-care activities and distressful symptoms. AB - PURPOSE: To explore patients' experience of their illness when undergoing pelvic radiotherapy by describing the presence and severity of distressful symptoms and to explore initiated self-care activities in response to illness and symptoms. METHODS: A mixed-method study was performed which included a core qualitative dataset and a supplementary quantitative dataset. Twenty-nine women undergoing five weeks of radiotherapy were prospectively interviewed during five weeks of treatment in order to capture experiences, distressful symptoms and quality of life during treatment. Grounded theory formed collection and analysis of the qualitative dataset and statistics were used to analyze the quantitative dataset. RESULTS: A maintained self-identity was concluded as being central during the trajectory of treatment. Initiated self-care activities served to alleviate physical, emotional, and social suffering; helping the respondents keep their integrity and sense of self. Previous life experiences influenced the process of being able to maintain self-identity. The gastrointestinal symptoms and pain caused most distress. CONCLUSIONS: In order to be able to maintain self-identity patients endure treatment by focusing on symptoms, on getting cured and on their self-image. Several distressful symptoms implied social limitations and a sense that the body would not take the strain. The result of this study can help health care professionals to gain a better understanding of the struggle to endure pelvic radiotherapy. Further, health care professionals should be more proactive in alleviating their patients' distressful symptoms. The results imply that previous life experiences should precede initiated interventions because these life experiences affect the patients' self-care activities. PMID- 25533807 TI - Clinical aspects of vitamin D-binding protein gene polymorphisms in hemodialysis patients. AB - INTRODUCTION: There are scarce data on the associations between vitamin D-binding protein gene (GC) polymorphisms and manifestations of chronic kidney disease. OBJECTIVES: We evaluated the frequency distribution of GC polymorphic variants in hemodialysis (HD) patients and healthy subjects as well as the differences in the prevalence of coronary artery disease (CAD) and myocardial infarction (MI) and selected clinical and laboratory indices of secondary hyperparathyroidism in HD patients (women and men) with different GC polymorphic variants. PATIENTS AND METHODS: HD patients (n = 1056; 625 men) and healthy controls (n = 313; 150 men) were enrolled into the study. The tested GC polymorphisms included rs2298849, rs7041, and rs1155563. We analyzed clinical data (prevalence of CAD and MI; treatment with parathyroidectomy or cinacalcet) and laboratory results (serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-hydroxy vitamin D [25(OH)D] in relation to the gene polymorphisms. RESULTS: There were no differences between the study groups themselves and between the study groups and controls in terms of the frequency distribution of GC polymorphisms (Ptrend <0.05). Lower plasma 25(OH)D levels were shown in subjects with the rs7041 TT genotype compared with those with the GG genotype (12.7, 5.7-20.9 ng/ml vs. 15.9, 8.0-50.0 ng/ml, P = 0.02). Women with the rs7041 TT genotype compared with those with the GG genotype showed higher serum phosphorus levels (5.58, 3.40-8.97 mg/dl vs. 5.03, 1.75-9.33 mg/dl, P = 0.007). CONCLUSIONS: HD patients do not differ in the distribution of GC polymorphisms rs2298849, rs7041, and rs1155563 from healthy subjects. In HD patients, the GC polymorphism is associated with plasma 25(OH)D levels. Sex-related factors may be important in the expression of associations between GC polymorphic variants and mineral disorders. PMID- 25533806 TI - Post-traumatic growth in stomach cancer survivors: Prevalence, correlates and relationship with health-related quality of life. AB - PURPOSE: Post-traumatic growth (PTG) is defined as positive psychological changes experienced as a result of struggle with highly challenging life circumstances. Interest in PTG has increased in cancer survivorship care; however, little is known about PTG among stomach cancer survivors. This study aimed to examine the prevalence and correlates of PTG, and to identify relationships between PTG and health-related quality of life (HRQOL). METHODS: Cross-sectional descriptive design. In total, 122 stomach cancer survivors were recruited from one university hospital in South Korea. Measurements included the Korean version of the Post traumatic Growth Inventory and the Functional Assessment of Cancer Therapy- General Population. RESULTS: Over half (53.3%) of the participants experienced moderate to high levels of PTG. 'Change of self-perception' was the most common growth domain, followed by 'relating to others', 'new possibilities' and 'spiritual change'. Older age, low socio-economic status (i.e. low education level and low monthly income) and lack of religion were associated with lower levels of PTG. Survivors with higher levels of PTG had better social/family well being (P < 0.001) and better functional well-being (P < 0.001). CONCLUSIONS: Psychological interventions to enhance PTG may have a positive effect on impaired HRQOL among stomach cancer survivors. PMID- 25533808 TI - Loss of Sprouty2 in human high-grade serous ovarian carcinomas promotes EGF induced E-cadherin down-regulation and cell invasion. AB - Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase signaling. Our Human Exonic Evidence-Based Oligonucleotide (HEEBO) microarray results showed that the mRNA levels of SPRY2, but not of SPRY1 or SPRY4, are down-regulated in high-grade serous ovarian carcinoma (HGSC) tissues and epithelial ovarian cancer (EOC) cell lines. Molecular inversion probe (MIP) copy number analysis showed the deletion of the SPRY2 locus in HGSC. Overexpression of SPRY2 reduced EGF-induced cell invasion by attenuating EGF induced E-cadherin down-regulation. Moreover, a positive correlation between SPRY2 and E-cadherin protein levels was observed in HGSC tissues. This study reveals the loss of SPRY2 in HGSC and indicates an important tumor-suppressive role for SPRY2 in mediating the stimulatory effect of EGF on human EOC progression. PMID- 25533809 TI - Absence of Annexin A1 impairs host adaptive immunity against Mycobacterium tuberculosis in vivo. AB - The role of Annexin A1 (ANXA1) in counter-regulating the activities of innate immune cells, such as the migration of neutrophils and monocytes, and the generation of pro-inflammatory mediators in various models of inflammatory and autoimmune diseases is well documented. However, while ANXA1 has been proposed as an important mediator of the adaptive immune response, its involvement in this respect has been less studied. Furthermore, while there have been numerous studies on the role of ANXA1 in inflammatory diseases, less has been reported on its influence in immunity against infection. A recent study reported a link between ANXA1 and tuberculosis, and proposed a model in which Mycobacterium tuberculosis exerts its virulence by manipulating the ANXA1-mediated host apoptotic response. This has prompted us to further investigate the role of ANXA1 in the pathogenesis of tuberculosis in vivo. Here, we show that ANXA1(-/-) mice are more susceptible to M. tuberculosis infection, as evidenced by a transient increase in the pulmonary bacterial burden, and exacerbated and disorganized granulomatous inflammation. These pathological manifestations correlated with an impaired ability of ANXA1(-/-) dendritic cells to activate naive T cells, thereby supporting a role for ANXA1 in shaping the adaptive immunity against M. tuberculosis. PMID- 25533810 TI - An alternative approach to describing agility in sports through establishment of a relationship between velocity and radius of curvature. AB - Agility is an essential part of many athletic activities. Currently, agility drill duration is the sole criterion used for evaluation of agility performance. The relationship between drill duration and factors such as acceleration, deceleration and change of direction, however, has not been fully explored. This paper provides a mathematical description of the relationship between velocity and radius of curvatures in an agility drill through implementation of a power law (PL). Two groups of skilled and unskilled participants performed a cyclic forward/backward shuttle agility test. Kinematic data was recorded using motion capture system at a sampling rate of 200 Hz. The logarithmic relationship between tangential velocity and radius of curvature of participant trajectories in both groups was established using the PL. The slope of the regression line was found to be 0.26 and 0.36, for the skilled and unskilled groups, respectively. The magnitudes of regression line slope for both groups were approximately 0.3 which is close to the expected 1/3 value. Results are an indication of how the PL could be implemented in an agility drill thus opening the way for establishment of a more representative measure of agility performance instead of drill duration. PMID- 25533811 TI - Endothelialization of drug eluting stents and its impact on dual anti-platelet therapy duration. AB - Coronary artery disease is a leading cause of death and disability worldwide with contemporary treatment strategies employing both optimal medical therapy and catheter based percutaneous coronary intervention (PCI) with drug eluting stents (DES). While DES have dramatically reduced restenosis rates, their use has been associated with an increased risk of late stent thrombosis and accelerated neointimal atherosclerosis (i.e. "neoatherosclerosis") both major contributors to late stent failure. The underlying substrate of late DES failure is likely related to vascular endothelial dysfunction such as poor endothelial regrowth and barrier function (i.e. "endothelial healing"). Initial concerns with 1st generation DES have lead to improvements in mechanical and biologic properties of current 2nd generation DES, which inhibit endothelial regrowth to a lesser extent, lessening late stent failure and resulting in an overall improved safety profile. Current guidelines recommend duration of at least one year of dual anti platelet therapy with aspirin and a thienopyridine agent such as clopidogrel or prasugrel as sufficient to prevent late thrombotic complications. Recent studies, however, suggest a shorter duration of dual anti-platelet therapy may be equally as safe and efficacious in preventing stent thrombosis with newer generation DES. However, higher risk populations such as patients receiving 1st generation DES or those with increased risk for future ischemic events may benefit from a longer duration (i.e. 30 months) of DAPT to prevent major cardiovascular events with the caveat that such an approach may be associated with an increased risk for bleeding. This review examines the vascular responses to 1st and second generation DES and recent clinical trials examining DAPT duration. PMID- 25533812 TI - Natural inhibitors of PI3K/AKT signaling in breast cancer: emphasis on newly discovered molecular mechanisms of action. AB - Epidermal growth factor receptor (EGFR) plays a critical role in the initiation and progression of a variety of human cancers, including breast cancer. An important signaling pathway downstream of EGFR is the PI3K/AKt pathway, which regulates cellular processes as diverse as cell growth, survival, proliferation and migration. Deregulated activity of this pathway may lead to uncontrolled cell growth, survival, migration and invasion, contributing to tumor formation. In this review, we evaluate natural compounds that, in vitro (breast cancer cell lines) and/or in vivo (animal model, clinical) studies, suppress breast cancer cells or tumors mainly by suppressing the PI3K/AKT signaling pathway. The effect of these compounds on cell cycle arrest, inhibition of cell migration and invasion, tumor angiogenesis and metastasis in breast cancer are discussed. PMID- 25533814 TI - Erratum to "Clinical Practice Guidelines for the Medical and Surgical Management of Primary Intracerebral Hemorrhage in Korea" by Kim JE, et al. (J Korean Neurosurg Soc 56 : 175-187, 2014). AB - [This corrects the article on p. 175 in vol. 56, PMID: 25368758.]. PMID- 25533813 TI - Novel approach for the percutaneous treatment of left ventricular pseudoaneurysms. AB - Left ventricular pseudoaneurysm (LVPA) is a rare yet serious complication that may follow cardiac surgery, myocardial infarction, trauma, or infection. If left untreated, reported rates of rupture and sudden cardiac death are high. Although surgical intervention has traditionally been the standard treatment for LVPA, percutaneous closure is now an attractive alternative in the high-risk patient. We report a case of a successful percutaneous LVPA closure using direct chest wall entry into the pseudoaneurysm. This novel approach can be useful when access to the LVPA is a challenge, especially in the setting of small ostial size, dense left ventricular trabeculations, angulated serpiginous tract, and presence of mechanical prostheses. PMID- 25533804 TI - A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation. AB - Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies. PMID- 25533815 TI - Calcium deficiency: where does the diagnostic criterion come from and by what is bone health influenced? PMID- 25533816 TI - Diagnostic accuracy of a single qualitative immunochemical fecal occult blood test coupled with physical measurements. AB - BACKGROUND: We aimed to improve the sensitivity of immunochemical fecal occult blood test (I-FOBT) to screen colorectal neoplasm among average-risk adults. METHODS: This is a diagnostic cohort study. All health examination participants receiving a single qualitative I-FOBT and a screening colonoscopy from January 2010 to June 2011 were included. Stool specimens were collected for I-FOBT before colonoscopy. Using pathology as gold standard, significant colorectal neoplasm was defined as advanced adenoma or malignancy. RESULTS: A total of 1 007 health examinees were identified. Fifty-five (5.5%) had borderline positive (+/-) I FOBT, while 38 (3.8%) had positive I-FOBT. Twenty-four (2.4%) had advanced adenoma, and five (0.5%) had carcinoma. Using borderline positive I-FOBT as cutoff value, the sensitivity and specificity for significant colorectal neoplasm were 34.5% (95% confidence interval (CI) 19.9%-52.7%) and 91.5% (95% CI 89.6% 93.1%), respectively. If combined with advanced age, high blood pressure (BP), and abdominal obesity, a fulfillment of either two criteria further increased the sensitivity to 72.4% (95% CI 54.3%-85.3%) with a specificity of 68.8% (95% CI 65.8%-71.6%). CONCLUSION: The sensitivity of a single qualitative I-FOBT for the detection of significant colorectal neoplasm can be increased by coupling with age, BP, and abdominal obesity. PMID- 25533817 TI - A scoring system for prediction of early recurrence after liver resection for Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. AB - BACKGROUND: The management of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) is controversial due to the early recurrence after curative hepatectomy, and many variables were related to the prognosis. The purpose of this study was to predict the tumor recurrence in early postoperative period of the patients with BCLC stage B HCC. METHODS: From January 2004 to January 2012, 104 patients with BCLC stage B HCC underwent hepatectomy. Clinicopathological factors and follow-up data were statistically analyzed to establish a predicting scoring system. RESULTS: The overall survival rates for one, three, and five years were 69.2%, 52.7%, and 42.3%, and the disease-free survival rates for one, three, and five years were 52.9%, 47.3%, and 37.5%, respectively. The multiple factors analysis showed that the micro-vessel invasion, lymph nodes metastasis, multiple lesions, and the high expression of HMGB1 were independent factors (P < 0.05). A scoring system was established to predict the early recurrence within one year after the surgery for BCLC stage B HCC, according to the analysis results with a specificity of 85.1% and a sensitivity of 80.3%. CONCLUSION: Variant clinicopathological factors were associated with early postoperative recurrence for BCLC stage B HCC and recurrence early after hepatectomy was more likely in patients with a higher score of the scoring system. PMID- 25533818 TI - Effects of HIV status notification on reducing the risk of sexual transmission of HIV in China. AB - BACKGROUND: The risk of HIV sexual transmission is much higher among people unaware of their HIV status than among those aware. Only a few studies have indicated that the incidence of unsafe sex can be reduced when people know their HIV status. This study was to investigate this effect in China. METHODS: A cohort study consisting of two surveys was conducted at two different times among a group of people living with HIV/AIDS, whose status was newly diagnosed with HIV via sexual contact, in Shanghai, Chongqing, and Kunming. The first survey was conducted among 823 people tested positive for HIV before notifying them of the HIV status. The second survey was conducted among 650 HIV-positive people at six months following the first survey (after notification of HIV status). The scope of survey covered unsafe sex practices, number of unsafe sexual partners, and frequency of unsafe sexual behaviors over the prior six months. Unsafe sex is defined as unprotected anal or vaginal sex with partners who are HIV positive or whose HIV status is unknown. RESULTS: The proportion of unsafe sex was reduced by about 85% after HIV status notification. The risk of HIV sexual transmission was 15 times higher among persons unaware of their HIV status than among those aware. Approximately 95% of new sexually transmitted HIV infections stemmed from 56% of the infected persons unaware of their HIV status in China. CONCLUSION: Timely HIV status notification has the potential to significantly reduce unsafe sex among HIV-infected persons and reduce the risk for HIV transmission via unsafe sex. PMID- 25533819 TI - Complication and safety of ultrasound guided percutaneous nephrolithotomy in 8,025 cases in China. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) was mostly performed with fluoroscopy and/or ultrasonography. The safety and feasibility of PCNL performed totally under ultrasound are not clearly defined. Therefore, we introduce the 9 year experience of 8 025 ultrasound guided PCNL procedures from multiple centers in China performed by the same surgeon, to evaluate the feasibility and security of this technique. METHODS: From September 2004 to August 2013, 8 025 cases, 4 398 males (54.8%) and 3 627 females (45.2%), whose age ranged from 6 months to 85 years old, with upper urinary tract stones, underwent PCNL in our center and the supported hospitals. Puncture site selection and channel dilation were all guided using only Doppler ultrasound. Single stones were treated in 1 356 cases, there were 2 817 cases of multi stones, and 3 852 cases of staghorn calculi. The pre- and post-operative imaging data, the intraoperative findings, operation time, perioperative complications, and related parameters were recorded. RESULTS: All procedures were successful. No patients died during the operation. Average operation time was 42 minutes (range 10 to 168 minutes), 4 cases converted to open surgery, and 2 patients lost the diseased kidney due to refractory bleeding in the early stage of the PCNL. Ninety-four (1.2%) patients received blood transfusions and 20 (0.25%) patients needed highly selective renal artery embolization. Fifteen (0.19%) patients had a pleural injury. 5 457 (68%) cases were completed by a single tract and 2 568 (32%) cases added more tracts. The mean stone size (longest diameter) was 2.8 cm (range 1.2 to 26.5 cm). The final stone-free rate was 85.5%. Residual stones occurred mainly in patients with renal dysfunction, medullary sponge kidney, and complete staghorn calculi with a slim calyceal neck. CONCLUSIONS: X-ray free Doppler ultrasound guided percutaneous nephrolithotomy is feasible and safe in a variety of cases of renal and/or upper ureteral stones. The probability of radiation hazard and adjacent organ injury is low. The morbidity from major complications was reduced remarkably after special training. It is worthy of wider use compared with fluoroscopy in patients with special kidneys (e.g. solitary kidney, spinal deformity, ectopic kidney) and in infants. PMID- 25533820 TI - A novel nonsense mutation in BBS4 gene identified in a Chinese family with Bardet Biedl syndrome. AB - BACKGROUND: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disease, and information about BBS in Chinese populations is very limited. The purpose of the present study was to determine the genetic cause of BBS in a Chinese Han family. METHODS: Clinical data were recorded for the 4-year-old female proband and the available family members. The proband was screened for mutation by Sanger sequencing for a total of 142 exons of the 12 BBS-causing genes (BBS1-BBS12). The variants detected in the proband were further confirmed in the other family members. RESULTS: We identified a novel homozygous nonsense mutation (c.70A>T, p.K24X) in the BBS4 gene exon 2 in the proband. Such mutant allele was predicted to cause a premature truncation in the N-terminal of the BBS4 protein, and probably induced the nonsense-mediated decay of BBS4 messenger RNAs. The proband's parents and brother were heterozygous for the nonsense mutant allele. It was absent in 50 Chinese control subjects. An additional rare heterozygous missense single nucleotide polymorphism (SNP) named rs200718870 in BBS10 gene was also detected in the proband, her father and her brother. Some manifestations of the proband including atypical retinitis pigmentosa, choroidal sclerosis, high myopia, and early onset of obesity might be associated with this mutation in BBS4 gene. The proband's father also reported surgical removal of an extra finger during childhood. CONCLUSIONS: The present study described a novel nonsense mutation in BBS4 gene in a Chinese family. This homozygous mutation was predicted to completely abolish the synthesis of the BBS4 protein. We also detected a rare heterozygous missense SNP in BBS10 gene in the family, but did not find sufficient evidence to support the triallelic inheritance. PMID- 25533821 TI - Postural control and sensory information integration abilities of boys with two subtypes of attention deficit hyperactivity disorder: a case-control study. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorder in childhood. ADHD children with overlapping symptoms and signs of motor problems have more serious prognosis than that of children with ADHD only. However, the motor and sensory processing problems in children with ADHD have not been studied well. Few people adopt the technique of computerized dynamic posturography (CDP) in the study of ADHD, which is applied widely in clinical and laboratory research to objectively evaluate human's balance performance. This study aimed to assess the characteristics of postural control and sensory information processing of boys with two subtypes of ADHD by using CDP, so as to provide the proof for non-drug therapy of ADHD. METHOD: From June 2003 to September 2004, a total of 73 boys (7-15 years of age) with ADHD and 73 normal developing boys matched by age and intelligence quotient from Peking University Institute of Mental Health were recruited in the study. The Sensory Organization Test was adopted to test the static balance performance under six sensory input conditions by SMART EquiTest 8.0 (NeuroCom) instrument. The sensory information from three sensory systems were available under condition 1, the visual inputs were removed or distorted under condition 2 or 3, the somatosensory inputs were in conflict with or without the visual inputs removed under condition 4 or 5, and both the visual and somatosensory inputs were in conflict under condition 6. The indexes of equilibrium score, somatosensory, vestibular, and visual ratios, and strategy scores were analyzed to indicate the subjects' postural control ability. RESULTS: ADHD boys had significantly lower composite equilibrium score (CES) than the normal group (P < 0.05). Under condition 1 and conditions 3-6, the equilibrium scores (ES) of the ADHD group were significantly lower (all P < 0.05) than those of the control. Significantly lower visual and vestibular ratios and strategy scores under conditions 4-6 were found in boys with ADHD compared with the control group (P < 0.05). Boys of ADHD predominantly inattentive (ADHD-I) type had a significantly lower CES and ES under conditions 4-6 than the controls (all P < 0.05) while the ESs of ADHD combined type (ADHD-C) boys under each condition were similar with that of boys with ADHD-I and no significant difference was found between boys with ADHD-C and the control group (all P > 0.05). Compared with the control group, the ADHD-I boys showed significantly lower visual and vestibular ratios and strategy scores under conditions 4-6 whereas the ADHD-C boys showed a trend of lower visual ratio (all P < 0.05). CONCLUSIONS: ADHD boys had a poorer static postural control ability and impaired function of processing visual and vestibular information compared with the normal control. Boys with ADHD-I showed particularly severe defect of static postural control and vestibular function integrating conflict information than normal boys. These deficits may be an important contributor to the clinical presentation of ADHD children and their cognitive deficits. Assessment and training of postural control function would be suggested during the diagnosis and treatment of ADHD children. PMID- 25533822 TI - Prognostic significance of neutrophil to lymphocyte ratio in patients with hepatocellular carcinoma after transcatheter arterial chemoembolization. AB - BACKGROUND: Accumulating evidence indicates that systemic inflammation response is associated with the prognosis of various cancers. The aim of this study was to investigate the neutrophil-lymphocyte ratio (NLR), which is one of the systemic inflammation markers, in the prognosis of hepatocellular carcinoma (HCC) after treatment of transcatheter arterial chemoembolization (TACE). METHODS: The clinical data of 178 HCC patients who received TACE were retrospectively analyzed. The optimal NLR cutoff was determined according to the receiver operating characteristic (ROC) analysis. All patients were divided into NLR normal group and NLR-elevated group according to the cutoff, and the clinical features of these two groups were comparatively analyzed. Meanwhile, the overall survival and disease free survival (DFS) were analyzed using the Kaplan-Meier method. The risk factors of postoperative survival were investigated using univariate and multivariate Cox regression analyses. RESULTS: The optimal NLR cutoff was defined at 1.85 and 42 (23.6%) patients had an elevated NLR (NLR>1.85). The median survival time was 9.5 months (range 1-99 months). The clinical data between the two groups were comparable, except for a-fetoprotein. Follow-up results showed that the median survival of patients with normal NLR was 17.5 months (range: 1-99 months) compared with 8 months (range: 8-68 months) of patients with elevated NLR. The 1, 3 and 5-year overall survival of patients in the NLR-normal group and NLR-elevated group were 57.3%, 44.1%, and 27.2% and 42.1%, 19.6%, and 9.5% respectively (chi(2) = 194.2, P < 0.001). Similarly, the disease free survival also has a significant difference (chi(2) = 39.3, P < 0.001). Multivariate Cox regression analysis showed that a high NLR was an independent factor affecting the survival rate of HCC after TACE (P = 0.04). CONCLUSION: Preoperative NLR was an important prognostic factor to predict the prognosis of patients with intermediate HCC treated with TACE. PMID- 25533823 TI - Left atrial appendage morphology in patients with atrial fibrillation in China: implications for stroke risk assessment from a single center study. AB - BACKGROUND: The left atrial appendage (LAA) is thought to be the main source of thrombi in patients with atrial fibrillation (AF). The purpose of this study was to describe the LAA orifice diameter, LAA length, and morphologic type of the LAA in Chinese patients with AF as well as to evaluate whether these LAA parameters are associated with a history of stroke in patients with AF from a single center in China. METHODS: The study population consisted of 219 consecutive patients with drug-refractory, symptomatic paroxysmal, or persistent AF scheduled to undergo radiofrequency catheter ablation in our single center. All patients underwent extensive clinical assessment and multidetector computed tomography to fully explore the anatomy of the LAA. RESULTS: Of the 219 patients who underwent catheter ablation procedures, chicken wing LAA morphology was found in 114 patients (52.2%), windsock in 52 (23.9%), cauliflower in 29 (13.0%), and cactus in 24 (10.9%). Compared with the windsock LAA morphology, cactus had a larger left atrial diameter ((42.40 +/- 3.68) and (37.91 +/- 4.32) mm, P = 0.005) and LAA orifice diameter ((27.38 +/- 3.70) and (24.14 +/- 3.58) mm, P = 0.048). The LAA length was significantly larger in the chicken wing morphology than in the windsock ((37.50 +/- 6.74) and (31.33 +/- 3.92) mm, P = 0.015) and cauliflower morphologies ((37.50 +/- 6.74) and (31.33 +/- 3.92) mm, P = 0.015). According to their medical records, 26 patients (11.9%) had suffered a prior stroke. Compared with patients who had no history of stroke, the prior-stroke patients were older (62.04 +/- 8.07 and 58.24 +/- 9.24, P = 0.047) and there were fewer patients with chicken wing (23.1% and 59.1%, P = 0.001) and more patients with cauliflower (26.9% and 9.8%, P = 0.046). Multivariate Logistic regression analysis demonstrated that age (odds ratio (OR) 1.26; 95% confidence interval (CI) 1.08 1.47; P = 0.003), non-chicken wing morphology (OR 5.82; 95% CI 1.61-21.03; P = 0.007), and LAA orifice diameter (OR 1.25; 95% CI 1.05-1.49; P = 0.014) were independent predictors of stroke after adjusting for all parameters that emerged as potential confounders with univariate analysis. CONCLUSION: LAA analysis can potentially be used to inform guidance on the implication for stroke risk assessment. PMID- 25533824 TI - Clinical manifestation of the SRSF2 gene mutation in Chinese patients with chronic myelomonocytic leukemia. AB - BACKGROUND: Spliceosome mutations have been recently identified and associated with hematological malignancies. SRSF2, one of components of the splicing machinery, has a high mutation frequency during chronic myelomonocytic leukemia, according to previous reports. However, the relevance of this finding in Chinese populations remains unknown. METHODS: We recruited 50 Chinese patients with chronic myelomonocytic leukemia to analyze the state of SRSF2 and to assess the corresponding clinical features by polymerase chain reaction followed by direct sequencing. RESULTS: Ten of 50 patients (20%) harbored SRSF2 mutations, including five P95R, two 95H, and three P95L point mutations. The patient group was older than the wild type group (P < 0.01). No significant statistical differences were observed with regard to the other clinical characteristics (sex, peripheral blood count, serum lactate dehydrogenase, karyotype, World Health Organization classification, etc.) between these two groups. Two of the patients showed an early evolution to acute myeloid leukemia. CONCLUSIONS: SRSF2 mutations are frequent in chronic myelomonocytic leukemia patients, but show a relatively lower incidence in Chinese patients. Moreover, the mutation can be related to old age and an unfavorable prognosis. Our results provide valuable insights for the development of a diagnostic marker, or for the identification of a therapeutic target for chronic myelomonocytic leukemia. PMID- 25533825 TI - Enhanced neuroprotection and improved motor function in traumatized rat spinal cords by rAAV2-mediated glial-derived neurotrophic factor combined with early rehabilitation training. AB - BACKGROUND: Spinal cord injury (SCI) is a serious neurological injury that often leads to permanent disabilities for the victims. The aim of this study was to determine the effects of glial-derived neurotrophic factor (GDNF) mediated by recombinant adeno-associated virus type 2 (rAAV2) alone or in combination with early rehabilitation training on SCI. METHODS: SCI was induced on the T8-9 segments of the spinal cord by laminectomy in adult male Sprague-Dawley rats. Then besides the sham operation group, the SCI rats were randomly divided into four groups: natural healing group, gene therapy group, rehabilitation training group, and combination therapy group (gene therapy in combination with rehabilitation training). Motor dysfunction, protein expression of GDNF, edema formation, and cell injury were examined 7, 14, and 21 days after trauma. RESULTS: The topical application of rAAV-GDNF-GFP resulted in strong expression of GDNF, especially after the 14th day, and could protect the motor neuron cells. Early rehabilitative treatment resulted in significantly improved motor function, reduced edema formation, and protected the cells from injury, especially after the 7th and 14th days, and increased the GDNF expression in the damaged area, which was most evident after Day 14. The combined application of GDNF and early rehabilitative treatment after SCI resulted in a significant reduction in spinal cord pathology and motor dysfunction after the 7th and 14th days. CONCLUSION: These observations suggest that rAAV2 gene therapy in combination with rehabilitation therapy has potential clinical value for the treatment of SCI. PMID- 25533826 TI - Multilocus sequence typing indicates diverse origins of invasive Candida tropicalis isolates in China. AB - BACKGROUND: According to data from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) 2010, Candida tropicalis (C. tropicalis) is the third most common pathogen causing invasive candidiasis. Moreover, the majority of fluconazole-resistant C. tropicalis isolates were from a single hospital. Therefore, a molecular epidemiological survey is necessary to investigate the genetic relatedness of C. tropicalis isolates in China. METHODS: In this study, 48 C. tropicalis isolates causing invasive fungal infections from four tertiary hospitals in China were studied. All the isolates were identified by sequencing the internal transcribed spacer region. Antifungal susceptibility to triazoles, amphotericin B, and caspofungin was determined by the Clinical and Laboratory Standards Institute standard broth microdilution method. Multilocus sequence typing (MLST) was performed, and phylogenetic analysis was further performed by the eBURST and maximum parsimony (MP) methods to characterize the genetic relatedness of isolates. RESULTS: MLST discriminated 40 diploid sequence types (DSTs) among 48 isolates, including 36 novel DSTs, and the XYR1 gene showed the highest discriminatory power. The DSTs obtained from this study were compared with those of previously reported C. tropicalis isolates, and there was poor type alignment with regional strains. Nine groups and 11 singletons were identified by eBURST, whereas two groups and 10 subgroups were clustered by MP analysis. Generally, there were no obvious correlations between clonal clusters generated and the specimen source or hospital origin. Seven fluconazole-resistant isolates were confirmed and assigned to three distinguishable branches. CONCLUSIONS: The results suggested diverse origins of invasive C. tropicalis isolates in China. Although most invasive C. tropicalis strains in the mainland of China were clustered with previously characterized Asian isolates, major C. tropicalis clusters identified in this study were genetically distinct from those of other geographic regions. PMID- 25533827 TI - Peptide tyrosine-tyrosine combined with its receptors exhibits an anti-cancer potential in pancreatic cancer MiaPaCa-2 cell. AB - BACKGROUND: Pancreatic cancer is a common malignant tumor of the digestive system. It is the fourth major cause of tumor-related death and its morbidity is increasing, and hence it is imperative to develop effective forms of therapy for pancreatic cancer. Peptide tyrosine-tyrosine (PYY) is an important gastrointestinal peptide hormone. According to previous literatures, PYY has been shown to inhibit tumor proliferation in cellular and animal models, but there has been limited research on the detailed mechanism of PYY in pancreatic cancer. This study was to observe the effects of PYY on pancreatic cancer cell and investigate the possible mechanism. METHODS: The expression of Y1, Y2, and Y5 receptors on pancreatic cancer cell lines were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The cytotoxicity of PYY toward the MiaPaCa-2 cell was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; the cell morphology and structure changes were observed under inverted microscope and transmission electron microscope respectively. Apoptosis and cell cycle were evaluated by flow cytometry. The activity of caspase-3 was determined by activity assay kits and Western blotting. The expression of survivin, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) were determined by RT-qPCR and Western blotting. RESULTS: Expression of Y2 receptor is the most abundant PYY receptor on pancreatic cancer cell. PYY inhibited MiaPaCa-2 cell proliferation, blocked it in G0/G1 phase, increased the proportion of apoptosis cells and caspase-3 activity, and reduced the expression of survivin, VEGF, and COX-2. CONCLUSIONS: PYY weakened the ability of the pancreatic MiaPaCa-2 cell viability through cell cycle blocking and apoptosis inducing. The inhibition effect of PYY may be mediated by the Y2 receptor. The increased caspase-3 activity and reduced expression of survivin, VEGF, and COX-2 may serve as a novel mechanism in PYY inhibition effect on MiaPaCa-2 cell. PMID- 25533828 TI - Up-regulation of TIMP-2 expression promotes SHI-1 leukemic cells proliferation and infiltration in immunodeficiency mice. AB - BACKGROUND: MMPs and TIMPs play important roles in tumor angiogenesis and invasion. Studies have shown that TIMP-2 has two roles in tumor invasion. However, its role in leukemic infiltration has not been well investigated. This study explored the roles of TIMP-2 in extramedullary infiltration of acute monocytic leukemic SHI-1 cells both in vitro and in vitro. METHODS: A retroviral vector carrying the human TIMP-2 cDNA was constructed and transfected into the monocytic leukemic cell line SHI-1. The expression of TIMP-2 in the positive clones was determined. The proliferation of SHI-1 cells was examined by MTT assay. Trans-Matrigel invasion assays were used to investigate the infiltration ability in vitro. SHI-1 cells were intravenously injected into pre-treated nu/nu mice to investigate the infiltration ability feature in vitro. RESULTS: The expression of TIMP-2 on the cell membrane was significantly elevated in SHI 1/TIMP-2 cells. Over-expression of TIMP-2 promoted the cells proliferation and the invasions in vitro. The SHI-1/TIMP-2 cells demonstrated higher infiltration ability when intravenously injected into nu/nu mice. CONCLUSION: Over-expression of TIMP-2, especially on the cell membrane, may play important roles in promoting the proliferation and infiltration of SHI-1 leukemic cells. PMID- 25533829 TI - Calcium requirements for Chinese adults by cross-sectional statistical analyses of calcium balance studies: an individual participant data and aggregate data meta-regression. AB - BACKGROUND: Chinese dietary reference intakes for calcium are largely based on foreign studies. We undertook meta-regression to estimate calcium requirements for Chinese adults derived from calcium balance data in Chinese adults. METHODS: We searched PubMed, Cochrane CENTRAL, and SinoMed from inception to March 5, 2014, by using a structured search strategy. The bibliographies of any relevant papers and journals were also screened for potentially eligible studies. We extracted a standardized data set from studies in Chinese adults that reported calcium balance data. The relationship between calcium intake and output was examined by an individual participant data (IPD) and aggregate data (AD) meta regression. RESULTS: We identified 11 metabolic studies in Chinese adults within 18-60 years of age. One hundred and forty-one IPD (n = 35) expressed as mg/d, 127 IPD (n = 32) expressed as mg*kg body wt(-1)*d(-1), and 44 AD (n = 132) expressed as mg/d were collected. The models predicted a neutral calcium balance (defined as calcium output (Y) equal to calcium intake (C)) at intakes of 460 mg/d (Y = 0.60C+183.98) and 8.27 mg*kg body wt(-1)*d(-1) (Y = 0.60C+3.33) for IPD, or 409 mg/d (Y = 0.66C+139.00) for AD. Calcium requirements at upper intakes were higher than that at lower intakes in all these models. CONCLUSION: Calcium requirement for Chinese adults 18-60 years of age approximately ranges between 400 mg/d and 500 mg/d when consuming traditional plant-based Chinese diets. PMID- 25533830 TI - Current strategies in the diagnosis and management of chronic neutrophilic leukemia. AB - OBJECTIVE: To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia (CNL). DATA SOURCES: Data cited in this review were obtained mainly from PubMed and Medline from 1993 to 2013 and highly regarded older publications were also included. The terms "chronic neutrophilic leukemia" and "diagnosis" were used for the literature search. STUDY SELECTION: We identified, retrieved and reviewed the information on the clinical and laboratory features, the new genetic findings, prognosis and disease evolution and management of CNL. RESULTS: The discovery of high-frequency granulocyte-colony stimulating factor receptor (CSF3R) mutations in CNL identifies a new major diagnostic criterion, and lends more specificity to the World Health Organization (WHO) diagnostic criteria for CNL, which are variably applied in routine clinical practice. CONCLUSIONS: In patients for whom the cause of neutrophilia is not easily discerned, the incorporation of CSF3R mutation testing can be a useful point-of-care diagnostic to evaluate the presence of a clonal myeloid disorder, as well as providing the potential for genetically informed therapy. The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of the SRC family-TNK2 and JAK kinases and may provide a new avenue for therapy. PMID- 25533831 TI - Extracorporeal blood therapy in sepsis and acute respiratory distress syndrome: the "purifying dream". AB - OBJECTIVE: To discuss the rationale, hypothesis, modality of extracorporeal blood purification (EBP) techniques for the critically ill animal models or patients, and to summarize the experimental and clinical studies with inconsistent data which explored the EBP's efficacy in the areas of critical care medicine. DATA SOURCES: Articles referred in this review were collected from the database of PubMed published in English up to June 2014. STUDY SELECTION: We had done a literature search by using the term "(sepsis OR acute lung injury OR acute respiratory distress syndrome) AND (extracorporeal blood purification OR hemofiltration OR hemoperfusion OR plasma exchange OR plasmapheresis OR adsorpiton)". Related original or review articles were included and carefully analyzed. RESULTS: Acute cellular and humoral immune disturbances occur in both sepsis and acute respiratory distress syndrome (ARDS). Treatments aimed at targeting one single pro-/anti-inflammatory mediator have largely failed with no proven clinical benefits. Such failure shifts the therapeutic rationale to the nonspecific, broad-spectrum methods for modulating the over-activated inflammatory and anti-inflammatory response. Therefore, EBP techniques have become the potential weapons with high promise for removing the circulating pro /anti-inflammatory mediators and promoting immune reconstitution. Over the years, multiple extracorporeal techniques for the critically ill animal models or patients have been developed, including hemofiltration (HF), high-volume hemofiltration (HVHF), high-cutoff hemofiltration (HCO-HF), hemo-perfusion or adsorption (HP/HA), coupled plasma filtration adsorption (CPFA), and plasma exchange (PE). These previous studies showed that EBP therapy was feasible and safe for the critically ill animal models or patients. However, data on their efficacy (especially on the clinical benefits, such as mortality) were inconsistent. CONCLUSIONS: It is not now to conclude that EBP intervention can purify septic or ARDS patients with high clinical efficacy from current experimental and clinical practice. Prospective, randomized controlled, and well designed clinical or experimental studies and most suitable EBP modalities should be further developed. PMID- 25533833 TI - Application of non-invasive ventilation in China over 20 years. PMID- 25533832 TI - Understanding of myofascial trigger points. AB - OBJECTIVE: To investigate the current practice of myofascial pain syndrome (MPS) including current epidemiology, pathology, diagnosis and treatment. DATA SOURCES: The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed, MedSci, Google scholar. The terms "myofasial trigger points" and "myofacial pain syndrome" were used for the literature search. STUDY SELECTION: Original articles with no limitation of research design and critical reviews containing data relevant to myofascial trigger points (MTrPs) and MPS were retrieved, reviewed, analyzed and summarized. RESULTS: Myofascial pain syndrome (MPS) is characterized by painful taut band, referred pain, and local response twitch with a prevalence of 85% to 95% of incidence. Several factors link to the etiology of MTrPs, such as the chronic injury and overload of muscles. Other factors, such as certain nutrient and hormone insufficiency, comorbidities, and muscle imbalance may also maintain the MTrP in an active status and induce recurrent pain. The current pathology is that an extra leakage acetylcholine at the neuromuscular junction induces persistent contracture knots, relative to some hypotheses of integration, muscle spindle discharges, spinal segment sensitization, ect. MTrPs can be diagnosed and localized based on a few subjective criteria. Several approaches, including both direct and supplementary treatments, can inactivate MTrPs. Direct treatments are categorized into invasive and conservative. CONCLUSION: This review provides a clear understanding of MTrP pain and introduces the most useful treatment approaches in China. PMID- 25533834 TI - Questions on the pain, agitation, and delirium practice guidelines for adult critically ill patients. PMID- 25533835 TI - Examining influence of violence against physicians on Chinese medical students' career choice. PMID- 25533836 TI - Clinicopathological study and diagnosis of rhabdoid tumor of kidney combined with metanephric adenoma. PMID- 25533837 TI - Medical humanity: how do we learn it? PMID- 25533838 TI - A novel approach: treating corneal perforation with corneal lenticule. PMID- 25533839 TI - Re: establishment of novel rat models for premalignant breast disease. PMID- 25533840 TI - A rare case of complex anomalous origin of coronary arteries with severe atherosclerosis. PMID- 25533841 TI - Dominique Bergmann: passionate about plant polarity. PMID- 25533842 TI - DisAp-dependent striated fiber elongation is required to organize ciliary arrays. AB - Cilia-organizing basal bodies (BBs) are microtubule scaffolds that are visibly asymmetrical because they have attached auxiliary structures, such as striated fibers. In multiciliated cells, BB orientation aligns to ensure coherent ciliary beating, but the mechanisms that maintain BB orientation are unclear. For the first time in Tetrahymena thermophila, we use comparative whole-genome sequencing to identify the mutation in the BB disorientation mutant disA-1. disA-1 abolishes the localization of the novel protein DisAp to T. thermophila striated fibers (kinetodesmal fibers; KFs), which is consistent with DisAp's similarity to the striated fiber protein SF-assemblin. We demonstrate that DisAp is required for KFs to elongate and to resist BB disorientation in response to ciliary forces. Newly formed BBs move along KFs as they approach their cortical attachment sites. However, because they contain short KFs that are rotated, BBs in disA-1 cells display aberrant spacing and disorientation. Therefore, DisAp is a novel KF component that is essential for force-dependent KF elongation and BB orientation in multiciliary arrays. PMID- 25533843 TI - Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair. AB - Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1-SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1-SNF2H-mediated relaxation for DSB repair. ACF1-SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1-mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1-SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair. PMID- 25533845 TI - Osmotic surveillance mediates rapid wound closure through nucleotide release. AB - Osmotic cues from the environment mediate rapid detection of epithelial breaches by leukocytes in larval zebrafish tail fins. Using intravital luminescence and fluorescence microscopy, we now show that osmolarity differences between the interstitial fluid and the external environment trigger ATP release at tail fin wounds to initiate rapid wound closure through long-range activation of basal epithelial cell motility. Extracellular nucleotide breakdown, at least in part mediated by ecto-nucleoside triphosphate diphosphohydrolase 3 (Entpd3), restricts the range and duration of osmotically induced cell migration after injury. Thus, in zebrafish larvae, wound repair is driven by an autoregulatory circuit that generates pro-migratory tissue signals as a function of environmental exposure of the inside of the tissue. PMID- 25533846 TI - In situ growth of surfactant-free gold nanoparticles on nitrogen-doped graphene quantum dots for electrochemical detection of hydrogen peroxide in biological environments. AB - In this work, we report a green and simple strategy for the in situ growth of surfactant-free Au nanoparticles (Au NPs) on nitrogen-doped graphene quantum dots (Au NPs-N-GQDs). The formation of hybrid was achieved by just mixing the N-GQDs and HAuCl4.4H2O without addition of any other reductant and surfactant. High resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) characterizations clearly showed the formation of Au nanoparticles with predominantly exposed (111) facets which can provide more adsorption sites. Such nonsurfactant-capped Au NPs can provide naked catalytic surface with highly electrocatalytic activity. The Au NPs-N-GQDs exhibit high sensitivity and selectivity for electrochemical detection of hydrogen peroxide (H2O2) with a low detection limit of 0.12 MUM and sensitivity of 186.22 MUA/mM cm(2). Importantly, the Au NPs-N-GQDs-based electrochemical biosensor has shown great potential applications for detection of H2O2 levels in human serum samples and that released from human cervical cancer cells with satisfactory results. The present study demonstrates that such novel Au NPs-N GQDs nanocomposite is promising for fabrication of nonenzymatic H2O2 biosensors. PMID- 25533844 TI - A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport. AB - Axon growth requires long-range transport of organelles, but how these cargoes recruit their motors and how their traffic is regulated are not fully resolved. In this paper, we identify a new pathway based on the class III PI3-kinase (PIK3C3), ankyrin-B (AnkB), and dynactin, which promotes fast axonal transport of synaptic vesicles, mitochondria, endosomes, and lysosomes. We show that dynactin associates with cargo through AnkB interactions with both the dynactin subunit p62 and phosphatidylinositol 3-phosphate (PtdIns(3)P) lipids generated by PIK3C3. AnkB knockout resulted in shortened axon tracts and marked reduction in membrane association of dynactin and dynein, whereas it did not affect the organization of spectrin-actin axonal rings imaged by 3D-STORM. Loss of AnkB or of its linkages to either p62 or PtdIns(3)P or loss of PIK3C3 all impaired organelle transport and particularly retrograde transport in hippocampal neurons. Our results establish new functional relationships between PIK3C3, dynactin, and AnkB that together promote axonal transport of organelles and are required for normal axon length. PMID- 25533847 TI - Genetic diversity of Rhizobium from nodulating beans grown in a variety of Mediterranean climate soils of Chile. AB - In spite of potentially being an important source of rhizobial diversity and a key determinant of common bean productivity, there is a paucity of data on Rhizobium genetic variation and species composition in the important bean producing area of Chile and only one species has been documented (Rhizobium leguminosarum). In this study, 240 Rhizobium isolates from Torcaza bean (Phaseolus vulgaris L.) nodules established in the highest bean producing area in Chile (33 degrees 34'S-70 degrees 38'W and 37 degrees 36'S-71 degrees 47'W) were characterized by PCR-RFLP markers for nodC gene, revealing eight banding patterns with the polymorphic enzyme Hinf I. The locality of San Agustin de Aurora in Central Chile (35 degrees 32'S-71 degrees 29'W) had the highest level of diversity. Isolates were classified by species using PCR-RFLP markers for 16S rDNA gene and were confirmed by sequencing an internal fragment of the 16S rDNA gene. The results confirmed the presence of R. leguminosarum and three other species of rhizobia nodulating beans in South Central Chile (R. etli, R. tropici and R. leucaenae). R. tropici and R. leucaenae showed the least genetic variation and were most commonly identified in acid soils, while R. etli was the most common species in slightly acidic to moderately alkaline soils, with higher levels of organic matter content. R. leguminosarum was identified in almost all soils, was the most genetically diverse, and was the most common, being documented in soils with pH that ranged between 5.3 and 8.2, and with organic matter content between 2.1 and 4 %. PMID- 25533848 TI - Microbial taxonomy in the post-genomic era: rebuilding from scratch? AB - Microbial taxonomy should provide adequate descriptions of bacterial, archaeal, and eukaryotic microbial diversity in ecological, clinical, and industrial environments. Its cornerstone, the prokaryote species has been re-evaluated twice. It is time to revisit polyphasic taxonomy, its principles, and its practice, including its underlying pragmatic species concept. Ultimately, we will be able to realize an old dream of our predecessor taxonomists and build a genomic-based microbial taxonomy, using standardized and automated curation of high-quality complete genome sequences as the new gold standard. PMID- 25533849 TI - Effect of starvation on survival and virulence expression of Aeromonas hydrophila from different sources. AB - Aeromonas hydrophila is an aquatic bacterium responsible for several human illnesses. The aim of this work was to investigate the survival ability and virulence expression of two strains from different sources (fish, strain 87 and surface water, strain LS) maintained in a seawater microcosm. The strains were analyzed for the total and viable bacterial counts, adhesion ability to Hep-2 cells and aerA gene expression by qPCR throughout the experiment (35 days). Both strains reached a putative VBNC state and lost adhesive properties but exhibited a different behavior in the expression of aerA. This could be due to the different origin of the two strains; the former adapted to a habitat rich of nutrient and the latter already used to survive in a more hostile environment. Moreover, our results indicate that the quantitative determination of aerA mRNA can be a useful indicator of virulence expression under stress conditions. PMID- 25533851 TI - Interprofessional competencies in the curriculum: Interpretations of educators from five health professions. AB - Interprofessional (IP) practice embraces a range of collaborations among health professionals that includes referral networks, case management, and simultaneous co-management models of healthcare. How IP competencies are interpreted and enacted in the curriculum falls to health educators. The aim of this research was to examine health educators' interpretations of IP competencies in five health professions (chiropractic, naturopathy, osteopathy, physiotherapy, and podiatry) in Australia. Semi-structured interviews were conducted with six educators. Transcripts were analysed using constant comparison to identify emergent themes. A number of interpretations of IP practice were evident (e.g. knowing professional scopes of practice and when to refer, and co-assessing and co managing patients). Lack of resources limited IP practice enactment in the curriculum, including complementary medicine participation in IP teams. PMID- 25533850 TI - Characterization of a novel reassortant influenza A virus (H2N2) from a domestic duck in Eastern China. AB - While H2N2 viruses have been sporadically isolated from wild and domestic birds, H2N2 viruses have not been detected among human populations since 1968. Should H2N2 viruses adapt to domestic poultry they may pose a risk of infection to people, as most anyone born after 1968 would likely be susceptible to their infection. We report the isolation of a novel influenza A virus (H2N2) cultured in 2013 from a healthy domestic duck at a live poultry market in Wuxi City, China. Sequence data revealed that the novel H2N2 virus was similar to Eurasian avian lineage avian influenza viruses, the virus had been circulating for >= two years among poultry, had an increase in alpha2,6 binding affinity, and was not highly pathogenic. Approximately 9% of 100 healthy chickens sampled from the same area had elevated antibodies against the H2 antigen. Fortunately, there was sparse serological evidence that the virus was infecting poultry workers or had adapted to infect other mammals. These findings suggest that a novel H2N2 virus has been circulating among domestic poultry in Wuxi City, China and has some has increased human receptor affinity. It seems wise to conduct better surveillance for novel influenza viruses at Chinese live bird markets. PMID- 25533852 TI - Examining the perceived social support and psychological symptoms among adolescents with leukemia. AB - PURPOSE: The purpose was to determine the perceived social support and psychological symptoms of adolescents with leukemia. DESIGN AND METHODS: The sample consisted of 70 adolescents with leukemia. The Brief Symptom Inventory (BSI), Multidimensional Perceived Social Support Scale (MPSSS), and a demographical data form were used for data collection. RESULTS: Scores of the Global Severity Index, Positive Symptom Distress Index (PSDI), and Positive Symptom Total (PST) of the BSI were higher than those of the healthy adolescents with the same age in other studies. There was a negative relationship between the MPSSS and negative self-image, depression, anxiety, PSDI, and PST of the BSI. PRACTICE IMPLICATIONS: It would likely be beneficial to increase adolescents' perceived social support in order to decrease psychological symptoms. PMID- 25533853 TI - Postimplant Shocks in a Totally Subcutaneous Defibrillator: What Is the Mechanism? PMID- 25533854 TI - Dietary quality in people with type 1 and type 2 diabetes compared to age, sex and BMI matched controls. AB - A case-control analysis involving 98 individuals with diabetes and 98 age, sex and BMI matched controls was conducted to determine dietary quality and adherence to dietary recommendations. Diet quality was comparable and intake of fat, saturated fat, fibre, fruit and vegetables did not meet recommendations in both groups. PMID- 25533855 TI - Patient characteristics predicting failure to receive indicated care for type 2 diabetes. AB - AIMS: To determine which patient characteristics were associated with failure to receive indicated care for diabetes over time. METHODS: English Longitudinal Study of Ageing participants aged 50 or older with diabetes reported receipt of care described by four diabetes quality indicators (QIs) in 2008-9 and 2010-11. Annual checks for glycated haemoglobin (HbA1c), proteinuria and foot examination were assessed as a care bundle (n=907). A further QI (n=759) assessed whether participants with cardiac risk factors were offered ACE inhibitors or angiotensin II receptor blockers (ARBs). Logistic regression modelled associations between failure to receive indicated care in 2010-11 and participants' socio-demographic, lifestyle and health characteristics, diabetes self-management knowledge, health literacy, and previous QI achievement in 2008-9. RESULTS: A third of participants (2008-9=32.8%; 2010-11=32.2%) did not receive all annual checks in the care bundle. Nearly half of those eligible were not offered ACE inhibitors/ARBs (2008 9=44.6%; 2010-11=44.5%). Failure to receive a complete care bundle was associated with lower diabetes self-management knowledge (odds ratio (OR) 2.05), poorer cognitive performance (1.78), or having previously received incomplete care (3.32). Participants who were single (OR=2.16), had low health literacy (1.50) or had received incomplete care previously (6.94) were more likely to not be offered ACE inhibitors/ARBs. Increasing age (OR=0.76) or body mass index (OR=0.70) was associated with lower odds of failing to receive this aspect of care. CONCLUSIONS: Quality improvement initiatives for diabetes might usefully target patients with previous receipt of incomplete care, poor knowledge of annual diabetes care processes, and poorer cognition and health literacy. PMID- 25533856 TI - Familial thrombotic risk based on the genetic background of Protein C Deficiency in a Portuguese Study. AB - INTRODUCTION: Inherited protein C (PC) deficiency is a well-known risk factor for venous thrombosis (VT). Plasma PC levels are reliable in moderate to severe deficiencies; however, in mildly deficient individuals, the levels may overlap with those considered normal. Genetic studies of PROC, which encodes PC, could help identify carriers; genome-wide association studies (GWAS) have shown that approximately 50% of phenotypic variation in PC deficiency is caused by the cumulative effects of mutations in several other loci, namely in the PROCR. PATIENTS AND METHODS: With the main objective of determining the genotype/phenotype correlation in 59 Portuguese individuals from 26 unrelated families with history of thrombosis and repeatedly low/borderline PC plasma levels, we conducted a molecular study by direct sequencing of PROC; PROC promoter haplotypes and PROCR c.4600A>G polymorphism (rs867186), which are known to influence plasma PC concentrations, were also screened. RESULTS: Twelve different PROC mutations were identified, one of them not previously reported, p.Cys105Arg. The mutation types and locations as well as haplotype combinations correlated with the phenotypic severity. The most frequent mutation, p.Arg199X, correlated with the CGTC haplotype and was identified in nine families containing patients with higher numbers of VT episodes. This mutation in homozygous individuals for the CGTC haplotype is a significant risk factor for VT in Portuguese. CONCLUSION: These genetic family studies allowed the identification of the unknown carriers and individuals at a higher thrombotic risk within each family, thus permitting the evaluation of the need for prophylactic measures, particularly in at-risk situations. PMID- 25533858 TI - Towards ending HIV/AIDS among drug users in China. PMID- 25533857 TI - Surgical treatment of sacral chordoma: prognostic variables for local recurrence and overall survival. AB - PURPOSE: Sacral chordomas (SC) are rare, locally invasive, malignant neoplasms. Despite surgical resection and adjuvant therapies, local recurrence (LR) is common and overall survival (OS) is poor. The objective of this study was to identify prognostic factors that have an impact on the local recurrence-free survival (LRFS) and OS of patients with SC. METHODS: Utilizing the AOSpine Knowledge Forum Tumor multicenter ambispective database, surgically treated SC cases were identified. Cox regression modeling was used to assess the effect of several clinically relevant variables on OS and LRFS. RESULTS: A total of 167 patients with surgically treated SC were identified. The male/female ratio was 98/69 with a mean age of 57 +/- 15 years at the time of surgery. The LR was 35% (n = 57), death occurred in 30% of patients (n = 50) during the study period. The median OS was 6 years post-surgery and LRFS was 4 years. In the univariate analysis, previous tumor surgery at the same site (P = 0.002), intralesional resection (P < 0.001), and larger tumor volume (P = 0.030) were significantly associated with LR. Increasing age (P < 0.001) and a preoperative motor deficit of C or D (P = 0.003) were significantly associated with poor OS, and nerve root sacrifice showed a trend towards significance (P = 0.088). In the multivariate models, previous surgery and intralesional resection were significantly related to LR, while increasing age and motor deficit of C or D were associated with poor OS. CONCLUSIONS: This study identified two predictive variables for LRFS (previous tumor surgery and type of surgical resection) and two for OS (age and impaired motor function) in surgically treated SC patients. Our results indicate that en bloc resection reduces LR but does not influence OS. However, this was likely due to short follow-up (3.2 years). PMID- 25533859 TI - Tracking the evolution of drug abuse in China, 2003-10: a retrospective, self controlled study. AB - AIM: To characterize trends in drug abuse in China before and after the 2005 initiation of the 'People's War on Drugs'. DESIGN: Retrospective self-controlled study. SETTING: Annual, nation-wide surveillance from 2003 to 2010 of all registered drug users in China's National Surveillance System on Drug Abuse (NSSDA). PARTICIPANTS: A total of 1,184,124 drug users registered in NSSDA were involved in this study and were classified into three groups based on registered dates-pre-war group (n=230,278) registered 2003-04, phase I group (n=518,651) registered 2005-07 and phase II group (n=435,195) registered 2008-10. MEASUREMENTS: Indicators included proportions of:(i) new and relapsed drug users, (ii) heroin and synthetic drug users among new users, (iii) people aged 35 years or younger and (iv) women. Comparisons were made across groups using annual data to describe temporal trends. FINDINGS: Between 2003 and 2010 the proportion of heroin users decreased by 52.3% and synthetic drugs use increased 860.7% among new users, while a 12.8% decrease in the proportion of heroin users and a 918.8% increase in synthetic drug use in all users was detected. Compared with the pre war group, the proportion of relapsed users decreased 2.6% and 29.1% in the phase I and phase II groups, respectively, but a significant increase in the proportion of new users was found in phase I (OR=1.24, CI=1.15-1.35, p<0.0001), followed by an apparent decrease in phase II compared with phase I (OR=0.75, CI=0.70-0.80, p<0.0001). Similarly, the proportion of heroin users decreased 15.1 and 24.2% among new drug users in phase I and phase II in comparison with the pre-war group. CONCLUSION: The decrease in proportions of drug users in China between 2003/4 and 2008/10 may suggest some positive influence of the 'People's War on Drugs', especially in the decreased proportion of relapsed users. In contrast, there was a rapid increase in new synthetic drug use over the same period. PMID- 25533860 TI - Club drug use and associated high-risk sexual behaviour in six provinces in China. AB - AIM: To investigate the characteristics of the different club drugs and associated high-risk sexual behaviours in China. DESIGN: Multicentre cross sectional study. SETTING: Drug Detoxification and Rehabilitation Centres in six provinces, China. PARTICIPANTS: A total of 1434 eligible club drug users were included. MEASUREMENTS: Participants were investigated by trained interviewers using a self-designed structured questionnaire to collect information on club drug use and associated behaviours. FINDINGS: Methamphetamine was the most commonly abused drug in participants (73.92%), who used it in their or their friends' homes by non-injection for the purpose of feeling euphoria. Among participants with sexual behaviours after club drug use, 75.21% reported having engaged in sex with multiple partners after club drug use during the past year and 79.84% had unprotected sex after using club drug during the past year. A two level logistic model showed that male gender [adjusted odds ratio (AOR)=7.14; 95% confidence interval (CI)=4.17-12.5], unmarried (AOR=1.71, 95% CI=1.04-2.79), long duration of club drug use during their life-time (AOR=1.76, 95% CI=1.28-2.42) and severe acute intoxication after using club drugs during the past year (AOR=2.11, 95% CI=1.07-4.15) were independent risk factors of multiple sex partners during the past year. Another two-level model showed that the club drug users who were female (AOR=1.79, 95% CI=1.03-3.11) and had polydrug use during their lifetime (AOR=1.55, 95% CI=1.01-2.34) had more risk for unprotected sex during the past year than without these characteristics. CONCLUSION: High-risk sexual behaviours are common among club drug users in China. The prevention and intervention of club drug use could decrease the risk of sexual behaviours which further prevent HIV transmission and other sexually transmitted infections in China. PMID- 25533861 TI - HIV epidemic among drug users in China: 1995-2011. AB - AIM: To describe trends in the HIV epidemic among drug users (DUs) in China from 1995 to 2011. DESIGN, SETTING AND PARTICIPANTS: Data sets from China's national HIV/AIDS case reporting and sentinel surveillance systems as of December 2011 were used separately for descriptive analysis. MEASURES: Changes in the geographic distribution of the number of HIV cases and HIV prevalence among injecting drug users (IDUs) and non-IDUs were examined. We also analysed changes in HIV prevalence among the broader DU population, and drug use-related behaviours including types of drugs used, recent injecting and recent needle sharing in the context of the rapid scale-up of DU sentinel sites and national harm reduction programmes. FINDINGS: The HIV epidemic among China's DUs is still highly concentrated in five provinces. Here, HIV prevalence peaked at 30.3% [95% confidence interval (CI)=28.6, 32.1] among IDUs in 1999, and then gradually decreased to 10.9% (95% CI=10.6, 11.2) by 2011. We observed a rapid increase in the use of 'nightclub drugs' among DUs from 1.3% in 2004 to 24.4% in 2011. A decline in recent needle sharing among current IDU from 19.5% (95% CI=19.4, 19.6) in 2006 to 11.3% (95% CI=11.2, 11.4) in 2011 was found to be correlated with the rapid scale-up of methadone maintenance treatment (MMT; r(4)=-0.94, P=0.003) harm reduction efforts. CONCLUSIONS: While HIV prevalence and needle sharing among current injecting drug users in China have declined dramatically and are correlated with the scale-up of national harm reduction efforts, the recent, rapid increased use of 'nightclub drugs' presents a new challenge. PMID- 25533862 TI - Who uses methadone services in China? Monitoring the world's largest methadone programme. AB - AIMS: To describe the data collected by the Chinese methadone maintenance treatment (MMT) system and the characteristics of clients entering the programme. DESIGN: Descriptive study using routinely collected data from the MMT data management system for the period March 2004 and March 2010. SETTING: All MMT clinics in China. PARTICIPANTS: Clients who enrolled for services between March 2004 and March 2010. MEASUREMENTS: Routinely collected data included: demographic information; drug use, sexual and criminal behaviours; status of infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) and syphilis; random urine-opiate test results; and the daily methadone dose received. Differences among clients by year were examined. FINDINGS: During the period examined, there were 251,974 clients attending 684 clinics in 27 provinces. Overall, the mean age was 34.4 years, 83.8% were male, 70.2% were unemployed, 75% had ever injected drugs, 17% had shared needles and 7.4% were HIV-positive. The profile of clients changed over time, with fewer HIV-positive individuals, fewer injecting drug users, fewer needle-sharers, fewer females and fewer unemployed. Half the clients dropped out within 6 months. The average final dose received was 49.4 mg. The estimated probability of interrupting treatment before 6 months was 52.5%. CONCLUSIONS: The profile of clients enrolling in methadone maintenance treatment in China is continually changing and appears to be associated with reduced risk of HIV. High dropout in the programme may limit its effectiveness. The availability of a centralized, real-time data system was extremely useful for monitoring the progress of the Chinese methadone maintenance treatment programme. PMID- 25533864 TI - Factors associated with depression and anxiety among patients attending community based methadone maintenance treatment in China. AB - AIM: To estimate the prevalence of, and identify factors associated with, depression and anxiety among community-based methadone maintenance treatment (MMT) clients in China. DESIGN: A cross-sectional survey. SETTING: Nine MMT clinics, three each from three Chinese provinces (Yunnan, Anhui and Jiangsu) between October 2008 and February 2009. PARTICIPANTS: A total of 1301 MMT clients. MEASUREMENTS: A questionnaire, including the Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Anxiety Scale (SAS), and on-site urine drug testing. FINDINGS: The prevalence of depression (SDS score>=53) and anxiety (SAS score>=50) in our sample was 38.3% [95% confidence interval (CI)=35.7, 40.9] and 18.4% (95% CI=16.3, 20.5), respectively, with 14.2% (95% CI=12.3, 16.1) displaying symptoms of both. Sample prevalence rates for depression [mean=49.69, standard deviation (SD)=10.34] and anxiety (mean=40.98, SD=10.66) were higher than the national average for each (t(0.05/2, 1300)=19.2, P<0.001 and t(0.05/2, 1300)=8.0, P<0.001, respectively). Employing multi-level modelling techniques, gender (P=0.03) and employment status (P<0.001) were found to be associated significantly with depression in a single-level model; however, in a multi-level mixed model, only employment status (P<0.001) was associated with depression. Gender (P=0.03), education level (P=0.02), marital status (P=0.04), employment status (P<0.001), positive urine drug test results (P=0.02) and daily methadone dose (P<0.001) were found to be associated significantly with anxiety in a single level model, while only employment status (P<0.01) and positive results for the urine drug test (P=0.04) were associated with anxiety in a multi-level mixed model. CONCLUSIONS: A considerable proportion of methadone maintenance treatment clients in China have experienced depression and anxiety during treatment. There is a need to provide tailored mental health interventions for this high-risk population. PMID- 25533863 TI - Predictors of accessing antiretroviral therapy among HIV-positive drug users in China's National Methadone Maintenance Treatment Programme. AB - AIMS: The objective of this study was to examine factors that predict antiretroviral therapy (ART) access among eligible, HIV-positive methadone maintenance treatment (MMT) clients. We also tested the hypothesis that sustained MMT participation increases the likelihood of accessing ART. DESIGN: A nation wide cohort study conducted from 1 March 2004 to 31 December 2011. SETTING: MMT clients were followed from the time of their enrolment in China's national MMT programme until their death or the study end date. PARTICIPANTS: Our cohort comprised 7111 ART-eligible, HIV-positive MMT clients, 49.2% of whom remained ART naive and 50.8% of whom received ART. MEASUREMENTS: Demographic variables, drug use history, MMT programme participation and HIV-related clinical characteristics of study participants who remained naive to ART and those who accessed ART were compared by univariate and multivariable analysis. FINDINGS: Predictors of accessing ART among this cohort included being retained in MMT at the time of first meeting ART eligibility [adjusted odds ratio (AOR)=1.84, confidence interval (CI)=1.54-2.21, P<0.001] compared to meeting ART eligibility before entering MMT (AOR=0.98, CI=0.80-1.21, P=0.849) or previously entering MMT and dropping out before meeting ART eligibility. Additional predictors were CD4<=200 cells/MUl when ART-eligibility requirement was first met (AOR=1.81, CI=1.61-2.05, P<0.001 compared to CD4=201-350 cells/MUl), and being in a stable partner relationship (married/cohabitating: AOR=1.14, CI=1.01-1.28, P=0.030). CONCLUSIONS: Retained participation in methadone maintenance treatment increases the likelihood that eligible clients will access antiretroviral therapy. These results highlight the potential benefit of colocalization of methadone maintenance treatment and antiretroviral therapy services in a 'one-stop-shop' model. PMID- 25533865 TI - Needle and syringe exchange programmes and prevalence of HIV infection among intravenous drug users in China. AB - AIM: To examine the association between needle and syringe exchange programme (NSEP) participation and human immunodeficiency virus (HIV) infection among intravenous drug users (IDUs) in China. DESIGN: Cross-sectional survey study design. SETTING: Six counties with active NSEP were selected from each of the seven provinces with active NSEP sampled, resulting in a sample of 42 counties in China. PARTICIPANTS: Subjects were aged more than 18 years and had injected drugs in the past month before the survey, but were excluded if they were currently enrolled in methadone maintenance treatment in order to avoid mixed effects. MEASUREMENTS: HIV prevalence was the primary measure. Odds ratios (ORs), 95% confidence intervals (CIs) and P-values were calculated to evaluate associations between HIV infection and NSEP participation. FINDINGS: A total of 3494 IDUs were interviewed, of whom 1928 (55.2%) were NSEP attendees (meaning they had attended NSEP at least once in their life-time). The unadjusted HIV prevalence was 13.9% among NSEP attendees and 16.5% among NSEP non-attendees (meaning IDUs who had never used NSEP services). After adjusting for potential confounders and taking into account the variation between counties, NSEP non-attendees were 1.67 times more likely to be HIV-positive compared to NSEP attendees (OR=1.67, CI=1.19-2.32, P=0.0031). CONCLUSIONS: Participation in needle and syringe exchange programmes was associated with a substantially lower risk of HIV infection among intravenous drug users in China. Needle and syringe exchange programmes should be expanded to include those who are needle and syringe exchange programme non-attendees. PMID- 25533867 TI - Heart failure symptom clusters and functional status - a cross-sectional study. AB - AIM: To identify symptom clusters in individuals with heart failure and evaluate the relationship of the identified clusters to functional status. BACKGROUND: Heart Failure is a global health problem affecting approximately 1-2% of the adult population in developed countries worldwide. Individuals with heart failure may experience as many as nine symptoms and may limit activities that worsen their symptoms or adjust the way they engage in activities. DESIGN: Cross sectional. METHODS: A convenience sample of individuals (n = 117) with a confirmed diagnosis of heart failure was recruited from an academic medical centre during 2011-2012. Prevalent heart failure symptoms and functional status outcomes (functional limitations and mobility) were evaluated. Factor analysis using the principal components method was used to extract symptom clusters. Regression analysis using a backwards stepwise model-building approach was used to examine the effects of the symptom clusters, age and co-morbidity on functional limitations and mobility. RESULTS: Three symptom clusters, sickness behaviour, discomforts of illness and gastrointestinal distress were extracted. When sickness behaviours and discomforts of illness were both present, functional limitations were more sensitive to sickness behaviours. Sickness behaviour and co morbidity were related to limited mobility. CONCLUSIONS: Individuals with heart failure may be helped to improve their functional status by managing sickness behaviour and discomforts of illness symptoms. Identification of symptom clusters may lead to the development of interventions focusing on a cluster of heart failure symptoms. PMID- 25533866 TI - Health promotion interventions and policies addressing excessive alcohol use: a systematic review of national and global evidence as a guide to health-care reform in China. AB - AIMS: Steady increases in alcohol consumption and related problems are likely to accompany China's rapid epidemiological transition and profit-based marketing activities. We reviewed research on health promotion interventions and policies to address excessive drinking and to guide health-care reform. METHODS: We searched Chinese- and English-language databases and included 21 studies in China published between 1980 and 2013 that covered each policy area from the World Health Organization (WHO) Global Strategy to Reduce the Harmful Use of Alcohol. We evaluated and compared preventive interventions to the global alcohol literature for cross-national applicability. RESULTS: In contrast with hundreds of studies in the global literature, 11 of 12 studies from mainland China were published in Chinese; six of 10 in English were on taxation from Taiwan or Hong Kong. Most studies demonstrated effectiveness in reducing excessive drinking, and some reported the reduction of health problems. Seven were randomized controlled trials. Studies targeted schools, drink-driving, work-places, the health sector and taxation. CONCLUSIONS: China is the world's largest alcohol market, yet there has been little growth in alcohol policy research related to health promotion interventions over the past decade. Guided by a public health approach, the WHO Global Strategy and health reform experience in Russia, Australia, Mexico and the United States, China could improve its public health response through better coordination and implementation of surveillance and evidence-based research, and through programmatic and legal responses such as public health law research, screening and early intervention within health systems and the implementation of effective alcohol control strategies. PMID- 25533868 TI - Barriers and facilitators to early mobilisation in Intensive Care: a qualitative study. AB - OBJECTIVES: To determine the barriers and facilitators of early mobilisation in the Intensive Care Unit. BACKGROUND: It is well established that mobilising critically ill patients has many benefits, however it is not occurring as frequently as expected. The causes and ways to change this are not clearly understood. METHODS: A qualitative descriptive study involving focus groups with medical, nursing and physiotherapy clinicians, from an Australian quaternary hospital Intensive Care Unit. RESULTS: The major themes related to barriers included the culture of the Intensive Care Unit; communication; and a lack of resources. Major themes associated with facilitating early mobilisation included organisational change; improved communication between medical units; and improved resources. CONCLUSIONS: Early mobilisation was considered an important aspect of critically ill patient's care by all clinicians. Several major barriers to mobilisation were identified, which included unit culture, lack of resources, prioritisation and leadership. A dedicated mobility team led by physiotherapists in the ICU setting could be a viable option to address the identified barriers related to mobility. PMID- 25533869 TI - Medical treatment of ureteral obstruction associated with ovarian remnants and/or endometriosis: report of three cases and review of the literature. AB - STUDY OBJECTIVE: Experience with low-dose intermittent danazol or prolonged gonadotropin-releasing hormone agonist (GnRH-a) with and without add-back therapy in endometriosis-associated ureteral obstruction. DESIGN: Retrospective case series (Canadian Task Force classification II-2). SETTING: University-affiliated teaching hospital. PATIENTS: Three women with endometriosis-associated ureteral obstruction. INTERVENTION: The regimen of GnRH-a alone or with add-back included (1) leuprolide acetate 3.75 mg intramuscularly monthly; (2) micronized 17alpha estradiol 1 mg/day by mouth; (3) pulsed norethinedrone 0.35 mg/day by mouth, 2 days on and/or 2 days off; and (4) letrozole 2.5 mg by mouth for the first 5 days of the first GnRH-a injection. Danazol, 100 mg/day by mouth, was prescribed as a regimen of 3 months on, 3 months off, for 4 years. MEASUREMENTS AND MAIN RESULTS: The first case was a 50-year-old woman, gravida 3, para 3, body mass index (BMI) 27 kg/m(2), with multiple surgeries, including hysterectomy and bilateral salpingo-oophorectomy (HBSO), and history of a stroke. She presented with right sided pain and hydro-uretero-nephrosis. Magnetic resonance imaging identified a right adnexal cyst (4.5 * 3.4 * 2.4 cm). She was treated with leuprolide acetate monthly injections and a ureteric stent. The cyst, pain, and hydro-uretero nephrosis resolved after 12 months. The second case was a 45-year-old woman, G2P2, BMI 28 kg/m(2) with multiple surgeries, including HBSO. She presented with left-sided pelvic pain. Ultrasound identified a left adnexal cyst and hydronephrosis. After 3 months of leuprolide acetate and add-back therapy, the cyst, pain, and hydronephrosis resolved. The third case was a 46-year-old woman, G2P2, BMI 25 kg/m(2), who presented with left flank and pelvic pain. Magnetic resonance imaging indicated moderate left hydronephrosis and left adnexal pelvic side-wall involvement with possible endometriosis. Due to many previous surgeries, this patient was a high-risk surgical candidate, and therefore, she was offered medical therapy. After a normal serum liver and lipid profile, she was started on danazol, 100 mg/day for 3 months. After 3 months of therapy, there was complete resolution of the patient's hydronephrosis and pain. She was then advised to continue with a 3-month on, 3-month off regimen. She discontinued the danazol and remained asymptomatic with no recurrence of hydronephrosis at 3 years. CONCLUSIONS: Low-dose intermittent danazol or GnRH-a alone or with add back, may be effective long-term therapies in endometriosis-associated ureteral obstruction when surgery is contraindicated, refused, or difficult to perform. PMID- 25533870 TI - Taking pills for developmental ails in Southern Brazil: The biologization of adolescence? AB - In the late 1990s researchers in Pelotas Southern Brazil began documenting what they considered to be unacceptably high rates of licensed psychotropic use among individuals of all ages, including youth. This came as a surprise, since the vast majority of psychiatrists in Pelotas draw on psychoanalytic theory and approach pharmaceutical use, especially for children and adolescents, in a consciously tempered way. Drawing from a longitudinal ethnographic sub-study, part of a larger 1982 birth cohort study, this paper follows the circuitous trajectories of emergent pharma-patterns among "shantytown" youth over a ten-year period, exploring the thickly layered and often moralized contingencies in which psychodynamic psychiatrists' intention to resist excessive pharmaceuticalization both succeed and crumble. I juxtapose these trajectories with the growing salience of an "anti-biologizing" explanatory framework that psychiatrists and researchers are using to pre-empt the kind of diagnostics-driven "biopsychiatrization" so prevalent in North America. My analysis suggests that psychiatrists' use of this framework ironically contributes to their failed attempts to "resist" pharmaceuticalization. PMID- 25533871 TI - Drugs, cancer and end-of-life care: a case study of pharmaceuticalization? AB - There is evidence from some countries of a trend towards increasingly aggressive pharmacological treatment of patients with advanced, incurable cancer. To what extent should this be understood as a progressive development in which technological innovations address previously unmet needs, or is a significant amount of this expansion explained by futile or even harmful treatment? In this article it is argued that while some of this growth may be consistent with a progressive account of medicines consumption, part of the expansion is constituted by the inappropriate and overly aggressive use of drugs. Such use is often explained in terms of individual patient consumerism and/or factors to do with physician behaviour. Whilst acknowledging the role of physicians and patients' expectations, this paper, drawing on empirical research conducted in the US, the EU and the UK, examines the extent to which upstream factors shape expectations and drive pharmaceuticalisation, and explores the value of this concept as an analytical tool. PMID- 25533874 TI - Microneedles for drug delivery: trends and progress. AB - In recent years, there has been a surge in the research and development of microneedles (MNs), a transdermal delivery system that combines the technology of transdermal patches and hypodermic needles. The needles are in the hundreds of micron length range and therefore allow relatively little or no pain. For example, biodegradable MNs have been researched in the literature and have several advantages compared with solid or hollow MNs, as they produce non-sharp waste and can be designed to allow rapid or slow release of drugs. However, they also pose a disadvantage as successful insertion into the stratum corneum layer of the skin relies on sufficient mechanical strength of the biodegradable material. This review looks at the various technologies developed in MN research and shows the rapidly growing numbers of research papers and patent publications since the first invention of MNs (using time series statistical analysis). This provides the research and industry communities a valuable synopsis of the trends and progress being made in this field. PMID- 25533872 TI - Pharmacologic modulation of hand pain in osteoarthritis: a double-blind placebo controlled functional magnetic resonance imaging study using naproxen. AB - OBJECTIVE: In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint. METHODS: A placebo controlled, double-blind, 2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between-period differences in brain activity. RESULTS: Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity. CONCLUSION: This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain. PMID- 25533873 TI - Stroke physician versus stroke neurologist: can anyone thrombolyse? AB - BACKGROUND/AIM: The aim of this study is to compare the outcomes of thrombolysis under standard clinical settings between subjects treated by a stroke neurologist versus those treated by a non-neurologist stroke physician. METHODS: Single centre, observational cohort study of subjects thrombolysed in a calendar year, stratified according to the physician type authorising thrombolysis. Endpoints measured include proportion of subjects with symptomatic intracranial haemorrhage, door-to-needle time, change in National Institute of Health Stroke Scale and discharge destination. RESULTS: Forty-nine subjects with a mean age 76 +/- 16 years underwent thrombolysis, 21 were under the care of a stroke neurologist and 28 by a non-neurologist stroke physician. No symptomatic intracranial haemorrhages were observed. There was no difference in terms of door to-needle time, proportion of individuals with haemorrhagic transformation, mortality or discharge destination between the two groups. CONCLUSION: Due to the single-centre, observational nature of this study, the equivalent outcomes between those thrombolysed by a stroke neurologist versus those thrombolysed by a stroke physician must be interpreted with caution pending further studies. Nevertheless, in the current setting, no signal for harm has been detected. This study is unique as it is the first to our knowledge comparing outcomes between a neurologist and non-neurologist following thrombolysis. PMID- 25533875 TI - Potential transbuccal delivery of l-DOPA methylester prodrug: stability in the environment of the oral cavity and ability to cross the mucosal tissue. AB - Levodopa (l-DOPA) is the most effective pharmacologic agent in Parkinson's disease and remains the "gold standard". Nevertheless, in long-term treatments, dyskinesias and motor complications can emerge. In this work, the combined use of l-DOPA methylester hydrochloride prodrug (LDME) with transbuccal drug delivery was supposed as a good alternative method to optimize the bioavailability of l DOPA, to maintain constant plasma levels and to decrease the drug unwanted effects. The effects of environmental pH on buccal delivery of LDME were evaluated ex vivo. The increase of pH value from 5.8 to 6.2 implies an improvement of drug permeation. Since the pH increase causes the raising of hydrolytic conversion of LDME to l-DOPA, the pH value 6.2 was considered as a good compromise between drug stability and permeation rate. It was found that during the passage through the biological tissue, LDME undergoes a primary conversion to l-DOPA catalyzed by membrane's enzymes. Supplementation of delivery with Tween 80(r) produces substantial enhancement of LDME passage through the membrane. The drug could be loaded in the IntelliDrug mechatronic device, released close to the buccal mucosa, so achieving and maintaining constant therapeutic blood levels for extensive time. PMID- 25533876 TI - Preparation and ocular pharmacokinetics of hyaluronan acid-modified mucoadhesive liposomes. AB - The aim of this research was to formulate a liposomal preparation of DOX to be applied topically, and to investigate the in vitro and in vivo performance of the prepared liposomes. DOX liposomes were prepared by the solvent evaporation method, and then modified with bioadhesive material HA. Through MTT assay, we found that the safe concentration of liposomes delivered would hit 1 mg/mL. Cellular uptake studies showed that DOX liposomes coated with HA are much more targetable to cell nucleus. Their ocular pharmacokinetics in rabbits were investigated through the comparison with those obtained after dosing with non modified liposomes and DOX solution. The in vitro transcorneal permeability of DOX in both kinds of liposomes was found to be slower than that of the solution because of sustained release. After in vivo instillation in rabbits, HA-modified liposomes had the longest retention time, following with naked liposomes. Significantly, the area under the curve of the aqueous humor concentration-time profiles of DOX liposomes was found to be 1.7-fold higher than that of DOX solution. The confocal experiment confirmed that HA-modified liposomes were able to maintain a higher DOX concentration and residence time than that of non modified liposomes and free DOX. These results suggest that our liposomal preparation was of great help to improve the bioavailability of DOX. PMID- 25533877 TI - Therapy with the Combination of Amlodipine and Irbesartan Has Persistent Preventative Effects on Stroke Onset Associated with BDNF Preservation on Cerebral Vessels in Hypertensive Rats. AB - Although calcium channel blockers, angiotensin II receptor blockers, and combination therapy are effective for hypertensive patients, the significant differences among them against stroke onset are undetermined. In this study, we investigated the significant beneficial effects of the combination therapy using amlodipine and irbesartan against stroke onset in hypertensive rats. The animals were fed an 8% sodium diet and assigned to (1) vehicle, (2) amlodipine (2 mg/kg/day), (3) irbesartan (20 mg/kg/day), and (4) amlodipine + irbesartan groups. The drugs were given orally until 35 days, and incidences of stroke related signs and mortality and blood pressure (BP) were monitored. Cerebral blood flow (CBF), brain water content, weight of the brain and left ventricle, and histological evaluations were conducted for the treated groups at 42 days after the start of the high-salt diet. Amlodipine and the combination therapy significantly reduced BP compared with the vehicle. Although the rates of stroke related signs and mortality were high in the vehicle group, the rats in the treatment groups were mostly healthy until 35 days. After all drugs were discontinued, stroke onset was frequently seen in the monotherapy groups until 42 days, but no signs were observed in the combination therapy group. Although there were no significant differences in CBF or brain edema, the combination therapy reduced blood-brain barrier disruption, white matter injury, and reactive astrocytes compared with irbesartan, and the combination also inhibited left ventricular hypertrophy and preserved brain-derived neurotrophic factor (BDNF) expression on cerebral vessels compared to the monotherapies. These data suggest that the combination therapy had a persistent preventive effect on stroke onset in hypertensive rats, and the effects might be associated with BDNF preservation on cerebral vessels. PMID- 25533878 TI - An update on inflammation in the acute phase of intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is a common and severe neurological disorder, which is associated with high rates of mortality and morbidity. Despite extensive research into the pathology of ICH, there are still no clinically approved neuroprotective treatments. Currently, increasing evidence has shown that inflammatory responses participate in the pathophysiological processes of brain injury following ICH. In this editorial, we summarized some promising advances in the field of inflammation and ICH, which contained animal and human investigations; discussed the role of neuroinflammation, systemic inflammatory responses, and some potential targets; and focused on the challenges of translation between pre-clinical and clinical studies and potential anti inflammatory therapeutic approaches after ICH. PMID- 25533879 TI - The accuracy of emergency department medication history as determined by mass spectrometry analysis of urine: a pilot study. AB - BACKGROUND: Emergency Department (ED) medication lists (ML) are considered inaccurate based on previous comparisons of ED ML with patients' self-reporting of medications and reviews of patients' pharmacy and medical records. OBJECTIVE: To determine the accuracy of ED ML using mass spectrometry analysis of urine samples. METHODS: This was a prospective observational study conducted at an urban tertiary care university hospital. Convenience sampling of patients who underwent ED triage was done. Included were patients 18 years or older who were capable of providing informed consent and who reported use of at least one medication. Excluded were patients unable to consent, prisoners, non-English speaking patients, and patients unwilling or unable to provide a urine sample. Mass spectrometry analysis was performed on enrolled patients' urine, and their ED triage ML were recorded. Urinalysis results were compared to ED triage ML. Concordance between respective ED triage ML and urinalysis results was determined. Medications were grouped by medication class. The top five discrepant medication classes were identified. RESULTS: There were 100 patients enrolled; 21 patients, although eligible, did not provide a urine sample and were excluded, and one patient withdrew. Mean age was 51 years, and 54 patients were male. Twenty-two medication classes were identified. No patient had 100% concordance of ED triage ML and urinalysis results. Opioid analgesic, sedative hypnotics, cardiac, psychiatric, and nonopioid analgesic medications were the top discrepant medication classes. CONCLUSIONS: ED triage ML obtained by patient recall are inaccurate when compared to medications detected in urine using mass spectrometry analysis. PMID- 25533880 TI - Inhaled antibiotics beyond aminoglycosides, polymyxins and aztreonam: A systematic review. AB - We sought to evaluate published evidence regarding clinical or microbiological outcomes related to the use of inhaled antibiotics other than aminoglycosides, polymyxins and aztreonam. A systematic search of PubMed and Scopus databases as well as bibliographies of eligible articles was performed. In total, 34 eligible studies were identified. Among several inhaled beta-lactams, ceftazidime was used with varying success in the prevention and treatment of ventilator-associated pneumonia (VAP) and improved clinical outcomes in chronic Pseudomonas aeruginosa lower respiratory tract infections (LRTIs) in patients with cystic fibrosis (CF) or bronchiectasis. Inhaled vancomycin, as an adjunctive therapy, was effective in treating Gram-positive VAP, whilst inhaled levofloxacin, ciprofloxacin and an inhaled combination of fosfomycin and tobramycin were associated with improved microbiological or clinical outcomes in chronic LRTI in patients with CF or bronchiectasis. In conclusion, published evidence is heterogeneous with regard to antibiotics used, studied indications, patient populations and study designs. Therefore, although the currently available data are encouraging, no safe conclusion regarding the effectiveness and safety of the drugs in question can be reached. PMID- 25533881 TI - Protocol adherence when managing massive bleeding following complex cardiac surgery: a study design pilot. AB - OBJECTIVE: High-quality prospective trials of hemostatic "rescue" therapy to control massive bleeding in cardiac surgery are lacking. Wide variability in the care of patients with severe bleeding following cardiopulmonary bypass has precluded accurate comparison of treatment groups in previous studies. This study identified the use of a management protocol for early identification and uniform treatment of patients with massive bleeding for application in future trials of hemostatic rescue agents. DESIGN: A prospective, nonblinded, interventional feasibility study. SETTING: A university teaching hospital. PARTICIPANTS: Forty three adult patients undergoing complex cardiac surgery. INTERVENTIONS: Study participants undergoing high-risk cardiac surgery received standardized treatment in accordance with a bleeding management protocol. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients (63%) had severe bleeding following heparin reversal and received conventional hemostatic resuscitation per protocol. Six patients had massive refractory bleeding. Compliance with protocol tasks was>=90% in 4 of 5 categories (anticoagulation, hemostasis scoring, recording blood loss, protocol transfusion) with the exception being submission of laboratory samples (76%). Measured bleeding rates (mL/h) following heparin reversal were clearly differentiated in those with hemostasis scores>=3 compared to those with scores<=2 (1,420+/-957 v 147+/-96; p<0.001). CONCLUSIONS: Adherence to a management protocol for massive bleeding is feasible and allows for homogenous treatment of patients before study arm randomization in future "rescue" therapy trials. The authors' protocol allowed for prompt and accurate identification of patients with severe bleeding refractory to conventional therapy. This review resolved several key barriers in the design of severe bleeding management trials. PMID- 25533882 TI - Prevalence of Therapeutic Drug Monitoring for Antidepressants and Antipsychotics in Stockholm, Sweden: A Longitudinal Analysis. AB - BACKGROUND: Although therapeutic drug monitoring (TDM) is considered an underused tool in psychiatric care, the prevalence of TDM is largely unknown. The aim of this study was to analyze the prevalence of TDM for antidepressants and antipsychotics during 2006-2013. METHODS: The study population consisted of individuals >=5 years of age residing in Stockholm County. The prevalence of TDM for each study year was calculated with the number of individuals in whom TDM had been performed as nominator (extracted from the TDM database at Karolinska University Laboratory) and the number of treated individuals as denominator (extracted from the Swedish Prescribed Drug Register). All data were obtained at the third and the fifth level of the anatomical therapeutic chemical classification system (pharmacological subgroup and chemical substance, respectively). The prevalence of TDM was compared between substances according to the level of TDM recommendation by guidelines. RESULTS: For antidepressants, the prevalence of TDM decreased from 0.48% (95% confidence interval, 0.45%-0.52%) in 2006 to 0.36% (0.33%-0.39%) in 2013 (among 133,275 and 162,998 treated individuals, respectively). For antipsychotics, the prevalence of TDM increased from 2.3% (2.2%-2.5%) to 4.1% (3.9%-4.3%) (31,463 and 32,534 treated individuals). For both drug groups, TDM was more common in men than in women. The most frequently analyzed drugs were clozapine, perphenazine, zuclopenthixol, nortriptyline, and flupentixol. Although not reaching statistical significance, the TDM prevalence was greater for substances strongly recommended for TDM than for substances with a lower level of recommendation, median (interquartile range): 5.6% (2.8%-22%) versus 1.1% (0.2%-2.2%), P = 0.063. CONCLUSIONS: The prevalence of TDM is generally low, more frequent, and increasing for antipsychotics, and more frequent for men and substances where TDM is strongly recommended. PMID- 25533883 TI - Protective effect of bisphosphonates on endometrial cancer incidence in data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. AB - BACKGROUND: Preclinical studies have demonstrated antitumor effects of bisphosphonates. The objective of the current study was to determine the effect of exposure to bisphosphonate on the incidence of endometrial cancer. METHODS: The authors used data from the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which collected data on all cancers. In year 5, all participants were asked to complete a self-administered supplemental questionnaire (SQX) that included questions regarding bone medication use. For women without a cancer diagnosis at the time of the SQX, the authors identified whether a woman reported current or former use of a nitrogenous bisphosphonate (NBP), defined as ever-use, and compared them with women never exposed to an NBP. Women with missing information were excluded as were women who reported undergoing a hysterectomy. Incidence rates and rate ratios were calculated with 95% confidence intervals (95% CIs). Cox proportional hazard ratios were also calculated and adjusted for covariates. RESULTS: A total of 29,254 women were included in the current analysis; an additional 77 cases of endometrial cancer have been diagnosed since the SQX. The incidence rate for endometrial cancer among women exposed to NBPs was 8.7 per 10,000 person-years versus 17.7 per 10,000 person-years among never-exposed women (rate ratio, 0.49; 95% CI, 0.30-0.80). The effect was similar after adjusting for all the covariates in the Cox proportional hazards analysis, with a hazard ratio of 0.56 (95% CI, 0.34-0.93). CONCLUSIONS: The results of the current study suggest that use of NBPs may have a protective effect on the incidence of endometrial cancer. However, additional studies are needed that include other potential confounders and a larger sample. PMID- 25533884 TI - Iatrogenic Cushing Syndrome due to Intranasal Dexamethasone. PMID- 25533885 TI - The "HEADS AT" Training Tool for Residents: A Roadmap for Caring for Children With Medical Complexity. PMID- 25533886 TI - Efficacy and safety of intravenous sulbactam/ampicillin 3 g 4 times daily in Japanese adults with moderate to severe community-acquired pneumonia: a multicenter, open-label, uncontrolled study. AB - Although sulbactam/ampicillin (SBT/ABPC) 3 g 4 times daily (QID) is widely used worldwide for patients with moderate to severe community-acquired pneumonia (CAP), the 3 g QID regimen was not available in Japan. In fact, there has been no evidence from a formal clinical study regarding the efficacy and safety of SBT/ABPC 3 g QID in these patients. We report the first results of a multicenter, unblinded, non-comparative, phase 3 study of SBT/ABPC 3 g QID in Japanese adults with moderate to severe CAP. Forty-seven subjects with moderate to severe CAP were enrolled and received SBT/ABPC 3 g QID intravenously for 3-14 days. The clinical responses assessed by the data review committee (DRC) were the primary endpoints. The secondary endpoints included the bacteriological responses assessed by the DRC. The clinical efficacy rate at the test of cure (TOC) was 94.6%. The bacterial eradication rate at TOC was 91.7%. Causative pathogens were isolated from sputum sample taken at baseline in 28 subjects (59.6%). Common causative pathogens included Streptococcus pneumoniae (14 strains), Haemophilus influenzae (9 strains), and Moraxella catarrhalis (8 strains). The clinical efficacy rate and the bacterial eradication rate at TOC of the common pathogens were, respectively, 92.3% and 90.0% in subjects with S. pneumoniae, 83.3% and 75.0% in subjects with H. influenzae, and 87.5% and 87.5% in subjects with M. catarrhalis. All treatment-related adverse events were mild or moderate in severity. SBT/ABPC 3 g QID was well tolerated and demonstrated excellent clinical and bacteriological responses. ClinicalTrials.gov Identifier: NCT01189487. PMID- 25533887 TI - Is elective inguinal radiotherapy necessary for locally advanced rectal adenocarcinoma invading anal canal? AB - BACKGROUND: We investigated whether routine elective irradiation of a clinically negative inguinal node (IGN) is necessary for patients with locally advanced distal rectal cancer and anal canal invasion (ACI). METHODS: We reviewed retrospectively 1,246 patients with locally advanced rectal adenocarcinoma managed using preoperative or postoperative chemoradiotherapy and radical surgery between 2001 and 2011. The patients' IGN was clinically negative at presentation and IGN irradiation was not performed. ACI was defined as the lower edge of the tumor being within 3 cm of the anal verge. Patients were divided into two groups, those with ACI (n = 189, 15.2%) and without ACI (n = 1,057, 84.8%). RESULTS: The follow-up period was a median of 66 months (range, 3-142 months). Among the 1,246 patients, 10 developed IGN recurrence; 7 with ACI and 3 without ACI. The actuarial IGN recurrence rate at 5 years was 0.7%; 3.5% and 0.2% in patients with and without ACI, respectively (p < 0.001). Isolated IGN recurrence occurred in three patients, all of whom had ACI tumors. These three patients received curative intent local treatments, and one was alive with no evidence of disease 10 years after IGN recurrence. Salvage treatments in the other two patients controlled successfully the IGN recurrence for >5 years, but they developed second malignancy or pelvic and distant recurrences. Seven patients with non isolated IGN recurrence died of disease at 5-22 months after IGN recurrence. CONCLUSION: The low IGN recurrence rate even with ACI and the feasibility of salvage of isolated IGN recurrence indicated that routine elective IGN irradiation is not necessary for rectal cancer with ACI. PMID- 25533888 TI - Dynamic behavior of molecular switches in crystal under pressure and its reflection on tactile sensing. AB - Molecular switches have attracted increasing interest in the past decades, due to their broad applications in data storage, optical gating, smart windows, and so on. However, up till now, most of the molecular switches are operated in solutions or polymer blends with the stimuli of light, heat, and electric fields. Herein, we demonstrate the first pressure-controllable molecular switch of a benzo[1,3]oxazine OX-1 in crystal. Distinct from the light-triggered tautomerization between two optical states, applying hydrostatic pressure on the OX-1 crystal results in large-scale and continuous states across the whole visible light range (from ~430 to ~700 nm), which has not been achieved with other stimuli. Based on detailed and systematic control experiments and theoretical calculation, the preliminary requirements and mechanism of pressure dependent tautomerization are fully discussed. The contributions of molecular tautomerization to the large-scale optical modulation are also stressed. Finally, the importance of studying pressure-responsive materials on understanding tactile sensing is also discussed and a possible mechanotransduction mode is proposed. PMID- 25533889 TI - Welfare Reform and Children's Health. AB - This study investigates the effect of the Temporary Aid to Needy Families (TANF) program on children's health outcomes using data from the Survey of Income and Program Participation over the period 1994 to 2005. The TANF policies have been credited with increased employment for single mothers and a dramatic drop in welfare caseload. Our results show that these policies also had a significant effect on various measures of children's medical utilization among low-income families. These health measures include a rating of the child's health status reported by the parents, the number of times that parents consulted a doctor, and the number of nights that the child stayed in a hospital. We compare the overall changes of health status and medical utilization for children with working and nonworking mothers. We find that the child's health status as reported by the parents is affected by the maternal employment status. PMID- 25533890 TI - Single crystal-to-single crystal site-selective postsynthetic metal exchange in a Zn-MOF based on semi-rigid tricarboxylic acid and access to bimetallic MOFs. AB - The metal ions in a neutral Zn-MOF constructed from tritopic triacid H3 L with inherent concave features, rigid core, and peripheral flexibility are found to exist in two distinct SBUs, that is, 0D and 1D. This has allowed site-selective postsynthetic metal exchange (PSME) to be investigated and reactivities of the metal ions in two different environments in coordination polymers to be contrasted for the first time. Site-selective transmetalation of Zn ions in the discrete environment is shown to occur in a single crystal-to-single crystal (SCSC) fashion, with metal ions such as Fe(3+) , Ru(3+) , Cu(2+) , Co(2+) , etc., whereas those that are part of 1D SBU sustain structural integrity, leading to novel bimetallic MOFs, which are inaccessible by conventional approaches. To the best of our knowledge, site-selective postsynthetic exchange of an intraframework metal ion in a MOF that contains metal ions in discrete as well as polymeric SBUs is heretofore unprecedented. PMID- 25533891 TI - Structure-guided Discovery of a Novel Non-peptide Inhibitor of Dengue Virus NS2B NS3 Protease. AB - Dengue fever is a fast emerging epidemic-prone viral disease caused by dengue virus serotypes 1-4. NS2B-NS3 protease of dengue virus is a validated target to develop antiviral agents. A major limitation in developing dengue virus protease inhibitors has been the lack of or poor cellular activity. In this work, we extracted and refined a pharmacophore model based on X-ray crystal structure and predicted binding patterns, followed by a three-dimensional flexible database filtration. These output molecules were screened according to a docking-based protocol, leading to the discovery of a compound with novel scaffold and good cell-based bioactivity that has potential to be further optimized. The discovery of this novel scaffold by combination of in silico methods suggests that structure-guided drug discovery can lead to the development of potent dengue virus protease inhibitors. PMID- 25533892 TI - Gold-catalyzed intermolecular anti-markovnikov hydroamination of alkylidenecyclopropanes. AB - The cationic gold phosphine complex [{PCy2 (o-biphenyl)}Au(NCMe)](+) SbF6 (-) (Cy=cyclohexyl) catalyzes the intermolecular, anti-Markovnikov hydroamination reaction of monosubstituted and cis- and trans-disubstituted alkylidenecyclopropanes (ACPs) with imidazolidin-2-ones and other nucleophiles. This reaction forms 1-cyclopropyl alkylamine derivatives in high yield and with high regio- and diastereoselectivity. NMR spectroscopic analysis of gold pi-ACP complexes and control experiments point to the sp hybridization of the ACP internal alkene carbon atom as controlling the regiochemistry of the ACP hydroamination reaction. PMID- 25533893 TI - Experience of adjunctive cannabis use for chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT) study. AB - BACKGROUND: There is increasing debate about cannabis use for medical purposes, including for symptomatic treatment of chronic pain. We investigated patterns and correlates of cannabis use in a large community sample of people who had been prescribed opioids for chronic non-cancer pain. METHODS: The POINT study included 1514 people in Australia who had been prescribed pharmaceutical opioids for chronic non-cancer pain. Data on cannabis use, ICD-10 cannabis use disorder and cannabis use for pain were collected. We explored associations between demographic, pain and other patient characteristics and cannabis use for pain. RESULTS: One in six (16%) had used cannabis for pain relief, 6% in the previous month. A quarter reported that they would use it for pain relief if they had access. Those using cannabis for pain on average were younger, reported greater pain severity, greater interference from and poorer coping with pain, and more days out of role in the past year. They had been prescribed opioids for longer, were on higher opioid doses, and were more likely to be non-adherent with their opioid use. Those using cannabis for pain had higher pain interference after controlling for reported pain severity. Almost half (43%) of the sample had ever used cannabis for recreational purposes, and 12% of the entire cohort met criteria for an ICD-10 cannabis use disorder. CONCLUSIONS: Cannabis use for pain relief purposes appears common among people living with chronic non-cancer pain, and users report greater pain relief in combination with opioids than when opioids are used alone. PMID- 25533894 TI - Delay to first treatment contact for alcohol use disorder. AB - BACKGROUND: This study explored the patterns and correlates of time to first treatment contact among people with alcohol use disorder (AUD) in Australia. Specifically it examined the relationship between sex, birth cohort, onset of AUD symptoms, severity, comorbidity, symptom type and time to first treatment contact (treatment delay) among those with alcohol abuse and dependence in a large population sample. METHODS: Data came from the 2007 Australian National Survey of Mental Health and Wellbeing (N=8841). A modified version of the World Health Organization's Composite International Diagnostic Interview was used to determine the presence and age of onset of DSM-IV AUD and other mental disorders and the age at which respondents first sought treatment for alcohol or other drug-related problems. RESULTS: Median time to first treatment contact for an AUD was 18 years (14 years dependence, 23 years abuse). Projected lifetime treatment rates were 78.1% for alcohol dependence and 27.5% for abuse. Those with earlier onset and from older cohorts reported longer delay and were less likely to ever seek treatment compared to those with later onset or from more recent cohorts. Those with comorbid anxiety but not mood disorder, or who reported alcohol-related role disruption or recurrent interpersonal problems were more likely to ever seek treatment and reported shorter delay compared to those who did not report these symptoms. CONCLUSIONS: Treatment delay for alcohol use disorder in Australia is substantial. Those with earlier onset and those with comorbid mood disorder should be a target for earlier treatment. PMID- 25533895 TI - How much of the cocaine market are we missing? Insights from respondent-driven sampling in a mid-sized American city. AB - BACKGROUND: Studying markets for illegal drugs is important, but difficult. Data usually come from a selected subset of consumers, such as arrestees, treatment clients, or household survey respondents. There are rarely opportunities to study how such groups may differ from other market participants or how much of total consumption they represent. METHODS: This paper uses respondent-driven sampling (RDS) of drug users in a mid-sized American city to estimate the shares of cocaine (powder and crack) users and expenditures that are attributable to different combinations of these groups. RESULTS: We find that those arrested in the last year accounted for 34% of past-month cocaine users and 40% of past-week cocaine spending in the RDS sample. Augmenting past-year arrestees with those who received treatment in the past year increases these values to 44% (users) and 55% (spending). CONCLUSIONS: Our results suggest that estimates based only on people who were arrested and/or treated in the past year would have to be inflated by 100-200% to capture the market totals. Adding those who own or rent their place of residence increased coverage in this study to 76% (users) and 81% (spending), suggesting that in theory the inflation factor could be reduced to 23-32% by supplementing data on arrestees and treatment populations with household data, although in practice rates of under-reporting by survey respondents may make coverage (sampling frame) a secondary concern for household surveys. PMID- 25533897 TI - [Selective biopsy of sentinel node in melanoma. Survey results of nuclear medicine services in Spain]. PMID- 25533896 TI - Family history density predicts long term substance use outcomes in an adolescent treatment sample. AB - AIMS: This study explored whether the density of family history (FH) of substance use disorders relates to post-treatment substance use outcomes in adolescents, with the primary aim of determining whether FH exerts a relatively stronger influence on longer-term outcomes. METHOD: The present investigation examined adolescents (ages 12-18, n=366) from two independent samples who were treated for alcohol/substance use disorder (ASUD) and re-assessed during the eight years following treatment with identical methodology. Primary substance use outcomes were assessed at 1, 2, 4, 6, and 8 years post-treatment and included total drinks, days using marijuana, and days using other drugs. RESULTS: In hierarchical linear models there were significant FH density*linear time interactions for total drinks (z=12.75, p<0.001) and marijuana use days (z=4.39, p<0.001); greater FH density predicted more total drinks and more marijuana use days, with both associations becoming stronger over time. The increasing linkage between FH and other drug use was not significant over time. CONCLUSIONS: Findings are consistent with previous research indicating that the risk associated with FH increases over time, especially in relation to quantity/frequency measures of alcohol and marijuana use. By extending these findings to an adolescent clinical sample, the current study highlights that FH density of alcohol and drug dependence is a risk factor for poorer long-term outcomes for adolescent-onset ASUD youth as they transition into adulthood. Future work should explore the mechanisms underlying greater post-treatment substance use for adolescents/young adults with greater FH density. PMID- 25533898 TI - Clinical NOTES appendectomy study: comparison of transvaginal NOTES appendectomy in hybrid technique with laparoscopic appendectomy. AB - PURPOSE: The proposed advantages of NOTES are aimed to assess the comparison with standard procedures. Complications are a major focus of its evaluation. We initiated a prospective comparison between transvaginal hybrid appendectomy versus laparoscopic appendectomy. PATIENTS AND METHODS: For each, NOTES and laparoscopic appendectomy, 10 consecutive female patients participated in the study with follow-up documentation for 35 days and after 1 year. Transvaginal appendectomy was considered a non-standard medical procedure and required individual patient's consent. Pre- and postoperative gynecological examinations were performed. Questionnaire-based evaluation included issues related to quality of life in addition to objective clinical findings. The study is approved by the ethics committee of the University of Rostock. RESULTS: All women returned questionnaires for evaluation. Age and BMI are comparable. Overall procedure time was significantly shorter in laparoscopy. The only postoperative complication consisted of an intra-abdominal abscess after laparoscopic appendectomy. One patient of the NOTES group suffered from new abdominal pain 3 weeks postoperatively; a mini-laparoscopy showed a normal situation. Significant differences (p < 0.05) of the questionnaire-based comparison with advantages for the NOTES group were found in following items: reduced activity at day 1-14, postoperative pain at day 1, general health conditions at day 1-3 and quality of life at day 3. NOTES patients wished significantly earlier to be discharged and started significantly earlier with activities, but no differences existed after 4 weeks. CONCLUSIONS: Transvaginal flexible appendectomy appears to be a safe procedure performed in hybrid technique. Data from the study point to shortened recovery intervals and improved quality of life. PMID- 25533899 TI - Erratum to: Sacral neuromodulation for faecal incontinence: is the outcome compromised in patients with high-grade internal rectal prolapse? PMID- 25533900 TI - Enhancing magnetic ordering in Cr-doped Bi2Se3 using high-TC ferrimagnetic insulator. AB - We report a study of enhancing the magnetic ordering in a model magnetically doped topological insulator (TI), Bi(2-x)Cr(x)Se(3), via the proximity effect using a high-TC ferrimagnetic insulator Y(3)Fe(5)O(12). The FMI provides the TI with a source of exchange interaction yet without removing the nontrivial surface state. By performing the elemental specific X-ray magnetic circular dichroism (XMCD) measurements, we have unequivocally observed an enhanced TC of 50 K in this magnetically doped TI/FMI heterostructure. We have also found a larger (6.6 nm at 30 K) but faster decreasing (by 80% from 30 to 50 K) penetration depth compared to that of diluted ferromagnetic semiconductors (DMSs), which could indicate a novel mechanism for the interaction between FMIs and the nontrivial TIs surface. PMID- 25533901 TI - The inferior turbinate flap: a novel technique for prosthetic preparation of a total rhinectomy defect. AB - For total rhinectomy defects, the decision to proceed with a prosthetic versus surgical reconstruction is multifactorial, taking into account patient risk factors, availability of donor tissues, the need for tumor surveillance, and personal preferences. When a prosthetic approach is chosen, the reconstructive surgeon is tasked with preparing the defect to maximize prosthetic retention and prevent ulcerations. Stable bone coverage is critical to achieve this aim. Although skin grafting has been described previously for bone coverage, the periosteum is often stripped. We present a novel use of the inferior turbinate flap for preparation of rhinectomy defects that can be utilized regardless of the presence or absence of the periosteum and provides a more durable coverage than skin grafts. PMID- 25533903 TI - Exercise training improves insulin release during glucose tolerance testing in stable chronic heart failure patients. AB - PURPOSE: Chronic heart failure (CHF) patients often present with (pre)diabetes, which negatively influences prognosis. Unlike the proven effect of exercise on glucose regulation in the general population, its effect in CHF is unclear. Therefore, this study aimed at investigating the effect of exercise training on glucose regulation in stable CHF patients. METHODS: Twenty-two CHF patients were randomized into training (EX, n = 15) and control (CON, n = 7) groups. Before and after a 12-week training intervention involving endurance and resistance training, glucose tolerance (2-hour oral glucose tolerance test), exercise tolerance (cardiopulmonary exercise test), muscle strength (isokinetic dynamometer), heart function (echocardiography), glycated hemoglobin, body composition (dual-energy x-ray absorptiometry), and quality of life (EQ5D) were assessed. RESULTS: At baseline, glucose levels 2 hours after glucose intake were elevated in both groups. Whereas area under the glucose curve did not change, area under the insulin curve decreased following training (EX, -13 +/- 23% vs CON, +22 +/- 33%; P < .05). Changes in the ratio of mitral peak velocity of early filling/early diastolic mitral annular velocity and waist-to-hip fat mass ratio were related to changes in the insulin curve. Exercise training resulted in improved oxygen uptake at the second ventilatory threshold (EX, +10 +/- 5% vs CON, -8 +/- 5%; P < .05) and isokinetic strength endurance of the upper leg (EX, +25 +/- 9% vs CON, -6 +/- 5%; P < 0.05). Lean body tissue was increased by 2.2 +/ 0.5% in EX versus 0.2 +/- 0.6% in CON (P < .05). CONCLUSION: Our data suggest that exercise training attenuates worsening of glucose regulation typically seen in a stable CHF population. PMID- 25533902 TI - A Telehealth Intervention Using Nintendo Wii Fit Balance Boards and iPads to Improve Walking in Older Adults With Lower Limb Amputation (Wii.n.Walk): Study Protocol for a Randomized Controlled Trial. AB - BACKGROUND: The number of older adults living with lower limb amputation (LLA) who require rehabilitation for improving their walking capacity and mobility is growing. Existing rehabilitation practices frequently fail to meet this demand. Nintendo Wii Fit may be a valuable tool to enable rehabilitation interventions. Based on pilot studies, we have developed "Wii.n.Walk", an in-home telehealth Wii Fit intervention targeted to improve walking capacity in older adults with LLA. OBJECTIVE: The objective of this study is to determine whether the Wii.n.Walk intervention enhances walking capacity compared to an attention control group. METHODS: This project is a multi-site (Vancouver BC, London ON), parallel, evaluator-blind randomized controlled trial. Participants include community dwelling older adults over the age of 50 years with unilateral transtibial or transfemoral amputation. Participants will be stratified by site and block randomized in triplets to either the Wii.n.Walk intervention or an attention control group employing the Wii Big Brain cognitive software. This trial will include both supervised and unsupervised phases. During the supervised phase, both groups will receive 40-minute sessions of supervised group training three times per week for a duration of 4 weeks. Participants will complete the first week of the intervention in groups of three at their local rehabilitation center with a trainer. The remaining 3 weeks will take place at participants' homes using remote supervision by the trainer using Apple iPad technology. At the end of 4 weeks, the supervised period will end and the unsupervised period will begin. Participants will retain the Wii console and be encouraged to continue using the program for an additional 4 weeks' duration. The primary outcome measure will be the "Two-Minute Walk Test" to measure walking capacity. Outcome measures will be evaluated for all participants at baseline, after the end of both the supervised and unsupervised phases, and after 1-year follow up. RESULTS: Study staff have been hired and trained at both sites and recruitment is currently underway. No participants have been enrolled yet. CONCLUSIONS: Wii.n.Walk is a promising in-home telehealth intervention that may have useful applications for older adults with LLA who are discharged from rehabilitation or live in remote areas having limited or no access to existing rehabilitation programs. TRIAL REGISTRATION: Clinicaltrial.gov NCT01942798; http://clinicaltrials.gov/ct2/show/NCT01942798 (Archived by WebCite at http://www.webcitation.org/6V0w8baKP). PMID- 25533905 TI - A maternal mouse diet with moderately high-fat levels does not lead to maternal obesity but causes mesenteric adipose tissue dysfunction in male offspring. AB - The impact of an increase in maternal fat consumption on fetal metabolic programming separately from maternal obesity remains unclear. The purpose of this study was to document the effect of in utero high-fat diet exposure on the development of metabolic syndrome characteristics in offspring. C57BL/6 female mice were fed either a control diet (10% fat) or a moderately high-fat (MHF) diet (45% fat) until delivery. All pups were fostered to mothers fed with the control diet. Pups were raised on the control diet and assessed until 35 weeks of age. The caloric intake from fat was significantly increased in the MHF dams compared with the control dams. There were no significant differences in the maternal weight at mating or at gestational Day 18 between the two groups. The MHF offspring did not become obese, but they developed hypertension and glucose intolerance. Moreover, the MHF offspring had significantly higher serum non esterified fatty acid and triglyceride levels during the refeeding state following fasting as compared with the control offspring. Serum adiponectin levels were significantly lower, and the cell size of the mesenteric adipose tissue was significantly larger in the MHF offspring than in the control offspring. The mRNA levels of the proinflammatory macrophage markers in the mesenteric adipose tissue were significantly higher in the MHF offspring than those of the control offspring. These results suggest that in utero high-fat diet exposure causes hypertension and glucose intolerance resulting from mesenteric adipose tissue dysfunction in offspring, independently of maternal obesity. PMID- 25533908 TI - Advances in the diagnosis and treatment of bipolar depression. PMID- 25533907 TI - A path forward in the debate over health impacts of endocrine disrupting chemicals. AB - Several recent publications reflect debate on the issue of "endocrine disrupting chemicals" (EDCs), indicating that two seemingly mutually exclusive perspectives are being articulated separately and independently. Considering this, a group of scientists with expertise in basic science, medicine and risk assessment reviewed the various aspects of the debate to identify the most significant areas of dispute and to propose a path forward. We identified four areas of debate. The first is about the definitions for terms such as "endocrine disrupting chemical", "adverse effects", and "endocrine system". The second is focused on elements of hormone action including "potency", "endpoints", "timing", "dose" and "thresholds". The third addresses the information needed to establish sufficient evidence of harm. Finally, the fourth focuses on the need to develop and the characteristics of transparent, systematic methods to review the EDC literature. Herein we identify areas of general consensus and propose resolutions for these four areas that would allow the field to move beyond the current and, in our opinion, ineffective debate. PMID- 25533906 TI - Extravirgin olive oil up-regulates CB1 tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms. AB - Extravirgin olive oil (EVOO) represents the typical lipid source of the Mediterranean diet, an eating habit pattern that has been associated with a significant reduction of cancer risk. Diet is the more studied environmental factor in epigenetics, and many evidences suggest dysregulation of epigenetic pathways in cancer. The aim of our study was to investigate the effects of EVOO and its phenolic compounds on endocannabinoid system (ECS) gene expression via epigenetic regulation in both human colon cancer cells (Caco-2) and rats exposed to short- and long-term dietary EVOO. We observed a selective and transient up regulation of CNR1 gene - encoding for type 1 cannabinoid receptor (CB1) - that was evoked by exposure of Caco-2 cells to EVOO (100 ppm), its phenolic extracts (OPE, 50 MUM) or authentic hydroxytyrosol (HT, 50 MUM) for 24 h. None of the other major elements of the ECS (i.e., CB2; GPR55 and TRPV1 receptors; and NAPE PLD, DAGL, FAAH and MAGL enzymes) was affected at any time point. The stimulatory effect of OPE and HT on CB1 expression was inversely correlated to DNA methylation at CNR1 promoter and was associated with reduced proliferation of Caco-2 cells. Interestingly, CNR1 gene was less expressed in Caco-2 cells when compared to normal colon mucosa cells, and again this effect was associated with higher level of DNA methylation at CNR1. Moreover, in agreement with the in vitro studies, we also observed a remarkable (~4-fold) and selective increase in CB1 expression in the colon of rats receiving dietary EVOO supplementation for 10 days. Consistently, CpG methylation of rat Cnr1 promoter, miR23a and miR-301a, previously shown to be involved in the pathogenesis of colorectal cancer and predicted to target CB1 mRNA, was reduced after EVOO administration down to ~50% of controls. Taken together, our findings demonstrating CB1 gene expression modulation by EVOO or its phenolic compounds via epigenetic mechanism, both in vitro and in vivo, may provide a new therapeutic avenue for treatment and/or prevention of colon cancer. PMID- 25533909 TI - Differential diagnosis of bipolar disorder and major depressive disorder. AB - BACKGROUND: Patients with bipolar disorder spend approximately half of their lives symptomatic and the majority of that time suffering from symptoms of depression, which complicates the accurate diagnosis of bipolar disorder. METHODS: Challenges in the differential diagnosis of bipolar disorder and major depressive disorder are reviewed, and the clinical utility of several screening instruments is evaluated. RESULTS: The estimated lifetime prevalence of major depressive disorder (i.e., unipolar depression) is over 3 and one-half times that of bipolar spectrum disorders. The clinical presentation of a major depressive episode in a bipolar disorder patient does not differ substantially from that of a patient with major depressive disorder (unipolar depression). Therefore, it is not surprising that without proper screening and comprehensive evaluation many patients with bipolar disorder may be misdiagnosed with major depressive disorder (unipolar depression). In general, antidepressants have demonstrated little or no efficacy for depressive episodes associated with bipolar disorder, and treatment guidelines recommend using antidepressants only as an adjunct to mood stabilizers for patients with bipolar disorder. Thus, correct identification of bipolar disorder among patients who present with depression is critical for providing appropriate treatment and improving patient outcomes. LIMITATIONS: Clinical characteristics indicative of bipolar disorder versus major depressive disorder identified in this review are based on group differences and may not apply to each individual patient. CONCLUSION: The overview of demographic and clinical characteristics provided by this review may help medical professionals distinguish between major depressive disorder and bipolar disorder. Several validated, easily administered screening instruments are available and can greatly improve the recognition of bipolar disorder in patients with depression. PMID- 25533910 TI - Current landscape, unmet needs, and future directions for treatment of bipolar depression. AB - BACKGROUND: Depression is the predominant pole of illness disability in bipolar disorder and, compared with acute mania, has less systematic research guiding treatment development. The aim of this review is to present the therapeutic options currently available for managing bipolar depression and to highlight areas of unmet need and future research. METHODS: Literature search of PubMed, PsycINFO, and Cochrane databases and bibliographies from 2000 to August 2013 for treatments that have regulatory approval for bipolar depression or early controlled preliminary data on efficacy. RESULTS: Treatment options for bipolar depression have increased over the last decade, most notably with regulatory approval for olanzapine/fluoxetine combination, quetiapine, and lurasidone. Conventional mood stabilizers lamotrigine and divalproex have meta-analyses suggesting acute antidepressant response. Manual-based psychotherapies also appear to be effective in treating bipolar depression. The therapeutic utility of unimodal antidepressants, as a class, for the treatment of patients with bipolar depression, as a group, remains to be confirmed. There is a substantially unmet need to develop new interventions that are efficacious, effective, and have low side effect burden. LIMITATIONS: Additional compounds are currently being developed that may ultimately be applicable to the treatment of bipolar depression and early open-trial data encourage further studies, but both of these topics are beyond the scope of this review. CONCLUSION: Future registrational trials will need to establish initial efficacy, but increasing interest for personalized or individualized medicine will encourage further studies on individual predictors or biomarkers of response. PMID- 25533911 TI - Balancing benefits and harms of treatments for acute bipolar depression. AB - BACKGROUND: Bipolar depression is more pervasive than mania, but has fewer evidence-based treatments. METHODS: Using data from multicenter, randomized, double-blind, placebo-controlled trials and meta-analyses, we assessed the number needed to treat (NNT) for response and the number needed to harm (NNH) for selected side effects for older and newer acute bipolar depression treatments. RESULTS: The 2 older FDA-approved treatments for bipolar depression, olanzapine fluoxetine combination (OFC) and quetiapine (QTP) monotherapy, were efficacious (response NNT=4 for OFC, NNT=6 for QTP), but similarly likely to yield harms (OFC weight gain NNH=6; QTP sedation/somnolence NNH=5). Commonly used unapproved agents (lamotrigine monotherapy and adjunctive antidepressants) tended to be well tolerated (with double-digit NNHs), although this advantage was at the cost of inadequate efficacy (response NNT=12 for lamotrigine, NNT=29 for antidepressants). In contrast, the newly approved agent lurasidone was not only efficacious (response NNT=5 for monotherapy, NNT=7 as adjunctive therapy), but also had enhanced tolerability (NNH=15 for akathisia [monotherapy], NNH=16 for nausea [adjunctive]). Although adjunctive armodafinil appeared well tolerated, its efficacy in bipolar depression has not been consistently demonstrated in randomized controlled trials. LIMITATIONS: NNT and NNH are categorical metrics; only selected NNHs were assessed; limited generalizability of efficacy (versus effectiveness) studies. CONCLUSION: For acute bipolar depression, older approved treatments may have utility in high-urgency situations, whereas lamotrigine and antidepressants may have utility in low-urgency situations. Newly approved lurasidone may ultimately prove useful in diverse situations. New drug development needs to focus on not only efficacy but also on tolerability. PMID- 25533912 TI - The prevalence and burden of bipolar depression. AB - BACKGROUND: Bipolar disorder is characterized by debilitating episodes of depression and mood elevation (mania or hypomania). For most patients, depressive symptoms are more pervasive than mood elevation or mixed symptoms, and thus have been reported in individual studies to impose a greater burden on affected individuals, caregivers, and society. This article reviews and compiles the literature on the prevalence and burden of syndromal as well as subsyndromal presentations of depression in bipolar disorder patients. METHODS: The PubMed database was searched for English-language articles using the search terms "bipolar disorder," "bipolar depression," "burden," "caregiver burden," "cost," "costs," "economic," "epidemiology," "prevalence," "quality of life," and "suicide." Search results were manually reviewed, and relevant studies were selected for inclusion as appropriate. Additional references were obtained manually from reviewing the reference lists of selected articles found by computerized search. RESULTS: In aggregate, the findings support the predominance of depressive symptoms compared with mood elevation/mixed symptoms in the course of bipolar illness, and thus an overall greater burden in terms of economic costs, functioning, caregiver burden, and suicide. LIMITATIONS: This review, although comprehensive, provides a study-wise aggregate (rather than a patient wise meta-analytic) summary of the relevant literature on this topic. CONCLUSION: In light of its pervasiveness and prevalence, more effective and aggressive treatments for bipolar depression are warranted to mitigate its profound impact upon individuals and society. Such studies could benefit by including metrics not only for mood outcomes, but also for illness burden. PMID- 25533913 TI - Managing the side effects associated with commonly used treatments for bipolar depression. AB - BACKGROUND: The most commonly used pharmacologic therapies for bipolar depression are mood stabilizers, atypical antipsychotics, and antidepressants. This paper reviews common side effects associated with these medications and provides recommendations for managing adverse medication effects in clinical practice. METHODS: Narrative review based on literature searches of Medline and evidence based treatment guidelines for agents that have been approved by the US Food and Drug Administration and/or are commonly used to treat bipolar depression. RESULTS: Side effects of bipolar depression pharmacotherapies are common and vary by medication, with weight gain, metabolic dysregulation, sedation/somnolence, and akathisia among those observed most frequently. These adverse events (weight gain and sedation/somnolence, in particular) negatively affect treatment adherence in patients with bipolar disorder. Furthermore, endocrine and metabolic comorbidities, weight gain, and obesity may reduce the likelihood of positive clinical responses to pharmacologic therapies. Clinicians may consider switching patients to bipolar depression medication(s) with a lower propensity for sedation or adverse metabolic effects. Lifestyle modification (e.g., dietary changes, exercise) is an important component in the treatment of weight gain/obesity, dyslipidemia, hypertension, and hyperglycemia; in addition, a wide range of medications are available as therapeutic options for patients in whom non pharmacologic management strategies are insufficient. The use of adjunctive medication may also reduce treatment-related sedation and somnolence. LIMITATIONS: The selection of relevant studies from the literature search relied primarily on the author's expertise in the area of bipolar depression and knowledge of the issues addressed. CONCLUSION: Successful treatment of bipolar depression extends beyond managing mood symptoms to also monitoring adverse medication events and managing associated medical disorders. PMID- 25533915 TI - [Is anatomic pathology frozen between a slide and a coverslip?]. PMID- 25533914 TI - Plasma levels of mannan-binding lectin-associated serine proteases MASP-1 and MASP-2 are elevated in type 1 diabetes and correlate with glycaemic control. AB - There is increasing evidence that the complement system plays an important role in diabetes and the development of diabetic vascular complications. In particular, mannan-binding lectin (MBL) levels are elevated in diabetes patients, and diabetes patients with diabetic nephropathy have higher MBL levels than diabetes patients with normal renal function. The MBL-associated serine proteases (MASPs) MASP-1, MASP-2 and MASP-3 and MBL-associated protein MAp44 have not yet been studied in diabetes patients. We therefore measured plasma levels of MASP-1, MASP-2, MASP-3 and MAp44 in 30 children with type 1 diabetes mellitus (T1DM) and 17 matched control subjects, and in 45 adults with T1DM and 31 matched control subjects. MASP-1 and MASP-2 levels were significantly higher in children and adults with T1DM than in their respective control groups, whereas MASP-3 and MAp44 levels did not differ between patients and controls. MASP-1 and MASP-2 levels correlated with HbA1c, and MASP levels decreased when glycaemic control improved. Because MASP-1 and MASP-2 have been shown to interact directly with blood coagulation, elevated levels of these proteins may play a role in the enhanced thrombotic environment and consequent vascular complications in diabetes. PMID- 25533916 TI - Mesenchymal tumors and tumor-like lesions of the breast: a contemporary approach review. AB - The classification of the breast tumors has been revised and recently published in 2012 in the WHO blue book. Contrary to the epithelial tumors in the breast, mesenchymal tumors are rare and the classification for benign and malignant tumors is based on the same criteria in both categories, since no other specific diagnostic criteria, which would have an impact on prognosis, exist to date. The present review deals with minor changes mirroring the recent developments in the benign mesenchymal tumors (new additions are nodular fasciitis and atypical vascular lesions, while the haemangiopericytoma is removed) focusing especially on criteria to diagnose sarcomas, which represent a wide spectrum including very difficult lesions. The majority of sarcomas of the breast arise as a component of a malignant phyllodes tumor, while the pure forms are very rare. When a pure primary sarcoma of the breast is diagnosed, pathologists are encouraged to categorize the lesion according to the type of differentiation and to provide to the clinicians all the important prognostic parameters for the best treatment choice. PMID- 25533917 TI - [Myxoid tumors of deep soft tissues]. AB - Myxoid soft tissue tumors form a heterogeneous group. Their biological potential encompasses the whole spectrum from benign to highly malignant. The present article focuses on myxoid tumors of the deep soft tissues: myxofibrosarcoma, low grade fibromyxoid sarcoma, myxoma, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma and nodular fasciitis. The last two decades have brought into practice multiple powerful tools that support pathologists in making precise diagnoses, even on small incisional biopsies: detection of fusion transcripts by rt-PCR, detection of chromosomal fusion or breakpoint by FISH, detection of point mutations by PCR and expression of specific markers by immunohistochemistry. Conventional morphology remains the mainstay of diagnosis, and it is essential to obtain adequate clinical and radiological information before interpreting small incisional biopsies. The present article is a summary of morphologic features used to diagnose the most common tumors of the deep soft tissues. PMID- 25533918 TI - [Adipocytic tumors]. AB - Adipocytic tumors are the most common mesenchymal neoplasms, liposarcoma accounting for approximately 20% of soft tissue sarcomas. The differential diagnosis between benign and malignant tumors is often problematic and represents a significant proportion of consultation cases. The goal of this article is to review liposarcoma subtypes, the main benign adipocytic neoplasms: lipoblastoma, hibernoma, spindle/pleomorphic cell lipoma, chondroid lipoma, as well as non adipocytic neoplasms with a lipomatous component such as lipomatous solitary fibrous tumor, emphasizing on practical differential diagnosis issues, and immunohistochemical and molecular tools allowing their resolution. PMID- 25533919 TI - [Molecular biology for sarcoma: useful or necessary?]. AB - Sarcomas are a heterogeneous group of tumors. Their diagnosis is based on morphology and immunohistochemical profile, with categories of tumors according to the type of tissue that they resemble. Nevertheless, for several tumors, cellular origin is unknown. Molecular analysis performed in recent years allowed, combining histophenotype and genomics, better classifying such sarcomas, individualizing new entities and grouping some tumors. Simple and recurrent genetic alterations, such as translocation, mutation, amplification, can be identified in one of two sarcomas and appear as new diagnostic markers. Their identification in specialized laboratories in molecular pathology of sarcomas is often useful and sometimes necessary for a good diagnosis, leading to a heavy and multidisciplinary multi-step treatment. PMID- 25533920 TI - Proteomic analysis of mitochondria in respiratory epithelial cells infected with human respiratory syncytial virus and functional implications for virus and cell biology. AB - OBJECTIVES: The aim of this study was to quantitatively characterise the mitochondrial proteome of airway epithelial cells infected with human respiratory syncytial virus (HRSV), a major cause of paediatric illness. METHODS: Quantitative proteomics, underpinned by stable isotope labelling with amino acids in cell culture, coupled to LC-MS/MS, was applied to mitochondrial fractions prepared from HRSV-infected and mock-infected cells 12 and 24 h post-infection. Datasets were analysed using ingenuity pathway analysis, and the results were validated and characterised using bioimaging, targeted inhibition and gene depletion. KEY FINDINGS: The data quantitatively indicated that antiviral signalling proteins converged on mitochondria during HRSV infection. The mitochondrial receptor protein Tom70 was found to act in an antiviral manner, while its chaperone, Hsp90, was confirmed to be a positive viral factor. Proteins associated with different organelles were also co-enriched in the mitochondrial fractions from HRSV-infected cells, suggesting that alterations in organelle dynamics and membrane associations occur during virus infection. CONCLUSIONS: Protein and pathway-specific alterations occur to the mitochondrial proteome in a spatial and temporal manner during HRSV infection, suggesting that this organelle may have altered functions. These could be targeted as part of potential therapeutic strategies to disrupt virus biology. PMID- 25533922 TI - "Was it a mistake to tell others that you are infected with HIV?": factors associated with regret following HIV disclosure among people living with HIV in five countries (Mali, Morocco, Democratic Republic of the Congo, Ecuador and Romania). Results from a community-based research. AB - This study examined regret following HIV serostatus disclosure and associated factors in under-investigated contexts (Mali, Morocco, Democratic Republic of the Congo, Ecuador and Romania). A community-based cross-sectional study was implemented by a mixed consortium [researchers/community-based organizations (CBO)]. Trained CBO members interviewed 1,500 PLHIV in contact with CBOs using a 125-item questionnaire. A weighted multivariate logistic regression was performed. Among the 1,212 participants included in the analysis, 290 (23.9 %) declared that disclosure was a mistake. Female gender, percentage of PLHIV's network knowing about one's seropositivity from a third party, having suffered rejection after disclosure, having suffered HIV-based discrimination at work, perceived seriousness of infection score, daily loneliness, property index and self-esteem score were independently associated with regret. Discrimination, as well as individual characteristics and skills may affect the disclosure experience. Interventions aiming at improving PLHIV skills and reducing their social isolation may facilitate the disclosure process and avoid negative consequences. PMID- 25533921 TI - Depression and Apathy Among People Living with HIV: Implications for Treatment of HIV Associated Neurocognitive Disorders. AB - Depression and apathy are common among people living with HIV (PLWH). However, in PLWH, it is unclear whether depression and apathy are distinct conditions, which contribute to different patterns of disruption to cognitive processing and brain systems. Understanding these conditions may enable the development of prognostic indicators for HIV associated neurocognitive disorders (HAND). The present study examined substance use behavior and cognitive deficits, associated with depression and apathy, in 120 PLWH, using hierarchical regression analyses. Higher levels of depression were associated with a history of alcohol dependence and greater deficits in processing speed, motor and global cognitive functioning. Higher levels of apathy were associated with a history of cocaine dependence. It is recommended that PLWH get screened appropriately for apathy and depression, in order to receive the appropriate treatment, considering the comorbidities associated with each condition. Future research should examine the neurological correlates of apathy and depression in PLWH. PMID- 25533923 TI - Gender Abuse and Incident HIV/STI Among Transgender Women in New York City: Buffering Effect of Involvement in a Transgender Community. AB - In a 3 year prospective study of 230 transgender women from the New York City Area, we further examined associations of gender-related abuse with HIV sexual risk behavior and incident HIV/STI, focusing here and the extent to which these associations are buffered by involvement in a transgender community. Largely consistent with the prior study, gender abuse was longitudinally associated with unprotected receptive anal intercourse (URAI) with casual and commercial sex partners, and the presumed biological outcome of this behavioral risk, new cases of HIV/STI. Both of these associations, gender abuse with URAI and HIV/STI, were significantly buffered by transgender community involvement (interaction effects). However, independent of these interaction effects, transgender community involvement was also positively associated with URAI and HIV/STI (direct effects). HIV prevention in this population should emphasize the benefits of interactions with transgender peers while also emphasizing the importance of resisting normative permission for HIV risk behavior from these same peers. PMID- 25533924 TI - Three cases of suprachoroidal hemorrhage associated with chest compression or asphyxiation and detected using postmortem computed tomography. AB - We report 3 cases of suprachoroidal hemorrhage (SCH) found to be triggered by increased intrathoracic pressure and detected using postmortem computed tomography (PMCT). Case 1 was a man aged in his 50s who was found dead at a landslide site. The autopsy showed clogging of the upper respiratory tract with soil debris from the landslide. The cause of death was determined to be asphyxia. PMCT showed SCH in both eyes, which was believed to be caused by chest compression or choking on the soil debris from the landslide. Case 2 was a woman aged in her 60s who was found dead in the sea. The autopsy revealed injuries primarily to her chest. We concluded that the cause of death was drowning. PMCT showed SCH in her right eye that was believed to be caused by chest compression. Case 3 was a woman aged in her 80s who was buried in a snowdrift and potentially died from hypothermia. PMCT showed SCH in both eyes, which was considered to be from an increase in intrathoracic pressure that might have been caused by the burial in the snow. Histological findings showed serous retinal detachment associated with retinal pigment epithelium damage due to SCH, which indicated that she was alive for several hours after the onset of SCH. The increase in intrathoracic pressure caused by dyspnea or chest compression was considered responsible for the onset of SCH in all of the present cases. PMCT might assist with the differential diagnosis of traumatic asphyxiation by SCH. PMID- 25533925 TI - Pericardial tear as a consequence of cardiopulmonary resuscitation (CPR) involving chest compression: a report of two postmortem cases of acute type A aortic dissection with hemopericardium. AB - We present two cases of a pericardial tear as a consequence of cardiopulmonary resuscitation involving chest compressions in fatal acute type A aortic dissection (AoD) with hemopericardium. For each case, postmortem computed tomography revealed a hematoma in the false lumen of the ascending aorta with a slight hemopericardium and a large left hemothorax, as well as focal pericardial dimpling and discontinuity around the left ventricle. At autopsy, we confirmed a convex lens-shape gaping pericardial tear at the left posterolateral site of the pericardium and a massive volume of bloody fluid in the left thoracic cavity. It has been hypothesized that the pericardium ruptured due to chest compressions during resuscitation in these cases of acute type A AoD with hemopericardium and that intrapericardial blood leakage through the pericardial tear resulted in a hemothorax. PMID- 25533926 TI - The Effects of Verb Argument Complexity on Verb Production in Persons with Aphasia: Evidence from a Subject-Object-Verb Language. AB - The purpose of the study was to investigate the effects of verb argument complexity on verb production in individuals with aphasia using a verb-final language. The verb-argument complexity was examined by the number of arguments (1 , 2-, and 3-place) and the types of arguments (unaccusative vs. unergative comparisons). Fifteen Korean-speaking individuals with aphasia and 16 normal controls participated in the study. A confrontation naming task was used to elicit verb production with a total of 36 items for each verb type (1-place unergative, 1-place unaccusative, 2-place, and 3-place verbs). Individuals with aphasia presented lower mean percentage correctness in 3-place than in 1-place verbs, and showed differentially greater difficulties with unaccusative constructions than with unergative verbs, compared to the control group. The effects of verb-argument complexity were clearly observed in Korean-speaking individuals with aphasia. The effects of the number of arguments were observed most clearly in Broca's and Wernicke's types of aphasia and individuals with lower overall aphasia severity. The effects of Korean unaccusativity manifested across aphasia groups. General patterns of verb-argument complexity in Korean were consistent with previous findings in English. PMID- 25533927 TI - GP commissioners are advised "if in doubt, disclose" when managing conflicts of interest. PMID- 25533928 TI - Transplantation of mouse ovarian tissue: comparison of the transplantation sites. AB - Many studies have shown that ischemic injuries during the transplantation process were more detrimental than cryoinjuries for follicle survival and death, and it has been reported that transplantation sites can affect the outcomes of grafted ovarian tissue (OT). The purpose of this study was to assess the impact of different OT transplantation sites on follicular integrity and function of OT grafts. B6D2F1 mice were randomly assigned to control (sham) and four experimental groups according to transplantation sites (back muscle [BM], fat pad [FP], kidney capsule [KC], and subcutaneous [SC]). The ovaries from four groups were autotransplanted to each site. The OT recovery ratios on Days 2, 7, and 21 were significantly decreased in the FP group. The mean numbers of follicles were significantly lower in all the grafting groups compared with the sham group, except in the KC group on Days 7 and 21 and the BM group on Day 21. On Day 2, all the experimental groups showed low intact (G1) follicle ratio when compared with the sham group; however, the BM, KC, and FP groups recovered their morphologic integrity on Day 7, and only the SC group presented a significant decrease in G1 follicle ratios. On Day 21, the G1 follicle ratios of the FP and KC groups were greater than the sham control group. The proportion of apoptotic follicles of the four OT graft groups was higher than in the sham group on Day 2, followed by a significant decrease in the KC group and an increase in the SC group on Day 7. The serum follicle-stimulating hormone levels were significantly increased in all grafting groups on Day 2. On Day 7, only the SC group showed the high follicle stimulating hormone level compared with the other groups. The mean numbers of oocytes from OT grafts were the highest in the KC group, except in the control group, and the lowest in the SC group. The ratios of mature oocytes were also significantly greater in the sham and KC groups. However, the ratios of normal spindle did not differ among the five groups. In conclusion, the KC was the optimal site for OT transplantation in this murine model, whereas the SC site was unfavorable for this procedure. In this study, we confirmed that the different grafting sites influenced the outcomes of transplantation. PMID- 25533929 TI - Identification of bovine prolactin in seminal fluid, and expression and localization of the prolactin receptor and prolactin-inducible protein in the testis and epididymis of bulls exposed to ergot alkaloids. AB - The objectives of this study were to determine (1) the presence and expression levels of bovine prolactin receptor (PRLR) and prolactin-inducible protein (PIP) in bovine testis and epididymis, and (2) the presence and concentrations of prolactin (PRL) present in seminiferous fluid in bulls consuming diets with (E+) or without (E-) ergot alkaloids. Bulls (n = 8) were sacrificed after 126 days (group A) of E+ or E- treatment or 60 days after all bulls (n = 6) were switched to the E- ration (group B). End point and real-time quantitative reverse transcription-polymerase chain reaction and immunohistochemistry were conducted on testis and epididymis samples to establish the presence and relative expression of PRLR and PIP. Seminal fluid samples obtained from bulls consuming E and E+ diets were subjected to RIA for PRL. Both PIP and PRLR were present in testis and epididymis as determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Prolactin-inducible protein mRNA abundance was affected by time of slaughter in testis and epididymis head, respectively (P < 0.05). Prolactin receptor mRNA expression was affected by time of slaughter in the epididymis (P < 0.05) and differed in testis samples because of treatment (P < 0.05). Radioimmunoassay establishes the presence of PRL in seminal fluid; however, differences in the concentration of PRL over two separate studies were inconsistent, possibly because of differences in diet. The presence and localization of the PRLR are consistent with expression data reported for other species, and the presence of PIP and PRL in seminal fluid is consistent with data generated in humans. PMID- 25533930 TI - The use of medical claims to assess incidence, diagnostic procedures and initial treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia in the Netherlands. AB - Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) may be underreported in cancer registries such as the Netherlands Cancer Registry (NCR). Analysis of Dutch medical claims can complement NCR data on MDS and CMML. We analyzed data on 3681 MDS patients and 235 CMML patients aged >=18 years with initial claims for MDS or CMML from the Dutch nationwide medical claims-based Diagnosis Treatment Combination Information System (DIS) between 2008 and 2010. Clinical information was available in the DIS. MDS and CMML were diagnosed without a bone marrow (BM) examination in almost half of the patients. The age standardized incidence rate (ASR) per 100,000 in the cohort that underwent BM examinations compared with NCR data was 2.8 vs. 3.3 for MDS and 0.2 vs. 0.4 for CMML in 2008-2010. A conservative treatment approach was associated with increasing age and absence of BM examination in MDS (p<0.001 for both) and CMML patients (p<0.033 for both). In conclusion, the ASR of MDS in the cohort that underwent BM examinations was comparable with the NCR. The majority of elderly patients, either with or without BM examinations, received no therapy. Together, MDS and CMML may be misdiagnosed and inappropriately managed without a BM confirmation. PMID- 25533931 TI - The hENT1 and DCK genes underlie the decitabine response in patients with myelodysplastic syndrome. AB - Decitabine is approved for the treatment of MDS, but resistance to this agent is common. To determine the mechanisms underlying decitabine resistance, we measured the mRNA expression of metabolism (hENT1, DCK, CDA) and apoptosis (BCL2L10) genes and found that the hENT1 mRNA level was significantly higher in response compared with non-response patients (P=0.004). Furthermore, the DCK level was significantly reduced for relapse (P=0.012) compared with those with continued marrow CR (P=0.222). These findings indicate that the decitabine metabolic pathway affects its therapeutic effects, lower hENT1 expression may induce primary resistance and down-regulated DCK expression may be related to secondary resistance. PMID- 25533933 TI - Sweat gland regeneration after burn injury: is stem cell therapy a new hope? AB - Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. The skin of patients with an extensive deep burn injury is repaired by a hypertrophic scar without regeneration of sweat glands and therefore loses the function of perspiration. Stem cell therapy provides the possibility of sweat gland regeneration. In particular, recent studies have reported the reprogramming of mesenchymal stromal cells into sweat gland-like (SGL) cells. We present an overview of recent researches into sweat gland regeneration with stem cells. Difficulties of sweat gland regeneration after deep burns have been elaborated. The advantage and disadvantage of several stem cell types in sweat gland regeneration have been discussed. Additionally, the possible mechanisms for reprogramming stem cells to SGL cells are summarized. A brief discussion on clinical application of stem cell-derived SGL cells is also presented. This review may possibly provide some implications for sweat gland regeneration. PMID- 25533934 TI - Challenges of cancer therapy with natural killer cells. AB - BACKGROUND AIMS: Natural killer (NK) cells from peripheral or cord blood especially if they are obtained from a human leukocyte antigen-mismatched (allogeneic) donor-are increasingly being considered for treatment of malignant diseases and to prevent or treat relapse after stem cell transplant. However, in addition to proving their efficacy, there are some more logistical and technical issues that must be addressed before NK cell infusions will be fully accepted by the medical community. METHODS: Issues include (i) the expansion of sufficient numbers of cells under conditions suitable, (ii) cryopreservation and (iii) optimization/standardization of shipping conditions if the cells are used at distant sites. Because the patient's own autologous cells usually are not fully functional because of inhibition by "self" major histocompatibility complex expression, better methods must be developed to target NK cells to tumor cells and overcome self-inhibition. RESULTS: Tumor-directed NK-cell therapy can be best accomplished through genetic engineering of NK cells expressing receptors for tumor antigens or combination with monoclonal antibodies that preferentially kill tumors through antibody-dependent cellular cytotoxicity. If allogeneic NK cells are used, T-lymphocytes in the cell collections that can cause acute graft-versus host disease in the recipient must be removed. CONCLUSIONS: In addition to showing efficacy in clinical trials, the production of NK cells for treatment must be cost-effective to be eligible for reimbursement by third-party players. PMID- 25533935 TI - Processing the 5-mL umbilical cord blood unit with the use of an automated wash procedure. PMID- 25533936 TI - Epigenetic effects of low perinatal doses of flame retardant BDE-47 on mitochondrial and nuclear genes in rat offspring. AB - Polybrominated diphenyl ethers (PBDEs) are known endocrine disrupting chemicals used commonly as flame retardants in everything from electronics to furniture. Exposure to PBDEs during early development has been linked to neurodevelopmental delays. Despite mounting evidence of neurological harm from PBDE exposure, the molecular mechanisms underlying these effects on brain function remain unknown. We examined the effects of perinatal exposure to BDE-47, the most biologically active and prevalent BDE congener in North America, on epigenetic patterns in the frontal lobe of Wistar rats. Dams were gavaged with BDE-47 (0.002 and 0.2mg/kg body weight) at gestation days 9 and 16, and postnatal days 1, 8, and 15. Frontal lobes from offspring at postnatal day 41 were collected to measure 5 methylcytosine (5mC) in mitochondrial cytochrome c oxidase genes (Mt-co1, Mt-co2, and Mt-co3), global nuclear 5-hydroxymethylcytosine (5hmC) content, 5mC in repetitive elements L1Rn, and 5mC in nuclear genes (Bdnf, Crhr1, Mc2r, Nr3c1, and Snca) related to behavioral and brain functions in the nuclear genome. We observed a significant decrease in %5mC in Mt-co2 (difference from control= 0.68%, p=0.01 at the 0.2mg/kg BDE-47). 5mC in repetitive elements L1Rn decreased at 0.002 mg/kg BDE-47 (difference=-1.23%, p=0.02). Decreased nuclear 5mC was observed in Bdnf and Nr3c1 in BDE-47 exposed rats. However, we did not observe significant effects of PBDE toxicity on DNA methylation patterns for the majority of genes in the brain. PMID- 25533938 TI - God gives IL-19 with both hands: anti-inflammatory but pro-angiogenic. PMID- 25533937 TI - Cardioprotection of recombinant human MG53 protein in a porcine model of ischemia and reperfusion injury. AB - Ischemic heart disease is a leading cause of death in human population and protection of myocardial infarction (MI) associated with ischemia-reperfusion (I/R) remains a challenge. MG53 is an essential component of the cell membrane repair machinery that protects injury to the myocardium. We investigated the therapeutic value of using the recombinant human MG53 (rhMG53) protein for treatment of MI. Using Langendorff perfusion of isolated mouse heart, we found that I/R caused injury to cardiomyocytes and release of endogenous MG53 into the extracellular solution. rhMG53 protein was applied to the perfusion solution concentrated at injury sites on cardiomyocytes to facilitate cardioprotection. With rodent models of I/R-induced MI, we established the in vivo dosing range for rhMG53 in cardioprotection. Using a porcine model of angioplasty-induced MI, the cardioprotective effect of rhMG53 was evaluated. Intravenous administration of rhMG53, either prior to or post-ischemia, reduced infarct size and troponin I release in the porcine model when examined at 24h post-reperfusion. Echocardiogram and histological analyses revealed that the protective effects of rhMG53 observed following acute MI led to long-term improvement in cardiac structure and function in the porcine model when examined at 4weeks post operation. Our study supports the concept that rhMG53 could have potential therapeutic value for treatment of MI in human patients with ischemic heart diseases. PMID- 25533939 TI - A systematic analysis of neonatal mouse heart regeneration after apical resection. AB - The finding that neonatal mice are able to regenerate myocardium after apical resection has recently been questioned. We determined if heart regeneration is influenced by the size of cardiac resection and whether surgical retraction of the ventricular apex results in an increase in cardiomyocyte cell cycle activity. We performed moderate or large apical ventricular resections on neonatal mice and quantified scar infiltration into the left ventricular wall at 21 days post surgery. Moderately resected hearts had 15+/-2% of the wall infiltrated by a collagen scar; significantly greater scar infiltration (23+/-4%) was observed in hearts with large resections. Resected hearts had higher levels of cardiomyocyte cell cycle activity relative to sham hearts. Surgically retracting the ventricle often resulted in fibrosis and induced cardiomyocyte cell cycle activity that were comparable to that of resected hearts. We conclude that apical resection in neonatal mice induces cardiomyocyte cell cycle activity and neomyogenesis, although scarring can occur. Surgical technique and definition of approach to assessing the extent of regeneration are both critical when using the neonatal mouse apical resection model. PMID- 25533942 TI - Immunotherapy: PD-1-PD-L1 axis: efficient checkpoint blockade against cancer. PMID- 25533943 TI - Lung cancer in 2014: optimizing lung cancer treatment approaches. AB - In 2014, developments in our understanding of escape signalling circuits implicated in resistance to targeted agents in patients with lung cancer have led to improvements in tackling such resistance. The potential role for PET in the management of erlotinib therapy, novel combination therapies and pharmacogenomic driven individualization of platinum-based chemotherapy represent other key advances. PMID- 25533945 TI - Haematological cancer: ASPIRE for unprecedented benefit with carfilzomib in MM. PMID- 25533946 TI - Haematological cancer: PD-1 blockade: opening the door to attack. PMID- 25533947 TI - Developing biomarker-specific end points in lung cancer clinical trials. AB - In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. Furthermore, although radiographic surrogate end points, such as PFS and response rate, generally correlate with clinical benefit in the setting of cytotoxic chemotherapy and molecular targeted therapies, novel immunotherapies might have atypical response kinetics, which confounds radiographic interpretation. In this Review, we discuss the need to develop alternative or surrogate end points for lung cancer clinical trials, and focus on several new biomarkers that could serve as surrogate end points, including functional imaging biomarkers, circulating factors (tumour proteins, DNA, and cells), and pharmacodynamic tumour markers. By enabling the size, duration, and complexity of cancer trials to be reduced, biomarker end points hold the promise to accelerate drug development and improve patient outcomes. PMID- 25533950 TI - Plant biology: Seeing the wood and the trees. PMID- 25533949 TI - A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. AB - Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 A co crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD(+) collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD(+)-dependent dimension to the physiological mechanism of resveratrol. PMID- 25533951 TI - Dissecting neural differentiation regulatory networks through epigenetic footprinting. AB - Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system. Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line. Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation. PMID- 25533952 TI - Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. AB - Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging. PMID- 25533954 TI - Cell division: Hold on and let go. PMID- 25533953 TI - An Arabidopsis gene regulatory network for secondary cell wall synthesis. AB - The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein-DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component. PMID- 25533955 TI - NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs. AB - A distinctive feature of prokaryotic gene expression is the absence of 5'-capped RNA. In eukaryotes, 5',5'-triphosphate-linked 7-methylguanosine protects messenger RNA from degradation and modulates maturation, localization and translation. Recently, the cofactor nicotinamide adenine dinucleotide (NAD) was reported as a covalent modification of bacterial RNA. Given the central role of NAD in redox biochemistry, posttranslational protein modification and signalling, its attachment to RNA indicates that there are unknown functions of RNA in these processes and undiscovered pathways in RNA metabolism and regulation. The unknown identity of NAD-modified RNAs has so far precluded functional analyses. Here we identify NAD-linked RNAs from bacteria by chemo-enzymatic capture and next generation sequencing (NAD captureSeq). Among those identified, specific regulatory small RNAs (sRNAs) and sRNA-like 5'-terminal fragments of certain mRNAs are particularly abundant. Analogous to a eukaryotic cap, 5'-NAD modification is shown in vitro to stabilize RNA against 5'-processing by the RNA pyrophosphohydrolase RppH and against endonucleolytic cleavage by ribonuclease (RNase) E. The nudix phosphohydrolase NudC decaps NAD-RNA and thereby triggers RNase-E-mediated RNA decay, while being inactive against triphosphate-RNA. In vivo, ~13% of the abundant sRNA RNAI is NAD-capped in the presence, and ~26% in the absence, of functional NudC. To our knowledge, this is the first description of a cap-like structure and a decapping machinery in bacteria. PMID- 25533956 TI - Meikin is a conserved regulator of meiosis-I-specific kinetochore function. AB - The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans. PMID- 25533957 TI - Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. AB - Intrinsically disordered proteins play important roles in cell signalling, transcription, translation and cell cycle regulation. Although they lack stable tertiary structure, many intrinsically disordered proteins undergo disorder-to order transitions upon binding to partners. Similarly, several folded proteins use regulated order-to-disorder transitions to mediate biological function. In principle, the function of intrinsically disordered proteins may be controlled by post-translational modifications that lead to structural changes such as folding, although this has not been observed. Here we show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of three mammalian proteins that bind eIF4E and suppress cap dependent translation initiation. In its non-phosphorylated state, 4E-BP2 interacts tightly with eIF4E using both a canonical YXXXXLPhi motif (starting at Y54) that undergoes a disorder-to-helix transition upon binding and a dynamic secondary binding site. We demonstrate that phosphorylation at T37 and T46 induces folding of residues P18-R62 of 4E-BP2 into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a partly buried beta-strand, blocking its accessibility to eIF4E. The folded state of pT37pT46 4E-BP2 is weakly stable, decreasing affinity by 100-fold and leading to an order-to disorder transition upon binding to eIF4E, whereas fully phosphorylated 4E-BP2 is more stable, decreasing affinity by a factor of approximately 4,000. These results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins. PMID- 25533958 TI - Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. AB - Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is both organ- and injury-specific. Current models in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. By contrast, here we define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells present within normal distal lung. Quiescent LNEPs activate a DeltaNp63 (a p63 splice variant) and cytokeratin 5 remodelling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signalling to activate the DeltaNp63 and cytokeratin 5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signalling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signalling. Our findings indicate that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signalling. PMID- 25533959 TI - Mechanosensory interactions drive collective behaviour in Drosophila. AB - Collective behaviour enhances environmental sensing and decision-making in groups of animals. Experimental and theoretical investigations of schooling fish, flocking birds and human crowds have demonstrated that simple interactions between individuals can explain emergent group dynamics. These findings indicate the existence of neural circuits that support distributed behaviours, but the molecular and cellular identities of relevant sensory pathways are unknown. Here we show that Drosophila melanogaster exhibits collective responses to an aversive odour: individual flies weakly avoid the stimulus, but groups show enhanced escape reactions. Using high-resolution behavioural tracking, computational simulations, genetic perturbations, neural silencing and optogenetic activation we demonstrate that this collective odour avoidance arises from cascades of appendage touch interactions between pairs of flies. Inter-fly touch sensing and collective behaviour require the activity of distal leg mechanosensory sensilla neurons and the mechanosensory channel NOMPC. Remarkably, through these inter-fly encounters, wild-type flies can elicit avoidance behaviour in mutant animals that cannot sense the odour--a basic form of communication. Our data highlight the unexpected importance of social context in the sensory responses of a solitary species and open the door to a neural-circuit-level understanding of collective behaviour in animal groups. PMID- 25533960 TI - Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. AB - The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the beta branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 A resolution. The structure reveals how suvorexant adopts a pi-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous pi-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends. PMID- 25533961 TI - CetZ tubulin-like proteins control archaeal cell shape. AB - Tubulin is a major component of the eukaryotic cytoskeleton, controlling cell shape, structure and dynamics, whereas its bacterial homologue FtsZ establishes the cytokinetic ring that constricts during cell division. How such different roles of tubulin and FtsZ evolved is unknown. Studying Archaea may provide clues as these organisms share characteristics with Eukarya and Bacteria. Here we report the structure and function of proteins from a distinct family related to tubulin and FtsZ, named CetZ, which co-exists with FtsZ in many archaea. CetZ X ray crystal structures showed the FtsZ/tubulin superfamily fold, and one crystal form contained sheets of protofilaments, suggesting a structural role. However, inactivation of CetZ proteins in Haloferax volcanii did not affect cell division. Instead, CetZ1 was required for differentiation of the irregular plate-shaped cells into a rod-shaped cell type that was essential for normal swimming motility. CetZ1 formed dynamic cytoskeletal structures in vivo, relating to its capacity to remodel the cell envelope and direct rod formation. CetZ2 was also implicated in H. volcanii cell shape control. Our findings expand the known roles of the FtsZ/tubulin superfamily to include archaeal cell shape dynamics, suggesting that a cytoskeletal role might predate eukaryotic cell evolution, and they support the premise that a major function of the microbial rod shape is to facilitate swimming. PMID- 25533963 TI - A Matter of Fat. AB - Acute respiratory disease syndrome (ARDS) is a common complication of critical illness, associated with significant morbidity, prolonged intensive care unit (ICU) and hospital stay, and increased mortality. Inflammation plays a central role in ARDS, with inflammatory eicosanoid mediators produced from the omega-6 fatty acid arachidonic acid, such as leukotriene B4, being involved. The omega-3 fatty acids found in fish oil exert anti-inflammatory effects, including decreasing production of inflammatory eicosanoids from arachidonic acid. The omega-3 fatty acids are effective in models relevant to ARDS. Several randomized controlled trials of enteral formulas rich in omega-3 fatty acids, often in combination with other bioactive substances, have been conducted in patients with ARDS. Four of these trials reported marked clinical benefits, 2 reported no effect, and 1 reported a negative impact. A systematic review and meta-analysis of these 7 trials identified no overall effect on ventilator-free days or on ICU free days. There was a small reduction in ICU length of stay and no overall effect on mortality. However, the authors formally identified that trials that used high fat in both treatment and control groups showed a significant reduction in mortality, while trials that used a high, or higher, fat treatment and a low fat control group showed a trend toward an increase in mortality. It is concluded that differences in outcome reported among these studies largely relate to the relative fat contents of the treatment and control formulas. Further, it is concluded that high-fat enteral formulas should not be used in this patient group. PMID- 25533964 TI - Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures. AB - BACKGROUND: Inorganic nitrite dilates small resistance arterioles via hypoxia facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries. METHODS AND RESULTS: We examined the effects of local and systemic administration of sodium nitrite on the radial artery (a muscular conduit artery), forearm resistance vessels (forearm blood flow), and systemic hemodynamics in healthy male volunteers (n=43). Intrabrachial sodium nitrite (8.7 MUmol/min) increased radial artery diameter by a median of 28.0% (25th and 75th percentiles, 25.7% and 40.1%; P<0.001). Nitrite (0.087-87 MUmol/min) displayed conduit artery selectivity similar to that of glyceryl trinitrate (0.013-4.4 nmol/min) over resistance arterioles. Nitrite dose-dependently increased local cGMP production at the dose of 2.6 MUmol/min by 1.1 pmol.min(-1).100 mL(-1) tissue (95% confidence interval, 0.5-1.8). Nitrite-induced radial artery dilation was enhanced by administration of acetazolamide (oral or intra-arterial) and oral raloxifene (P=0.0248, P<0.0001, and P=0.0006, respectively) but was inhibited under hypoxia (P<0.0001) and hyperoxia (P=0.0006) compared with normoxia. Systemic intravenous administration of sodium nitrite (8.7 MUmol/min) dilated the radial artery by 10.7% (95% confidence interval, 6.8-14.7) and reduced central systolic blood pressure by 11.6 mm Hg (95% confidence interval, 2.4-20.7), augmentation index, and pulse wave velocity without changing peripheral blood pressure. CONCLUSIONS: Nitrite selectively dilates conduit arteries at supraphysiological and near-physiological concentrations via a normoxia-dependent mechanism that is associated with cGMP production and is enhanced by acetazolamide and raloxifene. The selective central blood pressure-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events. PMID- 25533965 TI - Harnessing the nitrate-nitrite-nitric oxide pathway for therapy of heart failure with preserved ejection fraction. PMID- 25533968 TI - Making sense of genome-wide association studies: integrating genetic variation with gene expression to derive functional mechanisms underlying disease risk. PMID- 25533969 TI - Declining use rates of revascularization for Medicare patients: is this a real trend? PMID- 25533962 TI - Large-scale discovery of novel genetic causes of developmental disorders. AB - Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders. PMID- 25533967 TI - Integromic analysis of genetic variation and gene expression identifies networks for cardiovascular disease phenotypes. AB - BACKGROUND: Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. METHODS AND RESULTS: We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P<=5*10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. CONCLUSIONS: Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD. PMID- 25533966 TI - Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. AB - BACKGROUND: Inorganic nitrate (NO3(-)), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3(-) supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise. METHODS AND RESULTS: Seventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO3-rich beetroot juice (NO3(-), 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak VO2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma nitric oxide metabolites (median, 326 versus 10 MUmol/L; P=0.0003), peak VO2 (12.6+/-3.7 versus 11.6+/-3.1 mL O2.min(-1).kg(-1); P=0.005), and total work performed (55.6+/-35.3 versus 49.2+/-28.9 kJ; P=0.04). However, efficiency was unchanged. NO3(-) led to greater reductions in systemic vascular resistance ( 42.4+/-16.6% versus -31.8+/-20.3%; P=0.03) and increases in cardiac output (121.2+/-59.9% versus 88.7+/-53.3%; P=0.006) with exercise. NO3(-) reduced aortic augmentation index (132.2+/-16.7% versus 141.4+/-21.9%; P=0.03) and tended to improve mitochondrial oxidative function. CONCLUSIONS: NO3(-) increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and VO2. NO3(-) increased exercise vasodilatory and cardiac output reserves. NO3(-) also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01919177. PMID- 25533970 TI - Trends in coronary revascularization procedures among Medicare beneficiaries between 2008 and 2012. AB - BACKGROUND: This study reports on the trends in the volume and outcomes of coronary revascularization procedures performed on Medicare beneficiaries between 2008 and 2012. METHODS AND RESULTS: This retrospective study identifies all Medicare beneficiaries undergoing a coronary revascularization procedure: coronary artery bypass graft surgery or percutaneous coronary intervention (PCI) performed in either the nonadmission or inpatient setting. International Classification of Diseases, 9th Revision, Clinical Modification procedure codes (inpatient setting) and Current Procedural Terminology and Ambulatory Payment Classification codes (nonadmission) were used to identify revascularizations. The study population consists of 2,768,007 records. This study finds that the rapid growth in nonadmission PCIs performed on Medicare beneficiaries (60,405-106,495) has been more than offset by the decrease in PCI admissions (363,384-295,434) during the study period. There also were >18,000 fewer coronary artery bypass graft admissions in 2012 than in 2008. This study finds lower observed mortality rates (3.7%-3.2%) among Medicare beneficiaries undergoing any coronary artery bypass graft surgery and higher observed mortality rates (1.7%-1.9%) for Medicare beneficiaries undergoing any PCI encounter. This study also finds a growth in the number of facilities performing revascularization procedures during the study period: 268 (20.2%) more sites were performing nonadmission PCIs; 136 (8.2%) more sites were performing inpatient PCIs; and 19 (1.6%) more sites were performing coronary artery bypass graft surgery. CONCLUSIONS: The total number of revascularization procedures performed on Medicare beneficiaries peaked in 2010 and declined by >4% per year in 2011 and 2012. Observed mortality rates among all Medicare beneficiaries undergoing any coronary revascularization remained between 2.1% and 2.2% annually during the study period. PMID- 25533971 TI - Possible association of the BRCA2 gene C5972T variant with gastric cancer: a study on Polish population. AB - INTRODUCTION: Gastric cancer (GC) belongs to a group of cancers linked to BRCA2 gene mutations and observed in patients with a family history of breast and ovarian cancers. A common variant allele (C5972T) observed in the BRCA2 gene in the Polish population is associated with an increased risk of breast cancer. OBJECTIVES: The objective of the study was to assess a relationship between the BRCA2 C5972T variant and GC. PATIENTS AND METHODS: A total of 380 patients with GC (234 men and 146 women; mean age, 59.0 +/-12.8 years) and 380 sex- and age matched healthy individuals (234 men and 146 women; mean age, 59.0 +/-12.9 years) were included in this retrospective study. Polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) was used to detect the BRCA2 C5972T variant. We compared the frequency of BRCA2 allele carriers among patients and controls. We also compared selected clinical and pathological features between allele carriers and noncarriers among patients with GC. RESULTS: The BRCA2 C5972T variant was observed in 28 patients with GC (7.4%) and in 18 controls (4.7%) (P = 0.17). The odds ratio [OR] for GC in allele carriers was 1.59 (95% confidence interval [CI], 0.87-2.94). A comparison of selected clinical and pathological features between carriers and noncarriers did not show any significant differences. The analysis of a family history showed a trend for an increased risk of breast or ovarian cancer in the families of patients with GC carrying the C5972T allele (OR, 2.51; 95% CI, 0.80-7.88, P = 0.11). CONCLUSIONS: Our study showed that the C5972T allele is a low-penetrant variant of the BRCA2 gene, which tended to increase the risk of GC. Further research is needed to fully elucidate the role of BRCA2 polymorphisms in GC. PMID- 25533972 TI - Incidence and mechanisms of longitudinal stent deformation associated with Biomatrix, Resolute, Element, and Xience stents: Angiographic and case-by-case review of 1,800 PCIs. AB - BACKGROUND: There is conflicting evidence regarding the incidence of longitudinal stent deformation (LSD) in contemporary practice. METHODS AND RESULTS: To assess the incidence and mechanism of LSD across commonly used DES platforms, we performed a case-by-case review of 1,800 PCI cases involving 450 consecutive procedures using Biomatrix Flex, Resolute Integrity, Promus Element, and Xience V stents, respectively, between January 2009 and December 2011. LSD was detected in a higher proportion with Promus Element [15 (3.1%)] compared with other platforms (Xience V [4 (0.9%)], Biomatrix [3 (0.7%)], Resolute [3 (0.7%)]; P = 0.002). LSD was characterized as guide catheter/guide extension induced, or as impact from secondary devices such as postdilatation balloons or IVUS catheters. The incidence of guide catheter/guide extension LSD was similar across platforms; (Promus Element [5 (1.1%)], Xience V [4 (0.9%)], Biomatrix [3 (0.7%)], Resolute [3 (0.7%)]; P = 0.85). Secondary device LSD occurred exclusively with Promus Element (9/450 cases [2%] (P < 0.0001). Re-entering the deformed stent was more difficult in cases of secondary device LSD (6/9 compared with 0/12 treated cases; P < 0.001). Univariate predictors of LSD were previous CABG, culprit vessel, ostial involvement, and lesion tortuosity. Multivariate predictors of LSD were the Promus Element stent (OR 5.53 CI[1.54-19.85]), Guideliner use (OR 22.09 CI[4.73-103]), postdilation balloons (OR 5.47 CI[1.31-22.81]) and number of stents deployed (OR 2.06 CI[1.45-2.9]. CONCLUSION: LSD is more common than previously reported. LSD by a guide catheter/guide extension occurred equally with all platforms, however, LSD associated with secondary devices only occurred with the Element stent. These findings have important implications regarding current and future stent designs. PMID- 25533973 TI - DISC1 gene and affective psychopathology: a combined structural and functional MRI study. AB - The gene Disrupted-In-Schizophrenia-1 (DISC1) has been indicated as a determinant of psychopathology, including affective disorders, and shown to influence prefrontal cortex (PFC) and hippocampus functioning, regions of major interest for affective disorders. We aimed to investigate whether DISC1 differentially modulates brain function during executive and memory processing, and morphology in regions relevant for depression and anxiety disorders (affective disorders). 128 participants, with (n = 103) and without (controls; n = 25) affective disorders underwent genotyping for Ser704Cys (with Cys-allele considered as risk allele) and structural and functional (f) Magnetic Resonance Imaging (MRI) during visuospatial planning and emotional episodic memory tasks. For both voxel-based morphometry and fMRI analyses, we investigated the effect of genotype in controls and explored genotypeXdiagnosis interactions. Results are reported at p < 0.05 FWE small volume corrected. In controls, Cys-carriers showed smaller bilateral (para)hippocampal volumes compared with Ser-homozygotes, and lower activation in the anterior cingulate cortex (ACC) and dorsolateral PFC during visuospatial planning. In anxiety patients, Cys-carriers showed larger (para)hippocampal volumes and more ACC activation during visuospatial planning. In depressive patients, no effect of genotype was observed and overall, no effect of genotype on episodic memory processing was detected. We demonstrated that Ser704Cys genotype influences (para)hippocampal structure and functioning the dorsal PFC during executive planning, most prominently in unaffected controls. Results suggest that presence of psychopathology moderates Ser704Cys effects. PMID- 25533975 TI - [Prevention and treatment of postoperative cerebrospinal fluid leakage in spine]. PMID- 25533974 TI - Cognitive reappraisal of peer rejection in depressed versus non-depressed adolescents: functional connectivity differences. AB - BACKGROUND: Depression is the most common psychiatric disorder in adolescence, and is characterised by an inability to down-regulate negative emotional responses to stress. Adult studies suggest this may be associated with reduced functional connectivity between prefrontal and subcortical regions, yet the neurological mechanisms in adolescence remain unclear. METHODS: We developed a novel, age-appropriate, reappraisal paradigm to investigate functional connectivity during reappraisal of a real-life source of stress in 15 depressed and 15 non-depressed adolescents. During fMRI, participants i) attended to, and ii) implemented reappraisal techniques (learnt prior to fMRI) in response to, rejection. RESULTS: Reappraisal reduced negative mood and belief in negative thoughts in both groups alike, however during reappraisal (versus attend) trials, depressed adolescents showed greater connectivity between the right frontal pole and numerous subcortical and cortical regions than non-depressed adolescents. CONCLUSIONS: These findings tentatively suggest that, when instructed, depressed adolescents do have the ability to engage neural networks involved in emotion regulation, possibly because adolescence reflects a period of heightened plasticity. These data support the value of cognitive reappraisal as a treatment tool, identify neural markers that could be used to optimise current therapies, and lay the foundations for developing novel neuroscientific techniques for the treatment of adolescent depression. PMID- 25533976 TI - [Changes of sagittal balance of cervical spine after open-door expansive laminoplasty]. AB - OBJECTIVE: To explore the changes of sagittal balance of cervical spine after open-door expansive laminoplasty. METHODS: The clinical and radiological data were analyzed retrospectively for 90 patients undergoing open-door expansive laminoplasty due to cervical spondylotic myelopathy. The Japanese Orthopedic Association (JOA) score and 3 cervical sagittal parameters including C2-C7 SVA, C0-2 Cobb angle and T1-Slope on lateral view radiographs were recorded before operation and at the final follow-up. RESULTS: The average follow-up period was 16.7 (3-40) months. The post-operative JOA score rose to 14.6 +/- 0.2 from pre operative 12.2 +/- 0.3 with 43.5% +/- 4.2% recovery rate. The post-operative values of C2-C7 SVA, C0-2 Cobb angle and T1-Slope were significantly different from pre-operative ones (P = 0.022, P < 0.001, P = 0.002) . C2-C7 SVA increased to (23.0 +/- 1.2) mm from pre-operative (20.7 +/- 1.1) mm. C0-2 Cobb angle increased (23.1 +/- 0.8) degrees from pre-operative (19.9 +/- 0.8) degrees ; T1 Slope increased to (26.2 +/- 0.7) degrees from pre-operative (25.1 +/- 0.7) degrees . The changes of C0-2 Cobb angle and T1-Slope were correlated with that of C2-C7 SVA respectively (Pearson = 0.469, P < 0.001) (Pearson = 0.303, P = 0.004) . Patients with higher preoperative T1-Slope had less JOA improvement (31.5% vs 53.7%, P = 0.019) than those with lower preoperative T1-Slope after laminoplasty. CONCLUSION: The sagittal balance of cervical spine significantly changes after open-door expansive laminoplasty with forward tilting of cervical vertebra. And compensation occurs by excessive high-strength contraction of posterior muscles to maintain lordosis in upper cervical spine. A higher pre-OP T1-Slope affects the outcomes of open-door expansive laminoplasty. PMID- 25533977 TI - [Comparison of clinical efficacies of single segment transforaminal lumbar interbody fusion with cage versus autogenous morselized bone for degenerative lumbar spinal stenosis: a prospective randomized controlled study]. AB - OBJECTIVE: To compare the clinical efficacies of single segment transforaminal lumbar interbody fusion (TLIF) with cage versus autogenous morselized bone for degenerative lumbar spinal stenosis. METHODS: A total of 87 patients undergoing single segment TLIF were randomly divided into 2 groups. A cage was implanted into intervertebral space in group A patients while autogenous morselized bone in group B patients. Operative duration, blood loss, length of stay and cost of hospitalization of two groups were recorded. They were followed up at 1 week, 12, 24 months post-operation. Oswestry disability index (ODI), visual analogue scale (VAS) fusion rates, intervertebral space and foramen height restoration, lumbar lordosis and postoperative complications were compared between two groups. RESULTS: No significant inter-group difference existed in operative duration, blood loss or length of stay. However, the average hospitalization cost in group A were 18% higher than that of group B (P < 0.05). Both groups achieved excellent clinical outcomes within 2 years. ODI, VAS score improvement rates and postoperative complication rates were not statistically different. Lumbar fusion rate was 86.7% in group A versus 85.7% in group B after 2 years. And there was no significant difference (P > 0.05). The heights of intervertebral space and foramen in group A achieved a better recovery than those of group B. Both groups had similar improvements of lumbar lordosis. CONCLUSION: For degenerative lumbar spinal stenosis, usage of interbody cage is more effective in terms of recovery of intervertebral space and foraminal height compared with usage of bone graft. However it brings no better clinical efficacy while the usage of autogenous morselized bone is more cost-effective. Two grafting methods yield similar overall clinical outcomes. PMID- 25533978 TI - [Distribution of Schmorl's nodes in lumbar spine and their relationship with lumbar disc degeneration]. AB - OBJECTIVE: To explore the distribution of Schmorl's nodes (SN) in normal adult lumbar spine and determine the association of lumbar disc degeneration and lumbar spine motion. METHODS: A total of 1 179 individuals underwent magnetic resonance imaging (MRI) scans. They had an age range of 15-85 years and were grouped by 10 years. The distribution of SNs along lumbar spine and their relationship with age and gender were examined by single factor analysis of variance chi-square test. Spine specialists performed lumbar disc degeneration evaluations through the Pfirrmann's classification system. The relationship between SNs, age group, disc location and overall grades of lumbar disc degeneration were analyzed by multiple Logistic regression. RESULTS: The prevalence of SNs was 28.4%. And SNs were observed more frequently in males than females (34.6% vs 20.2%) (P < 0.01). No significant inter-group difference existed in the incidence of SNs (P = 0.18). SNs were more common at L2 and L3 vertebral bodies (14.3% vs 14.4%) while least common at S1 vertebral body (1.5%). The highest incidence of SNs was found in discs with degeneration grades III (41.9%) and IV (45.3%). The occurrence of SN, aging and disc location were positively correlated with lumbar disc degeneration grade. CONCLUSION: With a high incidence in healthy individuals, SNs occur in discs at all degrees of degeneration. And the occurrence of SNs is positively associated with lumbar disc degeneration. PMID- 25533979 TI - [Evaluations of diastolic functions with E/e' obtained by dual-Doppler simultaneous recording of flow and tissue Doppler velocities in coronary heart disease patients with preserved systolic function]. AB - OBJECTIVE: To evaluate the usefulness of ratio of early diastolic transmitral flow velocity (E) to mitral annular velocity (e') calculated by simultaneously recording E and e' in coronary heart disease (CHD) patients. METHODS: A total of 77 CHD patients with preserved systolic functions underwent echocardiography. Left ventricular catheterization was performed to measure left ventricular end diastolic pressure (LVEDP). The accuracy of E/e' was compared by recording the dual-Doppler and conventional methods for diagnosing diastolic dysfunction and the relationships between N-terminal pro-brain natriuretic peptide (NT-proBNP). The validity of E/e'dual Doppler and combined E/e'dual Doppler and NT-proBNP in estimating left ventricular diastolic dysfunction namely LVEDP >= 12 mmHg (1 mmHg = 0.133 kPa) were estimated. RESULTS: E/e'dual Doppler was correlated with left ventricular end diastolic pressure (LVEDP) and logNT-proBNP (r = 0.79, r = 0.47, respectively, P < 0.01). E/e'conventional was correlated with LVEDP and logNT proBNP (r = 0.61, P < 0.01, r = 0.35, P < 0.05, respectively). The area under curve (AUC) of E/e'dual Doppler and E/e'conventional was 0.87 and 0.82. The optimal cut-off of E/e'dual Doppler was 9.2 with a sensitivity of 74% and a specificity of 81%. And the optimal cut-off of plasma NT-proBNP was 108 ng/L with a sensitivity of 69% and a specificity of 86%, AUC 0.79.When E/e'dual Doppler >= 9.2 and NT-proBNP >= 108 ng/L were combined, the sensitivity and specificity for diagnosing diastolic dysfunction were 86% and 69%, AUC 0.89. CONCLUSION: The accuracy of E/e'dual Doppler is better than E/e'conventional for diagnosing left diastolic dysfunction. When E/e'dual Doppler and NT-proBNP are combined, it improves the evaluation accuracy of left diastolic dysfunction. PMID- 25533980 TI - [Relationship between E/Em ratio and exercise capacity in patients with atrial fibrillation]. AB - OBJECTIVE: To explore the relationship between the ratio of early diastolic transmitral velocity to early diastolic mitral annular velocity (E/Em) and exercise capacity in patients with atrial fibrillation. METHODS: A total of 94 consecutive patients with non-valvular atrial fibrillation and preserved left ventricular ejection fraction admitted into our department from December 2011 to June 2013 were included. Echocardiography and cardiopulmonary exercise test were performed. According to E/Em, they were divided into two groups of normal E/Em (E/Em <= 9) and elevated E/Em (E/Em>9). The parameters of exercise capacity, including VO2max/kg, anaerobic threshold/kg (AT/kg) and exercise time duration were compared between two groups. And the determinants of VO2max/kg were identified by multivariate regression analysis. RESULTS: The number of patients was 57(60.6%) with normal E/Em and 37 (39.4%) with elevated E/Em. As compared to those with normal E/Em, the patients with elevated E/Em had lower VO2max/kg [(26 +/- 4) vs (20 +/- 4) ml * min-1 * kg-1, P < 0.001], lower AT/kg [(25 +/- 4) vs (19 +/- 5) ml *min-1 * kg-1, P < 0.001] and shorter exercise time duration [(7.2 +/- 1.3) vs (5.8 +/- 1.3) min, P < 0.001]. Multivariate regression analysis revealed that three significant variables were independently associated with VO2max/kg: age (r = -0.412, P < 0.001), gender ((25 +/- 5) and (21 +/- 4) ml * min-1 * kg-1 for males and females separately, P < 0.001) and E/Em (r = -0.535, P < 0.001). CONCLUSION: E/Em was independently associated with exercise capacity in patients with atrial fibrillation. PMID- 25533981 TI - [The relevance of ADC value, T1intensive rate and the clinical activities in ankylosing spondylitis sacroiliitis]. AB - OBJECTIVE: To evaluate the value of judging for the activity in AS by diffusion weighted sequences (DWI) and enhance sequences MRI(DCE-MRI), to explore the correlation of Apparent diffusion coefficient(ADC) values, intensive rate and the clinical activity index in sacroiliitis (SIJ) of ankylosing spondylitis (AS). METHODS: 56 patients prospectively choiced and diagnosed were divided into two groupsas, active group (n = 32) and chronic group (n = 24) by rheumatologist according to BASDAI and laboratory parameters. Twenty healthy adults were as control group. The values of ADC and intensive rate of all sacroiliac joints (SIJs) were measured on MRI. BASDAI score were got by Bath ankylosing spondylitis disease activity index. ESR, CPR and were got by laboratory. Statisticaly to analysis whether the parameters were significantly different amang AS active, chronic, and the control group. To assess the correlation of the values of ADC, intensive rate and BASDAI score, ESR, CPR and in SIJ. RESULTS: the values of ADC and intensive rate were significantly different among AS active, chronic and the control group. There were the significant correlation between the values of ADC, intensive rate and BASDAI score. CONCLUSION: Diffusion-weighted sequences and Contrast-enhanced sequences is superior to other methods in judging the activity in AS.combined with clinical activity index, the accuracy can significantly be improved to explore whether the activities of AS are. PMID- 25533982 TI - [Pathophysiological roles of matrix metalloproteinases and nitric oxide synthase in cerebral aneurysm]. AB - OBJECTIVE: To explore the expressions of matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and inducible nitric oxide synthase (iNOS) in cerebral aneurysms, compare them with normal brain vessels tissue so as to gain a better understanding of the pathogenesis of cerebral aneurysms. METHODS: Twelve samples of cerebral aneurysms were obtained during operations and 10 cortical arteries as controls during surgery for temporal lobe epilepsy from 2009 to 2012 at Inner Mongolia People's Hospital and Beijing Tiantan Hospital. The activities of MMP-2, MMP-9 and iNOS in specimens were detected with spectrophotometry and substrate gel zymography. RESULTS: The MMP-2 and MMP-9 levels in cerebral aneurysm group were (199 598 +/- 125 288) gray scale area * mg-1 * L-1 and (719 253 +/- 376 519) gray scale area * mg-1 * L-1. Both in cerebral aneurysm group were significantly higher than that in control group (P < 0.05) . The TNOS and iNOS levels in cerebral aneurysm group were (23.6 +/- 6.6) and (11.4 +/- 2.6) U/mgprot. The difference of TNOS level was not significant between aneurysm and control groups (P > 0.05) while the levels of iNOS and iNOS/TNOS in cerebral aneurysm group were significantly higher than that in control group (P < 0.05). CONCLUSION: MMP-2, MMP-9 and iNOS are closely correlated with cerebral aneurysm. PMID- 25533983 TI - [Comparative analysis of neuroendoscope-assisted microsurgery and microscope treatment for small acoustic neuroma]. AB - OBJECTIVE: To explore the outcomes of surgery for the treatment of small acoustic neuroma by the neuroendoscope-assisted microsurgery and microscope. METHODS: From 2008 to 2013, 42 patients with small acoustic neuroma underwent neuroendoscope assisted microsurgery (n = 20) and microscopic tumoural resection (n = 22). Neurophysiological monitoring, 30-degree rigid neuroendoscope and microscope were employed intra-operatively. For the endoscope group, facial nerve and inner acoustic meatus could be visualized distinctly in each aspect, as for the microscope group, microscopic operation could be accomplished directly. The damage extents of facial nerve and inner acoustic meatus were compared between two groups. RESULTS: Total removal of acoustic neuroma and conservation of facial nerve were achieved in all patients. For the neuroendoscope-assisted group, the postoperative facial functions were Grade I (n = 6), Grade II (n = 10) and Grade III (n = 4). Internal acoustic canal was drilled 2-3 mm in 4 patients and no drilling in others. For the microscope group, Grade I (n = 5), Grade II (n = 6), Grade III (n = 8) and Grade III-IV (n = 3). Internal acoustic canal was drilled at least 3 mm in 12 patients and no drilling in others. No complication such as cerebrospinal fluid leakage occurred during the follow-ups. CONCLUSION: Endosocopic operation of acoustic neuroma surgery is superior to microscopic operation in terms of magnification, illumination, wide-angel and angulation. And the former procedure may yield better outcomes through alleviating the damage of facial nerve and decreasing the drilling degree of inner acoustic meatus. PMID- 25533984 TI - [Ultrasonic assessment of fetal thyroid function through ultrasound in pregnant women with hyperthyroidism]. AB - OBJECTIVE: To explore the value of prenatal ultrasound in assessing thyroid function in fetuses of hyperthyroidism pregnant women and establish the reference values of fetal thyroid transverse diameter and anteroposterior diameter for different gestational weeks. METHODS: For observation group, 30 cases of pregnant women diagnosed as hyperthyroidism were recruited from our hospital from November 2012 to November 2013. And another 100 cases of pregnant women during 20 to 40 weeks of gestational weeks were selected into control group. The measured ultrasonic parameters included fetal biparietal diameter, head circumference, abdominal circumference, femur length, amniotic fluid index, heart rate, fetal thyroid transverse diameter, anteroposterior diameter and fetal movement frequency. A fetus was considered as suspected positive when they were less than gestational age, thyroid measurement higher than 95% confidence interval, heart rate over 160 beats/min or less than 120 beats/min. In the observation group, the blood levels of thyroid stimulating hormone and thyroxine were measured after birth. RESULTS: The regression equation of fetal thymus transverse diameter and GA was: Y = 0.053X - 0.096, R2 = 0.758, P < 0.05; the regression equation of fetal thymus anteroposterior diameter and GA: Y = 0.034X - 0.397, R2 = 0.596, P < 0.05. The measured value of 95% confidence interval for 2 cases in observation group exceeded that in control group. There were fetal tachycardia (n = 2), bradycardia (n = 1), low TSH after birth (n = 2), T4 elevation after birth (n = 1) and clinical T4 high value (n = 1). CONCLUSION: Ultrasonic assessment of fetal thyroid function is timely and noninvasive. And it has an irreplaceable value in hyperthyroidism pregnant women. And normal reference values of fetal thyroid measurements are established for 20-40 gestation weeks. PMID- 25533985 TI - [Effects of levonorgestrel intrauterine system on the expressions of estrogen receptor, progesterone receptor and insulin-like growth factor-1]. AB - OBJECTIVE: To explore the effects of levonorgestrel intrauterine system on estrogen receptor (ER) and progesterone receptor (PR), insulin-like growth factor 1 (IGF-1) of endometrial polyps and surrounding endometrial tissue. METHODS: A total of 250 cases of hysteroscopic resection for endometrial polyps were divided into study group (n = 125) with placement of levonorgestrel intrauterine system after hysteroscopic electroresection and control group (n = 125) without placement. The intraoperative and postoperative expressions of ER, PR and IGF-1 in endometrial biopsy specimens were measured by immunohistochemistry. They were followed up for 2 years to analyze the recurrence of endometrial polyp. RESULTS: All patients had successful surgery. When intraoperative and postoperative specimens were compared with regards to the expressions of ER, PR and IGF-1, significant differences existed between two groups. During a 2-year follow-up, the recurrence of endometrial polyp was 10.89% in control group versus 0 in study group. CONCLUSION: Levonorgestrel intrauterine system may inhibit the recurrence and formation of endometrial polyp through lowering the expressions of ER, PR and IGF-1. PMID- 25533986 TI - [Experience of surgical treatment of huge mediastinal tumors]. AB - OBJECTIVE: The diagnosis and surgical treatment of 36 huge mediastinal tumors were summarized in order to evaluate the effect and safety of the operation. METHODS: Thirty-six huge mediastinal tumor patients treated in our department from June 2006 to June 2013 were retrospective analyzed, of whom clinical manifestations, diagnosis, surgical treatment and prognosis were carefully collected. Twenty-three cases were men and 13 were women. The average age was 39.2 years old. The pathology turned out to be benign in 23 cases and malignant in 13 cases. RESULTS: Complete resection was achieved in 34 cases while palliative resection in 2 cases with no perioperative death. Six cases had developed postoperative complications but all recovered after active treatment. Patients who had been diagnosed with benign tumors were all alive after follow-up periods of 6 months to 7 years. Nine malignat tumor patients developed recurrence or metastasis, including seven deaths. CONCLUSION: Surgery played a vital role in the diagnosis and treatment of huge mediastinal tumors. Preoperative diagnosis, accurate surgical approach and careful operation were the key to successful treatment. Benign huge mediastinal tumors had excellent prognosis with surgery. PMID- 25533987 TI - [Effect of stem fixing methods on stress and bone mineral density in the proximal femur following hip resurfacing arthroplasty]. AB - OBJECTIVE: To construct different 3-D finite element resurfacing arthroplasty of hip models and to explore the biomechanics influences of cement mantle varying in thickness on stress distribution and stressshielding in the proximal femur following hip resurfacing arthroplasty (RSAH), and evaluate the changes of bone mineral density in femur after RSAH , in order to find the adaptive methods to stem fixing. METHODS: A comparative study was carrie out in patients who underwent RSAH. The bone mineral Density of the proximal femur was measured through dual energy X-ray absorptiomenty of the four zone at post-operation and unoperation 6 months. Changes of bone mineral density ratio in proximal femur between post-operation and unoperation were compared and analyzed.the finite element models of RSAH with different thickness of cement mantle and normal femur were developed and stress analysis was performed under the load of body weight. RESULTS: The mean ration of bone mineral density of proximal femur in zone 1, 2 , 3 increased which was no significantly different from other areas (P > 0.05), the mean ration of bone mineral density of proximal femur in zone 4 and 5 increased which was significantly different from other areas (P < 0.05). Comparing with the 0 mm cement mantle model, the ratio of stress shielding of the cancellous bone around the stem in 1 mm cement mantle model has slightly increased, but also was less than 17%. The ratio of stress shielding was increased obviously in the 2 and 3 mm cement mantle mode and more than 17% in 1, 2 and 5 zone. CONCLUSION: The cement around stem not thicker than 1 mm produced slightly effect to the stress decreasing and did not result in marked stress shielding in the proximal femur following RSAH, and the bone stock of proximal femur can be well perserves and recovered. PMID- 25533988 TI - [The application of external fixator in CT guided 125I Seeds implantation to treat head and neck neoplasms]. AB - OBJECTIVE: To investigate the effect of external fixator in posture fixation during the interstitial of 125I seeds implantation for head and neck cancer under CT guidance. METHODS: 20 cases of head and neck cancer patients with CT guided radioactive 125I particle implantation were enrolled. 10 patients of group A for external fixator, the other 10 of group B used conventional bind belt. Spiral CT scanning was performed with 5 mm slices, and we chose the first and last serial CT images during the operation for image fusion with automatic registration software, then we could get 3D displacement errors. RESULTS: Patients in group A of X, Y, Z axis position deviation were 1.06 cm, 1.22 cm and 1.22 cm , respectively. As to group B, they were 8.76 cm (P = 0.041), 9.99 cm (P = 0.009) and 0.009 cm (P = 0.023), respectively. CONCLUSION: The external fixator could applied in the treatment of head and neck cancer during CT-guided 125I seed implantation, which fixed well in the operation, more comfortable, improve the positioning accuracy and reduce the extra rescanning radiation doses. PMID- 25533989 TI - [Malignant transformation of glioma stromal cells induced by glioma stem cells heterotopically inoculated in host liver]. AB - OBJECTIVE: Tumor stromal cells have the potential of undergoing malignant transformation induced by glioma stem cells (GSCs) in orthotopic glioma model. The purpose of this study was to explore whether malignant transformation of tumor stromal cells induced by GSCs is dependent on specific local microenvironment. METHODS: Human glioma stem/progenitor cell line SU3 transfected with red fluorescent protein (SU3-RFP) gene were implanted into the liver of nude mice with whole-body expressing green fluorescence protein (GFP). Then hepatic tumors were harvested to prepare single cell suspension and analyzed with routine pathological examinations. GFP cells with high proliferative abilities were obtained from the cultivation of single cell suspension. Immortalized glioma stromal cells only expressing GFP and double expressing GFP/RFP were further monocloned with micro-pipetting techniques and under continuous passages. Cell phenotypic analysis and tumorigenicity tests were also performed. RESULTS: SU3 RFP was transplanted into liver with a tumor formation rate of 83%. Immortalized glioma stromal cells were obtained from re-cultured xenograft tumor tissue. Three monoclonal cell lines B4, B9, B10 were established and proved to be host-derived cells. B4 was found to be a fusion cell co-expressing GFP/RFP and dendritic cell markers CD1 a, CD83 and CD86. Both B9 and B10 were GFP+ cells. B9 expressed macrophage markers CD68 and F4/80 while B10 produced fibroblast marker proteins FAP-alpha, alpha-SMA and S100. Three cells were all aneuploid with a tumorigenicity rate of 100% in nude mice. CONCLUSION: Tumor stromal cells have the potential of malignant transformation in a heterotopic xenograft glioma model. Malignant transformation may also occur outside the central nervous system and contribute to tumor heterogeneity. Further studies are warranted for elucidating the relationship between tumorigenesis, evolution and tumor microenvironment. PMID- 25533990 TI - [Protection of T-type calcium channel blocker in spiral ganglion neurons of adult C57BL/6J mice]. AB - OBJECTIVE: To explore the distribution and expression of three T-type calcium channel receptors (alpha1G; alpha1H; alpha1I) and understand their protective effects in spiral neurons of C57BL/6J mice. METHODS: The distribution and expression of three T-type calcium channel receptors in spiral ganglion neurons were observed by in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) in 6-8-week-old C57BL/6J mice. The mice of 24-26-week-old C57BL/6J were divided into 3 groups of zonisamide, benidipine and saline. And the expression changes of calcium-binding proteins calmodulin and calbindin were observed by immunohistochemistry. RESULTS: Three subunits were expressed in spiral ganglion neurons. The decremented quantities were alpha1H (24.21 +/- 0.10), alpha1I (14.88 +/- 0.04) and alpha1G (10.42 +/- 0.02). The expression level of calmodulin in spiral ganglion neurons was lower in the zonisamide treated group than that in the saline-treated group (0.336 +/- 0.041 vs 0.504 +/- 0.020, P < 0.05). The expression level of calbindin in spiral ganglion neurons was lower in the zonisamide (0.482 +/- 0.045) and benidipine-treated groups (0.511 +/- 0.032) than that in the saline-treated group (0.611 +/- 0.035, P < 0.05). CONCLUSION: The expressions of calcium-binding proteins decrease after 4 week dosing of T-type calcium channel blockers in 24-26-week C57BL/6J mice. It implies a relief of calcium overload. T-type calcium channel blockers may protect the murine spiral ganglion neurons from degeneration. PMID- 25533991 TI - Erratum to "Comparison of the Indications and Treatment Results of Burr-Hole Drainage at the Maximal Thickness Area versus Twist-Drill Craniostomy at the Pre Coronal Point for the Evacuation of Symptomatic Chronic Subdural Hematomas" by Kim GH, et al. (J Korean Neurosurg Soc 56 : 243-247, 2014). AB - [This corrects the article on p. 243 in vol. 56, PMID: 25368768.]. PMID- 25533992 TI - Performance-based financing in the context of selective free health-care: an evaluation of its effects on the use of primary health-care services in Burundi using routine data. AB - BACKGROUND: Performance-based financing (PBF) is an increasingly adopted strategy in low- and middle-income countries. PBF pilot projects started in Burundi in 2006, at the same time when a national policy removed user fees for pregnant women and children below 5 years old. METHODS: PBF was gradually extended to the 17 provinces of the country. This roll-out and data from the national health information system are exploited to assess the impact of PBF on the use of health care services. RESULTS: PBF is associated with an increase in the number of anti tetanus vaccination of pregnant women (around +20 percentage points in target population, P < 0.10). Non-robust positive effects are also found on institutional deliveries and prenatal consultations. Changes in outpatient visits, postnatal visits and children vaccinations are not significantly correlated with PBF. It is also found that more qualified nurses headed to PBF supported provinces. The limited quality of the data and the restricted size of the sample have to be taken into account when interpreting these results. Health facility-level figures from PBF-supported provinces show that most indicators but those relative to preventive care are growing through time. DISCUSSION: The dataset does not include indicators of the quality of care and does not allow to assess whether changes associated with PBF are resource-driven or due to the incentive mechanism itself. The results are largely consistent with other impact evaluations conducted in Burundi and Rwanda. The fact that PBF is mostly associated with positive changes in the use of services that became free suggests an important interaction effect between the two strategies. A possible explanation is that the removal of user fees increases accessibility to health care and acts on the demand side while PBF gives medical staffs incentives for improving the provision of services. More empirical research is needed to understand the sustainability of (the incentive mechanism of) PBF and the interaction between PBF and other health policies. PMID- 25533993 TI - [Ahmed valve in refractory pediatric glaucoma]. PMID- 25533994 TI - [Bilateral non-arteritic ischemic optic neuropathy during treatment of viral hepatitis C with pegylated interferon and Ribavirin]. AB - INTRODUCTION: Hepatitis C is a serious viral infection, for which the current treatment is based on the combination of pegylated interferon (IFN) and Ribavirin((r)). Ophthalmic complications observed with PEG-IFN are infrequent and of variable prognosis. They often include an ischemic retinopathy with typical cotton-wool spots, hemorrhage and retinal edema, and rarely acute non-arteritic anterior ischemic optic neuropathy as illustrated by our report. OBSERVATION: We report the case of a 51-year-old man followed for chronic active hepatitis C, who presented in the fourth month of treatment with pegylated interferon and vidarabine with a sharp decline in visual acuity secondary to acute bilateral non arteritic anterior ischemic optic neuropathy. The hepatitis C treatment was discontinued. His course was notable by the third week for a significant regression of papilledema with improvement in visual acuity in the right eye and no change in the left eye, remaining at counting fingers. After regressing for four years, the disease progressed to bilateral temporal optic atrophy without change in visual acuity. CONCLUSION: Pegylated interferon and Ribavirin((r)) are commonly used in the treatment of chronic hepatitis C. They are the source of various ophthalmologic complications of varied severity. The pathophysiology of this ocular toxicity currently remains hypothetical. Non-arteritic ischemic optic neuropathy is still a relatively rare complication with a poor functional prognosis, often requiring discontinuation of treatment. Thus, careful ophthalmologic monitoring before and during antiviral treatment of patients with hepatitis C appears necessary. PMID- 25533995 TI - [Combined cilioretinal artery and central retinal vein occlusion complicating sleep apnea syndrome]. PMID- 25533996 TI - Analysis of the transcriptomic profilings of Mandarin fish (Siniperca chuatsi) infected with Flavobacterium columnare with an emphasis on immune responses. AB - Flavobacterium columnare (FC) is the causative pathogen of columnaris which has caused great economic loss in fish culture worldwide, including in Mandarin fish (Siniperca chuatsi) culture. In the present study, the transcriptomic profiles of the head kidneys from FC-infected and non-infected Mandarin fish were obtained using HiSeqTM 2000 (Illumina). Totally 31,168 unigenes with high quality were obtained. Genes involved in protein folding, metabolism and energy, immune responses, oxidoreductase activity, cell growth and death were identified as enriched classes. 1019 differently expressed genes between the two groups were identified, including 603 up-regulated and 416 down-regulated genes. 27 differently expressed immune related genes were scrutinized, including 17 up regulated and 10 down-regulated genes. Six of the differently expressed genes were further validated by qRT-PCR. The roles of the immune related genes were discussed. Identification of the host genes in response to FC infection will shed a new light on the prevention of columnaris. PMID- 25533997 TI - Inverse fluoxetine effects on inhibitory brain activation in non-comorbid boys with ADHD and with ASD. AB - RATIONALE: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are often comorbid and have both performance and brain dysfunctions during motor response inhibition. Serotonin agonists modulate motor response inhibition and have shown positive behavioural effects in both disorders. AIMS: We therefore used functional magnetic resonance imaging (fMRI) to investigate the so far unknown shared and disorder-specific inhibitory brain dysfunctions in these two disorders, as well as the effects of a single dose of the selective serotonin reuptake inhibitor fluoxetine. METHODS: Age-matched boys with ADHD (18), ASD (19) and healthy controls (25) were compared with fMRI during a stop task measuring motor inhibition. Patients were scanned twice, under either an acute dose of fluoxetine or placebo in a double-blind, placebo-controlled randomised design. Repeated measures analyses within patients assessed drug effects. To test for potential normalisation effects of brain dysfunctions, patients under each drug condition were compared to controls. RESULTS: Under placebo, relative to controls, ASD boys showed overactivation in left and right inferior frontal cortex (IFC), while ADHD boys showed disorder-specific underactivation in orbitofrontal cortex (OFC) and basal ganglia. Under fluoxetine, the prefrontal dysfunctions were no longer observed, due to inverse effects of fluoxetine on these activations: fluoxetine downregulated IFC and OFC activation in ASD but upregulated them in ADHD. CONCLUSIONS: The findings show that fluoxetine normalises frontal lobe dysfunctions in both disorders via inverse effects, downregulating abnormally increased frontal activation in ASD and upregulating abnormally decreased frontal activation in ADHD, potentially reflecting inverse baseline serotonin levels in both disorders. PMID- 25533998 TI - The effects of acute treatment with ramelteon, triazolam, and placebo on driving performance, cognitive function, and equilibrium function in healthy volunteers. AB - RATIONALE: Hypnotics are widely used to treat insomnia but adverse effects of different hypnotics, especially benzodiazepine receptor agonists, are getting more attention lately. The effects of novel hypnotics have not been fully examined. OBJECTIVE: This study aims to assess the effects of two hypnotics, ramelteon and triazolam, on driving performance, cognitive function, and equilibrium function. METHODS: In this double-blinded, three-way crossover trial, 17 healthy males received acute doses of 8 mg ramelteon, 0.125 mg triazolam, and placebo. The subjects were administered three driving tasks-road-tracking, car following, and harsh-braking-using a driving simulator and three cognitive tasks Continuous Performance Test, N-back Test, and Trail-Making Test-at baseline and at 1 and 4 h post-dosing. The Stanford Sleepiness Scale scores and computerized posturography were also assessed. RESULTS: In the driving simulations, ramelteon and triazolam increased the number of subjects who slid off the road. Triazolam increased the standard deviation of lateral position compared to ramelteon and placebo at 1 h post-dosing. Ramelteon and triazolam significantly increased the time to complete of Trail-Making Test part A and the environmental area in posturography compared to placebo at 1 and 4 h post-dosing. Ramelteon and triazolam significantly increased subjective sleepiness compared to placebo at 1 h post-dosing. CONCLUSIONS: Ramelteon may affect road-tracking performance, visual attention and/or psychomotor speed measured by Trail-Making Test part A, and body balance in acute dosing. Lower dose of triazolam also impaired performance worse than ramelteon. Physicians should consider risks and benefits when prescribing both drugs, especially in the initial period of administration. PMID- 25534000 TI - How painful is a heelprick or a venipuncture in a newborn? AB - OBJECTIVE: Neonates undergo many painful procedures daily, in particular venipunctures and heelpricks. Our aim was to assess how painful these procedures actually are, and how effective are the common analgesic strategies to blunt this pain. METHODS: We performed a MEDLINE/PubMed research from 1999 to 2013. We retrieved all papers in English language that evaluated pain during neonatal heelprick or venipuncture and that used as score the Premature Infant Pain Profile (PIPP), a widely used scale for evaluate acute pain in term and preterm babies. RESULTS: Fifteen papers met the inclusion criteria, using different analgesic methods. Just in one case two studies used the same analgesic method. Most analgesic procedures show a relevant level of pain. We didn't find univocal difference between heelprick and venipuncture. Topic creams, systemic analgesics, posture and oral glucose 10% have scarce analgesic effectiveness. The most effective procedures are the use of oral sweet solutions (sucrose or glucose) at concentrations greater than 20%, multisensory stimulations and non-nutritive sucking used along with 10% glucose. CONCLUSIONS: A large amount of analgesic methods was used, making comparisons difficult. Nevertheless, in the absence of analgesic treatment, heelpricks and venipunctures are moderately-severely painful, and among the proposed analgesic procedures, few seem to be effective. PMID- 25533999 TI - bFGF attenuates endoplasmic reticulum stress and mitochondrial injury on myocardial ischaemia/reperfusion via activation of PI3K/Akt/ERK1/2 pathway. AB - Extensive research focused on finding effective strategies to prevent or improve recovery from myocardial ischaemia/reperfusion (I/R) injury. Basic fibroblast growth factor (bFGF) has been shown to have therapeutic potential in some heart disorders, including ischaemic injury. In this study, we demonstrate that bFGF administration can inhibit the endoplasmic reticulum (ER) stress and mitochondrial dysfunction induced in the heart in a mouse model of I/R injury. In vitro, bFGF exerts a protective effect by inhibiting the ER stress response and mitochondrial dysfunction proteins that are induced by tert-Butyl hydroperoxide (TBHP) treatment. Both of these in vivo and in vitro effects are related to the activation of two downstream signalling pathways, PI3K/Akt and ERK1/2. Inhibition of these PI3K/Akt and ERK1/2 pathways by specific inhibitors, LY294002 and PD98059, partially reduces the protective effect of bFGF. Taken together, our results indicate that the cardioprotective role of bFGF involves the suppression of ER stress and mitochondrial dysfunction in ischaemic oxidative damage models and oxidative stress-induced H9C2 cell injury; furthermore, these effects underlie the activation of the PI3K/Akt and ERK1/2 signalling pathways. PMID- 25534002 TI - Residual atrial signal or late ventricular signal after accessory pathway ablation: how to resolve the problem? PMID- 25534001 TI - Induced apoptosis in melanocytes cancer cell and oxidation in biomolecules through deuterium oxide generated from atmospheric pressure non-thermal plasma jet. AB - Recently, atmospheric-pressure non-thermal plasma-jets (APPJ) are being for the cancer treatment. However, APPJ still has drawbacks such as efficiency and rise in temperature after treatment. So, in this work, a synergetic agent D2O vapour is attached to APPJ which not only increase the efficiency of plasma source against cancer treatment, but also controlled the temperature during the treatment. OD generated by the combination of D2O + N2 plasma helped in enhancing the efficiency of APPJ. We observed OD induced apoptosis on melanocytes G361 cancer cells through DNA damage signalling cascade. Additionally, we observed that plasma induces ROS, which activated MAPK p38 and inhibits p42/p44 MAPK, leading to cancer cell death. We have also studied DNA oxidation by extracting DNA from treated cancer cell and then analysed the effects of OD/OH/D2O2/H2O2 on protein modification and oxidation. Additionally, we attempted molecular docking approaches to check the action of D2O2 on the apoptosis related genes. Further, we confirmed the formation of OD/OH simultaneously in the solution using optical emission spectroscopy. Moreover, the simultaneous generation of D2O2/H2O2 was detected by the use of confocal Raman spectroscopy and density measurements. PMID- 25534003 TI - Pharmaceuticals in the environment: biodegradation and effects on natural microbial communities. A review. AB - Environmental microorganisms play a key role in fundamental ecological processes such as biogeochemical cycling and organic contaminant degradation. Microorganisms comprise a large unexplored reservoir of genetic diversity and metabolic capability providing several ecosystem services, most importantly the maintenance of soil and water quality. Pharmaceutical occurrence in the environment can compromise microbial community structure and activities in different ways. The fate of a pharmaceutical in soil or water depends on numerous factors, including its inherent physic-chemical properties (e.g. water solubility, lipophilicity, vapour pressure), environmental factors and climate conditions (e.g. temperature, incident radiation, pH) and most importantly the presence and activity of microorganisms that possess the ability to biodegrade it. The presence of a natural microbial community is a necessary prerequisite for an effective response to the various chemicals that can contaminate an ecosystem. The recovery from contamination is only possible if toxicity does not hamper microbial activity. This review presents current knowledge on the effects on natural microbial communities of some pharmaceuticals and of some biocides commonly found as environmental microcontaminants. PMID- 25534005 TI - Review of 41 Neer's mini-open operations with up to nine-year follow-up and a study of the influence of occupational disease. AB - INTRODUCTION: The shoulder pain has been reported as the third most common site after low back pain and knee pain, mostly caused by impingement and rotator cuff syndromes. Surgery is indicated when non-operative treatment fails and can be open and/or arthroscopic. Are Neer's acromioplasty results still good? Are they modified when it is a professional disease (PD)? If yes is there any explanation? MATERIALS AND METHODS: It is a retrospective hospital-based study, including all cases of Neer's acromioplasty done from 2006 to 2011, by the same senior surgeon for subacromial impingement syndrome (SIS). Medical files were consulted and an auto Disabilities of the Arm, Shoulder and Hand (DASH) score file completed by patients. We compared two groups: "with PD" and "without PD". RESULTS: We had 41 patients (21 males/20 females). Mean age: 54 (34-79) years. The majority was workers those requiring force (29.3 %) or working in abduction situations (7.2 %). The two groups were otherwise comparable (clinical, imaging and surgery findings). Aggressive acromia were found in 15 cases (36.6 %), and there were 19 (46.3 %) rotator cuff perforations. A Neer's acromioplasty and bursectomy was done in all the cases. Eighteen perforations were sutured and one (the largest) was just released. Mean follow-up: 4 (2-9) years. Of the 26 (63.4 %) patients that could return to work, 16 (61.5 %) were not PD. This return was later in the "PD group" (p < 0.05). The DASH score elements in the "without PD" group were better, compared to the PD group: (a) 16 (79.2 %) very good results on the pain against 6 (30 %), (b) 13 (61.9 %) very good results concerning the strength against 3 (15 %), (c) 14 (66.7 %) very good results in the ability to work against 4 (20 %). The DASH global mean score was 35.1 over 100. The global scores for daily life, sport and professional activities were, respectively, 33, 37.8 and 48.2 over 100. In the PD group, the mean DASH score was 53.7 against 17.44 in the non-PD what is more than three times worst. DISCUSSION: Neer's mini-open acromioplasty is still an excellent pain killer operation and should not be abandoned. Very good results on the SIS pain after a mean follow-up of 4 years were observed. Its results are very good in the "without PD" group with 76.19 % of return to previous work after a mean period of 8 months. Earlier return to a new work or to the same work with accommodations is possible. We found no anatomical explanation for the differences between the two groups. PMID- 25534004 TI - Effects of twin-block appliance on the anatomy of pharyngeal airway passage (PAP) in class II malocclusion subjects. AB - BACKGROUND: The use of functional appliances for the correction of retrognathic mandible is very common in orthodontics. Similar appliances known as oral appliances are also frequently used in adults for the treatment of mild to moderate obstructive sleep apnea (OSA). Many studies have reported improvement of pharyngeal airway passage (PAP) dimensions following functional appliance therapy in children and oral appliance therapy in adults. There is only one study in the literature that discussed the effect of oral appliance therapy on posterior pharyngeal wall thickness (PPWT) among subjects with OSA. The effect of functional appliance therapy on PPWT has never been investigated. Thus the present study was conducted to evaluate the effects of twin-block appliance on pharyngeal airway passage (PAP) dimensions and posterior pharyngeal wall thickness (PPWT) in class II malocclusion subjects with retrognathic mandibles. METHODS: Thirty-eight class II malocclusion subjects in the age range of 8 to 14 years with mandibular retrusion were divided into a treatment (n = 20) and control (n = 18) group. Mandibular retrusion in the treatment group subjects was corrected by twin-block appliance. The effect of twin-block appliance on PAP and PPWT dimensions were evaluated from lateral cephalograms recorded prior-to and after 6 months of appliance therapy in the treatment group subjects and the changes were compared with the changes in the control group subjects. Student's t test was used for statistical analysis; P-value of 0.05 was considered a statistically significant level. RESULTS: The depth of the oropharynx was increased significantly in the treatment group subjects (P < 0.001) as compared to the control group subjects (P < 0.05). The depth of the hypopharynx increased significantly in treatment group subjects (P < 0.01). The PPWT at the level of the nasopharynx, oropharynx, and hypopharynx were maintained in the treatment group subjects; whereas in control group subjects, the PPWT was further reduced although the changes were not statistically significant. CONCLUSIONS: Correction of mandibular retrusion by twin-block appliance in class II malocclusion subjects increased the PAP dimensions and maintained the pre-treatment thickness of posterior pharyngeal wall. PMID- 25534006 TI - Endoscopic findings in the acute phase of food protein-induced enterocolitis syndromae. PMID- 25534007 TI - Study protocol for 'we DECide': implementation of advance care planning for nursing home residents with dementia. AB - AIM: To evaluate the effects of 'we DECide', an educational intervention for nursing home staff on shared decision-making in the context of advance care planning for residents with dementia. BACKGROUND: Advance care planning (preparing care choices for when persons no longer have decision-making capacity) is of utmost importance for nursing home residents with dementia, but is mostly not realized for this group. Advance care planning consists of discussing care choices and making decisions and corresponds to shared decision-making (the involvement of persons and their families in care and treatment decisions). DESIGN: This quasi-experimental pre-test-post-test study is conducted in 19 nursing homes (Belgium). Participants are nursing home staff. METHODS: 'We DECide' focuses on three crucial moments for discussing advance care planning: the time of admission, crisis situations and everyday conversations. The 'ACP audit' assesses participants' views on the organization of advance care planning (organizational level), the 'OPTION scale' evaluates the degree of shared decision-making in individual conversations (clinical level) and the 'IFC-SDM Questionnaire' assesses participants' views on Importance, Frequency and Competence of realizing shared decision-making (clinical level). (Project funded: July 2010). DISCUSSION: The study hypothesis is that 'we DECide' results in a higher realization of shared decision-making in individual conversations on advance care planning. A better implementation of advance care planning will lead to a higher quality of end-of-life care and more person-centred care. We believe our study will be of interest to researchers and to professional nursing home caregivers and policy-makers. PMID- 25534008 TI - All-cause mortality increased by environmental cadmium exposure in the Japanese general population in cadmium non-polluted areas. AB - The aim of the present study was to evaluate the effect of environmental cadmium (Cd) exposure indicated by urinary Cd on all-cause mortality in the Japanese general population. A 19-year cohort study was conducted in 1067 men and 1590 women aged 50 years or older who lived in three cadmium non-polluted areas in Japan. The subjects were divided into four quartiles based on creatinine adjusted U-Cd (ug g(-1) cre). The hazard ratio (HR) and 95% confidence interval (CI) for continuous U-Cd or the quartiles of U-Cd were estimated for all-cause mortality using a proportional hazards regression.The all-cause mortality rates per 1000 person years were 31.2 and 15.1 in men and women, respectively. Continuous U-Cd (+1 ug g(-1) cre) was significantly related to the all-cause mortality in men (HR 1.05, 95% CI: 1.02-1.09) and women (HR 1.04, 95% CI: 1.01-1.07). Furthermore in men, the third (1.96-3.22 ug g(-1) cre) and fourth quartile (>=3.23 ug g(-1) cre) of U-Cd showed a significant, positive HR (third: HR 1.35, 95% CI: 1.03-1.77, fourth: HR 1.64, 95% CI: 1.26-2.14) for all-cause mortality compared with the first quartile (<1.14 ug g(-1) cre). In women, the fourth quartile of U-Cd (>=4.66 ug g(-1) cre) also showed a significant HR (1.49, 95% CI 1.11-2.00) for all-cause mortality compared with the first quartile (<1.46 ug g(-1) cre).In the present study, U-Cd was significantly associated with increased mortality in the Japanese general population, indicating that environmental Cd exposure adversely affects the life prognosis in Cd non-polluted areas in Japan. PMID- 25534010 TI - Multifunctional radiolabeled nanoparticles: strategies and novel classification of radiopharmaceuticals for cancer treatment. AB - In this review, we emphasize the efforts on the development of radiolabeled nanoparticles (NPs) for cancer treatment, i.e. theranostic tools based on nanotechnology and nuclear medicine. Currently, radionuclide therapy remains to be an important treatment option. The ionizing radiation from radionuclides (not provided by drugs) can kill cells or inhibit the growth in the periphery and the inaccessible center of cancerous lesions. Sites of damage comprise all cellular levels, especially DNA in the nucleus of cells. In addition, recent developments in nanotechnology have made it possible to conjugate NPs to biological moieties for targeted therapy. This enables the more specific radiation dose delivery, preventing damage to healthy tissues. Before the introduction of these NPs-based radionuclide therapies in clinical practice, it is necessary perform investigations to demonstrate dosage-accurate radiation delivery, biocompatibility, pharmacokinetic/pharmacodynamic parameters and risk/benefit evaluations. Because of these issues, a transition to clinical trials is difficult. The properties of NPs make it possible to build theranostic devices with targeting and regulatory mechanisms offered by biological effectors against cancer. PMID- 25534009 TI - Complex coding of endogenous siRNA, transcriptional silencing and H3K9 methylation on native targets of germline nuclear RNAi in C. elegans. AB - BACKGROUND: Small RNA-guided transcriptional silencing (nuclear RNAi) is fundamental to genome integrity and epigenetic inheritance. Despite recent progress in identifying the capability and genetic requirements for nuclear RNAi in Caenorhabditis elegans, the natural targets and cellular functions of nuclear RNAi remain elusive. METHODS: To resolve this gap, we coordinately examined the genome-wide profiles of transcription, histone H3 lysine 9 methylation (H3K9me) and endogenous siRNAs of a germline nuclear Argonaute (hrde-1/wago-9) mutant and identified regions on which transcription activity is markedly increased and/or H3K9me level is markedly decreased relative to wild type animals. RESULTS: Our data revealed a distinct set of native targets of germline nuclear RNAi, with the H3K9me response exhibiting both overlapping and non-overlapping distribution with the transcriptional silencing response. Interestingly LTR retrotransposons, but not DNA transposons, are highly enriched in the targets of germline nuclear RNAi. The genomic distribution of the native targets is highly constrained, with >99% of the identified targets present in five autosomes but not in the sex chromosome. By contrast, HRDE-1-associated small RNAs correspond to all chromosomes. In addition, we found that the piRNA pathway is not required for germline nuclear RNAi activity on native targets. CONCLUSION: Germline nuclear RNAi in C. elegans is required to silence retrotransposons but not DNA transposon. Transcriptional silencing and H3K9me can occur independently of each other on the native targets of nuclear RNAi in C. elegans. Our results rule out a simple model in which nuclear Argonaute protein-associated-small RNAs are sufficient to trigger germline nuclear RNAi responses. In addition, the piRNA pathway and germline nuclear RNAi are specialized to target different types of foreign genetic elements for genome surveillance in C. elegans. PMID- 25534012 TI - [Louis Ombredanne (1871-1956) pediatric and plastic surgeon]. AB - One of the fathers of pediatric surgery in France, Louis Ombredanne (1871-1956) was a great plastic surgeon. During his residency he was initiated to plastic surgery by Charles Nelaton (1851-1911). Both wrote two books: "La rhinoplastie" and "Les autoplasties", taking stock of these techniques in the early 20th century. In 1906, he was the first to describe the pectoral muscle flap for immediate breast reconstruction after mastectomy. He used this flap in conjunction with an axillo thoracic flap. From 1908 to 1941, Louis Ombredanne practised pediatric surgery, most of which was devoted in reconstruction of congenital and acquire anomalies. From 1924 to 1941, he was Professor of pediatric surgery at the hospital Enfants-Malades in Paris. In 1907, Louis Ombredanne created a prototype of an ether inhaler as a safe anesthetic device. The device was successfully used for fifty years in Europe. PMID- 25534011 TI - The predictive role of renal function and systemic inflammation on the onset of de novo atrial fibrillation after cardiac surgery. AB - BACKGROUND: The association between postoperative atrial fibrillation (POAF) and renal function was previously grounded in patients undergoing coronary artery bypass grafting through unknown mechanisms. We aim to investigate the association between renal function and POAF in a cohort composed mostly of patients undergoing valve surgery and to explore the role of inflammation as a pathogenic mechanism linking renal dysfunction and arrhythmogenesis. METHODS: Altogether 444 patients who underwent cardiac surgery without previous history of atrial fibrillation were analysed. Serum creatinine and high sensitivity C-reactive protein (hs-CRP) concentrations were obtained at baseline and on the 3rd, 8th and 15th postoperative day; estimated glomerular filtration rate (eGFR) was calculated by the Modified Diet Renal Disease (MDRD) formula. Patients were divided into three groups on the basis of baseline eGFR. RESULTS: Overall, 173 (39%) patients developed POAF, 29.5% in the group with normal eGFR (>=90 ml/min/1.73 m(2)), 43.3% among patients with eGFR 60-90 ml/min/1.73 m(2) and 55.6% in the group with eGFR <=60 ml/min/1.73 m(2). Patients developing POAF had lower eGFR on all the samples. At baseline preoperatively hs-CRP levels did not differ in the two groups.On multivariate analysis, age and eGFR were identified as independent predictors of POAF. The risk of POAF progressively increased from mild impairment (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.01-2.50) to severe reduction of renal function (OR 2.35, 95% CI 1.25-4.48). CONCLUSIONS: Age and eGFR were identified as the strongest predictors of POAF in a population largely composed of valve surgery patients. Renal function, even from early stage, is independently associated with the increasing risk of developing POAF. PMID- 25534013 TI - A facile route to backbone-tethered N-heterocyclic carbene (NHC) ligands via NHC to aNHC rearrangement in NHC silicon halide adducts. AB - The reaction of 1,3-diisopropylimidazolin-2-ylidene (iPr2 Im) with diphenyldichlorosilane (Ph2 SiCl2 ) leads to the adduct (iPr2 Im)SiCl2 Ph2 1. Prolonged heating of isolated 1 at 66 degrees C in THF affords the backbone tethered bis(imidazolium) salt [((a) HiPr2 Im)2 SiPh2 ](2+) 2 Cl(-) 2 ("(a) " denotes "abnormal" coordination of the NHC), which can be synthesized in high yields in one step starting from two equivalents of iPr2 Im and Ph2 SiCl2 . Imidazolium salt 2 can be deprotonated in THF at room temperature using sodium hydride as a base and catalytic amounts of sodium tert-butoxide to give the stable N-heterocyclic dicarbene ((a) iPr2 Im)2 SiPh2 3, in which two NHCs are backbone-tethered with a SiPh2 group. This easy-to-synthesize dicarbene 3 can be used as a novel ligand type in transition metal chemistry for the preparation of dinuclear NHC complexes, as exemplified by the synthesis of the homodinuclear copper(I) complex [{(a) (ClCu?iPr2 Im)}2 SiPh2 ] 4. PMID- 25534015 TI - Synthesis, structure and near-infrared photoluminescence of hexanitratoneodymate ionic liquids. AB - Five hexanitratoneodymate-based rare earth complexes () were synthesized using a straightforward method. Purple plate crystals of were isolated and the crystal structure was determined by single-crystal X-ray diffraction with respect to the coordination mode of the nitrate anion to the central Nd(iii) ion. (: monoclinic system P21/c, a = 15.9460(3) A, b = 10.2457(6) A, c = 33.323(3) A, beta = 91.8108(17) degrees , V = 3109.11(11) A(3), Z = 4). The central Nd(iii) ion is surrounded by six bidentate nitrate ligands, with a major trend towards high symmetry of the [Nd(NO3)6](3-) anion as an icosahedron. Thermal properties were determined from differential scanning calorimetry (DSC) combined with thermogravimetric analysis (TGA) tests. Complexes are found to be room temperature liquids, and their excitation and emission spectra were recorded. These complexes exhibit intense near-infrared (NIR) luminescence emission, which originates from interconfigurational f-f transitions (4)F3/2->(4)IJ multiplet (J = 9/2-13/2). These liquid Nd(iii) complexes are of interest as potential NIR luminescent soft materials with high thermal stability. PMID- 25534014 TI - Use of FDG-PET to guide dose prescription heterogeneity in stereotactic body radiation therapy for lung cancers with volumetric modulated arc therapy: a feasibility study. AB - BACKGROUND: The aim of this study was to assess if FDG-PET could guide dose prescription heterogeneity and decrease arbitrary location of hotspots in SBRT. METHODS: For three patients with stage I lung cancer, a CT-simulation and a FDG PET were registered to define respectively the PTVCT and the biological target volume (BTV). Two plans involving volumetric modulated arc therapy (VMAT) and simultaneous integrated boost (SIB) were calculated. The first plan delivered 4 * 12 Gy within the PTV(CT) and the second plan, with SIB, 4 * 12 Gy and 13.8 Gy (115% of the prescribed dose) within the PTV(CT) and the BTV respectively. The Dmax-PTV(CT) had to be inferior to 60 Gy (125% of the prescribed dose). Plans were evaluated through the D95%, D99% and Dmax-PTV(CT), the D2 cm, the R50% and R100% and the dice similarity coefficient (DSC) between the isodose 115% and BTV. DSC allows verifying the location of the 115% isodose (ideal value = 1). RESULTS: The mean PTV(CT) and BTV were 36.7 (+/-12.5) and 6.5 (+/-2.2) cm3 respectively. Both plans led to similar target coverage, same doses to the OARs and equivalent fall-off of the dose outside the PTV(CT). On the other hand, the location of hotspots, evaluated through the DSC, was improved for the SIB plans with a mean DSC of 0.31 and 0.45 for the first and the second plans respectively. CONCLUSIONS: Use of PET to decrease arbitrary location of hotspots is feasible with VMAT and SIB for lung cancer. PMID- 25534016 TI - Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. AB - Elective therapeutic approaches are required since recurrent thrombosis remains a major challenge in the management of antiphospholipid syndrome (APS) despite an efficient anticoagulation. Several data suggest that hydroxychloroquine (HCQ) could play a role in the prevention of thrombosis. The goal of this review is to point out the different aspects that could suggest the usefulness and the efficacy of HCQ for the prevention of thrombosis relapse in APS. By Medline research we collected important data dealing with potential anti-thrombotic effects of HCQ. The mechanisms of action of HCQ, and clinical and experimental data in systemic lupus erythematosus (SLE) and APS are discussed. As HCQ reduces the risk of thrombosis in both SLE patients and animal models of APS (1-7), and possibly decreases the titre of aPL [8], its beneficial role as a potential antithrombotic could be suggested. PMID- 25534017 TI - Treatment outcomes in a cohort of patients with mucosal-predominant pemphigus vulgaris. AB - BACKGROUND: Pemphigus vulgaris (PV) is a rare autoimmune blistering condition. Treatment typically combines corticosteroids with another immunosuppressive agent, such as azathioprine, mycophenolate mofetil (MMF) or rituximab. AIM: This study aims to compare these second agents for their clinical efficacy and steroid sparing effect. METHODS: This was a single-centre, retrospective observational cohort study of 21 patients with oral PV over a 6-year period, 18 of whom were newly diagnosed. Of the latter, the first 13 were initially given azathioprine, progressing to MMF and then rituximab on treatment failure, while the next five patients started directly on MMF. RESULTS: Of the 13 newly diagnosed patients, 2/13 were intolerant of azathioprine, and only 1/11 was controlled, with a median time to treatment failure (MTTF) of 254 days. MMF was given to 17 patients, either de novo (5) or after azathioprine (12), and was significantly more effective, controlling activity in 4/17 patients, and for a significantly longer time (MTTF 395 days, P = 0.019). All 13 patients failing MMF received rituximab, seven required a second dose, and three, a third dose. All patients responded, with 11/13 able to cease steroids. Control was maintained for a similar time to MMF (MTTF 364 days, P = NS). Rituximab also had the best steroid-sparing effect followed by MMF, then azathioprine. Side-effects were common with azathioprine, while the other two agents were well tolerated. CONCLUSION: Rituximab was the most effective of the three immunosuppressives for PV, although repeat dosing was frequently required. These observations have significant implications for the choice of drugs for this condition. PMID- 25534018 TI - A common building block for the syntheses of amorfrutin and cajaninstilbene acid libraries toward efficient binding with peroxisome proliferator-activated receptors. AB - A common building block for the synthesis of amorfrutin and cajaninstilbene acid derivatives has been developed. The library of synthesized compounds has enabled identification of new nontoxic ligands of peroxisome proliferator-activated receptors (PPAR) and potential inhibitors of the transcriptional corepressor protein NCoR. The biological data holds promise in identification of new potential leads for the antidiabetic drug discovery process. PMID- 25534020 TI - Taxonomy and structure of Persian personality-descriptive trait terms. AB - We described the development of a taxonomy of Persian personality-descriptive terms in two studies. In Study 1, judges scanned Persian dictionaries and several Persian novels for person-descriptive terms. The resulting set of person descriptive terms was classified into different categories of description, including the category of dispositional trait-descriptive adjectives. Of the 544 most familiar traits, 126 traits were selected to collect self-ratings. In Study 2, self-ratings were provided by 2400 students. Ratings were factor analysed (Principal Components Analysis) followed by Varimax rotation. Factor structures with two to six factors were discussed. The two-factor structure and the three factor structure confirm the Big Two and the Big Three, respectively. Of the structures with five and six factors, the five-factor structure appears to be the more appropriate choice, with the factors labelled Morality, Positive versus Negative Emotionality, Achievement, Thoughtfulness and Affection. Gender differences were measured on both the five-factor structure and the six-factor structure. The discussion section emphasised both cross-cultural commonalities and cultural deviations in reference to the Big Five. PMID- 25534021 TI - Polyaromatic nanocapsules displaying aggregation-induced enhanced emissions in water. AB - V-shaped polyaromatic amphiphiles with phenanthrene or naphthalene rings spontaneously and quantitatively formed micelle-like nanocapsules in water at room temperature. In contrast to usual polyaromatic aggregates with weak fluorescent properties, the new capsules providing spherical polyaromatic shells with diameters of ~2 nm show strong fluorescent emissions due to an aggregation induced enhanced emission (AIEE) effect and moreover encapsulate a fluorescent coumarin dye to generate highly emissive host-guest composites. PMID- 25534019 TI - Long-term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold. AB - BACKGROUND: Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. In this study we tested the long term effects of their combination. METHODS: Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks later, those with an echocardiographically measured ejection fraction (EF) <=55% were re-operated on and randomly allocated to receive a cell-free fibrin patch (n = 25), a fibrin patch loaded with 700,000 human embryonic stem cells (ESC) pre-treated to promote early cardiac differentiation (SSEA-1(+) progenitors [n = 30]), or to serve as sham-operated animals (n = 25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the quantitative polymerase chain reaction (qPCR)-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed in a blinded manner. RESULTS: The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p = 0.002 for EF; p = 0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p = 0.006), which yielded the lowest heart failure score (p = 0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma identified. CONCLUSIONS: A fibrin scaffold loaded with ESC derived cardiac progenitors resulted in sustained improvement in contractility and attenuation of remodeling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect. PMID- 25534022 TI - How physician electronic health record screen sharing affects patient and doctor non-verbal communication in primary care. AB - OBJECTIVE: Use of electronic health records (EHRs) in primary-care exam rooms changes the dynamics of patient-physician interaction. This study examines and compares doctor-patient non-verbal communication (eye-gaze patterns) during primary care encounters for three different screen/information sharing groups: (1) active information sharing, (2) passive information sharing, and (3) technology withdrawal. METHODS: Researchers video recorded 100 primary-care visits and coded the direction and duration of doctor and patient gaze. Descriptive statistics compared the length of gaze patterns as a percentage of visit length. Lag sequential analysis determined whether physician eye-gaze influenced patient eye gaze, and vice versa, and examined variations across groups. RESULTS: Significant differences were found in duration of gaze across groups. Lag sequential analysis found significant associations between several gaze patterns. Some, such as DGP-PGD ("doctor gaze patient" followed by "patient gaze doctor") were significant for all groups. Others, such DGT-PGU ("doctor gaze technology" followed by "patient gaze unknown") were unique to one group. CONCLUSION: Some technology use styles (active information sharing) seem to create more patient engagement, while others (passive information sharing) lead to patient disengagement. PRACTICE IMPLICATIONS: Doctors can engage patients in communication by using EHRs in the visits. EHR training and design should facilitate this. PMID- 25534023 TI - Regioselective catalytic asymmetric C-alkylation of isoxazolinones by a base-free palladacycle-catalyzed direct 1,4-addition. AB - Isoxazolinones constitute a class of heterocycles utilized for the development of novel drug candidates. The cyclic oxime ester motif is also synthetically useful as it contains functional handles which have previously been used to provide access to an assortment of valuable compound classes not easily accessible by alternative approaches. However, asymmetric methods towards isoxazolinones are notoriously scarce. Herein we report the first catalytic asymmetric alkylations of isoxazolinones forming all-C-substituted quaternary stereocenters. The present studies were driven by the question of how to control the regioselectivity in the competition of different nucleophilic positions. The investigation of a direct 1,4-addition uncovered that a sterically demanding palladacycle catalyst directs the reactivity in the absence of a base nearly exclusively to the nucleophilic C atom, while at the same time it allows for high enantioselectivity and TONs up to 1900. PMID- 25534025 TI - Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by beta-amyloid plaques and intraneuronal tau aggregation usually associated with cerebral amyloid angiopathy (CAA). Both beta-amyloid plaques and CAA deposits contain fibrillar aggregates of the amyloid beta-peptide (Abeta). Abeta plaques and CAA develop first in neocortical areas of preclinical AD patients and, then, expand in a characteristic sequence into further brain regions with end-stage pathology in symptomatic AD patients. Abeta aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque- and non-CAA associated Abeta aggregates have been described. Amyloid fibrils are products of a complex self-assembly process that involves different types of transient intermediates. Amongst these intermediate species are protofibrils and oligomers. Different variants of Abeta peptides may result from alternative processing or from mutations that lead to rare forms of familial AD. These variants can exhibit different self-assembly and aggregation properties. In addition, several post translational modifications of Abeta have been described that result, for example, in the production of N-terminal truncated Abeta with pyroglutamate modification at position 3 (AbetaN3pE) or of Abeta phosphorylated at serine 8 (pSer8Abeta). Both AbetaN3pE and pSer8Abeta show enhanced aggregation into oligomers and fibrils. However, the earliest detectable soluble and insoluble Abeta aggregates in the human brain exhibit non-modified Abeta, whereas AbetaN3pE and pSer8Abeta are detected in later stages. This finding indicates the existence of different biochemical stages of Abeta aggregate maturation with pSer8Abeta being related mainly to cases with symptomatic AD. The conversion from preclinical to symptomatic AD could thereby be related to combined effects of increased Abeta concentration, maturation of aggregates and spread of deposits into additional brain regions. Thus, the inhibition of Abeta aggregation and maturation before entering the symptomatic stage of the disease as indicated by the accumulation of pSer8Abeta may represent an attractive treatment strategy for preventing disease progression. PMID- 25534024 TI - Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains. AB - Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer's disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6-9 months before they show onset of mutant tau transgene induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post injection. With longer post-injection survival intervals of up to 6 months, CBD Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD. PMID- 25534027 TI - Genome-wide DNA methylation patterns in wild samples of two morphotypes of threespine stickleback (Gasterosteus aculeatus). AB - Epigenetic marks such as DNA methylation play important biological roles in gene expression regulation and cellular differentiation during development. To examine whether DNA methylation patterns are potentially associated with naturally occurring phenotypic differences, we examined genome-wide DNA methylation within Gasterosteus aculeatus, using reduced representation bisulfite sequencing. First, we identified highly methylated regions of the stickleback genome, finding such regions to be located predominantly within genes, and associated with genes functioning in metabolism and biosynthetic processes, cell adhesion, signaling pathways, and blood vessel development. Next, we identified putative differentially methylated regions (DMRs) of the genome between complete and low lateral plate morphs of G. aculeatus. We detected 77 DMRs that were mainly located in intergenic regions. Annotations of genes associated with these DMRs revealed potential functions in a number of known divergent adaptive phenotypes between G. aculeatus ecotypes, including cardiovascular development, growth, and neuromuscular development. PMID- 25534028 TI - Recurrent loss of sex is associated with accumulation of deleterious mutations in Oenothera. AB - Sexual reproduction is nearly universal among eukaryotes. Theory predicts that the rarity of asexual eukaryotic species is in part caused by accumulation of deleterious mutations and heightened extinction risk associated with suppressed recombination and segregation in asexual species. We tested this prediction with a large data set of 62 transcriptomes from 29 species in the plant genus Oenothera, spanning ten independent transitions between sexual and a functionally asexual genetic system called permanent translocation heterozygosity. Illumina short-read sequencing and de novo transcript assembly yielded an average of 16.4 Mb of sequence per individual. Here, we show that functionally asexual species accumulate more deleterious mutations than sexual species using both population genomic and phylogenetic analysis. At an individual level, asexual species exhibited 1.8 * higher heterozygosity than sexual species. Within species, we detected a higher proportion of nonsynonymous polymorphism relative to synonymous variation within asexual compared with sexual species, indicating reduced efficacy of purifying selection. Asexual species also exhibited a greater proportion of transcripts with premature stop codons. The increased proportion of nonsynonymous mutations was also positively correlated with divergence time between sexual and asexual species, consistent with Muller's ratchet. Between species, we detected repeated increases in the ratio of nonsynonymous to synonymous divergence in asexual species compared with sexually reproducing sister taxa, indicating increased accumulation of deleterious mutations. These results confirm that an important advantage of sex is that it facilitates selection against deleterious alleles, which might help to explain the dearth of extant asexual species. PMID- 25534026 TI - Integrative view of alpha2,3-sialyltransferases (ST3Gal) molecular and functional evolution in deuterostomes: significance of lineage-specific losses. AB - Sialyltransferases are responsible for the synthesis of a diverse range of sialoglycoconjugates predicted to be pivotal to deuterostomes' evolution. In this work, we reconstructed the evolutionary history of the metazoan alpha2,3 sialyltransferases family (ST3Gal), a subset of sialyltransferases encompassing six subfamilies (ST3Gal I-ST3Gal VI) functionally characterized in mammals. Exploration of genomic and expressed sequence tag databases and search of conserved sialylmotifs led to the identification of a large data set of st3gal related gene sequences. Molecular phylogeny and large scale sequence similarity network analysis identified four new vertebrate subfamilies called ST3Gal III-r, ST3Gal VII, ST3Gal VIII, and ST3Gal IX. To address the issue of the origin and evolutionary relationships of the st3gal-related genes, we performed comparative syntenic mapping of st3gal gene loci combined to ancestral genome reconstruction. The ten vertebrate ST3Gal subfamilies originated from genome duplication events at the base of vertebrates and are organized in three distinct and ancient groups of genes predating the early deuterostomes. Inferring st3gal gene family history identified also several lineage-specific gene losses, the significance of which was explored in a functional context. Toward this aim, spatiotemporal distribution of st3gal genes was analyzed in zebrafish and bovine tissues. In addition, molecular evolutionary analyses using specificity determining position and coevolved amino acid predictions led to the identification of amino acid residues with potential implication in functional divergence of vertebrate ST3Gal. We propose a detailed scenario of the evolutionary relationships of st3gal genes coupled to a conceptual framework of the evolution of ST3Gal functions. PMID- 25534029 TI - Pooled sequencing and rare variant association tests for identifying the determinants of emerging drug resistance in malaria parasites. AB - We explored the potential of pooled sequencing to swiftly and economically identify selective sweeps due to emerging artemisinin (ART) resistance in a South East Asian malaria parasite population. ART resistance is defined by slow parasite clearance from the blood of ART-treated patients and mutations in the kelch gene (chr. 13) have been strongly implicated to play a role. We constructed triplicate pools of 70 slow-clearing (resistant) and 70 fast-clearing (sensitive) infections collected from the Thai-Myanmar border and sequenced these to high (~ 150-fold) read depth. Allele frequency estimates from pools showed almost perfect correlation (Lin's concordance = 0.98) with allele frequencies at 93 single nucleotide polymorphisms measured directly from individual infections, giving us confidence in the accuracy of this approach. By mapping genome-wide divergence (FST) between pools of drug-resistant and drug-sensitive parasites, we identified two large (>150 kb) regions (on chrs. 13 and 14) and 17 smaller candidate genome regions. To identify individual genes within these genome regions, we resequenced an additional 38 parasite genomes (16 slow and 22 fast-clearing) and performed rare variant association tests. These confirmed kelch as a major molecular marker for ART resistance (P = 6.03 * 10(-6)). This two-tier approach is powerful because pooled sequencing rapidly narrows down genome regions of interest, while targeted rare variant association testing within these regions can pinpoint the genetic basis of resistance. We show that our approach is robust to recurrent mutation and the generation of soft selective sweeps, which are predicted to be common in pathogen populations with large effective population sizes, and may confound more traditional gene mapping approaches. PMID- 25534032 TI - Population diversity and adaptive evolution in keratinization genes: impact of environment in shaping skin phenotypes. AB - Several studies have demonstrated the role of climatic factors in shaping skin phenotypes, particularly pigmentation. Keratinization is another well-designed feature of human skin, which is involved in modulating transepidermal water loss (TEWL). Although this physiological process is closely linked to climate, presently it is not clear whether genetic diversity is observed in keratinization and whether this process also responds to the environmental pressure. To address this, we adopted a multipronged approach, which involved analysis of 1) copy number variations in diverse Indian and HapMap populations from varied geographical regions; 2) genetic association with geoclimatic parameters in 61 populations of dbCLINE database in a set of 549 genes from four processes namely keratinization, pigmentation, epidermal differentiation, and housekeeping functions; 3) sequence divergence in 4,316 orthologous promoters and corresponding exonic regions of human and chimpanzee with macaque as outgroup, and 4) protein sequence divergence (Ka/Ks) across nine vertebrate classes, which differ in their extent of TEWL. Our analyses demonstrate that keratinization and epidermal differentiation genes are under accelerated evolution in the human lineage, relative to pigmentation and housekeeping genes. We show that this entire pathway may have been driven by environmental selection pressure through concordant functional polymorphisms across several genes involved in skin keratinization. Remarkably, this underappreciated function of skin may be a crucial determinant of adaptation to diverse environmental pressures across world populations. PMID- 25534031 TI - Inference of gorilla demographic and selective history from whole-genome sequence data. AB - Although population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole-genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor approximately 261 ka, and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage approximately 68 ka. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of 1.4 fold around 970 ka and a recent 5.6-fold contraction in population size 23 ka. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection. PMID- 25534030 TI - Comparative transcriptome analyses reveal core parasitism genes and suggest gene duplication and repurposing as sources of structural novelty. AB - The origin of novel traits is recognized as an important process underlying many major evolutionary radiations. We studied the genetic basis for the evolution of haustoria, the novel feeding organs of parasitic flowering plants, using comparative transcriptome sequencing in three species of Orobanchaceae. Around 180 genes are upregulated during haustorial development following host attachment in at least two species, and these are enriched in proteases, cell wall modifying enzymes, and extracellular secretion proteins. Additionally, about 100 shared genes are upregulated in response to haustorium inducing factors prior to host attachment. Collectively, we refer to these newly identified genes as putative "parasitism genes." Most of these parasitism genes are derived from gene duplications in a common ancestor of Orobanchaceae and Mimulus guttatus, a related nonparasitic plant. Additionally, the signature of relaxed purifying selection and/or adaptive evolution at specific sites was detected in many haustorial genes, and may play an important role in parasite evolution. Comparative analysis of gene expression patterns in parasitic and nonparasitic angiosperms suggests that parasitism genes are derived primarily from root and floral tissues, but with some genes co-opted from other tissues. Gene duplication, often taking place in a nonparasitic ancestor of Orobanchaceae, followed by regulatory neofunctionalization, was an important process in the origin of parasitic haustoria. PMID- 25534035 TI - Continuous precipitation of calcium carbonate using sonochemical reactor. AB - The continuous production of calcium carbonate (CaCO3) by precipitation method at room temperature was carried out in a stirred reactor under ultrasonic environment and was compared with the conventional stirring method. The effect of various operating parameters such as Ca(OH)2 slurry concentration, CO2 flow rate and Ca(OH)2 slurry flow rate on the particle size of CaCO3 was investigated. The calcium carbonate particles were characterized by Fourier transform infrared (FTIR), wide angle X-ray diffraction (WXRD) and particle size. The morphology was studied by using scanning electron microscopic (SEM) images. The particle size obtained in the presence of ultrasonic environment was found to be smaller as compared to conventional stirring method. The particle size is found to be reduced with an increase in the concentrations of Ca(OH)2 and increased with increasing CO2 flow rate for both the methods. The slurry flow rate had a major effect on the particle size and the particle size decreased with increased slurry flow rate. Only calcite phase of CaCO3 was predominantly present as confirmed by the characterization techniques for both the preparation methods. In most of the cases rhombohedral calcite particles were observed. PMID- 25534033 TI - Degeneration of the nonrecombining regions in the mating-type chromosomes of the anther-smut fungi. AB - Dimorphic mating-type chromosomes in fungi are excellent models for understanding the genomic consequences of recombination suppression. Their suppressed recombination and reduced effective population size are expected to limit the efficacy of natural selection, leading to genomic degeneration. Our aim was to identify the sequences of the mating-type chromosomes (a1 and a2) of the anther smut fungi and to investigate degeneration in their nonrecombining regions. We used the haploid a1 Microbotryum lychnidis-dioicae reference genome sequence. The a1 and a2 mating-type chromosomes were both isolated electrophoretically and sequenced. Integration with restriction-digest optical maps identified regions of recombination and nonrecombination in the mating-type chromosomes. Genome sequence data were also obtained for 12 other Microbotryum species. We found strong evidence of degeneration across the genus in the nonrecombining regions of the mating-type chromosomes, with significantly higher rates of nonsynonymous substitution (dN/dS) than in nonmating-type chromosomes or in recombining regions of the mating-type chromosomes. The nonrecombining regions of the mating-type chromosomes also showed high transposable element content, weak gene expression, and gene losses. The levels of degeneration did not differ between the a1 and a2 mating-type chromosomes, consistent with the lack of homogametic/heterogametic asymmetry between them, and contrasting with X/Y or Z/W sex chromosomes. PMID- 25534034 TI - Antibody-specific model of amino acid substitution for immunological inferences from alignments of antibody sequences. AB - Antibodies are glycoproteins produced by the immune system as a dynamically adaptive line of defense against invading pathogens. Very elegant and specific mutational mechanisms allow B lymphocytes to produce a large and diversified repertoire of antibodies, which is modified and enhanced throughout all adulthood. One of these mechanisms is somatic hypermutation, which stochastically mutates nucleotides in the antibody genes, forming new sequences with different properties and, eventually, higher affinity and selectivity to the pathogenic target. As somatic hypermutation involves fast mutation of antibody sequences, this process can be described using a Markov substitution model of molecular evolution. Here, using large sets of antibody sequences from mice and humans, we infer an empirical amino acid substitution model AB, which is specific to antibody sequences. Compared with existing general amino acid models, we show that the AB model provides significantly better description for the somatic evolution of mice and human antibody sequences, as demonstrated on large next generation sequencing (NGS) antibody data. General amino acid models are reflective of conservation at the protein level due to functional constraints, with most frequent amino acids exchanges taking place between residues with the same or similar physicochemical properties. In contrast, within the variable part of antibody sequences we observed an elevated frequency of exchanges between amino acids with distinct physicochemical properties. This is indicative of a sui generis mutational mechanism, specific to antibody somatic hypermutation. We illustrate this property of antibody sequences by a comparative analysis of the network modularity implied by the AB model and general amino acid substitution models. We recommend using the new model for computational studies of antibody sequence maturation, including inference of alignments and phylogenetic trees describing antibody somatic hypermutation in large NGS data sets. The AB model is implemented in the open-source software CodonPhyML (http://sourceforge.net/projects/codonphyml) and can be downloaded and supplied by the user to ProGraphMSA (http://sourceforge.net/projects/prographmsa) or other alignment and phylogeny reconstruction programs that allow for user-defined substitution models. PMID- 25534036 TI - Binding and Anticancer Properties of Plumbagin with Human Serum Albumin. AB - Plumbagin has received extensive attention as a promising anticancer drug. Therefore, we investigated the binding and anticancer properties of plumbagin with human serum albumin. Fluorescence results demonstrated that plumbagin interacts with human serum albumin, although its binding affinity may be affected to various extents by different compounds. The human serum albumin-plumbagin complex structure revealed that plumbagin binds to the hydrophobic cavity in the IIA subdomain of human serum albumin through hydrogen bonding and hydrophobic interactions. The plumbagin-human serum albumin complex enhances cytotoxicity by 2- to 3-fold particularly in cancer cells but has no effect on normal cells in vitro. Compared with the unbound drug, the human serum albumin-plumbagin complex promotes HeLa cell apoptosis and has a stronger capacity for cell cycle arrest at the G2/M phase of HeLa cells. In conclusion, this study contributes to the rational design and development of plumbagin-based drugs and a drug-human serum albumin delivery system. PMID- 25534037 TI - BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes. AB - Adult humans have a substantial amount of inducible-brown (or beige) fat, which is associated with increased energy expenditure and reduced weight gain via thermogenesis. Despite the identification of key regulators of beige adipogenesis, impacts of dietary factors on adaptive thermogenesis are largely unknown, partly due to a lack of validated human cell models. Bone morphogenetic protein 7 (BMP7) is known to promote brown adipogenesis in rodent and human progenitor cells. However, controversy still surrounds the cellular identity in BMP7-mediated transition of white to brown adipocytes. The aim of this study was to confirm BMP7-derived human adipocytes as a relevant in vitro model of human beige adipocyte by verifying the cellular lineage and metabolic activity. In this study, we hypothesized that pre-exposure of the stromal vascular (SV) fraction of primary human adipogenic precursor cells (hASC) to BMP7 would convert metabolically active brown adipocytes. Our results showed that exposure of hASC to human BMP7 was associated with significant escalation of (1) UCP1 gene expression, a signature gene of brown adipocytes, (2) beige specific marker gene expression (i.e., CD137 and TMEM26), (3) glucose and fatty acid uptake, and (4) basal and cAMP-stimulated oxygen consumption rate compared to white adipocyte control. Taken together, we demonstrated that BMP7 mediates conversion of hASC into metabolically active beige adipocytes. By confirming the cellular identity and metabolic activity, this BMP7-induced human beige adipocytes from hASC should aid in the discovery and assessment of bioactive molecules to promote adaptive thermogenesis. PMID- 25534038 TI - Normative data of frontal plane patellar alignment in athletes. AB - OBJECTIVE: The objective of this study was to provide normative data of frontal plane patellar alignment according to McConnell and Arno angles, verify the association between theses angles and identify the presence of patellar rotation in different sports. DESIGN: Cross-sectional. PARTICIPANTS: Nine participants (18 knees) were assessed in a preliminary study to verify the intra and inter examiner reliabilities of the patellar alignment measures. In the main study, 230 volleyball, basketball, gymnastics and soccer athletes (460 knees) were evaluated in order to obtain normative data of patellar alignment. MAIN OUTCOME MEASURES: Frontal plane patellar alignment (McConnell and Arno angles) measured in standing position by means of photogrammetry. RESULTS: The standardized method demonstrated intra and inter-examiner reliability coefficients varying from .85 to .98. The mean McConnell and Arno angles were 2.05 degrees (+/-5.9) and 2.89 degrees (+/-7.57), respectively. A low association was observed (r = .189, p < .0001) between these angles. There was a difference in distribution of medial and lateral rotations, according to the McConnell angle, between different sports (p < .014). CONCLUSIONS: The proposed procedure for measuring patellar alignment according to McConnell and Arno angles proved to be highly reliable. This made possible the establishment of normative data in a large sample of healthy athletes. PMID- 25534039 TI - An investigation of used electronics return flows: a data-driven approach to capture and predict consumers storage and utilization behavior. AB - Consumers often have a tendency to store their used, old or un-functional electronics for a period of time before they discard them and return them back to the waste stream. This behavior increases the obsolescence rate of used still functional products leading to lower profitability that could be resulted out of End-of-Use (EOU) treatments such as reuse, upgrade, and refurbishment. These types of behaviors are influenced by several product and consumer-related factors such as consumers' traits and lifestyles, technology evolution, product design features, product market value, and pro-environmental stimuli. Better understanding of different groups of consumers, their utilization and storage behavior and the connection of these behaviors with product design features helps Original Equipment Manufacturers (OEMs) and recycling and recovery industry to better overcome the challenges resulting from the undesirable storage of used products. This paper aims at providing insightful statistical analysis of Electronic Waste (e-waste) dynamic nature by studying the effects of design characteristics, brand and consumer type on the electronics usage time and end of use time-in-storage. A database consisting of 10,063 Hard Disk Drives (HDD) of used personal computers returned back to a remanufacturing facility located in Chicago, IL, USA during 2011-2013 has been selected as the base for this study. The results show that commercial consumers have stored computers more than household consumers regardless of brand and capacity factors. Moreover, a heterogeneous storage behavior is observed for different brands of HDDs regardless of capacity and consumer type factors. Finally, the storage behavior trends are projected for short-time forecasting and the storage times are precisely predicted by applying machine learning methods. PMID- 25534040 TI - Kinetic characterization of thermophilic and mesophilic anaerobic digestion for coffee grounds and waste activated sludge. AB - This study was conducted to characterize the kinetics of an anaerobic process (hydrolysis, acetogenesis, acidogenesis and methanogenesis) under thermophilic (55 degrees C) and mesophilic (35 degrees C) conditions with coffee grounds and waste activated sludge (WAS) as the substrates. Special focus was given to the kinetics of propionic acid degradation to elucidate the accumulation of VFAs. Under the thermophilic condition, the methane production rate of all substrates (WAS, ground coffee and raw coffee) was about 1.5 times higher than that under the mesophilic condition. However, the effects on methane production of each substrate under the thermophilic condition differed: WAS increased by 35.8-48.2%, raw coffee decreased by 76.3-64.5% and ground coffee decreased by 74.0-57.9%. Based on the maximum reaction rate (Rmax) of each anaerobic stage obtained from the modified Gompertz model, acetogenesis was found to be the rate-limiting step for coffee grounds and WAS. This can be explained by the kinetics of propionate degradation under thermophilic condition in which a long lag-phase (more than 18 days) was observed, although the propionate concentration was only 500 mg/L. Under the mesophilic condition, acidogenesis and hydrolysis were found to be the rate-limiting step for coffee grounds and WAS, respectively. Even though reducing the particle size accelerated the methane production rate of coffee grounds, but did not change the rate-limiting step: acetogenesis in thermophilic and acidogenesis in mesophilic. PMID- 25534041 TI - Effects of local application of simvastatin on bone regeneration in femoral bone defects in rabbit. AB - Simvastatin (SIM), which is widely used in hyperlipidemia treatment, has also attracted attention due to its anabolic effects on bones. This study is designed to investigate the effectiveness of 2 mg SIM combined with 3 different carriers as delivery systems. Bone defects were surgically created in the femoral bones of 14 New Zealand white rabbits. The carriers used were the inorganic bovine bone graft (BOS), the hydroxyapatite combined with calcium sulfate (HACS), and the collagen sponge (COS). The bone defects were divided for each time period into 7 groups, as follows: passive control group (CONT), active control groups (BOS), (HACS) and (COS) (no simvastatin), and groups (BOS + SIM), (HACS + SIM) (carrier and simvastatin combination). Animal were sacrificed at 4 and 8 weeks postoperatively, and bone defects areas were prepared for histological examination and histomorphometric evaluation. Analysis of variance demonstrated statistically significant differences between groups depending on the carrier used. At 4 weeks, the BOS + SIM group presented higher rates of new bone formation, whereas at 8 weeks more new bone formation was noted for the HACS + SIM group. This study suggests that local application of simvastatin, combined with an appropriate carrier, can promote new bone formation. PMID- 25534042 TI - Reconstruction of orbital floor blow-out fractures with autogenous iliac crest bone: a retrospective study including maxillofacial and ophthalmology perspectives. AB - This is a 10-year retrospective study of patients with an isolated unilateral orbital floor fracture reconstructed with an autogenous iliac crest bone graft. The following inclusion criteria applied: isolated orbital floor fracture without involvement of the orbital rim or other craniofacial injuries, pre-/post operative ophthalmological/orthoptic follow-up, pre-operative CT. Variables recorded were patient age and gender, aetiology of injury, time to surgery, follow-up period, surgical morbidity, diplopia pre- and post-operatively (Hess test), eyelid position, visual acuity, and the presence of en-/or exophthalmos (Hertel exophthalmometer). Twenty patients met the inclusion criteria. The mean age was 29 years. The mean follow up period was 26 months. No patient experienced significant donor site morbidity. There were no episodes of post-operative infection or graft extrusion. Three patients had diplopia in extremes of vision post-operatively, but no interference with activities of daily living. One patient had post-operative enophthalmos. Isolated orbital blow-out fractures may be safely and predictably reconstructed using autogenous iliac crest bone. The rate of complications in the group of patients studied was low. The value of pre- and post-operative ophthalmology consultation cannot be underestimated, and should be considered the standard of care in all patients with orbitozygomatic fractures, in particular those with blow-out fractures. PMID- 25534043 TI - [Concordance between a head circumference growth function and intellectual disability in relation with the cause of microcephaly]. AB - INTRODUCTION: Our aim was to investigate the correlations between patterns of head growth and intellectual disability among distinct aetiological presentations of microcephaly. PATIENTS AND METHODS: 3,269 head circumference (HC) charts of patients from a tertiary neuropediatric unit were reviewed and 136 microcephalic participants selected. Using the Z-scores of registered HC measurements we defined the variables: HC Minimum, HC Drop and HC Catch-up. We classified patients according to the presence or absence of intellectual disability (IQ below 71) and according to the cause of microcephaly (idiopathic, familial, syndromic, symptomatic and mixed). RESULTS: Using Discriminant Analysis a C function was defined as C=HC Minimum + HC Drop with a cut-off level of C=-4.32 Z score. In our sample 95% of patients scoring below this level, severe microcephaly, were classified in the disabled group while the overall concordance was 66%. In the symptomatic-mixed group the concordance between HC function and outcome reached 82% in contrast to only 54% in the idiopathic-syndromic group (P value=0.0002). CONCLUSIONS: We defined a HC growth function which discriminates intellectual disability of microcephalic patients better than isolated HC measurements, especially for those with secondary and mixed aetiologies. PMID- 25534044 TI - [Evolution of non-invasive ventilation in acute bronchiolitis]. AB - OBJECTIVES: The aim of the study was to analyse the evolution, over a12-year period, of the use of non-invasive (NIV) and invasive ventilation (IV) in children admitted to a Paediatric Intensive Care Unit (PICU) due to acute bronchiolitis. PATIENTS AND METHODS: A retrospective observational study was performed including all children who were admitted to the PICU requiring NIV or IV between 2001 and 2012. Demographic characteristics, ventilation assistance and clinical outcome were analysed. A comparison was made between the first six years and the last 6 years of the study. RESULTS: A total of 196 children were included; 30.1% of the subjects required IV and 93.3% required NIV. The median duration of IV was 9.5 days and NIV duration was 3 days. The median PICU length of stay was 7 days, and 2% of the patients died. The use of NIV increased from 79.4% in first period to 100% in the second period (P<.0001) and IV use decreased from 46% in first period to 22.6% in the last 6 years (P<.0001). Continuous positive airway pressure and nasopharyngeal tube were the most frequently used modality and interface, although the use of bi-level non-invasive ventilation (P<.001) and of nasal cannulas significantly increased (P<.0001) in the second period, and the PICU length of stay was shorter (P=.011). CONCLUSION: The increasing use of NIV in bronchiolitis in our PICU during the last 12 years was associated with a decrease in the use of IV and length of stay in the PICU. PMID- 25534046 TI - Erratum to: The Association of Religious Affiliation and Body Mass Index (BMI): An Analysis from the Health Survey for England. PMID- 25534045 TI - The information and decision support needs of older women (>75 yrs) facing treatment choices for breast cancer: a qualitative study. AB - OBJECTIVE: Primary Endocrine Therapy (PET) is a good alternative to surgery for breast cancer in older frailer women. Overall survival rates are equivalent although rates of local control are inferior. There is little research regarding the decision support needs of older patients faced with this choice. This qualitative study aimed to explore these among older breast cancer patients offered a choice of treatment, as the basis to develop an appropriate decision support tool. METHODS: Semi-structured interviews were undertaken with older women (>75 years) with breast cancer who had been offered a choice of PET or surgery at diagnosis. Women's involvement in their treatment decision and support for the process were explored and analysed using framework analysis. RESULTS: Thirty-three interviews were undertaken (median age 82, range 75-95 years, 22 PET, 11 surgery). Most women, regardless of treatment choice, wanted tailored information about the different treatment options, their impact on independence, the practicalities of treatment and the risk of recurrence and spread. Surgery was the treatment of choice in women wanting optimal disease control; those choosing PET felt that they were 'too old' for surgery and wanted minimal disruption. CONCLUSIONS: Older women described making active treatment decisions. However, some knowledge was inaccurate. Women wanted information and decision support from their clinicians along with a specific tailored information booklet to support this process. PMID- 25534047 TI - Erratum to: Nutritional Concepts and Frequency of Foodstuffs Mentioned in the Holy Quran. PMID- 25534048 TI - The new year. PMID- 25534049 TI - [Electronic cigarettes: A therapeutic tool, a social phenomenon or a business?]. AB - Smoking is the first avoidable cause of morbidity and mortality. It is estimated that there were around 14 million smokers in France in 2012 and that smoking results in 70,000 deaths per year. All types of interventions reducing with efficacy the incidence and prevalence of smoking are to consider in prolonging life expectancy. Electronic cigarettes (e.cig.) are a social phenomenon but they also are a system delivering pharmacologically active substances; their use concerns today several millions of individuals in France. By this fact, it became important for clinical practitioners to acquire some knowledge about e. cig. Most of the e.cig. contains nicotine, thus, e.cig. are now called in the medical literature as electronic nicotine delivery system (ENDS). It is highly plausible that ENDS, which are, as of today, consumer products and not health products, deliver nicotine with a good bioavailability and could, if largely used, help to reduce smoking prevalence. However, because of current lack of regulations, as of today, the risk/benefit ratio of ENDS as an aid to help smokers quit and their adverse effect profile cannot be established. It is of public health responsibility to promote evidence based knowledge about e.cig. to know with confidence their risk/benefit ratio. PMID- 25534050 TI - Changing trends in adult facial trauma epidemiology. AB - OBJECTIVE: The aim of this study was to determine whether the incidence of facial fractures has changed in the United States since 1990. STUDY DESIGN: This study is a retrospective review of all nonpediatric inpatient and outpatient facilities of the Detroit Medical Center from 1990 to 2011 and weighted national inpatient estimates from 1993 to 2010 using the National Inpatient Survey. METHODS: Facial fractures and surgical repairs were grouped according to fracture site and scaled to annual populations. Chow testing determined the year with the most significant change in trend, and regressions were performed before and after the break point. RESULTS: Chow testing showed the year 2000 as the most significant break point across all data sets. National inpatient and institutional data showed a significant decrease in total fractures and most subsites during the 1990s and an increase since 2000. Since 1990, the rate of fracture repairs decreased at our institution and during inpatient stays in the United States. Motor vehicle related injuries have decreased since the early 1990s. Assault rates have fallen nationally but increased slightly in Detroit. CONCLUSIONS: Evidence from the largest institutional series of adult facial fractures and the largest national inpatient database supports a decrease in fractures and repairs during the 1990s and an increase in fractures despite no change in repairs since 2000. These trends are likely related to increasing use of computed tomographic imaging, decreasing severity of facial injuries, and changing incidences of the major etiologies of facial fractures. PMID- 25534051 TI - Assessment of presurgical clefts and predicted surgical outcome in patients treated with and without nasoalveolar molding. AB - Obtaining an esthetic and functional primary surgical repair in patients with complete cleft lip and palate (CLP) can be challenging because of tissue deficiencies and alveolar ridge displacement. This study aimed to describe surgeons' assessments of presurgical deformity and predicted surgical outcomes in patients with complete unilateral and bilateral CLP (UCLP and BCLP, respectively) treated with and without nasoalveolar molding (NAM). Cleft surgeon members of the American Cleft Palate-Craniofacial Association completed online surveys to evaluate 20 presurgical photograph sets (frontal and basal views) of patients with UCLP (n = 10) and BCLP (n = 10) for severity of cleft deformity, quality of predicted surgical outcome, and likelihood of early surgical revision. Five patients in each group (UCLP and BCLP) received NAM, and 5 patients did not receive NAM. Surgeons were masked to patient group. Twenty-four percent (176/731) of surgeons with valid e-mail addresses responded to the survey. For patients with UCLP, surgeons reported that, for NAM-prepared patients, 53.3% had minimum severity clefts, 58.9% were anticipated to be among their best surgical outcomes, and 82.9% were unlikely to need revision surgery. For patients with BCLP, these percentages were 29.8%, 38.6%, and 59.9%, respectively. Comparing NAM-prepared with non-NAM-prepared patients showed statistically significant differences (P < 0.001), favoring NAM-prepared patients. This study suggests that cleft surgeons assess NAM-prepared patients as more likely to have less severe clefts, to be among the best of their surgical outcomes, and to be less likely to need revision surgery when compared with patients not prepared with NAM. PMID- 25534052 TI - Facial wound closure in children using a 7-0 absorbable suture dressing. AB - BACKGROUND: Management of pediatric facial wounds is more challenging compared to adults. Suture removal is difficult, and children are less likely to protect the suture line postoperatively. The purpose of this study was to determine the efficacy of a facial wound closure regimen designed to ensure the best possible outcome in the pediatric population. METHODS: Children 12 years or younger who had a skin lesion resected from the face between 2007 and 2013 were investigated. Patients who had their wound closed using 7-0 absorbable suture, glue, and tape were studied. Predictive variables included patient age, indication for the procedure, size of the excised lesion, and location of the repair. Outcome measures were infection, wound dehiscence, and scar appearance. RESULTS: Two hundred sixty-one children were included (151 girls, 110 boys). The mean (SD) age was 4.0 years (3.3 y). Types of lesions that were excised were nevus (24.9%), cyst (22.2%), vascular anomaly (19.5%), pilomatrixoma (13.8%), accessory tragus (11.9%), scar (4.6%), or other (3.1%). The mean (SD) area of the resected specimen was 2.2 cm(2) (3.9 cm(2)). The complication rate was 0.8% (infection, n = 1; dehiscence, n = 1). Four patients had an unfavorable appearing scar that widened (1.5%). DISCUSSION: A facial wound closure regimen using small absorbable sutures, glue, and tape optimizes outcomes in the pediatric population. Suture removal is not required, complications are rare, and scar appearance is excellent. PMID- 25534053 TI - Thermal shell fragment craniofacial injury: biophysics, pathophysiology, and management. AB - This article aims to bring attention to unique risks and burns by thermal shell fragment craniofacial soft tissue injury. Hot shrapnel may inflict burns to major vessel walls and lead to life-threatening hemorrhaging or death, which adds a new challenge for craniofacial surgeons. Morbidity of thermal deep tissue may lead to deep tissue necrosis and infection.Thermal energy (TE) physics, biophysics, and pathophysiological effects relate directly to the amount of heat generated from shell casing detonation, which transfers to skin, deep tissue, as well as brain and leads to life-threatening burning of organs; this is different from shrapnel kinetic energy injury.The unprecedented increase in using a large range of explosives and high-heat thermobaric weapons contributes to the superfluous and unnecessary suffering caused by thermal injury wounds.Surgeons and medics should recognize that a surprising amount of TE can be found in an explosion or detonation of a steel-encased explosive, resulting in TEs ranging from 400 F up to 1000 F. PMID- 25534054 TI - Direct brain recordings reveal impaired neural function in infants with single suture craniosynostosis: a future modality for guiding management? AB - BACKGROUND: Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population. METHODS: Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing. RESULTS: Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls. CONCLUSIONS: Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development. PMID- 25534055 TI - Evidence of olfactory deficits as part of the phenotypic spectrum of nonsyndromic orofacial clefting. AB - Improved understanding of the phenotypic spectrum associated with nonsyndromic orofacial clefting (OFC) has the potential to inform efforts to uncover the etiology of this complex trait. Prior studies report that individuals with OFC are characterized by impaired olfactory ability. In this study, we test whether olfactory dysfunction extends to the unaffected parents of children with OFC. The University of Pennsylvania Smell Identification Test was used to measure olfactory ability in a sample of 60 unaffected mothers and fathers with cleft affected children. The proportion of deficit was compared with reference data obtained from published sex- and age-specific norms on more than 2700 individuals. The proportion of deficit was significantly higher in unaffected parents compared with baseline control subjects (41.7% vs 12.6%; P < 0.001). Of unaffected fathers, 41.7% displayed evidence of deficit compared with 15.1% of male control subjects (P = 0.001), whereas 41.7% of mothers exhibited deficits compared with 10.4% of female control subjects (P < 0.001). Olfactory deficits are present at a high proportion in the unaffected parents of individuals with OFC. This suggests that the deficits observed in affected cases may not simply be a secondary consequence of surgical repair and may instead be an informative phenotype reflecting underlying etiology. PMID- 25534056 TI - Are endoscopic and open treatments of metopic synostosis equivalent in treating trigonocephaly and hypotelorism? AB - BACKGROUND: Patients with metopic craniosynostosis are traditionally treated with fronto-orbital advancement to correct hypotelorism and trigonocephaly. Alternatively, endoscopic-assisted treatment comprises narrow ostectomy of the fused suture followed by postoperative helmet therapy. Here we compare the preoperative and 1-year postoperative results in open versus endoscopic repairs. METHODS: We reviewed preoperative and 1-year postoperative three-dimensional reconstructed computed tomography scans of patients treated for nonsyndromic metopic craniosynostosis by either open (n = 15) or endoscopic (n = 13) technique. Hypotelorism was assessed by interzygomaticofrontal distance and intercanthal distance. Trigonocephaly was assessed by 2 independent angles: first, an axial-plane two-dimensional angle between zygomaticofrontal suture bilaterally and the glabella (ZF(R)-G-ZF(L)); second, an interfrontal angle (IFA) between the most anterior point from a reconstructed midsagittal plane and supraorbital notch bilaterally. Age-matched scans of unaffected patients (n = 28) served as controls for each postoperative scan. RESULTS: Patients with open repair (9.5 +/- 1.8 months) were older at time of surgery than patients with endoscopic repairs (3.3 +/- 0.4 months) (P = 0.004). Male-to-female ratios were equivalent at roughly 7:3 in both groups. Preoperatively, the endoscopic group had worse hypotelorism and ZF(R)-G-ZF(L) than the open group (P <= 0.04). After accounting for preoperative differences, all of the postoperative measurements (ie, interzygomaticofrontal distance, intercanthal distance, ZF(R)-G-ZF(L) angle, IFA) of the 2 groups were statistically equivalent (P >= 0.135). Trigonocephaly was significantly improved after repair in both the open (8 degrees [ZF(R)-G ZF(L)] and 18 degrees [IFA]) and endoscopic (13 degrees [ZF(R)-G-ZF(L)] and 16 degrees [IFA]) groups (P < 0.001). Postoperative measures in both groups were equivalent to controls (0.12 < P < 0.89). Intrarater reliability ranged from 0.93 to 0.99 for all measurements. CONCLUSION: Our retrospective series shows that endoscopic and open repairs of metopic craniosynostosis are equivalent in improving hypotelorism and trigonocephaly at 1-year follow-up. Additional studies are necessary to better define minor differences in morphology, which may result from the different techniques. PMID- 25534057 TI - Computed tomographic analysis of frontal sinus drainage pathway variations and frontal rhinosinusitis. AB - OBJECTIVE: The objective of this study was to radiologically determine frontal sinus drainage pathway variations with respect to superior attachment of uncinate process (SAUP) and their effect on prevalence of frontal rhinosinusitis. DESIGN: This was a retrospective cohort study. METHODS: Computed tomography scans of the 919 frontal sinus sides of 460 patients (252 female, 208 male; mean age, 35.1 +/- 10.5 years) who were candidates for endoscopic sinus surgery were evaluated retrospectively between August 2012 and January 2013 by 3 radiologists to determine the SAUP types and the presence of frontal rhinosinusitis. RESULTS: The frontal sinus outflow tract was localized medial to the SAUP in 651 frontal sinus sides and lateral to the SAUP in 268 sides. We determined 3 types (types 7, 8, and 9) of SAUP in addition to 6 types defined in literature. The most common type of SAUP was type 3 (n = 332, 36.1%) followed by type 2 (n = 256, 27.8%) and type 7 (n = 160, 17.4%). Of the evaluated sides, 316 (34.3%) had frontal rhinosinusitis. Frontal rhinosinusitis was more common in the sides where the frontal sinus outflow tract was localized medial to the SAUP than those localized lateral (37.2% vs 27.6%, P = 0.006). CONCLUSIONS: Endoscopic approach to frontal recess usually requires uncinectomy, and it is necessary to know SAUP to prevent postoperative retained superior portion of the uncinate process. The location of frontal sinus outflow tract on the SAUP affects the prevalence of frontal rhinosinusitis as well. Frontal rhinosinusitis is significantly more common when the frontal sinus outflow tract was localized medial rather than lateral to the SAUP. LEVEL OF EVIDENCE: 2b. PMID- 25534058 TI - Feasibility of purely endoscopic intramedullary fixation of mandibular condyle fractures. AB - The investigators of this study hypothesized that fractures of the mandibular condyle can be repaired using short-segment intramedullary implants and purely endoscopic surgical technique, using a basic science, human cadaver model in an academic center. Endoscopic instrumentation was used through a transoral mucosal incision to place intramedullary implants of 2 cm in length into osteotomized mandibular condyles. The surgical maneuvers that required to insert these implants, including condyle positioning, reaming, implant insertion, and seating of the mandibular ramus, are described herein. Primary outcome was considered as successful completion of the procedure. Ten cadaveric mandibular condyles were successfully repaired with rigid intramedullary internal fixation without the use of external incisions. Both insertion of a peg-type implant and screwing a threaded implant into the condylar head were possible. The inferior portion of the implant remained exposed, and the ramus of the mandible was manipulated into position on the implant using retraction at the sigmoid notch. The results of this study suggest that purely endoscopic repair of fractures of the mandibular condyle is possible by using short-segment intramedullary titanium implants and a transoral endoscopic approach without the need for facial incisions or punctures. The biomechanical advantages of these intramedullary implants, including improved strength and resistance to mechanical failure compared with miniplates, have been recently established. The combination of improved implant design and purely endoscopic technique may allow for improved fixation and reduced surgical- and implant-related morbidity in the treatment of condylar fractures. PMID- 25534059 TI - In search of the optimal processing technique for fat grafting. AB - OBJECTIVE: Unpredictability in graft retention remains a significant drawback of fat grafting. Processing of fat grafts has been the focus of several studies to improve graft survival. The objective of this study was to systematically review the outcomes of different fat graft processing techniques with the goal of (1) deriving clinically oriented insights and (2) identifying gaps in knowledge to stimulate future research. METHODS: PubMed, EMBASE, and Cochrane Databases were searched to identify studies that compared different fat graft processing techniques. Outcome measures of interest were any subjective or objective measures of fat graft survival or reports of adverse events. RESULTS: A total of 2056 abstracts were generated from the literature searches; 13 studies met the criteria for data extraction and analysis. Processing methods assessed included decantation, washing, gauze filtration, and centrifugation. Each processing method was found to be better than other methods, depending on the outcome measure used to study graft survival. As well, several studies found statistical equipoise in the outcome measures when analyzing the results of the different techniques. Adverse events were rarely reported and did not correlate with any processing method in particular. CONCLUSIONS: No firm concluding recommendation can be made to deem 1 processing technique superior to the others. However, it would seem that techniques, which use a combination of gentle washing and centrifugation, strike the optimal balance of preserving adipocyte viability while removing bulk of the contaminants. PMID- 25534060 TI - In support of using computer-aided design and modeling for periorbital osteotomies. AB - Three-dimensional virtual surgical planning using computer-aided design and modeling (CAD/CAM) has gained popularity in planning complex orthognathic and osteocutaneous free flap reconstructions of the head and neck because of its ability to guide complex geometric planning in three-dimensional space and save time in the operating room. The purpose of this study was to review our experience using CAD/CAM concepts in periorbital osteotomies. Three complex periorbital osteotomies were planned and performed: 1 case of bilateral vertical and horizontal orbital dystopia, 1 case of a Monobloc-Le Fort II in an Apert patient, and 1 case of recurrent hypertelorism in a patient with craniofrontal nasal dysplasia. The patients' charts were reviewed, including photographs, medical records, and CAD/CAM plans. The CAD/CAM planning sessions were held 3 to 6 weeks preoperatively and lasted approximately 1 hour. Both cutting guides and positioning guides were used, translating to significant precision of both the osteotomy as well as the final position of the orbits. Qualitatively, the cutting and positioning guides were easy to use and improved operating room efficiency. To conclude, in our hands, CAD/CAM virtual surgical planning is safe and effective in the performance of complex periorbital osteotomies. More work is needed to more clearly define surgical indications for this costly, new technology. PMID- 25534061 TI - A comparison and cost analysis of cranioplasty techniques: autologous bone versus custom computer-generated implants. AB - BACKGROUND: Cranioplasty can be performed either with gold-standard, autologous bone grafts and osteotomies or alloplastic materials in skeletally mature patients. Recently, custom computer-generated implants (CCGIs) have gained popularity with surgeons because of potential advantages, which include preoperatively planned contour, obviated donor-site morbidity, and operative time savings. A remaining concern is the cost of CCGI production. The purpose of the present study was to objectively compare the operative time and relative cost of cranioplasties performed with autologous versus CCGI techniques at our center. METHODS: A review of all autologous and CCGI cranioplasties performed at our institution over the last 7 years was performed. The following operative variables and associated costs were tabulated: length of operating room, length of ward/intensive care unit (ICU) stay, hardware/implants utilized, and need for transfusion. RESULTS: Total average cost did not differ statistically between the autologous group (n = 15; $25,797.43) and the CCGI cohort (n = 12; $28,560.58). Operative time (P = 0.004), need for ICU admission (P < 0.001), and number of complications (P = 0.008) were all statistically significantly less in the CCGI group. The length of hospital stay and number of cases needing transfusion were fewer in the CCGI group but did not reach statistical significance. CONCLUSION: The results of the present study demonstrated no significant increase in overall treatment cost associated with the use of the CCGI cranioplasty technique. In addition, the latter was associated with a statistically significant decrease in operative time and need for ICU admission when compared with those patients who underwent autologous bone cranioplasty. LEVEL OF EVIDENCE: IV, therapeutic. PMID- 25534062 TI - Evaluating the safety and efficacy of tranexamic acid administration in pediatric cranial vault reconstruction. AB - BACKGROUND: Blood loss is the leading cause of mortality after major craniofacial surgery. Autologous blood donation, short-term normovolemic hemodilution, and intraoperative blood salvage have shown low efficacy in decreasing transfusions. Tranexamic acid (TXA) is a synthetic antifibrinolytic drug that competitively decreases the conversion of plasminogen to plasmin, thereby suppressing fibrinolysis. The purpose of this study was to investigate the impact that TXA administration has on intraoperative blood loss and blood product transfusion in pediatric patients undergoing cranial vault reconstruction. METHODS: An Internal Review Board-approved retrospective study was conducted on a consecutive series of pediatric patients undergoing cranial vault reconstruction from January 2009 to June 2012. Seventeen consecutive patients who received TXA at the time of cranial vault reconstruction were compared with 20 patients who did not receive TXA. Criteria for blood product transfusion were identical for both groups. Outcomes including perioperative blood loss, volume of blood transfused, and adverse effects were analyzed. RESULTS: The TXA group had a significantly lower perioperative blood loss (9.4 versus 21.1 mL/kg, P < 0.0001) and lower volume of perioperative mean blood product transfusion (12.8 versus 31.3 mL/kg, P < 0.0001) compared with the non-TXA group. There was no significant difference in demographic data, infection rate, change in preoperative to postoperative hematocrit, duration of surgery, or complication rates between the TXA and non TXA groups. No drug-related adverse effects were identified in patients who received TXA. CONCLUSIONS: The use of TXA in pediatric cranial vault reconstruction significantly reduces perioperative blood loss and blood product transfusion requirements. The TXA administration is safe and may improve patient outcomes by decreasing the likelihood of adverse effects related to blood product transfusion. PMID- 25534063 TI - Facial changes after early treatment of unilateral coronal synostosis question the necessity of primary nasal osteotomy. AB - BACKGROUND: The premature fusion of unilateral coronal suture can cause a significant asymmetry of the craniofacial skeleton, with an oblique deviation of the cranial base that negatively impacts soft tissue facial symmetry. The purpose of this study was to assess facial symmetry obtained in patients with unilateral coronal synostosis (UCS) surgically treated by 2 different techniques. We hypothesized that nasal deviation should not be addressed in a primary surgical correction of UCS. METHODS: Consecutive UCS patients were enrolled in a prospective study and randomly divided into 2 groups. In group 1, the patients underwent total frontal reconstruction and transferring of onlay bone grafts to the recessive superior orbital rim (n = 7), and in group 2, the patients underwent total frontal reconstruction and unilateral fronto-orbital advancement (n = 5). Computerized photogrammetric analysis measured vertical and horizontal axis of the nose and the orbital globe in the preoperative and postoperative periods. Intragroup and intergroup comparisons were performed. RESULTS: Intragroup preoperative and postoperative comparisons showed a significant (all P < 0.05) reduction of the nasal axis and the orbital-globe axis in the postoperative period in the 2 groups. Intergroup comparisons showed no significant difference (all P > 0.05). CONCLUSIONS: Facial symmetry was achieved in the patients with UCS who underwent surgery regardless of surgical approach evaluated here. Our data showed a significant improvement in nasal and orbital globe deviation, leading us to question the necessity of primary nasal correction in these patients. PMID- 25534064 TI - Perioperative complications associated with intracranial procedures in patients with nonsyndromic single-suture craniosynostosis. AB - Within the diagnosis "craniosynostosis," there is a subset of patients who present with isolated, nonsyndromic, single-suture involvement. This study evaluates perioperative complications in this specific subset of patients over 4 decades at a single institution. To do so, we performed a retrospective review on consecutive patients undergoing correction of single-suture synostosis from May 1977 to January 2013 at a tertiary pediatric craniofacial center. Demographic information, operative details, and perioperative course were collected. Complications were categorized as either major or minor. A chi(2) test and Fisher exact test were used to compare all categorical variables. Continuous variables were analyzed using Wilcoxon rank-sum and Kruskal-Wallis tests.Seven hundred forty-six patients underwent surgical correction of nonsyndromic craniosynostosis. Of these, there were 307 (41.2%) sagittal, 201 (26.9%) metopic, and 238 (31.9%) unicoronal. Thirty-four patients had complications (4.6%). Eight were considered major (1.1%), including one postoperative mortality in a patient with hypoplastic left-sided heart syndrome. Minor complications occurred in 26 patients (3.5%) and included subgaleal hematoma (n = 3), seroma (n = 4), and superficial wound infection (n = 5). Metopic and sagittal suture involvement was significantly associated with a higher complication rate (P = 0.04). A child with isolated single suture synostosis and any comorbidity had a significantly greater risk of any complication (P < 0.001; odds ratio, 3.8) and specifically an increased risk of major complication (P = 0.031; odds ratio, 6.0). Subclassification of patients by time period yielded no statistically significant changes in perioperative morbidity. To conclude, these data allow us to counsel families more accurately with regard to morbidity and mortality and may potentially serve as a benchmark for future quality improvement work. PMID- 25534065 TI - Effectiveness of psychosocial intervention enhancing resilience among war affected children and the moderating role of family factors. AB - The study examines, first, the effectiveness of a psychosocial intervention based on Teaching Recovery Techniques (TRT) to increase resiliency among Palestinian children, exposed to a major trauma of war. Second, it analyses the role of family factors (maternal attachment and family atmosphere) as moderating the intervention impacts on resilience. School classes in Gaza were randomized into intervention (N=242) and control (N=240) groups. The percentage of girls (49.4%) and boys (50.6%) were equal, and the child age was 10-13 years in both groups. Children reported positive indicators of their mental health (prosocial behaviour and psychosocial well-being) at baseline (T1), post-intervention (T2) and at a six-month follow-up (T3). At T1 they accounted their exposure to war trauma. Mothers reported about their willingness to serve as an attachment figure, and the child reported about the family atmosphere. Resilience was conceptualized as a presence of positive indications of mental health despite trauma exposure. Against our hypothesis, the intervention did not increase the level of resilience statistically significantly, nor was the effect of the intervention moderated by maternal attachment responses or family atmosphere. PMID- 25534066 TI - Sex determination from calcification of costal cartilages in a Scottish sample. AB - The pelvic bones and skull are not always available when human remains are discovered in a forensic setting. This study investigates the suitability to a Scottish sample of existing methods of sexing based on calcification patterns in the costal cartilages. Radiographs of chest plates of 41 cadavers, 22 male and 19 female aged 57-96 years were analyzed for their calcification patterns according to the methods of McCormick et al. (1985, Am. J. Phys. Anthropol. 68:173-195) and Rejtarova et al. (2004, Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc. Czech. Repub. 148:241-243). With the method of Rejtarova et al. (2004, Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc. Czech. Repub. 148:241-243) none of the male specimens was sexed correctly. Of the chest plates that were suitable for sexing, the method of McCormick et al. (1985, Am. J. Phys. Anthropol. 68:173-195) correctly sexed 82.4% of the female specimens but only 41.2% of the males. To improve the reliability, we suggest a new method of sex determination based on whether the calcified deposits in the second to seventh costal cartilages are predominantly trabecular bone or sclerotic calcified deposits. Specimens with minimal amounts or similar amounts of trabecular bone or sclerotic deposits in the costal cartilages are not appropriate for our method. When such specimens (10 specimens) were excluded, our method correctly sexed 16 of 17 (94%) males and 12 of 14 (86%) females. The authors acknowledge that their sample is small and that many of their subjects were elderly and that the method should be tested on a larger sample group before application in a forensic context. PMID- 25534068 TI - Soil bacteria hold the key to root cluster formation. AB - Root clusters are bunches of hairy rootlets that enhance nutrient uptake among many plants. Since first being reported in 1974, the involvement of rhizobacteria in their formation has received conflicting support. Attempts to identify specific causative organisms have failed and their role has remained speculative. We set up a gnotobiotic experiment using two root-clustered species, Viminaria juncea (Fabaceae) and Hakea laurina (Proteaceae), and inoculated them with two plant-growth-promoting rhizobacteria (PGPR), Bradyrhizobium elkanii and Bacillus mageratium, that produce indole-3-acetic-acid (IAA). Plants were suspended in water culture with four combinations of nitrogen and phosphorus. Clusters only developed in the presence of PGPR in two treatments, were greatly enhanced in another four, suppressed in five, and unaffected in five. Nitrogen amendment was associated with a higher density of clusters. Bradyrhizobium promoted cluster formation in Hakea, whereas Bacillus promoted cluster formation in Viminaria and suppressed it in Hakea. Greater root cluster numbers were due either to a larger root system induced by PGPR (indirect resource effect) and/or to more clusters per unit length of parent root (direct morphogenetic effect). The results are interpreted in terms of greater IAA production by Bradyrhizobium than Bacillus and greater sensitivity of Viminaria to IAA than Hakea. PMID- 25534067 TI - Butter naturally enriched in cis-9, trans-11 CLA prevents hyperinsulinemia and increases both serum HDL cholesterol and triacylglycerol levels in rats. AB - BACKGROUND: Evidence from in vitro and animal studies indicates that conjugated linoleic acid (CLA) possesses anti-diabetic properties, which appear to be attributed to cis-9, trans-11 CLA, the major CLA isomer in ruminant fat. However, there is a shortage of studies addressing CLA from natural source. The present study aimed to evaluate the effects of butter naturally enriched in cis-9, trans 11 CLA on parameters related to glucose tolerance, insulin sensitivity and dyslipidemia in rats. METHODS: Forty male Wistar rats were randomly assigned to the following dietary treatments (n=10/group), for 60 days: 1) Normal fat-Soybean oil (NF-So): diet containing 4.0% soybean oil (SO); 2) High Fat-Control Butter (HF-Cb): diet containing 21.7% control butter and 2.3% SO; 3) High Fat-CLA enriched Butter (HF-CLAb): diet containing 21.7% cis-9, trans-11 CLA-enriched butter and 2.3% SO; and 4) High fat-Soybean oil (HF-So): diet containing 24.0% SO. HF-Cb and HF-CLAb diets contained 0.075% and 0.235% of cis-9, trans-11 CLA, respectively. RESULTS: HF-CLAb-fed rats had lower serum insulin levels at fasting than those fed with the HF-Cb diet, while the PPARgamma protein levels in adipose tissue was increased in HF-CLAb-fed rats compared to HF-Cb-fed rats. Furthermore, R-QUICK was lower in HF-Cb than in NF-So group, while no differences in R-QUICK were observed among NF-So, HF-CLAb and HF-So groups. Serum HDL cholesterol levels were higher in HF-CLAb-fed rats than in those fed NF-So, HF-Cb and HF-So diets, as well as higher in NF-So-fed rats than in HF-Cb and HF-So-fed rats. HF-CLAb, HF Cb and HF-So diets reduced serum LDL cholesterol levels when compared to NF-So, whereas serum triacylglycerol levels were increased in HF-CLAb. CONCLUSION: Feeding rats on a high-fat diet containing butter naturally enriched in cis-9, trans-11 CLA prevented hyperinsulinemia and increased HDL cholesterol, which could be associated with higher levels of cis-9, trans-11 CLA, vaccenic acid, oleic acid and lower levels of short and medium-chain saturated fatty acids from butter naturally modified compared to control butter. On the other hand CLA enriched butter also increased serum triacylglycerol levels, which could be associated with concomitant increases in the content of trans-9 and trans-10 C18:1 isomers in the CLA-enriched butter. PMID- 25534069 TI - Neurocognitive insight, treatment utilization, and cognitive training outcomes in schizophrenia. AB - BACKGROUND: The degree to which people with schizophrenia show awareness of cognitive dysfunction and whether this neurocognitive insight affects treatment use or outcome is understudied. We aimed to examine neurocognitive insight among a treatment-seeking sample of patients with psychotic disorders, and whether neurocognitive insight affected treatment utilization or outcome. METHOD: 69 individuals with schizophrenia-spectrum disorders enrolled in a trial comparing Compensatory Cognitive Training (CCT) to standard pharmacotherapy. Participants with objective cognitive impairment were identified and grouped into "intact" vs. "impaired" neurocognitive insight groups. These groups were then compared via ANCOVA on three treatment utilization variables and six post-treatment cognitive/functional variables. RESULTS: 43 participants demonstrated objective cognitive impairment. Among those individuals, 31 were considered to have intact neurocognitive insight and 12 showed impaired neurocognitive insight. These two groups did not differ on CCT attendance, satisfaction with the intervention, or self-reported cognitive strategy use at post-treatment. There were significant treatment group by neurocognitive insight group interactions for verbal memory and functional capacity outcomes, such that individuals with impaired neurocognitive insight who received treatment performed better than those who did not receive treatment. CONCLUSIONS: Even among individuals who self-select into a cognitive treatment study, many show minimal awareness of cognitive dysfunction. Impaired neurocognitive insight, however, was not associated with decreased treatment utilization, and was associated with positive treatment outcomes in some cognitive domains as well as functional capacity. As cognitive training treatments become increasingly available, impaired neurocognitive insight need not be a barrier to participation. PMID- 25534070 TI - Longitudinal changes in hippocampal volume in the Edinburgh High Risk Study of Schizophrenia. AB - Schizophrenia is associated with structural brain abnormalities that are likely to be present before disease onset. It remains unclear to what extent these represent general vulnerability indicators or are associated with the developing clinical state itself. It also remains unclear whether such state or trait alterations may be evident at any given time-point, or whether they progress over time. To investigate this, structural brain scans were acquired at two time points (mean scan-interval 1.87years) in a cohort of young unaffected individuals at high familial risk of schizophrenia (baseline, n=142; follow-up, n=64) and healthy controls (baseline, n=36; follow-up, n=18). Sub-cortical reconstructions of the hippocampus and amygdala were generated using the longitudinal pipeline available with Freesurfer. The high risk cohort was subdivided into individuals that remained well during the study (HR[well], baseline, n=68; follow-up, n=30), transient and/or partial symptoms that were insufficient to support a formal diagnosis (HR[symp], baseline, n=57; follow-up, n=26) and individuals that subsequently developed schizophrenia according to ICD-10 criteria (HR[ill], baseline, n=17; follow-up, n=8). Longitudinal change in the hippocampus and amygdala was compared, focusing first on overall differences between high-risk individuals and controls and then on sub-group differences within the high-risk cohort. We found a significantly altered developmental trajectory for all high risk individuals compared to controls, with controls showing a significant increase in hippocampal volume over time compared to those at high risk. We did not find evidence of altered longitudinal trajectories based on clinical outcome within the high risk cohort. These results suggest that an altered developmental trajectory of hippocampal volume is associated with a general familial predisposition to develop schizophrenia, as this alteration was not related to subsequent clinical outcome. PMID- 25534071 TI - Paragraph-reading comprehension ability in Mandarin-speaking children with cochlear implants. AB - OBJECTIVES: 1) To investigate different aspects of paragraph reading in Mandarin speaking students with cochlear implants (CIs) and the factors associated with unfavorable outcomes, and 2) to understand the replaceability of a paragraph reading test with a sentence-reading test. STUDY DESIGN: Cross-sectional, case controlled study. METHODS: Fifty-three students with CIs (aged 11.0 +/- 1.4 years) and 53 grade- and gender-matched children with normal hearing (NH) participated in the study. A paragraph-reading comprehension test was conducted. Sentence and word reading, speech perception, language skills, and child/family characteristics were examined. An unfavorable paragraph-reading outcome was defined as a score lower than one standard deviation below the NH mean. RESULTS: The CI subjects had significantly worse paragraph-reading comprehension than did the NH controls (P = 0.017, d = 0.54). Their performance in grades 5 to 6 was not significantly higher than of those with NH in grades 2 to 4. The CI children's abilities to understand semantics (P = 0.012) and syntax (P = 0.020) significantly fell behind the NH controls in grades 2 to 4, and the lag continued in grades 5 to 6 (P = 0.039, P = 0.002, respectively). Grade and sentence reading were independently associated with unfavorable paragraph-reading outcomes (R(2) = 0.453). The optimal sensitivity and specificity of the sentence-reading test in identifying unfavorable paragraph-reading outcomes were 90.9% and 90.0%, respectively (area under the curve = 0.923). CONCLUSIONS: Specialists should pay attention to CI students' development of different reading skills. Paragraph reading tests enable a multidimensional evaluation of reading competence. Use of sentence-reading tests is suggested only as a tool for preliminary screening for basic reading capacities. LEVEL OF EVIDENCE: 3b. PMID- 25534072 TI - Torsion and bending properties of OneShape and WaveOne instruments. AB - INTRODUCTION: The purpose of this study was to compare the torsion and bending properties of OneShape (OS; Micro Mega, Besancon, France) and WaveOne (WO; Dentsply Maillefer, Ballaigues, Switzerland) single-file systems. METHODS: The torsional strength of OS size #25, 0.06 taper and WO primary size #25, 0.08 taper was measured by using a torsiometer after fixing the apical 5 mm of the instrument rigidly. A scanning electron microscope was used to characterize the topographic features of the fracture surfaces of broken files. The files were tested for bending resistance by using the cantilever bending test. Data were statistically analyzed using the independent t test. Statistical significance level was set at P < .05. RESULTS: WO had a significantly higher torsional resistance than OS (P < .001). The average bending resistance as measured by the maximum force (gf) to bend instruments revealed that the WO had a significantly lower resistance to bend than OS (P < .001). Scanning electron microscopic analysis of the fractured cross-sectional surfaces revealed typical features of torsional failure including skewed dimples near the center of the fracture surface and circular abrasion streaks. CONCLUSIONS: The WO single-file system showed higher torsional resistance and flexibility than the OS single-file system. Different cross-sectional geometry and the alloy from which the instrument is manufactured could have significant influence on the torsional resistance and flexibility of the instruments. PMID- 25534073 TI - Prevalence of 3- and 4-rooted first and second mandibular molars in the Israeli population. AB - INTRODUCTION: Three-rooted mandibular molars are 1 of the anatomic variations of mandibular molars. The location of the additional root is distolingual (radix entomolaris) or mesiobuccal (radix paramolaris). The purpose of this retrospective study was to assess the prevalence of 3- and 4-rooted mandibular first and second molars in the Israeli population and to classify them according to dimension, curvature, and location of separation from the main root. METHODS: A total of 1020 Israel patients' cone-beam computed tomographic scans were screened and evaluated. The incidence of 3- and 4-rooted first and second mandibular molars were recorded and analyzed. One thousand four hundred sixty five mandibular second molars and 1,229 mandibular first molars were evaluated. RESULTS: The overall incidence of patients with 3-rooted mandibular first and second molars was 2.6% and 1.78%, respectively. The bilateral incidence of 3 rooted mandibular first and second molars was 26%. The incidence of 4-rooted mandibular second molar was 0.55%. No significant difference was found regarding sex or side of occurrence. CONCLUSIONS: The occurrence of 3-rooted mandibular first molars in the Israeli population was rare, but clinicians should be aware of the special characteristic of this anatomic variation to modify accordingly the form of pulp chamber opening and choose appropriate instrumentation. PMID- 25534074 TI - Erysipelothrix larvae sp. nov., isolated from the larval gut of the rhinoceros beetle, Trypoxylus dichotomus (Coleoptera: Scarabaeidae). AB - A novel, Gram-stain positive, facultative anaerobic, non-motile and straight to curve rod shaped bacterium, strain LV19(T) was isolated from the larval gut of the rhinoceros beetle, Trypoxylus dichotomus, which was collected from Yeong dong, Chuncheongbuk-do, South Korea. The colonies of the new isolate were convex, circular, cream white in color and 1-2 mm in diameter after 3 days incubation on Tryptic Soy Agar at 37 degrees C. Based on the 16S rRNA gene sequence similarity, the new isolate was most closely related to Erysipelothrix inopinata MF-EP02(T), E. rhusiopathiae ATCC 19414 (T) and E. tonsillarum T-305(T) (94.8, 93.8 and 93.7 % similarity, respectively). Strain LV19(T) grew optimally at 37 degrees C, at pH 8.0 and in the presence of 0.5 % (w/v) NaCl. Oxidase activity and catalase activity were negative. The major cellular fatty acids (>10 %) were C18:2 cis-9,12 (28.9 %), C18:1 cis-9 (22.3 %), C16:0 (22.2 %) and C18:0 (18.5 %). The cell-wall hydrolysates contained ribose as a major sugar. Major polar lipids were phosphatidylglycerol and three unidentified glycolipids. No quinone was detected. The G+C content of the genomic DNA was 36.3 mol%. The levels of DNA-DNA relatedness between strain LV19(T) and all the reference strains were less than 20 %. On the basis of polyphasic evidence from this study, the isolate is considered to represent a novel species of the genus Erysipelothrix, for which the name Erysipelothrix larvae sp. nov. is proposed; the type strain is LV19(T) (=KCTC 33523(T) = DSM 28480(T)). PMID- 25534075 TI - Reply to Letter: Transpulmonary hypothermia with cooled oxygen inhalation. PMID- 25534076 TI - Impact of contextualized pediatric resuscitation training on pediatric healthcare providers in Botswana. AB - BACKGROUND: Worldwide, 6.6 million children die each year, partly due to a failure to recognize and treat acutely ill children. Programs that improve provider recognition and treatment initiation may improve child survival. OBJECTIVES: Describe provider characteristics and hospital resources during a contextualized pediatric resuscitation training program in Botswana and determine if training impacts provider knowledge retention. DESIGN/METHODS: The American Heart Association's Pediatric Emergency Assessment Recognition and Stabilization (PEARS) course was contextualized to Botswana resources and practice guidelines in this observational study. A cohort of facility-based nurses (FBN) was assessed prior to and 1-month following training. Survey tools assessed provider characteristics, cognitive knowledge and confidence and hospital pediatric resources. Data analysis utilized Fisher's exact, Chi-square, Wilcoxon rank-sum and linear regression where appropriate. RESULTS: 61 healthcare providers (89% FBNs, 11% physicians) successfully completed PEARS training. Referral facilities had more pediatric specific equipment and high-flow oxygen. Median frequency of pediatric resuscitation was higher in referral compared to district level FBN's (5 [3,10] vs. 2 [1,3] p=0.007). While 50% of FBN's had previous resuscitation training, none was pediatric specific. Median provider confidence improved significantly after training (3.8/5 vs. 4.7/5, p<0.001), as did knowledge of correct management of acute pneumonia and diarrhea (44% vs. 100%, p<0.001, 6% vs. 67%, p<0.001, respectively). CONCLUSION: FBN's in Botswana report frequent resuscitation of ill children but low baseline training. Provider knowledge for recognition and initial treatment of respiratory distress and shock is low. Contextualized training significantly increased FBN provider confidence and knowledge retention 1-month after training. PMID- 25534077 TI - An "Intention-Focused" paradigm for improving bystander CPR performance. AB - Despite public education campaigns and a chest compression-only initiative, bystander cardiopulmonary resuscitation (CPR) is provided in approximately 30-40% of out of hospital cardiac arrests in the United States. Bystander CPR rates may not improve without addressing factors influencing bystanders' probability of performing CPR. We propose an "intention-focused" model for the bystander CPR performance utilizing validated behavioral theory. This model describes a framework that may predict CPR performance, with intention as the key determinant of this behavior. This model may provide specific targets for strengthening the intention to perform CPR, which could lead to increased bystander rates. PMID- 25534079 TI - Characterization of an intravenous lipopolysaccharide inflammation model in calves with respect to the acute-phase response. AB - Our objective was to develop a lipopolysaccharide (LPS) inflammation model in calves to evaluate the acute-phase response with respect to the release of pro inflammatory cytokines and acute-phase proteins, fever development and sickness behaviour. Fourteen 4-week-old male Holstein Friesian calves were included and randomly assigned to a negative control group (n=3) and an LPS-challenged group (n=11). The latter received an intravenous bolus injection of 0.5 MUg of LPS/kg body weight. Blood collection and clinical scoring were performed at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 18, 24, 28, 32, 48, 54 and 72 h post LPS administration (p.a.). In the LPS group, the following clinical signs were observed successively: tachypnoea (on average 18 min p.a.), decubitus (29 min p.a.), general depression (1.75 h p.a.), fever (5h p.a.) and tachycardia (5h p.a.). Subsequent to the recovery from respiratory distress, general depression was prominent, which deteriorated when fever increased. One animal did not survive LPS administration, whereas the other animals recovered on average within 6.1h p.a. Moreover, the challenge significantly increased plasma concentrations of tumour necrosis factor-alpha, interleukin 6, serum amyloid A and haptoglobin, with peaking levels at 1, 3.5, 24 and 18 h p.a., respectively. The present LPS model was practical and reproducible, caused obvious clinical signs related to endotoxemia and a marked change in the studied inflammatory mediators, making it a suitable model to study the immunomodulatory properties of drugs in future research. PMID- 25534080 TI - Passage-dependent morphological and phenotypical changes of a canine histiocytic sarcoma cell line (DH82 cells). AB - DH82 cells represent a permanent macrophage cell line isolated from a dog with histiocytic sarcoma (HS) and are commonly used in various fields of research upon infection and cancer, respectively. Despite its frequent use, data on cell surface antigen expression of this cell line are fragmentary and in part inconsistent. We therefore aimed at a detailed morphological and antigenic characterization of DH82 cells with respect to passage-dependent differences. Cellular morphology of early (<= 13) and late (>= 66) passages of DH82 cells was evaluated via scanning electron microscopy. Moreover, cells were labelled with 10 monoclonal antibodies directed against CD11c, CD14, CD18, CD44, CD45, CD80, CD86, MHC-I, MHC-II, and ICAM-1 for flow cytometric analysis. Early passage cells were characterized by round cell bodies with abundant small cytoplasmic projections whereas later passages exhibited a spindle-shaped morphology with large processes. The percentage of CD11c-, CD14-, CD18-, CD45-, and CD80 positive cells significantly decreased in late passages whereas the expression of CD44, CD86, MHC-I, MHC-II and ICAM-1 remained unchanged. DH82 cells represent a remarkably heterogeneous cell line with divergent antigenic and morphologic properties. The present findings have important implications for future studies, which should consider distinct characteristics with regard to the used passage. PMID- 25534081 TI - The s2D method: simultaneous sequence-based prediction of the statistical populations of ordered and disordered regions in proteins. AB - Extensive amounts of information about protein sequences are becoming available, as demonstrated by the over 79 million entries in the UniProt database. Yet, it is still challenging to obtain proteome-wide experimental information on the structural properties associated with these sequences. Fast computational predictors of secondary structure and of intrinsic disorder of proteins have been developed in order to bridge this gap. These two types of predictions, however, have remained largely separated, often preventing a clear characterization of the structure and dynamics of proteins. Here, we introduce a computational method to predict secondary-structure populations from amino acid sequences, which simultaneously characterizes structure and disorder in a unified statistical mechanics framework. To develop this method, called s2D, we exploited recent advances made in the analysis of NMR chemical shifts that provide quantitative information about the probability distributions of secondary-structure elements in disordered states. The results that we discuss show that the s2D method predicts secondary-structure populations with an average error of about 14%. A validation on three datasets of mostly disordered, mostly structured and partly structured proteins, respectively, shows that its performance is comparable to or better than that of existing predictors of intrinsic disorder and of secondary structure. These results indicate that it is possible to perform rapid and quantitative sequence-based characterizations of the structure and dynamics of proteins through the predictions of the statistical distributions of their ordered and disordered regions. PMID- 25534082 TI - The basis of asymmetry in the SecA:SecB complex. AB - During export in Escherichia coli, SecB, a homotetramer structurally organized as a dimer of dimers, forms a complex with two protomers of SecA, which is the ATPase that provides energy to transfer a precursor polypeptide through the membrane via the SecYEG translocon. There are two areas of contact on SecB that stabilize the SecA:SecB complex: the flat sides of the SecB tetramer and the C terminal 13 residues of SecB. These contacts within the complex are distributed asymmetrically. Breaking contact between SecA and the sides of SecB results in release of only one protomer of SecA yielding a complex of stoichiometry SecA1:SecB4. This complex mediates export; however, the coupling of ATP hydrolysis to movements of the precursor through the translocon is much less efficient than the coupling by the SecA2:SecB4 complex. Here we used heterotetrameric species of SecB to understand the source of the asymmetry in the contacts and its role in the functioning of the complex. The model of interactions presented suggests a way that binding between SecA and SecB might decrease the affinity of precursor polypeptides for SecB and facilitate the transfer to SecA. PMID- 25534083 TI - The RIT2 and STX1B polymorphisms are associated with Parkinson's disease. AB - INTRODUCTION: GWAS meta-analysis identified RIT2 rs12456492 and STX1B rs4889603 as PD susceptible loci. While proteins encoded by the genes, in particular RIT2, may involve in PD pathogenesis, the association of these two variants with PD remains to be further clarified. METHODS: We enrolled a Chinese cohort comprising 537 PD patients and 517 controls, determined the genotypes of rs12456492 and rs4889603, and analyzed these variants in relation to PD. RESULTS: Both rs12456492 and rs4889603 were associated with PD susceptibility (P = 0.012 and 0.03, respectively). The G allele of rs12456492 and the A allele of rs4889603 served as risk alleles toward PD. Statistical differences in genotype distribution between the patients and controls were observed both in rs12456492 (marginal, P = 0.042 for GG vs. AG vs. AA) and in rs4889603 (P = 0.021 for AA + AG vs. GG) CONCLUSION: Our data suggest that the RIT2 and STX1B polymorphisms are associated with PD etiology. The role of RIT2 in PD pathogenesis warrants further mechanistical investigation. PMID- 25534092 TI - Occupational sciatica 2. PMID- 25534084 TI - Impaired detrusor contractility is the pathognomonic urodynamic finding of multiple system atrophy compared to idiopathic Parkinson's disease. AB - INTRODUCTION: To investigate differences in urodynamic parameters between two groups: Parkinson's disease (PD) and multiple system atrophy (MSA) patients. METHODS: A retrospective study was performed in patients with PD and MSA who presented to three referral centers between 2005 and 2012. Patients referred to the urology department for lower urinary tract symptoms underwent urodynamic studies. Patients with other rare or ambiguous subtypes of PPS, urinary tract infection, urinary stones, or other neurogenic conditions were excluded from the analysis. RESULTS: A total of 581 consecutive patients (359 men and 222 women) were analyzed. The mean patient age was 69.2 (SD, 9.3) years. Among these patients, 390 (64.3%) had PD, and 191 (31.5%) had MSA. Patients with MSA showed a statistically significantly decreased maximal flow rate and increased post-void residual urine volume compared with patients with PD (P range, <0.001-0.005). In addition, voiding failure occurred more frequently in patients with MSA than in those with PD (odds ratio [OR] = 1.9; 95% confidence interval [CI], 1.26-2.73). Patients with MSA showed a higher prevalence of low-compliance (P = 0.001), decreased bladder contractility (P < 0.001), and an increased rate of voiding failure (P = 0.001). In patients with MSA, decreased detrusor contractility was more prominent in the cerebellar ataxia predominant subtype (MSA-C; P = 0.038). Multivariate analysis showed that the MSA subtype was the only independent risk factor for impaired detrusor contractility (men, OR = 2.692; P = 0.006; women, OR = 2.965; P = 0.007). CONCLUSION: Impaired detrusor contractility was the pathognomonic urodynamic finding that distinguished MSA from PD. PMID- 25534093 TI - Patients with atrial fibrillation undergoing percutaneous coronary intervention: current concepts and concerns: part II. AB - Atrial fibrillation (AF) and coronary artery disease (CAD) often present concomitantly. Given the increased risk of thrombotic complications with either of them but different pathogenesis of clot formation, combined antithrombotic therapy is necessary in patients developing acute coronary syndrome and/or undergoing percutaneous coronary intervention (PCI). Different antithrombotic regimens in this group of patients have been summarized and discussed earlier. Triple therapy remains the treatment of choice in these patients despite the increased risk of hemorrhagic complications. Given the absence of evidence from randomized controlled trials, balancing the risk of stroke and stent thrombosis against the risk of major bleeding is a challenge. Precise stroke and bleeding risk assessment is an essential part of the decision making process regarding antithrombotic management. Continuing the discussion of current concepts and concerns of antithrombotic management in AF patients undergoing PCI, we emphasize the importance of various strategies to reduce bleeding in the modern era, namely, radial access combined with careful selection of a P2Y12 receptor inhibitor, use of newer drug-eluting stents, and uninterrupted anticoagulation for patients undergoing procedures. We also focus on the role of the non-vitamin K oral anticoagulants (novel oral anticoagulants, eg, dabigatran, rivaroxaban, apixaban, and edoxaban) which are increasingly used for stroke prevention in AF. Finally, recent recommendations on the management of antithrombotic therapy in AF patients presenting with acute coronary syndrome and/or undergoing PCI as well as ongoing clinical trials and future directions are highlighted. PMID- 25534094 TI - [Importance of standardized treatment with bisphosphonate in breast cancer patients with bone matastases]. PMID- 25534096 TI - [Prognostic analyses of occult breast cancer]. AB - OBJECTIVE: To explore the prognosis of occult breast cancer. METHODS: From January 1978 to December 2008, retrospective analyses were conducted for 205 female patients with axillary lymph node metastasis from an unknown primary source. RESULTS: During a median follow-up time of 61 (4-158) months, the 5 and 10-year rates of disease-free survival (DFS) were 63.5% and 39.8% respectively. The median overall survival (OS) was 10 years. And the 5 and 10-year OS were 79.8% and 49.4% respectively. Significant differences existed in medical history, family history, estrogen receptor (ER), human epidermal growth factor receptor-2 (HER-2), infiltration of soft tissue, surgical option, neoadjuvant chemotherapy, chemotherapy, and radiotherapy with DFS of occult breast cancer (P < 0.05). The most important determinants of DFS and OS were ER, infiltration of soft tissue and neoadjuvant chemotherapy (P < 0.05). CONCLUSION: Radical mastectomy should be performed instead of modified radical mastectomy to improve the patient quality of life. PMID- 25534095 TI - [Roles of Y box-binding protein 1 in SK-BR-3 breast cancer proliferation]. AB - OBJECTIVE: To explore the roles of Y box-binding protein 1 (YB-1) in breast cancer cell proliferation. METHODS: Twenty cases of surgical removal of breast cancer tissue (diagnosed with invasive ductal carcinoma, stage II, by postoperative paraffin pathology) and normal breast tissues adjacent to carcinoma were collected during June 2013 to August 2013.Quantitative real-time PCR (qRT PCR) was performed to detect the YB1 mRNA levels. Cultured mammary epithelial cells (HBL-100) and breast cancer cells (MCF7, MDA-MB-231 & SK-BR-3 cells) were harvested and qRT-PCR was performed to detect the YB1 mRNA levels.SK-BR-3 cells were stimulated with various concentrations of PDGF-BB and YB1 expression levels were detected by qRT-PCR. Down-regulation or over-expression of YB1 by si-YB1 or Ad-GFP-YB1 was detected in SK-BR-3 cells. And MTS cell proliferation assay kit was used to detect cell proliferation. RESULTS: YB1 mRNA levels were significantly higher in breast cancer tissues and MDA-MB-231 and SK-BR-3 breast cancer cell lines than that in adjacent normal breast tissues and HBL-100 mammary epithelial cells respectively (P < 0.05).YB1 expression levels increased in PDGF BB stimulated SK-BR-3 cells in a dose-dependent manner. CONCLUSION: A down regulation of endogenous YB1 decreases and an over-expression of exogenous YB1 promotes the proliferation activity in SK-BR-3 cells. PMID- 25534097 TI - [Detection of circulating tumor cells and its clinical value for different stages and various subtypes of breast cancer]. AB - OBJECTIVE: To explore the prognostic value of applying a semi-automated detection system for detecting circulating tumor cells (CTC) for different stages and various subtypes of breast cancer. METHODS: Immunomagnetic separation and immunofluorescent staining were employed to detect the expressions of CTC and CTC HER-2. Chi-square test, univariate and multivariate analyses were used to examine the correlations between CTC and clinical characteristics. RESULTS: CTC was detected in 57.5% (138/240) of metastatic breast cancer (MBC). CTC enumeration, HER-2 status, number of metastasis and bone metastasis were relevant (P < 0.05). CTC was detected in 23.1% (6/26) of early-stage breast cancer (EBC). CTC enumeration, pathological type, estrogen receptor (ER), progesterone receptor (PR), Ki-67, tumor size and lymph node metastasis were irrelevant (P > 0.05). HER 2-positive MBC detected less CTC than HER-2-negative (chi(2) = 12.296, P < 0.001) . CTC HER-2 expression was different between HER-2-positive and negative patients in 99 MBC cases (chi(2) = 8.082, P = 0.004). CONCLUSION: CTC enumeration is different for various stages and different subtypes of breast cancer. CTC enumeration and bone metastasis are relevant. CTC detection in EBC may predict tumor relapse. And CTC HER-2 expression is different between HER-2-positive and negative MBC patients. PMID- 25534098 TI - [Hypermethylation of CpG island of DLC-1 gene and arsenic trioxide-induced DLC-1 gene demethylation in multiple myeloma]. AB - OBJECTIVE: To explore the role of hypemethylation of DLC-1 gene in the pathogenesis of multiple myeloma (MM) and examine the effects of arsenic trioxide (As(2)O(3))-induced demethylation of DLC-1 gene in U266 cell line. METHODS: The methylation status of DLC-1 gene was detected by methylation specific PCR (MSP) in MM patients from 2008 to 2012. And the expression of DLC-1 gene mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR). Methylation statuses of DLC-1 gene exposed to As(2)O(3) were detected by bisulfite sequencing PCR (BSP). And the mRNA expressions of DLC-1 and DNA methyltransferase (DNMT1, T3a and 3b) were determined by real-time fluorescence quantitative PCR (RTFQ-PCR). RESULTS: Hypermethylation of CpG island of DLC-1 gene was observed in 37/52 (71.15%) MM patients. DLC-1 gene was not expressed after methylation. As(2)O(3) could induce DLC-1 gene demethylation. After 72-houe treatments of 0.5, 1.0 and 2.0 umol/L As(2)O(3), the methylation rate of DLC-1 gene dropped from 95.38% to 63.07%, 30.00% and 7.69%. As compared with the untreated group, the expression of DLC-1 gene mRNA increased to (1.60 +/- 0.09), (3.66 +/- 0.17) and (5.29 +/- 0.15) folds after exposures (all P < 0.05) . And As(2)O(3) could induce the expression of DNMT1, DNMT3a, DNMT3b gene mRNA (all P < 0.05). CONCLUSIONS: Methylation of DLC-1 gene is essential in the pathogenesis of MM and may provide a new diagnostic technique and drug target for the treatment of MM. And As(2)O(3) may activate the expression of DLC-1 gene through demethylation. PMID- 25534099 TI - [Correlation of gene polymorphism of interleukin 4 receptor alpha peptide chain and total serum IgE levels in asthmatic children in Guiyang area]. AB - OBJECTIVE: To explore the correlation of gene polymorphism of interleukin 4 receptor alpha chain (IL-4Ralpha) and total serum IgE levels in children of bronchial asthma in Guiyang area. METHODS: A total of 160 asthmatic children at Affiliated Hospital, Guiyang Medical College from August 2010 to February 2011 were selected as asthma group. There were 96 males and 64 females with an average age of (6.9 +/- 3.3) years. During the same period, 143 healthy children from outpatient physical examination center of this hospital were chosen as control group. There were 75 males and 68 females with an average age of (4.9 +/- 3.9) years. Polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) and allele-specific polymerase chain reaction (AS-PCR) were used to determine the polymorphisms of Q576R on exon 12 and I75V on exon 5 of IL-4Ralpha in both groups. The total serum IgE levels were determined by enzyme-linked immune sorbent assay (ELISA). Comparisons of two groups were made for genotype and allele frequency, serum total IgE and different genotypes, different groups of total serum IgE levels. RESULTS: Three genotypes of AA, AG and GG existed on Q576R and I75V loci between two groups. The genotypic frequencies of two loci had significant differences in two groups (chi(2) = 30.972, 16.776, both P < 0.001). The subjects with variant allele on Q576R and I75V loci had higher risks for asthma than those without variant allele (chi(2) = 33.236, 13.845, both P < 0.001). The total serum levels of IgE in asthma group were higher than those in control group ((312 +/- 297) vs (61 +/- 48) U/ml, t = 9.959, P < 0.001). However, these three genotypes of two loci showed no significant inter-group difference (all P > 0.05). In mutation allele carriers and non-carriers of Q576R locus, total IgE levels showed no significant difference (t = -0.028, 1.279; P = 0.978, 0.203). Differences in total IgE levels between I75V polymorphic variant allele carriers and non-carriers were also not statistically significant in control group (t = -0.763, P = 0.447). However, in asthma group, total IgE levels of I75V polymorphic variant allele carriers were significantly higher than those of non carriers (t = -2.112, P = 0.036). CONCLUSIONS: The 576 and 75 loci of IL-4Ralpha are important candidate genes of asthmatic children in Guiyang area. And the serum total IgE levels of variant allele G at 75 locus in IL-4Ralpha are higher than those without it. PMID- 25534100 TI - [Correlation of serum 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome in aged males]. AB - OBJECTIVE: To explore the association of 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) with metabolic syndrome (MS) and its components in aged males. METHODS: For this cross-sectional study, 1 729 aged males aged over 60 years were selected from participants in a routine annual health examination at our hospital from May to June 2012. Their mean age was 75 +/- 10 years. Height, weight, blood pressure, blood glucose, blood lipids, alkaline phosphatase, calcium, phosphorus, 25(OH) D and PTH were measured. And the associations of 25(OH)D and PTH with the presence of MS and its components were analyzed. RESULTS: The prevalence of MS was 22.0%. The PTH levels were significantly higher in the MS and abnormal blood glucose and HDL-C group than in their control group [(42 +/- 16) vs (40 +/- 17), (42 +/- 16) vs (40 +/- 17), (47 +/- 18) vs (40 +/- 16) ng/L respectively, P < 0.05].However, there were no significant differences of 25(OH)D between these groups. The prevalence of MS showed a gradual increase according to the PTH quintiles (P < 0.05). When comparing the subjects in the highest and lowest quintile of PTH, the former group demonstrated a 1.51-fold increase in odds ratio for MS after adjusting for 25(OH)D levels and other confounding factors. Logistic regression analysis showed that the PTH level was an independent influencing factor for MS in aged males (OR = 1.007, 95%CI: 1.000 1.014, P = 0.047). The levels of 25 (OH) D were not associated with MS in the regression model (OR = 1.004, 95%CI: 0.992-1.016, P = 0.538). CONCLUSION: In aged males, the elevated level of PTH is a risk factor for the prevalence of MS. However, there was no association between 25 (OH) D and MS. PMID- 25534101 TI - [Roles of dermoscopy in differential diagnosis of psoriasis and eczema]. AB - OBJECTIVE: To describe the dermoscopic patterns of plaque psoriasis and chronic eczema and explore the roles of dermoscopy in their diagnosis and differential diagnosis. METHODS: A total of 68 patients with plaque psoriasis or chronic eczema were recruited from our department from December 2013 to May 2014 to undergo dermoscopic and histopathological examinations. Dermoscopic features of vascular morphology, vascular arrangement, background color, scale color and scale distribution were evaluated. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for predefined dermoscopic criteria in relation to the diagnosis of plaque psoriasis. RESULTS: Thirty-one patients with plaque psoriasis and 37 patients with chronic eczema were included. Dotted vessels in a regular arrangement (sensitivity 80.6%, specificity 73.0%) over a light red background (sensitivity 71.0%, specificity 75.7%) and white scales (sensitivity 71.0%, specificity 83.8%) were highly predictive for the diagnosis of plaque psoriasis. And chronic eczema more commonly showed yellow scales and dotted vessels in a patchy arrangement over a dull red background. Characteristic vascular structures of hairpin vessels and red loops were also found to be highly specific (91.9%, 94.6%) for the diagnosis of psoriasis. CONCLUSIONS: Plaque psoriasis shows specific dermoscopic patterns compared with chronic eczema. And dermoscopy is valuable in the diagnosis and differential diagnosis of psoriasis. PMID- 25534102 TI - [Clinical characteristics and prognostic factors of pulmonary tuberculosis with concurrent lung cancer]. AB - OBJECTIVE: To explore the clinical characteristics and prognostic factors of pulmonary tuberculosis with concurrent lung cancer. METHODS: Comprehensive analyses were conducted for 58 cases of pulmonary tuberculosis patients with lung cancer. Their clinical symptoms, signs and imaging results were analyzed between January 1998 and January 2005 at Qingdao Chest Hospital. Kaplan-Meier method was utilized to calculate their survival rates. Nine prognostic characteristics were analyzed. Single factor analysis was performed with Logrank test and multi-factor analysis with Cox regression model. RESULTS: The initial symptoms were cough, chest tightness, fever and hemoptysis. Chest radiology showed the coexistence of two diseases was 36 in the same lobe and 22 in different lobes. And there were pulmonary nodules (n = 24), cavities (n = 19), infiltration (n = 8) and atelectasis (n = 7). According to the pathological characteristics, there were squamous carcinoma (n = 33), adenocarcinoma (n = 17), small cell carcinoma (n = 4) and unidentified (n = 4) respectively. The TNM stages were I (n = 13), II(n = 22), III (n = 16) and IV (n = 7) respectively. The median survival period was 24 months. And the 1, 3, 5-year survival rates were 65.5%, 65.5% and 29.0% respectively. Single factor analysis showed that lung cancer TNM staging (P = 0.000) and tuberculosis activity (P = 0.024) were significantly associated with patient prognosis. And multi-factor analysis showed that lung cancer TNM staging (RR = 2.629, 95%CI: 1.759-3.928, P = 0.000) and tuberculosis activity (RR = 1.885, 95%CI: 1.023-3.471, P = 0.042) were relatively independent prognostic factors. CONCLUSIONS: The clinical and radiological characteristics contribute jointly to early diagnosis and therapy of tuberculosis with concurrent lung cancer. And TNM staging of lung cancer and activity of tuberculosis are major prognostic factors. PMID- 25534104 TI - [Neuromuscular effects of cisatracurium besylate in obese patients]. AB - OBJECTIVE: To explore the neuromuscular effects of cisatracurium besylate in morbidly obese patients when dosed according to real body weight under total intravenous anesthesia with propofol. METHODS: Thirty-six ASA I-II patients aged 18-65 years scheduled for elective procedures at our hospital during July 2012 to December 2012 were allocated into 2 groups according to body mass index (normal weight: body mass index: <24, overweight: body mass index >28). Anesthesia was induced with target-controlled infusion of propofol (Cp 3 ug/ml) and remifentanil (Ce 3-5 ng/ml). A bolus of cisatracurium 0.2 mg/kg was administered intravenously over 5-10 s as soon as a patient lost consciousness. Neuromuscular block was monitored with TOF-Watch SX (Oaganon, the Netherlands). Single stimulation (0.1 Hz) was applied to ulnar nerve at wrist. The maximal degree of neuromuscular block, onset time, clinical duration and recovery index were recorded. They were intubated and mechanically ventilated when neuromuscular block reached the maximal degree. The intubation condition was evaluated. RESULTS: The average onset time was (164 +/- 25) s in obese group versus (201 +/- 48) s in normal weight group. And there was significant difference between groups (t = 2.83, P < 0.05) . The clinical duration was (68.4 +/- 9.6) min in obese group versus (62.0 +/- 6.5) min in normal weight group. And there was significant difference between groups (t = 2.33, P < 0.05). The recovery index was (15.6 +/- 4.7) min in obese group versus (10.8 +/- 4.2) min in normal weight group. And there was significant difference between groups (t = 3.03, P < 0.05) . Also 75% recovery time was (83.9 +/- 11.5) min in obese group versus (73.0 +/- 9.2) min in normal weight group. And there was significant difference between groups (t = 2.94, P < 0.05). But no differences existed in intubation conditions. CONCLUSION: When dosed according to real body weight, onset time of cisatracurium is shorter while clinical duration and recovery index are prolonged in morbidly obese patients compared with normal weight counterparts. PMID- 25534103 TI - [Clinical analyses of 80 hemophagocytic lymphohistiocytosis patients with Epstein Barr viremia]. AB - OBJECTIVE: To analyze the clinical characteristics, treatment and prognosis of hemophagocytic lymphohistiocytosis (HLH) patients with Epstein-Barr viremia (EBV). METHODS: A retrospective study was conducted to analyze the clinical data of 80 HLH patients aged >= 14 years with EBV-DNA >1 000 copies/ml in peripheral blood from 2008 to 2013. RESULTS: There were EBV-HLH (n = 46), HLH-associated lymphoma (n = 30) and primary HLH (n = 4). Among the relevant laboratory parameters, inter-group statistical differences existed only in alanine transaminase (ALT) and aspartate aminotransferase (AST) (P = 0.021, 0.035). The median follow-up period was 2.0 (0.5-20.0) months. And the 1-month, 3-month, 6 month and 12-month overall survival rates were 58.8%, 37.5%, 29.7% and 19.6% respectively. CONCLUSIONS: HLH patients with EBV have a pernicious clinical course with a poor prognosis. And it makes little sense for distinguishing HLH associated lymphoma from EBV-HLH through routine laboratory tests. PMID- 25534105 TI - [Experimental role of cervical sympathetic block during facial nerve injury and regeneration in rats]. AB - OBJECTIVE: To explore the effects of cervical sympathetic block (CSB) on facial nerve regeneration in rats and seek the optimal timing of treatment. METHODS: A total of 72 adult Sprague-Dawley rats were divided randomly into 4 groups of sham operation (sham), model control (NS), CSB1 and CSB2 (n = 18 each). Except for sham group, the model of peripheral facial paralysis was established for three other groups. After treating facial nerves injury with CSB at different timepoints, the behavioral changes of rats were observed.Electroneurography (ENoG) of injured nerves was performed and the expressions of glial cell derived neurotrophic factor (GDNF) of facial nerve nucleus were detected at different stages. RESULTS: The facial whisker movement function scores in sham, NS, CSB1 and CSB2 groups were 3.87 +/- 0.35, 0.50 +/- 0.52, 1.07 +/- 0.62 and 0.81 +/- 0.42 (F = 2.934, P = 0.035) at Day 7, 3.85 +/- 0.37, 0.91 +/- 0.52, 1.57 +/- 0.65 and 1.07 +/- 0.62 (F = 2.537, P = 0.038) at Day 14 and 3.85 +/- 0.37, 1.71 +/- 0.47, 3.00 +/- 0.68 and 2.36 +/- 0.49 (F = 3.627, P = 0.024) at Day 28. At Day 7, LatSD and AmpSD were not detected in NS, CSB1 and CSB2 groups.However, at Day 14, the values of LatSD were (1.26 +/- 0.19), (6.67 +/- 0.36), (4.67 +/- 0.36) and (6.17 +/- 0.36) ms, showing a significant difference (F = 3.052, P = 0.024) and AmpSD (6.42 +/- 1.93), (2.16 +/- 1.87), (4.16 +/- 1.80) and (3.66 +/- 1.40) mv, also a significance (F = 3.634, P = 0.021). And at Day 28, LatSD were (1.31 +/- 0.17), (3.17 +/- 0.19), (1.93 +/- 0.12) and (2.60 +/- 0.22) ms (F = 2.729, P = 0.032) and AmpSD (6.82 +/- 2.30), (4.72 +/- 5.23), (6.22 +/- 3.50) and (5.82 +/- 4.10) mv (F = 3.827, P = 0.019). The expression quantities of GDNF in 4 groups produced significant differences at Day 7 (4.67 +/- 0.81, 13.52 +/- 0.58, 26.17 +/- 1.01 and 14.86 +/- 1.03, F = 3.637, P = 0.028), Day 14 (5.67 +/- 0.57, 24.41 +/- 2.86, 26.52 +/- 1.36 and 25.48 +/- 1.42, F = 2.946, P = 0.031) and Day 28 (5.37 +/- 0.92, 26.64 +/- 1.68, 27.38 +/- 1.66 and 25.69 +/- 1.99, F = 4.273, P = 0.012). CONCLUSION: During early stage of facial nerve injury, the treatment of CSB may increase the expression of GDNF of facial nerve nucleus at early stage and thus accelerate the recovery of facial nerve injury in rats. PMID- 25534106 TI - [Hesperetin attenuates angiotensin II-induced collagen expression in cardiac fibroblasts in vitro]. AB - OBJECTIVE: To explore the effect of hesperetin (HES) on collagen expression in cardiac fibroblasts in vitro induced by angiotensin II (AngII). METHODS: Cell growth was determined by trypan blue staining, reactive oxygen species (ROS) generation by microplate reader, the expressions of collagen I,III and matrix metalloproteinase 1 (MMP-1) by real-time polymerase chain reaction (PCR) and cell proliferation by cell counting kit-8. RESULTS: HES and AngII+HES had no effect on cellular activity. AngII significantly increased ROS generation (1.70 +/- 0.12 vs 1, P < 0.01), gene expression of collagen I,III both increased (1.31 +/- 0.08 vs 1, 1.40 +/- 0.09 vs 1, both P < 0.01) while MMP-1 decreased (0.68 +/- 0.03 vs 1, P < 0.01). Ang II also induced the proliferation of fibroblasts (1.91 +/- 0.18 vs 1, P < 0.01). While HES (25, 50, 100 umol/L) or NAC (1 mmol/L) reversed these effects during co-treating with AngII, ROS decreased versus the Ang II group(1.37 +/- 0.05, 1.16 +/- 0.08, 1.07 +/- 0.07, 1.12 +/- 0.07 vs 1.70 +/- 0.12, all P < 0.01) , gene expression of collagenI,III also decreased (1.22 +/- 0.08 and 1.27 +/- 0.07, 1.14 +/- 0.07 and 1.00 +/- 0.06, 1.02 +/- 0.06 and 0.99 +/- 0.05, 1.08 +/- 0.07 and 1.09 +/- 0.06 vs 1.31 +/- 0.08 and 1.40 +/- 0.09, all P < 0.01), MMP 1 increased (0.76 +/- 0.05, 0.88 +/- 0.07, 1.01 +/- 0.08, 0.96 +/- 0.07 vs 0.68 +/- 0.03, P < 0.01) versus the Ang II group. Cell proliferation was also inhibited (1.42 +/- 0.07, 1.38 +/- 0.03, 1.07 +/- 0.15, 1.16 +/- 0.11 vs 1.91 +/- 0.18, all P < 0.01). NAC had the same effect with HES. CONCLUSION: HES inhibits the synthesis of collagen and the Ang II-induced proliferation of fibroblast through suppressing the ROS generation. PMID- 25534107 TI - [Effects of hemoglobin on the expression and distribution of inducible nitric oxide synthase after intracerebral hemorrhage]. AB - OBJECTIVE: To explore the effects of hemoglobin on inducible nitric oxide synthase (iNOS) after intracerebral hemorrhage. METHODS: A total of 60 male Sprague-Dawley rats were randomized into hemoglobin (Hb) and sham-operated groups (n = 30 each). And each group was divided further into 6 subgroups (6 h, 12 h, 24 h, 48 h, 3 d and 7 d). At each timepoint, their neurological behaviors were observed. The expression and distribution of iNOS in perihematomal brain tissue were detected by immunohistochemical staining. The mean optical density of iNOS was assessed and semiquantitatively analyzed. RESULTS: After Hb injection, there was an onset of limb dysfunction. The Bederson score in Hb group increased significantly versus sham group (P < 0.05). At 6 hours post-injection, immunoreactivity of iNOS was obviously observed in astrocytes and inflammatory cells. In some cases, iNOS reactivity was detected in endothelial cells. Maximal expression occurred at 12 hours. The iNOS expression stay at high levels till 48 hours (P < 0.05, versus sham group) and then slowly diminished at 3 and 7 days. The iNOS expression was correlated significantly with the score of neurological behavior (r = 0.641, P < 0.05). CONCLUSION: After intracerebral hemorrhage, hemoglobin induces the expression of iNOS and participates in the course of brain edema. PMID- 25534108 TI - Hydrogen bonds in Al2O3 as dissipative two-level systems in superconducting qubits. AB - Dissipative two-level systems (TLS) have been a long-standing problem in glassy solids over the last fifty years, and have recently gained new relevance as sources of decoherence in quantum computing. Resonant absorption by TLSs in the dielectric poses a serious limitation to the performance of superconducting qubits; however, the microscopic nature of these systems has yet to be established. Based on first-principles calculations, we propose that hydrogen impurities in Al2O3 are the main source of TLS resonant absorption. Hydrogen is an ubiquitous impurity and can easily incorporate in Al2O3. We find that interstitial H in Al2O3 forms a hydrogen bond (O-H...O). At specific O-O distances, consistent with bond lengths found in amorphous Al2O3 or near Al2O3 surfaces or interfaces, the H atom feels a double well. Tunneling between two symmetric positions gives rise to resonant absorption in the range of 10 GHz, explaining the experimental observations. We also calculate the expected qubit TLS coupling and find it to lie between 16 and 20 MHz, consistent with experimental measurements. PMID- 25534111 TI - A frontotemporoparietal network common to initiating and responding to joint attention bids. AB - Joint attention is a fundamental cognitive ability that supports daily interpersonal relationships and communication. The Parallel Distributed Processing model (PDPM) postulates that responding to (RJA) and initiating (IJA) joint attention are predominantly supported by posterior-parietal and frontal regions respectively. It also argues that these neural networks integrate during development, supporting the parallel processes of self- and other-attention representation during interactions. However, direct evidence for the PDPM is limited due to a lack of ecologically valid experimental paradigms that can capture both RJA and IJA. Building on existing interactive approaches, we developed a virtual reality paradigm where participants engaged in an online interaction to complete a cooperative task. By including tightly controlled baseline conditions to remove activity associated with non-social task demands, we were able to directly contrast the neural correlates of RJA and IJA to determine whether these processes are supported by common brain regions. Both RJA and IJA activated broad frontotemporoparietal networks. Critically, a conjunction analysis identified that a subset of these regions were common to both RJA and IJA. This right-lateralised network included the dorsal portion of the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), precentral gyrus, posterior superior temporal sulcus (pSTS), temporoparietal junction (TPJ) and precuneus. Additional activation was observed in this network for IJA relative to RJA at MFG, IFG, TPJ and precuneus. This is the first imaging study to directly investigate the neural correlates common to RJA and IJA engagement, and thus support the assumption that a broad integrated network underlies the parallel aspects of both initiating and responding to joint attention. PMID- 25534112 TI - The discovery of processing stages: analyzing EEG data with hidden semi-Markov models. AB - In this paper we propose a new method for identifying processing stages in human information processing. Since the 1860s scientists have used different methods to identify processing stages, usually based on reaction time (RT) differences between conditions. To overcome the limitations of RT-based methods we used hidden semi-Markov models (HSMMs) to analyze EEG data. This HSMM-EEG methodology can identify stages of processing and how they vary with experimental condition. By combining this information with the brain signatures of the identified stages one can infer their function, and deduce underlying cognitive processes. To demonstrate the method we applied it to an associative recognition task. The stage-discovery method indicated that three major processes play a role in associative recognition: a familiarity process, an associative retrieval process, and a decision process. We conclude that the new stage-discovery method can provide valuable insight into human information processing. PMID- 25534109 TI - Virtual dissection and comparative connectivity of the superior longitudinal fasciculus in chimpanzees and humans. AB - Many of the behavioral capacities that distinguish humans from other primates rely on fronto-parietal circuits. The superior longitudinal fasciculus (SLF) is the primary white matter tract connecting lateral frontal with lateral parietal regions; it is distinct from the arcuate fasciculus, which interconnects the frontal and temporal lobes. Here we report a direct, quantitative comparison of SLF connectivity using virtual in vivo dissection of the SLF in chimpanzees and humans. SLF I, the superior-most branch of the SLF, showed similar patterns of connectivity between humans and chimpanzees, and was proportionally volumetrically larger in chimpanzees. SLF II, the middle branch, and SLF III, the inferior-most branch, showed species differences in frontal connectivity. In humans, SLF II showed greater connectivity with dorsolateral prefrontal cortex, whereas in chimps SLF II showed greater connectivity with the inferior frontal gyrus. SLF III was right-lateralized and proportionally volumetrically larger in humans, and human SLF III showed relatively reduced connectivity with dorsal premotor cortex and greater extension into the anterior inferior frontal gyrus, especially in the right hemisphere. These results have implications for the evolution of fronto-parietal functions including spatial attention to observed actions, social learning, and tool use, and are in line with previous research suggesting a unique role for the right anterior inferior frontal gyrus in the evolution of human fronto-parietal network architecture. PMID- 25534110 TI - EEG functional connectivity is partially predicted by underlying white matter connectivity. AB - Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales. PMID- 25534113 TI - Reliability and statistical power analysis of cortical and subcortical FreeSurfer metrics in a large sample of healthy elderly. AB - FreeSurfer is a tool to quantify cortical and subcortical brain anatomy automatically and noninvasively. Previous studies have reported reliability and statistical power analyses in relatively small samples or only selected one aspect of brain anatomy. Here, we investigated reliability and statistical power of cortical thickness, surface area, volume, and the volume of subcortical structures in a large sample (N=189) of healthy elderly subjects (64+ years). Reliability (intraclass correlation coefficient) of cortical and subcortical parameters is generally high (cortical: ICCs>0.87, subcortical: ICCs>0.95). Surface-based smoothing increases reliability of cortical thickness maps, while it decreases reliability of cortical surface area and volume. Nevertheless, statistical power of all measures benefits from smoothing. When aiming to detect a 10% difference between groups, the number of subjects required to test effects with sufficient power over the entire cortex varies between cortical measures (cortical thickness: N=39, surface area: N=21, volume: N=81; 10mm smoothing, power=0.8, alpha=0.05). For subcortical regions this number is between 16 and 76 subjects, depending on the region. We also demonstrate the advantage of within subject designs over between-subject designs. Furthermore, we publicly provide a tool that allows researchers to perform a priori power analysis and sensitivity analysis to help evaluate previously published studies and to design future studies with sufficient statistical power. PMID- 25534114 TI - Dynamic functional connectivity using state-based dynamic community structure: method and application to opioid analgesia. AB - We present a new method, State-based Dynamic Community Structure, that detects time-dependent community structure in networks of brain regions. Most analyses of functional connectivity assume that network behavior is static in time, or differs between task conditions with known timing. Our goal is to determine whether brain network topology remains stationary over time, or if changes in network organization occur at unknown time points. Changes in network organization may be related to shifts in neurological state, such as those associated with learning, drug uptake or experimental conditions. Using a hidden Markov stochastic blockmodel, we define a time-dependent community structure. We apply this approach to data from a functional magnetic resonance imaging experiment examining how contextual factors influence drug-induced analgesia. Results reveal that networks involved in pain, working memory, and emotion show distinct profiles of time-varying connectivity. PMID- 25534116 TI - Development and co-validation of porcine insulin certified reference material by high-performance liquid chromatography-isotope dilution mass spectrometry. AB - This article concerns the development and co-validation of a porcine insulin (pINS) certified reference material (CRM) produced by the National Institute of Metrology, People's Republic of China. Each CRM unit contained about 15 mg of purified solid pINS. The moisture content, amount of ignition residue, molecular mass, and purity of the pINS were measured. Both high-performance liquid chromatography-isotope dilution mass spectrometry and a purity deduction method were used to determine the mass fraction of the pINS. Fifteen units were selected to study the between-bottle homogeneity, and no inhomogeneity was observed. A stability study concluded that the CRM was stable for at least 12 months at -20 degrees C. The certified value of the CRM was (0.892 +/- 0.036) g/g. A co validation of the CRM was performed among Chinese, Japanese, and Korean laboratories under the framework of the Asian Collaboration on Reference Materials. The co-validation results agreed well with the certified value of the CRM. Consequently, the pINS CRM may be used as a calibration material or as a validation standard for pharmaceutical purposes to improve the quality of pharmaceutical products. PMID- 25534115 TI - ASPP2 enhances oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy. AB - Inactivation of p53-mediated cell death pathways is a central component of cancer progression. ASPP2 (apoptosis stimulated protein of p53-2) is a p53 binding protein that specially stimulates pro-apoptosis function of p53. Down-regulation of ASPP2 is observed in many human cancers and is associated with poor prognosis and metastasis. In this study, ASPP2 was found to enhance L-OHP-induced apoptosis in HCT116 p53(-/-) cells in a p53-independent manner. Such apoptosis-promoting effect of ASPP2 was achieved by inhibiting autophagy. Further experiments with ASPP2 RNA interference and autophagy inhibitor (3-methyladenine, 3-MA) confirmed that ASPP2 enhanced HCT116 p53(-/-) cell apoptosis via inhibiting the autophagy. The association of cell death and autophagy was also found in ASPP2(+/-) mice, where colon tissue with reduced ASPP2 expression displayed more autophagy and less cell death. Finally, colorectal tumours and their adjacent normal tissues from 20 colorectal cancer patients were used to examine ASPP2 expression, p53 expression and p53 mutation, to understand their relationships with the patients' outcome. Three site mutations were found in p53 transcripts from 16 of 20 patients. ASPP2 mRNA expressions were higher, and autophagy level was lower in the adjacent normal tissues, compared with the tumour tissues, which was independent of both p53 mutation and expression level. Taken together, ASPP2 increased tumour sensitivity to chemotherapy via inhibiting autophagy in a p53 independent manner, which was associated with the tumour formation, suggesting that both p53 inactivation and ASPP2 expression level were involved in the sensitivity of colorectal cancer to chemotherapy. PMID- 25534117 TI - Use of a daily disinfectant cleaner instead of a daily cleaner reduced hospital acquired infection rates. AB - BACKGROUND: Documenting effective approaches to eliminate environmental reservoirs and reduce the spread of hospital-acquired infections (HAIs) has been difficult. This was a prospective study to determine if hospital-wide implementation of a disinfectant cleaner in a disposable wipe system to replace a cleaner alone could reduce HAIs over 1 year when housekeeping compliance was >=80%. METHODS: In this interrupted time series study, a ready-to-use accelerated hydrogen peroxide disinfectant cleaner in a disposable wipe container system (DCW) was used once per day for all high-touch surfaces in patient care rooms (including isolation rooms) to replace a cleaner only. The HAI rates for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridium difficile were stratified by housekeeping cleaning compliance (assessed using ultraviolet-visible marker monitoring). RESULTS: When cleaning compliance was >=80%, there was a significant reduction in cases/10,000 patient days for MRSA (P = .0071), VRE (P < .0001), and C difficile (P = .0005). For any cleaning compliance level there was still a significant reduction in the cases/10,000 patient days for VRE (P = .0358). CONCLUSION: Our study data showed that daily use of the DCW applied to patient care high-touch environmental surfaces with a minimum of 80% cleaning compliance was superior to a cleaner alone because it resulted in significantly reduced rates of HAIs caused by C difficile, MRSA, and VRE. PMID- 25534118 TI - A combined application of lossless and lossy compression in ECG processing and transmission via GSM-based SMS. AB - This paper presents a software-based scheme for reliable and robust Electrocardiogram (ECG) data compression and its efficient transmission using Second Generation (2G) Global System for Mobile Communication (GSM) based Short Message Service (SMS). To achieve a firm lossless compression in high standard deviating QRS complex regions and an acceptable lossy compression in the rest of the signal, two different algorithms have been used. The combined compression module is such that it outputs only American Standard Code for Information Interchange (ASCII) characters and, hence, SMS service is found to be most suitable for transmitting the compressed signal. At the receiving end, the ECG signal is reconstructed using just the reverse algorithm. The module has been tested to all the 12 leads of different types of ECG signals (healthy and abnormal) collected from the PTB Diagnostic ECG Database. The compression algorithm achieves an average compression ratio of ~22.51, without any major alteration of clinical morphology. PMID- 25534119 TI - Erratum to "The Effectiveness of Endoscopic Radiofrequency Denervation of Medial Branch for Treatment of Chronic Low Back Pain" by Jeong SY, et al. (J Korean Neurosurg Soc 56 : 338-343, 2014). AB - [This corrects the article on p. 338 in vol. 56, PMID: 25371785.]. PMID- 25534120 TI - Upper extremity fractures among hospitalized road traffic accident adults. AB - BACKGROUND: Upper extremity fractures (UEFs) associated with road traffic accidents (RTAs) may result in long-term disability. Previous studies have examined UEF profiles with small patient populations. The objective of this study was to examine the injury profiles of UEFs in all mechanisms of injury related to RTAs. METHODS: Data on 71,231 RTA adult patients between 1997 and 2012 whose records were entered in a centralized country trauma database were reviewed. Data on UEFs related to mechanism of injury (car, motorcycle, bicycle, and pedestrian) including associated injuries, multiple UEFs, and frequency of UEF were analyzed. RESULTS: Of 71,231 adult RTA cases recorded in 1997-2012, 12,754 (17.9%) included UEFs. Motorcycle (27%) and bicycle riders (25%) had the greater risk for UEF (P<.0001). Of 12,754 patients with UEFs, 9701 (76%) had other injuries. Pedestrians (86%) and car occupants (81%) had the greater risk for associated injuries (P<.0001). Most of the injuries were head/face/neck (52%), lower extremities (49%), and chest (46%) injuries (P<.0001). Twenty-two percent of all cases had multiple UEFs. The motorcycle riders (27%) had the greater risk for multiple UEFs (P<.0001). Of 12,754 patients with UEFs we found 16,371 UEFs. Most of the fractures were in the radius (22%), humerus (19%), and clavicle (17%) (P<.0001). CONCLUSIONS: This study contributes the largest database on reported adult UEFs related to all mechanisms of injury in RTAs and finds the comparative epidemiology of associated injuries, multiple UEFs, and frequency of UEFs. It is important that the treating surgeon is aware of the complexity of the UEF patient, the strong possibility for associated injury, the possibility for multiple fractures in the upper limbs, and the most common fractures associated with each mechanism of accident. PMID- 25534121 TI - Point tenderness at 1 of 5 locations and limited elbow extension identify significant injury in children with acute elbow trauma: a study of diagnostic accuracy. AB - OBJECTIVE: Our goal was to determine whether the combination of tenderness at 1 of 5 commonly fractured sites and elbow extension accurately predicts the presence of acute elbow fractures or isolated effusions in children. METHODS: A prospective cohort study was performed using a convenience sample of patients. Children 0 to 18 years old with acute elbow injuries without elbow deformities or radial head subluxations were prospectively enrolled. The treating physicians assessed the injured elbow for the presence of tenderness at 5 locations and for abnormal active extension. The examination was defined as positive if any one component was present and negative if all were absent. The radiologist's report or a structured follow-up phone call was used as an a priori-determined composite reference standard for the diagnosis of (1) fracture or isolated effusion and (2) fracture. RESULTS: A total of 332 patients were enrolled; 183 (55.1%) were diagnosed with a fracture (31.0%) or effusion (24.1%). A negative examination result was present in 33 (9.9%), among whom 6 were diagnosed with a small effusion and 1 with a radial neck fracture. The examination's sensitivity, specificity, and positive and negative predictive values (95% confidence interval) were 96.2% (92.0-98.3), 17.4% (11.9-24.7), 58.4% (52.6-64.2), and 60.3% (47.8-72.9), respectively, for fracture or isolated effusion and 99.0% (97.1 100), 14.0% (9.5-18.5), 34.1% (28.7-39.5), and 97.0% (91.1-100.0), respectively, for fracture. A planned subgroup analysis of children younger than 3 years was performed; the elbow extension test was insensitive (sensitivity, 73.3% [51.0 95.7]) at excluding elbow injuries, albeit, when combined with point tenderness, it identified 100% of elbow fractures or effusions. CONCLUSION: The addition of point tenderness to the elbow extension test is highly sensitive at identifying injuries in children with acute elbow injuries, albeit nonspecific. Although the significance of omitting 10% of radiographs is questionable, a cost-benefit analysis would help clarify its potential savings in terms of expenditure and/or radiation exposure when compared to the risk of missing 2% of children with elbow injuries (albeit mainly small effusions). PMID- 25534122 TI - Is heart rate variability better than routine vital signs for prehospital identification of major hemorrhage? AB - OBJECTIVE: During initial assessment of trauma patients, metrics of heart rate variability (HRV) have been associated with high-risk clinical conditions. Yet, despite numerous studies, the potential of HRV to improve clinical outcomes remains unclear. Our objective was to evaluate whether HRV metrics provide additional diagnostic information, beyond routine vital signs, for making a specific clinical assessment: identification of hemorrhaging patients who receive packed red blood cell (PRBC) transfusion. METHODS: Adult prehospital trauma patients were analyzed retrospectively, excluding those who lacked a complete set of reliable vital signs and a clean electrocardiogram for computation of HRV metrics. We also excluded patients who did not survive to admission. The primary outcome was hemorrhagic injury plus different PRBC transfusion volumes. We performed multivariate regression analysis using HRV metrics and routine vital signs to test the hypothesis that HRV metrics could improve the diagnosis of hemorrhagic injury plus PRBC transfusion vs routine vital signs alone. RESULTS: As univariate predictors, HRV metrics in a data set of 402 subjects had comparable areas under receiver operating characteristic curves compared with routine vital signs. In multivariate regression models containing routine vital signs, HRV parameters were significant (P<.05) but yielded areas under receiver operating characteristic curves with minimal, nonsignificant improvements (+0.00 to +0.05). CONCLUSIONS: A novel diagnostic test should improve diagnostic thinking and allow for better decision making in a significant fraction of cases. Our findings do not support that HRV metrics add value over routine vital signs in terms of prehospital identification of hemorrhaging patients who receive PRBC transfusion. PMID- 25534123 TI - Comparison of in vivo 3D cone-beam computed tomography tooth volume measurement protocols. AB - BACKGROUND: The objective of this study is to analyze a set of previously developed and proposed image segmentation protocols for precision in both intra- and inter-rater reliability for in vivo tooth volume measurements using cone-beam computed tomography (CBCT) images. METHODS: Six 3D volume segmentation procedures were proposed and tested for intra- and inter-rater reliability to quantify maxillary first molar volumes. Ten randomly selected maxillary first molars were measured in vivo in random order three times with 10 days separation between measurements. Intra- and inter-rater agreement for all segmentation procedures was attained using intra-class correlation coefficient (ICC). RESULTS: The highest precision was for automated thresholding with manual refinements. CONCLUSIONS: A tooth volume measurement protocol for CBCT images employing automated segmentation with manual human refinement on a 2D slice-by-slice basis in all three planes of space possessed excellent intra- and inter-rater reliability. Three-dimensional volume measurements of the entire tooth structure are more precise than 3D volume measurements of only the dental roots apical to the cemento-enamel junction (CEJ). PMID- 25534124 TI - Reverse atrial remodeling following pulmonary vein isolation: the importance of the body mass index. AB - BACKGROUND: Pulmonary vein isolation (PVI) causes a reduction in left atrium size that is attributable to reverse atrial remodeling (RAR). The objective of this study was to identify predictors of RAR and determine its association with other parameters of improvement in cardiac function. METHODS: It is a prospective study with 74 patients (52 +/- 9 years old, 81% male), and 51% of patients had paroxysmal atrial fibrillation. Patients were serially assessed with transthoracic echocardiography; plasma N-terminal B-type natriuretic peptide (NT proBNP); and high-sensitivity C-reactive protein levels at baseline and 3, 6, and 12 months following the PVI. RAR was defined as a reduction in the left atrial volume index (LAV-index) >10% from baseline at the end of follow-up. A multivariate analysis was conducted to identify predictors of RAR. RESULTS: The LAV-index decreased significantly during follow-up in the entire population (P = 0.0005). RAR (experienced by 63.5% of the patients) was more frequent (76% vs. 42%; P = 0.004) and pronounced (reduction 16.65 +/- 14% vs. 8 +/- 14%; P = 0.015) in patients with a successful ablation (46 of 74 patients, 62.2%). Only patients with RAR showed significant improvement in NT-proBNP levels (P = 0.0001), systolic function (P = 0.035), and diastolic function (P = 0.005). Multivariable analysis revealed that a successful ablation (odds ratio [OR] = 4.6; 95% confidence interval [CI] 1.46-14.68; P = 0.009), LAV-index (OR = 1.15; 95% CI 1.03-1.2; P = 0.021), and patient's body mass index (OR = 0.84; 95% CI 0.74-0.96; P = 0.012) were independent predictors of RAR. CONCLUSIONS: Successful PVI ablation is the main predictor of RAR that is associated with other parameters of improvement in cardiac function. The patient's body mass index may have a negative effect on RAR. PMID- 25534125 TI - Interdigital direct neurorrhaphy for treatment of painful neuroma due to finger amputation. AB - BACKGROUND: Painful neuroma following amputation is a disabling condition for which treatments are not usually satisfactory. The aim of this study is to retrospectively evaluate the results of interdigital neurorrhaphy after neuroma resection as an option for the surgical treatment of painful digital neuroma. METHOD: We retrospectively analyzed data from seven patients submitted to interdigital neurorrhaphy for treatment of digital neuroma. For evaluation of the results, the visual analog scale (VAS) for pain assessment, measurements with Simmens-Weinstein filaments and a handgrip dynamometer, and quantification of the Disabilities of the Arm, Shoulder and Hand (DASH) score were all performed. The mean improvements on the VAS and DASH scores were calculated. RESULTS: The mean follow-up was 28.3 months. All patients presented some degree of improvement in upper limb functionality and pain, and handling the affected finger was possible in all cases. The mean improvement on the VAS and DASH scores was 29.8 and 55.5 %, respectively. No patients presented long-term complications. CONCLUSION: Although this study was based on a small number of patients, it indicates that interdigital neurorrhaphy seems to be a feasible surgical treatment for painful digital neuroma. PMID- 25534126 TI - What happens to the bone flap? Long-term outcome after reimplantation of cryoconserved bone flaps in a consecutive series of 92 patients. AB - BACKGROUND: Reimplantation of cryoconserved autologous bone flaps is a standard procedure after decompressive craniotomies. Aseptic necrosis and resorption are the most frequent complications of this procedure. At present there is no consensus regarding the definition of the relevant extent and indication for surgical revision. The objective of this retrospective analysis was to identify the incidence of bone flap resorption and the optimal duration of follow-up. METHODS: Between February 2009 and March 2012, 100 cryoconserved autologous bone flaps were reimplanted at the Department of Neurosurgery, Inselspital Bern. Three patients were not available for follow-up, and five patients died before follow up. All patients underwent follow-up at 6 weeks and a second follow-up more than 12 months postoperatively. A clinical and CT-based score was developed for judgment of relevance and decision making for surgical revision. RESULTS: Mean follow-up period was 21.6 months postoperatively (range: 12 to 47 months); 48.9 % (45/92) of patients showed no signs of bone flap resorption, 20.7 % (19/92) showed minor resorption with no need for surgical revision, and 30.4 % (28/92) showed major resorption (in 4 % of these the bone flap was unstable or collapsed). CONCLUSIONS: Aseptic necrosis and resorption of reimplanted autologous bone flaps occurred more frequently in our series of patients than in most reports in the literature. Most cases were identified between 6 and 12 months postoperatively. Clinical observation or CT scans of patients with autologous bone flaps are recommended for at least 12 months. Patient-specific implants may be preferable to autologous bone flaps. PMID- 25534127 TI - Authors' reply to "coincident pituitary adenoma and sellar meningioma". PMID- 25534128 TI - Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects. AB - Primary melanocytic tumors of the central nervous system (CNS) represent a spectrum of rare tumors. They can be benign or malignant and occur in adults as well as in children, the latter often in the context of neurocutaneous melanosis. Until recently, the genetic alterations in these tumors were largely unknown. This is in contrast with cutaneous and uveal melanomas, which are known to harbor distinct oncogenic mutations that can be used as targets for treatment with small molecule inhibitors in the advanced setting. Recently, novel insights in the molecular alterations underlying primary melanocytic tumors of the CNS were obtained, including different oncogenic mutations in tumors in adult patients (especially GNAQ, GNA11) vs. children (especially NRAS). In this review, the focus is on molecular characteristics of primary melanocytic tumors of the CNS. We summarize what is known about their genetic alterations and discuss implications for pathogenesis and differential diagnosis with other pigmented tumors in or around the CNS. Finally, new therapeutic options with targeted therapy are discussed. PMID- 25534129 TI - A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0501. AB - BACKGROUND: Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S 1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective. METHODS: In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40mg/m(2) on days 1, 8, 29 and 36) and S-1 (80mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary endpoint was the response rate. RESULTS: A partial response was observed in 37 patients (77%; 95% confidence interval: 63 88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis. CONCLUSIONS: This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC. PMID- 25534131 TI - Red cell distribution width in acute mesenteric ischemia. PMID- 25534130 TI - Parallel screening for ALK, MET and ROS1 alterations in non-small cell lung cancer with implications for daily routine testing. AB - OBJECTIVES: ALK, MET and ROS1 are prognostic and predictive markers in NSCLC, which need to be implemented in daily routine. To evaluate different detection approaches and scoring systems for optimal stratification of patients eligible for mutation testing in the future, we screened a large and unselected cohort of NSCLCs for all three alterations. MATERIAL AND METHODS: Using tissue microarrays, 473 surgically resected NSCLCs were tested for ALK and MET expression by IHC and genomic alterations in the ALK, MET and ROS1 gene by FISH. For MET IHC, two different criteria (MetMAb and H-score), for MET FISH, three different scoring systems (UCCC, Cappuzzo, PathVysion) were investigated. RESULTS: ALK and ROS1 positivity was seen in 2.6% and 1.3% of all ADCs, respectively, but not in pure SCCs. One ROS1 translocated tumor showed additional ROS1 amplification. MET IHC+/FISH+ cases were found in both histological subtypes (8.6% in all NSCLCs; 10.6% in ADCs; 5.0% in SCCs) and were associated with pleural invasion, lymphatic vessel invasion and lymph node metastasis. MET altered ADCs more frequently showed a papillary growth pattern. Whereas ALK testing revealed homogenous results in IHC and FISH, we saw discordant results for MET in about 10% of cases. Both METIHC scoring systems revealed almost identical results. We did not encounter any combined FISH positivity for ALK, MET or ROS1. However, three ALK positive cases harbored MET overexpression. CONCLUSION: In daily routine, IHC could support FISH in the identification of ALK altered NSCLCs. Further research is needed to assess the role of discordant MET results by means of IHC and FISH as well as the relevance of tumors with an increased ROS1 gene copy number. PMID- 25534133 TI - Measuring research success via bibliometrics: where they fit and how they help and hinder. PMID- 25534134 TI - Tl(I) and Tl(III) alter the expression of EGF-dependent signals and cyclins required for pheochromocytoma (PC12) cell-cycle resumption and progression. AB - The effects of thallium [Tl(I) and Tl(III)] on the PC12 cell cycle were evaluated without (EGF(-)) or with (EGF(+)) media supplementation with epidermal growth factor (EGF). The following markers of cell-cycle phases were analyzed: cyclin D1 (G1 ); E2F-1, cyclin E and cytosolic p21 (G1 ->S transition); nuclear PCNA and cyclin A (S); and cyclin B1 (G2). The amount of cells in each phase and the activation of the signaling cascade triggered by EGF were also analyzed. Tl(I) and Tl(III) (5-100 MUM) caused dissimilar effects on PC12 cell proliferation. In EGF(-) cells, Tl(I) increased the expression of G1 ->S transition markers and nuclear PCNA, without affecting cyclin A or cyclin B1. In addition to those, cyclin B1 was also increased in EGF(+) cells. In EGF(-) cells, Tl(III) increased the expression of cyclin D1, all the G1->S and S phase markers and cyclin B1. In EGF(+) cells, Tl(III) increased cyclin D1 expression and decreased all the markers of G1 ->S transition and the S phase. Even when these cations did not induce the activation of EGF receptor (EGFR) in EGF(-) cells, they promoted the phosphorylation of ERK1/2 and Akt. In the presence of EGF, the cations anticipated EGFR phosphorylation without affecting the kinetics of EGF-dependent ERK1/2 and Akt phosphorylation. Altogether, results indicate that Tl(I) promoted cell proliferation in both EGF(-) and EGF(+) cells. In contrast, Tl(III) promoted the proliferation of EGF(-) cells but delayed it in EGF(+) cells, which may be related to the toxic effects of this cation in PC12 cells. PMID- 25534135 TI - Evaluation of the clinical and aesthetic outcomes of Straumann((r)) Standard Plus implants supported single crowns placed in non-augmented healed sites in the anterior maxilla: a 5-8 years retrospective study. AB - PURPOSE: To evaluate the long-term aesthetic outcome of the single crowns supported by soft tissue level implants placed in healed sites in the anterior maxilla region via the pink aesthetic score (PES) and the white aesthetic score (WES). MATERIAL AND METHODS: According to the inclusion criteria, patients who had received a single Straumann((r)) Standard Plus implant in the anterior maxilla at the Shanghai 9th People's Hospital between 2005 and 2008 were invited for a re-examination based on a number of inclusion criteria and exclusion criteria. Clinical, radiographic and aesthetic outcomes (PES/WES) were assessed during their revisit at 5-8 years after crown placement. RESULTS: Forty-five patients were enrolled in the study. All 45 implants were successfully integrated and most of the implants did not show signs of peri-implant disease at the time of the assessment. The marginal bone resorption was 1.10 +/- 0.92 mm. The mean total PES was 8.48 +/- 2.62 at the baseline, 9.57 +/- 2.37 at the 6-10 months revisit and 9.01 +/- 2.45 at the 5-8 years follow-up. The scores of the mesial and distal papillae increased significantly between the baseline and 6-10 months follow-up, this improvement remained stable at the 5-8 years follow-up. The scores of soft tissue level, colour of the soft tissue, soft tissue texture and the alveolar process decreased significantly between the 6-10 months and 5-8 years revisits. The mean WES was 7.83 +/- 1.60 at the baseline and 7.72 +/- 1.43 at the 5-8 years revisit. There was no significant difference of the WES between the baseline and 5-8 years revisit. CONCLUSION: The possibility of spontaneous papillae regeneration after implant treatment and the long-term stability of the regenerated papillae were confirmed. However, recession of the facial soft tissue has been found. The incidence of the recession at thin biotype sites tended to be higher. PMID- 25534137 TI - Coordination geometry of lead carboxylates - spectroscopic and crystallographic evidence. AB - Despite their versatility, only a few single-crystal X-ray structures of lead carboxylates exist, due to difficulties with solubility. In particular, the structures of long-chain metal carboxylates have not been reported. The lone electron pair in Pb(ii) can be stereochemically active or inactive, leading to two types of coordination geometries commonly referred to as hemidirected and holodirected structures, respectively. We report (13)C and (207)Pb solid-state NMR and infrared spectra for a series of lead carboxylates, ranging from lead hexanoate (C6) to lead hexadecanoate (C18). The lead carboxylates based on consistent NMR parameters can be divided in two groups, shorter-chain (C6, C7, and C8) and longer-chain (C9, C10, C11, C12, C14, C16, and C18) carboxylates. This dichotomy suggests two modes of packing in these solids, one for the short chain lead carboxylates and one for long-chain lead carboxylates. The consistency of the (13)C and (207)Pb NMR parameters, as well as the IR data, in each group suggests that each motif represents a structure characteristic of each subgroup. We also report the single-crystal X-ray diffraction structure of lead nonanoate (C9), the first single-crystal structure to have been reported for the longer chain subgroup. Taken together the evidence suggests that the coordination geometry of C6-C8 lead carboxylates is hemidirected, and that of C9-C14, C16 and C18 lead carboxylates is holodirected. PMID- 25534136 TI - Inactivation of a common OGG1 variant by TNF-alpha in mammalian cells. AB - Reactive oxygen species threaten genomic integrity by inducing oxidative DNA damage. One common form of oxidative DNA damage is the mutagenic lesion 8 oxoguanine (8-oxodG). One driver of oxidative stress that can induce 8-oxodG is inflammation, which can be initiated by the cytokine tumor necrosis factor alpha (TNF-alpha). Oxidative DNA damage is primarily repaired by the base excision repair pathway, initiated by glycosylases targeting specific DNA lesions. 8-oxodG is excised by 8-oxoguanine glycosylase 1 (OGG1). A common Ogg1 allelic variant is S326C-Ogg1, prevalent in Asian and Caucasian populations. S326C-Ogg1 is associated with various forms of cancer, and is inactivated by oxidation. However, whether oxidative stress caused by inflammatory cytokines compromises OGG1 variant repair activity remains unknown. We addressed whether TNF-alpha causes oxidative stress that both induces DNA damage and inactivates S326C-OGG1 via cysteine 326 oxidation. In mouse embryonic fibroblasts, we found that S326C OGG1 was inactivated only after exposure to H2O2 or TNF-alpha. Treatment with the antioxidant N-acetylcysteine prior to oxidative stress rescued S326C-OGG1 activity, demonstrated by in vitro and cellular repair assays. In contrast, S326C OGG1 activity was unaffected by potassium bromate, which induces oxidative DNA damage without causing oxidative stress, and presumably cysteine oxidation. This study reveals that Cys326 is vulnerable to oxidation that inactivates S326C-OGG1. Physiologically relevant levels of TNF-alpha simultaneously induce 8-oxodG and inactivate S326C-OGG1. These results suggest a mechanism that could contribute to increased risk of cancer among S326C-Ogg1 homozygous individuals. PMID- 25534139 TI - A practical approach to imaging the axilla. AB - Imaging of the axilla typically occurs when patients present with axillary symptoms or newly diagnosed breast cancer. An awareness of the axillary anatomy is essential in order to generate an accurate differential diagnosis and guide patient management. The purpose of this article is to review the indications for axillary imaging, discuss the logistics of the scanning technique and percutaneous interventions, and present the imaging findings and management of a variety of breast diseases involving the axilla. Teaching points * Knowledge of normal axillary anatomy aids in determining the aetiology of an axillary mass. * The differential diagnosis of an axillary mass is broad and can be subdivided by the location of the lesion. * Imaging evaluation of the axilla usually entails diagnostic mammography and targeted ultrasound. * FNA or core needle biopsies are safe and accurate methods for diagnosis and guiding management. PMID- 25534138 TI - An SNP-based saturated genetic map and QTL analysis of fruit-related traits in cucumber using specific-length amplified fragment (SLAF) sequencing. AB - BACKGROUND: Cucumber, Cucumis sativus L., is an economically important vegetable crop which is processed or consumed fresh worldwide. However, the narrow genetic base in cucumber makes it difficult for constructing high-density genetic maps. The development of massively parallel genotyping methods and next-generation sequencing (NGS) technologies provides an excellent opportunity for developing single nucleotide polymorphisms (SNPs) for linkage map construction and QTL analysis of horticultural traits. Specific-length amplified fragment sequencing (SLAF-seq) is a recent marker development technology that allows large-scale SNP discovery and genotyping at a reasonable cost. In this study, we constructed a high-density SNP map for cucumber using SLAF-seq and detected fruit-related QTLs. RESULTS: An F2 population of 148 individuals was developed from an intra-varietal cross between CC3 and NC76. Genomic DNAs extracted from two parents and 148 F2 individuals were subjected to high-throughput sequencing and SLAF library construction. A total of 10.76 Gb raw data and 75,024,043 pair-end reads were generated to develop 52,684 high-quality SLAFs, out of which 5,044 were polymorphic. 4,817 SLAFs were encoded and grouped into different segregation patterns. A high-resolution genetic map containing 1,800 SNPs was constructed for cucumber spanning 890.79 cM. The average distance between adjacent markers was 0.50 cM. 183 scaffolds were anchored to the SNP-based genetic map covering 46% (168.9 Mb) of the cucumber genome (367 Mb). Nine QTLs for fruit length and weight were detected, a QTL designated fl3.2 explained 44.60% of the phenotypic variance. Alignment of the SNP markers to draft genome scaffolds revealed two mis assembled scaffolds that were validated by fluorescence in situ hybridization (FISH). CONCLUSIONS: We report herein the development of evenly dispersed SNPs across cucumber genome, and for the first time an SNP-based saturated linkage map. This 1,800-locus map would likely facilitate genetic mapping of complex QTL loci controlling fruit yield, and the orientation of draft genome scaffolds. PMID- 25534140 TI - Thoughts on the progression of type 2 diabetes drug discovery. AB - INTRODUCTION: Type 2 diabetes is a growing epidemic in need of effective treatments. There has been research in recent years involving numerous drug therapies and targets. This article is a review of the progress thus far in type 2 diabetes drug discovery. AREAS COVERED: This editorial reviews type 2 diabetes drug discovery mainly over the past decade through a literature search of PubMed. Furthermore, the author reviews several avenues of research, including the expansion of knowledge for possible drug therapies involving the beta-cell, such as targeting its proliferation, function and apoptosis. This knowledge has led to possible drug therapies in clinical trials, particularly insulin secretagogues that are glucose-dependent. Other areas of research in type 2 diabetes drug discovery discussed by the author relate to the new frontier of genome-wide association studies (GWAS), the challenges of oral insulin development and drug targets of inflammation. The author also reviews sirtuin activators and resveratrol, especially its relationship to insulin resistance. EXPERT OPINION: The progression of type 2 diabetes drug discovery holds much promise, but many agents are in the nascent stages of investigation and human trials proving efficacy are needed. Furthermore, basic science research into some of these agents may need to be further elucidated before clinical trials can be initiated. PMID- 25534141 TI - Six fucose-alpha(1-2) sugars and alpha-fucose assigned in the human brain using in vivo two-dimensional MRS. AB - A growing body of literature has indicated that fucose-alpha(1-2)-galactose sugars are implicated in the molecular mechanisms that underlie neuronal development, learning and memory in the human brain. An understanding of the in vivo roles played by these terminal fucose residues has been hampered by the lack of technology to non-invasively monitor their levels in the human brain. We have implemented in vivo two-dimensional MRS technology to examine the human brain in a 3-T clinical MR scanner, and report that six fucose-alpha(1-2)-galactose residues and free alpha-fucose are available for inspection. Fucose-alpha(1-3) galactose residues cannot yet be assigned using this technology as they resonate under the water resonance. This new application offers an unprecedented insight into the molecular mechanisms by which fucosylated sugars contribute to neuronal processes and how they alter during development, ageing and disease. PMID- 25534143 TI - Effect of age and residential status on the predictive performance of CURB-65 score. AB - BACKGROUND: The CURB-65 score was designed to predict 30-day mortality and decide the site of care of pneumonia. It is uncertain how age and residential status affect the accuracy of CURB-65 score in older patients. AIM: This study aimed to evaluate the effect of age and residential status on the performance of CURB-65 score in predicting 30-day all-cause mortality of pneumonia in older patients. METHODS: We used combined data from two prospective observational cohorts of adult patients with pneumonia. Older patients aged >= 65 years were analysed. RESULTS: Of 1644 patients, 1200 were living in the community and 464 residing in nursing homes. The 30-day mortality rates of community-acquired pneumonia (CAP) and nursing home-acquired pneumonia (NHAP) were 10.7% and 14.2% respectively. In each age group of CAP and NHAP, mortality increased with pneumonia severity. Mortality decreased with advancing age in NHAP, and the reverse was true for CAP. In NHAP but not CAP, the proportion of highly severe pneumonia (CURB-65 score >= 3) was lower in older patients. The overall predictive performance of CURB-65 score was comparable in CAP and NHAP. The accuracy deteriorated with advancing age in NHAP but not CAP. Using the cut-off score of >=3 (highly severe pneumonia), the CURB-65 score achieved high negative predictive values (>90%) in CAP and NHAP. CONCLUSIONS: Advancing age adversely affected the predictive performance of CURB-65 score in NHAP but not CAP. The score was not helpful in guiding the site of care at admission in older patients with pneumonia. PMID- 25534142 TI - CT-guidance interstitial (125)Iodine seed brachytherapy as a salvage therapy for recurrent spinal primary tumors. AB - BACKGROUND: Management of spinal neoplasms has relied on open surgery and external beam radiotherapy (EBRT). Although primary spinal tumors are rare, their treatment remains a pervasive problem. This analysis sought to evaluate the safety and efficacy of CT-guided (125)I seed brachytherapy for recurrent paraspinous and vertebral primary tumors. METHODS: From November 2002 to June 2014, 17 patients who met the inclusion criteria were retrospectively reviewed. 14 (82.4%) had previously undergone surgery, 15 (88.2%) had received conventional EBRT and 3 (17.6%) had chosen chemotherapy. The number of (125)I seeds implanted ranged from 7 to 122 (median 79) with specific activity of 0.5-0.8 mCi (median 0.7 mCi). The post-plan showed that the actuarial D90 of (125)I seeds were 90-183 Gy (median 137 Gy). The follow-up period ranged from 2 to 69 months (median 19 months). The local control rate was calculated by the Kaplan-Meier method. RESULTS: For 5 Chondrosarcomas, the 1-, 2-, 3-year local control rates were 75%, 37.5%, and 37.5%, respectively, with a median of 34 months (range, 4-39 months). For 4 chordomas, the local control rate was 50% with a median follow-up of 13 months (range, 3-17 months). For 3 fibromatosis, all of them were survival without local recurrence at the end of follow-up. During the follow-up period, 35.3% (6/17) died from metastases, 17.6% (3/17) developed local recurrence by 8, 14 and 34 months while 64.7% (11/17) remained alive. 100% experienced pain relief and normal or improved ambulation, without more than Frankel grade 3 radiation myelopathy. CONCLUSIONS: Percutaneous (125)I seed implantation can be an alternative or retreatment for recurrent spinal primary tumors. PMID- 25534144 TI - Ventilation and gas exchange in two turtles: Podocnemis unifilis and Phrynops geoffroanus (Testudines: Pleurodira). AB - Turtles (Testudines) have two major taxa, Pleurodira and Cryptodira. To date, only limited data are available regarding the respiratory physiology of pleurodirans. To begin to address this, we studied ventilation and gas exchange in Podocnemis unifilis and Phrynops geoffroanus. Breathing pattern in both species could be described as episodic with breathing episodes separated by large non-ventilatory periods. We measured duration of inspiration and expiration, breathing frequency, duration of the non-ventilatory period (time between episodes), tidal volume, and oxygen consumption when breathing normoxia, hypoxia and hypercarbia at 25 degrees C. In both species hypercarbia caused a greater increase in ventilation compared to hypoxia, increasing both breathing frequency and tidal volume. Minute ventilation and oxygen consumption in P. geoffroanus were the lowest described so far in testudines, indicating either extra-pulmonary gas exchange or a significantly lower metabolism. Oxidative costs of breathing, estimated using the regression method, was the highest described so far for any reptile. Further studies are necessary to better understand respiratory physiology in Phrynops and Podocnemis species. PMID- 25534147 TI - Reactivity of vinyl phosphonate containing diazoesters: formation, reactivity, and utility. AB - Treatment of diazo vinyl phosphonate with alcohols, amines, and thiols in the presence of Rh(II) results in the chemo- and stereoselective generation of enol ethers, enamines and vinyl sulfides via an X-H insertion process. The utility of the products from these reactions was demonstrated through their conversion into quaternary substituted heterocycles including furans and oxetanes as highlighted by the generation of a bicyclic phosphonate analogue of neodysiherbaine. PMID- 25534145 TI - Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction. AB - The mechanism of vascular endothelial dysfunction (VED) and cardiovascular disease in obstructive sleep apnea (OSA) is unknown. We performed a comprehensive evaluation of endothelial nitric oxide synthase (eNOS) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status. Nineteen OSA patients underwent gluteal biopsies before, and after effective treatment of OSA. We measured superoxide (O2(*-)) and nitric oxide (NO) in the microcirculatory endothelium using confocal microscopy. We evaluated the effect of the NOS inhibitor l-Nitroarginine-Methyl-Ester (l NAME) and the NOS cofactor tetrahydrobiopterin (BH4) on endothelial O2(*-) and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in OSA patients pre-treatment, and is a source of endothelial O2(* ) overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA. PMID- 25534146 TI - Persistent structural adaptation in the lungs of guinea pigs raised at high altitude. AB - Laboratory guinea pigs raised at high altitude (HA, 3800 m) for up to 6 mo exhibit enhanced alveolar growth and remodeling (Hsia et al., 2005. Resp. Physiol. Neurobiol. 147, 105-115). To determine whether initial HA-induced structural enhancement persists following return to intermediate altitude (IA), we raised weanling guinea pigs at (a) HA for 11-12 mo, (b) IA (1200 m) for 11-12 mo, and (c) HA for 4 mo followed by IA for 7-8 mo (HA-to-IA). Morphometric analysis was performed under light and electron microscopy. Body weight and lung volume were similar among groups. Prolonged HA residence increased alveolar epithelium and interstitium volumes while reducing alveolar-capillary blood volume. The HA-induced gains in type-1 epithelium volume and alveolar surface area were no longer present following return to IA whereas volume increases in type-2 epithelium and interstitium and the reduction in alveolar duct volume persisted. Results demonstrate persistent augmentation of some but not all aspects of lung structure throughout prolonged HA residence, with partial reversibility following re-acclimatization to IA. PMID- 25534148 TI - Evaluation of optimal RNA extraction method from human carotid atherosclerotic plaque. AB - Investigating molecular mechanisms involved in the formation of carotid atherosclerotic plaques has been challenging. Isolating high-quality RNA from plaque tissue can be difficult because of acellularity, calcification, and degradation. It is essential that the mRNA isolated from this tissue preserves and reflects the actual relative gene expression. Two common methods for RNA preservation, snap-freezing and stabilizing reagent, were compared using surgically resected human carotid atherosclerotic tissue. In addition, isolation methods were compared for integrity and quantity: column-based extraction, phenol based extraction, and a combination of the two. We found that using a stabilizing reagent with column filtration resulted in the lowest yield and quality. Phenol based extraction resulted in higher yields but also increased fragmentation. Snap frozen tissue coupled with column-based extraction yielded the highest quality. The higher quality and quantity RNA obtained when processing snap-frozen tissue with column-based extraction make it possible to use difficult sample types for molecular downstream applications. PMID- 25534149 TI - Multicultural personality and posttraumatic stress in U.S. service members. AB - OBJECTIVE: Modern military missions place numerous demands on service members, including tactical, personal, and cultural challenges. The purpose of this study was to explore how domains of multicultural personality (cultural empathy, open mindedness, social initiative, emotional stability, and flexibility) and combat exposure relate to posttraumatic stress disorder (PTSD) in service members. METHOD: Participants (N = 163) completed the Multicultural Personality Questionnaire, Combat Exposure Scale, and PTSD Checklist-Military as part of an online survey. The majority of participants were Caucasian (87%), mean age was 33 years, and all were deployed at least once to Iraq or Afghanistan RESULTS: Regression results indicated that higher levels of combat exposure and open mindedness and lower levels of flexibility and emotional stability were significant predictors of higher PTSD severity. The interactions between combat exposure and flexibility and combat exposure and openness were also significant. CONCLUSION: Higher levels of flexibility and emotional stability seem particularly important in their association with lower PTSD severity for service members. PMID- 25534150 TI - Nanoparticle-assisted NMR detection of organic anions: from chemosensing to chromatography. AB - Monolayer-protected nanoparticles provide a straightforward access to self organized receptors that selectively bind different substrates in water. Molecules featuring different kinds of noncovalent interactions (namely, hydrophobic, ion pairing, and metal-ligand coordination) can be grafted on the nanoparticle surface to provide tailored binding sites for virtually any class of substrate. Not only the selectivity but also the strength of these interactions can be modulated. Such recognition ability can be exploited with new sensing protocols, based on NMR magnetization transfer and diffusion-ordered spectroscopy (DOSY), to detect and identify organic molecules in complex mixtures. PMID- 25534152 TI - Identification of a candidate rad1 subunit for the kinetoplastid 9-1-1 (rad9-hus1 rad1) complex. AB - The trimeric 9-1-1 (Rad9-Hus1-Rad1) complex plays an important role in the eukaryotic DNA damage response by recruiting DNA repair factors and checkpoint mediators to damaged sites. Extensively characterised in mammals and yeast, evidence is now emerging that 9-1-1 function is conserved beyond the relatively narrow evolutionary range of the Opisthokonts. Kinetoplastid Rad9 and Hus1 proteins have been identified and shown to be involved in the DNA damage response but Rad1 has remained elusive. In this study, PSI-BLAST iterative database searching, phylogenetic and structural modeling techniques are used to identify and characterise candidate Rad1 proteins in kinetoplastid organisms. PMID- 25534153 TI - Longitudinal midbrain changes in early Parkinson's disease: iron content estimated from R2*/MRI. AB - OBJECTIVE: To determine whether, in patients with early Parkinson's disease (PD), longitudinal changes in midbrain iron content are associated with declining motor function over a period of three years. METHODS: Nineteen untreated subjects with early PD and 13 age- and sex-matched controls were followed clinically for 36 months. MRI with a 3 T magnet was performed at baseline, 18 months and 36 months with a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate R2*. R2* was calculated for midbrain and forebrain basal ganglia regions. RESULTS: A difference in R2* between patients and controls was observed at baseline (p = 0.035) but not at 18 or 36 months in the lateral substantia nigra pars compacta (SNc). Linear regression indicated significant correlations between the change in R2* in the lateral SNc and the change score in UPDRS III (p = 0.008) and the PDQ-39 -mobility sub-score (p = 0.03) from baseline to 36 months. R2* tended to increase in those with more advanced disease and to decrease in those with milder disease. CONCLUSIONS: High field MRI demonstrates lateral SNc abnormalities that progress over 3 years in early PD consistent with increased iron content in those with more advanced disease, corresponding to the known distribution of neuronal loss occurring in this disorder, and correlating with motor symptomatology. Larger and longer investigations with more precise mapping of iron-containing midbrain structures are needed to fully evaluate the potential of R2* as a biomarker of disease progression in PD. PMID- 25534151 TI - Lessons learned for follow-up phone booster counseling calls with substance abusing emergency department patients. AB - BACKGROUND: Post-visit "booster" sessions have been recommended to augment the impact of brief interventions delivered in the emergency department (ED). This paper, which focuses on implementation issues, presents descriptive information and interventionists' qualitative perspectives on providing brief interventions over the phone, challenges, "lessons learned", and recommendations for others attempting to implement adjunctive booster calls. METHOD: Attempts were made to complete two 20-minute telephone "booster" calls within a week following a patient's ED discharge with 425 patients who screened positive for and had recent problematic substance use other than alcohol or nicotine. RESULTS: Over half (56.2%) of participants completed the initial call; 66.9% of those who received the initial call also completed the second call. Median number of attempts to successfully contact participants for the first and second calls were 4 and 3, respectively. Each completed call lasted an average of about 22 minutes. Common challenges/barriers identified by booster callers included unstable housing, limited phone access, unavailability due to additional treatment, lack of compensation for booster calls, and booster calls coming from an area code different than the participants' locale and from someone other than ED staff. CONCLUSIONS: Specific recommendations are presented with respect to implementing a successful centralized adjunctive booster call system. Future use of booster calls might be informed by research on contingency management (e.g., incentivizing call completions), smoking cessation quitlines, and phone-based continuing care for substance abuse patients. Future research needs to evaluate the incremental benefit of adjunctive booster calls on outcomes over and above that of brief motivational interventions delivered in the ED setting. PMID- 25534154 TI - Design, Synthesis, and Biological Evaluation of 1,4-dihydropyridine Derivatives as Potent Antitubercular Agents. AB - A series of novel 1,4-dihydropyridine-3,5-dicarbamoyl derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via multicomponent Hantzsch reaction. The newly synthesized compounds were characterized by IR, (1) H NMR, (13) C NMR, and mass spectroscopy. The synthesized compounds 3a-p were screened for antitubercular activity. Among all the screened compounds, compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis with minimum inhibitory concentration of 0.02 MUg/mL and SI > 500, making it more potent than first-line antitubercular drug isoniazid. In addition, these compounds displayed relatively low cytotoxicity. PMID- 25534158 TI - Impact of luteal phase hysteroscopy and concurrent endometrial biopsy on subsequent IVF cycle outcome. PMID- 25534159 TI - Combined vagino-abdominal approach for management of vesicovaginal fistulas: a 10 years' experience. AB - BACKGROUND: Vesicovaginal fistulas (VVF) are an uncommon but serious complication of gynecological surgery. The aim of this study was to report our experience with the repair of VVF using combined vaginal and extraperitoneal abdominal approaches. MATERIALS AND METHODS: Between 2000 and 2012, 15 consecutive females with VVF were managed with combined vaginal and extraperitoneal abdominal procedures. After assessment by voiding cystourethrography and urethrocystoscopy, the operation was performed at the standard lithotomy position. RESULT: Fifteen patients were included in this study with mean age 51.8 +/- 11.9 years. The mean fistula size was 2.1 +/- 0.7 cm and all of them were located in supra-trigonal region except one case that fistula defect extend to the bladder trigon. Fourteen patients reported complete resolution of urinary incontinence during mean follow up of 3.5 years. Fistula was recurred in one female 1 year after repair due to cancer recurrence and radiotherapy treatment. No intraoperative complication including massive bleeding or ureteral damage was observed. CONCLUSION: Our experience with combined vaginal and extraperitoneal abdominal repair of a vesicovaginal fistula shows its feasibility and safety with good results. PMID- 25534160 TI - The incidence of complications by hysterectomy for benign disease in correlation to an assumed preoperative score. AB - BACKGROUND: Hysterectomies are preformed abdominally, vaginally, laparoscopic or with robotic assistance. When choosing the route of hysterectomy, the physician should take into consideration the safest and most cost-effective route to fulfill all needs of the patient. METHODS: Data were collected retrospectively from 953 patients who underwent hysterectomy between 2002 and 2010 for benign indications at UKSH, Germany. Preoperative risk scores were assigned to patients. The data were statistically evaluated to investigate relationship between the occurrence of the complication and the preoperative score at the time of the hysterectomy. For the preoperative score, patients who had undergone a previous laparoscopy were assigned 1 point; those who had undergone a previous Pfannenstiel laparotomy were assigned 2 points; those who had undergone 1 cesarean delivery were assigned 3 points; those who had undergone 2 cesarean deliveries were assigned 4 points; those who had undergone 3 cesarean deliveries were assigned 5 points; and those with no previous operations were assigned 0 points. The preoperative score was recorded for 785 patients. RESULTS: Of the 785 women with complete data, the mean preoperative score was 1.09 +/- 1.51 for AH, 0.75 +/- 0.96 for VH, 1.04 +/- 1.30 for LSH, 1.0 +/- 1.40 for LAVH, and 1.38 +/- 1.52 for TLH. The prevalent scores in the VH were 0 and 1, the LASH and TLH showed a prevalence over VH in the preoperative scores 3 and 4 and AH showed a prevalence over the other methods in the preoperative score 3-8. Intraoperative complications were recorded in 28 of 953 (2.9 %) cases: 10 (35.7 %) cases of VH; 13 (46.4 %) cases of AH; 3 (10.7 %) cases of LSH; 1 (3.6 %) case of LAVH; and 1 (3.6 %) case of TLH. The intraoperative complications appeared to be more frequently with heavier uterine weight showing a significant statically correlation (P < 0,001). Major postoperative complications occurred in 17 of 953 (1.8 %) cases. Minor postoperative complications were recorded in 56 of 953 (5.9 %) hysterectomies. Operation duration, hospital stay and hemoglobin decline correlated significantly with preoperative score (P < 0.001). CONCLUSION: The suggested preoperative score is apparently successful in screening out the high risk patients, despite the low incidence of intra and postoperative complications. The usefulness of the preoperative scoring system is worthy of further development and evaluation. The AH was favored as the 'fallback option' with high preoperative score. PMID- 25534161 TI - Consideration for safe and effective gynaecological laparoscopy in the obese patient. AB - BACKGROUND: The number of obese and morbidly obese patients within the developed world is dramatically increasing within the last 20 years. Apart from demographical changes, obese patients are especially prone to have oestrogen dependent morbidities and neoplasias, of which laparoscopic treatment should be the standard of care. The increasing number of patients with BMI >40 is concerning, making it necessary to summarise considerations for safe and effective Gynaecological Laparoscopic Surgery. CONSIDERATIONS: The sequel to successful laparoscopic surgery in obese patients comprises an interdisciplinary appreciation of laparoscopy. Preoperatively, anaesthetics and medical review are suggested to optimise treatment of comorbidities (i.e. infections and blood sugar levels). Positioning of the patient should consider anti-slip options and pannus fixation to ease laparoscopic access and decrease pressure to the chest. There is no standard port placement in obese patients and landmarks have to be the bony structures of the pelvis and ribs. Retraction of the bowel is essential and mobilisation of the sigmoid with fan retractors or endoloops can accomplish adequate vision. 30 degrees scopes can be considered for vision "around the obstacle". An experienced assistant with anticipation of surgical steps is favourable for successful surgery completion. Intra-operatively, good surgical techniques are essential. Vessel sealing systems reduce the need for instrument changes and may be helpful in following visualised tissue planes. A transvaginal vault closure may be advantageous compared to laparoscopic closure and Endostiches may be preferred to close the fascia of large trocar sites under vision. PMID- 25534162 TI - Ultrasonography-guided multidrug stratification interventional therapy for cesarean scar pregnancy. AB - PURPOSE: To explore the clinical value of ultrasonography-guided multidrug stratification interventional therapy for cesarean scar pregnancy (CSP). METHODS: Aspiration of gestational sac fluid, injection of methotrexate in the sac, injection of homeostatic agent and pituitrin in the uterine muscle layer, and injection of triple anti-inflammatory drugs around the uterus in 12 patients with CSP. The lesion volume, serum beta-hCG level, and blood flow were observed. RESULTS: The mean beta-hCG level continued to decrease posttreatment, and the greatest reduction occurred in week 1. The mean number of days needed for serum beta-hCG values to decrease to normal level was 39.1 +/- 10.1 days. Mass volumes reduced and the mean number of days for the masses to disappear was 24.6 +/- 14.1 days. The blood flow around the lesions continued to decrease. CONCLUSIONS: Ultrasonography-guided multidrug interventional therapy for CSP is a new, safe, effective, minimally invasive method. PMID- 25534163 TI - Sonographic weight estimation in fetal macrosomia: influence of the time interval between estimation and delivery. AB - PURPOSE: To evaluate the influence of the time interval between examination and delivery on the accuracy of sonographic weight estimation (WE) in fetal macrosomia. MATERIALS AND METHODS: 896 singleton pregnancies (birth weight > 4,000 g) with a total of 1,281 sonographic weight estimations were included in this retrospective cohort study. Fetuses were divided into six groups with regard to the time interval between estimation and delivery: group 1: scan-to-delivery interval: 0 days; group 2: scan-to-delivery interval: 1-3 days; group 3: scan-to delivery interval: 4-7 days; group 4: scan-to-delivery interval: 8-14 days; group 5: scan-to-delivery interval: 15-21 days; group 6: scan-to-delivery interval: 22 42 days. The accuracy of WE was compared between five commonly used formulas using means of percentage errors (MPE), random error, medians of absolute percentage errors (MAPE), and proportions of estimates within 10 % of actual birth weight. RESULTS: Significant differences were found between the time interval groups with regard to MAPE and MPE values (p < 0.001). All formulas showed a systematic underestimation of fetal weight (negative MPEs) (p < 0.05). MPE values were closest to zero in time interval group 1 and 2. From group 3 to 6, a continuous decrease was observed. The lowest MAPE was found with the Merz formula in group 1 and 2. Values increased continuously from group 3 to 6. Differences between time interval group one and three did not reach statistical significance. CONCLUSIONS: WE in fetal macrosomia shows the best results when examinations are performed within 7 days before delivery, using the formula of Merz et al. Accuracy significantly decreases after this time period. PMID- 25534165 TI - [Dermatologic emergencies]. PMID- 25534164 TI - Serum endocan concentration in women with pre-eclampsia. AB - PURPOSE: To investigate serum endocan levels in pregnant subjects with and without pre-eclampsia. METHODS: This cross-sectional study was conducted on 49 pregnant women with pre-eclampsia and 32 healthy pregnant women matched for gestational age. Maternal levels of serum endocan were measured with the use of an enzyme-linked immunosorbent assay kit. RESULTS: Mean endocan levels were not significantly different among groups (10.7 +/- 4.5 vs. 10.3 +/- 3.2 ng/mL, p 0.763). Mean uterine artery PI and RI were higher in the pre-eclampsia group (p < 0.001, p < 0.001). Mean endocan levels were negatively correlated with BMI at the time of blood sampling (r = -0.247, p = 0.044). There was no correlations between mean endocan levels and all the others parameters. CONCLUSION: These findings suggest that the role of endocan in the pathogenesis of pre-eclampsia was not related to pre-eclampsia; hence, further studies are needed to investigate the role of endocan in the pathogenesis of pre-eclampsia. PMID- 25534166 TI - Deep inspiration breath-hold technique for left-sided breast cancer: An analysis of predictors for organ-at-risk sparing. AB - To identify anatomic and treatment characteristics that correlate with organ-at risk (OAR) sparing with deep inspiration breath-hold (DIBH) technique to guide patient selection for this technique. Anatomic and treatment characteristics and radiation doses to OARs were compared between free-breathing and DIBH plans. Linear regression analysis was used to identify factors independently predicting for cardiac sparing. We identified 64 patients: 44 with intact breast and 20 postmastectomy. For changes measured directly on treatment planning scans, DIBH plans decreased heart-chest wall length (6.5 vs 5.0cm, p < 0.001), and increased lung volume (1074.4 vs 1881.3cm(3), p < 0.001), and for changes measured after fields are set, they decreased maximum heart depth (1.1 vs 0.3cm, p < 0.001) and heart volume in field (HVIF) (9.1 vs 0.9cm(3), p < 0.001). DIBH reduced the mean heart dose (3.4 vs 1.8Gy, p < 0.001) and lung V20 (19.6% vs 15.3%, p < 0.001). Regression analysis found that only change in HVIF independently predicted for cardiac sparing. We identified patients in the bottom quartile of the dosimetric benefits seen with DIBH and categorized the cause of this "minimal benefit." Overall, 29% of patients satisfied these criteria for minimal benefit with DIBH and the most common cause was favorable baseline anatomy. Only the reduction in HVIF predicted for reductions in mean heart dose; no specific anatomic surrogate for the dosimetric benefits of DIBH technique could be identified. Most patients have significant dosimetric benefit with DIBH, and this technique should be planned and evaluated for all patients receiving left-sided breast/chest wall radiation. PMID- 25534167 TI - Postoperative radiotherapy following mastectomy for patients with left-sided breast cancer: A comparative dosimetric study. AB - The purposes of this article were to compare the biophysical dosimetry for postmastectomy left-sided breast cancer using 4 different radiotherapy (RT) techniques. In total, 30 patients with left-sided breast cancer were randomly selected for this treatment planning study. They were planned using 4 RT techniques, including the following: (1) 3-dimensional conventional tangential fields (TFs), (2) tangential intensity-modulated therapy (T-IMRT), (3) 4 fields IMRT (4F-IMRT), and (4) single arc volumetric-modulated arc therapy (S-VMAT). The planning target volume (PTV) dose was prescribed 50Gy, the comparison of target dose distribution, conformity index, homogeneity index, dose to organs at risk (OARs), tumor control probability (TCP), normal tissue complication probability (NTCP), and number of monitor units (MUs) between 4 plans were investigated for their biophysical dosimetric difference. The target conformity and homogeneity of S-VMAT were better than the other 3 kinds of plans, but increased the volume of OARs receiving low dose (V5). TCP of PTV and NTCP of the left lung showed no statistically significant difference in 4 plans. 4F-IMRT plan was superior in terms of target coverage and protection of OARs and demonstrated significant advantages in decreasing the NTCP of heart by 0.07, 0.03, and 0.05 compared with TFs, T-IMRT, and S-VMAT plan. Compared with other 3 plans, TFs reduced the average number of MUs. Of the 4 techniques studied, this analysis supports 4F IMRT as the most appropriate balance of target coverage and normal tissue sparing. PMID- 25534169 TI - Sleep in psychogenic nonepileptic seizures and related disorders. AB - Psychogenic nonepileptic seizures (PNES), a form of functional neurological symptom disorder (FNSD), are very rarely seen in genuine, electroencephalography (EEG)-confirmed sleep. However, they are more commonly reported as a nocturnal occurrence, likely from a state that is misidentified as sleep (termed by some as "pseudosleep"). Sleep state can be helpful to distinguish FNSD from other neurological disorders. Pseudo-cataplexy, a form of "psychogenic" narcolepsy, "pseudo-parasomnia" and PNES can have a similar presentation. PNES and posttraumatic stress disorder (PTSD) frequently share previously experienced psychological trauma, and therefore the sleep abnormalities found in PTSD may be similarly present in PNES. Future research should use EEG monitoring to evaluate the sleep physiology of patients with FNSD such as PNES, as insights into sleep abnormalities may enable further understanding of the etiology and manifestations of PNES. PMID- 25534168 TI - Utility of propidium monoazide viability assay as a biomarker for a tuberculosis disease. AB - Reliable laboratory diagnosis of tuberculosis (TB), including laboratory biomarkers of cure, remains a challenge. In our study we evaluated the performance of a Propidium Monoazide (PMA) assay for the detection of viable TB bacilli in sputum specimens during anti-TB chemotherapy and its potential use as a TB biomarker. The study was conducted at three centres on 1937 sputum specimens from 310 adult bacteriologically confirmed pulmonary TB patients obtained before commencing anti-TB treatment and at regular intervals afterwards. Performance of the PMA assay was assessed using various readout assays with bacteriology culture results and time to positivity on liquid media used as reference standards. Treatment of sputum with N-acetyl-cysteine was found to be fully compatible with the PMA assay. Good sensitivity and specificity (97.5% and 70.7-80.0%) for detection of live TB bacilli was achieved using the Xpert((r)) MTB/RIF test as a readout assay. Tentative Ct and DeltaCt thresholds for the Xpert((r)) MTB/RIF system were proposed. Good correlation (r = 0.61) between Ct values and time to positivity of TB cultures on liquid media was demonstrated. The PMA method has potential in monitoring bacterial load in sputum specimens and so may have a role as a biomarker of cure in TB treatment. PMID- 25534170 TI - Sexual health communication between cancer survivors and providers: how frequently does it occur and which providers are preferred? AB - BACKGROUND: Sexual health concerns in cancer survivors are often unaddressed by providers. Study objectives were to assess cancer survivors' reported rates of communication with oncology providers about sexual health, preference for such communication with their oncology or primary care providers (PCPs), and factors associated with these communication rates and preferences. METHODS: Sixty-six patients attending a cancer survivorship clinic were asked how often their oncologist addressed and initiated discussion about sexual functioning and whether they wanted their oncologist or PCP to ask about their sexual health. We also assessed whether various sociodemographic characteristics and levels of depression, anxiety, and sexual satisfaction were associated with survivors' sexual health communication rates and preferences. RESULTS: 41% of patients wanted their oncologist to ask about sexual health and 58% of patients wanted their PCP to ask about sexual health. Over 90% of patients reported that their oncologist infrequently addressed sexual health concerns and that their oncologist was unlikely to initiate such discussions. Education level influenced whether patients wanted their oncologist to ask about sexual health. Age, education level, and insurance type influenced whether patients wanted their PCP to ask about sexual health. Levels of depression, anxiety, and sexual satisfaction were not associated with communication rates or preferences. CONCLUSIONS: Patients attending a survivorship clinic reported infrequent communication about sexual health with their oncology providers, despite wanting their providers to ask about sexual health concerns. PMID- 25534171 TI - Active encouragement of older women with urinary incontinence in primary care to undergo diagnosis and treatment: a matched-pair cluster randomized controlled trial. AB - OBJECTIVES: The URINO trial investigated the effect of offering treatment to older women with urinary incontinence in the general population, who had not sought help on their own initiative. STUDY DESIGN: In a cluster randomized trial, 14 general practitioners were matched into pairs and randomly allocated to an intervention or a control group. Women aged >= 55 years registered in the participating practices were asked about urinary incontinence via a postal questionnaire. Patients in the intervention group were assessed and treated whereas patients in the control group received standard care. MAIN OUTCOME MEASURES: Primary outcome was improvement (yes or no) of the severity of symptoms at 12-month follow-up measured with the Incontinence Severity Index. Secondary outcomes were the number of incontinence episodes per day and quality of life. The primary analysis was on an intention-to-treat basis with multiple imputation of missing data. A logistic regression model with correction for cluster randomization was fitted to estimate odds ratios (ORs). RESULTS: At 12 months, the severity of symptoms had improved in more patients in the intervention group (n166) than in the controls (n184) (OR 1.9; 95% CI 1.1-3.3). Also, the number of patients with fewer episodes of incontinence had increased (OR 2.5; 95% CI 1.5 4.1). No between-group differences in changes in quality of life were apparent (p0.14). CONCLUSIONS: It is recommended to encourage women in the general population aged >= 55 years with urinary incontinence to undergo diagnosis and treatment. PMID- 25534172 TI - Chinese medicine treatment for menopausal symptoms in the UK health service: is a clinical trial warranted? AB - OBJECTIVES: The aims of this pilot study were to evaluate treatment effects, ascertain safety and formulate best practice Chinese medicine protocols relevant for London women suffering from menopausal symptoms. STUDY DESIGN: This clinical pilot study employed a case series design within a wider action-based research project. 117 perimenopausal women between 45 and 55 years of age recruited from the general population were treated for menopausal symptoms by six experienced practitioners of Chinese medicine at the Polyclinic of the University of Westminster. Practitioners were instructed to treat as near to their usual practice style as possible. This involved using Chinese herbal medicine and/or acupuncture along with dietary and lifestyle advice. A maximum of 12 treatments over 6 months was allowed per patient. OUTCOME MEASURES: The menopause specific quality of life questionnaire (MenQoL), the Greene climacteric scale, and flushing diaries were used to evaluate treatment outcomes. Liver and kidney function tests were carried out at intake and after 1, 6 and 12 treatments to evaluate the safety particularly in relation to the use of herbal medicines. RESULTS: Patients showed significant improvement across all domains measured by the MenQoL and Greene climacteric scales. Reduction on the MenQoL scale between first and last visit was from 4.31 to 3.27 (p<0.001) and on the Green climacteric scale from 21.01 to 13.00 (p<0.001). Study participants did not reliably complete their flushing diaries. No adverse events or abnormal liver or kidney function values were observed during the course of the study. CONCLUSIONS: Further research that seeks to investigate the effects observed in more detail and to evaluate them against other forms of treatment and/or no-treatment controls is warranted. This could be achieved by way of a pragmatic randomized controlled trial that evaluated Chinese medicine against orthodox medical care. PMID- 25534173 TI - Mechanism for O-O bond formation in a biomimetic tetranuclear manganese cluster- A density functional theory study. AB - Density functional theory calculations have been used to study the reaction mechanism of water oxidation catalyzed by a tetranuclear Mn-oxo cluster Mn4O4L6 (L=(C6H4)2PO4(-)). It is proposed that the O-O bond formation mechanism is different in the gas phase and in a water solution. In the gas phase, upon phosphate ligand dissociation triggered by light absorption, the O-O bond formation starting with both the Mn4(III,III,IV,IV) and Mn4(III,IV,IV,IV) oxidation states has to take place via direct coupling of two bridging oxo groups. The calculated barriers are 42.3 and 37.1 kcal/mol, respectively, and there is an endergonicity of more than 10 kcal/mol. Additional photons are needed to overcome these large barriers. In water solution, water binding to the two vacant sites of the Mn ions, again after phosphate dissociation triggered by light absorption, is thermodynamically and kinetically very favorable. The catalytic cycle is suggested to start from the Mn4(III,III,III,IV) oxidation state. The removal of three electrons and three protons leads to the formation of a Mn4(III,IV,IV,IV)-oxyl radical complex. The O-O bond formation then proceeds via a nucleophilic attack of water on the Mn(IV)-oxyl radical assisted by a Mn bound hydroxide that abstracts a proton during the attack. This step was calculated to be rate-limiting with a total barrier of 29.2 kcal/mol. This is followed by proton-coupled electron transfer, O2 release, and water binding to start the next catalytic cycle. PMID- 25534174 TI - Evaluating laboratory key performance using quality indicators in Alexandria University Hospital Clinical Chemistry Laboratories. AB - BACKGROUND: The performance of clinical laboratories plays a fundamental role in the quality and effectiveness of healthcare. OBJECTIVES: To evaluate the laboratory performance in Alexandria University Hospital Clinical Laboratories using key quality indicators and to compare the performance before and after an improvement plan based on ISO 15189 standards. MATERIALS AND METHODS: The study was carried out on inpatient samples for a period of 7 months that was divided into three phases: phase I included data collection for evaluation of the existing process before improvement (March-May 2012); an intermediate phase, which included corrective, preventive action, quality initiative and steps for improvement (June 2012); and phase II, which included data collection for evaluation of the process after improvement (July 2012-September 2012). RESULTS: In terms of the preanalytical indicators, incomplete request forms in phase I showed that the total number of received requests were 31 944, with a percentage of defected request of 33.66%; whereas in phase II, there was a significant reduction in all defected request items (P<0.001) with a percentage of defected requests of 9.64%. As for the analytical indicators, the proficiency testing accuracy score in phase I showed poor performance of 10 analytes in which total error (TE) exceeded total error allowable (TEa), with a corresponding sigma value of less than 3, which indicates test problems and an unreliable method. The remaining analytes showed an acceptable performance in which TE did not exceed the TEa, with a sigma value of more than 6. Following an intervention of 3 months, the performance showed marked improvement. Error tracking in phase I showed a TE of (5.11%), whereas in phase II it was reduced to 2.48% (P<0.001).For the postanalytical indicators, our results in phase I showed that the percentage of nonreported critical results was 26.07%. In phase II, there was a significant improvement (P<0.001). The percentage of nonreported results was 11.37%, the reasons were either inability to contact the authorized doctor (8.24%), wrong patient identification (1.0%), lack of reporting by lab doctor (1.11%), and finally, lack of reporting by the lab technician (1.03%). CONCLUSION AND RECOMMENDATIONS: Standardization and monitoring of each step in the total testing process is very important and is associated with the most efficient and well organized laboratories. PMID- 25534175 TI - Methicillin-resistant Staphylococcus aureus nasal carriage among primary school aged children from Jordan: prevalence, antibiotic resistance and molecular characteristics. AB - BACKGROUND AND AIM: Colonization with methicillin-resistant Staphylococcus aureus (MRSA) increases the risk for subsequent infections with an increased mortality and morbidity. Children were suggested to be a major asymptomatic reservoir for community-associated (CA) MRSA with an ability to quickly spread the MRSA within community. Therefore, the availability of epidemiological and antibiotic susceptibility data of CA-MRSA will be useful for the infection control and management policies. This study aimed to assess the nasal carriage, molecular characteristics and antibiotic susceptibility of MRSA in primary school-aged children from Jordan. PATIENTS AND METHODS: A total of 210 nasal swabs were collected from children aged 6-11 years. Isolated MRSA and its SCCmec typing, Spa type and PVL (Panton-Valentine Leukociden) toxin were identified following culture, biochemical and PCR. Antibiogram was determined by the disc diffusion method. RESULTS: The prevalence of CA-MRSA was 7.1%. Allergic rhinitis and recent antibiotic exposure were the only significant risk factors for MRSA nasal carriage among children. Resistance to erythromycin, trimethoprim sulfamethoxazole and tetracycline was 33.4, 20 and 13.4%, respectively. All isolates were susceptible to the remaining non-beta-lactam antibiotics used in this study, in particular linezolid and mupirocin. All MRSA isolates were SCCmec type IV and PVL toxin negative and the majority were Spa type t223. CONCLUSION AND RECOMMENDATIONS: This is the first study to assess the MRSA prevalence among children aged 6-11 years in Jordan. The prevalence in community children is within the range compared with other studies in other countries. The antibiogram, SCCmec and Spa types of the isolated MRSA are much similar to what was found previously in Jordan. However, all isolates were PVL toxin negative. The study recommends increasing the public awareness of MRSA and the proper antibiotics dispensing. Future studies to follow-up on the changing epidemiology of the CA MRSA in Jordan are also recommended. PMID- 25534176 TI - Knowledge, attitude, and practices of pregnant women towards antenatal care in primary healthcare centers in Benghazi, Libya. AB - BACKGROUND AND AIM: Many underlying factors influence the capacity of women to survive from complications emerging during pregnancy and childbirth, including women's health and nutritional status starting from childhood and during pregnancy. Also, women's access to and the use of appropriate health services according to their knowledge, attitude, and behavior during pregnancy. This study was designed to assess the knowledge, the attitude, and practices of pregnant women toward antenatal care in primary healthcare centers in Benghazi, Libya. STUDY DESIGN AND PARTICIPANTS: A cross-sectional study was conducted on a sample of 300 pregnant women, who were chosen from three primary healthcare centers with the highest attendance rate of pregnant women in Benghazi, Libya, using a structured interview questionnaire. RESULTS: The highest percentage (85.3%) of pregnant women had a high knowledge score regarding antenatal care, and most of them (96.0%) showed a positive attitude; the highest percentage (76.4%) of pregnant women also had good practice scores.The level of overall knowledge had a significant direct correlation with the practices towards antenatal care (r=0.228, P<=0.001), whereas it had an insignificant correlation with the attitude (r=0.029, P=0.619). CONCLUSION AND RECOMMENDATIONS: The majority of the participants of the study tended to have a high level of knowledge and practices. Also, most of them had a positive attitude towards antenatal care. These findings can be used to plan a customized health intervention program aiming to improve maternal health practices regarding antenatal care and eventually improve the health status of Libyan women. PMID- 25534177 TI - Prevalence and predictors of depression and anxiety among the elderly population living in geriatric homes in Cairo, Egypt. AB - BACKGROUND: Anxiety and depression are common in the elderly and affect their quality of life. The rates of depression and anxiety are higher among those living in institutional settings and are usually undiagnosed. AIM: The aim of the study was to determine the prevalence and predictors of depression, anxiety and mixed form (i.e. depression and anxiety) in the elderly living at geriatric homes. PARTICIPANTS AND METHODS: A cross-sectional study was conducted on 240 elderly participants from four randomly selected geriatric homes in Cairo. A pretested interview questionnaire was used to collect data. A short version of the Geriatric Depression Scale (GDS-15), the Hamilton Anxiety Scale, the Katz scale for Activity of Daily living, the three-item loneliness scale and the Personal Wellbeing Index Scale were used. RESULTS: The prevalence of depression, anxiety and mixed disorder among the studied group were 37.5, 14.2 and 30%, respectively. Old age and the presence of comorbidities were predictors for depression and/or anxiety. Female sex, a lower social class, insufficient income, partial independence and loneliness feeling are significant predictors for depression. Being married and loneliness feeling are significant predictors for anxiety, whereas the functional status is a significant predictor for mixed depression and anxiety. CONCLUSION AND RECOMMENDATIONS: Depression and/or anxiety were found in more than 80% of the studied group. An older age, female sex, insufficient income, a lower social class, a partially independent functional status, the presence of comorbidities, more frequent loneliness feeling and being married or divorced were found to be significant predictors for these problems. This study reflects the need for the screening of the elderly in geriatric homes for depression and/or anxiety, especially among high-risk groups, and developing interventions to prevent and control such problems. PMID- 25534178 TI - Insomnia among community dwelling elderly in Alexandria, Egypt. AB - BACKGROUND: Insomnia is a common problem in the elderly population. Poor sleep quality is associated with decreased memory and concentration, increased risk of falls, cognitive decline, and higher rate of mortality. Inadequate sleep hygiene such as irregular sleep schedules, use of stimulants, and daytime naps may predispose to insomnia. AIM: The aim of this study was to determine the prevalence of insomnia among community dwelling elderly in Alexandria and to assess some of the risk factors and comorbid conditions related to insomnia. PARTICIPANTS AND METHODS: This is a cross-sectional study conducted among 380 elderly people taken from different clubs in Alexandria using a predesigned structured interview questionnaire. Data on sociodemographic characteristics, medical history, and personal and sleeping habits were collected. The Insomnia Severity Index was used to assess insomnia and the Depression Anxiety Stress Scale was used to measure depression, anxiety, and stress. RESULTS: One-third (33.4%) of the elderly suffered from insomnia. On logistic regression, the most independent factors that were significantly associated with insomnia were number of chronic diseases [odds ratio (OR)=7.25 for having >=5 diseases], being female (OR=2.37), anxiety (OR=1.91), watching television in bed before sleeping (OR=1.90), depression (OR=1.74), nocturia (OR=1.13), and daily sunlight exposure (OR=0.57). CONCLUSION AND RECOMMENDATIONS: Insomnia is a common problem among the elderly in Alexandria. Female sex, chronic diseases, mental health problems, and bad sleep hygiene practice increase the risk for insomnia. Improving knowledge among the elderly about the prevalence and risk factors of insomnia could help the development of effective public health prevention and intervention programs for better sleep quality. PMID- 25534179 TI - Seasonal variation and trend of chicken pox in the southern region of Saudi Arabia (2007-2012). AB - INTRODUCTION: Chicken pox is a contagious disease caused by varicella zoster virus. Children are most susceptible to infection. In 1998, the WHO recommended that routine childhood varicella vaccination be considered in countries where the disease is a relatively important public health concern. There are few data on the trends of chicken pox. We aimed to evaluate the trend of chicken pox in Saudi Arabia (KSA) during the period 2007-2012. MATERIALS AND METHODS: Data were collected by retrospective review of the existing anonymous surveillance records and book registries of chicken pox cases at the preventive medicine department of Armed Forces Hospital of the Southern Region of Saudi Arabia from 2007 to 2012. The collected data included the number, age, and sex of registered cases. RESULTS: A seasonal pattern was clearly demonstrated, with peak in March and April. There was also a decreasing trend from 2007 to 2012. Most cases occurred in the age group 4-15 years. The number of infected male patients was a little higher compared with female patients. These results indicate success in controlling the disease in the southern region of Saudi Arabia, which may be attributed to the implementation of public health interventions targeted at reducing infectious diseases (such as the introduction of varicella zoster vaccine in 2008). RECOMMENDATIONS: We recommend that a future study be conducted on the severity of chicken pox infection in adults (hospitalization, complications, and death) and a national survey among adults for the seroprevalence of markers of infection with varicella zoster. PMID- 25534180 TI - Metformin and survival in diabetic patients with breast cancer. AB - BACKGROUND: Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of breast cancer. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an 'insulin sensitizer' because it not only lowers blood glucose, but also reduces the hyperinsulinemia associated with insulin resistance. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there are little clinical data to support this. OBJECTIVE: The aim of the study was to determine whether metformin use was associated with better clinical outcomes in diabetic patients with breast cancer receiving adjuvant chemotherapy. PATIENTS AND METHODS: In this retrospective study, we reviewed the records of 460 consecutive patients with pathologically proved stage I-III breast cancer. These patients received adjuvant chemotherapy during the period from January 2008 to December 2008. Patients were compared by groups that consisted of 25 diabetic patients taking metformin, 14 diabetic patients not taking metformin, and 400 nondiabetic patients. RESULTS: In Kaplan-Meier analysis, metformin use during adjuvant chemotherapy significantly improved survival outcomes in diabetic patients' disease-free survival and overall survival. In multivariate Cox regression, metformin usage was a predictive factor that decreased the risk for breast cancer mortality. CONCLUSION: There is an association between metformin use and better survival outcome in diabetic breast cancer patients who received metformin during adjuvant chemotherapy. The choice of antidiabetic pharmacotherapy may influence prognosis of this group. PMID- 25534181 TI - Assessment of the effectiveness of orange (Citrus reticulata) peel in the recovery of nickel from electroplating wastewater. AB - BACKGROUND: Wastewater discharged from electroplating industry contains different concentrations of heavy metals, which when released into the environment pose a health hazard to human beings. OBJECTIVES: The aim of this study was to assess the effectiveness of orange peel as an adsorbent in the recovery of Nickel (Ni) from electroplating wastewater. MATERIALS AND METHODS: The effectiveness of orange peel as an adsorbent was assessed by determining the optimum conditions of adsorption (adsorbent dose, pH, and contact time), calculating the recovery percentage, and characterizing the orange peel sludge resulting from adsorption/desorption process as being hazardous or not. RESULTS: Under optimum conditions for adsorption, orange peel was found to be an effective adsorbent of Ni from electroplating wastewater. It achieved 59.28% removal of the metal from a solution containing 528 mg/l, at a dose of 60 g/l, at pH 7, and for 1-h contact time. The nickel uptake capacity of orange peel was calculated to be 5.2 mg/g. Using HCl for desorption of adsorbed Ni, a recovery of 44.46% of Ni discharged in the wastewater could be reached. Orange peel resulting from the adsorption/desorption process was characterized as being nonhazardous. CONCLUSION AND RECOMMENDATION: Orange peel was found to be effective in the recovery of nearly half of the amount of Ni discharged in electroplating wastewater. Further studies are required to determine (a) the impact of the recovered NiCl2 solution on the quality of the plated product, (b) the effect of activation of orange peel on the adsorption process, and (c) the number of cycles during which orange peel can be reused as an effective adsorbent. PMID- 25534183 TI - The 'bioscience problem' for nursing students: an integrative review of published evaluations of Year 1 bioscience, and proposed directions for curriculum development. AB - BACKGROUND: The difficulties that nursing students have in learning human biosciences have given cause for concern for over 20 years but the problem remains. OBJECTIVE: To conduct an integrative review of published primary research into the 'bioscience problem', evaluate their outcomes, and provide a contemporary analysis of potential directions for curriculum planners. REVIEW METHODS: A systematic search of electronic databases CINAHL, Medline, British Nursing Index and Google Scholar was conducted for empirical research studies, published between 1990 and 2013, designed to either predict performance of students in bioscience assessments in Year 1 of their studies or identify in course curriculum delivery issues. RESULTS: The search generated nineteen papers that met inclusion criteria. Twelve papers involved predictive factors for bioscience attainment and seven surveyed student views on curriculum issues. Four others that surveyed reflections of later-year students or qualified nurses on Year 1 outcomes were also retained for additional context. Prediction based on pre-admission academic achievement was not reliable. Student factors including age at entry, self-efficacy in science, and having appropriate study skills in particular appear to be confounding factors. In-course influences such as teaching strategy or lecturer skills are also inconsistent and likely to represent confounders operating at local, institutional level. CONCLUSIONS: The integrative review approach enabled analysis of incongruencies between studies that have been a barrier to curriculum development. Sound admissions criteria based on pre-university academic performance show promise in resolving the 'bioscience problem' but will likely be contingent on innovative support early in Year 1 for study skills and the fundamentals of human bioscience, plus attention to local quality assurance for curriculum delivery. PMID- 25534184 TI - Introduction to the Special Issue on Leadership Development for the MCH Workforce. PMID- 25534182 TI - Depression among adults with neurofibromatosis type 1: prevalence and impact on quality of life. AB - Neurofibromatosis type 1 (NF1) carries a significant psychosocial burden for affected individuals. The objective of this study was to measure the prevalence of depressive symptoms among a large sample of adults with NF1 and to quantify the impact of depressive symptoms on quality of life (QoL). This cross-sectional study used an Internet-based questionnaire to collect data from 498 adults who self-reported as having NF1. Using the Center for Epidemiologic Studies Depression (CESD) scale, 55% of all participants (61% of females and 43% of males) scored above 16, indicating a high likelihood of clinical depression. In a multivariate regression model controlling for demographics and potential confounders, depressive symptoms accounted for 32% of the variance in QoL as measured by the Quality of Life Index. This study is the largest to date and found the highest prevalence of depression compared to prior studies. Our data provide more compelling evidence that individuals with NF1 are at increased risk for psychiatric morbidity and suggest that this population should be routinely screened for depression. Because depression was found to be strongly associated with QoL and accounted for nearly one-third of the variance in QoL, it is likely that effectively treating depression may significantly enhance QoL for individuals with NF1. PMID- 25534185 TI - Impact of the clinical ultrasound elective course on retention of anatomical knowledge by second-year medical students in preparation for board exams. AB - Ultrasound has been integrated into a gross anatomy course taught during the first year at an osteopathic medical school. A clinical ultrasound elective course was developed to continue ultrasound training during the second year of medical school. The purpose of this study was to evaluate the impact of this elective course on the understanding of normal anatomy by second-year students. An anatomy exam was administered to students enrolled in the clinical ultrasound elective course before the start of the course and after its conclusion. Wilcoxon signed ranks tests were used to determine whether exam scores changed from the pre-test to the post-test. Scores from two classes of second-year students were analyzed. Students who took the elective course showed significant improvement in the overall anatomy exam score between the pre-test and post-test (P < 0.001). Scores for exam questions pertaining to the heart, abdomen, upper extremity, and lower extremity also significantly improved from the pretest to post-test (P < 0.001), but scores for the neck and eye showed no significant improvement. The clinical ultrasound elective course offered during the second year of medical school provided students with an important review of key anatomical concepts while preparing them for board exams. Our results suggested that more emphasis should be placed on head and neck ultrasound to improve student performance in those areas. Musculoskeletal, abdominal, and heart ultrasound labs were more successful for retaining relevant anatomical information. PMID- 25534186 TI - Virulence profiling and genetic relatedness of Shiga toxin-producing Escherichia coli isolated from humans and ruminants. AB - In the present study the occurrence, genotypic characteristics and relatedness of Shiga toxin-producing Escherichia coli (STEC) isolated from 235 fecal samples of diarrheic children (n=75), sheep (n=80), and cattle (n=80) were investigated. Overall, STEC was found in 4%, 61.2%, and 18.7% of diarrheic children, sheep and cattle, respectively. Three of the four STEC isolates from diarrheic children yielded the stx1/ehly profile. The predominant virulence profile of sheep isolates was stx1/ehly (85.2%), but cattle isolates were heterogeneous. Genetic relatedness and diversity of 36 selected isolates were analyzed by enterobacterial repetitive consensus sequences fingerprinting (ERIC) and phylogrouping. In total, 19 ERIC-types were observed in humans (n=2), sheep (n=5), and cattle (n=12) isolates. The majority of the sheep STEC were assigned into B1 phylogroup (83.3%), but cattle isolates belonged to different phylogroups with B1 predominance. Three human STEC isolates had the major characteristics of sheep isolates but revealed distinct fingerprint. These findings indicate that cattle can potentially carry a diverse group of STEC strains. PMID- 25534188 TI - Ebola: limitations of correcting misinformation. PMID- 25534187 TI - Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. AB - Acute administration of the primary psychoactive constituent of cannabis, Delta-9 tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8mg), CBD (16mg), THC+CBD (8mg+16mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling 'stoned' was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being 'stoned'. CBD did not influence feelings of 'stoned'. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces. PMID- 25534189 TI - Ebola: the battle plan must include specific treatments. PMID- 25534192 TI - Dynamic nuclear polarization of a glassy matrix prepared by solid state mechanochemical amorphization of crystalline substances. AB - A mechanochemical "solvent-free" route is presented for the preparation of solid samples ready to be employed in the Dynamic Nuclear Polarization (DNP). (1)H-DNP build-up curves at 3.46 T as a function of temperature and radical concentration show steady state nuclear polarization of 10% (0.5% TEMPO concentration at 1.75 K). PMID- 25534190 TI - Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. AB - BACKGROUND: In the current epidemic of Ebola virus disease in western Africa, many aid workers have become infected. Some of these aid workers have been transferred to specialised hospitals in Europe and the USA for intensified treatment, providing the potential for unique insight into the clinical course of Ebola virus disease under optimised supportive measures in isolation units. METHODS: A 38-year-old male doctor who had contracted an Ebola virus infection in Sierra Leone was airlifted to University Hospital Frankfurt, Germany, on day 5 after disease onset. Within 72 h of admission to the hospital's high-level isolation unit, the patient developed signs of severe multiorgan failure, including lungs, kidneys, and gastrointestinal tract. In addition to clinical parameters, the diagnostic work-up included radiography, ultrasound, pulse contour cardiac output technology, and microbiological and clinical chemistry analyses. Respiratory failure with pulmonary oedema and biophysical evidence of vascular leak syndrome needed mechanical ventilation. The patient received a 3 day treatment course with FX06 (MChE-F4Pharma, Vienna, Austria), a fibrin-derived peptide under clinical development for vascular leak syndrome. After FX06 administration and concurrent detection of Ebola-virus-specific antibodies and a fall in viral load, vascular leak syndrome and respiratory parameters substantially improved. We gave broad-spectrum empiric antimicrobial therapy and the patient needed intermittent renal replacement therapy. The patient fully recovered. FINDINGS: This case report shows the feasibility of delivery of successful intensive care therapy to patients with Ebola virus disease under biosafety level 4 conditions. INTERPRETATION: The effective treatment of vascular leakage and multiorgan failure by combination of ventilatory support, antibiotic treatment, and renal replacement therapy can sustain a patient with severe Ebola virus disease until virological remission. FX06 could potentially be a valuable agent in contribution to supportive therapy. FUNDING: University Hospital of Frankfurt. PMID- 25534194 TI - T1DM in 2014: Progress towards a bionic pancreas. PMID- 25534195 TI - Genetics: X-linked acrogigantism--genetic characterization of a newly described paediatric growth disorder. PMID- 25534196 TI - Immunology: ILC2s regulate obesity and drive beiging of white adipose tissue. PMID- 25534197 TI - Genetics: New mutations in Cushing disease identified. PMID- 25534198 TI - Treatment of pituitary tumours in 2014: Advances in therapy of adenomas secreting GH, ACTH and TSH. PMID- 25534199 TI - Bone: Fracture risk in the JUPITER trial--statin treatment or not? PMID- 25534200 TI - Obesity: The many faces of leptin--a novel role for leptin signalling in obesity induced hypertension. PMID- 25534201 TI - Loss of c-Cbl E3 ubiquitin ligase activity enhances the development of myeloid leukemia in FLT3-ITD mutant mice. AB - Mutations in the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase (RTK) occur frequently in acute myeloid leukemia (AML), with the most common involving internal tandem duplication (ITD) within the juxtamembrane domain. Fms-like tyrosine kinase 3-ITD mutations result in a mislocalized and constitutively activated receptor, which aberrantly phosphorylates signal transducer and activator of transcription 5 (STAT5) and upregulates the expression of its target genes. c-Cbl is an E3 ubiquitin ligase that negatively regulates RTKs, including FLT3, but whether it can downregulate mislocalized FLT3-ITD remains to be resolved. To help clarify this, we combined a FLT3-ITD mutation with a loss-of function mutation in the RING finger domain of c-Cbl that abolishes its E3 ligase activity. Mice transplanted with hematopoietic stem cells expressing both mutations rapidly develop myeloid leukemia, indicating strong cooperation between the two. Although the c-Cbl mutation was shown to cause hyperactivation of another RTK, c-Kit, it had no effect on enhancing FLT3-ITD protein levels or STAT5 activation. This indicates that c-Cbl does not downregulate FLT3-ITD and that the leukemia is driven by independent pathways involving FLT3-ITD's activation of STAT5 and mutant c-Cbl's activation of other RTKs, such as c-Kit. This study highlights the importance of c-Cbl's negative regulation of wild-type RTKs in suppressing FLT3-ITD-driven myeloid leukemia. PMID- 25534202 TI - La-related protein 4B maintains murine MLL-AF9 leukemia stem cell self-renewal by regulating cell cycle progression. AB - Our recent study identified a nonsense mutation of La-related protein 4B (LARP4B) from whole genome sequencing of a 3-year-old female monozygotic twin pair discordant for MLL-associated acute myeloid leukemia (AML). To study the role of LARP4B in AML, we established a LARP4B-knockdown MLL-AF9 AML mouse model. Using this mouse model, we found that LARP4B knockdown significantly decreased leukemia cells in the peripheral blood, spleen, and bone marrow and prolonged the survival of AML recipient mice. Additional studies showed that LARP4B knockdown reduced leukemia stem cells (LSCs) and impaired the self-renew capacity of LSCs. Cell cycle analysis revealed that LARP4B knockdown arrested more LSCs in the G0 phase. The transcription of the cell cycle inhibitors p16, p19, and p21 and of the lineage-specific transcription factor CCAAT-enhancer-binding protein alpha was increased in the LARP4B-knockdown LSCs. Thus, our results demonstrate that LARP4B plays an important role in the maintenance of LSCs and suggest that LARP4B may regulate the cell cycle of LSCs via suppressing the expression of the cell cycle inhibitors p16, p19, and p21 and the myeloid specific transcription factor CCAAT enhancer-binding protein alpha. PMID- 25534203 TI - A C-terminal mutant of CCAAT-enhancer-binding protein alpha (C/EBPalpha-Cm) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPalpha-Cm. AB - Two types of CCAAT-enhancer-binding protein alpha (C/EBPalpha) mutants are found in acute myeloid leukemia (AML) patients: N-terminal frame-shift mutants (C/EBPalpha-N(m)) generating p30 as a dominant form and C-terminal basic leucine zipper domain mutants (C/EBPalpha-C(m)). We have previously shown that C/EBPalpha K304_R323dup belonging to C/EBPalpha-C(m), but not C/EBPalpha-T60fsX159 belonging to C/EBPalpha-N(m), alone induced AML in mouse bone marrow transplantation (BMT) models. Here we show that various C/EBPalpha-C(m) mutations have a similar, but not identical, potential in myeloid leukemogenesis. Notably, like C/EBPalpha K304_R323dup, any type of C/EBPalpha-C(m) tested (C/EBPalpha-S299_K304dup, K313dup, or N321D) by itself induced AML, albeit with different latencies after BMT; C/EBPalpha-N321D induced AML with the shortest latency. By analyzing the gene expression profiles of C/EBPalpha-N321D- and mock-transduced c-kit(+)Sca 1(+)Lin(-) cells, we identified Csf1r as a gene downregulated by C/EBPalpha N321D. In addition, leukemic cells expressing C/EBPalpha-C(m) exhibited low levels of colony stimulating factor 1 receptor in mice. On the other hand, transduction with C/EBPalpha-N(m) did not influence Csf1r expression in c kit(+)Sca-1(+)Lin(-) cells, implying a unique role for C/EBPalpha-C(m) in downregulating Csf1r. Importantly, Csf1r overexpression collaborated with C/EBPalpha-N321D to induce fulminant AML with leukocytosis in mouse BMT models to a greater extent than did C/EBPalpha-N321D alone. Collectively, these results suggest that C/EBPalpha-C(m)-mediated downregulation of Csf1r has a negative, rather than a positive, impact on the progression of AML involving C/EBPalpha C(m), which might possibly be accelerated by additional genetic and/or epigenetic alterations inducing Csf1r upregulation. PMID- 25534204 TI - Hepatic stellate cell-conditioned myeloid cells provide a novel therapy for prevention of factor VIII antibody formation in mice. AB - A major complication of factor VIII (F.VIII) infusion therapies for the treatment of hemophilia A is the formation of antibodies (inhibitors) against F.VIII, a T cell-dependent, B-cell-mediated process. To date, attempts to inhibit formation of the inhibitors have been limited in success. We have shown that hepatic stellate cells (HSCs) promote the development of myeloid-derived suppressor cells (MDSCs). The HSC-induced MDSCs are potent regulators of T-cell and B-cell responses. Here we show that MDSCs can be propagated from hemophilia A mouse bone marrow cells in coculture with HSCs. These cells exhibit a suppressive phenotype and display a marked ability to inhibit T-cell proliferation induced by dendritic cells in response to F.VIII. MDSCs can also inhibit proliferation and activation of B cells stimulated by immunoglobulin M and interleukin 4. Administration of HSC-induced MDSCs induces CD4(+) T cell and B220(+) B-cell hyporesponsiveness to F.VIII and reduces inhibitor formation in hemophilia A mice. These results suggest that MDSCs could serve as a form of immunotherapy for preventing inhibitor formation via induction of immune tolerance. PMID- 25534205 TI - p38 Mitogen-activated protein kinase inhibition enhances in vitro erythropoiesis of Fanconi anemia, complementation group A-deficient bone marrow cells. AB - Bone marrow failure in Fanconi anemia (FA) has been linked in part to overproduction of inflammatory cytokines, to which FA stem and progenitor cells are hypersensitive. In cell lines and murine models p38 mitogen-activated protein kinase (MAPK)-dependent tumor necrosis factor alpha (TNF-alpha) overexpression can be induced by the Toll-like receptors (TLRs) 4 and 7/8 ligands Lipopolysaccharide (LPS) and R848. Ex vivo exposure of FA stem cells to TNF-alpha suppresses their replication and selects preleukemic clones. Here we show that inhibition of p38 MAPK also reduces TLR4 and 7/8-mediated TNF-alpha production in primary human FA complementation group A (FANCA)-deficient monocytes from nine patients and demonstrate that, while p38 MAPK inhibition also enhances clonal growth of FANCA-deficient erythroid progenitors, the effect was mediated indirectly by the influence of the inhibitor on auxiliary cells, not erythroid colony-forming units themselves. Taken together, these results support the view that inhibition of the p38 MAPK pathway in monocytes may improve hematopoiesis in FANCA patients. PMID- 25534206 TI - A new mechanochemical model: coupled Ginzburg-Landau and Swift-Hohenberg equations in biological patterns of marine animals. AB - In this work the skin coating of some vertebrate marine animals is modeled considering only dermis, epidermis and basal layers. The biological process takes into account: cellular diffusion of the epidermis, diffusion inhibition and long range spatial interaction (nonlocal effect on diffusive dispersal) for cells of dermal tissue. The chemical and physical interactions between dermis and epidermis are represented by coupling quadratic terms and nonlinear terms additional. The model presents an interesting property associated with their gradient form: a connection between some physical, chemical and biological systems. The model equations proposed are solved with numerical methods to study the spatially stable emergent configurations. The spatiotemporal dynamic obtained of the numerical solution of these equations, present similarity with biological behaviors that have been found recently in the cellular movement of chromatophores (as contact-dependent depolarization and repulsion movement between melanophores, xanthophores and iridophores). The numerical solution of the model shows a great variety of beautiful patterns that are robust to changes of boundary condition. The resultant patterns are very similar to the pigmentation of some fish. PMID- 25534207 TI - Patients with atrial fibrillation undergoing percutaneous coronary intervention. Current concepts and concerns: part I. AB - Atrial fibrillation (AF) and coronary artery disease (CAD) often coexist. Both conditions confer an increased risk of acute thrombotic complications. However, the pathogenesis of thrombus development in AF and CAD is different. Coagulation activation is the main pathway in AF, and platelet activation is the hallmark of coronary thrombosis. Antithrombotic prophylaxis is essential in both conditions. In patients with AF undergoing percutaneous coronary intervention (PCI), a combination of oral anticoagulation and antiplatelet therapy is required, which elevates the risk of major bleeding. This has to be balanced against the risk of stroke and stent thrombosis. In the first part of the present review, the prerequisites for antithrombotic management in AF patients undergoing PCI are discussed. We cover the epidemiology of concomitant presentation of AF and CAD as well as differences in the pathogenesis of thrombus formation in both conditions. We evaluate data regarding a variety of antithrombotic regimens including triple therapy in line with stroke and bleeding risk assessment. Overall, triple therapy is often warranted but should be for the shortest possible duration. Although much of the current guidance comes from observational data, well designed, adequately powered randomized clinical trials are emerging to further inform practice in this challenging area. PMID- 25534208 TI - ESRD from lupus nephritis in the United States, 1995-2010. AB - BACKGROUND AND OBJECTIVES: While ESRD from lupus nephritis (ESLN) increased in the United States after the mid-1990s and racial disparities were apparent, current trends are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective US Renal Data System data (n=1,557,117) were used to calculate standardized incidence ratios (standardized to 1995-1996) and outcomes of ESLN (n=16,649). For events occurring after initiation of RRT, follow-up ended on June 30, 2011. RESULTS: Overall ESLN rates (95% confidence intervals [95% CIs]) in 1995-1996 were 3.1 (2.9 to 3.2) cases per million per year. Rates were higher for subgroups characterized by African-American race (11.1 [95% CI, 10.3 to 11.9]); other race (4.9 [95% CI, 4.0 to 5.8]); female sex (4.9 [95% CI, 4.6 to 5.2]); and ages 20-29 years (4.9 [95% CI, 4.4 to 5.4]), 30-44 years (4.6 [95% CI, 4.2 to 5.0]), and 45-64 years (4.0 [95% CI, 3.7 to 4.4]). Standardized incidence ratios for the overall population in subsequent biennia were 1.19 (1.14 to 1.24) in 1997 1998, 1.17 (1.12 to 1.22) in 1999-2000, 1.17 (1.12 to 1.22) in 2001-2002, 1.21 (1.16 to 1.26) in 2003-2004, 1.18 (1.13 to 1.23) in 2005-2006, 1.16 (1.11 to 1.21) in 2007-2008, and 1.05 (1.01 to 1.09) in 2009-2010, respectively. During a median (interquartile range) follow-up of 4.4 (6.3) years, 42.6% of patients with ESLN died, 45.3% were listed for renal transplant, and 28.7% underwent transplantation. Patients with ESLN were more likely than matched controls to be listed for and to undergo transplantation, and mortality rates were similar. Among patients with ESLN, African Americans were less likely to undergo transplantation (adjusted hazard ratio, 0.54 [0.51 to 0.58]) and more likely to die prematurely (adjusted hazard ratio, 1.23 [1.17 to 1.30]). CONCLUSIONS: While ESLN appears to have stopped increasing in the last decade, racial disparities in outcomes persist. PMID- 25534209 TI - Long-term effect of computer-assisted decision support for antibiotic treatment in critically ill patients: a prospective 'before/after' cohort study. AB - OBJECTIVES: Antibiotic resistance has risen dramatically over the past years. For individual patients, adequate initial antibiotic therapy is essential for clinical outcome. Computer-assisted decision support systems (CDSSs) are advocated to support implementation of rational anti-infective treatment strategies based on guidelines. The aim of this study was to evaluate long-term effects after implementation of a CDSS. DESIGN: This prospective 'before/after' cohort study was conducted over four observation periods within 5 years. One preinterventional period (pre) was compared with three postinterventional periods: directly after intensive implementation efforts (post1), 2 years (post2) and 3 years (post3) after implementation. SETTING: Five anaesthesiological managed intensive care units (ICU) (one cardiosurgical, one neurosurgical, two interdisciplinary and one intermediate care) at a university hospital. PARTICIPANTS: Adult patients with an ICU stay of >48 h were included in the analysis. 1316 patients were included in the analysis for a total of 12,965 ICU days. INTERVENTION: Implementation of a CDSS. OUTCOME MEASURES: The primary end point was percentage of days with guideline adherence during ICU treatment. Secondary end points were antibiotic-free days and all-cause mortality compared for patients with low versus high guideline adherence. MAIN RESULTS: Adherence to guidelines increased from 61% prior to implementation to 92% in post1, decreased in post2 to 76% and remained significantly higher compared with baseline in post3, with 71% (p=0.178). Additionally, antibiotic-free days increased over study periods. At all time periods, mortality for patients with low guideline adherence was higher with 12.3% versus 8% (p=0.014) and an adjusted OR of 1.56 (95% CI 1.05 to 2.31). CONCLUSIONS: Implementation of computerised regional adapted guidelines for antibiotic therapy is paralleled with improved adherence. Even without further measures, adherence stayed high for a longer period and was paralleled by reduced antibiotic exposure. Improved guideline adherence was associated with reduced ICU mortality. TRIAL REGISTRATION NUMBER: ISRCTN54598675. PMID- 25534210 TI - Pulmonary tuberculosis among migrants in Shandong, China: factors associated with treatment delay. AB - OBJECTIVE: A timely initiation of treatment is crucial to better control tuberculosis (TB). The aim of this study is to describe treatment delay among migrant patients with TB and to identify factors associated with treatment delay, so as to provide evidence for strategy development and improvement of TB control among migrants in China. DESIGN: A cross-sectional study was conducted in Shandong province of China. A total of 314 confirmed smear positive migrant patients with pulmonary TB were included. Univariate logistic regression was used to analyse the association of variables with treatment delay among migrant patients with TB. A multilogistic regression model was developed to further assess the effect of variables on treatment delay. RESULTS: Of 314 migrant patients with TB, 65.6% experienced treatment delay (>1 day). Household income level, diagnosis symptom severity, understanding of whether TB is curable or not and knowledge about the free TB treatment policy are factors significantly associated with treatment delay. CONCLUSIONS: Economic status and knowledge about TB are key barriers to accessing TB treatment. An integrated policy of carrying out TB-related health education and publicising the free TB treatment policy among migrants is needed. Health insurance schemes for migrants should be modified to make them transferrable and pro-poor. PMID- 25534211 TI - Tobacco smoking and risk of endometriosis: a systematic review and meta-analysis. AB - OBJECTIVE: Since conflicting results have been published on the role of tobacco smoking on the risk of endometriosis, we provide an up-to-date summary quantification of this potential association. DESIGN: We performed a PubMed/MEDLINE search of the relevant publications up to September 2014, considering studies on humans published in English. We searched the reference list of the identified papers to find other relevant publications. Case-control as well as cohort studies have been included reporting risk estimates on the association between tobacco smoking and endometriosis. 38 of the 1758 screened papers met the inclusion criteria. The selected studies included a total of 13,129 women diagnosed with endometriosis. SETTING: Academic hospitals. MAIN OUTCOME MEASURE: Risk of endometriosis in tobacco smokers. RESULTS: We obtained the summary estimates of the relative risk (RR) using the random effect model, and assessed the heterogeneity among studies using the chi(2) test and quantified it using the I(2) statistic. As compared to never-smokers, the summary RR were 0.96 (95% CI 0.86 to 1.08) for ever smokers, 0.95 (95% CI 0.81 to 1.11) for former smokers, 0.92 (95% CI 0.82 to 1.04) for current smokers, 0.87 (95% CI 0.70 to 1.07) for moderate smokers and 0.93 (95% CI 0.69 to 1.26) for heavy smokers. CONCLUSIONS: The present meta-analysis provided no evidence for an association between tobacco smoking and the risk of endometriosis. The results were consistent considering ever, former, current, moderate and heavy smokers, and across type of endometriosis and study design. PMID- 25534213 TI - Epidemiology and outcome of adult out-of-hospital cardiac arrest of non-cardiac origin in Osaka: a population-based study. AB - OBJECTIVES: To evaluate epidemiological characteristics of out-of-hospital cardiac arrests (OHCAs) by detailed non-cardiac cause and factors associated with the outcomes after OHCAs of non-cardiac origin. DESIGN: A prospective, population based observational study. SETTING: The Utstein Osaka Project. PARTICIPANTS: 14,164 adult patients aged >=20 years old with OHCAs due to non-cardiac origin who were resuscitated by emergency-medical-service personnel or bystanders, and then were transported to medical institutions from January 2005 to December 2011. PRIMARY OUTCOME MEASURES: One-month survival after OHCA. Multiple logistic regression analysis was used to assess factors that were potentially associated with the outcome. RESULTS: During the study period, the 1-month survival rate was 5.3% (755/14,164). The proportion of 1-month survival was 6.2% (510/8239) in external causes, 6.5% (94/1148) in respiratory diseases, 0.8% (11/1309) in malignant tumours, 4.9% (55/1114) in strokes and 4.1% (85/2054) in others. As for external causes, the proportion of 1-month survival was 14.3% (382/2670) in asphyxia, 4.2% (84/1999) in hanging, 0.7% (9/1300) in fall, 1.1% (12/1062) in drowning, 1.6% (12/765) in traffic injury, 3.7% (7/187) in drug overuse and 1.6% (4/256) in unclassified external causes. In a multivariate analysis, adults aged <65 years old with arrests witnessed by bystanders, with normal activities of daily living before the arrests, having ventricular fibrillation arrests, having arrests in public places, intravenous fluid levels and early Emergency Medical Service response time were significant predictors for 1-month outcome after OHCAs of non-cardiac origin. The proportion of 1-month survival of all OHCAs of non cardiac origin did not significantly increase (from 4.3% (86/2023) in 2005 to 4.9% (105/2126) in 2011) and the adjusted OR for one-increment of year was 1.01 (95% CI 0.97 to 1.06). CONCLUSIONS: From a large OHCA registry in Osaka, we demonstrated that 1-month survival after OHCAs of non-cardiac origin was poor and stable. PMID- 25534212 TI - Perceived barriers to smoking cessation in selected vulnerable groups: a systematic review of the qualitative and quantitative literature. AB - OBJECTIVES: To identify barriers that are common and unique to six selected vulnerable groups: low socioeconomic status; Indigenous; mental illness and substance abuse; homeless; prisoners; and at-risk youth. DESIGN: A systematic review was carried out to identify the perceived barriers to smoking cessation within six vulnerable groups. DATA SOURCES: MEDLINE, EMBASE, CINAHL and PsycInfo were searched using keywords and MeSH terms from each database's inception published prior to March 2014. STUDY SELECTION: Studies that provided either qualitative or quantitative (ie, longitudinal, cross-sectional or cohort surveys) descriptions of self-reported perceived barriers to quitting smoking in one of the six aforementioned vulnerable groups were included. DATA EXTRACTION: Two authors independently assessed studies for inclusion and extracted data. RESULTS: 65 eligible papers were identified: 24 with low socioeconomic groups, 16 with Indigenous groups, 18 involving people with a mental illness, 3 with homeless groups, 2 involving prisoners and 1 involving at-risk youth. One study identified was carried out with participants who were homeless and addicted to alcohol and/or other drugs. Barriers common to all vulnerable groups included: smoking for stress management, lack of support from health and other service providers, and the high prevalence and acceptability of smoking in vulnerable communities. Unique barriers were identified for people with a mental illness (eg, maintenance of mental health), Indigenous groups (eg, cultural and historical norms), prisoners (eg, living conditions), people who are homeless (eg, competing priorities) and at-risk youth (eg, high accessibility of tobacco). CONCLUSIONS: Vulnerable groups experience common barriers to smoking cessation, in addition to barriers that are unique to specific vulnerable groups. Individual-level, community-level and social network-level interventions are priority areas for future smoking cessation interventions within vulnerable groups. TRIAL REGISTRATION NUMBER: A protocol for this review has been registered with PROSPERO International Prospective Register of Systematic Reviews (Identifier: CRD42013005761). PMID- 25534214 TI - The effect of the National Essential Medicines Policy on health expenditures and service delivery in Chinese township health centres: evidence from a longitudinal study. AB - OBJECTIVES: The government of China has introduced a National Essential Medicines Policy (NEMP) in the new round of health system reform. The objective of this paper is to analyse whether the NEMP can play a role in curbing the rise of medical expenditures without disrupting the availability of healthcare services at township hospitals in China. DESIGN: This study adopted a pre-post treatment control study design. A difference-in-differences method and fixed-effects model for panel data were employed to estimate the effect of the NEMP. SETTING: Chongqing, Jiangsu and Henan Province, in China, in 2009 and 2010. PARTICIPANTS: 296 township health centres. OUTCOME MEASURES: Outcomes for health expenditures were average outpatient drug expenses per visit, average inpatient drug expenses per discharged patient, average outpatient expenses per visit and average inpatient expenses per discharged patient. Outcomes for care delivery were the numbers of visits per certified doctor per day and the numbers of hospitalised patients per certified doctor per day. RESULTS: The township health centres that were enrolled in the NEMP reported 26% (p<0.01) lower drug expenditures for inpatient care. An 11% (p<0.05) decrease in average inpatient expenditures per discharged patient was found following the implementation of the NEMP. The impacts of the NEMP on average outpatient expenditures and outpatient drug expenditures were not statistically significant at the 5% level. No statistically significant associations were found between the NEMP and reduction in quantity of health service delivery. CONCLUSIONS: The NEMP was significant in its effect in reducing inpatient medication and health service expenditures. This study shows no evidence that the quantity of healthcare service declined significantly after introduction of the NEMP over the study period, which suggests that if appropriate matching policies are introduced, the side effects of the NEMP can be counteracted to some degree. Further research including a long-term follow-up study is needed. PMID- 25534215 TI - Historical cancer incidence and mortality assessment in an Illinois community proximal to a former manufactured gas plant. AB - OBJECTIVES: Concern has been raised that the occurrence of cancer may be increased in neighbourhoods around a former manufactured gas plant in Champaign, Illinois, USA. Thus, we compared historical rates of cancer in this area to comparison communities as well as with nationally standardised rates. DESIGN: Retrospective population-based community cancer assessment during 1990-2010. SETTING: Champaign County, Illinois, USA, and zip codes encompassing the location of the former manufactured gas plant to counties that were similar demographically. PARTICIPANTS: Residents of the counties and zip codes studied between 1990 and 2010. MAIN OUTCOME MEASURES: The relative risk (RR) and 95% CI were used to compare cancer incidence and mortality in the areas near the gas compression site to the comparison counties. Standardised incidence ratios (SIRs) were calculated to compare rates in the areas near the gas compression site to expected rates based on overall US cancer rates. RESULTS: Total cancer mortality (RR=0.91, 95% CI 0.88 to 0.94) and incidence (RR=0.95, 95% CI 0.94 to 0.97) were reduced significantly in Champaign County versus the comparison counties. Similarly, a reduced rate of total cancer was observed in analyses by zip code (proximal to the former gas plant) when compared with either similar counties (RR=0.89, 95% CI 0.86 to 0.93) or national standardised rates of cancer (SIR=0.88, 95% CI 0.85 to 0.91). CONCLUSIONS: This historical cancer assessment did not find an increased risk of total cancer or specific cancer types in communities near a former manufactured gas plant site. PMID- 25534217 TI - Plasticity in ploidy: a generalized response to stress. AB - Endoreduplication, the replication of the genome without mitosis, leads to an increase in the cellular ploidy of an organism over its lifetime, a condition termed 'endopolyploidy'. Endopolyploidy is thought to play significant roles in physiology and development through cellular, metabolic, and genetic effects. While the occurrence of endopolyploidy has been observed widely across taxa, studies have only recently begun to characterize and manipulate endopolyploidy with a focus on its ecological and evolutionary importance. No compilation of these examples implicating endoreduplication as a generalized response to stress has thus far been made, despite the growing evidence supporting this notion. We review here the recent literature of stress-induced endopolyploidy and suggest that plants employ endoreduplication as an adaptive, plastic response to mitigate the effects of stress. PMID- 25534216 TI - The efficacy and safety of different anticoagulants on patients with severe sepsis and derangement of coagulation: a protocol for network meta-analysis of randomised controlled trials. AB - INTRODUCTION: Sepsis is the leading cause of mortality in non-cardiological critically ill patients. There are as many as 20 million cases of sepsis annually worldwide, with a mortality rate of around 35%. It has been reported that the dysregulation of haemostatic system due to the interaction between coagulation system and inflammatory response is a strong predictor of mortality in patients with severe sepsis. In this context, several anticoagulants have been evaluated in recent years. However, the results of these studies were inconsistent and even contradictory. In addition, there is insufficient evidence comparing the efficacy and safety of different anticoagulants. The purpose of our study is to carry out a systematic review and network meta-analysis comparing the efficacy and safety of different anticoagulants for severe sepsis based on existing randomised controlled trials (RCTs) and ranking these anticoagulants for practical consideration. METHODS AND ANALYSIS: PubMed, EMBASE and Cochrane Library databases will be systematically searched for eligible studies. Randomised controlled trials (RCT) on anticoagulant therapy for severe sepsis with multiple outcome measures will be included. The Cochrane Risk of Bias Tool will be used to assess the quality of included studies. The primary outcomes are mortality and bleeding events. The secondary outcomes include the length of intensive care stay, the length of hospital stay and duration of mechanical ventilation. Direct pairwise meta-analysis (DMA), indirect treatment comparison meta-analysis (ITC) and network meta-analysis (NMA) will be conducted to compare different anticoagulants. ETHICS AND DISSEMINATION: Ethical approval is not required given that this is a protocol for a systematic review. The protocol of this systematic review will be disseminated in a peer-reviewed journal and presented at a relevant conference. TRIAL REGISTRATION NUMBER: This protocol has been registered in PROSPERO (http://www.crd.york.ac.uk/PROSPERO/) under registration number CRD42014013886. PMID- 25534218 TI - [Hemiconvulsion-hemiplegia-epilepsy syndrome in a girl with adrenogenital syndrome]. AB - Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a very rare condition caused by a fever-associated status epilepticus causing various degrees of hemiplegia and secondary epilepsy affecting children under the age of four. The aetiology is not fully understood. We report a case of a two-year-old girl with adrenogenital syndrome presenting with HHE syndrome in the course of a bacterial septicaemia. PMID- 25534219 TI - [Cholesteatoma must be considered in case of recurrent ear discharge]. AB - This case report describes delayed cholesteatoma detection in a six-year-old boy with recurrent ear discharge since the age of two with no history of vertigo. Removal of the cholesteatoma disclosed facial nerve dehiscence, exposure of the sigmoid sinus and the dura covering the posterior fossa, as well as two fistulas to the semicircular canals. Erosive breaches of extra- to intracranial barriers entail a risk of developing severe intracranial infections, cerebrospinal fluid leakage, irreversible deafness, and loss of vestibular function. Therefore, early diagnosis of cholesteatoma is of utmost importance. PMID- 25534220 TI - [Posttraumatic stress disorder is correlated to irritable bowel syndrome]. AB - Stress influences the whole body, including the gut. Irritable bowel syndrome (IBS) is a syndrome characterized by gastrointestinal symptoms, with the absence of clinical signs. IBS is seen in several psychiatric co-morbidities. Only few studies have examined the association between IBS and posttraumatic stress disorder (PTSD). There are several hypotheses of how this association can be explained, e.g. oxytocin dysregulation, hypothalamic-pituitary-adrenal axis dysfunction, the vulnerability of the patient group, post-infectious irritable bowel and side effects of the medical treatment of PTSD. PMID- 25534221 TI - [Tetanus can still be found in Denmark]. AB - Tetanus (lockjaw) is caused by toxins produced by Clostridium tetani, usually transmitted through contaminated wounds. We describe a case of tetanus in an unvaccinated, previously healthy 78-year-old woman. Twelve days after minor trauma to the right palm, initially treated with tetanus vaccination without immunoglobulins, she developed hoarseness, dyspnoea and difficulties swallowing and opening her mouth. She got severe, painful muscle cramps of especially the truncal muscles requiring large doses of sedatives and complicating respiratory insufficiency. She was treated in intensive care for 33 days, but recovered completely. PMID- 25534222 TI - [Giant xanthomas of all four extremities as a result of hyperlipidaemia in a 24 year-old]. AB - A young male had giant xanthomas of all four extremities. We chose surgical treatment and as a result he was able to wear shoes again. Aggressive treatment of xanthomas and the underlying heart disease is essential in treating young patients. PMID- 25534223 TI - [Perforation of the appendix and observation of Enterobius vermicularis]. AB - A nine-year-old girl was admitted to the paediatric ward due to fever and lower abdomen pain through a day. Acute laparoscopic exploration showed a large necrotic perforation at the distal end of the appendix. During the appendectomy multiple small, live Enterobius vermicularis (pinworms) were observed. The patient was admitted for three days of observation and received relevant treatment with intravenous antibiotics and antihelminthic treatment. The histology showed numerous pinworms in the lumen of the appendix and invasion of the pinworms of the submucosal layer and the wall of the appendix. PMID- 25534224 TI - [Fatal bleeding diarrhoea during dabigatran etexilate therapy]. AB - This is a case report of the fatal course of a 77-year-old bleeding patient in therapy with dabigatran etexilate. The report demonstrates that increased vigilance is needed for elderly patients in risk of decreased renal function. The impaired renal function may be due to seemingly benign conditions such as diarrhoea and low fluid intake during summer months. PMID- 25534225 TI - [Central venous access in adults]. AB - Central venous catheters (CVC) are most commonly used in patients undergoing major surgery, patients admitted to the intensive care unit and in haematological and oncological departments. The placement of a CVC allows life saving and life prolonging treatment. The choice of catheter depends on the disease of the patient, catheter requirement, intended treatment, local preferences and expected period of use. Complications associated with CVC can be severe and potentially life threatening. The incidence of infectious/thrombotic complications and catheter dysfunction increases with the number of indwelling days. PMID- 25534226 TI - Fifty years in neonatology. AB - Neonatology, the care and study of newborn infants, is a 'young' specialty. Over the last 50 years, there have been many advances in the way that neonatologists care for newborn infants, particularly those born preterm, leading to dramatic improvements in mortality. To illustrate these advances, we describe four eras in neonatology from the point of view of the junior hospital doctor. PMID- 25534227 TI - Soluble adenylyl cyclase (sAC) immunostaining distinguishes pseudomelanocytic nests in lichenoid tissue reaction. PMID- 25534228 TI - Role of visual input in the control of dynamic balance: variability and instability of gait in treadmill walking while blindfolded. AB - While vision obviously plays an essential role in orienting and obstacle avoidance, its role in the regulation of dynamic balance is not yet fully understood. The objective of this study was to assess dynamic stability while blindfolded, under optimal conditions that minimized the fear of falling. The hypothesis was that visual deprivation could be compensated for by using other sensory strategies to stabilize gait. One hundred healthy adults (aged 20-69 years) participated in the study. They were previously accustomed to blindfolded treadmill walking wearing a safety harness. Their preferred walking speeds (PWS) were assessed with eyes open (PWSEO) and with eyes closed (blindfolded, PWSEC). Three five-minute tests were performed: (A) normal walking at PWSEO, (B) blindfolded walking at PWSEC, and (C) normal walking at PWSEC. Trunk acceleration was measured with a lightweight inertial sensor. Dynamic stability was assessed by using (1) acceleration root mean square (RMS), which estimates the variability of the signal, and hence, the smoothness of the trunk movement and (2) local dynamic stability (LDS), which reflects the efficiency of the motor control to stabilize the trunk. Although walking at PWSEC with eyes open (comparing conditions A and C) had a slight impact on gait stability (relative difference: RMS +4 %, LDS -5 %), no destabilizing effect of visual deprivation (B vs. C, RMS 4 %, LDS -1 %) was observed. Therefore, it is concluded that when reassuring conditions are offered to individuals while walking, they are able to adopt alternative sensory strategies to control dynamic equilibrium without the help of vision. PMID- 25534231 TI - Laparoscopically assisted ventriculoperitoneal shunt placement: a prospective randomized controlled trial. AB - OBJECT In ventriculoperitoneal (VP) shunt surgery, laparoscopic assistance can be used for placement of the peritoneal catheter. Until now, the efficacy of laparoscopic shunt placement has been investigated only in retrospective and nonrandomized prospective studies, which have reported decreased distal shunt dysfunction rates in patients undergoing laparascopic placement compared with mini-laparotomy cohorts. In this randomized controlled trial the authors compared rates of shunt failure in patients who underwent laparoscopic surgery for peritoneal catheter placement with rates in patients who underwent traditional mini-laparotomy. METHODS One hundred twenty patients scheduled for VP shunt surgery were randomized to laparoscopic surgery or mini-laparotomy for insertion of the peritoneal catheter. The primary endpoint was the rate of overall shunt complication or failure within the first 12 months after surgery. Secondary endpoints were distal shunt failure, overall complication/ failure, duration of surgery and hospitalization, and morbidity. RESULTS The overall shunt complication/failure rate was 15% (9 of 60 cases) in the laparoscopic group and 18.3% (11 of 60 cases) in the mini-laparotomy group (p = 0.404). Patients in the laparoscopic group had no distal shunt failures; in contrast, 5 (8%) of 60 patients in the mini-laparotomy group experienced distal shunt failure (p = 0.029). Intraoperative complications occurred in 2 patients (both in the laparoscopic group), and abdominal pain led to catheter removal in 1 patient per group. Infections occurred in 1 patient in the laparoscopic group and 3 in the mini-laparotomy group. The mean durations of surgery and hospitalization were similar in the 2 groups. CONCLUSIONS While overall shunt failure rates were similar in the 2 groups, the use of laparoscopic shunt placement significantly reduced the rate of distal shunt failure compared with mini-laparotomy. PMID- 25534229 TI - Sequential actions of beta-catenin and Bmp pattern the oral nerve net in Nematostella vectensis. AB - Animal evolution is closely linked to the emergence of the nervous system. At present it is unknown how the basic mechanisms of neural induction and formation of central nervous systems evolved. We addressed this question in Nematostella vectensis, a member of cnidarians, the ancient sister group of bilaterians. We found that beta-catenin signalling is crucial for the early induction of the embryonic nervous system. beta-Catenin activity at the blastopore induces specific neurogenic genes required for development of the oral nervous system. beta-Catenin signalling induces also Bmp signalling, which, at later larval stages, becomes indispensible for the maintenance and asymmetric patterning of the oral nervous system along the primary and secondary (directive) axes. We hypothesize that the consecutive and functionally linked involvement of beta catenin and Bmp signalling in the formation of the cnidarian oral nervous system reflects an ancestral mechanism that evolved before the cnidarian/bilaterian split. PMID- 25534230 TI - Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer. AB - To investigate the prognostic role of the estrogen receptor (ER) in gastric cancer (GC) patients, tumor tissues from 932 patients with advanced GC were assessed for ER expression using immunohistochemistry, and their clinicopathologic features were evaluated. Forty patients (4.3%) had ER expression and they were more frequently associated with diffuse type gastric cancer and shorter disease free survival. Furthermore, we carried out in vitro analysis to evaluate the effect of ER modulation on the proliferation of GC cell lines. Estradiol enhanced proliferation of ER positive GC cells while it did not show any effect on ER negative GC cells. When ER was inhibited by fulvestrant and ER siRNA, estradiol-induced proliferation of ER positive GC cell was suppressed. Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant. Suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis. PMID- 25534232 TI - Incipient speciation with biased gene flow between two lineages of the Western Diamondback Rattlesnake (Crotalus atrox). AB - We used mitochondrial DNA sequence data from 151 individuals to estimate population genetic structure across the range of the Western Diamondback Rattlesnake (Crotalus atrox), a widely distributed North American pit viper. We also tested hypotheses of population structure using double-digest restriction site associated DNA (ddRADseq) data, incorporating thousands of nuclear genome wide SNPs from 42 individuals. We found strong mitochondrial support for a deep divergence between eastern and western C. atrox populations, and subsequent intermixing of these populations in the Inter-Pecos region of the United States and Mexico. Our nuclear RADseq data also identify these two distinct lineages of C. atrox, and provide evidence for nuclear admixture of eastern and western alleles across a broad geographic region. We identified contrasting patterns of mitochondrial and nuclear genetic variation across this genetic fusion zone that indicate partially restricted patterns of gene flow, which may be due to either pre- or post-zygotic isolating mechanisms. The failure of these two lineages to maintain complete genetic isolation, and evidence for partially-restricted gene flow, imply that these lineages were in the early stages of speciation prior to secondary contact. PMID- 25534233 TI - Ethical assessment of hepatitis C virus treatment: The lesson from first generation protease inhibitors. AB - Since chronic hepatitis C has mostly become curable, issues concerning choice and allocation of treatment are of major concern. We assessed the foremost ethical issues in hepatitis C virus therapy with 1st generation protease inhibitors using the personalist ethical framework within the health technology assessment methodology. Our aim was to identify values at stake/in conflict and to support both the physicians' choices in hepatitis C therapy and social (macro-) allocation decision-making. The ethical assessment indicates that: (1) safety/effectiveness profile of treatment is guaranteed if its use is restricted to the patients subgroups who may benefit from it; (2) patients should be carefully informed, particularly on treatment deferral, and widespread information on these therapies should be implemented; (3) since treatment was proven to be cost-effective, its use is acceptable respecting resource macro allocation. Concerning individual (micro-) location criteria: (a) criteria for eligibility to treatment should be clearly identified and updated periodically; (b) information on criteria for eligibility/deferral to treatment for specific patients' subgroups should be made widely known. Interferon-based regimens will disappear from use within the next year, with the introduction of highly effective/tolerable combination regimens of direct-acting antivirals, thus profoundly changing social choices. Nonetheless, our model could support future ethical assessment since the evaluation pertaining ethical domains remains generally applicable. PMID- 25534235 TI - Privileging and credentialing for interventional cardiology procedures. AB - Local institutional-specific credentialing and privileging for procedures is an important process for ensuring the quality of care provided by interventional cardiologists. Recently revised standards for coronary intervention and the blossoming of structural heart disease programs have generated controversy over these processes. How standards are set for credentialing and privileging is poorly understood by most interventional cardiologists, including those responsible for credentialing and privileging. Requirements from The Joint Commission dictate how credentialing and privileging is performed at hospitals they accredit. Physicians must be recredentialed every 2 years at each hospital, with privileges renewed at that time. Hospitals must review quality of physicians even more frequently using Ongoing Professional Practice Evaluations. Hospitals must also evaluate the performance of physicians when they join a hospital staff or when they begin performing new procedures using Focused Professional Practice Evaluations. Cardiology department directors and catheterization laboratory directors are responsible for recredentialing and reprivileging members of their departments. Individual physicians are responsible for cooperating with these processes, and for periodic recertification with specialty boards and governmental agencies. We provide specific guidance to help physicians navigate these processes. PMID- 25534234 TI - Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss. AB - BACKGROUND: Systemic inflammation and oxidative stress are crucial in mediating blood-brain barrier (BBB) integrity loss during sepsis. Simvastatin possess potent anti-inflammation and antioxidation capacity. We sought to elucidate whether an acute bolus of simvastatin could mitigate BBB integrity loss in a rodent model of polymicrobial sepsis. METHODS: A total of 96 adult male rats (200 250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus simvastatin, sham operation, or sham operation plus simvastatin (n = 24 in each group). After maintaining for 24 h, BBB integrity in the surviving rats was determined. RESULTS: CLP significantly induced BBB integrity loss, as grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels in rats receiving CLP were significantly higher than those receiving sham operation. In contrast, grading of Evans blue staining (P = 0.020), BBB permeability to Evans blue dye (P = 0.031), and brain edema levels (P = 0.009) in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP alone. Tight junction proteins claudin-3 and claudin-5 in endothelial cells are major structural components of BBB. Our data revealed that concentrations of claudin-3 and claudin-5 in rats receiving CLP were significantly lower than those receiving CLP plus simvastatin (P = 0.010 and 0.007). Immunohistochemistry further revealed significant fragmentation of claudin-3 and claudin-5 in rats receiving CLP. Moreover, levels of claudin-3 and claudin-5 fragmentation in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP. CONCLUSIONS: Simvastatin mitigates BBB integrity loss in a rodent model of polymicrobial sepsis. PMID- 25534236 TI - Cerebellin 4, a synaptic protein, enhances inhibitory activity and resistance of neurons to amyloid-beta toxicity. AB - Imbalances between excitatory and inhibitory transmissions in the brain anticipate the neuronal damage and death that occur in the neurodegenerative diseases like Alzheimer's disease (AD). We previously showed that amyloid-beta (Abeta), a natural peptide involved in the onset and development of AD, counteracts the neurotrophic activity of the nerve growth factor (NGF) by dampening the gamma-aminobutyric acid (GABA)ergic connectivity of cultured hippocampal neurons. Neuronal plasticity is partly controlled by the NGF-promoted expression of the homologue of enhancer-of-split 1 (Hes1), a transcription factor that regulates the formation of GABAergic synapses. We now show that Hes1 controls the expression of cerebellin 4 (Cbln4), a member of a small family of secreted synaptic proteins, and we present the evidence that Cbln4 plays an essential role in the formation and maintenance of inhibitory GABAergic connections. Cbln4 immunoreactivity was found in the hippocampus, mostly in the dendrites and somata of pyramidal neurons. In the CA1, the hippocampal region where the first neurons degenerate in AD, Cbln4 immunoreactivity was associated with GABAergic synapses (detected by vesicular inhibitory amino acid transporter [VGAT] immunostaining), which appear to surround and embrace the somata of CA1 pyramidal neurons (basket cells). Moreover, significant decreases of Hes1, Cbln4, and VGAT immunoreactivities and messenger RNA expression were found in the hippocampus of a mouse model of AD. We also found that either the overexpression of Cbln4 in cultured hippocampal neurons or the application of recombinant Cbln4 to the cultures increased the number of GABAergic varicosities, rescuing neurons from Abeta-induced death. In contrast, knockdown of Cbln4 gene in cultured neurons was followed by a large reduction of GABAergic connections. Such an effect was reverted by exogenously added Cbln4. These findings suggest a therapeutic potential for Cbln4 in the treatment of AD. PMID- 25534237 TI - Evidence for involvement of steroid receptors and coactivators in neuroepithelial and meningothelial tumors. AB - Steroid receptors such as androgen receptor (AR) and estrogen receptors (ER) ER alpha and ER-beta, and their receptor coactivators (steroid receptor coactivator, SRC) are widely localized in the brain. Although previous studies have investigated the expression of steroid receptors in brain tumors like astrocytoma, the studies on the expression of steroid receptors and SRCs in other brain tumors are lacking. Here, we investigated the expression of AR, ERs, and SRCs in neuroepithelial (medulloblastoma, ependymoma, oligodendroglioma) and meningothelial meningioma using tissue microarray immunohistochemistry. Compared to normal brain tissue, we found that the expression of SRC-1, SRC-3, and ER alpha significantly decreased in meningothelial tumor and neuroepithelial tumor, suggesting that the SRC-1/SRC-3 levels may be regulated by ER-alpha. Moreover, the levels of AR strongly correlated to the levels of ER-beta. Furthermore, correlation was also detected between SRC-3 and AR in neuroepithelial tumor, and between ER-alpha and ER-beta in meningothelial tumor. In addition, the decreased ratio of SRC-1/SRC-3 was associated with an increase of ER-beta in neuroepithelial tumor. These results indicate that expressions of different steroid receptors and activators may be tumor type dependent. While AR, ER-alpha, and ER-beta may be involved in the pathogenesis of meningothelial tumor, SRCs/ER beta axis and SRC-3/AR axis may play a role in the pathogenesis of neuroepithelial tumor. PMID- 25534239 TI - Meta-analysis comparing the safety and efficacy of metastatic colorectal cancer treatment regimens, capecitabine plus irinotecan (CAPIRI) and 5 fluorouracil/leucovorin plus irinotecan (FOLFIRI). AB - The relative efficacy and safety of first-line metastatic colorectal cancer (mCRC) treatment regimens, capecitabine with irinotecan (CAPIRI) and 5 fluorouracil/leucovorin plus irinotecan (FOLFIRI), are not well defined. We identified and subsequently examined seven independent, randomized controlled clinical trials, performing a meta-analysis to compare these two treatment regimens. Using Medline, EMBASE, Cochrane Library (CENTRAL), and the American Society of Clinical Oncology Annual Meeting to search available literature until February 2014, we identified seven studies comparing safety and efficacy of CAPIRI and FOLFIRI in mCRC patients. These studies were pooled and evaluated for rates of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and diarrhea. CAPIRI and FOLFIRI demonstrated similar efficacy outcomes, though CAPIRI was associated with a higher incidence of diarrhea. CAPIRI and FOLFIRI are equally effective options for first-line treatment of mCRC. PMID- 25534238 TI - Incorporation of biomarkers in phase II studies of recurrent glioblastoma. AB - The survival trends for glioblastoma (GBM) patients have remained largely static, reflecting a lack of improvement in the therapeutic options for patients. Less than 5 % of newly diagnosed GBM survives more than 5 years. Tumor relapse is nearly universal and the majority of patients do not respond to further systemic therapy. The results from phase II studies conducted with recurrent GBM patients have not translated to successful confirmatory studies and thus we have reached a significant roadblock in the development of new treatments for patients with recurrent GBM. The development of new, active, and potentially targeted drugs for the treatment of recurrent GBM represents a major unmet need. The incorporation of diagnostic/companion biomarker combinations into the phase II studies and appropriate stratification of the patients is lagging significantly behind other larger cancer groups such as breast, non-small cell lung cancer, and melanoma. We herein carried out a systematic review of the phase II clinical studies conducted in patients with recurrent GBM (2010-2013 inclusive) to assess the degree of biomarker incorporation within the clinical trial design. PMID- 25534240 TI - Transalveolar sinus floor elevation using osteotomes without grafting in severely atrophic maxilla: a 5-year prospective study. AB - OBJECTIVE: The aim of this study was to assess the clinical success of dental implants placed in severely atrophic maxilla (residual bone height <=4 mm) using transalveolar sinus floor elevation (TSFE) without grafting. Furthermore, the implant stability during the healing period was also evaluated. MATERIALS AND METHODS: Twenty five generally healthy patients with 37 Straumann((r)) Standard Plus SLA implants were included in the study. After a modified Summers TSFE without grafting was performed, the smooth collar was embedded 0.5-1 mm beneath the cortical bone level. Follow-ups were conducted at 12, 36, and 60 months after crown placement. Implant survival rate, resonance frequency analysis (RFA), and clinical and radiographic parameters were evaluated. RESULTS: At 5-year follow up, 35 implants fulfilled the survival criteria, representing a 5-year cumulative survival rate of 94.6% at implant level and 92% at subject level. The mean value of implant stability quotient (ISQ) ranged from 67.8 to 72.8, and the lowest values were reached at 4 weeks. No significant difference was found with the passage of time in modified plaque index (P = 0.92), pocket probing depth (P = 0.34), and modified bleeding index (P = 0.4). The average residual bone height was 2.81 mm (SD: 0.74 mm) in this study. The average crestal bone loss (CBL) significantly increased from 0.83 mm at 1-year examination to 1.47 mm at 3-year examination (P < 0.001). The average CBL remained stable at years 3 and 5 (1.47 vs. 1.54 mm, P = 0.083). CONCLUSION: According to the current evidence, it is feasible to place cylindrical implants in severely atrophic maxilla. High survival rate could be achieved following TSFE without grafting at least within 5 year follow-up. PMID- 25534241 TI - Can we predict the failure of electrical cardioversion of acute atrial fibrillation? The FinCV study. AB - BACKGROUND: Data on predictors of failure of electrical cardioversion of acute atrial fibrillation are scarce. METHODS: We explored 6,906 electrical cardioversions of acute (<48 hours) atrial fibrillation in 2,868 patients in a retrospective multicenter study. RESULTS: The success rate of electrical cardioversion was 94.2%. In 26% of unsuccessful cardioversions, the cardioversion was performed successfully later. Antiarrhythmic drug therapy, short (<12 hours) duration of atrial fibrillation episode, advanced age, permanent pacemaker, history of atrial fibrillation episodes within 30 days before cardioversion, and beta-blockers were independent predictors of unsuccessful electrical cardioversion. In the subgroup of patients with cardioversion of the first atrial fibrillation episode (N = 1,411), the short duration of episode (odds ratio [OR] = 2.28; 95% confidence interval [CI] 1.34-3.90, P = 0.003) and advanced age (OR = 1.03; 95% CI 1.02-1.05, P < 0.001) were the only independent predictors of unsuccessful cardioversion. After successful cardioversion, the rate of early (<30 days) clinical recurrence of atrial fibrillation was 17.3%. The index cardioversion being performed due to the first atrial fibrillation episode was the only predictor of remaining in the sinus rhythm. CONCLUSION: A short (<12 hours) duration of acute atrial fibrillation is a significant predictor of unsuccessful cardioversion, especially during the first attack. First atrial fibrillation episode was the only predictor of remaining in the sinus rhythm. PMID- 25534242 TI - A company I can trust? Organizational lay theories moderate stereotype threat for women. AB - Women remain under-represented in the leadership of corporate America. According to stereotype threat theory, this under-representation may persist because women are concerned about being stereotyped in business settings. Three studies investigated whether an entity (fixed), compared with an incremental (malleable), organizational lay theory is threatening for women evaluating a consulting company. Men and women viewed a company mission statement or website containing an entity or incremental theory. Results revealed that women--more so than men- trusted the entity company less than the incremental company. Furthermore, only women's mistrust of the entity company was driven by their expectations about being stereotyped by its management. Notably, when combined with high or low representations of female employees, only organizational lay theories predicted trust. Finally, people's--particularly women's--mistrust of the entity company led them to disengage more before interacting with a representative. Implications for women's experiences and outcomes in workplace settings are discussed. PMID- 25534243 TI - Dispositional envy revisited: unraveling the motivational dynamics of benign and malicious envy. AB - Previous research has conceptualized dispositional envy as a unitary construct. Recently however, episodic envy has been shown to emerge in two qualitatively different forms. Benign envy is related to the motivation to move upward, whereas malicious envy is related to pulling superior others down. In four studies (N = 1,094)--using the newly developed Benign and Malicious Envy Scale (BeMaS)--we show that dispositional envy is also characterized by two independent dimensions related to distinct motivational dynamics and behavioral consequences. Dispositional benign and malicious envy uniquely predict envious responding following upward social comparisons. Furthermore, they are differentially connected to hope for success and fear of failure. Corresponding to these links, dispositional benign envy predicted faster race performance of marathon runners mediated via higher goal setting. In contrast, dispositional malicious envy predicted race goal disengagement. The findings highlight that disentangling the two sides of envy opens up numerous research avenues. PMID- 25534244 TI - Environmental recourse, global warming and a conspicuous anomaly. PMID- 25534245 TI - Sequence search and analysis of gene products containing RNA recognition motifs in the human genome. AB - BACKGROUND: Gene expression is tightly regulated at both transcriptional and post transcriptional levels. RNA-binding proteins are involved in post-transcriptional gene regulation events. They are involved in a variety of functions such as splicing, alternative splicing, nuclear import and export of mRNA, RNA stability and translation. There are several well-characterized RNA-binding motifs present in a whole genome, such as RNA recognition motif (RRM), KH domain, zinc-fingers etc. In the present study, we have investigated human genome for the presence of RRM-containing gene products starting from RRM domains in the Pfam (Protein family database) repository. RESULTS: In Pfam, seven families are recorded to contain RRM-containing proteins. We studied these families for their taxonomic representation, sequence features (identity, length, phylogeny) and structural properties (mapping conservation on the structures). We then examined the presence of RRM-containing gene products in Homo sapiens genome and identified 928 RRM-containing gene products. These were studied for their predicted domain architectures, biological processes, involvement in pathways, disease relevance and disorder content. RRM domains were observed to occur multiple times in a single polypeptide. However, there are 56 other co-existing domains involved in different regulatory functions. Further, functional enrichment analysis revealed that RRM-containing gene products are mainly involved in biological functions such as mRNA splicing and its regulation. CONCLUSIONS: Our sequence analysis identified RRM-containing gene products in the human genome and provides insights into their domain architectures and biological functions. Since mRNA splicing and gene regulation are important in the cellular machinery, this analysis provides an early overview of genes that carry out these functions. PMID- 25534247 TI - Applying developmental threshold models to evolutionary ecology. AB - Process-based models of development predict developmental rates and phenology as a function of physiological responses to multiple dynamic environmental factors. These models can be adapted to analyze diverse processes in evolutionary ecology. By linking models across life stages, they can predict life cycles and generation times. By incorporating fitness, they can identify environmental and physiological factors that limit species distributions. By incorporating population variance, they can investigate mechanisms of intraspecific variation or synchronization. By incorporating genetics, they can predict genotype-specific phenology under diverse climatic scenarios and examine causes and consequences of pleiotropy across life stages. With further development, they have the potential to predict genotype-specific ranges and identify key genes involved in determining phenology and fitness in variable and changing environments. PMID- 25534248 TI - Acquired Capability for Suicide, Pain Tolerance, and Fearlessness of Pain Validation of the Pain Tolerance Scale of the German Capability for Suicide Questionnaire. AB - The interpersonal theory of suicide (Joiner, 2005) postulates that for a serious suicide attempt, one has to possess the acquired capability to commit suicide. Acquired capability includes higher pain tolerance, which is further assumed to comprise both an elevated physical pain tolerance and fearlessness of pain. Recently, the German Capability for Suicide Questionnaire (GCSQ) was validated. The aim of this study is further validation of the GCSQ's Pain Tolerance scale by investigating the scale's association with objective pain tolerance and fearlessness of pain in two undergraduate samples (N = 81; N = 76). Both associations were found indicating a strong criterion validity of the Pain Tolerance scale. PMID- 25534246 TI - Genomics and the challenging translation into conservation practice. AB - The global loss of biodiversity continues at an alarming rate. Genomic approaches have been suggested as a promising tool for conservation practice as scaling up to genome-wide data can improve traditional conservation genetic inferences and provide qualitatively novel insights. However, the generation of genomic data and subsequent analyses and interpretations remain challenging and largely confined to academic research in ecology and evolution. This generates a gap between basic research and applicable solutions for conservation managers faced with multifaceted problems. Before the real-world conservation potential of genomic research can be realized, we suggest that current infrastructures need to be modified, methods must mature, analytical pipelines need to be developed, and successful case studies must be disseminated to practitioners. PMID- 25534249 TI - Evaluation of revised polymerase chain reaction primers for more inclusive quantification of ammonia-oxidizing archaea and bacteria. AB - Ammonia-oxidizing archaea (AOA) and bacteria (AOB) fill key roles in the nitrogen cycle. Thus, well-vetted methods for characterizing their distribution are essential for framing studies of their significance in natural and managed systems. Quantification of the gene coding for one subunit of the ammonia monooxygenase (amoA) by polymerase chain reaction is frequently employed to enumerate the two groups. However, variable amplification of sequence variants comprising this conserved genetic marker for ammonia oxidizers potentially compromises within- and between-system comparisons. We compared the performance of newly designed non-degenerate quantitative polymerase chain reaction primer sets to existing primer sets commonly used to quantify the amoA of AOA and AOB using a collection of plasmids and soil DNA samples. The new AOA primer set provided improved quantification of model mixtures of different amoA sequence variants and increased detection of amoA in DNA recovered from soils. Although both primer sets for the AOB provided similar results for many comparisons, the new primers demonstrated increased detection in environmental application. Thus, the new primer sets should provide a useful complement to primers now commonly used to characterize the environmental distribution of AOA and AOB. PMID- 25534250 TI - Calcium mobilizing second messengers derived from NAD. AB - Nicotinamide adenine dinucleotide (NAD) has been known since a long period of time as co-factor of oxidoreductases. However, in the past couple of decades further roles have been assigned to NAD. Here, metabolism of NAD to the Ca2+ mobilizing second messengers cyclic adenosine diphosphoribose, nicotinic acid adenine dinucleotide phosphate and adenosine diphosphoribose is reviewed. Moreover, the mechanisms of Ca2+ mobilization by these adenine nucleotides and their putative target Ca2+ channels, ryanodine receptors and transient receptor potential channels are discussed. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio applications. PMID- 25534252 TI - Man in a barrel: acute central cord syndrome after minor injury. PMID- 25534253 TI - Structural diversities and related properties of four coordination polymers synthesized from original ligand of 3,3',5,5'-azobenzenetetracarboxylic acid. AB - Four new coordination polymers, namely [Co(H2O2abtc)(bibp)]n (), {[Mn1.5(Oabtc)(H2O)2].(H2bmib)0.5.H2O}n (), {[Cd1.5(O2abtc)].(H2bmib)0.5.2H2O}n (), and {[Cd(nip)(bibp)].0.5H2O}n (),were constructed under solvothermal conditions in the presence of two bis(imidazole) bridging linkers (bimb = 1,4 bis(2-methylimidazol-1-ylmethyl)benzene, bibp = 4,4'-bis(imidazol-1-yl)biphenyl). The unstable azo ligand of 3,3',5,5'-azobenzenetetracarboxylic acid (H4abtc) could be oxidized and resulted in three oxidized derivatives of H4Oabtc (one N atom was oxidized), H4O2abtc (two N atoms were oxidized), and H2nip (one H4abtc was oxidized to two 5-nitroisophthalic acids). Their structures were determined by single-crystal X-ray diffraction and further characterized by elemental analyses, IR spectroscopy, powder X-ray diffraction (PXRD), and thermogravimetric (TG) analysis. Complex exhibited an interestingly 2D + 2D -> 3D parallel entangled network based on 4-connected (4(4).6(2))-sql sheets. Complex was found to be a {Mn3(COO)6} trinuclear SBU based 2D (3,6)-connected (4(3))2(4(6).6(6).8(3))-kgd sheet. While complex displays a {Cd3(COO)8} trinuclear SBUs based 3D (4,8)-connected (4(6))2(4(12).6(12).8(4))-flu network. Complex can be regard as a {Cd2(COO)2} binuclear SBUs based 6-connected (4(4).6(11))-6T8 framework. In addition, the magnetic property of complexes , and the luminescence properties of complexes , were investigated. PMID- 25534251 TI - The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases. AB - Mesenchymal stem cells (MSCs) are a group of stem cells derived from the mesodermal mesenchyme. MSCs can be obtained from a variety of tissues, including bone marrow, umbilical cord tissue, umbilical cord blood, peripheral blood and adipose tissue. Under certain conditions, MSCs can differentiate into many cell types both in vitro and in vivo, including hepatocytes. To date, four main strategies have been developed to induce the transdifferentiation of MSCs into hepatocytes: addition of chemical compounds and cytokines, genetic modification, adjustment of the micro-environment and alteration of the physical parameters used for culturing MSCs. Although the phenomenon of transdifferentiation of MSCs into hepatocytes has been described, the detailed mechanism is far from clear. Generally, the mechanism is a cascade reaction whereby stimulating factors activate cellular signalling pathways, which in turn promote the production of transcription factors, leading to hepatic gene expression. Because MSCs can give rise to hepatocytes, they are promising to be used as a new treatment for liver dysfunction or as a bridge to liver transplantation. Numerous studies have confirmed the therapeutic effects of MSCs on hepatic fibrosis, cirrhosis and other liver diseases, which may be related to the differentiation of MSCs into functional hepatocytes. In addition to transdifferentiation into hepatocytes, when MSCs are used to treat liver disease, they may also inhibit hepatocellular apoptosis and secrete various bioactive molecules to promote liver regeneration. In this review, the capacity and molecular mechanism of MSC transdifferentiation, and the therapeutic effects of MSCs on liver diseases are thoroughly discussed. PMID- 25534254 TI - Hair cortisol in relation to sociodemographic and lifestyle characteristics in a multiethnic US sample. AB - PURPOSE: We investigated the feasibility of obtaining hair samples from men and women at community-based barbershops and hair salons for analysis of cortisol and assessed sociodemographic and lifestyle correlates of hair cortisol concentrations (HCCs). A total of 102 participants completed the study. METHODS: Research staff interviewed participants using a structured questionnaire, and samples of hair were collected. HCCs were determined using liquid chromatography tandem mass spectrometry. Age- and sex-adjusted linear regression models were used to evaluate the association of HCC with covariates. RESULTS: Analyses by race/ethnicity showed highest median HCC in blacks (12.5 [6.9-29.3]) pg/mg) followed by Hispanics (10.7 [5.8-14.9] pg/mg), whites (5.0 [3.8-10.8] pg/mg), and other participants (4.2 [3.3-15.7] pg/mg), P < .01. Current smokers had significantly higher median HCC (11.7 [8.8-18.9] pg/mg) compared with former smokers (4.6 [3.5-14.6] pg/mg) and those who had never smoked (6.9 [4.7-12.8] pg/mg), P = .04. After adjustment for age and sex, geometric mean HCC was 0.72 pg/mg lower in dyed hair compared with hair that was not dyed (beta = -0.72, standard error = 0.30, 95% confidence interval, -1.29 to -0.15, P = .02). CONCLUSIONS: HCC can be assessed in community-based studies. Future HCC studies should consider cosmetic hair treatment, cigarette smoking, and the potential role of psychosocial stressors in the association between race/ethnicity and HCC. PMID- 25534255 TI - (+)- and (-)-petromyroxols: antipodal tetrahydrofurandiols from larval sea lamprey (Petromyzon marinus L.) that elicit enantioselective olfactory responses. AB - (+)- and (-)-petromyroxol [(+)-1 and (-)-1, respectively], two novel tetrahydrofuran (THF)-diol fatty acid enantiomers, were isolated from water conditioned with larval sea lamprey. We herein describe their isolation and subsequent resolution using chiral chromatography. The absolute configuration of each enantiomer was determined by a combination of Mosher ester analysis and comparison with related natural and synthetic products. Electro-olfactogram (EOG) assays indicated that (+)-petromyroxol (1) possesses potent olfactory activity for sea lamprey. PMID- 25534256 TI - Screening and identification of phytotoxic volatile compounds in medicinal plants and characterizations of a selected compound, eucarvone. AB - Screening and identification of phytotoxic volatile compounds were performed using 71 medicinal plant species to find new natural compounds, and the characterization of the promising compound was investigated to understand the mode of action. The volatile compounds from Asarum sieboldii Miq. showed the strongest inhibitory effect on the hypocotyl growth of lettuce seedlings (Lactuca sativa L.cv. Great Lakes 366), followed by those from Schizonepeta tenuifolia Briquet and Zanthoxylum piperitum (L.) DC.. Gas chromatography-mass spectrometry (GC/MS) identified four volatile compounds, alpha-pinene (2,6,6 trimethylbicyclo[3.1.1]hept-2-ene), beta-pinene (6,6-dimethyl-2 methylenebicyclo[3.1.1]heptane), 3-carene (3,7,7-trimethylbicyclo[4.1.0]hept-3 ene), and eucarvone (2,6,6-trimethy-2,4-cycloheptadien-1-one), from A. sieboldii, and three volatile compounds, limonene (1-methyl-4-(1-methylethenyl) cyclohexene), menthone (5-methyl-2-(propan-2-yl)cyclohexan-1-one), and pulegone (5-methyl-2-propan-2-ylidenecyclohexan-1-one), from S. tenuifolia. Among these volatile compounds, eucarvone, menthone, and pulegone exhibited strong inhibitory effects on both the root and shoot growth of lettuce seedlings. Eucarvone-induced growth inhibition was species-selective. Cell death, the generation of reactive oxygen species (ROS), and lipid peroxidation were induced in susceptible finger millet seedlings by eucarvone treatment, whereas this compound (<=158 MUM) did not cause the increase of lipid peroxidation and ROS production in tolerant maize. The results of the present study show that eucarvone can have strong phytotoxic activity, which may be due to ROS overproduction and subsequent oxidative damage in finger millet seedlings. PMID- 25534257 TI - Metabolic shift from withasteroid formation to phenylpropanoid accumulation in cryptogein-cotransformed hairy roots of Withania somnifera (L.) Dunal. AB - Cotransformed hairy roots containing a gene that encodes a fungal elicitor protein, beta-cryptogein, were established in Withania somnifera, a medicinal plant widely used in Indian systems of medicine. To find out whether beta cryptogein protein endogenously elicits the pathway of withasteroid biosynthesis, withaferin A and withanolide A contents along with transcript accumulation of farnesyl pyrophosphate (FPP) synthase, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), and sterol glycosyltransferase (SGT) were analyzed in both cryptogein cotransformed and normal hairy roots of W. somnifera. It was observed that the withaferin A and withanolide A contents were drastically higher in normal hairy roots than cryptogein-cotransformed ones. Similar trends were also observed on the levels of transcript accumulation. Subsequently, the enzyme activity of phenylalanine ammonia lyase (PAL), one of the key enzymes of phenylpropanoid pathway, was measured in both cryptogein-cotransformed and normal hairy roots of W. somnifera along with the levels of PAL transcript accumulation. Upliftment of PAL activity was observed in cryptogein-cotransformed hairy roots as compared to the normal ones, and the PAL expression also reflected a similar trend, i.e., enhanced expression in the cryptogein-cotransformed lines. Upliftment of wall bound ferulic acid accumulation was also observed in the cryptogein-cotransformed lines, as compared to normal hairy root lines. Thus, the outcome of the above studies suggests a metabolic shift from withanolide accumulation to phenylpropanoid biosynthesis in cryptogein-cotransformed hairy roots of W. somnifera. PMID- 25534258 TI - Molecular phylogenetic studies based on rDNA ITS, cpDNA trnL intron sequence and cladode characteristics in nine Protasparagus taxa. AB - The genus Asparagus comprises three subgenera of cladode bearing plants: Protasparagus, Asparagus, and Myrsiphyllum. The interspecific delimitation of the subgenus Protasparagus is ill-defined till date. In the present study, interspecific phylogenetic relationships among nine taxa of Protasparagus based on ribosomal DNA internal transcribed spacer region (ITS1-5.8S-ITS2) sequence and the chloroplast DNA trnL intron sequence conservation with their cladode morphology, anatomy, and stomatal characteristics have been analyzed for the first time. The monophyletic subgenus Protasparagus could be resolved into four strongly supported distinct subclades (I, II, III and IV) suggesting that the rDNA and cpDNA molecular phylogenies are explicitly congruent with the cladode characteristics of the subgenus Protasparagus. The present study also confirms the existing subgeneric classification of the genus Asparagus with the monophyletic origin of the dioecious subgenus Asparagus. The present work brings out phylogenetic and taxonomic relationships within the studied taxa of the subgenus Protasparagus therefore providing important background information for further studies on biogeography of a wide range of species. PMID- 25534259 TI - Morphology and water permeability of red blood cells from green sea turtle (Chelonia mydas). AB - The morphology and diffusional water permeability (P d) of red blood cells (RBCs) from green sea turtle (GST) (Chelonia mydas) are presented for the first time. The RBCs had an ellipsoidal shape with full-axis lengths (diameters): D = 14.4 MUm; d = 10.2 MUm; h = 2.8 MUm. The values of P d (cm s(-1)) were 5.1 * 10(-3) at 15 degrees C, 5.7 * 10(-3) at 20 degrees C, 6.3 * 10(-3) at 25 degrees C, 6.8 * 10(-3) at 30 degrees C, and 7.9 * 10(-3) at 37 degrees C (i.e., significantly higher than in human RBCs in which it was measured to be 4.2 * 10(-3) at 25 degrees C, 5.0 * 10(-3) at 30 degrees C, and 6.2 * 10(-3) at 37 degrees C). There was a lack of inhibition of P d of GST RBCs by p-chloromercuribenzoate (PCMB), a well-known inhibitor of the RBC water channel proteins (WCPs). The activation energy of water diffusion (E a,d) in GST RBCs was 15.0 +/- 1.6 kJ mol( 1) which is lower than the E a,d for human RBCs (~25 kJ mol(-1)). These results indicate that in the membrane of GST RBCs, there were no WCPs that were inhibited by the mercurial reagent, while the lipid bilayer of this membrane is unusually permeable to water. This is likely to be a phylogenetically old trait, like that found in amphibians and even the later birds, all of which have nucleated erythrocytes; and it is also likely to be a result of the animal's adaptation to a herbivorous diet (algae and seagrasses). PMID- 25534260 TI - Pulmonary delivery of anti-inflammatory agents. AB - INTRODUCTION: Respiratory infections and diseases are accompanied by or exhibit inflammation. Recent advances in nanoparticle engineering technology, together with the increased knowledge of inflammatory pathophysiology, have ignited interest in the pulmonary delivery of anti-inflammatory agents (AIAs) to achieve local treatment of pulmonary inflammatory disorders. AREAS COVERED: This review summarizes and discusses the investigated formulation approaches for the pulmonary delivery of AIAs, including: inhalation of actives as suspensions or dry powder formulations, with polymeric micro- and nano-delivery carriers, or within liposomes and lipid nanoparticles. Some recent approaches for targeting AIAs to the pulmonary endothelium have also been reviewed. The discussion focuses on finding out whether the investigated approaches were really able to achieve lung targeting and reduce the side effects associated with the systemic administration of AIAs. EXPERT OPINION: The use of the inhalation route for the pulmonary delivery of AIAs is facing several challenges. Some of the investigated formulation approaches appear to be promising in overcoming these challenges. However, in order to create products that reach patients, more therapeutically oriented studies are still needed to ensure formulation stability, in-vivo sustained release behavior, pulmonary retention, and bypassing lung clearance mechanisms. PMID- 25534262 TI - [A woman with an abdominal mass]. AB - A 46-year-old woman presenting with gastroesophageal reflux complaints, unresponsive to treatment, was found to have a large lower abdominal mass during physical examination. CT-scanning revealed multiple fatty deposits under the right hemidiaphragm, besides the heterogenic lower abdominal mass. The mass and most of the deposits were removed surgically. Histological examination confirmed the diagnosis of a ruptured mature cystic teratoma with intraperitoneal deposits. PMID- 25534263 TI - [E-health: the Skin House]. AB - The Dutch Skin House (www.huidhuis.nl) is an innovative and interactive online platform for patients with skin conditions and others involved, including health care professionals. Currently the platform is primarily aimed at skin disease in children and adolescents. It offers reliable and specialist information about everything from diagnosis to treatment. Patients can also create their own online protected, personal health record in which they can start a diagnostic or treatment plan. The aim of the Skin House is to create transmural continuation of care which is centred upon the patient. Additionally, the Skin House is focusing on scientific research by means of fellow platform the Research House. PMID- 25534264 TI - [Doubts about the new oral anticoagulants]. AB - Recently, The British Medical Journal published three articles and an editorial on the RE-LY trial and the admission to the market of dabigatran. In these publications, concerns were raised regarding the data in this key trial and the registration process. Moreover, a lack of transparency was brought to light about the safety of unmonitored dabigatran use. The results of the RE-LY trial were important evidence for an advice of the Health Council of the Netherlands on the introduction of the new oral anticoagulants (NOACs) in the Netherlands, published in 2012. At present, the question arises whether dabigatran use requires monitoring and what the consequences are for the cost-effectiveness of NOACs. PMID- 25534265 TI - [Diabetologist 2.0; patients perform diabetic tests using a multilingual robot]. AB - Information technology can contribute to diabetes education and stimulate self management particularly in patients at high risk of complications of type 2 diabetes mellitus (T2DM) who are difficult to reach due to language barriers, as a computer can theoretically speak all languages. The patient can use the DiabetesStation to perform diabetic tests themselves. It provides an interactive interface that connects a touch screen playing instruction videos and written and spoken texts with measuring devices and information systems from the referring physicians and the patients. In our pilot study almost all patients were able to measure blood pressure and body weight and to take retinal fundus photographs independently, supervised by a virtual diabetologist on the multilingual DiabetesStation. The effect on quality of care for T2DM patients of applying information technology for virtual supervision must now be tested in primary health care. PMID- 25534266 TI - [e-Health interventions and improvement in treatment adherence]. AB - Poor adherence to medication is one of the most important determinants in the treatment of patients with chronic disorders. e-Health-based interventions may be able to improve treatment adherence. This article gives an overview of the available e-Health interventions and the extent to which they can improve adherence. We searched in the PubMed, Cinahl, PsycInfo, and Embase databases for e-Health interventions that aimed at improving adherence to treatment. Of the 16 included studies, 15 used a website and one used an app. Ten studies showed a significant improvement in treatment adherence by using the intervention. e Health interventions were generally complex. Simple interventions were the most successful in improving treatment adherence. PMID- 25534267 TI - [Telemedicine in Dutch intensive care]. AB - Telemedicine is a way to provide care over a distance. In teleconsultations the intensivist gives advice to his or her colleagues in a remote centre. In tele intensive care (tele-IC) the intensivist makes medical decisions for the remote patients and is fully responsible for the treatment of the intensive care patients in a remote centre. In the USA, 11% of ICU patients are currently being treated by tele-intensivists. Telemedicine has the potential of increasing the continuity of care and of providing expertise to patients in small ICUs where and when needed. In a pilot setting, the OLVG hospital has implemented a tele-ICU for the 3-bed ICU in the MC Zuiderzee hospital. The tele-ICU was set up on 3 December 2010. Although the tele-ICU performed sufficiently, several aspects, such as cost analysis, need clarification before the system can be widely implemented in the Netherlands. PMID- 25534268 TI - [Living a good live with e-health: anticipating ethical consequences and monitoring them]. AB - E-health incorporates a range of digital techniques that are interlinked because they promise to improve people's health and quality of life. The question of how these techniques actually contribute to "living a good live" is not so easy to answer, because scientific, commercial and patients' perspectives all come into play. Research on the unintended consequences of e-health applications clearly shows that it is necessary to anticipate social consequences as early as in the design phase. However, because it is not possible to predict some outcomes, it is also necessary to properly monitor how these techniques affect daily life. It is crucial to pay attention to how these techniques affect people with different educational backgrounds.. Digital techniques have a great capacity to democratise healthcare, but may also unintentionally increase health inequalities. The ethical consequences of e-health applications need to be anticipated and monitored in order to prevent this happening as much as possible. PMID- 25534269 TI - [A limited role for telemedicine on the Dutch intensive care]. AB - The use of telecommunication and information technology has evolved rapidly in many areas. However, it has not kept pace for the organisation of medicine. It can be expected that e-Health will revolutionise the landscape of medicine in the coming years. Due to a shortage of intensivists, with the 24/7 availability of an intensivist in less than 30% of ICUs, tele-ICU care has been introduced in the U.S. with proven beneficial effects on patient outcome and economics. This cannot be compared with the Dutch situation where there are short distances between hospitals, ubiquitous, excellent infrastructure for patient transport and a sufficient number of intensivists. Furthermore, an ICU is not only characterised by its own means in terms of human resources and equipment, but also by the 24/7 availability of other (critical) medical specialities in the hospital. The contribution of tele-ICU is therefore limited in the Netherlands but might play a role for second opinions and consultation for highly specialized expertise. PMID- 25534270 TI - [People with learning disabilities: an overview of the facts]. AB - This article gives a short overview of some basic facts about people with learning disabilities. The prevalence (1-3% worldwide) and stability of the incidence are described, as well as the causes and possible medical comorbidities.- People with learning disabilities are at significantly greater risk of developing cognitive and medical problems compared with the average population. Lastly, an overview of actual chronic care costs is given, as well as actual participation possibilities for people with learning disabilities. PMID- 25534271 TI - [E-learning with journal articles]. AB - E-learning is a popular method of continuous medical education (CME) which is becoming increasingly available to doctors. A specific form of E-learning is an online knowledge test accompanying a journal article. CME accreditation points can be obtained by reading an article and then answering test questions on it. This is a user-friendly form of CME which an increasing number of journals are offering as a service to their readers. The Dutch Journal of Medicine (NTvG) has been offering accredited tests to its readers since 2011. On comparison with international journals, a high standard has been set by the development of a test concept in which interpretation and reflection play integral roles. In the Dutch setting, the concept of the test was developed by professional bodies working closely together and it is a concept that is used as an example to other journals. PMID- 25534272 TI - [Is more expensive always better?]. AB - If left untreated, hepatitis C infection can lead to hepatitis, liver fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, the standard-of-care was peginterferon with ribavirin. Sofosbuvir is a novel direct antiviral acting agent that targets hepatitis C. Administration of sofosbuvir leads to high cure rates, but is very expensive. Here we question the concept of the value-based pricing of sofosbuvir, and argue that the spiralling price of new drugs leads to an unsustainable healthcare system. PMID- 25534274 TI - Coping skill as a moderator between negative life events and suicide among young people in rural China. AB - OBJECTIVE: In the present study, we aim to test whether the approach or the avoidance coping skill can be a moderator between negative life events and suicide, and to test the deficient coping strain in the strain theory. METHOD: This sample comprised 392 suicide cases and 416 community living controls, aged 15-34 years, from 16 rural counties in China. An established psychological autopsy method and a case-control design were used in this study. The 48-item Coping Response Inventory evaluated the degree of coping skills of the people who died by suicide. RESULTS: Results indicated that the avoidance coping skill, but not the approach coping skill, can moderate between negative life events and suicide. CONCLUSION: The low level of the avoidance coping skill may represent a promising variable for screening for suicide risk in rural China. PMID- 25534275 TI - Association between bone mineralization, body composition, and cardiorespiratory fitness level in young Australian men. AB - The critical age for attainment of peak bone mineralization is however 20-30 yr, but few studies have investigated bone mineralization and its association with body composition and cardiorespiratory fitness level in young men. This study aimed to investigate relationships between age, bone mineral measurements, body composition measurements, and cardiorespiratory fitness level in a group of young healthy Australian men. Thirty-five healthy men aged 18-25 yr had anthropometric measures, body composition, and cardiorespiratory fitness level assessed. Bone mineral content was significantly associated with height, body mass and lean mass, and bone mineral density positively correlated with lean mass and body mass. Bone mineral measurements did not correlate with fat mass, percentage of fat mass, or cardiorespiratory fitness level. Age was directly correlated with total body mass, body fat, and percentage of fat mass. Body mineral measurements correlated with lean mass but not with fat mass or with cardiorespiratory fitness in this group of young healthy men. Positive association between body fat and age in such young group suggests that more studies with young men are warranted and may help inform strategies to optimize increase in bone mineral measurements. PMID- 25534273 TI - "Turn-on" protein fluorescence: in situ formation of cyanine dyes. AB - Protein reengineering of cellular retinoic acid binding protein II (CRABPII) has yielded a genetically addressable system, capable of binding a profluorophoric chromophore that results in fluorescent protein/chromophore complexes. These complexes exhibit far-red emission, with high quantum efficiencies and brightness and also exhibit excellent pH stability spanning the range of 2-11. In the course of this study, it became evident that single mutations of L121E and R59W were most effective in improving the fluorescent characteristics of CRABPII mutants as well as the kinetics of complex formation. The readily crystallizable nature of these proteins was invaluable to provide clues for the observed spectroscopic behavior that results from single mutation of key residues. PMID- 25534277 TI - Bears benefit plants via a cascade with both antagonistic and mutualistic interactions. AB - Predators can influence primary producers by generating cascades of effects in ecological webs. These effects are often non-intuitive, going undetected because they involve many links and different types of species interactions. Particularly, little is understood about how antagonistic (negative) and mutualistic (positive) interactions combine to create cascades. Here, we show that black bears can benefit plants by consuming ants. The ants are mutualists of herbivores and protect herbivores from other arthropod predators. We found that plants near bear-damaged ant nests had greater reproduction than those near undamaged nests, due to weaker ant protection for herbivores, which allowed herbivore suppression by arthropod predators. Our results highlight the need to integrate mutualisms into trophic cascade theory, which is based primarily on antagonistic relationships. Predators are often conservation targets, and our results suggest that bears and other predators should be managed with the understanding that they can influence primary producers through many paths. PMID- 25534276 TI - Obesity and Fractures in Postmenopausal Women: A Primary-care Cross-Sectional Study at Santa Maria, Brazil. AB - Obesity and osteoporosis are chronic disorders with increasing prevalence worldwide. The aim of this study was to investigate the association between obesity and fracture in postmenopausal women from Santa Maria, Brazil. A cross sectional study was carried out at Santa Maria (parallel 29 degrees south), Brazil. Postmenopausal women aged >=55 yr who had at least 1 appointment at the primary care in the 2 years before the study were recruited from March 1, 2013 to August 31, 2013. The Global Longitudinal Study of Osteoporosis in Women study questionnaire was applied with permission of The Center for Outcomes Research, University of Massachusetts Medical School. Height and weight were measured according to the World Health Organization protocol. Bone fractures (excluding hand, feet, and head) that occurred after the age of 45 yr were considered as the outcome. Overall, 1057 women completed the study, of whom 984 had body mass index measured. The mean (standard deviation) age and body mass index of the women included in the study were 67.1 (7.6) yr and 29.2 (5.5) kg/m(2), respectively. The prevalence of fractures in obese and nonobese women was similar (17.3% vs 16.0%); 41.4% of all fractures occurred in obese women. Obese postmenopausal women make a substantial contribution to the overall burden of prevalent fractures in this population. Our results provide further evidence in support of the concept that obesity is not protective against fracture. PMID- 25534279 TI - Comment on the reference compound for chemical shift and Knight shift determination of (209)Bi nuclei. AB - Several groups exploring the (209)Bi NMR in solids, including usual insulators, metallic and magnetic materials and recently diamagnetic topological materials, use different standards (usually old and invalid) for chemical shift (Knight shift) determination, ignoring IUPAC recommendations. As a consequence the published shift values exhibit considerable differences (up to 17,500 ppm). PMID- 25534278 TI - Proposal of a post-prostatectomy clinical target volume based on pre-operative MRI: volumetric and dosimetric comparison to the RTOG guidelines. AB - BACKGROUND: Recurrence rates following radiotherapy for prostate cancer in the post-operative adjuvant or salvage setting remain substantial. Previous work from our institution demonstrated that published prostate bed CTV guidelines frequently do not cover the pre-operative MRI defined prostate. Inadequate target delineation may contribute to the high recurrence rates, but increasing target volumes may increase dose to organs at risk. METHODS: We propose guidelines for delineating post-prostatectomy target volumes based upon an individual's co registered pre-operative MRI. MRI-based CTVs and PTVs were compared to those created using the RTOG guidelines in 30 patients. Contours were analysed in terms of absolute volume, intersection volume (Jaccard Index) and the ability to meet the RADICALS and QUANTEC rectal and bladder constraints (tomotherapy IMRT plans with PTV coverage of V98% >=98%). RESULTS: CTV MRI was a mean of 18.6% larger than CTV RTOG: CTV MRI mean 138 cc (range 72.3 - 222.2 cc), CTV RTOG mean 116.3 cc (range 62.1 - 176.6 cc), (p < 0.0001). The difference in mean PTV was only 4.6%: PTV MRI mean 386.9 cc (range 254.4 - 551.2), PTV RTOG mean 370 cc (range 232.3 - 501.6) (p = 0.05). The mean Jaccard Index representing intersection volume between CTVs was 0.72 and 0.84 for PTVs. Both criteria had a similar ability to meet rectal and bladder constraints. Rectal DVH: 77% of CTV RTOG cases passed all RADICALS criteria and 37% all QUANTEC criteria; versus 73% and 40% for CTV MRI (p = 1.0 for both). Bladder DVH; 47% of CTV RTOG cases passed all RADICALS criteria and 67% all QUANTEC criteria, versus 57% and 60% for CTV MRI (p = 0.61for RADICALS, p = 0.79 for QUANTEC). CTV MRI spares more of the lower anterior bladder wall than CTV RTOG but increases coverage of the superior lateral bladder walls. CONCLUSION: CTV contours based upon the patient's co registered pre-operative MRI in the post-prostatectomy setting may improve coverage of the individual's prostate bed without substantially increasing the PTV size or dose to bladder/ rectum compared to RTOG CTV guidelines. Further evaluation of whether the use of pre-operative MRI improves local control rates is warranted. PMID- 25534280 TI - Induction chemotherapy followed by surgery for advanced oesophageal cancer. AB - BACKGROUND: Patients with locoregionally advanced oesophageal tumours or disputable distant metastases are referred for induction chemotherapy with the aim to downstage the tumour before an oesophagectomy is considered. STUDY DESIGN: Patients who underwent induction chemotherapy between January 2005 and December 2012 were identified from an institutional database. Treatment plan was discussed in the multidisciplinary team. Response to chemotherapy was assessed by CT. Survival was calculated using the Kaplan Meier method. Uni- and multivariable analyses were performed to identify prognostic factors for survival. RESULTS: In total 124 patients received induction chemotherapy mainly for locoregionally advanced disease (n = 80). Surgery was withheld in 35 patients because of progressive disease (n = 16) and persistent unresectability (n = 19). The median overall survival of this group was 13 months (IQR: 8-19). The remaining 89 patients underwent surgery of which 13 still had unresectable tumour or distant metastases. Of the 76 patients that underwent an oesophagectomy, 50 patients had tumour free resection margins (66%) with an estimated 5-year survival of 37%. A positive resection margin (HR 4.148, 95% CI 2.298-7.488, p < 0.0001) was associated with a worse survival in univariable analysis, but only pathological lymph node status with increasing hazard ratio's (6.283-10.283, p = 0.001) remained significant after multivariable analysis. CONCLUSION: Induction chemotherapy downstages the tumour and facilitates a radical oesophagectomy in patients with advanced oesophageal cancer. Pathological lymph node status is an independent prognostic factor for overall survival. PMID- 25534282 TI - Medical image segmentation on GPUs--a comprehensive review. AB - Segmentation of anatomical structures, from modalities like computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound, is a key enabling technology for medical applications such as diagnostics, planning and guidance. More efficient implementations are necessary, as most segmentation methods are computationally expensive, and the amount of medical imaging data is growing. The increased programmability of graphic processing units (GPUs) in recent years have enabled their use in several areas. GPUs can solve large data parallel problems at a higher speed than the traditional CPU, while being more affordable and energy efficient than distributed systems. Furthermore, using a GPU enables concurrent visualization and interactive segmentation, where the user can help the algorithm to achieve a satisfactory result. This review investigates the use of GPUs to accelerate medical image segmentation methods. A set of criteria for efficient use of GPUs are defined and each segmentation method is rated accordingly. In addition, references to relevant GPU implementations and insight into GPU optimization are provided and discussed. The review concludes that most segmentation methods may benefit from GPU processing due to the methods' data parallel structure and high thread count. However, factors such as synchronization, branch divergence and memory usage can limit the speedup. PMID- 25534283 TI - Non-invasive evaluation of breast cancer response to chemotherapy using quantitative ultrasonic backscatter parameters. AB - Tumor response to neoadjuvant chemotherapy in patients (n=30) with locally advanced breast cancer (LABC) was examined using quantitative ultrasound. Three ultrasound backscatter parameters, the integrated backscatter coefficient (IBC), average scatterer diameter (ASD), and average acoustic concentration (AAC), were estimated from tumors prior to treatment and at four times during neoadjuvant chemotherapy treatment (weeks 0, 1, 4, 8, and prior to surgery) and compared to ultimate clinical and pathological tumor responses. Results demonstrated that among all parameters, AAC was the best indicator of tumor response early after starting treatment. The AAC parameter increased substantially in treatment responding patients as early as one week after treatment initiation, further increased at week 4, and attained a maximum at week 8. In contrast, the backscatter parameters from non-responders did not show any changes after treatment initiation. The two patient populations exhibited a statistically significant difference in changes of AAC (p<0.001) and ASD (p=0.023) over all treatment times examined. The best prediction of treatment response was achieved with the combination of AAC and ASD at week 4 (82% sensitivity, 100% specificity, and 86% accuracy) of 12-18 weeks of treatment. The survival of patients with responsive ultrasound parameters was higher than patients with non-responsive ultrasound parameters (35 +/- 11 versus 27 +/- 11 months, respectively, p=0.043). This study demonstrates that ultrasound parameters derived from the ultrasound backscattered power spectrum can potentially serve as non-invasive early measures of clinical tumor response to chemotherapy treatments. PMID- 25534281 TI - Proteins directly interacting with mammalian 20S proteasomal subunits and ubiquitin-independent proteasomal degradation. AB - The mammalian 20S proteasome is a heterodimeric cylindrical complex (alpha7beta7beta7alpha7), composed of four rings each composed of seven different alpha or beta subunits with broad proteolytic activity. We review the mammalian proteins shown to directly interact with specific 20S proteasomal subunits and those subjected to ubiquitin-independent proteasomal degradation (UIPD). The published reports of proteins that interact with specific proteasomal subunits, and others found on interactome databases and those that are degraded by a UIPD mechanism, overlap by only a few protein members. Therefore, systematic studies of the specificity of the interactions, the elucidation of the protein regions implicated in the interactions (that may or may not be followed by degradation) and competition experiments between proteins known to interact with the same proteasomal subunit, are needed. Those studies should provide a coherent picture of the molecular mechanisms governing the interactions of cellular proteins with proteasomal subunits, and their relevance to cell proteostasis and cell functioning. PMID- 25534284 TI - Simultaneous genotyping of multiple somatic mutations by using a clamping PNA and PNA detection probes. AB - It has been very difficult to detect and quantify multiple somatic mutations simultaneously in single-tube qPCR. Here, a novel method for simultaneous detection of multiple mutations and a melting curve analysis was developed by using clamping PNA and detection PNA probes. Each PNA probe was designed to have a specific melting temperature by the introduction of gamma-PNA monomer. This technique was successfully applied to the detection of six genotypes in two different mutations of K-RAS at the same time. Such simultaneous analysis of an amplified curve and a melting curve in qPCR can be widely used for the early diagnosis of cancer and determining the prognosis of drug treatments. PMID- 25534285 TI - Hearing disorders in Turner's syndrome: a survey from Iran. AB - Turner syndrome (TS) is one of the most frequently encountered sex-linked chromosomal abnormalities, occurring in one per 2,000 female births. These patients present with short stature and failure to begin puberty. In this syndrome, there are multiple organ abnormalities, including auditory disorders. TS patients were referred to the ENT clinic by a pediatric endocrinologist. A questionnaire was filled out and the patients went through a complete otologic examination. They were then referred to the audiology clinic to undergo audiologic test battery plus high-frequency pure tone audiometry. From a total of 48 ears examined, 11 (22.9 %) had a normal audiometry. Mid-frequency sensorineural hearing loss (SNHL), high-frequency SNHL, combined and mixed hearing loss were diagnosed in 6 (12/5 %), 20 (41/7 %), 6 (12/5 %) and 1 (2/1 %) ear, respectively. Tympanogram results showed normal compliance (A, As, Ad) in the majority of cases. B and C patterns were found in a few cases. Speech discrimination score was normal in all patients whereas speech reception threshold was normal in 92 % of the ears. Audiometry abnormality especially SNHL is common in TS patients, with the high-frequency pattern being the most frequent. PMID- 25534286 TI - The analysis of the maxillary sinus volumes and the nasal septal deviation in patients with antrochoanal polyps. AB - The aim of this study was to evaluate the relationship between the maxillary sinus volumes and the nasal septal deviation angles in patients with antrochoanal polyps (ACP). 76 patients who underwent ACP surgery were included in the study. Of those 36 patients who had multislice computed tomography (MSCT) were evaluated to calculate maxillary sinus volume. The records of paranasal MSCT of 36 healthy people without any paranasal sinus diseases or surgery constituted age- and gender-matched healthy controls. Maxillary sinus volumes and septal deviation angles were calculated using the paranasal MSCT volume-rendering technique. Thirty-six patients in the ACP group were compared with 36 polyp side-matched healthy people. The mean age was 16.6 +/- 6.7 years in both groups. Statistically, the mean value of the maxillary sinus volume was significantly higher in the ACP group compared with the ACP side-matched control group (15.1 +/ 4.6 versus 12.0 +/- 3.5 mm(3)) (p = 0.002). Furthermore, the mean value of the maxillary sinus volume in the non-polyp side (14.2 +/- 4.7 mm(3)) was statistically higher in the ACP group compared with the side-matched control group volume (11.9 +/- 3.8 mm(3)) (p = 0.024). In addition, Fifty-three of 76 ACP patients had septal deviation. While the septal deviation was on the same side with the ACP in 17 patients, it was on the opposite side in 36 patients. In conclusion, the maxillary sinus volumes increased in ACP patients compared with the healthy control group. Many patients had nasal septal deviation on the opposite side of the ACP. PMID- 25534288 TI - Endoscopic Ho laser interstitial therapy for pharyngolaryngeal venous malformations in adults. AB - Many methods have been used to treat venous malformations, including sclerotherapy, laser therapy, and surgery. Nowadays, endoscopic laser surgery has become a popular therapeutic modality for most of pharyngolaryngeal venous malformations. There are various kinds of lasers that have been applied, but Holmium:YAG laser (Ho laser) has not been reported yet. Ho laser is produced by a kind of iraser which is made of yttrium aluminum garnet mixed with holmium, chromium and thulium. Aim of the current work is to evaluate the efficacy and safety of Ho laser interstitial therapy in pharyngolaryngeal venous malformations in adults. The clinical data of 42 patients with pharyngolaryngeal venous malformation treated with endoscopic Ho laser interstitial therapy over a 12-year period were retrospectively reviewed and analyzed. The wave length of Ho laser was 2.1 um and the diameter of optical fiber was 550 um. The pulse energy was 0.5 J and the time of duration was 600 us. The highest output power was 100 W. Outcomes were graded as cure (complete resolution), considerable reduction (>60 80 % reduction), and no obvious change (<50 % reduction). The lesions were well controlled without severe complications. Complete resolution of the lesion was observed in 95.1 % of the patients, while 4.9 % patients showed considerable reduction of the swelling. Complications occurred in 4.8 % of patients. No respiratory troubles or other severe complications occurred. Endoscopic Ho laser interstitial therapy is an effective and safe treatment modality for pharyngolaryngeal venous malformations in adults. PMID- 25534287 TI - The nutritional assessment of head and neck cancer patients. AB - Patients affected by head and neck cancer are particularly at risk for nutritional depletion. The aim of this study was to evaluate the nutritional status of patients affected by head and neck cancer at diagnosis. All adult patients with head and neck cancer between January 2009 and December 2013 were included. The following data were recorded: demographics, tobacco and/or alcohol consumption, weight, height, the reference weight 6 months before the diagnosis, tumor site, tumor stage, and laboratory data. Then, Body mass index (BMI), and Buzby nutrition risk index (NRI) were calculated. Statistical analysis was used to search for associations among multiple variables. 122 men and 22 women were enrolled. As for reference BMI, 77 patients were overweight, whereas just 7 subjects were underweight. At diagnosis, 72 subjects were overweight according to BMI, whereas 52 patients were underweight. Instead, according to NRI, 96 patients were severely malnourished, 42 patients were moderately malnourished, whereas just 6 patients had a normal value of NRI. The assessment of nutrition by BMI excluded from a thorough consideration all overweight and obese patients with head and neck cancer. Instead, NRI correctly identified both undernourished and overweight/obese patients as "malnourished" subjects. PMID- 25534289 TI - A new oxidovanadium(IV) complex of oxodiacetic acid and dppz: spectroscopic and DFT study. Antitumor action on MG-63 human osteosarcoma cell line. AB - The oxidovanadium(IV) complex of oxodiacetic acid (H2ODA) and dppz (dipyrido[3,2 a:2',3'-c] phenazine) of stoichiometry [VO(ODA)(dppz)].3H2O could be synthesized for the first time by reaction between [VO(ODA)(H2O)2] and dppz. It was characterized by infrared and electronic spectroscopies. Its optimized molecular structure was obtained by DFT calculations, as it was impossible to grow single crystals adequate for crystallographic studies. The antitumor action of the complex on MG-63 human osteosarcoma cell line was also investigated. It was found that it caused a concentration-related inhibitory effect in the concentration range between 5 and 25 MUM and diminished the cell viability ca. 45% in the range from 25 to 100 MUM, without dose/response effects in this range. These biological effects are, in general, similar to those previously reported for the related [VO(ODA)(ophen)].1.5H2O complex. PMID- 25534290 TI - Oxidative stress and imbalance of mineral metabolism contribute to lameness in dairy cows. AB - The objective of this study was to investigate correlations between oxidative stress, metabolism of mineral elements, and lameness in dairy cows. Forty multiparous Chinese Holstein dairy cows were selected and divided into two groups (healthy vs lame, n = 20) by gait score. The experiment lasted for 60 days and samples of hair, blood, and hoof were collected at days 0, 30, and 60 of experiment period, individually. Compared with healthy cows, elevation of MDA, CTX-II, COMP levels, and GSSG/GSH ratio together with depletion of SOD and MT levels in the serum were revealed in lame cows. Simultaneously, significant decreased contents of Zn, Cu, and Mn in the serum, hair, and hoof samples were shown in lame cows, but there was no obvious difference in contents of P, Mg, and Ca (except hoof Ca) in the serum, hair, and hoof between healthy and lame cows. In addition, histological examination and the hardness test demonstrated a poor hoof quality in lame cows. In summary, oxidative stress is implicated in the pathogenesis of lameness caused by imbalance of nutrients (especially selective minerals promoting healthy hoof growth) in dairy cows. PMID- 25534291 TI - Effects of terbium (III) on signaling molecules in horseradish. AB - Rare earth elements, especially terbium (Tb), are high-valence heavy metal elements that accumulate in the environment, and they show toxic effects on plants. Signaling molecules regulate many physiological and biochemical processes in plants. How rare earth elements affect signaling molecules remains largely unknown. In the present study, the effects of Tb(3+) on some extracellular and intracellular signaling molecules (gibberellic acid, abscisic acid, auxin, H2O2, and Ca(2+)) in horseradish leaves were investigated by using high-performance liquid chromatography, X-ray energy spectrometry, and transmission electron microscopy, and Tb(3+) was sprayed on the surface of leaves. Tb(3+) treatment decreased the auxin and gibberellic acid contents and increased the abscisic acid content. These changes in the contents of phytohormones (gibberellic acid, abscisic acid, and auxin) triggered excessive production of intracellular H2O2. Consequently, the increase in H2O2 content stimulated the influx of extracellular Ca(2+) and the release of Ca(2+) from Ca(2+) stores, leading to Ca(2+) overload and the resulting inhibition of physiological and biochemical processes. The effects outlined above were more evident with increasing the concentration of Tb(3+) sprayed on horseradish leaves. Our data provide a possible underlying mechanism of Tb(3+) action on plants. PMID- 25534292 TI - Arsenic concentrations and associated health risks in Laccaria mushrooms from Yunnan (SW China). AB - Some species of Laccaria have been known to contain relatively high levels of arsenic in Europe and are used as edible mushrooms in the southwest China. One population of Laccaria proxima and one population of L. vinaceoavellanea as well as topsoil (0-10 cm) they grew on were collected from natural habitats of Yunnan (SW China), while other samples such as Laccaria mushroom samples without soil were purchased from four different local markets in Yunnan. Concentrations of arsenic were determined in fruit bodies of the mushrooms and in the soils by using atomic fluorescence spectrometry to assess potential health risks of these species. The mean arsenic concentrations in caps were 135, 14.1-143, 5.5 and 130 163 mg kg(-1) dry weight (dw) for Laccaria amethystina, Laccaria laccata, L. proxima and L. vinaceoavellanea, respectively. The mean value for bioconcentration factor of arsenic in caps of L. vinaceoavellanea was 29.1 for soil with arsenic content at 5.6 mg kg(-1) dw, which indicate that L. vinaceoavellanea is an accumulator for arsenic. Caps of L. amethystina, L. laccata and L. vinaceoavellanea consumed at a volume of 300 g fresh weight for a single meal in a week can yield an exposure amount of arsenic at 4.1, 0.42-4.3 and 3.9-4.9 mg, respectively. These values are higher than the limit dose for the intake of inorganic arsenic recommended by the Joint FAO/WHO Expert Committee on Food Additives. PMID- 25534293 TI - Differentially regulated miRNAs as prognostic biomarkers in the blood of primary CNS lymphoma patients. AB - Despite improved therapeutic regimens, primary CNS lymphoma (PCNSL) remains a therapeutic challenge. A prognostic classification of PCNSL patients may represent an important step towards optimised patient-adapted therapy. However, only higher age and low Karnofsky Performance Status (KPS) have repeatedly been reported to be associated with shorter overall survival (OS). Here we characterised microRNA (miRNA) fingerprints in the blood of PCNSL patients with short-term survival (STS) versus long-term survival (LTS) to assess their potential as novel prognostic biomarkers. Blood was collected from patients enrolled in the G-PCNSL-SG1 trial, a phase III study for patients with newly diagnosed PCNSL. miRNAs were extracted from the blood and analysed by next generation sequencing. The STS group comprised 20 patients with a median OS of 3 months and was compared to 20 LTS patients with a median OS of 55 months. The cohorts were balanced for age and KPS. Twelve annotated miRNAs were significantly deregulated between the two groups. Among them, miR-151a-5p and miR-151b exhibited the most prominent differences. Importantly, the combination of several miRNA allowed for a good separation between short- and long-term survivors with maximal Area Under Curve (AUC) above 0.75. Besides the known miRNAs we identified putative novel miRNA candidates with potential regulatory influence of PCNSL. Finally, the differential regulation of the most promising candidate miRNAs was confirmed by real-time polymerase chain reaction (PCR) in a validation cohort consisting of 20 STS and LTS patients. In conclusion, peripheral blood miRNA expression patterns hold promise as a prognostic tool in PCNSL patients. PMID- 25534296 TI - Fatal influenza outbreak aboard a sport fishing vessel in San Diego, California. PMID- 25534295 TI - Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. AB - AIM: To perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial. PATIENTS AND METHODS: The international non-inferiority trial enrolled women with ROC that relapsed >6 months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) and stratified by treatment free interval (TFI). In this analysis, patients with a TFI>24 months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety. RESULTS: A total of 259 very platinum sensitive patients were included (n=131, CD; n=128, CP). Median PFS was 12.0 months for the CD arm and 12.3 months for CP [HR=1.05 (95% CI, 0.79-1.40); P=0.73 for superiority] and median OS was 40.2 months for CD and 43.9 for CP [HR=1.18 (95% CI 0.85-1.63); P=0.33 for superiority]. Overall response rates were 42% and 38%, respectively (P=0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P=0.025), nausea (4.8% versus 3.1%; P=0.47), allergic reaction (8% versus 3.1%; P=0.082) sensory neuropathy (4.8% versus 2.3%; P=0.27) and grade 2 alopecia (88% versus 9.2%; P<0.001). Grade 3/4 thrombocytopenia (12.2% versus 3.2%; P=0.007) and mucositis (2.3% versus 0%; P=0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P=0.089). CONCLUSION: CP and CD were equally effective treatment regimens for patients with very platinum sensitive ROC. The favourable risk-benefit profile suggests carboplatin-PLD as treatment of choice for these patients. PMID- 25534294 TI - Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomised, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer. AB - INTRODUCTION: The LUME-Lung 1 trial (NCT00805194; Study 1199.13) demonstrated a significant overall survival (OS) advantage for nintedanib plus docetaxel compared with placebo plus docetaxel as second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and adenocarcinoma histology. Patient reported outcomes (PROs) for symptoms and health-related quality of life (QoL) are reported here. METHODS: PROs were assessed at screening, on Day 1 of each 21 day treatment cycle, at the end of active treatment, and at the first follow-up visit. PRO instruments were the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 supplement, and the EuroQol disease-generic questionnaire (EQ-5D and EQ-VAS). Analyses of PRO items for lung cancer-specific symptoms of cough, dyspnoea and pain were prespecified. RESULTS: Rates of questionnaire completion were high. There was no significant difference in time to deterioration of global health status/QoL, or symptoms of cough, dyspnoea or pain, between the treatment groups for both the overall study population and the adenocarcinoma population. Time to deterioration of some gastrointestinal events was shorter with nintedanib versus placebo. Longitudinal analysis for the adenocarcinoma population showed comparable changes between the groups in symptom scores over time, with numerical differences in favour of nintedanib for cough and pain scales, and significant reductions in some pain items with nintedanib versus placebo. There was no statistically significant difference in EQ-5D or EQ-VAS between the groups. CONCLUSION: The significant OS benefit observed with the addition of nintedanib to docetaxel therapy was achieved with no detrimental effect on patient self-reported QoL. PMID- 25534298 TI - Effect of Tai Chi Chuan on balance in women with multiple sclerosis. AB - OBJECTIVE: To examine the effect of Tai Chi Chuan on balance in women with multiple sclerosis in Iran. DESIGN: 36 women with multiple sclerosis who were members of the Iranian Multiple Sclerosis Society participated in this study. 18 participants were allocated to the intervention group and 18 allocated to the control group. The intervention consisted of Yang style Tai Chi Chuan exercise sessions twice a week for 12 weeks. MAIN OUTCOME MEASURES: This study used a demographic questionnaire and the Berg Balance Scale (BBS) to collect data. RESULTS: After 12 weeks, the mean score of the BBS in the intervention group demonstrated a statistically significant improvement in comparison with baseline status. CONCLUSIONS: The results suggest that Tai Chi Chuan could be used as a safe complementary intervention to increase balance in patients with multiple sclerosis. PMID- 25534297 TI - Adherence to malaria prophylaxis among Peace Corps Volunteers in the Africa region, 2013. AB - BACKGROUND: Although malaria can be prevented with prophylaxis, it is diagnosed in over 100 Africa-region Peace Corps Volunteers annually. This suggests that prophylaxis non-adherence is a problem in these non-immune travelers. METHODS: We investigated Volunteers' knowledge, attitudes, and practices regarding prophylaxis using an internet-based survey during August 19-September 30, 2013. Adherence was defined as taking doxycycline or atovaquone-proguanil daily, or taking mefloquine doses no more than 8 days apart. RESULTS: The survey was sent to 3248 Volunteers. Of 781 whose responses were analyzed, 514 (73%) reported adherence to prophylaxis. The most common reasons for non-adherence were forgetting (n = 530, 90%); fear of long-term adverse effects (LTAEs; n = 316, 54%); and experiencing adverse events that Volunteers attributed to prophylaxis (n = 297, 51%). Two hundred fourteen (27%) Volunteers reported not worrying about malaria. On multivariate analysis controlling for sex and experiencing adverse events Volunteers attributed to prophylaxis, the factor most strongly associated with non-adherence was being prescribed mefloquine (OR 5.4, 95% confidence interval 3.2-9.0). CONCLUSIONS: We found moderate adherence and a prevailing fear of LTAEs among Volunteers. Strategies to improve prophylaxis adherence may include medication reminders, increasing education about prophylaxis safety and malaria risk, and promoting prompt management of prophylaxis side effects. PMID- 25534299 TI - Pilot study of single-day distress screening with the NCCN distress thermometer to evaluate the feasibility of routine distress screening in tertiary cancer center in rural India. PMID- 25534300 TI - Unraveling the mystery of postoperative atrial fibrillation. PMID- 25534301 TI - A time-related parametric risk factor analysis for postoperative atrial fibrillation after heart surgery. AB - OBJECTIVES: Multiple mechanisms may be involved in postoperative atrial fibrillation. Therefore, our objective was to determine the risk factors for postoperative atrial fibrillation as a function of time after coronary artery bypass grafting or valve surgeries to determine which risk factors might predominate at different times. METHODS: Parametric hazard functions were determined for 1583 patients and then in subgroups (coronary artery bypass grafting alone, mitral valve procedure, and aortic valve replacement +/- coronary artery bypass grafting). Multivariable risk factor analyses were performed, and the risk for postoperative atrial fibrillation was estimated. RESULTS: The risk for postoperative atrial fibrillation for all patients was highest immediately postoperatively and at 48 hours. The initial peak risk declined to approximately zero within 18 hours postoperatively. A second peak occurred at 48 hours, followed by a slow decline over the following 4 to 7 days. The time intervals encompassing these peaks were termed phase I and phase II. Predominant risk factors in phase I were older age (relative risk [RR], 1.6; P = .006), longer crossclamp time (RR, 1.3; P = .001), and mitral valve procedure (RR, 2.5; P = .0001). In phase II, these were older age (RR, 3.0; P < .0001), greater weight (RR, 1.6; P < .0001), and Caucasian race (RR, 2.5; P = .006). For patients receiving a mitral valve procedure, the risk for postoperative atrial fibrillation in phase II was higher and remained elevated for as long as 9 days postoperatively in comparison with isolated coronary artery bypass grafting, for which the risk returned to near baseline by postoperative day 6. CONCLUSIONS: Phase I and phase II periods are associated with distinct risk factors; therefore, it is likely that the mechanisms of postoperative atrial fibrillation change over time. PMID- 25534302 TI - When to cross the bridge over troubled water? PMID- 25534303 TI - Inflammation: the classic double-edged sword. PMID- 25534304 TI - Kicking the can down the road ... gently. PMID- 25534305 TI - The early dynamic behavior of lactate is linked to mortality in postcardiotomy patients with extracorporeal membrane oxygenation support: A retrospective observational study. AB - OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is used to support postcardiotomy cardiogenic shock patients. Elevated serum lactate levels might reflect hypoxia in the tissues, which is associated with mortality in critically ill patients. This study examined the association between the early dynamic behavior of lactate and mortality after ECMO support. METHODS: We included 123 adult patients who had undergone cardiac surgery and received venous-arterial ECMO implantation to treat refractory postcardiotomy cardiogenic shock. The dynamic behaviors of lactate within 6 hours and 12 hours after the beginning of the ECMO support were incorporated into 2 regression models. RESULTS: A total of 56% of the patients were successfully weaned from ECMO support. The in-hospital mortality was 65.9% overall. Univariate and multivariate analyses indicated that age (odds ratio [OR]: 1.1 in the 6-hour model; 1.1 in the 12-hour model), gender (female; OR: 5.6 in the 6-hour model; 7.7 in the 12-hour model), mean lactate concentration (OR: 1.1 in the 6-hour model; 1.2 in the 12-hour model) and lactate clearance (OR: 0.5 in the 6-hour model; 0.1 in the 12-hour model) were reliable predictors (P < .05) of in-hospital mortality. The mean lactate concentration (C statistic: 0.71) and lactate clearance (C statistic: 0.72) 12 hours after the initiation of ECMO support provided better prognostic guidance. The mean lactate concentration (OR: 1.2) and lactate clearance (OR: 0.3) were able to predict successful weaning from ECMO in the 12-hour model only. CONCLUSIONS: In addition to age and gender (female), early lactate behaviors, particularly lactate clearance, after ECMO support are highly associated with in-hospital mortality in postcardiotomy patients. Additionally, early lactate behavior is also predictive of successful weaning from ECMO. PMID- 25534307 TI - Science for surgeons: understanding pump thrombogenesis in continuous-flow left ventricular assist devices. PMID- 25534306 TI - Postoperative atrial fibrillation and total dietary antioxidant capacity in patients undergoing cardiac surgery: The Polyphemus Observational Study. AB - OBJECTIVE: Postoperative atrial fibrillation is a major cause of morbidity and mortality for stroke after cardiac surgery. Both systemic inflammation and oxidative stress play a role in the initiation of postoperative atrial fibrillation after cardiac surgery. The possible association between long-term intake of antioxidant-rich foods and postoperative atrial fibrillation incidence was examined in patients undergoing cardiac surgery. METHODS: A total of 217 consecutive patients (74% were men; median age, 68.4 years) undergoing cardiac surgery, mainly coronary artery bypass grafting and valve replacement or repair, were recruited from January 2010 to September 2012. Total antioxidant capacity was measured in foods by the Trolox equivalent antioxidant capacity assay. The European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary total antioxidant capacity assessment. The association among tertiles of dietary total antioxidant capacity and postoperative atrial fibrillation incidence was assessed using multivariable logistic analysis. RESULTS: The overall incidence of total arrhythmias and postoperative atrial fibrillation was 42.4% and 38.2%, respectively. In multivariable analysis, after adjustment for age, gender, use of hypoglycemic drugs, physical activity, education, previous diagnosis of atrial fibrillation, and total energy intake, patients in the highest tertile of dietary total antioxidant capacity had a lower risk of postoperative atrial fibrillation than patients in the 2 lowest tertiles (odds ratio, 0.46; 95% confidence interval, 0.22-0.95; P = .048). A restricted cubic spline transformation confirmed the nonlinear relationship between total antioxidant capacity (in continuous scale) and postoperative atrial fibrillation (P = .023). When considering only coronary artery bypass grafting, valve replacement/repair, and combined surgeries, the protective effect on postoperative atrial fibrillation of a diet rich in antioxidants was confirmed. CONCLUSIONS: Long-term consumption of antioxidant rich foods is associated with a reduced incidence of postoperative atrial fibrillation in patients undergoing cardiac surgery. PMID- 25534308 TI - Successful repair of a variant of mitral arcade. PMID- 25534309 TI - Mediterranean-style diet to prevent postoperative atrial fibrillation: Role of antioxidants? PMID- 25534310 TI - Out & Online; effectiveness of a tailored online multi-symptom mental health and wellbeing program for same-sex attracted young adults: study protocol for a randomised controlled trial. AB - BACKGROUND: Same-sex attracted young adults have been found to experience higher rates of mental health problems and greater difficulties in accessing specialist mental health care services compared to their heterosexual peers. Internet-based mental health interventions have the potential to be more engaging and accessible to young adults compared to those delivered face-to-face. However, they are rarely inclusive of lesbian women and gay men. Thus, the current study aims to evaluate the effectiveness of an online mental health and wellbeing program, Out & Online (http://www.outandonline.org.au), in comparison to a wait-list control group, for reducing anxiety and depressive symptoms in same-sex attracted young adults aged between 18 and 25 years. METHODS/DESIGN: We are recruiting, through media and community organisations, 200 same-sex attracted young adults with anxiety and/or depressive symptoms and mild to moderate psychological distress (Kessler-10 score between 16 to 21). Participants will be randomly allocated to the intervention (the online program) or the wait-list control group based on a permuted blocked randomisation method to allow for stratification by gender. Participants in the intervention group will receive a tailored program for up to three types of mental health difficulties simultaneously. The primary outcome of anxiety and/or depressive symptoms, and secondary outcomes related to psychological distress, wellbeing and health behaviour will be measured at pre intervention (0 week), post-intervention (8 weeks) and at a 3-month follow-up (20 weeks). DISCUSSION: This online mental health and wellbeing program will be one of the first online interventions to be designed specifically to be relevant for same-sex attracted individuals. If the program is found to be effective it will improve access to specialist same-sex attracted-relevant mental health services for young adults and will facilitate wellbeing outcomes for these individuals. This program will also be a significant development in the delivery of tailored interventions that target multiple types of mental health conditions simultaneously. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12611000700932. Date registered: 7 July 2011. PMID- 25534311 TI - Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency. AB - Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency (MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations. PMID- 25534313 TI - Response to the letter to the editor by Barry K. Komisaruk "re: Puppo V, Puppo G. 2014. Anatomy of sex: Revision of the new anatomical terms used for the clitoris and the female orgasm by sexologists". PMID- 25534314 TI - Application of a gender-based approach to conducting a community health assessment for rural women in Southern Illinois. AB - Rural populations in the United States experience unique challenges in health and health care. The health of rural women, in particular, is influenced by their knowledge, work and family commitments, as well as environmental barriers in their communities. In rural southern Illinois, the seven southernmost counties form a region that experiences high rates of cancer and other chronic diseases. To identify, understand, and prioritize the health needs of women living in these seven counties, a comprehensive gender-based community health assessment was conducted with the goal of developing a plan to improve women's health in the region. A gender-analysis framework was adapted, and key stakeholder interviews and focus groups with community women were conducted and analyzed to identify factors affecting ill health. The gender-based analysis revealed that women play a critical role in the health of their families and their communities, and these roles can influence their personal health. The gender-based analysis also identified several gender-specific barriers and facilitators that affect women's health and their ability to engage in healthy behaviors. These results have important implications for the development of programs and policies to improve health among rural women. PMID- 25534315 TI - Soft tissue fixation with a cortical button and interference screw: a novel technique in foot and ankle surgery. AB - Tendon transfers are commonly performed procedures in the foot and ankle. They have been described for multiple tendons and a myriad of pathologies. One issue with these procedures has always been inadequate fixation with several methods available to the surgeon. In this report, we describe a novel technique in foot and ankle surgery using a cortical button and an interference screw. PMID- 25534316 TI - Parents' and children's perception of parent-led Trauma-Focused Cognitive Behavioral Therapy. AB - This study explored parent and child experiences of a parent-led, therapist assisted treatment during Step One of Stepped Care Trauma-Focused Cognitive Behavioral Therapy (TF-CBT). Seventeen parents/guardians and 16 children who were between the ages of 8 and 12 years were interviewed after Step One and six weeks after the completion of a maintenance phase about their perceptions of the parent led, therapist-assisted treatment. Participants were asked what they liked and disliked about the treatment as well as what they found to be most and least helpful. Generally, parents and children liked the treatment and found it helpful. In terms of treatment components, children indicated that the relaxation exercises were the most liked/helpful component (62.5%) followed by trauma narrative activities (56.3%). A few children (18.8%) did not like or found least helpful the trauma narrative component as they wanted to avoid talking or thinking about the trauma. Parents indicated that the parent-child meetings were the most liked/helpful (82.4%) followed by the Stepping Together workbook (58.8%) and relaxation exercises (52.9%). Some parents (23.5%) noted that the workbook seemed too repetitive and some parents (17.6%) at times were uncertain if they were leading the parent-child meetings the best way. Parent-led, therapist assisted TF-CBT may be an acceptable type of service delivery for both parents and children, although more research is needed. PMID- 25534312 TI - Molecular regulation of UV-induced DNA repair. AB - Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the United States, as well as premature skin aging. In particular, UVB radiation causes formation of specific DNA damage photoproducts between pyrimidine bases. These DNA damage photoproducts are repaired by a process called nucleotide excision repair, also known as UV-induced DNA repair. When left unrepaired, UVB-induced DNA damage leads to accumulation of mutations, predisposing people to carcinogenesis as well as to premature aging. Genetic loss of nucleotide excision repair leads to severe disorders, namely, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS), which are associated with predisposition to skin carcinogenesis at a young age as well as developmental and neurological conditions. Regulation of nucleotide excision repair is an attractive avenue to preventing or reversing these detrimental consequences of impaired nucleotide excision repair. Here, we review recent studies on molecular mechanisms regulating nucleotide excision repair by extracellular cues and intracellular signaling pathways, with a special focus on the molecular regulation of individual repair factors. PMID- 25534317 TI - Gamma-linolenic acid inhibits hepatic PAI-1 expression by inhibiting p38 MAPK dependent activator protein and mitochondria-mediated apoptosis pathway. AB - Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor beta 1 (TGF-beta1), plays a role in inducing apoptosis, modulates fibrosis, and ECM accumulation. Plasminogen activator inhibitor 1 (PAI-1) plays an important role in the development hepatic fibrosis. The overexpression of PAI-1 induces ECM accumulation, the main hallmark of chronic liver diseases. Death of hepatocytes is a characteristic feature of chronic liver disease due to various causes. The TGF-beta1-mediated apoptotic pathway is regarded as a promising therapeutic target in hepatic fibrosis. Gamma-linolenic acid (GLA) is of special interest as it possesses anti-fibrosis, anti-inflammatory, and anti-cancer properties. However, the precise mechanism for GLA in chronic liver disease is not still clear. The aim of the present study was to determine whether GLA prevents hepatic PAI-1 expression and apoptosis through the inhibition of TGF-beta1-mediated molecular mediators. GLA attenuated TGF-beta1-stimulated PAI-1 expression, and inhibited PAI-1 promoter activity in AML12 cells. This effect was mediated by Smad3/4, the p38 pathways. We also found that GLA suppressed TGF-beta1-induced apoptotic activation of the Bcl-2 family and caspase family of proteins, which resulted in the inhibition of poly-ADP-ribose polymerase 1 cleavage. GLA ameliorates the pro-fibrotic and pro-apoptotic effects of TGF-beta1 in hepatocytes, suggesting GLA exerts a protective effect on hepatocytes and has a therapeutic potential for the treatment of chronic liver disease. PMID- 25534318 TI - p27kip1 overexpression regulates VEGF expression, cell proliferation and apoptosis in cell culture from eutopic endometrium of women with endometriosis. AB - We hypothesized that p27(kip1) overexpression can regulate endometriosis cell proliferation, apoptosis and vascular endothelial growth factor (VEGF) expression in the endometrium. The overexpression of p27(kip1) was obtained by transduction of p27(kip1) in primary cultures of endometrium obtained from women with endometriosis tissue with gene therapy technology. First generation bicistronic adenovirus: AdCMVhp27IRESEGFP (Adp27) and AdCMVNull (AdNull) were engineered in order to induce p27(kip1) expression in endometrial cells primary culture. The effect of p27(kip1) overexpression was elucidated through the cell proliferation evaluation and the expression of the cell cycle-related proteins p16, p21, p27, and p53. Cell cycle and apoptosis in endometrial cells from women with and without endometriosis were also evaluated. The VEGF levels were evaluated 1 and 7 days after transduction. The experiments were performed using Immunofluorescence stainings and flow cytometry technique. The cell proliferation statistically diminished markedly following p27(kip1) overexpression in the endometriosis group. This process was accompanied, however, by a statistically significant modulation of the cell cycle-related proteins p16, p21, p27 and p53 markedly increase following p27(kip1) overexpression in the endometriosis group (p < 0.001) and an increase in apoptotic cells was observed. In the endometriosis group, significant downregulation of VEGF expression was observed 7 days after p27(kip1) overexpression, attaining levels strikingly similar to those observed in the control endometrial cells. The findings of this study showed a link between the cell cycle control protein (p27(kip1)) and angiogenesis (VEGF). Our results, also reinforces the background of endometrial dysfunction as part of the origin of endometriosis. We believe that better knowledge of endometrium milieu and the establishment of the link between different, previously describe, altered pathways in this tissue can facilitate future genetic cell therapy. PMID- 25534322 TI - Stem cells: multiple routes to pluripotency. PMID- 25534323 TI - Human genetics: somatic mutations linked to future disease risk. PMID- 25534326 TI - Gene expression: you are not alone - cis and trans factors both contribute to ASE. PMID- 25534328 TI - Total bladder and posterior urethral reconstruction: salvage technique for defunctionalized bladder with recalcitrant posterior urethral stenosis. AB - PURPOSE: Recalcitrant posterior urethral stenosis is a challenging disease. When combined with a defunctionalized bladder, cutaneous urinary diversion is the most common surgical option. We present a novel technique of total lower urinary tract reconstruction, combining salvage cystectomy, ileal neobladder formation and urethral pull-through, as an orthotopic alternative in patients with a defunctionalized bladder and recalcitrant posterior urethral stenosis. MATERIALS AND METHODS: We completed a retrospective review of 8 patients who underwent salvage cystectomy, orthotopic ileal neobladder formation and urethral pull through. Artificial urinary sphincter placement was performed in a staged fashion. Six patients received prostate cancer treatment including radiation therapy, 1 had urethral disruption after robotic radical prostatectomy, and 1 experienced bladder rupture and urethral distraction injury during a motorcycle accident. Patient demographics, operative variables and postoperative outcomes were examined. RESULTS: No high grade complications were observed after salvage cystectomy, orthotopic neobladder formation and urethral pull-through. After staged artificial urinary sphincter placement, a median of 2 revision surgeries (range 0 to 4) was required to establish social continence. All patients maintained functional urinary storage, urethral patency and social continence at a median followup of 58 months. No patient had complications related to orthotopic neobladder formation, including ureteroileal anastomotic stricture or pyelonephritis, and no patient required cutaneous diversion. CONCLUSIONS: Total lower urinary tract reconstruction with cystectomy, ileal neobladder formation and urethral pull-through offers an orthotopic alternative for patients with recalcitrant posterior urethral stenosis and defunctionalized bladders. Although it requires staged placement of an artificial urinary sphincter, this approach can offer functional urinary storage, durable urethral patency and avoidance of cutaneous urinary diversion. PMID- 25534324 TI - Emerging roles of tRNA in adaptive translation, signalling dynamics and disease. AB - tRNAs, nexus molecules between mRNAs and proteins, have a central role in translation. Recent discoveries have revealed unprecedented complexity of tRNA biosynthesis, modification patterns, regulation and function. In this Review, we present emerging concepts regarding how tRNA abundance is dynamically regulated and how tRNAs (and their nucleolytic fragments) are centrally involved in stress signalling and adaptive translation, operating across a wide range of timescales. Mutations in tRNAs or in genes affecting tRNA biogenesis are also linked to complex human diseases with surprising heterogeneity in tissue vulnerability, and we highlight cell-specific aspects that modulate the disease penetrance of tRNA based pathologies. PMID- 25534329 TI - Estrogen attenuates TGF-beta1 induced elastogenesis in rat urethral smooth muscle cells by inhibiting Smad response elements. AB - PURPOSE: We investigated the effect and mechanism of estrogen on elastogenesis in urethral smooth muscle cells in vitro. MATERIALS AND METHODS: Urethral smooth muscle cells were isolated from normal adult female rats. For elastogenesis assay cells were treated with TGF-beta1, the potent TGF-beta1 receptor inhibitor SB431542 and estrogen for 2 weeks. Real-time polymerase chain reaction was performed to assay gene expression during this process. Activity of the TGF-beta1 responsive elements CAGA(12)-Luc and GCCG(12)-Luc were also assayed. Estrogen receptor and Smad2/3 interaction was evaluated by immunoprecipitation and Western blot. RESULTS: TGF-beta1 induced elastogenesis in rat urethral smooth muscle cells. This effect was partially blocked by estrogen and completely abrogated by SB431542. SB431542 completely inhibited activation of the Smad2/3 response element CAGA(12)-Luc and estrogen significantly inhibited activation. The Smad1/4 response element GCCG(12)-Luc was not affected by SB431542 treatment but estrogen partially inhibited the activation of GCCG(12)-Luc induced by TGF-beta1. Estrogen receptor bound to Smad 2 and 3 in vitro. CONCLUSIONS: Estrogen attenuated TGF beta1 induced elastogenesis via binding of its activated receptor to Smad2/3 to inhibit the TGF-beta1 response element in rat urethral smooth muscle cells. PMID- 25534330 TI - Management of pain in autosomal dominant polycystic kidney disease and anatomy of renal innervation. AB - PURPOSE: Chronic pain is a prominent feature of autosomal dominant polycystic kidney disease that is difficult to treat and manage, often resulting in a decrease in quality of life. Understanding the underlying anatomy of renal innervation and the various etiologies of pain that occur in autosomal dominant polycystic kidney disease can help guide proper treatments to manage pain. Reviewing previously studied treatments for pain in autosomal dominant polycystic kidney disease can help characterize treatment in a stepwise fashion. MATERIALS AND METHODS: We performed a literature search of the etiology and management of pain in autosomal dominant polycystic kidney disease and the anatomy of renal innervation using PubMed(r) and Embase(r) from January 1985 to April 2014 with limitations to human studies and English language. RESULTS: Pain occurs in the majority of patients with autosomal dominant polycystic kidney disease due to renal, hepatic and mechanical origins. Patients may experience different types of pain which can make it difficult to clinically confirm its etiology. An anatomical and histological evaluation of the complex renal innervation helps in understanding the mechanisms that can lead to renal pain. Understanding the complex nature of renal innervation is essential for surgeons to perform renal denervation. The management of pain in autosomal dominant polycystic kidney disease should be approached in a stepwise fashion. Acute causes of renal pain must first be ruled out due to the high incidence in autosomal dominant polycystic kidney disease. For chronic pain, nonopioid analgesics and conservative interventions can be used first, before opioid analgesics are considered. If pain continues there are surgical interventions such as renal cyst decortication, renal denervation and nephrectomy that can target pain produced by renal or hepatic cysts. CONCLUSIONS: Chronic pain in patients with autosomal dominant polycystic kidney disease is often refractory to conservative, medical and other noninvasive treatments. There are effective surgical procedures that can be performed when more conservative treatments fail. Laparoscopic cyst decortication has been well studied and results in the relief of chronic renal pain in the majority of patients. In addition, renal denervation has been used successfully and could be performed concurrently with cyst decortication. Nephrectomy should be reserved for patients with intractable pain and renal failure when other modalities have failed. PMID- 25534331 TI - Effect of transversus abdominis plane block on cost of laparoscopic cholecystectomy anesthesia. AB - BACKGROUND: Use of transversus abdominis plane (TAP) block for postoperative analgesia is continuously increasing. However, few studies have investigated intraoperative effects of TAP block. We aimed to study the effects of TAP block in terms of cost-effectiveness and consumption of inhalation agents. MATERIAL AND METHODS: Forty patients undergoing laparoscopic cholecystectomy were enrolled in this study. Patients were randomly divided into 2 groups: Group 1 (n=20) patients received TAP block and Group 2 (n=20) patients did not receive TAP block. Standard anesthesia induction was used in all patients. For the maintenance of anesthesia, fractional inspired oxygen (FIO2) of 50% in air with desflurane was used with a fresh gas flow of 4 L/min. All patients were monitored with electrocardiography and for peripheral oxygen saturation (SpO2), end-tidal carbon dioxide (ET), heart rate (HR), noninvasive mean blood pressure (MBP), and bispectral index (BIS). Bilateral TAP blocks were performed under ultrasound guidance to Group 1 patients. The BIS value was maintained at between 40 and 50 during the surgery. The Dion formula was used to calculate consumption of desflurane for each patient. RESULTS: There was no difference between the groups with respect to demographic characteristics of the patients. Duration of anesthesia, surgery time, and dosage of fentanyl were similar in the 2 groups. However, the cost and consumption of desflurane was significantly lower in Group 1. CONCLUSIONS: Total anesthesia consumption was lower and the cost-effectiveness of anesthesia was better in TAP block patients with general anesthesia than in non-TAP block patients undergoing laparoscopic cholecystectomy. PMID- 25534332 TI - Predictions and the brain: how musical sounds become rewarding. AB - Music has always played a central role in human culture. The question of how musical sounds can have such profound emotional and rewarding effects has been a topic of interest throughout generations. At a fundamental level, listening to music involves tracking a series of sound events over time. Because humans are experts in pattern recognition, temporal predictions are constantly generated, creating a sense of anticipation. We summarize how complex cognitive abilities and cortical processes integrate with fundamental subcortical reward and motivation systems in the brain to give rise to musical pleasure. This work builds on previous theoretical models that emphasize the role of prediction in music appreciation by integrating these ideas with recent neuroscientific evidence. PMID- 25534334 TI - Indigenous child health: are we making progress? AB - We identified 244 relevant articles pertinent to indigenous health (4% of the total) with a steady increase in number since 1995. Most Australian publications in the journal (with a small Indigenous population) have focussed on conditions such as malnutrition, diarrhoeal disease, iron deficiency, rheumatic fever, acute glomerulonephritis and respiratory and ear infections, and in settings where nearly all affected children are Indigenous. In contrast, New Zealand publications (with a large Maori and Pacific Islander population) have addressed important health issues affecting all children but emphasised the over representation of Maori and Pacific Islanders. Publications in the journal are largely descriptive studies with relatively few systematic reviews and randomised trials. Our review attempts to cover the important Indigenous health issues in our region as represented by articles published in the Journal. The studies do document definite improvements in indigenous child health over the last 50 years. PMID- 25534333 TI - Fungal and mycotoxin contamination of coffee beans in Benguet province, Philippines. AB - Coffee remains an important agricultural product in Benguet province, Philippines, but is highly susceptible to fungal and mycotoxin contamination in various stages of growth and processing and in different local climates. In this study, pre- and post-harvest coffee bean samples from temperate and warm farming areas were assessed for their fungal and mycotoxin contaminants. One hundred eighty-five fungal isolates belonging to six genera were isolated representing 88.1% of mycotoxigenic fungi. The predominant species belonged to the genus Aspergillus, which are known producers of mycotoxins. Coffee beans from the post harvest temperate group were found to have the highest percentage mycotoxigenic contamination of 98.4%, suggesting that the risk for fungal contamination is high after drying. Determination of the mycotoxins indicated 28.6% contamination. Ochratoxin A was found to be highest in dried whole cherries which contained 97.3 MUg kg(-1), whilst sterigmatocystin was also highest in dried whole cherries at 193.7 MUg kg(-1). These results indicate that there are risks of fungal and mycotoxin contamination of Benguet coffee at the post-harvest stage. PMID- 25534335 TI - [Your future is in your genes]. PMID- 25534336 TI - [Preventing needlestick injuries and blood-borne infections--not yet there]. PMID- 25534337 TI - [How do we strengthen kidney cancer treatment in Denmark?]. PMID- 25534338 TI - [Head and neck paragangliomas]. AB - Head and neck paragangliomas (HNPGs) are rare tumours of neural crest origin that are benign in the majority of cases. In this article HNPGs are outlined with emphasis on genetic predisposition, diagnostics and counselling. The literature on HNPGs identified using PubMed is reviewed. Several susceptibility genes have been identified and hereditary mutations are detectable in 30% of the patients with HNPGs. Genetic analyses, guided by the family history and clinical findings, should be offered to all patients with HNPGs and at risk relatives. PMID- 25534339 TI - [Fever of unknown origin diagnosed with FDG-PET/CT]. PMID- 25534340 TI - [Hemiconvulsion-hemiplegia-epilepsy syndrome]. AB - Hemiconvulsion-hemiplegia-epilepsy syndrome is a rare consequence of a status epilepticus in the course of a febrile illness in children under the age of four years. Various degrees of hemiplegia and within a variable interval, subsequent epilepsia follows. Neuroimaging show unilateral cytotoxic oedema at the initial convulsive state, followed by severe chronic atrophy of the affected hemisphere. The aetiology remains unclear. Several mechanisms may contribute to this condition. To improve the outcome, further studies are needed and early diagnosis is essential. PMID- 25534341 TI - [Presymptomatic genetic testing in minors should only be performed when intervention is possible]. AB - Presymptomatic genetic testing in minors is subject to debate. We reviewed guidelines on the subject from four large medical genetics societies. A general consensus exists regarding presymptomatic testing with the main justification for such testing being the direct benefit to the child through medical intervention or preventive measures. The child's best interest is central, but there is disagreement as to whether psychosocial and familial aspects should be included in this concept. Empirical evidence is lacking. We recommend increased awareness regarding the complexity of this issue. PMID- 25534342 TI - [Multidisciplinary treatment on vulvodynia--where is the evidence?]. AB - Vulvodynia is a chronic pain syndrome in vulva with a prevalence of nearly 15%. Due to poorly understood pathophysiology and lack of efficient treatment frustration is vastly spread among affected women and their physicians. Behavioural, medical and surgical interventions are widely used, but hardly any of them show significance compared to placebo effect. A multidisciplinary treatment is considered to be the new state of the art treatment, but evidence for such a model is hard to find. This article is a review and evaluation of the many treatment models and their evidence. PMID- 25534343 TI - [Transanal minimally invasive surgery for distal rectal cancer treatment]. AB - Laparoscopic total mesorectal excision (LTME) has become the standard surgical treatment of rectal cancer. There is however technical challenges when operating patients with a narrow pelvis with tumours located in distal or middle part of the rectum. We describe a case of a 71-year-old male operated for a rectal cancer by LTME assisted by transanal approach. The patient had an uneventful post operative course. Follow-up showed no signs of recurrence. PMID- 25534344 TI - [Pleomorphic adenoma causing a peritonsillar abscess]. AB - Pleomorphic adenoma located in the soft palate is extremely rare. We report a 42 year-old woman, who presented to the ear nose & throat department with a mucosal swelling of the right soft palate mimicking a peritonsillar abscess. Drainage was attempted several times without significant results. Emergency tonsillectomy was carried out, which showed a tumour intraorally beside the right tonsil. The tumour and the tonsil were radically excised. Histological analysis of the tumour revealed a pleomorphic adenoma. At three-month follow-up the patient was doing well and MRI scan revealed a residual tumour of 6 mm. PMID- 25534345 TI - A protocol for a systematic review of the use of process evaluations in knowledge translation research. AB - BACKGROUND: Experimental designs for evaluating knowledge translation (KT) interventions for professional behavior change can provide strong estimates of intervention effectiveness but offer limited insight how the intervention worked or not. Furthermore, trials provide little insight into the ways through which interventions lead to behavior change and how they are moderated by different facilitators and barriers. As a result, the ability to generalize the findings from one study to a different context, organization, or clinical problem is severely compromised. Consequently, researchers have started to explore the causal mechanisms in complementary studies (process evaluations) alongside experimental designs for evaluating KT interventions. This study focuses on improving process evaluations by synthesizing current evidence on process evaluations conducted alongside experimental designs for evaluating KT interventions. METHODS/DESIGN: A medical research librarian will develop and implement search strategies designed to identify evidence that is relevant to process evaluations in health research. Studies will not be excluded based on design. Included studies must contain a process evaluation component aimed at understanding or evaluating a KT intervention targeting professional behavior change. Two reviewers will perform study selection, quality assessment, and data extraction using standard forms. Disagreements will be resolved through discussion or third party adjudication. Data to be collected include study design, details about data collection approaches and types, theoretical influences, approaches to evaluate intervention dose delivered, intervention dose received, intervention fidelity, intervention reach, data analysis, and study outcomes. This study is not registered with PROSPERO. DISCUSSION: There is widespread acceptance that the generalizability of quantitative trials of KT interventions would be significantly enhanced to other contexts, health professional groups, and clinical conditions through complementary process evaluations alongside trials. This systematic review will serve as a 'state of the science' on methodological approaches to process evaluations and will allow us to: 1) take stock of current research approaches and 2) develop concrete recommendations for knowledge users (e.g., quality consultants and health services researchers) designing future KT process evaluations. PMID- 25534346 TI - A kinetic characterization of (Na+, K+)-ATPase activity in the gills of the pelagic seabob shrimp Xiphopenaeus kroyeri (Decapoda, Penaeidae). AB - We characterize the kinetic properties of a gill (Na(+), K(+))-ATPase from the pelagic marine seabob Xiphopenaeus kroyeri. Sucrose density gradient centrifugation revealed membrane fractions distributed mainly into a heavy fraction showing considerable (Na(+), K(+))-ATPase activity, but also containing mitochondrial F0F1- and Na(+)- and V-ATPases. Western blot analysis identified a single immunoreactive band against the (Na(+), K(+))-ATPase alpha-subunit with an Mr of ~ 110 kDa. The alpha-subunit was immunolocalized to the intralamellar septum of the gill lamellae. The (Na(+), K(+))-ATPase hydrolyzed ATP obeying Michaelis-Menten kinetics with VM = 109.5 +/- 3.2 nmol Pi min(-1) mg(-1) and KM = 0.03 +/- 0.003 mmol L(-1). Mg(2+) (VM = 109.8 +/- 2.1 nmol Pi min(-1 )mg(-1), K0.5 = 0.60 +/- 0.03 mmol L(-1)), Na(+) (VM = 117.6 +/- 3.5 nmol Pi min(-1 ) mg( 1), K0.5 = 5.36 +/- 0.14 mmol L(-1)), K(+) (VM = 112.9 +/- 1.4 nmol Pi min(-1 )mg(-1), K0.5 = 1.32 +/- 0.08 mmol L(-1)), and NH4 (+) (VM = 200.8 +/- 7.1 nmol Pi min(-1 )mg(-1), K0.5 = 2.70 +/- 0.04 mmol L(-1)) stimulated (Na(+), K(+)) ATPase activity following site-site interactions. K(+) plus NH4 (+) does not synergistically stimulate (Na(+), K(+))-ATPase activity, although each ion modulates affinity of the other. The enzyme exhibits a single site for K(+) binding that can be occupied by NH4 (+), stimulating the enzyme. Ouabain (KI = 84.0 +/- 2.1 umol L(-1)) and orthovanadate (KI = 0.157 +/- 0.001 umol L(-1)) inhibited total ATPase activity by ~ 50 and ~ 44 %, respectively. Ouabain inhibition increases ~ 80 % in the presence of NH4 (+) with a threefold lower KI, suggesting that NH4 (+) is likely transported as a K(+) congener. PMID- 25534347 TI - Electrotransfection and lipofection show comparable efficiency for in vitro gene delivery of primary human myoblasts. AB - Transfection of primary human myoblasts offers the possibility to study mechanisms that are important for muscle regeneration and gene therapy of muscle disease. Cultured human myoblasts were selected here because muscle cells still proliferate at this developmental stage, which might have several advantages in gene therapy. Gene therapy is one of the most sought-after tools in modern medicine. Its progress is, however, limited due to the lack of suitable gene transfer techniques. To obtain better insight into the transfection potential of the presently used techniques, two non-viral transfection methods--lipofection and electroporation--were compared. The parameters that can influence transfection efficiency and cell viability were systematically approached and compared. Cultured myoblasts were transfected with the pEGFP-N1 plasmid either using Lipofectamine 2000 or with electroporation. Various combinations for the preparation of the lipoplexes and the electroporation media, and for the pulsing protocols, were tested and compared. Transfection efficiency and cell viability were inversely proportional for both approaches. The appropriate ratio of Lipofectamine and plasmid DNA provides optimal conditions for lipofection, while for electroporation, RPMI medium and a pulsing protocol using eight pulses of 2 ms at E = 0.8 kV/cm proved to be the optimal combination. The transfection efficiencies for the optimal lipofection and optimal electrotransfection protocols were similar (32 vs. 32.5%, respectively). Both of these methods are effective for transfection of primary human myoblasts; however, electroporation might be advantageous for in vivo application to skeletal muscle. PMID- 25534349 TI - Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal like cancer cells that lack functional E-cadherin mediated cell cohesion. AB - The cholesterol reducing drugs, statins, exhibit anti-tumor effects against cancer stem cells and various cancer cell lines, exert potent additivity or synergy with existing chemotherapeutics in animal models of cancer and may reduce cancer incidence and cancer related mortality in humans. However, not all tumor cell lines are sensitive to statins, and clinical trials have demonstrated mixed outcomes regarding statins as anticancer agents. Here, we show that statin induced reduction in intracellular cholesterol levels correlate with the growth inhibition of cancer cell lines upon statin treatment. Moreover, statin sensitivity segregates with abundant cytosolic vimentin expression and absent cell surface E-cadherin expression, a pattern characteristic of mesenchymal-like cells. Exogenous expression of cell surface E-cadherin converts statin- sensitive cells to a partially resistant state implying that statin resistance is in part dependent on the tumor cells attaining an epithelial phenotype. As metastasizing tumor cells undergo epithelial to mesenchymal transition during the initiation of the metastatic cascade, statin therapy may represent an effective approach to targeting the cells most likely to disseminate. PMID- 25534356 TI - Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants. AB - Despite improved survival, many preterm infants undergo subsequent neurodevelopmental impairment. To date, no neuroprotective therapies have been implemented into clinical practice. Erythropoietin, a haematopoietic cytokine used for treatment of anaemia of prematurity, has been shown to have neuroprotective and neuroregenerative effects on the brain in many experimental studies. The aim of the study was to assess the effect of recombinant human erythropoietin on the microstructural development of the cerebral white matter using tract-based spatial statistics performed at term equivalent age. A randomized, double-blind placebo-controlled, prospective multicentre study applying recombinant human erythropoietin in the first 42 h after preterm birth entitled 'Does erythropoietin improve outcome in preterm infant' was conducted in Switzerland (NCT00413946). Preterm infants were given recombinant human erythropoietin (3000 IU) or an equivalent volume of placebo (NaCl 0.9%) intravenously before 3 h of age after birth, at 12-18 h and at 36-42 h after birth. High resolution diffusion tensor imaging was obtained at 3 T in 58 preterm infants with mean (standard deviation) gestational age at birth 29.75 (1.44) weeks, and at scanning at 41.1 (2.09) weeks. Imaging was performed at a single centre. Voxel-wise statistical analysis of the fractional anisotropy data was carried out using tract-based spatial statistics to test for differences in fractional anisotropy between infants treated with recombinant human erythropoietin and placebo using a general linear model, covarying for the gestational age at birth and the corrected gestational age at the time of the scan. Preterm infants treated with recombinant human erythropoietin demonstrated increased fractional anisotropy in the genu and splenium of the corpus callosum, the anterior and posterior limbs of the internal capsule, and the corticospinal tract bilaterally. Mean fractional anisotropy was significantly higher in preterm infants treated with recombinant human erythropoietin than in those treated with placebo (P < 0.001). We conclude that early recombinant human erythropoietin administration improves white matter development in preterm infants assessed by diffusion tensor imaging and tract-based spatial statistics. PMID- 25534357 TI - Bilirubin-induced neural impairment: a special focus on myelination, age-related windows of susceptibility and associated co-morbidities. AB - Bilirubin-induced neurologic dysfunction (BIND) and classical kernicterus are clinical manifestations of moderate to severe hyperbilirubinemia whenever bilirubin levels exceed the capacity of the brain defensive mechanisms in preventing its entrance and cytotoxicity. In such circumstances and depending on the associated co-morbidities, bilirubin accumulation may lead to short- or long term neurodevelopmental disabilities, which may include deficits in auditory, cognitive, and motor processing. Neuronal cell death, astrocytic reactivity, and microglia activation are part of the bilirubin-induced pathogenesis. Less understood is how abnormal growth and maturation of oligodendrocytes may impact on brain development, affecting the formation of myelin tracts. Based on in-vitro and in-vivo models, as well as in clinical cases presented here, we propose the existence of impaired myelination by bilirubin with long-term sequelae, mainly in pre-term infants. Sensitive time-windows are highlighted and centered on the different developmental-dependent impairments determined by bilirubin, and the influence of sepsis and hypoxia is reviewed. PMID- 25534358 TI - Bochum ultrasound score allows distinction of chronic inflammatory from multifocal acquired demyelinating polyneuropathies. AB - OBJECTIVE: The aim of this observational study was to evaluate the applicability of a recently introduced ultrasound score (Bochum ultrasound score; BUS) in distinguishing the chronic inflammatory demyelinating polyneuropathy (CIDP) from the multifocal motor neuropathy (MMN) or the multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). METHODS: The BUS underwent prospective evaluation of its applicability in a group of 13 patients (mean age 47.2, SD +/- 13.7, 9 women), who were referred to our department between January 2012 and August 2013 with the clinical picture of a chronic symmetrical or asymmetrical sensory/sensorimotor neuropathy. RESULTS: The cut-off value of >= 2 points in the "Bochum ultrasound score" showed a sensitivity of 80% and specificity of 87.5% (PPV=80%, NPV=87.5%) in distinguishing CIDP from MMN or MADSAM. CONCLUSIONS: The BUS seems to allow a reliable distinction of CIDP from multifocal acquired demyelinating polyneuropathies causing predominantly motor nerve dysfunction, such as MMN or MADSAM. Our ultrasound findings indicate a stronger relationship of MADSAM to MMN, than to CIDP. PMID- 25534348 TI - Mechanism of Ca2+-triggered ESCRT assembly and regulation of cell membrane repair. AB - In muscle and other mechanically active tissue, cell membranes are constantly injured, and their repair depends on the injury-induced increase in cytosolic calcium. Here, we show that injury-triggered Ca(2+) increase results in assembly of ESCRT III and accessory proteins at the site of repair. This process is initiated by the calcium-binding protein-apoptosis-linked gene (ALG)-2. ALG-2 facilitates accumulation of ALG-2-interacting protein X (ALIX), ESCRT III and Vps4 complex at the injured cell membrane, which in turn results in cleavage and shedding of the damaged part of the cell membrane. Lack of ALG-2, ALIX or Vps4B each prevents shedding, and repair of the injured cell membrane. These results demonstrate Ca(2+)-dependent accumulation of ESCRT III-Vps4 complex following large focal injury to the cell membrane and identify the role of ALG-2 as the initiator of sequential ESCRT III-Vps4 complex assembly that facilitates scission and repair of the injured cell membrane. PMID- 25534359 TI - Effect of the treatment of focal brain ablation in rat with bone marrow mesenchymal stromal cells on sensorimotor recovery and cytokine production. AB - Increased efficacy of the multipotent mesenchymal stromal cells (MSCs) for the treatment of CNS injuries has been shown when they are administrated within a collagen scaffold, an environment in three dimensions (3D), when compared to the cultivation over a plastic surface (2D). We evaluated the MSC therapeutic effect in the 2D and 3D conditions using the model of focal cortical ablation. Male Wistar rats were submitted to the ablation by aspiration. Intravenous injection (IV) of MSC cultured in 2D, and the intralesional administration (IL) of MSC cultured in 2D or 3D were tested. Administrations were made 24h after ablation. Unskilled and skilled forelimb movements were evaluated by sensorimotor tests. The level of cytokines was measured two days after ablation in the 2D IV groups. Only the MSC 3D IL promoted recovery of the skilled movements. MSC 2D IV promoted recovery of the unskilled movements in all tests, and the MSC 3D IL promoted it only in the adhesive test. MSC 2D IL was unable to promote any recovery. DAPI stained MSC was found in the perilesional parenchyma at the third post-ablation day after 2D and 3D IL. A significant reduction in the levels of cytokines by the MSC 2D IV was observed in the plasma. Our study strengthens the evidences of the MSC as a prospective therapeutic approach for the CNS injuries. PMID- 25534360 TI - Novel glycosylated VEGF decoy receptor fusion protein, VEGF-Grab, efficiently suppresses tumor angiogenesis and progression. AB - Antiangiogenic therapies targeting VEGFA have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has been limited, with drawbacks including acquisition of resistance and activation of compensatory pathways resulting from elevated circulating VEGFB and placental growth factor (PlGF). To bypass these disadvantages, we developed a novel glycosylated soluble decoy receptor fusion protein, VEGF-Grab, that can neutralize VEGFA, VEGFB, and PlGF. VEGF-Grab has the second and third immunoglobulin (Ig)-like domains of VEGF receptor 1 (VEGFR1) fused to IgG1 Fc, with three potential glycosylation sites introduced into the third Ig-like domain of VEGF-Grab by mutagenesis. Compared with VEGF-Trap, VEGF-Grab showed more potent decoy activity against VEGF and PlGF, mainly attributed to the VEGFR1 backbone. Most importantly, the negatively charged O-glycans attached to the third Ig-like domain of VEGFR1 counterbalanced the originally positively charged VEGFR1 backbone, minimizing nonspecific binding of VEGF-Grab to the extracellular matrix, and resulting in greatly improved pharmacokinetic profile. These advancements led to stronger and more durable antiangiogenic, antitumor, and antimetastatic efficacy in both implanted and spontaneous tumor models as compared with VEGF-Trap, while toxicity profiles were comparable with VEGF-Trap. Collectively, our results highlight VEGF-Grab as a promising therapeutic candidate for further clinical drug development. PMID- 25534361 TI - HAb18G/CD147 promotes radioresistance in hepatocellular carcinoma cells: a potential role for integrin beta1 signaling. AB - Radiotherapy has played a limited role in the treatment of hepatocellular carcinoma (HCC) due to the risk of tumor radioresistance. A previous study in our laboratory confirmed that CD147 interacts with integrin beta1 and plays an important role in modulating the malignant properties of HCC cells. In this study, we further evaluated the role of CD147 in the radioresistance of HCC and as a potential target for improving radiosensitivity. Upon irradiation, the colony formation, apoptosis, cell-cycle distribution, migration, and invasion of SMMC-7721, CD147-knockout SMMC-7721, HepG2, and CD147-knockdown HepG2 cells were determined. A nude mouse xenograft model and a metastatic model of HCC were used to detect the role of CD147 in radioresistance in vivo. Deletion of HAb18G/CD147 significantly enhanced the radiosensitivity of SMMC-7721 and HepG2 cells, and knocking out HAb18G/CD147 in SMMC-7721 cells attenuated irradiation-enhanced migration and invasion. The knockout and antibody blockade of CD147 decreased the tumor growth and metastatic potentials of HCC cells under irradiation. CD147 deleted SMMC-7721 cells showed diminished levels of calpain, cleaved talin, active integrin beta1, and decreased p-FAK (Tyr397) and p-Akt (Ser473) levels. FAK and PI3K inhibitors, as well as integrin beta1 antibodies, increased the radiation-induced apoptosis of SMMC-7721 cells. Our data provide evidence for CD147 as an important determinant of radioresistance via the regulation of integrin beta1 signaling. Inhibition of the HAb18G/CD147 integrin interaction may improve the efficiency of radiosensitivity and provide a potential new approach for HCC therapy. PMID- 25534362 TI - An educational review of cartilage repair: precepts & practice--myths & misconceptions--progress & prospects. AB - OBJECTIVE: The repair of cartilaginous lesions within synovial joints is still an unresolved and weighty clinical problem. Although research activity in this area has been indefatigably sustained, no significant progress has been made during the past decade. The aim of this educational review is to heighten the awareness amongst students and scientists of the basic issues that must be tackled and resolved before we can hope to escape from the whirlpool of stagnation into which we have fallen: cartilage repair redivivus! DESIGN: Articular-cartilage lesions may be induced traumatically (e.g., by sports injuries and occupational accidents) or pathologically during the course of a degenerative disease (e.g., osteoarthritis). This review addresses the biological basis of cartilage repair and surveys current trends in treatment strategies, focussing on those that are most widely adopted by orthopaedic surgeons [viz., abrasive chondroplasty, microfracturing/microdrilling, osteochondral grafting and autologous-chondrocyte implantation (ACI)]. Also described are current research activities in the field of cartilage-tissue engineering, which, as a therapeutic principle, holds more promise for success than any other experimental approach. RESULTS AND CONCLUSIONS: Tissue engineering aims to reconstitute a tissue both structurally and functionally. This process can be conducted entirely in vitro, initially in vitro and then in vivo (in situ), or entirely in vivo. Three key constituents usually form the building blocks of such an approach: a matrix scaffold, cells, and signalling molecules. Of the proposed approaches, none have yet advanced beyond the phase of experimental development to the level of clinical induction. The hurdles that need to be surmounted for ultimate success are discussed. PMID- 25534364 TI - Evaluation of the Diagnostic Accuracy of Conventional 2-Dimensional and 3 Dimensional Computed Tomography for Assessing Canine Sacral and Pelvic Fractures by Radiologists, Orthopedic Surgeons, and Veterinary Medical Students. AB - OBJECTIVE: To determine, using 3 groups of evaluators of varying experience reading orthopedic CT studies, if 3-dimensional computed tomography (3D-CT) provides a more accurate and time efficient method for diagnosis of canine sacral and pelvic fractures, and displacements of the sacroiliac and coxofemoral joints compared with 2-dimensional computed tomography (2D-CT). STUDY DESIGN: Retrospective clinical and prospective study. ANIMALS: Dogs (n = 23): 12 dogs with traumatic pelvic fractures, 11 canine cadavers with pelvic trauma induced by a lateral impactor. METHODS: All dogs had a 2D-CT exam of the pelvis and subsequent 3D-CT reconstructions from the 2D-CT images. Both 2D-CT and 3D-CT studies were anonymized and randomly presented to 2 veterinary radiologists, 2 veterinary orthopedic surgeons, and 2 veterinary medical students. Evaluators classified fractures using a confidence scale and recorded the duration of evaluation for each modality and case. RESULTS: 3D-CT was a more time-efficient technique for evaluation of traumatic sacral and pelvic injuries compared with 2D CT in all evaluator groups irrespective of experience level reading orthopedic CT studies. However, for radiologists and surgeons, 2D-CT was the more accurate technique for evaluating sacral and pelvic fractures. CONCLUSION: 3D-CT improves sacral and pelvic fracture diagnosis when added to 2D-CT; however, 3D-CT has a reduced accuracy for evaluation of sacral and pelvic fractures if used without concurrent evaluation of 2D-CT images. PMID- 25534363 TI - Soluble factors from the notochordal-rich intervertebral disc inhibit endothelial cell invasion and vessel formation in the presence and absence of pro inflammatory cytokines. AB - BACKGROUND: Chronic low back pain can be associated with the pathological ingrowth of blood vessels and nerves into intervertebral discs (IVDs). The notochord patterns the IVD during development and is a source of anti-angiogenic soluble factors such as Noggin and Chondroitin sulfate (CS). These factors may form the basis for a new minimally invasive strategy to target angiogenesis in the IVD. OBJECTIVE: To examine the anti-angiogenic potential of soluble factors from notochordal cells (NCs) and candidates Noggin and CS under healthy culture conditions and in the presence of pro-inflammatory mediators. DESIGN: NC conditioned media (NCCM) was generated from porcine NC-rich nucleus pulposus tissue. To assess the effects of NCCM, CS and Noggin on angiogenesis, cell invasion and tubular formation assays were performed using human umbilical vein endothelial cells (HUVECs) +/- tumor necrosis factor alpha (TNFalpha [10 ng/ml]). vascular endothelial growth factor (VEGF)-A, MMP-7, interleukin-6 (IL-6) and IL-8 mRNA levels were assessed using qRT-PCR. RESULTS: NCCM (10 & 100%), CS (10 and 100 MUg) and Noggin (10 and 100 ng) significantly decreased cell invasion of HUVECs with and without TNFalpha. NCCM 10% and Noggin 10 ng inhibited tubular formation with and without TNFalpha and CS 100 MUg inhibited tubules in Basal conditions whereas CS 10 MUg inhibited tubules with TNFalpha. NCCM significantly decreased VEGF-A, MMP-7 and IL-6 mRNA levels in HUVECs with and without TNFalpha. CS and Noggin had no effects on gene expression. CONCLUSIONS: We provide the first evidence that soluble factors from NCs can inhibit angiogenesis by suppressing VEGF signaling. Notochordal-derived ligands are a promising minimally invasive strategy targeting neurovascular ingrowth and pain in the degenerated IVD. PMID- 25534365 TI - Forward-masking recovery and the assumptions of the temporal masking curve method of inferring cochlear compression. AB - The temporal masking curve (TMC) method is a behavioral technique for inferring human cochlear compression. The method relies on the assumptions that in the absence of compression, forward-masking recovery is independent of masker level and probe frequency. The present study aimed at testing the validity of these assumptions. Masking recovery was investigated for eight listeners with sensorineural hearing loss carefully selected to have absent or nearly absent distortion product otoacoustic emissions. It is assumed that for these listeners basilar membrane responses are linear, hence that masking recovery is independent of basilar membrane compression. TMCs for probe frequencies of 0.5, 1, 2, 4, and 6 kHz were available for these listeners from a previous study. The dataset included TMCs for masker frequencies equal to the probe frequencies plus reference TMCs measured using a high-frequency probe and a low, off-frequency masker. All of the TMCs were fitted using linear regression, and the resulting slope and intercept values were taken as indicative of masking recovery and masker level, respectively. Results for on-frequency TMCs suggest that forward masking recovery is generally independent of probe frequency and of masker level and hence that it would be reasonable to use a reference TMC for a high-frequency probe to infer cochlear compression at lower frequencies. Results further show, however, that reference TMCs were sometimes shallower than corresponding on frequency TMCs for identical probe frequencies, hence that compression could be overestimated in these cases. We discuss possible reasons for this result and the conditions when it might occur. PMID- 25534366 TI - Association of leukoaraiosis with stroke recurrence within 5 years after initial stroke. AB - BACKGROUND: Leukoaraiosis (LA) is closely associated with stroke. Despite the fact that LA has consistently been shown to predict development of recurrent stroke, prior studies on the association of LA and stroke subtypes have been unsatisfactory. In this study, we sought to identify whether LA contributes to the recurrence of certain subtypes of stroke at long term. METHODS: Data from the Ege Stroke Registry were examined, and 5 years follow-up data for LA and stroke recurrence were analyzed. We performed survival curves using the Kaplan-Meier method (unadjusted) and log-rank tests in patients with stroke to determine the relationship between LA and recurrent stroke by stroke subtypes within a time period of 5 years. Multivariate survival analyses were undertaken using Cox proportional hazards models to determine the prognostic value of LA, stroke subtypes, and other vascular risk factors before recurrent stroke. RESULTS: Of 9522 patients with stroke, 1280 (26%) with LA and 901 (19%) without LA experienced a stroke recurrence within 5 years of follow-up (odds ratio, 1.53; 95% confidence interval, 1.39-1.69). After stratification by stroke subtypes, multivariable analysis revealed a significant association between LA and large artery disease (LAD; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.18 1.64), small artery disease (SAD; OR, 1.57; 95% CI, 1.27-1.94), and intracerebral hemorrhage (ICH; OR, 1.88; 95% CI, 1.32-2.66), except cardioembolic stroke and "other" stroke subtypes at 5 years after stroke onset. The survival analysis showed that stroke recurrence was significantly higher in patients with severe LA compared with those with mild/moderate LA (log-rank test [Mantel-Cox], P < .001). CONCLUSIONS: Our results showed that LA is related to the recurrent strokes in patients with stroke within 5 years after stroke, specifically to the LAD, SAD and ICH. PMID- 25534367 TI - Genetic polymorphisms of ALOX5AP and CYP3A5 increase susceptibility to ischemic stroke and are associated with atherothrombotic events in stroke patients. AB - BACKGROUND: The contributions of gene-gene interactions to pathogenesis of stroke remain largely elusive. The present study was designed to investigate the associations between genetic variations and ischemic stroke risk, the roles of gene-gene interactions in ischemic stroke, and their associations with atherothrombotic events. METHODS: Among 396 patients with ischemic stroke and 378 controls, we examined 8 variants from 5 genes, including ALOX5AP-SG13S32 (rs9551963), SG13S42 (rs4769060), SG13S89 (rs4769874), SG13S114 (rs10507391), EPHX2 G860A (rs751141), CYP2C9*2 C430T (rs1799853), CYP2C9*3 A1075C (rs1057910), and CYP3A5 A6986G (rs776746), using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Gene-gene interactions were determined by the generalized multifactor dimensionality reduction (GMDR) method. All ischemic stroke patients were followed up 12 months for atherothrombotic events, including recurrent ischemic stroke and other vascular events. RESULTS: Single-gene variant analysis showed no significant differences in the genotype distributions of the 8 variants between the 2 groups. However, the GMDR analysis showed a significant interaction between rs10507391 and rs776746, in those cases carrying rs10507391 AA and rs776746 GG, the risk of ischemic stroke increased by 2.014 times (95% confidence interval [CI], 1.896-6.299; P = .006), and the atherothrombotic events occurred more frequently in those patients during follow-up period (P < .001). Multiple Cox regression analysis showed that the interaction between rs10507391 AA and rs776746 GG was an independent risk factor for atherothrombotic events (relative risk = 2.921; 95% CI, 1.118-7.012; P = .008). CONCLUSIONS: The interaction between rs10507391 and rs776746 increases the susceptibility to ischemic stroke and is associated with atherothrombotic events in stroke patients. PMID- 25534368 TI - Neurovascular protection by telmisartan via reducing neuroinflammation in stroke resistant spontaneously hypertensive rat brain after ischemic stroke. AB - Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9 positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke. PMID- 25534370 TI - Morphologic changes of cerebral veins in hypertensive rats: venous collagenosis is associated with hypertension. AB - BACKGROUND: The aims of this study were to determine whether arterial hypertension could affect the venous system of brain and to find out the consequent pathologic changes of cerebral veins. METHODS: Thirty male Sprague Dawley rats were divided into 2 groups: a sham-clipped group and a stroke-prone renovascular hypertensive rat group. A 2-kidney 2-clip rat model was used to induce renovascular hypertension in the hypertensive group. Systolic blood pressure was measured by tail cuff once each week. Susceptibility-weighted imaging (SWI) was performed at 12, 16, and 20 weeks after surgery. All the rats were sacrificed after the SWI examination at 20 weeks after surgery. The brains were extracted and embedded in paraffin for histologic examination. Masson trichrome staining was performed to identify venous collagenosis. RESULTS: The sham group demonstrated less prominence of cerebral veins compared with hypertensive groups (P < .01); the hypertensive group showed significant venous collagenosis in cerebral venous walls compared with the sham group (P < .01). CONCLUSIONS: The increased visibility of cerebral veins on SWI as a sign of venous hypertension and the thickened cerebral venous walls (venous collagenosis), which may play a role in cerebral ischemia and/or infarction, are both consequences of long-term hypertension in hypertensive rats. PMID- 25534369 TI - Study design for the fostering eating after stroke with transcranial direct current stimulation trial: a randomized controlled intervention for improving Dysphagia after acute ischemic stroke. AB - GOAL: Dysphagia is a major stroke complication but lacks effective therapy that can promote recovery. Noninvasive brain stimulation with and without peripheral sensorimotor activities may be an attractive treatment option for swallowing recovery but has not been systematically investigated in the stroke population. This article describes the study design of the first prospective, single-center, double-blinded trial of anodal versus sham transcranial direct current stimulation (tDCS) used in combination with swallowing exercises in patients with dysphagia from an acute ischemic stroke. The aim of this study is to gather safety data on cumulative sessions of tDCS in acute-subacute phases of stroke, obtain information about effects of this intervention on important physiologic and clinically relevant swallowing parameters, and examine possible dose effects. METHODS: Ninety-nine consecutive patients with dysphagia from an acute unilateral hemispheric infarction with a Penetration and Aspiration Scale (PAS) score of 4 or more and without other confounding reasons for dysphagia will be enrolled at a single tertiary care center. Subjects will be randomized to either a high or low dose tDCS or a sham group and will undergo 10 sessions over 5 consecutive days concomitantly with effortful swallowing maneuvers. The main efficacy measures are a change in the PAS score before and after treatment; the main safety measures are mortality, seizures, neurologic, motor, and swallowing deterioration. CONCLUSIONS: The knowledge gained from this study will help plan a larger confirmatory trial for treating stroke-related dysphagia and advance our understanding of important covariates influencing swallowing recovery and response to the proposed intervention. PMID- 25534371 TI - Executive function as a strong predictor of recovery from disability in patients with acute stroke: a preliminary study. AB - BACKGROUND: Cognitive impairment impedes stroke rehabilitation. However, it is unclear whether cognitive impairment of specific domains or the degree of severity is more critical to functional recovery in patients with poststroke disability. METHODS: We identified 182 patients who were disabled at 3 months after acute stroke, as defined by a modified Rankin Scale score of 2-5. At a single time point between 3 months and 1 year after onset, the following 4 cognitive domains were assessed: executive function, visuospatial ability, language, and memory. With respect to the severity of cognitive impairment, the patients were classified as having vascular dementia (VD), vascular cognitive impairment no dementia (VCIND), or normal cognition. The primary outcome was functional recovery between 3 months and 1 year after onset. To examine the association between cognitive status and functional recovery, multiple logistic regression with backward stepwise analysis was performed. RESULTS: A total of 74 (40.7% of 182) patients demonstrated functional improvement at 1 year compared with 3 months. Patients with executive impairment demonstrated significantly less improvement in functional outcomes, with an adjusted odds ratio (OR) of .472 (95% confidence interval [CI], .245-.910). Patients with VD also demonstrated less functional recovery, with an adjusted OR of .289 (95% CI, .120-.700). The remaining 3 cognitive domains and VCIND were not significantly associated with functional recovery. CONCLUSIONS: Executive function is a strong predictor of recovery from disability in patients with acute stroke. In addition, functional recovery is significantly hampered by cognitive impairment due to VD, but not VCIND. PMID- 25534373 TI - Erinaceolactones A to C, from the culture broth of Hericium erinaceus. AB - Three novel compounds, erinaceolactones A to C (1-3), and a known compound (4) were isolated from the culture broth of Hericium erinaceus. The planar structures of 1-3 were determined by the interpretation of spectroscopic data. The absolute configuration of 3 was determined by X-ray crystallography. Although compound 4 had been synthesized, it was isolated from a natural source for the first time. In the bioassay examining plant-growth regulatory activity of these compounds (1 4) and other components of the fungus (5-8), compounds 1, 2, and 4-8 suppressed the growth of lettuce. PMID- 25534372 TI - The ecological genomic basis of salinity adaptation in Tunisian Medicago truncatula. AB - BACKGROUND: As our world becomes warmer, agriculture is increasingly impacted by rising soil salinity and understanding plant adaptation to salt stress can help enable effective crop breeding. Salt tolerance is a complex plant phenotype and we know little about the pathways utilized by naturally tolerant plants. Legumes are important species in agricultural and natural ecosystems, since they engage in symbiotic nitrogen-fixation, but are especially vulnerable to salinity stress. RESULTS: Our studies of the model legume Medicago truncatula in field and greenhouse settings demonstrate that Tunisian populations are locally adapted to saline soils at the metapopulation level and that saline origin genotypes are less impacted by salt than non-saline origin genotypes; these populations thus likely contain adaptively diverged alleles. Whole genome resequencing of 39 wild accessions reveals ongoing migration and candidate genomic regions that assort non-randomly with soil salinity. Consistent with natural selection acting at these sites, saline alleles are typically rare in the range-wide species' gene pool and are also typically derived relative to the sister species M. littoralis. Candidate regions for adaptation contain genes that regulate physiological acclimation to salt stress, such as abscisic acid and jasmonic acid signaling, including a novel salt-tolerance candidate orthologous to the uncharacterized gene AtCIPK21. Unexpectedly, these regions also contain biotic stress genes and flowering time pathway genes. We show that flowering time is differentiated between saline and non-saline populations and may allow salt stress escape. CONCLUSIONS: This work nominates multiple potential pathways of adaptation to naturally stressful environments in a model legume. These candidates point to the importance of both tolerance and avoidance in natural legume populations. We have uncovered several promising targets that could be used to breed for enhanced salt tolerance in crop legumes to enhance food security in an era of increasing soil salinization. PMID- 25534374 TI - Clearing of psoriasis documented by laser Doppler perfusion imaging contrasts remaining elevation of dermal expression levels of CD31. AB - BACKGROUND: Vascular modifications represent a key feature in psoriatic plaques. Previous research with Laser Doppler Perfusion Imaging (LDPI) revealed a remarkable heterogeneity in the cutaneous perfusion within homogenous-appearing psoriatic lesions. Insights in the relation between perfusion during treatment and related biological changes are lacking. OBJECTIVES: To study the effect of calcipotriol-betamethasone dipropionate ointment on the microcirculation and the expression levels of immunohistochemical markers in psoriatic lesions compared to the distant uninvolved skin. METHODS: Psoriatic lesions of fourteen patients were treated once a day during 8 weeks. Clinical SUM scores and the perfusion intensity by means of LDPI were assessed every 2 weeks. After 8 weeks, a biopsy from the target lesion and one from the distant uninvolved skin were taken and stained for psoriasis-related markers, like IL-17 and CD31. RESULTS: After 8 weeks, seven patients reached a SUM score of 0 or 1, and were classified as good responders. The other patients were classified moderate-responders. The perfusion intensity decreased in all lesions during therapy. In the good-responders, all investigated psoriasis-related proteins within the treated lesions reached the expression level found within the distant uninvolved skin. The expression of CD31, however, was significantly higher in the treated lesions as compared to the distant uninvolved skin (p = 0.0156). In the moderate responders, almost all expression levels remained significantly elevated compared to the uninvolved skin. CONCLUSIONS: In the skin of good-responders the expression of dermal CD31(+) endothelium remains significantly elevated within the treated lesions compared with the distant uninvolved skin, whereas a marked reduction in the perfusion intensity and SUM score was found. This indicates that clinical improvement might outrun endothelial changes. PMID- 25534376 TI - No Increased Risk of Second Cancer After Radiotherapy in Patients Treated for Rectal or Endometrial Cancer in the Randomized TME, PORTEC-1, and PORTEC-2 Trials. AB - PURPOSE: This study investigated the long-term probability of developing a second cancer in a large pooled cohort of patients treated with surgery with or without radiotherapy (RT). PATIENTS AND METHODS: All second cancers diagnosed in patients included in the TME, PORTEC-1, and PORTEC-2 trials were analyzed. In the TME trial, patients with rectal cancer (n = 1,530) were randomly allocated to preoperative external-beam RT (EBRT; 25 Gy in five fractions) or no RT. In the PORTEC trials, patients with endometrial cancer were randomly assigned to postoperative EBRT (46 Gy in 2-Gy fractions) versus no RT (PORTEC-1; n = 714) or EBRT versus vaginal brachytherapy (VBT; PORTEC-2; n = 427). RESULTS: A total of 2,554 patients were analyzed (median follow-up, 13.0 years; range 1.8 to 21.2 years). No differences were found in second cancer probability between patients who were treated without RT (10- and 15-year rates, 15.8% and 26.5%, respectively) and those treated with EBRT (10- and 15-year rates, 15.4% and 25.6%, respectively) or VBT (10-year rate, 14.9%). In the individual trials, no significant differences were found between treatment arms. All cancer survivors had a higher risk of developing a second cancer compared with an age- and sex matched general population. The standardized incidence ratio for any second cancer was 2.98 (95% CI, 2.82 to 3.14). CONCLUSION: In this pooled trial cohort of > 2,500 patients with pelvic cancers, those who underwent EBRT or VBT had no higher probability of developing a second cancer than patients who were treated with surgery alone. However, patients with rectal or endometrial cancer had an increased probability of developing a second cancer compared with the general population. PMID- 25534377 TI - Reply to A.V. Louie et al. PMID- 25534375 TI - Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. AB - PURPOSE: Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. PATIENTS AND METHODS: GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD L1, CTLA4, FOXP3) was measured in 481 tumors. RESULTS: Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rates >= 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2 positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P < .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P < .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P < .001). CONCLUSION: Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC. PMID- 25534378 TI - Dendritic cell disorders: matters of lineage and clinical drug testing in rare diseases. PMID- 25534379 TI - Dual-eligibility status: a marker of vulnerability and cancer-related disparities. PMID- 25534380 TI - Short-term risk of colorectal cancer in individuals with lynch syndrome: a meta analysis. AB - PURPOSE: For carriers of germline mutations in DNA mismatch repair genes, the most relevant statistic for cancer prevention is colorectal cancer (Lynch syndrome) risk, particularly in the short term. METHODS: We conducted a meta analysis of all independent published Lynch syndrome studies reporting age- and sex-dependent colorectal cancer risks. We estimated 5-year colorectal cancer risk over different age groups, separately for male and female mutation carriers, and number needed to screen to prevent one death. RESULTS: We pooled estimates from analyses of 1,114 Lynch syndrome families (508 with MLH1 mutations and 606 with MSH2 mutations). On average, one in 71 male and one in 102 female MLH1 or MSH2 mutation carriers in their 20s will be diagnosed with colorectal cancer in the next 5 years. These colorectal cancer risks increase with age, peaking in the 50s (one in seven males and one in 12 females), and then decrease with age (one in 13 males and one in 19 females in their 70s). Annual colonoscopy in 16 males or 25 females in their 50s would prevent one death from colorectal cancer over 5 years while resulting in almost no serious complications. In comparison, annual colonoscopy in 155 males or 217 females in their 20s would prevent one death while resulting in approximately one serious complication. CONCLUSION: For MLH1 or MSH2 mutation carriers, current guidelines recommend colonoscopy every 1 to 2 years starting in their 20s. Our findings support this regimen from age 30 years; however, it might not be justifiable for carriers who are in their 20s. PMID- 25534381 TI - Place of death and the differences in patient quality of death and dying and caregiver burden. AB - PURPOSE: To explore the associations between place of death and quality of death and dying and caregiver burden in terminally ill patients with cancer and their families. METHODS: Two bereavement surveys were conducted in October 2008 and October 2011. A total of 2,247 family caregivers of patients with cancer who were deceased responded to the mail surveys (response rate, 67%). Family members reported patient quality of death and dying and caregiver burden by using the Good Death Inventory and Caregiving Consequences Inventory. RESULTS: Patient quality of death and dying was significantly higher at home relative to other places of dying after adjustment for patient and/or family characteristics (adjusted means): 5.0 (95% CI, 4.9 to 5.2) for home, 4.6 (95% CI, 4.5 to 4.7) for palliative care units, and 4.3 (95% CI, 4.2 to 4.4) for hospitals. For all combinations, pairwise P < .001; the size of the difference between home and hospital was moderate (Hedges' g, 0.45). Home was superior to palliative care units or hospitals with respect to "dying in a favorite place," "good relationships with medical staff," "good relationships with family," and "maintaining hope and pleasure" (P < .001 for all combinations of home v palliative care units and home v hospitals). Home death was significantly associated with a lower overall (P = .03) and financial caregiver burden (P = .004) relative to hospital death. CONCLUSION: Dying at home may contribute to achieving good death in terminally ill patients with cancer without causing remarkably increased caregiver burden. Place of death should be regarded as an essential goal in end-of-life care. PMID- 25534382 TI - Treatment for high-risk patients with early-stage non-small-cell lung cancer. PMID- 25534383 TI - Clearer picture of PMS2-associated lynch syndrome is emerging. PMID- 25534384 TI - Emergency department attendance by patients with cancer in their last month of life: a systematic review and meta-analysis. AB - PURPOSE: To explore factors associated with emergency department (ED) attendance by patients with cancer in their last month of life. METHODS: Five electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Library) were searched through February 2014 for studies investigating ED attendance toward the end of life by adult patients (age 18 years or older) with cancer. No time or language limitations were applied. We performed meta-analysis of factors using a random-effects model, with results expressed as odds ratios (OR) for ED attendance. Sensitivity analyses explored heterogeneity. RESULTS: Thirty studies were identified, reporting three demographic, five clinical, and 13 environmental factors, combining data from five countries and 1,181,842 patients. An increased likelihood of ED attendance was found for men (OR, 1.24; 95% CI, 1.19 to 1.29; I(2), 58.2%), black race (OR, 1.45; 95% CI, 1.40 to 1.50; I(2), 0.0%; reference, white race), patients with lung cancer (OR, 1.17; 95% CI, 1.10 to 1.23; I(2), 59.5%; reference, other cancers), and those patients of the lowest socioeconomic status (SES; OR, 1.15; 95% CI, 1.10 to 1.19; I(2), 0.0%; reference, highest SES). Patients receiving palliative care were less likely to attend the ED in their last month of life (OR, 0.43; 95% CI, 0.36 to 0.51; I(2), 59.4%). CONCLUSION: We identified demographic (men; black race), clinical (lung cancer), and environmental (low SES; no palliative care) factors associated with an increased risk of ED attendance by patients with cancer in their last month of life. Our findings may be used to develop screening interventions and assist policy-makers to direct resources. Future studies should also investigate previously neglected areas of research, including psychosocial factors, and patients' and caregivers' emergency care preferences. PMID- 25534385 TI - Personalizing the duration of androgen-deprivation therapy use in the management of intermediate-risk prostate cancer. PMID- 25534386 TI - Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience. AB - PURPOSE: Outcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN). PATIENTS AND METHODS: We examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed. RESULTS: Fifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years. CONCLUSION: In this large early-stage breast cancer cohort, MN risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of MN must be balanced against the absolute survival benefit of adjuvant chemotherapy. PMID- 25534387 TI - Receipt of chemotherapy among medicare patients with cancer by type of supplemental insurance. AB - PURPOSE: Medicare beneficiaries with cancer bear a greater portion of their health care costs, because cancer treatment costs have increased. Beneficiaries have supplemental insurance to reduce out-of-pocket costs; those without supplemental insurance may face barriers to care. This study examines the association between type of supplemental insurance coverage and receipt of chemotherapy among Medicare patients with cancer who, per National Comprehensive Cancer Network treatment guidelines, should generally receive chemotherapy. PATIENTS AND METHODS: This retrospective, observational study included 1,200 Medicare patients diagnosed with incident cancer of the breast (stage IIB to III), colon (stage III), rectum (stage II to III), lung (stage II to IV), or ovary (stage II to IV) from 2000 to 2005. Using the National Cancer Institute Patterns of Care Studies and linked SEER-Medicare data, we determined each Medicare patient's supplemental insurance status (private insurance, dual eligible [ie, Medicare with Medicaid], or no supplemental insurance), consultation with an oncologist, and receipt of chemotherapy. Using adjusted logistic regression, we evaluated the association of type of supplemental insurance with oncologist consultation and receipt of chemotherapy. RESULTS: Dual eligible patients were significantly less likely to receive chemotherapy than were Medicare patients with private insurance. Patients with Medicare only who saw an oncologist had comparable rates of chemotherapy compared with Medicare patients with private insurance. CONCLUSION: Dual-eligible Medicare beneficiaries received recommended cancer chemotherapy less frequently than other Medicare beneficiaries. With the increasing number of Medicaid patients under the Affordable Care Act, there will be a need for patient navigators and sufficient physician reimbursement so that low-income patients with cancer will have access to oncologists and needed treatment. PMID- 25534389 TI - Hemophagocytic Lymphohistiocytosis With Cerebral Involvement in Richter's Syndrome. PMID- 25534388 TI - Duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trial 9910. AB - PURPOSE: To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer. PATIENTS AND METHODS: One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up. RESULTS: There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen-based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively. CONCLUSION: Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate risk prostate cancer. PMID- 25534390 TI - Magnetic resonance imaging improves breast screening sensitivity in BRCA mutation carriers age >= 50 years: evidence from an individual patient data meta-analysis. AB - PURPOSE: There is no consensus on whether magnetic resonance imaging (MRI) should be included in breast screening protocols for women with BRCA1/2 mutations age >= 50 years. Therefore, we investigated the evidence on age-related screening accuracy in women with BRCA1/2 mutations using individual patient data (IPD) meta analysis. PATIENTS AND METHODS: IPD were pooled from six high-risk screening trials including women with BRCA1/2 mutations who had completed at least one screening round with both MRI and mammography. A generalized linear mixed model with repeated measurements and a random effect of studies estimated sensitivity and specificity of MRI, mammography, and the combination in all women and specifically in those age >= 50 years. RESULTS: Pooled analysis showed that in women age >= 50 years, screening sensitivity was not different from that in women age < 50 years, whereas screening specificity was. In women age >= 50 years, combining MRI and mammography significantly increased screening sensitivity compared with mammography alone (94.1%; 95% CI, 77.7% to 98.7% v 38.1%; 95% CI, 22.4% to 56.7%; P < .001). The combination was not significantly more sensitive than MRI alone (94.1%; 95% CI, 77.7% to 98.7% v 84.4%; 95% CI, 61.8% to 94.8%; P = .28). Combining MRI and mammography in women age >= 50 years resulted in sensitivity similar to that in women age < 50 years (94.1%; 95% CI, 77.7% to 98.7% v 93.2%; 95% CI, 79.3% to 98%; P = .79). CONCLUSION: Addition of MRI to mammography for screening BRCA1/2 mutation carriers age >= 50 years improves screening sensitivity by a magnitude similar to that observed in younger women. Limiting screening MRI in BRCA1/2 carriers age >= 50 years should be reconsidered. PMID- 25534391 TI - Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation. AB - PURPOSE: There have been no randomized trials that have compared peripheral blood (PB) with bone marrow (BM) grafts in the setting of reduced-intensity conditioning (RIC) transplantations for hematologic malignancy. Because immune modulation plays a significant role in sustaining clinical remission after RIC, we hypothesize that higher graft-versus-host disease (GVHD) associated with PB transplantation may offer a survival advantage. PATIENTS AND METHODS: The primary outcome evaluated was overall survival. Cox regression models were built to study outcomes after transplantation of PB (n = 887) relative to BM (n = 219) for patients with acute myeloid leukemia, myelodysplastic syndrome, or non-Hodgkin lymphoma, the three most common indications for unrelated RIC transplantation. Transplantations were performed in the United States between 2000 and 2008. Conditioning regimens consisted of an alkylating agent and fludarabine, and GVHD prophylaxis involved a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). RESULTS: After adjusting for age, performance score, donor-recipient HLA-match, disease, and disease status at transplantation (factors associated with overall survival), there were no significant differences in 5-year rates of survival after transplantation of PB compared with BM: 34% versus 38% with CNI-MTX and 27% versus 20% with CNI-MMF GVHD prophylaxis. CONCLUSION: Survival after transplantation of PB and BM are comparable in the setting of nonirradiation RIC regimens for hematologic malignancy. The effect of GVHD prophylaxis on survival merits further evaluation. PMID- 25534392 TI - Influence of hospital volume on outcomes of percutaneous atrial septal defect and patent foramen ovale closure: a 10-years US perspective. AB - BACKGROUND: Contemporary data regarding percutaneous closure of atrial septal defect/patent foramen ovale (ASD/PFO) are lacking. We evaluated the current trends in utilization of ASD/PFO closure in adults and investigated the effect of annual hospital volume on in-hospital outcomes. METHODS: We queried the Nationwide Inpatient Sample between the years 2001 and 2010 using the International Classification of Diseases (ICD-9-CM) procedure code for percutaneous closure of ASD/PFO with device. Hierarchical mixed effects models were generated to identify the independent multivariate predictors of outcomes. RESULTS: A total of 7,107 percutaneous ASD/PFO closure procedures (weighted n = 34,992) were available for analysis. A 4.7-fold increase in the utilization of this procedure from 3/million in 2001 to 14/million adults in 2010 in US (P < 0.001) was noted. Overall, percutaneous ASD/PFO closure was associated with 0.5% mortality and 12% in-hospital complications. The utilization of intracardiac echocardiography (ICE) increased 15 fold (P < 0.001) during the study period. The procedures performed at the high volume hospitals [2nd (14-37 procedures/year) and 3rd (>38 procedures/year) tertile] were associated with significant reduction in complications, length of stay and cost of hospitalization when compared to those performed at lowest volume centers (<13 procedures/year). Majority (70.5%) of the studied hospitals were found to be performing <10 procedures/year hence deviating from the ACC/AHA/SCAI clinical competency guidelines. CONCLUSIONS: Low hospital volume is associated with an increased composite (mortality and procedural complications) adverse outcome following ASD/PFO closure. In the interest of patient safety, implementation of the current guidelines for minimum required annual hospital volume to improve clinical outcomes is warranted. PMID- 25534393 TI - Changes in inpatients' experiences of hospital care in England over a 12-year period: a secondary analysis of national survey data. AB - OBJECTIVES: Adult inpatient surveys generate approximately 70,000 responses per year about patients' experiences of National Health Service hospital care in England. We examine historical data to assess change between 2002 and 2013 and consider the factors that may have stimulated any change. METHODS: Archived national data from National Health Service Inpatient Surveys between 2002 and 2013 (comprising 840,077 patient responders) were obtained. Questions were selected for inter-year analysis if they had been replicated for at least seven years. The percentage of responses in the most positive category was compared for each question's earliest and most recent year. The statistical significance of differences was tested using chi-square. Also, since such large sample sizes mean that even 1% differences are statistically significant, effect sizes were used to assess the practical significance of those differences. RESULTS: There were statistically significant (p < .001) increases in positive responses to 35 questions, a significant deterioration for 8 questions and no change for 7 questions. There was one 'moderate' improvement (phi = 0.3), six 'small' improvements (phi > 0.1) and one 'small' decline, but differences were not meaningful for 42 questions. The greatest improvements were for patients receiving copies of doctors' letters; single sex ward areas; clinicians' hand washing; ward cleanliness and planned admission waiting times. The greatest decline was that fewer responders said their call bells were usually answered within 2 min. CONCLUSIONS: More aspects of care have improved than have deteriorated. This study highlights the need for a consistent repeated survey programme to detect changes over the long term, since year-to-year changes tend to be small. The greatest improvements are in areas that can be influenced by organisation-wide interventions and many are associated with top-down government policies, targets or media campaigns. Patients' evaluations of many aspects of their interactions with clinicians are unchanged or have declined. Further research could test whether ward-specific facilitated communication of survey results to clinicians could drive improvements in clinician-patient interactions. PMID- 25534395 TI - Probing the secrets of Alzheimer's disease using human-induced pluripotent stem cell technology. AB - Our understanding of Alzheimer's disease (AD) is still incomplete and, as a result, we lack effective therapies. Reprogramming to generate human-induced pluripotent stem cells provides a new approach to the generation of human neurons that carry the genomes of people with familial or sporadic AD. Differentiation of such stem cells to human neurons is already providing new insights into AD and molecular pathways that may provide new targets for effective therapy. These pathways include typical amyloid response pathways, as well as pathways leading from altered behavior of amyloid precursor protein to the elevated phosphorylation of tau protein. There is also a need for standardization of models so that isogenic lines differing only in the familial AD mutation can be compared. PMID- 25534396 TI - Nebulizers for drug delivery to the lungs. AB - INTRODUCTION: Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery. While use of nebulizers remains widespread in the hospital and home setting, certain newer nebulization technologies have enabled more portable use. Varied fundamental processes of droplet formation and breakup are used in modern nebulizers, and these processes impact device performance and suitability for nebulization of various formulations. AREAS COVERED: This review first describes basic aspects of nebulization technologies, including jet nebulizers, various high-frequency vibration techniques, and the use of colliding liquid jets. Nebulizer use in hospital and home settings is discussed next. Complications in aerosol droplet size measurement owing to the changes in nebulized droplet diameters due to evaporation or condensation are discussed, as is nebulization during mechanical ventilation. EXPERT OPINION: While the limelight may often appear to be focused on other delivery devices, such as pressurized metered dose and dry powder inhalers, the ease of formulating many drugs in water and delivering them as aqueous aerosols ensures that nebulizers will remain as a viable and relevant method of respiratory drug delivery. This is particularly true given recent improvements in nebulizer droplet production technology. PMID- 25534397 TI - Symbiotic bacteria contribute to increasing the population size of a freshwater crustacean, Daphnia magna. AB - The filter-feeding crustacean Daphnia is a key organism in freshwater ecosystems. Here, we report the effect of symbiotic bacteria on ecologically important life history traits, such as population dynamics and longevity, in Daphnia magna. By disinfection of the daphniid embryos with glutaraldehyde, aposymbiotic daphniids were prepared and cultured under bacteria-free conditions. Removal of bacteria from the daphniids was monitored by quantitative polymerase chain reaction for bacterial 16S rRNA gene. The population of aposymbiotic daphniids was reduced 10 folds compared with that of the control daphniids. Importantly, re-infection with symbiotic bacteria caused daphniids to regain bacteria and increase their fecundity to the level of the control daphniids, suggesting that symbiotic bacteria regulate Daphnia fecundity. To identify the species of symbiotic bacteria, 16S rRNA genes of bacteria in daphniids were sequenced. This revealed that 50% of sequences belonged to the Limnohabitans sp. of the Betaproteobacteria class and that the diversity of bacterial taxa was relatively low. These results suggested that symbiotic bacteria have a beneficial effect on D. magna, and that aposymbiotic Daphnia are useful tools in understanding the role of symbiotic bacteria in the environmental responses and evolution of their hosts. PMID- 25534398 TI - Extracellular 20S proteasome in BAL and serum of patients with alveolar proteinosis. AB - BACKGROUND AND OBJECTIVES: Pulmonary alveolar proteinosis (PAP) is characterized by alveolar accumulation of surfactant lipoproteins. Proteasomes are involved in the nonlysosomal protein degradation. We hypothesize that enzymatically active proteasome is increased in the alveolar space of PAP. PATIENTS AND METHODS: 31 PAP patients (29 with primary, 2 with secondary form), 14 disease controls (10 with COPD and 4 with emphysema) and 18 healthy controls were studied. 20S Proteasome was measured by ELISA in bronchoalveolar lavage fluid (BALF) and in serum. Enzyme activity of extracellular proteasome (pkat/mg) was measured through fluorogenic substrate cleavage. RESULTS: Proteasome concentration in BAL was higher in PAP patients than in disease controls or healthy subjects (566+/-420 vs 53+/-27 vs 60+/-42ng/ml, respectively, p<0.0001 for both). Serum proteasome levels were higher in PAP patients than in healthy controls (825+/-712 vs 405+/ 176ng/ml, p=0.018). PAP patients with active disease had higher serum levels than those who achieved remission (1317+/-1176 vs 439+/-422ng/ml, p=0.008). Proteasomal enzyme activity was increased in BAL of PAP patients (p<0.05). CONCLUSIONS: The 20S proteasome is increased and active in BAL of patients with PAP. Extracellular proteasome may contribute to the alveolar degradation of accumulated proteins in PAP. PMID- 25534394 TI - Targeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities. AB - Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD. PMID- 25534399 TI - Role of culture of postoperative drainage fluid in the prediction of infection of the surgical site after major oncological operations of the head and neck. AB - Infection of the surgical site after major oncological operations of the head and neck increases mortality and morbidity. The aim of this prospective pilot study was to assess the efficacy of culturing the exudate from the drain after cervical neck dissection to see if it predicted such infection. We studied 40/112 patients with squamous cell cancer of the head and neck who were treated during the last two years and met our inclusion criteria. Six patients developed infections (15%). Reconstruction with pedicled rather than local or microvascular flaps, duration of operation of over 7 hours, the presence of a tracheostomy, and bilateral neck dissection were considered risk factors (p=0.01). Culture of drainage fluid on postoperative day 3 that grew no pathogens predicted that the site would not become infected, with a negative predictive value of 96%. PMID- 25534400 TI - Effect of early tracheostomy on resource utilization and clinical outcomes in critically ill patients: meta-analysis of randomized controlled trials. AB - BACKGROUND: Early tracheostomy may decrease the duration of mechanical ventilation, sedation exposure, and intensive care stay, possibly resulting in improved clinical outcomes, but the evidence is conflicting. METHODS: Systematic review and meta-analysis of randomized trials in patients allocated to tracheostomy within 10 days of start of mechanical ventilation was compared with placement of tracheostomy after 10 days if still required. Medline, EMBASE, the Cochrane Controlled Clinical Trials Register, and Google Scholar were searched for eligible trials. The co-primary outcomes were mortality within 60 days, and duration of mechanical ventilation, sedation, and intensive care unit stay. Secondary outcomes were the number of tracheostomy procedures performed, and incidence of ventilator-associated pneumonia (VAP). Outcomes are described as relative risk or weighted mean difference with 95% confidence intervals. RESULTS: Of note, 4482 publications were identified and 14 trials enrolling 2406 patients were included. Tracheostomy within 10 days was not associated with any difference in mortality [risk ratio (RR): 0.93 (0.83-1.05)]. There were no differences in duration of mechanical ventilation [-0.19 days (-1.13-0.75)], intensive care stay [-0.83 days (-2.05-0.40)], or incidence of VAP. However, duration of sedation was reduced in the early tracheostomy groups [-2.78 days (-3.68 to -1.88)]. More tracheostomies were performed in patients randomly assigned to receive early tracheostomy [RR: 2.53 (1.18-5.40)]. CONCLUSION: We found no evidence that early (within 10 days) tracheostomy reduced mortality, duration of mechanical ventilation, intensive care stay, or VAP. Early tracheostomy leads to more procedures and a shorter duration of sedation. PMID- 25534401 TI - An examination of the evidence in culturally adapted evidence-based or empirically supported interventions. AB - Measurement yields perhaps the most critical evidence influencing whether culturally adapted evidence- based practice (EBP) and empirically supported treatments (EST) are deemed more effective for African Americans, Latino/a Americans, Asian/Pacific Islander Americans, Native Americans, and related immigrant groups than standard treatments, as well as for determining the validity of results of surveys of health conditions in nondominant populations internationally. However, little attention has been given to measuring the effects of race and ethnic culture, as experiential constructs rather than sociodemographic categories, on diagnosis, the treatment process, and outcomes. Three meta-analyses of culturally adapted treatments and three studies cited in them were analyzed to determine the ways in which researchers incorporated measurement of racial and ethnic cultural dynamics as explicit factors in any phase of their interventions. The analysis revealed that researchers did not report adapting standard measures to address cultural influences, nor did they define symptoms from participants' cultural or racial experiences. The author concludes that although there are criteria for judging good research designs, which may or not be feasible for research on nondominant racial and ethnic groups, there are no paradigms for developing measures or for interpreting existing measures to incorporate ethnicity and racialized experiences. Some principles from cross-cultural assessment research (i.e., functional, conceptual, metric, and linguistic equivalence) are adapted to suggest how measures for investigating the effectiveness of culturally adapted interventions for nondominant ethnic and racialized groups might be developed and/or used more appropriately throughout the course of the intervention. PMID- 25534403 TI - A reddish nodule on the nose. PMID- 25534402 TI - The risks of do-it-yourself and over-the-counter devices for tattoo removal. AB - The tattoo removal market has boomed over the years following the increased prevalence of tattooed individuals around the world. Surgery and laser are currently the gold standards for tattoo removal. However, both of them have drawbacks. Surgery is better suited for small tattoos in areas of adequate skin laxity but leave a scar, while laser removal is a long and painful procedure, with no guarantee of a complete efficacy. Both are expensive procedures, and not all individuals are ready to fund them privately. Consequently, some individuals are in the search of faster, easier, and cheaper procedures that can be performed either by themselves or by laypeople. The unregulated market of internet provides a favorable ground for many websites to offer various tattoo removal methods. Besides, some tattooists and other non-medical laypeople have started to get interested by such a growing market, especially as some laser devices manufactured in Asia are now available at competitive prices, and due to weaknesses in the EU legislation regarding the use of lasers for cosmetic procedures by non-medical laypeople. We review here different do-it-yourself and over-the-counter tattoo removal methods. We discuss the potential risks for tattooed individuals and stress the importance of a better regulation of such a market. PMID- 25534404 TI - Ten-year history of erythematous nodules on the lower extremities. PMID- 25534405 TI - The frequencies of haplotypes defined by three polymorphisms of the IL-31 gene: 1066, -2057, and IVS2+12 in Polish patients with atopic dermatitis. AB - BACKGROUND: Severe pruritus is one of the cardinal symptoms of atopic dermatitis (AD). Recently, the interleukin (IL)-31 cytokine has been implicated in the induction and maintenance of severe pruritus and chronic skin inflammation in several pruritic skin diseases, including AD. OBJECTIVE: We aimed to investigate the association of the IL-31 gene haplotypes with pruritus and severity of AD, as well as their correlation to the serum IL-31 levels. METHODS: A total of 127 patients with AD and 96 healthy controls were analyzed for polymorphic variants of the IL-31 gene using an amplification refractory mutation system-polymerase chain reaction method. IL-31 haplotype frequencies were estimated with the use of tagging single nucleotide polymorphisms, expectation-maximization, and Excoffier Laval-Balding algorithms. Serum IL-31 levels were measured using a standard enzyme-linked immunosorbent assay kit. RESULTS: The frequency of AAG, AGA, AGG, and GAA haplotypes of the IL-31 gene was higher in patients with AD than in controls. The mean IL-31 levels in serum were lower in controls than in the patients (P < 0.00001) and were higher in those with severe vs. mild AD (P = 0.008). No correlation was found between IL-31 and the severity of pruritus. The haplotype AAA was associated with a high IL-31 serum level (P = 0.008) and with severe AD (high SCORing Atopic Dermatitis index) (P = 0.013). The haplotype GAA was associated with a severe form of pruritus (P = 0.016) and the haplotype GGG with the mild one (P = 0.07). CONCLUSION: The results of this study suggest that the severity of AD in a Polish population is associated with some specific haplotypes of the IL-31 gene, which can indicate their prognostic role also renews the questions concerning the role of IL-31 in pruritus in AD. PMID- 25534406 TI - Factors associated with clinical characteristics and symptoms in a case series of oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is a relatively common chronic inflammatory disease whose etiopathogenesis is not completely understood. Several factors have been proposed in an attempt to explain the variety of clinical manifestations and periods of exacerbation and remission of symptoms of these lesions. The objective of this study was to associate local factors, systemic diseases, and level of anxiety with clinical characteristics of OLP. METHODS: The following factors were analyzed in 37 patients with OLP: presence of smoking, alcohol consumption, diabetes mellitus, hypertension, and hepatitis C virus infection. Anxiety was measured by the Spielberger State-Trait Anxiety Inventory. These variables were associated with clinical form and symptoms (chi-squared/Fisher's exact test). RESULTS: The erosive form was the most prevalent presentation (57.1%). Symptoms were reported by 45.7% of the patients. Most patients were non-smokers (97.3%), and none of them was an alcoholic. Diabetes and hypertension were present in 10.8% and 16.2% of the patients, respectively. Only one patient was hepatitis C virus seropositive, and 78.4% presented moderate levels of anxiety. No significant association was observed between the variables studied and clinical form or symptoms. CONCLUSIONS: In this study, no association was observed between local and systemic factors or level of anxiety and clinical characteristics of OLP. PMID- 25534407 TI - A clinicotherapeutic analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis with an emphasis on the predictive value and accuracy of SCORe of Toxic Epidermal Necrolysis. AB - BACKGROUND: The SCORTEN scale (SCORe of Toxic Epidermal Necrolysis) is widely used to predict mortality in patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Although it is largely a useful tool, the predictive ability of the scale is variable, and modifications to the existing scale have been suggested. In addition, there is controversy regarding the roles of active therapy and conservative management. OBJECTIVES: This study was conducted to assess outcomes in SJS/TEN patients managed conservatively and to analyze the predictive performance of SCORTEN. METHODS: Sixty patients were studied prospectively from October 2008 to September 2011. The accuracy of SCORTEN in predicting mortality was analyzed on days 1, 3, and 5 of admission. All patients were managed conservatively. RESULTS: The discriminative power of SCORTEN was acceptable, being best on day 5. The agreement between actual and predicted mortality was poor, as indicated by a low P-value of the Hosmer Lemeshow statistic. Only three parameters (heart rate, blood urea, and serum bicarbonate) were found to be significant on multivariate analysis, and all of these represented components within the original SCORTEN scale. The mortality rate was 16.7%. All deaths occurred within the first two weeks (8-12 days). CONCLUSIONS: Serial analysis using SCORTEN is better than analysis performed only on day 1. Although the scale is largely useful, its performance is influenced by the demographic profile of the study population; minor modifications based on the population studied may increase the predictive accuracy of the original SCORTEN. In addition, conservative management is a valid therapeutic option, is preferable to treatment with steroids and immunosuppressants, and is highly recommended. PMID- 25534408 TI - Pyoderma gangrenosum after aortic aneurysm repair: an umpteenth example of immunocompromised district. PMID- 25534409 TI - Proposing the demise of the terms "Asian skin" and "Asian skin type". PMID- 25534410 TI - Recognizing and treating retronychia. PMID- 25534411 TI - Cutaneous markers of systemic manifestations of tuberous sclerosis complex. PMID- 25534414 TI - Effects of diet on adenosine monophosphate-activated protein kinase activity and disease progression in an amyotrophic lateral sclerosis model. AB - OBJECTIVES: To study the effects of diet on disease progression and activity levels of adenosine monophosphate-activated protein kinase (AMPK), and its downstream targets, in an amyotrophic lateral sclerosis (ALS) animal model. METHODS: AMPK activity was measured in cerebral cortex, spinal cord, cerebellum and hindlimb muscle tissue using immunohistochemistry in transgenic mice overexpressing human superoxide dismutase-1 (SOD1(G93A)) fed a high-fat (HFD), standard ad libitum (AL) or calorie-restricted (CR) diet; AMPK activity was also measured in wild-type (SOD1(WT)) mice. Activity of AMPK and phospho-AMPK, acetyl coenzyme-A carboxylase (ACC), phospho-ACC and heat shock protein-70 (Hsp70) were also measured using Western blot. Food intake and grip strength were recorded; body composition was analysed using dual energy X-ray absorptiometry. Motor neuron survival was observed using Nissl staining. RESULTS: AMPK activity increased and Hsp70 expression decreased in AL SOD1(G93A) mice compared with SOD1(WT) mice in spinal cord and hindlimb muscle. Compared with AL SOD1(G93A) mice, CR SOD1(G93A) mice showed increased AMPK activity, downregulated Hsp70 expression, reduced motor neuron survival in spinal cord and hindlimb muscle and reduced lifespan; HFD SOD1(G93A) mice showed opposite effects. CONCLUSIONS: In this mouse model, increased AMPK activity seems to play a negative role in motor neuron survival, possibly through a novel mechanism involving Hsp70 downregulation. These changes can be modified by diet. Inhibition of AMPK may provide a therapeutic strategy for ALS. PMID- 25534415 TI - Reply to commentary on "spectral characterization of the binding and conformational changes of serum albumins upon interaction with an anticancer drug, anastrozole". PMID- 25534416 TI - A colorimetric and fluorescent turn on chemodosimeter for Pd(2+) detection. AB - A novel rhodamine derivative L had been successfully developed and well characterized by NMR, and Mass spectroscopy. Chemodosimeter L is a naked-eye fluorescent chemodosimeter for Pd(2+) in aqueous solution. More over the detection limit of Chemodosimeter L is in 10(-7)M level. The Ligand to L ratio was determined to be 1:2 according to the job's plot. PMID- 25534417 TI - The c-MET/PI3K signaling is associated with cancer resistance to doxorubicin and photodynamic therapy by elevating BCRP/ABCG2 expression. AB - Overexpression of BCRP/ABCG2, a xenobiotic efflux transporter, is associated with anticancer drug resistance in tumors. Proto-oncogene c-MET induces cancer cell proliferation, motility, and survival, and its aberrant activation was found to be a prognostic factor in advanced ovarian cancers. In the present study, we investigated the potential crossresistance of doxorubicin-resistant ovarian cancer cells to the pheophorbide a (Pba)-based photodynamic therapy (PDT), and suggest c-MET and BCRP/ABCG2 overexpression as an underlying molecular mechanism. The doxorubicin-resistant A2780 cell line (A2780DR), which was established by incubating A2780 with stepwise increasing concentrations of doxorubicin, showed low levels of cellular Pba accumulation and reactive oxygen species generation, and was more resistant to PDT cytotoxicity than A2780. In a microarray analysis, BCRP/ABCG2 was found to be the only drug transporter whose expression was upregulated in A2780DR; this increase was confirmed by Western blot and immunocytochemical analyses. As functional evidence, the treatment with a BCRP/ABCG2-specific inhibitor reversed A2780DR resistance to both doxorubicin and PDT. We identified that c-MET increase is related to BCRP/ABCG2 activation. The c MET downstream phosphoinositide 3-kinase (PI3K)/AKT signaling was activated in A2780DR and the inhibition of PI3K/AKT or c-MET repressed resistance to doxorubicin and PDT. Finally, we showed that the pharmacological and genetic inhibition of c-MET diminished levels of BCRP/ABCG2 in A2780DR. Moreover, c-MET inhibition could repress BCRP/ABCG2 expression in breast carcinoma MDA-MB-231 and colon carcinoma HT29, resulting in sensitization to doxorubicin. Collectively, our results provide a novel link of c-MET overexpression to BCRP/ABCG2 activation, suggesting that this mechanism leads to crossresistance to both chemotherapy and PDT. PMID- 25534418 TI - Gender differences in psychological distress in Spain. AB - BACKGROUND AND AIMS: Epidemiological and community-based surveys consistently report gender differences in mental health. This study examines gender differences in psychological distress by analyzing the relevance of stress, coping styles, social support and the time use. METHODS: Psychological tests were administered to a convenience sample of 1,337 men and 1,251 women from the Spanish general population, aged between 18 and 65 and with different socio demographic characteristics, although both the women and men groups had similar age and educational levels. RESULTS: Women had more psychological distress than men. Although psychological distress in the women and men groups have some common correlates such as more stress, more emotional and less rational coping and less social support, we find some gender differences. Work role dissatisfaction was more associated with distress in the men than in the women group. In addition, women's distress was associated with more daily time devoted to childcare and less to activities they enjoy, and men's distress was associated with more time devoted to housework and less to physical exercise. CONCLUSIONS: Social roles traditionally attributed to women and men - and the differences in the use of time that such roles entail - are relevant in gender differences in psychological distress. PMID- 25534419 TI - Obesity bias, medical technology, and the hormonal hypothesis: should we stop demonizing fat people? AB - There is adequate evidence to demonstrate that bias toward obese individuals by health professionals is common. Bias predisposes to errors in medical judgment and care. There is also evidence to show that the pathophysiology of obesity is more complex than eating too much and moving too little. Widespread obesity is a new phenomenon in the United States and reflects changes in culture, including food, at many levels. The modern abundance of low-cost, available, palatable, energy-dense processed foods and the ability of these foods to activate central nervous system centers that drive food preference and overeating appear to play an important role in the obesity epidemic. The usual hormonal systems that promote body weight homeostasis appear to have been counterbalanced by pleasurable (hedonic) influences these foods generate in higher neurologic networks, including the limbic system. The use of medical technology, such as functional magnetic resonance imaging, to quantitate hedonic responses to food, enhance taste, and effectively develop and market commercial food products has produced new areas of ethical concern and opportunities to better understand eating and satiety. These developments further demonstrate the urgency to address the bias that exists toward obese patients. PMID- 25534420 TI - Risk of venous thromboembolism in patients with rheumatoid arthritis: initiating disease-modifying antirheumatic drugs. AB - OBJECTIVES: Recent research suggests that rheumatoid arthritis increases the risk of venous thromboembolism. This study compared the risk of venous thromboembolism in patients with newly diagnosed rheumatoid arthritis initiating a biologic disease-modifying antirheumatic drug (DMARD) with those initiating methotrexate or a nonbiologic DMARD. METHODS: We conducted a population-based cohort study using US insurance claims data (2001-2012). Three mutually exclusive, hierarchical DMARD groups were used: (1) a biologic DMARD with and without nonbiologic DMARDs; (2) methotrexate without a biologic DMARD; or (3) nonbiologic DMARDs without a biologic DMARD or methotrexate. We calculated the incidence rates of venous thromboembolism. Cox proportional hazard models stratified by propensity score (PS) deciles after asymmetric PS trimming were used for 3 pairwise comparisons, controlling for potential confounders at baseline. RESULTS: We identified 29,481 patients with rheumatoid arthritis with 39,647 treatment episodes. From the pairwise comparison after asymmetric PS trimming, the incidence rate of hospitalization for venous thromboembolism per 1000 person years was 5.5 in biologic DMARD initiators versus 4.4 in nonbiologic DMARD initiators and 4.8 in biologic DMARD initiators versus 3.5 in methotrexate initiators. The PS decile-stratified hazard ratio of venous thromboembolism associated with biologic DMARDs was 1.83 (95% confidence interval [CI], 0.91 3.66) versus nonbiologic DMARDs and 1.39 (95% CI, 0.73-2.63) versus methotrexate. The hazard ratio of venous thromboembolism in biologic DMARD initiators was the highest in the first 180 days versus nonbiologic DMARD initiators (2.48; 95% CI, 1.14-5.39) or methotrexate initiators (1.80; 95% CI, 0.90-3.62). CONCLUSIONS: The absolute risk for venous thromboembolism was low in patients with newly diagnosed rheumatoid arthritis. Initiation of a biologic DMARD seems to be associated with an increased short-term risk of hospitalization for venous thromboembolism compared with initiation of a nonbiologic DMARD or methotrexate. PMID- 25534421 TI - Components of depression and 6-year mortality after an acute coronary syndrome. AB - BACKGROUND: Post-myocardial infarct depression includes both somatic depressive symptoms and nonsomatic cognitive symptoms. Their respective relationships to long-term survival are unclear. METHODS: Depression was diagnosed by measuring the Beck Depression Inventory-II (BDI-II) on consecutive patients who presented with acute coronary syndrome in 2005. Six-year mortality data were extracted from the National Health Index. This study investigated whether mortality was related to the somatic or cognitive elements of the BDI-II score, controlling for baseline characteristics including the Global Registry of Acute Coronary Events score. The BDI-II, somatic, and cognitive scores were treated as continuous variables. RESULTS: Of the 277 patients, 52 died over 6 years. Higher BDI-II score did not predict mortality at 6 years (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.98-1.06). In the Cognitive/Affective-Somatic model, somatic depressive symptoms (OR, 1.10; 95% CI, 1.01-1.20) predicted all-cause mortality, but cognitive/affective depressive symptoms (OR, 1.01; 95% CI, 0.96-1.08) did not. This association attenuated after controlling for age and sex (OR, 1.10; 95% CI, 0.99-1.22), and age, sex, and Global Registry of Acute Coronary Events score (OR, 1.09; 95% CI, 0.99-1.21). Results from the Somatic/Affective-Cognitive model did not reach statistical significance. Differences were small and unlikely to be of clinical importance. CONCLUSIONS: In patients with acute coronary syndrome, those who died had a higher baseline BDI-II score, particularly somatic score, although this did not reach statistical significance. PMID- 25534422 TI - Evaluation of pharmacist care for hypertension in the Veterans Affairs patient centered medical home: a retrospective case-control study. AB - OBJECTIVE: The study objective was to evaluate a pharmacist hypertension care management program within the patient-centered medical home. METHODS: This was a retrospective case-control study. Cases included all patients with hypertension who were referred to the care management program, and controls included patients with hypertension who were not referred to the program during the same 1-year period. Each case was matched to a maximum of 3 controls on the basis of primary care physician, age +/-5 years, gender, diagnoses of diabetes and kidney disease, baseline systolic blood pressure +/-10 mm Hg, and number of unique antihypertensive medications. Pharmacists provided a hypertension care management program under an approved scope of practice that allowed pharmacists to meet individually with patients, adjust medications, and provide patient education. Primary outcomes were systolic blood pressure and diastolic blood pressure at 6 and 12 months. Multivariate regression models compared each blood pressure end point between cases and controls adjusting for age, comorbidities, baseline blood pressure, and baseline number of blood pressure medications. RESULTS: A total of 573 patients were referred to the hypertension program; 86% (465/543) had at least 1 matched control and were included as cases in the analyses; 3:1 matching was achieved in 90% (418/465) of cases. At baseline, cases and controls did not differ with respect to age, gender, race, or comorbidity; baseline blood pressure was higher (139.9/80.0 mm Hg vs 136.7/78.2 mm Hg, P <= .0002) in the cases compared with controls. Multivariate regression modeling identified significantly lower systolic blood pressure for the cases compared with controls at both 6 and 12 months (6-month risk ratio [RR], 9.7; 95% confidence interval [CI], 2.7-35.3; 12-month RR, 20.3; 95% CI, 4.1-99.2; P < .01 for both comparisons). Diastolic blood pressure was significantly lower at 12 months (RR, 2.9; 95% CI, 1.2-7.1; P < .01) but not at 6 months (RR, 1.0; 95% CI, 0.31-3.4; P = .9) for the cases compared with controls. CONCLUSIONS: Patients who were referred to the pharmacist hypertension care management program had a significant improvement in most blood pressure outcomes. This program may be an effective method of improving blood pressure control among patients in a medical home model of primary care. PMID- 25534423 TI - Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry. AB - OBJECTIVE: Atrial fibrillation is often asymptomatic, but outcomes require further characterization. The study objective was to investigate the clinical presentation, management, and outcomes in asymptomatic and symptomatic patients with atrial fibrillation who were prospectively enrolled in the EurObservational Research Programme - Atrial Fibrillation (EORP-AF) Pilot General Registry. METHODS: A total of 3119 patients were enrolled, and 1237 (39.7%) were asymptomatic (European Heart Rhythm Association [EHRA] score I). Among symptomatic patients, 963 (51.2%) had mild symptoms (EHRA score II) and 919 (48.8%) had severe or disabling symptoms (EHRA III-IV). Permanent atrial fibrillation was 3-fold more common in asymptomatic patients than in symptomatic patients. RESULTS: On multivariate analysis, male gender (odds ratio [OR], 1.630; 95% confidence interval [CI], 1.384-1.921), older age (OR, 1.019; 95% CI, 1.012 1.026), previous myocardial infarction (OR, 1.681; 95% CI, 1.350-2.093), and limited physical activity (OR, 1.757; 95% CI, 1.495-2.064) were associated significantly with asymptomatic (EHRA I) atrial fibrillation. Fully asymptomatic atrial fibrillation (absence of current and previous symptoms) was present in 520 patients (16.7%) and was associated independently with male gender, age, and previous myocardial infarction. Appropriate guideline-based prescription of oral anticoagulants was lower in these patients, and aspirin was prescribed more frequently. Mortality at 1 year was more than 2-fold higher in asymptomatic patients compared with symptomatic patients (9.4% vs 4.2%, P < .0001) and was associated independently with older age and comorbidities, including chronic kidney disease and chronic heart failure. CONCLUSIONS: Asymptomatic atrial fibrillation is common in daily cardiology practice and is associated with elderly age, more comorbidities, and high thromboembolic risks. A higher 1-year mortality was found in asymptomatic patients compared with symptomatic patients. PMID- 25534424 TI - Spectroscopic properties of morin in various CH3OH-H2O and CH3CN-H2O mixed solvents. AB - The specific fluorescence properties of morin (3,2',4',5,7-pentahydroxyflavone) were studied in various CH3OH-H2O and CH3CN-H2O mixed solvents. Although the dihedral angle is large in the S0 state, morin has an almost planar molecular structure in the S1 state owing to the very low rotational energy barrier around the interring bond between B and the A, C ring. The excited state intramolecular proton transfer (ESIPT) at the S1 state cannot occur immediately after excitation, S1 -> S0 fluorescence can be observed. Two conformers, Morin A and B have been known. At the CH3OH-H2O, Morin B will be the principal species but at the CH3CN-H2O, Morin A is the principal species. At the CH3OH-H2O, owing to the large Franck-Condon (FC) factor for S2 -> S1 internal convernal (IC) and flexible molecular structure, only S1 -> S0 fluorescence was exhibited. At the CH3CN-H2O, as the FC factor for S2 -> S1 IC is small and molecular structure is rigid, S2 -> S0 and S1 -> S0 dual fluorescence was observed. This abnormal fluorescence property was further supported by the small pK1 value, effective delocalization of the lone pair electrons of C(2')-OH to the A, C ring, and a theoretical calculation. PMID- 25534425 TI - Identity disturbance and problems with emotion regulation are related constructs across diagnoses. AB - OBJECTIVE: This study examined the relation between identity disturbance and emotion dysregulation in a cross-diagnostic sample. We assessed whether these constructs are related and relevant beyond borderline personality disorder (BPD). METHOD: We recruited 127 participants who completed measures assessing identity disturbance, emotion dysregulation, anxiety, and depression. The sample included primarily depressed adults meeting criteria for multiple diagnoses as well as psychiatrically healthy participants. RESULTS: Identity disturbance was significantly higher among psychiatric participants with and without BPD compared to healthy controls. Emotion dysregulation was a significant predictor of identity disturbance, even when controlling for BPD diagnosis, depression, and anxiety. In particular, clarity in emotional situations and problems using emotion regulation strategies were most closely related to identity disturbance. CONCLUSION: The results of this study suggest that future research should examine identity disturbance and its relation with emotion regulation transdiagnostically. PMID- 25534427 TI - Down-regulation of miR-144 elicits proinflammatory cytokine production by targeting toll-like receptor 2 in nonalcoholic steatohepatitis of high-fat-diet induced metabolic syndrome E3 rats. AB - OBJECTIVE: To analyze regulatory microRNA(s) leading to increased TLR2 expression in livers of high-fat-diet induced metabolic syndrome (HFD-MetS) in rats with non alcoholic steatohepatitis (NASH). METHODS: TLRs, inflammatory cytokines, candidate miRNAs targeting key TLR and its cellular localization were determined in liver. The miR-144 targeting TLR2 and regulating TLR2 signaling were further determined by dual luciferase reporter assay and miR-144 mimics or inhibitor. RESULTS: Expression of miR-144 was negatively correlated with TLR2 expression in Kupffer cells. The miR-144 bound to 3'UTR of rat TLR2 mRNA. In addition, compared to control group, TLR2, TNF-alpha, IFN-gamma and activation of NF-kappaB decreased after miR-144 mimic challenge in NR8383 cells and BMM from E3 rats, which could be compensated by Pam3CSK4; while opposite effects on their expressions were observed after miR-144 inhibitor administration, augmented by Pam3CSK4. CONCLUSION: Decreased miR-144 could enhance TNF-alpha and IFN-gamma production by targeting TLR2 in vitro, and might contribute to TLR2 up-regulation and the progression of NASH in HFD-MetS E3 rats. This might offer a novel and potential target for NASH therapy. PMID- 25534429 TI - Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. AB - Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression. PMID- 25534428 TI - Calcitonin gene-related peptide: key regulator of cutaneous immunity. AB - Calcitonin gene-related peptide (CGRP) has been viewed as a neuropeptide and vasodilator. However, CGRP is more appropriately thought of as a pleiotropic signalling molecule. Indeed, CGRP has key regulatory functions on immune and inflammatory processes within the skin. CGRP-containing nerves are intimately associated with epidermal Langerhans cells (LCs), and CGRP has profound regulatory effects on Langerhans cell antigen-presenting capability. When LCs are exposed to CGRP in vitro, their ability to present antigen for in vivo priming of naive mice or elicitation of delayed-type hypersensitivity is inhibited in at least some situations. Administration of CGRP intradermally inhibits acquisition of immunity to Th1-dominant haptens applied to the injected site while augmenting immunity to Th2-dominant haptens, although the cellular targets of activity in these experiments remain unclear. Although CGRP can be a pro-inflammatory agent, several studies have demonstrated that administration of CGRP can inhibit the elicitation of inflammation by inflammatory stimuli in vivo. In this regard, CGRP inhibits the release of certain chemokines by stimulated endothelial cells. This is likely to be physiologically relevant as cutaneous blood vessels are innervated by sensory nerves. Exciting new studies suggest a significant role for CGRP in the pathogenesis of psoriasis and, most strikingly, that CGRP inhibits the ability of LCs to transmit the human immunodeficiency virus 1 to T lymphocytes. A more complete understanding of the role of CGRP in the skin immune system may lead to new and novel approaches for the therapy of immune-mediated skin disorders. PMID- 25534431 TI - Synthesis and preliminary biological evaluation of S-11C-methyl-D-cysteine as a new amino acid PET tracer for cancer imaging. AB - S-(11)C-methyl-L-cysteine (LMCYS) is an attractive amino acid tracer for clinical tumor positron emission tomography (PET) imaging. D-isomers of some radiolabeled amino acids are potential PET tracers for tumor imaging. In this work, S-(11)C methyl-D-cysteine (DMCYS), a D-amino acid isomer of S-(11)C-methyl-cysteine for tumor imaging was developed and evaluated. DMCYS was prepared by (11)C methylation of the precursor D-cysteine, with an uncorrected radiochemical yield over 50 % from (11)CH3I within a total synthesis time from (11)CO2 about 12 min. In vitro competitive inhibition studies showed that DMCYS uptake was primarily transported through the Na(+)-independent system L, and also the Na(+)-dependent system B(0,+) and system ASC, with almost no system A. In vitro incorporation experiments indicated that almost no protein incorporation was found in Hepa 1-6 hepatoma cell lines. Biodistribution studies demonstrated higher uptake of DMCYS in pancreas and liver at 5 min post-injection, relatively lower uptake in brain and muscle, and faster radioactivity clearance from most tissues than those of L isomer during the entire observation time. In the PET imaging of S180 fibrosarcoma-bearing mice and turpentine-induced inflammatory model mice, 2-(18)F fluoro-2-deoxy-D-glucose (FDG) exhibited significantly high accumulation in both tumor and inflammatory lesion with low tumor-to-inflammation ratio of 1.40, and LMCYS showed low tumor-to-inflammation ratio of 1.64 at 60 min post-injection. By contrast, DMCYS showed moderate accumulation in tumor and very low uptake in inflammatory lesion, leading to relatively higher tumor-to-inflammation ratio of 2.25 than (11)C-methyl-L-methionine (MET) (1.85) at 60 min post-injection. Also, PET images of orthotopic transplanted glioma models demonstrated that low uptake of DMCYS in normal brain tissue and high uptake in brain glioma tissue were observed. The results suggest that DMCYS is a little better than the corresponding L-isomers as a potential PET tumor-detecting agent and is superior to MET and FDG in the differentiation of tumor from inflammation. PMID- 25534430 TI - Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127% of normal), isoleucine (139%), and valine (147%) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients. PMID- 25534432 TI - Exploring oral health and hygiene practices in the Algonquin community of Rapid Lake, Quebec. AB - INTRODUCTION: Early childhood caries (ECC), a disease characterized by tooth decay in the primary teeth of children, has become particularly burdensome in Aboriginal communities in Canada. Prevalence estimates of ECC range between 50% and 100%. Most concerning are the severe cases of ECC that require treatment with restorative surgery under general anesthesia. These surgeries often displace children and families from their local communities to specialty hospitals for treatment; further, they are very costly to dental insurance payers such as the government. This study used community-based participatory research (CBPR) to explore oral health and hygiene practices in the Algonquin community of Rapid Lake, Quebec. A key goal of the study was to create a culturally adapted activity to promote children's oral health and hygiene practices. METHODS: Focused ethnography was used to explore oral health beliefs and practices, and factors related to child oral health promotion with community members. Participants included children, parents, educators, healthcare workers, youth workers and elders. Semi-structured interviews were conducted with key informants. Following, two focus group interviews were conducted: one with parents and one with school children. All data were audio-recorded, transcribed and analyzed iteratively using thematic analysis. Preliminary findings were then used to develop oral health promoting activities for children in the community. These activities were designed in collaboration with community workers. RESULTS: Three main themes emerged from the analysis: (1) a gap existed between oral health knowledge and oral health behaviors; (2) challenges for oral health promotion included attitudes and beliefs, access, and priorities; and (3) parents needed to be further integrated into health promotion strategies. Key outcomes included: (1) the development of Eagles & Otters, a game designed to increase children's oral health knowledge; (2) an activity sheet to promote child oral health behaviors in the home; and (3) increased capacity in oral health promotion in local youth, community research partners and the student researcher. CONCLUSIONS: The findings of this study highlight the importance of both local and broader systemic interventions to promote children's oral health. At the local level, child oral health and hygiene was promoted through the development of activities designed to increase children's oral health knowledge and behaviors both at school and in the home where parents were directly implicated. Systemic level interventions are needed to address factors related to the social determinants of health, including cultural traditions, economic security, food security, and housing status. These factors contribute to overall health and enable the necessary conditions to promote and sustain oral health. PMID- 25534434 TI - How Is ADHD Assessed and Documented? Examination of Psychological Reports Submitted to Determine Eligibility for Postsecondary Disability. AB - OBJECTIVE: To examine how ADHD evaluations are documented for postsecondary students requesting disability eligibility. METHOD: A total of 100 psychological reports submitted for eligibility determination were coded for documentation of Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, methods and instruments used in the evaluations, and recommended academic accommodations. RESULTS: Results showed that a minimal number of reports (<=1%) documented that students met all DSM criteria for ADHD. Psychologists rarely documented childhood impairment, symptoms across settings, or the use of rule-outs. Symptom severity was emphasized over current impairment. The majority of psychologists utilized a multi-informant, multi-method evaluation approach, but certain methods (e.g., symptom validity tests, record reviews) were limited in use. Most reports included recommendations for academic accommodations, with extended time being the most common (72%). CONCLUSION: This study raises awareness to the aspects of adequate ADHD evaluation and subsequent documentation that can be improved by psychologists. Recommendations are made regarding valid documentation of ADHD for disability determination purposes. PMID- 25534435 TI - A "simplified" culotte technique using two dedicated bifurcation stents and additional angiographic stent enhancement to treat a complex bifurcation lesion in non-ST segment elevation myocardial infarction with poor left ventricular function. AB - We present a case of a bifurcation lesion treated with two dedicated sirolimus eluting bifurcation stents, BiOSS Lim in the setting of non-ST elevation myocardial infarction and poor left ventricular function. We demonstrate the feasibility of a new technique, a "simplified" culotte technique. The key differences of this new technique compared with conventional culotte are: better sizing of the stent due to the specific design of the stent with a larger proximal diameter and smaller distal diameter, direct stenting of the second stent without predilatation of the stent struts of the first deployed stent, and possibility to perform post-dilatation directly with properly sized balloons without additional predilatation. PMID- 25534436 TI - Lanthanide-doped nanocrystals: strategies for improving the efficiency of upconversion emission and their physical understanding. AB - The fundamental understanding of lanthanide-doped upconverted nanocrystals remains a frontier area of research because of potential applications in photonics and biophotonics. Recent studies have revealed that upconversion luminescence dynamics depend on host crystal structure, size of the nanocrystals, dopant concentration, and core-shell structures, which influence site symmetry and the distribution and energy migration of the dopant ions. In this review, we bring to light the influences of doping/co-doping concentration, crystal phase, crystal size of the host, and core-shell structure on the efficiency of upconversion emission. Furthermore, the lattice strain, due to a change in the crystal phase and by the core-shell structure, strongly influences the upconversion emission intensity. Analysis suggests that the local environment of the ion plays the most significant role in modification of radiative and nonradiative relaxation mechanisms of overall upconversion emission properties. Finally, an outlook on the prospects of this research field is given. PMID- 25534433 TI - Reduced IFNlambda4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes. AB - Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNlambda4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNlambda4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNlambda4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNlambda4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance. PMID- 25534437 TI - Corticotropin-releasing hormone and urocortin promote phagocytosis of rat macrophages through convergent but distinct pathways. AB - AIMS: Phagocytosis plays essential roles during inflammation and immune response. This study aims to explore the underlying mechanism of corticotropin-releasing hormone (CRH) and urocortin (UCN)-promoted phagocytosis of rat macrophages. MAIN METHODS: To induce phagocytosis, rat macrophages were incubated with carboxylated fluorescent microspheres. The phagocytosis activity was evaluated by flow cytometric analysis. Actin reorganization was determined by immunostaining with TRITC-labeled phalloidin and transmission electron microscopy (TEM) analysis. Protein expressions of p-RhoA, p-Rac1, p-extracellular signal-related kinase (ERK)1/2 and GAPDH were examined by Western blotting. Protein kinase C (PKC) and protein kinase A (PKA) activities were examined using PreTag non-radio activity assay. KEY FINDINGS: Administration of CRH or UCN alone significantly enhanced phagocytosis of microspheres by rat macrophages, as well as actin reorganization. Ligation of CRH and UCN with CRH receptor increased the phosphorylation of both RhoA and Rac1. Inhibition of RhoA/Rac1 signal pathway suppressed CRH- or UCN enhanced phagocytosis and actin reorganization. Blockage of PKA signal by MDL 12330A decreased CRH or UCN-promoted p-RhoA and p-Rac1 expressions. Blockage of PKC signal by cholerythine choride decreased CRH or UCN-promoted p-Rac1 expression and UCN-promoted p-RhoA expression, but increased the CRH-induced p RhoA expression. ERK1/2 was also activated and served as upstream factor of RhoA/Rac1 signal pathway. SIGNIFICANCE: The results reveal that CRH and UCN promote phagocytosis of rat macrophages through convergent but dissociable pathways. PKA/PKC-ERK1/2-RhoA/Rac1 signal pathway plays an essential role in CRH- and UCN-enhanced phagocytosis. PMID- 25534438 TI - Prostaglandin D2 regulates human colonic ion transport via the DP1 receptor. AB - AIMS: Prostaglandin D2 is released by mast cells and is important in allergies. Its role in gastrointestinal function is not clearly defined. This study aimed to determine the effect of exogenous PGD2 on ion transport in ex vivo normal human colonic mucosa. MATERIALS AND METHODS: Mucosal sheets were mounted in Ussing chambers and voltage clamped to zero electric potential. Ion transport was quantified as changes in short-circuit current. In separate experiments epithelial monolayers or colonic crypts, isolated by calcium chelation, were treated with PGD2 and cAMP levels determined by ELISA or calcium levels were determined by fluorimetry. KEY FINDINGS: PGD2 caused a sustained, concentration dependent rise in short-circuit current by increasing chloride secretion (EC50=376nM). This effect of PGD2 is mediated by the DP1 receptor, as the selective DP1 receptor antagonist BW A686C inhibited PGD2-induced but not PGE2 induced rise in short-circuit current. PGD2 also increased intracellular cAMP in isolated colonic crypts with no measurable influence on cytosolic calcium. PGD2 induces chloride secretion in isolated human colonic mucosa in a concentration dependent manner with concomitant elevation of cytoplasmic cAMP in epithelial cells. SIGNIFICANCE: The involvement of DP2 receptor subtypes has not previously been considered in regulation of ion transport in human intestine. Since inflammatory stimuli may induce production of eicosanoids, selective regulation of these pathways may be pivotal in determining therapeutic strategies and in understanding disease. PMID- 25534439 TI - The use of delta-tocotrienol and lovastatin for anti-osteoporotic therapy. AB - AIMS: Statins are competitive inhibitors of HMGCoA reductase and are commonly used as antihypercholesterolemic agents. Experimental studies clearly demonstrate the beneficial effects of statins on bone. Tocotrienols have also been shown to have anti-osteoporotic effects on the skeletal system. This study was conducted to observe the effect of a combination of delta-tocotrienol and lovastatin on structural bone histomorphometry and bone biomechanical strength in a postmenopausal rat model at clinically tolerable doses, and to compare it with the effect of delta-tocotrienol or lovastatin. MAIN METHODS: Forty-eight female Sprague Dawley rats were randomly divided into six groups: baseline control; sham operated control; ovariectomised control; ovariectomised+11mg/kg lovastatin; ovariectomised+60mg/kg delta-tocotrienol and ovariectomised+60mg/kg delta tocotrienol+11mg/kg lovastatin. These treatments were given via oral gavage daily for eight weeks. After sacrificing the rats, the left and right femurs were dissected and processed for bone histomorphometric analysis and a bone biomechanical test, respectively. KEY FINDINGS: Delta-tocotrienol in combination with lovastatin significantly improved the trabecular volume, trabecular number, trabecular thickness and trabecular separation; and it significantly increased bone strength in oestrogen-deficient rats. Delta-tocotrienol alone enhanced bone formation and maintained bone strength in ovariectomised rats. Delta-tocotrienol plus lovastatin treatment promoted better trabecular volume and trabecular number and received higher load than delta-tocotrienol alone. Lovastatin alone was not effective. SIGNIFICANCE: Thus, the combination of delta-tocotrienol and lovastatin has the potential to be used for anti-osteoporotic therapy in postmenopausal women. PMID- 25534441 TI - Enhanced microglial activity in FAAH(-/-) animals. AB - AIMS: Several lines of evidence suggest that the endocannabinoid system is involved in the regulation of glial activity. Enhanced levels of the endocannabinoid N-arachidonoyl ethanolamine (AEA, also referred to as anandamide) as well as non-cannabinoid lipids like palmitoylethanolamine (PEA) due to genetic deletion or pharmacologic blockade of its degrading enzyme fatty acid amide hydrolase (FAAH) reduced neuroinflammatory changes in models of neurodegeneration. Now we addressed the question if genetic deletion of FAAH also influences age-related neuroinflammation. MAIN METHODS: To answer this question we compared the number and size of microglia in young and old wild-type and FAAH( /-) mice and analysed the distribution of microglia sizes in the four groups. Additionally, we analysed IL-6 and IL-1beta levels with ELISA and astrocyte activities as ratio of GFAP-positive areas in the hippocampus. KEY FINDINGS: Ageing was associated with an increased number and activity of microglia, elevated IL-6 and IL-1beta levels and enhanced area covered by astrocytes in wild type animals. Unexpectedly, in FAAH(-/-) animals the number of microglia and the ratio of activated microglia and IL-1beta level were already higher in young animals than in age-matched wild-type controls. There was no further age-related increase in these inflammation markers in the knockout line. SIGNIFICANCE: Our results suggest that AEA is involved in the regulation of microglia activity. Life-long elevation of AEA levels disturbs microglial regulation and leads to pro inflammatory changes. PMID- 25534443 TI - The AJT report. PMID- 25534440 TI - The PI3K-Akt-eNOS pathway is involved in aortic hyporeactivity to Phenylephrine associated with late pregnancy in spontaneously hypertensive rats. AB - AIM: This study aimed to evaluate the effects of Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), on aortic hyporeactivity to Phenylephrine (Phe) and nitric oxide bioavailability associated with pregnancy in hypertensive rats. MAIN METHODS: The intact aortic rings of pregnant and non-pregnant Wistar or spontaneously hypertensive rats (SHRs) were stimulated with Phe (1nmol/L to 10mmol/L) before and after incubation with Wortmannin (10nmol/L, 30min). Western blot experiments analyzed the expression of phosphorylated PI3K [p85-PI3K], Akt [p-Akt (Ser 473)] and eNOS [p-eNOS (Ser 1177)] in aorta homogenates of pregnant and non-pregnant Wistar rats or SHRs. The effect of Wortmannin (10nmol/L) on the cytosolic concentrations of nitric oxide (NO; measured using 4,5-diaminofluorescein diacetate [DAF-2DA], 10mmol/L), Ca(2+) (using Fluo 3-AM, 5MUmol/L) and reactive oxygen species (ROS; using dihydroethidium [DHE], 2.5mmol/L) were measured fluorimetrically in freshly isolated endothelial cells. KEY FINDINGS: Wortmannin increases the reactivity of the aorta to Phe and decreases NO concentrations in the aortic endothelial cells of pregnant Wistar rats and SHR. SIGNIFICANCE: The PI3/AKT/endothelial nitric oxide synthase (eNOS) pathway contributes to aortic hyporeactivity to Phenylephrine associated with pregnancy in normo- and hypertensive rats. PMID- 25534442 TI - Role of physical exercise on hepatic insulin, glucocorticoid and inflammatory signaling pathways in an animal model of non-alcoholic steatohepatitis. AB - AIMS: Pro-inflammatory mediators, glucocorticoids and transforming growth factor (TGF)-beta are implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH)-related insulin resistance. As physical activity is beneficial against NASH, we analyzed the voluntary physical activity (VPA) and endurance training (ET) (preventive and therapeutic strategies) effects on hepatic insulin, pro inflammatory and glucocorticoid signaling regulators/mediators in high-fat (Lieber-DeCarli) diet (HFD)-induced NASH. MAIN METHODS: Adult male Sprague-Dawley rats were divided in standard diet (SD) or HFD, with sedentary, VPA and ET animals in both diet regimens. Plasma glucose and insulin concentrations were analyzed; plasma insulin sensitivity index (ISI) was calculated. Hepatic insulin, pro-inflammatory and glucocorticoid signaling regulators/mediators were evaluated by Western blot or reverse transcriptase-PCR. KEY FINDINGS: ET improved ISI in both diet regimens. HFD-feeding increased interleukin-1beta and induced a similar pattern on interleukin-6 and TGF-beta, which were globally reduced by physical exercise. ET decreased HFD leukemia inhibitory factor level, SD+VPA animals presenting higher values than HFD+VPA animals. HFD increased the ratio of IRS 1(Ser307)/total IRS-1, which was completely mitigated by physical exercise. Physical exercise reduced total ERK and JNK (total and activated) expression in HFD. In SD vs. HFD, VPA presented higher activated JNK and ET presented higher total JNK. Generally, in HFD, the ratio (activated/total) of AKT, and each separately, decreased with exercise and also for activated AKT in SD. Overall, in both diets, exercise reduced 11beta-hydroxysteroid dehydrogenase type 1. ET increased glucocorticoid receptor and reduced PTP1B in HFD. SIGNIFICANCE: Physical exercise mitigates the expression of pro-inflammatory mediators and positively modulates insulin and glucocorticoid signaling in NASH. PMID- 25534445 TI - The future direction of the adult heart allocation system in the United States. AB - Ensuring equitable and fair organ allocation is a central charge of the United Network for Organ Sharing (UNOS) as the Organ Procurement and Transplantation Network (OPTN) through its contract with the Department of Health and Human Services (DHHS). The OPTN/UNOS Board initiated a reassessment of the current allocation system. This paper describes the efforts of the OPTN/UNOS Heart Subcommittee, acting on behalf of the OPTN/UNOS Thoracic Organ Transplantation Committee, to modify the current allocation system. The Subcommittee assessed the limitations of the current three-tiered system, outcomes of patients with status exceptions, emerging ventricular assist device (VAD) population, options for improved geographic sharing and status of potentially disenfranchised groups. They analyzed waiting list and posttransplant mortality rates of a contemporary cohort of patient groups at risk, in collaboration with the Scientific Registry of Transplant Recipients to develop a proposed multi-tiered allocation scheme. This proposal provides a framework for simulation modeling to project whether candidates would have better waitlist survival in the revised allocation system, and whether posttransplant survival would remain stable. The tiers are subject to change, based on further analysis by the Heart Subcommittee and will lead to the development of a more effective and equitable heart allocation system. PMID- 25534446 TI - Prospective iterative trial of proteasome inhibitor-based desensitization. AB - A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) * 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRbeta3, HLA DRbeta4 and HLA DRbeta5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 +/- 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization. PMID- 25534447 TI - Variation in biliary complication rates following liver transplantation: implications for cost and outcome. AB - Although biliary complications (BCs) have a significant impact on the outcome of liver transplantation (LT), variation in BC rates among transplant centers has not been previously analyzed. BC rate, LT outcome and spending were assessed using linked Scientific Registry of Transplant Recipients and Medicare claims (n = 16,286 LTs). Transplant centers were assigned to BC quartiles based upon risk adjusted observed to expected (O:E) ratio of BC separately for donation after brain death (DBD) and donation after cardiac death (DCD) donors. The median incidence of BC was 300% greater in the highest versus lowest DBD quartiles (19.0% vs. 5.9%) and varied 250% between DCD quartiles (20.3%-8.4%). Donor and recipient characteristics suggest that high BC centers actually used lower donor risk index organs, fewer split livers and fewer imports (p < 0.001 for all). Transplant at a center in the highest O:E quartile was associated with increased posttransplant mortality (adjusted hazard ratio [aHR] 2.53, p = 0.007) in DCD transplant and increased graft loss (aHR 1.21, p = 0.02) in DBD transplant. Medicare spending was $22,895 (p < 0.0001) higher at centers in highest versus lowest BC quartile. In summary, BC rates vary widely among transplant centers and higher rates are a marker for an increased risk of death, graft failure and health-care spending. PMID- 25534449 TI - Differential rates of ischemic cholangiopathy and graft survival associated with induction therapy in DCD liver transplantation. AB - Transplantation utilizing donation after circulatory death (DCD) donors is associated with ischemic cholangiopathy (IC) and graft loss. The University of Washington (UW) DCD experience totals 89 DCD liver transplants performed between 2003 and 2011. Overall outcome after DCD liver transplantation at UW demonstrates Kaplan-Meier estimated 5-year patient and graft survival rates of 81.6% and 75.6%, respectively, with the great majority of patient and graft losses occurring in the first-year posttransplant from IC. Our program has almost exclusively utilized either anti-thymocyte globulin (ATG) or basiliximab induction (86/89) for DCD liver transplantations. Analysis of the differential effect of induction agent on graft survival demonstrated graft survival of 96.9% at 1 year for ATG versus 75.9% for basiliximab (p = 0.013). The improved survival did not appear to be from a lower rate of rejection (21.9% vs. 22.2%) but rather a differential rate of IC, 35.2% for basiliximab versus 12.5% for ATG (p = 0.011). Multivariable analysis demonstrated induction agent to be independently associated with graft survival and IC free graft survival when analyzed against variables including donor age, fWIT, donor cold ischemia time and transplant era. PMID- 25534448 TI - Serine protease inhibitor-6 differentially affects the survival of effector and memory alloreactive CD8-T cells. AB - The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8 cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells. PMID- 25534451 TI - Lung mass in a kidney transplant recipient. PMID- 25534453 TI - Nasal changes after orthognathic surgery for patients with prognathism and Class III malocclusion: analysis using three-dimensional photogrammetry. AB - BACKGROUND/PURPOSE: Orthognathic surgery alters the position of maxilla and mandible, and consequently changes the nasal shape. The nasal change remains a concern to Asian patients. The aim of this study was to measure the nasal changes using a novel three-dimensional photographic imaging method. METHODS: A total of 38 patients with Class III malocclusion and prognathism were enrolled. All patients underwent two-jaw surgery with the standard technique. A nasal alar cinching suture was included at the end of procedure. Facial landmarks and nasal morphology were defined and measured from pre- and postoperative three dimensional photographic images. Intra-rater errors on landmark identification were controlled. Patient's reports of perceptual nasal changes were recorded. RESULTS: The average width of the alar base and subalare remained similar after surgery. Alar width was increased by 0.74 mm. Nasal height and length remained the same. Nasolabial angle increased significantly. The area of nostril show revealed a significant increase and was correlated with a decrease of columella inclination. Nasal tip projection decreased significantly, by 1.99 mm. Preoperative nasal morphology was different between patients with and without cleft lip/palate, but most nasal changes were concordant. In the self-perception, 37% of patients reported improved nasal appearance, 58% reported no change, and 5% were not satisfied with the nasal changes. CONCLUSION: After the surgery, characteristic nasal changes occurred with an increase of nasolabial angle and nostril show, but a preserved nasal width. The majority of patients did not perceive adverse nasal changes. PMID- 25534454 TI - [Medical certificates and the new firearm regulation in France]. AB - France has adopted a new firearms regulation. Firearms are now classified into four categories (A, B, C, and D). The administrative procedure for acquisition and possession of firearms of categories B and C requires medical advice. The medical certificate must be dated less than a month, and detail a state of health compatible with the acquisition and possession of a firearm. There are no guidelines mentioning the conditions that can lead to incompatibility. Compatibility does not apply to the handling and use of the firearm. If the applicant is undergoing or has undergone treatment in a psychiatric institution, he must also produce a medical certificate issued by a psychiatrist. The hunting license application requires a medical certificate mentioning a state of physical and mental health compatible with the possession of a firearm. Its validity is acquired for life. The practice of shooting sports or skeet requires an annual medical certificate of non-cons in reference to the rules of sports federations. PMID- 25534455 TI - Age estimation in undocumented migrant adolescents: medical response to judicial authorities. PMID- 25534456 TI - [Electronic-cigarette grows faster than the harmful tobacco products and will dominate. Author's response to the letter on the article: "Electronic cigarette: reliable and efficient?"]. PMID- 25534457 TI - [Angioedema]. PMID- 25534458 TI - Independent predictor factors of supine tachycardia in patients with type 2 diabetes mellitus. AB - INTRODUCTION: Supine tachycardia, frequently encountered in diabetic patients, is usually considered as an isolated diabetic complication in cardiac autonomic neuropathy. The objective of this study was to determine independent predictor factors of supine tachycardia among the clinical characteristics of type 2 diabetes mellitus. METHODS: This prospective study included type 2 diabetic patients. Supine tachycardia was considered as 10 minutes resting heart rate equal or higher than 80 beats/minutes. According to presence or not of supine tachycardia, two groups were identified: tachycardia diabetic patients and none tachycardia diabetic patients. Cardiovascular autonomic tests: deep breathing, hand-grip, and mental stress tests and blood tests were performed in all patients. Statistical analysis was done using the Student's t-test, and univariate and multivariate logistic regression analysis. RESULTS: We included 91 patients. The vagal response measured by the deep breathing test was 24.5 +/- 5.7% in tachycardia diabetic patients vs 35.6 +/- 6.8% in none tachycardia diabetic patients (P=0.007). The odds of supine tachycardia increased with serum creatinine (OR=1.350, 95% CI: 1.065-1.712, P=0.013) and serum uric acid levels (OR=1.034, 95% CI: 1.005-1.064, P=0.02) respectively, in diabetic patients. The prevalence of moderate renal failure was 45.5% in tachycardia diabetic patients vs. 21.6% in none tachycardia diabetic patients (P=0.034). CONCLUSION: A high frequency of supine tachycardia in type 2 diabetic patients was significantly related with an impairment of the parasympathetic nervous system but other independent predictor factors were associated to the occurrence of this supine tachycardia, such as higher levels of serum creatinine and uric acid and moderate renal failure. PMID- 25534459 TI - [Tamoxifen: a surprising prescription in a bodybuilder]. PMID- 25534460 TI - Sexual and relational satisfaction in couples where the woman has polycystic ovary syndrome: a dyadic analysis. AB - STUDY QUESTION: How are objective characteristics of polycystic ovary syndrome (PCOS) and PCOS-related concerns associated with the sexual and relational satisfaction of PCOS women and their partners? SUMMARY ANSWER: Both objective PCOS characteristics (parity, women's body mass index (BMI) and current unfulfilled wish to conceive) and PCOS-related concerns (women's infertility related and acne-related concerns) were associated with sexual and/or relational satisfaction, although some associations differed for PCOS women and their partners. WHAT IS KNOWN ALREADY: There is some evidence indicating an association between objective PCOS characteristics and sexual satisfaction of PCOS women, but this evidence is conflicting, scarce, and often validated questionnaires have not been used to evaluate sexual satisfaction. No evidence is available about the association of: (i) PCOS with relational satisfaction; (ii) PCOS-related concerns with sexual and relational satisfaction; and (iii) PCOS with sexual and relational satisfaction as experienced by partners of PCOS women. STUDY DESIGN, SIZE, DURATION: We set up a cross-sectional study from April 2007 until April 2009, including 31 overweight (BMI >= 25 kg/m(2)) women with PCOS and at a reproductive age as well as their partners with whom they had a committed intimate relationship at the time of recruitment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed at the fertility center of the Ghent University Hospital. Objective PCOS characteristics were registered and PCOS related concerns were evaluated by the PCOS Questionnaire. Sexual (SS) and relational (RS) satisfaction were measured by the Maudsley Marital Questionnaire (MMQ). Dyadic statistical analyses were performed using linear mixed models (alpha < 0.05). MAIN RESULTS AND THE ROLE OF CHANCE: A lower parity tended to be associated with higher levels of sexual and relational satisfaction, with a significantly stronger association in PCOS women than in their partners (p(SS) = 0.015 and p(RS) = 0.009). A higher BMI tended to be associated with lower and higher satisfaction levels (sexual and relational) in PCOS women and their partners, respectively, with a significantly stronger association in the partners (p(SS) = 0.029 and p(RS) = 0.021). The presence of a current unfulfilled wish to conceive and a higher level of infertility-related concerns was significantly more strongly associated with a higher level of relational satisfaction for PCOS women than for their partners (p(RS) = 0.021 and p(RS) = 0.011, respectively). Higher levels of acne-related concern were significantly associated with lower levels of sexual satisfaction in both PCOS women (p(SS) = 0.025) and their partners (p(SS) = 0.002). LIMITATIONS, REASONS FOR CAUTION: The fact that this study was performed in a sample of PCOS women who were all overweight and the small sample size are important limitations. Data were partially missing in some couples but this limitation was dealt with by using linear mixed models. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest a differential association of PCOS with sexual and relational satisfaction between PCOS women and their partners. This should be kept in mind during the psychological guidance of couples dealing with PCOS. STUDY FUNDING/COMPETING INTERESTS: V.D.F. is holder of a Special PhD Fellowship of the Flemish Foundation for Scientific Research (FWO Vlaanderen). P.D.S. is holder of a fundamental clinical research mandate of the Flemish Foundation for Scientific Research (FWO-Vlaanderen). This research also received financial support by Merck Serono and Artevelde University College Ghent. There are no competing interests. PMID- 25534462 TI - In situ synthesized 3D heterometallic metal-organic framework (MOF) as a high energy-density material shows high heat of detonation, good thermostability and insensitivity. AB - A reticular 3D heterometallic metal-organic framework (MOF), [Cu4Na(Mtta)5(CH3CN)]n () (N% = 40.08%), has been synthesized, using a 5-methyl tetrazole (Mtta) ligand formed from acetonitrile and azide, through in situ synthesis and structurally characterized by X-ray single crystal diffraction. The fluorescence spectra demonstrate that undergoes an interesting structural transformation in aqueous solution, yielding the compound [Cu4Na(Mtta)5H2O]n () as confirmed by (1)H NMR, IR and PXRD. Thermoanalysis showed that possesses excellent thermostability up to 335 degrees C. The calculated detonation properties and the sensitivity test illustrate that compound could be used as a potential explosive. In addition, the non-isothermal kinetics for were studied using the Kissinger and Ozawa-Doyle methods. The enthalpy of formation was obtained from the determination of the constant-volume combustion energy. PMID- 25534461 TI - Comparison of the ESHRE-ESGE and ASRM classifications of Mullerian duct anomalies in everyday practice. AB - STUDY QUESTION: Does the European Society of Human Reproduction and Embryology European Society for Gynaecological Endoscopy (ESHRE-ESGE) classification of female genital tract malformations significantly increase the frequency of septate uterus diagnosis relative to the American Society for Reproductive Medicine (ASRM) classification? SUMMARY ANSWER: Use of the ESHRE-ESGE classification, compared with the ASRM classification, significantly increased the frequency of septate uterus recognition. WHAT IS KNOWN ALREADY: The ESHRE ESGE criteria were supposed to eliminate the subjective diagnoses of septate uterus by the ASRM criteria and replace the complementary absolute morphometric criteria. However, the clinical value of the ESHRE-ESGE classification in daily practice is difficult to appreciate. The application of the ESHRE-ESGE criteria has resulted in a significantly increased recognition of residual septum after hysteroscopic metroplasty, with a possible risk of overdiagnosis of septate uterus and problems for its management. STUDY DESIGN, SIZE, AND DURATION: A prospective observational study was performed with 261 women consecutively enrolled between June and September 2013. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Non-pregnant women of reproductive age presented for evaluation to a private medical center. A gynecological examination and 3D ultrasonography were performed to assess the anatomy of the uterus, cervix and vagina. Congenital anomalies were diagnosed using the ASRM classification with additional morphometric criteria as well as with the ESHRE-ESGE classification. We compared the frequency and concordance of diagnoses of septate uterus and all congenital malformations of the uterus according to both classifications. The morphological characteristics of septate uterus recognized by both criteria were compared. MAIN RESULTS AND ROLE OF CHANCE: Of the 261 patients enrolled in this study, septate uterus was diagnosed in 44 (16.9%) and 16 (6.1%) patients using the ESGE-ESHRE and ASRM criteria, respectively [relative risk (RR)ESHRE-ESGE:ASRM 2.74; 95% confidence interval (CI), 1.6-4.72; P < 0.01]. At least one congenital anomaly were diagnosed in 58 (22.2%) and 43 (16.5%) patients using the ESHRE-ESGE and ASRM classifications (RRESHRE-ESGE:ASRM, 1.35; 95% CI, 0.95-1.92, P = 0.1), respectively. The two criteria had moderate strength of agreement in the diagnosis of septate uterus (kappa = 0.45, P < 0.01). There was good agreement in differentiation between anomaly and norm between the two assessment criteria (kappa = 0.79, P < 0.01). The percentages of all congenital malformations and results of the differentiation between the anomaly and norm were obtained after excluding the confounding original ESHRE-ESGE criterion of dysmorphic uterus (internal indentation <50% uterine wall thickness). The morphology of septa identified by the ESHRE-ESGE [length of internal fundal indentation (mm): median 10.7; lower-upper quartile, 8.1-20] significantly differed (P < 0.01) from that identified by the ASRM criteria [length of internal fundal indentation (mm): median, 21.1; lower-upper quartile, 18.8-33.1]. Internal fundal indentation in 16 out of 44 (36.4%) cases was <1 cm in the septate uterus by ESHRE-ESGE and met the criteria for normal uterus by ASRM. LIMITATIONS AND REASONS FOR CAUTION: The study participants were women who visited a diagnostic and treatment center specialized in uterine congenital malformations for a medical assessment, not from the general public. WIDER IMPLICATIONS OF THE FINDINGS: Septate uterus diagnosis by ESHRE-ESGE was quantitatively dominated by morphological states corresponding to arcuate uterus or cases that were not diagnosed as congenital malformations by ASRM. Relative overdiagnosis of septate uterus by ESHRE-ESGE in these cases may lead to unnecessary overtreatment without the expected benefits. The ESHRE-ESGE classification criteria should be redefined due to confusions in the methodology. Until the criteria are revised, septate uterus should not be diagnosed using this classification system and it should not be used as an eligibility criterion for hysteroscopic metroplasty. STUDY FUNDING/COMPETING INTERESTS: This work was supported by Jagiellonian University (grant no. K/ZDS/003821). The authors have no competing interests to declare. PMID- 25534463 TI - [Sarcoidosis after adalimumab treatment in inflammatory rheumatic diseases: a report of two cases and literature review]. AB - CONTEXT: TNF alpha antagonists (anti-TNF alpha) are widely used in inflammatory rheumatic diseases: rheumatoid arthritis (RA) and spondylarthropathy (SpA). The efficacy of the anti-TNF alpha monoclonal antibodies was also observed in unresponsive sarcoidosis to conventional therapy. In contrast, sarcoidosis in patients with inflammatory rheumatic disease treated with anti-TNF alpha keep on growing, with a suspected role of anti-TNF alpha in this pathological process. METHODS: We presented here two cases of sarcoidosis developing while the patient was on adalimumab (ADA) therapy for inflammatory rheumatic disease. In one case, the reintroduction of ADA led to increase in symptomatology. We also analyzed the 16 other cases of sarcoidosis developing under ADA treatment published in literature, mostly in RA patients. RESULTS: These cases show a possible paradoxical effect of ADA in sarcoidosis development in patients treated with anti-TNFalpha monoclonal antibodies. The iatrogenic mechanism remains unclear. These cases underline the importance of a drug-induced etiology survey facing any symptomatology suggesting the development of sarcoidosis in patients treated with anti-TNF alpha for an inflammatory rheumatic disease. PMID- 25534464 TI - [Active cardiac sarcoidosis: Diagnosis and adjustment of therapy with FDG PET/CT]. PMID- 25534465 TI - [Shouting in dementia]. AB - Shouting in dementia is a frequent manifestation in institution and is often considered to be extremely disruptive. It remains the most misunderstood behavioral disorder. Shouting or screaming is not a necessarily pejorative qualifier as defined by public authorities and institutions. It can take a multitude of meanings and be characterized alternately as a "reflex", a "behavior", a "language", an "aggression". Shouting has a multifactorial causation. It can translate organic or somatic disorders, but also psychological, cognitive and/or environmental disturbances that clinicians should look for. The 5W method is a reliable and easy to use method in clinical practice to allow analysis of shouting in dementia. There is still too early and massive use of pharmacological approach in taking charge of the repetitive shouts in dementia. Instead, it is necessary to use a first-line non-pharmacological approach based on patient-centered, environment-centered and/or entourage-centered interventions after careful multidisciplinary assessment of this behaviour by the healthcare team. PMID- 25534466 TI - [Gallbladder volvulus]. PMID- 25534467 TI - Acute high output heart failure revealing hereditary hemorrhagic telangiectasia in a pregnant woman. PMID- 25534468 TI - [Pancreatic heterotopia as an unusual cause of upper gastrointestinal bleeding]. PMID- 25534469 TI - [Management of diagnosis and treatment in ulcerative colitis]. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease limited to the mucosa and affecting the rectum and the colon continuously. Salicylates are the first line treatment for moderate forms. Corticosteroids are used to induce remission, but are not given as maintenance therapy. Thiopurines are indicated as maintenance therapy in case of failure of salicylates or cortico-dependence. Anti TNF alpha are indicated in cortico-resistant severe flares or if cortico- dependence. Vedolizumab (anti-integrin) is the first non anti-TNF alpha biotherapy available for the treatment of UC. Severe acute colitis is a medical emergency; diagnosis is based on Lichtiger score. An emergency colectomy for severe acute colitis is indicated in cases of surgical complication or resistance to medical therapy. UC patients with extension beyond splenic flexure are at risk of colorectal cancer, increasing with the duration of the disease, severity of mucosal inflammation, family history of colorectal cancer, and the existence of sclerosing cholangitis. Annual surveillance colonoscopy is required in patients with sclerosing cholangitis regardless of the extension of their UC. PMID- 25534470 TI - Copper-doped borosilicate bioactive glass scaffolds with improved angiogenic and osteogenic capacity for repairing osseous defects. AB - There is growing interest in the use of synthetic biomaterials to deliver inorganic ions that are known to stimulate angiogenesis and osteogenesis in vivo. In the present study, we investigated the effects of varying amounts of copper in a bioactive glass on the response of human bone marrow-derived mesenchymal stem cells (hBMSCs) in vitro and on blood vessel formation and bone regeneration in rat calvarial defects in vivo. Porous scaffolds of a borosilicate bioactive glass (composition 6Na2O, 8K2O, 8MgO, 22CaO, 36B2O3, 18SiO2, 2P2O5, mol.%) doped with 0.5, 1.0 and 3.0wt.% CuO were created using a foam replication method. When immersed in simulated body fluid, the scaffolds released Cu ions into the medium and converted to hydroxyapatite. At the concentrations used, the Cu in the glass was not toxic to the hBMSCs cultured on the scaffolds in vitro. The alkaline phosphatase activity of the hBMSCs and the expression levels of angiogenic related genes (vascular endothelial growth factor and basic fibroblast growth factor) and osteogenic-related genes (runt-related transcription factor 2, bone morphogenetic protein-2 and osteopontin) increased significantly with increasing amount of Cu in the glass. When implanted in rat calvarial defects in vivo, the scaffolds (3wt.% CuO) significantly enhanced both blood vessel formation and bone regeneration in the defects at 8weeks post-implantation. These results show that doping bioactive glass implants with Cu is a promising approach for enhancing angiogenesis and osteogenesis in the healing of osseous defects. PMID- 25534472 TI - Child protection: a 50-year perspective. AB - It has been 50 years since Kempe et al. published 'The Battered Child Syndrome', describing harm from inflicted injury mechanisms derived from parents and care givers. Since then, there has emerged a rapidly expanding literature on paediatric forensic medicine and child protection, which has offered new insights into injury mechanisms, informed us of the sequelae of abuse and neglect, aided diagnosis and guided clinical practice in the treatment and management of children who become involved in the child protection system. Through the scrutiny of government inquiries and at times uncomfortable media exposure, there have been improvements in child protection and forensic practices resulting in recognition of need for specialised forensic training, improved funding, development of resources and development of professional standards that support accountable, objective, safe and robust practice. From the perspective of an Australian child protection paediatrician, this paper chronicles some of the most significant and at times controversial research in the last 50 years in child protection that have played a key role in shaping our current understanding of child abuse and neglect. PMID- 25534473 TI - [The outbreak of Ebola: the local crisis should not blind us to the serious problem in Western Africa]. PMID- 25534474 TI - Autoimmune acquired rippling muscle disease and myasthenia gravis. PMID- 25534471 TI - Use of porous high-density polyethylene grafts in open rhinoplasty: no infectious complication seen in spreader and dorsal grafts. AB - OBJECTIVE: The aim of this study is to use porous high-density polyethylene grafts (Medpor) in open rhinoplasty and then assess complication rate and aesthetic outcomes. METHODS: In a prospective cohort study, we performed open rhinoplasty and employed Medpor as rhinoplasty grafts. Then we compared their complication rate. RESULTS: In a total of 64 patients, 84 Medpor grafts--8 dorsal grafts, 23 strut grafts, 8 rim grafts, 5 button grafts and 10 spreader grafts- were utilized. Moreover, 5septal perforation repairs with Medpor were performed. The complication rates were 5.3% in dorsal graft (complication in dorsal graft was only movement of implant), 21.7% in strut graft and 25.0% in rim graft. No complication was seen in spreader and button grafts. All 5septal perforation repairs were successfully performed with the same rhinoplasty approach. CONCLUSION: Medpor can be used as dorsal and spreader graft in reconstruction of severe nose deformity with lowest complication rate and without infectious complication and extrusion. PMID- 25534475 TI - Ganglion cell layer analysis unmasks axonal loss in anterior optic neuritis. AB - Optical coherence tomography is a valuable tool for evaluating patients with neuro-ophthalmic disorders. In the acute phase of anterior optic neuritis (ON), peripapillary retinal nerve fiber layer (pRNFL) measurements can underestimate the amount of damage as axonal swelling could mask the true degree of RNFL loss. Contrary to pRNFL evaluation, we hypothesize that macular ganglion cell layer analysis could detect true neuronal loss before swelling resolution in anterior ON. We describe 4 patients with anterior ON in whom ganglion cell layer and inner plexiform layer (GCIPL) thinning was detected earlier than pRNFL loss. GCIPL analysis may provide more accurate information than pRNFL thickness and serve as an early structural indicator of irreversible neuronal loss. PMID- 25534476 TI - Should plasma exchange be offered to patients with multiple sclerosis-associated optic neuritis? PMID- 25534477 TI - Successful treatment of Paecilomyces variotii peritonitis in a liver transplant patient. AB - Paecilomyces variotii has previously been reported as a causative pathogen for peritonitis in patients on continuous ambulatory peritoneal dialysis and shown to be usually sensitive to amphotericin B and resistant to voriconazole. We report the first case, to our knowledge, of P. variotii peritonitis in a liver transplant patient, which was unresponsive to initial liposomal amphotericin B (L AmB) treatment and resolved dramatically after the addition of voriconazole. The present case provides evidence for the clinical and microbiological effectiveness of voriconazole combined with L-AmB in treating P. variotii peritonitis refractory to initial L-AmB treatment. PMID- 25534478 TI - Self-setting particle-stabilized emulsion for hard-tissue engineering. AB - Injectable self-setting materials have recently attracted interest for use in minimally invasive medical treatments and tissue engineering. In particular, calcium phosphate cements (CPCs) offer certain specific advantages for the treatment of bone defects. Although the inner structures of set CPCs are important for the apposition and remodeling of new bone, there are still limitations to the design of cements with a well-controlled inner structure. In the present study, we explored self-setting CPCs that generate interconnected macroporous matrices using solid-particle-stabilized emulsion templates. alpha Tricalcium phosphate (alpha-TCP) and poly(ethylene phosphate) sodium salt-coated poly(D,L-lactide-co-glycolide) (PLGA) microparticles were mixed with castor oil and water to form an oil-in-water (o/w) emulsion. The alpha-TCP and PLGA microparticles functioned as an effective particulate emulsifier by adsorption at the oil-water interface. The resulting emulsion spontaneously set in a humidified atmosphere at ambient temperature. The setting behaviors of different emulsions were characterized through X-ray diffraction analysis and compressive-strength measurements. The PLGA microparticles did not hinder the rate of hardening of the emulsions, and they improved the compressive strengths of the set cements. The PLGA particles incorporated within the set cements were hydrolytically degraded, and the degradation of the PLGA particles resulted in the formation of an interconnected pore structure in the set cement. Finally, mouse osteoblastic (MC3T3-E1) cells were cultivated on the set CPCs. The adherent MC3T3-E1 cells adopted a spindle shape, and significant cellular invasion into the set CPCs was observed after degradation of the PLGA microparticles. In conclusion, self setting emulsions stabilized with alpha-TCP and PLGA microparticles constitute a novel candidate material for bone regeneration. PMID- 25534479 TI - First plasma glucose value after urgent admission and in-hospital mortality in acutely decompensated heart failure. AB - BACKGROUND: We used data from three <250-bed hospitals to test how plasma glucose (PG) values influenced in-hospital mortality (IHM) in acute heart failure in people without diabetes. METHODS AND RESULTS: We identified 788 HF admissions (62% female; median age 83.3 years). 20.9% had chronic kidney disease, 7.7% cancer history, 24.7% acute renal failure and 29.7% concomitant infection. Mean first PG was 124.3 +/- 32.4 mg/dl; 22.7% had stress hyperglycemia. Fifty-six people died (IHM = 7.1%). Women, older patients and people with infections showed higher PG values. People who died had higher PG values (136.3 +/- 43.9 vs. 123.4 +/- 31.2 mg/dl; p = 0.029). In a multivariate regression model with IHM as main outcome, the first PG (per mg/dl, odds ratio (OR): 1.01 [1.00-1.02]; p = 0.045), age (per year, OR: 1.06 [1.02-1.10]; p = 0.003) and acute renal failure (OR: 0.42 [0.24-0.74]; p = 0.003) remained significantly associated with IHM. CONCLUSIONS: The first PG value predicted IHM in participants without diabetes after admission for heart failure. PMID- 25534482 TI - TMS and drugs revisited 2014. AB - The combination of pharmacology and transcranial magnetic stimulation to study the effects of drugs on TMS-evoked EMG responses (pharmaco-TMS-EMG) has considerably improved our understanding of the effects of TMS on the human brain. Ten years have elapsed since an influential review on this topic has been published in this journal (Ziemann, 2004). Since then, several major developments have taken place: TMS has been combined with EEG to measure TMS evoked responses directly from brain activity rather than by motor evoked potentials in a muscle, and pharmacological characterization of the TMS-evoked EEG potentials, although still in its infancy, has started (pharmaco-TMS-EEG). Furthermore, the knowledge from pharmaco-TMS-EMG that has been primarily obtained in healthy subjects is now applied to clinical settings, for instance, to monitor or even predict clinical drug responses in neurological or psychiatric patients. Finally, pharmaco-TMS-EMG has been applied to understand the effects of CNS active drugs on non-invasive brain stimulation induced long-term potentiation-like and long-term depression like plasticity. This is a new field that may help to develop rationales of pharmacological treatment for enhancement of recovery and re-learning after CNS lesions. This up-dated review will highlight important knowledge and recent advances in the contribution of pharmaco-TMS-EMG and pharmaco-TMS-EEG to our understanding of normal and dysfunctional excitability, connectivity and plasticity of the human brain. PMID- 25534480 TI - Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson's disease patients. AB - BACKGROUND: Depigmentation of the substantia nigra (SN) and locus coeruleus (LC) is a conspicuous pathological feature of Parkinson's disease (PD) and is related to the loss of neuromelanin, whose paramagnetic properties result in high signal on specific T1-weighted magnetic resonance imaging (MRI). Recent studies have suggested that neuromelanin decrease in the SN and LC of PD patients may emerge as a possible diagnostic biomarker. The SN neuromelanin signal in de novo and early stage PD patients was studied to assess its diagnostic accuracy. This is the first study based on a semi-automated MRI analysis of the neuromelanin signal in de novo PD patients. METHODS: The inclusion criteria were untreated de novo PD and a 2-5 year disease duration; in addition, age matched healthy controls were enrolled. These were studied with a high-resolution T1-weighted MRI sequence at 3 T to visualize neuromelanin. The primary outcome was SN high signal area, length and neuromelanin/midbrain ratio obtained with semi-automated methods. RESULTS: A total of 12 de novo PD patients and 10 PD patients with a 2-5 year disease duration were evaluated. The area, length of the SN T1 high signal and the SN neuromelanin/midbrain ratio were markedly decreased in the PD groups compared with age-matched controls, with a substantial overlap between the two PD groups. CONCLUSIONS: Neuromelanin-sensitive MRI techniques can discriminate PD patients from healthy individuals with high sensitivity and specificity. Our findings are consistent with recent findings showing that PD neuromelanin changes remain stable during the course of the disease. PMID- 25534483 TI - Central mechanisms of itch. AB - Itch is a complex sensory and emotional experience. Functional brain imaging studies have been performed to identify brain regions associated with this complex experience, and these studies reported that several brain regions are activated by itch stimuli. The possible roles of these regions in itch perception and difference in cerebral mechanism between healthy subjects and chronic itch patients are discussed in this review article. Additionally, the central itch modulation system and cerebral mechanisms of contagious itch, pleasurable sensation evoked by scratching have also been investigated in previous brain imaging studies. We also discuss how these studies advance our understanding of these mechanisms. PMID- 25534484 TI - Influence of interconfigurational electronic States On Fe, Co, Ni-silicene materials selection for spintronics. AB - Growth through controlled adsorption of ferromagnetic elements such as Fe, Co and Ni on two-dimensional silicene provides an alternative route for silicon-based spintronics. Plane wave DFT calculations show that Fe, Co and Ni adatoms are strongly chemisorbed via strong sigma bonds, with adsorption energies (1.55 - 2.29 eV) that are two to six times greater compared to adsorption on graphene. All adatoms adsorb more strongly at the hole site than at the atom site, with Ni adsorbing strongest. Of the dimer configurations investigated, the hole--hole, b atom--hole, vertically stacked at hole, vertically stacked at b-atom and bridge sites were found to be stable. The Co and Ni dimers are most stable when adsorbed in the hole-hole configuration while the Fe dimer is most stable when adsorbed in the atom-hole configuration. Metal-to-silicene and interconfigurational s-to-d electron transfer processes underpin the trends observed in adsorption energies and magnetic moments for both adatoms and dimers. Adsorption of these metals induces a small band gap at the Dirac Cone. In particular Co adatom adsorption at the hole site induces the largest spin-polarized band gaps of 0.70 eV (spin-up) and 0.28 eV (spin-down) making it a potential material candidate for spintronics applications. PMID- 25534485 TI - Prevention of ischemia-reperfusion injury in cardiac surgery: therapeutic strategies targeting signaling pathways. PMID- 25534486 TI - Efficacy and feasibility of a novel and noninvasive computed tomography-guided marking technique for peripheral pulmonary nodules. PMID- 25534487 TI - The immunoprotective activity of baicalin in mouse model of cecal ligation and puncture-induced sepsis. AB - The purpose of the study was to probe the therapeutic effect of baicalin on immunosuppression in the mouse model of cecal ligation and puncture (CLP)-induced sepsis. Mouse model was established by employing the procedure of CLP. The proliferation of T lymphocytes was measured using CFDA-SE staining and MTT method, and the proliferation index was determined to assess the proliferation status of the outer peripheral and mesenteric cells of the lymph node in various treatment groups. Griess reagent was used to detect serum NO concentrations. The CLP mice treated with baicalin showed reduced mortality and improved physical appearance as compared to the untreated animals. The locomotion and coat color of the baicalin-treated mice were normal compared to those of untreated CLP mice. Additionally, upon dissecting, only little abscess and adhesions were observed in their peritoneal cavity. The atrophy of thymus gland and spleen in the septic mice was significantly ameliorated in baicalin-treated CLP mice. Baicalin also suppressed the serum NO levels and promoted the proliferation of peripheral lymphocytes in CLP mice. Baicalin reduced the mortality in septic mice, exhibiting a thymus gland and spleen protecting effect. The results suggest that baicalin mediated its protective effect against CLP-induced sepsis by inhibiting T lymphocytes apoptosis and serum NO concentrations. PMID- 25534488 TI - Effect of Mechanism of Action of Different omega-6/omega-3 Polyunsaturated Fatty Acids Ratio on the Growth of Endometrial Carcinoma Mice. AB - To explore the effect and mechanism of action of different omega-6/omega-3 polyunsaturated fatty acids (PUFAs) ratio on the expression of AKT and mTOR in mice bearing endometrial carcinoma. Once the human endometrial carcinoma xenograft models were successfully established, 40 BALB/C mice were randomized into five groups: group A (omega-6 PUFAs), group B (10:1 omega-6/omega-3 PUFAs), group C (control group), group D (1:1 omega-6/omega-3 PUFAs), and group E (omega 3 PUFAs). Six weeks post-treatment, mice were sacrificed and the xenograft tissues were harvested for immunohistochemical SP analysis of AKT and mTOR expression. AKT and mTOR mRNA expression was determined by reverse transcription polymerase chain reaction. Group A and group B had the highest positive expression of AKT and mTOR, with increased mRNA expression. Group D and group E had the lowest positive expression of AKT and mTOR, with decreased mRNA expression. There was a positive correlation between the expression of AKT and that of mTOR (r = 0.92). Thus, omega-6/omega-3 PUFAs in different proportions are associated with the mRNA expression of AKT and mTOR in the tissues of mouse xenograft model of human endometrial cancer. PMID- 25534489 TI - Discussion on a Public Hospital's Practice in Culture Shaping and Innovative Development. AB - Culture shaping is an important part of a hospital's quality management to enhance its medical service, improve doctor-patient relations, and cement its brand image (Jianping and Hong in Chinese Hospital Management 29(1):36-37, 2009). First built in 1953, Xuzhou Central Hospital is a tertiary general hospital in the Huaihai Economic Zone and has won a series of honorary titles for its reforms, innovations, and the level of medical services provided. In recent years, the hospital has increased its efforts in culture shaping through the construction of special departments, medical services, hospital culture, and professional ethics. This has resulted in substantial progress in the hospital's medical capabilities and service quality, and laid a solid foundation to achieve its ambitious goal of becoming a nationally prestigious hospital, among the best in Jiangsu and a regional healthcare center in the Huaihai Economic Zone. PMID- 25534490 TI - A Controlled Study of Alprostadil Liposomal Preparation in the Treatment of Blue Toe Syndrome. AB - The aim of this study is to examine the efficacy of alprostadil liposomal preparation in the treatment of blue toe syndrome. As many as 32 patients with blue toe syndrome were randomized into the test group and a control group. Patients out of the test group were treated with alprostadil liposomal preparation, while those out of the control group received placebo administration. Inter-group comparisons were conducted for the post-therapeutic changes of microcirculation and improvements of clinical symptoms. In the test group, there were eight subjects with marked response (50.0 %), six subjects with partial response (37.5 %), and two subjects with no response (12.5 %), with the overall response rate of 87.5 %. In the control group, there were three cases (18.8 %), one case (6.4 %), and 12 cases (75 %), respectively, with the overall response rate of 25.0 %. The inter-group difference of response was statistically significant (Chi (2) = 12.987, P = 0.002 < 0.05). In the test group, there was one case of administration site redness which could be resolved spontaneously. No other adverse drug reactions were reported. No any complaints were reported for the control group. The inter-group difference of nail-fold microcirculation was not statistically significant (P > 0.05). The post-therapeutic points of nail fold microcirculation in the test group decreased significantly (P < 0.05), but no significant changes were observed for the control group (P > 0.05). The post therapeutic waveform changes of photoelectric plethysmography were significant for the test group in comparison to the control. The safety and efficacy of alprostadil liposomal preparation have been demonstrated in the treatment of blue toe syndrome. PMID- 25534491 TI - The predictive value of the uterine artery pulsatility index during the early third trimester for the occurrence of adverse pregnancy outcomes depending on the maternal obesity. AB - PURPOSE: To identify the correlation between the pre-gravid maternal obesity and the uterine artery pulsatility index (UtA-PI) at 28-34 weeks' gestation, and to evaluate the predictive value of the UtA-PI for the occurrence of adverse outcomes depending on the maternal obesity. METHODS: Between January 2010 and December 2011, 229 pregnant women were prospectively observed and analyzed. The UtA-PI during 28-34 weeks' gestation was estimated, with abnormal UtA-PI defined if the value was above the 95th centile for gestational age. The patients were classified, using a cut-off value for body mass index (BMI) of 25kg/m(2), into obese (pre-gravid BMI>=25kg/m(2)) and non-obese (pre-gravid BMI<25kg/m(2)) groups. We analyzed the association between the pre-gravid BMI and occurrence of abnormal UtA-PI and estimated their contributions to adverse outcomes using regression analyses. RESULTS: The occurrence of abnormal UtA-PI in the women with pre-gravid BMI over 25kg/m(2) was significantly higher than those with normal pre gravid BMI (OR: 2.49; 95% CI: 1.22-5.12). In multivariate analyses, the combination with abnormal UtA-PI and pre-gravid BMI over 25kg/m(2) contributed to the occurrence of preterm delivery (OR: 33.5; 95% CI: 7.63-147.21), gestational diabetes (OR: 3.98; 95% CI: 1.17-13.56) and pregnancy induced hypertension (OR: 12.71; 95% CI: 3.45-46.87), compared to the control group with pre-gravid BMI of 25kg/m(2) and less, and normal UtA-PI. CONCLUSION: Women with pre-gravid BMI over 25kg/m(2) show increased tendency of abnormal uterine artery pulsatility index during 28-34 weeks, which increases the risk of adverse pregnancy outcomes. PMID- 25534492 TI - Novel oesophago-gastro-duodenal stenting for gastric leaks after laparoscopic sleeve gastrectomy. AB - The management of gastric leak after laparoscopic sleeve gastrectomy (LSG) can be complex and challenging. Whilst operative interventions are mostly complicated and reserved for unstable or refractory cases, endoscopic self-expandable metal stenting (SEMS) is increasingly preferred as a safer treatment option. Yet, SEMS carries the problems of frequent stent migration and inconsistent healing as ordinary SEMS is designed mainly for stenotic disease. We hereby present two cases of early and chronic post-LSG leakage that were respectively failed to be treated by surgery and ordinary SEMS but were successfully managed by a dedicated extra-long oesophago-gastro-duodenal stent. In oesophago-gastro-duodenal stenting, the characteristics of extra-long stent length allow total gastric exclusion between the mid-oesophagus and the first part of duodenum to prevent stent migration and to equalise high pressure gradient within the gastric sleeve to promote fistula healing. PMID- 25534493 TI - The EEG as a diagnostic tool in distinguishing between dementia with Lewy bodies and Alzheimer's disease. AB - OBJECTIVE: Current diagnostic criteria for dementia with Lewy bodies (DLB) regard electroencephalogram (EEG) abnormalities as a supportive feature. It has also been suggested that EEG abnormalities in DLB are more extensive than in Alzheimer's disease (AD). Still, the use of qualitative EEG analysis as a diagnostic tool to distinguish between DLB and AD remains rare in daily clinical practice because of conflicting studies and absence of a reliable scoring method. The Grand Total EEG (GTE) score has been used in one study to differentiate DLB from AD with good sensitivity and specificity (Roks et al., 2008). METHODS: EEGs from 29 patients with DLB and 54 with AD were visually rated according to the GTE score. RESULTS: Patients with DLB had significantly higher median scores than patients with AD: 9 vs. 4. Patients with DLB could be distinguished from those with AD at a GTE cut-off score of 6.5 with a sensitivity of 79% and a specificity of 76%. The association between GTE and DLB was independent of age, gender, Mini Mental State Examination and use of medication. Frontal intermittent rhythmic delta activity (FIRDA) was found in 17.2% of patients with DLB compared to 1.8% with AD. Except for the lower cut-off score our results are comparable to the previous study on the GTE score. CONCLUSION: The GTE score has proven to be a reliable and simple scoring method applicable to daily clinical practice. Qualitative EEG analysis can help to differentiate DLB from AD with good sensitivity and specificity. SIGNIFICANCE: EEG should play a more prominent role in daily clinical practice as a diagnostic tool in differentiating DLB from AD. Future revisions of the diagnostic criteria for DLB should consider the other EEG abnormalities as mentioned in the GTE score, especially FIRDA. PMID- 25534494 TI - Auditory startle reflex and startle reflex to somatosensory inputs in generalized dystonia. AB - OBJECTIVE: Startle reflex is a generalized defense reaction after unexpected auditory, visual, or tactile stimuli. Auditory startle reflex (ASR) and startle reflex to somatosensory inputs (SSS) have never been studied in generalized dystonia. Here, we aimed to study the characteristics and changes of ASR and SSS in this group. METHODS: We have examined ASR and SSS in patients with generalized dystonia (n=11) and healthy subjects (n=25) under the same conditions. ASRs and SSSs were recorded over the orbicularis oculi (O.oc), sternocleidomastoid, biceps brachii (BB), and abductor pollicis brevis (APB) muscles after bilateral auditory stimulation and unilateral median nerve electrical stimulation at the wrist, respectively. RESULTS: Both ASR and SSS showed the same sequence of muscle activation in both groups. However, the presence rates over the APB and BB muscles after both modalities of stimuli were significantly higher in the generalized dystonia group. ASR did not habituate in the dystonia group. CONCLUSIONS: Both ASR and SSS are disinhibited, and both show a similar sequence of muscle recruitment in generalized dystonia. SIGNIFICANCE: Higher probabilities over caudal muscles probably depend on the higher excitability of motor neurons secondary to central modulation. PMID- 25534495 TI - Disrupted cortical hubs in functional brain networks in social anxiety disorder. AB - OBJECTIVE: The network hubs, characterized by the large number of connections to other regions, play important roles in the proper and effective transfer of information. Previous functional neuroimaging studies have demonstrated that patients with social anxiety disorder (SAD) have aberrant functional connectivity. The changing pattern in functional network hubs in SAD, however, remains incompletely understood. METHODS: Twenty SAD patients and 20 matched healthy controls were recruited. Resting-state fMRI data were obtained using a gradient-recalled echo-planar imaging sequence. Whole-brain voxel-wise functional networks were constructed by measuring the temporal correlations of each pair of brain voxels and then hubs were identified by using the graph theory method. Specifically, a functional connectivity strength (FCS) map was computed in each subject and the regions with higher FCS value were considered as functional network hubs. RESULTS: Compared with healthy controls, SAD patients showed significantly decreased FCS in the bilateral precuneus and significantly increased FCS in the right fusiform gyrus. Furthermore, a significantly negative correlation was observed between the FCS value in the precuneus and the illness duration. CONCLUSION: The present study demonstrated for the first time that disrupted cortical hubs existed in patients with SAD during resting state. SIGNIFICANCE: These findings may provide novel insight into understanding of pathophysiological mechanisms underlying SAD. PMID- 25534497 TI - Maternal mortality secondary to acute respiratory failure in Colombia: a population-based analysis. AB - PURPOSE: To estimate the mortality rate and trends of respiratory failure in the pregnant and postpartum population of Colombia. METHODS: A retrospective analysis of the national registry of mortality in Colombia was performed from 1998 to 2009. Maternal death was defined as death that occurred during pregnancy or up to 42 days postpartum. Two independent investigators reviewed maternal deaths to determine deaths caused by respiratory failure. Inter-rater agreement was assessed by kappa correlation coefficient. Causes of respiratory failure were identified according to the International Classification of Diseases (ICD-10). RESULTS: During the study period, 8,637,486 live births were reported with 6,676 maternal deaths for an overall maternal mortality rate (MMR) of 82.9 per 100,000 live births. Of these, a total of 835 cases were related to respiratory failure, with a specific MMR of 9.69 per 100,000 live births. The main causes of maternal deaths due to respiratory failure included pulmonary sepsis (284 cases, or 3.58 per 100,000 live births), pulmonary embolism (119 cases or 1.50 per 100,000 live births), and preeclampsia-related pulmonary edema (112 cases or 1.41 per 100,000 live births). All-cause maternal mortality ratio decreased yearly from 1998 to 2009 by -3.76% (95% CI -4.83 to -2.67), while the trend of mortality secondary to respiratory failure remained stable over time (P = 0.449). CONCLUSIONS: Respiratory failure is an important cause of mortality in the obstetric population in Colombia, with pulmonary sepsis as the lead cause of respiratory failure among maternal deaths. While overall maternal mortality rates have decreased in the last decade, respiratory failure-related deaths have remained stable over time. PMID- 25534496 TI - A heavy burden on young minds: the global burden of mental and substance use disorders in children and youth. AB - BACKGROUND: Mental and substance use disorders are common and often persistent, with many emerging in early life. Compared to adult mental and substance use disorders, the global burden attributable to these disorders in children and youth has received relatively little attention. METHOD: Data from the Global Burden of Disease Study 2010 was used to investigate the burden of mental and substance disorders in children and youth aged 0-24 years. Burden was estimated in terms of disability-adjusted life years (DALYs), derived from the sum of years lived with disability (YLDs) and years of life lost (YLLs). RESULTS: Globally, mental and substance use disorders are the leading cause of disability in children and youth, accounting for a quarter of all YLDs (54.2 million). In terms of DALYs, they ranked 6th with 55.5 million DALYs (5.7%) and rose to 5th when mortality burden of suicide was reattributed. While mental and substance use disorders were the leading cause of DALYs in high-income countries (HICs), they ranked 7th in low- and middle-income countries (LMICs) due to mortality attributable to infectious diseases. CONCLUSIONS: Mental and substance use disorders are significant contributors to disease burden in children and youth across the globe. As reproductive health and the management of infectious diseases improves in LMICs, the proportion of disease burden in children and youth attributable to mental and substance use disorders will increase, necessitating a realignment of health services in these countries. PMID- 25534498 TI - Microstructural changes in the retina related to prematurity. AB - PURPOSE: To assess retinal morphology changes in patients born at different stages of prematurity, accounting for the presence or absence of retinopathy of prematurity (ROP) and comorbidity, using spectral-domain optical coherence tomography (SD OCT). DESIGN: Retrospective cohort study. METHODS: Preterm and term infants underwent an ophthalmologic assessment (best-corrected visual acuity, stereoacuity, cycloplegic refraction and funduscopy). Retinal layers were imaged, segmented, and measured by SD-OCT. In total 114 full term controls and 60 preterm children, classified as late preterm (32-36 weeks gestational age), early preterm (<32 weeks of gestational age) without ROP, and early preterm with previously treated ROP, were included in the study. RESULTS: No retinal structure differences were observed in preterm infants with no treated ROP compared to term infants. Early preterm infants with previous treated ROP had decreased retinal nerve fiber layer (RNFL) thickness in the superior and nasal quadrants, increased RNFL in the temporal quadrant, and a thinner ganglion cell and inner plexiform layer complex (GCL-IPL). Low birthweight percentile was associated with increased foveal thickness and ganglion cell damage (RNFL and GCL-IPL) independent of gestational age. Among all the coexisting events, inflammation and hypoxia were correlated with more severe detrimental effects. CONCLUSIONS: In the absence of treated ROP, prematurity was not associated with disturbed retinal structure. Severe ROP and low birthweight were related to neuronal and axonal damage in the inner retinal layers. Detailed comorbidity should be reviewed when evaluating preterm infants. PMID- 25534499 TI - Comparison of 2-year outcomes between zotarolimus-eluting and everolimus-eluting new-generation cobalt-chromium alloy stents in real-world diabetic patients. AB - BACKGROUND: To date, it remains unknown whether different types of new-generation drug-eluting stents have a differential impact on long-term outcomes in diabetic patients. METHODS AND RESULTS: In this historical cohort study (two Italian centers), we analyzed 400 diabetic patients with 553 coronary lesions treated with new-generation CoCr zotarolimus-eluting stents (R-ZES: 136 patients, 196 lesions) or everolimus-eluting stents (EES: 264 patients, 357 lesions) between October 2006 and August 2012. Primary endpoint was the occurrence of major adverse cardiac events (MACE) over a 2-year follow-up period. MACE was defined as all-cause mortality, any myocardial infarction (MI) and/or target lesion revascularization (TLR). Multivessel revascularization, intervention for restenotic lesion and use of intravascular ultrasound were significantly higher in the R-ZES group, whereas small stent (<=2.5 mm) deployment was significantly higher in the EES group. At 2-year follow-up, there was no significant difference in occurrence of MACE (R-ZES vs EES: 22.8% vs 18.9%, P = 0.39). Similarly, no significant differences were observed in the composite endpoint of all-cause mortality/MI (10.0% vs 10.3%, P = 0.86) or TLR (12.4% vs 7.4%, P = 0.11). Adjustment for confounders and baseline propensity-score matching did not alter the aforementioned associations. CONCLUSION: After 2 years of follow up similar outcomes (MACE, all-cause mortality/MI, TLR) were observed in real-world diabetic patients, including those with complex lesions and patient characteristics, treated with R-ZES and EES. PMID- 25534500 TI - Do child abuse and maternal care interact to predict military sexual trauma? AB - OBJECTIVE: The present research tested the hypothesis that maternal care moderates the relationship between childhood sexual abuse and subsequent military sexual trauma (MST). METHOD: Measures of childhood sexual abuse, maternal care, and MST were administered to 197 Iraq and Afghanistan war veterans. RESULTS: After accounting for gender, age, and the main effects of maternal care and childhood sexual abuse, the maternal care x childhood sexual abuse interaction was a significant predictor of MST (odds ratio = .28, beta = -1.26, 95% confidence intervals of .10, .80). As hypothesized, rates of MST were higher among veterans who reported childhood sexual abuse and low levels of maternal care (43%) compared with veterans who reported childhood sexual abuse and high levels of maternal care (11%). CONCLUSION: These findings suggest that high levels of maternal care may act as a protective factor against future revictimization among military service members. These findings have the potential to inform both prevention and intervention efforts. PMID- 25534501 TI - Effects of alpha-lipoic acid on spatial learning and memory, oxidative stress, and central cholinergic system in a rat model of vascular dementia. AB - Brain oxidative stress due to chronic cerebral hypoperfusion was considered to be the major risk factor in the pathogenesis of vascular dementia. In this study, we investigated the protective efficacy of alpha-lipoic acid, an antioxidant, against vascular dementia in rats, as well as the potential mechanism. Bilateral common carotid arteries occlusion (BCCAO) induced severe cognitive deficits tested by Morris water maze (MWM), along with oxidative stress and disturbance of central cholinergic system. However, administration of alpha-lipoic acid (50mg/kg, i.p.) for 28 days significantly restored cognitive deficits induced by BCCAO. Biochemical determination revealed that alpha-lipoic acid markedly decreased the production of malondialdehyde (MDA) and the generation of reactive oxidative species (ROS), and increased the level of reduced glutathione (GSH) in the hippocampal tissue. Additionally, alpha-lipoic acid raised the level of acetylcholine (ACh) and choline acetyltransferase (ChAT) and decreased the activity of acetycholinesterase (AChE) in the hippocampus. These results indicated that treatment with alpha-lipoic acid significantly improved behavioral alterations, protected against oxidative stress, and restored central cholinergic system in the rat model of vascular dementia induced by BCCAO. PMID- 25534502 TI - Intrathecal nefopam-induced antinociception through activation of descending serotonergic projections involving spinal 5-HT7 but not 5-HT3 receptors. AB - We examined the involvement of spinal 5-HT(5-hydroxytryptamine) receptor 3(5 HT3R) and 7(5-HT7R) as well as the overall role of descending serotonergic projections in the analgesic effects of intrathecal(i.t.) nefopam for two rat models of formalin and paw incision test. I.t. nefopam produced an antinociceptive effect in a dose-dependent manner in both tests. Lesioning the spinal serotonergic projections using i.t. 5,7-dihydroxytryptamine(5,7-DHT) did not influence the intensity of allodynia in the paw incision test, but i.t. 5,7 DHT abolished the effect of nefopam. In the formain test, i.t. 5,7-DHT alone significantly diminished the flinches, but the effect of nefopam was not affected by i.t. 5,7-DHT. Antagonism study showed that i.t. 5-HT7R antagonist, SB269970 significantly blocked the antinociceptive effect of nefopam in both tests, but i.t. 5-HT3R antagonist, ondansetron has no influence on the effect of nefopam. The present study demonstrates that descending spinal serotonergic projections play a vital role in antinociceptive effect of i.t. nefopam in the paw incision test, but indeterminate in the formalin test. In both tests, the antinociceptive effect of i.t. nefopam involves the spinal 5-HT7R, but not 5-HT3R. PMID- 25534504 TI - Deconstructing environmental predictability: seasonality, environmental colour and the biogeography of marine life histories. AB - Environmental predictability is predicted to shape the evolution of life histories. Two key types of environmental predictability, seasonality and environmental colour, may influence life-history evolution independently but formal considerations of both and how they relate to life history are exceedingly rare. Here, in a global biogeographical analysis of over 800 marine invertebrates, we explore the relationships between both forms of environmental predictability and three fundamental life-history traits: location of larval development (aplanktonic vs. planktonic), larval developmental mode (feeding vs. non-feeding) and offspring size. We found that both dispersal potential and offspring size related to environmental predictability, but the relationships depended on both the environmental factor as well as the type of predictability. Environments that were more seasonal in food availability had a higher prevalence of species with a planktonic larval stage. Future studies should consider both types of environmental predictability as each can strongly affect life-history evolution. PMID- 25534505 TI - IBS in 2014: Developments in pathophysiology, diagnosis and management. PMID- 25534506 TI - Liver: Does angiogenesis have a role in the resolution of liver fibrosis? PMID- 25534507 TI - Orchestrating care: nursing practice with hospitalised older adults. AB - BACKGROUND: The increased incidence of health challenges with aging means that nurses are increasingly caring for older adults, often in hospital settings. Research about the complexity of nursing practice with this population remains limited. OBJECTIVE: To seek an explanation of nursing practice with hospitalised older adults. METHODS: Design. A grounded theory study guided by symbolic interactionism was used to explore nursing practice with hospitalised older adults from a nursing perspective. Glaserian grounded theory methods were used to develop a mid-range theory after analysis of 375 hours of participant observation, 35 interviews with 24 participants and review of selected documents. RESULTS: The theory of orchestrating care was developed to explain how nurses are continuously trying to manage their work environments by understanding the status of the patients, their unit, mobilising the assistance of others and stretching available resources to resolve their problem of providing their older patients with what they perceived as 'good care' while sustaining themselves as 'good' nurses. They described their practice environments as hard and under-resourced. Orchestrating care is comprised of two subprocesses: building synergy and minimising strain. These two processes both facilitated and constrained each other and nurses' abilities to orchestrate care. CONCLUSIONS: Although system issues presented serious constraints to nursing practice, the ways in which nurses were making meaning of their work environment both aided them in managing their challenges and constrained their agency. IMPLICATIONS FOR PRACTICE: Nurses need to be encouraged to share their important perspective about older adult care. Administrators have a role to play in giving nurses voice in workplace committees and in forums. Further research is needed to better understand how multidisciplinary teams influence care of hospitalized older adults. PMID- 25534508 TI - Cytokine systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates. AB - BACKGROUND: The recent emergence of a novel coronavirus in the Middle East (designated MERS-CoV) is a reminder of the zoonotic and pathogenic potential of emerging coronaviruses in humans. Clinical features of Middle East respiratory syndrome (MERS) include atypical pneumonia and progressive respiratory failure that is highly reminiscent of severe acute respiratory syndrome (SARS) caused by SARS-CoV. The host response is a key component of highly pathogenic respiratory virus infection. Here, we computationally analyzed gene expression changes in a human airway epithelial cell line infected with two genetically distinct MERS-CoV strains obtained from human patients, MERS-CoV SA 1 and MERS-CoV Eng 1. RESULTS: Using topological techniques, including persistence homology and filtered clustering, we performed a comparative transcriptional analysis of human Calu-3 cell host responses to the different MERS-CoV strains, with MERS-CoV Eng 1 inducing early kinetic changes, between 3 and 12 hours post infection, compared to MERS-CoV SA 1. Robust transcriptional changes distinguished the two MERS-CoV strains predominantly at the late time points. Combining statistical analysis of infection and cytokine-stimulated Calu-3 transcriptomics, we identified differential innate responses, including up-regulation of extracellular remodeling genes following MERS-CoV Eng 1 infection and differential pro inflammatory responses. CONCLUSIONS: Through our genomics-based approach, we found topological differences in the kinetics and magnitude of the host response to MERS-CoV SA 1 and MERS-CoV Eng 1, with differential expression of innate immune and pro-inflammatory responsive genes as a result of IFN, TNF and IL 1alpha signaling. Predicted activation for STAT3 mediating gene expression relevant for epithelial cell-to-cell adherens and junction signaling in MERS-CoV Eng 1 infection suggest that these transcriptional differences may be the result of amino acid differences in viral proteins known to modulate innate immunity during MERS-CoV infection. PMID- 25534511 TI - Rethinking the relationship between footprints and LCA. PMID- 25534510 TI - Cumulative socioeconomic disadvantage and cardiovascular disease mortality in the Alameda County Study 1965 to 2000. AB - PURPOSE: Socioeconomic disadvantage is often evaluated at single points in the adult life course in health research. Social mobility models suggest that socioeconomic patterns may also influence disease risk. This study examines cumulative socioeconomic disadvantage (CSD) in relation to cardiovascular disease mortality (CVDM). METHODS: Data were from the Alameda County Study (n = 2530). The CSD indices included father's education, the respondent's education, and either average or latent variable trajectory models of adulthood household income (1965-1994). Proportional hazards models were used to assess the associations between CSD and CVDM. RESULTS: The CSD measures were not associated with CVDM in men. Among women, the magnitude of the association between CSD and CVDM was greater for the income trajectory (hazard ratio3 vs 0 = 4.73, 95% confidence interval = 2.20-10.18) compared with the average income (hazard ratio3 vs 0 = 3.78, 95% confidence interval = 1.67-8.53) CSD measure. CONCLUSIONS: Measures of CSD that incorporate patterning of resources over the life course were associated with CVDM for women but not men. Patterning of available socioeconomic resources may differentially influence chronic disease risk and mortality by gender, and future work should continue to investigate how greater patterns variability in available resources influences health outcomes. PMID- 25534509 TI - Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. AB - PURPOSE: To summarize the relative risks (RRs) and attributable risks (ARs) of major health outcomes associated with use of combined oral contraceptives (OCs) and menopausal hormone therapy (HT). METHODS: For OCs, measures of association are from meta-analyses of observational studies. For HT, these measures are from the Women's Health Initiative, a large randomized trial of HT for chronic disease prevention in postmenopausal women aged 50 to 79 years. RESULTS: Current OC use increases risks of venous thromboembolism and ischemic stroke. However, women of reproductive age are at low baseline risk, so the ARs are small. OC use also increases risk of breast and liver cancer and reduces risk of ovarian, endometrial, and colorectal cancer; the net effect is a modest reduction in total cancer. The Women's Health Initiative results show that HT does not prevent coronary events or overall chronic disease in postmenopausal women as a whole. Subgroup analyses suggest that timing of HT initiation influences the relation between such therapy and coronary risk, and its overall risk-benefit balance, with more favorable effects (on a relative scale) in younger or recently menopausal women than in older women or those further past the menopausal transition. However, even if the RR do not vary by these characteristics, the low absolute baseline risks of younger or recently menopausal women translate into low ARs in this group. CONCLUSIONS: OC and HT can safely be used for contraception and treatment of vasomotor symptoms, respectively, by healthy women at low baseline risk for cardiovascular disease and breast cancer. PMID- 25534512 TI - The genetic and environmental roots of variance in negativity toward foreign nationals. AB - This study quantified genetic and environmental roots of variance in prejudice and discriminatory intent toward foreign nationals and examined potential mediators of these genetic influences: right-wing authoritarianism (RWA), social dominance orientation (SDO), and narrow-sense xenophobia (NSX). In line with the dual process motivational (DPM) model, we predicted that the two basic attitudinal and motivational orientations-RWA and SDO-would account for variance in out-group prejudice and discrimination. In line with other theories, we expected that NSX as an affective component would explain additional variance in out-group prejudice and discriminatory intent. Data from 1,397 individuals (incl. twins as well as their spouses) were analyzed. Univariate analyses of twins' and spouses' data yielded genetic (incl. contributions of assortative mating) and multiple environmental sources (i.e., social homogamy, spouse-specific, and individual-specific effects) of variance in negativity toward strangers. Multivariate analyses suggested an extension to the DPM model by including NSX in addition to RWA and SDO as predictor of prejudice and discrimination. RWA and NSX primarily mediated the genetic influences on the variance in prejudice and discriminatory intent toward foreign nationals. In sum, the findings provide the basis of a behavioral genetic framework integrating different scientific disciplines for the study of negativity toward out-groups. PMID- 25534514 TI - Organic non-volatile resistive photo-switches for flexible image detector arrays. AB - A unique implementation of an organic image detector using resistive photo switchable pixels is presented. This resistive photo-switch comprises the vertical integration of an organic photodiode and an organic resistive switching memory element. The photodiodes act as a photosensitive element while the resistive switching elements simultaneously store the detected light information. PMID- 25534515 TI - Frequency distribution of apolipoprotein e genotypes in elderly han chinese population and relationship with senile dementia. AB - AIM: The aim of the study was to determine the relationship between Apo Eepsilon4 genotype and senile dementia (SD) by analyzing the Apo E allelic frequency distributions among the elderly Han Chinese population. METHODS: For this purpose, a total of 316 Chongqing residents, aged >=60yrs, were classified as SD or control groups following the criteria of National Institute of Neurological and Communicative Disorders and Stroke--Alzheimer's Disease and Related Disorders Association. Genomic DNA was isolated from the peripheral blood lymphocytes and exon 4 of the ApoE gene with polymorphism sites was amplified by PCR and genotypes determined by restriction fragment length polymorphism (RFLP). RESULTS: We found that the most prevalent genotype was Apo Eepsilon3/3, followed in order by Apo Eepsilon3/4 and Apo Eepsilon2/2. The estimated ApoE allelic frequencies in individuals with SD were 0.095, 0.560, and 0.345 for epsilon2, epsilon3, and epsilon4, respectively. In controls, the corresponding Apo E allelic frequencies were 0.146, 0.699, and 0.155. The percentage of epsilon4 allele carriers in SD group was significantly higher than that in control group (P<0.01); while those of epsilon2 and epsilon3 genotypes were lower in SD group as compared with control group. CONCLUSION: We concluded that in the elderly Han Chinese residents of Chongqing aged 60 years and over, Apo Eepsilon3/3 and Apo Eepsilon2/2 were the most and least prevalent genotypes, respectively. Further, based on strong linkage, Apo Eepsilon4 allele might be a significant risk factor for the development of senile dementia. PMID- 25534516 TI - The subjective experience of power mobility. PMID- 25534517 TI - [Direct oral anticoagulant, useful pharmacological characteristics in clinical practice]. AB - Direct oral anticoagulants offer an alternative to vitamin K antagonist drugs in the prevention and treatment of thromboembolic events. Unlike the latter, they inhibit directly and specifically coagulation factors (Xa, IIa). Their pharmacological properties allow a fixed dose administration and no biological monitoring for the majority of patients. However, their pharmacokinetics dependent of membrane transporters (P-gp) and cytochrome P450 (CYP3A4) expose them to significant drug-drug interactions. Dose adjustment may then become necessary as in some clinical situations, such as kidney and liver failure. However, some questions remain open, particularly on the optimal handling of these molecules in some population (elderly patients, renal and hepatic impairment or polymedicated). PMID- 25534513 TI - Photoperiodic flowering: time measurement mechanisms in leaves. AB - Many plants use information about changing day length (photoperiod) to align their flowering time with seasonal changes to increase reproductive success. A mechanism for photoperiodic time measurement is present in leaves, and the day length-specific induction of the FLOWERING LOCUS T (FT) gene, which encodes florigen, is a major final output of the pathway. Here, we summarize the current understanding of the molecular mechanisms by which photoperiodic information is perceived in order to trigger FT expression in Arabidopsis as well as in the primary cereals wheat, barley, and rice. In these plants, the differences in photoperiod are measured by interactions between circadian-clock-regulated components, such as CONSTANS (CO), and light signaling. The interactions happen under certain day-length conditions, as previously predicted by the external coincidence model. In these plants, the coincidence mechanisms are governed by multilayered regulation with numerous conserved as well as unique regulatory components, highlighting the breadth of photoperiodic regulation across plant species. PMID- 25534518 TI - Impact of pregnancy on psychotropic medication prescription: a French cohort study. AB - OBJECTIVES: To determine if and when prescription of psychotropic medication in women is modified by pregnancy. METHOD: Psychotropic prescription of 87 213 pregnant women affiliated with the French General Health System was examined. Period of analyses lasted 17 months to cover 4 months before and after pregnancy. A comparable cohort of 87 213 non pregnant women constituted the control group. RESULTS: More than half of pregnant women to whom a psychoactive drug was prescribed were novel users during all three trimesters and after delivery. Prevalence of psychotropic medication before pregnancy is comparable to that of non-pregnant women. Rate of psychotropic medication during the peripartum stayed high, even though it decreased by half during the first trimester, showing a "pregnancy impact effect". CONCLUSIONS: Data show a dramatic impact of pregnancy. More information on specific patterns of prescription needs to be gained in order to establish decision-making models for psychotropic prescription during pregnancy. PMID- 25534519 TI - Spa therapy for generalized osteoarthritis: an open, observational, preliminary study. AB - OBJECTIVES: Open, prospective study to evaluate the effect of spa therapy on generalized osteoarthritis (GOA). METHODS: Patients diagnosed as GOA were recruited from a private outpatient clinic. The treatment protocol was designed with 6 different spa modalities, 3 for each consecutive day, during 18 days. Interventions were Berthollet's technique (local mineral water cloud application), peloidotherapy, hydrotherapy, under water /standard (dry) massage, supervised water exercise, bath in hydro-massage pool, bath in tub with hydro jets, free immersion in mineral water pool. The primary outcome was a clinically relevant improvement in 50% of patients at the end of the treatment. Statistical analyses were based on intention-to-treat method. Health care providers were blinded to the study. RESULTS: Ninety nine patients were included between March 7th-April 29th 2011 and all were analyzed for the primary outcome. Clinically relevant improvement was observed in 61% of the patients at the end of the treatment, and 68% at the 8th month. Patient acceptable symptom state was achieved in 33% of the patients at the 3rd week and 75% at the 8th month and Outcome Measures in Rheumatology-Osteoarthritis Research Society International Criteria (OMERACT-OARSI criteria) response in 41% of the patients at the 3rd week and 19% at the 8th month. Improvement was also observed in other judgment criteria evaluating pain, function and quality of life and continued until the 8th month for some of the parameters. No serious adverse effect was observed. CONCLUSIONS: Spa treatment may improve the clinical status of patients with GOA and seems to be well tolerated. PMID- 25534520 TI - Alteration of the Fetal Heart Rate Pattern Induced by the Use Of Clozapine during Pregnancy. AB - Patients treated with clozapine show autonomic dysregulation and cardiac repolarisation changes. As clozapine crosses the placenta, it could have an impact on the fetus heart rate. We reported a case of reduction of the fetal heart rate variability in a patient treated with clozapine during her pregnancy. This anomaly disappeared with fetal maturation and it did not jeopardize the fetal well-being. This side effect had already been described and pharmacologists and obstetricians should be aware that clozapine may be responsible for these fetal heart rate alterations. PMID- 25534521 TI - [Developing a terminology in the French language for clinical practice and research in drug safety]. AB - While several attempts have been made to clarify the English terminology of drug related iatrogeny, a consensus has still not been reached in the French language. We set up a multidisciplinary task force to propose a terminology that differs from the one used in pharmacovigilance and risk management. We prefer the term "adverse drug event" (ADE) over "adverse drug reaction", and recommend avoiding the term "adverse event", which is too general. We propose to classify ADEs as "direct drug effect" or "drug involvement in a multifactorial pathological condition", taking into account the close relationship commonly found between drug and non-drug etiologies of a pathology. The consistent association between the notions "error" and "preventability" is also questionable, and we suggest assessing the "ameliorability" of ADEs rather than their "preventability". "Misuse" (i.e., the non-respect by the patient of the drug label) must be distinguished from "off-label use or substance abuse". PMID- 25534522 TI - [Impact of a regional pharmacovigilance network on notification of adverse drug reactions: results at 3 years]. AB - AIM: To stimulate spontaneous reporting of adverse drug reactions and to enable information sharing on drug's safety between Rennes Pharmacovigilance Regional Center and hospitals of its territory. METHODS: After having outlined objectives of the network to 11 major public institutions, the network was launched. It is coordinated by a dedicated pharmacist thanks to animation of monthly videoconference and diffusion of a quarterly newsletter. It relies on a local correspondent in each hospital who disseminates information to healthcare professionals and becomes their local contact for pharmacovigilance. RESULTS: The quality and usefulness of information sharing are emphasized by every one. We observed an increase in notifications and information requests multiplied by 3.4 and 2.4 % respectively between 2008 and 2013. CONCLUSIONS: The existence of a dedicated coordinator and implication of the correspondents are key elements enabling the network to be efficient. The increase of spontaneous notifications is noteworthy. The next step is to officially enlarge the network to private hospitals. PMID- 25534523 TI - Brain and arterial abnormalities following prenatal X-ray irradiation in mice assessed by magnetic resonance imaging and angiography. AB - The present study aimed to quantitatively characterize changes in the whole brain and arterial morphology in response to prenatal ionizing irradiation. Magnetic resonance imaging (MRI) and angiography (MRA) were used to evaluate brain and arterial abnormalities in 8-week-old male mice prenatally exposed to X-ray radiation at a dose of 0.5 or 1.0 Gy on embryonic day (E) 13. Irradiated mice demonstrated decreased brain volume, increased ventricular volume, and arterial malformation. Additionally, MRA signal intensity and arterial thickness in the anterior cerebral artery, middle cerebral artery, and basilar artery were lower in radiation-exposed mice than in control mice. MRI and MRA are useful tools for assessing brain and arterial abnormalities after prenatal exposure to radiation. PMID- 25534524 TI - Role of thalamic diffusion for disease differentiation between multiple sclerosis and ischemic cerebral small vessel disease. AB - INTRODUCTION: Cerebral small vessel disease (CSVD) and multiple sclerosis (MS) both harbor multiple, T2-hyperintense white matter lesions on conventional magnetic resonance imaging (MRI).We aimed to determine the microstructural changes via diffusion-weighted imaging (DWI) in normal appearing thalami. We hypothesized that the apparent diffusion coefficient (ADC) values would be different in CSVD and MS, since the extent of arterial involvement is different in these two diseases. METHODS: DWI was performed for 50 patients with CSVD and 35 patients with MS along with gender- and age-matched controls whose conventional MRI revealed normal findings. DWI was done with 1.5 Tesla MR devices using echo planar imaging (EPI) for b = 0, 1000 s/mm(2). ADC values were obtained from the thalami which appeared normal on T2-weighted and FLAIR images. Standard oval regions of interest (ROIs) of 0.5 cm(2) which were oriented parallel to the long axis of the thalamus were used for this purpose. RESULTS: The mean ADC value of the thalamus was (0.99 +/- 0.16) * 10(-3) mm(2)/s in patients with CSVD, whereas the mean ADC value was (0.78 +/- 0.06) * 10(-3) mm(2)/s in the control group. The mean ADC value was significantly higher in patients with CSVD compared to the controls (p < 0.001). The mean ADC values of the thalamus were (0.78 +/- 0.08) * 10(-3) mm(2)/s in MS patients, and (0.75 +/- 0.08) * 10(-3) mm(2)/s in the control group, which are not significantly different (p > 0.05). CONCLUSION: Our study revealed a difference in the diffusion of the thalami between CSVD and MS. DWI may aid in the radiological disease differentiation. PMID- 25534525 TI - Prevalence of superficial siderosis following singular, acute aneurysmal subarachnoid hemorrhage. AB - INTRODUCTION: Superficial siderosis is presumably a consequence of recurrent bleeding into the subarachnoid space. The objective of this study was to assess the prevalence of superficial siderosis after singular, aneurysmal subarachnoid hemorrhage (SAH) in the long term. METHODS: We retrospectively identified all patients who presented with a singular, acute, aneurysmal SAH at our institution between 2010 and 2013 and in whom a magnetic resonance imaging (MRI) including T2*-weighted imaging was available at least 4 months after the acute bleeding event. MRI scans were judged concerning the presence and distribution of superficial siderosis. Influence of clinical data, Fisher grade, localization, and cause of SAH as well as the impact of neurosurgical interventions on the occurrence of superficial siderosis was tested. RESULTS: Seventy-two patients with a total of 117 MRIs were included. Mean delay between SAH and the last available MRI was 47.4 months (range 4-129). SAH was Fisher grade 1 in 2 cases, 2 in 4 cases, 3 in 10 cases, and 4 in 56 cases. Superficial siderosis was detected in 39 patients (54.2%). In all patients with more than one MRI scan, localization and distribution of superficial siderosis did not change over time. Older age (p = 0.02) and higher degree of SAH (p = 0.03) were significantly associated with the development of superficial siderosis. CONCLUSION: Superficial siderosis develops in approximately half of patients after singular, aneurysmal SAH and might be more common in patients with an older age and a greater amount of blood. However, additional factors must play a role in whether a patient is prone to develop superficial siderosis or not. PMID- 25534526 TI - Thymic epithelial tumors: prognostic determinants among clinical, histopathologic, and computed tomography findings. AB - BACKGROUND: The Masaoka-Koga staging system has been known as the strongest prognostic factor for both survival and recurrence of thymic epithelial tumor (TET). The purpose of our study was to find prognostic determinants among computed tomography (CT), histopathologic, and clinical features of TET. METHODS: Two radiologists reviewed retrospectively CT findings of 437 patients (male 242, female 195; mean age, 51 years) with TET. With medical record review, surgico histopathologic results were subcategorized into Masaoka-Koga stages I through IV and World Health Organization histopathologic classifications A-B1, B2-B3, and carcinoma. Overall survival and progression-free survival were analyzed. Clinical, histopathologic, and CT features were correlated from each other. RESULTS: In all, 437 tumors were in Masaoka-Koga stage I (n = 147, 33.6%), stage II (n = 121, 27.7%), stage III (n = 76, 17.4%), or stage IV (n = 93, 21.3%); A and B1 (n = 114, 26.1%) and B2 and B3 TET (n = 223, 51.0%); and thymic carcinoma (n = 100, 22.9%). In multivariable analyses, age, Masaoka-Koga stage IV, thymic carcinoma, and CT stages III and IV were significantly correlated with overall survival (p < 0.05), whereas adjuvant treatment, Masaoka-Koga stages III and IV, World Health Organization B2 and B3, thymic carcinoma, R2 resection, CT size, and CT stage IV were significantly associated with progression-free survival (p < 0.05). Computed tomography stages showed moderate association with Masaoka-Koga stages (K = 0.621). CONCLUSIONS: For TET, CT staging is effective in distinguishing both overall survival and progression-free survival, and patients with Masaoka-Koga stage IV or thymic carcinoma or CT stage IV have the worst prognosis. PMID- 25534527 TI - Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma. AB - BACKGROUND: This comprehensive meta-analysis was conducted to answer the question as to which procedure, pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP) is more beneficial to malignant pleural mesothelioma patients' outcome. METHODS: Original research studies that evaluated long-term outcomes of P/D versus EPP were identified, from January 1990 to January 2014. The combined percent perioperative and 2-year mortality, and median survival were calculated according to both a fixed and a random effect model. The Q statistics and I(2) statistic were used to test for heterogeneity between the studies. RESULTS: There were 24 distinct data sets, for a total of 1,512 patients treated with P/D, and 1,391 treated with EPP. There was a significantly higher proportion of short-term deaths in the EPP group versus the P/D group (percent mortality meta estimate; 4.5% vs 1.7%; p < 0.05). There was no statistically significant difference in 2-year mortality between the 2 groups, but there was significant heterogeneity. CONCLUSIONS: The reanalysis of the large number of studies comparing P/D to EPP suggests that P/D is associated with a 2 1/2-fold lower short-term mortality (perioperatively and within 30 days) than EPP. Pleurectomy decortication should therefore be preferred when technically feasible. PMID- 25534528 TI - Neonatal pulmonary artery reconstruction during shunting to treat and prevent juxtaductal coarctation. AB - BACKGROUND: Coarctation of the pulmonary artery may lead to its early obstruction. We investigated the outcomes of a strategy of aggressive reconstruction of the pulmonary arteries in the neonatal period. METHODS: From 2000 to 2013 a total of 162 consecutive neonates (< 90 days) underwent systemic to-pulmonary shunting. Twenty-eight of them underwent the following concomitant reconstruction of the central pulmonary arteries: end-to-end anastomosis (4), patch reconstruction of the pulmonary arteries (24) with 0.4 mm Gore-Tex (W. L. Gore & Associates, Newark, DE) patch (18), or autologous pericardium (6). Ten patients were directed to univentricular palliation and 18 to biventricular repair. RESULTS: There was 1 in-hospital death (4%) and 2 deaths after hospital discharge (inter-stage mortality, 7%). The follow-up of the 25 survivors was complete. After a mean of 3 +/- 3 years, patients with single ventricle palliation reached the following stages: shunts (2); one and a half ventricle repair (1); bidirectional cavopulmonary shunt (4); and Fontan (2). Fourteen of the patients destined for biventricular physiology reached complete repair while 2 patients were still with shunts. There was no pulmonary artery occlusion. Focal narrowing or pulmonary artery hypoplasia was the main indication for 10 of the subsequent 36 reinterventions. CONCLUSIONS: Neonatal pulmonary artery reconstruction effectively prevents pulmonary artery occlusion and warrants pulmonary artery growth in the majority of cases of juxtaductal pulmonary artery coarctation. A number of these patients needed enlargement of their central pulmonary arteries in subsequent procedures. Indications of this reconstruction at the time of systemic-to-pulmonary shunting remains to be specified. PMID- 25534529 TI - Clinical outcomes of mitral valve replacement with the 16-mm ATS advanced performance valve in neonates and infants. AB - BACKGROUND: Although mitral valve repair is the preferred treatment for mitral regurgitation in neonates and infants, mitral valve replacement (MVR) is sometimes necessary. METHODS: From 1999 through 2013, 18 patients younger than 1 year underwent MVR with the smallest (16 mm) commercially available mechanical valve. At surgery, mean age was 4.0 +/- 1.8 months (range, 4 days to 7 months), and mean body weight was 5.3 +/- 1.6 kg (range, 3.2 to 8.3 kg). Prosthetic valves were implanted in the supra-annular position in 17 of the 18 patients. RESULTS: All patients were followed up, and the mean follow-up period was 4.5 +/- 3.8 years (range, 0.2 to 14 years). The rates of overall survival and freedom from redo MVR at 10 years were 88.9% and 57.8%, respectively. The causes of redo MVR were pulmonary hypertension in patients with left ventricular outflow obstruction (n = 2), hemolysis (n = 1), and a stuck valve (n = 1). The estimated effective orifice area index (effective orifice area/body surface area) was significantly inversely correlated with peak transmitral pressure gradient (r = -0.784, p < 0.01). The rate of freedom from permanent pacemaker implantation at 10 years was 71.2%. Three of the 5 pacemaker implantation procedures were for postoperative sick sinus syndrome. Although intracranial hemorrhage developed in 3 infants, all neurologic sequelae resolved. CONCLUSIONS: The implanted valves were durable, and no premature increase in transmitral pressure gradient was observed. Complications included injury of the sinus node artery and hemorrhage related to anticoagulation therapy. PMID- 25534533 TI - Quorum sensing restrains growth and is rapidly inactivated during domestication of Sinorhizobium meliloti. AB - Microbial cooperative behaviours, such as quorum sensing (QS), improve survival and this explains their prevalence throughout the microbial world. However, relatively little is known about the mechanisms by which cooperation promotes survival. Furthermore, cooperation typically requires costly contributions, e.g. exopolysaccharides, which are produced from limited resources. Inevitably, cooperation is vulnerable to damaging mutations which results in mutants that are relieved of the burden of contributing but nonetheless benefit from the contributions of their parent. Unless somehow prevented, such mutants may outcompete and replace the parent. The bacterium Sinorhizobium meliloti uses QS to activate the production of copious levels of exopolysaccharide (EPS). Domestication of this bacterium is typified by the appearance of spontaneous mutants incapable of EPS production, which take advantage of EPS production by the parent and outcompete the parent. We found that all of the mutants were defect in QS, implying that loss of QS is a typical consequence of the domestication of this bacterium. This instability was traced to several QS regulated processes, including a QS-dependent restraint of growth, providing the mutant with a significant growth advantage. A model is proposed whereby QS restrains population growth to prevent overcrowding and prepares the population for the survival of severe conditions. PMID- 25534534 TI - Veterinary hospital surveillance systems. AB - We cannot manage what we do not measure. In order to provide optimal patient care appropriate effort must be given to the prevention of infectious disease transmission through the development and maintenance of an infection control program that is founded on results obtained through organized surveillance efforts. Every facility is unique - thus efforts should be tailored to distinctive physical attributes and organizational limitations of individual practices. There is not only an ethical responsibility to do so, but there is a legal responsibility to meet the minimum standard of practice with respect to veterinary infection prevention and control. PMID- 25534535 TI - Zoonotic disease risks for immunocompromised and other high-risk clients and staff: promoting safe pet ownership and contact. AB - Pets can be a source of disease (zoonoses) for humans. The disease risks associated with pet contact are highest among young children, the elderly, pregnant women, and immunocompromised hosts. These individuals and household members display limited knowledge of pet-associated disease, rarely recall receipt of pet-associated disease information, and report pet ownership practices that are often at odds with established disease prevention recommendations. Veterinary staff are in a key position to promote safe pet ownership and contact practices. Encouraging and safeguarding client disclosure of immunocompromising health conditions and promoting veterinarian-physician communications are critical for effectively providing this service. PMID- 25534536 TI - Infection control in veterinary small animal practice. PMID- 25534537 TI - Selected reviews from the 2015 BMT tandem meetings. PMID- 25534538 TI - Pretransplant induction regimens for multiple myeloma. PMID- 25534539 TI - Changes in donor heart allocation in the United States without fundamental changes in the system: rearranging deck chairs and elephants in the room. PMID- 25534540 TI - Hour-glass magnetic excitations induced by nanoscopic phase separation in cobalt oxides. AB - The magnetic excitations in the cuprate superconductors might be essential for an understanding of high-temperature superconductivity. In these cuprate superconductors the magnetic excitation spectrum resembles an hour-glass and certain resonant magnetic excitations within are believed to be connected to the pairing mechanism, which is corroborated by the observation of a universal linear scaling of superconducting gap and magnetic resonance energy. So far, charge stripes are widely believed to be involved in the physics of hour-glass spectra. Here we study an isostructural cobaltate that also exhibits an hour-glass magnetic spectrum. Instead of the expected charge stripe order we observe nano phase separation and unravel a microscopically split origin of hour-glass spectra on the nano scale pointing to a connection between the magnetic resonance peak and the spin gap originating in islands of the antiferromagnetic parent insulator. Our findings open new ways to theories of magnetic excitations and superconductivity in cuprate superconductors. PMID- 25534542 TI - In silico mechanistic disposition and in vivo evaluation of zero-order drug release from a novel triple-layered tablet matrix. AB - OBJECTIVES: The purpose of this study was to formulate novel triple-layered tablet (TLT) matrices employing modified polyamide 6,10 (mPA6,10) and salted-out poly(lactic-co-glycolic acid) (s-PLGA) in an attempt to achieve stratified zero order drug release. METHODS: mPA6,10 and s-PLGA were employed as the outer drug carrier matrices, whereas poly(ethylene oxide) (PEO) was used as the middle-layer drug matrix. Diphenhydramine HCl, ranitidine HCl and promethazine were selected as model drugs to pre-optimize the TLT, whereas atenolol, acetylsalicylic acid and simvastatin were employed as a comparable fixed dose combination to test the TLT prototype in vitro and in vivo (Large White Pig model). A total of 17 formulations that varied in terms of polymer stoichiometry, salt addition and polymer-polymer ratios were generated using a Box-Behnken experimental design. RESULTS: The in vitro drug release analysis revealed that release from the mPA6,10 layer was relatively linear with a burst release, which upon addition of sodium sulfate was reduced. Furthermore, formulations with higher quantities of mPA6,10 provided more controlled zero-order drug release and increased the matrix hardness. The addition of PEO to the s-PLGA layer significantly reduced the initial burst release that occurred when s-PLGA was used alone. CONCLUSIONS: The formulation with a lower s-PLGA:PEO ratio displayed superior zero-order release. Relatively, linear drug release was achieved from the middle-layer. The in vivo results proved the applicability of optimized TLT formulation in a therapeutic cardiovascular drug treatment regimen. PMID- 25534541 TI - Overview of computational vaccinology: vaccine development through information technology. AB - Pathogenic organisms, causes of various infectious diseases, possess a rich repository of antigenic proteins that engender an immune response in a host. These types of diseases are usually treated with the use of pharmaceuticals; unfortunately, many of these also have a potential to induce fatal side effects, especially allergic responses in the diseased host. In addition, many pathogens evolve (by selective survival) single or multi-drug resistance (MDR). Therefore, a means to prevent the host from becoming susceptible to the pathogen from the onset, rather than trying to devise pharmacologic protocols to treat an ongoing infection, are increasingly seen as desirable to reduce the incidence of infectious diseases altogether. To this end, cost-effective development and use of "safe" vaccines is key. This paper provides an overview on the new and expanding area of computational vaccinology and a brief background on pathogen antigenicity, identification of pathogen-specific antigens, and screening of candidate antigens using various tools and databases developed in the recent past. PMID- 25534545 TI - Ethical animal research--a pathway to zero tolerance. PMID- 25534543 TI - A R2R3-MYB transcription factor that is specifically expressed in cotton (Gossypium hirsutum) fibers affects secondary cell wall biosynthesis and deposition in transgenic Arabidopsis. AB - Secondary cell wall (SCW) is an important industrial raw material for pulping, papermaking, construction, lumbering, textiles and potentially for biofuel production. The process of SCW thickening of cotton fibers lays down the cellulose that will constitute the bulk (up to 96%) of the fiber at maturity. In this study, a gene encoding a MYB-domain protein was identified in cotton (Gossypium hirsutum) and designated as GhMYBL1. Quantitative real-time polymerase chain reaction (RT-PCR) analysis revealed that GhMYBL1 was specifically expressed in cotton fibers at the stage of secondary wall deposition. Further analysis indicated that this protein is a R2R3-MYB transcription factor, and is targeted to the cell nucleus. Overexpression of GhMYBL1 in Arabidopsis affected the formation of SCW in the stem xylem of the transgenic plants. The enhanced SCW thickening also occurred in the interfascicular fibers, xylary fibers and vessels of the GhMYBL1-overexpression transgenic plants. The expression of secondary wall associated genes, such as CesA4, CesA7, CesA8, PAL1, F5H and 4CL1, were upregulated, and consequently, cellulose and lignin biosynthesis were enhanced in the GhMYBL1 transgenic plants. These data suggested that GhMYBL1 may participate in modulating the process of secondary wall biosynthesis and deposition of cotton fibers. PMID- 25534546 TI - Science in brief: Highlights from the biomechanics and physiotherapy abstracts at the International Conference on Equine Exercise Physiology. PMID- 25534547 TI - Barking up the wrong tree: would international guidelines improve safety in equine anaesthesia? PMID- 25534548 TI - Effects of pioglitazone and fenofibrate co-administration on bone biomechanics and histomorphometry in ovariectomized rats. AB - Pioglitazone, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist is an effective therapy for type 2 diabetes, but has been associated with increased risk for bone fracture. Preclinical studies suggest that PPAR-alpha agonists (e.g., fenofibrate) increase bone mineral density/content, although clinical data on bone effects of fibrates are lacking. We investigated the effects of pioglitazone (10 mg/kg/day) and fenofibrate (25 mg/kg/day) on bone strength and bone histomorphometric parameters in osteopenic ovariectomized (OVX) rats. An additional group of rats received a combination of pioglitazone + fenofibrate to mimic the effects of a dual PPAR-alpha/gamma agonist. The study consisted of a 13-week treatment phase followed by a 6-week treatment-free recovery period. Pioglitazone significantly reduced biomechanical strength at the lumbar spine and femoral neck compared with rats administered fenofibrate. Co treatment with pioglitazone + fenofibrate had no significant effect on bone strength in comparison with OVX vehicle controls. Histomorphometric analysis of the proximal tibia revealed that pioglitazone suppressed bone formation and increased bone resorption at both cancellous and cortical bone sites relative to OVX vehicle controls. In contrast, fenofibrate did not affect bone resorption and only slightly suppressed bone formation. Discontinuation of pioglitazone treatment, both in the monotherapy and in the combination therapy arms, resulted in restoration of bone formation and resorption rates, demonstrating reversibility of effects. The above data support the concept that dual activation of PPAR-gamma and PPAR-alpha attenuates the negative effects of PPAR-gamma agonism on bone strength. PMID- 25534549 TI - [Acute renal failure secondary to diarrhea due to sprue like-enteropathy associated with olmesartan]. PMID- 25534550 TI - The role of concentration--effect relationships in the QTc interval prolongation: case sotalol. PMID- 25534551 TI - [COPD: Patients speak to doctors. Survey from the Federation francaise des associations et amicales de malades insuffisants ou handicapes respiratoires (FFAAIR)]. AB - AIM: The aim of this study was to hear COPD patients about their condition, their symptoms, the course of their condition and their knowledge about their disease. METHOD: Questionnaires were offered to COPD patients attending pulmonary physicians, rehabilitation centers and patients associations from February to June 2012. RESULTS: A total of 348 patients (mean age 66 years) completed the questionnaire. Among them, 67% were male, 21% were active smokers and 68% were ex smokers. Two third of the patients had been exposed to passive smoking and half to occupational toxic inhalations. The Body Mass Index was above 25 for the majority of the patients. Patients reported that symptoms were frequently experienced for a long time before COPD: essentially dyspnea, cough, sputum and iterative acute bronchitis. General symptoms were observed in two third of the cases and comorbidities were present in 91% of the cases. These symptoms motivated a consultation to general practitioners but diagnosis was actually made by pneumologists in 91% of the cases. For 39% of responders, delay before diagnosis was more than 4 years. Prior to diagnosis, the word "COPD" was unknown to 80% of the patients. Following the diagnosis, 63% of patients did not know their COPD severity stage. CONCLUSION: This survey underlines the role of passive smoking and exposure to occupational inhalation, and the frequency of general symptoms, comorbidities and typical signs of COPD a long time before diagnosis. This delay is usually several years. A minority of patients know the name and the stage of their illness. PMID- 25534552 TI - [Bronchial thermoplasty in the treatment of severe adult asthma]. AB - Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma. PMID- 25534553 TI - Akap12 is essential for the morphogenesis of muscles involved in zebrafish locomotion. AB - Swimming behavior in fish is driven by coordinated contractions of muscle fibers. In zebrafish, slow muscle cell migration is crucial for the formation of the muscle network; slow myoblasts, which arise from medial adaxial cells, migrate radially to the lateral surface of the trunk and tail during embryogenesis. This study found that the zebrafish A-kinase anchoring protein (akap)12 isoforms akap12alpha and akap12beta are required for muscle morphogenesis and locomotor activity. Embryos deficient in akap12 exhibited reduced spontaneous coiling, touch response, and free swimming. Akap12-depleted slow but not fast muscle cells were misaligned, suggesting that the behavioral abnormalities resulted from specific defects in slow muscle patterning; indeed, slow muscle cells and muscle pioneers in these embryos showed abnormal migration in a cell-autonomous manner. Taken together, these results suggest that akap12 plays a critical role in the development of zebrafish locomotion by regulating the normal morphogenesis of muscles. PMID- 25534555 TI - Tasimelteon: a selective and unique receptor binding profile. AB - Hetlioz((r)) (tasimelteon) is the first approved treatment in the United States for Non-24-Hour Sleep-Wake Disorder (Non-24). We present here data on the in vitro binding affinity of tasimelteon for both human melatonin receptors MT1 and MT2, as well as the extended screen of other receptors and enzymes. Results indicate that tasimelteon is a potent Dual Melatonin Receptor Agonist (DMRA) with 2.1-4.4 times greater affinity for the MT2 receptor believed to mediate circadian rhythm phase-shifting (Ki = 0.0692 nM and Ki = 0.17 nM in NIH-3T3 and CHO-K1 cells, respectively), than for the MT1 receptor (Ki = 0.304 nM and Ki = 0.35 nM, respectively). Tasimelteon was also shown to have no appreciable affinity for more than 160 other pharmacologically relevant receptors and several enzymes. PMID- 25534554 TI - Crystal structure of afadin PDZ domain-nectin-3 complex shows the structural plasticity of the ligand-binding site. AB - Afadin, a scaffold protein localized in adherens junctions (AJs), links nectins to the actin cytoskeleton. Nectins are the major cell adhesion molecules of AJs. At the initial stage of cell-cell junction formation, the nectin-afadin interaction plays an indispensable role in AJ biogenesis via recruiting and tethering other components. The afadin PDZ domain (AFPDZ) is responsible for binding the cytoplasmic C-terminus of nectins. AFPDZ is a class II PDZ domain member, which prefers ligands containing a class II PDZ-binding motif, X-Phi-X Phi (Phi, hydrophobic residues); both nectins and other physiological AFPDZ targets contain this class II motif. Here, we report the first crystal structure of the AFPDZ in complex with the nectin-3 C-terminal peptide containing the class II motif. We engineered the nectin-3 C-terminal peptide and AFPDZ to produce an AFPDZ-nectin-3 fusion protein and succeeded in obtaining crystals of this complex as a dimer. This novel dimer interface was created by forming an antiparallel beta sheet between beta2 strands. A major structural change compared with the known AFPDZ structures was observed in the alpha2 helix. We found an approximately 2.5 A-wider ligand-binding groove, which allows the PDZ to accept bulky class II ligands. Apparently, the last three amino acids of the nectin-3 C terminus were sufficient to bind AFPDZ, in which the two hydrophobic residues are important. PMID- 25534556 TI - [Complement terminal fraction deficiency revealed at first invasive meningococcal infection]. AB - Prevalence of complement protein deficiency in the general population is rare and its association with an increased risk of meningococcal infection is well established. However, management of these patients with potentially serious infections and indications warranting a search for such a deficiency have not met with consensus. We report the case of a 3-year-old child with no significant medical history who consulted in an emergency department for a fever after a stay in Senegal. Medical explorations concluded in septicemia and meningococcal W meningitis with a favorable outcome. Secondarily, we highlighted a complete deficiency of complement component C6. We diagnosed the same deficit in his twin sister who presented no infection. A long-term prophylactic antibiotic therapy and a meningococcal conjugate vaccine A,C,Y,W were set up for the twins. Recurrent invasive meningococcal infections and highlighting certain meningococcal serogroups are currently indications for complement protein exploration. We suggest expanding the search criteria for a complement protein deficiency after a single event of invasive meningococcal infection. This is an easy, rapid, and cost-effective screening system by dosage of CH50, C3, C4, and AP50. The arrival of the new meningococcal B vaccine will contribute to improving these patients' care. Family screening is necessary for prophylactic therapy. PMID- 25534557 TI - [Impact of a targeted educational intervention on respiratory syncytial virus bronchiolitis prevention in full-term and preterm infants]. AB - OBJECTIVES: Palivizumab, a humanized monoclonal antibody directed against respiratory syncytial virus (RSV), is the only existent immunoprophylaxis therapy for prevention of serious lower respiratory tract disease caused by RSV in infants (up to 2 years of age), particularly in those who meet high-risk criteria (preterm infants and/or those with bronchopulmonary or congenital heart disease). In our region, the monthly injections are not given at the hospital but by private pediatricians during the epidemic season. We aimed to assess the influence of an educational and personalized support of preterm infants treated with Palivizumab on patient compliance during the last season. METHODS: A three level educational intervention was conducted: the parents were advised in the neonatology units, then at the hospital pharmacy where the treatment was delivered, and finally by their referent pediatrician. We evaluated the impact of this intervention by measuring patient compliance, defined by two criteria, and by measuring the rate of rehospitalization for RSV bronchiolitis. We compared these results to those of the previous season (2011-2012) in which no interventional program was conducted. RESULTS: Compliance was better in the group of patients followed (2012-2013); 59.7% of them received all the palivizumab doses, while only 32.9% of the infants not followed received all doses. The number of injections given at appropriate intervals remained stable between the two groups and no significant difference was found in the rate of RSV bronchiolitis rehospitalizations. CONCLUSION: This educational intervention program, coordinated by doctors and pharmacists, is associated with improved treatment compliance in high-risk of RSV bronchiolitis infants. To optimize such a care program, we have planned to set up and then evaluate a call center procedure involving extensive counseling for parents and reminder telephone calls. PMID- 25534558 TI - [Winter viral ecology in a pediatric intensive care unit: a prospective study]. AB - INTRODUCTION: Viral respiratory infections are common in children, most of which are due to a virus. They can lead to serious infections, and these children may require treatment in a pediatric intensive care unit (PICU). This prospective study evaluated the epidemiology of respiratory viruses and associated illnesses among children hospitalized in a PICU during the three winter months of 2012 2013. METHODS: All the children admitted to the PICU, University Hospital of Caen, France, were included. Nasal swabs were collected and specimens were tested using a single real-time PCR (polymerase chain reaction). RESULTS: Of the 105 patients admitted to the PICU during the study period, 84 fulfilled the inclusion criteria. The "respiratory group" included 37 patients with respiratory symptoms at admission while the "nonrespiratory group" included 47 patients with no respiratory symptoms. The 84 nasal swabs collected included 54 that were considered positive (64.3%) and 70 viruses were detected. The most commonly detected virus was RSV (n=28; 40.0% positive samples), followed by HRV (n=24; 34.3%). Viruses were more frequently detected in the respiratory (86.5%) than in the nonrespiratory (42.6%) group (P<0.001). Statistical analysis by subgroups revealed that RSV infections were significantly more frequent in the respiratory group (54.1%) than in the nonrespiratory group (6.4%) (P<0.001). There was no difference for HRV (32.4% and 27.7%) or for the other viruses. No difference in duration of hospitalization or duration of mechanical ventilation was demonstrated depending on the virus detected. DISCUSSION: The use of the very sensitive multiplex PCR technique increased virus detection rates in both symptomatic and asymptomatic subjects. CONCLUSION: We have confirmed the frequency of RSV infections in a PICU and found that many patients without respiratory symptoms have respiratory infections caused by viruses. The impact of these infections on patient outcome should now be analyzed in order to demonstrate the role played by respiratory viruses. PMID- 25534559 TI - [Pattern and outcome of severe malarial anemia in Congolese children]. PMID- 25534560 TI - Molecular genetic analysis of trinucleotide repeat disorders (TRDs) in Indian population and application of repeat primed PCR. AB - Trinucleotide repeat disorders (TRDs) are a set of genetic disorders caused by trinucleotide repeat expansion in certain genes that exceed the normal, stable threshold, which varies from gene to gene. A dynamic mutation in a healthy gene may increase the repeat count and result in a defective gene. At present there are 14 pathogenic trinucleotide repeat disorders that are known to affect humans. The occurrence of these "triplet repeat diseases" within populations ranges from fairly common (Fragile X syndrome and Myotonic dystrophy type 1) to rare (Dentatorubral-pallidoluysian atrophy). In the present study we report a detailed scenario of TRDs in India mostly in respect to the 9 most common disorders namely; Fragile X syndrome, Myotonic dystrophy type 1, Spinocerebellar ataxia (type 1, 2, 3, 6 and 7), Friedreich Ataxia and Huntington Disease. PMID- 25534561 TI - Not just minor wild edible forest products: consumption of pteridophytes in sub Saharan Africa. AB - BACKGROUND: Gathering of wild edible plant resources by people in sub-Saharan Africa is discussed with reference to pteridophytes, which is an ancient plant group. Pteridophytes are crucial to food diversity and security in sub-Saharan Africa, although they are notably neglected as a result of inadequate research and agricultural development. Current research and agricultural development agenda still appear to focus on the popular and commonly used food crops, vegetables and fruits; ignoring minor and underutilized plant species such as pteridophytes which have shown significant potential as sources of macro and micro nutrients required to improve the diet of children and other vulnerable groups in sub-Saharan Africa. Documentation of edible pteridophytes is needed to reveal the importance of this plant group in the region and the associated indigenous knowledge about them; so that this knowledge can be preserved and utilized species used to combat dietary deficiencies as well as improve food security in the region. The aim of this study is to present an overview of food value of pteridophytes in sub-Saharan Africa using available literature and to highlight their potential in addressing dietary deficiencies in impoverished communities in the region. METHODS: This study is based on review of the literature published in scientific journals, books, reports from national, regional and international organizations, theses, conference papers and other grey materials obtained from libraries and electronic search of Google Scholar, ISI Web of Science and Scopus. RESULTS: A total of 24 taxa belonging to 14 genera and 11 families are used in sub-Saharan Africa as fodder and human food. Pteridium aquilinum (L.) Kuhn is the most common edible pteridophyte in sub Saharan Africa, used as human food in Angola, Cameroon, DRC, Gabon, Madagascar, Nigeria and South Africa, followed by Ophioglossum reticulatum L. (South Africa, Swaziland and Zanzibar), Ceratopteris thalictroides (L.) Brongn. (Madagascar and Swaziland), Diplazium sammatii (Kuhn) C.Chr. (DRC and Nigeria), Nephrolepis biserrata Sw. (DRC and Nigeria) and Ophioglossum polyphyllum A. Braun (Namibia and South Africa). The majority of edible pteridophytes are eaten as vegetables or potherbs (66.7%), with some eaten raw or as salad or edible rhizomes (12.5% each). Literature search revealed that some of the documented pteridophytes have high macro and micro nutrient content comparable to recommended FAO/WHO daily nutrient intake from conventional food crops and vegetables. CONCLUSION: This study demonstrated the capability of literature research to reveal traditional knowledge on edible pteridophytes in sub-Saharan Africa from dispersed primary ethnobotanical data. Findings from this study suggest that edible pteridophytes could make an important contribution to provision of macro and micro nutrients to the sub-Saharan African population. This study also provided evidence of the importance of pteridophytes as food sources, and can therefore, used to enhance food security in the region by complementing the major food crops, vegetables and fruits. PMID- 25534562 TI - Congenital Gerbode Defect in a Patient With an Acute Myocardial Infarction and Cardiogenic Shock Masquerading as an Acute Ventricular Septal Defect. PMID- 25534563 TI - Surgical Aortic Valve Replacement in an Adult Patient With Congenital Factor VII Deficiency: A Case Report of Perioperative Coagulation Management. PMID- 25534564 TI - Aneurysm Repair in a Patient With Systemic Mastocytosis. PMID- 25534565 TI - Lung Injury From Use of a Suction Catheter via the Double-Lumen Tube. PMID- 25534566 TI - [Expectations of relatives of critically ill patients regarding medical information. Qualitative research study]. AB - OBJECTIVE: To determine and analyse the expectations, needs and experiences of relatives of critically ill patients as regards medical information and the level of their understanding. To find keys for improving communication and to draw up best practices in clinical information. MATERIAL AND METHODS: Qualitative research study through semi-structured interviews carried out in a polyvalent adult intensive care unit (ICU) in a University Hospital. PARTICIPANTS: relatives of patients who were admitted to the ICU and who were discharged alive from the Unit. Ten interviews were performed taking into account diversification variables such as, type of family relationship with patients, patient age, length of ICU stay, origin, and location at the time of the interview. RESULTS: The results of the analysis of 10 interviews focused on: the subjective position of the family in the ICU (the agonizing wait), what the ICU represents for the family (surveillance and monitoring of a situation between life and death), perceived care (complete delegation of care), and medical information (what and how they expect and what and how they receive it), as much in the first information (sincerity, hope, delicacy) as in the successive. CONCLUSIONS: There is divergence between what families expect and what they get as regards medical information. To know the expectations of the families will help to provide higher quality care and more humane treatment in the ICU. PMID- 25534567 TI - [Unplanned extubation in ICU, and the relevance of non-dependent patient variables the quality of care]. AB - OBJECTIVE: To evaluate, for a consecutive year, the magnitude of unplanned extubation, looking for non-dependent patient variables. MATERIAL AND METHODS: Prospective, observational study of cases and controls in a mixed intensive care unit within in a tertiary hospital. Patients were considered cases with more than 24 hours who had an episode of unplanned extubation. Prospective collection of variables case as time of unplanned extubation (collection time), identification of the box where the patient was admitted, presence and type of physical restraint, development of ventilator-associated pneumonia (VAP) and death. RESULTS: There were 17 unplanned extubation in 15 patients, 1.21 unplanned extubation per 100 days of MV. The unplanned extubation had an inhomogeneous spatial distribution (number of boxes). The time distribution of cases compared with controls showed significant differences in time distribution (P=.02). The comparative analysis between cases and controls, showed increased mortality, increased length of ICU stay, longer hospital stay and increased risk for VAP when patients suffer an episode of unplanned extubation. DISCUSSION: Unplanned extubation occurs most frequently in a given time slot of the day, may play a role in the spatial location of the patient; occurs most often in patients who are in the process of weaning from mechanical ventilation, and develop greater VAP. PMID- 25534568 TI - [Perceived quality in hospitals of the Andalusia Healthcare System. The case of neurosurgery departments]. AB - OBJECTIVE: To analyse the characteristics of the perceived quality in hospitals of the Andalusia healthcare system and compare this with that in Andalusian Neurosurgery departments. MATERIAL AND METHODS: Randomised surveys, adjusted for working age, were performed in Andalusia using a telephone questionnaire based on the SERVQUAL model with the appropriate modification, with the subsequent selection of a subgroup associated with neurosurgery. Perceived quality was classified as; technical, functional and infrastructure quality. RESULTS: The overall satisfaction was 76.3%. Frequency analysis found that variables related to the technical quality (good doctors, successful operations, trained staff, etc.) obtained more favourable outcomes. Those related to time (wait, consulting, organizing schedules) obtained worse outcomes. The care of families variables obtained poor results. There was no difference between the overall Andalusian healthcare system and neurosurgery departments. In the mean analysis, women and older people gave more favourable responses, especially for variables related to infrastructure quality. In the "cluster" analysis, there were more favourable responses by elderly people, with no differences in gender (P<.009). CONCLUSIONS: There is no difference in perceived quality between the Andalusian healthcare system overall and neurosurgery departments. The perceived quality of the Andalusian healthcare system is higher in the elderly people. The analysis of perceived quality is useful for promoting projects to improve clinical management. PMID- 25534569 TI - Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder. AB - There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted. PMID- 25534570 TI - Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth. AB - Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells. PMID- 25534571 TI - [Bilateral diaphragmatic paralysis due to Parsonage-Turner syndrome]. AB - We report the case of a 49-years-old patient who presented to the accident and emergency department with sudden onset dyspnea associated with acute shoulder pain. He was breathless at rest with supine hypoxemia. He had an amyotrophic left shoulder with localized paresis of the shoulder. Both hemi-diaphragms were elevated on chest X-rays. Pulmonary function tests showed a restrictive pattern and both phrenic nerve conduction velocities were decreased. At night, alveolar hypoventilation was evidenced by elevated mean capnography (PtcCO2: 57mmHg). Neuralgic amyotrophy, Parsonage-Turner syndrome was the final diagnosis. This syndrome is a brachial plexus neuritis with a predilection for the suprascapular and axillary nerves. Phrenic nerve involvement is rare but where present can be the most prominent clinical feature as in our case report. PMID- 25534572 TI - Five-year outcomes of catheter ablation in patients with atrial fibrillation and left ventricular systolic dysfunction. AB - BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapy for symptomatic patients. The long-term efficacy and impact of catheter ablation among patients with severe systolic heart failure (SHF) requires additional study to understand if outcomes achieved at 1 year are maintained and mechanisms of AF recurrence. METHODS: Three groups with SHF and 5 years of follow up were matched 1:4:4 by age (+/-5 years) and sex: AF ablation patients receiving their first ablation (n = 267), AF patients that did not receive an ablation (n = 1,068), and SHF patient without AF (n = 1,068). SHF was based upon clinical diagnosis and an ejection fraction (EF) <=35%. Patients were followed for 5-year primary outcomes of AF recurrence, heart failure, stroke, death, and cardiac function. RESULTS: At 5 years, 60.7% of patients had clinical recurrence of AF. Diabetes and a prior heart attack were significant predictors of long-term risk of AF recurrence. Long-term mortality rates were 27%, 55%, 50%, in the AF ablation, AF, and no AF groups, respectively (P < 0.0001), with the lower rates attributed to lower cardiovascular mortality. At 5 years, there was no difference in EF, yet HF hospitalizations were lower following AF ablation compared to patients with AF and no ablation. Stroke rates at 5 years trended to be lower in the AF ablation group, but the difference was not statistically significant. CONCLUSION: Recurrence rates of AF in patients with SHF after ablation are common at 5 years with an anticipated ongoing increase. Long-term AF-related comorbidities tended to be less in the AF ablation group. PMID- 25534575 TI - Effects of Horticultural Therapy on Psychosocial Health in Older Nursing Home Residents: A Preliminary Study. AB - This preliminary study examined the effect of horticultural therapy on psychosocial health in older nursing home residents. A combined quantitative and qualitative design was adopted. Convenience sampling was used to recruit 10 older residents from a nursing home in Taichung, Taiwan. Participants joined a 10-week indoor horticultural program once a week, with each session lasting for about 1.5 hours. A single-group design with multiple measurements was adopted for the quantitative component of this study. Interviews held 1-2 days before the intervention (T0) were used to collect baseline data. The two outcome variables of this study, depression and loneliness, were reassessed during the 5th (T1) and 10th (T2) weeks of the intervention. Generalized estimating equations were used to test the mean differences among T0, T1, and T2 measures. After the 10-week program, qualitative data were collected by asking participants to share their program participation experiences. The results of generalized estimating equation showed significant improvements in depression and loneliness. Four categories emerged from the qualitative data content analysis: social connection, anticipation and hope, sense of achievement, and companionship. Given the beneficial effects of the horticulture therapy, the inclusion of horticultural activities in nursing home activity programs is recommended. PMID- 25534573 TI - Factors predictive of treatment-emergent adverse events of prucalopride: an integrated analysis of four randomized, double-blind, placebo-controlled trials. AB - BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently re-ported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on pa-tients treated with prucalopride 2 mg or placebo were ana-lyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly as-sociated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differ ences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to expe-rience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. Con-clusions Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians. (Gut Liver, 2015;9208-213). PMID- 25534577 TI - Histology and immunohistochemistry of the developing juxta-oral organ in mice. AB - The juxta-oral organ is a persistent bilateral organ in the mammalian bucca. It consists of epithelial parenchyma and surrounding mesenchymal sheath with connective tissue rich in nerve fibers and sensory receptors between them. The organ develops from the embryonic oral epithelium and is separated from the oral mucosa. The morphology of this organ is very different in mice compared to humans. Although several reports have described the histology of the juxta-oral organ in rodents, its developmental changes have rarely been reported. In the present study, histological development and ultrastructure of the juxta-oral organ, with special attention to its epithelial parenchyma and mesenchymal sheath, were investigated in mice during several developmental stages. Immunohistochemical staining for pan-cytokeratin (CK) on serial paraffin sections of the head allowed easier detection of this organ. The juxta-oral organ was innervated by the buccal nerve from an early stage of organogenesis at E13.5. The organ was located adjacent to the fascia of the masticatory muscles during all developmental stages examined. The parenchymal cells were immunohistochemically positive for p63 and CK14 in both newborn and adult mice, suggesting that these epithelial cells possess characteristics of the basal cells of the stratified epithelium. Furthermore, the parenchyma was ensheathed by layers of mesenchymal cells with perineurial characteristics as shown by immunohistochemical staining and electron microscopy. Unique sensory endings and bundles of elastic fibers were observed between the epithelial parenchyma and mesenchymal sheath. The present findings concerning the structure of mouse juxta-oral organ, especially that of epithelial parenchyma and mesenchymal sheath provide baseline knowledge for the further understanding of the unique morphological features, developmental changes and functional details of this organ. PMID- 25534576 TI - Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study. AB - Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors. PMID- 25534578 TI - A gender-informed model to train community health workers in maternal mental health. AB - The New Haven Mental Health Outreach for MotherS (MOMS) Partnership is a community-academic partnership that works to develop public health approaches to ensure that pregnant and parenting women living in the City of New Haven achieve the highest possible level of mental health. The MOMS Partnership developed a training model for community health workers specializing in maternal mental health. Six community health workers (termed Community Mental Health Ambassadors or CMHAs) were trained on key topics in this gender-informed maternal mental health curriculum. Pre- and post-test questionnaires assessed changes in attitudes, perceived self-efficacy and control using standardized scales. The results indicated preliminary acceptability of the training curriculum in transforming knowledge and attitudes about maternal mental health among community health workers. PMID- 25534580 TI - The use of a modified, oscillating positive expiratory pressure device reduced fever and length of hospital stay in patients after thoracic and upper abdominal surgery: a randomised trial. AB - QUESTION: Does the use of an oscillating positive expiratory pressure (PEP) device reduce postoperative pulmonary complications in thoracic and upper abdominal surgical patients? DESIGN: A multi-centre, parallel-group, randomised controlled trial with intention-to-treat analysis, blinding of some outcomes, and concealed allocation. PARTICIPANTS: A total of 203 adults after thoracic or upper abdominal surgery with general anaesthesia. INTERVENTION: Participants in the experimental group used an oscillating PEP device, thrice daily for 5 postoperative days. Both the experimental and control groups received standard medical postoperative management and early mobilisation. OUTCOME MEASURES: Fever, days of antibiotic therapy, length of hospital stay, white blood cell count, and possible adverse events were recorded for 28 days or until hospital discharge. RESULTS: The 99 participants in the experimental group and 104 in the control group were well matched at baseline and there was no loss to follow-up. Fever affected a significantly lower percentage of the experimental group (22%) than the control group (42%), with a RR of 0.56 (95% CI 0.36 to 0.87, NNT 6). Similarly, length of hospital stay was significantly shorter in the experimental group, at 10.7 days (SD 8.1), than in the control group, at 13.3 days (SD 11.1); the mean difference was 2.6 days (95% CI 0.4 to 4.8). The groups did not differ significantly in the need for antibiotic therapy, white blood cell count or total expense of treatment. CONCLUSION: In adults undergoing thoracic and upper abdominal surgery, postoperative use of an oscillating PEP device resulted in fewer cases of fever and shorter hospital stay. However, antibiotic therapy and total hospital expenses were not significantly reduced by this intervention. TRIAL REGISTRATION: NCT00816881. PMID- 25534581 TI - Obstructive sleep apnea syndrome and secondary polycythemia: analysis of the nationwide inpatient sample. PMID- 25534579 TI - Cognitive training in Parkinson's disease reduces cognitive decline in the long term. AB - BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) are at high risk for cognitive dysfunction. Non-pharmacological interventions have attracted increasing interest for enhancing PD patients' cognitive functions. METHODS: One year follow-up data (T2 ) of a randomized controlled trial evaluating two 6-week cognitive trainings - a structured (NEUROvitalis, NV) and an unstructured (mentally fit, MF) program - compared with a waiting list control group (CG) in non-demented PD patients (Hoehn and Yahr I-III) are presented. Forty-seven PD patients were examined at T2 . Effects on overall cognitive functions (Mini Mental State Examination and DemTect) were compared between all groups with repeated measurement analyses of variance. A combined score of the percentage change value from baseline (T0 ) to T2 was calculated to identify patients who retained or improved their cognitive state (responders). The risk of developing mild cognitive impairment (MCI) was analyzed. RESULTS: Significant time * treatment effects on overall cognitive functions were found for both training groups, each compared separately to the CG (DemTect, P < 0.05). Nine patients (56.3%) of the NV group, seven (41.2%) of the MF group and three (21.4%) of the CG were responders. Comparing NV to CG the odds ratio was 4.7 [95% confidence interval (0.8; 33.3)], and comparing MF to CG it was 2.6 [95% confidence interval (0.4; 17.4)]. MCI risk for patients without prior MCI was 40.0% in CG, 18.2% in MF and 18.2% in NV. The odds ratio was 3 comparing NV to CG, MF to CG. DISCUSSION: This study gives evidence that cognitive training may be effective to prevent cognitive decline and onset of MCI in PD patients. PMID- 25534582 TI - Daytime sleepiness associated with poor sustained attention in middle and late adulthood. AB - OBJECTIVE: We aimed to determine the association between psychomotor vigilance task (PVT) performance and sleep-related factors including sleep duration, daytime sleepiness, poor sleep quality, insomnia, and habitual snoring in a population-based sample. METHODS: This was a cross-sectional analysis from the ongoing prospective cohort study, the Korean Genome and Epidemiology Study. We measured PVT performance and documented demographics, sleep-related factors, life style, and medical conditions in community dwelling adults (N = 2499; mean age 57.1 +/- 7.3; male 1259). Associations between PVT parameters and sleep-related factors were tested, adjusting for age, gender, smoking, alcohol use, education, body mass index, hypertension, diabetes, depression, and the interval between mid sleep time and PVT test. RESULTS: High Epworth Sleepiness Scale (ESS, >=8) was associated with slower mean reciprocal response speed (mean RRT) (3.69 +/- 0.02 vs. 3.77 +/- 0.01, p < 0.001), higher probability for increased lapses (>=4) (OR 1.48, CI 1.12-1.88, p = 0.001), and more negative RRT slope (-0.036 +/- 0.002 vs. -0.030 +/- 0.001, p = 0.02). Older age, female gender, low education level, depressive mood, and the interval between mid-sleep and PVT test were also associated with poor performance. Sleep duration, habitual snoring, insomnia, or poor sleep quality (the Pittsburgh Sleep Quality Index score > 5) was not related to PVT parameters. CONCLUSIONS: At the population level, our results revealed important modifiers of PVT performance, which included subjective reports of daytime sleepiness. PMID- 25534584 TI - A polyoxometalate-organic supramolecular nanotube with high chemical stability and proton-conducting properties. AB - The use of 1H-1,2,4-triazole-3-thiol (H2trzS) has led to a rare inorganic-organic hybrid supramolecular nanotube built from novel Ni5-substituted polyoxotungstates, which presents interesting structural characteristics, high chemical stability, and proton-conducting properties. PMID- 25534583 TI - Comprehensive profiling analysis of actively resorbing osteoclasts identifies critical signaling pathways regulated by bone substrate. AB - As the only cells capable of efficiently resorbing bone, osteoclasts are central mediators of both normal bone remodeling and pathologies associates with excessive bone resorption. However, despite the clear evidence of interplay between osteoclasts and the bone surface in vivo, the role of the bone substrate in regulating osteoclast differentiation and activation at a molecular level has not been fully defined. Here, we present the first comprehensive expression profiles of osteoclasts differentiated on authentic resorbable bone substrates. This analysis has identified numerous critical pathways coordinately regulated by osteoclastogenic cytokines and bone substrate, including the transition from proliferation to differentiation, and sphingosine-1-phosphate signaling. Whilst, as expected, much of this program is dependent upon integrin beta 3, the pre eminent mediator of osteoclast-bone interaction, a surprisingly significant portion of the bone substrate regulated expression signature is independent of this receptor. Together, these findings identify an important hitherto underappreciated role for bone substrate in osteoclastogenesis. PMID- 25534585 TI - Editorial comment. PMID- 25534586 TI - Editorial comment. PMID- 25534587 TI - Editorial comment. PMID- 25534588 TI - Editorial comment. PMID- 25534589 TI - Editorial comment. PMID- 25534591 TI - Use of labeled tomato lectin for imaging vasculature structures. AB - Intravascular injections of fluorescent or biotinylated tomato lectin were tested to study labeling of vascular elements in laboratory mice. Injections of Lycopersicon esculentum agglutinin (tomato lectin) (50-100 ug/100 ul) were made intravascularly, through the tail vein, through a cannula implanted in the jugular vein, or directly into the left ventricle of the heart. Tissues cut for thin 10- to 12-um cryostat sections, or thick 50- to 100-um vibratome sections, were examined using fluorescence microscopy. Tissue labeled by biotinylated lectin was examined by bright field microscopy or electron microscopy after tissue processing for biotin. Intravascular injections of tomato lectin led to labeling of vascular structures in a variety of tissues, including brain, kidney, liver, intestine, spleen, skin, skeletal and cardiac muscle, and experimental tumors. Analyses of fluorescence in serum indicated the lectin was cleared from circulating blood within 2 min. Capillary labeling was apparent in tissues collected from animals within 1 min of intravascular injections, remained robust for about 1 h, and then declined markedly until difficult to detect 12 h after injection. Light microscopic images suggest the lectin bound to the endothelial cells that form capillaries and endothelial cells that line some larger vessels. Electron microscopic studies confirmed the labeling of luminal surfaces of endothelial cells. Vascular labeling by tomato lectin is compatible with a variety of other morphological labeling techniques, including histochemistry and immunocytochemistry, and thus appears to be a sensitive and useful method to reveal vascular patterns in relationship to other aspects of parenchymal development, structure, and function. PMID- 25534590 TI - Radiolabeling strategies for radionuclide imaging of stem cells. AB - The interest in the use of stem cells as a source for therapy has increased dramatically over the last decades. Different stem cell types have been tested in both in vitro and in vivo models, because of their properties such as differentiation potential, trophic effects and immune modulatory properties. To further optimize the use of different stem cell types for the treatment of disease in a clinical setting, it is necessary to know more about the in vivo behavior of these cells following engraftment. Until now, the golden standard to preclinically evaluate cell therapy was histology, which is an invasive method as the animals need to be sacrificed. This hampers the generation of dynamic information and results in only one single point in time available for analysis per animal. For more information regarding cell migration, in situ persistence, viability, proliferation and differentiation, molecular imaging can be used for imaging cells after transplantation dynamically and longitudinally, in a noninvasive way. With this technology, it becomes possible to track cells within the same subjects over a long period of time. PMID- 25534593 TI - Prenatal marijuana exposure, age of marijuana initiation, and the development of psychotic symptoms in young adults. AB - BACKGROUND: Studies have demonstrated that an early age of onset of marijuana use (EAOM) is associated with a higher risk of developing psychotic symptoms (PS) compared to initiating marijuana use at a later age or not at all. Research has also found that prenatal marijuana exposure (PME) predicts EAOM. This report evaluates the relationships among PME, EAOM, and PS. METHOD: Subjects were initially interviewed in their fourth prenatal month. Women and offspring who completed the birth assessment (n = 763) were selected for follow-up. Women and their offspring were followed until the offspring were 22 years of age: 596 offspring were evaluated. At age 22, PS were assessed in the offspring with the Diagnostic Interview Schedule using DSM-IV criteria. Analyses controlled for significant covariates including other prenatal substance exposures, race, gender, and offspring substance use at 22 years. RESULTS: PME and EAOM significantly predicted increased rates of PS at 22 years controlling for other significant covariates. The direct effect of PME on PS was marginally significant (p = 0.06) when EAOM was entered into the model and other covariates were fixed. In the mediation analysis, EAOM did not significantly mediate the association between PME and PS, controlling for significant covariates, nor was the indirect pathway significant when structural equation modeling was used. The total effect of the direct and indirect pathways was significant. CONCLUSIONS: In addition to EAOM, PME may also play a role in the association between marijuana use and the development of PS. This could highlight a new area for prevention. PMID- 25534592 TI - High-resolution MALDI mass spectrometric imaging of lipids in the mammalian retina. AB - Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI MSI) is emerging as a powerful tool for the analysis of molecular distributions in biological samples in situ. When compared to classical histology, the major benefit of this method is the ability to identify and localize many molecules in a single tissue sample. MALDI-MSI spatial resolution currently falls short of traditional microscopic methods as it is limited by instrumentation and sample preparation. Tissue preparation steps, such as matrix deposition, are critical when considering strategies to further enhance the spatial resolution. The mammalian retina was selected as the tissue of choice for method development; its stratified anatomy renders it an ideal tissue to test high-resolution MALDI-MSI as the different layers correspond to specific neuronal classes and cellular structures. We compared alcohol-fixed, paraffin-embedded retina to fresh-frozen samples and matrix that had been deposited by spray or by sublimation. We present a lipid imaging method based on MALDI-MSI of frozen retinal sections with sublimated 2,5-dihydroxybenzoic acid matrix, which results in a highly advanced resolution compared to previous established methods. Hierarchical clustering of the primary data allows robust detection and differentiation of molecular distributions at a spatial resolution between 10 and 20 MUm, thus approaching single-cell resolution. PMID- 25534594 TI - Catalytic behaviour in the ring-opening polymerisation of organoaluminiums supported by bulky heteroscorpionate ligands. AB - A series of alkyl organoaluminium complexes based on bulky heteroscorpionate ligands were designed as catalysts for the ring-opening polymerisation of cyclic esters. Thus, the treatment of AlX3 (X = Me, Et) with bulky acetamide or thioacetamide heteroscorpionate ligands nbptamH (1) [nbptamH = N-naphthyl-2,2 bis(3,5-dimethylpyrazol-1-yl)thioacetamide], fbpamH (2) [fbpamH = N-fluorenyl-2,2 bis(3,5-dimethylpyrazol-1-yl)acetamide], ptbptamH (3) [ptbptamH = N-phenyl-2,2 bis(3,5-di-tert-butylpyrazol-1-yl)thioacetamide], ntbptamH (4) [ntbptamH = N naphthyl-2,2-bis(3,5-di-tert-butylpyrazol-1-yl)thioacetamide], ptbpamH (5) [ptbpamH = N-phenyl-2,2-bis(3,5-di-tert-butylpyrazol-1-yl)acetamide] and (S) mtbpamH (6) [(S)-mtbpamH = (S)-(-)-N-alpha-methylbenzyl-2,2-bis(3,5-di-tert butylpyrazol-1-yl)acetamide] for 1 hour at 0 degrees C afforded the dialkyl aluminium complexes [AlX2{kappa(2)-nbptam}] (X = Me 7, Et 8), [AlX2{kappa(2) fbpam}] (X = Me 9, Et 10), [AlX2{kappa(2)-ptbptam}] (X = Me 11, Et 12), [AlX2{kappa(2)-ntbptam}] (X = Me 13, Et 14), [AlX2{kappa2(-)ptbpam}] (X = Me 15, Et 16) and [AlX2{kappa(2)-(S)-mtbpam}] (X = Me 17, Et 18). The structures of the complexes were determined by spectroscopic methods and the X-ray crystal structure of 14 was also established. The alkyl-containing aluminium complexes 7 18 can act as efficient single-component initiators for the ring-opening polymerisation of epsilon-caprolactone and rac-lactide. The polymerisations are living, as evidenced by the narrow polydispersities of the isolated polymers and the linear nature of the number average molecular weight versus conversion plot. Finally, a comparative study of ring-opening polymerisation for new bulky heteroscorpionate aluminium initiators and the less congested aluminium analogues is reported. PMID- 25534596 TI - New self-incubation IVF not yet cheaper. PMID- 25534595 TI - Evaluation of the effects of amyloid beta aggregation from seaweed extracts by a microliter-scale high-throughput screening system with a quantum dot nanoprobe. AB - Inhibitors of amyloid beta (Abeta) aggregation have the potential to serve as lead compounds for anti-Alzheimer's disease (AD) agents because Abeta aggregation is a key step in AD pathogenesis. Recently, we developed a novel microliter-scale high-throughput screening (MSHTS) system for Abeta aggregation inhibitors that applied fluorescence microscopic analysis with quantum dot nanoprobes, and attempted to comprehensively screen the inhibitors from spices using this system (Ishigaki et al., PLoS One, 8, e72992, 2013). In this study, we tried to evaluate the inhibitory activities of 11 seaweed extracts on Abeta aggregation using the MSHTS system. The half-maximal effective concentration (EC50) of the ethanolic extracts from all seaweeds exceeded 4.9 mg/ml, indicating that the extracts inhibit Abeta aggregation although this activity was significantly lower than that displayed by members of the Lamiaceae, a family of herbal spices that showed highest activity among 52 spices tested in our 2013 study. On the other hand, the EC50 of boiling water extracts was 0.013-0.42 mg/ml which was comparable with the EC50 of the extracts from the Lamiaceae family. These results suggest that the extraction efficiency of the inhibitors by boiling water extraction was higher than that by ethanolic extraction. Moreover, analysis of fluorescence micrographs, which were obtained from the MSHTS system, revealed that the morphology of the Abeta aggregates coincubated with boiling water extracts differed from control aggregates, suggesting that the MSHTS system is also useful for screening substances that affect the morphology of aggregates. PMID- 25534597 TI - Floppy eyelid syndrome. PMID- 25534599 TI - A 24-year-old man with suspected sacroiliitis. PMID- 25534600 TI - Unsanctioned travel restrictions related to Ebola unravel the global social contract. PMID- 25534601 TI - 10 health stories that mattered in 2014. PMID- 25534598 TI - Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4. AB - BACKGROUND: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion-transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. METHODS: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n=51,523) or azithromycin (n=52,518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and all-cause mortality. All outcomes were assessed within 30 days after co-prescription. RESULTS: Compared with the control group, patients co prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. INTERPRETATION: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes. PMID- 25534602 TI - Outrage at planned changes to Quebec IVF. PMID- 25534603 TI - Grief's extraordinary power. PMID- 25534604 TI - Caution issued against use of morcellators. PMID- 25534605 TI - Prostitution laws failing sex workers: CPHA. PMID- 25534607 TI - Photoisomerization of silyl-substituted cyclobutadiene induced by sigma -> pi* excitation: a computational study. AB - Photoinduced chemical processes upon Franck-Condon (FC) excitation in tetrakis(trimethylsilyl)-cyclobutadiene (TMS-CBD) have been investigated through the exploration of potential energy surface crossings among several low-lying excited states using the complete active space self-consistent field (CASSCF) method. Vertical excitation energies are also computed with the equation-of motion coupled-cluster model with single and double excitations (EOM-CCSD) as well as the multireference Moller-Plesset (MRMP) methods. Upon finding an excellent coincidence between the computational results and experimental observations, it is suggested that the Franck-Condon excited state does not correspond to the first pi-pi* single excitation state (S1, 1(1)B1 state in terms of D2 symmetry), but to the second (1)B1 state (S3), which is characterized as a sigma-pi* single excitation state. Starting from the Franck-Condon region, a series of conical intersections (CIs) are located along one isomerization channel and one dissociation channel. Through the isomerization channel, TMS-CBD is transformed to tetrakis(trimethylsilyl)-tetrahedrane (TMS-THD), and this isomerization process could take place by passing through a "tetra form" conical intersection. On the other hand, the dissociation channel yielding two bis(trimethylsilyl)-acetylene (TMS-Ac) molecules through further stretching of the longer C-C bonds might be more competitive than the isomerization channel after excitation into S3 state. This mechanistic picture is in good agreement with recently reported experimental observations. PMID- 25534606 TI - Time-resolved visible and infrared difference spectroscopy for the study of photosystem I with different quinones incorporated into the A1 binding site. AB - Room (298 K) and low (77K) temperature time-resolved visible and infrared difference spectroscopy has been used to study photosystem I particles with phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone), menadione (2-methyl-1,4 naphthoquinone) and plastoquinone 9 (2,3-dimethyl-5-prenyl-l,4-benzoquinone), incorporated into the A1 binding site. Concentrated samples in short path-length (~5 MUm) sample cells are typically used in FTIR experiments. Measurements were undertaken using standard "dilute" samples at 298 K, and concentrated (~5*) samples at both 298 and 77K. No concentration induced alterations in the flash induced absorption changes were observed. Concentrated samples in short path length cells form a transparent film at 77K, and could therefore be studied spectroscopically at 77K without addition of a cryoprotectant. At 298 K, for photosystem I with plastoquinone 9/menadione/phylloquinone incorporated, P700+FA/B- radical pair recombination is characterized by a time constant of 3/14/80 ms, and forward electron transfer from A1A- to Fx by a time constant of 211/3.1/0.309 MUs, respectively. At 77K, for concentrated photosystem I with menadione/phylloquinone incorporated, P700+A1- radical pair recombination is characterized by a time constant of 240/340 MUs, with this process occurring in 58/39% of the PSI particles, respectively. The origin of these differences is discussed. Marcus electron transfer theory in combination with kinetic modeling is used to simulate the observed electron transfer time constants at 298 K. This simulation allows an estimate of the redox potential for the different quinones in the A1 binding site. PMID- 25534608 TI - Amphirionin-2, a novel linear polyketide with potent cytotoxic activity from a marine dinoflagellate Amphidinium species. AB - A novel linear polyketide, amphirionin-2 (1), with two unique hexahydrofuro[3,2 b]furan moieties has been isolated from the cultivated algal cells of a benthic dinoflagellate Amphidinium sp. (strain KCA09051). The structure was elucidated on the basis of detailed analyses of 2D NMR data, and the absolute configuration of C-5 was determined by using modified Mosher's method. Amphirionin-2 (1) exhibited potent cytotoxic activity against human colon carcinoma Caco-2 cells and human lung adenocarcinoma A549 cells. PMID- 25534609 TI - Mechanisms of glyphosate resistance in two perennial ryegrass (Lolium perenne) populations. AB - BACKGROUND: Perennial ryegrass (Lolium perenne) has developed resistance to glyphosate within New Zealand vineyards following many years of herbicide application. The objectives of this work were to confirm resistance within two populations obtained from affected vineyards, and to determine the mechanism of resistance to glyphosate. RESULTS: Population O was confirmed to have a 25-fold resistance to glyphosate, whereas population J had a sevenfold resistance. Results of genotyping assays demonstrated a single nucleotide substitution at codon 106 of 5-enolpyruvylshikimate-3-phosphate synthase in population O but not population J. Glyphosate-resistant and glyphosate-susceptible populations did not differ in glyphosate absorption. However, in both resistant populations, much more of the absorbed (14) C-glyphosate remained in the treated leaf than occurred in the susceptible population. Significantly more glyphosate was found in the pseudostem region of susceptible plants compared with resistant plants. CONCLUSION: Both target-site and non-target-site mechanisms of glyphosate resistance were found in the perennial ryegrass population with 25-fold resistance, whereas only the non-target-site mechanism of resistance was found in the population with sevenfold resistance. This is the first study of the mechanism of glyphosate resistance in perennial ryegrass. PMID- 25534610 TI - Categories that should be removed from mental disorders classifications: perspectives and rationales of clinicians from eight countries. AB - OBJECTIVE: To explore the rationales of mental health professionals (mainly psychiatrists and psychologists) from 8 countries for removing specific diagnostic categories from mental disorders classification systems. METHOD: As part of a larger study, 505 participants indicated which of 60 major disorders should be omitted from mental disorders classification systems and provided rationales. Rationale statements were analyzed using inductive content analysis. RESULTS: The majority of clinicians (60.4%) indicated that 1 or more disorders should be removed. The most common rationales were (a) problematic boundaries between normal and psychopathological conditions (45.9% of total removal recommendations), (b) problematic boundaries among mental disorders (25.4%), and (c) problematic boundaries between mental and physical disorders (24.0%). The categories most frequently recommended for deletion were gender identity disorder, sexual dysfunction, and paraphilias, usually because clinicians viewed these categories as being based on stigmatization of a way of being and behaving. A range of neurocognitive disorders were described as better conceptualized as nonpsychiatric medical conditions. Results were analyzed by country and country income level. Although gender identity disorder was the category most frequently recommended for removal overall, clinicians from Spain, India, and Mexico were most likely to do so and clinicians from Nigeria and Japan least likely, probably because of social and systemic factors that vary by country. Systematic differences in removal rationales by country income level may be related to the development, structure, and functioning of health systems. CONCLUSION: Implications for development and dissemination of the classification of mental and behavioral disorders in WHO's ICD-11 are discussed. PMID- 25534611 TI - Redox control of viral carcinogenesis: The human papillomavirus paradigm. AB - BACKGROUND: Cervical cancer is the second most common neoplastic disease among women worldwide. The initiating event of such cancer is the infection with certain types of human papillomavirus (HPV), a very common condition in the general population. However, the majority of HPV infections is subclinical and transitory and is resolved spontaneously. Intriguingly, viral oncogene expression, although necessary, is not per se sufficient to promote cervical cancer and other factors are involved in the progression of infected cells to the full neoplastic phenotype. In this perspective it has been suggested that the redox balance and the oxidative stress (OS) may represent interesting and under explored candidates as promoting factors in HPV-initiated carcinogenesis. SCOPE OF THE REVIEW: The current review discusses the possible interplay between the viral mechanisms modulating cell homeostasis and redox sensitive mechanisms. Experimental data and indirect evidences are presented on the activity of viral dependent functions on i) the regulation of enzymes and compounds involved in OS; ii) the protection from oxidation of detoxifying/antiapoptotic enzymes and redox sensitive transcription factors; iii) the suppression of apoptosis; and iv) the modulation of host microRNAs regulating genes associated with antioxidant defense. MAJOR CONCLUSIONS: The resulting tangled scenario suggests that viral hosting cells adapt their metabolisms in order to support their growth and survival in the increasingly oxidant micro-environment associated with HPV tumor initiation and progression. GENERAL SIGNIFICANCE: HPV can modulate the host cell redox homeostasis in order to favor infection and possibly tumor transformation. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25534613 TI - Self-medication with antibiotics among non-medical university students of Karachi: a cross-sectional study. AB - BACKGROUND: The prevalence of self -medication with antibiotics is quite high in developing countries as opposed to developed countries. Antibiotics are often taken erroneously for certain ailments, without having the appropriate knowledge of their use. This carries potential risks for the individual as well as the community, in form of several side effects such as antibiotic resistance. Therefore the prevalence of self-medicated antibiotics in developing countries needs to be studied. METHODS: A descriptive cross-sectional study was carried out at six different non-medical universities of Karachi. 431 students were included in the study. Data was collected using self-administered questionnaires and analyzed using SPSS version 19. RESULTS: 50.1% students reported having self medicated themselves in the past 6 months and 205 (47.6%) reported self medication with antibiotics. Amoxicillin was the most self-prescribed antibiotic (41.4%). Awareness of the adverse effects of antibiotics was demonstrated by 77.3% of the students and sleep disturbance was the most commonly known (46.5%) side effect. 63.1% denied having any knowledge about antibiotic resistance and only 19.9% correctly knew that indiscriminate use of antibiotics can lead to increased antibiotic resistance. CONCLUSION: The prevalence of self-medication with antibiotics among the non-medical university students was high despite the awareness of adverse effects. Antibiotic resistance was a relatively unknown terminology. PMID- 25534614 TI - An improved method to set significance thresholds for beta diversity testing in microbial community comparisons. AB - Exploring the variation in microbial community diversity between locations (beta diversity) is a central topic in microbial ecology. Currently, there is no consensus on how to set the significance threshold for beta diversity. Here, we describe and quantify the technical components of beta diversity, including those associated with the process of subsampling. These components exist for any proposed beta diversity measurement procedure. Further, we introduce a strategy to set significance thresholds for beta diversity of any group of microbial samples using rarefaction, invoking the notion of a meta-community. The proposed technique was applied to several in silico generated operational taxonomic unit (OTU) libraries and experimental 16S rRNA pyrosequencing libraries. The latter represented microbial communities from different biological rapid sand filters at a full-scale waterworks. We observe that beta diversity, after subsampling, is inflated by intra-sample differences; this inflation is avoided in the proposed method. In addition, microbial community evenness (Gini > 0.08) strongly affects all beta diversity estimations due to bias associated with rarefaction. Where published methods to test beta significance often fail, the proposed meta community-based estimator is more successful at rejecting insignificant beta diversity values. Applying our approach, we reveal the heterogeneous microbial structure of biological rapid sand filters both within and across filters. PMID- 25534616 TI - Microbiota: Gut bacteria cross malaria. PMID- 25534615 TI - Evaluation of real-time PCR and pyrosequencing for screening incubating blood culture bottles from adults with suspected bloodstream infection. AB - Several molecular platforms can identify bacteria associated with bloodstream infections but require positive culture bottles as starting material. Here, we describe results of screening 1140 blood cultures at 8h postinoculation, from 918 eligible adults being evaluated for bloodstream infection. DNA was extracted and analyzed by 16S and/or 23S rRNA real-time PCR/pyrosequencing. Compared to culture, PCR/pyrosequencing displayed 90.9% sensitivity, 99.6% specificity, 95.7% positive predictive value, and 99.1% negative predictive value. Overall concordance rate was 98.9% (1127/1140). In 4 cases with molecular positive/culture-negative results, medical chart reviews provided evidence of identical bacteria from subsequent blood or concomitant urine/sputum cultures. Nine culture-positive/molecular-negative cases were associated with either polymicrobial growth, grew only in the anaerobic bottle of the clinical pair, and/or were detected by PCR/pyrosequencing after 8h. In summary, this approach accurately detected and identified bacteria in ~91% of culture-confirmed cases significantly sooner than the phenotypic identification was available, having the potential to improve antibiotic stewardship. PMID- 25534617 TI - T cells: Flexibility in humans. PMID- 25534618 TI - Inflammasome: Stiffening up defences against Salmonella. PMID- 25534619 TI - Epigenetic control of myeloid cell differentiation, identity and function. AB - Myeloid cells are crucial effectors of the innate immune response and important regulators of adaptive immunity. The differentiation and activation of myeloid cells requires the timely regulation of gene expression; this depends on the interplay of a variety of elements, including transcription factors and epigenetic mechanisms. Epigenetic control involves histone modifications and DNA methylation, and is coupled to lineage-specifying transcription factors, upstream signalling pathways and external factors released in the bone marrow, blood and tissue environments. In this Review, we highlight key epigenetic events controlling myeloid cell biology, focusing on those related to myeloid cell differentiation, the acquisition of myeloid identity and innate immune memory. PMID- 25534620 TI - Dendritic cell metabolism. AB - The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism. PMID- 25534624 TI - Tonsillectomy for asymmetrical tonsils, are we over-diagnosing and managing: a review of 157 cases: Our Experience. PMID- 25534621 TI - Periodontitis: from microbial immune subversion to systemic inflammation. AB - Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites. PMID- 25534622 TI - Clinical blockade of PD1 and LAG3--potential mechanisms of action. AB - Dysfunctional T cells can render the immune system unable to eliminate infections and cancer. Therapeutic targeting of the surface receptors that inhibit T cell function has begun to show remarkable success in clinical trials. In this Review, we discuss the potential mechanisms of action of the clinical agents that target two of these receptors, programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 protein (LAG3). We also suggest correlative studies that may define the predominant mechanisms of action and identify predictive biomarkers. PMID- 25534623 TI - Type 2 inflammation in asthma--present in most, absent in many. AB - Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation--into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes)- has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation. PMID- 25534625 TI - Comparative analysis of modeled nitrogen removal by shellfish farms. AB - The use of shellfish aquaculture for nutrient removal and reduction of coastal eutrophication has been proposed. Published literature has indicated that nitrogen contained in harvested shellfish can be accurately estimated from shell length:nitrogen content ratios. The range of nitrogen that could be removed by a typical farm in a specific estuarine or coastal setting is also of interest to regulators and planners. Farm Aquaculture Resource Management (FARM) model outputs of nitrogen removal at the shellfish farm scale have been summarized here, from 14 locations in 9 countries across 4 continents. Modeled nitrogen removal ranged from 105 lbs acre(-1) year(-1) (12 g m(-2) year(-1)) to 1356 lbs acre(-1) year(-1) (152 g m(-2) year(-1)). Mean nitrogen removal was 520 lbs acre( 1) year(-1) (58 g m(-2) year(-1)). These model results are site-specific in nature, but compare favorably to reported nitrogen removal effectiveness of agricultural best management practices and stormwater control measures. PMID- 25534626 TI - Chemical comparison and acute toxicity of water accommodated fraction (WAF) of source and field collected Macondo oils from the Deepwater Horizon spill. AB - Two Source oils and five field collected oil residues from the Deepwater Horizon incident were chemically characterized. Water accommodated fractions (WAFs) of the Source oils and two of the field-weathered oils were prepared to evaluate the impact of natural weathering on the chemical composition and the acute toxicity of the WAFs. Toxicity test species representing different tropic levels were used (the primary producer Skeletonema costatum (algae) and the herbivorous copepod Acartia tonsa). The results suggest that the potential for acute toxicity is higher in WAFs from non-weathered oils than WAFs from the field weathered oils. The Source oils contained a large fraction of soluble and bioavailable components (such as BTEX (benzene, toluene, ethyl benzene, xylenes) and naphthalene), whereas in the surface collected oils these components were depleted by dissolution into the water column as the oil rose to the surface and by evaporative loss after reaching the sea surface. PMID- 25534627 TI - Repeated rapid assessment surveys reveal contrasting trends in occupancy of marinas by non-indigenous species on opposite sides of the western English Channel. AB - Rapid assessment surveys of non-indigenous species (NIS) of sessile invertebrates were made at seven marinas in NW France and 10 marinas in SW England in 2010, and repeated in 2013. Fourteen NIS were recorded, 12 of which were seen on both coasts. Site occupancy differed between the opposite sides of the western English Channel. In Brittany, most species occurred at most sites in both 2010 and 2013. In 2010, site occupancy in Devon & Cornwall was distinctly lower; by 2013, the difference compared to Brittany had narrowed considerably, largely because of rapid colonisation of additional sites by species that were infrequent in 2010. Three more of the recent NIS are present in Devon & Cornwall but have still not become widespread. It is concluded that the recently introduced fouling animals studied here are longer established in NW France than in SW England, and have probably spread northwards across the Channel. PMID- 25534628 TI - Atmospheric dry deposition of mineral dust to the Gulf of Aqaba, Red Sea: rate and trace elements. AB - Atmospheric dry deposition to the Gulf of Aqaba (GoA) is particularly a significant source of trace elements. Amid desert regions, the Gulf receives high fluxes of mineral dust with an average rate of 34.68 g/m(2)/year measured in 2012. Patterns of dry deposition showed seasonal fluxes with highest rates observed in summer and lowest in winter. The observed variations were attributed to wind direction, timing of deposition and sources of dust. The average dry fluxes of Al, Fe, Mn, Cr, Cd, Cu, Pb and Zn were 551, 440, 10.29, 1.42, 0.04, 0.68, 1.42 and 4.02 mg/m(2)/year, respectively. While the dry deposition fluxes were enriched in Cd, Cu, Pb and Zn indicating their dominant anthropogenic sources, they appeared to be less influenced compared to the neighboring Mediterranean area and other industrial countries, but were similar to or slightly higher than those in remote areas. The enrichment values for Fe and Mn were low, consistent with their crustal origin. The fluxes of all elements suggested the impacts of both crustal (due to climate change) and anthropogenic sources became stronger in this region. The Sahara dust was probably a minor contributor to dry deposition in the GoA. PMID- 25534629 TI - The positive relationship between ocean acidification and pollution. AB - Ocean acidification and pollution coexist to exert combined effects on the functions and services of marine ecosystems. Ocean acidification can increase the biotoxicity of heavy metals by altering their speciation and bioavailability. Marine pollutants, such as heavy metals and oils, could decrease the photosynthesis rate and increase the respiration rate of marine organisms as a result of biotoxicity and eutrophication, facilitating ocean acidification to varying degrees. Here we review the complex interactions between ocean acidification and pollution in the context of linkage of multiple stressors to marine ecosystems. The synthesized information shows that pollution-affected respiration acidifies coastal oceans more than the uptake of anthropogenic carbon dioxide. Coastal regions are more vulnerable to the negative impact of ocean acidification due to large influxes of pollutants from terrestrial ecosystems. Ocean acidification and pollution facilitate each other, and thus coastal environmental protection from pollution has a large potential for mitigating acidification risk. PMID- 25534631 TI - Modelling the transport and accumulation of floating marine debris in the Mediterranean basin. AB - In the era of plastic and global environmental issues, when large garbage patches have been observed in the main oceanic basins, this work is the first attempt to explore the possibility that similar permanent accumulation structures may exist in the Mediterranean Sea. The questions addressed in this work are: can the general circulation, with its sub-basins scale gyres and mesoscale instabilities, foster the concentration of floating items in some regions? Where are the more likely coastal zones impacted from open ocean sources? Multi-annual simulations of advected surface passive debris depict the Tyrrhenian Sea, the north-western Mediterranean sub-basin and the Gulf of Sirte as possible retention areas. The western Mediterranean coasts present very low coastal impact, while the coastal strip from Tunisia to Syria appears as the favourite destination. No permanent structure able to retain floating items in the long-term were found, as the basin circulation variability brings sufficient anomalies. PMID- 25534630 TI - Oil spill contamination probability in the southeastern Levantine basin. AB - Recent gas discoveries in the eastern Mediterranean Sea led to multiple operations with substantial economic interest, and with them there is a risk of oil spills and their potential environmental impacts. To examine the potential spatial distribution of this threat, we created seasonal maps of the probability of oil spill pollution reaching an area in the Israeli coastal and exclusive economic zones, given knowledge of its initial sources. We performed simulations of virtual oil spills using realistic atmospheric and oceanic conditions. The resulting maps show dominance of the alongshore northerly current, which causes the high probability areas to be stretched parallel to the coast, increasing contamination probability downstream of source points. The seasonal westerly wind forcing determines how wide the high probability areas are, and may also restrict these to a small coastal region near source points. Seasonal variability in probability distribution, oil state, and pollution time is also discussed. PMID- 25534633 TI - Are animal models useful or confusing in understanding the human feto-maternal relationship? A debate. AB - The proposition "This house agrees that the proper study of man is woman" was debated. For those negating the proposition, the alternative was that "animal models are useful in understanding the human feto-maternal relationship." Evidence for the proposition emphasized molecular and structural differences between the human and animal placenta and placentation. Evidence against the proposition and in favor of the alternative focused on functional and structural homologies, emphasizing that different molecules could be used in humans to achieve similar functional effects seen in animal (e.g., mouse) models. It was agreed that one always needed to test the validity of animal data by studying humans. The advantages and limitations of animal models were discussed. PMID- 25534634 TI - Evaluation of the charges, safety, and mortality of percutaneous renal thermal ablation using the nationwide inpatient sample. AB - PURPOSE: To perform a national analysis of safety, charges, complications, and mortality of percutaneous image-guided renal thermal ablation and compare outcomes by hospital volume. MATERIALS AND METHODS: Using the Nationwide Inpatient Sample, trends in the proportion of inpatient percutaneous renal thermal ablation procedures performed at high-volume centers in the United States from 2007-2011 were evaluated. In-hospital mortality, discharge to long-term care facility, length of stay, hospitalization charges, and postoperative complications were compared between high-volume and low-volume ablation centers. High volume was set at the 90th percentile for renal thermal ablation volume, which equated to seven or more patients per year. A multivariate logistic regression analysis adjusting for hospital volume, age, sex, Charlson Comorbidity Index, obesity, race, and insurance status was performed to analyze the influence of hospital volume on the above-listed outcomes. RESULTS: This study included 874 patients. The number of hospitals ranged from 59-77 depending on year. Overall, 328 patients (37.5%) were treated at high-volume ablation centers. The proportion of patients treated at high-volume centers decreased from 42.0% in 2007-2009 to 28.5% in 2010-2011. High-volume hospitals also performed significantly more partial nephrectomies than low-volume hospitals. On multivariate logistic regression analysis, increasing hospital volume was associated with lower odds of in-hospital mortality (odds ratio [OR] = 0.31, 95% confidence interval [CI] = 0.02-0.95) and lower odds of discharge to a long-term care facility (OR = 0.00, 95% CI = 0.00-0.66). Increasing hospital volume was also associated with lower odds of blood transfusion (OR = 0.84, 95% CI = 0.72-0.94). Length of stay decreased with increasing hospital volume (P = .03). CONCLUSIONS: Patient safety may be maximized when renal ablation is performed at high-volume centers as a result of both greater procedural experience and potentially multidisciplinary triage and periprocedural management. PMID- 25534632 TI - Simultaneous analysis of large-scale RNAi screens for pathogen entry. AB - BACKGROUND: Large-scale RNAi screening has become an important technology for identifying genes involved in biological processes of interest. However, the quality of large-scale RNAi screening is often deteriorated by off-targets effects. In order to find statistically significant effector genes for pathogen entry, we systematically analyzed entry pathways in human host cells for eight pathogens using image-based kinome-wide siRNA screens with siRNAs from three vendors. We propose a Parallel Mixed Model (PMM) approach that simultaneously analyzes several non-identical screens performed with the same RNAi libraries. RESULTS: We show that PMM gains statistical power for hit detection due to parallel screening. PMM allows incorporating siRNA weights that can be assigned according to available information on RNAi quality. Moreover, PMM is able to estimate a sharedness score that can be used to focus follow-up efforts on generic or specific gene regulators. By fitting a PMM model to our data, we found several novel hit genes for most of the pathogens studied. CONCLUSIONS: Our results show parallel RNAi screening can improve the results of individual screens. This is currently particularly interesting when large-scale parallel datasets are becoming more and more publicly available. Our comprehensive siRNA dataset provides a public, freely available resource for further statistical and biological analyses in the high-content, high-throughput siRNA screening field. PMID- 25534636 TI - Testicular arteries originating from accessory renal arteries. PMID- 25534635 TI - Comparison of combination therapies in the management of hepatocellular carcinoma: transarterial chemoembolization with radiofrequency ablation versus microwave ablation. AB - PURPOSE: To compare retrospectively the outcomes and complications of transcatheter arterial chemoembolization with drug-eluting embolic agents combined with radiofrequency (RF) ablation or microwave (MW) ablation in treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From 2003 2011, 89 patients with HCC received a combination therapy-transcatheter arterial chemoembolization plus RF ablation in 38 patients and transcatheter arterial chemoembolization plus MW ablation in 51 patients. Local tumor response, tumor progression-free survival (PFS), overall PFS, overall survival (OS), and complications were compared. Overall PFS and OS were compared between the two treatment groups in multivariate analysis controlling for Child-Pugh class, Barcelona Clinic Liver Classification stage, and index tumor size. RESULTS: Complete local tumor response was achieved in 37 (80.4%) of the tumors treated with transcatheter arterial chemoembolization plus RF ablation and 49 (76.6%) of the tumors treated with transcatheter arterial chemoembolization plus MW ablation (P = .67). The median tumor PFS and overall PFS were 20.8 months and 9.3 months (P = .72) for transarterial chemoembolization plus RF ablation and 21.8 months and 9.2 months for transarterial chemoembolization plus MW ablation (P = .32). The median OS of the transcatheter arterial chemoembolization plus RF ablation group was 23.3 months, and the median OS of the transcatheter arterial chemoembolization plus MW ablation group was 42.6 months, with no significant difference in the survival experience between the two groups (log-rank test, P = .10). In the multivariate analysis, Barcelona Clinic Liver Classification stage was the only factor associated with overall PFS and OS. One patient in the transcatheter arterial chemoembolization plus RF ablation cohort (3%) and two patients in the transcatheter arterial chemoembolization plus MW ablation cohort (4%) required prolonged hospitalization (< 48 h) for pain management after the procedure (P = 1.00). CONCLUSIONS: Based on similar safety and efficacy outcomes, both combination therapies, transcatheter arterial chemoembolization plus RF ablation and transcatheter arterial chemoembolization plus MW ablation, are effective treatments for HCC. PMID- 25534637 TI - Central venous stenosis is more often symptomatic in hemodialysis patients with grafts compared with fistulas. AB - PURPOSE: To determine whether hemodialysis patients with central venous stenosis (CVS) are more frequently symptomatic if they have grafts versus fistulas. MATERIALS AND METHODS: A retrospective review was performed of 500 consecutive discrete patients, half with fistulas and half with grafts, who had fistulograms performed over a 4-year period. All fistulograms were evaluated for CVS, which was graded into quartiles. The presence of collaterals was noted and graded. Patient records were analyzed for symptoms of CVS, including face, neck, breast, or limb swelling. Statistical analysis was performed to determine the association between access type, degree of stenosis, location of stenosis, and symptoms. RESULTS: Of 500 fistulograms, 31 were excluded because of inadequate or absent central imaging. Of the remaining 469 patients, 235 had fistulas and 234 had grafts. CVS was present in 51% of patients with fistulas (119 of 237) and 51% of patients with grafts (118 of 237). When CVS was present, 29% (35 of 119) of patients with fistulas were symptomatic versus 52% (62 of 118) of patients with grafts (P = .0005). Overall, only 15% of patients with fistulas in the entire cohort were symptomatic compared with 27% of patients with grafts (P = .002). Sex, access side, and transposition did not influence symptoms; however, patients with upper arm access were more likely than patients with forearm access to be symptomatic (P < .0001), independent of access type. CONCLUSIONS: CVS is more likely to be symptomatic in patients with grafts versus fistulas, and patients with upper arm access are more likely than patients with forearm access to be symptomatic. PMID- 25534638 TI - An improved method for extraction of high-quality total RNA from oil seeds. AB - Seeds of oilseed plants that contain large amounts of oil, polysaccharides, proteins and polyphenols are not amenable to conventional RNA isolation protocols. The presence of these substances affects the quality and quantity of isolated nucleic acids. Here, a rapid and efficient RNA isolation protocol that, in contrast to other methods tested, allows high purify, integrity and yield of total RNA from seeds of sesame, corn, sunflower, flax and rapeseed was developed. The average yields of total RNA from 70 mg oil seeds ranged from 84 to 310 ug with A260/A280 between 1.9 and 2.08. The RNA isolated with this protocol was verified to be suitable for PCR, quantitative real-time PCR, semi-quantitative RT PCR, cDNA synthesis and expression analysis. PMID- 25534639 TI - Physiology, biomechanics, and biomimetics of hagfish slime. AB - Hagfishes thwart attacks by fish predators by producing liters of defensive slime. The slime is produced when slime gland exudate is released into the predator's mouth, where it deploys in a fraction of a second and clogs the gills. Slime exudate is composed mainly of secretory products from two cell types, gland mucous cells and gland thread cells, which produce the mucous and fibrous components of the slime, respectively. Here, we review what is known about the composition of the slime, morphology of the slime gland, and physiology of the cells that produce the slime. We also discuss several of the mechanisms involved in the deployment of both mucous and thread cells during the transition from thick glandular exudate to ultradilute material. We review biomechanical aspects of the slime, along with recent efforts to produce biomimetic slime thread analogs, and end with a discussion of how hagfish slime may have evolved. PMID- 25534640 TI - Neurocysticercosis: A natural human model of epileptogenesis. AB - OBJECTIVE: To develop a better understanding of mechanisms of seizures and long term epileptogenesis using neurocysticercosis. METHODS: A workshop was held bringing together experts in epilepsy and epileptogenesis and neurocysticercosis. RESULTS: Human neurocysticercosis and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures. Inflammatory responses to degenerating forms and later-stage calcified parasite granulomas are associated with seizures and epilepsy. Other mechanisms may also be involved in epileptogenesis. SIGNIFICANCE: Naturally occurring brain infections with neurocysticercosis offer a unique opportunity to develop treatments for one of the world's most common causes of epilepsy and for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state. PMID- 25534641 TI - The non-biological meaning of the term "prokaryote" and its implications. AB - The meaning of the term prokaryote is critically analyzed. The conclusion reached is that this term does not have a real biological sense, above all because we are not able to link to this term a specific biological characteristic, i.e. the hypothetical evolutionary stage of the prokaryote would seem to have been unable to result in a completed cell, which could possibly be due to the recapitulation of the fundamental characteristics that might have been common to bacteria and archaea. This would define a biological immaturity of this evolutionary stage because otherwise we would have found traits already clearly defined at this level of cellular evolution. Therefore, the lack of well-defined traits characterising the prokaryote would seem to imply an evolutionary stage still in rapid evolution, i.e. with a tempo and a mode of evolution typical of a progenote. This in turn would seem to imply that the last universal common ancestor (LUCA) has been a progenote at least when the domains of life are only two-the bacterial and archaeal domains-because, in this case, the LUCA's node should coincide with that of prokaryote on the tree of life. Instead, if the root of the tree of life would be placed in the bacterial domain or in the archaeal one, we might again, very likely, have a LUCA with a character of progenote being, under these conditions, the LUCA a prokaryote-like organism. PMID- 25534643 TI - Effects of supplementation with green tea by-products on growth performance, meat quality, blood metabolites and immune cell proliferation in goats. AB - Forty-eight castrated male goats were used to determine the effects of feeding green tea by-products (GTB) on growth performance, meat quality, blood metabolites and immune cell proliferation. Experimental treatments consisted of basal diets supplemented with four levels of GTB (0%, 0.5%, 1.0% or 2.0%). Four replicate pens were assigned to each treatment with three goats per replicate. Increasing dietary GTB tended to linearly increase the overall average weight gain and feed intake (p = 0.09). Water holding capacity, pH and sensory attributes of meat were not affected by GTB supplementation, while cooking loss was reduced both linearly and quadratically (p < 0.01). The redness (linear; p = 0.02, quadratic; p < 0.01) and yellowness (quadratic; p < 0.01) values of goat meat were improved by GTB supplementation. Increasing dietary GTB quadratically increased protein and decreased crude fat (p < 0.05), while linearly decreased cholesterol (p = 0.03) content of goat meat. The proportions of monounsaturated fatty acid, polyunsaturated fatty acid (PUFA) and n-6 PUFA increased linearly (p < 0.01) and n-3 PUFA increased quadratically (p < 0.05) as GTB increased in diets. Increasing dietary GTB linearly increased the PUFA/SFA (saturated fatty acid) and tended to linearly and quadratically increase (p <= 0.10) the n-6/n-3 ratio. The thiobarbituric acid-reactive substances values of meat were lower in the 2.0% GTB-supplemented group in all storage periods (p < 0.05). Dietary GTB linearly decreased plasma glucose and cholesterol (p < 0.01) and quadratically decreased urea nitrogen concentrations (p = 0.001). The growth of spleen cells incubated in concanavalin A and lipopolysaccharides medium increased significantly (p < 0.05) in response to GTB supplementation. Our results suggest that GTB may positively affect the growth performance, meat quality, blood metabolites and immune cell proliferation when supplemented as a feed additive in goat diet. PMID- 25534642 TI - Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility. AB - Genome-wide association studies have found variation within the complement factor H gene family links to host susceptibility to meningococcal disease caused by infection with Neisseria meningitidis (Davila et al., 2010). Mechanistic insights have been challenging since variation within this locus is complex and biological roles of the factor H-related proteins, unlike factor H, are incompletely understood. N. meningitidis subverts immune responses by hijacking a host-immune regulator, complement factor H (CFH), to the bacterial surface (Schneider et al., 2006; Madico et al., 2007; Schneider et al., 2009). We demonstrate that complement factor-H related 3 (CFHR3) promotes immune activation by acting as an antagonist of CFH. Conserved sequences between CFH and CFHR3 mean that the bacterium cannot sufficiently distinguish between these two serum proteins to allow it to hijack the regulator alone. The level of protection from complement attack achieved by circulating N. meningitidis therefore depends on the relative levels of CFH and CFHR3 in serum. These data may explain the association between genetic variation in both CFH and CFHR3 and susceptibility to meningococcal disease. PMID- 25534649 TI - ChemMedChem has reached...?The Big TEN! PMID- 25534652 TI - Intercepting wrong-patient orders in a computerized provider order entry system. AB - STUDY OBJECTIVE: We evaluate the short- and long-term effect of a computerized provider order entry-based patient verification intervention to reduce wrong patient orders in 5 emergency departments. METHODS: A patient verification dialog appeared at the beginning of each ordering session, requiring providers to confirm the patient's identity after a mandatory 2.5-second delay. Using the retract-and-reorder technique, we estimated the rate of wrong-patient orders before and after the implementation of the intervention to intercept these errors. We conducted a short- and long-term quasi-experimental study with both historical and parallel controls. We also measured the amount of time providers spent addressing the verification system, and reasons for discontinuing ordering sessions as a result of the intervention. RESULTS: Wrong-patient orders were reduced by 30% immediately after implementation of the intervention. This reduction persisted when inpatients were used as a parallel control. After 2 years, the rate of wrong-patient orders remained 24.8% less than before intervention. The mean viewing time of the patient verification dialog was 4.2 seconds (SD=4.0 seconds) and was longer when providers indicated they placed the order for the wrong patient (4.9 versus 4.1 seconds). Although the display of each dialog took only seconds, the large number of display episodes triggered meant that the physician time to prevent each retract-and-reorder event was 1.5 hours. CONCLUSION: A computerized provider order entry-based patient verification system led to a moderate reduction in wrong-patient orders that was sustained over time. Interception of wrong-patient orders at data entry is an important step in reducing these errors. PMID- 25534653 TI - Preventing iatrogenic overdose: a review of in-emergency department opioid related adverse drug events and medication errors. AB - STUDY OBJECTIVE: We describe characteristics of patients with in-emergency department (ED) opioid-related adverse drug events, medication errors, and harm resulting from medication errors; identify patient-, provider-, and system-based factors associated with in-ED opioid-related medication errors and harm; and create a list of strategies to prevent future events. METHODS: This retrospective study was conducted at 2 urban academic EDs. Potential iatrogenic opioid overdoses were identified by querying the ED electronic medical record for cases when naloxone was administered after an opioid was administered in the ED. Cases involving medication errors resulting in harm were reviewed qualitatively for common patient-, provider-, and systems-based factors that might have contributed to the event. RESULTS: Of 73 ED patients with in-ED opioid-related adverse events that required reversal with naloxone, 43 had a medication error resulting in harm. Patient-, provider-, and systems-based factors that might have contributed to the events included chronic health conditions that could predispose an individual to an opioid-related adverse event, failure to adjust opioid dosing in the elderly and for hepatic or renal impairment, multiple doses and routes of administration of opioids, coadministration of opioids with other sedating medications, and systems-based problems with patient handoffs and pharmacy oversight. CONCLUSION: We identified patient-, provider-, and systems-based factors related to opioid-related adverse drug events and medication errors among ED patients who had received naloxone. The results from our assessment can be used to inform educational and policy initiatives aimed to prevent in-ED opioid related adverse drug events and medication errors. PMID- 25534654 TI - Association of emergency department opioid initiation with recurrent opioid use. AB - STUDY OBJECTIVE: Acute pain complaints are commonly treated in the emergency department (ED). Short courses of opioids are presumed to be safe for acute pain; however, the risk of recurrent opioid use after receipt of an ED opioid prescription is unknown. We describe the risk of recurrent opioid use in patients receiving an opioid prescription from the ED for an acute painful condition. METHODS: This is a retrospective cohort study of all patients discharged from an urban academic ED with an acute painful condition during a 5-month period. Clinical information was linked to data from Colorado's prescription drug monitoring program. We compared opioid-naive patients (no opioid prescription during the year before the visit) who filled an opioid prescription or received a prescription but did not fill it to those who did not receive a prescription. The primary outcome was the rate of recurrent opioid use, defined as filling an opioid prescription within 60 days before or after the first anniversary of the ED visit. RESULTS: Four thousand eight hundred one patients were treated for an acute painful condition; of these, 52% were opioid naive and 48% received an opioid prescription. Among all opioid-naive patients, 775 (31%) received and filled an opioid prescription, and 299 (12%) went on to recurrent use. For opioid naive patients who filled a prescription compared with those who did not receive a prescription, the adjusted odds ratio for recurrent use was 1.8 (95% confidence interval 1.3 to 2.3). For opioid-naive patients who received a prescription but did not fill it compared with those who did not receive a prescription, the adjusted odds ratio for recurrent use was 0.8 (95% confidence interval 0.5 to 1.3). CONCLUSION: Opioid-naive ED patients prescribed opioids for acute pain are at increased risk for additional opioid use at 1 year. PMID- 25534656 TI - Report from a forum on US heart allocation policy. AB - Since the latest revision in US heart allocation policy (2006), the landscape and volume of transplant waitlists have changed considerably. Advances in mechanical circulatory support (MCS) prolong survival, but Status 1A mortality remains high. Several patient subgroups may be disadvantaged by current listing criteria and geographical disparity remains in waitlist time. This forum on US heart allocation policy was organized to discuss these issues and highlight concepts for consideration in the policy development process. A 25-question survey on heart allocation policy was conducted. Among attendees/respondents were 84 participants with clinical/published experience in heart transplant representing 51 US transplant centers, and OPTN/UNOS and SRTR representatives. The survey results and forum discussions demonstrated very strong interest in change to a further-tiered system, accounting for disadvantaged subgroups and lowering use of exceptions. However, a heart allocation score is not yet viable due to the long term viability of variables (used in the score) in an ever-developing field. There is strong interest in more refined prioritization of patients with MCS complications, highly sensitized patients and those with severe arrhythmias or restrictive physiology. There is also strong interest in distribution by geographic boundaries modified according to population. Differences of opinion exist between small and large centers. PMID- 25534657 TI - Epidermal growth factor receptor mutations in East European non-small cell lung cancer patients. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations are recurrently observed in non-small cell lung carcinomas (NSCLCs), and it has been found that they may serve as specific therapeutic targets. The aim of the present study was to determine the prevalence of EGFR gene mutations in NSCLCs in an East European (Bulgarian) population in different histological subtypes, in cytological versus histological samples and in primary versus metastatic lesions. METHODS: In this study 1427 NSCLC samples were included. DNA was extracted from either formalin-fixed paraffin embedded (FFPE) tissues or cytology specimens and analyzed for the presence of 29 recurrent EGFR gene mutations using SARMS PCR. RESULTS: EGFR gene mutations were found to occur significantly more often in female than in male patients (19.4% vs. 5.4%; p<0.001), in adenocarcinomas than in squamous cell carcinomas or other histological subtypes (12.5% vs. 6.2%, and 7.6%, respectively; p=0.009), and in never smokers than in ex-smokers and current smokers (22.9% vs. 8.5% and 4.9%, respectively; p<0.001). No significant differences were observed in the occurrence of EGFR gene mutations in primary tumors compared to metastases (7.9% vs. 11.2%; p=0.092), or in FFPE samples compared to cytological samples (8.9% vs. 8.1%; p=0.813). CONCLUSIONS: Our data show that the overall frequency of EGFR gene mutations in lung adenocarcinomas in the East European cohort studied is within the range of that observed in North American and West European populations, but that its frequency in squamous cell carcinomas is higher than that in any population reported to date. All specimens appeared to be suitable for EGFR gene mutation analysis, irrespective nature or origin. PMID- 25534660 TI - Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer. AB - INTRODUCTION: Over the past decade, treatment options for men with metastatic castration-resistant prostate cancer (CRPC) have expanded with the addition of abiraterone acetate (AA), enzalutamide, sipuleucel-T, radium-223, docetaxel and cabazitaxel. The optimal sequencing of therapies in the context of efficacy and known cross-resistance remains uncertain. AREAS COVERED: We review the development of enzalutamide (MDV3100, Xtandi), a novel second-generation androgen receptor (AR), and AA (Zytiga), a selective, irreversible inhibitor of cytochrome P17. In addition to discussing the clinical evidence, we also address evolving evidence of mechanisms of resistance and clinical cross-resistance during sequential therapy with these agents. EXPERT OPINION: AA and enzalutamide have both demonstrated tolerability and clinical benefit for multiple outcomes in patients with CRPC, in both post-chemotherapy and pre-chemotherapy settings. Both agents target the androgen-signaling pathway and have similar efficacy; however, they differ in prednisone use and their toxicity profiles, impacting the decision of upfront therapy. Mechanisms of resistance emerging after treatment include both alterations in AR signaling as well as mechanisms that bypass the AR. Retrospective analyses have demonstrated evidence that sequential treatment with these agents results in limited clinical benefit, supporting mechanisms of cross resistance. Trials are ongoing to determine optimal timing, sequence and combination of these agents. PMID- 25534661 TI - Cold acclimation induces distinctive changes in the chromatin state and transcript levels of COR genes in Cannabis sativa varieties with contrasting cold acclimation capacities. AB - Little is known about the capacity of Cannabis sativa to cold-acclimate and develop freezing tolerance. This study investigates the cold acclimation (CA) capacity of nine C. sativa varieties and the underlying genetic and epigenetic responses. The varieties were divided into three groups based on their contrasting CA capacities by comparing the survival of non-acclimated and cold acclimated plants in whole-plant freeze tests. In response to the CA treatment, all varieties accumulated soluble sugars but only the varieties with superior capacity for CA could maintain higher levels throughout the treatment. In addition, the varieties that acclimated most efficiently accumulated higher transcript levels of cold-regulated (COR) genes and genes involved in de novo DNA methylation while displaying locus- and variety-specific changes in the levels of H3K9ac, H3K27me3 and methylcytosine (MeC) during CA. Furthermore, these hardy C. sativa varieties displayed significant increases in MeC levels at COR gene loci when deacclimated, suggesting a role for locus-specific DNA methylation in deacclimation. This study uncovers the molecular mechanisms underlying CA in C. sativa and reveals higher levels of complexity regarding how genetic, epigenetic and environmental factors intertwine. PMID- 25534659 TI - Lymphatic system: an active pathway for immune protection. AB - Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which may include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases. PMID- 25534658 TI - N-linked sugar-regulated protein folding and quality control in the ER. AB - Asparagine-linked glycans (N-glycans) are displayed on the majority of proteins synthesized in the endoplasmic reticulum (ER). Removal of the outermost glucose residue recruits the lectin chaperone malectin possibly involved in a first triage of defective polypeptides. Removal of a second glucose promotes engagement of folding and quality control machineries built around the ER lectin chaperones calnexin (CNX) and calreticulin (CRT) and including oxidoreductases and peptidyl prolyl isomerases. Deprivation of the last glucose residue dictates the release of N-glycosylated polypeptides from the lectin chaperones. Correctly folded proteins are authorized to leave the ER. Non-native polypeptides are recognized by the ER quality control key player UDP-glucose glycoprotein glucosyltransferase 1 (UGT1), re-glucosylated and re-addressed to the CNX/CRT chaperone binding cycle to provide additional opportunity for the protein to fold in the ER. Failure to attain the native structure determines the selection of the misfolded polypeptides for proteasome-mediated degradation. PMID- 25534663 TI - Incorporation of uranium into a biomimetic apatite: physicochemical and biological aspects. AB - Bone is the main target organ for the storage of several toxic metals, including uranium. But the mode of action of uranium on bones remains poorly understood. To better assess the impact of uranium on bone cells, synthetic biomimetic apatites encompassing a controlled amount of uranium were prepared and analyzed. This study revealed the physicochemical impact of uranium on apatite mineralization: the presence of the metal induces a loss of crystallinity and a lower mineralization rate. The prepared samples were then used as substrates for bone cell culture. Osteoblasts were not sensitive to the presence of uranium in the support, whereas previous results showed a deleterious effect of uranium introduced into a cell culture solution. This work should therefore have some original prospects within the context of toxicological studies concerning the effect of metallic cations on bone cell systems. PMID- 25534662 TI - Phosphonomethyl iminodiacetic acid-conjugated cobalt oxide nanoparticles liberate Co(++) ion-induced stress associated activation of TNF-alpha/p38 MAPK/caspase 8 caspase 3 signaling in human leukemia cells. AB - The aim of this work is to understand the potential health effects of metal nanoparticles by exposing human leukemic cell lines (jurkat, K562 and KG1A cells) to nanosize phosphonomethyl iminodiacetic acid coated cobalt oxide (PMIDA-CoO) NPs. The synthesized PMIDA-CoO NPs were characterized by XRD, dynamic light scattering, transmission electron microscopy and scanning electron microscopy. Our results showed that exposure of leukemic cell lines to PMIDA-CoO NPs caused reactive oxygen species (ROS) generation by increasing the concentration of free Co(++) ions in cancer microenvironment. But at physiological pH, PMIDA-CoO liberates little amount of Co(++) ions into media and exerts lower toxicity to normal cells up to a certain dose. PMIDA-CoO NPs caused DNA damage in leukemic cell lines, which was reflected by an increase in apoptosis of jurkat, KG-1A and K562 cells. PMIDA-CoO NPs induced apoptosis by increasing pro-inflammatory cytokines, primarily TNF-alpha. The in vivo study shows that PMIDA-CoO NPs were efficiently killed DLA cells. These findings have important implications for understanding the potential anticancer property induced by surface-modified cobalt oxide nanoparticles. PMID- 25534664 TI - Predictors of Food Insecurity among Older Adults in the United States. AB - OBJECTIVE: Food insecurity among U.S. households is a national concern. Since 2010, the U.S. Healthy People goal has been to reduce food insecurity to 6%. Despite this goal, 14.5% of households remained food insecure in 2013 (U.S. Department of Agriculture). The purpose of this study was to examine the antecedents of food insecurity among older adults through the lens of the social ecological model. DESIGN AND SAMPLE: This retrospective cross-sectional study utilized secondary data from the National Health and Nutrition Examination Survey (NHANES) from the years 2007 and 2008 from a sample that included 2,045 adults 60 years of age and older. MEASURES: Variables related to the constructs of the social ecological model were examined using descriptive, chi-square, and logistic regression analyses. RESULTS: Analyses of the model indicated that the severity of depression, reports of financial support, and having ever received household food stamp benefits had statistically significant main effects on food insecurity among older adults. CONCLUSIONS: The study findings have implications for nursing practice, education, and research and could facilitate the development of screening methods, interventions, and policy evaluation that focus on food insecurity at multiple spheres of influence among the targeted population. PMID- 25534655 TI - European sea bass genome and its variation provide insights into adaptation to euryhalinity and speciation. AB - The European sea bass (Dicentrarchus labrax) is a temperate-zone euryhaline teleost of prime importance for aquaculture and fisheries. This species is subdivided into two naturally hybridizing lineages, one inhabiting the north eastern Atlantic Ocean and the other the Mediterranean and Black seas. Here we provide a high-quality chromosome-scale assembly of its genome that shows a high degree of synteny with the more highly derived teleosts. We find expansions of gene families specifically associated with ion and water regulation, highlighting adaptation to variation in salinity. We further generate a genome-wide variation map through RAD-sequencing of Atlantic and Mediterranean populations. We show that variation in local recombination rates strongly influences the genomic landscape of diversity within and differentiation between lineages. Comparing predictions of alternative demographic models to the joint allele-frequency spectrum indicates that genomic islands of differentiation between sea bass lineages were generated by varying rates of introgression across the genome following a period of geographical isolation. PMID- 25534665 TI - Burden of disease and cost of illness of atrial fibrillation in Portugal. AB - INTRODUCTION AND OBJECTIVES: Atrial fibrillation is the most prevalent sustained arrhythmia. This paper estimates the burden and cost of illness attributable to atrial fibrillation in Portugal based on demographic and health statistics. METHODS: Mortality data by cause of death came from the European Detailed Mortality Database of the World Health Organization (WHO). Hospital data were taken from the Portuguese diagnosis-related groups database. The burden of disease was measured using DALYs (disability-adjusted life years), a metric adopted by the WHO. Costs studied included resource use and lost productivity. The burden and cost of illness are those attributable to atrial fibrillation and its main complication, ischemic stroke. RESULTS: In Portugal, 4070 deaths were attributable to atrial fibrillation in 2010, corresponding to 3.8% of all deaths. In total, the burden of disease attributable to atrial fibrillation was estimated at 23,084 DALYs: 10,521 resulting from premature deaths (1.7% of the total DALYs due to death in 2010 in Portugal), and 12,563 resulting from disability. The total estimated direct costs attributable to atrial fibrillation at 2013 prices were ?115 million: ?34 million for inpatient care and ?81 million for outpatient care. Indirect costs resulting from lost production due to disability were estimated at ?25 million. CONCLUSIONS: Atrial fibrillation has an important social impact in Portugal due to its associated mortality and morbidity, and was responsible in 2013 for a total cost of ?140 million, about 0.08% of gross domestic product. PMID- 25534666 TI - A case of perforating dermatofibroma with floret-like giant cells. AB - Dermatofibromas are slow-growing solitary nodules, composed mostly of a dermal proliferation of spindle cells and epithelioid cells. Some dermatofibromas present with multinucleated giant cells, such as Touton, foreign body, and osteoclast-like cells. We report a case of dermatofibroma containing both Touton giant cells and floret-type cells. A 12-year-old boy presented with a 6-mm, firm, nontender, dusky-red to greyish dermal nodule on his left popliteal fossa. As suggested clinically by the central opening, perforation of the epidermis with partial extrusion of the dermal components, including macrophages and vertically oriented collagen bundles, via transepidermal elimination, were detected. In the upper dermis, collagen trapping and mostly epithelioid cells with many giant cells were seen, while the lower part contained mainly spindle cells in a storiform pattern. Multinucleated giant cells scattered in the upper dermis were mainly floret-type multinucleated giant cells with star-shaped cytoplasmic projections, associated with some Touton giant cells. To our knowledge, this is the first report of a perforating dermatofibroma with floret-type multinucleated giant cells. PMID- 25534667 TI - Re: Michael T. Schweizer, Xian C. Zhou, Hao Wang, et al. The Influence of Prior Abiraterone Treatment on the Clinical Activity of Docetaxel in Men with Metastatic Castration-resistant Prostate Cancer. Eur Urol 2014;66:646-52. PMID- 25534668 TI - [Ewing/PNET sarcoma family of tumors: towards a new paradigm?]. AB - Ewing sarcoma family of tumors are mainly aggressive sarcomas of bone and also arising in soft tissues, which share common features: morphological features of basophilic round cell tumors, immunohistochemical features by expression of membrane CD99 protein, and genetic features with a translocation involving EWS and FLI1 in approximately 90% of cases. The discovery of this translocation has made it possible to unify in a single entity several lesions such as PNET, neuropitheliomas, Askin tumors, Ewing sarcomas... Since then, the extensive use of molecular/genetic methods has helped to identify an increasing number of molecular anomalies in unclassified round cell sarcomas, these sarcomas often harboring an atypical morphology and a less frequent CD99 positivity. Besides the rearrangements between the FET family of genes (EWS or FUS) and the wide ETS family of genes (FLI1, ERG, FEV, ETV...), new partner genes are gradually identified: cases with EWS-non ETS partners are extremely rare, but there are more important groups which are CIC-DUX4 and BCOR-CCNB3 translocation-positive sarcomas. These findings raise the problem of the nosological borders of the Ewing/PNET entity and its links with new "Ewing-like" groups of tumors, and raise the therapeutic problems. The forward-looking identification of new round cell sarcomas should enable studies of wider series to try to answer these questions. PMID- 25534669 TI - The self-healing potential of triazole-pyridine-based metallopolymers. AB - The development of artificial self-healing materials represents an emerging and challenging field in material science. Inspired by nature-for instance by the self-healing of mussel byssus threads-metallopolymers gain more and more attention as attractive self-healing materials. These compounds are able to combine the properties of both polymers and metal-ligand interactions. A novel metallopolymer is developed consisting of attached bidentate triazole-pyridine (TRZ-py) ligands and a low glass transition temperature (T g ) lauryl methacrylate backbone. The polymer is cross-linked with different Fe(II) and Co(II) salts. The resulting materials exhibit promising self-healing performance within time intervals of 5.5 to 26.5 h at moderate temperatures of 50 to 100 degrees C. The materials are characterized by X-ray scattering (SAXS), UV-Vis spectroscopy, and light microscopy. PMID- 25534671 TI - Clinical time series prediction: Toward a hierarchical dynamical system framework. AB - OBJECTIVE: Developing machine learning and data mining algorithms for building temporal models of clinical time series is important for understanding of the patient condition, the dynamics of a disease, effect of various patient management interventions and clinical decision making. In this work, we propose and develop a novel hierarchical framework for modeling clinical time series data of varied length and with irregularly sampled observations. MATERIALS AND METHODS: Our hierarchical dynamical system framework for modeling clinical time series combines advantages of the two temporal modeling approaches: the linear dynamical system and the Gaussian process. We model the irregularly sampled clinical time series by using multiple Gaussian process sequences in the lower level of our hierarchical framework and capture the transitions between Gaussian processes by utilizing the linear dynamical system. The experiments are conducted on the complete blood count (CBC) panel data of 1000 post-surgical cardiac patients during their hospitalization. Our framework is evaluated and compared to multiple baseline approaches in terms of the mean absolute prediction error and the absolute percentage error. RESULTS: We tested our framework by first learning the time series model from data for the patients in the training set, and then using it to predict future time series values for the patients in the test set. We show that our model outperforms multiple existing models in terms of its predictive accuracy. Our method achieved a 3.13% average prediction accuracy improvement on ten CBC lab time series when it was compared against the best performing baseline. A 5.25% average accuracy improvement was observed when only short-term predictions were considered. CONCLUSION: A new hierarchical dynamical system framework that lets us model irregularly sampled time series data is a promising new direction for modeling clinical time series and for improving their predictive performance. PMID- 25534672 TI - Lifting the fog of health delivery and costs. PMID- 25534670 TI - Clinical and research measurement techniques of the pulmonary circulation: the present and the future. AB - There has been a lot of progress in measurement techniques of the pulmonary circulation in recent years, and this has required updating of basic physiological knowledge. Pulmonary artery pressures (PAP) are normally low and dependent on left atrial pressure (LAP) and cardiac output (CO). Therefore, defining the functional state of the pulmonary circulation for the detection of pulmonary vascular disease or evaluation of disease progression requires measurements of PAP, LAP and CO. Invasive measurements have lately improved by a better definition of zero leveling and of the effects of intrathoracic pressure changes, and understanding of the inherent limitations of fluid-filled thermodilution catheters. The effects of LAP and pulmonary flow on PAP in health and disease are now integrated in the hemodynamic diagnosis of pulmonary hypertension. Development of alternative noninvasive approaches is critically dependent on their potential to quantify pulmonary vascular pressures and CO. Doppler echocardiography and magnetic resonance imaging are coming close. Both approaches are performant for flow measurements, but pressures remain indirectly assessed from flow velocities and/or structural changes. Doppler echocardiography or magnetic resonance imaging has been shown to be accurate, allowing for valid population studies, but with insufficient precision for single number-derived clinical decision making. PMID- 25534673 TI - Nanoparticle-triggered release from lipid membrane vesicles. AB - Superparamagnetic iron oxide nanoparticles are used in a rapidly expanding number of research and practical applications in biotechnology and biomedicine. We highlight how recent developments in iron oxide nanoparticle design and understanding of nanoparticle membrane interactions have led to applications in magnetically triggered, liposome delivery vehicles with controlled structure. Nanoscale vesicles actuated by incorporated nanoparticles allow for controlling location and timing of compound release, which enables e.g. use of more potent drugs in drug delivery as the interaction with the right target is ensured. This review emphasizes recent results on the connection between nanoparticle design, vesicle assembly and the stability and release properties of the vesicles. While focused on lipid vesicles magnetically actuated through iron oxide nanoparticles, these insights are of general interest for the design of capsule and cell delivery systems for biotechnology controlled by nanoparticles. PMID- 25534674 TI - Systems Biocatalysis: Development and engineering of cell-free "artificial metabolisms" for preparative multi-enzymatic synthesis. AB - Systems Biocatalysis is an emerging concept of organizing enzymes in vitro to construct complex reaction cascades for an efficient, sustainable synthesis of valuable chemical products. The strategy merges the synthetic focus of chemistry with the modular design of biological systems, which is similar to metabolic engineering of cellular production systems but can be realized at a far lower level of complexity from a true reductionist approach. Such operations are free from material erosion by competing metabolic pathways, from kinetic restrictions by physical barriers and regulating circuits, and from toxicity problems with reactive foreign substrates, which are notorious problems in whole-cell systems. A particular advantage of cell-free concepts arises from the inherent opportunity to construct novel biocatalytic reaction systems for the efficient synthesis of non-natural products ("artificial metabolisms") by using enzymes specifically chosen or engineered for non-natural substrate promiscuity. Examples illustrating the technology from our laboratory are discussed. PMID- 25534675 TI - Bisphenol a exposure promotes the migration of NCM460 cells via estrogen receptor mediated integrin beta1/MMP-9 pathway. AB - Bisphenol A (BPA) is a widely used industrial chemical and also an environmental endocrine disruptor (EED), which serves as a monomer in the manufacture of polycarbonate plastics. BPA enters human body mainly through oral intake, and has been reported as being linked to oncogenesis in many tissues. However, the association of BPA intake with gastrointestinal cancer, such as colon cancer, has received less attention. The present study was conducted to investigate the effects of BPA on the migration of normal colon epithelial cells (NCM460 cells) and further elucidate the underlying mechanisms. Our data showed that 1 * 10(-8) M (equivalent to environmental concentration) of BPA potently promoted the migration of NCM460 cells. Interestingly, BPA treatment induced an increase of integrin beta1 expression, and the functional blocking of integrin beta1 abolished the migration-promoting effects of BPA. Moreover, the results showed that it was estrogen receptor beta but not estrogen receptor alpha that was involved in this migration promotion. In addition, cellular exposure of BPA stimulated the expression and activity of MMP-9, a well-known factor of cell migration. Taken together, these results indicate that environmental concentration of BPA exposure promotes cell migration through activating ERbeta mediated integrin beta1/MMP-9 pathway, suggesting exposure to BPA in the colon may present a potential cancer risk. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 799-807, 2016. PMID- 25534676 TI - Species spectrum and antifungal susceptibility profile of vaginal isolates of Candida in Kuwait. AB - OBJECTIVE: The study was undertaken to determine the prevalence of vulvovaginal candidiasis (VVC) among patients with vaginitis, frequency of different Candida species, and their susceptibility profile. PATIENTS AND METHODS: Over six months period, high vaginal swabs were cultured on Sabouraud's dextrose agar and isolates were identified by culture on CHROMagar Candida and Vitek2 yeast identification system or/and API 20C (BioMerieux, France). Antifungal susceptibility of the Candida isolates was determined by E-test against amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole and caspofungin. RESULTS: One thousand seven hundred and fifty-two women with vaginitis were screened for the prevalence of Candida spp. Vaginal swab cultures of 231 (13.2%) women yielded Candida spp. The isolation rates of different species were as follows: Candida albicans (73.9%), Candida glabrata (19.8%), Candida kefir (1.94%), Candida tropicalis (0.96%), Candida parapsilosis (0.96%), Candida krusei (0.96%), Candida guilliermondii (0.96%), and Saccharomyces cerevisiae (0.52%). All strains of C. albicans and non-C. albicans were susceptible to most of the antifungal agents tested. CONCLUSION: The high frequency with which C. albicans was recovered and its azole susceptibility support the continued use of azole agents for empirical therapy of uncomplicated VVC. However, a larger controlled study is required to determine the role of non C. albicans in recurrent VVC. PMID- 25534677 TI - Electrophysiologic findings and long-term outcomes in patients undergoing third or more catheter ablation procedures for atrial fibrillation. AB - INTRODUCTION: Pulmonary vein (PV) status, arrhythmia sources, and outcomes with >=3 ablation procedures have not been characterized. METHODS AND RESULTS: All patients with >=3 procedures were included and underwent antral reisolation of reconnected PVs and ablation of non-PV triggers. Of 2,886 patients who underwent PVI, 181 (6%) had more than 2 ablation procedures (3 procedures in 146 and >=4 procedures in 35). In 12 patients, the clinical arrhythmia was other than AF. Of the remaining 169 patients, 69 (41%) had 4 reconnected PVs, 27 (16%) had 3, 31 (18%) had 2, and 29 (17%) had 1. Only 13 (8%) had all PVs still isolated. Provocative techniques in 127 patients initiated PV triggers in 92 patients, including AF or PV atrial tachycardia in 64 (50%), and reproducible PV APDs in 28 (22%). Thirty-six (20%) had a new non-PV trigger targeted. At a mean of 36 months (12-119 months) after last procedure, 63 patients (47%) had no AF off antiarrhythmic drugs (AAD); 28 (21%) had no AF with AAD; and 18 (13%) had rare AF with good symptom control; 26 patients (19%) had recurrent AF. CONCLUSIONS: At time of third or greater AF ablation, PV reconnection is the rule (92%) and PV triggers initiating AF can be demonstrated. Following repeat PVI and targeting non-PV triggers, 81% of patients had clinical AF control. Our findings suggest that PV reisolation and attempts to identify and eliminate non-PV triggers are effective and support the role of multiple repeat procedures for AF recurrence. PMID- 25534678 TI - Hyperemesis gravidarum: a holistic overview and approach to clinical assessment and management. AB - Hyperemesis gravidarum (HG) is a rare and severe form of nausea and vomiting of pregnancy associated with significant costs and psychosocial impacts. The etiology of HG remains largely unknown, although maternal genetics and placental factors are suspected. Prompt recognition and treatment of HG are essential to minimize associated maternal and fetal morbidity. Diagnosis is made on the basis of typical presentation, with exclusion of other causes of severe nausea and vomiting of pregnancy. Validated clinical tools are available to assess severity of symptoms and guide plans of care. Evidence to guide management of HG is limited, but many nonpharmacologic and pharmacologic interventions are available with published guidelines to inform implementation. Care of the woman with HG requires compassion and acknowledgement of individual needs and responses to interventions. PMID- 25534680 TI - Erratum to: Evaluation of Skin Permeation of beta-Blockers for Topical Drug Delivery. PMID- 25534679 TI - Synthesis, characterization, antimicrobial activity and mechanism of a novel hydroxyapatite whisker/nano zinc oxide biomaterial. AB - Postoperative infections remain a risk factor that leads to failures in oral and maxillofacial artificial bone transplantation. This study aimed to synthesize and evaluate a novel hydroxyapatite whisker (HAPw) / nano zinc oxide (n-ZnO) antimicrobial bone restorative biomaterial. A scanning electron microscope (SEM), energy dispersive spectroscopy (EDS) and x-ray diffraction (XRD) were employed to characterize and analyze the material. Antibacterial capabilities against Staphylococcus aureus, Escherichia coli, Candida albicans and Streptococcus mutans were determined by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), and kinetic growth inhibition assays were performed under darkness and simulated solar irradiation. The mode of antibiotic action was observed by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). The MIC and MBC were 0.078-1.250 mg ml(-1) and 0.156 2.500 mg ml(-1), respectively. The inhibitory function on the growth of the microorganisms was achieved even under darkness, with gram-positive bacteria found to be more sensitive than gram-negative, and enhanced antimicrobial activity was exhibited under simulated solar excitation compared to darkness. TEM and CLSM images revealed a certain level of bacterial cell membrane destruction after treatment with 1 mg ml(-1) of the material for 12 h, causing the leakage of intracellular contents and bacteria death. These results suggest favorable antibiotic properties and a probable mechanism of the biomaterial for the first time, and further studies are needed to determine its potential application as a postoperative anti-inflammation method in bone transplantation. PMID- 25534681 TI - Erratum to: Laurate Permeates the Paracellular Pathway for Small Molecules in the Intestinal Epithelial Cell Model HT-29/B6 via Opening the Tight Junctions by Reversible Relocation of Claudin-5. PMID- 25534682 TI - Modeling and simulation support eltrombopag dosing in thrombocytopenic patients with chronic HCV infection. AB - PURPOSE: The pharmacokinetics of eltrombopag and its stimulation of platelet production were characterized in patients with chronic hepatitis C virus (HCV) infection to optimize an eltrombopag dosing regimen for treatment of HCV-related thrombocytopenia before and throughout peginterferon (pegIFN)-based antiviral therapy. METHODS: Population pharmacokinetic analysis for eltrombopag included 663 individuals (healthy subjects, n = 28; patients with HCV, n = 635). Population pharmacokinetic/pharmacodynamic analysis for platelet response involved patients with HCV only. Simulations were conducted using various dosing scenarios in the same patient population. RESULTS: Eltrombopag pharmacokinetics were described by a two-compartment model with dual sequential first-order absorption and elimination. Age, race, sex, and severity of hepatic impairment were predictors of eltrombopag clearance. The effect of eltrombopag on platelet counts was adequately described by a model with four transit compartments in which eltrombopag concentrations stimulated the production rate of platelet precursors in an Emax manner. CONCLUSIONS: Modeling and simulation results support once-daily eltrombopag 25 mg as an appropriate starting dosing regimen followed by biweekly dose escalation (in 25-mg increments) up to once-daily eltrombopag 100 mg to raise platelet counts sufficiently for initiation of pegIFN based antiviral therapy in patients with HCV. Biweekly dose adjustment allows patients to stay on the lowest possible eltrombopag dose during antiviral therapy. PMID- 25534683 TI - Exploring advantages/disadvantages and improvements in overcoming gene delivery barriers of amino acid modified trimethylated chitosan. AB - PURPOSE: Present study aimed at exploring advantages/disadvantages of amino acid modified trimethylated chitosan in conquering multiple gene delivery obstacles and thus providing comprehensive understandings for improved transfection efficiency. METHODS: Arginine, cysteine, and histidine modified trimethyl chitosan were synthesized and employed to self-assemble with plasmid DNA (pDNA) to form nanocomplexes, namely TRNC, TCNC, and THNC, respectively. They were assessed by structural stability, cellular uptake, endosomal escape, release behavior, nuclear localization, and in vitro and in vivo transfection efficiencies. Besides, sodium tripolyphosphate (TPP) was added into TRNC to compromise certain disadvantageous attributes for pDNA delivery. RESULTS: Optimal endosomal escape ability failed to bring in satisfactory transfection efficiency of THNC due to drawbacks in structural stability, cellular uptake, pDNA liberation, and nuclear distribution. TCNC evoked the most potent gene expression owing to multiple advantages including sufficient stability, preferable uptake, efficient pDNA release, and high nucleic accumulation. Undesirable stability and insufficient pDNA release adversely affected TRNC-mediated gene transfer. However, incorporation of TPP could improve such disadvantages and consequently resulted in enhanced transfection efficiencies. CONCLUSIONS: Coordination of multiple contributing effects to conquer all delivery obstacles was necessitated for improved transfection efficiency, which would provide insights into rational design of gene delivery vehicles. PMID- 25534686 TI - Attention deficit/hyperactivity disorder medication and dental caries in children. AB - PURPOSE: Few studies have been conducted to investigate the effects, if any, of specific medication used to manage the symptoms of attention deficit/hyperactivity disorder (ADHD) as a risk factor for dental caries. A reported side-effect of the medication is a reduction in saliva. Healthy saliva has been shown to play many important functions in the prevention of dental caries. The focus of this review is to determine if any evidence exists to confirm that stimulant medication used to treat the symptoms of ADHD in children increases the risk of dental caries by virtue of its effect on the reduction of salivary flow. METHODS: A MEDLINE search was conducted for relevant studies. Search terms used were dental caries, attention deficit/hyperactivity disorder, ADHD, pharmacologic treatment of ADHD, stimulant medication, xerostomia, dry mouth and saliva flow. Publication dates ranged from 2002 to 2012. RESULTS: Although dental caries prevalence has been found to be higher in children with ADHD, decreased salivary flow as a side-effect of pharmacological treatment does not appear to be responsible. CONCLUSION: Dental caries is a multi-factorial disease process. The most effective method of reducing dental caries in ADHD children is more frequent recare visits focusing on home plaque removal practices along with dietary counseling to reduce the consumption of cariogenic foods and drinks. This can only be accomplished with inclusion of the parent/guardian in the process. PMID- 25534684 TI - Ionic liquid versus prodrug strategy to address formulation challenges. AB - PURPOSE: A poorly water soluble acidic active pharmaceutical ingredient (API) was transformed into an ionic liquid (IL) aiming at faster and higher oral availability in comparison to a prodrug. METHODS: API preparations were characterized in solid state by single crystal and powder diffraction, NMR, DSC, IR and in solution by NMR and ESI-MS. Dissolution and precipitation kinetics were detailed as was the role of the counterion on API supersaturation. Transepithelial API transport through Caco-2 monolayers and counterion cytotoxicity were assessed. RESULTS: The mechanism leading to a 700 fold faster dissolution rate and longer duration of API supersaturation of the ionic liquid in comparison to the free acid was deciphered. Transepithelial transport was about three times higher for the IL in comparison to the prodrug when substances were applied as suspensions with the higher solubility of the IL outpacing the higher permeability of the prodrug. The counterion was nontoxic with IC50 values in the upper MUM / lower mM range in cell lines of hepatic and renal origin as well as in macrophages. CONCLUSION: The IL approach was instrumental for tuning physico-chemical API properties, while avoiding the inherent need for structural changes as required for prodrugs. PMID- 25534687 TI - Numb chin syndrome: a signal of underlying concern. AB - PURPOSE: The purpose of this article is to present a case study of a patient with chin numbness and to review its relationship, through research, to possible underlying diseases and conditions. Mental nerve neuropathy, better known as numb chin syndrome, is a rare condition. Research suggests that there are a high number of cases where numb chin syndrome runs parallel with progression or relapses of metastatic cancer. Clinical presentation of numb chin syndrome is characterized by patient complaints of localized numbness to the mandible. Since this syndrome has been associated with serious conditions such as diabetes, multiple scleroses and metastatic disease, patients who present with signs and report unexplained symptoms of numbness should be examined thoroughly. Dental professionals who encounter patients with this symptom should refer them for further medical evaluation can potentially save lives. PMID- 25534688 TI - A qualitative analysis of oral health care needs in arkansas nursing facilities: the professional role of the dental hygienist. AB - PURPOSE: Frail elders and nursing home residents are vulnerable to poor oral health and frequently lack access to dental care. The purpose of this study was to determine why residents in Arkansas skilled nursing facilities have limited access to oral health care. METHODS: This study utilized qualitative research methodology. Data was collected from oral health care personnel through open ended responses in a written survey (n=23) and through telephone interviews (n=21). The investigators applied the constant comparative method to analyze and unitize the data and ultimately reach consensus. RESULTS: Data analysis resulted in consensus on 2 emergent themes: policy and access. CONCLUSION: This qualitative case study suggests access to oral health care for residents living in both long-term care (LTC) and assisted living I and II facilities in Arkansas is affected by public and facility policies and access to oral health care as a function of the patient's health status and availability of oral health care providers. Access for residents residing in assisted living I and II facilities is also limited by the residents' inability to assume responsibility for accessing oral health care. The outcomes from this study may serve to inform policymakers and advocates for access to oral health care as they develop new policies to address this growing need. PMID- 25534689 TI - Perceptions of Kansas Extended Care Permit dental hygienists' impact on dental care. AB - PURPOSE: In 2003, Kansas addressed their access to oral health care needs with amended state dental practice act for registered dental hygienists. The Extended Care Permits (ECP) I, II and III have expanded the dental hygiene scope of practice, allowing dental hygienists to provide oral care to Kansans in different settings beyond the dental office. The purpoase of this study was to examine the perceptions of Kansas ECP dental hygienists on change to oral care in Kansas. METHODS: A questionnaire was mailed to all ECP dental hygienists (n=158) registered with the Kansas Dental Board. Questions were open-ended, close-ended and Likert scale. Information was sought regarding demographics, areas of employment, work related activities and impact to oral health care. Study exclusions included ECP providers no longer practicing in Kansas, practice more than 50% in another state or no longer practice dental hygiene at all. RESULTS: A total of 69 surveys were returned, with 9 surveys excluded for exclusion criteria. Most respondents (92%) agreed the ECP is a solution to oral health care access issues in Kansas. Barriers to utilizing their permits fully included: difficulty locating a sponsoring dentist (12%), locating start up finances (22%), limited work space (14%) and difficulty with facility administrators (39%). Many respondents (62%) agreed the proposed registered dental practitioner would improve access to oral health care to Kansans. CONCLUSION: The Extended Care Permit providers in Kansas appear to be satisfied with their current employment situations and feel oral health care has improved for their patients served but they are unable to utilize their permits fully for various reasons. PMID- 25534690 TI - Educational Deficiencies Recognized by Independent Practice Dental Hygienists and their Suggestions for Change. AB - PURPOSE: The purpose of this study was to determine the perceived level of preparedness Maine Independent Practice Dental Hygienists (IPDHs) received from their standard undergraduate dental hygiene education, and recognize areas necessary for further preparation in order to explore careers beyond the private practice dental model. METHODS: A convenience sample of 6 IPDHs participated in a survey exploring their educational experience in public health and alternative practice settings. The survey also asked for their recommendations to advance dental hygiene education to meet the needs of those wishing to pursue alternative practice careers. RESULTS: This study found that participants felt underprepared by their dental hygiene education with deficits in exposure to public health, business skills necessary for independent practice, communication training and understanding of situations which require referral for treatment beyond the IPDH scope of practice. CONCLUSION: As the dental hygiene profession evolves, dental hygiene education must as well. The IPDH participants' recommendations for dental hygiene programs include increased exposure to alternative settings and underserved populations as well as elective courses for those students interested in alternative practice and business ownership. PMID- 25534691 TI - A comparison of dental hygienists' salaries to state dental supervision levels. AB - PURPOSE: The purpose of this study is to evaluate the effect of dental supervision on registered dental hygienists' salaries in the 50 states and District of Columbia by comparing the average dental hygiene salaries from the largest metropolitan city within each state from May 2011, the most recent valid data, in relation to the required level of dental supervision. METHODS: A retrospective contrasted-group quasi-experimental design analysis was conducted using the most current mean dental hygiene salaries for the largest metropolitan city within each state and the District of Columbia which was matched to the appropriate dental supervision level. In addition, a dental assisting salary control group was utilized and correlated to the appropriate dental hygienist salary in the same metropolitan city and state. Samples were obtained from the U.S. Department of Labor. A multivariate analysis of variance (MANOVA) statistical analysis was utilized to assess the relationship of the 5 levels of dentist supervision, with the registered dental hygienist salaries. The MANOVA analysis was also utilized to assess the control group, dental assistant salaries. RESULTS: No statistically significant results were found among the dental supervision levels on the measures of dental hygiene salaries and dental assistant salaries. Wilks's Lambda=0.81, F (8, 90)=1.29, p=0.26. Analyses of variances (ANOVA) on the dependent variables were also conducted as follow-up tests to the MANOVA. CONCLUSION: Study results suggest dental hygienists who are required to have a dentist on the premises to complete any dental treatment obtain similar salaries to those dental hygienists who are allowed to work in some settings unsupervised by a dentist. Therefore, dental supervision does not seem to have an impact on dental hygienists' salaries. PMID- 25534692 TI - Comparison of Corded and Cordless Handpieces on Forearm Muscle Activity, Procedure Time and Ease of Use during Simulated Tooth Polishing. AB - PURPOSE: Dental professionals suffer from a high prevalence of work-related musculoskeletal disorders (MSD). Dental hygienists in particular have a high prevalence of pain in the forearms and hands. The objective of this study was to compare 1 cordless handpiece to 2 corded handpieces during simulated tooth polishing in terms of the muscle loads (recorded as electromyography (EMG) activity), duration of polishing procedure, and dental hygienist opinion about ease of use. METHODS: EMG was used to quantify muscle electrical activity of 4 forearm muscles during simulated dental polishing with 2 corded handpieces (HP-A and HP-B) and 1 cordless handpiece (HP-C). A convenience sample of 30 dental hygienists (23 to 57 years of age) with 1 to 20+ years of clinical practice experience completed the study. Each participant spent approximately 5 minutes polishing 3 predetermined teeth in each of the 4 quadrants. The sequence of the handpieces was randomly assigned. At the end of the study, participants completed a subjective end user evaluation of handpiece preference. RESULTS: Muscle activity levels of 10th, 50th and 90th percentiles did not differ significantly between the 3 handpieces tested (p>0.05). However, total muscle workload (integrated EMG) was lowest for the cordless handpiece (HP-C), but this was only significantly less than HP-A (p<0.05). Polishing using the cordless handpiece (HP C) (M=257 seconds, SD=112 seconds) took significantly less time than either the HP-A corded (M=290 seconds, SD=137 seconds) or HP-B corded handpiece (M=290 seconds, SD=126 seconds) (p<0.05). Overall, 50% of the study participants preferred the cordless handpiece, 37% preferred HP-A and 13% preferred HP-B (p<0.05). CONCLUSION: Use of the cordless handpiece reduced the duration of polishing, which in turn led to less total muscle activity, but not muscle intensity. Overall, dental hygienists preferred the cordless handpiece. PMID- 25534693 TI - Exploration of critical thinking in dental hygiene education. AB - PURPOSE: This qualitative study explores the perceptions of dental hygiene faculty regarding issues surrounding critical thinking skills integration within their associate degree dental hygiene programs. METHODS: Twenty faculty participated in the study, as drawn from 11 accredited associate degree dental hygiene programs in one Midwest state. Multiple sources of data were collected, including email questionnaires, individual follow-up phone interviews and artifacts. Interpretive analysis was conducted. RESULTS: Data analysis revealed that faculty generally understood critical thinking, but interpretations varied. Most do not use varied teaching strategies to promote critical thinking skills, and focus on one particular strategy--that of case studies. The participants identified the need for allied health-focused faculty development opportunities, and noted that calibration of instruction was needed. Despite challenges, faculty felt responsible for teaching critical thinking skills, and identified the need for time to build critical thinking skills into the curriculum. CONCLUSION: This study was conducted in response to the American Dental Education Association Commission on Change and Innovation's challenge for dental hygiene educators to comprehend their own knowledge on the concept of critical thinking related to research-based pedagogical approaches to teaching and learning. Findings revealed a strong desire among the dental hygiene faculty in this study to incorporate critical thinking into their work. They want to do what they believe is the right thing, but their actual knowledge of the definitional and application theories about critical thinking is still in the early stages of development. Regular and targeted faculty development opportunities are needed. PMID- 25534696 TI - alpha-Alkylation of a norbornene-derived tricyclic ketone: are steric factors really in control? AB - Density functional theory (DFT) has been used to investigate the alpha-alkylation of a chiral tricyclic ketone. These calculations reveal that torsional strain and a strong conformational preference, rather than steric influences, are responsible for the high levels of observed stereoselectivity and suggest a way by which alternative stereoisomers could be accessed. PMID- 25534695 TI - MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury. AB - The liver can be thought of as a mysterious organ, because it has an elegant regenerative capability. This phenomenon has been well known since ancient times and is already applied to medical treatments for severe hepatic disorders by transplanting portions of liver received from living donors. However, it was not until quite recently that the mechanism underlying the principle of liver regeneration was investigated more deeply. Recent advances in the technologies for characterizing cell properties and examining the molecular nature of cells are enabling us to understand what occurs in the regenerating liver. After acute liver damage, hepatocytes actively proliferate in response to external stimulation by humoral factors. However, in the chronically injured liver, hepatocytes cannot proliferate well, but biliary cells appearing after chronic liver damage form primitive ductules around portal veins of the liver. These biliary cells may have a multiple origin, including hepatocytes, and contain progenitor cells giving rise to both hepatocytes and biliary cells, or represent cells that can be directly converted into hepatocytes. Although liver regeneration is more complicated than we had thought, unremitting efforts by researchers will certainly connect the numerous findings obtained in basic research with the development of new therapeutic strategies for liver diseases. PMID- 25534694 TI - Consumption of a high n-3 polyunsaturated fatty acid diet during gradual mild physiological stress in rats. AB - n-3 Polyunsaturated fatty acids (n-3PUFAs) may be beneficial for anxiety and depression under stressful conditions. Studies however, typically utilise physical or sudden physiological stress, while gradual physiological stress is also relevant to human conditions. Using deoxycorticosterone acetate (DOCA) administration to induce gradual physiological stress, this study investigated the impact of n-3PUFAs under gradual physiological stress in rats. Animals (aged 2 months) (N=8-12/group) received daily injections of DOCA or vehicle and were concurrently fed a high n-3PUFA or control diet for eight weeks. Behavioural measures were taken throughout. Behavioural tests and physiological measures were conducted after six and eight weeks respectively. DOCA administration decreased plasma renin, plasma proteins and relative adrenal weight, and increased water intake, relative kidney weight, and anxiety in the open field. These findings demonstrate disruptions to the renin-angiotensin-aldosterone system, a result of mild physiological stress, that also impact on anxiety behaviours. No effects of n-3PUFAs were found. PMID- 25534697 TI - Role of Pediatricians in the Ambulatory Care of Children in Taiwan, 1999-2011. AB - BACKGROUND: Pediatricians are physicians trained to provide comprehensive nonsurgical health care for children, but parents may consult other specialists when seeking medical help for their children. This study was designed to analyze the role of pediatricians and the changes in the patterns of ambulatory visits among different specialties for children under the age of 18 years in Taiwan during the past 13 years. METHODS: Data on ambulatory visits of children aged 0 17 years from 1999 to 2011 were retrieved from the National Health Insurance Research Database. The physician's specialty, level of the hospital, year of visit, age of the patient, and diagnoses of each ambulatory visit were analyzed. Four of the most commonly visited specialties-pediatrics, otolaryngology, family medicine, and internal medicine-were compared. The yearly trend of ambulatory visits to different specialties, difference in various age groups, influence of hospital levels, and the top 10 diagnoses were analyzed. RESULTS: A total of 1,618,033 ambulatory visits were identified and enrolled into our study. A comparison of the proportions of ambulatory visits between 1999-2003 and 2007 2011 showed that the proportions of visits increased from 27.1 +/- 1.3% to 35.4 +/- 1.0% for pediatricians, decreased from 32.8 +/- 1.8% to 17.0 +/- 0.8% for family physicians, and did not change for otolaryngologists and internal medicine physicians. Specifically, pediatricians were visited more often if the children were younger, or if the health-care facility (level of hospital) was either a medical center or a regional hospital. Upper respiratory tract infection was the top diagnosis, followed by acute bronchitis, and acute and chronic tonsillitis. CONCLUSIONS: The role of pediatricians in children's ambulatory care increased in importance from 1999 to 2011 in Taiwan. However, approximately two thirds of children sought ambulatory medical help from nonpediatric physicians. Thus, it is important to educate and encourage parents to visit pediatricians if their children require medical help. PMID- 25534698 TI - Pulmonary drug delivery by surfactant. PMID- 25534699 TI - Exposure levels, determinants and IgE mediated sensitization to bovine allergens among Danish farmers and non-farmers. AB - BACKGROUND: Bovine allergens can induce allergic airway diseases. High levels of allergens in dust from stables and homes of dairy farmers have been reported, but sparse knowledge about determinants for bovine allergen levels and associations between exposure level and sensitization is available. OBJECTIVE: To investigate levels and determinants of bovine allergen exposure among dairy, pig and mink farmers (bedroom and stable), and among former and never farmers (bedroom), and to assess the prevalence of bovine allergen sensitization in these groups. METHODS: In 2007-2008, 410 settled dust samples were collected in stables and in bedrooms using an electrostatic dust-fall collector over a 14 day period among 54 pig farmers, 27 dairy farmers, 3 mink farmers as well as 71 former and 48 never farmers in Denmark. For farmers sampling was carried out both during summer and winter. Bovine allergen levels (MUg/m(2)) were measured using a sandwich ELISA. Determinants for bovine allergen exposure in stables and bedrooms were explored with mixed effect regression analyses. Skin prick test with bovine allergen was performed on 48 pig farmers, 20 dairy farmers, 54 former and 31 never farmers. RESULTS: Bovine allergen levels varied by five orders of magnitude, as expected with substantially higher levels in stables than bedrooms, especially for dairy farmers. Bovine allergen levels in bedrooms were more than one order of magnitude higher for dairy farmers compared to pig farmers. Former and never farmers had low levels of bovine allergens in their bedroom. Bovine allergen levels during summer appeared to be somewhat higher than during winter. Increased bovine allergen levels in the bedroom were associated with being a farmer or living on a farm. Mechanical ventilation in the bedroom decreased bovine allergen level, significant for dairy farmers beta=-1.4, p<0.04. No other significant effects of either sampling or residence characteristics were seen. Allergen levels in dairy stables were associated to type of dairy stable, but not to other stable or sampling characteristics. Sensitization to bovine allergens was only found in one pig farmer. CONCLUSION: This study confirms high bovine allergen levels in dairy farms, but also suggests sensitization to bovine allergens among Danish farmers to be uncommon. Furthermore the importance of a carrier home effect on allergen load is emphasized. Whether the risk for bovine sensitization is related to the allergen level in the stable or the dwelling remains to be determined. PMID- 25534700 TI - Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling. AB - Smad1, Smad5 and Smad9 (also known as Smad8) are activated by phosphorylation by bone morphogenetic protein (BMP)-bound type I receptor kinases. We examined the role of Smad1, Smad5, and Smad9 by creating constitutively active forms (Smad(DVD)). Transcriptional activity of Smad9(DVD) was lower than that of Smad1(DVD) or Smad5(DVD), even though all three Smad(DVD)s associated with Smad4 and bound to the target DNA. The linker region of Smad9 was sufficient to reduce transcriptional activity. Smad9 expression was increased by the activation of BMP signaling, similar to that of inhibitory Smads (I-Smads), and Smad9 reduced BMP activity. In contrast to I-Smads, however, Smad9 did not inhibit the type I receptor kinase and suppressed the constitutively active Smad1(DVD). Smad9 formed complexes with Smad1 and bound to DNA but suppressed the transcription of the target gene. Taken together, our findings suggest that Smad9 is a new type of transcriptional regulator in BMP signaling. PMID- 25534701 TI - Reliability of real-time elastography to diagnose thyroid nodules previously read at FNAC as indeterminate: a meta-analysis. AB - The main limit of thyroid fine-needle aspiration cytology (FNAC) is represented by indeterminate report. Recently, real-time elastography (RTE) has been described in the management of these cases. Here, we performed a meta-analysis of published studies specifically focused on the use of RTE in indeterminate thyroid nodules. A comprehensive literature search of PubMed/MEDLINE and Google Scholar databases was conducted by using the combination of the terms "thyroid" and "indeterminate" and "elastography." Pooled sensitivity, specificity, accuracy, PPV and NPV of RTE as predictor of malignancy in thyroid nodules with indeterminate FNAC were calculated, including 95% confidence intervals (95% CI). The area under the summary ROC curve (AUC) was also assessed. Databases found 572 papers, and eight were included in the meta-analysis. Of these, six studies had prospective design and two were retrospective. Pooled malignancy rate was 31%. As common denominator, all studies set the prevalence of hardness within the nodule as risk factor for malignancy of the lesion. Sensitivity of RTE ranged from 11 to 89% (pooled estimate of 69%; 95% CI 55-82%), specificity varied from 6 to 100% (pooled estimate of 75%; 95% CI 42-96%), and accuracy was comprised between 35 and 94% (pooled estimate of 73%; 95% CI 54-89%). The AUC was 0.77. RTE has suboptimal diagnostic accuracy to diagnose thyroid nodules previously classified as indeterminate. Then, RTE alone should not be used for selecting these patients for surgery or not. We advice for further studies using other elastographic approaches and combined RTE and B-mode ultrasonography. PMID- 25534702 TI - Nicotinamide adenine dinucleotide phosphate oxidase-4-dependent upregulation of nuclear factor erythroid-derived 2-like 2 protects the heart during chronic pressure overload. AB - The transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) controls a network of cytoprotective genes. Neither how Nrf2 is activated in the heart under hemodynamic overload nor its role and mechanism of action are known. This study aimed to investigate the activation and role of Nrf2 during chronic cardiac pressure overload. We first compared the responses of Nrf2(-/-) mice and wild-type littermates to chronic pressure overload. Hearts of Nrf2(-/-) mice showed impaired antioxidant gene expression, increased hypertrophy, and worse function compared with those of wild-type littermates after overload. Hearts of Nrf2(-/-) mice had increased mitochondrial DNA damage, a caspase 8/BH3 interacting domain death agonist-related cleavage of mitochondrial apoptosis inducing factor, nuclear DNA damage, and cell death. Nrf2 activation was under the control of the endogenous reactive oxygen species-generating enzyme nicotinamide adenine dinucleotide phosphate oxidase-4, both in vivo and in vitro. In mice with cardiac-specific overexpression of nicotinamide adenine dinucleotide phosphate oxidase-4, Nrf2 deletion significantly attenuated their protective phenotype during chronic pressure overload. This study identifies nicotinamide adenine dinucleotide phosphate oxidase-4-dependent upregulation of Nrf2 as an important endogenous protective pathway that limits mitochondrial damage and apoptosis-inducing factor-related cell death in the heart under hemodynamic overload. PMID- 25534703 TI - Prolonged corrected QT interval is predictive of future stroke events even in subjects without ECG-diagnosed left ventricular hypertrophy. AB - We attempted to evaluate whether subjects who exhibit prolonged corrected QT (QTc) interval (>=440 ms in men and >=460 ms in women) on ECG, with and without ECG-diagnosed left ventricular hypertrophy (ECG-LVH; Cornell product, >=244 mV*ms), are at increased risk of stroke. Among the 10 643 subjects, there were a total of 375 stroke events during the follow-up period (128.7+/-28.1 months; 114 142 person-years). The subjects with prolonged QTc interval (hazard ratio, 2.13; 95% confidence interval, 1.22-3.73) had an increased risk of stroke even after adjustment for ECG-LVH (hazard ratio, 1.71; 95% confidence interval, 1.22-2.40). When we stratified the subjects into those with neither a prolonged QTc interval nor ECG-LVH, those with a prolonged QTc interval but without ECG-LVH, and those with ECG-LVH, multivariate-adjusted Cox proportional hazards analysis demonstrated that the subjects with prolonged QTc intervals but not ECG-LVH (1.2% of all subjects; incidence, 10.7%; hazard ratio, 2.70, 95% confidence interval, 1.48-4.94) and those with ECG-LVH (incidence, 7.9%; hazard ratio, 1.83; 95% confidence interval, 1.31-2.57) had an increased risk of stroke events, compared with those with neither a prolonged QTc interval nor ECG-LVH. In conclusion, prolonged QTc interval was associated with stroke risk even among patients without ECG-LVH in the general population. PMID- 25534704 TI - Elevated blood pressure in preterm-born offspring associates with a distinct antiangiogenic state and microvascular abnormalities in adult life. AB - Preterm-born individuals have elevated blood pressure. We tested the hypothesis that this associates with an enhanced antiangiogenic circulating profile and that this association is mediated by variations in capillary density. We studied 204 adults aged 25 years (range, 20-30 years), of which 102 had been followed up prospectively since very preterm birth (mean gestational age, 30.3+/-2.5 weeks) and 102 were born term to uncomplicated pregnancies. A panel of circulating biomarkers, including soluble endoglin and soluble fms-like tyrosine kinase-1, were compared between groups and related to perinatal history and adult cardiovascular risk. Associations with cardiovascular phenotype were studied in 90 individuals who had undergone detailed assessment of microvascular, macrovascular, and cardiac structure and function. Preterm-born individuals had elevations in soluble endoglin (5.64+/-1.03 versus 4.06+/-0.85 ng/mL; P<0.001) and soluble fms-like tyrosine kinase-1 (88.1+/-19.0 versus 73.0+/-15.3 pg/mL; P<0.001) compared with term-born individuals, proportional to elevations in resting and ambulatory blood pressure, as well as degree of prematurity (P<0.05). Maternal hypertensive pregnancy disorder was associated with additional increases in soluble fms-like tyrosine kinase-1 (P=0.002). Other circulating biomarkers, including those of inflammation and endothelial activation, were not related to blood pressure. There was a specific graded association between soluble endoglin and degree of functional and structural capillary rarefaction (P=0.002 and P<0.001), and in multivariable analysis, there were capillary density-mediated associations between soluble endoglin and blood pressure. Preterm-born individuals exhibit an enhanced antiangiogenic state in adult life that is specifically related to elevations in blood pressure. The association seems to be mediated through capillary rarefaction and is independent of other cardiovascular structural and functional differences in the offspring. PMID- 25534705 TI - Microvessel mechanobiology in pulmonary arterial hypertension: cause and effect. PMID- 25534706 TI - Nuclear factor (erythroid-derived 2)-like 2, the brake in oxidative stress that nicotinamide adenine dinucleotide phosphate-oxidase-4 needs to protect the heart. PMID- 25534707 TI - Central aortic reservoir-wave analysis improves prediction of cardiovascular events in elderly hypertensives. AB - Several morphological parameters based on the central aortic pressure waveform are proposed as cardiovascular risk markers, yet no study has definitively demonstrated the incremental value of any waveform parameter in addition to currently accepted biomarkers in elderly, hypertensive patients. The reservoir wave concept combines elements of wave transmission and Windkessel models of arterial pressure generation, defining an excess pressure superimposed on a background reservoir pressure. The utility of pressure rate constants derived from reservoir-wave analysis in prediction of cardiovascular events is unknown. Carotid blood pressure waveforms were measured prerandomization in a subset of 838 patients in the Second Australian National Blood Pressure Study. Reservoir wave analysis was performed and indices of arterial function, including the systolic and diastolic rate constants, were derived. Survival analysis was performed to determine the association between reservoir-wave parameters and cardiovascular events. The incremental utility of reservoir-wave parameters in addition to the Framingham Risk Score was assessed. Baseline values of the systolic rate constant were independently predictive of clinical outcome (hazard ratio, 0.33; 95% confidence interval, 0.13-0.82; P=0.016 for fatal and nonfatal stroke and myocardial infarction and hazard ratio, 0.38; 95% confidence interval, 0.20-0.74; P=0.004 for the composite end point, including all cardiovascular events). Addition of this parameter to the Framingham Risk Score was associated with an improvement in predictive accuracy for cardiovascular events as assessed by the integrated discrimination improvement and net reclassification improvement indices. This analysis demonstrates that baseline values of the systolic rate constant predict clinical outcomes in elderly patients with hypertension and incrementally improve prognostication of cardiovascular events. PMID- 25534708 TI - Complications after laparotomy for trauma: a retrospective analysis in a level I trauma centre. AB - PURPOSE: Laparotomy is a potential life-saving procedure after traumatic abdominal injury. There is limited literature about morbidity and mortality rates after trauma laparotomy. The primary aim of this study is to describe the complications which may occur due to laparotomy for trauma. METHODS: Retrospective evaluated single-centre study with data registry up to 1 year after initial laparotomy for trauma was performed in a level 1 trauma centre in The Netherlands. Between January 2000 and January 2011, a total of 2390 severely injured trauma patients (ISS >= 16) were transported to the VUMC. Patient demographics; mechanism of injury; injury patterns defined by Abbreviated Injury Scale (AIS), Injury Severity Score (ISS) and Revised Trauma Score (RTS); surgical interventions and findings; and morbidity and mortality were documented. RESULTS: A total of 92 trauma patients who underwent a trauma laparotomy met the inclusion criteria. Of these patients, 71 % were male. Median age was 37 years. Median ISS was 27. Mechanisms of injury comprised of car accidents (20 %), fall from height (17 %), motorcycle accidents (12 %), pedestrian/cyclist hit by a vehicle (9 %) and other in three patients (5 %). Penetrating injuries accounted for 37 % of the injuries, consisting of stab wounds (21 %) and gunshot wounds (16 %). Complications classified by the Clavien-Dindo Classification of Surgical Complications showed grade I complications in 21 patients (23 %), grade II in 36 patients (39 %), grade III in 21 patients (23 %), grade IV in 2 patients (2 %) and grade V in 16 patients (17 %). CONCLUSION: Laparotomy for trauma has a high complication rate resulting in significant morbidity and mortality. Most events occur in the early postoperative period. Further prospective research needs to be conducted in order to identify possibilities to improve care in the future. PMID- 25534709 TI - Diagnostic value of the REM sleep behavior disorder screening questionnaire in Parkinson's disease. AB - OBJECTIVE: We aimed to validate the rapid eye movement (REM) sleep behavior disorder (RBD) screening questionnaire (RBDSQ) in 2 independent samples of patients with Parkinson's disease (PD) using different settings when performing the investigations. METHODS: The RBDSQ was administered to two independent samples of 52 and 75 consecutive PD patients investigated with video polysomnography (vPSG). RESULTS: In sample A, the RBDSQ identified 46/52 (88.5%) patients correctly. In sample B, 50/75 (66.7%) patients were identified correctly. Considering a cut-off score of >= 5 as a positive test result, sample A showed a sensitivity of 0.90 and a specificity of 0.87, sample B showed a sensitivity of 0.68 and a specificity of 0.63. Main differences between both groups were that patients of sample A underwent a sleep history including RBD assessment prior to administration of the RBDSQ, whereas in sample B the RBDSQ was administered during routine work-up. CONCLUSIONS: The diagnostic value of the RBDSQ strongly depends on the clinical setting and may be influenced by the individual's awareness on RBD. This finding is a critical issue which deserves clarification before use of this and other questionnaires can be recommended in epidemiological studies. PMID- 25534710 TI - Direct comparison of cortical excitability to transcranial magnetic stimulation in obstructive sleep apnea syndrome and restless legs syndrome. AB - OBJECTIVE: Changes to transcranial magnetic stimulation (TMS) have been reported in obstructive sleep apnea syndrome (OSAS) and restless legs syndrome (RLS), although no direct comparison study is available. The aim of this new investigation is to assess and compare cortical excitability of OSAS and RLS patients using the same methodology and under the same experimental conditions. METHODS: Fourteen patients with OSAS and 12 with RLS were compared to 14 age matched controls. All patients were untreated and had a severe degree of disease. Resting motor threshold (rMT), cortical silent period (CSP) and motor evoked potentials MEPs, as well as intracortical inhibition (ICI) and facilitation at interstimulus interval (ISI) of 3 and 10 ms, respectively, were explored from the right first dorsal interosseous muscle, during wakefulness. RESULTS: rMT was higher in OSAS than in RLS and controls. CSP was shorter in RLS only when compared to apneic patients, whereas it was similar between OSAS and controls. OSAS subjects exhibited slightly prolonged central motor conductivity, whereas MEP amplitude was smaller in both patient groups. The ICI ratio at ISI of 3 ms was decreased in RLS patients only. CONCLUSIONS: Distinct changes of responses at TMS were found, probably connected with the different neurophysiological substrates underlying OSAS and RLS and could not be interpreted as a mere reflection of the effects of sleep architecture alteration. TMS can be considered an additional tool for the understanding of clinical and pathophysiological aspects of sleep disorders, and possibly for the evaluation of the effect of therapy. PMID- 25534711 TI - The etiologic role of genetic and environmental factors in criminal behavior as determined from full- and half-sibling pairs: an evaluation of the validity of the twin method. AB - BACKGROUND: Twin studies have shown that criminal behavior (CB) is influenced by both genetic and shared environmental factors. Could these results be replicated using full-siblings and half-siblings? METHOD: In 911 009 full-siblings reared together (FSRT), 41 872 half-siblings reared together (HSRT) and 52 590 half siblings reared apart (HSRA), CB was assessed from the Swedish Crime Register. Modeling, including testing for age differences and rearing status, was performed using the OpenMx package. RESULTS: Five sibling models were fitted examining FSRT and HSRT 0-2 years different in age, and both FSRT and HSRT, and FSRT, HSRT and HSRA 0-10 years different in age with and without a specified shared environment indexing age differences. Heritability estimates for CB ranged from 33 to 55% in females and 39 to 56% in males, similar to those found in our prior twin study on the same population. Estimates for the shared environment varied from 1 to 14% in females and 10 to 23% in males, lower than those estimated in the twin study. The specified shared environment indexed by sibling age differences was significant in all models tested. CONCLUSIONS: Heritability estimates for CB from full- and half-siblings closely approximated those found from twins in the same population, validating the twin method. Shared environmental estimates were lower, suggesting the presence of shared environmental factors for CB specific to twins. When rearing status can be assessed, full- and half-siblings offer an additional method for assessing the role of genetic and environmental factors in complex disorders. However, age differences in siblings may need to be included in the models. PMID- 25534712 TI - Parental relationships and behavioral approach system dysregulation in young adults with bipolar disorder. AB - OBJECTIVES: Expressed emotion (EE), or the presence of criticism/hostility/emotional overinvolvement in a family relationship, predicts poorer outcomes in bipolar disorder; however, the mechanism of this is unclear. The present study investigated whether, in a sample of young adults (aged 18-40 years) with bipolar disorder, parental criticism was associated with Behavioral Approach System (BAS) dysregulation, including emotional reactivity to negative feedback and cognitive schemas of self-criticism/perfectionism. METHOD: Twenty two young adults with bipolar I disorder and 22 matched control participants completed an interview, questionnaires, and a computer-based task with false negative feedback; emotional reactivity to this feedback was assessed. RESULTS: Compared to control participants, clinical participants exhibited higher levels (p = 0.001) of self-criticism, and a trend towards a greater decrease in positive affect after negative feedback (p = 0.053), even when controlling for mood symptoms. Among clinical participants, perceived criticism from paternal caregivers was associated with self-criticism and perfectionism, and low perceived paternal care was associated with decrease in positive affect. CONCLUSION: Strain in parental relationships may be associated with BAS dysregulation for individuals with bipolar disorder. PMID- 25534713 TI - Comparative study of interactions of aliskiren and AT1 receptor antagonists with lipid bilayers. AB - The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin is the rate limiting enzyme of the RAAS and aliskiren is a highly potent and selective inhibitor of the human renin. Renin is known to be active both in the circulating blood stream as well as locally, when bound to the (pro)-renin receptor ((P)RR). In this study we have investigated a possible mechanism of action of aliskiren, in which its accumulation in the plasma membrane is considered as an essential step for effective inhibition. Aliskiren's interactions with model membranes (cholesterol rich and poor) have been investigated by applying different complementary techniques: differential scanning calorimetry (DSC), Raman spectroscopy, magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and small- and wide-angle X-ray scattering (SAXS and WAXS). In addition, in silico molecular dynamics (MD) calculations were applied for further confirmation of the experimental data. Aliskiren's thermal effects on the pre- and main transition of dipalmitoyl phosphatidylcholine (DPPC) membranes as well as its topographical position in the bilayer show striking similarities to those of angiotensin II type 1 receptor (AT1R) antagonists. Moreover, at higher cholesterol concentrations aliskiren gets expelled from the membrane just as it has been recently demonstrated for the angiotensin receptor blocker (ARB) losartan. Thus, we propose that both the AT1R and the (P)RR-bound renin active sites can be efficiently blocked by membrane bound ARBs and aliskiren when cholesterol rich membrane rafts/caveolae are formed in the vicinity of the receptors. PMID- 25534714 TI - Migration mechanism of mesenchymal stem cells studied by QD/NSOM. AB - The migration of mesenchymal stem cells (MSCs) plays a key role in tumor-targeted delivery vehicles and tumor-related stroma formation. However, there so far has been no report on the distribution of cell surface molecules during the VEGF induced migration of MSCs. Here, we have utilized near-field scanning optical microscopy (NSOM) combined with fluorescent quantum dot (QD)-based nano technology to capture the functional relationship between CD44 and CD29 adhesion molecules on MSCs and the effect of their spatial rearrangements. Before VEGF induced migration of MSCs, both CD44 and CD29 formed 200-220 nm nano-domains respectively, with little co-localization between the two types of domains. Surprisingly, the size of the CD44 nano-domain rapidly increased in size to 295 nm and apparently larger aggregates were formed following MSC treatment with VEGF for 10 min, while the area of co-localization increased to 0.327 MUm2. Compared with CD44, CD29 was activated obviously later, for the fact that CD29 aggregation didn't appear until 30 min after VEGF treatment. Consistently, its co localization area increased to 0.917 MUm2. The CD44 and CD29 nano-domains further aggregated into larger nano-domains or even formed micro-domains on the membrane of activated MSCs. The aggregation and co-localization of these molecules promoted FAK formation and cytoskeleton rearrangement. All of the above changes induced by VEGF contributed to MSC migration. Taken together, our data of NSOM based dual color fluorescent imaging demonstrated for the first time that CD44, together with CD29, involved in VEGF-induced migration of MSCs through the interaction between CD44 and its co-receptor of VEGFR-2. PMID- 25534716 TI - CH3(+) Formation in the Dissociation of Energy-Selected CH3F(+) Studied by Double Imaging Electron/Ion Coincidences. AB - The dissociation of energy-selected methyl fluoride ion CH3F(+) along the CH3(+) and F formation channel has been investigated in detail in the 12.2-19.8 eV energy range. Three low-lying electronic states of the CH3F(+) ion, X(2)E, A(2)A1, and B(2)E, were prepared and analyzed by the method of double imaging photoelectron photoion coincidence (i(2)PEPICO). Three types of CH3(+) fragment ions corresponding to the dissociation of X(2)E, A(2)A1, and B(2)E electronic states have been observed and identified through their kinetic energy release distribution (KERD) curves, showing that the dissociation of the CH3F(+) ion in the different electronic states along the CH3(+) formation channel is state specific, even outside of the Franck-Condon region. Highly excited vibrational levels of the X(2)E ground state can be populated through a resonant or near resonant autoionization process and undergo vibrational predissociation into CH3(+) fragment ions. The A(2)A1 first excited state is repulsive along the F loss coordinate, and its dissociation is direct and fast. The CH3F(+) ions in the B(2)E excited state first undergo an internal conversion toward the hot cation ground state X(2)E and then statistically dissociate into CH3(+) and F fragments. PMID- 25534715 TI - Efficacy of an alphabaculovirus-based biological insecticide for control of Chrysodeixis chalcites (Lepidoptera: Noctuidae) on tomato and banana crops. AB - BACKGROUND: Chrysodeixis chalcites (Esper) is a major pest of tomato in Mediterranean countries and attacks banana in the Canary Islands (Spain). The efficacy of Chrysodeixis chalcites single nucleopolyhedrovirus (ChchSNPV-TF1) was evaluated in plant growth chambers and greenhouse trials performed on tomato and banana plants respectively. Treatments were applied using a compressed air sprayer. RESULTS: Mean (+/- SE) lethal infection varied from 77 +/- 10% to 94 +/- 3% in second-instar larvae fed for 2 days on tomato plants treated with 2 * 10(6) to 5 * 10(7) virus occlusion bodies (OBs) L(-1) , increasing to ~100% infection after 7 days. Mortality of larvae collected from banana at different intervals post-application varied from 54 +/- 10% to 96 +/- 4% in treatments involving 1 * 10(8) -1 * 10(9) OBs L(-1) , whereas indoxacarb (Steward 30% WG) and Bacillus thuringiensis var. kurstaki (Biobit 16% WP) treatments produced between 22 +/- 6% and 32 +/- 5% pest mortality. All treatments significantly reduced plant defoliation compared with untreated controls. Application of 1 * 10(9) OBs L(-1) was 3-4-fold more effective than chemical or B. thuringiensis treatments. Larvae acquired lethal infection more rapidly when feeding on tomato than banana plants, but this difference disappeared following >60 min of feeding. CONCLUSION: This information should prove useful in the registration of ChchSNPV-TF1 as a bioinsecticide in the Canary Islands and Europe. PMID- 25534717 TI - Altersolanol A: a selective cytotoxic anthraquinone from a Phomopsis sp. AB - The cytotoxic compound Altersolanol A, an anthraquinone derivative was isolated from PM0409092 a fungus of Nyctanthes arbor-tristis (family Oleaceae). It was identified as a Phomopsis sp. by DNA amplification and sequencing of the ITS region. The chemical structure of Altersolanol A was elucidated from its physicochemical properties, 2D NMR spectroscopy and other spectroscopic data. The compound has in vitro cytotoxic activity against 34 human cancer cell lines with mean IC50 (IC70) values of 0.005 MUg ml(-1) (0.024 MUg ml(-1)) respectively. Altersolanol A, a kinase inhibitor, induces cell death by apoptosis through the cleavage by Caspase-3 and -9 and by decreased anti-apoptotic protein expression. There are several previous reports of the anticancer activity of Altersolanol A, but we report here an extensive study using 36 cell lines which gives wider spectrum of results. SIGNIFICANCE AND IMPACT OF THE STUDY: This study confirms the cytotoxic potential of Altersolanol A isolated from the endophyte Phomopsis sp. (PM0409092) of the plant Nyctanthes arbor-tristis. The compound exhibits in vitro cytotoxicity against 34 human cancer cell lines with mean IC50 (IC70) value of 0.005 MUg ml(-1) (0.024 MUg ml(-1)). This is an in-depth report of Altersolanol A against a panel of 34 human cancer cell lines and extends observations from previous studies indicating that Altersolanol A can be used for the development of chemotherapeutics. Altersolanol A, a kinase inhibitor, induces cell death by apoptosis through the cleavage of Caspase-3 and -9 and by decreased anti-apoptotic protein expression. PMID- 25534718 TI - Heterogeneity in hormone-receptor status and survival outcomes among women with synchronous and metachronous bilateral breast cancers. AB - To examine whether discordance in the hormone-receptor status predicts clinical outcomes in patients with bilateral synchronous (SBC) or metachronous breast cancer (MBC), we analyzed data from the Surveillance, Epidemiology, and End Results program (1998-2011) using Cox models. After excluding 10,231 patients with missing data on hormone receptors in at least one tumor, 4403 SBC and 7159 MBC were included in the study. Among SBC cases, patients with estrogen receptor (ER)-discordant tumors had higher mortality risk (multivariable-adjusted hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.60-2.40) than patients with ER concordant-positive tumors, whereas patients with ER concordant-negative tumors had the highest risk (HR = 2.49, 95% CI 2.03-3.07). Among MBC cases, patients with a positive-to-negative change in ER status (HR = 1.32, 95% CI: 1.08-1.62) or ER concordant-negative tumors (HR = 1.48, 95% CI: 1.19-1.85) had worse survival than patients with ER concordant-positive tumors. In conclusion, discordance in the hormone-receptor status was an independent predictor of survival outcomes. PMID- 25534719 TI - Audiovisual perception of natural speech is impaired in adult dyslexics: an ERP study. AB - The present study used event-related brain potentials (ERPs) to investigate audiovisual integration processes in the perception of natural speech in a group of German adult developmental dyslexic readers. Twelve dyslexic and twelve non dyslexic adults viewed short videos of a male German speaker. Disyllabic German nouns served as stimulus material. The auditory and the visual stimulus streams were segregated to create four conditions: in the congruent condition, the spoken word and the auditory word were identical. In the incongruent condition, the auditory and the visual word (i.e., the lip movements of the utterance) were different. Furthermore, on half of the trials, white noise (45 dB SPL) was superimposed on the auditory trace. Subjects had to say aloud the word they understood after they viewed the video. Behavioral data. Dyslexic readers committed more errors compared to normal readers in the noise conditions, and this effect was particularly present for congruent trials. ERPs showed a distinct N170 component at temporo-parietal electrodes that was smaller in amplitude for dyslexic readers. Both, normal and dyslexic readers, showed a clear effect of noise at centro-parietal electrodes between 300 and 600 ms. An analysis of error trials reflecting audiovisual integration (verbal responses in the incongruent noise condition that are a mix of the visual and the auditory word) revealed more positive ERPs for dyslexic readers at temporo-parietal electrodes 200-500 ms poststimulus. For normal readers, no such effect was present. These findings are discussed as reflecting increased effort in dyslexics under circumstances of distorted acoustic input. The superimposition of noise leads dyslexics to rely more on the integration of auditory and visual input (lip reading). Furthermore, the smaller N170-amplitudes indicate deficits in the processing of moving faces in dyslexic adults. PMID- 25534720 TI - The inhibitory actions by lacosamide, a functionalized amino acid, on voltage gated Na+ currents. AB - The effect of lacosamide (LCS), a functionalized molecule with anti-convulsant properties, on ion channels was investigated, with the aid of patch clamp technology and simulation modeling. In NSC-34 neuronal cells, LCS was found to block voltage-gated Na(+) current (INa) in a frequency- and concentration dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of INa was found in the presence of LCS. However, with repetitive stimulation, the pulse-to-pulse reduction in peak current was shown to be exponential, with a rate linearly related to both the inter-stimulus interval and the LCS concentration. In addition, the frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage dependent mixture of NaV channels harboring either an accessible or an inaccessible binding site. LCS also increased the dimension of inactivation space of NaV-channel states, thereby producing the adaptive response of neurons to previous firing. LCS (30 MUM) had no effects on the non-inactivating component of INa, while it slightly decreased the amplitude of delayed-rectifier K(+) current. Moreover, LCS suppressed the peak amplitude of INa in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of INa, in a concentration-dependent fashion. The unique effects of LCS on NaV currents presented here may contribute to its in vivo modulation of cellular excitability. PMID- 25534722 TI - Fidaxomicin therapy in critically ill patients with Clostridium difficile infection. AB - Fidaxomicin use to treat proven Clostridium difficile infection (CDI) was compared between 20 patients receiving care in critical care units (CCUs) and 30 patients treated on general medical floors. At baseline, the CCU patients had more initial CDI episodes, more severe and complicated disease, and more concurrent broad-spectrum antibiotic coverage. On multivariate analysis, the response to fidaxomicin therapy among the critically ill patients was comparable to that among patients in the general medical wards. PMID- 25534723 TI - Characterization of the novel DNA gyrase inhibitor AZD0914: low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae. AB - The unmet medical need for novel intervention strategies to treat Neisseria gonorrhoeae infections is significant and increasing, as rapidly emerging resistance in this pathogen is threatening to eliminate the currently available treatment options. AZD0914 is a novel bacterial gyrase inhibitor that possesses potent in vitro activities against isolates with high-level resistance to ciprofloxacin and extended-spectrum cephalosporins, and it is currently in clinical development for the treatment of N. gonorrhoeae infections. The propensity to develop resistance against AZD0914 was examined in N. gonorrhoeae and found to be extremely low, a finding supported by similar studies with Staphylococcus aureus. The genetic characterization of both first-step and second step mutants that exhibited decreased susceptibilities to AZD0914 identified substitutions in the conserved GyrB TOPRIM domain, confirming DNA gyrase as the primary target of AZD0914 and providing differentiation from fluoroquinolones. The analysis of available bacterial gyrase and topoisomerase IV structures, including those bound to fluoroquinolone and nonfluoroquinolone inhibitors, has allowed the rationalization of the lack of cross-resistance that AZD0914 shares with fluoroquinolones. Microbiological susceptibility data also indicate that the topoisomerase inhibition mechanisms are subtly different between N. gonorrhoeae and other bacterial species. Taken together, these data support the progression of AZD0914 as a novel treatment option for the oral treatment of N. gonorrhoeae infections. PMID- 25534725 TI - Caprylic acid and glyceryl trinitrate combination for eradication of biofilm. AB - There is a growing need for biocompatible, broad-spectrum, nonantibiotic, antimicrobial treatments because of the frequent ineffectiveness of antibiotics against biofilms and the increasing incidence of antibiotic resistance. In this study, we demonstrate rapid and complete biofilm eradication in an in vitro model with synergistic combinations of glyceryl trinitrate and caprylic acid against resistant Gram-positive, Gram-negative, and fungal biofilms. PMID- 25534724 TI - Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections. AB - Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C. difficile that is comparable to or greater than that of other clinically used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. This multicenter, randomized, evaluator-blind, and active controlled study evaluated the safety, efficacy, and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The PK parameters were calculated from drug concentrations measured in serum and fecal samples. The systemic exposure following oral administration of 200 mg of LFF571 four times per day for 10 days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/ml, whereas the levels in feces at the end of treatment were between 107 and 12,900 MUg/g. In comparison, the peak vancomycin level observed in serum was considerably higher, at 2.73 MUg/ml; the levels of vancomycin in feces were not measured. Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571. These results are consistent with the retention of LFF571 in the lumen of the gastrointestinal tract. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.). PMID- 25534726 TI - Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers. AB - This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean +/- SD) at steady state (Cmax_ss) were 9.60 +/- 1.84 and 11.04 +/- 2.18 MUg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 +/- 8.62 and 65.82 +/- 10.78 MUg . h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 +/- 1.47, 8.17 +/- 1.76, and 9.96 +/- 2.23 MUg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 +/- 9.52, 54.17 +/- 12.10, and 71.34 +/- 17.79 MUg . h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was <=1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.). PMID- 25534727 TI - Multicenter, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections. AB - Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventy-two patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.). PMID- 25534728 TI - In vitro susceptibility of characterized beta-lactamase-producing strains tested with avibactam combinations. AB - Avibactam, a broad-spectrum beta-lactamase inhibitor, was tested with ceftazidime, ceftaroline, or aztreonam against 57 well-characterized Gram negative strains producing beta-lactamases from all molecular classes. Most strains were nonsusceptible to the beta-lactams alone. Against AmpC-, extended spectrum beta-lactamase (ESBL)-, and KPC-producing Enterobacteriaceae or Pseudomonas aeruginosa, avibactam lowered ceftazidime, ceftaroline, or aztreonam MICs up to 2,048-fold, to <=4 MUg/ml. Aztreonam-avibactam MICs against a VIM-1 metallo-beta-lactamase-producing Enterobacter cloacae and a VIM-1/KPC-3-producing Escherichia coli isolate were 0.12 and 8 MUg/ml, respectively. PMID- 25534729 TI - Involvement of Holliday junction resolvase in fluoroquinolone-mediated killing of Mycobacterium smegmatis. AB - The absence of the Holliday-junction Ruv resolvase of Mycobacterium smegmatis increased the bacteriostatic and bactericidal activities of the fluoroquinolone moxifloxacin, an important antituberculosis agent. The treatment of ruvAB deficient cells with thiourea and 2,2'-bipyridyl lowered moxifloxacin lethality to wild-type levels, indicating that the absence of ruvAB stimulates a lethal pathway involving reactive oxygen species. A hexapeptide that traps the Holliday junction substrate of RuvAB potentiated moxifloxacin-mediated lethality, supporting the development of small-molecule enhancers for moxifloxacin activity against mycobacteria. PMID- 25534730 TI - In Vitro activities of combinations of rifampin with other antimicrobials against multidrug-resistant Acinetobacter baumannii. AB - The antimicrobial treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections has become a great challenge for medical staff all over the world. Increasing numbers of MDR A. baumannii infections have been identified and reported, but effective clinical treatments for them are decreasing. The objective of this study was to investigate the in vitro activities of combinations of rifampin (an established antimicrobial) and other antimicrobials, including biapenem, colistin, and tigecycline, against 73 clinical isolates of MDR A. baumannii. In total, 73 clinical isolates of MDR A. baumannii were collected from two A-level general hospitals in Beijing, and the MICs of rifampin, biapenem, colistin, and tigecycline were determined. The checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs), that is, whether the combinations acted synergistically against these isolates. The MIC50, MIC90, and MICrange of rifampin combined with biapenem, colistin, and tigecycline against the isolates were clearly lower than those for four antimicrobials (rifampin, biapenem, colistin, and tigecycline) that were used alone. Combinations of rifampin with biapenem, colistin, and tigecycline individually demonstrated the following interactions: synergistic interactions (FICI <= 0.5) for 31.51%, 34.25%, and 31.51% of the isolates, partially synergistic interactions (0.5 < FICI < 1) for 49.31%, 43.83%, and 47.94% of the isolates, and additive interactions (FICI = 1) for 19.18%, 21.92%, and 20.55% of the isolates, respectively. There were no indifferent (1 < FICI < 4) or antagonistic (FICI >= 4) interactions. Therefore, combinations of rifampin with biapenem, colistin, or tigecycline may be future therapeutic alternatives for the treatment of MDR A. baumannii infections. PMID- 25534731 TI - Posaconazole prophylaxis in experimental azole-resistant invasive pulmonary aspergillosis. AB - We investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistant Aspergillus fumigatus isolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR34/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective in A. fumigatus with posaconazole MICs of <=0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter. PMID- 25534732 TI - The MSPDBL2 codon 591 polymorphism is associated with lumefantrine in vitro drug responses in Plasmodium falciparum isolates from Kilifi, Kenya. AB - The mechanisms of drug resistance development in the Plasmodium falciparum parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms of Pfmspdbl2 for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P = 0.04). The high frequency of Pfmspdbl2 codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem). PMID- 25534733 TI - Doripenem MICs and ompK36 porin genotypes of sequence type 258, KPC-producing Klebsiella pneumoniae may predict responses to carbapenem-colistin combination therapy among patients with bacteremia. AB - Treatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producing Klebsiella pneumoniae were significantly more likely if both agents were inactive in vitro, as defined by a colistin MIC of >2 MUg/ml and the presence of either a major ompK36 porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134-135 GD], IS5 promoter insertion [P = 0.007]) or a doripenem MIC of >8 MUg/ml (P = 0.01). Major ompK36 mutations among KPC-K. pneumoniae strains are important determinants of carbapenem-colistin responses in vitro and in vivo. PMID- 25534734 TI - Sialic acid-binding protein Sp2CBMTD protects mice against lethal challenge with emerging influenza A (H7N9) virus. AB - Compounds that target the cellular factors essential for influenza virus replication represent an innovative approach to antiviral therapy. Sp2CBMTD is a genetically engineered multivalent protein that masks sialic acid-containing cellular receptors on the respiratory epithelium, which are recognized by influenza viruses. Here, we evaluated the antiviral potential of Sp2CBMTD against lethal infection in mice with an emerging A/Anhui/1/2013 (H7N9) influenza virus and addressed the mechanistic basis of its activity in vivo. Sp2CBMTD was administered to mice intranasally as a single or repeated dose (0.1, 1, 10, or 100 MUg) before (day -7, -3, and/or -1) or after (6 or 24 h) H7N9 virus inoculation. A single Sp2CBMTD dose (10 or 100 MUg) protected 80% to 100% of the mice when administered 7 days before the H7N9 lethal challenge. Repeated Sp2CBMTD administration conferred the highest protection, resulting in 100% survival of the mice even at the lowest dose tested (0.1 MUg). When treatment began 24 h after exposure to the H7N9 virus, a single administration of 100 MUg of Sp2CBMTD protected 40% of the mice from death. The administration of Sp2CBMTD induced the pulmonary expression of proinflammatory mediators (interleukin-6 [IL-6], IL 1beta, RANTES, monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein-1alpha [MIP-1alpha], and inducible protein [IP-10]) and recruited neutrophils to the respiratory tract before H7N9 virus infection, which resulted in less pronounced inflammation and rapid virus clearance from mouse lungs. Sp2CBMTD administration did not affect the virus-specific adaptive immune response, which was sufficient to protect against reinfection with a higher dose of homologous H7N9 virus or heterologous H5N1 virus. Thus, Sp2CBMTD was effective in preventing H7N9 infections in a lethal mouse model and holds promise as a prophylaxis option against zoonotic influenza viruses. PMID- 25534735 TI - In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. AB - Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections. PMID- 25534736 TI - Novel quorum-quenching agents promote methicillin-resistant Staphylococcus aureus (MRSA) wound healing and sensitize MRSA to beta-lactam antibiotics. AB - The dwindling repertoire of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) calls for novel treatment options. Quorum-quenching agents offer an alternative or an adjuvant to antibiotic therapy. Three biaryl hydroxyketone compounds discovered previously (F1, F12, and F19; G. Yu, D. Kuo, M. Shoham, and R. Viswanathan, ACS Comb Sci 16:85-91, 2014) were tested for efficacy in MRSA-infected animal models. Topical therapy of compounds F1 and F12 in a MRSA murine wound infection model promotes wound healing compared to the untreated control. Compounds F1, F12, and F19 afford significant survival benefits in a MRSA insect larva model. Combination therapy of these quorum quenching agents with cephalothin or nafcillin, antibiotics to which MRSA is resistant in monotherapy, revealed additional survival benefits. The quorum quenching agents sensitize MRSA to the antibiotic by a synergistic mode of action that also is observed in vitro. An adjuvant of 1 MUg/ml F1, F12, or F19 reduces the MIC of nafcillin and cephalothin about 50-fold to values comparable to those for vancomycin, the antibiotic often prescribed for MRSA infections. These findings suggest that it is possible to resurrect obsolete antibiotic therapies in combination with these novel quorum-quenching agents. PMID- 25534737 TI - A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections. AB - New drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drug-resistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 MUg/ml and 0.08 to 5.48 MUg/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 MUg/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 MUg/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc 486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections. PMID- 25534738 TI - Fluoroquinolone resistance does not impose a cost on the fitness of Clostridium difficile in vitro. AB - Point mutations conferring resistance to fluoroquinolones were introduced in the gyr genes of the reference strain Clostridium difficile 630. Only mutants with the substitution Thr-82->Ile in GyrA, which characterizes the hypervirulent epidemic clone III/027/NAP1, were resistant to all fluoroquinolones tested. The absence of a fitness cost in vitro for the most frequent mutations detected in resistant clinical isolates suggests that resistance will be maintained even in the absence of antibiotic pressure. PMID- 25534739 TI - Protection against Klebsiella pneumoniae using lithium chloride in an intragastric infection model. AB - Intragastric Klebsiella pneumoniae infections of mice can cause liver abscesses, necrosis of liver tissues, and bacteremia. Lithium chloride, a widely prescribed drug for bipolar mood disorder, has been reported to possess anti-inflammatory properties. Using an intragastric infection model, the effects of LiCl on K. pneumoniae infections were examined. Providing mice with drinking water containing LiCl immediately after infection protected them from K. pneumoniae induced death and liver injuries, such as necrosis of liver tissues, as well as increasing blood levels of aspartate aminotransferase and alanine aminotransferase, in a dose-dependent manner. LiCl administered as late as 24 h postinfection still provided protection. Monitoring of the LiCl concentrations in the sera of K. pneumoniae-infected mice showed that approximately 0.33 mM LiCl was the most effective dose for protecting mice against infections, which is lower than the clinically toxic dose of LiCl. Surveys of bacterial counts and cytokine expression levels in LiCl-treated mice revealed that both were effectively inhibited in blood and liver tissues. Using in vitro assays, we found that LiCl (5 MUM to 1 mM) did not directly interfere with the growth of K. pneumoniae but made K. pneumoniae cells lose the mucoid phenotype and become more susceptible to macrophage killing. Furthermore, low doses of LiCl also partially enhanced the bactericidal activity of macrophages. Taken together, these data suggest that LiCl is an alternative therapeutic agent for K. pneumoniae-induced liver infections. PMID- 25534740 TI - The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents. AB - Previous studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs against Mycobacterium tuberculosis in in vitro and in vivo combination studies. When used alone, timcodar weakly inhibited M. tuberculosis growth in broth culture (MIC, 19 MUg/ml); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline, and clofazimine but not with other anti-TB agents. When M. tuberculosis was cultured in host macrophage cells, timcodar had about a 10-fold increase (50% inhibitory concentration, 1.9 MUg/ml) in the growth inhibition of M. tuberculosis and demonstrated synergy with rifampin, moxifloxacin, and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid, conferring 1.0 and 0.4 log10 reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a mouse model of long-term, chronic infection with treatment with a combination of rifampin, isoniazid, and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase the plasma exposure of bedaquiline. These data suggest that the antimycobacterial drug-potentiating activity of timcodar is complex and drug dependent and involves both bacterial and host-targeted mechanisms. Further study of the improvement of the potency of antimycobacterial drugs and drug candidates when used in combination with timcodar is warranted. PMID- 25534741 TI - Targeting Mycobacterium tuberculosis topoisomerase I by small-molecule inhibitors. AB - We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and M. tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the M. tuberculosis and M. smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules. PMID- 25534742 TI - Molecular diagnosis of fluoroquinolone resistance in Mycobacterium tuberculosis. AB - As a consequence of the use of fluoroquinolones (FQ), resistance to FQ has emerged, leading to cases of nearly untreatable and extensively drug-resistant tuberculosis. Mutations in DNA gyrase represent the main mechanism of FQ resistance. A full understanding of the pattern of mutations found in FQ resistant (FQ(r)) clinical isolates, and of their proportions, is crucial for improving molecular methods for the detection of FQ resistance in Mycobacterium tuberculosis. In this study, we reviewed the detection of FQ resistance in isolates addressed to the French National Reference Center for Mycobacteria from 2007 to 2012, with the aim of evaluating the performance of PCR sequencing in a real-life context. gyrA and gyrB sequencing, performed prospectively on M. tuberculosis clinical isolates, was compared for FQ susceptibility to 2 mg/liter ofloxacin by the reference proportion method. A total of 605 isolates, of which 50% were multidrug resistant, were analyzed. The increase in FQ(r) strains among multidrug-resistant (MDR) strains during the time of the study was alarming (8% to 30%). The majority (78%) of the isolates with gyrA mutations were FQ(r), whereas only 36% of those with gyrB mutations were FQ(r). Only 12% of the FQ(r) isolates had a single mutation in gyrB. Combined gyrA and gyrB sequencing led to >93% sensitivity for detecting resistance. The analysis of the four false positive and the five false-negative results of gyrA and gyrB sequencing illustrated the actual limitations of the reference proportion method. Our data emphasize the need for combined gyrA and gyrB sequencing in the investigation of FQ susceptibility in M. tuberculosis and challenge the validity of the current phenotype-based approach as the diagnostic gold standard for determining FQ resistance. PMID- 25534743 TI - Molecular analysis of codon 548 in the rpoB gene involved in Mycobacterium tuberculosis resistance to rifampin. AB - Most Mycobacterium tuberculosis rifampin-resistant strains have been associated with mutations in an 81-bp rifampin resistance-determining region (RRDR) in the gene rpoB. However, if this region alone were targeted, rifampin-resistant strains with mutations outside the RRDR would not be detected. In this study, among 51 rifampin-resistant clinical isolates analyzed by sequencing 1,681-bp long DNA fragments containing the RRDR, 47 isolates contained mutations within the RRDR, three isolates contained mutations both within and outside the RRDR, and only one isolate had a single missense mutation (Arg548His) located outside the RRDR. A drug susceptibility test of recombinant Mycobacterium smegmatis and M. tuberculosis isolates carrying mutated rpoB (Arg548His) showed an increased MIC for rifampin compared to that of the control strains. Modeling of the Arg548His mutant RpoB-DNA complex revealed that the His548 side chain formed a more stable hydrogen bond structure than did Arg548, reducing the flexibility of the rifampin-resistant cluster II region of RpoB, suggesting that the RpoB Arg548His mutant does not effectively interact with rifampin and results in bacterial resistance to the drug. This is the first report on the relationship between the mutation in codon 548 of RpoB and rifampin resistance in tuberculosis. The novel mutational profile of the rpoB gene described here will contribute to the comprehensive understanding of rifampin resistance patterns and to the development of a useful tool for simple and rapid drug susceptibility tests. PMID- 25534744 TI - Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City. AB - Eravacycline demonstrated in vitro activity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC50/MIC90 values, respectively, for Escherichia coli of 0.12/0.5 MUg/ml, Klebsiella pneumoniae of 0.25/1 MUg/ml, Enterobacter aerogenes of 0.25/1 MUg/ml, Enterobacter cloacae 0.5/1 MUg/ml, and Acinetobacter baumannii of 0.5/1 MUg/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of the adeB gene. PMID- 25534745 TI - Effect of asparagine substitutions in the YXN loop of a class C beta-lactamase of Acinetobacter baumannii on substrate and inhibitor kinetics. AB - Class C cephalosporinases are a growing threat, and inhibitors of these enzymes are currently unavailable. Studies exploring the YXN loop asparagine in the Escherichia coli AmpC, P99, and CMY-2 enzymes have suggested that interactions between C6' or C7' substituents on penicillins or cephalosporins and this Asn are important in determining substrate specificity and enzymatic stability. We sought to characterize the YXN loop asparagine in the clinically important ADC-7 class C beta-lactamase of Acinetobacter baumannii. Mutagenesis at the N148 position in ADC-7 yields functional mutants (N152G, -S, -T, -Q, -A, and -C) that retain cephalosporinase activity. Using standard assays, we show that N148G, -S, and -T variants possess good catalytic activity toward cefoxitin and ceftaroline but that cefepime is a poor substrate. Because N152 variants of CMY-2, another class C beta-lactamase, are more readily inhibited by tazobactam due to higher rates of inactivation, we also tested if the N148 substitutions in ADC-7 would affect inactivation by sulfone inhibitors, sulbactam and tazobactam, class A beta lactamase, and A. baumannii penicillin-binding protein (PBP) inhibitors with in vitro activity against ADC-7. The 50% inhibitory concentrations (IC50s) for tazobactam and sulbactam were improved, with 7-fold and 2-fold reductions, respectively, for the N148S variant. A homology model of the N148S ADC-7 enzyme in a Michaelis-Menten complex with tazobactam showed a loss of interaction between N148 and the sulfone moiety of the inhibitor. We postulate that this may result in more-rapid secondary ring opening of the inhibitor, as the unbound sulfone is an excellent leaving group, leading to more-rapid formation of the stable linearized inhibitor. PMID- 25534748 TI - Independence of nitrate and nitrite inhibition of Desulfovibrio vulgaris Hildenborough and use of nitrite as a substrate for growth. AB - Sulfate-reducing microbes, such as Desulfovibrio vulgaris Hildenborough, cause "souring" of petroleum reservoirs through produced sulfide and precipitate heavy metals, either as sulfides or by alteration of the metal reduction state. Thus, inhibitors of these microbes, including nitrate and nitrite ions, are studied in order to limit their impact. Nitrite is a potent inhibitor of sulfate reducers, and it has been suggested that nitrate does not inhibit these microbes directly but by reduction to nitrite, which serves as the ultimate inhibitor. Here we provide evidence that nitrate inhibition of D. vulgaris can be independent of nitrite production. We also show that D. vulgaris can use nitrite as a nitrogen source or terminal electron acceptor for growth. Moreover, we report that use of nitrite as a terminal electron acceptor requires nitrite reductase (nrfA) as a D. vulgaris nrfA mutant cannot respire nitrite but remains capable of utilizing nitrite as a nitrogen source. These results illuminate previously uncharacterized metabolic abilities of D. vulgaris that may allow niche expansion in low-sulfate environments. Understanding these abilities may lead to better control of sulfate reducing bacteria in industrial settings and more accurate prediction of their interactions in the environment. PMID- 25534747 TI - Population pharmacokinetic and pharmacodynamic modeling of transformed binary effect data of triflusal in healthy Korean male volunteers: a randomized, open label, multiple dose, crossover study. AB - BACKGROUND: Triflusal is a drug that inhibits platelet aggregation. In this study we investigated the dose-exposure-response relationship of a triflusal formulation by population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of its main active metabolite, hydroxy-4-(trifluoromethyl) benzoic acid (HTB). METHODS: This study was a randomized, open-label, multiple-dose, two-period, two treatment, comparative crossover design. All volunteers received a single oral loading dose of 900 mg of triflusal on Day 1, followed by a dose of 600 mg/day from Day 2 to 9. Using data from 34 healthy volunteers, 476 HTB plasma concentration data points and 340 platelet aggregation data points were used to construct PK and PD models respectively using NONMEM (version 6.2). As the PD endpoint was qualitative, we implemented binary analysis of 'inhibition' and 'non inhibition' rather than using the actual value of the test. The final PK-PD model was evaluated using a visual predictive check (VPC) and bootstrap. RESULTS: The time-concentration profile of HTB over the entire dosing period was described by a one-compartment model with a first-order formation rate constant for HTB. Weight was selected as a covariate for clearance and volume of triflusal, respectively. The structure and the population estimates for triflusal PK were as follows: oral clearance (CL/F) = 0.2 . (weight/71.65)(0.845) L/h, oral volume of distribution (V/F) = 8.3 . (weight/71.65) L, and k f = 0.341 h(-1). A sigmoid relationship between triflusal concentration and the probability of significant inhibition with shape factor was chosen as the final PD model. No time delay between concentration and response was identified. The final structure between predicted concentration (C(y)(pred,ij) and the probability of inhibition of platelet aggregation (IPA) relationship was as follows: Probability of IPA = C(19)(pred,ij)/((84.9)(19) ug/mL + C(19)(pred,ij)). Thus, we concluded this relationship is more like quantal concentration-response relationship. The current dosing regimen was considered to be efficacious based on the EC 50 estimate of 84.9 MUg/mL obtained in this study. CONCLUSIONS: A PK and binary probability PD model of triflusal was successfully developed for Korean healthy volunteers. The model may be used to further prediction inhibition of platelet aggregation by triflusal. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0001299 (Registered December 5, 2014). PMID- 25534746 TI - A high-affinity native human antibody neutralizes human cytomegalovirus infection of diverse cell types. AB - Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation. PMID- 25534749 TI - EssOilDB: a database of essential oils reflecting terpene composition and variability in the plant kingdom. AB - Plant essential oils are complex mixtures of volatile organic compounds, which play indispensable roles in the environment, for the plant itself, as well as for humans. The potential biological information stored in essential oil composition data can provide an insight into the silent language of plants, and the roles of these chemical emissions in defense, communication and pollinator attraction. In order to decipher volatile profile patterns from a global perspective, we have developed the ESSential OIL DataBase (EssOilDB), a continually updated, freely available electronic database designed to provide knowledge resource for plant essential oils, that enables one to address a multitude of queries on volatile profiles of native, invasive, normal or stressed plants, across taxonomic clades, geographical locations and several other biotic and abiotic influences. To our knowledge, EssOilDB is the only database in the public domain providing an opportunity for context based scientific research on volatile patterns in plants. EssOilDB presently contains 123 041 essential oil records spanning a century of published reports on volatile profiles, with data from 92 plant taxonomic families, spread across diverse geographical locations all over the globe. We hope that this huge repository of VOCs will facilitate unraveling of the true significance of volatiles in plants, along with creating potential avenues for industrial applications of essential oils. We also illustrate the use of this database in terpene biology and show how EssOilDB can be used to complement data from computational genomics to gain insights into the diversity and variability of terpenoids in the plant kingdom. EssOilDB would serve as a valuable information resource, for students and researchers in plant biology, in the design and discovery of new odor profiles, as well as for entrepreneurs--the potential for generating consumer specific scents being one of the most attractive and interesting topics in the cosmetic industry. Database URL: http://nipgr.res.in/Essoildb/ PMID- 25534752 TI - Corrigendum. AB - Lebourg M, Martinez-Diaz S, Garcia-Giralt N, Torres-Claramunt R, Ribelles JL, Vila-Canet G, Monllau JC. (2014) Cell-free cartilage engineering approachusing hyaluronic acid-polycaprolactone scaffolds: A study in vivo. Journal of Biomaterials Applications 28(9): 1304-1315. (Original DOI: 10.1177/0885328213507298) In this article author J. A. Gomez-Tejedor is inadvertently missed from the author list. On page 1304, the author names should read M Lebourg(1), S Martinez-Diaz(2), N Garcia-Giralt(2), R Torres-Claramunt(2), JA Gomez-Tejedor(3), JL Gomez Ribelles(1,3), G Vila-Canet(4) and JC Monllau(4,5). PMID- 25534751 TI - The MqsR/MqsA toxin/antitoxin system protects Escherichia coli during bile acid stress. AB - Toxin/antitoxin (TA) systems are ubiquitous within bacterial genomes, and the mechanisms of many TA systems are well characterized. As such, several roles for TA systems have been proposed, such as phage inhibition, gene regulation and persister cell formation. However, the significance of these roles is nebulous due to the subtle influence from individual TA systems. For example, a single TA system has only a minor contribution to persister cell formation. Hence, there is a lack of defining physiological roles for individual TA systems. In this study, phenotype assays were used to determine that the MqsR/MqsA type II TA system of Escherichia coli is important for cell growth and tolerance during stress from the bile salt deoxycholate. Using transcriptomics and purified MqsR, we determined that endoribonuclease toxin MqsR degrades YgiS mRNA, which encodes a periplasmic protein that promotes deoxycholate uptake and reduces tolerance to deoxycholate exposure. The importance of reducing YgiS mRNA by MqsR is evidenced by improved growth, reduced cell death and reduced membrane damage when cells without ygiS are stressed with deoxycholate. Therefore, we propose that MqsR/MqsA is physiologically important for E. coli to thrive in the gallbladder and upper intestinal tract, where high bile concentrations are prominent. PMID- 25534750 TI - dbPPT: a comprehensive database of protein phosphorylation in plants. AB - As one of the most important protein post-translational modifications, the reversible phosphorylation is critical for plants in regulating a variety of biological processes such as cellular metabolism, signal transduction and responses to environmental stress. Numerous efforts especially large-scale phosphoproteome profiling studies have been contributed to dissect the phosphorylation signaling in various plants, while a large number of phosphorylation events were identified. To provide an integrated data resource for further investigations, here we present a comprehensive database of dbPPT (database of Phosphorylation site in PlanTs, at http://dbppt.biocuckoo.org), which contains experimentally identified phosphorylation sites in proteins from plants. The phosphorylation sites in dbPPT were manually curated from the literatures, whereas datasets in other public databases were also integrated. In total, there were 82,175 phosphorylation sites in 31,012 proteins from 20 plant organisms in dbPPT, presenting a larger quantity of phosphorylation sites and a higher coverage of plant species in comparison with other databases. The proportions of residue types including serine, threonine and tyrosine were 77.99, 17.81 and 4.20%, respectively. All the phosphoproteins and phosphorylation sites in the database were critically annotated. Since the phosphorylation signaling in plants attracted great attention recently, such a comprehensive resource of plant protein phosphorylation can be useful for the research community. Database URL: http://dbppt.biocuckoo.or PMID- 25534753 TI - Cortical Thickness in Individuals at High Familial Risk of Mood Disorders as They Develop Major Depressive Disorder. AB - BACKGROUND: Frontal and temporal cortical thickness abnormalities have been observed in mood disorders. However, it is unknown whether cortical thickness abnormalities reflect early adverse effects of genetic and environmental risk factors predisposing to mood disorders or emerge at illness onset. METHODS: Magnetic resonance imaging was conducted at baseline and after a 2-year follow-up interval in 111 initially unaffected young adults at high familial risk of mood disorders and 93 healthy control subjects (HC). During the follow-up period, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the remainder remaining well (HR-well). Cortical surface reconstruction was applied to measure cortical thickness of frontal and temporal regions of interest. Mixed effects models were used to investigate differences and longitudinal changes in cortical thickness. RESULTS: Reduced cortical thickness in the right parahippocampal and fusiform gyrus across both time points was found in both high risk groups. HR-MDD also had thinner parahippocampi than HR-well individuals. Over time, HR-well and HC individuals had progressive thickness reductions in the left inferior frontal and precentral gyrus, which were greater in HR-well subjects. HR-MDD showed left inferior frontal gyrus thickening relative to HR well subjects and left precentral gyrus thickening relative to HR-well and HC individuals. CONCLUSIONS: Reduced right parahippocampal and fusiform gyrus thickness are familial trait markers for vulnerability to mood disorders. Increased risk for mood disorders is associated with progressive cortical thinning in the left inferior frontal and precentral gyri in subjects who remain well. In contrast, onset of depression is associated with increasing left inferior frontal and precentral thickness. PMID- 25534754 TI - Ghrelin's Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders. AB - Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders. PMID- 25534756 TI - Mental disorders in Italian prisoners: results of the REDiMe study. AB - The goal of the study was to estimate the prevalence of current and lifetime mental disorders in a consecutive sample (n=300) of detainees and prison inmates held in an Italian prison and compare it with the prevalence observed in a sample randomized from the community (n=300) within the same age interval (18-55 years) and sex proportion of prisoners, and with a similar socio-economic status. Psychiatric disorders were identified with the Mini International Neuropsychiatric Interview (MINI). Current psychiatric disorders were present in 58.7% of prisoners and 8.7% of the comparison group. Lifetime psychiatric disorders were present in 88.7% of prisoners and 15.7% of the comparison group. Current anxiety disorders and current stress-related disorders were related to prisoners serving their first-ever prison sentence. A variable fraction of prisoners with an ongoing psychopathology is not diagnosed or does not receive proper treatment. The provision of effective treatment to prisoners with psychiatric disorders might have potentially substantial public health benefits. PMID- 25534758 TI - Mixed-footedness is a more relevant predictor of schizotypy than mixed handedness. AB - Mixed-handedness was reported indicative of schizotypy, relevant to psychosis and schizophrenia. However, studies suffered from validity threats and did not systematically investigate associations with footedness. Moreover, there is a dearth of studies in the general population and it is currently untested whether widely used self-report scales measure schizotypy in a comparable way in student and community samples. The present study used two large and independent community and student samples (total N>2800) and utilized latent class analysis (LCA) for the classification of handedness and footedness. Psychometric properties and measurement equivalence of the Schizotypal Personality Questionnaire-Brief form (SPQ-B) in the two samples were also examined. We found that mixed-handedness (<6% prevalence), but also much more common mixed-footedness (25% prevalence), was specifically and similarly associated with higher schizotypy in both samples, Cohen d=0.15-0.18. Findings indicate that schizotypal traits in conjunction with mixed lateral preferences are thus more prevalent in the overall population than previously assumed, and that footedness may be the more relevant predictor of schizotypy than handedness. Findings are further consistent with evidence on neurodevelopmental instability, but also epigenetic mechanisms involving the sex chromosomes, regarding possible common causes of both mixed-handedness and psychosis-relevant traits. PMID- 25534757 TI - Verbal versus physical aggression in Intermittent Explosive Disorder. AB - Intermittent Explosive Disorder (IED) is the only adult psychiatric diagnosis for which pathological aggression is primary. DSM-IV criteria focused on physical aggression, but Diagnostic and Statistical Manual of Mental Disorders (DSM-5) allows for an IED diagnosis in the presence of frequent verbal aggression with or without concurrent physical aggression. It remains unclear how individuals with verbal aggression differ from those with physical aggression with respect to cognitive-affective deficits and psychosocial functioning. The current study compared individuals who met IED criteria with either frequent verbal aggression without physical aggression (IED-V), physical aggression without frequent verbal aggression (IED-P), or both frequent verbal aggression and physical aggression (IED-B) as well as a non-aggressive personality-disordered (PD) comparison group using behavioral and self-report measures of aggression, anger, impulsivity, and affective lability, and psychosocial impairment. Results indicate all IED groups showed increased anger/aggression, psychosocial impairment, and affective lability relative to the PD group. The IED-B group showed greater trait anger, anger dyscontrol, and aggression compared to the IED-V and IED-P groups. Overall, the IED-V and IED-P groups reported comparable deficits and impairment. These results support the inclusion of verbal aggression within the IED criteria and suggest a more severe profile for individuals who engage in both frequent verbal arguments and repeated physical aggression. PMID- 25534755 TI - A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity? AB - BACKGROUND: Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. METHODS: Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. RESULTS: Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. CONCLUSIONS: In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD. PMID- 25534759 TI - "Air" in the aortic arch after cannulation for cardiopulmonary bypass: devastating complication or benign explanation? PMID- 25534760 TI - "Unicuspid" aortic valve bioprosthesis: a complication of surgery for a left hip Morel-Lavallee lesion? PMID- 25534761 TI - The pulsatile perfusion debate in cardiac surgery: answers from the microcirculation? PMID- 25534762 TI - Minority Parents' Perspectives on Racial Socialization and School Readiness in the Early Childhood Period. AB - OBJECTIVE: To describe how minority parents help their young children navigate issues of race and racism and discuss implications this racial socialization may have for school readiness. METHODS: Sixteen focus groups were conducted among 114 African American, English language-primary Latino, Spanish language-primary Latino, and Korean language-primary Korean parents of children ages 0 to 4 years old. Transcripts were coded for major themes and subsequently compared across the 4 language-ethnicity groups. Parents also shared demographic and parenting data by survey, from which group-specific proportions provide context for identified themes. RESULTS: In this sample, nearly half of surveyed parents had already talked to their young child about unfair treatment due to race. The proportion of such conversations ranged from one-fifth of Korean parents to two-thirds of Spanish language-primary parents. In focus groups, Korean parents reported fewer experiences with racism than African American and Latino parents. Within each language-ethnicity group, fewer fathers than mothers reported addressing race issues with their young children. All focus groups endorsed messages of cultural pride, preparation for bias, and a strong focus on the individual. The majority of parents viewed racial socialization as an important part of school readiness. CONCLUSIONS: Racial socialization was believed to be salient for school readiness, primarily practiced by mothers, and focused at the individual level. The smaller role of fathers and systems-based approaches represent opportunities for intervention. These results may inform the development of culturally tailored parenting interventions designed to decrease the race-based achievement gap and associated health disparities. PMID- 25534763 TI - Hierarchical porous plasmonic metamaterials for reproducible ultrasensitive surface-enhanced Raman spectroscopy. AB - Hierarchical porous plasmonic metamaterials consisting of periodic nanoholes with tunable diameter and uniformly distributed mesopores over the bulk are developed as a new class of 3D surface-enhanced Raman spectroscopy (SERS) substrates. This multiscale architecture not only facilitates efficient cascaded electromagnetic enhancement but also provides an enormous number of Raman-active binding sites, exhibiting excellent reproducibility and ultrasensitive detection of aromatic molecules down to 10(-13) M. PMID- 25534764 TI - Effect of body mass index <20 kg/m(2) on events in patients who underwent transcatheter aortic valve replacement. AB - The Valve Academic Research Consortium-2 has defined body mass index (BMI) <20 as indicative of frailty, which may be one of the co-morbidities not captured by traditional risk factors after transcatheter aortic valve replacement (TAVR). This study aimed to assess the impact of low BMI on clinical outcomes after TAVR. A total of 777 consecutive patients scheduled for TAVR were classified into 3 groups as BMI <20 (n = 56), 20 to 24.9 (n = 322), and >=25 (n = 399). Procedural complications and clinical outcomes were compared among the 3 groups. They were also analyzed according to propensity-matching model A (BMI <20 [n = 50] vs >=20 [n = 50]), model B (BMI <20 [n = 50] vs 20 to 24.9 [n = 50]), and model C (BMI <20 [n = 47] vs >=25 [n = 47]). The differences in baseline characteristics among the 3 groups were adequately adjusted in 3 matched models. Valve Academic Research Consortium-2-defined end points and other complications were similar among the 3 groups in each model. Kaplan-Meier curves indicated no significant differences in cumulative 30-day survival (BMI <20 [91.0%] vs 20 to 24.9 [86.3%], p = 0.33; BMI <20 [91.0%] vs >=25 [91.4%], p = 0.91, respectively) and 1-year survival (BMI <20 [74.3%] vs 20 to 24.9 [71.8%], p = 0.71; BMI <20 [74.3%] vs >=25 [77.0%], p = 0.71; respectively). These survival rates were also similar in each of the 3 matched models. In conclusion, BMI <20 was not associated with increased early or midterm mortality. BMI <20 alone may not constitute an additional co-morbidity factor in patients who underwent TAVR. PMID- 25534765 TI - Impact of liver disease after the fontan operation. AB - Liver disease is being reported with increased frequency in survivors of the Fontan operation. The clinical impact of structural hepatic abnormalities in these patients remains largely unknown. We sought to assess if, and how, cardiologists are screening for hepatic disease in these patients to evaluate for clinical or laboratory correlates of structural hepatic disease and determine the prevalence and clinical impact of such disease. Retrospective data analysis from tertiary institutions was performed. Hepatic imaging studies and serology performed over the last decade were reviewed and clinical and laboratory correlates of structural hepatic alterations on liver imaging or biopsy were sought. Outcomes were determined. In this cohort study, 53 of 60 adult survivors (88%) underwent hepatic imaging with computed tomography, magnetic resonance imaging, or ultrasound with a median number of 2 (0 to 10) studies over the past decade. The frequency of hepatic imaging varied widely with 70% of patients undergoing serial studies. Cirrhosis with or without abnormal hepatic nodules was seen in 29 of 53 patients (55%) at 18.4 +/- 5.6 years after the Fontan procedure. Adverse hepatic-related outcome occurred in 22% of the entire patient cohort and was unrelated to time from Fontan operation. In conclusion, there exists significant variability in the type and timing of testing for hepatic complications after the Fontan procedure. Structural hepatic alterations are common and can be associated with significant morbidity and mortality. Routine imaging, and serologic evaluation, is recommended in all Fontan survivors. PMID- 25534766 TI - Comparative genomic analysis of Acinetobacter baumannii clinical isolates reveals extensive genomic variation and diverse antibiotic resistance determinants. AB - BACKGROUND: Acinetobacter baumannii is an important nosocomial pathogen that poses a serious health threat to immune-compromised patients. Due to its rapid ability to develop multidrug resistance (MDR), A. baumannii has increasingly become a focus of attention worldwide. To better understand the genetic variation and antibiotic resistance mechanisms of this bacterium at the genomic level, we reported high-quality draft genome sequences of 8 clinical isolates with various sequence types and drug susceptibility profiles. RESULTS: We sequenced 7 MDR and 1 drug-sensitive clinical A. baumannii isolates and performed comparative genomic analysis of these draft genomes with 16 A. baumannii complete genomes from GenBank. We found a high degree of variation in A. baumannii, including single nucleotide polymorphisms (SNPs) and large DNA fragment variations in the AbaR like resistance island (RI) regions, the prophage and the type VI secretion system (T6SS). In addition, we found several new AbaR-like RI regions with highly variable structures in our MDR strains. Interestingly, we found a novel genomic island (designated as GIBJ4) in the drug-sensitive strain BJ4 carrying metal resistance genes instead of antibiotic resistance genes inserted into the position where AbaR-like RIs commonly reside in other A. baumannii strains. Furthermore, we showed that diverse antibiotic resistance determinants are present outside the RIs in A. baumannii, including antibiotic resistance-gene bearing integrons, the blaOXA-23-containing transposon Tn2009, and chromosomal intrinsic antibiotic resistance genes. CONCLUSIONS: Our comparative genomic analysis revealed that extensive genomic variation exists in the A. baumannii genome. Transposons, genomic islands and point mutations are the main contributors to the plasticity of the A. baumannii genome and play critical roles in facilitating the development of antibiotic resistance in the clinical isolates. PMID- 25534768 TI - Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. AB - We quantified, by liquid chromatography tandem mass spectrometry, transporter protein expression of BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1 in our human liver bank (n = 55) and determined the relationship between protein expression and sex, age and genotype. These data complement our previous work in the same liver bank where we quantified the protein expression of OATPs, BCRP, MDR1, and MRP2. In addition, we quantified and compared the interspecies differences in expression of the hepatobiliary transporters, corresponding to the above human transporters, in liver tissue and hepatocytes of male beagle dogs, cynomolgus monkeys, Sprague Dawley rats, and Wistar rats. In all the species, the sinusoidal OATPs/Oatps were the most abundant hepatic transporters. However, there were notable interspecies differences in the relative abundance of the remaining transporters. For example, the next most abundant transporter in humans and monkeys was OCT1/Oct1, whereas it was Mrp2 and Ntcp in dogs/Wistar rats and Sprague-Dawley rats, respectively. In contrast, the protein expression of the efflux transporters BCRP/Bcrp, MDR1/Mdr1, MRP3/Mrp3, MRP4/Mrp4, and MATE1/Mate1 was much lower across all the species. For most transporters, the expression in the liver tissues was comparable to that in the unplated cryopreserved hepatocytes. These data on human liver transporter protein expression complete the picture of the expression of major human hepatobiliary transporters important in drug disposition and toxicity. In addition, the data on expression of the corresponding hepatobiliary transporters in preclinical species will be helpful in interpreting and extrapolating pharmacokinetic, pharmacological, and toxicological results from preclinical studies to humans. PMID- 25534767 TI - Legionella pneumophila utilizes a single-player disulfide-bond oxidoreductase system to manage disulfide bond formation and isomerization. AB - Legionella pneumophila uses a single homodimeric disulfide bond (DSB) oxidoreductase DsbA2 to catalyze extracytoplasmic protein folding and to correct DSB errors through protein-disulfide isomerase (PDI) activity. In Escherichia coli, these functions are separated to avoid futile cycling. In L. pneumophila, DsbA2 is maintained as a mixture of disulfides (S-S) and free thiols (SH), but when expressed in E. coli, only the SH form is observed. We provide evidence to suggest that structural differences in DsbB oxidases (LpDsbB1 and LpDsbB2) and DsbD reductases (LpDsbD1 and LpDsbD2) (compared with E. coli) permit bifunctional activities without creating a futile cycle. LpdsbB1 and LpdsbB2 partially complemented an EcdsbB mutant while neither LpdsbD1 nor LpdsbD2 complemented an EcdsbD mutant unless DsbA2 was also expressed. When the dsb genes of E. coli were replaced with those of L. pneumophila, motility was restored and DsbA2 was present as a mixture of redox forms. A dominant-negative approach to interfere with DsbA2 function in L. pneumophila determined that DSB oxidase activity was necessary for intracellular multiplication and assembly/function of the Dot/Icm Type IVb secretion system. Our studies show that a single-player system may escape the futile cycle trap by limiting transfer of reducing equivalents from LpDsbDs to DsbA2. PMID- 25534769 TI - Therapeutic efficacy of Wuzhi tablet (Schisandra sphenanthera Extract) on acetaminophen-induced hepatotoxicity through a mechanism distinct from N acetylcysteine. AB - Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury. PMID- 25534770 TI - The allosteric binding sites of sulfotransferase 1A1. AB - Human sulfotransferases (SULTs) comprise a small, 13-member enzyme family that regulates the activities of thousands of compounds-endogenous metabolites, drugs, and other xenobiotics. SULTs transfer the sulfuryl-moiety (-SO3) from a nucleotide donor, PAPS (3'-phosphoadenosine 5'-phosphosulfate), to the hydroxyls and primary amines of acceptors. SULT1A1, a progenitor of the family, has evolved to sulfonate compounds that are remarkably structurally diverse. SULT1A1, which is found in many tissues, is the predominant SULT in liver, where it is a major component of phase II metabolism. Early work demonstrated that catechins and nonsteroidal anti-inflammatory drugs inhibit SULT1A1 and suggested that the inhibition was not competitive versus substrates. Here, the mechanism of inhibition of a single, high affinity representative from each class [epigallocatechin gallate (EGCG) and mefenamic acid] is determined using initial rate and equilibrium-binding studies. The findings reveal that the inhibitors bind at sites separate from those of substrates, and at saturation turnover of the enzyme is reduced to a nonzero value. Further, the EGCG inhibition patterns suggest a molecular explanation for its isozyme specificity. Remarkably, the inhibitors bind at sites that are separate from one another, and binding at one site does not affect affinity at the other. For the first time, it is clear that SULT1A1 is allosterically regulated, and that it contains at least two, functionally distinct allosteric sites, each of which responds to a different class of compounds. PMID- 25534771 TI - Birth weight and childhood wheezing disorders: a systematic review and meta analysis. AB - BACKGROUND: Previous observational studies have claimed that birth weight and childhood wheezing disorders are associated although the results remained inconsistent. One systematic review and two systematic reviews that included meta analyses reported inconsistent results. We aimed to conduct a systematic review and meta-analysis to investigate this. METHODS: An online search of published papers linking childhood asthma and wheezing disorders with birth weight up to February 2014 was carried out using EMBASE and Medline medical research databases. Summary ORs were estimated using random-effects models. Subgroup meta analyses were performed to assess the robustness of risk associations and between study heterogeneity. RESULTS: A total of 37 studies comprising 1,71, 737 participants were included in our meta-analysis. The unadjusted summary ORs for risk of childhood wheezing disorders associated with low birth weight (<2.5 kg) were 1.60 (95% CI 1.39 to 1.85, p<0.001) and 1.37 (95% CI 1.05 to 1.79, p=0.02) when compared with >=2.5 and 2.5-4.0 kg birthweight groups, respectively. The overall summary OR for high birth weight (>4 kg) as compared to the 2.5-4.0 kg birthweight group was 1.02 (95% CI 0.99 to 1.04, p=0.13). There was substantial heterogeneity in the unadjusted low birth weight risk estimates which was not accounted for by predefined study characteristics. There was no significant heterogeneity in the high birth weight risk estimates. There was some evidence of funnel plot asymmetry and small study effects in the low birth weight (2.5 vs >=2.5 kg and <2.5 vs 2.5-4 kg) OR estimates. CONCLUSIONS: Our results suggest that low birth (<2.5 kg) is an independent risk factor for wheezing disorders during childhood and adolescence although there was substantial heterogeneity among the risk estimates. However, we found no significant association of high birth weight with wheezing disorders. PMID- 25534772 TI - One-pot synthesis of core-shell Cu@SiO2 nanospheres and their catalysis for hydrolytic dehydrogenation of ammonia borane and hydrazine borane. AB - Ultrafine copper nanoparticles (Cu NPs) within porous silica nanospheres (Cu@SiO2) were prepared via a simple one-pot synthetic route in a reverse micelle system and characterized by SEM, TEM, EDX, XRD, N2 adsorption-desorption, CO-TPD, XPS, and ICP methods. The characterized results show that ultrafine Cu NPs with diameter of around 2 nm are effectively embedded in the center of well proportioned spherical SiO2 NPs of about 25 nm in diameter. Compared to commercial SiO2 supported Cu NPs, SiO2 nanospheres supported Cu NPs, and free Cu NPs, the synthesized core-shell nanospheres Cu@SiO2 exhibit a superior catalytic activity for the hydrolytic dehydrogenation of ammonia borane (AB, NH3BH3) and hydrazine borane (HB, N2H4BH3) under ambient atmosphere at room temperature. The turnover frequencies (TOF) for the hydrolysis of AB and HB in the presence of Cu@SiO2 nanospheres were measured to be 3.24 and 7.58 mol H2 (mol Cu min)(-1), respectively, relatively high values for Cu nanocatalysts in the same reaction. In addition, the recycle tests show that the Cu@SiO2 nanospheres are still highly active in the hydrolysis of AB and HB, preserving 90 and 85% of their initial catalytic activity even after ten recycles, respectively. PMID- 25534773 TI - Determinants of nursing competence of nursing students in Taiwan: the role of self-reflection and insight. AB - BACKGROUND: A nursing practicum course is critical to strengthening the nursing competence of nursing students. Research has found that practice stress and coping behaviors can have either a negative or positive influence on the learning and practice performance of nursing students. Nevertheless, there are few evidence-based studies related to the relationship between self-reflection and insight and nursing competence in Taiwanese nursing students. OBJECTIVE: To test the determinants and the effect of self-reflection and insight on nursing competence in nursing students during the first 2 months of their practice experience. DESIGN: Cross-sectional and correlational research designs were employed. METHODS: From September to November 2013, a total of 312 nursing students at a junior college in southern Taiwan served as participants in this study. Four questionnaires were used to collect data: Self-reflection and Insight Scale (SRIS), Perceived Stress Scale (PSS), Coping Behavior Inventory (CBI), and Holistic Nursing Competence Scale (HNCS). The research model was evaluated through structural equation modeling (SEM), with the use of the partial least squares (PLS) method. RESULTS: Results indicated that self-reflection and insight, practice stress, and practice coping behavior were statistically significantly associated with nursing competence. In addition, self-reflection and insight were significantly and positively associated with practice coping behavior and negatively associated with practice stress. Students' coping behavior partially mediates the effect of self-reflection and stress on nursing competence. Overall, these variables explained 39.4% of the variance in these students' nursing competence. CONCLUSION: Self-reflection and insight affected nursing competence during the practice period. These variables have not only had a direct influence on nursing competence but also an indirect effect through the mediating effect of coping behavior and stress. PMID- 25534774 TI - 'Doing the writing' and 'working in parallel': how 'distal nursing' affects delegation and supervision in the emerging role of the newly qualified nurse. AB - BACKGROUND: The role of the acute hospital nurse has moved away from the direct delivery of patient care and more towards the management of the delivery of bedside care by healthcare assistants. How newly qualified nurses delegate to and supervise healthcare assistants is important as failures can lead to care being missed, duplicated and/or incorrectly performed. OBJECTIVES: The data described here form part of a wider study which explored how newly qualified nurses recontextualise knowledge into practice, and develop and apply effective delegation and supervision skills. This article analyses team working between newly qualified nurses and healthcare assistants, and nurses' balancing of administrative tasks with bedside care. METHODS AND ANALYSIS: Ethnographic case studies were undertaken in three hospital sites in England, using a mixed methods approach involving: participant observations; interviews with 33 newly qualified nurses, 10 healthcare assistants and 12 ward managers. Data were analysed using thematic analysis, aided by the qualitative software NVivo. FINDINGS: Multiple demands upon the newly qualified nurses' time, particularly the pressures to maintain records, can influence how effectively they delegate to, and supervise, healthcare assistants. While some nurses and healthcare assistants work successfully together, others work 'in parallel' rather than as an efficient team. CONCLUSIONS: While some ward cultures and individual working styles promote effective team working, others lead to less efficient collaboration between newly qualified nurses and healthcare assistants. In particular the need for qualified nurses to maintain records can create a gap between them, and between nurses and patients. Newly qualified nurses require more assistance in managing their own time and developing successful working relationships with healthcare assistants. PMID- 25534775 TI - Using ultrashort optical pulses to couple ferroelectric and ferromagnetic order in an oxide heterostructure. AB - A new approach to all-optical detection and control of the coupling between electric and magnetic order on ultrafast timescales is achieved using time resolved second-harmonic generation (SHG) to study a ferroelectric (FE)/ferromagnet (FM) oxide heterostructure. We use femtosecond optical pulses to modify the spin alignment in a Ba(0.1)Sr(0.9)TiO3 (BSTO)/La(0.7)Ca(0.3)MnO3 (LCMO) heterostructure and selectively probe the ferroelectric response using SHG. In this heterostructure, the pump pulses photoexcite non-equilibrium quasiparticles in LCMO, which rapidly interact with phonons before undergoing spin-lattice relaxation on a timescale of tens of picoseconds. This reduces the spin-spin correlations in LCMO, applying stress on BSTO through magnetostriction. This then modifies the FE polarization through the piezoelectric effect, on a timescale much faster than laser-induced heat diffusion from LCMO to BSTO. We have thus demonstrated an ultrafast indirect magnetoelectric effect in a FE/FM heterostructure mediated through elastic coupling, with a timescale primarily governed by spin-lattice relaxation in the FM layer. PMID- 25534776 TI - Use of Lactobacillus casei rhamnosus to Prevent Cholangitis in Biliary Atresia After Kasai Operation. AB - OBJECTIVES: Recurrent cholangitis may aggravate cholestatic liver cirrhosis in biliary atresia (BA) after the Kasai operation. This pilot study aimed to investigate whether Lactobacillus casei rhamnosus has the prophylactic efficacy for recurrent cholangitis in comparison with the conventional neomycin prophylaxis. METHODS: Twenty jaundice-free patients with BA ages 0 to 3 years who underwent a Kasai operation were enrolled and randomized into 2 groups with 10 patients each: neomycin (25 mg . kg . day for 4 days/wk) and L casei rhamnosus (8 * 10 colony-forming unit per day) groups. The treatment duration was 6 months. Bacterial stool cultures were performed before treatment and 1, 3, and 6 months after starting treatment. In addition, 10 patients with BA with similar status but without prophylaxis served as the historical control group. RESULTS: In the Lactobacillus group, 2 patients (20%, mean 0.03 +/- 0.07 episodes per month) developed cholangitis during the study period, with the same frequency as in the neomycin group and significantly lower than that in the control group (80%, P = 0.005, mean 0.22 +/- 0.16 episodes per month). The mean change in body weight z score during the 6 months in the Lactobacillus group was 0.97 +/- 0.59, which was significantly better than that in the control group (-0.01 +/- 0.79, P = 0.006). In bacterial stool cultures, the Lactobacillus and Escherichia coli populations significantly increased and decreased, respectively, in the Lactobacillus group. CONCLUSIONS: The use of L casei rhamnosus was as effective as neomycin in preventing cholangitis in patients with BA who underwent Kasai operation, and therefore could be considered as a potential alternative prophylactic regimen. PMID- 25534777 TI - Multidisciplinary intervention for childhood feeding difficulties. AB - OBJECTIVE: The aim of the study was to determine whether operant conditioning (OC) or systematic desensitization (SysD) intervention resulted in more improvements in dietary variety/intake, and more reductions in difficult mealtime behaviors. METHODS: Children 2 to 6 years with autism spectrum disorder or with a nonmedically complex history were recruited. Feeding difficulties were confirmed based on clinical assessment. Participants were randomized to receive 10 OC or SysD sessions (parents could opt for intervention once per week, or intensively within a week). Immersive parent education was delivered across both arms. A 3 month review was provided to measure outcomes postintervention. RESULTS: In total, 68 participants (87%) completed the study. There were no significant differences in outcome measures between the OC and SysD intervention groups from baseline to 3-month review. When the data were combined across both groups, however, significant improvements in primary outcome measures were observed (P < 0.05). Although not statistically significant, it was considered clinically significant that participants in the OC arm demonstrated more increases in dietary variety (mean difference 3.3 foods, 95% confidence interval -0.1 to 6.8, P = 0.06) compared with the SysD arm. There were limited differences in response observed between the autism spectrum disorder and nonmedically complex history groups, and the intensive and weekly arms. CONCLUSIONS: Favorable results were observed regardless of intervention, intensity, or etiological group. Results suggest that, when delivered to a protocol by experienced therapists and coupled with parent education, these 2 intervention approaches are effective. Further research is required in exploring these interventions across other subgroups, and examining outcomes for longer periods. PMID- 25534778 TI - Discriminative identification of miRNA let-7 family members with high specificity and sensitivity using rolling circle amplification. AB - Rolling circle amplification (RCA) is a new method based on virus DNA reproduction, which has been widely used in the field of miRNA detection. However, discrimination of highly homologous miRNAs is a bottleneck in the research of miRNA. In this study, the RCA process was creatively used to conduct the discrimination of miRNAs. Results showed that T4 RNA ligase 2 could reach the highest circularization efficiency during the RCA process with higher specificity. By using RCA technology, a member of highly homologous miRNAs, let 7, could be discriminated at the amount of 2.5 fmol. This sensitivity could not be achieved by using traditional reverse transcription quantitative polymerase chain reaction (RT-qPCR) method. In addition, detection of miRNAs by using RCA could reach the amount limit of fmol with a good linearity. Optimal RCA technology used in this study is better than RT-qPCR in discriminating highly homologous family miRNAs. Results from this study can promote the applications of RCA in clinical diagnosis, environment protection, health care, disease inspection and prevention, and national security. PMID- 25534779 TI - Single amino acid mutation alters thermostability of the alkaline protease from Bacillus pumilus: thermodynamics and temperature dependence. AB - Dehairing alkaline protease (DHAP) from Bacillus pumilus BA06 has been demonstrated to have high catalytic efficiency and good thermostability, with potential application in leather processing. In order to get insights into its catalytic mechanism, two mutants with single amino acid substitution according to the homology modeling and multiple sequence alignment were characterized in thermodynamics of thermal denaturation and temperature dependence of substrate hydrolysis. The results showed that both mutants of V149I and R249E have a systematic increase in catalytic efficiency (kcat/Km) in a wide range of temperatures, mainly due to an increase of k1 (substrate diffusion) and k2 (acylation) for V149I and of k2 and k3 (deacylation) for R249E. In comparison with the wild-type DHAP, the thermostability is increased for V149I and decreased for R249E. Thermodynamic analysis indicated that the free energy (DeltaGa degrees ) of activation for thermal denaturation may govern the thermostability. The value of DeltaGa degrees is increased for V149I and decreased for R249E. Based on these data and the structural modeling, it is suggested that substitution of Val149 with Ile may disturb the local flexibility in the substrate-binding pocket, leading to enhancement of binding affinity for the substrate. In contrast, substitution of Arg249 with Glu leads to interruption of interaction with the C-terminal of enzyme, thus resulting in less thermostability. This study indicates that amino acid residues in the active center or in the substrate binding pocket may disturb the catalytic process and can be selected as the target for protein engineering in the bacterial alkaline proteases. PMID- 25534780 TI - Proteomic analysis of silkworm midgut cellular proteins interacting with the 5' end of infectious flacherie virus genomic RNA. AB - The flacherie disease in the silkworm is caused by the infectious flacherie virus (IFV). IFV relies on its 5' region of genomic RNA to recruit host-related factors to implement viral translation and replication. To identify host proteins bound to the 5'-region of IFV RNA and identify proteins important for its function, mass spectrometry was used to identify proteins from silkworm midgut extracts that were obtained using RNA aptamer-labeled 5' region of IFV RNA. We found 325 protein groups (unique peptide>=2) bound to the 5' region of IFV RNA including translation-related factors (16 ribosomal subunits, 3 eukaryotic initiation factor subunits, 1 elongation factor subunit and 6 potential internal ribosome entry site trans-acting factors), cytoskeleton-related proteins, membrane-related proteins, metabolism enzymes, and other proteins. These results can be used to study the translation and replication related factors of IFV interacting with host silkworm and to control flacherie disease in silkworm. PMID- 25534781 TI - Effect of an Integrated Health Management Program Based on Successful Aging in Korean Women. AB - OBJECTIVES: This study evaluates the efficacy of an integrated health management program (IHMP) based on successful aging in older women. DESIGN AND SAMPLE: A single group pretest and posttest research design was employed, with a sample of 33 older Korean women over 60 years registered in a public health center. The intervention, including exercise, health education, and social activities, was performed 3 hr per week for 12 weeks. MEASURES: Demographic characteristics, body composition, physical fitness, biomarkers, depression, and social support were measured. Data were analyzed with a Wilcoxon signed-rank test, statistical significance levels were set at p < .05. RESULTS: After the intervention, body mass index was significantly decreased (p = .003) and skeletal muscle mass was significantly increased (p = .002). Chair stand (p = .023) and straight walking test (p < .001) were significantly improved. Systolic blood pressure (p < .003), diastolic blood pressure (p = .030), and blood cholesterol (p = .011) were significantly decreased. Depression (p = .043) was significantly decreased, and social support (p < .001) was significantly increased. CONCLUSIONS: Adopting and maintaining an IHMP can be useful to promote physical, psychological, and social functioning that lead to successful aging in older Korean women. PMID- 25534782 TI - Insight into inhibition of the human amyloid beta protein precursor (APP: PDB ID ) using (E)-N-(pyridin-2-ylmethylene)arylamine (LR) models: structure elucidation of a family of ZnX2-LR complexes. AB - The amyloid beta precursor protein (APP) and its neurotoxic cleavage product amyloid beta (Abeta) are a cause of Alzheimer's disease and appear essential for neuronal development and cell homeostasis. Proteolytic processing of APP is influenced by metal ions and protein ligands, however the structural and functional mechanism of APP regulation is not known so far. In this context, molecular modeling studies were performed to understand the molecular behavior of (E)-N-(pyridin-2-ylmethylene)arylamines (LR) with an E2 domain of the APP in its complex with zinc (APP; PDB ID: ). Docking results indeed confirmed that the LR interacts with Zn in the binding site of the protein between two alpha-helical chains. In view of these findings, LR was further investigated for complexation reactions with Zn(2+) in order to establish the structural models in solution and in the solid state. Five new Zn(2+) complexes of compositions viz. [Zn(Br)2(L2 Me)] (), [Zn(Br)2(L2-OMe)] (), [Zn(i)2(L2-OMe)] (), [Zn(NO3)2(L2-OMe)(H2O)] () and [Zn(L4-Me)2(H2O)2](NO3)2 () were synthesized and their structures were ascertained by microanalysis, IR and (1)H NMR spectroscopy, and single-crystal X ray diffraction. The zinc atom in complex exhibits a distorted tetrahedral geometry while the crystal structures of complexes and show distorted square pyramidal geometries. The zinc cation in and has an octahedral coordination environment, but in the zinc coordination geometry is less distorted. The Zn(ii) cations take part in one ( and ) or two () 5-membered metallacycles imposed by the NN or NNO chelation modes of LR. The significant intermolecular pipi interactions are also discussed. PMID- 25534783 TI - Sense and nonsense of miniaturized LC-MS/MS for bioanalysis. PMID- 25534784 TI - What is the potential of measuring the enantiomeric ratio of drugs using supercritical fluid chromatography-MS? PMID- 25534785 TI - The use of a rapid MS-based method for the quantification of the CYP 3A4 protein directly from hepatocyte cell lysate for CYP induction studies. AB - BACKGROUND: Most P450 protein quantitation methods involved the time-consuming preparation of microsomes and therefore are not amenable for high-throughput analysis. We here report a new method to measure P450 CYP3A4 protein levels directly from cell lysates. RESULTS: A direct sample preparation method from hepatocyte cell lysate has been developed for the quantification of CYP3A4 protein levels by combining a modified semi-automated precipitation with a filter aided sample preparation. This novel LC-MS/MS-based method provides simple, subfemtomole sensitivity and rapid quantitation of CYP3A4 protein levels directly from hepatocyte lysate without the need for microsome preparation. CONCLUSION: A rapid, accurate and sensitive method has been developed and implemented to quantify CYP3A4 protein in hepatocytes down to 0.05 million cells in CYP induction studies. The number of cells required for quantitation was well below the typical 0.25 million cells used in a CYP induction study. PMID- 25534787 TI - Development of a high-throughput UHPLC-MS/MS (SRM) method for the quantitation of endogenous glucagon from human plasma. AB - BACKGROUND: Published LC-MS/MS methods are not sensitive enough to quantify endogenous levels of glucagon. RESULTS: An ultra high performance liquid chromatography-MS/MS (SRM) method for the quantitation of endogenous levels glucagon was successfully developed and qualified. A novel 2D extraction procedure was used to reduce matrix suppression, background noise and interferences. Glucagon levels in samples from healthy volunteers were found to agree with radioimmunoassay (RIA) derived literature values. Bland-Altman analysis showed a concentration-dependent positive bias of the LC/MS-MS assay versus an RIA. Both assays produced similar pharmacokinetic profiles, both of which were feasible considering the nature of the study. CONCLUSION: Our method is the first peer reviewed LC-MS/MS method for the quantitation of endogenous levels of glucagon, and offers a viable alternative to RIA-based approaches. PMID- 25534786 TI - Novel sandwich immunoassays for the measurement of total and active FGF21. AB - BACKGROUND: FGF21 is involved in glucose and lipid metabolism. Our objective was to develop two novel sandwich immunoassays that measure active and total levels of FGF21 in human plasma. RESULTS: Both immunoassays utilized affinity-optimized monoclonal antibodies generated specifically for either the mid-domain or the intact C-terminus of the respective FGF21 peptides. Total FGF21 levels measured from normal human plasma samples ranged from 42 to 462 pg/ml, while active FGF21 levels ranged from 11 to 399 pg/ml. The data also suggested no significant differences in the concentrations of active FGF21 when measured from pre- and post-prandial samples. CONCLUSION: We have successfully developed sensitive assays to measure active and total FGF21, which show the majority of total FGF21 in plasma is active FGF21. PMID- 25534788 TI - Direct comparison of radioimmunoassay and LC-MS/MS for PK assessment of insulin glargine in clinical development. AB - BACKGROUND: A direct comparison of radioimmunoassay (RIA) and LC-MS/MS for insulin glargine quantification in human plasma is provided. RESULTS: Compared with the RIA, the LC-MS/MS assay exhibited comparable/improved sensitivity (LLOQ at 0.1 ng/ml [~16.7 pM or 2.8 MUU/ml] for glargine and its metabolites M1 and M2, respectively) and ruggedness. Most importantly, it demonstrated a superior specificity advantage against the interference from endogenous insulin, exogenous insulin analogs (e.g., Novolog((r)), Humalog((r)) or Levemir((r)), routine treatment for diabetes mellitus) and potentially pre-existing anti-insulin antibodies in patient samples. The data obtained from diabetic patients suggested the LC-MS/MS assay substantially improved pharmacokinetic characterization of glargine. CONCLUSION: LC-MS/MS overcame common limitations of RIA, and provided critically needed specificity to support glargine clinical development, without sacrificing assay sensitivity and ruggedness. PMID- 25534789 TI - Surface plasmon resonance: advances of label-free approaches in the analysis of biological samples. AB - Surface plasmon resonance sensors have made vast advancements in the sensing technology and the number of applications achievable. New developments in surface plasmon resonance sensors have gained considerable momentum promoted by the urgent needs of fast, reliable and label-free methods for detection and quantification of analytes in molecular biology, medicine and other life sciences. However, even if enormous improvements in the limits of detections have been achieved, this technology still faces important challenges to be translated to clinical practice or in-field measurements. This paper reviews the important recent advances of this technology for the label-free detection in real biological samples and we discussed the key challenges to be overcome to transit from prototypes to commercial biosensors. PMID- 25534790 TI - Introduction of a routine quan/qual approach into research DMPK: experiences and evolving strategies. AB - After graduating with an Oceanography degree from Swansea University, Lloyd has spent over 20 years in the field of bioanalysis and metabolite profiling. He started his career in large pharma at Wyeth UK, where he was involved in setting up the first GC and LC-MS/MS systems for both QC and early DMPK assays, employing EI/CI, thermospray, and the then new electrospray ionization techniques. Lloyd then joined Celltech, now UCB, where he is primarily tasked with metabolite profiling by LC-MS and NMR to support both early research projects and late-stage clinical studies. The application of liquid chromatography high-resolution mass spectrometry for simultaneous quantitative and qualitative (quan/qual) analysis has gained momentum across a range of different scientific arenas in recent years. The ability to acquire high quality quantitative data, whilst also capturing qualitative data for either parallel or retrospective analysis, is a powerful resource, especially in view of ever-reducing cycle times, laboratory space and budgets. The quan/qual approach employing a Q-ExactiveTM Orbitrap high resolution mass spectrometer has been successfully introduced into UCB's research DMPK department. This article describes our experiences in introducing quan/qual, issues that we discovered in establishing this new working paradigm, the evolution of the strategy and its future potential. PMID- 25534791 TI - Incurred sample reanalysis in bioequivalence studies for abbreviated new drug applications. PMID- 25534793 TI - Recent advances in affinity capillary electrophoresis for binding studies. AB - The present review covers recent advances and important applications of affinity capillary electrophoresis (ACE). It provides an overview about various ACE types, including ACE-MS, the multiple injection mode, the use of microchips and field amplified sample injection-ACE. The most common scenarios of the studied affinity interactions are protein-drug, protein-metal ion, protein-protein, protein-DNA, protein-carbohydrate, carbohydrate-drug, peptide-peptide, DNA-drug and antigen antibody. Approaches for the improvements of ACE in term of precision, rinsing protocols and sensitivity are discussed. The combined use of computer simulation programs to support data evaluation is presented. In conclusion, the performance of ACE is compared with other techniques such as equilibrium dialysis, parallel artificial membrane permeability assay, high-performance affinity chromatography as well as surface plasmon resonance, ultraviolet, circular dichroism, nuclear magnetic resonance, Fourier transform infrared, fluorescence, MS and isothermal titration calorimetry. PMID- 25534792 TI - 2014 White Paper on recent issues in bioanalysis: a full immersion in bioanalysis (Part 3 - LBA and immunogenicity). AB - The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years' editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for Large molecules bioanalysis using LBA and Immunogenicity. Part 1 (Small molecules bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies' Input) were published in the Bioanalysis issues 6(22) and 6(23), respectively. PMID- 25534794 TI - Challenges of analyzing different classes of metabolites by a single analytical method. AB - Complex biological samples include thousands of metabolites that range widely in both physiochemical properties and concentration. Simultaneously analyzing metabolites with different properties using a single analytical method is very challenging. The analytical process for metabolites comprises multiple steps including sampling, quenching, sample preparation, separation and detection. Each step can have a significant effect on the reliability and precision of ultimate analytic results. The aim of review is a discussion of considerations and challenges for the simultaneous analysis of metabolites using LC- and GC-MS systems. The review discusses available methodology for each analytical step, and presents the limitations and advantages of each method for the large-scale targeted metabolomics analysis of human and animal biological samples. PMID- 25534795 TI - Affinity biosensors for tumor-marker analysis. AB - The use of cancer biomarkers is emerging as one of the most promising strategies for early detection and management of cancer. Biosensors can provide advanced platforms for biomarker analysis with the advantages of being easy to use, inexpensive, rapid and offering multi-analyte testing capability. The intention of this article is to discuss recent advances and trends in affinity biosensors for cancer diagnosis, prognosis and even theragnosis. The different types of affinity biosensors will be reviewed in terms of molecular recognition element. Current challenges and trends for this technology will be also discussed, with a particular emphasis on recent developments in miRNA detection. PMID- 25534806 TI - Antimicrobials: New tricks for old drugs. PMID- 25534807 TI - Microbiome: Gut bacteria cross malaria. PMID- 25534805 TI - Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors. AB - The innate immune system recognizes conserved microorganism-associated molecular patterns (MAMPs), some of which are sensed by G protein-coupled receptors (GPCRs), and this leads to chemotactic leukocyte influx. Recent studies have indicated that these processes are crucial for host defence and rely on a larger set of chemotactic MAMPs and corresponding GPCRs than was previously thought. Agonists, such as bacterial formyl peptides, enterococcal pheromone peptides, staphylococcal peptide toxins, bacterial fermentation products and the Helicobacter pylori peptide HP(2-20), stimulate specific GPCRs. The importance of leukocyte chemotaxis in host defence is highlighted by the fact that some bacterial pathogens produce chemotaxis inhibitors. How the various chemoattractants, receptors and antagonists shape antibacterial host defence represents an important topic for future research. PMID- 25534808 TI - Polintons: a hotbed of eukaryotic virus, transposon and plasmid evolution. AB - Polintons (also known as Mavericks) are large DNA transposons that are widespread in the genomes of eukaryotes. We have recently shown that Polintons encode virus capsid proteins, which suggests that these transposons might form virions, at least under some conditions. In this Opinion article, we delineate the evolutionary relationships among bacterial tectiviruses, Polintons, adenoviruses, virophages, large and giant DNA viruses of eukaryotes of the proposed order 'Megavirales', and linear mitochondrial and cytoplasmic plasmids. We hypothesize that Polintons were the first group of eukaryotic double-stranded DNA viruses to evolve from bacteriophages and that they gave rise to most large DNA viruses of eukaryotes and various other selfish genetic elements. PMID- 25534810 TI - Bacterial physiology: FtsZ and FtsA find the right place. PMID- 25534809 TI - Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? AB - The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER), which also invokes innate immune signalling in response to invading microorganisms. Although it has been known for some time that the UPR is modulated by various viruses, recent evidence indicates that it also has multiple roles during bacterial infections. In this Review, we describe how bacteria interact with the ER, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR contributes to innate immune responses against invading bacteria. PMID- 25534811 TI - What is a resistance gene? Ranking risk in resistomes. AB - Metagenomic studies have shown that antibiotic resistance genes are ubiquitous in the environment, which has led to the suggestion that there is a high risk that these genes will spread to bacteria that cause human infections. If this is true, estimating the real risk of dissemination of resistance genes from environmental reservoirs to human pathogens is therefore very difficult. In this Opinion article, we analyse the current definitions of antibiotic resistance and antibiotic resistance genes, and we describe the bottlenecks that affect the transfer of antibiotic resistance genes to human pathogens. We propose rules for estimating the risks associated with genes that are present in environmental resistomes by evaluating the likelihood of their introduction into human pathogens, and the consequences of such events for the treatment of infections. PMID- 25534813 TI - Deltamethrin-induced oxidative stress and mitochondrial caspase-dependent signaling pathways in murine splenocytes. AB - Deltamethrin (DLM) is a well-known pyrethroid insecticide used extensively in pest control. Exposure to DLM has been demonstrated to cause apoptosis in various cells. However, the immunotoxic effects of DLM on mammalian system and its mechanism is still an open question to be explored. To explore these effects, this study has been designed to first observe the interactions of DLM to immune cell receptors and its effects on the immune system. The docking score revealed that DLM has strong binding affinity toward the CD45 and CD28 receptors. In vitro study revealed that DLM induces apoptosis in murine splenocytes in a concentration-dependent manner. The earliest markers of apoptosis such as enhanced reactive oxygen species and caspase 3 activation are evident as early as 1 h by 25 and 50 uM DLM. Western blot analysis demonstrated that p38 MAP kinase and Bax expression is increased in a concentration-dependent manner, whereas Bcl 2 expression is significantly reduced after 3 h of DLM treatment. Glutathione depletion has been also observed at 3 and 6 h by 25 and 50 uM concentration of DLM. Flow cytometry results imply that the fraction of hypodiploid cells has gradually increased with all the concentrations of DLM at 18 h. N-acetyl cysteine effectively reduces the percentage of apoptotic cells, which is increased by DLM. In contrast, buthionine sulfoxamine causes an elevation in the percentage of apoptotic cells. Phenotyping data imply the effect of DLM toxicity in murine splenocytes. In brief, the study demonstrates that DLM causes apoptosis through its interaction with CD45 and CD28 receptors, leading to oxidative stress and activation of the mitochondrial caspase-dependent pathways which ultimately affects the immune functions. This study provides mechanistic information by which DLM causes toxicity in murine splenocytes. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 808-819, 2016. PMID- 25534812 TI - Influence of dietary tender cluster beans (Cyamopsis tetragonoloba) on biliary proteins, bile acid synthesis and cholesterol crystal growth in rat bile. AB - Tender cluster beans (CBs; Cyamopsis tetragonoloba) are observed to possess anti lithogenic potential in experimental mice. Formation of cholesterol gallstones in gallbladder is controlled by procrystallizing and anticrystallizing factors present in bile in addition to supersaturation of cholesterol. This study aimed at evaluating the influence of CB on biliary glycoproteins, low molecular weight (LMW) and high molecular weight (HMW) proteins, cholesterol nucleation time, and cholesterol crystal growth in rat hepatic bile. Groups of rats were fed for 10 weeks with 0.5% cholesterol to render the bile lithogenic. Experimental dietary interventions were: 10% freeze-dried CB, 1% garlic powder or their combination. Incorporation of CB into HCD decreased the cholesterol saturation index in bile, increased bile flow and biliary glycoproteins. Dietary CB prolonged cholesterol nucleation time in bile. Electrophoresis of biliary proteins showed the presence of high concentration of 27 kDa protein which might be responsible for the prolongation of cholesterol nucleation time in the CB fed group. Proteins of 20 kDa and 18 kDa were higher in CB treated animals, while the same were less expressed in HCD group. Biliary proteins from CB fed animals reduced cholesterol crystal growth index which was elevated in the presence of proteins from HCD group. Cholesterol-7alpha-hydroxylase and cholesterol-27-hydroxylase mRNA expression was increased in CB treated animals contributing to the bile acid synthesis. Thus, the beneficial anti-lithogenic effect of dietary CB which primarily is due to reduced cholesterol saturation index was additionally affected through a modulation of the nucleating and anti-nucleating proteins that affect cholesterol crystallization. PMID- 25534814 TI - Extracorporeal membrane oxygenation rewarming in the ED: an opportunity for success. AB - On average, approximately 1300 Americans die of hypothermia each year. Although accidental hypothermia is commonly associated with severely cold regions or mountain accident victims, hypothermia also commonly occurs in urban centers. Contributing factors often include homelessness, mental illness, and substance abuse. Hypothermia can profoundly affect the cardiovascular system. As the myocardium cools, the conduction system slows down,which results in prolongation of the QT interval as well as propensity for arrhythmias. Eventually, bradycardia, atrial fibrillation, and ventricular fibrillation (VF) can develop. The risk of cardiac arrest increases as the core temperature drops below 32 degrees C and increases substantially when less than 28 degrees C. PMID- 25534815 TI - Point pattern analysis with spatially varying covariate effects, applied to the study of cerebrovascular deaths. AB - This article proposes a modeling approach for handling spatial heterogeneity present in the study of the geographical pattern of deaths due to cerebrovascular disease.The framework involvesa point pattern analysis with components exhibiting spatial variation. Preliminary studies indicate that mortality of this disease and the effect of relevant covariates do not exhibit uniform geographic distribution. Our model extends a previously proposed model in the literature that uses spatial and non-spatial variables by allowing for spatial variation of the effect of non-spatial covariates. A number of relative risk indicators are derived by comparing different covariate levels, different geographic locations, or both. The methodology is applied to the study of the geographical death pattern of cerebrovascular deaths in the city of Rio de Janeiro. The results compare well against existing alternatives, including fixed covariate effects. Our model is able to capture and highlight important data information that would not be noticed otherwise, providing information that is required for appropriate health decision-making. PMID- 25534816 TI - Professor Christopher Nordin: in memoriam. PMID- 25534819 TI - Detection of tick-borne encephalitis virus in I. ricinus ticks collected from autumn migratory birds in Latvia. AB - Birds have a potential of spreading ticks via bird migration routes. In this study, we screened 170 ticks removed during autumn 2010 from 55 birds belonging to 10 species for the presence of tick-borne encephalitis virus (TBEV). In total, TBEV RNA was detected in 14% of I. ricinus tick samples obtained from different birds species. The results of this study indicate the possible role of migrating birds in the dispersal of TBEV-infected ticks along the southward migration route. PMID- 25534820 TI - 2014--it's been quite a year. PMID- 25534817 TI - mTOR inhibition rescues osteopenia in mice with systemic sclerosis. AB - Fibrillin-1 (FBN1) deficiency-induced systemic sclerosis is attributed to elevation of interleukin-4 (IL4) and TGF-beta, but the mechanism underlying FBN1 deficiency-associated osteopenia is not fully understood. We show that bone marrow mesenchymal stem cells (BMMSCs) from FBN1-deficient (Fbn1(+/-)) mice exhibit decreased osteogenic differentiation and increased adipogenic differentiation. Mechanistically, this lineage alteration is regulated by IL4/IL4Ralpha-mediated activation of mTOR signaling to down-regulate RUNX2 and up regulate PPARgamma2, respectively, via P70 ribosomal S6 protein kinase (P70S6K). Additionally, we reveal that activation of TGF-beta/SMAD3/SP1 signaling results in enhancement of SP1 binding to the IL4Ralpha promoter to synergistically activate mTOR pathway in Fbn1(+/-) BMMSCs. Blockage of mTOR signaling by osteoblastic-specific knockout or rapamycin treatment rescues osteopenia phenotype in Fbn1(+/-) mice by improving osteogenic differentiation of BMMSCs. Collectively, this study identifies a previously unrecognized role of the FBN1/TGF-beta/IL4Ralpha/mTOR cascade in BMMSC lineage selection and provides experimental evidence that rapamycin treatment may provide an anabolic therapy for osteopenia in Fbn1(+/-) mice. PMID- 25534824 TI - A rare cause of finger amputation. PMID- 25534822 TI - Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma. AB - BACKGROUND: Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG). We explored in vitro on new DIPG models the efficacy of dasatinib, a multi-tyrosine kinase inhibitor targeting this receptor. METHODS: Gene expression profiles were generated from 41 DIPGs biopsied at diagnosis and compared with the signature associated with sensitivity/resistance to dasatinib. A panel of 12 new DIPG cell lines were established from biopsy at diagnosis, serially passaged, and characterized by gene expression analyses. Effects of dasatinib (1-10 MUM) on proliferation, invasion, and cytotoxicity were determined on 4 of these cell lines using live cell imaging and flow cytometry assays. Downstream signaling and receptor tyrosine kinases (RTKs) were assessed by western blot and phospho-RTK array. The effect of the combination with the c-Met inhibitor cabozantinib was studied on cellular growth and invasion analyzed by the Chou-Talaly method. RESULTS: DIPG primary tumors and cell lines exhibited the gene expression signature of sensitivity to dasatinib. Dasatinib reduced proliferation (half-maximal inhibitory concentration = 10-100 nM) and invasion (30%-60% reduction) at 100 nM in 4/4 cultures and induced apoptosis in 1 of 4 DIPG cell lines. Activity of downstream effectors of dasatinib targets including activin receptor 1 was strongly reduced. Since multiple RTKs were activated simultaneously in DIPG cell lines, including c-Met, which can be also amplified in DIPG, the benefit of the combination of dasatinib with cabozantinib was explored for its synergistic effects on proliferation and migration/invasion in these cell lines. CONCLUSION: Dasatinib exhibits antitumor effects in vitro that could be increased by the combination with another RTK inhibitor targeting c-Met. PMID- 25534823 TI - Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. AB - BACKGROUND: Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. METHODS: Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. RESULTS: Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1 deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1 deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning. CONCLUSION: These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials. PMID- 25534825 TI - Recovery of salivary DNA from the skin after showering. AB - PURPOSE: After sexual assault there is a limited amount of time before the DNA evidence on the surface of the victim's body is not recoverable. During an assault, the offender may leave saliva on the victim's skin. Traditional examination methods use a swabbing technique to collect saliva for DNA testing. Victim activity, especially hygiene activity such as showering, may negatively affect DNA recovery. METHODS: In this experiment, we compared two techniques for recovery of salivary DNA from the skin's surface after a victim showers. We compared the traditional swabbing method to a "wet-vacuum" method using the M Vac(c) to collect saliva from four body regions (neck, arm, stomach, and leg). In our research, we tested whether either collection technique obtained enough salivary DNA for autosomal and Y-STR analysis. In addition, we tested whether the M-Vac(c) is more effective at collecting DNA from large surface areas than traditional methods, by determining the amount of DNA collected. RESULTS: With both collection techniques, we were able to obtain male salivary DNA from at least one body region of the female after she had showered. There was no statistical difference in the amount of DNA collected between the swabbing technique and the M-Vac(c). Autosomal STR analysis failed to detect the male contributor's DNA; therefore, we used Y-STRs. With Y-STR analysis, 47 samples returned a full male profile, and 26 samples returned a partial male profile after sample concentration. CONCLUSIONS: This research shows that salivary DNA can be collected from skin after showering and successfully analyzed using Y STRs. PMID- 25534826 TI - High frequency of enterovirus D68 in children hospitalised with respiratory illness in Norway, autumn 2014. AB - OBJECTIVES: An unexpectedly high proportion of children were admitted for severe respiratory infections at the Oslo University Hospital, Ulleval, Norway, during September and October, 2014. In light of the ongoing outbreak of enterovirus-D68 (EV-D68) in North America a real-time RT-PCR for screening of enterovirus and enterovirus D68 was established. DESIGN: We developed a duplex real-time RT-PCR for rapid screening of enterovirus D68. The method target the 5' non-translated region (NTR) of the HEV genome at a location generally used for enterovirus detection. SAMPLE: Nasopharyngeal samples (n = 354), from children <15 years of age, received for respiratory virus analysis in OUH during September 1st and October 31nd, 2014, were tested for enterovirus and screened for enterovirus D68. MAIN OUTCOME MEASURES AND RESULTS: The duplex real-time RT-PCR method was an efficient tool for rapid screening for EV-D68 in respiratory specimens. Enterovirus was detected in 66 (22%) of 303 pediatric nasopharyngeal samples collected from children hospitalised with acute respiratory infection within the two-month period. Out of these, 33 (50%) were EV-D68. EV-D68 was associated with acute flaccid paralysis in one child. CONCLUSIONS: An unexpectedly high proportion of children admitted for severe respiratory infections at the Oslo University Hospital, Ulleval, Norway, were diagnosed with EV- D68 during September 1st and October 31nd, 2014. These results emphasise that greater vigilance is required throughout Europe as enteroviruses are cause of severe respiratory disease. PMID- 25534827 TI - C-kit overexpression correlates with KIT gene copy numbers increases in phyllodes tumors of the breast. AB - We determined c-kit expression in the stroma and epithelia of benign, borderline, and malignant phyllodes tumors (PTs), respectively, as well as the relationship between c-kit expression in stromal elements and KIT gene copy number variations (CNVs). To assess c-kit expression and KIT CNVs, 348 PT cases were studied: 120 (34.4 %) benign cases, 115 (33.1 %) borderline cases, and 113 (32.5 %) malignant cases. All of these cases were evaluated for c-kit (CD117) expression using immunohistochemistry. Forty-two cases (29 c-kit-positive in the stromal cells cases and 13 negative cases) were investigated for KIT gene CNVs via genomic polymerase chain reaction (PCR). The overall rate of c-kit positivity in the stroma was 46.8 %, as well as 24.2, 53.1, and 64.6 %, respectively, in PTs of three different grades. However, in the majority of cases, the epithelia were c kit positive (98.2 %), and the positivity was 100, 99.1, and 95 % in PTs of three different grades, respectively. There was a significant change in the expression of c-kit in the stroma and epithelia according to grade (P < 0.001, P = 0.014). From the genomic PCR results, we can confirm that c-kit positivity in the stroma is directly correlated with KIT gene copy numbers increases (P = 0.003, P = 0.041). We demonstrated that c-kit expression in the stroma of PTs is positively associated with malignancy. c-Kit epithelial positivity was inversely correlated with PTs malignancy. c-Kit overexpression in the stroma was related to KIT gene copy numbers increases. PMID- 25534828 TI - "Laughing 'til it hurts": an unusual case report of mirth and migraine. PMID- 25534829 TI - Development of a High-Throughput Screening Assay to Identify Inhibitors of the Lipid Kinase PIP5K1C. AB - Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) regulate a variety of cellular processes, including signaling through G protein-coupled receptors (GPCRs), endocytosis, exocytosis, and cell migration. These lipid kinases synthesize phosphatidylinositol 4,5-bisphosphate (PIP2) from phosphatidylinositol 4-phosphate [PI(4)P]. Because small-molecule inhibitors of these lipid kinases did not exist, molecular and genetic approaches were predominantly used to study PIP5K1 regulation of these cellular processes. Moreover, standard radioisotope based lipid kinase assays cannot be easily adapted for high-throughput screening. Here, we report a novel, high-throughput, microfluidic mobility shift assay to identify inhibitors of PIP5K1C. This assay uses fluorescently labeled phosphatidylinositol 4-phosphate as the substrate and recombinant human PIP5K1C. Our assay exhibited high reproducibility, had a calculated adenosine triphosphate Michaelis constant (Km) of 15 uM, performed with z' values >0.7, and was used to screen a kinase-focused library of ~4700 compounds. From this screen, we identified several potent inhibitors of PIP5K1C, including UNC3230, a compound that we recently found can reduce nociceptive sensitization in animal models of chronic pain. This novel assay will allow continued drug discovery efforts for PIP5K1C and can be adapted easily to screen additional lipid kinases. PMID- 25534830 TI - Detection and quantification of allosteric modulation of endogenous m4 muscarinic acetylcholine receptor using impedance-based label-free technology in a neuronal cell line. AB - Allosteric modulators of G protein-coupled receptors have the potential to achieve greater receptor subtype selectivity compared with ligands targeting the orthosteric site of this receptor family. However, the high attrition rate in GPCR drug discovery programs has highlighted the need to better characterize lead compounds in terms of their allosteric action, as well as the signals they elicit. Recently, the use of label-free technologies has been proposed as an approach to overcome some limitations of endpoint-based assays and detect global changes in the ligand-stimulated cell. In this study, we assessed the ability of an impedance-based label-free technology, xCELLigence, to detect allosteric modulation in a neuronal cell line natively expressing rodent M4 muscarinic acetylcholine receptors. We were able to demonstrate that positive allosteric modulation of the endogenous M4 muscarinic acetylcholine receptor can be detected using this technology. Importantly, the allosteric parameters estimated from the label-free approach are comparable to those estimated from endpoint-based assays. PMID- 25534831 TI - Use of the site-specific retargeting jump-in platform cell line to support biologic drug discovery. AB - Biologics represent a fast-growing class of therapeutics in the pharmaceutical sector. Discovery of therapeutic antibodies and characterization of peptides can necessitate high expression of the target gene requiring the generation of clonal stably transfected cell lines. Traditional challenges of stable cell line transfection include gene silencing and cell-to-cell variability. Our inability to control these can present challenges in lead isolation. Recent progress in site-specific targeting of transgene to specific genomic loci has transformed the ability to generate stably transfected mammalian cell lines. In this article, we describe how the use of the Jump-In platform (Life Technologies, Carlsbad, CA) has been applied to drug discovery projects. It can easily and rapidly generate homogeneous high-expressing cell pools with a high degree of reproducibility. Their use in cell-based screening to identify specific binders, identify binding to relevant species variants, or detect functionally relevant therapeutic antibodies is central in driving drug discovery. PMID- 25534832 TI - The utility of hand transplantation in hand amputee patients. AB - PURPOSE: To measure the desirable health outcome, termed utility, and the expected quality-adjusted life years (QALYs) gained with hand composite tissue allotransplantation (CTA) using hand amputee patients and the general public. METHODS: Using the standard gamble (SG) and time trade-off (TTO) techniques, utilities were obtained from 30 general public participants and 12 amputee patients. The health utility and net QALYs gained or lost with transplantation were computed. A sensitivity analysis was conducted to account for the effects of lifelong immunosuppression on the life expectancy of transplant recipients. Higher scores represent greater utility. RESULTS: Hand amputation mean health utility as measured by the SG and TTO methods, respectively, was 0.72 and 0.80 for the general public and 0.69 and 0.70 for hand amputees. In comparison, hand CTA mean health utility was 0.74 and 0.82 for the general public and 0.83 and 0.86 for amputees. Hand CTA imparted an expected gain of 0.9 QALYs (SG and TTO) in the general public and 7.0 (TTO) and 7.8 (SG) QALYs in hand amputees. A loss of at least 1.7 QALYs was demonstrated when decreasing the life expectancy in the sensitivity analysis in the hand amputee group. CONCLUSIONS: Hand amputee patients did not show a preference toward hand CTA with its inherent risks. With this procedure being increasingly adopted worldwide, the benefits must be carefully weighed against the risks of lifelong immunosuppressive therapy. This study does not show clear benefit to advocate hand CTA. PMID- 25534833 TI - Commentary on "The utility of hand transplantation in hand amputee patients". PMID- 25534834 TI - Conservative treatment of thumb base osteoarthritis: a systematic review. AB - PURPOSE: To provide a systematic review of randomized controlled trials regarding the conservative treatment of thumb base osteoarthritis (OA). METHODS: A systematic literature search was conducted in the electronic bibliographic databases Medline (Pubmed) and Embase (both starting year to May 2014) using predetermined criteria for studies on nonoperative treatment of thumb base OA. RESULTS: Twenty-three articles fulfilled our inclusion criteria. Systematic evaluation demonstrated the following: (1) Hand therapy can possibly reduce pain. However, owing to the lack of good-quality (randomized controlled) trials with sufficient follow-up time, no proper conclusions can be drawn. (2) Although both steroid and hyaluronate intra-articular injections can provide pain relief, most authors conclude that injection of hyaluronate is more effective. Follow-up is rather short with a maximum of 12 months in 1 study. Furthermore, study comparison is hampered by heterogeneity of study design and outcome parameters. (3) The use of orthoses reduces pain without effect on function, strength, or dexterity. Included studies used various types of orthoses. Follow-up times varied (2 wk-7 y). (4) There is no justification for the use of transdermal steroid delivery. (5) There is insufficient evidence justifying the use of leech therapy. (6) There are no high-level evidence studies specifically evaluating the effect of analgesics and patient education in joint protection in patients with thumb base OA. CONCLUSIONS: There are only a few high-quality studies addressing the conservative treatment of trapeziometacarpal OA. Available evidence suggests only some effect of orthoses and intra-articular hyaluronate or steroid injections. PMID- 25534835 TI - Commentary to "Conservative treatment of thumb base osteoarthritis: a systematic review". PMID- 25534836 TI - Quantifying scaphoid malalignment based upon height-to-length ratios obtained by 3-dimensional computed tomography. AB - PURPOSE: To determine if 3-dimensional height-to-length (H/L) measurements including coronal plane assessment will improve malalignment detection of scaphoid fractures and to determine if more waist than proximal pole nonunions are malaligned. METHODS: Computed tomography scans of uninjured wrists (n = 74) were used to obtain 3-dimensional models of healthy scaphoids. These models were used to determine 95% normal ranges of the H/L ratio in standard sagittal and coronal planes in an automated fashion. Subsequently, the H/L ratios of fibrous nonunions (n = 26) were compared with these normal ranges and were classified as either aligned or malaligned. RESULTS: The mean normal H/L ratio in the sagittal plane was 0.61 (range, 0.54-0.69) and in the coronal plane 0.42 (range, 0.36 0.48). The mean H/L ratios of the nonunions differed from those of the healthy scaphoids in these planes: 0.65 and 0.48, respectively. Based on sagittal plane evaluation of all nonunions, 46% exceeded the normal H/L range versus 54% based on combining sagittal and coronal plane measurements. More waist nonunions (71%) than proximal pole nonunions (22%) exceed the normal H/L range. CONCLUSIONS: Evaluation of the H/L ratio in the coronal plane provided valuable additional information for the detection of scaphoid deformities. More malaligned cases were found for waist nonunions than for proximal pole nonunions. CLINICAL RELEVANCE: This method may be a helpful diagnostic tool to detect malalignment and to choose between in situ fixation or reconstruction. PMID- 25534837 TI - In vivo 3-dimensional analysis of stage III Kienbock disease: pattern of carpal deformity and radioscaphoid joint congruity. AB - PURPOSE: To examine 3-dimensional carpal alignment and radioscaphoid joint (RSJ) congruity among normal wrists and those with Lichtman stage III Kienbock disease or scapholunate dislocation (SLD). METHODS: We conducted 3-dimensional analysis based on computed tomographic data to compare 10 wrists of stage III Kienbock disease (5 IIIa and 5 IIIb) with 5 normal wrists and 3 wrists with SLD. A markerless bone registration technique was used to investigate the 3-dimensional position of the scaphoid relative to the radius. To evaluate RSJ congruency, the inferred contact area between the scaphoid proximal pole and the distal radius was calculated from 3-dimensional bone models. RESULTS: The scaphoid position was not significantly different from normal wrists in stage IIIa Kienbock disease. Stage IIIb Kienbock disease was meaningfully associated with a flexed scaphoid and proximal translation of the centroid, but not dorsal translation of the scaphoid proximal pole, where RSJ congruity was preserved. With SLD, the scaphoid flexed to the same extent as that in stage IIIb Kienbock disease, and the proximal pole translated dorsally together with the capitate, producing RSJ incongruity. CONCLUSIONS: The patterns of carpal collapse differed between stage IIIb Kienbock disease and SLD in terms of RSJ congruity. Our study showed that stage IIIb Kienbock disease did not involve dorsal subluxation of the scaphoid proximal pole and that RSJ congruity was retained, unlike SLD. CLINICAL RELEVANCE: Our results suggest that carpal collapse in Kienbock disease is not associated with RSJ incongruity, which may explain why there are asymptomatic patients with Kienbock disease and carpal collapse. PMID- 25534838 TI - Intrinsic reconstruction in a tetraplegic grip/extension model--the challenge of extrapolating from the cadaver to the patient. PMID- 25534839 TI - Proximal tendon-prosthesis junction for active tendon implants of the hand: a biomechanical comparison of 2 techniques. AB - PURPOSE: To study the biomechanical characteristics (percent stretch, stiffness, and ultimate load) of 2 tendon-prosthesis techniques used to connect the proximal tendon stump to silicone active tendon implants used in reconstruction of flexor tendons. METHODS: We evaluated percent stretch following cyclic loading and at failure, stiffness during load to failure, and ultimate load of 16 tendon prosthesis junctions using cadaveric canine flexor digitorum profundus tendons to re-create 2 junction techniques: the tendon loop (TL) and the polyester weave (PW). RESULTS: The TL junction showed greater percent stretch at a static load of 2 N, following 500 cycles of loading between 2 N and 50 N, and at peak load. The PW junction displayed greater stiffness from 50 to 150 N during load to failure. Both junctions failed at a mean ultimate load greater than 220 N. CONCLUSIONS: The described proximal junction techniques for active tendon implants were strong enough to resist early active motion in the immediate postoperative period without significant elongation. The PW technique displayed greater stiffness and ultimate load compared with the TL. CLINICAL RELEVANCE: Data on tendon-prosthesis characteristics of these 2 methods may aid the surgeon in choosing which junction technique to use, during surgical tensioning decisions, and in considering activity protocols after surgery. These data may also serve as a baseline for further investigations regarding active tendon implants. PMID- 25534840 TI - Epidemiology of congenital upper limb anomalies in a midwest United States population: an assessment using the Oberg, Manske, and Tonkin classification. AB - PURPOSE: To examine the relative presentation frequency of children with upper limb congenital anomalies at 3 Midwestern referral centers using the Oberg, Manske, and Tonkin (OMT) classification and to assess the utility of this new classification system. METHODS: 641 individuals with 653 congenital upper extremity anomalies were identified at 3 hospitals in 2 large metropolitan areas during a 1-year interval. Patients were identified prospectively and the specific upper extremity anomaly and any associated syndromes were confirmed using medical records and radiographs. We applied the OMT classification that categorizes anomalies using a dysmorphology outline as malformations, dysplasias, deformations, and syndromes, and assessed its utility and ease of use. RESULTS: There were 480 extremities (74%) with a limb malformation including 184 involving the entire limb. Arthrogryposis was the most common of these (53 extremities). Anomalies affecting only the hand plate accounted for 62% (296) of the malformations. Of these, radial polydactyly (15%) was the most common specific anomaly, followed by symbrachydactyly (13%) and cleft hand (11%). Dysplasias were noted in 86 extremities; 55 of these were multiple hereditary exostoses. There were 87 extremities with deformations and 58 of these were trigger digits. A total of 109 children had a syndrome or association. Constriction ring sequence was most common. The OMT was straightforward to use and most anomalies could be easily assigned. There were a few conditions, such as Madelung deformity and symbrachydactyly, that would benefit from clarification on how to best classify them. CONCLUSIONS: Malformations were the most common congenital anomalies in the 653 upper extremities evaluated over a 1-year period at 3 institutions. We were able to classify all individuals using the OMT classification system. PMID- 25534841 TI - Minimally invasive thumb carpometacarpal joint arthrodesis with headless screws and arthroscopic assistance. AB - We describe a minimally invasive arthrodesis technique using an arthroscope and fixation with headless screws. From February 2007 to March 2010, we treated 11 thumbs in 11 patients with posttraumatic carpometacarpal joint osteoarthritis. All patients reported pain at the thumb carpometacarpal joint. Preoperatively, mean grip and pinch strength was 38 and 5.9 kg, respectively. At a mean time of 9 weeks, all patients achieved complete union at the fusion site. Mean follow-up was 46 months. At the final follow-up, mean grip and pinch strength was 47 and 7.7 kg, respectively. Based on the Kapandji opposition score (full scored = 10), the mean thumb opposition score was 7. All patients had pain relief. There were 6 excellent, 3 good, and 2 fair results. PMID- 25534842 TI - Recovery from distal radius fracture. PMID- 25534843 TI - In reply. PMID- 25534844 TI - Letter regarding "Oblique triangular neurovascular osteocutaneous flap for hook nail deformity correction". PMID- 25534845 TI - In reply. PMID- 25534846 TI - Reply to "Acute hand infections". PMID- 25534847 TI - A thioesterase bypasses the requirement for exogenous fatty acids in the plsX deletion of Streptococcus pneumoniae. AB - PlsX is an acyl-acyl carrier protein (ACP):phosphate transacylase that interconverts the two acyl donors in Gram-positive bacterial phospholipid synthesis. The deletion of plsX in Staphylococcus aureus results in a requirement for both exogenous fatty acids and de novo type II fatty acid biosynthesis. Deletion of plsX (SP0037) in Streptococcus pneumoniae did not result in an auxotrophic phenotype. The DeltaplsX S. pneumoniae strain was refractory to myristic acid-dependent growth arrest, and unlike the wild-type strain, was susceptible to fatty acid synthesis inhibitors in the presence of exogenous oleate. The DeltaplsX strain contained longer chain saturated fatty acids imparting a distinctly altered phospholipid molecular species profile. An elevated pool of 18- and 20-carbon saturated fatty acids was detected in the DeltaplsX strain. A S. pneumoniae thioesterase (TesS, SP1408) hydrolyzed acyl-ACP in vitro, and the DeltatesS DeltaplsX double knockout strain was a fatty acid auxotroph. Thus, the TesS thioesterase hydrolyzed the accumulating acyl-ACP in the DeltaplsX strain to liberate fatty acids that were activated by fatty acid kinase to bypass a requirement for extracellular fatty acid. This work identifies tesS as the gene responsible for the difference in exogenous fatty acid growth requirement of the DeltaplsX strains of S. aureus and S. pneumoniae. PMID- 25534848 TI - A complement C5 gene mutation, c.754G>A:p.A252T, is common in the Western Cape, South Africa and found to be homozygous in seven percent of Black African meningococcal disease cases. AB - Patients with genetically determined deficiency of complement component 5 are usually diagnosed because of recurrent invasive Neisseria meningitidis infections. Approximately 40 individual cases have been diagnosed worldwide. Nevertheless, reports of the responsible genetic defects have been sporadic, and we know of no previous reports of C5 deficiency being associated with a number of independent meningococcal disease cases in particular communities. Here we describe C5 deficiency in seven unrelated Western Cape, South African families. Three different C5 mutations c.55C>T:p.Q19X, c.754G>A:p.A252T and c.4426C>T:p.R1476X were diagnosed in index cases from two families who had both presented with recurrent meningococcal disease. p.Q19X and p.R1476X have already been described in North American Black families and more recently p.Q19X in a Saudi family. However, p.A252T was only reported in SNP databases and was not associated with disease until the present study was undertaken in the Western Cape, South Africa. We tested for p.A252T in 140 patients presenting with meningococcal disease in the Cape Town area, and found seven individuals in five families who were homozygous for the mutation p.A252T. Very low serum C5 protein levels (0.1-4%) and correspondingly low in vitro functional activity were found in all homozygous individuals. Allele frequencies of p.A252T in the Black African and Cape Coloured communities were 3% and 0.66% and estimated homozygosities are 1/1100 and 1/22,500 respectively. In 2012 we reported association between p.A252T and meningococcal disease. Molecular modelling of p.A252T has indicated an area of molecular stress in the C5 molecule which may provide a mechanism for the very low level in the circulation. This report includes seven affected families indicating that C5D is not rare in South Africa. PMID- 25534850 TI - Fucci-guided purification of hematopoietic stem cells with high repopulating activity. AB - Fluorescent ubiquitination-based cell cycle indicator (Fucci) technology utilizing the cell cycle-dependent proteolysis of ubiquitin oscillators enables visualization of cell cycle progression in living cells. The Fucci probe consists of two chimeric fluorescent proteins, FucciS/G2/M and FucciG1, which label the nuclei of cells in S/G2/M phase green and those in G1 phase red, respectively. In this study, we generated Fucci transgenic mice and analyzed transgene expression in hematopoietic cells using flow cytometry. The FucciS/G2/M-#474 and FucciG1 #639 mouse lines exhibited high-level transgene expression in most hematopoietic cell populations. The FucciG1-#610 line expressed the transgene at high levels predominantly in the hematopoietic stem cell (HSC) population. Analysis of the HSC (CD34(-)KSL: CD34(-/low)c-Kit(+)Sca-1(+)lineage marker(-)) population in the transgenic mice expressing both FucciS/G2/M and FucciG1 (#474/#610) confirmed that more than 95% of the cells were in G0/G1 phase, although the FucciG1(red) intensity was heterogeneous. An in vivo competitive repopulation assay revealed that repopulating activity resided largely in the FucciG1(red)(high) fraction of CD34(-)KSL cells. Thus, the CD34(-)KSL HSC population can be further purified on the basis of the Fucci intensity. PMID- 25534849 TI - Cyclooxygenase-2 or tumor necrosis factor-alpha inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle. AB - Maximal homing of infused stem cells to diseased tissue is critical for regenerative medicine. Pulsed focused ultrasound (pFUS) is a clinically relevant platform to direct stem cell migration. Through mechanotransduction, pFUS establishes local gradients of cytokines, chemokines, trophic factors (CCTF) and cell adhesion molecules (CAM) in treated skeletal muscle that subsequently infused mesenchymal stromal cells (MSC) can capitalize to migrate into the parenchyma. Characterizing molecular responses to mechanical pFUS effects revealed tumor necrosis factor-alpha (TNFalpha) drives cyclooxygenase-2 (COX2) signaling to locally increase CCTF/CAM that are necessary for MSC homing. pFUS failed to increase chemoattractants and induce MSC homing to treated muscle in mice pretreated with ibuprofen (nonspecific COX inhibitor) or etanercept (TNFalpha inhibitor). pFUS-induced MSC homing was also suppressed in COX2 knockout mice, demonstrating ibuprofen blocked the mechanically induced CCTF/CAM by acting on COX2. Anti-inflammatory drugs, including ibuprofen, are administered to muscular dystrophy (MD) patients, and ibuprofen also suppressed pFUS-induced homing to muscle in a mouse model of MD. Drug interactions with cell therapies remain unexplored and are not controlled for during clinical cell therapy trials. This study highlights potentially negative drug-host interactions that suppress stem cell homing and could undermine cell-based approaches for regenerative medicine. PMID- 25534851 TI - Paraventricular NUCB2/nesfatin-1 is directly targeted by leptin and mediates its anorexigenic effect. AB - An adipokine leptin plays a central role in the regulation of feeding and energy homeostasis via acting on the hypothalamus. However, its downstream neuronal mechanism is not thoroughly understood. The neurons expressing nucleobindin-2 (NUCB2)-derived nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) have been implicated in feeding and energy homeostasis. The present study aimed to explore the role of PVN NUCB2/nesfatin-1 in the leptin action, by using adeno associated virus (AAV) vectors encoding shRNA targeting NUCB2 (AAV-NUCB2-shRNA). Leptin directly interacted and increased cytosolic Ca(2+) in single neurons isolated from the PVN, predominantly in NUCB2/nesftin-1-immunoreactive neurons. Treatment with leptin in vivo and in vitro markedly increased NUCB2 mRNA expression in the PVN. Peripheral and central injections of leptin failed to significantly inhibit food intake in mice receiving AAV-NUCB2. These results indicate that PVN NUCB2/nesfatin-1 is directly targeted by leptin, and mediates its anorexigenic effect. PMID- 25534852 TI - ERalpha regulates chromosome alignment and spindle dynamics during mitosis. AB - Estrogen receptors are activated by the hormone estrogen and they control cell growth by altering gene expression as a transcription factor. So far two estrogen receptors have been found: ERalpha and ERbeta. Estrogen receptors are also implicated in the development and progression of breast cancer. Here, we found that ERalpha localized on the spindle and spindle poles at the metaphase during mitosis. Depletion of ERalpha generated unaligned chromosomes in metaphase cells and lagging chromosomes in anaphase cells in a transcription-independent manner. Furthermore, the levels of beta-tubulin and gamma-tubulin were reduced in ERalpha depleted cells. Consistent with this, polymerization of microtubules in ERalpha depleted cells and turnover rate of alpha/beta-tubulin were decreased than in control cells. We suggest that ERalpha regulates chromosome alignment and spindle dynamics by stabilizing microtubules during mitosis. PMID- 25534853 TI - IRAP deficiency attenuates diet-induced obesity in mice through increased energy expenditure. AB - Activation of the adipose renin-angiotensin system contributes to the development of obesity and metabolic syndrome. Insulin-regulated aminopeptidase (IRAP) has been identified a key regulator of GLUT4 transporter as well as angiotensin IV (AngIV) receptor (AT4R). Although AngII-AT1R axis appears as anorexigenic and as an effector of energy expenditure, the impact of AngIV-IRAP/AT4R axis on energy metabolism remains unknown. The aim was to determine the role of IRAP in energy metabolism in mice. METHODS AND RESULTS: In adipocyte culture, plasminogen activator inhibitor type 1 (PAI-1) expression levels were diminished in IRAP knockout (IRAP(-/-)) if compared with those of wild-type (C57Bl/6J, WT) mice. Mice were fed high-fat diet (32% fat) at age of 8 weeks. At the entry, body weight, body fat content, and parameters of saccharometabolism were similar between groups. However, IRAP(-/-) mice exhibited blunted body weight gain compared to that of WT mice, despite comparable food intake and physical activity. At 20weeks of age, IRAP(-/-) mice had 25% lower body weight than WT mice. Glucose and insulin tolerance tests revealed that the glucose disposal and the hypoglycemic effect of insulin were pronounced in IRAP(-/-) mice after a high fat diet. Indirect calorimetry demonstrated that whole-body oxygen consumption rates were significantly higher in IRAP(-/-) mice by 18% with mild hyperthermia. Analysis of brown adipose tissue (BAT) in IRAP(-/-) showed increased levels of uncoupling protein-1 (UCP-1) at basal level and adaptive thermogenesis was not impaired. CONCLUSIONS: IRAP deficiency may lead to suppression of PAI-1 expression in adipocytes and upregulation of UCP-1-mediated thermogenesis in BAT and increased energy expenditure to prevent the development of obesity, and these facts suggest a therapeutic potential of IRAP/AT4R blockade in diet-induced obesity. PMID- 25534854 TI - Characterization and homologous overexpression of an N-acetylglucosaminidase Nag1 from Trichoderma reesei. AB - Trichoderma reesei is thought to be a promising recombinant host for the production and secretion of complex proteins due to its ability to secrete large amounts of proteins. In this study we identified a functional N-acetyl-beta glucosaminidase (NAGase) gene Nag1 in T. reesei. Nag1, a putative gene encoding a GH 20 family NAGase in T. reesei, was cloned and homologous overexpressed in the T. reesei RutC30DeltaU3 with a strong cellobiohydrolase1 gene (cbh1) promoter. Nag1 was secreted in its active form and the highest expression level was around 499.85IU/ml. Nag1 has a molecular mass of 80kDa. The optimum pH and temperature were 4.0 and 60 degrees C, respectively. PMID- 25534855 TI - HuR represses Wnt/beta-catenin-mediated transcriptional activity by promoting cytoplasmic localization of beta-catenin. AB - beta-Catenin is the key transcriptional activator of canonical Wnt signaling in the nucleus; thus, nuclear accumulation of beta-catenin is a critical step for expressing target genes. beta-Catenin accumulates in the nucleus of cancer cells where it activates oncogenic target genes. Hu antigen R (HuR) is a RNA binding protein that regulates multiple post-transcriptional processes including RNA stability. Thus, cytoplasmic HuR protein may be involved in tumorigenesis by stabilizing oncogenic transcripts, but the molecular mechanism remains unclear. Here, we observed that Wnt/beta-catenin signaling induced export of the HuR protein, whereas HuR overexpression promoted accumulation of the beta-catenin protein in the cytoplasm. Thus, Wnt/beta-catenin-mediated transcriptional activity in the nucleus was reduced by overexpressing HuR. These results suggest novel and uncharacterized cytoplasmic beta-catenin functions related to HuR mediated RNA metabolism in cancer cells. PMID- 25534856 TI - The histone demethylase KDM4B interacts with MyoD to regulate myogenic differentiation in C2C12 myoblast cells. AB - Enzymes that mediate posttranslational modifications of histone and nonhistone proteins have been implicated in regulation of skeletal muscle differentiation. However, functions of histone demethylases that could counter the actions of H3 K9 specific histone methyltransferases remain still obscure. Here we present evidences that KDM4B histone demethylase regulates expression of myogenic regulators such as MyoD and thereby controls myogenic differentiation of C2C12 myoblast cells. We demonstrate that expression of KDM4B gradually increases during myogenic differentiation and depletion of KDM4B using shRNA results in inhibition of differentiation in C2C12 myoblast cells, which is correlated with decreased expression of MyoD and myogenin. In addition, we find that KDM4B shRNA represses expression of MyoD promoter-driven luciferase reporter and exogenous expression of MyoD rescues myogenic potential in KDM4B-depleted myoblast cells. We further show that KDM4B interacts with MyoD, binds to MyoD and myogenin promoters in vivo, and finally, is involved in demethylation of tri-methylated H3 K9 on promoters of MyoD and myogenin. Taken together, our data suggest that KDM4B plays key roles in myogenic differentiation of C2C12 cells, presumably by its function as a H3-K9 specific histone demethylase. PMID- 25534857 TI - Crt10 directs the cullin-E3 ligase Rtt101 to nonfunctional 25S rRNA decay. AB - Nonfunctional mutant ribosomal RNAs in 40S or 60S subunits are selectively degraded in eukaryotic cells (nonfunctional rRNA decay, NRD). We previously reported that NRD of 25S rRNA required cullin-E3 ligase Rtt101 and its associating factor Mms1, both of which are involved in DNA repair. Although Mms22, an accessory component of the E3 complex, was suggested to direct the E3 complex to DNA repair, the factor that directs the complex to 25S NRD currently remains unknown. We herein demonstrated that another accessory component, Crt10 was required for 25S NRD, but not for DNA repair, suggesting that this accessory component specifies the function of the E3 complex differently. We also identified two distinct Crt10-containing E3 complexes, one of which contained the Paf1 complex, a Pol-II binding complex that modulates the transcription of stress related genes. Our results showed the convergence of multiple pathways for stresses that harm nucleic acids and provided a molecular framework for the substrate diversity of the E3 complex. PMID- 25534859 TI - A memory of rejection? PMID- 25534858 TI - Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin-angiotensin system activation. AB - Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for the development of acute kidney injury (AKI). Although bone-marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render the BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated transgenic BMSCs (TG-BMSCs) from young end-organ-disease-free rats with increased RAS activation [human angiotensinogen/renin double transgenic rats (dTGRs)] that eventually develop hypertension and die of end-organ damage and kidney failure at 8 weeks of age. Control cells (SD-BMSCs) were isolated from wild-type Sprague-Dawley rats. Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells' therapeutic efficacy was evaluated in a rat model of acute ischaemia/reperfusion-induced AKI. Serum urea and creatinine were measured at 24 h and 48 h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation [monocyte chemoattractant protein (MCP-1), ED-1], and kidney injury [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL)]. TG BMSCs showed distinct mitochondrial morphology, decreased cell respiration and increased production of ROS. Gene expression profiling revealed a pronounced pro inflammatory phenotype. In contrast with the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by causing a shift into a pro-inflammatory phenotype with mitochondrial dysfunction. PMID- 25534860 TI - Next-generation sequencing of genomic DNA fragments bound to a transcription factor in vitro reveals its regulatory potential. AB - Several transcription factors (TFs) coordinate to regulate expression of specific genes at the transcriptional level. In Arabidopsis thaliana it is estimated that approximately 10% of all genes encode TFs or TF-like proteins. It is important to identify target genes that are directly regulated by TFs in order to understand the complete picture of a plant's transcriptome profile. Here, we investigate the role of the LONG HYPOCOTYL5 (HY5) transcription factor that acts as a regulator of photomorphogenesis. We used an in vitro genomic DNA binding assay coupled with immunoprecipitation and next-generation sequencing (gDB-seq) instead of the in vivo chromatin immunoprecipitation (ChIP)-based methods. The results demonstrate that the HY5-binding motif predicted here was similar to the motif reported previously and that in vitro HY5-binding loci largely overlapped with the HY5 targeted candidate genes identified in previous ChIP-chip analysis. By combining these results with microarray analysis, we identified hundreds of HY5-binding genes that were differentially expressed in hy5. We also observed delayed induction of some transcripts of HY5-binding genes in hy5 mutants in response to blue-light exposure after dark treatment. Thus, an in vitro gDNA-binding assay coupled with sequencing is a convenient and powerful method to bridge the gap between identifying TF binding potential and establishing function. PMID- 25534861 TI - Does tranexamic acid reduce blood transfusion cost for primary total hip arthroplasty? A case-control study. AB - Peri-operative tranexamic acid (TXA) significantly reduces the need for allogeneic blood transfusion in total hip arthroplasty (THA) and thus hospital costs are reduced. Before employing TXA in primary THA at our institution, facility costs were $286.90/THA for blood transfusion and required 0.45 man hours/THA (transfusion rate 19.87%). After incorporating TXA, the cost for intravenous application was $123.38/THA for blood transfusion and TXA medication and 0.07 man-hours/THA (transfusion rate 4.39%) and the cost for topical application was $132.41/THA for blood transfusion and TXA and 0.14 man-hours/THA (transfusion rate 12.86%). TXA has the potential to reduce the facility cost per THA and the man-hours/THA from blood transfusions. PMID- 25534862 TI - Cost-effective prophylaxis against venous thromboembolism after total joint arthroplasty: warfarin versus aspirin. AB - Although recent guidelines suggest aspirin for venous thromboembolism (VTE) prophylaxis in low risk patients following total hip arthroplasty (THA) and total knee arthroplasty (TKA), there are no cost-effectiveness studies comparing aspirin and warfarin. In a Markov cohort cost-effectiveness analysis, we found that aspirin cost less and saved more quality-adjusted life-years (QALYs) than warfarin in all age groups. Cost per QALY gained by aspirin was $24,506.20 at age of 55 and $47,148.10 at the age of 85 following THA and $15,117.20 and $24,458.10 after TKA, which were greater than warfarin. In patients undergoing THA/TKA without prior VTE, aspirin is more cost-effective prophylactic agent than warfarin. Warfarin might be a better prophylaxis in TKA patients with high probability of VTE and very low probability of bleeding. PMID- 25534863 TI - Letter to the editor: Comparison of topical and intravenous tranexamic Acid on blood loss and transfusion rates in total hip arthroplasty. PMID- 25534864 TI - The efficacy of combined use of intraarticular and intravenous tranexamic acid on reducing blood loss and transfusion rate in total knee arthroplasty. AB - The purpose of this study is to investigate the effect of preoperative intravenous (IV) and intraoperative topical administration of tranexamic acid (TXA) in total knee arthroplasty (TKA). A total of 120 patients were and randomly allocated to either topical group, combined group, or control group. The mean total blood loss was lower in the combined and topical groups (705 mL and 579 mL, respectively) in comparison with control group (949 mL, P < 0.001). There was a significant difference in transfusion rate among groups (P = 0.009). The postoperative hemoglobin drop and total drain amount were significantly less in the combined group compared to other groups. In conclusion, combining preoperative IV injection and topical administration of TXA can effectively reduce blood loss and transfusion rate. PMID- 25534865 TI - Which measures of adiposity predict subsequent left ventricular geometry? Evidence from the Bogalusa Heart Study. AB - BACKGROUND AND AIMS: Left ventricular (LV) hypertrophy increases the risk of future cardiovascular events. The relationship between obesity in young adulthood and later LV geometry is unknown. We examined the association between long-term changes in measures of adiposity and subsequent LV geometry among 1073 young adults from the Bogalusa Heart Study. METHODS AND RESULTS: Echocardiography measured LV geometry was classified into normal (N = 796), concentric remodeling (N = 124), eccentric hypertrophy (N = 99), and concentric hypertrophy (N = 54) by integrating relative wall thickness and LV mass index. The mean age of our population was 38 years when the LV geometry was measured. Body mass index (BMI) increased by a mean of 4.9 kg/m(2) over a median of 20 years, waist circumference (WC) by 10.9 cm over 17 years, waist/hip ratio by 0.02 over 10 years, waist/height ratio by 0.06 over 17 years, abdominal height by 0.9 cm over 10 years, body fat (BF) percentage by 12.7% over 20 years, and Visceral Adiposity Index by 0.30 over 17 years. In polytomous logistic regression models corrected for multiple comparisons, participants with one-standard-deviation increases in BMI, WC, waist/height ratio, and BF had 2.00 (95% confidence interval (CI): 1.53 2.61), 1.33 (1.06-1.68), 1.35 (1.07-1.70), and 1.60 (1.26-2.03) times the risk of eccentric hypertrophy, respectively, after adjustment for demographic, lifestyle, metabolic risk factors, and follow-up time. Likewise, the rates of change in BMI, WC, waist/height ratio, and BF were associated with eccentric hypertrophy. There was no association with concentric remodeling or concentric hypertrophy. CONCLUSIONS: Our findings suggest that increases in BMI, WC, waist/height ratio, and BF were strong predictors of eccentric hypertrophy in middle age. PMID- 25534866 TI - Impact of cholesterol lowering treatment on plasma kynurenine and tryptophan concentrations in chronic kidney disease: relationship with oxidative stress improvement. AB - BACKGROUND AND AIM: Tryptophan (Trp) degradation via indoleamine (2,3) dioxygenase (IDO), with consequent increased in kynurenine (Kyn) concentrations, has been proposed as marker of immune system activation. Oxidative stress (OS) might contribute to the pro-inflammatory state in chronic kidney disease (CKD) through the activation of NF-kB, with consequent activation and recruitment of immune cells. METHODS AND RESULTS: Serum concentrations of Trp and Kyn, oxidative stress indices malondialdehyde (MDA) and allantoin/uric acid (All/UA) ratio and anti-oxidant amino acid taurine were measured in 30 CKD patients randomized to 40 mg/day simvastatin (group 1), ezetimibe/simvastatin 10/20 mg/day (group 2) or ezetimibe/simvastatin 10/40 mg/day (group 3) and treated for 12 months. Baseline Kyn and Kyn/Trp ratio were higher in CKD patients vs. healthy controls (1.67 +/- 0.62 MUmol/L vs 1.25 +/- 0.40 MUmol/L, p < 0.01 and 0.036 +/- 0.016 vs 0.023 +/- 0.010, p < 0.001 respectively). Both Kyn and Kyn/Trp ratio significantly decreased after cholesterol lowering treatment, to values comparable with healthy controls after one year treatment (1.67 +/- 0.62 MUmol/L vs 1.31 +/- 0.51 MUmol/L, p < 0.0001 and 0.036 +/- 0.016 vs 0.028 +/- 0.012 p < 0.0001, respectively). This was paralleled by a significant decrease in MDA (218 +/- 143 nmol/L vs 176 +/- 123 nmol/L, p < 0.01) and All/UA ratio (1.47 +/- 0.72 vs 1.19 +/- 0.51, p < 0.01) in CKD patients. CONCLUSIONS: Amelioration of both oxidative and inflammation status after cholesterol lowering treatment in CKD might be mediated by restoration of antioxidant taurine concentrations during therapy (from 51.1 +/- 13.3 MUmol/L at baseline to 63.1 +/- 16.4 MUmol/L, p < 0.001 by ANOVA), suggesting that improvement of both oxidative and inflammation status in CKD patients could be explained, at least partly, by the cholesterol lowering effects. PMID- 25534868 TI - The APSES family proteins in fungi: Characterizations, evolution and functions. AB - The APSES protein family belongs to transcriptional factors of the basic helix loop-helix (bHLH) class, the originally described members (APSES: Asm1p, Phd1p, Sok2p, Efg1p and StuAp) are used to designate this group of proteins, and they have been identified as key regulators of fungal development and other biological processes. APSES proteins share a highly conserved DNA-binding domain (APSES domain) of about 100 amino acids, whose central domain is predicted to form a typical bHLH structure. Besides APSES domain, several APSES proteins also contain additional domains, such as KilA-N and ankyrin repeats. In recent years, an increasing number of APSES proteins have been identified from diverse fungi, and they involve in numerous biological processes, such as sporulation, cellular differentiation, mycelial growth, secondary metabolism and virulence. Most fungi, including Aspergillus fumigatus, Aspergillus nidulans, Candida albicans, Fusarium graminearum, and Neurospora crassa, contain five APSES proteins. However, Cryptococcus neoformans only contains two APSES proteins, and Saccharomyces cerevisiae contains six APSES proteins. The phylogenetic analysis showed the APSES domains from different fungi were grouped into four clades (A, B, C and D), which is consistent with the result of homologous alignment of APSES domains using DNAman. The roles of APSES proteins in clade C have been studied in detail, while little is known about the roles of other APSES proteins in clades A, B and D. In this review, the biochemical properties and functional domains of APSES proteins are predicted and compared, and the phylogenetic relationship among APSES proteins from various fungi are analyzed based on the APSES domains. Moreover, the functions of APSES proteins in different fungi are summarized and discussed. PMID- 25534867 TI - Sodium Excretion and Cardiovascular Structure and Function in the Nonhypertensive Population: The Korean Genome and Epidemiology Study. AB - BACKGROUND: The effect of sodium intake on the cardiovascular system remains controversial. The purpose of this study is to investigate the relation between sodium intake and cardiovascular structure and function in the nonhypertensive population. METHODS: We performed a cross-sectional analysis in 1,586 nonhypertensive subjects who participated in the Korean Genome Epidemiology Study (2007-2008). Sodium intake was assessed by estimating the 24-hour urinary sodium excretion from a spot urine sample. Changes in cardiovascular structure and function were assessed by using tissue Doppler echocardiography, the carotid intima-media thickness (CIMT), and the brachial-ankle pulse wave velocity (baPWV). RESULTS: Systolic and diastolic blood pressures increased with increasing tertiles of estimated 24-hour urinary sodium excretion. In multivariate analyses adjusting for covariates, there were stepwise decreases in the baPWV (P = 0.003) and CIMT (P = 0.001) values as the estimated 24-hour urinary sodium excretion increased, whereas no significant differences in left ventricular (LV) structural and functional parameters were observed across the tertiles of estimated 24-hour urinary sodium excretion. Multiple linear regression analyses revealed that the estimated 24-hour urinary sodium excretion was independently and inversely associated with baPWV (P < 0.001) and CIMT (P = 0.001), but not with LV parameters. CONCLUSIONS: In the nonhypertensive population, urinary sodium excretion was inversely related to baPWV and CIMT. However, there were no associations between urinary sodium excretion and LV structure or function. PMID- 25534869 TI - The association of CD28 polymorphism, rs3116496, with Cancer: A meta-analysis. AB - OBJECTIVE: To determine the relationship between CD28 polymorphisms, rs3116496, and cancer. DESIGN: Meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and Cochrane library databases were searched to identify studies reporting the association between CD28 polymorphism and cancer. Two authors selected identified studies, extracted, and analyzed the data independently. RESULTS: Individuals carrying a T allele (TT homozygotes and TT+TC heterozygotes) at rs3116496 had a lower incidence of cancer than carriers of a C allele. Subgroup analysis showed that this association held true for Asians, but not Europeans. CONCLUSION: CD28 polymorphism, rs3116496, contributes to cancer susceptibility in the case of multiple cancers. PMID- 25534870 TI - Growth differentiation factor 11 is a protective factor for osteoblastogenesis by targeting PPARgamma. AB - Growth and differentiation factor 11 (GDF11) is a TGF-beta family member that is expressed widely and plays multiple roles, including regulating axial skeletal patterning during development. However, the function of GDF11 in the bone is barely understood. Here we identify GDF11 as a potent regulator of bone homeostasis. GDF11 level is significantly decreased in the plasma and bone marrow of aging mice and mice with osteoporosis. Pharmacologic GDF11 gain of function leads to a striking increase in osteoblastogenesis and inhibits adipogenesis from bone marrow mesenchymal stem cells by altering the gene expression pattern. GDF11 inhibits the activity of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) by promoting its SUMOylation. Therefore, GDF11 is a critical rheostat for bone turnover and a key integrator of bone homeostasis. These results reveal that skeletal fragility may be reduced by chronic GDF11 administration. PMID- 25534872 TI - Structural, Raman spectroscopic and microwave dielectric studies on Ni1 x(Zn1/2Zr1/2)xW1-xNbxO4 ceramic compounds with wolframite structure. AB - Ni1-x(Zn1/2Zr1/2)xW1-xNbxO4 (x = 0.0-1.0) compositions were synthesized via conventional solid-state reaction method. Structural and lattice vibrational characteristics of these compositions were studied with the help of powder X-ray diffraction and Raman spectroscopic measurements. Rietveld refinements confirm the formation of all these compositions in monoclinic wolframite structure with P2/c space group. When moving towards Ni(2+)-poor compositions, splitting in the X-ray reflections was observed and is explained with lattice parameter variation. With increasing value of x, Raman spectra show two additional Raman active modes and the possible reasons for observing these modes are discussed in terms of electronegativity difference of the randomly distributed cations in B-site of these compositions. X-ray photoelectron spectroscopic measurements were done to understand the chemical bonding states of different elements in these compositions. Surface morphology studies reveal that the average grain size increases with increasing x. Microwave dielectric properties such as dielectric constant and quality factor were measured using Hakki-Coleman and reflection cavity techniques and enhancement in these values with x is correlated with intrinsic parameters such as polarizability and 3d electrons present in the constituent ions of these compositions. Temperature coefficient of resonant frequency was measured using an invar cavity attached to a programmable hot plate and is explained with B-site octahedral distortion of these compositions. Well dense Ni1-x(Zn1/2Zr1/2)xW1-xNbxO4 (x = 0.0-1.0) compositions possess good microwave dielectric properties. PMID- 25534871 TI - pH-switchable self-assembled materials. AB - Self-assembled materials, which are able to respond to external stimuli, have been extensively studied over the last decades. A particularly exciting stimulus for a wide range of biomedical applications is the pH value of aqueous solutions, since deprotonation-protonation events are crucial for structural and functional properties of biopolymers. In living cells and tissues, intra- and extracellular pH values are stringently regulated, but can deviate from pH neutral as observed for example in tumorous, inflammatory sites, in endocytic pathways, and specific cellular compartments. By using a pH-switch as a stimulus, it is thereby possible to address specific targets in order to cause a programmed response of the supramolecular material. This strategy has not only been successfully applied in fundamental research but also in clinical studies. In this feature article, current strategies that have been used in order to design materials with pH responsive properties are illustrated. This discussion only addresses selected examples from the last four years, the self-assembly of polymer-based building blocks, assemblies emerging from small molecules including surfactants or derived from biological macromolecules, and finally the controlled self-assembly of oligopeptides. PMID- 25534873 TI - Pre-closure of Large-Sized Arterial Access Sites in Adults Undergoing Transcatheter Structural Interventions. AB - INTRODUCTION: Patients undergoing structural heart interventions often require large-sized sheath insertion into femoral arteries and veins. Clinical outcome data on the use of suture-mediated devices for large femoral arterial access in structural heart interventions is limited. We assessed the efficacy of the PercloseTM (Abbott Vascular Devices, Santa Clara, CA, USA) suture-mediated device using the pre-closure technique in achieving hemostasis in femoral arterial access sites following large sheath insertion (>=8 Fr). METHODS: One hundred consecutive patients underwent 101 femoral artery access sites closures with the Perclose device using the pre-closure technique. Sixty-two percent of the patients were male and their mean (SD) age was 52 (+/-26) years. All patients received heparin. RESULTS: Mean arterial access site sheath diameter was 13 +/- 2 Fr. Immediate hemostasis was achieved in 96/101 (96%) procedures (<=2 min). Two patients (2%) had access site-related complications requiring further interventions. On clinical follow up [mean (SD) follow-up of 24 (+/-12) months and median follow-up of 8.5 months], no complications were seen in the arterial access sites. CONCLUSION: Pre-closure of large-size femoral arterial access sheath sites using the suture-mediated Perclose device is efficacious in achieving rapid hemostasis in patients undergoing structural interventions. On 1 year follow-up, there were no arterial access site complications requiring further investigations or interventions. PMID- 25534874 TI - Vasovagal syncope: an update on the latest pharmacological therapies. AB - INTRODUCTION: Syncope is an abrupt loss of consciousness in response to reduced perfusion to the brain. Neurocardiogenic or vasovagal syncope results from a complex neurologic reflex, and treatments to prevent recurrence attempt to modulate aspects of that reflex. AREAS COVERED: Pharmacologic treatments for vasovagal syncope address the syncope reflex in multiple ways. Fludrocortisone and sodium chloride increase systemic fluid volume. Midodrine, beta blockers and norepinephrine transport inhibitors modulate the sympathetic nervous system. Other treatments for syncope modulate other neurotransmitters or affect heart rate. The most recent trials evaluating established and novel therapies are reviewed. EXPERT OPINION: To reduce recurrence of vasovagal syncope, conservative measures are first line. If these fail to prevent recurrence, the most promising medical therapy includes midodrine. Randomized placebo-controlled data evaluating fludrocortisone, midodrine and beta blockers in older patients are awaited. Because of the significance of the placebo effect in this condition, any treatment must be evaluated in a randomized double-blind placebo-controlled trial before being accepted as effective. PMID- 25534876 TI - Cinnamyl alcohol dehydrogenases in the mesocarp of ripening fruit of Prunus persica genotypes with different flesh characteristics: changes in activity and protein and transcript levels. AB - Development of fruit flesh texture quality traits may involve the metabolism of phenolic compounds. This study presents molecular and biochemical results on the possible role played by cinnamyl alcohol dehydrogenase (CAD; EC 1.1.1.195) during ripening [S3, S4 I (pre-climacteric) and S4 III (climacteric) stages] of peach [Prunus persica (L.) Batsch] fruit with different flesh firmness [non-melting flesh (NMF) 'Oro A'/melting flesh (MF) 'Springcrest' and 'Sanguinella'] and color (blood-flesh Sanguinella). A total of 24 putative full-length PRUPE_CAD genes were identified (in silico analysis) in the peach genome. The most abundant CAD isoforms, encoded by genes located on scaffolds 8 and 6, were probed by specifically developed anti-PRUPE_CAD sc8 and by anti-FaCAD (PRUPE_CAD sc6) polyclonal antibodies, respectively. PRUPE_CAD sc8 proteins (SDS-PAGE and native PAGE/western blot) appeared responsible for the CAD activity (in vitro/in-gel assays) that increased with ripening (parallel to PRUPE_ACO1 transcripts accumulation and ethylene evolution) only in the mesocarp of Oro A and blood flesh Sanguinella. Accumulation of PRUPE_CAD sc8 transcripts (semi-quantitative RT-PCR) occurred in all three cultivars, but in Oro A and Springcrest it was not always accompanied by that of the related proteins, suggesting possible post transcriptional regulation. Flesh firmness, as well as levels of lignin, total phenolics and, where present (Sanguinella), anthocyanins, declined with ripening, suggesting that, at least in the studied peach cultivars, CAD activity is related to neither lignification nor differences in flesh firmness (NMF/MF). Further studies are necessary to clarify whether the high levels of CAD activity/expression in Sanguinella play a role in determining the characteristics of this blood-flesh fruit. PMID- 25534877 TI - Glycemic variability and diabetes retinopathy: a missing link. AB - Daily glucose variability, such as fasting plasma glucose fluctuation or postprandial hyperglycemia, has been proposed as contributors to diabetes-related macrovascular complications. However, its impacts on microvascular complications, such as diabetes retinopathy remain controversial. We reviewed the current evidence of the relationship between glycemic variability and diabetes retinopathy in patients with type 1 or type 2 diabetes. In general, the short term glycemic fluctuation, either expressed as standard deviation of fasting glucose or mean glucose levels, may contribute to the development or progression of diabetic retinopathy in patients with type 2 diabetes, whereas long-term glycemic fluctuation, reflected by variation of levels of HbA1c, appeared to show a stronger association with diabetes retinopathy both in patients with type 1 and type 2 diabetes. These findings emphasize the need to reduce glycemic variability by various measures in order to reduce development and progression of diabetes retinopathy both in type 1 and type 2 diabetes patients. PMID- 25534878 TI - Cancer risk in people with diabetes: Does physical activity and adiposity modify the association? Prospective data from the HUNT Study, Norway. AB - AIMS: To examine whether physical activity and adiposity modify the increased risk of cancer associated with diabetes. METHODS: We prospectively examined the association of diabetes and risk of cancer among 73,726 persons stratified by physical activity and body mass index (BMI). Adjusted hazard ratios (HRs) with 95% confidence intervals (CI) were estimated from Cox regression. RESULTS: During a median follow-up of 22.0 years, 9572 people were diagnosed with incident cancer. There was no clear association between diabetes and cancer risk in those reporting high levels of physical activity (>=2.0h per week) (HR 0.93; 95% CI: 0.70-1.24) or those with a normal weight (BMI <25kg/m2) (HR 1.02; 95% CI: 0.84 1.25). However, among people with diabetes who reported low levels of physical activity (<2.0h per week), diabetes was associated with an HR of 1.15 (95% CI: 1.01-1.31). Correspondingly, diabetes was associated with an HR of 1.21 (95% CI: 1.07-1.37) among overweight or obese people (BMI >=25kg/m2). CONCLUSIONS: There was evidence that the increased risk of cancer associated with diabetes was confined to persons who reported low levels of physical activity, or who were overweight or obese. PMID- 25534879 TI - Preoperative carbohydrate supplementation attenuates post-surgery insulin resistance via reduced inflammatory inhibition of the insulin-mediated restraint on muscle pyruvate dehydrogenase kinase 4 expression. AB - BACKGROUND & AIMS: We hypothesized that the so far poorly understood improvement in postoperative insulin sensitivity, when surgery is preceded by a carbohydrate (CHO) drink, occurs via attenuation of skeletal muscle inflammatory responses to surgery, improved insulin signaling and attenuated expression of muscle pyruvate dehydrogenase kinase (PDK) 4. METHODS: Vastus lateralis muscle biopsies, collected before and after major abdominal surgery and during postoperative hyperinsulinaemic-euglycaemic clamping from 16 pigs randomized to either 200 ml of a CHO-supplemented drink 2 h before surgery (CHO, 25 g; n = 8), or preoperative overnight fasting (fasted; n = 8), were analyzed by fast qRT-PCR and IR-Western blotting. RESULTS: During clamping, expression of IKKbeta, SOCS3 and the ratio of phosphorylated/total JNK2 proteins were lower in the CHO group than in the fasted group (-1.0 vs. 2.9-fold, P < 0.001; -0.6 vs. 3.2-fold, P < 0.01; and -0.5 vs. 1.1-fold, P < 0.02, respectively). Furthermore, the ratio of Ser(307)-phosphorylated (inhibition)/total IRS1 protein was reduced only in the CHO group (-2.4 fold, P < 0.02), whereas FOXO1 phosphorylation (inactivation), which correlated negatively with PDK4 mRNA (r(2) = 0.275, P < 0.05), was lower in the CHO group than in the fasted group (-1.1-fold, P > 0.05 vs. -2.3-fold, P = 0.05). Post-surgery, PDK4 mRNA increased ~20-fold (P < 0.01) in both groups, but was reversed to a greater extent by insulin in the CHO group (-40.5 vs. -22.7 fold, P < 0.05), resulting in 5-fold lower PDK4 protein levels, which correlated negatively with insulin-stimulated whole-body glucose disposal rates (r(2) = 0.265, P < 0.05). CONCLUSIONS: Preoperative carbohydrate supplementation was found to ameliorate postoperative insulin sensitivity by reducing muscle inflammatory responses and improved insulin inhibition of FOXO1-mediated PDK4 mRNA and protein expression after surgery. PMID- 25534880 TI - Optimization of entrapping conditions to improve the release of BMP-2 from PELA carriers by response surface methodology. AB - A microcapsule prepared from triblock copolymer poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA, PELA) was investigated as a controlled release carrier for recombinant human bone morphogenetic protein-2 (rhBMP-2). The rhBMP-2/PELA microspheres were prepared using the water-in-oil-in-water (W/O/W) solvent evaporation method. This work was conducted to optimize the entrapping conditions of the rhBMP-2 loaded PELA copolymer. The effects on encapsulation efficiency (EE) of different molecular weights (MW) of PEG in the copolymer, the amount of PELA, the amount of rhBMP-2, the span-20 concentration, the polyvinyl alcohol (PVA) concentration and stirring time were tested. On the basis of single factor experiments, the optimum parameters were achieved using response surface methodology (RSM). The results showed that the highest EE of BMP-2 was achieved with a span-20 concentration of 0.5%, PEG MW 4000 Da, a stirring time of 30 min at 800 rpm min(-1), 282.3 mg of PELA, 1 MUg of rhBMP-2 and PVA concentration 0.79%. Under these optimal conditions, it was predicted that the highest EE to be achieved would be 76.5%; the actual EE achieved was 75%. PMID- 25534881 TI - SILAC-iPAC: a quantitative method for distinguishing genuine from non-specific components of protein complexes by parallel affinity capture. AB - Pull-down assays can identify members of protein complexes but suffer from co isolation of contaminants. The problem is particularly acute when the specifically interacting partners are of low-abundance and/or bind transiently with low affinity. To differentiate true interacting partners from contaminants, we have combined SILAC labelling with a proteomic method called "Interactomes by Parallel Affinity Capture" (iPAC). In our method, a cell-line stably expressing a doubly tagged target endogenous protein and its tag-less control cell-line are differentially SILAC labelled. Lysates from the two cell-lines are mixed and the tagged protein is independently purified for MS analysis using multiple affinity resins in parallel. This allows the quantitative identification of tagged proteins and their binding partners. SILAC-iPAC provides a rigorous and sensitive approach that can discriminate between genuine binding partners and contaminants, even when the contaminants in the pull-down are in large excess. We employed our method to examine the interacting partners of phosphatidyl inositol 5-phosphate 4 kinase 2beta subunit (PI5P4K2beta) and the Fanconi anaemia core complex in the chicken pre-B cell-line DT40. We confirmed known components of these two complexes, and we have identified new potential binding partners. Combining the iPAC approach with SILAC labelling provides a sensitive and fully quantitative method for the discrimination of specific interactions under conditions where low signal to noise ratios are unavoidable. In addition, our work provides the first characterisation of the most abundant proteins within the DT40 proteome and the non-specific DT40 'beadomes' (non-specific proteins binding to beads) for common epitope tags. Given the importance and widespread use of the DT40 cell-line, these will be important resources for the cell biology and immunology communities. Biological significance SILAC-iPAC provides an improved method for the analysis of low-affinity and/or low abundance protein-protein interactions. We use it to clarify two examples where the nature of the protein complexes are known, or are currently unclear. The method is simple and quantitative and will be applicable to many problems in cell and molecular biology. We also report the first chicken beadomes. PMID- 25534882 TI - Comparative analysis of the uropathogenic Escherichia coli surface proteome by tandem mass-spectrometry of artificially induced outer membrane vesicles. AB - Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections. For successful colonisation of the urinary tract, UPEC employ multiple surface-exposed or secreted virulence factors, including adhesins and iron uptake systems. Whilst individual UPEC strains and their virulence factors have been the focus of extensive research, there have been no outer membrane (OM) proteomic studies based on large clinical UPEC collections, primarily due to limitations of traditional methods. In this study, a high-throughput method based on tandem mass-spectrometry of EDTA heat-induced outer membrane vesicles (OMVs) was developed for the characterisation of the UPEC surface-associated proteome. The method was applied to compare the OM proteome of fifty-four UPEC isolates, resulting in the identification of 8789 proteins, consisting of 619 unique proteins, which were subsequently interrogated for their subcellular origin, prevalence and homology to characterised virulence factors. Multiple distinct virulence-associated proteins were identified, including two novel putative iron uptake proteins, an uncharacterised type of chaperone-usher fimbriae and various highly prevalent hypothetical proteins. Our results give fundamental insight into the physiology of UPEC and provide a framework for understanding the composition of the UPEC OM proteome. BIOLOGICAL SIGNIFICANCE: In this study a high-throughput method based on tandem mass-spectrometry of EDTA heat-induced outer membrane vesicles was used to define the outer membrane proteome of a large uropathogenic E. coli (UPEC) collection. Our results provide an inventory of proteins expressed on the surface of UPEC, and provide a framework for understanding the composition of the UPEC OM proteome. The method enables the rapid characterisation of the E. coli surface proteome and could easily be applied to the large-scale outer membrane protein profiling of other Gram-negative bacteria. PMID- 25534883 TI - Reevaluating the Trypanosoma cruzi proteomic map: The shotgun description of bloodstream trypomastigotes. AB - Chagas disease is a neglected disease, caused by the protozoan Trypanosoma cruzi. This kinetoplastid presents a cycle involving different forms and hosts, being trypomastigotes the main infective form. Despite various T. cruzi proteomic studies, the assessment of bloodstream trypomastigote profile remains unexplored. The aim of this work is T. cruzi bloodstream form proteomic description. Employing shotgun approach, 17,394 peptides were identified, corresponding to 7514 proteins of which 5901 belong to T. cruzi. Cytoskeletal proteins, chaperones, bioenergetics-related enzymes, and trans-sialidases are among the top scoring. GO analysis revealed that all T. cruzi compartments were assessed; and majority of proteins are involved in metabolic processes and/or presented catalytic activity. The comparative analysis between the bloodstream trypomastigotes and cultured-derived or metacyclic trypomastigote proteomic profiles pointed to 2202 proteins exclusively detected in the bloodstream form. These exclusive proteins are related to: (a) surface proteins; (b) non-classical secretion pathway; (c) cytoskeletal dynamics; (d) cell cycle and transcription; (e) proteolysis; (f) redox metabolism; (g) biosynthetic pathways; (h) bioenergetics; (i) protein folding; (j) cell signaling; (k) vesicular traffic; (l) DNA repair; and (m) cell death. This large-scale evaluation of bloodstream trypomastigotes, responsible for the parasite dissemination in the patient, marks a step forward in the comprehension of Chagas disease pathogenesis. BIOLOGICAL SIGNIFICANCE: The hemoflagellate protozoan T. cruzi is the etiological agent of Chagas disease and affects people by the millions in Latin America and other non endemic countries. The absence of efficient drugs, especially for treatment during the chronic phase of the disease, stimulates the continuous search for novel molecular targets. The identification of essential molecules, particularly those found in clinically relevant forms of the parasite, could be crucial. Inside the vertebrate host, trypomastigotes circulate in the bloodstream before infecting various tissues. The exposure of bloodstream forms of the parasite to the host immune system likely leads to differential protein expression in the parasite. In this context, an extensive characterization of the proteomic profile of bloodstream trypomastigotes could help to find not only promising drug targets but also antigens for vaccines or diagnostics. This work is a large-scale proteomic assessment of bloodstream trypomastigotes that show a considerable number of proteins belonging to different metabolic pathways and functions exclusive to this parasitic form, and provides a valuable dataset for the biological understanding of this clinically relevant form of T. cruzi. PMID- 25534884 TI - Salivary peptidomic as a tool to disclose new potential antimicrobial peptides. AB - Antimicrobial peptides (AMPs) and peptidomimetics are among the new generation of antibiotics due to their broad spectrum of activity towards pathogenic agents. Considering the fact that the oral cavity is a relevant entryway for pathogenic microorganisms, it must be armed with several defenses in order to maintain homeostasis. Thus, we aimed at disclosing potential AMPs in saliva from humans, pigs and mice. We enriched salivary peptides by filtration and then separated and identified multiple peptides by nanoHPLC-MALDI-TOF/TOF. Using this approach, we identified 45 different peptides from mice's saliva and 94 from pig's saliva. Almost all peptides from pig and mice saliva were new assignments, encouraging the application of this technique to other mammals' saliva. The potential antimicrobial activity was then calculated in silico with an available CAMP's algorithm. Eight peptides from pig's basic proline-rich protein, as well as 6 peptides resulting from human's P-B peptide, 1 from P-C peptide fragmentation and 1 from statherin were found to have potential antimicrobial activity. Therefore, the peptides GPPPQGGRPQG and RFGYGYGPYQPVPEQPLYPQ were synthetically obtained and their antimicrobial properties evaluated in vitro for different bacterial strains. These showed to exert an antibacterial effect in Staphylococcus aureus. This report validates the prospection of mammal's saliva to find new alternatives to antibiotics. BIOLOGICAL SIGNIFICANCE: With the growing problem of antibiotic resistance, the identification of new routes in antibiotic therapy is on the scientific agenda worldwide. Antimicrobial peptides (AMPs) and peptidomimetics are among the new generation of antibiotics due to their broad spectrum of activity towards pathogenic agents and owing to a less probable microbial resistance that can arise from their use. Thus, we explored the saliva from humans, pigs and mice to identify potential AMPs using a peptidomic approach. At the end, eight peptides from pig's basic proline-rich protein, six peptides resulting from human's P-B peptide, one from P-C peptide fragmentation and one from statherin were found to have potential antimicrobial activity. From this, the peptides GPPPQGGRPQG and RFGYGYGPYQPVPEQPLYPQ were tested showing to have antibacterial effect in S. aureus which highlights the potential of mammal's saliva to find new alternatives to antibiotics. PMID- 25534885 TI - Aortic prosthesis-patient mismatch in patients with paradoxical low flow severe aortic stenosis: a dreadful combination. PMID- 25534887 TI - Layer-by-layer growth of CH3NH3PbI(3-x)Clx for highly efficient planar heterojunction perovskite solar cells. AB - A layer-by-layer approach is developed to prepare uniform and compact CH3NH3PbI(3 x)Clx perovskite films for perovskite solar cells with a high efficiency up to 15.12% and an improved stability. Moreover, a record high efficiency of 12.25% is achieved for these flexible perovskite solar cells. This study represents an important step forward in developing high-performance and stable perovskite solar cells. PMID- 25534886 TI - Prognostic markers of acute decompensated heart failure: the emerging roles of cardiac biomarkers and prognostic scores. AB - Rapidly assessing outcome in patients with acute decompensated heart failure is important but prognostic factors may differ from those used routinely for stable chronic heart failure. Multiple plasma biomarkers, besides the classic natriuretic peptides, have recently emerged as potential prognosticators. Furthermore, prognostic scores that combine clinical and biochemical data may also be useful. However, compared with the scores used in chronic heart failure, scores for acute decompensated heart failure have not been validated. This article reviews potential biomarkers, with a special focus on biochemical biomarkers, and possible prognostic scores that could be used by the clinician when assessing outcome in patients with acute heart failure. PMID- 25534888 TI - Hypophysitis: a single-center case series. AB - PURPOSE: The authors review their treatment experience and summarize clinical outcomes for patients with hypophysitis over the past 15 years. METHODS: A retrospective analysis was conducted on patients with lymphocytic, granulomatous or IgG4-related hypophysitis treated from 1997 to 2014 at a single academic center. Patients' medical records were reviewed and binary logistic regression analysis was used to assess whether various clinical parameters were associated with improved outcomes including endocrine function, radiographic appearance and disease recurrence. RESULTS: Twenty-one patients (13 women and 8 men) were identified with a median diagnosis age of 37.4 years. All but two patients (90%) were diagnosed histopathologically and the remaining two were diagnosed clinically with lymphocytic hypophysitis. 16 patients (76%) had lymphocytic hypophysitis, 3 (14%) had granulomatous hypophysitis, 1 (5%) had IgG4-related hypophysitis and 1 (5%) had mixed lymphocytic-granulomatous. Patients presented with various symptoms of expanding sellar mass with most common signs including headache (57%), polyuria/polydipsia (52%), vision changes (52%) and amenorrhea or decreased libido (48%). Pre-treatment endocrine evaluation revealed that 12 (57%) patients had complete anterior hypopituitarism, 11 patients (52%) had diabetes insipidus, ten patients (48%) had mild hyperprolactinemia and three patients (14%) had isolated endocrine axis deficiencies with partial gland function. We observed a broad diversity in pre-treatment imaging with common findings including uniform contrast enhancement (62%), thickened infundibulum (57%) and loss of hypophysis bright spot on T1 imaging (43%). Patients were treated with steroids and hormone supplementation as needed. 16 patients (76%) had recorded post-treatment MRI scans which revealed that half had radiographic improvement and half had stable or worsened post-treatment imaging. Only female gender was found to significantly predict improved odds of post-steroid radiographic improvement. For post-treatment endocrine evaluation, six patients (29%) did not have an evaluation on record, four patients (19%) had some improvement in at least one axis, seven patients (33%) had stable but non-worsened endocrine function and four patients (19%) had worsened endocrine function post-steroids. CONCLUSIONS: Hypophysitis is an increasingly recognized diagnosis that can present with a broad array of radiographic and clinical features. Surgical biopsy can be helpful to make definitive diagnosis and may guide treatment decision making. PMID- 25534890 TI - Macromolecular transport in synapse to nucleus communication. AB - Local signaling events at synapses or axon terminals must be communicated to the nucleus to elicit transcriptional responses. The lengths of neuronal processes pose a significant challenge for such intracellular communication. This challenge is met by mechanisms ranging from rapid signals encoded in calcium waves to slower macromolecular signaling complexes carried by molecular motors. Here we summarize recent findings on macromolecular signaling from the synapse to the nucleus, in comparison to those employed in injury signaling along axons. A number of common themes emerge, including combinatorial signal encoding by post translational mechanisms such as differential phosphorylation and proteolysis, and conserved roles for importins in coordinating signaling complexes. Neurons may integrate ionic flux with motor-transported signals as a temporal code for synaptic plasticity signaling. PMID- 25534889 TI - Silent corticotroph adenomas. AB - PURPOSE: Silent corticotroph adenomas (SCAs) comprise 20% of all corticotroph adenomas and 3-19% of nonfunctioning adenomas (NFAs). As they do not manifest clinical or biochemical hypercortisolism, they are diagnosed after pathologic examination of resected tumor tissue demonstrates positive ACTH expression. While preoperative features are similar to those of NFAs, SCAs may have more cavernous sinus invasion. Further, patients with SCAs tend to have more frequent and earlier recurrences than those with NFAs, often necessitating multiple surgeries and other modalities of treatment. This article reviews the incidence, pathogenesis, and clinical behavior of SCAs. METHODS: A systematic literature review was performed using PubMed for information regarding SCAs. RESULTS: Up to date findings regarding epidemiology, pathogenesis, pathology, clinical presentation, postoperative course, and management of patients with SCAs are presented. CONCLUSION: This review highlights the necessity of rigorous monitoring for recurrences and hypopituitarism in patients with SCAs. PMID- 25534892 TI - Meeting the needs of the future. PMID- 25534893 TI - The gluten-free labeling rule: what registered dietitian nutritionists need to know to help clients with gluten-related disorders. PMID- 25534891 TI - Elucidating the role of the TRPM7 alpha-kinase: TRPM7 kinase inactivation leads to magnesium deprivation resistance phenotype in mice. AB - TRPM7 is an unusual bi-functional protein containing an ion channel covalently linked to a protein kinase domain. TRPM7 is implicated in regulating cellular and systemic magnesium homeostasis. While the biophysical properties of TRPM7 ion channel and its function are relatively well characterized, the function of the TRPM7 enzymatically active kinase domain is not understood yet. To investigate the physiological role of TRPM7 kinase activity, we constructed mice carrying an inactive TRPM7 kinase. We found that these mice were resistant to dietary magnesium deprivation, surviving three times longer than wild type mice; also they displayed decreased chemically induced allergic reaction. Interestingly, mutant mice have lower magnesium bone content compared to wild type mice when fed regular diet; unlike wild type mice, mutant mice placed on magnesium-depleted diet did not alter their bone magnesium content. Furthermore, mouse embryonic fibroblasts isolated from TRPM7 kinase-dead animals exhibited increased resistance to magnesium deprivation and oxidative stress. Finally, electrophysiological data revealed that the activity of the kinase-dead TRPM7 channel was not significantly altered. Together, our results suggest that TRPM7 kinase is a sensor of magnesium status and provides coordination of cellular and systemic responses to magnesium deprivation. PMID- 25534894 TI - A new breed of evidence and the tools to generate it: introducing ANDHII. PMID- 25534895 TI - Approaches to ethical decision-making. PMID- 25534896 TI - Advancing health through sustained collaboration: how the history of corporate relations extended the Academy's reach. PMID- 25534897 TI - What is the Whipple procedure and what is the appropriate nutrition therapy for it? PMID- 25534898 TI - The incidental pulmonary nodule in a child: a conundrum. PMID- 25534899 TI - Emergency care and referral among isolated island populations in the Bahamas. AB - BACKGROUND: Isolated island populations face unique health challenges. In the Bahamas, the islands of Mayaguana, Inagua, Crooked Island, Acklins, and Long Cay referred to as the MICAL Constituency-are among the most isolated. OBJECTIVES: Our objective was to better understand regional emergency care needs and capabilities, and determine how emergency care can be optimized among island populations. METHODS: During the summer of 2013, the project team conducted semi structured key-informant interviews and small-group discussions among all health care teams in the MICAL region, as well as a community-based household survey on the island of Mayaguana. The interviews and small-group discussions consisted of open-response questions related to health care services, equipment, supplies, medications, and human resources. The community-based survey examined the prevalence of chronic noncommunicable diseases (CNCDs) and associated risk factors affecting the inhabitants of the region. RESULTS: The average number of annual emergency referrals from each of the MICAL islands was approximately 25 30, and reasons for referrals off-island included chest pain, abdominal pain, trauma, and dysfunctional uterine bleeding. Traditional prehospital care is not established in the MICAL Constituency. Providers reported feelings of isolation from the distant health system in Nassau. Whereas most clinics have a well stocked pharmacy of oral medications, diagnostic capabilities are limited. The household survey showed a high prevalence of CNCDs and associated risk factors. CONCLUSION: Ongoing in-service emergency care training among MICAL providers is needed. Additional equipment could significantly improve emergency care capabilities, specifically, equipment to manage chest pain, fractures, and other trauma. Community-based preventive services and education could improve the overall health of the island populations. PMID- 25534900 TI - Intravenous lipid emulsion in the emergency department: a systematic review of recent literature. AB - BACKGROUND: Intravenous lipid emulsion (ILE) has been broadly attempted in the resuscitation of neurologic and cardiac toxic drug overdoses, however, the role of ILE in the emergency department is poorly defined. OBJECTIVE: This review aims to identify recent literature on the use of ILE in humans as an antidote and to familiarize emergency providers with the indications, availability, dosing recommendations, and adverse reactions associated with ILE use. METHODS: A systemic literature search of MEDLINE, EMBASE, and major toxicology conference abstracts was performed for human cases using ILE as an antidote with documented clinical outcomes through January 2014. RESULTS: Ninety-four published articles and 40 conference abstracts were identified, 85% of which had positive outcomes. The most common indication for ILE was for local anesthetic systemic toxicity (LAST). The most common nonlocal anesthetic xenobiotics were tricyclic antidepressants and verapamil. DISCUSSION: No standard of care is defined for the use of ILE, although the American Heart Association recommends use in LAST, and the American College of Medical Toxicology recommends consideration for circumstances of hemodynamic instability resultant from lipid-soluble xenobiotics. ILE should be administered per American Society of Regional Anesthesia and Pain Medicine dosing recommendations. Laboratory interference, pancreatitis, respiratory distress syndrome, and interference with vasopressors should be considered as risks but are uncommon. CONCLUSIONS: In the setting of severe hemodynamic compromise by lipid-soluble xenobiotics, ILE may be considered for resuscitation by emergency physicians. As such, ILE may be stocked in emergency departments in close proximity to resuscitation rooms and areas where local nerve blocks are performed. PMID- 25534901 TI - Is it time to repair a Fairly Fast SAAB Convertible? Testing an evidence-based mnemonic for the secondary prevention of cardiovascular disease. AB - OBJECTIVES: Optimising secondary prevention of cardiovascular disease has the greatest potential to reduce recurrent events, yet despite major guidelines there are ongoing treatment gaps. FFSAABC (Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers and Clopidogrel) is one mnemonic previously adopted to assist clinicians in remembering medications for use in secondary prevention. The aim of this narrative review is to examine the current evidence base for medications recommended for patients with established cardiovascular disease and the current applicability of this, or a revised mnemonic for their use. STUDY DESIGN: Randomised controlled trials and systematic reviews were sought examining Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers or Clopidogrel vs placebo in secondary prevention. The emerging evidence base for other contemporary therapies including the P2Y12 inhibitors (ticagrelor and prasugrel) and aldosterone antagonists was also reviewed. RESULTS: Definitive evidence supports the use of statins, aspirin, angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, and P2Y12 antagonists (clopidogrel, ticagrelor or prasugrel) for the secondary prevention of cardiovascular disease. Aldosterone antagonists have strong evidence in the presence of systolic heart failure. There is a weaker evidence base for the routine use of omega-3 fatty acid supplementation although this therapy carries minimal harms. Fenofibrate reduces cardiovascular events in dyslipidaemic patients, with additional benefits in patients with diabetes. CONCLUSIONS: Mnemonic upgrading from a Fairly Fast SAAB Convertible to a Fairly Fast SA(2)A(2)B (Fish oils, Fibrate, Statin, Antiplatelets (Aspirin+Other), ACE/ARB, Aldosterone Antagonist, Beta-blocker) may help to ensure patients receive best practice evidence-based pharmacotherapies for the secondary prevention of cardiovascular disease. PMID- 25534903 TI - Correcting for non-compliance in randomized non-inferiority trials with active and placebo control using structural models. AB - The three-arm clinical trial design, which includes a test treatment, an active reference, and placebo control, is the gold standard for the assessment of non inferiority. In the presence of non-compliance, one common concern is that an intent-to-treat (ITT) analysis (which is the standard approach to non-inferiority trials), tends to increase the chances of erroneously concluding non-inferiority, suggesting that the per-protocol (PP) analysis may be preferable for non inferiority trials despite its inherent bias. The objective of this paper was to develop statistical methodology for dealing with non-compliance in three-arm non inferiority trials for censored, time-to-event data. Changes in treatment were here considered the only form of non-compliance. An approach using a three-arm rank preserving structural failure time model and G-estimation analysis is here presented. Using simulations, the impact of non-compliance on non-inferiority trials was investigated in detail using ITT, PP analyses, and the present proposed method. Results indicate that the proposed method shows good characteristics, and that neither ITT nor PP analyses can always guarantee the validity of the non-inferiority conclusion. A Statistical Analysis System program for the implementation of the proposed test procedure is available from the authors upon request. PMID- 25534902 TI - Narrative review comparing the benefits of and participation in cardiac rehabilitation in high-, middle- and low-income countries. AB - BACKGROUND: Cardiovascular disease is a leading cause of morbidity worldwide. Cardiac rehabilitation (CR) is a comprehensive secondary prevention approach, with established benefits in reducing morbidity in high-income countries (HICs). The objectives of this review were to summarise what is known about the benefits of CR, including consideration of cost-effectiveness, in addition to rates of CR participation and adherence in high-, as well as low- and middle-income countries (LMICs). METHODS: A literature search of Medline, Excerpta Medica Database (EMBASE), and Google Scholar was conducted for published articles from database inception to October 2013. The search was first directed to identify meta analyses and reviews reporting on the benefits of CR. Then, the search was focussed to identify articles reporting CR participation and dropout rates. Full text versions of relevant abstracts were summarised qualitatively. RESULTS: Based on meta-analysis, CR significantly reduced all-cause mortality by 13%-26%, cardiac mortality by 20%-36%, myocardial re-infarction by 25%-47%, and risk factors. CR is cost-effective in HICs. In LMICs, CR is demonstrated to reduce risk factors, with no studies on mortality or cost-effectiveness. Based on available data, CR participation rates are <50% in the majority of countries, with documented dropout rates up to 56% and 82% in high- and middle-income countries, respectively. CONCLUSIONS: CR is a beneficial intervention for heart patients in high and LMICs, but is underutilised with low participation and adherence rates worldwide. While more research is needed in LMICs, strategies shown to increase participation and program adherence should be implemented. PMID- 25534904 TI - Iron(III)-binding of the anticancer agents doxorubicin and vosaroxin. AB - The Fe(iii)-binding constant of vosaroxin, an anticancer quinolone derivative, has been determined spectrophotometrically and compared with the analogous Fe(iii) complex formed with doxorubicin. The in vivo metabolic stability and iron coordination properties of the quinolones compared to the anthracylines may provide significant benefit to cardiovascular safety. The mechanism of action of both molecules target the topoisomerase II enzyme. Both doxorubicin (Hdox, log betaFeL3 = 33.41, pM = 17.0) and vosaroxin (Hvox, log betaFeL3 = 33.80(3), pM = 15.9) bind iron(iii) with comparable strength; at physiological pH however, [Fe(vox)3] is the predominant species in contrast to a mixture of species observed for the Fe:dox system. Iron(iii) nitrate and gallium(iii) nitrate at a 1 : 3 ratio with vosaroxin formed stable tris(vosaroxacino)-iron(iii) and tris(vosaroxino)gallium(iii) complexes that were isolated and characterized. Their redox behavior was studied by CV, and their stereochemistry was further explored in temperature dependent (1)H NMR studies. The molecular pharmacology of their interaction with iron(iii) may be one possible differentiation in the safety profile of quinolones compared to anthracyclines in relation to cardiotoxicity. PMID- 25534906 TI - Effects of vipoxin and its components on HepG2 cells. AB - Snake venom Phospholipases A2 (svPLA2) are among the main toxic venom components with a great impact on different tissues and organs based on their catalytic specificity and a variety of pharmacological effects, whose mechanism is still under debate. The main toxic component, isolated from the venom of Vipera ammodytes meridionalis, is the heterodimeric postsynaptic ionic complex vipoxin, composed of a basic and toxic PLA2 enzyme subunit (GIIA secreted PLA2) and an acidic, enzymatically inactive and nontoxic subunit - vipoxin acidic component (VAC). This study demonstrates for the first time that vipoxin and its individual subunits affect integrity and viability of HepG2 cells displaying differences in their pharmacological activities. Under the experimental conditions, the individual PLA2 subunit induces cytotoxicity, cytoskeletal rearrangements and triggers early apoptosis in a concentration-dependent manner related to its enzymatic activity. Vipoxin and VAC do not affect cell viability but manifest high degree of genotoxicity, whereas DNA damage induced by PLA2 subunit could be defined as moderate and not associated with its catalytic activity. Our results suggest that the interactions between vipoxin subunits play an important role in HepG2 cell response and most likely affect the observed distinction between cyto- and genotoxicity. PMID- 25534907 TI - [Possible Kawasaki disease in a 56 years-old male patient diagnosed in sequelae phase]. AB - We present a 56 years-old male patient with an acute ischemic episode. The patient showed significant dilation of the left main coronary artery and proximal segments of the left descending artery, as well as a right coronary artery with a 10mm diameter in the proximal and medial segments. These findings are compatible with a Kawasaki's disease in a chronic phase. PMID- 25534905 TI - Susceptibility loci revealed for bovine respiratory disease complex in pre-weaned holstein calves. AB - BACKGROUND: Bovine respiratory disease complex (BRDC) is an infectious disease of cattle that is caused by a combination of viral and/or bacterial pathogens. Selection for cattle with reduced susceptibility to respiratory disease would provide a permanent tool for reducing the prevalence of BRDC. The objective of this study was to identify BRDC susceptibility loci in pre-weaned Holstein calves as a prerequisite to using genetic improvement as a tool for decreasing the prevalence of BRDC. High density SNP genotyping with the Illumina BovineHD BeadChip was conducted on 1257 male and 757 female Holstein calves from California (CA), and 767 calves identified as female from New Mexico (NM). Of these, 1382 were classified as BRDC cases, and 1396 were classified as controls, with all phenotypes assigned using the McGuirk health scoring system. During the acquisition of blood for DNA isolation, two deep pharyngeal and one mid-nasal diagnostic swab were obtained from each calf for the identification of bacterial and viral pathogens. Genome-wide association analyses were conducted using four analytical approaches (EIGENSTRAT, EMMAX-GRM, GBLUP and FvR). The most strongly associated SNPs from each individual analysis were ranked and evaluated for concordance. The heritability of susceptibility to BRDC in pre-weaned Holstein calves was estimated. RESULTS: The four statistical approaches produced highly concordant results for 373 top ranked SNPs that defined 126 chromosomal regions for the CA population. Similarly, in NM, 370 SNPs defined 138 genomic regions that were identified by all four approaches. When the two populations were combined (i.e., CA + NM) and analyzed, 324 SNPs defined 116 genomic regions that were associated with BRDC across all analytical methods. Heritability estimates for BRDC were 21% for both CA and NM as individual populations, but declined to 13% when the populations were combined. CONCLUSIONS: Four analytical approaches utilizing both single and multi-marker association methods revealed common genomic regions associated with BRDC susceptibility that can be further characterized and used for genomic selection. Moderate heritability estimates were observed for BRDC susceptibility in pre-weaned Holstein calves, thereby supporting the application of genomic selection to reduce the prevalence of BRDC in U.S. Holsteins. PMID- 25534910 TI - Differential effects between one week and four weeks exposure to same mass of SO2 on synaptic plasticity in rat hippocampus. AB - Sulfur dioxide (SO2 ) is a ubiquitous air pollutant. The previous studies have documented the adverse effects of SO2 on nervous system health, suggesting that acutely SO2 inhalation at high concentration may be associated with neurotoxicity and increase risk of hospitalization and mortality of many brain disorders. However, the remarkable features of air pollution exposure are lifelong duration and at low concentration; and it is rarely reported that whether there are different responses on synapse when rats inhaled same mass of SO2 at low concentration with a longer term. In this study, we evaluated the synaptic plasticity in rat hippocampus after exposure to same mass of SO2 at various concentrations and durations (3.5 and 7 mg/m(3) , 6 h/day, for 4 weeks; and 14 and 28 mg/m(3) , 6 h/day, for 1 week). The results showed that the mRNA level of synaptic plasticity marker Arc, glutamate receptors (GRIA1, GRIA2, GRIN1, GRIN2A, and GRIN2B) and the protein expression of memory related kinase p-CaMKpalpha were consistently inhibited by SO2 both in 1 week and 4 weeks exposure cases; the protein expression of presynaptic marker synaptophysin, postsynaptic density protein 95 (PSD-95), protein kinase A (PKA), and protein kinase C (PKC) were increased in 1 week exposure case, and decreased in 4 weeks exposure case. Our results indicated that SO2 inhalation caused differential synaptic injury in 1 week and 4 weeks exposure cases, and implied the differential effects might result from different PKA- and/or PKC-mediated signal pathway. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 820-829, 2016. PMID- 25534911 TI - Melanopsin ganglion cells extend dendrites into the outer retina during early postnatal development. AB - Melanopsin ganglion cells express the photopigment melanopsin and are the first functional photoreceptors to develop in the mammalian retina. They have been shown to play a variety of important roles in visual development and behavior in the early postnatal period (Johnson et al., 2010; Kirkby and Feller, 2013; Rao et al., 2013; Renna et al., 2011). Here, we probed the maturation of the dendritic arbors of melanopsin ganglion cells during this developmental period in mice. We found that some melanopsin ganglion cells (mainly the M1-subtype) transiently extend their dendrites not only into the inner plexiform layer (where they receive synaptic inputs from bipolar and amacrine cells) but also into the outer plexiform layer, where in mature retina, rod and cone photoreceptors are thought to contact only bipolar and horizontal cells. Thus, some immature melanopsin ganglion cells are biplexiform. This feature is much less common although still present in the mature retina. It reaches peak incidence 8-12 days after birth, before the eyes open and bipolar cells are sufficiently mature to link rods and cones to ganglion cells. At this age, some outer dendrites of melanopsin ganglion cells lie in close apposition to the axon terminals of cone photoreceptors and express a postsynaptic marker of glutamatergic transmission, postsynaptic density 95 protein (PSD-95). These findings raise the possibility of direct, monosynaptic connections between cones and melanopsin ganglion cells in the early postnatal retina. We provide a detailed description of the developmental profile of these processes and consider their possible functional and evolutionary significance. PMID- 25534912 TI - Motor neuron disease in 2014. Biomarkers for ALS--in search of the Promised Land. AB - The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS) research. Two trials were completed, with negative results, but the discovery of novel ALS-associated genes, and body fluid and imaging biomarkers warrants cautious optimism. Here, we provide a snapshot of some of the main findings in 2014. PMID- 25534913 TI - Can we measure long-term treatment effects in multiple sclerosis? AB - The gold standard for measuring treatment effects is the randomized controlled trial. In patients with multiple sclerosis (MS), trial durations are typically 2 3 years, and the long-term effects of drugs for MS can only be assessed through trial extensions or observational studies that take advantage of data from registries or large single-centre databases. The main limitation of observational studies is an unavoidable selection bias that is introduced through nonrandom assignment of the intervention. Propensity score methods can mitigate this bias by balancing the groups with respect to baseline covariates, but this approach cannot correct for unmeasurable confounding factors. Extensions of clinical trials are free from selection biases because of the initial randomization, but they can only provide an assessment of early versus delayed treatment effects. Here, we discuss these methodological issues and analyse how they have been managed in studies of the long-term effects of IFN-beta in patients with MS. PMID- 25534914 TI - Traumatic brain injury: age at injury influences dementia risk after TBI. PMID- 25534915 TI - Parkinson disease. Gut reactions--can changes in the intestinal microbiome provide new insights into Parkinson disease? PMID- 25534917 TI - The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink. AB - PURPOSE: Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality. METHODS: Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality. RESULTS: Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses. CONCLUSIONS: There was little evidence of associations between pre-diagnostic use of warfarin and cancer specific mortality in lung, prostate, breast, or colorectal cancer patients. PMID- 25534918 TI - Fish consumption and n-3 polyunsaturated fatty acids, and risk of hepatocellular carcinoma: systematic review and meta-analysis. AB - PURPOSE: To investigate the association between fish consumption and n-3 polyunsaturated fatty acids (n-3 PUFA) and the risk of hepatocellular carcinoma (HCC). METHODS: We identified eligible studies in MEDLINE and EMBASE up to July 2014 and the reference lists of original studies and review articles on this topic. Summary relative risks (SRR) with their 95 % confidence intervals (CI) were calculated with a random effects model. RESULTS: Eleven studies (three cohort studies, seven retrospective case-control studies, and one nested case control study) met eligibility criteria. Ten articles investigated fish consumption, two articles investigated n-3 PUFA, and two articles investigated alpha-linolenic acid (ALA). The current data suggest that fish consumption was associated with 35 % reduction in HCC risk (highest vs. lowest category SRRs = 0.65, 95 % CI 0.51-0.79; test for heterogeneity p = 0.057, I (2) = 44.1 %). n-3 PUFA was associated with 51 % reduction in HCC risk (highest vs. lowest category SRRs = 0.49, 95 % CI 0.19-0.79). However, no significant inverse association was found in ALA (SRRs = 0.70, 95 % CI 0.30-1.10). CONCLUSION: Our meta-analysis of observational studies provides evidence that fish consumption and n-3 PUFA has inverse association with the risk of HCC. PMID- 25534919 TI - World alliance against antibiotic resistance: The WAAAR declaration against antibiotic resistance. AB - We must change how antibiotics are used and adopt proactive strategies, similar to those used to save endangered species. Preservation of the efficacy of antibiotics and to stabilization of antibiotic-susceptible bacterial ecosystems should be global goals. PMID- 25534916 TI - Risk factors for endometrial cancer in black and white women: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2). AB - PURPOSE: Endometrial cancer (EC) is the most common gynecologic cancer in the USA. Over the last decade, the incidence rate has been increasing, with a larger increase among blacks. The aim of this study was to compare risk factors for EC in black and white women. METHODS: Data from seven cohort and four case-control studies were pooled. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95 % confidence intervals for each risk factor in blacks and whites separately. RESULTS: Data were pooled for 2,011 black women (516 cases and 1,495 controls) and 19,297 white women (5,693 cases and 13,604 controls). BMI >= 30 was associated with an approximate threefold increase in risk of EC in both black and white women (ORblack 2.93, 95 % CI 2.11, 4.07 and ORwhite 2.99, 95 % CI 2.74, 3.26). Diabetes was associated with a 30-40 % increase in risk among both groups. Increasing parity was associated with decreasing risk of EC in blacks and whites (p value = 0.02 and <0.001, respectively). Current and former smoking was associated with decreased risk of EC among all women. Both black and white women who used oral contraceptives for 10 +years were also at reduced risk of EC (OR 0.49, 95 % CI 0.27, 0.88 and OR 0.69, 95 % CI 0.58, 0.83, respectively). Previous history of hypertension was not associated with EC risk in either group. CONCLUSIONS: The major known risk factors for EC exert similar effects on black and white women. Differences in the incidence rates between the two populations may be due to differences in the prevalence of risk factors. PMID- 25534920 TI - Activation of S1P1 receptor regulates PI3K/Akt/FoxO3a pathway in response to oxidative stress in PC12 cells. AB - FTY720 (fingolimod) is a sphingosine analogue that, when phosphorylated, becomes a prototypical sphingosine-1-phosphate (S1P) receptor modulator. It can enter the CNS and act on S1PRs expressed by most neural lineages. Recently, FTY720 neuroprotective and regenerative actions in the CNS have been demonstrated. In the present study, we have investigated whether the PI3K-Akt-FoxO3a axis is downstream to the S1P1 receptor modulation and involved in the cytoprotective effect of FTY720 in PC12 cells exposed to hydrogen peroxide (H2O2). The data showed that oxidative stress induces cell death in parallel with a significant decrease in PI3K, Akt and Akt target, and FoxO3a phosphorylation. FTY720 pretreatment increased cell survival which can be attributed to enhanced levels of inactive phosphorylated FoxO3a, a transcription factor playing critical role in oxidative stress-induced cell death. FTY720-phosphate (p-FTY720), a pan agonist of S1P receptors, as well as SEW2871, a selective S1P1 receptor agonist, similarly exerted cytoprotective effects. W123, a S1P1 receptor antagonist, abolished the effects of all three drugs, and concomitant application of DMS, a sphingosine kinase inhibitor, prevented the protective effects of FTY720. The data suggests that S1P1 receptor activation in the context of oxidative stress maintains PI3K/Akt signaling to prevent activation of FoxO3a, thereby promoting PC12 cell survival. PMID- 25534923 TI - Phagocytic index of neutrophil granulocytes and monocytes in healthy and preeclamptic pregnancy. AB - Neutrophil granulocytes and monocytes have been intensively studied, but there is no scientific data on one of their most important functions, namely the phagocyte function in pregnancy and preeclampsia. The aim of this study was to examine this function. Twenty-five healthy pregnant, 25 preeclamptic pregnant, and 20 healthy, non-pregnant women were enrolled into our study. Cells were isolated from peripheral blood samples, marked and evaluated for the phagocytic index with an immunofluorescent microscope after phagocytosing the zymosan molecules. The phagocytic function of monocytes and neutrophil granulocytes decreased significantly in healthy pregnancy compared with non-pregnant women and in preeclampsia, and it decreased significantly compared with healthy pregnancy. Decreased phagocytic function in healthy pregnancy can be a part of the maternal immunosuppression, which is essential for the protection of the hemiallograft fetus. Further reduction of phagocytic function may be one of the immunoregulatory abnormalities found in preeclampsia. PMID- 25534921 TI - Silencing of PINK1 inhibits insulin-like growth factor-1-mediated receptor activation and neuronal survival. AB - The etiology of Parkinson's disease remains unknown. Mutations in PINK1 have provided an understanding of the molecular mechanisms of this pathology. PINK1 and Parkin are important in the dismissal of dysfunctional mitochondria. However, the role of PINK1 in the control of neuronal survival pathways is not clear. To determine the role of PINK1 in the control of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediated by insulin-like grow factor type 1 (IGF-1), we use a model of mesencephalic neurons (CAD cells), which were transfected with lentiviral PINK1 shRNA or control shRNA constructs. Silencing of PINK1 was determined by RT-PCR and immunoblotting; cell viability was analyzed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays; proteins of the PI3K/Akt signaling pathway were tested by immunoblotting and IGF-1 receptor, and mitochondria were examined using fluorescence microscopy. PINK1 shRNA-transfected cells showed a reduction in cell survival compared to control shRNA cells. Exposure to IGF-1 induced a rapid and high increase in the phosphorylation level of IGF-1 receptor in control shRNA transfected cells; however, silencing of PINK1 decreases phosphorylation level of IGF-1 receptor and downstream target proteins such as Akt, GSK3-beta, IRS-1, and hexokinase. Our results further suggest that PINK1 may be regulating the PI3K/Akt neuronal survival pathway through tyrosine kinase receptors such as IGF-1 receptor. PMID- 25534924 TI - Maternal-fetal interactions, predictive markers for preeclampsia, and programming. AB - During pregnancy close interactions between the maternal system and the fetal system via the placenta exist that result in a powerful crosstalk between both individuals. Looking for predictive biomarkers in maternal blood is extremely difficult because of this crosstalk as such markers may be derived from only maternal sources, only placental sources or both. In particular, the concentrations of markers derived from both sources may vary because of the huge variety of reasons and sources. During the last decade this has misled a number of scientists and clinicians who tried to decipher the sources of markers and the impact of the placenta and/or the maternal vascular system. A few examples for predictive biomarkers are presented, the placenta-specific marker placental protein 13 (PP13) and the angiogenic marker PlGF being released from both mother and placenta. Finally, a further reason why biomarkers may not be successful in predicting all cases of preeclampsia is that different causative routes lead to the development of preeclampsia. The differences in the development of preeclampsia not only explain why markers may or may not have a predictive value, but also why some mothers and/or children may display long-term effects later in life. PMID- 25534925 TI - qEMF3, a novel QTL for the early-morning flowering trait from wild rice, Oryza officinalis, to mitigate heat stress damage at flowering in rice, O. sativa. AB - A decline in rice (Oryza sativa L.) production caused by heat stress is one of the biggest concerns resulting from future climate change. Rice spikelets are most susceptible to heat stress at flowering. The early-morning flowering (EMF) trait mitigates heat-induced spikelet sterility at the flowering stage by escaping heat stress during the daytime. We attempted to develop near-isogenic lines (NILs) for EMF in the indica-type genetic background by exploiting the EMF locus from wild rice, O. officinalis (CC genome). A stable quantitative trait locus (QTL) for flower opening time (FOT) was detected on chromosome 3. A QTL was designated as qEMF3 and it shifted FOT by 1.5-2.0 h earlier for cv. Nanjing 11 in temperate Japan and cv. IR64 in the Philippine tropics. NILs for EMF mitigated heat-induced spikelet sterility under elevated temperature conditions completing flower opening before reaching 35 degrees C, a general threshold value leading to spikelet sterility. Quantification of FOT of cultivars popular in the tropics and subtropics did not reveal the EMF trait in any of the cultivars tested, suggesting that qEMF3 has the potential to advance FOT of currently popular cultivars to escape heat stress at flowering under future hotter climates. This is the first report to examine rice with the EMF trait through marker-assisted breeding using wild rice as a genetic resource. PMID- 25534926 TI - Neighborhood income and the expression of callous-unemotional traits. AB - Callous-unemotional (CU) traits, including an uncaring nature and reduced empathy, represent a strongly heritable pattern of socio-emotional responding linked with elevated risk for severe, persistent delinquent behavior. Although evidence suggests that CU traits vary continuously across the population, research linking CU traits and delinquency is often conducted with incarcerated or clinical samples, obscuring potential heterogeneity in this relationship across the full range of high-CU individuals. Using a nationally representative sample, this study examines the role of neighborhood income in moderating the association between CU traits and delinquency in terms of both level and type of offending. Findings corroborate the link between CU traits and delinquency and suggest that the link between high-CU traits and violent delinquency may be unique to youth living in low-income neighborhoods. PMID- 25534927 TI - Ten-year trends in adolescents' self-reported emotional and behavioral problems in the Netherlands. AB - Changes in social, cultural, economic, and governmental systems over time may affect adolescents' development. The present study examined 10-year trends in self-reported emotional and behavioral problems among 11- to 16-year-old adolescents in the Netherlands. In addition, gender (girls versus boys), ethnic (Dutch versus non western) and educational (vocational versus academic) differences in these trends were examined. By means of the Strengths and Difficulties Questionnaire, trends in emotional and behavioral problems were studied in adolescents belonging to one of five independent population representative samples (2003: n = 6,904; 2005: n = 5,183; 2007: n = 6,228; 2009: n = 5,559; 2013: n = 5,478). Structural equation models indicated rather stable levels of emotional and behavioral problems over time. Whereas some small changes were found between different time points, these changes did not represent consistent changes in problem levels. Similarly, gender, ethnic and educational differences in self-reported problems on each time point were highly comparable, indicating stable mental health inequalities between groups of adolescents over time. Future internationally comparative studies using multiple measurement moments are needed to monitor whether these persistent mental health inequalities hold over extended periods of time and in different countries. PMID- 25534928 TI - Contextual variability of ADHD symptoms: embracement not erasement of a key moderating factor. PMID- 25534929 TI - Maternal Smokeless Tobacco Use in Pregnancy and Adverse Health Outcomes in Newborns: A Systematic Review. AB - BACKGROUND: Perinatal morbidity and mortality are important indicators of maternal health and the future health of the child. Smokeless tobacco (ST) use during pregnancy is associated with low birth weight (LBW), preterm births, stillbirths, and small for gestation age (SGA). This study systematically reviews and summarizes evidence on the association of maternal ST use with these adverse health outcomes in newborns. METHODS: Electronic databases (Medline, Embase, Lilacs) were searched in July 2013 using appropriate keywords complemented with reference list searching. Observational studies of maternal ST use and these outcomes were considered; LBW, preterm, stillbirth, SGA. A comprehensive assessment of quality and risk of bias in all included studies was performed. RevMan software was used for data analysis. Results are expressed as crude odds ratios with 95% confidence intervals. Chi-square and I(2) tests checked for heterogeneity and quantified inconsistency between results. RESULTS: There were 9 studies (16 reports) included (7 cohort-studies, 1 case-control study, and 1 cross-sectional study). They were clinically and methodologically diverse. Significant associations with ST use were seen in 5/7 studies for LBW, in 3/6 studies for preterm, in all 4 studies for stillbirth and in 1/2 studies assessing SGA. Heterogeneity between results was moderate for LBW (I(2) = 44%) and stillbirth (I(2) = 52%), and high for preterm (I(2) = 87%) and SGA (I(2) = 65%). Meta-analysis was considered inappropriate due to risk of bias and confounding. CONCLUSIONS: Although most studies show an association between ST use in pregnancy and adverse health effects in newborns, these results may be limited by confounding and bias. Quality observational studies are needed to strengthen this evidence base. PMID- 25534930 TI - Perceived 10-year change in respiratory health: reliability and predictive ability. AB - OBJECTIVE: To investigate the usefulness of a self-reported respiratory health transition question over 10 years through reliability, ability to capture long term asthma trajectory and predictive ability. SETTINGS: In two 20-year cohorts (Asthma-E3N, n = 16,371, 61-88 years; EGEA, n = 1254, 27-82 years), perceived 10 year change in respiratory health ("Overall, in the last 10 years, do you think that your bronchial or respiratory health has changed?" if yes: "Has it improved/deteriorated?") was studied in relation with change in respiratory medication dispensation and lung function, with change in asthma status measured over the same period of time, and with subsequent asthma-related outcomes. RESULTS: Perceived deterioration (14% in Asthma-E3N) was associated with increased dispensations of respiratory medications over time (from 17% with >2 dispensations in 2004 to 26% in 2010). Report of perceived deterioration (13% in EGEA) was related to a lung function decline steeper by 9.3 mL/year as compared to perceived improvement. In both cohorts, change (improvement or deterioration) was more often perceived by participants with than without asthma (>45% vs <20%) and was dominant among participants with persistent current asthma (77%). Perceived deterioration was related to poorer asthma control 7 years later and to higher use of oral corticosteroids in the following 18 months. CONCLUSION: The proposed simple self-reported respiratory health transition question over 10 years allows predicting part of the long-term trajectory of asthma. PMID- 25534931 TI - Accuracy of Alcohol Use Disorders Identification Test for detecting problem drinking in 18-35 year-olds in England: method comparison study. AB - AIMS: To assess the accuracy of Alcohol Use Disorders Identification Test (AUDIT) scores for problem drinking in males and females aged 18-35 in England. METHODS: A method comparison study with 420 primary care patients aged 18-35. Test measures were AUDIT and AUDIT-C. Reference standard measures were (a) Time-Line Follow-Back interview for hazardous drinking; World Mental Health Composite International Diagnostic Interview for (b) DSM-IV alcohol abuse, (c) DSM-IV alcohol dependence, (d) DSM-5 alcohol use disorders. RESULTS: Area under the curve (AUC) was (a) 0.79 (95% CI 0.73-0.85; males) and 0.84 (0.79-0.88; females); (b) 0.62 (0.54-0.72; males) and 0.65 (0.57-0.72; females); (c) 0.77 (0.65-0.87; males) and 0.76 (0.67-0.74; females); (d) 0.70 (0.60-0.78; males) and 0.73 (CI 0.67-0.78; females). Identification of threshold cut-point scores from the AUC was not straightforward. Youden J statistic optimal cut-point scores varied by 4 6 AUDIT scale points for each outcome according to whether sensitivity or specificity were prioritized. Using Bayes' Theorem, the post-test probability of drinking problems changed as AUDIT score increased, according to the slope of the probability curve. CONCLUSION: The full AUDIT scale showed good or very good accuracy for all outcome measures for males and females, except for alcohol abuse which had sufficient accuracy. In a screening scenario where sensitivity might be prioritized, the optimal cut-point is lower than established AUDIT cut-points of 8+ for men and 6+ for women. Bayes' Theorem to calculate individual probabilities for problem drinking offers an alternative to arbitrary cut-point threshold scores in screening and brief intervention programmes. PMID- 25534932 TI - Marchiafava-Bignami disease presenting as acute dysarthria and ataxia. PMID- 25534933 TI - Drinking patterns and victimization among male and female students in Mexico. AB - AIMS: The purpose of this study is to estimate the prevalence of alcohol use and alcohol-related consequences, identify drinking profiles using latent profile analysis (LPA), and investigate associations between profiles and violent victimization among young people in Mexico. METHODS: LPA identified profiles of drinking behavior in a survey of entering first year university students. Multinomial and logistic regression examined associations between drinking patterns, socio-demographic variables and violent victimization. RESULTS: The LPA identified five profiles of behaviors and consequences among the 22,224 current, former and never drinkers: Non/Infrequent-No Consequences, Occasional-Few Consequences, Regular-Some Consequences, Heavy-Many Consequences and Excessive Many Consequences drinkers. The Occasional-Few Consequences profile comprised the largest, and the Excessive-Many Consequences profile the smallest, group of drinkers. Multinomial regression showed males and older students more likely to be Heavy or Excessive-Many Consequences drinkers. Living alone was associated with higher odds, and higher maternal education with lower odds, of being a Non/Infrequent-No Consequences drinker. Heavier drinking profiles were more likely to experience violent victimization adverse consequences. Logistic regression showed male and female Heavy and Excessive-Many Consequences drinkers had the highest odds, and Non/Infrequent drinkers the lowest odds, of experiencing any victimization. CONCLUSION: Findings suggest changes in male and female drinking behavior and a continuation of the established pattern of infrequent but high consumption among Mexican youths. Both male and female Heavy and Excessive-Many Consequences drinkers were at elevated risk for experiencing victimization. Identifying cultural gender norms about drinking including drinker expectations and drinking context that contribute to these patterns can inform prevention efforts. PMID- 25534934 TI - Laparoscopic Radical Nephrectomy and Inferior Vena Cava Thrombectomy in the Treatment of Renal Cell Carcinoma. AB - BACKGROUND: Radical nephrectomy with inferior vena cava (IVC) thrombectomy is the preferred treatment for renal cell carcinoma (RCC) with IVC thrombus. However, IVC thrombectomy using a laparoscopic approach has not been reported for high level thrombi. OBJECTIVE: To describe the surgical technique for laparoscopic IVC thrombectomy in patients with different thrombus levels and to assess its safety and feasibility. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of medical records for 11 patients with right-side RCC, including six patients with level II IVC thrombus and five patients with level IV thrombus. SURGICAL PROCEDURE: Laparoscopic thrombectomy for level II thrombus was performed after clamping the infrarenal IVC, left renal vein, and infrahepatic IVC. Laparoscopic thrombectomy and thoracoscope-assisted open atriotomy for level IV thrombus were performed after establishing cardiopulmonary bypass and clamping the infrarenal IVC, left renal vein, and hepatoduodenal ligament. MEASUREMENTS: The intraoperative variables, postoperative complications, and surgical outcomes were assessed. RESULTS AND LIMITATIONS: The median operative time was 210min. The median IVC clamping time for patients with level II and level IV thrombus was 16.5 and 31min, respectively. The median estimated blood loss was 510ml, and no major intraoperative or postoperative complications occurred. One patient with level IV thrombus died of brain metastasis 6 mo after the operation, and the remaining ten patients had no local recurrence or distant metastasis during a median follow-up period of 31 mo. CONCLUSIONS: Laparoscopic IVC thrombectomy for level II thrombus and well-selected level IV thrombus may be a safe and technically feasible alternative to open surgery. PATIENT SUMMARY: We studied the treatment of patients with an inferior vena cava thrombus at different levels using a laparoscopic approach. This technique was safe and feasible in well selected patients. PMID- 25534935 TI - Major breeding plumage color differences of male ruffs (Philomachus pugnax) are not associated with coding sequence variation in the MC1R gene. AB - Sequence variation in the melanocortin-1 receptor (MC1R) gene explains color morph variation in several species of birds and mammals. Ruffs (Philomachus pugnax) exhibit major dark/light color differences in melanin-based male breeding plumage which is closely associated with alternative reproductive behavior. A previous study identified a microsatellite marker (Ppu020) near the MC1R locus associated with the presence/absence of ornamental plumage. We investigated whether coding sequence variation in the MC1R gene explains major dark/light plumage color variation and/or the presence/absence of ornamental plumage in ruffs. Among 821bp of the MC1R coding region from 44 male ruffs we found 3 single nucleotide polymorphisms, representing 1 nonsynonymous and 2 synonymous amino acid substitutions. None were associated with major dark/light color differences or the presence/absence of ornamental plumage. At all amino acid sites known to be functionally important in other avian species with dark/light plumage color variation, ruffs were either monomorphic or the shared polymorphism did not coincide with color morph. Neither ornamental plumage color differences nor the presence/absence of ornamental plumage in ruffs are likely to be caused entirely by amino acid variation within the coding regions of the MC1R locus. Regulatory elements and structural variation at other loci may be involved in melanin expression and contribute to the extreme plumage polymorphism observed in this species. PMID- 25534936 TI - Neural correlates of mirth and laughter: a direct electrical cortical stimulation study. AB - Laughter consists of both motor and emotional aspects. The emotional component, known as mirth, is usually associated with the motor component, namely, bilateral facial movements. Previous electrical cortical stimulation (ES) studies revealed that mirth was associated with the basal temporal cortex, inferior frontal cortex, and medial frontal cortex. Functional neuroimaging implicated a role for the left inferior frontal and bilateral temporal cortices in humor processing. However, the neural origins and pathways linking mirth with facial movements are still unclear. We hereby report two cases with temporal lobe epilepsy undergoing subdural electrode implantation in whom ES of the left basal temporal cortex elicited both mirth and laughter-related facial muscle movements. In one case with normal hippocampus, high-frequency ES consistently caused contralateral facial movement, followed by bilateral facial movements with mirth. In contrast, in another case with hippocampal sclerosis (HS), ES elicited only mirth at low intensity and short duration, and eventually laughter at higher intensity and longer duration. In both cases, the basal temporal language area (BTLA) was located within or adjacent to the cortex where ES produced mirth. In conclusion, the present direct ES study demonstrated that 1) mirth had a close relationship with language function, 2) intact mesial temporal structures were actively engaged in the beginning of facial movements associated with mirth, and 3) these emotion-related facial movements had contralateral dominance. PMID- 25534937 TI - A Cronobacter turicensis O1 antigen-specific monoclonal antibody inhibits bacterial motility and entry into epithelial cells. AB - Cronobacter turicensis is an opportunistic foodborne pathogen that can cause a rare but sometimes lethal infection in neonates. Little is known about the virulence mechanisms and intracellular lifestyle of this pathogen. In this study, we developed an IgG monoclonal antibody (MAb; MAb 2G4) that specifically recognizes the O1 antigen of C. turicensis cells. The antilipopolysaccharide antibody bound predominantly monovalently to the O antigen and reduced bacterial growth without causing cell agglutination. Furthermore, binding of the antibody to the O1 antigen of C. turicensis cells caused a significant reduction of the membrane potential which is required to energize flagellar rotation, accompanied by a decreased flagellum-based motility. These results indicate that binding of IgG to the O antigen of C. turicensis causes a direct antimicrobial effect. In addition, this feature of the antibody enabled new insight into the pathogenicity of C. turicensis. In a tissue culture infection model, pretreatment of C. turicensis with MAb 2G4 showed no difference in adhesion to human epithelial cells, whereas invasion of bacteria into Caco-2 cells was significantly inhibited. PMID- 25534938 TI - Antisecretory factor peptide AF-16 inhibits the secreted autotransporter toxin stimulated transcellular and paracellular passages of fluid in cultured human enterocyte-like cells. AB - Both the endogenous antisecretory factor (AF) protein and peptide AF-16, which has a sequence that matches that of the active N-terminal region of AF, inhibit the increase in the epithelial transport of fluid and electrolytes induced by bacterial toxins in animal and ex vivo models. We conducted a study to investigate the inhibitory effect of peptide AF-16 against the increase of transcellular passage and paracellular permeability promoted by the secreted autotransporter toxin (Sat) in a cultured cellular model of the human intestinal epithelial barrier. Peptide AF-16 produced a concentration-dependent inhibition of the Sat-induced increase in the formation of fluid domes, in the mucosal-to serosal passage of D-[1-(14)C]mannitol, and in the rearrangements in the distribution and protein expression of the tight junction (TJ)-associated proteins ZO-1 and occludin in cultured human enterocyte-like Caco-2/TC7 cell monolayers. In addition, we show that peptide AF-16 also inhibits the cholera toxin-induced increase of transcellular passage and the Clostridium difficile toxin-induced effects on paracellular permeability and TJ protein organization in Caco-2/TC7 cell monolayers. Treatment of cell monolayers by the lipid raft disorganizer methyl-beta-cyclodextrin abolished the inhibitory activity of peptide AF-16 at the transcellular passage level and did not modify the effect of the peptide at the paracellular level. PMID- 25534939 TI - Pathogenic Leptospira species acquire factor H and vitronectin via the surface protein LcpA. AB - Upon infection, pathogenic Leptospira species bind several complement regulators in order to overcome host innate immunity. We previously characterized a 20-kDa leptospiral surface protein which interacts with C4b binding protein (C4BP): leptospiral complement regulator-acquiring protein A (LcpA). Here we show that LcpA also interacts with human factor H (FH), which remains functionally active once bound to the protein. Antibodies directed against short consensus repeat 20 (SCR20) inhibited binding of FH to LcpA by approximately 90%, thus confirming that this particular domain is involved in the interaction. We have also shown for the first time that leptospires bind human vitronectin and that the interaction is mediated by LcpA. Coincubation with heparin blocked LcpA vitronectin interaction in a dose-dependent manner, strongly suggesting that binding may occur through the heparin binding domains of vitronectin. LcpA also bound to the terminal pathway component C9 and inhibited Zn(2+)-induced polymerization and membrane attack complex (MAC) formation. Competitive binding assays indicated that LcpA interacts with C4BP, FH, and vitronectin through distinct sites. Taken together, our findings indicate that LcpA may play a role in leptospiral immune evasion. PMID- 25534940 TI - Protective and pathological functions of CD8+ T cells in Leishmania braziliensis infection. AB - Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a strong Th1 response that leads to skin lesion development. In areas where L. braziliensis transmission is endemic, up to 15% of healthy subjects have tested positive for delayed-type hypersensitivity to soluble leishmania antigen (SLA) and are considered to have subclinical (SC) infection. SC subjects produce less gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) than do CL patients, but they are able to control the infection. The aim of this study was to characterized the role of CD8(+) T cells in SC infection and in CL. Peripheral blood mononuclear cells (PBMC) were stimulated with SLA to determine the frequencies of CD4(+) IFN-gamma(+) and CD8(+) IFN-gamma(+) T cells. Monocytes from PBMC were infected with L. braziliensis and cocultured with CD8(+) T cells, and the frequencies of infected monocytes and levels of cytotoxicity markers, target cell apoptosis, and granzyme B were determined. The frequency of CD8(+) IFN-gamma(+) cells after SLA stimulation was higher for SC individuals than for CL patients. The frequency of infected monocytes in SC cells was lower than that in CL cells. CL CD8(+) T cells induced more apoptosis of infected monocytes than did SC CD8(+) T cells. Granzyme B production in CD8(+) T cells was higher in CL than in SC cells. While the use of a granzyme B inhibitor decreased the number of apoptotic cells in the CL group, the use of z-VAD-FMK had no effect on the frequency of these cells. These results suggest that CL CD8(+) T cells are more cytotoxic and may be involved in pathology. PMID- 25534941 TI - Divergent targets of Aspergillus fumigatus AcuK and AcuM transcription factors during growth in vitro versus invasive disease. AB - In Aspergillus nidulans, the AcuK and AcuM transcription factors form a complex that regulates gluconeogenesis. In Aspergillus fumigatus, AcuM governs gluconeogenesis and iron acquisition in vitro and virulence in immunosuppressed mice. However, the function of AcuK was previously unknown. Through in vitro studies, we found that A. fumigatus DeltaacuK single and DeltaacuK DeltaacuM double mutants had impaired gluconeogenesis and iron acquisition, similar to the DeltaacuM mutant. Also, the DeltaacuK, DeltaacuM, and DeltaacuK DeltaacuM mutants had similar virulence defects in mice. However, the DeltaacuK mutant had a milder defect in extracellular siderophore activity and induction of epithelial cell damage in vitro than did the DeltaacuM mutant. Moreover, overexpression of acuM in the DeltaacuK mutant altered expression of 3 genes and partially restored growth under iron-limited conditions, suggesting that AcuM can govern some genes independently of AcuK. Although the DeltaacuK and DeltaacuM mutants had very similar transcriptional profiles in vitro, their transcriptional profiles during murine pulmonary infection differed both from their in vitro profiles and from each other. While AcuK and AcuM governed the expression of only a few iron responsive genes in vivo, they influenced the expression of other virulence related genes, such as hexA and dvrA. Therefore, in A. fumigatus, while AcuK and AcuM likely function as part of the same complex, they can also function independently of each other. Furthermore, AcuK and AcuM have different target genes in vivo than in vitro, suggesting that in vivo infection stimulates unique transcriptional regulatory pathways in A. fumigatus. PMID- 25534942 TI - Enterohemorrhagic Escherichia coli colonization of human colonic epithelium in vitro and ex vivo. AB - Enterohemorrhagic Escherichia coli (EHEC) is an important foodborne pathogen causing gastroenteritis and more severe complications, such as hemorrhagic colitis and hemolytic uremic syndrome. Pathology is most pronounced in the colon, but to date there is no direct clinical evidence showing EHEC binding to the colonic epithelium in patients. In this study, we investigated EHEC adherence to the human colon by using in vitro organ culture (IVOC) of colonic biopsy samples and polarized T84 colon carcinoma cells. We show for the first time that EHEC colonizes human colonic biopsy samples by forming typical attaching and effacing (A/E) lesions which are dependent on EHEC type III secretion (T3S) and binding of the outer membrane protein intimin to the translocated intimin receptor (Tir). A/E lesion formation was dependent on oxygen levels and suppressed under oxygen rich culture conditions routinely used for IVOC. In contrast, EHEC adherence to polarized T84 cells occurred independently of T3S and intimin and did not involve Tir translocation into the host cell membrane. Colonization of neither biopsy samples nor T84 cells was significantly affected by expression of Shiga toxins. Our study suggests that EHEC colonizes and forms stable A/E lesions on the human colon, which are likely to contribute to intestinal pathology during infection. Furthermore, care needs to be taken when using cell culture models, as they might not reflect the in vivo situation. PMID- 25534943 TI - Dynamics and establishment of Clostridium difficile infection in the murine gastrointestinal tract. AB - Clostridium difficile infection (CDI) following antibiotic therapy is a major public health threat. While antibiotic disruption of the indigenous microbiota underlies the majority of cases of CDI, the early dynamics of infection in the disturbed intestinal ecosystem are poorly characterized. This study defines the dynamics of infection with C. difficile strain VPI 10463 throughout the gastrointestinal (GI) tract using a murine model of infection. After inducing susceptibility to C. difficile colonization via antibiotic administration, we followed the dynamics of spore germination, colonization, sporulation, toxin activity, and disease progression throughout the GI tract. C. difficile spores were able to germinate within 6 h postchallenge, resulting in the establishment of vegetative bacteria in the distal GI tract. Spores and cytotoxin activity were detected by 24 h postchallenge, and histopathologic colitis developed by 30 h. Within 36 h, all infected mice succumbed to infection. We correlated the establishment of infection with changes in the microbiota and bile acid profile of the small and large intestines. Antibiotic administration resulted in significant changes to the microbiota in the small and large intestines, as well as a significant shift in the abundance of primary and secondary bile acids. Ex vivo analysis suggested the small intestine as the site of spore germination. This study provides an integrated understanding of the timing and location of the events surrounding C. difficile colonization and identifies potential targets for the development of new therapeutic strategies. PMID- 25534944 TI - ERF022 impacts the induction of somatic embryogenesis in Arabidopsis through the ethylene-related pathway. AB - MAIN CONCLUSION: The ERF022 gene was found to affect embryogenic transition in somatic cells in Arabidopsis via the ethylene-related pathway. The study provides evidence that ERF022 - LEC2 interaction is involved in the auxin-ethylene crosstalk that operates in somatic embryogenesis induction. The ERF022 gene of the ERF family was previously identified among the transcription factor genes that were differentially expressed in an embryogenic culture of Arabidopsis. A strong inhibition of the gene was found to be associated with the induction of somatic embryogenesis (SE) and an erf022 mutant was indicated to display a substantially impaired capacity for SE. Therefore, the molecular function of ERF022 in the induction of SE was studied in the present work. A phenotype of an erf022 mutant was indicated as being related to an increased content of ethylene. The results further suggest that the ERF022 controls the genes that are involved in both the biosynthesis (ACS7) and signalling (ERF1, ETR1) of ethylene and indicate that the ERF022 is a new regulatory element in ethylene-related responses that negatively control the ethylene content and perception. It is proposed that the negative impact of ethylene on the induction of SE may result from a modulation of the auxin-related genes that control the embryogenic transition in somatic cells. Among them, the LEC2, which is a key regulator of the induction of SE through the stimulation of auxin synthesis, was possibly related to ERF022. The results of the study provide new hormone-related clues to define the genetic network that governs SE. A putative model of the regulatory pathway is proposed that is involved in the induction of SE in which the auxin ethylene interactions are controlled by ERF022 and LEC2 and their targets. PMID- 25534945 TI - Identification, validation and cross-species transferability of novel Lavandula EST-SSRs. AB - MAIN CONCLUSION: We identified and characterized EST-SSRs with strong discrimination power against Lavandula angustifolia and Lavandula x intermedia . The markers also showed considerable cross-species transferability rate into six related Lavandula species. Lavenders (Lavandula) are important economical crops grown around the globe for essential oil production. In an attempt to develop genetic markers for these plants, we analyzed over 13,000 unigenes developed from L. angustifolia and L. x intermedia EST databases, and identified 3,459 simple sequence repeats (SSR), which were dominated by trinucleotides (41.2 %) and dinucleotides (31.45 %). Approximately, 19 % of the unigenes contained at least one SSR marker, over 60 % of which were localized in the UTRs. Only 252 EST-SSRs were 18 bp or longer from which 31 loci were validated, and 24 amplified discrete fragments with 85 % polymorphism in L. x intermedia and L. angustifolia. The average number of alleles in L. x intermedia and L. angustifolia were 3.42 and 3.71 per marker with average PIC values of 0.47 and 0.52, respectively. These values suggest a moderate to strong level of informativeness for the markers, with some loci producing unique fingerprints. The cross-species transferability rate of the markers ranges 50-100 % across eight species. The utility of these markers was assessed in eight Lavandula species and 15 L. angustifolia and L. x intermedia cultivars, and the dendrogram deduced from their similarity indexes successfully delineated the species into their respective sections and the cultivars into their respective species. These markers have potential for application in fingerprinting, diversity studies and marker-assisted breeding of Lavandula. PMID- 25534947 TI - Classic and emergent psychosocial work factors and mental health. AB - BACKGROUND: Little is known about associations between emergent psychosocial work factors and mental health. AIMS: To explore associations between classical and emergent psychosocial work factors and depression and anxiety symptoms in employees in France. METHODS: A national cross-sectional study (the SUrveillance Medicale des Expositions aux Risques professionnels (SUMER) survey) assessed psychosocial work factors including psychological demands, decision latitude, social support, reward and its sub-dimensions (esteem, job security and job promotion), bullying, verbal abuse, physical violence and sexual assault, long working hours, shift and night work, unsociable work days, predictability and demands for responsibility. We also measured depression and anxiety symptoms using the Hospital Anxiety and Depression scale. We used gender-stratified generalized linear models to adjust for age, occupation and economic activity. RESULTS: A total of 26883 men and 20079 women participated (response rate 87%). Low decision latitude, high psychological demands, low social support, low reward, bullying and verbal abuse were associated with depression and anxiety in both genders (beta coefficients from 0.14 to 1.40). In men, low predictability was associated with both depression and anxiety (beta = 0.12 [95% confidence interval (CI) 0.01, 0.24] and 0.19 [95% CI 0.06, 0.32]) and long working hours were associated with anxiety (beta = 0.48 [95% CI 0.27, 0.69]). The strongest associations were observed for bullying, reward (especially esteem) and psychological demands. Using a less conservative approach, we found more factors to be significantly associated with mental health symptoms. CONCLUSIONS: Most psychosocial work factors studied are associated with depression and/or anxiety symptoms. Comprehensive prevention policies may help to reduce exposure to psychosocial work factors, including emergent ones, and improve mental health at work. PMID- 25534946 TI - Light and abscisic acid independently regulated FaMYB10 in Fragaria * ananassa fruit. AB - MAIN CONCLUSION: Light and ABA independently regulated anthocyanin biosynthesis via activation of FaMYB10 expression. FaMYB10 accelerated anthocyanin synthesis of pelargonidin 3-glucoside and cyanidin 3-glucoside during strawberry fruit ripening. Light is an integral factor in fruit ripening. Ripening in non climacteric fruit is also effected by the plant hormone abscisic acid (ABA). However, how light and/or ABA regulate fruit ripening processes, such as strawberry color development remains elusive. Results of the present study showed light and ABA regulated strawberry fruit coloration via activation of FaMYB10 expression, an R2R3 MYB transcription factor. Light exposure increased FaMYB10 transcript levels, flavonoid pathway genes, and anthocyanin content. Exogenous ABA promoted FaMYB10 expression, and anthocyanin content, accompanied by increased ABA-responsive transcript levels and flavonoid pathway genes. ABA biosynthesis inhibitor treatment, and RNAi-mediated down-regulation of the ABA biosynthetic gene (9-cis epoxycarotenoid dioxygenase: FaNCED1), and ABA receptor (magnesium chelatase H subunit: FaCHLH/ABAR) showed inverse ABA effects. Furthermore, additive effects were observed in anthocyanin accumulation under combined light and ABA, indicating independent light and ABA signaling pathways. FaMYB10 down-regulation by Agrobacterium-mediated RNA interference (RNAi) in strawberry fruits showed decreased pelargonidin 3-glucoside and cyanidin 3 glucoside levels, accompanied by consistent flavonoid pathway gene expression levels. FaMYB10 over-expression showed opposite FaMYB10 RNAi phenotypes, particularly cyanidin 3-glucoside synthesis by FaMYB10, which was correlated with FaF3'H transcript levels. These data provided evidence that light and ABA promoted FaMYB10 expression, resulting in anthocyanin accumulation via acceleration of flavonoid pathway gene expression. Finally, our results suggested FaMYB10 serves a role as a signal transduction mediator from light and ABA perception to anthocyanin synthesis in strawberry fruit. PMID- 25534948 TI - The reliability of the ELEPAP clinical protocol for the 3D kinematic evaluation of upper limb function. AB - Upper limb (UL) kinematic assessment protocols are becoming integrated into clinical practice due to their development over the last few years. We propose the ELEPAP UL protocol, a contemporary UL kinematic protocol that can be applied to different pathological conditions. This model is based on ISB modeling recommendations, uses functional joint definitions, and models three joints of the shoulder girdle. The specific aim of this study was to determine the within and between session reliability of the ELEPAP UL model. Ten healthy subjects (mean age: 13.6+/-4.3 years) performed four reach-to-grasp and five functional tasks, which included a novel throwing task to assess a wide spectrum of motor skills. Three trials of every task in two different sessions were analyzed. The reliability of angular waveforms was evaluated by measurement error (sigma) and coefficient of multiple correlation (CMC). Spatiotemporal parameters were assessed by standard error of measurement (SEM). Generally joint kinematics presented low sigmaw and sigmab errors (<100). A selection of angular waveforms errors was presented to inspect error fluctuation in different phases, which was found to be related to the demands of the different movements. CMCw and CMCb values (>0.60) were found, demonstrating good to excellent reliability especially in joints with larger ranges of motion. The throwing task proved equally reliable, enhancing the universal application of the protocol. Compared to the literature, this study demonstrated higher reliability of the thorax, scapula and wrist joints. This was attributed to the highly standardized procedure and the implementation of recent methodological advancements. In conclusion, ELEPAP protocol was proved a reliable tool to analyze UL kinematics. PMID- 25534949 TI - Dehydration among lactating mothers in the Amazon: A neglected problem. AB - OBJECTIVES: The purpose of this study was to compare hydration status between lactating and non-lactating women in the hot-humid Amazon. METHODS: Fifty-four women (15-81 years) from two villages at different distances to the market provided urine samples, anthropometric measurements, and health recalls. Urine samples were analyzed for urine specific gravity (USG). Bivariate and multiple linear and logistic regressions tested differences in USG and dehydration (USG > 1.020) between women of different lactating status. RESULTS: Lactating women (1.024 g/ml; 78% dehydrated) had significantly higher USG levels (beta = 0.004; P = 0.011) than non-lactating women (1.020 g/ml; 50% dehydrated) and were significantly more likely to be dehydrated adjusting for covariates (OR: 4.05; 95% CI 1.1-14.7). CONCLUSIONS: Women living in hot-humid rural environments with minimal access to clean water are at greater risk of dehydration when breastfeeding. Future research should examine lactating women longitudinally and assess whether chronic dehydration affects breast milk composition. PMID- 25534950 TI - Chronic traumatic encephalopathy: The unknown disease. AB - Chronic traumatic encephalopathy is a neurodegenerative disease produced by accumulated minor traumatic brain injuries; no definitive premortem diagnosis and no treatments are available for chronic traumatic encephalopathy. Risk factors associated with chronic traumatic encephalopathy include playing contact sports, presence of the apolipoprotein E4, and old age. Although it shares certain histopathological findings with Alzheimer disease, chronic traumatic encephalopathy has a more specific presentation (hyperphosphorylated tau protein deposited as neurofibrillary tangles, associated with neuropil threads and sometimes with beta-amyloid plaques). Its clinical presentation is insidious; patients show mild cognitive and emotional symptoms before progressing to parkinsonian motor signs and finally dementia. Results from new experimental diagnostic tools are promising, but these tools are not yet available. The mainstay of managing this disease is prevention and early detection of its first symptoms. PMID- 25534951 TI - Hypoglycemic and antihyperglycemic effects of phytopreparations and limonoids from Swietenia humilis. AB - An aqueous extract from the seeds of Swietenia humilis (31.6-100mg/kg bw) lowered (p<0.05) blood glucose levels in normal and nicotinamide-streptozotocin (NA-STZ) induced hyperglycemic mice. Furthermore, when administered to fructose-fed rats with metabolic syndrome, the decoction showed significant antihyperglycemic, hypoglycemic and hypolipidemic effects, as well as an augmentation of hepatic glycogen. Limonoids 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), humulin B (2), methyl-2-hydroxy-3-beta-isobutyroxy-1-oxomeliac-8(30)-enate (3), methyl-2 hydroxy-3-beta-tigloyloxy-1-oxomeliac-8(30)-enate (4), humilinolide G (5), humilinolide C (6), methyl-2-hydroxy-3-beta-isobutyoyl-8alpha,30alpha-epoxy-1-oxo meliacate (7), and humilinolide H (8), were isolated from a CH2Cl2-MeOH (1:1) extract of the seeds. Compounds 5 and 8 are analogs of compounds 6 and 7. The structure of 5 was unequivocally established by X-ray analysis. When tested in normal and NA-STZ-hyperglycemic mice, compounds 1, 2, and 4 (3.16-31.6 mg/kg bw) decreased glycemia during an oral glucose tolerance test. The present investigation sustains the contemporary popular uses of S. humilis seeds for treating metabolic disorders, including diabetes and dyslipidemia and demonstrates the potential of the mexicanolides as antihyperglycemic agents. PMID- 25534952 TI - NMR spectroscopic search module for Spektraris, an online resource for plant natural product identification--Taxane diterpenoids from Taxus * media cell suspension cultures as a case study. AB - Development and testing of Spektraris-NMR, an online spectral resource, is reported for the NMR-based structural identification of plant natural products (PNPs). Spektraris-NMR allows users to search with multiple spectra at once and returns a table with a list of hits arranged according to the goodness of fit between query data and database entries. For each hit, a link to a tabulated alignment of (1)H NMR and (13)C NMR spectroscopic peaks (query versus database entry) is provided. Furthermore, full spectroscopic records and experimental meta information about each database entry can be accessed online. To test the utility of Spektraris-NMR for PNP identification, the database was populated with NMR data (total of 466 spectra) for ~ 250 taxanes, which are structurally complex diterpenoids (including the anticancer drug taxol) commonly found in the genus Taxus. NMR data generated with metabolites purified from Taxus cell suspension cultures were then used to search Spektraris-NMR, and enabled the identification of eight taxanes with high confidence. A ninth isolated metabolite could be assigned, based on spectral searches, to a taxane skeletal class, but no high confidence hit was produced. Using various spectroscopic methods, this metabolite was characterized as 2-deacetylbaccatin IV, a novel taxane. These results indicate that Spektraris-NMR is a valuable resource for rapid and reliable identification of known metabolites and has the potential to contribute to de replication efforts in novel PNP discovery. PMID- 25534954 TI - Simultaneous in-situ synthesis and characterization of Co@Cu core-shell nanoparticle arrays. AB - Core-shell particle ensembles are fabricated by pulsed-laser-induced dewetting of initially continuous, ultrathin alloy films through a combination of morphological and chemical instability. The synthesis of these arrays is monitored in situ with high spatial and temporal resolutions, which, when combined with ex situ composition analysis, provides insight to the morphological and chemical evolution pathways leading to core-shell particle formation. PMID- 25534953 TI - Antiproliferative quillaic acid and gypsogenin saponins from Saponaria officinalis L. roots. AB - Nine quillaic acid and five gypsogenin bisdesmosides were isolated from roots of Saponaria officinalis L. (Caryophyllaceae). Seven of the quillaic acid saponins possessed a 3-O-beta-D-galactopyranosyl-(1 -> 2)-[beta-D-xylopyranosyl-(1 -> 3)] beta-D-glucuronopyranosyl unit, but differed from each other in oligosaccharide units linked to the C-28 ester. The five gypsogenin saponins isolated from the roots all possessed the 3-O-beta-D-galactopyranosyl-(1 -> 2)-[beta-D xylopyranosyl-(1 -> 3)]-beta-D-glucuronopyranosyl unit, with their oligosaccharide units linked to the C-28 ester differing. Structures were elucidated by extensive 1D and 2D NMR spectroscopy and mass spectrometry. The saponins were evaluated for growth inhibitory activity in two human cancer cell lines and hemolytic activity in sheep red blood cells. PMID- 25534955 TI - Use of a modular tapered fluted femoral component in revision total hip arthroplasty following resection of a previously infected total hip: minimum 5 year follow-up. AB - Femoral reconstruction in the setting of two stage reimplantation can be difficult and substantial reoperation rates due to implant loosening have been reported. We retrospectively reviewed 28 male and 29 female patients who underwent a two-stage reimplantation using a modular, tapered femoral stem. The mean clinical follow-up was 62 months. The mean Harris Hip score at 5-year follow up was 76. Two stems were revised for aseptic loosening. Reinfection occurred in 16% of patients. Stem survivorship was 87% at 5-years. Use of a modular tapered stem provided a high rate of stable femoral fixation and acceptable rate of reinfection in two stage treatment of infected THA. PMID- 25534956 TI - Higher Rate of Revision in PFC Sigma Primary Total Knee Arthroplasty With Mismatch of Femoro-Tibial Component Sizes. AB - Total knee arthroplasty (TKA) systems permit a degree of femoro-tibial component size mismatch. The effect of mismatched components on revision rates has not been evaluated in a large study. We reviewed 21,906 fixed-bearing PFC Sigma primary TKAs using the Australian Orthopaedic Association National Joint Replacement Registry, dividing patients into three groups: no femoro-tibial size mismatch, tibial component size > femoral component size, and femoral component > tibial component. Revision rates were higher when the femoral size was greater than the tibia, compared to both equal size (HR = 1.20 (1.00, 1.45), P = 0.047) and to tibial size greater than femoral (HR = 1.60 (1.08, 2.37), P = 0.019). Potential mechanisms to explain these findings include edge loading of polyethylene and increased tibial component stresses. PMID- 25534957 TI - Interpretation of p16(INK4a) /Ki-67 dual immunostaining for the triage of human papillomavirus-positive women by experts and nonexperts in cervical cytology. AB - BACKGROUND: The triage of human papillomavirus (HPV)-positive women is needed to avoid overreferral to colposcopy. p16(INK4a) immunostaining is an efficient triage method. p16(INK4a) /Ki-67 dual staining was introduced mainly to increase reproducibility and specificity compared with stand-alone p16(INK4a) staining. METHODS: Within a pilot project, HPV-positive women were referred to colposcopy if cytology was abnormal or unsatisfactory or HPV testing was still positive after 1 year. For 500 consecutive women, a slide obtained during colposcopy was immunostained for p16(INK4a) /Ki-67 and independently interpreted by 7 readers without previous experience with dual staining. Four of these readers were experts in cervical pathology and 3 were not. Kappa values for multiple raters, sensitivity, and specificity for cervical intraepithelial neoplasia type 2 positive histology were computed. Because women with normal cytology were underrepresented, estimates for all HPV-positive women were obtained as weighted means of cytology-specific estimates. RESULTS: The overall kappa for HPV-positive women was 0.70 (95% confidence interval [95% CI], 0.60-0.77). Kappa values were not found to be significantly different between expert and nonexpert readers with regard to cervical cytology but were significantly increased (P =. 0066) after consensus discussion. The overall specificity estimate for HPV-positive women was 64.0% (95% CI, 57.4%-70.2%): 66.7% (95% CI, 59.8%-73.0%) for experts and 60.5% (95% CI, 59.8%-73.0%) for nonexperts. Among women with abnormal cytology, the sensitivity was 85.5% (95% CI, 77.9%-90.8%): 85.8% (95% CI, 77.9%-91.2%) for experts and 85.1% (95% CI, 76.6%-90.9%) for nonexperts. CONCLUSIONS: p16(INK4a) /Ki-67 immunostaining demonstrated good reproducibility and specificity when triaging HPV-positive women. Dual-staining interpretation can be performed, after short training, even by staff who are not experts in cervical cytology. This allows HPV-based screening with triage to be performed in settings in which such expert staff is not available. PMID- 25534958 TI - PredHydroxy: computational prediction of protein hydroxylation site locations based on the primary structure. AB - Compared to well-known and extensively studied protein phosphorylation, protein hydroxylation attracts much less attention and the molecular mechanism of the hydroxylation is still incompletely understood. And yet annotation of hydroxylation in proteomes is a first-critical step toward decoding protein function and understanding their physiological roles that have been implicated in the pathological processes and providing useful information for the drug designs of various diseases related with hydroxylation. In this work, we present a novel method called PredHydroxy to automate the prediction of the proline and lysine hydroxylation sites based on position weight amino acids composition, 8 high quality amino acid indices and support vector machines. The PredHydroxy achieved a promising performance with an area under the receiver operating characteristic curve (AUC) of 82.72% and a Matthew's correlation coefficient (MCC) of 69.03% for hydroxyproline as well as an AUC of 87.41% and a MCC of 66.68% for hydroxylysine in jackknife cross-validation. The results obtained from both the cross validation and independent tests suggest that the PredHydroxy might be a powerful and complementary tool for further experimental investigation of protein hydroxylation. Feature analyses demonstrate that hydroxylation and non hydroxylation have distinct location-specific differences; alpha and turn propensity is of importance for the hydroxylation of proline and lysine residues. A user-friendly server is freely available on the web at: . PMID- 25534959 TI - Nevasic audio program for the prevention of chemotherapy induced nausea and vomiting: A feasibility study using a randomized controlled trial design. AB - PURPOSE: Pharmacological therapy is only partially effective in preventing or treating chemotherapy induced nausea and vomiting (CINV). Therefore, exploring the complementary role of non-pharmacological approaches used in addition to pharmacological agents is important. Nevasic uses specially constructed audio signals hypothesized to generate an antiemetic reaction. The aim of this study was to examine the feasibility of conducting a randomized controlled trial (RCT) to evaluate the effectiveness of Nevasic to control CINV. METHODS: A mixed methods design incorporating an RCT and focus group interviews. For the RCT, female breast cancer patients were randomized to receive either Nevasic plus usual care, music plus usual care, or usual care only. Data were analysed using descriptive statistics and linear mixed-effects models. Five focus group interviews were conducted to obtain participants' views regarding the acceptability of the interventions in the trial. RESULTS: 99 participants were recruited to the RCT and 15 participated in focus group interviews. Recruitment targets were achieved. Issues of Nevasic acceptability were highlighted as weaknesses of the program. This study did not detect any evidence for the effectiveness of Nevasic; however, the results showed statistically significant less use of anti-emetics (p = 0.003) and borderline non-significant improvement in quality of life (p = 0.06). CONCLUSIONS: Conducting a non-pharmacological intervention using such an audio program is feasible, although difficulties and limitations exist with its use. Further studies are required to investigate the effectiveness of Nevasic from perspectives such as anti-emetic use, as well as its overall effect on the levels of nausea and vomiting. PMID- 25534960 TI - Dietary nitrate supplementation in COPD: an acute, double-blind, randomized, placebo-controlled, crossover trial. AB - BACKGROUND: The acute consumption of dietary nitrate has been shown to improve exercise capacity in athletes, healthy adults and subjects with peripheral vascular disease. Many COPD patients have reduced exercise capacity. We hypothesized that acute nitrate consumption might increase incremental shuttle walk test (ISWT) distance in COPD subjects. METHODS: Eleven COPD subjects were randomly assigned to consume either a high nitrate or a matched, low nitrate beverage in a double-blind, randomized, placebo-controlled, crossover design. ISWT distance was measured both before and 3 h after the beverage and change was recorded. After a 7-day washout, ISWT distances were re-measured before and 3 h after the alternate beverage and changes were recorded. RESULTS: We observed an increase in ISWT distance after consuming the high nitrate juice (25 m) compared with a reduction after the low nitrate juice (14 m) (p < 0.01). This improvement in exercise capacity was associated with significant increases in serum nitrate (p < 0.000005) and nitrite (p < 0.01) levels and a significant lowering of resting blood pressure (<0.05). CONCLUSIONS: In patients with stable COPD, the acute consumption of dietary nitrate increased serum nitrate/nitrite levels and exercise capacity and was associated with a decrease in resting blood pressure. Nitrate consumption might alter exercise capacity in COPD patients. PMID- 25534961 TI - Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover. AB - BACKGROUND: Most of the alkaline phosphatase (ALP) isoenzymes are derived from the bones and liver. High levels of ALP are often encountered during routine blood investigation in elderly patients. However, because ALP includes various isoenzymes from other tissues, an accurate diagnosis is usually not possible on the basis of elevated ALP alone. AIMS: To identify the cause of increased ALP in postmenopausal women. METHODS: We measured serum ALP in a group of 626 postmenopausal osteoporotic women before and after treatment with a bisphosphonate (either alendronate or risedronate). We analyzed the correlations between ALP levels and bone metabolic markers or hepatic function markers. RESULTS: The ALP and BAP levels of people in their 80s were significantly higher than those of people in their 60s. With bisphosphonate therapy, the BAP decreased, and the elevated ALP decreased to normal range levels. ALP was highly and significantly correlated with BAP both before and after treatment. The changes in levels of ALP correlated well with the changes in BAP levels before and after bisphosphonate therapy. Markers of liver function correlated with total ALP (p < 0.01), but the correlation was much smaller than that between ALP and BAP. DISCUSSION: Bisphosphonate treatment lowered ALP levels, and this decrease was strongly correlated with a decrease in BAP. Among blood test data, the decrease in BAP had the strongest correlation with the ALP decrease. CONCLUSION: For treatment of osteoporosis, ALP is an acceptable alternative to BAP. Elevated ALP in postmenopausal women is mainly caused by high bone turnover. PMID- 25534962 TI - A critical look at prospective surveillance using a scan statistic. AB - The scan statistic is a very popular surveillance technique for purely spatial, purely temporal, and spatial-temporal disease data. It was extended to the prospective surveillance case, and it has been applied quite extensively in this situation. When the usual signal rules, as those implemented in SaTScan(TM) (Boston, MA, USA) software, are used, we show that the scan statistic method is not appropriate for the prospective case. The reason is that it does not adjust properly for the sequential and repeated tests carried out during the surveillance. We demonstrate that the nominal significance level alpha is not meaningful and there is no relationship between alpha and the recurrence interval or the average run length (ARL). In some cases, the ARL may be equal to infinity, which makes the method ineffective. This lack of control of the type-I error probability and of the ARL leads us to strongly oppose the use of the scan statistic with the usual signal rules in the prospective context. PMID- 25534963 TI - The possible role of liver kinase B1 in hydroquinone-induced toxicity of murine fetal liver and bone marrow hematopoietic stem cells. AB - Epidemiological studies suggest that the increasing incidence of childhood leukemia may be due to maternal exposure to benzene, which is a known human carcinogen; however, the mechanisms involved remain unknown. Liver Kinase B1 (LKB1) acts as a regulator of cellular energy metabolism and functions to regulate hematopoietic stem cell (HSC) homeostasis. We hypothesize that LKB1 contributes to the deregulation of fetal or bone hematopoiesis caused by the benzene metabolite hydroquinone (HQ). To evaluate this hypothesis, we compared the effects of HQ on murine fetal liver hematopoietic stem cells (FL-HSCs) and bone marrow hematopoietic stem cells (BM-HSCs). FL-HSCs and BM-HSCs were isolated and enriched by a magnetic cell sorting system and exposed to various concentrations of HQ (0, 1.25, 2.5, 5, 10, 20, and 40 MUM) for 24 h. We found that the inhibition of differentiation and growth, as well as the apoptosis rate of FL-HSCs, induced by HQ were consistent with the changes in BM-HSCs. Furthermore, G1 cell cycle arrest was observed in BM-HSCs and FL-HSCs in response to HQ. Importantly, FL-HSCs were more sensitive than BM-HSCs after exposure to HQ. The highest induction of LKB1 and adenosine monophosphate-activated protein kinase (AMPK) was observed with a much lower concentration of HQ in FL-HSCs than in BM-HSCs. LKB1 may play a critical role in apoptosis and cell cycle arrest of HQ-treated HSCs. This research has developed innovative ideas concerning benzene induced hematopoietic toxicity or embryotoxicity, which can provide a new experimental evidence for preventing childhood leukemia. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 830-841, 2016. PMID- 25534965 TI - Blood pressure-lowering treatment should be based on the level of cardiovascular risk, not on the level of blood pressure. PMID- 25534964 TI - Social networks in primates: smart and tolerant species have more efficient networks. AB - Network optimality has been described in genes, proteins and human communicative networks. In the latter, optimality leads to the efficient transmission of information with a minimum number of connections. Whilst studies show that differences in centrality exist in animal networks with central individuals having higher fitness, network efficiency has never been studied in animal groups. Here we studied 78 groups of primates (24 species). We found that group size and neocortex ratio were correlated with network efficiency. Centralisation (whether several individuals are central in the group) and modularity (how a group is clustered) had opposing effects on network efficiency, showing that tolerant species have more efficient networks. Such network properties affecting individual fitness could be shaped by natural selection. Our results are in accordance with the social brain and cultural intelligence hypotheses, which suggest that the importance of network efficiency and information flow through social learning relates to cognitive abilities. PMID- 25534967 TI - Bortezomib-based antibody reduction therapy: the first step to "true" desensitization? PMID- 25534966 TI - Longitudinal Assessment of Self-Harm Statements of Youth in Foster Care: Rates, Reporters, and Related Factors. AB - Self-harm in youth is a risk factor related to mental health and future morbidity, yet, relatively little is known about the rates and course of self harm in youth residing in foster care. This study examined self-harm talk in foster youth based on caregiver and child report for 135 children between the ages of 8- and 11-years old. Longitudinal data on course of self-harm talk from both youth and caregivers also are provided. Caregivers identified that 24% of youth participants had disclosed a desire to die or to hurt themselves. Youth self-report revealed that 21% of children indicated a desire for self-harm, and rates of self-harm from both reporters decreased over time. While overall rates were similar across reporters, findings show discrepancies between youth self report and caregiver report within individuals. Also, caregivers for youth in residential facilities were more likely to report youth self-harm talk than caregivers from foster home settings. PMID- 25534968 TI - Remediation of PAH-contaminated soil by the combination of tall fescue, arbuscular mycorrhizal fungus and epigeic earthworms. AB - A 120-day experiment was performed to investigate the effect of a multi-component bioremediation system consisting of tall fescue (Festuca arundinacea), arbuscular mycorrhizal fungus (AMF) (Glomus caledoniun L.), and epigeic earthworms (Eisenia foetida) for cleaning up polycyclic aromatic hydrocarbons (PAHs)-contaminated soil. Inoculation with AMF and/or earthworms increased plant yield and PAH accumulation in plants. However, PAH uptake by tall fescue accounted for a negligible portion of soil PAH removal. Mycorrhizal tall fescue significantly enhanced PAH dissipation, PAH degrader density and polyphenol oxidase activity in soil. The highest PAH dissipation (93.4%) was observed in the combination treatment: i.e., AMF+earthworms+tall fescue, in which the soil PAH concentration decreased from an initial value of 620 to 41 mg kg(-1) in 120 days. This concentration is below the threshold level required for Chinese soil PAH quality (45 mg kg(-1) dry weight) for residential use. PMID- 25534969 TI - Myc proteins in cell biology and pathology. PMID- 25534970 TI - The Adh1 gene of the fungus Metarhizium anisopliae is expressed during insect colonization and required for full virulence. AB - Zymography of alcohol dehydrogenase (ADH) activity in the entomopathogenic fungus Metarhizium anisopliae grown under various conditions revealed that micro-aerobic growth was associated with increased ADH activity. The major ADH protein, AdhIp, was purified to homogeneity by affinity chromatography and has an estimated molecular weight of 41kDa and an isoelectric point (pI) of 6.4. Peptide mass fingerprint analysis allowed the identification and cloning of the gene that encodes this protein, Adh1, as annotated in the M. anisopliae genome database. AdhIp is related to the medium-chain dehydrogenase/reductase (MDR)/zinc-dependent alcohol dehydrogenase-like family and contains conserved ADH sequence motifs, such as the zinc-containing ADH signature, the FAD/NAD binding domain and amino acid residues that are conserved in most microbial ADHs. Semi-quantitative RT-PCR analysis revealed that Adh1 gene expression occurs at low levels during early Plutella xylostella infection and that the Adh1 gene was primarily expressed at larval death and as mycelia emerge from the insect cuticle before conidiation. Antisense-RNA experiments indicated that NAD(+)-dependent ADH activity was diminished by 20-75% in the transformants, and the transformants that had lower ADH activity showed allyl alcohol resistance, which indicates that reduction in ADH activity also occurs in vivo. Bioassays performed using antisense adh1 transformants, which have lower ADH activity, showed that LC50 values were two to five times higher than the wild-type, indicating that AdhIp is required for full capability of the fungus to penetrate and/or colonize the insect. PMID- 25534972 TI - Analysis of pig movements across eastern Indonesia, 2009-2010. AB - Knowledge of live animal movement through markets and from farm-to-farm is needed to inform strategies for control of trans-boundary animal diseases (TADs) in south-east Asia, particularly due to consumer preference for fresh meat. In eastern Indonesia a TAD of principal interest for control is classical swine fever (CSF) due to its impacts on smallholder farmers. Pig movement is considered a contributor to failure of current CSF control efforts but pig movement patterns are not well understood. This study investigated movement of live pigs in West Timor, Flores and Sumba islands during 2009-2010, with the aim of informing CSF control policies for Nusa Tenggara Timor province. A market survey of 292 pig sellers and 281 pig buyers across nine live pig markets and a farmer survey across 18 villages with 289 smallholder farmers were conducted and information collected on pig movements. The data obtained was used for social network analysis (SNA) on formal (via a market) and informal (village-to-village) movements using information on trading practices, source and destination locations, and the number of pigs being moved. Both inter- and intra-island movements were identified, however inter-island movement was only observed between Flores and Sumba islands. West Timor and Sumba had highly connected networks where large numbers of villages were directly and indirectly linked through pig movement. Further for West Timor, both formal and informal pig movements linked the capital Kupang, on the eastern end of the island to the western districts bordering East Timor connecting all five districts and demonstrating that informal movement transports pigs over distances similar to formal movement on this island. Sumba had a higher potential for pigs to move to a greater number of sequential locations across the entire island. Flores was found to have a more fragmented network, with pig movements concentrated in its eastern or western regions, influenced by terrain. Markets were confirmed as high risk locations for the introduction and spread of disease, having over 20 contacts (based on in- and out-degree values) depending on operational day. Villages considered high-risk for CSF spread via informal movements were characterised by higher volume of pig exits and/or linkage to higher numbers of other villages. These findings demonstrate that informal movement (often related to cultural practices) can be extensive and the high level of connectivity dictates that control strategies for CSF and other highly transmissible diseases must be formulated at the provincial level and in collaboration with East Timor. PMID- 25534971 TI - Combination of miRNA499 and miRNA133 exerts a synergic effect on cardiac differentiation. AB - Several studies have demonstrated that miRNA are involved in cardiac development, stem cell maintenance, and differentiation. In particular, it has been shown that miRNA133, miRNA1, and miRNA499 are involved in progenitor cell differentiation into cardiomyocytes. However, it is unknown whether different miRNA may act synergistically to improve cardiac differentiation. We used mouse P19 cells as a cardiogenic differentiation model. miRNA499, miRNA1, or miRNA133 were transiently over-expressed in P19 cells individually or in different combinations. The over expression of miRNA499 alone increased the number of beating cells and the association of miRNA499 with miRNA133 exerted a synergistic effect, further increasing the number of beating cells. Real-time polymerase chain reaction showed that the combination of miRNA499 + 133 enhanced the expression of cardiac genes compared with controls. Western blot and immunocytochemistry for connexin43 and cardiac troponin T confirmed these findings. Importantly, caffeine responsiveness, a clear functional parameter of cardiac differentiation, was increased by miRNA499 in association with miRNA133 and was directly correlated with the activation of the cardiac troponin I isoform promoter. Cyclic contractions were reversibly abolished by extracellular calcium depletion, nifedipine, ryanodine, and IP3R blockade. Finally, we demonstrated that the use of miRNA499 + 133 induced cardiac differentiation even in the absence of dimethyl sulfoxide. Our results show that the areas spontaneously contracting possess electrophysiological and pharmacological characteristics compatible with true cardiac excitation-contraction coupling. The translational relevance of our findings was reinforced by the demonstration that the over-expression of miRNA499 and miRNA133 was also able to induce the differentiation of human mesenchymal stromal cells toward the cardiac lineage. PMID- 25534974 TI - Synthesis and photophysical properties of platinum-acetylide copolymers with thiophene, selenophene and tellurophene. AB - A series of platinum-acetylide copolymers with thiophene, selenophene, and tellurophene have been synthesized and studied. Photoluminescence experiments show that polymers undergo intersystem crossing to triplet states, leading to phosphorescence. The observed phosphorescence decreases in intensity moving down the group. DFT calculations are used to further understand the optical properties. PMID- 25534973 TI - Evaluating the cost implications of a radio frequency identification feeding system for early detection of bovine respiratory disease in feedlot cattle. AB - New technologies to identify diseased feedlot cattle in early stages of illness have been developed to reduce costs and welfare impacts associated with bovine respiratory disease (BRD). However, the economic value of early BRD detection has never been assessed. The objective was to simulate cost differences between two BRD detection methods during the first 61 d on feed (DOF) applied in moderate- to large-sized feedlots using an automated recording system (ARS) for feeding behavior and the current industry standard, pen-checking (visual appraisal confirmed by rectal temperature). Economic impact was assessed with a cost analysis in a simple decision model. Scenarios for Canadian and US feedlots with high- and low-risk cattle were modeled, and uncertainty was estimated using extensive sensitivity analyses. Input costs and probabilities were mainly extracted from publicly accessible market observations and a large-scale US feedlot study. In the baseline scenario, we modeled high-risk cattle with a treatment rate of 20% within the first 61 DOF in a feedlot of >8000 cattle in Canada. Early BRD detection was estimated to result in a relative risk of 0.60 in retreatment and 0.66 in mortality compared to pen-checking (based on previously published estimates). The additional cost of monitoring health with ARS in Canadian dollar (CAD) was 13.68 per steer. Scenario analysis for similar sized US feedlots and low-risk cattle with a treatment rate of 8% were included to account for variability in costs and probabilities in various cattle populations. Considering the cost of monitoring, all relevant treatment costs and sale price, ARS was more costly than visual appraisal during the first 61 DOF by CAD 9.61 and CAD 9.69 per steer in Canada and the US, respectively. This cost difference increased in low-risk cattle in Canada to CAD 12.45. Early BRD detection with ARS became less expensive if the costs for the system decreased to less than CAD 4.06/steer, or if the underlying true BRD incidence (not treatment rate) within the first 61 DOF exceeded 47%. The model was robust to variability in the remaining input variables. Some of the assumptions in the baseline analyses were conservative and may have underestimated the real value of early BRD detection. Systems such as ARS may reduce treatment costs in some scenarios, but the investment costs are currently too high to be cost-effective when used solely for BRD detection compared to pen-checking. PMID- 25534975 TI - Diagnosis of subclinical B. ovis infection. PMID- 25534976 TI - Expert Review of Clinical Immunology 10-year anniversary issue. Foreword. PMID- 25534977 TI - Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. AB - HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases. PMID- 25534979 TI - Abdominal aortic coarctation in a middle aged adult. PMID- 25534980 TI - Pseudoaneurysm of the thoracic aorta as an unprecedented complication of esophageal stenting. PMID- 25534978 TI - Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve? AB - Autoimmune diseases are complex and enigmatic, and have presented particular challenges to researchers seeking to define their etiology and explain progression. Previous studies have implicated epigenetic influences in the development of autoimmunity. Epigenetics describes changes in gene expression related to environmental influences without alterations in the underlying genomic sequence, generally classified into three main groups: cytosine genomic DNA methylation, modification of various sidechain positions of histone proteins and noncoding RNAs feedback. The purpose of this article is to review the most relevant literature describing alterations of epigenetic marks in the development and progression of four common autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and Sjogren's syndrome. The contribution of DNA methylation, histone modification and noncoding RNA for each of these disorders is discussed, including examples both of candidate gene studies and larger epigenomics surveys, and in various tissue types important for the pathogenesis of each. The future of the field is speculated briefly, as is the possibility of therapeutic interventions targeting the epigenome. PMID- 25534983 TI - Erratum to: Linking Host Prokaryotic Physiology to Viral Lifestyle Dynamics in a Temperate Freshwater Lake (Lake Pavin, France). PMID- 25534982 TI - Identification of low temperature stress regulated transcript sequences and gene families in Italian cypress. AB - Cold acclimation is a complex transcriptionally controlled process regulated by many different genes and genic-interactions in plants. The northward spreading of woody species is mainly limited by winter harshness. To increase our knowledge about the biological processes underlying cold acclimation, plants evolved in warmer climates can serve as models. In this work, a Suppression Subtractive Hybridization approach using PCR-select was used to isolate Italian cypress (Cupressus sempervirens L.) transcript sequences putatively expressed under low temperature stress. After assessing the reliability of the subtractive step, a total of 388 clones were selected and sequenced. Following sequence assembly and removal of the redundant cDNAs, 156 unique transcripts were identified and annotated in order to assign them a putative functional class. Most of the identified transcripts were functionally classified pertaining to stress in cellular and chloroplast membranes, which are previously known to be severely damaged by cold treatment. Among the identified functional gene families, the extensively represented ones were dehydrins, early light-inducible proteins, senescence-associated genes and oleosins. The last three gene families were further selected for phylogenetic analysis, with the corresponding protein sequences across the complete genomes of the model plants Populus trichocarpa, Vitis vinifera, Physcomitrella patens, and Arabidopsis thaliana. The relationship with the ortholog sequences coming from these species and their further implications are discussed. PMID- 25534981 TI - Advancing beyond the "heart-healthy diet" for peripheral arterial disease. AB - OBJECTIVE: Peripheral arterial disease (PAD) is a burdensome cardiovascular condition that results from chronic inflammatory insults to the arterial vasculature. Key risk factors include age, gender, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hyperhomocysteinemia, smoking, lack of physical fitness, and poor diet, the latter three being modifiable in the development and progression of PAD. A growing body of evidence indicates that imbalanced nutrient intake may contribute to the development and progression of PAD. The purpose of this review is to summarize current knowledge about nutritional patterns among patients with PAD and to ascertain whether certain health-promoting foods and nutrients could benefit patients with this condition. METHODS: We conducted a comprehensive literature review to examine primary source evidence for or against the nutrients that are commonly associated with PAD and their potential utility as therapies. RESULTS: We summarized nine categories of nutrients, as well as four diets endorsed by the American Heart Association that may be prescribed to patients with or at risk for PAD. The nutrients reviewed included omega-3 polyunsaturated fatty acids (n-3 PUFAs), folate and B-series vitamins, and antioxidants. The diet plans described include the Dietary Approaches to Stop Hypertension (DASH) diet, Mediterranean diet, low-fat diet, low carbohydrate diet, Dr Dean Ornish's Spectrum Diet and Dr Andrew Weil's Anti Inflammatory Diet. CONCLUSIONS: PAD is a chronic inflammatory condition that is associated with longstanding poor nutrition habits. We advocate for an intensified use of diet in PAD therapy, and we specifically recommend following eating patterns that are rich in nutrients with anti-inflammatory and antioxidant properties. PMID- 25534984 TI - Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study. AB - AIM: To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD). METHODS: Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use. RESULTS: Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78-1.05) or repaglinide use (aHR 0.80; 95% CI 0.63 1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome. CONCLUSIONS: In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae. PMID- 25534985 TI - Cardiac troponin I as a prognostic factor in critically ill pneumonia patients in the absence of acute coronary syndrome. AB - PURPOSE: Elevated cardiac troponin (cTn) has been associated with worse outcomes in critically ill patients, but few studies have focused on whether these markers are related to outcomes in patients with severe pneumonia. We investigated the levels of cTnI in critically ill patients hospitalized for severe pneumonia and whether elevated levels of cTnI correlated with the clinical outcome of this patient group. MATERIALS AND METHODS: We conducted a retrospective study of patients admitted to the medical intensive care unit (ICU) with severe pneumonia with levels of cTnI obtained within 24 hours of admittance. Patients with evidence of acute coronary syndrome were excluded. A cTnI level greater than 0.034 ng/mL was considered positive. P value < .05 was considered significant. RESULTS: A total of 152 patients (community-acquired pneumonia [39.5%], health care-associated pneumonia [40.8%], and hospital-acquired pneumonia [19.7%]) were included in the study. Eighty-eight (58%) patients had detectable cTnI levels (median, 0.049 ng/mL). Patients with increased cTnI levels showed higher in-ICU mortality (38.6% vs 21.9%, P = .028). The association between elevated cTnI levels and mortality remained significant after adjustment using a multivariate model (adjusted hazard ratio = 1.398; 95% confidence interval, 1.005-1.945; P = .047). CONCLUSIONS: Increased levels of cTnI are an independent predictor of ICU mortality in patients hospitalized with severe pneumonia without evidence of acute coronary syndrome. PMID- 25534986 TI - Anxiety, depression, and satisfaction in close relatives of patients in an open visiting policy intensive care unit in Brazil. AB - PURPOSE: The purpose of the study is to evaluate the satisfaction and symptoms of anxiety and depression in family members in an open visiting intensive care unit (ICU). MATERIAL AND METHODS: A prospective study conducted in a 22-bed mixed ICU in a tertiary hospital in Sao Paulo, Brazil. Family members were enrolled 2 days after admission, and they completed a modified version of Critical Care Family Needs Inventory and the Hospital Anxiety and Depression Scale (HADS). RESULTS: A total of 471 families were interviewed between March 2011 and 2013. Prevalence of anxiety and depression were of 34% and 17%, respectively. We found a high satisfaction score, median of 13 (12-14), and 5% of families were dissatisfied. The daily visiting time was 12 (8-22) hours, and until 10 hours per day, there was a positive association between visiting hours and satisfaction (P = .004). Dissatisfied families reported higher rates of anxiety and depression (P < .001). Visiting hours presented negative interaction between HADS and Critical Care Family Needs Inventory. Patients' severity had a trend toward dissatisfaction (P = .08) and affected emotional disorders (P < .001). CONCLUSIONS: Family members in an open visit ICU reported low rates of symptoms of anxiety and depression and high satisfaction. Visiting hours were associated with the satisfaction score and were a protective factor for family members with higher HADS score. PMID- 25534987 TI - Unfractionated heparin dosing for therapeutic anticoagulation in critically ill obese adults. AB - PURPOSE: Research evaluating unfractionated heparin (UFH) dosing in obese critically ill populations is limited. This study aimed to determine optimal weight-based and total therapeutic infusion rates of UFH in this population. METHODS: This retrospective cohort study compared adults on UFH infusions in intensive care units from May 2011 through October 2013 across 3 weight strata: 95 to 104 kg (control), 105 to 129 kg (high weight), and greater than or equal to 130 kg (higher weight). Primary outcomes included total and weight-based infusion rates for therapeutic anticoagulation. RESULTS: To achieve therapeutic activated partial thromboplastin times, higher weight patients had higher mean infusion rates compared with control (2017 vs 1582 U/h; P = .002). Mean weight-based therapeutic infusion rate was lower in the higher weight group compared with control (13.1 vs 15.8 U kg(-1) h(-1); P = .008). Post hoc analyses indicated mean weight-based infusion rate to achieve therapeutic anticoagulation was 15 U kg(-1) h(-1) in patients less than 165 kg and 13 U kg(-1) h(-1) in patients greater than 165 kg. CONCLUSIONS: Patients greater than or equal to 130 kg have lower weight based heparin requirements compared with patients 95 to 104 kg. This difference appears to be driven by patients greater than 165 kg. Patients greater than 165 kg have lower weight-based heparin requirements, whereas patients from 105 to 164 kg have weight-based requirements similar to a normal-weight patient population. Initiating heparin at appropriate weight-based doses for obese patients may optimize anticoagulation. PMID- 25534988 TI - The liver-selective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet. AB - BACKGROUND AND PURPOSE: There is an unmet medical need for novel NAFLD treatments. Here we have examined the effects of liver-selective NO donor (V PYRRO/NO) as compared with metformin on hepatic steatosis and glucose tolerance in mice fed high fat diet. MATERIAL AND METHODS: Effects of V-PYRRO/NO (5 mgkg( 1)) or metformin (616 mgkg(-1)) were examined in C57BL/6J mice fed high fat diet (HF, 60 kcal% fat). Quantitative determination of steatosis, liver fatty acid composition and western blot analysis of selected proteins involved in mitochondrial biogenesis, fatty acid de novo synthesis and oxidation, triacylglycerols and cholesterol transport from the liver were performed. Liver NOx and nitrate concentration and blood biochemistry were also analyzed. RESULTS: V-PYRRO/NO and metformin reduced liver steatosis with simultaneous reduction of total liver triacylglycerols, diacylglycerols and ceramides fraction and reversed HF-induced decrease in UFA/SFA ratio. V-PYRRO/NO substantially improved postprandial glucose tolerance, while the effect of metformin was modest and more pronounced on HOMA IR index. The anti-steatotic mechanism of V-PYRRO/NO was dependent on NO release, differed from that of metformin and involved improved glucose tolerance and inhibition of de novo fatty acid synthesis by Akt activation and ACC phosphorylation. In turn, major mechanism of metformin action involved increased expression of proteins implicated in mitochondrial biogenesis and metabolism (PGC-1alpha, PPARalpha, COX IV, cytochrome c, HADHSC). CONCLUSIONS: V-PYRRO/NO acts as a liver-specific NO donor prodrug affording pronounced anti-steatotic effects and may represent an efficient, mechanistically novel approach to prevent liver steatosis and insulin resistance. PMID- 25534989 TI - Lipophilic prodrug conjugates allow facile and rapid synthesis of high-loading capacity liposomes without the need for post-assembly purification. AB - Abstract Dihydropyridopyrazoles are simplified synthetic analogues of podophyllotoxin that can effectively mimic its molecular scaffold and act as potent mitotic spindle poisons in dividing cancer cells. However, despite nanomolar potencies and ease of synthetic preparation, further clinical development of these promising anticancer agents is hampered due to their poor aqueous solubility. In this article, we developed a prodrug strategy that enables incorporation of dihydropyridopyrazoles into liposome bilayers to overcome the solubility issues. The active drug was covalently connected to either myristic or palmitic acid anchor via carboxylesterase hydrolyzable linkage. The resulting prodrugs were self-assembled into liposome bilayers from hydrated lipid films using ultrasound without the need for post-assembly purification. The average particle size of the prodrug-loaded liposomes was about 90 nm. The prodrug incorporation was verified by differential scanning calorimetry, spectrophotometry and gel filtration reaching maximum at 0.3 and 0.35 prodrug/lipid molar ratios for myristic and palmitic conjugates, respectively. However, the ratio of 0.2 was used in the particle size and biological activity experiments to maintain long-term stability of the prodrug-loaded liposomes against phase separation during storage. Antiproliferative activity was tested against HeLa and Jurkat cancer cell lines in vitro showing that the liposomal prodrug retained antitubulin activity of the parent drug and induced apoptosis mediated cancer cell death. Overall, the established data provide a powerful platform for further clinical development of dihydropyridopyrazoles using liposomes as the drug delivery system. PMID- 25534990 TI - Effect of sucrose as a lyoprotectant on the integrity of paclitaxel-loaded liposomes during lyophilization. AB - CONTEXT: The stability of liposomes in the form of dispersion is a major concern due to drug leakage and fusion or aggregation. The stability can be improved by lyophilization, but the stress induced by the lyophilization process can affect the integrity of liposomes. OBJECTIVE: The objective of this study was to evaluate the lyoprotective effect of sucrose on drug leakage and vesicle size of paclitaxel-loaded liposomes during the lyophilization process. MATERIALS AND METHODS: Paclitaxel-loaded liposomal dispersions were prepared with sucrose at several lipid-sugar ratios, and internal-external sugar ratios, and then lyophilized. The entrapped paclitaxel content and vesicle size were monitored before and after lyophilization. The stability of the formulation was evaluated at 5 and 25 degrees C. RESULTS: A significant increase in free paclitaxel and vesicle size was observed with the liposomes lyophilized without sucrose. Inclusion of sucrose in the formulation significantly reduced the free paclitaxel concentration and minimized the changes in vesicle size. The extent of protection improved further when sucrose was also present in the internal portion of the bilayer. The lyophilized formulation was stable at 5 degrees C for 3 months. DISCUSSION: A significant (p < 0.05) correlation was observed between free paclitaxel content and the average diameter of the liposomes with respect to sucrose concentrations in the formulation. Sucrose protected the liposomes from drug leakage and aggregation/fusion induced by the lyophilization process in a concentration dependent manner. CONCLUSION: The integrity of paclitaxel-loaded liposomes was preserved during lyophilization by optimal levels of lyoprotectant sucrose in the formulation. PMID- 25534991 TI - Promoting responsible drinking? A mass media campaign affects implicit but not explicit alcohol-related cognitions and attitudes. AB - OBJECTIVES: Rigorous tests are not usually applied to determine whether mass media campaigns that promote responsible drinking are useful, that is whether they lead to responsible drinking or not. In two experiments, we investigated the effectiveness of a mass media campaign that runs in Germany since 2009. This campaign used posters, which emphasized negative alcohol-related outcome expectancies and challenged the positive expectancies. Based on models of alcohol use, we investigated the influence of the campaign on alcohol-related outcome expectancies, implicit and explicit attitudes, and drinking intentions. DESIGN: In Experiment 1, we investigated alcohol-related outcome expectancies via ratings and response latencies among 81 young adult light drinkers. Employing an affective priming task, Experiment 2 was designed to assess implicit attitudes before and after mass media campaign exposure among 83 young adult light drinkers. In both experiments, the effects of the posters were investigated before and after poster exposure as well as compared to a control group. RESULTS: Experiment 1 revealed that the campaign affected only the implicit associations of young adult drinkers, whereas explicit outcome expectancies remained unaffected. Experiment 2 showed that implicit attitudes towards alcohol were turned into more negative ones, but explicit attitudes as well as drinking intentions were not influenced. CONCLUSIONS: The mass media campaign was deemed effective even though its influence occurred on an implicit level. This research highlights the need for experimental investigations of mass media campaigns. Reasons that the findings were obtained on an implicit but not on an explicit level are discussed. PMID- 25534992 TI - Kidney cancer: Inhibition of TK better than mTOR. PMID- 25534993 TI - Prostate cancer: Enzalutamide--differential cross resistance with taxanes. PMID- 25534995 TI - Stones in 2014: Advancing our understanding--aetiology, prevention and treatment. PMID- 25534999 TI - Sexual dysfunction: Shock treatment for erectile dysfunction. PMID- 25535001 TI - Bladder cancer: Stem cells repopulate tumours. PMID- 25534997 TI - Ureteral stent-associated complications--where we are and where we are going. AB - Ureteral stents are one of the most commonly used devices in the treatment of benign and malignant urological diseases. However, they are associated with common complications including encrustation, infection, pain and discomfort caused by ureteral tissue irritation and possibly irregular peristalsis. In addition, stent migration and failure due to external compression by malignancies or restenosis occur, albeit less frequently. As these complications restrict optimal stent function, including maintenance of adequate urine drainage and alleviation of hydronephrosis, novel stent materials and designs are required. In recent years, progress has been made in the development of drug-eluting expandable metal stents and biodegradable stents. New engineering technologies are being investigated to provide stents with increased biocompatibility, decreased susceptibility to encrustation and improved drug-elution characteristics. These novel stent characteristics might help eliminate some of the common complications associated with ureteral stenting and will be an important step towards understanding the behaviour of stents within the urinary tract. PMID- 25535000 TI - Robotic surgery in urological oncology: patient care or market share? AB - Surgical robotic use has grown exponentially in spite of limited or uncertain benefits and large costs. In certain situations, adoption of robotic technology provides value to patients and society. In other cases, however, the robot provides little or no increase in surgical quality, with increased expense, and, therefore, does not add value to health care. The surgical robot is expensive to purchase, maintain and operate, and can contribute to increased consumerism in relation to surgical procedures, and increased reliance on the technology, thus driving future increases in health-care expenditure. Given the current need for budget constraints, the cost-effectiveness of specific procedures must be evaluated. The surgical robot should be used when cost-effective, but traditional open and laparoscopic techniques also need to be continually fostered. PMID- 25535003 TI - Obtaining from grape pomace an enzymatic extract with anti-inflammatory properties. AB - Grape pomace, a winemaking industry by-product, is a rich source of bioactive dietary compounds. Using proteases we have developed an enzymatic process for obtaining a water-soluble extract (GP-EE) that contains biomolecules such as peptides, carbohydrates, lipids and polyphenols in soluble form. Of especial interest is its high polyphenol content (12%), of which 77% are flavonoids and 33% are phenolic acids. The present study evaluates in vitro the potential anti inflammatory effect of GP-EE by monitoring the expression of inflammatory molecules on N13 microglia cells stimulated with lipopolysaccharide (LPS). GP-EE decreases the mRNA levels of the inflammatory molecules studied. The molecules under study were as follows: inducible nitric oxide synthase (iNOS), tumor necrosis factor- alpha (TNF-alpha), interleukin-1beta (IL-1beta), the ionized calcium binding adaptor molecule-1(Iba-1) and the Toll like receptor-4 (TLR-4), as well as the iNOS protein level in LPS-stimulated microglia. Our findings suggest that, as a result of its ability to regulate excessive microglial activation, GP-EE possesses anti-inflammatory properties. Therefore, acting as a chemopreventive agent, it may be of therapeutic interest in neurodegenerative diseases involving neuroinflammation. We can, therefore, propose GP-EE as a useful natural extract and one that would be beneficial to apply in the field of functional foods. PMID- 25535004 TI - Phenolic acids of the two major blueberry species in the US Market and their antioxidant and anti-inflammatory activities. AB - Highbush (cultivated) and lowbush (wild) are the two major blueberry species in the US market. Eight phenolic acids were detected and quantified from these two species by HPLC-MS. Chlorogenic acid was found to be the predominant phenolic acid in both species, with 0.44 mg/g fresh weight in lowbush blueberries and 0.13 mg/g fresh weight in highbush blueberries. Total phenolic content in lowbush blueberries is over three times higher than that of highbush blueberries. The phenolic acid mixtures representing those in the two species were prepared by using authentic standards to assess their contribution to total antioxidant and anti-inflammatory activities of the whole berries. Neither lowbush nor highbush blueberry phenolic acid mixture contributed significantly to the total antioxidant capacity of their relevant whole berries measured by oxygen radical absorbance capacity (ORAC). Both phenolic acid mixtures were able to enter the cell and showed in cell antioxidant activities from the cell based antioxidant protection of erythrocytes (CAP-e) assay. Lowbush blueberry phenolic acid mixture was found to show anti-inflammatory activities by inhibiting the nuclear factor kappaB (NF-kappaB) activation and the production of inflammatory cytokines (TNF alpha and IL-6) at the high dose. PMID- 25535005 TI - On the possible roles of microsaccades and drifts in visual perception. AB - During natural viewing large saccades shift the visual gaze from one target to another every few hundreds of milliseconds. The role of microsaccades (MSs), small saccades that show up during long fixations, is still debated. A major debate is whether MSs are used to redirect the visual gaze to a new location or to encode visual information through their movement. We argue that these two functions cannot be optimized simultaneously and present several pieces of evidence suggesting that MSs redirect the visual gaze and that the visual details are sampled and encoded by ocular drifts. We show that drift movements are indeed suitable for visual encoding. Yet, it is not clear to what extent drift movements are controlled by the visual system, and to what extent they interact with saccadic movements. We analyze several possible control schemes for saccadic and drift movements and propose experiments that can discriminate between them. We present the results of preliminary analyses of existing data as a sanity check to the testability of our predictions. PMID- 25535006 TI - Determination of ATP-activity as a useful tool for monitoring microbial load in aqueous humidifier samples. AB - Air humidifier water tanks are potential sources of microbial contaminants. Aerosolization of these contaminants is associated with the development of airway and lung diseases; therefore, implementation of preventive strategies including monitoring of the microbial contamination is recommended. So far, culture-based methods that include measuring colony forming units (CFU) are widely used to monitor microbial load. However, these methods are time consuming and have considerable drawbacks. As a result, alternative methods are needed which provide not only clear and accurate results concerning microbial load in water samples, but are also rapid and easy to use in the field. This paper reports on a rapid test for ATP quantification as an alternative method for microbial monitoring, including its implementation, validation and application in the field. For this purpose, 186 water samples were characterized with different methods, which included ATP analysis, culture-based methods, endotoxin activity (common and rapid test), pyrogenic activity and number of particles. Half of the samples was measured directly in the field and the other half one day later in the laboratory. The results of both tests are highly correlated. Furthermore, to check how representative the result from one sample of a water source is, a second sample of the same water tank were collected and measured. Bioluminescence results of the undiluted samples covered a range between 20 and 25,000 relative light units (RLU) and correlated with the results obtained using the other methods. The highest correlation was found between bioluminescence and endotoxin activity (rs=0.79) as well as pyrogenic activity (rs=0.75). Overall, the results of this study indicate that ATP measurement using bioluminescence is a suitable tool to obtain rapid, reproducible and sensitive information on the microbial load of water samples, and is suitable to use in the field. However, to use ATP measurement as an indicator of water quality, criteria of assessment has to be discussed. PMID- 25535007 TI - 10 year course of IQ in first-episode psychosis: relationship between duration of psychosis and long-term intellectual trajectories. AB - A substantial proportion of patients suffering from schizophrenia-spectrum disorders (SSDs) exhibit a general intellectual impairment at illness onset, but the subsequent intellectual course remains unclear. Relationships between accumulated time in psychosis and long-term intellectual functioning are largely uninvestigated, but may identify subgroups with different intellectual trajectories. Eighty-nine first-episode psychosis patients were investigated on IQ at baseline and at 10-years follow-up. Total time in psychosis was defined as two separate variables; Duration of psychosis before start of treatment (i.e. duration of untreated psychosis: DUP), and duration of psychosis after start of treatment (DAT). The sample was divided in three equal groups based on DUP and DAT, respectively. To investigate if diagnosis could separate IQ-trajectories beyond that of psychotic duration, two diagnostic categories were defined: core versus non-core SSDs. No significant change in IQ was found for the total sample. Intellectual course was not related to DUP or stringency of diagnostic category. However, a subgroup with long DAT demonstrated a significant intellectual decline, mainly associated with a weaker performance on test of immediate verbal recall/working memory (WAIS-R Digit Span). This indicates a relationship between accumulated duration of psychosis and long-term intellectual course, irrespective of diagnostic category, in a significant subgroup of patients. PMID- 25535008 TI - Perceptually or conceptually driven recognition: on the specificities of the memory deficit in schizophrenia. AB - This study explored the effects of exemplar changes on visual object recognition in patients with schizophrenia and paired control subjects. The experimental design was derived from the process-dissociation procedure (PDP: Jacoby, 1991). The objects presented at test could be the same exemplar as at study (physically identical picture), a different exemplar of the same object category, or a new, non-studied object. In the inclusion task, participants had to generalize their recognition to the conceptual level by accepting both different and identical exemplars as old. In the exclusion task, on the other hand, they had to accept only the same exemplars of the studied objects as old. Overall, performance was better on the inclusion task than on the exclusion task; schizophrenia patients performed worse than controls on the inclusion task but not the exclusion task, misrecognizing different exemplars more often than healthy controls. The present findings reveal that both recollection and familiarity are impaired in patients with schizophrenia, who present a relational, conceptually driven memory deficit. This deficit does not allow them to recognize an object as a member of a specific category independently of perceptual variations. This retrieval mode influences their subjective awareness of items' familiarity, and should be considered as a target for remediation. PMID- 25535009 TI - The role of the potassium channel gene KCNK2 in major depressive disorder. AB - Six single nucleotide polymorphisms (SNPs) of the KCNK2 gene were investigated for their association with major depressive disorder (MDD) and treatment efficacy in 590 MDD patients and 441 controls. The A homozygotes of rs10779646 were significantly more frequent in patients than controls whereas G allele of rs7549184 was associated with the presence of psychotic symptoms and the severity of disease. Evaluating the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) dataset, we confirmed our findings. PMID- 25535010 TI - Assessing DSM-5 latent subtypes of acute stress disorder dissociative or intrusive? AB - Acute Stress Disorder (ASD) was first included in the DSM-IV in 1994. It was proposed to account for traumatic responding in the early post trauma phase and to act as an identifier for later Posttraumatic Stress Disorder (PTSD). Unlike PTSD it included a number of dissociative indicators. The revised DSM-5 PTSD criterion included a dissociative-PTSD subtype. The current study assessed if a dissociative-ASD subtype may be present for DSM-5 ASD. Moreover, we assessed if a number of risk factors resulted in an increased probability of membership in symptomatic compared to a baseline ASD profile. We used data from 450 bank robbery victims. Latent profile analysis (LPA) was used to uncover latent profiles of ASD. Multinomial logistic regression was used to determine if female gender, age, social support, peritraumatic panic, somatization, and number of trauma exposures increased or decreased the probability of profile membership. Four latent profiles were uncovered and included an intrusion rather than dissociative subtype. Increased age and social support decreased the probability of individuals being grouped into the intrusion subtype whereas increased peritraumatic panic and somatization increased the probability of individuals being grouped into the intrusion subtype. Findings are discussed in regard to the ICD-11 and the DSM-5. PMID- 25535011 TI - A pilot study of actigraphy as an objective measure of SSRI activation symptoms: results from a randomized placebo controlled psychopharmacological treatment study. AB - Selective serotonin reuptake inhibitors (SSRIs) are an efficacious and effective treatment for pediatric obsessive-compulsive disorder (OCD) but have received scrutiny due to a potential side effect constellation called activation syndrome. While recent research introduced a subjective measure of activation syndrome, objective measures have not been tested. This pilot study, using data from a larger randomized-controlled trial, investigated the potential of actigraphy to provide an objective measure of activation symptoms in 44 youths with OCD beginning an SSRI medication regimen. Data were collected over the first four weeks of a multi-site, parallel, double-blind, randomized, placebo controlled psychopharmacological treatment study and statistical modeling was utilized to test how activation syndrome severity predicts daily and nightly activity levels. Results indicated that youths with higher activation symptoms had lower daytime activity levels when treatment averages were analyzed; in contrast youths who experienced onset of activation symptoms one week were more likely to have higher day-time and night-time activity ratings that week. Results support actigraphy as a potential objective measure of activation symptoms. Subsequent studies are needed to confirm these findings and test clinical applications for use by clinicians to monitor activation syndrome during SSRI treatment. National Institutes of Health (5UO1 MH078594-01); NCT00382291. PMID- 25535013 TI - Well, you have hepatic metastases: Use of technical language by medical students in simulated patient interviews. AB - OBJECTIVE: This research explored medical students' use and perception of technical language in a practical training setting to enhance skills in breaking bad news in oncology. METHODS: Terms potentially confusing to laypeople were selected from 108 videotaped interviews conducted in an undergraduate Communication Skills Training. A subset of these terms was included in a questionnaire completed by students (N=111) with the aim of gaining insight into their perceptions of different speech registers and of patient understanding. Excerpts of interviews were analyzed qualitatively to investigate students' communication strategies with respect to these technical terms. RESULTS: Fewer than half of the terms were clarified. Students checked for simulated patients' understanding of the terms palliative and metastasis/to metastasize in 22-23% of the interviews. The term ambulatory was spontaneously explained in 75% of the interviews, hepatic and metastasis/to metastasize in 22-24%. Most provided explanations were in plain language; metastasis/to metastasize and ganglion/ganglionic were among terms most frequently explained in technical language. CONCLUSION: A significant number of terms potentially unfamiliar and confusing to patients remained unclarified in training interviews conducted by senior medical students, even when they perceived the terms as technical. PRACTICE IMPLICATIONS: This exploration may offer important insights for improving future physicians' skills. PMID- 25535012 TI - Empirical relationships between health literacy and treatment decision making: a scoping review of the literature. AB - OBJECTIVES: This study asked: What is known from the existing literature about the empirical relationships between health literacy (HL) and the three stages of the treatment decision making (TDM) process: information exchange, deliberation, and deciding on the treatment to implement? METHODS: A scoping review of the literature was conducted. Four databases were searched and a total of 2772 records were returned. After de-duplication and three levels of relevance screening, 41 primary studies were included. RESULTS: Relationships between HL and information exchange were studied more often than relationships between HL and deliberation and deciding on the treatment to implement. Across the 41 studies, there was little overlap in terms the measure(s) of HL adopted, the aspect of TDM considered, and the characteristics of the study populations- making comparisons of the findings difficult. Multiple knowledge gaps and measurement-related problems were identified; including, the possibility that the process of TDM influences HL. CONCLUSION: The importance of HL to the three stages of TDM is unclear because of the knowledge gaps and measurement-related problems that exist. PRACTICE IMPLICATIONS: There are many uncertainties about how TDM, or the design and use of patient decision aids, should respond to patients with different levels of HL. PMID- 25535014 TI - Factors influencing intercultural doctor-patient communication: a realist review. AB - OBJECTIVE: Due to migration, doctors see patients from different ethnic backgrounds. This causes challenges for the communication. To develop training programs for doctors in intercultural communication (ICC), it is important to know which barriers and facilitators determine the quality of ICC. This study aimed to provide an overview of the literature and to explore how ICC works. METHODS: A systematic search was performed to find literature published before October 2012. The search terms used were cultural, communication, healthcare worker. A realist synthesis allowed us to use an explanatory focus to understand the interplay of communication. RESULTS: In total, 145 articles met the inclusion criteria. We found ICC challenges due to language, cultural and social differences, and doctors' assumptions. The mechanisms were described as factors influencing the process of ICC and divided into objectives, core skills and specific skills. The results were synthesized in a framework for the development of training. CONCLUSION: The quality of ICC is influenced by the context and by the mechanisms. These mechanisms translate into practical points for training, which seem to have similarities with patient-centered communication. PRACTICE IMPLICATIONS: Training for improving ICC can be developed as an extension of the existing training for patient-centered communication. PMID- 25535015 TI - Mechanisms of change within motivational interviewing in relation to health behaviors outcomes: a systematic review. AB - OBJECTIVE: Motivational interviewing (MI) has been identified as an effective treatment for health behaviors. Understanding the mechanisms of MI could have practical implications for MI delivery. This review is the first to examine mechanisms within MI that affect health behavior outcomes and summarizes and evaluates the evidence. METHODS: A systematic literature search was conducted in PSYCHINFO, MEDLINE and EMBASE to identify studies that delivered individual MI in the context of health behaviors, excluding addictions, and investigated mechanisms of MI. Effect sizes were calculated. RESULTS: 291 studies were identified and 37 met the inclusion criteria. Few of the 37 studies included, conducted mediation analyses. MI spirit and motivation were the most promising mechanisms of MI. Although self-efficacy was the most researched, it was not identified as a mechanism of MI. Study quality was generally poor. CONCLUSION: Although this review has indicated possible mechanisms by which MI could influence health behavior outcomes, it also highlights that more high quality research is needed, looking at other possible mechanisms or causal pathways within health behavior outcomes. PRACTICE IMPLICATIONS: MI spirit possibly plays an important role within MI and may potentially be used to evoke change talk which links to outcomes. PMID- 25535017 TI - Practical aspects of setting up obstetric skills laboratories--a literature review and proposed model. AB - OBJECTIVE: the use of simulation training in obstetrics is an important strategy to improve health-care providers' competence to manage obstetric cases. As an increasing number of international programmes focus on simulation training, more information is needed about the practical aspects of planning for and organising skills laboratories. METHODS: systematic review of peer reviewed literature published between January 2000 and June 2014. Thematic summary of 31 papers meeting inclusion criteria. FINDINGS: skills laboratories need to reflect the clinical working environment and are ideally located at or near a health-care facility. A mix of low and high fidelity manikins combined with patient actors is recommended to be used with clear instructions, scenario setting and short lectures including audio-visual teaching aids. Motivated trainers are vital and a focus on 'team training' in smaller groups is beneficial. Practical information needed to set up and run a skills laboratory is provided with a proposed outline of a skills laboratory for obstetric simulation training. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: obstetric skills laboratories can play a substantial role in increasing competency and confidence of staff via 'skills and drills' type training. When considering setting up skills laboratories, this can be simply done using low fidelity manikins in the first instance with training facilitated by motivated trainers using realistic clinical scenarios. Overall, the review findings highlight the need for better documentation of factors that promote and/or are barriers to the effective use of skills laboratories. SYNOPSIS: 31 papers detailing the planning and organisation of skills laboratories were reviewed in order to assess the factors necessary for their effectiveness and the vital role they play in increasing staff competencies. Setting up obstetric skills laboratories is worthwhile but requires in-depth planning. PMID- 25535016 TI - A systematic review of types and efficacy of online interventions for cancer patients. AB - OBJECTIVE: This review examines the evidence-based literature surrounding the use of online resources for adult cancer patients. The focus is online resources that connect patients with their healthcare clinician and with supportive and educational resources, their efficacy and the outcome measures used to assess them. METHODS: The following databases were systematically searched for relevant literature: MEDLINE, PsychINFO, Cochrane Central Register of Controlled Trials, CINAHL, Inspec and Computers and Applied Science. Included were studies conducted in an outpatient setting, and reporting a measurable, clinically relevant outcome. Fourteen studies satisfied the inclusion criteria. RESULTS: The efficacy of online interventions was varied, with some demonstrating positive effects on quality of life and related measures, and two demonstrating poorer outcomes for intervention participants. The majority of interventions reported mixed results. Included interventions were too heterogeneous for meta-analysis. CONCLUSIONS: The overall benefit of online interventions for cancer patients is unclear. Although there is a plethora of interventions reported without analysis, current interventions demonstrate mixed efficacy of limited duration when rigorously evaluated. PRACTICE IMPLICATIONS: The efficacy of on-line interventions for cancer patients is unclear. All on-line interventions should be developed using the available evidence-base and rigorously evaluated to expand our understanding of this area. PMID- 25535018 TI - Combined visual illusion effects on the perceived index of difficulty and movement outcomes in discrete and continuous fitts' tapping. AB - The speed-accuracy trade-off is a fundamental movement problem that has been extensively investigated. It has been established that the speed at which one can move to tap targets depends on how large the targets are and how far they are apart. These spatial properties of the targets can be quantified by the index of difficulty (ID). Two visual illusions are known to affect the perception of target size and movement amplitude: the Ebbinghaus illusion and Muller-Lyer illusion. We created visual images that combined these two visual illusions to manipulate the perceived ID, and then examined people's visual perception of the targets in illusory context as well as their performance in tapping those targets in both discrete and continuous manners. The findings revealed that the combined visual illusions affected the perceived ID similarly in both discrete and continuous judgment conditions. However, the movement outcomes were affected by the combined visual illusions according to the tapping mode. In discrete tapping, the combined visual illusions affected both movement accuracy and movement amplitude such that the effective ID resembled the perceived ID. In continuous tapping, none of the movement outcomes were affected by the combined visual illusions. Participants tapped the targets with higher speed and accuracy in all visual conditions. Based on these findings, we concluded that distinct visual motor control mechanisms were responsible for execution of discrete and continuous Fitts' tapping. Although discrete tapping relies on allocentric information (object-centered) to plan for action, continuous tapping relies on egocentric information (self-centered) to control for action. The planning control model for rapid aiming movements is supported. PMID- 25535020 TI - Patient-specific targeting guides compared with traditional instrumentation for glenoid component placement in shoulder arthroplasty: a multi-surgeon study in 70 arthritic cadaver specimens. AB - HYPOTHESIS AND BACKGROUND: The purpose of this study was to compare the accuracy of patient-specific guides for total shoulder arthroplasty (TSA) with traditional instrumentation in arthritic cadaver shoulders. We hypothesized that the patient specific guides would place components more accurately than standard instrumentation. MATERIALS AND METHODS: Seventy cadaver shoulders with radiographically confirmed arthritis were randomized in equal groups to 5 surgeons of varying experience levels who were not involved in development of the patient-specific guidance system. Specimens were then randomized to patient specific guides based off of computed tomography scanning, standard instrumentation, and anatomic TSA or reverse TSA. Variances in version or inclination of more than 10 degrees and more than 4 mm in starting point were considered indications of significant component malposition. RESULTS: TSA glenoid components placed with patient-specific guides averaged 5 degrees of deviation from the intended position in version and 3 degrees in inclination; those with standard instrumentation averaged 8 degrees of deviation in version and 7 degrees in inclination. These differences were significant for version (P = .04) and inclination (P = .01). Multivariate analysis of variance to compare the overall accuracy for the entire cohort (TSA and reverse TSA) revealed patient specific guides to be significantly more accurate (P = .01) for the combined vectors of version and inclination. Patient-specific guides also had fewer instances of significant component malposition than standard instrumentation did. CONCLUSION: Patient-specific targeting guides were more accurate than traditional instrumentation and had fewer instances of component malposition for glenoid component placement in this multi-surgeon cadaver study of arthritic shoulders. Long-term clinical studies are needed to determine if these improvements produce improved functional outcomes. PMID- 25535021 TI - A race for an Ebola vaccine: promises and obstacles. AB - While several impeding factors have limited Ebola vaccine development, the current epidemic has provided a surge which may lead to a record pace for a vaccine against Ebola. Consequently, multiple FDA trials are currently underway using two promising vaccine platforms; one has recently demonstrated durable immunity within non-human primates. PMID- 25535019 TI - A review of ideomotor approaches to perception, cognition, action, and language: advancing a cultural recycling hypothesis. AB - The term "cultural recycling" derives from the neuronal recycling hypothesis, which suggests that representations of cultural inventions like written words, Arabic numbers, or tools can occupy brain areas dedicated to other functions. In the present selective review article, we propose a recycling hypothesis for the ideomotor mechanism. The ideomotor approach assumes that motor actions are controlled by the anticipation of the expected perceptual consequences that they aim to generate in the environment. Arguably, such action-perception mechanisms contribute to motor behaviour for human and non-human animals since millions of years. However, recent empirical studies suggest that the ideomotor mechanism can also contribute to word processing, number representation, and arithmetic. For instance, it has been shown that the anticipatory simulation of abstract semantics, like the numerical quantitative value of three items can prime processing of the associated Arabic number "3". Arabic numbers, words, or tools represent cultural inventions, so that, from a theoretical perspective, we suggest an ideomotor recycling hypothesis for the interaction with such artefacts. In this view, the ideomotor mechanism spreads its influence to other functions beyond motor control, and is recycled to flexibly adapt different human behaviours towards dealing with more abstract concepts. PMID- 25535022 TI - Identification of the small research tetra peptide Epitalon, assumed to be a potential treatment for cancer, old age and Retinitis Pigmentosa in two illegal pharmaceutical preparations. PMID- 25535023 TI - Liver transplantation in Turkey: historical review and future perspectives. AB - Since the first successful liver transplantation by Starzl et al. in 1967, liver transplantation has become the standard therapy for many liver diseases, mainly chronic liver disease. Most liver transplantations performed in Europe and North America utilize deceased donors while a considerable portion of organ requirements is supplied by living donors in Asian countries including Turkey. The actual history of solid organ transplantation in Turkey began with the pioneering work of Dr. Haberal in collaboration with Thomaz E. Starzl in 1974 in Colorado University at Denver. The first successful solid organ transplantation in Turkey was accomplished by Haberal in 1975 with a living donor renal transplantation. Subsequently, legislations no 2238 and 2594 dated 1979 and 1982, respectively, were passed, paving the way for cadaveric tissue/organ utilization and preservation in Turkey. The first deceased donor liver transplantation and the first living donor liver transplantation were performed in 1988 and 1990, respectively. There are currently 45 liver transplantation centers in Turkey. Of these, 25 are state universities, 8 are private (foundation) universities, 9 are private hospitals, and 3 are training and research hospitals belonging to the Ministry of Health. A total of 7152 liver transplantations were performed in Turkey between January 2002 and May 2014. Of these, 4848 (67.8%) used living donors and 2304 (32.2%) used deceased donors. These figures indicate that, despite widespread organ donation campaigns and media-sponsored propaganda, desired targets have not been met yet in providing deceased organ donation. Despite unsatisfactory levels attained in supplying deceased donors, both the number of annual liver transplantations and improvements in overall survival rates of organ transplanted patients continues to increase. Actually, the one year patient survival rate after liver transplantation in 2013 was 80.5%. This rate is getting better with each passing year and believed to be close to 90% in the next few years. PMID- 25535024 TI - Extended vertical lower trapezius island myocutaneous flap versus pectoralis major myocutaneous flap for reconstruction in recurrent oral and oropharyngeal cancer. AB - BACKGROUND: The purpose of this study was to compare the use of an extended vertical lower trapezius island myocutaneous flap (TIMF) and a pectoralis major myocutaneous flap (PMMF). METHODS: A total of 39 patients with advanced recurrent oral and oropharyngeal squamous cell carcinoma (SCC) underwent salvage surgery followed by placement of either an extended lower vertical TIMF or PMMF for reconstruction. Twenty-one patients received extended lower vertical TIMFs, whereas 18 received PMMFs. RESULTS: The pedicle length of the TIMF was longer than that of the PMMF, and the skin paddle of the TIMF was both wider and longer than the PMMF. No major complication developed in any of the patients. The TIMF group experienced a lower rate of minor flap failure than did the PMMF group. CONCLUSION: Use of an extended vertical lower TIMF, which has a longer pedicle flap and a larger skin paddle than a PMMF, is optimal for reconstruction of major defects. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E159-E164, 2016. PMID- 25535025 TI - The necessity of routine histologic examination of hernia sac, revisited. AB - PURPOSE: To validate the need of continuing the current practice of histologic examination of hernia sacs (HS). METHODS: All HS received by our laboratory over 15 years were reviewed for any pathological findings. Cases harboring these results were selectively re-examined histologically by a pathologist and their charts were reviewed by a surgeon checking for clinical significance. Moreover, previous studies were analyzed to reach a final conclusion. RESULTS: Pathological findings were noted in only 13.7 and 12.8% of adults and kids HS, respectively. None of these had significant impact on patient care. CONCLUSIONS: Serious pathologies reported in HS in the literature are rare. This, coupled with our data, suggest that the current practice of routine microscopic examination of HS is not justified. Criteria are proposed for categorizing cases as eligible for histologic evaluation. This will significantly reduce the workload and contain the cost. PMID- 25535026 TI - Identification of the tropomyosin (HL-Tm) in Haemaphysalis longicornis. AB - Haemaphysalis longicornis tropomyosin (HL-Tm) was amplified by RT-PCR. The cDNA contained a 825 bp open reading frame coding for 274 amino acids with a predicted theoretical isoelectric point (pI) of 4.55 and molecular weight of 31.7 kDa. Real time RT-PCR analysis showed that the expression levels of the HL-Tm in the unfed females were significantly higher than in other tested developmental stages (eggs, unfed-larvae and unfed-nymphs). Western blot analysis showed that rabbit anti-serum against H. longicornis unfed-adult ticks recognized the recombinant HL Tm protein (rHL-Tm). Immunization of rabbits with the rHL-Tm resulted in a statistically significant reduction of female engorgement and oviposition. Silencing of HL-Tm by RNAi showed a decrease in tick engorgement and oviposition, which is consistent with the effect of recombinant protein vaccine on the adults. These results showed that tick HL-Tm might be involved in the regulation of ticks blood-feeding, growth and oviposition. PMID- 25535027 TI - Correction: A metabolomic and pharmacokinetic study on the mechanism underlying the lipid-lowering effect of orally administered berberine. AB - Correction for 'A metabolomic and pharmacokinetic study on the mechanism underlying the lipid-lowering effect of orally administered berberine' by Shenghua Gu et al., Mol. BioSyst., 2015, DOI: . PMID- 25535028 TI - How much do workers' health examinations add to health and safety at the workplace? Occupational preventive usefulness of routine health examinations. AB - OBJECTIVE: Despite no evidence in favour, routine workers' health examinations, mostly pre-employment and periodic, are extensively performed worldwide with important allocation of resources. In Spain they are performed within a theoretical job-specific health surveillance system. Our objective was to ascertain their occupational preventive usefulness from the perspective of occupational health professionals. METHODS: Cross sectional study. Online survey addressed to all physicians and nurses members of the Catalan Society of Safety and Occupational Medicine (n=539) in 2011. Univariate and bivariate analyses of prevalence and prevalence differences of answers. RESULTS: Response rate 53% (n=285). According to more than 70% of respondents the health surveillance system isn't cost-effective, doesn't meet the goal of early detection of health damage related to work, and doesn't contribute to improve the occupational risk prevention system. Further deficiencies were identified regarding specificity and scientific basis for health examinations, quality of collective health surveillance and referral of suspected cases to mutual insurance companies for diagnosis and treatment. Bivariate analysis showed a significantly more negative opinion for several items amongst physicians (versus nurses) and amongst professionals working in external prevention services (versus internal services). CONCLUSIONS: This study raises serious concerns about how health examinations are performed within our workers' health surveillance system, which should be reviewed to ensure the fulfilment of its occupational preventive objective. Our results might encourage other countries with similar practices to assess them in order to assure their fitness for purpose. PMID- 25535029 TI - The Critical Care Communication project: improving fellows' communication skills. AB - PURPOSE: The aim of this study was to develop an evidence-based communication skills training workshop to improve the communication skills of critical care fellows. MATERIALS AND METHODS: Pulmonary and critical care fellows (N = 38) participated in a 3-day communication skills workshop between 2008 and 2010 involving brief didactic talks, faculty demonstration of skills, and faculty supervised small group skills practice sessions with simulated families. Skills included the following: giving bad news, achieving consensus on goals of therapy, and discussing the limitations of life-sustaining treatment. Participants rated their skill levels in a pre-post survey in 11 core communication tasks using a 5 point Likert scale. RESULTS: Of 38 fellows, 36 (95%) completed all 3 days of the workshop. We compared pre and post scores using the Wilcoxon signed rank test. Overall, self-rated skills increased for all 11 tasks. In analyses by participant, 95% reported improvement in at least 1 skill; with improvement in a median of 10 of 11 skills. Ninety-two percent rated the course as either very good/excellent, and 80% recommended that it be mandatory for future fellows. CONCLUSIONS: This 3-day communication skills training program increased critical care fellows' self-reported family meeting communication skills. PMID- 25535030 TI - Histologic study of the effects of chemoembolization with preloaded doxorubicin beads in patients with hepatocellular carcinoma. AB - OBJECTIVE: To determine the degree of tumor necrosis in surgical specimens of hepatocellular carcinomas treated with microspheres preloaded with doxorubicin and to analyze the relationship between the degree of necrosis and a) morphologic factors and b) imaging biomarkers. MATERIAL AND METHODS: We studied the livers of 21 patients who had undergone selective arterial chemoembolization with DC beads (Biocompatibles, UK) before receiving liver transplants. RESULTS: Imaging techniques detected 43 nodules (mean size, 25 mm). Angiography showed 25 hypervascularized nodules, 12 slightly vascularized nodules, and 6 avascular nodules. A total of 81 hepatocellular carcinomas (mean size, 15 mm) were detected in the specimens: two were capsular and two had vascular infiltration. The mean degree of necrosis after chemoembolization was 39%; necrosis was greater than 60% in 28 hepatocellular carcinomas and less than 60% in 52. The degree of necrosis correlated significantly with the time elapsed between the last chemoembolization treatment and liver transplantation (the degree of necrosis decreased as time increased), with the number of nodules in the specimen, and with capsular infiltration. When imaging techniques detected 1 or 2 nodules, there was a greater probability of achieving greater than 90% necrosis. No relation with the degree of necrosis achieved was found for the size of the nodules detected at imaging, the enhancement pattern, or the number of chemoembolization treatments. CONCLUSION: The degree of necrosis achieved depends on the time spent on the waiting list, on the number of nodules in the specimen, and on whether capsular infiltration is present. PMID- 25535031 TI - Desmethyl bosentan displays a similar in vitro interaction profile as bosentan. AB - The endothelin-1 receptor antagonists bosentan and ambrisentan used for the treatment of pulmonary arterial hypertension remarkably differ in their potential to act as perpetrators in pharmacokinetic drug-drug interactions. So far, it is not clear whether the metabolites of bosentan and ambrisentan contribute to the extent of drug interactions. We therefore investigated the effects of 4 hydroxymethyl ambrisentan, hydroxy bosentan, desmethyl bosentan, and hydroxy desmethyl bosentan on targets which are inhibited or induced by the parent compounds. The hydroxylated metabolites of ambrisentan and bosentan neither induced any of the genes investigated at the mRNA level, nor inhibited P glycoprotein (P-gp) measured by calcein assay in L-MDR1 cells, and only weakly inhibited organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 measured by 8-fluorescein-cAMP uptake in HEK-OATP1B1 and HEK-OATP1B3 cells. In contrast, desmethyl bosentan induced mRNA expression of cytochrome P450 3A4 (CYP3A4, about 6-fold at 50 MUM), ABCB1 (P-gp, about 4.5-fold at 50 MUM), and ABCG2 (breast cancer resistance protein, about 2-fold at 50 MUM), whereas CYP2C19, ABCB11, and ABCC2 (multidrug resistance-associated protein 2) were not induced in LS180 cells. In a reporter gene assay, desmethyl bosentan activated pregnane X receptor with the highest potency of all metabolites tested. Whereas desmethyl bosentan did not inhibit P-gp, it inhibited OATP1B1 with an IC50 of 3.8 MUM (1.9-7.6) (geometric mean, 95% CI) and OATP1B3 with an IC50 of 7.4 MUM (2.6-21.52). In conclusion, our data demonstrate that desmethyl bosentan exhibits a similar pharmacokinetic interaction profile as bosentan and might contribute to the inducing effects of the parent compound. PMID- 25535032 TI - A fast and activatable cross-linking strategy for hydrogel formation. AB - Strain-promoted oxidation-controlled cyclo-octyne-1,2-quinone cycloaddition (SPOCQ) is a fast and activatable cross-linking strategy for hydrogel formation. Gelation is induced by oxidation, which is performed both chemically using sodium periodate and enzymatically using mushroom tyrosinase. Due to the fast reaction kinetics, SPOCQ-formed hydrogels can be functionalized in one-pot with an azido containing moiety using SPAAC cross-linking. PMID- 25535033 TI - Exposure-response relationships for inhalant wheat allergen exposure and asthma. AB - BACKGROUND: A few studies have investigated exposure-response relationships for sensitisation to wheat, work-related symptoms and wheat allergen exposure. IgG4 is suggested to protect against the development of allergic sensitisation. The main aim of this current study was to explore the nature of exposure-response relationships for a range of clinically relevant endpoints among bakery workers, and to investigate the role of IgG4 in these relationships. METHODS: A cross sectional study of 517 supermarket bakery workers in 31 bakeries used a questionnaire, serum-specific IgE and IgG4 to wheat, and methacholine challenge testing. Exposure models were developed previously using job, bakery size, tasks and specific ingredients used. These models were used to predict average personal exposure to wheat allergens. RESULTS: The exposure-response relationships for average exposure followed a linear relationship for sensitisation, but a bell shaped curve for allergic symptoms and probable occupational asthma, increasing up to 10-15 ug/m(3) wheat allergen concentration after which they plateau off and decrease at higher exposure concentrations. This relationship was modified by atopic status. IgG4 levels were strongly exposure related: a clear increase in prevalence of higher IgG4 with increase in wheat allergen exposure was observed among those sensitised and non-sensitised to wheat, with IgG4 even more strongly associated with exposure than IgE to wheat. CONCLUSIONS: The bell-shaped exposure response relationship in the current study is consistent with the findings of previous studies. IgG4 showed no protective effect for sensitisation, confirming the findings of previous studies, suggesting that the pattern is probably related to a healthy worker effect. PMID- 25535035 TI - Normative adductor squeeze tests scores in rugby. AB - BACKGROUND: Groin pain is a common problem. Adductor squeeze tests are used to diagnose, monitor and prophylactically determine the risk of developing groin pain. This study defines normative adductor squeeze scores in professional rugby that will facilitate strength monitoring during screening. METHODS: Using a sphygnamometer, squeeze scores were collected, at one professional rugby club as part of the pre-season screening for two seasons. Scores were collected in four positions. For all positions mean strength and 95% confidence intervals were calculated. RESULTS: Data were collected for 81 athletes. Mean strength for adduction at 60 degrees was 220.1 (212.2-228.1); 0 degrees 211.1 (201.7-220.5); 90 degrees 90 degrees 198.8 (190.0-207.7); 90 degrees 90 degrees supported 224.9 (214.9-234.9). Backs had lower squeeze scores than forwards for 0 degrees , 90 degrees :90 degrees and 90 degrees :90 degrees supported (p > 0.05 for all four tests); older players had lower scores, as did shorter and lighter players (p > 0.05 except for height with test 60 degrees p = 0.048 and test 90 degrees :90 degrees supported p = 0.035). CONCLUSION: This study establishes references ranges for adductor squeeze tests for normative pre-season data in non-injured rugby players. This information will enable evaluation and inform return to play judgements following adductor related injury. PMID- 25535036 TI - So what does this all mean? PMID- 25535034 TI - Role of glycine N-methyltransferase in the regulation of T-cell responses in experimental autoimmune encephalomyelitis. AB - Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt(-/-) mice developed hepatocellular carcinoma, we hypothesized that Gnmt(-/-) mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt(-/-) mice. Pathological examination of the spinal cords revealed that Gnmt(-/-) mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-gamma and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt(-/-) than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG) specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG(35-55)-induced Gnmt(-/-) mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt(-/-) CD4(+) T cells via an IL-2- and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4(+) T cells was much milder than in those with wild-type CD4(+) T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4(+) T-cell functions. PMID- 25535037 TI - Cutaneous B-cell lymphomas: 2015 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Approximately one-fourth of cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). DIAGNOSIS: DIAGNOSIS and disease classification is based on histologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. Risk-stratification: Disease histology remains the most important prognostic determinant. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: PCFCL and PCMZL patients with solitary or relatively few skin lesions may be affectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL. PMID- 25535039 TI - Toxic effects of methamidophos on paraoxonase 1 activity and on rat kidney and liver and ameliorating effects of alpha-tocopherol. AB - The role of alpha-tocopherol on nephrotoxicity and hepatotoxicity induced by methamidophos (MT) was investigated in wistar rats. Animals were given via gavage, for four weeks, a low dose of MT (MT1), a high dose of MT (MT2), vitamin E (200 mg/kg of bw) or both MT2 plus vitamin E (Vit E) and control group was given distillate water. MT treatment resulted in a significant decrease in the body weight of MT2-treated group. Moreover, MT-treated groups had significantly lower butyrylcholinesterase (p < 0.01) and paraoxonase 1 (PON1) activities compared with the control group (p < 0.05). However, MT2-treated group had significantly higher alkaline phosphatase activity compared with untreated rats (p < 0.05). Both MT-treated groups had significantly higher urea (p < 0.01) and uric acid levels (p < 0.05) compared with the control group. However, significant low uric acid level (p < 0.05) was noted in MT2 plus vit E-treated rats compared with MT2-treated group. Histopathological changes in organ tissues were observed in both MT-treated groups and MT2 plus vit E-treated rats. However, the damage was reduced in MT2 plus vit E-treated rats. Therefore, this study deduces that alpha-tocopherol administration may ameliorate the adverse effects of subacute exposure to MT on rat liver and kidney and this antioxidant can protect PON1 from oxidative stress induced by this organophosphorus pesticide. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 842-854, 2016. PMID- 25535040 TI - Retinal structure and function preservation by polysaccharides of wolfberry in a mouse model of retinal degeneration. AB - Retinitis pigmentosa (RP) is a heterogeneous group of inherited disorders caused by mutations in a variety of genes that are mostly expressed by rod cells, which results in initial death of rod photoreceptors followed by gradual death of cone photoreceptors. RP is currently untreatable and usually leads to partial or complete blindness. Here, we explored the potential neuroprotective effects of polysaccharides of wolfberry, which are long known to possess primary beneficial properties in the eyes, on photoreceptor apoptosis in the rd10 mouse model of RP. We found that these polysaccharides provided long-term morphological and functional preservation of photoreceptors and improved visual behaviors in rd10 mice. Moreover, we demonstrated that polysaccharides exerted neuroprotective effects through antioxidant, anti-inflammatory and anti-apoptotic mechanisms. Furthermore, we identified that polysaccharides modulated inflammation and apoptosis partly through inhibition of NF-kappaB and HIF-1alpha expressions, respectively. Overall, we demonstrated the synergistic protective effects of polysaccharides in preserving photoreceptors against degeneration in rd10 mice. Our study provides rationale and scientific support on using polysaccharides of wolfberry as one supplementary treatment of RP patients in the future. PMID- 25535041 TI - Determining the Cost-Savings Threshold for HIV Adherence Intervention Studies for Persons with Serious Mental Illness and HIV. AB - Persons with serious mental illnesses are at increased risk for contracting and transmitting HIV and often have poor adherence to medication regimens. Determining the economic feasibility of different HIV adherence interventions among individuals with HIV and serious mental illness is important for program planners who must make resource allocation decisions. The goal of this study was to provide a methodology to estimate potential cost savings from an HIV medication adherence intervention program for a new study population, using data from prior published studies. The novelty of this approach is the way CD4 count data was used as a biological marker to estimate costs averted by greater adherence to anti-retroviral treatment. Our approach is meant to be used in other adherence intervention studies requiring cost modeling. PMID- 25535042 TI - Predictors of Serious Psychological Distress in an Urban Population. AB - While there are state and national estimates of serious psychological distress (SPD), these are not useful for targeting local mental health interventions or for addressing the needs of sub-populations at increased risk for SPD. This cross sectional study uses data from the population-based 2010 Health of Houston Survey (n = 5,116) to examine (1) the prevalence of SPD and its determinants in Houston area and (2) predictors of the utilization of mental health services among people with SPD. The prevalence of SPD among the Houston area adult population was 7 %, more than twice the national average. Correlates of SPD included: being female, under 65, lacking emotional support, smoking, having poor health status and financial distress. The odds of utilizing health services by those with SPD were affected by financial distress, insurance, employment and perceived need for services, among other factors. Interventions should be tailored to mitigate risk factors for SPD and to improve access to mental health services in the SPD sub population. PMID- 25535043 TI - The Discriminative Ability of the Azeri Version of the Strengths and Difficulties Questionnaire in Outpatient Practice. AB - In this study we examined the validity of the Azeri version of the Strengths and Difficulties Questionnaire (SDQ). The SDQ was administered to the parents of two samples of 4-16-year-old children: the case group was drawn from children presenting to the psychiatric outpatient service (n = 347) and the comparison group from the pediatric outpatient service (n = 267). The total difficulties score and the scores for each subscale were compared between two groups. The proportion of children with the total difficulties score in the abnormal range was higher in the case group than in the comparison group (74 and 34 %, p < 0.001). The mean difficulties score difference between two groups was significant (mean difference = 6.3, p < 0.001). The Receiver Operating Characteristics analysis showed good discriminative ability for the total difficulties score and difficulties subscales (p < 0.001). SDQ distinguished well between groups. PMID- 25535044 TI - Risk Factors of High Burden Caregivers of Dementia Patients Institutionalized at Day-Care Centres. AB - We examined which variables are associated with day care centres utilization among caregivers of dementia patients. A cross-sectional analysis of socio demographic variables, relationship with caring and psychological aspects was conducted in 58 informal caregivers with intense burden. 58.6 % used day care assistance and 41.4 % did not. The results showed the importance of the commitment between the caregiver and their family and friends. The use of day care services is independent of the age, gender, educational level, marital status, occupation and relationship with the patient. However, in the multivariate analysis the provision of help by families and friends predicted the use of day care assistance. The bivariate analysis showed a significant relationship between depressive symptoms and self-rated health with day care attendance. Screening the help provision from families and friends in caregivers of dementia patients with intense burden would be relevant to design interventions which delay their institutionalization and reduce costs. PMID- 25535045 TI - Evaluating Explicit and Implicit Stigma of Mental Illness in Mental Health Professionals and Medical Students. AB - The study investigated explicit and implicit attitudes towards people with mental illness among medical students (non-professionals) with no previous contact with mentally ill patients and psychiatrists and psychotherapists (professionals) who had at least 2 years of professional contact with mentally ill patients. Explicit attitudes where assessed by self-report. Implicit attitudes were measured with the Go/No-Go Association Task, a variant of the Implicit Association Test that does not require the use of a comparison category. Compared to non-professionals, mental health professionals reported significantly higher approach emotions than non-professionals towards people with mental illness, showed a lesser tendency to discriminate against them, and held less restrictive attitudes. Both groups reported negative implicit attitudes towards mentally ill. Results suggest that both non-professionals and professionals display ambivalent attitudes towards people with mental illness and that professional, long-term contact with people with mental illness does not necessarily modify negative implicit attitudes. PMID- 25535046 TI - Workforce Development Innovations with Direct Care Workers: Better Jobs, Better Services, Better Business. AB - This study describes findings from a national search to identify innovative workforce practices designed to improve the lives of direct care workers serving individuals with mental health and substance use conditions, while simultaneously improving client care, and the business vitality of the employer. The search process, conducted by The Annapolis Coalition on the Behavioral Health Workforce, resulted in the selection of five programs to receive the Pacesetter Award from among 51 nominations received. Awardees understood the value of investing in direct care workers, who constitute an essential, but often overlooked, group within the behavioral health workforce. A review of these innovations yielded six cross-cutting principles that should inform future workforce efforts (a) supporting educational and career development (b) increasing wages and benefits PMID- 25535047 TI - The Relationship Between the Perceived Risk of Harm by a Family Member with Mental Illness and the Family Experience. AB - Family members of people with serious mental illness (SMI) at times report that they act to stop their ill relative from self harm or harming others. This study examines the relationship between the perception of risk of harm and family distress, burden, empowerment, coping, physical and mental health, appraisal of the caregiving experience, family communication, and family functioning. The study is a secondary analysis of baseline data collected for a randomized study of the family-to-family peer driven education program (FTF). Four hundred thirty four enrolled individuals who were seeking to participate in FTF completed survey items that asked if they had tried to stop or prevent their ill family member from harming themselves or others in the last 30 days. Participants who perceived a recent risk of harm by their ill relative reported more negative appraisals of caregiving, greater psychological distress, poorer mental health and greater objective burden compared with those who did not perceive a recent risk of harm. The results suggest that families of persons with SMI should be asked about perceived risk of harm to self and others, and the presence of perceived risk of harm should serve as a red flag indicating the need for further evaluation of the family experience and additional support for the family. PMID- 25535048 TI - Exploring Factors Associated with the Psychosocial Impact of Stigma Among People with Schizophrenia or Affective Disorders. AB - Stigmatization can exert a variety of pernicious effects on the lives of persons with mental illnesses. The purpose of this study was to explore factors related to the psychosocial impact of stigma among 229 people receiving psychiatric treatment: 123 with schizophrenia [International Classification of Diseases, 10th Revision (ICD-10): F20] and 106 with affective disorders (ICD-10: F31-F33). In the whole sample, the factors most prominently associated with a greater impact of stigma on personal and family life were schizophrenia diagnosis, current inpatient treatment, actually experienced stigma and self-stigma. However, the patterns of predictors varied between the two diagnostic categories. For the schizophrenia group, only self-stigma significantly contributed to a stronger stigma impact. In the affective group, a more severe impact of stigma was significantly predicted by inpatient status and experienced stigma. Anti-stigma programs should address the specific features of stigmatization associated with various psychiatric diagnoses. PMID- 25535049 TI - Individual peer support: a qualitative study of mechanisms of its effectiveness. AB - Peer-delivered services for individuals with psychiatric conditions have proliferated over the past three decades. The values and principles underlying peer support have been explored, but we lack an understanding of its mechanisms of action. To shed light on the processes of peer support, we conducted a study with individuals who had received substantial individual peer support. We completed individual interviews, audiotaped, transcribed, and examined them using a thematic analysis approach. Our analyses suggest that individual peer support provided various practical, emotional, and social supports which were perceived as beneficial. Participants valued having someone to rely on, a friend, and someone to socialize with. We, however, found that individuals' expectations of peer support did not always comport with available services. Participants viewed peer support as especially valuable because of the opportunity for a non treatment based, normalizing relationship. We conclude that peer support complements rather than supplants needed traditional mental health services. PMID- 25535051 TI - Perceptions and dietary intake of self-described healthy and unhealthy eaters with severe mental illness. AB - The aim of this exploratory study was to examine how community-dwelling adults with severe mental illness describe themselves as eaters and how these eating identities relate to dietary intake. Twenty participants completed one in-depth qualitative interview and three 24-h dietary recalls. Two distinct groups were identified; self-described healthy eaters (n = 10) and self-described unhealthy eaters (n = 10). Healthy eaters emphasized fruits and vegetables, limiting sweets, three meals a day, overcoming cost concerns, and benefits of healthy eating. Unhealthy eaters emphasized junk foods, fried foods, few fruits and vegetables, cost and household barriers to healthy eating, and concerns about consequences of unhealthy eating. Self-described healthy eaters consumed significantly more vegetables and less kilocalories, carbohydrates, fat, and saturated fat than self-described unhealthy eaters. Understanding how eating identities relate to dietary intake provides important insights for development of more effective approaches to promote healthy eating in this high risk population. PMID- 25535050 TI - Factors Influencing Time Lag Between Initial Parental Concern and First Visit to Child Psychiatric Services Among ADHD Children in Japan. AB - The aim of this study was to examine the factors associated with a time lag between initial parental concern about ADHD symptoms and the first visit to a hospital in Japan that offers child psychiatric services. We investigated the demographic characteristic, symptoms, diagnosis, and healthcare system factors including duration between initial parental concern about symptoms and the first visit to a hospital (N = 387). The mean time lag between initial parental concern and the first visit to a hospital was 2.6 years. Risk factors for a longer time lag include the young age of a child, behavioral problems of the child, lower maternal education, difficulty in determining appropriate medical institution, referral route, and the distance from home to the hospital. A more established connection between a hospital with child psychiatric services and other health institutions is recommended for earlier referral to an appropriate hospital. PMID- 25535053 TI - The effect of parent and peer attachment on suicidality: the mediation effect of self-control and anomie. AB - We explore the influence of psycho-social factors including the attachment to parent and peer, self-control, and anomie on suicidality. Research questionnaires were distributed among 336 students of Shahid Chamran University of Ahvaz in Iran. The results demonstrated that mother and peer attachments had an indirect effect on suicidality via self-control and anomie, and self-control had a direct effect on suicidality and an indirect effect via anomie. Self-control and anomie had the most efficient role in the model with a large effect size. Findings are discussed theoretically and with regards to the socio-cultural sphere of Iranian society. PMID- 25535052 TI - Utilization of psychiatric services by postpartum women in a predominantly minority, low-socioeconomic-status, urban population. AB - This study describes the utilization of health care services related to psychiatric diagnoses in an inner city community health organization with a largely Hispanic population of low socioeconomic status. We reviewed the frequency and timing of postpartum mental health diagnoses among 5,731 patients who delivered babies and were followed-up for postpartum care. 286 women (5 %) had at least one mental health diagnosis. The rates in white, black, and Hispanic women were 12, 8, and 5 % respectively (p < .05). White and black women were 2.5 (95 % CI 1.24, 5.07), and 1.62 (95 % CI 1.09, 2.40) times more likely to have a mental health diagnosis, respectively, compared to Hispanic women. The most common diagnoses were mood disorders (64 %) followed by anxiety disorders (29 %). 87 % of cases were diagnosed after 4 weeks postpartum. The postpartum mental health diagnosis rate seen here is lower than might be expected, particularly among Hispanic women. Possible explanations are discussed. PMID- 25535054 TI - Implementation of an Evidence Based Guideline for Assessment and Documentation of the Civil Commitment Process. AB - The purpose of this quality improvement project was to implement an evidence based practice guideline for assessment and documentation of the civil commitment process. Participants included six civil commitment examiners who conduct court ordered psychiatric evaluations at two crisis intervention centers in rural area of southeaster state. Data collection was conducted utilizing a chart audit tool both pre and post intervention of 100 civil commitment evaluations. The intervention included the development of an evidenced based form for documentation of civil commitment evaluations and a one on one educational training session was conducted for each participant. Descriptive statistics (t test) was utilized to analyze the data collected. The project demonstrated a significant increase as 25.5 % of evaluations contained the America Psychiatric Association's recommended 11 domains of assessment prior to implementation compared to 65.6 % (p value = 0.018) post implementation. Moreover, participants with family practice training showed an increase in commitment rates from 60 to 77.3 % (p value = 0.066). Whereas, psychiatric trained participants showed a decrease from 83.75 to 77.66 % (p value = 0.38). Demonstrating that court ordered evaluations guided by a standardized form based on evidence affected examiners recommendations for commitments. PMID- 25535056 TI - Longitudinal Magnetic Resonance Imaging (MRI) Analysis of the Developmental Changes of Tourette Syndrome Reveal Reduced Diffusion in the Cortico-Striato Thalamo-Cortical Pathways. AB - There is evidence that cortico-striato-thalamo-cortical pathways are involved in Tourette syndrome. We performed a longitudinal imaging study in 22 patients and 21 healthy controls in order to examine the development of tics and its correlation with magnetic resonance imaging (MRI) findings. Patients were divided in a group with persisting and a group with remission of tics. We found a decrease in volume of left putamen in controls, but not in patients. We found changes in mean diffusivity between patients and controls in right caudate nucleus, thalamus, and frontal lobe. In contrast to controls, parallel and perpendicular diffusivity decreased in patients and were most pronounced in the patients with persisting tics compared to those with remission. The findings suggest that the development of the brain in patients with remission resembles the normal development more than in patients with persistent tics. This could reflect a change in brain structure or compensatory mechanisms in the brain. PMID- 25535055 TI - Medical-School Partnership in Guiding Return to School Following Mild Traumatic Brain Injury in Youth. AB - Mild traumatic brain injury is recognized as a prevalent and significant risk concern for youth. Appropriate school return is particularly challenging. The medical and school systems must be prepared partners to support the school return of the student with mild traumatic brain injury. Medical providers must be trained in assessment and management skills with a focused understanding of school demands. Schools must develop policies and procedures to prepare staff to support a gradual return process with the necessary academic accommodations. Ongoing communication between the family, student, school, and medical provider is essential to supporting recovery. A systematic gradual return to school process is proposed including levels of recommended activity and criteria for advancement. Targets for intervention are described with associated strategies for supporting recovery. A 10-element Progressive Activities of Controlled Exertion (PACE) model for activity-exertion management is introduced to manage symptom exacerbation. A strong medical-school partnership will maximize outcomes for students with mild traumatic brain injury. PMID- 25535057 TI - Optimizing Care With a Standardized Management Protocol for Patients With Infantile Spasms. AB - The primary aim of this quality improvement initiative was to increase the number of patients receiving first-line therapy (adrenocorticotropic hormone, corticosteroids, vigabatrin) as the initial treatment for infantile spasms. We implemented a standardized management protocol for infantile spasms based on the best available data and expert consensus. To assess the impact of this intervention, we compared the 3-month remission rates between prestandardization (January 2009 to August 2012) and poststandardization (September 2012 to May 2014) cohorts. We found that the percentage of patients receiving first-line therapy as the initial treatment was 57% (31/54) in the prestandardization cohort and 100% (35/35) in the poststandardization cohort (P < .001). The rate of infantile spasms remission was higher poststandardization compared to prestandardization (78.8% vs 30.6%, P < .001). Management standardization led to all patients receiving first-line therapy as the initial treatment and was associated with a significantly improved rate of infantile spasms remission 3 months after diagnosis. PMID- 25535059 TI - Prenatal Diagnosis and Postnatal Outcome of Schizencephaly. AB - The aim of this study was to present our experience with 5 cases of fetal schizencephaly in terms of prenatal diagnostic features, and postnatal outcome. The database of prenatal diagnosis unit was searched for antenatally diagnosed cases with schizencephaly. Maternal characteristics, ultrasonography, prenatal postnatal magnetic resonance imaging (MRI) findings, and postnatal outcome were noted. Of 5 cases, 2 had definitive prenatal diagnoses on ultrasound and 3 cases were diagnosed by fetal MRI. All cases had cerebral cortical migration anomalies including polymicrogyria, subependymal heterotopia, and lissencephaly, and 2 cases had additional extracranial malformations. Three cases showed regression of the cerebral clefts on follow-up postnatal MRIs. Three cases had moderate to severe psychomotor retardation, and 1 case needed repeated ventriculoperitoneal shunt operation due to hydrocephaly. Prenatal diagnosis of schizencephaly with ultrasonography is not straightforward and required further evaluation with fetal MRI. Additional cerebral anomalies worsen the prognosis of schizencephaly. PMID- 25535058 TI - Early-Onset Aicardi-Goutieres Syndrome: Magnetic Resonance Imaging (MRI) Pattern Recognition. AB - Aicardi-Goutieres syndrome is an inherited leukodystrophy with calcifying microangiopathy and abnormal central nervous system myelination. As fewer diagnostic computed tomographic (CT) scans are being performed due to increased availability of magnetic resonance imaging (MRI), there is a potential for missed diagnoses on the basis of calcifications. We review a series of patients with MRIs selected from IRB-approved leukodystrophy biorepositories to identify MRI patterns for recognition of early-onset Aicardi-Goutieres syndrome and scored for a panel of radiologic predictors. Each individual predictor was tested against disease status using exact logistic regression. Features for pattern recognition of Aicardi-Goutieres syndrome are temporal lobe swelling followed by atrophy with temporal horn dilatation, early global cerebral atrophy and visible calcifications, as evidenced by 94.44% of cases of Aicardi-Goutieres syndrome correctly classified with a sensitivity of 90.9% and specificity of 96.9%. We identify a panel of MRI features predictive of Aicardi-Goutieres syndrome in young patients that would differentiate it from other leukoencephalopathies. PMID- 25535060 TI - The Yield of Neuroimaging in Children Presenting to the Emergency Department With Acute Ataxia in the Post-Varicella Vaccine Era. AB - To determine the yield of neuroimaging in children presenting to the emergency department with acute ataxia in the post-varicella vaccine era, we conducted a cross-sectional study between 1995 and 2013 at a single pediatric tertiary care center. We included children aged 1-18 years evaluated for acute ataxia of <7 days' duration. The main outcome was clinically urgent intracranial pathology defined as a radiologic finding that changed initial management. We identified 364 children, among whom neuroimaging was obtained in 284 (78%). Forty-two children had clinically urgent intracranial pathology (13%, 95% confidence interval 9%-17%); tumors and acute disseminated encephalomyelitis were the leading findings. Age <=3 years and symptoms <=3 days of duration were predictors of low risk (0.7%, 95% confidence interval 0%-4.4%). In conclusion, neuroimaging may be indicated for most patients presenting with acute ataxia. Neuroimaging may be deferred in younger children with short duration of symptoms contingent on close follow-up. PMID- 25535061 TI - On the quantitativeness of EDS STEM. AB - Chemical mapping using energy dispersive X-ray spectroscopy (EDS) in scanning transmission electron microscopy (STEM) has recently shown to be a powerful technique in analyzing the elemental identity and location of atomic columns in materials at atomic resolution. However, most applications of EDS STEM have been used only to qualitatively map whether elements are present at specific sites. Obtaining calibrated EDS STEM maps so that they are on an absolute scale is a difficult task and even if one achieves this, extracting quantitative information about the specimen - such as the number or density of atoms under the probe - adds yet another layer of complexity to the analysis due to the multiple elastic and inelastic scattering of the electron probe. Quantitative information may be obtained by comparing calibrated EDS STEM with theoretical simulations, but in this case a model of the structure must be assumed a priori. Here we first theoretically explore how exactly elastic and thermal scattering of the probe confounds the quantitative information one is able to extract about the specimen from an EDS STEM map. We then show using simulation how tilting the specimen (or incident probe) can reduce the effects of scattering and how it can provide quantitative information about the specimen. We then discuss drawbacks of this method - such as the loss of atomic resolution along the tilt direction - but follow this with a possible remedy: precession averaged EDS STEM mapping. PMID- 25535062 TI - Immunohistochemical study of KiSS1 and KiSS1R expression in human primary breast cancer: Association with breast cancer receptor status, proliferation markers and clinicopathological features. AB - Recent studies have raised doubts about the protective role of KiSS1/KiSS1R in breast malignancy progression. However, the role of the KiSS1/KiSS1R system in primary breast cancer remains largely unknown. The aim of the present study was to characterize the biology and invasiveness potential of primary breast cancer through evaluation of KiSS1/KiSS1R protein expression and cellular localization with regard to lymph node metastasis status, receptor status (ERs, PR and HER 2/neu), and expression of aromatase, MMP-9, Ki-67 and Cyclin D1 in primary invasive breast cancer tissues. We showed increased protein expression of both KiSS1/KiSS1R and MMP-9 in the cancerous tissues compared with noncancerous tissue adjacent to the breast tumour. In the studied group of breast cancer samples, we observed a positive correlation between KiSS1 and MMP-9. We also showed a positive correlation between KiSS1R and aromatase expression in all studied breast cancers. We did not notice any associations between system and cell cycle regulators. KiSS1/KiSS1R did not correlate either with Cyclin D1 and Ki-67 or with receptor status. However, we showed higher levels of KiSS1R expression in ERalpha-negative cases than in ERalpha-positive cases in patients with lymph node metastasis. Present data do not confirm the protective role of KiSS1/KiSS1R in breast cancer progression, but our results do support the hypothesis that the KiSS1/KiSS1R system is activated even in primary breast cancer and sustained during invasion to local lymph nodes. PMID- 25535063 TI - The current status of endoscopy in transsphenoidal surgery: an international survey. AB - OBJECTIVE: A survey-based study was designed to assess opinions related to transsphenoidal endoscopy, to evaluate the current global attitudes of neurosurgeons regarding the use of this procedure, and to solicit basic data from key institutions worldwide, with the advantage that large series of cases become available for analysis. METHODS: A web-based multi-item questionnaire was distributed to the surgical departments of 393 neurosurgical centers by means of an invitation e-mail. The questionnaire was composed of 2 sections: section 1 focused on the surgical technique for pituitary adenomas (standard technique), and section 2 concentrated on surgery for skull base tumors (extended technique). Each section was composed of 2 parts: multiple choice questions and free textual responses. RESULTS: From a total of 393 neurosurgical centers, from 23 countries, that received the questionnaire, 87 of them (22%) submitted complete or incomplete responses. The surgical procedure, in 60 cases had been performed by a neurosurgeon, in 53 cases by a neurosurgeon and an otolaryngologist, and in 4 cases by an otolaryngologist only. The endoscope (2- and 3-dimensional) was used in 85.2% of transsphenoidal procedures versus the microscope in 14.8% of cases. The endonasal route was used for approach in 93.2% versus the sublabial route in 6.8% of cases. Computer-guided navigation was used by survey population in 71 cases, micro-Doppler in 51 cases, and Cavitron Ultrasonic Surgical Aspirator in 43 cases. Several hundreds of extrasellar tumors were operated using the extended technique. CONCLUSIONS: Transsphenoidal endoscopy for pituitary and anterior skull base tumors has become established as a routine method of dealing with a variety of lesions. The level of interest in the neurosurgical surgery community is reflected by the geometric expansion of contributions to the literature on endoscopic surgery. PMID- 25535064 TI - Prevalence of Vitamin D Deficiency in Patients Undergoing Elective Spine Surgery: A Cross-Sectional Analysis. AB - OBJECTIVE: Decreased bone density secondary to osteoporosis and osteomalacia represents a significant risk factor for bony fracture and spinal instrumentation failure. We evaluated the incidence of vitamin D deficiency in patients undergoing elective spinal instrumentation to investigate which patient-level risk factors are associated with deficient vitamin D levels. METHODS: Serum 25-OH vitamin D levels were evaluated postoperatively (<72 hours) in patients undergoing elective spinal fusion from 2011 through 2012. Patients >18 years with a diagnosis of degenerative spinal spondylosis or spinal instability treated with spinal fusion were included. Risk factors for vitamin D deficiency (<20 ng/mL) were analyzed using univariate and multiple logistic regression to identify independent predictors of deficiency. RESULTS: The mean preoperative neck and Oswestry disability indexes of the 230 consecutive patients (mean, 57 +/- 13.9 years) were 21.0 +/- 9.8 and 22.2 +/- 8.5, respectively. Mean 25-OH vitamin D level was 25.9 +/- 12.4 ng/mL (range, 6-77 ng/mL). Sixty-nine (30.0%) patients had laboratory-confirmed vitamin D deficiency and 89 (38.9%) had laboratory confirmed vitamin D insufficiency (20-30 ng/mL). The risk of vitamin D deficiency was greater in men (odds ratio [OR] 2.53; P = 0.009), patients aged 40-60 years (OR 2.45; P = 0.018), and those who had body mass index >40 (OR 7.55; P = 0.004), an existing diagnosis of diabetes (OR 3.29; P = 0.019), or no vitamin D supplementation (OR 4.96; P = 0.043). CONCLUSIONS: Vitamin D deficiency was common in patients with degenerative spondylosis undergoing spinal fusion. Middle aged patients, men, the morbidly obese, those with a history of diabetes, and those with no history of supplementation had a higher incidence of vitamin D deficiency. PMID- 25535065 TI - Patients Experience High Levels of Anxiety 2 Years Following Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: To explore anxiety levels during the first 2 years after rupture of aneurysmal subarachnoid hemorrhage. METHODS: A consecutive sample of patients with aneurysmal subarachnoid hemorrhage (aSAH) (n = 88, 84.6% of eligible) from a Swedish neurosurgical clinic were followed-up with a prospective cohort design at 3 time points; 6 months, 1 year, and 2 years after the onset. Data were collected by postal questionnaires and telephone interviews: State trait anxiety inventory, Hospital anxiety and depression scales, Barthel index, Telephone interview for cognitive status, and a set of study-specific questions. RESULTS: Most of the respondents scored above the State trait anxiety inventory Swedish norm value on anxiety levels at all 3 follow-up time points. About 59% (n = 52) of respondents scored above the cutoff value for clinical significant level of anxiety in at least 1 time point during the first 2 years after rupture of aSAH. There were no significant differences in levels of anxiety versus the observational period and the 3 follow-up time points. The most significant explanatory variable to high levels of anxiety at all 3 follow-up time points was low perceived recovery. CONCLUSIONS: Levels of anxiety remained high and stable throughout the first 2 years after rupture of aSAH. High levels of anxiety may reduce health-related quality of life substantially. Identification of individuals with high levels of anxiety and supportive care could therefore potentially improve long-term outcome. PMID- 25535066 TI - Functional and Structural Traumatic Brain Injury in Equestrian Sports: A Review of the Literature. AB - OBJECTIVE: Sports-related concussions and traumatic brain injury (TBI) represent a growing public health concern. We reviewed the literature regarding equestrian related brain injury, ranging from concussion to severe TBI. METHODS: A literature review was performed to address the epidemiology of sports-related concussion and TBI in equestrian-related sports. MEDLINE and PUBMED databases were searched to identify all studies pertaining to brain injury in equestrian related sports. We included two broad types of brain injury using a distinction established in the literature: 1) TBI with functional impairment, including concussion, or mild TBI, with negative imaging findings; and 2) TBI with structural impairment, with positive imaging and at least one of the following pathologies identified: subdural hemorrhage, epidural hemorrhage, subarachnoid hemorrhage, intraparenchymal hemorrhage, cerebral contusions, and skull fractures. RESULTS: Our literature search yielded 199 results. We found 26 studies describing functional TBI and 25 mentioning structural TBI, and 8 including both. Of all modern sporting activities, equestrian sports were found to cause some of the highest rates of total bodily injury, severe brain injury, and mortality. Concussions comprise 9.7%-15% of all equestrian-related injuries brought to hospitals for evaluation. Structural TBI was rare, and documentation of these injuries was poor. Although demographic risk factors like age and sex are minimally discussed in the literature, two studies identified a protective effect of increasing rider experience on all forms of bodily injury. However, it remains unclear whether increasing rider experience protects specifically against head injury. Finally, rates of helmet use in horseback riding remain dismally low ranging from 9%-25%, depending on the activity. These low rates have persisted over time, despite evidence in this literature that helmets lead to an absolute risk reduction for head injury of 40%-50% in equestrian sports. CONCLUSIONS: Equestrian-related functional and structural TBI represent a significant public health burden. Rider and horse characteristics make the sport uniquely dangerous, as the athlete has limited control over an animal weighing a thousand pounds. Helmet use rates remain very low despite clear evidence of risk reduction. Health care providers are strongly urged to lobby professional and governmental organizations for mandatory helmet use in all equestrian sports. PMID- 25535067 TI - The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. AB - BACKGROUND: Atypical meningiomas (AMs) frequently recur after gross total resection (GTR). OBJECTIVE: We conducted a meta-analysis to evaluate the benefit of adjuvant therapy after GTR of AMs. METHODS: A PubMed/MEDLINE search identified studies detailing AMs treated by GTR alone or GTR and adjuvant radiotherapy (RT) published between 1984 and 2012. Original data from 14 retrospective studies were combined and analyzed. Odds ratio (OR) and chi(2) testing were used when appropriate. Selected datasets were used to generate each variable, where available. RESULTS: A total of 757 patients (male/female ratio 9:10) with AMs were included; 72.52% (n = 549) of AMs were treated by GTR alone, and 27.47% (n = 208) underwent adjuvant RT after GTR to a median dose of 54 Gy. The crude recurrence rate was twice as high without adjuvant RT (33.7% vs. 15%, P = 0.005). The 1-year local control rate was 90% for GTR and 97% for GTR + RT (OR = 3.36, P = 0.11). The median 5-year local control rate was 62% for GTR and 73% for GTR + RT, respectively (OR = 1.71, P = 0.06). The 5-year overall survival for each group was 90% (OR = 0.97, P = 0.95). A total of 85% of recurrences were salvaged, 33% by RT and 67% by surgery. Radiation-related toxicity was <10%, at a median follow-up of 42 months. CONCLUSIONS: Postoperative RT for AMs may decrease risk for relapse of disease and improve local control, although most tumors are salvageable with surgery or radiation. Although the data suggest little or no impact of postoperative RT on survival, further investigation regarding the long term efficacy and toxicity of radiation is warranted. PMID- 25535069 TI - The use of vancomycin powder in modern spine surgery: systematic review and meta analysis of the clinical evidence. AB - BACKGROUND: Surgical-site infections (SSIs) can lead to greater postoperative morbidity, mortality, and health care costs. Despite current prophylactic measures, rates of SSIs have been reported in up to 15% of patients undergoing spine surgery. The adjunctive local application of vancomycin powder in spine surgery is a low-cost strategy to help reduce SSIs. Vancomycin is active against skin pathogens that can potentially contaminate the wound during spinal surgery. The local application of vancomycin in its powder form ensures adequate surgical site concentrations while minimizing adverse effects caused by undetectable systemic distribution. However, clinical studies have produced conflicting results, and the clinical evidence behind the use of vancomycin powder in modern spinal surgery practices is not clear. PURPOSE: To examine the current clinical evidence on the use of vancomycin powder in spine surgery. STUDY DESIGN: Systematic review and meta-analysis of literature. METHODS: A comprehensive search of the English literature was conducted with PubMed (MEDLINE). The inclusion criteria consisted of intrawound vancomycin powder use in spine surgery as a prophylactic agent for SSIs. Studies that investigated nonspine surgeries, selected patients on the basis of clinical suspicion, or included patients with infections were excluded. Studies that compared intrawound vancomycin in spine surgery against their standard practice were pooled in the meta-analysis using a random-effects model. RESULTS: A total of 671 abstracts were reviewed, and 18 papers met inclusion/exclusion criteria and were included in this review. These included 1 randomized controlled trial, 13 comparative studies, and 4 case series. The level of evidence in hierarchical order was as follows: 1 level II, 13 level III, and 4 level IV. Fourteen of the studies, 1 randomized controlled trial and 13 comparative studies, were eligible for the meta-analysis. The odds of developing a deep infection with intrawound vancomycin powder were 0.23 times the odds of experiencing an infection without intrawound vancomycin (95% confidence interval 0.11-0.50, P = 0.0002, I(2) = 47%). For combined superficial and deep infections the odds ratio was 0.43 (95% confidence interval 0.22-0.82, P = 0.01, I(2) = 36%). CONCLUSIONS: Numerous clinical studies have confirmed the safety of using vancomycin powder in the surgical site. The pooled clinical data supports the use of vancomycin to prevent SSIs in adult spine surgeries. The majority of the supporting literature is class III evidence. Existing studies use different definitions for surgical site infections and different pre-, peri-, and postoperative antibiotic regimens. Further high-quality investigations should use standardized protocols to confirm these findings. PMID- 25535068 TI - Modified World Federation of Neurosurgical Societies subarachnoid hemorrhage grading system. AB - OBJECT: A modified World Federation of Neurosurgical Societies scale (m-WFNS scale) for aneurysmal subarachnoid hemorrhage (SAH) recently has been proposed, in which patients with Glasgow Coma Scale (GCS) scores of 14 are assigned to grade II and those with GCS scores of 13 are assigned to grade III regardless of the presence of neurologic deficits. The study objective was to evaluate outcome predictability of the m-WFNS scale in a large cohort. METHODS: This was a multicenter prospective observational study conducted in Japan. A total of 1656 patients with SAH were registered during the 2.5-year study period, and the outcome predictability, using the Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) scores at discharge and at 90 days after onset, was evaluated by comparing the m-WFNS with the original WFNS scale. We focused on whether significant differences in these scores were present between the neighboring grades. RESULTS: In the m-WFNS scale, significant difference between any neighboring grades was observed both in the mean GOS and mRS scores at 90 days except between grades III/IV. However, differences were not significant between grades II/III and between grades III/IV in the original WFNS scale. CONCLUSIONS: SAH-induced brain injury may be substantially severer in patients with GCS 13 than those with GCS 14, which may explain why grade III patients faired significantly worse than grade II patients by the modified WFNS scale. Although further validation is necessary, the m-WFNS scale has a potential of providing neurosurgeons with simpler and more reliable prognostication of patients with SAH. PMID- 25535070 TI - A prospective, multi-institutional comparative effectiveness study of lumbar spine surgery in morbidly obese patients: does minimally invasive transforaminal lumbar interbody fusion result in superior outcomes? AB - BACKGROUND: Obese and morbidly obese patients undergoing lumbar spinal fusion surgery are a challenge to the operating surgeon. Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and open-TLIF have been performed for many years with good results; however, functional outcomes after lumbar spine surgery in this subgroup of patients remain poorly understood. Furthermore, whether index MIS-TLIF or open-TLIF for the treatment of degenerative disc disease or spondylolisthesis in morbidly obese results in superior postoperative functional outcomes remains unknown. METHODS: A total of 148 (MIS-TLIF: n = 40, open-TLIF: n = 108) obese and morbidly obese patients undergoing index lumbar arthrodesis for low back pain and/or radiculopathy between January 2003 and December 2010 were selected from a multi-institutional prospective data registry. We collected and analyzed data on patient demographics, postoperative complications, back pain, leg pain, and functional disability over 2 years. Patients completed the Oswestry Disability Index (ODI), Medical Outcomes Study Short-Form 36 (SF-36), and back and leg pain numerical rating scores before surgery and then at 12 and 24 months after surgery. Clinical outcomes and complication rates were compared between both patient cohorts. RESULTS: Compared with preoperative status, Visual Analog Scale (VAS) back and leg pain, ODI, and SF-36 physical component score/mental component score were improved in both groups. Both MIS-TLIF and open-TLIF patients showed similar 2 year improvement in VAS for back pain (MIS-TLIF: 2.42 +/- 3.81 vs. open-TLIF: 2.33 +/- 3.67, P = 0.89), VAS for leg pain (MIS-TLIF: 3.77 +/- 4.53 vs. open TLIF: 2.67 +/- 4.10, P = 0.18), ODI (MIS-TLIF: 11.61 +/- 25.52 vs. open-TLIF: 14.88 +/- 22.07, P = 0.47), and SF-36 physical component score (MIS-TLIF: 8.61 +/ 17.72 vs. open-TLIF: 7.61 +/- 15.55, P = 0.93), and SF-36 mental component score (MIS-TLIF: 4.35 +/- 22.71 vs. open-TLIF: 5.96 +/- 21.09, P = 0.69). Postoperative complications rates between both cohorts were also not significantly divergent between (12.50% vs. 11.11%, P = 0.51). CONCLUSION: MIS-TLIF is a safe and viable option for lumbar fusion in morbidly obese patients and, compared with open-TLIF, resulted in similar improvement in pain and functional disability. Postoperative complications rates between both cohorts were also not significantly divergent. PMID- 25535071 TI - Acute Traumatic Cervical Cord Injury in Pediatric Patients with os Odontoideum: A Series of 6 Patients. AB - OBJECTIVE: Os odontoideum can lead to instability of the atlantoaxial joint and places the spinal cord at significant risk for acute traumatic catastrophic events or chronic neurologic change. The purpose of this study was to retrospectively review acute cervical cord injury after minor trauma in 6 pediatric patients with os odontoideum. METHODS: Between 2012 and 2013, 6 pediatric patients with os odontoideum who suffered acute traumatic cervical cord injury were reviewed retrospectively. Their clinical history, neurologic symptoms, radiological investigations, follow-up period, American Spinal Injury Association (ASIA) impairment classification, and motor score were reviewed. RESULTS: There were 2 male and 4 female subjects ranging in age from 4 to 18 years (mean 11.8 years). Before the traumatic injury, 2 cases were asymptomatic and 4 complained of myelopathic feature with unsteadiness on feet. Falls were the most common injury (n = 5), followed by a minor motor vehicle accident (n = 1). Atlantoaxial instability and cord compression were presented in all cases with dynamic cervical lateral radiographs and magnetic resonance imaging. Most patients presented with spinal cord thinning and hyperintensity on T2-weighted sequences in magnetic resonance imaging. Spinal cord compression was anterior in 2 cases and both anterior and posterior in 4. Two patients was classified as ASIA B, 1 as ASIA C, and 3 as ASIA D category on admission. Two patients presented with respiratory failure with mechanical ventilation for over 2 weeks in perioperative period. Postoperatively, all patients improved neurologically and clinically after underwent posterior atlantoaxial fixation and fusion. CONCLUSIONS: Pediatric patients with asymptomatic or myelopathic atlantoaxial instability secondary to os odontoideum are at risk for acute spinal cord injury even after minor traumatic injury. Sufficient fixation and fusion should be undertaken as prophylactic treatment of developing myelopathy and to improve neurologic symptoms with acute traumatic cervical cord injury in pediatric patients with os odontoideum. PMID- 25535072 TI - Regulation of angiogenesis by aminoacyl-tRNA synthetases. AB - In addition to their canonical roles in translation the aminoacyl-tRNA synthetases (ARSs) have developed secondary functions over the course of evolution. Many of these activities are associated with cellular survival and nutritional stress responses essential for homeostatic processes in higher eukaryotes. In particular, six ARSs and one associated factor have documented functions in angiogenesis. However, despite their connection to this process, the ARSs are mechanistically distinct and exhibit a range of positive or negative effects on aspects of endothelial cell migration, proliferation, and survival. This variability is achieved through the appearance of appended domains and interplay with inflammatory pathways not found in prokaryotic systems. Complete knowledge of the non-canonical functions of ARSs is necessary to understand the mechanisms underlying the physiological regulation of angiogenesis. PMID- 25535073 TI - Inhibitory effects of benzaldehyde derivatives from the marine fungus Eurotium sp. SF-5989 on inflammatory mediators via the induction of heme oxygenase-1 in lipopolysaccharide-stimulated RAW264.7 macrophages. AB - Two benzaldehyde derivatives, flavoglaucin (1) and isotetrahydro-auroglaucin (2), were isolated from the marine fungus Eurotium sp. SF-5989 through bioassay- and 1H NMR-guided investigation. In this study, we evaluated the anti-inflammatory effects of these compounds in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We demonstrated that compounds 1 and 2 markedly inhibited LPS induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression without affecting cell viability. We also demonstrated that the compounds reduced the secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). Furthermore, compounds 1 and 2 inhibited LPS-induced nuclear factor kappaB (NF-kappaB) activation by suppressing phosphorylation of IkappaB (IkappaB). These results indicated that the anti-inflammatory effects of these benzaldehyde derivatives in LPS-stimulated RAW264.7 macrophages were due to the inactivation of the NF-kappaB pathway. In addition, compounds 1 and 2 induced heme oxygenase-1 (HO-1) expression through the nuclear transcription factor-E2 related factor 2 (Nrf2) translocation. The inhibitory effects of compounds 1 and 2 on the production of pro-inflammatory mediators and on NF-kappaB binding activity were reversed by HO-1 inhibitor tin protoporphyrin (SnPP). Thus, the anti-inflammatory effects of compounds 1 and 2 also correlated with their ability of inducing HO-1 expression. PMID- 25535074 TI - When isolated at full receptivity, in vitro fertilized wheat (Triticum aestivum, L.) egg cells reveal [Ca2+]cyt oscillation of intracellular origin. AB - During in vitro fertilization of wheat (Triticum aestivum, L.) in egg cells isolated at various developmental stages, changes in cytosolic free calcium ([Ca2+]cyt) were observed. The dynamics of [Ca2+]cyt elevation varied, reflecting the difference in the developmental stage of the eggs used. [Ca2+]cyt oscillation was exclusively observed in fertile, mature egg cells fused with the sperm cell. To determine how [Ca2+]cyt oscillation in mature egg cells is generated, egg cells were incubated in thapsigargin, which proved to be a specific inhibitor of the endoplasmic reticulum (ER) Ca2+-ATPase in wheat egg cells. In unfertilized egg cells, the addition of thapsigargin caused an abrupt transient increase in [Ca2+]cyt in the absence of extracellular Ca2+, suggesting that an influx pathway for Ca2+ is activated by thapsigargin. The [Ca2+]cyt oscillation seemed to require the filling of an intracellular calcium store for the onset of which, calcium influx through the plasma membrane appeared essential. This was demonstrated by omitting extracellular calcium from (or adding GdCl3 to) the fusion medium, which prevented [Ca2+]cyt oscillation in mature egg cells fused with the sperm. Combined, these data permit the hypothesis that the first sperm induced transient increase in [Ca2+]cyt depletes an intracellular Ca2+ store, triggering an increase in plasma membrane Ca2+ permeability, and this enhanced Ca2+ influx results in [Ca2+]cyt oscillation. PMID- 25535076 TI - Rise-time of FRET-acceptor fluorescence tracks protein folding. AB - Uniform labeling of proteins with fluorescent donor and acceptor dyes with an equimolar ratio is paramount for accurate determination of Forster resonance energy transfer (FRET) efficiencies. In practice, however, the labeled protein population contains donor-labeled molecules that have no corresponding acceptor. These FRET-inactive donors contaminate the donor fluorescence signal, which leads to underestimation of FRET efficiencies in conventional fluorescence intensity and lifetime-based FRET experiments. Such contamination is avoided if FRET efficiencies are extracted from the rise time of acceptor fluorescence upon donor excitation. The reciprocal value of the rise time of acceptor fluorescence is equal to the decay rate of the FRET-active donor fluorescence. Here, we have determined rise times of sensitized acceptor fluorescence to study the folding of double-labeled apoflavodoxin molecules and show that this approach tracks the characteristics of apoflavodoxin's complex folding pathway. PMID- 25535077 TI - Characterization and study of transgenic cultivars by capillary and microchip electrophoresis. AB - Advances in biotechnology have increased the demand for suitable analytical techniques for the analysis of genetically modified organisms. Study of the substantial equivalence, discrimination between transgenic and non-transgenic cultivars, study of the unintended effects caused by a genetic modification or their response to diverse situations or stress conditions (e.g., environmental, climatic, infections) are some of the concerns that need to be addressed. Capillary electrophoresis (CE) is emerging as an alternative to conventional techniques for the study and characterization of genetically modified organisms. This article reviews the most recent applications of CE for the analysis and characterization of transgenic cultivars in the last five years. Different strategies have been described depending on the level analyzed (DNA, proteins or metabolites). Capillary gel electrophoresis (CGE) has shown to be particularly useful for the analysis of DNA fragments amplified by PCR. Metabolites and proteins have been mainly separated using capillary zone electrophoresis (CZE) using UV and MS detection. Electrophoretic chips have also proven their ability in the analysis of transgenic cultivars and a section describing the new applications is also included. PMID- 25535079 TI - The promise of novel molecular markers in bladder cancer. AB - Bladder cancer is the fourth most common malignancy in the US and is associated with the highest cost per patient. A high likelihood of recurrence, mandating stringent surveillance protocols, has made the development of urinary markers a focus of intense pursuit with the hope of decreasing the burden this disease places on patients and the healthcare system. To date, routine use of markers is not recommended for screening or diagnosis. Interests include the development of a single urinary marker that can be used in place of or as an adjunct to current screening and surveillance techniques, as well identifying a molecular signature for an individual's disease that can help predict progression, prognosis, and potential therapeutic response. Markers have shown potential value in improving diagnostic accuracy when used as an adjunct to current modalities, risk stratification of patients that could aid the clinician in determining aggressiveness of surveillance, and allowing for a decrease in invasive surveillance procedures. This review discusses the current understanding of emerging biomarkers, including miRNAs, gene signatures and detection of circulating tumor cells in the blood, and their potential clinical value in bladder cancer diagnosis, as prognostic indicators, and surveillance tools, as well as limitations to their incorporation into medical practice. PMID- 25535078 TI - Emerging biomarkers in heart failure and cardiac cachexia. AB - Biomarkers are objective tools with an important role for diagnosis, prognosis and therapy optimization in patients with heart failure (HF). To date, natriuretic peptides are closest to optimal biomarker standards for clinical implications in HF. Therefore, the efforts to identify and test new biomarkers in HF are reasonable and justified. Along the natural history of HF, cardiac cachexia may develop, and once at this stage, patient performance and prognosis is particularly poor. For these reasons, numerous biomarkers reflecting hormonal, inflammatory and oxidative stress pathways have been investigated, but only a few convey relevant information. The complex pathophysiology of HF appears far too complex to be embraced by a single biomarker; thus, a combined approach appears reasonable. With these considerations, we have reviewed the recent developments in the field to highlight key candidates with diagnostic, prognostic and therapy optimization properties, either alone or in combination. PMID- 25535080 TI - PLGA biodegradable nanoparticles containing perphenazine or chlorpromazine hydrochloride: effect of formulation and release. AB - In our study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles loaded with perphenazine (PPH) and chlorpromazine hydrochloride (CPZ-HCl) were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol) (PVA) concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 +/- 32.4 to 374.3 +/- 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM) presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v) in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4) by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles. PMID- 25535081 TI - Candida parapsilosis biofilm identification by Raman spectroscopy. AB - Colonies of Candida parapsilosis on culture plates were probed directly in situ using Raman spectroscopy for rapid identification of specific strains separated by a given time intervals (up to months apart). To classify the Raman spectra, data analysis was performed using the approach of principal component analysis (PCA). The analysis of the data sets generated during the scans of individual colonies reveals that despite the inhomogeneity of the biological samples unambiguous associations to individual strains (two biofilm-positive and two biofilm-negative) could be made. PMID- 25535075 TI - The role of reactive oxygen species in microvascular remodeling. AB - The microcirculation is a portion of the vascular circulatory system that consists of resistance arteries, arterioles, capillaries and venules. It is the place where gases and nutrients are exchanged between blood and tissues. In addition the microcirculation is the major contributor to blood flow resistance and consequently to regulation of blood pressure. Therefore, structural remodeling of this section of the vascular tree has profound implications on cardiovascular pathophysiology. This review is focused on the role that reactive oxygen species (ROS) play on changing the structural characteristics of vessels within the microcirculation. Particular attention is given to the resistance arteries and the functional pathways that are affected by ROS in these vessels and subsequently induce vascular remodeling. The primary sources of ROS in the microcirculation are identified and the effects of ROS on other microcirculatory remodeling phenomena such as rarefaction and collateralization are briefly reviewed. PMID- 25535085 TI - Carotid artery stenting: an update. AB - In patients with carotid disease, the purpose of carotid artery revascularization is stroke prevention. For >50 years, carotid endarterectomy has been considered the standard treatment for severe asymptomatic and symptomatic carotid stenoses. Carotid artery stenting (CAS) has emerged in the last 15 years as minimally invasive alternative to surgery. However, the value of the endovascular approach in the management of carotid disease patients remains highly controversial. The aims of this review are to elucidate the current role of CAS, to describe the major technology advancements in the field, and to speculate about the future of this therapy. PMID- 25535083 TI - From end to end: tRNA editing at 5'- and 3'-terminal positions. AB - During maturation, tRNA molecules undergo a series of individual processing steps, ranging from exo- and endonucleolytic trimming reactions at their 5'- and 3'-ends, specific base modifications and intron removal to the addition of the conserved 3'-terminal CCA sequence. Especially in mitochondria, this plethora of processing steps is completed by various editing events, where base identities at internal positions are changed and/or nucleotides at 5'- and 3'-ends are replaced or incorporated. In this review, we will focus predominantly on the latter reactions, where a growing number of cases indicate that these editing events represent a rather frequent and widespread phenomenon. While the mechanistic basis for 5'- and 3'-end editing differs dramatically, both reactions represent an absolute requirement for generating a functional tRNA. Current in vivo and in vitro model systems support a scenario in which these highly specific maturation reactions might have evolved out of ancient promiscuous RNA polymerization or quality control systems. PMID- 25535084 TI - MicroRNA-199b Modulates Vascular Cell Fate During iPS Cell Differentiation by Targeting the Notch Ligand Jagged1 and Enhancing VEGF Signaling. AB - AIMS: Recent ability to derive endothelial cells (ECs) from induced pluripotent stem (iPS) cells holds a great therapeutic potential for personalized medicine and stem cell therapy. We aimed that better understanding of the complex molecular signals that are evoked during iPS cell differentiation toward ECs may allow specific targeting of their activities to enhance cell differentiation and promote tissue regeneration. METHODS AND RESULTS: In this study, we have generated mouse iPS cells from fibroblasts using established protocol. When iPS cells were cultivated on type IV mouse collagen-coated dishes in differentiation medium, cell differentiation toward vascular lineages were observed. To study the molecular mechanisms of iPS cell differentiation, we found that miR-199b is involved in EC differentiation. A step-wise increase in expression of miR-199 was detected during EC differentiation. Notably, miR-199b targeted the Notch ligand JAG1, resulting in vascular endothelial growth factor (VEGF) transcriptional activation and secretion through the transcription factor STAT3. Upon shRNA mediated knockdown of the Notch ligand JAG1, the regulatory effect of miR-199b was ablated and there was robust induction of STAT3 and VEGF during EC differentiation. Knockdown of JAG1 also inhibited miR-199b-mediated inhibition of iPS cell differentiation toward smooth muscle markers. Using the in vitro tube formation assay and implanted Matrigel plugs, in vivo, miR-199b also regulated VEGF expression and angiogenesis. CONCLUSIONS: This study indicates a novel role for miR-199b as a regulator of the phenotypic switch during vascular cell differentiation derived from iPS cells by regulating critical signaling angiogenic responses. Stem Cells 2015;33:1405-1418. PMID- 25535082 TI - Inhalation of silver nanomaterials--seeing the risks. AB - Demand for silver engineered nanomaterials (ENMs) is increasing rapidly in optoelectronic and in health and medical applications due to their antibacterial, thermal, electrical conductive, and other properties. The continued commercial up scaling of ENM production and application needs to be accompanied by an understanding of the occupational health, public safety and environmental implications of these materials. There have been numerous in vitro studies and some in vivo studies of ENM toxicity but their results are frequently inconclusive. Some of the variability between studies has arisen due to a lack of consistency between experimental models, since small differences between test materials can markedly alter their behaviour. In addition, the propensity for the physicochemistry of silver ENMs to alter, sometimes quite radically, depending on the environment they encounter, can profoundly alter their bioreactivity. Consequently, it is important to accurately characterise the materials before use, at the point of exposure and at the nanomaterial-tissue, or "nanobio", interface, to be able to appreciate their environmental impact. This paper reviews current literature on the pulmonary effects of silver nanomaterials. We focus our review on describing whether, and by which mechanisms, the chemistry and structure of these materials can be linked to their bioreactivity in the respiratory system. In particular, the mechanisms by which the physicochemical properties (e.g., aggregation state, morphology and chemistry) of silver nanomaterials change in various biological milieu (i.e., relevant proteins, lipids and other molecules, and biofluids, such as lung surfactant) and affect subsequent interactions with and within cells will be discussed, in the context not only of what is measured but also of what can be visualized. PMID- 25535086 TI - Antiplasmodial compounds from the stem bark of Neoboutonia macrocalyx pax. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plant Neoboutonia macrocalyx has been reported in traditional medicine to be used in the treatment of malaria. AIM OF THE STUDY: To study the in vitro antiplasmodial activity of compounds from the stem bark of Neoboutonia macrocalyx. MATERIALS AND METHODS: Compounds were extracted and purified from stem bark of Neoboutonia macrocalyx and their structure identified and confirmed by spectroscopic methods. The crude ethyl acetate extract, aqueous extract and the isolated compounds were evaluated for antiplasmodial activity against the chloroquine sensitive Sierra Leone I (D6) and chloroquine-resistant Indochina I (W2) strains of Plasmodium falciparum. RESULTS: Chemical investigation of the ethyl acetate extract of Neoboutonia macrocalyx bark resulted in the identification of one new diterpenoid; neoboutomacroin (1) in addition to the four known compounds which included, a phenanthrene; 3,6 dihyroxy-1,7-dimethyl-9-methoxyphenanthrene (2), a sterol; 3-O-Acetyloleuritolic acid (3) and two diterpenoids; simplexin (4) and montanin (5). Compounds 1 and 5 displayed good antiplasmodial activity of IC50 values less than 10 MUg/mL against both strains. However, all the compounds tested displayed high cytotoxic activity against MRC5 cell line with IC50 less than 10 MUM. CONCLUSIONS: Despite an indirect in vitro antiplasmodial activity of some compounds isolated from the stem bark of Neoboutonia macrocalyx, the identification of these bioactive compounds indicates that they may play a role in the pharmacological properties of this plant. PMID- 25535087 TI - Effects of Xie-Zhuo-Chu-Bi-Fang on miR-34a and URAT1 and their relationship in hyperuricemic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xie-Zhuo-Chu-Bi-Fang (XZCBF) is an empirical formula that was developed based on the principles of traditional Chinese medicine, for the therapeutic purpose of treating hyperuricemia. XZCBF has been clinically utilized in the Department of Traditional Chinese Medicine at General Hospital of Guangzhou Military Command of PLA for many years and has exhibited favorable efficacy. The aim of the study is to evaluate the effects of XZCBF on the expression of uric acid transporter 1 (URAT1) and miR-34a in hyperuricemic mice and to determine, the correlation between the two expression levels. MATERIALS AND METHODS: A hyperuricemic animal model was created by administering adenine and allantoxanic acid potassium salt to mice. The blood uric acid levels were measured in these model mice after treatment with XZCBF for 15 days. The potential targets of miR-34a were screened. The expression levels of miR-34a and URAT1 in the renal tissues collected from the model mice were determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and their correlation was further established by immunohistochemistry and in situ hybridization. RESULTS: The uric acid levels in the model mice were significantly higher than those in the blank controls (P<0.05). These levels were significantly lower in the three groups receiving different doses of XZCBF (P<0.05), which was, in agreement with the downregulation of URAT1 and the upregulation of miR-34a in each group. The mRNA expression level of URAT1 was positively correlated with the concentration of uric acid but, negatively correlated with the expression level of miR-34a. CONCLUSIONS: The ability of XZCBF to facilitate the excretion of uric acid and to lower its level in the model group was mediated by the upregulation of miR-34a and the inhibition of URAT1 mRNA expression, which suggests that XZCBF could be an option for the treatment of hyperuricemia in mice. PMID- 25535088 TI - Synthetic protein switches: design principles and applications. AB - Protein switches are ubiquitous in biological signal transduction systems, enabling cells to sense and respond to a variety of molecular queues in a rapid, specific, and integrated fashion. Analogously, tailor-engineered protein switches with custom input and output functions have become invaluable research tools for reporting on distinct physiological states and actuating molecular functions in real time and in situ. Here, we analyze recent progress in constructing protein based switches while assessing their potential in the assembly of defined signaling motifs. We anticipate such systems will ultimately pave the way towards a new generation of molecular diagnostics and facilitate the construction of artificial signaling systems that operate in parallel to the signaling machinery of a host cell for applications in synthetic biology. PMID- 25535089 TI - Screening methods for AMP-activated protein kinase modulators: a patent review. AB - INTRODUCTION: AMP-activated protein kinase (AMPK) functions as a cellular energy gauge that maintains cellular homeostasis and has been suggested to play important roles in tumorigenesis, lifespan and autophagy. Accordingly, AMPK is a potential target of drugs for controlling a growing number of human diseases ranging from metabolic disorders to cancer, highlighting the need for rational and robust screening systems for identifying compounds that modulate AMPK. AREAS COVERED: The relevant screening methods in the patent and scientific literature were analyzed, and key features of direct AMPK modulators are discussed in the context of their physiological relevance and the three-dimensional structure of the AMPK complex. EXPERT OPINION: The mechanism of action of modulators is important in designing drugs with enhanced efficacy, specificity and stability. Most patented assay formats for identifying AMPK modulators are based on classical enzyme assays that monitor AMPK activity or changes in AMPK-dependent cellular physiology. However, these systems do not provide information about underlying mechanisms. Two patented assay systems use a specific domain or the three-dimensional structure of AMPK to identify AMPK modulators. The recent identification of two AMPK modulators, A-769662 and C-2 (or its prodrug, C-13), suggests the promise of structure-based assays in discovering more potent and specific modulators of AMPK. PMID- 25535090 TI - Synthesis, structure and dehydrogenation of zirconium borohydride octaammoniate. AB - A new metal borohydride ammoniate (MBA), Zr(BH4)4.8NH3, was synthesized via ammoniation of the Zr(BH4)4 crystal. Zr(BH4)4.8NH3 has a distinctive structure and the highest coordination number of NH3 groups among all the known MBAs. This compound could quickly dehydrogenate at 130 degrees C, enabling it a potential hydrogen storage material. PMID- 25535092 TI - Facile domain rearrangement abrogates expression recalcitrance in a rabbit scFv. AB - Rabbit-derived recombinant antibodies have traditionally been viewed as intractable molecules due to the presence of a cysteine in position 80 of the VL domain that becomes rendered 'aberrant' when present in the 'unpaired' context of a single chain Fv (scFv) and chimeric Fab formats. This aberrant Cys80 can severely impinge on the achievable expression levels when rabbit recombinant antibodies are produced in prokaryote systems. The unpaired Cys residue also renders purification problematic. Consequently, researchers often disregard rabbit antibody libraries due to perceived limitations in accessible repertoire diversity. We have shown that by switching the orientation of the VH and VL domains in an aberrant-Cys-containing rabbit scFv isolated in a bona fide screening campaign, it was possible to substantially increase the expression and purification yields of this clone. Furthermore, by incorporating a novel rabbit C kappa constant fusion domain, we were able to potentiate a further increase in expression level and purify this antibody to a high degree of homogeneity, hitherto impossible to achieve using the aberrant-Cys-containing wild-type scFv. Cumulatively, these findings demonstrate that facile re-formatting can help make the rabbit antibody repertoire, a very valuable resource, more accessible to researchers in the field. PMID- 25535093 TI - Coexpression of Lactobacillus brevis ADH with GDH or G6PDH in Arxula adeninivorans for the synthesis of 1-(R)-phenylethanol. AB - The yeast Arxula adeninivorans was used for the overexpression of an ADH gene of Lactobacillus brevis coding for (R)-specific alcohol dehydrogenase (LbADH) to synthesise enantiomerically pure 1-(R)-phenylethanol. Glucose dehydrogenase gene from Bacillus megaterium (BmGDH) or glucose 6-phosphate dehydrogenase of Bacillus pumilus (BpG6PDH) were coexpressed in Arxula to regenerate the cofactor NADPH by oxidising glucose or glucose 6-phosphate. The yeast strain expressing LbADH and BpG6PDH produced 5200 U l(-1) ADH and 370 U l(-1) G6PDH activity, whereas the strain expressing LbADH and BmGDH produced 2700 U l(-1) ADH and 170 U l(-1) GDH activity. However, the crude extract of both strains reduced 40 mM acetophenone to pure 1-(R)-phenylethanol with an enantiomeric excess (ee) of >99 % in 60 min without detectable by-products. An increase in yield was achieved using immobilised crude extracts (IEs), Triton X-100 permeabilised cells (PCs) and permeabilised immobilised cells (PICs) with PICs being most stable with GDH regeneration over 52 cycles. Even though the activity and synthesis rate of 1-(R) phenylethanol with the BpG6PDH and LbADH coexpressing strain was higher, the BmGDH-LbADH strain was more stable over successive reaction cycles. This, combined with its higher total turnover number (TTN) of 391 mol product per mole NADP(+), makes it the preferred strain for continuous reaction systems. The initial non-optimised semi-continuous reaction produced 9.74 g l(-1) day(-1) or 406 g kg(-1) dry cell weight (dcw) day(-1) isolated 1-(R)-phenylethanol with an ee of 100 % and a TTN of 206 mol product per mole NADP(+). In conclusion, A. adeninivorans is a promising host for LbADH and BpG6PDH or BmGDH production and offers a simple method for the production of enantiomerically pure alcohols. PMID- 25535091 TI - Combination of PPT with LiCl Treatment Prevented Bilateral Ovariectomy-Induced Hippocampal-Dependent Cognition Deficit in Rats. AB - Estrogen deprivation is a high risk of cognitive dysfunction in neurodegenerative diseases, and the early used estrogen replacement has been proved effective in many studies. Because of the adverse actions, selective estrogen receptor modulating has been raised to substitute for estrogen replacement. In this study, we observed in hippocampus of bilaterally ovariectomized rats that the level of estrogen receptor alpha (ERalpha) was decreased in nuclei with activated glycogen synthase kinase-3beta (GSK-3beta) in cytoplasm at 8 weeks after operation. The level of nuclear ERalpha is important for its transcriptional property, and the inhibition of GSK-3beta benefits to ERalpha nuclear translocation. Then, we used 4,4k,4a-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl) trisphenol (PPT) (1 mg/kg/day), an agonist of ERalpha, combined with LiCl (40 mg/kg/day), an inhibitor of GSK-3beta, to treat the ovariectomized rats. After the combination treatment of these two drugs (PPT + LiCl), the improved learning and memory abilities of ovariectomized rats in Morris water maze, increased dendritic spines in CA1 region, and decreased tau phosphorylation at Ser-396 in hippocampus were observed. Furthermore, PPT + LiCl treatment significantly increased ERalpha level in the nuclear fraction of hippocampus, and in the cytoplasmic fraction, the total level of GSK-3beta was declined after treatment with its increased phosphorylation at Ser-9 (inactivation form). This study suggested that PPT + LiCl treatment could inhibit the activation of cytoplasmic GSK-3beta and promote the nuclear translocation of ERalpha, and ERalpha together with GSK-3beta maybe the targets to preserve hippocampus-dependent cognitive ability after long-term ovariectomy. PMID- 25535094 TI - Bringing functions together with fusion enzymes--from nature's inventions to biotechnological applications. AB - It is a mammoth task to develop a modular protein toolbox enabling the production of posttranslational organized multifunctional enzymes that catalyze reactions in complex pathways. However, nature has always guided scientists to mimic evolutionary inventions in the laboratory and, nowadays, versatile methods have been established to experimentally connect enzymatic activities with multiple advantages. Among the oldest known natural examples is the linkage of two or more juxtaposed proteins catalyzing consecutive, non-consecutive, or opposing reactions by a native peptide bond. There are multiple reasons for the artificial construction of such fusion enzymes including improved catalytic activities, enabled substrate channelling by proximity of biocatalysts, higher stabilities, and cheaper production processes. To produce fused proteins, it is either possible to genetically fuse coding open reading frames or to connect proteins in a posttranslational process. Molecular biology techniques that have been established for the production of end-to-end or insertional fusions include overlap extension polymerase chain reaction, cloning, and recombination approaches. Depending on their flexibility and applicability, these methods offer various advantages to produce fusion genes in high throughput, different orientations, and including linker sequences to maximize the flexibility and performance of fusion partners. In this review, practical techniques to fuse genes are highlighted, enzymatic parameters to choose adequate enzymes for fusion approaches are summarized, and examples with biotechnological relevance are presented including a focus on plant biomass-degrading glycosyl hydrolases. PMID- 25535095 TI - The impact of electronic decision support on transfusion practice: a systematic review. AB - Decision support systems (DSSs) provide clinicians with tailored treatment recommendations by combining individual patient information and local guidelines. The objective of this systematic review was to assess the effects of electronic DSS on blood product ordering practices. Eligible studies were identified from searches of MEDLINE, Embase, CINAHL, The Cochrane Library, PubMed, and the Transfusion Evidence Library from January 2000 to April 2014. Of these, 23 articles were eligible, resulting in the inclusion of 20 independent studies in this systematic review. There was a significant variation in study population, the type of DSS used, and outcome reporting. All but one study used a before after design without any element of randomization. Overall, there is good evidence that implementation of a DSS improves red blood cell usage. The effect of a DSS on plasma, platelets, and cryoprecipitate usage is less clear probably because fewer studies have been conducted focusing on these products. In addition, the introduction of a DSS resulted in cost savings in the 7 studies that reported financial outcomes. Patient outcomes were generally not studied in detail, and there were few data on the sustainability of the effect of DSS. Further data are needed to assess the effect of a DSS on blood products other than red blood cell, and future studies should standardize reporting of outcomes. PMID- 25535096 TI - Instrumented mouthguard acceleration analyses for head impacts in amateur rugby union players over a season of matches. AB - BACKGROUND: Direct impacts with the head (linear acceleration or pressure) and inertial loading of the head (rotational acceleration or strain) have been postulated as the 2 major mechanisms of head-related injuries such as concussion. Although data are accumulating for soccer and American football, there are no published data for nonhelmeted collision sports such as rugby union. PURPOSE: To quantify head impacts via instrumented mouthguard acceleration analyses for rugby union players over a season of matches. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data on impact magnitude and frequency were collected with molded instrumented mouthguards worn by 38 premier amateur senior rugby players participating in the 2013 domestic season of matches. RESULTS: A total of 20,687 impacts >10g (range, 10.0-164.9g) were recorded over the duration of the study. The mean +/- SD number of impacts per player over the duration of the season of matches was 564 +/- 618, resulting in a mean +/- SD of 95 +/- 133 impacts to the head per player, per match over the duration of the season of matches. The impact magnitudes for linear accelerations were skewed to the lower values (Sp = 3.7 +/- 0.02; P < .001), with a mean linear acceleration of 22.2 +/- 16.2g. Rotational accelerations were also skewed to the lower values (Sp = 2.0 +/- 0.02; P < .001), with a mean rotational acceleration of 3902.9 +/- 3948.8 rad/s(2). CONCLUSION: The acceleration magnitudes and number of head impacts in amateur rugby union players over a season of matches, measured via instrumented mouthguard accelerations, were higher than for most sports previously reported. Mean linear acceleration measured over a season of matches was similar to the mean linear accelerations previously reported for youth, high school, and collegiate American football players but lower than that for female youth soccer players. Mean rotational acceleration measured over a season of matches was similar to mean rotational accelerations for youth, high school, and collegiate American football players but less than those for female youth soccer players, concussed American collegiate players, collegiate American football players, and professional American football players. PMID- 25535097 TI - Arthroscopic repair of partial-thickness and small full-thickness rotator cuff tears: tendon quality as a prognostic factor for repair integrity. AB - BACKGROUND: The healing failure rate is high for partial-thickness or small full thickness rotator cuff tears. PURPOSE: To retrospectively evaluate and compare outcomes after arthroscopic repair of high-grade partial-thickness and small full thickness rotator cuff tears and factors affecting rotator cuff healing. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Included in the study were 55 consecutive patients (mean age, 57.9 +/- 7.2 years) who underwent arthroscopic repair for high-grade partial-thickness (n = 34) and small full-thickness (n = 21) rotator cuff tears. The study patients also underwent magnetic resonance imaging (MRI) preoperatively and computed tomography arthrography (CTA) at least 6 months postoperatively, and their functional outcomes were evaluated preoperatively and at the last follow-up (>24 months). All partial-thickness tears were repaired after being converted to full-thickness tears; thus, the repair process was almost the same as for small full-thickness tears. The tendinosis of the torn tendon was graded from the MRI images using a 4-point scale, and the reliabilities were assessed. The outcomes between high-grade partial-thickness tears that were converted to small full-thickness tears and initially small full-thickness tears were compared, and factors affecting outcomes were evaluated. RESULTS: The inter- and intraobserver reliabilities of the tendinosis grade were good (intraclass correlation coefficient, 0.706 and 0.777, respectively). Failure to heal as determined by CTA was observed in 12 patients with a high-grade partial-thickness tear (35.3%; complete failure in 4 and partial failure in 8) and in 3 patients with a small full-thickness tear (14.3%; complete failure in 1 and partial failure in 2). The patients with high grade partial-thickness rotator cuff tears showed a higher tendinosis grade than did those with small full-thickness tears (P = .014), and the severity of the tendinosis was related to the failure to heal (P = .037). Tears with a higher tendinosis grade showed a 7.64-times higher failure rate (95% CI, 1.43-36.04) than did those with a lower tendinosis grade (P = .013). All functional outcome scores improved after surgery (all P < .001); however, there was no difference between groups. CONCLUSION: The high-grade partial-thickness rotator cuff tears showed more severe tendinosis compared with the small full-thickness tears in this study. Contrary to previous impressions that tear size or fatty infiltration is the factor that most influences healing, tendinosis severity assessed by preoperative MRI was the only factor associated with failure to heal, given the numbers available for analysis, in patients with partial-thickness and small full thickness rotator cuff tears. Surgeons should pay more attention to tendon quality during repair surgery or rehabilitation in smaller rotator cuff tears, especially in high-grade partial-thickness tears with severe tendinosis. PMID- 25535098 TI - Intramuscular vascular malformations: a rare cause of exertional leg pain and a novel treatment approach with ultrasound-guided doxycycline sclerotherapy. PMID- 25535099 TI - Group cohesion and between session homework activities predict self-reported cognitive-behavioral skill use amongst participants of SMART Recovery groups. AB - SMART Recovery groups are cognitive-behaviorally oriented mutual support groups for individuals with addictions. The aim of the study was to assess the extent to which the quality of group facilitation, group cohesion and the use of between session homework activities contribute to self-rated use of cognitive-behavioral skills amongst group participants. Participants attending SMART Recovery groups in Australia completed a cross sectional survey (N=124). The survey included measures of cognitive and behavioral skill utilization, group cohesion, quality of group facilitation and a rating of how frequently participants leave group meetings with an achievable between session homework plan. On average, participants had been attending SMART Recovery meetings for 9 months. Participants were most likely to attend SMART Recovery for problematic alcohol use. Regression analyses indicated that group cohesion significantly predicted use of cognitive restructuring, but that only provision of homework at the end of each group session predicted self-reported behavioral activation. Both group cohesion and leaving a group with an achievable homework plan predicted participant use of cognitive behavioral skills. The concrete actions associated with homework activities may facilitate behavioral activation. There is a need for longitudinal research to examine the relationship between the utilization of cognitive and behavioral skills and participant outcomes (e.g. substance use, mental health) for people attending SMART Recovery groups. PMID- 25535100 TI - Predicting prostate cancer-specific outcome after radical prostatectomy among men with very high-risk cT3b/4 PCa: a multi-institutional outcome study of 266 patients. AB - BACKGROUND: The value of radical prostatectomy (RP) as an approach for very high risk prostate cancer (PCa) patients is controversial. To examine the risk of 10 year cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathological characteristics of very high-risk cT3b/4 PCa patients treated with RP as the primary treatment option. METHODS: In a multi institutional cohort, 266 patients with very high-risk cT3b/4 PCa treated with RP were identified. All patients underwent RP and pelvic lymph-node dissection. Competing-risk analyses assessed 10-year CSM and OCM before and after stratification for age and Charlson comorbidity index (CCI). RESULTS: Overall, 34 (13%) patients died from PCa and 73 (28%) from OCM. Ten-year CSM and OCM rates ranged from 5.6% to 12.9% and from 10% to 38%, respectively. OCM was the leading cause of death in all subgroups. Age and comorbidities were the main determinants of OCM. In healthy men, CSM rate did not differ among age groups (10-year CSM rate for ?64, 65-69 and ?70 years: 16.2%, 11.5% and 17.1%, respectively). Men with a CCI ?1 showed a very low risk of CSM irrespective of age (10-year CSM: 5.6 6.1%), whereas the 10-year OCM rates increased with age up to 38% in men ?70 years. CONCLUSION: Very high-risk cT3b/4 PCa represents a heterogeneous group. We revealed overall low CSM rates despite the highly unfavorable clinical disease. For healthy men, CSM was independent of age, supporting RP even for older men. Conversely, less healthy patients had the highest risk of dying from OCM while sharing very low risk of CSM, indicating that this group might not benefit from an aggressive surgical treatment. Outcome after RP as the primary treatment option in cT3b/4 PCa patients is related to age and comorbidity status. PMID- 25535102 TI - Electroporation for therapeutic DNA vaccination in patients. AB - DNA vaccination has historically failed to raise strong immune responses in humans. Recent delivery techniques such as the gene gun and in vivo electroporation (EP)/electrotransfer (ET) have completely changed the efficiency of DNA vaccines in humans. In vivo EP exerts multiple effects that contribute to its efficiency. The two central factors are most likely the increased DNA uptake due to the transient membrane destabilization, and the local tissue damage acting as an adjuvant. To date, several studies in humans have used in vivo EP/ET to deliver DNA. Some of these results have been quite promising with strong T cell responses and/or transient effects on the viral replication. This suggests that improved strategies of in vivo EP/ET can be a future way to deliver DNA in humans. PMID- 25535103 TI - A review of technologies and performances of thermal treatment systems for energy recovery from waste. AB - The aim of this work is to identify the current level of energy recovery through waste thermal treatment. The state of the art in energy recovery from waste was investigated, highlighting the differences for different types of thermal treatment, considering combustion/incineration, gasification and pyrolysis. Also different types of wastes - Municipal Solid Waste (MSW), Refuse Derived Fuel (RDF) or Solid Refuse Fuels (SRF) and some typologies of Industrial Waste (IW) (sludge, plastic scraps, etc.) - were included in the analysis. The investigation was carried out mainly reviewing papers, published in scientific journals and conferences, but also considering technical reports, to gather more information. In particular the goal of this review work was to synthesize studies in order to compare the values of energy conversion efficiencies measured or calculated for different types of thermal processes and different types of waste. It emerged that the dominant type of thermal treatment is incineration associated to energy recovery in a steam cycle. When waste gasification is applied, the produced syngas is generally combusted in a boiler to generate steam for energy recovery in a steam cycle. For both the possibilities--incineration or gasification--co generation is the mean to improve energy recovery, especially for small scale plants. In the case of only electricity production, the achievable values are strongly dependent on the plant size: for large plant size, where advanced technical solutions can be applied and sustained from an economic point of view, net electric efficiency may reach values up to 30-31%. In small-medium plants, net electric efficiency is constrained by scale effect and remains at values around 20-24%. Other types of technical solutions--gasification with syngas use in internally fired devices, pyrolysis and plasma gasification--are less common or studied at pilot or demonstrative scale and, in any case, offer at present similar or lower levels of energy efficiency. PMID- 25535101 TI - Therapeutic vaccination and immunomodulation in the treatment of chronic hepatitis B: preclinical studies in the woodchuck. AB - Infection with hepatitis B virus (HBV) may lead to subclinical, acute or chronic hepatitis. In the prevaccination era, HBV infections were endemic due to frequent mother to child transmission in large regions of the world. However, there are still estimated 240 million chronic HBV carriers today and ca. 620,000 patients die per year due to HBV-related liver diseases. Recommended treatment of chronic hepatitis B with interferon-alpha and/or nucleos(t)ide analogues does not lead to satisfactory results. Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients with or without therapeutic reduction of viral load did not result in effective immune control of HBV infection, suggesting that combination of antiviral treatment with new formulations of therapeutic vaccines is needed. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. In this review, we summarize these encouraging results obtained with these therapeutic vaccines. In addition, we present potential innovations in immunostimulatory strategies by blocking the interaction of the inhibitory programmed death receptor 1 with its ligand in this animal model. PMID- 25535104 TI - Trends in chemoradiation use in elderly patients with head and neck cancer: Changing treatment patterns with cetuximab. AB - BACKGROUND: Cetuximab was approved for use in chemoradiation therapy (CRT) for locally advanced head and neck squamous cell carcinoma (HNSCC) in 2006. METHODS: Among 3705 patients with locally advanced HNSCC identified in the linked Surveillance Epidemiology and End Results (SEER) Medicare database, we assessed treatment trends, including surgery, radiation therapy (RT), CRT, and specific agents used in CRT. We examined the influence of demographic and clinical characteristics on the likelihood of receiving CRT before and after 2006. RESULTS: Chemoradiation use increased from 29% of patients diagnosed in 2001 to 61% in 2009 (p < .0001). Compared to before 2006, neither age nor comorbidity score was associated with receipt of CRT after 2006. Platinum combinations were the most commonly used concurrent chemotherapies before 2006, but, since then, cetuximab has become the most commonly used agent. CONCLUSION: The use of CRT has increased substantially and cetuximab may have increased CRT use, especially in older and sicker patients. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E165 E171, 2016. PMID- 25535105 TI - Covering implantable left ventricular assist device (DuraHeart) with free flap. AB - Severe donor shortage in Japan makes the waiting period for heart transplantation extremely long and the left ventricular assist devices (LVADs) are often used for bridge-to-transplant. We present three cases of infected and exposed DuraHeart LVAD system treated with free flaps. Four free flaps (two latissimus flaps and two anterolateral thigh flaps) were transferred using the right internal thoracic vessels or left deep inferior epigastric vessels as recipients. The potential significance of the continuous low pressure blood flow generated by the LVAD system on microvascular patency has not been previously reported. All flaps survived and worked efficiently to control the infection and cover the devices. Heart transplantation was conducted in the two of three patients. Free flap transfer is an efficient treatment for the patients with infected and exposed implantable LVAD. PMID- 25535106 TI - Possible role for microRNAs as inter-species mediators of epigenetic information in disease pathogenesis: is the non-coding dark matter of the genome responsible for epigenetic interindividual or interspecies communication? AB - MicroRNAs are short non-coding RNA molecules involved in the posttranscriptional epigenetic regulation of gene expression. Recent data show that microRNAs can be found in body fluids, and these microRNAs might enter cells giving rise to a hormone like way of action. MicroRNAs released in body fluids might affect other individuals, and there are some data of potential cross-species action of microRNAs, as well. Here, the authors discuss hypotheses concerning the potential pathogenic relevance of interindividual and cross-species action of microRNAs including food-derived microRNAs. Supposing that microRNAs might traverse the gastrointestinal tract, microRNAs might wander via the food-chain and even master regulatory microRNAs might be envisaged that could influence gene expression in a wide range of species and might thereby link different species via common gene expression signatures. Since many microRNA genes are located in the non-protein coding "dark matter" of the genome, a novel function of this "dark matter" is raised regarding interindividual and cross-species epigenetic communication via information transfer by gene products coded by the non-protein coding part of the genome. PMID- 25535107 TI - Implantation of glued intraocular lenses in eyes with microcornea. AB - PURPOSE: To evaluate the intraoperative modifications for and vision outcomes after implantation of glued intraocular lenses (IOLs) in eyes with microcornea. SETTING: Dr. Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. DESIGN: Prospective case series. METHODS: Eyes with a horizontal cornea of 10.0 mm or less were evaluated for intraoperative modifications and postoperative vision after implantation of a glued IOL. The type of surgery, type of IOL, incision and optic sizes, haptic length modifications, uncorrected (UDVA) and corrected (CDVA) distance visual acuity, and postoperative complications were analyzed. RESULTS: A glued IOL was implanted in 15 eyes to treat subluxated cataract (9 eyes), aphakia (5), and intraoperative capsule loss (1). In cases involving a subluxated cataract, implantation of the glued IOL was followed by lensectomy (7 eyes) or intracapsular cataract extraction (2 eyes). The mean follow-up was 22.4 months +/- 17.2 (SD). The mean horizontal corneal diameter and axial length were 8.0 +/- 0.6 mm and 21.0 +/- 2.4 mm, respectively. The mean amount of IOL haptic trimmed intraoperatively was 1.54 +/- 0.33 mm. There was significant correlation between the horizontal corneal diameter and the amount of haptic trimmed (P = .000). The mean size of the main incision was 3.70 +/- 0.98 mm. Three-piece foldable IOLs with a 6.0 mm optic were used. There were no cases of haptic extrusion or subconjunctival haptic placement. There was statistically significant improvement in CDVA (P = .032) and UDVA (P = .012) after surgery. CONCLUSION: Glued IOLs were safely implanted in eyes with microcornea using modifications such as custom haptic trimming and 6.0 mm optic foldable IOLs. FINANCIAL DISCLOSURE: Dr. Amar Agarwal is a paid consultant to Staar Surgical Co. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25535108 TI - Long-term follow-up of epikeratophakia. AB - We report a 28-year follow-up of epikeratophakia surgery after extracapsular extraction of a congenital cataract. The patient's ocular history included the diagnosis of bilateral cortical congenital cataracts at 2 years of age, which was more severe in the right eye than in the left. One year later, the visual acuity in the right eye progressively worsened, and extracapsular cataract extraction without intraocular lens implantation was performed. After contact lens fitting failed, an epikeratophakia procedure was performed in the right eye. Twenty-eight years after the procedure, the patient was referred to Bascom Palmer Eye Institute for progressive loss of visual acuity in the left eye. It was discovered that the right eye had remained stable; the corrected distance visual acuity was 20/30 with a manifest refraction of -8.75 + 0.50 * 105. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25535109 TI - Reevaluating intracameral cefuroxime as a prophylaxis against endophthalmitis after cataract surgery in India. AB - PURPOSE: To determine whether an intracameral injection of cefuroxime sodium at the conclusion of cataract surgery lowers the incidence of acute-onset postoperative endophthalmitis. SETTING: Tertiary eye care center, Bhubaneswar, India. DESIGN: Prospective comparative interventional cohort study. METHODS: Under a uniform protocol, cataract surgery with posterior chamber intraocular lens (PC IOL) implantation was performed from September 27, 2006, to July 31, 2010 (Group 1). All eyes were evaluated 1 day, 7 days, and 5 weeks +/- 1 (SD) postoperatively. Treatment of eyes suspected to have developed infectious endophthalmitis was managed by retina-vitreous surgeons. From August 1, 2010, to August 31, 2012, the same surgeons performed cataract surgery with PC IOL implantation in another group of eyes, in which they administered intracameral cefuroxime prophylaxis (Group 2). All other protocols of postoperative care and microbiological investigation of the vitreous samples were similar. The rate of clinical and culture-positive endophthalmitis was compared between the 2 study groups: eyes without intracameral cefuroxime (Group 1) and eyes with intracameral cefuroxime (Group 2). RESULTS: The incidence of clinical endophthalmitis in Group 1 (0.155% [12/7756 eyes]) and in Group 2 (0.108% [8/7366 eyes]) was not significantly different (P = .57). The culture positivity rate in Group 1 (0.09 % [7 eyes]) and in Group 2 (0.04% [3 eyes]) was also not significantly different (P = .38). In the treatment without intracameral cefuroxime, there was a minimal, statistically insignificant increase in postoperative acute endophthalmitis (odds ratio, 1.42; 95% confidence interval, 0.53-4.02; P = .506). CONCLUSION: There is not strong evidence to support use of intracameral cefuroxime to reduce the rate of acute endophthalmitis after cataract surgery; however, the marginal benefit might justify its use. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25535110 TI - [Awareness and understanding of consent in Alzheimer's disease]. AB - Before a patient can take part in a clinical research, French legislation requires his/her free, express and informed consent. In the same way, the information must be given in a clear, fair and appropriate manner. However, in the context of Alzheimer's disease, one might wonder about the patient's capacity to consent. The goal of our research was to study the capacity to provide informed consent in a group of patients with mild Alzheimer's disease and in a control group, using two specialized clinical vignettes inspired by Marson's studies. The aim of the study was to assess discernment in capacity to consent to a treatment and to determinate the possible links between impaired capacities to consent and cognitive and behavioral impairments involved in Alzheimer's disease. The data collected confirm that the capacity to make and maintain a choice is preserved while the capacities to appreciate the consequences of choosing a treatment, to reason and to understand the treatment situation are already impaired in mild Alzheimer's disease. The impairment of these capacities can be linked to dysexecutive syndrome, apathy and impaired self-awareness. Caregivers and family should take into account the risk of weakened capacities of discernment as soon as possible. PMID- 25535111 TI - Impact of long-term moderate hypercapnia and elevated temperature on the energy budget of isolated gills of Atlantic cod (Gadus morhua). AB - Effects of severe hypercapnia have been extensively studied in marine fishes, while knowledge on the impacts of moderately elevated CO2 levels and their combination with warming is scarce. Here we investigate ion regulation mechanisms and energy budget in gills from Atlantic cod acclimated long-term to elevated PCO2 levels (2500 MUatm) and temperature (18 degrees C). Isolated perfused gill preparations were established to determine gill thermal plasticity during acute exposures (10-22 degrees C) and in vivo costs of Na(+)/K(+)-ATPase activity, protein and RNA synthesis. Maximum enzyme capacities of F1Fo-ATPase, H(+)-ATPase and Na(+)/K(+)-ATPase were measured in vitro in crude gill homogenates. After whole animal acclimation to elevated PCO2 and/or warming, branchial oxygen consumption responded more strongly to acute temperature change. The fractions of gill respiration allocated to protein and RNA synthesis remained unchanged. In gills of fish CO2-exposed at both temperatures, energy turnover associated with Na(+)/K(+)-ATPase activity was reduced by 30% below rates of control fish. This contrasted in vitro capacities of Na(+)/K(+)-ATPase, which remained unchanged under elevated CO2 at 10 degrees C, and earlier studies which had found a strong upregulation under severe hypercapnia. F1Fo-ATPase capacities increased in hypercapnic gills at both temperatures, whereas Na(+)/K(+)ATPase and H(+)-ATPase capacities only increased in response to elevated CO2 and warming indicating the absence of thermal compensation under CO2. We conclude that in vivo ion regulatory energy demand is lowered under moderately elevated CO2 levels despite the stronger thermal response of total gill respiration and the upregulation of F1Fo-ATPase. This effect is maintained at elevated temperature. PMID- 25535112 TI - Ultraviolet radiation does not increase oxidative stress in the lizard Psammodromus algirus along an elevational gradient. AB - Lizards, as ectotherms, spend much time basking for thermoregulating exposed to solar radiation. Consequently, they are subjected to ultraviolet radiation (UVR), which is the most harmful component of solar radiation spectrum. UVR can provoke damages, from the molecular to tissue level, even cause death. Photooxidation triggered by UVR produces reactive oxidative species (ROS). When antioxidant machinery cannot combat the ROS concentration, oxidative stress occurs in the organisms. Given that UVR increases with elevation, we hypothesised that lizards from high elevations should be better adapted against UVR than lizards from lower elevations. In this work, we test this hypothesis in Psammodromus algirus along an elevation gradient (three elevational belts, from 300 to 2500 m above sea level). We ran an experiment in which lizards from each elevation belt were exposed to 5-hour doses of UVR (UV-light bulb, experimental group) or photosynthetically active radiation (white-light bulb, control group) and, 24 h after the exposure, we took tissue samples from the tail. We measured oxidative damage (lipid and protein peroxidation) and antioxidant capacity as oxidative stress biomarkers. We found no differences in oxidative stress between treatments. However, consistent with a previous work, less oxidative damage appeared in lizards from the highlands. We conclude that UVR is not a stressor agent for P. algirus; however, our findings suggest that the lowland environment is more oxidative for lizards. Therefore, P. algirus is well adapted to inhabit a large elevation range, and this would favour the lizard in case it ascends in response to global climate change. PMID- 25535113 TI - [Lumbar spinal anesthesia with cervical nociceptive blockade. Critical review of a series of 1,330 procedures]. AB - BACKGROUND AND OBJECTIVES: The manufacture of minimally traumatic needles and synthesis of pharmacological adjuncts with safe and effective action on inhibitory and neuromodulatory synapses distributed along the nociceptive pathways were crucial for a new expansion phase of spinal anesthesia. The objectives of this paper are present our clinical experience with 1,330 lumbar spinal anesthesia performed with purposeful nociceptive blockade of the thoracic and cervical spinal nerves corresponding to dermatomes C4 or C3; warn about the method pathophysiological risks, and emphasize preventive standards for the safe application of the technique. CONTENT: Review of the historical background and anatomical spinal anesthesia with cervical levels of analgesia. Description of the technique used in our institution; population anesthetized; and surgery performed with the described method. Critical exposition of the physiological, pathophysiological, and clinical effects occurred and registered during anesthesia-surgery and postoperative period. CONCLUSION: Spinal anesthesia with nociceptive blockade to dermatome C4, or C3, is an effective option for surgery on somatic structures distal to the metamer of the third cervical spinal nerve, lasting no more than four or five hours. The method safety depends on the unrestricted respect for the essential rules of proper anesthesia. PMID- 25535114 TI - Micro/macroporous system: MFI-type zeolite crystals with embedded macropores. AB - Zeolite crystals with an embedded and interconnected macropore system are prepared by using mesoporous silica particles as a silica source and as a sacrificial macroporogen. These novel hierarchical zeolite crystals are expected to reduce diffusion limitations in all zeolite-catalyzed reactions, especially in the transformation of larger molecules like in the catalytic cracking of polymers and the conversion of biomass. PMID- 25535115 TI - Isolation of colorectal cancer stem-like cells. AB - This study is aimed at isolating colorectal cancer stem-like cells in vitro using a neurosphere assay method employed in isolating gliobastoma multiforme tumor cells. This was followed with confirmation of the isolated cells by flow cytometry, pluripotent genes expression and in vivo tumorigenicity assay. Using this culture assay, stem-like and non-stem-like CRC cells were isolated and expanded in vitro from purchased Balb/c mice induced with CT26 colorectal cancer (CRC) cell line. The procedure includes an initial mechanical dissociation and chemical digestion of tumor tissue and subsequently plating the resulting single cell suspension in serum-free medium (SFM) or serum-containing medium (SCM). This selectively permits growth of cancer stem-like cells in SFM and eliminates non stem-like cancer cells through the process of anoikis or apoptosis. CRC stem cells derived cultures proliferated as non-adherent spheres in vitro in different shapes and sizes. These cells expressed cell surface markers previously reported for tumor stem cells, including CD44, CD133, CD166 and CD26 and formed tumors when implanted in severe combined immunodeficient mice in a concentration dependent manner. Importantly, the stem-like cells had self-renewal properties with significantly higher expression of the pluripotent stem cell genes NANOG, OCT4, and SOX2 compared to the adherent non-stem cells. Collectively, the results of this study indicate that SFM is a defined culture medium that enriches for CRC stem-like cells and represents a suitable in vitro model for the study of CRC stem-like cells. This finding may be useful in developing therapeutic strategies aimed at eradicating the tumorigenic subpopulation within colorectal cancer. PMID- 25535116 TI - Erratum to: Evidence of MAPK-JNK1/2 activation by hepatitis E virus ORF3 protein in cultured hepatoma cells. PMID- 25535117 TI - Marker profile for the evaluation of human umbilical artery smooth muscle cell quality obtained by different isolation and culture methods. AB - Even though umbilical cord arteries are a common source of vascular smooth muscle cells, the lack of reliable marker profiles have not facilitated the isolation of human umbilical artery smooth muscle cells (HUASMC). For accurate characterization of HUASMC and cells in their environment, the expression of smooth muscle and mesenchymal markers was analyzed in umbilical cord tissue sections. The resulting marker profile was then used to evaluate the quality of HUASMC isolation and culture methods. HUASMC and perivascular-Wharton's jelly stromal cells (pv-WJSC) showed positive staining for alpha-smooth muscle actin (alpha-SMA), smooth muscle myosin heavy chain (SM-MHC), desmin, vimentin and CD90. Anti-CD10 stained only pv-WJSC. Consequently, HUASMC could be characterized as alpha-SMA+ , SM-MHC+ , CD10- cells, which are additionally negative for endothelial markers (CD31 and CD34). Enzymatic isolation provided primary HUASMC batches with 90-99 % purity, yet, under standard culture conditions, contaminant CD10+ cells rapidly constituted more than 80 % of the total cell population. Contamination was mainly due to the poor adhesion of HUASMC to cell culture plates, regardless of the different protein coatings (fibronectin, collagen I or gelatin). HUASMC showed strong attachment and long-term viability only in 3D matrices. The explant isolation method achieved cultures with only 13-40 % purity with considerable contamination by CD10+ cells. CD10+ cells showed spindle-like morphology and up-regulated expression of alpha-SMA and SM-MHC upon culture in smooth muscle differentiation medium. Considering the high contamination risk of HUASMC cultures by CD10+ neighboring cells and their phenotypic similarities, precise characterization is mandatory to avoid misleading results. PMID- 25535119 TI - Confirming the diagnosis of amyloid cardiomyopathy: usefulness of non-invasive techniques. PMID- 25535118 TI - Measuring the impact of a burns school reintegration programme on the time taken to return to school: A multi-disciplinary team intervention for children returning to school after a significant burn injury. AB - INTRODUCTION: Returning to school can be a major step for burn-injured children, their family, and staff and pupils at the receiving school. Previous literature has recognised the difficulties children may face after a significant injury and factors that may influence a successful reintegration. AIM: A regional paediatric burns service recognised that some patients were experiencing difficulties in returning to school. A baseline audit confirmed this and suggested factors that hindered or facilitated this process, initiating the development of a school reintegration programme (SRP). Since the programme's development in 2009, it has been audited annually. The aim of this paper was to evaluate the impact of the SRP by presenting data from the 2009 to 2011 audits. METHOD: For the baseline audit, the burn care team gathered information from clinical records (age, gender, total body surface area burned (TBSA), skin grafting and length of stay) and telephone interviews with parents and teachers of the school returners. For the re-audits, the same information was gathered from clinical records and feedback questionnaires. RESULTS: Since its introduction, the mean length of time from discharge to return to school has dropped annually for those that opted into the programme, when compared to the baseline by 62.3% (53 days to 20 days). Thematic analysis highlights positive responses to the programme from all involved. Increased awareness and feeling supported were amongst the main themes to emerge. CONCLUSIONS: Returning to school after a significant burn injury can be challenging for all involved, but we hypothesise that outreach interventions in schools by burns services can have a positive impact on the time it takes children to successfully reintegrate. PMID- 25535120 TI - In response to "Cauda equina syndrome: evaluation of clinical outcome" more insights on sexual and defecational recovery in cauda equina syndrome. PMID- 25535121 TI - Perilimphatic fistula test: a video clip demonstration. AB - Perilymphatic fistula (PLF) is an abnormal condition in which a communication is present between the perilymphatic space of the inner ear and the middle ear or mastoid, secondary to a dehiscence in the otic capsule, oval or round window. LF may induce hearing loss, tinnitus, aural fullness, vertigo, disequilibrium, or a combination of these symptoms; the vagueness of symptoms caused by PLF and the lack of specificity of clinical signs and symptoms make the diagnosis elusive. We report a video of a positive PLF test induced by the application of pressure on the tragus, just anterior to the left external auditory canal in a patient with cholesteatoma and PLF of lateral semicircular canal confirmed by CT scan imaging. https://www.youtube.com/watch?v=x5MhSILF9O4. PMID- 25535122 TI - Should transplant ureter be stented routinely or not? AB - OBJECTIVE: To compare early complications in patients with/without stents following renal transplantation and to determine whether routine stenting should be used in all renal transplant patients or not. PATIENTS AND METHODS: 194 patients (108 males, 86 females, mean age: 45.2 +/- 13.2 years) who were followed up at the Division of Nephrology of Istanbul Bilim University between 2006 and 2013 were included in the study. Demographic characteristics, etiologies of renal disease, comorbidities, type of renal transplantation, early complications, delayed graft function were retrospectively recorded. All patients were divided into two groups according to stent replacement. Early complications were compared. RESULTS: 101 patients were inserted double-J(DJ) stent (48 females, mean age 46.5 +/- 13.7 years, mean body mass index [BMI] 26.1 +/- 4.7 kg/m2) and 93 patients were not inserted stent (38 females, mean age 43.7 +/- 12.6 years, mean BMI 24.3 +/- 4.2 kg/m2). The rate of early complications of urinary tract infections, lymphocele, urinary leaks, wound infection and perirenal hemorrhage of patients with stent were 28.9%,3.0%,4.0%, 5.1% and 1.3%, respectively, while these rates among patients without stent were 35.5%, 2.2%,3.2%,6.5% and 1.2%,respectively. There was no significant difference between with stent and without stent groups with regard to early complications. CONCLUSIONS: Routine DJ stenting in all renal transplant patients is not necessary. Prophylactic use of DJ stent has no effect on early complications. Prophylactic DJ stent replacement can be used in obese patients, in patients receiving cadaveric transplants or in patients receiving transplants from unrelated donors. PMID- 25535123 TI - Bioinformatics analysis of molecular mechanisms of chronic obstructive pulmonary disease. AB - OBJECTIVE: This study was designed to explore the molecular mechanisms of Chronic Obstructive Pulmonary Disease (COPD) with DNA Microarray. MATERIALS AND METHODS: The gene expression profile GSE475 was downloaded from Gene Expression Omnibus (GEO) database. There were 7 tissue samples of human diaphragm muscle available, including 4 normal samples and 3 samples from COPD patients. The differentially expressed genes (DEGs) were identified by LIMMA package in R language and were further analyzed using bioinformatics methods. Firstly, DEGs were classified into different COG clusters by BLAST. Then, the protein-protein interaction (PPI) network was constructed by STRING and pathways of DEGs were analyzed by FuncAssociate. Finally, the DEGs enriched diseases were obtained by EASE. RESULTS: We selected 524 DEGs including 118 down-regulated DEGs and 406 up regulated DEGs. The most significant pathway was JAK/STAT signaling pathway and the DEGs of IL6 and SOCS3 were directly participated in this pathway. Furthermore, the DEGs of SOCS3, IL4, IL18R1, IL1R1, and IL6 were participated in the disease of pulmonary fibrosis. CONCLUSIONS: Our findings suggest that IL6 and SOCS3 play important roles in COPD and have the potential to serve as therapeutic targets of COPD. PMID- 25535124 TI - Roxithromycin reduces the viability of cultured airway smooth muscle cells from a rat model of asthma. AB - OBJECTIVES: The purpose of this study was to investigate the effect of roxithromycin on apoptosis of airway smooth muscle cells (ASMCs) from a rat model of asthma and uncover signaling pathway underlying the cytotoxicity of roxithromycin. MATERIALS AND METHODS: ASMCs were isolated from a rat model of asthma and treated with or without roxithromycin for 48 h before parameter detection. Cell viability was assessed by WST-8 assay and flow cytometry after Annexin V/PI double staining. Changes in the mitochondrial membrane potential (DeltaPsim) were measured by flow cytometry using JC-1. Cytochrome C (Cyt c), cleaved Caspase-9/3 and P27 were evaluated by Western Blot. RESULTS: Incubation with roxithromycin reduced ASMCs proliferation and enhanced apoptosis in a dose dependent manner. Flow cytometry revealed a loss of DeltaPsim and Western Blot displayed Caspase-9/3 activation as well as Cyt c release from mitochondria to the the cytosol after the treatment of roxithromycin. In addition, P27 were more strongly expressed in AMSCs treated with roxithromycin compared with the control group. CONCLUSIONS: Roxithromycin induced apoptosis of ASMCs derived from a rat model of asthma in a dose-dependent manner via a caspase-3- and caspase-9 dependent mitochondrial pathway, involving the up-regulation of P27. PMID- 25535125 TI - Glucocorticoid induced autophagy in N1511 chondrocyte cells. AB - OBJECTIVE: To determine whether autophagy was involved in chondrocyte cells post Glucocorticoids (GCs) treatment. MATERIALS AND METHODS: LC3-GFP reporter plasmid transfection and western blotting analysis were conducted to determine the autophagic vesicles and autophagy-associated molecules in the N1511 chondrocyte cells post dexamethasone (Dex) treatment. And the N1511 cell viability was also determined by MTT assay. RESULTS: We found that autophagy was induced in the N1511 chondrocyte cells post treatment with Dex of 5 uM to 1 mM, and the autophagy-induction by Dex could be inhibited by 3 MA and RU486, a GC antagonist. And the autophagy induced by the high dose of Dex (200 uM or 1 mM) was associated with a reduction of N1511 cell viability. CONCLUSIONS: These results suggested that GCs could induce autophagy, as might contribute to the viability reduction of chondrocyte cells. PMID- 25535126 TI - Effects of osteopontin on the expression of IL-6 and IL-8 inflammatory factors in human knee osteoarthritis chondrocytes. AB - OBJECTIVE: Osteoarthritis (OA) is a chronic musculoskeletal disease characterized by progressive destruction of articular cartilage, OA lead to chronic pain and functional restrictions in affected joints. The present study was to investigate the role of osteopontin (OPN) in the athogenesis of OA through studying the effect of OPN on expression of IL-6 and IL-8 inflammatory factors in human OA chondrocytes. PATIENTS AND METHODS: One-step type II collagenase digestive method was used to isolate OA chondrocytes from sectional cartilage specimens of 16 primary knee OA patients received total knee replacement surgery. Synchronized first-generation chondrocytes were then treated with OPN (100 ng/ml or 1 ug/mL). The changes in cell morphology of OA chondrocytes were analyzed before and after treated with OPN; and the expression levels of IL-6 and IL-8 were evaluated by real-time q-PCR. RESULTS: Chondrocytes were successfully isolated from human OA knee cartilage, and the viability of isolated chondrocytes was 92.11+/-3.13%. Adherent chondrocytes formed clusters of irregular polygonal shape with intercellular pseudopodia extension. After OPN treatment, cells became fusiform or irregularly shaped, and the number of intercellular pseudopodia decreased significantly. The mRNA expression of IL-6 increased to 1.83 times at 0.1 ug/ml of OPN and 3.1 times at the dose of 1 ug/ml; the expression of IL-8 increased to 1.57 and 3.27 times at the dose of 0.1 ug/ml and 1 ug/ml respectively. CONCLUSIONS: OPN could up-regulate expression of IL-6 and IL-8 cytokines in human OA chondrocytes, and the expression increased with the increasing concentration of OPN, which might be one of the potential mechanisms of OPN in the development of OA. PMID- 25535127 TI - Total knee arthroplasty treatment of active tuberculosis of the knee: a review of 10 cases. AB - OBJECTIVE: To discuss the surgical methods of total knee arthroplasty (TKA) in the patients with active tuberculosis of the knee and find out its curative effect after TKA. PATIENTS AND METHODS: We analyzed 10 patients with active tuberculosis of the knee who received TKA in our department from March 2006 to March 2010, whose ages were from 22 to 64 years old (average age was 40.6 +/- 1 years). The following parameters were measured in the pre- and post-operation periods: HSS score, range of motion (ROM). From x-ray to find out post-operate curative effect of TKA. RESULTS: All cases had pain and elevated ESR. Deep vein thrombosis (DVT) and nerve damage were not found in these cases. There were 4 cases that had sinuses on the skin: the skin healed before the operation took place. Pre-operation HSS average scores were 25.0 +/- 2. All patients received TKA by the para-patellar medial approach. Eight cases were followed-up for 6-28 months; the average follow-up period was 14 +/- 0.5 months. Post-operation we took an HSS score and X-rays to find out its curative effect after TKA operation. There were also no patients with dislocation, aseptic loosening or fracture of prosthesis, although 1 case had recurrence. Post-operation's HSS average scores were 86.75 +/- 5.45. The average ROM was improved to 95 +/- 5 degrees . CONCLUSIONS: Recent clinical results indicate that TKA is effective to treat the patients with active tuberculosis of the knee joint. TKA can significantly improve the function of the joint and relieve pain, improving patients' living conditions. PMID- 25535128 TI - Relationship between blood glucose fluctuation and macrovascular endothelial dysfunction in type 2 diabetic patients with coronary heart disease. AB - OBJECTIVE: To evaluate the relationship between blood glucose fluctuation and macrovascular dysfunction. PATIENTS AND METHODS: Eighty-eight type 2 diabetes mellitus (T2DM) patients with or without coronary heart disease (CHD) and 30 healthy control subjects were recruited. Glycosylated hemoglobin A1c (HbA1c), fasting insulin (FIns), and C-reaction protein (CRP) and some other general clinical variables were measured. A 72-hour continuous glucose monitoring (CGM) and brachial artery endothelium-dependent flow-mediated dilation (FMD) assessment were performed. The glucose excursion, MAGE (mean amplitude of glycemic excursions), LAGE (largest amplitude of glycemic excursions), MPPGE (mean postprandial glycemic excursions), MODD (absolute means of daily differences), and IAUC70 (incremental area under the curve below 70 mg/dl) during the CGM were analyzed. Correlations between the various variables were analyzed. RESULTS: Enhanced blood glucose fluctuation was observed in T2DM patients with CHD as compared to other participants. And blood glucose fluctuation was correlated with FMD, CRP and HOMA-IR. CONCLUSIONS: Blood glucose fluctuation is an important factor that affects inflammatory response and possibly induces CHD in T2DM patients. PMID- 25535129 TI - Binary logistic regression analysis of solid thyroid nodules imaged by high frequency ultrasonography, acoustic radiation force impulse, and contrast enhanced ultrasonography. AB - OBJECTIVE: The common clinical techniques used for examining thyroid tumors include palpation, imaging, immunoassays and tissue biopsy. Ultrasonography is easy, non-invasive, non-radioactive and highly reproducible imaging technique; however, due to the disease polytropism, diagnosis may become difficult sometimes. Ultrasound elastography, particularly acoustic radiation force impulse (ARFI) imaging and contrast-enhanced ultrasonography (CEUS) have been successfully used to diagnose the thyroid tumors. The objective of this retrospective study was to analyze and compare the solid thyroid nodules imaged by high-frequency ultrasonography (HFUS), ARFI imaging, and CEUS. PATIENTS AND METHODS: For this purpose, images of the 80 solid thyroid nodules (58 benign and 22 malignant) with surgical pathology were obtained and data were compared using binary logistic regression analysis. RESULTS: Morphology (p < 0.001), and internal calcification (p = 0.007) were statistically different. The mean shear wave velocity (SWV) measured by ARFI was significantly different (p = 0.029). Three sets of comparison on CEUS (p = 0.019) and time to peak (TTP) of CEUS were significantly different (p = 0.001). The logistic regression analysis indicated that the morphology, mean SWV of ARFI and TTP were independent risk factors for malignancy. The diagnostic accuracy for solid thyroid nodules was 85.1% (68/80) and the area under the receiver operating characteristic (ROC) curve was 0.945+/ 0.033. CONCLUSIONS: Logistic regression analysis can effectively screen significant parameters for the differential diagnosis of solid thyroid nodules imaged by ultrasonography. PMID- 25535130 TI - Autoimmune thyroid disease: mechanism, genetics and current knowledge. AB - Recent epidemiological studies recognized a steady increase in the incidence of different autoimmune endocrine disorders, including autoimmune thyroid disease (AITD). The etiology of AITD is multifactorial and involves genetic and environmental factors and apparently with a strong preponderance in females. There are mainly two types of AITD, Graves' disease and Hashimoto's disease and both of these show strong association in age groups above 45-50 years. Among environmental factors smoking and alcohol have significant effects, both protective as well as for aggravating the disease, even though the precise nature of these effects are not clearly known. There are elevated levels of circulating antibodies against the thyroid proteins, mainly thyroid oxidase, thyroglobulin and thyroid stimulating hormone receptor, in patients with Graves' disease or Hashimoto's disease. Linkage and association studies in AITD identified several major genes that are relevant for the onset of AITD, including the thyroid specific genes, thyroglobulin and thyroid-stimulating hormone receptor and also many immune-regulatory genes. In this review we addressed many aspects of AITD including disease mechanisms, involved thyroid antigens, environmental factors and genetic factors. PMID- 25535131 TI - Evaluation of optimal match between gantry rotation time and cardiac cycle on multislice spiral CT coronary angiography imaging. AB - OBJECTIVE: To evaluate the relationship between gantry rotation time, heart rate and image quality during multislice spiral CT coronary angiography (MSCTCA). PATIENTS AND METHODS: Data of 83 patients who underwent MSCTCA were reviewed. Based on the ratio between cardiac cycle and gantry rotation time, the patients were divided into two groups. Patients whose heart rates fell in the resonance frequency (the cardiac cycle / gantry rotational time ratio of 1.5, 2 or 2.5) +/- 2 bpm were classified as synchronous (25 cases), while the remaining 58 patients (included a subgroup of 34 cases in whom heart rates were the same as in synchronous group but who had a different gantry rotation time). comprised the asynchronous group. Image qualities were compared between both groups. RESULTS: In the synchronous group, most (199/287; 69.33%) images were poor. When gantry rotation time was changed in the subgroup of the asynchronous group, the majority (423/442 or 95.70%) of images improved. There was a significant difference (p < 0.001) in the image quality among these patients. In 58 patients from asynchronous group, 757 segments of coronary arteries were evaluated, and 716 segments were of best quality (716/757; 94.58%). CONCLUSIONS: When heart rate and gantry rotation time correlate and synchronous, the so-called frequency harmonics, coronary artery image quality is poor. However, by changing gantry rotation time to avoid the harmonic helps to improve the image quality on MSCTCA. Based on the patient's heart rate, appropriate gantry rotation time can be selected in order to avoid resonance and obtain high quality images. PMID- 25535132 TI - Glioblastoma multiforme and hepatitis B: do the right thing(s). AB - OBJECTIVE: Hepatitis B virus (HBV) reactivation is a well-known complication related to immunosuppression. Clinical manifestations of HBV relapse range from self-limiting anicteric hepatitis to acute hepatic failure. Temozolomide (TMZ) is an alkylating agent used for the treatment of glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors. CASE REPORT: We report the case of a 52-year old man with a history of serological positivity for hepatitis B surface antigen (HBsAg) who was diagnosed with GBM. Since the tumor was multifocal and thus inoperable, the patient received radiotherapy with concomitant TMZ and corticosteroids, without a prophylactic therapy for HBV infection. Acute hepatitis developed five months later the beginning of anticancer therapy. We started antiviral entecavir, which led to a decrease of HBV-DNA titer to 20 IU/ml, allowing the prosecution of the TMZ therapy. CONCLUSIONS: Up to now only four other cases of HBV relapse during TMZ therapy have been reported in literature. These cases underline the need of HBV screening and antiviral prophylaxis before starting TMZ administration. PMID- 25535133 TI - Expression and significance of glucosylceramide synthase in colorectal carcinoma tissues. AB - OBJECTIVE: To investigate the impression of glucosylceramide synthase (GCS) in colorectal carcinoma tissues. MATERIALS AND METHODS: Immunohistochemical method was used to detect the expression of GCS in 188 cases of colorectal carcinoma tissues and 80 cases of non-cancerous colorectal tissues. The expression of GCS and the relation with age, gender, tumor location, Tumor stage, differentiation, lymph node metastasis were analyzed. Thus, we further discussed whether to accept neoadjuvant chemotherapy can affect the expression of GCS. RESULTS: GCS was overexpressed in colorectal carcinoma tissues compared with non-cancerous colorectal tissues; the expression of GCS was associated with lymph node metastasis, but not associated with age, gender, tumor location, differentiation and Tumor stage. What's more, the positive expression rate of GCS in patients who receiving neoadjuvant chemotherapy was higher than that in untreated patients. CONCLUSIONS: GCS was upregulated in colorectal carcinoma tissues. It might not only play an important role in controlling the generation and progression of colorectal carcinoma, but also be a factor of MDR. PMID- 25535134 TI - Imaging, clinical and pathological features of salivary gland adenolymphoma. AB - OBJECTIVE: Adenolymphoma (Warthin's tumor) is a common salivary gland benign tumors with poor diagnosis and ranking second after the parotid tumors. Presently, a rising tendency of the incidence of adenolymphoma has been noted. The aim of this study was to investigate the clinical, pathological and imaging features of this tumor. PATIENTS AND METHODS: 24 cases of confirmed adenolymphoma were retrospectively analyzed with clinical features, pathological data and CT imaging. RESULTS: Among 24 cases, 22 (91.7%) patients were male, two patients were female, 23 (95.8%) patients were more than 50 years old; 38 lesions were found in 24 patients including isolated lesions in 16 patients (66.7%), and multiple lesions in 8 patients (33.3%). 81.6% adenolymphoma lesions (31/38) were located in the posterior and inferior quadrant. The shapes of lesions were more oval or round, well-circumscribed, homogeneous (n=26) or inhomogeneous (n=12) with high density. 27 lesions were demonstrated with enhancement after contrast enhancement and 10 lesions showed small vessels penetrating through or surrounding the mass. CONCLUSIONS: Adenolymphoma of the parotid (Warthin tumor) should be first considered by the clinical data including age, gender, location and imaging manifestations of the lesions. PMID- 25535135 TI - Association of cognitive performance with the physical activity and body mass index in middle-aged and older rural inhabitants. AB - OBJECTIVE: Last few decades have witnessed rapid ageing of the population. The prevalence of mild cognitive impairment and dementia is significantly higher in people aged 60 and over than in younger. The aim of the study was the assessment of the putative associations between physical activity and cognitive functioning in elderly inhabitants of a rural area. PATIENTS AND METHODS: The participants underwent physical assessment, physical activity, cognitive functions, depression were assessed. RESULTS: Highly active participants had better results in tests assessing psychomotor speed and in measuring attention and its flexibility comparing to groups of medium and low physical activity. Active people made fewer errors in the test measuring visual memory and new learning, and had significantly better results in the spatial-recognition memory test. Persons with symptoms of depression performed worse in visuospatial memory and working memory tests. Associations between physical activity and cognitive test results as well as association between body mass index and blood pressure and cognitive performance were observed. CONCLUSIONS: The results of the study suggest an association between higher physical activity and better cognitive functioning in the field of working memory and visual and spatial-recognition, attention and attention flexibility. Symptoms of depression, hypertension and increased BMI may adversely affect cognitive performance in elderly. PMID- 25535136 TI - Sequential therapy for non-thalamus supratentorial hypertensive intracerebral hemorrhages. AB - OBJECTIVE: We sought to assess the effectiveness of sequential therapy for non thalamus supratentorial hypertensive intracerebral hemorrhage (NTS-HICH). PATIENTS AND METHODS: We retrospectively analyzed clinical data of 110 patients with HICH. The patients were admitted 72 hours after disease onset, and 43 patients received sequential therapy. The length of hospital stay, treatment costs, incidence of pulmonary infections, mortality rates and Modified Rankin Score (mRS) 1 and 3 months after NTS-HICH were compared between patients who received sequential or non-sequential therapies. RESULTS: The length of hospital stay, treatment costs, and 1-month mortality rates were not significantly different between both groups. However, mortality rates at 3 months, incidence of pulmonary infection, and mRS at both 1 and 3 months were significantly better in patients who received sequential therapy. CONCLUSIONS: Sequential therapy significantly improves the prognosis for patients with NTS-HICH. PMID- 25535137 TI - Olfactory disfunction and its relation olfactory bulb volume in Parkinson's disease. AB - OBJECTIVE: Olfactory dysfunction is the most frequently seen non-motor symptom of Idiopathic Parkinson's disease (IPD). The aim of this study is to analyze selective olfactory dysfunction, and olfactory bulb volume (OBV) in subtypes of IPD, and compare them with those of the healthy controls. PATIENTS AND METHODS: Our study included 41 patients with IPD and age and gender matched 19 healthy controls. IPD patients were either tremor dominant (65.9%; TDPD) or non-tremor dominant (34.1%; NTDPD) type. All patients underwent neurological, ear, nose, and throat examinations, and orthonasal olfaction testing. Magnetic resonance imaging (MRI) technique was used to measure the volume of the olfactory bulb. RESULTS: A significant decrease in olfactory identification scores was found in the patient group. The patients had difficulty in discriminating between odors of mothballs, chocolate, Turkish coffee and soap. OBV did not differ between the patient, and the control groups. In the TDPD group, odor identification ability was decreased when compared to the control group. However, odor test results of NTDPD, control and TDPD groups were similar. OBV estimates of the TDPD group were not different from those of the control group, while in the NTDPD group OBVs were found to be decreased. In all patients with Parkinson's disease OBV values did not vary with age of the patients, duration of the disease, age at onset of the disease, and Unified Parkinson's Disease Rating Scale motor scores (UPDRS-m). CONCLUSIONS: Olfactory function is a complex process involving olfactory, and cortical structures as well. In Idiopathic Parkinson's disease, changes in OBV do not seem to be directly related to olfactory dysfunction. PMID- 25535138 TI - The usefulness of the Loewenstein Occupational Therapy Cognition Assessment in evaluating cognitive function in patients with stroke. AB - OBJECTIVE: We wished to evaluate the usefulness of the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) in early detection of the Vascular Cognitive Impairment, No Dementia (VCIND) in patients with stroke. We also wanted to compare LOTCA with the Mini-Mental State Examination (MMSE). PATIENTS AND METHODS: Thirty patients with stroke and cognitive impairment comprised the cognitive impairment group. Another 30 patients with stroke and no cognitive impairment served as the stroke control group, while 30 healthy individuals served as the normal control group. RESULTS: The age, gender, and education level were comparable among three study groups. All subjects were assessed with both tests. Total LOTCA scores strongly and positively correlated with total MMSE scores in patients with cognitive impairment (r = 0.934, p < 0.001). The correlations were also present between every sub-items of LOTCA and those of MMSE (p < 0.01). In addition, total scores and sub-item scores in LOTCA were significantly lower in the cognitive impairment group compared with both stroke control and normal control groups (p < 0.01), especially, with regard to scores of thinking operations, orientation, and visuomotor organization. The sub-item scores in LOTCA, including thinking operations, visuomotor organization, attention, orientation, and spatial perception were significantly lower in the stroke control group compared with normal control group (p < 0.01), especially in thinking operations and visuomotor organization. There is a good agreement between LOTCA and MMSE. CONCLUSIONS: Compared with MMSE, LOTCA can detect VCIND earlier and more comprehensively, and can, thus, be used clinically for VCIND detection. PMID- 25535139 TI - Study on plasmatic metabolomics of Uygur patients with essential hypertension based on nuclear magnetic resonance technique. AB - OBJECTIVE: Metabolomics is the analysis of the global constitution of endogenous metabolites in cells, tissue, and bodily fluids based on analysis techniques with high output, high sensitivity, and high resolution. The physiological and pathological state of the subject investigated could be identified and analyzed through examining metabolite changes. In this study, 1H-NMR metabolomics was employed to study plasma metabolites of both Uygur patients with hypertension and healthy people, thereby filtering out characteristic metabolites for Uygur patients with hypertension. The pathogenesis of hypertension was discussed via metabolic pathways. PATIENTS AND METHODS: A total of 256 Uygur subjects were recruited for this study and divided into two groups, namely hypertension group (157 Uygur patients with hypertension) and normal group (99 healthy Uygur subjects). They were all taken from epidemiological surveys on the Uygur people of Qira County, Hotan, and Xinjiang between 2009 and 2012 conducted by Hypertension Research Group of Xinjiang Medical University. Furthermore, all subjects have Uygur blood within three generations. For the hypertension group, the recruitment criteria is systolic blood pressure (SBP) >= 140 mmHg (lmmHg = 0.133 kPa) and/or diastolic blood pressure (DBP) >= 90 mmHg at rest. Patients who had taken antihypertensive drugs within two weeks and those who were diagnosed with essential hypertension (EH) were also included in this group, while patients with secondary hypertension, myocardiosis, congenital heart disease, and rheumatic valvular heart disease were not included. In the healthy normal pressure group, blood pressures were within normal range: SBP < 140 mmHg, DBP < 90 mmHg, without history of antihypertensive drugs, cardiovascular and cerebrovascular diseases, and liver/kidney diseases. All subjects were measured separately with Inova600 nuclear magnetic resonance (NMR) spectrometer to conduct the 1H-NMR experiment. Serum specimens from both the hypertension group and the healthy control group were used for NMR spectrograms before data pre-processing, where aggregate analysis was performed for NMR data/metabolic information with principal component analysis (PCA). Then, partial least squares discriminant analysis (PLS-DA) was employed to classify and predict different groups of specimens, and orthogonal partial least squares discriminant analysis (OPLS-DA) was conducted to cross-validate the quality of the models. Statistical analysis was further performed to test significance of the correlation coefficient to determine differential metabolic components in serums of both groups of subjects. Based on the information from the differential metabolic components, a metabolic pathway network related to hypertension could be constructed, thereby revealing potential biomarkers for hypertension. RESULTS: Clinical data showed that subjects in the two groups were not significantly different with respect to age, weight, and height, as well as lipid indices, including TG, LDL (p > 0.05), while FPG, SBP, DBP, HDL, and TC were significantly different between the two groups (p < 0.05). OPLS-DA results demonstrated that integral quantities of principal components were mainly distributed within four areas of the ellipse scatter diagram (95% confidence interval). From the score plot and 3D distribution diagram, it can be observed that the distribution areas for the two groups are completely separate, thereby indicating that the serum of the Uygur hypertension patients is significantly different from that of healthy subjects in terms of metabolic components. OPLS-DA results indicate that differences in metabolic components are significant between the two groups, and 12 different metabolites were identified. Compared to healthy subjects, patients with hypertension possess a much lower quantity of many amino acids, including valine, alanine, pyroracemic acid, inose, p-hydroxyphenylalanine, and methylhistidine, among others (p < 0.05), with a significant increase in VLDL, LDL, lactic acid, and acetone (p < 0.05). CONCLUSIONS: The 1H-NMR metabolomics process, in combination with OPLS-DA pattern identification, is an effective way to differentiate the serum metabolites characteristic of hypertension patients. Pattern identification analysis of NMR spectrum data with OPLS-DA could identify metabolites of hypertension patients versus healthy subjects. The metabolic phenotype of Uygur hypertension patients shows significant heteromorphosis, with the 12 characteristic metabolites as potential biomarkers of hypertension. PMID- 25535140 TI - Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. AB - AIM: To investigate the mechanism of melatonin (MT) protection of adult rate myocardial ischemia-reperfusion injury and its influence on rat's hemodynamic recovery. MATERIALS AND METHODS: 48 rats were randomly divided into MT group (n=36) and the control group (n=12), MT group was divided into three sub-groups according to different dosages: Group I (n=12) was administered with 2.5 mg/kg MT; Group II (n=12) was administered with 5 mg/kg MT; Group III (n=12) was administered with 10 mg/kg MT. The electrocardiogram of four groups was observed with the left coronary artery blocked for 10min at first and then reperfused for 15min. Hemodynamic evolving was observed and changes in energy metabolism of rat myocardium were monitored. TUNEL and immunohistochemistry were applied to detect the cell apoptosis index, protein expression of Bcl-2 and Bax. RESULTS: LVDP (left ventricular developed pressure) and +/- dp/dt in MT group presented better recovery at various time points than the control group. Among them, Group III had the optimal recovery degree (p < 0.05). After MT administration, ATP content in myocardial cells in MT group was significantly higher than the control group. Compared with the control group, the concentration of mitochondrial MDA and Ca2+ in myocardial cells in MT group showed a downward trend. But its GSH concentration was significantly higher than the control group (p < 0.05). The improvement degree of ATP, MDA, GSH and Ca2+ concentration in Group II over performed Group I (p < 0.05). MT-intervened myocardial apoptosis index (AI) and Bax positive expression index declined while Bcl-2 positive expression index increased (p < 0.01). CONCLUSIONS: MT effectively inhibited myocardial apoptosis during the myocardial ischemia-reperfusion of rats, protected the structural integrity of mitochondria in myocardial cells, promoted ATP synthesis, and avoided heart damage in many ways. This protection mechanism was related with anti-oxidative damage. Meanwhile, MT could promote the hemodynamic recovery after myocardial ischemia-reperfusion in rats. PMID- 25535141 TI - Comparison of coronary artery flow impairment in diabetic and hypertensive patients with stable microvascular angina. AB - OBJECTIVE: Stable microvascular angina (SMVA) describes patients with angina, findings compatible with myocardial ischemia and normal coronary angiograms. The aim of this study was to evaluate the impact of diabetes on the coronary microcirculation troughs angiography indexes (TIMI Frame Count, Myocardial Blush Grade, Total Myocardial Blush Score) and a new index: Total TIMI Frame Count (TTFC). PATIENTS AND METHODS: The study population included 310 patients with SMVA that we split into two populations: diabetic-non hypertensive (164 patients) and non-diabetic-hypertensive (146 patients). We calculated, on angiographic images of each patient, TIMI Frame Count (TFC), Myocardial Blush Grade (MBG) and Total Myocardial Blush Score (TMBS) using the protocol described by Gibson and Yusuf. On the basis of Yusuf's experience we imagined a new index: TTFC like sum of the three coronary TFC. RESULTS: We found a worse coronary microcirculation in diabetic-non hypertensive patients with lower values of TFC, MBG and TMBS (p = 0.02), compared with non-diabetic hypertensive. New index TTFC is usually higher in diabetics-non hypertensive than non-diabetic hypertensive patients. Patients with positive scintigraphy had a worse TMBS than patients with a negative one, with a high statistical significance (p = 0.003). CONCLUSIONS: Analysis of diabetic non hypertensive and non-diabetic and hypertensive patients with cardiac syndrome X has led to asses that the diabetic population has a greater involvement of microcirculation. Also the new index, TTFC, proved to be a good marker, in agreement with results of other indexes. PMID- 25535143 TI - Beneficial therapeutic effects of hemoperfusion in the treatment of severe Stevens-Johnson syndrome/toxic epidermal necrolysis: preliminary results. AB - OBJECTIVE: Most of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug eruptions. There is currently no established treatment due to a lack of controlled/blinded studies. High-dose glucocorticoids and intravenous immunoglobulins (IVIG) therapy have been widely used, but these approaches remain controversial. This study introduces a novel method by which to treat severe SJS/TEN patients who were refractory to glucocorticoids and IVIG. PATIENTS AND METHODS: Seven patients with SJS and three patients with TEN were enrolled in this non-blinded, uncontrolled study. The average patient age was 8.1 years. The male to female ratio was 1:1. Hemoperfusion was conducted daily using a HA280 resin sorbent column until new skin lesions ceased appearing and the skin started healing with visible re-epithelialization. RESULTS: The average BSA involvement in SJS and TEN was 8.57% and 75%, respectively. The number of hemoperfusion sessions ranged from 3 to 5. Hemoperfusion led to prompt improvements in general health and halted the disease progression. All children were discharged and recovered completely. The average length of stay was 14.4 days. Four patients experienced adverse reactions: femoral vein thrombosis (N = 2), hypotension (N = 1), and cardiac palpitation (N = 1). CONCLUSIONS: Hemoperfusion may be a useful adjunct treatment for patients with severe SJS/TEN if the initial treatment with glucocorticoids and IVIG fails. PMID- 25535142 TI - Safety and efficacy of intracoronary tirofiban administration in patients with serious thrombus burden and ST-elevation myocardial infarction undergoing percutaneous coronary intervention. AB - OBJECTIVE: This work aims to explore the safety and efficacy of intracoronary tirofiban administration in patients with serious thrombus burden and ST elevation myocardial infarction (STEMI) undergoing emergency percutaneous coronary intervention (PCI). PATIENTS AND METHODS: A total of 104 patients with serious thrombus burden and acute STEMI were randomly divided into treatment (intracoronary tirofiban administration, 56 cases) and control (48 cases) groups. Comparison of coronary blood flow, ST-segment resolution (STR), duration of hospital stay, 30-day major adverse cardiac events (MACE) and complications such as hemorrhage was conducted. RESULTS: In treatment group, the percentage of thrombolysis in myocardial infarction-3 (TIMI-3) flow in the infarct-related artery (IRA) increased (89.3% to 85.4, p < 0.05), blood flow in the IRA calculated with TIMI frame count method enhanced [(1.68 +/- 0.23) ml/s to (1.42 +/- 0.31) ml/s, p < 0.05], STR on electrocardiogram (ECG) enlarged [(64.3 +/- 7.84)% to (48.6 +/- 6.47)%, p < 0.05)] and the prevalence of MACE decreased (10.7% to 18.8%, p < 0.05), all of which were significantly different from those of control group, but no statistical difference in complications was observed between two groups (p > 0.05). CONCLUSIONS: It was simple, safe and effective to perform intracoronary tirofiban administration in patients with serious thrombus burden and STEMI when undergoing emergency PCI. PMID- 25535144 TI - In vitro gene and chromosome characterization of expanded bone marrow mesenchymal stem cells for musculo-skeletal applications. AB - OBJECTIVE: A number of studies have shown the role of expanded Bone Marrow derived Mesenchymal Stem Cells in the repair and regeneration of musculo-skeletal tissues. The current European regulations define in vitro expanded cells for clinical purposes as substantially manipulated and include them in the class of Advanced-Therapy Medicinal Products to be manufactured in compliance with current Good Manufacturing Practice. Among the characteristics that such cells should display, genomic stability has recently become a major safety concern. The aim of this study is to perform a chromosomal and genetic characterization of Bone Marrow-derived Mesenchymal Stem Cells expanded in compliance with Good Manufacturing Practice for a potential clinical use in orthopaedics. MATERIALS AND METHODS: Mesenchymal Stem Cells, isolated from bone marrow, were expanded for six weeks in compliance with current Good Manufacturing Practice. DNA profiling analyses were applied to test cross-contamination absence. Genomic stability was evaluated by means of karyotyping, sequencing of TP53, p21/CDKN1A and MDM2 genes and the expression analysis of c-MYC and H-RAS oncogenes, p21/CDKN1A, TP53, p16/CDKN2A, RB1 and p27/CDKN1B tumor suppressor genes and hTERT gene. RESULTS: The DNA profiling analysis showed a unique genetic profile for each Mesenchymal Stem Cell culture, indicating the absence of cross-contamination. Karyotyping evidentiated some chromosomal abnormalities within the 10% limit set by the Cell Products Working Party review, except for one patient. In all cases, the molecular biology analyses did not revealed DNA point mutations, acquisition or changes in gene expression. hTERT levels were undetectable. CONCLUSIONS: Cultured Mesenchymal Stem Cells do not seem to be prone to malignant transformation. In fact, although some chromosomal aberrations were found, molecular biology analyses demonstrated that the expansion phase did not induce the acquisition of de novo genetic changes. PMID- 25535145 TI - Application of the perineal ostomy in severe organophosphate poisoned patients after catharsis. AB - OBJECTIVE: To investigate the efficacy of the one-piece ostomy bags for severe organophosphate poisoned patients after catharsis. PATIENTS AND METHODS: Sixty cases of severe organophosphate poisoned patients who were given rhubarb catharsis after thorough nasal lavage were divided into two groups. The observation group used the one-piece ostomy bags whilst the control group used the disposable changing mats. The perineal skin changes, average daily hours of care, and cost of care rates were compared between the two groups. RESULTS: The rates of perineal skin changes were lower in the observation group than the control group (p < 0.05). The average daily hours of nursing and the cost of care were lower in the observation group than in the control group (p < 0.05). CONCLUSIONS: The application of one-piece perineal paste ostomy bag in poisoned patients after the catharsis can prevent the risk of nursing by protecting and promoting the care quality, reducing the nursing workload and improving their work efficiency. It can enhance the nurses' self-esteem, reduce patients' expenses and provide an objective basis for assessing the treatments. PMID- 25535146 TI - alpha-Lipoic acid treatment of aged type 2 diabetes mellitus complicated with acute cerebral infarction. AB - OBJECTIVE: This study aims to evaluate the efficacy and safety of alpha-lipoic acid in the treatment of aged type 2 diabetes mellitus (T2DM) complicated with acute cerebral infarction. PATIENTS AND METHODS: 90 patients were randomly divided into two groups, on the basis of conventional treatment. The experiment group was administrated with alpha-lipoic acid, while only Vitamin C for the control group, for 3 consecutive weeks. Before and after the experiment, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels were measured and scored with the NIHSS (National Institutes of Health Stroke Scale), and the changes of blood glucose, insulin function and other indicators were observed. RESULTS: After the treatment, the plasma SOD and GSH-Px levels increased, while MDA decreased (p < 0.05), with statistical significance when compared with the control group (p < 0.01). NIHSS score, blood glucose, blood lipids and HOMA-IA of the experiment group decreased significantly (p < 0.01); and no significant adverse reactions were found in both groups. CONCLUSIONS: alpha-lipoic acid was safe and effective in the treatment of aged T2DM complicated with acute cerebral infarction, significantly reducing the patient's oxidative stress, blood glucose and lipid levels and being able to improve islet function. PMID- 25535147 TI - Effects of N-acetyl-cysteine and acetylsalicylic acid on the tonsil bacterial biofilm tissues by light and electron microscopy. AB - OBJECTIVE: The present study aimed to investigate the effects of the bacterial biofilm formation on the tonsil surface exposed N-acetyl-cysteine (NAC) and acetylsalicylic acid (ASA) of patients undergoing tonsillectomy by light and electron microscopy. The general process of biofilm formation comprises adhesion of free-living or planktonic bacteria to a surface, which subsequently develop into microcolonies and form a biofilm. Based on studies that have shown the presence of biofilms in common sites of chronic infections, it has become clear that bacteria may persist on mucosal surfaces through formation of biofilms. PATIENTS AND METHODS: Ten patients between 4 and 39 years of age (mean, 11.9 +/- 11.2 years). In all cases, periodic acide Schiff (PAS) staining was found to be an accurate predictor of the presence or absence of biofilm using light microscopy as a control standard. Therapeutic doses of NAC and ASA were identificated as the effective on the tonsil bacterial biofilm using light and electron microscopy. RESULTS: Biofilm formation was detected on all samples. Tonsils removed from patients with ASA-10 had showed higher-grade inhibitory effect at the biofilm formation than the other group (p <= 0.0001). The correlation was found between drug dose and decrease at the biofilm formation. CONCLUSIONS: In chronic or recurrent tonsillitis patients, decrease on the tonsils surface biofilm formation may be associated with ASA dose. Whether effect on the tonsils surface biofilm formation of other agent have a role is not known. Key Words: Acetylsalicylic acid, Chronic tonsillitis, In vitro, Mucosal biofilm, N-Acetyl-cysteine. PMID- 25535148 TI - Protective effects of ulinastatin on intestinal injury during the perioperative period of acute superior mesenteric artery ischemia. AB - OBJECTIVE: This work aims to explore the protective effects of ulinastatin on intestinal injury during the perioperative period of acute superior mesenteric artery ischemia (ASMAI). PATIENTS AND METHODS: 28 patients undergoing revascularization were divided into 2 groups, with 14 cases each. The cases in the observation group (OG) were treated with ulinastatin 300,000 U intravenously 30 min before the operation, and continuously treated with 300,000 U every 4 hr thereafter until 24 hr of the operation, while those in the control group (CG) were not given the intervention of ulinastatin. Patients' circular intestinal fatty acid binding protein (I-FABP) levels were measured at the following time points to reflect the intestinal injury: 30 min before the operation, before revascularization, then 1, 12 and 24 hr after the operation. The white blood cell counting (WBC), serum alanine aminotransferase (ALT), serum creatinine (Cr), D dimer, and serum endotoxin (ET) were also measured simultaneously for the analysis of the significance of their values with the intestinal injury. RESULTS: There were no significant differences (p > 0.05) in ischemia duration, length of the affected intestinal segments, WBC, ALT and Cr levels at the above time points between the 2 groups, and all the indicators of the 2 groups, including the mean circular I-FABP levels before the operation and the revascularization, showed no significant difference (p > 0.05). After the blood supply was restored, the I FABP levels in OG dropped significantly as compared with those in CG. The pattern of circular ET levels appeared the similar manner as the circular I-FABP levels did. CONCLUSIONS: Our study showed a protective effects of ulinastatin on intestinal injury during the perioperative period of ASMAI, as revealed by the circular I-FABP levels which mainly happened after the blood supply was restored. PMID- 25535149 TI - Iodine status in Danish pregnant and breastfeeding women including studies of some challenges in urinary iodine status evaluation. AB - Denmark was previously iodine deficient with regional differences. Moderate iodine deficiency appeared in West Denmark and mild iodine deficiency in East Denmark and also Danish pregnant and breastfeeding women suffered from iodine deficiency. The Danish mandatory iodine fortification of salt was introduced in the year 2000 and has increased iodine intake in the Danish population. However, median urinary iodine concentration in the general population and in pregnant and breastfeeding women is still below the level recommended, corresponding to mild iodine deficiency. Certain characteristics may challenge the evaluation of urinary iodine status in pregnancy and during breastfeeding. This review also addresses methodological challenges related to spot urine sampling conditions and the use of iodine supplement and discusses the use of non-pregnant population groups as a proxy for iodine intake in pregnant women. PMID- 25535151 TI - Pathological and molecular diagnosis of the 2013 African swine fever outbreak in Lusaka, Zambia. AB - African swine fever (ASF) is a highly contagious and fatal hemorrhagic viral disease of domestic pigs. The disease is widespread in sub-Saharan Africa and has repeatedly been introduced into other continents. The current study describes the diagnostic investigations of a hemorrhagic disease that was reported in pigs in Lusaka (October 2013), Zambia. Necropsy, histopathology, and molecular diagnosis using polymerase chain reaction and sequence analysis confirmed the disease to be ASF. The sequences obtained showed high similarity to previously isolated ASF viruses. Consistent surveillance and rapid diagnosis of the disease is recommended to prevent future outbreaks and economic losses as there is currently no vaccine against the disease. PMID- 25535150 TI - Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner. AB - Intracellular Vitamin C (VC) is maintained at high levels in the developing brain by the activity of sodium-dependent VC transporter 2 (Svct2), suggesting specific VC functions in brain development. A role of VC as a cofactor for Fe(II)-2 oxoglutarate-dependent dioxygenases has recently been suggested. We show that VC supplementation in neural stem cell cultures derived from embryonic midbrains greatly enhanced differentiation toward midbrain-type dopamine (mDA) neurons, the neuronal subtype associated with Parkinson's disease. VC induced gain of 5 hydroxymethylcytosine (5hmC) and loss of H3K27m3 in DA phenotype gene promoters, which are catalyzed by Tet1 and Jmjd3, respectively. Consequently, VC enhanced DA phenotype gene transcriptions in the progenitors by Nurr1, a transcription factor critical for mDA neuron development, to be more accessible to the gene promoters. Further mechanism studies including Tet1 and Jmjd3 knockdown/inhibition experiments revealed that both the 5hmC and H3K27m3 changes, specifically in the progenitor cells, are indispensible for the VC-mediated mDA neuron differentiation. We finally show that in Svct2 knockout mouse embryos, mDA neuron formation in the developing midbrain decreased along with the 5hmC/H3k27m3 changes. These findings together indicate an epigenetic role of VC in midbrain DA neuron development. PMID- 25535152 TI - Lifetime and per year productivity of sows in four pig farms in the tropics of Mexico. AB - The objectives of this study were to estimate the lifetime and per year productivity of sows and to determine the effect of some factor on those traits in four pig farms in the tropics of Mexico. Data from 7526 sows for lifetime number of piglets born alive per sow (LBA), lifetime kilograms of piglets at farrowing (LKF), number of piglets born alive per year (NPF/Y), and kilograms of piglets at farrowing per year (KPF/Y); and data from 7230 sows for lifetime number of piglets weaned (LPW), lifetime kilograms of piglets weaned (LKW), number of piglets weaned per year (NPW/Y), and kilograms of piglets weaned per year (KPW/Y) per sow were used. The statistical model for all traits included the fixed effects of farm, year of first farrowing, season of first farrowing, litter size at first farrowing, age at first farrowing, removal reason, simple interactions, and the error term. The means for LBA, LKF, NPF/Y, and KPF/Y were 45.1 piglets, 67.1 kg, 22.7 piglets, and 33.7 kg, respectively. The means for LPW, LKW, NPW/Y, and KPW/Y were 43.2 piglets, 251.9 kg, 21.5 piglets, and 125.1 kg, respectively. All factors were significant for all traits, except for age at first farrowing on LPW and LKW. Sows with large litter sizes and those that farrowed the first time, at an early age, had the highest lifetime and per year productivity. Therefore, more care and better management should be provided to those types of sows to improve the farms profit. PMID- 25535153 TI - The trajectory of hope: pathways to find meaning and reconstructing the self after a spinal cord injury. AB - STUDY DESIGN: This is a qualitative study. OBJECTIVES: To evaluate and track the importance and the continuum of hope, and its trajectory, from the point of view of the individual with a spinal cord injury (SCI) and a rehabilitation psychologist. SETTING: This study was conducted in the Indian Spinal Injuries Centre, New Delhi, India, and in patients' homes in the National Capital Region, India. METHODS: Twenty individuals with an SCI were interviewed for the study at intervals of 2 weeks, 6 months, 1 year and 2 years since the time of the injury. Semi-structured interviews were conducted, in which the following theoretical research questions were investigated: 'What is the meaning, relevance and significance of hope in the individual's life following an SCI? Does the meaning and subject of hope change at different points in time?' RESULTS: Three distinctive themes markedly emerged in the trajectory of hope: (1) Hope for a complete recovery; (2) hope for self-reliance despite the injury; and (3) hope for an optimum quality of life. The make-up of each theme, its significance and contribution to recovery and/or rehabilitation, while tracking the influence of time since injury, family and friends, as well as other agencies and pathways, are discussed. CONCLUSION: After sustaining a life-altering injury, hope becomes the force that spurs individuals. Psychologists and rehabilitation counselors need to focus on instilling realistic hope, goal setting, sustaining motivation, enabling adaptive appraisals and problem-solving. Further recommendations include developing and testing interventions against the context of the continuum of hope. PMID- 25535154 TI - Mechanisms inducing autonomic dysreflexia during urinary bladder distention in rats with spinal cord injury. AB - Objectives:This study investigated the mechanisms inducing autonomic dysreflexia due to enhanced bladder-to-vascular reflexes in rats with spinal cord injury (SCI).Methods:SCI was produced by the transection of the Th4-5 spinal cord in female Sprague-Dawley rats. At 4 weeks after SCI, changes in blood pressure during graded increases in intravesical pressure (20-60 cm H2O) were measured in spinal-intact (SI) and SCI rats under urethane anesthesia. In five animals, effects of C-fiber desensitization induced by intravesical application of resiniferatoxin (RTX), a TRPV1 agonist, on the bladder-to-vascular reflex were also examined. Nerve growth factor (NGF) levels of mucosa and detrusor muscle layers of the bladder were measured by enzyme-linked immunosorbent assay. The expression levels of TRPV1 and TRPA1 channels were also examined in laser captured bladder afferent neurons obtained from L6 DRG, which were labeled by DiI injected into the bladder wall.Results:In SI and SCI rats, systemic arterial blood pressure was increased in a pressure-dependent manner during increases in the intravesical pressure, with significantly higher blood pressure elevation at the intravesical pressure of 20 cm H2O in SCI rats vs SI rats. The arterial blood pressure responses to bladder distention were significantly reduced by RTX induced desensitization of C-fiber bladder afferent pathways. SCI rats had higher NGF protein levels in the bladder and higher TRPV1 and TRPA1 mRNA levels in bladder afferent neurons compared with SI rats.Conclusions:The bladder-to vascular reflex induced by TRPV1-expressing C-fiber afferents during bladder distention is enhanced after SCI in association with increased expression of NGF in the bladder and TRP channels in bladder afferent neurons.Spinal Cord advance online publication, 23 December 2014; doi:10.1038/sc.2014.233. PMID- 25535155 TI - How to grade level of evidence of physical interventions for people with spinal cord injury? PMID- 25535156 TI - Antegrade continence enema procedure: impact on quality of life in patients with spinal cord injury. AB - Study design:This is a prospective cohort study.Objectives:Patients with spinal cord injury (SCI) often suffer from severe constipation/fecal incontinence. The antegrade continence enema (ACE) procedure is often used to control these distressing symptoms when medical management fails. Improvement in the quality of life (QOL) following the ACE procedure has been demonstrated in patients with fecal incontinence of various etiologies. We assess the impact of the ACE procedure on QOL in patients with fecal incontinence due to SCI.Setting:This study was conducted in the United States.Methods:We measured the impact of fecal incontinence on QOL in patients with SCI undergoing ACE using the validated fecal incontinence quality of life (FIQL) QOL instrument. The FIQL scores QOL in four domains: lifestyle, coping/behavior, depression/self-perception and embarrassment. Surveys were prospectively administered before and after surgery. Preoperative and postoperative survey scores were compared using two-sample T test.Results:Between 2003 and 2010, the ACE procedure was performed on 17 patients with SCI, including 10 paraplegic and seven quadriplegic patients with an average age of 33 years at the time of surgery. Scores in all four QOL realms assessed by the FIQL instrument improved significantly following the ACE procedure. Stomal stenosis requiring channel revision occurred in three patients and was the most common complication.Conclusions:This is the first study to our knowledge that assesses the impact of the ACE procedure on the QOL in patients with SCI. Using a validated questionnaire, we demonstrated significant improvement in QOL related to fecal incontinence following the ACE procedure in these patients who are severely affected by their bowel dysfunction.Spinal Cord advance online publication, 23 December 2014; doi:10.1038/sc.2014.223. PMID- 25535157 TI - Long-term outcome of transanal irrigation for children with spina bifida. AB - Study design:Experimental, prospective study.Objectives:We evaluated the long term clinical efficacy of transanal irrigation (TAI) and its effect on the quality of life of spina bifida children and their caregivers.Setting:Republic of Korea.Method:Forty-four spina bifida pediatric patients with constipation, fecal incontinence or both, underwent a TAI program at our spina bifida clinic between December 2010 and October 2013. The children and their caregivers were evaluated using a self-administered questionnaire before TAI and at 3 months and 3 years after initiation of the program.Results:Successful treatment outcome was achieved in 38 (86.4%) children after a mean follow-up duration of 33 months (range, 30 36). The mean number of fecal incontinence episodes per week, the number of diaper changes and the total time for bowel care per day before the program decreased at the latest follow-up examination from 7.3 to 0.4 (P<0.001), 1.6 to 0.2 (P<0.001) and 29.2 to 19.4 min (P=0.038), respectively. These results remained constant from short-term follow-up at 3 months to 3 years. Caregivers and children could go out more often (P=0.002), and the emotional impact of bowel care on caregivers decreased (P<0.001). The reported mean overall satisfaction with TAI was 8/10. The common adverse effect during TAI was abdominal discomfort (60.5%).Conclusion:We observed a sustained significant improvement in defecation symptoms and quality of life for 3 years in spina bifida children who underwent continuous TAI.Spinal Cord advance online publication, 23 December 2014; doi:10.1038/sc.2014.234. PMID- 25535158 TI - [Nodular skin lesions revealing fusariosis in a severe aplastic anemia patient]. PMID- 25535159 TI - [Histaminergic angioedema and chronic urticaria]. AB - Most angioedemas are histaminergic and correspond to deep urticarial swelling. Recurrent histaminergic angioedema led to the diagnosis of chronic urticaria, even when there are no superficial associated hives. Chronic urticaria is a benign disease, and autoimmune in 40 % of cases. The occurrence of angioedema in chronic urticaria is not a sign of severity. The occurrence of angioedema in chronic urticaria is associated with a longer duration of urticarial disease. NSAIDs and/or systemic corticotherapy are classic triggers of angioedema in chronic urticaria. In the absence of clinical endpoints, there is no need to make further assessment in chronic urticaria good responders to antihistamines. PMID- 25535160 TI - [Electroencephalograph outcome and cerebral magnetic resonance imaging during a sporadic Creutzfeldt-Jakob's disease]. PMID- 25535161 TI - [Angioedema: differential diagnosis]. AB - Angioedema (AO) is a clinical syndrome defined by a local swelling of the deep dermis or subcutaneous/submucosal tissues. AO is of rapid installation, non pruritic, always circumscribed and transitory without any sequellae. A swelling not fulfilling these characteristics is not an AO. Characterization of the bradykinic or histaminic mechanism should not be started until it is firmly established that the patient has an AO. Among differential diagnosis of AO, two clinical situations can be particularly misleading: generalized edema with flare and remission or with a subjective or objective localized predominance; permanent localized edema but with fluctuation during time. Diagnosis of AO should be questioned if the evolution is unusual or if there is a resistance to the treatment. Hereditary AO are rare diseases whereas histaminic AO are much more frequent (beware of overdiagnosis of a rare disease). Even in patients with a known and real AO, a differential diagnosis should be evoked when a new clinical manifestation is atypical or is treatment resistant. PMID- 25535162 TI - [Foreign body granuloma: a diagnosis not to be forgotten]. PMID- 25535163 TI - [Evolution of Devic's neuromyelitis optica spectrum disorders]. AB - Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system affecting mostly the optic nerve and the spinal cord. These last few years have been characterized by a dramatic improvement of NMO knowledge and care. A unique feature of NMO is the presence of autoantibodies directed against aquaporin-4 (AQP4-Ab). Identification of this biomarker has enlarged the clinical spectrum of the disease to a broad variety of symptoms and syndromes including brain, brainstem and hypothalamus involvement. This modifies the acknowledged definition of NMO, switching from a clinical phenotype to a biological one and introducing the concept of "aquaporinopathy" or "autoimmune AQP4 channelopathy". AQP4-Ab plays an important role in NMO pathophysiology. In vitro and ex vivo experiments showed that AQP4-Ab can induce either direct astrocyte loss through complement activation (neuroinflammation) or astrocyte changes via internalization of AQP4 (neuromodulation). Recently, T cell involvement in NMO has been suggested. Based on relatively small retrospective and prospective case series, several treatments appear to be likely effective in preventing attacks and stabilizing disability in NMO patients. Relapse prevention in NMO is based on early and maintenance immunosuppressive treatments. Considering the antibody driven hypothesis, treatment should target B-cells. MS-approved therapies are not currently recommended for NMO patients, several series suggesting poor efficacy or harmful effects. Despite recent improvement of the detection method, some patients remain seronegative for AQP4-Ab. This group expresses specific demographic and disease-related features different for AQP4-Ab positive ones. This raises the question of the place of seronegative AQP4-Ab NMO patients in the spectrum, of their intimate physiopathology and finally of the therapeutic strategy to adopt in such patients. PMID- 25535164 TI - [Potentially inappropriate prescribing cardiovascular medications in the aged population: prospective study in a district hospital centre (France)]. AB - OBJECTIVES: Cardiovascular disease is a leading cause of morbidity and mortality in the elderly population. We evaluated the adequacy of prescribing (miss and under used) with respect to STOPP-START criteria. METHODS: A sample of 100 patients hospitalized in cardiovascular specialty divisions (medicine or surgery) or in the different sectors making up the geriatric network (day-care hospital, short or rehabilitation ward, nursing home) has been considered. Drug prescriptions at the admission time were analysed. RESULTS: Eight hundred and seventy-four prescriptions were analysed. In 65% of patients, from 5 to 10 medications were prescribed and in 28% over 10. Fifty-four percent of patients had, at least, one potentially inappropriate prescription (PIP) by STOPP. Among them, 48% of PIP prescriptions contained 1, 41% 2 and 11% 3 or more. The omission of one medication according to START criteria concerned 57% of the sample. Among them, 46% had one omission, 44% 2 to 3 and 10% 4 omissions or over. The cardiovascular system is the one most concerned by the PIP. Whether 28.1% of the PIP by STOPP criteria concerned cardiovascular drugs, the omission of prescription, according to START criteria, was 41.8%. There was no significant difference between the different settings studied. There was no effect of age or sex on the impact of PIP (P>0.20) or being polymedique (P=0.44). According to the criteria STOPP-A, the prescription of antiplatelet (indication and dose) was highlighted. Prescribing omission also concerned antiplatelet agents but also statins in patients with atherosclerosis as well as antiplatelet and anticoagulant in patients with permanent atrial fibrillation and inhibitor of angiotensin converting enzyme (ACE) after myocardial infarction or with chronic heart failure. CONCLUSION: Potentially inappropriate prescribing medications were very common in elderly patients with cardiovascular conditions. They concerned as much as underusing of important drugs with potential benefits and prescribing commission of treatment that did not fit with patients' comorbidities and/or characteristics. PMID- 25535165 TI - [Phytobezoar, an unusual cause of small bowel obstruction]. PMID- 25535166 TI - [Acquired angioedema]. AB - Acquired angioedema are rare. They are associated with monoclonal gammapathies of uncertain significance (MGUS) or lymphomas. They give the same symptoms as the hereditary form and the same laryngeal risk. They are characterized by a low level of C4, C1Inh and C1q. They are linked to the consumption of C1Inh by the lymphoid cells or to the presence of anti-C1Inh autoantibodies. They must be treated by symptomatic treatment when attack occur (C1Inh concentrate and icatibant). The use of rituximab needs to prove its efficiency. PMID- 25535167 TI - Emphysematous pancreatitis. A rare cause of fulminant multiorgan failure. PMID- 25535168 TI - [Medical therapies for locally advanced/metastatic kidney cancer]. AB - AIMS: To analyze the medical literature concerning the results of the international randomized muticentric trials concerning therapeutic innovations, mainly targeted therapies in locally advanced and or metastatic renal cell cancer and to evaluate the benefit of these TT. METHODS: We performed a review of publications that concerned this topic published from 2000 to 2014. RESULTS: They concerned the large randomized trials have showed a benefit of the targeted therapies in the treatment of clear cell carcinomas in terms of progression-free survival. CONCLUSION: Advances in molecular biology have allowed the development of these targeted therapies that have all proved their role in the treatment of metastatic renal cell carcinoma. PMID- 25535169 TI - Salvage procedures after restorative proctocolectomy: a systematic review and meta-analysis. PMID- 25535170 TI - Postoperative delirium in older adults: best practice statement from the American Geriatrics Society. PMID- 25535171 TI - Intussusception non-operative reduction outcome indices (response to "Sonography guided hydrostatic reduction of ileocolic intussusception in children: analysis of failure and success in consecutive patients presenting timely to the hospital"). PMID- 25535172 TI - Cushing syndrome after bilateral lensectomy. AB - Iatrogenic Cushing syndrome induced by oral and parenteral corticosteroid administration is a well-known complication, and necessary precautions have to be taken. Cushing syndrome, however, following treatment with glucocorticoid containing eye drops is a very rare complication. To the best of our knowledge, there have been only four reported cases in the literature. Herein, we present an infant boy who developed Cushing syndrome after receiving dexamethasone containing eye drops after bilateral cataract extraction to prevent postoperative inflammatory complications. At the age of 5 months, after approx. 3 months of dexamethasone therapy, the patient presented with cushingoid facies, nephrocalcinosis and failure to grow. Iatrogenic Cushing syndrome was diagnosed and dexamethasone-containing eye drops were reduced and eventually stopped. Follow-up examinations revealed catch-up growth. CONCLUSION: Ocularly administered corticosteroids may have substantial systemic side effects in infants. PMID- 25535173 TI - Understanding the impact of statural height on health-related quality of life in German adolescents: a population-based analysis. AB - Improving health-related quality of life (HrQoL) is one aim of growth hormone treatment for short-statured patients. Yet, evidence of the relationship between height and HrQoL is inconclusive, especially for young people. This study investigates the association of height and HrQoL in the general German adolescent population. A total of 6646 adolescents and 6388 parents from the German Health Interview and Examination Survey for Children and Adolescents (KIGGS) were included in the analysis. An analysis of covariance was used to evaluate the effect of height deviation on HrQoL as assessed with the KINDL-R in adolescent self-report and parent-report, taking into account sociodemographic and health related variables. Height was found to be a weak predictor of HrQoL in both adolescent-report and parent-report. Short and tall adolescents did not substantially differ from the normal statured. Sociodemographic and health related variables failed to significantly interact with height. In contrast, psychosocial variables contributed to the explained HrQoL variance. CONCLUSION: Height does not appear to be a strong determinant of HrQoL on the population level. These results suggest that the height gain in short stature treatment may not be the most important objective. Contrary to prevalent stereotypes, short adolescents can experience a high HrQoL. PMID- 25535175 TI - Stent distortion after sutureless aortic valve implantation: a new complication seen with a novel surgical technique. AB - In recent years, sutureless aortic valves have grown in popularity. As these valves do not need to be anchored with sutures, shorter cardiac ischaemia and extracorporeal circulation times can potentially be achieved. In addition, the absence of a sewing ring in these valves results in a greater effective orifice area for any given size. Postoperative outcome may be improved using sutureless valves especially when combined with minimally invasive surgical techniques. However, sutureless aortic valves present unique surgical risks. We report 2 cases of delayed distortion of a sutureless aortic valve stent resulting in paravalvular leakage and increased transvalvular gradients. One patient underwent a reoperation with an aortic valve replacement using a standard biological aortic valve, the other patient was treated with balloon dilatation of the aortic valve stent. PMID- 25535176 TI - Inverted-Takotsubo cardiomyopathy: severe refractory heart failure in poly-trauma patients saved by emergency extracorporeal life support. AB - OBJECTIVES: The sequelae of severe poly-trauma may include myocardial dysfunction followed by acute heart failure and death. Inverted-Takotsubo cardiomyopathy (ITC) is a variant of stress cardiomyopathy, characterized by a contractile abnormality with extensive left ventricular circumferential dyskinesia or akinesia with a hyperkinetic apex. We report our experience with refractory cardiogenic shock and/or cardiac arrest, treated with extracorporeal life support. METHODS: From June 2008 to December 2011, we treated 4 adult poly-trauma patients (3 men, 1 woman, mean age: 27.7 +/- 13.5 years, mean ISS score 53.2 +/- 15.9) with veno-arterial (V-A) extracorporeal life support for cardiopulmonary failure/cardiac arrest refractory to conventional treatment, due to inverted Takotsubo cardiomyopathy. We used a miniaturized extracorporeal life support (ECLS) device. RESULTS: ITC myocardial dysfunction appeared 15.4 +/- 11.6 h after intensive care unit admission and rapidly evolved to refractory cardiopulmonary failure and cardiac arrest (within 4.8 +/- 2.5 h of the onset). At ECLS, initiation median pH was 7.12 +/- 0.14 (6.91-7.25), median lactate was 6.7 +/- 2.8 (4-10) mmol/l and median vasoactive-inotropic score was 192.1 +/- 50.6 ug/kg/min. Tissue perfusion improved significantly within 4 h on ECLS. Cardiac function improved gradually but consistently. Initial median ejection fraction was 14.2 +/- 4.7% and median global longitudinal strain test was -7.4 +/- 4.7. At complete cardiac recovery, they were 62.73 +/- 7.8 and -18.43 +/- 2.4%, respectively. After that, 2 patients survived and were sent to neurological rehabilitation before hospital discharge. In the other 2 cases, post-traumatic cerebral death occurred and they underwent organ explantation. CONCLUSIONS: Rapid heparin-free ECLS may improve outcome in the most severe cases of poly traumatized patients demonstrating refractory inverted-Takotsubo cardiomyopathy. PMID- 25535174 TI - Neurotrophin blood-based gene expression and social cognition analysis in patients with autism spectrum disorder. AB - Autism spectrum disorders (ASD) comprise neurodevelopmental disorders with clinical onset during the first years of life. The identification of peripheral biomarkers could significantly impact diagnosis and an individualized, early treatment. Although the aetiology of ASD remains poorly understood, there is increasing evidence that neurotrophins and their receptors represent a group of candidate genes for ASD pathophysiology and biomarker research. Total messenger RNA (mRNA) from whole blood was obtained from adolescents and adults diagnosed as ASD (n = 21) according to DSM-IV criteria and confirmed by the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) algorithms, as well as healthy controls (n = 10). The mRNA expression of neurotrophins (BDNF, NT3 and NT4) and their receptors (TrkA, TrkB and p75 (NTR) ) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, social cognition abilities of ASD patients and controls were determined according to three Theory of Mind (ToM) tests (Reading the Mind in the Eyes, Faux pas, and Happe stories). The NT3 and NT4 mRNA expression in the whole blood was significantly lower in ASD compared to healthy controls, while p75(NTR) was higher (P < 0.005). In addition, lower scores in three of the ToM tests were observed in ASD subjects compared to controls. A significant (P < 0.005) ToM impairment in Happe stories test was demonstrated in ASD. Nevertheless, no correlations were observed between neurotrophins and their receptors expressions and measures of ToM. Given their potential as peripheral blood-based biomarkers, NT3, NT4 and p75 (NTR) mRNA expression patterns may be useful tools for a more personalized diagnostics and therapy in ASD. Further investigations with larger numbers of samples are needed to verify these results. PMID- 25535177 TI - Preoperative renal function and surgical outcomes in patients with acute type A aortic dissection?. AB - OBJECTIVES: There are few data concerning the impact of preoperative renal function, assessed using estimated glomerular filtration rate, on surgical outcomes following acute type A aortic dissection. We investigated the accuracy of estimated glomerular filtration rate (in ml/min/1.73 m(2)) in predicting in hospital mortality and postoperative renal replacement therapy in such cases. METHODS: We reviewed 114 consecutive patients with non-dialysis-dependent renal dysfunction who underwent thoracic aortic surgery for acute type A aortic dissection between 1997 and 2012. Preoperative renal function was categorized as normal (estimated glomerular filtration rate >90; n = 15) or as mild (60-89; n = 39), moderate I (45-59; n = 39), moderate II (30-44; n = 14) or severe (15-29; n = 7) renal dysfunction. RESULTS: In-hospital mortality was 14.9%. Eighteen (15.8%) of 114 patients required renal replacement therapy. A more severe stage stratified by preoperative estimated glomerular filtration rate levels could effectively predict postoperative renal replacement therapy (area under the receiver operating characteristic curve 0.786). The best cut-off value of estimated glomerular filtration rate for predicting postoperative renal replacement therapy was 60 (sensitivity 95%, specificity 59%). On multiple regression analysis, the independent preoperative and intraoperative risk factors for postoperative renal replacement therapy were estimated glomerular filtration rate (P < 0.0001), coronary ischaemic time (P < 0.01) and total arch replacement (P < 0.01). Cardiopulmonary bypass time was the sole independent risk factor for in-hospital mortality (P < 0.001). On the other hand, among the morbidities, stroke [odds ratio (OR), 8.68; P < 0.01] and postoperative renal replacement therapy (OR, 5.47; P < 0.01) were independent risk factors of in-hospital mortality, according to multiple logistic regression analysis. CONCLUSIONS: Preoperative estimated glomerular filtration rate can effectively predict the need for renal replacement therapy after surgery for acute type A aortic dissection. However, it is not an effective diagnostic tool to predict in hospital mortality. The complexity of the characteristics of patients who undergo surgical procedures may make prediction of surgical outcomes difficult. Risk models to predict hospital mortality and morbidities are needed to assist clinicians in determining the optimal treatment. PMID- 25535178 TI - Should we consider beating-heart on-pump coronary artery bypass grafting over conventional cardioplegic arrest to improve postoperative outcomes in selected patients? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether beating-heart on-pump coronary artery bypass grafting (BH-ONCAB) offered superior mortality and morbidity outcomes when compared with conventional on-pump coronary artery bypass grafting (C-ONCAB). Morbidity outcomes consisted of renal failure, stroke (transient or permanent), myocardial infarction, angina, congestive cardiac failure, reintervention and arrhythmias. Best evidence papers investigating BH-ONCAB versus C-ONCAB were considered. Where data were duplicated, the more credible evidence-based and recently published study was included. Two hundred and thirty one papers were found using the reported search, of which 11 represented the best evidence to answer the clinical question. Two were prospective randomized controlled trials and the remaining 10 observational studies, of which one was propensity-matched. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Five of these studies demonstrated significantly improved mortality following BH-ONCAB; however, one study exhibited better survival after C-ONCAB. Notably, this study incorporated BH-ONCAB patients with significantly more haemodynamic instability, thus possibly explaining the worse mortality outcomes. In terms of morbidity, a slightly more mixed picture is drawn. Five studies report morbidity in favour of BH-ONCAB, whereas three studies include individual outcomes favouring C-ONCAB. The remaining studies showed equivalent mortality and morbidity data. In summary, the results presented here suggest that BH-ONCAB may improve survival following coronary artery bypass surgery. A key observation is that the greatest benefits of BH-ONCAB appear to be in studies including patients with considerably higher risk characteristics at the time of surgery (haemodialysis, end-stage coronary artery disease, emergency surgery, low ejection fraction). There are limitations of the current evidence presented. Only two studies were randomized controlled trials. There was variability in sample size, selection criteria and preoperative risk profiles between the studies. The studies span many years, and the outcomes may have been affected by evolving technologies and differing patient profiles between these periods. PMID- 25535179 TI - Surgical repair of Shone's complex with anomalous origin of the left coronary artery arising from the right pulmonary artery. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly. ALCAPA from the right pulmonary artery (RPA) is a small subset of this anomaly, with only a few reported cases to date. We describe an extremely uncommon association of Shone's complex with ALCAPA from the RPA in a case where simultaneous surgery for both anomalies was successfully carried out in a neonate. PMID- 25535180 TI - Mediastinoscopy-assisted oesophagectomy in T1 oesophageal cancer patients with serious comorbidities: a 5-year long-term follow-up. AB - OBJECTIVES: Transthoracic oesophagectomy is associated with high morbidity and mortality. Some oesophageal cancer (OC) patients with serious comorbidities cannot tolerate transthoracic oesophagectomy. Therefore, we have adopted a minimally invasive approach to oesophagectomy for such patients. METHODS: Eighty five OC patients, who could not tolerate transthoracic oesophagectomy, received mediastinoscopy-assisted oesophagectomy (MAO) from January 2007 to January 2010 in our hospital. Seventy patients were confirmed to be in T1 stage by postoperative pathological diagnosis, and their complications and outcomes were retrospectively analysed in this study. The impact of invasion depth, tumour length and lymph node metastases on the 5-year survival rate of these patients was also analysed. RESULTS: The operation time was 150.0 +/- 15.0 min, and the perioperative bleeding volume was 202.0 +/- 12.8 ml. Some patients had anastomotic leakage (5 cases), pneumonia (4 cases) and chylothorax (1 case). No patient died during hospitalization. The median postoperative hospital stay was 10 (7-22) days. The number of lymph nodes resected was 13.8 +/- 4.4. The overall 5-year survival rate was 71%. Kaplan-Meier estimates revealed that tumour length (<2 vs >= 2 cm), lymph node metastasis (N0 vs N1) and depth of invasion (T1a vs T1b) could influence the 5-year survival rate (P <0.05). Multivariate analysis by Cox regression showed that lymph node metastasis and tumour length were independent prognostic factors for the 5-year survival rate (P <0.05). CONCLUSIONS: MAO could be performed for T1 OC patients with serious comorbidities who cannot tolerate transthoracic oesophagectomy. Lymph node metastasis and tumour length were independent prognostic factors for these patients. PMID- 25535182 TI - Liver biliopancreatic workshop surgery. PMID- 25535181 TI - Endotoxin deposits on the inner surfaces of closed-face cassettes during bioaerosol sampling: a field investigation at composting facilities. AB - A set of 270 bioaerosol samples was taken from 15 composting facilities using polystyrene closed-face filter cassettes (CFCs). The objective was to measure the quantity of endotoxin deposits on the inner surfaces of the cassettes (sometimes referred to as 'wall deposits'). The results show that endotoxins are deposited on the inner surfaces of the CFCs through sampling and/or handling of samples. The quantity of endotoxins measured on inner surfaces range between 0.05 (the limit of detection of the method) and 3100 endotoxin units per cassette. The deposits can represent a large and variable percentage of the endotoxins sampled. More than a third of the samples presented a percentage of inner surface deposits >40% of the total quantity of endotoxins collected (filter + inner surfaces). Omitting these inner surface deposits in the analytical process lead to measurement errors relative to sampling all particles entering the CFC sampler, corresponding to a developing consensus on matching the inhalable particulate sampling convention. The result would be underestimated exposures and could affect the decision as to whether or not a result is acceptable in comparison to airborne concentration limits defined in terms of the inhalability convention. The results of this study suggest including the endotoxins deposited on the inner surfaces of CFCs during analysis. Further researches are necessary to investigate endotoxin deposits on the inner cassette surfaces in other working sectors. PMID- 25535183 TI - The Aquamantys(r) system as alternative for parenchymal division and hemostasis in liver resection for hepatocellular carcinoma: a preliminary study. AB - OBJECTIVE: To evaluate the clinical feasibility and safety of a new technique for liver resection using a new saline-coupled bipolar sealing device (Aquamantys(r)) that has shown high performance in the animal setting. PATIENTS AND METHODS: Twelve Child-Pugh A cirrhotic patients with hepatocellular carcinoma underwent partial hepatectomies using Aquamantys(r). Our primary end-point was to observe occurrence of early specific surgical complications as bleeding, biliary leakage and abscess development. Our secondary end-point was to evaluate local recurrence along resection margin after a minimum follow-up of 1 year. RESULTS: One bisegmentectomy, five monosegmentectomies and six atypical resections were performed. Mean resection time was 45 minutes (range, 30-100 min). Mean blood loss was 20 mL (range 5-80 mL). Mean post-operative stay was 6 days (range 5-16 days). All specimens presented negative margins (R0) at pathological examination. No blood transfusion were required both intra-operatively and post-operatively. No mortality was observed within 30-days post-operatively. One fluid collection occurred after 6-7 bisegmentectomy and was successfully treated by ultrasound guided percutaneous drainage. At 1 year follow-up two patients died: one because of new lesions into the liver and one because of distant metastases and multifocal new liver disease. Ten patient are alive disease free at 1 year follow up. CONCLUSIONS: Liver resection using Aquamantys(r) is feasible and safe and allows to achieve almost bloodless parenchymal division with minimal necrosis and negative margins even in atipycal resection. Comparative trials are needed to confirm our preliminary results. PMID- 25535184 TI - Combined microwave thermal ablation and liver resection for single step treatment of otherwise unresectable colorectal liver metastases; a monoistitutional experiences. AB - OBJECTIVE: Over half of colorectal cancer patients will develop liver metastases. BACKGROUND: Thermal ablation with or without associated liver resection for colorectal hepatic metastasis has been suggested as an alternative method to improve survival if radical surgical resection is not achievable. A retrospective case series of patients treated with microwave ablation(MWA) associated with hepatic resection in one step procedure, was reviewed to analyze the clinical outcome. MATERIALS AND METHODS: In a group of 40 patients surgically cured for liver tumors in our Department, 5 patients with technically unresectable disease underwent combined treatment LR-MWA. RESULTS: Four patients were treated with multiple segmentectomies and MWA and one patient received a left lobectomy (S2 S3) and MWA. Only 1 patient (20%) developed post surgical complication which was a liver abscess (grade II of Dindo classification). CONCLUSIONS: Hepatic resection combined with MWA expanded indications for operative treatment of multiple bilobar liver metastasis. This procedure promise to have good long-term outcomes. PMID- 25535185 TI - Cirrhotic patients are still at risk of developing hepatocellular carcinoma despite Interferon-induced sustained virological response. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a common cause of chronic liver disease and hepatocellular carcinoma (HCC). The prevalence of HCC significantly declines among patients achieving a sustained virological response (SVR) after antiviral therapy with pegylated(PEG)-interferon (IFN) and ribavirin. However, up to 5% of patients with SVR may develop HCC. PATIENTS AND METHODS: We investigated the epidemiological, clinical, biochemical and virological characteristics of a small cohort of patients with chronic hepatitis C (CHC) who developed HCC after being successfully treated with PEG-IFN-alpha and ribavirin. RESULTS: Between September 2000 and January 2003, 598 patients with CHC underwent a complete course of treatment with PEG-IFN-alpha and ribavirin; 221 out of 598 (37%) patients obtained a SVR. Throughout the 10-year post-treatment follow up, 13 of 221 ( 5.8% ) SVR patients developed HCC. All 13 patients were male and were affected with Child A liver cirrhosis; in addition, at baseline they were significantly older (p < 0.05) and had higher alpha-fetoprotein levels (p < 0.05) in comparison with those who did not develop HCC. Nine patients (69.3%) developed HCC within the first 3 years after antiviral treatment completion, one patient (7.7%) between 3 and 5 years and 3 subjects (23%) between 5 and 10 years; 12 of 13 had a solitary lesion with a mean diameter of 2.5+/- 0.5 cm. Eleven cases (84.6%) underwent surgical resection, one (7.7%) received liver transplantation, one (7.7%) received palliative care. CONCLUSIONS: The risk of developing HCC after achieving SVR persists in patients with HCV-related cirrhosis. As a consequence, these patients should continue to undergo long-term surveillance for HCC, in order to early detect and treat it. PMID- 25535186 TI - Cystic pancreatic tumors: should we resect all of them? AB - OBJECTIVE: Pancreatic cystic tumors are relatively rare tumors and only 1% of them are malignant. They are often asymptomatic and detected as incidental findings through diagnostic imaging. Currently there are no universal guide lines for the correct clinical approach to pancreatic cystic lesions. Cross-sectional imaging demonstrates some typical morphological features that determine the pre operative diagnosis of the pancreatic cystic lesions (serous or mucinous cystadenoma, intraductal papillary mucinous neoplasms). In addition, endoscopic ultrasonography permits the collection and analysis of the fluid content. The aim of this paper is to describe our case load in the management of pancreatic cystic neoplasms and propose some criteria for choosing between surgical or conservative approaches. PATIENTS AND METHODS: 12 patients with pancreatic cystic neoplasms were retrospectively evaluated. They were studied using cross-sectional imaging modalities (computed tomography and magnetic resonance); endoscopic ultrasonography was performed in 7 patients. RESULTS: In each patient a careful evaluation of several factors (age, comorbidity, imaging features, symptoms, life expectancy) conditioned our clinical decision. Among our 12 patients, surgical resection was performed in 7 cases. DISCUSSION: The treatment of pancreatic cystic lesions is still a dilemma because even in the presence of malignant potential, pancreatic surgery remains very complicated and demolitive. Many factors need to be considered in the management of cystic pancreatic tumors. The most important include histological type, location, size, age and clinical condition of the patient. CONCLUSIONS: A correct multidisciplinary pre-operative diagnosis is mandatory. Surgery should only be performed in selected cases. PMID- 25535187 TI - Laparoscopic treatment of intrasplenic pancreatic pseudocyst. AB - INTRODUCTION: Pseudocyst formation commonly follows pancreatitis, but erosion into the spleen is rare and potentially life threatening. We report a case of an intrasplenic pancreatic pseudocyst treated laparoscopically with distal pancreatectomy and splenectomy. METHODS: A 50 year old male with a history of chronic alcoholic pancreatitis, presented with abdominal pain for 3 months, worsening over the past several days. A CT scan showed a broad 9 cm subcapsular fluid collection suspicious for an intra-splenic pseudocyst. The patient underwent laparoscopic distal pancreatectomy and splenectomy. RESULTS: There were no intraoperative complications and the patient was discharged on day 8. The final pathology revealed a benign cystic lesion measuring 9 x 6 x 3 cm that was not communicating with the pancreatic duct, and 2 smaller pseudocysts in the pancreatic body and tail. A previous scan did not reveal any abnormalities in the spleen, and showed the other pancreatic pseudocysts. At 8 month follow up the patients was symptom free, with no new pseudocysts. CONCLUSIONS: Splenic parenchyma involvement is an unusual complication of pancreatic pseudocyst. The optimal treatment is controversial. Percutaneous drainage carries a high recurrence rate and risk of hemorrhage. Open surgery is effective, but associated with significant morbidity. Laparoscopy offers an effective method of treatment without the potential complication of a large abdominal incision. PMID- 25535188 TI - Synchronous double cancers of the colon and the pancreas: a case report. AB - The authors report a clinical case of a synchronous double cancer of the colon and pancreas. Having carefully examined the scarce literature, they dwell on the incidence of this disease referring to frequencies that in the literature range from 0.06% and 0.55% while considering that some series do not show any association between the two neoplasms. The authors analyze the role of the colorectal follow-up. In fact, such a follow-up, even if only providing a relative improvement in disease-free survival, has allowed for a treatment of the two certainly not-advanced tumors ensuring the patient a good prognosis. Finally, the authors analyze how endoscopic ultrasound-guided fine-needle aspiration made possible a preoperative diagnosis of small pancreatic cancer, and show that, the positive predictive value (PPV) of this method was 100%. PMID- 25535189 TI - Surgical resection for neuroendocrine tumors of the pancreas: a fourteen years single institutional observation. AB - OBJECTIVE: Pancreatic neuroendocrine tumors (PNETs) are a rare entity that can present with symptoms of hormone overproduction with surgical resection being the only chance for cure despite the poorly defined tumor behavior. Their management involves a variety of therapies which require a well coordinated multidisciplinary team with the effort to optimize outcomes. PATIENTS AND METHODS: A retrospective analysis of 25 consecutive patients was performed by means of our single institution prospectively maintained database. All patients' files from 1999 to 2013, with histologically proven neuroendocrine tumors of the pancreas, were reviewed for clinical presentation, functional status, treatment, postoperative morbidity and mortality. RESULTS: Of 25 patients a total of 22 patients (11 females, 11 males, average age 49.7 years) underwent surgery with curative intent. We had 3 female patients that underwent palliative surgery because of unresectable disease. Nineteen of the 25 were not functional tumor. For the resected patients the overall morbidity was 38.8%. The 30-day mortality rate was zero. The overall median length of hospital stay was 10.4 days (range 4 23 days). CONCLUSIONS: Surgical resection with regional lymph node dissection is the only potentially curative therapy for patients with localized PNETs with the exceptions of most insulinomas where simple enucleation may be the standard of treatment. The anatomic considerations for determining the resecability are the same as those for pancreatic adenocarcinomas. Careful follow-up after surgery is essential because up to 50% of patients who undergo complete resection develop metachronous liver metastasis. Distant metastatic disease should be resected if possible. PMID- 25535190 TI - Treatment of the pancreatic stump after DCP. AB - OBJECTIVE: With improvement in methods, mortality after duodeno-cefalo pancreatectomy (DCP) has decreased to 5% even if complication rate is still high (30-50%). The pancreatic fistula still occurs in 25-50% of cases. Various methods of treating pancreatic stump have been proposed aimed to improve this rate. PATIENTS AND METHODS: The AA, surgeons of suburban hospital, have performed in five years, 2009-2013, 12 DCP. The pancreatic anastomosis has been in all cases an end-to-end duct-to-mucosa pancreatic-jejunostomy. RESULTS: The prevalence of fistula has been 33% (4 cases, 3 grade A and 1 grade B according with ISGPF score). CONCLUSIONS: Soft pancreas and small size of pancreatic duct are recognized as the mayor factor of risk for pancreatic fistula. In these cases are usually preferred pancreatic-jejunostomy (PJ) and pancreatic-gastro-anastomosis (PG). Both techniques show advantages and disadvantages: some randomized and prospective studies have demonstrated the absence of significative differences respect to the prevalence of pancreatic fistulas. Whipple method has been the most often used reconstructive method: a single loop with bile-pancreatic anastomosis and gastro-pancreatic anastomosis in sequence. A careful evaluation of pancretic tissue and Wirsung size with the aim of choosing the most suitable technique and an accurate execution are the most effective methods to prevent pancreatic fistula,even considering particular setting as elderly patient or HIV infection. PMID- 25535191 TI - Laparoscopic cholecystectomy in the treatment of acute cholecystitis: comparison of outcomes and costs between early and delayed cholecystectomy. AB - BACKGROUND: Several trials showed that early laparoscopic cholecystectomy is superior to delayed laparoscopic cholecystectomy for the treatment of acute cholecystitis. However actual practice does not conform to current evidence. The aim of this study is to compare outcomes and total hospital costs between early and delayed laparoscopic cholecystectomy for acute cholecystitis. PATIENTS AND METHODS: A retrospective analysis of patients with acute cholecystitis that underwent a laparoscopic cholecystectomy at our institutions was performed. Patients were divided into 2 groups on the basis of the treatment received and statistical analysis was performed. RESULTS: The study included 91 patients, 52 female and 39 male, with a mean age of 55. Early surgery was performed in 32 cases and delayed surgery in 59 cases. The two groups were comparable for demographics data and severity of disease on admission. There was a no significant difference (p = 0.174) in the mean operative time between early (54.8 min) and delayed group (47.8 min). Conversion rate was higher in the early group (34.3% vs. 20.3%), but difference was not statistically significant (p = 0.223). The overall complications rate was comparable (18.7% early vs. 16.9% delayed, p = 0.941). Length of postoperative stay (4.3 vs. 3.8 days) was similar (p = 0.437), but total hospital stay was significantly 4 days shorter in the early group (p < 0.0001). The mean total cost was higher for the delayed group (4171 vs. 6041), with a significant difference of 1870 Euro (p < 0.0001). CONCLUSIONS: Early laparoscopic cholecystectomy has an outcome comparable to the delayed procedure, with a shorter total hospital stay and lower total costs, and it should be considered as the preferred approach in treatment of acute cholecystitis. PMID- 25535192 TI - Lymph node evaluation in gallbladder cancer: which role in the prognostic and therapeutic aspects. Update of the literature. AB - OBJECTIVE: The widespread use of laparoscopy has changed the outcome of gallbladder cancer as a consequence of increasing referral and incidental discovering of earlier stages cancer. Nevertheless, GBC is still associated with a poor prognosis and lymphnodal involvement is a main prognostic factor, important both for staging and for evaluating surgery quality. No consensus exists about the extension of lymphadenectomy to be performed nor about contraindications to extensive resection. A review of literature was so designed to identify the actual role, extension and limits of lymphadenectomy. MATERIALS AND METHODS: A search on Pubmed and Scopus has been performed using the following keywords: gallbladder cancer, gallbladder neoplasm, surgery, laparoscopy, lymphadenectomy to evaluate the prognostic and the therapeutic role of the lymphadenectomy in gallbladder cancer. The retrieved articles were analyzed aimed to evaluate the impact of lymphectomy and of its extension on overall and disease free survival. RESULTS: Although no consensus still exists over the extension of ideal lymphadenectomy, some points are already clearly established: a part from T1a neoplasms, that do not require further surgery, and T1b for which a regional lymphectomy (N1) is safe and mandatory, more advanced stages require a more aggressive surgery but the fate of paraortic nodal station is still under evaluation. In fact some Authors still believe that the involvement of these nodes determine a so poor prognosis to make uselessly risky their surgical aggression. Other Authors conversely, show that there is not any difference in survival, among node positive patients, between paraortic node positive and no paraortic node positive patients. CONCLUSIONS: The prognosis of gallbladder cancer remains poor because in most patients the diagnosis is made at an advanced stage. Complete surgical resection provides the only curative treatment option in this disease. In order to improve long-term outcome, several surgeons have advocated aggressive surgical resection, including major hepatectomy, pancreatoduodenectomy and extended lymphadenectomy. Even a para-aortic nodal disease shouldn't discourage from pursuing this objective. PMID- 25535193 TI - Laparoscopic cholecystectomy: ultrasonic energy versus monopolar electrosurgical energy. AB - OBJECTIVE: Nowadays, laparoscopic cholecystectomy (LC) is undoubtedly considered the "gold standard" in the surgical treatment of symptomatic gallstones, gallbladder adenomas and acute cholecystitis. Among the alternative energy sources proposed (monopolar, bipolar electric scalpel, radiofrequency sealers) with the aim to dissect and/or seal, the ultrasonic energy has been frequently adopted, however without a widespread acceptance among surgeons for routine or emergency laparoscopic cholecystectomy. This study investigates the possible beneficial aspects of ultrasonic dissection and its efficacy in the closure of the cystic artery and duct. PATIENTS AND METHODS: Patients were retrospectively divided into 2 groups according to the instruments used for division of the cystic artery and duct as well as for dissection of the liver bed: 121 patients in whom dissection and coagulation were performed using monopolar coagulation and 43 patients who were all treated with the ultrasonically activated scalpel harmonic ACE (Ethicon Endo-Surgery) as the sole instrument used in the whole procedure. RESULTS: The mean operative time, was significantly shorter in the harmonic group than in the traditional group (35.36 + 10.15 min vs. 55.6+12.10 vs. respectively; p < 0.0001). The rate of gallbladder perforation was significantly higher in the traditional group than in the harmonic group 20.66% (25 patients) vs. 6.98% (3 patients), respectively; p < 0.05). Intraoperative volume blood loss was significantly more in the traditional group than in the HS group (29.32+14.21 vs. 12.41+8.22; p < 0.0001). The mean amount of postoperative drainage was not significantly different among the two group (18.41+6.54 vs. 15.96+8.69 ml, p > 0.05). No considerable visceral injury has been recorded in either group. The postoperative parameters observed included postoperative hospital stay and morbidity for each group. The hospital stay was not significantly shorter in harmonic group (48.15+4.29 vs. 49.06+2.94 h, p > 0.05). The overall morbidity rate was 14.02 % (not significant). CONCLUSIONS: The use of the harmonic scalpel shows some statistically significant advantages limited to a few intraoperative parameters. We conclude that a wider use of harmonic scalpel not offers such advantages to make it the reference technique. PMID- 25535194 TI - Preoperative risk factors for conversion from laparoscopic to open cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy has become the standard treatment for symptomatic gallstones. However, a conversion to open surgery is sometimes still required to complete the procedure safely. The aim of this study is to identify the predictive factors of conversion from laparoscopic to open cholecystectomy in both elective and emergency cases. PATIENTS AND METHODS: A retrospective review of all patients underwent laparoscopic cholecystectomy for symptomatic gallstones from January 2011 to October 2013 was performed. Data considered for analysis were: demographic data, comorbidities, preoperative laboratory values, preoperative ERCP, indication for surgery, and the timing of the intervention in acute cholecystitis. Conversion to open cholecystectomy was chosen as the dependent variable for both, univariate and multivariate analysis. RESULTS: 414 patients underwent laparoscopic cholecystectomy. 245 were female (59.1%) and 169 (40.8%) male, with a mean age of 51.7+/-16.4 years. The indication for surgery was acute cholecystitis in 91 cases (21.9%). Lithiasis of the bile duct was found in 40 patients (9.6%), and it was identified preoperatively in 37 patients, all treated with a preoperative ERCP. Conversion to open occurred in 33 cases (7.9%). Univariate analysis revealed as risk factor for conversion: increased age, acute cholecystitis, comorbidities, elevated white blood cell count, increased level of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, C-reactive protein, and fibrinogen. Multivariate logistic regression analysis showed that acute cholecystitis (OR 5.63) and age > 65 years (OR 3.025) were independent predictive factors for conversion. CONCLUSIONS: These patients should be properly informed of their increased risk of conversion and should be operated by surgeons skilled in laparoscopic procedures to reduce this risk. PMID- 25535195 TI - Reconstitution of a secondary cell wall in a secondary cell wall-deficient Arabidopsis mutant. AB - The secondary cell wall constitutes a rigid frame of cells in plant tissues where rigidity is required. Deposition of the secondary cell wall in fiber cells contributes to the production of wood in woody plants. The secondary cell wall is assembled through co-operative activities of many enzymes, and their gene expression is precisely regulated by a pyramidal cascade of transcription factors. Deposition of a transmuted secondary cell wall in empty fiber cells by expressing selected gene(s) in this cascade has not been attempted previously. In this proof-of-concept study, we expressed chimeric activators of 24 transcription factors that are preferentially expressed in the stem, in empty fiber cells of the Arabidopsis nst1-1 nst3-1 double mutant, which lacks a secondary cell wall in fiber cells, under the control of the NST3 promoter. The chimeric activators of MYB46, SND2 and ANAC075, as well as NST3, reconstituted a secondary cell wall with different characteristics from those of the wild type in terms of its composition. The transgenic lines expressing the SND2 or ANAC075 chimeric activator showed increased glucose and xylose, and lower lignin content, whereas the transgenic line expressing the MYB46 chimeric activator showed increased mannose content. The expression profile of downstream genes in each transgenic line was also different from that of the wild type. This study proposed a new screening strategy to identify factors of secondary wall formation and also suggested the potential of the artificially reconstituted secondary cell walls as a novel raw material for production of bioethanol and other chemicals. PMID- 25535196 TI - The characterization of six auxin-induced tomato GH3 genes uncovers a member, SlGH3.4, strongly responsive to arbuscular mycorrhizal symbiosis. AB - In plants, the GH3 gene family is widely considered to be involved in a broad range of plant physiological processes, through modulation of hormonal homeostasis. Multiple GH3 genes have been functionally characterized in several plant species; however, to date, limited works to study the GH3 genes in tomato have been reported. Here, we characterize the expression and regulatory profiles of six tomato GH3 genes, SlGH3.2, SlGH3.3, SlGH3.4, SlGH3.7, SlGH3.9 and SlGH3.15, in response to different phytohormone applications and arbuscular mycorrhizal (AM) fungal colonization. All six GH3 genes showed inducible responses to external IAA, and three members were significantly up-regulated in response to AM symbiosis. In particular, SlGH3.4, the transcripts of which were barely detectable under normal growth conditions, was strongly activated in the IAA-treated and AM fungal-colonized roots. A comparison of the SlGH3.4 expression in wild-type plants and M161, a mutant with a defect in AM symbiosis, confirmed that SlGH3.4 expression is highly correlated to mycorrhizal colonization. Histochemical staining demonstrated that a 2,258 bp SlGH3.4 promoter fragment could drive beta-glucuronidase (GUS) expression strongly in root tips, steles and cortical cells of IAA-treated roots, but predominantly in the fungal-colonized cells of mycorrhizal roots. A truncated 654 bp promoter failed to direct GUS expression in IAA-treated roots, but maintained the symbiosis-induced activity in mycorrhizal roots. In summary, our results suggest that a mycorrhizal signaling pathway that is at least partially independent of the auxin signaling pathway has evolved for the co-regulation of the auxin- and mycorrhiza-activated GH3 genes in plants. PMID- 25535197 TI - Genome-wide characterization of rice black streaked dwarf virus-responsive microRNAs in rice leaves and roots by small RNA and degradome sequencing. AB - MicroRNAs (miRNAs) are small, non-coding RNAs which typically function by guiding cleavage of target mRNAs. They play important roles in development, abiotic stress and responses to pathogens. Four small RNA libraries and four degradome libraries were constructed from the leaves and roots of healthy rice and plants infected with Rice black streaked dwarf virus (RBSDV). Analysis of the deep sequencing results showed that the expression patterns of 14 miRNAs in leaves and 16 miRNAs in roots changed significantly in response to RBSDV infection. Some responses were similar in roots and leaves, but many miRNAs responded differently in different tissues. The results were confirmed for selected miRNAs by quantitative real-time PCR. By using degradome sequencing, a total of 104 target transcripts for 17 conserved and 16 non-conserved miRNAs were shown to be responsive to RBSDV infection. Fifteen novel miRNAs were also identified by small RNA and degradome sequencing. The results provide new insights into the regulatory networks of miRNAs and their targets in different plant tissues in response to virus infection. PMID- 25535198 TI - Effectiveness of balneotherapy and spa therapy for the treatment of chronic low back pain: a review on latest evidence. AB - In most European countries, balneotherapy and spa therapy are widely prescribed by physicians and preferred by European citizens for the treatment of musculoskeletal problems including chronic low back pain (LBP). We aimed to review and evaluate the recent evidence on the effectiveness of balneotherapy and spa therapy for patients with LBP. We comprehensively searched data bases for randomized controlled trials (RCTs) published in English between July 2005 and December 2013. We identified all trials testing balneotherapy or spa therapy for LBP that reported that the sequence of allocation was randomized. We finally included total of eight RCTs: two on balneotherapy and six on spa therapy. All reviewed trials reported that balneotherapy was superior in long term to tap water therapy in relieving pain and improving function and that spa therapy combining balneotherapy with mud pack therapy and/or exercise therapy, physiotherapy, and/or education was effective in the management of low back pain and superior or equally effective to the control treatments in short and long terms. We used Jadad scale to grade the methodological quality. Only three out of total eight had a score of above 3 indicating the good quality. The data from the RCTs indicates that overall evidence on effectiveness of balneotherapy and spa therapy in LBP is encouraging and reflects the consistency of previous evidence. However, the overall quality of trials is generally low. Better quality RCTs (well designed, conducted, and reported) are needed testing short- and long-term effects for relieving chronic back pain and proving broader beneficial effects. PMID- 25535199 TI - A case-control study of quadrivalent human papillomavirus vaccine-associated autoimmune adverse events. AB - GARDASIL (Merck & Co., Inc., Whitehouse Station, NJ, USA) is a quadrivalent human papillomavirus (HPV4) vaccine. An epidemiological study was undertaken to evaluate concerns about the potential for HPV4 vaccination to induce serious autoimmune adverse events (SAAEs). The vaccine adverse event reporting system (VAERS) database was examined for adverse event reports associated with vaccines administered from January 2006 through December 2012 to recipients between 18 and 39 years old with a listed residence in the USA and a specified female gender. It was observed that cases with the SAAE outcomes of gastroenteritis (odds ratio (OR) = 4.6, 95% confidence interval (CI) = 1.3-18.5), arthritis (OR = 2.5, 95% CI = 1.4-4.3), systemic lupus erythematosus (OR = 5.3, 95% CI = 1.5-20.5), vasculitis (OR = 4, 95% CI = 1.01-16.4), alopecia (OR = 8.3, 95% CI = 4.5-15.9), or CNS conditions (OR = 1.8, 95% CI = 1.04-2.9) were significantly more likely than controls to have received HPV4 vaccine (median onset of SAAE symptoms from 6 to 55 days post-HPV4 vaccination). Cases with the outcomes of Guillain-Barre syndrome (OR = 0.75, 95% CI = 0.42-1.3) or thrombocytopenia (OR = 1.3, 95% CI = 0.48-3.5) were no more likely than controls to have received HPV4 vaccine. Cases with the general health outcomes of infection (OR = 0.72, 95% CI = 0.27-1.7), conjunctivitis (OR = 0.88, 95% CI = 0.29-2.7), or diarrhea (OR = 1.01, 95% CI = 0.83-1.22) were no more likely than controls to have received HPV4 vaccine. Previous case series of SAAEs and biological plausibility support the observed results. Additional studies should be conducted to further evaluate the potential biological mechanisms involved in HPV4 vaccine-associated SAAEs in animal model systems, and to examine the potential epidemiological relationship between HPV4 vaccine-associated SAAEs in other databases and populations. PMID- 25535200 TI - Spectrum of infections and outcome among hospitalized South Africans with systemic lupus erythematosus. AB - Our aim was to determine reasons for admission, the prevalence and spectrum of infections, and the outcomes in a multiethnic cohort of hospitalized systemic lupus erythematosus (SLE) patients in Durban, South Africa. We reviewed the records of hospitalized SLE patients seen over a 79-month period; the demographic data, clinical manifestations, laboratory findings, reasons for admission, nature of infection, and outcome were recorded. Our 167 patients, comprising 59.3% Indians, 33.5% African Blacks, 5.4% Coloreds, and 1.8% Whites, had 327 admissions. Active disease and infections accounted for 218 (66.7%) and 115 (35.2%) admissions respectively, with 58 (17.7%) due to both active disease and infection. Features of active disease were mucocutaneous 33.0%, hematological 30.3%, renal 28.9%, and vasculitis 27.1%. Overall, 83 patients (49.7%) had 155 infections; pneumonia (36.8%), cutaneous sepsis (18.1%), tuberculosis (13.5%), urinary tract infections (12.9%), and septicemia (7.1%) were the most common. The organisms commonly isolated were Staphylococcus aureus 25.4%, Escherichia coli 20.3%, and Klebsiella species and Mycobacterium tuberculosis in 13.6% each. Serositis (odds ratio (OR) = 2.7, p = 0.005) and seizures (OR = 4.8, p = 0.007) were associated with increased risk of infection. Twenty-four (14.4%) patients died from infection and active disease; the patients who died had higher SLEDAI scores (p = 0.02) and longer duration of hospitalization (p = 0.03) but no significant associations on multiple logistic regression analysis. Bacterial infections, including tuberculosis, are common in SLE, and they are a major cause of mortality. PMID- 25535201 TI - Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients. AB - Fibromyalgia is a clinical syndrome that currently does not have any specific pathological finding to aid in diagnosis. Therefore, fibromyalgia is most likely a heterogeneous group of diseases with similar symptoms. Identifying and understanding the pathological basis of fibromyalgia will allow physicians to better categorize patients, increasing prospective treatment options, and improving potential therapeutic endeavors. Recent work has demonstrated that approximately 50% of patients diagnosed with fibromyalgia have damage to their small unmyelinated nerve fibers. A skin punch biopsy is a sensitive and specific diagnostic test for this damage as a reduction in nerve fiber density allows for the diagnosis of small fiber neuropathy. Small fiber neuropathy is a disease with symptoms similar to fibromyalgia, but it often has a definable etiology. Identifying small fiber neuropathy and its underlying cause in fibromyalgia patients provides them with a succinct diagnosis, increases treatment options, and facilitates more specific studies for future therapeutics. PMID- 25535202 TI - Role of dentin MMPs in caries progression and bond stability. AB - Dentin can be described as a biological composite with collagen matrix embedded with nanosized hydroxyapatite mineral crystallites. Matrix metalloproteinases (MMPs) and cysteine cathepsins are families of endopeptidases. Enzymes of both families are present in dentin and collectively capable of degrading virtually all extracellular matrix components. This review describes these enzymes and their presence in dentin, mainly focusing on their role in dentin caries pathogenesis and loss of collagen in the adhesive hybrid layer under composite restorations. MMPs and cysteine cathepsins present in saliva, mineralized dentin, and/or dentinal fluid may affect the dentin caries process at the early phases of demineralization. Changes in collagen and noncollagenous protein structure may participate in observed decreases in mechanical properties of caries-affected dentin and reduce the ability of caries-affected dentin to remineralize. These endogenous enzymes also remain entrapped within the hybrid layer during the resin infiltration process, and the acidic bonding agents themselves (irrespective of whether they are etch-and-rinse or self-etch) can activate these endogenous protease proforms. Since resin impregnation is frequently incomplete, denuded collagen matrices associated with free water (which serves as a collagen cleavage reagent for these endogenous hydrolase enzymes) can be enzymatically disrupted, finally contributing to the degradation of the hybrid layer. There are multiple in vitro and in vivo reports showing that the longevity of the adhesive interface is increased when nonspecific enzyme-inhibiting strategies are used. Different chemicals (i.e., chlorhexidine, galardin, and benzalkonium chloride) or collagen cross-linker agents have been successfully employed as therapeutic primers in the bonding procedure. In addition, the incorporation of enzyme inhibitors (i.e., quaternary ammonium methacrylates) into the resin blends has been recently promoted. This review will describe MMP functions in caries and hybrid layer degradation and explore the potential therapeutic role of MMP inhibitors for the development of improved intervention strategies for MMP-related oral diseases. PMID- 25535203 TI - Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-kappaB ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid metabolites as therapeutic agents for BRONJ. PMID- 25535205 TI - Who may operate on acute aortic dissections? The squaring of the circle. PMID- 25535204 TI - Amelogenins as potential buffers during secretory-stage amelogenesis. AB - Amelogenins are the most abundant protein species in forming dental enamel, taken to regulate crystal shape and crystal growth. Unprotonated amelogenins can bind protons, suggesting that amelogenins could regulate the pH in enamel in situ. We hypothesized that without amelogenins the enamel would acidify unless ameloblasts were buffered by alternative ways. To investigate this, we measured the mineral and chloride content in incisor enamel of amelogenin-knockout (AmelX(-/-)) mice and determined the pH of enamel by staining with methyl-red. Ameloblasts were immunostained for anion exchanger-2 (Ae2), a transmembrane pH regulator sensitive for acid that secretes bicarbonate in exchange for chloride. The enamel of AmelX( /-) mice was 10-fold thinner, mineralized in the secretory stage 1.8-fold more than wild-type enamel and containing less chloride (suggesting more bicarbonate secretion). Enamel of AmelX(-/-) mice stained with methyl-red contained no acidic bands in the maturation stage as seen in wild-type enamel. Secretory ameloblasts of AmelX(-/-) mice, but not wild-type mice, were immunopositive for Ae2, and stained more intensely in the maturation stage compared with wild-type mice. Exposure of AmelX(-/-) mice to fluoride enhanced the mineral content in the secretory stage, lowered chloride, and intensified Ae2 immunostaining in the enamel organ in comparison with non-fluorotic mutant teeth. The results suggest that unprotonated amelogenins may regulate the pH of forming enamel in situ. Without amelogenins, Ae2 could compensate for the pH drop associated with crystal formation. PMID- 25535206 TI - Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function. AB - OBJECTIVES: Da Silva's cone repair is a novel technique for surgical reconstruction of the tricuspid valve and the right ventricle (RV) in Ebstein's anomaly. The technique consists of extensive leaflet mobilization, longitudinal plication of the atrialized ventricle and cone-shaped reconstruction of the tricuspid valve, allowing for leaflet-to-leaflet coaptation. We evaluated the influence of Da Silva's cone repair on tricuspid competency, right ventricular size and function. METHODS: From February 2010 until July 2013, 20 patients (median age 30.0 years, range 6.6-68.3 years) underwent Da Silva's cone repair. A 4- to 6-mm interatrial communication was left in all patients. Echocardiographic studies and magnetic resonance imaging (MRI) before and after the repair were evaluated. RESULTS: Median follow-up was 11 (0.5-36) months. There were 2 early deaths and no late death. Echocardiography at follow-up revealed mild or absent tricuspid regurgitation in 16 patients. Two patients showed moderate tricuspid insufficiency. MRI studies showed that the mean functional RV end-diastolic volume decreased after surgery (pre 334 [135-656] ml; post 175 [115-404] ml, P < 0.001). The mean RV ejection fraction decreased (pre 47 +/- 10%; post 35 +/- 13%, P = 0.001), and the mean antegrade net stroke volume of the RV increased (pre 65 +/- 28 ml; post 75 +/- 30 ml, P = 0.057). CONCLUSIONS: Da Silva's cone repair for Ebstein's anomaly creates excellent valve function in all patients. Consecutively, the size of the RV decreases and the antegrade net stroke volume increases 6 months after the operation. PMID- 25535207 TI - In search of ideal surgical palliation for drug refractory pulmonary hypertension. PMID- 25535208 TI - Can child injury prevention include healthy risk promotion? AB - To reflect on the role of risk-taking and risky play in child development and consider recommendations for the injury prevention field, a symposium was held prior to the November 2013 Canadian Injury Prevention and Safety Promotion Conference. Delegates heard from Canadian and international researchers, practitioners and play safety experts on child development, play space design and playground safety, provision of recreation, and legal and societal perceptions of risk and hazard. The presenters provided multidisciplinary evidence and perspectives indicating the potential negative effect on children's development of approaches to injury prevention that prioritise safety and limit children's opportunities for risky play. Delegates considered the state of the field of injury prevention and whether alternative approaches were warranted. Each presenter prepared a discussion paper to provide the opportunity for dialogue beyond attendees at the symposium. The resulting discussion papers provide a unique opportunity to consider and learn from multiple perspectives in order to develop a path forward. PMID- 25535209 TI - Structural and biochemical characteristics of citrus flowers associated with defence against a fungal pathogen. AB - The constitutive characters of plants can be structural or biochemical and play an important role in their defence against pathogens. Citrus postbloom fruit drop (PFD) caused by Colletotrichum spp. is one of the most important fungal diseases of citrus. The pathogen infects the flowers, leading to premature fruit drop and reducing citrus production. However, flower buds smaller than 8 mm long are usually not infected by Colletotrichum spp. Thus, this study investigated whether there are constitutive mechanisms in flower buds related to Colletotrichum spp. infection. We studied flower buds that were 2, 3, 4, 8, 12 and 15 mm long and petals, after anthesis, of sweet orange 'Valencia' using light and scanning electron microscopy and histochemistry. We evaluated the effect of volatile organic compounds (VOCs) in flowers (R-limonene and linalool) on the in vitro growth of Colletotrichum acutatum. We found that the arrangement of the epidermal papillae in the petal primordia, the occurrence of prismatic crystals and the distribution of oil glands are the main differences between buds smaller than 8 mm and buds 8-15 mm long. Osmophores at the tips of petals produced and accumulated phenols, terpenes and lipophilic compounds. Flower buds smaller than 8 mm long have constitutive structural and biochemical barriers to Colletotrichum spp. infection. In addition, this is the first time that osmophores have been reported in citrus. Our study shows that natural terpenes of Citrus flowers inhibit the fungal growth in vitro, highlighting the potential use of terpenes for the chemical control of PFD in citrus. PMID- 25535210 TI - Multicentre study to develop a medication safety package for decreasing inpatient harm from omission of time-critical medications. AB - QUALITY ISSUE: Omitting time-critical medications leads to delays in treatment and may result in patient harm. INITIAL ASSESSMENT: Published studies show that omission of prescribed medication doses is common. Although most are inconsequential, up to 86% of omitted medications place patients at some risk of harm. SOLUTION: Funding was obtained to develop a medication safety package to facilitate decreasing omitted dose incidents by audit, education and feedback. IMPLEMENTATION: A panel of nursing and pharmacy hospital staff in Victoria, Australia, reviewed existing audit tools and published studies to develop a critical medication list and audit tool. The tool, definitions and instructions were tested in 11 rural, urban and teaching hospitals. Qualitative feedback was sought to refine the tool using a Plan-Do-Study-Act model. An educational presentation was developed using reported incidents. EVALUATION: Staff in 11 hospitals tested the audit tool in 321 patients receiving 17 361 doses of medication. Feedback indicated audit data were useful for informing improvements in practice and for accreditation. The educational material consists of the User Guide, plus a presentation for nursing staff illustrated by six cases with questions, with instructions on how to decrease harm from omitted doses by ensuring correct documentation and prioritising time-critical medications. LESSONS LEARNED: A medication safety package using standard definitions and a critical medication list was successfully tested. It is now used by nursing and pharmacy staff across the state. Several interstate hospitals are using the tools as part of their hospital medication safety programmes. PMID- 25535211 TI - Absence of bacterial DNA in culture-negative urine from cats with and without lower urinary tract disease. AB - A diagnosis of bacterial cystitis commonly relies on a positive microbiological culture demonstrating the presence of a significant number of colony-forming units/ml urine, as urine within the upper urinary tract, bladder and proximal urethra generally is considered sterile. Recent studies from human and veterinary medicine indicate the presence of non-culturable bacteria in culture-negative urine samples. The aim of the present study was to determine the occurrence of bacterial DNA in culture-negative urine samples from cats with signs of feline lower urinary tract disease (FLUTD) and healthy control cats by 16S ribosomal DNA PCR and subsequent sequencing. The study sample included 38 culture-negative urine samples from cats with FLUTD and 43 culture-negative samples from control cats. Eight culture-positive urine samples from cats with FLUTD were included as external positive controls in addition to negative reaction controls. Of possible methodological limitations, degradation of DNA due to storage, the use of non sedimented urine for DNA isolation and lack of internal positive reaction controls should be mentioned. The positive controls were recognised, but occurrence of bacterial DNA in culture-negative urine from cats with or without signs of lower urinary tract disease was not demonstrated. However, considering the possible methodological limitations, the presence of bacterial DNA in the urine of culture-negative FLUTD cats cannot be excluded based on the present results alone. Therefore, a prospective study reducing the possibility of degradation of DNA due to storage, in combination with modifications enhancing the chance of detecting even lower levels of bacterial DNA in culture-negative samples, seems warranted. PMID- 25535212 TI - Survey of dietary and medication practices of owners of cats with chronic kidney disease. AB - The objective of this study was to describe the dietary and medication patterns of cats with chronic kidney disease (CKD). In this prospective, cross-sectional descriptive study, owners of cats with CKD were asked to complete a web-based survey. The study was advertised on CKD-, pet-, veterinary- and breed-associated websites and list serves. Owners of 1089 cats with CKD participated in the study. The mean reported age of the cats with CKD was 13.7 +/- 4.2 years. Forty percent (430/1089) of cats had concurrent diseases, with hyperthyroidism, heart disease and inflammatory bowel disease being the most common. Veterinarian recommendation was the most common reason reported (684/1032; 66%) for diet selection, and 51% (556/1089) of owners fed a veterinary therapeutic diet formulated for kidney disease as some component of the diet. Many owners (466/1079; 43%) reported that their cats had an abnormal appetite; of these owners, 52% responded that their cats had a poor appetite or required coaxing to eat 5-7 days per week. Forty seven percent and 51% of cats were receiving subcutaneous fluids and oral medications, respectively; however, most cats (811/1036; 78%) were not receiving phosphorus-binding medications. Fifty-six percent and 38% of cats received commercial cat treats and dietary supplements, respectively. Anorexia or hyporexia is a common problem in cats with CKD and may lead to cats being fed suboptimal diets for their disease. This information may be useful for treating or designing nutritional studies for cats with CKD. PMID- 25535213 TI - Giving gluten early and coeliac disease. PMID- 25535215 TI - Echocardiographic and clinical factors related to paravalvular leak incidence in low-gradient severe aortic stenosis patients post-transcatheter aortic valve implantation. AB - BACKGROUND: Paravalvular leak (PVL) following transcatheter aortic valve implantation (TAVI) is associated with poor outcomes. The association of clinical and echocardiographic parameters in the occurrence of even mild PVL in patients with low-gradient severe aortic stenosis (LGSAS) after TAVI and predictors of all cause mortality and re-hospitalization during 2-year follow-up was studied, as data are sparse in the literature. METHODS: Seventy-five consecutive LGSAS patients (age 80 +/- 8 years, 68% male, 89% Caucasians) were enrolled and followed-up for PVL development at hospital discharge, as well as mortality or re hospitalization for cardiovascular disease, during a 2-year follow-up period. Patients' characteristics were retrospectively extracted from hospital's database. Mortality was determined either by chart review or the Social Security Death Index. RESULTS: PVL was evident in 29 out of 75 patients. Patients with PVL had higher death rates at 6-month, 1-year of follow-up (27 vs. 7%, P = 0.05, 32 vs. 8%, P = 0.04, respectively) and lower stroke rates (0 vs. 7%, P = 0.009), compared with those who had no PVL. Patients with PVL were older, had lower BMI, higher prevalence of atrial fibrillation, higher brain natriuretic peptide (BNP), lower rest left ventricular ejection fraction, higher aortic cross-sectional area (Aa), lower stroke volume index, higher aortic resistance, stroke work, and higher energy loss index at rest and during dobutamine stress. Multivariable predictors of PVL post-TAVI were pre-procedural BNP levels and Aa. CONCLUSIONS: PVL remains a common complication after TAVI, related to adverse events in LGSAS patients. Aa and BNP levels remain the most important predictors of PVL. PMID- 25535214 TI - C-11 acetate has excellent reproducibility for quantification of myocardial oxidative metabolism. AB - AIMS: C-11 acetate PET imaging allows quantification of myocardial oxidative metabolism. We sought to assess the reproducibility of such analysis with the Carimas software. METHODS AND RESULTS: The myocardial oxygen consumption rate was assessed via a kmono index--the clearance rate constant of a mono-exponential function fitted to a C-11 acetate clearance curve. Two observers of different experience levels--a novice and an expert--analysed 53 C-11 acetate PET studies- each study twice. These results were compared using Bland-Altman (BA) plots with the global kmono-s obtained earlier with a validated reference method. We also assessed intra- and interobserver reproducibility on global, regional, and segmental [17-segment model (AHA)] levels--a linear mixed model for the repeated measures was fitted to our data--using intraclass correlation coefficients (ICCs) and differences between repeats and the observers. Carimas kmono values were lower than the reference--by 10.7% in the novice and by 9.6% in the expert, and were in substantial agreement with it--R(2) values were 0.944 and 0.943 correspondingly; the coefficients of repeatability--1.96 SD of biases in BA plots -were 11.2% in both the observers. The intra- and interobserver ICCs were high on global and regional levels--above 0.99 in the novice and 0.96 in the expert. The intra- and interobserver differences were low on global and regional levels, the most pronounced being the left anterior descending artery (LAD) interobserver difference of 2.2%. CONCLUSION: The study showed extremely good reproducibility both intra- and interobserver-for C-11 acetate PET analysis of myocardial oxidative metabolism. PMID- 25535216 TI - 'Black box warning' on food and drug administration criteria for drug-induced heart valve disease? PMID- 25535217 TI - Nurses negotiating professional-familial care boundaries: striving for balance within double duty caregiving. AB - The purpose of this sequential, two-phase mixed-methods study was to examine the health of male and female nurses who provided care to older relatives (i.e., double duty caregivers). We explored the experiences of 32 double duty caregivers, which led to the development of an emergent grounded theory, Negotiating Professional-Familial Care Boundaries with two broad dialectical processes: professionalizing familial care and striving for balance. This article examines striving for balance, which is the process that responds to familial care expectations in the midst of available resources and reflects the health experiences of double duty caregivers. Two subprocesses of striving for balance, reaping the benefits and taking a toll, are presented in three composite vignettes, each representing specific double duty caregiving (DDC) prototypes (making it work, working to manage, living on the edge). This emergent theory extends current thinking of family caregiving that will inform the development and refinement of practices and policies relevant to DDC. PMID- 25535218 TI - Prospective evaluation of the cost of diagnosis and treatment of invasive fungal disease in a cohort of adult haematology patients in the UK. AB - OBJECTIVES: The direct cost of invasive fungal disease (IFD) includes antifungal drugs as well as diagnostic tests. The aim of this study was to determine these costs. METHODS: A total of 203 haematology patients were enrolled into the study and followed for a median of 556 days. Data were prospectively collected on antifungal drugs, diagnostic tests, length of stay and antibiotic usage. RESULTS: The overall mean (IQR) cost of care per patient (using UK-based reference costs) was L88 911 (45 339-121 594), L61 509 (39 748-78 383), L50 332 (23 037-72 057) and L34 075 (19 928-43 900) for proven/probable IFD, possible IFD, not classified and no evidence of IFD, respectively (P<0.001). The attributable cost of IFD was L54 836. Inpatient hospital stay accounted for nearly 74% of costs. In proven/probable IFD inpatient care, antifungals, antibiotics and IFD status accounted for 68%, 25%, 5% and 2%, respectively, compared with 85%, 11%, 2% and 2%, respectively, for no IFD (P<0.001). Among the allogeneic transplant patients, L36 914 (60%) of the total cost (L60 917) was used during the first 100 days. CONCLUSIONS: IFD was associated with longer length of stay and higher total overall cost of care, with attributable costs greater than L50 000 per case of IFD. Costs for inpatient stay far outstrip the cost of antifungal agents. PMID- 25535219 TI - Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. AB - OBJECTIVES: Bedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5-6 months), complicating evaluations of drug-drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach. METHODS: Pharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments. RESULTS: Rifamycin co administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks. CONCLUSIONS: Rifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment. PMID- 25535220 TI - Neuroleptics as a cause of painful legs and moving toes syndrome. AB - Painful legs and moving toes syndrome is rare. It is predominantly diagnosed in middle-aged adults following a history of spinal cord surgery or trauma. The syndrome consists of abnormal repetitive movements, most commonly in the lower extremities, accompanied by pain in the affected limb. Pain usually precedes the movements. We report a case in a young patient that we believe was induced by the intake of a low-potency neuroleptic, which was prescribed to him for anxiety. The patient was treated with carbamazepine with mild relief of pain and later on with botulinum injection, which significantly reduced the movements and mildly improved the pain. After stopping the treatment, the beneficial effect lasted for about 3 months after which his condition gradually returned to its initial state. PMID- 25535221 TI - Disseminated Mycobacterium chelonae infection causing pacemaker lead endocarditis in an immunocompetent host. AB - Pacemaker infection with Mycobacterium chelonae has not been reported previously. We report the first case of pacemaker lead endocarditis due to M. chelonae, which was successfully treated with multidrug regimen. M. chelonae is regarded as an environmental bacterium and its pathogenicity has been recognised recently. The present case illustrates its ability as a primary invader should not be underestimated, especially in an immunocompetent patient with indwelling devices. Epidemiology and management of this rare cause of culture-negative endocarditis is discussed. PMID- 25535222 TI - Unprovoked deep venous thrombosis in a young adult associated with membranous obstruction of inferior vena cava. AB - Unprovoked deep venous thrombosis (DVT) in young adults is an unusual phenomenon, but it is associated with significant morbidity. Developmental anomalies of the inferior vena cava (IVC) should be considered as a possible aetiological factor, and appropriate investigations should be performed to determine the conclusive diagnosis and necessary treatment plan. We report a case of spontaneous thrombosis of the IVC and bilateral iliac venous system in a young man, associated with membranous obstruction of the IVC. He was diagnosed using several different investigational techniques, and successfully treated with mechanical thrombectomy, thrombolysis therapy and anticoagulation. PMID- 25535223 TI - Late-onset congenital lateral dermal sinus tract. AB - Cases of laterally located, congenital dermal sinus tracts are extremely rare, with only six having been reported to date. We describe a case of a 14-year-old girl who developed symptoms of this type of sinus tract at an age that was considerably older than is usually reported. At the age of 12 years, the patient exhibited a purulent discharge from a pit on the right buttock. MRI indicated the presence of two tracts running from the right buttock skin to a cystic lesion that had formed on the right ala of the sacral spine. The lesion was surgically resected and successfully reconstructed using a partial iliocostalis lumborum muscle flap, without any functional morbidity. From our experience, such flaps appear to be appropriate treatment choices for lateral congenital dermal sinus tracts that develop late and result in large defects. PMID- 25535224 TI - Life-saving implantable cardioverter defibrillator therapy in cardiac AL amyloidosis. AB - Cardiac involvement is the main determinant of prognosis in systemic monoclonal immunoglobulin light chain (AL) amyloidosis. Ventricular arrhythmias and sudden cardiac death are not uncommon. The electrical events that precede sudden death, and their potential to be treated effectively, remain undefined. There are no European guidelines for the use of implantable cardioverter defibrillator (ICD) in amyloidosis. ICDs in general are not usually offered to patients with a life expectancy of less than 1 year. We describe a patient who presented with cardiac AL amyloidosis who underwent prophylactic ICD implantation for the prevention of sudden cardiac death during treatment with chemotherapy, in whom life-threatening ventricular arrhythmia was successfully terminated over a 3-year period. PMID- 25535225 TI - Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman. AB - An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide. PMID- 25535226 TI - Rectal ulcer associated with SpaceOAR hydrogel insertion during prostate brachytherapy. AB - We present a case of rectal ulceration associated with SpaceOAR hydrogel insertion during low-dose-rate (LDR) brachytherapy in a patient with prostate cancer. PMID- 25535227 TI - Postsurgical large adrenal cyst recurrence: treatment by means of percutaneous alcohol ablation. AB - We describe a case of a 28-year-old man who presented with symptomatic, right sided, large adrenal cyst recurrence 9 months after laparoscopic decortication. Final treatment was achieved by means of percutaneous aspiration and ethanol ablation. On 6-month follow-up the patient was asymptomatic and the cyst remained minimised. In our opinion, percutaneous treatment with alcohol ablation of primary benign symptomatic or recurrent uncomplicated adrenal cysts should be considered as an effective alternative method when patients are frail or surgery fails to resolve the problem. PMID- 25535228 TI - Cardiac tamponade in a neonate: a dreadful condition--need for functional echo. AB - Cardiac tamponade is a clinical emergency. Detection of a swinging heart rate is one of the earliest markers of large pericardial effusion, in which the four cardiac chambers are free to float in a phasic manner. We present a case of a preterm baby, one of the twins, who developed sudden onset of deterioration in the form of swinging heart rate, fluctuation in blood pressure and desaturation, requiring emergency intubation and inotropic support. Bedside functional echo was performed, which demonstrated cardiac tamponade; an immediate echocardiography guided tap was initiated and fluid was aspirated from the pericardial space. PMID- 25535229 TI - Posterior gastric diverticulum mimicking adrenal adenoma on imaging. PMID- 25535231 TI - Traumatic intracerebral infarction due to vertebral and carotid artery dissection. PMID- 25535230 TI - Florid urticarial vasculitis heralding a flare up of ulcerative colitis. AB - A 75-year-old man with ulcerative colitis (UC) and diet controlled diabetes mellitus presented with a 3-week history of slightly itchy, red plaques on both lower limbs ascending gradually to cover the trunk and arms. One week later, he developed a flare up of his UC. Routine blood tests showed modest drop in haemoglobin (122 g/L) and C reactive protein (85 mg/L). Serology was remarkable for high antiproteinase 3 (c-ANCA). Serum electrophoresis showed a mildly positive paraprotein band (gamma region). Stool culture was negative. Urine analysis showed proteinuria. Skin biopsy showed features of urticarial vasculitis (UV). He underwent a flexible sigmoidoscopy after the flare up showed mildly active UC. The patient was given hydrocortisone for 7 days and then prednisolone. Both rash and UC subsided. Electrophoresis was repeated 4 weeks later showing normal pattern. Prednisolone has been gradually reduced. Although rare, UV can be considered as one of the skin manifestations of UC. PMID- 25535232 TI - Haemoptysis in a teenager: late diagnosis of unnoticed foreign body aspiration. AB - Chest X-ray in a 17-year-old boy, presenting with haemoptysis, revealed a radiopaque foreign body (FB) in the right lower lobe. There was no history of aspiration. CT located the needle-shaped FB in the right posterobasal lower lobe segment bronchus. In bronchoscopy, the FB turned out to be a pin, of which the radiolucent plastic head was embedded in the peribronchial tissue. Extraction by flexible and rigid bronchoscopy failed; finally, thoracotomy and bronchotomy had to be performed to remove the pin. In delayed diagnosis of a tracheobronchial FB, CT scan is not only necessary to localise the FB but also to depict or rule out secondary pulmonary changes. Nevertheless, radiolucent components of a metallic FB might be invisible even in CT, leading to underestimation of its size and extension. Late diagnosis complicates removal of tracheobronchial foreign bodies and may even necessitate open surgery, including pulmonary resections. PMID- 25535233 TI - Localised bullous eruptions and epidermal detachment from the extravasation of hydroxyethyl starch (Voluven). AB - Extravasation occurs frequently with intravenous infusions. In this case report we describe the occurrence of epidermal detachment and multiple cutaneous bullous eruptions in a patient's forearm following the extravasation of hydroxyethyl starch (Voluven, Fresenius Kabi)-a colloid solution derived from corn starch, which is used to replace lost blood volume. The patient's affected body surface area was managed under the direction of our plastic surgical team. Despite a prolonged admission in hospital from other perioperative complications, he made a full recovery and was successfully discharged home. The probable pathogenesis relevant to extravasation of Voluven is discussed; as well as its management principles. PMID- 25535234 TI - A case of rheumatic valvular heart disease and autoimmune gastritis. AB - We present a case of a 50-year-old female patient with a history of depressive disorder and anaemia (attributed to menorrhagias). She was admitted to the cardiology department with symptoms of fatigue on moderate exertion for several months, with worsening in the month before hospitalisation. Echocardiography revealed a severe mitral stenosis of rheumatic aetiology. Laboratory tests showed microcytic and hypochromic anaemia, reduced iron stores and vitamin B12 levels, and positive serum antiparietal cells autoantibodies. Endoscopy showed focal areas of erythema in the stomach, corresponding histologically to chronic atrophic gastritis. In this context, two distinct clinical entities were diagnosed in the same patient: severe rheumatic mitral stenosis and autoimmune gastritis. The patient was started on vitamin B12 and iron supplementation and underwent surgical correction of the valvular disease. There was symptomatic improvement in her signs of fatigue. PMID- 25535235 TI - Midline prostatic cyst in a young man with lower urinary tract symptoms. PMID- 25535236 TI - Skin lesions in a patient with epilepsy. PMID- 25535237 TI - Unusual rectal foreign body for drug screen evasion. PMID- 25535238 TI - Metastatic breast cancer presenting as detrusor overactivity. AB - Breast carcinoma metastatic to the bladder is rare and accounts for approximately 3% of all secondary bladder neoplasms. We examine a case of breast cancer metastatic to the bladder with normal findings at cystoscopy. A 53-year-old woman with a history of breast carcinoma presented with a 6-month history of severe urgency and urgency incontinence. Treatment with multiple antimuscarinic therapies was unsuccessful. Vaginal examination demonstrated a non-mobile uterus with a suggestion of parametrial thickening. Urodynamic studies confirmed detrusor overactivity. CT showed a thickened bladder wall and cystoscopy revealed normal bladder mucosa with reduced bladder capacity. Bladder biopsies identified a poorly differentiated adenocarcinoma with strong oestrogen receptor staining. This was reported as a secondary deposit from a primary breast malignancy. The patient is currently under the care of the breast team and undergoing palliative chemotherapy. PMID- 25535239 TI - Glassidium brokenosis. PMID- 25535240 TI - A finding with a diagnosis: I just can't put my finger on it. AB - A 72-year-old man with metastatic squamous cell carcinoma of the lung presents with new lesions in the distal phalanx of right fifth finger (painful) and left great toe (painless due to long-standing peripheral neuropathy). Initially a complication of cytotoxic chemotherapy is considered and a dermatological opinion is requested. Enlargement of the lesions over the space of a week leads to plain X-ray, with findings of destruction of the distal phalanx of the involved digits confirming metastatic disease. Palliative radiotherapy is administered to decrease pain and reduce the likelihood of cutaneous and infectious complications. The patient died from systemic disease progression soon after finishing his radiotherapy. Digital metastasis (acrometastasis) should be considered by clinicians in the workup of patients with persistent digital symptoms, particularly in those with known cancer or those at high risk of cancer. PMID- 25535241 TI - Absence of left circumflex with superdominant right coronary artery. AB - Congenital anomalies of coronary arteries are a group of diseases that are infrequently found. Their prevalence has been reported from 0.6% to 1.3%. Most clinical manifestations are benign and asymptomatic. Congenital absence of the left circumflex artery is a very rare congenital anomaly of the coronary circulation, and only a few cases have been reported in the literature. We report a case of a 51-year-old man who underwent a cardiac catheterisation. Coronary angiography showed a left anterior descending coronary artery with no circumflex and a dominant right coronary artery. PMID- 25535242 TI - CONSRANK: a server for the analysis, comparison and ranking of docking models based on inter-residue contacts. AB - SUMMARY: Herein, we present CONSRANK, a web tool for analyzing, comparing and ranking protein-protein and protein-nucleic acid docking models, based on the conservation of inter-residue contacts and its visualization in 2D and 3D interactive contact maps. AVAILABILITY AND IMPLEMENTATION: CONSRANK is accessible as a public web tool at https://www.molnac.unisa.it/BioTools/consrank/. CONTACT: romina.oliva@uniparthenope.it. PMID- 25535244 TI - PBOOST: a GPU-based tool for parallel permutation tests in genome-wide association studies. AB - MOTIVATION: The importance of testing associations allowing for interactions has been demonstrated by Marchini et al. (2005). A fast method detecting associations allowing for interactions has been proposed by Wan et al. (2010a). The method is based on likelihood ratio test with the assumption that the statistic follows the chi(2) distribution. Many single nucleotide polymorphism (SNP) pairs with significant associations allowing for interactions have been detected using their method. However, the assumption of chi(2) test requires the expected values in each cell of the contingency table to be at least five. This assumption is violated in some identified SNP pairs. In this case, likelihood ratio test may not be applicable any more. Permutation test is an ideal approach to checking the P-values calculated in likelihood ratio test because of its non-parametric nature. The P-values of SNP pairs having significant associations with disease are always extremely small. Thus, we need a huge number of permutations to achieve correspondingly high resolution for the P-values. In order to investigate whether the P-values from likelihood ratio tests are reliable, a fast permutation tool to accomplish large number of permutations is desirable. RESULTS: We developed a permutation tool named PBOOST. It is based on GPU with highly reliable P-value estimation. By using simulation data, we found that the P-values from likelihood ratio tests will have relative error of >100% when 50% cells in the contingency table have expected count less than five or when there is zero expected count in any of the contingency table cells. In terms of speed, PBOOST completed 10(7) permutations for a single SNP pair from the Wellcome Trust Case Control Consortium (WTCCC) genome data (Wellcome Trust Case Control Consortium, 2007) within 1 min on a single Nvidia Tesla M2090 device, while it took 60 min in a single CPU Intel Xeon E5-2650 to finish the same task. More importantly, when simultaneously testing 256 SNP pairs for 10(7) permutations, our tool took only 5 min, while the CPU program took 10 h. By permuting on a GPU cluster consisting of 40 nodes, we completed 10(12) permutations for all 280 SNP pairs reported with P values smaller than 1.6 * 10-12 in the WTCCC datasets in 1 week. AVAILABILITY AND IMPLEMENTATION: The source code and sample data are available at http://bioinformatics.ust.hk/PBOOST.zip. CONTACT: gyang@ust.hk; eeyu@ust.hk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25535243 TI - A Bayesian framework for de novo mutation calling in parents-offspring trios. AB - MOTIVATION: Spontaneous (de novo) mutations play an important role in the disease etiology of a range of complex diseases. Identifying de novo mutations (DNMs) in sporadic cases provides an effective strategy to find genes or genomic regions implicated in the genetics of disease. High-throughput next-generation sequencing enables genome- or exome-wide detection of DNMs by sequencing parents-proband trios. It is challenging to sift true mutations through massive amount of noise due to sequencing error and alignment artifacts. One of the critical limitations of existing methods is that for all genomic regions the same pre-specified mutation rate is assumed, which has a significant impact on the DNM calling accuracy. RESULTS: In this study, we developed and implemented a novel Bayesian framework for DNM calling in trios (TrioDeNovo), which overcomes these limitations by disentangling prior mutation rates from evaluation of the likelihood of the data so that flexible priors can be adjusted post-hoc at different genomic sites. Through extensively simulations and application to real data we showed that this new method has improved sensitivity and specificity over existing methods, and provides a flexible framework to further improve the efficiency by incorporating proper priors. The accuracy is further improved using effective filtering based on sequence alignment characteristics. AVAILABILITY AND IMPLEMENTATION: The C++ source code implementing TrioDeNovo is freely available at https://medschool.vanderbilt.edu/cgg. CONTACT: bingshan.li@vanderbilt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25535245 TI - The CatSper channel controls chemosensation in sea urchin sperm. AB - Sperm guidance is controlled by chemical and physical cues. In many species, Ca(2+) bursts in the flagellum govern navigation to the egg. In Arbacia punctulata, a model system of sperm chemotaxis, a cGMP signaling pathway controls these Ca(2+) bursts. The underlying Ca(2+) channel and its mechanisms of activation are unknown. Here, we identify CatSper Ca(2+) channels in the flagellum of A. punctulata sperm. We show that CatSper mediates the chemoattractant-evoked Ca(2+) influx and controls chemotactic steering; a concomitant alkalization serves as a highly cooperative mechanism that enables CatSper to transduce periodic voltage changes into Ca(2+) bursts. Our results reveal intriguing phylogenetic commonalities but also variations between marine invertebrates and mammals regarding the function and control of CatSper. The variations probably reflect functional and mechanistic adaptations that evolved during the transition from external to internal fertilization. PMID- 25535247 TI - Microexons--tiny but mighty. PMID- 25535249 TI - Considering the Genetic and Environmental Overlap Between Bullying Victimization, Delinquency, and Symptoms of Depression/Anxiety. AB - Emerging evidence from longitudinal research suggests that bullied children are more likely to develop antisocial tendencies and mental health problems later in life. Less research, however, has used genetically sensitive research designs to control for genetic confounding and examine whether the well-supported association between bullying victimization and maladaptive development is partially accounted for by common genetic and environmental influences. Using sibling data from the National Longitudinal Survey of Youth 1997, the current study used a series of bivariate liability-threshold models to disentangle the genetic and environmental influences on observed covariance between repeated bullying victimization, delinquent involvement, and symptoms of depression/anxiety. Results revealed that common additive genetic and nonshared environmental effects accounted for the covariance in liability between bullying victimization and delinquent involvement as well as bullying victimization and symptoms of depression/anxiety. The results suggest the presence of genotype environment correlation (rGE) between repeated victimization and maladaptive development. PMID- 25535246 TI - A THEMIS:SHP1 complex promotes T-cell survival. AB - THEMIS is critical for conventional T-cell development, but its precise molecular function remains elusive. Here, we show that THEMIS constitutively associates with the phosphatases SHP1 and SHP2. This complex requires the adapter GRB2, which bridges SHP to THEMIS in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Consistent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knock-down increased TCR-induced CD3-zeta phosphorylation, Erk activation and CD69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP1 knock-down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK-mediated resistance towards SHP1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T-cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T-cell development and differentiation. PMID- 25535250 TI - Development and Psychometric Evaluation of the Child Neglect Questionnaire. AB - Neglect poses a significant risk for children throughout their development and is often linked with serious consequences that reach into adulthood. The Child Neglect Questionnaire (CNQ) fills existing gaps by incorporating multiple perspectives from both parents and the child, as well as measuring the complex phenomenon of neglect multidimensionally. Furthermore, this measure addresses the need for an instrument specifically developed for late childhood (ages 10-12), as much of the extant evidence and corresponding measures focus on young children and their mothers. A panel of three psychologists, using Cicchetti's model of child neglect as a theoretical guide, began by selecting items from an existing database. Results of exploratory and confirmatory factor analyses and item response theory demonstrated the unidimensionality of physical, emotional, educational, and supervision neglect as well as a second-order construct of child neglect. Analyses controlling for risk status due to father's substance use disorder, socioeconomic status, and child's ethnicity demonstrated that father's and mother's (parental) neglect, particularly in the child's versions, had sound concurrent and predictive validity. Concurrently, at age 10-12, the child's version of both parents' neglect correlated with their parenting behaviors evaluated by other available measures. Prospectively, from 10-12 years of age to 11-13 years of age, parental neglect predicted child's drug use frequency with coexisting psychological dysregulation, psychiatric symptoms, antisocial behavior, non-normative sexual behavior, involvement with deviant peers and leisure activities thus demonstrating sound predictive validity. Also, internal consistency and inter-rater reliability were excellent. The CNQ, particularly the child's version, may thus be useful for detecting children at high risk for parental neglect. PMID- 25535248 TI - Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer. AB - Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) approach, we find that agonist liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinct transcriptional outcomes in prostate cancer cells. Further analysis on clinical prostate tissues reveals that the binding of AR to these two distinct motifs is involved in prostate carcinogenesis. Together, these results suggest that unique ligands may switch DNA motifs recognized by ligand-dependent transcription factors in vivo. Our findings also provide a broad mechanistic foundation for understanding ligand specific induction of gene expression profiles. PMID- 25535251 TI - Size Matters: Are Physically Large People More Likely to be Violent? AB - A number of studies suggest that physical size is associated with violent behavior. However, few, if any, studies have examined this relationship using population-based samples. Moreover, limited evidence exists on the relationship between physical size and violence with respect to gender, race/ethnicity, and exposure to childhood maltreatment. The present study, using data from Waves I and II (N = 34,653) of the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC), aims to address these gaps by comparing the prevalence of violent behavior among individuals in the top quintiles in height and weight with that of the general population. Significant associations were identified for both males and females between physical size and bullying/intimidation, intentional injury of other persons, and hitting someone so hard that they required medical attention. Stratified analyses revealed that the magnitude of the relationship between physical size and violence is greater among Hispanics than among non Hispanic Whites and African Americans. Childhood abuse and neglect significantly moderated the relationship between physical size and violent behavior. While an important degree of variability can be observed with respect to gender, race/ethnicity, and exposure to child maltreatment, results indicate that, in general, physically larger individuals are more likely than their relatively smaller counterparts to be violent. PMID- 25535252 TI - Discrepant Perspectives on Conflict Situations Among Urban Parent-Adolescent Dyads. AB - Parents influence urban youths' violence-related behaviors. To provide effective guidance, parents should understand how youth perceive conflict, yet little empirical research has been conducted regarding parent and youth perceptions of conflict. The aims of this article are to (a) report on the nature of discrepancies in attribution of fault, (b) present qualitative data about the varying rationales for fault attribution, and (c) use quantitative data to identify correlates of discrepancy including report of attitudes toward violence, parental communication, and parents' messages about retaliatory violence. Interviews were conducted with 101 parent/adolescent dyads. The study population consisted of African American female caretakers (n = 92; that is, mothers, grandmothers, aunts) and fathers (n = 9) and their early adolescents (mean age = 13.6). A total of 53 dyads were discrepant in identifying instigators in one or both videos. When discrepancy was present, the parent was more likely to identify the actor who reacted to the situation as at fault. In the logistic regression models, parental attitudes about retaliatory violence were a significant correlate of discrepancy, such that as parent attitudes supporting retaliatory violence increased, the odds of discrepancy decreased. The results suggest that parents and adolescents do not always view conflict situations similarly, which may inhibit effective parent-child communication, parental advice, and discipline. Individuals developing and implementing family-based violence prevention interventions need to be cognizant of the complexity of fault attribution and design strategies to promote conversations around attribution of fault and effective conflict management. PMID- 25535253 TI - New TB treatments hiding in plain sight. PMID- 25535256 TI - Precollege and in-college bullying experiences and health-related quality of life among college students. AB - BACKGROUND AND OBJECTIVES: Bullying is a commonly occurring problem behavior in youths that could lead to long-term health effects. However, the impact of school bullying experiences on health-related quality of life (HRQOL) among college students has been relatively underexplored. This study aimed to describe school bullying experiences and to empirically examine their associations with HRQOL among college students in Taiwan. METHODS: Self-administered survey data (response rate 84.2%) were collected from 1452 college students in 2013 by using proportional stratified cluster sampling. Different types of bullying experiences (ie, physical, verbal, relational, and cyber) before and in college, for bullies and victims, were measured. HRQOL was assessed by the World Health Organization Quality of Life (WHOQOL-BREF) Taiwan version. RESULTS: College students with cyber bullying-victimization experiences before college (beta 0.060) reported significantly higher HRQOL in physical health. Regarding social relationships, those with verbal (beta -0.086) and relational (beta -0.056) bullying victimization experiences, both before and in college, reported significantly lower HRQOL, whereas those with verbal (beta 0.130) and relational (beta 0.072) bullying-perpetration experiences in both periods reported significantly higher HRQOL. Students with cyber bullying-victimization experiences in college (beta 0.068) reported significantly higher HRQOL in the environment domain. Last, the effects of verbal and relational bullying-victimization experiences on psychological HRQOL could be mediated and manifested through depression. CONCLUSIONS: Various types of bullying experiences occurring before and in college were differentially associated with HRQOL in different domains. These findings underscore the importance of developing school policies and health education initiatives to prevent school bullying and ameliorate its short-term and long-term effects on HRQOL. PMID- 25535254 TI - Functional drug screening reveals anticonvulsants as enhancers of mTOR independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. AB - Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug resistant mycobacterial infection. PMID- 25535257 TI - State-specific differences in school sports preparticipation physical evaluation policies. AB - OBJECTIVE: This study evaluated the current preparticipation physical evaluation (PPE) administrative policies and cardiovascular screening content of all 50 states and Washington, DC. METHODS: PPE policies, documents, and forms from all 50 states and Washington, DC, were compared with the preparticipation physical evaluation-fourth edition (PPE-4) consensus recommendations. All electronic documents were publicly available and obtained from state interscholastic athletic associations. RESULTS: Fifty (98%) states required a PPE before participation. Most states (53%, n = 27) required a specific PPE form, whereas 24% (n = 12) of states recommended a specific form. Twenty-three states (45%) required or recommended use of the PPE-4 form or a modified version of it, and 27 states (53%) required or recommended use of outdated or unidentifiable forms. Ten states (20%) had not revised their PPE forms in >5 years. States permitted 9 different health care providers to administer PPEs. Only 22 states (43%) addressed all 12 of the PPE-4 personal and family history cardiovascular screening items, and 2 states (4%) addressed between 8 and 11 items. For the remaining 26 states, most (29%) addressed <=3 screening items. CONCLUSIONS: Our results show that inconsistencies in PPE policies exist nationwide. Most states have been slow to adopt PPE-4 recommendations and do not adequately address the personal and family cardiovascular history questions. Findings suggest a need for PPE standardization nationwide and adoption of an electronic PPE process. This approach would enable creation of a national database and benefit the public by facilitating a more evidenced PPE. PMID- 25535255 TI - Modulation of TNF-alpha mRNA stability by human antigen R and miR181s in sepsis induced immunoparalysis. AB - Immunoparalysis is an important pathological mechanism in sepsis. However, an effective small molecule therapy is lacking. Here, we show that ouabain, a Na(+),K(+)-ATPase ligand, can reverse immunoparalysis in vitro, in vivo, and in clinical samples. Notably, the effect of ouabain was critically dependent on TNF alpha expression. However, ouabain had opposing effects on the stability of TNF alpha mRNA: Ouabain triggered miR-181 transcription, which promoted TNF-alpha mRNA degradation and induced immunoparalysis, and ouabain triggered the nuclear export of human antigen R (HuR), which stabilized TNF-alpha mRNA and suppressed immuno-paralysis. Interestingly, because the miR-181 binding site is located within the HuR binding site in the 3'-untranslated region of TNF-alpha, in ouabain-treated cells, HuR competed with miR-181 for binding to TNF-alpha mRNA and recruited TNF-alpha mRNA to stress granules, thereby stabilizing TNF-alpha mRNA and reversing immunoparalysis. Ouabain also induced GM-CSF and interferon gamma expression in a HuR-dependent manner. Hence, the fine-tuning of TNF-alpha mRNA stability by HuR and miR181 plays a crucial role in immunoparalysis, and Na(+),K(+)-ATPase ligands are promising agents for immunoparalysis therapy. PMID- 25535258 TI - Hormonal contraceptive agents: a need for pediatric-specific studies. PMID- 25535259 TI - Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency. AB - Mevalonate kinase deficiency (MKD) is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype that may be expressed as a spectrum of disease phenotypes, from those with prevailing autoinflammatory syndrome and variable response to anti-inflammatory therapies, to mevalonic aciduria, which is associated with dysmorphic features, severe neurologic involvement, and the worst prognosis. We describe a boy, aged 2 years, 10 months, with severe phenotype of mevalonate kinase deficiency who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical unrelated cord blood because his condition had failed to improve with antiinflammatory treatment as first-line therapy and an anticytokine drug as second-line therapy. The child had a sustained remission of febrile attacks and inflammation after transplant, and during a 5-year follow-up period, psychomotor and neurologic development were normal, without signs of underlying disease or late transplant-related effects. This case confirms that allogeneic HSCT is a safe and effective cure for patients affected by MKD in whom anticytokine drugs alone are insufficient for the management of autoinflammatory syndrome and for the unfavorable outcome of the disease. PMID- 25535260 TI - Psychosocial outcomes of fetal alcohol syndrome in adulthood. AB - BACKGROUND AND OBJECTIVE: Primary disabilities in children prenatally exposed to alcohol have a major impact on their daily life. It is suggested that these issues persist into adulthood, but few studies have addressed the outcome in adults with prenatal exposure, especially those with fetal alcohol syndrome (FAS). The aim of this follow-up study was to investigate outcome variables, such as education, employment, health, and criminal acts, in 79 adults diagnosed with FAS. METHODS: We carried out a national register-based study of 79 adults with an FAS diagnosis, at a mean age of 32. Education, social adjustment, and mental health outcomes were analyzed and compared with 3160 comparison individuals matched on age, gender, and place of birth. RESULTS: The FAS group was much more likely to have received special education (25% vs 2%), be unemployed (51% vs 15%), and receive a disability pension (31% vs 3%) than the comparisons, but the levels of criminal offenses were similar. The FAS group had higher hospital admission rates for alcohol abuse (9% vs 2%) and psychiatric disorders (33% vs 5%) and was more likely to be prescribed psychotropic drugs (57% vs 27%). CONCLUSIONS: Swedish children with FAS have quite diverse psychosocial outcomes in adulthood, considerably worse than for majority population peers. Potential risk and protective factors within the FAS group deserve study to enable development of effective interventions. PMID- 25535261 TI - Insulin and BMI as predictors of adult type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVES: Fasting insulin concentrations are increasingly being used as a surrogate for insulin resistance and risk for type 2 diabetes (T2DM), although associations with adult outcomes are unclear. Our objective was to determine whether fasting insulin concentrations in childhood associate with later T2DM. METHODS: Fasting insulin values were available from 2478 participants in the longitudinal Cardiovascular Risk in Young Finns Study at baseline age 3 to 18 years, along with data on adult T2DM (N = 84, mean age = 39.6 years). RESULTS: Among 3- to 6-year-olds, a 1-SD increase in fasting insulin was associated with a relative risk (RR) of 2.04 (95% confidence interval [CI], 1.54-2.70) for later T2DM, which remained significant after we adjusted for BMI and parental history of T2DM. For those aged 9 to 18 years, a 1-SD increase in insulin was associated with an RR of 1.32 (95% CI, 1.06-1.65) for T2DM, but this became nonsignificant after we adjusted for BMI and parental history of T2DM. In the latter age group, a 1-SD increase in BMI was associated with an RR of 1.45 (95% CI, 1.21-1.73) for T2DM, with adjustment for insulin and parental history of T2DM not improving this association. BMI in younger children was not associated with later T2DM. In life course analyses, those with T2DM had higher fasting insulin levels in early childhood and later adulthood but not in peripubertal years. CONCLUSIONS: Elevated fasting insulin concentrations in early childhood, but not adolescence, are independently associated with an elevated risk of T2DM in adulthood. PMID- 25535262 TI - Validity of self-assessment of pubertal maturation. AB - BACKGROUND AND OBJECTIVES: Studies of adolescents often use self-assessment of pubertal maturation, the reliability of which has shown conflicting results. We aimed to examine the reliability of child and parent assessments of healthy boys and girls. METHODS: A total of 898 children (418 girls, 480 boys, age 7.4-14.9 years) and 1173 parents (550 daughters, 623 sons, age 5.6-14.7 years) assessed onset of puberty or development of breasts, genitals, and pubic hair according to Tanner stages by use of a questionnaire and drawings. Physicians' assessments were blinded and set as the gold standard. Percentage agreement, kappa, and Kendall's correlation were used to analyze the agreement rates. RESULTS: Breast stage was assessed correctly by 44.9% of the girls (kappa = 0.28, r = 0.74, P < .001) and genital stage by 54.7% of the boys (kappa = 0.33, r = 0.61, P < .001). For pubic hair stage 66.8% of girls (kappa = 0.55, r = 0.80, P < .001) and 66.1% of boys (kappa = 0.46, r = 0.70, P < .001) made correct assessments. Of the parents, 86.2% correctly assessed onset of puberty in girls (kappa = 0.70, r = 0.71, P < .001) and 68.4% in boys (kappa = 0.30, r = 0.37, P < .001). Children who underestimated were younger and children who overestimated older than their peers who made correct assessments. Girls and their parents tended to underestimate, whereas boys overestimated their pubertal stage. CONCLUSIONS: Pubertal assessment by the child or the parents is not a reliable measure of exact pubertal staging and should be augmented by a physical examination. However, for large epidemiologic studies self-assessment can be sufficiently accurate for a simple distinction between prepuberty and puberty. PMID- 25535263 TI - Case report: rapidly healing epidermolysis bullosa wound after ablative fractional resurfacing. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by generalized skin fragility, severe blistering, and wounding that heals with mutilating scarring. Patients are in constant need of effective wound therapies as they often succumb to aggressive metastatic squamous cell carcinomas or to sepsis that may develop from their chronic wounds. Herein, we demonstrate accelerated wound healing with use of a fractionated CO2 laser protocol in a 22 year-old man with RDEB. His 9-month-old, non-healing wound decreased from 7 cm in diameter to 2 cm in diameter (a 92% reduction in wound surface area) within 4 weeks of a single laser treatment, and he had near-complete re-epithelialization within 4 weeks of his second laser treatment without blistering or other adverse effects. This novel intervention of using fractionated CO2 for photo microdebridement could help revolutionize wound care for patients who have RDEB and whose chronic wounds serve as one of their greatest sources of morbidity and mortality. Dissemination to a pediatric audience is critical so that laser protocols might be more thoroughly investigated and incorporated into wound management strategies for this uniquely vulnerable population. PMID- 25535264 TI - A common thread: pediatric advocacy training. PMID- 25535265 TI - A school health center intervention for abusive adolescent relationships: a cluster RCT. AB - BACKGROUND AND OBJECTIVES: Few evidence-based interventions address adolescent relationship abuse in clinical settings. This cluster randomized controlled trial tested the effectiveness of a brief relationship abuse education and counseling intervention in school health centers (SHCs). METHODS: In 2012-2013, 11 SHCs (10 clusters) were randomized to intervention (SHC providers received training to implement) or standard-of-care control condition. Among 1062 eligible students ages 14 to 19 years at 8 SHCs who continued participation after randomization, 1011 completed computer-assisted surveys before a clinic visit; 939 completed surveys 3 months later (93% retention). RESULTS: Intervention versus control adjusted mean differences (95% confidence interval) on changes in primary outcomes were not statistically significant: recognition of abuse = 0.10 (-0.02 to 0.22); intentions to intervene = 0.03 (-0.09 to 0.15); and knowledge of resources = 0.18 (-0.06 to 0.42). Intervention participants had improved recognition of sexual coercion compared with controls (adjusted mean difference = 0.10 [0.01 to 0.18]). In exploratory analyses adjusting for intensity of intervention uptake, intervention effects were significant for increased knowledge of relationship abuse resources and self-efficacy to use harm reduction behaviors. Among participants reporting relationship abuse at baseline, intervention participants were less likely to report such abuse at follow-up (mean risk difference = -0.17 [-0.21 to -0.12]). Adolescents in intervention clinics who reported ever being in an unhealthy relationship were more likely to report disclosing this during the SHC visit (adjusted odds ratio = 2.77 [1.29 to 5.95]). CONCLUSIONS: This is the first evidence of the potential benefit of a SHC intervention to address abusive relationships among adolescents. PMID- 25535266 TI - Maternal depressive symptoms during childhood and risky adolescent health behaviors. AB - OBJECTIVE: Maternal depression is a risk factor for adolescent depression; however, the effect of childhood exposure to maternal depression on adolescent engagement in health risk behaviors (eg, substance use, delinquency) is unclear. METHODS: We examined the relationship between maternal depressive symptoms (child's age 4-15) and engagement in health risk behaviors at age 16 to 17 by using data from 2910 mother-youth pairs in a nationally representative prospective Canadian cohort. Maternal depressive trajectories were estimated through finite mixture modeling, and multiple regression analyses examined the relationship between maternal depressive symptoms and engagement in various health risk behaviors (linear regression) and age of debut of various behaviors (Cox regression). RESULTS: Five trajectories of maternal depressive symptoms were found: recurrent maternal symptoms, midchildhood exposure to maternal symptoms, adolescent exposure to maternal symptoms, mild maternal symptoms, and low symptoms. Adolescents exposed to maternal depressive symptoms during middle childhood were more likely to use common substances (alcohol, cigarettes, marijuana), engage in violent and nonviolent delinquent behavior, and have an earlier debut ages of cigarette, alcohol, marijuana, and hallucinogen use. CONCLUSIONS: The results of this study suggest that exposure to maternal depressive symptoms, particularly in middle childhood, is associated with greater and earlier engagement in health risk behaviors. PMID- 25535267 TI - Children's academic achievement and foster care. AB - BACKGROUND AND OBJECTIVES: Poor school outcomes for children in out-of-home placement (OHP) raise concerns about the adequacy of child welfare and educational policy for this vulnerable population. We analyzed the relation between OHP and academic achievement, focusing on reading and math achievement in grades 3 through 8. METHODS: Linked administrative data were used for our analytic sample comprising 529 597 child-year observations for 222 049 children who experienced OHP or were in a comparison group. Three models were estimated: a pooled ordinary least squares regression that considered placement status and test scores net of the full set of control variables; an identical model that added the previous year's test scores as an additional control; and a final model that included child-specific fixed effects. RESULTS: Children in OHP settings had achievement test scores at least 0.6 SD below average. However, we found similar deficits across children with past, current, and future exposure to OHP and, in our preferred model, OHP (past, current, or future placement) had no statistically discernible relation with either reading or math achievement. CONCLUSIONS: OHP by itself is not significantly related to school achievement; however, evidence reveals consistently low average math and reading achievement among children involved with Child Protective Services. PMID- 25535268 TI - Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals. AB - Autism spectrum disorders (ASDs) affect up to 1 in 68 children. Autism-specific autoantibodies directed against fetal brain proteins have been found exclusively in a subpopulation of mothers whose children were diagnosed with ASD or maternal autoantibody-related autism. We tested the impact of autoantibodies on brain development in mice by transferring human antigen-specific IgG directly into the cerebral ventricles of embryonic mice during cortical neurogenesis. We show that autoantibodies recognize radial glial cells during development. We also show that prenatal exposure to autism-specific maternal autoantibodies increased stem cell proliferation in the subventricular zone (SVZ) of the embryonic neocortex, increased adult brain size and weight, and increased the size of adult cortical neurons. We propose that prenatal exposure to autism-specific maternal autoantibodies directly affects radial glial cell development and presents a viable pathologic mechanism for the maternal autoantibody-related prenatal ASD risk factor. PMID- 25535269 TI - Photoheterotrophic fluxome in Synechocystis sp. strain PCC 6803 and its implications for cyanobacterial bioenergetics. AB - This study investigated metabolic responses in Synechocystis sp. strain PCC 6803 to photosynthetic impairment. We used 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU; a photosystem II inhibitor) to block O2 evolution and ATP/NADPH generation by linear electron flow. Based on (13)C-metabolic flux analysis ((13)C-MFA) and RNA sequencing, we have found that Synechocystis sp. PCC 6803 employs a unique photoheterotrophic metabolism. First, glucose catabolism forms a cyclic route that includes the oxidative pentose phosphate (OPP) pathway and the glucose-6 phosphate isomerase (PGI) reaction. Glucose-6-phosphate is extensively degraded by the OPP pathway for NADPH production and is replenished by the reversed PGI reaction. Second, the Calvin cycle is not fully functional, but RubisCO continues to fix CO2 and synthesize 3-phosphoglycerate. Third, the relative flux through the complete tricarboxylic acid (TCA) cycle and succinate dehydrogenase is small under heterotrophic conditions, indicating that the newly discovered cyanobacterial TCA cycle (via the gamma-aminobutyric acid pathway or alpha ketoglutarate decarboxylase/succinic semialdehyde dehydrogenase) plays a minimal role in energy metabolism. Fourth, NAD(P)H oxidation and the cyclic electron flow (CEF) around photosystem I are the two main ATP sources, and the CEF accounts for at least 40% of total ATP generation from photoheterotrophic metabolism (without considering maintenance loss). This study not only demonstrates a new topology for carbohydrate oxidation but also provides quantitative insights into metabolic bioenergetics in cyanobacteria. PMID- 25535270 TI - Activation of the sigmaE-dependent stress pathway by conjugative TraR may anticipate conjugational stress. AB - Horizontal gene transfer by conjugation plays a major role in bacterial evolution, allowing the acquisition of new traits, such as virulence and resistance to antibacterial agents. With the increased antibiotic resistance in bacterial pathogens, a better understanding of how bacteria modulate conjugation under changing environments and the genetic factors involved is needed. Despite the evolutionary advantages conjugation may confer, the process can be quite stressful for the donor cell. Here, we characterize the ability of TraR, encoded on the episomal F' plasmid, to upregulate the sigma(E) extracytoplasmic stress pathway in Escherichia coli. TraR, a DksA homolog, modulates transcription initiation through the secondary channel of RNA polymerase. We show here that TraR activates transcription directly; however, unlike DksA, it does so without using ppGpp as a cofactor. TraR expression can stimulate the sigma(E) extracytoplasmic stress response independently of the DegS/RseA signal transduction cascade. In the absence of TraR, bacteria carrying conjugative plasmids become more susceptible to external stress. We propose that TraR increases the concentrations of periplasmic chaperones and proteases by directly activating the transcription of sigma(E)-dependent promoters; this increased protein folding capacity may prepare the bacterium to endure the periplasmic stress of sex pilus biosynthesis during mating. PMID- 25535271 TI - Physiology and substrate specificity of two closely related amino acid transporters, SerP1 and SerP2, of Lactococcus lactis. AB - The serP1 and serP2 genes found adjacently on the chromosome of Lactococcus lactis strains encode two members of the amino acid-polyamine-organocation (APC) superfamily of secondary transporters that share 61% sequence identity. SerP1 transports L-serine, L-threonine, and L-cysteine with high affinity. Affinity constants (Km) are in the 20 to 40 MUM range. SerP2 is a DL-alanine/DL serine/glycine transporter. The preferred substrate appears to be DL-alanine for which the affinities were found to be 38 and 20 MUM for the D and L isomers, respectively. The common substrate L-serine is a high-affinity substrate of SerP1 and a low-affinity substrate of SerP2 with affinity constants of 18 and 356 MUM, respectively. Growth experiments demonstrate that SerP1 is the main L-serine transporter responsible for optimal growth in media containing free amino acids as the sole source of amino acids. SerP2 is able to replace SerP1 in this role only in medium lacking the high-affinity substrates L-alanine and glycine. SerP2 plays an adverse role for the cell by being solely responsible for the uptake of toxic D-serine. The main function of SerP2 is in cell wall biosynthesis through the uptake of D-alanine, an essential precursor in peptidoglycan synthesis. SerP2 has overlapping substrate specificity and shares 42% sequence identity with CycA of Escherichia coli, a transporter whose involvement in peptidoglycan synthesis is well established. No evidence was obtained for a role of SerP1 and SerP2 in the excretion of excess amino acids during growth of L. lactis on protein/peptide rich media. PMID- 25535272 TI - A prl mutation in SecY suppresses secretion and virulence defects of Listeria monocytogenes secA2 mutants. AB - The bulk of bacterial protein secretion occurs through the conserved SecY translocation channel that is powered by SecA-dependent ATP hydrolysis. Many Gram positive bacteria, including the human pathogen Listeria monocytogenes, possess an additional nonessential specialized ATPase, SecA2. SecA2-dependent secretion is required for normal cell morphology and virulence in L. monocytogenes; however, the mechanism of export via this pathway is poorly understood. L. monocytogenes secA2 mutants form rough colonies, have septation defects, are impaired for swarming motility, and form small plaques in tissue culture cells. In this study, 70 spontaneous mutants were isolated that restored swarming motility to L. monocytogenes secA2 mutants. Most of the mutants had smooth colony morphology and septated normally, but all were lysozyme sensitive. Five representative mutants were subjected to whole-genome sequencing. Four of the five had mutations in proteins encoded by the lmo2769 operon that conferred lysozyme sensitivity and increased swarming but did not rescue virulence defects. A point mutation in secY was identified that conferred smooth colony morphology to secA2 mutants, restored wild-type plaque formation, and increased virulence in mice. This secY mutation resembled a prl suppressor known to expand the repertoire of proteins secreted through the SecY translocation complex. Accordingly, the DeltasecA2prlA1 mutant showed wild-type secretion levels of P60, an established SecA2-dependent secreted autolysin. Although the prl mutation largely suppressed almost all of the measurable SecA2-dependent traits, the DeltasecA2prlA1 mutant was still less virulent in vivo than the wild-type strain, suggesting that SecA2 function was still required for pathogenesis. PMID- 25535273 TI - Transcriptional regulation of the vanillate utilization genes (vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-like repressor. AB - Corynebacterium glutamicum is able to utilize vanillate, the product of lignin degradation, as the sole carbon source. The vanillate utilization components are encoded by the vanABK operon. The vanA and vanB genes encode the subunits of vanillate O-demethylase, converting vanillate to protocatechuate, while VanK is the specific vanillate transporter. The vanABK operon is regulated by a PadR-type repressor, VanR. Heterologous gene expression and variations of the vanR open reading frame revealed that the functional VanR contains 192 residues (21 kDa) and forms a dimer, as analyzed by size exclusion chromatography. In vivo, ferulate, vanillin, and vanillate induced PvanABK in C. glutamicum, while only vanillate induced the activity of PvanABK in Escherichia coli lacking the ferulate catabolic system. Differential scanning fluorimetry verified that vanillate is the only effector of VanR. Interaction between the PvanABK DNA fragment and the VanR protein had an equilibrium dissociation constant (KD) of 15.1 +/- 1.7 nM. The VanR-DNA complex had a dissociation rate constant (Kd) of (267 +/- 23) * 10(-6) s(-1), with a half-life of 43.5 +/- 3.6 min. DNase I footprinting localized the VanR binding site at PvanABK, extending from +9 to +45 on the coding strand. Deletion of the nucleotides +18 to +27 inside the VanR binding site rendered PvanABK constitutive. Fusion of the T7 promoter and the wild-type VanR operator, as well as its shortened versions, indicated that the inverted repeat AACTAACTAA(N4)TTAGGTATTT is the specific VanR binding site. It is proposed that the VanR-DNA complex contains two VanR dimers at the VanR operator. PMID- 25535274 TI - A novel DNA-binding protein plays an important role in Helicobacter pylori stress tolerance and survival in the host. AB - The gastric pathogen Helicobacter pylori must combat chronic acid and oxidative stress. It does so via many mechanisms, including macromolecule repair and gene regulation. Mitomycin C-sensitive clones from a transposon mutagenesis library were screened. One sensitive strain contained the insertion element at the locus of hp119, a hypothetical gene. No homologous gene exists in any (non-H. pylori) organism. Nevertheless, the predicted protein has some features characteristic of histone-like proteins, and we showed that purified HP119 protein is a DNA-binding protein. A Deltahp119 strain was markedly more sensitive (viability loss) to acid or to air exposure, and these phenotypes were restored to wild-type (WT) attributes upon complementation of the mutant with the wild-type version of hp119 at a separate chromosomal locus. The mutant strain was approximately 10-fold more sensitive to macrophage-mediated killing than the parent or the complemented strain. Of 12 mice inoculated with the wild type, all contained H. pylori, whereas 5 of 12 mice contained the mutant strain; the mean colonization numbers were 158-fold less for the mutant strain. A proteomic (two-dimensional PAGE with mass spectrometric analysis) comparison between the Deltahp119 mutant and the WT strain under oxidative stress conditions revealed a number of important antioxidant protein differences; SodB, Tpx, TrxR, and NapA, as well as the peptidoglycan deacetylase PgdA, were significantly less expressed in the Deltahp119 mutant than in the WT strain. This study identified HP119 as a putative histone-like DNA-binding protein and showed that it plays an important role in Helicobacter pylori stress tolerance and survival in the host. PMID- 25535275 TI - Effects of the global regulator CsrA on the BarA/UvrY two-component signaling system. AB - The hybrid sensor kinase BarA and its cognate response regulator UvrY, members of the two-component signal transduction family, activate transcription of CsrB and CsrC noncoding RNAs. These two small RNAs act by sequestering the RNA binding protein CsrA, which posttranscriptionally regulates translation and/or stability of its target mRNAs. Here, we provide evidence that CsrA positively affects, although indirectly, uvrY expression, at both the transcriptional and translational levels. We also demonstrate that CsrA is required for properly switching BarA from its phosphatase to its kinase activity. Thus, the existence of a feedback loop mechanism that involves the Csr and BarA/UvrY global regulatory systems is exposed. PMID- 25535277 TI - International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function. AB - Urotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. Subsequently, UII was characterized in tetrapods including humans. Phylogenetic studies and synteny analysis indicate that UII and its paralogous peptide urotensin II-related peptide (URP) belong to the somatostatin/cortistatin superfamily. In mammals, the UII and URP genes are primarily expressed in cholinergic neurons of the brainstem and spinal cord. UII and URP mRNAs are also present in various organs notably in the cardiovascular, renal, and endocrine systems. UII and URP activate a common G protein-coupled receptor, called UT, that exhibits relatively high sequence identity with somatostatin, opioid, and galanin receptors. The UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including the retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle. Structure-activity relationship studies and NMR conformational analysis have led to the rational design of a number of peptidic and nonpeptidic UT agonists and antagonists. Consistent with the wide distribution of UT, UII has now been shown to exert a large array of biologic activities, in particular in the CNS, the cardiovascular system, and the kidney. Here, we review the current knowledge concerning the pleiotropic actions of UII and discusses the possible use of antagonists for future therapeutic applications. PMID- 25535276 TI - A terD domain-encoding gene (SCO2368) is involved in calcium homeostasis and participates in calcium regulation of a DosR-like regulon in Streptomyces coelicolor. AB - Although Streptomyces coelicolor is not resistant to tellurite, it possesses several TerD domain-encoding (tdd) genes of unknown function. To elucidate the function of tdd8, the transcriptomes of S. coelicolor strain M145 and of a tdd8 deletion mutant derivative (the Deltatdd8 strain) were compared. Several orthologs of Mycobacterium tuberculosis genes involved in dormancy survival were upregulated in the deletion mutant at the visual onset of prodiginine production. These genes are organized in a putative redox stress response cluster comprising two large loci. A binding motif similar to the dormancy survival regulator (DosR) binding site of M. tuberculosis has been identified in the upstream sequences of most genes in these loci. A predicted role for these genes in the redox stress response is supported by the low NAD(+)/NADH ratio in the Deltatdd8 strain. This S. coelicolor gene cluster was shown to be induced by hypoxia and NO stress. While the tdd8 deletion mutant (the Deltatdd8 strain) was unable to maintain calcium homeostasis in a calcium-depleted medium, the addition of Ca(2+) in Deltatdd8 culture medium reduced the expression of several genes of the redox stress response cluster. The results shown in this work are consistent with Tdd8 playing a significant role in calcium homeostasis and redox stress adaptation. PMID- 25535278 TI - Limits to compensatory adaptation and the persistence of antibiotic resistance in pathogenic bacteria. AB - Antibiotic resistance carries a fitness cost that could potentially limit the spread of resistance in bacterial pathogens. In spite of this cost, a large number of experimental evolution studies have found that resistance is stably maintained in the absence of antibiotics as a result of compensatory evolution. Clinical studies, on the other hand, have found that resistance in pathogen populations usually declines after antibiotic use is stopped, suggesting that compensatory adaptation is not effective in vivo. In this article, we argue that this disagreement arises because there are limits to compensatory adaptation in nature that are not captured by the design of current laboratory selection experiments. First, clinical treatment fails to eradicate antibiotic-sensitive strains, and competition between sensitive and resistant strains leads to the rapid loss of resistance following treatment. Second, laboratory studies overestimate the efficacy of compensatory adaptation in nature by failing to capture costs associated with compensatory mutations. Taken together, these ideas can potentially reconcile evolutionary theory with the clinical dynamics of antibiotic resistance and guide the development of strategies for containing resistance in clinical pathogens. PMID- 25535280 TI - Clinic staff attitudes towards the use of mHealth technology to conduct perinatal depression screenings: a qualitative study. AB - BACKGROUND: The use of mHealth technology is an innovative approach for screening low-income mothers for depression. Past studies show that the use of technology removes barriers such as literacy issues, language challenges, concerns about privacy and lack of transportation and can also increase reliability. However, little is known about staff attitudes and perceptions towards using mHealth technology for screening low-income women for depression in clinics. METHODS: Four focus groups were conducted with staff members in a supplemental nutrition program for women, infants and children located in a public health clinic. A semi structured focus group interview guide was used to examine staff perceptions related to depression screening with tablet technology. All interviews were audio recorded and transcribed verbatim. Thematic analysis was used to analyse all focus group data. RESULTS: Three major benefits and two major barriers were found. The benefits of using technology for perinatal depression screenings were reduction of literacy and language barriers, reduction of redundancy and errors and increased privacy for clients. The barriers were increased network issues and responsibility for technology, which included fear of the devices being lost, stolen or broken. IMPLICATIONS: Before implementing mHealth tablet technology for depression screening in a public health clinic, it is important to address the concerns of staff members to make the transition more effective. This study provides timely information on staff-perceived benefits and barriers when implementing mHealth technology in a public health setting. PMID- 25535281 TI - Zebrafish IRF1 regulates IFN antiviral response through binding to IFNphi1 and IFNphi3 promoters downstream of MyD88 signaling. AB - In mammals, type I IFNs (mainly IFN-alpha/beta) are primarily regulated by transcription factors of the IFN regulatory factor (IRF) family. Fish IFNs do not show a one-to-one orthologous relationship with mammalian type I IFN homologues. Using a bacterial one-hybrid reporter screening system and an overexpression approach to explore the molecular mechanism underlying fish IFN induction, we identified zebrafish Danio rerio IRF (DrIRF)1 as a positive regulator of the fish IFN antiviral response. Among 12 zebrafish IRF family genes, DrIRF1 is most abundant in zebrafish immune tissues, including head kidney and spleen; upon virus infection, it is one of most significantly induced genes. Overexpression of DrIRF1 induces the expression of IFN and IFN-stimulated genes, hence protecting epithelioma papulosum cyprini cells against spring viremia of carp virus infection. As a transcription factor with constitutively nuclear retention, DrIRF1 directly binds to the IFN-stimulated regulatory element/IRF-binding element sites of zebrafish IFN promoters, which are dependent on four conserved amino acids of the N-terminal DNA-binding domain helix alpha3 motif. Mutation of either residue reveals a differential requirement for DrIRF1-mediated activation of zebrafish IFNphi1 and IFNphi3 promoters. Notably, C-terminal phosphorylation of DrIRF1 is observed and is not required for in vitro binding of DrIRF1 to fish IFN promoters. Unlike DrIRF3 and DrIRF7, which are responsible for differential expression of zebrafish IFNphi1 and IFNphi3 through the retinoic acid-inducible gene I-like receptor pathway, DrIRF1 works in concert with MyD88 to activate zebrafish IFNphi3 but not IFNphi1. These results provide insights into the evolving function of IRF1 as a positive IFN regulator. PMID- 25535279 TI - CESA TRAFFICKING INHIBITOR inhibits cellulose deposition and interferes with the trafficking of cellulose synthase complexes and their associated proteins KORRIGAN1 and POM2/CELLULOSE SYNTHASE INTERACTIVE PROTEIN1. AB - Cellulose synthase complexes (CSCs) at the plasma membrane (PM) are aligned with cortical microtubules (MTs) and direct the biosynthesis of cellulose. The mechanism of the interaction between CSCs and MTs, and the cellular determinants that control the delivery of CSCs at the PM, are not yet well understood. We identified a unique small molecule, CESA TRAFFICKING INHIBITOR (CESTRIN), which reduces cellulose content and alters the anisotropic growth of Arabidopsis (Arabidopsis thaliana) hypocotyls. We monitored the distribution and mobility of fluorescently labeled cellulose synthases (CESAs) in live Arabidopsis cells under chemical exposure to characterize their subcellular effects. CESTRIN reduces the velocity of PM CSCs and causes their accumulation in the cell cortex. The CSC associated proteins KORRIGAN1 (KOR1) and POM2/CELLULOSE SYNTHASE INTERACTIVE PROTEIN1 (CSI1) were differentially affected by CESTRIN treatment, indicating different forms of association with the PM CSCs. KOR1 accumulated in bodies similar to CESA; however, POM2/CSI1 dissociated into the cytoplasm. In addition, MT stability was altered without direct inhibition of MT polymerization, suggesting a feedback mechanism caused by cellulose interference. The selectivity of CESTRIN was assessed using a variety of subcellular markers for which no morphological effect was observed. The association of CESAs with vesicles decorated by the trans-Golgi network-localized protein SYNTAXIN OF PLANTS61 (SYP61) was increased under CESTRIN treatment, implicating SYP61 compartments in CESA trafficking. The properties of CESTRIN compared with known CESA inhibitors afford unique avenues to study and understand the mechanism under which PM associated CSCs are maintained and interact with MTs and to dissect their trafficking routes in etiolated hypocotyls. PMID- 25535282 TI - Atg7 enhances host defense against infection via downregulation of superoxide but upregulation of nitric oxide. AB - Pseudomonas aeruginosa is an opportunistic bacterium that can cause serious infection in immunocompromised individuals. Although autophagy may augment immune responses against P. aeruginosa infection in macrophages, the critical components and their role of autophagy in host defense are largely unknown. In this study, we show that P. aeruginosa infection-induced autophagy activates JAK2/STAT1alpha and increases NO production. Knocking down Atg7 resulted in increased IFN-gamma release, excessive reactive oxygen species, and increased Src homology-2 domain containing phosphatase 2 activity, which led to lowered phosphorylation of JAK2/STAT1alpha and subdued expression of NO synthase 2 (NOS2). In addition, we demonstrated the physiological relevance of dysregulated NO under Atg7 deficiency as atg7(-/-) mice were more susceptible to P. aeruginosa infection with increased mortality and severe lung injury than wild-type mice. Furthermore, P. aeruginosa infected atg7(-/-) mice exhibited increased oxidation but decreased bacterial clearance in the lung and other organs compared with wild-type mice. Mechanistically, atg7 deficiency suppressed NOS2 activity by downmodulating JAK2/STAT1alpha, leading to decreased NO both in vitro and in vivo. Taken together, these findings revealed that the JAK2/STAT1alpha/NOS2 dysfunction leads to dysregulated immune responses and worsened disease phenotypes. PMID- 25535284 TI - Fixed expression of single influenza virus-specific TCR chains demonstrates the capacity for TCR alpha- and beta-chain diversity in the face of peptide-MHC class I specificity. AB - The characteristics of the TCR repertoire expressed by epitope-specific CD8(+) T cells can be an important determinant of the quality of immune protection against virus infection. Most studies of epitope-specific TCR repertoires focus solely on an analysis of TCR beta-chains, rather than the combined TCRalphabeta heterodimers that confer specificity. Hence, the importance of complementary alpha- and beta-chain pairing in determining TCR specificity and T cell function is not well understood. Our earlier study of influenza-specific TCR repertoires in a C57BL/6J mouse model described a structural basis for preferred TCRalphabeta pairing that determined exquisite specificity for the D(b)PA224 epitope from influenza A virus. We have now extended this analysis using retrogenic mice engineered to express single TCR alpha- or beta-chains specific for the D(b)NP366 or D(b)PA224 epitopes derived from influenza A virus. We found that particular TCRalphabeta combinations were selected for recognition of these epitopes following infection, indicating that pairing of certain alpha- and beta-chain sequences is key for determining TCR specificity. Furthermore, we demonstrated that some TCRalphabeta heterodimers were preferentially expanded from the naive repertoire in response to virus infection, suggesting that appropriate alphabeta pairing confers optimal T cell responsiveness to Ag. PMID- 25535283 TI - Differential expression of the transcription factor ARID3a in lupus patient hematopoietic progenitor cells. AB - Although hematopoietic stem/progenitor cells (HSPCs) are used for transplantation, characterization of the multiple subsets within this population in humans has lagged behind similar studies in mice. We found that expression of the DNA-binding protein, ARID3a, in mouse stem cells was important for normal development of hematopoietic lineages; however, progenitors expressing ARID3a in humans have not been defined. We previously showed increased numbers of ARID3a(+) B cells in nearly half of systemic lupus erythematosus (SLE) patients, and total numbers of ARID3a(+) B cells were associated with increased disease severity. Because expression of ARID3a in those SLE patients occurred throughout all B cell subsets, we hypothesized that ARID3a expression in patient HSPCs might also be increased relative to expression in healthy controls. Our data now show that ARID3a expression is not limited to any defined subset of HSPCs in either healthy controls or SLE patients. Numbers of ARID3a(+) HSPCs in SLE patients were increased over numbers of ARID3a(+) cells in healthy controls. Although all SLE derived HSPCs exhibited poor colony formation in vitro compared with controls, SLE HSPCs with high numbers of ARID3a(+) cells yielded increased numbers of cells expressing the early progenitor marker, CD34. SLE HSPCs with high numbers of ARID3a(+) cells also more readily generated autoantibody-producing cells than HSPCs with lower levels of ARID3a in a humanized mouse model. These data reveal new functions for ARID3a in early hematopoiesis and suggest that knowledge regarding ARID3a levels in HSPCs could be informative for applications requiring transplantation of those cells. PMID- 25535285 TI - Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues. AB - In this study, we showed that aly/aly mice, which are devoid of lymph nodes and Peyer's patches, acutely rejected fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts also were rejected acutely by splenectomized aly/aly (aly/aly-spl(-)) mice devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8(+) T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected by aly/aly-spl(-) mice. Actually, aly/aly spl(-) mice that spontaneously accepted a heart allotransplant and displayed donor-specific tolerance also accepted skin grafts from the same, but not a third party, donor via a mechanism involving CD4(+) regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic transplants, can occur in recipient mice lacking secondary lymphoid organs. PMID- 25535286 TI - Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance. AB - Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene (Mogat2(-/-)) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2(-/-) pups grew slower than wild-type littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is sufficient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2-inactivating mutation. Mice with adult-onset MGAT2 deficiency (Mogat2(AKO)) exhibited a transient decrease in food intake like Mogat2(-/-) mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2( /-) mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar protective effects were also observed in mice that had gained weight on a high-fat diet before inactivating MGAT2. These findings suggest that adult-onset MGAT2 deficiency mitigates metabolic disorders induced by high-fat feeding and that MGAT2 modulates early postnatal nutrition and may program metabolism later in life. PMID- 25535291 TI - Correction. PMID- 25535288 TI - Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol. AB - Pharmacologically increased estrogen levels have been shown to lower hepatic and plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in animals and humans. We hypothesized that physiological changes in estrogen levels influence circulating PCSK9, thereby contributing to the known wide inter individual variation in its plasma levels, as well as to the established increase in LDL cholesterol (LDL-C) with normal aging. Circulating PCSK9, estradiol, and other metabolic factors were determined in fasting samples from 206 female and 189 male healthy volunteers (age 20-85 years), The mean levels of PCSK9 were 10% higher in females than in males (P < 0.05). PCSK9 levels were 22% higher in postmenopausal than in premenopausal (P < 0.001) females. Within the group of premenopausal females, circulating PCSK9 correlated inversely to estrogen levels, and PCSK9 was higher (305 ng/ml) in the follicular phase than in the ovulatory (234 ng/ml) or the luteal (252 ng/ml) phases (P < 0.05). Changes in endogenous estrogen levels during the menstrual cycle likely contribute to the broad inter individual variation in PCSK9 and LDL-C in normal females. PCSK9 levels increase in females after menopause but not in men during this phase in life. This likely contributes to why LDL-C in women increases in this period. PMID- 25535287 TI - Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. AB - Adipocyte fatty acid binding protein 4, aP2, contributes to the pathogenesis of several common diseases including type 2 diabetes, atherosclerosis, fatty liver disease, asthma, and cancer. Although the biological functions of aP2 have classically been attributed to its intracellular action, recent studies demonstrated that aP2 acts as an adipokine to regulate systemic metabolism. However, the mechanism and regulation of aP2 secretion remain unknown. Here, we demonstrate a specific role for lipase activity in aP2 secretion from adipocytes in vitro and ex vivo. Our results show that chemical inhibition of lipase activity, genetic deficiency of adipose triglyceride lipase and, to a lesser extent, hormone-sensitive lipase blocked aP2 secretion from adipocytes. Increased lipolysis and lipid availability also contributed to aP2 release as determined in perilipin1-deficient adipose tissue explants ex vivo and upon treatment with lipids in vivo and in vitro. In addition, we identify a nonclassical route for aP2 secretion in exosome-like vesicles and show that aP2 is recruited to this pathway upon stimulation of lipolysis. Given the effect of circulating aP2 on glucose metabolism, these data support that targeting aP2 or the lipolysis dependent secretory pathway may present novel mechanistic and translational opportunities in metabolic disease. PMID- 25535292 TI - Response to: What characteristics of primary care and patients are associated with early death in patients with lung cancer in the UK? PMID- 25535293 TI - E-cigarette use and intentions to smoke among 10-11-year-old never-smokers in Wales. AB - BACKGROUND: E-cigarettes are seen by some as offering harm reduction potential, where used effectively as smoking cessation devices. However, there is emerging international evidence of growing use among young people, amid concerns that this may increase tobacco uptake. Few UK studies examine the prevalence of e-cigarette use in non-smoking children or associations with intentions to smoke. METHODS: A cross-sectional survey of year 6 (10-11-year-old) children in Wales. Approximately 1500 children completed questions on e-cigarette use, parental and peer smoking, and intentions to smoke. Logistic regression analyses among never smoking children, adjusted for school-level clustering, examined associations of smoking norms with e-cigarette use, and of e-cigarette use with intentions to smoke tobacco within the next 2 years. RESULTS: Approximately 6% of year 6 children, including 5% of never smokers, reported having used an e-cigarette. By comparison to children whose parents neither smoked nor used e-cigarettes, children were most likely to have used an e-cigarette if parents used both tobacco and e-cigarettes (OR=3.40; 95% CI 1.73 to 6.69). Having used an e cigarette was associated with intentions to smoke (OR=3.21; 95% CI 1.66 to 6.23). While few children reported that they would smoke in 2 years' time, children who had used an e-cigarette were less likely to report that they definitely would not smoke tobacco in 2 years' time and were more likely to say that they might. CONCLUSIONS: E-cigarettes represent a new form of childhood experimentation with nicotine. Findings are consistent with a hypothesis that children use e cigarettes to imitate parental and peer smoking behaviours, and that e-cigarette use is associated with weaker antismoking intentions. PMID- 25535296 TI - Cancer screening in older adults: risks and benefits. PMID- 25535297 TI - Emerging databases streamline cancer research and treatment. PMID- 25535298 TI - Leroy Hood looks forward to P4 medicine: predictive, personalized, preventive, and participatory. PMID- 25535294 TI - Different profiles of carcinogen exposure in Chinese compared with US cigarette smokers. AB - BACKGROUND: Differences in carcinogen exposure from different cigarette products could contribute to differences in smoking-associated cancer incidence among Chinese compared with US smokers. METHODS: Urine concentrations of metabolites of nicotine, the tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL), and polycyclic aromatic hydrocarbon metabolites (PAHs) were compared in 238 Chinese and 203 US daily smokers. RESULTS: Comparing Chinese versus US smokers, daily nicotine intake and nicotine intake per cigarette smoked were found to be similar. When normalised for cigarettes per day, urine NNAL excretion was fourfold higher in US smokers, while the excretion of urine metabolites of the PAHs fluorene, phenanthrene and pyrene metabolites was 50% to fourfold higher in Chinese smokers (all, p<0.0001). Similar results were seen when NNAL and PAHs excretion was normalised for daily nicotine intake. CONCLUSIONS: Patterns of carcinogen exposure differ, with lower exposure to TSNA and higher exposure to PAHs in Chinese compared with US smokers. These results most likely reflect country differences in cigarette tobacco blends and manufacturing processes, as well as different environmental exposures. TRIAL REGISTRATION NUMBER: NCT00264342. PMID- 25535299 TI - New approaches tackle rising pancreatic cancer rates. PMID- 25535302 TI - Microvascular endothelial cells poised to take center stage in experimental renal fibrosis. PMID- 25535301 TI - Tissue Inhibitor Metalloproteinase-2 (TIMP-2)?IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI. AB - Tissue inhibitor metalloproteinase-2 (TIMP-2) and IGF-binding protein-7 (IGFBP7) have been validated for risk stratification in AKI. However, the association of urinary TIMP-2 and IGFBP7 with long-term outcomes is unknown. We evaluated the 9 month incidence of a composite end point of all-cause mortality or the need for RRT in a secondary analysis of a prospective observational international study of critically ill adults. Two predefined [TIMP-2]?[IGFBP7] cutoffs (0.3 for high sensitivity and 2.0 for high specificity) for the development of AKI were evaluated. Cox proportional hazards models were used to determine risk for the composite end point. Baseline [TIMP-2]?[IGFBP7] values were available for 692 subjects, of whom 382 (55.2%) subjects developed stage 1 AKI (defined by Kidney Disease Improving Global Outcomes guidelines) within 72 hours of enrollment and 217 (31.4%) subjects met the composite end point. Univariate analysis showed that [TIMP-2]?[IGFBP7]>2.0 was associated with increased risk of the composite end point (hazard ratio [HR], 2.11; 95% confidence interval [95% CI], 1.37 to 3.23; P<0.001). In a multivariate analysis adjusted for the clinical model, [TIMP 2]?[IGFBP7] levels>0.3 were associated with death or RRT only in subjects who developed AKI (compared with levels<=0.3: HR, 1.44; 95% CI, 1.00 to 2.06 for levels>0.3 to <=2.0; P=0.05 and HR, 2.16; 95% CI, 1.32 to 3.53 for levels>2.0; P=0.002). In conclusion, [TIMP-2]?[IGFBP7] measured early in the setting of critical illness may identify patients with AKI at increased risk for mortality or receipt of RRT over the next 9 months. PMID- 25535304 TI - Urinary Biomarkers: Alone Are They Enough? PMID- 25535303 TI - Curtailing endothelial TGF-beta signaling is sufficient to reduce endothelial mesenchymal transition and fibrosis in CKD. AB - Excessive TGF-beta signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-beta signaling on development of fibrosis, there is a lack of information on ablating TGF-beta signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-beta receptor knockout (TbetaRII(endo+/-)) mice to explore whether curtailed TGF-beta signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TbetaRII(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TbetaRII(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TbetaRII(endo+/+) counterparts. In addition, partial deletion of TbetaRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-beta-induced canonical Smad2 signaling was reduced in TbetaRII(+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TbetaRII(+/-) ECs remained unaffected. Furthermore, the S endoglin/L-endoglin mRNA expression ratio was significantly lower in TbetaRII(+/ ) ECs compared with TbetaRII(+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-beta signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-beta signaling and EndoMT in regulating angiogenic and fibrotic responses to injury. PMID- 25535306 TI - Deep brain stimulation for treatment of dystonia secondary to stroke or trauma. PMID- 25535305 TI - Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution. AB - OBJECTIVE: Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce. METHODS: We retrospectively evaluated the long-term clinical evolution, and genotype phenotype correlations in 35 genetically identified BM patients (23 index cases). RESULTS: Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12 novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease. CONCLUSIONS: Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping. PMID- 25535307 TI - The neural correlates of road sign knowledge and route learning in semantic dementia and Alzheimer's disease. AB - BACKGROUND: Although there is a growing body of research on driving and Alzheimer's disease (AD), focal dementias have been understudied. Moreover, driving has never been explored in semantic dementia (SD). METHODS: An experimental battery exploring road sign knowledge and route learning was applied to patients with SD and AD selected in the early-moderate stage of disease and to a group of healthy participants. Neuropsychological data were correlated to cerebral hypometabolism distribution, investigated by means of positron emission tomography. RESULTS: The two dementias showed opposite profiles. Patients with SD showed poor road sign knowledge and normal performance in route learning. By contrast, patients with AD showed low performance in route learning test with preservation of semantic knowledge of road signs. In SD, there was a correlation of semantic knowledge impairment with hypometabolism in the left temporolateral cortex. No correlation between the AD region of interests (ROIs) and the relevant behavioural indices was found, while in the whole-brain analysis there was a significant correlation between route learning and the superior frontal gyrus. DISCUSSION AND CONCLUSIONS: For the first time, driving skills were explored in SD, and it is showed a differential profile from the one detected in AD. We demonstrate that the left anterior temporal cortex is implicated in road sign knowledge, while a distributed cortical network, including the frontal cortex, is likely to process route learning. PMID- 25535308 TI - Acute illness is associated with suppression of the growth hormone axis in Zimbabwean infants. AB - Frequent infections contribute to childhood stunting in developing countries but the causal pathways are uncertain. We tested the hypothesis that intercurrent illnesses suppress the growth hormone axis through reductions in insulin-like growth factor 1 (IGF-1). In a birth cohort of 202 HIV-unexposed Zimbabwean infants, we analyzed data on 7-day illness recall and measured plasma interleukin 6, C-reactive protein, alpha-1-acid glycoprotein, and IGF-1 by enzyme-linked immunosorbent assay, at age 6 weeks, and then 3, 6, 12, and 18 months. Children with recent acute illness had lower IGF-1 concentrations than healthy children and IGF-1 correlated inversely (P < 0.05) with inflammatory biomarkers at most time points between 3 and 18 months. Using path analysis, we showed that cough and fever had a predominantly indirect effect on suppressing IGF-1, through the acute-phase response, whereas diarrhea had a predominantly direct effect on IGF 1. Acute illness may therefore impact the growth hormone axis through both direct and indirect pathways. PMID- 25535309 TI - Cross-sectional survey of Rift Valley fever virus exposure in Bodhei village located in a transitional coastal forest habitat in Lamu county, Kenya. AB - Few studies have focused on Rift Valley fever virus (RVFV) transmission in less arid, transitional landscapes surrounding known high-risk regions. The objective of this study was to identify evidence of RVFV exposure in Bodhei Village in a forested area at the edge of the RVFV-epidemic Garissa region. In a household cluster-based survey conducted between epidemics in early 2006, 211 participants were enrolled. Overall seroprevalence for anti-RVFV was high (18%) and comparable with rates in the more arid, dense brush regions farther north. Seroprevalence of adults was 28%, whereas that of children was significantly lower (3%; P < 0.001); the youngest positive child was age 3 years. Males were more likely to be seropositive than females (25% versus 11%; P < 0.01), and animal husbandry activities (birthing, sheltering, and butchering) were strongly associated with seropositivity. The results confirm that significant RVFV transmission occurs outside of recognized high-risk areas and independent of known epidemic periods. PMID- 25535310 TI - Comparing risk factors for primary multidrug-resistant tuberculosis and primary drug-susceptible tuberculosis in Jiangsu province, China: a matched-pairs case control study. AB - To find out the reason why some people get infected directly with multidrug resistant tuberculosis (MDR-TB), whereas some get infected with drug-susceptible tuberculosis (DS-TB), a 1:1:1 matched-pairs case-control study was conducted to identify predictors associated with primary MDR-TB and primary DS-TB against the control in Jiangsu Province, China. All three groups were geographically matched (by neighborhood) and matched on sex and age (+/-5 years). In total, 110 participants were enrolled in each of three matched groups. Conditional logistic regression analysis showed that predictors independently associated with primary MDR-TB were illiteracy or primary school education, annual per capita income <= US$2,000, per capita living space < 40 m(2), and interval >= 7 days of eating fruits; predictors with primary DS-TB were body mass index <= 20 and feeling higher life pressure. This indicates that there are different predictors impacting the transmission range of primary MDR-TB and primary DS-TB in the general population. PMID- 25535311 TI - Induced sputum is safe and well-tolerated for TB diagnosis in a resource-poor primary healthcare setting. AB - Improved tuberculosis (TB) diagnostics are required. Induced sputum sampling is superior to spontaneous sputum analysis for diagnosis of pulmonary TB. Therefore, we examined the applicability of induced sputum in primary health centers of the Peruvian TB program and studied the safety and tolerability of this procedure. We show that induced sputum is safe, inexpensive, and well-tolerated in a resource limited environment. Widespread use of induced sputum at primary health centers can be implemented and may improve TB diagnosis. PMID- 25535312 TI - My experience as an Ebola patient. PMID- 25535313 TI - Imported pythium insidiosum keratitis after a swim in Thailand by a contact lens wearing traveler. AB - A 30-year-old woman with a history of contact lens wear and exposure to swimming pool water in Thailand presented with a non-responsive, progressive corneal ulcer of the right eye. Confocal microscopy evidenced septate linear branching structures, raising suspicion of fungal keratitis. She was promptly treated with topical antibiotics and both topical and intravenous caspofungin plus voriconazole. Worsening of the clinical picture after 1 month of intensive medical therapy led to a large therapeutic penetrating keratoplasty being performed. Corneal cultures grew a mold-like organism, which was identified by sequencing as Pythium insidiosum, an aquatic oomycete. After 4 years of follow up, the graft exhibits no infection relapse, but graft transparency has been lost after two rejection episodes. Keratoplasty combined with antifungal treatment may offer a cure to P. insidiosum keratitis, although long-term preservation of corneal transparency is difficult to obtain. PMID- 25535314 TI - An autochthonous case of severe Plasmodium knowlesi malaria in Thailand. AB - A 58-year-old Thai man was infected with Plasmodium knowlesi in Chantaburi Province, eastern Thailand. In addition to pyrexia, the patient developed hypotension, renal failure, jaundice, and severe thrombocytopenia. The parasitemia at the time of admission was 16.67% or ~503,400 parasites/MUL. With artesunate treatment and supportive care, the patient recovered uneventfully. The occurrence of complicated knowlesi malaria in a low-endemic area underscores the risk of high morbidity from this simian malaria. PMID- 25535315 TI - Molecular detection of HIV-1 subtype B, CRF01_AE, CRF33_01B, and newly emerging recombinant lineages in Malaysia. AB - A molecular genotyping assay for human immunodeficiency virus type 1 (HIV-1) circulating in Southeast Asia is difficult to design because of the high level of genetic diversity. We developed a multiplex real-time polymerase chain reaction (PCR) assay to detect subtype B, CRF01_AE, CRF33_01B, and three newly described circulating recombinant forms, (CRFs) (CRF53_01B, CRF54_01B, and CRF58_01B). A total of 785 reference genomes were used for subtype-specific primers and TaqMan probes design targeting the gag, pol, and env genes. The performance of this assay was compared and evaluated with direct sequencing and phylogenetic analysis. A total of 180 HIV-infected subjects from Kuala Lumpur, Malaysia were screened and 171 samples were successfully genotyped, in agreement with the phylogenetic data. The HIV-1 genotype distribution was as follows: subtype B (16.7%); CRF01_AE (52.8%); CRF33_01B (24.4%); CRF53_01B (1.1%); CRF54_01B (0.6%); and CRF01_AE/B unique recombinant forms (4.4%). The overall accuracy of the genotyping assay was over 95.0%, in which the sensitivities for subtype B, CRF01_AE, and CRF33_01B detection were 100%, 100%, and 97.7%, respectively. The specificity of genotyping was 100%, inter-subtype specificities were > 95% and the limit of detection of 10(3) copies/mL for plasma. The newly developed real time PCR assay offers a rapid and cost-effective alternative for large-scale molecular epidemiological surveillance for HIV-1. PMID- 25535317 TI - Ebola: my head is full of stories. PMID- 25535319 TI - Improving public health from an Epicurean perspective. PMID- 25535316 TI - Genetic characterization of Echinococcus granulosus from a large number of formalin-fixed, paraffin-embedded tissue samples of human isolates in Iran. AB - Cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus, presents an important medical and veterinary problem globally, including that in Iran. Different genotypes of E. granulosus have been reported from human isolates worldwide. This study identifies the genotype of the parasite responsible for human hydatidosis in three provinces of Iran using formalin-fixed paraffin-embedded tissue samples. In this study, 200 formalin-fixed paraffin embedded tissue samples from human CE cases were collected from Alborz, Tehran, and Kerman provinces. Polymerase chain reaction amplification and sequencing of the partial mitochondrial cytochrome c oxidase subunit 1 gene were performed for genetic characterization of the samples. Phylogenetic analysis of the isolates from this study and reference sequences of different genotypes was done using a maximum likelihood method. In total, 54.4%, 0.8%, 1%, and 40.8% of the samples were identified as the G1, G2, G3, and G6 genotypes, respectively. The findings of the current study confirm the G1 genotype (sheep strain) to be the most prevalent genotype involved in human CE cases in Iran and indicates the high prevalence of the G6 genotype with a high infectivity for humans. Furthermore, this study illustrates the first documented human CE case in Iran infected with the G2 genotype. PMID- 25535318 TI - Parental experiential avoidance as a potential mechanism of change in a parenting intervention for parents of children with pediatric acquired brain injury. AB - OBJECTIVE: To consider the relationship of parental experiential avoidance (EA) to psychological symptoms and problematic parenting strategies after pediatric acquired brain injury (ABI). METHODS: Using available data from a randomized controlled trial of a group-based Acceptance and Commitment Therapy (ACT) workshop plus a behavioral family intervention (BFI) for parents of children with ABI (n = 59), correlational and mediational analyses were conducted to consider the role of parental EA as a process of change for parent outcomes. RESULTS: Parent EA positively correlated with ineffective parenting behaviors and levels of psychological distress, both cross-sectionally and longitudinally. Reductions in EA mediated the treatment effect on reducing ineffective parenting behaviors and parent distress, but issues of temporality were present. CONCLUSIONS: EA is related to parent outcomes following pediatric ABI. A larger and methodologically rigorous study is called for to further elucidate this finding and specifically determine the benefits of targeting EA with interventions such as ACT, in conjunction with evidence-based BFIs. PMID- 25535320 TI - Freedom from frozen: the first British military use of lyophilised plasma in forward resuscitation. AB - Prehospital use of blood products may improve survival. However, transfusion support with frozen blood components is logistically burdensome and constrains the configuration of prehospital medical support. Alternatives to frozen plasma, including lyophilised plasma, offer the potential for advanced resuscitation in the prehospital environment. We describe the successful use of lyophilised plasma by a UK patrol in the prehospital environment during operations in Afghanistan in 2012 and reflect on recent military experience and the need for further developments. PMID- 25535321 TI - Costal bone abnormalities: an unusual cause of spontaneous bilateral breast implant deflation?. AB - Augmentation mammoplasty is the most common aesthetic surgical procedure performed in the USA. Prosthetic failure is a major reason for surgical reintervention. A number of causes for this have been documented, but costal bone abnormalities leading to perforation of the prosthesis are very unusual. We present the case of a woman who experienced spontaneous deflation of both saline implants in close succession, and who was found to have sharp bony spicules on both sides of her chest. Pathology examination reported reactive changes, suggestive of heterotopic bone. Examination of the implants showed no defects besides small punctures on the back wall, which coincided with the position of the spicules of bone. There are a number of possible causes for these bony growths which we examine in turn. The chest wall should be examined in all cases where unexplained implant deflation has occurred. PMID- 25535322 TI - Definition of herpes simplex virus helper functions for the replication of adeno associated virus type 5. AB - Adeno-associated virus (AAV) type 5 represents the genetically most distant AAV serotype and the only one isolated directly from human tissue. Seroepidemiological evidence suggests herpes simplex virus (HSV) as a helper virus for human AAV5 infections, underlining the in vivo relevance of the AAV herpesvirus relationship. In this study we analysed, for the first time, HSV helper functions for productive AAV5 replication, and compared these to AAV2. Using a combination of HSV strains and plasmids for individual genes, the previously defined HSV helper functions for AAV2 replication were shown to induce AAV5 gene expression, DNA replication and production of infectious progeny. The helper functions comprise the replication genes for ICP8 (UL29), helicase-primase (UL5/8/52), and DNA polymerase (UL30/42). HSV immediate-early genes for ICP0 and ICP4 further enhanced AAV5 replication, mainly by induction of rep gene expression. In the presence of HSV helper functions, AAV5 Rep co-localized with ICP8 in nuclear replication compartments, and HSV alkaline exonuclease (UL12) enhanced AAV5 replication, similarly to AAV2. UL12, in combination with ICP8, was shown to induce DNA strand exchange on partially double-stranded templates to resolve and repair concatemeric HSV replication intermediates. Similarly, concatemeric AAV replication intermediates appeared to be processed to yield AAV unit-length molecules, ready for AAV packaging. Taken together, our findings show that productive AAV5 replication is promoted by the same combination of HSV helper functions as AAV2. PMID- 25535324 TI - Characterization of a novel circo-like virus in Aedes vexans mosquitoes from Germany: evidence for a new genus within the family Circoviridae. AB - Over recent decades, metagenomic studies have expanded the number of newly described, often unclassified, viruses within the family Circoviridae. Using broad-spectrum circovirus and cyclovirus PCRs, we characterized a novel circo like virus in Aedes vexans mosquitoes from Germany whose main putative ORFs shared very low amino acid identity with those of previously characterized circoviruses and cycloviruses. Phylogenetic and genetic distance analysis revealed that this new virus species defined, together with previously described mosquito- and bat faeces-derived circo-like viruses, a different genus, tentatively called Krikovirus, within the family Circoviridae. We further demonstrated that viruses of the putative genus Krikovirus all shared a genomic organization that was unique among the family Circoviridae. Further investigations are needed to determine the host range, tissue tropism and transmission route(s). This report increases the current knowledge of the genetic diversity and evolution of the members of the family Circoviridae. PMID- 25535325 TI - Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation. AB - Infection with hepatitis C virus (HCV) is characterized by systemic oxidative stress that is caused by either viral core protein or chronic inflammation. It is well recognized that reactive oxygen species (ROS) such as H2O2 can induce apoptotic cell death and can therefore function as anti-tumorigenic species. However, the detailed mechanisms by which ROS induce apoptotic cell death and HCV copes with the oxidative conditions are largely unknown. In the present study, we found that H2O2 induced apoptotic cell death in p53-positive human hepatocytes, but not in p53-negative human hepatocytes. For this effect, H2O2 upregulated levels of p14, increased ubiquitin-dependent degradation of mouse double minute 2 (MDM2), and reduced the interaction between MDM2 and p53 to prevent p53 degradation, resulting in accumulation of p53 and subsequent activation of p53 dependent apoptotic pathways. Interestingly, HCV core repressed p14 expression via promoter hypermethylation to abolish the potential of H2O2 to activate the p14-MDM2-p53 pathway. As a consequence, HCV core-expressing cells could overcome p53-mediated apoptosis provoked by H2O2. Taken together, HCV core could contribute to hepatocellular carcinoma formation by removing deleterious roles of ROS inducing cell death. PMID- 25535323 TI - Rapid evolution of the env gene leader sequence in cats naturally infected with feline immunodeficiency virus. AB - Analysing the evolution of feline immunodeficiency virus (FIV) at the intra-host level is important in order to address whether the diversity and composition of viral quasispecies affect disease progression. We examined the intra-host diversity and the evolutionary rates of the entire env and structural fragments of the env sequences obtained from sequential blood samples in 43 naturally infected domestic cats that displayed different clinical outcomes. We observed in the majority of cats that FIV env showed very low levels of intra-host diversity. We estimated that env evolved at a rate of 1.16*10(-3) substitutions per site per year and demonstrated that recombinant sequences evolved faster than non recombinant sequences. It was evident that the V3-V5 fragment of FIV env displayed higher evolutionary rates in healthy cats than in those with terminal illness. Our study provided the first evidence that the leader sequence of env, rather than the V3-V5 sequence, had the highest intra-host diversity and the highest evolutionary rate of all env fragments, consistent with this region being under a strong selective pressure for genetic variation. Overall, FIV env displayed relatively low intra-host diversity and evolved slowly in naturally infected cats. The maximum evolutionary rate was observed in the leader sequence of env. Although genetic stability is not necessarily a prerequisite for clinical stability, the higher genetic stability of FIV compared with human immunodeficiency virus might explain why many naturally infected cats do not progress rapidly to AIDS. PMID- 25535329 TI - DEAD-box RNA helicase Dbp4 is required for small-subunit processome formation and function. AB - DEAD-box RNA helicase Dbp4 is required for 18S rRNA synthesis: cellular depletion of Dbp4 impairs the early cleavage reactions of the pre-rRNA and causes U14 small nucleolar RNA (snoRNA) to remain associated with pre-rRNA. Immunoprecipitation experiments (IPs) carried out with whole-cell extracts (WCEs) revealed that hemagglutinin (HA)-tagged Dbp4 is associated with U3 snoRNA but not with U14 snoRNA. IPs with WCEs also showed association with the U3-specific protein Mpp10, which suggests that Dbp4 interacts with the functionally active U3 RNP; this particle, called the small-subunit (SSU) processome, can be observed at the 5' end of nascent pre-rRNA. Electron microscopy analyses indicated that depletion of Dbp4 compromised SSU processome formation and cotranscriptional cleavage of the pre-rRNA. Sucrose density gradient analyses revealed that depletion of U3 snoRNA or the Mpp10 protein inhibited the release of U14 snoRNA from pre-rRNA, just as was seen with Dbp4-depleted cells, indicating that alteration of SSU processome components has significant consequences for U14 snoRNA dynamics. We also found that the C-terminal extension flanking the catalytic core of Dbp4 plays an important role in the release of U14 snoRNA from pre-rRNA. PMID- 25535330 TI - Progenitor stage-specific activity of a cis-acting double GATA motif for Gata1 gene expression. AB - GATA1 is a master regulator of erythropoiesis, expression of which is regulated by multiple discrete cis-acting elements. In this study, we examine the activity of a promoter-proximal double GATA (dbGATA) motif, using a Gata1 bacterial artificial chromosome (BAC)-transgenic green fluorescent protein (GFP) reporter (G1BAC-GFP) mouse system. Deletion of the dbGATA motif led to significant reductions in GFP expression in hematopoietic progenitors, while GFP expression was maintained in erythroblasts. Consistently, in mice with a germ line deletion of the dbGATA motif (Gata1(DeltadbGATA) mice), GATA1 expression in progenitors was significantly decreased. The suppressed GATA1 expression was associated with a compensatory increase in GATA2 levels in progenitors. When we crossed Gata1(DeltadbGATA) mice with Gata2 hypomorphic mutant mice (Gata2(fGN/fGN) mice), the Gata1(DeltadbGATA)::Gata2(fGN/fGN) compound mutant mice succumbed to a significant decrease in the progenitor population, whereas both groups of single mutant mice maintained progenitors and survived to adulthood, indicating the functional redundancy between GATA1 and GATA2 in progenitors. Meanwhile, the effects of the dbGATA site deletion on Gata1 expression were subtle in erythroblasts, which showed increased GATA1 binding and enhanced accumulation of active histone marks around the 1st-intron GATA motif of the DeltadbGATA locus. These results thus reveal a novel role of the dbGATA motif in the maintenance of Gata1 expression in hematopoietic progenitors and a functional compensation between the dbGATA site and the 1st-intron GATA motif in erythroblasts. PMID- 25535331 TI - Antagonistic controls of chromatin and mRNA start site selection by Tup family corepressors and the CCAAT-binding factor. AB - The Tup family corepressors contribute to critical cellular responses, such as the stress response and differentiation, presumably by inducing repressive chromatin, though the precise repression mechanism remains to be elucidated. The Schizosaccharomyces pombe fission yeast Tup family corepressors Tup11 and Tup12 (Tup11/12), which are orthologs of Tup1 in Saccharomyces cerevisiae budding yeast and Groucho in Drosophila, negatively control chromatin and the transcriptional activity of some stress-responsive genes. Here, we demonstrate that Tup11/12 repress transcription of a gluconeogenesis gene, fbp1+, by three distinct mechanisms. First, Tup11/12 inhibit chromatin remodeling in the fbp1+ promoter region where the Atf1 and Rst2 transcriptional activators bind. Second, they repress the formation of an open chromatin configuration at the fbp1+ TATA box. Third, they repress mRNA transcription per se by regulating basic transcription factors. These inhibitory actions of Tup11/12 are antagonized by three different types of transcriptional activators: CREB/ATF-type Atf1, C2H2zinc finger-type Rst2, and CBF/NF-Y-type Php5 proteins. We also found that impaired chromatin remodeling and fbp1+ mRNA transcription in php5Delta strains are rescued by the double deletions of tup11+ and tup12+, although the distribution of the transcription start sites becomes broader than that in wild-type cells. These data reveal a new mechanism of precise determination of the mRNA start site by Tup family corepressors and CBF/NF-Y proteins. PMID- 25535332 TI - Role of lamin b1 in chromatin instability. AB - Nuclear lamins play important roles in the organization and structure of the nucleus; however, the specific mechanisms linking lamin structure to nuclear functions are poorly defined. We demonstrate that reducing nuclear lamin B1 expression by short hairpin RNA-mediated silencing in cancer cell lines to approximately 50% of normal levels causes a delay in the cell cycle and accumulation of cells in early S phase. The S phase delay appears to be due to the stalling and collapse of replication forks. The double-strand DNA breaks resulting from replication fork collapse were inefficiently repaired, causing persistent DNA damage signaling and the assembly of extensive repair foci on chromatin. The expression of multiple factors involved in DNA replication and repair by both nonhomologous end joining and homologous repair is misregulated when lamin B1 levels are reduced. We further demonstrate that lamin B1 interacts directly with the promoters of some genes associated with DNA damage response and repair, including BRCA1 and RAD51. Taken together, the results suggest that the maintenance of lamin B1 levels is required for DNA replication and repair through regulation of the expression of key factors involved in these essential nuclear functions. PMID- 25535333 TI - An Arf-Egr-C/EBPbeta pathway linked to ras-induced senescence and cancer. AB - Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19(Arf) or other tumor suppressors can be transformed. The transcription factor C/EBPbeta is required for OIS in primary fibroblasts but is downregulated by H-Ras(V12) in immortalized NIH 3T3 cells through a mechanism involving p19(Arf) loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3(Ras) cells and directly and redundantly control Cebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in the Cebpb promoter and associate transiently with this region after serum stimulation, coincident with Cebpb induction. Codepletion of all three Egrs prevented Cebpb expression, and serum induction of Egrs was significantly blunted in 3T3(Ras) cells. Egr2 and Egr3 levels were also reduced in Ras(V12)-expressing p19(Arf) null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf deficient but not wild-type (WT) MEFs, leading to Cebpb downregulation. Analysis of human cancers revealed a strong correlation between EGR levels and CEBPB expression, regardless of whether CEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines induced CEBPB and inhibited proliferation. Thus, our findings identify the Arf-Egr-C/EBPbeta axis as an important determinant of cellular responses (senescence or transformation) to oncogenic Ras signaling. PMID- 25535335 TI - Poly(ADP-ribosyl) glycohydrolase prevents the accumulation of unusual replication structures during unperturbed S phase. AB - Poly(ADP-ribosyl)ation (PAR) has been implicated in various aspects of the cellular response to DNA damage and genome stability. Although 17 human poly(ADP ribose) polymerase (PARP) genes have been identified, a single poly(ADP-ribosyl) glycohydrolase (PARG) mediates PAR degradation. Here we investigated the role of PARG in the replication of human chromosomes. We show that PARG depletion affects cell proliferation and DNA synthesis, leading to replication-coupled H2AX phosphorylation. Furthermore, PARG depletion or inhibition per se slows down individual replication forks similarly to mild chemotherapeutic treatment. Electron microscopic analysis of replication intermediates reveals marked accumulation of reversed forks and single-stranded DNA (ssDNA) gaps in unperturbed PARG-defective cells. Intriguingly, while we found no physical evidence for chromosomal breakage, PARG-defective cells displayed both ataxia telangiectasia-mutated (ATM) and ataxia-Rad3-related (ATR) activation, as well as chromatin recruitment of standard double-strand-break-repair factors, such as 53BP1 and RAD51. Overall, these data prove PAR degradation to be essential to promote resumption of replication at endogenous and exogenous lesions, preventing idle recruitment of repair factors to remodeled replication forks. Furthermore, they suggest that fork remodeling and restarting are surprisingly frequent in unperturbed cells and provide a molecular rationale to explore PARG inhibition in cancer chemotherapy. PMID- 25535334 TI - Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes. AB - Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor alpha (PPARalpha)/PGC-1alpha and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1alpha. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. PMID- 25535336 TI - The application of different appendicular skeletal muscle cutoff points and research definitions associated with health-related quality of life in Korean older people: data from KNHANES 2008-2011. AB - BACKGROUND: This study was conducted to determine the prevalence of a low appendicular skeletal muscle index (ASMI) using three cut-off points (mean ASMI 2SD of a gender-specific young reference group (aged 18-39 years), mean ASMI-1SD of a gender-specific young reference group, and the lower 20 percentile value of a gender-specific older group (aged >= 65 years)) in Korean older people and the relationship between ASMI and subjective health-related quality of life. METHODS: This study utilized data acquired during the Korean National Health and Nutrition Examination Survey (KNHANES) from 2008-2011. Dual-energy X-ray absorptiometry body compositional data was obtained from a subsample of 6538 subjects (men 2804, women 3734) aged 18-39 and 4413 subjects (men 1872, women 2541) aged 65 years and older. The three definitions of low appendicular skeletal muscle and the EQ-5D-3 L-Korean descriptive system were applied to Korean older people. RESULTS: For the ASMI cutoff points used, in men, the three cutoff points were ASMI 2SD (6.09 kg/m2), ASMI 20 (6.48 kg/m2), and ASMI 1SD (6.95 kg/m2). In women, ASMI 2SD (4.38 kg/m2) was the lowest, followed by ASMI 1SD (4.96 kg/m2) and ASMI 20 (5.33 kg/m2). Proportions of older subjects with a low ASMI using the three cutoff points were 9.7% (ASMI 2SD) and 40.9% (ASMI 1SD) in men, and 0.7% (ASMI 2SD) and 7.4% (ASMI 1SD) in women. By multivariate ordinal logistic regression analysis, men with a low ASMI had significantly high odd ratios for the three domains of mobility (p < 0.001), self-care (p = 0.005), and usual activities (p = 0.004) among the five domains of the EQ-5D and EQ-5D index (p = 0.010). CONCLUSIONS: The ASMI 2SD cut-off points for older Koreans, 6.09 kg/m2 for men and 4.38 kg/m2 for women, resulted in low prevalences of a low ASM, that is, 9.7% for men and 0.7% for women, and showed low clinical usefulness due to very low determined prevalence in women. Hence, we suggest that the cut-off point of the lowest 20% of Korean older people (men: 6.48 kg/m2, women; 5.33 kg/m2) be used for older Koreans. PMID- 25535337 TI - Subtle genetic modifications transformed an enteropathogen into a flea-borne pathogen. PMID- 25535338 TI - Gas1 is a receptor for sonic hedgehog to repel enteric axons. AB - The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Galphai proteins that can couple with Smo, G protein alpha Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance. PMID- 25535339 TI - Controlling cell-cell interactions using surface acoustic waves. AB - The interactions between pairs of cells and within multicellular assemblies are critical to many biological processes such as intercellular communication, tissue and organ formation, immunological reactions, and cancer metastasis. The ability to precisely control the position of cells relative to one another and within larger cellular assemblies will enable the investigation and characterization of phenomena not currently accessible by conventional in vitro methods. We present a versatile surface acoustic wave technique that is capable of controlling the intercellular distance and spatial arrangement of cells with micrometer level resolution. This technique is, to our knowledge, among the first of its kind to marry high precision and high throughput into a single extremely versatile and wholly biocompatible technology. We demonstrated the capabilities of the system to precisely control intercellular distance, assemble cells with defined geometries, maintain cellular assemblies in suspension, and translate these suspended assemblies to adherent states, all in a contactless, biocompatible manner. As an example of the power of this system, this technology was used to quantitatively investigate the gap junctional intercellular communication in several homotypic and heterotypic populations by visualizing the transfer of fluorescent dye between cells. PMID- 25535340 TI - Dipeptides catalyze rapid peptide exchange on MHC class I molecules. AB - Peptide ligand selection by MHC class I molecules, which occurs by iterative optimization, is the centerpiece of immunodominance in antiviral and antitumor immune responses. For its understanding, the molecular mechanisms of peptide binding and dissociation by class I molecules must be elucidated. To this end, we have investigated dipeptides that bind to the F pocket of class I molecules. We find that they accelerate the dissociation of prebound peptides of both low and high affinity, suggesting a mechanism of action for the peptide-exchange chaperone tapasin. Peptide exchange on class I molecules also has practical uses in epitope discovery and T-cell monitoring. PMID- 25535342 TI - The curious case of the Arctic mastodons. PMID- 25535341 TI - Free-energy landscape of ion-channel voltage-sensor-domain activation. AB - Voltage sensor domains (VSDs) are membrane-bound protein modules that confer voltage sensitivity to membrane proteins. VSDs sense changes in the transmembrane voltage and convert the electrical signal into a conformational change called activation. Activation involves a reorganization of the membrane protein charges that is detected experimentally as transient currents. These so-called gating currents have been investigated extensively within the theoretical framework of so-called discrete-state Markov models (DMMs), whereby activation is conceptualized as a series of transitions across a discrete set of states. Historically, the interpretation of DMM transition rates in terms of transition state theory has been instrumental in shaping our view of the activation process, whose free-energy profile is currently envisioned as composed of a few local minima separated by steep barriers. Here we use atomistic level modeling and well tempered metadynamics to calculate the configurational free energy along a single transition from first principles. We show that this transition is intrinsically multidimensional and described by a rough free-energy landscape. Remarkably, a coarse-grained description of the system, based on the use of the gating charge as reaction coordinate, reveals a smooth profile with a single barrier, consistent with phenomenological models. Our results bridge the gap between microscopic and macroscopic descriptions of activation dynamics and show that choosing the gating charge as reaction coordinate masks the topological complexity of the network of microstates participating in the transition. Importantly, full characterization of the latter is a prerequisite to rationalize modulation of this process by lipids, toxins, drugs, and genetic mutations. PMID- 25535343 TI - Influenza viral neuraminidase primes bacterial coinfection through TGF-beta mediated expression of host cell receptors. AB - Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-beta. Because TGF-beta can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-beta during IAV infection contributes to secondary bacterial infection by up regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and alpha5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-beta signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-beta. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-beta signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-beta, leading to increased bacterial loading in the lungs. Our results suggest that TGF beta and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection. PMID- 25535346 TI - Downsides of social capital. PMID- 25535344 TI - Arabidopsis ribosomal proteins control vacuole trafficking and developmental programs through the regulation of lipid metabolism. AB - The vacuole is the most prominent compartment in plant cells and is important for ion and protein storage. In our effort to search for key regulators in the plant vacuole sorting pathway, ribosomal large subunit 4 (rpl4d) was identified as a translational mutant defective in both vacuole trafficking and normal development. Polysome profiling of the rpl4d mutant showed reduction in polysome bound mRNA compared with wild-type, but no significant change in the general mRNA distribution pattern. Ribsomal profiling data indicated that genes in the lipid metabolism pathways were translationally down-regulated in the rpl4d mutant. Live imaging studies by Nile red staining suggested that both polar and nonpolar lipid accumulation was reduced in meristem tissues of rpl4d mutants. Pharmacological evidence showed that sterol and sphingolipid biosynthetic inhibitors can phenocopy the defects of the rpl4d mutant, including an altered vacuole trafficking pattern. Genetic evidence from lipid biosynthetic mutants indicates that alteration in the metabolism of either sterol or sphingolipid biosynthesis resulted in vacuole trafficking defects, similar to the rpl4d mutant. Tissue specific complementation with key enzymes from lipid biosynthesis pathways can partially rescue both vacuole trafficking and auxin-related developmental defects in the rpl4d mutant. These results indicate that lipid metabolism modulates auxin mediated tissue differentiation and endomembrane trafficking pathways downstream of ribosomal protein function. PMID- 25535345 TI - Effects of anthropogenic emissions on aerosol formation from isoprene and monoterpenes in the southeastern United States. AB - Secondary organic aerosol (SOA) constitutes a substantial fraction of fine particulate matter and has important impacts on climate and human health. The extent to which human activities alter SOA formation from biogenic emissions in the atmosphere is largely undetermined. Here, we present direct observational evidence on the magnitude of anthropogenic influence on biogenic SOA formation based on comprehensive ambient measurements in the southeastern United States (US). Multiple high-time-resolution mass spectrometry organic aerosol measurements were made during different seasons at various locations, including urban and rural sites in the greater Atlanta area and Centreville in rural Alabama. Our results provide a quantitative understanding of the roles of anthropogenic SO2 and NOx in ambient SOA formation. We show that isoprene-derived SOA is directly mediated by the abundance of sulfate, instead of the particle water content and/or particle acidity as suggested by prior laboratory studies. Anthropogenic NOx is shown to enhance nighttime SOA formation via nitrate radical oxidation of monoterpenes, resulting in the formation of condensable organic nitrates. Together, anthropogenic sulfate and NOx can mediate 43-70% of total measured organic aerosol (29-49% of submicron particulate matter, PM1) in the southeastern US during summer. These measurements imply that future reduction in SO2 and NOx emissions can considerably reduce the SOA burden in the southeastern US. Updating current modeling frameworks with these observational constraints will also lead to more accurate treatment of aerosol formation for regions with substantial anthropogenic-biogenic interactions and consequently improve air quality and climate simulations. PMID- 25535347 TI - Helical buckling of actin inside filopodia generates traction. AB - Cells can interact with their surroundings via filopodia, which are membrane protrusions that extend beyond the cell body. Filopodia are essential during dynamic cellular processes like motility, invasion, and cell-cell communication. Filopodia contain cross-linked actin filaments, attached to the surrounding cell membrane via protein linkers such as integrins. These actin filaments are thought to play a pivotal role in force transduction, bending, and rotation. We investigated whether, and how, actin within filopodia is responsible for filopodia dynamics by conducting simultaneous force spectroscopy and confocal imaging of F-actin in membrane protrusions. The actin shaft was observed to periodically undergo helical coiling and rotational motion, which occurred simultaneously with retrograde movement of actin inside the filopodium. The cells were found to retract beads attached to the filopodial tip, and retraction was found to correlate with rotation and coiling of the actin shaft. These results suggest a previously unidentified mechanism by which a cell can use rotation of the filopodial actin shaft to induce coiling and hence axial shortening of the filopodial actin bundle. PMID- 25535348 TI - Carbonate formation events in ALH 84001 trace the evolution of the Martian atmosphere. AB - Carbonate minerals provide critical information for defining atmosphere hydrosphere interactions. Carbonate minerals in the Martian meteorite ALH 84001 have been dated to ~ 3.9 Ga, and both C and O-triple isotopes can be used to decipher the planet's climate history. Here we report Delta(17)O, delta(18)O, and delta(13)C data of ALH 84001 of at least two varieties of carbonates, using a stepped acid dissolution technique paired with ion microprobe analyses to specifically target carbonates from distinct formation events and constrain the Martian atmosphere-hydrosphere-geosphere interactions and surficial aqueous alterations. These results indicate the presence of a Ca-rich carbonate phase enriched in (18)O that formed sometime after the primary aqueous event at 3.9 Ga. The phases showed excess (17)O (0.70/00) that captured the atmosphere-regolith chemical reservoir transfer, as well as CO2, O3, and H2O isotopic interactions at the time of formation of each specific carbonate. The carbon isotopes preserved in the Ca-rich carbonate phase indicate that the Noachian atmosphere of Mars was substantially depleted in (13)C compared with the modern atmosphere. PMID- 25535349 TI - Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation. AB - Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process. PMID- 25535350 TI - No evidence for intracellular magnetite in putative vertebrate magnetoreceptors identified by magnetic screening. AB - The cellular basis of the magnetic sense remains an unsolved scientific mystery. One theory that aims to explain how animals detect the magnetic field is the magnetite hypothesis. It argues that intracellular crystals of the iron oxide magnetite (Fe3O4) are coupled to mechanosensitive channels that elicit neuronal activity in specialized sensory cells. Attempts to find these primary sensors have largely relied on the Prussian Blue stain that labels cells rich in ferric iron. This method has proved problematic as it has led investigators to conflate iron-rich macrophages with magnetoreceptors. An alternative approach developed by Eder et al. [Eder SH, et al. (2012) Proc Natl Acad Sci USA 109(30):12022-12027] is to identify candidate magnetoreceptive cells based on their magnetic moment. Here, we explore the utility of this method by undertaking a screen for magnetic cells in the pigeon. We report the identification of a small number of cells (1 in 476,000) with large magnetic moments (8-106 fAm(2)) from various tissues. The development of single-cell correlative light and electron microscopy (CLEM) coupled with electron energy loss spectroscopy (EELS) and energy-filtered transmission electron microscopy (EFTEM) permitted subcellular analysis of magnetic cells. This revealed the presence of extracellular structures composed of iron, titanium, and chromium accounting for the magnetic properties of these cells. Application of single-cell CLEM to magnetic cells from the trout failed to identify any intracellular structures consistent with biogenically derived magnetite. Our work illustrates the need for new methods to test the magnetite hypothesis of magnetosensation. PMID- 25535351 TI - Only three driver gene mutations are required for the development of lung and colorectal cancers. AB - Cancer arises through the sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, how many such mutations are required for a normal human cell to progress to an advanced cancer? The best estimates for this number have been provided by mathematical models based on the relation between age and incidence. For example, the classic studies of Nordling [Nordling CO (1953) Br J Cancer 7(1):68-72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1-12] suggest that six or seven sequential mutations are required. Here, we describe a different approach to derive this estimate that combines conventional epidemiologic studies with genome-wide sequencing data: incidence data for different groups of patients with the same cancer type were compared with respect to their somatic mutation rates. In two well-documented cancer types (lung and colon adenocarcinomas), we find that only three sequential mutations are required to develop cancer. This conclusion deepens our understanding of the process of carcinogenesis and has important implications for the design of future cancer genome-sequencing efforts. PMID- 25535352 TI - Gracility of the modern Homo sapiens skeleton is the result of decreased biomechanical loading. AB - The postcranial skeleton of modern Homo sapiens is relatively gracile compared with other hominoids and earlier hominins. This gracility predisposes contemporary humans to osteoporosis and increased fracture risk. Explanations for this gracility include reduced levels of physical activity, the dissipation of load through enlarged joint surfaces, and selection for systemic physiological characteristics that differentiate modern humans from other primates. This study considered the skeletal remains of four behaviorally diverse recent human populations and a large sample of extant primates to assess variation in trabecular bone structure in the human hip joint. Proximal femur trabecular bone structure was quantified from microCT data for 229 individuals from 31 extant primate taxa and 59 individuals from four distinct archaeological human populations representing sedentary agriculturalists and mobile foragers. Analyses of mass-corrected trabecular bone variables reveal that the forager populations had significantly higher bone volume fraction, thicker trabeculae, and consequently lower relative bone surface area compared with the two agriculturalist groups. There were no significant differences between the agriculturalist and forager populations for trabecular spacing, number, or degree of anisotropy. These results reveal a correspondence between human behavior and bone structure in the proximal femur, indicating that more highly mobile human populations have trabecular bone structure similar to what would be expected for wild nonhuman primates of the same body mass. These results strongly emphasize the importance of physical activity and exercise for bone health and the attenuation of age-related bone loss. PMID- 25535353 TI - Patterns of genome evolution that have accompanied host adaptation in Salmonella. AB - Many bacterial pathogens are specialized, infecting one or few hosts, and this is often associated with more acute disease presentation. Specific genomes show markers of this specialization, which often reflect a balance between gene acquisition and functional gene loss. Within Salmonella enterica subspecies enterica, a single lineage exists that includes human and animal pathogens adapted to cause infection in different hosts, including S. enterica serovar Enteritidis (multiple hosts), S. Gallinarum (birds), and S. Dublin (cattle). This provides an excellent evolutionary context in which differences between these pathogen genomes can be related to host range. Genome sequences were obtained from ~ 60 isolates selected to represent the known diversity of this lineage. Examination and comparison of the clades within the phylogeny of this lineage revealed signs of host restriction as well as evolutionary events that mark a path to host generalism. We have identified the nature and order of events for both evolutionary trajectories. The impact of functional gene loss was predicted based upon position within metabolic pathways and confirmed with phenotyping assays. The structure of S. Enteritidis is more complex than previously known, as a second clade of S. Enteritidis was revealed that is distinct from those commonly seen to cause disease in humans or animals, and that is more closely related to S. Gallinarum. Isolates from this second clade were tested in a chick model of infection and exhibited a reduced colonization phenotype, which we postulate represents an intermediate stage in pathogen-host adaptation. PMID- 25535355 TI - Wrinkling crystallography on spherical surfaces. AB - We present the results of an experimental investigation on the crystallography of the dimpled patterns obtained through wrinkling of a curved elastic system. Our macroscopic samples comprise a thin hemispherical shell bound to an equally curved compliant substrate. Under compression, a crystalline pattern of dimples self-organizes on the surface of the shell. Stresses are relaxed by both out-of surface buckling and the emergence of defects in the quasi-hexagonal pattern. Three-dimensional scanning is used to digitize the topography. Regarding the dimples as point-like packing units produces spherical Voronoi tessellations with cells that are polydisperse and distorted, away from their regular shapes. We analyze the structure of crystalline defects, as a function of system size. Disclinations are observed and, above a threshold value, dislocations proliferate rapidly with system size. Our samples exhibit striking similarities with other curved crystals of charged particles and colloids. Differences are also found and attributed to the far-from-equilibrium nature of our patterns due to the random and initially frozen material imperfections which act as nucleation points, the presence of a physical boundary which represents an additional source of stress, and the inability of dimples to rearrange during crystallization. Even if we do not have access to the exact form of the interdimple interaction, our experiments suggest a broader generality of previous results of curved crystallography and their robustness on the details of the interaction potential. Furthermore, our findings open the door to future studies on curved crystals far from equilibrium. PMID- 25535354 TI - Recent origin of low trabecular bone density in modern humans. AB - Humans are unique, compared with our closest living relatives (chimpanzees) and early fossil hominins, in having an enlarged body size and lower limb joint surfaces in combination with a relatively gracile skeleton (i.e., lower bone mass for our body size). Some analyses have observed that in at least a few anatomical regions modern humans today appear to have relatively low trabecular density, but little is known about how that density varies throughout the human skeleton and across species or how and when the present trabecular patterns emerged over the course of human evolution. Here, we test the hypotheses that (i) recent modern humans have low trabecular density throughout the upper and lower limbs compared with other primate taxa and (ii) the reduction in trabecular density first occurred in early Homo erectus, consistent with the shift toward a modern human locomotor anatomy, or more recently in concert with diaphyseal gracilization in Holocene humans. We used peripheral quantitative CT and microtomography to measure trabecular bone of limb epiphyses (long bone articular ends) in modern humans and chimpanzees and in fossil hominins attributed to Australopithecus africanus, Paranthropus robustus/early Homo from Swartkrans, Homo neanderthalensis, and early Homo sapiens. Results show that only recent modern humans have low trabecular density throughout the limb joints. Extinct hominins, including pre-Holocene Homo sapiens, retain the high levels seen in nonhuman primates. Thus, the low trabecular density of the recent modern human skeleton evolved late in our evolutionary history, potentially resulting from increased sedentism and reliance on technological and cultural innovations. PMID- 25535356 TI - Natural asynchronies in audiovisual communication signals regulate neuronal multisensory interactions in voice-sensitive cortex. AB - When social animals communicate, the onset of informative content in one modality varies considerably relative to the other, such as when visual orofacial movements precede a vocalization. These naturally occurring asynchronies do not disrupt intelligibility or perceptual coherence. However, they occur on time scales where they likely affect integrative neuronal activity in ways that have remained unclear, especially for hierarchically downstream regions in which neurons exhibit temporally imprecise but highly selective responses to communication signals. To address this, we exploited naturally occurring face- and voice-onset asynchronies in primate vocalizations. Using these as stimuli we recorded cortical oscillations and neuronal spiking responses from functional MRI (fMRI)-localized voice-sensitive cortex in the anterior temporal lobe of macaques. We show that the onset of the visual face stimulus resets the phase of low-frequency oscillations, and that the face-voice asynchrony affects the prominence of two key types of neuronal multisensory responses: enhancement or suppression. Our findings show a three-way association between temporal delays in audiovisual communication signals, phase-resetting of ongoing oscillations, and the sign of multisensory responses. The results reveal how natural onset asynchronies in cross-sensory inputs regulate network oscillations and neuronal excitability in the voice-sensitive cortex of macaques, a suggested animal model for human voice areas. These findings also advance predictions on the impact of multisensory input on neuronal processes in face areas and other brain regions. PMID- 25535357 TI - TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1alpha activity. AB - The p53-family member TAp73 is known to function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis; however, its role in tumor angiogenesis is poorly understood. Here we demonstrate that TAp73 regulates tumor angiogenesis through repression of proangiogenic and proinflammatory cytokines. Importantly, loss of TAp73 results in highly vascularized tumors, as well as an increase in vessel permeability resulting from disruption of vascular endothelial-cadherin junctions between endothelial cells. In contrast, loss of the oncogenic p73 isoform DeltaNp73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated DeltaNp73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1alpha and up-regulation of HIF-1alpha target genes. Taken together, our data demonstrate that loss of TAp73 or DeltaNp73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression. PMID- 25535358 TI - Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. AB - In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short wavelength-enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety. PMID- 25535359 TI - TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1alpha degradation. AB - Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (alpha) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1alpha polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer. PMID- 25535360 TI - Transdermal deferoxamine prevents pressure-induced diabetic ulcers. AB - There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor 1 alpha (HIF-1alpha). In diabetes, HIF-1alpha function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1alpha transactivation. We examined whether local enhancement of HIF-1alpha activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1alpha activity we designed a transdermal drug delivery system (TDDS) containing the FDA approved small molecule deferoxamine (DFO), an iron chelator that increases HIF 1alpha transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation. PMID- 25535361 TI - Stochastic approach to the molecular counting problem in superresolution microscopy. AB - Superresolution imaging methods--now widely used to characterize biological structures below the diffraction limit--are poised to reveal in quantitative detail the stoichiometry of protein complexes in living cells. In practice, the photophysical properties of the fluorophores used as tags in superresolution methods have posed a severe theoretical challenge toward achieving this goal. Here we develop a stochastic approach to enumerate fluorophores in a diffraction limited area measured by superresolution microscopy. The method is a generalization of aggregated Markov methods developed in the ion channel literature for studying gating dynamics. We show that the method accurately and precisely enumerates fluorophores in simulated data while simultaneously determining the kinetic rates that govern the stochastic photophysics of the fluorophores to improve the prediction's accuracy. This stochastic method overcomes several critical limitations of temporal thresholding methods. PMID- 25535362 TI - Image statistics underlying natural texture selectivity of neurons in macaque V4. AB - Our daily visual experiences are inevitably linked to recognizing the rich variety of textures. However, how the brain encodes and differentiates a plethora of natural textures remains poorly understood. Here, we show that many neurons in macaque V4 selectively encode sparse combinations of higher-order image statistics to represent natural textures. We systematically explored neural selectivity in a high-dimensional texture space by combining texture synthesis and efficient-sampling techniques. This yielded parameterized models for individual texture-selective neurons. The models provided parsimonious but powerful predictors for each neuron's preferred textures using a sparse combination of image statistics. As a whole population, the neuronal tuning was distributed in a way suitable for categorizing textures and quantitatively predicts human ability to discriminate textures. Together, we suggest that the collective representation of visual image statistics in V4 plays a key role in organizing the natural texture perception. PMID- 25535363 TI - Arabidopsis ROCK1 transports UDP-GlcNAc/UDP-GalNAc and regulates ER protein quality control and cytokinin activity. AB - The formation of glycoconjugates depends on nucleotide sugars, which serve as donor substrates for glycosyltransferases in the lumen of Golgi vesicles and the endoplasmic reticulum (ER). Import of nucleotide sugars from the cytosol is an important prerequisite for these reactions and is mediated by nucleotide sugar transporters. Here, we report the identification of REPRESSOR OF CYTOKININ DEFICIENCY 1 (ROCK1, At5g65000) as an ER-localized facilitator of UDP-N acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc) transport in Arabidopsis thaliana. Mutant alleles of ROCK1 suppress phenotypes inferred by a reduced concentration of the plant hormone cytokinin. This suppression is caused by the loss of activity of cytokinin-degrading enzymes, cytokinin oxidases/dehydrogenases (CKXs). Cytokinin plays an essential role in regulating shoot apical meristem (SAM) activity and shoot architecture. We show that rock1 enhances SAM activity and organ formation rate, demonstrating an important role of ROCK1 in regulating the cytokinin signal in the meristematic cells through modulating activity of CKX proteins. Intriguingly, genetic and molecular analysis indicated that N-glycosylation of CKX1 was not affected by the lack of ROCK1-mediated supply of UDP-GlcNAc. In contrast, we show that CKX1 stability is regulated in a proteasome-dependent manner and that ROCK1 regulates the CKX1 level. The increased unfolded protein response in rock1 plants and suppression of phenotypes caused by the defective brassinosteroid receptor bri1-9 strongly suggest that the ROCK1 activity is an important part of the ER quality control system, which determines the fate of aberrant proteins in the secretory pathway. PMID- 25535364 TI - Fear and C-reactive protein cosynergize annual pulse increases in healthy adults. AB - Recent international terror outbreaks notably involve long-term mental health risks to the exposed population, but whether physical health risks are also anticipated has remained unknown. Here, we report fear of terror-induced annual increases in resting heart rate (pulse), a notable risk factor of all-cause mortality. Partial least squares analysis based on 325 measured parameters successfully predicted annual pulse increases, inverse to the expected age related pulse decline, in approximately 4.1% of a cohort of 17,380 apparently healthy active Israeli adults. Nonbiased hierarchical regression analysis among 27 of those parameters identified pertinent fear of terror combined with the inflammatory biomarker C-reactive protein as prominent coregulators of the observed annual pulse increases. In comparison, basal pulse primarily depended on general physiological parameters and reduced cholinergic control over anxiety and inflammation, together indicating that consistent exposure to terror threats ignites fear-induced exacerbation of preexisting neuro-immune risks of all-cause mortality. PMID- 25535365 TI - Deep conservation of wrist and digit enhancers in fish. AB - There is no obvious morphological counterpart of the autopod (wrist/ankle and digits) in living fishes. Comparative molecular data may provide insight into understanding both the homology of elements and the evolutionary developmental mechanisms behind the fin to limb transition. In mouse limbs the autopod is built by a "late" phase of Hoxd and Hoxa gene expression, orchestrated by a set of enhancers located at the 5' end of each cluster. Despite a detailed mechanistic understanding of mouse limb development, interpretation of Hox expression patterns and their regulation in fish has spawned multiple hypotheses as to the origin and function of "autopod" enhancers throughout evolution. Using phylogenetic footprinting, epigenetic profiling, and transgenic reporters, we have identified and functionally characterized hoxD and hoxA enhancers in the genomes of zebrafish and the spotted gar, Lepisosteus oculatus, a fish lacking the whole genome duplication of teleosts. Gar and zebrafish "autopod" enhancers drive expression in the distal portion of developing zebrafish pectoral fins, and respond to the same functional cues as their murine orthologs. Moreover, gar enhancers drive reporter gene expression in both the wrist and digits of mouse embryos in patterns that are nearly indistinguishable from their murine counterparts. These functional genomic data support the hypothesis that the distal radials of bony fish are homologous to the wrist and/or digits of tetrapods. PMID- 25535366 TI - An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma. AB - High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs. PMID- 25535368 TI - In vivo albumin labeling and lymphatic imaging. AB - The ability to accurately and easily locate sentinel lymph nodes (LNs) with noninvasive imaging methods would assist in tumor staging and patient management. For this purpose, we developed a lymphatic imaging agent by mixing fluorine-18 aluminum fluoride-labeled NOTA (1,4,7-triazacyclononane-N,N',N''-triacetic acid) conjugated truncated Evans blue ((18)F-AlF-NEB) and Evans blue (EB) dye. After local injection, both (18)F-AlF-NEB and EB form complexes with endogenous albumin in the interstitial fluid and allow for visualizing the lymphatic system. Positron emission tomography (PET) and/or optical imaging of LNs was performed in three different animal models including a hind limb inflammation model, an orthotropic breast cancer model, and a metastatic breast cancer model. In all three models, the LNs can be distinguished clearly by the apparent blue color and strong fluorescence signal from EB as well as a high-intensity PET signal from (18)F-AlF-NEB. The lymphatic vessels between the LNs can also be optically visualized. The easy preparation, excellent PET and optical imaging quality, and biosafety suggest that this combination of (18)F-AlF-NEB and EB has great potential for clinical application to map sentinel LNs and provide intraoperative guidance. PMID- 25535367 TI - A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. AB - Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism. PMID- 25535369 TI - Hooking She3p onto She2p for myosin-mediated cytoplasmic mRNA transport. AB - The segregation of approximately two dozen distinct mRNAs from yeast mother to daughter cell cytoplasm is a classical paradigm for eukaryotic mRNA transport. The information for transport resides in an mRNA element 40-100 nt in length, known as "zipcode." Targeted transport requires properly positioned actin filaments and cooperative loading of mRNA cargo to myosin. Cargo loading to myosin uses myosin 4 protein (Myo4p), swi5p-dependent HO expression 2 protein (She2p) and 3 protein (She3p), and zipcode. We previously determined a crystal structure of Myo4p and She3p, their 1:2 stoichiometry and interactome; we furthermore showed that the motor complex assembly requires two Myo4p?She3p heterotrimers, one She2p tetramer, and at least a single zipcode to yield a stable complex of [Myo4p?She3p?She2p?zipcode] in 2:4:4:1 stoichiometry in vitro. Here, we report a structure at 2.8-A resolution of a cocrystal of a She2p tetramer bound to a segment of She3p. In this crystal structure, the She3p segment forms a striking hook that binds to a shallow hydrophobic pocket on the surface of each She2p subunit of the tetramer. Both She3p hook and cognate She2p binding pocket are composed of highly conserved residues. We also discovered a highly conserved region of She3p upstream of its hook region. Because this region consists of basic and aromatic residues, it likely represents part of She3p's binding activity for zipcode. Because She2p also exhibits zipcode-binding activity, we suggest that "hooking" She3p onto She2p aligns each of their zipcode binding activities into a high-affinity site, thereby linking motor assembly to zipcode. PMID- 25535370 TI - Stabilization of morphine tolerance with long-term dosing: association with selective upregulation of mu-opioid receptor splice variant mRNAs. AB - Chronic morphine administration is associated with the development of tolerance, both clinically and in animal models. Many assume that tolerance is a continually progressive response to chronic opioid dosing. However, clinicians have long appreciated the ability to manage cancer pain in patients for months on stable opioid doses, implying that extended dosing may eventually result in a steady state in which the degree of tolerance remains constant despite the continued administration of a fixed morphine dose. Preclinical animal studies have used short-term paradigms, typically a week or less, whereas the clinical experience is based upon months of treatment. Chronic administration of different fixed morphine doses produced a progressive increase in the ED50 that peaked at 3 wk in mice, consistent with prior results at shorter times. Continued morphine dosing beyond 3 wk revealed stabilization of the level of tolerance for up to 6 wk with no further increase in the ED50. The degree of tolerance at all time points was dependent upon the dose of morphine. The mRNA levels for the various mu opioid receptor splice variants were assessed to determine whether stabilization of morphine tolerance was associated with changes in their levels. After 6 wk of treatment, mRNA levels of the variants increased as much as 300-fold for selected variants in specific brain regions. These findings reconcile preclinical and clinical observations regarding the development of morphine tolerance. PMID- 25535372 TI - Iron stable isotopes track pelagic iron cycling during a subtropical phytoplankton bloom. AB - The supply and bioavailability of dissolved iron sets the magnitude of surface productivity for ~ 40% of the global ocean. The redox state, organic complexation, and phase (dissolved versus particulate) of iron are key determinants of iron bioavailability in the marine realm, although the mechanisms facilitating exchange between iron species (inorganic and organic) and phases are poorly constrained. Here we use the isotope fingerprint of dissolved and particulate iron to reveal distinct isotopic signatures for biological uptake of iron during a GEOTRACES process study focused on a temperate spring phytoplankton bloom in subtropical waters. At the onset of the bloom, dissolved iron within the mixed layer was isotopically light relative to particulate iron. The isotopically light dissolved iron pool likely results from the reduction of particulate iron via photochemical and (to a lesser extent) biologically mediated reduction processes. As the bloom develops, dissolved iron within the surface mixed layer becomes isotopically heavy, reflecting the dominance of biological processing of iron as it is removed from solution, while scavenging appears to play a minor role. As stable isotopes have shown for major elements like nitrogen, iron isotopes offer a new window into our understanding of the biogeochemical cycling of iron, thereby allowing us to disentangle a suite of concurrent biotic and abiotic transformations of this key biolimiting element. PMID- 25535371 TI - Evolutionary pattern in the OXT-OXTR system in primates: coevolution and positive selection footprints. AB - Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system. PMID- 25535373 TI - Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain. AB - BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6-Ubl4A dimer demonstrates that Bag6-BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein alpha to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6. PMID- 25535374 TI - Evolutionary meandering of intermolecular interactions along the drift barrier. AB - Many cellular functions depend on highly specific intermolecular interactions, for example transcription factors and their DNA binding sites, microRNAs and their RNA binding sites, the interfaces between heterodimeric protein molecules, the stems in RNA molecules, and kinases and their response regulators in signal transduction systems. Despite the need for complementarity between interacting partners, such pairwise systems seem to be capable of high levels of evolutionary divergence, even when subject to strong selection. Such behavior is a consequence of the diminishing advantages of increasing binding affinity between partners, the multiplicity of evolutionary pathways between selectively equivalent alternatives, and the stochastic nature of evolutionary processes. Because mutation pressure toward reduced affinity conflicts with selective pressure for greater interaction, situations can arise in which the expected distribution of the degree of matching between interacting partners is bimodal, even in the face of constant selection. Although biomolecules with larger numbers of interacting partners are subject to increased levels of evolutionary conservation, their more numerous partners need not converge on a single sequence motif or be increasingly constrained in more complex systems. These results suggest that most phylogenetic differences in the sequences of binding interfaces are not the result of adaptive fine tuning but a simple consequence of random genetic drift. PMID- 25535375 TI - Magnesium stable isotope ecology using mammal tooth enamel. AB - Geochemical inferences on ancient diet using bone and enamel apatite rely mainly on carbon isotope ratios (delta(13)C) and to a lesser extent on strontium/calcium (Sr/Ca) and barium/calcium (Ba/Ca) elemental ratios. Recent developments in nontraditional stable isotopes provide an unprecedented opportunity to use additional paleodietary proxies to disentangle complex diets such as omnivory. Of particular relevance for paleodietary reconstruction are metals present in large quantity in bone and enamel apatite, providing that biologically mediated fractionation processes are constrained. Calcium isotope ratios (delta(44)Ca) meet these criteria but exhibit complex ecological patterning. Stable magnesium isotope ratios (delta(26)Mg) also meet these criteria but a comprehensive understanding of its variability awaits new isotopic data. Here, 11 extant mammal species of known ecology from a single locality in equatorial Africa were sampled for tooth enamel and, together with vegetation and feces, analyzed for delta(26)Mg, delta(13)C, Sr/Ca, and Ba/Ca ratios. The results demonstrate that delta(26)Mg incorporated in tooth enamel becomes heavier from strict herbivores to omnivores/faunivores. Using data from experimentally raised sheep, we suggest that this (26)Mg enrichment up the trophic chain is due to a (26)Mg enrichment in muscle relative to bone. Notably, it is possible to distinguish omnivores from herbivores, using delta(26)Mg coupled to Ba/Ca ratios. The potential effects of metabolic and dietary changes on the enamel delta(26)Mg composition remain to be explored but, in the future, multiproxy approaches would permit a substantial refinement of dietary behaviors or enable accurate trophic reconstruction despite specimen-limited sampling, as is often the case for fossil assemblages. PMID- 25535376 TI - Rare allele of a previously unidentified histone H4 acetyltransferase enhances grain weight, yield, and plant biomass in rice. AB - Grain weight is an important crop yield component; however, its underlying regulatory mechanisms are largely unknown. Here, we identify a grain-weight quantitative trait locus (QTL) encoding a new-type GNAT-like protein that harbors intrinsic histone acetyltransferase activity (OsglHAT1). Our genetic and molecular evidences pinpointed the QTL-OsglHAT1's allelic variations to a 1.2-kb region upstream of the gene body, which is consistent with its function as a positive regulator of the traits. Elevated OsglHAT1 expression enhances grain weight and yield by enlarging spikelet hulls via increasing cell number and accelerating grain filling, and increases global acetylation levels of histone H4. OsglHAT1 localizes to the nucleus, where it likely functions through the regulation of transcription. Despite its positive agronomical effects on grain weight, yield, and plant biomass, the rare allele elevating OsglHAT1 expression has so far escaped human selection. Our findings reveal the first example, to our knowledge, of a QTL for a yield component trait being due to a chromatin modifier that has the potential to improve crop high-yield breeding. PMID- 25535377 TI - gammadelta T cells affect IL-4 production and B-cell tolerance. AB - gammadelta T cells can influence specific antibody responses. Here, we report that mice deficient in individual gammadelta T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of alphabeta T cells. One strain with a partial gammadelta deficiency that increases IgE antibodies also displayed increases in IL-4-producing T cells (both residual gammadelta T cells and alphabeta T cells) and in systemic IL-4 levels. Its B cells expressed IL-4-regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4-inducible IL-4 receptor alpha and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all gammadelta T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially gammadelta-deficient mice. Our data suggest that gammadelta T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance. PMID- 25535378 TI - B-cell repertoire responses to varicella-zoster vaccination in human identical twins. AB - Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicella zoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall B-cell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus. PMID- 25535379 TI - Patterns of accumulation of miRNAs encoded by herpes simplex virus during productive infection, latency, and on reactivation. AB - The key events in herpes simplex virus (HSV) infections are (i) replication at a portal of entry into the body modeled by infection of cultured cells; (ii) establishment of a latent state characterized by a sole latency-associated transcript and microRNAs (miRNAs) modeled in murine peripheral ganglia 30 d after inoculation; and (iii) reactivation from the latent state modeled by excision and incubation of ganglia in medium containing anti-NGF antibody for a timespan of a single viral replicative cycle. In this report, we examine the pattern of synthesis and accumulation of 18 HSV-1 miRNAs in the three models. We report the following: (i) H2-3P, H3-3P, H4-3P, H5-3P, H6-3P, and H7-5P accumulated in ganglia harboring latent virus. All but H4-3P were readily detected in productively infected cells, and most likely they originate from three transcriptional units. (ii) H8-5P, H15, H17, H18, H26, and H27 accumulated during reactivation. Of this group, only H26 and H27 could be detected in productively infected cells. (iii) Of the 18 we have examined, only 10 miRNAs were found to accumulate above background levels in productively infected cells. The disparity in the accumulation of miRNAs in cell culture and during reactivation may reflect differences in the patterns of regulation of viral gene expression during productive infection and during reactivation from the latent state. PMID- 25535380 TI - Measuring the effectiveness of scientific gatekeeping. AB - Peer review is the main institution responsible for the evaluation and gestation of scientific research. Although peer review is widely seen as vital to scientific evaluation, anecdotal evidence abounds of gatekeeping mistakes in leading journals, such as rejecting seminal contributions or accepting mediocre submissions. Systematic evidence regarding the effectiveness--or lack thereof--of scientific gatekeeping is scant, largely because access to rejected manuscripts from journals is rarely available. Using a dataset of 1,008 manuscripts submitted to three elite medical journals, we show differences in citation outcomes for articles that received different appraisals from editors and peer reviewers. Among rejected articles, desk-rejected manuscripts, deemed as unworthy of peer review by editors, received fewer citations than those sent for peer review. Among both rejected and accepted articles, manuscripts with lower scores from peer reviewers received relatively fewer citations when they were eventually published. However, hindsight reveals numerous questionable gatekeeping decisions. Of the 808 eventually published articles in our dataset, our three focal journals rejected many highly cited manuscripts, including the 14 most popular; roughly the top 2 percent. Of those 14 articles, 12 were desk-rejected. This finding raises concerns regarding whether peer review is ill--suited to recognize and gestate the most impactful ideas and research. Despite this finding, results show that in our case studies, on the whole, there was value added in peer review. Editors and peer reviewers generally--but not always-made good decisions regarding the identification and promotion of quality in scientific manuscripts. PMID- 25535381 TI - Sound credit scores and financial decisions despite cognitive aging. AB - Age-related deterioration in cognitive ability may compromise the ability of older adults to make major financial decisions. We explore whether knowledge and expertise accumulated from past decisions can offset cognitive decline to maintain decision quality over the life span. Using a unique dataset that combines measures of cognitive ability (fluid intelligence) and of general and domain-specific knowledge (crystallized intelligence), credit report data, and other measures of decision quality, we show that domain-specific knowledge and expertise provide an alternative route for sound financial decisions. That is, cognitive aging does not spell doom for financial decision-making in domains where the decision maker has developed expertise. These results have important implications for public policy and for the design of effective interventions and decision aids. PMID- 25535382 TI - HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation. AB - Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington's disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner. PMID- 25535383 TI - Multifarious assembly mixtures: systems allowing retrieval of diverse stored structures. AB - Self-assembly materials are traditionally designed so that molecular or mesoscale components form a single kind of large structure. Here, we propose a scheme to create "multifarious assembly mixtures," which self-assemble many different large structures from a set of shared components. We show that the number of multifarious structures stored in the solution of components increases rapidly with the number of different types of components. However, each stored structure can be retrieved by tuning only a few parameters, the number of which is only weakly dependent on the size of the assembled structure. Implications for artificial and biological self-assembly are discussed. PMID- 25535384 TI - Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection. AB - Autophagy is a process by which misfolded and damaged proteins are sequestered into autophagosomes, before degradation in and recycling from lysosomes. We have extensively studied the role of autophagy in varicella-zoster virus (VZV) infection, and have observed that vesicular cells are filled with >100 autophagosomes that are easily detectable after immunolabeling for the LC3 protein. To confirm our hypothesis that increased autophagosome formation was not secondary to a block, we examined all conditions of VZV infection as well as carrying out two assessments of autophagic flux. We first investigated autophagy in human skin xenografts in the severe combined immunodeficiency (SCID) mouse model of VZV pathogenesis, and observed that autophagosomes were abundant in infected human skin tissues. We next investigated autophagy following infection with sonically prepared cell-free virus in cultured cells. Under these conditions, autophagy was detected in a majority of infected cells, but was much less than that seen after an infected-cell inoculum. In other words, inoculation with lower-titered cell-free virus did not reflect the level of stress to the VZV infected cell that was seen after inoculation of human skin in the SCID mouse model or monolayers with higher-titered infected cells. Finally, we investigated VZV-induced autophagic flux by two different methods (radiolabeling proteins and a dual-colored LC3 plasmid); both showed no evidence of a block in autophagy. Overall, therefore, autophagy within a VZV-infected cell was remarkably different from autophagy within an HSV-infected cell, whose genome contains two modifiers of autophagy, ICP34.5 and US11, not present in VZV. PMID- 25535385 TI - Avian influenza H5N1 viral and bird migration networks in Asia. AB - The spatial spread of the highly pathogenic avian influenza virus H5N1 and its long-term persistence in Asia have resulted in avian influenza panzootics and enormous economic losses in the poultry sector. However, an understanding of the regional long-distance transmission and seasonal patterns of the virus is still lacking. In this study, we present a phylogeographic approach to reconstruct the viral migration network. We show that within each wild fowl migratory flyway, the timing of H5N1 outbreaks and viral migrations are closely associated, but little viral transmission was observed between the flyways. The bird migration network is shown to better reflect the observed viral gene sequence data than other networks and contributes to seasonal H5N1 epidemics in local regions and its large-scale transmission along flyways. These findings have potentially far reaching consequences, improving our understanding of how bird migration drives the periodic reemergence of H5N1 in Asia. PMID- 25535386 TI - Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease. AB - Huntington's disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical and striatal neurons, as well as morbidity in midlife. Human genetic studies led to the identification of the causative gene, huntingtin. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death. However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has complicated efforts to understand the etiology of this disease, and to date no curative therapeutic exists. To address the general problem of identifying the disease-phenotype contributing genes from a large number of correlative studies, here we develop a synthetic lethal screening methodology for the mammalian central nervous system, called SLIC, for synthetic lethal in the central nervous system. Applying SLIC to the study of Huntington's disease, we identify the age regulated glutathione peroxidase 6 (Gpx6) gene as a modulator of mutant huntingtin toxicity and show that overexpression of Gpx6 can dramatically alleviate both behavioral and molecular phenotypes associated with a mouse model of Huntington's disease. SLIC can, in principle, be used in the study of any neurodegenerative disease for which a mouse model exists, promising to reveal modulators of neurodegenerative disease in an unbiased fashion, akin to screens in simpler model organisms. PMID- 25535388 TI - Effects of income supplementation on health of the poor elderly: the case of Mexico. AB - We use an income supplementation experiment we designed in the state of Yucatan in Mexico for residents 70 y and older to evaluate health impacts of additional income. Two cities in the State of Yucatan, Valladolid (treatment) and Motul (control), were selected for the income supplementation experiment. Elderly residents of Valladolid were provided the equivalent of an additional $67 per month, a 44% increase in average household income. We designed a survey given to residents of both cities before and 6 mo after the income supplement about their health and other aspects of overall well-being. Both baseline and follow-up surveys collect self-reported data on health, physical functioning, and biomarkers. Anthropometric measurements for every age-eligible respondent, including height, weight, and waist circumference, were collected. We also collected lung capacity, grip strength, a series of balance tests, and a timed walk. Our results show significant health benefits associated with the additional income. Relative to the control site, there was a statistically significant improvement in lung function and an improvement in memory. These improvements are equivalent to a reduction in age of 5-10 y. Residents used their extra income to go to the doctor, buy their medications, and alleviate their hunger. The fear that this extra income could be undone by reduced transfers from other family members or unwise expenditures by the poor elderly appears to be unfounded. PMID- 25535387 TI - Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling. AB - Exocytosis is tightly regulated in many cellular processes, from neurite expansion to tumor proliferation. Rab8, a member of the Rab family of small GTPases, plays an important role in membrane trafficking from the trans-Golgi network and recycling endosomes to the plasma membrane. Rabin8 is a guanine nucleotide exchange factor (GEF) and major activator of Rab8. Investigating how Rabin8 is activated in cells is thus pivotal to the understanding of the regulation of exocytosis. Here we show that phosphorylation serves as an important mechanism for Rabin8 activation. We identified Rabin8 as a direct phospho-substrate of ERK1/2 in response to EGF signaling. At the molecular level, ERK phosphorylation relieves the autoinhibition of Rabin8, thus promoting its GEF activity. We further demonstrate that blocking ERK1/2-mediated phosphorylation of Rabin8 inhibits transferrin recycling to the plasma membrane. Together, our results suggest that ERK1/2 activate Rabin8 to regulate vesicular trafficking to the plasma membrane in response to extracellular signaling. PMID- 25535389 TI - Osteopetrosis in TAK1-deficient mice owing to defective NF-kappaB and NOTCH signaling. AB - The MAP kinase TGFbeta-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis. Mechanistically, Tak1 deficiency correlated with increased NUMB-like (NUMBL) levels. Accordingly, forced expression of Numbl abrogated osteoclastogenesis whereas its deletion partially restored osteoclastogenesis and reversed the phenotype of Tak1 deficiency. Tak1 deletion also down-regulated Notch intracellular domain (NICD), but increased the levels of the transcription factor recombinant recognition sequence binding protein at Jkappa site (RBPJ), consistent with NUMBL regulating notch signaling through degradation of NICD, a modulator of RBPJ. Accordingly, deletion of Rbpj partially corrected osteopetrosis in Tak1-deficient mice. Furthermore, expression of active IKK2 in RBPJ/TAK1-deficient cells significantly restored osteoclastogenesis, indicating that activation of NF-kappaB is essential for complete rescue of the pathway. Thus, we propose that TAK1 regulates osteoclastogenesis by integrating activation of NF-kappaB and derepression of NOTCH/RBPJ in myeloid cells through inhibition of NUMBL. PMID- 25535390 TI - Cultivation of a human-associated TM7 phylotype reveals a reduced genome and epibiotic parasitic lifestyle. AB - The candidate phylum TM7 is globally distributed and often associated with human inflammatory mucosal diseases. Despite its prevalence, the TM7 phylum remains recalcitrant to cultivation, making it one of the most enigmatic phyla known. In this study, we cultivated a TM7 phylotype (TM7x) from the human oral cavity. This extremely small coccus (200-300 nm) has a distinctive lifestyle not previously observed in human-associated microbes. It is an obligate epibiont of an Actinomyces odontolyticus strain (XH001) yet also has a parasitic phase, thereby killing its host. This first completed genome (705 kb) for a human-associated TM7 phylotype revealed a complete lack of amino acid biosynthetic capacity. Comparative genomics analyses with uncultivated environmental TM7 assemblies show remarkable conserved gene synteny and only minimal gene loss/gain that may have occurred as TM7x adapted to conditions within the human host. Transcriptomic and metabolomic profiles provided the first indications, to our knowledge, that there is signaling interaction between TM7x and XH001. Furthermore, the induction of TNF-alpha production in macrophages by XH001 was repressed in the presence of TM7x, suggesting its potential immune suppression ability. Overall, our data provide intriguing insights into the uncultivability, pathogenicity, and unique lifestyle of this previously uncharacterized oral TM7 phylotype. PMID- 25535391 TI - Terpene synthases are widely distributed in bacteria. AB - Odoriferous terpene metabolites of bacterial origin have been known for many years. In genome-sequenced Streptomycetaceae microorganisms, the vast majority produces the degraded sesquiterpene alcohol geosmin. Two minor groups of bacteria do not produce geosmin, with one of these groups instead producing other sesquiterpene alcohols, whereas members of the remaining group do not produce any detectable terpenoid metabolites. Because bacterial terpene synthases typically show no significant overall sequence similarity to any other known fungal or plant terpene synthases and usually exhibit relatively low levels of mutual sequence similarity with other bacterial synthases, simple correlation of protein sequence data with the structure of the cyclized terpene product has been precluded. We have previously described a powerful search method based on the use of hidden Markov models (HMMs) and protein families database (Pfam) search that has allowed the discovery of monoterpene synthases of bacterial origin. Using an enhanced set of HMM parameters generated using a training set of 140 previously identified bacterial terpene synthase sequences, a Pfam search of 8,759,463 predicted bacterial proteins from public databases and in-house draft genome data has now revealed 262 presumptive terpene synthases. The biochemical function of a considerable number of these presumptive terpene synthase genes could be determined by expression in a specially engineered heterologous Streptomyces host and spectroscopic identification of the resulting terpene products. In addition to a wide variety of terpenes that had been previously reported from fungal or plant sources, we have isolated and determined the complete structures of 13 previously unidentified cyclic sesquiterpenes and diterpenes. PMID- 25535392 TI - Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins. AB - The discovery of light-inducible protein-protein interactions has allowed for the spatial and temporal control of a variety of biological processes. To be effective, a photodimerizer should have several characteristics: it should show a large change in binding affinity upon light stimulation, it should not cross react with other molecules in the cell, and it should be easily used in a variety of organisms to recruit proteins of interest to each other. To create a switch that meets these criteria we have embedded the bacterial SsrA peptide in the C terminal helix of a naturally occurring photoswitch, the light-oxygen-voltage 2 (LOV2) domain from Avena sativa. In the dark the SsrA peptide is sterically blocked from binding its natural binding partner, SspB. When activated with blue light, the C-terminal helix of the LOV2 domain undocks from the protein, allowing the SsrA peptide to bind SspB. Without optimization, the switch exhibited a twofold change in binding affinity for SspB with light stimulation. Here, we describe the use of computational protein design, phage display, and high throughput binding assays to create an improved light inducible dimer (iLID) that changes its affinity for SspB by over 50-fold with light stimulation. A crystal structure of iLID shows a critical interaction between the surface of the LOV2 domain and a phenylalanine engineered to more tightly pin the SsrA peptide against the LOV2 domain in the dark. We demonstrate the functional utility of the switch through light-mediated subcellular localization in mammalian cell culture and reversible control of small GTPase signaling. PMID- 25535393 TI - Pan-vertebrate comparative genomics unmasks retrovirus macroevolution. AB - Although extensive research has demonstrated host-retrovirus microevolutionary dynamics, it has been difficult to gain a deeper understanding of the macroevolutionary patterns of host-retrovirus interactions. Here we use recent technological advances to infer broad patterns in retroviral diversity, evolution, and host-virus relationships by using a large-scale phylogenomic approach using endogenous retroviruses (ERVs). Retroviruses insert a proviral DNA copy into the host cell genome to produce new viruses. ERVs are provirus insertions in germline cells that are inherited down the host lineage and consequently present a record of past host-viral associations. By mining ERVs from 65 host genomes sampled across vertebrate diversity, we uncover a great diversity of ERVs, indicating that retroviral sequences are much more prevalent and widespread across vertebrates than previously appreciated. The majority of ERV clades that we recover do not contain known retroviruses, implying either that retroviral lineages are highly transient over evolutionary time or that a considerable number of retroviruses remain to be identified. By characterizing the distribution of ERVs, we show that no major vertebrate lineage has escaped retroviral activity and that retroviruses are extreme host generalists, having an unprecedented ability for rampant host switching among distantly related vertebrates. In addition, we examine whether the distribution of ERVs can be explained by host factors predicted to influence viral transmission and find that internal fertilization has a pronounced effect on retroviral colonization of host genomes. By capturing the mode and pattern of retroviral evolution and contrasting ERV diversity with known retroviral diversity, our study provides a cohesive framework to understand host-virus coevolution better. PMID- 25535394 TI - Superresolution microscopy reveals spatial separation of UCP4 and F0F1-ATP synthase in neuronal mitochondria. AB - Because different proteins compete for the proton gradient across the inner mitochondrial membrane, an efficient mechanism is required for allocation of associated chemical potential to the distinct demands, such as ATP production, thermogenesis, regulation of reactive oxygen species (ROS), etc. Here, we used the superresolution technique dSTORM (direct stochastic optical reconstruction microscopy) to visualize several mitochondrial proteins in primary mouse neurons and test the hypothesis that uncoupling protein 4 (UCP4) and F0F1-ATP synthase are spatially separated to eliminate competition for the proton motive force. We found that UCP4, F0F1-ATP synthase, and the mitochondrial marker voltage dependent anion channel (VDAC) have various expression levels in different mitochondria, supporting the hypothesis of mitochondrial heterogeneity. Our experimental results further revealed that UCP4 is preferentially localized in close vicinity to VDAC, presumably at the inner boundary membrane, whereas F0F1 ATP synthase is more centrally located at the cristae membrane. The data suggest that UCP4 cannot compete for protons because of its spatial separation from both the proton pumps and the ATP synthase. Thus, mitochondrial morphology precludes UCP4 from acting as an uncoupler of oxidative phosphorylation but is consistent with the view that UCP4 may dissipate the excessive proton gradient, which is usually associated with ROS production. PMID- 25535396 TI - Do acute elevations of serum creatinine in primary care engender an increased mortality risk? AB - BACKGROUND: The significant impact Acute Kidney Injury (AKI) has on patient morbidity and mortality emphasizes the need for early recognition and effective treatment. AKI presenting to or occurring during hospitalisation has been widely studied but little is known about the incidence and outcomes of patients experiencing acute elevations in serum creatinine in the primary care setting where people are not subsequently admitted to hospital. The aim of this study was to define this incidence and explore its impact on mortality. METHODS: The study cohort was identified by using hospital data bases over a six month period. INCLUSION CRITERIA: People with a serum creatinine request during the study period, 18 or over and not on renal replacement therapy.The patients were stratified by a rise in serum creatinine corresponding to the Acute Kidney Injury Network (AKIN) criteria for comparison purposes. Descriptive and survival data were then analysed.Ethical approval was granted from National Research Ethics Service (NRES) Committee South East Coast and from the National Information Governance Board. RESULTS: The total study population was 61,432. 57,300 subjects with 'no AKI', mean age 64.The number (mean age) of acute serum creatinine rises overall were, 'AKI 1' 3,798 (72), 'AKI 2' 232 (73), and 'AKI 3' 102 (68) which equates to an overall incidence of 14,192 pmp/year (adult). Unadjusted 30 day survival was 99.9% in subjects with 'no AKI', compared to 98.6%, 90.1% and 82.3% in those with 'AKI 1', 'AKI 2' and 'AKI 3' respectively. After multivariable analysis adjusting for age, gender, baseline kidney function and co-morbidity the odds ratio of 30 day mortality was 5.3 (95% CI 3.6, 7.7), 36.8 (95% CI 21.6, 62.7) and 123 (95% CI 64.8, 235) respectively, compared to those without acute serum creatinine rises as defined. CONCLUSIONS: People who develop acute elevations of serum creatinine in primary care without being admitted to hospital have significantly worse outcomes than those with stable kidney function. PMID- 25535395 TI - Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. AB - The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5(+)) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5(+) progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways. PMID- 25535397 TI - Impact of breast cancer stage, time from diagnosis and chemotherapy on plasma and cellular biomarkers of hypercoagulability. AB - BACKGROUND: In breast cancer patients routine thromboprophylaxis is not recommended but individualized risk assessment is encouraged. The incorporation of hypercoagulability biomarkers could increase the sensitivity of risk assessment models (RAM) to identify patients at VTE risk. To this aim we investigated the impact of cancer-related characteristics on hypercoagulability biomarkers. METHODS: Thrombin generation (TG) assessed with the Thrombogramme Thrombinoscope(r), levels of platelet derived microparticles (Pd-MP) assessed with flow cytometry, procoagulant phospholid dependent clotting time (PPL-ct) measured with a clotting assay and D-Dimers (were assessed in a cohort of 62 women with breast cancer and in 30 age matched healthy women. RESULTS: Patients showed significantly higher TG, Pd-MP, D-Dimers levels and shortened PPL-ct compared to the controls. The PPL-ct was inversely correlated with the levels of Pd-MP, which were increased in 97% of patients. TG and D-Dimers were increased in 76% and 59% of patients respectively. In any stage of the disease TG was significantly increased as compared to the controls. There was no significant difference of TG in patients with local, regional of metastatic stage. There was no significant difference in Pd-MP or Pd-MP/PS+ between the subgroups of patients with local or regional stage of cancer. Patients with metastatic disease had significantly higher levels of Pd-MP and Pd-MP/PS+ compared to those with regional stage. The D-Dimers increased in patients with metastatic stage. In patients on chemotherapy with less than 6 months since diagnosis TG was significantly higher compared to those on chemotherapy who diagnosed in interval > 6 months. Patients with metastatic disease had significantly higher levels of Pd-MP and D-Dimers compared to those with non-metastatic disease. CONCLUSION: In breast cancer patients the stage, the time elapsed since the diagnosis and the administration of chemotherapy are determinants of cellular and plasma hypercoagulability. The levels and the procoagulant activity of Pd-MP are interconnected with the biological activity and the overall burden of cancer. TG reflects the procoagulant properties of both breast cancer and chemotherapy in the initial period of cancer diagnosis. Thus the weighted incorporation of the biomarkers of cellular and plasma hypercoagulabilty in RAM for VTE might improve their predictive value. PMID- 25535398 TI - INTRAGO: intraoperative radiotherapy in glioblastoma multiforme-a phase I/II dose escalation study. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. METHODS/DESIGN: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. TRIAL REGISTRATION: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014). PMID- 25535399 TI - Paclitaxel-induced neuropathy: potential association of MAPT and GSK3B genotypes. AB - BACKGROUND: Paclitaxel treatment produces dose-limiting peripheral neurotoxicity, which adversely affects treatment and long-term outcomes. In the present study, the contribution of genetic polymorphisms to paclitaxel-induced neurotoxicity were assessed in 21 patients, focusing on polymorphisms involved in the tau microtubule pathway, an important target of paclitaxel involved in neurotoxicity development. METHODS: Polymorphisms in the microtubule-associated protein tau (MAPT) gene (haplotype 1 and rs242557 polymorphism) and the glycogen synthase kinase-3beta (GSK3beta) gene (rs6438552 polymorphism) were investigated. Neurotoxicity was assessed using neuropathy grading scales, neurophysiological studies and patient questionnaires. RESULTS: A significant relationship between the GSK-3B rs6438552 polymorphism and paclitaxel-induced neurotoxicity was evident. CONCLUSIONS: Polymorphisms in tau-associated genes may contribute to the development of paclitaxel-induced neurotoxicity, although larger series will be necessary to confirm these findings. PMID- 25535400 TI - The association between histone 3 lysine 27 trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters. AB - BACKGROUND: It is well established that genetic and epigenetic alterations are common events in prostate cancer, which may lead to aberrant expression of critical genes. The importance of epigenetic mechanisms in prostate cancer carcinogenesis is increasingly evident. In this study, the focus will be on histone modifications and the primary objectives are to map H3K27me3 marks and quantify RAR beta 2, ER alpha, SRC3, RGMA, PGR, and EZH2 gene expressions in prostate cancer tissues compared to normal tissues. In addition, a data analysis was made in connection with the clinicopathological parameters. METHODS: 71 normal specimens and 66 cancer prostate tissues were randomly selected in order to assess the proportion of the repressive H3K27me3 mark and gene expression. H3K27me3 level was evaluated by ChIP-qPCR and mRNA expression using RT-qPCR between prostate cancer and normal tissues. Subsequently, western-blotting was performed for protein detection. The analysis of variance (ANOVA) was performed, and Tukey's test was used to correct for multiple comparisons (p-value threshold of 0.05). The principal component analysis (PCA) and discriminant factorial analysis (DFA) were used to explore the association between H3K27me3 level and clinicopathological parameters. RESULTS: The study demonstrated that H3K27me3 level was significantly enriched at the RAR beta 2, ER alpha, PGR, and RGMA promoter regions in prostate cancer tissues compared to normal tissues. After stratification by clinicopathological parameters, the H3K27me3 level was positively correlated with Gleason score, PSA levels and clinical stages for RAR beta 2, ER alpha, PGR, and RGMA. High H3K27me3 mark was significantly associated with decreased RAR beta 2, ER alpha, PGR and RGMA gene expressions in prostate cancer sample compared to the normal one. Moreover, the results showed that mRNA level of EZH2, AR and SRC3 are upregulated in prostate cancer compared to normal prostate tissues and this correlates positively with Gleason score, PSA levels and clinical stages. Obviously, these observations were confirmed by protein level using western-blot. CONCLUSIONS: This data clearly demonstrated that H3K27me3 level correlated with aggressive tumor features. Also this study revealed that reverse correlation of RAR beta 2, ER alpha, PGR, and RGMA expressions with EZH2, SRC3, and AR expressions in prostate cancer tissues suggests that these genes are the target of EZH2. Therefore, all therapeutic strategies leading to histone demethylation with epigenetic drugs such as histone methyltransferase inhibitor may be relevant treatments against prostate cancer. PMID- 25535401 TI - How does unemployment affect self-assessed health? A systematic review focusing on subgroup effects. AB - BACKGROUND: Almost all studies on the effect on health from unemployment have concluded that unemployment is bad for your health. However, only a few review articles have dealt with this relation in recent years, and none of them have focused on the analysis of subgroups such as age, gender, and marital status. The objective of our article is to review how unemployment relates to self-assessed health with a focus on its effect on subgroups. METHODS: A search was performed in Web of Science to find articles that measured the effect on health from unemployment. The selection of articles was limited to those written in English, consisting of original data, and published in 2003 or later. Our definition of health was restricted to self-assessed health. Mortality- and morbidity-related measurements were therefore not included in our analysis. For the 41 articles included, information about health measurements, employment status definitions, other factors included in the statistical analysis, study design (including study population), and statistical method were collected with the aim of analysing the results on both the population and factor level. RESULTS: Most of the studies in our review showed a negative effect on health from unemployment on a population basis. Results at the factor levels were most common for gender (25 articles), age (11 articles), geographic location (8 articles), and education level (5 articles). The analysis showed that there was a health effect for gender, age, education level, household income, and geographic location. However, this effect differed between studies and no clear pattern on who benefits or suffers more among these groups could be determined. The result instead seemed to depend on the study context. The only clear patterns of association found were for socioeconomic status (manual workers suffer more), reason for unemployment (being unemployed due to health reasons is worse), and social network (a strong network is beneficial). CONCLUSIONS: Unemployment affects groups of individuals differently. We believe that a greater effort should be spent on specific groups of individuals, such as men or women, instead of the population as a whole when analysing the effect of unemployment on health. PMID- 25535402 TI - Administration of a Salmonella Enteritidis DeltahilAssrAfliG strain by coarse spray to newly hatched broilers reduces colonization and shedding of a Salmonella Enteritidis challenge strain. AB - Consumption of contaminated poultry meat is still an important cause of Salmonella infections in humans. Colonization inhibition (CI) occurs when a live Salmonella strain is administered to chickens and subsequently protects against challenge with another Salmonella strain belonging to the same serotype. A Salmonella Enteritidis hilAssrAfliG deletion mutant has previously been proven to reduce colonization and shedding of a wild-type Salmonella Enteritidis strain in newly hatched broilers after experimental infection. In this study, we compared two administration routes for this strain. Administering the Salmonella Enteritidis DeltahilAssrAfliG strain through drinking water on the first day of life resulted in decreased fecal shedding and cecal colonization of a wild-type Salmonella Enteritidis challenge strain administered 24 h later using a seeder bird model. When administering the CI strain by coarse spray on newly hatched broiler chicks, an even more pronounced reduction of cecal colonization was observed, and fecal shedding of the Salmonella Enteritidis challenge strain ceased during the course of the experiment. These data suggest that administering a Salmonella Enteritidis DeltahilAssrAfliG strain to newly hatched chicks using a coarse spray is a useful and effective method that reduces colonization and shedding of a wild-type Salmonella Enteritidis strain after early challenge. PMID- 25535403 TI - Ovarian follicle selection and granulosa cell differentiation. AB - The reproductive strategy for avian species that produce a sequence (or clutch) of eggs is dependent upon the maintenance of a small cohort of viable, undifferentiated (prehierarchal) follicles. It is from this cohort that a single follicle is selected on an approximate daily basis to initiate rapid growth and final differentiation before ovulation. This review describes a working model in which follicles within this prehierarchal cohort are maintained in an undifferentiated state by inhibitory cell signaling until the time of selection. Ultimately, follicle selection represents a process in which a single undifferentiated follicle per day is predicted to escape such inhibitory mechanisms to begin rapid growth and final maturation before ovulation. Several processes initiated within the granulosa cell layer at selection are dependent upon G protein-coupled receptors signaling via cyclic adenosine monophosphate (cAMP), and several critical processes are described herein. Finally, reference is made to several practical outcomes that can result from understanding the process of selection, including applications within the poultry industry. Proximal factors and processes that mediate follicle selection can either extend or decrease the length of the laying sequence, and thus directly influence overall egg production. In particular, any aberration that results in the selection of more than one follicle per day will result in decreased egg production. More generally, in wild birds these processes are modified by prevailing environmental conditions and by social interactions to influence clutch size. The elucidation of cellular processes that regulate follicle selection can assist in the development of assisted reproductive technologies for application in threatened and endangered avian species. PMID- 25535404 TI - Nicotine replacement therapy use among smokers and ex-smokers: associated attitudes and beliefs: a qualitative study. AB - BACKGROUND: Smokers who are unwilling or unable to quit smoking may benefit from using nicotine replacement therapy (NRT) for harm reduction. This may include the partial or complete substitution of cigarettes with NRT. A taxonomy of the characteristics of those using NRT for harm reduction would be helpful in tailoring advice and treatment. Although attempts to categorize those using NRT for harm reduction have been made, these have largely been based on quantitative data. In order to provide further in-depth exploration of views, beliefs and experiences, the current study probed issues surrounding NRT and harm reduction qualitatively to better understand barriers and facilitators to this approach. METHODS: Three groups of participants (n = 15) were recruited from a student sample: current smokers with a history of NRT use, smokers without a history of NRT use, and ex-smokers with a history of NRT use. Participants were asked about their demographic characteristics, smoking behaviours, intention and perceived ability to quit smoking, awareness and use of NRT, beliefs about the health consequences of using NRT, and the safety and efficacy of NRT, using semi structured telephone interviews. RESULTS: Twenty-four themes were identified; these themes were clustered into three main issues of cross-cutting themes: attitudes towards smoking and motivation to quit; smoking reduction and quit attempts; and beliefs, use and concerns about NRT. Those with a history of NRT use were more motivated and engaged with the quitting process than non-users. However, irrespective of smoking status and past NRT use, all participants showed misperceptions about NRT, such as the health consequences associated with NRT use. CONCLUSIONS: NRT users are more motivated to quit smoking than non-users and are more likely to employ techniques to assist their cessation attempts. The majority of smokers have misperceptions regarding the safety and efficacy of NRT which may act as a barrier to its usage. PMID- 25535407 TI - Prevalence and causes of visual impairment and rate of wearing spectacles in schools for children of migrant workers in Shanghai, China. AB - BACKGROUND: To assess the prevalence of visual impairment and rate of wearing spectacles in schools for children of migrant workers in Shanghai, China. METHODS: Children from grade 1 to 5 in schools for children of migrant workers were randomly chosen for ocular examinations. All children were screened for uncorrected visual acuity and presenting visual acuity. After screening, the children whose uncorrected visual acuity was 20/40 or less received ocular motility evaluation, cycloplegic refraction/non-cycloplegic refraction, and external eye, anterior segment, media, and fundus examinations. RESULTS: A total of 9673 children were enumerated and 9512 (98.34%) participated in this study. The prevalence of uncorrected, presenting, and best-corrected visual acuity of 20/40 or worse in the better eye were 13.33%, 11.26%, and 0.63%, respectively. The rate of wearing spectacles of the children with visual impairment in one or both eyes was 15.50%. Of these, 26.05% were wearing spectacles with inaccurate prescriptions. Refractive error was a major cause of visual impairment, accounting for 89.48% of all the visual impairment causes. Other causes of visual impairment included amblyopia accounting for 10.12%; congenital cataract, 0.1%; congenital nystagmus, 0.1%; ocular prosthesis, 0.1%; macular degeneration, 0.05%; and opaque cornea, 0.05%. CONCLUSIONS: This is the first study of the prevalence and causes of visual impairment in schools for children of migrant workers in Shanghai, China. The visual impairment rate in schools for children of migrant workers in suburbs of Shanghai in the best eye before vision correction was lower than those of urban children in mainstream schools in Guangzhou in 2012, and higher than students in rural of Beijing in 1998 and in suburb of Chongqing in 2007. The refractive error was the principal cause of the visual impairment of the children of migrant workers. The rate of wearing spectacles was low and the percentage of inaccurate prescriptions, among those who wore spectacles, was high. Uncorrected refractive error was a significant cause of visual impairment in migrant children. PMID- 25535409 TI - Network Ecology and Adolescent Social Structure. AB - Adolescent societies-whether arising from weak, short-term classroom friendships or from close, long-term friendships-exhibit various levels of network clustering, segregation, and hierarchy. Some are rank-ordered caste systems and others are flat, cliquish worlds. Explaining the source of such structural variation remains a challenge, however, because global network features are generally treated as the agglomeration of micro-level tie-formation mechanisms, namely balance, homophily, and dominance. How do the same micro-mechanisms generate significant variation in global network structures? To answer this question we propose and test a network ecological theory that specifies the ways features of organizational environments moderate the expression of tie-formation processes, thereby generating variability in global network structures across settings. We develop this argument using longitudinal friendship data on schools (Add Health study) and classrooms (Classroom Engagement study), and by extending exponential random graph models to the study of multiple societies over time. PMID- 25535410 TI - Blood transfusion in anaesthesia and critical care: Less is more! PMID- 25535408 TI - Making the invisible, visible: a cross-sectional study of late presentation to HIV/AIDS services among men who have sex with men from a large urban center of Brazil. AB - BACKGROUND: Late presentation to testing, treatment and continued care has detrimental impacts on the health of HIV-positive individuals as well as their sexual partners' health. Men who have sex with men (MSM) experience disproportionately high rates of HIV both globally and in Brazil. However, the factors that inhibit linkage to care among MSM remain unclear. METHODS: We conducted a cross-sectional study of HIV-positive MSM (n = 740) enrolled in HIV/AIDS services in a large urban center of Brazil from August 2010 to June 2011. Descriptive, bivariate and multivariate statistics were conducted using STATA 12 to examine the relationship between a range of variables and late presentation, defined as having a first CD4 count <350 cells/mm3. RESULTS: Within the sample, the prevalence of LP was 63.1%. Men who self-identified as heterosexual (AOR 1.54 and 95% CI 1.08 - 2.20) compared to men who self identified as homosexual and bisexual were at increased odds of late presentation. Additionally, men age 30 and older (AOR 1.56, 95% CI 1.01 - 2.43) compared to individuals age 18-29 experienced increased odds of late presentation among MSM. CONCLUSIONS: The prevalence of LP in this population was higher than noted in the global literature on LP among MSM. Heterosexual men and older age individuals experienced substantial barriers to HIV care. The stigma around same sex behaviors and the current focus of HIV prevention and treatment campaigns on younger age individuals may limit patients' and providers' awareness of the risk for HIV and access to available services. In addition to addressing HIV-specific barriers to care, developing effective strategies to reduce late presentation in Brazil will require addressing social factors - such as stigma against diverse sexualities - to concretely identify and eliminate barriers to available services. Only in so doing can we make currently invisible people, visible. PMID- 25535411 TI - Overview of the coagulation system. AB - Coagulation is a dynamic process and the understanding of the blood coagulation system has evolved over the recent years in anaesthetic practice. Although the traditional classification of the coagulation system into extrinsic and intrinsic pathway is still valid, the newer insights into coagulation provide more authentic description of the same. Normal coagulation pathway represents a balance between the pro coagulant pathway that is responsible for clot formation and the mechanisms that inhibit the same beyond the injury site. Imbalance of the coagulation system may occur in the perioperative period or during critical illness, which may be secondary to numerous factors leading to a tendency of either thrombosis or bleeding. A systematic search of literature on PubMed with MeSH terms 'coagulation system, haemostasis and anaesthesia revealed twenty eight related clinical trials and review articles in last 10 years. Since the balance of the coagulation system may tilt towards bleeding and thrombosis in many situations, it is mandatory for the clinicians to understand physiologic basis of haemostasis in order to diagnose and manage the abnormalities of the coagulation process and to interpret the diagnostic tests done for the same. PMID- 25535412 TI - Blood groups systems. AB - International Society of Blood Transfusion has recently recognized 33 blood group systems. Apart from ABO and Rhesus system, many other types of antigens have been noticed on the red cell membranes. Blood grouping and cross-matching is one of the few important tests that the anaesthesiologist orders during perioperative period. Hence, a proper understanding of the blood group system, their clinical significance, typing and cross-matching tests, and current perspective are of paramount importance to prevent transfusion-related complications. Nonetheless, the knowledge on blood group system is necessary to approach blood group-linked diseases which are still at the stage of research. This review addresses all these aspects of the blood groups system. PMID- 25535413 TI - Overview of blood components and their preparation. AB - The whole blood which is a mixture of cells, colloids and crystalloids can be separated into different blood components namely packed red blood cell (PRBC) concentrate, platelet concentrate, fresh frozen plasma and cryoprecipitate. Each blood component is used for a different indication; thus the component separation has maximized the utility of one whole blood unit. Different components need different storage conditions and temperature requirements for therapeutic efficacy. A variety of equipments to maintain suitable ambient conditions during storage and transportation are in vogue. The blood components being foreign to a patient may produce adverse effects that may range from mild allergic manifestations to fatal reactions. Such reactions are usually caused by plasma proteins, leucocytes, red cell antigens, plasma and other pathogens. To avoid and reduce such complications, blood products are modified as leukoreduced products, irradiated products, volume reduced products, saline washed products and pathogen inactivated products. The maintenance of blood inventory forms a major concern of blood banking particularly of rare blood groups routinely and common blood groups during disasters. PRBCs can be stored for years using cryopreservation techniques. New researches in red cell cultures and blood substitutes herald new era in blood banking. PMID- 25535414 TI - Indications for blood and blood product transfusion. AB - Transfusion of blood products carries certain inherent risks and hence it should be undertaken only if it improves patient outcome. A review of the literature was carried out to find the indications and effects of transfusion on morbidity and mortality of patients. There is high-quality evidence showing that restrictive blood transfusion with a transfusion trigger of haemoglobin of 7-8 g/dl or the presence of symptoms of anaemia is safe and not associated with increased mortality compared with liberal transfusion. Thus, restrictive strategy is strongly recommended in surgical and critically ill-patients. There is moderate evidence for the use of plasma and platelet transfusion in patients receiving massive blood transfusion. There is not enough evidence to support the use of plasma, platelets and cryoprecipitate in any other clinical setting. Retrospective studies show improved survival after high plasma and platelet to red blood cell ratio of 1:1:1, but this has not been confirmed in randomised trials. PMID- 25535415 TI - Adverse events related to blood transfusion. AB - The acute blood transfusion reactions are responsible for causing most serious adverse events. Awareness about various clinical features of acute and delayed transfusion reactions with an ability to assess the serious reactions on time can lead to a better prognosis. Evidence-based medicine has changed today's scenario of clinical practice to decrease adverse transfusion reactions. New evidence based algorithms of transfusion and improved haemovigilance lead to avoidance of unnecessary transfusions perioperatively. The recognition of adverse events under anaesthesia is always challenging. The unnecessary blood transfusions can be avoided with better blood conservation techniques during surgery and with anaesthesia techniques that reduce blood loss. Better and newer blood screening methods have decreased the infectious complications to almost negligible levels. With universal leukoreduction of red blood cells (RBCs), selection of potential donors such as use of male donors only plasma and restriction of RBC storage, most of the non-infectious complications can be avoided. PMID- 25535416 TI - Transfusion transmitted diseases in perioperative and intensive care settings. AB - Patients in the perioperative period and intensive care unit are commonly exposed to blood transfusion (BT). They are at increased risk of transfusion transmitted bacterial, viral and protozoal diseases. The risk of viral transmission has decreased steadily, but the risk of bacterial transmission remains same. Bacterial contamination is more in platelet concentrates than in red cells and least in plasma. The chances of sepsis, morbidity and mortality depend on the number of transfusions and underlying condition of the patient. Challenges to safe BT continue due to new emerging pathogens and various management problems. Strategies to restrict BT, optimal surgical and anaesthetic techniques to reduce blood loss and efforts to develop transfusion alternatives should be made. Literature search was performed using search words/phrases blood transfusion, transfusion, transfusion transmitted diseases, transfusion transmitted bacterial diseases, transfusion transmitted viral diseases, transfusion transmitted protozoal diseases or combinations, on PubMed and Google Scholar from 1990 to 2014. PMID- 25535417 TI - Legal and ethical issues in safe blood transfusion. AB - Legal issues play a vital role in providing a framework for the Indian blood transfusion service (BTS), while ethical issues pave the way for quality. Despite licensing of all blood banks, failure to revamp the Drugs and Cosmetic Act (D and C Act) is impeding quality. Newer techniques like chemiluminescence or nucleic acid testing (NAT) find no mention in the D and C Act. Specialised products like pooled platelet concentrates or modified whole blood, therapeutic procedures like erythropheresis, plasma exchange, stem cell collection and processing technologies like leukoreduction and irradiation are not a part of the D and C Act. A highly fragmented BTS comprising of over 2500 blood banks, coupled with a slow and tedious process of dual licensing (state and centre) is a hindrance to smooth functioning of blood banks. Small size of blood banks compromises blood safety. New blood banks are opened in India by hospitals to meet requirements of insurance providers or by medical colleges as this a Medical Council of India (MCI) requirement. Hospital based blood banks opt for replacement donation as they are barred by law from holding camps. Demand for fresh blood, lack of components, and lack of guidelines for safe transfusion leads to continued abuse of blood. Differential pricing of blood components is difficult to explain scientifically or ethically. Accreditation of blood banks along with establishment of regional testing centres could pave the way to blood safety. National Aids Control Organisation (NACO) and National Blood Transfusion Council (NBTC) deserve a more proactive role in the licensing process. The Food and Drug Administration (FDA) needs to clarify that procedures or tests meant for enhancement of blood safety are not illegal. PMID- 25535418 TI - Coagulation testing in the perioperative period. AB - Perioperative coagulation management is a complex task that has a significant impact on the perioperative journey of patients. Anaesthesia providers play a critical role in the decision-making on transfusion and/or haemostatic therapy in the surgical setting. Various tests are available in identifying coagulation abnormalities in the perioperative period. While the rapidly available bedside haemoglobin measurements can guide the transfusion of red blood cells, blood product administration is guided by many in vivo and in vitro tests. The introduction of newer anticoagulant medications and the implementation of the modified in vivo coagulation cascade have given a new dimension to the field of perioperative transfusion medicine. A proper understanding of the application and interpretation of the coagulation tests is vital for a good perioperative outcome. PMID- 25535419 TI - Perioperative blood management. AB - Perioperative anaemia and allogenic blood transfusion (ABT) are known to increase the risk of adverse clinical outcomes. The quality, cost and availability of blood components are also major limitations with regard to ABT. Perioperative patient blood management (PBM) strategies should be aimed at minimizing and improving utilization of blood components. The goals of PBM are adequate preoperative evaluation and optimization of haemoglobin and bleeding parameters, techniques to minimize blood loss, blood conservation technologies and use of transfusion guidelines with targeted therapy. Attention to these details can help in cost reduction and improved patient outcome. PMID- 25535420 TI - Red blood cell transfusion strategies and Maximum surgical blood ordering schedule. AB - Blood transfusion is one of the practices that is in vogue because it expands blood volume and purportedly improves the oxygen carrying capacity. Despite this supposed physiological benefit, paradoxically, both anaemia and transfusion are independently associated with organ injury and increased morbidity. Historically, transfusion was used to maintain blood haemoglobin concentration above 10 g/dL and a haematocrit above 30%. There is now a greater emphasis on interventions to reduce the use of transfusion as it is a scarce and expensive resource with many serious adverse effects. Institutional maximum surgical blood ordering schedule algorithm developed with data analysis and consensus of surgeons, anaesthesiologists and blood banks can reduce the overuse of blood. A PubMed search was performed with search words/combination of words 'erythrocyte transfusion, adverse effects, economics, mortality, therapy, therapeutic use and utilisation'. Search yielded a total of 1541 articles that were screened for clinical relevance for the purpose of this review. PMID- 25535421 TI - Massive transfusion and massive transfusion protocol. AB - Haemorrhage remains a major cause of potentially preventable deaths. Rapid transfusion of large volumes of blood products is required in patients with haemorrhagic shock which may lead to a unique set of complications. Recently, protocol based management of these patients using massive transfusion protocol have shown improved outcomes. This section discusses in detail both management and complications of massive blood transfusion. PMID- 25535422 TI - Approach to bleeding patient. AB - Managing a bleeding patient is very challenging for the perioperative physician. Bleeding in a patient would be due to inherited or acquired disorders of haemostasis. Identifying the patients at risk of bleeding and utilising prophylactic treatment protocols has good outcomes. Along with clinical signs, trends in monitoring coagulation parameters and analysing blood picture are necessary. Management of patients in the postoperative period and in intensive care unit should be focused on normalization of coagulation profile as early as possible with available blood and its products. Available recombinant factors should be given priority as per the approved indications. Exploring the surgical site should be considered for persistent bleeding because haemodynamic compromise, excessive transfusion of fluids, blood and its products and more inotropic support may have a negative impact on the patient outcome. PMID- 25535423 TI - Disseminated intravascular coagulation. AB - Disseminated intravascular coagulation (DIC) is a reflection of an underlying systemic disorder which affects the coagulation system, simultaneously resulting in pro-coagulant activation, fibrinolytic activation, and consumption coagulopathy and finally may result in organ dysfunction and death. Though septicaemia is the most common cause of DIC, several other conditions can also lead to it. A diagnosis of DIC should be made only in the presence of a causative factor supported by repeated laboratory tests for coagulation profile and clotting factors. An effective scoring system helps to detect an overt DIC and a high score closely correlates with mortality. Treatment of DIC is aimed at combating the underlying disorder followed by supportive management. Low molecular weight heparin is advocated in special situations whereas anti-thrombin III and activated protein C are of doubtful value. Early diagnosis and prompt treatment backed by laboratory support can reduce the morbidity and mortality associated with it. The methodology of search for this review article involved hand search from text books and internet search using Medline (via PubMed) using key words DIC, thrombosis, fibrin degradation products, anti-thrombin and tissue factor for the last 25 years and also recent evidence-based reviews. PMID- 25535424 TI - Transfusion practices in trauma. AB - Resuscitation of a severely traumatised patient with the administration of crystalloids, or colloids along with blood products is a common transfusion practice in trauma patients. The determination of this review article is to update on current transfusion practices in trauma. A search of PubMed, Google Scholar, and bibliographies of published studies were conducted using a combination of key-words. Recent articles addressing the transfusion practises in trauma from 2000 to 2014 were identified and reviewed. Trauma induced consumption and dilution of clotting factors, acidosis and hypothermia in a severely injured patient commonly causes trauma-induced coagulopathy. Early infusion of blood products and early control of bleeding decreases trauma-induced coagulopathy. Hypothermia and dilutional coagulopathy are associated with infusion of large volumes of crystalloids. Hence, the predominant focus is on damage control resuscitation, which is a combination of permissive hypotension, haemorrhage control and haemostatic resuscitation. Massive transfusion protocols improve survival in severely injured patients. Early recognition that the patient will need massive blood transfusion will limit the use of crystalloids. Initially during resuscitation, fresh frozen plasma, packed red blood cells (PRBCs) and platelets should be transfused in the ratio of 1:1:1 in severely injured patients. Fresh whole blood can be an alternative in patients who need a transfusion of 1:1:1 thawed plasma, PRBCs and platelets. Close monitoring of bleeding and point of care coagulation tests are employed, to allow goal-directed plasma, PRBCs and platelets transfusions, in order to decrease the risk of transfusion-related acute lung injury. PMID- 25535425 TI - Blood transfusion practices in cardiac anaesthesia. AB - The primary reasons for blood transfusion in cardiac surgery are to correct anaemia and to improve tissue oxygen delivery. However, there is a considerable debate regarding the actual transfusion trigger at which the benefits of transfusion overweight the risk. The association between extreme haemodilution, transfusion and adverse outcome after cardio pulmonary bypass (CPB) is not clear and the current available literature is not sufficient to provide a strong recommendation regarding the safe haematocrit range during CPB. There is no quality evidence to support use of fresh red blood cell except during massive transfusion or exchange transfusion in neonate. Overall concern regarding the safety of allogeneic blood transfusion resulted in the search for autologous blood transfusion and perioperative blood salvage. The aim of this review is to provide cardiac surgery specific clinically useful guidelines pertaining to transfusion triggers, optimal haemodilution during CPB, autologous blood transfusion and role of perioperative blood salvage based on available evidence. PMID- 25535426 TI - Blood transfusion practices in neuroanaesthesia. AB - Neuroanaesthesia practice is associated with risk of significant blood loss resulting in anaemia in the intraoperative and postoperative period. The transfusion triggers in a neurologically injured brain are not clearly defined. Both a low haematocrit and a high haematocrit have not shown any improvement in the outcome. Transfusion of red blood cells may improve the cerebral oxygenation on neurophysiological monitors. However, these benefits have not been translated into clinical practice. Transfusion in subarachnoid haemorrhage leads to increased incidence of vasospasm and a poor outcome. Restrictive transfusion strategy is seen to have a lower incidence of pneumonia, urinary tract infection, bacteremia and septic shock in severe head injury. Current evidence suggests that a haemoglobin (Hb) level of <7 g/dl may be deleterious to the neurosurgical population. Target Hb of 8-9 g/dl may be desirable intraoperatively. Different transfusion triggers may hold true for different neurosurgical pathologies. PMID- 25535427 TI - Blood transfusion practices in obstetric anaesthesia. AB - Blood transfusion is an essential component of emergency obstetric care and appropriate blood transfusion significantly reduces maternal mortality. Obstetric haemorrhage, especially postpartum haemorrhage, remains one of the major causes of massive haemorrhage and a prime cause of maternal mortality. Blood loss and assessment of its correct requirement are difficult in pregnancy due to physiological changes and comorbid conditions. Many guidelines have been used to assess the requirement and transfusion of blood and its components. Infrastructural, economic, social and religious constraints in blood banking and donation are key issues to formulate practice guidelines. Available current guidelines for transfusion are mostly from the developed world; however, they can be used by developing countries keeping available resources in perspective. PMID- 25535428 TI - Blood transfusion practices in cancer surgery. AB - Cancer patients are commonly transfused with blood products immediately before, during or after major surgery. Blood loss and haemodilution are the most common causes of red blood cells (RBCs) administration and coagulopathies are the indications for the infusion of fresh-frozen plasma (FFP), cryoprecipitates and platelets. Transfusion-related immune modulation is a complication associated with the administration of blood products. A decreased immune surveillance as a consequence of blood transfusions has been linked to cancer recurrence and progression. Moreover, soluble factors present in packed RBCs, platelets and FFP can directly stimulate tumour growth and spread. Two meta-analyses suggest that the administration of blood products is associated with shorter recurrence-free survival and overall survival after colorectal cancer surgery. More studies are needed to show such association in different cancer patient populations. PMID- 25535429 TI - Blood transfusion practices in sepsis. AB - Sepsis is a clinical syndrome characterised by systemic inflammation due to infection. There is a spectrum with severity ranging from sepsis to severe sepsis and septic shock. Even with optimal treatment, mortality due to severe sepsis or septic shock is significant and poses a challenge to management. Antibiotics, source control, resuscitation with fluids, vasopressor and inotropic agents are the main-stay of treatment for septic shock. These may be supplemented with transfusion of red blood cells and or blood products, in the case of anaemia to sustain sufficient oxygen delivery([1]) or to manage associated haematological issues. Transfusion in sepsis has always been a debatable issue, especially in relation to choice of the fluid and the role of blood or blood product transfusion. PMID- 25535430 TI - Blood transfusion practices in liver transplantation. AB - Blood loss and blood transfusion have been inherently associated with liver transplantation. Bleeding has been attributed to the various factors which are associated with chronic liver dysfunction. Various surgical and anaesthetic strategies have been developed over the years to reduce bleeding and also to optimise the usage of various blood and blood products perioperatively. The present day success of liver transplantation can be attributed to these issues where transfusion practices have changed. Although several centres are successfully performing liver transplantations in large numbers, there is still a large variability in the usage of blood and blood products perioperatively among the institutions and even among different anaesthesiologists from the same institution. The present article deals with the various factors confounding this concept of blood transfusion practices and the various strategies adopted to reduce the transfusion requirements in the perioperative period. PMID- 25535431 TI - Perioperative neonatal and paediatric blood transfusion. AB - Paediatric patients undergoing surgical procedures commonly require some volume of blood or blood component replacement in the perioperative period. Paediatric patients undergoing major surgery associated with substantial blood loss should be evaluated pre-operatively. Pre-operative correction of anaemia may be done considering the age, plasma volume status, clinical status and comorbidities. Maximum allowable blood loss (MABL) for surgery must be calculated, and appropriate quantity of blood and blood components should be arranged. Intraoperative monitoring of blood loss should be done, and volume of transfusion should be calculated in a protocol based manner considering the volemia and the trigger threshold for transfusion for the patient and the MABL. Early haemostasis should be achieved by judicious administration of red blood cells, blood components and pharmacological agents. PMID- 25535432 TI - Management of patients who refuse blood transfusion. AB - A small group of people belonging to a certain religion, called Jehovah's witness do not accept blood transfusion or blood products, based on biblical readings. When such group of people are in need of health care, their faith and belief is an obstacle for their proper treatment, and poses legal, ethical and medical challenges for attending health care provider. Due to the rapid growth in the membership of this group worldwide, physicians attending hospitals should be prepared to manage such patients. Appropriate management of such patients entails understanding of ethical and legal issues involved, providing meticulous medical management, use of prohaemostatic agents, essential interventions and techniques to reduce blood loss and hence, reduce the risk of subsequent need for blood transfusion. An extensive literature search was performed using search engines such as Google scholar, PubMed, MEDLINE, science journals and textbooks using keywords like 'Jehovah's witness', 'blood haemodilution', 'blood salvage' and 'blood substitutes'. PMID- 25535433 TI - The hypercoagulable states in anaesthesia and critical care. AB - Hypercoagulable disorders are now diagnosed more frequently than before. These patients are, usually, managed with multiple anticoagulant and antiplatelet medications. Left unmonitored and unevaluated, there can be disastrous haemorrhagic or thrombotic complications. Appropriate perioperative and anaesthetic management of these patients will invite an aetiological diagnosis, severity analysis and the on-going treatment review. Different assays, thromboelastography and molecular cytogenetics have helped to diagnose these conditions precisely and thus guide the long-term management. Besides this, there are varieties of clinical conditions that will predispose to the hypercoagulability. These need to be defined and classified in order to offer a suitable therapeutic option. Pregnancy is one such important condition and can have more than one responsible factor favouring hypercoagulability. With such diverse kinds of disorders, it would be essential to note the anaesthetic implications, to avoid adverse perioperative outcomes. Available evidence based guidelines will help to make the therapeutic approach more precise. Selection of the appropriate technique of anaesthesia, offering the appropriate anticoagulation bridging as necessary and defining an appropriate interval and time for the intervention will help to minimise the complications. PMID- 25535434 TI - Role of therapeutic apheresis and phlebotomy techniques in anaesthesia and critical care. AB - Therapeutic transfusion techniques such as apheresis and phlebotomy are frequently used in intensive care units. Use of the apheresis technique for the treatment of various diseases in critically ill patients is growing day by day. There are increasing evidences for using apheresis as a primary therapy or as an adjunct to other therapies for various diseases such as thrombotic thrombocytopenic purpura, haemolytic uremic syndrome, drug toxicities, autoimmune disease, sepsis and fulminant hepatic failure. Apheresis is an invasive procedure. It has significant physiologic consequences, so the care of these patients requires continuous supervision. Phlebotomy is performed as an intervention for some disease management. Its use is nowadays restricted to conditions such as polycythaemia, haemochromatosis and porphyria cutanea tarda. In this review, we have looked at various indications, procedure and complications of apheresis and phlebotomy in critical care unit. PMID- 25535435 TI - Pensions and the health of older people in South Africa: is there an effect? PMID- 25535436 TI - Establishing linkages between emotional intelligence and transformational leadership. PMID- 25535437 TI - (De-) criminalization of attempted suicide in India: A review. AB - Attempted suicide is a serious problem requiring mental health interventions, but it continues to be treated as a criminal offence under the section 309 of Indian Penal Code. The article reviews the international legal perspective across various regions of the world, discusses the unintended consequences of section 309 IPC and highlights the need for decriminalization of attempted suicide in India. The Mental Health Care Bill, 2013, still under consideration in the Rajya Sabha (upper house), has proposed that attempted suicide should not be criminally prosecuted. Decriminalization of suicidal attempt will serve to cut down the undue stigma and avoid punishment in the aftermath of incident, and lead to a more accurate collection of suicide-related statistics. From a policy perspective, it will further emphasize the urgent need to develop a framework to deliver mental health services to all those who attempt suicide. PMID- 25535438 TI - Central registry in psychiatry: A structured review. AB - BACKGROUND: Central registry in psychiatry is being practiced in few countries and has been found useful in research and clinical management. Role of central registry has also expanded over the years. MATERIALS AND METHODS: All accessible internet database Medline, Scopus, Embase were accessed from 1990 till date. Available data were systematically reviewed in structured manner and analyzed. RESULTS: Central registry was found useful in epidemiological analysis, association studies, outcome studies, comorbidity studies, forensic issue, effective of medication, qualitative analysis etc.. CONCLUSION: Central registry proves to be effective tool in quantitative and qualitative understanding of psychiatry practice. Findings of studies from central registry can be useful in modifying best practice and evidence based treatment in psychiatry. PMID- 25535439 TI - Prevalence of stress level among Bank employees in urban Puducherry, India. AB - BACKGROUND AND OBJECTIVE: Stress is an important health area of concern among bank employees. The study aims to assess the stress level and its associated factors among bank employees. MATERIALS AND METHODS: A cross-sectional study was conducted among 192 bank employees in urban Puducherry, India. Stress level was assessed by Cohen's Perceived Stress scale and classified into low (0-11), average (12-15), high (16-20), and very high (21 and above) based on the stress scores. Collected data were analyzed by using univariate analysis. RESULTS: Majority of them had high and very high level of stress (75.5%, confidence interval: 69.4-81.6%). The variables that include age group, sex, category of work, smoking and alcohol use were not found to be significantly associated with the stress level (P > 0.05). With respect to question items, handling personal problems and things were going their way were answered as fairly often and very often by the majority of the subjects. CONCLUSION: Stress level among bank employees is high, which necessitates intervention measures for this vulnerable group. PMID- 25535440 TI - Clozapine response and pre-treatment EEG-is there some kind of relationship. AB - BACKGROUND: Clozapine has been used widely in the management of treatment resistant schizophrenia. The present study aims at determining whether pre treatment electroencephalography (EEG) abnormalities would serve as a marker for response to clozapine treatment. SUBJECTS AND METHODS: This was a cross-sectional study done in a tertiary care center in Mumbai where patients diagnosed with schizophrenia using DSM-IV criteria and resistant schizophrenia using Kane criteria were assessed using EEG prior to starting clozapine treatment. They were rated for symptomatic improvement using the Positive and Negative Syndrome Scale (PANSS) along with Clinical Global Improvement for Severity (CGI-S). The results were statistically analysed and presented. RESULTS: 55 out of the 80 patients in the study showed baseline EEG abnormalities. The mean duration of illness in the patients were 2.65 years. Slow wave and background EEG abnormalities were common in pre-treatment EEG. 36.4% patients in the study showed clinical response. Patients with negative symptoms and baseline EEG abnormalities showed better response. CONCLUSIONS: The study was circumscribed and had many limitations due to a small sample size. The relation between pre-treatment EEG abnormalities and clozapine response could not be statistically correlated and it could not be ascertained to be a marker for response to clozapine therapy. PMID- 25535441 TI - Assessment of sleep quality in post-graduate residents in a tertiary hospital and teaching institute. AB - OBJECTIVES: To evaluate subjective sleep quality, day-time sleepiness, prevalence of substance use, satisfaction with life among residents at our institute. To evaluate association of sleep qualitywith satisfaction with life and day-time sleepiness. To compare the findings between residents in clinical and para clinical departments. MATERIALS AND METHODS: Eighty-four residents filled questionnaires to obtain socio-demographic information and use of substance (s). Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Satisfaction With Life scale (SWLS) were also used. Association between sleep quality and sleepiness and satisfaction with life was evaluated. From the data collected, comparisons were made between the clinical and para-clinical department residents. RESULTS: A significant number of residents belonging to the clinical faculty were poorsleepers; reported high levels of abnormal day-time sleepiness and less satisfaction with life compared to residents in para-clinical faculties. The differences in correlation between sleepiness and satisfaction with life with sleep quality among the two groups were not found to be significant. A larger percentage of clinical residents reported use of at least one substance during the residency period compared to the para-clinical residents. CONCLUSIONS: Poor sleep quality is perceived greatly by the resident doctors in our public hospital, especially among clinical faculties. Interventions are thus necessary in order to ensure adequate sleep among them. PMID- 25535443 TI - Role models and occupational ambitions of in-school male adolescents. AB - BACKGROUND: A role model is perceived as worthy of imitation, their selection can indicate significant elements of psychosocial health and self-projection in adolescents. Patterns of behavior and lifestyle choices established during adolescence can have immediate and lasting effects on health. MATERIALS AND METHODS: Cross-sectional study was undertaken in the schools of Aligarh, Uttar Pradesh, India. The sample frame was 2347, out of which a sample of 390 students was studied. Data collected were entered and analyzed by SPSS for Windows version 10%). RESULTS: Majority (62.7%) of adolescents revealed that their role models were Film Star (34.8%) and their Teachers (27.9%), Parents (14.3%), Sportsman (12.0%). Politicians as the role models were opted by least proportion (1.2%). Desire of future occupation was Businessmen (27.9%), Doctor (18.6), and Engineer (14.4%). CONCLUSION: Nearly all adolescents had a role model. There is greater impact of cinema on the minds of adolescents, which resulted in choosing film actors as their role model. Aspiration of future occupation was not related to the characteristics of the role model. PMID- 25535442 TI - Efficacy of amisulpride and olanzapine for negative symptoms and cognitive impairments: An open-label clinical study. AB - BACKGROUND: Negative symptoms and diminished cognitive ability are also considered as core features of schizophrenia. There are many studies in which negative symptoms and cognitive impairments are individually treated with atypical antipsychotic in comparison with either a placebo or a typical antipsychotic. There is paucity of studies comparing the efficacy of olanzapine and amisulpride on improvement of negative symptoms and cognitive impairments. AIM: To examine the effectiveness of amisulpride and olanzapine in treatment of negative symptoms and cognitive impairments in schizophrenia. MATERIALS AND METHODS: Total 40 adult inpatients diagnosed as schizophrenia fulfilling inclusion/exclusion criteria were included in the study with their informed consent. These patients were recruited consecutively to one of the two drug regimen group, i.e. tab Amisulpride (100-300 mg/day) and tab Olanzapine (10-20 mg). Patients were evaluated on day 0 and day 60 with various rating scales like Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), Schizophrenia Cognition Rating Scale (SCoRS), Brief Psychiatric Rating Scale (BPRS), Calgary Depression Scale for Schizophrenia (CDSS), and three different scales to measure drug side effects. RESULTS: The mean SANS score in amisulpride and olanzapine group at day 0 and day 60 were 83.89 (+/-12.67) and 21.00 (+/-11.82) and 84.40 (+/-13.22) and 26.75 (+/-12.41), respectively. The mean rank of SCoRS global in amisulpride and olanzapine group at day 0 and day 60 were 4.78 (+/-1.13) and 2.78 (+/-0.63) and 4.85 (+/-1.18) and 3.30 (+/-1.12), respectively. The percentage improvement in SANS, SAPS, SCoRS interviewer, and SCoRS global in amisulpride group are 74.96%, 13.36%, 54.14%, and 42.00%, respectively. Similarly in olanzapine group percentage improvement in SANS, SAPS, SCoRS interviewer, and SCoRS global are 68.30%, 30.28%, 35.22%, and 31.95%, respectively. There is significant improvement in SANS, SCoRS, SAS, BPRS, and PANSS (Insight) in both amisulpride and olanzapine groups at the two time points. However, there is no significant difference between amisulpride and olanzapine group of patients. CONCLUSION: Both amisulpride and olanzapine group patients showed significant improvement in negative and cognitive symptoms from baseline to endpoint, but there was no significant difference between amisulpride and olanzapine group of patients. PMID- 25535444 TI - Crosssectional study of quality of life after renal transplant in end stage renal disease. AB - BACKGROUND: End stage renal disease (ERD) is a psychologically debilitating illness with considerable emotional morbidity. There is variation in quality of life and mental health status among recipients and donor at different stages of kidney transplantation. MATERIALS AND METHODS: The study is an observational analytic study. Sample for the study comprised of forty (40) consecutive patients including 20 recipients and 20 donors of 20 kidney transplantations, male and female, and who themselves/whose relatives provided written informed consent were included in the study. Both recipients and donors were followed-up from 2 weeks prior to transplant surgery to 6 months post-operatively by phone and when they came for review in Nephrology Out-Patient Department (OPD). Quality of life and mental health status was compared between the two groups. RESULTS: Study groups were homogeneous on age, education, gender and marital status. After transplantation recipient's mean score in all parameters had increased and all changes were statistically significant (<0.05). CONCLUSION: In this study significant changes in quality of life (QOL), and mental health status in recipients and donors before and after transplantation were noted. It is recommended to evaluate mental health related aspects of both donors and recipients. PMID- 25535445 TI - Allelic variants of ADH, ALDH and the five factor model of personality in alcohol dependence syndrome. AB - BACKGROUND: The etiology of alcohol dependence is a complex interplay of biopsychosocial factors. The genes for alcohol-metabolizing enzymes: Alcohol dehydrogenase (ADH2 and ADH3) and aldehyde dehydrogenase (ALDH2) exhibit functional polymorphisms. Vulnerability of alcohol dependence may also be in part due to heritable personality traits. AIM: To determine whether any association exists between polymorphisms of ADH2, ADH3 and ALDH2 and alcohol dependence syndrome in a group of Asian Indians. In addition, the personality of these patients was assessed to identify traits predisposing to alcoholism. MATERIALS AND METHODS: In this study, 100 consecutive males with alcohol dependence syndrome attending the psychiatric outpatient department of a tertiary care service hospital and an equal number of matched healthy controls were included with their consent. Blood samples of all the study cases and controls were collected and genotyped for the ADH2, ADH3 and ALDH2 loci. Personality was evaluated using the neuroticism, extraversion, openness (NEO) personality inventory and sensation seeking scale. RESULTS: Allele frequencies of ADH2*2 (0.50), ADH3*1 (0.67) and ALSH2*2 (0.09) were significantly low in the alcohol dependent subjects. Personality traits of NEO personality inventory and sensation seeking were significantly higher when compared to controls. CONCLUSIONS: The functional polymorphisms of genes coding for alcohol metabolizing enzymes and personality traits of NEO and sensation seeking may affect the propensity to develop dependence. PMID- 25535446 TI - Psychiatric morbidities among mentally ill wives of Nepalese men working abroad. AB - INTRODUCTION: Husband working abroad may have not only favorable outcomes for wives and other family members but also adverse consequences, including psychological problems. Present study intended to look into psychiatric morbidity profiles of the Nepalese female psychiatric patients and the stressors related with their husband working abroad. MATERIALS AND METHODS: This is a hospital based descriptive study with convenient sampling method. Hundred consecutive female psychiatric patients, with the particular stressor, coming into the contact of the investigating team were enrolled within the study period of 12 months. The psychiatric morbidities/diagnoses were sorted out according to the International classification of disease and infirmity, 10(th) edition (ICD-10) criteria. RESULTS: Average age of the enrolled cases was 29 years. Nearly half of the women were illiterate or barely literate. Some other stressors, besides the one of husband working abroad were found to precipitate the illness in about 60%, main being relational and health problems. Common presenting complaints were mood, anxiety, and physical symptoms. Almost 30% of the subjects had some mental illness in their past too and similar proportion had in their blood relatives. About one-third admitted to use substances, mainly alcohol and cigarettes. The common psychiatric diagnoses were mood, anxiety, neurotic, and stress-related disorders. Nearly 10% had presented for suicide attempt. CONCLUSIONS: The status of husband working abroad may have adverse consequences in mental health of women. Mood affect, anxiety, and stress-related disorders are common psychiatric illness among them. PMID- 25535447 TI - Analysis of variables affecting drug compliance in schizophrenia. AB - CONTEXT: As compliance of the patient during management of schizophrenia is crucial, the current study was conducted to find out the factors that affected compliance. AIMS: The aim of the study was to analyze the prevalence of noncompliance and to find out different factors affecting compliance in schizophrenic patients. MATERIALS AND METHODS: Observational cross-sectional study was conducted on 100 adult schizophrenic patients. Noncompliance was assessed using the rating of medication influence (ROMI) scale. Severity of illness was measured using positive and negative syndrome scale (PANSS). RESULTS: Prevalence of noncompliance was 37%. Using ROMI scale; positive relationship with psychiatrist, family pressure for taking medications, stigma, and substance abuse were found to be significant factors. Severity of illness was also found as determining factor. CONCLUSION: To improve the compliance in schizophrenia patients, roles of both psychiatrists and family members are crucial. PMID- 25535448 TI - Suicidal behavior among alcohol dependents: Relationship with anger and personality dimensions. AB - BACKGROUND: Alcohol dependents have high percentage of nonfatal suicidal behaviors. There is no substantial data on anger and personality correlates of suicidal behaviors among alcohol users. The present work explored the relationship of anger and personality with suicidal behaviors among alcohol dependent individuals. MATERIALS AND METHODS: Sociodemographic data sheet, State Trait Anger Expression Inventory (STAXI), and Neo Five-Factor Inventory (NFFI) were administered on 30 subjects who had lifetime history of suicidal attempt. RESULTS: A total of 80% attempted suicide in the intoxicated states, 56.7% were high on trait anger, and 60% were high on anger expression outward. A significant negative correlation was found between expressing feelings (verbally/physically) openness, conscientiousness, and agreeableness. A significant positive correlation was found between anger expression inward and neuroticism. CONCLUSIONS: It helped in understanding the psychological variables associated with suicidal behavior among alcohol-dependent individuals and has implications for addressing neuroticism openness, conscientiousness, and agreeableness for bringing change in anger expression. PMID- 25535449 TI - An unusual case of xylophagia (paper-eating). AB - Xylophagia is a condition involving the consumption of paper and form of eating disorder known as pica. Pica is an unusual craving for ingestion of either edible or inedible substances. Inhalants are volatile substances, which produce chemical vapors that can be inhaled to induce a psycho-active or mind altering effect. Although, pica is not linked to solvent abuse, here we report an adolescent case of paper-eating with solvent dependence. PMID- 25535450 TI - Munchausen syndrome: Playing sick or sick player. AB - Munchausen syndrome is rare factitious disorder which entails frequent hospitalization, pathological lying and intentional production of symptoms for sick role. Management requires collateral history taking, sound clinical approach, exclusion of organicity and addressing psychological issues. A case which presented with unusual symptoms of similar dimension is discussed here. The case brings out finer nuances in evaluation and management of this entity. PMID- 25535451 TI - Cerebral hemi atrophy as a consequence of cerebral insult in infancy: Is it difficult to diagnose? PMID- 25535452 TI - Silverman revisited: A relook at some of the pitfalls and challenges in suicide nomenclature and few suggestions. PMID- 25535453 TI - Propensity score method for partially matched omics studies. AB - This paper focuses on the problem of partially matched samples in the presence of confounders. We propose using propensity score matching to adjust for confounding factors for the subset of data with incomplete pairs, followed by integrating the P-values computed from the complete and incomplete paired samples, respectively. Several simulations and a case study on DNA methylation are considered to evaluate the operating characteristics of the proposed method. PMID- 25535455 TI - Insights into Ebola and Other Emerging and Re-emerging Infectious Disease Risks. PMID- 25535454 TI - Feasibility of applying the life history calendar in a population of chronic opioid users to identify patterns of drug use and addiction treatment. AB - Uncovering patterns of drug use and treatment access is essential to improving treatment for opioid dependence. The life history calendar (LHC) could be a valuable instrument for capturing time-sensitive data on lifetime patterns of drug use and addiction treatment. This study describes the methodology applied when collecting data using the LHC in a sample of individuals with long-term opioid dependence and aims to identify specific factors that impact the feasibility of administering the LHC interview. In this study, the LHC allowed important events such as births, intimate relationships, housing, or incarcerations to become reference points for recalling details surrounding drug use and treatment access. The paper concludes that the administration of the LHC was a resource-intensive process and required special attention to interviewer training and experience with the study population. These factors should be considered and integrated into study plans by researchers using the LHC in addiction research. PMID- 25535456 TI - Canadian Society of Plastic Surgeons Strategic Planning 2014: Plotting the way ahead. PMID- 25535457 TI - Influence of preoperative velar closing ratio and lateral wall movement on outcomes of Furlow palatoplasty for velopharyngeal incompetence. AB - Currently, there is no consensus regarding how to determine the optimal surgical procedure for a patient with velopharyngeal incompetence (VPI) post-primary palate repair. The purpose of the present study was to assess the effect of preoperative velar closing ratio (VCR) and lateral wall movement (LWM) on nasal emission and hypernasality after Furlow double-opposing Z-plasty. A retrospective analysis involving patients with VPI post-primary palatoplasty whose VPI was treated with double-opposing Z-plasty by a single surgeon was performed. Ten consecutive patients with VPI postpalatoplasty were reviewed. Videonasendoscopy, videofluoroscopy and perceptual speech examinations were performed preoperatively and postoperatively. VCR improved from an mean of 0.5 preoperatively (range 0.1 to 0.95) to 0.9 postoperatively (range 0.55 to 1.0). Postoperative mean LWM was 0.5 (range 0.3 to 0.9), unchanged from preoperative ratings. A trend toward an inverse relationship between preoperative VCR and improvement in hypernasality and resolution of nasal emission was observed. No relationship was noted between the degree of preoperative LWM and mean improvement in hypernasality. However, patients with worse preoperative LWM experienced better resolution of nasal emission postoperatively. PMID- 25535458 TI - Variability of expression of oral-facial-digital syndrome type I in 15 Saudi girls: Why is there a high rate of median cleft lip in the phenotype? AB - BACKGROUND: It is well known that the incidence of nonsyndromal cleft lip and palate varies greatly according to ancestry: 0.3 to 0.4 per 1000 live births in blacks, one in 1000 in Caucasians, and two in 1000 in Asians and individuals from the central province of Saudi Arabia. Median cleft lip is a variable feature in oral-facial-digital syndrome type I (OFD-I). OBJECTIVE: To test the hypothesis that genetic factors may determine the lip phenotype in OFD-I patients. METHODS: A study involving 15 Saudi girls (from the central province of Saudi Arabia) with OFD-I showed a high rate (93.3%) of median cleft lip and palate. This rate in OFD I patients is known to range from 33% to 56% in Caucasians and also known to be very low in blacks. The authors compared the rate of median cleft lip with or without cleft palate in the Arabian series (93.3%) with the rate in Caucasians and blacks. RESULTS: The difference in median cleft lip with or without cleft palate among the three groups was significant. CONCLUSION: This supports the hypothesis that ancestral genetic factors may determine the lip phenotype in OFD I patients. PMID- 25535459 TI - Propranolol therapy for infantile hemangioma is less toxic but longer in duration than corticosteroid therapy. AB - BACKGROUND: Infantile hemangioma is the most common benign, self-limiting tumour of childhood. Treatment is reserved for hemangiomas that obstruct vital structures or cause significant disfigurement. Traditionally, corticosteroids have been the medical treatment of choice. Since 2008, however, propranolol has been rapidly adopted as an effective pharmacological treatment for infantile hemangioma. Published data regarding the long-term side effects of propranolol are currently lacking. OBJECTIVE: To describe the long-term effects of propranolol and corticosteroids on anthropometric measurements (height, body mass index [BMI]) and blood pressure in children. METHODS: A prospective database analysis of all infantile hemangioma patient visits to the pediatric vascular abnormality clinic at the authors' institution between October 2007 and February 2012 was performed. Anthropometric measures (height and BMI) and blood pressure were analyzed. RESULTS: A total of 290 visits (119 patients) to the pediatric vascular abnormality clinic were reviewed. Of these, 18 patients received medical treatment and their anthropometry was analyzed. BMI percentile increased significantly in patients treated with corticosteroids (P=0.0039). Corticosteroid treatment also resulted in a significant decrease in height percentile (P=0.0078). Anthropometric measures did not cross percentiles in children treated with propranolol. A significant decrease in systolic blood pressure was noted in the propranolol group (P=0.03), but no hypotensive values were recorded. Median treatment duration was significantly longer when patients received propranolol (372 versus 133 days; P=0.0033). CONCLUSION: Propranolol for the treatment of infantile vascular abnormalities does not share the unfavourable effects on patient anthropometry that corticosteroids exhibit; however, a longer duration of therapy is required. PMID- 25535460 TI - Plastic surgeons' self-reported operative infection rates at a Canadian academic hospital. AB - BACKGROUND: Surgical site infection rates are of great interest to patients, surgeons, hospitals and third-party payers. While previous studies have reported hospital-acquired infection rates that are nonspecific to all surgical services, there remain no overall reported infection rates focusing specifically on plastic surgery in the literature. OBJECTIVE: To estimate the reported surgical site infection rate in plastic surgery procedures over a 10-year period at an academic hospital in Canada. METHODS: A review was conducted on reported plastic surgery surgical site infection rates from 2003 to 2013, based on procedures performed in the main operating room. For comparison, prospective infection surveillance data over an eight-year period (2005 to 2013) for nonplastic surgery procedures were reviewed to estimate the overall operative surgical site infection rates. RESULTS: A total of 12,183 plastic surgery operations were performed from 2003 to 2013, with 96 surgical site infections reported, corresponding to a net operative infection rate of 0.79%. There was a 0.49% surgeon-reported infection rate for implant-based procedures. For non-plastic surgery procedures, surgical site infection rates ranged from 0.04% for cataract surgery to 13.36% for high-risk abdominal hysterectomies. DISCUSSION: The plastic surgery infection rate at the study institution was found to be <1%. This rate was equal to, or somewhat less than, surgical site infection rates. However, these results do not report patterns of infection rates germane to procedures, season, age groups or sex. To provide more in-depth knowledge of this topic, multicentre studies should be conducted. PMID- 25535461 TI - Do plastic surgery division heads and program directors have the necessary tools to provide effective leadership? AB - BACKGROUND: Effective leadership is imperative in a changing health care landscape driven by increasing expectations in a setting of rising fiscal pressures. Because evidence suggests that leadership abilities are not simply innate but, rather, effective leadership can be learned, it is prudent for plastic surgeons to evaluate the training and challenges of their leaders because there may be opportunities for further growth and support. OBJECTIVE: To investigate the practice profiles, education/training, responsibilities and challenges of leaders within academic plastic surgery. METHODS: Following research ethics board approval, an anonymous online survey was sent to division heads and program directors from all university-affiliated plastic surgery divisions in Canada. Survey themes included demographics, education/training, job responsibilities and challenges. RESULTS: A response rate of 74% was achieved. The majority of respondents were male (94%), promoted to their current position at a mean age of 48 years, did not have a leadership-focused degree (88%), directly manage 30 people (14 staff, 16 faculty) and were not provided with a job description (65%). Respondents worked an average of 65 h per week, of which 18% was devoted to their leadership role, 59% clinically and the remainder on teaching and research. A discrepancy existed between time spent on their leadership role (18%) and related compensation (10%). Time management (47%) and managing conflict (24%) were described as the greatest leadership challenges by respondents. CONCLUSIONS: Several gaps were identified among leaders in plastic surgery including predominance of male sex, limitations in formal leadership training and requisite skill set, as well as compensation and human resources management (emotional intelligence). Leadership and managerial skills are key core competencies, not only for trainees, but certainly for those in a position of leadership. The present study provides evidence that academic departments, universities and medical centres may benefit by re-evaluating how they train, promote and support their leaders in plastic surgery. PMID- 25535462 TI - Prevalence of brachial plexus injuries in patients with scapular fractures: A National Trauma Data Bank review. AB - BACKGROUND: Studies investigating the prevalence of brachial plexus injuries associated with scapular fractures are sparse, and are frequently limited by small sample sizes and often restricted to single-centre experience. OBJECTIVE: To determine the prevalence of brachial plexus injuries associated with scapular fractures; to determine how the prevalence varies with the region of the scapula injured; and to assess which specific nerves of the brachial plexus were involved. METHODS: The present study was a retrospective review of data from the National Trauma Data Bank over a five-year period (2007 to 2011). RESULTS: Of 68,118 patients with scapular fractures, brachial plexus injury was present in 1173 (1.72%). In patients with multiple scapular fractures, the prevalence of brachial plexus injury was 3.12%, and ranged from 1.52% to 2.22% in patients with single scapular fractures depending on the specific anatomical location of the fracture. Of the 426 injuries with detailed information on nerve injury, 208 (49%) involved the radial nerve, 113 (26.5%) the ulnar nerve, 65 (15%) the median nerve, 36 (8.5%) the axillary nerve and four (1%) the musculocutaneous nerve. CONCLUSION: The prevalence of brachial plexus injuries in patients with scapular fractures was 1.72%. The prevalence was similar across anatomical regions for single scapular fracture and was higher with multiple fractures. The largest percentage of nerve injuries were to the radial nerve. PMID- 25535463 TI - Follicular unit transplantation for the treatment of secondary cicatricial alopecia. AB - BACKGROUND: Cicatricial alopecia encompasses a diverse group of disorders characterized by the permanent destruction of hair follicles and irreversible hair loss. Follicular unit transplantation was developed in 1994. However, large scale clinical trials are necessary to study follicular unit transplantation for treating Chinese cicatricial alopecia patients. OBJECTIVE: To investigate the efficacy of follicular unit transplantation in the treatment of cicatricial alopecia in Chinese patients. METHODS: Patients with cicatricial alopecia were enrolled. The designated recipient area, follicular unit density of the donor site, transplanted density and operative time were recorded. Postoperative follow up was conducted within six to 24 months; the density of hair in the recipient area was calculated using a Folliscope (Hansderma Co, USA). Patients' self reported satisfaction and long-term complications were recorded. RESULTS: Thirty seven patients were enrolled. Cicatricial alopecia was caused by burns (n=8), trauma (n=21) and plastic surgery (cleft lip and palate repair [n=8]). Burn patients had a significantly larger bald area than the other patients (P<0.01). The operative time was significantly correlated with recipient area. The longest operation was 14.5 h; the largest transplanted area was 96 cm(2). At follow-up, the surviving follicular unit density/transplanted follicular unit density rate was 64.29% to 95.00% (mean 78.96%); the surviving/transplanted (S/T) area was 100% for 30 patients, 90% to 100% for five patients and <90% for two patients. The lowest S/T area was 82.81%. The S/T index was significantly and inversely correlated with operative time. Regarding long-term complications, two patients had postoperative epidermoid cysts that healed with local treatment. CONCLUSION: Follicular unit transplantation is an effective method for treating cicatricial alopecia. It is relatively safe and yields satisfactory postoperative results. Extending the results of the present study to Chinese clinical practice is warranted. PMID- 25535464 TI - Long-term follow-up of unoperated, nonscissoring spiral metacarpal fractures. AB - BACKGROUND: Spiral metacarpal fractures can result in shortening of the metacarpal shaft, which may lead to extension lag at the metacarpophalangeal joint and reduced grip strength. These fractures have been surgically treated to restore metacarpal length; however, there are complications associated with surgery, postoperative management and wound healing, which further threaten power recovery in the hand. OBJECTIVE: To determine the effect of conservative management of un-operated, nonscissoring spiral metacarpal fractures. METHODS: Sixty-one consecutive patients presenting with nonscissoring spiral metacarpal fractures were treated nonoperatively and studied prospectively to determine the natural history of their power outcome. Thumb fractures and those requiring surgical intervention for scissoring were excluded. RESULTS: Follow-up data of a minimum of five months (mean follow-up 87 weeks) were available for 13 patients. Mean grip strength at final follow-up was 36.18 kg on the uninjured side and 36.58 kg on the injured side. The strength-difference values did not differ significantly from zero (P=0.72). CONCLUSION: The loss of metacarpal length associated with these fractures may not cause a power deficit sufficiently large to significantly affect grip strength and functional recovery in the hand. A prospective randomized controlled trial of operated versus unoperated, nonscissoring metacarpal fractures is warranted. PMID- 25535466 TI - Third-degree burns caused by ignition of chlorhexidine: A case report and systematic review of the literature. AB - Ignition of chlorhexidine by an electrocautery unit is rare but can have devastating consequences for the patient and the surgeon. A case involving a 77 year-old man who underwent removal of an indwelling artificial urethral sphincter is presented. The chlorhexidine was ignited when the urologist activated the electrocautery unit, causing third-degree burns to the patient. A plastic surgeon treated the burns with surgical debridement and split-thickness skin grafting. A systematic review of the literature was performed with best practice recommendations. To the authors' knowledge, the present case is the ninth such case reported. PMID- 25535465 TI - Incidence of positive screening for obstructive sleep apnea in patients with isolated cleft lip and/or palate. AB - OBJECTIVE: To determine the incidence of obstructive sleep apnea (OSA) in children with isolated cleft lip and/or palate (CL/P). METHODS: The present prospective study was performed at a pediatric tertiary care centre. Consecutive patients evaluated at the cleft clinic from January 2011 to August 2013 were identified. Patients' families prospectively completed the Pediatric Sleep Questionnaire (PSQ), a validated tool used to predict moderate to severe OSA. Patients with CL/P and an underlying syndrome or other craniofacial diagnosis were excluded. A positive OSA screen was recorded if the ratio of positive to total responses was >0.33. Risk factors associated with a positive screen were identified using the Student's t or ANOVA test. RESULTS: A total of 867 patients completed the PSQ, 489 of whom with isolated CL/P met inclusion criteria. The mean age was 8.4 years. The overall incidence of positive screening was 14.7%. The most commonly reported symptoms among positive screeners were 'fidgets with hands or feet' (73.6%), 'interrupts others' (69.4%) and 'mouth breather during the day' (69.4%). The most sensitive items were 'stops breathing during the night' and 'trouble breathing during sleep', with positive predictive values of 0.78 and 0.67, respectively. Sex, body mass index, ancestry and cleft type were not significantly associated with increased risk for positive screening. CONCLUSION: One in seven children with isolated CL/P screened positively for OSA according to the PSQ. This finding highlights the potential importance of routine screening in this at-risk group. PMID- 25535467 TI - Update on anaplastic large cell lymphoma in women with breast implants. AB - Since 1997, reports from the scientific community have suggested a possible association, without causation, between breast implants and anaplastic large cell lymphoma (ALCL). Analysis of these patients has been challenging. Many studies have been under-reported while others have been duplicated. In 2011, a United States Food & Drug Administration (FDA) 'white paper' analyzed 34 of the 60 cases reported worldwide. All 34 patients had undergone secondary surgery for breast swelling, firmness or pain. ALCL was an incidental finding. Diagnosis of ALCL is made by hematoxylin and eosin histology and immunochemistry for the CD30 marker. ALCL occurred with all types of implants. Subsequent studies have suggested that textured implants may have a greater risk. In all cases, ALCL cells were found in the capsule, in the seroma or within a mass adjacent to the implant. There was no invasion of cells beyond the capsule into the breast parenchyma. From the FDA study, the risk of developing ALCL after receiving implants appears to be approximately one in one million per year. All cases appear to be negative for the anaplastic lymphoma kinase marker. ALCL in most of these patients may represent a new entity with less aggressive behaviour. In most patients with capsule-confined disease, proper management may prove to be implant removal and capsulectomy. Patients with a distinct mass adjacent to their implant may have a more aggressive clinical course that may become systemic. They may require chemotherapy in addition to implant removal and capsulectomy. All cases of ALCL should be referred to an appropriate specialist and reported to the FDA. PMID- 25535468 TI - What's the difference between a hedge fund and a mutual fund? PMID- 25535469 TI - Oral exam. PMID- 25535470 TI - Effect of ginseng and ginsenosides on melanogenesis and their mechanism of action. AB - Abnormal changes in skin color induce significant cosmetic problems and affect quality of life. There are two groups of abnormal change in skin color; hyperpigmentation and hypopigmentation. Hyperpigmentation, darkening skin color by excessive pigmentation, is a major concern for Asian people with yellow-brown skin. A variety of hypopigmenting agents have been used, but treating the hyperpigmented condition is still challenging and the results are often discouraging. Panax ginseng has been used traditionally in eastern Asia to treat various diseases, due to its immunomodulatory, neuroprotective, antioxidative, and antitumor activities. Recently, several reports have shown that extract, powder, or some constituents of ginseng could inhibit melanogenesis in vivo or in vitro. The underlying mechanisms of antimelanogenic properties in ginseng or its components include the direct inhibition of key enzymes of melanogenesis, inhibition of transcription factors or signaling pathways involved in melanogenesis, decreasing production of inducers of melanogenesis, and enhancing production of antimelanogenic factor. Although there still remain some controversial issues surrounding the antimelanogenic activity of ginseng, especially in its effect on production of proinflammatory cytokines and nitric oxide, these recent findings suggest that ginseng and its constituents might be potential candidates for novel skin whitening agents. PMID- 25535471 TI - Effect of Korean Red Ginseng supplementation on dry eye syndrome in glaucoma patients - A randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Many patients with glaucoma have difficulty using antiglaucoma eye drops because of dry eye symptom. In this prospective, randomized, double-blind, placebo-controlled study, we evaluated the effect of Korean Red Ginseng on dry eye syndrome in patients with glaucoma treated with antiglaucoma eye drops. METHODS: Forty-nine participants were allocated to the Korean Red Ginseng (3 g/day; n = 24) or placebo (n = 25) groups for 8 weeks. Tear film stability, fluorescein corneal staining, conjunctival hyperemia, tear production, grade of meibomian gland dysfunction, and dry eye questionnaire (Ocular Surface Disease Index) were evaluated at baseline and on completion of the treatment. RESULTS: Almost all patients displayed dry eye symptoms and signs at baseline. After the 8 week intervention, Korean Red Ginseng supplementation significantly improved the tear film stability and total Ocular Surface Disease Index score, as compared to placebo (p < 0.01). CONCLUSION: Korean Red Ginseng supplementation may provide an additional treatment option for dry eye and patients with glaucoma using antiglaucoma eye drops. PMID- 25535472 TI - American ginseng attenuates azoxymethane/dextran sodium sulfate-induced colon carcinogenesis in mice. AB - BACKGROUND: Colorectal cancer is a leading cause of cancer-related death, and inflammatory bowel disease is a risk factor for this malignancy. We previously reported colon cancer chemoprevention potential using American ginseng (AG) in a xenograft mice model. However, the nude mouse model is not a gut-specific colon carcinogenesis animal model. METHODS: In this study, an experimental colitis and colitis-associated colorectal carcinogenesis mouse model, chemically induced by azoxymethane/dextran sodium sulfate (DSS) was established and the effects of oral AG were evaluated. The contents of representative ginseng saponins in the extract were determined. RESULTS: AG significantly reduced experimental colitis measured by the disease activity index scores. This suppression of the experimental colitis was not only evident during DSS treatment, but also very obvious after the cessation of DSS, suggesting that the ginseng significantly promoted recovery from the colitis. Consistent with the anti-inflammation data, we showed that ginseng very significantly attenuated azoxymethane/DSS-induced colon carcinogenesis by reducing the colon tumor number and tumor load. The ginseng also effectively suppressed DSS-induced proinflammatory cytokines activation using an enzyme-linked immunosorbent assay array, in which 12 proinflammatory cytokine levels were assessed, and this effect was supported subsequently by real time polymerase chain reaction data. CONCLUSION: AG, as a candidate of botanical based colon cancer chemoprevention, should be further investigated for its potential clinical utility. PMID- 25535473 TI - Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells. AB - BACKGROUND: Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models. METHODS: MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release. RESULTS: SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells. CONCLUSION: SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types. PMID- 25535474 TI - Ginsenoside fractions regulate the action of monocytes and their differentiation into dendritic cells. AB - BACKGROUND: Panax ginseng (i.e., ginseng) root is extensively used in traditional oriental medicine. It is a modern pharmaceutical reagent for preventing various human diseases such as cancer. Ginsenosides-the major active components of ginseng-exhibit immunomodulatory effects. However, the mechanism and function underlying such effects are not fully elucidated, especially in human monocytes and dendritic cells (DCs). METHODS: We investigated the immunomodulatory effect of ginsenosides from Panax ginseng root on CD14(+) monocytes purified from human adult peripheral blood mononuclear cells (PBMCs) and on their differentiation into DCs that affect CD4(+) T cell activity. RESULTS: After treatment with ginsenoside fractions, monocyte levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 increased through phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK). After treatment with ginsenoside fractions, TNF-alpha production and phosphorylation of ERK1/2 and JNK decreased in lipopolysaccharide (LPS)-sensitized monocytes. We confirmed that DCs derived from CD14(+) monocytes in the presence of ginsenoside fractions (Gin-DCs) contained decreased levels of the costimulatory molecules CD80 and CD86. The expression of these costimulatory molecules decreased in LPS-treated DCs exposed to ginsenoside fractions, compared to their expression in LPS-treated DCs in the absence of ginsenoside fractions. Furthermore, LPS-treated Gin-DCs could not induce proliferation and interferon gamma (IFN-gamma) production by CD4(+) T cells with the coculture of Gin-DCs with CD4+ T cells. CONCLUSION: These results suggest that ginsenoside fractions from the ginseng root suppress cytokine production and maturation of LPS-treated DCs and downregulate CD4(+) T cells. PMID- 25535475 TI - Comparative study of Korean White Ginseng and Korean Red Ginseng on efficacies of OVA-induced asthma model in mice. AB - BACKGROUND: Korean ginseng is a well-known medicinal herb that has been widely used in traditional medicine to treat various diseases, including asthma. Ginseng can be classified as white ginseng (WG) or red ginseng (RG), according to processing conditions. In this study, the authors compared the efficacies of these two ginseng types in a mouse model of acute asthma. METHODS: To produce the acute asthma model, BALB/c mice were sensitized with ovalbumin (OVA) and aluminum hydroxide, and then challenged with OVA. WG and RG extracts were administered to mice orally. The influences of WG and RG on airway hyperresponsiveness (AHR), immune cell distributions in bronchoalveolar lavage fluid (BALF), and OVA specific immunoglobulin E (IgE), IgG1, and IgG2a in serum were investigated. Cytokine production by lymphocytes isolated from peribronchial lymph nodes and histopathological changes was also examined. RESULTS: In OVA-sensitized mice, both WG and RG reduced AHR and suppressed immune cell infiltration in bronchoalveolar regions. BALF OVA-specific IgE levels were significantly lower in RG-treated OVA-sensitized mice than in the OVA-sensitized control group. WG and RG also suppressed inflammatory cytokine production by peribronchial lymphocytes. Histopathological findings showed reduced inflammatory cell infiltration and airway remodeling (e.g., epithelial hyperplasia) in WG- and RG-treated OVA mice compared with OVA controls. CONCLUSION: In this study, WG and RG showed antiasthmatic effects in an OVA-sensitized mouse model, and the efficacies of RG were found to be better than those of WG. PMID- 25535476 TI - Protective effect of Korean Red Ginseng against glucocorticoid-induced osteoporosis in vitro and in vivo. AB - BACKGROUND: Glucocorticoids (GCs) are commonly used in many chemotherapeutic protocols and play an important role in the normal regulation of bone remodeling. However, the prolonged use of GCs results in osteoporosis, which is partially due to apoptosis of osteoblasts and osteocytes. In this study, effects of Korean Red Ginseng (KRG) on GC-treated murine osteoblastic MC3T3-E1 cells and a GC-induced osteoporosis mouse model were investigated. METHODS: MC3T3-E1 cells were exposed to dexamethasone (Dex) with or without KRG and cell viability was measured by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Real time polymerase chain reaction was performed to evaluate the apoptotic gene expression; osteogenic gene expression and alkaline phosphatase (ALP) activity were also measured. Western blotting was performed to evaluate the mitogen activated protein kinase (MAPK) proteins. A GC-induced osteoporosis animal model was used for in vivo study. RESULTS AND CONCLUSION: The MTT assay revealed that Korean Red Ginseng (KRG) prevents loss of cell viability caused by Dex-induced apoptosis in MC3T3E1 cells. Real-time polymerase chain reaction data showed that groups treated with both Dex and KRG exhibited lower mRNA levels of caspase-3 and -9, whereas the mRNA levels of Bcl2, IAPs, and XIAP increased. Moreover, groups treated with both Dex and KRG demonstrated increased mRNA levels of ALP, RUNX2, and bone morphogenic proteins as well as increased ALP activity in MC3T3-E1 cells, compared to cells treated with Dex only. In addition, KRG increased protein kinase B (AKT) phosphorylation and decreased c-Jun N-terminal kinase (JNK) phosphorylation. Moreover, microcomputed tomography analysis of the femurs showed that GC implantation caused trabecular bone loss. However, a significant reduction of bone loss was observed in the KRG-treated group. These results suggest that the molecular mechanism of KRG in the GC-induced apoptosis may lead to the development of therapeutic strategies to prevent and/or delay osteoporosis. PMID- 25535477 TI - Matrix metalloproteinase-13 downregulation and potential cartilage protective action of the Korean Red Ginseng preparation. AB - BACKGROUND: The present study was designed to prepare and find the optimum active preparation or fraction from Korea Red Ginseng inhibiting matrix metalloproteinase-13 (MMP-13) expression, because MMP-13 is a pivotal enzyme to degrade the collagen matrix of the joint cartilage. METHODS: From total red ginseng ethanol extract, n-BuOH fraction (total ginsenoside-enriched fraction), ginsenoside diol-type-enriched fraction (GDF), and ginsenoside triol-type enriched fraction (GTF) were prepared, and ginsenoside diol type-/F4-enriched fraction (GDF/F4) was obtained from Panax ginseng leaf extract. RESULTS: The n BuOH fraction, GDF, and GDF/F4 clearly inhibited MMP-13 expression compared to interleukin-1beta-treated SW1353 cells (human chondrosarcoma), whereas the total extract and ginsenoside diol-type-enriched fraction did not. In particular, GDF/F4, the most effective inhibitor, blocked the activation of p38 mitogen activated protein kinase (p38 MAPK), c-Jun-activated protein kinase (JNK), and signal transducer and activator of transcription-1/2 (STAT-1/2) among the signal transcription pathways involved. Further, GDF/F4 also inhibited the glycosaminoglycan release from interleukin-1alpha-treated rabbit cartilage culture (30.6% inhibition at 30 MUg/mL). CONCLUSION: Some preparations from Korean Red Ginseng and ginseng leaves, particularly GDF/F4, may possess the protective activity against cartilage degradation in joint disorders, and may have potential as new therapeutic agents. PMID- 25535478 TI - Molecular mechanism of protopanaxadiol saponin fraction-mediated anti inflammatory actions. AB - BACKGROUND: Korean Red Ginseng (KRG) is a representative traditional herbal medicine with many different pharmacological properties including anticancer, anti-atherosclerosis, anti-diabetes, and anti-inflammatory activities. Only a few studies have explored the molecular mechanism of KRG-mediated anti-inflammatory activity. METHODS: We investigated the anti-inflammatory mechanisms of the protopanaxadiol saponin fraction (PPD-SF) of KRG using in vitro and in vivo inflammatory models. RESULTS: PPD-SF dose-dependently diminished the release of inflammatory mediators [nitric oxide (NO), tumor necrosis factor-alpha, and prostaglandin E2], and downregulated the mRNA expression of their corresponding genes (inducible NO synthase, tumor necrosis factor-alpha, and cyclooxygenase-2), without altering cell viability. The PPD-SF-mediated suppression of these events appeared to be regulated by a blockade of p38, c-Jun N-terminal kinase (JNK), and TANK (TRAF family member-associated NF-kappa-B activator)-binding kinase 1 (TBK1), which are linked to the activation of activating transcription factor 2 (ATF2) and interferon regulatory transcription factor 3 (IRF3). Moreover, this fraction also ameliorated HCl/ethanol/-induced gastritis via suppression of phospho-JNK2 levels. CONCLUSION: These results strongly suggest that the anti inflammatory action of PPD-SF could be mediated by a reduction in the activation of p38-, JNK2-, and TANK-binding-kinase-1-linked pathways and their corresponding transcription factors (ATF2 and IRF3). PMID- 25535480 TI - Soil properties of cultivation sites for mountain-cultivated ginseng at local level. AB - BACKGROUND: Identifying suitable site for growing mountain-cultivated ginseng is a concern for ginseng producers. This study was conducted to evaluate the soil properties of cultivation sites for mountain-cultivated ginseng in Hamyang-gun, which is one of the most well-known areas for mountain-cultivated ginseng in Korea. METHODS: The sampling plots from 30 sites were randomly selected on or near the center of the ginseng growing sites in July and August 2009. Soil samples for the soil properties analysis were collected from the top 20 cm at five randomly selected points. RESULTS: Mountain-cultivated ginseng was grown in soils that varied greatly in soil properties on coniferous, mixed, and deciduous broad-leaved stand sites of elevations between > 200 m and < 1,000 m. The soil bulk density was higher in Pinus densiflora than in Larix leptolepis stand sites and higher in the < 700-m sites than in > 700-m sites. Soil pH was unaffected by the type of stand sites (pH 4.35-4.55), whereas the high-elevation sites of > 700 m were strongly acidified, with pH 4.19. The organic carbon and total nitrogen content were lower in the P. densiflora stand sites than in the deciduous broad leaved stand sites. Available phosphorus was low in all of the stand sites. The exchangeable cation was generally higher in the mixed and low-elevation sites than in the P. densiflora and high-elevation sites, respectively. CONCLUSION: These results indicate that mountain-cultivated ginseng in Korea is able to grow in very acidic, nutrient-depleted forest soils. PMID- 25535479 TI - Korean Red Ginseng inhibits apoptosis in neuroblastoma cells via estrogen receptor beta-mediated phosphatidylinositol-3 kinase/Akt signaling. AB - BACKGROUND: Ginseng has been shown to exert antistress effects both in vitro and in vivo. However, the effects of ginseng on stress in brain cells are not well understood. This study investigated how Korean Red Ginseng (KRG) controls hydrogen peroxide-induced apoptosis via regulation of phosphatidylinositol-3 kinase (PI3K)/Akt and estrogen receptor (ER)-beta signaling. METHODS: Human neuroblastoma SK-N-SH cells were pretreated with KRG and subsequently exposed to H2O2. The ability of KRG to inhibit oxidative stress-induced apoptosis was assessed in MTT cytotoxicity assays. Apoptotic protein expression was examined by Western blot analysis. The roles of ER-beta, PI3K, and p-Akt signaling in KRG regulation of apoptosis were studied using small interfering RNAs and/or target antagonists. RESULTS: Pretreating SK-N-SH cells with KRG decreased expression of the proapoptotic proteins p-p53 and caspase-3, but increased expression of the antiapoptotic protein BCL2. KRG pretreatment was also associated with increased ER-beta, PI3K, and p-Akt expression. Conversely, ER-beta inhibition with small interfering RNA or inhibitor treatment increased p-p53 and caspase-3 levels, but decreased BCL2, PI3K, and p-Akt expression. Moreover, inhibition of PI3K/Akt signaling diminished p-p53 and caspase-3 levels, but increased BCL2 expression. CONCLUSION: Collectively, the data indicate that KRG represses oxidative stress induced apoptosis by enhancing PI3K/Akt signaling via upregulation of ER-beta expression. PMID- 25535481 TI - Seasonal changes in soil acidity and related properties in ginseng artificial bed soils under a plastic shade. AB - BACKGROUND: In Changbai Mountains, Panax ginseng (ginseng) was cultivated in a mixture of the humus and albic horizons of albic luvisol in a raised garden with plastic shade. This study aimed to evaluate the impact of ginseng planting on soil characteristics. METHODS: The mixed-bed soils were seasonally collected at intervals of 0-5 cm, 5-10 cm, and 10-15 cm for different-aged ginsengs. Soil physico-chemical characteristics were studied using general methods. Aluminum was extracted from the soil solids with NH4Cl (exchangeable Al) and Na-pyrophosphate (organic Al) and was measured with an atomic absorption spectrophotometer. RESULTS: A remarkable decrease in the pH, concentrations of exchangeable calcium, NH4 (+), total organic carbon (TOC), and organic Al, as well as a pronounced increase in the bulk density were observed in the different-aged ginseng soils from one spring to the next. The decrease in pH in the ginseng soils was positively correlated with the [Formula: see text] (r = 0.463, p < 0.01), exchangeable calcium (r = 0.325, p < 0.01) and TOC (r = 0.292, p < 0.05) concentrations. The [Formula: see text] showed remarkable surface accumulation (0 5 cm) in the summer and even more in the autumn but declined considerably the next spring. The exchangeable Al fluctuated from 0.10 mg g(-1) to 0.50 mg g(-1) for dry soils, which was positively correlated with the [Formula: see text] (r = 0.401, p < 0.01) and negatively correlated with the TOC (r = -0.329, p < 0.05). The Al saturation varied from 10% to 41% and was higher in the summer and autumn, especially in the 0-5 cm and 5-10 cm layers. CONCLUSION: Taken together, our study revealed a seasonal shift in soil characteristics in ginseng beds with plastic shade. PMID- 25535482 TI - Checklist of butterflies (Insecta: Lepidoptera) from Serra do Intendente State Park - Minas Gerais, Brazil. AB - In order to contribute to the butterflies' biodiversity knowledge at Serra do Intendente State Park - Minas Gerais, a study based on collections using Van Someren-Rydon traps and active search was performed. In this study, a total of 395 butterflies were collected, of which 327 were identified to species or morphospecies. 263 specimens were collected by the traps and 64 were collected using entomological hand-nets; 43 genera and 60 species were collected and identified. PMID- 25535483 TI - Taxonomic notes and distribution extension of Durga Das's leaf-nosed bat Hipposiderosdurgadasi Khajuria, 1970 (Chiroptera: Hipposideridae) from south India. AB - Durga Das's leaf-nosed bat Hipposiderosdurgadasi Khajuria, 1970 is endemic to India, and was known only from Katanga, Katangi, and Richhai villages, in Jabalpur district, Madhya Pradesh. During surveys conducted in Kolar district, Karnataka, India, we successfully mist-netted a few individuals belonging to the bicolor species group which, upon detailed external, craniodental and bacular studies were identified as Durga Das's leaf-nosed bat. This paper reports the presence of this species in southern India, extending its distribution range by almost 1300 km. We also provide a detailed morphological description for this species. PMID- 25535484 TI - Three new country records from the genus Limnephilus Leach, 1815 (Trichoptera: Limnephilidae) from the Republic of Kosovo. AB - New faunistic data on Trichoptera from Kosovo based on sampling carried out during the autumn of 2013 and first half of 2014 are presented. Limnephilusbipunctatus was found in a small stream in Kaqandoll village located in northern Kosovo and in Shtutice village located in central Kosovo. Two male specimens of Limnephilusdecipiens were found at Gurrat e Hasan Ages Springs and Bistrica e Lloqanit River, an alpine area in the Lloqan mountains, which belong to the Bjeshket e Nemuna mountains. A single male specimen of Limnephilusstigma was found in Kline, located in central Kosovo. All three species are rare in Kosovo. A preliminary checklist of eight species of Limnephilus from Kosovo is provided along with biogeographical and ecological notes. This paper is a further contribution to the faunistic list of Trichoptera of Kosovo, one of the least explored countries in Europe. PMID- 25535485 TI - A new species of Cordyligaster Macquart, reared from caterpillars in Area de Conservacion Guanacaste, northwestern Costa Rica. AB - We describe a new species of Cordyligaster Macquart (Diptera: Tachinidae) from Area de Conservacion Guanacaste (ACG) in northwestern Costa Rica. Cordyligastercapellii sp. n., is described and photographed. All specimens of C.capellii were reared from Syngamiaflorella (Stoll, 1781) (Lepidoptera, Crambidae, Spilomelinae), a leaf-rolling caterpillar collected in ACG rain forest. By coupling morphology, photographic documentation, life history and molecular data, we provide a clear and concise description of this new species. In addition the authors provide new distribution and host records for C.fuscipennis (Macquart) reared in ACG. PMID- 25535486 TI - A semi-automated workflow for biodiversity data retrieval, cleaning, and quality control. AB - The compilation and cleaning of data needed for analyses and prediction of species distributions is a time consuming process requiring a solid understanding of data formats and service APIs provided by biodiversity informatics infrastructures. We designed and implemented a Taverna-based Data Refinement Workflow which integrates taxonomic data retrieval, data cleaning, and data selection into a consistent, standards-based, and effective system hiding the complexity of underlying service infrastructures. The workflow can be freely used both locally and through a web-portal which does not require additional software installations by users. PMID- 25535487 TI - Unveiling of a cryptic Dicranomyia (Idiopyga) from northern Finland using integrative approach (Diptera, Limoniidae). AB - The subgenus Idiopyga Savchenko, 1987 is a northern hemisphere group of short palped crane flies (Diptera, Limoniidae). In the current article we describe a new species, Dicranomyia (I.) boreobaltica Salmela sp.n., and redescribe the male and female post-abdomen of a closely related species, D. (I.) intricata Alexander. A standard DNA barcoding fragment of 5' region of the cytochrome c oxidase I (COI) gene of the new species is presented, whilst the K2P minimum distances between the new species and 10 other species of the subgenus were found to range from 5.1 to 15.7 % (mean 11.2 %). Phylogenetic analyses (parsimony and maximum likelihood) based on COI sequences support the identity of the new species and its close relationship with D. (I.) intricata and D. (I.) esbeni (Nielsen). The new species is known from the northern Baltic area of Finland. The new species has been mostly collected from Baltic coastal meadows but an additional relict population is known from a calcareous rich fen that was estimated to have been at sea level circa 600-700 years ago. Dicranomyia (I.) intricata (syn. D.suecica Nielsen) is a Holarctic species, occurring in the north boreal and subarctic vegetation zones in Fennoscandia. PMID- 25535488 TI - Expect the unexpected: a case of isolated eosinophilic meningitis in toxocariasis. AB - We present the case of a young police officer suffering from headache without other neurological symptoms caused by isolated eosinophilic meningitis, which resulted from an infection with Toxocara cati, along with a discussion of the differential diagnosis. PMID- 25535489 TI - Initiation of immunoglobulin therapy by subcutaneous administration in immunodeficiency patients naive to replacement therapy. AB - BACKGROUND: Patients with immunodeficiency diseases require lifelong treatment with immunoglobulin (Ig), yet few studies have vetted dosing strategies and effectiveness of Ig in older patient populations. Patients requiring subcutaneous (SC) Ig (SCIG) typically start with intravenous dosing before transitioning to SCIG weekly maintenance. In this retrospective review, we investigated an alternate strategy with higher initial SC doses among an older patient population with antibody deficiency syndromes. FINDINGS: Records of 13 patients (mean age, 70 years) with antibody deficiencies who were naive to treatment with Ig were assessed. SCIG (Vivaglobin(r) [Immune Globulin Subcutaneous (Human), 16% Liquid] or Hizentra(r) [Immune Globulin Subcutaneous (Human), 20% Liquid]) was given twice weekly (100 mg/kg) for 2 weeks, followed by weekly (100 mg/kg) administration The mean pretreatment IgG level was 460 mg/dL; at 1, 3, and 6 months after SCIG initiation, mean IgG serum levels were 852, 907, and 943 mg/dL, respectively. Maintenance doses were unchanged during 6 months of follow-up. All patients remain on SCIG (median, 44 months). One patient developed sepsis/cholangitis unrelated to treatment 3 months after starting SCIG; no other serious bacterial infections were reported. CONCLUSIONS: Initiation of SCIG by doubling the maintenance dose over 2 weeks may be a well-tolerated and effective option for patients with antibody deficiencies requiring Ig replacement, especially among older patients. PMID- 25535490 TI - Emporiatrics: The growing area of concern. PMID- 25535491 TI - Low-dose spinal neostigmine further enhances the analgesic effect of spinal bupivacaine combined with epidural dexamethasone, following orthopedic surgery. AB - BACKGROUND: Opioids are considered mainstream for combined spinal-epidural anesthesia, but frequently limited by adverse effects. The aim of this study was to examine whether low-dose spinal neostigmine, epidural dexamethasone or their combination enhances analgesia from spinal bupivacaine without adverse effects. MATERIALS AND METHODS: A total of 60 patients undergoing orthopedic surgery were randomized to one of four groups and evaluated for 24-h after surgery for analgesia (time to first rescue analgesic) and rescue analgesic consumption. Patients received 15 mg bupivacaine plus the test drug intrathecally (saline or 1 microgram (MUg) neostigmine). The epidural test drug was either saline or 10 mg dexamethasone. The Control group (CG) received spinal and epidural saline. The Neostigmine group (NG), spinal neostigmine and epidural saline; the Dexamethasone group (DG), spinal saline and epidural dexamethasone; and the Neostigmine dexamethasone group (NDG), spinal neostigmine and epidural dexamethasone. RESULTS: The CG (282 +/- 163 min) and NG (524 +/- 142 min) were similar in their times to first rescue analgesic and analgesic consumption. The time to first rescue analgesic was longer for the DG (966 +/- 397 min) compared with CG and NG (P < 0.0002), and the DG had less ketoprofen consumption and lower overall visual analogue scale-pain sores compared with CG and NG (P < 0.0005). Addition of 1 mg neostigmine (NDG) resulted in longer time to rescue analgesic (1205 +/- 303 min; P < 0.02) and lower ketoprofen consumption (P < 0.05) compared to DG. Sporadic cases of vesical catheterization and emesis were observed, however adverse effects were similar among groups. CONCLUSION: Spinal 1 microgram (MUg) neostigmine further enhanced analgesia from spinal bupivacaine combined with epidural dexamethasone, without increasing the incidence of adverse effects. PMID- 25535492 TI - Impact of antenatal depression on perinatal outcomes and postpartum depression in Korean women. AB - BACKGROUND: Maternal prenatal mental health has been shown to be associated with adverse consequences for the mother and the child. However, studies considering the effect of prenatal depressive symptoms are lacking. The aim of this study was to examine the influence of antenatal depressive symptoms on obstetric outcomes and to determine associations between antenatal and postpartum depressions. MATERIALS AND METHODS: This was a prospective cohort study. The Edinburgh postnatal depression scale (EPDS) questionnaire was completed by pregnant women receiving obstetrical care at Seoul St. Mary's hospital in the third trimester of gestation. The electronic medical records were reviewed after delivery and perinatal outcomes were evaluated. The association between antenatal and postpartum depression was analyzed using the EPDS questionnaire, which was completed by the same women within 2 months of delivery. RESULTS: Of the 467 participants, 26.34% (n = 123) had antenatal depressive symptoms, with EPDS scores of >=10. There were no significant perinatal outcomes associated with antenatal depressive symptoms. During the postpartum period, 192 of the women in the initial study cohort were given the EPDS again as a follow-up. Of the 192 participants, 56 (29.17%) scored >10. Spearman correlation coefficient between the antenatal and postpartum EPDS scores was 0.604, which was statistically significant (P < 0.001). CONCLUSION: Antenatal depression does not lead to unfavorable perinatal outcomes. However, screening for antenatal depression may be helpful to identify women at risk of postpartum depression. PMID- 25535493 TI - A randomized clinical trial on comparison of corticosteroid injection with or without splinting versus saline injection with or without splinting in patients with lateral epicondylitis. AB - BACKGROUND: Lateral epicondylitis is a common problem affecting 1-3% of the population. There has been much debate about the best treatment modality for this condition. There is, however, no conclusive evidence in support of any of the proposed treatment modalities. In this trial, we have studied the effect of corticosteroid injection (with or without splinting) with normal saline injection (with or without splinting). MATERIALS AND METHODS: In this double-blind, randomized clinical trial, individuals were randomly assigned to either of four treatment groups and received either 40 mg depomedrol injection alone, 40 mg depomedrol injection with splinting, normal saline injection alone, or normal saline injection with splinting. They were evaluated using the visual analog scale (VAS) at weeks 2, 4 and 24 and with the Oxford elbow scale (OES) at 24 weeks. RESULTS: A total of 79 patients were participated in the study. The corticosteroid injection groups had better pain relief as measured by VAS at 2 and 4 weeks compared with the two saline injection groups. Mean VAS difference at week 0 versus week 2 was 4.5 +/- 0.9 and 2.8 +/- 0.6 in corticosteroid injection groups and saline injection groups respectively (P < 0.01) but at 24 weeks, there was only moderate benefit reported for the group which received steroid injection and splinting (P < 0.01) compared to the saline injection groups. The saline injection groups reported better improvement in OES scores (20.1 +/- 3.7) at the end of the trial compared corticosteroid injection groups (16.1 +/- 2.9) (P < 0.05). CONCLUSION: Our results indicate that despite the clear pain reduction benefit associated with steroid injection in short term, this benefit in comparison with normal saline injection fades by the 24(th) week of follow-up. PMID- 25535494 TI - Assessment of technical equipment supply in healthcare institutions: example of Almaty. AB - BACKGROUND: The share of healthcare-related expenditure in the Gross Domestic Product of Kazakhstan is relatively small, and it is strategically important to restructure budgetary expenses in favor of healthcare with simultaneous redistribution of resources in accordance with changing demands and prioritization of high-quality medical care. The aim of this study was to analyze resource provision to healthcare organizations in Kazakhstan and its structure and level assessment. MATERIALS AND METHODS: The study is based on a comparative assessment of technical and technological equipment of medical institutions in Almaty, Kazakhstan. We analyzed the scope and structure of the financial component of the resource base in Almaty. We carried out information processing and analysis methods, content analysis, mathematical treatment, as well as conducted case studies. Also, we held opinion poll among medical staff (specialists, managerial staff) (n = 300) P for trend < 0.001 and patients (n = 210) P for trend < 0.001. RESULTS: About 18.8% of patients do not receive medical care because of defects of the equipment, whereas 19.9% of patients claim that the reason of refusal of the provision of medical services is an equipment overload. CONCLUSION: Most of the respondents referred to on poor technical equipment, mismatch with the world standards of performance and competitiveness. Lack of advanced medical technology, inadequate financing, insufficient supply of domestic medical equipment, and inadequate procurement by tender were also noted. The obtained data point to the need for optimization and upgrading medical equipment at various levels of healthcare. PMID- 25535495 TI - The association of immunoglobulin A, immunoglobulin G and anti-cyclic citrullinated peptide antibodies with disease activity in seronegative rheumatoid arthritis patients. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease that is associated with progressive disability, systemic complications, and early death. The present study was aimed to investigate the level of immunoglobulin G (IgG) and IgA isotypes and anti-cyclic citrullinated peptide (CCP) antibody and to assess their association with disease severity based on disease activity score (DAS-28) in patients with IgM rheumatoid factor (IgM-RF) negative RA. MATERIALS AND METHODS: In this cross-sectional study, 62 RA patients with IgM-RF negative were assessed. Radiographs were obtained for all RA patients. The RF (IgG, and IgA) and anti-CCP were measured by using the enzyme-linked immunosorbent assay. Values of cut-off points over 15 UI/mL for IgA IgA-RF, 20 UI/mL for IgG-RF and over 20 units for anti-CCP were considered positive. DAS-28 score was compared in regard to the IgA-RF and IgG-RF and anti-CCP positivity using Mann-Whitney test. RESULTS: DAS-28 score in IgA-RF positive was significantly higher than IgA-RF negative (mean score, 6.03 +/- 0.33 vs. 5.44 +/- 0.76 respectively, P = 0.035). In IgG-RF positive patients, DAS-28 score was similar to patients with IgG-RF negative (5.64 +/- 0.59 vs. 5.46 +/- 0.78 respectively, P = 0.396). Furthermore, in patients with anti-CCP positive DAS-28 score was significantly higher than patients with anti-CCP negative (5.72 +/- 0.61 vs. 5.38 +/- 0.79 respectively, P = 0.049). CONCLUSION: Findings indicated that there was a significant association between the amounts of IgA and anti-CCP with severity of disease in RF negative RA patients while there was no significant association between the amounts of IgG and severity of RA disease. PMID- 25535496 TI - Effect of a multispecies probiotic on inflammatory markers in critically ill patients: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Impairment of intestinal barrier function and increased translocation of bacteria to the systemic blood flow contribute to the emergence of sepsis. Probiotics might be of beneficial effects on critically ill-patients, modulating intestinal barrier function and reducing inflammation. The aim of this trial was to determine the effect of probiotics on inflammatory markers in critically ill patients in Intensive Care Unit (ICU). MATERIALS AND METHODS: This trial was conducted on 40 critically ill-patients admitted to the ICU. Patients were randomly assigned to receive placebo or probiotic containing Lactobacillus, Bifidobacterium and Streptococcus thermophilus (VSL#3) for 7 days. Acute Physiology and Chronic Health Evaluation (APACHE II) score Sequential Organ Failure Assessment (SOFA) and systemic concentrations of interleukin-6 (IL-6), procalcitonin (PCT) and protein C were measured before initiation of the study and on days 4 and 7. RESULTS: A significant difference in IL-6 (P = 0.003), PCT (P = 0.014) and protein C (P < 0.001) levels, and also APACHE II and SOFA scores (P < 0.001) was seen over the treatment period between two groups. Moreover, there was a significant decrease in serum IL-6 levels (from 211.85 +/- 112.76 to 71.80 +/- 28.41) (P < 0.001) and PCT levels (from 1.67 +/- 1.27 to 0.47 +/- 0.41) (P < 0.001) and a significant increase in serum protein C levels (from 7.47 +/- 3.61 to 12.87 +/- 3.63) (P < 0.001) in probiotic group during the study. CONCLUSION: Probiotics could reduce inflammation in critically ill-patients and might be considered as an adjunctive therapy in the treatment of critically ill patients. PMID- 25535497 TI - A cross-sectional population-based study on the association of personality traits with anxiety and psychological stress: Joint modeling of mixed outcomes using shared random effects approach. AB - BACKGROUND: Previous studies have showed some evidences about the relationship between personality traits particularly neuroticism and extroversion, separately, with psychological stress and anxiety. In the current study, we clarified the magnitude of joint interdependence (co-morbidity) of anxiety (continuous) and Psychological stress (dichotomous) as dependent variables of mixed type with five factor personality traits as independent variables. MATERIALS AND METHODS: Data from 3180 participants who attended in the cross-sectional population-based "study on the epidemiology of psychological, alimentary health and nutrition" and completed self-administered questionnaires about demographic and life style, gastrointestinal disorders, personality traits, perceived intensity of stress, social support, and psychological outcome was analyzed using shared random effect approach in R Free software. RESULTS: The results indicated high scores of neuroticism increase the chance of high psychological stress (odds ratio [OR] = 5.1; P < 0.001) and anxiety score (B = 1.73; P < 0.001) after adjustment for the probable confounders. In contrast, those who had higher scores of extraversion and conscientiousness experienced lower levels of anxiety score (B = -0.54 and 0.23, respectively, P < 0.001) and psychological stress (OR = 0.36 and 0.65, respectively, P < 0.001). Furthermore, higher score of agreeableness had significant negative relationship with anxiety (B = -0.32, P < 0.001). CONCLUSION: The present study indicated that the scores of neuroticism, extraversion, agreeableness and conscientiousness strongly predict both anxiety and psychological stress in Iranian adult population. Due to likely mechanism of genetic and environmental factors on the relationships between personality traits and psychological disorders, it is suggested to perform longitudinal studies focusing on both genetic and environmental factors in Iranian population. PMID- 25535498 TI - Risk factors for ectopic pregnancy: A case-control study. AB - BACKGROUND: Ectopic pregnancy (EP) is a condition presenting as a major health problem for women of childbearing age. This study aimed to identify potential risk factors for EP and to evaluate the contribution of the risk factors associated to EP. MATERIALS AND METHODS: This retrospective nested case-control study was conducted from 2006 to 2011. In case group, there were a total of 83 women diagnosed with EP, while in the control group; there was a total of 340 women who gave birth. The basic recorded information included surgical, gynecological, obstetrics, sexual, contraceptive, and infectious histories; demographic characteristics; smoking habits; fertility markers; as well as reproductive outcome after EP. The association between EP and the factors studied was analyzed by logistic regression. RESULTS: The findings reveal that the following factors were associated with increased risk of EP, including: Maternal age (odds ratio [OR] =1.11, confidence interval [CI] [1.06-1.16], P < 0.0001), spouse's cigarette smoking (OR = 1.73, CI [1.05-2.85], P = 0.02), gravidity (OR = 1.50, CI [1.25-1.80], P < 0.0001), prior spontaneous abortions (OR = 1.93, CI [1.11-3.36], P = 0.01), history of EP (OR = 17.16, CI [1.89-155.67], P = 0.01), tubal blockage (OR = 10.85, CI [2.02-58.08], P = 0.01), use of intrauterine device (IUD) (OR = 4.39, CI [1.78-10.81], P = 0.001), tubal damage (OR = 2.704, CI [1.26-5.78], P = 0.01), first pregnancy interval (OR = 1.01, CI [1.00-1.02], P < 0.0001) and history of infertility (OR = 6.13, CI [2.70-13.93], P < 0.0001). CONCLUSION: By identifying risk factors being amenable to modification, such as cigarette smoking and use of IUD and first pregnancy interval the effective risk reduction strategies can be devised. PMID- 25535499 TI - Prevalence of hypertension and type 2 diabetes mellitus in patients with colorectal cancer and their median survival time: A cohort study. AB - BACKGROUND: Type 2 diabetes mellitus (DM) and hypertension are worldwide epidemic. Association between DM and colon cancer was obtained in previous studies. Prevalence of DM and hypertension in the patients with colorectal cancer (CRC) has not been reported in Iran. The present study was aimed to investigate the prevalence of hypertension and type 2 DM and their effect on median survival time in patients with CRC. MATERIALS AND METHODS: Overall, 2570 individual-year follow-ups were conducted for 1127 patients with CRC. For the diagnosis of type 2 DM, fasting blood sugar test and glycosylated hemoglobin test were used and for hypertension, blood pressure was measured in two turns. The descriptive indices were calculated, and the mean and median survival from CRC diagnosis time was calculated using survival analysis and a comparison among survival times was done through log-rank test. Stata software 12 (Stata Corp. 2011. Stata Statistical Software: Release 12. College Station, TX: Stata Corp LP) was used for data analysis. RESULTS: The prevalence of hypertension and type 2 DM in the patients with CRC was respectively 13.38% (95% confidence interval [CI]: 11.1-15.8) and 8.69% (95% CI: 7-10.7). Median survival time in patients with hypertension and DM were 8.52 and 4.9 years. According to log-rank test, no significant difference was observed between the survival time of CRC patients suffering from hypertension and diabetes type 2. CONCLUSION: The obtained findings in this study indicate that survival time in patients with type 2 DM less than hypertension but two metabolic diseases have the same effect on survival rate of the patients with CRC. Understanding the risk factors for CRC may guide the development of strategies targeted toward its prevention. PMID- 25535500 TI - Acute tramadol poisoning and its clinical and laboratory findings. AB - BACKGROUND: Tramadol is a centrally acting analgesic with opioid and nonopioid properties, which extensively used in the relief of mild to moderate pain. Tramadol poisoning is a common cause of acute pharmaceutical poisoning in Iran. There are a few studies about clinical and laboratory findings related to acute tramadol poisoning. Therefore, the aim of this study was to demonstrate the clinical and laboratory findings in tramadol acute poisoning cases. MATERIALS AND METHODS: This was a retrospective descriptive study of patients with acute tramadol poisoning who referred to Loghman Hakim Hospital Poison Center during January to April 2012. Data such as patient's age, sex, time of ingestion, ingested dose, cause of poisoning, mean duration of hospitalization, patient's clinical presentations, laboratory findings, therapeutic measures, and patient's outcome have collected in a predesigned checklist. RESULTS: A total of 144 patients including 111 men (77%) and 33 women (23%) with acute tramadol poisoning was included in this study. The mean ingested dose was 1971.2 mg (100-20000 mg). Seizure (47.91%) was the most frequent clinical symptom. Blood gas on admission showed pH (7.3 +/- 0.1), PCO2 (49.7 +/- 8.6 mmHg) and HCO3 (-) (24.1 +/- 3.8 mEq/L), indicating pure acute respiratory acidosis may be occurred in tramadol intoxicated patients. There were significant differences between tramadol intoxicated cases with and without a seizure with regard to the time interval between ingestion and admission on hospital, ingested dose and PCO2. CONCLUSION: Seizure and rise of PCO2 were the most findings in this study. PMID- 25535501 TI - Assessment of the effects of ketamine-fentanyl combination versus propofol remifentanil combination for sedation during endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) as a diagnostic and treatment procedure is used in most biliary tract and pancreatic. Either sedation or general anesthesia could be considered for this procedure. Combining a sedative with an opioid agent can provide effective moderate sedation. This study compared the impact of ketamine-fentanyl (KF) versus propofol-remifentanil (PR) on sedation scale in patients undergoing ERCP. MATERIALS AND METHODS: As a double-blinded randomized clinical trial, 80 patients selected by convenient sampling, allocated randomly into two groups. KF group received ketamine 0.5 mg/kg body weight intravenously over 60 s and then fentanyl 1 mcg/kg body weight intravenously. PR group received propofol l mg/kg body weight intravenously over 60 s and then remifentanil 0.05 mcg/kg body weight/min intravenously. Intravenous (IV) infusion of propofol was maintained by 50 mcg/kg body weight/min throughout ERCP. Ramsay Sedation Score, vital signs, oxygen saturation (SpO2), recovery score (modified Aldrete score) and visual analog scales of pain intensity, and endoscopist's satisfaction were considered as measured outcomes. All analysis were analyzed by SPSS Statistics version 22 and using t-test, Chi-square and repeated measured ANOVA and Mann-Whitney tests for data analysis. RESULTS: Respiratory rate and SpO2 level during the time intervals were lower in PR group (P < 0.001). Sedation score at intervals was not significantly different (P = 0.07). The frequency of apnea in PR group was significantly higher than the KF group (P = 0.003). The percentage of need to supplemental oxygen in PR group was 35.1% that was also significantly higher than 8.8% in the KF group (P = 0.008), but the dosage frequency was significantly higher in KF group (P < 0.001). The KF and PR groups average length of stay in the recovery room were 50.71 standard deviation (SD = 9.99) and 42.57 (SD = 11.99) minutes, respectively, indicating a significant difference (P = 0.003). The mean severity of nausea in KF and PR groups was, respectively, 2.74 confidence interval (CI = 1.68-3.81) and 0.43 (CI = 0.11-0.75), that was significantly higher in KF group (P < 0.001). The average score of surgeon satisfaction in both KF and PR groups were 7.69 (CI = 7.16-8.21) and 8.65 (CI = 8.25-9.05), respectively, which was higher in KF group (P = 0.004), but the average level of patients satisfaction in KF group was 8.86 (CI = 8.53-9.19) and in PR group was 8.95 (CI - 8.54-9.35) that were not significantly different (P = 0.074). CONCLUSION: There is no statistically significant difference between KF and PR combinations in sedation score, but PR combination provides better pain control, with less nausea and shorter recovery time while causing more respiratory side effects, that is, apnea and need to oxygen. PMID- 25535502 TI - Hypertonic saline solution reduces the oxidative stress responses in traumatic brain injury patients. AB - BACKGROUND: Oxidative stress processes play an important role in the pathogenesis of secondary brain injury after traumatic brain injury (TBI). Hypertonic saline (HTS) has advantages as being preferred osmotic agent, but few studies investigated oxidant and antioxidant effects of HTS in TBI. This study was designed to compare two different regimens of HTS 5% with mannitol on TBI-induced oxidative stress. MATERIALS AND METHODS: Thirty-three adult patients with TBI were recruited and have randomly received one of the three protocols: 125 cc of HTS 5% every 6 h as bolus, 500 cc of HTS 5%as infusion for 24 h or 1 g/kg mannitol of 20% as a bolus, repeated with a dose of 0.25-0.5 g/kg every 6 h based on patient's response for 3 days. Serum total antioxidant power (TAP), reactive oxygen species (ROS) and nitric oxide (NO) were measured at baseline and daily for 3 days. RESULTS: Initial serum ROS and NO levels in patients were higher than control(6.86+/- [3.2] vs. 1.57+/- [0.5] picoM, P = 0.001, 14.6+/- [1.6] vs. 7.8+/ [3.9] mM, P = 0.001, respectively). Levels of ROS have decreased for all patients, but reduction was significantly after HTS infusion and mannitol (3. 08 [+/-3.1] to 1.07 [+/-1.6], P = 0.001, 5.6 [+/-3.4] to 2.5 [+/-1.8], P = 0.003 respectively). During study, NO levels significantly decreased in HTS infusion but significantly increased in mannitol. TAP Levels had decreased in all patients during study especially in mannitol (P = 0.004). CONCLUSION: Hypertonic saline 5% has significant effects on the oxidant responses compared to mannitol following TBI that makes HTS as a perfect therapeutic intervention for reducing unfavorable outcomes in TBI patients. PMID- 25535503 TI - The effect of calcium and vitamin D supplementation on menstrual cycle, body mass index and hyperandrogenism state of women with poly cystic ovarian syndrome. AB - BACKGROUND: Poly cystic ovary syndrome (PCOS) is considered one of the most common endocrine disorders of women in reproductive age. The aim of this study was evaluating the efficacy of calcium and Vitamin D supplementation on the regularity of menstrual cycles, body mass index (BMI) and hyper androgenism state of women with PCOS. MATERIALS AND METHODS: In this clinical trial, 80 women with PCOS were evaluated. They randomly located in four groups receiving metformin (group 1), metformin plus calcium and Vitamin D (group 2), calcium and Vitamin D (group 3) and placebo (group 4) for 4 months. BMI, regularity of menstrual cycles, hyperandrogenism (hirsutism and acne) and serum calcium and Vitamin D levels were compared in four studying groups at baseline and 4 months after the trial. RESULTS: All studied subjects were similar at baseline (P > 0.05). After trial, the frequency of hirsutism and acne were not different among groups. Frequency regular menstrual cycle and dominant follicle were significantly higher in group 1 and 2 than others (P < 0.05). After trial, there was no significant difference with respect to BMI among groups. CONCLUSION: Vitamin D and calcium supplementation in addition to metformin therapy in women with PCOS could result in a better outcome in a variety of PCOS symptoms including menstrual regularity, and ovulation. PMID- 25535504 TI - Calcium and vitamin D plasma concentration and nutritional intake status in patients with chronic spinal cord injury: A referral center report. AB - BACKGROUND: Nutritional status influences bone health spinal cord injury (SCI). This study evaluates serum levels of 25-hydroxy-vitamin-D and calcium along with dietary intakes in patients with chronic SCI. MATERIALS AND METHODS: Total of 160 patients participated in this investigation. Dietary intakes were assessed by semi-quantitative food-frequency questionnaire. Serum calcium, phosphorus and 25(OH)-vitamin-D level were measured. RESULTS: Mean of serum calcium and 25(OH) vitamin-D were 9.54 +/- 0.64 mg/dl (standard error of the mean [SE]: 0.05) and 13.6 +/- 10.99 MUg/dl (SE: 0.9), respectively. Dairy intake was below recommended amount (1.8 +/- 0.74 per serving (SE: 0.06), recommended: 4). A high prevalence (53.1%) of Vitamin D deficiency (25(OH) Vitamin D <13 ng/ml) was found. CONCLUSION: This study shows below adequate intake of calcium and Vitamin D in Iranian patients with SCI. These results insist on the importance of dietary modifications among these patients. PMID- 25535505 TI - A Systematic Review on methods of evaluate sentence production deficits in agrammatic aphasia patients: Validity and Reliability issues. AB - BACKGROUND: The grammar assessment in aphasia has been done by few standard tests, but today these tests cannot precise evaluate the sentence production in agrammatic patients. In this study, we review structures and contents of tests or tasks designed to find more frequent methods for sentence production ability in aphasia patients. MATERIALS AND METHODS: We searched the Cochrane library, Medline by PubMed, Science Direct, Scopus, and Google Scholar from 1980 to October 1, 2013 and evaluated all of exist tests or tasks included in the articles and systematic reviews. The sentence production has been studied in three methods. It contains the use of sentence production in spontaneous speech, tasks designed and both methods. The quality of studies was assessed using Critical Appraisal Skills Program. RESULTS: The 160 articles were reviewed and 38 articles were studied according to inclusion and exclusion criteria. They were classified into three categories based on assessment methods of sentence production. In 39.5% studies, researchers have used tasks designed, 7.9% articles have applied spontaneous speech and 52.6% articles have used both methods for evaluation production. Inter-rater reliability was between 90% and 100% and intra rater reliability was between 96% and 98% in studied. CONCLUSION: Agrammatic aphasia has syntax disorders, especially in sentence production. Most researchers and clinicians used both methods for evaluation production. PMID- 25535507 TI - Regional ventilation/perfusion mismatch pattern in patient with Swyer James (MacLeod's) syndrome. AB - Swyer James (McLeod's) syndrome (SJMS) is an uncommon disease, which occurs as a result of childhood bronchiolitis obliterans. Patients may not be diagnosed until later in their life. A 46-year-old man underwent ventilation/perfusion scintigraphy for acute onset of dyspnea. The scan showed markedly diminished ventilation and perfusion unilaterally on the right middle and inferior lobes. However, mismatched ventilation-perfusion pattern was shown on the upper right lobe, which was consistent with pulmonary embolism. Unilaterally matched ventilation/perfusion defect can see in SJMS in lung scintigraphy; however, when pulmoner embolism may accompany, scintigraphy should be carefully examined. PMID- 25535506 TI - Epidemiology of VIM-1-imipenem resistant Pseudomonas aeruginosa in Iran: A systematic review and meta-analysis. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic human pathogen which causes serious problems, especially in people who have immunodeficiency. Metallo beta-lactamase (MBL) resistance in this bacterium has led some difficulties in treating bacterial infections. MBLs are being reported with increasing frequency worldwide. The aim of the present systematic review and meta-analysis was to collect data about the relative frequency (RF) of VIM-1-imipenem resistant P. aeruginosa (VIM-1-IRPA) in different regions of Iran and report an overall prevalence if possible. MATERIALS AND METHODS: PubMed, ISI web of science, Scopus and Google Scholar were searched using following key terms: "P. aeruginosa," "imipenem," "VIM-1" and "Iran" were. Articles/abstracts, which used clinical specimens and had done polymerase chain reaction to detect the VIM-1 gene of MBL genes, were included in this review. STATA SE version 11.2 (StataCorp, College Station, TX, USA) was used for statistical analysis. RESULTS: Out of 5457 results found, 10 articles were eligible to be included in our systematic review and meta analysis. These studies were carried out in Tehran, Isfahan, Kurdistan, Ahvaz, Markazi and Northwest of Iran (Orumieh and Tabriz). Pooled estimation of 1972 P. aeruginosa samples showed that 13% (95% confidence interval = 10.5-16.5%]) of strains were VIM-1 positive. VIM-1-IRPA RF in different studies varied from 0% to 19.5% in Isfahan and Markazi provinces, respectively. We found a moderate heterogeneity (Chochran Q-test, P = 0.032, I-squared = 50.7%) of VIM-1-IRPA RF among studies. CONCLUSION: According to the results of this study VIM-1-IRPA RF in Iran is in low-level Prevention strategies to reduce the prevalence rates of VIM-1 positive strains in Iran are needed. PMID- 25535508 TI - Cavernous sinus thrombosis syndrome and brainstem involvement in patient with leptospirosis: Two rare complications of leptospirosis. AB - Leptospirosis is a bacterial disease that is caused by pathogenic spirochetes of the genus Leptospira. It can affect humans and animals. In humans, it can lead to a wide spectrum of symptoms. It is known as the most common zoonosis in the world. The typical presentation of the disease is an acute biphasic febrile illness with or without jaundice. Less common clinical manifestations may result from involvement of different human body systems. In many places, this disease may be under-diagnosed, especially when associated with neurological complications. Moreover, without treatment, leptospirosis can lead to organ damages, and even death. Neurological complications are uncommon and are reported in a few cases. Cavernous sinus thrombosis syndrome and brainstem involvement are rare complications of leptospirosis and are associated with a high mortality risk. To our knowledge, no such cases have been reported in the literature. PMID- 25535509 TI - On the occasion of world hypertension day 2014: A nephrology point of view. PMID- 25535510 TI - Alzheimer's disease and infections, where we stand and where we go. PMID- 25535511 TI - Relationship between Initial Lens Transparency and Ocular Circulation in Adolescents with Type-1 Diabetes Mellitus, Unstable Glycaemia and Lipid Parameters. AB - BACKGROUND: The aim of this study was to determine the relationships between lens opacity, vascular and lipid factors and retrobulbar blood flow parameters in type 1 diabetic (DM) adolescents. MATERIAL/METHODS: Glycated haemoglobin (HbA1c), total cholesterol (TCH), high- and low-density cholesterol, triglycerides (TG) and apolipoprotein B (ApoB) were determined in 28 patients with (DM-1) and without (DM-0) lens opacity and 18 controls. In the ophthalmic, central retinal (CRA) and temporal posterior ciliary (TPCA) arteries, the systolic (PSV), end diastolic and mean blood flow velocities as well as pulsatility and resistance (RI) indices were measured. RESULTS: Ten (35.71%) diabetic patients exhibited lens opacification. Higher TG and TCH levels in the DM-1 group and HbA1c level in the DM-0 and DM-1 groups were observed (P<=0.05). Diabetic patients had lower PSV and higher RI within CRA and TPCA (P<=0.05). Significant correlations between biochemical and blood flow parameters were found. CONCLUSIONS: Glycaemic and lipid factors may play a vasoconstrictive role in retrobulbar endotheliopathy. PMID- 25535512 TI - Superciliary keyhole approach for unruptured anterior circulation aneurysms: surgical technique, indications, and contraindications. AB - Neurosurgeons have been trying to reduce surgical invasiveness by applying minimally invasive keyhole approaches. Therefore, this paper clarifies the detailed surgical technique, its limitations, proper indications, and contraindications for a superciliary keyhole approach as a minimally invasive modification of a pterional approach. Successful superciliary keyhole surgery for unruptured aneurysms requires an understanding of the limitations and the use of special surgical techniques. Essentially, this means the effective selection of surgical indications, usage of the appropriate surgical instruments with a tubular shaft, and refined surgical techniques, including straightforward access to the aneurysm, clean surgical dissection, and the application of clips with an appropriate configuration. A superciliary keyhole approach allows unruptured anterior circulation aneurysms to be clipped safely, rapidly, and less invasively on the basis of appropriate surgical indications. PMID- 25535513 TI - Intra-Spinal Bone Marrow Mononuclear Cells Transplantation Inhibits the Expression of Nuclear Factor-kappaB in Acute Transection Spinal Cord Injury in Rats. AB - OBJECTIVE: To assess the effect of bone marrow mononuclear cells (BMMNCs) transplantation in the expression of nuclear factor-kappaB (NF-kappaB) in spinal cord injury (SCI) in rats. METHODS: BMMNCs were isolated from tibia and femur by a density gradient centrifugation. After establishment of acute transection SCI, rats were divided into experiment (BMMNCs), experiment control (0.1 M PBS infused) and sham surgery groups (laminectomy without any SCI). Locomotor function was assessed weekly for 5 weeks post-injury using BBB locomotor score and urinary bladder function daily for 4 weeks post-injury. Activity of NF-kappaB in spinal cord was assessed by immunohistochemistry and reverse transcriptase polymerase chain reaction. RESULTS: At each time point post-injury, sham surgery group had significantly higher Basso, Beattie, Bresnahan locomotor and urinary bladder function scores than experiment and experiment control group (p<0.05). At subsequent time interval there were gradual improvement in both experiment and experiment control group, but experiment group had higher score in comparison to experiment control group (p<0.05). Comparisons were also made for expression of activated NF-kappaB positive cells and level of NF-kappaB messenger RNA in spinal cord at various time points between the groups. Activated NF-kappaB immunoreactivity and level of NF-kappaB mRNA expression were significantly higher in control group in comparison to experiment and sham surgery group (p<0.05). CONCLUSION: BMMNCs transplantation attenuates the expression of NF-kappaB in injured spinal cord tissue and thus helps in recovery of neurological function in rat models with SCI. PMID- 25535514 TI - Enhanced efficacy of human brain-derived neural stem cells by transplantation of cell aggregates in a rat model of Parkinson's disease. AB - OBJECTIVE: Neural tissue transplantation has been a promising strategy for the treatment of Parkinson's disease (PD). However, transplantation has the disadvantages of low-cell survival and/or development of dyskinesia. Transplantation of cell aggregates has the potential to overcome these problems, because the cells can extend their axons into the host brain and establish synaptic connections with host neurons. In this present study, aggregates of human brain-derived neural stem cells (HB-NSC) were transplanted into a PD animal model and compared to previous report on transplantation of single-cell suspensions. METHODS: Rats received an injection of 6-OHDA into the right medial forebrain bundle to generate the PD model and followed by injections of PBS only, or HB-NSC aggregates in PBS into the ipsilateral striatum. Behavioral tests, multitracer (2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) and [(18)F]-N-(3 fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([(18)F]-FP-CIT) microPET scans, as well as immunohistochemical (IHC) and immunofluorescent (IF) staining were conducted to evaluate the results. RESULTS: The stepping test showed significant improvement of contralateral forelimb control in the HB-NSC group from 6-10 weeks compared to the control group (p<0.05). [(18)F]-FP-CIT microPET at 10 weeks posttransplantation demonstrated a significant increase in uptake in the HB-NSC group compared to pretransplantation (p<0.05). In IHC and IF staining, tyrosine hydroxylase and human beta2 microglobulin (a human cell marker) positive cells were visualized at the transplant site. CONCLUSION: These results suggest that the HB-NSC aggregates can survive in the striatum and exert therapeutic effects in a PD model by secreting dopamine. PMID- 25535516 TI - Are blood blister-like aneurysms a specific type of dissection? A comparative study of blood blister-like aneurysms and ruptured mizutani type 4 vertebral artery dissections. AB - OBJECTIVE: Blood blister-like aneurysms (BBAs) resemble arterial dissections. The purpose of this study was to investigate the relationship between these two disease entities and highlight commonalities and distinct features. METHODS: Among 871 consecutive patients with aneurysmal subarachnoid hemorrhage, 11 BBAs of internal carotid artery and seven vertebral artery dissections (VADs) with a short segmental eccentric dilatation (Mizutani type 4), which is morphologically similar to a BBA, were selected. The following clinical factors were studied in each group : age, gender, risk factors, Hunt and Hess grade (HHG), Fisher grade (FG), vasospasms, hydrocephalus, perioperative rebleeding rate, and treatment outcome. RESULTS: The mean age was 47.9 years in the BBAs group and 46.4 years in the type 4 VADs group. All the BBA patients were female, whereas there was a slight male predominance in the type 4 VAD group (male : female ratio of 4 : 3). In the BBA and type 4 VAD groups that underwent less aggressive treatment to save the parent artery, 29% (n=2/7) and 66.6% (n=2/3), respectively, eventually required retreatment. Perioperative rebleeding occurred in 72.7% (n=8) and 28.6% (n=2) of patients in the BBA and type 4 VAD groups, respectively. There was no statistical difference in the other clinical factors in both groups, except for the male dominancy in the type 4 VAD group (p=0.011). CONCLUSION: BBAs and ruptured type 4 VADs have a similar morphological appearance but there is a distinct clinical feature in gender and perioperative rebleeding rates. Complete isolation of an aneurysm from the parent artery might be the most important discipline for the treatment of these diseases. PMID- 25535515 TI - Delayed improvement after endoscopic carpal tunnel release. AB - OBJECTIVE: In most patients with carpal tunnel syndrome (CTS), pain and/or paresthesia disappeared or decreased in a month after endoscopic carpal tunnel release (ECTR). However, subpopulation of patients showed delayed improvement following ECTR. We analyzed the delayed improvement hands to investigate the characteristics of those patients and to determine the predictable factors of delayed improvement. METHODS: Single-portal ECTRs were performed in 1194 hands of 793 CTS patients from 2002 to 2011. Five-hundred seventy hands with minimal 1 year postoperative follow-up were included. We divided the 545 satisfied hands into early (group A) and delayed (group B) groups according to improvement period of 1 month. Demographic data, clinical severity and electrodiagnostic abnormality were compared between groups. RESULTS: Group A included 510 hands and group B included 35 hands. In group B, 11 hands improved in 2 months, 15 hands in 3 months and 9 hands in 6 months, respectively. In group A/B, according to clinical severity, 60/1 hands were graded to I, 345/24 hands to II, 105/10 hands to III. In group A/B, based on electrodiagnostic abnormality, 57/3 hands were classified to mild, 221/11 hands to moderate and 222/21 hands to severe group. Statistical analysis between groups did not reach significance but electrodiagnostic or clinical severity had a tendency to affect the delayed response. CONCLUSION: It is difficult to predict the factors contributing to postoperatively-delayed response in subpopulation of CTS patients. However, we recommend that postoperative observation for at least 6 months is necessary in patients without symptomatic improvement. PMID- 25535517 TI - Quantitative analysis of factors affecting cobalt alloy clip artifacts in computed tomography. AB - OBJECTIVE: Clip artifacts limit the visualization of intracranial structures in CT scans from patients after aneurysmal clipping with cobalt alloy clips. This study is to analyze the parameters influencing the degree of clip artifacts. METHODS: Postoperative CT scans of 60 patients with straight cobalt alloy-clipped aneurysms were analyzed for the maximal diameter of white artifacts and the angle and number of streak artifacts in axial images, and the maximal diameter of artifacts in three-dimensional (3-D) volume-rendered images. The correlation coefficient (CC) was determined between each clip artifact type and the clip blade length and clip orientation to the CT scan (angle a, lateral clip inclination in axial images; angle b, clip gradient to scan plane in lateral scout images). RESULTS: Angle b correlated negatively with white artifacts (r= 0.589, p<0.001) and positively with the angle (r=0.636, p<0.001) and number (r=0.505, p<0.001) of streak artifacts. Artifacts in 3-D images correlated with clip blade length (r=0.454, p=0.004). Multiple linear regression analysis revealed that angle b was the major parameter influencing white artifacts and the angle and number of streak artifacts in axial images (p<0.001), whereas clip blade length was a major factor in 3-D images (p=0.034). CONCLUSION: Use of a clip orientation perpendicular to the scan gantry angle decreased the amount of white artifacts and allowed better visualization of the clip site. PMID- 25535518 TI - Outcome of endoscopic transsphenoidal surgery in combination with somatostatin analogues in patients with growth hormone producing pituitary adenoma. AB - OBJECTIVE: To determine the efficacy of endoscopic surgery in combination with long-acting somatostatin analogues (SSAs) in treating patients with growth hormone (GH)-secreting pituitary tumor. METHODS: We performed retrospective analysis of 133 patients with GH producing pituitary adenoma who underwent pure endoscopic transsphenoidal surgery in our center from January 2007 to July 2012. Patients were followed up for a range of 3-48 months. The radiological remission, biochemical remission and complication were evaluated. RESULTS: A total of 110 (82.7%) patients achieved radiological complete resection, 11 (8.2%) subtotal resection, and 12 (9.0%) partial resection. Eighty-eight (66.2%) patients showed nadir GH level less than 1 ng/mL after oral glucose administration. No mortality or severe disability was observed during follow up. Preoperative long-acting SSA successfully improved left ventricle ejection fraction (LVEF) and blood glucose in three patients who subsequently underwent success operation. Long-acting SSA (20 mg every 30 days) achieved biochemical remission in 19 out 23 (82.6%) patients who showed persistent high GH level after surgery. CONCLUSION: Endoscopic transsphenoidal surgery can biochemically cure the majority of GH producing pituitary adenoma. Post-operative use of SSA can improve biochemical remission. PMID- 25535519 TI - Clinical analysis of epidural fluid collection as a complication after cranioplasty. AB - OBJECTIVE: The epidural fluid collection (EFC) as a complication of cranioplasty is not well-described in the literature. This study aimed to identify the predictive factors for the development of EFC as a complication of cranioplasty, and its outcomes. METHODS: From January 2004 to December 2012, 117 cranioplasty were performed in our institution. One-hundred-and-six of these patients were classified as either having EFC, or not having EFC. The two groups were compared to identify risk factors for EFC. Statistical significance was tested using the t test and chi-square test, and a logistic regression analysis. RESULTS: Of the 117 patients undergoing cranioplasty, 59 (50.4%) suffered complications, and EFC occurred in 48 of the patients (41.0%). In the t-test and chi-test, risk factors for EFC were size of the skull defect (p=0.003) and postoperative air bubbles in the epidural space (p<0.001). In a logistic regression, the only statistically significant factor associated with development of EFC was the presence of postoperative air bubbles. The EFC disappeared or regressed over time in 30 of the 48 patients (62.5%), as shown by follow-up brain computed tomographic scan, but 17 patients (35.4%) required reoperation. CONCLUSION: EFC after cranioplasty is predicted by postoperative air bubbles in the epidural space. Most EFC can be treated conservatively. However, reoperation is necessary to resolve about a third of the cases. During cranioplasty, special attention is required when the skull defect is large, since EFC is then more likely. PMID- 25535520 TI - Progressive manifestations of reversible cerebral vasoconstriction syndrome presenting with subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarction. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by sudden onset headache with focal neurologic deficit and prolonged but reversible multifocal narrowing of the distal cerebral arteries. Stroke, either hemorrhagic or ischemic, is a relatively frequent presentation in RCVS, but progressive manifestations of subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction in a patient is seldom described. We report a rare case of a 56-year old woman with reversible cerebral vasoconstriction syndrome consecutively presenting as cortical subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarction. When she complained of severe headache with subtle cortical subarachnoid hemorrhage, her angiography was non-specific. But, computed tomographic angiography showed typical angiographic features of this syndrome after four days. Day 12, she suffered mental deterioration and hemiplegia due to contralateral intracerebral hematoma, and she was surgically treated. For recurrent attacks of headache, medical management with calcium channel blockers has been instituted. Normalized angiographic features were documented after 8 weeks. Reversible cerebral vasoconstriction syndrome should be considered as differential diagnosis of non-aneurysmal subarachnoid hemorrhage, and repeated angiography is recommended for the diagnosis of this under-recognized syndrome. PMID- 25535521 TI - Angiographically progressive change of traumatic pseudoaneurysm arising from the middle meningeal artery. AB - Traumatic pseudoaneurysms of the middle meningeal artery (MMA) are rare phenomenon, which are usually associated with head trauma such as an underlying skull fracture. They were usually known to cause acute or delayed epidural hematomas but can be associated with subdural, subarachnoid, or even intracerebral hemorrhage. Sometimes, a high mortality rate was reported in these circumferences. But the natural course of these pseudoaneurysms is not well recognized. The indication and guideline of treatment for pseudoaneurysm are also unclear. This report describes a rare case of angiographically progressive change of traumatic pseudoaneurysm of the middle meningeal artery for one week, which was treated with endovascular embolization. PMID- 25535522 TI - Fatal Traumatic Subarachnoid Hemorrhage due to Acute Rebleeding of a Pseudoaneurysm Arising from the Distal Basilar Artery. AB - Isolated traumatic pseudoaneurysms of the basilar artery are extremely rare but often fatal resulting in a mortality rate as high as 50%. A 51-year-old man presented with craniofacial injury after blunt trauma. A brain computed tomography (CT) scan showed thick basal subarachnoid hemorrhage associated with multiple craniofacial fractures, while CT angiography revealed contrast extravasation at the distal basilar artery with pseudoaneurysm formation. After this primary survey, the condition of the patient suddenly deteriorated. Conventional angiography confirmed the contrast extravasation resulted from pseudoaneurysm formation, which was successfully treated with endovascular coil embolization. Decompressive craniectomy and coma therapy with propofol were also performed. However, the patient died on the 7th hospital day because of the poor initial clinical condition. The current case is the first report of acute pseudoaneurysm rupture arising from the basilar artery within the first day after trauma. Our findings suggest the possibility that pseudoaneurysm rupture should be considered if brain CT shows thick traumatic subarachnoid hemorrhage on the basal cistern with a basal skull fracture. PMID- 25535523 TI - Total en bloc thoracic and lumbar spondylectomy for non-small cell lung cancer with favorable prognostic indicators: is it merely indicated for solitary spinal metastasis? AB - A fifty-year-old female non-smoker with no other specific medical history visited our institute. She complained of axial back pain with no other neurological deficit. Chest X-ray, chest computed tomography (CT) scan, CT-guided needle aspiration biopsy, whole-body positron emission tomography, spine CT and spine magnetic resonance image findings suggested NSCLC with epidermal growth factor receptor (EGFR) mutation, multiple brain metastases, and two isolated metastases to the T3 and L3 vertebral bodies. She underwent chemotherapy with gefitinib (IressaTM) for NSCLC and gamma knife surgery for multiple brain metastases. We performed a two-staged, total en bloc spondylectomy of the T3 and L3 vertebral bodies based on several good prognostic characteristics, such as the lack of metastases to the appendicular bone, good preoperative performance status, and being an excellent responder (Asian, never-smoker and adenocarcinoma histology) to EGFR inhibitors. Improved axial back pain after the surgery enabled her to walk with the aid of a thoracolumbosacral orthosis brace on the third postoperative day. Her Karnofsky performance status score (KPS) was 90 at the time of discharge and has been maintained to date 3 years after surgery. In selected NSCLC patients with good prognostic characteristics, we suggest that locally curative treatment such as total en bloc spondylectomy or radiosurgery should be emphasized to achieve longer term survival for the selected cases. PMID- 25535524 TI - Intramedullary sarcoidosis presenting with delayed spinal cord swelling after cervical laminoplasty for compressive cervical myelopathy. AB - Sarcoidosis is a systemic disease of unknown etiology that may affect any organ in the body. The nervous system is involved in 5-16% of cases of sarcoidosis. Here, we report a case of intramedullary sarcoidosis presenting with delayed spinal cord swelling after laminoplasty for the treatment of compressive cervical myelopathy. A 56-year-old woman was admitted to our hospital complaining of upper extremity pain and gait disturbance. The patient had undergone laminoplasty for compressive cervical myelopathy 3 months previously. Follow-up magnetic resonance imaging revealed a large solitary intramedullary lesion with associated extensive cord swelling, signal changes, and heterogeneous enhancement of spinal cord from C2 to C7. Spinal cord biopsy revealed non-necrotizing granulomas with signs of chronic inflammation. The final diagnosis of sarcoidosis was based upon laboratory data, imaging findings, histological findings, and the exclusion of other diagnoses. Awareness of such presentations and a high degree of suspicion of sarcoidosis may help arrive at the correct diagnosis. PMID- 25535525 TI - Delayed cerebral hyperperfusion syndrome three weeks after carotid artery stenting presenting as status epilepticus. AB - Cerebral hyperperfusion syndrome (CHS) is increasingly recognized as an uncommon, but serious, complication subsequent to carotid artery stenting (CAS) and carotid endarterectomy (CEA). The onset of CHS generally occurs within two weeks of CEA and CAS, and a delay in the onset of CHS of over one week after CAS is quite rare. We describe a patient who developed CHS three weeks after CAS with status epilepticus. PMID- 25535526 TI - Cerebral phaeohyphomycosis: a rare cause of brain abscess. AB - Cerebral phaeohyphomycosis (CP) is a very rare but serious form of central nervous system fungal infection that is caused by dematiaceous fungi. It is commonly associated with poor prognosis irrespective of the immune status of the patient. In this study, the authors describe the first case of CP in Korea that occurred in a 75-year-old man without immunodeficiency and showed favorable outcome after surgical excision and antifungal therapy. In addition, the authors herein review the literature regarding characteristics of this rare clinical entity with previously reported cases. PMID- 25535527 TI - Status epilepticus caused by nefopam. AB - Nefopam, a centrally acting analgesic, has been used to control postoperative pain. Reported adverse effects are anticholinergic, cardiovascular or neuropsychiatric. Neurologic adverse reactions to nefopam are confusion, hallucinations, delirium and convulsions. There are several reports about fatal convulsive seizures, presumably related to nefopam. A 71-year-old man was admitted for surgery for a lumbar spinal stenosis. He was administered intravenous analgesics : ketorolac, tramadol, orphenadrine citrate and nefopam HCl. His back pain was so severe that he hardly slept for several days; he even needed morphine and pethidine. At 4 days of administration of intravenous analgesics, the patient suddenly started generalized tonic-clonic seizures for 15 seconds, and subsequently, status epilepticus; these were not responsive to phenytoin and midazolam. After 3 days of barbiturate coma therapy the seizures were controlled. Convulsive seizures related to nefopam appear as focal, generalized, myoclonic types, or status epilepticus, and are not dose-related manifestations. In our case, the possibility of convulsions caused by other drugs or the misuse of drugs was considered. However, we first identified the introduced drugs and excluded the possibility of an accidental misuse of other drugs. Physicians should be aware of the possible occurrence of unpredictable and serious convulsions when using nefopam. PMID- 25535528 TI - The necessity for emotional support of severely diseased children: a world-wide role model from iran. PMID- 25535529 TI - Fundamental Movement Skills Development under the Influence of a Gymnastics Program and Everyday Physical Activity in Seven-Year-Old Children. AB - OBJECTIVE: The objectives of this study were: a) to examine the influence of an 18-week basic artistic gymnastics program on fundamental movement skills (FMS) development in seven-year-old children; b) to determine correlations between children's daily activities and successful performance of FMS and basic artistic gymnastics skills. METHODS: Seventy five first grade primary school children took part in this study. A physical education teacher specialized in artistic gymnastics conducted a gymnastics program for 18 weeks, three times a week. The level of gymnastics skills and FMS were identified at the beginning and at the end of the program. The level of gymnastics skills was evaluated by performance of eight artistic gymnastics skills, while FMS were evaluated by the use of FMS polygon. Physical activity and inactivity was evaluated by using a proxy questionnaire "Netherlands Physical Activity Questionnaire" (NPAQ). FINDINGS: According to the dependent samples t test, significant differences were found in the FMS-polygon and all gymnastics skills before and after the 18-week gymnastics program. Increasing correlations were established over time between gymnastics skills and the FMS-polygon. Unorganized daily activity of children significantly correlated with their mastering of gymnastics skills and FMS. The presented findings confirm: (1) the thesis that basic artistic gymnastics skills and FMS could be developed simultaneously, (2) the theory of positive transfer of similar skills between FMS and artistic gymnastic skills. CONCLUSION: Mastering basic artistic gymnastics skills will provoke improvement of FMS and finally become a prerequisite for successful introduction of learning more complex gymnastics skills. The obtained results imply that an increase of children's unorganized daily activities can improve the mastering of basic gymnastics skills and simultaneously the development of FMS. PMID- 25535530 TI - Acute flaccid paralysis and its differential diagnosis in in kurdistan province, Western iran; an 11-year surveillance. AB - OBJECTIVE: The surveillance of acute flaccid paralysis (AFP) is a key strategy for monitoring the progress of poliomyelitis eradication and is a sensitive measure for detecting potential cases of poliomyelitis and poliovirus infection. This study was conducted to describe the characteristics of patients reported with AFP, and to evaluate the performance of the surveillance system in Kurdistan province, western Iran, using indicators recommended by the World Health Organization (WHO). METHODS: This observational study was conducted from January 2000 to December 2010 at the Kurdistan Center for Disease Control and the Department of Pediatrics. All children who fulfilled the WHO definition for AFP were included in our study. The stool samples of all the children were sent for poliovirus isolation. All the patients were evaluated for 60 days after the onset of symptoms to identify the signs of residual weakness. FINDINGS: One-hundred thirty nine children aged <15 years were reported to the Center for Diseases Control with AFP. In 138 (99%) stool samples no poliovirus was isolated. None of the patients was diagnosed as having acute poliomyelitis or polio-compatible paralysis. Guillain-Barre syndrome was the most frequent final diagnosis (79 cases) followed by Transverse Myelitis (7 cases) and Encephalitis (6 cases). By detecting 1.3 to 3.6 (mean 3.2) AFP cases per 100 000 population in Kurdistan during the study period, we achieved the WHO target for AFP surveillance. All performance indicators but one consistently met the WHO requirements and therefore demonstrated the effectiveness of the AFP surveillance program in Kurdistan. CONCLUSION: The effective surveillance system in Kurdistan and its evaluation may serve as a model for the surveillance of other infectious diseases. PMID- 25535531 TI - Magnitude and factors associated with child abuse in a mega city of developing country pakistan. AB - OBJECTIVE: Child abuse is one of the major challenges for health care providers. This study was conducted to determine the burden of child abuse (physical & emotional) and the factors associated with it in an urban city of Pakistan. METHODS: This cross-sectional study was conducted in primary care clinics affiliated with a tertiary care hospital in Karachi, Pakistan between March to December 2010. Mothers with children aged between 6 and 12 years were included in the study. Those mothers' suffering from any acute illness like high grade fever, were excluded. A total of 412 mothers were recruited through consecutive sampling and written informed consent was taken. A pre-tested questionnaire was used to seek information about child abuse. Data was analyzed using SPSS version 19 and multivariable logistic regression was used to identify the factors (age, gender of child, family structure, educational status of parents, and mother's perception of her home environment) associated with child abuse. FINDINGS: Of the total 412 mothers, final analysis was conducted on 379 mothers. In all, 32.5% of children had been abused, 25.5% physically and 17.9% emotionally. Abuse was reported more among children whose mothers had minimal or no schooling (P=0.02), who were abused by their husbands (P<0.001), not satisfied with their marital life (P<0.001), and stressful home environment (P=0.02). In the multivariate analysis, the factors found to be independently associated with child abuse were mothers abused by their husbands (AOR=4.2; 95%CI: 2.2-7.9) and child being a girl (AOR=8.7; 95%CI: 4.5-16.8). CONCLUSION: The prevention of child abuse can be achieved through comprehensive, multifaceted and integrated approaches requiring joint efforts by the government, policy makers, stake holders, social workers, educationists, and public health practitioners. PMID- 25535532 TI - The role of lung ultrasound in diagnosis of respiratory distress syndrome in newborn infants. AB - OBJECTIVE: The aim of this study was to evaluate the value of lung ultrasound in the diagnosis of respiratory distress syndrome (RDS) in newborn infants. METHODS: From March 2012 to May 2013, 100 newborn infants were divided into two groups: RDS group (50 cases) and control group (50 cases). According to the findings of chest x-ray, there were 10 cases of grade II RDS, 15 grade III cases, and 25 grade IV cases in RDS group. Lung ultrasound was performed at bedside by a single expert. The ultrasound indexes observed in this study included pleural line, A line, B-line, lung consolidation, air bronchograms, bilateral white lung, interstitial syndrome, lung sliding, lung pulse etc. FINDINGS: In all of the infants with RDS, lung ultrasound consistently showed generalized consolidation with air bronchograms, bilateral white lung or interstitial syndrome, pleural line abnormalities, A-line disappearance, pleural effusion, lung pulse, etc. The simultaneous demonstration of lung consolidation, pleural line abnormalities and bilateral white lung, or lung consolidation, pleural line abnormalities and A line disappearance co-exists with a sensitivity and specificity of 100% for the diagnosis of neonatal RDS. CONCLUSION: This study indicates that using an ultrasound to diagnose neonatal RDS is accurate and reliable tool. A lung ultrasound has many advantages over other techniques. Ultrasound is non-ionizing, low-cost, easy to operate, and can be performed at bedside, making this technique ideal for use in NICU. PMID- 25535533 TI - A prospective study of brucellosis in children: relative frequency of pancytopenia. AB - OBJECTIVE: Hematological complications of brucellosis are common. Pancytopenia, although mainly reported in adults, has also been described in children with brucellosis. This investigation was conducted to estimate the relative frequency of pancytopenia in children with brucellosis. METHODS: The current study was conducted in Al-Khafji Joint Operations Hospital, Saudi Arabia. Sixty patients with brucellosis were enrolled in the study. Complete blood count (CBC) and blood culture were performed for all cases. Bone marrow (BM) aspiration was considered only in those with pancytopenia. FINDINGS: Out of 60 children with brucellosis, 50 (83%) ingested raw animal milk and 27 (45%) had a positive family history of brucellosis. The common presenting symptoms and signs included: excessive sweating (68%), bone aches (62%), chills (55%), arthritis (32%), hepatomegaly (18%) and splenomegaly (15%). The main hematological manifestations included: anemia (43%), leukopenia (38%) and leukocytosis (20%). Pancytopenia was detected in 11 (18%) patients. Blood culture for Brucella was positive in 38% (23 patients). B. melitensis from 21 patients was cultured in vitro. Out of 9 BM aspirate cultures, 3 were positive for B. melitensis. Out of 11 patients with pancytopenia, 9 (82%) patients had bone aches and weakness, 7 (64%) patients sweating and chills, 6 (55%) patients petechiae and purpura. CONCLUSION: The current study concludes that although pancytopenia is an uncommon complication of brucellosis in children, it does occur. Therefore, brucellosis should be considered in the differential diagnosis of pancytopenia in children, particularly in endemic areas such as Saudi Arabia. PMID- 25535534 TI - Effect of Growth Hormone treatment on Height Velocity of Children with Pycnodysotosis. AB - OBJECTIVE: Pycnodysostosis is a rare autosomal recessive osteochondrodysplasia resulting from osteoclast dysfunction. Growth hormone (GH) secretion impairment and low insulin growth factor 1 (IGF-I) concentrations have been reported in these patients. The present study aims to describe GH effect on linear growth of eight children with pycnodysostosis. METHODS: This study was conducted on 8 children suffering from pycnodysostosis. After evaluating systemic diseases, adrenal insufficiency, and hypothyroidism, bone age, height standard deviation score (HtSDS), body mass index (BMI), and some demographical characteristics were measured. To measure the serum GH, we performed two clonidine tests in two different days with an interval of 24 hours. With initiation of the trial, human GH was injected subcutaneously once a day 6 days a week for a period of 1.5 years. The patients were followed up every 3 months to document their height and BMI until 6 months after the end of the treatment. FINDINGS: All of the patients had growth hormone deficiency. HtSDS at the first visit continued to decrease during the 6 months before starting the treatment; however, HtSDS started to increase after beginning of GH administration. This value again declined after discontinuing the GH. Overall, the mean of linear growth was improved after GH administration in the patients. CONCLUSION: The present clinical study revealed that GH administration had a positive impact on the linear growth of the children suffering from pycnodysostosis. PMID- 25535535 TI - Evaluation of oxidative stress and erythrocyte properties in children with henoch shoenlein purpura. AB - OBJECTIVE: Pathogenesis of Henoch-Schonlein purpura (HSP) is not clearly defined. The present study was conducted to investigate the alterations in erythrocyte deformability and oxidative stress in HSP and to examine the possible relationship between erythrocyte deformability and organ involvement in this disease. METHODS: Plasma malondialdehyde (MDA) levels, total antioxidant status (TAS), erythrocyte deformability and aggregation were measured in 21 children with HSP at the disease onset and during the remission period in comparison with healthy subjects. FINDINGS: HSP patients at the active stage had significantly higher MDA and lower TAS levels (P<0.05). Erythrocyte deformability was decreased at the active-stage and increased again at the remission period of HSP (P<0.05). Erythrocyte deformability was significantly decreased at four different shear stresses in patients with gastrointestinal system or renal involvement; and decreased at six different shear stresses in patients with gastrointestinal system, and renal involvement compared to the patients without organ involvement (P<0.05). No significant difference was observed in aggregation parameters (P>0.05). CONCLUSION: The present findings emphasize the association between impaired erythrocyte deformability and organ involvement in HSP. PMID- 25535536 TI - A Randomized Clinical Trial of Insulin Glargine and Aspart, Compared to NPH and Regular Insulin in Children with Type 1 Diabetes Mellitus. AB - OBJECTIVE: Appropriate treatment of patients with Type 1 diabetes mellitus (T1DM) is necessary to avoid further complications. This study was performed to compare the efficacy of insulin Glargine and Aspart with NPH insulin and regular insulin regimen in a group of children with T1DM. METHODS: Forty patients with T1DM were enrolled in this study. During run-in, all subjects were treated with conventional therapy consisting of twice-daily NPH and thrice-daily regular. Following randomization, 20 subjects received Glargine and Aspart and 20 subjects received NPH and Regular insulin. FINDINGS: Mean HbA1c was 8.8% and 8.6% at first and 8.4% and 8.2% at the end of study for subjects randomized initially to Glargine and Aspart and for those randomized to NPH and Regular, respectively (P>0.05). Mean fasting blood glucose (FBS) of the subjects randomized initially to Glargine and Aspart was 217+/-101 mg/dL, with no significant difference to 196+/-75 mg/dL for those randomized to NPH and Regular (P=0.48). This was also true at the end of the study. The difference in total cholesterol and triglyceride between the two groups in the beginning of study and at the end did not show any significance. CONCLUSION: The current study showed no significant difference in glycemic control [Glycated hemoglobin (HbA1c) and FBS] and lipid profile (total cholesterol and triglyceride) between two regimes. PMID- 25535537 TI - Apneas in Infants with Postconceptional Age bellow 60 Weeks Undergoing Herniorrhaphy. AB - OBJECTIVE: Postoperative apnea is a major concern in infants undergoing surgery. In this study, we evaluated incidence and related factors for postoperative apnea in infants less than 60 weeks postconceptual age after herniorrhaphy. METHODS: One-hundred fifty infants with post conceptional age (PCA) less than 60 weeks who underwent elective herniorrhaphy were studied over eight months in 2012. General anesthesia was induced by sevoflurane and maintained by remifentanil, atracurium, and N2O 60%. Postoperatively, they were monitored for two hours in the recovery room and ten hours in the ward using pulse oximetry and nasal capnography. FINDINGS: Totally, 31 (20.7%) cases of postoperative apnea were reported. By comparing the patients, factors associated with postoperative apnea included postconceptional age, birth weight, and history of apnea, oxygen therapy, metabolic diseases, icterus, or cardiac disease. Twenty-seven (18%) apnea cases occurred in recovery room in infants with gestational age (GA) of 35.64+/-2.73 weeks, while only four (2.6%) patients of GA 36.02+/-2.0 weeks developed delayed apnea). CONCLUSION: In our study, the incidence of postoperative apnea following inguinal herniorrhaphy under general anesthesia in infants younger than 60 weeks PCA was 20.7%, which is considerable. We recommend longer surveillance and monitoring in recovery room for these infants with high-risk of postoperative apnea. This should be followed by evaluation of risk factors to determine the indication for elective intensive care unit transfer for longer-term monitoring of higher-risk patients. PMID- 25535538 TI - Postanesthetic Emergence Agitation in Pediatric Patients under General Anesthesia. AB - OBJECTIVE: Postanesthetic emergence agitation is a common problem in pediatric postanesthetic care unit with an incidence ranging from 10 to 80%. This study was done to determine the prevalence of emergence agitation and associated risk factors in pediatric patients who underwent general anesthesia. METHODS: This cross-sectional descriptive and analytic study was performed on 747 pediatric patients aged 3- 7 years that underwent general anesthesia for various elective surgeries at Bou-Ali Sina Hospital in Sari, Iran between January 2010 and January 2011. A non-probability quota sampling technique was used. The presence of emergence agitation was recorded using Pediatric Anesthesia Emergence Delirium Scale. The factors linked with Emergence Agitation were recorded in a questionnaire. The data were analyzed using SPSS software 16 and independent sample t-test, chi(2) and binary logistic regression. P-values less than 0.05 were considered as significant. FINDINGS: One hundred thirty-four (17.9%) children had emergence agitation. The most frequent surgical procedures were ENT surgical procedures 315 (42.2%), abdominal surgery 177 (23.7%), orthopedic surgery 137 (18.3%), urology 97 (13%) and ophthalmic surgery 24 (3.2%). Otorhinolaryngological surgical procedures (P=0.001), pain (P<0.05) and induction behavior of children (P<0.005) were associated with higher rates of post anesthetic emergence agitation (P=0.001). CONCLUSION: This study identified the multiple independent risk factors which are associated with emergence agitation in children. To minimize the incidence of postanesthetic emergence agitation, these risk factors should be considered in the routine care by care providers in postanesthetic care unit. PMID- 25535539 TI - Risk factors of germinal matrix intraventricular hemorrhage in premature infants. AB - OBJECTIVE: To determine whether some clinical parameters can be used to predict the hemorrhage and whether the relationship between these clinical variables and the grades of hemorrhage is linear. METHODS: A total of 230 premature infants, born at a gestational age less than 34 weeks were retrospectively reviewed. Germinal matrix-intraventricular hemorrhage (GM-IVH), the grade of the hemorrhage, and clinical data were assessed with a checklist. Variables were analyzed by using Mann Whitney U and Fisher's exact tests and then multiple logistic regression analysis was used to evaluate the independent risk factors. FINDINGS: Resuscitation, gestational age, hypotension, multiple birth, and birth weight were found to be independent risk factors. We determined non-linear relationship between the grades of hemorrhage and the clinical parameters. But when we classified hemorrhages as grade 1, grade 2-3 and grade 4, the relationships were found linear. CONCLUSION: Premature infants who had resuscitation, low gestational age, hypotension, multiple birth, and low birth weight are more likely to have GM-IVH. The relationship between the clinical variables and the grades of GM-IVH does not seem to be linear. PMID- 25535541 TI - Comparison of nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure treatments using parametric survival models. AB - OBJECTIVE: The Cox model is the dominant tool in clinical trials to compare treatment options. This model does not specify any specific form to the hazard function. On the other hand, parametric models allow the researcher to consider an appropriate shape of hazard function for the event of interest. The aim of this article is to compare performance of Cox and parametric models. METHODS: We used data collected in a prospective clinical trial that aimed to compare performance of nasal intermittent positive pressure ventilation (NIPPV) and nasal continuous positive airway pressure (NCPAP) treatments in terms of survival of newborn infants who had respiratory distress syndrome (RDS). Performance of Cox, exponential, Weibull, and log-logistic models were compared in terms of goodness of fit. FINDINGS: Fitting the Cox model, we have seen that infants who received NCPAP were 4.23 (Hazard Ratio= 4.23, 95% Confidence Interval: 1.87-9.59) times more likely to fail than those received NIPPV (P=0.001). Adequacy of the exponential model was rejected. We have seen a decreasing hazard rate over time, in both treatment groups. This decrease was sharper in NCPAP group. Akiake information criterion corresponded to the log-logistic model and was lower than all other models followed by Weibull model. CONCLUSION: Our results demonstrate the benefit of parametric survival models over traditional Cox regression model in terms of modeling of shape of hazard function. We saw a decreasing hazard that confirms the flexibility of parametric models in terms of the modeling of hazard rate. PMID- 25535542 TI - Study of foreign-body extraction from the upper third of the esophagus in children. AB - BACKGROUND: Throat-operating forceps are an auxiliary tool used for tracheal intubation during general anesthesia as well as for artificial respiration and during airway emergency when tracheal intubation is necessary. These forceps are a commonly used tool particularly for introducing the distal end of the endotracheal catheter into the airway at the epiglottis during difficult airway intubation and nasotracheal intubation. Throat-operating forceps have a required radian for operation at the intraoral epiglottis and have different types (large, medium, and small) that are suitable for patients of different ages. These tools have flexible forceps clamps and target-like, smooth distal ends that do not injure mucous membranes. Given these advantages, throat-operating forceps are used for pediatric endoesophageal foreign-body removal. CASE PRESENTATION: Pediatric patients were anesthetized using different methods according to their age. A total of 15 patients five years to nine years of age were recruited. Foreign bodies were successfully removed without any complications. CONCLUSION: Tracheal intubation forceps successfully removes esophageal foreign bodies in children because of the distinct shape of the forceps. The method is simple, feasible, and safe. PMID- 25535540 TI - Comparison of oral and buccal midazolam for pediatric dental sedation: a randomized, cross-over, clinical trial for efficacy, acceptance and safety. AB - OBJECTIVE: Providing a safe and efficient dental treatment for a young patient is a challenge for the dentist and the child. The purpose of this study was to investigate the effectiveness, safety and acceptability of buccal midazolam in dental pediatric patients and to compare it with oral Midazolam. METHODS: Eighteen uncooperative healthy children aged 2.5-6 years were randomized to each of buccal midazolam (0.3mg/kg) or oral midazolam (0.5mg/kg) at the first visit, the alternative has been used at the second visit in a cross-over manner. The study took place at pediatric dentistry clinic of Shahed University, Tehran, from November 2011 to June 2012. The patients' vital signs and behavioral scores were recorded. The patient, the operator and the observer were blinded to the applied medication. Post operatively, patients' and parents' satisfaction were assessed by Visual Analogue Score and a questionnaire respectively. The P-value was set at 0.05 for significance level. FINDINGS: There were no significant differences in physiologic factors in the medication groups at time 0, 10, 20, 30 minutes and discharge. There was also no significant difference between the two groups in behavioral parameters. The majority of parents rated both sedative agents as "effective" or "very effective" and their children mostly were without anxiety or with minor anxiety. CONCLUSION: Buccal midazolam may be safely and efficiently used in sedation of pediatric dental patients. PMID- 25535543 TI - A case of tuberculous osteomyelitis of the sternum with discharging sinus in an Indian girl. PMID- 25535544 TI - Primitive neuroectodermal tumor, a rare cause of musculoskeletal manifestations in a child. PMID- 25535545 TI - A case of isolated congenital left ventricular diverticulum with acute myocarditis. PMID- 25535546 TI - Feminizing adrenal tumor: a rare presentation. PMID- 25535547 TI - Holoprosencephaly and klinefelter syndrome. PMID- 25535549 TI - A heterogeneous thermal environment enables remarkable behavioral thermoregulation in Uta stansburiana. AB - Ectotherms can attain preferred body temperatures by selecting specific temperature microhabitats within a varied thermal environment. The side-blotched lizard, Uta stansburiana may employ microhabitat selection to thermoregulate behaviorally. It is unknown to what degree habitat structural complexity provides thermal microhabitats for thermoregulation. Thermal microhabitat structure, lizard temperature, and substrate preference were simultaneously evaluated using thermal imaging. A broad range of microhabitat temperatures was available (mean range of 11 degrees C within 1-2 m(2)) while mean lizard temperature was between 36 degrees C and 38 degrees C. Lizards selected sites that differed significantly from the mean environmental temperature, indicating behavioral thermoregulation, and maintained a temperature significantly above that of their perch (mean difference of 2.6 degrees C). Uta's thermoregulatory potential within a complex thermal microhabitat structure suggests that a warming trend may prove advantageous, rather than detrimental for this population. PMID- 25535548 TI - Human umbilical endothelial cells (HUVECs) have a sex: characterisation of the phenotype of male and female cells. AB - BACKGROUND: Human umbilical endothelial cells (HUVECs) are widely used to study the endothelial physiology and pathology that might be involved in sex and gender differences detected at the cardiovascular level. This study evaluated whether HUVECs are sexually dimorphic in their morphological, proliferative and migratory properties and in the gene and protein expression of oestrogen and androgen receptors and nitric oxide synthase 3 (NOS3). Moreover, because autophagy is influenced by sex, its degree was analysed in male and female HUVECs (MHUVECs and FHUVECs). METHODS: Umbilical cords from healthy, normal weight male and female neonates born to healthy non-obese and non-smoking women were studied. HUVEC morphology was analysed by electron microscopy, and their function was investigated by proliferation, viability, wound healing and chemotaxis assays. Gene and protein expression for oestrogen and androgen receptors and for NOS3 were evaluated by real-time PCR and Western blotting, respectively, and the expression of the primary molecules involved in autophagy regulation [protein kinase B (Akt), mammalian target of rapamycin (mTOR), beclin-1 and microtubule associated protein 1 light chain 3 (LC3)] were detected by Western blotting. RESULTS: Cell proliferation, migration NOS3 mRNA and protein expression were significantly higher in FHUVECs than in MHUVECs. Conversely, beclin-1 and the LC3 II/LC3-I ratio were higher in MHUVECs than in FHUVECs, indicating that male cells are more autophagic than female cells. The expression of oestrogen and androgen receptor genes and proteins, the protein expression of Akt and mTOR and cellular size and shape were not influenced by sex. Body weights of male and female neonates were not significantly different, but the weight of male babies positively correlated with the weight of the mother, suggesting that the mother's weight may exert a different influence on male and female babies. CONCLUSIONS: The results indicate that sex differences exist in prenatal life and are parameter-specific, suggesting that HUVECs of both sexes should be used as an in vitro model to increase the quality and the translational value of research. The sex differences observed in HUVECs could be relevant in explaining the diseases of adulthood because endothelial dysfunction has a crucial role in the pathogenesis of cardiovascular diseases, diabetes mellitus, neurodegeneration and immune disease. PMID- 25535550 TI - Inbreeding alters intersexual fitness correlations in Drosophila simulans. AB - Intralocus sexual conflict results from sexually antagonistic selection on traits shared by the sexes. This can displace males and females from their respective fitness optima, and negative intersexual correlations (r mf) for fitness are the unequivocal indicator of this evolutionary conflict. It has recently been suggested that intersexual fitness correlations can vary depending on the segregating genetic variation present in a population, and one way to alter genetic variation and test this idea is via inbreeding. Here, we test whether intersexual correlations for fitness vary with inbreeding in Drosophila simulans isolines reared under homogenous conditions. We measured male and female fitness at different times following the establishment of isofemale lines and found that the sign of the association between the two measures varied with time after initial inbreeding. Our results are consistent with suggestions that the type of genetic variation segregating within a population can determine the extent of intralocus sexual conflict and also support the idea that sexually antagonistic alleles segregate for longer in populations than alleles with sexually concordant effects. PMID- 25535551 TI - Experimental evidence that the Ornstein-Uhlenbeck model best describes the evolution of leaf litter decomposability. AB - Leaf litter decomposability is an important effect trait for ecosystem functioning. However, it is unknown how this effect trait evolved through plant history as a leaf 'afterlife' integrator of the evolution of multiple underlying traits upon which adaptive selection must have acted. Did decomposability evolve in a Brownian fashion without any constraints? Was evolution rapid at first and then slowed? Or was there an underlying mean-reverting process that makes the evolution of extreme trait values unlikely? Here, we test the hypothesis that the evolution of decomposability has undergone certain mean-reverting forces due to strong constraints and trade-offs in the leaf traits that have afterlife effects on litter quality to decomposers. In order to test this, we examined the leaf litter decomposability and seven key leaf traits of 48 tree species in the temperate area of China and fitted them to three evolutionary models: Brownian motion model (BM), Early burst model (EB), and Ornstein-Uhlenbeck model (OU). The OU model, which does not allow unlimited trait divergence through time, was the best fit model for leaf litter decomposability and all seven leaf traits. These results support the hypothesis that neither decomposability nor the underlying traits has been able to diverge toward progressively extreme values through evolutionary time. These results have reinforced our understanding of the relationships between leaf litter decomposability and leaf traits in an evolutionary perspective and may be a helpful step toward reconstructing deep time carbon cycling based on taxonomic composition with more confidence. PMID- 25535552 TI - The impact of transmission mode on the evolution of benefits provided by microbial symbionts. AB - While past work has often examined the effects of transmission mode on virulence evolution in parasites, few studies have explored the impact of horizontal transmission on the evolution of benefits conferred by a symbiont to its host. Here, we identify three mechanisms that create a positive covariance between horizontal transmission and symbiont-provided benefits: pleiotropy within the symbiont genome, partner choice by the host, and consumption of host waste by products by symbionts. We modify a susceptible-infected model to incorporate the details of each mechanism and examine the evolution of symbiont benefits given variation in either the immigration rate of susceptible hosts or the rate of successful vertical transmission. We find conditions for each case under which greater opportunity for horizontal transmission (higher migration rate) favors the evolution of mutualism. Further, we find the surprising result that vertical transmission can inhibit the evolution of benefits provided by symbionts to hosts when horizontal transmission and symbiont-provided benefits are positively correlated. These predictions may apply to a number of natural systems, and the results may explain why many mutualisms that rely on partner choice often lack a mechanism for vertical transmission. PMID- 25535553 TI - Weakening density dependence from climate change and agricultural intensification triggers pest outbreaks: a 37-year observation of cotton bollworms. AB - Understanding drivers of population fluctuation, especially for agricultural pests, is central to the provision of agro-ecosystem services. Here, we examine the role of endogenous density dependence and exogenous factors of climate and human activity in regulating the 37-year population dynamics of an important agricultural insect pest, the cotton bollworm (Helicoverpa armigera), in North China from 1975 to 2011. Quantitative time-series analysis provided strong evidence explaining long-term population dynamics of the cotton bollworm and its driving factors. Rising temperature and declining rainfall exacerbated the effect of agricultural intensification on continuously weakening the negative density dependence in regulating the population dynamics of cotton bollworms. Consequently, ongoing climate change and agricultural intensification unleashed the tightly regulated pest population and triggered the regional outbreak of H. armigera in 1992. Although the negative density dependence can effectively regulate the population change rate to fluctuate around zero at stable equilibrium levels before and after outbreak in the 1992, the population equilibrium jumped to a higher density level with apparently larger amplitudes after the outbreak. The results highlight the possibility for exogenous factors to induce pest outbreaks and alter the population regulating mechanism of negative density dependence and, thus, the stable equilibrium of the pest population, often to a higher level, posing considerable risks to the provision of agro-ecosystem services and regional food security. Efficient and timely measures of pest management in the era of Anthropocene should target the strengthening and revival of weakening density dependence caused by climate change and human activities. PMID- 25535554 TI - Can phenotypic rescue from harvest refuges buffer wild sheep from selective hunting? AB - Human harvests can unwittingly drive evolution on morphology and life history, and these selective effects may be detrimental to the management of natural resources. Although theory suggests that harvest refuges, as sources of unselected animals, could buffer the effects of human exploitation on wild populations, few studies have assessed their efficiency. We analyzed records from >7000 trophy bighorn rams (Ovis canadensis) harvested in Alberta, Canada, between 1974 and 2011 to investigate if the movement of rams from refuges toward harvested areas reduced the effects of selective harvesting on horn size through phenotypic rescue. Rams taken near refuges had horns on average about 3% longer than rams shot far from refuges and were slightly older, suggesting migration from refuges into hunted areas. Rams from areas adjacent to and far from harvest refuges, however, showed similar declines in horn length and increases in age at harvest over time, indicating a decreasing rate of horn growth. Our study suggests that the influx of rams from refuges is not sufficient to mitigate the selective effects of sheep trophy harvest. Instead, we suggest that selective hunting of highly mobile animals may affect the genetic structure of populations that spend part of the year inside protected areas. PMID- 25535556 TI - Changes in pollinator fauna affect altitudinal variation of floral size in a bumblebee-pollinated herb. AB - Geographic trait variations are often caused by locally different selection regimes. As a steep environmental cline along altitude strongly influences adaptive traits, mountain ecosystems are ideal for exploring adaptive differentiation over short distances. We investigated altitudinal floral size variation of Campanula punctata var. hondoensis in 12 populations in three mountain regions of central Japan to test whether the altitudinal floral size variation was correlated with the size of the local bumblebee pollinator and to assess whether floral size was selected for by pollinator size. We found apparent geographic variations in pollinator assemblages along altitude, which consequently produced a geographic change in pollinator size. Similarly, we found altitudinal changes in floral size, which proved to be correlated with the local pollinator size, but not with altitude itself. Furthermore, pollen removal from flower styles onto bees (plant's male fitness) was strongly influenced by the size match between flower style length and pollinator mouthpart length. These results strongly suggest that C. punctata floral size is under pollinator mediated selection and that a geographic mosaic of locally adapted C. punctata exists at fine spatial scale. PMID- 25535555 TI - Insights from ecological niche modeling on the taxonomic distinction and niche differentiation between the black-spotted and red-spotted tokay geckoes (Gekko gecko). AB - The black-spotted tokay and the red-spotted tokay are morphologically distinct and have largely allopatric distributions. The black-spotted tokay is characterized by a small body size and dark skin with sundry spots, while the red spotted tokay has a relatively large body size and red spots. Based on morphological, karyotypic, genetic, and distribution differences, recent studies suggested their species status; however, their classifications remain controversial, and additional data such as ecological niches are necessary to establish firm hypotheses regarding their taxonomic status. We reconstructed their ecological niches models using climatic and geographic data. We then performed niche similarity tests (niche identity and background tests) and point based analyses to explore whether ecological differentiation has occurred, and whether such differences are sufficient to explain the maintenance of their separate segments of environmental ranges. We found that both niche models of the black- and the red-spotted tokay had a good fit and a robust performance, as indicated by the high area under the curve (AUC) values ("black" = 0.982, SD = +/ 0.002, "red" = 0.966 +/- 0.02). Significant ecological differentiation across the entire geographic range was found, indicating that the involvement of ecological differentiation is important for species differentiation. Divergence along the environmental axes is highly associated with climatic conditions, with isothermality being important for the "black" form, while temperature seasonality, precipitation of warmest quarter, and annual temperature range together being important for the "red" form. These factors are likely important factors in niche differentiation between the two forms, which result in morphological replacement. Overall, beside morphological and genetic differentiation information, our results contribute to additional insights into taxonomic distinction and niche differentiation between the black- and the red spotted tokay. PMID- 25535557 TI - Parasitism in early life: environmental conditions shape within-brood variation in responses to infection. AB - Parasites play key ecological and evolutionary roles through the costs they impose on their host. In wild populations, the effect of parasitism is likely to vary considerably with environmental conditions, which may affect the availability of resources to hosts for defense. However, the interaction between parasitism and prevailing conditions is rarely quantified. In addition to environmental variation acting on hosts, individuals are likely to vary in their response to parasitism, and the combined effect of both may increase heterogeneity in host responses. Offspring hierarchies, established by parents in response to uncertain rearing conditions, may be an important source of variation between individuals. Here, we use experimental antiparasite treatment across 5 years of variable conditions to test how annual population productivity (a proxy for environmental conditions) and parasitism interact to affect growth and survival of different brood members in juvenile European shags (Phalacrocorax aristotelis). In control broods, last-hatched chicks had more plastic growth rates, growing faster in more productive years. Older siblings grew at a similar rate in all years. Treatment removed the effect of environment on last-hatched chicks, such that all siblings in treated broods grew at a similar rate across environmental conditions. There were no differences in nematode burden between years or siblings, suggesting that variation in responses arose from intrinsic differences between chicks. Whole-brood growth rate was not affected by treatment, indicating that within-brood differences were driven by a change in resource allocation between siblings rather than a change in overall parental provisioning. We show that gastrointestinal parasites can be a key component of offspring's developmental environment. Our results also demonstrate the value of considering prevailing conditions for our understanding of parasite effects on host life-history traits. Establishing how environmental conditions shape responses to parasitism is important as environmental variability is predicted to increase. PMID- 25535559 TI - Genetic and metal analyses of fragmented populations of Betula papyrifera (Marsh) in a mining reclaimed region: identification of population-diagnostic molecular marker. AB - White birch (Betula papyrifera) is an open pollinate species that is, dominant in the Northern Ontario after land reclamation. In fact, this species represents 65% of all trees in the region. We hypothesized that the exchange of genetic information between fragmented populations by range-wide paternal introgression is possible in wind-pollinated species such as B. papyrifera. On the other hand, the effects of heavy metal contamination from the mining activities on plant growth and population dynamics are well documented. The main objectives of this study were (1) to assess the level of genetic variation, gene flow, and population sustainability of B. papyrifera after land reclamation; and (2) to determine the level of phytoavailable metals in soil and their accumulation in trees. We found that B. papyrifera is a Ni and Zn accumulator with a translocation factor of 6.4 and 81, respectively, and an indicator of Cu and Pb. The level of polymorphic loci, Shannon index, Nei's genetic diversity, observed number of alleles, and gene flow were determined for the fragmented populations within the targeted region. The percent of polymorphic loci ranged from 28% to 56%; the gene flow was also low with a value of 0.89, and the population differentiation was very high with a value of 0.36. Two population-diagnostic ISSR markers were identified. They were cloned, sequenced, and converted to SCAR markers. Overall, the fragmented populations of B. papyrifera in Northern Ontario are genetically sustainable based on the moderate level of intrapopulation variability. PMID- 25535558 TI - Demographic histories and genetic diversities of Fennoscandian marine and landlocked ringed seal subspecies. AB - Island populations are on average smaller, genetically less diverse, and at a higher risk to go extinct than mainland populations. Low genetic diversity may elevate extinction probability, but the genetic component of the risk can be affected by the mode of diversity loss, which, in turn, is connected to the demographic history of the population. Here, we examined the history of genetic erosion in three Fennoscandian ringed seal subspecies, of which one inhabits the Baltic Sea 'mainland' and two the 'aquatic islands' composed of Lake Saimaa in Finland and Lake Ladoga in Russia. Both lakes were colonized by marine seals after their formation c. 9500 years ago, but Lake Ladoga is larger and more contiguous than Lake Saimaa. All three populations suffered dramatic declines during the 20th century, but the bottleneck was particularly severe in Lake Saimaa. Data from 17 microsatellite loci and mitochondrial control-region sequences show that Saimaa ringed seals have lost most of the genetic diversity present in their Baltic ancestors, while the Ladoga population has experienced only minor reductions. Using Approximate Bayesian computing analyses, we show that the genetic uniformity of the Saimaa subspecies derives from an extended founder event and subsequent slow erosion, rather than from the recent bottleneck. This suggests that the population has persisted for nearly 10,000 years despite having low genetic variation. The relatively high diversity of the Ladoga population appears to result from a high number of initial colonizers and a high post-colonization population size, but possibly also by a shorter isolation period and/or occasional gene flow from the Baltic Sea. PMID- 25535560 TI - Panmixia defines the genetic diversity of a unique arthropod-dispersed fungus specific to Protea flowers. AB - Knoxdaviesia proteae, a fungus specific to the floral structures of the iconic Cape Floral Kingdom plant, Protea repens, is dispersed by mites phoretic on beetles that pollinate these flowers. Although the vectors of K. proteae have been identified, little is known regarding its patterns of distribution. Seed bearing infructescences of P. repens were sampled from current and previous flowering seasons, from which K. proteae individuals were isolated and cultured. The genotypes of K. proteae isolates were determined using 12 microsatellite markers specific to this species. Genetic diversity indices showed a high level of similarity between K. proteae isolates from the two different infructescence age classes. The heterozygosity of the population was high (0.74 +/- 0.04), and exceptional genotypic diversity was encountered (G = 97.87%). Population differentiation was negligible, owing to the numerous migrants between the infructescence age classes (N m = 47.83) and between P. repens trees (N m = 2.96). Parsimony analysis revealed interconnected genotypes, indicative of recombination and homoplasies, and the index of linkage disequilibrium confirmed that outcrossing is prevalent in K. proteae ([Formula: see text] = 0.0067; P = 0.132). The high diversity and panmixia in this population is likely a result of regular gene flow and an outcrossing reproductive strategy. The lack of genetic cohesion between individuals from a single P. repens tree suggests that K. proteae dispersal does not primarily occur over short distances via mites as hypothesized, but rather that long-distance dispersal by beetles plays an important part in the biology of these intriguing fungi. PMID- 25535561 TI - Integrative tracking methods elucidate the evolutionary dynamics of a migratory divide. AB - Migratory divides, the boundary between adjacent bird populations that migrate in different directions, are of considerable interest to evolutionary biologists because of their alleged role in speciation of migratory birds. However, the small size of many passerines has traditionally limited the tools available to track populations and as a result, restricted our ability to study how reproductive isolation might occur across a divide. Here, we integrate multiple approaches by using genetic, geolocator, and morphological data to investigate a migratory divide in hermit thrushes (Catharus guttatus). First, high genetic divergence between migratory groups indicates the divide is a region of secondary contact between historically isolated populations. Second, despite low sample sizes, geolocators reveal dramatic differences in overwintering locations and migratory distance of individuals from either side of the divide. Third, a diagnostic genetic marker that proved useful for tracking a key population suggests a likely intermediate nonbreeding location of birds from the hybrid zone. This finding, combined with lower return rates from this region, is consistent with comparatively lower fitness of hybrids, which is possibly due to this intermediate migration pattern. We discuss our results in the context of reproductive isolating mechanisms associated with migration patterns that have long been hypothesized to promote divergence across migratory divides. PMID- 25535562 TI - No evidence for induction or selection of mutant sodium channel expression in the copepod Acartia husdsonica challenged with the toxic dinoflagellate Alexandrium fundyense. AB - Some species in the dinoflagellate genus Alexandrium spp. produce a suite of neurotoxins that block sodium channels, known as paralytic shellfish toxins (PST), which have deleterious effects on grazers. Populations of the ubiquitous copepod grazer Acartia hudsonica that have co-occurred with toxic Alexandrium spp. are better adapted than naive populations. The mechanism of adaptation is currently unknown. We hypothesized that a mutation in the sodium channel could account for the grazer adaptation. We tested two hypotheses: (1) Expression of the mutant sodium channel could be induced by exposure to toxic Alexandrium fundyense; (2) in the absence of induction, selection exerted by toxic A. fundyense would favor copepods that predominantly express the mutant isoform. In the copepod A. hudsonica, both isoforms are expressed in all individuals in varying proportions. Thus, in addition to comparing expression ratios of wild type to mutant isoforms for individual copepods, we also partitioned copepods into three groups: those that predominantly express the mutant (PMI) isoform, the wild-type (PWI) isoform, or both isoforms approximately equally (EI). There were no differences in isoform expression between individuals that were fed toxic and nontoxic food after three and 6 days; induction of mutant isoform expression did not occur. Furthermore, the hypothesis that mutant isoform expression responds to toxic food was also rejected. That is, no consistent evidence showed that the wild-type to mutant isoform ratios decreased, or that the relative proportion of PMI individuals increased, due to the consumption of toxic food over four generations. However, in the selected line that was continuously exposed to toxic food sources, egg production rate increased, which suggested that adaptation occurred but was unrelated to sodium channel isoform expression. PMID- 25535563 TI - The effect of call libraries and acoustic filters on the identification of bat echolocation. AB - Quantitative methods for species identification are commonly used in acoustic surveys for animals. While various identification models have been studied extensively, there has been little study of methods for selecting calls prior to modeling or methods for validating results after modeling. We obtained two call libraries with a combined 1556 pulse sequences from 11 North American bat species. We used four acoustic filters to automatically select and quantify bat calls from the combined library. For each filter, we trained a species identification model (a quadratic discriminant function analysis) and compared the classification ability of the models. In a separate analysis, we trained a classification model using just one call library. We then compared a conventional model assessment that used the training library against an alternative approach that used the second library. We found that filters differed in the share of known pulse sequences that were selected (68 to 96%), the share of non-bat noises that were excluded (37 to 100%), their measurement of various pulse parameters, and their overall correct classification rate (41% to 85%). Although the top two filters did not differ significantly in overall correct classification rate (85% and 83%), rates differed significantly for some bat species. In our assessment of call libraries, overall correct classification rates were significantly lower (15% to 23% lower) when tested on the second call library instead of the training library. Well-designed filters obviated the need for subjective and time consuming manual selection of pulses. Accordingly, researchers should carefully design and test filters and include adequate descriptions in publications. Our results also indicate that it may not be possible to extend inferences about model accuracy beyond the training library. If so, the accuracy of acoustic-only surveys may be lower than commonly reported, which could affect ecological understanding or management decisions based on acoustic surveys. PMID- 25535566 TI - A histopathological and biometric comparison between catfish (Pisces, Ariidae) from a harbor and a protected area, Brazil. AB - BACKGROUND: Histopathological lesions and biometric variations in catfish species are statistically associated with chemical contaminant exposure. A histopathological and biometric database for the catfish Sciades herzbergii and Bagre bagre from Sao Luis Island (Port Area) and Caranguejos Island (Reference Area) is presented. Branchial and hepatic lesions were classified into three reaction patterns: 1) circulatory or inflammatory disturbances; 2) regressive changes; 3) progressive changes. This paper summarizes research efforts aimed at characterizing the biomonitoring potential of catfish from two islands in Brazil, which exhibit great habitat diversity and different levels of human intervention. RESULTS: The weights and lengths of the catfish caught at the Port Area were smaller than those from the Reference Area. No histopathological lesions were observed in S. herzbergii examined at the reference site (Caranguejos Island). In contrast, 90% of S. herzbergii from sites located in the Port Area (Sao Luis Island) had one or more types of branchial and hepatic lesions. One or more of the five lesions were observed on 16 B. bagre from Sao Luis Island and Caranguejos Island. CONCLUSION: The utility of histopathological lesions and biometric data as sensitive indicators of the health of wild catfish populations has been demonstrated. Sciades herzbergii proved to be a better species for biomonitoring because it was more sensitive to the impacted site (Port Area) compared with the region relatively free of contaminants (Reference Area). PMID- 25535564 TI - The aging biological clock in Neurospora crassa. AB - The biological clock affects aging through ras-1 (bd) and lag-1, and these two longevity genes together affect a clock phenotype and the clock oscillator in Neurospora crassa. Using an automated cell-counting technique for measuring conidial longevity, we show that the clock-associated genes lag-1 and ras-1 (bd) are true chronological longevity genes. For example, wild type (WT) has an estimated median life span of 24 days, while the double mutant lag-1, ras-1 (bd) has an estimated median life span of 120 days for macroconidia. We establish the biochemical function of lag-1 by complementing LAG1 and LAC1 in Saccharomyces cerevisiae with lag-1 in N. crassa. Longevity genes can affect the clock as well in that, the double mutant lag-1, ras-1 (bd) can stop the circadian rhythm in asexual reproduction (i.e., banding in race tubes) and lengthen the period of the frequency oscillator to 41 h. In contrast to the ras-1 (bd), lag-1 effects on chronological longevity, we find that this double mutant undergoes replicative senescence (i.e., the loss of replication function with time), unlike WT or the single mutants, lag-1 and ras-1 (bd). These results support the hypothesis that sphingolipid metabolism links aging and the biological clock through a common stress response. PMID- 25535567 TI - Magnetic resonance imaging findings in probable Creutzfeld-Jacob disease: comparison with electroencephalography and cerebrospinal fluid characteristics. AB - BACKGROUND: Creutzfeld-Jacob disease (CJD) is a rare, progressive disease that has a vast clinical manifestation range. Cranial magnetic resonance imaging (MRI), electroencephalography (EEG), and measurement of 14-3-3 in cerebrospinal fluid (CSF) may offer a pragmatic approach in the diagnosis of CJD as an alternative to histopathological confirmation. PURPOSE: To present the symptoms and signs of the CJD patients in regard to radiological and neurophysiological findings. MATERIAL AND METHODS: We collected all cases with the diagnosis of probable CJD admitted to our neurology department between June 2010 and June 2014. The medical records and laboratory data, clinical features, results of MRI (including diffusion weighted images), EEG and CSF evaluations, and other laboratory data to exclude other possible diagnoses were recorded. None of the patients underwent biopsy or autopsy for histological diagnosis. RESULTS: Of 20 patients, 11 (55%) were men and nine (45%) were women. The mean age at disease onset was 60.0 +/- 9.5 years (age range, 47-80 years). All patients without exception had characteristic abnormalities in DWI and/or FLAIR on admission, about 4 months after the initial symptom. Periodic complexes on EEGs characteristic for CJD were detected only in 10 patients (50%) on admission and in 13 patients (65%) during disease course. Out of 14 patients who underwent CSF examination, 11 (78.5%) were positive for 14-3-3 protein. CONCLUSION: Although the definite diagnosis of CJD is made histopathologically, we aimed to discuss the value of magnetic resonance imaging in the diagnosis of CJD in respect to EEG findings and protein 14-3-3 levels in CSF. PMID- 25535568 TI - Aberrant internal carotid artery presenting as a retrotympanic vascular mass. AB - We report a case of a young woman with an aberrant right internal carotid artery (ICA) presenting as a retrotympanic reddish mass. This variant of the ICA represents the collateral pathway that is formed as a result of an embryological agenesis of the cervical segment of the ICA. The embryonic inferior tympanic artery is recruited to bypass the absent carotid segment. This hypertrophied vessel may be seen otoscopically and wrongfully considered to be a vascular middle ear tumor. Informing the otorhinolaryngologist of this important vascular variant not only obviates biopsy but also helps in careful preoperative planning of eventual middle ear procedures. PMID- 25535569 TI - A case of a temporal bone meningioma presenting as a serous otitis media. AB - We report the imaging features of a case of a temporal bone meningioma extending into the middle ear cavity and clinically presenting as a serous otitis media. Temporal bone meningioma extending in the mastoid or the middle ear cavity, however, is very rare. In case of unexplained or therapy-resistant serous otitis media and a nasopharyngeal tumor being ruled out, a temporal bone computed tomography (CT) should be performed. If CT findings are suggestive of a temporal bone meningioma, a magnetic resonance imaging (MRI) examination with gadolinium will confirm diagnosis and show the exact extension of the lesion. PMID- 25535570 TI - Imaging features of bilateral breast plasmacytoma as unusual initial presentation of multiple myeloma: case report and literature review. AB - Breast plasmacytoma (BP) is an extremely rare extramedullary manifestation of multiple myeloma (MM). We report the imaging findings of an unusual case in which BP was the initial presentation of MM. A 53-year-old woman with no contributory medical history underwent chest computed tomography to evaluate intermittent nocturnal anterior chest pain, and bilateral multiple breast masses were found. Following an ultrasound-guided core needle biopsy, these lesions were confirmed to be BP. PMID- 25535571 TI - Hepatic capsular retraction: spectrum of diagnosis at MRI. AB - Hepatic capsular retraction is an imaging feature that deserves the attention of the radiologist. Hepatic capsular retraction is associated with a number of hepatic lesions, benign or malignant, treated or untreated. The purpose of this pictorial review is to discuss the most common benign and malignant hepatic lesions associated with this feature with an emphasis on magnetic resonance imaging (MRI). PMID- 25535572 TI - Whole-body MRI as an unconventional diagnostic tool in a pediatric patient with systemic infection. AB - Anaplasma phagocytophilum, an obligate intracellular bacterium, is the causative agent of human granulocytic anaplasmosis (HGA), a tickborne infection usually manifesting as fever, malaise, cytopenia, spleen enlargement, and hepatitis. Herein, we report a case of a 14-year-old girl with HGA whose whole-body magnetic resonance imaging (MRI) disclosed an unusual picture characterized by small, widespread punctuate millimetric nodules, hypointense on T1-weighted and hyperintense on STIR sequences. This firstly reported finding may represent an alternative tool for identifying atypical infectious diseases. PMID- 25535573 TI - Severe complications with irreversible electroporation of the pancreas in the presence of a metallic stent: a warning of a procedure that never should be performed. AB - Irreversible electroporation (IRE) is an ablation technique that is being investigated as a potential treatment of pancreatic cancer. However, many of these patients have a metallic stent in the bile duct, which is recognized as a contraindication for IRE ablation. We report a case in which an IRE ablation in the region of the pancreatic head was performed on a patient with a metallic stent which led to severe complications. After the treatment, the patient suffered from several complications including perforation of the duodenum and transverse colon, and bleeding from a branch of the superior mesenteric artery which eventually lead to her death. Therefore, we believe it is important to be aware of this if an IRE ablation close to a metallic stent is considered. PMID- 25535574 TI - When to do, and when (definitively) not to do an interventional procedure. PMID- 25535575 TI - Thanks. PMID- 25535576 TI - Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia. AB - Medical therapy for Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH) is generally administered for a limited time before surgery. Aberrant receptors antagonists show inconsistent efficacy in the long run to prevent adrenalectomy. We present a patient with BMAH, treated for 10 years with low doses of ketoconazole to control cortisol secretion. A 48-year-old woman presented with headaches and hypertension. Investigations showed the following: no clinical signs of Cushing's syndrome; enlarged lobulated adrenals; normal creatinine, potassium, and aldosterone; normal urinary aldosterone and metanephrines; elevated urinary free cortisol and steroid metabolites; and suppressed plasma renin activity and ACTH. A screening protocol for aberrant adrenal receptors failed to show any illegitimate hormone dependence. Ketoconazole caused rapid normalisation of cortisol and ACTH that persists over 10 years on treatment, while adrenals show no change in shape or size. Ketoconazole decreases cortisol in patients with Cushing's syndrome, and may prevent adrenal overgrowth. Steroid secretion in BMAH is inefficient as compared with normal adrenals or secreting tumours and can be controlled with low, well tolerated doses of ketoconazole, as an alternative to surgery. LEARNING POINTS: Enlarged, macronodular adrenals are often incidentally found during the investigation of hypertension in patients harboring BMAH. Although laboratory findings include low ACTH and elevated cortisol, the majority of patients do not display cushingoid features.Bilateral adrenalectomy, followed by life-long steroid replacement, is the usual treatment of this benign condition, and alternative medical therapy is sought. Therapy based on aberrant adrenal receptors gives disappointing results, and inhibitors of steroidogenesis are not always well tolerated.However, ketoconazole at low, well-tolerated doses appeared appropriate to control adrenal steroid secretion indefinitely, while preventing adrenal overgrowth. This treatment probably constitutes the most convenient long term alternative to surgery. PMID- 25535577 TI - Tuberculosis in the pituitary fossa: a common pathology in an uncommon site. AB - Tuberculosis (TB) is an important cause of mortality and morbidity across the world. In 2-5% of all cases of systemic TB, the C is affected, with lesions reported in the meninges, cortex and ventricles. Intrasellar tuberculomas, however, are extremely rare. We report the interesting case of a young female patient who presented with secondary hypothyroidism and hyperprolactinaemia. She was treated successfully for pituitary TB. We also highlight and discuss some interesting (and hitherto unreported) endocrine issues. Radiological and histological features and treatment of pituitary TB are discussed using this case as an example. LEARNING POINTS: Intrasellar TB continues to be a rare presentation, but incidence and prevalence are expected to grow with increasing numbers of multidrug-resistant TB and shrinking geographical boundaries across the world.Pituitary TB can present with features of a typical adenoma, but has certain radiological and histological features that help to differentiate from an adenoma.Patients can present with a variety of endocrine abnormalities at different times.The presence of an intrasellar mass in individuals at a high risk of developing TB, or with a previous history of systemic TB, should prompt the diagnosis of pituitary TB. In such individuals, it may be worth considering a trial of anti-tuberculous therapy, before considering surgery. PMID- 25535578 TI - Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma? AB - Short-course preoperative radiotherapy (RT) is widely used in northern Europe for locally advanced resectable rectal cancer, but its role in the era of advanced imaging techniques is uncertain. Here, we reviewed articles and abstracts on SCRT published from 1974 through 2013 with the goal of identifying patients who might be best suited for short-course RT. We included relevant articles comparing surgery with or without preoperative radiation published before and after the advent of total mesorectal excision. We also analyzed two randomized trials directly comparing short-course RT with conventionally fractionated chemoradiation (the Polish Colorectal Study Group and the Trans-Tasman Radiation Oncology Group) that compared short-course RT with conventional chemoradiotherapy. We conclude from our review that short-course RT can be generally applied for operable rectal cancer and produces high rates of pelvic control with acceptable toxicity; it reduces local recurrence rates but does not increase overall survival. SCRT seems to be best used for tumors considered "low risk," i.e., those that are >5 cm from the anal margin, without circumferential margin involvement, and involvement of fewer than 4 lymph nodes. Whether sequential chemotherapy can further improve outcomes remains to be seen, as does the best time for surgery (immediately or 6-8 weeks after RT). We further recommend that selection of patients for short-course RT should be based on findings from magnetic resonance imaging or transrectal ultrasonography. PMID- 25535579 TI - Bystander effects and radiotherapy. AB - Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy. PMID- 25535580 TI - Are breast cancer patients treated with radiotherapy younger now than ten years ago? AB - AIM: The aim of the present study was to analyze the age of breast cancer patients managed with curative approach at the time of treatment with radiotherapy. BACKGROUND: Breast cancer is the most frequent neoplasm in women. Little is known with regard to the age of patients at diagnosis, and some authors have suggested that breast cancer is now affecting women who are younger than before. MATERIALS AND METHODS: We performed a descriptive study of our series of breast cancer patients from 1998 to 2011. The age of patients, city of residence, year of treatment and uni- or bilateral location were extracted from the administrative database of the Radiation Oncology Department. The demographical and reference populational data were extracted from the Catalan Institute of Statistics. RESULTS: 3382 patients were obtained. The mean age was 57.79 years. No statistical differences were observed in the mean age during the period of study (p > 0.05), nor in patients with bilateral neoplasias with regard to unilateral tumours (p > 0.5). Patients aged less than 30, 40, 50 and 65 years were 0.3%, 6.3%, 27.0% and 69.1%, respectively. The proportion of patients aged less, equal or more than 40 and 50 years was not statistically different. CONCLUSIONS: Breast cancer patients treated with adjuvant radiotherapy after radical surgery have not experienced significant changes in their mean age at treatment. The subgroups of patients that remain out of the mammographic screening programmes were unchanged as well. The observed differences can be explained by demographical disparities and by a probable increase in the indications for adjuvant radiotherapy. PMID- 25535581 TI - Comparison of two treatment strategies for irradiation of regional lymph nodes in patients with breast cancer: Lymph flow guided portals versus standard radiation fields. AB - AIM AND BACKGROUND: Radiotherapy being an essential part of breast cancer treatment, we evaluate various radiotherapy strategies in patients with breast cancer. MATERIALS AND METHODS: Lymph node (LN) scintigraphy was performed in 172 primary patients with BC. LN visualization started 30-360 min after intratumoral injection of 75-150 MBq of 99mTc-nanocolloids. Our standard recommendation for postoperative radiotherapy in patients with LN invasion by BC were as follows: for patients with external localization of tumour - breast + axillary (Ax) + sub supraclavicular (SSCL) regions; with internal localization - all above + internal mammary nodes (IM). Proposed strategy of lymph flow guided radiotherapy is based on the assumption that only regions that contain 'hot' LNs must be included in a treatment volume. RESULTS: Among 110 patients with external localization of BC, Ax LNs were visualized in all cases and in 62 patients it was the only region with 'hot' LN. Twenty-three patients (20.9%) had drainage to Ax + SSCL, 12 (10.9%) - Ax + IM, 13 (11.8%) - Ax + SSCL + IM regions. After the visualization of lymph flow patterns, standard treatment volume was changed in 87/110 cases (79.1%): in 56.4%, reduced, in 22.7%, enlarged or changed. In 62 patients with tumours in internal quadrants, we revealed the following patterns of lymph-flow: only to the Ax region in 23 (37.1%); Ax + IM, 13 (21%); Ax + SSCL, 15 (24.2%); Ax + IM + ISSCL, 11 (17.7%) cases. After lymph-flow visualization, the standard irradiation volume was reduced in 53/62 (85.5%) cases. CONCLUSION: Visualization of an individual lymph flow pattern from BC can be used for the optimization of standard fields used for irradiation of regional LNs. PMID- 25535582 TI - Brain metastases from stomach cancer - The role of different treatment modalities and efficacy of palliative radiotherapy. AB - AIM: To evaluate different treatment modalities, sequences, and prognostic factors in patients with brain metastases from stomach cancer. BACKGROUND: Brain metastases from gastric cancer are rare and late manifestation of the disease, occurring in less than 1% of gastric cancer patients. The prognosis is poor and median overall survival is 1.3-2.4 months. The standard treatment scheme has not yet been described. Most studies present small sample sizes. The choice of treatment scheme is individually based on performance status, number, location and size of metastases, the status of primary tumor and the presence of other metastases. MATERIALS AND METHODS: Sixteen patients diagnosed with brain metastases from gastric cancer in Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch. Patients, mostly men (69%) aged 51-75 years, (median 68.5 years). Thirteen (81.25%) had treatment of primary tumor before diagnosis of brain metastases. Primary metastatic gastric cancer was diagnosed in 6 patients (37.5%), in 3 cases (18.75%) brain was the site of those metastases. Treatment schemes were individually based. RESULTS: We identified prognostic factors influencing OS: performance status, number of brain metastases, type of treatment. Median OS was 2.8 months. Median time to brain metastases was 12.3 months and it was shorter in patients with pretreatment metastases to other organs. Patients treated with combined treatment had median survival of 12.3 months. CONCLUSIONS: Aggressive treatment schemes are needed to improve the outcome. Prognostic factors such as performance status, number of metastases, dissemination to other organs are helpful in considering the best treatment options. PMID- 25535583 TI - Displacements of fiducial markers in patients with prostate cancer treated with image guided radiotherapy: A single-institution descriptive study. AB - AIM: To describe daily displacements when using fiducial markers as surrogates for the target volume in patients with prostate cancer treated with IGRT. BACKGROUND: The higher grade of conformity achieved with the use of modern radiation technologies in prostate cancer can increase the risk of geographical miss; therefore, an associated protocol of IGRT is recommended. MATERIALS AND METHODS: A single-institution, retrospective, consecutive study was designed. 128 prostate cancer patients treated with daily on-line IGRT based on 2D kV orthogonal images were included. Daily displacement of the fiducial markers was considered as the difference between the position of the patient when using skin tattoos and the position after being relocated using fiducial markers. Measures of central tendency and dispersion were used to describe fiducial displacements. RESULTS: The implant itself took a mean time of 15 min. We did not detect any complications derived from the implant. 4296 sets of orthogonal images were identified, 128 sets of images corresponding to treatment initiation were excluded; 91 (2.1%) sets of images were excluded from the analysis after having identified that these images contained extreme outlier values. If IGRT had not been performed 25%, 10% or 5% of the treatments would have had displacements superior to 4, 7 or 9 mm respectively in any axis. CONCLUSIONS: Image guidance is required when using highly conformal techniques; otherwise, at least 10% of daily treatments could have significant displacements. IGRT based on fiducial markers, with 2D kV orthogonal images is a convenient and fast method for performing image guidance. PMID- 25535584 TI - Adjuvance in refractory keloids using electron beams with a spoiler: Recent results. AB - AIM: To present clinical results of adjuvant irradiation of excised refractory keloid wounds using a novel bolus-free technique developed within our group to irradiate the skin surface with a linear accelerator. BACKGROUND: The use of a bolus to increase surface dose over a newly excised keloid presents several problems. Previous solutions are unsatisfactory. Our technique is promising but needs to be evaluated in practice. MATERIALS AND METHODS: Twenty refractory skin keloids in 19 patients were excised and irradiated in Hospital Plato (Barcelona, Spain) using a 6 MeV electron beam with a 4-mm aluminium spoiler. 15 Gy in fractions of 3 Gy were delivered to the excision site plus a safety margin. All patients were examined during the follow-up (median: 40 months, interval: 12-68 months) and toxicities were recovered. RESULTS: At the end of the follow-up period, 76% of the cases had not recurred, while the complete response rate amounted to 53%. Residual hypertrophic scars were classified as partial responses. After therapy, itching and pain were observed in 30% of the patients, as well as one telangiectasia and two hyperchromatic scars. CONCLUSION: Our technique avoids using a bolus while combining the benefits of electron beam therapy in keloids (fewer secondary effects, and fewer and shorter treatments) with a dose deposition adequate for skin surface treatments. Our results are in line with the most successful therapies evaluated in the literature, as secondary effects are acceptable and recurrence rates are low. PMID- 25535585 TI - The effect of lymphadenectomy and radiotherapy on recurrence and survival in endometrial carcinoma. Experience in a population reference centre. AB - AIM: To evaluate the effect of lymphadenectomy and/or radiotherapy on recurrence and survival patterns in endometrial carcinoma (EC) in a radiotherapy reference centre population. MATERIAL AND METHODS: A retrospective population-based review was conducted on 261 patients with stages I-III EC. Univariate and multivariate analyses were carried out. Both recurrence and survival were analysed according to patient age, FIGO stage, tumour size, myometrial invasion, tumour grade, lymphadenectomy, external beam irradiation (EBI), and brachytherapy (BT). RESULTS: Median age: 64.8 years. Median follow-up: 151 months. The following treatments were administered: surgery, 97.32%; lymph-node dissection, 54.4%; radiotherapy, 162 patients (62%) (EBI and BT: 64.1%, BT alone: 30.2%, EBI alone: 5.6%). Twenty-six patients (9.96%) suffered loco-regional recurrence, whilst 27 (10.34%) suffered distant failure. The 5-year overall survival (OS) for all stages was 80.1%. The 5-year disease free survival (DFS) was 92.1% for all patients. The 10-year DFS was 89.9%. The independent significant prognostic factors for a good outcome identified through the multivariate analysis were: age <75 years (p = 0.001); tumour size <=2 cm (p = 0.003); myometrial invasion <=50% (p = 0.011); lymphadenectomy (p = 0.02); EBI (p = 0.001); and BT (p = 0.031). Toxicity occurred in 114 of the 162 patients who received radiotherapy (70.5%). The toxicity was mainly acute, and late in only 28.3% (n = 45) of cases. The majority experienced G1-2 toxicity, and only 3% of patients experienced G3 late toxicity (5/162). CONCLUSIONS: Our results suggest that age <75 years, tumour size <=2 cm, myometrial invasion <=50%, lymphadenectomy, EBI, and BT, are predictors of a good outcome in EC. PMID- 25535586 TI - A study on the correlation between plan complexity and gamma index analysis in patient specific quality assurance of volumetric modulated arc therapy. AB - AIM: To evaluate the new Octavius 4D system for patient specific quality assurance and to study the correlation between plan complexity and gamma index analysis in patient specific quality assurance of VMAT using the Octavius 4D system. BACKGROUND: McNiven (2010) proposed a study to evaluate the utility of a complexity metric, the Modulation Complexity Score, to evaluate the relationship of the metric with deliverability in IMRT. MATERIALS AND METHODS: Evaluation of the Octavius 4D system was carried out by gamma evaluation of user defined MLC created patterns and AAPM TG 119 benchmark plans. The relationship between plan complexity expressed as Modulation Complexity Score (MCS) and the gamma index analysis was established by a planar and volumetric gamma analysis of 106 clinically approved VMAT patient plans of different sites. RESULTS: Average volumetric 3D global gamma evaluation (3 mm/3%) results for the evaluation plans was 97.41% for 6 MV X-rays and 98.30% for 15 MV X-rays. Average MCS values for the head and neck, pelvic and thoracic plans were 0.2224, 0.3615 and 0.1874. Average volumetric 3D global gamma analysis (3 mm/3%) results for the head and neck, pelvic and thoracic VMAT plans were 95.45%, 97.51% and 96.98%, respectively. Out of 90 correlation analyses between the MCS and gamma passing rate, only 3 had the r value greater than 0.5. CONCLUSIONS: The Octavius 4D system is a suitable device for patient specific pretreatment QA. Global and local gamma analysis results showed a weak correlation with the MCS. PMID- 25535587 TI - Implementation of intensity modulated radiotherapy for prostate cancer in a private radiotherapy service in Mexico. AB - Intensity modulated radiation therapy (IMRT) allows physicians to deliver higher conformal doses to the tumour, while avoiding adjacent structures. As a result the probability of tumour control is higher and toxicity may be reduced. However, implementation of IMRT is highly complex and requires a rigorous quality assurance (QA) program both before and during treatment. The present article describes the process of implementing IMRT for localized prostate cancer in a radiation therapy department. In our experience, IMRT implementation requires careful planning due to the need to simultaneously implement specialized software, multifaceted QA programs, and training of the multidisciplinary team. Establishing standardized protocols and ensuring close collaboration between a multidisciplinary team is challenging but essential. PMID- 25535588 TI - Synchronous primary mammary osteosarcoma and invasive breast cancer. A case report - Pathohistological and immunohistochemical analysis. AB - Primary osteogenic sarcoma of the breast is a rare neoplasm, diagnosed mainly by pathohistological and immunohistochemical analysis. We hereby present a case of primary osteogenic sarcoma in the right breast of a 62-year-old woman with synchronous appearance of an invasive ductal carcinoma. Clinical findings are manifested with two separate painless formations 2.5 cm/2 cm and 1.5 cm/1 cm in size, located on the border of the upper and lower lateral quadrant of the right breast. No axillary lymphadenopathy was diagnosed. The pathohistological and immunohistochemistry findings of both tumors revealed a synchronous manifestation of two distinct neoplasms - epithelial and non-epithelial. Multimodality treatment consisted of Patey's radical mastectomy; 3 cycles of adjuvant chemotherapy; postoperative 50 Gy radiotherapy to the chest wall followed by additional 3 cycles of chemotherapy and anti-estrogen hormonotherapy. Due to the rarity of osteogenic mammary sarcoma, even more so in a combination with epithelial breast tumors, its clinical features are unclear and optimal treatment remains controversial. Considering the poor prognosis of the combination of both malignomas, we discuss a number of diagnostic and therapeutic issues. PMID- 25535589 TI - The experience of melanoma follow-up care: an online survey of patients in australia. AB - Investigating patients' reports on the quality and consistency of melanoma follow up care in Australia would assist in evaluating if this care is effective and meeting patients' needs. The objective of this study was to obtain and explore the patients' account of the technical and interpersonal aspects of melanoma follow-up care received. An online survey was conducted to acquire details of patients' experience. Participants were patients treated in Australia for primary melanoma. Qualitative and quantitative data about patient perceptions of the nature and quality of their follow-up care were collected, including provision of melanoma specific information, psychosocial support, and imaging tests received. Inconsistencies were reported in the provision and quality of care received. Patient satisfaction was generally low and provision of reassurance from health professionals was construed as an essential element of quality of care. "Gaps" in follow-up care for melanoma patients were identified, particularly provision of adequate psychosocial support and patient education. Focus on strategies for greater consistency in the provision of support, information, and investigations received, may generate a cost dividend which could be reinvested in preventive and supportive care and benefit patient well-being. PMID- 25535591 TI - Validation of a whole slide imaging system for primary diagnosis in surgical pathology: A community hospital experience. AB - Guidelines for validating whole slide imaging (WSI) for primary diagnosis in surgical pathology have been recommended by an expert panel commissioned by the College of American Pathologists. The implementation of such a system using these validation guidelines has not been reported from the community hospital setting. The objective was to implement a WSI system, validate each pathologist using the system and run the system in parallel with routine glass slide interpretation. Six pathologists re-reviewed approximately 300 previously diagnosed specimens each, divided equally between glass slides and digital images (scanned at *20). Baseline intraobserver discordance rates (glass to glass) were calculated and compared to discordance rates between the original glass slide interpretation and the reviewed digital slide interpretation. A minimum of 3 months was used as the washout period. After validation, a subset of daily cases was diagnosed in parallel using traditional microscopy (TM) and WSI over an 8-month period. The TM and WSI discordance rates ranged from 3.3% to 13.3% and 2.1% to 10.1%, respectively. There was no statistically significant difference among the pathologists. The parallel study yielded similar rates of discordances. In our laboratory, after appropriate implementation and training, there was no difference between the WSI and TM methods. PMID- 25535590 TI - Molecular Characterization of Sudanese and Southern Sudanese Chicken Breeds Using mtDNA D-Loop. AB - The objective of this study was to assess the genetic relationships and diversity and to estimate the amount of gene flow among the five chicken populations from Sudan and South Sudan and commercial strain of egg line White Leghorn chickens. The chicken populations were genotyped using mtDNA D-loop as a molecular marker. PCR product of the mtDNA D-loop segment was 600 bp and 14 haplotypes were identified. The neighbor-joining phylogenetic tree indicated that the indigenous Sudanese chickens can be grouped into two clades, IV and IIIa only. Median joining networks analysis showed that haplotype LBB49 has the highest frequency. The hierarchal analysis of molecular variance (AMOVA) showed that genetic variation within the population was 88.6% and the differentiation among the population was 11.4%. When the populations was redefined into two geographical zones, rich and poor Savanna, the results were fractioned into three genetic variations: between individuals within population 95.5%, between populations within the group 0.75%, and genetic variation between groups 3.75%. The pair wise F st showed high genetic difference between Betwil populations and the rest with F st ranging from 0.1492 to 0.2447. We found that there is large number of gene exchanges within the Sudanese indigenous chicken (Nm = 4.622). PMID- 25535592 TI - 21(st) century workflow: A proposal. AB - Digital pathology is rapidly developing, but early systems have been slow to gain traction outside of niche applications such as: Second-opinion telepathology, immunostain interpretation, and intraoperative telepathology. Pathologists have not yet developed a well-articulated plan for effectively utilizing digital imaging technology in their work. This paper outlines a proposal that is intended to begin meaningful progress toward achieving helpful computer-assisted pathology sign-out systems, such as pathologists' computer-assisted diagnosis (pCAD). pCAD is presented as a hypothetical intelligent computer system that would integrate advanced image analysis and better utilization of existing digital pathology data from lab information systems. A detailed example of automated digital pathology is presented, as an automated breast cancer lymph node sign-out. This proposal provides stakeholders with a conceptual framework that can be used to facilitate development work, communication, and identification of new automation strategies. PMID- 25535593 TI - Guest editor's message: aloha kakou! PMID- 25535594 TI - Impact of diabetes on prolonged hospital stay among Native Hawaiians and other Pacific Islanders with ischemic stroke. AB - Recent evidence suggests that minority groups have prolonged hospital stays after ischemic stroke. However, disparities in the hospital stay after ischemic stroke among Native Hawaiians and other Pacific Islanders (NHPI) have not been studied. A retrospective study on consecutive patients hospitalized for ischemic stroke at a single tertiary center in Honolulu between 2008 and 2010 was performed. Logistic regression analyses were performed to assess the independent predictors of prolonged hospital stay (hospitalization > 12 days after admission) after ischemic stroke. A total of 740 patients (whites 22%, Asians 53%, NHPI 21%, others 4%) hospitalized for ischemic stroke were studied. NHPI were significantly younger (59 +/- 14 years vs 72 +/- 13 years) and had significantly higher prevalence of female sex (51% vs 38%), no insurance (10% vs 4%), diabetes (53% vs 18%), hypertension (82% vs 62%), obesity (55% vs 20%) and prolonged hospital stay (20% vs 11%), and lower prevalence of residence outside of O'ahu (12% vs 23%) compared to whites. Univariate analyses showed that NHPI were more likely to have prolonged hospital stay (OR 1.87, 95% CI: 1.01, 3.49) compared to whites. After adjusting for age, sex, race, risk factors, health insurance status, and geographical factor, diabetes (OR 1.76, 95% CI: 1.07, 2.89) was the only independent predictor of prolonged hospital stay. NHPI are associated with prolonged hospitalization after ischemic stroke. However, this effect was attenuated by the impact of diabetes. Further prospective studies are needed to understand the relationship between diabetes and prolonged hospital stay after ischemic stroke. PMID- 25535595 TI - Disparities in diabetes-related preventable hospitalizations among working-age Native Hawaiians and Asians in Hawai'i. AB - Elderly (65+) Native Hawaiian, Filipino, and Japanese men and Filipino women have a higher risk of diabetes-related potentially preventable hospitalizations than Whites even when demographic factors and the higher diabetes prevalence in these populations is considered. The study objective was to determine if similar disparities are seen among the non-elderly (< 65). We used discharge data for all non-maternity hospitalizations by working-age adults (18-64 years) in Hawai'i from December 2006 to December 2010. Annual diabetes-related preventable hospitalization rates (by population diabetes prevalence) were compared by race/ethnicity (Japanese, Chinese, Native Hawaiian, Filipino, and White) and gender. Adjusted rate ratios (aRR) were calculated relative to Whites using multivariable models controlling for insurer, comorbidity, residence location, and age. After adjusting for ethnic-specific prevalence of diabetes and demographic factors, preventable hospitalizations rates were significantly higher for Native Hawaiians males (aRR:1.48; 95%CI:1.08-2.05) compared to Whites, but significantly lower for Chinese men (aRR:0.43;95%CI:0.30-0.61) and women (aRR:0.18;95%CI: 0.08-0.37), Japanese men (aRR:0.33;95%CI: 0.25-0.44) and women (aRR:0.34; 95%CI:0.23-0.51), and Filipino men (aRR:0.35;95%CI:0.28-0.43) and women (aRR:0.47;95%CI: 0.36-0.62). Rates for Native Hawaiian females did not differ significantly from Whites. Disparities in diabetes-related preventable hospitalizations were seen for working-age (18-64) Native Hawaiian men even when their higher population-level diabetes prevalence was considered. Further research is needed to determine factors affecting these disparities and to develop targeted interventions to reduce them. Significantly lower preventable hospitalization rates were seen among Asian groups compared to Whites. A better understanding of these findings may provide guidance for improving rates among Asian elderly as well as other non-elderly groups with disparities. PMID- 25535596 TI - Association of modifiable risk factors and left ventricular ejection fraction among hospitalized Native Hawaiians and Pacific Islanders with heart failure. AB - BACKGROUND: Heart failure (HF) disproportionately affects Native Hawaiians and Other Pacific Islanders (NHOPIs). This study examines risk factors associated with left ventricular ejection fraction (LVEF) among 151 hospitalized NHOPI HF patients enrolled at a single tertiary care hospital between June 2006 and April 2010. METHODS: Enrollment criteria: (1) NHOPI by self-identification. (2) Age >= 21 yrs. (3) Diagnosis of HF defined: (a) left ventricular ejection fraction (LVEF) <= 40% or LVEF <= 60% with abnormal diastolic function and (b) classic HF signs/symptoms. LVEF was measured by echocardiography within 6 weeks of hospitalization. Clinical measures, medical history, and questionnaires were assessed using standardized protocols. Linear regression modeling was used to examine the association of significant correlates of LVEF, which were then included en bloc into the final model. A P-value < .05 was considered statistically significant. RESULTS: Of 151 participants, 69% were men, mean age 54.3 +/- 13.5 years, blood pressure 112 +/- 20/69 +/- 15 mmHg, and body mass index (BMI) 36.9 +/- 9 kg/m(2). Twenty-five percent of participants were smokers, 45% used alcohol and 23% reported a history of methamphetamine use. Clinically, 72% had hypertension, 49% were diabetic and 37% had a prior myocardial infarction. Nearly 60% had moderate to severe LVEF (< 35%). Higher LVEF was independently associated with female sex and greater BMI (P < .04) while pacemaker/defibrillator and methamphetamine use was independently associated with lower LVEF (P < .05). CONCLUSIONS: Methamphetamine use and BMI may be important modifiable risk factors associated with LVEF and may be important targets for improving HF morbidity and mortality. PMID- 25535598 TI - Case report from the field: integrating Hawaiian and Western healing arts in Papakolea. AB - Papakolea, the only Native Hawaiian (NH) homestead community located in urban Honolulu, has one of the highest proportions of NHs living in a single geographic area. Despite prior attempts dating back to the 1920s to improve the health of the community, many health disparities remain within the Papakolea community. This is the story of how the Papakolea community decided to confront the health of its community by integrating Hawaiian and Western healing arts. The purpose of this "Case Report from the Field" is to share the journey the Papakolea community started back in 1992 to build capacity within their own community by forming its first 501c3 community based non-profit organization entitled Kula no na Po'e Hawai'i (referred to as Kula). Through Kula, a unique traditional healing training program was started called Na Lomilomi O Papakolea (NLOP). NLOP became the first self-sustaining health program for training lomilomi practitioners (traditional NH therapeutic massage) in the Papakolea community. This case report describes how lomilomi practitioners and medical practitioners began sharing their skills and expertise to heal their clients and in the process began to heal the community itself. The purpose of this paper is to describe their journey with the intent of sharing how one dedicated group of people has been successful in healing their community and is now on the road to better health and sustained well being by working together. PMID- 25535597 TI - Kumu hula perspectives on health. AB - To prepare for research studies that would evaluate the impact of hula as part of a clinical intervention, including cardiovascular disease (CVD) prevention and management programs, kumu hula defined as "culturally recognized hula educators and experts," were interviewed. Investigators sought to elicit their views regarding hula's traditional and contemporary connections to health and well being, assess the cultural appropriateness of such projects, and suggest ways to maintain hula's cultural integrity throughout clinical intervention programs. Six prominent kumu hula from five different Hawaiian Islands participated in semi structured key informant interviews lasting between 60 and 90 minutes. Each was asked open-ended questions regarding their attitudes, beliefs, and experiences regarding the connections of hula to health as well as their recommendations on maintaining the integrity of the dance's cultural traditions when developing and implementing a hula-based CVD program. All kumu hula endorsed the use of hula in a CVD intervention program and articulated the strong, significant, and enduring connections of hula to health and well-being. Each kumu hula also recognized that health is the full integration of physical, mental, emotional, and spiritual well being. When care is taken to preserve its cultural integrity, hula may be an effective integrated modality for interventions designed to improve health and wellness. PMID- 25535599 TI - The PILI 'Ohana Project: a community-academic partnership to achieve metabolic health equity in Hawai'i. AB - Native Hawaiians and Pacific Islanders (NHPI) have higher rates of excess body weight and related medical disorders, such as diabetes and cardiovascular disease, compared to other ethnic groups in Hawai'i. To address this metabolic health inequity, the Partnership for Improving Lifestyle Intervention (PILI) 'Ohana Project, a community-academic partnership, was formed over eight years ago and developed two community-placed health promotion programs: the PILI Lifestyle Program (PLP) to address overweight/obesity and the Partners in Care (PIC) to address diabetes self-care. This article describes and reviews the innovations, scientific discoveries, and community capacity built over the last eight years by the PILI 'Ohana Project's (POP) partnership in working toward metabolic health equity. It also briefly describes the plans to disseminate and implement the PLP and PIC in other NHPI communities. Highlighted in this article is how scientific discoveries can have a real-world impact on health disparate populations by integrating community wisdom and academic expertise to achieve social and health equity through research. PMID- 25535600 TI - Addressing health disparities by building organizational capacity in the community: a case study of the Wai'anae Coast Comprehensive Health Center. AB - Native Hawaiians and other residents living in economically disadvantaged communities suffer disproportionately from many health conditions, especially chronic diseases. Reversing this trend requires a comprehensive approach encompassing more than just improvement in healthcare delivery. Indeed, societal changes at multiple levels must occur, including environmental, systems, and policy change, in order to bring about sustainable improvements in community health and wellness. A key strategy to accomplish these upstream changes is an increase in the capacity of community-based organizations to provide leadership in health advocacy, support community health promotion, prioritize resource allocation, and participate in community health research. In disadvantaged communities where health disparities are the most severe, community health centers (CHC) are well positioned to take a pivotal role in these efforts. This report is a case study to describe processes taking place at Hawai'i's largest CHC to build organizational capacity and bring about upstream changes that improve community health and wellness. Ongoing processes at the CHC include (1) Institutional: commitment to address health disparities, expand the CHC research infrastructure, and develop a comprehensive worksite wellness program (2) Collaborative: development of a network of community partners committed to the common goal of improving the health and wellness of community residents, and (3) Systems and Policy: activities to strengthen the CHC's and community's ability to influence systems changes and policies that reduce health disparities. Preliminary results are encouraging although the processes and timelines involved require a long-term commitment in order to affect tangible results that can be measured. PMID- 25535601 TI - Ebola virus infection: what should be known? AB - Ebola virus infection is the present global consideration. This deadly virus can result in a deadly acute febrile hemorrhagic illness. The patient can have several clinical manifestations. As a new emerging infection, the knowledge on this infection is extremely limited. The interesting issues to be discussed include a) the atypical clinical presentation, b) new diagnostic tool, c) new treatment, and d) disease prevention. Those topics will be discussed in this special review. PMID- 25535602 TI - Awareness of Forensic Odontology among Legal Professionals, Chennai, India. AB - BACKGROUND: The forensic discipline of law is a multidisciplinary team comprising of specialists in forensic medicine, forensic odontology, security and law. AIM: The study was to find the awareness level of scope and utility of forensic odontology among lawyers in Chennai, South India. MATERIALS AND METHODS: A cross sectional study using a self administered structured questionnaire was conducted in 200 lawyers between August and September of 2013. The data was analyzed depending on age, gender, type and years of practice. RESULTS: Lawyers above 40 years of experience were more aware of palatal rugae analysis (P = 0.02), and those with more than 20 years were aware of lip print (P = 0.001) and bite mark analysis (P = 0.001). Males were more aware of forensic odontology with respect to criminal identification (P = 0.001). The knowledge of bite mark analysis was higher among male lawyers (P = 0.001), civil and criminal practicing lawyers (P = 0.004). All participants were aware that loss or fracture of tooth constitutes a grievous injury under Indian Penal Code (IPC) 320 clause 7(5). CONCLUSION: This study highlighted the knowledge of forensic odontology among legal professionals and also identified the areas in which they need further appraisal. PMID- 25535604 TI - Laparoscopic cholecystectomy under epidural anesthesia: a feasibility study. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is normally performed under general anesthesia. But of late this operation has been tried under regional anesthesia successfully without any added complications like epidural anesthesia. AIMS: The aim of the study was to study the feasibility of performing LC under epidural anesthesia in normal patients so that the benefits could be extended to those high-risk patients having symptomatic gallstone disease and compromised cardio pulmonary status where general anesthesia is contraindicated. MATERIALS AND METHODS: In all, 20 patients with the American Society of Anesthesiologist's class I or II were enrolled in the study. The level of epidural block and satisfaction score, both for the patient and the surgeon, were noted in the study. RESULTS: The LC was performed successfully under epidural anesthesia in all but two patients who had severe shoulder pain in spite of giving adequate analgesia and were converted to general anesthesia. CONCLUSIONS: The LC can be performed safely under epidural anesthesia with understanding between patient and surgeon. However, careful assessment of complications in the patients should be done to make the procedure safer. PMID- 25535603 TI - Genetic Variants of Interleukin-10 Gene Promoter are Associated with Schizophrenia in Saudi Patients: A Case-Control Study. AB - BACKGROUND: Interleukin-10 (IL-10) gene is considered as a potential candidate gene in schizophrenia association studies. The polymorphisms on IL-10 gene have been reported to be linked with susceptibility to the development of schizophrenia within consistent results. AIMS: The aim of this case-control study was to examine whether the -1082A/G, -819T/C, and -592A/C polymorphisms in IL-10 gene are implicated in schizophrenia development in the Saudi population. MATERIALS AND METHODS: Molecular genotyping of IL-10 gene polymorphisms was performed to analyze the genotypes and alleles distribution of three single nucleotide polymorphisms (SNPs) in patients (n = 181) and healthy individuals as control group (n = 211). RESULTS: The frequencies of GA genotype at -1082, and CC genotype at positions -592 and -819 were significantly higher in schizophrenia patients compared to healthy subjects suggesting that GA, CC, and CC genotypes are susceptible to schizophrenia. The ACC haplotype known to be associated with intermediate production of IL-10 are more prevalent in our schizophrenia patients. On the other hand, genotypes -1082 GG, -819 CT, and -592 CA of IL-10 were more prevalent in healthy controls suggesting protective effects of GA, CT, and CA genotypes against schizophrenia. There was no significant association of IL-10 polymorphisms with sex or positive or negative symptoms of schizophrenia. CONCLUSION: This study indicates that the IL-10 gene polymorphisms play a significant role in the etiology of schizophrenia in Saudi Arabians patients. PMID- 25535606 TI - Association between fecal incontinence and objectively measured physical activity in u.s. Adults. AB - BACKGROUND: Brisk physical activity may facilitate fecal incontinence due to physical activity-induced colonic motility. However, there currently are no studies that have examined the relationship between fecal incontinence and free living physical activity behavior. AIM: Therefore, the purpose of this study was to examine the association between fecal incontinence and objectively measured physical activity among adults. MATERIALS AND METHODS: A national sample of adults in the United States (n = 2565, 20-85 years) completed the Fecal Incontinence Severity Index questionnaire and wore an accelerometer for a week to objectively measure physical activity behavior. RESULTS: After adjustments, fecal incontinence was positively associated with moderate-to-vigorous physical activity (beta = 0.85, P = 0.04), suggesting that lower perceived severity of fecal incontinence was associated with greater engagement in moderate-to-vigorous physical activity. Fecal incontinence was not significantly associated with light intensity physical activity (P = 0.27). CONCLUSION: Our results suggest that adults in the United States with greater perceived severity of fecal incontinence engage in less moderate-to-vigorous physical activity; however, those with greater severity of fecal incontinence do not appear to have different levels of light-intensity physical activity behavior. Given the emerging research showing beneficial effects of light-intensity physical activity, health care professionals should encourage light-intensity physical activity to their patients with fecal incontinence. PMID- 25535605 TI - Psychosocial characteristics of oromucosal diseases in psychiatric patients: observational study from Indian dental college. AB - BACKGROUND: Psychiatric diseases like anxiety, depression, schizophrenia and bipolar disorders can affect the mental and physical statuses of an individual. AIM: The study was to investigate the different oromucosal diseases (OMD) in psychiatric patients and to evaluate the correlation between these OMD to severity of anxiety and depression. MATERIALS AND METHODS: A cross-sectional study was carried out during a six-month period. Patients reporting to psychiatry department with anxiety, depression, schizophrenia and bipolar disorder as diagnosed by an experienced psychiatrist, were subjected to complete oral examination by a skilled oral diagnostician to check for OMD like oral lichen planus (OLP), aphthous stomatitis (AS) and burning mouth syndrome (BMS). During the above mentioned time interval, 1320 patients with any of the above mentioned psychiatric diseases were included in this study. Of these, 278 had anxiety, 398 had depression, 295 had schizophrenia and 349 had bipolar disorder. Equal number of individuals reported to the Oral Medicine and Radiology department for routine oral screening with no mucosal diseases were included as control group. RESULTS: In this study, statistically significant increase in the OMD of the psychiatric patients was recorded when compared with the control group. The OMD were significantly higher in patients with anxiety (20.86%) followed by patients with depression (9.04%), schizophrenia (7.7%), bipolar disorder (7.4%) and control group (5.17%), respectively. Most prevalent OMD in patients with anxiety was AS (12%) followed by OLP (5.7%), and BMS (2.87%) respectively. Patients with moderate to severe anxiety and depression showed significantly higher prevalence of these OMD compared to the ones with mild anxiety and depression. The AS and OLP were significantly more in the younger age group (18-49 year) and BMS was higher in 50-77 year age group in both the study and control groups. CONCLUSION: A positive association was established between psychological alterations and OMD. Emotional alterations may act as a precipitating factor that could influence the initiation and development of different OMD. Hence, better harmonization is essential between dentist and psychiatrists for comprehensive management of psychosomatic disorders of the oral mucosa. PMID- 25535608 TI - An endocrine hypothesis for the genesis of atrial fibrillation: the hypothalamic pituitary-adrenal axis response to stress and glycogen accumulation in atrial tissues. AB - BACKGROUND: The underlying role of intracellular glycogen in atrial fibrillation is unknown. Experimental models developed in the goat have shown an increase of intracellular glycogen concentration in atrial myocytes resulting from prolonged pacing induced atrial fibrillation (AF). These observed glycogen molecules are as a result of structural remodeling and are known to replace the intracellular myofibrils causing myolysis in studies done in different animal models. The accumulation of glycogen is progressively and directly related to the duration of pacing-induced AF. Similar responses have been seen in clinically derived atrial tissues. AIMS: We intend to present an endocrine hypothesis supported by published evidence that stress acting through the hypothalamic-pituitary-adrenal axis (HPA) is a contributing metabolic factor responsible for the increase of glucose levels via the hormone cortisol. This excess glucose is then metabolized by the myocytes during each heart beat and stored as glycogen. A literature search was done, and published evidence supporting stress was shown to be the main factor for the formation of glucose leading to glycogen deposition to in the cardiac myocytes. RESULTS: Stress on the HPA axis stimulates the adrenal glands to release the hormone cortisol in the blood stream; this in turn increases the cardiac tissue glycogen concentration. It is also known that during each beat, excess glucose is removed by the myocytes and stored as glycogen. As aforementioned, in the cardiac myocytes, dense glycogen content with/without loss of myofibrils has been detected in both human and animal models of AF. CONCLUSIONS: We hypothesize that the increase of the intrinsic glycogen concentration and distribution is a result of a metabolic disruption caused by stress through the HPA Axis. For example, in atrial myocytes, the glycogen molecules impede the normal intercellular communications leading to areas of slow conduction favoring reentrant-based AF. PMID- 25535607 TI - The Risk of Coronary Heart Disease in Patients with Kidney Stones: A Systematic Review and Meta-analysis. AB - BACKGROUND: The reported risk of coronary heart disease (CHD) in patients with a history of kidney stones is conflicting. AIMS: The objective of this meta analysis was to assess the association between a history of kidney stones and CHD risk. MATERIALS AND METHODS: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception until April 04, 2014. Studies that reported odds ratios or hazard ratios comparing the risk of CHD in patients with a history of kidney stones versus those without a history of kidney stones were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Seven study populations from four cohort studies and one cross sectional study were identified and included in the data analysis. The pooled risk ratio (RR) of CHD in patients with kidney stones was 1.24 (95% CI, 1.10 1.40). This result remained significant (RR, 1.23 [95% CI, 1.08-1.41]) when the sensitivity analysis was restricted to only cohort studies. A history of kidney stones was associated with increased CHD risk in females (RR, 1.43 [95% CI, 1.12 1.82]), whereas the association was not significant in males (RR, 1.14 [95% CI, 0.94-1.38]). CONCLUSIONS: Our study demonstrates a statistically significant increased risk of CHD in female patients with prior kidney stones. This finding suggests that a history of kidney stones is a risk factor for CHD in females and may impact clinical management. PMID- 25535609 TI - Rapid Response of Long-Standing, Treatment-Resistant Non-Catatonic Mutism in Paranoid Schizophrenia with Single ECT session. AB - CONTEXT: Mutism is a common manifestation of catatonia, but mutism due to other forms of psychopathology and neurological disorders have also been described. Although not common, long-standing mutism has also been a feature of non catatonic schizophrenia and traditionally responds less to conventional therapies. CASE REPORT: We describe a rare case of paranoid schizophrenia presenting with continuous mutism for about 4 years. This 26-year-old male had symptoms of schizophrenia without catatonia. After failed trial of adequate pharmacotherapy and psychological intervention and considering his level of dysfunction, he was started on electroconvulsive therapy (ECT). To our surprise, he improved with a single session of ECT while he was on concurrent pharmacotherapy. We also discuss the possible explanation for this rapid effect of ECT in such clinical presentation. To our knowledge, this is the first case of non-catatonic mutism of schizophrenia of this long duration responding so promptly to ECT, although there are other reports as well in literature, but multiple ECT sessions were applied in those cases. CONCLUSION: Non-catatonic mutism is perhaps presenting as a cultural variant in this part of the world and whenever encountered, ECT should be an option. Further research should be carried out to validate this idea. PMID- 25535610 TI - Unexplained facial scar: child abuse or ehlers-danlos syndrome? AB - CONTEXT: Child abuse is a serious problem, and its physical manifestations can be mimicked by certain diseases and conditions. These conditions can include genetic, congenital and other disorders that may result in poor weight gain, bone fractures or skin lesions that look like bruises or burns. CASE REPORT: This paper reports the case of a seven-year-old girl with Ehlers-Danlos Syndrome (EDS), which was misdiagnosed as child abuse. This child was referred to us for treatment of an unexplained facial scar that was alleged to be the result of child abuse. CONCLUSION: When unusual skin presentations are observed, dermatologists should consider the possibility of child abuse to protect the child. Furthermore, they should be aware of the cutaneous abnormalities that mimic injuries associated with abuse to avoid the unnecessary reporting of child abuse. PMID- 25535611 TI - Perforated jejunal diverticulum in the use of mycophenolate mofetil. AB - CONTEXT: Jejunal diverticulosis is a rare disease. Common acute complications include diverticulitis, intestinal obstruction, bleeding and perforation. Gastrointestinal tract perorations have also been rarely observed in the use of mycophenolate mofetil. CASE REPORT: We report a 44-year-old man with end-stage renal disease post failed kidney transplant on low-dose mycophenolate mofetil who presented with acute onset of abdominal pain. He was successfully given the diagnosis of perforated jejunal diverticulum. The patient successfully underwent a segmental jejunal resection and anastomosis. He unfortunately developed a recurrent jejunal perforation a month later and again had the second segmental jejunal resection operation. Mycophenolate mofetil then was discontinued. CONCLUSION: The present case illustrates jejunal diverticulum perforation in the use of mycophenolate mofetil. Physicians should increase the awareness of this association of perforated jejunal diverticulum in patients using mycophenolate mofetil. PMID- 25535612 TI - Inferior vena cava anomaly: a risk for deep vein thrombosis. AB - CONTEXT: Inferior vena cava (IVC) anomalies have a 0.5% incidence rate and could be associated with other congenital abnormalities. In later stage of the disease, trophic ulcers with or without deep vein thrombosis (DVT) is consistent finding. CASE REPORT: A 29-year-old male patient presented with recurrent lower extremity ulcers. Further workup revealed an absent infrahepatic inferior vena cava, prominently dilated azygos and hemiazygos veins with enlarged retroperitoneal collaterals without DVT. CONCLUSION: IVC anomaly should be suspected in a young patient presenting with unexplained venous thrombosis and recurrent ulcers of a lower extremity. IVC anomaly would inherently lead to blood flow stasis and endothelial injury. Thus per Virchow's triad, other risk factors for hypercoagulability such as physical inactivity, smoking tobacco, oral contraceptive pills should be avoided and when hereditary thrombophilias or other irreversible risk factors are present, lifelong anticoagulation should be considered. PMID- 25535613 TI - Levels of soluble E-cadherin in breast, gastric, and colorectal cancers. AB - Soluble E-cadherin is a 80 kDa protein fragment coming from the proteolytic cleavage of the extracellular domain of the full length epithelial cadherin, a molecule involved in cell adhesion/polarity and tissue morphogenesis. In comparison with normal epithelia, cancer cells show a decreased cadherin-mediated intercellular adhesion, and sE-cad levels normally increase in body fluids (blood and urine). This review focuses on soluble E-cadherin in sera of patients affected by three solid cancers (breast, gastric, and colorectal cancers) and how its levels correlate or not with some cancer parameters (e.g., dimension, progression, and localisation). We will describe the main proteomics approaches adopted to measure sE-cad both in vivo and in vitro and the most important findings about its behaviour in cancer dynamics. PMID- 25535614 TI - Efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic osteonecrosis. AB - The purpose of the current review was to determine the efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic avascular osteonecrosis of femoral head (ANFH). Five randomized controlled trials (RCTs) involving 305 hips were included in this review, of which 3 studies investigated alendronate versus control/placebo and the other 2 studies compared the combination of alendronate and extracorporeal shockwave therapy (ESWT) with ESWT alone. Our results suggested that even the patients with extensive necrosis encountered much less collapse in the alendronate group than control group. In these RCTs, their data also indicated a positive short- and middle-term efficacy of alendronate treatment in joint function improvement and hip pain diminishment. With the presence of the outlier study, only insignificant overall efficacy of alendronate could be observed with substantial heterogeneities. In addition, we did not find any additive benefits of alendronate in combination with ESWT for preventing collapse compared to ESWT alone. In conclusion, there is still lack of strong evidence for supporting application of alendronate in adult patients with nontraumatic ANFH, which justified that large scale, randomized, and double-blind studies should be developed to demonstrate the confirmed efficacies, detailed indication, and optimized strategy of alendronate treatment. PMID- 25535615 TI - Different angiogenic abilities of self-setting calcium phosphate cement scaffolds consisting of different proportions of fibrin glue. AB - To investigate the different angiogenic abilities of the self-setting calcium phosphate cement (CPC) consisting of different proportions of fibrin glue (FG), the CPC powder and the FG solution were mixed at the powder/liquid (P/L) ratios of 1 : 0.5, 1 : 1, and 1 : 2 (g/mL), respectively, and pure CPC was used as a control. After being implanted into the lumbar dorsal fascia of the rabbit, the angiogenic process was evaluated by histological examination and CD31 immunohistochemistry to detect the new blood vessels. The result of the new blood vessel showed that the P/L ratio of 1 : 1 group indicated the largest quantity of new blood vessel at 4 weeks, 8 weeks, and 12 weeks after implantation, respectively. The histological evaluation also showed the best vascular morphology in the 1 : 1 group at 4 weeks, 8 weeks, and 12 weeks after the operation, respectively. Our study indicated that the CPC-FG composite scaffold at the P/L ratio of 1 : 1 (g/mL) stimulated angiopoiesis better than any other P/L ratios and has significant potential as the bioactive material for the treatment of bone defects. PMID- 25535618 TI - What pharmacy practitioners need to know about ethics in scientific publishing. AB - Pharmacy practice is an ever-changing science and profession. We are witnessing many advancement of pharmacy technology, drug-related information and applied clinical pharmacy literature, which influence our every day's life. Thus, new knowledge generated by research and clinical experience widen the knowledge; change the understanding of drugs and their application in therapeutics and every days life. Thus, policy makers, pharmacists, clinicians and researchers must evaluate and use the information existing in the literature to implement in their healthcare delivery. This paper is prepared for pharmacy researchers and pharmacy students and analyzes the major principles of ethical conduct in general science and also closely related topics on ghost authorship, conflict of interest, assigning co-authorship, redundant/repetitive and duplicate publication. Furthermore, the paper provides an insight into fabrication and falsification of data, as the most common form of scientific fraud. Scientific misconduct goes against everything that normal scientific method wants to reach for and pharmacy practitioners as one the first line available health care professionals all round the world should be enough aware of its importance and details when they want to evaluate the medical and pharmaceutical literature and deliver unbiased and ethically published knowledge of drugs both for the research or during consultations for patients care. PMID- 25535617 TI - Can Pharmacy Doctors act as valuable assets in rural areas with a physician shortage? PMID- 25535616 TI - On the feasibility of utilizing allogeneic bone blocks for atrophic maxillary augmentation. AB - PURPOSE: This systematic review was aimed at assessing the feasibility by means of survival rate, histologic analysis, and causes of failure of allogeneic block grafts for augmenting the atrophic maxilla. MATERIAL AND METHODS: A literature search was conducted by one reviewer in several databases. Articles were included in this systematic review if they were human clinical trials in which outcomes of allogeneic bone block grafts were studied by means of survival rate. In addition other factors were extracted in order to assess their influence upon graft failure. RESULTS: Fifteen articles fulfilled the inclusion criteria and subsequently were analyzed in this systematic review. A total of 361 block grafts could be followed 4 to 9 months after the surgery, of which 9 (2.4%) failed within 1 month to 2 months after the surgery. Additionally, a weighed mean 4.79 mm (95% CI: 4.51-5.08) horizontal bone gain was computed from 119 grafted sites in 5 studies. Regarding implant cumulative survival rate, the weighed mean was 96.9% (95% CI: 92.8-98.7%), computed from 228 implants over a mean follow-up period of 23.9 months. Histologic analysis showed that allogeneic block grafts behave differently in the early stages of healing when compared to autogenous block grafts. CONCLUSION: Atrophied maxillary reconstruction with allogeneic bone block grafts represents a reliable option as shown by low block graft failure rate, minimal resorption, and high implant survival rate. PMID- 25535619 TI - A two-year utilization of the pharmacist-operated drug information center in Iran. AB - OBJECTIVE: To assess and describe the call services delivered by drug and poison information call center (DPIC) of 13-Aban pharmacy, which is closely operated by the Department of Clinical Pharmacy, College of Pharmacy affiliated to Tehran University of Medical Sciences. METHODS: All calls services including counseled and follow-up calls provided by 13-Aban DPIC to health care professionals and public were collected, documented, and evaluated in a 2 years period from July 2010 to June 2012 using the designed software. Data analysis was done by SPSS version 16.0. FINDINGS: Totally 110,310 calls services delivered during a 2 years period. Among healthcare professionals, pharmacists, general physicians, and nurses requested more call services respectively (P = 0.001). DPIC could detect 585 potential cases of adverse drug reactions (ADRs) and 420 cases of major drug drug interactions (DDIs). CONCLUSION: This study by analyzing and reporting the two-years activities of one of the major DPICs in Iran, showed that DPICs can offer drug consultation for healthcare professional and public as well as detect and prevent ADRs and DDIs, and therefore can promote patients' health regarding drug therapy. PMID- 25535620 TI - Evaluation of Magnesium as an adjuvant in Ropivacaine-induced supraclavicular brachial plexus block: A prospective, double-blinded randomized controlled study. AB - OBJECTIVE: Different additives have been used to prolong brachial plexus block. We evaluated the effect of adding magnesium sulfate to ropivacaine for supraclavicular brachial plexus blockade. The primary endpoints were the onset and duration of sensory and motor block and duration of analgesia. METHODS: One hundred patients (25-55 years) posted for elective forearm and hand surgeries under supraclavicular brachial plexus block were divided into two equal groups (Groups RM and RN) in a randomized, double-blind fashion. In group RM (n = 50), 30 ml 0.5% ropivacaine plus 150 mg (in 1 ml 0.9% saline) magnesium sulfate and in group RN (n = 50), 30 ml 0.5% ropivacaine plus 1 ml normal saline were administered in supraclavicular block. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative visual analog scale (VAS), hemodynamic variables, and side effects were recorded for each patient. FINDINGS: Though with similar demographic profile and block (sensory and motor) onset time, the sensory and motor block duration and time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in group RM (P = 0.026) than group RN. Postoperative VAS values at 24 h were significantly lower in group RM (P = 0.045). Intraoperative hemodynamics was comparable among two groups and no appreciable side effect was noted throughout the study period. CONCLUSION: It can be concluded from this study that adding magnesium sulfate to supraclavicular brachial plexus block may increase the sensory and motor block duration and time to first analgesic use, and decrease total analgesic needs, with no side effects. PMID- 25535621 TI - Adverse reactions of Methylphenidate in children with attention deficit hyperactivity disorder: Report from a referral center. AB - OBJECTIVE: The aim of the current study was to determine various aspects of methylphenidate adverse reactions in children with attention deficit hyperactivity disorder (ADHD) in Iran. METHODS: During the 6 months period, all children under methylphenidate treatment alone or along with other agents attending a university-affiliated psychology clinic were screened regarding all subjective and objective adverse drug reactions (ADRs) of methylphenidate. Causality and seriousness of detected ADRs were assessed by relevant World Health Organization definitions. The Schumock and Thornton questionnaire was used to determine preventability of ADRs. FINDINGS: Seventy-one patients including 25 girls and 46 boys with ADHD under methylphenidate treatment were enrolled within the study period. All (100%) ADHD children under methylphenidate treatment developed at least one ADR. Anorexia (74.3%), irritability (57.1%), and insomnia (47.2%) were the most frequent methylphenidate-related adverse reactions. Except for one, all other detected ADRs were determined to be mild. In addition, no ADR was considered to be preventable and serious. CONCLUSION: Our data suggested that although methylphenidate related adverse reactions were common in children with ADHD, but they were mainly mild and nonserious. PMID- 25535622 TI - Intrathecal Meperidine versus intrathecal Fentanyl for prevention of shivering in lower limb orthopedic surgeries under spinal anesthesia: A randomized double blind placebo-controlled trial. AB - OBJECTIVE: Shivering is an unpleasant sensation for patients who undergoing spinal anesthesia. This randomized double-blind clinical trial study was designed to compare the effect of intrathecal fentanyl with intrathecal meperidine for prevention of shivering in lower limb orthopedic surgeries under spinal anesthesia. METHODS: Ninety patients were randomly recruited to receive either 3 ml of 0.5% hyperbaric bupivacaine plus 20 MUg of fentanyl (Group F), or 3 ml of 0.5% hyperbaric bupivacaine plus 0.2 mg/kg of meperidine (Group M), or 3 ml of 0.5% hyperbaric bupivacaine plus normal saline (Group S). The incidence and intensity of shivering were compared in three groups. Data were analyzed by analysis of variances, Mann-Whitney U-test followed by Chi-square test. FINDINGS: There were not statistically differences in complications and side-effects between three groups. Total incidence of shivering was similar between Groups F and M (16.7% vs. 13.3% respectively, P = 0.72) whereas it was significantly different to Group S (43.3%) (P = 0.025 for Group F vs. S, and P = 0.011 for Group M vs. S). Also the intensity of shivering between Groups F and M was similar (P = 0.66), while it was significantly less in these groups compared to Group S (P = 0.013 and P = 0.004, respectively). CONCLUSION: Addition of fentanyl 20 MUg or meperidine 0.2 mg/kg to 0.5% bupivacaine intrathecally significantly decreased the incidence of shivering in lower limb orthopedic surgeries. There was no significant difference between two drugs with this respect. PMID- 25535623 TI - Possible unaware intoxication by anticoagulant rodenticide. AB - Superwarfarin toxicity may be a serious problem. It needs high clinical suspicious in patients with bleeding diathesis without hematologic or liver diseases even in patients with apparent negative history of warfarin or other anticoagulant accessibility. Here we reported a patient with a negative history of any medical diseases or drug administration who was referred with generalized ecchymosis. Increased international normalized ratio and decreased vitamin K dependent coagulation factors were detected in this patient. His hematologic and liver evaluations were normal. Clinical pharmacist emphasis in taking history revealed using anticoagulant rodenticide all over the farm the patient lived in that might result in unaware intoxication in this patient who suffered dementia. PMID- 25535624 TI - Counterfeit medicines sale on online pharmacies in India. PMID- 25535625 TI - Evaluation of medicine prescription pattern. PMID- 25535626 TI - Prolonging the lifetime of wireless sensor networks interconnected to fixed network using hierarchical energy tree based routing algorithm. AB - This research work proposes a mathematical model for the lifetime of wireless sensor networks (WSN). It also proposes an energy efficient routing algorithm for WSN called hierarchical energy tree based routing algorithm (HETRA) based on hierarchical energy tree constructed using the available energy in each node. The energy efficiency is further augmented by reducing the packet drops using exponential congestion control algorithm (TCP/EXP). The algorithms are evaluated in WSNs interconnected to fixed network with seven distribution patterns, simulated in ns2 and compared with the existing algorithms based on the parameters such as number of data packets, throughput, network lifetime, and data packets average network lifetime product. Evaluation and simulation results show that the combination of HETRA and TCP/EXP maximizes longer network lifetime in all the patterns. The lifetime of the network with HETRA algorithm has increased approximately 3.2 times that of the network implemented with AODV. PMID- 25535628 TI - Reciprocal effects of the chirality and the surface functionalization on the drug delivery permissibility of carbon nanotubes. AB - The drug delivery admissibility of nanomaterials such as carbon nanotubes and their uncertain interactions with live tissues and organs have sparked ongoing research efforts. To boost the selective diffusivity of single walled carbon nanotubes (SWCNTs), surface functionalization was adopted in several experimental attempts. Numerous studies had identified polyethylene glycol (PEG) as a bio compatible surfactant to carbon nanotubes. In this study, a large scale, atomistic molecular dynamic simulation was utilized to disclose the cellular exposure and uptake mechanisms of PEG-functionalized single walled carbon nanotubes (f-SWCNTs) into a lipid bilayer cell membrane. Results showed that with PEGs attached to a SWCNT, the penetration depth and speed can be controlled. Also, the simulations revealed that the adhesion energy between the nanotube and the lipid membrane is affected considerably, in the presence of PEGs, by the chirality of the SWCNTs. PMID- 25535627 TI - The Cleveland Clinic experience with supraclavicular and popliteal ambulatory nerve catheters. AB - Continuous peripheral nerve blocks (CPNB) are commonly used for intraoperative and postoperative analgesia. Our study aimed at describing our experience with ambulatory peripheral nerve catheters. After Institutional Review Board approval, records for all patients discharged with supraclavicular or popliteal catheters between January 1, 2009 and December 31, 2011 were reviewed. A licensed practitioner provided verbal and written instructions to the patients prior to discharge. Daily follow-up phone calls were conducted. Patients either removed their catheters at home with real-time simultaneous telephone guidance by a member of the Acute Pain Service or had them removed by the surgeon during a regular office visit. The primary outcome of this analysis was the incidence of complications, categorized as pharmacologic, infectious, or other. The secondary outcome measure was the average daily pain score. Our study included a total of 1059 patients with ambulatory catheters (769 supraclavicular, 290 popliteal). The median infusion duration was 5 days for both groups. Forty-two possible complications were identified: 13 infectious, 23 pharmacologic, and 6 labeled as other. Two patients had retained catheters, 2 had catheter leakage, and 2 had shortness of breath. Our study showed that prolonged use of ambulatory catheters for a median period of 5 days did not lead to an increased incidence of complications. PMID- 25535629 TI - Imaging and spectroscopic comparison of multi-step methods to form DNA arrays based on the biotin-streptavidin system. AB - Three multi-step multi-molecular approaches using the biotin-streptavidin system to contact-print DNA arrays on SiO2 surfaces modified with (3 glycidoxypropyl)trimethoxysilane are examined after each deposition/reaction step by atomic force microscopy, X-ray photoelectron spectroscopy and time of flight secondary ion mass spectrometry. Surface modification involves the spotting of preformed conjugates of biotinylated oligonucleotides with streptavidin onto surfaces coated with biotinylated bovine serum albumin b-BSA (approach I) or the spotting of biotinylated oligonucleotides onto a streptavidin coating, the latter prepared through a reaction with immobilized b-BSA (approach II) or direct adsorption (approach III). AFM micrographs, quantified by autocorrelation and height histogram parameters (e.g. roughness), reveal uniform coverage after each modification step with distinct nanostructures after the reaction of biotinylated BSA with streptavidin or of a streptavidin conjugate with biotinylated oligonucleotides. XPS relates the immobilization of biomolecules with covalent binding to the epoxy-silanized surface. Protein coverage, estimated from photoelectron attenuation, shows that regarding streptavidin the highest and the lowest immobilization efficiency is achieved by following approaches I and III, respectively, as confirmed by TOF-SIMS microanalysis. The size of the DNA spot reflects the contact radius of the printed droplet and increases with protein coverage (and roughness) prior to the spotting, as epoxy-silanized surfaces are hardly hydrophilic. Representative TOF-SIMS images show sub-millimeter spots: uniform for approach I, doughnut-like (with a small non-zero minimum) for approach II, both with coffee-rings or peak-shaped for approach III. Spot features, originating from pinned contact lines and DNA surface binding and revealed by complementary molecular distributions (all material, DNA, streptavidin, BSA, epoxy, SiO2), indicate two modes of droplet evaporation depending on the details of each applied approach. PMID- 25535645 TI - CoRILISA: a local similarity based receptor dependent QSAR method. AB - Molecular similarity methods have played a crucial role in the success of structure-based and computer-assisted drug design. However, with the exception of CoMSIA, the current approaches for estimating molecular similarity yield a global picture thereby providing limited information about the local spatial molecular features responsible for the variation of activity with the 3D structure. Application of molecular similarity measures, each related to the functional "pieces" of a ligand-receptor complex, is advantageous over a composite molecular similarity alone and will provide more insights to rationally interpret the activity based on the receptor and ligand structural features. Building on the ideas of our previously published methodologies-CoRIA and LISA, we present here a local molecular similarity based receptor dependent QSAR method termed CoRILISA which is a hybrid of the two approaches. The method improves on previous techniques by inclusion of receptor attributes for the calculation and comparison of similarity between molecules. For validation studies, the CoRILISA methodology was applied on three large and diverse data sets-glycogen phosphorylase b (GPb), human immunodeficiency virus-1 protease (HIV PR), and cyclin dependent kinase 2 (CDK2) inhibitors. The statistics of the CoRILISA models were benchmarked against the standard CoRIA approach and with other published approaches. The CoRILISA models were found to be significantly better, especially in terms of the predictivity for the test set. CoRILISA is able to identify the thermodynamic properties associated with residues that define the active site and modulate the variation in the activity of the molecules. It is a useful tool in the fragment based drug discovery approach for ligand activity prediction. PMID- 25535646 TI - Highly efficient and selective oxidation of aromatic alcohols photocatalyzed by nanoporous hierarchical Pt/Bi2WO6 in organic solvent-free environment. AB - Selective conversion of aromatic alcohols into corresponding aldehydes is important from energy and environmental stance. Here, we describe highly selective (>99%) and efficient conversion (>99%) of aromatic alcohols (e.g., 4 methoxybenzyl alcohol and 4-nitrobenzyl alcohol) into their corresponding aldehydes in the presence of Pt-modified nanoporous hierarchical Bi2WO6 spheres in water under simulated sunlight at ambient conditions. Overoxidation of p anisaldehyde, formed during photooxidation process, was not observed until comprehensive alcohol oxidation was attained. Furthermore, the catalyst showed substantial oxidation under dark and course of conversion was different than that of under light. Dependency of alcohol oxidation on substrate concentration, photocatalyst amount, and Pt loading was studied. The effect of various radical scavengers was investigated, and the rate-determining step was elucidated. It has been envisaged that the reduction site of semiconductor photocatalysts plays more decisive role in determining the selectivity as alcohol preferably get oxidized over that of water. Furthermore, the chemical stability and recyclability of the photocatalyst were investigated. PMID- 25535647 TI - Expression of HIF-1alpha and VEGF in skeletal muscle of plateau animals in response to hypoxic stress. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) transcriptionally regulates expression of several target genes in protecting tissues against hypoxia. With hypoxic stress, vascular endothelial growth factor (VEGF) is a signal protein produced by cells and further contributes to improvement of vascular functions and restoring the oxygen supply to tissues. In this current study, we first hypothesized that the protein levels of HIF-1alpha and VEGF are reduced in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (ochotona curzoniae)] in response to hypoxia as compared with control animals [normal lowland Sprague-Dawley (SD) rats]. We further hypothesized that HIF 1alpha plays a role in regulating expression of VEGF in skeletal muscle. Note that HIF-1alpha and VEGF were determined by using two-site immunoenzymatic assay (ELISA) methods. Our results demonstrated that hypoxic stress induced by exposure of lower O(2) (6 h) significantly increased the levels of HIF-1alpha and VEGF in the oxidative and glycolytic muscles of SD rats and pikas (P<0.05 vs. normoxic conditions). Notably, the increases in HIF-1alpha and VEGF were significantly less in pikas (P<0.05, vs. SD controls) than in SD rats. In addition, a linear relationship was observed between amplified HIF-1alpha and VEGF in oxidative muscle (r=0.76 and P<0.01) and glycolytic muscle (r=0.72 and P<0.01) and inhibiting HIF-1alpha significantly decreased expression of VEGF induced by hypoxic stress in skeletal muscles (P<0.05). Overall, our findings suggest that (1) responsiveness of HIF-1alpha and VEGF in skeletal muscles to hypoxic stress is blunted in plateau animals, and (2) HIF-1alpha has a regulatory effect on VEGF under hypoxic environment. PMID- 25535648 TI - Biomechanical energetic analysis of technique during learning the longswing on the high bar. AB - Biomechanical energetic analysis of technique can be performed to identify limits or constraints to performance outcome at the level of joint work, and to assess the mechanical efficiency of techniques. The aim of this study was to investigate the biomechanical energetic processes during learning the longswing on the high bar. Twelve male, novice participants took part in a training study. Kinematic and kinetics data were collected during swing attempts in eight weekly testing sessions. Inverse dynamics analysis was performed from known zero forces at the toes. Joint work, total energy, and bar energy were calculated. Biomechanical constraints to action, that is, limits to novice performance, were identified as "total work" and "shoulder work". The most biomechanically efficient technique was associated with an onset of the hip functional phase and joint work that occurred between 10-45 degrees before the bottom of the swing. The learning of gross motor skills is realised through the establishment of a set of techniques with task specific biomechanical constraints. Knowledge of the biomechanical constraints to action associated with more effective and efficient techniques will be useful for both assessing learning and establishing effective learning interventions. PMID- 25535649 TI - Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy. AB - PURPOSE: Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30 min to 90 min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in vitro analysis of oxaliplatin stability in both chloride-containing and choride deficient carrier solutions and discuss the implications for oxaliplatin-based CRS-HIPEC procedures. METHODS: 5 mg of oxaliplatin was added to 50 mL of various carrier solutions at 42 degrees C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal((r)) PD4 glucose 1.36% solution for peritoneal dialysis and 0.14 M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC-UV); oxaliplatin degradation products were identified using HPLC mass spectometry. RESULTS: In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30 min (the standard peritoneal perfusion time in most clinical CRS-HIPEC protocols) and <20% degradation after 120 min at 42 degrees C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2]. CONCLUSIONS: The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS HIPEC procedures. PMID- 25535651 TI - Effect of NAPL Source Morphology on Mass Transfer in the Vadose Zone. AB - The generation of vapor-phase contaminant plumes within the vadose zone is of interest for contaminated site management. Therefore, it is important to understand vapor sources such as non-aqueous-phase liquids (NAPLs) and processes that govern their volatilization. The distribution of NAPL, gas, and water phases within a source zone is expected to influence the rate of volatilization. However, the effect of this distribution morphology on volatilization has not been thoroughly quantified. Because field quantification of NAPL volatilization is often infeasible, a controlled laboratory experiment was conducted in a two dimensional tank (28 cm * 15.5 cm * 2.5 cm) with water-wet sandy media and an emplaced trichloroethylene (TCE) source. The source was emplaced in two configurations to represent morphologies encountered in field settings: (1) NAPL pools directly exposed to the air phase and (2) NAPLs trapped in water-saturated zones that were occluded from the air phase. Airflow was passed through the tank and effluent concentrations of TCE were quantified. Models were used to analyze results, which indicated that mass transfer from directly exposed NAPL was fast and controlled by advective-dispersive-diffusive transport in the gas phase. However, sources occluded by pore water showed strong rate limitations and slower effective mass transfer. This difference is explained by diffusional resistance within the aqueous phase. Results demonstrate that vapor generation rates from a NAPL source will be influenced by the soil water content distribution within the source. The implications of the NAPL morphology on volatilization in the context of a dynamic water table or climate are discussed. PMID- 25535652 TI - Plutonium isotopes in the terrestrial environment at the Savannah River Site, USA: a long-term study. AB - This work presents the findings of a long-term plutonium (Pu) study at Savannah River Site (SRS) conducted between 2003 and 2013. Terrestrial environmental samples were obtained at the Savannah River National Laboratory (SRNL) in the A Area. Plutonium content and isotopic abundances were measured over this time period by alpha particle and thermal ionization mass spectrometry (3STIMS). We detail the complete process of the sample collection, radiochemical separation, and measurement procedure specifically targeted to trace plutonium in bulk environmental samples. Total plutonium activities were determined to be not significantly above atmospheric global fallout. However, the (238)Pu/(239+240)Pu activity ratios attributed to SRS are substantially different than fallout due to past (238)Pu production on the site. The (240)Pu/(239)Pu atom ratios are reasonably consistent from year to year and are lower than fallout indicating an admixture of weapons-grade material, while the (242)Pu/(239)Pu atom ratios are higher than fallout values, again due to actinide production activities. Overall, the plutonium signatures obtained in this study reflect a distinctive mixture of weapons-grade, heat source, and higher burn-up plutonium with fallout material. This study provides a unique opportunity for developing and demonstrating a blue print for long-term low-level monitoring of trace plutonium in the environment. PMID- 25535650 TI - Early treatment of psoriatic arthritis is associated with improved patient reported outcomes: findings from the etanercept PRESTA trial. AB - OBJECTIVES: The present paper aims to investigate the effect of psoriatic arthritis (PsA) disease duration on the outcome of treatment with etanercept (ETN) in patients with PsA who also have moderate-to-severe psoriasis. METHODS: Patients from the PRESTA trial who received >=1 ETN 50 mg once weekly (QW) dose and had >=1 post-baseline value were evaluated. Baseline and after-treatment changes were compared between patients with PsA <=2 years versus PsA >2 years in efficacy measures (physician global assessment [PGA] arthritis, swollen joint count and Psoriasis Area and Severity Index [PASI]) and patient reported outcomes (PROs; joint pain, arthritis activity, Euro-Qol [EQ-5D] utility and visual analogue score [VAS]) using linear regression analysis. RESULTS: Baseline efficacy measures were similar between the PsA <=2 years (n=103) and PsA >2 years (n=269) groups, with the exception of PGA arthritis (p=0.006). At week 24, improvements in efficacy measures were observed in both groups but were significantly greater for PGA arthritis in the PsA <=2 years group (p=0.03). Quality of life (QoL), measured using PROs, was generally lower at baseline in patients with PsA >2 years. Clinically meaningful improvements were seen in QoL with ETN treatment in both groups, but the change from baseline scores at week 24 were significantly higher in PsA <=2 years group for joint pain (p=0.007), arthritis activity (p=0.01), EQ-5D utility (p=0.046) and EQ-5D VAS (p=0.04) responses. CONCLUSIONS: PsA patients responded to ETN 50 mg QW treatment irrespective of disease duration; however, patients with shorter PsA duration had greater improvements in arthritis scores and several PRO measures. PMID- 25535653 TI - Extraintestinal manifestations in Crohn's disease and ulcerative colitis: results from a prospective, population-based European inception cohort. AB - BACKGROUND: In chronic inflammatory bowel disease (IBD) (Crohn's disease [CD] and ulcerative colitis [UC]), symptoms from outside the gastrointestinal tract are frequently seen, and the joints, skin, eyes, and hepatobiliary area are the most usually affected sites (called extraintestinal manifestations [EIM]). The reported prevalence varies, explained by difference in study design and populations under investigation. The aim of our study was to determine the prevalence of EIM in a population-based inception cohort in Europe and Israel. METHODS: IBD patients were incepted into a cohort that was prospectively followed from 1991 to 2004. A total of 1145 patients were followed for 10 years. RESULTS: The cumulative prevalence of first EIM was 16.9% (193/1145 patients) over a median follow-up time of 10.1 years. Patients with CD were more likely than UC patients to have immune-mediated (arthritis, eye, skin, and liver) manifestations: 20.1% versus 10.4% (p < 0.001). Most frequently seen was arthritis which was significantly more common in CD (12.9%) than in UC (8.1%), p = 0.01. Pan-colitis compared to proctitis in UC increased the risk of EIM. CONCLUSION: In a European inception cohort, EIMs in IBD were consistent with that seen in comparable studies. Patients with CD are twice as likely as UC patients to experience EIM, and more extensive distribution of inflammation in UC increases the risk of EIM. PMID- 25535654 TI - Coupled diffusion in lipid bilayers upon close approach. AB - Biomembrane interfaces create regions of slowed water dynamics in their vicinity. When two lipid bilayers come together, this effect is further accentuated, and the associated slowdown can affect the dynamics of larger-scale processes such as membrane fusion. We have used molecular dynamics simulations to examine how lipid and water dynamics are affected as two lipid bilayers approach each other. These two interacting fluid systems, lipid and water, both slow and become coupled when the lipid membranes are separated by a thin water layer. We show in particular that the water dynamics become glassy, and diffusion of lipids in the apposed leaflets becomes coupled across the water layer, while the "outer" leaflets remain unaffected. This dynamic coupling between bilayers appears mediated by lipid-water-lipid hydrogen bonding, as it occurs at bilayer separations where water-lipid hydrogen bonds become more common than water-water hydrogen bonds. We further show that such coupling occurs in simulations of vesicle-vesicle fusion prior to the fusion event itself. Such altered dynamics at membrane-membrane interfaces may both stabilize the interfacial contact and slow fusion stalk formation within the interface region. PMID- 25535657 TI - Associations between early radiographic and computed tomographic measures and canine hip joint osteoarthritis at maturity. AB - OBJECTIVE: To evaluate associations of measures assessed by radiography, 2-D CT, and 3-D CT of the hip joints of immature dogs with osteoarthritis in the same joints at maturity. ANIMALS: 46 hound-type dogs from a colony predisposed to osteoarthritis. PROCEDURES: Images of hip joints (1/dog) were obtained at 16, 32, and 104 weeks of age. Radiographic measures included Norberg angle, distraction index, and osteoarthritis score. Two-dimensional CT measures included acetabular index, percentage of femoral head coverage, and center edge, horizontal toit externe, acetabular anteversion, and ventral, dorsal, and horizontal acetabular sector angles. Three-dimensional CT measures were femoral head and neck volume, femoral neck angle, and femoral head and neck radius. Differences among measures at 16 and 32 weeks in dogs with different osteoarthritis scores at later time points, relationships among variables at each time point, and relationships of single and combined measures with the presence of osteoarthritis at 104 weeks were evaluated. RESULTS: The 16- and 32-week distraction index, center edge angle, dorsal acetabular sector angle, horizontal acetabular sector angle, percentage of femoral head coverage, acetabular index, and Norberg angle and the 32-week femoral neck angle varied significantly with osteoarthritis severity at 104 weeks. Presence of osteoarthritis in mature dogs was most strongly associated with 16-week combined measures of distraction index and center edge angle and 32 week combined measures of dorsal acetabular sector angle and Norberg angle. CONCLUSIONS AND CLINICAL RELEVANCE: Changes in hip joint morphology associated with radiographic signs of osteoarthritis were detectable as early as 16 weeks of age and varied with osteoarthritis severity in adult dogs. The use of combined hip joint measures may improve early identification of dogs predisposed to hip joint osteoarthritis. PMID- 25535658 TI - Quantitative computed tomographic assessment of bone mineral density changes associated with administration of prednisolone or prednisolone and alendronate sodium in dogs. AB - OBJECTIVE: To evaluate whether a low-dosage regimen of prednisolone induces bone loss and whether administration of alendronate sodium prevents glucocorticoid induced osteopenia in dogs by measuring trabecular bone mineral density (BMD) with quantitative CT. ANIMALS: 8 healthy Beagles. PROCEDURES: In 4 dogs, prednisolone was administered PO at a dosage of 2 mg/kg once daily for 2 weeks, 1 mg/kg once daily for 4 weeks, and 0.5 mg/kg once daily for 3 weeks. In the other 4 dogs, alendronate sodium (2 mg/kg, PO, q 24 h) was whether administered for 9 weeks in addition to the same dosage of prednisolone used in the prednisolone treated dogs. Before (day 0 [baseline]) and 21, 42, 63, and 150 days after the start of treatment, BMD of the lumbar vertebrae was measured by quantitative CT. RESULTS: BMD in the prednisolone treatment group decreased to 84.7% of the baseline value on day 42, increased to 87.9% on day 63, and recovered to 91.6% on day 150. In the prednisolone-alendronate treatment group, BMD decreased to 91% of the baseline value on day 21, increased to 93.8% on day 63, and then recovered to 96.7% on day 150. Bone mineral density in the prednisolone treatment group was generally lower, albeit not significantly, than that of the prednisolone alendronate treatment group on each examination day. CONCLUSIONS AND CLINICAL RELEVANCE: BMD temporarily decreased after low-dosage prednisolone administration; however, it gradually improved during tapering of the prednisolone dosage. These results have suggested that a low dosage of prednisolone can be used with little concern for development of osteopenia in dogs. PMID- 25535659 TI - Procoagulant phospholipid concentration in canine erythrocyte concentrates stored with or without prestorage leukoreduction. AB - OBJECTIVE: To evaluate canine erythrocyte concentrates (ECs) for the presence of procoagulant phospholipid (PPL), determine whether PPL concentration changes during the course of storage of ECs, and ascertain whether prestorage leukoreduction (removal of leukocytes via gravity filtration) reduces the development of PPL. SAMPLE: 10 whole blood units (420 g each) collected from 10 random-source, clinically normal dogs (1 U/dog). PROCEDURES: The dogs were randomized to 1 of 2 groups. Of the 10 whole blood units collected, 5 were processed through a standard method, and 5 underwent leukoreduction. Whole blood units were processed to generate ECs, from which aliquots were aseptically collected from each unit weekly for 5 weeks. Supernatants from the concentrates were evaluated for procoagulant activity, which was converted to PPL concentration, by use of an automated assay and by measurement of real-time thrombin generation. RESULTS: Supernatants from stored canine ECs contained procoagulant activity as measured by both assays. In general, the PPL concentration gradually increased during the storage period, but leukoreduction reduced the development of increased procoagulant activity over time. CONCLUSIONS AND CLINICAL RELEVANCE: The presence of PPL in canine ECs may be associated with procoagulant and proinflammatory effects in vivo, which could have adverse consequences for dogs treated with ECs. PMID- 25535660 TI - Comparison of radiographic and computed tomographic images of the lungs in healthy neonatal foals. AB - OBJECTIVE: To compare CT and radiographic images of the lungs in sedated healthy foals positioned in sternal recumbency and to investigate whether a relationship exists between CT-derived measurements of lung attenuation and Paco2 and Pao2. ANIMALS: 6 healthy Standardbred foals < 14 days of age. PROCEDURES: Thoracic CT images were acquired followed by radiographic views with each foal sedated and positioned in sternal recumbency. For each foal, both CT and radiographic images were evaluated for severity and extent of changes by lung regions on the basis of a subjective scoring system by 3 investigators. Quantitative analysis of CT images was also performed. Assessments of Pao2 and Paco2 were performed before sedation, following sedation prior to CT, and after CT prior to radiography. RESULTS: Interobserver agreement for CT and radiographic image scoring was strong (0.73) and fair (0.65), respectively; intraobserver agreement was near perfect for CT (0.97) and radiographic (0.94) image scoring. Increased CT attenuation and radiographic changes were identified for all foals and were preferentially distributed in the caudoventral portion of the lungs. Radiographic scores were significantly lower than CT image scores. A positive correlation (r = 0.872) between lung attenuation and CT image score was identified. A significant increase in Paco2 was not considered clinically relevant. Significant changes in Pao2 were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that interpretation of CT images may be less subjective, compared with interpretation of radiographic images. These findings may aid in the evaluation of CT and radiographic images of neonatal foals with respiratory tract disease. PMID- 25535661 TI - Medical infrared thermal imaging of cats with hyperthyroidism. AB - OBJECTIVE: To determine the usefulness of medical infrared thermal imaging (MITI) as a screening tool for hyperthyroidism in cats, evaluate the need for hair clipping over the ventral aspect of the neck to achieve optimal images, and determine whether there is a change in thermal patterns at 1 and 3 months after radioactive sodium iodide I 131 treatment. ANIMALS: 17 cats with and 12 control cats without hyperthyroidism. PROCEDURES: All cats underwent MITI first with the hair present and then after the hair was clipped. Each cat with hyperthyroidism was subsequently appropriately treated SC with radioiodide; reevaluations, including MITI before and after hair clipping and measurement of serum thyroxine concentration, were performed 1 and 3 months after treatment. RESULTS: The MITI had 80.5% and 87.5% accuracy in differentiating hyperthyroid cats from clinically normal cats before and after the hair over the ventral aspect of the neck was clipped. Among cats with an initial serum thyroxine concentration > 4.0 MUg/dL, the success rate for MITI-detected response to radioiodide treatment at the 1 month reevaluation was 92.86% in unshaved cats and 85.71% in shaved cats. The success rate for MITI-detected response to radioiodide treatment at the 3-month reevaluation was 100% in unshaved and shaved cats. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that MITI was successful in differentiating between hyperthyroid cats and clinically normal cats and identifying patients with thyroxine concentration within reference interval after radioactive sodium iodide I 131 treatment. PMID- 25535662 TI - Assessment of the excretion time of electronic capsules placed in the intestinal lumen of cows with cecal dilatation-dislocation, healthy control cows, and cows with left displacement of the abomasum. AB - OBJECTIVE: To analyze the transit time from various locations in the intestines of cows with cecal dilatation-dislocation (CDD), healthy control cows, and cows with left displacement of the abomasum (LDA). ANIMALS: 15 cows with naturally occurring CDD (group 1), 14 healthy control cows (group 2), and 18 cows with LDA (group 3). PROCEDURES: 5 electronic transmitters were encased in capsules and placed in the lumen of the ileum, cecum, proximal portion of the colon, and 2 locations in the spiral colon (colon 1 and colon 2) and used to measure the transit time (ie, time between placement in the lumen and excretion of the capsules from the rectum). Excretion time of the capsules from each intestinal segment was compared among groups. RESULTS: Cows recovered well from surgery, except for 1 cow with relapse of CDD 4 days after surgery and 2 cows with incisional infection. High variability in capsule excretion times was observed for all examined intestinal segments in all groups. Significant differences were detected for the excretion time from the colon (greater in cows with CDD than in healthy control cows) and cecum (less in cows with LDA than in cows of the other 2 groups). CONCLUSIONS AND CLINICAL RELEVANCE: The technique developed to measure excretion time of capsules from bovine intestines was safe and reliable; however, the large variability observed for all intestinal segments and all groups would appear to be a limitation for its use in assessment of intestinal transit time of cattle in future studies. PMID- 25535664 TI - Determination of tonicity effects of ketoacids and lactate by use of two canine red blood cell assays. AB - OBJECTIVE: To determine the tonicity effects of beta-hydroxybutyrate, acetoacetate, and lactate in canine RBCs. SAMPLE: RBCs from approximately 40 dogs. PROCEDURES: 2 in vitro methods were used to conduct 4 experiments. The modified osmotic fragility assay was used to measure the ability of ketoacid salts added to serial sucrose dilutions to protect RBCs from osmotic hemolysis. In a second assay, a handheld cell counting device was used to measure changes in RBC diameter to assess the tonicity effect of solutions of ketoacid and lactate salts. RESULTS: For the modified osmotic fragility assay, all ketoacid salts had an osmoprotective effect, but the effect was determined to be completely attributable to the tonicity effect of added cations (sodium and lithium) and not the ketoacid moieties. However, both the sodium and lithium lactate salts provided osmoprotection attributable to both the cation and lactate anion. For the second assay, RBC diameter was significantly increased with the addition of urea (an ineffective osmole) but did not change with the addition of glucose (an effective osmole), which established the behaviors of ineffective and effective osmoles in this assay. The RBC diameter was significantly increased over that of control samples by the addition of sodium beta-hydroxybutyrate, lithium acetoacetate, and lithium lactate but was decreased by the addition of sodium lactate. CONCLUSIONS AND CLINICAL RELEVANCE: For both assays, beta hydroxybutyrate and acetoacetate acted as ineffective osmoles, whereas lactate acted as an effective osmole in 3 of 4 experiments. PMID- 25535665 TI - Comparison among the euglycemic-hyperinsulinemic clamp, insulin-modified frequently sampled intravenous glucose tolerance test, and oral glucose tolerance test for assessment of insulin sensitivity in healthy Standardbreds. AB - OBJECTIVE: To compare, in horses, estimates of insulin sensitivity obtained from minimal model analysis (MMA) of a frequently sampled IV glucose tolerance test (FSIGTT) with estimates from the euglycemic-hyperinsulinemic clamp (EHC) and to evaluate the validity of surrogate estimates of insulin sensitivity derived from an oral glucose tolerance test (OGTT). ANIMALS: 18 mature Standardbreds (mean +/- SD body weight, 428.9 +/- 35.9 kg; mean +/- SD body condition score, 4.4 +/- 1.0 [on a scale of 1 to 9]). PROCEDURES: All horses underwent at least 2 of the 3 procedures (EHC [n = 15], insulin-modified FSIGTT [18], and OGTT [18]) within a 10-day time frame to evaluate insulin sensitivity. RESULTS: Insulin sensitivity variables derived from the EHC and FSIGTT were strongly correlated (r = 0.88). When standardized to the same units of measure, these measures were still strongly correlated (r = 0.86) but were not equivalent. Area under the curve, peak insulin concentration, insulin concentration at 120 minutes, and 2 calculated indices from glucose and insulin data from the OGTT were significantly correlated with the EHC- and FSIGTT-derived estimates of insulin sensitivity. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy Standardbreds with moderate body condition score, insulin sensitivities from the EHC and FSIGTT were strongly correlated but not equivalent. Estimates derived from an OGTT also may be useful to estimate insulin sensitivity. PMID- 25535663 TI - Temporal and spatial dynamics of porcine reproductive and respiratory syndrome virus infection in the United States. AB - OBJECTIVE: To measure incidence and estimate temporal and spatial dynamics of porcine reproductive and respiratory syndrome virus (PRRSV) infection in US sow herds. ANIMALS: 371 sow herds in the United States from 14 production companies. PROCEDURES: The exponentially weighted moving average was used to monitor incident PRRSV infections for onset of an epidemic. The spatial scan statistic was used to identify areas at significantly high risk of PRRS epidemics. A chi(2) test was used to estimate whether there were significant differences in the quarterly and annual PRRS incidence among time periods, and a bivariable logistic regression model was used to estimate whether PRRSV infection during a given year increased the odds of that herd being infected in the following year. RESULTS: During the 4-year period of this study, 29% (91/319; 2009 to 2010), 33% (106/325; 2010 to 2011), 38% (135/355; 2011 to 2012), and 32% (117/371; 2012 to 2013) of the herds reported new infections. Weekly incidence was low during spring and summer and high during fall and winter. The exponentially weighted moving average signaled the onset of a PRRSV epidemic during the middle 2 weeks of October each year. Disease incidence was spatially clustered. Infection in the previous year increased the odds of infection in 2010 to 2011 and 2011 to 2012. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated a striking repeatability in annual PRRSV temporal and spatial patterns across 4 years of data among herds from 14 production companies, which suggested that efforts to control PRRSV at a regional level should continue to be supported. PMID- 25535666 TI - West Nile virus-specific immunoglobulin isotype responses in vaccinated and infected horses. AB - OBJECTIVE: To compare antibody responses of horses naturally infected with West Nile virus (WNV) and those vaccinated against WNV, to identify whether vaccination interferes with the ability to diagnose WNV infection, and to determine the duration of antibody responses after vaccination. SAMPLE: Sera from horses naturally infected with WNV (n = 10) and adult WNV-naive horses before and after vaccination with a live canarypox virus-vectored vaccine (7) or a killed virus vaccine (8). PROCEDURES: An established WNV IgM capture ELISA was used to measure IgM responses. Newly developed capture ELISAs were used to measure responses of 8 other WNV-specific immunoglobulin isotypes. A serum neutralization assay was used to determine anti-WNV antibody titers. RESULTS: WNV-specific IgM responses were typically detected in the sera of WNV-infected horses but not in sera of horses vaccinated against WNV. Natural infection with and vaccination against WNV induced an immunoglobulin response that was primarily composed of IgG1. West Nile virus-specific IgG1 was detected in the sera of most horses 14 days after vaccination. Serum anti-WNV IgG1 and neutralizing antibody responses induced by the killed-virus vaccines were higher and lasted longer than did those induced by the live canarypox virus-vectored vaccine. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of these findings, we recommend that horses be vaccinated against WNV annually near the beginning of mosquito season, that both IgM and IgG1 responses against WNV be measured to distinguish between natural infection and vaccination, and that a WNV IgG1 ELISA be used to monitor anti-WNV antibodies titers in vaccinated horses. PMID- 25535667 TI - Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions. AB - The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively. PMID- 25535668 TI - Telomere length measurement on the Roche LightCycler 480 Platform. AB - BACKGROUND: The average length of telomeres as measured in genomic DNA from human peripheral blood leukocytes is proving to be a potential biomarker of great interest, particularly with respect to studies of aging, specific diseases, and the effects of various stresses on overall health. AIMS: The aim of this study was to establish an effective real-time quantitative polymerase chain reaction (qPCR) method for telomere length measurement on the Roche LightCycler(r) 480 (LC480) real-time PCR platform. METHODS: Measurement of relative average telomere length was achieved by comparing products amplified from telomere-specific primers and single copy reference gene primers in a ratio (T/S). RESULTS: Extensive testing led us to conclude that a modification of the original two plate T/S assay was more compatible with this platform than the recently developed single-plate assay, and that choice of hot-start Taq polymerase and intercalating dye were critical factors. CONCLUSIONS: This modified assay generates reliable measurements as judged by correlation with data derived by the telomeric restriction fragment Southern blot-based method. PMID- 25535669 TI - Charging of poly(methyl methacrylate) (PMMA) colloids in cyclohexyl bromide: locking, size dependence, and particle mixtures. AB - We studied suspensions of sterically stabilized poly(methyl methacrylate) (PMMA) particles in the solvent cyclohexyl bromide (CHB; epsilonr = 7.92). We performed microelectrophoresis measurements on suspensions containing a single particle species and on binary mixtures, using confocal microscopy to measure the velocity profiles of the particles. We measured the charge of so-called locked PMMA particles, for which the steric stabilizer, a comb-graft stabilizer of poly(12 hydroxystearic acid) (PHSA) grafted on a backbone of PMMA, was covalently bonded to the particle, and for unlocked particles, for which the stabilizer was adsorbed to the surface of the particle. We observed that locked particles had a significantly higher charge than unlocked particles. We found that the charge increase upon locking was due to chemical coupling of 2-(dimethylamino)ethanol to the PMMA particles, which was used as a catalyst for the locking reaction. For particles of different size we obtained the surface potential and charge from the electrophoretic mobility of the particles. For locked particles we found that the relatively high surface potential (~ +5.1 kBT/e or +130 mV) was roughly constant for all particle diameters we investigated (1.2 MUm < sigma < 4.4 MUm), and that the particle charge was proportional to the square of the diameter. PMID- 25535670 TI - In vitro immunomodulatory activity of interferon alpha on toll-like receptor 9 signaling pathway in chronic hepatitis B. AB - Interferon alpha (IFN-alpha) is registered for chronic hepatitis B (CHB) treatment. However, the antiviral mechanism of IFN-alpha and the biological function of many IFN-alpha responsive genes have not been fully elucidated. We investigated to determine the regulative effect of IFN-alpha on toll-like receptor (TLR) 9 signaling in peripheral blood mononuclear cells (PBMCs) from CHB patients in vitro. We examined the changes of expression and function of TLR9 signaling pathway in the PBMCs with different treatment methods and investigated the synergism of IFN-alpha and TLR9 ligand on antiviral cytokine secretions in vitro. The data showed that, for the TLR9 signaling pathway, IFN-alpha not only augmented the expressions of TLR9 signal transduction molecules but also activated the TLR9 signal function. This study has clearly demonstrated that the TLR9 ligand could stimulate PBMCs that have been pretreated with IFN-alpha. Furthermore, the quantity of antiviral cytokines secreted by the pretreated PBMCs was greater than those without pretreatment. The interaction between IFN-alpha and TLR9 ligand appears to be synergistic. Data revealed IFN-alpha could influence TLR9 signaling transduction and synergistically improve the immune efficacy of TLR9 ligand against CHB. The present study suggests a potential novel mechanism for the antiviral activity against hepatitis B virus and a new individualized antiviral strategy. PMID- 25535671 TI - New Zealanders' attitudes toward physician-assisted dying. AB - OBJECTIVES: Physician-assisted dying (PAD) is legal in several countries in Europe and some states of the United States. Despite regular societal debate in New Zealand about assisted dying, little is known about what the New Zealand public think about this issue. The present study was the first to examine New Zealanders' attitudes toward assisted dying in the context of various parameters of patient suffering, and as a public policy issue. METHODS: Stratified random sampling techniques were used to elicit 677 participants from the electoral roll. They completed an anonymous questionnaire asking about the most appropriate medical response to patients who explicitly request assistance in dying, as well as their opinions around legalization of PAD. RESULTS: Overall, 78% felt PAD was the most appropriate response in certain situations while 82% felt it should be legalized. When the patient was suffering from loss of dignity, PAD was considered the most appropriate response to patients' requests for assistance in dying by 75% of respondents; when the patient was suffering from intractable pain, 65% of respondents considered PAD the most appropriate response. Almost 65% of those who wanted PAD to be legalized felt it should only be accessible to those suffering unbearably with little hope of recovery, and 46% felt that the presence of mental illness should be an exclusionary factor. CONCLUSIONS: The results have highlighted the high value respondents place on patient autonomy with regards to end-of-life choices; however the choice to hasten death is not a 'right' that should be available to all. RESULTS have clearly shown that New Zealanders believe regulation will play a key role in maintaining compliance with any assisted dying legislation, and in restricting access, so that only patients who are suffering intolerably and hopelessly are able to legally gain medical assistance to end their life. PMID- 25535672 TI - Rapid diversification of sexual signals in Hawaiian Nesosydne planthoppers (Hemiptera: Delphacidae): the relative role of neutral and selective forces. AB - Changes in sexual signals have the potential to promote rapid divergence and reproductive isolation among populations of animals. Thus, identifying processes contributing to variation in signals is key to understanding the drivers of speciation. However, it is difficult to identify the processes initiating changes in signals in empirical systems because (1) the demographic history of populations under study is usually unclear, and (2) there is no unified hypothesis-testing framework for evaluating the simultaneous contribution of multiple processes. A unique system for study in the Hawaiian Islands, the planthopper species Nesosydne chambersi, offers a clear demographic context to disentangle these factors. By measuring variation in male vibratory sexual signals across different genetic populations on the island of Hawaii, we found that that multiple signal traits varied significantly between populations. We developed a mixed modelling framework to simultaneously test competing hypotheses about which processes contribute to changes in signal traits: genetic drift, sensory drive or reproductive character displacement. Our findings suggest that signal divergence proceeds along different axes for different signal traits under the influence of both neutral and selective processes. They are the first, to our knowledge, to document the relative importance of multiple processes on divergence in sexual signals. PMID- 25535673 TI - Raman microimaging of murine lungs: insight into the vitamin A content. AB - The composition of the lung tissue of mice was investigated using Raman confocal microscopy at 532 nm excitation wavelength and was supported with various staining techniques as well as DFT calculations. This combination of experimental and theoretical techniques allows for the study of the distribution of lung lipofibroblasts (LIFs), rich in vitamin A, as well as the chemical structure of vitamin A. The comparison of the Raman spectra derived from LIFs with the experimental and theoretical spectra of standard retinoids showed the ability of LIFs to store all-trans retinol, which is partially oxidized to all-trans retinal and retinoic acid. Moreover, we were able to visualize the distribution of other lung tissue components including the surfactant and selected enzymes (lipoxygenase/glucose oxidase). PMID- 25535674 TI - Chemoradiotherapy in elderly patients with advanced head and neck cancer under intensive nutritional support. AB - AIM: To evaluate treatment tolerance, toxicities and survival in elderly patients with advanced head and neck cancer who received inpatient-based intensive nutritional support with concurrent chemoradiotherapy in comparison with younger patients undergoing the same treatment. METHODS: We retrospectively analyzed the records of 126 stage III, IVA and IVB head and neck cancer patients who were treated with concurrent chemoradiotherapy between 2007 and 2009 under an inpatient-based nutritional support program. The clinical characteristics, treatment tolerance, toxicities and survival of patients older than 65 years were compared with those of identically treated patients younger than 65 years. RESULTS: There were 21 patients older than 65 years and 105 patients younger than 65 years. Clinical characteristics and treatment toxicities were similar between the groups, except that the elderly were less likely to tolerate cisplatin, experienced more weight loss, required more feeding tube support and tended to have >grade 3 hematological toxicities and to develop sepsis during the period of chemoradiotherapy. The 1- and 2-year disease-free survival and disease-specific survival rates were nearly identical. CONCLUSION: Age alone should not be considered a contraindication to aggressive chemoradiotherapy for advanced head and neck cancer. Older patients require more careful multidisciplinary assessment of their supportive care needs to ensure successful completion of treatment and avoid further treatment-related toxicity. PMID- 25535675 TI - Exploring medical device design and use through layers of distributed cognition: how a glucometer is coupled with its context. AB - Medical devices are becoming more interconnected and complex, and are increasingly supported by fragmented organizational systems, e.g. through different processes, committees, supporting staff and training regimes. Distributed Cognition has been proposed as a framework for understanding the design and use of medical devices. However, it is not clear that it has the analytic apparatus to support the investigation of such complexities. This paper proposes a framework that introduces concentric layers to DiCoT, a method that facilitates the application of Distributed Cognition theory. We use this to explore how an inpatient blood glucose meter is coupled with its context. The analysis is based on an observational study of clinicians using a newly introduced glucometer on an oncology ward over approximately 150h (11days and 4 nights). Using the framework we describe the basic mechanics of the system, incremental design considerations, and larger design considerations. The DiCoT concentric layers (DiCoT-CL) framework shows promise for analyzing the design and use of medical devices, and how they are coupled with their context. PMID- 25535676 TI - Occurrence and duration of various operational definitions of sedentary bouts and cross-sectional associations with cardiometabolic health indicators: the ENERGY project. AB - OBJECTIVE: This study examined the occurrence and duration of sedentary bouts and explored the cross-sectional association with health indicators in children applying various operational definitions of sedentary bouts. METHODS: Accelerometer data of 647 children (10-13 years old) were collected in five European countries. We analyzed sedentary time (<100 cpm) accumulated in bouts of at least 5, 10, 20 or 30 min based on four operational definitions, allowing 0, 30 or 60s >=100 cpm within bouts. Health indicators included anthropometrics (i.e. waist circumference and body mass index (BMI)) and in a subsample from two European countries (n=112) fasting capillary blood levels of glucose, C-peptide, high-density- and low-density cholesterol, and triglycerides. Data collection took place from March to July 2010. Associations were adjusted for age, gender, moderate-to-vigorous physical activity, total wear time and country. RESULTS: Occurrence of sedentary bouts varied largely between the various definitions. Children spent most of their sedentary time in bouts of >=5 min while bouts of >=20 min were rare. Linear regression analysis revealed few significant associations of sedentary time accumulated in bouts of >=5-30 min with health indicators. Moreover, we found that more associations became significant when allowing no tolerance time within sedentary bouts. CONCLUSION: Despite a few significant associations, we found no convincing evidence for an association between sedentary time accumulated in bouts and health indicators in 10-13 year old children. PMID- 25535677 TI - Gender differences in physical activity patterns among older adults who fall. AB - OBJECTIVE: This study describes gender differences in the level and pattern of physical activity in groups of older adults who were frequent fallers, intermittent fallers, or non-fallers. METHODS: Interviews were conducted with adults aged 50 years and older (N=1834) at senior centers across Pennsylvania from 2010 to 2011. Self-reported falls and validated measures of physical activity were collected at baseline and at 6- and 12-month follow-up assessments. RESULTS: Complete follow-up data were available for 1487 participants. Men who fell frequently decreased in recreational/leisure activity and household/yard work compared to the intermittent fallers and non-fallers. This association remained even when controlling for baseline health status. All women-regardless of fall group-engaged in similar levels of recreational/leisure activity and household/yard work over time. For both men and women, frequent fallers also showed a greater decrease in walking activities compared to intermittent fallers and non-fallers. DISCUSSION: Frequent falling among older adults is associated with declines in common leisure, household, and walking activities. The effect of falling frequency on physical activity appears to affect men and women differently, generating the hypothesis that interventions to promote physical activity among fallers need to be gender specific. PMID- 25535678 TI - Water pipe tobacco smoking in the United States: findings from the National Adult Tobacco Survey. AB - OBJECTIVE: To report prevalence and correlates of water pipe tobacco smoking (WTS) use among U.S. adults. METHODS: Data were from the 2009-2010 National Adult Tobacco Survey, a nationally representative sample of U.S. adults. Estimates of WTS ever and current use were reported overall, and by sex, age, race/ethnicity, educational attainment, annual household income, sexual orientation, and cigarette smoking status. State-level prevalence rates of WTS ever were reported using choropleth thematic maps for the overall population and by sex. RESULTS: The national prevalence of WTS ever was 9.8% and 1.5% for current use. WTS ever was more prevalent among those who are male (13.4%), 18-24 years old (28.4%) compared to older adults, non-Hispanic White (9.8%) compared to non-Hispanic Black, with some college education (12.4%) compared to no high school diploma, and reporting sexual minority status (21.1%) compared to heterosexuals. States with highest prevalence included DC (17.3%), NV (15.8%), and CA (15.5%). CONCLUSION: WTS is now common among young adults in the US and high in regions where cigarette smoking prevalence is the lowest and smoke-free policies have a longer history. To reduce its use, WTS should be included in smoke-free regulations and state and federal regulators should consider policy development in other areas, including taxes, labeling, and distribution. PMID- 25535679 TI - Combinatorial approach to estimate copy number genotype using whole-exome sequencing data. AB - Copy number variations (CNVs) are known risk factors in complex diseases. Array based approaches have been widely used to detect CNVs, but limitations of array based CNV detection methods, such as noisy signal and low resolution, have hindered detection of small CNVs. Recently, the development of next-generation sequencing techniques has increased rapidly owing to declines in cost. Particularly, whole-exome sequencing has proved useful for finding causal genes and variants in complex diseases. Because gene copy number may affect expression, CNV genotyping can be very valuable in disease association studies. However, almost all current CNV detection tools consider only two types of CNV genotypes. In this study, we propose a CNV genotype estimation approach using a combination of existing methods. Our approach was comprehensively compared with the customized Agilent array-comparative genomic hybridization. We found that our genotyping approach proved to be accurate, and reproducible, suggesting that it can complement existing CNV genotyping methods. PMID- 25535680 TI - VennBLAST-whole transcriptome comparison and visualization tool. AB - RNA-seq is the method of choice for getting a primary list of genes for non-model organisms. Once this is achieved, one would proceed to annotate the newly discovered genes and consequently strive to position the organism in an evolutionary context. These kinds of studies involving high-throughput sequencing generate large amounts of data, whose analysis might be time consuming for the non-specialist user and merit computational skills. Here we describe VennBLAST, a set of high-performance utilities that combines fast parallelized BLAST filtering with a visualization tool for whole-transcriptomic alignment comparison using Venn diagrams. The software accurately illustrates simple set relationships between numbers of matching sequences and identifies transcriptome conservation among different organisms. The intuitive Venn diagram visualization allows researchers to easily select a desired subset of genes for further inspection, using the DAVID functional annotation tools, for instance, which enables investigators to understand biological meaning behind large lists of genes. PMID- 25535681 TI - Bariatric surgery and the changing current scope of general surgery practice: implications for general surgery residency training. AB - IMPORTANCE: The scope of general surgery practice has evolved tremendously in the last 20 years. However, clinical experience in general surgery residency training has undergone relatively little change. OBJECTIVE: To evaluate the current scope of academic general surgery and its implications on surgical residency. DESIGN, SETTING, AND PARTICIPANTS: The University HealthSystem Consortium and Association of American Medical Colleges established the Faculty Practice Solution Center (FPSC) to characterize physician productivity. The FPSC is a benchmarking tool for academic medical centers created from revenue data collected from more than 90,000 physicians who practice at 95 institutions across the United States. MAIN OUTCOMES AND MEASURES: The FPSC database was queried to evaluate the annual mean procedure frequency per surgeon (PFS) in each calendar year from 2006 through 2011. The associated work relative value units (wRVUs) were also examined to measure physician effort and skill. RESULTS: During the 6-year period, 146 distinct Current Procedural Terminology codes were among the top 100 procedures, and 16 of these procedures ranked in the top 10 procedures in at least 1 year. The top 10 procedures accounted for more than half (range, 52.5%-57.2%) of the total 100 PFS evaluated for each year. Laparoscopic Roux-en-Y gastric bypass was consistently among the top 10 procedures in each year (PFS, 18.2-24.6). The other most frequently performed procedures included laparoscopic cholecystectomy (PFS, 30.3-43.5), upper gastrointestinal tract endoscopy (PFS, 26.5-34.3), mastectomy (PFS, 16.5-35.0), inguinal hernia repair (PFS, 15.5-22.1), and abdominal wall hernia repair (PFS, 21.6-26.1). In all years, laparoscopic Roux-en-Y gastric bypass generated the highest number of wRVUs (wRVUs, 491.0-618.2), and laparoscopic cholecystectomy was regularly the next highest (wRVUs, 335.8-498.7). CONCLUSIONS AND RELEVANCE: A significant proportion of academic general surgery is composed of bariatric surgery, yet surgical training does not sufficiently emphasize the necessary exposure to technical expertise and clinical management of the patient undergoing bariatric surgery. As the scope of general surgery practice continues to evolve, general surgery residency training will need to better integrate the exposure to bariatric surgery. PMID- 25535683 TI - Thermo-responsive fibrinogen nanogels: a viable thermo-responsive drug delivery agent for breast cancer therapy? PMID- 25535684 TI - Redox-active nanoparticles in combating neurodegeneration. PMID- 25535685 TI - Recombinant protein materials for bioengineering and nanomedicine. AB - Proteins are essential macromolecules supporting life. Being efficient catalyzers and offering specific cross-molecular contacts, proteins are largely exploited in biotechnology and biomedicine as therapeutics, in industrial catalysis or as molecular reagents. Recombinant enzymes, hormones, immunogens and antibodies are produced aiming to different applications, on the basis of their ability to interact with or modify substrates or biological targets. In nature, proteins also perform task-specific architectonic roles, and they can organize in supramolecular complexes with intriguing physical properties such as elasticity and adhesiveness, and with regulatable stiffness, flexibility and mechanical strength. Proteins have recently gained interest as materials for bioengineering and nanomedicine as they can combine these features with functionality, biocompatibility and degradability in unusually versatile composites. We revise here the fundamental properties of the diverse categories of emerging protein materials resulting from biological synthesis and how they can be genetically re designed to engineer the interplay between mechanical and biological properties in a medically oriented exploitable way. PMID- 25535686 TI - Sequence-defined polymers for the delivery of oligonucleotides. AB - Short synthetic oligonucleotides (ONs) are a group of therapeutic molecules with enormous clinical potential owing to their high specificity and ability to target the expression of virtually any single or group of genes. Clinical translation of ONs is hampered by the inadequate bioavailability in the target cells due to the substantial extracellular and intracellular barriers exposed to these molecules. Different cationic polymers have been successfully deployed for the delivery of ONs. However, heterogeneous nature of these classical polymers is not suitable for clinical applications and hence vectors with completely defined structure are required. In this review, we discuss recent advances with sequence-defined polymers and their application for the delivery of short ONs. PMID- 25535687 TI - Bupivacaine in combination with fentanyl or sufentanil in epidural/intrathecal analgesia for labor: a meta-analysis. AB - This study is to compare the effectiveness of combinational use of bupivacaine with fentanyl (BUPI-FEN) and sufentanil (BUPI-SUF) in epidural/intrathecal analgesia for labor. Electronic databases were searched for relevant research papers published between 1985 and 2014. Meta-analyses of mean differences or odds ratios were performed and statistical heterogeneity between the studies tested by I(2) index. Ten studies recruiting a total of 728 women in labor were selected. Concentrations of the anesthetics used as mean +/- sd were bupivacaine 0.115 +/- 0.056%, fentanyl 0.0007 +/- 0.001%, and sufentanil 0.00017 +/- 0.00022%. Duration of analgesia was not significantly different between BUPI-SUF and BUPI-FEN administered mothers (mean difference [95%CI] of -33.55 [-74.94, 7.83] minutes; P = .11) under random effects. The onset of analgesia was also not significantly different between both groups (mean difference [95%CI] of -0.61 [-1.38, 0.16] minutes; P = .12). The number of neonates with Apgar score < 7 was significantly lower in BUPI-FEN group (odd ratio [95%CI] of 0.31 [0.10, 0.95]; P < .05). Pruritus incidence was similar. In conclusion, BUPI-FEN combination exhibits significantly better tolerability at an approximate ratio of 6 FEN:1 SUF, albeit, both fentanyl and sufentanil in combination with bupivacaine provide similar analgesic properties via the epidural or intrathecal routes for labor pain relief. PMID- 25535688 TI - Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. AB - PURPOSE: To determine the mechanism by which topically applied AR-13324, a rho kinase inhibitor, and an inhibitor of the norepinephrine transporter, reduces intraocular pressure (IOP) in normotensive monkey eyes. METHODS: Seven normotensive monkeys were used. Tonographic outflow facility (C) was measured before drug administration and repeated 6 hours after administration of 50 uL (25 uL*2) of 0.04% AR-13324 to 1 eye and an equal volume of vehicle to the contralateral control eye. Baseline aqueous humor flow rates (F) were measured hourly for 6 hours beginning at 10:00 AM on day 1. On day 2, 50 uL (25 uL*2) of 0.04% AR-13324 was applied to 1 eye of each animal and vehicle to the fellow eye at 8:00 AM. Aqueous humor flow rates were measured at the same times as on the baseline day beginning 2 hours after dosing. RESULTS: Six hours after a single dose of 0.04% AR-13324 to 7 normal monkey eyes, C was increased (P<0.05) by 53% in drug-treated eyes compared with either contralateral vehicle-treated control eyes or baseline measurements. The IOP measured by pneumatonometer in treated eyes was reduced (P<0.005) by 25% when compared with baseline measurements and by 24% when compared with contralateral vehicle-treated eyes. For 6 hours after a single dose of 0.04% AR-13324, F was reduced (P<0.05) by 20% and 23% when compared with contralateral vehicle-treated eyes and baseline values, respectively. CONCLUSIONS: AR-13324 reduces IOP in normotensive monkey eyes. A dual mechanism of action, increase in tonographic outflow facility, and decrease of aqueous humor flow rates, accounts for the IOP reduction in normotensive monkey eyes. PMID- 25535689 TI - Publication performance of women compared to men in German cardiology. AB - BACKGROUND: Abstract presentations at scientific congresses are a preparation for publication in peer reviewed journals. The present study aimed to investigate the prediction of abstract acceptance of peer reviewed publications focusing on the difference between male and female first authors. METHODS: We evaluated 8411 abstracts submitted to the German Cardiac Society by 2090 females and 6321 male scientists. Abstract grading (3 to 9 reviewers, blinded on a 5-point scale) separated those accepted and rejected followed by a bibliometric analysis of Medline publications from 2006 to 2012. RESULTS: While rating of abstracts was not different between males and females (p=0.475), publication rate of females was lower compared to males (17.5% vs 24.4 >=%, p<0.001). Female authors achieved a higher impact factor in their publications (5.1 +/- 0.2 vs 4.4 +/- 0.1, p=0.0003) and were more often listed on papers in highly ranked journals (impact factor >= 5) than males. Although, more accepted abstracts than rejected ones were published in high rank journals, a considerable number of papers were generated from rejected abstracts (22%). CONCLUSIONS: Female cardiologists had a better publication success than males concerning high rank peer reviewed publications. Acceptance in blinded abstract evaluation often detects work published later, while rejected contributions still might represent high quality work suitable for publication in peer reviewed journals. PMID- 25535690 TI - New predictors of mortality in adults with congenital heart disease and pulmonary hypertension: Midterm outcome of a prospective study. AB - BACKGROUND: Patients with CHD-PAH have a limited prognosis. In daily practice, combination therapy is often initiated after a clinical event. Although clinical events have been associated with a poor prognosis in idiopathic PAH, data on this association are limited in CHD-PAH. The aim of this study was to determine whether baseline characteristics and clinical events associate with mortality in patients with pulmonary hypertension (PAH) due to congenital heart disease (CHD). METHODS: In total 91 consecutive adults (42 +/- 14 year) with CHD-PAH were referred for therapy between January 2005 and June 2013. Cox proportional hazard analysis was performed to identify determinants of mortality, including clinical events as time dependent covariates. RESULTS: Twenty-four patients (nine with Down) died during the median follow-up of 4.7 (range 0.1-7.9) years. The one and eight year mortality rates were 7.3% and 37.3%, respectively. Clinical events included admission for heart failure (n=9), arrhythmias (n=9), haemoptysis (n=5), change to a worse NYHA class (n=16), vascular events (n=1), syncope (n=1) and need for red blood cell depletion (n=4). In univariate analysis, both baseline characteristics and clinical events were associated with mortality. In multivariate analysis, only baseline NT-pro-BNP serum level >= 500 ng/L and TAPSE<15mm at echocardiography were significant determinants of mortality. None of the clinical events remained significant. Patients with both a NT-pro-BNP serum level >= 500 ng/L and TAPSE<15mm at echocardiography have a nine fold higher mortality rate than patients without both risk factors. CONCLUSION: Prognosis is still poor in contemporary patients with CHD-PAH. Both baseline NT pro-BNP serum level and right ventricular function are superior to clinical events in prognostication. These two baseline characteristics should have a major impact on therapeutic management in patients with CHD-PAH, such as initiation of combination therapy. PMID- 25535691 TI - Does isolation of the left atrial posterior wall improve clinical outcomes after radiofrequency catheter ablation for persistent atrial fibrillation?: A prospective randomized clinical trial. AB - INTRODUCTION: Although posterior wall of left atrium (LA) is known to be arrhythmogenic focus, little is known about the effect of posterior wall isolation (PWI) in patients who undergo radiofrequency catheter ablation (RFCA) for persistent atrial fibrillation (PeAF). METHODS: We randomly assigned 120 consecutive PeAF patients to additional PWI [PWI (+), n=60] or control [PWI (-), n=60] groups. In all patients, linear ablation was performed after circumferential pulmonary vein isolation (PVI). Linear lesions included roof, anterior perimitral, and cavotricuspid isthmus lines with conduction block. In PWI (+) group, posterior inferior linear lesion was also conducted. Creatine kinase-MB (CK-MB) and troponin-T levels were measured 1day after RFCA. LA emptying fraction (LAEF) was assessed before and 12 months after RFCA. RESULTS: A total of 120 subjects were followed for 12 months after RFCA. There were no significant differences between two groups in baseline demographics and LA volume (LAV). The levels of CK-MB and troponin-T and procedure time were not significantly different between the groups. AF termination during RFCA was more frequently observed in PWI (+) than control (P=0.035). During follow-up period, recurrence occurred in 10 (16.7%) patients in PWI (+) and 22 (36.7%) in control (P=0.02). The change in LAEF was not significantly different between the groups. On multivariate analysis, smaller LAV and additional PWI were independently associated with procedure outcome. CONCLUSIONS: PWI in addition to PVI plus linear lesions was an efficient strategy without deterioration of LA pump function in patients who underwent RFCA for PeAF. PMID- 25535692 TI - Key role of MIF in the migration of endothelial progenitor cells in patients during cardiac surgery. PMID- 25535694 TI - Lipidomic approach towards deciphering anandamide effects in rat decidual cell. AB - Altered phospholipid (PL) metabolism has been associated with pregnancy disorders. Moreover, lipid molecules such as endocannabinoids (eCBs) and prostaglandins (PGs) are important mediators of reproductive events. In humans, abnormal decidualization has been linked with unexplained infertility, miscarriage and endometrial pathologies. Anandamide (AEA), the major eCB, induces apoptosis in rat decidual cells. In this study, the PL profile of rat decidual cells was characterized by a Mass spectrometry (MS) based lipidomic approach. Furthermore, we analyzed a possible correlation between changes in PL of rat decidual cells' membrane and AEA-induced apoptosis. We found an increase in phosphatidylserine and a reduction of cardiolipin and phophatidylinositol relative contents. In addition, we observed an increase in the content of alkyl(alkenyl) acylPL, plasmalogens, and of long chain fatty acids especially with high degrees of unsaturation, as well as an increase in lipid hydroperoxides in treated cells. These findings provide novel insights on deregulation of lipid metabolism by anandamide, which may display further implications in decidualization process. PMID- 25535695 TI - A melanoma trend forecast from 2002 - What happened then? AB - In 2002, a paper was published that highlighted the strong correlation noticed between melanoma incidence and the number of surrounding frequency modulation (FM) transmitters in the Nordic countries since 1955. In the report the development of future numbers of melanoma cases in Estonia were estimated since they got the FM broadcasting system rolled out not until 1992. Here, we report what happened since then in Estonia regarding melanoma cases per year. We also comment on the recent development in the Nordic countries, which is not very reassuring from a public health point of view. The last 10 years of melanoma incidence trends, increasing at an exponential rate, suggest that responsible authorities now need to consider possible influences also from other radiation sources in addition to UV radiation from the sun. PMID- 25535696 TI - Phosphorylation control of protein tyrosine phosphatase A activity in Mycobacterium tuberculosis. AB - Protein tyrosine phosphatase A (PtpA) has been shown to play a key role in human macrophage infection by Mycobacterium tuberculosis (Mtb). Protein tyrosine kinase A (PtkA) was the first protein tyrosine kinase shown to phosphorylate PtpA. Here, we found that PtkA-mediated phosphorylation of PtPA on Tyr-128 and Tyr-129 enhances the PtPA phosphatase activity. Moreover, ex-vivo protein-protein interaction assays showed that PtpA can be phosphorylated by several eukaryotic like Ser/Thr protein kinases, such as protein kinase A (PknA). PknA was found to regulate PtpA phosphatase activity through Thr-45 phosphorylation. These results indicate that members of two independent families of protein kinases tune PtpA activity in Mtb. PMID- 25535697 TI - Construction of a genome-scale metabolic network of the plant pathogen Pectobacterium carotovorum provides new strategies for bactericide discovery. AB - We reconstructed the first genome-scale metabolic network of the plant pathogen Pectobacterium carotovorum subsp. carotovorum PC1 based on its genomic sequence, annotation, and physiological data. Metabolic characteristics were analyzed using flux balance analysis (FBA), and the results were afterwards validated by phenotype microarray (PM) experiments. The reconstructed genome-scale metabolic model, iPC1209, contains 2235 reactions, 1113 metabolites and 1209 genes. We identified 19 potential bactericide targets through a comprehensive in silico gene-deletion study. Next, we performed virtual screening to identify candidate inhibitors for an important potential drug target, alkaline phosphatase, and experimentally verified that three lead compounds were able to inhibit both bacterial cell viability and the activity of alkaline phosphatase in vitro. This study illustrates a new strategy for the discovery of agricultural bactericides. PMID- 25535698 TI - Practice gaps. Pediatric atopic dermatitis and associated morbidities. PMID- 25535699 TI - Purkinje cell dendritic atrophy induced by prenatal stress is mitigated by early environmental enrichment. AB - BACKGROUND: Prenatal stress (PS) in experimental animals causes long-lasting changes in Purkinje cell dendritic morphology. Furthermore, these structural changes are associated with an increase in anxiogenic behaviors in the elevated plus maze (EPM) and open-field (OF) test. OBJECTIVES: As environmental enrichment (EE) has significant restorative effects on brain neurons and behavior, the aim of this study was to evaluate if postweaning EE mitigates the decrease in Purkinje cell dendritic expansion and exploratory behavior induced by PS in mice. MATERIALS AND METHODS: Restraint stress was induced from gestational day 14 (G14) to G21. Approximately 50% of the PS animals were submitted to the EE paradigm between postnatal days 22 (P22) and P52. At P52 and P82, male animals were behaviorally evaluated, and then the morphology of the cerebellar vermal Purkinje cells was analyzed. RESULTS: We found that EE significantly ameliorates the Purkinje cell dendritic atrophy and anxiety-like behavior in the EPM. CONCLUSION: Our data show that long-lasting Purkinje cell dendritic impairments and anxiety like behavior can be mitigated by postweaning EE. PMID- 25535700 TI - Comparison of different tractography algorithms and validation by intraoperative stimulation in a child with a brain tumor. AB - BACKGROUND: Advanced modalities such as functional magnetic resonance imaging (MRI) and diffusion MR tractography offer in vivo information about brain networks and are therefore increasingly used for neurosurgical planning in children also. AIM: This study aims to study the application of routine and advanced tractography algorithms and its comparison with intraoperative subcortical electrical stimulation. METHOD: Presurgical functional MRI and MR diffusion tractography were performed on a 6-year-old patient presenting with seizures, but no motor symptoms, due to a neuroectodermal tumor in the left central region. Three different tractography algorithms were compared: deterministic diffusion tensor imaging (DTI)-tracking, probabilistic DTI tracking, and probabilistic constrained spherical deconvolution tracking (pCSD). RESULTS: All three tractography algorithms could localize the core of the corticospinal tract with good agreement. The pCSD-tracking algorithm was more sensitive in revealing the anatomically most realistic fiber distribution and a proportion of fibers traversing a solid part of the tumor. Intraoperative stimulation confirmed these fibers close to the tumor. As a result, only a subtotal resection was performed, preventing postoperative sensorimotor deficits. CONCLUSION: Although, all tractography algorithms successfully identified the core of the corticospinal pathway, deterministic DTI-tractography, as widely used in clinical neuronavigation software, only insufficiently visualized critical fibers here. We believe these results argue for a stronger consideration of advanced tractography approaches in neurosurgical planning. PMID- 25535693 TI - Molecularly targeted therapies in non-small-cell lung cancer annual update 2014. AB - There have been significant advances in the understanding of the biology and treatment of non-small-cell lung cancer (NSCLC) during the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC. We are beginning to understand the mechanisms of acquired resistance after exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next-generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies, and immunotherapy. PMID- 25535701 TI - Lactotransferrin Gene (LTF) Polymorphisms and Dental Implant Loss: A Case-Control Association Study. AB - BACKGROUND: Dental implants have been widely used to replace missing teeth, accomplishing aesthetics and function. Due to its large use worldwide, the small percentage of implant loss becomes significant in number of cases. Lactotransferrin (LTF) is a pleiotropic protein, expressed in various body tissues and fluids, which modulates the host immune-inflammatory response and bone metabolism, and might be involved in dental implant osseointegration. Recently, a few studies have been investigating genetic aspects underlying dental implant failure. PURPOSE: This case-control study aimed to investigate the association of genetic markers (tag SNPs) in LTF gene and clinical parameters with dental implant loss. MATERIAL AND METHODS: 278 patients, both sexes, mean age 51 years old, divided into 184 without and 94 with implant loss, were genotyped for sixteen tag SNPs, representative of the whole LTF gene. Also, clinical oral and systemic parameters were analyzed. Univariate and Multivariate Logistic Regression model were used to analyze the results (p < .05). RESULTS: No association was found between the tag SNPs and implant loss in the study population. Clinical association was found with medical treatment, hormonal reposition, edentulism, number of placed implants, plaque, calculus, and mobility. CONCLUSION: Clinical variables, but not LTF gene polymorphisms, were associated with implant loss. PMID- 25535702 TI - Chemoselective efficient synthesis of functionalized beta-oxonitriles through cyanomethylation of Weinreb amides. AB - A synthesis of beta-oxonitriles is reported via the generation of R(1)R(2)CLiCN species followed by the trapping with variously decorated Weinreb amides. The optimization study revealed that lithiation of acetonitriles is best accomplished by deprotonation with MeLi-LiBr at low temperature. The protocol can be conveniently adapted to the synthesis of alpha-mono or alpha,alpha-disubstituted cyanoketones. (15)N- and (17)O-NMR data are reported for selected compounds. PMID- 25535704 TI - A polymer in a crowded and confined space: effects of crowder size and poly dispersity. AB - DNA compaction in a bacterial cell is in part carried out by entropic (depletion) forces induced by "free" proteins or crowding particles in the cytoplasm. Indeed, recent in vitro experiments highlight these effects by showing that they alone can condense the E. coli chromosome to its in vivo size. Using molecular dynamics simulations and a theoretical approach, we study how a flexible chain molecule can be compacted by crowding particles with variable sizes in a (cell-like) cylindrical space. Our results show that with smaller crowding agents the compaction occurs at a lower volume fraction but at a larger concentration such that doubling their size is equivalent to increasing their concentration fourfold. Similarly, the effect of polydispersity can be correctly mimicked by adjusting the size of crowders in a homogeneous system. Under different conditions, however, crowding particles can induce chain adsorption onto the cylinder wall, stretching the chain, which would otherwise remain condensed. PMID- 25535705 TI - Bioremediation of vegetable and agrowastes by Pleurotus ostreatus: a novel strategy to produce edible mushroom with enhanced yield and nutrition. AB - Pleurotus ostreatus was grown on paddy straw as well as other vegetable and agricultural wastes i.e. pea pod shell, cauliflower leaves, radish leaves and brassica straw in various combinations with paddy straw. The mushroom did not grow on the vegetable wastes separately. The cumulative yield and biological efficiency of the edible oyster mushroom P. ostreatus grown on substrate containing paddy straw in various combinations with different vegetable wastes i.e. 20% and 30 % vegetable wastes mixed with 80% and 70% (w/w) of paddy straw was found to be better, when compared with yield and biological efficiency obtained on paddy straw (100%) alone. The protein content and six essential amino acid contents (Leu, Ile, Val, Thr, Met, Phe) showed a significant increase and total sugar and reducing sugar contents showed decrease in the mushroom fruit bodies grown at different combinations of vegetable wastes with paddy straw as compared to paddy straw alone. However, there was not any significant change in moisture content of mushroom cultivated on different groups of wastes. Hence, results of this investigation suggest that the vegetable wastes which are generally left to rot in situ in many cities and villages causing outbreak of diseases can be bioremediated by edible mushroom P. ostreatus. The added advantage is that we get edible mushroom fruit body with improved nutrition. PMID- 25535706 TI - Biotransformation of arsenic by bacterial strains mediated by oxido-reductase enzyme system. AB - The present study deals with the enzyme mediated biotransformation of arsenic in five arsenic tolerant strains (Bacillus subtilis, Bacillus megaterium, Bacillus pumilus, Paenibacillus macerans and Escherichia coli). Biotransformation ability of these isolates was evaluated by monitoring arsenite oxidase and arsenate reductase activity. Results showed that arsenic oxidase activity was exclusively present in P. macerans and B. pumilus while B. subtilis, B. megaterium and E. coli strains showed presence of Arsenic oxido-reductase enzyme. The reversible nature of arsenic oxido- reductase suggested that same enzyme can carry out oxidation and reduction of arsenic depending upon the relative concentration of arsenic species. Lineweaver-Burk plot of the arsenite oxidase activity in P. macerans showed highest Km value (Km- 200 MUM) and lower Vmax (0.012 MUmol mg-1 protein min-1) indicating lowest affinity of the enzyme for arsenite. On the contrary, E. coli showed the lower Km value ( Km- 38.46 MUM) and higher Vmax (0.044 MUmol mg-1 protein min-1) suggesting for higher affinity for the arsenite. Lineweaver-Burk plot of arsenate reductase activity showed the presence of this enzyme in B. subtilis, B. megaterium and E. coli which were in the range of 200 360 MUM Km and Vmax value between 0.256- 0.129 mmol mg-1 protein min-1. These results suggested that affinity of the as reductase enzyme is lowest for arsenate than that for the arsenite. Thus, arsenite oxidase system appears to be a predominant mechanism of cellular defense in these bacterial strains. PMID- 25535707 TI - Direct red decolorization and ligninolytic enzymes production by improved strains of Pleurotus using basidiospore derived monokaryons. AB - In the present investigation the efficiency of three species of Pleurotus and their improved dikaryons (heterokaryons) was assessed for decolorization of direct red and production of lignin peroxidase (LiP), manganese peroxidase (MnP) and laccase enzymes. All the species of Pleurotus i.e. P. flabellatus, P. ostreatus, and P. citrinopileatus decolorized the dye Direct Red well. However, Pfo 6X9 and Poc 9X6 decolorized the dye more effectively than three species of Pleurotus. The improved dikaryons also showed higher ligninolytic activity than the parental species. Poc 9X6 showed higher LiP (76.27U), MnP (623.24U) and laccase activity (594.80U). In the present work different pH, age and concentration of inoculum and effect of surfactant i.e. sodium dodecyl sulphate (SDS) and Tween—80 were analyzed in order to determine the optimum ones to decolorize maximum concentration of dye. 5 ml of 10 days old culture on pH 5.5 and 0.1% Tween—80 supported maximum decolorization of direct red dye. PMID- 25535708 TI - Biodegradation of pyrene and phenanthrene by bacterial consortium and evaluation of role of surfactant. AB - High molecular weight poly aromatic hydrocarbons (HMW PAHs) are well known for their hydrophobicity and they get strongly adsorbed onto the soil particles. Generally, surfactants facilitate the biodegradation of PAH by enhancing their solubility and desorption of hydrophobic compounds from soil particles. To investigate the role of synthetic surfactant in biodegradation of PAHs, two bacterial strains BP10 and P2 were incubated in soil spiked with pyrene and phenantherene (100 MUg g-1of soil each) in isolation and in combination with/without Tween 80. After 14 days of incubation, pyrene and phenantherene were degraded by a combination of BP10 and P2 to the extent of 98% and 99%, respectively. Addition of tween 80 reduced the degradation of pyrene and phenantherene by 35 and 10%, respectively. Biosurfactant produced by selected strains i.e. BP10 and P2 could enhance desorption of pyrene (100 MUg g-1of soil) by about 27% and 12%, respectively. However, desorption activity was relatively higher (32 and 29%, respectively) in case of phenanthrene (100 MUg g-1of soil) from the spiked soil. Present study showed that in spite of additional chemical surfactant, bioaugmentation of highly petroleum hydrocarbon degrading bacterial combination was very effective in boosting the bioremediation of PAHs- contaminated sites. PMID- 25535709 TI - Biodegradation of wheat straw by Pleurotus ostreatus. AB - Wheat straw pretreated with chemicals as well as hot water was subjected to degradation by edible mushroom Pleurotus ostreatus. Lignin, cellulose and hemicelluloses component of both chemically as well as hot water treated wheat straw was degraded by the fungus and in turn the edible and nutritious fruiting body of the mushroom was produced. Biodegradation of wheat straw in terms of loss of lignin, cellulose and hemicellulose showed positive correlation with cellulases, xylanase, laccase and polyphenol oxidase (PPO) activity of the fungus. During vegetative growth of the fungus, lignin degradation was faster and during fructification, lignin degradation was slower than cellulose and hemicellulose. The carbon content of the wheat straw decreased while, nitrogen content increased during degradation of the waste. Hot water treated wheat straw supported better production of enzymatic activity and degraded more efficiently than chemically sterilized substrate. The cumulative yield and biological efficiency (BE) of the mushroom was maximum on the hot water treated substrate. Degradation of the hot water treated wheat straw was better and faster than chemically treated substrate. PMID- 25535710 TI - Phycoremediation of textile wastewater by unicellular microalga Chlorella pyrenoidosa. AB - The potential application of microalga Chlorella pyrenoidosa was investigated for phycoremediation of textile wastewater. Two 15 days batch experiment containing autoclaved and unautoclaved textile wastewater were performed to measure the efficiency of alga to remediate the wastewater. Experiments were set at equivalent external conditions and pollutant load was measured on alternate of 5 days to determine the pollutant removal efficiency of alga. Alga was found to be more efficient in removal of pollutants load in autoclaved wastewater; agents of eutrophication such as nitrate and phosphate are reduced by 62% +/-0.5 and 87% +/ 0.7 respectively while organic load in terms of BOD is reduced by 81% +/-0.2 whereas, In unautoclaved wastewater in presence of algal-bacterial consortium, nitrate and phosphate were removed by 81% +/-1 and 36% +/-2.2 while BOD is reduced by 73% +/-1.6 only. Another time dependent experiment of dye removal was also performed to measure the adsorption potential of selected dried algal biomass. An equal amount of dried algal biomass was introduced to various range of textile wastewater simulated with methylene blue (MB) dye. The maximum colour removal was observed afterduration of 30 minutes by dry algal biomass. PMID- 25535711 TI - Production of ligninolytic enzymes by white rot fungi on lignocellulosic wastes using novel pretreatments. AB - Production of extracellular ligninolytic enzymes (laccase and polyphenol oxidase) secreted by three species of white rot fungi (Pleurotus florida, P. flabellatus and P. sajor—caju) under in vivo condition was studied on two lignocellulosic substrates i.e., paddy straw and wheat straw. These lignocellulosic substrates were treated with neem (Azadirachta indica) oil and ashoka (Saraca indica) leaves extract. Between the two lignocellulosic substrates, paddy straw pretreated with neem oil supported maximum activity of laccase and polyphenol oxidase (PPO). The activities of both the enzymes were low on the 5th day of cultivation which increased on the 10th day and reached at peak on the 15th day. Thereafter, there was continuous decrease in the enzymatic activity. Among the three species, P. flabellatus (P3) showed maximum ligninolytic enzymatic activity followed by P. florida (P2)and P. sajor—caju (P1). PMID- 25535712 TI - Effect of environmental factors on bacterial quorum sensing. AB - Biodegradation of complex hydrocarbons usually requires the cooperation of more than a single species of microorganisms including bacteria. This is particularly true in pollutants that are made up of many different compounds such as crude oil or petroleum, and where complete mineralization to CO2 and H2O is desired. An effort has been made to form the consortium of bacterial isolates (Qs1, Qs2 and Qs5) which are isolated from oil contaminated soil, and the effects of different environmental factors on these consortium has been studied . The growth of the consortium was studied at 6.5 pH and 35 degrees C like the individual bacterial isolates on the different hydrocarbons (xylene, toluene, hexane, diesel, benzene and petrol). These consortium of bacterial isolates, shared more efficient utilization of hydrocarbon as carbon source. This consortium shows confluent growth- at pH 6.0, 5.5, and 5.0 but survival rate decreases at pH above 6.5. Extremes in pH were shown to have a negative influence on the ability of microbial populations to degrade hydrocarbons. They also show the higher growth rate at the higher temperature range (up to 40 degrees C) but their growth rate decreases at lower temperature range (below 25 degrees C). It is suggested that the use of above bacterial consortium (at 35 degrees C temperature and 6.5pH) will be an effective and eco-friendly technology for the remediation of hydrocarbons. PMID- 25535713 TI - Alterations in lipid and fatty acid composition of the cyanobacterium Scytonema geitleri bharadwaja under water stress. AB - The composition of the glycerolipids [monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG), sulfoquinovosyl diacylglycerol (SQDG) and phosphatidylglycerol (PG)] and alterations in their saturation and unsaturation levels in response to osmotic and matric water potential have been investigated in the cyanobacterium Scytonema geitleri Bharadwaja. The level of MGDG in S. geitleri was high followed by PG, DGDG and SQDG. Whereas, the amount of fatty acids namely palmitic, stearic, oleic, linoleic and linolenic acid were high, arachidic and behenic acid were, however, present in traces in the four glycerolipids. A significant reduction in the level of total lipid as well as individual class lipid was observed in S. geitleri in response to matric water potential to that of its total lipid and individual class lipid in response to osmotic water potential. The levels of polyunsaturated and unsaturated fatty acids also increased in response to matric water potential to that of osmotic water potential. PMID- 25535714 TI - Production of cellulolytic enzymes by Pleurotus species on lignocellulosic wastes using novel pretreatments. AB - In the present investigation three species of Pleurotus i.e. P. sajor—caju (P1), P. florida (P2) and P. flabellatus (P3) along with two lignocellulosic substrates namely paddy straw and wheat straw were selected for evaluation of production of extracellular cellulolytic enzymes. During the cultivation of three species of Pleurotus under in vivo condition, the two lignocellulosic substrates were treated with plants extracts (aqueous extracts of ashoka leaves (A) and neem oil (B)), hot water (H) and chemicals (C).Among all treatments, neem oil treated substrates supported better enzyme production followed by aqueous extract of ashoka leaves, hot water and chemical treatment. Between the two substrates paddy straw supported better enzyme production than wheat straw. P. flabellatus showed maximum activity of exoglucanase, endoglucanase and β—glucosidase followed by P. florida and P. sajor—caju. PMID- 25535715 TI - Removal of Cr (VI) by a halotolerant bacterium Halomonas sp. CSB 5 isolated from sambhar salt lake Rajastha (India). AB - A halotolerant chromate reducing bacterium CSB 5 isolated from the Sambhar Salt Lake (Rajasthan) was identified as Halomonas sp. CSB 5 by 16SrDNA sequence analysis. The isolate could tolerate up to 25% NaCl (w/v) and100 MUg mL-1of Chromium hexavalent in the complex medium (CM). Removal of Cr (VI) at concentration of 20, 40 and 60 MUg mL-1 was found to be 98%, 90.2%, and 65.7% within a period of 60 hour.Effect of factors like pH and temperature on the total removal of Cr (VI) at 60MUg mL-1concentration showed maximum removal at pH 8.0 (77.9 %) and temperature 35 degrees C (82.6%) in 60 hour. The maximum intracellular uptake and surface adsorption (3.22 +/- 0.09 and 14.16 +/- 0.49 MUg mg-1 dry wt.) in CMB 5 bacterium was observed at 75 MUg mL-1 of Cr (VI) concentration in 45 min.The results showed that contribution of surface binding was about 4-5 fold higher than the intracellular uptake. Bacterium showed concentration dependent increase in the chromate reductase activity with saturating rate at 60 MUg mL-1 concentration of chromium. The values of Km and Vmax with NADH of the bacterium was found to be 0.818 MUg mL-1 and 0.085 MUg mL 1.min-1.mg-1 protein, respectively. Fourier Transform Infrared Spectroscopy (FTIR) analysis of Cr (VI) binding on membrane surface showed changes in wavenumber between 3300-2800 cm-1due to involvement of proteins and fatty acids in the binding of Cr (VI). The absorption peaks at wavenumbers 1654.9, 1580.3 cm 1, 1248 and 1085.6 cm-1 shifted to lower frequencies due to interaction of Cr (VI) with functional groups like amides and phosphodiester. These results suggested that the isolated CSB 5 bacterium can be used as potential bioremediating agent for removal of Cr (VI) in salt loaded waste water. PMID- 25535716 TI - Talc based exopolysaccharides formulation enhancing growth and production of Hellianthus annuus under saline conditions. AB - Stress tolerating strain of Pseudomonas aeruginosa PF07 possessing plant growth promoting activity was screened for the production of exopolysaccharides (EPS). EPS production was monitored in the cell free culture supernatant (CFCS) and extracted EPS was further purified by thin layer chromatography. EPS producing cells were taken to design talc based formulation and its efficacy was checked on oilseed crop sunflower (Hellianthus annuus), under in vivo saline conditions (soil irrigated with 125 mM of saline water). Application of bioformulation significantly enhanced the yield and growth attributes of the plant in comparison to control (untreated seeds) under stress and non—stress conditions. Germination rate, plant length, dry weight and seed weight increased remarkably. The above findings suggest the application and benefits of utilizing EPS formulation in boosting early seedling emergence, enhancing plant growth parameters, increasing seed weight and mitigating stress in saline affected regions. Such bioformulation may enhance RAS/RT (Root Adhering Soil to Root Tissue ratio), texture of the soil, increase porosity, improve uptake of nutrients, and hence may be considered as commercially important formulation for renovation of stressed sites and enhancing plant growth. PMID- 25535717 TI - Identification and structure elucidation of antimicrobial compounds from Lyngbya aestuarii and Aphanothece bullosa. AB - Cyanobacteria are known to produce array of compounds. In an earlier report, we reported antibacterial and antifungal activities in methanolic crude extracts of laboratory grown Lyngbya aestuarii and Aphanothece bullosa isolated from Chilka Lake and local paddy field respectively. In this report the same methanolic crude extracts were subjected to TLC purification twice by altering the solvents and UV—illuminated bands bioassayed. Such UV illuminated potent bands obtained after 2nd TLC were subjected to spectroscopic analysis (UV, IR, 1H NMR and LCMS/MS). We have screened malyngolide and dragonamide C from L. aestuarii and a diterpenoid and majusculoic acid from A. bullosa. Dragonamide C and malyngolide were found to be antifungal while majusculoic acid and a diterpenoid as antibacterial. As far as our knowledge goes, this is the first ever report where fresh water A. bullosa was found to be a source of diterpenoid and majusculoic acid. Likewise, L. aestuarii was also established as a source of malyngolide and dragonamide C. This again indicated that cyanobacteria are inherently endowed with the capacity to produce metabolites according to niche and species specific manner emphasising fresh water cyanobacterial strain are as important as marine one. PMID- 25535718 TI - Chromium (VI) induced oxidative stress in halotolerant alga Dunaliella salina and D. tertiolecta isolated from sambhar salt lake of Rajasthan (India). AB - Chromium (Cr) is one of the most serious pollutants in aquatic systems. This study was performed to understand the effect of Cr (VI) on halophilic algal strains of D. salina and D. tertiolecta. The results revealed good tolerance of D. salina towards chromium (VI) up to 8 ppm concentration, whereas tolerance level in D. tertiolecta was up to 2 ppm concentration. Cr (VI) not only inhibited the growth of D. tertiolecta, but also showed increased inhibition in the level of photosynthetic pigments, protein and carbohydrate. Results have revealed that chromium (VI) induced higher increase in lipid peroxidation and H2O2 production in D. tertiolecta than the D. salina, particularly at higher concentration of chromium (VI). Chromium (VI) induced increase in the rate of RNO bleaching, loss of pigments and thiol (-SH) group was relatively higher in D. tertiolecta than the D. salina, which is indicating that D. tertiolecta was prone to Cr (VI) induced oxidative stress. Results on RNO bleaching in the presence of radical quenchers suggested that OH degrees radical played an important role in the chromium (VI)-induced general oxidative stress in D. tertiolecta. PMID- 25535719 TI - Histone demethylases and control of gene expression in plants. AB - Covalent histone modifications, chromatin remodeling and incorporation of histone variants regulate the dynamics of chromatin structure. Among covalent histone modifications, histone methylation mediates by histone methylases that influence the gene expression in heterochromatin silencing, genomic imprinting and transcription. In contrast to methylases, histone demethylases remove the methyl groups from lysine or arginine residues of histones and have enormous impact on gene expression via modified chromatin structures. Two types of histone lysie demethylases have been identified, including lysine specific demethylases 1 (LSD1) and Jmj (Jumonji) domain containing family proteins. The human demethyliminase (PADI4) converts monomethyl arginine residue to citrulline by the arginine demethylimination. In this review we summarize recent advances to understand the mechanism of demethylases in regulation of plant gene expression. In addition we are highlighting the function of four human like LSD1 (LDL) and jmj domain containing genes of Arabidopsis that regulate the defense related, flowering controlling and brassinosteroid response genes. PMID- 25535720 TI - Importance of algae as a potential source of biofuel. AB - Algae have a great potential source of biofuels and also have unique importance to reduce gaseous emissions, greenhouse gases, climatic changes, global warming receding of glaciers, rising sea levels and loss of biodiversity. The microalgae, like Scenedesmus obliquus, Neochloris oleabundans, Nannochloropsis sp., Chlorella emersonii, and Dunaliella tertiolecta have high oil content. Among the known algae, Scenedesmus obliquus is one of the most potential sources for biodiesel as it has adequate fatty acid (linolenic acid) and other polyunsaturated fatty acids. Bio—ethanol is already in the market of United States of America and Europe as an additive in gasoline. Bio—hydrogen is the cleanest biofuel and extensive efforts are going on to bring it to market at economical price. This review highlights recent development and progress in the field of algae as a potential source of biofuel. PMID- 25535721 TI - Role of free living, immobilized and non-viable biomass of Nostoc muscorum in removal of heavy metals: an impact of physiological state of biosorbent. AB - Biosorption of Pb and Cd by using free living, immobilized living and non-viable forms of Nostocmuscorum was studied as a function of pH (3-8), contact time (5 240 min) and metal concentration (10-100 MUg ml-1), to find out the most efficient physiological formfor metal removal. Results revealed that optimum conditions for biosorption of both the metals by different states of biosorbentwere almost same (contact time- 30 min, metal concentration- 100 MUg ml 1 and pH- 5.1 and 6, for Pb and Cd, respectively) however, the immobilized biomass of N. muscorum was found to be more suitable for the development of an efficient biosorbent as evident from theqmax(1000 mg g-1protein) and Kf (0.08 mg g-1protein) values obtained from the Langmuir and Freundlich isotherms. A pseudo second order kinetics was found more suitable for describing the nature of biosorption of both the metals by all the three forms of N. muscorum. An analysis of correlation revealed that as the metal concentration increases, the removal of Pb and Cd by N. muscorum also increases significantly. The regression analysis showed that the rate of removal of Pb by free living and dead biomass was 1.89 and 1.58 times higher than the rate of removal of Cd by respective biomass. In contrast, the rate of removal of Cd by immobilized biomass was 1.46 times higher than that of Pb. PMID- 25535722 TI - Isolation, characterization and cardiac differentiation of human thymus tissue derived mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) are promising candidate donor cells for replacement of cardiomyocyte loss during ischemia and in vitro generation of myocardial tissue. We have successfully isolated MSCs from the discarded neonatal thymus gland during cardiac surgery. The thymus MSCs were characterized by cell surface antigen expression. These cells have high ability for proliferation and are able to differentiate into osteoblasts and adipocytes in vitro. For cardiac differentiation, the cells were divided into 3 groups: untreated control; 5 azacytidine group and sequential exposure to 5-azacytidine, bone morphogenetic protein 4, and basic fibroblast growth factor. Thymus MSCs showed a fibrolast like morphology and some differentiated cells increased in size, formed a ball like appearance over time and spontaneously contracting cells were observed in sequential exposure group. Immunostaining studies, cardiac specific genes/protein expression confirmed the cardiomyocyte phenotype of the differentiated cells. These results demonstrate that thymus MSCs can be a promising cellular source for cardiac cell therapy and tissue engineering. PMID- 25535723 TI - Laparoscopic remnant cholecystectomy and transcystic common bile duct exploration for gallbladder/cystic duct remnant with stones and choledocholithiasis after cholecystectomy. AB - BACKGROUND: Postcholecystectomy syndrome has been a long-standing source of frustration for surgeons. The objective of this study was to assess the feasibility and safety of laparoscopic remnant cholecystectomy (LRC) and laparoscopic transcystic common bile duct (CBD) exploration (LTCBDE) when adopted as the management for gallbladder/cystic duct remnant with stones and choledocholithiasis (GRSC) after cholecystectomy. PATIENTS AND METHODS: This is a retrospective study of 11 patients who underwent surgeries for GRSC: the first 4 patients (Group 1) underwent open remnant cholecystectomy and CBD exploration, whereas the last 7 patients (Group 2) underwent LRC with LTCBDE successfully. Demographic data and perioperative parameters were analyzed and compared between the two groups. RESULTS: All 11 patients had undergone cholecystectomy for symptomatic gallstone diseases. These patients had a mean age of 62 years. The time interval between cholecystectomy and the diagnosis of GRSC ranged from 4 years to 23 years (mean, 13 years). There was a significant reduction in postoperative hospital stay (5.00+/-1.41 versus 2.14+/-1.77 days, P=.034) and blood loss (35.00+/-10.00 versus 14.29+/-7.87 mL, P=.011) in Group 2 compared with Group 1. The 30-day morbidity rate was 9.1%. At a mean follow-up of 24 months (range, 6-45 months), no symptoms had recurred, and no mortality was recorded in this study. CONCLUSIONS: LRC and LTCBDE for GRSC are safe and feasible and could be offered as a choice in centers performing advanced laparoscopic procedures. PMID- 25535725 TI - Mossbauer and computational investigation of a functional [NiFe] hydrogenase model complex. AB - Developing biomimetic complexes that model the active site of [NiFe] hydrogenase enzymes in order to catalyze the activation of H2 is a topic of major interest. A functional [NiFe] hydrogenase model complex has recently been described by Ogo et al. (Science, 2013, 339, 682-683). Here, we report a Mossbauer and computational investigation of this model complex. This study affords deeper understanding of the electronic structure, the reactivity and the mechanism of H2 activation by this complex. PMID- 25535724 TI - Simultaneous measurement of cytosolic and mitochondrial calcium levels: observations in TRPC1-silenced hepatocellular carcinoma cells. AB - INTRODUCTION: The measurement of intracellular Ca(2+), cytosolic or stored in organelles, i.e., mitochondria, gave valuable data for numerous areas of research. In case of tumor cells, mitochondrial Ca(2+) levels play essential roles in apoptosis along with endoplasmic reticulum (ER) Ca(2+). In this study, we describe a Ca(2+) monitoring system that allows studying both adherent cells and tissues and discuss data obtained from hepatocellular carcinoma cells and rat thoracic aorta by using this system. METHODS: For this purpose, two apparatus, one for adherent cells and the other for intact rat aorta, were designed and produced. With this system, changes in cytosolic Ca(2+) levels following store operated calcium (SOC) entry induced by sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) blockers were recorded in different hepatocellular carcinoma cells. Furthermore, cytosolic and mitochondrial Ca(2+) levels were simultaneously measured in TRPC1-silenced Huh7 hepatocellular carcinoma cells. In addition, the effects of trifluoromethylphenylimidazole (TRIM) on cyclopiazonic acid (CPA)-, serotonin (5-HT)-, and phenylephrine (PE)-induced changes in isometric force and cytosolic Ca(2+) levels were determined simultaneously in rat thoracic aorta. The effects of aging on PE-induced responses were also investigated. RESULTS: After SOC entry activation, cytosolic Ca(2+) levels were increased, as expected in all hepatocellular carcinoma cells. Mitochondrial Ca(2+) levels following CPA-induced ER depletion were significantly (p<.05) diminished in TRPC1-silenced Huh7 cells. In addition, TRIM partially inhibited both 5-HT-induced contractions and cytosolic Ca(2+) levels without affecting CPA and PE responses. PE-induced contractions and cytosolic Ca(2+) levels were similar in aorta from young and old (3 and 22 months, respectively) rats. DISCUSSION: We confirmed that the system provides valuable data about intracellular Ca(2+) dynamics by allowing simultaneous measurements and sequential addition of compounds in adherent cells. The decrease in mitochondrial Ca(2+) loading following CPA-induced ER depletion in TRPC1-silenced Huh7 cells suggests a possible role of TRPC1 in hepatocellular carcinoma cell apoptosis. The system also enables the simultaneous measurement of isometric force and cytosolic Ca(2+) levels and promotes understanding vascular physiology and disease. PMID- 25535726 TI - Association between KRAS mutation and lung metastasis in advanced colorectal cancer. AB - BACKGROUND: KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development. METHODS: We retrospectively evaluated data from patients with mCRC whose tumour was tested for KRAS mutation from 2008 to 2010. The relationships of KRAS mutational status with time-to-lung metastasis (TTLM) and overall survival (OS) were analysed. RESULTS: Of the 494 patients identified, 202 (41%) had tumours with KRAS mutation. KRAS mutations were associated with a shorter TTLM (median 15.2 vs 22.4 months; hazard ratio=1.40; P=0.002) and a two-fold greater odds of developing lung metastases during the disease course in patients with liver-limited mCRC at diagnosis (72 vs 56%, P=0.007). Overall survival did not differ by KRAS status. CONCLUSIONS: Lung metastasis was more likely to develop during the disease course in patients whose tumour had a KRAS mutation than in those whose tumour did not have a KRAS mutation. This finding may have an impact on decision making for surgical resection of metastatic disease. PMID- 25535728 TI - Reexamining treatment of high-grade T1 bladder cancer according to depth of lamina propria invasion: a prospective trial of 200 patients. AB - BACKGROUND: Management of high-grade T1 (HGT1) bladder cancer represents a major challenge. We studied a treatment strategy according to substaging by depth of lamina propria invasion. METHODS: In this prospective observational cohort study, patients received initial transurethral resection (TUR), mitomycin-C, and BCG. Subjects with shallower lamina propria invasion (HGT1a) were followed without further surgery, whereas subjects with HGT1b received a second TUR. Association of clinical and histological features with outcomes (primary: progression; secondary: recurrence and cancer-specific survival) was assessed using Cox regression. RESULTS: Median age was 71 years; 89.5% were males, with 89 (44.5%) cases T1a and 111 (55.5%) T1b. At median follow-up of 71 months, disease progression was observed in 31 (15.5%) and in univariate analysis, substaging, carcinoma in situ, tumour size, and tumour pattern predicted progression. On multivariate analysis only substaging, associated carcinoma in situ, and tumour size remained significant for progression. CONCLUSIONS: In HGT1 bladder cancer, the strategy of performing a second TUR only in T1b cases results in a global low progression rate of 15.5%. Tumours deeply invading the lamina propria (HGT1b) showed a three-fold increase in risk of progression. Substaging should be routinely evaluated, with HGT1b cases being thoroughly evaluated for cystectomy. Inclusion in the TNM system should also be carefully considered. PMID- 25535729 TI - Boiled coffee consumption and the risk of prostate cancer: follow-up of 224,234 Norwegian men 20-69 years. AB - BACKGROUND: There is insufficient epidemiological evidence on the relationship between type of coffee and the risk of prostate cancer. METHODS: The risk of prostate cancer by use of boiled vs not boiled coffee were assessed in a prospective study of 224,234 men 20-69 years. 5740 incident prostate cancers were identified. RESULTS: With no coffee as reference group the hazard ratios of <1-4, 5-8 and 9+ cups per day of boiled coffee only were 0.84 (0.73-0.96), 0.80 (0.70 0.92) and 0.66 (0.55-0.80), P-trend=0.00. The corresponding figures for not boiled coffee were 0.89 (0.80-0.99), 0.91 (0.81-1.02) and 0.86 (0.74-1.00), P trend=0.22. CONCLUSION: An inverse relationship between number of cups per day and the risk of prostate cancer was present only for the boiled coffee type. PMID- 25535731 TI - Enthusiasm for cancer screening in Great Britain: a general population survey. AB - BACKGROUND: With growing concerns about risk of harm from cancer screening, particularly from overdiagnosis, this study aimed to assess public attitudes to cancer screening in Great Britain. METHODS: We used a population-based survey to assess attitudes to cancer screening, screening history and demographic characteristics, in men and women aged 50-80 years. Data were collected using face-to-face computer-assisted interviews in 2012. RESULTS: In our sample of 2024, attitudes to cancer screening were overwhelmingly positive with almost 90% believing that screening is 'almost always a good idea' and 49% saying they would be tested for cancer even if it was untreatable. Attitudes were particularly positive among those who had previously taken part in breast or colorectal screening. CONCLUSIONS: Our findings suggest that attitudes to cancer screening are very positive in Great Britain. Widespread enthusiasm for cancer screening may hamper attempts to encourage a greater appreciation of the limitations and potential harms of screening. PMID- 25535727 TI - MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity. AB - BACKGROUND: The phosphoinositide-3 kinase (PI3K) pathway is an attractive therapeutic target. However, difficulty in predicting therapeutic response limits the clinical implementation of PI3K inhibitors. This study evaluates the utility of clinically relevant magnetic resonance imaging (MRI) biomarkers for noninvasively assessing the in vivo response to the dual PI3K/mTOR inhibitor BEZ235 in two ovarian cancer models with differential PI3K pathway activity. METHODS: The PI3K signalling activity of TOV-21G and TOV-112D human ovarian cancer cells was investigated in vitro. Cellular and vascular response of the xenografts to BEZ235 treatment (65 mg kg(-1), 3 days) was assessed in vivo using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE)-MRI. Micro-computed tomography was performed to investigate changes in vascular morphology. RESULTS: The TOV-21G cells showed higher PI3K signalling activity than TOV-112D cells in vitro and in vivo. Treated TOV-21G xenografts decreased in volume and DW-MRI revealed an increased water diffusivity that was not found in TOV-112D xenografts. Treatment-induced improvement in vascular functionality was detected with DCE-MRI in both models. Changes in vascular morphology were not found. CONCLUSIONS: Our results suggest that DW- and DCE-MRI can detect cellular and vascular response to PI3K/mTOR inhibition in vivo. However, only DW-MRI could discriminate between a strong and weak response to BEZ235. PMID- 25535732 TI - Prognostic relevance of the mitotic count and the amount of viable tumour after neoadjuvant chemotherapy for primary, localised, high-grade soft tissue sarcoma. AB - BACKGROUND: We sought to examine whether mitotic count (MC) and the amount of viable tumour (VT) following neoadjuvant systemic chemotherapy (SC) for primary, localised, high-grade soft tissue sarcoma (STS) correlate with prognosis. METHODS: Retrospective analysis of 57 patients who underwent SC involving a combination of an anthracycline and an alkylating agent, followed by surgical resection between 2001 and 2011. RESULTS: The amount of VT after chemotherapy was significantly associated with disease-specific survival (DSS) and event-free survival (EFS). Patients with <10% VT had a DSS of 94% at 5 years, compared with 61% for patients with ?10% VT (P=0.033); EFS was 75%, compared with 48% (P=0.030). Patients with an MC of ?20/10 high power fields (HPF) after chemotherapy had a significantly lower DSS (33% vs 84% at 5 years, P<0.001) and EFS (40% vs 63% at 5 years, P=0.019) than patients with an MC of <20/10 HPF. CONCLUSIONS: The MC and the amount of VT after neoadjuvant therapy for primary, localised, high-grade STS appear to correlate with prognosis. If these results are validated prospectively, then they could provide a rational for the design of neoadjuvant treatment modification/escalation studies, analogue to the EURAMOS-1 trial for bone sarcomas. PMID- 25535730 TI - Predictors of complications in gynaecological oncological surgery: a prospective multicentre study (UKGOSOC-UK gynaecological oncology surgical outcomes and complications). AB - BACKGROUND: There are limited data on surgical outcomes in gynaecological oncology. We report on predictors of complications in a multicentre prospective study. METHODS: Data on surgical procedures and resulting complications were contemporaneously recorded on consented patients in 10 participating UK gynaecological cancer centres. Patients were sent follow-up letters to capture any further complications. Post-operative (Post-op) complications were graded (I V) in increasing severity using the Clavien-Dindo system. Grade I complications were excluded from the analysis. Univariable and multivariable regression was used to identify predictors of complications using all surgery for intra operative (Intra-op) and only those with both hospital and patient-reported data for Post-op complications. RESULTS: Prospective data were available on 2948 major operations undertaken between April 2010 and February 2012. Median age was 62 years, with 35% obese and 20.4% ASA grade ?3. Consultant gynaecological oncologists performed 74.3% of operations. Intra-op complications were reported in 139 of 2948 and Grade II-V Post-op complications in 379 of 1462 surgeries. The predictors of risk were different for Intra-op and Post-op complications. For Intra-op complications, previous abdominal surgery, metabolic/endocrine disorders (excluding diabetes), surgical complexity and final diagnosis were significant in univariable and multivariable regression (P<0.05), with diabetes only in multivariable regression (P=0.006). For Post-op complications, age, comorbidity status, diabetes, surgical approach, duration of surgery, and final diagnosis were significant in both univariable and multivariable regression (P<0.05). CONCLUSIONS: This multicentre prospective audit benchmarks the considerable morbidity associated with gynaecological oncology surgery. There are significant patient and surgical factors that influence this risk. PMID- 25535733 TI - The requirement for freshly isolated human colorectal cancer (CRC) cells in isolating CRC stem cells. AB - BACKGROUND: Isolation of colorectal cancer (CRC) cell populations enriched for cancer stem cells (CSCs) may facilitate target identification. There is no consensus regarding the best methods for isolating CRC stem cells (CRC-SCs). We determined the suitability of various cellular models and various stem cell markers for the isolation of CRC-SCs. METHODS: Established human CRC cell lines, established CRC cell lines passaged through mice, patient-derived xenograft (PDX) derived cells, early passage/newly established cell lines, and cells directly from clinical specimens were studied. Cells were FAC-sorted for the CRC-SC markers CD44, CD133, and aldehyde dehydrogenase (ALDH). Sphere formation and in vivo tumorigenicity studies were used to validate CRC-SC enrichment. RESULTS: None of the markers studied in established cell lines, grown either in vitro or in vivo, consistently enriched for CRC-SCs. In the three other cellular models, CD44 and CD133 did not reliably enrich for stemness. In contrast, freshly isolated PDX-derived cells or early passage/newly established CRC cell lines with high ALDH activity formed spheres in vitro and enhanced tumorigenicity in vivo, whereas cells with low ALDH activity did not. CONCLUSIONS: PDX-derived cells, early passages/newly established CRC cell lines and cells from clinical specimen with high ALDH activity can be used to identify CRC-SC-enriched populations. Established CRC cell lines should not be used to isolate CSCs. PMID- 25535735 TI - Iron deficiency in infancy: is an immigrant more at risk? AB - QUESTIONS UNDER STUDY: Iron deficiency with or without anaemia is the most common deficiency in the world. Its prevalence is higher in developing countries and in low socioeconomic populations. We aimed at determining and comparing the prevalence of iron deficiency in an immigrant and non-immigrant population. METHODS: Every child scheduled for a routine check-up at 12 months of age was allowed to participate in the study. Haemoglobin, ferritin, anthropometric data, familial and nutritional status were measured. RESULTS: 586 infants were eligible and 463 were included in the study as they had assessment data at 12 months. Children were divided into two groups: immigrants' children and non-immigrants' children. The global prevalence of iron deficiency was 5.7% at 12 months. A significant difference for iron deficiency was noticed between the groups at 12 months (p = 0.01). Among risk factors, immigration (odds ratio 2.91; 95% CI 1.05 8.04) and unemployment (odds ratio 6.08; 95% CI 1.18-31.30) had the higher odds in the multivariable analysis. CONCLUSION: The prevalence of iron deficiency in the immigrant population is higher than in non-immigrants. Immigration and the category of employment are risk factors for iron deficiency, as starting baby cereals before 9 months is a protective factor. Good socioeconomic conditions in Switzerland, the quality of food for pregnant women and young infants may be the explanation. A study up to five years of age is necessary before drawing general conclusions on infancy. PMID- 25535737 TI - Yellowstone wolves and the forces that structure natural systems. AB - Since their introduction in 1995 and 1996, wolves have had effects on Yellowstone that ripple across the entire structure of the food web that defines biodiversity in the Northern Rockies ecosystem. Ecological interpretations of the wolves have generated a significant amount of debate about the relative strength of top-down versus bottom-up forces in determining herbivore and vegetation abundance in Yellowstone. Debates such as this are central to the resolution of broader debates about the role of natural enemies and climate as forces that structure food webs and modify ecosystem function. Ecologists need to significantly raise the profile of these discussions; understanding the forces that structure food webs and determine species abundance and the supply of ecosystem services is one of the central scientific questions for this century; its complexity will require new minds, new mathematics, and significant, consistent funding. PMID- 25535734 TI - Identification of novel vascular targets in lung cancer. AB - BACKGROUND: Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer. METHODS: Enzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients. Endothelial isolates from the healthy and tumour lung tissue were subjected to whole human genome expression profiling using microarray technology. RESULTS: Bioinformatics analysis identified tumour endothelial expression of angiogenic factors, matrix metalloproteases and cell-surface transmembrane proteins. Predicted novel tumour vascular targets were verified by RNA-seq, quantitative real-time PCR analysis and immunohistochemistry. Further detailed expression profiling of STEAP1 on 82 lung cancer patients confirmed STEAP1 as a novel target in the tumour vasculature. Functional analysis of STEAP1 using siRNA silencing implicates a role in endothelial cell migration and tube formation. CONCLUSIONS: The identification of cell-surface tumour endothelial markers in lung is of interest in therapeutic antibody and vaccine development. PMID- 25535736 TI - Interleukin-34 restores blood-brain barrier integrity by upregulating tight junction proteins in endothelial cells. AB - Interleukin-34 (IL-34) is a newly discovered cytokine as an additional ligand for colony stimulating factor-1 receptor (CSF1R), and its functions are expected to overlap with colony stimulating factor-1/macrophage-colony stimulating factor. We have previously shown that the IL-34 is primarily produced by neurons in the central nervous system (CNS) and induces proliferation and neuroprotective properties of microglia which express CSF1R. However, the functions of IL-34 in the CNS are still elucidative. Here we show that CNS capillary endothelial cells also express CSF1R. IL-34 protected blood-brain barrier integrity by restored expression levels of tight junction proteins, which were downregulated by pro inflammatory cytokines. The novel function of IL-34 on the blood-brain barrier may give us a clue for new therapeutic strategies in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease. PMID- 25535738 TI - Development and characterization of a novel fusion protein of a mutated granulocyte colony-stimulating factor and human serum albumin in Pichia pastoris. AB - The purpose of the present work was to develop a novel, long-acting and potent human serum albumin/granulocyte colony stimulating factor (HSA/G-CSF) therapeutic fusion protein. The novel fusion protein, called HMG, was constructed by genetically fusing mutated human derived G-CSF (mG-CSF) to the C-terminal of HSA and then prepared in Pichia pastoris. The molecular mass of HMG was about 85 kDa and the isoelectric point was 5.3. Circular dichroism spectroscopy suggested that mG-CSF retained nearly all of its native secondary structure, regardless of fusion. The binding capabilities of mG-CSF moiety to G-CSF receptor and HSA moiety to warfarin showed very little change after fusing. The bioactivity of HMG (11.0*10(6) IU/mg) was more than twice that of rHSA/G-CSF (4.6*10(6) IU/mg). A mutation was made at the 718th amino acid of HMG, substituting Ala for Thr, to investigate the glycosylation of HMG expressed in P. pastoris. Data indicated that HMG was modified at Thr718, speculatively with the addition of a mannose chain. In conclusion, a novel HSA/G-CSF fusion protein was successfully constructed based on a mutated G-CSF. This protein showed more potent bioactivity than rHSA/G-CSF and thus may be a suitable long-acting G-CSF. PMID- 25535739 TI - Psychiatric correlates of snuff and chewing tobacco use. AB - Compared to the association between cigarette smoking and psychiatric disorders, relatively little is known about the relationship between smokeless tobacco use and psychiatric disorders. To identify the psychiatric correlates of smokeless tobacco use, the analysis used a national representative sample from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) wave 1. Smokeless tobacco use was classified as exclusive snuff use, exclusive chewing tobacco, and dual use of both snuff and chewing tobacco at some time in the smokeless tobacco user's life. Lifetime psychiatric disorders were obtained via structured diagnostic interviews. The results show that the prevalence of lifetime exclusive snuff use, exclusive chewing tobacco, and dual use of both snuff and chewing tobacco was 2.16%, 2.52%, and 2.79%, respectively. After controlling for sociodemographic variables and cigarette smoking, the odds of exclusive chewing tobacco in persons with panic disorder and specific phobia were 1.53 and 1.41 times the odds in persons without those disorders, respectively. The odds of exclusive snuff use, exclusive chewing tobacco, and dual use of both products for individuals with alcohol use disorder were 1.97, 2.01, and 2.99 times the odds for those without alcohol use disorder, respectively. Respondents with cannabis use disorder were 1.44 times more likely to use snuff exclusively than those without cannabis use disorder. Respondents with inhalant/solvent use disorder were associated with 3.33 times the odds of exclusive chewing tobacco. In conclusion, this study highlights the specific links of anxiety disorder, alcohol, cannabis, and inhalant/solvent use disorders with different types of smokeless tobacco use. PMID- 25535740 TI - Attenuated NER expressions of XPF and XPC associated with smoking are involved in the recurrence of bladder cancer. AB - The varied NER genes and smoking are two important risk factors of bladder cancer, but the mechanism of the NER protein and smoking in cancer progression, however, remains unclear. In this report, we compared the expressions of NER genes in 79 bladder cancer tissues with or without any recurrence by real-time PCR and then analyzed the varied NER genes by immunochemistry in 219 bladder cancer tissue samples. Based on the clinical data, we analyzed the clinical value of varied NER genes and smoking in 219 bladder cancers by the Kaplan-Meier method and Cox proportional hazards regression. We found the expressions of the NER gene XPF and XPC were significantly lower in bladder cancer tissues with a recurrence compared with those without a recurrence at mRNA level. Also, the patients with the XPF and XPC defect had a statistically significant lower median recurrence free survival time than those without the XPF and XPC defect, and smoking can make this difference more remarkable. Our results suggest that XPF and XPC expression may be a potential predictive factor for bladder cancer, and smoking can not only influence the recurrence of bladder cancer as a single factor but also aggravate the results of the XPF defect and XPC defect. PMID- 25535741 TI - Spatio-temporal dynamic of Tuber magnatum mycelium in natural truffle grounds. AB - Tuber magnatum produces the world's most expensive truffle. This fungus produces very rare ectomycorrhizas which are difficult or even impossible to detect in the field. A "real-time" PCR assay was recently developed to quantify and to track T. magnatum mycelium in soil. Here, this technique was used to investigate the spatial distribution of T. magnatum extra-radical mycelium in soil productive patches and its dynamic across seasons. This study was carried out in four different natural T. magnatum truffle grounds located in different Italian regions. During the fruiting seasons, the amount of T. magnatum mycelium was significantly higher around the fruiting points and decreased going farther away from them. Moreover, T. magnatum mycelium inside the productive patches underwent seasonal fluctuations. In early spring, the amount of T. magnatum mycelium was significantly higher than in summer. In summer, probably due to the hot and dry season, T. magnatum mycelium significantly decreased, whereas in autumn it increased again and was concentrated at the putative fruiting points. These results give new insights on T. magnatum ecology and are useful to plan the most appropriate sampling strategy for evaluating the management of a truffle ground. PMID- 25535742 TI - Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes. AB - INTRODUCTION: Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 uM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1~100 uM) suppressed IKr in hiPSC-CMs by 67%~84% with IC50 ranged from 0.91 to 2.47 uM. Moreover, Mitragynine (10 uM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0+/-11.6 vs. 585.2+/-45.5 ms and 536.0+/ 22.6 vs. 705.9+/-46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression, and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine. CONCLUSIONS: Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes. PMID- 25535744 TI - Preoperative physical activity level has no relationship to the degree of recovery one year after primary total hip or knee arthroplasty: a cohort study. AB - BACKGROUND: When it comes to prevalidation, it is assumed that a higher preoperative level of physical activity leads to better postoperative recovery. However current literature is inconclusive about the effect of prevalidation on functional recovery of patients with primary osteoarthritis (OA) who underwent a THA or TKA. Therefore the aim of this study is to analyse one of the major assumptions underlying the potential effectiveness of prevalidation namely the relationship between preoperative physical activity level and postoperative recovery one year after THA or TKA in a group of 658 OA patients. METHODS AND RESULTS: From 2006 to 2012, 1061 patients underwent a primary THA or TKA at University Medical Center Groningen. Preoperative and one-year postoperative patients filled in the SQUASH questionnaire to get an impression of their physical activity level, and the WOMAC questionnaire to obtain insight into degree of recovery. Missing data were multiply imputed. No relationship was found between the preoperative total (B-coefficient = 0.03, CI95% = -0.033-0.093) and leisure-time physical activity level (B-coefficient = 0.042, CI95% = -0.009 0.093) neither for preoperative compliance with the Dutch Recommendation for Health-Enhancing Physical Activity (B-coefficient = 0.002, CI95% = -0.053 0.057), and the degree of recovery one year after surgery. CONCLUSION: The preoperative physical activity level had no relation with the degree of recovery one year after THA or TKA. The results do not support one of the major assumptions behind prevalidation, which assumes that a higher preoperative physical activity level will lead to a better recovery after THA or TKA. PMID- 25535745 TI - Acute cardiac sympathetic disruption and left ventricular wall motion abnormality in takotsubo syndrome. AB - Takotsubo syndrome (TS) is characterized by a unique pattern of transient circumferential left ventricular wall motion abnormality (LVWMA). The LVWMA in TS may be localized to the apical, mid-apical, mid-ventricular, mid-basal or basal regions of the left ventricle. Focal and generialized (global) LVWMA have also been reported. In the acute phase of TS, the hyperkinetic valve-like motion of the basal segments and/or the hyperkinetic slingshot-like motion of the apical segments combined with the firm stunned a-, hypokinetic segments result in a conspicuous left ventricular ballooning during systole. The LVWMA in TS follows most probably the local cardiac sympathetic nerve distribution and caused by local cardiac sympathetic disruption and noradrenaline spillover. PMID- 25535743 TI - Expression of inducible heat shock proteins Hsp27 and Hsp70 in the visual pathway of rats subjected to various models of retinal ganglion cell injury. AB - Inducible heat shock proteins (Hsps) are upregulated in the central nervous system in response to a wide variety of injuries. Surprisingly, however, no coherent picture has emerged regarding the magnitude, duration and cellular distribution of inducible Hsps in the visual system following injury to retinal ganglion cells (RGCs). The current study sought, therefore, to achieve the following two objectives. The first aim of this study was to systematically characterise the patterns of Hsp27 and -70 expression in the retina and optic nerve in four discrete models of retinal ganglion cell (RGC) degeneration: axonal injury (ON crush), somato-dendritic injury (NMDA-induced excitotoxicity), chronic hypoperfusion (bilateral occlusion of the carotid arteris) and experimental glaucoma. The second aim was to document Hsp27 and -70 expression in the optic tract, the subcortical retinorecipient areas of the brain, and the visual cortex during Wallerian degeneration of RGC axons. Hsp27 was robustly upregulated in the retina in each injury paradigm, with the chronic models, 2VO and experimental glaucoma, displaying a more persistent Hsp27 transcriptional response than the acute models. Hsp27 expression was always associated with astrocytes and with a subset of RGCs in each of the models excluding NMDA. Hsp27 was present within astrocytes of the optic nerve/optic tract in control rats. During Wallerian degeneration, Hsp27 was upregulated in the optic nerve/optic tract and expressed de novo by astrocytes in the lateral geniculate nucleus and the stratum opticum of the superior colliculus. Conversely, the results of our study indicate Hsp70 was minimally induced in any of the models of injury, either in the retina, or in the optic nerve/optic tract, or in the subcortical, retinorecipient areas of the brain. The findings of the present study augment our understanding of the involvement of Hsp27 and Hsp70 in the response of the visual system to RGC degeneration. PMID- 25535746 TI - Accumulation of self-reactive naive and memory B cell reveals sequential defects in B cell tolerance checkpoints in Sjogren's syndrome. AB - Sjogren's syndrome (SS) is an autoimmune disease characterised by breach of self tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naive and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naive and memory compartment of SS patients. Single CD27-IgD+ naive, CD27+IgD+ memory unswitched and CD27+IgD- memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naive (n = 66) and memory (n = 48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naive B cells (with germline VH and VL genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naive (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naive and memory B cells. PMID- 25535748 TI - Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta analysis in a Chinese population. AB - Mutations of glucocerebrosidase (GBA) confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls) and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77-10.68, p<0.00001), and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23-26.06, p<0.00001). No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results. PMID- 25535750 TI - Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review and meta-analysis. AB - OBJECTIVES: The aim of this study was to investigate the relationship between rheumatoid arthritis (RA) and the occurrence of diabetes mellitus (DM). METHODS: A meta-analysis was conducted to explore the risk of DM in RA patients. All relevant studies were identified by searching PUBMED, EMBASE and MEDLINE database prior to 1 January 2014. Pooled risk estimates were calculated with random effects models using STATA 11.0. RESULTS: A total of 11 case-control studies and 8 cohort studies were included in the final analysis. The pooled risk estimate of 11 case-control studies showed a statistically significant increased risk of DM prevalence among RA individuals (OR=1.40, 95% CI: 1.34-1.47). The pooled risk estimate of 8 cohort studies also showed a statistically significant increasing risk of DM (RR=1.43, 95%CI: 1.38-1.47). In a subgroup analysis for case-control studies, the pooled risk estimate of individuals with RA increased the incidence of T1DM (type 1 diabetes mellitus) and the incidence of T2DM (type 2 diabetes mellitus) (OR, 4.78 vs. 1.41). In a subgroup analysis for cohort studies, RA was also found to have a statistically significant increasing risk of T2DM (RR=1.24, 95%CI: 1.14-1.35). Begg funnel plot and Egger test showed no evidence of publication bias. CONCLUSIONS: RA is associated with increased risk of DM, including T1DM and T2DM. PMID- 25535749 TI - A pharmaco-metabonomic study on chronic kidney disease and therapeutic effect of ergone by UPLC-QTOF/HDMS. AB - Chronic kidney disease (CKD) is an important public health problem. Ergone has been proved to prevent the progression of CKD. UPLC-QTOF/HDMS was employed for metabolic profiling of adenine-induced CKD and to investigate the nephroprotective effects of ergone. Pharmacology parameters including blood biochemistry, histopathological evaluation and Western blot analysis were performed concurrently. The UPLC-MS data were analyzed by partial least squares discriminate analysis, correlation analysis, heatmap analysis and mapped to KEGG pathways. Blood and serum biochemistry were observed to be significantly different in the CKD group than in the control group. In conjunction with biochemistry, histopathology and protein expression results, identified metabolites indicated perturbations in fatty acid metabolism, purine metabolism and amino acid metabolism as changes associated with adenine-induced CKD and the interventions of ergone. Upregulated expression of TGF-beta1, ED-1, CTGF, bFGF and collagen I was observed in the CKD group. However, downregulated expression of these proteins was observed after oral administration of ergone. These results suggest that expression changes in these proteins had implications for fatty acid metabolism, purine metabolism and amino acid metabolism in the development of CKD and that ergone treatment could delay the development of CKD by normalizing or blocking abnormal changes in biomarker metabolites and protein expression in the CKD group. PMID- 25535751 TI - Cytomegalovirus, and possibly Epstein-Barr virus, shedding in breast milk is associated with HIV-1 transmission by breastfeeding. AB - OBJECTIVE: Postnatal HIV-1 mother-to-child transmission (MTCT) occurs in spite of antiretroviral therapy. Co-infections in breast milk with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are associated with increased HIV-1 shedding in this compartment. We investigated CMV levels and EBV detection in breast milk as potential risk factors for MTCT of HIV-1 via breastfeeding. METHODS: Cell-free HIV-1 RNA, cell-associated HIV-1 DNA, CMV and EBV DNA were quantified in breast milk from 62 HIV-infected mothers and proven postnatal MTCT of HIV-1 via breastfeeding. Controls were 62 HIV-positive mothers with HIV-uninfected infants. RESULTS: Median (interquartile range) CMV DNA viral load was significantly higher in cases [88,044 (18,586-233,904)] than in controls [11,167 (3221-31,152)] copies/10 breast milk cells (P < 0.001). Breast milk CMV DNA level correlated positively with breast milk HIV-1 RNA level in cases and controls. EBV DNA was detectable in a higher proportion of breast milk samples of cases (37.1%) than controls (16.1%; P = 0.009). HIV-1 MTCT was strongly associated with HIV-1 RNA shedding in breast milk and plasma. In multivariable analysis, every 1 log10 increase in breast milk CMV DNA was associated with a significant 2.5-fold greater odds of MTCT of HIV-1, independent of breast milk and plasma HIV-1 levels; the nearly three-fold increased risk of HIV-1 MTCT with breast milk EBV DNA detection did not reach significance. CONCLUSION: We provide the first evidence of an independent association between CMV in breast milk, and postnatal MTCT of HIV-1. This association could fuel persistent shedding of HIV-1 in breast milk in women receiving antiretroviral therapy. EBV DNA detection in breast milk may also be associated with MTCT of HIV-1, but only marginally so. PMID- 25535752 TI - The impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guerin vaccination. AB - OBJECTIVE: The objective of this study is to assess the effect of maternal HIV and Mycobacterium tuberculosis (Mtb) infection on cellular responses to bacille Calmette-Guerin (BCG) immunization. DESIGN: A mother-infant cohort study. METHODS: Samples were collected from mother-infant pairs at delivery. Infants were BCG-vaccinated at 6 weeks of age and a repeat blood sample was collected from infants at 16 weeks of age. BCG-specific T-cell proliferation and intracellular cytokine expression were measured by flow cytometry. Secreted cytokines and chemokines in cell culture supernatants were analysed using a Multiplex assay. RESULTS: One hundred and nine (47 HIV-exposed and 62 HIV unexposed) mother-infants pairs were recruited after delivery and followed longitudinally. At birth, proportions of mycobacteria-specific proliferating T cells were not associated with either in-utero HIV exposure or maternal Mtb sensitization. However, in-utero HIV exposure affected infant-specific T-cell subsets [tumour necrosis factor-alpha (TNF-alpha) single positive proliferating CD4+ T cells and interferon-gamma (IFN-gamma), TNF-alpha dual-positive CD4+ T cells]. Levels of TNF-alpha protein in cell culture supernatants were also significantly higher in HIV-exposed infants born to Mtb-sensitized mothers. In the presence of maternal Mtb sensitization, frequencies of maternal and newborn BCG-specific proliferating CD4+ T cells were positively correlated. Following BCG vaccination, there was no demonstrable effect of HIV exposure or maternal Mtb infection on infant BCG-specific T-cell proliferative responses or concentrations of secreted cytokines and chemokines. CONCLUSION: Effects of maternal HIV and Mtb infection on infant immune profiles at birth are transient only, and HIV-exposed, noninfected infants have the same potential to respond to and be protected by BCG vaccination as HIV-unexposed infants. PMID- 25535754 TI - [Radiologic diagnosis of Ormond's disease as an incidental finding during the investigation of a "symptomatic abdominal aortic aneurysm"]. PMID- 25535753 TI - Trends in HIV acquisition, risk factors and prevention policies among youth in Uganda, 1999-2011. AB - OBJECTIVE: The objective of this study is to understand how trends in HIV acquisition among youth can be influenced by change in HIV risk factors, social factors and prevention and treatment programmes. DESIGN: Trends in HIV incidence (per 1000 person-years), by sex and age group, were estimated using data from youth (15-24 years: n = 22,164) in the Rakai Community Cohort Study. Trends in HIV incidence were compared with trends in previously identified HIV risk factors, social factors and programmes. METHODS: Poisson and linear regression were used to test for statistical significance and decomposition was used to calculate attribution of risk factors to HIV incidence. RESULTS: Substantial declines between 1999 and 2011 occurred in sexual experience, multiple partners and sexual concurrency among adolescents and young adults. HIV acquisition declined substantially (86%, P = 0.006) among adolescent women (15-19 years) but not among men or young adult women. Changes in HIV incidence and risk behaviours coincided with increases in school enrolment, decline in adolescent marriage, availability of antiretroviral therapy (ART) and increases in male medical circumcision (MMC). Much of the decline in HIV incidence among adolescent women (71%) was attributable to reduced sexual experience; the decline in sexual experience was primarily attributable to increasing levels of school enrolment. CONCLUSION: Dramatic decreases in HIV incidence occurred among adolescent women in Rakai. Changes in school enrolment and sexual experience were primarily responsible for declining HIV acquisition over time among adolescent women. Given limited improvement among young men and young adult women, the need for effective HIV prevention for young people remains critical. PMID- 25535755 TI - [Osteochondrosis of ischiopubic Synchondrosis -- Van Neck Disease (VND)]. PMID- 25535756 TI - Systematic review of educational programs and strategies for developing students' and nurses' writing skills. AB - The purpose of this article is to describe the outcomes of a systematic review of educational programs and strategies for developing the writing skills of nursing students and nurses. Of 728 screened citations, 80 articles were included in the review. Writing assignments in nursing courses were the most common, followed by strategies for writing across the curriculum and specific courses to improve the writing skills of nursing students. To improve nurses' writing skills, workshops were used most frequently. Only 28 (35%) of the articles were data based, and most articles described the writing program, strategy, or assignment but did not evaluate its effectiveness. PMID- 25535757 TI - Innovative point assignment for clinical attendance in an associate degree program. AB - Students gain experience and meet learning outcomes through clinical experiences in health care settings. However, increased student absences threatened the completion of these outcomes within the associate degree in nursing program. In response to increased student absences, and faculty maintenance of fair expectations of all students, a pilot project was developed to initiate an innovative clinical point assignment system. Within this pilot project, students earned points for attending clinical experiences as part of the total points earned for the course. Alternative options, challenges, opportunities, and the evaluation of the new clinical point assignment system are revealed. This pilot project greatly reduced absences, eliminated make-up days, and resulted in cost savings to the college. PMID- 25535758 TI - An alphabetical mnemonic teaching strategy for constructing nursing care plans. AB - The strategy of mnemonics has long been used as an aid to learning biology, physiology, pathophysiology, and health assessment in nursing. An application of an alphabetical mnemonics strategy to teaching and learning nursing processes and constructing care plans has been explored for patients with increased intracranial pressure (ICP), hepatic failure, and chronic renal failure. A specific application of this strategy for teaching care planning for patients with ICP is described. Student feedback appears to be positive, and reviews of the teaching-learning experience have received approval in students' evaluation of instruction. The mnemonics strategy presented has the potential for applicability and transferability to other areas of nursing care planning and other course contexts. PMID- 25535759 TI - Evaluation of embedded audio feedback on writing assignments. AB - The purpose of this pilot study was to compare embedded audio feedback (EAF), which faculty provided using the iPad((r)) application iAnnotate((r)) PDF to insert audio comments and written feedback (WF), inserted electronically on student papers in a series of writing assignments. Goals included determining whether EAF provides more useful guidance to students than WF and whether EAF promotes connectedness among students and faculty. An additional goal was to ascertain the efficiency and acceptance of EAF as a grading tool by nursing faculty. The pilot study was a quasi-experimental, cross-over, posttest-only design. The project was completed in an Informatics in Health Care course. Faculty alternated the two feedback methods on four papers written by each student. Results of surveys and focus groups revealed that students and faculty had mixed feelings about this technology. Student preferences were equally divided between EAF and WF, with 35% for each, and 28% were undecided. PMID- 25535760 TI - Clinical judgment in reflective journals of prelicensure nursing students. AB - Clinical judgment is an essential skill needed by RNs. Employers expect new graduate nurses to enter the work-force with established clinical judgment skills. Therefore, nurse educators must ensure that prelicensure nursing students develop clinical judgment before graduation. This qualitative, interpretive description study reviewed the reflective journals of 30 prelicensure nursing students who participated in four progressive high-fidelity simulation (HFS) scenarios during a medical-surgical nursing course. Eight themes were identified in the reflective journals: (a) expectations about the patient, (b) recognition of a focused assessment, (c) interpretation of medications, laboratory data, and diagnostics, (d) communication with the patient, (e) collaboration and interprofessionalism, (f) prioritizing interventions, (g) skillfulness with interventions, and (h) incorporation of skills and information into real patient situations. This study indicated that reflective journaling following progressive HFS scenarios may be an effective teaching-learning strategy to assist prelicensure nursing students in the development of clinical judgment. PMID- 25535761 TI - Preparing students for the emotional challenges of nursing: an integrative review. AB - A gap exists between how nurse educators teach nursing students to identify and manage the emotional challenges of nursing and nurses' experiences after they enter practice. An integrative review was conducted to synthesize the literature on how nurse educators prepare students for the emotional challenges of practice. The literature (n = 14) revealed that the concept "emotional challenges of nursing" lacks a clear definition and conceptual clarity. Reflection was a common element found in the educational approaches identified. Research was directed at qualitatively exploring students' subjective experiences, and most researchers did not address educational outcomes beyond subjective perceptions. Although the authors recognized the importance of teaching in the affective domain, research that used a quantitative experimental design (n = 1) was scarce. A research agenda, including intervention studies, is needed to support the development of evidence-based teaching pedagogies to prepare students for the emotional challenges of practice. PMID- 25535762 TI - Assessing undergraduate nursing students' knowledge, attitudes, and cultural competence in caring for lesbian, gay, bisexual, and transgender patients. AB - Lesbian, gay, bisexual, and transgender (LGBT) patients experience barriers to health care that include fear of discrimination, as well as insensitivity and lack of knowledge about LGBT-specific health needs among providers. This study examined the effectiveness of an educational intervention designed to improve knowledge and attitudes of baccalaureate nursing students regarding LGBT patient care. Education focused on key terminology, health disparities, medical needs of transgender patients, and culturally sensitive communication skills for competent LGBT patient care. Knowledge level and attitudes were evaluated before and after the intervention using a survey based on a modified Attitudes Toward Lesbians and Gay Men Scale and two assessment tools developed for this study. A statistically significant increase in positive attitudes and knowledge level was found immediately after the intervention. Findings from this study support the inclusion of education related to LGBT patient health care in undergraduate nursing curricula to promote cultural competence and sensitivity. PMID- 25535764 TI - Stepwise microhydration of aromatic amide cations: formation of water solvation network revealed by infrared spectra of formanilide(+)-(H2O)(n) clusters (n <= 5). AB - Hydration of peptides and proteins has a strong impact on their structure and function. Infrared photodissociation spectra (IRPD) of size-selected clusters of the formanilide cation, FA(+)-(H2O)n (n = 1-5), are analyzed by density functional theory calculations at the omegaB97X-D/aug-cc-pVTZ level to determine the sequential microhydration of this prototypical aromatic amide cation. IRPD spectra are recorded in the hydride stretch and fingerprint ranges to probe the preferred interaction motifs and the cluster growth. IRPD spectra of cold Ar tagged clusters, FA(+)-(H2O)n-Ar, reveal the important effects of temperature and entropy on the observed hydration motifs. At low temperature, the energetically most stable isomers are prominent, while at higher temperature less stable but more flexible isomers become increasingly populated because of entropy. In the most stable structures, the H2O ligands form a hydrogen-bonded solvent network attached to the acidic NH proton of the amide, which is stabilized by large cooperative effects arising from the excess positive charge. In larger clusters, hydration bridges the gap between the NH and CO groups (n >= 4) solvating the amide group rather than the more positively charged phenyl ring. Comparison with neutral FA-(H2O)n clusters reveals the strong impact of ionization on the acidity of the NH proton, the strength and topology of the interaction potential, and the structure of the hydration shell. PMID- 25535766 TI - A novel and functional single-layer sheet of ZnSe. AB - The recently synthesized freestanding four-atom-thick double-layer sheet of ZnSe holds great promise as an ultraflexible and transparent photoelectrode material for solar water splitting. In this work, we report theoretical studies on a novel three-atom-thick single-layer sheet of ZnSe that demonstrates a strong quantum confinement effect by exhibiting a large enhancement of the band gap (2.0 eV) relative to the zinc blende (ZB) bulk phase. Theoretical optical absorbance shows that the largest absorption of this ultrathin single-layer sheet of ZnSe occurs at a wavelength similar to its four-atom-thick double-layer counterpart, suggesting a comparable behavior on incident photon-to-current conversion efficiency for solar water splitting, among a wealth of potential applications. The results presented herein for ZnSe may be generalized to other group II-VI analogues. PMID- 25535765 TI - Prevalence and risk factors for chronic kidney disease in a rural region of Haiti. AB - BACKGROUND: In the Caribbean region chronic kidney disease (CKD) is an increasing challenge. High rates of non-communicable and infectious diseases and the rise in people suffering from diabetes and hypertension explain the observed and further expected increase of CKD. However, data about the magnitude of the problem are rare and in some countries such as Haiti completely lacking. The aim of our study was to generate data about the prevalence and risk factors for CKD in a rural region in Haiti. METHODS: In this prospective cross-sectional study, adult patients visiting the medical outpatient clinic of the Hopital Albert Schweitzer (HAS) in Deschapelles Haiti were included. CKD was assessed by estimated glomerular filtration rate (eGFR) and measurement of proteinuria by dipstick test. Risk factors for CKD were assessed by clinical examinations and questionnaires. RESULTS: Overall 608 patients were screened for CKD, of whom 27% had CKD. CKD stages 1 to 2 were found in 15.3% and stages 3 to 5 in 11.7%. The prevalence of hypertension and diabetes mellitus was 49.2% and 36.3%, respectively. Risk factors independently associated with CKD were hypertension (p = 0.0002) and HIV infection (p = 0.019) and age >60 years (p = 0.0052), whereas diabetes mellitus was not independently associated (p = 0.72). CONCLUSION: Our data show a high prevalence of CKD and traditional risk factors, and their association with CKD in Haiti. These findings have now to be confirmed in other regions in longitudinal analyses as a basic step to build up screening and prevention programmes for CKD. PMID- 25535767 TI - Highly selective molybdenum ONO pincer complex initiates the living ring-opening metathesis polymerization of strained alkynes with exceptionally low polydispersity indices. AB - The pseudo-octahedral molybdenum benzylidyne complex [TolC=Mo(ONO)(OR)].KOR (R = CCH3(CF3)2) 1, featuring a stabilizing ONO pincer ligand, initiates the controlled living polymerization of strained dibenzocyclooctynes at T > 60 degrees C to give high molecular weight polymers with exceptionally low polydispersities (PDI ~ 1.02). Kinetic analyses reveal that the growing polymer chain attached to the propagating catalyst efficiently limits the rate of propagation with respect to the rate of initiation (kp/ki ~ 10(-3)). The reversible coordination of KOCCH3(CF3)2 to the propagating catalyst prevents undesired chain-termination and -transfer processes. The ring-opening alkyne metathesis polymerization with 1 has all the characteristics of a living polymerization and enables, for the first time, the controlled synthesis of amphiphilic block copolymers via ROAMP. PMID- 25535768 TI - Cotemplating synthesis of a rare borate Ni(en)3.Hen.[B9O13(OH)4].H2O with a chiral polyanonic chain constructed from two different clusters. AB - Ni(en)3.Hen.[B9O13(OH)4].H2O was prepared under the cotemplating effect of [Ni(en)3](2+) and Hen(+). It was the first example of a cotemplated borate with an unusual chiral polyanionic chain, which was constructed from [B5O8(OH)2] and [B4O7(OH)2] clusters. PMID- 25535769 TI - A VPT2 route to near-infrared spectroscopy: the role of mechanical and electrical anharmonicity. AB - Following the previous developments to simulate fully anharmonic spectra within the vibrational second-order perturbation level of theory [ J. Chem. Phys. 2012 , 126 , 134108 ], an extension to transitions up to three quanta is presented here. A general formulation including the mechanical and electrical anharmonicities is adopted to facilitate the support of additional properties, and thus spectroscopies. In addition to providing more accurate theoretical band shapes, inclusion of overtones and combination bands up to three quanta paves the way to a more complete interpretation of near-infrared spectra. PMID- 25535770 TI - Red blood cell distribution width: A simple parameter with multiple clinical applications. AB - The red blood cell distribution width (RDW) is a simple and inexpensive parameter, which reflects the degree of heterogeneity of erythrocyte volume (conventionally known as anisocytosis), and is traditionally used in laboratory hematology for differential diagnosis of anemias. Nonetheless, recent evidence attests that anisocytosis is commonplace in human disorders such as cardiovascular disease, venous thromboembolism, cancer, diabetes, community acquired pneumonia, chronic obstructive pulmonary disease, liver and kidney failure, as well as in other acute or chronic conditions. Despite some demographic and analytical issues related to the routine assessment that may impair its clinical usefulness, an increased RDW has a high negative predictive value for diagnosing a variety of disorders, but also conveys important information for short- and long-term prognosis. Even more importantly, the value of RDW is now being regarded as a strong and independent risk factor for death in the general population. Although it has not been definitely established whether an increased value of RDW is a risk factor or should only be considered an epiphenomenon of an underlying biological and metabolic imbalance, it seems reasonable to suggest that the assessment of this parameter should be broadened far beyond the differential diagnosis of anemias. An increased RDW mirrors a profound deregulation of erythrocyte homeostasis involving both impaired erythropoiesis and abnormal red blood cell survival, which may be attributed to a variety of underlying metabolic abnormalities such as shortening of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia, hypertension, erythrocyte fragmentation and alteration of erythropoietin function. As such, the aim of this article is to provide general information about RDW and its routine assessment, to review the most relevant implications in health and disease and give some insights about its potential clinical applications. PMID- 25535771 TI - Different paths to the same end: a response to the question: quo vadis? PMID- 25535763 TI - Structural basis for regulation of RNA-binding proteins by phosphorylation. AB - Ribonucleoprotein complexes involved in pre-mRNA splicing and mRNA decay are often regulated by phosphorylation of RNA-binding proteins. Cells use phosphorylation-dependent signaling pathways to turn on and off gene expression. Not much is known about how phosphorylation-dependent signals transmitted by exogenous factors or cell cycle checkpoints regulate RNA-mediated gene expression at the atomic level. Several human diseases are linked to an altered phosphorylation state of an RNA binding protein. Understanding the structural response to the phosphorylation "signal" and its effect on ribonucleoprotein assembly provides mechanistic understanding, as well as new information for the design of novel drugs. In this review, I highlight recent structural studies that reveal the mechanisms by which phosphorylation can regulate protein-protein and protein-RNA interactions in ribonucleoprotein complexes. PMID- 25535774 TI - Experiences of Infertility in British and Pakistani Women: A Cross-Cultural Qualitative Analysis. AB - The psychosocial impact of infertility is affected by cultural factors. In this cross-cultural qualitative study we explored the experience of infertility among six women living in Pakistan and eight living in the UK. Although infertile women in the UK and Pakistan had many shared experiences related to their own desires for motherhood and the hopes of others, they also faced unique psychosocial challenges shaped by cultural context. Based on our findings, we suggest a need for further resources and networks to support women, particularly women living in cultures that allow women few fulfilling social roles other than motherhood. PMID- 25535773 TI - Diagnostic utility of major salivary gland ultrasonography in primary Sjogren's syndrome. AB - OBJECTIVES: To investigate major salivary gland ultrasonography (US) in relation to symptoms and findings of oral and ocular dryness, and autoimmune disease, for potential use in diagnosis and follow-up of patients with primary Sjogren's syndrome (pSS). METHODS: Patients with pSS were recruited from the Department of Rheumatology, Haukeland University Hospital. The parotid and submandibular salivary glands were examined by US using a simplified scoring system for glandular homogeneity and hypoechogenic areas. Scans were graded on a scale 0-3, grades 0-1 considered corresponding to normal/non-specific changes and grades 2-3 to pathological changes. Sicca symptoms of the mouth and eyes, salivary gland capacity, tear secretion, minor salivary gland inflammation, serum autoantibodies, and fatigue were also investigated. RESULTS: US was performed in 97 patients. Oral and ocular sicca symptoms correlated with US score and decreased saliva levels. Fatigue VAS correlated with oral sicca symptoms but was inversely correlated with age. Patients with normal/non-specific US findings tended to be older than patients with pathological US findings. US score correlated with unstimulated and stimulated salivary secretion and tear secretion. Minor salivary gland inflammation correlated with major salivary gland US findings, and lymphoid organisation, germinal centre (GC)-like structures, in the minor salivary gland tissue biopsies was seemingly related to US pathology. Serum autoantibodies against Ro/SSA and/or La/SSB were associated with US pathology. CONCLUSIONS: US findings in major salivary glands correlate with subjective and objective oral and ocular items as well as systemic autoimmune features of pSS. US represents a useful imaging tool for diagnostics and follow up of pSS. PMID- 25535772 TI - Unilateral Lobe Resection by Video-Assisted Thoracoscopy Leads to the Most Optimal Functional Improvement in Severe Emphysema. AB - Background Lung volume reduction surgery (LVRS) is a well-established treatment option for pulmonary emphysema, but the most advantageous technical approach remains debatable. Methods Short- and long-term outcomes were comparably assessed in pulmonary emphysema patients who underwent unilateral LVRS with either lobe or sublobe (segment or wedge) resection. Patients were consecutively enrolled in the study after careful conventional and computer-based definition of the target region. Results A total of 36 patients with a mean age of 62.1 +/- 8.9 years (range, 41-79 years) were recruited. Video-assisted thoracoscopy (VATS) was performed in 33 patients, while 3 patients with additional early-stage lung cancer received anterolateral thoracotomy. Surgery duration was longer for lobectomy (median 93 minutes, range 44-168 minutes) as compared with sublobe resection (median 52 minutes, range 25-131 minutes; p = 0.0007), but complication rates were similar. After 90 days postsurgery, mortality was zero and lung function improved to a similar degree in both the groups. After 1 year, total lung capacity (TLC) was still reduced by 17.2 +/- 20.6% predicted as compared with the baseline values for lobe resection, while TLC was increased by 12.1 +/- 14.5% predicted for sublobe resection. In addition, the 6-minute walking distance improved following LVRS, with slightly better results in lobe resection patients. Conclusions By careful definition of the target region, unilateral VATS-LVRS with lobe resection in severely affected pulmonary emphysema patients is a safe procedure that is superior to unilateral sublobe VATS resection in terms of improving long-term 1-year lung hyperinflation. Therefore, unilateral VATS lobe resection is a promising treatment approach that should be further evaluated by randomized controlled trials. PMID- 25535775 TI - Development of a conceptual model of oral health for malocclusion patients. AB - OBJECTIVES: To provide an empirical test of the applicability of Locker's conceptual model of oral health for malocclusion patients, and to suggest alternative models of the effect of malocclusion on well-being. MATERIALS AND METHODS: Data from a survey of 323 adolescents attending for orthodontic treatment were analyzed to develop a new oral health model for malocclusion patients. Oral health-related quality of life (OHRQoL) was measured using the 14 item Oral Health Impact Profile; malocclusion was measured using the Dental Health Component (DHC) of the Index of Orthodontic Treatment Need (IOTN). Using structural equation modeling, the relationship between conceptual domains in Locker's model was explored and three models of their interrelationship tested for goodness of fit. RESULTS: Fit indexes for Locker's model indicated that it did not fit the data well. Therefore, a modified model was developed to incorporate additional paths between other levels to better fit the data. The best fit was provided by a model in which the direct effects of malocclusion on pain, discomfort, and handicapping-and the direct effect of pain on disability were removed. A direct effect of functional limitation on disability was allowed. The modified Oral Health Impact Profile model proved to be a good fit to the data (root mean square error of approximation = 0.069). CONCLUSION: The pathways identified in Locker's (1988) conceptual model of oral health may not be appropriate for describing the relationships between OHRQoL constructs in individuals with malocclusion. An alternative model is proposed. PMID- 25535776 TI - Red wines and flavonoids diminish Staphylococcus aureus virulence with anti biofilm and anti-hemolytic activities. AB - The emergence of antibiotic resistant Staphylococcus aureus presents a worldwide problem that requires non-antibiotic strategies. This study investigated the anti biofilm and anti-hemolytic activities of four red wines and two white wines against three S. aureus strains. All red wines at 0.5-2% significantly inhibited S. aureus biofilm formation and hemolysis by S. aureus, whereas the two white wines had no effect. Furthermore, at these concentrations, red wines did not affect bacterial growth. Analyses of hemolysis and active component identification in red wines revealed that the anti-biofilm compounds and anti hemolytic compounds largely responsible were tannic acid, trans-resveratrol, and several flavonoids. In addition, red wines attenuated S. aureus virulence in vivo in the nematode Caenorhabditis elegans, which is killed by S. aureus. These findings show that red wines and their compounds warrant further attention in antivirulence strategies against persistent S. aureus infection. PMID- 25535777 TI - Detection of Turner Syndrome by quantitative PCR of SHOX and VAMP7 genes. AB - Turner Syndrome (TS) is an unfavorable genetic condition with a prevalence of 1:2500 in newborn girls. Prompt and effective diagnosis is very important to appropriately monitor the comorbidities. The aim of the present study was to propose a feasible and practical molecular diagnostic tool for newborn screening by quantifying the gene dosage of the SHOX, VAMP7, XIST, UBA1, and SRY genes by quantitative polymerase chain reaction (qPCR) in individuals with a diagnosis of complete X monosomy, as well as those with TS variants, and then compare the results to controls without chromosomal abnormalities. According to our results, the most useful markers for these chromosomal variants were the genes found in the pseudoautosomic regions 1 and 2 (PAR1 and PAR2), because differences in gene dosage (relative quantification) between groups were more evident in SHOX and VAMP7 gene expression. Therefore, we conclude that these markers are useful for early detection in aneuploidies involving sex chromosomes. PMID- 25535778 TI - Sealing composite with defective margins, good care or over treatment? Results of a 10-year clinical trial. AB - PURPOSE: The objective of this study was to clinically evaluate sealed composite restorations after 10 years and compare their behavior with respect to controls. METHODS AND MATERIALS: The cohort consisted of 20 patients aged 18 to 80 years with 80 composite restorations. All participants in the sealing and no-treatment groups presented with clinical features for the marginal adaptation that deviated from the ideal and were rated Bravo (United States Public Health Service criteria). Composites with Alfa values for the marginal adaptation were used as the positive control. RESULTS: The marginal adaptation behavior was similar between the sealing and control (+) groups, with a high frequency of Bravo values in the 10th year (80% and 51%, respectively). Most of the no-treatment (-) group maintained the Bravo values (91%) for 10 years, although some restorations (9%) progressed to Charlie values. The anatomy parameter differed significantly between the first and 10th years, with deterioration in all three groups (p<0.05). The secondary caries parameter had a similar behavior in the three groups (p>0.05). CONCLUSIONS: Sealing the margins of the composite resin restorations had no significant effect compared with the control groups, under the conditions of this study. Sealing the restorations substantially improved the marginal staining and marginal adaptation parameters, although by the tenth year they were similar to the group without intervention. PMID- 25535779 TI - Failure Strengths of Composite Additions and Repairs. AB - PURPOSE: When adding composite to a cured composite restoration, the intent is to achieve the same failure strength as the original restorative material. This study evaluated the failure strengths of added or repaired composite using various chemical and/or mechanical surface treatments. METHODS: Failure strengths were determined using a four-point bending test. Beam-shaped specimens were fabricated by adding new composite to cured composite (Filtek Supreme Ultra). The cured composites were either fresh or aged seven days (N=10-14). The composite surfaces were left unground or were ground before treatment with various combinations of roughening, acid etching, silane, and dental adhesives (conventional Adper SingleBond Plus or new multimode Scotchbond Universal) and/or tribochemistry (CoJet system). Monolithic composite specimens were the control. Failure strengths were statistically analyzed using one-way analysis of variance and the Fisher protected least significant difference (alpha=0.05). RESULTS: Failure strengths (mean +/- standard deviation) when composite was added to unground freshly cured composites (111+/-25 MPa) and aged composites using a new multimode adhesive with (102+/-22 MPa) or without (98+/-22 MPa) tribochemical treatment were not significantly lower than the monolithic specimens (122+/-23 MPa). Grinding the surfaces of freshly cured composite significantly reduced failure strength, either with (81+/-30 MPa) or without (86+/-31 MPa) use of conventional adhesive. Failure strengths of aged composites were also significantly lower (51+/-21 MPa with SingleBond Plus), even after tribochemical treatment (71+/-29 MPa with SingleBond Plus; 73+/-35 MPa with Silane-Visiobond). CONCLUSIONS: Using a new multimode adhesive when adding composite to freshly cured or aged composite substrates recovered the failure strength to that of the original monolithic composite. PMID- 25535780 TI - Bonding ability of paste-paste glass ionomer systems to tooth structure: in vitro studies. AB - This study investigated the effect of nonrinse conditioners (ie, Ketac Nano Primer [KNP] and GC Self Conditioner [SC]) used as substrate pretreatment and their respective paste-paste resin-modified glass-ionomer cement (RMGIC) (ie, Ketac Nano [KN] and Fuji Filling LC [FF]) on microtensile bond strength to dentin and marginal sealing when compared with traditional RMGIC (ie, Photac Fil [PF] and Fuji II LC [FII]) used in association with polyacrylic acid (ie, Ketac Cavity Conditioner [KC] and GC Cavity Conditioner [CC]). A total of 192 extracted human molars were allocated into eight groups: KNP-KN, KC-KN, KNP-PF, KC-PF, SC-FF, CC FF, SC-FII, and CC-FII. For microtensile bond strength, the teeth were sectioned to expose occlusal dentin and restored according to the group. After 24 hours the teeth were cut to yield nine beams per tooth (+/-0.8 mm(2)). Testing was done using a universal testing machine followed by failure mode classification. For microleakage testing, standardized cavity preparations were made on the buccal cementoenamel junction and restored according to the group. The teeth were thermocycled (500 cycles, 8 degrees C to 48 degrees C), sealed, immersed in methylene blue for 24 hours, and then assessed for microleakage using a stereomicroscope. Microtensile bond strengths in megapascals (mean+/-SE) were KNP KN: 14.9 +/- 1.6, KC-KN: 17.2 +/- 1.5, KNP-PF: 31.2 +/- 1.6, KC-PF: 26.2 +/- 1.2, SC-FF: 23.6 +/- 1.5, SC-FII: 31.2 +/- 1.5, and CC-FII: 21.9 +/- 1.5. Cervical margins showed more microleakage compared with occlusal margins. Overall, the use of nonrinse conditioners in association with traditional RMGICs demonstrated superior microtensile bond strengths to dentin when compared with the paste-paste RMGICs. Meanwhile, the association between polyacrylic acid (CC) and a traditional RMGIC (FII) led to the least microleakage for cervical locations when compared with all other groups. PMID- 25535781 TI - Tooth fragment reattachment: a case report. AB - The aim of this article is to present a case report for the multidisciplinary treatment of anterior tooth fractures with invasion of the biologic width and pulpectomy. Successful esthetic and functional results were achieved by bonding the crown fragment, without any form of preparation or the utilization of intracanal posts. PMID- 25535782 TI - Effect of ceramic etching protocols on resin bond strength to a feldspar ceramic. AB - This study sought to evaluate the resin microtensile bond strength (MTBS) stability of a leucite-reinforced ceramic after different ceramic etching protocols. The microtensile test had 40 ceramic blocks (5*5*6 mm) assigned to five groups (n=8), in accordance with the following surface etching protocols: NE nonetched (control); 9HF: hydrofluoric (HF) acid etching (9%HF)+wash/dry; 4HF: 4%HF+wash/dry; 5HF: 5%HF+wash/dry; and 5HF+N: 5%HF+neutralizer+wash/dry+ultrasonic-cleaning. Etched ceramic surfaces were treated with a silane agent. Next, resin cement blocks were built on the prepared ceramic surface and stored for 24 hours in distilled water at 37 degrees C. The specimens were then sectioned to obtain microtensile beams (32/block), which were randomly assigned to the following conditions, nonaged (immediate test) and aged (water storage for 150 days plus 12,000 thermal cycles), before the microtensile test. Bond strength data were submitted to one-way analysis of variance and Tukey test (alpha=0.05). Additional ceramic samples were subjected to the different ceramic etching protocols and evaluated using a scanning electron microscope (n=2) and atomic force microscopy (n=2). Aging led to a statistically significant decrease in the MTBS for all groups, except the untreated one (NE). Among the groups submitted to the same aging conditions, the untreated (NE) revealed inferior MTBS values compared to the 9HF and 4HF groups. The 5HF and 5HF+N groups had intermediate mean values, being statistically similar to the higher values presented by the 9HF and 4HF groups and to the lower value associated with the NE group. The neutralization procedure did not enhance the ceramic/resin cement bond strength. HF acid etching is a crucial step in resin/ceramic bonding. PMID- 25535783 TI - Evaluation of genotoxicity and efficacy of at-home bleaching in smokers: a single blind controlled clinical trial. AB - OBJECTIVE: This single-blind controlled study evaluated the genotoxicity and efficacy of at-home bleaching in smokers and nonsmokers. METHODS: We selected 60 patients with central incisors A2 or darker: 30 smokers (experimental group) and 30 nonsmokers (control group). The bleaching was carried out with 10% carbamide peroxide for three hours a day for three weeks. The color was evaluated using a shade guide, Vita Bleachedguide 3D-Master, at baseline, during bleaching (first, second, and third weeks), and one week and one month after bleaching. Smears were obtained with a moistened wooden spatula from marginal gingiva. All the cytologic smears were stained with Giemsa solution. From each slide, 1000 cells were examined under 40* magnification and where micronuclei (MN) were located, they were examined under 100* magnification. The change in shade guide units at the different assessment periods and the frequency of MN were subjected to a two-way repeated measures analysis of variance and Tukey test (alpha=0.05). RESULTS: In both groups we detected a whitening of approximately 4 to 5 shade guide units, without color rebound after one month (p>0.05). The frequency of MN was significantly higher in the experimental group than in the control group, regardless of the bleaching treatment (p>0.001). CONCLUSION: The efficacy of bleaching does not appear to be affected by the smoking habit. Additionally, at home bleaching did not induce DNA damage to the gingival tissue during the bleaching period. PMID- 25535784 TI - Influence of Etching Protocol and Silane Treatment with a Universal Adhesive on Lithium Disilicate Bond Strength. AB - OBJECTIVES: To measure the effects of hydrofluoric acid (HF) etching and silane prior to the application of a universal adhesive on the bond strength between lithium disilicate and a resin. METHODS AND MATERIALS: Sixty blocks of lithium disilicate (e.max CAD, Ivoclar Vivadent) were sectioned into coupons and polished. Specimens were divided into six groups (n=10) based on surface pretreatments, as follows: 1) no treatment (control); 2) 5% HF etch for 20 seconds (5HF); 3) 9.5% HF etch for 60 seconds (9.5HF); 4) silane with no HF (S); 5) 5% HF for 20 seconds + silane (5HFS); and 6) 9.5% HF for 60 seconds + silane (9.5HFS). All etching was followed by rinsing, and all silane was applied in one coat for 20 seconds and then dried. The universal adhesive (Scotchbond Universal, 3M ESPE) was applied onto the pretreated ceramic surface, air thinned, and light cured for 10 seconds. A 1.5-mm-diameter plastic tube filled with Z100 composite (3M ESPE) was applied over the bonded ceramic surface and light cured for 20 seconds on all four sides. The specimens were thermocycled for 10,000 cycles (5 degrees C-50 degrees C/15 s dwell time). Specimens were loaded until failure using a universal testing machine at a crosshead speed of 1 mm/min. The peak failure load was used to calculate the shear bond strength. Scanning electron microscopy images were taken of representative e.max specimens from each group. RESULTS: A two-way analysis of variance (ANOVA) determined that there were significant differences between HF etching, silane treatment, and the interaction between HF and silane treatment (p<0.01). Silane treatment provided higher shear bond strength regardless of the use or concentration of the HF etchant. Individual one-way ANOVA and Tukey post hoc analyses were performed for each silane group. Shear bond strength values for each etch time were significantly different (p<0.01) and could be divided into significantly different groups based on silane treatment: no silane treatment: 0 HF < 5% HF < 9.5% HF; and RelyX silane treatment: 0 HF < 5% HF and 9.5% HF. CONCLUSIONS: Both HF and silane treatment significantly improved the bond strength between resin and lithium disilicate when used with a universal adhesive. PMID- 25535785 TI - Air abrasion before and/or after zirconia sintering: surface characterization, flexural strength, and resin cement bond strength. AB - The purpose of this in vitro study was to evaluate the effect of air abrasion/zirconia sintering order on the yttria partially stabilized tetragonal zirconia polycrystal (Y-TZP) surface characterization (roughness, morphology, and phase transformation), flexural strength (FS), and shear bond strength (SBS) to a resin cement. Y-TZP specimens were air abraded with 50-MUm Al2O3 particles after (AS), before (BS), or before and after zirconia sintering (BAS). For roughness (Ra), 30 block specimens (12*12*3.0 mm; n=10) had their surfaces analyzed by a profilometer. Next, on the air-abraded surfaces of these specimens, composite resin discs (n=30) were bonded with RelyX ARC. The bonded specimens were stored for 24 hours in distilled water at 37 degrees C before shear testing. Failure mode was determined with a stereomicroscope (20*). The surface morphology (n=2) was evaluated by SEM (500*). For the four-point flexural strength test (EMIC DL2000), 39 bar-shaped specimens (20*4.0*1.2 mm; n=13) were air abraded according to the three conditions proposed, and an additional group (nonabraded) was evaluated (n=13). The quantitative analysis of phase transformation (n=1) was completed with Rietveld refinement with X-ray diffraction data. Ra (MUm) and SBS (MPa) data were analyzed by one-way analysis of variance (ANOVA) and the Tukey test (alpha=0.05). Pearson correlation analysis was used to determine if there was a correlation between roughness and SBS. For FS (MPa) data, one-way ANOVA and the Dunnett C-test (alpha=0.05) were used. The air-abrasion/zirconia sintering order influenced significantly (p<0.001) Ra, SBS, and FS. The BS and AS groups presented the highest (1.3 MUm) and the lowest (0.7 MUm) Ra. The highest SBS (7.0 MPa) was exhibited by the BAS group, followed by the AS group (5.4 MPa) and finally by the BS group (2.6 MPa). All groups presented 100% adhesive failure. A weak correlation (r=-0.45, p<0.05) was found between roughness and SBS. The air abrasion/zirconia sintering order provided differences in the surface morphology. The nonabraded (926.8 MPa) and BS (816.3 MPa) groups exhibited statistically similar FS values but lower values than the AS (1249.1 MPa) and BAS (1181.4 MPa) groups, with no significant difference between them. The nonabraded, AS, BS, and BAS groups exhibited, respectively, percentages of monoclinic phase of 0.0 wt%, 12.2 wt%, 0.0 wt%, and 8.6 wt%. The rougher surface provided by the air-abrasion before zirconia sintering may have impaired the bonding with the resin cement. The morphological patterns were consistent with the surface roughness. Considering the short-term SBS and FS, the BAS group exhibited the best performance. Air abrasion, regardless of its performance order, provides tetragonal to monoclinic transformation, while sintering tends to zero the monoclinic phase content. PMID- 25535786 TI - Effects of the concentration and composition of in-office bleaching gels on hydrogen peroxide penetration into the pulp chamber. AB - In tooth whitening, the hydrogen peroxide (HP) diffuses in the enamel and dentin, reaching the pulp. This in vitro study aimed to quantify the penetration of HP in the pulp chamber in teeth submitted to bleaching agents of different concentrations of HP without calcium (HP 20% [20CF], HP 35% [35CF]) and with calcium (HP 20% [20CC], HP 35% [35CC]). METHOD: Fifty human premolars were sectioned 3 mm from the cemento-enamel junction and the pulp tissue was removed. The teeth were divided into five groups according to treatment and with a control group (n=10). An acetate buffer solution was placed in the pulp chamber of all teeth. The control group was exposed only to distilled water, while the other groups were treated with a bleaching procedure, according to the manufacturer's recommendations. After treatment, the acetate buffer solution was transferred to a glass tube in which leuco-crystal violet and peroxidase solutions were added, resulting in a blue solution. The optical density of this blue solution was determined spectrophotometrically and converted into micrograms equivalent to the HP. Data were analyzed using analysis of variance and Tukey tests (alpha=0.05). RESULTS: The HP concentration did not affect the HP inside the pulp chamber, but the presence of calcium significantly reduced it (p<0.0001). CONCLUSION: The amount of HP that reaches the pulp chamber depends on the bleaching protocol and the product employed, and it seems to be less affected by HP concentration. PMID- 25535787 TI - The Effect of Combining Radiographs and DIAGNOdent With Visual Examination on Detection and Treatment Decisions of Noncavitated Occluso-dentinal Caries. AB - The aim of this laboratory study was to evaluate the effectiveness of incorporating radiographic examination and DIAGNOdent with visual examination for the detection and treatment of noncavitated occluso-dentinal caries. Four examiners examined the occlusal surfaces of 160 extracted posterior teeth. Teeth were examined three times with a one-month interval in between. The first examination was visual (V), the second examination was visual with radiograph (VR), and the third examination was visual with radiograph and DIAGNOdent (VRD). Examiners were asked to detect the presence of caries (if any) and identify the extent of caries (if present; ie, enamel or dentin). The examiners were also asked to choose a treatment for each tooth. The examined teeth were later sectioned, and the presence of caries was charted as 0 = no caries, 1 = caries confined to enamel, 2 = caries in the outer dentin, and 3 = caries in the inner dentin. Sensitivity, specificity, area under the curve (Az values), rank correlation coefficient, interexaminer reproducibility, and McNemar chi(2) tests were calculated. VR had statistically higher specificity and lower sensitivity than V and VRD. The means of Az values ranged from 0.58 to 0.63, with no statistical difference between the three examinations (p>0.05). The means of the rank correlation coefficients with histology for detection of dentinal caries were 0.48, 0.23, and 0.44 using V, VR, and VRD, respectively. Interexaminer reproducibility was best for V alone. The percentages of teeth indicated for restorative treatment were 31%, 33%, and 41% using V, VR, and VRD, respectively. The percentages of teeth correctly treated according to histology were 69.4%, 70.0%, and 67.5% using V, VR, and VRD, respectively. There was no difference in the accuracy of treatment decisions between the three examination points (p>0.05). The addition of radiographs and DIAGNOdent to visual examination did not have a significant effect on the improvement of the detection or treatment decisions of examiners of noncavitated occluso-dentinal carious lesions. PMID- 25535789 TI - From Goals of Care to Improved Family Outcomes in the NICU: Determining the Intervention. PMID- 25535788 TI - Handedness- and brain size-related efficiency differences in small-world brain networks: a resting-state functional magnetic resonance imaging study. AB - The human brain has been described as a complex network, which integrates information with high efficiency. However, the relationships between the efficiency of human brain functional networks and handedness and brain size remain unclear. Twenty-one left-handed and 32 right-handed healthy subjects underwent a resting-state functional magnetic resonance imaging scan. The whole brain functional networks were constructed by thresholding Pearson correlation matrices of 90 cortical and subcortical regions. Graph theory-based methods were employed to further analyze their topological properties. As expected, all participants demonstrated small-world topology, suggesting a highly efficient topological structure. Furthermore, we found that smaller brains showed higher local efficiency, whereas larger brains showed higher global efficiency, reflecting a suitable efficiency balance between local specialization and global integration of brain functional activity. Compared with right-handers, significant alterations in nodal efficiency were revealed in left-handers, involving the anterior and median cingulate gyrus, middle temporal gyrus, angular gyrus, and amygdala. Our findings indicated that the functional network organization in the human brain was associated with handedness and brain size. PMID- 25535790 TI - Unraveling the potential of CRISPR-Cas9 for gene therapy. AB - The molecular machinery from the prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas immune system has broadly been repurposed for genome editing in eukaryotes. In particular, the sequence-specific Cas9 endonuclease can be flexibly harnessed for the genesis of precise double-stranded DNA breaks, using single guide RNAs that are readily programmable. The endogenous DNA repair machinery subsequently generates genome modifications, either by random insertion or deletions using non-homologous end joining (NHEJ), or designed integration of mutations or genetic material using homology-directed repair (HDR) templates. This technology has opened new avenues for the investigation of genetic diseases in general, and for gene therapy applications in particular. PMID- 25535791 TI - Purification and interaction analyses of two human lysosomal vitamin B12 transporters: LMBD1 and ABCD4. AB - Mutations in human LMBRD1 and ABCD4 prevent lysosomal export of vitamin B(12) to the cytoplasm, impairing the vitamin B(12)-dependent enzymes methionine synthase and methylmalonyl-CoA mutase. The gene products of LMBRD1 and ABCD4 are implicated in vitamin B(12) transport at the lysosomal membrane and are proposed to act in complex. To address the mechanism for lysosomal vitamin B(12) transport, we report the novel recombinant production of LMBD1 and ABCD4 for detailed biophysical analyses. Using blue native PAGE, chemical crosslinking, and size exclusion chromatography coupled to multi-angle light scattering (SEC-MALS), we show that both detergent-solubilized LMBD1 and detergent-solubilized ABCD4 form homodimers. To examine the functional binding properties of these proteins, label-free surface plasmon resonance (SPR) provides direct in vitro evidence that: (i) LMBD1 and ABCD4 interact with low nanomolar affinity; and (ii) the cytoplasmic vitamin B(12)-processing protein MMACHC also interacts with LMBD1 and ABCD4 with low nanomolar affinity. Accordingly, we propose a model whereby membrane-bound LMBD1 and ABCD4 facilitate the vectorial delivery of lysosomal vitamin B(12) to cytoplasmic MMACHC, thus preventing cofactor dilution to the cytoplasmic milieu and protecting against inactivating side reactions. PMID- 25535792 TI - Ascending in utero herpes simplex virus infection in an initially healthy appearing premature infant. AB - The usual route of acquisition for intrauterine herpes simplex virus (HSV) infection is transplacental. We evaluated a premature infant with in utero acquisition of HSV resulting from ascending infection. Histopathologic evidence of chronic chorioamnionitis and positive staining with immunohistochemistry for HSV in the placenta and umbilical cord established the diagnosis. The clinical presentation was also of interest in that the infant was initially healthy appearing. PMID- 25535793 TI - The neuronal architecture of the mushroom body provides a logic for associative learning. AB - We identified the neurons comprising the Drosophila mushroom body (MB), an associative center in invertebrate brains, and provide a comprehensive map describing their potential connections. Each of the 21 MB output neuron (MBON) types elaborates segregated dendritic arbors along the parallel axons of ~2000 Kenyon cells, forming 15 compartments that collectively tile the MB lobes. MBON axons project to five discrete neuropils outside of the MB and three MBON types form a feedforward network in the lobes. Each of the 20 dopaminergic neuron (DAN) types projects axons to one, or at most two, of the MBON compartments. Convergence of DAN axons on compartmentalized Kenyon cell-MBON synapses creates a highly ordered unit that can support learning to impose valence on sensory representations. The elucidation of the complement of neurons of the MB provides a comprehensive anatomical substrate from which one can infer a functional logic of associative olfactory learning and memory. PMID- 25535796 TI - Frustrated Lewis pairs: from concept to catalysis. AB - CONSPECTUS: Frustrated Lewis pair (FLP) chemistry has emerged in the past decade as a strategy that enables main-group compounds to activate small molecules. This concept is based on the notion that combinations of Lewis acids and bases that are sterically prevented from forming classical Lewis acid-base adducts have Lewis acidity and basicity available for interaction with a third molecule. This concept has been applied to stoichiometric reactivity and then extended to catalysis. This Account describes three examples of such developments: hydrogenation, hydroamination, and CO2 reduction. The most dramatic finding from FLP chemistry was the discovery that FLPs can activate H2, thus countering the long-existing dogma that metals are required for such activation. This finding of stoichiometric reactivity was subsequently evolved to employ simple main-group species as catalysts in hydrogenations. While the initial studies focused on imines, subsequent studies uncovered FLP catalysts for a variety of organic substrates, including enamines, silyl enol ethers, olefins, and alkynes. Moreover, FLP reductions of aromatic anilines and N-heterocycles have been developed, while very recent extensions have uncovered the utility of FLP catalysts for ketone reductions. FLPs have also been shown to undergo stoichiometric reactivity with terminal alkynes. Typically, either deprotonation or FLP addition reaction products are observed, depending largely on the basicity of the Lewis base. While a variety of acid/base combinations have been exploited to afford a variety of zwitterionic products, this reactivity can also be extended to catalysis. When secondary aryl amines are employed, hydroamination of alkynes can be performed catalytically, providing a facile, metal-free route to enamines. In a similar fashion, initial studies of FLPs with CO2 demonstrated their ability to capture this greenhouse gas. Again, modification of the constituents of the FLP led to the discovery of reaction systems that demonstrated stoichiometric reduction of CO2 to either methanol or CO. Further modification led to the development of catalytic systems for the reduction of CO2 by hydrosilylation and hydroboration or deoxygenation. As each of these areas of FLP chemistry has advanced from the observation of unusual stoichiometric reactions to catalytic processes, it is clear that the concept of FLPs provides a new strategy for the design and application of main-group chemistry and the development of new metal-free catalytic processes. PMID- 25535798 TI - Titanium complex formation of organic ligands in titania gels. AB - Thin films of organic ligand-dispersing titania gels were prepared from titanium alkoxide sols containing ligand molecules by steam treatment without heating. The formation of the ligand-titanium complex and the photoinduced electron transfer process in the systems were investigated by photoelectrochemical measurements. The complex was formed between the 8-hydroxyquinoline (HQ) and titanium species, such as the titanium ion, on the titania nanoparticle surface through the oxygen and nitrogen atoms of the quinolate. A photocurrent was observed in the electrodes containing the complex due to the electron injection from the LUMO of the complex into the titania conduction band. A bidentate ligand, 2,3 dihydroxynaphthalene (DHN), formed the complex on the titania surface through dehydration between its two hydroxyl groups of DHN and two TiOH groups of the titania. The electron injection from the HOMO of DHN to the titania conduction band was observed during light irradiation. This direct electron injection was more effective than the two-step electron injection. PMID- 25535794 TI - Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila. AB - Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ~2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several associative learning tasks and in sleep regulation, revealing the extent to which information flow is segregated into distinct channels and suggesting possible roles for the multi-layered MBON network. We also show that optogenetic activation of MBONs can, depending on cell type, induce repulsion or attraction in flies. The behavioral effects of MBON perturbation are combinatorial, suggesting that the MBON ensemble collectively represents valence. We propose that local, stimulus-specific dopaminergic modulation selectively alters the balance within the MBON network for those stimuli. Our results suggest that valence encoded by the MBON ensemble biases memory-based action selection. PMID- 25535799 TI - Activation of persulfate by irradiated magnetite: implications for the degradation of phenol under heterogeneous photo-Fenton-like conditions. AB - We show that phenol can be effectively degraded by magnetite in the presence of persulfate (S2O8(2-)) under UVA irradiation. The process involves the radical SO4(-*), formed from S2O8(2-) in the presence of Fe(II). Although magnetite naturally contains Fe(II), the air-exposed oxide surface is fully oxidized to Fe(III) and irradiation is required to produce Fe(II). The magnetite + S2O8(2-) system was superior to the corresponding magnetite + H2O2 one in the presence of radical scavengers and in a natural water matrix, but it induced phenol mineralization in ultrapure water to a lesser extent. The leaching of Fe from the oxide surface was very limited, and much below the wastewater discharge limits. The reasonable performance of the magnetite/persulfate system in a natural water matrix and the low levels of dissolved Fe are potentially important for the removal of organic contaminants in wastewater. PMID- 25535795 TI - Domain-domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel. AB - Voltage-gated ion channels generate electrical currents that control muscle contraction, encode neuronal information, and trigger hormonal release. Tissue specific expression of accessory (beta) subunits causes these channels to generate currents with distinct properties. In the heart, KCNQ1 voltage-gated potassium channels coassemble with KCNE1 beta-subunits to generate the IKs current (Barhanin et al., 1996; Sanguinetti et al., 1996), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (Wrobel et al., 2012; Sun et al., 2012; Abbott, 2014). These changes are essential for the physiological role of IKs (Silva and Rudy, 2005); however, after 18 years of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent interactions that functionally couple the voltage-sensing domains (VSDs) to the pore. PMID- 25535797 TI - Dissolution of cellulose in room temperature ionic liquids: anion dependence. AB - The dissolution of cellulosic biomass in room temperature ionic liquids (RTILs) is studied through free energy calculations of its monomer, viz., cellobiose, within a molecular dynamics simulation approach. The solvation free energy (SFE) of cellobiose in ionic liquids containing any of seven different anions has been calculated. The ranking of these liquids based on SFE compares well with experimental data on the solubility of cellulose. The dissolution is shown to be enthalpically dominated, which is correlated with the strength of intermolecular hydrogen bonding between cellobiose and the anions of the IL. Large entropic changes upon solvation in [CF3SO3](-) and [OAc](-) based ionic liquids have been explained in terms of the solvent-aided conformational flexibility of cellobiose. PMID- 25535800 TI - SwissScoring--a nationwide survey of SAPS II assessing practices and its accuracy. AB - OBJECTIVE: The first description of the simplified acute physiology score (SAPS) II dates back to 1993, but little is known about its accuracy in daily practice. Our purpose was to evaluate the accuracy of scoring and the factors that affect it in a nationwide survey. METHODS: Twenty clinical scenarios, covering a broad range of illness severities, were randomly assigned to a convenience sample of physicians or nurses in Swiss adult intensive care units (ICUs), who were asked to assess the SAPS II score for a single scenario. These data were compared to a reference that was defined by five experienced researchers. The results were cross-matched with demographic characteristics and data on the training and quality control for the scoring, structural and organisational properties of each participating ICU. RESULTS: A total of 345 caregivers from 53 adult ICU providers completed the SAPS II evaluation of one clinical scenario. The mean SAPS II scoring was 42.6 +/- 23.4, with a bias of +5.74 (95%CI 2.0-9.5) compared to the reference score. There was no evidence of bias variation according to the case severity, ICU size, linguistic area, profession (physician vs. nurse), experience, initial SAPS II training, or presence of a quality control system. CONCLUSION: This nationwide survey revealed substantial variability in the SAPS II scoring results. On average, SAPS II scoring was overestimated by more than 13%, irrespective of the profession or experience of the scorer or of the structural characteristics of the ICUs. PMID- 25535801 TI - Aqueous Solution-Deposited Molybdenum Oxide Films as an Anode Interfacial Layer for Organic Solar Cells. AB - In this study, we report the growth of molybdenum oxide (MoOx) film by polymer assisted deposition (PAD), an environmentally friendly strategy in an aqueous system. The MoOx film has good crystal quality and is dense and smooth. The transparency of the film is >95% in the wavelength range of 300-900 nm. The device based on P3HT:PCBM absorber material was fabricated. The solar cell with PAD-MoOx as an anode interfacial layer exhibits great performance, even better than that of a solar cell with PEDOT: PSS or evaporated MoOx as an anode interfacial layer. More importantly, the solar cells based on the growth of MoOx have a longer term stability than that of solar cells based on PEDOT: PSS. These results demonstrate the aqueous PAD technology provides an alternative strategy not only for the thin films' growth of applied materials but also for the solution processing for the low-cost fabrication of future materials to be applied in the field of solar cells. PMID- 25535802 TI - Temperature-driven changes of the graphene edge structure on Ni(111): substrate vs hydrogen passivation. AB - Atomic-scale description of the structure of graphene edges on Ni(111), both during and post growth, is obtained by scanning tunneling microscopy (STM) in combination with density functional theory (DFT). During growth, at 470 degrees C, fast STM images (250 ms/image) evidence graphene flakes anchored to the substrate, with the edges exhibiting zigzag or Klein structure depending on the orientation. If growth is frozen, the flake edges hydrogenate and detach from the substrate, with hydrogen reconstructing the Klein edges. PMID- 25535804 TI - Influence of the pendant arm, halide, and solvent on high-efficient-tuning [1 + 1] and [2 + 2] schiff-base macrocyclic complexes via a zinc-ion template. AB - A series of pendant-armed Schiff-base macrocyclic complexes 1-7 have been prepared by the condensation between extended dialdehydes with pendant arms (H2hpdd/H2pdd) and 1,3-propanediamine in the presence of ZnX2 (X = Cl, Br, I), where 18-membered [1 + 1] mononuclear and 36-membered [2 + 2] half-fold trinuclear macrocyclic zinc(II) complexes are yielded. Three experimental variables, i.e., the pendant arm, halide, and solvent, are found to influence the organization of final macrocyclic complexes, in addition to the conventional metal-ion template effect promoting reversible formation and cleavage of Schiff base imine bonds. It is noted that all of the reactions produce singular macrocyclic complexes in high yields if the experimental variables are fixed, and the selection of different pendant arms and halide counterions will generate different [1 + 1] mononuclear and [2 + 2] trinuclear macrocyclic zinc(II) complexes. More interestingly, [1 + 1] and [2 + 2] macrocyclic zinc(II) complexes 2 and 3 can be produced in methanol and ethanol, respectively, in the case of the reaction between ZnBr2, H2pdd, and 1,3-propanediamine. Further experiments reveal that red solid 2 and yellow-green solid 3 can be transformed to each other just by altering the type of solvent, and this tuning is complete and reversible. PMID- 25535803 TI - Epoxide hydrolase-lasalocid a structure provides mechanistic insight into polyether natural product biosynthesis. AB - Biosynthesis of some polyether natural products involves a kinetically disfavored epoxide-opening cyclic ether formation, a reaction termed anti-Baldwin cyclization. One such example is the biosynthesis of lasalocid A, an ionophore antibiotic polyether. During lasalocid A biosynthesis, an epoxide hydrolase, Lsd19, converts the bisepoxy polyketide intermediate into the tetrahydrofuranyl tetrahydropyran product. We report the crystal structure of Lsd19 in complex with lasalocid A. The structure unambiguously shows that the C-terminal domain of Lsd19 catalyzes the intriguing anti-Baldwin cyclization. We propose a general mechanism for epoxide selection by ionophore polyether epoxide hydrolases. PMID- 25535805 TI - Analytical and Semi-Analytical Tools for the Design of Oscillatory Pumping Tests. AB - Oscillatory pumping tests-in which flow is varied in a periodic fashion-provide a method for understanding aquifer heterogeneity that is complementary to strategies such as slug testing and constant-rate pumping tests. During oscillatory testing, pressure data collected at non-pumping wells can be processed to extract metrics, such as signal amplitude and phase lag, from a time series. These metrics are robust against common sensor problems (including drift and noise) and have been shown to provide information about aquifer heterogeneity. Field implementations of oscillatory pumping tests for characterization, however, are not common and thus there are few guidelines for their design and implementation. Here, we use available analytical solutions from the literature to develop design guidelines for oscillatory pumping tests, while considering practical field constraints. We present two key analytical results for design and analysis of oscillatory pumping tests. First, we provide methods for choosing testing frequencies and flow rates which maximize the signal amplitude that can be expected at a distance from an oscillating pumping well, given design constraints such as maximum/minimum oscillator frequency and maximum volume cycled. Preliminary data from field testing helps to validate the methodology. Second, we develop a semi-analytical method for computing the sensitivity of oscillatory signals to spatially distributed aquifer flow parameters. This method can be quickly applied to understand the "sensed" extent of an aquifer at a given testing frequency. Both results can be applied given only bulk aquifer parameter estimates, and can help to optimize design of oscillatory pumping test campaigns. PMID- 25535806 TI - Modulating the charge transfer of D-S-A molecules: structures and NLO properties. AB - Very recently, the investigation of an Li atom doped effect on the "through space" electronic interaction (S) of a donor-S-acceptor (D-S-A, 1) shows that the Li-doping effect can modulate the first hyperpolarizability of 1 ( Dyes Pigm. 2014 , 106 , 7 - 13 ). Can we further enhance the first hyperpolarizability (betatot) of 1 by modulating the charge transfer of D-S-A molecules? The present work indicates that the betatot value can be successfully modulated by replacing the sp(2)-hybridized CH?CH moiety connected with substituted para-cyclophane (PCP). On the other hand, the NO2 contributes more than NH2 to the betatot value. The results of time-dependent density functional theory (TD-DFT) provide a good explanation for the variation in the betatot value. Interestingly, the betatot value of 3 (4.09 * 10(3) au) is larger than 1.52 * 10(3) au of 4, while the difference between the dipole moments (DeltaMU) of the ground state and the crucial excited state of 3 (2.93 D) is smaller than that of 4 (7.79 D). Further, the charge-transfer excitation length (D(CT)) of 3 (1.41 A) is smaller than that of 4 (2.89 A). Therefore, D(CT) is the major factor in determining the DeltaMU value. PMID- 25535807 TI - The short-term effects of C-peptide on the early diabetes-related ultrastructural changes to the podocyte slit diaphragm of glomeruli in rats. AB - OBJECTIVE: This study aimed to investigate the structural changes in the slit diaphragm, caused by early diabetes, and the nephroprotective effect of C peptide. METHODS: Streptozotocin-induced type 1 diabetic Wistar rats were divided into control, control plus C-peptide, early diabetes, and early diabetes plus C peptide groups. C-peptide was infused into rats for one day. The slit diaphragm component proteins podocin, CD2AP, and nephrin, were stained immunofluorescently and their distribution quantitatively analyzed by determining the overlapping area ratio. The interfoot process gap length was measured from electron microscopic images. RESULTS: Diabetic duration correlated best with the area ratio of podocin and CD2AP (r = 0.626), followed by other protein combinations, showing progressive change in the slit diaphragm structure. C-peptide-treatment did not alter area ratios. The interfoot process gap length was wider in diabetic rats (p < 0.05) and did not narrow with C-peptide-treatment in either control or diabetic rats (both p < 0.05). CONCLUSIONS: Diabetes widened the interfoot process gap length and distorted the slit diaphragm structure progressively and heterogeneously in rats with early diabetes; this was not altered by C-peptide treatment. The nephroprotective effect of C-peptide in decreasing the glomerular filtration rate appears to be functional rather than structural. PMID- 25535808 TI - Canadian Stroke Best Practice Recommendations: secondary prevention of stroke guidelines, update 2014. AB - Every year, approximately 62,000 people with stroke and transient ischemic attack are treated in Canadian hospitals. The 2014 update of the Canadian Secondary Prevention of Stroke guideline is a comprehensive summary of current evidence based recommendations for clinicians in a range of settings, who provide care to patients following stroke. Notable changes in this 5th edition include an emphasis on treating the highest risk patients who present within 48 h of symptom onset with transient or persistent motor or speech symptoms, who need to be transported to the closest emergency department with capacity for advanced stroke care; a recommendation for brain and vascular imaging (of the intra- and extracranial vessels) to be completed urgently using computed tomography/computed tomography angiography; prolonged cardiac monitoring for patients with suspective cardioembolic stroke but without evidence for atrial fibrillation on electrocardiogram or holter monitoring; and de-emphasizing the need for routine echocardiogram. The Canadian Stroke Best Practice Recommendations include a range of supporting materials such as implementation resources to facilitate the adoption of evidence to practice, and related performance measures to enable monitoring of uptake and effectiveness of the recommendations using a standardized approach. The guidelines further emphasize the need for a systems approach to stroke care, involving an interprofessional team, with access to specialists regardless of patient location, and the need to overcome geographical barriers to ensure equity in access within a universal health-care system. PMID- 25535809 TI - Cone-Beam Computed Tomography Evaluation of Horizontal and Vertical Dimensional Changes in Buccal Peri-Implant Alveolar Bone and Soft Tissue: A 1-Year Prospective Clinical Study. AB - PURPOSE: This study evaluated changes in the horizontal and vertical dimensions of the buccal alveolar bone and soft tissue over a 1-year period following implant prosthesis. MATERIALS AND METHODS: Thirty-three participants with no history of guided bone regeneration or soft tissue augmentation underwent dental implant placement with different types of connections. The dimensions of the buccal alveolar bone and soft tissue were evaluated immediately and at 1 year after prosthesis from reconstructions of cross-sectional cone-beam computed tomography images. RESULTS: The vertical and horizontal loss of buccal bone and soft tissue around implants with conical connections were lower than around those with external or internal connections. Statistically significant negative correlations were observed between initial horizontal bone thickness and changes in vertical bone and soft tissue height (p < .05), and between initial horizontal soft tissue thickness and the change in vertical soft tissue height (p < .05). CONCLUSION: Implants with a conical connection preserve peri-implant alveolar bone and soft tissue more effectively than other connection types. Furthermore, the initial buccal alveolar bone and soft tissue thickness around the implant platform may influence their vertical dimensional changes at 1 year after implant prosthesis. PMID- 25535810 TI - Trends in indoor tanning among US high school students, 2009-2013. PMID- 25535812 TI - Accelerated Development of Supramolecular Corneal Stromal-Like Assemblies from Corneal Fibroblasts in the Presence of Macromolecular Crowders. AB - Tissue engineering by self-assembly uses the cells' secretome as a regeneration template and biological factory of trophic factors. Despite the several advantages that have been witnessed in preclinical and clinical settings, the major obstacle for wide acceptance of this technology remains the tardy extracellular matrix formation. In this study, we assessed the influence of macromolecular crowding (MMC)/excluding volume effect, a biophysical phenomenon that accelerates thermodynamic activities and biological processes by several orders of magnitude, in human corneal fibroblast (HCF) culture. Our data indicate that the addition of negatively charged galactose derivative (carrageenan) in HCF culture, even at 0.5% serum, increases by 12-fold tissue-specific matrix deposition, while maintaining physiological cell morphology and protein/gene expression. Gene analysis indicates that a glucose derivative (dextran sulfate) may drive corneal fibroblasts toward a myofibroblast lineage. Collectively, these results indicate that MMC may be suitable not only for clinical translation and commercialization of tissue engineering by self-assembly therapies, but also for the development of in vitro pathophysiology models. PMID- 25535811 TI - Tracking early readmission after pancreatectomy to index and nonindex institutions: a more accurate assessment of readmission. AB - IMPORTANCE: Readmission after pancreatectomy is common, but few data compare patterns of readmission to index and nonindex hospitals. OBJECTIVES: To evaluate the rate of readmission to index and nonindex institutions following pancreatectomy at a tertiary high-volume institution and to identify patient level factors predictive of those readmissions. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of a prospectively collected institutional database linked to statewide data of patients who underwent pancreatectomy at a tertiary care referral center between January 1, 2005, and December 2, 2010. EXPOSURE: Pancreatectomy. MAIN OUTCOMES AND MEASURES: The primary outcome was unplanned 30-day readmission to index or nonindex hospitals. Risk factors and reasons for readmission were measured and compared by site using univariable and multivariable analyses. RESULTS: Among all 623 patients who underwent pancreatectomy during the study period, 134 (21.5%) were readmitted to our institution (105 [78.4%]) or to an outside institution (29 [21.6%]). Fifty-six patients (41.8%) were readmitted because of a gastrointestinal or nutritional problem related to surgery and 42 patients (31.3%) because of a postoperative infection. On multivariable analysis, factors independently associated with readmission included age 65 years or older (odds ratio [OR], 1.80; 95% CI, 1.19 2.71), preexisting liver disease (OR, 2.28; 95% CI, 1.23-4.24), distal pancreatectomy (OR, 1.77; 95% CI, 1.11-2.84), and postoperative drain placement (OR, 2.81; 95% CI, 1.00-7.14). CONCLUSIONS AND RELEVANCE: In total, 21.5% of patients required early readmission after pancreatectomy. Even in the setting of a tertiary care referral center, 21.6% of these readmissions were to nonindex institutions. Specific patient-level factors were associated with an increased risk of readmission. PMID- 25535813 TI - Fetal Brain MRI: Novel Classification and Contribution to Sonography. AB - PURPOSE: 1) To evaluate and classify the indications for fetal brain MRI in a tertiary referral center. 2) To assess the contribution of fetal brain MRI to fetal neurosonography. MATERIALS AND METHODS: A retrospective study in a tertiary medical center during a two-year period (2011 - 2012) included pregnant women who underwent fetal brain MRI. MRI was implemented at 32 weeks of gestation unless a severe abnormality possibly requiring earlier medical intervention was suspected. RESULTS: 633 patients were included, 40 (6.3%) underwent repeated examinations with a total of 733 fetal MRI scans. Patients were classified to three main indication cohorts: Suspected primary brain anomaly (52.9%), non-CNS disorders (32.5%) and obstetrical complications (14.6%). These cohorts were further divided into 16 separate groups with lateral ventricle abnormalities being the most common (23.7%), followed by exposure to TORCH (17.5%) and cerebral cortex abnormalities (13%). 149 (19.3%) fetal MRI scans demonstrated additional findings. Repeated examinations were commonly implemented in complicated monochorionic-biamniotic (MCBA) twin pregnancies (34.6%) and in cases of supra tentorial cysts (19%). The average gestational age for MRI scan in the MCBA group was 26 +/- 5 weeks in comparison to >= 31st weeks in all other groups (p < 0.001). CONCLUSION: The current study describes a detailed picture of fetal brain MRI indications. Most patients were referred because of CNS anomalies. The impressive diversity of 16 separate entities emphasizes the expanding use of fetal brain MRI. Complicated MCBA pregnancies, which may have dramatic events, constitute a unique challenge due to early and repetitive MRI examinations and may serve as a role model for the contribution of fetal MRI during antenatal evaluation. The contribution of MRI to prenatal evaluation in various indications is discussed. PMID- 25535814 TI - AUY922 effectively targets against activated B cell subtype of diffuse large B cell lymphoma and low-grade lymphoma cells harboring genetic alteration associated nuclear factor-kappaB activation. AB - Recurrent genetic alterations that are frequently observed in some low-grade lymphomas, such as activated B cell subtype of diffuse large B-cell lymphoma (ABC DLBCL) and mucosa-associated lymphoid tissue type lymphoma (MALT lymphoma) are usually associated with nuclear factor-kappaB (NF-kappaB) activation and confer resistance to therapy. In this study, we investigated the therapeutic efficacy and molecular mechanisms of AUY922, a novel Hsp90 inhibitor, in representative cell lines OCI-Ly3 (ABC-DLBCL) and MA-1 (a low-grade lymphoma cell line with t(14;18)/IgH-MALT1translocation) to explore its potential use in the treatment of refractory B-cell lymphoma. Our results showed that AUY922 effectively induced growth inhibition and apoptosis of OCI-Ly3 and MA-1 cells, which were accompanied by down-regulation of the expression levels of NF-kappaB and Bcl-2 family proteins, as well as molecules of multiple signaling pathways involving cell proliferation, growth and survival. The growth inhibitory effect of AUY922 was further confirmed in a mouse xenograft model. These findings indicate the potential use of AUY922 in B cell lymphomas. PMID- 25535815 TI - Incidence of chronic myeloid leukemia and patient survival: results of five French population-based cancer registries 1980-2009. AB - The treatment of chronic myeloid leukemia (CML) has seen several major advances over the past 30 years, notably with the introduction of interferon followed by Bcr-Abl tyrosine kinase inhibitors. We analyzed trends in the incidence of CML and patient survival in France. All cases recorded in five population-based registries between 1980 and 2009 were included. European (ESR) and world (WSR) standardized incidence rates as well as relative survival (RS) rates were estimated. We analyzed data for 781 patients (9863/3: 13.6%; 9875/3: 82.2%; 9876/3: 4.2%). ESR was 1.02 [95% confidence interval (CI) = 0.93-1.11] and WSR was 0.81 [95% CI = 0.72-0.90]. The five RS rates among patients with Philadelphia chromosome positive (Ph+) CML were 43.7% [30.9-61.9] when diagnosed in 1980-1986, 63.8% [56.9-71.5] in 1987-1999 and 88.7% [84.5-93.0] in 2000-2009. The 8-year RS rate of patients with Ph+ CML diagnosed in 2000-2009 was 83.3% [77.5-89.4]. Therapeutic innovations have thus led to a significant increase in long-term survival in the general CML patient-population. PMID- 25535817 TI - Predicting resistance to dasatinib therapy for patients with Philadelphia positive leukemia with prior tyrosine kinase inhibitor failure. PMID- 25535819 TI - Should Sexual Problems Be Included in the Internalizing Spectrum? A Comparison of Dimensional and Categorical Models. AB - Preliminary research has suggested that sexual problems should be included in the internalizing spectrum alongside depressive and anxiety disorders. This study aimed to empirically examine and compare an extended internalizing spectrum model with a categorical framework model implied by the current nosological structure. Responses to an online survey from a community sample (n = 518) were analyzed to compare the fit of six alternative models of the relationship between sexual problems and depressive and anxiety disorders, separately for men and women. The best model for women (n = 336) was a dimensional spectrum model that included sexual arousal, orgasm, and pain difficulties in the internalizing spectrum. The results for men (n = 182) were less clear-cut: there were apparent categorical relationships for a small group (n = 8), and the spectrum model showed a good fit for 96% of the sample. These findings are consistent with a nosology that maintains discrete disorders and diagnostic chapters while recognizing the relationships between them, as in the new structure of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. As such, this study offers further evidence that there are dimensional relationships between sexual problems and depressive and anxiety disorders, which should be explicitly recognized in diagnostic systems. PMID- 25535818 TI - Serum calprotectin: review of its usefulness and validity in paediatric rheumatic diseases. AB - In most childhood rheumatic diseases, specific diagnostic markers are not yet available. Therefore, a major emphasis in medical research today is directed to the discovery of new inflammation molecules, like calprotectin. Calprotectin (MRP8/MRP14) is a complex of calcium- and zinc-binding proteins that belong to the S100 protein family. This protein is directly released by leukocytes during the interaction with inflammatory activated endothelium at the site of inflammation. Increased plasma calprotectin levels have been found in inflammatory chronic diseases such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel diseases (IBD), multiple sclerosis, cystic fibrosis and systemic lupus erythematosus (SLE). In these diseases, serum calprotectin has been shown to correlate with disease activity and laboratory variables of inflammation such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). This review outlines the validity and the possible applications of calprotectin as a new inflammation marker in paediatric rheumatic diseases. PMID- 25535816 TI - Impact of disease status on outcome in relapsed and refractory multiple myeloma treated with lenalidomide. AB - The introduction of immunomodulatory drugs such as lenalidomide combined with dexamethasone (Len/Dex) has improved the outcome of patients with relapsed/refractory multiple myeloma (RRMM). Few data are currently available which investigate whether paraprotein relapse represents an indication for starting a new treatment. The aim of our retrospective, single-center study was to analyze the impact of disease status (relapsed/refractory) and type of relapse (clinical/paraprotein) on response rate and time-to-next-treatment (TNT). We included 74 patients (median age 70 years) with RRMM treated with Len/Dex until progression or unacceptable toxicity from 2008 to 2012. Age and disease status were not factors affecting overall response rate (ORR) and median TNT, but TNT was significantly longer in patients with asymptomatic compared to clinical relapse (34 vs. 19 months, p<0.008). In conclusion, Len/Dex represents an effective treatment with satisfactory ORR and outcomes in RRMM, especially for patients starting therapy in asymptomatic relapse. PMID- 25535820 TI - Universal electronics for miniature and automated chemical assays. AB - This minireview discusses universal electronic modules (generic programmable units) and their use by analytical chemists to construct inexpensive, miniature or automated devices. Recently, open-source platforms have gained considerable popularity among tech-savvy chemists because their implementation often does not require expert knowledge and investment of funds. Thus, chemistry students and researchers can easily start implementing them after a few hours of reading tutorials and trial-and-error. Single-board microcontrollers and micro-computers such as Arduino, Teensy, Raspberry Pi or BeagleBone enable collecting experimental data with high precision as well as efficient control of electric potentials and actuation of mechanical systems. They are readily programmed using high-level languages, such as C, C++, JavaScript or Python. They can also be coupled with mobile consumer electronics, including smartphones as well as teleinformatic networks. More demanding analytical tasks require fast signal processing. Field-programmable gate arrays enable efficient and inexpensive prototyping of high-performance analytical platforms, thus becoming increasingly popular among analytical chemists. This minireview discusses the advantages and drawbacks of universal electronic modules, considering their application in prototyping and manufacture of intelligent analytical instrumentation. PMID- 25535821 TI - Matched sibling donors versus alternative donors in allogeneic hematopoietic stem cell transplantation for pediatric severe aplastic anemia in Mexico. AB - Objectives Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the preferred initial treatment for children with severe aplastic anemia (SAA). Unfortunately, only about 30% of patients have a suitable human leukocyte antigen-matched sibling. Methods We have analyzed the outcome of 42 patients who received HSCT (22 MSD and 20 alternative donors (AD)) for SAA at the seven major pediatric HSCT centers in Mexico between 2001 and 2013. Results With a median follow-up of 30 months (range, 0.4-144), the 5-year overall survival in children transplanted from MSD was 86.4 + 7.3 vs. 49.5 + 11% for children after AD-HSCT (P = 0.013). The cumulative incidence of treatment-related mortality (TRM) was in the MSD-HSCT 9.1 + 3.9% vs. 47.6 + 9.1% in the AD-HSCT context (P = 0.007). Infectious complications contributed to death (91%) of most patients who received AD-HSCT. Discussion Even when the results of patients given MSD-HSCT are adequate, there is still much room for improvement particularly in children allografted with AD and in the supportive care. The development of an economicwise designed prospective project with MSD or matched unrelated donor HSCTs as a first line of treatment of children with SAA as a unified national trial could address these issues. PMID- 25535822 TI - American Thoracic Society member survey on climate change and health. AB - The American Thoracic Society (ATS), in collaboration with George Mason University, surveyed a random sample of ATS members to assess their perceptions of, clinical experiences with, and preferred policy responses to climate change. An e-mail containing an invitation from the ATS President and a link to an online survey was sent to 5,500 randomly selected U.S. members; up to four reminder e mails were sent to nonrespondents. Responses were received from members in 49 states and the District of Columbia (n = 915); the response rate was 17%. Geographic distribution of respondents mirrored that of the sample. Survey estimates' confidence intervals were +/-3.5% or smaller. Results indicate that a large majority of ATS members have concluded that climate change is happening (89%), that it is driven by human activity (68%), and that it is relevant to patient care ("a great deal"/"a moderate amount") (65%). A majority of respondents indicated they were already observing health impacts of climate change among their patients, most commonly as increases in chronic disease severity from air pollution (77%), allergic symptoms from exposure to plants or mold (58%), and severe weather injuries (57%). A larger majority anticipated seeing these climate-related health impacts in the next 2 decades. Respondents indicated that physicians and physician organizations should play an active role in educating patients, the public, and policy makers on the human health effects of climate change. Overall, ATS members are observing that human health is already adversely affected by climate change and support responses to address this situation. PMID- 25535824 TI - IDBA-MTP: A Hybrid Metatranscriptomic Assembler Based on Protein Information. AB - Metatranscriptomic analysis provides information on how a microbial community reacts to environmental changes. Using next-generation sequencing (NGS) technology, biologists can study the microbe community by sampling short reads from a mixture of mRNAs (metatranscriptomic data). As most microbial genome sequences are unknown, it would seem that de novo assembly of the mRNAs is needed. However, NGS reads are short and mRNAs share many similar regions and differ tremendously in abundance levels, making de novo assembly challenging. The existing assembler, IDBA-MT, designed specifically for the assembly of metatranscriptomic data and performs well only on high-expressed mRNAs. This article introduces IDBA-MTP, which adopts a novel approach to metatranscriptomic assembly that makes use of the fact that there is a database of millions of known protein sequences associated with mRNAs. How to effectively use the protein information is nontrivial given the size of the database and given that different mRNAs might lead to proteins with similar functions (because different amino acids might have similar characteristics). IDBA-MTP employs a similarity measure between mRNAs and protein sequences, dynamic programming techniques, and seed-and extend heuristics to tackle the problem effectively and efficiently. Experimental results show that IDBA-MTP outperforms existing assemblers by reconstructing 14% more mRNAs. PMID- 25535825 TI - Clinical, microbiological, and genetic characteristics of heteroresistant vancomycin-intermediate Staphylococcus aureus bacteremia in a teaching hospital. AB - The emergence of vancomycin intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) is of major concern worldwide. Our objective was to investigate the prevalence, phenotypic and molecular features of hVISA strains isolated from bacteremic patients and to determine the clinical significance of the hVISA phenotype in patients with bacteremia. A total of 104 S. aureus blood isolates were collected from a teaching hospital of Argentina between August 2009 and November 2010. No VISA isolate was recovered, and 3 out of 92 patients (3.3%) were infected with hVISA, 2 of them methicillin-resistant S. aureus (MRSA) (4.5% of MRSA). Macro Etest and prediffusion method detected 3/3 and 2/3 hVISA respectively. Considering the type of bacteremia, the three cases were distributed as follows: two patients had suffered multiple episodes of bacteremia (both hVISA strains recovered in the second episode), while only one patient had suffered a single episode of bacteremia with hVISA infection. MRSA bloodstream isolates exhibiting the hVISA phenotype were related to HA-MRSA Cordobes clone (ST5-SCCmec I-spa t149) and MRSA Argentinean pediatric clone (ST100-SCCmec IVNV spa t002), but not to CA-MRSA-ST30-SCCmec IV-spa t019 clone that was one of the most frequent in our country. Although still relatively infrequent in our hospital, hVISA strains were significantly associated with multiple episodes of bacteremia (p=0.037) and genetically unrelated. PMID- 25535826 TI - Palmitate-induced impairments of beta-cell function are linked with generation of specific ceramide species via acylation of sphingosine. AB - Prolonged exposure to palmitate impairs beta-cell function and mass. One of the proposed mechanisms is alteration in ceramide (Cer) generation. In the present study, exposure to palmitate induced the level of palmitoyl transferase and Cer synthases, enzymes of the Cer de novo and salvage pathways, and doubled total Cer levels, which was associated with decreased insulin secretion and augmented apoptosis in MIN6 cells and human islets. By inhibiting enzymes of the pathways pharmacologically with myriocin (ISP-1) or fumonisin B1 or by small interfering RNA (siRNA), we showed that Cer(14:0), Cer(16:0), Cer(20:1), and Cer(24:0) species, generated by the salvage pathway, are linked to the harmful effect of palmitate on beta-cells. Oleate attenuates negative effects of palmitate on beta cells. When oleate was included during culture of MIN6 cells with palmitate, the palmitate-induced up-regulation of the enzymes of the de novo and salvage pathways was prevented resulting in normalized levels of all Cer species except Cer(20:1). Our data suggest that enhanced Cer generation in response to elevated palmitate levels involves both de novo and salvage pathways. However, the negative effects of palmitate on beta-cells are attributed to generation of Cer species Cer(14:0), Cer(16:0), and Cer(24:0) via acylation of sphingosine. PMID- 25535828 TI - Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K cells of the upper small intestine and has a critical role in GIP secretion after fat ingestion. AB - Gastric inhibitory polypeptide (GIP) is an incretin secreted from enteroendocrine K cells in response to meal ingestion. Recently free fatty acid receptor G protein-coupled receptor (GPR) 120 was identified as a lipid sensor involved in glucagon-like peptide-1 secretion. However, Gpr 120 gene expression and its role in K cells remain unclear, partly due to difficulties in separation of K cells from other intestinal epithelial cells. In this study, we purified K cells using GIP-green fluorescent protein (GFP) knock-in mice, in which K cells can be visualized by GFP fluorescence. GFP-positive cells (K cells) were observed in the small intestine but not in the stomach and colon. K cell number and GIP content in K cells were significantly higher in the upper small intestine than those in the lower small intestine. We also examined the expression levels of several free fatty acid receptors in K cells. Among free fatty acid receptors, GPR120 was highly expressed in the K cells of the upper small intestine compared with the lower small intestine. To clarify the role of GPR120 on K cells in vivo, we used GPR120-deficient mice (GPR120(-/-)). GPR120(-/-) exhibited significantly lower GIP secretion (75% reduction, P < .01) after lard oil ingestion compared with that in wild-type mice. Consistently, pharmacological inhibition of GPR120 with grifolic acid methyl ether in wild-type mice significantly attenuated lard oil induced GIP secretion. In conclusion, GPR120 is expressed abundantly in K cells of the upper small intestine and plays a critical role in lipid-induced GIP secretion. PMID- 25535823 TI - Age-related Defects in Ocular and Nasal Mucosal Immune System and the Immunopathology of Dry Eye Disease. AB - Dry eye disease (DED) is a prevalent public health concern that affects up to 30% of adults and is particularly chronic and severe in the elderly. Two interconnected mechanisms cause DED: (1) an age-related dysfunction of lacrimal and meibomian glands, which leads to decreased tear production and/or an increase in tear evaporation; and (2) an age-related uncontrolled inflammation of the surface of the eye triggered by yet-to-be-determined internal immunopathological mechanisms, independent of tear deficiency and evaporation. In this review we summarize current knowledge on animal models that mimic both the severity and chronicity of inflammatory DED and that have been reliably used to provide insights into the immunopathological mechanisms of DED, and we provide an overview of the opportunities and limitations of the rabbit model in investigating the role of both ocular and nasal mucosal immune systems in the immunopathology of inflammatory DED and in testing novel immunotherapies aimed at delaying or reversing the uncontrolled age-related inflammatory DED. PMID- 25535830 TI - PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO). AB - Translocator protein (TSPO) is a mitochondrial outer membrane protein of unknown function with high physiological expression in steroidogenic cells. Using TSPO gene-deleted mice, we recently demonstrated that TSPO function is not essential for steroidogenesis. The first link between TSPO and steroidogenesis was established in studies showing modest increases in progesterone production by adrenocortical and Leydig tumor cell lines after treatment with PK11195. To reconcile discrepancies between physiological and pharmacological interpretations of TSPO function, we generated TSPO-knockout MA-10 mouse Leydig tumor cells (MA 10:TspoDelta/Delta) and examined their steroidogenic potential after exposure to either dibutyryl-cAMP or PK11195. Progesterone production in MA 10:TspoDelta/Delta after dibutyryl-cAMP was not different from control MA 10:Tspo+/+ cells, confirming that TSPO function is not essential for steroidogenesis. Interestingly, when treated with increasing concentrations of PK11195, both control MA-10:Tspo+/+ cells and MA-10:TspoDelta/Delta cells responded in a similar dose-dependent manner showing increases in progesterone production. These results show that the pharmacological effect of PK11195 on steroidogenesis is not mediated through TSPO. PMID- 25535831 TI - An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. AB - Gut endocrine cells are generally thought to have distinct localization and secretory products. Recent studies suggested that the cells are highly related and have potential to express more than one hormone. We studied the coexpression and cosecretion of gut hormones in separate segments of rat small intestine. We measured secretion of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), neurotensin, glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) from proximal and distal half of the small intestine, isolated from male rats and perfused ex vivo. Hormone secretion was stimulated by bombesin, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, and peptones. Furthermore, tissue samples collected along the intestine were analyzed for expression, hormone content, and cell densities including colocalization. Most hormones responded to all three stimuli (but no GIP response to bombesin). GLP-1 secretion was similar from proximal and distal intestine, whereas PYY was secreted only from the distal half. CCK and GIP were mainly secreted proximally, whereas neurotensin was equally secreted from both parts. Cell densities, hormone concentrations, and expression patterns were generally parallel, with increasing values distally for GLP-1 and PYY, an exclusively proximal pattern for CCK, even distribution for neurotensin and GIP except for the most distal segments. PYY nearly always colocalized with GLP-1. Approximately 20% of GLP-1 cells colocalized with CCK and neurotensin, whereas GLP-1/GIP colocalization was rare. Our findings indicate that two L cell types exist, a proximal one secreting GLP-1 (and possibly CCK and neurotensin), and a distal one secreting GLP-1 and PYY. GIP seems to be secreted from cells that are not cosecreting other peptides. PMID- 25535829 TI - Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice. AB - Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome. PMID- 25535827 TI - Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats. AB - During gestation, hyperphagia is necessary to cope with the metabolic demands of embryonic development. There were three main aims of this study: Firstly, to investigate the effect of pregnancy on hypothalamic fatty acid metabolism, a key pathway for the regulation of energy balance; secondly, to study whether pregnancy induces resistance to the anorectic effect of fatty acid synthase (FAS) inhibition and accumulation of malonyl-coenzyme A (CoA) in the hypothalamus; and, thirdly, to study whether changes in hypothalamic AMPK signaling are associated with brown adipose tissue (BAT) thermogenesis during pregnancy. Our data suggest that in pregnant rats, the hypothalamic fatty acid pathway shows an overall state that should lead to anorexia and elevated BAT thermogenesis: decreased activities of AMP-activated protein kinase (AMPK), FAS, and carnitine palmitoyltransferase 1, coupled with increased acetyl-CoA carboxylase function with subsequent elevation of malonyl-CoA levels. This profile seems dependent of estradiol levels but not prolactin or progesterone. Despite the apparent anorexic and thermogenic signaling in the hypothalamus, pregnant rats remain hyperphagic and display reduced temperature and BAT function. Actually, pregnant rats develop resistance to the anorectic effects of central FAS inhibition, which is associated with a reduction of proopiomelanocortin (POMC) expression and its transcription factors phospho-signal transducer and activator of transcription 3, and phospho-forkhead box O1. This evidence demonstrates that pregnancy induces a state of resistance to the anorectic and thermogenic actions of hypothalamic cellular signals of energy surplus, which, in parallel to the already known refractoriness to leptin effects, likely contributes to gestational hyperphagia and adiposity. PMID- 25535832 TI - Acyl ghrelin acts in the brain to control liver function and peripheral glucose homeostasis in male mice. AB - Recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pair-fed or ad libitum feeding conditions. Mice received intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), ghrelin, and allowed to eat ad libitum (icv ghrelin ad lib) or ghrelin and pair-fed to the aCSF group (icv ghrelin pf). Minipumps delivered acyl ghrelin at a dose of 0.25 MUg/h at 0.5 MUL/h for 7 days. There was no difference in daily blood glucose, insulin, glucagon, triglycerides, or nonesterified fatty acids. Body weight gain and food intake was significantly higher in icv ghrelin ad lib mice. However, both icv ghrelin ad lib and icv ghrelin pf groups exhibited heavier white adipose mass. Icv ghrelin pf mice exhibited better glucose tolerance than aCSF or icv ghrelin ad lib mice during a glucose tolerance test, although both icv ghrelin ad lib and icv ghrelin pf increased insulin release during the glucose tolerance test. Central acyl ghrelin infusion and pair feeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Icv ghrelin pf mice had an increase in plasma blood glucose during a pyruvate tolerance test relative to icv ghrelin ad lib or aCSF mice. Our results suggest that under conditions of negative energy (icv ghrelin pf), central acyl ghrelin engages a neural circuit that influences hepatic glucose function. Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis. PMID- 25535833 TI - Gonadoblastoma in patients with Ullrich-Turner syndrome. AB - Ullrich-Turner syndrome (UTS) is a common chromosomal abnormality caused by partial or complete X chromosome monosomy. One half of the patients have a 45,X karyotype, whereas the remaining patients display other X chromosome anomalies. In 6% to 11% of UTS, a normal or partly deleted Y chromosome has been found. A 10% to 30% risk of developing gonadoblastoma was found in the latter patients. The aim of this study was to evaluate the prevalence of Y chromosome-derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplasms in patients with UTS. Of 217 patients studied with UTS and chromosome analysis of peripheral-blood lymphocytes, Y chromosome material was found in 20 patients. Fluorescence in situ hybridization (FISH) testing was performed to characterize the structurally abnormal Y chromosome in 13 cases. Molecular analysis of the SRY gene could only be performed in 20 patients with 45,X karyotype. Two patients had the SRY genomes. Of the 20 patients with Y chromosome derived material, 17 underwent gonadectomy. The incidence of gonadoblastoma development in our series was 35.5%. Furthermore, 1 patient also showed a pure dysgerminoma, and another showed a mixed dysgerminoma and embryonal carcinoma. We emphasize the importance of complete processing of the gonadectomy specimen, including step sections, molecular studies, and FISH, in addition to the classic cytogenetic searching for Y chromosome sequences, in patients who present with a nonmosaic 45,X karyotype. Finally, we propose to routinely collect a sample for storage in the tumor bank for future studies. PMID- 25535835 TI - Construction of the tricyclic core of steenkrotin-type diterpenoids via intramolecular [3 + 2] cycloaddition. AB - A concise and diastereoselective route to the angularly fused [5-6-7] tricyclic carbon framework of the steenkrotin-type diterpenoids was reported. The key features of the strategy are based on an intramolecular nitrile oxide/alkene [3 + 2] cycloaddition and a regio-selective aldol/dehydration sequence. PMID- 25535836 TI - Regulation of RNA granule dynamics by phosphorylation of serine-rich, intrinsically disordered proteins in C. elegans. AB - RNA granules have been likened to liquid droplets whose dynamics depend on the controlled dissolution and condensation of internal components. The molecules and reactions that drive these dynamics in vivo are not well understood. In this study, we present evidence that a group of intrinsically disordered, serine-rich proteins regulate the dynamics of P granules in C. elegans embryos. The MEG (maternal-effect germline defective) proteins are germ plasm components that are required redundantly for fertility. We demonstrate that MEG-1 and MEG-3 are substrates of the kinase MBK-2/DYRK and the phosphatase PP2A(PPTR-1/2). Phosphorylation of the MEGs promotes granule disassembly and dephosphorylation promotes granule assembly. Using lattice light sheet microscopy on live embryos, we show that GFP-tagged MEG-3 localizes to a dynamic domain that surrounds and penetrates each granule. We conclude that, despite their liquid-like behavior, P granules are non-homogeneous structures whose assembly in embryos is regulated by phosphorylation. PMID- 25535837 TI - Gap junctions composed of connexins 41.8 and 39.4 are essential for colour pattern formation in zebrafish. AB - Interactions between all three pigment cell types are required to form the stripe pattern of adult zebrafish (Danio rerio), but their molecular nature is poorly understood. Mutations in leopard (leo), encoding Connexin 41.8 (Cx41.8), a gap junction subunit, cause a phenotypic series of spotted patterns. A new dominant allele, leo(tK3), leads to a complete loss of the pattern, suggesting a dominant negative impact on another component of gap junctions. In a genetic screen, we identified this component as Cx39.4 (luchs). Loss-of-function alleles demonstrate that luchs is required for stripe formation in zebrafish; however, the fins are almost not affected. Double mutants and chimeras, which show that leo and luchs are only required in xanthophores and melanophores, but not in iridophores, suggest that both connexins form heteromeric gap junctions. The phenotypes indicate that these promote homotypic interactions between melanophores and xanthophores, respectively, and those cells instruct the patterning of the iridophores. PMID- 25535838 TI - Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1. AB - Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. PMID- 25535842 TI - Potent affinity material for tracing acetone and related analytes based on molecular recognition by halogen bonds. AB - Affinity materials based on halogen bonds turned out to be a powerful tool for the molecular recognition of acetone or related carbonyl compounds in the presence of ubiquitous protic molecules. The superior selectivity and sensitivity were found by the gravimetric detection of volatile organic compounds by quartz crystal microbalances. PMID- 25535843 TI - Raman changes induced by electrochemical oxidation of poly(triarylamine)s: toward a relationship between molecular structure modifications and charge generation. AB - Linear, alternating polymers of aromatic amines (p-phenylenediamine, bis(p aminophenyl)amine, and diaminocarbazole) and either m-phenylene or 3,5-pyridine have been synthesized and characterized by electrochemical and spectroscopic means. The presence of radical cations in their electrochemically oxidized forms is manifested by new bands in the UV-vis-NIR spectra whose appearance can be correlated with reversible redox couples registered in the corresponding cyclic voltammograms at approximately the same potentials as well as with pronounced evolutions of their resonance Raman spectra. Detailed analysis of the Raman data gives information about the locations and the distribution of radical cations and spinless dication in the macromolecule. This approach can provide a new insight into the formation of high-spin states in these polymers. PMID- 25535839 TI - Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation. AB - The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding. PMID- 25535840 TI - Developmental mechanism of the periodic membrane skeleton in axons. AB - Actin, spectrin, and associated molecules form a periodic sub-membrane lattice structure in axons. How this membrane skeleton is developed and why it preferentially forms in axons are unknown. Here, we studied the developmental mechanism of this lattice structure. We found that this structure emerged early during axon development and propagated from proximal regions to distal ends of axons. Components of the axon initial segment were recruited to the lattice late during development. Formation of the lattice was regulated by the local concentration of betaII spectrin, which is higher in axons than in dendrites. Increasing the dendritic concentration of betaII spectrin by overexpression or by knocking out ankyrin B induced the formation of the periodic structure in dendrites, demonstrating that the spectrin concentration is a key determinant in the preferential development of this structure in axons and that ankyrin B is critical for the polarized distribution of betaII spectrin in neurites. PMID- 25535841 TI - Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF. AB - Pigment Epithelium Derived Factor (PEDF) is a secreted factor that has broad biological activities. It was first identified as a neurotrophic factor and later as the most potent natural antiangiogenic factor, a stem cell niche factor, and an inhibitor of cancer cell growth. Numerous animal models demonstrated its therapeutic value in treating blinding diseases and diverse cancer types. A long standing challenge is to reveal how PEDF acts on its target cells and the identities of the cell-surface receptors responsible for its activities. Here we report the identification of transmembrane proteins PLXDC1 and PLXDC2 as cell surface receptors for PEDF. Using distinct cellular models, we demonstrate their cell type-specific receptor activities through loss of function and gain of function studies. Our experiments suggest that PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain can have profound effects on receptor activities. PMID- 25535844 TI - To vaccinate or let it be--current recommendations and the reality about yellow fever vaccination. PMID- 25535845 TI - MUGC * MUGC: comprehensive two-dimensional gas chromatographic separations with microfabricated components. AB - The development and characterization of a microanalytical subsystem comprising silicon-micromachined first- and second-dimension separation columns and a silicon-micromachined thermal modulator (MUTM) for comprehensive two-dimensional (i.e., MUGC * MUGC) separations are described. The first dimension consists of two series-coupled 3.1 cm * 3.1 cm MUcolumn chips with etched channels 3 m long and 250 MUm * 140 MUm in cross section, wall-coated with a poly(dimethylsiloxane) (PDMS) stationary phase. The second dimension consists of a 1.2 cm * 1.2 cm MUcolumn chip with an etched channel 0.5 m long and 46 MUm * 150 MUm in cross section wall-coated with either a trigonal tricationic room-temperature ionic liquid (RTIL) or a commercial poly(trifluoropropylmethyl siloxane) (OV-215) stationary phase. The two-stage, cryogen-free MUTM consists of a Si chip containing two series-coupled, square spiral channels 4.2 cm and 2.8 cm long and 250 MUm * 140 MUm in cross section wall-coated with PDMS. Conventional injection methods and flame ionization detection were used. Temperature-ramped separations of a simple alkane mixture using the RTIL-coated second-dimension ((2)D) MUcolumn produced reasonably good peak shapes and modulation numbers; however, strong retention of polar compounds on the RTIL-coated (2)D MUcolumn led to excessively broad peaks with low (2)D resolution. Substituting OV-215 as the (2)D MUcolumn stationary phase markedly improved the performance, and a structured 22 min chromatogram of a 36-component mixture spanning a vapor pressure range of 0.027 to 13 kPa was generated with modulated peak fwhm (full width at half-maximum) values ranging from 90 to 643 ms and modulation numbers of 1-6. PMID- 25535846 TI - Sortase-mediated ligation of PsaE-modified photosystem I from Synechocystis sp. PCC 6803 to a conductive surface for enhanced photocurrent production on a gold electrode. AB - Sortase-mediated ligation was used to attach the photosystem I (PSI) complex from Synechocystis sp. PCC 6803 in a preferential orientation to enhance photoinduced electron flow to a conductive gold surface. Ideally, this method can result in a uniform monolayer of protein, covalently bound unidirectionally to the electrode surface. The exposed C-termini of the psaE subunits of the PSI trimer were targeted to contain an LPETG-sortase recognition sequence to increase noncompeting electron transfer by uniformly orienting the PSI stromal side proximal to the surface. Surface characterization with atomic force microscopy suggested that monolayer formation and optimal surface coverage occurred when the gold surfaces were incubated with peptide at 100 to 500 MUM concentrations. When photochronoamperometry with potassium ferrocyanide and ferricyanide as redox mediators was used, photocurrents in the range of 100 to 200 nA/cm(2) were produced, which is an improvement over other attachment techniques for photosystem monolayers that produce approximately 100 nA/cm(2) or less. This work demonstrated that sortase-mediated ligation aided in the control of PSI orientation on modified gold surfaces with a distribution of 94% stromal side proximal and 6% lumenal side proximal to the surface for current-producing PSI. PMID- 25535847 TI - Heating-rate-induced porous alpha-Fe2O3 with controllable pore size and crystallinity grown on graphene for supercapacitors. AB - Porous alpha-Fe2O3/graphene composites (S-PIGCs) have been synthesized by a simple hydrothermal method combined with a slow annealing route. The S-PIGCs as a supercapacitors electrode material exhibit an ultrahigh specific capacitance of 343.7 F g(-1) at a current density of 3 A g(-1), good rate capability, and excellent cycling stability. The enhanced electrochemical performances are attributed to the combined contribution from the optimally architecture of the porous alpha-Fe2O3, as a result of a slow annealing, and the extraordinary electrical conductivity of the graphene sheets. PMID- 25535848 TI - Solvent driving force ensures fast formation of a persistent and well-separated radical pair in plant cryptochrome. AB - The photoreceptor protein cryptochrome is thought to host, upon light absorption, a radical pair that is sensitive to very weak magnetic fields, endowing migratory birds with a magnetic compass sense. The molecular mechanism that leads to formation of a stabilized, magnetic field sensitive radical pair has despite various theoretical and experimental efforts not been unambiguously identified yet. We challenge this unambiguity through a unique quantum mechanical molecular dynamics approach where we perform electron transfer dynamics simulations taking into account the motion of the protein upon the electron transfer. This approach allows us to follow the time evolution of the electron transfer in an unbiased fashion and to reveal the molecular driving force that ensures fast electron transfer in cryptochrome guaranteeing formation of a persistent radical pair suitable for magnetoreception. We argue that this unraveled molecular mechanism is a general principle inherent to all proteins of the cryptochrome/photolyase family and that cryptochromes are, therefore, tailored to potentially function as efficient chemical magnetoreceptors. PMID- 25535849 TI - Porous microspheres of amorphous calcium phosphate: block copolymer templated microwave-assisted hydrothermal synthesis and application in drug delivery. AB - Amorphous calcium phosphate (ACP) microspheres with a porous and hollow structure have been prepared using an aqueous solution containing CaCl2 as a calcium source, adenosine triphosphate disodium salt (Na2ATP) as a phosphorus source in the presence of a block copolymer methoxyl poly(ethylene glycol)-block-poly(D,L lactide) (mPEG-PLA) by the microwave-assisted hydrothermal method. The effects of microwave hydrothermal temperature and the concentrations of CaCl2 and Na2ATP on the crystal phase and morphology of the product are investigated. The as-prepared ACP porous hollow microspheres have a relatively high specific surface area of 232.9 m(2) g(-1) and an average pore size of 9.9 nm. A typical anticancer drug, docetaxel, is used to evaluate the drug loading ability and drug release behavior of ACP porous hollow microspheres in phosphate buffered saline (PBS) with different pH values of 4.5 and 7.4. The experiments reveal that the ACP porous hollow microspheres have a high drug loading capacity and favorable pH-responsive drug release property, and the ACP porous hollow microsphere drug delivery system shows a high ability to damage tumor cells. It is expected that the as-prepared ACP porous hollow microspheres are promising for the applications in various biomedical fields such as drug delivery. PMID- 25535850 TI - Amine protection/alpha-activation with the tert-butoxythiocarbonyl group: application to azetidine lithiation-electrophilic substitution. AB - tert-Butoxythiocarbonyl (Botc), the long-neglected thiocarbonyl analogue of Boc, facilitates (unlike its alkoxycarbonyl cousin) alpha-lithiation and electrophile incorporation on N-Botc-azetidine. N,N,N',N'-endo,endo-Tetramethyl-2,5 diaminonorbornane proved optimal as a chiral ligand, generating adducts with er up to 92:8. Facile deprotection, under conditions that left the corresponding N Boc systems intact, was achieved using either TFA or via thermolysis in ethanol. PMID- 25535851 TI - To excise or ablate endometriosis: a discussion about terminology and study design. PMID- 25535853 TI - To excise or ablate endometriosis? The temptation of the overstatement. PMID- 25535852 TI - Reply: To PMID 25196160. PMID- 25535854 TI - The effects of experimental warming on the timing of a plant-insect herbivore interaction. AB - The phenology of many species is shifting in response to climatic changes, and these shifts are occurring at varying rates across species. This can potentially affect species' interactions and individual fitness. However, few studies have experimentally tested the influence of warming on the timing of species interactions. This is an important gap in the literature given the potential for different direct and indirect effects of temperature via phenological change. Our aim was to test the effects of warming on the western tent caterpillar (Malacosoma californicum pluviale). In addition to the direct effects of warming, we considered the two primary indirect effects mediated by warming-driven changes in its host plant, red alder (Alnus rubra): changes in resource availability due to phenological mismatch (i.e. changes in the relative timing of the interaction), and changes in resource quality associated with leaf maturation. We experimentally warmed egg masses and larvae of the western tent caterpillar placed on branches of red alder in the field. Warming advanced the timing of larval but not leaf emergence. This led to varying degrees of phenological mismatch, with larvae emerging as much as 25 days before to 10 days after the emergence of leaves. Even the earliest-emerging larvae, however, had high survival in the absence of leaves for up to 3 weeks, and they were surprisingly resistant to starvation. In addition, although warming created phenological mismatch that initially slowed the development of larvae that emerged before leaf emergence, it accelerated larval development once leaves were available. Therefore, warming had no net effect on our measures of insect performance. Our results demonstrate that the indirect effects of warming, in creating phenological mismatch, are as important to consider as the direct effects on insect performance. Although future climatic warming might influence plants and insects in different ways, some insects may be well adapted to variation in the timing of their interactions. PMID- 25535856 TI - Study of dispersion forces with quantum Monte Carlo: toward a continuum model for solvation. AB - We present a general method to compute dispersion interaction energy that, starting from London's interpretation, is based on the measure of the electronic electric field fluctuations, evaluated on electronic sampled configurations generated by quantum Monte Carlo. A damped electric field was considered in order to avoid divergence in the variance. Dispersion atom-atom C6 van der Waals coefficients were computed by coupling electric field fluctuations with static dipole polarizabilities. The dipole polarizability was evaluated at the diffusion Monte Carlo level by studying the response of the system to a constant external electric field. We extended the method to the calculation of the dispersion contribution to the free energy of solvation in the framework of the polarizable continuum model. We performed test calculations on pairs of some atomic systems. We considered He in ground and low lying excited states and Ne in the ground state and obtained a good agreement with literature data. We also made calculations on He, Ne, and F(-) in water as the solvent. Resulting dispersion contribution to the free energy of solvation shows the reliability of the method illustrated here. PMID- 25535855 TI - Maternal separation increases methamphetamine-induced damage in the striatum in male, but not female rats. AB - Methamphetamine abuse impacts the global economy through costs associated with drug enforcement, emergency room visits, and treatment. Previous research has demonstrated early life stress, such as childhood abuse, increases the likelihood of developing a substance abuse disorder. However, the effects of early life stress on neuronal damage induced by binge methamphetamine administration are unknown. We aimed to elucidate the effects of early life stress on methamphetamine induced dopamine damage in the striatum. Pups were separated from dams for 3h per day during the first two weeks of development or 15 min for control. In adulthood, rats received either subcutaneous 0.9% saline or 5.0mg/kg METH injections every 2h for a total of four injections. Rectal temperatures were taken before the first injection and 1h after each subsequent injection. Seven days after treatment, rats were euthanized and striatum was collected for quantification of tyrosine hydroxylase (TH) and dopamine transporters (DAT) content by Western blot. Methamphetamine significantly elevated core body temperature in males and decreased striatal DAT and TH content, and this effect was potentiated by early life stress. Females did not exhibit elevated core body temperatures or changes in DAT or TH in either condition. Results indicate maternal separation increases methamphetamine induced damage, and females are less susceptible to methamphetamine induced damage. PMID- 25535857 TI - Cytokine polymorphisms and plasma levels are associated with sleep onset insomnia in adults living with HIV/AIDS. AB - Sleep disturbance has been associated with inflammation and cytokine activity, and we previously described genetic associations between cytokine polymorphisms and sleep maintenance and duration among adults with HIV/AIDS. Although sleep onset insomnia (SOI) is also a commonly reported sleep problem, associations between cytokine biomarkers and SOI have not been adequately studied. The purpose of this study was to describe SOI in relation to cytokine plasma concentrations and gene polymorphisms in a convenience sample of 307 adults (212 men, 72 women, and 23 transgender) living with HIV/AIDS. Based on the Pittsburgh Sleep Quality Index item that asks the time it usually took to fall asleep in the past month, participants were categorized as either >30min to fall asleep (n=70, 23%) or 30min or less to fall asleep (n=237). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. After adjusting for genomic estimates of ancestry, self-reported race/ethnicity and viral load, SOI was associated with higher IL-13 plasma levels and with six single nucleotide polymorphisms (SNPs): IL1B rs1143642 and rs1143623, IL6 rs4719714, IL13 rs1295686, NFKB1 rs4648110, and TNFA rs2857602. In addition, the IL1B rs1143642 polymorphism was associated with plasma levels of IL-1beta in adjusted analyses. This study strengthens the evidence for an association between inflammation and sleep disturbance, particularly self-report of habitual SOI. In this chronic illness population, the cytokine polymorphisms associated with SOI provide direction for future personalized medicine intervention research. PMID- 25535859 TI - Effects of an interleukin-1 receptor antagonist on human sleep, sleep-associated memory consolidation, and blood monocytes. AB - Pro-inflammatory cytokines like interleukin-1 beta (IL-1) are major players in the interaction between the immune system and the central nervous system. Various animal studies report a sleep-promoting effect of IL-1 leading to enhanced slow wave sleep (SWS). Moreover, this cytokine was shown to affect hippocampus dependent memory. However, the role of IL-1 in human sleep and memory is not yet understood. We administered the synthetic IL-1 receptor antagonist anakinra (IL 1ra) in healthy humans (100mg, subcutaneously, before sleep; n=16) to investigate the role of IL-1 signaling in sleep regulation and sleep-dependent declarative memory consolidation. Inasmuch monocytes have been considered a model for central nervous microglia, we monitored cytokine production in classical and non classical blood monocytes to gain clues about how central nervous effects of IL 1ra are conveyed. Contrary to our expectation, IL-1ra increased EEG slow wave activity during SWS and non-rapid eye movement (NonREM) sleep, indicating a deepening of sleep, while sleep-associated memory consolidation remained unchanged. Moreover, IL-1ra slightly increased prolactin and reduced cortisol levels during sleep. Production of IL-1 by classical monocytes was diminished after IL-1ra. The discrepancy to findings in animal studies might reflect species differences and underlines the importance of studying cytokine effects in humans. PMID- 25535858 TI - Tired telomeres: Poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women. AB - Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean=35.4, SD=3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b=-56.8 base pairs per one point increase in PSQI, SE=20.4, p=0.007) and CD4+ T cells (b=-37.2, SE=15.9, p=0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and disease risk in obese individuals. PMID- 25535860 TI - Pre and post-natal antigen exposure can program the stress axis of adult zebra finches: evidence for environment matching. AB - Both maternal exposure to stressors and exposure of offspring to stressors during early life can have lifelong effects on the physiology and behavior of offspring. Stress exposure can permanently shape an individual's phenotype by influencing the development of the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for the production and regulation of glucocorticoids such as corticosterone (CORT). In this study we used captive zebra finches (Taeniopygia guttata) to examine the effects of matching and mismatching maternal and early post-natal exposure to one of two types of antigens or a control on HPA axis reactivity in adult offspring. Prior to breeding, adult females were injected with lipopolysaccharide (LPS), keyhole limpet hemocyanin (KLH) or a control. Offspring of females in each of the three treatments were themselves exposed to LPS, KLH or a control injection at 5 and 28days post-hatch. When offspring were at least 18months of age, standardized capture and restraint stress tests were conducted to determine the impact of the treatments on adult stress responsiveness. We found significant interaction effects between maternal and offspring treatments on stress-induced CORT levels, and evidence in support of the environment matching hypothesis for KLH-treated birds, not LPS-treated birds. KLH-treated offspring of KLH-treated mothers exhibited reduced stress-induced CORT levels, whereas LPS-treated or control offspring of KLH-treated mothers exhibited elevated stress-induced CORT levels. Although the treatment effects on baseline CORT were non-significant, the overall pattern was similar to the effects observed on stress-induced CORT levels. Our results highlight the complex nature of HPA axis programming, and to our knowledge, provide the first evidence that a match or mismatch between pre and post-natal antigen exposure can have life-long consequences for HPA axis function. PMID- 25535862 TI - The acute salinity changes activate the dual pathways of endocrine responses in the brain and pituitary of tilapia. AB - To analyze and compare the stress and osmoregulatory hormones and receptors in pituitary during acute salinity changes, the expression patterns of corticotropin releasing hormone (crh) in hypothalamus, prolactin (prl) releasing peptide (pRrp) in telencephalon and diencephalon, glucocorticoid receptors 2 (gr2), and mineralocorticoid receptor (mr), crh-r, pro-opiomelanocorticotropin (pomc), pRrp, prl, dopamine 2 receptor (d2-r), growth hormone (gh), gh-receptor (gh-r) and insulin-like growth hormone (igf-1) transcripts in pituitary were characterized in euryhaline tilapia. The results indicate that the crh transcripts increased in the hypothalamus and rostral pars distalis of the pituitary after the transfer of fish to SW. Similarly, the pRrp transcripts were more abundant in SW acclimated tilapia forebrain and hypothalamus. The crh-r, gr2 and mr transcripts were more expressed in rostral pars distalis and pars intermedia of pituitary at SW than FW tilapia. The data indicate that the SW acclimation stimulates these transcripts in the specific regions of the brain and pituitary which may be related to the activation of the hypothalamic-pituitary-interrenal (HPI)-axis. The results of dual in situ hybridization reveal that the transcripts of crh-r, gr2 and mr with pomc are highly co-localized in corticotrophs of pituitary. Furthermore, we demonstrate high expression of pRrp in the brain and low expression of pRrp and prl transcripts in the pituitary of SW fish. No crh-r and corticosteroid receptors were co-localized with prl transcripts in the pituitary. The gh-r and igf-1 mRNA levels were significantly increased in SW acclimated tilapia pituitary whereas there was no difference in the gh mRNA levels. The data suggest that the locally produced pRrp and d2-r may control and regulate the expression of prl mRNA in pituitary. Therefore, the dual roles of pRrp are involved in the stress (via brain-pituitary) and osmoregulatory (via pituitary) pathways in tilapia exposed to acute salinity changes. PMID- 25535861 TI - Gender differences in the association of sleep apnea and inflammation. AB - Over the last 15years, many studies have established an association of sleep apnea with inflammation and metabolic aberrations. However, no controlled studies have examined potential gender effects in this association. We recruited 120 middle-aged, predominantly non-obese mild-to-moderate sleep apneics and controls (62 males, 58 females). All participants underwent a clinical history, physical examination, and 1-night 8-h polysomnography recording and provided a single fasting blood sample for assessment of interleukin-6 (IL-6), tumor necrosis factor receptor 1 (TNFR1), C-reactive protein (CRP), leptin, and adiponectin levels. Among non-sleep apneics, females had higher levels of TNFR1 (p=0.01), CRP (p=0.005), leptin (p<0.001), and adiponectin (p<0.001) compared to males, independent of age and body mass index. When analyzed separately by gender, sleep apneic men had elevated TNFR1 (p=0.04), CRP (p=0.06) and IL-6 (p=0.11) relative to control men; in sleep apneic females, only CRP was elevated (p=0.04). Furthermore, CRP was associated with apnea severity in a dose-response manner (p linear=0.04 in both genders) and was independently associated with comorbid hypertension in apnea (p-linear=0.005 for women; p-linear=0.09 for men). In conclusion, although women have naturally higher levels of inflammatory and metabolic markers than men, sleep apneic men appear to have a more severe inflammatory profile compared to women. Our findings suggest that these markers should be analyzed and interpreted separately in men and women, and that a single measure of plasma CRP appears to be a clinically-useful marker of apnea severity and comorbid cardiovascular morbidity. PMID- 25535863 TI - Knee osteoarthritis radiographic progression and associations with pain and function prior to knee arthroplasty: a multicenter comparative cohort study. AB - OBJECTIVES: We determined the radiographic osteoarthritic worsening rate prior to knee arthroplasty (TKA) and whether this worsening was associated with worsening pain and function as compared to a non-surgical matched sample. METHODS: We used the Osteoarthritis Initiative 5-year datasets. Extent of knee OA 2 years prior to total knee arthroplasty (TKA) was matched to knees of persons who did not undergo TKA. Western Ontario and McMaster Universities Arthritis Index (WOMAC) Function and Knee injury and Osteoarthritis Outcome Score (KOOS) Pain scales were used to quantify functional deficit and functionally relevant pain respectively. A total of 167 persons with isolated TKA and 300 persons with matched symptomatic knee OA but no TKA were studied. RESULTS: During the 2 years prior to TKA, worsening by at least one Kellgren and Lawrence (KL) grade occurred in 27.4% (95% CI = 20.6 34.2) of the surgical knees compared to 6.6% (95% CI = 3.8-9.4) of matched non surgical knees. Osteoarthritis radiographic progression was strongly associated with WOMAC Function and KOOS Pain worsening (P < 0.001) in the 2 years prior to TKA. KL worsening was strongly associated with future arthroplasty (Odds ratio = 5.0, 95% CI = 2.6-9.8) after adjustment for potential confounders. CONCLUSIONS: Persons undergoing TKA 2 years later had substantial worsening pain and function over the 2-year pre-operative period as compared to a non-surgical sample matched based on KL grades. Almost 30% of persons who elect to undergo TKA undergo rapid disease progression and symptom worsening during the 2 years prior to TKA. PMID- 25535864 TI - Inducible expression of noggin selectively expands neural progenitors in the adult SVZ. AB - Multipotent, self-renewing stem cells are present throughout the developing nervous system remaining in discrete regions of the adult brain. In the subventricular zone (SVZ) signaling molecules, including the bone morphogenetic proteins and their secreted inhibitor, noggin appear to play a critical role in controlling neural stem cell (NSC) behavior. To examine the function of this signaling pathway in the intact nervous system, we developed a transgenic mouse model in which noggin expression can be induced specifically in NSC via a nestin driven reverse tetracycline-controlled transactivator (rtTA). In adult animals, the induction of noggin expression promotes the proliferation of neural progenitors in the SVZ, and shifts the differentiation of B cells (NSC) from mature astrocytes to transit amplifying C cells and oligodendrocyte precursor cells without depleting the NSC population. Noggin expression significantly increases neuronal and oligodendrocyte differentiation both in vivo and in vitro when NSCs are grown as neurospheres. These results demonstrate that noggin/BMP interactions tightly control cell fate in the SVZ. PMID- 25535866 TI - Outcomes in hepatitis B surface antigen-positive renal transplant recipients. PMID- 25535868 TI - Refractory giardiasis in renal transplantation: a case report. PMID- 25535865 TI - Long term maintenance of myeloid leukemic stem cells cultured with unrelated human mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) support the growth and differentiation of normal hematopoietic stem cells (HSCs). Here we studied the ability of MSCs to support the growth and survival of leukemic stem cells (LSCs) in vitro. Primary leukemic blasts isolated from the peripheral blood of 8 patients with acute myeloid leukemia (AML) were co-cultured with equal numbers of irradiated MSCs derived from unrelated donor bone marrow, with or without cytokines for up to 6weeks. Four samples showed CD34(+)CD38(-) predominance, and four were predominantly CD34(+)CD38(+). CD34(+) CD38(-) predominant leukemia cells maintained the CD34(+) CD38(-) phenotype and were viable for 6weeks when co-cultured with MSCs compared to co-cultures with cytokines or medium only, which showed rapid differentiation and loss of the LSC phenotype. In contrast, CD34(+) CD38(+) predominant leukemic cells maintained the CD34(+)CD38(+) phenotype when co-cultured with MSCs alone, but no culture conditions supported survival beyond 4weeks. Cell cycle analysis showed that MSCs maintained a higher proportion of CD34(+) blasts in G0 than leukemic cells cultured with cytokines. AML blasts maintained in culture with MSCs for up to 6weeks engrafted NSG mice with the same efficiency as their non cultured counterparts, and the original karyotype persisted after co-culture. Chemosensitivity and transwell assays suggest that MSCs provide pro-survival benefits to leukemic blasts through cell-cell contact. We conclude that MSCs support long-term maintenance of LSCs in vitro. This simple and inexpensive approach will facilitate basic investigation of LSCs and enable screening of novel therapeutic agents targeting LSCs. PMID- 25535869 TI - IgG4-related disease: an unusual cause of renal 'masses'. PMID- 25535867 TI - Role of Tacrolimus only therapy in modified Ponticelli regimen resistant idiopathic membranous glomerulonephritis. PMID- 25535871 TI - ET-1 increases reactive oxygen species in hypoxic glomeruli during high salt intake. PMID- 25535870 TI - Severe linezolid-induced lactic acidosis in a cirrhosis patient. PMID- 25535872 TI - Fascin expression is increased in metastatic lesions but does not correlate with progression nor outcome in melanoma. AB - Levels of the actin bundling protein fascin correlate with invasion and metastasis and reveal prognostic value in many epithelial carcinomas. However, we know very little about the potential role of fascin in melanoma. The purpose of this study is to compare fascin expression in primary melanomas and melanoma metastasis. Fascin expression was examined through the immunohistochemistry of paraffin embedded tissue microarrays including 560 cores of primary tumour and metastasis. Fascin expression was significantly elevated in 48 metastases compared with 254 primary tumours (P=0.034). In 187 patients with primary melanomas, fascin was not correlated with survival (P=0.067), whereas low fascin was significantly correlated with the presence of ulceration (P=0.005). Our results indicate that fascin status does not correlate with progression in melanoma. Upregulated fascin expression was detected in melanoma metastases, but was not correlated to patient outcome. PMID- 25535873 TI - Role of the Pseudomonas quinolone signal (PQS) in sensitising Pseudomonas aeruginosa to UVA radiation. AB - One of the main stress factors that bacteria face in the environment is solar ultraviolet-A (UVA) radiation, which leads to lethal effects through oxidative damage. The aim of this work was to investigate the role of 2-heptyl-3-hydroxi-4 quinolone (the Pseudomonas quinolone signal or PQS) in the response of Pseudomonas aeruginosa to UVA radiation. PQS is an intercellular quorum sensing signal associated to membrane vesicles which, among other functions, regulates genes related to iron acquisition, forms stable complexes with iron and participates in oxidative phenomena. UVA exposure of the wild-type PAO1 strain and a pqsA mutant unable to produce PQS revealed a sensitising role for this signal. Research into the mechanism involved in this phenomenon revealed that catalase, an essential factor in the UVA defence, is not related to PQS-mediated UVA sensitivity. Absorption of UVA by PQS produced its own photo-degradation, oxidation of the probe 2',7'- dichlorodihydrofluorescein and generation of singlet oxygen and superoxide anion, suggesting that this signal could be acting as an endogenous photosensitiser. The results presented in this study could explain the high sensitivity to UVA of P. aeruginosa when compared to enteric bacteria. PMID- 25535874 TI - Mary Edwards Walker: the soul ahead of her time. AB - Mary Edwards Walker was a gallant woman who stood for women's rights, embodied the true American spirit, and served the Union Army in the Civil War as a surgeon. She later became the first and only woman in United States history to be awarded the Congressional Medal of Honor. PMID- 25535875 TI - High-dynamic-range dermoscopy imaging and diagnosis of hypopigmented skin cancers. PMID- 25535876 TI - Can low pulse pressure have an adverse effect in octogenarians? PMID- 25535877 TI - Dependence of arterial stiffness on pressure quantified in the realm of the cardiac cycle: towards a patient-specific approach? PMID- 25535878 TI - Feasibility and affordability of cardiovascular disease prevention in sub-Saharan Africa. PMID- 25535879 TI - Should blood pressure medication be taken in the morning or evening? PMID- 25535880 TI - Effect of serum C-reactive protein and plasma fibrinogen levels on recurrent preeclampsia. PMID- 25535881 TI - Diuretics and potassium. PMID- 25535882 TI - Reply: To PMID 25105457. PMID- 25535883 TI - Long Term Follow-Up of Dental Implants Placed in Autologous Onlay Bone Graft. AB - PURPOSE: The aim of this study was to evaluate the efficacy of autologous intraoral onlay bone grafting (OBG) in correlation with long-term survival rates of dental implants placed in the augmented bone. MATERIALS AND METHODS: A retrospective study was conducted on 214 patients who received a total of 633 dental implants placed in 224 autologous intraoral block OBG augmentations, combined with Bio-Oss - mixed with platelet-rich plasma (PRP) and covered by platelet-poor plasma (PPP) - as scaffold, with a follow-up time up to 137 months (mean 39.9 +/- 30.9 months). RESULTS: A total of 216 OBG cases were successful (96.4%), and most of the augmentations were uneventful (88.4%). Bone graft exposure was moderately associated with bone graft failure (chi(2) = 3.76, p = .052). The healing period after implant placement was 4-6 months (mean 5.6 +/- 2.56). The majority of the 591 implants survived (93.4%). The cumulative survival rate of the implants was 83%. CONCLUSIONS: We suggest that augmentation of severely atrophied jaw bone through the placement of horizontal and/or vertical intraoral OBGs in combination with Bio-Oss saturated with PRP and covered by PPP should be considered a reliable, safe, and very effective surgical technique for obtaining high bone graft survival rate and high long-term implant survival rate. PMID- 25535884 TI - Buschke-Lowenstein tumor. PMID- 25535885 TI - Endothelial dysfunction in injury and inflammation. PMID- 25535887 TI - Thoracoscopy for internal mammary node dissection of metastatic breast cancer. AB - INTRODUCTION: Diagnosis of metastatic breast carcinoma to the internal mammary lymph nodes is important both as a prognostic factor and for planning adjuvant chemoradiotherapy. Establishing lymph node dissection is often performed by Chamberlain's procedure, which involves intercostal incision with spreading of the pectoralis and the intercostal muscles and can be associated with complications, including bleeding from the internal mammary artery or damage to intercostal vessels and nerves. A technique is presented for video-assisted thoracoscopic internal mammary node dissection using both sentinel node evaluation and dissection. PATIENTS AND METHODS: This technique was performed on 2 female patients undergoing internal mammary node evaluation after they presented with invasive ductal breast carcinoma. RESULTS: Video-assisted dissection of the thoracoscopic internal mammary lymph nodes was successfully performed with no intraoperative complications. The postoperative course was uneventful. CONCLUSIONS: This approach can avoid damage to the internal mammary artery and intercostal spaces while providing useful information for the guidance of further therapy and achieving local control if clinically indicated. PMID- 25535886 TI - Circadian rhythms of cellular immunity in rheumatoid arthritis: a hypothesis generating study. AB - OBJECTIVES: The circadian rhythm of clinical symptoms in rheumatoid arthritis (RA) has been primarily attributed to circadian variations in humoral factors and hormones. In this study, we investigated circadian rhythms of cellular immunity in RA (CiRA study). METHODS: Peripheral blood of female postmenopausal patients with active RA (DAS 28 >= 4.2) (n=5) and female postmenopausal non-RA controls (n=5) was collected every 2 hours for 24 hours and analysed by flow cytometry, cytokine multiplex suspension array and quantitative RT-PCR of clock gene expression in isolated CD14+ monocytes. Endogenous circadian rhythms of macrophages were investigated by BMAL1-luciferase bioluminescence. Significance of circadian rhythms was tested by Cosinor analysis. RESULTS: We found (i) circadian rhythms in the relative frequency of peripheral blood cell populations that were present in postmenopausal non-RA controls but absent in patients with active RA, (ii) circadian rhythms that were absent in non-RA controls but present in patients with RA and (iii) circadian rhythms that were present in both groups but with differences in peak phase or amplitude or amplitude/magnitude. The circadian rhythm in expression of the clock genes PER2 and PER3 in CD14+ monocytes was lost in patients with RA. The amplitude of BMAL1-luciferase bioluminescence tended to be lower in patients with RA than in non-RA controls. CONCLUSIONS: We conclude that (i) in RA some immune cell populations lose their normal circadian rhythms whereas others establish new 'inflammatory' circadian rhythms and (ii) these findings provide a good basis for further identifying pathophysiological aspects of RA chronobiology with potential therapeutic implications. PMID- 25535888 TI - Meta-analysis on effectiveness of hydroxyurea to treat transfusion-dependent beta thalassemia. AB - Objective To determine the efficacy of hydroxyurea therapy on transfusion dependent beta-thalassemia patients. Methods This study collected articles from databases, applied inclusion and exclusion criteria, and analyzed them for bias. The effects of hydroxyurea on transfusion requirements were categorized according to the following definitions. 'Good responders' were participants who became transfusion independent after treatment. 'Moderate responders' were participants who were still transfusion dependent, however, experienced a significant decline in their transfusion requirements. 'Poor responders' were defined as participants who did not respond to hydroxyurea. Results A total of 13 studies met all the inclusion and exclusion criteria providing a total of 1196 study participants. The weighted average of the odds ratio using the random effect model (P < 0.001) was determined to be 0.493 for good responders, 0.270 for moderate responders, and 0.229 for poor responders. Discussion Until now, there has not been any double-blinded placebo-controlled studies performed looking at the effectiveness of hydroxyurea with this regard, and this substantially limits this meta analysis. More studies should be conducted to determine whether hydroxyurea preferentially treats particular type of mutations over others. Conclusion This study suggests that hydroxyurea provides some benefit to patients, and therefore, in certain clinical situations, it may be understandable to start a trial therapy of hydroxyurea to qualifying patients. However, a double-blinded placebo controlled studies should be performed before its efficacy can be considered established. PMID- 25535889 TI - Sex Education Groups in a Psychiatric Day Hospital: Clinical Observations. AB - Although the prevalence of sexual dysfunction is high among individuals diagnosed with severe and chronic mental illness, the topic of sexuality is often not part of standard psychiatric assessment. Discussions about sexuality could improve patients' quality of life. This article outlines the development and implementation of a sex education group for patients admitted to a psychiatric day hospital in Montreal, Quebec, Canada, along with clinical observations. The series was well received by patients who felt that attending the group helped normalize their sexual concerns by providing a safe place in which to learn and to talk about sexuality. PMID- 25535890 TI - Cone Beam Computerized Tomography Measurement of Alveolar Ridge at Posterior Mandible for Implant Graft Estimation. AB - Damaging the inferior alveolar nerve (IAN) is the most serious complication when harvesting an autogenous graft from posterior mandible. The objective of this study was to use cone beam computerized tomography (CBCT) to measure dimensions of the alveolar ridge in the posterior mandible for estimation of a safe graft size, and then analyze how it is related to the gender, age, and dentition status of subjects. CBCT scans were screened to include 59 subjects without interfering pathologies. Alveolar height was measured from the alveolar crest to superior border of IAN and also to the inferior border of the mandible. Alveolar width (from buccal to lingual cortical plates) and buccal bone thickness (from buccal cortical plate to mandibular molar mesial root buccal surface) were measured at the coronal, middle, and apical thirds divided from the alveolar crest to the IAN. It was found that males and dentate sites had larger alveolar dimensions than did females and edentulous sites, respectively. Bone volume did not correlate significantly with age. Buccal bone thicknesses increased from coronal to apical and from the first to the third molar generally. A larger bone graft could be harvested from male than female patients, with a mean harvestable graft dimension (height * width in mm) for male was 15.5 * 3.2, and for female was 14.1 * 2.9. In conclusion, males and dentate arches demonstrate larger alveolar volumes than do females and edentulous regions, respectively. Larger alveolar grafts can be harvested from males compared to the females. Age does not seem to affect alveolar dimension/graft volume. PMID- 25535892 TI - BET bromodomain inhibitors--a novel epigenetic approach in castration-resistant prostate cancer. AB - The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. There has been some success in therapies targeting AR signaling which have been shown to extend survival in men with castration-resistant prostate cancer (CRPC). However, durable responses to these therapies have been limited and there is a need to identify additional therapeutic targets within the AR-signaling network. Recently a group at University of Michigan Medical School outlined the potential for BET bromodomain protein inhibitors as a novel epigenetic approach to treatment of CRPC. In prostate cancer cell lines, BET bromodomain inhibitor, JQ1, was shown to induce apoptosis and down-regulate AR-regulated gene transcription. Bromodomain and the extra-terminal (BET) subfamily of human bromodomain proteins, with a focus on BRD4, were shown to play a major role in AR signaling and interact with AR via bromodomain (BD) 1/2. JQ1 inhibits this BRD4-AR bond, resulting in removal of RNA polymerase II from AR target genes, causing reduced AR gene transcription and subsequent diminished AR signaling. JQ1 lead to a significant reduction in tumor volume and weight in VCaP xenograft mice. PMID- 25535891 TI - Glucocorticoid regulation of lung development: lessons learned from conditional GR knockout mice. AB - Glucocorticoid (GC) steroid hormones have well-characterized roles in the regulation of systemic homeostasis, yet less understood is their known role in utero to mature the developing respiratory system in preparation for birth. During late gestation, endogenously produced GCs thin the interstitial tissue of the lung, causing the vasculature and future airspaces to come into close alignment, allowing for efficient gas exchange at birth. More potent synthetic GCs are also used worldwide to reduce the severity of respiratory distress suffered by preterm infants; however, their clinical benefits are somewhat offset by potential detrimental long-term effects on health and development. Here, we review the recent literature studying both global and conditional gene-targeted respiratory mouse models of either GC deficiency or glucocorticoid receptor ablation. Although some discrepancies exist between these transgenic mouse strains, these models have revealed specific roles for GCs in particular tissue compartments of the developing lung and identify the mesenchyme as the critical site for glucocorticoid receptor-mediated lung maturation, particularly for the inhibition of cell proliferation and epithelial cell differentiation. Specific mesenchymal and epithelial cell-expressed gene targets that may potentially mediate the effect of GCs have also been identified in these studies and imply a GC-regulated system of cross talk between compartments during lung development. A better understanding of the specific roles of GCs in specific cell types and compartments of the fetal lung will allow the development of a new generation of selective GC ligands, enabling better therapeutic treatments with fewer side effects for lung immaturity at birth in preterm infants. PMID- 25535893 TI - Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer. AB - The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. PMID- 25535894 TI - Bioactive insulin-like growth factors as a possible molecular target for non islet cell tumor hypoglycemia. AB - Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia with a wide variety of solid tumors. It is considered to cause hypoglycemia by increasing the insulin-like bioactivity of the circulating insulin-like growth factor (IGF) system, however, the precise mechanism of hypoglycemia remains unclear. In this manuscript, we report on a patient suffering from NICTH caused by a small cell carcinoma of the colon. This is the first report focusing on the role of bioactive IGFs for this pathological condition. First, we demonstrated that the IGF signal pathway has been activated in this tumor in an autocrine and/or paracrine manner using immunohistochemical analysis. Second, we confirmed that bioactive IGFs in the patient's serum were increased using a modified kinase receptor activation assay, thus bioactive IGFs (mainly IGF-2) could be considered to play a major pathogenic role in enhanced hypoglycemic insulin-like activity. Third, increased IGF bioactivity in the patient's serum was completely inhibited by an anti-IGF neutralizing antibody in vitro. These results suggest that neutralization of bioactive IGFs might become a novel therapeutic strategy for NICTH to relieve the hypoglycemic symptoms together with the tumor suppressive effect. PMID- 25535895 TI - A breast cancer cell microarray (CMA) as a rapid method to characterize candidate biomarkers. AB - Tissue microarrays (TMAs) have become an invaluable tool in cancer research to evaluate expression and subcellular localization of proteins in cells and tissues. As the catalogs of candidate biomarkers and therapeutic targets become more extensive, there is a need to characterize and validate these targets and biomarkers in cell lines as a primary biological system in research laboratories. Thus, cell microarrays (CMAs) are useful as a high-throughput screening tool. Here, we constructed a CMA containing 32 publicly available immortalized breast cell lines with the goal of creating a method to rapidly screen for antigens of interest in breast cancer research in a relatively easy, rapid and cost-effective manner. As proof of concept, we performed immunocytochemical staining of the HER2 receptor, as the status of this protein is relevant to breast cancer and has previously been reported for these cell lines. We observed a complete concordance of our staining with the published status of HER2 in these cell lines. In addition, we examined the expression of CD44, epithelial markers EpCAM and E cadherin and tyrosine phosphoproteins. The labeling of these proteins correlates with the known biology of the cell lines. Our results demonstrate the utility of our method to screen for potential biomarkers and therapeutic targets in breast cancer and we suggest that CMAs be used as a general approach in breast cancer research. PMID- 25535896 TI - Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3 TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers. PMID- 25535897 TI - Enhancement of cellular radiation sensitivity through degradation of Chk1 by the XIAP-XAF1 complex. AB - X-linked inhibitor of apoptosis (XIAP) and Chk1 are potential molecular targets in radiotherapy. However, their molecular association in the regulation of radiation sensitivity has been rarely studied. Here, we show that XIAP modulates radiation sensitivity by regulating stability of Chk1 in lung cancer cells. Both Chk1 and XIAP are highly expressed in various lung cancer cells. Overexpression of XIAP increased cell survival following genotoxic treatments by preventing downregulation of Chk1. However, XIAP reversed Chk1-protective activity in the presence of XIAP-associated factor 1 (XAF1) by degrading Chk1 via ubiquitination dependent proteasomal proteolysis. The XIAP-XAF1 complex-mediated Chk1 degradation also required CUL4A and DDB1. Chk1 or XIAP was associated with DDB1 and CUL4A. Depletion of CUL4A or DDB1 prevented the XIAP-XAF1-mediated Chk1 degradation suggesting involvement of a CUL4A/DDB1-based E3 ubiquitin ligase in the process or its collaboration with XIAP E3 ligase activity. Taken together, our findings show that XIAP plays a dual role in modulation of Chk1 stability and cell viability following IR. In the absence of XAF1, XIAP stabilizes Chk1 under IR with corresponding increase of cell viability. By contrast, when XAF1 is overexpressed, XIAP facilitates Chk1 degradation, which leads to enhancement of radiation sensitivity. This selective regulation of Chk1 stability by XIAP and XAF1 could be harnessed to devise a strategy to modulate radiation sensitivity in lung cancer cells. PMID- 25535898 TI - Gli2 silencing enhances TRAIL-induced apoptosis and reduces tumor growth in human hepatoma cells in vivo. AB - Our previous studies have showed that Gli2 played a predominant role in proliferation and apoptosis resistance to TRAIL in hepatoma cells. The purpose of this study was to explore whether Gli2 silencing enhances efficiency of TRAIL for hepatoma in vivo. SMMC-7721-shRNA cells were implanted subcutaneously into nude mices and TRAIL was injected into the peritoneal space. TUNEL assay was used to detect apoptosis of tumor cells. The expression of Gli2, c-FLIPL, c-FLIPS, and Bcl-2 protein was determined by immunohistochemistry, respectively. Apoptosis and the level of caspases proteins in SMMC-7721 and HepG2 cells were detected by Flow cytometry and Western blot. Transcriptional activity of c-FLIP induced by Gli2 was measured by luciferase reporter gene assay. The results showed that lower volumes and weights of tumor were found in mice xenografted with SMMC-7721-shRNA cells as compared with control cells in the presence of TRAIL (P < 0.05). TUNEL assay showed significantly higher apoptosis index (AI) in the SMMC-7721-shRNA group than in the control groups (P < 0.05). There were remarkable positive correlations between Gli2 and c-FLIPL, c-FLIPS, Bcl-2 protein expression. Over expression of c-FLIP or Bcl-2 in HepG2 cells attenuated TRAIL-induced apoptosis via suppression of caspase-8 or caspase-9 activity, respectively. Luciferase reporter gene assay found a regulatory sequence by which Gli2 activated transcription between -1007 to -244 in the c-FLIP promoter region. This study demonstrates that Gli2 showed regulatory activity on transcription of c-FLIP gene, and Gli2 silencing enhances TRAIL-induced apoptosis via down-regulation of c-FLIP and Bcl-2 in human hepatoma cells in vivo. PMID- 25535899 TI - EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells. AB - Metastatic colon cancer has a 5-year survival of less than 10% despite the use of aggressive chemotherapeutic regimens. As signaling from epidermal growth factor receptor (EGFR) is often enhanced and epigenetic regulation is often altered in colon cancer, it is desirable to enhance the efficacy of EGFR-directed therapy by co-targeting an epigenetic pathway. We showed that the histone methyltransferase EZH2, which catalyzes methylation of histone H3 lysine 27 (H3K27), was upregulated in colon cancers in The Cancer Genome Atlas (TCGA) database. Since co inhibition of both EGFR and EZH2 has not been studied in colon cancer, we examined the effects of co-inhibition of EGFR and EZH2 on 2 colon cancer cell lines, HT-29 and HCT-15. Co-inhibition of EZH2 and EGFR with the small molecules UNC1999 and gefitinib, led to a significant decrease in cell number and increased apoptosis compared to inhibition of either pathway alone, and similar results were noted after EZH2 shRNA knockdown. Moreover, co-inhibition of EZH2 and EGFR also significantly induced autophagy, indicating that autophagy may play a role in the observed synergy. Together, these findings suggest that inhibition of both EZH2 and EGFR serves as an effective method to increase the efficacy of EGFR inhibitors in suppressing colon cancer cells. PMID- 25535902 TI - Cervical ectopic pregnancy treated with systemic methotrexate and following successful term pregnancy: case report. PMID- 25535900 TI - Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells. AB - Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT 737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers. PMID- 25535903 TI - Male partner involvement in female contraceptive choices in Nigeria. AB - Opposition by male partners is one of the barriers to contraceptive use in sub Saharan Africa. The study aimed at determining the extent of male partner involvement in female contraceptive (FP) choices in Enugu, south-east Nigeria. Questionnaires were administered to 243 consecutive women attendee of family planning clinic, University of Nigeria Teaching Hospital (UNTH), Enugu from January to June, 2012. A total of 137 women made contraceptive decisions jointly with their partners, which gave a male involvement rate of 56.4%. Only respondents' higher age (>= 35 years) had significant association with male partner involvement in FP choices (odds ratio (OR) = 2.1; 95% confidence interval: 1.22, 3.51; p = 0.008). Covert contraceptive use rate was 4.9% (12/243). A majority of women attending the FP clinic of UNTH, Enugu involved their partners when making contraceptive choices. Male-partner-targeted family planning programme has the potential to increase uptake of contraception in our environment. PMID- 25535901 TI - Distinct DNA damage determines differential phosphorylation of Chk2. AB - Checkpoint kinase 2 (Chk2) has been implicated in DNA damage signaling. By using BJ human fibroblasts, HCT116 colorectal cancer cells and HeLa cervical cancer cells, we further detailed phosphorylation kinetics of Chk2 under treatment with neocarcinostatin (NCS) or doxorubicin (Dox). After NCS treatment, phosphorylation of Chk2 Thr68 occurs in 3 min, followed by phosphorylation of Ser19 and Ser33/35. In ATM deficient fibroblasts, NCS does not induce phosphorylation of NBS1 Ser343 and Chk2 Ser19 and Ser33/35, however Chk2 Thr68 is still phosphorylated, indicating that ATM is essential for phosphorylation of these residues when treated with NCS. By using Chk2-deficient HCT116 cells re-expressing phospho mutant Chk2 (T68A), we found that inhibition of Thr68 phosphorylation enhances Ser19 phosphorylation in NCS treated cells. Interestingly, in contrast to NCS, Dox does not induce Ser33/35 phosphorylation in HeLa and HCT116 cells. Phosphorylation of Thr68 is sustained until 3 to 4 hours, and phosphorylation of Ser19 occurs 70 to 80 min after Dox treatment. These results demonstrate that Chk2 s involved in the early stages of DNA damage response. Differential phosphorylation kinetics of these residues suggests that DNA damage determines intermolecular and intramolecular interaction of Chk2, which may regulate phosphorylation. PMID- 25535904 TI - Consumer attitudes on cough and cold: US (ACHOO) survey results. AB - OBJECTIVE: The Attitudes of Consumers Toward Health, Cough, and Cold (ACHOO) survey was developed to better inform health care providers on the natural history and impact of common cold and cough, and related consumer experience and behaviors. RESEARCH DESIGN AND METHODS: Randomly selected US Internet/mobile device users were invited to participate in an online survey (N = 3333) in October 2012. Response quotas modeled upon 2010 US Census data ensured a demographically representative sample. To reduce potential bias from the quota design, 75% of the completed surveys were randomly selected as the primary analysis pool. MAIN OUTCOME MEASURES: Survey questions assessed participant demographics, frequency and duration of cough/cold symptoms, impact of symptoms on daily life, treatment preferences, and knowledge about cough/cold pathophysiology. RESULTS: In the past year, 84.6% of respondents had experienced at least one cold. Colds typically started with sore/scratchy throat (39.2%), nasal congestion (9.8%), and runny nose (9.3%) and lasted 3-7 days. Cough, the most common cold symptom (73.1%), had a delayed onset (typically 1-5 days after cold onset) and a long duration (>6 days in 35.2%). Nasal congestion and cough were the most bothersome symptoms. Many respondents waited until symptoms were 'bad enough' (42.6%) or multiple symptoms were present (20.2%) before using nonprescription medications. Drivers of choice included effectiveness in relieving symptoms, safety, and past experience. Respondents rarely consulted clinicians regarding treatment, and more than three-quarters had never received instructions from a clinician on how to choose a nonprescription cough/cold medication. Misperceptions regarding etiology and treatment of the common cold were prevalent. The main limitation is potential recall bias, since respondents had to recall cough/cold episodes over the prior year. CONCLUSIONS: The ACHOO survey confirms that cold is a common, bothersome experience and that there are gaps in consumers' knowledge of pathophysiology and appropriate management of cough/cold. PMID- 25535906 TI - A QM/MM study of Kemptide phosphorylation catalyzed by protein kinase A. The role of Asp166 as a general acid/base catalyst. AB - In this work a theoretical study of the gamma-phosphoryl group transfer from ATP to Ser17 of the synthetic substrate Kemptide (LRRASLG) in protein kinase A (PKA) has been carried out with a solvated model of the PKA-Mg2ATP-Kemptide system based on the X-ray crystallographic structure. We have used high levels (B3LYP/MM and MP2/MM) of theory to determine the overall reaction paths of the so-called concerted loose mechanism trying to clarify some aspects of that mechanism still under debate. Our calculations demonstrate for the first time in a complete model of the ternary system the viability of the final step of the catalytic mechanism in which the protonation of the phosphokemptide product by Asp166 takes place. Asp166 is a base catalyst that abstracts the HgammaSer17 of Kemptide thus facilitating the phosphoryl transfer, but it also acts as an acid catalyst by donating the proton just accepted from Ser17 to the O2gammaATP atom of the phosphoryl group. PMID- 25535905 TI - Serum pentosidine levels after 3 years of bisphosphonate treatment in post menopausal osteoporotic women. AB - The present study measured changes in plasma pentosidine and bone turnover markers in elderly patients with osteoporosis treated using bisphosphonate. The relationship between pentosidine and bone turnover markers and bone mineral density (BMD) was investigated. This study consisted of post-menopausal osteoporotic women who could be treated using bisphosphonate for 3 years were included in the present analysis. The study population consisted of 58 cases, all women, ranging in age from 53 to 86 years (mean, 67.1 years). Bisphosphonate treatment significantly increased BMD of the lumbar spine to 0.914 +/- 0.141 g/cm(2) and BMD of the femoral neck to 0.708 +/- 0.086 g/cm(2) after 3 years (p < 0.001 versus baseline). The mean BAP level was 27.3 +/- 8.3 U/L in patients at baseline. After bisphosphonate treatment, BAP significantly decreased to 18.1 +/- 7.2 U/L at 3 years (p < 0.001). Urinary NTX also decreased after bisphosphonate treatment. After 3 years of treatment, urinary NTX significantly decreased from 50.0 +/- 19.0 nmol BCE/mmol Cr to 24.6 +/- 10.2 nmol BCE/mmol Cr at 3 years (p < 0.001). Serum pentosidine levels were 0.0413 +/- 0.0094 MUg/mL at baseline and 0.0413 +/- 0.0122 MUg/mL after 3 years. They were not significantly changed by bisphosphonate treatment. Serum pentosidine levels were not changed by treatment with bisphosphonates. Thus, serum pentosidine may not be suitable as a marker of bone quality after 3 years of bisphosphonate treatment. PMID- 25535907 TI - Sleep-disordered breathing in patients with post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) and sleep-disordered breathing (SDB) are shared by many patients. They both affect sleep and the quality of life of affected subjects. A critical review of the literature supports an association between the two disorders in both combat-related and non-combat-related PTSD. The exact mechanism linking PTSD and SDB is not fully understood. A complex interplay between sleep fragmentation and neuroendocrine pathways is suggested. The overlap of symptoms between PTSD and SDB raises diagnostic challenges that may require a novel approach in the methods used to diagnose the coexisting disorders. Similar therapeutic challenges face patients and providers when treating concomitant PTSD and SDB. Although continuous positive airway pressure therapy imparts a mitigating effect on PTSD symptomatology, lack of both acceptance and adherence are common. Future research should focus on ways to improve adherence to continuous positive airway pressure therapy and on the use of alternative therapeutic methods for treating SDB in patients with PTSD. PMID- 25535908 TI - miR-155 Regulates Glioma Cells Invasion and Chemosensitivity by p38 Isforms In Vitro. AB - The critical role of microRNAs in cancer development has been extensively described. miRNAs are both specific markers and putative therapy targets. miR-155 has been identified to be an oncomiRNA and is highly expressed in several solid cancers, including glioblastoma. In this study, we found that miR-155 is a good potential therapy target. Knockdown of miR-155 sensitizes glioma cells to the chemotherapy of temozolomide (TMZ) by targeting the p38 isoforms mitogen activated protein kinase 13 [MAPK13, also known as p38 MAPKdelta or stress activated protein kinase 4 (SAPK4)] and MAPK14 (also known as p38 MAPKalpha). As tumor suppressor genes, MAPK13 and MAPK14 play important roles in lowering the accumulation of reactive oxygen species (ROS), inducing cell apoptosis, and slowing the progression of cancer. Knockdown of miR-155 enhanced the anticancer effect of TMZ on glioma by targeting the MAPK13 and MAPK14-mediated oxidative stress and apoptosis, but did not affect the secretion of MMP2 and MMP9. PMID- 25535910 TI - Patients treated with first-generation HCV protease inhibitors exhibit high ribavirin concentrations. AB - Anemia is a well-known RBV-related event in HCV therapy which is exacerbated by the addition of telaprevir and boceprevir. This retrospective study evaluated and compared ribavirin exposure and parameters able to influence hemoglobin decrease in a large population of patients treated with dual or triple therapy. Patients on triple therapy had higher ribavirin concentrations at week 12 of treatment (3460 ng/mL vs. 1843 ng/mL; P < .0001). An association was also observed between week 12 eGFR and ribavirin concentration only for patients on triple therapy (P = .002). The proportion of patients with a >20 mL/min/1.73 m(2) decrease in eGFR at week 12 was higher among patients on triple therapy: 32%, 14%, and 5% for boceprevir, telaprevir, and dual therapy, respectively (P = .025 and .026). No correlation was observed between boceprevir and telaprevir concentrations and hemoglobin or eGFR decrease. Exacerbation of anemia in patients on triple therapy is related to higher ribavirin concentrations. We provide an explanation for this increase in plasma RBV concentration. Triple therapy with PEG-IFN, RBV, and telaprevir or boceprevir will remain the only HCV treatment option for many patients. Our data show that the RBV dose can be decreased while maintaining adequate plasma concentrations and reducing anemia. PMID- 25535911 TI - Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. AB - The NLRP3 inflammasome is a caspase-1-containing multi-protein complex that controls the release of IL-1beta and plays important roles in the development of inflammatory disease. Here, we report that resveratrol, a polyphenolic compound naturally produced by plants, inhibits NLRP3 inflammasome-derived IL-1beta secretion and pyroptosis in macrophages. Resveratrol inhibits the activation step of the NLRP3 inflammasome by suppressing mitochondrial damage. Resveratrol also induces autophagy by activating p38, and macrophages treated with an autophagy inhibitor are resistant to the suppressive effects of resveratrol. In addition, resveratrol administration mitigates glomerular proliferation, glomerular sclerosis, and glomerular inflammation in a mouse model of progressive IgA nephropathy. These findings were associated with decreased renal mononuclear leukocyte infiltration, reduced renal superoxide anion levels, and inhibited renal NLRP3 inflammasome activation. Our data indicate that resveratrol suppresses NLRP3 inflammasome activation by preserving mitochondrial integrity and by augmenting autophagy. PMID- 25535912 TI - Unleashing mesenchymal chemotaxis. AB - In this issue of Developmental Cell, Asokan and colleagues (2014) report that the phospholipase Cgamma (PLCgamma)-diacyl glycerol (DAG) protein kinase Calpha (PKCalpha) signaling axis inhibits actomyosin bundling. This preferentially occurs at the leading edge of chemotactic mesenchymal cells via noncanonical phosphorylation of the regulatory light chain (RLC) of nonmuscle myosin II. PMID- 25535913 TI - Senescence helps regeneration. AB - Cellular senescence is a response to damage that involves inflammation and extracellular matrix remodeling and that resolves with the phagocytic elimination of the senescent cells. Demaria et al. (2014) in this issue of Developmental Cell demonstrate that cellular senescence plays an active and positive role during tissue regeneration. PMID- 25535914 TI - Close encounter of the third kind: the ER meets endosomes at fission sites. AB - The endoplasmic reticulum (ER) forms functional contacts with several cellular organelles and regulates processes such as mitochondrial fission. In a recent issue of Cell, Rowland et al. (2014) extend these findings to endosomes, showing that the ER contacts endosomes at sites containing the WASH subunit FAM21, where it forecasts fission events. PMID- 25535915 TI - Cullins keep autophagy under control. AB - Autophagy removes protein aggregates, damaged organelles, and intracellular pathogens from cells and helps to recycle lipids and protein building blocks. However, regulatory mechanisms of the initial, rapid response are largely unknown. In this issue of Developmental Cell, Antonioli et al. (2014) provide mechanistic insights into autophagy induction and termination by Cullin E3 ligases. PMID- 25535916 TI - Differential regulation of microtubule severing by APC underlies distinct patterns of projection neuron and interneuron migration. AB - Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. The two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial versus tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT-severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex. PMID- 25535919 TI - The notochord breaks bilateral symmetry by controlling cell shapes in the zebrafish laterality organ. AB - Kupffer's vesicle (KV) is the zebrafish organ of laterality, patterning the embryo along its left-right (LR) axis. Regional differences in cell shape within the lumen-lining KV epithelium are essential for its LR patterning function. However, the processes by which KV cells acquire their characteristic shapes are largely unknown. Here, we show that the notochord induces regional differences in cell shape within KV by triggering extracellular matrix (ECM) accumulation adjacent to anterior-dorsal (AD) regions of KV. This localized ECM deposition restricts apical expansion of lumen-lining epithelial cells in AD regions of KV during lumen growth. Our study provides mechanistic insight into the processes by which KV translates global embryonic patterning into regional cell shape differences required for its LR symmetry-breaking function. PMID- 25535917 TI - Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells. AB - Acquisition and maintenance of vascular smooth muscle fate are essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of vascular smooth muscle cells (vSMCs) can result in structural alterations associated with aneurysms and vascular wall calcification. Here we report that maturation of sclerotome-derived vSMCs depends on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time, Notch/Jag1-mediated repression of sclerotome transcription factors Pax1, Scx, and Sox9 is necessary to fully enable vSMC maturation. Specifically, Notch signaling in vSMCs antagonizes sclerotome and cartilage transcription factors and promotes upregulation of contractile genes. In the absence of the Notch ligand Jag1, vSMCs acquire a chondrocytic transcriptional repertoire that can lead to ossification. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming, and promote vascular wall integrity. PMID- 25535920 TI - Systematic study of Drosophila microRNA functions using a collection of targeted knockout mutations. AB - MicroRNAs are abundant in animal genomes, yet little is known about their functions in vivo. Here, we report the production of 80 new Drosophila miRNA mutants by targeted homologous recombination. These mutants remove 104 miRNAs. Together with 15 previously reported mutants, this collection includes 95 mutants deleting 130 miRNAs. Collectively, these genes produce over 99% of all Drosophila miRNAs, measured by miRNA sequence reads. We present a survey of developmental and adult miRNA phenotypes. Over 80% of the mutants showed at least one phenotype using a p < 0.01 significance threshold. We observed a significant correlation between miRNA abundance and phenotypes related to survival and lifespan, but not to most other phenotypes. miRNA cluster mutants were no more likely than single miRNA mutants to produce significant phenotypes. This mutant collection will provide a resource for future analysis of the biological roles of Drosophila miRNAs. PMID- 25535921 TI - Pleura nodosum: fetal squamous debris in an unusual location. AB - We present a pathologic-radiologic case of a fetus with a right extralobar bronchopulmonary sequestration that required intervention in the form of a thoraco-amniotic shunt for management of a right pleural effusion. The intervention was successful in reducing the pleural effusion and the infant was born at 39 weeks gestational age but required some respiratory support for the 1st day of life. The pulmonary sequestration was excised on day 7 of life and demonstrated several small nodules on its pleural surface. Histologic examination demonstrated that the nodules consisted of granulomatous plaques containing squamous epithelium and hairs. The nodules are similar to those described in amnion nodosum, when the amniotic membrane incorporates fetal skin within the superficial tissue layers of the placenta in cases of oligohydramnios. To our knowledge, this is the 1st reported case of nodules containing amniotic fetal squamous debris to occur on lung visceral pleura. PMID- 25535922 TI - Comprehensive analysis of the mouse brain proteome sampled in mass spectrometry imaging. AB - On-tissue enzymatic digestion is performed in mass spectrometry imaging (MSI) experiments to access larger proteins and to assign protein identities. Most on tissue digestion MSI studies have focused on method development rather than identifying the molecular features observed. Herein, we report a comprehensive study of the mouse brain proteome sampled by MSI. Using complementary proteases, we were able to identify 5337 peptides in the matrix-assisted laser desorption/ionization (MALDI) matrix, corresponding to 1198 proteins. 630 of these peptides, corresponding to 280 proteins, could be assigned to peaks in MSI data sets. Gene ontology and pathway analyses revealed that many of the proteins are involved in neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease. PMID- 25535923 TI - Following the aggregation of human prion protein on Au(111) surface in real-time. AB - Aggregations of human prion protein (23-231) were monitored by atomic force microscopy in real-time under pH 4. Prion dimers and trimers were determined as the basic units by AFM images and simulated structures. Aggregates aligned with the herringbone structures of an Au(111) reconstructed surface via Au-S bonds as the first layer, while the second layer was formed by non-covalent interactions. PMID- 25535924 TI - Carbon-armored Co9S8 nanoparticles as all-pH efficient and durable H2-evolving electrocatalysts. AB - Splitting water to produce hydrogen requires the development of non-noble-metal catalysts that are able to make this reaction feasible and energy efficient. Herein, we show that cobalt pentlandite (Co9S8) nanoparticles can serve as an electrochemically active, noble-metal-free material toward hydrogen evolution reaction, and they work stably in neutral solution (pH 7) but not in acidic (pH 0) and basic (pH 14) media. We, therefore, further present a carbon-armoring strategy to increase the durability and activity of Co9S8 over a wider pH range. In particular, carbon-armored Co9S8 nanoparticles (Co9S8@C) are prepared by direct thermal treatment of a mixture of cobalt nitrate and trithiocyanuric acid at 700 degrees C in N2 atmosphere. Trithiocyanuric acid functions as both sulfur and carbon sources in the reaction system. The resulting Co9S8@C material operates well with high activity over a broad pH range, from pH 0 to 14, and gives nearly 100% Faradaic yield during hydrogen evolution reaction under acidic (pH 0), neutral (pH 7), and basic (pH 14) media. To the best of our knowledge, this is the first time that a transition-metal chalcogenide material is shown to have all-pH efficient and durable electrocatalytic activity. Identifying Co9S8 as the catalytically active phase and developing carbon-armoring as the improvement strategy are anticipated to give a fresh impetus to rational design of high performance noble-metal-free water splitting catalysts. PMID- 25535925 TI - Fluoride ion sensing in aqueous medium by employing nitrobenzoxadiazole postgrafted mesoporous silica nanoparticles (MCM-41). AB - A mesoporous silica-based inorganic-organic hybrid material (NBD-AP-MCM) has been designed and developed as a fluorescent chemosensor for the detection of fluoride in aqueous medium. The system was developed by covalently anchoring 7-nitro-2,1,3 benzoxadiazole (NBD) dye onto the surface of mesoporous silica nanoparticles, MCM 41. The system was characterized using several conventional analytical methods comprising spectroscopic, microscopic and thermo-gravimetric techniques. The sensory action of the material was investigated by carrying out steady state absorbance, fluorescence and time resolved fluorescence studies on the system in the absence and presence of several biologically and environmentally important anions in aqueous solution. The photophysical data of the present system (NBD-AP MCM) have also been compared with the free dye (NBD) molecules. A significant decrease in the fluorescence quantum yield of the fluorophore in the hybrid material NBD-AP-MCM has been observed as compared to the unbound NBD. The decrease in fluorescence efficiency in the hybrid material is attributed to the aggregation caused quenching (ACQ) phenomenon. Interestingly, the system displays more than six-fold fluorescence enhancement in the presence of fluoride ions in aqueous solution. Enhancement of the fluorescence lifetime of the fluorescing moiety (NBD) has also been observed during fluorescence time-resolved studies. No significant optical changes have been observed with other commonly encountered anions rendering the present system highly selective towards fluoride detection. The fluorescence enhancement has been attributed to the cleavage of Si-O bonds due to the addition of fluoride. The silyl cleavage detaches the fluorophore from the solid support thereby making the fluorophore "free" in solution, which in turn recovers its original fluorescence which was decreased because of the aggregation on the solid silica support. Furthermore, the suitability of the present system in cellular imaging has also been demonstrated. PMID- 25535918 TI - Sex- and tissue-specific functions of Drosophila doublesex transcription factor target genes. AB - Primary sex-determination "switches" evolve rapidly, but Doublesex (DSX)-related transcription factors (DMRTs) act downstream of these switches to control sexual development in most animal species. Drosophila dsx encodes female- and male specific isoforms (DSX(F) and DSX(M)), but little is known about how dsx controls sexual development, whether DSX(F) and DSX(M) bind different targets, or how DSX proteins direct different outcomes in diverse tissues. We undertook genome-wide analyses to identify DSX targets using in vivo occupancy, binding site prediction, and evolutionary conservation. We find that DSX(F) and DSX(M) bind thousands of the same targets in multiple tissues in both sexes, yet these targets have sex- and tissue-specific functions. Interestingly, DSX targets show considerable overlap with targets identified for mouse DMRT1. DSX targets include transcription factors and signaling pathway components providing for direct and indirect regulation of sex-biased expression. PMID- 25535926 TI - Stereoelectronic effects: a simple yet powerful tool to manipulate anion affinity. AB - Different strategies are employed in designing strong and selective anion receptors but stereoelectronic effects have been largely ignored. In this work, the stereo configuration of a non-interacting ether is found to have a large impact of more than two orders of magnitude on the binding of a rigid diol with tetrabutylammonium chloride in acetonitrile-d3. A favorable carbon-oxygen dipole and an intramolecular C-HOH hydrogen bond in an equatorially substituted ether is found to be energetically more important than a stabilizing hydrogen bond in the corresponding axially oriented alcohol. IR spectroscopy is also used to probe the structures of the bound complexes and several binding motifs are identified. PMID- 25535927 TI - Light and electron microscopic study on the effect of antischizophrenic drugs on the structure of seminiferous tubules of adult male albino rats. AB - INTRODUCTION: Sexual dysfunction and infertility are symptoms which have been rarely studied in patients treated with antischizophrenic drugs, aripiprazole and olanzapine, for long period. This work aimed to investigate the effects of aripiprazole and olanzapine on the structure of seminiferous tubules of rats at both light microscopic and ultrastructural levels. MATERIAL AND METHODS: Sixty adult male rats were divided into 3 groups (n = 20): control group (Group I) and two experimental ones (II and III). Rats in Group II received 2 mg/kg/day aripiprazole while rats in Group III received 0.5 mg/kg/day olanzapine for 14 weeks. Thereafter, testis were removed and processed for both light and electron microscopic study. Qualitative morphological analyses and histomorphometric measurements of seminiferous tubules were performed. RESULTS: Rats in Group II showed reduction of testicular weight, seminiferous tubules' diameter, epithelial height, spermatogenic count, spermatogenic index and spermatogenic score whereas Sertoli cells count was increased. Olanzapine-treated rats also showed epithelial desquamation, separation and apoptotic changes of germ cells. Sertoli cells showed vacuolization, dilatation of smooth endoplasmic reticulum and accumulation of lipid droplets. Abnormality in the shape and structure of late spermatids and presence of giant cells were also demonstrated. Aripiprazole induced less adverse histological changes in rat testis than olanzapine. CONCLUSIONS: Olanzapine followed by aripiprazole had adverse histological effects on the structure of the seminiferous tubules, which may affect spermatogenesis. PMID- 25535928 TI - Postpartum triage, services provided, and length of stay for infants born at 35 weeks gestation. AB - OBJECTIVES: The aim of this article is to (1) compare the care setting to which 35-week infants are initially triaged postpartum to the level of services subsequently provided; and (2) identify factors known at delivery or immediately postpartum associated with services received and length of stay during the birth hospitalization. STUDY DESIGN: In this multicenter retrospective study of 35-week infants born between 2007 and 2008, service capabilities of the initial postpartum care setting were categorized as level 1 or neonatal intensive care unit (NICU) using American Academy of Pediatrics definitions. Subsequent services actually provided were categorized as routine care, level 1, or >level 1. RESULTS: Over half of 431 studied infants were sent to a level 1 nursery postpartum. Of these, over 90% ultimately received routine care or level 1 services. Of 200 infants triaged to a NICU, the majority received only routine care or level 1 services. The great majority of infants requiring > level 1 services were identified promptly postpartum. Initial triage to the NICU was associated with significantly (p < 0.05) increased length of stay despite provision of similar services. CONCLUSIONS: This study suggests a need for improved triage of 35-week infants and provides tools for this purpose. Validation of the models presented here is warranted. PMID- 25535930 TI - Effects of yoga intervention during pregnancy: a review for current status. AB - OBJECTIVES: The purpose of this article is to review all randomized control trials (RCTs) that have looked at the health effects of yoga on pregnancy, and to present their evidence on the specific ways in which pregnant women, and their infants can benefit from yoga intervention. The purpose is also to determine whether yoga intervention during pregnancy is more beneficial than other physical exercises. METHODS: Four databases were searched using the terms "yoga and (pregnancy or pregnant or prenatal or postnatal or postpartum)." Databases were searched from January 2004 to February 2014. RESULTS: Ten randomized controlled trials were evaluated. The findings consistently indicate that yoga intervention presented with lower incidences of prenatal disorders (p <= 0.05), and small gestational age (p < 0.05), lower levels of pain and stress (p < 0.05), and higher score of relationship (p < 0.05). In addition, yoga can be safely used for pregnant women who are depressed, at high-risk, or experience lumbopelvic pain. Moreover, yoga is a more effective exercise than walking or standard prenatal exercises. CONCLUSIONS: The findings suggest that yoga is a safe and more effective intervention during pregnancy. However, further RCTs are needed to provide firmer evidence regarding the utility and validity of yoga intervention. PMID- 25535929 TI - Outcomes for symmetrical and asymmetrical small for gestational age preterm infants in Canadian tertiary NICUs. AB - OBJECTIVE: This study aimed to compare the outcomes for symmetrical (sSGA) versus asymmetrical (aSGA) small for gestational age (SGA) < 32 weeks preterm infants. STUDY DESIGN: A total of 12,179 eligible infants admitted to the Canadian tertiary neonatal intensive care units (NICUs) over a 7-year-period in the Canadian Neonatal Network database were subcategorized as aSGA (n = 536), sSGA (n = 732), or appropriate for GA (AGA, n = 10,911). Baseline demographics, mortality, and major morbidities were compared using multivariable analysis to calculate adjusted odds ratios (AOR) and 95% confidence interval (CI). RESULTS: sSGA had higher GA (p < 0.01) and more antenatal tobacco exposure (p = 0.03). Although both the SGA groups had worse outcomes than AGA controls, aSGA versus sSGA comparison revealed lower odds (AOR [CI]) for mortality and chronic lung disease (CLD) for aSGA in the entire cohort (0.45 [0.27, 0.75] and 0.61 [0.44, 0.84], respectively) as well as for infants < 28 weeks GA (0.50 [0.27, 0.92] and 0.47 [0.29, 0.77], respectively). aSGA infants < 28 weeks GA had comparable outcomes to AGA except higher odds for CLD (1.61 [1.13, 2.27]). sSGA infants needed longer hospital stay and had higher use of oxygen and continuous positive airway pressure than aSGA. CONCLUSION: Among SGA infants < 32 weeks GA, significant intragroup differences exist in the neonatal outcomes and hospital resource utilization depending upon the presence or absence of relative "head sparing." PMID- 25535931 TI - Use of antenatal corticosteroids in the management of preterm delivery. AB - OBJECTIVE: This narrative review of the literature explores the current evidence and recommendations in favor of antenatal corticosteroids use during impending preterm deliveries as well as related issues and concerns. STUDY DESIGN: Synthesis of findings from published medical literature on antenatal corticosteroids and prematurity, retrieved from searches of computerized databases and authoritative texts. RESULTS: It is now recognized that an intramuscular course of betamethasone or dexamethasone given to a woman expected to deliver preterm not only accelerates pulmonary epithelial development but also matures other organ systems, significantly decreasing the chances of neonatal morbidities and increasing chances of survival. CONCLUSION: There remain uncertainties over the efficacy of the established protocol in populations such as the very early preterm, the late preterm, and multiple gestations. Alternative regimens remain controversial because of fear of adverse effects and doubts regarding whether benefits outweigh risks. PMID- 25535933 TI - The functionalization of nanodiamonds (diamondoids) as a key parameter of their easily controlled self-assembly in micro- and nanocrystals from the vapor phase. AB - We detail herein readily accessible processes to control previously unobserved robust self-assemblies of nanodiamonds (diamondoids) in micro- and nanocrystals from their mild vapor deposition. The chemical functionalization of uniform and discernible nanodiamonds was found to be a key parameter, and depending on the type of functional group (hydroxy, fluorine, etc.) and its position on the diamondoid, the structure of the discrete deposits can vary dramatically. Thus, well-defined anisotropic structures such as rod, needle, triangle or truncated octahedron shapes can be obtained, and self-assembled edifices of sizes ranging from 20 nm to several hundred micrometers formed with conservation of a similar structure for a given diamondoid. Key thermodynamic data including sublimation enthalpy of diamondoid derivatives are reported, and the SEM of the self assemblies coupled with EDX analyses and XRD attest the nature and purity of nanodiamond crystal deposits. This attractive method is simple and outperforms in terms of deposit quality dip-coating methods we used. This vapor phase deposition approach is expected to allow for an easy formation of diamondoid nanoobjects on different types of substrates. PMID- 25535934 TI - Gel-free electrophoresis of DNA and proteins on chips featuring a 70 nm capillary well motif. AB - We present an integrated glass capillary system on silicon for size-based sieving of distinct mixtures of proteins, short DNA, and long DNA fragments into sharp peaks. The minimum resolvable size difference achieved is noted as 3.45 kDa for 45-52.8 kDa proteins, 20 bp for 200-300 bp DNA strands, and 182 bp for 5.6-5.8 kbp DNA chains. This high-resolution sieving arises from vastly steep entropic barriers created at the onsets of extremely restrictive (resistive) capillary segments and their pivotal role in shifting the equilibrium entropic sieving to intense fields (>1000 V/cm). DNA fragments of various sizes are shown fully resolved in less than 7 min at a steady voltage of 2000 V being directly applied across the length of a 2 cm long sieve featuring thousands of entropic barriers. The utility of higher field strengths and longer sieves is also demonstrated without triggering dielectric breakdown by time-division multiplexing up to 2000 V across the 1 cm long sieve segments. The self-enclosed 70 nm diameter capillaries were fabricated using coarse (>1 MUm) photolithography and standard semiconductor manufacturing techniques. PMID- 25535935 TI - A new class of marine Euryarchaeota group II from the Mediterranean deep chlorophyll maximum. AB - We have analyzed metagenomic fosmid clones from the deep chlorophyll maximum (DCM), which, by genomic parameters, correspond to the 16S ribosomal RNA (rRNA) defined marine Euryarchaeota group IIB (MGIIB). The fosmid collections associated with this group add up to 4 Mb and correspond to at least two species within this group. From the proposed essential genes contained in the collections, we infer that large sections of the conserved regions of the genomes of these microbes have been recovered. The genomes indicate a photoheterotrophic lifestyle, similar to that of the available genome of MGIIA (assembled from an estuarine metagenome in Puget Sound, Washington Pacific coast), with a proton-pumping rhodopsin of the same kind. Several genomic features support an aerobic metabolism with diversified substrate degradation capabilities that include xenobiotics and agar. On the other hand, these MGIIB representatives are non-motile and possess similar genome size to the MGIIA-assembled genome, but with a lower GC content. The large phylogenomic gap with other known archaea indicates that this is a new class of marine Euryarchaeota for which we suggest the name Thalassoarchaea. The analysis of recruitment from available metagenomes indicates that the representatives of group IIB described here are largely found at the DCM (ca. 50 m deep), in which they are abundant (up to 0.5% of the reads), and at the surface mostly during the winter mixing, which explains formerly described 16S rRNA distribution patterns. Their uneven representation in environmental samples that are close in space and time might indicate sporadic blooms. PMID- 25535936 TI - Relationships between protein-encoding gene abundance and corresponding process are commonly assumed yet rarely observed. AB - For any enzyme-catalyzed reaction to occur, the corresponding protein-encoding genes and transcripts are necessary prerequisites. Thus, a positive relationship between the abundance of gene or transcripts and corresponding process rates is often assumed. To test this assumption, we conducted a meta-analysis of the relationships between gene and/or transcript abundances and corresponding process rates. We identified 415 studies that quantified the abundance of genes or transcripts for enzymes involved in carbon or nitrogen cycling. However, in only 59 of these manuscripts did the authors report both gene or transcript abundance and rates of the appropriate process. We found that within studies there was a significant but weak positive relationship between gene abundance and the corresponding process. Correlations were not strengthened by accounting for habitat type, differences among genes or reaction products versus reactants, suggesting that other ecological and methodological factors may affect the strength of this relationship. Our findings highlight the need for fundamental research on the factors that control transcription, translation and enzyme function in natural systems to better link genomic and transcriptomic data to ecosystem processes. PMID- 25535938 TI - Diversity of viral photosystem-I psaA genes. AB - Marine photosynthesis is one of the major contributors to the global carbon cycle and the world's oxygen supply. This process is largely driven by cyanobacteria, namely Synechococcus and Prochlorococcus. Genes encoding photosystem-II (PSII) reaction center proteins are found in many cyanophage genomes, and are expressed during the infection of their hosts. On the basis of metagenomics, cyanophage photosystem-I (PSI) gene cassettes were recently discovered with two gene arrangements psaJF->C->A->B->K->E->D and psaD->C->A->B. It was suggested that the horizontal transfer of PSII and PSI genes is increasing phage fitness. To better understand their diversity, we designed degenerate primers to cover a wide diversity of organisms, and using PCR we targeted the psaC->A arrangement, which is unique to cyanophages cassettes. We examined viral concentrates from four islands in the Pacific Ocean and found samples containing the psaC->A arrangement. Analyses of the amplified viral psaA gene revealed six subgroups varying in their level of similarity and %G+C content, suggesting that the diversity of cyanophage PSI genes is greater than originally thought. PMID- 25535941 TI - Mapping intracellular diffusion distribution using single quantum dot tracking: compartmentalized diffusion defined by endoplasmic reticulum. AB - The crowded intracellular environment influences the diffusion-mediated cellular processes, such as metabolism, signaling, and transport. The hindered diffusion of macromolecules in heterogeneous cytoplasm has been studied over years, but the detailed diffusion distribution and its origin still remain unclear. Here, we introduce a novel method to map rapidly the diffusion distribution in single cells based on single-particle tracking (SPT) of quantum dots (QDs). The diffusion map reveals the heterogeneous intracellular environment and, more importantly, an unreported compartmentalization of QD diffusions in cytoplasm. Simultaneous observations of QD motion and green fluorescent protein-tagged endoplasmic reticulum (ER) dynamics provide direct evidence that the compartmentalization results from micron-scale domains defined by ER tubules, and ER cisternae form perinuclear areas that restrict QDs to enter. The same phenomenon was observed using fluorescein isothiocyanate-dextrans, further confirming the compartmentalized diffusion. These results shed new light on the diffusive movements of macromolecules in the cell, and the mapping of intracellular diffusion distribution may be used to develop strategies for nanoparticle-based drug deliveries and therapeutics. PMID- 25535939 TI - The effect of nutrients on carbon and nitrogen fixation by the UCYN-A-haptophyte symbiosis. AB - Symbiotic relationships between phytoplankton and N2-fixing microorganisms play a crucial role in marine ecosystems. The abundant and widespread unicellular cyanobacteria group A (UCYN-A) has recently been found to live symbiotically with a haptophyte. Here, we investigated the effect of nitrogen (N), phosphorus (P), iron (Fe) and Saharan dust additions on nitrogen (N2) fixation and primary production by the UCYN-A-haptophyte association in the subtropical eastern North Atlantic Ocean using nifH expression analysis and stable isotope incubations combined with single-cell measurements. N2 fixation by UCYN-A was stimulated by the addition of Fe and Saharan dust, although this was not reflected in the nifH expression. CO2 fixation by the haptophyte was stimulated by the addition of ammonium nitrate as well as Fe and Saharan dust. Intriguingly, the single-cell analysis using nanometer scale secondary ion mass spectrometry indicates that the increased CO2 fixation by the haptophyte in treatments without added fixed N is likely an indirect result of the positive effect of Fe and/or P on UCYN-A N2 fixation and the transfer of N2-derived N to the haptophyte. Our results reveal a direct linkage between the marine carbon and nitrogen cycles that is fuelled by the atmospheric deposition of dust. The comparison of single-cell rates suggests a tight coupling of nitrogen and carbon transfer that stays balanced even under changing nutrient regimes. However, it appears that the transfer of carbon from the haptophyte to UCYN-A requires a transfer of nitrogen from UCYN-A. This tight coupling indicates an obligate symbiosis of this globally important diazotrophic association. PMID- 25535937 TI - Comparative metagenomic and metatranscriptomic analyses of microbial communities in acid mine drainage. AB - The microbial communities in acid mine drainage have been extensively studied to reveal their roles in acid generation and adaption to this environment. Lacking, however, are integrated community- and organism-wide comparative gene transcriptional analyses that could reveal the response and adaptation mechanisms of these extraordinary microorganisms to different environmental conditions. In this study, comparative metagenomics and metatranscriptomics were performed on microbial assemblages collected from four geochemically distinct acid mine drainage (AMD) sites. Taxonomic analysis uncovered unexpectedly high microbial biodiversity of these extremely acidophilic communities, and the abundant taxa of Acidithiobacillus, Leptospirillum and Acidiphilium exhibited high transcriptional activities. Community-wide comparative analyses clearly showed that the AMD microorganisms adapted to the different environmental conditions via regulating the expression of genes involved in multiple in situ functional activities, including low-pH adaptation, carbon, nitrogen and phosphate assimilation, energy generation, environmental stress resistance, and other functions. Organism-wide comparative analyses of the active taxa revealed environment-dependent gene transcriptional profiles, especially the distinct strategies used by Acidithiobacillus ferrivorans and Leptospirillum ferrodiazotrophum in nutrients assimilation and energy generation for survival under different conditions. Overall, these findings demonstrate that the gene transcriptional profiles of AMD microorganisms are closely related to the site physiochemical characteristics, providing clues into the microbial response and adaptation mechanisms in the oligotrophic, extremely acidic environments. PMID- 25535942 TI - Lewis acid catalyzed intramolecular [3 + 2] cross cycloadditions of cobalt alkynylcyclopropane 1,1-diesters with carbonyls for construction of medium-sized and polycyclic skeletons. AB - A Lewis acid catalyzed intramolecular [3 + 2] cross cycloaddition of cobalt alkynylcyclopropane 1,1-diesters with carbonyls has been successfully developed. Together with simple and efficient postcycloadditions of the cobalt-alkyne moiety, a general and efficient strategy for construction of structurally complex and diverse medium-sized skeletons and related polycycles was supplied successfully. PMID- 25535940 TI - Clay minerals and metal oxides strongly influence the structure of alkane degrading microbial communities during soil maturation. AB - Clay minerals, charcoal and metal oxides are essential parts of the soil matrix and strongly influence the formation of biogeochemical interfaces in soil. We investigated the role of these parental materials for the development of functional microbial guilds using the example of alkane-degrading bacteria harbouring the alkane monooxygenase gene (alkB) in artificial mixtures composed of different minerals and charcoal, sterile manure and a microbial inoculum extracted from an agricultural soil. We followed changes in abundance and community structure of alkane-degrading microbial communities after 3 and 12 months of soil maturation and in response to a subsequent 2-week plant litter addition. During maturation we observed an overall increasing divergence in community composition. The impact of metal oxides on alkane-degrading community structure increased during soil maturation, whereas the charcoal impact decreased from 3 to 12 months. Among the clay minerals illite influenced the community structure of alkB-harbouring bacteria significantly, but not montmorillonite. The litter application induced strong community shifts in soils, maturated for 12 months, towards functional guilds typical for younger maturation stages pointing to a resilience of the alkane-degradation function potentially fostered by an extant 'seed bank'. PMID- 25535943 TI - Reactive oxygen species-mediated breast cell carcinogenesis enhanced by multiple carcinogens and intervened by dietary ergosterol and mimosine. AB - Most breast cancers occur sporadically due to long-term exposure to low-dose carcinogens in the diet and the environment. Specifically, smoke, polluted air, and high-temperature cooked meats comprise multiple carcinogens, such as 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[alpha]pyrene (B[alpha]P), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). We sought to determine if these carcinogens act together to induce breast cell carcinogenesis, and if so, whether noncytotoxic dietary agents could intervene. We demonstrated that coexposure to physiologically achievable doses of NNK, B[alpha]P, and PhIP (NBP) holistically enhanced initiation and progression of breast cell carcinogenesis. Reactive oxygen species (ROS) and activation of the ERK pathway were transiently induced by NBP in each exposure, and cross talk between reinforced ROS elevation and ERK activation played an essential role in increased DNA oxidation and damage. After cumulative exposures to NBP, this cross talk contributed to enhanced initiation of cellular carcinogenesis and led to enhanced acquisition of cancer-associated properties. Using NBP-induced transient changes, such as ROS elevation and ERK pathway activation, and cancer-associated properties as targeted endpoints, we revealed, for the first time, that two less studied dietary compounds, ergosterol and mimosine, at physiologically achievable noncytotoxic levels, were highly effective in intervention of NBP-induced cellular carcinogenesis. Combined ergosterol and mimosine were more effective than individual agents in blocking NBP-induced transient endpoints, including ROS mediated DNA oxidation, which accounted for their preventive ability to suppress progression of NBP-induced cellular carcinogenesis. Thus, dietary components, such as mushrooms containing ergosterol and legumes containing mimosine, should be considered for affordable prevention of sporadic breast cancer associated with long-term exposure to environmental and dietary carcinogens. PMID- 25535944 TI - Population genetics of Trypanosoma brucei gambiense in sleeping sickness patients with treatment failures in the focus of Mbuji-Mayi, Democratic Republic of the Congo. AB - Human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) is caused by the protozoan Trypanosoma brucei gambiense. Until recently, all patients in the second or neurological stage of the disease were treated with melarsoprol. At the end of the past and the beginning of the present century, alarmingly high relapse rates in patients treated with melarsoprol were reported in isolated HAT foci. In the Mbuji-Mayi focus of DRC, a particular mutation that confers cross resistance for pentamidine and melarsoprol was recently found for all strains studied. Nevertheless, treatment successfully cured a significant proportion of patients. To check for the existence of other possible genetic factors of the parasites, we genotyped trypanosomes isolated from patients before and after treatment (relapsing patients) with eight microsatellite markers. We found no evidence of any genetic correlation between parasite genotype and treatment outcome and we concluded that relapse or cure probably depend more on patients' factors such as disease progression, nutritional or immunological status or co-infections with other pathogens. The existence of a melarsoprol and pentamidine resistance associated mutation at such high rates highlights an increasing problem, even for other drugs, especially those using the same transporters as melarsoprol and pentamidine. PMID- 25535945 TI - Cryptic diversity and habitat partitioning in an economically important aphid species complex. AB - Cardamom Bushy Dwarf Virus (CBDV) is an aphid-borne nanovirus which infects large cardamom, Amomum subulatum (Zingiberaceae family), in the Himalayan foothills of Northeast India, Nepal and Bhutan. Two aphid species have been reported to transmit CBDV, including Pentalonia nigronervosa and Micromyzus kalimpongensis (also described as Pentalonia kalimpongensis). However, P. nigronervosa was recently split into two species which exhibit different host plant affiliations. Whilst P. nigronervosa primarily feeds on banana plants, Pentaloniacaladii (previously considered a 'form' of P. nigronervosa) typically feeds on plants belonging to the Araceae, Heliconiaceae and Zingiberaceae families. This raises the possibility that CBDV vectors that were originally described as P. nigronervosa correspond to P. caladii. Accurate identification of vector species is important for understanding disease dynamics and for implementing management strategies. However, closely related species can be difficult to distinguish based on morphological characteristics. In this study, we used molecular markers (two mitochondrial loci and one nuclear locus) and Bayesian phylogenetic analyses to identify aphid specimens collected from 148 CBDV infected plants at a range of locations and elevations throughout Sikkim and the Darjeeling district of West Bengal (Northeast India). Our results revealed the presence of a diversity of lineages, comprising up to six distinct species in at least two related genera. These included the three species mentioned above, an unidentified Pentalonia species and two lineages belonging to an unknown genus. Surprisingly, P. caladii was only detected on a single infected plant, indicating that this species may not play an important role in CBDV transmission dynamics. Distinct elevation distributions were observed for the different species, demonstrating that the community composition of aphids which feed on large cardamom plants changes across an elevation gradient. This has implications for understanding how competent vector species could influence spatial and temporal transmission patterns of CBDV. PMID- 25535947 TI - Growth under visible light increases conidia and mucilage production and tolerance to UV-B radiation in the plant pathogenic fungus Colletotrichum acutatum. AB - Light conditions can influence fungal development. Some spectral wavebands can induce conidial production, whereas others can kill the conidia, reducing the population size and limiting dispersal. The plant pathogenic fungus Colletotrichum acutatum causes anthracnose in several crops. During the asexual stage on the host plant, Colletototrichum produces acervuli with abundant mucilage-embedded conidia. These conidia are responsible for fungal dispersal and host infection. This study examined the effect of visible light during C. acutatum growth on the production of conidia and mucilage and also on the UV tolerance of these conidia. Conidial tolerance to an environmentally realistic UV irradiance was determined both in conidia surrounded by mucilage on sporulating colonies and in conidial suspension. Exposures to visible light during fungal growth increased production of conidia and mucilage as well as conidial tolerance to UV. Colonies exposed to light produced 1.7 times more conidia than colonies grown in continuous darkness. The UV tolerances of conidia produced under light were at least two times higher than conidia produced in the dark. Conidia embedded in the mucilage on sporulating colonies were more tolerant of UV than conidia in suspension that were washed free of mucilage. Conidial tolerance to UV radiation varied among five selected isolates. PMID- 25535948 TI - Nanoclusters of the resting T cell antigen receptor (TCR) localize to non-raft domains. AB - In the last decade an increasing number of plasma membrane (PM) proteins have been shown to be non-randomly distributed but instead forming submicron-sized oligomers called nanoclusters. Nanoclusters exist independently of the ligand bound state of the receptors and their existence implies a high degree of lateral organisation of the PM and its proteins. The mechanisms that drive receptor nanoclustering are largely unknown. One well-defined example of a transmembrane receptor that forms nanoclusters is the T cell antigen receptor (TCR), a multisubunit protein complex whose nanoclustering influences its activity. Membrane lipids, namely cholesterol and sphingomyelin, have been shown to contribute to TCR nanoclustering. However, the identity of the membrane microdomain in which the TCR resides remains controversial. Using a GFP-labeled TCR we show here that the resting TCR localized in the disordered domain of giant PM vesicles (GPMVs) and PM spheres (PMSs) and that single and nanoclustered TCRs are found in the high-density fractions in sucrose gradients. Both findings are indicative of non-raft localization. We discuss possible mechanisms of TCR nanoclustering in T cells. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. PMID- 25535949 TI - The plethora of PMCA isoforms: Alternative splicing and differential expression. AB - In this review the four different genes of the mammalian plasma membrane calcium ATPase (PMCA) and their spliced isoforms are discussed with respect to their tissue distribution, their differences during development and their importance for regulating Ca2+ homeostasis under different conditions. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25535946 TI - Culicoides Latreille (Diptera: Ceratopogonidae) taxonomy: current challenges and future directions. AB - Culicoides Latreille biting midges (Diptera: Ceratopogonidae) cause a significant biting nuisance to humans, livestock and equines, and are the biological vectors of a range of internationally important pathogens of both veterinary and medical importance. Despite their economic significance, the delimitation and identification of species and evolutionary relationships between species within this genus remains at best problematic. To date no phylogenetic study has attempted to validate the subgeneric classification of the genus and the monophyly of many of the subgenera remains doubtful. Many informal species groupings are also known to exist but few are adequately described, further complicating accurate identification. Recent contributions to Culicoides taxonomy at the species level have revealed a high correlation between morphological and molecular analyses although molecular analyses are revealing the existence of cryptic species. This review considers the methods for studying the systematics of Culicoides using both morphological and genetic techniques, with a view to understanding the factors limiting our current understanding of Culicoides biology and hence arbovirus epidemiology. In addition, we examine the global status of Culicoides identification, highlighting areas that are poorly addressed, including the potential implementation of emerging technologies. PMID- 25535950 TI - Quantum chemical study on HKrC5N, HXeC5N, and related rare gas compounds. AB - The recent identification of HRgC5N (Rg = Kr, Xe) in a cryogenic matrix calls for an in-depth theoretical study on these compounds. Here we present the results of CCSD(T), MP2, and DFT calculations concerning the molecular structure, stability, and vibrational spectroscopy. The procedure combining CCSD(T) calculations for variable H-Rg distances with the anharmonic description of the corresponding stretching vibration, based on a Morse-type potential energy function, was proposed and has led to good agreement between computational and experimental values for H-Rg stretching frequencies, at relatively low computational costs. High Raman scattering activity of HRgC5N and of its isomers, predicted at the DFT level, gives some prospects for the detection of these molecules with a method alternative to the IR absorption spectroscopy. PMID- 25535951 TI - Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. AB - BACKGROUND AND AIMS: The recently developed histological scoring system for non alcoholic fatty liver disease (NAFLD) by the NASH Clinical Research Network (NASH CRN) has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models. METHODS: The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system). For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart. RESULTS: The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter observer reproducibility (evaluated using the Intraclass Correlation Coefficient) between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively) and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively). The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively) and very high for the analysis of inflammation (ICC = 0.931, p<0.001). CONCLUSIONS: We established a simple NAFLD scoring system with high reproducibility that is applicable for different rodent models and for all stages of NAFLD etiology. PMID- 25535953 TI - Nuclear blebbing of biologically active organoselenium compound towards human cervical cancer cell (HeLa): in vitro DNA/HSA binding, cleavage and cell imaging studies. AB - New pharmacophore organoselenium compound (1) was designed, synthesized and characterized by various spectroscopic methods (IR, ESI-MS, (1)H, (13)C and (77)Se NMR) and further confirmed by X-ray crystallography. Compound 1 consists of two 3,5-bis(trifluoromethyl)phenyl units which are connected to the selenium atom via the organometallic C-Se bond. In vitro DNA binding studies of 1 was investigated by absorption and emission titration methods which revealed that 1 recognizes the minor groove of DNA in accordance with molecular docking studies with the DNA duplex. Gel electrophoretic assay demonstrates the ability of 1 to cleave pBR322 DNA through hydrolytic process which was further validated by T4 religation assay. To understand the drug-protein interaction of which ultimate molecular target was DNA, the affinity of 1 towards HSA was also investigated by the spectroscopic and molecular modeling techniques which showed hydrophobic interaction in the subdomain IIA of HSA. Furthermore, the intracellular localization of 1 was evidenced by cell imaging studies using HeLa cells. PMID- 25535954 TI - Drivers of aggregation in a novel arboreal parasite: the influence of host size and infra-populations. AB - As a novel arboreal parasite, New Zealand's largest endemic moth, Aenetus virescens, is a biological oddity. With arguably the most unusual lepidopteran life history on earth, larvae grow to 100mm, spending ~6 years as wood-boring parasites feeding on host tree phloem. Parasite fitness is a product of host suitability. Parasite discrimination between heterogeneous hosts in fragmented populations shapes parasite aggregation. We investigated whether A. virescens aggregation among hosts occurs randomly (target area effect), or if larvae select hosts based on host quality (ideal free distribution). Using long-term larval growth as an indicator of energy intake, we examined A. virescens aggregation in relation to host size and infra-population. Using a generalised linear model, the relationship between parasite intensity and host tree size was analysed. Reduced major axis regression was used to evaluate A. virescens growth after 1 year. Linear mixed-effects models inferred the influence of parasite infra-population on parasite growth, with host tree as a random factor. Results indicate parasite intensity scaled positively with host size. Furthermore, parasite growth remained consistent throughout ontogeny regardless of host size or parasite infra population. Aenetus virescens aggregation among hosts violates the ideal free distribution hypothesis, occurring instead as a result of host size, supporting the target area effect. PMID- 25535952 TI - Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents. AB - Tumor suppressor protein p53 regulates the cell cycle and inhibits tumor growth. It is inactivated by mutation or binding with human double minute 2 (HDM2) protein. The HDM2 is a promising target for treatment of p53 protein related cancers. Molecular modeling techniques such as 2D-QSAR, pharmacophore mapping and 3D-QSAR analyses were performed on 155 structurally diverse HDM2 inhibitors to understand structural and physicochemical requirements for higher activity. The linear and spline 2D-QSAR models were developed through multiple linear regression and genetic functional algorithm methods. The 2D-QSAR models suggested that number of fluorine, chlorine, tertiary nitrogen atoms as well as donor feature, stereogenic centers and higher value of solvent accessible surface area are important features in defining activity. Monte Carlo method was applied to generate QSAR models that determined structural indicators (alerts) for increase or decrease of the biological activity. Ligand-based pharmacophore mapping showed importance of two hydrophobic, one hydrophobic aromatic, one ring aromatic and one donor features. The structure-based pharmacophore model demonstrated significance of two hydrophobic, one ring aromatic and two acceptor features. The pharmacophore (ligand) aligned structures were subjected to 3D-QSAR analyses. The structure-based pharmacophore was also used for pharmacophore restraint molecular docking to analyze ligand-receptor interactions and for adjudging predictability as well as validation of different modeling techniques. These comparative molecular modeling techniques may help to design novel HDM2 inhibitors. PMID- 25535956 TI - Residence time and kinetic efficiency analysis of extracellular signal-regulated kinase 2 inhibitors. AB - The RAS/RAF/MEK/ERK signal transduction cascade plays an important role in the regulation of critical cellular processes such as cell proliferation, migration, and differentiation. The up-regulation of this pathway can negatively affect cell homeostasis and is responsible for the development of various forms of cancer and inflammation processes. Therefore, there is a strong interest in pursuing drug programs targeting some of the enzymes involved in this pathway. In addition to the determination of Ki, Kd, IC50, and/or EC50, a more thorough kinetic analysis can provide useful information for the selection of the best lead series during the early stage of the drug discovery process. This study describes a medium throughput fluorescent probe displacement assay for the rapid determination of the k(off) constant, residence time, and kinetic efficiency for ERK (extracellular signal-regulated kinase) inhibitors. Using this method, we have identified several inhibitors that we have subjected to further kinetic analysis by comparing k(off) constants determined for these time-dependent inhibitors using either the active or inactive form of ERK2. PMID- 25535955 TI - Bone protein extraction without demineralization using principles from hydroxyapatite chromatography. AB - Historically, extraction of bone proteins has relied on the use of demineralization to better retrieve proteins from the extracellular matrix; however, demineralization can be a slow process that restricts subsequent analysis of the samples. Here, we developed a novel protein extraction method that does not use demineralization but instead uses a methodology from hydroxyapatite chromatography where high concentrations of ammonium phosphate and ammonium bicarbonate are used to extract bone proteins. We report that this method has a higher yield than those with previously published small-scale extant bone extractions, with and without demineralization. Furthermore, after digestion with trypsin and subsequent high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis, we were able to detect several extracellular matrix and vascular proteins in addition to collagen I and osteocalcin. Our new method has the potential to isolate proteins within a short period (4h) and provide information about bone proteins that may be lost during demineralization or with the use of denaturing agents. PMID- 25535957 TI - Preoperative three-dimensional echocardiography to assess risk of right ventricular failure after left ventricular assist device surgery. AB - BACKGROUND: Right ventricular failure (RVF) is associated with significant morbidity after left ventricular assist device (LVAD) surgery. Hemodynamic, clinical, and 2-dimensional echocardiographic variables poorly discriminate patients at risk of RVF. We examined the utility of 3-dimensional echocardiography (3DE) right ventricular (RV) volumetric assessment to identify patients at risk for RVF. METHODS AND RESULTS: RVF was defined as the need for inotropic infusion for >14 days after LVAD surgery or the need for biventricular assist device support. Preoperative RV volumes and ejection fraction (EF) were measured, blinded to clinical data, from transthoracic 3DE full volume data sets in 26 patients. Baseline variables and 3DE RV indices were compared between patients with and without RVF. Twenty-four patients received continuous-flow LVADs, and 2 required biventricular support devices. Ten patients required prolonged inotropes after LVAD placement. Baseline characteristics associated with RVF included higher right atrial pressure, higher right atrial pressure to pulmonary capillary wedge pressure ratio, and lower cardiac index and RV stroke work index (RVSWI). Echocardiographic indices associated with RVF included 3DE indexed RV end-diastolic and end-systolic volumes (RVEDVI and RVESVI) and RV ejection fraction (RVEF). The relationship between 3DE quantification of RV volumes and the development of RVF was independent from RVSWI: RVEDVI: odds ratio (OR) 1.16, 95% confidence interval (CI) 1.00-1.33 (P = .04); RVESVI: OR 1.14, 95% CI 1.01-1.28 (P = .03). CONCLUSIONS: Quantitative 3DE is a promising method for pre-LVAD RV assessment. RV volumes assessed by 3DE are predictive of RVF in LVAD recipients independently from hemodynamic correlates of RV function. PMID- 25535958 TI - Welcome to the new, all electronic Journal of Viral Hepatitis. PMID- 25535960 TI - Accuracy of self-reported sleep position in late pregnancy. AB - BACKGROUND: There is emerging research to suggest that supine maternal sleep position in late pregnancy may adversely affect fetal wellbeing. However, these studies have all been based on maternal report of sleeping position. Before recommendations to change sleep position can be made it is important to determine the validity of these studies by investigating how accurate pregnant women are in reporting their sleep position. If avoiding the supine sleeping position reduces risk of poor pregnancy outcome, it is also important to know how well women can comply with the instruction to avoid this position and sleep on their left. METHOD: Thirty women in late pregnancy participated in a three-night observational study and were asked to report their sleeping position. This was compared to sleep position as recorded by a night capable video recording. The participants were instructed to settle to sleep on their left side and if they woke overnight to settle back to sleep on their left. RESULTS: There was a moderate correlation between reported and video-determined left-side sleep time (r = 0.48), mean difference = 3 min (SD = 3.5 h). Participants spent an average of 59.60% (SD = 16.73%) of time in bed on their left side (ICC across multiple nights = 0.67). Those who included left side among their typical sleep positions reported significantly longer sleep during the study (p<0.01). CONCLUSIONS: On average participant reports of sleep position were relatively accurate but there were large individual differences in reporting accuracy and in objectively determined time on left side. Night-to-night consistency was substantial. For those who do not ordinarily sleep on that side, asking participants to sleep on their left may result in reduced sleep duration. This is an important consideration during a sleep-critical time such as late pregnancy. PMID- 25535962 TI - Does a diagnosis of atrophic vaginitis on Papanicolaou test signify the presence of inflammation? AB - OBJECTIVE: Vaginal atrophy in menopause shows increased parabasal cells on cytology. This may be accompanied by abundant neutrophils. A shift in maturation index in the absence of significant inflammation is more accurately termed "atrophic pattern." This study aims to determine whether a diagnosis of "atrophic vaginitis" or atrophic pattern on Papanicolaou test is a reliable indicator of what is present on the slide. METHODS: A retrospective review of Papanicolaou test slides from University Hospital Newark was performed. Cases that had been diagnosed as either atrophic vaginitis (n = 100) or atrophic pattern (n = 100) were selected. Exclusion criteria included any additional diagnosis of neoplasia. Slides were re-reviewed and scored based on abundance of neutrophils: 0 to 5, 6 to 10, or more than 10 neutrophils per high-power field (*40), with 10 fields per slide reviewed. Data were analyzed by chi analysis. RESULTS: Among 200 cases with atrophic vaginitis or atrophic pattern, the proportion of those diagnosed with atrophic vaginitis to those diagnosed with atrophic pattern increased across three neutrophil categories (P < 0.0001). CONCLUSIONS: A diagnosis of atrophic vaginitis on Papanicolaou test is reliably associated with increased numbers of neutrophils. A diagnosis of atrophic pattern is indicative of low numbers of neutrophils. As the Papanicolaou test diagnosis of atrophic vaginitis does not correlate with clinical symptoms, a single diagnostic term that does not suggest a disease process would more reliably communicate cytology findings to clinicians. PMID- 25535959 TI - Gestational age and neonatal brain microstructure in term born infants: a birth cohort study. AB - OBJECTIVE: Understanding healthy brain development in utero is crucial in order to detect abnormal developmental trajectories due to developmental disorders. However, in most studies neuroimaging was done after a significant postnatal period, and in those studies that performed neuroimaging on fetuses, the quality of data has been affected due to complications of scanning during pregnancy. To understand healthy brain development between 37-41 weeks of gestational age, our study assessed the in utero growth of the brain in healthy term born babies with DTI scanning soon after birth. METHODS: A cohort of 93 infants recruited from maternity hospitals in Singapore underwent diffusion tensor imaging between 5 to 17 days after birth. We did a cross-sectional examination of white matter microstructure of the brain among healthy term infants as a function of gestational age via voxel-based analysis on fractional anisotropy. RESULTS: Greater gestational age at birth in term infants was associated with larger fractional anisotropy values in early developing brain regions, when corrected for age at scan. Specifically, it was associated with a cluster located at the corpus callosum (corrected p<0.001), as well as another cluster spanning areas of the anterior corona radiata, anterior limb of internal capsule, and external capsule (corrected p<0.001). CONCLUSIONS: Our findings show variation in brain maturation associated with gestational age amongst 'term' infants, with increased brain maturation when born with a relatively higher gestational age in comparison to those infants born with a relatively younger gestational age. Future studies should explore if these differences in brain maturation between 37 and 41 weeks of gestational age will persist over time due to development outside the womb. PMID- 25535964 TI - Diagnostic methods for fast-track identification of endometrial cancer in women with postmenopausal bleeding and endometrial thickness greater than 5 mm. AB - OBJECTIVE: This study aims to evaluate the diagnostic efficiency of pattern recognition by transvaginal ultrasonography (TVS) and gel infusion sonography (GIS) for identifying endometrial pathology and to compare this setup with a standard setup of endometrial sampling (ES), hysteroscopy with pattern evaluation (HY(pattern)), or magnetic resonance imaging (MRI). METHODS: This study used a prospective cohort of 174 women with postmenopausal bleeding and endometrial thickness of 5 mm or greater. Resectoscopic biopsy (hysteroscopy with biopsy) samples or hysterectomy served as reference standard. Malignant and benign endometrial patterns were evaluated with TVS, GIS and HY(pattern) were then added. The efficiency of each diagnostic strategy, including ES and MRI findings (n = 83), was compared and evaluated against the reference standard. RESULTS: ES, TVS, GIS, and HY(pattern) had high diagnostic efficiency (area under the curve) for malignancy diagnosis (ES, 0.90; TVS, 0.88; GIS, 0.92; HY(pattern), 0.91). When insufficient samples were incorporated, ES was less efficient than the other techniques. ES was not more efficient in the subgroup of women without localized lesions than in the subgroup of women with localized lesions. MRI and HY(pattern) added limited efficiency, whereas hysteroscopy with biopsy was most efficient. CONCLUSIONS: As a first-line technique, pattern recognition on TVS, GIS, and HY(pattern) correctly identifies 9 of 10 women with malignancy and is superior to pattern recognition on ES when insufficient samples are included. Endometrial pattern evaluated with TVS and GIS is a fast and efficient first-line diagnostic tool that outperforms ES in women with or without localized lesions. Malignant patterns on TVS/GIS should warrant fast-track evaluation, whereas women with benign patterns may be selected for office or operative hysteroscopy. A fast track diagnostic setup based on pattern recognition is presented. PMID- 25535961 TI - Argon inhalation attenuates retinal apoptosis after ischemia/reperfusion injury in a time- and dose-dependent manner in rats. AB - PURPOSE: Retinal ischemia and reperfusion injuries (IRI) permanently affect neuronal tissue and function by apoptosis and inflammation due to the limited regenerative potential of neurons. Recently, evidence emerged that the noble gas Argon exerts protective properties, while lacking any detrimental or adverse effects. We hypothesized that Argon inhalation after IRI would exert antiapoptotic effects in the retina, thereby protecting retinal ganglion cells (RGC) of the rat's eye. METHODS: IRI was performed on the left eyes of rats (n = 8) with or without inhaled Argon postconditioning (25, 50 and 75 Vol%) for 1 hour immediately or delayed after ischemia (i.e. 1.5 and 3 hours). Retinal tissue was harvested after 24 hours to analyze mRNA and protein expression of Bcl-2, Bax and Caspase-3, NF-kappaB. Densities of fluorogold-prelabeled RGCs were analyzed 7 days after injury in whole-mounts. Histological tissue samples were prepared for immunohistochemistry and blood was analyzed regarding systemic effects of Argon or IRI. Statistics were performed using One-Way ANOVA. RESULTS: IRI induced RGC loss was reduced by Argon 75 Vol% inhalation and was dose-dependently attenuated by lower concentrations, or by delayed Argon inhalation (1504+/-300 vs. 2761+/ 257; p<0.001). Moreover, Argon inhibited Bax and Bcl-2 mRNA expression significantly (Bax: 1.64+/-0.30 vs. 0.78+/-0.29 and Bcl-2: 2.07+/-0.29 vs. 0.99+/ 0.22; both p<0.01), as well as caspase-3 cleavage (1.91+/-0.46 vs. 1.05+/-0.36; p<0.001). Expression of NF-kappaB was attenuated significantly. Immunohistochemistry revealed an affection of Muller cells and astrocytes. In addition, IRI induced leukocytosis was reduced significantly after Argon inhalation at 75 Vol%. CONCLUSION: Immediate and delayed Argon postconditioning protects IRI induced apoptotic loss of RGC in a time- and dose-dependent manner, possibly mediated by the inhibition of NF-kappaB. Further studies need to evaluate Argon's possible role as a therapeutic option. PMID- 25535965 TI - Physical activity, pain responses to heat stimuli, and conditioned pain modulation in postmenopausal women. AB - OBJECTIVE: Postmenopausal women (PMW) are at high risk for disabling pain and physical inactivity. This study sought to enhance the understanding of relationships between physical activity (PA) and pain among PMW using heat pain sensitivity test and conditioned pain modulation test. We hypothesized that, compared with active women, (i) inactive women would report higher pain intensity and pain unpleasantness ratings; (ii) inactive women in disabling pain would report higher pain intensity and pain unpleasantness at high, but not low, stimulus intensities; and (iii) inactive women would have less modulation. METHODS: Sixty-eight PMW rated the pain intensity and pain unpleasantness of hot stimuli presented to the thenar eminence of the hand. A subset of 31 women rated the pain intensity of a test stimulus (noxious heat) and a conditioning stimulus (cold water) as part of the conditioned pain modulation task. PA was assessed objectively with accelerometry. RESULTS: Mixed-model analysis of variance (2 * 4 * 2; PA * Temperature * Pain Status) showed that inactive women in disabling pain rated pain unpleasantness higher than active women in disabling pain (F3,192 = 3.526, ?eta = 0.052, P = 0.016). Significantly lower pain unpleasantness ratings were found at the highest stimulus intensity (49 degrees C) only for active women in disabling pain compared with inactive women in disabling pain (t11 = 2.523, P = 0.028). The other hypotheses were not supported. CONCLUSIONS: PA is associated with a reduced sensitivity to the unpleasantness of painful high-intensity heat stimuli among women in disabling pain. PMID- 25535963 TI - Exploratory comparison of vaginal glycogen and Lactobacillus levels in premenopausal and postmenopausal women. AB - OBJECTIVE: Previous studies have suggested that glycogen expression in the vaginal epithelium decreases during menopause, resulting in reduced levels of lactobacilli. However, free glycogen in genital fluids and its relationship with Lactobacillus levels have not been compared in premenopausal and postmenopausal women. METHODS: Eighty-two cervicovaginal lavage samples were collected at different phases of the menstrual cycle from 11 premenopausal (4 HIV-uninfected and 7 HIV-infected) and 12 postmenopausal (7 HIV-uninfected and 5 HIV-infected) women during a 1- to 3-month period. Free glycogen was quantified in genital fluids. Lactobacillus levels were quantified by real-time polymerase chain reaction. Estrogen and progesterone levels in blood were determined by enzyme linked immunosorbent assay. RESULTS: Free glycogen was detected in both premenopausal and postmenopausal women. Across all samples, those from postmenopausal women had significantly lower levels of free glycogen than those from premenopausal women (median, 0.002 vs 0.065 MUg/MUL, respectively; P = 0.03). Lactobacillus levels correlated positively with free glycogen in both premenopausal (Spearman r = 0.68, P < 0.0001) and postmenopausal (r = 0.60, P < 0.002) women. Samples from premenopausal women had higher Lactobacillus levels and lower vaginal pH (median log, 8.1; median pH, 4) than those from postmenopausal women (median log, 7.1; median pH, 4.6), although these differences were not significant. HIV status had no significant effect on these relationships. CONCLUSIONS: Free glycogen is detected in both premenopausal and postmenopausal women and correlates with Lactobacillus in both groups. These results point to the complexity of the relationship between menopause and vaginal microbiota and indicate that more careful studies of the role of glycogen are warranted. PMID- 25535966 TI - No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis. AB - Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins. PMID- 25535968 TI - Transmission/disequilibrium tests incorporating unaffected offspring. AB - We propose a new method for family-based tests of association and linkage called transmission/disequilibrium tests incorporating unaffected offspring (TDTU). This new approach, constructed based on transmission/disequilibrium tests for quantitative traits (QTDT), provides a natural extension of the transmission/disequilibrium test (TDT) to utilize transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. TDTU can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. When the study sample contains only case-parent trios, the TDTU is equivalent to TDT. Informative-transmission disequilibrium test (i-TDT) and generalized disequilibrium test(GDT) are another two methods that can use information of both unaffected offspring and affected offspring. In contract to i-TDT and GDT, the test statistic of TDTU is simpler and more explicit, and can be implemented more easily. Through computer simulations, we demonstrate that power of the TDTU is slightly higher compared to i-TDT and GDT. All the three methods are more powerful than method that uses affected offspring only, suggesting that unaffected siblings also provide information about linkage and association. PMID- 25535967 TI - T-cell populations and cytokine expression are impaired in thymus and spleen of protein malnourished BALB/c mice infected with Leishmania infantum. AB - Visceral leishmaniasis (VL) is a parasitic infectious disease that causes significant morbidity and mortality in the tropical and subtropical regions of the world. Although infections with visceralizing Leishmania may be asymptomatic, factors such as undernutrition increase the likelihood of progressing to clinical disease. Protein malnutrition, the most deleterious cause of malnutrition in developing countries, has been considered as a primary risk factor for the development of clinical VL. However, data regarding the immunological basis of this association are scarce. With the aim to analyze the effects of protein malnutrition on Leishmania infantum infection, we used BALB/c mice subjected to control or low protein isocaloric diets. Each animal group was divided into two subgroups and one was infected with L. infantum resulting in four study groups: animals fed 14% protein diet (CP), animals fed 4% protein diet (LP), animals fed 14% protein diet and infected (CPi), and animals fed 4% protein diet and infected (LPi).The susceptibility to L. infantum infection and immune responses were assessed in terms of body and lymphoid organ weight, parasite load, lymphocyte subpopulations, and cytokine expression. LPi mice had a significant reduction of body and lymphoid organ weight and exhibited a severe decrease of lymphoid follicles in the spleen. Moreover, LPi animals showed a significant decrease in CD4+CD8+ T cells in the thymus, whereas there was an increase of CD4+ and CD8+ T cells percentages in the spleen. Notably, the cytokine mRNA levels in the thymus and spleen of protein malnourished-infected animals were altered compared to the CP mice. Protein malnutrition results in a drastic dysregulation of T cells and cytokine expression in the thymus and spleen of L. infantum-infected BALB/c mice, which may lead to defective regulation of the thymocyte population and an impaired splenic immune response, accelerating the events of a normal course of infection. PMID- 25535969 TI - Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock. AB - Histone lysine (K) residues, which are modified by methyl- and acetyl transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones. KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3A performs diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. Here, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (p-KDM3A), which is enriched in the regulatory regions of gene loci in the human genome. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate p KDM3A target genes under heat shock conditions. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A in the heat-shocked cells. In contrast to heat shock, IFN-gamma treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to thermal stress. PMID- 25535970 TI - The absoluteness of semantic processing: lessons from the analysis of temporal clusters in phonemic verbal fluency. AB - BACKGROUND: For word production, we may consciously pursue semantic or phonological search strategies, but it is uncertain whether we can retrieve the different aspects of lexical information independently from each other. We therefore studied the spread of semantic information into words produced under exclusively phonemic task demands. METHODS: 42 subjects participated in a letter verbal fluency task, demanding the production of as many s-words as possible in two minutes. Based on curve fittings for the time courses of word production, output spurts (temporal clusters) considered to reflect rapid lexical retrieval based on automatic activation spread, were identified. Semantic and phonemic word relatedness within versus between these clusters was assessed by respective scores (0 meaning no relation, 4 maximum relation). RESULTS: Subjects produced 27.5 (+/-9.4) words belonging to 6.7 (+/-2.4) clusters. Both phonemically and semantically words were more related within clusters than between clusters (phon: 0.33+/-0.22 vs. 0.19+/-0.17, p<.01; sem: 0.65+/-0.29 vs. 0.37+/-0.29, p<.01). Whereas the extent of phonemic relatedness correlated with high task performance, the contrary was the case for the extent of semantic relatedness. CONCLUSION: The results indicate that semantic information spread occurs, even if the consciously pursued word search strategy is purely phonological. This, together with the negative correlation between semantic relatedness and verbal output suits the idea of a semantic default mode of lexical search, acting against rapid task performance in the given scenario of phonemic verbal fluency. The simultaneity of enhanced semantic and phonemic word relatedness within the same temporal cluster boundaries suggests an interaction between content and sound-related information whenever a new semantic field has been opened. PMID- 25535971 TI - Early mortality and primary causes of death in mothers of children with intellectual disability or autism spectrum disorder: a retrospective cohort study. AB - INTRODUCTION: Mothers of children with intellectual disability or autism spectrum disorder (ASD) have poorer health than other mothers. Yet no research has explored whether this poorer health is reflected in mortality rates or whether certain causes of death are more likely. We aimed to calculate the hazard ratios for death and for the primary causes of death in mothers of children with intellectual disability or ASD compared to other mothers. METHODS: The study population comprised all mothers of live-born children in Western Australia from 1983-2005. We accessed state-wide databases which enabled us to link socio demographic details, birth dates, diagnoses of intellectual disability or ASD in the children and dates and causes of death for all mothers who had died prior to 2011. Using Cox Regression with death by any cause and death by each of the three primary causes as the event of interest, we calculated hazard ratios for death for mothers of children intellectual disability or ASD compared to other mothers. RESULTS AND DISCUSSION: During the study period, mothers of children with intellectual disability or ASD had more than twice the risk of death. Mothers of children with intellectual disability were 40% more likely to die of cancer; 150% more likely to die of cardiovascular disease and nearly 200% more likely to die from misadventure than other mothers. Due to small numbers, only hazard ratios for cancer were calculated for mothers of children with ASD. These mothers were about 50% more likely to die from cancer than other mothers. Possible causes and implications of our results are discussed. CONCLUSION: Similar studies, pooling data from registries elsewhere, would improve our understanding of factors increasing the mortality of mothers of children with intellectual disability or ASD. This would allow the implementation of informed services and interventions to improve these mothers' longevity. PMID- 25535972 TI - Nonhealing tongue ulcer in an Indian man. PMID- 25535976 TI - Photoacoustic imaging using acoustic reflectors to enhance planar arrays. AB - Planar sensor arrays have advantages when used for photoacoustic imaging: they do not require the imaging target to be enclosed, and they are easier to manufacture than curved arrays. However, planar arrays have a limited view of the acoustic field due to their finite size; therefore, not all of the acoustic waves emitted from a photoacoustic source can be recorded. This loss of data results in artifacts in the reconstructed photoacoustic image. A detection array configuration which combines a planar Fabry-Perot sensor with perpendicular acoustic reflectors is described and experimentally implemented. This retains the detection advantages of the planar sensor while increasing the effective detection aperture in order to improve the reconstructed photoacoustic image. PMID- 25535973 TI - Global warming and mass mortalities of benthic invertebrates in the Mediterranean Sea. AB - Satellite data show a steady increase, in the last decades, of the surface temperature (upper few millimetres of the water surface) of the Mediterranean Sea. Reports of mass mortalities of benthic marine invertebrates increased in the same period. Some local studies interpreted the two phenomena in a cause-effect fashion. However, a basin-wide picture of temperature changes combined with a systematic assessment on invertebrate mass mortalities was still lacking. Both the thermal structure of the water column in the Mediterranean Sea over the period 1945-2011 and all documented invertebrate mass mortality events in the basin are analysed to ascertain if: 1- documented mass mortalities occurred under conditions of positive temperature trends at basin scale, and 2- atypical thermal conditions were registered at the smaller spatial and temporal scale of mass mortality events. The thermal structure of the shallow water column over the last 67 years was reconstructed using data from three public sources: MEDAR-MEDATLAS, World Ocean Database, MFS-VOS programme. A review of the mass mortality events of benthic invertebrates at Mediterranean scale was also carried out. The analysis of in situ temperature profiles shows that the Mediterranean Sea changed in a non homogeneous fashion. The frequency of mass mortalities is increasing. The areas subjected to these events correspond to positive thermal anomalies. Statistically significant temperature trends in the upper layers of the Mediterranean Sea show an increase of up to 0.07 degrees C/yr for a large fraction of the basin. Mass mortalities are consistent with both the temperature increase at basin scale and the thermal changes at local scale, up to 5.2 degrees C. Our research supports the existence of a causal link between positive thermal anomalies and observed invertebrate mass mortalities in the Mediterranean Sea, invoking focused mitigation initiatives in sensitive areas. PMID- 25535975 TI - Ocular damage induced by a Vis-infrared supercontinuum source. AB - Supercontinuum (SC) source is a new kind of artificial light source, having the characteristics of both laser and traditional incoherent light source, i.e., high brightness, good direction, and super broadband spectrum. The rapid development of SC source stimulates our concern on its ocular damage potency. However, the damage effects of SC source have never been explored. The retinal damage threshold of chinchilla grey rabbit induced by a Vis-infrared SC source was determined for the first time. Additionally, a theoretical method was also developed for analyzing the hazard risks of SC source. PMID- 25535978 TI - The antileukemia roles of PP242 alone or in combination with daunorubicin in acute leukemia. AB - PP242 is a novel dual mammalian target of rapamycin (mTOR) inhibitor that simultaneously inhibits mTORC1 and mTORC2, and its antileukemia effect has been sufficiently investigated here. The human acute leukemia cell lines and primary blasts were treated with PP242 alone or in combination with daunorubicin (DNR). Cell proliferation was examined using an MTT assay. The phosphorylation expression of the Akt/mTORC1/eIF4E signaling pathway was assessed by western blot analysis. The assembly of the eIF4F translation initiation complex was examined using a 7-methyl-guanosine cap affinity assay. PP242 significantly induced cytotoxicity in human acute leukemia cells, especially in combination with DNR. The phosphorylation levels of eIF4E (p-eIF4E) at Ser209 influence the antileukemia roles of PP242. As expected, the antiproliferative effects of PP242 on leukemia cells with low p-eIF4E expression, such as the acute promyelocytic leukemia NB4 cell line and AML-M3 primary blasts, were poor. Surprisingly, the effects of PP242 in leukemia cells with high p-eIF4E expression, such as the acute myelomonocytic leukemia THP-1 cell line and M4-M5 primary blasts, were also weak. In contrast, PP242 exerted a significant antiproliferative effect in the Ph+ acute lymphoblastic leukemia SUP-B15 cell line and the mantle cell lymphoma JEKO-1 cell line, which had intermediate p-eIF4E levels. PP242 inhibited the translation of the antiapoptotic protein Mcl-1 by downregulating the Akt/mTORC1/eIF4E signaling pathway. More importantly, DNR activated the Akt/mTORC1/eIF4E signaling pathway, whereas PP242 effectively eliminated this deleterious side effect of DNR and synergistically enhanced the anticancer ability of DNR treatment. PP242, especially in combination with DNR, exerts significant antileukemia effects. PMID- 25535979 TI - Chemotherapeutic effect of tamoxifen on temozolomide-resistant gliomas. AB - Tamoxifen, a selective estrogen receptor modulator, is widely used in the chemotherapy of estrogen receptor-positive breast cancer. Recent studies have indicated that tamoxifen might have a potential chemotherapeutic effect on glioma. In the present study, we determined the chemotherapeutic action of tamoxifen on human glioma cell lines. Methylation of 06-methylguanine-DNA methyltransferase was identified in A172, U251, and BT325 glioma cell lines, but not in the U87 cell line. Consistently, A172, U251, and BT325 cell lines are resistant to temozolomide. Tamoxifen induced significant cytotoxic action in A172, U251, BT325, and U87 cell lines. Further, Hoechst 33342 staining and apoptosis flow cytometric analysis demonstrated that tamoxifen induced apoptosis in the BT325 cell line. Mitochondrial complex analysis indicated that tamoxifen, but not other estrogen receptor modulators, dose-dependently inhibits complex I activity. In summary, our study suggests that tamoxifen might have a chemotherapeutic effect on temozolomide-resistant glioma through its direct action on mitochondrial complex I inhibition and could provide further evidence to support future clinical trials of tamoxifen for the treatment of glioblastoma. PMID- 25535980 TI - Maxillary Sinus Augmentation with a New Xenograft: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Insufficient residual alveolar bone height is a common deterrent in the placement of dental implants in the posterior maxilla. The use of autografts, xenografts, allografts and alloplasts or a combination between them has been demonstrated to be effective for increasing bone height and bone volume in the deficient posterior maxilla. PURPOSE: The aim of this clinical trial is to comparatively determine the density of newly formed in sinus floor augmentation bone after a 24-week healing period treatment with a new bovine xenograft. MATERIALS AND METHODS: The sinus floor was grafted with Bio-Oss(r) (n = 10) and Osseous(r) (n = 10). Histological sections were examined with a focus on the presence of connective tissue (CT) and newly formed bone (NFB). The sections were histomorphometrically evaluated and the definitive crown was inserted after 3 months. RESULTS: After 6 months, the mean value of new bone formation was 24.60 (+/-2.503), the CT was 42.60 (+/-4.006) and the remaining biomaterial was 25.40 (+/-2.547) in Bio-Oss group. In Osseous group, the mean value of new bone formation was 24.90 (+/-3.542), the CT was 45.70 (+/-7.040) and the remaining biomaterial was 22.90 (+/-3.247). CONCLUSIONS: Both biomaterials afforded a favorable implant position and the prosthetic rehabilitation. PMID- 25535981 TI - Low-cost liquid-based pap test. PMID- 25535982 TI - Vulvar seborrheic keratosis and human papillomavirus. PMID- 25535983 TI - Response to "Vulvar seborrheic keratosis and human papillomavirus". PMID- 25535985 TI - Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose. AB - OBJECTIVES: This prospective long-term follow-up study evaluated the effects of half-dose etanercept (25 mg weekly) on clinical remission and radiographic progression in a large cohort of patients with rheumatoid arthritis (RA) in clinical remission after etanercept 25 mg bi-weekly. METHODS: 524 biologic-naive RA patients were treated with etanercept 25 mg bi-weekly after failure of conventional drugs. Patients achieving remission (DAS28 <2.6) for >=12 months were randomised to receive etanercept 25 mg weekly or 25 mg bi-weekly. Patients were assessed at baseline and every 12 weeks. Remission rates, radiographic progression, incidence of infections and costs of the regimens were compared. RESULTS: After a mean follow-up of 18+/-11 months, 347 patients (66.2%) achieved DAS28 remission; 323 were randomised to one of two dose regimens: etanercept 25 weekly (group A, 159 patients) and etanercept 25 mg bi-weekly (group B, 164 patients). At the end of follow-up, 81.8% patients of group A maintained remission for a mean of 3.6+/-1.5 years. Radiographic progression occurred in a small number of patients of group A and the rate of radiographic progression (TSS >0) was not significantly different in the two groups (18.85% vs. 19.0% after the first year and 16.9% vs. 21.6% after the second year, respectively). The incidence ratio of severe infections was 2.3/1.000 patient-years in group A. Etanercept half-dose regimen resulted in a saving of ?3.190.545 with a cost saving up to ?827.318 per year. CONCLUSIONS: Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with RA even after reduction of standard-dose etanercept. PMID- 25535984 TI - Sorting nexin 6 enhances lamin a synthesis and incorporation into the nuclear envelope. AB - Nuclear lamins are important structural and functional proteins in mammalian cells, but little is known about the mechanisms and cofactors that regulate their traffic into the nucleus. Here, we demonstrate that trafficking of lamin A, but not lamin B1, and its assembly into the nuclear envelope are regulated by sorting nexin 6 (SNX6), a major component of the retromer that targets proteins and other molecules to specific subcellular locations. SNX6 interacts with lamin A in vitro and in vivo and links it to the outer surface of the endoplasmic reticulum in human and mouse cells. SNX6 transports its lamin A cargo to the nuclear envelope in a process that takes several hours. Lamin A protein levels in the nucleus augment or decrease, respectively, upon gain or loss of SNX6 function. We further show that SNX6-dependent lamin A nuclear import occurs across the nuclear pore complex via a RAN-GTP-dependent mechanism. These results identify SNX6 as a key regulator of lamin A synthesis and incorporation into the nuclear envelope. PMID- 25535988 TI - Enucleation of the Incisive Canal for Implant Placement: A Comprehensive Literature Review and Case Report. PMID- 25535987 TI - What to expect from a third step in treatment resistant depression: A prospective open study on escitalopram. AB - OBJECTIVES: Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. METHODS: A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). RESULTS: Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. CONCLUSIONS: Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters. PMID- 25535986 TI - Liver retraction by double-sling suture for laparoscopic gastrectomy. AB - BACKGROUND: To provide an optimal operative view for upper abdominal laparoscopic surgery, we developed a liver retraction method using a double-sling suture (DSS). The current report describes this method and compares the clinical results with the liver puncture (LP) retraction method. MATERIALS AND METHODS: The data and video recordings of patients who underwent laparoscopic gastrectomy for gastric adenocarcinoma by a single surgeon from May 2009 to October 2013 were retrospectively analyzed. RESULTS: Of the 189 patients included, 73 underwent surgery with the DSS method, and 116 underwent surgery with the LP method. Both groups exhibited no complications directly related to liver retraction. Compared with the LP group, the DSS group had a higher American Society of Anesthesiologists' physical status score, shorter operation time (153.2 +/- 42.1 minutes versus 224.8 +/- 83.3 minutes [P<.001]), shorter liver retraction time (200.1 +/- 76.8 seconds versus 231.4 +/- 97.5 seconds [P=.023]), and less elevation of activities of liver enzymes. CONCLUSIONS: Our DSS liver retraction method provided rapid and safe liver retraction for laparoscopic gastrectomy compared with the LP method. This method should also be useful for other laparoscopic upper abdominal surgery requiring liver retraction. PMID- 25535989 TI - Micronisation of simvastatin by the supercritical antisolvent technique: in vitro in vivo evaluation. AB - Micronisation of simvastatin dissolved in acetone, dimethyl sulfoxide and ethanol with supercritical carbon dioxide as antisolvent was successfully performed using a supercritical antisolvent technique. The effect of a few process parameters such as precipitation temperature, the pressure and solute concentration in the liquid solution has been studied to evaluate their influence on morphology and size of particles. The micronised simvastatin were evaluated for drug content, particle size analysis and in vitro dissolution profiles. Fourier transform infrared spectroscopy, differential scanning calorimetry and PXRD patterns was used to study the possible changes after micronisation of simvastatin. The dissolution rate was increased after micronised compared with pure simvastatin in distilled water, pH 1.2 buffer and pH 7.0 buffer. In vivo performance of the optimised formulation was evaluated in rats using pharmacodynamic marker parameters like serum total cholesterol (CH) and triglycerides (TG) for 21 days. Pharmacodynamic studies of micronised simvastatin revealed improved reduction in CH and TG values as compared with pure simvastatin indicating improved bioavailability. In vivo pharmacokinetics in rats showed an increase in bioavailability of micronised simvastatin (3.14 times) compared with plain simvastatin. PMID- 25536000 TI - Fabrication of a PMN-PT single crystal-based transcranial Doppler transducer and the power regulation of its detection system. AB - Doppler sonographic measurement of flow velocity in the basal cerebral arteries through the intact skull was developed using a pulsed Doppler technique and 2 MHz emitting frequency. Relaxor-based ferroelectric single crystals Pb(Mg1/3Nb2/3)O3 PbTiO3 (PMN-PT) were chosen to be the piezoelectric transducer material due to their ultrahigh piezoelectric coefficients, high electromechanical coupling coefficients and low dielectric loss. The pulse-echo response of the transducer was measured using the conventional pulse-echo method in a water bath at room temperature. The -6 dB bandwidth of the transducer is 68.4% and the sensitivity is -17.4 dB. In order to get a good match between transducer and detection system, different transmission powers have been regulated by changing the impedance of the transmitting electric circuit. In the middle cerebral artery (MCA) measurement photograph results, as the transmission power is increasing, the detection results become clearer and clearer. A comparison at the same transmission power for different transducers shows that the detection photograph obtained by the crystal transducer was clearer than that obtained with a commercial transducer, which should make it easier for doctors to find the cerebral arteries. PMID- 25535999 TI - Prebiotics in infant formula. AB - The gastrointestinal microbiota of breast-fed babies differ from classic standard formula fed infants. While mother's milk is rich in prebiotic oligosaccharides and contains small amounts of probiotics, standard infant formula doesn't. Different prebiotic oligosaccharides are added to infant formula: galacto oligosaccharides, fructo-oligosaccharide, polydextrose, and mixtures of these. There is evidence that addition of prebiotics in infant formula alters the gastrointestinal (GI) microbiota resembling that of breastfed infants. They are added to infant formula because of their presence in breast milk. Infants on these supplemented formula have a lower stool pH, a better stool consistency and frequency and a higher concentration of bifidobacteria in their intestine compared to infants on a non-supplemented standard formula. Since most studies suggest a trend for beneficial clinical effects, and since these ingredients are very safe, prebiotics bring infant formula one step closer to breastmilk, the golden standard. However, despite the fact that adverse events are rare, the evidence on prebiotics of a significant health benefit throughout the alteration of the gut microbiota is limited. PMID- 25536002 TI - An architecture for measuring joint angles using a long period fiber grating based sensor. AB - The implementation of signal filters in a real-time form requires a tradeoff between computation resources and the system performance. Therefore, taking advantage of low lag response and the reduced consumption of resources, in this article, the Recursive Least Square (RLS) algorithm is used to filter a signal acquired from a fiber-optics-based sensor. In particular, a Long-Period Fiber Grating (LPFG) sensor is used to measure the bending movement of a finger. After that, the Gaussian Mixture Model (GMM) technique allows us to classify the corresponding finger position along the motion range. For these measures to help in the development of an autonomous robotic hand, the proposed technique can be straightforwardly implemented on real time platforms such as Field Programmable Gate Array (FPGA) or Digital Signal Processors (DSP). Different angle measurements of the finger's motion are carried out by the prototype and a detailed analysis of the system performance is presented. PMID- 25536003 TI - High frequency amplitude detector for GMI magnetic sensors. AB - A new concept of a high-frequency amplitude detector and demodulator for Giant Magneto-Impedance (GMI) sensors is presented. This concept combines a half wave rectifier, with outstanding capabilities and high speed, and a feedback approach that ensures the amplitude detection with easily adjustable gain. The developed detector is capable of measuring high-frequency and very low amplitude signals without the use of diode-based active rectifiers or analog multipliers. The performances of this detector are addressed throughout the paper. The full circuitry of the design is given, together with a comprehensive theoretical study of the concept and experimental validation. The detector has been used for the amplitude measurement of both single frequency and pulsed signals and for the demodulation of amplitude-modulated signals. It has also been successfully integrated in a GMI sensor prototype. Magnetic field and electrical current measurements in open- and closed-loop of this sensor have also been conducted. PMID- 25536001 TI - An electrochemical microsensor based on a AuNPs-modified microband array electrode for phosphate determination in fresh water samples. AB - This work describes the fabrication, characterization, and application of a gold microband array electrode (MAE) for the determination of phosphate in fresh water samples. The working principle of this MAE is based on the reduction of a molybdophosphate complex using the linear sweep voltammetric (LSV) method. The calibration of this microsensor was performed with standard phosphate solutions prepared with KH2PO4 and pH adjusted to 1.0. The microsensor consists of a platinum counter electrode, a gold MAE as working electrode, and an Ag/AgCl electrode as reference electrode. The microelectrode chips were fabricated by the Micro Electro-Mechanical System (MEMS) technique. To improve the sensitivity, gold nanoparticles (AuNPs) were electrodeposited on the working electrode. With a linear range from 0.02 to 0.50 mg P/L, the sensitivity of the unmodified microsensor is 2.40 uA per (mg P/L) (R2 = 0.99) and that of the AuNPs-modified microsensor is 7.66 uA per (mg P/L) (R2 = 0.99). The experimental results showed that AuNPs-modified microelectrode had better sensitivity and a larger current response than the unmodified microelectrode. PMID- 25536004 TI - Robust Huber-based iterated divided difference filtering with application to cooperative localization of autonomous underwater vehicles. AB - A new algorithm called Huber-based iterated divided difference filtering (HIDDF) is derived and applied to cooperative localization of autonomous underwater vehicles (AUVs) supported by a single surface leader. The position states are estimated using acoustic range measurements relative to the leader, in which some disadvantages such as weak observability, large initial error and contaminated measurements with outliers are inherent. By integrating both merits of iterated divided difference filtering (IDDF) and Huber's M-estimation methodology, the new filtering method could not only achieve more accurate estimation and faster convergence contrast to standard divided difference filtering (DDF) in conditions of weak observability and large initial error, but also exhibit robustness with respect to outlier measurements, for which the standard IDDF would exhibit severe degradation in estimation accuracy. The correctness as well as validity of the algorithm is demonstrated through experiment results. PMID- 25536005 TI - Hypovitaminosis D in type 2 diabetes: relation with features of the metabolic syndrome and glycemic control. AB - AIM: To assess the association of hypovitaminosis D with clinical and biochemical characteristics of type 2 diabetic patients and to determine the effect of glycemic control optimization on 25-hydroxyvitamin D (25(OH)D) concentrations. METHODS: Cross-sectional study of 63 patients with type 2 diabetes (mean age 60 +/- 9.8 years, 69.8% men). Twenty of the 63 patients were also studied before and after glycemic control optimization. RESULTS: Mean 25(OH)D concentrations were 63.64 +/- 25.51 nmol/L and 74.6% of patients had hypovitaminosis D. Compared with patients with vitamin D sufficiency, patients with hypovitaminosis D had higher prevalence of overweight or obesity (72.3% versus 37.5%; p = 0.012) and higher VLDL cholesterol (VLDL-c) (0.71 (0.24-3.59) versus 0.45 (0.13-1.6) mmol/L; p = 0.011) and C-reactive protein (3.28 (0.36-17.69) versus 1.87 (0.18-17.47) mg/L; p = 0.033) concentrations. The composition of HDL particles also differed in both groups, with higher relative content of triglycerides and lower of cholesterol in patients with hypovitaminosis D. After adjustment for age, seasonality and BMI, differences remained significant for VLDL-c and triglyceride content of HDL. No differences were found regarding other diabetes characteristics. Improvement of glycemic control (HbA1c 9.4 (7.6-14.8) versus 7.3 (6.2-8.7)%; p = 0.000) was accompanied by a decrease in 25(OH)D concentrations (72.7 +/- 33.3 to 59.0 +/- 21.0 nmol/L; p = 0.035). Correlation analysis revealed that changes in 25(OH)D concentrations were negatively associated to changes in HbA1c (r - 0.482; p = 0.032). CONCLUSION: Hypovitaminosis D is associated with features of the metabolic syndrome in type 2 diabetes and improvement of glycemic control decreases 25(OH)D concentrations. PMID- 25536006 TI - Relation between oxidative stress and climacteric symptoms in early postmenopausal women. AB - OBJECTIVES: To evaluate the relation between climacteric symptoms or other risk factors for cardiovascular disease and oxidative status of postmenopausal women. METHODS: Cross-sectional investigation performed at the outpatient service for the menopause at the University Hospital, on 50 apparently healthy women in physiological postmenopause. The whole-blood free oxygen radical test (FORT), free oxygen radical defence (FORD), age, months since menopause, weight, body mass index, waist circumference, waist-to-hip ratio, estradiol, lipids, glucose, insulin, insulin resistance (glucose/insulin and HOMA-IR), and fibrinogen were evaluated. The Greene Climacteric Scale with its subscales was used to evaluate climacteric symptoms. The pulsatility index, an index of downstream blood flow resistance, was determined for both the internal carotid artery and the brachial artery. RESULTS: The waist-to-hip ratio (r = 0.540; p = 0.0001), estradiol (r = 0.548; p = 0.0004) and waist circumference (r = 0.345; p = 0.02) were independently related to blood FORT. The score in the Greene vasomotor subscale was the only parameter independently related to blood FORD (r = 0.554; p = 0.0001). FORT was not related to the artery pulsatility index, while FORD was negatively related to the pulsatility index of both the internal carotid (r = 0.549; p = 0.0001) and the brachial (r = 0.484; p = 0.0001) arteries. DISCUSSION: In postmenopausal women, abdominal adiposity and hypoestrogenism increase oxidative stress. Climacteric symptoms, particularly vasomotor symptoms, markedly reduce antioxidant defences. Lower antioxidant defences are associated with higher resistance to blood flow in the great arteries. In women early after the menopause, visceral fat, hypoestrogenism and climacteric symptoms may increase the risk for cardiovascular disease. PMID- 25536007 TI - Management of menopause in women with breast cancer. AB - Increasing breast cancer incidence and decreasing mortality have highlighted the importance of survivorship issues related to breast cancer. A consideration of the issues related to menopause is therefore of great importance to both women and clinicians. Menopause/menopausal symptoms, with significant negative effects on quality of life and potential long-term health impacts, may in women with breast cancer be associated with: (1) natural menopause occurring concurrently with a breast cancer diagnosis; (2) recurrence of menopausal symptoms following cessation of hormone replacement therapy; (3) treatment-induced menopause (chemotherapy, ovarian ablation/suppression) and adjuvant endocrine therapy. A variety of non-hormonal pharmacological and non-pharmacological therapies have been investigated as therapeutic options for menopausal symptoms with mixed results, and ongoing research is required. This review presents a summary of the causes, common problematic symptoms of menopause (vasomotor, genitourinary and sexual dysfunction), and longer-term consequences (cardiovascular disease and osteoporosis) related to menopause. It proposes an evidenced-based multidisciplinary approach to the management of menopause/menopausal symptoms in women with breast cancer. PMID- 25536009 TI - Scientific evidence supports stronger limits on ozone. PMID- 25536010 TI - Age and body size of captive hawksbill turtles at the onset of follicular development. AB - The aim of this study was to record the age and body size of 23 captive female hawksbill turtles at the onset of follicular development. The age, straight carapace length (SCL), and body mass (BM) of the turtles were recorded between 2006 and 2014 at follicular development (determined via ultrasonography) these parameters were 17.7 +/- 1.7 years (range: 13-20 years), 77.7 +/- 3.3 cm (73.3 83.5 cm), and 61.1 +/- 8.0 kg (48.2-76.1 kg), respectively. When the year of the onset of follicular development was designated year 0, the increase in SCL in years -7-0 and 0-3 averaged 2.2 cm and 1.0 cm, respectively. Correspondingly, the increase in BM in years -7-0 and 0-3 averaged 5.0 kg and 2.2 kg, respectively. This is the first study to report the age and body size of captive female hawksbill turtles at the onset of follicular development, which indicates the beginning of sexual maturation. The reduction in growth after follicular development suggests that at the onset of sexual maturation, female hawksbills may utilize energy for follicular development rather than growth. PMID- 25536008 TI - Acute dietary nitrate supplementation does not augment submaximal forearm exercise hyperemia in healthy young men. AB - Despite the popularity of dietary nitrate supplementation and the growing evidence base of its potential ergogenic and vascular health benefits, there is no direct information about its effects on exercising limb blood flow in humans. We hypothesized that acute dietary nitrate supplementation from beetroot juice would augment the increases in forearm blood flow, as well as the progressive dilation of the brachial artery, during graded handgrip exercise in healthy young men. In a randomized, double-blind, placebo-controlled crossover study, 12 young (22 +/- 2 years) healthy men consumed a beetroot juice (140 mL Beet-It Sport, James White Juice Company) that provided 12.9 mmol (0.8 g) of nitrate or placebo (nitrate-depleted Beet-It Sport) on 2 study visits. At 3 h postconsumption, brachial artery diameter, flow, and blood velocity were measured (Doppler ultrasound) at rest and during 6 exercise intensities. Nitrate supplementation raised plasma nitrate (19.5-fold) and nitrite (1.6-fold) concentrations, and lowered resting arterial pulse wave velocity (PWV) versus placebo (all p < 0.05), indicating absorption, conversion, and a biological effect of this supplement. The supplement-associated lowering of PWV was also negatively correlated with plasma nitrite (r = -0.72, p = 0.0127). Despite these systemic effects, nitrate supplementation had no effect on brachial artery diameter, flow, or shear rates at rest (all p >= 0.28) or during any exercise workload (all p >= 0.18). These findings suggest that acute dietary nitrate supplementation favorably modifies arterial PWV, but does not augment blood flow or brachial artery vasodilation during nonfatiguing forearm exercise in healthy young men. PMID- 25536011 TI - Rational design of an orthosteric regulator of hIAPP aggregation. AB - Developing compounds regulating amyloid toxic oligomer but not fibril formation should constitute an effective strategy for the treatment of diabetes. Based on the full understanding of the folding mechanism, we designed an orthosteric helix regulator that can promote hIAPP to assemble into large non-cytotoxic oligomers. As a result, the islet cells were protected. PMID- 25536013 TI - Adiponectin prevents reduction of lipid-induced mitochondrial biogenesis via AMPK/ACC2 pathway in chicken adipocyte. AB - Adiponectin (APN) stimulates mitochondrial biogenesis and reduces lipid content in human and animal adipocytes. However, the mechanism of adiponectin in regulating mitochondrial biogenesis in chicken adipocytes has never been reported. The objective of this study is to examine the mechanism that adiponectin plays in lipid-induced mitochondrial biogenesis and mitochondrial function in chicken adipocytes. We found that the overexpression of adiponectin reduced the membrane DAG content and elevated the membrane translocation of PKCtheta. In contrast to control groups, the overexpression of adiponectin increased mitochondrial density and mitochondrial DNA contents and peroxisome proliferator-activated receptor alphacoactivator 1alpha (PGC1-alpha) expression. Mitochondrial membrane potential and cytochrome C (Cyt C) content were detected by JC-1 fluorescent staining and immunofluorescence which indicated that overexpression of adiponectin enhanced mitochondrial ATP synthesis. Moreover, AMPK/ACC2 signaling pathway was activated along with the elevation of PGC1-alpha and TFAM by the overexpression of adiponectin, meanwhile the lipid transcription marker genes were down-regulated. This effect was alleviated by reducing adiponectin and a specific inhibitor of AMPK pathway. We concluded that adiponectin could prevent reduction of lipid-induced mitochondrial biogenesis via AMPK/ACC2 pathway in chicken adipocytes. PMID- 25536014 TI - KMUP-1 Promotes Osteoblast Differentiation Through cAMP and cGMP Pathways and Signaling of BMP-2/Smad1/5/8 and Wnt/beta-Catenin. AB - Phosphodiesterase (PDE) inhibitors have been suggested as a possible candidate for the treatment of osteopenia, including osteoporosis. KMUP-1 is a novel xanthine derivative with inhibitory activities on the PDE 3, 4, and 5 iso-enzymes to suppress the degradation of cAMP and cGMP. This study aimed to investigate the effect of KMUP-1 on osteoblast differentiation and the underlying cellular and molecular mechanisms. Primary osteoblasts and osteoblastic MC3T3-E1 cells were examined. KMUP-1 enhanced alkaline phosphatase (ALP) activity and mineralization compared to untreated controls in primary osteoblasts and MC3T3-E1 cells. KMUP-1 also increased the mRNA expression of the osteoblastic differentiation markers, including collagen type 1a, ALP, osteocalcin, osteoprotegerin, BMP-2, and Runx2, a key transcription regulator for osteoblastic differentiation. The osteogenic effect of KMUP-1 was abolished by BMP signaling inhibitor, noggin. Furthermore, we found that KMUP-1 upregulated Smad1/5/8 phosphorylations with subsequent BRE Luc activation confirmed by transient transfection assay. In addition, KMUP-1 inactivated glycogen synthase kinase-3beta (GSK-3beta), with associated nuclear translocation of beta-catenin. Co-treatment with H89 and KT5823, cAMP and cGMP pathway inhibitors, respectively, reversed the KMUP-1-induced activations of Smad1/5/8, beta-catenin, and Runx2. The findings demonstrate for the first time that KMUP-1 can promote osteoblast maturation and differentiation in vitro via BMP-2/Smad1/5/8 and Wnt/beta-catenin pathways. These effects are mediated, in part, by the cAMP and cGMP signaling. Thus, KMUP-1 may be a novel osteoblast activator and a potential new therapy for osteoporosis. PMID- 25536015 TI - Adaptation of Leishmania donovani to cutaneous and visceral environments: in vivo selection and proteomic analysis. AB - Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa. Two main forms are found in the Old World, self-limited cutaneous leishmaniasis and potentially fatal visceral leishmaniasis, with parasite dissemination to liver, bone marrow, and spleen. The Leishmania donovani species complex is the causative agent of visceral leishmaniasis worldwide, but atypical L. donovani strains can cause cutaneous leishmaniasis. We hypothesized that L. donovani can adapt to survive in response to restrictions imposed by the host environment. To assess this, we performed in vivo selection in BALB/c mice with a cutaneous L. donovani clinical isolate to select for parasites with increased capacity to survive in visceral organs. We then performed whole cell proteomic analysis and compared this visceral-selected strain to the original cutaneous clinical isolate and to a visceral leishmaniasis clinical isolate. Overall, there were no major shifts in proteomic profiles; however, translation, biosynthetic processes, antioxidant protection, and signaling were elevated in visceral strains. Conversely, transport and trafficking were elevated in the cutaneous strain. Overall, these results provide new insight into the adaptability of Leishmania parasites to the host environment and on the factors that mediate their ability to survive in different organs. PMID- 25536017 TI - Improving the conductivity of PEDOT:PSS hole transport layer in polymer solar cells via copper(II) bromide salt doping. AB - Copper(II) bromide (CuBr2) salt has been applied to dope poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as the hole transport layer (HTL) in polymer solar cells (PSCs), improving dramatically the conductivity of PEDOT:PSS film and consequently the device power conversion efficiency (PCE). Under the optimized doping concentration of CuBr2 of 10 mmol.L(-1), PCE of the CuBr2:PEDOT:PSS HTL-incorporated BHJ-PSC device based on poly[N-9"-hepta-decanyl 2,7-carbazole-alt-5,5- (4',7'-di-2-thienyl-2',1',3'- benzothiadiazole) (PCDTBT) and [6,6]-phenyl C71-butyric acid methyl ester (PC71BM) (PCDTBT:PC71BM) reaches 7.05%, which is improved by ~20.7% compared to that of the reference device based on pristine PEDOT:PSS HTL (5.84%) and represents the highest PCE for PCDTBT:PC71BM-based PSC devices without an electron transport layer (ETL) reported so far. The dramatic improvement of the conductivity of PEDOT:PSS film is interpreted by the weakening of the Coulombic attractions between PEDOT and PSS components. The work function of CuBr2:PEDOT:PSS slightly increases compared to that of the undoped PEDOT:PSS as inferred from scanning Kelvin probe microscopy (SKPM) measurements, contributing to the improved PCE due to the increases of the open-current voltage (Voc) and fill factor (FF). PMID- 25536016 TI - Green and Red Light Reduces the Disease Severity by Pseudomonas cichorii JBC1 in Tomato Plants via Upregulation of Defense-Related Gene Expression. AB - Light influences many physiological processes in most organisms. To investigate the influence of light on plant and pathogen interaction, we challenged tomato seedlings with Pseudomonas cichorii JBC1 by flood inoculation and incubated the seedlings under different light conditions. Tomato seedlings exposed to green or red light showed a significant reduction in disease incidence compared with those grown under white light or dark conditions. To understand the underlying mechanisms, we investigated the effects of each light wavelength on P. cichorii JBC1 and tomato plants. Treatment with various light wavelengths at 120 umol m( 2) s(-1) revealed no significant difference in growth, swarming motility, or biofilm formation of the pathogen. In addition, when we vacuum-infiltrated P. cichorii JBC1 into tomato plants, green and red light also suppressed disease incidence which indicated that the reduced disease severity was not from direct influence of light on the pathogen. Significant upregulation of the defense related genes, phenylalanine ammonia-lyase (PAL) and pathogenesis-related protein 1a (PR-1a) was observed in P. cichorii JBC1-infected tomato seedlings grown under green or red light compared with seedlings grown under white light or dark conditions. The results of this study indicate that light conditions can influence plant defense mechanisms. In particular, green and red light increase the resistance of tomato plants to infection by P. cichorii. PMID- 25536020 TI - Synthesis and enhanced fluorescence of Ag doped CdTe semiconductor quantum dots. AB - Doping with intentional impurities is an intriguing way to tune the properties of semiconductor nanocrystals. However, the synthesis of some specific doped semiconductor nanocrystals remains a challenge and the doping mechanism in this strongly confined system is still not clearly understood. In this work, we report, for the first time, the synthesis of stable and water-soluble Ag-doped CdTe semiconductor quantum dots (SQDs) via a facile aqueous approach. Experimental characterization demonstrated the efficient doping of the Ag impurities into the CdTe SQDs with an appropriate reaction time. By doping 0.3% Ag impurities, the Stokes shift is decreased by 120 meV, the fluorescence intensity is enhanced more than 3 times, the radiative rate is enhanced 4.2 times, and the non-radiative rate is efficiently suppressed. These observations reveal that the fluorescence enhancement in Ag-doped CdTe SQDs is mainly attributed to the minimization of surface defects, filling of the trap states, and the enhancement of the radiative rate by the silver dopants. Our results suggest that the silver doping is an efficient method for tuning the optical properties of the CdTe SQDs. PMID- 25536018 TI - Using DNA aptamer probe for immunostaining of cancer frozen tissues. AB - Tissue immunostaining is critically important in clinical applications, and antibodies have been used extensively as the molecular probes. Recently, aptamer, as a new class of probes, have attracted much attention for their potential clinical and research value. Epithelial cell adhesion molecule (EpCAM) is a specific biomarker which is overexpressed in many cancers of epithelial origin. Here, a DNA-based EpCAM aptamer SYL3C is reported as a probe for the immunostaining of frozen and paraffin-embedded sections of colorectal cancer tissues. Commercialized EpCAM antibodies were also used as a standard control. EpCAM aptamer SYL3C specifically recognized and immunostained cancer nests of colorectal tumor sections, but it neither reacted with background cells within tumor sites nor exhibited cross-reaction to the benign lesions or inflammation of colorectal tissues. No cross-linking to EpCAM-negative malignant tumor sections occurred. Compared with standard antibody staining, our EpCAM aptamer SYL3C protocol is simpler to implement with a shorter reaction time. Moreover, SYL3C can specifically bind with either frozen or paraffin-embedded tissue sections. Since the histopathology of frozen tissue is closer to that of fresh tissue and since frozen sections can be produced more quickly than paraffin-embedded sections, SYL3C immunostaining of frozen sections is a quick protocol that is easy to implement. PMID- 25536021 TI - The utilization of copper flow reactors in organic synthesis. AB - The use of flow chemistry techniques has flourished over the past decade, with the field expanding to include the use of copper flow reactors in bench-top organic synthesis in recent years. These reactors are available in a variety of forms and possess a number of advantages over their batch reaction counterparts, in terms of both safety and yield. This review will highlight the current research employing copper flow reactors, such as 1,3-dipolar cycloadditions ('click' chemistry), macrocyclizations (via 'click' chemistry), Sonogashira C-C couplings, Ullmann couplings, decarboxylations, and other reported findings. PMID- 25536022 TI - Herbal medicine for low-back pain. AB - BACKGROUND: Low-back pain (LBP) is a common condition and imposes a substantial economic burden upon people living in industrialized societies. A large proportion of people with chronic LBP use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in treating people with LBP. This is an update of a Cochrane Review first published in 2006. OBJECTIVES: To determine the effectiveness of herbal medicine for non-specific LBP. SEARCH METHODS: We searched the following electronic databases up to September 2014: MEDLINE, EMBASE, CENTRAL, CINAHL, Clinical Trials.gov, World Health Organization International Clinical Trials Registry Portal and PubMed; checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area. SELECTION CRITERIA: We included randomized controlled trials (RCTs) examining adults (over 18 years of age) suffering from acute, sub acute, or chronic non-specific LBP. The interventions were herbal medicines which we defined as plants used for medicinal purposes in any form. Primary outcome measures were pain and function. DATA COLLECTION AND ANALYSIS: A library scientist with the Cochrane Back Review Group conducted the database searches. One review author contacted content experts and acquired relevant citations. We downloaded full references and abstracts of the identified studies and retrieved a hard copy of each study for final inclusion decisions. Two review authors assessed risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were compared to assessments by a third individual. Two review authors assessed clinical relevance and resolved any disagreements by consensus. MAIN RESULTS: We included 14 RCTs (2050 participants) in this review. One trial on Solidago chilensis M. (Brazilian arnica) (20 participants) found very low quality evidence of reduction in perception of pain and improved flexibility with application of Brazilian arnica-containing gel twice daily as compared to placebo gel. Capsicum frutescens cream or plaster probably produces more favourable results than placebo in people with chronic LBP (three trials, 755 participants, moderate quality evidence). Based on current evidence, it is not clear whether topical capsicum cream is more beneficial for treating people with acute LBP compared to placebo (one trial, 40 participants, low quality evidence). Another trial found equivalence of C. frutescens cream to a homeopathic ointment (one trial, 161 participants, very low quality evidence). Daily doses of Harpagophytum procumbens (devil's claw), standardized to 50 mg or 100 mg harpagoside, may be better than placebo for short-term improvements in pain and may reduce use of rescue medication (two trials, 315 participants, low quality evidence). Another H. procumbens trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (Vioxx(r)) but was of very low quality (one trial, 88 participants, very low quality). Daily doses of Salix alba (white willow bark), standardized to 120 mg or 240 mg salicin, are probably better than placebo for short-term improvements in pain and rescue medication (two trials, 261 participants, moderate quality evidence). An additional trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (one trial, 228 participants) but was graded as very low quality evidence. S. alba minimally affected platelet thrombosis versus a cardioprotective dose of acetylsalicylate (one trial, 51 participants). One trial (120 participants) examining Symphytum officinale L. (comfrey root extract) found low quality evidence that a Kytta-Salbe comfrey extract ointment is better than placebo ointment for short-term improvements in pain as assessed by VAS. Aromatic lavender essential oil applied by acupressure may reduce subjective pain intensity and improve lateral spine flexion and walking time compared to untreated participants (one trial, 61 participants,very low quality evidence). No significant adverse events were noted within the included trials. AUTHORS' CONCLUSIONS: C. frutescens (Cayenne) reduces pain more than placebo. Although H. procumbens, S. alba, S. officinale L., S. chilensis, and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions. PMID- 25536023 TI - Micromotors with step-motor characteristics by controlled magnetic interactions among assembled components. AB - In this study, we investigated the control of the rotation dynamics of an innovative type of rotary micromotors with desired performances by tuning the magnetic interactions among the assembled micro/nanoscale components. The micromotors are made of metallic nanowires as rotors, patterned magnetic nanodisks as bearings and actuated by external electric fields. The magnetic forces for anchoring the rotors on the bearings play an essential role in the rotation dynamics of the micromotors. By varying the moment, orientation, and dimension of the magnetic components, distinct rotation behaviors can be observed, including repeatable wobbling and rolling in addition to rotation. We understood the rotation behaviors by analytical modeling, designed and realized micromotors with step-motor characteristics. The outcome of this research could inspire the development of high-performance nanomachines assembled from synthetic nanoentities, relevant to nanorobotics, microfluidics, and biomedical research. PMID- 25536026 TI - A novel alkali extractable polysaccharide from Plantago asiatic L. Seeds and its radical-scavenging and bile acid-binding activities. AB - A new acidic polysaccharide (PLP) was isolated and characterized from Plantago asiatic L. seeds by hot alkali extraction and chromatographic purification using DEAE cellulose and Sephacryl S-400 columns. PLP has a molecular weight of 1.15 * 10(6) Da, and a monosaccharide composition of xylose (Xyl), arabinose (Ara), glucuronic acid (GlcA), and galactose (Gal) in a molar ratio of 18.8:7.2:6.1:1. The results of methylation analysis, FT-IR, and 1D and 2D NMR indicated that PLP was a highly branched heteroxylan of beta-1,4-linked Xylp backbone with three alpha-GlcAp-(1->3)-Araf attached to the O-3 position and one alpha-T-linked-GlcAp and one alpha-Araf-(1->5)-Araf attached to the O-2 position every eight monosaccharide residues. PLP exhibited scavenging abilities against hydroxyl, peroxyl anion, and DPPH radicals in vitro and showed significant binding capacities against cholic and chenodeoxycholic acids, suggesting its possible cholesterol-lowering activity. The results demonstrated the potential use of PLP in functional foods and nutraceuticals. PMID- 25536027 TI - Synthesis of polysubstituted pyrroles via Pd-catalyzed oxidative alkene C-H bond arylation and amination. AB - A novel Pd(II)-catalyzed oxidative approach to construct polysubstituted pyrroles from N-homoallylicamines and arylboronic acids was developed. This transformation is supposed to proceed through cascade formation of C-C and C-N bonds via oxidative arylation of unactive alkenes, followed by intramolecular aza-Wacker cyclization. PMID- 25536028 TI - 9-Silafluorenes via base-promoted homolytic aromatic substitution (BHAS)--the electron as a catalyst. AB - Transition-metal-free intramolecular radical silylation of 2-diphenylsilylbiaryls via base-promoted homolytic aromatic substitution (BHAS) to give 9-silafluorenes is reported. 2-Diphenylsilylbiaryls are readily prepared, and cross dehydrogenative silylation occurs with tert-butylhydroperoxide (TBHP) as a cheap stoichiometric oxidant in the presence of a small amount of tetrabutylammonium iodide (TBAI) as an initiator. These cyclizations are catalyzed by the electron. PMID- 25536025 TI - Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. AB - Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBalpha and beta, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour. These data are consistent with increased anxiety-like behaviour of REV-ERBbeta null mice, in which REV-ERB agonists have no effect. These results indicate that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety. PMID- 25536029 TI - Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-alpha. AB - Dysfunction of complex I (CI) of the mitochondrial electron transport chain (ETC) features prominently in human pathology. Cell models of ETC dysfunction display adaptive survival responses that still are poorly understood but of relevance for therapy development. Here we comprehensively examined how primary human skin fibroblasts adapt to chronic CI inhibition. CI inhibition triggered transient and sustained changes in metabolism, redox homeostasis and mitochondrial (ultra)structure but no cell senescence/death. CI-inhibited cells consumed no oxygen and displayed minor mitochondrial depolarization, reverse-mode action of complex V, a slower proliferation rate and futile mitochondrial biogenesis. Adaptation was neither prevented by antioxidants nor associated with increased PGC1-alpha/SIRT1/mTOR levels. Survival of CI-inhibited cells was strictly glucose dependent and accompanied by increased AMPK-alpha phosphorylation, which occurred without changes in ATP or cytosolic calcium levels. Conversely, cells devoid of AMPK-alpha died upon CI inhibition. Chronic CI inhibition did not increase mitochondrial superoxide levels or cellular lipid peroxidation and was paralleled by a specific increase in SOD2/GR, whereas SOD1/CAT/Gpx1/Gpx2/Gpx5 levels remained unchanged. Upon hormone stimulation, fully adapted cells displayed aberrant cytosolic and ER calcium handling due to hampered ATP fueling of ER calcium pumps. It is concluded that CI dysfunction triggers an adaptive program that depends on extracellular glucose and AMPK-alpha. This response avoids cell death by suppressing energy crisis, oxidative stress induction and substantial mitochondrial depolarization. PMID- 25536030 TI - Photosynthetic biomaterials: a pathway towards autotrophic tissue engineering. AB - Engineered tissues are highly limited by poor vascularization in vivo, leading to hypoxia. In order to overcome this challenge, we propose the use of photosynthetic biomaterials to provide oxygen. Since photosynthesis is the original source of oxygen for living organisms, we suggest that this could be a novel approach to provide a constant source of oxygen supply independently of blood perfusion. In this study we demonstrate that bioartificial scaffolds can be loaded with a solution containing the photosynthetic microalgae Chlamydomonas reinhardtii, showing high biocompatibility and photosynthetic activity in vitro. Furthermore, when photosynthetic biomaterials were engrafted in a mouse full skin defect, we observed that the presence of the microalgae did not trigger a native immune response in the host. Moreover, the analyses showed that the algae survived for at least 5 days in vivo, generating chimeric tissues comprised of algae and murine cells. The results of this study represent a crucial step towards the establishment of autotrophic tissue engineering approaches and suggest the use of photosynthetic cells to treat a broad spectrum of hypoxic conditions. PMID- 25536031 TI - Engineered cell instructive matrices for fetal membrane healing. AB - Iatrogenic preterm prelabour rupture of fetal membranes (iPPROM) occurs in 6-45% of the cases after fetoscopic procedures, posing a significant threat to fetal survival and well-being. The number of diagnostic and therapeutic prenatal interventions available is increasing, thus developing treatment options for iPPROM is becoming more important than ever before. Fetal membranes exhibit very restricted regeneration and little is known about factors which might modulate their healing potential, rendering various materials and strategies to seal or heal fetal membranes pursued over the past decades relatively fruitless. Additionally, biocompatible materials with tunable in vivo stability and mechanical and biological properties have not been available. Using poly(ethylene glycol)-based biomimetic matrices, we provide evidence that, upon presentation of appropriate biological cues in three dimensions, mesenchymal progenitor cells from the amnion can be mobilized, induced to proliferate and supported in maintaining their native extracellular matrix production, thus creating a suitable environment for healing to take place. These data suggest that engineering materials with defined mechanical and biochemical properties and the ability to present migration- and proliferation-inducing factors, such as platelet-derived growth factor, basic fibroblast growth factor or epidermal growth factor, could be key in resolving the clinical problem of iPPROM and allowing the field of fetal surgery to move forward. PMID- 25536032 TI - Can you forgive? It depends on how happy you are. AB - This paper examined how individual group status and happiness influence forgiveness. In Study 1, happiness was treated as a trait difference: highly happy people, compared with very unhappy people, were found to be more willing to forgive murderers. More important, an interaction effect between happiness and group status on forgiveness was found, that is, highly happy people tended to be more forgiving when either ingroup or outgroup members were killed; unhappy people, however, tended to be less forgiving about murder when ingroup rather than outgroup members were killed. In Study 2, happiness was treated as an emotional state difference: happiness, rather than sadness, was found to bring greater forgiveness. Moreover, consistent with the interaction effect displayed in Study 1, happy participants tended to forgive more when ingroup or outgroup members were hurt; sad participants tended to forgive less when ingroup members rather than outgroup members were hurt. Implications for connections between happiness, group membership, and forgiveness are discussed. PMID- 25536033 TI - Amyloid beta-mediated Zn2+ influx into dentate granule cells transiently induces a short-term cognitive deficit. AB - We examined an idea that short-term cognition is transiently affected by a state of confusion in Zn2+ transport system due to a local increase in amyloid-beta (Abeta) concentration. A single injection of Abeta (25 pmol) into the dentate gyrus affected dentate gyrus long-term potentiation (LTP) 1 h after the injection, but not 4 h after the injection. Simultaneously, 1-h memory of object recognition was affected when the training was performed 1 h after the injection, but not 4 h after the injection. Abeta-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn2+ is involved in Abeta action. When Abeta was injected into the dentate gyrus, intracellular Zn2+ levels were increased only in the injected area in the dentate gyrus, suggesting that Abeta induces the influx of Zn2+ into cells in the injected area. When Abeta was added to hippocampal slices, Abeta did not increase intracellular Zn2+ levels in the dentate granule cell layer in ACSF without Zn2+, but in ACSF containing Zn2+. The increase in intracellular Zn2+ levels was inhibited in the presence of CaEDTA, an extracellular zinc chelator, but not in the presence of CNQX, an AMPA receptor antagonist. The present study indicates that Abeta mediated Zn2+ influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn2+ may play a key role for transiently Abeta-induced cognition deficits. PMID- 25536034 TI - MicroRNA-503 acts as a tumor suppressor in osteosarcoma by targeting L1CAM. AB - Deregulated microRNAs and their roles in tumorigenesis have attracted much attention in recent years. Although miR-503 was shown to be important in tumorigenesis, its role in osteosarcoma remains unknown. In this study, we focused on the expression and mechanisms of miR-503 in osteosarcoma development. We found that miR-503 was down-regulated in osteosarcoma cell lines and primary tumor samples, and the restoration of miR-503 reduced cell proliferation, migration and invasion. Low level of miR-503 in patients with osteosarcoma was associated with considerably shortened disease-free survival. Furthermore, bioinformatic prediction and experimental validation revealed that the anti-tumor effect of miR-503 was probably exerted through targeting and repressing of L1CAM expression. L1CAM was up-regulated in osteosarcoma cell lines and primary tumor samples and the expression level of L1CAM were negatively correlated with miR-503 levels in osteosarcoma tissues. Collectively, our data identify the important roles of miR-503 in osteosarcoma pathogenesis, indicating its potential application in cancer therapy. PMID- 25536036 TI - Frozen cropland soil in northeast China as source of N2O and CO2 emissions. AB - Agricultural soils are important sources of atmospheric N2O and CO2. However, in boreal agro-ecosystems the contribution of the winter season to annual emissions of these gases has rarely been determined. In this study, soil N2O and CO2 fluxes were measured for 6 years in a corn-soybean-wheat rotation in northeast China to quantify the contribution of wintertime N2O and CO2 fluxes to annual emissions. The treatments were chemical fertilizer (NPK), chemical fertilizer plus composted pig manure (NPKOM), and control (Cont.). Mean soil N2O fluxes among all three treatments in the winter (November-March), when soil temperatures are below -7 degrees C for extended periods, were 0.89-3.01 ug N m(-2) h(-1), and in between the growing season and winter (October and April), when freeze-thaw events occur, 1.73-5.48 ug N m(-2) h(-1). The cumulative N2O emissions were on average 0.27 1.39, 0.03-0.08 and 0.03-0.11 kg N2O_N ha(-1) during the growing season, October and April, and winter, respectively. The average contributions of winter N2O efflux to annual emissions were 6.3-12.1%. In all three seasons, the highest N2O emissions occurred in NPKOM, while NPK and Cont. emissions were similar. Cumulative CO2 emissions were 2.73-4.94, 0.13-0.20 and 0.07-0.11 Mg CO2-C ha(-1) during growing season, October and April, and winter, respectively. The contribution of winter CO2 to total annual emissions was 2.0-2.4%. Our results indicate that in boreal agricultural systems in northeast China, CO2 and N2O emissions continue throughout the winter. PMID- 25536035 TI - Evaluation of intradural stimulation efficiency and selectivity in a computational model of spinal cord stimulation. AB - Spinal cord stimulation (SCS) is an alternative or adjunct therapy to treat chronic pain, a prevalent and clinically challenging condition. Although SCS has substantial clinical success, the therapy is still prone to failures, including lead breakage, lead migration, and poor pain relief. The goal of this study was to develop a computational model of SCS and use the model to compare activation of neural elements during intradural and extradural electrode placement. We constructed five patient-specific models of SCS. Stimulation thresholds predicted by the model were compared to stimulation thresholds measured intraoperatively, and we used these models to quantify the efficiency and selectivity of intradural and extradural SCS. Intradural placement dramatically increased stimulation efficiency and reduced the power required to stimulate the dorsal columns by more than 90%. Intradural placement also increased selectivity, allowing activation of a greater proportion of dorsal column fibers before spread of activation to dorsal root fibers, as well as more selective activation of individual dermatomes at different lateral deviations from the midline. Further, the results suggest that current electrode designs used for extradural SCS are not optimal for intradural SCS, and a novel azimuthal tripolar design increased stimulation selectivity, even beyond that achieved with an intradural paddle array. Increased stimulation efficiency is expected to increase the battery life of implantable pulse generators, increase the recharge interval of rechargeable implantable pulse generators, and potentially reduce stimulator volume. The greater selectivity of intradural stimulation may improve the success rate of SCS by mitigating the sensitivity of pain relief to malpositioning of the electrode. The outcome of this effort is a better quantitative understanding of how intradural electrode placement can potentially increase the selectivity and efficiency of SCS, which, in turn, provides predictions that can be tested in future clinical studies assessing the potential therapeutic benefits of intradural SCS. PMID- 25536037 TI - Dopamine receptors antagonistically regulate behavioral choice between conflicting alternatives in C. elegans. AB - Caenorhabditis elegans is a useful model to study the neuronal or molecular basis for behavioral choice, a specific form of decision-making. Although it has been implied that both D1-like and D2-like dopamine receptors may contribute to the control of decision-making in mammals, the genetic interactions between D1-like and D2-like dopamine receptors in regulating decision-making are still largely unclear. In the present study, we investigated the molecular control of behavioral choice between conflicting alternatives (diacetyl and Cu2+) by D1-like and D2-like dopamine receptors and their possible genetic interactions with C. elegans as the assay system. In the behavioral choice assay system, mutation of dop-1 gene encoding D1-like dopamine receptor resulted in the enhanced tendency to cross the Cu2+ barrier compared with wild-type. In contrast, mutations of dop 2 or dop-3 gene encoding D2-like dopamine receptor caused the weak tendency to cross the Cu2+ barrier compared with wild-type. During the control of behavioral choice, DOP-3 antagonistically regulated the function of DOP-1. The behavioral choice phenotype of dop-2; dop-1dop-3 triple mutant further confirmed the possible antagonistic function of D2-like dopamine receptor on D1-like dopamine receptor in regulating behavioral choice. The genetic assays further demonstrate that DOP-3 might act through Galphao signaling pathway encoded by GOA-1 and EGL 10, and DOP-1 might act through Galphaq signaling pathway encoded by EGL-30 and EAT-16 to regulate the behavioral choice. DOP-1 might function in cholinergic neurons to regulate the behavioral choice, whereas DOP-3 might function in GABAergic neurons, RIC, and SIA neurons to regulate the behavioral choice. In this study, we provide the genetic evidence to indicate the antagonistic relationship between D1-like dopamine receptor and D2-like dopamine receptor in regulating the decision-making of animals. Our data will be useful for understanding the complex functions of dopamine receptors in regulating decision making in animals. PMID- 25536039 TI - On social and cognitive influences: relating adolescent networks, generalized expectancies, and adolescent smoking. AB - We examine the moderating role of friendship and school network characteristics in relationships between 1) youths' friends smoking behavior and youths' own generalized expectancies regarding risk and future orientation and 2) generalized expectancies of youths' friends and youths' own generalized expectancies. We then relate these constructs to smoking. Using a longitudinal sample from the National Longitudinal Study of Adolescent Health (N = 15,142), the relationship between friends' generalized expectancies and youths' expectancies is stronger for those more central in the network, with more reachability, or stronger network ties, and weaker for those with denser friendship networks. Risk expectancies exhibited an inverted U shaped relationship with smoking at the next time point, whereas future orientation expectancies displayed a nonlinear accelerating negative relationship. There was also a feedback effect in which smoking behavior led to higher risk expectancies and lower future orientation expectancies in instrumental variable analyses. PMID- 25536040 TI - Changes in health care expenditure after the loss of a spouse: data on 6,487 older widows and widowers in the Netherlands. AB - BACKGROUND: In ageing populations, informal care holds great potential to limit rising health care expenditure. The majority of informal care is delivered by spouses. The loss of informal care due to the death of the spouse could therefore increase expenditure levels for formal care. OBJECTIVE: To investigate the impact of the death of the spouse on health care expenditure by older people through time. Additionally, to examine whether the impact differs between socio demographic groups, and what health services are affected most. DESIGN: Longitudinal data on health care expenditure (from July 2007 through 2010) from a regional Dutch health care insurer was matched with data on marital status (2004 2011) from the Central Bureau of Statistics. Linear mixed models with log transformed health care expenditure, generalized linear models and two-part models were used to retrieve standardized levels of monthly health care expenditure of 6,487 older widowed subjects in the 42 months before and after the loss of the spouse. RESULTS: Mean monthly health care expenditure in married subjects was ? 502 in the 42 months before the death of the spouse, and expenditure levels rose by ? 239 (48%) in the 42 months after the death of the spouse. The increase in expenditure after the death of the spouse was highest for men (? 319; 59%) and the oldest old (? 553; 82%). Expenditure levels showed the highest increase for hospital and home care services (together ? 166). CONCLUSIONS: The loss of the spouse is associated with an increase in health care expenditure. The relatively high rise in long-term care expenses suggests that the loss of informal care is an important determinant of this rise. PMID- 25536041 TI - Managing carbon sinks in rubber (Hevea brasilensis) plantation by changing rotation length in SW China. AB - Extension of the rotation length in forest management has been highlighted in Article 3.4 of the Kyoto Protocol to help the countries in their commitments for reduction in greenhouse gas emissions. CO2FIX Model Ver.3.2 was used to examine the dynamics of carbon stocks (C stocks) in a rubber plantation in South Western China with the changing rotation lengths. To estimate the efficiency of increasing the rotation length as an Article 3.4 activity, study predicted that the rubber production and C stocks of the ecosystem increased with the increasing rotation (25, 30, 35, 40 and 45 years). While comparing the pace of growth both in economical (rubber production) and ecological (C stocks) terms in each rotation, 40 years rotation length showed maximum production and C stocks. After elongation of 40 year rotation to four consecutive cycles, it was concluded that the total C stocks of the ecosystem were 186.65 Mg ha(-1). The longer rotation lengths showed comparatively increased C stocks in below ground C stock after consecutive four rotations. The pace of C input (Mg C ha(-1) yr(-1)) and rubber production indicated that 40 years rotation is best suited for rubber plantation. The study has developed carbon mitigation based on four rotation scenarios. The possible stimulated increase in C stocks of the entire ecosystem after consecutive long rotations indicated that the emphasis must be paid on deciding the rotation of rubber plantation in SW China for reporting under article 3.4 of the Kyoto Protocol. PMID- 25536038 TI - Breaking an epigenetic chromatin switch: curious features of hysteresis in Saccharomyces cerevisiae telomeric silencing. AB - In addition to gene network switches, local epigenetic modifications to DNA and histones play an important role in all-or-none cellular decision-making. Here, we study the dynamical design of a well-characterized epigenetic chromatin switch: the yeast SIR system, in order to understand the origin of the stability of epigenetic states. We study hysteresis in this system by perturbing it with a histone deacetylase inhibitor. We find that SIR silencing has many characteristics of a non-linear bistable system, as observed in conventional genetic switches, which are based on activities of a few promoters affecting each other through the abundance of their gene products. Quite remarkably, our experiments in yeast telomeric silencing show a very distinctive pattern when it comes to the transition from bistability to monostability. In particular, the loss of the stable silenced state, upon increasing the inhibitor concentration, does not seem to show the expected saddle node behavior, instead looking like a supercritical pitchfork bifurcation. In other words, the 'off' state merges with the 'on' state at a threshold concentration leading to a single state, as opposed to the two states remaining distinct up to the threshold and exhibiting a discontinuous jump from the 'off' to the 'on' state. We argue that this is an inevitable consequence of silenced and active regions coexisting with dynamic domain boundaries. The experimental observations in our study therefore have broad implications for the understanding of chromatin silencing in yeast and beyond. PMID- 25536042 TI - Evolution of RNA-protein interactions: non-specific binding led to RNA splicing activity of fungal mitochondrial tyrosyl-tRNA synthetases. AB - The Neurospora crassa mitochondrial tyrosyl-tRNA synthetase (mtTyrRS; CYT-18 protein) evolved a new function as a group I intron splicing factor by acquiring the ability to bind group I intron RNAs and stabilize their catalytically active RNA structure. Previous studies showed: (i) CYT-18 binds group I introns by using both its N-terminal catalytic domain and flexibly attached C-terminal anticodon binding domain (CTD); and (ii) the catalytic domain binds group I introns specifically via multiple structural adaptations that occurred during or after the divergence of Peziomycotina and Saccharomycotina. However, the function of the CTD and how it contributed to the evolution of splicing activity have been unclear. Here, small angle X-ray scattering analysis of CYT-18 shows that both CTDs of the homodimeric protein extend outward from the catalytic domain, but move inward to bind opposite ends of a group I intron RNA. Biochemical assays show that the isolated CTD of CYT-18 binds RNAs non-specifically, possibly contributing to its interaction with the structurally different ends of the intron RNA. Finally, we find that the yeast mtTyrRS, which diverged from Pezizomycotina fungal mtTyrRSs prior to the evolution of splicing activity, binds group I intron and other RNAs non-specifically via its CTD, but lacks further adaptations needed for group I intron splicing. Our results suggest a scenario of constructive neutral (i.e., pre-adaptive) evolution in which an initial non specific interaction between the CTD of an ancestral fungal mtTyrRS and a self splicing group I intron was "fixed" by an intron RNA mutation that resulted in protein-dependent splicing. Once fixed, this interaction could be elaborated by further adaptive mutations in both the catalytic domain and CTD that enabled specific binding of group I introns. Our results highlight a role for non specific RNA binding in the evolution of RNA-binding proteins. PMID- 25536043 TI - Role of hypoxia inducing factor-1beta in alcohol-induced autophagy, steatosis and liver injury in mice. AB - Chronic alcohol causes liver hypoxia and steatosis, which eventually develops into alcoholic liver disease (ALD). While it has been known that alcohol consumption activates hepatic hypoxia inducing factor-1alpha (HIF-1alpha), conflicting results regarding the role of HIF-1alpha in alcohol-induced liver injury and steatosis in mice have been reported. In the present study, we aimed to use hepatocyte-specific HIF-1beta knockout mice to eliminate the possible compensatory effects of the single knockout of the 1alpha subunit of HIF to study the role of HIFs in ALD. C57BL/6 wild type mice were treated with acute ethanol to mimic human binge drinking. Matched wild-type and hepatocyte specific HIF 1beta knockout mice were also subjected to a recently established Gao-binge alcohol model to mimic chronic plus binge conditions, which is quite common in human alcoholics. We found that acute alcohol treatment increased BNIP3 and BNIP3L/NIX expression in primary cultured hepatocytes and in mouse livers, suggesting that HIF may be activated in these models. We further found that hepatocyte-specific HIF-1beta knockout mice developed less steatosis and liver injury following the Gao-binge model or acute ethanol treatment compared with their matched wild type mice. Mechanistically, protection against Gao-binge treatment-induced steatosis and liver injury was likely associated with increased FoxO3a activation and subsequent induction of autophagy in hepatocyte-specific HIF-1beta knockout mice. PMID- 25536045 TI - Rescue of retinal function by BDNF in a mouse model of glaucoma. AB - Vision loss in glaucoma is caused by progressive dysfunction of retinal ganglion cells (RGCs) and optic nerve atrophy. Here, we investigated the effectiveness of BDNF treatment to preserve vision in a glaucoma experimental model. As an established experimental model, we used the DBA/2J mouse, which develops chronic intraocular pressure (IOP) elevation that mimics primary open-angle glaucoma (POAG). IOP was measured at different ages in DBA/2J mice. Visual function was monitored using the steady-state Pattern Electroretinogram (P-ERG) and visual cortical evoked potentials (VEP). RGC alterations were assessed using Brn3 immunolabeling, and confocal microscope analysis. Human recombinant BDNF was dissolved in physiological solution (0.9% NaCl); the effects of repeated intravitreal injections and topical eye BDNF applications were independently evaluated in DBA/2J mice with ocular hypertension. BDNF level was measured in retinal homogenate by ELISA and western blot. We found a progressive decline of P ERG and VEP responses in DBA/2J mice between 4 and 7 months of age, in relationship with the development of ocular hypertension and the reduction of Brn3 immunopositive RGCs. Conversely, repeated intravitreal injections (BDNF concentration = 2 ug/ul, volume = 1 ul, for each injection; 1 injection every four days, three injections over two weeks) and topical eye application of BDNF eye-drops (12 ug/ul, 5 ul eye-drop every 48 h for two weeks) were able to rescue visual responses in 7 month DBA/2J mice. In particular, BDNF topical eye treatment recovered P-ERG and VEP impairment increasing the number of Brn3 immunopositive RGCs. We showed that BDNF effects were independent of IOP reduction. Thus, topical eye treatment with BDNF represents a promisingly safe and feasible strategy to preserve visual function and diminish RGC vulnerability to ocular hypertension. PMID- 25536047 TI - Laminar and spatial localization of the islands of Calleja in mice. AB - The islands of Calleja (IC) are dense clusters of cells localized within the ventral striatum. The IC have been described as variable in both number and localization from animal-to-animal, however, a quantitative investigation of this variability is unavailable. Further, it is presently unknown whether the IC occupy select areas of the olfactory tubercle (OT), the ventral striatum structure which possesses the IC in mice. To address these questions, we examined the IC of adult C57bl/6 mice. As previously noted, we found substantial inter hemispheric and inter-mouse variations in the total number of IC. While the IC were observed in all three cell layers of the OT, the bulk of IC occupied layer iii. The span of the IC along the anterior-posterior and medial-lateral axes of the OT was variant. Further, localizations of the IC within the OT also differed across animals. Notably, the probability of observing an IC in the medial OT was greater than that of observing one in the lateral. These data provide a fundamental characterization of both differences and similarities regarding the IC in mice and will be informative for future in vivo studies seeking to perturb and possibly record from the IC. Further, we predict that inter-animal diversity in the IC may be a mechanism for inter-animal differences in behavior, especially reward-related and motivational behaviors. PMID- 25536046 TI - Roles of nicotinic acetylcholine receptor beta subunit cytoplasmic loops in acute desensitization and single-channel features. AB - To evaluate physiological roles of the large, second cytoplasmic loops (C2) situated between the M3 and M4 transmembrane domains of nicotinic acetylcholine receptor (nAChR) subunits. We have constructed chimeric beta2 (beta2chi) and beta4 (beta4chi) subunits in which the "nested" C2 domains (but not the "proximal" sequences of ~14 residues immediately adjacent to the M3 or M4 domains) of these beta subunits were replaced by the corresponding sequence from the serotonin 5-HT3A receptor subunit. We previously reported that heterologously expressed nAChR containing alpha4 and beta2chi subunits displayed a faster whole cell current decay in its agonist response compared to responses of all-wild-type alpha4beta2-nAChR. This suggests an unexpected, functional role for the C2 domain of the beta2 subunit in alpha4beta2-nAChR acute desensitization. Here we report that there also is faster desensitization of alpha4beta4chi-nAChR relative to alpha4beta4-nAChR stably and heterologously expressed in the human SH-EP1 cell line. In addition, cell-attached, single-channel recording shows that both acetylcholine-activated alpha4beta2chi- and alpha4beta4chi-nAChR have a significantly lower mean open probability, shorter mean open-time, and a longer mean closed-time than their fully wild-type counterparts while not having different conductance amplitudes. These findings reveal microscopic bases for the faster desensitization of alpha4(*)-nAChR containing chimeric instead of wild type beta subunits. Our findings also remain consistent with novel and unexpected roles of beta subunit-nested C2 domains in modulation of alpha4(*)-nAChR function. PMID- 25536048 TI - Neuroprotective effect of hemeoxygenase-1/glycogen synthase kinase-3beta modulators in 3-nitropropionic acid-induced neurotoxicity in rats. AB - The present study has been designed to explore the possible interaction between hemeoxygenase-1 (HO-1) and glycogen synthase kinase-3beta (GSK-3beta) pathway in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. 3-NP produces neurotoxicity by inhibition of the mitochondrial complex II (enzyme succinate dehydrogenase) and by sensitizing the N-methyl-D-aspartate receptor. Recent studies have reported the therapeutic potential of HO-1/GSK-3beta modulators in different neurodegenerative disorders. However, their exact role is yet to be explored. The present study is an attempt to investigate the effect of pharmacological modulation of HO-1/GSK-3beta pathway against 3-NP-induced behavioral, biochemical and molecular alterations in rat. Behavioral observation, oxidative stress, pro-inflammatory [tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta)], HO-1 and GSK-3beta activity were evaluated post 3 NP treatment. Findings of the present study demonstrate a significant alteration in the locomotor activity, motor coordination, oxidative burden (increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidants), pro inflammatory mediators [TNF-alpha, IL-1beta], HO-1 and GSK-3beta activity in 3-NP treated animals. Further, administration of hemin (10- and 30-mg/kg; i.p.) and lithium chloride (LiCl) (25- and 50-mg/kg; i.p.) prevented the alteration in body weight, motor impairments, oxidative stress and cellular markers. In addition, combined administration of hemin (10-mg/kg) and LiCl (25-mg/kg) showed synergistic effect on 3-NP-treated rats. Pretreatment with Tin (IV) protoporphyrin (40 MUM/kg), HO-1 inhibitor reversed the beneficial effect of LiCl and hemin. Outcomes of the present study suggest that HO-1 and GSK-3beta enzymes are involved in the pathophysiology of HD. The modulators of both the pathways might be used as adjuvants or prophylactic therapy for the treatment of HD-like symptoms. PMID- 25536049 TI - Central obesity and high blood pressure in pediatric patients with atopic dermatitis. AB - IMPORTANCE: Atopic dermatitis (AD) is associated with multiple potential risk factors for obesity and high blood pressure (BP), including chronic inflammation, sleep disturbance, and mental health comorbidity. Previous studies found associations between general obesity and AD. However, it is unknown whether AD is associated with central obesity and/or high BP. OBJECTIVES: To determine whether central obesity and high BP are increased in pediatric AD. DESIGN, SETTING, AND PARTICIPANTS: This case-control study performed in multicenter pediatric dermatology practices in the United States recruited 132 children (age range, 4 17 years) with active moderate to severe AD and 143 healthy controls from April 1, 2009, through December 31, 2012. EXPOSURES: Diagnosis and severity of AD assessed by a pediatric dermatologist. MAIN OUTCOMES AND MEASURES: Body mass index, waist circumference, waist to height ratio, systolic BP, and diastolic BP. RESULTS: Moderate to severe AD was associated with body mass index for age and sex of 97th percentile or greater (logistic regression; odds ratio [OR], 2.64; 95% CI, 1.15-6.06), International Obesity Task Force obesity cutoffs (OR, 2.38; 95% CI, 1.06-5.34), waist circumference in the 85th percentile or greater (OR, 3.92; 95% CI, 1.50-10.26), and waist to height ratio of 0.5 or greater (OR, 2.22; 95% CI, 1.10-4.50). Atopic dermatitis was associated with higher BP for age, sex, and height percentiles (systolic BP: OR, 2.94; 95% CI, 1.04-8.36; diastolic BP: OR, 3.68; 95% CI, 1.19-11.37), particularly a systolic BP in the 90th percentile or higher (OR, 2.06; 95% CI, 1.09-3.90), in multivariate models that controlled for demographics, body mass index and waist circumference percentiles, and history of using prednisone or cyclosporine. Atopic dermatitis was associated with higher systolic BP in Hispanics/Latinos (general linear model; beta, .23; 95% CI, .04-.43) and Asians (beta, .16; 95% CI, .03-.30). Severe to very severe AD was associated with systolic BP in the 90th percentile or higher (adjusted OR, 3.14; 95% CI, 1.13-8.70). Atopic dermatitis was associated with a family history of hypertension (adjusted OR, 1.88; 95% CI, 1.14-3.10) and type 2 diabetes mellitus (adjusted OR, 1.64; 95% CI, 1.02-2.68) but not obesity or hyperlipidemia. CONCLUSIONS AND RELEVANCE: Moderate to severe pediatric AD may be associated with central obesity and increased systolic BP. PMID- 25536050 TI - Stark absorption spectroscopy on the carotenoids bound to B800-820 and B800-850 type LH2 complexes from a purple photosynthetic bacterium, Phaeospirillum molischianum strain DSM120. AB - Stark absorption spectroscopy was applied to clarify the structural differences between carotenoids bound to the B800-820 and B800-850 LH2 complexes from a purple photosynthetic bacterium Phaeospirillum (Phs.) molischianum DSM120. The former complex is produced when the bacteria are grown under stressed conditions of low temperature and dim light. These two LH2 complexes bind carotenoids with similar composition, 10% lycopene and 80% rhodopin, each with the same number of conjugated CC double bonds (n=11). Quantitative classical and semi-quantum chemical analyses of Stark absorption spectra recorded in the carotenoid absorption region reveal that the absolute values of the difference dipole moments |DeltaMU| have substantial differences (2 [D/f]) for carotenoids bound to either B800-820 or B800-850 complexes. The origin of this striking difference in the |DeltaMU| values was analyzed using the X-ray crystal structure of the B800 850 LH2 complex from Phs. molischianum DSM119. Semi-empirical molecular orbital calculations predict structural deformations of the major carotenoid, rhodopin, bound within the B800-820 complex. We propose that simultaneous rotations around neighboring CC and CC bonds account for the differences in the 2 [D/f] of the |DeltaMU| value. The plausible position of the rotation is postulated to be located around C21-C24 bonds of rhodopin. PMID- 25536051 TI - Evaluation of the adhesive properties of the cornea by means of optical coherence tomography in patients with meibomian gland dysfunction and lacrimal tear deficiency. AB - OBJECTIVE: The aim was to determine the influence of meibomian gland dysfunction (MGD) and aqueous tear deficiency dry eye (ADDE) on the adhesive properties of the central cornea by means of optical coherence tomography (OCT), and to investigate the relationship between corneal adhesiveness and classical tear tests, as well as the reliability of results, in these lacrimal functional unit disorders. DESIGN: Prospective, case-control study. METHODS: Twenty-eight patients with MGD and 27 patients with ADDE were studied. A group of 32 healthy subjects of similar age and gender distribution served as a control group. The adhesive properties of the anterior corneal surface were measured by OCT, based on the retention time of adhesion marker above it, in all participants. RESULTS: An excellent (>=5 minutes), borderline (within 3-5 minutes), fair (within 1-3 minutes) and poor (<1 minute) values of corneal adhesiveness were found, respectively, in 0%, 7.1%, 64.3% and 28.6% of MGD, in 0%, 7.4%, 63% and 29.6% of ADDE, and in 31.3%, 65.6%, 3.1% and 0% of healthy patients. The differences in time of corneal adhesiveness between MGD and healthy patients, as well as between ADDE and healthy patients, were found to be statistically significant (p<0.001; p<0.001; respectively). Conversely, no statistical significant differences between MGD and ADDE were found (p = 0.952). Data analysis revealed a statistically significant correlation between corneal adhesiveness and clinical tests of dry eye, as well as an excellent degree of inter-rater reliability and reproducibility for OCT measurements (p<0.001). CONCLUSION: ADDE and MGD share similar abnormalities on OCT imaging. Decreased adhesive properties of the anterior cornea were identified as a common feature of MGD and ADDE. This simple OCT approach may provide new clues into the mechanism and evaluation of dry eye syndrome. PMID- 25536052 TI - Involvement of miR-518c-5p to growth and metastasis in oral cancer. AB - We have previously demonstrated that a stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral cancer. Recently, small non coding RNAs, microRNAs (miRNAs) have been shown to be involved in the metastatic process of several types of cancers. However, the miRNAs that contribute to metastases induced by the SDF-1/CXCR4 system in oral cancer are largely unknown. In this study, we examined the metastasis-related miRNAs induced by the SDF-1/CXCR4 system using B88-SDF-1 oral cancer cells, which exhibit functional CXCR4 and distant metastatic potential in vivo. Through miRNA microarray analysis, we identified the upregulation of miR-518c-5p in B88-SDF-1 cells, and confirmed the induction by real-time PCR analysis. Although an LNA based miR-518c-5p inhibitor did not affect cell growth of B88-SDF-1 cells, it did significantly inhibit the migration of the cells. Next, we transfected a miR-518c expression vector into parental B88 cells and CAL27 oral cancer cells and isolated stable transfectants, B88-518c and CAL27-518c cells, respectively. The anchorage-dependent and -independent growth of miR-518c transfectants was significantly enhanced compared with the growth of mock cells. Moreover, we detected the enhanced migration of these cells. The LNA-based miR-518c-5p inhibitor significantly impaired the enhanced cell growth and migration of miR 518c transfectants, indicating that these phenomena were mainly dependent on the expression of miR-518c-5p. Next, we examined the function of miR-518c-5p in vivo. miR-518c transfectants or mock transfectants were inoculated into the masseter muscle or the blood vessels of nude mice. Tumor volume, lymph nodes metastasis, and lung metastasis were significantly increased in the mice inoculated with the miR-518c transfectants. These results indicated that miR-518c-5p regulates the growth and metastasis of oral cancer as a downstream target of the SDF-1/CXCR4 system. PMID- 25536053 TI - Characterization of G6PD genotypes and phenotypes on the northwestern Thailand Myanmar border. AB - Mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in red blood cells with increased susceptibility to oxidative damage. Significant haemolysis can be caused by primaquine and other 8-aminoquinoline antimalarials used for the radical treatment of Plasmodium vivax malaria. The distribution and phenotypes of mutations causing G6PD deficiency in the male population of migrants and refugees in a malaria endemic region on the Thailand-Myanmar border were characterized. Blood samples for G6PD fluorescent spot test (FST), G6PD genotyping, and malaria testing were taken from 504 unrelated males of Karen and Burman ethnicities presenting to the outpatient clinics. The overall frequency of G6PD deficiency by the FST was 13.7%. Among the deficient subjects, almost 90% had the Mahidol variant (487G>A) genotype. The remaining subjects had Chinese-4 (392G>T), Viangchan (871G>A), Acores (595A>G), Seattle (844G>C) and Mediterranean (563C>T) variants. Quantification of G6PD activity was performed using a modification of the standard spectrophotometric assay on a subset of 24 samples with Mahidol, Viangchan, Seattle and Chinese-4 mutations; all samples showed a residual enzymatic activity below 10% of normal and were diagnosed correctly by the FST. Further studies are needed to characterise the haemolytic risk of using 8-aminoquinolines in patients with these genotypes. PMID- 25536054 TI - Role of calcitonin gene-related peptide in functional adaptation of the skeleton. AB - Peptidergic sensory nerve fibers innervating bone and periosteum are rich in calcitonin gene-related peptide (CGRP), an osteoanabolic neurotransmitter. There are two CGRP isoforms, CGRPalpha and CGRPbeta. Sensory fibers are a potential means by which the nervous system may detect and respond to loading events within the skeleton. However, the functional role of the nervous system in the response of bone to mechanical loading is unclear. We used the ulna end-loading model to induce an adaptive modeling response in CGRPalpha and CGRPbeta knockout mouse lines and their respective wildtype controls. For each knockout mouse line, groups of mice were treated with cyclic loading or sham-loading of the right ulna. A third group of mice received brachial plexus anesthesia (BPA) of the loaded limb before mechanical loading. Fluorochrome labels were administered at the time of loading and 7 days later. Ten days after loading, bone responses were quantified morphometrically. We hypothesized that CGRP signaling is required for normal mechanosensing and associated load-induced bone formation. We found that mechanically-induced activation of periosteal mineralizing surface in mice and associated blocking with BPA were eliminated by knockout of CGRPalpha signaling. This effect was not evident in CGRPbeta knockout mice. We also found that mineral apposition responses to mechanical loading and associated BPA blocking were retained with CGRPalpha deletion. We conclude that activation of periosteal mineralizing surfaces in response to mechanical loading of bone is CGRPalpha dependent in vivo. This suggests that release of CGRP from sensory peptidergic fibers in periosteum and bone has a functional role in load-induced bone formation. PMID- 25536057 TI - The novel 10-item asthma prediction tool: external validation in the German MAS birth cohort. AB - BACKGROUND: A novel non-invasive asthma prediction tool from the Leicester Cohort, UK, forecasts asthma at age 8 years based on 10 predictors assessed in early childhood, including current respiratory symptoms, eczema, and parental history of asthma. OBJECTIVE: We aimed to externally validate the proposed asthma prediction method in a German birth cohort. METHODS: The MAS-90 study (Multicentre Allergy Study) recorded details on allergic diseases prospectively in about yearly follow-up assessments up to age 20 years in a cohort of 1,314 children born 1990. We replicated the scoring method from the Leicester cohort and assessed prediction, performance and discrimination. The primary outcome was defined as the combination of parent-reported wheeze and asthma drugs (both in last 12 months) at age 8. Sensitivity analyses assessed model performance for outcomes related to asthma up to age 20 years. RESULTS: For 140 children parents reported current wheeze or cough at age 3 years. Score distribution and frequencies of later asthma resembled the Leicester cohort: 9% vs. 16% (MAS-90 vs. Leicester) of children at low risk at 3 years had asthma at 8 years, at medium risk 45% vs. 48%. Performance of the asthma prediction tool in the MAS-90 cohort was similar (Brier score 0.22 vs. 0.23) and discrimination slightly better than in the original cohort (area under the curve, AUC 0.83 vs. 0.78). Prediction and discrimination were robust against changes of inclusion criteria, scoring and outcome definitions. The secondary outcome 'physicians' diagnosed asthma at 20 years' showed the highest discrimination (AUC 0.89). CONCLUSION: The novel asthma prediction tool from the Leicester cohort, UK, performed well in another population, a German birth cohort, supporting its use and further development as a simple aid to predict asthma risk in clinical settings. PMID- 25536056 TI - Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation. AB - BACKGROUND: Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications. METHODS AND FINDINGS: Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus. CONCLUSIONS: Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary. PMID- 25536060 TI - Lysostaphin-coated titan-implants preventing localized osteitis by Staphylococcus aureus in a mouse model. AB - The increasing incidence of implant-associated infections induced by Staphylococcus aureus (SA) in combination with growing resistance to conventional antibiotics requires novel therapeutic strategies. In the current study we present the first application of the biofilm-penetrating antimicrobial peptide lysostaphin in the context of bone infections. In a standardized implant associated bone infection model in mice beta-irradiated lysostaphin-coated titanium plates were compared with uncoated plates. Coating of the implant was established with a poly(D,L)-lactide matrix (PDLLA) comprising lysostaphin formulated in a stabilizing and protecting solution (SPS). All mice were osteotomized and infected with a defined count of SA. Fractures were fixed with lysostaphin-coated locking plates. Plates uncoated or PDLLA-coated served as controls. All mice underwent debridement and lavage on Days 7, 14, 28 to determine the bacterial load and local immune reaction. Fracture healing was quantified by conventional radiography. On Day 7 bacterial growth in the lavages of mice with lysostaphin-coated plates showed a significantly lower count to the control groups. Moreover, in the lysostaphin-coated plate groups complete fracture healing were observed on Day 28. The fracture consolidation was accompanied by a diminished local immune reaction. However, control groups developed an osteitis with lysis or destruction of the bone and an evident local immune response. The presented approach of terminally sterilized lysostaphin coated implants appears to be a promising therapeutic approach for low grade infection or as prophylactic strategy in high risk fracture care e.g. after severe open fractures. PMID- 25536059 TI - Multiplex networks of cortical and hippocampal neurons revealed at different timescales. AB - Recent studies have emphasized the importance of multiplex networks- interdependent networks with shared nodes and different types of connections--in systems primarily outside of neuroscience. Though the multiplex properties of networks are frequently not considered, most networks are actually multiplex networks and the multiplex specific features of networks can greatly affect network behavior (e.g. fault tolerance). Thus, the study of networks of neurons could potentially be greatly enhanced using a multiplex perspective. Given the wide range of temporally dependent rhythms and phenomena present in neural systems, we chose to examine multiplex networks of individual neurons with time scale dependent connections. To study these networks, we used transfer entropy- an information theoretic quantity that can be used to measure linear and nonlinear interactions--to systematically measure the connectivity between individual neurons at different time scales in cortical and hippocampal slice cultures. We recorded the spiking activity of almost 12,000 neurons across 60 tissue samples using a 512-electrode array with 60 micrometer inter-electrode spacing and 50 microsecond temporal resolution. To the best of our knowledge, this preparation and recording method represents a superior combination of number of recorded neurons and temporal and spatial recording resolutions to any currently available in vivo system. We found that highly connected neurons ("hubs") were localized to certain time scales, which, we hypothesize, increases the fault tolerance of the network. Conversely, a large proportion of non-hub neurons were not localized to certain time scales. In addition, we found that long and short time scale connectivity was uncorrelated. Finally, we found that long time scale networks were significantly less modular and more disassortative than short time scale networks in both tissue types. As far as we are aware, this analysis represents the first systematic study of temporally dependent multiplex networks among individual neurons. PMID- 25536061 TI - Intradermal administration of the Type II heat-labile enterotoxins LT-IIb and LT IIc of enterotoxigenic Escherichia coli enhances humoral and CD8+ T cell immunity to a co-administered antigen. AB - Vaccinations are extremely effective at combating infectious diseases. Many conserved antigen (Ag) targets, however, are poorly immunogenic. Protein subunit vaccines frequently elicit only humoral immune responses and fail to confer protection against serious intracellular pathogens. These barriers to vaccine development are often overcome by the use of appropriate adjuvants. Heat-labile enterotoxins (HLT) produced by enterotoxigenic strains of Escherichia coli are potent adjuvants when administered by mucosal or systemic routes. The efficacy of the type II HLT, however, has not been well-defined when administered by the intradermal (ID) route. Using a murine ID immunization model, the adjuvant properties of LT-IIb and LT-IIc, two type II HLTs, were compared with those of LT I, a prototypical type I HLT. While all three HLT adjuvants enhanced Ag-specific humoral responses to similar levels, LT-IIb and LT-IIc, in contrast to LT-I, induced a more vigorous Ag-specific CD8+ T cell response and proffered faster clearance of Listeria monocytogenes in a challenge model. Additionally, LT-IIb and LT-IIc induced distinct differences in the profiles of the Ag-specific CD8+ T cell responses. While LT-IIc stimulated a robust and rapid primary CD8+ T cell response, LT-IIb exhibited slower CD8+ T cell expansion and contraction kinetics with the formation of higher percentages of effector memory cells. In comparison to LT-I and LT-IIc, LT-IIb evoked better long-term protection after immunization. Furthermore, LT-IIb and LT-IIc enhanced the total number of dendritic cells (DC) in the draining lymph node (DLN) and expression of costimulatory molecules CD80, CD86, and CD40 on DCs. In contrast to LT-I, LT-IIb and LT-IIc induced less edema, cellular infiltrates, and general inflammation at the site of ID injection. Thus, LT-IIb and LT-IIc are attractive comprehensive ID adjuvants with unique characteristic that enhance humoral and cellular immunity to a co-administered protein Ag. PMID- 25536055 TI - Genetic diversity of Giardia duodenalis: multilocus genotyping reveals zoonotic potential between clinical and environmental sources in a metropolitan region of Brazil. AB - BACKGROUND: Giardia duodenalis is a flagellate protozoan that parasitizes humans and several other mammals. Protozoan contamination has been regularly documented at important environmental sites, although most of these studies were performed at the species level. There is a lack of studies that correlate environmental contamination and clinical infections in the same region. The aim of this study is to evaluate the genetic diversity of a set of clinical and environmental samples and to use the obtained data to characterize the genetic profile of the distribution of G. duodenalis and the potential for zoonotic transmission in a metropolitan region of Brazil. METHODOLOGY/PRINCIPAL FINDINGS: The genetic assemblages and subtypes of G. duodenalis isolates obtained from hospitals, a veterinary clinic, a day-care center and important environmental sites were determined via multilocus sequence-based genotyping using three unlinked gene loci. Cysts of Giardia were detected at all of the environmental sites. Mixed assemblages were detected in 25% of the total samples, and an elevated number of haplotypes was identified. The main haplotypes were shared among the groups, and new subtypes were identified at all loci. Ten multilocus genotypes were identified: 7 for assemblage A and 3 for assemblage B. CONCLUSIONS/SIGNIFICANCE: There is persistent G. duodenalis contamination at important environmental sites in the city. The identified mixed assemblages likely represent mixed infections, suggesting high endemicity of Giardia in these hosts. Most Giardia isolates obtained in this study displayed zoonotic potential. The high degree of genetic diversity in the isolates obtained from both clinical and environmental samples suggests that multiple sources of infection are likely responsible for the detected contamination events. The finding that many multilocus genotypes (MLGs) and haplotypes are shared by different groups suggests that these sources of infection may be related and indicates that there is a notable risk of human infection caused by Giardia in this region. PMID- 25536063 TI - Implications of targeted genomic disruption of beta-catenin in BxPC-3 pancreatic adenocarcinoma cells. AB - Pancreatic adenocarcinoma (PA) is among the most aggressive human tumors with an overall 5-year survival rate of <5% and available treatments are only minimal effective. WNT/beta-catenin signaling has been identified as one of 12 core signaling pathways that are commonly mutated in PA. To obtain more insight into the role of WNT/beta-catenin signaling in PA we established human PA cell lines that are deficient of the central canonical WNT signaling protein beta-catenin by using zinc-finger nuclease (ZFN) mediated targeted genomic disruption in the beta catenin gene (CTNNB1). Five individual CTNNB1 gene disrupted clones (BxPC3DeltaCTNNB1) were established from a BxPC-3 founder cell line. Despite the complete absence of beta-catenin, all clones displayed normal cell cycle distribution profiles, overall normal morphology and no elevated levels of apoptosis although increased doubling times were observed in three of the five BxPC3DeltaCTNNB1 clones. This confirms that WNT/beta-catenin signaling is not mandatory for long term cell growth and survival in BxPC-3 cells. Despite a normal morphology of the beta-catenin deficient cell lines, quantitative proteomic analysis combined with pathway analysis showed a significant down regulation of proteins implied in cell adhesion combined with an up-regulation of plakoglobin. Treatment of BxPC3DeltaCTNNB1 cell lines with siRNA for plakoglobin induced morphological changes compatible with a deficiency in the formation of functional cell to cell contacts. In addition, a re-localization of E-cadherin from membranous in untreated to accumulation in cytoplasmatic puncta in plakoglobin siRNA treated BxPC3DeltaCTNNB1 cells was observed. In conclusion we describe in beta-catenin deficient BxPC-3 cells a rescue function for plakoglobin on cell to cell contacts and maintaining the localization of E-cadherin at the cellular surface, but not on canonical WNT signaling as measured by TFC/LEF mediated transcription. PMID- 25536065 TI - E-health use in african american internet users: can new tools address old disparities? AB - OBJECTIVE: Web-based health information may be of particular value among the African American population due to its potential to reduce communication inequalities and empower minority groups. This study explores predictors of e health behaviors and activities for African American Internet users. MATERIALS AND METHODS: We used the 2010 Pew Internet and American Life Health Tracking Survey to examine sociodemographic and health status predictors of e-health use behaviors among African Americans. E-health use behaviors included searching for e-health information, conducting interactive health-related activities, and tracking health information online. RESULTS: In the African American subsample, 55% (n=395) were at least "occasional" Internet users. Our model suggests that searching for health information online was positively associated with being helped/knowing someone helped by online information (odds ratio [OR]=5.169) and negatively associated with lower income (OR=0.312). Interactive health activities were associated with having a college education (OR=3.264), being 65 years of age or older (OR=0.188), having a family member living with chronic conditions (OR=2.191), having a recent medical crisis (OR=2.863), and being helped/knowing someone helped by online information (OR=8.335). E-tracking behaviors were significantly stronger among African Americans who had health insurance (OR=3.907), were helped/knowing someone helped by online information (OR=4.931), and were social media users (OR=4.799). CONCLUSIONS: Findings suggest significant differences in e-health information-seeking behaviors among African American Internet users-these differences are mostly related to personal and family health concerns and experiences. Targeted online e-health resources and interventions can educate and empower a significant subset of the population. PMID- 25536064 TI - Factors associated with tobacco smoking and cessation among HIV-infected individuals under care in Rio de Janeiro, Brazil. AB - Worldwide the prevalence of smoking among people living with HIV/AIDS is elevated compared to the general population. This probably reflects the cluster of individual characteristics that have shared risk factors for HIV infection and smoking. A cross-sectional study, enrolling a convenience sample from a Brazilian HIV clinical cohort was conducted to evaluate the prevalence of tobacco smoking and the factors associated with current smoking and abstinence. A total of 2,775 HIV-infected individuals were interviewed: 46.2% have never smoked, 29.9% were current smokers and 23.9% were former smokers. Current smokers had a higher prevalence of alcohol and illicit drug use when compared to the other two groups. A higher proportion of heterosexual individuals were former smokers or never smokers while among men who have sex with men (MSM) a higher proportion were current smokers. Former smokers had been more frequently diagnosed with high blood pressure, diabetes mellitus, cardiovascular diseases and depression, while for current smokers lung diseases were more frequent. Former smokers and current smokers were more likely to have had any hospital admission (42.0% and 41.2%, respectively) than participants who never smoked (33.5%) (p<0.001). Multivariate model results showed that current smokers (versus never smokers) were more likely to be less educated, to report the use of alcohol, crack and cocaine and to present clinical comorbidities. Former smokers (versus current smokers) were more likely to be older, to have smoked for a shorter amount of time and to have smoked >31 cigarettes/day. MSM (compared to heterosexuals) and cocaine users (versus non-users) had lower odds of being former smokers. Considering our results, smoking cessation interventions should be tailored to younger individuals, MSM and substance users. PMID- 25536066 TI - Interpretation of the longitudinal (13)C nuclear spin relaxation and chemical shift data for five bromoazaheterocycles supported by nonrelativistic and relativistic DFT calculations. AB - The longitudinal relaxation times of (13)C nuclei and NOE enhancement factors for 2-bromopyridine (1), 6-bromo-9-methylpurine (2), 3,5-dibromopyridine (3), 2,4 dibromopyrimidine (4), and 2,4,6-tribromopyrimidine (5) have been measured at 25 degrees C and B0 = 11.7 T. The most important contributions to the overall relaxation rates of nonbrominated carbons, i.e., the relaxation rates due to the (13)C-(1)H dipolar interactions and the shielding anisotropy mechanism, have been separated out. For 3 and 5, additionally, the T2,Q((14)N) values have been established from (14)N NMR line widths. All of these data have been used to determine rotational diffusion tensors for the investigated molecules. The measured saturation recovery curves of brominated carbons have been decomposed into two components to yield relaxation times, which after proper corrections provided parameters characterizing the scalar relaxation of the second kind for (13)C nuclei of (79)Br- and (81)Br-bonded carbons. These parameters and theoretically calculated quadrupole coupling constants for bromine nuclei have allowed the values of one-bond (13)C-(79)Br spin-spin coupling constants to be calculated. Independently, the coupling constants and magnetic shielding constants of the carbon nuclei have been calculated theoretically using the nonrelativistic and relativistic DFT methods F/6-311++G(2d,p)/PCM and so ZORA/F/TZ2P/COSMO (F = BHandH or B3LYP), respectively. The agreement between the experimental and theoretical values of these parameters is remarkably dependent on the theoretical method used. PMID- 25536067 TI - On the role of the patella, ACL and joint contact forces in the extension of the knee. AB - Traditional descriptions of the knee suggest that the function of the patella is to facilitate knee extension by increasing the moment arm of the quadriceps muscles. Through modelling and evidence from the literature it is shown in this paper that the presence of the patella makes the ability of the quadriceps to rotate the thigh greater than their ability to rotate the tibia. Furthermore, this difference increases as the knee is flexed, thus demonstrating a pattern that is consistent with many human movements. This paper also shows that the anterior cruciate ligament plays a previously unheralded role in extending the shank and that translation at the tibiofemoral and patellofemoral joints is important in improving the capacity for thigh rotation when the knee is flexed. This study provides new insights as to how the structure of the knee is adapted to its purpose and illustrates how the functional anatomy of the knee contributes to its extension function. PMID- 25536068 TI - Participants' perceptions of a group based program incorporating hands-on meal preparation and pedometer-based self-monitoring in type 2 diabetes. AB - BACKGROUND: Nutrition education (portion sizes, balanced meals) is a cornerstone of diabetes management; however, moving from information to behavior change is challenging. Through a single arm intervention study, we recently demonstrated that combining education with group-based meal preparation training has measureable effects on weight, eating behaviour, and glycemic control in adults with type 2 diabetes. In the present study, we conducted an in-depth examination of participants' perceptions of this strategy, through focus group discussion, to delineate effective elements of the strategy from participants' perspectives. METHODS: Participants who had completed the nutrition education/meal preparation training program were invited to attend one of four focus group discussions. These were led by experienced facilitators and guided by questions addressing experiences during the intervention and their perceived impact. Audiotapes were transcribed and qualitative content analysis of transcripts was performed. We report herein themes that achieved saturation across the four discussions. RESULTS: Twenty-nine (80.6%, 29/36) attended a focus group discussion. The program elements perceived as effective by participants included the hands-on interactive learning approach to meal preparation, the grocery store tour, pedometer-based self-monitoring, experiencing the link between food consumption/physical activity and glucose changes during the program, and peer support. Discussants reported changes in eating and walking behaviour, greater confidence in ability to self-manage diabetes, reductions in glucose levels and/or need for glucose-lowering medications, and, in some cases, weight loss. Family members and friends were facilitators for some and barriers for others in terms of achieving health behavior changes. CONCLUSIONS: Among adults with type 2 diabetes, a group based program that included hands-on meal preparation and pedometer-based self-monitoring was perceived as effective in conveying information, developing skills, building confidence, and changing health behaviors. PMID- 25536069 TI - The increased risk of road crashes in attention deficit hyperactivity disorder (ADHD) adult drivers: driven by distraction? Results from a responsibility case control study. AB - BACKGROUND AND OBJECTIVE: Both distractions (external and internal) and attention deficit/hyperactivity disorder (ADHD) are serious risk factors for traffic crashes and injuries. However, it is still unknown if ADHD (a chronic condition) modifies the effect of distractions (irregular hazards) on traffic crashes. The objective of this study was to assess the effects of distractions and ADHD on traffic crash responsibility. METHODS: A responsibility case-control study was conducted in the adult emergency department of Bordeaux University Hospital, France. Subjects were recruited among drivers injured in a motor vehicle crash between April 2010 and August 2011. Responsibility levels were estimated using a standardized method. Frequencies of exposures were compared between drivers responsible and drivers not responsible for the crash. Independent risk factors were identified using a multivariate logistic regression including test interactions between distractions and ADHD. RESULTS: A total of 777 subjects were included in the analysis. Factors associated with responsibility were distraction induced by an external event (adjusted OR (aOR) = 1.47; 95% confidence interval (CI) [1.06-2.05]), distraction induced by an internal thought (aOR = 2.38; CI: [1.50-3.77]) and ADHD (aOR = 2.18 CI: [1.22-3.88]). The combined effect of ADHD and external distractions was strongly associated with responsibility for the crash (aOR = 5.79 CI: [2.06-16.32]). Interaction assessment showed that the attributable proportion due to the interaction among participants with both exposures was 68%. DISCUSSION: Adults with ADHD are a population at higher risk of being responsible for a road traffic crash when exposed to external distractions. This result reinforces the need to diagnose adult ADHD and to include road safety awareness messages delivered by the physician. Developing advanced driver assistance systems devoted to the management of attention lapses is also increasingly relevant for these drivers. PMID- 25536070 TI - Fungal endophytes of Alpinia officinarum rhizomes: insights on diversity and variation across growth years, growth sites, and the inner active chemical concentration. AB - In the present study, the terminal-restriction fragment length polymorphism (T RFLP) technique, combined with the use of a clone library, was applied to assess the baseline diversity of fungal endophyte communities associated with rhizomes of Alpinia officinarum Hance, a medicinal plant with a long history of use. A total of 46 distinct T-RFLP fragment peaks were detected using HhaI or MspI mono digestion-targeted, amplified fungal rDNA ITS sequences from A. officinarum rhizomes. Cloning and sequencing of representative sequences resulted in the detection of members of 10 fungal genera: Pestalotiopsis, Sebacina, Penicillium, Marasmius, Fusarium, Exserohilum, Mycoleptodiscus, Colletotrichum, Meyerozyma, and Scopulariopsis. The T-RFLP profiles revealed an influence of growth year of the host plant on fungal endophyte communities in rhizomes of this plant species; whereas, the geographic location where A. officinarum was grown contributed to only limited variation in the fungal endophyte communities of the host tissue. Furthermore, non-metric multidimensional scaling (NMDS) analysis across all of the rhizome samples showed that the fungal endophyte community assemblages in the rhizome samples could be grouped according to the presence of two types of active indicator chemicals: total volatile oils and galangin. Our present results, for the first time, address a diverse fungal endophyte community is able to internally colonize the rhizome tissue of A. officinarum. The diversity of the fungal endophytes found in the A. officinarum rhizome appeared to be closely correlated with the accumulation of active chemicals in the host plant tissue. The present study also provides the first systematic overview of the fungal endophyte communities in plant rhizome tissue using a culture-independent method. PMID- 25536071 TI - Hepatic hemodynamics and fetal growth: a relationship of interest for further research. AB - BACKGROUND: It is well known that hepatic hemodynamics is an important physiologic mechanism in the regulation of cardiac output (CO). It has been reported that maternal cardiac output relates to neonatal weight at birth. AIMS: In this study, we assessed the correlation between maternal hepatic vein Doppler flow parameters, cardiac output and neonatal birth weight. METHODS: Healthy women with uncomplicated second or third trimester pregnancy attending the outpatient antenatal clinic of Ziekenhuis Oost-Limburg in Genk (Belgium), had a standardized combined electrocardiogram-Doppler ultrasound with Impedance Cardiography, for measurement of Hepatic Vein Impedance Index (HVI = [maximum velocity - minimum velocity]/maximum velocity), venous pulse transit time (VPTT = time interval between corresponding ECG and Doppler wave characteristics) and cardiac output (heart rate x stroke volume). After delivery, a population-specific birth weight chart, established from a cohort of 27000 neonates born in the index hospital, was used to define customized birth weight percentiles (BW%). Correlations between HVI, VPTT, CO and BW% were calculated using Spearman's rho, linear regression analysis and R2 goodness of fit in SPSS 22.0. RESULTS: A total of 73 women were included. There was a negative correlation between HVI and VPTT (rho = -0.719, p < 0.001). Both HVI and VPTT correlated with CO (rho = -0.403, p < 0.001 and rho = 0.332, p < 0.004 resp.) and with BW% (rho = -0.341, p < 0.003 and rho = 0.296, p < 0.011 resp.). CONCLUSION: Our data illustrate that the known contribution of hepatic hemodynamics in the regulation of cardiac output is also true for women with uncomplicated pregnancies. Our study is the first to illustrate a potential link between maternal hepatic hemodynamics and neonatal birth weight. Whether this link is purely associative or whether hepatic vascular physiology has a direct impact on fetal growth is to be evaluated in more extensive clinical and experimental research. PMID- 25536072 TI - Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries. AB - BACKGROUND: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decision making. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peer-reviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. METHODS AND FINDINGS: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2 = 94.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2 = 98.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6-2.5). The probability of publication within two years after study completion ranged from 7% to 30%. CONCLUSIONS: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased. PMID- 25536073 TI - Measuring affinity constants of 1450 monoclonal antibodies to peptide targets with a microarray-based label-free assay platform. AB - Monoclonal antibodies (mAbs) are major reagents for research and clinical diagnosis. For their inherently high specificities to intended antigen targets and thus low toxicity in general, they are pursued as one of the major classes of new drugs. Yet binding properties of most monoclonal antibodies are not well characterized in terms of affinity constants and how they vary with presentations and/or conformational isomers of antigens, buffer compositions, and temperature. We here report a microarray-based label-free assay platform for high-throughput measurements of monoclonal antibody affinity constants to antigens immobilized on solid surfaces. Using this platform we measured affinity constants of over 1410 rabbit monoclonal antibodies and 46 mouse monoclonal antibodies to peptide targets that are immobilized through a terminal cysteine residue to a glass surface. The experimentally measured affinity constants vary from 10 pM to 200 pM with the median value at 66 pM. We compare the results obtained from the microarray-based platform with those from a benchmarking surface-plasmon resonance-based (SPR) sensor (Biacore 3000). PMID- 25536075 TI - Isolation of Tacaribe virus, a Caribbean arenavirus, from host-seeking Amblyomma americanum ticks in Florida. AB - Arenaviridae are a family of single stranded RNA viruses of mammals and boid snakes. Twenty-nine distinct mammalian arenaviruses have been identified, many of which cause severe hemorrhagic disease in humans, particularly in parts of sub Saharan Africa, and in Central and South America. Humans typically become infected with an arenavirus through contact with excreta from infected rodents. Tacaribe virus (TCRV) is an arenavirus that was first isolated from bats and mosquitoes during a rabies surveillance survey conducted in Trinidad from 1956 to 1958. Tacaribe virus is unusual because it has never been associated with a rodent host and since that one time isolation, the virus has not been isolated from any vertebrate or invertebrate hosts. We report the re-isolation of the virus from a pool of 100 host-seeking Amblyomma americanum (lone star ticks) collected in a Florida state park in 2012. TCRV was isolated in two cell lines and its complete genome was sequenced. The tick-derived isolate is nearly identical to the only remaining isolate from Trinidad (TRVL-11573), with 99.6% nucleotide identity across the genome. A quantitative RT-PCR assay was developed to test for viral RNA in host-seeking ticks collected from 3 Florida state parks. Virus RNA was detected in 56/500 (11.2%) of surveyed ticks. As this virus was isolated from ticks that parasitize humans, the ability of the tick to transmit the virus to people should be evaluated. Furthermore, reservoir hosts for the virus need to be identified in order to develop risk assessment models of human infection. PMID- 25536074 TI - Interrogation of the Burkholderia pseudomallei genome to address differential virulence among isolates. AB - Infection by the Gram-negative pathogen Burkholderia pseudomallei results in the disease melioidosis, acquired from the environment in parts of southeast Asia and northern Australia. Clinical symptoms of melioidosis range from acute (fever, pneumonia, septicemia, and localized infection) to chronic (abscesses in various organs and tissues, most commonly occurring in the lungs, liver, spleen, kidney, prostate and skeletal muscle), and persistent infections in humans are difficult to cure. Understanding the basic biology and genomics of B. pseudomallei is imperative for the development of new vaccines and therapeutic interventions. This formidable task is becoming more tractable due to the increasing number of B. pseudomallei genomes that are being sequenced and compared. Here, we compared three B. pseudomallei genomes, from strains MSHR668, K96243 and 1106a, to identify features that might explain why MSHR668 is more virulent than K96243 and 1106a in a mouse model of B. pseudomallei infection. Our analyses focused on metabolic, virulence and regulatory genes that were present in MSHR668 but absent from both K96243 and 1106a. We also noted features present in K96243 and 1106a but absent from MSHR668, and identified genomic differences that may contribute to variations in virulence noted among the three B. pseudomallei isolates. While this work contributes to our understanding of B. pseudomallei genomics, more detailed experiments are necessary to characterize the relevance of specific genomic features to B. pseudomallei metabolism and virulence. Functional analyses of metabolic networks, virulence and regulation shows promise for examining the effects of B. pseudomallei on host cell metabolism and will lay a foundation for future prediction of the virulence of emerging strains. Continued emphasis in this area will be critical for protection against melioidosis, as a better understanding of what constitutes a fully virulent Burkholderia isolate may provide for better diagnostic and medical countermeasure strategies. PMID- 25536078 TI - Solid-supported hydrazone of 4-(4'-formyl-3'-methoxyphenoxy)butyric acid as a new traceless linker for solid-phase synthesis. AB - The use of a hydrazine derived from a backbone amide linker as a new hydrazone based traceless linker for solid-phase organic synthesis is described. The stability of the linker was tested under various conditions, including treatment with acids, bases, and borohydrides. Final compounds can be released by selective cleavage using trimethylsilanolate. To demonstrate the versatility of the linker, the synthesis of a model compound under various reaction conditions was performed with good results. PMID- 25536077 TI - Overexpression of CD90 (Thy-1) in pancreatic adenocarcinoma present in the tumor microenvironment. AB - CD90 (Thy-1) plays important roles in oncogenesis and shows potential as a candidate marker for cancer stem cells (CSCs) in various malignancies. Herein, we investigated the expression of CD90 in pancreatic adenocarcinoma (PDAC), with a comparison to normal pancreas and non-malignant pancreatic disease, by immunohistochemical (IHC) analysis of tissue microarrays containing 183 clinical tissue specimens. Statistical analysis was performed to evaluate the correlation between CD90 expression and the major clinicopathological factors after adjustment of age and gender. The IHC data showed that CD90 was significantly overexpressed in PDAC and its metastatic cancers as compared to chronic pancreatitis and benign islet tumors, while it was negative in normal pancreas and 82.7% of adjacent normal pancreas tissues. The abundant CD90 expression was predominantly present in PDAC stroma, such as fibroblasts and vascular endothelial cells, which could serve as a promising marker to distinguish pancreatic adenocarcinoma from normal pancreas and non-malignant pancreatic diseases. Double immunostaining of CD90 with CD24, a CSC marker for PDAC, showed that there was little overlap between these two markers. However, CD90+ fibroblast cells were clustered around CD24+ malignant ducts, suggesting that CD90 may be involved in the tumor-stroma interactions and promote pancreatic cancer development. Furthermore, CD90 mostly overlapped with alpha-smooth muscle actin (alphaSMA, a marker of activated pancreatic stellate cells (PSCs)) in PDAC stroma, which demonstrated that CD90+ stromal cells consist largely of activated PSCs. Double immunostaining of CD90 and a vascular endothelial cell marker CD31 demonstrated that CD90 expression on vascular endothelial cells was significantly increased in PDACs as compared to normal pancreas and non-malignant pancreatic diseases. Our findings suggest that CD90 could serve as a promising marker for pancreatic adenocarcinoma where desmoplastic stroma plays an important role in tumor growth and angiogenesis. PMID- 25536079 TI - The relationship between secondhand smoke exposure, pro-tobacco social influences, and smoking susceptibility among nonsmoking Zambian adolescents. AB - BACKGROUND: We tested the hypothesis that the extent of secondhand smoke (SHS) exposure among nonsmoking adolescents would be associated with their overall exposure to pro-tobacco social influences. METHODS: Data were analyzed using descriptive and multivariate methods from the 2011 Zambia Global Youth Tobacco Survey. RESULTS: The odds of SHS exposure increased with increasing exposure to pro-tobacco advertisements. About 39.5% of the gap in SHS exposure between nonsmokers with low versus high smoking susceptibility was attributable to differences in parental or peer smoking. CONCLUSIONS: Sustained efforts are needed to denormalize tobacco use in order to reduce youth susceptibility to tobacco use. PMID- 25536076 TI - Patterns in place of cancer death in the State of Qatar: a population-based study. AB - BACKGROUND: International studies show that most people prefer to die at home; however, hospitals remain the most common place of death (PoD). This study aims to investigate the patterns in PoD and the associated factors, which are crucial for end-of-life cancer care enhancement. METHOD: This retrospective, population based study analyzed all registered cancer deaths in Qatar between January 1, 2006 and December 31, 2012 (n = 1,224). The main outcome measures were patient characteristics: age, gender, nationality, cancer diagnosis, year of death, and PoD. Time trends for age-standardized proportions of death in individual PoDs were evaluated using chi-square analysis. Odds ratio (OR) were determined for variables associated with the most preferred (acute palliative care unit [APCU] and hematology/oncology ward) versus least preferred (ICU and general medicine ward) PoDs in Qatar, stratified by nationality. RESULTS: The hematology/oncology ward was the most common PoD (32.4%; 95% CI 26.7-35.3%) followed by ICU (31.4%; 95% CI 28.7-34.3%), APCU (26.9%; 95% CI 24.3-29.6%), and general medicine ward (9.2%; 95% CI 7.6-11.1%). APCU trended upward (+0.057/year; p<0.001), while the hematology/oncology ward trended downward (-0.055/year; p<0.001). No statistically significant changes occurred in the other PoDs; home deaths remained low (0.4%; 95% Cl 0.38-0.42). Qataris who died from liver cancer (OR 0.23) and aged 65 or older (OR 0.64) were less likely to die in the APCU or hematology/oncology ward (p<0.05). Non-Qataris who died from pancreatic cancer (OR 3.12) and female (OR 2.05) were more likely to die in the APCU or hematology/oncology ward (p<0.05). Both Qataris and non-Qataris who died from hematologic malignancy (OR 0.18 and 0.41, respectively) were more likely to die in the ICU or general medicine ward (p<0.05). CONCLUSION: A high percentage of cancer deaths in Qatar occur in hospital. As home was the preferred PoD for most people, effective home care and hospice programs are needed to improve end-of life cancer care. PMID- 25536083 TI - A systematic review of behavioural interventions to increase maternal calcium intake. AB - Pregnancy and lactation are a time when adequate calcium consumption is essential for the development of the fetus and to ensure the health of the mother. Over 50% of Canadian women of childbearing and rearing age fail to meet the recommended daily intake of calcium. Identification of effective behavioural intervention strategies for increasing calcium intake is needed within this specific population. This paper brings together all published behavioural interventions designed to increase calcium consumption in pregnant, lactating or post-partum mothers in a systematic review. Relevant studies were obtained through searches of MEDLINE, EMBASE, PsycINFO, CINAHL and the Cochrane Library with no date restrictions. Studies were evaluated using previously published criteria for evaluating calcium behaviour change interventions. This systematic literature review identified five behavioural calcium interventions conducted within this population. Three interventions aimed to improve overall dietary behaviours, the fourth aimed to promote breastfeeding (including increasing calcium consumption) and the fifth aimed to increase daily servings of yoghurt. Only one of the five interventions yielded large effect sizes, with a mean change of 954 mg of calcium per day post-intervention. The number of behavioural change techniques did not appear to be related to intervention efficacy. Only one study used a theoretical framework to guide the intervention. This review highlights the lack of research examining behaviour change interventions aimed at increasing calcium consumption in pregnant, lactating and post-partum women and provides practical suggestions for researchers wishing to intervene with this population in the future. PMID- 25536080 TI - Degradation of acetaldehyde and its precursors by Pelobacter carbinolicus and P. acetylenicus. AB - Pelobacter carbinolicus and P. acetylenicus oxidize ethanol in syntrophic cooperation with methanogens. Cocultures with Methanospirillum hungatei served as model systems for the elucidation of syntrophic ethanol oxidation previously done with the lost "Methanobacillus omelianskii" coculture. During growth on ethanol, both Pelobacter species exhibited NAD+-dependent alcohol dehydrogenase activity. Two different acetaldehyde-oxidizing activities were found: a benzyl viologen reducing enzyme forming acetate, and a NAD+-reducing enzyme forming acetyl-CoA. Both species synthesized ATP from acetyl-CoA via acetyl phosphate. Comparative 2D PAGE of ethanol-grown P. carbinolicus revealed enhanced expression of tungsten dependent acetaldehyde: ferredoxin oxidoreductases and formate dehydrogenase. Tungsten limitation resulted in slower growth and the expression of a molybdenum dependent isoenzyme. Putative comproportionating hydrogenases and formate dehydrogenase were expressed constitutively and are probably involved in interspecies electron transfer. In ethanol-grown cocultures, the maximum hydrogen partial pressure was about 1,000 Pa (1 mM) while 2 mM formate was produced. The redox potentials of hydrogen and formate released during ethanol oxidation were calculated to be EH2 = -358+/-12 mV and EHCOOH = -366+/-19 mV, respectively. Hydrogen and formate formation and degradation further proved that both carriers contributed to interspecies electron transfer. The maximum Gibbs free energy that the Pelobacter species could exploit during growth on ethanol was -35 to -28 kJ per mol ethanol. Both species could be cultivated axenically on acetaldehyde, yielding energy from its disproportionation to ethanol and acetate. Syntrophic cocultures grown on acetoin revealed a two-phase degradation: first acetoin degradation to acetate and ethanol without involvement of the methanogenic partner, and subsequent syntrophic ethanol oxidation. Protein expression and activity patterns of both Pelobacter spp. grown with the named substrates were highly similar suggesting that both share the same steps in ethanol and acetalydehyde metabolism. The early assumption that acetaldehyde is a central intermediate in Pelobacter metabolism was now proven biochemically. PMID- 25536084 TI - Interplanting annual ryegrass, wheat, oat, and corn to mitigate iron deficiency in dry beans. AB - This study evaluated whether grass intercropping can be used to alleviate Fe deficiency chlorosis in dry beans (Phaseolus vulgaris L.) grown in high pH, calcareous soils with low organic matter. Field studies were conducted at the University of Wyoming Sustainable Agriculture Research and Extension Center in 2009 and 2010. Black- and navy beans were grown alone or intercropped with annual ryegrass (Lolium multiflorum Lam.), oat (Avena sativa L.), corn (Zea mays L.), or spring wheat (Triticum aestivum L.) in a two-factor factorial strip-plot randomized complete block design. All four grass species increased chlorophyll intensity in dry beans. However, grass species did not increase iron (Fe) concentration in dry bean tissues suggesting inefficient utilization of Fe present in the dry bean tissues. In 2009, nitrate-nitrogen (NO3-N) and manganese (Mn) concentration in bean tissue were greater in bean monoculture than in grass intercropped beans. Bean monoculture also had greater soil NO3-N concentrations than grass intercropped treatments. In 2009, grass intercrops reduced dry bean yield >25% compared to bean monoculture. Annual ryegrass was the least competitive of the four annual grass species. This suggests that competition from grasses for nutrients, water, or light may have outweighed benefits accruing from grass intercropping. Additional studies are required to determine the appropriate grass and dry bean densities, as well as the optimum time of grass removal. PMID- 25536081 TI - Visualization of subunit interactions and ternary complexes of protein phosphatase 2A in mammalian cells. AB - Protein phosphatase 2A (PP2A) is a ubiquitous phospho-serine/threonine phosphatase that controls many diverse cellular functions. The predominant form of PP2A is a heterotrimeric holoenzyme consisting of a scaffolding A subunit, a variable regulatory B subunit, and a catalytic C subunit. The C subunit also associates with other interacting partners, such as alpha4, to form non-canonical PP2A complexes. We report visualization of PP2A complexes in mammalian cells. Bimolecular fluorescence complementation (BiFC) analysis of PP2A subunit interactions demonstrates that the B subunit plays a key role in directing the subcellular localization of PP2A, and confirms that the A subunit functions as a scaffold in recruiting the B and C subunits to form a heterotrimeric holoenzyme. BiFC analysis also reveals that alpha4 promotes formation of the AC core dimer. Furthermore, we demonstrate visualization of specific ABC holoenzymes in cells by combining BiFC and fluorescence resonance energy transfer (BiFC-FRET). Our studies not only provide direct imaging data to support previous biochemical observations on PP2A complexes, but also offer a promising approach for studying the spatiotemporal distribution of individual PP2A complexes in cells. PMID- 25536085 TI - Psychological sequelae of the station nightclub fire: Comparing survivors with and without physical injuries using a mixed-methods analysis. AB - BACKGROUND: Surveying survivors from a large fire provides an opportunity to explore the impact of emotional trauma on psychological outcomes. METHODS: This is a cross-sectional survey of survivors of The Station Fire. Primary outcomes were post-traumatic stress (Impact of Event Scale - Revised) and depressive (Beck Depression Inventory) symptoms. Linear regression was used to examine differences in symptom profiles between those with and without physical injuries. The free response section of the survey was analyzed qualitatively to compare psychological sequelae of survivors with and without physical injuries. RESULTS: 104 participants completed the study survey; 47% experienced a burn injury. There was a 42% to 72% response rate range. The mean age of respondents was 32 years, 62% were male, and 47% experienced a physical injury. No significant relationships were found between physical injury and depressive or post-traumatic stress symptom profiles. In the qualitative analysis, the emotional trauma that survivors experienced was a major, common theme regardless of physical injury. Survivors without physical injuries were more likely to experience survivor guilt, helplessness, self-blame, and bitterness. Despite the post-fire challenges described, most survivors wrote about themes of recovery and renewal. CONCLUSIONS: All survivors of this large fire experienced significant psychological sequelae. These findings reinforce the importance of mental health care for all survivors and suggest a need to understand factors influencing positive outcomes. PMID- 25536086 TI - Honey for acute cough in children. AB - BACKGROUND: Cough causes concern for parents and is a major cause of outpatient visits. It can impact on quality of life, cause anxiety and affect sleep in parents and children. Several remedies, including honey, have been used to alleviate cough symptoms. OBJECTIVES: To evaluate the effectiveness of honey for acute cough in children in ambulatory settings. SEARCH METHODS: We searched CENTRAL (2014, Issue 10), MEDLINE (1950 to October week 4, 2014), EMBASE (1990 to November 2014), CINAHL (1981 to November 2014), Web of Science (2000 to November 2014), AMED (1985 to November 2014), LILACS (1982 to November 2014) and CAB abstracts (2009 to January 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing honey given alone, or in combination with antibiotics, versus nothing, placebo or other over-the-counter (OTC) cough medications to participants aged from one to 18 years for acute cough in ambulatory settings. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results for eligible studies and extracted data on reported outcomes. MAIN RESULTS: We included three RCTs, two at high risk of bias and one at low risk of bias, involving 568 children. The studies compared honey with dextromethorphan, diphenhydramine, 'no treatment' and placebo for the effect on symptomatic relief of cough using a seven-point Likert scale. The lower the score, the better the cough symptom being assessed.Moderate quality evidence showed that honey may be better than 'no treatment' in reducing the frequency of cough (mean difference (MD) -1.05; 95% confidence interval (CI) -1.48 to -0.62; I(2) statistic 23%; two studies, 154 participants). High quality evidence also suggests that honey may be better than placebo for reduction of cough frequency (MD -1.85; 95% Cl -3.36 to 0.33; one study, 300 participants). Moderate quality evidence suggests that honey does not differ significantly from dextromethorphan in reducing cough frequency (MD -0.07; 95% CI -1.07 to 0.94; two studies, 149 participants). Low quality evidence suggests that honey may be slightly better than diphenhydramine in reducing cough frequency (MD -0.57; 95% CI -0.90 to -0.24; one study, 80 participants).Adverse events included mild reactions (nervousness, insomnia and hyperactivity) experienced by seven children (9.3%) from the honey group and two (2.7%) from the dextromethorphan group; the difference was not significant (risk ratio (RR) 2.94; 95% Cl 0.74 to 11.71; two studies, 149 participants). Three children (7.5%) in the diphenhydramine group experienced somnolence (RR 0.14; 95% Cl 0.01 to 2.68; one study, 80 participants). When honey was compared with placebo, four children (1.8%) in the honey group and one (1.3%) from the placebo group complained of gastrointestinal symptoms (RR 1.33; 95% Cl 0.15 to 11.74). However, there was no significant difference between honey versus dextromethorphan, honey versus diphenhydramine or honey versus placebo. No adverse event was reported in the 'no treatment' group. AUTHORS' CONCLUSIONS: Honey may be better than 'no treatment', diphenhydramine and placebo for the symptomatic relief of cough, but it is not better than dextromethorphan. None of the included studies assessed the effect of honey on 'cough duration' because intervention and follow-up were for one night only. There is no strong evidence for or against the use of honey. PMID- 25536087 TI - HIV prevalence and associated factors among foreign brides from Burma in Yunnan Province, China. AB - BACKGROUND: Many Burmese women have migrated to Yunnan Province and married local residents over the past few decades; however, limited information is available on their HIV prevalence and ability to cope with HIV. This study aims to assess the prevalence of HIV and knowledge related to AIDS, as well as to discover possible risk factors of HIV infection among foreign brides from Burma in Yunnan Province. METHODS: A cross-sectional study was taken of all Burmese cross-border wives residing in Tengchong County using standardized questionnaires. HIV and syphilis testing was conducted at the same time. RESULTS: Among 600 Burmese brides, the HIV prevalence was 2.17%. Those aged 21-30, those with higher education levels and those who had resided in China less than one year had higher infection rates. The AIDS awareness rate of 39.50% was very low in this population. Only 28.67% of participants had ever been involved in prevention services. The rate of condom use was low. Classification by age, education, occupation, prior HIV testing and prior use of HIV prevention services showed a statistically significant association with mean knowledge score (p < 0.05). Residing in China less than one year (OR = 3.86, 95% CI = 1.09-13.70) and having casual sex in the last year (OR = 10.49, 95% CI = 1.20-91.59) were risk factors for HIV infection. CONCLUSIONS: Burmese brides in China are not only exposed to a high risk of HIV infection, but also seriously lack response capabilities. Educational interventions and control efforts are practical approaches that need to be strengthened among this population. PMID- 25536088 TI - Laparoscopic versus Open Adrenalectomy for Stage I/II Adrenocortical Carcinoma: Meta-Analysis of Outcomes. AB - AIM: The aim of the present meta-analysis was to investigate the safety and oncologic efficacy of laparoscopic adrenalectomy for stage I and II adrenocortical carcinoma. The issue of level I evidence is entirely unreturned. METHODS: Electronic databases were used to search for articles from 1992 to 2014 in the English language literature. The primary end point of the study was to evaluate the safety of the laparoscopic procedure in terms of complications and the oncologic effectiveness of the procedure comparing the R0 resection, disease free survival and overall survival of patients treated with open adrenalectomy versus laparoscopic adrenalectomy. RESULTS: Differences in postoperative complications and R0 resections did not reach statistical significance between treatment arms. There were not statistical significant differences between treatment arms considering the two-year, three-year, four-year overall survival while five-year overall survival was in favor of open adrenalectomy group. There were not statistical significant differences between treatment arms considering the two-year, three-year, four-year, and five-year disease free survival. CONCLUSIONS: It seems that postoperative complications, R0-resection, overall, and disease free survival of stage I/II adrenocortical carcinoma are comparable and independent to the procedure though the five-year survival was in favor of the open group. Further research is likely to have an important impact on our confidence in the estimates of effect and may change the estimates. PMID- 25536089 TI - Detection of Thyroid Papillary Carcinoma Lymph Node Metastases Using One Step Nucleic Acid Amplification (OSNA): Preliminary Results. AB - Purpouse: One Step Nucleic Acid Amplification (OSNA) has been previously proposed for the diagnosis of lymph node metastases (LNMs) from several malignant conditions by quantifying the number of copies of cytokeratin 19 mRNA. Our aim was to evaluate the results obtained by OSNA in the lymph nodes of patients with papillary thyroid carcinoma (PTC) by comparing our results with the findings observed using standard pathological examination. MATERIALS AND METHODS: Fifty human lymph nodes (from five patients with diagnosed PTC) were studied. Each node was divided into two: one half was used for molecular study ("OSNA-node"), and the other half was used for conventional staining with hematoxylin and eosin ("HE non-OSNA node"). Three cytological imprints using Papanicolaou and May-Grunwald Giemsa strains were obtained from both node halves. The results from each technique were compared, and ROC analysis was performed. RESULTS: The OSNA study showed 22 positive samples for LNM (44%), which demonstrate a high concordance rate with the results observed using conventional pathological examination (cytology of "OSNA-node" and HE of "Non-OSNA node") with specificity and sensitivity values greater than 86% and 89%, respectively. However, both comparisons differed in the number of copies of mRNA as the best cut-off (260 copies in the first case and 93 in the second case). CONCLUSIONS: The OSNA results for the detection of LNM in patients with PTC are comparable with those observed using conventional techniques. However, its quantitative nature could be useful to more accurately detect lymph node involvement. PMID- 25536090 TI - Carriebowlinol, an antimicrobial tetrahydroquinolinol from an assemblage of marine cyanobacteria containing a novel taxon. AB - A combined biodiversity- and bioassay-guided natural products discovery approach was used to explore new groups of marine cyanobacteria for novel secondary metabolites with ecologically relevant bioactivities. Phylogenetic analysis of cyanobacterial collections from Belize revealed a new taxon not previously well explored for natural products. The new alkaloid 5-hydroxy-4-(chloromethyl) 5,6,7,8-tetrahydroquinoline (1), named carriebowlinol, and the known compound lyngbic acid (2) were isolated from a nonpolar extract and identified by NMR and MS techniques. Compounds 1 and 2 inhibited the growth of pathogenic and saprophytic marine fungi, and 1 inhibited the growth of marine bacteria, suggesting an antimicrobial ecological function. PMID- 25536092 TI - Postoperative opioid-induced respiratory depression: a closed claims analysis. AB - BACKGROUND: Postoperative opioid-induced respiratory depression (RD) is a significant cause of death and brain damage in the perioperative period. The authors examined anesthesia closed malpractice claims associated with RD to determine whether patterns of injuries could guide preventative strategies. METHODS: From the Anesthesia Closed Claims Project database of 9,799 claims, three authors reviewed 357 acute pain claims that occurred between 1990 and 2009 for the likelihood of RD using literature-based criteria. Previously cited patient risk factors for RD, clinical management, nursing assessments, and timing of events were abstracted from claim narratives to identify recurrent patterns. RESULTS: RD was judged as possible, probable, or definite in 92 claims (kappa = 0.690) of which 77% resulted in severe brain damage or death. The vast majority of RD events (88%) occurred within 24 h of surgery, and 97% were judged as preventable with better monitoring and response. Contributing and potentially actionable factors included multiple prescribers (33%), concurrent administration of nonopioid sedating medications (34%), and inadequate nursing assessments or response (31%). The time between the last nursing check and the discovery of a patient with RD was within 2 h in 42% and within 15 min in 16% of claims. Somnolence was noted in 62% of patients before the event. CONCLUSIONS: This claims review supports a growing consensus that opioid-related adverse events are multifactorial and potentially preventable with improvements in assessment of sedation level, monitoring of oxygenation and ventilation, and early response and intervention, particularly within the first 24 h postoperatively. PMID- 25536091 TI - Up-regulation of microRNA-21 mediates isoflurane-induced protection of cardiomyocytes. AB - BACKGROUND: Anesthetic cardioprotection reduces myocardial infarct size after ischemia-reperfusion injury. Currently, the role of microRNA in this process remains unknown. MicroRNAs are short, noncoding nucleotide sequences that negatively regulate gene expression through degradation or suppression of messenger RNA. In this study, the authors uncovered the functional role of microRNA-21 (miR-21) up-regulation after anesthetic exposure. METHODS: MicroRNA and messenger RNA expression changes were analyzed by quantitative real-time polymerase chain reaction in cardiomyocytes after exposure to isoflurane. Lactate dehydrogenase release assay and propidium iodide staining were conducted after inhibition of miR-21. miR-21 target expression was analyzed by Western blot. The functional role of miR-21 was confirmed in vivo in both wild-type and miR-21 knockout mice. RESULTS: Isoflurane induces an acute up-regulation of miR-21 in both in vivo and in vitro rat models (n = 6, 247.8 +/- 27.5% and 258.5 +/- 9.0%), which mediates protection to cardiomyocytes through down-regulation of programmed cell death protein 4 messenger RNA (n = 3, 82.0 +/- 4.9% of control group). This protective effect was confirmed by knockdown of miR-21 and programmed cell death protein 4 in vitro. In addition, the protective effect of isoflurane was abolished in miR-21 knockout mice in vivo, with no significant decrease in infarct size compared with nonexposed controls (n = 8, 62.3 +/- 4.6% and 56.2 +/- 3.2%). CONCLUSIONS: The authors demonstrate for the first time that isoflurane mediates protection of cardiomyocytes against oxidative stress via an miR 21/programmed cell death protein 4 pathway. These results reveal a novel mechanism by which the damage done by ischemia/reperfusion injury may be decreased. PMID- 25536093 TI - Quantification of sperm specific mRNA transcripts (PRM1, PRM2, and TNP2) in teratozoospermia and normozoospermia: New correlations between mRNA content and morphology of sperm. AB - Sperm mRNAs could be used as a predictor of fertilization capacity since the transcriptional profile of a gamete is critical for the production of viable human sperm. The aim of this study was to determine if PRM1, PRM2, and TNP2 transcripts in spermatozoa from normozoospermic and teratozoospermic men correlate with sperm morphology and/or assisted-reproduction outcomes. Human ejaculates were collected from 138 men referred to an infertility clinic, and were separated in two groups, teratozoospermic (n =72) and normozoospermic (n =66), based on World Health Organization criteria (2010). Chromomycin A3 and analine blue staining were used to evaluate protamination and chromatin integrity, respectively. Quantitative reverse-transcriptase PCR was performed for PRM1, PRM2, and TNP2. This analysis revealed significantly higher PRM1 and PRM2 mRNA copy numbers in normozoospermic versus teratozoospermic samples (P < 0.001). In contrast, TNP2 transcript abundance was significantly higher in teratozoospermic versus normozoospermic samples (P < 0.001) and positively correlated with sperm-head defects (P < 0.05). Sperm-tail defects negatively correlated (P < 0.05) with both PRM1 and PRM2 transcripts in normozoospermic samples. No significant differences were observed between the two groups when comparing transcript levels to the outcome of intracytoplasmic sperm injection cycles (P > 0.05), and a normal PRM1/PRM2 mRNA ratio (~1) was observed in more than 70% of successful cycles. Thus, the quantity of PRM1, PRM2, and TNP2 transcripts and the PRM1/PRM2 mRNA ratio affect spermiogenesis, sperm morphology, and the function of mature human sperm. These mRNAs could therefore be used as biomarkers for the diagnosis of male infertility. PMID- 25536094 TI - Human monocyte response to S-nitrosoglutathione-loaded nanoparticles: uptake, viability, and transcriptome. AB - S-Nitrosoglutathione (GSNO) is a good candidate for nitric oxide (NO(*)) delivery, and its nanoformulation improves NO(*) stability and bioavailability. We have compared the effect of empty Eudragit nanoparticles (eENP), GSNO-loaded ENP (gENP), and free GSNO on THP-1 human monocytic cell line. We investigated cellular viability and growth by WST-1 and trypan blue tests. ENP uptake was studied using transmission electron microscopy, confocal microscopy, and flow cytometry. Transcriptomic profiles were obtained using microarray. ENP entered cells by clathrin- and caveolae-mediated endocytosis. Exposure to either free GSNO or gENP induced an activation of genes from the same clusters, in favor of intracellular delivery of GSNO by ENP. GSNO nanoformulation might be a therapeutic option for NO(*) delivery. PMID- 25536095 TI - Platelet-Rich Fibrin in Maxillary Sinus Augmentation: A Systematic Review. AB - The aim of this study was to systemically assess the efficacy of platelet-rich fibrin (PRF) on maxillary sinus augmentation using the lateral approach. A PubMed search and a hand search of relevant journals and the bibliographies of selected articles were performed. Clinical studies using PRF with open maxillary sinus augmentation were included. The search provided 290 titles; only 8 studies fulfilled the inclusion criteria. Identified studies showed heterogeneity regarding surgical technique, grafting material, implant placement time, protocol, outcome measures, healing time for biopsy, and implant placement, as well as follow-up period. From the 8 identified studies, 3 studies used PRF as a sole filling material, whereas the other 5 studies used PRF with bone substitutes. PRF showed promising results as a sole filling material for sinus lift with simultaneous implant placement, and PRF seemed to accelerate maturation of a demineralized freeze dried bone allograft. Conversely, it had no effect on deproteinized bovine maturation. PRF fibrin membranes represent an easy and successful method to cover the sinus membrane or osteotomy window. PMID- 25536096 TI - Role of oxygen vacancies in the surface evolution of H at CeO2(111): a charge modification effect. AB - Diffusion processes and reactions of H at stoichiometric and reduced CeO2(111) surfaces have been studied by using density functional theory calculations corrected by on-site Coulomb interactions (DFT + U). Oxygen vacancies on the surface are determined to be able to significantly affect the behavior of H by modifying the charge of surface lattice O through the occurrence of Ce(3+). It has been found that, at the reduced CeO2(111) surface, the adsorption strength of H as well as the H coupling barrier can be dramatically reduced compared to those at the stoichiometric surface, while H2O formation barrier is not significantly affected. Moreover, the diffusion of H at the reduced surface or into the bulk can occur more readily than that at stoichiometric CeO2(111). PMID- 25536097 TI - Borderline personality disorder and bipolar disorder: what is the difference and why does it matter? AB - Borderline personality disorder (BPD) and bipolar disorder (types I and II) are frequently confused because of their symptomatic overlap. Although affective instability is a prominent feature of each, the pattern is entirely different. BPD is characterized by transient mood shifts that occur in response to interpersonal stressors, whereas bipolar disorder is associated with sustained mood changes. These disorders can be further distinguished by comparing their phenomenology, etiology, family history, biological studies, outcome, and response to medication. Their distinction is of great clinical importance because misdiagnosis can deprive the patient of potentially effective treatment, whether it is psychotherapy for BPD or medication for bipolar disorder. On the basis of a comprehensive literature review, guidelines for differential diagnosis are suggested, and priorities for further research are recommended. PMID- 25536098 TI - Borderline personality disorder: a disorder in search of advocacy. AB - Compared with bipolar disorder, borderline personality disorder (BPD) is as frequent (if not more frequent), as impairing (if not more impairing), and as lethal (if not more lethal). Yet, BPD has received less than one-tenth the funding from the National Institutes of Health than has bipolar disorder. More than other reviewers of the literature on the interface between bipolar disorder and BPD, Paris and Black (Paris J and Black DW (2015) Borderline Personality Disorder and Bipolar Disorder: What is the Difference and Why Does it Matter? J Nerv Ment Dis 203:3-7) emphasize the clinical importance of correctly diagnosing BPD and not overdiagnosing bipolar disorder, with a focus on the clinical feature of affective instability and how the failure to recognize the distinction between sustained and transient mood perturbations can result in misdiagnosing patients with BPD as having bipolar disorder. The review by Paris and Black, then, is more of an advocacy for BPD than other reviews in this area have been. In the present article, the author will illustrate how the bipolar disorder research community has done a superior job of advocating for and "marketing" their disorder compared with researchers of BPD. Specifically, researchers of bipolar disorder have conducted multiple studies highlighting the problem with underdiagnosis, written commentaries about the problem with underdiagnosis, developed and promoted several screening scales to improve diagnostic recognition, published numerous studies of the operating characteristics of these screening measures, attempted to broaden the definition of bipolar disorder by advancing the concept of the bipolar spectrum, and repeatedly demonstrated the economic costs and public health significance of bipolar disorder. In contrast, researchers of BPD have almost completely ignored each of these issues and thus have been less successful in highlighting the public health significance of the disorder. PMID- 25536099 TI - Borderline personality disorder and bipolar disorder: commentary on Paris and Black. PMID- 25536100 TI - Aripiprazole adjunct treatment in bipolar I or II disorder, depressed state: a 2 year clinical study. AB - The symptomatic course of bipolar disorder (BPD) is chronic and dominated by depression. As recurrence rates are high, maintenance therapy is required. Although efficacious, mood stabilizers may be hampered by poor adherence, and second-generation antipsychotic medications may be associated with weight gain and metabolic abnormalities. There is evidence to suggest that aripiprazole is beneficial in major depressive disorder and BPD with depression. We therefore investigated 2-year clinical outcomes with aripiprazole adjunct therapy at 5 to 15 mg once daily alongside a mood stabilizer in 40 patients with BPD. All patients experienced marked improvements in Montgomery-Asberg Depression Rating Scale scores by 6 weeks and substantial reductions in Clinical Global Impressions Scale scores by 6 months. All patients were able to return to optimal or premorbid functioning by 6 months to 1 year. By 1 year, all patients made a complete functional recovery on the Sheehan Disability Scale. Improvements were maintained on all measures up to 2 years. There were minimal adverse events, all of which decreased during therapy. Our findings indicate that aripiprazole adjunct treatment is safe and effective as an acute and maintenance therapy for BPD. However, the findings will need to be replicated by larger studies. PMID- 25536102 TI - Methodological queries regarding "exploratory quantum resonance spectrometry" (Zhang et al., 2014). PMID- 25536101 TI - The role of a critical time intervention on the experience of continuity of care among persons with severe mental illness after hospital discharge. AB - We investigated the impact of critical time intervention (CTI) on self-reported indicators of quality of continuity of care (COC) after discharge from inpatient psychiatric treatment with data from a randomized controlled trial that assessed the effectiveness of the intervention in reducing recurrent homelessness. Postdischarge COC outcome measures among previously homeless persons with severe mental illness randomly assigned to receive usual services only (n = 73) or 9 months of CTI in addition to usual services (n = 77) were compared. Those assigned to CTI had greater perceived access to care than the usual services group did, with this impact extending beyond the point at which the intervention ended. A time-limited care coordination intervention provided immediately after hospital discharge may improve COC, but further studies are needed to substantiate an effect of CTI on long-term continuity outcomes. PMID- 25536103 TI - Response to Baguley et al. concerning the use of the quantum resonance spectrometer to detect psychiatric symptoms. PMID- 25536105 TI - A combined enrichment and aptamer pulldown assay for Francisella tularensis detection in food and environmental matrices. AB - Francisella tularensis, a Gram-negative bacterium and causative agent of tularemia, is categorized as a Class A select agent by the Centers for Disease Control and Prevention due to its ease of dissemination and ability to cause disease. Oropharyngeal and gastrointestinal tularemia may occur due to ingestion of contaminated food and water. Despite the concern to public health, little research is focused on F. tularensis detection in food and environmental matrices. Current diagnostics rely on host responses and amplification of F. tularensis genetic elements via Polymerase Chain Reaction; however, both tools are limited by development of an antibody response and limit of detection, respectively. During our investigation to develop an improved culture medium to aid F. tularensis diagnostics, we found enhanced F. tularensis growth using the spent culture filtrate. Addition of the spent culture filtrate allowed for increased detection of F. tularensis in mixed cultures of food and environmental matrices. Ultraperformance liquid chromatography (UPLC)/MS analysis identified several unique chemicals within the spent culture supernatant of which carnosine had a matching m/z ratio. Addition of 0.625 mg/mL of carnosine to conventional F. tularensis medium increased the growth of F. tularensis at low inoculums. In order to further enrich F. tularensis cells, we developed a DNA aptamer cocktail to physically separate F. tularensis from other bacteria present in food and environmental matrices. The combined enrichment steps resulted in a detection range of 1-106 CFU/mL (starting inoculums) in both soil and lettuce backgrounds. We propose that the two-step enrichment process may be utilized for easy field diagnostics and subtyping of suspected F. tularensis contamination as well as a tool to aid in basic research of F. tularensis ecology. PMID- 25536104 TI - Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. AB - BACKGROUND: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. METHODS: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318 chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. RESULTS: There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. CONCLUSION: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications. PMID- 25536106 TI - Identification of molecular markers associated with Verticillium wilt resistance in alfalfa (Medicago sativa L.) using high-resolution melting. AB - Verticillium wilt, caused by the soilborne fungus, Verticillium alfalfae, is one of the most serious diseases of alfalfa (Medicago sativa L.) worldwide. To identify loci associated with resistance to Verticillium wilt, a bulk segregant analysis was conducted in susceptible or resistant pools constructed from 13 synthetic alfalfa populations, followed by association mapping in two F1 populations consisted of 352 individuals. Simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers were used for genotyping. Phenotyping was done by manual inoculation of the pathogen to replicated cloned plants of each individual and disease severity was scored using a standard scale. Marker-trait association was analyzed by TASSEL. Seventeen SNP markers significantly associated with Verticillium wilt resistance were identified and they were located on chromosomes 1, 2, 4, 7 and 8. SNP markers identified on chromosomes 2, 4 and 7 co-locate with regions of Verticillium wilt resistance loci reported in M. truncatula. Additional markers identified on chromosomes 1 and 8 located the regions where no Verticillium resistance locus has been reported. This study highlights the value of SNP genotyping by high resolution melting to identify the disease resistance loci in tetraploid alfalfa. With further validation, the markers identified in this study could be used for improving resistance to Verticillium wilt in alfalfa breeding programs. PMID- 25536108 TI - Stochastic cortical neurodynamics underlying the memory and cognitive changes in aging. AB - The relatively random spiking times of individual neurons provide a source of noise in the brain. We show how this noise interacting with altered depth in the basins of attraction of networks involved in short-term memory, attention, and episodic memory provide an approach to understanding some of the cognitive changes in normal aging. The effects of the neurobiological changes in aging that are considered include reduced synaptic modification and maintenance during learning produced in part through reduced acetylcholine in normal aging, reduced dopamine which reduces NMDA-receptor mediated effects, reduced noradrenaline which increases cAMP and thus shunts excitatory synaptic inputs, and the effects of a reduction in acetylcholine in increasing spike frequency adaptation. Using integrate-and-fire simulations of an attractor network implementing memory recall and short-term memory, it is shown that all these changes associated with aging reduce the firing rates of the excitatory neurons, which in turn reduce the depth of the basins of attraction, resulting in a much decreased probability in maintaining in short-term memory what has been recalled from the attractor network. This stochastic dynamics approach opens up new ways to understand and potentially treat the effects of normal aging on memory and cognitive functions. PMID- 25536109 TI - Current nanotechnology approaches for the treatment and management of diabetic retinopathy. AB - Diabetic retinopathy (DR) is a consequence of diabetes mellitus at the ocular level, leading to vision loss, and contributing to the decrease of patient's life quality. The biochemical and anatomic abnormalities that occur in DR are discussed in this review to better understand and manage the development of new therapeutic strategies. The use of new drug delivery systems based on nanoparticles (e.g. liposomes, dendrimers, cationic nanoemulsions, lipid and polymeric nanoparticles) is discussed along with the current traditional treatments, pointing out the advantages of the proposed nanomedicines to target this ocular disease. Despite the multifactorial nature of DR, which is not entirely understood, some strategies based on nanoparticles are being exploited for a more efficient drug delivery to the posterior segment of the eye. On the other hand, the use of some nanoparticles also seems to contribute to the development of DR symptoms (e.g. retinal neovascularization), which are also discussed in light of an efficient management of this ocular chronic disease. PMID- 25536107 TI - Benchmark dose estimation for cadmium-induced renal tubular damage among environmental cadmium-exposed women aged 35-54 years in two counties of China. AB - BACKGROUND: A number of factors, including gender, age, smoking habits, and occupational exposure, affect the levels of urinary cadmium. Few studies have considered these influences when calculating the benchmark dose (BMD) of cadmium. In the present study, we aimed to calculate BMDs and their 95% lower confidence bounds (BMDLs) for cadmium-induced renal tubular effects in an age-specific population in south-central China. METHODS: In this study, urinary cadmium, beta2 microglobulin, and N-acetyl-beta-D-glucosaminidase levels were measured in morning urine samples from 490 randomly selected non-smoking women aged 35-54 years. Participants were selected using stratified cluster sampling in two counties (counties A and B) in China. Multiple regression and logistic regression analyses were used to investigate the dose-response relationship between urinary cadmium levels and tubular effects. BMDs/BMDLs corresponding to an additional risk (benchmark response) of 5% and 10% were calculated with assumed cut-off values of the 84th and 90th percentile of urinary beta2-microglobulin and N acetyl-beta-D-glucosaminidase levels of the controls. RESULTS: Urinary levels of beta2-microglobulin and N-acetyl-beta-D-glucosaminidase increased significantly with increasing levels of urinary cadmium. Age was not associated with urinary cadmium levels, possibly because of the narrow age range included in this study. Based on urinary beta2-microglobulin and N-acetyl-beta-D-glucosaminidase, BMDs and BMDLs of urinary cadmium ranged from 2.08 to 3.80 (1.41-2.18) ug/g cr for subjects in county A and from 0.99 to 3.34 (0.74-1.91) ug/g cr for those in county B. The predetermined benchmark response of 0.05 and the 90th percentiles of urinary beta2-microglobulin and N-acetyl-beta-D-glucosaminidase levels of the subjects not exposed to cadmium (i.e., the control group) served as cut-off values. CONCLUSIONS: The obtained BMDs of urinary cadmium were similar to the reference point of 1 ug/g cr, as suggested by the European Food Safety Authority, indicating that cadmium exposure must be reduced to protect human health. PMID- 25536110 TI - Specific surface, crystallinity, and dissolution of lyophilized fibrinogen. A study by combined small- and wide-angle X-ray scattering (SWAXS). AB - The nano-structural properties of six different batches of lyophilized fibrinogen at various contents of residual humidity (6-20%) were studied by small- and wide angle X-ray scattering (SWAXS) and related to the dissolution properties. As structural parameters, the specific surface and relative degree of crystallinity, from SAXS and WAXS, respectively, were used, and correlated to the dissolution rates. BET surface area and electron microscopy were used as ancillary methods. The results show a complex, biphasic behavior: above 9% water content the crystallinity increased, and the specific surface decreased with increasing water contents; at the lowest water contents (6%), however, where the WAXS patterns showed amorphous structure of the fibrinogens, the specific surface and dissolution rates diverged over a wide range of values. Systematic correlations could be established between specific surface and dissolution rates for the water contents below 13%: the dissolution rates were found to decrease with increasing specific surface, most notably in the amorphous form, in contrast to expectations from classical thermodynamics. Protein conformational changes and hydrophobic surface formation upon depletion of water could be possible causes. This is supported by the protective effect of the high-HLB surfactant PS-80, which was found to enlarge the specific surface. PMID- 25536111 TI - New method and characterization of self-assembled gelatin-oleic nanoparticles using a desolvation method via carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction. AB - In this study, we investigated a new method for the preparation of gelatin-oleic conjugate (GOC) as an amphiphilic biomaterial to load model anti-cancer drugs into self-assembled nanoparticles (NPs). Oleic acid (OA) was covalently bound to gelatin via carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction in water-ethanol cosolvent to form a GOC. Fourier transform infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance ((1)H NMR) clearly indicated the successful synthesis of GOC. The percentage of gelatin amino groups reacted with OA was up to 50% as determined using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) method. Subsequently, gelatin-oleic nanoparticles (GONs) were prepared using a desolvation method with glutaraldehyde or genipin used as a crosslinker for comparison. Irinotecan hydrochloride (IRT) was used as a model drug to load into GONs using incubation or an in-process adding method for comparison. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) data showed that the sizes of GONs and IRT-loaded GONs (IRT-GONs) were below 250 nm. The zeta potentials of the GONs and irinotecan-loaded IRT-GONs were below -20 mV, which was found to be stable in suspension against the aggregation process. The incubation method was more suitable for drug loading because it did not affect the process of GON formation and thus did not increase their size much compared to the change in size with the in-process adding method. The lipophilic property of the oleic moiety in the GOC increased the affinity between GOC molecules, thus reducing the amount of crosslinking agents needed to stabilize GONs compared to gelatin nanoparticles (GNs). As novel approaches for the synthesis of protein fatty acid complexes, chemical reaction has been suggested for the synthesis of GOC. The above results show that GOC synthesized via new method is a promising biomaterial based upon preparation of nanoparticles. PMID- 25536114 TI - Near infrared activation of an anticancer Pt(IV) complex by Tm-doped upconversion nanoparticles. AB - The Pt(IV) complex cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] is photoactivated by near infrared light (980 nm) using NaYF4:Yb(3+)/Tm(3+)@NaYF4 core-shell upconversion nanoparticles. Coupling of this cisplatin precursor with the biocompatible PEGylated phospholipid DSPE-PEG(2000)-NH2 affords a valuable approach to decorate the surface of the nanoparticles, providing novel photoactivatable nanomaterials capable of releasing Pt(II) species upon NIR light excitation. PMID- 25536113 TI - Polyene-based cationic lipids as visually traceable siRNA transfer reagents. AB - Cationic lipids are promising non-viral vectors for the cellular delivery of nucleic acids. Important considerations for the development of new delivery vectors are enhanced uptake efficiency, low toxicity and traceability. Traceable gene transfer systems however typically require the inclusion of a labeled excipient, and highly sensitive imaging instrumentation to detect the presence of the label. Recently, we reported the synthesis and characterization of colored, polyene cationic phospholipidoids composed of a rigid, polyenoic acid of predetermined dimension (C20:5 and C30:9) paired with flexible saturated alkyl chains of varying lengths (12:0, 14:0, 16:0, 18:0, 20:0 carbons). Herein, the potential of these cationic phospholipids as siRNA carriers was evaluated through standard liposomal formulations in combination with a neutral helper lipid DOPE. The polyene-based lipids were compared with a standard cationic lipid for siRNA delivery into luciferase expressing HR5-CL11 cells. Within the series of lipids screened, knockdown results indicated that polyene cationic phospholipids paired with longer saturated alkyl chains are more effective as gene transfer agents, and perform comparably with the commercial lipid EPC. Furthermore, the chromophore associated with the polyene chain allowed tracking of the siRNA delivery using direct observation. The polyene lipoplexes were tracked on both a macroscopic and microscopic level either as a single-component or as a multi component lipoplex formulation. When combined with a reference EPC, effective knockdown and tracking abilities were combined in a single preparation. PMID- 25536112 TI - Treatment of ocular disorders by gene therapy. AB - Gene therapy to treat ocular disorders is still starting, and current therapies are primarily experimental, with most human clinical trials still in research state, although beginning to show encouraging results. Currently 33 clinical trials have been approved, are in progress, or have been completed. The most promising results have been obtained in clinical trials of ocular gene therapy for Leber Congenital Amaurosis, which have prompted the study of several ocular diseases that are good candidates to be treated with gene therapy: glaucoma, age related macular degeneration, retinitis pigmentosa, or choroideremia. The success of gene therapy relies on the efficient delivery of the genetic material to target cells, achieving optimum long-term gene expression. Although viral vectors have been widely used, their potential risk associated mainly with immunogenicity and mutagenesis has promoted the design of non-viral vectors. In this review, the main administration routes and the most studied delivery systems, viral and non viral, for ocular gene therapy are presented. The primary ocular disease candidates to be treated with gene therapy have been also reviewed, including the genetic basis and the most relevant preclinical and clinical studies. PMID- 25536115 TI - On-line combination of high performance liquid chromatography with comprehensive two-dimensional gas chromatography-triple quadrupole mass spectrometry: a proof of principle study. AB - The present contribution is focused on the on-line combination of high performance liquid chromatography (HPLC), cryogenically modulated comprehensive two-dimensional gas chromatography (GC * GC), and triple quadrupole mass spectrometry (QqQ MS), generating a very powerful unified separation-science tool. The instrument can be used in seven different combinations ranging from one dimensional HPLC with a photodiode array detector to on-line LC * GC * GC/QqQ MS. The main focus of the present research is directed to the LC-GC * GC/QqQ MS configuration, with its analytical potential shown in a proof-of-principle study involving a very complex sample, namely, coal tar. Specifically, a normal-phase LC process enabled the separation of three classes of coal tar compounds: (1) nonaromatic hydrocarbons; (2) unsaturated compounds (with and without S); (3) oxygenated constituents. The HPLC fractions were transferred to the GC * GC instrument via a syringe-based interface mounted on an autosampler. Each fraction was subjected to a specific programmed temperature vaporizer GC * GC/QqQ MS untargeted or targeted analysis. For example, the coal tar S-containing compounds were pinpointed through multiple-reaction-monitoring analysis, while full-scan information was attained for the oxygenated constituents. PMID- 25536116 TI - Implications of an absolute simultaneity theory for cosmology and universe acceleration. AB - An alternate Lorentz transformation, Absolute Lorentz Transformation (ALT), has similar kinematics to special relativity yet maintains absolute simultaneity in the context of a preferred reference frame. In this study, it is shown that ALT is compatible with current experiments to test Lorentz invariance only if the proposed preferred reference frame is locally equivalent to the Earth-centered non-rotating inertial reference frame, with the inference that in an ALT framework, preferred reference frames are associated with centers of gravitational mass. Applying this theoretical framework to cosmological data produces a scenario of universal time contraction in the past. In this scenario, past time contraction would be associated with increased levels of blueshifted light emissions from cosmological objects when viewed from our current perspective. The observation that distant Type Ia supernovae are dimmer than predicted by linear Hubble expansion currently provides the most direct evidence for an accelerating universe. Adjusting for the effects of time contraction on a redshift-distance modulus diagram produces a linear distribution of supernovae over the full redshift spectrum that is consistent with a non-accelerating universe. PMID- 25536117 TI - Intracranial hemorrhage: frequency, location, and risk factors identified in a TeleStroke network. AB - Intracranial hemorrhages are associated with high rates of disability and mortality. Telemedicine in general provides clinical healthcare at a distance by using videotelephony and teleradiology and is used particularly in acute stroke care medicine (TeleStroke). TeleStroke considerably improves quality of stroke care (for instance, by increasing thrombolysis) and may be valuable for the management of intracranial hemorrhages in rural hospitals and hospitals lacking neurosurgical departments, given that surgical/interventional therapy is only recommended for a subgroup of patients. The aim of this study was to analyze the frequency, anatomical locations of intracranial hemorrhage, risk factors, and the proportion of patients transferred to specialized hospitals. We evaluated teleconsultations conducted between 2008 and 2010 in a large cohort of patients consecutively enrolled in the Telemedical Project for Integrated Stroke Care (TEMPiS) network. In cases in which intracranial hemorrhage was detected, all images were re-examined and analyzed with a focus on frequency, location, risk factors, and further management. Overall, 6187 patients presented with stroke like symptoms. Intracranial hemorrhages were identified in 631 patients (10.2%). Of these, intracerebral hemorrhages were found in 423 cases (67.0%), including 174 (41.1%) in atypical locations and 227 (53.7%) in typical sites among other locations. After 14 days of hospitalization in community facilities, the mortality rate in patients with intracranial hemorrhages was 15.1% (95/631). Two hundred and twenty-three patients (35.3%) were transferred to neurological/neurosurgical hospitals for diagnostic workup or additional treatment. Community hospitals are confronted with patients with intracranial hemorrhage, whose management requires specific neurosurgical and hematological expertise with respect to hemorrhage subtype and clinical presentation. TeleStroke networks help select patients who need advanced neurological and/or neurosurgical care. The relatively low proportion of interhospital transfers shown in this study reflects a differentiated decision process on the basis of both guidelines and standard operating procedures. PMID- 25536118 TI - SIRT2 is required for lipopolysaccharide-induced activation of BV2 microglia. AB - It has been reported that inhibition of sirtuin 2 (SIRT2), a sirtuin family protein, can decrease cellular and tissue injuries in models of Parkinson's disease (PD) and Huntington's disease (HD); however, the mechanisms underlying these observations have remained unclear. Because inflammation plays key pathological roles in multiple major neurological disorders including PD and HD, in our current study we tested our hypothesis that SIRT2 plays an important role in microglial activation. We found that treatment of BV2 microglia with lipopolysaccharides led to significant increases in NO and inducible nitric oxide synthase mRNA levels, as well as increases in the levels of tumor necrosis factor alpha and interleukin 6 mRNA, which indicated microglial activation. These increases were significantly decreased in the cells with SIRT2 silencing-produced decreases in the SIRT2 level. These observations suggest that SIRT2 is required for lipopolysaccharide-induced microglial activation. The findings also suggest that SIRT2 may be a therapeutic target for inhibiting the inflammatory responses in neurological disorders such as PD and HD. PMID- 25536119 TI - Frontal midline theta power as an index of listening effort. AB - Attempts to identify physiological correlates of listening effort have mainly focused on peripheral measures (e.g. pupillometry) and auditory-evoked/event related potentials. Although nonauditory studies have suggested that sustained time-frequency electroencephalographic (EEG) features in the theta-band (4-7 Hz) are correlated with domain-general mental effort, little work has characterized such features during effortful listening. Here, high-density EEG data was collected while listeners performed a sentence-recognition task in noise, the signal-to-noise ratio (SNR) of which varied across blocks. Frontal midline theta (Fmtheta), largely driven by sources localized in or near the medial frontal cortex, showed greater power with decreasing SNR and was positively correlated with self-reports of effort. Increased Fmtheta was present before speech onset and during speech presentation. Fmtheta power also differed across SNRs when including only trials in which all words were recognized, suggesting that the effects were unrelated to performance differences. Results suggest that frontal cortical networks play a larger role in listening as acoustic signals are increasingly masked. Further, sustained time-frequency EEG features may usefully supplement previously used peripheral and event-related potential measures in psychophysiological investigations of effortful listening. PMID- 25536120 TI - Introduction to Microelectrode Arrays, the Site-Selective Functionalization of Electrode Surfaces, and the Real-Time Detection of Binding Events. AB - Microelectrode arrays have great potential as analytical tools because currents can be independently measured at each electrode in the array. In principle, these currents can be monitored in order to follow in real time the binding events that occur between the members of a molecular library and a biological target. To capitalize on this potential, the surface of the array must be selectively functionalized so that each unique member of the molecular library is associated with a unique individually addressable electrode or set of electrodes in the array. To this end, this instructional review summarizes methods for coating the arrays with porous polymers that allow for the attachment of molecules to the surface of the array, selectively conducting reactions at individual electrodes in the array, characterizing molecules that are placed on the arrays, and running the analytical experiments needed to monitor in real time binding events between molecules on the array and a biological target. PMID- 25536121 TI - Linear-array-based photoacoustic imaging of human microcirculation with a range of high frequency transducer probes. AB - Photoacoustic imaging (PAI) with a linear-array-based probe can provide a convenient means of imaging the human microcirculation within its native structural context and adds functional information. PAI using a multielement linear transducer array combined with multichannel collecting system was used for in vivo volumetric imaging of the blood microcirculation, the total concentration of hemoglobin (HbT), and the hemoglobin oxygen saturation (sO2) within human tissue. Three-dimensional (3-D) PA and ultrasound (US) volumetric scans were acquired from the forearm skin by linearly translating the transducer with a stepper motor over a region of interest, while capturing two-dimensional images using 15, 21, and 40 MHz frequency transducer probes. For the microvasculature imaging, PA images were acquired at 800- and 1064-nm wavelengths. For the HbT and sO2 estimates, PA images were collected at 750- and 850-nm wavelengths. 3-D microcirculation, HbT, and sO2 maps of the forearm skin were obtained from normal subjects. The linear-array-based PAI has been found promising in terms of resolution, imaging depth, and imaging speed for in vivo microcirculation imaging within human skin. We believe that a reflection type probe, similar to existing clinical US probes, is most likely to succeed in real clinical applications. Its advantages include ease of use, speed, and familiarity for radiographers and clinicians. PMID- 25536124 TI - Formation of a zwitterionic boronium species from the reaction of a stable carbenoid with borane: CO2 reduction. AB - The treatment of Li2C(PPh2NMes)2 (1, Mes = 2,4,6-Me3C6H2) with hexachloroethane yielded the corresponding carbenoid 2 in good yields. The reactivity of 2 was studied with BH3.SMe2 to give a zwitterionic boronium species 4, also a stable carbenoid. Both carbenoid species were found to be excellent catalysts for the CO2 reduction by BH3.SMe2. PMID- 25536123 TI - Oxidized Titanium Implants Enhance Osseointegration via Mechanisms Involving RANK/RANKL/OPG Regulation. AB - BACKGROUND: The role of implant surface properties for bone formation and bone remodeling, that is, the major events during osseointegration, are incompletely understood. PURPOSE: This experimental study aimed to investigate the relation between molecular and morphological patterns at the bone interface for machined and oxidized implants. MATERIALS AND METHODS: Machined and anodically oxidized titanium implants were inserted in rat tibiae. The implants and surrounding tissue were retrieved at 1, 3, 6, 14, or 28 days for gene expression, histology, histomorphometry, backscatter scanning electron microscopy, and transmission electron microscopy. RESULTS: Compared with machined-surface implants, a higher degree of mineralized bone was found in contact with the oxidized-surface implants. After 3 days, cells adherent to the oxidized implants demonstrated a markedly higher expression of receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG). Whereas the OPG expression was higher at the machined implants at 6, 14, and 28 days, a higher RANKL/OPG ratio was detected at the oxidized implants. Between 3 and 14 days, both implants demonstrated a temporal increase in RANKL/OPG, corresponding to the remodeling phase at the bone-implant interface. For both implant types, the RANKL/OPG ratio sharply decreased to a low level after 28 days. CONCLUSIONS: The present results show that oxidized implants rapidly promote a high degree of mineralized bone apposition to the surface. As determined by the gene expression data, the mechanisms involve an early induction of osteoclastic differentiation and subsequently more intensive bone remodeling, which accelerates the maturation of the bone-implant interface. The present study suggests that the RANKL/OPG ratio is a sensitive indicator for monitoring the remodeling process during osseointegration. PMID- 25536125 TI - Filler complications. Preface. PMID- 25536122 TI - Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. AB - OBJECTIVES: Methotrexate (MTX) is considered the 'anchor drug' in the therapy of rheumatoid arthritis (RA), yet many physicians do not optimise MTX regimens in spite of high RA disease activity. The recent development of an auto-injector for the subcutaneous (subQ) administration of MTX has prompted re-evaluation of MTX utilisation. The purpose of this systematic literature review is to determine the optimal dose, drug level, and route of administration for MTX in the context of relevant pharmacokinetics and pharmacogenomics. METHODS: A systematic literature review was performed in Medline searching specifically for randomised controlled trials, systematic reviews, case control and cohort studies evaluating outcomes related to MTX dose and route of administration. Articles fulfilling these inclusion criteria were reviewed. Data on MTX dose, route of administration, clinical response, drug levels and adverse events were evaluated. RESULTS: Our search identified 420 articles of which 6 were eligible for inclusion using the above criteria. These included 2 systematic reviews, 2 randomised open label trials, one longitudinal study and one retrospective cohort study. CONCLUSIONS: Efficacy and toxicity for MTX appear related to absorbed dose of MTX, not to route of administration. While bioavailability is greater for parenteral MTX, there is no evidence yet that splitting the oral dose of MTX is less advantageous, less safe or less tolerable than administering parenteral MTX. However, there appear to be modest benefits in beginning with higher doses of MTX, and switching to parenteral MTX when the clinical response to an oral dose is inadequate. PMID- 25536126 TI - Adverse effects of fillers and their histopathology. AB - Injectable fillers nowadays represent a pillar in facial rejuvenation and make a significant contribution to the success of the treatment. Despite their obvious benefits, a wide range of possible complications such as immediate, late, delayed, temporary, or irreversible adverse effects have to be respected. Differentiating the various filler materials, these effects are assigned to histopathology findings and currently available treatment options. PMID- 25536127 TI - Complications of collagen fillers. AB - As the skin ages, a deficiency in collagen occurs, thus injectable collagen products have become a sensible and popular option for dermal filling and volume enhancement. Several types of collagen have been developed over the years, including animal sources such as bovine and porcine collagen, as well as human based sources derived from pieces of the patient's own skin, cadaver skin, and later cultured from human dermal fibroblasts. While collagen overall has a relatively safe, side effect profile, there are several complications, both early and late onset, that practitioners and patients should be aware of. Early complications, occurring within days of the procedure, can be divided into non hypersensitivity and hypersensitivity reactions. The non-hypersensitive reactions include injection site reactions, discoloration, maldistribution, infection, skin necrosis, and the very rare but dreaded risk of vision loss, whereas the hypersensitivity reactions present usually as delayed type IV reactions, but can also rarely present as an immediate type I reaction. Late complications, occurring within weeks to even years after injection, include granuloma formation, foreign body reactions, and infection secondary to atypical mycobacteria or biofilms. This review will give a detailed overview of the complications secondary to cutaneous collagen injections. PMID- 25536128 TI - Management of complications of injectable silicone. AB - Soft tissue augmentation is a common procedure, and a wide variety of injectable fillers are used. Liquid injectable silicone (LIS) was the first highly popularized injectable filler. LIS is a permanent filler and can be used in the correction of facial furrows and wrinkles. Some complications are inherent to the procedure and can resolve spontaneously, such as redness, swelling, and immediate hypersensitivity reactions. Unintended reactions, such as granulomas, infections, vascular occlusion, can also follow the treatment with LIS and may appear several years after the injections. These can be difficult to manage, show little or no tendency to spontaneous resolutions, and rarely resolve completely. Injecting physicians must be aware of these potential complications caused by LIS because early medical care and treatment, including psychological support for these patients, can minimize the consequences for patients and physicians, and may also help obtaining better outcomes when treating complications. PMID- 25536129 TI - Prevention and treatment of complications after polymethylmethacrylate microspheres injections. AB - The present article focuses on the peculiarities of polymethylmethacrylate as facial filler highlighting the injection technique, known adverse effects, and all options for complication management. Supplemented by a historical overview and case series, the authors share their experience with this widespread and in the last decade heavily criticized injectable filler substance. PMID- 25536130 TI - Oil-soluble vitamins: illegal use for lip augmentation. AB - Fillers for lip augmentation have become more and more popular in recent years and seem to be indispensable in the cosmetic market nowadays. A series of six young females is presented who developed massive swellings and pain after vitamins A and/or E lip augmentation. The vitamins were extracted from gelatinous capsules (Gericaps [Adipharm EAD, Sofia, Bulgaria], Geritamins [Actavis EAD, Balkanpharma-Dubnitsa AD, Bulgaria], or vitamin E yellow gel capsules) and injected by unprofessional physicians and beauticians in different cosmetic centers. Physical examination revealed firm indurations of the lips and perioral skin, tenderness, erythema, and hard dermal nodules. Histological analysis revealed numerous round-to-ovoid cavities of varying sizes, resulting in a Swiss cheese-like appearance, consistent with lipogranulomas. The patients were treated with systemic and intralesional triamcinolone injections and broad-spectrum antibiotics with good clinical response. In conclusion, these cases demonstrate the danger of the use of unregistered products as fillers injected by unprofessional physicians and beauticians. PMID- 25536132 TI - Diagnosis and management of filler adverse effects: an algorithm. AB - Fillers are frequently used in beautifying procedures. Despite major advancements of the chemical and biological features of injected materials, filler-related adverse events may occur, and can substantially impact the clinical outcome. Filler granulomas become manifest as visible grains, nodules, or papules around the site of the primary injection. Early recognition and proper treatment of filler-related complications is important because effective treatment options are available. In this report, we provide a comprehensive overview of the differential diagnosis and diagnostics and develop an algorithm of successful therapy regimens. PMID- 25536131 TI - Alginate (novabel): a new class of injectable filler. AB - A new class of biodegradable, injectable filler made of alginate, Novabel (Merz Aesthetics, Merz Pharma, UK), was launched in the European market in 2010. This product was supposed to be perfect to fill hollow eye rings and practitioners were immediately enthusiastic. Unfortunately, complications occurred as firm inflammatory nodules after a few months. Histological examinations revealed granulomatous reactions around spheroidal deposits. Treatment by triamcinolone injections was effective in some cases. Because of these complications, the company withdrew the alginate Novabel from the market. This is a didactic example of how a well-meant development with an insufficient test phase can turn into its opposite. Health authorities are exhorted to supervise not only drugs, but also injectables and other medical devices before they are launched, and during their application. PMID- 25536133 TI - Functional reconstruction of large medial canthal defects. AB - The aim of this study is to describe a surgical technique for the reconstruction of large medial canthal defects involving the lacrimal apparatus following excision of medial canthal tumors. Many different techniques for constructing a neopassage from the lacrimal sac to the nasal sinuses have been investigated and described in the literature. However, there continues to be difficulty with successful functional reconstruction of the lacrimal outflow tract without the long-term use of an indwelling tube. We herein describe a technique utilizing a paramedian forehead flap combined with AlloDerm (LifeCell Corporation, Township of Branchburg, NJ) as the conduit for reconstruction of the medial canthus and lacrimal outflow tract. We present a case series of three patients successfully reconstructed with the above technique and describe their presentation, treatment, and postoperative course. We provide a detailed description of the surgical technique and document the success of the technique in regard to patency and postprocedure function of the lacrimal conduit. PMID- 25536134 TI - Nasal lift-nasal valve lift and nasal tip lift-preliminary results of a new technique using noninvasive self-retaining unidirectional nasal suspension with threads. AB - In the context of nasal obstruction treatment, an alternative, no invasive technique is described. It consists in the suspension of the nasal valve or in the association of the suspension of the valve and rotation of the tip, through the placement of one or two absorbable threads, already known in aesthetic medicine. This technique allows to open the nasal valve and to correct the moderate closure of the nasolabial angle obtaining an immediate benefit of breathing. Functional improvement has been evaluated at regular intervals, that is, 1, 3, 6, and 12 months and then provided for every 6 months, through the use of a visual scale of 0/10 to 10/10. In our experience, the technique allows to obtain satisfactory results, avoiding more invasive techniques and postoperative recovery days. PMID- 25536136 TI - New flap for the reconstruction of the perinasal region. AB - Various reconstructive methods ranging from secondary healing to free flap applications are used for the reconstruction of perinasal defects caused by trauma or tumor surgery. The method to be used for the reconstruction of this region is chosen considering many factors because of specific determining structures. The number of studies on the subcutaneous tissue and vascular configurations of this region are gradually increasing along with the accumulation of knowledge in this region. Herein, we describe the nasal superficial musculoaponeurotic system-pedicled island skin flap for the reconstruction of the nasal tip, supratip, lateral nasal margin, and infraorbital area. The described skin flap was performed for defects resulting from basal cell carcinoma excision in all the patients. Of the patients, 12 were females and 5 were males. The mean age was 67.8 years (range, 56-82 years). All patients were operated on under general anesthesia. The flap donor areas were closed primarily. None of the patients developed flap necrosis. Although mild edema and venous insufficiency were observed in the flaps in the acute period only in patients who underwent nasal tip reconstruction, these improved during follow-up. In the operated patients, no problem was observed in the donor area and nasal dorsal skin. The nasal superficial musculoaponeurotic system-pedicled island skin flap which we describe for the perinasal area reconstruction is a safe, easily performed and versatile flap. The multidimensional use of this flap together with a relatively easy reconstruction plan and surgical procedure would be effective in flap choice. PMID- 25536135 TI - PRFM enhance wound healing process in skin graft. AB - Facial plastic and reconstructive surgery often used skin graft on defects that cannot be covered primarily by a local flap. However, wound healing using skin graft is slow, most of the time the graft is contractured and the take of graft is not optimal. Platelet rich fibrin matrix (PRFM) is a new generation of concentrated platelets that produce natural fibrin and reported to speed up the healing process. Application of PRFM in the skin graft implants is expected to increase the survival of the graft. We used porcine as animal models to elucidate the effect of autologous PRFM on wound healing in full-thickness (FTSG) and split thickness (STSG) skin grafts. Survival level of the skin graft was determined by using ImageJ software based on the formation of collagen type 1 and graft take. We observed that the use of PRFM in FTSG and STSG increased type 1 collagen formation. We also found that PRFM addition in STSG gave the best skin graft take. PMID- 25536137 TI - Cranial tip suture in nasal tip contouring. AB - The creation of both a functionally and aesthetically pleasing nasal tip contour is demanding and depends on various different parameters. Typically, procedures are performed with emphasis on narrowing the nasal tip structure. Excisional techniques alone inevitably lead to a reduction in skeletal support and are often prone to unpredictable deformities. But also long-term results of classical suture techniques have shown unfavorable outcomes. Particularly, pinching of the ala and a displacement of the caudal margin of the lateral crus below the cephalic margin belong to this category. A characteristic loss of structural continuity between the domes and the alar lobule and an undesirable shadowing occur. These effects lead to an unnatural appearance of the nasal tip and frequently to impaired nasal breathing. Stability and configuration of the alar cartilages alone do not allow for an adequate evaluation of the nasal tip contour. Rather a three-dimensional approach is required to describe all nasal tip structures. Especially, the rotational angle of the alar surface as well as the longitudinal axis of the lateral crus in relation to cranial septum should be considered in the three-dimensional analysis. Taking the various parameters into account, the authors present new aspects in nasal tip surgery which contribute to the creation of a functionally and aesthetically pleasing as well as durable nasal tip contour. PMID- 25536138 TI - Photoprotection: fundamental in organ transplant patients. PMID- 25536139 TI - Bilateral auricular pseudocyst: recognizing and treating. AB - An auricular pseudocyst is a benign cystic lesion of the auricular cartilage. When not recognized, it is a clinical presentation that can easily be misdiagnosed and subsequently be mistreated leading to unsatisfactory esthetical results or disease recurrence. A patient was presented with bilateral pseudocysts, which were surgically excised. The aim of the treatment of a pseudocyst is to have recurrence-free resolution and to restore the original auricular architecture while removing the cystic lesion. Three alternatives to surgery are described in the literature and all seem not to be sufficient. When the pseudocyst is treated at an early stage, surgical excision shows high success rates and preservation of the auricular architecture. According to the success rate described in the literature combined with the preservation of the auricular architecture, we recommend surgical excision for the management of auricular pseudocysts. PMID- 25536141 TI - Waist-to-height ratio is independently associated with chronic kidney disease in overweight type 2 diabetic patients. AB - OBJECTIVE: Chronic kidney disease (CKD) is one of the most serious complications in obesity-induced type 2 diabetes mellitus (T2DM). Body mass index (BMI), waist to-hip ratio (WHR), waist circumference (WC) and waist-to-height ratio (WHtR) are recognised as sensitive obesity measures. We aimed to investigate the association of BMI, WC, WHR and WHtR with CKD prevalence in overweight T2DM patients. DESIGN, SUBJECTS AND METHODS: We obtained 125 overweight T2DM patients coming for their in-patient annual visit. Metabolic profiles and anthropometric indices were measured and calculated. Urine albumin excretion (UAE) was determined as the mean of 24-h urine from two consecutive days. Serum creatinine was measured from fasting blood sample in order to calculate the estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients were divided into two groups according to CKD prevalence. RESULTS: Thirty-six (28.8%) patients met diagnostic criteria for CKD. The WHtR and WC were higher in the group with CKD. WHtR correlated positively with UAE (r = 0.828, p < 0.001) and negatively with eGFR (r = -0.262, p = 0.015). No significant correlation was observed with WC in relation to UAE (p = 0.335) nor eGFR (p = 0.121). WHtR yielded the significant and great OR in association with nephropathy after adjustment for all confounding risk factors. CONCLUSION: WHtR might be of a greater importance in association to CKD compared to other anthropometric parameters that indicate central obesity. Whether it is a best measure of central obesity and its exact role in CKD pathology is yet to be investigated. PMID- 25536142 TI - Psychological well-being in adolescents with excess weight. AB - BACKGROUND: Self-esteem, perceived health, weight satisfaction, eating habits, physical activity, friendships, intimate relationships, smoking and substance use habits can be regarded as important correlates of psychological well-being in adolescence. AIM: The present study aimed to determine whether problems in the above-mentioned elements of psychological well-being were more prevalent among mid-adolescent pupils with excess weight than among their healthy-weight peers. METHODS: The study participants comprised 178 adolescents with excess weight and 1087 healthy-weight peers with a mean age of 14.7 years attending the 8th grade at secondary school. The Rosenberg Self-Esteem Scale, the Eating Disorder Inventory and a questionnaire assessing health- and food-related attitudes and habits were used. RESULTS: The adolescents with excess weight more often reported weight dissatisfaction, abnormal eating habits and signs of eating disorder pathology than those with healthy weight. No significant difference in self esteem was observed between weight groups. The proportion of adolescents who were non-smokers, did not use alcohol and had one or more close friends did not differ between those with excess and healthy weight. However, a lower proportion of excess-weight adolescents had dating experience. Inadequate physical activity was highly prevalent among adolescents in both weight groups. CONCLUSIONS: Despite the high prevalence of eating pathology and weight dissatisfaction, most mid adolescent pupils with excess weight expressed good psychological health. Targeted psychological interventions should be offered to some adolescents with overweight problems. PMID- 25536143 TI - Involuntary psychiatric admission: Characteristics of the referring doctors and the doctors' experiences of being pressured. AB - BACKGROUND: In Norway, doctors may make the decision to refer patients to involuntary psychiatric treatment. This is a difficult decision, as it involves a range of medical, legal and ethical challenges. The decision to commit is presumed based on an independent assessment of the patient and whether a set of medico-legal criteria is met. AIMS: To examine characteristics of GPs that admitted patients involuntarily to a psychiatric hospital, and to examine how the GPs assessed this process. METHODS: 74 doctors who had referred patients to involuntary admission at one major Norwegian psychiatric hospital participated in semi-structured interviews. The questions posed were in part factual and in part about the participating doctors' assessments and considerations with respect to the involuntary admission of psychiatric patients. RESULTS: Approximately half of the participating doctors worked at the public out-of-hours clinics, while a fifth were the patients' family doctors. Those working at the out-of-hours clinics had less work experience and fewer had prior knowledge of the patients they committed. About half the doctors felt it was difficult to apply the medico legal criteria. More than half had felt pressured/advised to refer the patient to hospital and about half had felt pressured/advised to do so involuntarily. CONCLUSIONS: While doctors considering the commitment of psychiatric patients are presumed to make independent assessments of patients based on medico-legal criteria, this study suggests that many doctors feel pressured to commit. CLINICAL IMPLICATIONS: The assessment made by doctors who refer patients involuntarily to psychiatric hospital may be influenced by other parts of the health service, the patient's family and the police. Many doctors feel that it is difficult to apply the medico-legal criteria when referring patients involuntarily. PMID- 25536144 TI - Quantitative analysis of respiration-related movement for abdominal artery in multiphase hepatic CT. AB - OBJECTIVES: Respiration-induced motion in the liver causes potential errors on the measurement of contrast medium in abdominal artery from multiphase hepatic CT scans. In this study, we investigated the use of hepatic CT images to quantitatively estimate the abdominal artery motion due to respiration by optical flow method. MATERIALS AND METHODS: A total of 132 consecutive patients were included in our patient cohort. We apply the optical flow method to compute the motion of the abdominal artery due to respiration. RESULTS: The minimum and maximum displacement of the abdominal artery motion were 0.02 and 30.87 mm by manual delineation, 0.03 and 40.75 mm calculated by optical flow method, respectively. Both high consistency and correlation between the present method and the physicians' manual delineations were acquired with the regression equation of movement, y = 0.81x + 0.25, r = 0.95, p < 0.001. CONCLUSION: We estimated the motion of abdominal artery due to respiration using the optical flow method in multiphase hepatic CT scans and the motion estimations were validated with the visualization of physicians. The quantitative analysis of respiration-related movement of abdominal artery could be used for motion correction in the measurement of contrast medium passing though abdominal artery in multiphase CT liver scans. PMID- 25536145 TI - Donor-acceptor cocrystal based on hexakis(alkoxy)triphenylene and perylenediimide derivatives with an ambipolar transporting property. AB - An organic donor-acceptor cocrystal with an ambipolar transporting property was constructed based on N,N'-bis(1-ethylpropyl)-perylene-3,4,9,10-tetracarboxylic diimide (EP-PDI) and 2,3,6,7,10,11-hexakis-(hexyloxy)-triphenylene (H6TP). The cocrystal with an alternating stacking of H6TP and EP-PDI molecules was formed through both drop-casting and spin-coating processes, especially at the optimized ratios of H6TP/EP-PDI (2/1, 1/1). The formation of the cocrystal was driven by the strong pi-pi interaction and the weaker steric hindrance, resulting from the smaller side groups, between the donor and acceptor molecules. Field effect transistors (FETs) based on the H6TP/EP-PDI cocrystal exhibited relatively balanced hole/electron transport, with a hole mobility of 1.14 * 10(-3) cm(2) V( 1) s(-1) and an electron mobility of 1.40 * 10(-3) cm(2) V(-1) s(-1). PMID- 25536146 TI - Preliminary evaluation of a novel thoracoscopic infant lobectomy simulator. AB - PURPOSE: Thoracoscopic lobectomy in infants requires advanced minimally invasive skills. Simulation-based education has the potential to improve complex procedural skills without exposing the patient to undue risks. The study purposes were (1) to create a size-appropriate infant lobectomy simulator and (2) to evaluate validity evidence to support or refute its use in surgical education. MATERIALS AND METHODS: In this Institutional Review Board-exempt study, a size appropriate rib cage for a 3-month-old infant was created. Fetal bovine tissue completed the simulator. Thirty-three participants performed the simulated thoracoscopic lobectomy. Participants completed a self-report, 26-item instrument consisting of 25 4-point rating scales (from 1=not realistic to 4=highly realistic) and a one 4-point Global Rating Scale. Validity evidence relevant to test content and response processes was evaluated using the many-facet Rasch model, and evidence of internal structure (inter-item consistency) was estimated using Cronbach's alpha. RESULTS: Experienced surgeons (observed average=3.6) had slightly higher overall rating than novice surgeons (observed average=3.4, P=.001). The highest combined observed averages were for the domain Physical Attributes (3.7), whereas the lowest ratings were for the domains Realism of Experience and Ability to Perform Tasks (3.4). The global rating was 2.9, consistent with "this simulator can be considered for use in infant lobectomy training, but could be improved slightly." Inter-item consistency for items used to evaluate the simulator's quality was high (alpha=0.90). CONCLUSIONS: With ratings consistent with high physical attributes and realism, we successfully created an infant lobectomy simulator, and preliminary evidence relevant to test content, response processes, and internal structure was supported. Participants rated the model as realistic, relevant to clinical practice, and valuable as a learning tool. Minor improvements were suggested prior to its full implementation as an educational and testing tool. PMID- 25536150 TI - Sarcosine and betaine crystals upon cooling: structural motifs unstable at high pressure become stable at low temperatures. AB - The crystal structures of N-methyl derivatives of the simplest amino acid glycine, namely sarcosine (C3H7NO2) and betaine (C5H11NO2), were studied upon cooling by single-crystal X-ray diffraction and single-crystal polarized Raman spectroscopy. The effects of decreasing temperature and increasing hydrostatic pressure on the crystal structures were compared. In particular, we have studied the behavior upon cooling of those structural motifs in the crystals, which are involved in structural rearrangement during pressure-induced phase transitions. In contrast to their high sensitivity to hydrostatic compression, the crystals of both sarcosine and betaine are stable to cooling down to 5 K. Similarly to most alpha-amino acids, the crystal structures of the two compounds are most rigid upon cooling in the direction of the main structural motif, namely head-to-tail chains (linked via the strongest N-H...O hydrogen bonds and dipole-dipole interactions in the case of sarcosine, or exclusively by dipole-dipole interactions in the case of betaine). The anisotropy of linear strain in betaine does not differ much upon cooling and on hydrostatic compression, whereas this is not the case for sarcosine. Although the interactions between certain structural motifs in sarcosine and betaine weaken as a result of phase transitions induced by pressure, the same interactions strengthen when volume reduction results from cooling. PMID- 25536149 TI - Cholate-based synthesis of size-tunable cage compounds. AB - We describe cholate-based cage amphiphiles with a unique architecture that combines elements of structural rigidity and flexibility. The cage compounds are built by extending and bridging three polar chains underneath the concave steroid rings of cholate and capping with another rigid, symmetrically trifunctionalized cyanuric acid moiety. The connecting chains are varied to include, for instance, oligo(ethylene glycol) or chains containing 1,2,3-triazole units to present flexibility in the chemical and structural space and potentially deliver functional molecules for molecular recognition applications. PMID- 25536151 TI - Synergistic photogeneration of reactive oxygen species by dissolved organic matter and C60 in aqueous phase. AB - We investigated the photogeneration of reactive oxygen species (ROS) by C60 under UV irradiation, when humic acid (HA) or fulvic acid (FA) is present. When C60 and dissolved organic matter (DOM) were present as a mixture, singlet oxygen ((1)O2) generation concentrations were 1.2-1.5 times higher than the sum of (1)O2 concentrations that were produced when C60 and DOM were present in water by themselves. When C60 and HA were present as a mixture, superoxide radicals (O2(* )) were 2.2-2.6 times more than when C60 and HA were present in water by themselves. A synergistic ROS photogeneration mechanism involved in energy and electron transfer between DOM and C60 was proposed. Enhanced (1)O2 generation in the mixtures was partly due to (3)DOM* energy transfer to O2. However, it was mostly due to (3)DOM* energy transfer to C60 producing (3)C60*. (3)C60* has a prolonged lifetime (>4 MUs) in the mixture and provides sufficient time for energy transfer to O2, which produces (1)O2. The enhanced O2(*-) generation for HA/C60 mixture was because (3)C60* mediated electron transfer from photoionized HA to O2. This study demonstrates the importance of considering DOM when investigating ROS production by C60. PMID- 25536152 TI - Programming of shape memory natural rubber for near-discrete shape transitions. AB - Typical shape memory polymers are hot-programmed and show a shape transition over a broad temperature range of 10 K and more. Cold-programmed shape memory natural rubber (SMNR) recovers more than 80% of its original shape within 1 K. The trigger point can be increased upon aging the stretched SMNR over several weeks without losing the narrow trigger range. This process can be accelerated by treatment of the stretched SMNR with nonaffine solvent vapors. Affine solvent vapors of low concentrations afford higher trigger points than that achieved by aging. This way, even higher cross-linked natural rubber can be cold-programmed. PMID- 25536148 TI - Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer. AB - RATIONALE: Recent studies indicate that tumor-associated macrophages (MPhi) with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized. OBJECTIVES: This study investigated the role of tumor-associated MPhi in lung cancer. METHODS: Coculturing of MPhi with mouse Lewis lung carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) caused up-regulation of CCR2/CCL2 and CX3CR1/CX3CL1 in both the cancer cells and the MPhi. MEASUREMENTS AND MAIN RESULTS: In the MPhi-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony stimulating factor, and MIP1alpha were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and MPhi M2 polarization. In vivo, MPhi depletion (clodronate, MPhi Fas induced apoptosis mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated MPhi toward M1 polarization, suppressed tumor vessel growth, and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2, showing reduced tumor growth and metastasis. In human lung cancer samples, tumor MPhi infiltration and CCR2 expression correlated with tumor stage and metastasis. CONCLUSIONS: Tumor-associated MPhi play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between MPhi and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression. PMID- 25536153 TI - Solitary liver metastasis from follicular variant papillary thyroid carcinoma: A case report and literature review. AB - INTRODUCTION: Papillary (PTC) and follicular (FTC) thyroid carcinomas, together known as differentiated thyroid carcinomas (DTC), are among the most curable of cancers. Sites of metastases from FTC are usually osseous and those from PTC are in regional nodal basins and the lungs. Visceral metastases are rare and when they do occur, they tend do so in multiple sites. We present the case of a patient with a follicular variant of PTC and a solitary metastasis to the liver then review the relevant literature. PRESENTATION OF CASE: An otherwise healthy 68-year-old woman was diagnosed with follicular variant papillary thyroid cancer in 2003 and subsequently underwent thyroidectomy. The patient's endocrinologist conducted surveillance of her thyroid cancer. In 2012, due to rise in thyroglobulin, a whole body radioiodine scan was obtained which revealed an iodine-avid left liver lobe mass. Three cycles of radioiodine ablation therapy were unsuccessful and eventually the patient was referred for surgical resection. Metastatic evaluation including a PET scan was negative with the exception of an isolated enhancing 4cm mass in segment 4B of the liver. Anatomic segmental resection of liver was performed without complications. Intraoperative ultrasonography was used to guide resection of the liver mass. Pathology reports confirmed metastatic follicular variant of PTC. Surgical margins were free of tumor. Patient was discharged home and is doing well one year after surgery. The latest thyroglobulin level was undetectable. DISCUSSION: Post-operative surveillance by PCP, endocrinologist or surgeon for patients with thyroid carcinoma should be performed routinely. If identified, a solitary liver metastasis from primary thyroid carcinoma should be considered for surgical resection. Due to sparse data available in literature, collecting more data to establish algorithms for treatment of such rare metastatic cancers may be able to aid physicians to achieve better outcomes. CONCLUSION: Rare distant sites of metastases from DTC include eyes, pharynx, skin, muscle, ovaries, adrenal glands, kidneys, esophagus, pancreas and liver. Isolated, resectable liver metastases from PTC are exceedingly rare. Literature review revealed only 10 reported cases of liver metastases from DTC. As in our patient, solitary liver metastasis from PTC should be considered for surgical resection which offers the best chance for prolonged survival. PMID- 25536155 TI - Exploring why junk foods are 'essential' foods and how culturally tailored recommendations improved feeding in Egyptian children. AB - In Egypt, the double burden of malnutrition and rising overweight and obesity in adults mirrors the transition to westernized diets and a growing reliance on energy-dense, low-nutrient foods. This study utilized the trials of improved practices (TIPs) methodology to gain an understanding of the cultural beliefs and perceptions related to feeding practices of infants and young children 0-23 months of age and used this information to work in tandem with 150 mothers to implement feasible solutions to feeding problems in Lower and Upper Egypt. The study triangulated in-depth interviews (IDIs) with mothers participating in TIPs, with IDIs with 40 health providers, 40 fathers and 40 grandmothers to gain an understanding of the influence and importance of the role of other caretakers and health providers in supporting these feeding practices. Study findings reveal high consumption of junk foods among toddlers, increasing in age and peaking at 12-23 months of age. Sponge cakes and sugary biscuits are not perceived as harmful and considered 'ideal' common complementary foods. Junk foods and beverages often compensate for trivial amounts of food given. Mothers are cautious about introducing nutritious foods to young children because of fears of illness and inability to digest food. Although challenges in feeding nutritious foods exist, mothers were able to substitute junk foods with locally available and affordable foods. Future programming should build upon cultural considerations learned in TIPs to address sustainable, meaningful changes in infant and young child feeding to reduce junk foods and increase dietary quality, quantity and frequency. PMID- 25536154 TI - MicroRNA-139-5p Suppresses 3T3-L1 Preadipocyte Differentiation Through Notch and IRS1/PI3K/Akt Insulin Signaling Pathways. AB - MicroRNAs (miRNAs) participate in the regulation of adipogenesis. Identification of the full repertoire of miRNAs expressed in adipose tissue is likely to significantly improve our understanding of adipose tissue growth and development. Here, miR-139-5p was identified as an inhibitor of 3T3-L1 adipocyte differentiation with significantly down-regulating the expression levels of adipogenic marker genes PPAR gamma (P < 0.01), aP2 (P < 0.01) and FAS (P < 0.01). Importantly, flow cytometry and EdU incorporation assay indicated that this inhibition was partly due to the dysfunction of clonal expansion. Furthermore, we firstly demonstrated that miR-139-5p blocked adipogenesis via directly targeted the 3' untranslated regions (UTRs) of Notch1 and IRS1 mRNAs, a key member of Notch signaling and IRS1/PI3K/Akt insulin signaling, respectively. In addition, the overexpression of Notch1 or IRS1 partially restored the suppressive effects miR-139-5p on differentiation of 3T3-L1 cells. To our knowledge, this was the first report that miR-139-5p functioned negatively by targeting Notch1 and IRS1 during 3T3-L1 adipogenesis, regulating the transition from clonal expansion to terminal differentiation. PMID- 25536156 TI - Comparison of the Therapeutic Efficacy of Surgery with or without Adjuvant Radiotherapy versus Radiotherapy Alone for Metastatic Spinal Cord Compression: A Meta-Analysis. AB - BACKGROUND: Spinal metastases are 20 times more common than primary spinal tumors and often cause metastatic spinal cord compression (MSCC). Clinical manifestations (e.g., pain and neurologic dysfunction) adversely affect patients' quality of life. Radiotherapy (RT), chemotherapy, and surgery are the major therapeutic strategies for MSCC. There is some evidence that combining surgery with adjuvant RT may be a better option. METHODS: This meta-analysis compared the therapeutic efficacy of surgery (with or without adjuvant RT) with RT alone in treatment of MSCC. Comparative studies of surgery (with or without adjuvant RT) versus RT alone for the treatment of MSCC were retrieved from the MEDLINE, EMBASE, and Cochrane Library databases. Primary (1-year survival) and secondary (motor function and complications) outcomes were compared by meta-analysis. RESULTS: Of the 26 studies originally identified, 20 were excluded (not original research, lack of relevance, no group comparison, or lack of comparable data). Compared with RT alone, surgery (with or without adjuvant RT) was associated with improvement of ambulation (odds ratio = 1.74, 95% confidence interval = 1.35 2.25, P < 0.05), pain relief (odds ratio = 3.61, 95% confidence interval = 2.75 4.74, P < 0.05), and 1-year survival (odds ratio = 1.92; 95% confidence interval = 1.37-2.71, P < 0.01). No differences in regaining walking ability and substantially longer hospital stays were observed. Surgery showed better therapeutic efficacy than RT alone with regard to quality of life and life expectancy, without additional complications. CONCLUSIONS: Further studies are needed to investigate the effects of these interventions on quality of life and to identify the best therapeutic strategy for patients with MSCC. PMID- 25536157 TI - T lymphocytes control microbial composition by regulating the abundance of Vibrio in the zebrafish gut. AB - Dysbiosis of the intestinal microbial community is considered a risk factor for development of chronic intestinal inflammation as well as other diseases such as diabetes, obesity and even cancer. Study of the innate and adaptive immune pathways controlling bacterial colonization has however proven difficult in rodents, considering the extensive cross-talk between bacteria and innate and adaptive immunity. Here, we used the zebrafish to study innate and adaptive immune processes controlling the microbial community. Zebrafish lack a functional adaptive immune system in the first weeks of life, enabling study of the innate immune system in the absence of adaptive immunity. We show that in wild type zebrafish, the initial lack of adaptive immunity associates with overgrowth of Vibrio species (a group encompassing fish and human pathogens), which is overcome upon adaptive immune development. In Rag1-deficient zebrafish (lacking adaptive immunity) Vibrio abundance remains high, suggesting that adaptive immune processes indeed control Vibrio species. Using cell transfer experiments, we confirm that adoptive transfer of T lymphocytes, but not B lymphocytes into Rag1 deficient recipients suppresses outgrowth of Vibrio. In addition, ex vivo exposure of intestinal T lymphocytes to Rag1-deficient microbiota results in increased interferon-gamma expression by these T lymphocytes, compared to exposure to wild type microbiota. In conclusion, we show that T lymphocytes control microbial composition by effectively suppressing the outgrowth of Vibrio species in the zebrafish intestine. PMID- 25536158 TI - The SNP rs3128965 of HLA-DPB1 as a genetic marker of the AERD phenotype. AB - BACKGROUND: Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population. METHODS: A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups. RESULTS: The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively). CONCLUSIONS: This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype. PMID- 25536164 TI - Temporal transcriptome changes induced by methyl jasmonate in Salvia sclarea. AB - Salvia sclarea is a traditional medicinal and aromatic plant that grows in Europe and produces various economically important compounds, including phenylpropanoid derivatives and terpenoids. Methyl jasmonate (MeJA) is commonly used to elicit plant stress responses. However, how MeJA enhances production of secondary metabolites in S. sclarea is not well understood. We performed a genome-wide analysis of temporal gene expression in S. sclarea leaves and roots. The transcriptome profiles 0, 10 and 26 h after MeJA treatment were analyzed by Illumina RNA-Seq. A total of 16,142 isogenes (average length 866bp; N50 1035bp) were obtained by de novo assembly of 35,757,567 raw sequencing reads. When these sequencing reads were mapped onto the assembled Unigenes, 3236, 2792 and 798 Unigenes were found to be expressed differentially between 0 and 10h, 0 and 26 h, and 10 and 26h, respectively. These included many secondary metabolite biosynthesis, stress and defense-related genes. A qRT-PCR analysis confirmed the expression profiles of selected differentially expressed genes (DEGs) revealed by RNA-Seq data, and also extended our analysis of differential gene expression to 73 h. Our investigations revealed temporal differences in the responses of S. sclarea to MeJA treatment. MeJA treatment induced the expression of a large number of genes involved in phenylpropanoid biosynthesis, especially between 0 and 10h, and 0 and 26 h. Additionally, many genes encoding transcription factors, cytochrome P450s, glycosyltransferases, methyltransferases and transporters were shown to respond to MeJA elicitation. DEGs related to structural molecule activity and cell death showed a significant temporal variation. A chromatographic analysis of metabolites at 26h, 73h and six days after MeJA treatment indicated that these transcriptomic changes precede MeJA-induced changes in secondary metabolite content. This study sheds light on the molecular mechanisms of MeJA elicitation and is helpful in understanding how exogenous MeJA treatment mediates extensive plant transcriptome reprogramming/remodeling. Our results can be utilized to characterize genes related to secondary metabolism and their regulation, and in breeding S. sclarea for desirable chemotypes. PMID- 25536165 TI - Internal transcribed spacer (ITS) evolution in populations of the hyperparasitic European mistletoe pathogen fungus, Sphaeropsis visci (Botryosphaeriaceae): The utility of ITS2 secondary structures. AB - We investigated patterns of nucleotide polymorphism in the internal transcribed spacer (ITS) region for Sphaeropsis visci, a hyperparasitic fungus that causes the leaf spot disease of the hemiparasite European mistletoe (Viscum album). Samples of S. visci were obtained from Hungary covering all major infected forest areas. For obtaining PCR products we used a fast and efficient direct PCR approach based on a high fidelity DNA polymerase. A total of 140 ITS sequences were subjected to an array of complementary sequence analyses, which included analyses of secondary structure stability, nucleotide polymorphism patterns, GC content, and presence of conserved motifs. Analysed sequences exhibited features of functional rRNAs. Overall, polymorphism was observed within less conserved motifs, such as loops and bulges, or, alternatively, as non-canonical G-U pairs within conserved regions of double stranded helices. The secondary structure of ITS2 provides new opportunities for obtaining further valuable information, which could be used in phylogenetic analyses, or at population level as demonstrated in our study. This is due to additional information provided by secondary structures and their models. The combined score matrix was used with the methods implemented in the programme 4SALE. Besides the pseudoprotein coding method of 4SALE, the molecular morphometric character coding also has potential for gaining further information for phylogenetic analyses based on the geometric features of the sub structural elements of the ITS2 RNA transcript. PMID- 25536167 TI - Toward brain-based guidance of clinical practice. PMID- 25536166 TI - Zinc finger nuclease technology: advances and obstacles in modelling and treating genetic disorders. AB - Zinc finger nucleases (ZFNs) are engineered restriction enzymes designed to target specific DNA sequences within the genome. Assembly of zinc finger DNA binding domain to a DNA-cleavage domain enables the enzyme machinery to target unique locus in the genome and invoke endogenous DNA repair mechanisms. This machinery offers a versatile approach in allele editing and gene therapy. Here we discuss the architecture of ZFNs and strategies for generating targeted modifications within the genome. We review advances in gene therapy and modelling of the disease using these enzymes and finally, discuss the practical obstacles in using this technology. PMID- 25536168 TI - Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice. AB - OBJECTIVES: To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. METHODS: We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100 mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. RESULTS: We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 +/- 1.0, 4.8 +/- 1.0, and 4.7 +/- 1.9, respectively, at baseline to 2.4 +/- 1.2, 3.3 +/- 1.5, and 2.5 +/- 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 +/- 1.2 before to 3.6 +/- 1.3 12 weeks after the dose increase. Oral corticosteroid therapy >= 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. CONCLUSIONS: Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice. PMID- 25536169 TI - Uncovering intense protein diversification in a cone snail venom gland using an integrative venomics approach. AB - Marine cone snail venoms are highly complex mixtures of peptides and proteins. They have been studied in-depth over the past 3 decades, but the modus operandi of the venomous apparatus still remains unclear. Using the fish-hunting Conus consors as a model, we present an integrative venomics approach, based on new proteomic results from the venom gland and data previously obtained from the transcriptome and the injectable venom. We describe here the complete peptide content of the dissected venom by the identification of numerous new peptides using nanospray tandem mass spectrometry in combination with transcriptomic data. Results reveal extensive mature peptide diversification mechanisms at work in the venom gland. In addition, by integrating data from three different venom stages, transcriptome, dissected, and injectable venoms, from a single species, we obtain a global overview of the venom processing that occurs from the venom gland tissue to the venom delivery step. In the light of the successive steps in this venom production system, we demonstrate that each venom compartment is highly specific in terms of peptide and protein content. Moreover, the integrated investigative approach discussed here could become an essential part of pharmaceutical development, as it provides new potential drug candidates and opens the door to numerous analogues generated by the very mechanisms used by nature to diversify its peptide and protein arsenal. PMID- 25536172 TI - Initial gas phase reactions between Al(CH3)3/AlH3 and ammonia: theoretical study. AB - Mechanisms of initial stages of gas phase reactions between trimethylaluminum and ammonia have been explored by DFT studies. Subsequent substitution of CH3 groups in AlMe3 by amido groups and substitution of hydrogen atoms in ammonia by AlMe2 groups have been considered. Structures of Al(CH3)x(NH2)3-x, NHx(Al(CH3)2)3-x (x = 0-3) and related donor-acceptor complexes, dimerization products, and reaction pathways for the methane elimination have been obtained. The transition state for the first methane elimination from Al(CH3)3NH3 adduct is the highest point on the reaction pathway; subsequent processes are exothermic and do not require additional activation energy. In excess ammonia, subsequent methane elimination reactions may lead to formation of [Al(NH2)3]2, while in excess trimethylaluminum, formation of N(AlMe2)3 is feasible. Formation of [AlMe2NH2]2 dimer is very favorable thermodynamically. Studies on model reactions between AlH3 and NH3 indicate that reaction barriers obtained for hydrogen-substituted species may serve as an upper estimate in studying the reactivity of methyl substituted analogues in more complex systems. PMID- 25536170 TI - Purified anthocyanins from bilberry and black currant attenuate hepatic mitochondrial dysfunction and steatohepatitis in mice with methionine and choline deficiency. AB - The berries of bilberry and black currant are a rich source of anthocyanins, which are thought to have favorable effects on nonalcoholic steatohepatitis (NASH). This study was designed to examine whether purified anthocyanins from bilberry and black currant are able to limit the disorders related to NASH induced by a methionine-choline-deficient (MCD) diet in mice. The results showed that treatment with anthocyanins not only alleviated inflammation, oxidative stress, steatosis, and even fibrosis but also improved depletion of mitochondrial content and damage of mitochondrial biogenesis and electron transfer chain developed concomitantly in the liver of mice fed the MCD diet. Furthermore, anthocyanins treatment promoted activation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha). These data provide evidence that anthocyanins possess significant protective effects against NASH and mitochondrial defects in response to a MCD diet, with a mechanism maybe through affecting the AMPK/PGC-1alpha signaling pathways. PMID- 25536173 TI - A retrospective observational study to assess adverse transfusion reactions of patients with and without prior transfusion history. AB - BACKGROUND AND OBJECTIVES: This study compares the frequency of adverse transfusion reactions (ATRs) after first transfusions with the frequency of ATRs for subsequent (non-first) transfusions. MATERIALS AND METHODS: Five hospitals agreed to systematically collect and share 2 years of data. This was a retrospective observational analysis of data including the number of transfusion episodes and ATRs for red blood cells (RBCs), fresh frozen plasma (FFP) and platelet concentrates (PCs) given to first-time transfusion recipients and to those previously transfused. RESULTS: First transfusion ATRs to RBCs, FFP and PCs were 1.08%, 2.84% and 3.34%, respectively. These are higher than ATR incidences to RBCs (0.69%), FFP (1.91%) and PCs (2.75%) on subsequent transfusions. Specifically, first transfusion incidences of febrile non-haemolytic transfusion reactions (FNHTRs) to RBCs (0.43%) and allergic reactions to FFP (2.51%) were higher than on subsequent transfusions (RBCs: 0.23%, FFP: 1.65%). CONCLUSION: There are risks of ATRs on the first transfusion as well as transfusions of patients with transfusion history. PMID- 25536171 TI - B cell TLR1/2, TLR4, TLR7 and TLR9 interact in induction of class switch DNA recombination: modulation by BCR and CD40, and relevance to T-independent antibody responses. AB - Ig class switch DNA recombination (CSR) in B cells is crucial to the maturation of antibody responses. It requires IgH germline IH-CH transcription and expression of AID, both of which are induced by engagement of CD40 or dual engagement of a Toll-like receptor (TLR) and B cell receptor (BCR). Here, we have addressed cross-regulation between two different TLRs or between a TLR and CD40 in CSR induction by using a B cell stimulation system involving lipopolysaccharides (LPS). LPS-mediated long-term primary class-switched antibody responses and memory-like antibody responses in vivo and induced generation of class-switched B cells and plasma cells in vitro. Consistent with the requirement for dual TLR and BCR engagement in CSR induction, LPS, which engages TLR4 through its lipid A moiety, triggered cytosolic Ca2+ flux in B cells through its BCR engaging polysaccharidic moiety. In the presence of BCR crosslinking, LPS synergized with a TLR1/2 ligand (Pam3CSK4) in CSR induction, but much less efficiently with a TLR7 (R-848) or TLR9 (CpG) ligand. In the absence of BCR crosslinking, R-848 and CpG, which per se induced marginal CSR, virtually abrogated CSR to IgG1, IgG2a, IgG2b, IgG3 and/or IgA, as induced by LPS or CD154 (CD40 ligand) plus IL-4, IFN-gamma or TGF-beta, and reduced secretion of class switched Igs, without affecting B cell proliferation or IgM expression. The CSR inhibition by TLR9 was associated with the reduction in AID expression and/or IgH germline IH-S-CH transcription, and required co-stimulation of B cells by CpG with LPS or CD154. Unexpectedly, B cells also failed to undergo CSR or plasma cell differentiation when co-stimulated by LPS and CD154. Overall, by addressing the interaction of TLR1/2, TLR4, TLR7 and TLR9 in the induction of CSR and modulation of TLR-dependent CSR by BCR and CD40, our study suggests the complexity of how different stimuli cross-regulate an important B cell differentiation process and an important role of TLRs in inducing effective T independent antibody responses to microbial pathogens, allergens and vaccines. PMID- 25536174 TI - Transcription factor NF-kappaB associates with microtubules and stimulates apoptosis in response to suppression of microtubule dynamics in MCF-7 cells. AB - NF-kappaB, a master regulator of several signaling cascades, is known to be actively transported in the nucleus in response to various stimuli. Here, we found that NF-kappaB is associated with polymeric tubulin and co-localized with microtubules in MCF-7 cells. Using TN16, a known microtubule targeting agent, we found that microtubule dynamics plays a critical role in NF-kappaB-microtubule interaction. Treatment of cells with low concentrations of TN16 (25 and 50 nM) that suppressed microtubule dynamics without visibly affecting microtubule organization enhanced the association of NF-kappaB with microtubules and facilitated nuclear translocation of NF-kappaB. Colchicine and vinblastine also produced similar nuclear translocation of NF-kappaB. Further, nuclear import of NF-kappaB activated apoptotic pathway in the cells that were blocked in mitosis by TN16 treatment suggesting that NF-kappaB acts as a pro-apoptotic protein in response to the suppression of microtubule dynamics. Interestingly, in the presence of high concentrations of TN16 that extensively disrupted the microtubule network, though there was an increase in the apoptotic cell death, the interaction of NF-kappaB with microtubules and its nuclear import were significantly reduced. Under these conditions, we detected an increase in the level of phosphorylation and nuclear accumulation of ERK, a MAP kinase, suggesting that the induction of apoptosis was caused by ERK signaling. The results indicate that the interaction of NF-kappaB with microtubules, its nuclear accumulation and subsequent gene transcription are critically dependent on microtubule dynamics. The data suggest a correlation between the functional status of microtubules and different apoptotic mechanisms invoked in response to microtubule inhibitors. PMID- 25536176 TI - Coastal eutrophication in Europe caused by production of energy crops. AB - In Europe, the use of biodiesel may increase rapidly in the coming decades as a result of policies aiming to increase the use of renewable fuels. Therefore, the production of biofuels from energy crops is expected to increase as well as the use of fertilisers to grow these crops. Since fertilisers are an important cause of eutrophication, the use of biodiesel may have an effect on the water quality in rivers and coastal seas. In this study we explored the possible effects of increased biodiesel use on coastal eutrophication in European seas in the year 2050. To this end, we defined a number of illustrative scenarios in which the biodiesel production increases to about 10-30% of the current diesel use. The scenarios differ with respect to the assumptions on where the energy crops are cultivated: either on land that is currently used for agriculture, or on land used for other purposes. We analysed these scenarios with the Global NEWS (Nutrient Export from WaterSheds) model. We used an existing Millennium Ecosystem Assessment Scenario for 2050, Global Orchestration (GO2050), as a baseline. In this baseline scenario the amount of nitrogen (N) and phosphorus (P) exported by European rivers to coastal seas decreases between 2000 and 2050 as a result of environmental and agricultural policies. In our scenarios with increased biodiesel production the river export of N and P increases between 2000 and 2050, indicating that energy crop production may more than counterbalance this decrease. Largest increases in nutrient export were calculated for the Mediterranean Sea and the Black Sea. Differences in nutrient export among river basins are large. PMID- 25536175 TI - Merging two waste streams, wood ash and biowaste, results in improved composting process and end products. AB - A trial was carried out to evaluate the influence of wood ash admixture on biowaste composting. The aim was to find the optimal dosage of ash addition to enhance the composting process without endangering the final compost characteristics and use. Six treatments including an unamended control (K0) and composts with additions of 3% (K3), 6% (K6), 9% (K9), 12% (K12) and 15% (K15) of wood ash (w/w) were studied. The composting process was monitored in situ for 49days, by measuring temperature, CO2, O2, and CH4 in the piles and pH, electric conductivity (EC), and inorganic N in the laboratory. At the end of the process, the products were tested for Reifegrad (maturity), toxicity and quality. The addition of up to 15% of wood ash to biowaste did not negatively affect the composting process, and the initial differences found between both the low and high ash-treated composts were attenuated with the ongoing process development. Nevertheless, and mainly due to Cd level, composts with higher ash amendment did not comply with the highest quality standards established by the Austrian Compost Ordinance. The failure of obtaining class A+ quality after ash amendment emphasizes the need for a rigid quality selection of (bottom) ashes and thus reducing environmental risks related to high pollutant loads originating from the ashes. PMID- 25536177 TI - Levels and temporal trends of persistent organic pollutants (POPs) in arctic foxes (Vulpes lagopus) from Svalbard in relation to dietary habits and food availability. AB - Temporal trends of persistent organic pollutants (POPs) in arctic foxes (Vulpes lagopus) from Svalbard, Norway, were investigated in relation to feeding habits and seasonal food availability. Arctic foxes from Svalbard forage in both marine and terrestrial ecosystems and the availability of their food items are impacted by climatic variability. Concentrations of polychlorinated biphenyls (PCBs), organochlorinated pesticides (OCPs) and brominated flame retardants (polybrominated diphenyl ethers [PBDEs] and hexabromocyclododecane [HBCDD]) were analyzed in the liver of 141 arctic foxes collected between 1997 and 2013. Stable carbon isotope values (delta13C) were used as a proxy for feeding on marine versus terrestrial prey. The annual number of recovered reindeer carcasses and sea ice cover were used as proxies for climate influenced food availability (reindeers, seals). Linear models revealed that concentrations of PCBs, chlordanes, p,p'-DDE, mirex and PBDEs decreased 4-11% per year, while no trends were observed for hexachlorobenzene (HCB) or beta-hexachlorocyclohexane (beta HCH). Positive relationships between POP concentrations and delta13C indicate that concentrations of all compounds increase with increasing marine dietary input. Increasing reindeer mortality was related to lower HCB concentrations in the foxes based on the linear models. This suggests that concentrations of HCB in arctic foxes may be influenced by high mortality levels of Svalbard reindeer. Further, beta-HCH concentrations showed a positive association with sea ice cover. These results in addition to the strong effect of delta13C on all POP concentrations suggest that climate-related changes in arctic fox diet are likely to influence contaminant concentrations in arctic foxes from Svalbard. PMID- 25536178 TI - Noncoding RNAs in diabetes vascular complications. AB - Diabetes mellitus is the most common metabolic disorder and is recognised as a dominant health threat of our time. Diabetes induces a widespread damage of the macro- and microvasculature in different organs and tissues and disrupts the endogenous vascular repair mechanisms, thus causing diffuse and severe complications. Moreover, diabetic patients respond poorly to surgical interventions aiming to "revascularise" (i.e., to restore blood flow supply) the ischemic myocardium or lower limbs. The molecular causes underpinning diabetes vascular complications are still underappreciated and druggable molecular targets for therapeutic interventions have not yet clearly emerged. Moreover, diabetes itself and diabetes complications are often silent killers, requiring new prognostic, diagnostic and predictive biomarkers for use in the clinical practice. Noncoding RNA (ncRNAs) are emerging as new fundamental regulators of gene expression. The small microRNAs (miRNAs, miRs) have opened the field capturing the attention of basic and clinical scientists for their potential to become new therapeutic targets and clinical biomarkers. More recently, long ncRNAs (lncRNAs) have started to be actively investigated, leading to first exciting reports, which further suggest their important and yet largely unexplored contribution to vascular physiology and disease. This review introduces the different ncRNA types and focuses at the ncRNA roles in diabetes vascular complications. Furthermore, we discuss the potential value of ncRNAs as clinical biomarkers, and we examine the possibilities for therapeutic intervention targeting ncRNs in diabetes. This article is part of a Special Issue titled: Non-coding RNAs. PMID- 25536179 TI - Calcium signaling regulates ventricular hypertrophy during development independent of contraction or blood flow. AB - In utero interventions aimed at restoring left ventricular hemodynamic forces in fetuses with prenatally diagnosed hypoplastic left heart syndrome failed to stimulate ventricular myocardial growth during gestation, suggesting chamber growth during development may not rely upon fluid forces. We therefore hypothesized that ventricular hypertrophy during development may depend upon fundamental Ca(2+)-dependent growth pathways that function independent of hemodynamic forces. To test this hypothesis, zebrafish embryos were treated with inhibitors or activators of Ca(2+) signaling in the presence or absence of contraction during the period of chamber development. Abolishment of contractile function alone in the setting of preserved Ca(2+) signaling did not impair ventricular hypertrophy. In contrast, inhibition of L-type voltage-gated Ca(2+) influx abolished contraction and led to reduced ventricular hypertrophy, whereas increasing L-type voltage-gated Ca(2+) influx led to enhanced ventricular hypertrophy in either the presence or absence of contraction. Similarly, inhibition of the downstream Ca(2+)-sensitive phosphatase calcineurin, a known regulator of adult cardiac hypertrophy, led to reduced ventricular hypertrophy in the presence or absence of contraction, whereas hypertrophy was rescued in the absence of L-type voltage-gated Ca(2+) influx and contraction by expression of a constitutively active calcineurin. These data suggest that ventricular cardiomyocyte hypertrophy during chamber formation is dependent upon Ca(2+) signaling pathways that are unaffected by heart function or hemodynamic forces. Disruption of Ca(2+)-dependent hypertrophy during heart development may therefore represent one mechanism for impaired chamber formation that is not related to impaired blood flow. PMID- 25536181 TI - Nanoscale analysis of ryanodine receptor clusters in dyadic couplings of rat cardiac myocytes. AB - The contractile properties of cardiac myocytes depend on the calcium (Ca(2+)) released by clusters of ryanodine receptors (RyRs) throughout the myoplasm. Accurate quantification of the spatial distribution of RyRs has previously been challenging due to the comparatively low resolution in optical microscopy. We have combined single-molecule localisation microscopy (SMLM) in a super resolution modality known as dSTORM with immunofluorescence staining of tissue sections of rat ventricles to resolve a wide, near-exponential size distribution of RyR clusters that lined on average ~57% of the perimeter of each myofibril. The average size of internal couplons is ~63 RyRs (nearly 4 times larger than that of peripheral couplons) and the largest clusters contain many hundreds of RyRs. Similar to previous observations in peripheral couplons, we observe many clusters with one or few receptors; however >=80% of the total RyRs were detected in clusters containing >=100 receptors. ~56% of all clusters were within an edge to-edge distance sufficiently close to co-activate via Ca(2+)-induced Ca(2+) release (100nm) and were grouped into 'superclusters'. The co-location of superclusters with the same or adjacent t-tubular connections in dual-colour super-resolution images suggested that member sub-clusters may be exposed to similar local luminal Ca(2+) levels. Dual-colour dSTORM revealed high co localisation between the cardiac junctional protein junctophilin-2 (JPH2) and RyR clusters that confirmed that the majority of the RyR clusters observed are dyadic. The increased sensitivity of super-resolution images revealed approximately twice as many RyR clusters (2.2clusters/MUm(3)) compared to previous confocal measurements. We show that, in general, the differences of previous confocal estimates are largely attributable to the limited spatial resolution of diffraction-limited imaging. The new data can be used to inform the construction of detailed mechanistic models of cardiac Ca(2+) signalling. PMID- 25536180 TI - NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFkappaB activation. AB - Recent work has highlighted the role of NR4A receptors in atherosclerosis and inflammation. In vascular smooth muscle cell (VSMC) proliferation, however, NOR-1 (neuron-derived orphan receptor-1) exerts antagonistic effects to Nur77 and Nurr1. The aim of this study was to analyse the effect of NOR-1 in VSMC inflammatory response. We assessed the consequence of a gain-of-function of this receptor on the response of VSMC to inflammatory stimuli. In human VSMC, lentiviral over-expression of NOR-1 reduced lipopolysaccharide (LPS)-induced up regulation of cytokines (IL-1beta, IL-6 and IL-8) and chemokines (MCP-1 and CCL20). Similar effects were obtained in cells stimulated with TNFalpha or oxLDL. Conversely, siRNA-mediated NOR-1 inhibition significantly increased the expression of pro-inflammatory mediators. Interestingly, in the aortas from transgenic mice that over-express human NOR-1 in VSMC (TgNOR-1), the up regulation of cytokine/chemokine by LPS was lower compared to wild-type littermates. Similar results were obtained in VSMC from transgenic animals. NOR-1 reduced the transcriptional activity of NFkappaB sensitive promoters (in transient transfections), and the binding of NFkappaB to its responsive element (in electrophoretic mobility shift assays). Furthermore, NOR-1 prevented the activation of NFkappaB pathway by decreasing IkappaBalpha phosphorylation/degradation and inhibiting the phosphorylation and subsequent translocation of p65 to the nucleus (assessed by Western blot and immunocytochemistry). These effects were associated with an attenuated phosphorylation of ERK1/2, p38 MAPK and Jun N-terminal kinase, pathways involved in the activation of NFkappaB. In mouse challenged with LPS, the activation of the NFkappaB signalling was also attenuated in the aorta from TgNOR-1. Our data support a role for NOR-1 as a negative modulator of the acute response elicited by pro-inflammatory stimuli in the vasculature. PMID- 25536184 TI - Minimal clinically important difference: a novel approach to measure changes in outcome in perioperative medicine. PMID- 25536183 TI - Immunonutrition as an adjuvant therapy for burns. AB - BACKGROUND: With burn injuries involving a large total body surface area (TBSA), the body can enter a state of breakdown, resulting in a condition similar to that seen with severe lack of proper nutrition. In addition, destruction of the effective skin barrier leads to loss of normal body temperature regulation and increased risk of infection and fluid loss. Nutritional support is common in the management of severe burn injury, and the approach of altering immune system activity with specific nutrients is termed immunonutrition. Three potential targets have been identified for immunonutrition: mucosal barrier function, cellular defence and local or systemic inflammation. The nutrients most often used for immunonutrition are glutamine, arginine, branched-chain amino acids (BCAAs), omega-3 (n-3) fatty acids and nucleotides. OBJECTIVES: To assess the effects of a diet with added immunonutrients (glutamine, arginine, BCAAs, n-3 fatty acids (fish oil), combined immunonutrients or precursors to known immunonutrients) versus an isonitrogenous diet (a diet wherein the overall protein content is held constant, but individual constituents may be changed) on clinical outcomes in patients with severe burn injury. SEARCH METHODS: The search was run on 12 August 2012. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), ISI WOS SCI EXPANDED & CPCI-S and four other databases. We handsearched relevant journals and conference proceedings, screened reference lists and contacted pharmaceutical companies. We updated this search in October 2014, but the results of this updated search have not yet been incorporated. SELECTION CRITERIA: Randomised controlled trials comparing the addition of immunonutrients to a standard nutritional regimen versus an isonitrogenated diet or another immunonutrient agent. DATA COLLECTION AND ANALYSIS: Two review authors were responsible for handsearching, reviewing electronic search results and identifying potentially eligible studies. Three review authors retrieved and reviewed independently full reports of these studies for inclusion. They resolved differences by discussion. Two review authors independently extracted and entered data from the included studies. A third review author checked these data. Two review authors independently assessed the risk of bias of each included study and resolved disagreements through discussion or consultation with the third and fourth review authors. Outcome measures of interest were mortality, hospital length of stay, rate of burn wound infection and rate of non-wound infection (bacteraemia, pneumonia and urinary tract infection). MAIN RESULTS: We identified 16 trials involving 678 people that met the inclusion criteria. A total of 16 trials contributed data to the analysis. Of note, most studies failed to report on randomisation methods and intention-to-treat principles; therefore study results should be interpreted with caution. Glutamine was the most common immunonutrient and was given in seven of the 16 included studies. Use of glutamine compared with an isonitrogenous control led to a reduction in length of hospital stay (mean stay -5.65 days, 95% confidence interval (CI) -8.09 to -3.22) and reduced mortality (pooled risk ratio (RR) 0.25, 95% CI 0.08 to 0.78). However, because of the small sample size, it is likely that these results reflect a false-positive effect. No study findings suggest that glutamine has an effect on burn wound infection or on non-wound infection. All other agents investigated showed no evidence of an effect on mortality, length of stay or burn wound infection or non wound infection rates. AUTHORS' CONCLUSIONS: Although we found evidence of an effect of glutamine on mortality reduction, this finding should be taken with care. The number of study participants analysed in this systematic review was not sufficient to permit conclusions that recommend or refute the use of glutamine. Glutamine may be effective in reducing mortality, but larger studies are needed to determine the overall effects of glutamine and other immunonutrition agents. PMID- 25536182 TI - TNF-related weak inducer of apoptosis (TWEAK) regulates junctional proteins in tubular epithelial cells via canonical NF-kappaB pathway and ERK activation. AB - The tubular epithelium may be intrinsically involved in promoting kidney injury by junctional instability, epithelial-mesenchymal transition (EMT) and extracellular matrix remodelling. In this work, we investigated whether the pleiotropic and proinflammatory cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), could be able to disturb junctional protein expression and to induce EMT of tubular cells. In cultured murine proximal tubular cells TWEAK induced phenotypic changes that were accompanied by F-actin redistribution, loss of epithelial adherent (E-cadherin, Cadherin-16, beta-catenin) and tight junction (ZO-1) proteins, and re-expression of the mesenchymal protein Vimentin. The transcriptional repressors Snail and HNF1beta were also modulated by TWEAK. In a murine model of obstructive renal pathology, TWEAK expression correlated with the appearance of the mesenchymal marker alphaSMA in kidney tubular cells. Mechanistically, the epithelial changes induced by TWEAK, including loss of epithelial integrity and EMT, via Fn14 were TGF-beta1 independent, but mediated by several intracellular signaling systems, including the canonical NF-kappaB, ERK activation and the vitamin D receptor modulation. These results highlight potential contributions of TWEAK-induced inflammatory mechanisms that could unveil new pathogenic effects of TWEAK starting tubulointerstitial damage and fibrosis. PMID- 25536185 TI - The medical procedure pathway: creating a global standard methodology to benefit patients. PMID- 25536186 TI - Standardisation of perioperative outcome measures. PMID- 25536187 TI - When may systematic reviews and meta-analyses be considered reliable? PMID- 25536188 TI - Factors affecting the ability of the spectral domain optical coherence tomograph to detect photographic retinal nerve fiber layer defects. AB - PURPOSE: To evaluate the ability of normative database classification (color coded maps) of spectral domain optical coherence tomograph (SDOCT) in detecting wedge shaped retinal nerve fiber layer (RNFL) defects identified on photographs and the factors affecting the ability of SDOCT in detecting these RNFL defects. METHODS: In a cross-sectional study, 238 eyes (476 RNFL quadrants) of 172 normal subjects and 85 eyes (103 RNFL quadrants with wedge shaped RNFL defects) of 66 glaucoma patients underwent RNFL imaging with SDOCT. Logistic regression models were used to evaluate the factors associated with false positive and false negative RNFL classifications of the color-coded maps of SDOCT. RESULTS: False positive classification at a p value of <5% was seen in 108 of 476 quadrants (22.8%). False negative classification at a p value of <5% was seen in 16 of 103 quadrants (15.5%). Of the 103 quadrants with RNFL defects, 64 showed a corresponding VF defect in the opposite hemisphere and 39 were preperimetric. Higher signal strength index (SSI) of the scan was less likely to have a false positive classification (odds ratio: 0.97, p = 0.01). Presence of an associated visual field defect (odds ratio: 0.17, p = 0.01) and inferior quadrant RNFL defects as compared to superior (odds ratio: 0.24, p = 0.04) were less likely to show false negative classifications. CONCLUSIONS: Scans with lower signal strengths were more likely to show false positive RNFL classifications, and preperimetric and superior quadrant RNFL defects were more likely to show false negative classifications on color-coded maps of SDOCT. PMID- 25536190 TI - Feasibility of popular m-health technologies for activity tracking among individuals with serious mental illness. AB - Obesity prevalence is nearly double among individuals with serious mental illness (SMI), including schizophrenia spectrum disorders, bipolar disorder, or major depressive disorder, compared with the general population. Emerging mobile health (m-health) technologies are increasingly available and offer the potential to support lifestyle interventions targeting weight loss, yet the practical feasibility of using these technologies in this high-risk group has not been established. We evaluated the feasibility and acceptability of popular m-health technologies for activity tracking among overweight and obese individuals with SMI. We provided wearable activity monitoring devices (FitBit [San Francisco, CA] ZipTM or Nike Inc. [Beaverton, OR] FuelBand) and smartphones (Apple [Cupertino, CA] iPhone((r)) 4S) for accessing the smartphone application for each device to participants with SMI enrolled in a weight loss program. Feasibility of these devices was measured by the frequency of use over time. Acceptability was measured through qualitative follow-up interviews with participants. Ten participants with SMI wore the devices for a mean of 89% (standard deviation=13%) of the days in the study. Five participants wore the devices 100% of the time. Participants reported high satisfaction, stating the devices were easy to use, helpful for setting goals, motivational, and useful for self-monitoring. Several participants liked the social connectivity feature of the devices where they could see each other's progress on the smartphone application, noting that "friendly" competition increased motivation to be more physically active. This study supports using popular m-health technologies for activity tracking among individuals with SMI. These findings can inform the design of weight loss interventions targeting this vulnerable patient population. PMID- 25536191 TI - Characterisation of cyanobacterial bicarbonate transporters in E. coli shows that SbtA homologs are functional in this heterologous expression system. AB - Cyanobacterial HCO3(-) transporters BCT1, SbtA and BicA are important components of cyanobacterial CO2-concentration mechanisms. They also show potential in applications aimed at improving photosynthetic rates and yield when expressed in the chloroplasts of C3 crop species. The present study investigated the feasibility of using Escherichia coli to assess function of a range of SbtA and BicA transporters in a heterologous expression system, ultimately for selection of transporters suitable for chloroplast expression. Here, we demonstrate that six beta-forms of SbtA are active in E. coli, although other tested bicarbonate transporters were inactive. The sbtA clones were derived from Synechococcus sp. WH5701, Cyanobium sp. PCC7001, Cyanobium sp. PCC6307, Synechococcus elongatus PCC7942, Synechocystis sp. PCC6803, and Synechococcus sp. PCC7002. The six SbtA homologs varied in bicarbonate uptake kinetics and sodium requirements in E. coli. In particular, SbtA from PCC7001 showed the lowest uptake affinity and highest flux rate and was capable of increasing the internal inorganic carbon pool by more than 8 mM relative to controls lacking transporters. Importantly, we were able to show that the SbtB protein (encoded by a companion gene near sbtA) binds to SbtA and suppresses bicarbonate uptake function of SbtA in E. coli, suggesting a role in post-translational regulation of SbtA, possibly as an inhibitor in the dark. This study established E. coli as a heterologous expression and analysis system for HCO3(-) transporters from cyanobacteria, and identified several SbtA transporters as useful for expression in the chloroplast inner envelope membranes of higher plants. PMID- 25536192 TI - Folate receptor-targeted multimodality imaging of ovarian cancer in a novel syngeneic mouse model. AB - A new transplantable ovarian tumor model is presented using a novel folate receptor (FR) positive, murine ovarian cancer cell line that emulates the human disease and induces widespread intraperitoneal (i.p.) tumors in immunocompetent mice within 4-8 weeks of implantation. Tumor development was monitored using a new positron emission tomography (PET) FR-targeting reporter with PET/computerized tomography (PET/CT) and fluorescence molecular tomography (FMT) using a commercial FR-targeting reporter. Conventional structural magnetic resonance imaging (MRI) was also performed. Adult female C57BL/6 mice were injected i.p. with 6 * 10(6) MKP-L FR+ cells. Imaging was performed weekly beginning 2 weeks after tumor induction. The albumin-binding, FR-targeting ligand cm09 was radiolabeled with the positron emitter (68)Ga and used to image the tumors with a small animal PET/CT. The FR-reporter FolateRSense 680 (PerkinElmer) was used for FMT and flow cytometry. Preclinical MRI (7 T) without FR-targeting was compared with the PET and FMT molecular imaging. Tumors were visible by all three imaging modalities. PET/CT had the highest imaging sensitivity at 3-3.5 h postadministration (mean %IA/g mean > 6) and visualized tumors earlier than the other two modalities with lower kidney uptake (mean %IA/g mean < 17) than previously reported FR-targeting agents in late stage disease. FMT showed relatively low FR-targeted agent in the bladder and kidneys, but yielded the lowest anatomical image resolution. MRI produced the highest resolution images, but it was difficult to distinguish tumors from abdominal organs during early progression since a FR-targeting MRI reporter was not used. Nevertheless, there was good correlation of imaging biomarkers between the three modalities. Tumors in the mouse ovarian cancer model could be detected using FR-targeted imaging as early as 2 weeks post i.p. injection of tumor cells. An imaging protocol should combine one or more of the modalities, e.g., PET/CT or PET/MRI for optimal tumor detection and delineation from surrounding tissues. PMID- 25536193 TI - Two-stage genome-wide search for epistasis with implementation to Recombinant Inbred Lines (RIL) populations. AB - OBJECTIVE AND METHODS: This paper proposes an inegrative two-stage genome-wide search for pairwise epistasis on expression quantitative trait loci (eQTL). The traits are clustered into multi-trait complexes that account for correlations between them that may result from common epistasis effects. The search is done by first screening for epistatic regions and then using dense markers within the identified regions, resulting in substantial reduction in the number of tests for epistasis. The FDR is controlled using a hierarchical procedure that accounts for the search structure. Each combination of trait and marker-pair is tested using a model that accounts for both statistical and functional interpretations of epistasis and considers orthogonal effects, such that their contributions to heritability can be estimated individually. We examine the impact of using multi trait complexes rather than single traits, and of using a hierarchical search for epistasis rather than skipping the initial screen for epistatic regions. We apply the proposed algorithm on Arabidopsis transcription data. PRINCIPAL FINDINGS: Both epistasis detection power and heritability contributed by epistasis increased when using multi-trait complexes rather than single traits. Epistatic effects common to the eQTLs included in the complexes have higher chance of being identified by analysis of multi-trait complexes, particularly when epistatic effects on individual traits are small. Compared to direct testing for all potential epistatic effects, the hierarchical search was substantially more powerful in detecting epistasis, while controlling the FDR at the desired level. Association in functional roles within genomic regions was observed, supporting an initial screen for epistatic QTLs. PMID- 25536194 TI - Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation. AB - Prolonged ingestion of a cholesterol- or saturated fatty acid-enriched diet induces chronic, often systemic, auto-inflammatory responses resulting in significant health problems worldwide. In vivo information regarding the local and direct inflammatory effect of these dietary components in the intestine and, in particular, on the intestinal epithelium is lacking. Here we report that both mice and zebrafish exposed to high-fat (HFDs) or high-cholesterol (HCDs) diets develop acute innate inflammatory responses within hours, reflected in the localized interleukin-1beta-dependent accumulation of myeloid cells in the intestine. Acute HCD-induced intestinal inflammation is dependent on cholesterol uptake via Niemann-Pick C1-like 1 and inflammasome activation involving apoptosis associated Speck-like protein containing a caspase recruitment domain, which leads to Caspase-1 activity in intestinal epithelial cells. Extended exposure to HCD results in localized, inflammation-dependent, functional dysregulation as well as systemic pathologies. Our model suggests that dietary cholesterol initiates intestinal inflammation in epithelial cells. PMID- 25536195 TI - CDDO-Me protects normal lung and breast epithelial cells but not cancer cells from radiation. AB - Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs). In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ~18 hours before radiation in epithelial cells (average dose modifying factor (DMF) = 1.3), and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs) with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients. PMID- 25536197 TI - A Clinical Comparison of EMLA Cream and Ethyl Chloride Spray Application for Pain Relief of Forehead Botulinum Toxin Injection. AB - OBJECTIVES: This study aims to analyze the efficiency of EMLA cream and ethyl chloride spray application for pain alleviation before botulinum toxin injection. METHODS: Forty-five patients were divided into 3 treatment groups. Skin cooling with ethyl chloride spray (in group 1), topical anesthetic cream (EMLA) (in group 2), was used on the forehead area on one side previous to injection; the opposite side served as the control. In the third group (n = 15), cold was applied using ethyl chloride spray to one side, and to the other side topical anesthetic cream (EMLA) was applied. A visual analog scale was used for pain intensity. RESULTS: In the first group, the average pain score was 3.20 +/- 1.20 on the side where ethyl chloride spray was applied and 7.26 +/- 1.94 on the control side (P < 0.05). It was 4.20 +/- 1.37 on the side receiving EMLA and 7.66 +/- 1.54 (P < 0.05) on the control side in the second group. In the third group, the average score was 6.80 +/- 1.37 for the EMLA side and 2.93 +/- 1.03 for the ethyl chloride sprayed side (P < 0.05). CONCLUSIONS: Skin cooling with ethyl chloride spray significantly decreases the pain associated during forehead botulinum toxin injections. PMID- 25536196 TI - Effect of maternal body mass index on hormones in breast milk: a systematic review. AB - BACKGROUND: Maternal Body Mass Index (BMI) is positively associated with infant obesity risk. Breast milk contains a number of hormones that may influence infant metabolism during the neonatal period; these may have additional downstream effects on infant appetite regulatory pathways, thereby influencing propensity towards obesity in later life. OBJECTIVE: To conduct a systematic review of studies examining the association between maternal BMI and the concentration of appetite-regulating hormones in breast milk. METHOD: Pubmed was searched for studies reporting the association between maternal BMI and leptin, adiponectin, insulin, ghrelin, resistin, obestatin, Peptide YY and Glucagon-Like Peptide 1 in breast milk. RESULTS: Twenty six studies were identified and included in the systematic review. There was a high degree of variability between studies with regard to collection, preparation and analysis of breast milk samples. Eleven of fifteen studies reporting breast milk leptin found a positive association between maternal BMI and milk leptin concentration. Two of nine studies investigating adiponectin found an association between maternal BMI and breast milk adiponectin concentration; however significance was lost in one study following adjustment for time post-partum. No association was seen between maternal BMI and milk adiponectin in the other seven studies identified. Evidence for an association between other appetite regulating hormones and maternal BMI was either inconclusive, or lacking. CONCLUSIONS: A positive association between maternal BMI and breast milk leptin concentration is consistently found in most studies, despite variable methodology. Evidence for such an association with breast milk adiponectin concentration, however, is lacking with additional research needed for other hormones including insulin, ghrelin, resistin, obestatin, peptide YY and glucagon-like peptide-1. As most current studies have been conducted with small sample sizes, future studies should ensure adequate sample sizes and standardized methodology. PMID- 25536198 TI - Buttock Reshaping With Intramuscular Gluteal Augmentation in an Asian Ethnic Group: A Six-Year Experience With 130 Patients. AB - Although the definition of what constitutes "beautiful buttocks" has been changing with time, the buttocks are generally perceived as an important element of sexual attraction and beauty in every culture. In Asian culture, "beautiful buttocks" are defined by an aggregate of the following 4 components: S-shaped curvature from the lower back to the buttocks, sufficient muscle volume, sufficient fat volume, and appropriate skin elasticity. The goal of our gluteal augmentation was therefore to restore the back curvature, provide sufficient hip volume (projection), and reposition the point of maximal gluteal projection to be higher than the pubic hair. The purpose of this study was to review the authors' 6-year (2008-2014) experience with intramuscular gluteal augmentation techniques using an oval-shaped smooth-surface silicon elastomer. After intergluteal fusiform incisions were made, we bluntly dissected the subcutaneous tissue deep down to the gluteus maximus muscle by using the xyz method introduced by Dr. Gonzalez. Most of the patients in this case series underwent additional procedures at the time of the gluteal augmentation, whereas 90% of patients underwent concomitant liposuction. The results were assessed objectively using serial photography and subjectively according to patients' assessment on a 5 score scale.The mean rating for patient satisfaction with the procedure was 4.6 of 5, whereas consensus ratings by 2 independent plastic surgeons showed a mean score of 4.2 of 5. The intramuscular gluteal augmentation technique using an oval shaped smooth surface silicon elastomer resulted in excellent cosmetic outcomes and permitted successful reshaping of the buttocks. PMID- 25536199 TI - Effects of Obesity on Postoperative Complications After Breast Reconstruction Using Free Muscle-Sparing Transverse Rectus Abdominis Myocutaneous, Deep Inferior Epigastric Perforator, and Superficial Inferior Epigastric Artery Flap: A Systematic Review and Meta-analysis. AB - BACKGROUND: Although several studies have found obesity to increase the risk of postoperative morbidity in autologous breast reconstruction, there remains some controversy over the influence of obesity for muscle-conserving abdominal flaps, including muscle-sparing transverse rectus abdominis myocutaneous (msTRAM), deep inferior epigastric perforator (DIEP), and superficial inferior epigastric artery (SIEA) flaps. This review evaluates the effects of obesity on complications in breast reconstruction using muscle-conserving abdominal flaps and compares them to those for conventional free transverse rectus abdominis myocutaneous (TRAM) flaps. METHODS: A literature search was conducted using MEDLINE, Ovid, and Cochrane databases for studies reporting complication rates for obese and nonobese patients undergoing breast reconstruction using msTRAM, DIEP, and SIEA flaps and conventional free TRAM flaps. The pooled relative risks (RRs) of the obesity for flap-related and donor complications were estimated in the muscle conserving flaps by meta-analytic methodology and the pooled complication rates in obese patients were compared between muscle-conserving flaps and conventional TRAM flaps. Here, only those studies following the World Health Organization definition of obesity (body mass index >= 30 kg/m) were included. RESULTS: A total of 17 articles were analyzed. Eight studies were used to compute the obesity-related risks of flap-related and donor complications for msTRAM, DIEP, and SIEA flaps. Obesity increased the risk of total flap loss [RR, 1.68; 95% confidence interval (CI), 0.85-3.33], partial flap loss (RR, 2.26; 95% CI, 1.01 5.02), abdominal bulge or hernia (RR, 1.72; 95% CI, 1.00-2.95), and overall abdominal complications (RR, 1.53; 95% CI, 1.10-2.14). The results of a pooled analysis with 15 studies are consistent with those of the meta-analysis. In comparison to free TRAM flaps, muscle-conserving abdominal flaps showed a lower pooled incidence of flap loss, fat necrosis, and abdominal bulge or hernia in obese patients. CONCLUSIONS: This review suggests that obesity increases the risk of both flap-related and donor-site complications in breast reconstruction using msTRAM, DIEP, and SIEA flaps. In comparison to conventional TRAM flaps, however, muscle-conserving abdominal flaps may have an advantage in reducing the morbidity in obese patients. PMID- 25536200 TI - The extended distally based sural neurocutaneous flap for foot and ankle reconstruction a restrospective review of 10 years of experience: reply. PMID- 25536202 TI - Effect of Reduction Mammaplasty on Sexual Activity. AB - AIM: This study aimed to evaluate the effects of reduction mammaplasty operation on sexual functions of the patients with macromastia and of their partners. MATERIALS AND METHODS: Thirty-nine patients with macromastia and their partners were assessed for their sexual function before and 6 months after reduction mammaplasty. Sexual function of the women and their partners were evaluated using the Index of Female Sexual Function (IFSF) and the International Index of Erectile Function (IIEF), respectively. Controls (n = 33) were chosen from healthy hospital staff and their partners. Preoperative and postoperative scores were statistically compared with the controls' scores by using Student t test. Also, preoperative and postoperative scores were compared by using paired t test. RESULTS: The mean of age and body mass index of the women and their partners in the patient and control group were similar (P = 0.07). Before the operation, the mean of IFSF scores in the patient and control group were 22.75 (3.45) and 27.28 (5.05), respectively (P < 0.001). After the operation, the mean of IFSF scores in the patient group increased significantly to 27.67 (P < 0.001). The postoperative scores of all IFSF subscales except lubrication subscale were higher than the preoperative scores. Although there was no significant difference between preoperative and postoperative IIEF-total scores, postoperative IIEF-erectile function and IIEF-intercourse satisfaction scores were significantly reduced (P < 0.05). CONCLUSIONS: We found that macromastia adversely affected female sexual function but reduction mammaplasty eliminated this adverse effect. We also found that the partners' erectile function and intercourse satisfaction reduced after the operation. This reduction may be due to psychological effects. PMID- 25536201 TI - How to avoid pectus bar displacement in the MIRPE or MOVARPE technique: results of 12 years' experience: reply. PMID- 25536203 TI - When the Gastrointestinal Conduit for Total Esophageal Reconstruction Is Not an Option: Review of the Role of Skin Flaps and Report of Salvage With a Single Stage Tubed Anterolateral Thigh Flap. AB - This review adds to the limited body of literature describing the use of skin flaps for reconstruction of the esophagus and includes a report of a successful 1 stage, intrathoracic reconstruction of the cervical and thoracic esophagus after failed gastrointestinal conduit. Already widely used for reconstruction of the pharynx and cervical esophagus, the versatile anterolateral thigh flap can be considered an option for more extensive defects of the cervical and thoracic esophagus in this challenging patient population when gastric, jejunal, or colon conduits are not available. The authors believe the anterolateral thigh flap should be considered in 1-stage anatomic reconstruction of the cervical and thoracic esophagus in the absence of feasible gastrointestinal conduits. PMID- 25536204 TI - Sexual Function and Depression Outcomes Among Breast Hypertrophy Patients Undergoing Reduction Mammaplasty: A Randomized Controlled Trial. AB - PURPOSE: The breasts are important symbols of femininity and sensuality. Alterations such as breast hypertrophy can affect several aspects of women's quality of life. Breast hypertrophy is a prevalent health condition, which is treated by reduction mammaplasty. The aim of the present study was to assess sexual function and depression outcomes among breast hypertrophy patients undergoing reduction mammaplasty. METHODS: Sixty breast hypertrophy patients were randomly allocated to a control group (CG) (n = 30) or a breast reduction group (BRG) (n = 30). The patients in the CG were assessed at the first appointment as well as 3 and 6 months later. The patients in the BRG were assessed preoperatively as well as 3 and 6 months postoperatively. Validated instruments, the Female Sexual Function Index and the Beck Depression Inventory, were used to assess sexual function and depression among the subjects. The results of these assessments were compared within and between groups. RESULTS: Twenty-seven and 29 patients in the CG and the BRG, respectively, completed the 6-month follow-up period. At baseline, the groups did not differ significantly with regard to the main demographic data. In the initial assessment, the groups did not differ significantly with regard to Female Sexual Function Index or Beck Depression Inventory scores. Compared with the CG, the BRG reported better sexual function 3 (P = 0.015) and 6 (P = 0.009) months postoperatively. Regarding depression scores, the reduction mammaplasty group had better results 6 months postoperatively (P = 0.014). CONCLUSIONS: Reduction mammaplasty positively affected sexual function and depression levels in breast hypertrophy patients. PMID- 25536205 TI - Concomitant Lipoma and Ganglion Causing Ulnar Nerve Compression at the Wrist: A Case Report and Review of Literature. AB - We present a rare case of ulnar nerve compression caused by concurrent lumps-a lipoma and a ganglion at the wrist, with no prior report cited in the English literature. This case illustrates the possibility of dual concurrent pathologies causing ulnar neuropathy and the importance of not missing one. PMID- 25536206 TI - A Systematic Meta-analysis of Prosthetic-Based Breast Reconstruction in Irradiated Fields With or Without Autologous Muscle Flap Coverage. AB - BACKGROUND: The popularity of implant-based breast reconstruction, along with the well-established benefits of radiation therapy, unfortunately can lead to device placement into irradiated fields. Here, we compare prosthetic reconstructions with latissimus dorsi (LD) or subpectoral implants alone via systematic meta analysis. METHODS: A literature search identified articles involving prosthetic based breast reconstruction in the setting of prior irradiation with or without an LD flap. The primary outcomes of interest, including device loss, capsular contracture, reoperation, and infection, were analyzed via head-to-head meta analysis. RESULTS: Thirty-one studies and 1275 reconstructions were included. Average age was 48.9 years and average follow-up was 42.8 months. The head-to head odds ratio for implant loss with implant-only versus LD-assisted reconstruction was 4.33 (P = 0.0003, I = 7%), favoring LD-assisted reconstruction. Implant loss in pooled analysis was 5.0% for LD-assisted reconstruction and 15.0% for implant-only (P < 0.001). CONCLUSIONS: In previously irradiated fields, prostheses placed with an LD flap demonstrated a clinically significant reduction in device loss, infection, and reoperation. PMID- 25536207 TI - Extensor Hallucis Brevis Tendon Transfer for the Correction of Drop Toe Deformity After Dorsalis Pedis Tendocutaneous Free Flap Harvest. AB - The dorsalis pedis tendocutaneous (DPTC) free flap is an ideal option for the reconstruction of the combined defect of the dorsal hand skin and multiple extensor tendons, whereas it possess not only soft tissue problems, but also symptomatic drop toe deformity in the donor site. We have corrected this drop toe deformity with a tendon transfer technique, using the extensor hallucis brevis muscle, which was preserved during the DPTC free flap harvest. The donor site exposing the transferred tendons was covered with another thin free flap. Two cases that underwent this technique exhibited satisfactory alignment and active extension of the toes. This tendon transfer technique combined with free flap coverage overcomes almost all the problems in the donor site of the DPTC free flap, achieving excellent contours of both the dorsal hand and the foot. PMID- 25536208 TI - The Readability of Online Resources for Mastopexy Surgery. AB - BACKGROUND: As more patients use Internet resources for health information, there is increasing interest in evaluating the readability of available online materials. The National Institutes of Health and American Medical Association recommend that patient educational content be written at a sixth-grade reading level. This study evaluates the most popular online resources for information about mastopexy relative to average adult literacy in the United States. METHODS: The 12 most popular sites returned by the largest Internet search engine were identified using the search term "breast lift surgery." Relevant articles from the main sites were downloaded and formatted into text documents. Pictures, captions, links, and references were excluded. The readability of these 100 articles was analyzed overall and subsequently by site using 10 established readability tests. Subgroup analysis was performed for articles discussing the benefits of surgery and those focusing on risks. RESULTS: The overall average readability of online patient information was 13.3 (range, 11.1-15). There was a range of average readability scores overall across the 12 sites from 8.9 to 16.1, suggesting that some may be more appropriate than others for patient demographics with different health literacy levels. Subgroup analysis revealed that articles discussing the risks of mastopexy were significantly harder to read (mean, 14.1) than articles about benefits (11.6). CONCLUSIONS: Patient-directed articles from the most popular online resources for mastopexy information are uniformly above the recommended reading level and likely too difficult to be understood by a large number of patients in the United States. PMID- 25536211 TI - 2-Iodoisatogens: versatile intermediates for the synthesis of nitrogen heterocycles. AB - A Cu-promoted cyclization of 2-nitrophenyl iodoacetylenes provides a direct route to a range of 2-iodoisatogens. These compounds represent useful intermediates for the late-stage elaboration of the C-I bond to furnish isatins and a range of alternative heterocyclic products. PMID- 25536210 TI - Role of focal adhesion kinase in oocyte-follicle communication. AB - Germ cells require communication with associated somatic cells for normal gametogenesis, as exemplified by an oocyte that interacts with granulosa cells via paracrine factors as well as gap junctions located at sites of contact between these two cell types. The objective of the present study was to define the mechanisms by which cell-cell contact with the oocyte is controlled and to determine the extent that the oocyte actively participates in this association. Proline-rich tyrosine kinase 2 (PTK2), a focal adhesion kinase, was found to be activated at sites of contact between the oocyte and trans-zonal cell processes from the surrounding granulosa cells. In order to determine the functional significance of oocyte-derived PTK2 signaling in oocyte-follicle communication, an oocyte-specific Ptk2 knockout was produced through a breeding strategy pairing a floxed Ptk2-CAT-eGFP mouse with the Zp3-Cre line. Since Ptk2-null mice never develop to birth, this represents the first opportunity to define the role of PTK2 in oocyte-follicle communication. Ablation of Ptk2 within the developing oocyte resulted in lower fertility with reduced numbers of pups, lower rates of blastocyst formation, and reduced cell numbers per blastocyst. Follicles containing Ptk2-null oocytes exhibited reduced oocyte diameter, reduced numbers of connexin 37 and 43 foci at the oocyte surface, and impaired dye coupling between oocyte and granulosa cells. These findings are consistent with a model in which PTK2 plays a critical role in establishing or maintaining oocyte-granulosa cell contacts that are essential for gap junction-mediated communication between granulosa cells and the oocyte. PMID- 25536212 TI - Delayed Primary Closure of Fasciotomy Incisions in the Lower Leg: Do We Need to Change Our Strategy? AB - OBJECTIVES: The primary purpose of this study is to determine whether a strategy of bringing patients back to the operating room for successive debridements allows for the eventual delayed primary closure (DPC) of fasciotomy wounds. DESIGN: Retrospective cohort study. Data were collected from medical records and radiographs. SETTING: Two urban level 1 trauma centers. PATIENTS: One hundred four adult patients with acute compartment syndrome in the setting of a tibia fracture (open or closed). INTERVENTION: All patients underwent decompressive fasciotomies with closure by either DPC or split-thickness skin grafting (STSG) during a subsequent surgical procedure. MAIN OUTCOME MEASURE: Number of fasciotomy wounds closed by DPC after the initial fasciotomy procedure. RESULTS: Of the 104 patients brought to the operating room for their first debridement after their fasciotomies, 19 patients (18%) were treated with DPC, whereas 42 patients (40%) were closed with STSG because they were believed to be too swollen to allow for primary closure by the treating surgeon. Three of the remaining 43 patients were treated with DPC during their second debridement. No patients who underwent more than 2 washouts could be treated with DPC. No patients who sustained open fractures were able to be closed by DPC (P = 0.02). Patients who underwent STSG on their first postfasciotomy procedure had a significantly shorter hospital stay than patients who underwent additional procedures before closure (12.2 vs. 17.4 days; P = 0.005). CONCLUSIONS: Fasciotomy wounds that are not able to be primarily closed during their first postfasciotomy surgical procedure are rarely closed through DPC techniques. Early skin grafting of these wounds should be considered, especially in the clinical setting of an open injury, because it significantly decreases the length of hospital stay. Other techniques that avoid repeated debridements and attempted closures might also help reduce hospital stay. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25536209 TI - Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations. AB - CONTEXT: Bile acids and fibroblast growth factor 19 (FGF19) have been suggested as key mediators of the improvements in glucose metabolism after Roux-en-Y gastric bypass (RYGB). OBJECTIVE: To describe fasting and postprandial state total bile acid (TBA) and FGF19 concentrations before and after RYGB and relate them to parameters of glucose metabolism, glucagon-like peptide-1, cholecystokinin, and cholesterol fractions. DESIGN AND SETTING: A prospective descriptive study was performed at the Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark. PATIENTS: Thirteen type 2 diabetic (T2D) patients and 12 normal glucose tolerant (NGT) subjects participated in the study. INTERVENTION: A 4-hour liquid meal test was performed before and 1 week, 3 months, and 1 year after RYGB. MAIN OUTCOME MEASURES: We measured fasting and postprandial TBA and FGF19 concentrations. RESULTS: Fasting TBA concentrations decreased in NGT subjects (P < .001) and were unchanged in T2D patients 1 week after surgery, but then increased gradually in both groups with time from surgery (ANOVA Ptime < .001). Area under the curve (AUC) TBA was decreased in NGT subjects 1 week after RYGB (before surgery, 567 mmol * min/L [interquartile range, 481-826]; 1 wk, 419 [381-508]; P = .009) and was unchanged in T2D patients (894 [573-1002]; 695 [349-1147]; P = .97) but then increased with time from surgery in both groups (Ptime < .001). Fasting FGF19 concentrations were unchanged acutely after RYGB (NGT, 140 pg/mL [100-162], 134 [119-204], P = .42; T2D, 162 [130-196], 154 [104-164], P = .68) and remained unchanged throughout the follow-up period. AUC FGF19 increased gradually with time after surgery (Ptime < .001), resembling the changes seen with AUC TBA. One week after RYGB, glucose metabolism improved, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol decreased, and cholecystokinin and glucagon-like peptide 1 secretion increased, whereas FFA concentrations were unchanged. CONCLUSION: TBA and FGF19 do not explain acute changes in glucose metabolism, cholesterol fractions, and gut hormone secretion after RYGB. PMID- 25536213 TI - Clinical and Economic Impact of Duplicated Radiographic Studies in Trauma Patients Transferred to a Regional Trauma Center. AB - OBJECTIVES: Many trauma patients are evaluated at community hospitals and rural emergency departments before transfer to regional trauma centers. Radiographic studies are often duplicated, leading to significant additional costs to the healthcare system. Our purpose is to identify the reasons for duplicate studies, the costs associated with this practice, and potential clinical effects to patients. METHODS: The institutional trauma database was queried to identify patients with orthopaedic injuries transferred to our regional trauma center. Patient demographics, mechanism of injury, referring hospital, reason for transfer, payor source, injury severity score, and Glasgow Coma Score (GCS) were recorded. Duplicate imaging studies were identified and confirmed with each outlying hospital radiology department. The radiation exposure was estimated based on average reported values. The cost of duplicated studies was derived from the Medicare fee schedule. RESULTS: In 1 calendar year, a total of 513 patients were accepted in transfer from 36 outlying facilities. Almost half of the patients (47.7%) had at least 1 radiographic study repeated. There was a significant association between repeated study and age (P < 0.0001), Injury Severity Score (P < 0.0001), and GCS (P < 0.0001). No association was identified for size of transferring institution, injury mechanism, or payor status. Reasons listed for duplication included inadequate data transfer, poor quality, inadequate study, and physician preference. The additional cost to the healthcare system is estimated to be $94,000. CONCLUSIONS: The duplication of imaging studies at regional trauma centers is a common problem that represents a significant opportunity for cost savings and reduction of patient exposure to radiation by implementing imaging protocols at outlying facilities and improving the transfer of imaging data through information technology solutions. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25536214 TI - Triple and quadruple disruptions of the superior shoulder suspensory complex. AB - OBJECTIVES: The purpose of this study is to report on a series of patients who sustained triple and quadruple disruptions to the superior shoulder suspensory complex (SSSC), their associated injuries, and functional outcomes of open reduction and internal fixation. DESIGN: Prospective observational study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Patients who sustained more than 2 lesions to the SSSC that underwent surgery. OUTCOME MEASUREMENTS: Disabilities of the Arm, Shoulder, and Hand (DASH) scores, range of motion, and shoulder strength measurements. RESULTS: Fifteen patients with greater than 2 disruptions (12 triple and 3 quadruple) were identified. There were 14 scapula neck fractures, 8 clavicle fractures, 6 acromioclavicular separations, 10 coracoid, and 10 acromion fractures. Rib fractures were present in 87% (13 of 15) patients. Thirteen patients (87%) sustained nerve injuries with 13 lesions distal to the brachial plexus, 5 at the level of the brachial plexus, 3 nerve root, and 2 spinal cord injuries. At final follow-up (14 of 15 patients, mean follow-up = 30.7 months), DASH scores averaged 14.9 and mean range of motion when expressed as the percentage of injured shoulder over the contralateral shoulder was 95% forward flexion, 92% abduction, and 78% external rotation. Mean strength measured by a hand-held dynamometer and expressed as the percentage of injured over contralateral was 67% forward flexion, 61% abduction, and 65% external rotation. CONCLUSIONS: Patients with triple and quadruple disruptions of the SSSC had a high rate of associated injuries including a majority with spinal and peripheral nerve lesions. Treatment with open reduction internal fixation of the scapula was associated with satisfactory functional outcomes despite decreases in shoulder strength measurements. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25536216 TI - Transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin (thymoglobulin) administered before allogeneic stem cell transplantation. AB - Because antithymocyte globulin (ATG) is increasingly used to prevent graft-versus host disease (GVHD), we performed a retrospective study in adult patients transplanted at our center between January 2008 and December 2012 to explore incidence, characteristics, potential risk factors, and consequences of severe acute hepatotoxicity (SAH) of rabbit ATG (Thymoglobulin) defined as a grade 3 to 4 increase of transaminases. Two hundred twelve patients were included. SAH was diagnosed in 55 patients, representing an incidence of 26%. SAH occurred at a median time of 2 days (range, 1 to 3) after ATG administration, reaching maximum median levels of aspartate aminotransferase and alanine aminotransferase of 8.7 * upper limit of normal (ULN; range, 1.2 to 160) and 11.7 * ULN (range, 4-100), respectively. The International Normalized Ratio was beyond the normal range in 44% of patients. Transaminases decreased below 2 * ULN after a median time of 9 days. We do not report any deleterious impact of SAH on survival, nonrelapse mortality, relapse, or GVHD. Blood systolic pressure < 90 mm Hg during administration of ATG and 2 previous autologous SCT were identified as risk factors for SAH. We believe physicians should be aware of this common toxicity immediately after the administration of ATG to avoid any potential hepatotoxic drug before the resolution and to prevent any risk of hemorrhagic accident. PMID- 25536215 TI - Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. AB - The aim of this study was to describe the fate of patients with newly diagnosed acute myeloid leukemia (AML) who did not achieve an initial remission while being treated on a contemporary cooperative group trial. We analyzed the outcome of patients entered into S0106, a recently reported cooperative group trial for patients with newly diagnosed AML. A total of 589 eligible patients was treated, of whom 150 (25%) did not achieve a remission while on study and were available for further analysis. The 4-year survival rate for the entire cohort of 150 patients was 23%. Among the 64 patients who received an allogeneic hematopoietic cell transplant, the 4-year survival rate was 48% compared with 4% for the 86 patients who did not undergo transplantation. Among those transplanted, we could not detect a difference in outcome according to remission status, donor source, type of preparative regimen, or cytogenetic risk category. More than 20% of patients with newly diagnosed AML who fail induction therapy can still be cured, particularly if they are able to receive an allogeneic hematopoietic cell transplant. These results suggest that early HLA typing and donor identification are important components of the initial therapy of AML. PMID- 25536218 TI - A randomized, placebo controlled pilot trial of botulinum toxin for paratonic rigidity in people with advanced cognitive impairment. AB - OBJECTIVE: Evaluate safety and efficacy of Incobotulinumtoxin A in elderly patients with dementia and paratonia. SETTING: University-affiliated hospital, spasticity management Clinic. PARTICIPANTS: Ten subjects were enrolled. INCLUSION CRITERIA: 1) severe cognitive impairment 2) diagnosis of Alzheimer's disease, vascular dementia, or frontotemporal dementia, and 3) score >3 on the paratonic assessment instrument, with posture in an arm(s) interfering with provision of care. EXCLUSION CRITERIA: 1) alternate etiologies for increased tone and 2) injection with botulinum toxin within the 6 months preceding the study. DESIGN: Single center, randomized, double blind, placebo-controlled, crossover trial with two treatment cycles of 16 weeks. Assessments occurred at 2, 6, 12 and16 weeks following injections. Subjects received up to 300 U of Incobotulinumtoxin A in arm(s). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was the modified caregiver burden scale (mCBS); exploratory secondary outcome measures were also performed. Analysis of variance and mixed modeling techniques were used to evaluate treatment effects. RESULTS: Incobotulinumtoxin A treatment produced significant improvement in mCBS total score -1.11 (-2.04 to -0.18) (Treatment effect and 95% CI), dressing sub-score -0.36 (-0.59 to 0.12), and cleaning under the left and right armpits sub-score -0.5 (-0.96 to -0.04), -0.41 (-0.79 to 0.04) respectively. PROM in the left and right elbow increased by 27.67 degrees (13.32-42.02) and 22.07 degrees (9.76-34.39) respectively. PROM in the left and right shoulder increased by 11.92 degrees (5.46-18.38) and 8.58 degrees (3.73 13.43) respectively. No significant treatment effect was found for GAS, VAS and PAINAD scales or change in time to perform care. No adverse drug reactions occurred. CONCLUSIONS: Administration of Incobotulinumtoxin A in elderly people with advanced dementia and paratonia may be an efficacious and safe treatment to increase range of motion and reduce functional burden. Further studies are needed to confirm results. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02212119. PMID- 25536220 TI - A perfluorinated moiety-grafted carbon nanotube electrode for the non-aqueous lithium-oxygen battery. AB - A perfluorinated alkyl chain grafted to carbon nanotubes is employed in the lithium-oxygen (Li-O2) cell. We demonstrate a highly localized Li-O2 electrochemical reaction in close proximity to the perfluorinated moiety owing to its high O2 affinity. This hydrophobic modification can provide an enhancement in capacity for a very thin microbattery system. PMID- 25536217 TI - Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation. AB - Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL. PMID- 25536219 TI - Matrix metalloproteinase-3 causes dopaminergic neuronal death through Nox1 regenerated oxidative stress. AB - In the present study we investigated the interplay between matrix metalloproteinase 3 (MMP3) and NADPH oxidase 1 (Nox1) in the process of dopamine (DA) neuronal death. We found that MMP3 activation causes the induction of Nox1 via mitochondrial reactive oxygen species (ROS) production and subsequently Rac1 activation, eventually leading to Nox1-derived superoxide generation in a rat DA neuronal N27 cells exposed to 6-OHDA. While a MMP3 inhibitor, NNGH, largely attenuated mitochondrial ROS and subsequent Nox1 induction, both apocynin, a putative Nox inhibitor and GKT137831, a Nox1 selective inhibitor failed to reduce 6-OHDA-induced mitochondrial ROS. However, both inhibitors for MMP3 and Nox1 similarly attenuated 6-OHDA-induced N27 cell death. RNAi-mediated selective inhibition of MMP3 or Nox1 showed that knockdown of either MMP3 or Nox1 significantly reduced 6-OHDA-induced ROS generation in N27 cells. While 6-OHDA induced Nox1 was abolished by MMP3 knockdown, Nox1 knockdown did not alter MMP3 expression. Direct overexpression of autoactivated MMP3 (actMMP3) in N27 cells or in rat substantia nigra (SN) increased expression of Nox1. Selective knockdown of Nox1 in the SN achieved by adeno-associated virus-mediated overexpression of Nox1 specific shRNA largely attenuated the actMMP3-mediated dopaminergic neuronal loss. Furthermore, Nox1 expression was significantly attenuated in Mmp3 null mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Together we established novel molecular mechanisms underlying oxidative stress-mediated dopaminergic neuronal death in which MMP3 activation is a key upstream event that leads to mitochondrial ROS, Nox1 induction and eventual dopaminergic neuronal death. Our findings may lead to the development of novel therapeutic approach. PMID- 25536221 TI - The inhibitory effects of Npas4 on seizures in pilocarpine-induced epileptic rats. AB - To explore the effects of neuronal Per-Arnt-Sim domain protein 4 (Npas4) on seizures in pilocarpine-induced epileptic rats, Npas4 expression was detected by double-label immunofluorescence, immunohistochemistry, and Western blotting in the brains of pilocarpine-induced epileptic model rats at 6 h, 24 h, 72 h, 7 d, 14 d, 30 d, and 60 d after status epilepticus. Npas4 was localized primarily in the nucleus and in the cytoplasm of neurons. The Npas4 protein levels increased in the acute phase of seizures (between 6 h and 72 h) and decreased in the chronic phases (between 7 d and 60 d) in the rat model. Npas4 expression was knocked down by specific siRNA interference. Then, the animals were treated with pilocarpine, and the effects on seizures were evaluated on the 7th day. The onset latencies of pilocarpine-induced seizures were decreased, while the seizure frequency, duration and attack rate increased in these rats. Our study indicates that Npas4 inhibits seizure attacks in pilocarpine-induced epileptic rats. PMID- 25536224 TI - Microbial Leakage at the Implant-Abutment Connection Due to Implant Insertion Maneuvers: Cross-Sectional Study 5 Years Postloading in Healthy Patients. AB - The aim of this study was to test if stress on the prosthetic connection during insertion maneuvers can induce micro-warping at the implant connection. From September 2011 to July 2013, patients with implants loaded for at least 5 years that were placed with 2 different insertion implant mounters-MP (conventional) and ME (mountless)-were selected from all of those who had received dental implant therapy in the past and were attending routine check-up or spontaneous visits during the study period. Samples were obtained from inside the connection and the abutment surface using absorbent sterile paper tips. Quantitative real time polymerase chain reaction was performed for total bacterial counts and loads of Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Tannerella forsythensis (Tf), Treponema denticola (Td), Prevotella intermedia (Pi), Peptostreptococcus micros (Pm), Fusobacterium nucleatum (Fn), Campylobacter rectus (Cr), Eikenella corrodens (Ec), and Candida albicans (Ca). The analysis of variance test was used to test for differences. Nine patients (20 implants) were included in the MP group and 5 patients (10 implants) in the ME group. Regarding the red complex, Tf was seen in 80% and 30% of MP and ME implants, respectively (P < .001). Significant differences were also found in microbial load. For Td, proportions were 45% vs 10% (P = .022), with no significant differences at load levels. Regarding the orange complex, higher prevalence values were found in MP implants, although differences were nonsignificant. Microbial load levels for orange complex bacteria were higher for MP than ME, and these differences were statistically significant for Fn (4.94 vs 3.09; P = .001). Finally, Ec was detected only in the MP group, and Ca and Aa were not found in either group. Within its limitation (small sample size, retrospective analysis, indirect measurement method), the present study suggests that a mounter not affecting the prosthetic connection should be used to reduce microbial contamination of implants. PMID- 25536225 TI - [Factors Influencing Participation in Financial Incentive Programmes of Health Insurance Funds. Results of the Study 'German Health Update']. AB - AIM OF THE STUDY: The statutory health insurance can offer their insured incentive programmes that will motivate for healthy behaviour through a financial or material reward. This study will show results about what factors influence financial incentive programme participation (BPT) including all sorts of statutory health insurance funds and taking into account gender differences. METHODS: For the cross-sectional analysis, data were used from 15,858 participants in the study 'Germany Health Update' (GEDA) from 2009, who were insured in the statutory health insurance. The selection of potential influencing variables for a BPT is based on the "Behavioural Model for Health Service Use" of Andersen. Accordingly, various factors were included in logistic regression models, which were calculated separately by gender: predisposing factors (age, education, social support, and health awareness), enabling factors (income, statutory health insurance fund, and family physician), and need factors (smoking, fruit and vegetable consumption, sports, body mass index, and general health status). RESULTS: In consideration of all factors, for both sexes, BPT is associated with age, health awareness, education, use of a family physician, smoking, and sports activities. In addition, income, body mass index, and diet are significant in women and social support and kind of statutory health insurance fund in men. It is found that predisposing, enabling and need factors are relevant. CONCLUSIONS: Financial incentive programmes reach population groups with greatest need less than those groups who already have a health-conscious behaviour, who receive a reward for this. In longitudinal studies, further research on financial incentive programmes should investigate the existence of deadweight effects and whether incentive programmes can contribute to the reduction of the inequity in health. PMID- 25536223 TI - BK polyomavirus reactivation after reduced-intensity double umbilical cord blood cell transplantation. AB - Serial serum samples from 27 patients who underwent double umbilical cord blood transplantation (dUCBT) were analyzed for BK polyomavirus (BKPyV) DNA by real time PCR and BKPyV-specific immune globulin by ELISA. Clinical data were collected on all patients. All pre-transplant sera had detectable anti-BKPyV IgG. Fifteen patients (56%) had detectable serum BKPyV DNA (median 8.9 * 10(4) copies/ml; range 4.1 * 10(3)-7.9 * 10(6) copies/ml) a median of 40 days (range, 27-733 days) after dUCBT, with highest viral loads on Day 100 assessment. The cumulative probability of developing BKPyV viremia by Day 100 was 0.52 (95% CI, 0.33-0.71). Six of 15 patients with BKPyV viremia experienced hemorrhagic cystitis by Day 100. By Day 100, there was a trend towards higher BKPyV viral loads in sera of patients with hemorrhagic cystitis than in those BKPyV viremic patients without hemorrhagic cystitis (p = 0.06). BKPyV viremia was associated with significantly higher anti-BKPyV IgM values at 6 months post-dUCBT (P = 0.003). BKPyV viremia occurs early after dUBCT and is associated with a detectable humoral immune response by 6 months post-dUBCT. PMID- 25536222 TI - SOX10 transactivates S100B to suppress Schwann cell proliferation and to promote myelination. AB - Schwann cells are an important cell source for regenerative therapy for neural disorders. We investigated the role of the transcription factor sex determining region Y (SRY)-box 10 (SOX10) in the proliferation and myelination of Schwann cells. SOX10 is predominantly expressed in rat sciatic nerve-derived Schwann cells and is induced shortly after birth. Among transcription factors known to be important for the differentiation of Schwann cells, SOX10 potently transactivates the S100B promoter. In cultures of Schwann cells, overexpressing SOX10 dramatically induces S100B expression, while knocking down SOX10 with shRNA suppresses S100B expression. Here, we identify three core response elements of SOX10 in the S100B promoter and intron 1 with a putative SOX motif. Knockdown of either SOX10 or S100B enhances the proliferation of Schwann cells. In addition, using dissociated cultures of dorsal root ganglia, we demonstrate that suppressing S100B with shRNA impairs myelination of Schwann cells. These results suggest that the SOX10-S100B signaling axis critically regulates Schwann cell proliferation and myelination, and therefore is a putative therapeutic target for neuronal disorders. PMID- 25536226 TI - Serum interleukin-17 in primary Sjogren's syndrome: association with disease duration and parotid gland swelling. PMID- 25536227 TI - Comparison of True and Smoothed Puff Profile Replication on Smoking Behavior and Mainstream Smoke Emissions. AB - To estimate exposures to smokers from cigarettes, smoking topography is typically measured and programmed into a smoking machine to mimic human smoking, and the resulting smoke emissions are tested for relative levels of harmful constituents. However, using only the summary puff data--with a fixed puff frequency, volume, and duration--may underestimate or overestimate actual exposure to smoke toxins. In this laboratory study, we used a topography-driven smoking machine that faithfully reproduces a human smoking session and individual human topography data (n = 24) collected during previous clinical research to investigate if replicating the true puff profile (TP) versus the mathematically derived smoothed puff profile (SM) resulted in differences in particle size distributions and selected toxic/carcinogenic organic compounds from mainstream smoke emissions. Particle size distributions were measured using an electrical low pressure impactor, the masses of the size-fractionated fine and ultrafine particles were determined gravimetrically, and the collected particulate was analyzed for selected particle-bound, semivolatile compounds. Volatile compounds were measured in real time using a proton transfer reaction-mass spectrometer. By and large, TP levels for the fine and ultrafine particulate masses as well as particle-bound organic compounds were slightly lower than the SM concentrations. The volatile compounds, by contrast, showed no clear trend. Differences in emissions due to the use of the TP and SM profiles are generally not large enough to warrant abandoning the procedures used to generate the simpler smoothed profile in favor of the true profile. PMID- 25536228 TI - Responding to vaccine safety signals during pandemic influenza: a modeling study. AB - BACKGROUND: Managing emerging vaccine safety signals during an influenza pandemic is challenging. Federal regulators must balance vaccine risks against benefits while maintaining public confidence in the public health system. METHODS: We developed a multi-criteria decision analysis model to explore regulatory decision making in the context of emerging vaccine safety signals during a pandemic. We simulated vaccine safety surveillance system capabilities and used an age structured compartmental model to develop potential pandemic scenarios. We used an expert-derived multi-attribute utility function to evaluate potential regulatory responses by combining four outcome measures into a single measure of interest: 1) expected vaccination benefit from averted influenza; 2) expected vaccination risk from vaccine-associated febrile seizures; 3) expected vaccination risk from vaccine-associated Guillain-Barre Syndrome; and 4) expected change in vaccine-seeking behavior in future influenza seasons. RESULTS: Over multiple scenarios, risk communication, with or without suspension of vaccination of high-risk persons, were the consistently preferred regulatory responses over no action or general suspension when safety signals were detected during a pandemic influenza. On average, the expert panel valued near-term vaccine-related outcomes relative to long-term projected outcomes by 3:1. However, when decision makers had minimal ability to influence near-term outcomes, the response was selected primarily by projected impacts on future vaccine-seeking behavior. CONCLUSIONS: The selected regulatory response depends on how quickly a vaccine safety signal is identified relative to the peak of the pandemic and the initiation of vaccination. Our analysis suggested two areas for future investment: efforts to improve the size and timeliness of the surveillance system and behavioral research to understand changes in vaccine-seeking behavior. PMID- 25536229 TI - The role of hormones in the differences in the incidence of breast cancer between Mongolia and the United Kingdom. AB - BACKGROUND: There are striking differences in breast cancer incidence between Asian and western women. Rates vary substantially within Asia also, with Mongolia's even lower than China's. These profound differences have been speculated to be due in part to diet, mediated by circulating hormone concentrations. METHODS: Sex steroid hormone concentrations were measured in women living in Ulaanbaatar, Mongolia and the United Kingdom (U.K.). Diet was obtained by interview and national survey data. Mean hormone differences were compared by country, and systematic variation by number of days since last menstrual period was modeled and adjusted for age and parity; difference in overall area under the curves was assessed. FINDINGS: The diet in Mongolia was higher in meat and dairy than in the U.K. Mean testosterone concentrations were 18.5% lower (p<0.0001) while estradiol concentrations were 19.1% higher (p = 0.02) in Mongolian than British women, adjusted for age and parity. Progesterone was almost 50% higher in Mongolian women (p = 0.04), particularly during the follicular phase and early luteal surge. Hormone concentrations generally were similar in Mongolian women born in Ulaanbaatar compared with those born in rural areas, although there was a decreasing progesterone trend by degree of westernization (rural Mongolia; urban Mongolia; U.K.). Mean hormone differences were similar when restricted to parous women, and with further adjustment for body mass index, height, and smoking status. INTERPRETATION: These data augment accumulating evidence that circulating estrogens are unlikely to explain reduced breast cancer rates in Asia compared with the west, and suggest casting a wider net with respect to biomarkers. Lower testosterone and higher progesterone in Mongolian women raise the possibility that these hormones may be important to consider. In addition, the almost exclusive dietary reliance of Mongolians on meat and dairy argues against beneficial effects of a low-fat diet on circulating hormones explaining international breast cancer differences. PMID- 25536231 TI - The relative biological effectiveness of low-dose mammography quality X rays in the human breast MCF-10A cell line. AB - Mammography is used to screen a large fraction of the population for breast cancer, and mammography quality X rays are speculated to be more damaging than the higher energy X rays used for other diagnostic procedures. The radiation dose delivered to breast cells as a result of these screening exposures may be a concern. The purpose of this current study was to determine the relative biological effectiveness (RBE) of low-energy mammography X rays for radiation induced DNA double-strand breaks evaluated using a highly sensitive automated 53BP1 assay. Automation of the 53BP1 assay enabled the quantification and analysis of meaningful image-based features, including foci counting, within the cell nuclei. Nontumorigenic, human breast epithelial MCF-10A cells were irradiated in the low-dose range with approximately 3-30 mGy of 29 kVp mammography X rays or (137)Cs (662 keV) gamma rays. The induction and resolution of the 53BP1 foci did not differ significantly between exposures to (137)Cs gamma rays and 29 kVp X rays. The RBE was calculated to be 1.1 with a standard deviation of 0.2 for the initial number of radiation-induced double-strand breaks. The radiation dose from a single mammogram did not yield a significant change in the number of detectable foci. However, analysis of additional features revealed subtle differences in the distribution of 53BP1 throughout the nuclei after exposure to the different radiation qualities. A single mammogram was sufficient to alter the distribution of 53BP1 within the nuclear area, but not into discrete foci, while a dose-matched gamma exposure was not sufficient to alter the distribution of 53BP1. Our results indicate that exposure to clinically relevant doses of low-energy mammography quality X rays does not induce more DNA double-strand breaks than exposure to higher energy photons. PMID- 25536230 TI - Evaluation of three sources of validity evidence for a laparoscopic duodenal atresia repair simulator. AB - PURPOSE: Laparoscopic duodenal atresia (DA) repair is a relatively uncommon pediatric operation requiring advanced minimally invasive skills. Currently, there are no commercial simulators available that address surgeons' needs for refining skills associated with this procedure. The purposes of this study were (1) to create an anatomically correct, size-relevant model and (2) to evaluate the content validity of the simulator. MATERIALS AND METHODS: Radiologic images were used to create an abdominal domain consistent with a full-term infant. Fetal bovine tissue was used to complete the simulator. Following Institutional Review Board exempt determination, 18 participants performed the simulated laparoscopic DA repair. Participants completed a self-report, six-domain, 24-item instrument consisting of 4-point rating scales (from 1=not realistic to 4=highly realistic). Validity evidence relevant to test content and response processes was evaluated using the many-facet Rasch model, and evidence of internal structure (inter-item consistency) was estimated using Cronbach's alpha. RESULTS: The highest observed averages were for "Value as a training and testing tool" (both observed averages=3.9), whereas the lowest ratings were "Palpation of liver" (observed average=3.3) and "Realism of skin" (observed average=3.2). The Global opinion rating was 3.2, indicating the simulator can be considered for use as is, but could be improved slightly. Inter-item consistency was high (alpha=0.89). CONCLUSIONS: We have successfully created a size-appropriate laparoscopic DA simulator. Participants agreed that the simulator was relevant and valuable as a learning/testing tool. Prior to implementing this simulator as a training tool, minor improvements should be made, with subsequent evaluation of additional validation evidence. PMID- 25536232 TI - NEMO modulates radiation-induced endothelial senescence of human umbilical veins through NF-kappaB signal pathway. AB - Recently several laboratories have reported that radiation induces senescence in endothelial cells. Senescent cells can secrete multiple growth-regulatory proteins, some of which affect tumor growth, survival, invasion or angiogenesis. The purpose of this study was to explore the mechanisms of radiation-induced senescence and its effects on angiogenesis in human umbilical vein endothelial cells (HUVECs). HUVECs were either pretreated with or without PS1145 prior to irradiation with 0-8 Gy. PS1145 is a novel, highly specific small-molecule inhibitor of nuclear factor kappa B essential modulator (NEMO). MTT assays showed that in HUVECs untreated with PS1145, there was an increase in the number of radiation-induced senescence-like endothelial cells 5 days after 8 Gy irradiation, while pretreatment with PS1145 significantly ameliorated the induction in senescence of HUVECs compared to the control group. Electrophoretic mobility shift assay (EMSA) showed that pretreatment with PS1145 inhibited the radiation-induced NF-kappaB activation, which regulates cell fate in response to genotoxic stress. In addition, Western blotting demonstrated less translocation of p65 from cytoplasm to nucleus. Furthermore, real-time polymerase chain reaction (PCR) showed that pretreatment with PS1145 inhibited the increase of mRNA expressions of interleukin-6 (IL-6) and p53-induced death domain (PIDD) protein, which have been show to play crucial roles in both senescence and apoptosis (P < 0.05). TUNEL staining revealed an increase in apoptotic HUVECs in the group pretreated with PS1145 after irradiation. The series of functional assays further showed that radiation-induced senescence-like HUVECs had malfunctions in migration, invasion and formation of capillary-like structures, compared with the sham-irradiated and untreated, irradiated groups. Taken together, these findings indicate that the angiogenic capacity of radiation induced senescence-like HUVECs decreased, and that irradiation caused vascular endothelial cells to gain a senescence-like phenotype through the DSB/NEMO/NF kappaB signal pathway. The data suggests that NEMO may be a critical switch that regulates cellular senescence and apoptosis caused by exposure to radiation, and provides new clues for the clinical potential of the combination of radiotherapy and angiogenesis inhibitors. PMID- 25536233 TI - Finite-time synchronization control of a class of memristor-based recurrent neural networks. AB - This paper presents a global and local finite-time synchronization control law for memristor neural networks. By utilizing the drive-response concept, differential inclusions theory, and Lyapunov functional method, we establish several sufficient conditions for finite-time synchronization between the master and corresponding slave memristor-based neural network with the designed controller. In comparison with the existing results, the proposed stability conditions are new, and the obtained results extend some previous works on conventional recurrent neural networks. Two numerical examples are provided to illustrate the effective of the design method. PMID- 25536235 TI - Auditory imagery forces motor action. AB - A large number of neuroimaging studies have investigated imagined sensory processing and motor behaviours. These studies have reported neural activation patterns for imagined processes that resemble those of real sensory and motor events. The widespread use of such methods has raised questions about the extent to which imagined sensorimotor events mimic their overt counterparts, including their ability to elicit sensorimotor interactions. Direct behavioural evidence of imagery-induced multisensory interactions has been found recently in tasks involving auditory and visual processing. An influence of sensory imagery on the control of motor action, however, has not been investigated previously. Here, we show that both real and imagined moving sounds induce involuntary ocular movement in a nonvisual tracking task. The present data build on the results of previous studies of sensory imagery by showing that such conditions activate sensory neural areas. Moreover, we show an engagement of functional sensorimotor networks for imagined stimuli in a manner similar to the processing of real auditory stimuli. PMID- 25536236 TI - Ethnic identity, drinking motives, and alcohol consequences among Alaska Native and non-Native college students. AB - This research involves the examination of drinking motives, alcohol consequences, and ethnic identity in a sample of Native and non-Native college student drinkers in Alaska. Although more Alaska Native students are abstinent from alcohol compared to any other ethnic group, Native students who do drink experience greater alcohol consequences and dependence symptoms. Therefore, we attempted to examine the influence of ethnic identity on alcohol consequences in a diverse sample of Native and non-Native students in Alaska. Findings showed that drinking motives, as measured by the Drinking Motives Questionnaire (social, coping, enhancement, and conformity), significantly predicted alcohol consequences after controlling for frequency of monthly binge drinking. In addition, after controlling for depression, binge drinking, and drinking motives, one aspect of ethnic identity (Affirmation, Belonging, and Commitment) was significantly negatively related to alcohol consequences, whereas another aspect of ethnic identity (Ethnic Identity Search) was not. Taken together, these findings suggest that interventions for college student alcohol misuse that target Native students should be culturally grounded and focused on enhancing the Affirmation, Belonging, and Commitment to one's ethnic heritage and should address drinking motives, especially drinking to cope, as a way to reduce alcohol related harm. PMID- 25536239 TI - Oxen and logging wagon (1): Maud Lewis. PMID- 25536240 TI - Ebola perspectives from opposite sides of the globe. PMID- 25536234 TI - Increased glutamate levels observed upon functional activation in the anterior cingulate cortex using the Stroop Task and functional spectroscopy. AB - It has been shown in recent studies that it is possible to detect changes in the main excitatory neurotransmitter, glutamate, upon functional activation with visual and motor paradigms using a 7 T MRI and functional magnetic resonance spectroscopy. A cognitive task would be desirable for this technique because it could then be used to examine psychiatric disorders that have cognitive deficiencies. The aim of the work presented here was to use functional magnetic resonance spectroscopy with a 7 T MRI to show that increases in glutamate can be observed within the anterior cingulate cortex using the Stroop Task as the activation paradigm in healthy controls. Significant glutamate increases (0.24+/ 0.09 umol/g, P<0.025), comparable with what has been reported in the studies of the occipital cortex and motor cortex, were observed when the participants (n=7) performed the task, followed by a trend toward returning to baseline in the post task recovery period (-0.23+/-0.13 umol/g). This method would be ideal for the study of neuropsychiatric disorders that have been shown to have abnormal resting glutamate levels and cognitive deficiencies in the anterior cingulate cortex, such as schizophrenia. This exploratory study is the first to demonstrate functional magnetic resonance spectroscopy in the anterior cingulate with a cognitive task using a 7 T MRI. PMID- 25536241 TI - Transparency in action: "the imperfect is our paradise". PMID- 25536249 TI - Quality measures and sociodemographic risk factors: to adjust or not to adjust. PMID- 25536250 TI - A piece of my mind. Trust worthy. PMID- 25536251 TI - Depth and duration of cooling for perinatal asphyxial encephalopathy. PMID- 25536252 TI - Patient-centered medical home for high-risk children with chronic illness. PMID- 25536255 TI - Effect of an enhanced medical home on serious illness and cost of care among high risk children with chronic illness: a randomized clinical trial. AB - IMPORTANCE: Patient-centered medical homes have not been shown to reduce adverse outcomes or costs in adults or children with chronic illness. OBJECTIVE: To assess whether an enhanced medical home providing comprehensive care prevents serious illness (death, intensive care unit [ICU] admission, or hospital stay >7 days) and/or reduces costs among children with chronic illness. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of high-risk children with chronic illness (>=3 emergency department visits, >=2 hospitalizations, or >=1 pediatric ICU admissions during previous year, and >50% estimated risk for hospitalization) treated at a high-risk clinic at the University of Texas, Houston, and randomized to comprehensive care (n = 105) or usual care (n = 96). Enrollment was between March 2011 and February 2013 (when predefined stopping rules for benefit were met) and outcome evaluations continued through August 31, 2013. INTERVENTIONS: Comprehensive care included treatment from primary care clinicians and specialists in the same clinic with multiple features to promote prompt effective care. Usual care was provided locally in private offices or faculty-supervised clinics without modification. MAIN OUTCOMES AND MEASURES: Primary outcome: children with a serious illness (death, ICU admission, or hospital stay >7 days), costs (health system perspective). Secondary outcomes: individual serious illnesses, medical services, Medicaid payments, and medical school revenues and costs. RESULTS: In an intent-to-treat analysis, comprehensive care decreased both the rate of children with a serious illness (10 per 100 child-years vs 22 for usual care; rate ratio [RR], 0.45 [95% CI, 0.28-0.73]), and total hospital and clinic costs ($16,523 vs $26,781 per child-year, respectively; cost ratio, 0.58 [95% CI, 0.38-0.88]). In analyses of net monetary benefit, the probability that comprehensive care was cost neutral or cost saving was 97%. Comprehensive care reduced (per 100 child-years) serious illnesses (16 vs 44 for usual care; RR, 0.33 [95% CI, 0.17-0.66]), emergency department visits (90 vs 190; RR, 0.48 [95% CI, 0.34-0.67]), hospitalizations (69 vs 131; RR, 0.51 [95% CI, 0.33-0.77]), pediatric ICU admissions (9 vs 26; RR, 0.35 [95% CI, 0.18-0.70]), and number of days in a hospital (276 vs 635; RR, 0.36 [95% CI, 0.19-0.67]). Medicaid payments were reduced by $6243 (95% CI, $1302-$11,678) per child-year. Medical school losses (costs minus revenues) increased by $6018 (95% CI, $5506-$6629) per child year. CONCLUSIONS AND RELEVANCE: Among high-risk children with chronic illness, an enhanced medical home that provided comprehensive care to promote prompt effective care vs usual care reduced serious illnesses and costs. These findings from a single site of selected patients with a limited number of clinicians require study in larger, broader populations before conclusions about generalizability to other settings can be reached. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02128776. PMID- 25536256 TI - Effect of maternal multiple micronutrient vs iron-folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh: the JiVitA-3 randomized trial. AB - IMPORTANCE: Maternal micronutrient deficiencies may adversely affect fetal and infant health, yet there is insufficient evidence of effects on these outcomes to guide antenatal micronutrient supplementation in South Asia. OBJECTIVE: To assess effects of antenatal multiple micronutrient vs iron-folic acid supplementation on 6-month infant mortality and adverse birth outcomes. DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized, double-masked trial in Bangladesh, with pregnancy surveillance starting December 4, 2007, and recruitment on January 11, 2008. Six-month infant follow-up ended August 30, 2012. Surveillance included 127,282 women; 44,567 became pregnant and were included in the analysis and delivered 28,516 live-born infants. Median gestation at enrollment was 9 weeks (interquartile range, 7-12). INTERVENTIONS: Women were provided supplements containing 15 micronutrients or iron-folic acid alone, taken daily from early pregnancy to 12 weeks postpartum. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause infant mortality through 6 months (180 days). Prespecified secondary outcomes in this analysis included stillbirth, preterm birth (<37 weeks), and low birth weight (<2500 g). To maintain overall significance of alpha = .05, a Bonferroni-corrected alpha = .01 was calculated to evaluate statistical significance of primary and 4 secondary risk outcomes (.05/5). RESULTS: Among the 22,405 pregnancies in the multiple micronutrient group and the 22,162 pregnancies in the iron-folic acid group, there were 14,374 and 14,142 live-born infants, respectively, included in the analysis. At 6 months, multiple micronutrients did not significantly reduce infant mortality; there were 764 deaths (54.0 per 1000 live births) in the iron-folic acid group and 741 deaths (51.6 per 1000 live births) in the multiple micronutrient group (relative risk [RR], 0.95; 95% CI, 0.86-1.06). Multiple micronutrient supplementation resulted in a non statistically significant reduction in stillbirths (43.1 vs 48.2 per 1000 births; RR, 0.89; 95% CI, 0.81-0.99; P = .02) and significant reductions in preterm births (18.6 vs 21.8 per 100 live births; RR, 0.85; 95% CI, 0.80-0.91; P < .001) and low birth weight (40.2 vs 45.7 per 100 live births; RR, 0.88; 95% CI, 0.85 0.91; P < .001). CONCLUSIONS AND RELEVANCE: In Bangladesh, antenatal multiple micronutrient compared with iron-folic acid supplementation did not reduce all cause infant mortality to age 6 months but resulted in a non-statistically significant reduction in stillbirths and significant reductions in preterm births and low birth weight. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00860470. PMID- 25536257 TI - Cause-specific risk of hospital admission related to extreme heat in older adults. AB - IMPORTANCE: Heat exposure is known to have a complex set of physiological effects on multiple organ systems, but current understanding of the health effects is mostly based on studies investigating a small number of prespecified health outcomes such as cardiovascular and respiratory diseases. OBJECTIVES: To identify possible causes of hospital admissions during extreme heat events and to estimate their risks using historical data. DESIGN, SETTING, AND POPULATION: Matched analysis of time series data describing daily hospital admissions of Medicare enrollees (23.7 million fee-for-service beneficiaries [aged >=65 years] per year; 85% of all Medicare enrollees) for the period 1999 to 2010 in 1943 counties in the United States with at least 5 summers of near-complete (>95%) daily temperature data. EXPOSURES: Heat wave periods, defined as 2 or more consecutive days with temperatures exceeding the 99th percentile of county-specific daily temperatures, matched to non-heat wave periods by county and week. MAIN OUTCOMES AND MEASURES: Daily cause-specific hospitalization rates by principal discharge diagnosis codes, grouped into 283 disease categories using a validated approach. RESULTS: Risks of hospitalization for fluid and electrolyte disorders, renal failure, urinary tract infection, septicemia, and heat stroke were statistically significantly higher on heat wave days relative to matched non-heat wave days, but risk of hospitalization for congestive heart failure was lower (P < .05). Relative risks for these disease groups were 1.18 (95% CI, 1.12-1.25) for fluid and electrolyte disorders, 1.14 (95% CI, 1.06-1.23) for renal failure, 1.10 (95% CI, 1.04-1.16) for urinary tract infections, 1.06 (95% CI, 1.00-1.11) for septicemia, and 2.54 (95% CI, 2.14-3.01) for heat stroke. Absolute risk differences were 0.34 (95% CI, 0.22-0.46) excess admissions per 100,000 individuals at risk for fluid and electrolyte disorders, 0.25 (95% CI, 0.12-0.39) for renal failure, 0.24 (95% CI, 0.09-0.39) for urinary tract infections, 0.21 (95% CI, 0.01-0.41) for septicemia, and 0.16 (95% CI, 0.10-0.22) for heat stroke. For fluid and electrolyte disorders and heat stroke, the risk of hospitalization increased during more intense and longer-lasting heat wave periods (P < .05). Risks were generally highest on the heat wave day but remained elevated for up to 5 subsequent days. CONCLUSIONS AND RELEVANCE: Among older adults, periods of extreme heat were associated with increased risk of hospitalization for fluid and electrolyte disorders, renal failure, urinary tract infection, septicemia, and heat stroke. However, the absolute risk increase was small and of uncertain clinical importance. PMID- 25536259 TI - Patient satisfaction and quality of life in psoriasis and psoriatic arthritis. PMID- 25536260 TI - Antibiotics for acute bronchitis. AB - CLINICAL QUESTION: Are antibiotics associated with improved outcomes in patients with acute bronchitis? BOTTOM LINE: Prescribing antibiotics for acute bronchitis was associated with reduced overall and nighttime cough and with an approximately half-day reduction in duration of cough, in days feeling ill, and in days with impaired activities. However, at follow-up, there were no significant differences in patients receiving antibiotics compared with those receiving placebo in overall clinical improvements or limitations in work or other activities. There was a significant increase in adverse effects in the antibiotic group, particularly gastrointestinal symptoms. PMID- 25536258 TI - Metformin in patients with type 2 diabetes and kidney disease: a systematic review. AB - IMPORTANCE: Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE: To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION: In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta analyses, and a clinical trial. RESULTS: Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE: Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function. PMID- 25536261 TI - Parathyroid hormone in the evaluation of hypercalcemia. PMID- 25536262 TI - Eligibility for and prescription of urate-lowering treatment in patients with incident gout in England. PMID- 25536263 TI - Voluntary medical male circumcision in Kenya. PMID- 25536264 TI - Energy intake and weight loss. PMID- 25536265 TI - Voluntary medical male circumcision in Kenya--reply. PMID- 25536266 TI - Calorie labeling on menus and menu boards. PMID- 25536267 TI - Energy intake and weight loss--reply. PMID- 25536268 TI - Calorie labeling on menus and menu boards--reply. PMID- 25536270 TI - Winter sports and health. PMID- 25536271 TI - JAMA patient page. Hemorrhoids. PMID- 25536273 TI - Incidence of First Implant Failure: A Retroprospective Study of 27 Years of Implant Operations at One Specialist Clinic. AB - BACKGROUND: Even though there are many studies available reporting on implant failures, there are few studies that follow implant failures over time in large populations. PURPOSE: The purpose of this article is to present an overview of the annual incidence of reported implant failures for patients and operations over a 28-year period. MATERIALS AND METHODS: A total of 8,528 patients were consecutively provided with 39,077 implants in 10,719 implant operations during a 27-year period (1986-2012) at one specialist clinic. All patients with reported failures of implants during a 28-year routine follow-up period (1986-2013) were included, and data from the patients' files were retrieved and reported. RESULTS: Altogether, 857 patients (882 jaws/operations) were identified with one or more failures (10.0% of patients/8.5% of operations). Mean annual incidence of first failure showed obvious variations between years, even between seemingly clinically similar situations. However, incidence of first implant failure was higher for upper than lower jaws (p < .05), within 1 year of surgery (69%) than after 1 year (p < .05), and for implants with a turned surface compared with implants with a moderately rough surface (p < .05). CONCLUSIONS: With regard to annual failure incidence in relation to total number of operations over time, obvious variations in failure rate can be observed between seemingly similar clinical situations, as well as significant differences in incidence of first implant failure between the first year after surgery and later time points, between upper and lower jaws using implants with turned surfaces, and between operations to install implants with turned surfaces and those to install implants with moderately rough surfaces. PMID- 25536274 TI - The effect of a prefabricated foot orthotic on frontal plane joint mechanics in healthy runners. AB - The mechanism of action of a foot orthotic is poorly understood. The purpose of this study was to use principal components analysis (PCA) to analyze the effects of a prefabricated foot orthotic on frontal plane knee and ankle mechanics during running. Thirty-one healthy subjects performed running trials with and without a foot orthotic and PCA was performed on the knee and ankle joint angles and moments to identify the dominant modes of variation. MANOVAs were conducted on the retained principal components of each waveform and dependent t tests (P < .05) were performed in the case of significance. Mechanics of the ankle were not affected by the foot orthotic. However, mechanics of the knee were significantly altered as subjects demonstrated an increase in the magnitude of the knee abduction moment waveform in an orthotic condition. Subjects also demonstrated a significant shift in the timing of the knee abduction moment waveform toward later in the stance phase in the orthotic condition. These orthotic effects were not related to subject's foot mobility, measured using the navicular drop test. The mechanism of action of a foot orthotic may be related to their effect on the timing of frontal plane knee loading. PMID- 25536254 TI - Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. AB - IMPORTANCE: Hypothermia at 33.5 degrees C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models. OBJECTIVE: To determine if longer duration cooling (120 hours), deeper cooling (32.0 degrees C), or both are superior to cooling at 33.5 degrees C for 72 hours in neonates who are full term with moderate or severe hypoxic ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: A randomized, 2 * 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013. INTERVENTIONS: Neonates were assigned to 4 hypothermia groups; 33.5 degrees C for 72 hours, 32.0 degrees C for 72 hours, 33.5 degrees C for 120 hours, and 32.0 degrees C for 120 hours. MAIN OUTCOMES AND MEASURES: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5 degrees C depth vs 32.0 degrees C depth (predefined secondary outcomes). RESULTS: The NICU death rates were 7 of 95 neonates (7%) for the 33.5 degrees C for 72 hours group, 13 of 90 neonates (14%) for the 32.0 degrees C for 72 hours group, 15 of 96 neonates (16%) for the 33.5 degrees C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0 degrees C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92 2.04) and for the 32.0 degrees C group vs 33.5 degrees C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0 degrees C group vs 33.5 degrees C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%. CONCLUSIONS AND RELEVANCE: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5 degrees C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776. PMID- 25536275 TI - Iron catalysed cross-couplings of azetidines - application to the formal synthesis of a pharmacologically active molecule. AB - A protocol for the coupling of 3-iodoazetidines with Grignard reagents in the presence of an iron catalyst has been developed. A variety of aryl, heteroaryl, vinyl and alkyl Grignards were shown to participate in the coupling process to give the products in good to excellent yields. Furthermore, a short formal synthesis towards a pharmacologically active molecule was shown. PMID- 25536277 TI - Self-assembled 3D hierarchical sheaf-like Nb3O7(OH) nanostructures with enhanced photocatalytic activity. AB - Novel three-dimensional (3D) hierarchical Nb3O7(OH) nanostructures with a sheaf like nanoarchitecture were fabricated for the first time by a hydrothermal process. Interestingly, the nanosheafs are composed of nanorods with an average diameter of about 25 nm. The as-prepared 3D hierarchical nanostructures possess a high surface area of 77 m(2) g(-1) with pore diameters of ca. 4.2-12.5 nm. A possible growth mechanism based on the combined Ostwald ripening and self assembly process was proposed. It is found that both the valence-band top and the conduction-band bottom consist of O 2p and Nb 4d orbitals. Importantly, the 3D hierarchical Nb3O7(OH) nanostructures exhibit enhanced photocatalytic activity for the degradation of Rhodamine B (RhB) under UV-visible light, which is attributed to the unusual hierarchical structure, high surface area, and hybridization of energy bands. PMID- 25536278 TI - Lead toxicity to the performance, viability, and community composition of activated sludge microorganisms. AB - Lead (Pb) is a prominent toxic metal in natural and engineered systems. Current knowledge on Pb toxicity to the activated sludge has been limited to short-term (<=24 h) toxicity. The effect of extended Pb exposure on process performance, bacterial viability, and community compositions remains unknown. We quantified the 24-h and 7-day Pb toxicity to chemical oxygen demand (COD) and NH3-N removal, bacterial viability, and community compositions using lab-scale experiments. Our results showed that 7-day toxicity was significantly higher than the short-term 24-h toxicity. Ammonia-oxidizing bacteria were more susceptible than the heterotrophs to Pb toxicity. The specific oxygen uptake rate responded quickly to Pb addition and could serve as a rapid indicator for detecting Pb pollutions. Microbial viability decreased linearly with the amount of added Pb at extended exposure. The bacterial community diversity was markedly reduced with elevated Pb concentrations. Surface analysis suggested that the adsorbed form of Pb could have contributed to its toxicity along with the dissolved form. Our study provides for the first time a systematic investigation of the effect of extended exposure of Pb on the performance and microbiology of aerobic treatment processes, and it indicates that long-term Pb toxicity has been underappreciated by previous studies. PMID- 25536276 TI - Lymphocytic alveolitis is associated with the accumulation of functionally impaired HIV-specific T cells in the lung of antiretroviral therapy-naive subjects. AB - RATIONALE: Lymphocytic alveolitis in HIV-1-infected individuals is associated with multiple pulmonary complications and a poor prognosis. Although lymphocytic alveolitis has been associated with viremia and an increased number of CD8(+) T cells in the lung, its exact cause is unknown. OBJECTIVES: To determine if HIV-1 specific T cells are associated with lymphocytic alveolitis in HIV-1-infected individuals. METHODS: Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and untreated HIV-1-infected individuals, we examined the frequency and functional capacity of HIV-1-specific T cells. MEASUREMENTS AND MAIN RESULTS: We found that HIV-1-specific T cells were significantly elevated in the BAL compared with blood of HIV-1-infected individuals and strongly correlated with T-cell alveolitis. Expression of Ki67, a marker of in vivo proliferation, was significantly reduced on HIV-1-specific T cells in BAL compared with blood, suggesting a diminished proliferative capacity. In addition, HIV-1-specific CD4(+) and CD8(+) T cells in BAL had higher expression of programmed death 1 (PD 1) and lower cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression than those in the blood. A strong correlation between PD-1, but not CTLA-4, and HIV-1-specific T-cell proliferation was seen, and blockade of the PD-1/PD-L1 pathway augmented HIV-1-specific T-cell proliferation, suggesting that the PD-1 pathway was the main cause of reduced proliferation in the lung. CONCLUSIONS: These findings suggest that alveolitis associated with HIV-1 infection is caused by the recruitment of HIV-1-specific CD4(+) and CD8(+) T cells to the lung. These antigen-specific T cells display an impaired proliferative capacity that is caused by increased expression of PD-1. PMID- 25536279 TI - Novel reddish-orange-emitting BaLa2Si2S8:Eu(2+) thiosilicate phosphor for LED lighting. AB - A novel reddish-orange-emitting BaLa2Si2S8:Eu(2+) thiosilicate was prepared in a sealed fused silica ampule and its crystal structure was refined using Rietveld methods. The BaLa2Si2S8:Eu(2+) phosphor is excitable over a broad range from UV to blue (350-450 nm) and generated a reddish-orange broadband emission peaking at 645 nm with a quantum efficiency of ~24%. The thermal luminescence quenching of BaLa2Si2S8:Eu(2+) was investigated over the range 25 to 150 degrees C. This phosphor was utilized to incorporate with two commercially available phosphors, blue BaMgAl10O17:Eu(2+) and green (Ba,Sr)2SiO4:Eu(2+), and a near-UV LED chip (405 nm), a white light with Ra of ~94 was obtained. PMID- 25536280 TI - A scalable, nonenzymatic synthesis of highly stereopure difunctional C4 secondary methyl linchpin synthons. AB - In response to the continuing widespread use of heterodifunctional C4 secondary methyl building blocks in asymmetric synthesis, we have developed a mole-scale, two-step synthesis of a 1:1 mixture of the diastereomers of 3-bromo-2-methyl-1 propyl camphorsulfonate (casylate). One isomer (2S) has been crystallized to >99:1 dr in ~25% yield. Equilibration of the mother liquor (enriched in 2R) to a 1:1 mixture and recrystallization significantly raises the overall yield of 2S. Applications of 2S include chemoselective Grignard coupling, enabling the very short synthesis of highly stereopure long-chain natural products containing remote, methyl-bearing stereogenic centers [e.g., (R)-tuberculostearic acid], with complete control of configuration. Also, Ag-mediated, completely chemoselective Br displacement from 2S leads to a range of >99:1 er difunctional synthons. Both applications incorporate concurrent recovery of CasO. The enantiomer of 2S can be made from commercial (1R)-10-CasOH. PMID- 25536281 TI - 'A place for healthy activity': parent and caregiver perspectives on smokefree playgrounds. AB - Restrictions on outdoor smoking are increasingly common, especially for spaces associated with children. In Canada, playground smoking bans are in effect in 102 municipalities. A survey of parents and caregivers at three playgrounds in neighbourhoods of varying income levels was undertaken in Edmonton, Alberta in July 2013. Respondents expressed very strong support for smokefree playgrounds, informed by knowledge of smoking as a health risk that was out of place. Levels of support did not vary significantly across the three sites. Social enforcement of smokefree rules was complicated by low levels of awareness, and fears of confrontation. PMID- 25536283 TI - Determinants of child stunting in the Royal Kingdom of Bhutan: an in-depth analysis of nationally representative data. AB - Stunting is associated with poor survival and development in children. Our analysis identifies the factors most significantly associated with child stunting in Bhutan using a nationally representative sample of 2085 children 0-23 months old. We find that 27.5% of children were stunted and almost half (42.6%) of the stunted children were severely stunted. Children's mean height-for-age z-score deteriorated significantly with age (from -0.23 in infants 0-5 months old to 1.60 in children 18-23 months old) and levels of severe stunting were significantly higher among boys. Multivariate regression analysis indicates that children from the Eastern/Western regions had a 64% higher odds of being stunted than children from the Central region (OR 1.64; 95% CI 1.29-2.07); similarly, children from the two lower wealth quintiles had 37% higher odds of being stunted than children from the two upper wealth quintiles (OR 1.37; 95% CI 1.00-1.87). Children whose mothers received three or fewer antenatal care visits during the last pregnancy had a 31% higher odds of being stunted (OR 1.31; 95% CI 1.01-1.69) while children whose mothers did not receive antenatal care from a doctor, nurse or midwife had a 51% higher odds of being stunted (OR 1.51; 95% CI 1.18-1.92). Recommended complementary feeding practices tended to be associated with lower odds of stunting, particularly in the first year of life. Specifically, children who were not fed complementary foods at 6-8 months had about threefold higher odds of being severely stunted than children who were fed complementary foods (OR 2.73; 95% CI 1.06-7.02). PMID- 25536282 TI - Heparan sulfate D-glucosaminyl 3-O-sulfotransferase-3B1 (HS3ST3B1) promotes angiogenesis and proliferation by induction of VEGF in acute myeloid leukemia cells. AB - Heparan sulfate (HS) are complex polysaccharides that reside on the plasma membrane of almost all mammalian cells, and play an important role in physiological and pathological conditions. Heparan sulfate D-glucosamine 3-O sulfotransferase 3B1 (HS3ST3B1) participates in the last biosynthetic steps of HS and transfers sulfate to the 3-O-position of glucosamine residues to yield mature sugar chains. To date very few biological processes or proteins have been described that are modulated by HS3ST3B1. In this study, we observed that HS3ST3B1 positively contributed to acute myeloid leukemia (AML) progression in vitro and in vivo, and these activities were associated with an induction of the proangiogenic factor VEGF expression and shedding. Moreover, the effects of HS3ST3B1 on VEGF release can be attenuated after treatment of heparanase inhibitor suramin, which prevented VEGF secretion and subsequently blocked VEGF induced activation of ERK and AKT, suggesting that 3-O-sulfation of HS by HS3ST3B1 facilitated VEGF shedding; the effects of HS3ST3B1 on activation of ERK and AKT can also be blocked by VEGFR inhibitor axitinib, suggestive of a relationship between 3-O-sulfation of HS and VEGF-activated signaling pathways. Taken together, our findings support that VEGF is an important functional target of HS3ST3B1 and provide a new mechanism of HS3ST3B1 in AML. PMID- 25536284 TI - Comparative study of the growth and survival of recombinant Mycobacterium smegmatis expressing Mce4A and Mce4E from Mycobacterium bovis. AB - Cholesterol is important for the growth and persistence of Mycobacterium tuberculosis in macrophages. The mce4 locus, which is conserved in both M. tuberculosis and Mycobacterium bovis, is thought to be responsible for cholesterol transport into the bacteria. However, the exact roles of specific genes within the sophisticated mce4 system remain poorly understood. In this study, Mce4A and Mce4E of M. bovis, two proteins that are encoded by the mce4 locus, were expressed in Mycobacterium smegmatis. The recombinant strain expressing the Mce4E protein (M. smeg::E) performed better than that expressing the Mce4A protein (M. smeg::A) in a minimal medium with and without glycerol or cholesterol, which may be the reason why M. smeg::E showed better survival in ANA 1 macrophages than did M. smeg::A. Cytokine expression profiles were similar in macrophages infected with either recombinant strain. We also investigated the role of CD36 in recognizing Mce4A and Mce4E proteins. However, CD36 did not appear to be specific for these proteins and showed little impact on the ultimate clearance of the recombinant strains. Reduced interleukin-1beta, inducible nitric oxide synthase, and tumor necrosis factor-alpha mRNA expression at 6 h postinfection in macrophages infected with M. smeg::E was observed using a CD36 specific monocular antibody to block the receptor, whereas no obvious changes in the expression of these cytokines were observed in cells infected with M. smeg::A with or without exposure to the CD36 antibody. Conclusively, the different performances of the recombinant strains suggest that the Mce4A and Mce4E proteins enhance mycobacterial adaptation to the harsh environment within macrophages after phagocytosis. PMID- 25536285 TI - A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients. AB - PURPOSE: Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. METHODS: We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. RESULTS: Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. CONCLUSION: Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy. PMID- 25536286 TI - Role of secretory IgA in the mucosal sensing of commensal bacteria. AB - While the gut epithelium represents the largest mucosal tissue, the mechanisms underlying the interaction between intestinal bacteria and the host epithelium lead to multiple outcomes that remain poorly understood at the molecular level. Deciphering such events may provide valuable information as to the mode of action of commensal and probiotic microorganisms in the gastrointestinal environment. Potential roles of such microorganisms along the privileged target represented by the intestinal immune system include maturation processes prior, during and after weaning, and the reduction of inflammatory reactions in pathogenic conditions. As commensal bacteria are naturally coated by natural and antigen-specific SIgA in the gut lumen, understanding the consequences of such an interaction may provide new clues on how the antibody contributes to homeostasis at mucosal surfaces. This review discusses several aspects of the role of SIgA in the essential communication existing between the host epithelium and members of its microbiota. PMID- 25536288 TI - Plants used to treat snakebites in Santarem, western Para, Brazil: an assessment of their effectiveness in inhibiting hemorrhagic activity induced by Bothrops jararaca venom. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The poor distribution and limited availability of antivenoms in Brazil have led to greater use of plants to treat snakebites. Very often such plants are the only alternative available to riverside communities. MATERIALS AND METHODS: Direct questionnaire-based interviews were conducted with members of the Cucuruna, Sao Pedro and Alter do Chao communities in Santarem, Para, Brazil. For each of the 12 most frequently mentioned species aqueous extracts were prepared and the phytochemical profiles determined by thin layer chromatography. The concentrations of phenolic compounds (tannins and flavonoids) in the aqueous extracts were determined by colorimetric assays. To assess inhibition of the hemorrhagic activity of Bothrops jararaca venom, solutions containing the venom mixed with aqueous extracts in the ratios 1:12 and 1:48 were tested (w/w). SDS-PAGE and Western blot were used to assess the action of the extracts on Bothrops jararaca venom. RESULTS: In all, 24 plants belonging to 19 families were mentioned in the survey as being used to treat snakebites. Leaves (84%), seeds (60.9%) and inner bark (53%) were cited as the most frequently used parts in folk remedies, which were usually prepared in the form of a decoction (62.5%), tincture (45%) or maceration (22.5%). Hemorrhage induced by Bothrops jararaca venom was completely inhibited by aqueous extracts of Bellucia dichotoma, Connarus favosus, Plathymenia reticulata and Philodendron megalophyllum, which had a high phenolic content and contained condensed and hydrolyzable tannins. The results of SDS-PAGE showed that some venom protein bands were not visible when the venom was preincubated with the extracts that had completely inhibited hemorrhagic activity of the venom. Western blot showed that the extracts did not have any enzymatic action on the proteins in the venom as it failed to detect low-molecular-weight bands, which are indicative of possible enzymatic cleavage. CONCLUSIONS: Traditional use of plants to treat snakebites is a common practice in the western region of Para, Brazil. Our findings show that some plant extracts were able to inhibit snake venom-induced hemorrhage in vitro. In vivo studies are being carried out to validate the traditional use of these species to treat snakebites. PMID- 25536290 TI - Mobile technologies in the early detection of cognitive decline. AB - The identification of biological and pathophysiological processes implicated in different forms of dementia is itself dependent on reliable descriptions of cognitive performance and capacities. However, traditional instruments are often unable to detect subtle declines in cognitive functions due to natural variation at the time of testing. Mobile technologies permit the repeated assessment of cognitive functions and may thereby provide more reliable descriptions of early cognitive difficulties that are inaccessible to clinic or hospital-based instruments. This assessment strategy is also able to characterize in real-time the dynamic associations between cognitive performance and specific daily life behaviors or activities. In a cohort of elderly rural residents, 60 individuals were administered neuropsychological and neuroimaging exams as well as a one-week period of electronic ambulatory monitoring of behavior, semantic memory performance, and daily life experiences. Whereas imaging markers were unrelated to traditional neuropsychological test scores, they were significantly associated with mobile assessments of semantic memory performance. Moreover, certain daily life activities such as reading or completing crossword puzzles were associated with increases in semantic memory performance over the subsequent hours of the same day. The revolution in mobile technologies provides unprecedented opportunities to overcome the barriers of time and context that characterize traditional hospital and clinical-based assessments. The combination of both novel and traditional methods should provide the best opportunity for identifying the earliest risk factors and biomarkers for Alzheimer's disease and other forms of dementia. PMID- 25536291 TI - Characterization of selenium-enriched mycelia of Catathelasma ventricosum and their antihyperglycemic and antioxidant properties. AB - This is the first report concerning the selenium enrichment of Catathelasma ventricosum mycelia. The selenium-containing proteins present in selenium enriched mycelia (Se-MC) were identified using size-exclusion chromatography inductively coupled plasma-mass spectrometry (SEC-ICP-MS). The selenium containing amino acids liberated by hydrolysis of these proteins were identified using anion exchange-ICP-MS. Se-MC was found to contain selenoproteins with molecular weights ranging from 1.7 to 60.5 kDa. The main selenium-containing amino acids within them were selenomethionine and selenocysteine. Furthermore, Se MC possessed excellent antihyperglycemic and antioxidant properties. Se-MC normalized biochemical parameters like insulin level, blood glucose level, body weight, and antioxidant enzyme activity in streptozocin-induced diabetic mice. It also inhibited the alpha-amylase and alpha-glucosidase activities present in in vitro gastric and intestinal models. In conclusion, Se-MC has the potential to serve as a dietary supplement of selenium, an antioxidant, or an ingredient for the formulation of nutraceuticals. PMID- 25536289 TI - Cardiovascular risk prediction models for people with severe mental illness: results from the prediction and management of cardiovascular risk in people with severe mental illnesses (PRIMROSE) research program. AB - IMPORTANCE: People with severe mental illness (SMI), including schizophrenia and bipolar disorder, have excess rates of cardiovascular disease (CVD). Risk prediction models validated for the general population may not accurately estimate cardiovascular risk in this group. OBJECTIVE: To develop and validate a risk model exclusive to predicting CVD events in people with SMI incorporating established cardiovascular risk factors and additional variables. DESIGN, SETTING, AND PARTICIPANTS: We used anonymous/deidentified data collected between January 1, 1995, and December 31, 2010, from the Health Improvement Network (THIN) to conduct a primary care, prospective cohort and risk score development study in the United Kingdom. Participants included 38,824 people with a diagnosis of SMI (schizophrenia, bipolar disorder, or other nonorganic psychosis) aged 30 to 90 years. During a median follow-up of 5.6 years, 2324 CVD events (6.0%) occurred. MAIN OUTCOMES AND MEASURES: Ten-year risk of the first cardiovascular event (myocardial infarction, angina pectoris, cerebrovascular accidents, or major coronary surgery). Predictors included age, sex, height, weight, systolic blood pressure, diabetes mellitus, smoking, body mass index (BMI), lipid profile, social deprivation, SMI diagnosis, prescriptions for antidepressants and antipsychotics, and reports of heavy alcohol use. RESULTS: We developed 2 CVD risk prediction models for people with SMI: the PRIMROSE BMI model and the PRIMROSE lipid model. These models mutually excluded lipids and BMI. In terms of discrimination, from cross-validations for men, the PRIMROSE lipid model D statistic was 1.92 (95% CI, 1.80-2.03) and C statistic was 0.80 (95% CI, 0.76 0.83) compared with 1.74 (95% CI, 1.63-1.86) and 0.78 (95% CI, 0.75-0.82) for published Cox Framingham risk scores. The corresponding results in women were 1.87 (95% CI, 1.76-1.98) and 0.79 (95% CI, 0.76-0.82) for the PRIMROSE lipid model and 1.58 (95% CI, 1.48-1.68) and 0.77 (95% CI, 0.73-0.81) for the Cox Framingham model. Discrimination statistics for the PRIMROSE BMI model were comparable to those for the PRIMROSE lipid model. Calibration plots suggested that both PRIMROSE models were superior to the Cox Framingham models. CONCLUSIONS AND RELEVANCE: The PRIMROSE BMI and lipid CVD risk prediction models performed better in SMI compared with models that include only established CVD risk factors. Further work on the clinical effectiveness and cost-effectiveness of the PRIMROSE models is needed to ascertain the best thresholds for offering CVD interventions. PMID- 25536292 TI - Quantitative PCR analysis of DNA aptamer pharmacokinetics in mice. AB - DNA aptamer oligonucleotides and their protein conjugates show promise as therapeutics in animal models of diseases such as multiple sclerosis. These molecules are large and highly charged, raising questions about their biodistribution and pharmacokinetics in mammals. Here we exploit the power of quantitative polymerase chain reaction to accurately quantitate the tissue distribution of 40-nucleotide DNA aptamers and their streptavidin conjugates after intraperitoneal injection in mice. We show remarkably rapid distribution to peripheral tissues including the central nervous system. Modeling of tissue distribution data reveals the importance of DNA aptamer sequence, 3' modification, and protein conjugation in enhancing tissue exposure. These data help to interpret the previously observed effectiveness of aptamer conjugates, as opposed to free aptamers, in stimulating central nervous system remyelination in a mouse model of multiple sclerosis. PMID- 25536294 TI - Quantitative glycome analysis of N-glycan patterns in bladder cancer vs normal bladder cells using an integrated strategy. AB - Diagnosis of bladder cancer, one of the most common types of human cancer, at an early (nonmuscle-invasive) stage is the best way to reduce the mortality rate. Tumor malignancy in general is closely associated with alterations of glycan expression. Glycosylation status, particularly global glycomes, in bladder cancer has not been well studied. We integrated lectin microarray and mass spectrometry (MS) methods to quantitatively analyze and compare glycan expression in four bladder cancer cell lines (KK47, YTS1, J82, T24) and one normal bladder mucosa cell line (HCV29). Glycopattern alterations were analyzed using lectin microarray analysis and confirmed by lectin staining and lectin blotting. Associations of glycopatterns with diverging stages were evaluated by lectin histochemistry on tissue microarrays. N-Glycans were derivatized by amidation of sialylated glycans with acetohydrazide and reductive amination with the stable isotope tags [(12)C6] and [(13)C6]-aniline, and were quantitatively analyzed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/TOF-MS). N Glycan biosynthesis-associated proteins were quantitatively analyzed by a stable isotope labeling by amino acids in cell culture (SILAC) proteomics method, which revealed significant differences in expression of 13 glycosyltransferases and 4 glycosidases. Our findings indicate that sialyl Lewis X (sLe(x)), terminal GalNAc and Gal, and high mannose-type N-glycans were more highly expressed in bladder cancer cells and tissues than in normal cells. Bladder cancer cells showed high expression of core-fucosylated N-glycans but low expression of terminally fucosylated N-glycans. Each of these glycome changes may be directly related to bladder cancer progression. PMID- 25536295 TI - Wild-type and specific mutant androgen receptor mediates transcription via 17beta estradiol in sex hormone-sensitive cancer cells. AB - We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)alpha, but not the androgen receptor (AR), in breast cancer MCF-7 cells. Here, we investigated whether such aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed large amounts of AR at negligible levels of ERalpha/beta or progesterone receptor. Both suppression of PTHrP and activation of prostate-specific antigen genes were observed after independent administration of 17beta-estradiol (E2), DHT, or R5020. Consistent with the notion that the LNCaP AR lost its ligand specificity due to a mutation (Thr-Ala877), experiments with siRNA targeting the respective NR revealed that the AR monopolized the role of the mediator of shared hormone-dependent regulation, which was invariably associated with nuclear translocation of this mutant AR. Microarray analysis of gene regulation by DHT, E2, or R5020 disclosed that more than half of the genes downstream of the AR (Thr-Ala877) overlapped in the LNCaP cells. Of particular interest, we realized that the AR (wild-type [wt]) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescence microscopy experiments demonstrated that both EGFP-AR (wt) and EGFP AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Furthermore, reporter assays revealed that some other cancer cells exhibited aberrant E2-AR (wt) signaling similar to that in the LNCaP cells. We herein postulate the presence of entangled interactions between wt AR and E2 in certain hormone-sensitive cancer cells. PMID- 25536293 TI - Assembly states of FliM and FliG within the flagellar switch complex. AB - At the base of the bacterial flagella, a cytoplasmic rotor (the C-ring) generates torque and reverses rotation sense in response to stimuli. The bulk of the C-ring forms from many copies of the proteins FliG, FliM, and FliN, which together constitute the switch complex. To help resolve outstanding issues regarding C ring architecture, we have investigated interactions between FliM and FliG from Thermotoga maritima with X-ray crystallography and pulsed dipolar ESR spectroscopy (PDS). A new crystal structure of an 11-unit FliG:FliM complex produces a large arc with a curvature consistent with the dimensions of the C ring. Previously determined structures along with this new structure provided a basis to test switch complex assembly models. PDS combined with mutational studies and targeted cross-linking reveal that FliM and FliG interact through their middle domains to form both parallel and antiparallel arrangements in solution. Residue substitutions at predicted interfaces disrupt higher-order complexes that are primarily mediated by contacts between the C-terminal domain of FliG and the middle domain of a neighboring FliG molecule. Spin separations among multi-labeled components fit a self-consistent model that agree well with electron microscopy images of the C-ring. An activated form of the response regulator CheY destabilizes the parallel arrangement of FliM molecules to perturb FliG alignment in a process that may reflect the onset of rotation switching. These data suggest a model of C-ring assembly in which intermolecular contacts among FliG domains provide a template for FliM assembly and cooperative transitions. PMID- 25536297 TI - It is more than "breast is best"-promoting breastfeeding in the modern world. PMID- 25536296 TI - A combined oral contraceptive affects mucosal SHIV susceptibility factors in a pigtail macaque (Macaca nemestrina) model. AB - BACKGROUND: Injectable hormonal contraception may increase women's risk of HIV acquisition and can affect biological risk factors in animal models of HIV. We established, for the first time, a model to investigate whether combined oral contraceptives (COC) alter SHIV susceptibility in macaques. METHODS: Seven pigtail macaques were administered a monophasic levonorgestrel (LNG)/ethinyl estradiol (EE) COC at 33% or 66% of the human dose for 60 days. Menstrual cycling, vaginal epithelial thickness, and other SHIV susceptibility factors were monitored for a mean of 18 weeks. RESULTS: Mean vaginal epithelial thicknesses were 290.8 MUm at baseline and 186.2 MUm during COC (P = 0.0141, Mann-Whitney U test). Vaginal pH decreased from 8.5 during treatment to 6.5 post-treatment (0.0176 two-tailed t-test). Measured microflora was unchanged. CONCLUSIONS: COC caused thinning of the vaginal epithelium and vaginal pH changes, which may increase SHIV susceptibility. 0.033 mg LNG + .0066 mg EE appeared effective in suppressing ovulation. PMID- 25536298 TI - European Code Against Cancer: what does the Spanish population know and think about its recommendations? AB - The aim of this study was to evaluate the Spanish population's knowledge of and beliefs regarding the European Code Against Cancer (ECAC) recommendations. This was a cross-sectional, observational, multicentric study that used self administered surveys. Ten individuals, between the ages of 15 and 69 years old, were enrolled by each participating primary care professional in their respective surgery consultations. This study used 2058 individuals who were recruited by 205 professionals from 106 health centres. Their average age was 41.5 years (52.2% women). The majority believe that smoking [94.1%; 95% confidence interval (CI): 93.1-95.2], sun exposure (91%; 95% CI: 89.7-92.3) and alcoholism (72.1%; 95% CI: 70.1-74.1) are factors related to cancer. The least relevant are infection by the hepatitis B virus (25.7%; 95% CI: 23.8-27.7) and having multiple sexual partners (25%; 95% CI: 23.1-26.9). In all, 86.7% (95% CI: 85.2-88.2) had never heard about the ECAC. Patients adequately identify the carcinogenic effect of tobacco, alcohol or sun exposure. Moreover, they inadequately identify having hepatitis B and multiple sexual partners as being related to cancer. A large majority of individuals have not heard of the ECAC, which raises the need to conduct outreach campaigns at an institutional level and/or through scientific associations and activities promoting health education among primary care professionals. PMID- 25536299 TI - Could in-vitro studies on Ishikawa cell lines explain the endometrial safety of raloxifene? Systematic literature review and starting points for future oncological research. AB - To evaluate all the in-vitro raloxifene (RAL) mechanisms of action on normal, Ishikawa, and different endometrium-derived cell lines to explain the in-vivo RAL endometrial effects, a systematic literature search was performed in the electronic databases MEDLINE, EMBASE ScienceDirect, and the Cochrane Library for the time period between 2002 and 2012. Outcomes were considered in relation to in vitro stimulatory, inhibitory, or neutral actions of RAL in Ishikawa cell lines compared with different endometrial-derived cell lines (both cancerous and normal endometrium). We also considered all the RAL molecular mechanisms responsible for the in-vitro effects observed. More than 150 articles were available in the scientific database literature, but only 21 fulfilled our selection criteria. Although in-vitro studies appear to yield conflicting results, most evidence has shown that RAL seems to induce endometrial cell mitochondria-mediated apoptosis, and to inhibit estrogen-related cell proliferation and endometrial carcinogenesis by inducing antiangiogenic factors, and reducing cytoskeletal reorganization. If the endometrial safety profile of RAL is confirmed, in the near future, selective estrogen receptor modulators could represent an efficient alternative adjuvant treatment to tamoxifen (TAM) in women with breast cancer considered to be at an increased risk of endometrial disease. The confirmation of the endometrial safety profile could enable the proposal of RAL by clinicians as the most appropriate treatment for BRCA1-2 patients after prophylactic salpingo-oophorectomy. PMID- 25536300 TI - Combined impacts of future climate and land use changes on discharge, nitrogen and phosphorus loads for a Canadian river basin. AB - Both climate and land use changes can influence water quality and quantity in different ways. Thus, for predicting future water quality and quantity trends, simulations should ideally account for both projected climate and land use changes. In this paper, land use projections and climate change scenarios were integrated with a hydrological model to estimate the relative impact of climate and land use projections on a suite of water quality and quantity endpoints for a Canadian watershed. Climatic time series representing SRES change scenario A2 were generated by downscaling the outputs of the Canadian Regional Climate Model (version 4.1.1) using a combination of quantile-quantile transformation and nearest neighbor search. The SWAT (Soil and Water Assessment Tool) model was used to simulate streamflow, nitrogen and phosphorus loading under different climate and land use scenarios. Results showed that a) climate change will drive up maximum monthly streamflow, nitrate loads, and organic phosphorus loads, while decreasing organic nitrogen and nitrite loads; and b) land use changes were found to drive the same water quality/quantity variables in the same direction as climate change, except for organic nitrogen loads, for which the effects of the two stressors had a reverse impact on loading. PMID- 25536301 TI - Are primary care providers prepared to care for survivors of breast cancer in the safety net? AB - BACKGROUND: With the growing number of survivors of breast cancer outpacing the capacity of oncology providers, there is pressure to transition patients back to primary care. Primary care providers (PCPs) working in safety-net settings may have less experience treating survivors, and little is known about their knowledge and views on survivorship care. The current study was performed to determine the knowledge, attitudes, and confidence of PCPs in the safety net at delivering care to survivors of breast cancer. METHODS: A modified version of the National Cancer Institute's Survey of Physician Attitudes Regarding Care of Cancer Survivors was given to providers at 2 county hospitals and 5 associated clinics (59 providers). Focus groups were held to understand barriers to survivorship care. RESULTS: Although the majority of providers believed PCPs have the skills necessary to provide cancer-related follow-up, the vast majority were not comfortable providing these services themselves. Providers were adherent to American Society of Clinical Oncology recommendations for mammography (98%) and physical examination (87%); less than one-third were guideline-concordant for laboratory testing and only 6 providers (10%) met all recommendations. PCPs universally requested additional training on clinical guidelines and the provision of written survivorship care plans before transfer. Concerns voiced in qualitative sessions included unfamiliarity with the management of endocrine therapy and confusion regarding who would be responsible for certain aspects of care. CONCLUSIONS: Safety-net providers currently lack knowledge of and confidence in providing survivorship care to patients with breast cancer. Opportunities exist for additional training in evidence-based guidelines and improved coordination of care between PCPs and oncology specialists. PMID- 25536302 TI - Mineralized rods and cones suggest colour vision in a 300 Myr-old fossil fish. AB - Vision, which consists of an optical system, receptors and image-processing capacity, has existed for at least 520 Myr. Except for the optical system, as in the calcified lenses of trilobite and ostracod arthropods, other parts of the visual system are not usually preserved in the fossil record, because the soft tissue of the eye and the brain decay rapidly after death, such as within 64 days and 11 days, respectively. The Upper Carboniferous Hamilton Formation (300 Myr) in Kansas, USA, yields exceptionally well-preserved animal fossils in an estuarine depositional setting. Here we show that the original colour, shape and putative presence of eumelanin have been preserved in the acanthodii fish Acanthodes bridgei. We also report on the tissues of its eye, which provides the first record of mineralized rods and cones in a fossil and indicates that this 300 Myr-old fish likely possessed colour vision. PMID- 25536303 TI - Diffusion tensor imaging and MR spectroscopy of microstructural alterations and metabolite concentration changes in the auditory neural pathway of pediatric congenital sensorineural hearing loss patients. AB - PURPOSE: Our objective was to evaluate age-dependent changes in microstructure and metabolism in the auditory neural pathway, of children with profound sensorineural hearing loss (SNHL), and to differentiate between good and poor surgical outcome cochlear implantation (CI) patients by using diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: Ninety-two SNHL children (49 males, 43 females; mean age, 4.9 years) were studied by conventional MR imaging, DTI and MRS. Patients were divided into three groups: Group A consisted of children<=1 years old (n=20), Group B consisted of children 1-3 years old (n=31), and group C consisted of children 3-14 years old (n=41). Among the 31 patients (19 males and 12 females, 12m- 14y ) with CI, 18 patients (mean age 4.8+/-0.7 years) with a categories of auditory performance (CAP) score over five were classified into the good outcome group and 13 patients (mean age, 4.4+/-0.7 years) with a CAP score below five were classified into the poor outcome group. Two DTI parameters, fractional anisotropy (FA) and apparent diffusion coefficient (ADC), were measured in the superior temporal gyrus (STG) and auditory radiation. Regions of interest for metabolic change measurements were located inside the STG. DTI values were measured based on region-of-interest analysis and MRS values for correlation analysis with CAP scores. RESULTS: Compared with healthy individuals, 92 SNHL patients displayed decreased FA values in the auditory radiation and STG (p<0.05). Only decreased FA values in the auditory radiation was observed in Group A. Decreased FA values in the auditory radiation and STG were both observed in B and C groups. However, in Group C, the N-acetyl aspartate/creatinine ratio in the STG was also significantly decreased (p<0.05). Correlation analyses at 12 months post-operation revealed strong correlations between the FA, in the auditory radiation, and CAP scores (r=0.793, p<0.01). CONCLUSIONS: DTI and MRS can be used to evaluate microstructural alterations and metabolite concentration changes in the auditory neural pathway that are not detectable by conventional MR imaging. The observed changes in FA suggest that children with SNHL have a developmental delay in myelination in the auditory neural pathway, and it also display greater metabolite concentration changes in the auditory cortex in older children, suggest that early cochlear implantation might be more effective in restoring hearing in children with SNHL. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25536304 TI - Effect of environmental enrichment on dopamine and serotonin transporters and glutamate neurotransmission in medial prefrontal and orbitofrontal cortex. AB - Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [(3)H]dopamine uptake in mPFC, but increased Vmax for [(3)H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [(3)H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability. PMID- 25536306 TI - Mechanism of enhanced oral absorption of morin by phospholipid complex based self nanoemulsifying drug delivery system. AB - Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs. PMID- 25536305 TI - Unconditioned oromotor taste reactivity elicited by sucrose and quinine is unaffected by extensive bilateral damage to the gustatory zone of the insular cortex in rats. AB - Rats display stereotypical oromotor and somatic responses to small volumes of intraorally infused taste solutions. These behaviors, known as taste reactivity, are categorized by their association with ingestion or rejection and are thought to reflect the palatability of the stimulus. Because supracollicular decerebrate rats display normal taste reactivity responses, it would appear that forebrain structures are not necessary for generating them. However, because moving the plane of transection rostrally, or damaging or manipulating specific ventral forebrain sites disrupts normal taste reactivity behavior, lesions of the gustatory cortex, a region that has been suggested to be involved with palatability processing, may do the same. In the current study, rats received two injections of either ibotenic acid (N=12) or vehicle (N=8), targeting the conventionally defined gustatory cortex in each hemisphere, and were implanted with intraoral cannulae. Following recovery, their responses to intraoral infusions (0.23ml in 1min) of dH2O, sucrose (1.0M and 0.1M), and quinine hydrochloride (3mM and 0.3mM) were video recorded. Analysis of brains with sufficient bilateral lesions (N=10) revealed that, on average, approximately 94% of the gustatory cortex was destroyed. These extensive bilateral lesions had no significant effect on taste reactivity; the numbers of ingestive and aversive responses to sucrose and quinine were similar between groups. Though these findings do not rule out involvement of the gustatory cortex in palatability processing, they make evident that the region of insular cortex destroyed is not necessary for the normal expression of unconditioned affective behavioral responses to taste stimuli. PMID- 25536309 TI - Review of one-dimensional and two-dimensional nanostructured materials for hydrogen generation. AB - Hydrogen is an attractive alternative to fossil fuels in terms of environmental and other advantages. Of the various production methods for H2, photocatalysis requires further development so that it can be applied economically on an industrial scale. One- and two-dimensional nanostructures in both pristine and modified forms have shown great potential as catalysts in the generation of H2. We review here recent developments in these nanostructure catalysts and their efficiency in the generation of H2 under UV/visible/simulated solar light. Despite much research effort, many photocatalysts do not yet meet the practical requirements for the generation of H2, such as visible light activity. H2 production is dependent on a variety of parameters and factors. To meet future energy demands, several challenges in H2 production still need to be solved. We address here the factors that influence the efficiency of H2 production and suggest alternatives. The nanostructures are classified based on their morphology and their efficiency is considered with respect to the influencing parameters. We suggest effective ways of engineering catalyst combinations to overcome the current performance barriers. PMID- 25536308 TI - Active Negative Pressure Peritoneal Therapy After Abbreviated Laparotomy: The Intraperitoneal Vacuum Randomized Controlled Trial. AB - OBJECTIVE: To determine whether active negative pressure peritoneal therapy with the ABThera temporary abdominal closure device reduces systemic inflammation after abbreviated laparotomy. BACKGROUND: Excessive systemic inflammation after abdominal injury or intra-abdominal sepsis is associated with poor outcomes. METHODS: We conducted a single-center, randomized controlled trial. Forty-five adults with abdominal injury (46.7%) or intra-abdominal sepsis (52.3%) were randomly allocated to the ABThera (n = 23) or Barker's vacuum pack (n = 22). On study days 1, 2, 3, 7, and 28, blood and peritoneal fluid were collected. The primary endpoint was the difference in the plasma concentration of interleukin-6 (IL-6) 24 and 48 hours after temporary abdominal closure application. RESULTS: There was a significantly lower peritoneal fluid drainage from the ABThera at 48 hours after randomization. Despite this, there was no difference in plasma concentration of IL-6 at baseline versus 24 (P = 0.52) or 48 hours (P = 0.82) between the groups. There was also no significant intergroup difference in the plasma concentrations of IL-1beta, -8, -10, or -12 p70 or tumor necrosis factor alpha between these time points. The cumulative incidence of primary fascial closure at 90 days was similar between groups (hazard ratio, 1.6; 95% confidence interval, 0.82-3.0; P = 0.17). However, 90-day mortality was improved in the ABThera group (hazard ratio, 0.32; 95% confidence interval, 0.11-0.93; P = 0.04). CONCLUSIONS: This trial observed a survival difference between patients randomized to the ABThera versus Barker's vacuum pack that did not seem to be mediated by an improvement in peritoneal fluid drainage, fascial closure rates, or markers of systemic inflammation. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01355094. PMID- 25536311 TI - Diverse inhibition and working memory of word recognition for dyslexic and typically developing children. AB - The present study focuses on (1) comparing dyslexic and typically developing children's cognitive and behavioural inhibitory abilities; (2) examining the relationship between word recognition, inhibition, and working memory in dyslexic and typically developing children by correlation, regression and path analyses. Participants in the present study were sampled from 3rd and 4th graders in Taiwan. Results indicated that dyslexic and typically developing children did not significantly differ in behavioural inhibition. In contrast, dyslexic children showed significantly lower levels of cognitive inhibition compared to typically developing children. Dyslexic children also showed that only cognitive inhibition significantly contributed to their word recognition, and typically developing children showed similar phenomenon. Finally, models of dyslexic and typically developing children's working memory, inhibition and word recognition were similar in that working memory and cognitive inhibition significantly contributed to word recognition for both dyslexic and typically developing children. Moreover, the contribution of the combination of working memory and inhibition was greater than the contribution of only inhibition; both of typically developing and dyslexic children's working memory showed more contributions than inhibition. PMID- 25536312 TI - Role of tetraspanin CD9 molecule in fertilization of mammals. AB - Fertilization process is a very clever and unique process comprising some essential steps resulting in formation of zygote. Tetraspanin CD9 is considered to be a serious candidate molecule participating in these events. The importance of CD9 has been discussed in relation to acrosome reaction, sperm-binding, sperm penetration, sperm-egg fusion and eventually, egg activation. The abundant expression of CD9 oocyte plasma membrane and the presence of CD9-containing vesicles in the perivitelline space of intact oocytes have been confirmed. Despite the fact that majority of authors analyzed CD9 expressed on oocytes, several studies considered the function of sperm CD9, too. To understand CD9 involvement, various conditions of in vitro fertilization (IVF) assays using polyclonal as well as monoclonal antibodies or knockout mice were carried out. However, ambiguous data have been obtained about the importance of CD9 in sperm egg binding or fusion. Although the current findings did not prove any hypothesis, the indispensable role of CD9 in fertilization process was not excluded and the precise role of CD9 remains unexplained. PMID- 25536313 TI - An enhanced cAMP pathway is responsible for the colonic hyper-secretory response to 5-HT in acute stress rats. AB - 5-hydroxytryptamine (5-HT) is involved in the stress-induced alteration of colonic functions, specifically motility and secretion, but its precise mechanisms of regulation remain unclear. In the present study, we have investigated the effects of 5-HT on rat colonic mucosal secretion after acute water immersion restraint stress, as well as the underlying mechanism of this phenomenon, using short circuit current recording (I(SC)), real-time polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbance assays. After 2 h of water immersion restraint stress, the baseline I(SC) and 5-HT induced I(SC) responses of the colonic mucosa were significantly increased. Pretreatment with selective 5-HT(4) receptor antagonist, SB204070, inhibited the 5-HT-induced colonic I(SC) response by 96 % in normal rats and 91.2 % in acute stress rats. However, pretreatment with the selective antagonist of 5-HT(3) receptor, MDL72222 or Y-25130, had no obvious effect on 5-HT-induced I(SC) responses under either set of conditions. Total protein expression of both the mucosal 5-HT(3) receptors and the 5-HT(4) receptors underwent no significant changes following acute stress. Both colonic basal cAMP levels and foskolin induced I(SC) responses were significantly enhanced in acute stress rats. 5-HT significantly enhanced the intracellular cAMP level via 5-HT(4) receptors in the colonic mucosa from both control and stressed animals, and 5-HT-induced cAMP increase in stressed rats was not more than that in control rats. Taken together, the present results indicate that acute water immersion restraint stress enhances colonic secretory responses to 5-HT in rats, a process in which increased cellular cAMP accumulation is involved. PMID- 25536307 TI - A comparison between the sixth and seventh editions of the UICC/AJCC staging system for nasopharyngeal carcinoma in a Chinese cohort. AB - BACKGROUND: The International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging system of nasopharyngeal carcinoma (NPC) is the most important system for survival prediction. The TNM 7th edition UICC/AJCC TNM staging system for NPC was adopted in January 2009, and is now internationally recommended. In comparison with the TNM 6th edition, there were several revisions in the new edition staging system. This study aims to evaluate the prognostic value of the TNM 7th edition for NPC patients in comparison with the TNM 6th edition. METHOD: Clinical data of 2,629 NPC patients from the Sun Yat-sen University Cancer Center between January 2006 and December 2010 were retrospectively collected and all the patients were restaged according to the criteria of the TNM 6th edition and TNM 7th edition UICC/AJCC staging manual. Univariate and multivariate COX proportional hazards analyses were applied to evaluate the prognostic values between adjacent stage categories of the TNM 6th edition and TNM 7th edition. RESULTS: In comparison with the TNM 6th edition, a significant alteration of the distribution of N categories was observed when the TNM 7th edition was applied (chi2 = 20.589, P<0.001), with 119 (119/670, 17.8%) patients up-staging from N0 to N1. With regard to T and overall stage, 37 (37/561, 6.6%) patients were down-staged from T2a with the TNM 6th edition to T1 with the TNM 7th edition, and finally two patients were up-staged to overall stage II (2/118, 1.7%). Moreover, the survival curves were significantly segregated (P<0.05) between T1 and T2 as well as N1 and N2 with the TNM 7th edition. CONCLUSIONS: The TNM 7th edition led to a significant alteration in the distribution of N categories and it is superior to the TNM 6th edition in predicting the frequency of overall survival and distant metastasis-free survival. PMID- 25536314 TI - Involvement of actin microfilament in regulation of pacemaking activity increased by hypotonic stress in cultured ICCs of murine intestine. AB - Distension is a regular mechanical stimulus in gastrointestinal (GI) tract. This study was designed to investigate the effect of hypotonic stress on pacemaking activity and determine whether actin microfilament is involved in its mechanism in cultured murine intestinal interstitial cells of Cajal (ICCs) by using whole cell patch-clamp and calcium imaging techniques. Hypotonic stress induced sustained inward holding current from the baseline to -650+/-110 pA and significantly decreased amplitudes of pacemaker current. Hypotonic stress increased the intensity of basal fluorescence ratio (F/F0) from baseline to 1.09+/-0.03 and significantly increased Ca(2+) oscillation amplitude. Cytochalasin-B (20 microM), a disruptor of actin microfilaments, significantly suppressed the amplitudes of pacemaker currents and calcium oscillations, respectively. Cytochalasin-B also blocked hypotonic stress-induced sustained inward holding current and hypotonic stress-induced increase of calcium oscillations. Phalloidin (20 microM), a stabilizer of actin microfilaments, significantly enhanced the amplitudes of pacemaker currents and calcium oscillations, respectively. Despite the presence of phalloidin, hypotonic stress was still able to induce an inward holding current and increased the basal fluorescence intensity. These results suggest that hypotonic stress induces sustained inward holding current via actin microfilaments and the process is mediated by alteration of intracellular basal calcium concentration and calcium oscillation in cultured intestinal ICCs. PMID- 25536315 TI - Antioxidant defense is increased in aged hearts following omega-3 supplementation in the absence of changes in inflammation. AB - The purpose of this study was to determine the effect of a 15-week omega-3 rich diet on age-related differences in myocardial antioxidant defense and inflammation. 20 mature (M) (6 mo.) and 20 old (O) (15 mo.) male Fisher 344 rats were assigned to two diet groups: Control (CON) or Fish Oil (FO). Following the diet, animals were sacrificed and left ventricular (LV) heart tissue was harvested for biochemical assays and western blot analysis. No differences were observed in expression of LV interleukin-6 (IL-6) and tumor necrosis factor-alpha as well as hydrogen peroxide (H(2)O(2)) production between MCON and OCON. However, LV catalase protein expression and activity were increased in OCON vs. MCON and accompanied by increased expression of superoxide dismutase (SOD)-1. In contrast, LV IL-6 was lower in MFO vs. old rats, and LV H(2)O(2) was decreased in MFO and OFO relative to respective control groups. Protein expression and activity of LV catalase and SOD-1 expression were increased in OFO similarly to OCON, but LV SOD activity was also increased in OFO vs. mature rats. In summary, FO supplementation increased myocardial antioxidant defense in all animals and augmented age-associated increases in antioxidant capacity in the absence of changes in inflammation. PMID- 25536317 TI - Chronic stress promotes the progression of pressure overload-induced cardiac dysfunction through inducing more apoptosis and fibrosis. AB - Stress serves as a risk factor in the etiology of hypertension. The present study was designed to decipher the effect and mechanism of chronic stress on the progression of pressure overload-induced cardiac dysfunction. We used abdominal aortic constriction (AAC) to induce pressure overload with or without chronic restraint stress to establish the animal models. Echocardiographic analysis showed pressure overload-induced cardiac dysfunction was worsened by chronic stress. Compared with the AAC rats, there is a significant increase in cardiac hypertrophy, injury, apoptosis and fibrosis of the AAC + stress rats. Furthermore, we found the secretion of norepinephrine (NE) increased after the AAC operation, while the level of NE was higher in the AAC + stress group. Cardiomyocytes and cardiac fibroblasts isolated from neonatal rats were cultured and separately treated with 1, 10, 100 microM NE. The higher concentration NE induced more cardiomyocytes hypertrophy and apoptosis, cardiac fibroblasts proliferation and collagen expression. These results revealed that high level of NE-induced cardiomyocytes hypertrophy and apoptosis, cardiac fibroblasts proliferation and collagen expression further contributes to the effect of chronic stress on acceleration of pressure overload-induced cardiac dysfunction. PMID- 25536318 TI - Dopamine 2 and somatostatin 1-5 receptors coexpression in clinically non functioning pituitary adenomas. AB - This study investigated quantitated expression of dopamine 2 receptor (D2R) and somatostatin receptors of the five types (SSTR1-SSTR5) in a large series of clinically non-functioning pituitary adenomas (CNFAs). Co-expression of these receptors in individual adenomas was studied as well as correlation between receptor types. Adenoma tissue from 198 patients who underwent surgery for CNFAs was analyzed by immunohistochemistry and quantitative real-time PCR. D2R and SSTR1-3 mRNA was expressed in all 198 adenomas. SSTR4 and SSTR5 were detectable in 85 % and 61 % of adenomas, respectively. Expression of D2R was significantly higher than that of the somatostatin receptors. The median relative expressions were as follows from highest D2R >> SSTR3 > SSTR2 > SSTR1 > SSTR5 > SSTR4. High relative expression (ratio to beta-glucuronidase mRNA > 1) of D2R was found in 60 % of tumors, high expression of SSTR1 in 7.5 %, SSTR2 in 7 %, SSTR3 in 4 % and SSTR5 in 0.5 %. The quantity of D2R correlated positively with expression of SSTR2 and SSTR3, and negatively with SSTR1 and SSTR5. Among histological adenoma types, SSTR1 was significantly higher in null-cell adenomas and SSTR3 was lower in silent corticotroph adenomas. In conclusions, in CNFAs, high expression of somatostatin receptors is much less common than that of D2R, and co-expression of both these receptors is exceptional. D2R and SSTR3 seem to be the most promising targets for pharmacological treatment. PMID- 25536316 TI - Rosuvastatin ameliorates inflammation, renal fat accumulation, and kidney injury in transgenic spontaneously hypertensive rats expressing human C-reactive protein. AB - Recently, we derived "humanized" spontaneously hypertensive rats (SHR-CRP) in which transgenic expression of human CRP induces inflammation, oxidative stress, several features of metabolic syndrome and target organ injury. In addition, we found that rosuvastatin treatment of SHR-CRP transgenic rats can protect against pro-inflammatory effects of human CRP and also reduce cardiac inflammation and oxidative damage. In the current study, we tested the effects of rosuvastatin (5 mg/kg) on kidney injury in SHR-CRP males versus untreated SHR-CRP and SHR controls. All rats were fed a high sucrose diet. In SHR-CRP transgenic rats, treatment with rosuvastatin for 10 weeks, compared to untreated transgenic rats and SHR controls, was associated with significantly reduced systemic inflammation which was accompanied with activation of antioxidative enzymes in the kidney, lower renal fat accumulation, and with amelioration of histopathological changes in the kidney. These findings provide evidence that, in the presence of high CRP levels, rosuvastatin exhibits significant anti-inflammatory, anti-oxidative, and renoprotective effects. PMID- 25536319 TI - Activation of Nrf2 by ischemic preconditioning and sulforaphane in renal ischemia/reperfusion injury: a comparative experimental study. AB - Objectives of the study were to investigate impact of ischemic preconditioning (Ipre) and sulforaphane (SFN) and combination of them on nuclear factor 2 erythroid related factor 2 (Nrf2) gene and its dependent genes, heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase1 (NQO-1) and inflammatory cytokines TNF alpha, IL1beta, and intercellular adhesion molecule-1 (ICAM1) and caspase-3 in renal ischemia/reperfusion (I/R) injury. Ninety male Sprague Dawely rats were classified into 5 groups (each consists of 18 rats): sham, control, Ipre, sulforaphane and Sulfo+Ipre. Each group was subdivided into 3 subgroups each containing 6 rats according to time of harvesting kidney and taking blood samples; 24 h, 48 h, and 7 days subgroups. Renal functions including serum creatinine, BUN were measured at basal conditions and by the end of experiment. Expression of Nrf2, HO-1, NQO-1, TNF-alpha, IL-1beta, and ICAM-1 was measured by real time PCR in kidney tissues by the end of experiment. Also, immunohistochemical localization of caspase-3 and chemical assay of malondialdehyde (MDA), GSH and SOD activity were measured in kidney tissues. Both Ipre and SFN improved kidney functions, enhanced the expression of Nrf2, HO-1, and NQO-1, attenuated the expression of inflammatory (TNF-alpha, IL-1, and ICAM 1) and apoptotic (caspase-3) markers. However, the effect of sulforaphane was more powerful than Ipre. Also, a combination of them caused more improvement in antioxidant genes expression and more attenuation in inflammatory genes but not caspase-3 than each one did separately. Sulforaphane showed more powerful effect in renoprotection against I/R injury than Ipre as well as there might be a synergism between them at the molecular but not at the function level. PMID- 25536320 TI - Arterial stiffening contributes to impairment of cerebrovascular reactivity in patients with coronary artery disease without carotid stenosis. AB - Impaired cerebrovascular reactivity (CVR), an important risk factor for future stroke, is affected by a presence carotid stenosis. However, in some cases CVR can be impaired in the absence of carotid stenosis due to several poorly characterized mechanisms. We hypothesized that arterial stiffening as observed in coronary heart disease (CHD) could be associated with alteration in CVR in CHD patients without carotid stenosis. The study population consisted of patients referred for coronary angiography without significant carotid stenosis (<50 %). CVR was evaluated by breath holding index (BHI) measured with transcranial color code duplex ultrasound. Arterial stiffness was assessed by pulse wave velocity (PWV) measured by the oscillometric method. The extent of coronary atherosclerosis was quantified by Gensini score (GS). Out of 186 subjects, sixty two patients fulfilled the inclusion and exclusion criteria. BHI decreased with increasing PWV (r = -0.47, p<0.001). Decrease in BHI was significantly inversely associated with GS (r = -0.61, p<0.001). GS was associated with PWV (p<0.001). In conclusion, impaired CVR was associated with increased arterial stiffening in CHD patients in the absence of significant carotid stenosis. Thus, we speculate that increased arterial stiffness may at least partially contribute to the pathophysiology of CVR alteration in coronary artery disease. PMID- 25536321 TI - The relationship between iodine intake and serum thyroglobulin in the general population. AB - The relationship is shown between a concentration of urinary iodine and serum thyroglobulin in population studies carried out on a general population that was randomly selected from the registry of the General Health Insurance Company (individuals aged 6-98 years, 1751 males, 2420 females). The individuals were divided into subgroups with a urinary iodine concentration of <50, 50-99, 100 199, 200-299 and >/=300 microg/l. The mean and median of thyroglobulin were calculated in these subgroups. Tg concentrations were dependent on gender (males=10(-7) M and stimulation maxima (?Isc ~25 MUA?cm(-2)) at 10(-6) M. The basolateral addition of bumetanide (200 MUM) abolished >75% of the effect of IT on Cl(-) secretion. In turn, AVT had a dual effect on killifish opercular Isc: an immediate response (~3min) with Isc reduction in an inverted bell-shaped dose-response manner with higher current decrease (-22 MUA?cm(-2)) at 10(-8) M AVT, and a sustained dose-dependent stimulation of Cl(-) secretion (stable up to 1h), with a threshold significant effect at 10(-8) M and maximal stimulation (~20 MUA?cm(-2)) at 10(-6)M. Both effects of AVT appear receptor type specific. The V1-receptor antagonist SR 49059 abolished Isc reduction in response to AVT, while the specific V2-receptor antagonist (Tolvaptan, 1 MUM) abolished the stimulatory action of AVT on Cl(-) secretion. According to these results, we propose a modulatory role for AVT and IT in Cl(-) (NaCl) secretion across the opercular epithelium of marine teleost. PMID- 25536333 TI - Sex-related differences in steroid concentrations in the blue mussel (Mytilus edulis trossulus) from the southern Baltic Sea. AB - This paper reports on sex-related differences in free steroid hormone concentrations including the concentrations of three naturally occurring estrogens (17beta-estradiol E2, estrone E1, and estriol E3) and one androgen (testosterone T) in the tissues (gills and gonads) of the blue mussel Mytilus edulis trossulus sampled from the Gulf of Gdansk (Baltic Sea, Poland). The dissimilarity in steroid concentrations between tissues was particularly evident in the T concentration with a level in gills almost three times higher compared to gonads (on average, 15.38 ng/g w.w. and 5.31 ng/g w.w., respectively, p=0.00008), suggesting its exogenous origin. In general, a tendency towards a skewed steroid profile related to sex, with E2 more abundant for males and T for females, was observed. Female gonads were characterized by a higher level of T than testis (4.61 ng/g w.w. for females and 0.70 ng/g w.w. for males, p=0.0121). At the same time, the level of E2 found in the testis was higher than in the ovary (4.81 ng/g w.w. and 3.86 ng/g w.w., respectively); however, the difference was not statistically significant. As for gills, similar trend with T and E2 being more abundant in males was observed. At the same time, no disturbances in the sex ratio and gametogenesis process were observed which suggests i) efficient deactivation of free forms of steroids, and/or ii) their little or no physiological role. PMID- 25536334 TI - How to make a beetle out of wood: multi-elemental stoichiometry of wood decay, xylophagy and fungivory. AB - The majority of terrestrial biomass is wood, but the elemental composition of its potential consumers, xylophages, differs hugely from that of wood. This causes a severe nutritional imbalance. We studied the stoichiometric relationships of 11 elements (C, N, P, K, Ca, Mg, Fe, Zn, Mn, Cu, Na) in three species of pine-xylem feeding insects, Stictoleptura rubra, Arhopalus rusticus (Coleoptera, Cerambycidae) and Chalcophora mariana (Coleoptera, Buprestidae), to elucidate their mechanisms of tissue growth and to match their life histories to their dietary constraints. These beetles do not differ from other Coleoptera in their absolute elemental compositions, which are approximately 1000 (N), 100 (P, Cu) and 50 (K, Na) times higher than in dead but undecayed pine wood. This discrepancy diminishes along the wood decay gradient, but the elemental concentrations remain higher by an order of magnitude in beetles than in highly decayed wood. Numerical simulation of the life history of S. rubra shows that feeding on nutrient-poor undecayed wood would extend its development time to implausible values, whereas feeding on highly decomposed wood (heavily infected with fungi) would barely balance its nutritional budget during the long development period of this species. The changes in stoichiometry indicate that the relative change in the nutrient levels in decaying wood cannot be attributed solely to carbon loss resulting from decomposer respiration: the action of fungi substantially enriches the decaying wood with nutritional elements imported from the outside of the system, making it a suitable food for wood-eating invertebrates. PMID- 25536336 TI - Continuing effectiveness of serogroup A meningococcal conjugate vaccine, Chad, 2013. AB - In 2011, vaccination with a serogroup A meningococcal polysaccharide conjugate vaccine was implemented in 3 of 23 regions in Chad. Cases of meningitis declined dramatically in vaccinated areas, but an epidemic continued in the rest of Chad. In 2012, the remaining Chad population was vaccinated, and the epidemic was halted. PMID- 25536337 TI - A Rh-catalyzed 1,2-sulfur migration/aza-Diels-Alder cascade initiated by aza vinyl carbenoids from sulfur-tethered N-sulfonyl-1,2,3-triazoles. AB - A novel Rh(ii) catalyzed intramolecular 1,2-sulfur rearrangement/intermolecular aza-Diels-Alder cascade initiated by azavinyl carbenes has been developed, efficiently affording sulfur-containing tetrahydropyridine derivatives or alpha,beta-unsaturated imines with a broad substrate scope. PMID- 25536338 TI - Neuroinformatics of the Allen Mouse Brain Connectivity Atlas. AB - The Allen Mouse Brain Connectivity Atlas is a mesoscale whole brain axonal projection atlas of the C57Bl/6J mouse brain. Anatomical trajectories throughout the brain were mapped into a common 3D space using a standardized platform to generate a comprehensive and quantitative database of inter-areal and cell-type specific projections. This connectivity atlas has several desirable features, including brain-wide coverage, validated and versatile experimental techniques, a single standardized data format, a quantifiable and integrated neuroinformatics resource, and an open-access public online database (http://connectivity.brain map.org/). Meaningful informatics data quantification and comparison is key to effective use and interpretation of connectome data. This relies on successful definition of a high fidelity atlas template and framework, mapping precision of raw data sets into the 3D reference framework, accurate signal detection and quantitative connection strength algorithms, and effective presentation in an integrated online application. Here we describe key informatics pipeline steps in the creation of the Allen Mouse Brain Connectivity Atlas and include basic application use cases. PMID- 25536335 TI - A low-testosterone state associated with endometrioma leads to the apoptosis of granulosa cells. AB - Although endometriosis is suspected to be a cause of premature ovarian insufficiency (POI), the mechanism(s) underlying this process have not been elucidated. Recently, androgens were shown to promote oocyte maturation and to play a role in folliculogenesis. In addition, several reports have documented low testosterone levels in the follicular fluid obtained from endometriosis patients. We therefore examined whether the low levels of serum testosterone are associated with the apoptosis of granulosa cells in follicles obtained from endometriosis patients. Serum samples were collected from 46 patients with endometriosis and from 62 patients without endometriosis who received assisted reproductive therapy. Specimens of the ovaries obtained from 10 patients with endometrioma were collected using laparoscopy. The mean serum testosterone concentration in the patients with endometriosis was significantly lower than that observed in the patients without endometriosis. Furthermore, high expression of a pro-apoptotic Bcl-2 member, BimEL, in the follicles was found to be associated with a low serum testosterone level. We clarified the underlying mechanisms using a basic approach employing human immortalized granulosa cells derived from a primary human granulosa cell tumor, the COV434 cell line. The in vitro examination demonstrated that testosterone inhibited apoptosis induced by sex steroids depletion via the PI3K/Akt-FoxO3a pathway in the COV434 cells. In conclusion, we elucidated the mechanism underlying the anti-apoptotic effects of testosterone on granulosa cells, and found that a low-testosterone status is a potentially important step in the development of premature ovarian insufficiency in patients with endometriosis. PMID- 25536339 TI - Nontraumatic Implant Explantation: A Biomechanical and Biological Analysis in Sheep Tibia. AB - Preclinical research in a sheep tibia model has been conducted to evaluate the underlying mechanisms of the nontraumatic implant explantation of failed implants, which allow placing a new one in the bone bed. Twelve dental implants were placed in sheep diaphysis tibia and once osseointegrated they were explanted using a nontraumatic implant explantation approach. Implant osseointegration and explantation were monitored by means of frequency resonance, removal torque, and angle of rotation measurement. The host bone bed and the explanted implant surface were analyzed by conventional microscopy and scanning electron microscope. Results show that osseointegration was broken with an angular displacement of less than 20 degrees . In this situation the implant returns to implant stability quotient values in the same range of their primary stability. Moreover, the explantation technique causes minimal damage to the surrounding bone structure and cellularity. This nontraumatic approach allows the straightforward replacement of failed implants and emerges as a promising strategy to resolve clinically challenging situations. PMID- 25536340 TI - Lichen sclerosus Mistaken for Sexual Abuse--Prevention of Victimization. AB - This case report describes the forensic examination of 7 girls aged between 4-11 years with suspected sexual abuse. The children had been reported by local pediatricians, hospital physicians or authorities such as the youth welfare office and police due to mucosal changes in the anogenital area. All children presented with a clearly delimited, porcelain-like white discoloration of the skin in the anal and genital area with atrophic conversion to parchment-like skin. The markedly vulnerable skin exhibited very different manifestations of hemorrhagic dermal and mucosal defects in the area of the labia, the clitoris, the perineum and the perianal region. The hymen was intact in all cases. The skin changes are typical of lichen sclerosus et atrophicus, which is more common in prepubertal girls and post-menopausal women. Due to the chronic course, affected persons can develop sclerotic plaques, synechia of the labia minora and stenoses of the urinary tract and of the vaginal orifice, so that an early diagnosis is crucial. This condition is not infrequently taken by attending physicians as a sign of suspected sexual abuse, as the relevant findings are not recognized correctly. Furthermore, there are far-reaching consequences for the affected families, who are often faced with criminal prosecution, a breakdown of social familial structures and an enormous psychological burden for the affected persons. To avoid victimization there is an urgent need for more information about the differential diagnoses of sexual abuse and a call for interdisciplinary co-operation when evaluating abnormal anogenital findings in children. PMID- 25536341 TI - Adalimumab arrests bone loss in the spine and hip of active rheumatoid arthritis patients with osteopenia. PMID- 25536342 TI - Reprogramming cellular signaling machinery using surface-modified carbon nanotubes. AB - Nanoparticles, such as carbon nanotubes (CNTs), interact with cells and are easily internalized, causing various perturbations to cell functions. The mechanisms involved in such perturbations are investigated by a systematic approach that utilizes modified CNTs and various chemical-biological assays. Three modes of actions are (1) CNTs bind to different cell surface receptors and perturb different cell signaling pathways; (2) CNTs bind to a receptor with different affinity and, therefore, strengthen or weaken signals; (3) CNTs enter cells and bind to soluble signaling proteins involved in a signaling pathway. Understanding of such mechanisms not only clarifies how CNTs cause cytotoxicity but also demonstrates a useful method to modulate biological/toxicological activities of CNTs for their various industrial, biomedical, and consumer applications. PMID- 25536343 TI - In vitro manganese-dependent cross-talk between Streptococcus mutans VicK and GcrR: implications for overlapping stress response pathways. AB - Streptococcus mutans, a major acidogenic component of the dental plaque biofilm, has a key role in caries etiology. Previously, we demonstrated that the VicRK two component signal transduction system modulates biofilm formation, oxidative stress and acid tolerance responses in S. mutans. Using in vitro phosphorylation assays, here we demonstrate for the first time, that in addition to activating its cognate response regulator protein, the sensor kinase, VicK can transphosphorylate a non-cognate stress regulatory response regulator, GcrR, in the presence of manganese. Manganese is an important micronutrient that has been previously correlated with caries incidence, and which serves as an effector of SloR-mediated metalloregulation in S. mutans. Our findings supporting regulatory effects of manganese on the VicRK, GcrR and SloR, and the cross-regulatory networks formed by these components are more complex than previously appreciated. Using DNaseI footprinting we observed overlapping DNA binding specificities for VicR and GcrR in native promoters, consistent with these proteins being part of the same transcriptional regulon. Our results also support a role for SloR as a positive regulator of the vicRK two component signaling system, since its transcription was drastically reduced in a SloR-deficient mutant. These findings demonstrate the regulatory complexities observed with the S. mutans manganese dependent response, which involves cross-talk between non-cognate signal transduction systems (VicRK and GcrR) to modulate stress response pathways. PMID- 25536344 TI - T cell factor-1 controls the lifetime of CD4+ CD8+ thymocytes in vivo and distal T cell receptor alpha-chain rearrangement required for NKT cell development. AB - Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) Valpha14-Jalpha18 gene. Temporal regulation and late appearance of Valpha14 Jalpha18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF)-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR Valpha14 Jalpha18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits Valpha14-Jalpha18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of RORgammat, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo. PMID- 25536347 TI - Acute effects of two different tennis sessions on dorsal and lumbar spine of adult players. AB - The aim of the study was to evaluate the dorsal and lumbar spine of expert and recreational tennis players before (pre) and after (post) two different training sessions. The sample consisted of 17 male tennis players, nine expert and eight recreational males (age 21.2 +/- 1.6 years). We assessed the back surface by rasterstereography pre and post two different training sessions both lasting 1.5 h: a standard training and a specific over-shoulder shots training session, respectively. Lordotic and kyphotic angle, length, imbalance, inclination for trunk, pelvic torsion, left and right lateral deviation and surface rotation were measured. Tennis expertise (expert versus recreational) significantly affected the surface rotation and right lateral deviation (P < 0.05). Trunk length was affected by intervention (pre versus post) (P < 0.05). Left lateral deviation differed both for type of session (session 1 versus session 2) and intervention (P < 0.001, P < 0.05). Expert tennis players had higher values on surface rotation and right lateral deviation, around or just above physiological values (0-5 degrees and 0-5 mm, respectively). Type of session significantly affected left lateral deviation, indicating that over-shoulder shots lead to a higher stress for the spine; the workload produced by both single sessions led to a shortening effect on trunk length. A single training session can induce acute modifications in some parameters of dorsal and lumbar spine of players. PMID- 25536348 TI - Practice and education: partnering to create a pipeline of nurse leaders. PMID- 25536345 TI - Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. AB - In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs) tested on human neuroblastoma IMR-32 (0.5 * 10(4) cells/100 ul of IMR) cells (EPA > DHA > ALA = GLA = AA > DGLA = LA: ~ 60, 40, 30, 10-20% respectively) at the maximum doses used. Of all the prostaglandins (PGE1, PGE2, PGF2alpha, and PGI2) and leukotrienes (LTD4 and LTE4) tested; PGE1, PGE2 and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A4 (LXA4), 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA) and 10(S),17(S) dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid (protectin: 10(S),17(S)DiHDoHE), metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA) at 60 and 20 ug/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions. PMID- 25536349 TI - Improve the function of multigenerational teams. PMID- 25536346 TI - Oxidant exposure induces cysteine-rich protein 61 (CCN1) via c-Jun/AP-1 to reduce collagen expression in human dermal fibroblasts. AB - Human skin is a primary target of oxidative stress from reactive oxygen species (ROS) generated from both extrinsic and intrinsic sources. Oxidative stress inhibits the production of collagen, the most abundant protein in skin, and thus contributes to connective tissue aging. Here we report that cysteine-rich protein 61 (CCN1), a negative regulator of collagen production, is markedly induced by ROS and mediates loss of type I collagen in human dermal fibroblasts. Conversely, antioxidant N-acetyl-L-cysteine significantly reduced CCN1 expression and prevented ROS-induced loss of type I collagen in both human dermal fibroblasts and human skin in vivo. ROS increased c-Jun, a critical member of transcription factor AP-1 complex, and increased c-Jun binding to the AP-1 site of the CCN1 promoter. Functional blocking of c-Jun significantly reduced CCN1 promoter and gene expression and thus prevented ROS-induced loss of type I collagen. Targeting the c-Jun/CCN1 axis may provide clinical benefit for connective tissue aging in human skin. PMID- 25536350 TI - Harnessing technology to promote patient-centered care. PMID- 25536352 TI - HCAHPS series part 1: transforming care transitions. PMID- 25536353 TI - 2014 visionary leader. PMID- 25536354 TI - Acuity-based staffing: reducing costs, increasing quality. PMID- 25536355 TI - Accountability and teamwork: tools for a fall-free zone. PMID- 25536356 TI - Empowering change with traditional or virtual journal clubs. PMID- 25536357 TI - Beyond a piece of paper: learning to hire with synergy. PMID- 25536358 TI - Leadership Q&A. PMID- 25536359 TI - Laparoscopic simple oblique duodenoduodenostomy in management of congenital duodenal obstruction in children. AB - INTRODUCTION: The aim of this report is to present our technique of laparoscopic simple oblique duodenoduodenostomy (LSOD) and its results in management of congenital duodenal obstruction (CDO) in children. PATIENTS AND METHODS: Medical records of patients with the diagnosis of CDO undergoing LSOD at our center from March 2009 to December 2013 were reviewed. The LSOD used one infra- or transumbilical 5-mm port for the camera and two 3-mm ports for instruments. After mobilization of the distant part of the duodenum, a 5-0 polydioxanone seromuscular suture was placed on the duodenal wall proximal and distal to the obstruction and tacked to the anterior abdominal wall for traction. The lower duodenum was incised longitudinally distal to the traction suture. The upper duodenum incision was placed away from the traction suture and extended downward obliquely. The duodenoduodenostomy was performed as a "simple" anastomosis. RESULTS: Forty-eight patients were identified with a median age at operation of 11 days. The median weight at operation was 2650 g. Duodenal atresia and annular pancreas were found in 81.2% and 18.8% of patients, respectively. The median operative time was 90 minutes. There was no conversion to open surgery, anastomotic leakage, or stenosis. The median time from the operation to initial oral feeding was 4 days. Of the 48 patients, 97.9% were discharged in good health with a median postoperative hospital stay of 7 days CONCLUSIONS: The LSOD technique is safe and efficacious and can be a viable option in the management of select cases of CDO in children at experienced centers. PMID- 25536360 TI - A literature review: addressing indigenous parental substance use and child welfare in Aotearoa: a Whanau Ora framework. AB - Parental substance use disorders (SUDs) for Maori, the indigenous people of Aotearoa/New Zealand and an ethnic minority, are considered to be contributors to adverse effects on outcomes for their children. This article offers a review of international and Aotearoa literature in regard to key considerations for Maori parents with SUDs who present to an Alcohol and Drug specialist for assessment and treatment. Factors to increase positive outcomes for Maori children of parents with SUDs are promoted. Effective adult AoD services provide support to parents with SUDs through comprehensive assessment and intervention plans that consider both individual and familial risk and protective factors. In this context, it is imperative that possible child welfare issues are identified early to ensure prevention or intervention. The AoD workforce must have the knowledge and skills to facilitate access to other relevant sectors, such as education, employment, and housing. An AoD workforce that is effective with Maori must not only have these abilities, but also have at least some basic knowledge and skills in Whanau Ora philosophy and Whanau-centered best practice. To address these processes, AoD specialist services need to acquire a set of knowledge and skills. These include increasing the knowledge and skills associated with the realities of lifestyles centered in low socioeconomic communities and co-occurring issues that contribute to poor health outcomes. To assist Maori, several key processes are proposed. This includes working in a Whanau-centered approach with Whanau as a collective entity, based on Maori foundations; understanding intergenerational dynamics; and endorsing a group capacity for self-determination. Research and training in Whanau ora philosophy and Whanau-centered best practices will be essential for developing an appropriate AoD workforce, which would provide the foundations for improving AoD service delivery for Maori parents with SUDs. PMID- 25536361 TI - Single-Tooth Rehabilitations Supported by Dental Implants Used in an Immediate Provisionalization Protocol: Report on Long-Term Outcome with Retrospective Follow-Up. AB - BACKGROUND: There is a need for long-term studies evaluating the outcome of single-tooth rehabilitations supported by dental implants in immediate loading. PURPOSE: To report the long-term outcome (in excess of 5 years) of single-tooth rehabilitations supported by dental implants in an immediate-provisionalization protocol. MATERIALS AND METHODS: This retrospective cohort study included 332 consecutive patients (189 females and 143 males) with an average age of 47 years (range: 16 to 82 years) who were rehabilitated between 1996 and 2006 with 594 single crowns supported by dental implants in immediate loading. Implant success rates were calculated based on implant function and using life tables. Marginal bone levels were measured at 5 and 10 years. Mechanical and biological complications were calculated for the follow-up period between implant insertion and 5 years and every 6 months thereafter. RESULTS: Fifty-four patients dropped out of the study (16.5%). Nineteen patients lost a total of 25 implants (n = 23 in the maxilla; n = 2 in the mandible), rendering a cumulative survival rate of 95.7% at both 5 and 10 years of follow-up. The mean marginal bone levels were 1.56 mm (standard deviation 0.78 mm) and 1.75 mm (standard deviation 0.29 mm) at 5 and 10 years of follow-up. Mechanical complications occurred in 83 patients and 116 implants (19.5%) up to the 10-year follow-up, namely prosthetic screw loosening (2.4%), abutment complications (4.4%), fracture of provisional crowns (9.6%), and fracture of definitive ceramic crowns (3.5%). Biological complications occurred in 58 patients and 79 implants (13.3%) up to the 10-year follow-up, with the majority consisting in peri-implant pathology. CONCLUSIONS: Considering the high survival rates and stable marginal bone levels after 10 years, it can be concluded within the limitations of the present study that replacement of single teeth with dental implants in an immediate provisionalization protocol is a viable and safe treatment option for both maxilla and mandible. PMID- 25536364 TI - Supracolloidal polymer chains of diblock copolymer micelles. AB - Directional attraction with lateral repulsion between colloidal nanoparticles can create their supracolloidal chains. Here, we demonstrate supracolloidal polymers of diblock copolymer micelles, which were polymerized by adjusting the polarity of the solvent. We also synthesized supracolloidal random and block copolymer chains. PMID- 25536363 TI - Role of synaptic structural plasticity in impairments of spatial learning and memory induced by developmental lead exposure in Wistar rats. AB - Lead (Pb) is found to impair cognitive function. Synaptic structural plasticity is considered to be the physiological basis of synaptic functional plasticity and has been recently found to play important roles in learning and memory. To study the effect of Pb on spatial learning and memory at different developmental stages, and its relationship with alterations of synaptic structural plasticity, postnatal rats were randomly divided into three groups: Control; Pre-weaning Pb (Parents were exposed to 2 mM PbCl2 3 weeks before mating until weaning of pups); Post-weaning Pb (Weaned pups were exposed to 2 mM PbCl2 for 9 weeks). The spatial learning and memory of rats was measured by Morris water maze (MWM) on PND 85-90. Rat pups in Pre-weaning Pb and Post-weaning Pb groups performed significantly worse than those in Control group (p<0.05). However, there was no significant difference in the performance of MWM between the two Pb-exposure groups. Before MWM (PND 84), the number of neurons and synapses significantly decreased in Pre weaning Pb group, but not in Post-weaning Pb group. After MWM (PND 91), the number of synapses in Pre-weaning Pb group increased significantly, but it was still less than that of Control group (p<0.05); the number of synapses in Post weaning Pb group was also less than that of Control group (p<0.05), although the number of synapses has no differences between Post-weaning Pb and Control groups before MWM. In both Pre-weaning Pb and Post-weaning Pb groups, synaptic structural parameters such as thickness of postsynaptic density (PSD), length of synaptic active zone and synaptic curvature increased significantly while width of synaptic cleft decreased significantly compared to Control group (p<0.05). Our data demonstrated that both early and late developmental Pb exposure impaired spatial learning and memory as well as synaptic structural plasticity in Wistar rats. PMID- 25536366 TI - Knee joint loading during lineman-specific movements in American football players. AB - Linemen are at high risk for knee cartilage injuries and osteoarthritis. High intensity movements from squatting positions (eg, 3-point stance) may produce high joint loads, increasing the risk for cartilage damage. We hypothesized that knee moments and joint reaction forces during lineman-specific activities would be greater than during walking or jogging. Data were collected using standard motion analysis techniques. Fifteen NCAA linemen (mean +/- SD: height = 1.86 +/- 0.07 m, mass = 121.45 +/- 12.78 kg) walked, jogged, and performed 3 unloaded lineman-specific blocking movements from a 3-point stance. External 3-dimensional knee moments and joint reaction forces were calculated using inverse dynamics equations. MANOVA with subsequent univariate ANOVA and post hoc Tukey comparisons were used to determine differences in peak kinetic variables and the flexion angles at which they occurred. All peak moments and joint reaction forces were significantly higher during jogging than during all blocking drills (all P < .001). Peak moments occurred at average knee flexion angles > 70 degrees during blocking versus < 44 degrees in walking or jogging. The magnitude of moments and joint reaction forces when initiating movement from a 3-point stance do not appear to increase risk for cartilage damage, but the high flexion angles at which they occur may increase risk on the posterior femoral condyles. PMID- 25536365 TI - Annexin-A1 regulates microRNA-26b* and microRNA-562 to directly target NF-kappaB and angiogenesis in breast cancer cells. AB - Annexin 1 (ANXA1) is an endogenous anti-inflammatory protein implicated in cancer. ANXA1 was previously shown to be regulated by hsa-miR-196a. However, whether ANXA1 itself regulates microRNA (miR) expression is unknown. Therefore, we investigated the regulation of miR by ANXA1 in MCF7 breast cancer cells. MCF7 EV (Empty vector) and MCF7-V5 (ANXA1-V5 expressing cells) were subjected to a miR microarray. Microarray analysis revealed a number of miRNAs which were dysregulated in MCF7-V5 cells. 2 novel miRNAs (miR562 and miR26b*) were validated, cloned and functionally characterized. As ANXA1 constitutively activates NF-kappaB activity to modulate breast cancer metastasis, we found that miR26b* and miR562 directly targeted the canonical NF-kappaB pathway by targeting the 3' UTR and inhibiting expression of Rel A (p65) and NF-kappaB1 (p105) respectively. MiR562 inhibited wound healing, which was reversed when ANXA1 was overexpressed. Overexpression of either miR562 or miR26b* in MCF-7 cells enhanced endothelial tube formation when cocultured with human umbilical cord endothelial cells while conversely, treatment of MCF7 cells with either anti-miR562 or anti miR26b* inhibited endothelial tube formation after co-culture. Further analysis of miR562 revealed that miR562-transfected cell conditioned media enhances endothelial cell tube formation, indicating that miR562 increased angiogenic secreted factors from MCF-7 breast tumor cells. TNFalpha was increased upon overexpression of miR562, which was reversed when ANXA1 was co-transfected In conclusion, this data suggests that ANXA1-regulated miR26b* and miR562 may play a role in wound healing and tumor-induced endothelial cell tube formation by targeting NF-kappaB expression and point towards a potential therapeutic target for breast cancer. PMID- 25536368 TI - Preparing a pseudo-solid by the reinforcement of a polydentate thioether using silver nanoparticles. AB - The design of networks from polymers and noble metal nanoparticles requires thorough control over topological polymer-particle arrangements. This study explores the interaction between a linear polydentate poly(propylene sulfide) (PPrS) ligand and silver nanoparticles (AgNPs) with an aim to study its effect on mechanical and viscoelastic properties. Very low amounts (0.30 vol%) of silver nanoparticles lead to significant mechanical reinforcement of PPrS, yielding viscoelastic properties of an unfastened network with solid-like elastic responses on mechanical stimulation. The materials are made by ring-opening anionic polymerization of propylene sulfide to yield high molar mass PPrS with a total of 593 thioether functionalities per chain, followed by a simple in situ "grafting to" method to homogeneously incorporate AgNPs into the polymer matrix. From investigations on the chain dynamics using dynamic rheology it is concluded that well-dispersed AgNPs impose additional topological constraints on the polymer chains. Calculations of the statistical interparticle distances support a tele-bridging polymer-particle arrangement. PMID- 25536367 TI - Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs. AB - Infants with cardiopulmonary disorders associated with hypoxia develop pulmonary hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates pulmonary hypertension in newborn piglets. Rescue treatments, initiated after the onset of pulmonary hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L citrulline after the onset of pulmonary hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess NO production and eNOS dimer-to monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse pulmonary hypertension in infants suffering from cardiopulmonary conditions associated with hypoxia. PMID- 25536369 TI - The anti-inflammatory potential of a moderately hydrolysed casein and its 5 kDa fraction in in vitro and ex vivo models of the gastrointestinal tract. AB - Bioactive peptides from milk can impart a wide range of physiological benefits without the allergies and intolerance associated with the consumption of whole milk. The objective of this study was to characterise the anti-inflammatory properties of intact sodium caseinate (NaCAS), a moderately hydrolysed NaCAS enzyme hydrolysate (EH) and its 5 kDa fraction (5kDaR), in both in vitro and ex vivo systems. In vitro, Caco-2 cells were stimulated with tumor necrosis factor (TNF) alpha and co-treated +/- casein hydrolysates or dexamethasone (control). The inflammatory marker interleukin (IL)-8 was measured by ELISA in the supernatant at 24 h. Ex vivo, porcine colonic tissues were stimulated with lipopolysaccharide (LPS) and co-treated with casein hydrolysates for 3 h from which the relative expression of a panel of cytokines was measured in vitro. While the steroid dexamethasone brought about a 41.6% reduction in the IL-8 concentration in the supernatant, the 5kDaR reduced IL-8 by 59% (P < 0.05) when compared to the TNFalpha stimulated Caco-2 cells. In the ex vivo system, 5kDaR was associated with decreases in IL-1alpha, IL-1beta, IL-8 and TGF-beta expression and an increase in IL-17 expression (P < 0.05) relative to the LPS challenged tissues. We concluded, that a 5 kDa casein fraction demonstrates potent anti-inflammatory effects both in in vitro and ex vivo models of the gastrointestinal tract. PMID- 25536370 TI - Temperature control of light transmission using mixed system of silica hollow particles with nanoparticle shell and organic components. AB - We reported before that a silica hollow particle whose shell consists of silica nanoparticle (SHP-NP) has a high light reflection ability to prevent light transmission through the particle, which is caused from the intensive light diffusion by the hollow structure and the nanoparticle of the shell. Since the difference in the refractive indices between silica and air is responsible for the strong light reflection, the mixing of the particle with organic components having refractive indices close to that of silica such as tetradecane produced transparent mixtures by suppression of the light reflection. The transparency of the mixtures thus prepared could be controlled by temperature variation. For example, the mixture of the particle SHP-NP with tetradecane was transparent at 20 degrees C and opaque at 70 degrees C, while the mixture with n-hexyl cyclohexane was opaque at 20 degrees C and transparent at 70 degrees C. As the refractive indices of organic components changed with temperature more than 10 times wider than that of silica, the temperature alternation produced a significant change in the difference of the refractive indices between them to achieve complete control of the transparency of the mixtures. This simple control of the light transmission that can automatically regulate sunlight into the room with temperature alteration is expected to be suitable for smart glass technology for energy conservation. PMID- 25536371 TI - Extracellular polymeric substances govern the surface charge of biogenic elemental selenium nanoparticles. AB - The origin of the organic layer covering colloidal biogenic elemental selenium nanoparticles (BioSeNPs) is not known, particularly in the case when they are synthesized by complex microbial communities. This study investigated the presence of extracellular polymeric substances (EPS) on BioSeNPs. The role of EPS in capping the extracellularly available BioSeNPs was also examined. Fourier transform infrared (FT-IR) spectroscopy and colorimetric measurements confirmed the presence of functional groups characteristic of proteins and carbohydrates on the BioSeNPs, suggesting the presence of EPS. Chemical synthesis of elemental selenium nanoparticles in the presence of EPS, extracted from selenite fed anaerobic granular sludge, yielded stable colloidal spherical selenium nanoparticles. Furthermore, extracted EPS, BioSeNPs, and chemically synthesized EPS-capped selenium nanoparticles had similar surface properties, as shown by zeta-potential versus pH profiles and isoelectric point measurements. This study shows that the EPS of anaerobic granular sludge form the organic layer present on the BioSeNPs synthesized by these granules. The EPS also govern the surface charge of these BioSeNPs, thereby contributing to their colloidal properties, hence affecting their fate in the environment and the efficiency of bioremediation technologies. PMID- 25536374 TI - NFIL3 suppresses hypoxia-induced apoptotic cell death by targeting the insulin like growth factor 2 receptor. AB - The insulin-like growth factor-II/mannose 6-phosphate receptor (IGF2R) over expression correlates with heart disease progression. The IGF2R is not only an IGF2 clearance receptor, but it also triggers signal transduction, resulting in cardiac hypertrophy, apoptosis and fibrosis. The present study investigated the nuclear factor IL-3 (NFIL3), a transcription factor of the basic leucine zipper superfamily, and its potential pro-survival effects in cardiomyocytes. NFIL3 might play a key role in heart development and act as a survival factor in the heart, but the regulatory mechanisms are still unclear. IGF2 and IGF2R protein expression were highly increased in rat hearts subjected to hemorrhagic shock. IGF2R protein expression was also up-regulated in H9c2 cells exposed to hypoxia. Over-expression of NFIL3 in H9c2 cardiomyoblast cells inhibited the induction of hypoxia-induced apoptosis and down-regulated IGF2R expression levels. Gel shift assay, double-stranded DNA pull-down assay and chromatin immune-precipitation analyses indicated that NFIL3 binds directly to the IGF2R promoter region. Using a luciferase assay, we further observed NFIL3 repress IGF2R gene promoter activity. Our results demonstrate that NFIL3 is an important negative transcription factor, which through binding to the promoter of IGF2R, suppresses the apoptosis induced by IGF2R signaling in H9c2 cardiomyoblast cells under hypoxic conditions. PMID- 25536373 TI - Association between lung function in adults and plasma DDT and DDE levels: results from the Canadian Health Measures Survey. AB - BACKGROUND: Although DDT [1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane] has been banned in many countries since the 1970s, it may still pose a risk to human respiratory health. In agriculture, DDT exposures have been associated with asthma and chronic bronchitis. However, little is known about the effect of DDT on lung function. METHODS: We used data on 1,696 participants 20-79 years of age from the Canadian Health Measures Survey (CHMS) and conducted multiple regression analysis to estimate associations between plasma p,p'-DDT/DDE and lung function. RESULTS: Almost all participants (> 99.0%) had detectable concentrations of plasma p,p'-DDE, but only 10.0% had detectable p,p'-DDT. Participants with detectable p,p'-DDT had significantly lower mean FVC (difference = 311 mL; 95% CI: -492, -130; p = 0.003) and FEV1 (difference = 232 mL; 95% CI: -408, -55; p = 0.015) than those without. A 100-ng/g lipid increase in plasma p,p'-DDE was associated with an 18.8-mL decrease in mean FVC (95% CI: -29, -9) and an 11.8-mL decrease in mean FEV1 (95% CI: -21, -3). Neither exposure was associated with FEV1/FVC ratio or FEF25%-75%. CONCLUSIONS: DDT exposures, which may have occurred decades ago, were still detectable among Canadians. Plasma DDT and DDE were negatively associated with lung function parameters. Additional research on the potential effects of DDT use on lung function is warranted. PMID- 25536375 TI - The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta-Analysis. AB - Cyclosporine A (CsA) is a substrate of the multi-drug efflux pump P-glycoprotein (P-gp) encoded by ABCB1. Among the various single nucleotide polymorphisms (SNPs) of ABCB1, C3435T has been extensively investigated to determine the relationship with the pharmacokinetics of CsA. However, the results are controversial. This meta-analysis was designed to evaluate the influence of C3435T SNP on the dose adjusted trough (C0 /D) and peak (Cmax /D) concentrations of CsA. Based on a literature search of four authoritative databases, 13 studies since 2001 concerning 1293 kidney transplant recipients were included. The results indicated a significant difference of C0 /D and Cmax /D between 3435CC and 3435TT genotype carriers (weighted mean difference (WMD) of C0 /D: 4.18 (ng ml(-1))/(mg kg(-1)), 95% CIs: 1.00-7.37, p = 0.01; WMD of Cmax /D: 20.85 (ng ml(-1))/(mg kg(-1)), 95% CIs: 2.25-39.46, p = 0.03). Subgroup analysis by ethnicity demonstrated that C0 /D was lower in Asian CC versus TT genotype carriers (WMD = 10.32 (ng ml(-1))/(mg kg(-1)), 95% CIs: 4.78-15.85, p = 0.0003) but did not vary by genotype for Caucasian recipients. Moreover, significant variation of C0 /D was found at 1 week and 1-3 months after transplantation between CC and TT genotype carriers. Therefore, this meta-analysis showed a correlation between ABCB1 C3435T polymorphism and the dose-adjusted concentration of CsA. Patients with 3435CC genotype will require a higher dose of CsA to achieve target therapeutic concentrations when compared with 3435TT carriers after kidney transplantation, especially in the Asian population and especially during the early and middle time periods after transplantation. PMID- 25536376 TI - AMPK activation inhibits expression of proinflammatory mediators through downregulation of PI3K/p38 MAPK and NF-kappaB signaling in murine macrophages. AB - Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in energy homeostasis and regulation of inflammatory responses. The present study is aimed to investigate the anti-inflammatory effects of ENERGI-F704, a nucleobase analogue isolated from bamboo leaves, on expression of proinflammatory mediators in murine macrophage RAW264.7 in response to lipopolysaccharide (LPS). ENERGI-F704 enhanced phosphorylation of AMPK(T172) but insignificantly affected the viability of RAW264.7 cells. Further investigation showed that ENERGI-F704 decreased mRNA expression of interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-alpha), cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) induced by LPS, as well as suppressed the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Additionally, the inhibitory effects of ENERGI-F704 on the LPS-induced proinflammatory mediators were diminished by pretreatment of AMPK inhibitor Compound C. ENERGI-F704 also inhibited LPS-triggered activation of nuclear factor kappa B (NF-kappaB), phosphatidylinositol 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38), whereas extracellular signal-regulated kinase (Erk)1/2 and c-Jun N-terminal kinase (JNK) were insignificantly influenced. Our findings indicate that ENERGI-F704 may exert anti-inflammatory activity on RAW264.7 cells in response to LPS through the activation of AMPK and suppression of PI3K/P38/NF-kappaB signaling and the consequent decreased expression of proinflammatory mediators, suggesting that ENERGI-F704 is beneficial to the amelioration of inflammatory disorders. PMID- 25536377 TI - A surprising sweetener from enteropathogenic Escherichia coli. AB - Infections with enteropathogenic Escherichia coli (EPEC) are remarkably devoid of gut inflammation and necrotic damage compared to infections caused by invasive pathogens such as Salmonella and Shigella. Recently, we observed that EPEC blocks cell death using the type III secretion system (T3SS) effector NleB. NleB mediated post-translational modification of death domain containing adaptor proteins by the covalent attachment of N-acetylglucosamine (GlcNAc) to a conserved arginine in the death domain. N-linked glycosylation of arginine has not previously been reported in mammalian cell biology and the precise biochemistry of this modification is not yet defined. Although the addition of a single GlcNAc to arginine is a seemingly slight alteration, the impact of NleB is considerable as arginine in this location is critical for death domain interactions and death receptor induced apoptosis. Hence, by blocking cell death, NleB promotes enterocyte survival and thereby prolongs EPEC attachment to the gut epithelium. PMID- 25536378 TI - Reasons underlying behaviour of motorcyclists disregarding traffic regulations in urban areas of Indonesia. AB - Over the last decade, motorcycle use has been rapidly increasing in Indonesia as have violations of traffic rules committed by motorcyclists. This study aims to explore the impacts of motorcyclists' attitudes, habits, preferences, and travel patterns on their behaviour in disregarding traffic regulations in three cities in Indonesia. The theory of planned behaviour and structural equation modelling are employed to explore these relationships. Consistent with results from previous studies in developed countries, an individual's beliefs and attitudes, social norms and perceived behaviour control significantly influence behaviour in disregarding traffic rules. Young adults and students are found to be more likely to frequently violate traffic regulations. However, unlike previous findings from developed countries, in Indonesia, males are less likely to disregard traffic rules than females. Overall, pushing the motorcycle through a (very) narrow gap, speeding, driving recklessly, and overtaking on the wrong side are the most frequent traffic violations that make up repetitive violation behaviour among urban motorcyclists in Indonesia. The results highlight the need to revisit Indonesian National Traffic Law traffic violation classification and penalties and separate violations that are likely to cause fatal results, thus requiring tougher law enforcement, from violations that are unlikely to have fatal consequences. PMID- 25536383 TI - Protein glycation - Between tissue aging and protection. AB - Non-enzymatic formation of advanced glycation endproducts (AGEs) is associated with degenerative diseases. Chronic accumulation of AGEs with age in tissues especially in the extracellular matrix is well known and at least in part responsible for e.g., collagen crosslinking, tissue stiffening and thus induction of high blood pressure or diastolic heart failure. Binding of soluble AGEs to the receptor for AGEs, RAGE, induces an inflammatory response whereas the soluble form of RAGE (sRAGE) can inhibit inflammatory tissue injury like arteriosclerosis in mouse models. However, there are a number of indications that AGEs have protective effects as well. AGEs may inhibit lung tumor growth, glyoxal induced AGE modification of human heart muscle can reduce an ischemia reperfusion injury and AGEs from nutrition can reduce ROS induced cell damage. CONCLUSIONS: In summary, this indicates that protein glycation behaves like a double-edged sword. It induces tissue aging and degenerative diseases on the one hand, on the other hand, may also have protective effects, indicating a hormetic response. PMID- 25536385 TI - Correction to "Structural Effects of pH and Deacylation on Surfactant Protein C in an Organic Solvent Mixture: A Constant-pH MD Study". PMID- 25536387 TI - Role of light wavelengths in synchronization of circadian physiology in songbirds. AB - This study investigated whether at identical duration and equal energy level birds presented with short (450nm; blue, B) and long (640nm; red, R) light wavelengths would differentially interpret them and exhibit wavelength-dependent circadian behavioral and physiological responses, despite the difference in their breeding latitudes. Temperate migratory blackheaded buntings (Emberiza melanocephala) and subtropical non-migratory Indian weaverbirds (Ploceus philippinus) initially entrained to 12h light:12h darkness (12L:12D; L=0.33MUM/m(2)/s, D=0MUM/m(2)/s) in two groups of each, groups 1 and 2, were subjected to constant light (LL, 0.33MUM/m(2)/s), which rendered them arrhythmic in the activity behavior. They were then exposed for about two weeks each to 12B:12R and 12R:12B (group 1) or 12R:12B and 12B:12R (group 2) at 0.33MUM/m(2)/s light energy level. Blue and red light periods were interpreted as the day and night, respectively, with activity and no-activity in non-migratory weaverbirds or activity and intense activity (Zugunruhe, migratory night restlessness) in the migratory buntings. Consistent with this, plasma melatonin levels under B:R, not R:B, light cycle were low and high in blue and red light periods, respectively. A similar diurnal pattern was absent in the cortisol levels, however. These results show an important role of light wavelengths in synchronization of the circadian clock governed behavior and physiology to the photoperiodic environment, and suggest that photoperiodic timing might be a conserved physiological adaptation in many more birds, regardless of the difference in breeding latitudes, than has been generally envisaged. PMID- 25536384 TI - Neuroanatomical characteristics associated with response to dorsal anterior cingulotomy for obsessive-compulsive disorder. AB - IMPORTANCE: Approximately 10% of patients with obsessive-compulsive disorder (OCD) have symptoms that are refractory to pharmacologic and cognitive-behavioral therapies. Neurosurgical interventions can be effective therapeutic options in these patients, but not all individuals respond. The mechanisms underlying this response variability are poorly understood. OBJECTIVE: To identify neuroanatomical characteristics on preoperative imaging that differentiate responders from nonresponders to dorsal anterior cingulotomy, a neurosurgical lesion procedure used to treat refractory OCD. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed preoperative T1 and diffusion magnetic resonance imaging sequences from 15 patients (9 men and 6 women) who underwent dorsal anterior cingulotomy. Eight of the 15 patients (53%) responded to the procedure. MAIN OUTCOMES AND MEASURES: We used voxel-based morphometry (VBM) and diffusion tensor imaging to identify structural and connectivity variations that could differentiate eventual responders from nonresponders. The VBM and probabilistic tractography metrics were correlated with clinical response to the cingulotomy procedure as measured by changes in the Yale-Brown Obsessive Compulsive Scale score. RESULTS: Voxel-based morphometry analysis revealed a gray matter cluster in the right anterior cingulate cortex, anterior to the eventual lesion, for which signal strength correlated with poor response (P = .017). Decreased gray matter in this region of the dorsal anterior cingulate cortex predicted improved response (mean [SD] gray matter partial volume for responders vs nonresponders, 0.47 [0.03] vs 0.66 [0.03]; corresponding to mean Yale-Brown Obsessive Compulsive Scale score change, -60% [19] vs -11% [9], respectively). Hemispheric asymmetry in connectivity between the eventual lesion and the caudate (for responders vs nonresponders, mean [SD] group laterality for individual lesion seeds, -0.79 [0.18] vs -0.08 [0.65]; P = .04), putamen (-0.55 [0.35] vs 0.50 [0.33]; P = .001), thalamus (-0.82 [0.19] vs 0.41 [0.24]; P = .001), pallidum (-0.78 [0.18] vs 0.43 [0.48]; P = .001), and hippocampus (-0.66 [0.33] vs 0.33 [0.18]; P = .001) also correlated significantly with clinical response, with increased right sided connectivity predicting greater response. CONCLUSIONS AND RELEVANCE: We identified features of anterior cingulate cortex structure and connectivity that predict clinical response to dorsal anterior cingulotomy for refractory OCD. These results suggest that the variability seen in individual responses to a highly consistent, stereotyped procedure may be due to neuroanatomical variation in the patients. Furthermore, these variations may allow us to predict which patients are most likely to respond to cingulotomy, thereby refining our ability to individualize this treatment for refractory psychiatric disorders. PMID- 25536389 TI - Effect of NAD on PARP-mediated insulin sensitivity in oleic acid treated hepatocytes. AB - High serum free fatty acids levels are associated with the development of insulin resistance in type 2 diabetes; however, the precise mechanisms underlying this lipid toxicity are unclear. To investigate whether PARP1 activation and NAD depletion are involved in the impairment of insulin sensitivity associated with lipotoxicity, HepG2 cells were cultured with 500 MUM oleic acid for 48 h. Oleic acid-treated cells exhibited increased ROS generation, lipid accumulation and PARP1 activation. Treatment with the PARP1 inhibitor PJ34 and transfection with PARP1 small interfering RNA both prevented the oleic acid-induced impairment of the insulin signaling pathway. Furthermore, treatment with PJ34 reversed the oleic acid-induced decrease in intracellular NAD concentration, while exogenous NAD protected cells against oleic acid-induced insulin insensitivity. Combined NAD and PJ34 administration did not enhance the effects obtained by treatment with either NAD or PJ34 alone. Interestingly, when cells were treated with the SIRT1 inhibitor EX527, the protective effects of PJ34 and NAD treatment were diminished. Taken together, these data suggest that NAD depletion by PARP1 activation is essential for the modulation of insulin sensitivity in oleic acid induced lipotoxicity. PMID- 25536388 TI - Protein denaturants at aqueous-hydrophobic interfaces: self-consistent correlation between induced interfacial fluctuations and denaturant stability at the interface. AB - The notion of direct interaction between denaturing cosolvent and protein residues has been proposed in dialogue relevant to molecular mechanisms of protein denaturation. Here we consider the correlation between free energetic stability and induced fluctuations of an aqueous-hydrophobic interface between a model hydrophobically associating protein, HFBII, and two common protein denaturants, guanidinium cation (Gdm(+)) and urea. We compute potentials of mean force along an order parameter that brings the solute molecule close to the known hydrophobic region of the protein. We assess potentials of mean force for different relative orientations between the protein and denaturant molecule. We find that in both cases of guanidinium cation and urea relative orientations of the denaturant molecule that are parallel to the local protein-water interface exhibit greater stability compared to edge-on or perpendicular orientations. This behavior has been observed for guanidinium/methylguanidinium cations at the liquid-vapor interface of water, and thus the present results further corroborate earlier findings. Further analysis of the induced fluctuations of the aqueous hydrophobic interface upon approach of the denaturant molecule indicates that the parallel orientation, displaying a greater stability at the interface, also induces larger fluctuations of the interface compared to the perpendicular orientations. The correlation of interfacial stability and induced interface fluctuation is a recurring theme for interface-stable solutes at hydrophobic interfaces. Moreover, observed correlations between interface stability and induced fluctuations recapitulate connections to local hydration structure and patterns around solutes as evidenced by experiment (Cooper et al., J. Phys. Chem. A 2014, 118, 5657.) and high-level ab initio/DFT calculations (Baer et al., Faraday Discuss 2013, 160, 89). PMID- 25536391 TI - Mindful Creativity Scale (MCS): Validation of a German version of the Langer Mindfulness Scale with patients with severe TBI and controls. AB - BACKGROUND: Mindfulness may have an impact on the recovery process in patients who have suffered severe traumatic brain injury (TBI). In order to make an instrument for measuring mindfulness within the German speaking clinical community available, a short, easily usable scale and a cross-cultural adaptation is needed. OBJECTIVES: To validate the Langer Mindfulness Scale (LMS) with German speaking patients with severe TBI and their relatives (healthy controls). RESEARCH DESIGN: In a prospective cohort study of patients with severe TBI, test re-test interviews were carried out at 6-month intervals. SAMPLE: A total of 225 participants responded to the first survey and 230 completed the second survey. MEASURES: LMS, self-report questions on personality, openness and attention, as well as health and clinical evaluations (including cognitive and behavioural assessments). RESULTS: On the basis of factor analysis, principal component analysis and item response analysis, the initial 21-items were reduced to six items. The resulting unidimensional scale showed high internal consistency (alpha = 0.82) and good test-re-test reliability (intra-class correlation for total score = 0.46). External validity was confirmed for the entire sample. CONCLUSION: It was concluded that the German short form of the original LMS (MCS) is a valid and reliable measure of mindful creativity. PMID- 25536390 TI - Chronic subdural haematoma evolving from traumatic subdural hydroma. AB - OBJECTIVE: This study aimed to investigate the incidence and clinical characteristics of chronic subdural haematoma (CSDH) evolving from traumatic subdual hydroma (TSH). METHODS: The clinical characteristics of 44 patients with CSDH evolving from TSH were analysed retrospectively and the relevant literature was reviewed. RESULTS: In 22.6% of patients, TSH evolved into CSDH. The time required for this evolution was 14-100 days after injury. All patients were cured with haematoma drainage. CONCLUSIONS: TSH is one possible origin of CSDH. The clinical characteristics of TSH evolving into CSDH include polarization of patient age and chronic small effusion. The injuries usually occur during deceleration and are accompanied by mild cerebral damage. PMID- 25536392 TI - Point-of-care troponin T is inferior to high-sensitivity troponin T for ruling out acute myocardial infarction in the emergency department. AB - OBJECTIVE: Point-of-care testing (POCT) cardiac troponin (cTn) measurements are being used increasingly, despite the fact that evidence on the safety of their use is outdated, not taking into account current 'gold standard' high-sensitivity cardiac troponin (hs-cTn) assays. In the present study, we aimed to compare the analytical and diagnostic performance of the AQT90-flex POCT cTnT assay (which is the POCT assay with the lowest reported 99th percentile cutoff currently available) with the laboratory-based Roche Modular E170 hs-cTnT assay. MATERIALS AND METHODS: During a 4-month prospective observational cohort study, laboratory based hs-cTnT and POCT cTn were measured simultaneously in 261 undifferentiated chest-pain patients presenting to the emergency department (ED) of the Medical Centre Leeuwarden to determine the diagnostic accuracy of both assays in predicting acute myocardial infarction (AMI) at presentation. RESULTS: The POCT cTn assay had a lower sensitivity [68 (49-82) vs. 91 (75-98)] and a lower negative predictive value [95 (91-97) vs. 98 (95-100)%] for the prediction of AMI at presentation compared with the hs-cTnT assay. Furthermore, in three patients, the POCT cTnT assay yielded unexpectedly high results, whereas hs-cTnT results were negative. None of these patients had an AMI, and no possible explanation could be found. CONCLUSION: The AQT90-flex POCT cTnT assay is not yet sensitive and reliable enough to be used to exclude AMI in the ED with a single blood draw at the time of presentation in the ED, and therefore, may have limited applicability in the ED setting. PMID- 25536393 TI - Corrosion of high-level radioactive waste iron-canisters in contact with bentonite. AB - Several countries favor the encapsulation of high-level radioactive waste (HLRW) in iron or steel canisters surrounded by highly compacted bentonite. In the present study the corrosion of iron in contact with different bentonites was investigated. The corrosion product was a 1:1 Fe layer silicate already described in literature (sometimes referred to as berthierine). Seven exposition test series (60 degrees C, 5 months) showed slightly less corrosion for the Na bentonites compared to the Ca-bentonites. Two independent exposition tests with iron pellets and 38 different bentonites clearly proved the role of the layer charge density of the swelling clay minerals (smectites). Bentonites with high charged smectites are less corrosive than bentonites dominated by low charged ones. The type of counterion is additionally important because it determines the density of the gel and hence the solid/liquid ratio at the contact to the canister. The present study proves that the integrity of the multibarrier-system is seriously affected by the choice of the bentonite buffer encasing the metal canisters in most of the concepts. In some tests the formation of a patina was observed consisting of Fe-silicate. Up to now it is not clear why and how the patina formed. It, however, may be relevant as a corrosion inhibitor. PMID- 25536395 TI - Fibrosis: dysfunctional fatty acid oxidation in renal fibrosis. PMID- 25536394 TI - Renal artery embolization-indications, technical approaches and outcomes. AB - Owing to improvements in catheters and embolic agents, renal artery embolization (RAE) is increasingly used to treat nephrological and urological disease. RAE has become a useful adjunct to medical resuscitation in severe penetrating, iatrogenic or blunt renal traumatisms with active bleeding, and might avoid surgical intervention, particularly among patients that are haemodynamically stable. The role of RAE in pre-operative or palliative management of advanced malignant renal tumours remains debated; however, RAE is recommended as a first line therapy for bleeding angiomyolipomas and can be used as a preventative treatment for angiomyolipomas at risk of bleeding. RAE represents an alternative to nephrectomy in various medical conditions, including severe uncontrolled hypertension among patients with end-stage renal disease, renal graft intolerance syndrome or autosomal dominant polycystic kidney disease. RAE is increasingly used to treat renal artery aneurysms or symptomatic renal arteriovenous malformations, with a low complication rate as compared with surgical alternatives. This Review highlights the potential use of RAE as an adjunct in the management of renal disease. We first compare and contrast the technical approaches of RAE associated with the various available embolization agents and then discuss the complications associated with RAE and alternative procedures. PMID- 25536396 TI - HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. AB - Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1beta (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ~50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B associated disease. PMID- 25536400 TI - Validation of the A&D BP UA-651 device with a wide-range cuff for home blood pressure measurement according to the European Society of Hypertension International Protocol revision 2010. AB - The aim of this study was to determine the accuracy of the A&D BP UA-651 device coupled to a wide-range cuff for home blood pressure (BP) measurement according to the International Protocol of the European Society of Hypertension. The device was evaluated in 33 patients. The mean age of the patients was 56.5+/-15.1 years. The mean systolic BP was 144.3+/-23.8 mmHg (range 88 : 196), the mean diastolic BP was 87.5+/-15.8 mmHg (range 38 : 132), and the mean arm circumference was 29.0+/-3.4 cm (range 22 : 36). The protocol requirements were followed precisely. The device passed all requirements, fulfilling the standards of the protocol. On average, the device overestimated the systolic BP by 0.7+/-3.4 mmHg and underestimated the diastolic BP by 0.8+/-3.6 mmHg. The measurement error was unrelated to the patient's arm circumference. These data show that the A&D BP UA 651 device coupled to a wide-range cuff fulfilled the requirements for validation by the International Protocol over a wide range of arm circumferences and can be recommended for clinical use in the adult population. PMID- 25536398 TI - An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood. AB - Temporally controlled mechanisms that define the unique features of ventricular and atrial cardiomyocyte identities are essential for the construction of a coordinated, morphologically intact heart. We have previously demonstrated an important role for nkx genes in maintaining ventricular identity, however, the specific timing of nkx2.5 function in distinct cardiomyocyte populations has yet to be elucidated. Here, we show that heat-shock induction of a novel transgenic line, Tg(hsp70l:nkx2.5-EGFP), during the initial stages of cardiomyocyte differentiation leads to rescue of chamber shape and identity in nkx2.5(-/-) embryos as chambers emerge. Intriguingly, our findings link an early role of this essential cardiac transcription factor with a later function. Moreover, these data reveal that nkx2.5 is also required in the second heart field as the heart tube forms, reflecting the temporal delay in differentiation of this population. Thus, our results support a model in which nkx genes induce downstream targets that are necessary to maintain chamber-specific identity in both early- and late differentiating cardiomyocytes at discrete stages in cardiac morphogenesis. Furthermore, we show that overexpression of nkx2.5 during the first and second heart field development not only rescues the mutant phenotype, but also is sufficient for proper function of the adult heart. Taken together, these results shed new light on the stage-dependent mechanisms that sculpt chamber-specific cardiomyocytes and, therefore, have the potential to improve in vitro generation of ventricular cells to treat myocardial infarction and congenital heart disease. PMID- 25536397 TI - Lipo-chitin oligosaccharides, plant symbiosis signalling molecules that modulate mammalian angiogenesis in vitro. AB - Lipochitin oligosaccharides (LCOs) are signaling molecules required by ecologically and agronomically important bacteria and fungi to establish symbioses with diverse land plants. In plants, oligo-chitins and LCOs can differentially interact with different lysin motif (LysM) receptors and affect innate immunity responses or symbiosis-related pathways. In animals, oligo chitins also induce innate immunity and other physiological responses but LCO recognition has not been demonstrated. Here LCO and LCO-like compounds are shown to be biologically active in mammals in a structure dependent way through the modulation of angiogenesis, a tightly-regulated process involving the induction and growth of new blood vessels from existing vessels. The testing of 24 LCO, LCO like or oligo-chitin compounds resulted in structure-dependent effects on angiogenesis in vitro leading to promotion, or inhibition or nil effects. Like plants, the mammalian LCO biological activity depended upon the presence and type of terminal substitutions. Un-substituted oligo-chitins of similar chain lengths were unable to modulate angiogenesis indicating that mammalian cells, like plant cells, can distinguish between LCOs and un-substituted oligo-chitins. The cellular mode-of-action of the biologically active LCOs in mammals was determined. The stimulation or inhibition of endothelial cell adhesion to vitronectin or fibronectin correlated with their pro- or anti-angiogenic activity. Importantly, novel and more easily synthesised LCO-like disaccharide molecules were also biologically active and de-acetylated chitobiose was shown to be the primary structural basis of recognition. Given this, simpler chitin disaccharides derivatives based on the structure of biologically active LCOs were synthesised and purified and these showed biological activity in mammalian cells. Since important chronic disease states are linked to either insufficient or excessive angiogenesis, LCO and LCO-like molecules may have the potential to be a new, carbohydrate-based class of therapeutics for modulating angiogenesis. PMID- 25536399 TI - Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration. AB - In the early mouse embryo, a specialized population of extraembryonic visceral endoderm (VE) cells called the distal VE (DVE) arises at the tip of the egg cylinder stage embryo and then asymmetrically migrates to the prospective anterior, recruiting additional distal cells. Upon migration these cells, called the anterior VE (AVE), establish the anterior posterior (AP) axis by restricting gastrulation-inducing signals to the opposite pole. The Nodal-signaling pathway has been shown to have a critical role in the generation and migration of the DVE/AVE. The Nodal gene is expressed in both the VE and in the pluripotent epiblast, which gives rise to the germ layers. Previous findings have provided conflicting evidence as to the relative importance of Nodal signaling from the epiblast vs. VE for AP patterning. Here we show that conditional mutagenesis of the Nodal gene specifically within the VE leads to reduced Nodal expression levels in the epiblast and incomplete or failed DVE/AVE migration. These results support a required role for VE Nodal to maintain normal levels of expression in the epiblast, and suggest signaling from both VE and epiblast is important for DVE/AVE migration. PMID- 25536401 TI - Transcriptional Regulation of CXCL5 in HIV-1-Infected Macrophages and Its Functional Consequences on CNS Pathology. AB - Human immunodeficiency virus-1 (HIV-1)-infected monocytes/macrophages and microglia release increased levels of proinflammatory cytokines and chemokines, including ELR+ (containing glutamic acid-leucine-arginine motif) chemokines. To investigate the role of HIV-1 infection on chemokine regulation, monocyte-derived macrophages (MDMs) from normal donors were infected with HIV-1 and the expression of chemokines and their downstream biological functions were evaluated. Among the tested chemokines, CXCL5 was upregulated significantly both at the mRNA and protein level in the HIV-1-infected MDMs compared with mock-infected cultures. Upregulation of CXCL5 in the HIV-1-infected MDMs is, in part, regulated by increased interleukin-1beta (IL-1beta) production and phosphorylation of ERK1/2. Functional analyses indicate that HIV-1-induced overexpression of CXCL5 has enhanced the ability to attract neutrophils, as observed by chemotaxis assay. However, exposure of NT2, SH-SY5Y cells, and primary neurons to HIV-1-infected MDM supernatants resulted in cell death that was not rescued by anti-CXCL5 antibody suggesting that CXCL5 does not have direct effect on neuronal death. Together, these results suggest that the increased level of CXCL5 in tissue compartments, including the central nervous system of HIV-1-infected individuals might alter the inflammatory response through the infiltration of neutrophils into tissue compartment, thus causing secondary effects on resident cells. PMID- 25536404 TI - Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self administration in rats. AB - The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6 acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy. PMID- 25536406 TI - Presumed Larsen syndrome in a child: a case with a 12-year follow-up. AB - Larsen syndrome (OMIM 150250) was first described in 1950 as an entity characterized by distinct facial features and dislocations of the multiple large joint, and cleft palate, hearing loss, and spinal abnormalities were occasionally observed. The prevalence of Larsen syndrome is estimated to be one in 100,000 live births . Management of multiple large-joint dislocations often proves difficult with a tendency toward recurrence, particularly if a patient has complete dislocation of the knee .We treated a boy with the clinical phenotype of Larsen syndrome using 10 orthopedic procedures, but failed to achieve a satisfactory outcome.The aim of this report is to review the surgical course and report results of surgical treatments for this patient with 12 years of follow up. PMID- 25536405 TI - Human papillomavirus infection in 674 Chinese patients with laryngeal squamous cell carcinoma. AB - OBJECTIVES: Previous reports suggest a strong association between human papillomavirus (HPV) and the etiology of laryngeal squamous cell carcinoma (LSCC). However, clinical data regarding the HPV infection rate among LSCC patients remain largely inconsistent. METHODS: In total, 674 LSCC patients from three major hospitals in Shanghai were enrolled in this study. We determined the patients' HPV infection status using immunohistochemistry and the GenoArray HPV genotyping assay and calculated their long-term survival rate using the Kaplan Meier method. RESULTS: The total P16-positive rate according to immunostaining results was 7.57% (51/674). None of the P16-negative patients were HPV-positive according to the HPV genotyping test. The rate of HPV infection among patients with LSCC was 4.9% (33/674). HPV infection was more common among nonsmokers (P<0.05), nondrinkers (P<0.05), and patients with supraglottic LSCC (P<0.05). Of the 33 HPV-positive patients, 28 (84.8%) were infected with HPV-16, 2 with HPV 18, 1 with HPV-31, 1 with HPV-33 and 1 with HPV-45. The 3-year overall survival rate and progression-free survival rate were higher in HPV-positive than HPV negative patients, but the difference was not statistically significant (76.3% vs. 70.7%, P = 0.30 and 65.1% vs. 58.3%, P = 0.37, respectively). CONCLUSION: HPV was not a main causal factor in LSCC carcinogenesis in this Chinese population. HPV infection did not alter patients' overall survival or progression-free survival rates in this study. PMID- 25536407 TI - Zebrafish liver (ZFL) cells are able to mount an anti-viral response after stimulation with Poly (I:C). AB - The zebrafish (Danio rerio) is a widely used model species for biomedical research and is also starting to be a model for aquaculture research. The ZFL cell line, established from zebrafish liver, has been mostly used in toxicological and ecotoxicological studies. However, no studies have previously characterised this cell line in regard to its immunological response. The aim of this work was to study the gene expression response of the ZFL cell line after incubation with different prototypical immune stimuli, such as lipopolysaccharide (LPS), peptidoglycan (PGN), zymosan, and with a special focus on the dsRNA Poly (I:C). Using PCR, microarrays, and confocal microscopy we have explored the response of the ZFL cells against Poly (I:C). This study shows that the ZFL is able to uptake very efficiently the Poly (I:C) and mount a strong anti-viral response. We can conclude that ZFL could be used not only in toxicological studies, but also in studying anti-viral responses in zebrafish. PMID- 25536408 TI - Molecular characterization and expression of three preprosomatostatin genes and their association with growth in common carp (Cyprinus carpio). AB - Somatostatins (SSs) are a structurally diverse family of peptides that play important roles in the regulation of growth, development and metabolism in vertebrates. In this study, three preprosomatostatin genes (PSSs) in the common carp, Cyprinus carpio (Cc) were identified and characterized. Based on cloned sequences and genome BLAST, six isoforms of the PSS gene in C. carpio (CcPSS) were identified and included CcPSS1a and CcPSS1b, CcPSS2a and CcPSS2b, and finally, CcPSS3a and CcPSS3b. The open reading frames (ORF) of CcPSS1a, CcPSS2a and CcPSS3a consist of 345, 336 and 363 nucleotides. During embryonic development, the expressions of CcPSS2 and CcPSS3 were first observed at the stage of optic vesicle, and CcPSS1 mRNA was initially detected at the stage of muscular effect. The highest mRNA levels of CcPSS1, CcPSS2 and CcPSS3 were observed at 1-day post-hatch (dph), 2-dph and the stage of heart beating, respectively. In the adult brain, the distributions of three CcPSS mRNAs were differential but overlapping in the hypothalamus, telencephalon and medulla oblongata. For peripheral tissues, all three CcPSS mRNAs were detected in the mid intestine, and CcPSS1 and CcPSS3 mRNAs were also expressed in the liver. Owing to the importance of somatostatins on regulating growth, functional mutations of CcPSSs were identified in a C. carpio population. A total of 23 polymorphic sites were detected in CcPSS1a and CcPSS3a. Of them, two SNPs (CcPSS1a-g.922C>T, and CcPSS3a-g.1125C>A) were significantly associated with growth traits, indicating their potential applications in gene (marker)-assisted selective breeding in C. carpio. PMID- 25536409 TI - Spectral overlap-free quantum dot-based determination of benzo[a]pyrene-induced cancer stem cells by concurrent monitoring of CD44, CD24 and aldehyde dehydrogenase 1. AB - In this study, it was found that breast cancer stem cells (CSCs) are formed from MCF-7 cells by benzo[a]pyrene (BP)-induced mutation. The breast CSCs were detected through simultaneous monitoring of CD44, CD24 and aldehyde dehydrogenase 1 (ALDH1) by hypermulticolor cellular imaging using an acousto-optical tunable filter (AOTF) and quantum dots (Q-dots). PMID- 25536410 TI - Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003-2012. AB - During 2003-2012, there was a significant increase in the percentage of adults aged 40 and over who used a prescription cholesterol-lowering medication. In 2003 2004, one in five adults reported using a prescription cholesterol-lowering medication in the past 30 days. By 2011-2012, that number had risen to one in four adults. In 2011-2012, the majority of adults using a cholesterol-lowering medication reported using a statin alone (83%). Ten percent used both a statin and a nonstatin and another 7% used only a nonstatin. Simvastatin was the most commonly used medication, with 42% of all cholesterol-lowering medication users reporting its use, followed by atorvastatin (20.2%). Use of a prescription cholesterol-lowering medication increased with age but was similar between men and women and race and Hispanic origin groups. Adults aged 40-64 who reported having health insurance or prescription medication coverage were more likely to take prescription cholesterol-lowering medications. Hypercholesterolemia or high cholesterol is one of the most common preventable risk factors for atherosclerotic CVD. In 2011-2012, more than 30 million Americans aged 20 and over (13%) had measured high total cholesterol (5). There is extensive and consistent evidence supporting the use of cholesterol-lowering medication, especially statins, in addition to lifestyle changes, to treat lipid disorders and reduce atherosclerotic CVD events. The 2013 cholesterol treatment guidelines updated recommendations for statin therapy on the basis of low-density lipid cholesterol levels and atherosclerotic CVD risks (6). Approximately 71% of adults with diagnosed CVD, 63% of those with diagnosed diabetes, and 54% of those with diagnosed hypercholesterolemia reported taking prescription cholesterol-lowering medications. PMID- 25536411 TI - Astakine LvAST binds to the beta subunit of F1-ATP synthase and likely plays a role in white shrimp Litopeneaus vannamei defense against white spot syndrome virus. AB - Cytokines play a critical role in innate and adaptive immunity. Astakines represent a group of invertebrate cytokines that are related to vertebrate prokineticin and function in promoting hematopoiesis in crustaceans. We have identified an astakine from the white shrimp Litopeneaus vannamei and named it LvAST in a previous research. In the present research, we investigated the interactions among LvAST, the envelope protein VP37 of white spot syndrome virus (i.e., WSSV), and the beta subunit of F1-ATP synthase (ATPsyn-beta) of the white shrimp (i.e., BP53) using binding assays and co-precipitations. We also examined the effects of LvAST on shrimp susceptibility to WSSV. We found that LvAST and VP37 competitively bound to BP53, but did not bind to each other. Shrimps that had been injected with recombinant LvAST exhibited significantly lower mortality and longer survival time in experimental infections by WSSV. In contrast, shrimps whose LvAST gene expression had been inhibited by RNA interference showed significantly higher WSSV infection intensity and shorter survival time following viral challenges. These results suggested that LvAST and WSSV both likely use ATPsyn-beta as a receptor and LvAST plays a role in shrimp defense against WSSV infection. This represented the first research showing the involvement of astakines in host antiviral immunity. PMID- 25536412 TI - Subsystem-DFT potential-energy curves for weakly interacting systems. AB - Kohn-Sham density-functional theory (DFT) within the local-density approximation (LDA) or the generalized-gradient approximation (GGA) is known to fail for the correct description of London dispersion interactions. Often, not even bound potential-energy surfaces are obtained for van der Waals complexes, unless special correction schemes are employed. In contrast to that, there has been some evidence for the fact that subsystem-based density functional theory produces interaction energies for weakly bound systems which are superior to Kohn-Sham DFT results without dispersion corrections. This is usually attributed to an error cancellation between the approximate exchange-correlation and non-additive kinetic-energy functionals employed in subsystem DFT. Here, we investigate the accuracy of subsystem DFT for weakly interacting systems in detail, paying special attention to the shape of the potential-energy surfaces (PESs). Our test sets include the extensive S22x5 and S66x8 data sets. Our results indicate that subsystem DFT PESs strongly vary depending on the functional. LDA results are usually quite good, but behave differently from their KS counterparts. GGA results from the popular Perdew-Wang (PW91) set of functionals produce PESs that are often, but not in general overbinding. Results from Becke-Perdew (BP86) GGAs, by contrast, show the typical problems known from the corresponding KS results. We provide some preliminary results for empirical corrections for both PW91 and BP86 in subsystem DFT. PMID- 25536416 TI - Predictors of immunological failure of antiretroviral therapy among HIV infected patients in Ethiopia: a matched case-control study. AB - BACKGROUND: In resource constrained settings, immunological assessment through CD4 count is used to assess response to first line Highly Active Antiretroviral Therapy (HAART). In this study, we aim to investigate factors associated with immunological treatment failure. METHODS: A matched case-control study design was used. Cases were subjects who already experienced immunological treatment failure and controls were those without immunological failure after an exactly or approximately equivalent duration of first line treatment with cases. Data were analyzed using SPSS v16.0. Conditional logistic regression was carried out. RESULTS: A total of 134 cases and 134 controls were included in the study. At baseline, the mean age +/- 1 SD of cases was 37.5 +/- 9.7 years whereas it was 36.9 +/- 9.2 years among controls. The median baseline CD4 counts of cases and controls were 121.0 cells/ul (IQR: 47-183 cells/ul) and 122.0 cells/ul (IQR: 80.0 189.8 cells/ul), respectively. The median rate of CD4 cells increase was comparable for the two groups in the first six months of commencing HAART (P = 0.442). However, the median rate of CD4 increase was significantly different for the two groups in the next 6 months period (M6 to M12). The rate of increment was 8.8 (IQR: 0.5, 14.6) and 1.8 (IQR: 8.8, 11.3) cells/ul/month for controls and cases, respectively (Mann-Whitney U test, P = 0.003). In conditional logistic regressions grouped baseline CD4 count (P = 0.028), old age group and higher educational status (P<0.001) were significant predictors of immunological treatment failure. CONCLUSION: Subjects with immunological treatment failure have an optimal rate of immunological recovery in the first 6 months of treatment with first line HAART, but relative to the non-failing group the rate declines at a later period, notably between 6 and 12 months. Low baseline CD4 count, old age and higher educational status were associated with immunological treatment failure. PMID- 25536417 TI - Biosynthesis and analysis of plant oxylipins. AB - The term oxylipin is applied to the generation of oxygenated products of polyunsaturated fatty acids that can arise either through non-enzymatic or enzymatic processes generating a complex array of products, including alcohols, aldehydes, ketones, acids and hydrocarbon gases. The biosynthetic origin of these products has revealed an array of enzymes involved in their formation and more recently a radical pathway. These include lipoxygenases and alpha-dioxygenase that insert both oxygen atoms in to the acyl chain to initiate the pathways, to specialised P450 monooxygenases that are responsible for their downstream processing. This latter group include enzymes at the branch points such as allene oxide synthase, leading to jasmonate signalling, hydroperoxide lyase, responsible for generating pathogen/pest defensive volatiles and divinyl ether synthases and peroxygenases involved in the formation of antimicrobial compounds. The complexity of the products generated raises significant challenges for their rapid identification and quantification using metabolic screening methods. Here the current developments in oxylipin metabolism are reviewed together with the emerging technologies required to expand this important field of research that underpins advances in plant-pest/pathogen interactions. PMID- 25536418 TI - Detection of the halogenating activity of heme peroxidases in leukocytes by aminophenyl fluorescein. AB - The formation of hypochlorous and hypobromous acids by heme peroxidases is a key property of certain immune cells. These products are not only involved in defense against pathogenic microorganisms and in regulation of inflammatory processes, but contribute also to tissue damage in certain pathologies. After a short introduction about experimental approaches for the assessment of the halogenating activity in vitro and in cell suspensions, we are focusing on novel applications of fluorescent dye systems to detect the formation of hypochlorous acid (HOCl) in leukocytes. Special attention is directed to properties and applications of the non-fluorescent dye aminophenyl fluorescein that is converted by HOCl, HOBr, and other strong oxidants to fluorescein. This dye allows the detection of the halogenating activity in samples containing free myeloperoxidase and eosinophil peroxidase as well as in intact granulocytes using fluorescence spectroscopy and flow cytometry, respectively. PMID- 25536419 TI - Analytical methods for (oxidized) plasmalogens: Methodological aspects and applications. AB - Plasmalogens are a unique class of glycerophospholipids (GPLs) containing a fatty alcohol linked by a vinyl-ether moiety at the sn-1 position of the glycerol backbone. There is normally a polyunsaturated fatty acyl residue at the sn-2 position. These two features provide interesting properties to the plasmalogen GPL. Their physiological roles have been challenging to elucidate, although plasmalogens represent up to 20% of the total membrane GPLs in humans. Recent studies have revealed plasmalogen deficiencies associated with several human disorders; therefore, plasmalogens are likely to be specific to different tissues, metabolic processes, and developmental stages. The first chapter of this review will discuss the molecular structure and chemistry of plasmalogens, their biological roles, and their distributions in cells and tissues in different species. In the second chapter, currently used methods of analyzing plasmalogens and their degradation products are described. Although chromatographic methods will be also discussed, special attention will be given to ((31)P) nuclear magnetic resonance spectroscopy and soft ionization mass spectrometry (MS) techniques such as electrospray ionization and matrix-assisted laser desorption and ionization time-of-flight MS. Finally, in the third chapter of this review selected human diseases and disorders, which are presumably characterized by changes in plasmalogen contents and compositions, are described and the analytical methods used are discussed. PMID- 25536422 TI - The brain, the coronary arteries, and the Kounis syndrome. PMID- 25536421 TI - Interfacial polymerization for colorimetric labeling of protein expression in cells. AB - Determining the location of rare proteins in cells typically requires the use of on-sample amplification. Antibody based recognition and enzymatic amplification is used to produce large amounts of visible label at the site of protein expression, but these techniques suffer from the presence of nonspecific reactivity in the biological sample and from poor spatial control over the label. Polymerization based amplification is a recently developed alternative means of creating an on-sample amplification for fluorescence applications, while not suffering from endogenous labels or loss of signal localization. This manuscript builds upon polymerization based amplification by developing a stable, archivable, and colorimetric mode of amplification termed Polymer Dye Labeling. The basic concept involves an interfacial polymer grown at the site of protein expression and subsequent staining of this polymer with an appropriate dye. The dyes Evans Blue and eosin were initially investigated for colorimetric response in a microarray setting, where both specifically stained polymer films on glass. The process was translated to the staining of protein expression in human dermal fibroblast cells, and Polymer Dye Labeling was specific to regions consistent with desired protein expression. The labeling is stable for over 200 days in ambient conditions and is also compatible with modern mounting medium. PMID- 25536420 TI - Curcumin ameliorates streptozotocin-induced liver damage through modulation of endoplasmic reticulum stress-mediated apoptosis in diabetic rats. AB - We investigated the effect of curcumin on liver injury in diabetic rats induced by streptozotocin (STZ) through modulation of endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). Experimental diabetes was induced by a single intraperitoneal injection of STZ (55 mg/kg), and curcumin was given at 100 mg/kg by gavage for 56 days. We observed that curcumin improved the morphological and histopathological changes, significantly decreased hepatic ERS marker protein: glucose-regulated protein 78, and improved liver function in diabetic rats. Moreover, treatment with curcumin markedly decreased the sub-arm of the UPR signaling protein such as phospho-double-stranded RNA-dependent protein kinase like ER kinase, CCAAT/enhancer-binding protein homologous protein, tumor necrosis factor receptor-associated factor 2, and inositol-requiring enzyme1alpha; and inhibited tumor necrosis factor alpha, interleukin 1beta, phospho-p38 mitogen activated protein kinase, and apoptosis signal-regulating kinase 1 in liver tissues of diabetic rats. Apoptotic and anti-apoptotic signaling proteins, such as cleaved caspase-3 and B-cell lymphoma 2, were significantly increased and decreased, respectively in diabetic rats; curcumin treatment prevented all of these alterations. In summary, our results indicate that curcumin has the potential to protect the diabetic liver by modulating hepatic ERS-mediated apoptosis, and provides a novel therapeutic strategy for the diabetic liver damage. PMID- 25536423 TI - Neural-Event-Triggered fMRI of large-scale neural networks. AB - Brains are dynamic systems, consisting of huge number of massively interconnected elementary components. The activity of these components results in an initial condition-sensitive evolution of network states through highly non-linear, probabilistic interactions. The dynamics of such systems cannot be described merely by studying the behavior of their components; instead their study benefits from employing multimodal methods. Neural-Event-Triggered (NET) fMRI is a novel method allowing identification of events that can be used to examine multi structure activity in the brain. First results offered insights into the networks that might be involved in memory consolidation. On-going work examines the physiological underpinnings of the up and down modulation of metabolic activity, mapped with this methodology. PMID- 25536425 TI - Thoracoscopic plication for diaphragmatic eventration after surgery for congenital heart disease in children. AB - OBJECTIVE: The aim of this study was to clarify the role of thoracoscopic plication for diaphragmatic eventration after surgery for congenital heart disease (CHD) in children. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of pediatric patients who had undergone thoracoscopic plication of diaphragmatic eventration after surgery for CHD between 2008 and 2013 at our department. RESULTS: Five patients were identified during the study period. The median age and body weight of the patients were 7.6 months and 6.6 kg, respectively. The associated CHDs were pulmonary artery atresia in 3 patients, truncus arteriosus in 1 patient, and double-outlet right ventricle in 1 patient. Four patients needed preoperative mechanical respiratory support. At operation, all the patients received CO2 insufflation (4 mm Hg), and single-lung ventilation was attempted in 3 patients using a bronchial blocker. A sufficient operative field was maintained by CO2 insufflation in all the patients regardless of single lung ventilation. The procedure was not converted to open operation in any patient. Postoperative extubation was performed in the operating room in 1 patient, on the day of operation in 2 patients, and on postoperative Days 1 and 2 in 2 patients. Air embolism was not observed in any of the patients. Diaphragmatic eventration did not recur in any of the patients after thoracoscopic plication. CONCLUSIONS: Thoracoscopic plication is a safe and effective procedure for pediatric diaphragmatic eventration after surgery for CHD. Considering the sufficient operative field maintained by CO2 insufflation, single-lung ventilation using a bronchial blocker would be unnecessary for this procedure. With its safety and good outcome, early thoracoscopic plication is a good treatment option for pediatric patients with symptomatic diaphragmatic eventration after surgery for CHD. PMID- 25536426 TI - [Ebola virus disease, an overview of the problem]. PMID- 25536424 TI - Acute simulated soccer-specific training increases PGC-1alpha mRNA expression in human skeletal muscle. AB - The aim of the current study was to quantify oxygen uptake, heart rate and molecular responses of human skeletal muscle associated with mitochondrial biogenesis following an acute bout of simulated soccer training. Muscle biopsies (vastus lateralis) were obtained from nine active men immediately pre-completion, post-completion and 3 h post-completion of a laboratory-based soccer-specific training simulation on a motorised treadmill. The soccer-specific simulation was a similar intensity (55 +/- 6% [Formula: see text]) and duration (60 min) as that observed in professional soccer training (e.g. standing 41%, walking 37%, jogging 11%, high-speed running 9% and sprinting 2%). Post-exercise, muscle glycogen decreased (Pre; 397 +/- 86 mmol?kg(-1) dw, Post; 344 +/- 64 mmol?kg(-1) dw; P = 0.03), plasma lactate increased (P < 0.001) up to ~4-5 mmol?L(-1), non-esterified fatty acids and glycerol increased (P < 0.001) to values of 0.6 +/- 0.2 mmol?L( 1) and 145 +/- 54 MUmol?L(-1), respectively. PGC-1alpha mRNA increased (P = 0.009) fivefold 3 h post-exercise. We provide novel data by demonstrating that soccer-specific training is associated with increases in PGC-1alpha mRNA. These data may have implications for practitioners in better understanding the metabolic and muscle responses to soccer-specific training protocols in the field. PMID- 25536427 TI - [Characterization of gene expression associated with both the AcrAB/TolC system and the membrane permeability, in Salmonella spp isolates with and without gyrA mutation]. AB - Introduction. The marA, soxS, ramA, acrB and ompF genes have been studied in order to characterize mechanisms of AcrAB-TolC active efflux pumps and membrane permeability alterations that reduce fluoroquinolones susceptibility in Salmonella spp. Methods. Mutations in marA, soxS, ramA, acrB and ompF genes were detected, as well as their expression levels in presence and absence of ciprofloxacin, calculating the level of change between them by qPCR. Data were analysed by using SPSS 19.0. Results. No mutations in these genes were found, but both AcrAB-TolC regulatory genes and structural acrB gene expression were affected by ciprofloxacin in both mutant strains and wild type bacterial strains (WT). The activation of the marA gene in presence of drug was higher in WT strains (level of change 0.823) than in mutants strains (level of change 0.158; p=0.049). In gyrA mutants, a reduction in ompF gene expression in presence of ciprofloxacin was found (level of change -0.949 p=0.017). Conclusion. The reduction of fluoroquinolones susceptibility in Salmonella spp is a complex process, in which several different bacterial mechanisms are involved. This study has found a high difference in the degree of participation among studied mechanisms, between bacterial strains with and without gyrA mutation. Whereas WT strains activated efflux pumps especially through marA gene, mutants supressed ompF gene expression related to porins. PMID- 25536428 TI - [Prospective follow-up of results of tuberculosis treatment]. AB - Objective. The aim of the study was to analyze tuberculosis treatment outcomes in a health area of the National Health System. Material and Methods. Analytical cohort study of tuberculosis' cases treated in the hospital care of the health area of Salamanca (Spain) 6 months. The clinical record constituted the basic source of data, whose information was complemented by a clinical interview to the patient. The microbiological records were additionally used for classifying the therapeutic outcomes in satisfactory outcome (SO), potentially unsatisfactory outcome (PUO) and death. A total of 146 patients met the inclusion criteria; 108 patients were interviewed. Their average age was 49 years. Out of them, 29.6% (32/108) showed some social risk factor (SRF). Results. The SO level was 55.6% (IC 95%: 55.6+/-9); the variables associated with the SO were young elderly patients, living in family and patterns of 6 months. The PUO proportion stood at 40.7% (IC 95%: 40.7+/-9); the variables which increased the PUO probability were adulthood, residing in other provinces, living alone, comorbidity, human immunodeficiency virus (HIV), alcoholism and social maladjustment. The variables included in the final model for PUO in logistic regression were adult, comorbidity and SFR, while the institutional conditions associated the mortality. Conclusions. The SO rates can be improved. The PUO level is conditioned by high loss rates, 31.5% (95% CI: 31.5 +/- 9), so measures should be established for reduction and improve the effectiveness of the overall treatment. PMID- 25536430 TI - [Trend in the susceptibility of the most frequent bacterial pathogens isolated at Hospital General La Mancha Centro over 2010-2012 period]. AB - Introduction. Our objective was to determine the trend of the antimicrobial susceptibility of the most common bacterial pathogens isolated in La Mancha Centro Hospital (MCH) between 2010-2012. Material and methods. Isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa from patients admitted to MCH were studied. These data and their antibiotic susceptibility were obtained from the database OBSERVA (BioMerieux). Results. The percentages of susceptibility for S. aureus were: 50% methicillin resistant-S. aureus (MRSA) (higher co-resistance to erythromycin and levofloxacin), 46% erythromycin, 73% clindamycin, 45% levofloxacin, 99% rifampin and 100% cotrimoxazole, glycopeptides, linezolid and daptomycin. Increased resistance in ICU was observed (63% MRSA), with 50% of S. aureus (susceptible and methicillin-resistant strains) with vancomycin MIC values >= 0.5 mg/L. E. coli susceptibility: 62% amoxicillin-clavulanate, 55% ciprofloxacin, 60% cotrimoxazole, 84% gentamicin and 95% fosfomycin. K. pneumoniae susceptibility: 74% amoxicillin-clavulanate, 71% ciprofloxacin, 78% cotrimoxazole, 94% gentamicin and 87% fosfomycin. The percentage of BLEE strains was 17% and 21% for E. coli and K. pneumoniae, respectively, without detection of resistance to carbapenems. P. aeruginosa susceptibility: 80% ceftazidime and carbapenems, 63% ciprofloxacin and higher than 90% aminoglycosides. A decreasing trend of susceptibility to ceftazidime and carbapenems was observed in ICU and increasing trend to ciprofloxacin. Conclusions. Resistance percentages were higher in ICU than in the rest of the hospital, highlighting 63% of MRSA strains. Our percentage of BLEE and MRSA strains were higher than the Spanish media. Rifampicin and cotrimoxazole maintain good susceptibility to S. aureus, fosfomycin and aminoglycosides to Enterobacteriaceae and carbapenems to P. aeruginosa. PMID- 25536429 TI - [Empirical antimicrobial therapy in ICU admitted patients. Influence of microbiological confirmation on the length of treatment]. AB - Introduction. Most patients admitted to the Intensive Care Units (ICU) receive antimicrobial treatment. A proper therapeutic strategy may be useful in decreasing inappropriate empirical antibiotic treatments. When the infection is not microbiologically confirmed, the antimicrobial streamlining may be difficult. Nevertheless, there is scant information about the influence of the microbiological confirmation of the infections on empirical antimicrobial treatment duration. Method. Post-hoc analysis of prospective data (ENVIN-UCI register) and observational study of patients admitted (> 24 hours) in a medico surgical ICU, through the three-months annual surveillance interval for a period of ten years, receiving antimicrobial treatment for treating an infection. Demographic, infection and microbiological data were collected as well as empirical antimicrobial treatment and causes of adaptation. The main goal was to establish the influence of microbiological confirmation on empirical antimicrobial treatment duration. Results. During the study period 1,526 patients were included, 1,260 infections were diagnosed and an empirical antibiotic treatment was started in 1,754 cases. Infections were microbiologically confirmed in 1,073 (62.2%) of the empirical antibiotic treatment. In 593 (55.3%) cases, the antimicrobial treatment was considered appropriate. The main cause of treatment adaptation in the microbiologically confirmed infections was streamlining (39%). The microbiological confirmation of the infection was not associated with significantly shorter empirical antibiotic treatments (6.6 +/- 5.2 VS. 6.8 +/- 4.5 days). Conclusion. The microbiological confirmation of infections in patients admitted to UCI was associated with a higher reduction of antimicrobial spectrum, although had no effect on the length of empirical antimicrobial therapy. PMID- 25536431 TI - [Isolation of Pasteurella dagmatis after a tiger bite]. PMID- 25536432 TI - [Microbiological study of vulvovaginitis in prepubertal girls]. PMID- 25536433 TI - [Primary peritonitis due to Streptococcus pyogenes]. PMID- 25536434 TI - [Evaluation E-test method to determine the antimicrobial activity of ceftaroline against methicillin-resistant strains of Staphylococcus aureus]. PMID- 25536436 TI - Wide Bandpass and Narrow Bandstop Microstrip Filters based on Hilbert fractal geometry: design and simulation results. AB - This paper presents new Wide Bandpass Filter (WBPF) and Narrow Bandstop Filter (NBSF) incorporating two microstrip resonators, each resonator is based on 2nd iteration of Hilbert fractal geometry. The type of filter as pass or reject band has been adjusted by coupling gap parameter (d) between Hilbert resonators using a substrate with a dielectric constant of 10.8 and a thickness of 1.27 mm. Numerical simulation results as well as a parametric study of d parameter on filter type and frequency responses are presented and studied. WBPF has designed at resonant frequencies of 2 and 2.2 GHz with a bandwidth of 0.52 GHz, -28 dB return loss and -0.125 dB insertion loss while NBSF has designed for electrical specifications of 2.37 GHz center frequency, 20 MHz rejection bandwidth, -0.1873 dB return loss and 13.746 dB insertion loss. The proposed technique offers a new alternative to construct low-cost high-performance filter devices, suitable for a wide range of wireless communication systems. PMID- 25536435 TI - Synchrotron X-ray diffraction to detect glass or ice formation in the vitrified bovine cumulus-oocyte complexes and morulae. AB - Vitrification of bovine cumulus-oocyte complexes (COCs) is not as successful as bovine embryos, due to oocyte's complex structure and chilling sensitivity. Synchrotron X-ray diffraction (SXRD), a powerful method to study crystal structure and phase changes, was used to detect the glass or ice formation in water, tissue culture medium (TCM)-199, vitrification solution 2 (VS2), and vitrified bovine COCs and morulae. Data revealed Debye's rings and peaks associated with the hexagonal ice crystals at 3.897, 3.635, 3.427, 2.610, 2.241, 1.912 and 1.878 A in both water and TCM-199, whereas VS2 showed amorphous (glassy) appearance, at 102K (-171 degrees C). An additional peak of sodium phosphate monobasic hydrate (NaH2PO4.H2O) crystals was observed at 2.064 A in TCM 199 only. All ice and NaH2PO4.H2O peaks were detected in the non-vitrified (control) and vitrified COCs, except two ice peaks (3.145 and 2.655 A) were absent in the vitrified COCs. The intensities of majority of ice peaks did not differ between the non-vitrified and vitrified COCs. The non-vitrified bovine morulae in TCM-199 demonstrated all ice- and NaH2PO4.H2O-associated Debye's rings and peaks, found in TCM-199 alone. There was no Debye's ring present in the vitrified morulae. In conclusion, SXRD is a powerful method to confirm the vitrifiability of a solution and to detect the glass or ice formation in vitrified cells and tissues. The vitrified bovine COCs exhibited the hexagonal ice crystals instead of glass formation whereas the bovine morulae underwent a typical vitrification. PMID- 25536438 TI - All-on-4(r) Treatment Concept for the Rehabilitation of the Completely Edentulous Mandible: A 7-Year Clinical and 5-Year Radiographic Retrospective Case Series with Risk Assessment for Implant Failure and Marginal Bone Level. AB - BACKGROUND: Studies are needed to evaluate long-term outcomes of the All-on-4(r) treatment concept (Nobel Biocare AB) for rehabilitation of edentulous mandibles by assessing marginal bone levels and risk indicators for implant failure. PURPOSE: To evaluate 7-year clinical outcomes and 5-year radiographic outcomes of the All-on-4 treatment concept. MATERIALS AND METHODS: This retrospective case series included patients admitted for implant rehabilitations in the mandible, who were followed for 7 years clinically and 5 years radiographically. Primary outcome measures were cumulative prosthetic and implant survival using patient as the unit of analysis (Kaplan-Meier product limit estimator). Secondary outcome measure was marginal bone level (MBL) at 5 years. Variables associated with implant failure were analyzed using the Cox proportional hazards regression model to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Binary logistic regression was used to compute odds ratio (OR) with 95% CIs for variables associated with MBL >=2.8 mm at 5 years. RESULTS: A total of 324 patients (194 women, 130 men, average age = 58.9 years) were rehabilitated with 1,296 implants supporting 324 full-arch fixed immediately loaded mandibular prostheses. Sixty-four patients (19.8%) were lost to follow-up. Prosthetic survival was 323/324 (99.7%), and 14 patients lost 18 implants, with an estimated cumulative survival rate of 95.4% at 7 years. Variables associated with implant failure were smoking (HR = 5.28; 95% CI: 1.33, 20.91]) and the learning curve effect (0.69 < HR < 0.33 for more experienced levels). Mean MBL at 5 years was 1.81 mm (95% CI: 1.70, 1.92), and smoking was associated with MBL >=2.8 mm (OR = 2.4; 95% CI: 1.02, 5.62). CONCLUSIONS: The high implant and prosthetic survival rates and excellent MBL outcome confirm the predictability and safety of the All on-4 treatment concept over a longer term than previously reported. PMID- 25536437 TI - RFC-1 80G>A polymorphism in case-mother/control-mother dyads is associated with risk of nephroblastoma and neuroblastoma. AB - AIM: Embryonic tumors are associated with an interruption during normal organ development; they may be related to disturbances in the folate pathway involved in DNA synthesis, methylation, and repair. Prenatal supplementation with folic acid is associated with a decreased risk of neuroblastoma, brain tumors, retinoblastoma, and nephroblastoma. The aim of this study was to investigate the association between MTHFR rs1801133 (C677T) and RFC-1 rs1051266 (G80A) genotypes with the risk of developing nephroblastoma and neuroblastoma. MATERIALS AND METHODS: Case-mother/control-mother dyad study. Samples from Brazilian children with nephroblastoma (n=80), neuroblastoma (n=66), healthy controls (n=453), and their mothers (case n=93; control n=75) were analyzed. Genomic DNA was isolated from peripheral blood cells and/or buccal cells and genotyped to identify MTHFR C677T and RFC-1 G80A polymorphisms. Differences in genotype distribution between patients and controls were tested by multiple logistic regression analysis. RESULTS: Risk for nephroblastoma and neuroblastoma was two- to fourfold increased among children with RFC-1 polymorphisms. An increased four- to eightfold risk for neuroblastoma and nephroblastoma was seen when the child and maternal genotypes were combined. CONCLUSION: Our results suggest that mother and child RFC-1 G80A genotypes play a role on the risk of neuroblastoma and nephroblastoma since this polymorphism may impair the intracellular levels of folate, through carrying fewer folate molecules to the cell interior, and thus, the intracellular concentration is not enough to maintain regular DNA synthesis and methylation pathways. PMID- 25536439 TI - Electric field-directed growth and photoelectrochemical properties of cross linked Au-ZnO hetero-nanowire arrays. AB - We demonstrate a simple and effective strategy for vertically growing Au nanowires over ZnO nanowire arrays to construct a cross-linked hierarchical architecture under the synergistic effects of the electric field direction and photoreduction, which exhibit excellent photoelectrochemical performances under visible light irradiation. PMID- 25536440 TI - Spatiotemporal Gait Patterns During Overt and Covert Evaluation in Patients With Parkinson's Disease and Healthy Subjects: Is There a Hawthorne Effect? AB - Parkinson's disease (PD) and aging lead to gait impairments. Some of the disturbances of gait are focused on step length, cadence, and temporal variability of gait cycle. Under experimental conditions gait can be overtly evaluated, but patients with PD are prone to expectancy effects; thus it seems relevant to determine if such evaluation truly reflects the spontaneous gait pattern in such patients, and also in healthy subjects. Thirty subjects (15 subjects with PD and 15 healthy control subjects) were asked to walk using their natural, preferred gait pattern. In half of the trials subjects were made aware that they were being evaluated (overt evaluation), while in the rest of the trials the evaluation was performed covertly (covert evaluation). During covert evaluation the gait pattern was modified in all groups. Gait speed was significantly increased (P = .022); step cadence and average step length were also significantly modified, the average step length increased (P = .002) and the cadence was reduced (P <= .001). Stride cycle time variability was unchanged significantly (P = .084). These changes were not significantly different compared between elderly and young healthy controls either. Due to the small sample size, a note of caution is in order; however, the significant results suggest that covert evaluation of gait might be considered to complement experimental evaluations of gait. PMID- 25536441 TI - The CRISPR/Cas9 system for plant genome editing and beyond. AB - Targeted genome editing using artificial nucleases has the potential to accelerate basic research as well as plant breeding by providing the means to modify genomes rapidly in a precise and predictable manner. Here we describe the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 (Cas9) system, a recently developed tool for the introduction of site-specific double-stranded DNA breaks. We highlight the strengths and weaknesses of this technology compared with two well-established genome editing platforms: zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). We summarize recent results obtained in plants using CRISPR/Cas9 technology, discuss possible applications in plant breeding and consider potential future developments. PMID- 25536442 TI - Evaluation of shoulder pathology: three-dimensional enhanced T1 high-resolution isotropic volume excitation MR vs two-dimensional fast spin echo T2 fat saturation MR. AB - OBJECTIVE: To evaluate the diagnostic accuracy of three-dimensional (3D) enhanced T1 high-resolution isotropic volume excitation (eTHRIVE) shoulder MR for the detection of rotator cuff tears, labral lesions and calcific tendonitis of the rotator cuff in comparison with two-dimensional (2D) fast spin echo T2 fat saturation (FS) MR. METHODS: This retrospective study included 73 patients who underwent shoulder MRI using the eTHRIVE technique. Shoulder MR images were interpreted separately by two radiologists. They evaluated anatomic identification and image quality of the shoulder joint on routine MRI sequences (axial and oblique coronal T2 FS images) and compared them with the reformatted eTHRIVE images. The images were scored on a four-point scale (0, poor; 1, questionable; 2, adequate; 3, excellent) according to the degree of homogeneous and sufficient fat saturation to penetrate bone and soft tissue, visualization of the glenoid labrum and distinction of the supraspinatus tendon (SST). The diagnostic accuracy of eTHRIVE images compared with routine MRI sequences was evaluated in the setting of rotator cuff tears, glenoid labral injuries and calcific tendonitis of the SST. RESULTS: Fat saturation scores for eTHRIVE were significantly higher than those of the T2 FS for both radiologists. The sensitivity and accuracy of the T2 FS in diagnosing rotor cuff tears were >90%, whereas sensitivity and accuracy of the eTHRIVE method were significantly lower. The sensitivity, specificity and accuracy of both images in diagnosing labral injuries and calcific tendonitis were similar and showed no significant differences. The specificity of both images for the diagnosis of labral injuries and calcific tendonitis was higher than the sensitivities. CONCLUSION: The accuracy of 3D eTHRIVE imaging was comparable to that of 2D FSE T2 FS for the diagnosis of glenoid labral injury and calcific tendonitis of SST. The 3D eTHRIVE technique was superior to 2D FSE T2 FS in terms of fat saturation. Overall, 3D eTHRIVE was inferior to T2 FS in the evaluation of rotator cuff tears because of poor contrast between joint fluid and tendons. ADVANCES IN KNOWLEDGE: The accuracy of 3D eTHRIVE imaging is comparable to that of 2D FSE T2 FS for the diagnosis of glenoid labral injury and calcific tendonitis of SST. PMID- 25536443 TI - Using breast radiographers' reports as a second opinion for radiologists' readings of microcalcifications in digital mammography. AB - OBJECTIVE: The aim of this study was to investigate a practical method for incorporating radiographers' reports with radiologists' readings of digital mammograms. METHODS: This simulation study was conducted using data from a free response receiver operating characteristic observer study obtained with 75 cases (25 malignant, 25 benign and 25 normal cases) of digital mammograms. Each of the rating scores obtained by six breast radiographers was utilized as a second opinion for four radiologists' readings with the radiographers' reports. A logical "OR" operation with various criteria settings was simulated for deciding an appropriate method to select a radiographer's report in all combinations of radiologists and radiographers. The average figure of merit (FOM) of the radiologists' performances was statistically analysed using a jackknife procedure (JAFROC) to verify the clinical utility of using radiographers' reports. RESULTS: Potential improvement of the average FOM of the radiologists' performances for identifying malignant microcalcifications could be expected when using radiographers' reports as a second opinion. When the threshold value of 2.6 in Breast Imaging-Reporting and Data System (BI-RADS(r)) assessment was applied to adopt/reject a radiographer's report, FOMs of radiologists' performances were further improved. CONCLUSION: When using breast radiographers' reports as a second opinion, radiologists' performances potentially improved when reading digital mammograms. It could be anticipated that radiologists' performances were improved further by setting a threshold value on the BI-RADS assessment provided by the radiographers. ADVANCES IN KNOWLEDGE: For the effective use of a radiographer's report as a second opinion, radiographers' rating scores and its criteria setting for adoption/rejection would be necessary. PMID- 25536444 TI - Effect of secondary particles on image quality of dynamic flat panels in carbon ion scanning beam treatment. AB - OBJECTIVE: Real-time markerless tumour tracking using radiographic fluoroscopic imaging is one of the better solutions to improving respiratory-gated radiotherapy. However, particle beams cause secondary particles from patients, which could affect radiographs. Here, we evaluated the quality of radiographs during carbon ion pencil beam scanning (CPBS) irradiation for respiratory gating. METHODS: A water phantom and chest phantom were used. The phantoms were irradiated with CPBS at 290 MeV n(-1) from orthogonal directions. Dose rates were 3.4 * 10(8), 1.14 * 10(8) and 3.79 * 10(7) particles per second. A dynamic flat panel detector (DFPD) was installed on the upstream (DFPD1) or downstream (DFPD2) side of the vertical irradiation port. DFPD images were acquired during CPBS at 15.00, 7.50 and 3.75 frames per second (fps). Charge on the DFPD was cleaned using fast readout technique every 30 fps. DFPD images were acquired during CPBS with radiographic exposure, and results with and without fast readout technique were compared. RESULTS: Secondary particles were visualized as spots or streak like shapes. Capture of secondary particles from the horizontal beam direction was lower with fast readout technique than without it. With regard to beam irradiation direction dependency, CPBS from the horizontal direction resulted in a greater magnitude of secondary particles reaching DFPD2 than reaching DFPD1. When CPBS was delivered from the vertical direction, however, the magnitude of secondary particles on both DFPDs was very similar. CONCLUSION: Fast readout technique minimized the effect of secondary particles on DFPD images during CPBS. ADVANCES IN KNOWLEDGE: This technique may be useful for markerless tumour tracking for respiratory gating. PMID- 25536445 TI - Enrichment of ACE inhibitory peptides in navy bean (Phaseolus vulgaris) using lactic acid bacteria. AB - The present study was conducted to explore a novel strategy to enhance angiotensin I-converting enzyme (ACE) inhibitory activities of navy bean by preparation of navy bean milk (NBM) which was then subjected to fermentation of four lactic acid bacteria (LAB) strains, namely, Lactobacillus bulgaricus, Lactobacillus helveticus MB2-1, Lactobacillus plantarum B1-6, and Lactobacillus plantarum 70810. With the exception of L. helveticus MB2-1, the other three selected strains had good growth performances in NBM with viable counts increased to log 8.30-8.39 cfu ml(-1) during 6 h of fermentation, and thus were selected for the following investigations. Protein contents of NBM significantly reduced when treated with L. bulgaricus and L. plantarum B1-6, and the electrophoresis patterns showed the preferable proteins for LAB strains to hydrolyze were alpha- and beta-type phaseolins, whereas gamma-type phaseolin was resistant to hydrolysis. RP-HPLC analysis demonstrated all fermented NBM had higher intensities of peaks with retention times between 2.5 and 3.5 min indicative of formation of small peptides. All fermented NBM showed higher ACE inhibitory activity compared to the unfermented ones, for which 2 h, 3 h, and 5 h were found to be the optimum fermentation periods for respectively L. plantarum 70810, L. plantarum B1-6 and L. bulgaricus, with IC50 values of 109 +/- 5.1, 108 +/- 1.1, and 101 +/- 2.2 MUg protein ml(-1). The subsequent in vitro gastrointestinal simulation afforded all fermented extracts reduced IC50 values and the extracts fermented by L. plantarum B1-6 exerted the lowest IC50 value of 21 +/- 2.1 MUg protein ml(-1). The research has broadened our knowledge bases on the effect of LAB fermentation on the degradation of navy bean proteins and the capacity to release ACE inhibitory peptides. The approach was promising to obtain probiotic products with potential to serve as functional ingredients targeting hypertension. PMID- 25536446 TI - Pregnancy exposure to olanzapine, quetiapine, risperidone, aripiprazole and risk of congenital malformations. A systematic review. AB - To review available data on first-trimester exposure to olanzapine, quetiapine, risperidone and aripiprazole and risk of congenital malformations. We performed a systematic literature search in accordance with PRISMA guidelines identifying studies containing original data on first-trimester exposure and pregnancy outcome with respect to congenital malformations. Cumulated data for olanzapine were 1090 first-trimester-exposed pregnancies with 38 malformations resulting in a malformation rate of 3.5%. The corresponding numbers for quetiapine, risperidone and aripiprazole were 443/16 (3.6%), 432/22 (5.1%) and 100/5 (5.0%), respectively. Relative risk estimates and 95% confidence intervals were 1.0 (0.7 1.4) (olanzapine), 1.0 (0.6-1.7) (quetiapine), 1.5 (0.9-2.2) (risperidone) and 1.4 (0.5-3.1) (aripiprazole). First-trimester exposure to olanzapine is not associated with an increased risk of congenital malformation. Data for quetiapine and risperidone do not suggest a substantially increased risk, while the risk estimate for aripiprazole remains imprecise owing to a low amount of data. PMID- 25536447 TI - Tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) upregulates p27 to decrease gastic cancer cell proliferation. AB - The pathogenesis of gastric cancer is not completely understood. Tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) has recently been identified as a novel negative regulator gene of the immune system, and studies in mice and humans have suggested its inhibitory action in both inflammation and cancer. In this study, we examined the expression levels of TIPE2 in human gastric cancer tissues and also samples of paraneoplastic control tissue, and found that TIPE2 expression was reduced in gastric cancer. To investigate the role of TIPE2 in gastric cell carcinogenesis, a TIPE2 plasmid was introduced into gastric cell lines and TIPE2 function was examined. Colony-forming assays showed that restoration of TIPE2 expression in gastric cells significantly suppressed cell proliferation. Analysis by flow cytometry showed that the number of cells in the S phase of the cell cycle was reduced concomitant with TIPE2 expression, and cell apoptosis was maintained at a low level. Microarray and western blot analyses revealed that TIPE2 selectively up-regulated N-ras and p27 expression. The role of p27 in mediating TIPE2-associated cell growth inhibition was verified by a p27 siRNA interference assay. In this study, we proved that TIPE2 is an inhibitor of gastric cancer cell growth, and suggest that TIPE2 might promote a p27-associated signaling cascade that leads to restored control of the cell cycle and cell division. Our results provide a new molecular mechanism by which TIPE2 may regulate proliferation of gastric cells. PMID- 25536449 TI - Subclinical hypothyroidism: summary of evidence in 2014. AB - Subclinical hypothyroidism, which is defined as elevated thyroid-stimulating hormone (TSH) levels with free thyroxine concentrations within the reference range, is a common disorder that increases with age and affects up to 18% of the elderly, with a higher prevalence in women compared to men. Prospective data have shown an increased risk of coronary heart disease events, heart failure, and cardiovascular mortality among affected adults. Conflicting results have been found on the association between subclinical hypothyroidism and cognitive impairment, depression and the risk of fractures. Management strategies including screening and treatment of subclinical hypothyroidism are still controversial, while the ongoing European randomised controlled trial "TRUST" targets to solve these uncertainties. This narrative review aims to assess current evidence on the clinical aspects, as well as screening and treatment recommendations in adults with subclinical hypothyroidism. PMID- 25536450 TI - How determinant is N-terminal to C-terminal coupling for protein folding? AB - This work investigates the role of N- to C- termini coupling in the folding transition of small, single domain proteins via extensive Monte Carlo simulations of both lattice and off-lattice models. The reported results provide compelling evidence that the existence of native interactions between the terminal regions of the polypeptide chain (i.e. termini coupling) is a major determinant of the height of the free energy barrier that separates the folded from the denatured state in a two-state folding transition, therefore being a critical modulator of protein folding rates and thermodynamic cooperativity. We further report that termini interactions are able to substantially modify the kinetic behavior dictated by the full set of native interactions. Indeed, a native structure of high contact order with "switched-off" termini-interactions actually folds faster than its circular permutant of lowest CO. PMID- 25536451 TI - An examination of clinicians' experiences of collaborative culturally competent service delivery to immigrant families raising a child with a physical disability. AB - PURPOSE: Although collaborative, culturally competent care has been shown to increase positive health outcomes and client satisfaction with services, little is known about the ways that clinicians implement service delivery models with immigrant families having a child with a disability. The purpose of this study is to examine the experiences of clinicians working with immigrant families raising a child with a physical disability and to examine the views and experiences of clinicians providing collaborative, culturally competent care to immigrant families raising a child with a physical disability. METHOD: This study draws on in-depth interviews with 43 clinicians within two pediatric centers in Toronto and Quebec. RESULTS: Our findings show that clinicians remove or create barriers for immigrant families in different ways, which affect their ability to provide culturally competent care for immigrant families raising a child with a physical disability. CONCLUSIONS: Our findings suggest that there is a need for more institutional support for collaborative, culturally competent care to immigrant families raising a child with a physical disability. There is a lack of formal processes in place to develop collaborative treatment plans and approaches that would benefit immigrant families. Implications for Rehabilitation Clinicians need greater institutional support and resources to spend more time with families and to provide more rehabilitative care in families' homes. Building rapport with families includes listening to and respecting families' views and experiences. Facilitate collaboration and culturally competent care by having team meetings with parents to formulate treatment plans. PMID- 25536452 TI - Frequency-dependent alterations in the amplitude of low-frequency fluctuations in social anxiety disorder. AB - BACKGROUND: Recent studies on resting-state functional magnetic resonance imaging (fMRI) have found an abnormal temporal correlation between low-frequency oscillations (LFO) in social anxiety disorder (SAD). However, alterations in the amplitudes of these LFO remain unclear. METHODS: This study included 20 SAD patients and 20 age-, gender-, and education-matched healthy controls. Resting state fMRI data were acquired using a gradient-echo echo-planar imaging sequence, and the amplitudes of LFO were investigated using the amplitude of low-frequency fluctuation (ALFF) approach. Two frequency bands (slow-5: 0.01-0.027Hz; slow-4: 0.027-0.073Hz) were analyzed. RESULTS: Significant differences in ALFF were observed between the two bands in widespread regions including the postcentral gyrus, precentral gyrus, medial prefrontal cortex (MPFC), orbitofrontal cortex, hippocampus, thalamus, caudate, putamen, and insula. Compared with the healthy controls, the SAD patients showed lower ALFF in the dorsolateral prefrontal cortex (DLPFC), MPFC, superior temporal gyrus, and insula but higher ALFF in the middle occipital gyrus. Furthermore, we found that the SAD patients had reduced ALFF in the MPFC in the slow-5 band. LIMITATION: The small sample size may decrease the statistical power of the results. CONCLUSIONS: SAD patients had frequency-dependent alteration in intrinsic brain activity. This finding may provide insights into the understanding of the pathophysiology of SAD. PMID- 25536454 TI - Synthesis and physico-chemical properties of the first water soluble Cu(ii)@hemicryptophane complex. AB - A hemicryptophane ligand soluble in water at neutral pH was obtained thanks to the derivatization of the cyclotribenzylene unit with three carboxylate groups. The corresponding Cu(ii) complex was then synthesized and its spectroscopic and electrochemical properties in water were investigated, showing that water solubilisation retains the geometry of the complex around the metal center but strongly affects its redox properties, compared to previously reported Cu(ii)@hemicryptophane complexes soluble in organic solvents. PMID- 25536453 TI - Synthesis, spectroscopic characterization and in vitro antimicrobial, anticancer and antileishmanial activities as well interaction with Salmon sperm DNA of newly synthesized carboxylic acid derivative, 4-(4-methoxy-2-nitrophenylamino)-4 oxobutanoic acid. AB - This paper stresses on the synthesis, characterization of novel carboxylic acid derivative and its application in pharmaceutics. Carboxylic acid derivatives have a growing importance in medicine, particularly in oncology. A novel carboxylic acid, 4-(4-methoxy-2-nitrophenylamino)-4-oxobutanoic acid, was synthesized and characterized by elemental analysis, FT-IR, NMR ((1)H, and (13)C), mass spectrometry and single crystal X-ray structural analysis. The structure of the title compound, C11H12N2O6, shows the molecules dimerised by short intramolecular OH?O hydrogen bonds. The compound was screened for in vitro antimicrobial, anticancer, and antileishmanial activities as well as interaction with SS-DNA. The compound was also checked for in vitro anticancer activity against BHK-21, H 157 and HCEC cell lines, and showed significant anticancer activity. The compound was almost non-toxic towards human corneal epithelial cells (HCEC) and did not show more than 7.4% antiproliferative activity when used at the 2.0MUg/mL end concentration. It was also tested for antileishmanial activity against the promastigote form of leishmania major and obtained attractive result. DNA interaction study exposes that the binding mode of the compound with SS-DNA is an intercalative as it results in hypochromism along with minor red shift. A new and efficient strategy to identify pharmacophores sites in carboxylic acid derivative for antibacterial/antifungal activity using Petra, Osiris and Molinspiration (POM) analyses was also carried out. PMID- 25536455 TI - Toward a clarification of the taxonomy of "bias" in epidemiology textbooks. AB - Epidemiology textbooks typically divide biases into 3 general categories confounding, selection bias, and information bias. Despite the ubiquity of this categorization, authors often use these terms to mean different things. This hinders communication among epidemiologists and confuses students who are just learning about the field. To understand the sources of this problem, we reviewed current general epidemiology textbooks to examine how the authors defined and categorized biases. We found that much of the confusion arises from different definitions of "validity" and from a mixing of 3 overlapping organizational features in defining and differentiating among confounding, selection bias, and information bias: consequence, the result of the problem; cause, the processes that give rise to the problem; and cure, how these biases can be addressed once they occur. By contrast, a consistent taxonomy would provide (1) a clear and consistent definition of what unites confounding, selection bias, and information bias and (2) a clear articulation and consistent application of the feature that distinguishes these categories. Based on a distillation of these textbook discussions, we provide an example of a taxonomy that we think meets these criteria. PMID- 25536456 TI - Evolving methods for inference in the presence of healthy worker survivor bias. AB - Healthy worker survivor bias may occur in occupational studies due to the tendency for unhealthy individuals to leave work earlier, and consequently accrue less exposure, compared with their healthier counterparts. If occupational data are not analyzed using appropriate methods, this bias can result in attenuation or even reversal of the estimated effects of exposures on health outcomes. Recent advances in computing power, coupled with state-of-the-art statistical methods, have greatly increased the ability of analysts to control healthy worker survivor bias. However, these methods have not been widely adopted by occupational epidemiologists. We update the seminal review by Arrighi and Hertz-Picciotto (Epidemiology.1994; 5: 186-196) of the sources and methods to control healthy worker survivor bias. In our update, we discuss methodologic advances since the publication of that review, notably with a consideration of how directed acyclic graphs can inform the choice of appropriate analytic methods. We summarize and discuss methods for addressing this bias, including recent work applying g methods to account for employment status as a time-varying covariate affected by prior exposure. In the presence of healthy worker survivor bias, g-methods have advantages for estimating less biased parameters that have direct policy implications and are clearly communicated to decision-makers. PMID- 25536457 TI - Education and imaging. Gastrointestinal: Impacted gastric balloon in small bowel. PMID- 25536458 TI - Education and imaging. Gastrointestinal: Recurrent pancreatitis due to pancreatic arteriovenous malformation. PMID- 25536460 TI - Education and imaging. Hepatology: Fascioliasis: a rare cause of hepatic pseudoaneurysmal rupture. PMID- 25536461 TI - Education and imaging. Hepatology: Esophageal bullae and hemorrhage in portal hypertension. PMID- 25536459 TI - Education and imaging. Gastrointestinal: Heavy stomach. PMID- 25536462 TI - Decreased wait times after institution of office-based hand surgery in a Veterans Administration setting. PMID- 25536464 TI - Temporal properties of material categorization and material rating: visual vs non visual material features. AB - Humans can visually recognize material categories of objects, such as glass, stone, and plastic, easily. However, little is known about the kinds of surface quality features that contribute to such material class recognition. In this paper, we examine the relationship between perceptual surface features and material category discrimination performance for pictures of materials, focusing on temporal aspects, including reaction time and effects of stimulus duration. The stimuli were pictures of objects with an identical shape but made of different materials that could be categorized into seven classes (glass, plastic, metal, stone, wood, leather, and fabric). In a pre-experiment, observers rated the pictures on nine surface features, including visual (e.g., glossiness and transparency) and non-visual features (e.g., heaviness and warmness), on a 7 point scale. In the main experiments, observers judged whether two simultaneously presented pictures were classified as the same or different material category. Reaction times and effects of stimulus duration were measured. The results showed that visual feature ratings were correlated with material discrimination performance for short reaction times or short stimulus durations, while non visual feature ratings were correlated only with performance for long reaction times or long stimulus durations. These results suggest that the mechanisms underlying visual and non-visual feature processing may differ in terms of processing time, although the cause is unclear. Visual surface features may mainly contribute to material recognition in daily life, while non-visual features may contribute only weakly, if at all. PMID- 25536466 TI - Investigating perceptual qualities of static surface appearance using real materials and displayed images. AB - Recent experimental evidence supports the idea that human observers are good at recognizing and categorizing materials. Fleming et al. reported that perceptual qualities and material classes are closely related using projected images (Journal of Vision 13(8) (2013) 9). In this paper, we further investigated their findings using real materials and degraded image versions of the same materials. We constructed a real material dataset, as well as four image datasets by varying chromaticity (color vs. gray) and resolution (high vs. low) of the material images. To investigate the fundamental properties of materials' static surface appearance, we used stimuli that lacked shape and saturated color information. We then investigated the relationship between these perceptual qualities and the various types of image representation through psychophysical experiments. Our results showed that the representation method of some materials affected their perceptual qualities. These cases could be classified into the following three types: (1) perceptual qualities decreased by reproducing the materials as images, (2) perceptual qualities decreased by creating gray images, and (3) perceptual qualities such as "Hardness" and "Coldness" tended to increase when the materials were reproduced as low-quality images. Through methods such as principal component analysis and k-means clustering, we found that material categories are more likely to be confused when materials are represented as images, especially gray images. PMID- 25536463 TI - The structures of the colonic mucosa-associated and luminal microbial communities are distinct and differentially affected by a prolonged murine stressor. AB - The commensal microbiota of the human gastrointestinal tract live in a largely stable community structure, assisting in host physiological and immunological functions. Changes to this structure can be injurious to the health of the host, a concept termed dysbiosis. Psychological stress is a factor that has been implicated in causing dysbiosis, and studies performed by our lab have shown that restraint stress can indeed shift the cecal microbiota structure as well as increase the severity of a colonic infection caused by Citrobacter rodentium. However, this study, like many others, have focused on fecal contents when examining the effect of dysbiosis-causing stimuli (e.g. psychological stress) upon the microbiota. Since the mucosa-associated microbiota have unique properties and functions that can act upon the host, it is important to understand how stressor exposure might affect this niche of bacteria. To begin to understand whether chronic restraint stress changes the mucosa-associated and/or luminal microbiota mice underwent 7 16-hour cycles of restraint stress, and the microbiota of both colonic tissue and fecal contents were analyzed by sequencing using next-gen bacterial tag-encoded FLX amplicon technology (bTEFAP) pyrosequencing. Both control and stress groups had significantly different mucosa associated and luminal microbiota communities, highlighting the importance of focusing gastrointestinal community structure analysis by microbial niche. Furthermore, restraint stress was able to disrupt both the mucosa-associated and luminally-associated colonic microbiota by shifting the relative abundances of multiple groups of bacteria. Among these changes, there was a significant reduction in the immunomodulatory commensal genus Lactobacillus associated with colonic mucosa. The relative abundance of Lactobacillus spp. was not affected in the lumen. These results indicate that stressor-exposure can have distinct effects upon the colonic microbiota situated at the mucosal epithelium in comparison to the luminal-associated microbiota. PMID- 25536467 TI - The effective reference frame in perceptual judgments of motion direction. AB - The retinotopic projection of stimulus motion depends both on the motion of the stimulus and the movements of the observer. In this study, we aimed to quantify the contributions of endogenous (retinotopic) and exogenous (spatiotopic and motion-based) reference frames on judgments of motion direction. We used a variant of the induced motion paradigm and we created different experimental conditions in which the predictions of each reference frame were different. Finally, assuming additive contributions from different reference frames, we used a linear model to account for the data. Our results suggest that the effective reference frame for motion perception emerges from an amalgamation of motion based, retinotopic and spatiotopic reference frames. In determining the percept, the influence of relative motion, defined by a motion-based reference frame, dominates those of retinotopic and spatiotopic motions within a finite region. We interpret these findings within the context of the Reference Frame Metric Field (RFMF) theory, which states that local motion vectors might have perceptual reference-frame fields associated with them, and interactions between these fields determine the selection of the effective reference frame. PMID- 25536465 TI - A physiological perspective on fixational eye movements. AB - For a behavioral neuroscientist, fixational eye movements are a double-edged sword. On one edge, they make control of visual stimuli difficult, but on the other edge they provide insight into the ways the visual system acquires information from the environment. We have studied macaque monkeys as models for human visual systems. Fixational eye movements of monkeys are similar to those of humans but they are more often vertically biased and spatially more dispersed. Eye movements scatter stimuli from their intended retinal locations, increase variability of neuronal responses, inflate estimates of receptive field size, and decrease measures of response amplitude. They also bias against successful stimulation of extremely selective cells. Compensating for eye movements reduced these errors and revealed a fine-grained motion pathway from V1 feeding the cortical ventral stream. Compensation is a useful tool for the experimenter, but rather than compensating for eye movements, the brain utilizes them as part of its input. The saccades and drifts that occur during fixation selectively activate different types of V1 neurons. Cells that prefer slower speeds respond during the drift periods with maintained discharges and tend to have smaller receptive fields that are selective for sign of contrast. They are well suited to code small details of the image and to enable our fine detailed vision. Cells that prefer higher speeds fire transient bursts of spikes when the receptive field leaves, crosses, or lands on a stimulus, but only the most transient ones (about one-third of our sample) failed to respond during drifts. Voluntary and fixational saccades had very similar effects, including the presence of a biphasic extraretinal modulation that interacted with stimulus-driven responses. Saccades evoke synchronous bursts that can enhance visibility but these bursts may also participate in the visual masking that contributes to saccadic suppression. Study of the small eye movements of fixation may illuminate some of the big problems in vision. PMID- 25536468 TI - The effects of saliency on manual reach trajectories and reach target selection. AB - Reaching trajectories curve toward salient distractors, reflecting the competing activation of reach plans toward target and distractor stimuli. We investigated whether the relative saliency of target and distractor influenced the curvature of the movement and the selection of the final endpoint of the reach. Participants were asked to reach a bar tilted to the right in a context of gray vertical bars. A bar tilted to the left served as distractor. Relative stimulus saliency was varied via color: either the distractor was red and the target was gray, or vice versa. Throughout, we observed that reach trajectories deviated toward the distractor. Surprisingly, relative saliency had no effect on the curvature of reach trajectories. Moreover, when we increased time pressure in separate experiments and analyzed the curvature as a function of reaction time, no influence of relative stimulus saliency was found, not even for the fastest reaction times. If anything, curvature decreased with strong time pressure. In contrast, reach target selection under strong time pressure was influenced by relative saliency: reaches with short reaction times were likely to go to the red distractor. The time course of reach target selection was comparable to saccadic target selection. Implications for the neural basis of trajectory deviations and target selection in manual and eye movements are discussed. PMID- 25536469 TI - 3D surface configuration modulates 2D symmetry detection. AB - We investigated whether three-dimensional (3D) information in a scene can affect symmetry detection. The stimuli were random dot patterns with 15% dot density. We measured the coherence threshold, or the proportion of dots that were the mirror reflection of the other dots in the other half of the image about a central vertical axis, at 75% accuracy with a 2AFC paradigm under various 3D configurations produced by the disparity between the left and right eye images. The results showed that symmetry detection was difficult when the corresponding dots across the symmetry axis were on different frontoparallel or inclined planes. However, this effect was not due to a difference in distance, as the observers could detect symmetry on a slanted surface, where the depth of the two sides of the symmetric axis was different. The threshold was reduced for a hinge configuration where the join of two slanted surfaces coincided with the axis of symmetry. Our result suggests that the detection of two-dimensional (2D) symmetry patterns is subject to the 3D configuration of the scene; and that coplanarity across the symmetry axis and consistency between the 2D pattern and 3D structure are important factors for symmetry detection. PMID- 25536471 TI - Novel lift-off technique for Transmission Electron Microscopy imaging of block copolymer films. AB - We have developed a simple technique to allow for the lift-off and subsequent transfer of poly(styrene-block-ethylene glycol) films to Transmission Electron Microscopy (TEM) grids. The block copolymer is spin coated onto carbon coated mica and annealed. After the thin film is produced it can easily be floated onto water and picked up by a TEM grid. This method offers better control over film processing than dip coating the TEM grid and is also a significant improvement over methods using etchants such as hydrofluoric acid. PMID- 25536470 TI - Binocular eyelid closure promotes anatomical but not behavioral recovery from monocular deprivation. AB - Deprivation of patterned vision of frontal eyed mammals early in postnatal life alters structural and functional attributes of neurones in the central visual pathways, and can produce severe impairments of the vision of the deprived eye that resemble the visual loss observed in human amblyopia. A traditional approach to treatment of amblyopia has been the occlusion of the stronger fellow eye in order to force use of the weaker eye and thereby strengthen its connections in the visual cortex. Although this monocular treatment strategy can be effective at promoting recovery of visual acuity of the amblyopic eye, such binocular visual functions as stereoscopic vision often remain impaired due in part to the lack of concordant vision during the period of unilateral occlusion. The recent development of binocular approaches for treatment of amblyopia that improve the possibility for binocular interaction have achieved success in promoting visual recovery. The full and rapid recovery of visual acuity observed in amblyopic kittens placed in complete darkness is an example of a binocular treatment whose success may in part derive from a restored balance of visually-driven neural activity. In the current study we examined as an alternative to dark rearing the efficacy of binocular lid suture (BLS) to stimulate anatomical and visual recovery from a preceding amblyogenic period of monocular deprivation. In the dorsal lateral geniculate nucleus (dLGN) of monocularly deprived kittens, darkness or BLS for 10days produced a complete recovery of neurone soma size within initially deprived layers. The growth of neurone somata within initially deprived dLGN layers after darkness or BLS was accompanied by an increase in neurotrophin-4/5 labeling within these layers. Although anatomical recovery was observed in both recovery conditions, BLS failed to promote any improvement of the visual acuity of the deprived eye no matter whether it followed immediately or was delayed with respect to the prior period of monocular deprivation. Notwithstanding the lack of visual recovery with BLS, all animals in the BLS condition that were subsequently placed in darkness exhibited a substantial recovery of visual acuity in the amblyopic eye. We conclude that the balanced binocular visual input provided by BLS does not stimulate the collection of neural events necessary to support recovery from amblyopia. The complete absence of visually-driven activity that occurs with dark rearing evidently plays an important role in the recovery process. PMID- 25536472 TI - Environmental forensics evaluation of sources of sediment hydrocarbon contamination in Milford Haven Waterway. AB - Current and historic petroleum-related activities in Milford Haven Waterway (MHW; Wales, UK) contribute to hydrocarbon contamination of surficial sediments. Three main hydrocarbon components of sediments were analyzed: (1) aliphatic hydrocarbons of predominantly biogenic origin, representing about 5-15% of total hydrocarbons (THC); (2) polycyclic aromatic hydrocarbons (PAHs) from recent petrogenic and mainly older pyrogenic sources, representing about 2-6% of THC; (3) unresolved complex mixture from spill-related and heavily-weathered petrogenic sources, representing as much as 70-85% of THC. Environmental forensics evaluation of the data demonstrate that although 72,000 tonnes (t) crude oil spilled from the Sea Empress in 1996, the Forties blend cargo was not identified in 2010. However, using biomarkers, heavy fuel oil (HFO) from Sea Empress' bunkers (480 t spilled) was detected further upstream and more widely than previously. Iranian crude (100 t) spilled by the El Omar in 1988 and fuel (130,000 t) lost during bombing in 1940 also were tentatively identified. The PAH source ratios demonstrate that the historic pyrogenic PAHs come mainly from biomass and coal combustion. The distribution pattern of PAHs appeared more pyrogenic in 2012 than in 1996, as if recovering from the more petrogenic signature, in places, of the Sea Empress. The heavier PAH distributions were pyrogenic at most stations, and similar to those in sediments from oil terminal berths up to 2006, when dredging operations peaked. Partly as a result of this, in 2007 the concentrations of PAHs peaked throughout the waterway. Apart from effluent, atmospheric and runoff inputs, most of the identified inputs to the surficial sediments are historic. Therefore, likely processes include disturbance by construction (e.g. pile-driving) and dredging of contaminants sequestered in sediments, followed by their wide redistribution via suspended sediment transport. PMID- 25536473 TI - Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxic human colorectal cancer cells. AB - Dichloroacetate (DCA) is a small molecule that inhibits pyruvate dehydrogenase kinase (PDK) to constrain the aerobic glycolytic pathway observed in many cancer cells and effectively kill them with limited cytotoxicity on normal cells. We previously showed that DCA induced a cytoprotective effect in different human colorectal cancer (CRC) cell lines under anoxic conditions. In this study, we investigated the molecular and metabolic changes that may be providing this cytoprotection. The expression profiles of PDK isoforms in SW480 and LS174T cells along with subsequent changes in pyruvate dehydrogenase (PDH) phosphorylation were assessed following DCA exposure. Changes in mitochondrial activity and subsequent glucose consumption and lactate production were then examined. We show evidence of differential regulation in PDH phosphorylation between different human CRC cells leading to differences in mitochondrial activity following DCA exposure. However, these effects did not lead to significant changes in cellular metabolism nor growth. In conclusion, DCA may only be beneficial in treating a subset of tumor types based on their molecular profiles of different PDK isoforms. PMID- 25536474 TI - A hyaluronic acid-based compound inhibits fibroblast senescence induced by oxidative stress in vitro and prevents oral mucositis in vivo. AB - Virtually all patients receiving radio- and chemotherapy for cancer develop oral mucositis, a severe and highly debilitating condition. The onset of mucositis is thought to involve the production of reactive oxygen species (ROS) in the submucosa. Here we investigated a possible protective effect of a commercial formulation of hyaluronic acid (HA) enriched with amino acids (Mucosamin((r))) against the damage induced by oxidative stress both in vitro and in vivo. Transient exposure of normal human oral fibroblasts to hydrogen peroxide (H(2)O(2)) led to irreversible senescence, as demonstrated by sustained increase in the levels of p16(INK4A) and SA-betaGal. Conditioned media from senescent fibroblasts induced detrimental effects on keratinocytes, as shown by reduced metabolic activity and migration capability. Pre-treatment with Mucosamin((r)) prevented H(2)O(2) -induced, but not TGF-beta-induced, fibroblast senescence with a concomitant reduction of fibroblast-induced loss of keratinocyte vitality and functional activity. Finally, data from a case-series of patients undergoing radio/chemotherapy strongly suggested that prophylactic use of the hyaluronic acid-based compound in the form of a spray may be effective in preventing the onset of oral mucositis. PMID- 25536480 TI - The dawning age of genetic testing for sports injuries. PMID- 25536481 TI - American Medical Society for Sports Medicine position statement: interventional musculoskeletal ultrasound in sports medicine. AB - The use of diagnostic and interventional ultrasound has significantly increased over the past decade. A majority of the increased utilization is by nonradiologists. In sports medicine, ultrasound is often used to guide interventions such as aspirations, diagnostic or therapeutic injections, tenotomies, releases, and hydrodissections. This American Medical Society for Sports Medicine (AMSSM) position statement critically reviews the literature and evaluates the accuracy, efficacy, and cost-effectiveness of ultrasound-guided injections in major, intermediate, and small joints, and soft tissues, all of which are commonly performed in sports medicine. New ultrasound-guided procedures and future trends are also briefly discussed. Based on the evidence, the official AMSSM position relevant to each subject is made. PMID- 25536482 TI - American Medical Society for Sports Medicine recommended sports ultrasound curriculum for sports medicine fellowships. AB - The following sports ultrasound (SPORTS US) curriculum is a revision of the curriculum developed by the American Medical Society for Sports Medicine (AMSSM) in 2010. Several changes have been made to the curriculum with the primary aim of providing a pathway by which a sports medicine fellow can obtain sufficient SPORTS US training to become proficient in the core competencies of SPORTS US. The core competencies of SPORTS US are outlined in the learning objectives section of this document. The term "SPORTS US" was purposefully chosen rather than "musculoskeletal ultrasound" (MSK US) because it was recognized by the panel that the evolving field of SPORTS US encompasses non-MSK applications of ultrasound such as the FAST examination (focused assessment with sonography for trauma). Although the SPORTS US core competencies in this curriculum are all MSK in nature, they represent the minimum SPORTS US knowledge a sports medicine fellow should acquire during fellowship. However, additional training in more advanced MSK and non-MSK applications of ultrasound can be provided at the fellowship director's discretion. Completion of this SPORTS US curriculum fulfills the American Institute of Ultrasound in Medicine's (AIUM) requirements to perform an MSK US examination and the prerequisites for the American Registry for Diagnostic Medical Sonography's (ARDMS) MSK sonography certification examination. PMID- 25536483 TI - Clinical genetics in 2014: New monogenic diseases span the immunological disease continuum. AB - Three monogenic diseases, with features of both autoinflammation and autoimmunity, were described for the first time in 2014. As well as providing insights into the molecular basis of several rare immunological disorders, the discoveries have implications for their diagnosis and treatment. PMID- 25536484 TI - Rheumatoid arthritis in 2014: Exciting times for RA research. AB - 2014 saw the emergence of a novel rheumatoid arthritis therapy to rival methotrexate, as well as advances in our understanding of mouse T.cell biology and of the cross-talk between the nervous system and the immune system. How will these advances affect the future of rheumatoid arthritis research and therapy? PMID- 25536485 TI - A vascular mechanistic approach to understanding Raynaud phenomenon. AB - During exposure to cold, our bodies attempt to maintain normal core temperature by restricting heat loss through cutaneous vasoconstriction, and by increasing heat production through shivering and nonshivering thermogenesis. In selected areas of human skin (including on the fingers and toes), the vascular system has specialized structural and functional features that enable it to contribute to thermoregulation. These features include arteriovenous anastomoses, which directly connect the arterial and venous systems and bypass the nutritional capillaries supplying blood to the skin tissue. Of note, Raynaud phenomenon predominantly affects the arterial territories supplying these specialized areas of skin. Indeed, Raynaud phenomenon can be considered a disorder of vascular thermoregulatory control. This Review presents an understanding of Raynaud phenomenon in the context of vascular and thermoregulatory control mechanisms, including the role of unique thermosensitive vascular structural and functional specialization, and describes the potential role of thermogenesis in this disorder. This new approach provides remarkable insight into the disease process and builds a framework to critically appraise the existing knowledge base. This paradigm also explains the deficiencies in some current therapeutic approaches, and highlights new areas of potential relevance to the pathogenesis and treatment of Raynaud phenomenon that should be expanded and explored. PMID- 25536488 TI - Engineering an iterative polyketide pathway in Escherichia coli results in single form alkene and alkane overproduction. AB - Alkanes and alkenes are ideal biofuels, due to their high energy content and ability to be safely transported. To date, fatty acid-derived pathways for alkane and alkene bioproduction have been thoroughly explored. In this study, we engineered the pathway of the iterative Type I polyketide synthase (PKS) SgcE with the cognate thioesterase (TE) SgcE10 in Escherichia coli, with the goal of overproducing pentadecaheptaene (PDH) followed by its hydrogenation to pentadecane (PD). Based on initial in vitro titration assays, we learned that PDH production is strongly dependent on the SgcE10:SgcE ratio. Thus, we engineered a high-yield E. coli strain by fine-tuning SgcE10 expression via synthetic promoters. We analyzed engineered E. coli strains using a modified multiple reactions monitoring mass spectrometry (MRM-MS)-based targeted proteomic approach, using a chimeric SgcE10 and SgcE fusion construct to gain insight into expression levels of the two proteins. Lastly, through fed-batch fermentation followed by flow chemical hydrogenation, we obtained a PD yield of nearly 140mg/L in single-alkane form. Thus, we not only employed a metabolic engineering approach to the iterative polyketide pathway, we highlighted the potential of PKS shunt products to play a role in the production of single-form and high-value chemicals. PMID- 25536489 TI - Neurocognitive responses to a single session of static squats with whole body vibration. AB - The purpose of this study was to determine if the head accelerations using a common whole body vibration (WBV) exercise protocol acutely reduced neurocognition in healthy subjects. Second, we investigated differential responses to WBV plates with 2 different delivery mechanisms: vertical and rotational vibrations. Twelve healthy subjects (N = 12) volunteered and completed a baseline (BASE) neurocognitive assessment: the Immediate Postconcussion Assessment and Cognitive Test (ImPACT). Subjects then participated in 3 randomized exercise sessions separated by no more than 2 weeks. The exercise sessions consisted of five 2-minute sets of static hip-width stance squats, with the knees positioned at a 45 degrees angle of flexion. The squats were performed with no vibration (control [CON]), with a vertically vibrating plate (vertical vibration [VV]), and with a rotational vibrating plate (rotational vibration [RV]) set to 30 Hz with 4 mm of peak-to-peak displacement. The ImPACT assessments were completed immediately after each exercise session and the composite score for 5 cognitive domains was analyzed: verbal memory, visual memory, visual motor speed, reaction time, and impulse control. Verbal memory scores were unaffected by exercise with or without vibration (p = 0.40). Likewise, visual memory was not different (p = 0.14) after CON, VV, or RV. Significant differences were detected for visual motor speed (p = 0.006); VV was elevated compared with BASE (p = 0.01). There were no significant differences (p = 0.26) in reaction time or impulse control (p = 0.16) after exercise with or without vibration. In healthy individuals, 10 minutes of 30 Hz, 4-mm peak-to-peak displacement vibration exposure with a 45 degrees angle of knee flexion did not negatively affect neurocognition. PMID- 25536487 TI - Origin and function of cartilage stem/progenitor cells in osteoarthritis. AB - Articular cartilage is a physiologically non-self-renewing avascular tissue with a singular cell type, the chondrocyte, which functions as the load-bearing surface of the arthrodial joint. Injury to cartilage often progresses spatiotemporally from the articular surface to the subchondral bone, leading to development of degenerative joint diseases such as osteoarthritis (OA). Although lacking intrinsic reparative ability, articular cartilage has been shown to contain a population of stem cells or progenitor cells, similar to those found in many other adult tissues, that are thought to be involved in the maintenance of tissue homeostasis. These so-called cartilage-derived stem/progenitor cells (CSPCs) have been observed in human, equine and bovine articular cartilage, and have been identified, isolated and characterized on the basis of expression of stem-cell-related surface markers, clonogenicity and multilineage differentiation ability. However, the origin and functions of CSPCs are incompletely understood. We review here the current status of CSPC research and discuss the possible origin of these cells, what role they might have in cartilage repair, and their therapeutic potential in OA. PMID- 25536490 TI - Membrane ion transport in non-excitable tissues. AB - The facilitated movement of ions across cell membranes can be characterized as occurring through active (ATP-dependent), secondary active (coupled), or passive transport processes. Each of these processes is mediated by a diverse group of membrane proteins. Over the past fifteen years, studies of membrane transport in C. elegans have benefited from the fact that worms are anatomically simple, easily and economically cultured, and genetically tractable. These experimental advantages have been instrumental in defining how membrane transport processes contribute to whole organism physiology. The focus of this review is to survey the recent advances in our understanding of membrane transport that have arisen from integrative physiological approaches in the nematode C. elegans. PMID- 25536486 TI - Sequencing the functional antibody repertoire--diagnostic and therapeutic discovery. AB - The development of high-throughput DNA sequencing technologies has enabled large scale characterization of functional antibody repertoires, a new method of understanding protective and pathogenic immune responses. Important parameters to consider when sequencing antibody repertoires include the methodology, the B-cell population and clinical characteristics of the individuals analysed, and the bioinformatic analysis. Although focused sequencing of immunoglobulin heavy chains or complement determining regions can be utilized to monitor particular immune responses and B-cell malignancies, high-fidelity analysis of the full length paired heavy and light chains expressed by individual B cells is critical for characterizing functional antibody repertoires. Bioinformatic identification of clonal antibody families and recombinant expression of representative members produces recombinant antibodies that can be used to identify the antigen targets of functional immune responses and to investigate the mechanisms of their protective or pathogenic functions. Integrated analysis of coexpressed functional genes provides the potential to further pinpoint the most important antibodies and clonal families generated during an immune response. Sequencing antibody repertoires is transforming our understanding of immune responses to autoimmunity, vaccination, infection and cancer. We anticipate that antibody repertoire sequencing will provide next-generation biomarkers, diagnostic tools and therapeutic antibodies for a spectrum of diseases, including rheumatic diseases. PMID- 25536491 TI - Ultrasensitive electrochemical detection of breast cancer cells based on DNA rolling-circle-amplification-directed enzyme-catalyzed polymerization. AB - An ultrasensitive cytosensor based on DNA-rolling-circle-amplification-directed enzyme-catalyzed polymerization is demonstrated. As a proof of concept, the cytosensor shows excellent sensitivity for MCF-7 cell detection with a lower detection limit of 12 cells per mL. PMID- 25536492 TI - Procedural pain management in the treatment of scleroderma digital ulcers. AB - OBJECTIVES: Digital ulcers (DU) may develop in half of systemic sclerosis (SSc) patients; they are often resistant to treatments. Deep wound debridement is crucial for DU healing, but very difficult to carry out without adequate procedural pain management. Here, we report the results of our experience on procedural pain management in scleroderma DU. METHODS: The study included 51 DU observed in 32 consecutive SSc patients; procedural pain was treated following a definite schedule: local lidocaine and prilocaine (25 mg of either agent per gram of cream, EMLA 5%) were initially used in all cases, followed by local and oral morphine, according to the severity of pain scored on a 10 cm visual analogue scale (VAS). RESULTS: At baseline, higher pain VAS was recorded in more severe (p=0.0001) and/or infected DU (p=0.0001). Good compliance to DU debridement was observed in patients with mild pain (VAS <=4) treated with only EMLA, and in 5 cases with moderate-severe pain (VAS >4) at baseline. While, the majority of DU with moderate-severe pain (34/39) needed a combined therapy with EMLA and local morphine (8/34) or with EMLA, local and oral morphine (26/34). On the whole, pain management during DU debridement required only EMLA application in 33% of cases, EMLA plus local morphine in 16%, while combined EMLA, local and oral morphine were necessary in 51%, generally with more severe and/or infected lesions. CONCLUSIONS: The present study showed valuable control of procedural pain during DU debridement with sequential, combined analgesic treatment. PMID- 25536494 TI - Comparison between balanced steady-state free precession and standard spoiled gradient echo magnetization transfer ratio imaging in multiple sclerosis: methodical and clinical considerations. AB - Different pathological processes like demyelination and axonal loss can alter the magnetisation transfer ratio (MTR) in brain tissue. The standard method to measure this effect is to scan the respective tissue twice, one with and one without a specific saturation pulse. A major drawback of this technique based on spoiled gradient echo (GRE) sequences relates to its long acquisition time due to the saturation pulses. Recently, an alternative concept for MT imaging based on balanced steady state free precession (bSSFP) has been proposed. Modification of the duration of the radiofrequency pulses for imaging allows scanning MT sensitive and non-sensitive images. The steady-state character of bSSFP with high intrinsic signal-to-noise ratio (SNR) allows three-dimensional (3D) whole brain MTR at high spatial resolution within short and thus clinically feasible acquisition times. In the present study, both bSSFP-MT and 2D GRE-MT imaging were used in a cohort of 31 patients with multiple sclerosis (MS) to characterize different normal appearing (NA) and pathological brain structures. Under the constraint of identical SNR and scan time, a 3.4 times higher voxel size could be achieved with bSSFP. This increased resolution allowed a more accurate delineation of the different brain structures, especially of cortex, hippocampus and MS lesions. In a multiple linear regression model, we found an association between MTR of cortical lesions and a clinical measure of disability (r= -0.407, p=0.035) in the bSSFP dataset only. The different relaxation weighting of the base images (T2/T1 in bSSFP, proton density in GRE) had no effects besides a larger spreading of the MTR values of the different NA structures. This was demonstrated by the nearly perfect linearity between the NA matter MTR of both techniques as well as in the absolute MTR differences between NA matter and the respective lesions. PMID- 25536493 TI - Connectivity in the human brain dissociates entropy and complexity of auditory inputs. AB - Complex systems are described according to two central dimensions: (a) the randomness of their output, quantified via entropy; and (b) their complexity, which reflects the organization of a system's generators. Whereas some approaches hold that complexity can be reduced to uncertainty or entropy, an axiom of complexity science is that signals with very high or very low entropy are generated by relatively non-complex systems, while complex systems typically generate outputs with entropy peaking between these two extremes. In understanding their environment, individuals would benefit from coding for both input entropy and complexity; entropy indexes uncertainty and can inform probabilistic coding strategies, whereas complexity reflects a concise and abstract representation of the underlying environmental configuration, which can serve independent purposes, e.g., as a template for generalization and rapid comparisons between environments. Using functional neuroimaging, we demonstrate that, in response to passively processed auditory inputs, functional integration patterns in the human brain track both the entropy and complexity of the auditory signal. Connectivity between several brain regions scaled monotonically with input entropy, suggesting sensitivity to uncertainty, whereas connectivity between other regions tracked entropy in a convex manner consistent with sensitivity to input complexity. These findings suggest that the human brain simultaneously tracks the uncertainty of sensory data and effectively models their environmental generators. PMID- 25536495 TI - Is functional integration of resting state brain networks an unspecific biomarker for working memory performance? AB - Is there one optimal topology of functional brain networks at rest from which our cognitive performance would profit? Previous studies suggest that functional integration of resting state brain networks is an important biomarker for cognitive performance. However, it is still unknown whether higher network integration is an unspecific predictor for good cognitive performance or, alternatively, whether specific network organization during rest predicts only specific cognitive abilities. Here, we investigated the relationship between network integration at rest and cognitive performance using two tasks that measured different aspects of working memory; one task assessed visual-spatial and the other numerical working memory. Network clustering, modularity and efficiency were computed to capture network integration on different levels of network organization, and to statistically compare their correlations with the performance in each working memory test. The results revealed that each working memory aspect profits from a different resting state topology, and the tests showed significantly different correlations with each of the measures of network integration. While higher global network integration and modularity predicted significantly better performance in visual-spatial working memory, both measures showed no significant correlation with numerical working memory performance. In contrast, numerical working memory was superior in subjects with highly clustered brain networks, predominantly in the intraparietal sulcus, a core brain region of the working memory network. Our findings suggest that a specific balance between local and global functional integration of resting state brain networks facilitates special aspects of cognitive performance. In the context of working memory, while visual-spatial performance is facilitated by globally integrated functional resting state brain networks, numerical working memory profits from increased capacities for local processing, especially in brain regions involved in working memory performance. PMID- 25536496 TI - A method for estimating and removing streaking artifacts in quantitative susceptibility mapping. AB - Quantitative susceptibility mapping (QSM) is a novel MRI method for quantifying tissue magnetic property. In the brain, it reflects the molecular composition and microstructure of the local tissue. However, susceptibility maps reconstructed from single-orientation data still suffer from streaking artifacts which obscure structural details and small lesions. We propose and have developed a general method for estimating streaking artifacts and subtracting them from susceptibility maps. Specifically, this method uses a sparse linear equation and least-squares (LSQR)-algorithm-based method to derive an initial estimation of magnetic susceptibility, a fast quantitative susceptibility mapping method to estimate the susceptibility boundaries, and an iterative approach to estimate the susceptibility artifact from ill-conditioned k-space regions only. With a fixed set of parameters for the initial susceptibility estimation and subsequent streaking artifact estimation and removal, the method provides an unbiased estimate of tissue susceptibility with negligible streaking artifacts, as compared to multi-orientation QSM reconstruction. This method allows for improved delineation of white matter lesions in patients with multiple sclerosis and small structures of the human brain with excellent anatomical details. The proposed methodology can be extended to other existing QSM algorithms. PMID- 25536497 TI - Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics. AB - In rodent studies, elevated cholinergic neurotransmission in right prefrontal cortex (PFC) is essential for maintaining attentional performance, especially in challenging conditions. Apparently paralleling the rises in acetylcholine seen in rodent studies, fMRI studies in humans reveal right PFC activation at or near Brodmann's areas 9 (BA 9) increases in response to elevated attentional demand. In the present study, we leveraged human genetic variability in the cholinergic system to test the hypothesis that the cholinergic system contributes to the BA 9 response to attentional demand. Specifically, we scanned (BOLD fMRI) participants with a polymorphism of the choline transporter gene that is thought to limit choline transport capacity (Ile89Val variant of the choline transporter gene SLC5A7, rs1013940) and matched controls while they completed a task previously used to demonstrate demand-related increases in right PFC cholinergic transmission in rats and right PFC activation in humans. As hypothesized, we found that although controls showed the typical pattern of robust BA 9 responses to increased attentional demand, Ile89Val participants did not. Further, pattern analysis of activation within this region significantly predicted participant genotype. Additional exploratory pattern classification analyses suggested that Ile89Val participants differentially recruited orbitofrontal cortex and parahippocampal gyrus to maintain attentional performance to the level of controls. These results contribute to a growing body of translational research clarifying the role of cholinergic signaling in human attention and functional neural measures, and begin to outline the risk and resiliency factors associated with potentially suboptimal cholinergic function with implications for disorders characterized by cholinergic dysregulation. PMID- 25536499 TI - (S)-citalopram influences amygdala modulation in healthy subjects: a randomized placebo-controlled double-blind fMRI study using dynamic causal modeling. AB - Citalopram and Escitalopram are gold standard pharmaceutical treatment options for affective, anxiety, and other psychiatric disorders. However, their neurophysiologic function on cortico-limbic circuits is incompletely characterized. Here we studied the neuropharmacological influence of Citalopram and Escitalopram on cortico-limbic regulatory processes by assessing the effective connectivity between orbitofrontal cortex (OFC) and amygdala using dynamic causal modeling (DCM) applied to functional MRI data. We investigated a cohort of 15 healthy subjects in a randomized, crossover, double-blind design after 10days of Escitalopram (10mg/d (S)-citalopram), Citalopram (10mg/d (S) citalopram and 10mg/d (R)-citalopram), or placebo. Subjects performed an emotional face discrimination task, while undergoing functional magnetic resonance imaging (fMRI) scanning at 3 Tesla. As hypothesized, the OFC, in the context of the emotional face discrimination task, exhibited a down-regulatory effect on amygdala activation. This modulatory effect was significantly increased by (S)-citalopram, but not (R)-citalopram. For the first time, this study shows that (1) the differential effects of the two enantiomers (S)- and (R)-citalopram on cortico-limbic connections can be demonstrated by modeling effective connectivity methods, and (2) one of their mechanisms can be linked to an increased inhibition of amygdala activation by the orbitofrontal cortex. PMID- 25536498 TI - A voxel-based analysis of brain activity in high-order trigeminal pathway in the rat induced by cortical spreading depression. AB - Cortical spreading depression (SD) is a self-propagating wave of depolarization that is thought to be an underling mechanism of migraine aura. Growing evidence demonstrates that cortical SD triggers neurogenic meningeal inflammation and contributes to migraine headaches via subsequent activation of trigeminal afferents. Although direct and indirect evidence shows that cortical SD activates the trigeminal ganglion (peripheral pathway) and the trigeminal nucleus caudalis (TNC, the first central site of the trigeminal nociceptive pathway), it is not yet known whether cortical SD activates the high-order trigeminal nociceptive pathway in the brain. To address this, we induced unilateral cortical SD in rats, and then examined brain activity using voxel-based statistical parametric mapping analysis of FDG-PET imaging. The results show that approximately 40h after the induction of unilateral cortical SD, regional brain activity significantly increased in several regions, including ipsilateral TNC, contralateral ventral posteromedial (VPM) and posterior thalamic nuclei (Po), the trigeminal barrel field region of the primary somatosensory cortex (S1BF), and secondary somatosensory cortex (S2). These results suggest that cortical SD is a noxious stimulus that can activate the high-order trigeminal nociceptive pathway even after cortical SD has subsided, probably due to prolonged meningeal inflammation. PMID- 25536500 TI - Age-related changes in reappraisal of appetitive cravings during adolescence. AB - The ability to regulate temptation and manage appetitive cravings is an important aspect of healthy adolescent development, but the neural systems underlying this process are understudied. In the present study, 60 healthy females evenly distributed from 10 to 23years of age used reappraisal to regulate the desire to consume personally-craved and not craved unhealthy foods. Reappraisal elicited activity in common self-regulation regions including the dorsal and ventral lateral prefrontal cortex (specifically superior and inferior frontal gyri), dorsal anterior cingulate cortex, and inferior parietal lobule. Viewing personally-craved foods (versus not craved foods) elicited activity in regions including the ventral striatum, as well as more rostral and ventral anterior cingulate cortex extending into the orbitofrontal cortex. Age positively correlated with regulation-related activity in the right inferior frontal gyrus, and negatively correlated with reactivity-related activity in the right superior and dorsolateral prefrontal cortices. Age-adjusted BMI negatively correlated with regulation-related activity in the predominantly left lateralized frontal and parietal regions. These results suggest that the age-related changes seen in the reappraisal of negative emotion may not be as pronounced in the reappraisal of food craving. Therefore, reappraisal of food craving in particular may be an effective way to teach teenagers to manage cravings for other temptations encountered in adolescence, including alcohol, drugs, and unhealthy food. PMID- 25536503 TI - Dynamic quantitative trait locus analysis of seed vigor at three maturity stages in rice. AB - Seed vigor is an important characteristic of seed quality. In this study, one rice population of recombinant inbred lines (RILs) was used to determine the genetic characteristics of seed vigor, including the germination potential, germination rate, germination index and time for 50% of germination, at 4 (early), 5 (middle) and 6 weeks (late) after heading in two years. A total of 24 additive and 9 epistatic quantitative trait loci (QTL) for seed vigor were identified using QTL Cartographer and QTLNetwork program respectively in 2012; while 32 simple sequence repeat (SSR) markers associated with seed vigor were detected using bulked segregant analysis (BSA) in 2013. The additive, epistatic and QTL * development interaction effects regulated the dry maturity developmental process to improve seed vigor in rice. The phenotypic variation explained by each additive, epistatic QTL and QTL * development interaction ranged from 5.86 to 40.67%, 4.64 to 11.28% and 0.01 to 1.17%, respectively. The QTLs were rarely co-localized among the different maturity stages; more QTLs were expressed at the early maturity stage followed by the late and middle stages. Twenty additive QTLs were stably expressed in two years which might play important roles in establishment of seed vigor in different environments. By comparing chromosomal positions of these stably expressed additive QTLs with those previously identified, the regions of QTL for seed vigor are likely to coincide with QTL for grain size, low temperature germinability and seed dormancy; while 5 additive QTL might represent novel genes. Using four selected RILs, three cross combinations of seed vigor for the development of RIL populations were predicted; 19 elite alleles could be pyramided by each combination. PMID- 25536505 TI - Tranversus abdominis plane block during abdominoplasty to improve postoperative patient comfort. AB - BACKGROUND: The transversus abdominis plane (TAP) block is an effective regional nerve block for the anterior abdominal wall. An anesthesiologist typically administers the TAP block preoperatively with ultrasound guidance. It is not yet commonly used during abdominoplasty, where postprocedural pain remains a major concern for patients and surgeons. OBJECTIVES: The author investigated the feasibility of administering the TAP block under direct vision and compared postoperative narcotic use in patients who received analgesia by TAP block vs by a standard nerve block, both performed under direct vision during abdominoplasty with or without flank liposuction. METHODS: In this pilot study, 32 consecutive patients received either a TAP block (n = 16) or a combination of pararectus injections and ilioinguinal/iliohypogastric nerve blocks (n = 16) during abdominoplasty. Patients in both groups also received an injection of bupivacaine in the rectus plication. All patients were then monitored for narcotic use patterns during the first 16 hours after surgery. Statistical significance was ascertained with the t test. RESULTS: Patients in the TAP block group required a significantly smaller mean dose of postoperative hydromorphone (TAP block group: 2.63 mg; standard treatment group: 4.31 mg; P = .024) and had a significantly longer mean time to first request for as-needed pain medication (TAP block group: 3 hours 11 minutes; standard treatment group: 1 hour 27 minutes; P = .022). CONCLUSIONS: The open TAP block provided more effective analgesia than a standard nerve block in the observation period after abdominoplasty with or without flank liposuction. Larger studies are needed to confirm the results. PMID- 25536504 TI - Patient-reported quality-of-life outcomes of breast reduction evaluated with generic questionnaires and the breast reduction assessed severity scale. AB - BACKGROUND: The effects of breast reduction on quality of life (QOL) have been evaluated in patients with macromastia, but few investigators have performed condition-specific assessments. OBJECTIVES: The authors employed generic and condition-specific questionnaires to examine the QOL of patients with macromastia and determined the responsiveness of the Turkish version of Breast Reduction Assessed Severity Scale (BRASS). METHODS: This prospective cohort study included patients with breast hypertrophy who underwent breast reduction (n = 94). Patients completed the Turkish versions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), the BRASS, and the Rosenberg Self-Esteem Scale preoperatively and 4 months postoperatively. Differences in responses were evaluated by paired t-test and by comparing change effect sizes. Multiple regression analyses were performed to evaluate improvements in QOL in response to adjustments in baseline differences across patients. RESULTS: Preoperative and postoperative questionnaires were completed by 78 patients (83%). Significant postoperative improvements in self-esteem (Rosenberg Self-Esteem Scale; P < .001) and in all domains of the BRASS (P < .001) were noted. Mean preoperative scores for 5 of 8 domains in the SF-36 were lower than those of a normative population. Postoperatively, all 5 mean scores improved significantly, but the score for bodily pain remained less than that of a normative population. CONCLUSIONS: The results of this study indicate significant improvements in health-related QOL at 4 months after breast reduction in a population of patients with macromastia. The authors also demonstrate excellent responsiveness of the BRASS. PMID- 25536506 TI - Efficient and product-controlled depolymerization of lignin oriented by metal chloride cooperated with Pd/C. AB - An efficient lignin depolymerization process with highly controllable product distribution was presented using metal chloride (MClx) cooperated with Pd/C. The catalytic performances of MClx were investigated. The effect of reaction conditions on the lignin depolymerization and products distribution were also studied. Results showed that more than 35.4% yield of phenolic monomer including 7.8% phenols and 1.1% guaiacols could be obtained under optimized condition. And the product distribution can be efficiently controlled by the modification of the metal cation through different pathway of Lewis acid catalysis and coordination catalysis. Furthermore, the Pd/C catalyst showed an excellent recyclability, where no significant loss of the catalytic activity was exhibited after 3 runs. Moreover, the product control mechanism was proposed. PMID- 25536507 TI - Simultaneous microbial and electrochemical reductions of vanadium (V) with bioelectricity generation in microbial fuel cells. AB - Simultaneous microbial and electrochemical reductions of vanadium (V) with bioelectricity generation were realized in microbial fuel cells (MFCs). With initial V(V) concentrations of 75 mg/l and 150 mg/l in anolyte and catholyte, respectively, stable power output of 419+/-11 mW/m(2) was achieved. After 12h operation, V(V) concentration in the catholyte decreased to the value similar to that of the initial one in the anolyte, meanwhile it was nearly reduced completely in the anolyte. V(IV) was the main reduction product, which subsequently precipitated, acquiring total vanadium removal efficiencies of 76.8+/-2.9%. Microbial community analysis revealed the emergence of the new species of Deltaproteobacteria and Bacteroidetes as well as the enhanced Spirochaetes mainly functioned in the anode. This study opens new pathways to successful remediation of vanadium contamination. PMID- 25536508 TI - Study on the preparation of wood vinegar from biomass residues by carbonization process. AB - In the paper, the production of wood vinegar from Chinese fir sawdust (FS), cotton stalk (CS) and bamboo sawdust (BS) by carbonization process was addressed. The wood vinegar yield was investigated and the organic compounds contained were determined by gas chromatography and mass spectrometry. It was found that the refined wood vinegar yield of FS increased firstly and then decreased with increasing carbonization temperature and the highest yield reached about 25% in 350-450 degrees C. The relative contents of acids and ketones from FS decreased and that of phenols increased with increasing temperature. The relative contents of acids and phenols in the wood vinegars produced from the samples were in the order of BS>CS>FS and that of ketones reversed. KCl solution treatment caused a decrease in the relative contents of the phenols and ketones, but an increase in that of the acids in FS wood vinegar. PMID- 25536509 TI - Novel method for screening microbes for application in microbial fuel cell. AB - The ability to produce and to transport exo-electrons by microbes either to external acceptors or to electrodes are reported in our study. All investigated microorganisms (exception of Lactobacillus plantarum) exhibited strong iron reducing capabilities in the absence of mediator meaning production and secretion of exo-electrons to the growth medium. L.plantarum, Saccharomyces cerevisiae and Escherichia coli need an electron shuttle molecule to reduce Fe(3+) ion. Significant correlation was observed between growth and iron-reducing capacity, as well as between initial cell counts and iron-reducing capacity. Changes of bio current generated in MFC and iron-reduction were experimentally monitored, and a mathematical model was established by regression analysis. Based on these results, a novel and rapid screening method was developed for the selection of microorganisms for potential application in MFC. The method is based on the measurement of absorbance of bacterial and yeast cultures at 460 nm, providing a robust and high sample throughput approach. PMID- 25536510 TI - Co-fermentation of hemicellulose and starch from barley straw and grain for efficient pentoses utilization in acetone-butanol-ethanol production. AB - This study aims to efficiently use hemicellulose-based biomass for ABE (acetone butanol-ethanol) production by co-fermentation with starch-based biomass. Two processes were investigated: (I) co-fermentation of sugars derived from hemicellulose and starch in a mixture of barley straw and grain that was pretreated with dilute acid; (II) co-fermentation of straw hemicellulosic hydrolysate and gelatinized grain slurry in which the straw was pretreated with dilute acid. The two processes produced 11.3 and 13.5 g/L ABE that contains 7.4 and 7.8 g/L butanol, respectively. In process I, pretreatment with 1.0% H2SO4 resulted in better ABE fermentability than with 1.5% H2SO4, but only 19% of pentoses were consumed. In process II, 95% of pentoses were utilized even in the hemicellulosic hydrolysate pretreated with more severe condition (1.5% H2SO4). The results suggest that process II is more favorable for hemicellulosic biomass utilization, and it is also attractive for sustainable biofuel production due to great biomass availability. PMID- 25536511 TI - Energetic approach of biomass hydrolysis in supercritical water. AB - Cellulose hydrolysis can be performed in supercritical water with a high selectivity of soluble sugars. The process produces high-pressure steam that can be integrated, from an energy point of view, with the whole biomass treating process. This work investigates the integration of biomass hydrolysis reactors with commercial combined heat and power (CHP) schemes, with special attention to reactor outlet streams. The innovation developed in this work allows adequate energy integration possibilities for heating and compression by using high temperature of the flue gases and direct shaft work from the turbine. The integration of biomass hydrolysis with a CHP process allows the selective conversion of biomass into sugars with low heat requirements. Integrating these two processes, the CHP scheme yield is enhanced around 10% by injecting water in the gas turbine. Furthermore, the hydrolysis reactor can be held at 400 degrees C and 23 MPa using only the gas turbine outlet streams. PMID- 25536512 TI - Metabolic engineering of Saccharomyces cerevisiae ethanol strains PE-2 and CAT-1 for efficient lignocellulosic fermentation. AB - In this work, Saccharomyces cerevisiae strains PE-2 and CAT-1, commonly used in the Brazilian fuel ethanol industry, were engineered for xylose fermentation, where the first fermented xylose faster than the latter, but also produced considerable amounts of xylitol. An engineered PE-2 strain (MEC1121) efficiently consumed xylose in presence of inhibitors both in synthetic and corn-cob hydrolysates. Interestingly, the S. cerevisiae MEC1121 consumed xylose and glucose simultaneously, while a CEN.PK based strain consumed glucose and xylose sequentially. Deletion of the aldose reductase GRE3 lowered xylitol production to undetectable levels and increased xylose consumption rate which led to higher final ethanol concentrations. Fermentation of corn-cob hydrolysate using this strain, MEC1133, resulted in an ethanol yield of 0.47 g/g of total sugars which is 92% of the theoretical yield. PMID- 25536513 TI - Intralesional Rituximab in the Treatment of Refractory Oral Pemphigus Vulgaris. AB - IMPORTANCE: Oral lesions of pemphigus vulgaris are usually recalcitrant and respond slowly to treatments. Corticosteroid injection is considered to be the most effective local treatment in oral pemphigus vulgaris. However, intralesional corticosteroids are not effective in all remnant lesions. In 3 such patients with pemphigus vulgaris, we evaluated the utility of 2 injections (on days 1 and 15) of intralesional rituximab, 5 mg/cm2, in terms of accelerated healing, limitation of the use of systemic immunosuppressants, and reduction of their adverse effects. OBSERVATIONS: Three patients (1 man and 2 women) received 2 doses of intralesional rituximab in March and April 2013. All 3 patients responded to the treatment. In patients 1 and 2, the objective severity score was reduced to 0 at the final visit from a baseline score of 4 and 5, respectively (range, 0-11). The subject severity score in these patients was reduced to 1.0 and 0 from a baseline score of 22.0 and 22.5, respectively. After clinical remission was achieved, patient 3 developed a relapse of mucosal lesions. At the final visit, all of the patients were satisfied with the treatment, with a mean satisfaction score of 8 (maximum score, 10). We found a marked decline in the CD19 cell count from a pretreatment mean count of 287 cells/uL to 6 cells/uL on day 15 after a single intralesional rituximab injection. Adverse events were limited to local pain in 1 patient. CONCLUSIONS AND RELEVANCE: Intralesional rituximab administration lacks the adverse effects of intravenous administration. This method reduces the amount of drug administered and therefore is less expensive. Encouraging results from our study should prompt further evaluation of this novel route of rituximab administration in patients with refractory oral pemphigus vulgaris. PMID- 25536514 TI - Spatial dynamics of bovine tuberculosis in the Autonomous Community of Madrid, Spain (2010-2012). AB - Progress in control of bovine tuberculosis (bTB) is often not uniform, usually due to the effect of one or more sometimes unknown epidemiological factors impairing the success of eradication programs. Use of spatial analysis can help to identify clusters of persistence of disease, leading to the identification of these factors thus allowing the implementation of targeted control measures, and may provide some insights of disease transmission, particularly when combined with molecular typing techniques. Here, the spatial dynamics of bTB in a high prevalence region of Spain were assessed during a three year period (2010-2012) using data from the eradication campaigns to detect clusters of positive bTB herds and of those infected with certain Mycobacterium bovis strains (characterized using spoligotyping and VNTR typing). In addition, the within-herd transmission coefficient (beta) was estimated in infected herds and its spatial distribution and association with other potential outbreak and herd variables was evaluated. Significant clustering of positive herds was identified in the three years of the study in the same location ("high risk area"). Three spoligotypes (SB0339, SB0121 and SB1142) accounted for >70% of the outbreaks detected in the three years. VNTR subtyping revealed the presence of few but highly prevalent strains within the high risk area, suggesting maintained transmission in the area. The spatial autocorrelation found in the distribution of the estimated within-herd transmission coefficients in herds located within distances <14 km and the results of the spatial regression analysis, support the hypothesis of shared local factors affecting disease transmission in farms located at a close proximity. PMID- 25536515 TI - Effects of pressure support ventilation mode on emergence time and intra operative ventilatory function: a randomized controlled trial. AB - We tested the hypothesis that pressure-support ventilation (PSV) allows a reduction in emergence time and laryngeal mask airway (LMA) removal time after general anesthesia compared to volume-controlled mechanical ventilation (CMV). Because spontaneous breathing (SB) is often used with LMA under general anesthesia, patients were allocated randomly to three groups (CMV, SB and PSV). Thirty-six consecutive ASA I-II patients scheduled for knee arthroscopic surgery under general anesthesia with a LMA and breathing throughout the ventilator circuit were included. Hemodynamic and ventilatory variables were recorded before and 10-min after general anesthesia-induction, at the surgical incision, at the end of anaesthetic drugs infusion and when the patient was totally awake (which defines emergence time). LMA removal time, drug consumption were recorded at the end of the surgical procedure. Leak fraction around the LMA was also evaluated. LMA removal time was significantly higher in the CMV-group (18 +/- 6 min) compared to both SB (8 +/- 4 min) and PSV (7 +/- 4 min, P < 0.05) groups as well as for emergence time: CMV-group (32 +/- 12 min), SB (17 +/- 7 min) and PSV (13 +/- 6 min, P < 0.05) groups. Total propofol consumption was significantly lower in the PSV-group (610 +/- 180 mg) than in both CMV (852 +/- 330 mg) and SB (734 +/- 246 mg, P < 0.05) groups. Air leaks around the LMA was significantly higher in the CMV-group than in the SB and PSV groups (16% vs 3% and 7%, all P<0.05). In conclusion, in knee arthroscopic surgery, in comparison to CMV, PSV use during general anesthesia in unparalyzed patients decreases LMA removal time, propofol consumption and leaks around LMA while improving ventilatory variables without adverse effects. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN17382426. PMID- 25536516 TI - Sensitivity and Specificity of Stability Criteria for Immediately Loaded Splinted Maxillary Implants. AB - BACKGROUND: To assess the suitability of dental implants for immediate loading, primary stability is usually evaluated intraoperatively. PURPOSE: This retrospective study aimed to assess the suitability of three stability parameters - namely, insertion torque (IT), implant stability quotient (ISQ; measured by resonance frequency analysis), and Periotest (PT) values - as potential predictors for the risk of nonosseointegration of immediately loaded splinted implants. The stability parameters were routinely collected under immediate loading. MATERIALS AND METHODS: Nineteen patients with 11 edentulous and 8 partially edentulous maxillae were treated with 105 dental implants, which were immediately loaded using temporary fixed dentures. The IT results, PT values, and ISQ results were recorded. Receiver operating characteristic analysis was performed to assess the quality of each parameter as a diagnostic test. RESULTS: After a 3-month observation period, 11 implants in four patients were not osseointegrated. The IT and ISQ (IT 25.0 +/- 12.5 Ncm and 8.4 +/- 2.3 Ncm; PT 1.5 +/- 3.0 and +2.7 +/- 3.0; and ISQ 62.6 +/- 6.7 and 54.7 +/- 6.2) differed significantly between the osseointegrated and failed implants (p < .005). The IT showed the greatest specificity at a sensitivity of 1 and the greatest area under the curve (AUC; 0.929), followed by the PT value (AUC = 0.836) and ISQ (AUC = 0.811). CONCLUSIONS: Among the intraoperative parameters analyzed, IT showed the highest specificity at a high sensitivity of 1. Therefore, the IT can be considered the most valid prognostic factor for osseointegration of immediately loaded splinted dental implants. PMID- 25536517 TI - A Novel Device to Preserve Physical Activities of Daily Living in Healthy Older People. AB - OBJECTIVE: To determine the effectiveness of exercise in improving sensorimotor function and functional performance, crucial parts of activities of daily living in healthy older adults. DESIGN: RCT. SETTING: Laboratory. PARTICIPANTS: 39 subjects (M = 71.8 years, range: 61-89 years). INTERVENTION: Task-oriented visual feedback balance training. PRIMARY OUTCOME MEASURE: Timed Up & Go (TUG). SECONDARY OUTCOME MEASURES: Chair stand test (CST), self-paced walk test, maximum isometric torque, quiet stand posturography, and dynamic balance (DB). RESULTS: Postintervention comparison of the treatment group (TG) and control group (CG) showed better TUG (p < .01), CST (p < .001), and DB (p < .025) for the TG. Pre post intervention comparison of the TG showed better clinically-relevant outcomes in TUG (p < .001), CST (p < .001), and DB (p < .001). CONCLUSION: Active driven visual feedback balance training is effective in improving functional performance and dynamic balance in older adults. PMID- 25536519 TI - Cholesterol side chain analogs but not its ether analogs possess cholesterol lowering activity. AB - Cholesterol analogs can be used to treat hypercholesterolemia. The present study was to test the effects of cholesteryl 3beta-ethoxy (CE) and cholesteryl 3beta methoxy (CM) on plasma total cholesterol (TC) compared with that of beta sitosterol (SI) in hamsters fed a high cholesterol diet. CM and CE are the methoxy and ethoxy analogs of cholesterol while SI is an analog of cholesterol having an additional ethyl group on the side chain. Results showed that SI at a dose of 0.1% could effectively reduce plasma TC by 18%. The analysis of sterols in the plasma and liver did not detect the presence of SI, proving that it was poorly absorbed in the intestine. In contrast, both CE and CM had no effect on plasma TC. However, CE and CM were found to accumulate in both plasma and liver, indicating that they could be well absorbed in the intestine. It was therefore concluded that analogs having different side chains possessed plasma TC-lowering activity, while analogs or derivatives on the hydroxyl group had no hypocholesterolemic activity. PMID- 25536518 TI - Development of an in vitro renal epithelial disease state model for xenobiotic toxicity testing. AB - There is a growing impetus to develop more accurate, predictive and relevant in vitro models of renal xenobiotic exposure. As part of the EU-FP7, Predict-IV project, a major aim was to develop models that recapitulate not only normal tissue physiology but also aspects of disease conditions that exist as predisposing risk factors for xenobiotic toxicity. Hypoxia, as a common micro environmental alteration associated with pathophysiology in renal disease, was investigated for its effect on the toxicity profile of a panel of 14 nephrotoxins, using the human proximal tubular epithelial RPTECT/TERT1 cell line. Changes in ATP, glutathione and resazurin reduction, after 14 days of daily repeat exposure, revealed a number of compounds, including adefovir dipivoxil with enhanced toxicity in hypoxia. We observed intracellular accumulation of adefovir in hypoxia and suggest decreases in the efflux transport proteins MRP4, MRP5, NHERF1 and NHERF3 as a possible explanation. MRP5 and NHERF3 were also down regulated upon treatment with the HIF-1 activator, dimethyloxalylglycine. Interestingly, adefovir dependent gene expression shifted from alterations in cell cycle gene expression to an inflammatory response in hypoxia. The ability to investigate aspects of disease states and their influence on renal toxin handling is a key advantage of in vitro systems developed here. They also allow for detailed investigations into mechanisms of compound toxicity of potential importance for compromised tissue exposure. PMID- 25536520 TI - No evidence for AID/MBD4-coupled DNA demethylation in zebrafish embryos. AB - The mechanisms responsible for active DNA demethylation remain elusive in Metazoa. A previous study that utilized zebrafish embryos provided a potent mechanism for active demethylation in which three proteins, AID, MBD4, and GADD45 are involved. We recently found age-dependent DNA hypomethylation in zebrafish, and it prompted us to examine if AID and MBD4 could be involved in the phenomenon. Unexpectedly, however, we found that most of the findings in the previous study were not reproducible. First, the injection of a methylated DNA fragment into zebrafish eggs did not affect either the methylation of genomic DNA, injected methylated DNA itself, or several loci tested or the expression level of aid, which has been shown to play a role in demethylation. Second, aberrant methylation was not observed at certain CpG islands following the injection of antisense morpholino oligonucleotides against aid and mbd4. Furthermore, we demonstrated that zebrafish MBD4 cDNA lacked a coding region for the methyl-CpG binding domain, which was assumed to be necessary for guidance to target regions. Taken together, we concluded that there is currently no evidence to support the proposed roles of AID and MBD4 in active demethylation in zebrafish embryos. PMID- 25536521 TI - Resveratrol potentiates vitamin D and nuclear receptor signaling. AB - The 1,25-dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle. We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (VDRE) and mammalian 2-hybrid (M2H) transcriptional system technology. Via VDRE-based assays in kidney, colon and myoblast cells, VDR-mediated transcription was activated by resveratrol, and a cooperative effect on transactivation was observed with resveratrol plus 1,25D. The M2H assay revealed a modest, resveratrol-induced dimerization of VDR with its retinoid X receptor (RXR) heteropartner. Cells treated with both resveratrol and 1,25D displayed synergistic stimulation of VDR-RXR heterodimerization, while resveratrol antagonized rexinoid-mediated RXR-RXR homodimerization. Increased transactivation in response to resveratrol was also observed with a subset of other nuclear receptors and their respective cognate responsive elements. Evaluation of wild-type versus a ligand-binding domain mutant VDR revealed that hormone-responsiveness to 1,25D was severely depressed, while the response to resveratrol was only moderately attenuated. Moreover, radiolabeled 1,25D displacement assays demonstrated an increase in VDR-bound 1,25D in the presence of resveratrol. Thus, resveratrol may affect VDR and other nuclear receptors indirectly, likely via the ability of resveratrol to: (1) potentiate 1,25D binding to VDR; (2) activate RXR; and/or (3) stimulate SIRT1, an enzyme known to deacetylate nuclear receptors. The results of this study elucidate a possible pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol, both of which converge on VDR signaling. PMID- 25536522 TI - General management of nonagenarian patients: a review of the literature. AB - The number of nonagenarian people in the world is steadily growing. This phenomenon will increase in future years: in 2050, world population prospects estimate 71.16 million people aged 90 years or older. The two main causes of death among people aged 85 years or more in Europe in 2003 were cardiovascular and cerebrovascular diseases and cancers. However, the elderly are often excluded from clinical trials; they are underrepresented in clinical registries and especially nonagenarians. Care (medical, surgical, oncology) of these very elderly is currently insufficiently based on scientific recommendations. For the physician, the choice to treat or not to treat very elderly patients (for fear of side effects) is difficult. Oncology is particularly affected by this problem. Here we review these different fields of internal medicine management of nonagenarian patients with a special focus on oncology and on comprehensive geriatric assessment as a base for all care decision taking. PMID- 25536525 TI - Phosphate modulates receptor sulfotyrosine recognition by the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). AB - Tyrosine sulfation is a widespread post-translational modification that mediates the interactions of secreted and membrane-associated proteins in such varied biological processes as peptide hormone action, adhesion, blood coagulation, complement activation and regulation of leukocyte trafficking. Due to the heterogeneous nature of tyrosine sulfation, detailed biochemical and biophysical studies of tyrosine sulfation rely on homogenous, synthetic sulfopeptides. Here we describe the synthesis of a fluorescent sulfopeptide (FL-R2D) derived from the chemokine receptor CCR2 and the application of FL-R2D in direct and competitive fluorescence anisotropy assays that enable the efficient measurement of binding affinities between sulfopeptides and their binding proteins. Using these assays, we have found that the binding of the chemokine monocyte chemoattractant protein 1 (MCP-1) to sulfated peptides derived from the chemokine receptor CCR2 is highly dependent on the assay buffer. In particular, phosphate buffer at close to physiological concentrations competes with the receptor sulfopeptide by binding to the sulfopeptide binding pocket on the chemokine surface. Thus, physiological phosphate may modulate the receptor binding selectivity of chemokines. PMID- 25536524 TI - Drinking songs: alcohol effects on learned song of zebra finches. AB - Speech impairment is one of the most intriguing and least understood effects of alcohol on cognitive function, largely due to the lack of data on alcohol effects on vocalizations in the context of an appropriate experimental model organism. Zebra finches, a representative songbird and a premier model for understanding the neurobiology of vocal production and learning, learn song in a manner analogous to how humans learn speech. Here we show that when allowed access, finches readily drink alcohol, increase their blood ethanol concentrations (BEC) significantly, and sing a song with altered acoustic structure. The most pronounced effects were decreased amplitude and increased entropy, the latter likely reflecting a disruption in the birds' ability to maintain the spectral structure of song under alcohol. Furthermore, specific syllables, which have distinct acoustic structures, were differentially influenced by alcohol, likely reflecting a diversity in the neural mechanisms required for their production. Remarkably, these effects on vocalizations occurred without overt effects on general behavioral measures, and importantly, they occurred within a range of BEC that can be considered risky for humans. Our results suggest that the variable effects of alcohol on finch song reflect differential alcohol sensitivity of the brain circuitry elements that control different aspects of song production. They also point to finches as an informative model for understanding how alcohol affects the neuronal circuits that control the production of learned motor behaviors. PMID- 25536526 TI - Self-compassion as a moderator of thinness-related pressures' associations with thin-ideal internalization and disordered eating. AB - During situations that threaten personal adequacy, people high in self-compassion are kind and caring toward themselves, mindful of their distress, and recognize that being imperfect is part of the human experience. Therefore, self-compassion may offset certain disorders (e.g., eating disorders) associated with environmental threats (e.g., thinness-related pressures). In this cross-sectional study, we explored self-compassion's associations with threats involving thinness related pressures (from friends, family, partners, and media), thin-ideal internalization, and disordered eating among an online sample of 435 U.S. community women. Findings indicated that self-compassion buffered the links from media thinness-related pressure to disordered eating and thin-ideal internalization. Furthermore, higher self-compassion was directly associated with fewer perceived thinness-related pressures, lower thin-ideal internalization, and lower disordered eating. Collectively, these findings add to the growing conceptualization of self-compassion as beneficial to eating behavior and help justify pursuing rigorous longitudinal and clinical examinations of self compassion as a protective factor of disordered eating. PMID- 25536527 TI - Latest food and drug administration's efforts to improve safe contact lens use. PMID- 25536528 TI - Scleral lenses: a literature review. AB - OBJECTIVE: To present a comprehensive review of current and historical literature on scleral lenses. METHODS: A comprehensive search of several databases from each database's earliest inception to May 23, 2014 was conducted by an experienced librarian with input from the author to locate articles related to scleral lens design, fabrication, prescription, and management. RESULTS: A total of 899 references were identified, 184 of which were directly related to scleral lenses. References of interest were organized by date, topic, and study design. Most of articles published before 1983 presented lens design and fabrication techniques or indications for scleral lens therapy. Case reviews published after 1983 identified major indications for scleral lenses (corneal ectasia, ocular surface disease, and refractive error) and visual and functional outcomes of scleral lens wear. Statistically significant improvements in visual acuity, vision-related quality of life, and ocular surface integrity were reported. Reviews of ocular and systemic conditions suggested that comprehensive management strategies for these conditions could include scleral lenses. Early work investigating scleral lens fitting characteristics, optical qualities, and potential physiological impact on anterior ocular structures have been published in the past 5 years. CONCLUSIONS: Indications for scleral lens wear are well-established. Developing areas of research on the physiologic impact of scleral lens wear on the ocular surface, the use of technology to improve scleral lens vision and fit, and the impact of these devices on the quality of life should further enhance our understanding of scleral lenses in the future. PMID- 25536529 TI - Community practice patterns for bacterial corneal ulcer evaluation and treatment. AB - OBJECTIVE: To examine current practice patterns in the management of bacterial keratitis among U.S. ophthalmologists and differences in the management and opinions between cornea specialists and non-cornea specialists. METHODS: A questionnaire was distributed to randomly selected ophthalmologists in July 2011 using an online survey system. It inquired about the number of patients with corneal ulcers seen monthly, frequency of Gram staining and culturing corneal ulcers, maintenance of diagnostic supplies, opinions on when culturing is necessary for corneal ulcers, treatment preferences for different severities of bacterial corneal ulcers, and opinions regarding relative efficacy of fourth generation fluoroquinolones and fortified broad-spectrum antibiotics. RESULTS: One thousand seven hundred one surveys were distributed, and 486 (28.6%) surveys were returned. A minority of corneal ulcers was Gram stained (23.7%+/-34.1%, mean+/-SD) or cultured (35.1%+/-38.0%), but cornea specialists were more likely to perform both. The most popular antibiotic for the treatment of less severe ulcers was moxifloxacin (55.4%), and the most popular treatment of more severe ulcers was fortified broad-spectrum antibiotics (62.7%). Cornea specialists were significantly more likely than non-cornea specialists to prescribe fortified antibiotics for more severe corneal ulcers (78.1% vs. 53.7%, P<0.0001). A greater number of cornea specialists stated that fourth-generation fluoroquinolones were less effective than fortified antibiotics for the treatment of more severe corneal ulcers (79.6% of cornea specialists vs. 60.9% of non-cornea specialists, P<0.001). CONCLUSIONS: Cornea specialists and non-cornea specialists manage bacterial keratitis differently, with cornea specialists more likely to perform diagnostic testing and prescribe fortified broad-spectrum antibiotics for severe bacterial keratitis. Additional prospective studies demonstrating visual outcomes after differential treatment of bacterial keratitis are needed. PMID- 25536530 TI - Comparison of surface roughness and bacterial adhesion between cosmetic contact lenses and conventional contact lenses. AB - OBJECTIVE: To compare physical characteristics of cosmetic contact lenses (Cos CLs) and conventional contact lenses (Con-CLs) that might affect susceptibility to bacterial adhesion on the contact lens (CL) surface. METHODS: Surface characteristics of Cos-CLs and Con-CLs made from the same material by the same manufacturer were measured by atomic force microscopy (AFM) and scanning electron microscopy. To determine the extent and rate of bacterial adhesion, Cos-CL and Con-CL were immersed in serum-free Roswell Park Memorial Institute media containing Staphylococcus aureus or Pseudomonas aeruginosa. Additionally, the rate of removal of adherent bacteria was evaluated using hand rubbing or immersion in multipurpose disinfecting solutions (MPDS). RESULTS: The mean surface roughness (root mean square and peak-to-valley value) measured by AFM was significantly higher for Cos-CL than for Con-CL. At each time point, significantly more S. aureus and P. aeruginosa adhered to Cos-CL than to Con-CL, which correlated with the surface roughness of CL. In Cos-CL, bacteria were mainly found on the tinted surface rather than on the noncolored or convex areas. Pseudomonas aeruginosa attached earlier than S. aureus to all types of CL. However, P. aeruginosa was more easily removed from the surface of CL than S. aureus by hand rubbing or MPDS soaking. CONCLUSIONS: Increased surface roughness is an important physical factor for bacterial adhesion in Cos-CL, which may explain why rates of bacterial keratitis rates are higher in Cos-CL users in CL physical characteristics. PMID- 25536531 TI - Changes in ultraviolet transmittance of hydrogel and silicone hydrogel contact lenses induced by wear. PMID- 25536532 TI - Interactions between serotonin and glutamate-nitric oxide pathways in zebrafish scototaxis. AB - NMDA receptors have been implicated in the acute response to stress, possibly mediated the nitric oxide pathway; serotonin has also been implicated in these responses, and has recently been shown to modulate the nitric oxide pathway via 5 HT1 and 5-HT2 receptors. In this work, we compare the effects of NMDA and a 5 HT1A receptor ligands on light/dark preference in adult zebrafish, and investigate whether nitric oxide mediates the effects of such drugs. The noncompetitive NMDA receptor antagonist MK-801 decreased dark preference (scototaxis), while NMDA increased it; the effects of NMDA were completely blocked by pretreatment with the nitric oxide synthase (NOS) antagonist L-NAME. SNP, a nitric oxide donor, produced a bell-shaped dose-response profile on scototaxis. Treatment with 5-HTP increased scototaxis, an effect which was potentiated by pre-treatment with NMDA, but not MK-801, and partially blocked by L-NAME. The 5-HT1A receptor antagonist WAY 100,635 decreased scototaxis, an effect which was completely blocked by L-NAME. These results suggest that tonic NOS inhibition is an important downstream effector of 5-HT1A receptors in the regulation of dark preference behavior in zebrafish, and that NOS is also under phasic independent control by NMDA receptors. PMID- 25536533 TI - In vivo ZW800-microbead imaging of retinal and choroidal vascular leakage in mice. AB - The eye is an attractive organ for non-invasive discovery and monitoring of disease progression. Traditionally, fluorescein angiography (FA) and indocyanine green angiography (ICGA) have been used for dynamic evaluation of the retina and its vasculature. However, both fluorescein and indocyanine green (ICG) possess considerable disadvantages. FA is limited to assessing superficial retinal blood flow and often results in an unclear view due to fluorescein leakage. This obscures important pathologies such as neovascularization, ischemia and inflammation. ICG, a near-infrared fluorophore (NIRF), has nonspecific binding, high uptake and retention in tissues, as well as detrimental effects on the hepatobiliary tract. Here, we present a potential contrast agent for imaging ocular vascular permeability with ZW800, a heptamethine indocyanine NIRF, conjugated to polystyrene latex beads (ZW800m). ZW800 is an excellent alternative for near-infrared imaging, as it has excellent contrast, superior clearance, and is amendable to conjugation. ZW800m conjugation is an easy, attractive method of in vivo imaging and real-time tracking of ocular vascular pathologies. ZW800m is readily imaged via commercially available laser ophthalmoscope (SLO, HRA OCT, Spectralis) to assess vascular permeability in the mouse retina and choroid. In Type 1 diabetic Ins2Akita mice, ZW800m was observed in mouse retina but not in wild-type mice. After laser-induced choroidal neovascularization (CNV), ZW800m was observed in mouse choroid but not in control. In both CNV and diabetic mice, ZW800 imaging showed increased hyperfluorescence on ICG modality (ICGA) not seen on FA. Presence of ZW800m in respective tissues was confirmed ex vivo with flatmounts visualized with EVOS 800 nm light cube. ZW800 imaging may be easily employed in the research laboratory. PMID- 25536535 TI - Can experimentally induced positive affect attenuate generalization of fear of movement-related pain? AB - Recent experimental data show that associative learning processes are involved not only in the acquisition but also in the spreading of pain-related fear. Clinical studies suggest involvement of positive affect in resilience against chronic pain. Surprisingly, the role of positive affect in associative learning in general, and in fear generalization in particular, has received scant attention. In a voluntary movement paradigm, in which one arm movement (reinforced conditioned stimulus [CS+]) was followed by a painful stimulus and another was not (unreinforced conditioned stimulus [CS-]), we tested generalization of fear inhibition in response to 5 novel but related generalization movements (GSs; within-subjects) after either a positive affect induction or a control exercise (Group = between-subjects) in healthy participants (N = 50). The GSs' similarity with the original CS+ movement and CS- movement varied. Fear learning was assessed via verbal ratings. Results indicated that there was an interaction between the increase in positive affect and the linear generalization gradient. Stronger increases in positive affect were associated with steeper generalization curves because of relatively lower pain unconditioned stimulus expectancy and less fear of stimuli more similar to the CS . There was no Group by Stimulus interaction. Results thus suggest that positive affect may enhance safety learning through promoting generalization from known safe movements to novel yet related movements. Improved safety learning may be a central mechanism underlying the association between positive affect and increased resilience against chronic pain. PERSPECTIVE: We investigated the extent to which positive affect influences the generalization (ie, spreading) of pain-related fear inhibition in response to situations similar to the original, pain-eliciting situation. Results suggest that increasing positive affect in the acute pain stage may limit the spreading of pain-related fear, thereby potentially inhibiting transition to chronic pain conditions. PMID- 25536534 TI - Analysis of a method for establishing a model with more stable chronic glaucoma in rhesus monkeys. AB - In this study, we utilized yellow-wavelength laser treatment and measured aqueous outflow facility to establish a model for chronic glaucoma in rhesus monkeys. We then compared the effects of photocoagulation resulting from exposure to the yellow laser or to a green laser. Twelve rhesus monkeys were used to establish the model, and the yellow and green lasers were utilized for 360 degrees photocoagulation in the anterior-chamber angles of the right eye in all subjects. After certain periods of time before and after the creation of the glaucoma model, the cornea, aqueous humor, optic cup, intraocular pressure (IOP), outflow facility, retinal nerve fiber layer (RNFL), and pathology of the trabecular meshwork were analyzed. Both the yellow and green lasers caused an increase in IOP compared with before photocoagulation (18.6 +/- 2.6 mm Hg and 16.1 +/- 1.8 mm Hg, respectively), with an average photocoagulation from the yellow and green lasers of 39.2 +/- 7.9 mm Hg and 30.3 +/- 4.7 mm Hg, respectively (P < 0.01). However, the success rate of a second photocoagulation treatment in the yellow laser group was significantly higher than in the green laser group (P < 0.05). After the increase in IOP, both groups exhibited an inflammatory response in the anterior segment, enlarged cupping, and a decrease in the average thickness of the RNFL. However, the yellow laser caused less corneal edema than the green laser (P < 0.05), and the outflow facility of the two groups (0.33 +/- 0.09 and 0.30 +/- 0.07 MUl/min/mm Hg for the yellow and green lasers, respectively) showed different degrees of differences (0.05 +/- 0.02 and 0.07 +/- 0.02 MUl/min/mm Hg for the yellow and green lasers, respectively) into the abnormal range after photocoagulation. Pathological examination revealed that the depth of destruction of the trabecular meshwork appeared to be deeper in the yellow laser group than in the green laser group. In conclusion, application of a yellow laser combined with measuring aqueous outflow facility produced a glaucoma model with a minor inflammatory response and few IOP fluctuations. PMID- 25536537 TI - Anthropometry and Performance in Wheelchair Basketball. AB - This study investigated whether anthropometric characteristics, generic and specific sprinting, agility, strength, and endurance capacity could differentiate between First-Division and Third-Division wheelchair basketball (WB) players. A First-Division WB team (n = 8; age = 36.05 +/- 8.25 years, sitting body height = 91.38 +/- 4.24 cm, body mass = 79.80 +/- 12.63 kg) and a Third-Division WB team (n = 11; age = 31.10 +/- 6.37 years, sitting body height = 85.56 +/- 6.48 cm, body mass = 71.18 +/- 17.63 kg) participated in the study. Wheelchair sprint, agility, strength, and endurance tests were performed. The First-Division team was faster (8.7%) in 20 m without the ball, more agile (13-22%), stronger (18 33%), covered more distance (20%) in the endurance test, and presented higher values of rate of perceived exertion for the exercise load (48%) than the Third Division team. Moreover, the individual 20-m sprint time values correlated inversely with the individual strength/power values (from r = -0.54 to -0.77, p <= 0.05, n = 19). Wheelchair basketball coaches should structure strength and conditioning training to improve sprint and agility and evaluate players accordingly, so that they can receive appropriate training stimuli to match the physiological demands of their competitive level. PMID- 25536538 TI - Oxygen recovery kinetics in the forearm flexors of multiple ability groups of rock climbers. AB - The purpose of this study was to determine muscle tissue oxidative capacity and recovery in intermediate, advanced, and elite rock climbers. Forty-four male participants performed (a) sustained and (b) intermittent contractions at 40% of maximal volitional contraction (MVC) on a sport-specific fingerboard until volitional fatigue. Near-infrared spectroscopy was used to assess muscle tissue oxygenation during both the exercise and the 5-minutes passive recovery period, in the flexor digitorum profundus (FDP) and flexor carpi radialis (FCR). During the sustained contraction only, muscle tissue deoxygenation (O2 debt) in the FDP and FCR was significantly greater in elite climbers compared with the control, intermediate, and advanced groups (FDP: 32 vs. 15, 19, 22%; FCR: 19 vs. 11, 8, 15%, respectively). However, elite climbers had a significantly quicker time to half recovery (T1/2) than the control and intermediate groups in the FDP (8 vs. 95 and 47 seconds, respectively) and the FCR (7 vs. 30 and 97 seconds, respectively) because the O2% recovered per second being significantly greater (FDP: 4.2 vs. 0.7 and 0.3; FCR: 4.8 vs. 0.1 and 0.2, respectively). Furthermore, during the intermittent contraction, T1/2 in elite climbers was significantly quicker compared with the control and intermediate groups in the FDP (8 vs. 93 and 83 seconds, respectively) and FCR (16 vs. 76 and 50 seconds, respectively). Consequently, lower-level climbers should focus training on specific intermittent fatigue protocols. Competition or elite climbers should make use of appropriate rests on route to aid recovery and increase the chances of reaching the next hold. PMID- 25536536 TI - Physical and psychological correlates of fatigue and physical function: a Collaborative Health Outcomes Information Registry (CHOIR) study. AB - Fatigue is a multidimensional construct that has significant implications for physical function in chronic noncancer pain populations but remains relatively understudied. The current study characterized the independent contributions of self-reported ratings of pain intensity, sleep disturbance, depression, and fatigue to ratings of physical function and pain-related interference in a diverse sample of treatment-seeking individuals with chronic pain. These relationships were examined as a path modeling analysis of self-report scores obtained from 2,487 individuals with chronic pain from a tertiary care outpatient pain clinic. Our analyses revealed unique relationships of pain intensity, sleep disturbance, and depression with self-reported fatigue. Further, fatigue scores accounted for significant proportions of the relationships of both pain intensity and depression with physical function and pain-related interference and accounted for the entirety of the unique statistical relationship between sleep disturbance and both physical function and pain-related interference. Fatigue is a complex construct with relationships to both physical and psychological factors that has significant implications for physical functioning in chronic noncancer pain. The current results identify potential targets for future treatment of fatigue in chronic pain and may provide directions for future clinical and theoretical research in the area of chronic noncancer pain. PERSPECTIVE: Fatigue is an important physical and psychological variable that factors prominently in the deleterious consequences of pain intensity, sleep disturbance, and depression for physical function in chronic noncancer pain. PMID- 25536539 TI - Evidence that the talk test can be used to regulate exercise intensity. AB - The Talk Test (TT) has been shown to be a surrogate of the ventilatory threshold and to be a viable alternative to standard methods of prescribing exercise training intensity. The TT has also been shown to be responsive to manipulations known to change physiologic function including blood donation and training. Whether the TT can be used independently to regulated training intensity is not known. Physically active volunteers (N = 16) performed an incremental exercise test to identify stages of the TT (Last Positive [LP], Equivocal [EQ], and Negative [NEG]). In subsequent, randomly ordered, 30-minute steady-state runs, the running velocity was regulated solely by "clamping" the TT response desired and then monitoring the response of conventional markers of exercise intensity (heart rate, blood lactate, rating of perceived exertion). All subjects were able to complete the LP stage, but only 13 of 16 and 2 of 16 subjects were able to complete the EQ and NEG stages, respectively. Physiologic responses were broadly within those predicted from the incremental exercise test and within the appropriate range of physiologic responses for exercise training. Thus, in addition to correlating with convenient physiological markers, the TT can be used proactively to guide exercise training intensity. The LP stage produced training intensities compatible with appropriate training intensity in healthy adults and with recovery sessions or long duration training sessions in athletes. The EQ and NEG stages produced intensities compatible with higher intensity training in athletes. The results demonstrate that the TT can be used as a primary method to control exercise training intensity. PMID- 25536540 TI - Benefits of Strength and Skill-based Training During Primary School Physical Education. AB - Physical education (PE) programs are evolving from a traditional skill-centered model to a health-centered model that focuses on time engaged in moderate to vigorous physical activity (MVPA). However, improvements in muscular fitness and fundamental movement skills are prerequisites for continuous participation in MVPA. The purpose of this study was to examine the effects of integrative strength and skill-based training on measures of physical fitness in children during primary school PE. Children from two fourth grade PE classes were cluster randomized into either a fundamental integrative training (FIT) group (n = 20) or a control (CON) group (n = 21). The 8-week FIT program was performed twice per week during the first ~ 1 5 minutes of each PE class and consisted of a circuit of strength and skill-based exercises. All participants were assessed for health- and skill-related fitness before and after the intervention. The outcome variables were analyzed via 2 * 2 repeated measures analysis of variance with post hoc analysis. A significant (p <= 0.05) interaction of group by time was observed in FIT participants with improvements in aerobic capacity, push-ups, sit and reach flexibility, and single-leg hop. There were no groups by time effects for the sit-up and long jump tests. No injuries were reported. These findings highlight the potential benefits of integrating both health- and skill-related fitness components into primary school PE as evidenced by improvements in measures of aerobic capacity and muscular fitness in children. PMID- 25536541 TI - Co-administration of a probiotic strain Lactobacillus plantarum LS/07 CCM7766 with prebiotic inulin alleviates the intestinal inflammation in rats exposed to N,N-dimethylhydrazine. AB - The aim of this study was to determine the anti-inflammatory effects of preventive administration of a probiotic strain Lactobacillus plantarum LS/07 CCM7766 alone or in combination with prebiotic inulin or with flax-seed oil in the gut of rats, which developed chronic inflammation following administration of the pro-carcinogen N,N-dimethylhydrazine (DMH). After 28weeks administration of probiotic/prebiotic-containing diet, rats were killed and their colons were examined by immunohistological criteria, whereas cytokines were determined in the jejunal mucosa. Application of DMH triggered the production of pro-inflammatory cytokines IL-2, IL-6, IL-17, and TNF-alpha, expression of pro-inflammatory mediators NF-kappaB, COX-2 and iNOS and caused depletion of goblet cells. Supplementing the diet with L. plantarum and its combination with the prebiotic abolished DMH-induced inflammatory process in the jejunal mucosa by inhibiting the production of pro-inflammatory cytokines and by stimulation of anti inflammatory IL-10 cytokine synthesis, whereas concentration of TGF-beta1 was not influenced significantly. Diet prevented a decrease in goblet cell numbers but numbers of mast cells were lowered only moderately. However, combined treatment of rats with L. plantarum and flax-seed oil had no significant effect on the parameters examined, except for decreased expression of NF-kappaB, in comparison with the negative control. Results indicate that the preventive administration of probiotic L. plantarum LS/07 CCM7766 alone or in combination with prebiotic inulin to rats with DMH-induced chronic inflammation can reduce inflammatory process in the jejunal and colon mucosa, probably indirectly, and involves down regulation of synthesis of pro-inflammatory cytokines and suppression of NF kappaB activity in mucosal cells. PMID- 25536542 TI - Clinically-relevant cyclosporin and rapamycin concentrations enhance regulatory T cell function to a similar extent but with different mechanisms: an in-vitro study in healthy humans. AB - Evidence indicates that regulatory T cells (Tregs) are profoundly involved in promoting allograft tolerance after organ transplantation. Since a successful transplantation currently still requires a long-term immunosuppressive treatment, clarifying the specific impact of these drugs on Tregs may be of high clinical relevance. Conflicting results arise from the literature, particularly as concerns cyclosporine (CsA). The specific aim of this work was to evaluate in vitro the direct effects of clinically-relevant drug concentrations of three widely used immunosuppressive drugs, i.e. CsA, rapamycin (RAPA) and mycophenolic acid (MPA), on Treg activity, number and forkhead/winged helix transcription factor (FoxP3) expression in humans. Tregs (CD4(+)CD25(+)) isolated from healthy donors were cultured in the presence of different concentrations of CsA, RAPA or MPA. The suppressive activity of Tregs was evaluated in mixed lymphocyte reactions with CD4(+)CD25(-) T cells. Phenotype analysis and FoxP3 expression were assessed by flow cytometry. Clinically-relevant CsA and RAPA concentrations significantly enhanced to a similar extent the suppressive activity of Tregs. Although this effect was associated with an increase in Treg number as well as in FoxP3 expression with both drugs, the driving mechanism seemed to be primarily quantitative (i.e. increase of the cell number) for RAPA, whereas mainly qualitative (i.e. increase in FoxP3 levels) for CsA, respectively. Conversely, MPA did not show any effect on Treg function and number. These findings suggest that both RAPA and CsA may be beneficial in promoting Treg-dependent allograft tolerance after organ transplantation. PMID- 25536543 TI - Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 +/- 2.88%), neuron-like (52.63 +/- 4.16%), and astrocyte -like (22.36 +/- 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. PMID- 25536544 TI - State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" - research activities and scientific advance in 2013. AB - Research activities and scientific advance achieved in 2013 at the State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" (NRCRM) concerning medical problems of the Chornobyl disaster, radiation medicine, radiobiology, radiation hygiene and epidemiology in collaboration with the WHO network of medical preparedness and assistance in radiation accidents are outlined in the annual report. Key points include the research results of XRCC1 and XPD gene polymorphism in thyroid cancer patients, CD38 gene GG genotype as a risk factor for chronic lymphocytic leukemia, frequency of 185delAG and 5382insC mutations in BRCA1 gene in women with breast cancer, cognitive function and TERF1, TERF2, TERT gene expression both with telomere length in human under the low dose radiation exposure. The "source-scattering/shielding structures- man" models for calculation of partial dose values to the eye lens and new methods for radiation risk assessment were developed and adapted. Radiation risks of leukemia including chronic lymphocytic leukemia in the cohort of liquidators were published according to the "case control" study results after 20 years of survey. Increase of non-tumor morbidity in liquidators during the 1988-2011 with the maximum level 12-21 years upon irradiation was found. Incidence in evacuees appeared being of two-peak pattern i.e. in the first years after the accident and 12 years later. Experimental studies have concerned the impact of radio-modifiers on cellular systems, reproductive function in the population, features of the child nutrition in radiation contamination area were studied. Report also shows the results of scientific and organizational, medical and preventive work, staff training, and implementation of innovations. The NRCRM Annual Report was approved at the Scientific Council meeting of NAMS on March 3, 2014. PMID- 25536545 TI - Regulation of the radionuclide content in commodities produced in areas affected by the Chornobyl accident. AB - This paper discusses the approaches to regulation of the content of radionuclides in commodities and compares the international and Ukrainian standards, which establish permissible levels of the content of radionuclides in food-stuffs produced in the Chornobyl-affected areas. The paper gives the actual monitoring data and discusses the main causes of differences between Ukrainian, European and international standards. The need for improvement of current approaches to the regulation of the content of radionuclides in commodities is highlighted. PMID- 25536546 TI - Medical radiography examinations and carcinogenic effects. AB - The purpose of the review was the synthesis of the literature data and the results of our radiobiological (biodosimetric) research on the development of radiation-associated tumors as a result of medical radiography (X-ray) diagnostic. Medical X-ray examinations contribute the most to the excess of radiation exposure of the population, much of which is subject to examination to diagnose the underlying disease, the dynamic observation of the patient during treatment, the research of related deseases, and preventative examinations. The review provides arguments for the necessity of developing a more balanced indication for preventative radiological examination of the population in the aftermath of radio-ecological crisis caused by the Chornobyl accident, taking into account the likelihood of radiation carcinogenesis. The problems and tasks of biological (cytogenetic) dosimetry in radiology are formulated. PMID- 25536547 TI - Radiation-induced instability of human genome. AB - A brief review is dedicated to the phenomenon of radiation-induced genomic instability where the increased level of genomic changes in the offspring of irradiated cells is characteristic. Particular attention is paid to the problems of genomic instability induced by the low-dose radiation, role of the bystander effect in formation of radiation-induced instability, and its relationship with individual radiosensitivity. We believe that in accordance with the paradigm of modern radiobiology the increased human individual radiosensitivity can be formed due to the genome instability onset and is a significant risk factor for radiation-induced cancer. PMID- 25536548 TI - Dose- and age-dependent cardiovascular mortality among inhabitants of the Chornobyl contaminated areas. 1988-2010 observation period. AB - Objective. The goal of this study was to conduct a descriptive epidemiological analysis of cardiovascular disease mortality among people living in contaminated areas of Ukraine with regard for total cumulative effective doses and age at the time of the Chornobyl accident. Materials and methods. Depending on respective total cumulative effective doses for 1986-2010 the people living in contaminated areas of Ukraine were divided into cohorts of those exposed to 5.6-20.99 mSv (cohort 1) and 21.00-50.99 mSv (cohort 2) radiation doses. Each one was stratified by age categories - younger than 18 years old, aged 18-39 and 40-60 respectively. Death rate (ID/10^3 person-years) and mean error (+/-m) were calculated and Student's test (t) was applied to estimate the mortality from cardiovascular diseases for 1988-2010 period. Results. The significantly higher (ID/10^3 person-years is 8.08 +/- 0.10) cardiovascular disease mortality was revealed within 1988-2010 observation period among inhabitants of contaminated areas exposed to 21.00-50.00 mSv total effective radiation doses accumulated over 1986-2010 as compared to that in cohort 1 (ID/10^3 person-years is 6.29 +/- 0.06) for the same period. In the age groups (under 18, 18-39 and 40-60 years old) exposed to 21.0-50.0 mSv doses the mortality rate was significantly higher than in the corresponding age groups of the inhabitants with 5.6-20.99 mSv exposure (1.31 +/- 0.08 ID/10^3 person-years, 8.50 +/- 0.19, 48.95 +/- 0.33 vs 0.75 +/- 0.04, 5.00 +/- 0.11, 23.52 +/- 0.24 respectively). In the elder age groups with higher radiation doses the mortality was significantly higher (p < 0.05) than in those with lower doses: ID/10^3 person-years was 1.31 +/- 0.08 vs. 0.75 +/- 0.04 (those under 18 years); 8.50 +/- 0.19 vs. 5.00 +/- 0,11 (those aged 18-39); 48.95 +/- 0.33 vs. 23.54 +/- 0.24 (people aged 40-60). Among inhabitants with higher radiation doses the mortality rates for certain groups of cardiovascular diseases (coronary heart disease, cerebrovascular disease, arterial hypertension, diseases of arteries, arterioles and capillaries) were significantly higher compared to those having lower radiation doses. Conclusions. Cardiovascular mortality among inhabitants of contaminated areas of Ukraine is dependent on the total cumulative effective doses and age at the time of the Chornobyl accident. It is proved by a significantly higher (p < 0.05) mortality in people exposed to 21.00-50.0 mSv radiation doses compared to those having 5.6-20.99 mSv exposures. Mortality was significantly higher (p < 0.05) in age groups with higher doses as opposed to those with low ones. Maximum mortality was observed among inhabitants aged 40-60, while the lowest death rate in patients younger than 18 years old. The data obtained also suggest that the radiation factor can be considered here as one accelerating the aging and pathophysiological abnormalities in survivors. Coronary heart disease, cerebrovascular disease, arterial hypertension, diseases of arteries, arterioles and capillaries are the main causes of death from cardiovascular disease in people under investigation. PMID- 25536549 TI - Role of radiation and non-radiation factors on the development of coronary heart disease in the Chornobyl clean-up workers: epidemiological study results. AB - Objective. The objective of this study was to establish the risks for coronary heart disease in the Chornobyl clean-up workers with regard to a whole-body external radiation dose and non-radiation (biological, social-and-hygienic and behavioral) factors. Materials and methods. Risk-analysis was based on the cohort of the Chornobyl male clean-up workers 1986-1987 (8,625 men, including 3,623 with available whole-body external doses). Data of clinical-and-epidemiological registry, National Research Centre for Radiation Medicine were used for 1992-2013 monitoring period. We used the internal control group with radiation doses less than 0.05 Gy. Results. Statistically significant radiation risks in the Chornobyl clean-up workers were established for the coronary heart disease at doses 0.15 0.249 Gy, 0.25-0.99 Gy, 1 Gy and more (dose group 0.15-0.249 Gy RRY=1.9 (1.2; 3.1), ERR=4.6 (1.5; 14.9) Gy-1, EAR=64.2 cases per 1000 person-years, Gy); among exposed people aged 40 years and older - at doses 0.5-0.99 Gy (RRY=1.4 (1.05; 1.81), ERR=0.5 (0.03; 1.1) Gy-1, EAR=30.5 cases per 1000 person-years, Gy). Statistically significant risks for the disease under consideration were also identified with regard to non-radiation factors (smoking, improper physical training, adverse working conditions, diseases etc; age and psychoemotional overstrain were of a particular impact). Non-radiation factors are at most responsible for development of coronary heart disease. For this reason the control of potential confounding factors is required to assess the effect of the radiation factor both at a stage of comparison groups selection and analysis using the Mantel-Haenszel method. PMID- 25536550 TI - Individualized internal exposure doses reconstruction for the persons of Ukraine State Register: Report 1. Locally-specific models and doses of persons living in Rokytne raion of Rivne oblast, Ovruch raion of Zhytomyr oblast and Ivankiv raion of Kyiv oblast. AB - Study objective. Dosimetric support of the Ukrainian State Register of persons, affected due to the Chornobyl accident (SRU). Development the system of models and procedures for the individualized internal doses reconstruction for the subjects of SRU residing in radioactive contaminated territories of Rokytne raion of Rivne oblast, Ovruch raion of Zhytomyr oblast and Ivankiv raion of Kyiv oblast. Materials and methods. A detailed description for the schematic diagram of the methodology and mathematical relations of ecological-dosimetric models are given. It allows to reconstruct the individualized doses from the ingestion of food contaminated by radiocesium after the Chornobyl accident for the subjects of SRU from three raions of Rivne, Zhytomyr and Kyiv oblasts. Phenomenologically, the developed models are close to the previously developed complex of ecological and dosimetric models intended to estimate the reference doses for the entire population of Ukraine. Calibration of model parameters is based on mathematical treatment for results of extensive radioecological (radiocesium milk contamination) and dosimetric (radiocesium burden in human body) monitorings, that were provided in the period of 1986-2012 in the settlements of raions under consideration. Completeness and periodicity of radioecological and dosimetric monitorings allowed to realize the settlement-specific approach for dose reconstruction, wherein for each settlement either the function of radiocesium intake with diet or the function of time-variation of radiocesium concentration in the local cow's milk were established. Absolute raion milk equivalent of the diet (ARMEr) and relative age dependent intake of radiocesium with diet are specified as a raion-specific functions for each raion. ARMEr is used to calculate the doses of adults in the settlement for which the function was specified. RRI is used to calculate the doses for the subjects of four children age groups (< 2 years old, 3-7 years old, 8-12 years old, 13-17 years old). Results and conclusions. Models for individualized internal exposure doses reconstruction of SRU subjects are developed. The individualized doses are estimated for 28711 SRU subjects from Rokytne raion, 18790 SRU subjects from Ivankiv raion and 41585 SRU subjects from Ovruch raion. Results of doses individualization are given as annual average doses for the period of 1987-2012. The distribution of SRU subjects of different raions over the intervals of doses accumulated over the entire observation period is also given. Values of total (from internal and external exposure) doses for SRU subjects of the raions under consideration are given, as well. PMID- 25536551 TI - Individualized internal exposure doses reconstruction for the persons of Ukraine State Register: Report 2. Locally-specific models and doses of persons living in Kozelets and Ripky raions of Chernihiv oblast. AB - Study objective. Development a system of models and procedures for the individualized internal exposure doses reconstruction for the subjects of Ukrainian State Register of persons, affected due to the Chornobyl accident (SRU) and residing in radioactive contaminated territories of Kozelets and Ripky raions of Chernihiv oblast. Materials and methods. A description the schematic diagram and mathematical equations of ecological-dosimetric models are given that allow to reconstruct the individualized exposure doses from consumption of food contaminated with radiocesium of Chornobyl origin for inhabitants of two raions of Chernihiv oblast. Parameterization of the reconstruction models is based on the mathematical analysis of results for radioecological (radiocesium milk contamination) and dosimetric (radiocesium human body burden) monitorings, that were calculated in the period of 1986-2012 in the settlements of raions under consideration. Due to quite low level of radioactive cesium depositions on the ground in 1986, the territory of these raions was divided into two "territorial zones": TZ-1, an area where the 137Cs ground depositions density in 1986 exceeds 37 kBq/m2, and TZ-2, an area where this rate does not exceeds 37 kBq/m2. For each territorial zone in each raion, the initial time moment (year) was introduced in the reconstruction model. Since this year the concept of the so-called "reference dose" has been using. Its value was assigned to all persons, regardless of the results and availability of monitoring. The results of radioecological and dosimetric monitorings were used for setting in raion specific functions: the annual average concentration of 137Cs in milk per unit of 137Cs ground depositions for Kozelets raion, function of the temporary dynamic of 137Cs concentration in milk for Ripky raion, absolute raion milk equivalent of the diet (ARMEr), and relative age dependent intake of radiocesium with the diet. Results and conclusions. Models for individualized internal exposure doses reconstruction were applied to 27811 SRU subjects from Kozelets raion and 14553 SRU subjects from Ripky raion. Results of doses individualization are given as annual average values of internal and summarized (internal and external) exposure doses for the period of 1987-2012, as well as the distribution of SRU subjects of different raions according to the intervals of accumulat-ed doses over the entire period of observation. PMID- 25536552 TI - Foodstuff contamination and pattern of consumption by population of foremost radioactively contaminated territories in Ukraine during the remote period of the Chornobyl disaster clean-up. AB - Objective. The goal of the study was to estimate, from the perspective and in terms of hygienic provisions, the level of local food contamination by 137Cs and their pattern of consumption by residents of foremost radionuclide contaminated territories of Ukraine (Zhytomyr, Kyiv and Rivne oblasts) in the remote period of the Chornobyl disaster. Materials and methods. The article presents analytical data from the National Statistics Office of Ukraine concerning production and consumption of agricultural products in the territories of foremost severe radioactive contamination (TRC) i.e. Zhytomyr, Kyiv and Rivne oblasts (provinces). Data on levels of food contamination (milk, meat, fruits and vegetables, wild mushrooms and berries) received from the regional radiological control centers (RCC) and sanitary and epidemiological agencies/bureaus (SEA) were analyzed. According to results of questionnaire survey of residents in TRC of investigated regions (oblasts) the public awareness of radioactive contamination levels in local food production, their level of consumption and the use of cooking measures to reduce internal dose were assayed. Analytical, mathematical, statistical, sociological, and software engineering methods were applied. Results and conclusions. It was found that in the country and in study areas as well there is more than a half decrease of milk and meat production and consumption, and almost half times increased production of potato. It was shown that locally produced food and wide use of wild berries and mushrooms are dominated in the diet of TRC residents in the remote period after the Chornobyl disaster. Ecological and hygienic monitoring of foodstuffs in TRC proves the probability of product consumption with high content of radioactive materials. Residents territories of the foremost severe radioactive contamination in Zhytomyr, Kyiv and Rivne oblasts are aware about possible contamination of locally produced food with substances of Chornobyl origin and about the ways to reduce the contamination by means of cooking. In order to reduce the levels of possible internal exposure to radiation in population of TRC the agricultural amelioration and monitoring of radioactive contamination of wild and agricultural products should be continued. PMID- 25536553 TI - Social living environment of population in the surveillance area of Rivne nuclear power plant. AB - Objective. The purpose of this study was to determine the key factors of social well-being of the population in surveillance zone Rivne NPP. Materials and methods. Sociological, hygienic and mathematical methods i.e. comparison of generalized performance characteristics such as relative and average values, expression of interactions between factors using a pairwise correlation (r) were used in the paper. A questionnaire was developed for the public opinion polls with independent blocks of issues: the study of living environment/conditions through the assay of adequacy of ten major areas of life, assessment of satisfaction with the quality of life in household sphere and components and cost items of family budget, satisfaction level of medical care, "Integral Index of Social Well-being" Test (IISW). The sample was representative by age and gender for population of the surveillance zone of Rivne NPP (n=220, 6.7% sampling error). Results. According to opinion polls there is a negative impact on social well-being of low sufficiency in issues of socio-political life, social security and social relations. More than a half of population feels no any socio-economic compensation for the risk of Rivne NPP function in their daily lives. The overall satisfaction index in recreational and cultural sphere is close to the national average value, which may indirectly indicate to a positive impact of subventions to the social infrastructure of surveillance zone. However, satisfaction of population in the required medical care is extremely low, as is the case throughout Ukraine, due to several factors, such as lack of specialists, poor providing with essential medicines, and high cost of medicines. Conclusions. The list of benefits and compensations associated with living near the functioning NPP needs improvement and coordination with opinion of local communities. Their implementation at that needs a permanent information support. Some links are established between areas that are important in shaping of social feelings and assessment of environmental situation, perception of radiation situation, possibility of socio-political, man-made and natural emergencies. The more confident respondents in welfare of ecological state of residence, the higher level is in their social comfort. PMID- 25536554 TI - Quarter of century since the Chornobyl accident: sancer risks in affected groups of population. AB - Objective. The goal of this study was to define levels and dynamic trends of cancer incidence at whole and some separate sites in groups of Ukrainian population affected by the Chornobyl accident during a long period of observation. Materials and methods. Those groups were Chornobyl accident recovery operation workers (CRW) of 1986-1987 years of participation, evacuees from Prypyat town and 30-km zone and residents of the most contaminated territories of Ukraine. Analysis was carried out with the standard methods of descriptive epidemiology: calculation of crude, age-specific and age-adjusted incidence rates with standard errors and confidence intervals. Results, discussion and conclusions. This study showed that all cancer incidences exceeded the national level only in CRW group. Decrease of cancer incidence rate in the recent years might be caused by shortened average life expectancy in Ukrainian population, especially in males. Statistically significant increase of leukemia incidence in CRW group was registered as well. Besides, in all three main affected groups there was revealed significant excess of thyroid cancer. Irradiation of thyroid due to radioactive iodine fallouts might be a main cause of this phenomenon. Increase of thyroid cancer incidence was registered not only in children, but also in adolescents and adults. Appearance of excess thyroid cancer cases as an effect of radiation exposure tends to increase during the time. Significant excess was also revealed for breast cancer in female CRW group. Because latency period for different nosological forms of radiation-induced malignant tumors varies widely, profound attention in further studies should be drawn not only to thyroid, breast cancers and leukemia, but also to malignancies with longer latent period: lung, stomach, colon, ovary, urinary bladder, kidney cancer and multiple myeloma. PMID- 25536555 TI - TERF1 and TERF2 downregulate telomere length in cognitive deficit at the late period after low-dose exposure. AB - Purpose - to explore the role of radiation dose on gene regulation of telomere length and its influence on the patho-genesis of cerebrovascular neurocognitive deficit at the remote period of low-dose irradiation as a result of the Chornobyl accident. Materials and methods. We performed a study of TERF1, TERF2 and TERT genes expression (GE) by RT-PCR, and relative telomere length (RTL) by flow-FISH in 258 clean-up workers of Chornobyl accident divided by radiation dose groups (range 22-2800 mSv) and 78 controls with vascular cognitive deficit. Detailed psychometric interviews were performed to obtain quantitative data on the stage of cognitive deficit. Results. Statistically significant telomere shortening was demonstrated in groups of clean-up workers with radiation doses in 100-250 mSv and 250-500 mSv range (subsequently M +/- SD: 15.85 +/- 0.27; p< 0.02; 15.89 +/- 0,33; p< 0.02; control: 17.21 +/- 0,23). A decrease in RTL was in parallel to radiation dose increase and overexpression of negative telomere length regulators: TERF2 genes and, to a lesser extent TERF1; the opposite tendency was demonstrated for TERT GE. In exposed over 500 mSv a significant TERT overexpression was combined with decreased TERF1 and TERF2 GE, and absence of significant RTL changes in comparison with clean-up workers exposed to lower doses indicating a certain independency between gene expression and telomere length changes and possible threshold effects at this dose range. Analysis of the group of exposed in comparison with non-exposed demonstrated a significant decrease (p = 0.03) both of the mean MMSE and RTL parameters suggesting influence of previous exposure. Conclusion. This study shows parallel changes in decline of cognitive function and telomere length and differences in TERF2, TERT and TERF1 gene regulation at the late period after low dose and over 500 mSv exposure. PMID- 25536556 TI - Expression of gamma-H2AX histone in lymphocytes of the Chornobyl "Shelter" object staff exposed to ionizing radiation in occupational limits. AB - Objective. To compare the effect of radiation dose and time after exposure on formation of gamma-H2AX histone in Chornobyl clean-up workers and personnel who perform work activities at the zone of high radiation risks. Materials and Methods. The expression of gamma-H2AX histone in peripheral blood lymphocytes of 68 patients, including 33 "Shelter" workers after recent radiation exposure in professional limits and comparison group of 35 Chornobyl clean-up workers exposed 24-27 years before, the study by flow cytometry. Results. An increase of the expression of gamma-H2AX histone in lymphocytes was revealed in "Shelter" staff after leaving the area of work (0,70+/-0,93) (M+/-SD), comparing with Chornobyl clean-up workers (0,51 +/- 0,27) (M +/- SD), r < 0,001. Analysis subgroups of clean-up workers divided by doses (100-250 mSv, n = 20 and 250-1000 mSv, n = 16) we found connection between radiation dose and the percentage of gamma-H2AX positive cells. The number of gamma-H2AX positive cells was higher in a subgroup with higher doses (0,49 +/- 0,05 and 0,55 +/- 0,08, (M +/- SD, respectively, p < 0.01)). Conclusions. Our study suggests the possibility of determining gamma-H2AX histone as a marker of cellular radiosensitivity and possibility to use it as a diagnostic tool of a recent radiation exposure at low doses in humans. PMID- 25536557 TI - Rationale treatment and preventive measures for correction of bone structure in children with acute leukemia, exposed to ionizing radiation due to the Chornobyl accident. AB - Objective. To justify and evaluate the effectiveness of treatment and preventive measures taken to correct the bio-chemical and biophysical changes in the structure of bone in children exposed to ionizing radiation due to Chornobyl accident in the dynamics of leukemic process. Materials and methods. The study involved 144 patients with acute lymphoid and myeloid leukemia. Serum calcium, total protein, alkaline phosphatase, cortisol and thyroid-stimulating hormone were investigated, as well as calcium and phosphate excretion, amino acids composition in the urine, acid-base balance and buffer systems of blood, bone density. Results. A reduction of bone densitometry, calcium and cortisol levels and increase of serum alkaline phosphatase and urine oxyproline were found in children with acute leukemia in acute I phase and during the chemotherapy. In the period of remission the majority of patients did not differ from the comparison group. The signs of osteopenic syndrome that require monitoring of the bone structure status were revealed in 10.0 % of children of the comparison group. Radiation doses of leukemia patients were 3.66 +/- 0.11 mSv. No relationship between radiation dose and indicators that reflect the state of the bone tissue structures has been established. The use of complex health care measures in children with acute leukemia in remission, contributed to the positive effect of 62.0 %. Worser effect was observed in patients with an unfavorable course of the disease. Conclusions. Results of the study of bone tissue metabolism prove fore a change in the organic and mineral matrix in patients with acute leukemia exposed to ionizing radiation as a result of the Chonobyl NPP accident, and persons without hematologic diseases, and the need for treatment and prevention. PMID- 25536558 TI - Cytogenetic indices in blood lymphocites of individuals from the staff working on new confinement buildining in Chornobyl NPP zone. AB - Objective. Sytogenetic indication of possible exposure of contracting staff individuals, performing work on dismantling the ventilation pipe of "Shelter" object of Chornobyl NPP (ShO). Materials and methods. Cytogenetic examination of 12 individuals among the employees of contractors performing work on dismantling the ventilation pipe of ShO was provided. For comparison individuals who had no contact with the radiation factors for the profession activity were examined. Routine analysis method of uniformly stained chromosomes of peripheral blood lymphocytes was used. 11 388 metaphase plates were analyzed. Results. In contracting staff mean group frequency of aberrant lymphocytes, chromosome (dicentrics, acentrics, abnormal monocentrics) and chromatide type aberrations is significantly higher than such frequency in the comparison group. Three staff persons had individual frequency of specific markers of exposure - dicentric chromosomes with accompanying fragments significantly higher than their mean population level and the average frequency in the comparison group. It indicates the probability of their excess radiation when working in Chornobyl NPP local zone. Cells with two chromosome exchanges and one multiaberrant cell were registered in staff with the absence of such in control persons. The calculated estimated radiation doses of two staff persons were 87-123 mGy and and one person 210-240 mGy of acute exposure respectively. Conclusion. Calculated by frequency of dicentric chromosomes tentative "biological" doses of three staff persons show a more significant radiation effect comparing to the data of physical dosimetry. PMID- 25536559 TI - Radiation and non-radiation factors and their impact on the natural history of coronary heart disease in Chornobyl accident clean-up workers. AB - The objective of the study was to evaluate the impact of a range of risk factors and ionizing radiation on the severity of clinical presentation of coronary heart disease (CHD) in Chornobyl accident clean-up workers (ACW). Materials and methods. A total of 376 ACW and 123 Kiev city residents with no exposure to radiation participated in the study. Study scope included the case history recording, clinical check-up, electrocardiography (ECG), daily ECG-monitoring, daily arterial blood pressure monitoring, exercise ECG, Doppler ultrasound (Doppler echocardiography), and serum lipid profile assay. The severity of CHD was scored as a sum of functional class (FC) of angina pectoris and stage of heart failure (HF) to estimate the combined impact of several risk factors. Participation in the clean-up work, age, gender, body mass excess, hypercholesterolemia, CHD, diabetes mellitus (DM), survived myocardial infarction (MI) and acute cerebral stroke, heart rhythm abnormalities, and a complete bundle branch block were accounted as risk factors. Both separate and combined impact of those factors was assayed. The combined effect was scored as a sum where value zero corresponded to no sign and value one corresponded to its presence, whereas values from 1 to 4 explained the expression of a sign according to severity or stage of a disease according to contemporary classifications. Results and conclusions. Despite the fact that clinical characterization, functional state of cardiovascular system, and comorbidities in ACW were almost similar to that in control group the onset of CHD in ACW was significantly earlier (55.9 vs. 59.8 years old). According to Spearman's rank-order correlation data there was a reliable link of FC grades and HF severity values sum to the sum of indices scoring the age group of patients, their gender, presence of arterial hypertension, MI in a history, DM type 2, heart rhythm abnormalities, and a complete bundle branch block. Cluster of risk factors impacting the CHD natural history was of higher correlation vs. separate factor. No significant link was found between participation in the accident clean-up work and external radiation dose and respectively the angina pectoris FC and HF. PMID- 25536560 TI - Gene polymorphisms of p53-mediated apoptosis in chronic lymphocytic leukemia patients: features of distribution depending on radiation factor in anamnesis. AB - Objective. To set of p53-mediated apoptosis gene polymorphisms (TP53 codon 72 Arg/Pro, r21 codon 31 Ser/Arg, MDM2 SNP309) for the occurrence of CLL in patients who were exposed to ionizing radiation (IR) from the Chornobyl accident. Methods. Polymorphisms of p53-mediated apoptosis were determined in 320 patients with CLL of B-cell origin: 107 irradiated by the Chornobyl accident patients, 213 patients with CLL who had no history of exposure to IR, 73 individuals without a cancer and hematologic diseases that were affected by the Chornobyl disaster and 72 residents of Kyiv without affecting by IR in anamnesis. Determination of polymorphisms of p53-mediated apoptosis was performed by polymerase chain reaction followed by restriction. Results. The distribution of genotypes in patients with CLL did not differ from controls, except for reduced the frequency of homozygotes Arg/Arg TP53 among patients with CLL (p = 0.01). Compared with non irradiated CLL patients in the subgroup of patients affected by the accident, an increase in the frequency of polymorphic alleles of the gene r21 (p = 0.033) was found, especially in combination with Arg allels (genotypes Arg/Arg and Arg/Pro) of TP53 gene and genotype TT SNP309 of MDM2 gene (p = 0.009). Conclusion. Preliminary studies indicated the likely contribution of rs1801270 polymorphism of the gene r21 in the pathogenesis of CLL in patients who had been exposed to IR. The effects of SNPs rs1042522 of TP53 gene and SNP309 of MDM2 gene on the risk of CLL in the Chornobyl accident sufferers were not revealed. PMID- 25536561 TI - Structure of comorbid diseases in patients with non-alcoholic fatty liver disease, exposed to ionizing radiation as a result of the Chornobyl NPP accident. AB - Objective - to study of the structure of comorbid diseases in patients with nonalcoholic fatty liver disease (NAFLD), exposed to ionizing radiation due to the Chornobyl accident, and in the groups of comparison. Materials and methods. Array of surveyed males was divided into 4 groups: the main group - 136 patients with NAFLD affected by the Chornobyl NPP accident, the first comparison group (I CG) - 28 affected by Chornobyl NPP accident without liver disease, the second comparison group (II CG) - 50 patients with NAFLD not exposed to factors of the Chornobyl disaster, and the third comparison group (III CG) - 16 unexposed persons without liver disease. Results. A significant amount of co-morbid pathology was found in all studied groups but III CG: at the average from 4.1 +/- 0.4 diseases in II CG to 5.2 +/- 0.2 in the main group of patients (p < 0.05), among which in 6.6-7.1 % of cases more than 10 diseases were established. The most common disorders were cardiovascular and cerebrovascular and endocrine diseases. Structure of comorbid pathology in NAFLD in the main study group differed from this in II CG by a significantly greater frequency of detection of cerebrovascular diseases (73.5 and 56 %, p < 0.05). As for features of the metabolic syndrome in Chornobyl accident sufferers essential hypertension (71.3 % ), discirculatory encephalopathy (48.5 %) and thyroid diseases (47.1 %) were more frequent than in II GC: correspondingly 58 % (p < 0.001), 28 %, (p < 0.01), and 30 %, (p < 0.05). Essential hypertension in only 35.7 % patients without NAFLD (I CG) was detected (71.3 % in the study group, p < 0.01), and chronic cerebrovascular insufficiency in 71.4 % (39.7 % in the study group, p < 0.01). Conclusion. Structure of comorbid pathology in NAFLD patients sufferers of the Chornobyl NPP accident was different both in a large number of identified diseases and nosological structure. The most common disorders were cardiovascular, cerebrovascular, and endocrine diseases. Significantly higher incidence of essential hypertension, vascular encephalopathy, and thyroid disease was determined. PMID- 25536562 TI - The efficiency of tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia exposed to ionizing radiation due to the Chornobyl nuclear power plant accident. AB - Objective. To study the efficiency of tyrosine kinase inhibitors (TKI) therapy in patients with chronic myeloid leukemia (CML) exposed to ionizing radiation due to the Chornobyl NPP accident, based on the data of cytogenetic and molecular monitoring. Material and methods. 29 CML patients with confirmed radiation exposure due to Chornobyl NPP accident were examined. Of these, 20 patients were treated with imatinib; 103 patients with CML without radiation history treated with TKI were a comparison group. Cytogenetic and molecular genetic disturbances before and on the different stage of TKI therapy were analysed. Results. Additional chromosomal abnormalities as well as special pattern of BCR/ABL transcripts were not revealed in CML patients exposed to ionizing radiation. Complete cytogenetic response (CCR) was shown in 50 and 48.5 % of patients from study and comparison group, respectively. Major molecular response (MMR) was achieved in 20 % of patients with radiation exposure in anamnesis and in 27.6 % of patients from comparison group. The vast majority of CCR and MMR was reached in patients with the pretreatment term up to 6 months, when imatinib was used as a first line therapy. There were less cases of primary imatinib resistance in the same group of patients. In CML patients who had a history of radiation exposure, secondary resistance developed more frequently than in the comparison group and was 25 %. Conclusion. Laboratory monitoring based on the registration of CCR and MMR demonstrated high efficiency of TKI in the CML treatment of patients, exposed due to Chornobyl accident. Extension of pretreatment term leads to the loss of TKI therapy efficiency and increases the likelihood of primary resistance. CML patients exposed to ionizing radiation develop secondary resistence more often than CML patients without radiation exposure in anamnesis. PMID- 25536563 TI - Peculiarities of non-malignant endocrine disease in the Chornobyl NPP accident survivors, and hormonal interaction role. AB - Study objective. Identification of the role of intersystemic hormonal interactions in development of most prevalent central and peripheral non malignant clinical/metabolic endocrine disorders in the Chornobyl NPP accident (ChNPPA) survivors. Materials and methods. Retrospective assay of non-malignant radiation effects on endocrine system was applied in 18,192 survivors of the ChNPPA. Data from the Clinical/Epidemiological Register of the SI "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" for the period of 1993-2003 were involved. Anthropometric values, biochemical and hormonal assay indices, diagnostic thyroid ultrasound data, external radiation dose values were taken into account both with calculated insulin resistance index. Results. Thyroid disease incidence in ChNPPA survivors increased dramatically 10 years upon radiation impact being 39.33 % in average, 14.35 % (r < 0.01 vs. entire population) for nodular goiter, and about 8 % for autoimmune thyroiditis (r < 0.01 vs. the same). As a result of an advanced examination of ChNPPA survivors the incidence of diffuse non-toxic goiter was 40.4 % (chi2Yates = 73.82; r = 0), of nodular goiter - 23.1 % (chi2Yates = 14.13; r = 0.002) vs. values in the control group (4.8 % and 17.6 % respectively). Some hormonal interactions were identified in study subjects indicating the thyroid disease onset under radiation impact through insulin resistance at the background of adipose tissue excess followed by body mass index increase, elevation of serum C-peptide and leptin levels, and onset of lipid metabolic disorders. Conclusions. Significant increase of the incidence of thyroid disease (1.5-3-fold), diabetes mellitus (3-7-fold), pre-obesity and obesity (in 25.67 %), and metabolic syndrome (5-fold) vs. entire population of Ukraine was found in remote terms upon the accident. Intricate pathogenetic intersystemic hormonal interactions were identified predisposing to thyroid disease due to insulin resistance, accompanying hyperinsulinemia, increased body mass index and some other hormonal and biochemical factors. PMID- 25536564 TI - Morbidity pattern of non-cancer endocrine disease in ChNPP accident emergency workers (1992-2013 Clinical/Epidemiological Registry data). AB - Objective. The study examined the morbidity pattern of non-cancer endocrine disease in ChNPP accident emergency workers (AEW) versus the entire population of Ukraine. Materials and methods. The study included a retrospective estimation of the examination data from 10,771 ChNPP AEW of the so-called iodine and non-iodine periods (main study group). Data were received from the RCRM Clinical/Epidemiological Registry for the survey period of 22 years (1992-2013) on persons been either healthy or having a range of endocrine disease. Anthropometric measures both with biochemical and hormonal assay data and external radiation dose values were taken into account. Diagnostic thyroid ultrasound was applied. Results. There is a significant (2-10-fold) and reliable (p < 0.01) increase of the incidence of non-cancer endocrine disease in the ChNPP AEW, namely by 23.20 % of nodular goiter (0.53 % in control, chi2 = 9602, r < 0.0001), by 13.37 % of autoimmune thyroiditis (0.35 % in control; chi2 = 5381, r < 0.0001), by 11.89 % in average and by 16.29 % in last years of type 2 diabetes mellitus (chi2 = 2527, r < 0.0001), by 41.67 % of pre-obesity (chi2 = 10.92, r < 0.01), and by 38.12 % of obesity (chi2 = 41.50, r < 0.01) compared to the entire population. Conclusions. Effects of ionizing radiation and other hazardous factors on endocrine system in the ChNPP AEW appeared upon 15-25 years. There was a significant (2-10-fold) and reliable (p < 0.01) increase of the incidence of the nodular goiter, autoimmune thyroiditis, obesity, type 2 diabetes mellitus. And there is a trend to further increase. PMID- 25536565 TI - Gut microbiota among children living in areas contaminated by radiation and having the cardiac connective tissue dysplasia syndrome. AB - Objective. The study examined the gut (colonic) microbiota in children being domiciled in contaminated zones and suffering the cardiac connective tissue dysplasia syndrome (CCTDS). Materials and methods. The study included 99 children living in contaminated zones. Study subjects were divided into subgroup IA (a comparison subgroup) of 44 children with no signs of CCTDS and subgroup IB of 55 children having the CCTDS. The control group included 24 children aged from 7 to 17 years old. Study groups were of the same gender and age. Results. In the absence of any specific complaints the abnormal gut microbiota was revealed in children living in contaminated areas with a high incidence of 96.36 % featuring both quantitative and qualitative abnormalities that can be considered a dysadaptation phenomenon of both digestive system and body as a whole. Under the concomitant CCTDS these disorders are more expressive, being characterized by a significant decrease in the number of obligate gut flora and failure of its protective capabilities. Incidence of dysbacteriosis grade III in children having the CCTDS is significantly higher vs. children of the control group and comparison subgroup. Under CCTDS the gut microbiota abnormalities were represented with a severe bowel contamination by E. coli with altered enzymatic properties, various types of opportunistic microorganisms, and a high identification incidence of genus Candida fungi at the background of a significant depression of normal colonic flora. Presence of 3-5-component associations of opportunistic pathogens in the colon was found with high incidence. Conclusion. According to received results the examination of intestinal bacterial flora is expedient in children living in areas contaminated by radiation. Application of health care arrangements aimed at normalization of gut microbiota is obligate. PMID- 25536566 TI - Peculiarities of gastrointestinal disease concomitant to heart connective tissue dysplasia in children born from persons exposed to ionizing radiation in childhood after the ChNPP accident. AB - Study objective. The study examined the peculiarities of upper gastrointestinal tract diseases in children suffering from a syndrome of heart connective tissue dysplasia (HCTDS) born from persons exposed to ionizing radiation in a childhood after the ChNPP accident. Materials and methods. The study included 120 children suffering from HCTDS (group I) and 75 persons having no signs of the syndrome (Group II). Diagnosis of HCTDS was obtained from echocardiography in Band M-modes and Doppler echocardiography. Esophagogastroduodenoscopy was performed using a flexible endoscope "OLYMPUS" model GIF-P3. Abdominal diagnostic ultrasound was used to assay the structure of abdominal parenchymal viscera. Results. Upper gastrointestinal tract diseases (UGITD) manifest earlier in children suffering the HCTDS (beginning from a preschool age). Along with age the systemic pattern of organ and system injury becomes evident i.e. there were 6.8 clinical/nosological entities per one child in Group I and 4.9 in Group II. Clinical presentation of chronic UGITD diseases in children suffering concomitant HCTDS were characterized by more frequent exacerbation after the psychoemotional and physical strain, more frequent intestinal motor dysfunction, nervous system disorders (80 %), and chronic infections (62.2 %). Endoscopic pattern of chronic UGITD with concomitant HCTDS featured a combination of mucosal inflammation (a range of various forms of esophagitis, erythematous and hypertrophic gastroduodenopathy) with abnormal gastrointestinal motor function i.e. gastroesophageal and duodenogastric reflux (73.34 %). Destructive lesions at most of duodenal zone were found in 20 %. Conclusions. UGITD namely chronic gastroduodenitis with typically concomitant involvement of several parts of digestive tract are most prevalent within all digestive system diseases in remote period upon the Chornobyl disaster in children born from persons exposed to ionizing radiation in a childhood. Presentation of UGITD occurs earlier in children suffering HCTDS with evident systemic pattern of organ and system injury along with an age. Refluxes of various nature and localization are the leading factors for UGITD onset in children suffering HCTDS. Thus a range of multidirectional tools of reflux disease prophylaxis is required for inclusion to the disease management. PMID- 25536568 TI - MYC gene rearrangements detected by interphase fluorescence in situ hybridization in diffuse large B-cell lymphomas. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, including approximately 30-40% of all B-cell non-Hodgkin lymphomas (B-NHL). Chromosomal translocations are the hallmark of genetic aberrations in B-lymphoma and are often associated with a specific subtype of B-NHL. MYC gene dysregulation due to chromosomal translocations is characteristic for the most cases of Burkitt's lymphoma. Objective. The goal of this study was to improve the diagnostic accuracy of DLBCL. Identification of chromosome 8 and 14 abnormalities including the translocation of MYC gene t(8; 14)(q24; q32) in substrate cells of lymph nodes was applied using the method of tri-color interphase fluorescence in situ hybridization (I-FISH). Materials and methods. Lymph node biopsy specimens of 17 patients with diffuse large B-cell lymphoma and three patients with Burkitt's lymphoma (including one participant of liquidation of consequences of the catastrophe at the Chornobyl NPP) were studied. The age of patients ranged from 10 to 66 years old (41.3 +/- 3.7 average). Biopsy specimens fixed in paraffin. I-FISH-analysis was performed using the commercial test Vysis IGH/MYC, CEP 8 tri-color, dual fusion translocation probe (Abbott Molecular, USA). Results and conclusions. MYC gene and immunoglobulin heavy chain (IGH) gene translocations were found in four out of twenty persons. Consequently the I-FISH method allows identification of of MYC and IGH gene rearrangements in tissue cells substrate of lymphoma fixed in paraffin. Using this method the molecular cytogenetic abnormalities were found in eight of twenty patients with B-cell lymphoma providing verification of the lymphoma diagnosis, prediction of their clinical course and advance in management i.e increase the effectiveness of therapy, in refractory lymphoma cases among others. PMID- 25536567 TI - Balance of autonomic nervous system in children having signs of endothelial dysfunction, that were born and are domiciled in contaminated territories. AB - Objective. The study examined the features of functional state of the autonomic nervous system in children having endothelial dysfunction and permanently residing in contaminated areas. Materials and methods. Clinical and instrumental examination of 101 children aged 7-18 years that were born and are domiciled in contaminated territories, including 37 persons with signs of endothelial dysfunction (subgroup IA) and 64 ones with no signs of endothelial dysfunction (IB subgroup) was conducted. The control group being comparable to the subgroups IA and IB by age, gender and clinical examination results included 37 children neither been domiciled in contaminated areas nor were belonging to the contingent of Chornobyl accident survivors. There were 20 apparently healthy children also examined. Results. Due to peculiarities of physiological pathways providing adaptive responses the children having signs of endothelial dysfunction are characterized by a more pronounced dysregulation of autonomous nervous system both in a resting state and under a functional load simulation, and also by a high strain of adaptation pathways. The lack of autonomous support of cardiovascular system is caused by inadequate adaptive responses of both central regulatory bodies (hypothalamus, vasomotor center) and peripheral receptors. Mainly the failure of segmental autonomous (parasympathetic) structures was revealed. The mode of their response to stress in this case corresponds to that in healthy individuals but at a lower functional level. There is a reduced aerobic capacity of the organism by the Robinson index, contributing to low adaptive range to non-specific stress in children being domiciled on contaminated territories including children having the endothelial dysfunction. Conclusions. Endothelial dysfunction was associated with more pronounced manifestations of autonomic dysregulation and reduced aerobic capacity of the organism being the risk factors of development of a range of somatic diseases requiring the development of prevention measures in children permanently residing in contaminated areas. KEYWORDS: autonomous nervous system balance, endothelial dysfunction, children, Chornobyl accident. PMID- 25536569 TI - Peculiarities of induction and persistence of hidden chromosome instability in peripheral blood lymphocytes of persons occupationally exposed to ionizing radiation. AB - Objective - to investigate the induction of hidden chromosome instability in persons occupationally exposed to ionizing radiation and its persistence in vitro in successive mitoses. Materials and methods. Using two tests ("G2-bleomycin sensitivity assay" and two-term cultivation of human peripheral blood lymphocytes) voluntary cytogenetic examination of 15 individuals participated in the conversion of the "Shelter" ("Chornobyl NPP") into ecologically safe system had been carried out. Total 24 034 metaphase had been analyzed, of which 12 243 - without additional mutagenic exposure, 11 791 - exposed to bleomycin in vitro at concentration of 0.05 MUg/ml. Results. The magnitude and dynamics of background as well as bleomycin-induced cytogenetic effects in both terms of lymphocytes' cultivation in occupational group differed significantly from the group of comparison towards increasing of chromosome instability indices with significant interindividual fluctuations. Conclusion. Interindividual differences in persistence of radiation-induced hidden chromosome instability in successive generations of human somatic cells had been found. PMID- 25536570 TI - Changes in stable metabolites of nitric oxide in children-residents of radioactively contaminated territories. AB - Objective. An evaluation of the changes in nitric oxide system by the level of its stable metabolites in the blood serum and their comparison with content of 137Ss in the body of children-residents of radioactively contaminated territories. Materials and methods. The children of school age, the residents of radioactively contaminated territories were examined. The levels of nitrogen compounds (NO2- and NO3-) were determined by the standard method using Grissreagent. 137Ss content was determined in the children body by whole radioactive body counter. Results. Studies of nitric oxide metabolite content in the blood serum revealed the decrease in nitrite level under an absence of the significant changes in nitrate content and sum of NO metabolites in the children residents of radioactively contaminated territories. An increase in 137Cs content in the body was accompanied by a decrease of nitrite level in the blood serum of a significant part of children. PMID- 25536571 TI - Analysis of risk factors for chronic obstructive pulmonary disease in clean-up workers of the Chornobyl accident. AB - Objective. To analyze the effects of ionizing exposure, age and smoking on the development of chronic non-specific lung disease in a cohort of liquidators of the Chornobyl consequences included in the Clinical and Epidemiological Registry SI "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine". Materials and methods. The analysis included data on 7156 of the Chornobyl liquidators, of which 6 257 (87.4 %) men and 899 (12.6 %) women who were examined between 1993 and 2010 by pulmonologist. Results. Chronic bronchopulmonary diseases were detected in 50.0 % of the surveyed persons. The overall exposure dose was significantly higher among liquidators, which developed bronchopulmonary diseases (24.29 +/- 0.82 sSv) compared with those without bronchopulmonary disease (14.58 +/- 0.62 sSv), p = 0.001. In smokers the incidence of chronic obstructive pulmonary disease was twice higher than in those who did not smoke (10.2 and 5.16 %, respectively, p = 0.0001). Conclusion. The negative effect of ionizing radiation amplified by other risk factors for chronic bronchopulmonary disease: association between exposure doses and somatic pathology manifested in the surveyed people over the age of 45 years; at the same exposure dose risk of bronchopulmonary diseases was higher for smokers. PMID- 25536572 TI - Late effects of ionizing radiation on functional status of bronchopulmonary system in COPD patients among the clean-up workers of the Chornobyl NPP accident. AB - The objective of the study was to determine the effects of ionizing radiation on the functional condition of the bronchopulmonary system in clean-up workers of Chornobyl NPP patients with COPD in a remote post-emergency period. Materials and methods. The study of functional characteristics was carried out in 272 patients 197 clean-up workers of Chornobyl NPP accident (ChNPPA) with radiation exposure from 25 to 988 mSv; 75 - group of nosological control and 20 healthy persons. Results and conclusions. For the clean-up workers of Chornobyl NPP with exposure doses over 500 mSv demonstrated correlation between respiratory function parameters and dose which is confirmed for these patients, compared with irradiated in doses less than 500 mSv and nosology control, a significant decreasing of VC (76,3 +/- 8,5%, 82,4 +/- 8,5% and 82,7 +/- 8,1% accordingly, p <0,05), FVC (78,2 +/- 8,3%, 84,3 +/- 7,9% i 86,1 +/- 9,7%, p <0,05), FEF 50 (26,1 +/- 11,5%, 32,6 +/- 10,6% i 32,1 +/- 12,7%, p <0, 05) i FEF 75 (23,8 +/- 8,1%, 27,8 +/- 9,3% i 27,6 +/- 9,2%, p <0,05). These changers combined with decrease in lung diffusion capacity in cases more than 500 mSv, and indicate severe respiratory disorders in patients with COPD among clean-up workers of ChNPPA. PMID- 25536573 TI - Peculiarities of viruses Herpesviridae family persistence in patients with non alcoholic fatty liver disease who had been exposed to the factors of Chornobyl NPP accident. AB - Objective - to define the features of viruses persistence belonging to the Herpesviridae family in patients with non-alcoholic fatty liver disease (NAFLD) who had been exposed to the factors of Chornobyl NPP accident. Material and methods. The main group included 45 male NAFLD patients sufferers of Chornobyl NPP accident with absorbed doses of external irradiation in the range of 10-580 mSv. The group of nosology comparison consisted of 20 male NAFLD patients with the doses of irradiation within the limits of natural radiation background and regulated doses of medical irradiation. Antibodies to the viruses of herpes simplex 1/2 types (anti-HSV-1/2 IgG), cytomegalovirus (anti-CMV IgG) and Epstein Barr virus (anti-EBV IgG) were determined by ELISA according to instructions of manufacturer. Results. There were no patients in both groups without IgG antibodies characterizing persistence of some Herpesviridae representative. Tendencies to the increase of antibodie levels to the viruses of herpes simplex, cytomegaly and Epstein-Barr in the seropositive patients, who had been exposed to the factors of Chornobyl NPP accident relative to the patients of group of nosology comparison were found. There were no differences between the subgroups of patients with steatohepatosis (SH) and nonalcoholic steatohepatitis (NASH) in the main group by anti-HSV-1/2 IgG and anti-CMV IgG levels while in the group of comparison SH patients had 60.5 % higher level of anti-HSV-1/2 IgG (p < 0.05) than NASH patients and anti-CMV IgG - 88.2 % respectively. Besides for NASH patients of main group anti-CMV IgG level exceeded 79.6 % (p = 0,02) analogical level for NASH patients in the group of comparison. The mixt infection by the viruses of 1/2 types herpes simplex and cytomegaly was most often determined in all groups with the direct correlation between the levels of anti-HSV-1/2 IgG and anti-CMV IgG. The markers of cytomegalovirus monoinfection were registered only in NASH patients both in main group and in the group of comparison. Conclusion. According to the presence of class IgG antiviral antibodies, NAFLD patients regardless of radiation influence in anamnesis have high prevalence of Herpesviridae family viral infection: herpes simplex 1/2 types, cytomegalovirus and Epstein-Barr virus. In the group of patients who had been exposed to the factors of Chornobyl NPP accident greater part of seropositive results and higher mean values of the probed antibodies titres were registered than in the groups of comparison. The mixt infection by the viruses of herpes simplex 1/2 types and cytomegaly was registered in most patients with existence of direct correlation between the levels of anti-HSV-1/2 IgG and anti-CMV IgG. PMID- 25536574 TI - Investigation of modification X-ray induced bystander effect in vitro. AB - Objective - to investigate the modification of bystander effect induced by X irradiation of human peripheral blood in vitro by application of antioxidant vitamin medication. Material and methods. Modeling of radiation-induced bystander effect in vitro in mixed lymphocyte cultures exposed to dose of 1 Gy and non irradiated blood lymphocytes of persons of different sexes, GTG-staining of metaphase chromosomes and their cytogenetic analysis; application of antioxidant preparation (soluble forms of vitamins E, C and A) in concentration 40 MUg/ml. Results. Under the introduction of antioxidant preparation into mixed culture before lymphocytes cultivation frequency of chromosomal aberrations in bystander cells did not significantly different from the control (p > 0.05). CONCLUSIONS: application of antioxidant preparation modifies the radiation-induced bystander effect in unirradiated human peripheral blood lymphocytes under their joint cultivation with lymphocytes irradiated in dose of 1 Gy. Antioxidant prevents the development of secondary oxidative stress in unirradiated cells, eliminates the development in them of radiation-induced bystander effect and ensures the preservation of stability of their chromosome apparatus. PMID- 25536575 TI - Allelic polymorphism of DNA repair gene XRCC1 in patients with thyroid cancer who were exposed to ionizing radiation as a result of the Chornobyl accident. AB - Objective - to determine and compare the features of DNA repair gene XRCC1 Arg399Gln polymorphisms in patients with thyroid cancer (TC), who were exposed to ionizing radiation as a result of the Chornobyl disaster, and in patients without exposure to ionizing radiation in history. Materials and methods. Determination of gene XRCC1 Arg399Gln polymorphisms was performed by polymerase chain reaction (PCR) in 102 patients with thyroid cancer: 38 people, who were exposed to ionizing radiation due to Chornobyl disaster (clean-up workers, evacuees and residents from controlled areas contaminated with radionuclides) and 64 individuals without exposure to ionizing radiation in anamnesis. The literature data on control groups of populations of Russia and Belarus were used for comparison of the data on spontaneous and radiation-associated thyroid cancer and calculation of allele frequencies differences and risk of cancer pathology. Results. Frequency of minor allele Arg399Gln XRCC1 gene and homozygous carriers of this allele in patients with thyroid cancer, who were exposed to ionizing radiation due to Chornobyl disaster was significantly higher than in patients without exposure to ionizing radiation in anamnesis (0.57 and 0.37, p = 0.006 and 34.21 % and 7.81 %, p = 0.001, respectively). Comparing to the literature data on XRCC1 Arg399Gln polymorphisms in radiation-exposed individuals without cancer pathology, the risk of thyroid cancer in homozygous minor allele XRCC1 Gln399Gln carriers, who were exposed to ionizing radiation was significantly increased: OR = 4.14, p = 0.001 (CI95 % 1.72-9.93). Conclusions. The carrying of homozygous minor allele Gln399Gln of DNA repair gene XRCC1 is a risk factor for thyroid cancer under the influence of ionizing radiation in research group of Ukrainian population. PMID- 25536576 TI - Fractionate effect of ionizing radiation and nitric oxide on tumor growth in rats. AB - Objective. To investigate the effect of ionizing radiation and nitrogen oxides on the growth and development of Guerin's carcinoma transplanted in rats. Materials and methods. Studies have been conducted on white nonlinear male rats weighing 125-160 g. Animals were exposed of nitrogen oxides and/or ionizing radiation, and then were transplanted Guerin's carcinoma. The dynamics of tumor growth and changes of free radical processes in the blood system by biophysical and biochemical methods were investigated. Results. It is shown that the effect of the studied environmental factors leads to disruption of oxidative processes in the animal's organism, which contributes to the growth and development of tumors. Conclusion. Pre-exposure to low doses of ionizing radiation and/or exogenous nitrogen oxides significantly accelerates the growth of Guerin's carcinoma. This process is accompanied by a disturbance of oxidative metabolism and the development of oxidative stress. PMID- 25536577 TI - Features of biological effects in cell culture in the combined exposure to ionizing radiation and copper ions. AB - The objective of the work was to research the features of monoand combined impact of ionizing radiation and copper salts on cell viability in vitro. Materials and methods. The studies were performed on a passaged line L929 cell culture. Copper ions of different concentrations were added to the culture medium 1 hour after exposure to irradiation at doses of 0.5; 5.0 and 10.0 Gy. There were evaluated the structure of the cell populations, the proliferative and mitotic activity and apoptosis. Results and conclusions. After incubation of the cells with copper ions of various concentrations there were seen both the activation and inhibition of proliferative and mitotic activity. Cell survival and mitotic activity were decreased in exposure to increasing doses of radiation but the polykaryocyte index was increased. After the combined in vitro exposure to ionizing radiation and copper ions there were seen morphofunctional changes of cell properties, which were not in direct proportional dependence on the dose or the copper ions concentration. PMID- 25536578 TI - Analysis of the antioxidantive qualities of sperm after total body X-irradiation of animals. AB - OBJECTIVE: To study dynamics of natural antioxidant levels and antioxidant enzymes activities in rabbit seminal fluid in conditions of single total body X ray irradiation in different doses. Materials and methods. Soviet Shinshilla white rabbit males 30-36 months old were taken into investigation. Sperm was collected by artificial vagina. Seminal fluid was purified from spermatozoa by centrifugation at 2500g during 12 min. Animals were irradiated by X-rays on RUM 17 device (Russia) in doses 1.0; 2.0; 5.0 and 7.0 Gy with dose rate 2.8x10-3 Gy/sec. Sperm was gathered on 10th and 90th day after irradiation. Free glutathione and thiol concentration were assessed by spectrophotometry using 2.2 dithiobisnitrobenzoic acid, lipid peroxidation was evaluated by measuring of TBA active products concentration. Enzymatic activities of superoxiddismutase, catalase, glutathionperoxidase and glutathionreductase were estimated in substrate specific reactions spectrophotometrically. Results. Dose-dependant up regulation of antioxidant enzymatic activity of seminal fluid on the 10th day after exposure to 1.0-7.0 Gy dose range of total X-ray irradiation was shown. This effect was accompanied by the decrease of free thiols concentration, from the one hand, and both TBA-active products and oxidized glutathione contents elevation, from the other hand. This seminal plasma state was shown to be temporal and partially normalized on 90th day after exposure. Conclusions. Total X-ray irradiation of rabbits leads to significant up-regulation of antioxidant processes of both enzymatic and non-enzymatic type on the 10th day after radiation exposure in seminal plasma. This effect was shown to be dose-dependant. Then antioxidant activity dropped and metabolic activities gradually normalized according to studied parameters within 90 days after exposure in 1.0 and 2.0 Gy. PMID- 25536579 TI - Impact of gadolinium-157 containing nanoscale magnetosensitive composites on morfofunctional properties of cells in vitro. AB - Objective - to investigate the morphofunctional cells properties under the action of magneticallybased nanocomposites containing gadolinium-157. Materials and methods. Experimental studies are performed in cell culture line L929 Nanocomposites based on magnetite modified by functional amino groups chemically fixed by diethylenetriaminepentaacetic acid (DTPA) and gadolinium - (Fe3O4/gamma APS/DTPA-Gd) were studied (1), also by meso-2,3-dimercaptosuccinic acid (DMSA) - (Fe3O4/DMSA-Gd), which binds to the hydroxyl group of magnetite surface (2); gadolinium was adsorbed from a solution of gadolinium sulfate. Reagent 3 - magnetic substance Fe3O4 with sodium oleate. Morphofunctional characteristics of cell culture were evaluated in various terms by standard indicators of sustainability: proliferative and mitotic activity and the number of giant multinuclear cells, apoptosis. Results and conclusions. We established that magnetdriven nanocomposites with gadolinium modified by DTPA and DMSA, were more biocompatibile to cells: incubation of cells with neutron capture agents (NCA) in the studied range of concentrations showed no toxicity, except maximum concentration, while decreasing cells adhesive properties. For all nanocomposites we observed decrease in mitotic activity in the background of the control cell population density, which may indicate synchronization of cell division. We found that the stabilized by sodium oleate ferrite caused destructive changes in cell culture only at concentrations of 500 MUg / ml, but reduced mitotic activity in cell culture in 3-5 times in the whole range of concentrations. It is shown that magnetdriven nanocomposites induce different levels of apoptosis in cultured cells depending on the concentration of the reactants. PMID- 25536580 TI - The assessment of maize plants (Zea mays L.) adaptation to the cadmium chloride influence using the radiocapacity factor. AB - Objective. Show the possibility of method of the radiocapacity factor using for the study the phenomenon of adaptation of maize plants to the action of toxic factor - namely , introducing into the habitat of cadmium chloride solution. This method is proposed as convenient and adequate indicator of change of state of the objects under chemical stressor influence. Materials and methods. Experiments were performed in the laboratory, the object of research were the processes of water culture of maize plants (Zea Mays L.) variety Prydnistrovska adapting to the toxic metal action. Cadmium chloride solution was entered to the culture medium of plants at concentrations, selected according to the standard adaptive scheme of the experiment. Under this scheme, adaptive concentration (1 MUM/L and 2 MUM/L of salt CdCl2) was entered first, and through certain time (Deltat) - test concentration (25 MUM/L of salt CdCl2). The assessment of maize plants adaptation was carried out by the changing of growth parameters and of radiocapacity factor. The radiocapacity factor defined as the ratio of current activity in water (medium) by the specifically inserted tracer - 137Cs to the initial. Results and conclusions. The radiocapacity factor concentration dependence and dependencies under adaptive and stress influences to plants was obtained. The dependence of adaptation on the time interval between the test and adapting concentrations of cadmium chloride was revealed. And the effect of sensibilization on the growth and absorbing characteristics of plants of salt CdCl2 when the test concentration 25 MUM/L entered at 4 hours after adaptive concentrations (1 MUM/L and 25 MUM/L) application was observed. It is shown that the radiocapacity factor is adequate, sensitive and efficient indicator manifesting the response of plants to stress influence in the conditions of adaptive schemes of influence using. PMID- 25536581 TI - Peculiarity of changes of peripheral blood hematological indices in rats under N stearoilethanolamine administration conditioned by combined effects of ionizing radiation and stress. AB - Objective - to investigate the peculiarities of peripheral blood indices changes in rats under the N-stearoiletanolamine treatment before and after combined effects of ionizing radiation and stress. METHODS: hematological, statistical. RESULTS: Per oral administration of NSE (10,0 mg / kg) before and after the combined effects of single whole-body irradiation (6.0 Gy) and emotionally algesic stress (foot-shock) leads to reduction in the number of circulating peripheral blood cells, increasing signs of damage of the hematopoietic system with accelerated exhaustion processes. Conclusions. NSE administration (10,0 mg / kg) in rats under the combined influence of ionizing radiation (6 Gy) and emotionally-algesic stress slows down the course of regenerative processes and accelerates the depletion of the hematopoietic system, proving for its radiosensitizing effects. PMID- 25536582 TI - Radiation-induced chromosomal instability of human lymphocytes as a marker of breast cancer risk. AB - OBJECTIVE: to assess the variability of the levels of chromosome aberrations induced by the in vitro irradiation of lymphocytes of breast cancer (BC) patients in comparison with healthy individuals. Materials and methods. Samples of peripheral blood for lymphocyte cultures were obtained from 44 healthy women and 37 primary patients with BC (T1-2N1M0). Lymphocyte X-ray irradiation was carried out at G0 and G2 phase of lymphocyte cell cycle (G0 and G2 assay) with the dose of 1,5 Gy before PHA stimulation in G0 assay and 0,5 Gy - at 47 h of cultivation in G2 assay. Preparations of metaphase chromosomes were made according standard protocols. Results and conclusions. Inter-individual variation of G2 chromosome aberration yields was significantly higher in comparison with G0 chromosomal radiosensitivity in both examined groups. According to G2 assay the fraction of individuals with elevated chromosomal radiosensitivity among healthy women and BC patients was 11.4 and 38 %, respectively. The results obtained support the concept of association between predisposition to BC, radiationinduced G2 chromosomal instability and efficiency of DNA repair activated by cell irradiation in G2 phase. It is assumed that individuals with elevated G2 aberration scores from the control group need further examinations on the BC risk and primary prevention of radiation induced cancer. PMID- 25536583 TI - Application of photo-magnetic therapy for treatment of skin radiation damage in rats. AB - OBJECTIVE: To improve methods of prevention and treatment of local radiation injury to the skin using the photomagnetic therapy. Materials and methods. Study was conducted on 60 male Wistar rats with 180-200 g bodyweight. The femoral area right hind limb of rats was locally irradiated by X-ray unit at a dose of 80.0 Gy. Exposed animals were divided into 2 groups: control and experimental. The rats of the experimental group received 2 courses of photo-magnetic therapy on the irradiated skin. The observations were carried out for 60 days. Methods - clinical, histological and statistical. Results. Local irradiation of rat skin causes the development of radiation ulcers in 60-70 % of the animals with the destruction of the structure in all layers of the skin. Spontaneous healing of radiation ulcer lasts at least two months with no complete skin recovery. Photo magnetic therapy applied immediately after irradiation resulted in two folddecrease of frequency of radiation ulcer incidence, accelerated the complete healing for 3 weeks and to ameliorated their progress. Histological examination showed that the photo-magnetic therapy reduced the extent of damage to all layers of the skin with restoration of epidermis and dermis structure and reduced the degree of inflammatory and destructive processes in the dermis. Conclusions. Photo-magnetic therapy produces a significant positive treatment effect by significantly reducing the inflammatory and destructive processes in all layers of the skin, stimulates the blood flow recovery in damaged tissue both with fibroblast proliferation and synthesis activation of native collagen fibers and other components of connective tissue, so almost a month accelerates ulcer healing radiation. PMID- 25536584 TI - Radiation,induced changes in connective tissue matrix of rat organs at total body X-ray exposure. AB - Objective. To study the nature of radiation-induced changes in the connective tissue matrix of rats under single total body X-ray exposure in minimal lethal and sublethal doses. Materials and methods. Experiments conducted on white male rats weighing 160-180 g, which were exposed to the influence of X-radiation doses LD15/30 and LD60/30 at the installation RUM-17 in standard specifications. Assessment of connective tissue matrix was performed by the total content of collagen, soluble (SC) and insoluble (ISC) collagen, collagen destruction rate by free hydroxyproline, collagenlytic activity (CLA), individual glycosaminoglycans (GAG). Experiments were performed on days 3, 7 and 14 and 30th, 90th and 180th days. The age control was used to each term of experiments. Statistical analysis of data was performed using Wilcoxon-Mann-Whitney criterion and Student's t-test using packet Biostatistics v.4.03 for Windows. Results. The changes of collagen (3-7 days) were characterized by violation of ratio SC and ISC, accelerated disintegration of collagen by free hydroxyproline in the lungs - 1.7 times, the skin - 1.2 times, rising of metal-depending CLA in the lungs - 2.0 times and metal-independing CLA in the skin - 2.2 times, an increase of hyaluronic acid in the lungs - 1.7 times, in the skin - 1.5 times. At the late period (180 days) an increase of the total content of collagen was determined with a 1.4 times predominance of IC in the lungs and 1.3 times in the skin. During this period changes of individual GAG were characterized by - 1.7 times increase of chondroitin sulfate A and C in the lungs, 1.6 times dermatan sulfate in the skin and 1.7 times heparan sulfate in both organs. Conclusion. Revealed radiation induced changes in the connective tissue matrix of rats in their direction were not dependent on the dose of X-rays, were organ-specific and determined by time after exposure. PMID- 25536585 TI - Oxidative phosphorylation in mitochondria of small-intestinal enterocytes at chronic and single exposure to low power ionizing radiation. AB - Objective - to investigate the intensity of oxidation and phosphorylation processes in the small intestine enterocytes mitochondria of the rats under chronic and single exposure to ionizing radiation of low power. Materials and methods. The single irradiation of the rats with X-rays was performed using the RUM-17 equipment (at the dose of 0.055 Gy/min) for absorbed doses of 0.1; 0.5 and 1.0 Gy. The functional state of mitochondria was evaluated in 1 h and 24 h after irradiation. The chronic external gamma-irradiation (at the dose rate of 0.72 cGy/min to achieve a total dose of 0.3; 0.6 and 1.0 Gy was performed using the "Etalon" equipment which contained 60Co. The intensity of the oxidation and phosphorylation activity of the small intestine enterocytes mitochondria was assessed by the polarographic method. Results. The use of malate as exogenous substrate allowed to assess the functioning of all areas of the electron transport chain of mitochondria in experimental conditions. The increase in the intensity of mitochondrial respiration was found in all conditions and terms of research in response to irradiation. In chronic ionizing radiation appears partial separation of interface processes of oxidation and phosphorylation, as evidenced by the decrease in value of the index control and ADP / O and reducing efficiency phosphorylation (decrease of value Vf). For single exposure disconnection of coupling processes oxidation and phosphorylation were not accompanied by changes in the index of oxidative phosphorylation, however, was characterized by reduced ratio V4S/V4ATP. Conclusions. Single and chronic exposure to low power of ionizing radiation leads to an increase in intensity of respiration and disruption of oxidative phosphorylation as a result of separation of interface processes of oxidation and phosphorylation. In chronic exposure received changes were accompanied by inhibition of ATP from ADP and FN because no change of ATP hydrolase activity of mitochondria was noticed. The identified functional disruption of enterocytes mitochondria by ionizing radiation may be associated with structural and functional changes of the respiratory chain, activity both enzymes of electron transport chain and H+ -ATPase. Effects of ionizing radiation of low power can lead to disruption of mitochondrial bioenergetic function - one of the earliest manifestations of cellular dysfunction. PMID- 25536586 TI - Cytogenetic analysis of radioprotective properties of sodium lignogumate after gamma-exposure in Allium-test. AB - Objective. Comprehensive cytogenetic analysis of the effects of sodium lignohumate in induced gamma-irradiation mutagenesis in Allium-test. Materials and methods. Analysis of the root meristem cells of Allium cepa L. seeds carried by ana-telophase. Lignohumate investigated the effect of sodium (100 mg/l) on cytogenetic effects gamma-irradiation (137Cs) at doses of 5, 10 and 20 Gy. Results. Polyfunctionality lignohumate sodium antimutagen as provided by the presence not only antioxidant properties, but other antimutagenic mechanisms. Thus Lignohumate sodium exhibits radioprotective properties of the therapeutic. Stimulation of repair processes influenced lignohumate depends on the radiation dose. It is most effective at a dose of 5 Gy. Upon irradiation at doses of 10 Gy and 20 predominate, other mechanisms, including stimulation of apoptosis and repopulation. Spotted differential activity of the drug with respect to various types of aberrations are most effectively reducing the frequency of radiation markers mutagenesis - chromosomal aberrations manifested in lower efficiency of long term survivors against potential changes of chromosomes compared with short lived. Conclusions. Revealed multiple mechanisms for implementing antimutagenic properties lignohumate sodium gamma-irradiation-induced mutagenesis in Allium test. PMID- 25536587 TI - Hepatocellular carcinoma: insights in the biological treatment beyond sorafenib. AB - Hepatocellular carcinoma has an increasing incidence and an impressive mortality. At present, the only authorized systemic treatment is the multi-kinase inhibitor sorafenib. A multitude of clinical trials are aimed at improving outcomes, both in firstY- and in second-line therapy. In this multitude of clinical trials, the purpose of our article was to familiarize physicians with the mechanisms of action of new biological therapies and to offer an algorithm for optimal trial selection for each patient, based on clinical and biological indicators. The available data were structured as follows: antiangiogenic therapy, c -MET inhibitors, combinations of chemotherapy with sorafenib, immune response modulators, cellular metabolism modulators, mTOR inhibitors, other multi-kinase inhibitors. CONCLUSION: Treatment of advanced hepatocellular carcinoma remains a challenge for oncologists. Choosing the "right" trial may be the only chance of prolonging patient survival and improve his/her clinical status. PMID- 25536588 TI - Immunotherapy for hepatocellular carcinoma following thermal ablation. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignant disease and the third leading cause of cancer- associated deaths worldwide, and is characterized by a dismal prognosis. Despite the significant improvements achieved in liver transplantation, surgical resection, transcatheter arterial chemoembolization (TACE) and local ablative therapies such as percutaneous ethanol injection (PEI), radiofrequency ablation (RFA) and microwave ablation (MWA), the 5-year survival rate still remains unsatisfactory. The main reason is the high recurrence and metastasis rates after treatment. Immunotherapy based on the stimulation of antitumor immune response could represent a new strategy to control HCC recurrence and metastasis. Liver is an immunity organ itself and thermal ablation promotes the release of tumor-associated antigens. Based on the immune status of HCC patients before and after thermal ablation and tumor-associated antigens, this mini-review concisely discusses the potential of immunotherapy in HCC. PMID- 25536589 TI - Outcome of 561 non-metastatic triple negative breast cancer patients: multi center experience from Turkey. AB - PURPOSE: Triple-negative breast cancers account for 15% of breast carcinomas and, when present as early-stage disease, they are associated with higher rates of recurrence and early distant metastasis risk when compared to hormone receptor positive and human epidermal growth factor receptor (HER-2) positive breast cancers. In this study we aimed to explore the basic clinicopathological characteristics, prognostic factors and recurrence patterns of non-metastatic triple negative breast cancer patients. METHODS: In this study 561 non-metastatic triple-negative breast cancer female patients admitted to 8 different cancer centers in Turkey between 2000 and 2010 were retrospectively evaluated through their medical records, to identify the basic clinico-pathological characteristics, prognostic factors and recurrence patterns. RESULTS: The ratio of triple-negative breast cancer was 12%. The median age of patients was 48 years, of whom 311 (55.4%) were premenopausal. The majority had early-stage breast cancer at the time of diagnosis (16.8% stage I, 48.1% stage II, 35.1 % stage III) and the most commonly identified variant was invasive ductal carcinoma (84.1%). Grade II and III tumors were 27.1 and 48.5%, respectively. Adjuvant chemotherapy was administered to 90.5% of women and adjuvant radiotherapy to 41.2%. Median patient follow up was 28 months (range 3-290). During the follow up period 134 (23.8%) patients developed metastatic disease. In most of these cases, metastatic sites were bone, soft tissue, and lung. Factors affecting disease free survival (DFS) and overall survival (OS) were age (both p<0.001), lymph node involvement (both p<0.001), lymphovascular invasion (LVI) (p<0.001 and p=0.004, respectively), tumor stage (both p<0.001), adjuvant administration of anthracycline-based chemotherapy (both <0.001) and type of surgery (not significant for DFS but p=0.05 for OS). Three-year DFS and OS were 72.0 and 93.0%, respectively. CONCLUSION: Age, lymph node involvement, LVI, stage, and adjuvant chemotherapy were determined as prognostic factors for DFS and OS. The most common recurrence sites were bone, soft tissue and the lung. Further prospective randomised trials are needed to confirm the prognostic and predictive factors identified in this study. PMID- 25536590 TI - Clinical importance of discordance of hormone receptors and Her2/neu status after neoadjuvant chemotherapy in breast cancer. AB - PURPOSE: The aim of this study was to compare the hormone receptors' (HR) and HER2/neu status between core needle biopsy (CNB) and residual tumor after surgery of breast cancer treated with neoadjuvant chemotherapy (NAC), and also to evaluate the impact of discordance and other clinicopathological factors on survival. METHODS: Oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu status were evaluated by immunohistochemistry (IHC) on 90 CNBs of primary tumors and surgical specimens after NAC (study group); 53 patients without NAC served as control group, and discordance was compared between the two groups. The association between discordance of HR status after NAC and various other clinicopathological factors was tested with Spearman's test. RESULTS: Pathological complete response (PCR) was achieved in 10 (11.1%) patients after NAC. ER and PR changed significantly more in the study than in the control group. ER and PR discordance was detected in 10 (12.5%) and 17 (21.2%) patients in the NAC group and in 1 (1.8%) and 2 (3.7%) patients in the control group (p=0.04 and p=0.005, respectively). ER discordance was related with HER2/neu change. Furthermore, PR discordance correlated with CNB, ER and treatment response, while HER2/ neu discordance was associated with treatment response (p=0.05). ER discordance was found to be an independent prognostic factor for progression-free survival (PFS) (p=0.02). CONCLUSION: NAC might cause alterations in ER, PR or HER2//neu status in breast cancer, and they should be re-tested in the residual tumor after NAC to optimize adjuvant therapy. PMID- 25536591 TI - Survey on Chinese breast cancer patients' husbands toward breast conserving surgery. AB - PURPOSE: Husband, as an important member of the family, greatly impacts the treatment decision. In this study, we sought to evaluate the attitudes toward breast conserving surgery (BCS) in Chinese breast cancer patients' husbands and explore the influencing factors. METHODS: A self-structured questionnaire was distributed to the husbands of 1600 wives with breast cancer, eliciting information on their general information, the level of understanding of BCS, attitudes toward BCS and affecting reasons. RESULTS: In all, 1468 (91.8%) husbands completed the questionnaire. Collation of the responses showed that only 3.0% had a good understanding of BCS and 81.5% did not favor BCS. Patients' husbands perception were associated with their age, religion, occupation, educational background, method of payment of medical expenses, understanding the disease condition and doctor's recommendations (p<0.05). The top reason was "fear of incomplete resection, which could easily lead to recurrence and metastasis". CONCLUSIONS: This study indicates that Chinese husbands have skepticism and lack comprehensive and correct understanding for BCS. Meanwhile, their desire of obtaining knowledge was not strong. The results suggest a need for fundamental changes in husbands' education to ensure that they are able to obtain enough information so that they can help their wives make educated decisions. PMID- 25536592 TI - Micronuclei and other nuclear anomalies in exfoliated buccal mucosa cells of Mexican women with breast cancer. AB - PURPOSE: Breast cancer (BC) is the most frequently diagnosed form of cancer and the leading cause of cancer-related deaths among females in the world. RESULTS of several studies showed that the genome of primary cancer patients (naive for any treatment) is unstable. The purpose of the present study was to evaluate the genomic instability in BC patients by means of buccal cells micronucleus (MN) cytome assay Methods: The frequencies of nuclear anomalies including MN, binucleates (BN), broken eggs (BE), condensed chromatin (CC), karyorrhexis (KR) and karyolysis (KL) were evaluated in exfoliated buccal mucosa cells of Mexican women with primary BC and healthy women. Buccal cells were collected from 21 BC patients (9 with stage I and 12 with stage II) and from 20 healthy females used as control group. RESULTS: The results of the evaluation of cells showed that the frequencies of MN, BN, BE, KR and KL were significantly increased in the pooled group of BC patients compared with the control group. However, no one parameter of buccal MN-cytome assay in patients with stage I BC was significant compared with controls and BC patients with stage II. CONCLUSION: Application of the buccal MN-cytome assay for the study of genomic instability in primary BC patients showed that both genotoxic and cytotoxic effects can be evaluated in such patients. PMID- 25536593 TI - PTEN loss is not associated with trastuzumab resistance in metastatic breast cancer. AB - PURPOSE: Although the clinical benefits of trastuzumab are well known, intrinsic or acquired resistance is a commonly encountered clinical condition. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensine homologue (PTEN). This study investigated the relationship between trastuzumab response and loss of PTEN in metastatic breast cancer patients. METHODS: Patients with histologically confirmed human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer, who were treated with trastuzumab were enrolled into the study. PTEN expression was immunohistochemically evaluated. RESULTS: The patient median age was 50 years. Of 38 patients, 6 (15.8%) showed PTEN loss. No statistically significant difference was found between trastuzumab response, overall survival (OS) and progression free survival (PFS) and PTEN loss (p=0.538). CONCLUSION: The activation of phosphatidylinositol 3-kinase (PI3K) pathway resulting from PTEN loss was not found to be correlated with trastuzumab response and survival. PTEN loss should not lead to exclusion of patients from the potential to benefit from trastuzumab administration. PMID- 25536594 TI - Adjuvant chemotherapy outcomes in patients over 65 years with early stage colorectal carcinoma. AB - PURPOSE: To evaluate the clinicopathological characteristics and the outcomes of adjuvant chemotherapy of patients with colorectal cancer aged >= 65 years. METHODS: Between March 2003 and December 2010, the medical files of 562 colorectal cancer patients >= 65 years of age who were under follow-up in Ankara Numune Educational Hospital, Department of Medical Oncology, were retrospectively analyzed. Only 210 patients with non-metastatic disease at the time of diagnosis and those who had undergone surgical resection were included in the study. RESULTS: The patient median age was 71 years (range 65-87). Of the patients, 115 (54.8%) were males and 95 (45.2%) females. The most common involvement site was the rectum (41.4%), followed by sigmoid colon (21.9%). According to the TNM staging, 12.4% patients had stage I, 48.6% stage II, and 39% stage III disease. At the time of diagnosis 19 patients (9%) had ECOG PS 0, 112 (53.3%) ECOG PS 1, 61 (29%) ECOG PS 2, and 16 (7.7%) ECOG PS 3. Of the patients, 141 (66.5%) were administered adjuvant chemotherapy, whereas 69 patients (33%) were not. Thirty nine (18.6%) patients with adjuvant chemotherapy received fluorouracil/folinic acid (FUFA%) weekly, 59 (28%) received FUFA infusion, and 43 (21%) received oxaliplatin, folinic acid and 5-fluorouracil (FOLFOX-4) regimen. The median follow-up was 27 months (range 1-116). Disease free survival (DFS) was not reached during the follow-up period. The estimated overall survival (OS) was 68.8 months (range 48.5-73.0). Sixty six (31%) patients died during follow-up. CONCLUSION: Elderly patients with high risk for recurrence of colorectal cancer must receive adjuvant chemotherapy after curative surgery. Infusional FUFA seems more effective than other regimens. PMID- 25536595 TI - Quality assessment of decision-making in colorectal cancer multidisciplinary meetings. AB - PURPOSE: The quality of decision-making in the colorectal multidisciplinary team (MDT) meetings can significantly affect the quality of care delivered to patients with colorectal cancer. We performed a prospective study to assess the quality of the MDT meetings in a specialized colorectal unit using an externally observational validated tool. METHODS: An externally validated observational tool, the Colorectal Multidisciplinary Team Metric for Observation of Decision Making (cMDT-MODe), was used to assess the quality of clinical decision-making in 64 cases. RESULTS: Although case history information presented by the responsible surgeon was rated high (4.4/5), the quality of radiological and histopathological information regarding each patient's case which was available at the time was less adequate, scoring 3.9/5 and 3.8/5, respectively. Moreover, the precise knowledge of patients' personal views and circumstances was a field requiring further improvement. In a general overview however, the quality and extent of the available information enabled the MDT to provide a clear recommendation regarding the patients' treatment plans in 87.5% of the cases. CONCLUSIONS: The cMDT-MODe tool can be used to prospectively audit the quality of clinical decision-making in the colorectal MDT meetings and highlight the fields of potential improvement. PMID- 25536596 TI - Hypertension as a predictive biomarker for efficacy of bevacizumab treatment in metastatic colorectal cancer: a meta-analysis. AB - PURPOSE: Bevacizumab has demonstrated survival benefit in patients with metastatic colorectal cancer (mCRC) when combined with chemotherapy. However, no validated predictors currently exist for its efficacy. Hypertension has been evaluated as a surrogate marker for efficacy of bevacizumab, although analyses, to date, have yielded conflicting results. The aim of this meta-analysis was to dissect the association between hypertension and efficacy of bevacizumab treatment in mCRC. METHODS: We searched PubMed, EMBASE, Chinese Biomedical Database (CBM), and Wan Fang Digital Journals before September, 2013. The primary clinical outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Relative risk (RR) or summary hazard ratio (HR) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Studies meeting our search criteria were assessed. RESULTS: Nine studies were considered eligible, with 1674 mCRC patients included. Six (308 patients, 104 with hypertension), 8 (1661 patients, 431 with hypertension) and 5 (1512 patients, 408 with hypertension) studies were eligible for the ORR, PFS and OS meta-analysis, respectively. Bevacizumab-related hypertension was associated with increased ORR (RR= 1.63; 95% CI 1.26-2.12; p=0.0002), improved PFS (HR=0.68; 95% CI 0.58-0.79; p<0.00001) and OS (HR=0.52; 95% CI 0.42-0.66; p<0.00001). There was no statistically significant difference between-study heterogeneity. CONCLUSION: These analyses suggest that hypertension may be a potential biomarker for efficacy of bevacizumab treatment in mCRC. Additional large prospective trials are required to confirm its predictive role. PMID- 25536597 TI - Effect of Bcl-xL gene expression silenced by RNA interference on invasion of human colorectal cancer cells. AB - PURPOSE: To investigate the effect and possible mechanisms of Bcl-xL gene on the invasive capacity of human colon cancer cells. METHODS: HT29 human colorectal carcinoma cell line was transfected by small interfering RNA (siRNA) of Bcl-xL gene. Quantitative real-time (RT)-PCR and Western blot were used to detect the transfection, and soft agar colony culture experiments and Boyden chamber model test were used for cancer cell proliferation and invasion, respectively. Western blot was used to detect the protein changes of urokinase-type plasminogen activator (uPA) in cancer cells. RESULTS: Compared with the control group, the number of soft agar colonies and the number of penetrating membrane cells significantly reduced in the siRNA transfection group, and had dose-dependent characteristics; the uPA protein decreased significantly in the siRNA transfected cells. CONCLUSION: Bcl-xL gene may play an important role in the invasion of colon cancer cells, and the mechanism may be related to regulation of uPA expression. PMID- 25536598 TI - Phase II clinical trial of h-R3 combined with radiotherapy in locally advanced nasopharyngeal carcinoma. AB - PURPOSE: The purpose of this study was to evaluate the short- and long-term efficacy and toxicity of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody h-R3 when combined with radiotherapy for the treatment of locally advanced nasopharyngeal carcinoma (NPC). METHODS: 35 patients with stage III-IVb NPC with moderate- or strong-intensity EGFR expression were randomly divided into either a radiotherapy alone group or a group receiving radiotherapy combined with h-R3. RESULTS: The complete remission (CR) rates of the combination group at three time points were significantly higher (p<0.05) than those of the radiotherapy alone group. Overall survival, 3-year local control rate, and no distant metastasis rate did not differ between the two groups. No severe toxicity was noticed. CONCLUSION: h-R3 is an agent with good safety profile which could help enhance the radiation antitumor effect in locally advanced NPC, but it did not seem to exhibit significant long-term efficacy. PMID- 25536599 TI - Pretreatment perfusion CT and CT volumetry in squamous cell carcinoma of the head and neck region. AB - PURPOSE: Perfusion computed tomography imaging (PCT) is a robust, reproducible, widely accessible non-invasive method. The objective of our study was to assess whether prospectively collected pretreatment PCT parameters and volumetric measurements of locoregionally advanced squamous cell carcinoma (SCCA) of the oral cavity, oropharynx and hypopharynx could predict the response to concomitant chemoradiotherapy with cisplatin Methods: Pretreatment contrast enhanced PCT was performed in 30 patients. Radiologic response criteria (RECIST) were used to evaluate tumor response. The correlation and predictive value of baseline PCT parameters and tumor volume were examined by using the Student's t-test, Pearson's correlation coefficient and receiver operating characteristic (ROC) curves. RESULTS: Baseline tumor volume, blood volume (BV) and blood flow (BF) were significantly higher in responders than in non-responders. Permeability surface (PS) did not show any significant difference between the two groups. Pretreatment tumor volume correlated with baseline BV (r=-0.4; p=0.01). Pretreatment tumor volume had 100% sensitivity and specificity (p=0.0001) and BV and BF also showed satisfactory sensitivity and specificity (100% and 65%, p=0.0002; 78% and 80.2%, p=0.01, respectively) for prediction of tumor response to concomitant chemoradiotherapy with cisplatin. CONCLUSION: Baseline BV, BF and tumor volume values were significantly different between responders and non responders and could predict response to concomitant chemoradiotherapy with cisplatin in locoregionally advanced SCCA. PMID- 25536601 TI - Dosimetric evaluation of nasopharyngeal carcinomas irradiated with different IMRT techniques. AB - PURPOSE: To evaluate the performance of volumetric arc therapy (VMAT), dynamic intensity modulated radiotherapy (IMRT) and step-and-shoot IMRT techniques in nasopharyngeal cancer (NPC) patients. METHODS: IMRT plans of 48 NPC patients treated between May 2010 and December 2012, were evaluated. Twenty two patients were planned with VMAT, 18 with dynamic IMRT and 8 with step-and-shoot IMRT. Conformity index (CI) and homogeneity index (HI), the dosimetry of the planning target volumes (PTVs) and organs at risk (OARs) and the monitor units (MU) were evaluated for each IMRT modality. RESULTS: The conformity indices of VMAT and dynamic IMRT were better than step-and-shoot IMRT plans (p<0.05). Step-and-shoot IMRT plans provided better homogeneity than VMAT (p=0.01). MUs for dynamic IMRT were much higher compared to VMAT (p<0.01) and step and- shoot IMRT (p<0.01). There was no significant difference between the 3 techniques in terms of PTV70 mean doses. When compared with step-and-shoot IMRT, VMAT and dynamic IMRT had a better sparing effect on optic nerves, eyes and optic chiasm (p<0.05). VMAT plans performed better sparing for brain stem than dynamic IMRT (p=0.01). There was a remarkable decrease in the maximum doses of VMAT to the eye. CONCLUSIONS: VMAT outperforms dynamic IMRT by effectively reducing the MU and the dose to some OARs, with adequate PTV coverage. Also, VMAT provides better sparing of normal tissue and conformity than step-and-shoot IMRT. Differences between step-and shoot IMRT and dynamic IMRT are thought to be due to technical differences of linear accelerator devices like fiber size, variable fiber, dose rate and gantry. PMID- 25536602 TI - Tissue expression of VEGF in cervical intraepithelial neoplasia and cervical cancer. AB - PURPOSE: To examine the expression of vascular endothelial growth factor (VEGF) in the cervical tissue of individuals divided into the control group (normal cervix), group A (HSIL lesions), and group B (cervical cancer, FIGO stage I-IIA). Analyzed was also the expression of VEGF between groups and subgroups in group A and B. The expression of VEGF was also compared with histopathological parameters in group B. METHODS: Examined was the histopathological material taken from 109 operated patients. The patients were divided into 3 groups based on the definitive histopathological findings: control group (30 patients), group A (33 patients), and group B (46 patients). Immunohistochemistry was performed to examine the expression of VEGF. RESULTS: The expression of VEGF was negative in the control group, while in 11 patients (33.33%) from group A and 28 patients (60.87%) from group B it was significantly different (p<0.05) compared to the control group. There was neither statistically significant difference in the expression of VEGF in group A regarding the type of intraepithelial lesion, nor in group B regarding the FIGO disease stage (p>0.05). In patients with poor histopathological prognostic parameters such as tumor diameter >= 2 cm (24/46), depth of stromal invasion >= 10 mm (32/46), positive lymph nodes (17/46), and with infiltration of the uterine body (11/46) a statistically significant difference was confirmed regarding the expression of VEGF. CONCLUSION: The increased VEGF expression in groups A and B compared with the control group indicated the importance of VEGF as a proangiogenic factor in neoangiogenesis in precancerous and cancerous changes in the cervix. The frequent expression of VEGF in the subgroup of patients with poor histopathological prognostic factors (group B) indicated the importance of the activity of proangiogenic factors in the process of cervical cancer neoangiogenesis. Further investigations should be aimed at these markers as prognostic factors in the high risk group of patients with cervical cancer who should receive adjuvant therapy after radical operation and consider using antiangiogenic drugs as part of adjuvant treatment. PMID- 25536600 TI - Clinical significance of Cyclin D1, FGF3 and p21 protein expression in laryngeal squamous cell carcinoma. AB - PURPOSE: Laryngeal squamous cell carcinoma (LSCC) represents one of the most common cancers of the head and neck and the search for molecular markers is required for early diagnosis, prognosis and optimal therapy. The purpose of this study was to investigate the clinical significance of Cyclin D1, FGF3, p16 and p21 protein expression in LSCC and laryngeal dysplasia (LD) and to evaluate the associations between their expression levels and clinicopathological parameters of patients with LSCC. METHODS: Immunohistochemistry was employed to detect and quantify the expression levels of Cyclin D1, FGF3, p16 and p21 in the laryngeal tissues of 48 LSCC patients, 32 patients with LD and 28 subjects with healthy laryngeal mucosa (HLM). RESULTS: Significantly higher percentage of LSCC patients had positive Cyclin D1 expression compared with LD patients and HLM subjects (both p<0.01) and positive FGF3 expression than HLM subjects (p<0.05), while no differences in p16 and p21 positive expression were found among studied groups. The levels of Cyclin D1, FGF3 and p16 expression, as evaluated by immunostaining score, were significantly higher in patients with LSCC compared with LD and HLM groups (all p<0.05). Cyclin D1 proved to be highly sensitive and specific marker in differentiating LSCC from LD (sensitivity 81.2%, specificity 83.9%), while high sensitivity (81.2%) and lower specificity (41.4%) was observed in differentiating from HLM. Cyclin D1 and p21 expression levels were associated with regional lymph node metastases (both p<0.05) and Cyclin D1 expression levels significantly correlated with LSCC lymphatic invasion (x(2)=8.862; df=3; ?=0.031). CONCLUSIONS: Cyclin D1, FGF3 and p16 are overexpressed in patients with LSCC. Cyclin D1 is a highly sensitive marker in differentiating LSCC from LD or HLM. Cyclin D1 and p21 expression levels may be useful as predictive markers of metastases in LSCC. PMID- 25536603 TI - Systematic evaluation of bevacizumab in recurrent ovarian cancer treatment. AB - PURPOSE: This study aimed to evaluate the efficacy and safety of bevacizumab in the treatment of recurrent ovarian cancer. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched. Data regarding the use of bevacizumab in recurrent ovarian cancer were collected from randomized controlled trials (RCTs). Data were evaluated with the Cochrane systematic method, and statistical analysis was performed with the RevMan 5.2 software. Two RCTs comprising a total of 845 patients were included. RESULTS: Bevacizumab combined with conventional chemotherapy prolonged the progression-free survival (PFS) (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.41-0.56), without significantly altering the overall survival (OS) (HR 1.03; 95% CI 0.79-1.33). Adverse events (NCI-CTCAE v.4.0) associated with bevacizumab were >= grade 3 hypertension (relative risk [RR] 2.30; 95% CI 1.39-3.83) and bleeding (RR 4.76; 95% CI 1.38-16.37). CONCLUSIONS: Bevacizumab prolonged the PFS of patients with recurrent ovarian cancer. Additional high-quality randomized controlled trials are needed to verify these results. PMID- 25536604 TI - Overall human papilloma virus and types 16/18 prevalence in women with normal cervical cytology in Serbia: is it time for human papillomavirus testing and/or vaccination? AB - PURPOSE: Infection with high-risk human papilloma viruses (HR-HPV), especially types 16/18, is the main factor in cervical carcinogenesis. Although the incidence of cervical cancer in Serbia is among the highest ones in Europe, data about HPV infection are insufficient. The aim of this study was to investigate the presence of overall and HPV16/18 infections in women with healthy appearance and cytologically (Pap) normal cervix. METHODS: The study was performed on women who participated in this cervical cancer screening pilot study. Cervical HPV infection was detected by GP5+/6+ PCR. HPV16/18 were detected by amplification of E7/E1 viral gene, respectively. RESULTS: In 350 women we got the following results: cytological abnormalities (10.3%); visible cervical changes (20.3%); previous precancerous lesion (2.3%); normal Pap and speculum finding without history of precancerous lesion (67.1%). In the last group overall HPV prevalence was 41.3%, with 10.5% HPV16 and 23.7% HPV18. The rate of multiple HPV16 plus HPV18 infections was 2.6%. HR-HPV16/18 comprised 31.6% of the total HPV positive participants. CONCLUSION: Owing to the high prevalence of overall and HPV16/18 infections in women with healthy appearance and cytologically normal cervix, we postulate that testing/ prophylaxis for these HR-HPV types could be introduced in cervical cancer screening and preventive programmes in Serbia. PMID- 25536605 TI - Prolonged progression-free survival with maintenance metronomic oral cyclophosphamide and etoposide treatment in macroscopic residual disease or recurrent/advanced stage ovarian cancer. AB - PURPOSE: In ovarian cancer permanent remission may be provided with optimal cytoreductive surgery and adjuvant chemotherapy. However survival is short in patients with residual macroscopic disease after surgery or recurrent ovarian cancer. Applicable maintenance therapies with low toxicity are required to prolong progression-free survival (PFS) for patients with no curative treatment options. In this study, we investigated the effect of maintenance metronomic oral cyclophosphamide and etoposide (CE) in ovarian cancer patients with post operative residual or recurrent disease. METHODS: Forty five patients that received metronomic oral CE (cyclophosphamide 50 mg/daily and etoposide 50 mg for 1-5 days, every 21 days) as maintenance therapy for residual disease due to incomplete surgical resection or recurrent advanced-stage ovarian cancer were evaluated. The time between the beginning of oral CE and disease progression was also evaluated. RESULTS: The mean patient age was 58 years, the vast majority had serous adenocarcinoma (78%) and received a mean of 2 (range 1-4) lines of various intravenous regimens for postoperative residual or recurrent disease. Mean duration of oral CE was 11.3 months (range 2.9-29). Median PFS was 10.3 months (range 7.9-12.8). Only 5 patients discontinued treatment due to intolerance and grade 3-4 toxicity was recorded in 3 patients (7%). CONCLUSION: Maintenance metronomic oral CE treatment was found effective, minimally toxic and sustainable in patients with macroscopic residual or recurrent advanced-stage ovarian cancer. However, randomized and placebo-controlled well designed studies are required. PMID- 25536606 TI - JAK2V617F mutation and endogenous erythroid colony formation in patients with polycythaemia vera. AB - PURPOSE: The purpose of this study was to investigate the frequency of JAK2V617F gene mutation in patients with polycythemia vera (PV) and to compare the results with the presence of endogenous erythroid colony (EEC) formation. METHODS: Peripheral blood and bone marrow samples of 28 patients with PV were analyzed. The diagnosis of PV was established according to the bone marrow criteria of the World Health Organization (WHO). Mutation of JAK2V617F was determined by allele specific PCR (AS-PCR) analysis. For detection of EEC formation we used assays of human clonogenic heamatopoietic progenitor cells with agar-leukocyte conditioned medium (Agar-LCM) without recombinant human erythropoietin (EPO). RESULTS: Mutation was found in the samples of the peripheral blood in 26/28 (92.9%) PV patients. EEC formation was obtained in the sample of bone marrow in 27/28 (96.4%) PV patients. In 25/28 (89.2%) patients we detected presence of EEC formation and mutation of JAK2V617F at the same time. CONCLUSION: Considering these results, we hypothesized that the EEC formation observed in myeloproliferative disorders could be partially due to the JAK2-dependent activation signaling pathway. PMID- 25536607 TI - Synergistic effect of ponatinib and epigallocatechin-3-gallate induces apoptosis in chronic myeloid leukemia cells through altering expressions of cell cycle regulatory genes. AB - PURPOSE: Ponatinib (P) has been used for the treatment of chronic myeloid leukemia (CML) and it is known that inhibition of BCR-ABL fusion protein by ponatinib induces apoptosis of CML cells. Epigallocatechin-3-gallate (EGCG), which is a polyphenol in green tea, induces apoptosis in different types of cancer cells. The purpose of this study was to determine the cytotoxic and apoptotic effects of ponatinib and EGCG combination in K562 CML cell line. This study also aimed to detect alterations of the expression levels of cell cycle regulation related genes after ponatinib and EGCG combination in K562 CML cell line. METHODS: The cytotoxic effects of the compounds on K562 cells were determined in a time-and dose-dependent manner by using WST-1 analysis. The combination index (CI) isobologram was used to analyze the data. Apoptotic effects of P-EGCG were defined by flow cytometry and gene expressions were detected by RT-qPCR. RESULTS: IC50values of ponatinib and EGCG were 87.13 nM and 50MUM, respectively. CI value of the P-EGCG was 0.658 and the combination showed synergistic effect (ED90 value: 28.39 nM ponatinib, 117.12 MUg/ml EGCG). Ponatinib, EGCG and P-EGCG induced apoptosis compared to control cells. CyclinD1 and CDC25A were downregulated by P-EGCG by 2.49 and 2.63-fold, respectively. TGF beta2 was upregulated by 4.57-fold. CONCLUSION: EGCG possesses cytotoxic and apoptotic properties and may cooperate with the growth inhibiting activity of ponatinib synergistically against CML cells. P-EGCG mediated apoptosis might be associated with upregulation of TGF-beta2 gene and downregulation of cyclinD1 and CDC25A genes. PMID- 25536608 TI - Myelodysplastic syndromes in adults aged less than 50 years: incidence and clinicopathological data. AB - PURPOSE: Myelodysplastic syndrome (MDS) is rarely seen in patients younger than 50 years, but rapidly increases with advancing age. Data on MDS biology in young patients are yet scarce but more than necessary. The purpose of this study was to estimate the proportion of MDS patients <50 years of age and to compare the clinicopathological data between younger and older patients. METHODS: Of our total MDS cases comprising 587 adult patients we studied 83 adults (14.14%) aged < 50 years with primary MDS. RESULTS: MDS patients were classified in those aged < 50 years and those aged >= 50 years. Younger MDS patients were characterized by female preponderance (p<0.001), better performance status (p=0.0035), less severe anaemia (p=0.008), better preserved kidney function (p=0.037), less often blast infiltration in bone marrow (p=0.015), more cases of RA (p<0.001) and RCUD (p=0.0066), lower MD Anderson score (p<0.001), longer overall survival (OS) (p<0.001), but similar progression rate (p=0.591). Median OS of young MDS patients was 39.7 months and 19 months of patients >50 years (p<0.001). In this group, 24 patients (28.92%) progressed to acute myeloid leukaemia (AML) vs 111 (22.02%) patients>50 years (p=0.402). Multivariate analysis identified platelet count (p=0.008) and percent of blasts in bone marrow (p=0.024) to be predictive for shorter OS in patients < 50 years of age; the same factors (p<0.001) together with IPSS-R cytogenetic risk group (p<0.001) were identified in patients >50 years of age. Platelet count (p=0.003) and percent of blasts in bone marrow (p=0.001) were predictive for higher risk of transformation to AML in patients <50 years, and bone marrow infiltration (p=0.022) and IPSS-R cytogenetic risk group (p=0.027) for patients >50 years of age. CONCLUSION: Presenting features in young MDS patients may identify subjects at higher risk for unfavorable outcome. PMID- 25536609 TI - The effects of mesenchymal stem cells on lymphoblastic leukemia cell proliferation. AB - PURPOSE: Mesenchymal stem cells (MSCs) represent a new approach to the treatment of several neoplastic or non-neoplastic disorders. Their potential to repair damaged tissues through trans differentiation in conjunction with their immunomodulatory ability made them promising candidates for cell-based immunotherapy and regenerative medicine. In the present study, we aimed to determine the effects of MSCs on proliferation, apoptosis and gene expression profile of the acute lymphoblastic leukemia (ALL) cell line CCRF-CEM. METHODS: The experiments were performed after MSCs and CCRF-CEM cells were co-cultured for 72 hrs. We analyzed the gene expression patterns to predict oncogenic pathway dysregulation in the cell groups by quantitative RT-PCR and immunohistochemical staining. RESULTS: Cell proliferation was significantly inhibited in co-cultured CCRF-CEM cells compared to the control. Furthermore, growth factors, p53, Bax and Caspase-9 expressions were increased and cell-signaling gene expressions decreased significantly. Despite increased levels of growth factors (CTGF, VEGF, FGF, EGFR), the increased apoptosis level was triggered by p53/ Bax. CONCLUSION: In this study we have shown that human MSCs have inhibitory effect on their neighboring malignant leukemia cells. PMID- 25536610 TI - Pleural fluid glucose: A predictor of unsuccessful pleurodesis in a preselected cohort of patients with malignant pleural effusion. AB - PURPOSE: To assess whether exclusion of patients with conditions that could lead to large fluctuations of serum glucose, would increase the accuracy of pleural fluid glucose in predicting pleurodesis outcome in patients with malignant pleural effusion subjected to bleomycin pleurodesis. METHODS: A retrospective analysis of 162 patients with recurrent, symptomatic malignant pleural disease was performed. Patients with diabetes mellitus or other causes of hyperglycemia were excluded, as pleural fluid glucose has been reported to be sensitive to serum glucose fluctuations. Assessment of pleurodesis outcome was based on radiologic appearance 30 days post-bleomycin pleurodesis. RESULTS: Successful pleurodesis was achieved in 64.8% of patients. Univariate analysis showed that pleural fluid glucose (p<0.001), pH (p<0.001), total proteins (p<0.001), albumin (p<0.001) and cholesterol (p<0.05) were significantly lower in patients with pleurodesis failure, while LDH was significantly higher (p<0.05). Pleural fluid glucose was the only independent predictor of pleurodesis outcome and with a cut off point of 65 mg/dl had a high sensitivity (90.7%) with an acceptable specificity (76.8%) (p<0.001). The regression model exhibiting the highest predictive accuracy included pleural fluid glucose and albumin (sensitivity 89.3%, specificity 84.5%, p<0.001). Furthermore, a product of glucose and albumin less than 152 could predict pleurodesis failure with 88.9% sensitivity and 82.8% specificity (p<0.001). CONCLUSIONS: Pleural glucose levels may reliably predict pleurodesis failure in patients without conditions that could lead to hyperglycemia, and its accuracy can increase if combined with pleural fluid albumin in an-easy-to calculate formula. PMID- 25536611 TI - The influence of methylenetetrahydrofolate reductase and thymidylate synthetase gene polymorphisms on lung adenocarcinoma occurrence. AB - PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthetase (TYMS) are suggested as risk factors for lung cancer. The purpose of this study was to analyze the association of MTHFR C677T polymorphism and variable number tandem repeat 2R/3R and single nucleotide polymorphism G>C in the 3R allele of the TYMS gene with lung adenocarcinoma. METHODS: A case-control study including lung adenocarcinoma patients and healthy subjects was performed. Restriction fragment length polymorphism analysis was used for genotyping. Descriptive analyses included genotype and allelic frequencies; the odds ratio and 95% confidence interval were calculated as an estimate of relative risk. Significance was set at p<0.05. RESULTS: A significant difference in CC vs TT+CT MTHFR genotype distribution was observed between patients and controls. There was no significant association between the TYMS polymorphisms and the risk of lung adenocarcinoma. CONCLUSIONS: The MTHFR 677T allele is likely to have a protective effect against lung adenocarcinoma development. PMID- 25536612 TI - Efficacy of stereotactic radiotherapy as salvage treatment for recurrent malignant gliomas. AB - PURPOSE: To evaluate the efficacy and toxicity of CyberKnife stereotactic radiotherapy (SRT) for recurrent glial tumors previously treated with high-dose radiotherapy. METHODS: CyberKnife SRT was performed in 37 patients with recurrent glial tumors who presented to our hospital between January 2007 and March 2012. The patients were subjected to a dose ranging from 20 to 28 Gy using the CyberKnife system with an average of two fractions. The median follow-up duration after SRT was 14 months (range 1.8-57). RESULTS: The median survival time of the patients after recurrence was 22.3 months (95% confidence interval/95% Cl 12.5 32). The median survival times of the high- and low-grade patients were 29 and 19 months, respectively. No significant toxicity due to radiation was noticed during the follow-up period. No factor influencing mortality was found in either the univariate or multivariate analysis. CONCLUSION: SRT using CyberKnife is an effective and safe treatment choice for recurrent glial tumors. SRT achieves a more favorable outcome in the treatment of recurrent tumors, particularly in high grade ones. PMID- 25536613 TI - Factors predicting recurrence in patients with grade III glial tumors: impact of adjuvant temozolomide on recurrence. AB - PURPOSE: The purpose of this study was to evaluate the clinicopathological features of patients with grade III glial tumors associated with recurrence after treatment. METHODS: A retrospective analysis was carried out on 67 patients with grade III glial tumors between May 2007 and June 2013. Data were retrieved from patient electronic medical records and paper charts. RESULTS: The patient median age was 43 years (range 19-707 rpar;. Of these, 50.7% (N=34) had anaplastic astrocytoma, 29.9% (N=20) anaplastic oligoastrocytoma and 19.4% (N=13) anaplastic oligodendroglioma. Among these 67 patients, 41 (61.2%) developed local recurrence. Fifty seven of them (80.6%) received radiotherapy (RT) with concomitant temozolomide. Of these patients, 14 (20.9%) received RT with concomitant temozolomide alone, and 43 (64.2%) were treated with concomitant chemoradiotherapy followed by adjuvant temozolomide. Time to recurrence (TTR) of patients who received adjuvant temozolomide after concomitant chemoradiation (TTR=14 months, 95% CI 9.3-22.77 rpar; as initial treatment for grade III glial tumors was not superior to RT with concomitant temozolomide alone (TTR=21 months, 95% CI 14.8-35.2; p=0.224) In multivariate analysis, histologic subtype (p=0.015), age (p=0.019) and presence of neurologic symptoms (p=0.021) were independent predictive factors of recurrence. CONCLUSION: This analysis demonstrated that histologic subtype, age and presence of neurologic symptoms were significantly associated with recurrence in patients with grade III glial tumors. Adjuvant temozolomide was not significantly associated with recurrence in patients with grade III glial tumors. The identification of these predictors may be important for the patient follow-up and better treatment modifications. PMID- 25536614 TI - Promoter methylation assay of SASH1 gene in hepatocellular carcinoma. AB - PURPOSE: To analyse the relationship between the expression of SASH1 and its methylation level in human hepatocellular carcinoma. METHODS: Expression levels of SASH1 were examined with real-time PCR (RT-PCR) in tissues and cells, and methylation analysis was performed with MassArray. RESULTS: The expression levels of SASH1 were strongly reduced in liver cancer tissues compared with adjacent normal tissues. Quantitative methylation analysis by MassArray revealed different CpG sites in SASH1 promoter shared similar methylation pattern between liver cancer tissues and adjacent normal tissues and the CpG sites of significant difference in methylation level were found as follows: CpG_3, CpG_17, CpG_21.22, CpG_25, CpG_26.27, CpG_28, CpG_34.35.36 and CpG_51.52. Moreover, 5-aza-2' deoxycytidine treatment of Hep-G2 cell line caused significant elevation of SASH1 mRNA. CONCLUSIONS: Based on these data, we propose that increase of DNA methylation degree in the promoter region of SASH1 gene, particularly CpG_26.27 sites, possibly repressed SASH1 expression in liver cancer. PMID- 25536615 TI - Cytotoxic effects of suramin against HepG2 cells through activation of intrinsic apoptotic pathway. AB - PURPOSE: To investigate the cytotoxic activity of suramin against HepG2 human HCC cell line. METHODS: HepG2 cells were treated with 15, 30 and 45 MUM suramin. HepG2 cell proliferation was measured by MTT and lactate dehydrogenase (LDH) assays. Heparan sulfate proteoglycans (HSPGs), glucuronic acid and glucosamine levels were measured. Moreover, apoptosis was assessed by measuring caspase-8 and caspase-9 activities. The effect of suramin on HepG2 cells was compared with the same doses of a standard drug, cisplatin. RESULTS: Suramin blocked heparanase leading to dose-dependent increase in HSPGs and reduction in glucuronic acid and glucosamine levels. Suramin reduced HepG2 cells survival and showed cell cytotoxicity in a dose-dependent manner with LD50 45.04 MUM, compared with cisplatin (LD50 28.9 MUM) (p<0.05). Moreover, suramin was able to increase the activity of caspase-9 but not of caspase-8. CONCLUSION: Suramin possesses cytotoxic properties, which can be partially explained by its ability to inhibit heparanase and restore HSPGs. Suramin activates intrinsic apoptosis without affecting the extrinsic pathway. PMID- 25536616 TI - Enhanced cytotoxicity and apoptosis by thymoquinone in combination with zoledronic acid in hormone- and drug-resistant prostate cancer cell lines. AB - PURPOSE: Thymoquinone (TQ), an active ingredient of black seed oil (Nigella Sativa), has been shown to possess cytotoxic activity against a variety of cancer cell lines. Our purpose was to investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the TQ in hormone- and drug-refractory prostate cancer cells PC-3 and DU-145. METHODS: XTT cell proliferation assay was used to assess cytotoxicity; DNA fragmentation and caspase 3/7 activity were also measured. RESULTS: The combination of TQ and ZA resulted in a significant synergistic cytotoxic activity and DNA fragmentation when compared to any single agent alone, in a dose- and time-dependent manner. In addition, TQ and ZA combination increased the caspase 3/7 activity in PC-3 cell line, while this activity could not be demonstrated in DU-145 cell line. CONCLUSION: TQ and ZA had minimal hematological and non-hematological toxicity profile compared to cytotoxic agents. So, this combination may be an alternative approach for patients who are unable to be treated by conventional treatments because of poor performance status. PMID- 25536617 TI - Sequential therapy and prognostic factors in metastatic renal cell carcinoma: single centre experience. AB - PURPOSE: In advanced stage renal cell cancer (RCC), overall survival (OS) of patients has been prolonged due to targeted therapies. To date, there are several prognostic risk models that have been developed for metastatic RCC (mRCC). The purpose of this study was to evaluate the outcomes of the sequential therapy (IFN alpha, tyrosine kinase inhibitors/TKIs, m-TOR inhibitor) and prognostic factors in patients with mRCC, especially those with bone metastasis. METHODS: We retrospectively examined the data of 82 patients with pathologically proven mRCC who were followed-up and treated at the Medical Oncology Clinic of the Dr A.Y Oncology Hospital between 2005 and 2013. RESULTS: Median OS was 23 months in all patients with mRCC and 20 months in patients treated with TKIs. According to MSKCC and HENG risk classifications, median OS differed between the groups (p=0.02, p<0.001, respectively). Median OS was lower in patients with isolated bone metastasis compared to those with lung metastasis (16 vs 24 months, p=0.25). Median OS improved with increasing number of sequential therapies (p=0.08). CONCLUSION: This study confirmed the correlation between MSKCC and HENG risk models and survival data. Additionally, it was shown that increase of the number of therapeutic lines in sequential therapy prolonged survival and that bone metastases were negative prognostic factors. PMID- 25536618 TI - Chemotherapy-related toxicity in childhood neoplasia. AB - PURPOSE: To evaluate the incidence and time of occurrence of chemotherapy-related toxic events in 100 children admitted to the Hematology-Oncology Ward of "Sfanta Maria" Children's Emergency Hospital in Iasi, Romania, over a 4-year period. METHODS: An analytical, descriptive and comparative, retrospective and prospective study covering a 4-year period on the incidence of chemotherapy side effects, was performed on 100 children admitted for solid tumors or hematologic malignancies. The probability of each adverse event to appear and the time period from chemotherapy initiation to the moment of side effect appearance were assessed. RESULTS: The most frequent toxicity was alopecia (79.5%), followed by medullary aplasia (71.1%), oral candidiasis (65.3%), diarrhea and emesis (64% each), toxic hepatitis (61%), and Cushing's syndrome (21.5%). Oral herpes and thrush were less frequent (13.2% and 12.2%, respectively). Remissions of the underlying disease were achieved in 69.9% of the cases. Alopecia, medullary aplasia and oral candidiasis developed during the first 14 months of treatment. Mucositis, emetic syndrome and toxic hepatitis were diagnosed within the first 12 months of treatment. Diarrhea and oral herpes or thrush appeared during the first 15 months, while Cushing's syndrome developed during the first 6 months. All remissions were obtained during the first 4 months of treatment. CONCLUSIONS: While alopecia and medullary aplasia were the most frequent side effects of chemotherapy in our study group, the earliest were Cushing's syndrome, emetic syndrome and toxic hepatitis. PMID- 25536619 TI - The effects of environmental and dietary factors on the development of gastric cancer. AB - PURPOSE: Gastric cancer is the most frequent digestive system cancer in Turkey. The purpose of this study was to investigate the effect of sociodemographic, environmental, dietary and reproductive factors on the development of this malignancy. METHODS: 150 patients diagnosed with gastric cancer and 300 healthy controls were included in the present study. Sociodemographic, environmental, dietary and reproductive factors that might affect the risk of gastric cancer were retrospectively investigated. RESULTS: Examination of the dietary menus revealed that consumption of animal fats, pickled and salted foods were considerably higher (p<0.001) in gastric cancer compared to controls. Consumption of meat and eggs were significantly different (p=0.048) between gastric cancer patients and the control group. Consumption of bread and cereal products (p<0.001), milk and milk products (p<0.001), orange juice (p=0.022), tea and coffee (p=0.004 and p=0.002) was markedly lower in the gastric cancer patients. Consumption of pickles was an independent risk factor for development of gastric cancer. Eating too hot foods and barbecued meat was also shown to increase the risk of gastric cancer (p<0.001). In addition, the educational level of the patients was also lower compared to those of the control group (p=0.033). Women with onset of menarche at 15 years and above also possessed a higher risk for gastric cancer (p<0.001). CONCLUSION: Environmental and dietary factors play a significant role in the development of gastric cancer. PMID- 25536620 TI - Samarium-153Sm-EDTMP as an equivalent variant to pharmaceutical analgesic treatment. AB - PURPOSE: Cancer pain is the most serious symptom for patients, especially during their terminal phase, when palliative medicine is needed. Our study tried to verify the usefulness of single-shot intravenous administration of Samarium (Sm) 153EDTMP in patients with bone metastases (group-A, N=53, males=25, females=28, age range: 30-69 years), as well as to compare a series of variables, using as a control group (group-B, N=37, males=17, females=20, age range: 30-69 years) with patients who were under drug treatment given from a physician specialized in palliative medicine. METHODS: Both groups answered the following questionnaires: Greek Brief Pain Inventory (GBPI), Brief Multidimensional Life Satisfaction Scale (BMLSS), Hospital Anxiety Depression Scale (HADS) and ECOG performance status. RESULTS: Pain severity and pain interference improvement p=0.0005 for both groups. HADS-anxiety: Samarium group, p= 0.397, drugs group p= 0.031. HADS depression improvement for both groups p=0.031 and p=0.003, respectively. BMLSS improvement p=0.029 and p=0.265, while EGOG PS improvement was p=0.005 and p=0.014, respectively (numeric values). CONCLUSION: Intravenous administration of Sm-153EDTMP was equivalent to drug treatment against cancer pain for patients with multiple bone metastasis, an option for those patients who are intolerant or resistant to drug treatment. Samarium-treated patients needed less or not at all pain killers, having a better cost-effective result. PMID- 25536621 TI - Quantitative assessment of the association between GNB3 C825T polymorphism and cancer risk. AB - PURPOSE: The association between GNB3 C825T polymorphism and cancer risk has been investigated. However, results remain inconclusive. In this study we aimed to obtain a more precise estimation of this association. METHODS: A meta-analysis of 8 eligible studies including 1,812 cancer cases and 3,731 controls was conducted with odds ratios (ORs) and the corresponding 95% confidence interval (95% CI). RESULTS: The results demonstrated a borderline association between the GNB3 C825T polymorphism and the risk of overall cancer in the dominant model (TT+TC vs CC, OR=1.13, 95% CI=1.00-1.28, PH=0.71, p=0.05). In the stratified analysis by cancer type, significant association of cancer risk was observed in thyroid carcinoma (TC vs CC, OR=1.26, 95% CI=1.02-1.54, PH=0.63, p=0.03; TT+TC vs CC, OR=1.24, 95% CI=1.02-1.51, PH=0.70, p=0.04). After further stratified analysis based on country, the GNB3 C825T polymorphism showed statistically significant association with increased risk of cancer in Austria (TT vs CC, OR=1.44, 95% CI=1.01-2.04, PH 0.88, p-0.04; TT vs TT+TC, OR=1.49, 95% CI=1.07-2.64, PH=0.87, p=0.02) and Germany (TC vs CC, OR=1.25, 95% CI=1.02-1.53; PH=0.87, p=0.03; TT+TC vs CC, OR=1.23, 95% CI=1.02-1.49, PH-0.90, p-0.04). CONCLUSION: The current meta analysis suggested that the GNB3 C825T polymorphism may contribute to increased risk of cancer, especially of thyroid carcinoma. PMID- 25536622 TI - Genetic G2548A polymorphism of leptin gene and risk of cancer: a meta-analysis of 6860 cases and 7956 controls. AB - PURPOSE: The results from the published studies on the association between LEP (leptin) genetic polymorphism and cancer risk are conflicting. The common G2548A genetic polymorphism has been reported to be functional and may contribute to genetic susceptibility to cancers. However, the association between LEP G2548A genetic polymorphism and cancer risk remains inconclusive. METHODS: To better understand the role of LEP G2548A genetic polymorphism in global cancer, we conducted this comprehensive meta-analysis encompassing 6860 cases and 7956 controls. RESULTS: Overall, the LEP G2548A genetic polymorphism was associated with higher cancer risk in three genetic models (AA vs GG, AA vs AG/GG, A vs G). In the stratified analysis, there was significant association of LEP G2548A variant with non-Hodgkin's lymphoma (NHL) under homozygous co-dominant model (OR=1.27, 95% CI 1.01-1.60) and additive genetic model (OR=1.14, 95% CI 1.01 1.28). Moreover, a significantly increased cancer risk was found in three genetic models (AA vs GG, AA vs AG/GG, A vs G) among Caucasian population. For Asians, no significant associations were observed in any genetic model tested. CONCLUSIONS: These findings suggest that the LEP G2548A genetic polymorphism may increase the susceptibility of cancers in NHL, especially in the homozygote co-dominant model and the additive genetic model among Caucasian populations. The phenomenon also indicates that the SNP functions as a recessive mutation, which needs to be verified or linked with functional studies. PMID- 25536623 TI - Impact of energy variation on Cone Ratio, PDD10, TMR20/10 and IMRT doses for flattening filter free (FFF) beam of TomoTherapy Hi-Art(TM)machines. AB - PURPOSE: The beam energy (PDD10: Percent depth dose) of a Tomotherapy Hi-ArtTM machine was varied in a controlled experiment from -1.64 to +1.66%, while keeping the output at 100% and the effect of this on IMRT output, MU chamber ratio (MUR), cone ratio (CR) and Tissue Maximum Ratio (TMR20/10) was studied METHODS: In this study, Injector Current Voltage (VIC) and Pulse Forming Network Voltage (VPFN) were changed in steps such that the PDD10 was varied from golden beam value incrementally between -1.64 to +1.66%. The effect of this on other energy indicators was studied to verify the sensitivity of TMR20/10, MUR, and detector data-based-CR. To quantify the effect of energy variation on Intensity Modulated Radiation Therapy (IMRT) dose, multiple ion-chamber based dose measurements were recorded by irradiating a cylindrical phantom with standard IMRT plans. Dose variation across each commissioned Field width (FW) was tabulated against energy variation. RESULTS: Good agreement between PDD10 and TMR20/10, MUR, CR was observed. CR was more sensitive to energy change than PDD10. More variation was observed across standard IMRT plan with increasing energy. CONCLUSION: CR is more sensitive to energy changes compared to PDD10, and CR with MUR can definitely be used as surrogates for checks on a daily/weekly basis. Variation in output across the 6 standard IMRT plans can vary up to 2.8% for a 1.6% increase in energy. Hence, it is of utmost importance to manage the PDD10 tightly around +0.5% in order to regulate standard IMRT QA agreement to within 1% and patient IMRT QA within +/-3%. PMID- 25536624 TI - Costs differences among monoclonal antibodies-based first-line oncology cancer protocols for breast cancer, colorectal carcinoma and non-Hodgkin's lymphoma. AB - PURPOSE: To assess and compare the costs of first-line monoclonal antibodies (mAbs) treatment protocols in breast cancer, non-Hodgkin lymphoma and colorectal carcinoma in South-Eastern Europe. METHODS: A retrospective, bottom-up case series study design was implemented with one-year time horizon and payer's perspective. The study sample size was 265 patients (breast cancer, N=137; colorectal cancer, N=44; and non-Hodgkin lymphoma, N=84), while treatment protocols included adjuvant mAbs: trastuzumab (N=137), bevacizumab (N=28), rituximab (N=16) and cetuximab (N=84). ICD-10 related resources use included history of medical services utilization, chronology (time out of service provision) and unit consumption of examinations, drugs prescribed, imaging, radiotherapy and surgical procedures provided etc., direct medical and lost productivity costs (?) across treatment groups during 2010-2013. RESULTS: The average length of observation was 125+97 days per patient. Total mean direct and indirect costs of care were: trastuzumab for breast cancer group ? 17,740 per patient; bevacizumab for colorectal carcinoma group ?8,775 per patient; cetuximab for colorectal carcinoma group ? 27,181 per patient; and rituximab for non Hodgkin lymphoma group ?19,431 per patient. An average mAbs-treated patient incurred ?17,897 costs of medical care. The total combined budget of these 330 patients was ?4,742,775. CONCLUSIONS: The use of mAbs strongly correlated with high costs in first-line cancer medical care and dominated other cost domains. Cetuximab-based treatment protocols in colorectal carcinoma patients was substantially more expensive compared to trastuzumab (C50), bevacizumab (C20), and rituximab (C80) alternatives. Extremely high costs of mAbs are the key-issue for Eastern European policy makers by crossing the upper limits of affordability in middle-income economies. PMID- 25536625 TI - Immunohistochemical expression of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins in urothelial bladder carcinoma: correlation with clinicopathological parameters. AB - PURPOSE: To reevaluate the expression levels of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins and their potential association with standard clinicopathological parameters, including tumor stage and grade, in urothelial bladder carcinoma (UBC). METHODS: Immunohistochemistry was performed in 100 transurethral resection specimens obtained from prospectively identified patients with primary UBC. RESULTS: Overall, 26, 41 and 75% of the cases showed positive staining for p53, p63 and c-myc, respectively, while p21(WAF1/cip1) and p27(kip1) expression levels were altered in 75 and 88% of the cases, respectively. Positive staining for p53 was associated with increased tumor stage (pT2) (p=0.037), while altered expression of p27(kip1) was strongly associated with male gender (p=0.009). CONCLUSION: The results of our study imply that p53 overexpression may be a useful marker of tumor invasion in UBC. In contrast, we failed to demonstrate any statistically significant correlation between the remaining markers evaluated and tumor stage or grade. PMID- 25536626 TI - Anaplastic variant of diffuse large B-cell lymphoma associated with cutaneous fistulas; an unusual presentation. PMID- 25536627 TI - Alternative oncological treatment: psychological support for cancer patients - means for a better quality of life or better survival. PMID- 25536628 TI - Acute erythroid leukemia in a patient with chronic lymphocytic leukemia. PMID- 25536629 TI - Management of primary ovarian malignant fibrous histiocytoma. PMID- 25536630 TI - Gastric cancer with diffuse hepatic metastases and complete radiological response to triplet chemotherapy. PMID- 25536632 TI - Reply to Drs Liu and Xia. PMID- 25536631 TI - Comment on Zhao et al. article: IL-17A G197A and IL-17F T7488C polymorphisms and cancer risk in Asian populations: a meta-analysis. PMID- 25536633 TI - Comment on Liu et al.'s article: "The true role of mRECIST guideline: does it really estimate viable tumor or merely improve accuracy in hepatocellular carcinoma response evaluation?". PMID- 25536634 TI - Reply to Dr. Moschouris et al.'s comment. PMID- 25536635 TI - Charles-Emile Troisier (1844-1919) and the clinical description of signal node. AB - Charles-Emile Troisier's research concerning the enlarged left supraclavicular lymph node and its connection not only with gastric carcinoma but also with several other abdominal malignancies contributed to the diagnosis of cancer during the last part of the 19th century. Troisier's name is connected along with that of his German colleague Rudolf Virchow (1821-1902) concerning the development of modern pathology. PMID- 25536637 TI - Traditional Chinese Medicine and herbal hepatotoxicity: a tabular compilation of reported cases. AB - Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analyzed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM. PMID- 25536638 TI - Portal vein thrombosis: what is new? AB - Portal vein thrombosis (PVT) is one of the most common vascular disorders of the liver with significant morbidity and mortality. Large cohort studies have reported a global prevalence of 1%, but in some risk groups it can be up to 26%. Causes of PVT are cirrhosis, hepatobiliary malignancy, abdominal infectious or inflammatory diseases, and myeloproliferative disorders. Most patients with PVT have a general risk factor. The natural history of PVT results in portal hypertension leading to splenomegaly and the formation of portosystemic collateral blood vessels and esophageal, gastric, duodenal, and jejunal varices. Diagnosis of PVT is made by imaging, mainly Doppler ultrasonography. According to its time of development, localization, pathophysiology, and evolution, PVT should be classified in every patient. Some clinical features such as cirrhosis, hepatocellular carcinoma, and hepatic transplantation are areas of special interest and are discussed in this review. The goal of treatment of acute PVT is to reconstruct the blocked veins. Endoscopic variceal ligation is safe and highly effective in patients with variceal bleeding caused by chronic PVT. In conclusion, PVT is the most common cause of vascular disease of the liver and its prevalence has being increasing, especially among patients with an underlying liver disease. All patients should be investigated for thrombophilic conditions, and in those with cirrhosis, anticoagulation prophylaxis should be considered. PMID- 25536639 TI - Effects on anemia of drug adjustment in patients with chronic hepatitis C during telaprevir-combined therapy. AB - AIM: Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. MATERIAL AND METHODS: This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha 2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR standard (n = 28) and TVR-reduced (n = 25) groups. RESULTS: No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). CONCLUSIONS: TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients. PMID- 25536640 TI - Interferon-based therapy delays but metabolic comorbidity accelerates progression of chronic hepatitis C. AB - BACKGROUND: We compared mortality and complications of chronic hepatitis C between treated and untreated Mexican patients after long-term follow-up. We used a time-to-event analysis and identified the prognostic factors. MATERIAL AND METHODS: Seventy-four patients with chronic hepatitis C were studied. They were >= 18 years of age and had a molecular diagnosis of chronic hepatitis C and >= 6 months of follow-up. Patients with neoplasia or those infected with human immunodeficiency virus or hepatitis B Virus were excluded. Kaplan-Meier analysis, log-rank test, annualized incidence per 100 person-years, and stepwise discriminant analysis were used to analyse mortality and complications. RESULTS: The end-point of annualized incidence was lowest in sustained virological responders, intermediate in non-responders, and highest in untreated patients. The absence of treatment impacted adversely on cirrhosis development and the occurrence of portal hypertension and hepatic decompensation/hepatocellular carcinoma (logrank, p < 0.05). Diabetes impacted adversely on liver-related death/liver transplantation among untreated patients. Stepwise discriminant analysis showed that diabetes, high blood pressure, and no retreatment predicted cirrhosis development (eigenvalue >= 0.8; p < 0.05). A MELD score >= 18 and age >= 50 years predicted hepatic decompensation/hepatocellular carcinoma (eigenvalue < 0.8; p < 0.05). APRI >= 1.5 predicted mortality/liver transplantation and liver related death/liver transplantation (eigenvalue < 0.8; p < 0.05). CONCLUSIONS: This is the first long-term study of chronic hepatitis C among Mexican patients. Treated patients showed less progression of liver disease. Treated patients showed less progression of liver disease; and older patients, those with metabolic comorbidities, with MELD score >= 18 and APRI >= 1.5 exhibited adverse effects. PMID- 25536641 TI - Boceprevir and telaprevir for chronic genotype 1 hepatitis C virus infection. A systematic review and meta-analysis. AB - BACKGROUND: Treatment of hepatitis C virus (HCV) infection with newer direct acting antivirals is unrealistic in some countries because of the lack of availability. AIM: Assess benefits and harms of boceprevir (BOC) and telaprevir (TLV) in treatment of genotype 1 HCV infection, and identifying subgroups with most benefit. MATERIAL AND METHODS: Search from 2009-2013 in PubMed, EMBASE, and "gray literature" of published and unpublished randomized trials reporting sustained viral response (SVR) or adverse events (AE) with BOC or TLV + pegylated interferon and ribavirin (PR) in HCV-infected patients; cohorts or case reports for comparison protease inhibitors (PI), evaluation of predictors of SVR, and resistant variants. Cochrane guidelines were applied. Comparisons between PI + PR vs. PR were performed. Main outcomes were expressed as risk-ratios with 95% CIs. Meta-regression and trial sequential analysis were performed. RESULTS: 33 studies (10,525 patients) were analyzed. SVR was higher for PI + PR (RR, 2.05; 95% CI 1.70-2.48). In meta-regression, previously treated patients exhibited greater benefit from PI + PR (RR, 3.47; 95% CI, 2.78-4.33). AE were higher with PI + PR (RR, 1.01; 95% CI, 1-1.03; NNH 77.59), also the discontinuation rate (RR, 1.69; 95% CI, 1.36-2.10, NNH, 18). Predictors of SVR were IL-28 TT, nonblack race, low viral load, age, no cirrhosis, statin use, undetectable viral load at the first anemia episode and at week 2 of treatment, and low IL-6 levels. In conclusion SVR was higher in patients treated with PIs, patients previously exposed to PR showed superior response rates. Specific predictors will determine the best candidates for treatments that will offer real-life therapeutic alternatives. PMID- 25536642 TI - Factors associated with recurrence and survival in liver transplant patients with HCC--a single center retrospective study. AB - INTRODUCTION: Hepatocellular carcinoma is the most common primary tumor of the liver and is diagnosed in more than a half million people worldwide each year. This study aims to assess factors associated with the recurrence and survival of patients with hepatocellular carcinoma and liver transplantation in a cohort of patients from Medellin, Colombia. MATERIAL AND METHODS: This was a descriptive retrospective study of a consecutive series of liver transplant patients from the Pablo Tobon Uribe Hospital of Medellin from January 2004 to May 2013. Demographic, clinical, imaging, and pathology variables were analyzed. RESULTS: Three hundred thirty liver transplants were performed during the study period, 54 cases (16.4%) had one or more hepatocellular carcinomas in the explant, and 79.6% of these patients were men. Cirrhotic patients had different etiologies, but most of them were due to alcohol abuse (22.2%), followed by hepatitis B virus infection (20.4 %), and hepatitis C virus infection (18.5%). In the pathology specimen, 51.9% had only one focus of hepatocellular carcinoma, 22.2% had two foci and 12.9% had three tumors. Recurrence of hepatocellular carcinoma occurred in 7.4% patients with an average time of 81 months. During follow-up, 25.9% of the patients died in an average time of 67.9 months (CI95 59.1-80.1 months). CONCLUSION: Recurrence and survival of patients with liver transplantation for hepatocellular carcinoma in this study had a similar behavior as that reported in the world literature. The factors associated with these outcomes were vascular invasion, poor tumor differentiation and satellitosis. PMID- 25536643 TI - Wnt/beta-catenin signaling pathway in hepatocellular carcinomas cases from Colombia. AB - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most common primary liver cancer diagnosed worldwide. Deregulation of Wnt/beta-catenin pathway has been associated with the development of HCC in a substantial number of cases in Europe and far less in Asia. Nothing is known about this pathway in HCC cases from South America. This study aimed to investigate the frequency of mutations in beta-catenin gene (CTNNB1) and the subcellular localization of beta-catenin in HCC cases from Colombia. MATERIAL AND METHODS: We determine by direct sequencing the frequency of mutations in exon 3 of CTNNB1 gene and by immunohistochemistry the subcellular localization of beta-catenin in 54 samples of HCC obtained from three pathology units in Bogota and Medellin cities. RESULTS: Only three HCC cases (5.6%) were found mutated at residues (G34E, S45P, P44S, T41I) important for phosphorylation and ubiquitination of beta-catenin protein. Strikingly, nuclear or cytoplasmic accumulation of beta-catenin, hallmark of Wnt pathway activation, was found in 42.6% HCC cases (23/54). Interestingly, beta-catenin accumulation was significantly more frequent in young patients and hepatitis B virus-related HCC. CONCLUSIONS: Although, CTNNB1 exon 3 mutations are not frequent in HCC from Colombian patients, our findings indicate that Wnt/beta catenin signaling is activated in 42.6% of HCC samples. Furthermore, Wnt signaling was demonstrated in HCC cases associated of HBV infection, one of the most important HCC risk factors in Colombia. PMID- 25536645 TI - The performance of prognostic models as predictors of mortality in patients with acute decompensation of cirrhosis. AB - BACKGROUND: Although several prognostic models have been proposed for cirrhotic patients listed for transplantation, the performance of these scores as predictors of mortality in patients admitted for acute decompensation of cirrhosis has not been satisfactorily investigated. AIMS: To study MELD, MELD-Na, MESO, iMELD, Refit-MELD and Refit MELD-Na models as prognostic predictors in cirrhotic patients admitted for acute decompensation, and to compare their performance between admission and 48 hours of hospitalization to predict in hospital mortality. MATERIAL AND METHODS: This cohort study included cirrhotic patients admitted to hospital due to complications of the disease. Individuals were evaluated on admission and after 48 h of hospitalization, and mortality was evaluated during the present admission. RESULTS: One hundred and twenty-three subjects with a mean age of 54.26 +/- 10.79 years were included; 76.4% were male. Mean MELD score was 16.43 +/- 7.08 and 52.0% of patients were Child-Pugh C. Twenty-seven patients (22.0%) died during hospitalization. Similar areas under the curve (AUROCs) for prognosis of mortality were observed when different models were compared on admission (P > 0.05) and after 48 h of hospitalization (P > 0.05). When models executed after 48 h of hospitalization were compared to their corresponding model calculated on admission, significantly higher AUROCs were obtained for all models (P < 0.05), except for MELD-Na (P = 0.075) and iMELD (P = 0.119). CONCLUSION: The studied models showed similar accuracy as predictors of in-hospital mortality in cirrhotic patients admitted for acute decompensation. However, the performance of these models was significantly better when applied 48 h after admission when compared to their calculation on admission. PMID- 25536646 TI - Thrombosis and hemorrhage in the critically ill cirrhotic patients: five years retrospective prevalence study. AB - BACKGROUND: Cirrhotic patients present a complex interaction between deficient synthetic liver function, hemodynamic abnormalities and superimposed conditions that alter coagulation system. This alters both coagulation and fibrinolytic processes,increasing bleeding and thrombosis risks. Particularly, critically ill cirrhotic patients represent a diagnostic challenge since they have multiple comorbidities making the thrombotic and bleeding risks unpredictable. The prevalence of bleeding and thrombosis in this subset of patients remains poorly described. The main aim of this article is to describe the prevalence of thrombotic and hemorrhagic complications in cirrhotic patients admitted between 2007 and 2012 at Medica Sur Clinic and Foundation ICU. MATERIAL AND METHODS: We performed a five years retrospective study including every cirrhotic patient admitted to ICU between January 2007 and December 2012. RESULTS: The incidence of hemorrhage was 48.5%, the overall incidence of thrombotic complications was 13.66%. Variceal bleeding was the most prevalent hemorrhagic event and portal vein thrombosis the most common thrombotic event. Factors associated with presenting a bleeding episode included kidney injury, infection an thrombosis. Factors associated with increased thrombotic risk included ascitis,infection and bleeding. CONCLUSION: Critically ill cirrhotic patients have an high risk for both thrombotic and bleeding episodes. The association between the presence of bleeding and thrombotic events was statistically significant. PMID- 25536647 TI - Factors associated with 25-hydroxyvitamin D levels in patients with liver cirrhosis. AB - INTRODUCTION: Lower 25-hydroxyvitamin D [25(OH)D] levels have been observed in cirrhotic patients and have been related to disease severity. However, most previous studies included patients with very advanced disease, lacking an adequate control for other variables that could interfere with vitamin D levels. We sought to investigate the prevalence of hypovitaminosis D and the factors related to its occurrence. MATERIAL AND METHODS: This cross-sectional study included 133 cirrhotic patients and 30 healthy controls. Bivariate and multivariate analyses were performed to determine factors associated with 25(OH)D levels below the lower tertile. Thirty patients who had been recently hospitalized were compared in two time points. RESULTS: Mean 25(OH)D levels were 32.34 +/- 11.38 in controls and 27.03 +/- 6.22 ng/mL in patients (P = 0.018). 25(OH)D levels were < 30 ng/mL in 69.9% and < 20 ng/mL in 14.3% of the sample. Levels of 25(OH)D below the lower tertile (< 24 ng/mL) were independently associated with higher triceps skinfold and non-Caucasian race. Parathyroid hormone above the reference value (65 pg/mL) was found in 24.6% of patients without association with 25(OH)D or severity of liver disease. Significantly lower levels of 25(OH)D were found at the time of acute decompensation of cirrhosis. CONCLUSIONS: In conclusion, hypovitaminosis D was prevalent in cirrhotics and it was associated with adiposity and non-Caucasian race in stable patients with relatively well preserved liver function. However, significantly lower levels were observed during admission for acute decompensation suggesting an impact of systemic inflammation or liver dysfunction on 25(OH)D levels. PMID- 25536644 TI - Hepatocellular carcinoma in chronic HBV-HCV co-infection is correlated to fibrosis and disease duration. AB - Hepatocellular carcinoma (HCC) is a development of severe liver disease frequently due to HBV and/or HCV infection. The aim of this retrospective study was to evaluate the development of HCC in patients with HBV-HCV chronic infection compared with patients with single HBV or HCV infection and the viral and host factors correlated to HCC in co-infected patients. We studied 268 patients with histology proven chronic hepatitis: 56 had HBV-HCV co-infection (HBV-HCV group), 46 had HBV infection (HBV group) and 166 had HCV infection (HCV group). Patients were followed up for at least 3 years. Viral and host factors were studied. HCC was more frequent in HBV-HCV group (14%) compared with HBV (2%, p = 0.006) and HCV monoinfected (4%, p = 0.006). The Mantel-Haenszel test used to investigate the relationship between HBV-HCV co-infection and development of HCC indicated an association between development of HCC and HBV-HCV co-infection (p < 0.001). In the HBV-HCV group, patients with HCC were significantly older (p = 0.000), had longer disease duration (p = 0.001), higher blood glucose levels (p = 0.001), lower levels of steatosis (p = 0.02), higher levels of fibrosis (p = 0.000), higher HCV RNA (p = 0.01) than those without HCC. ALT, lipid profile, PNPLA3 variant distribution and HBV viral load did not differ among co-infected patients with or without HCC. In conclusion HCC was more frequent in our patients with HBV HCV co-infection, than in those with HBV or HCV mono-infection; possible associated risk factors for HCC development seem a long duration of disease, high levels of fibrosis and carbohydrate intolerance. PMID- 25536648 TI - Effects of a low-fat diet on the hepatic expression of adiponectin and its receptors in rats with NAFLD. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is correlated with obesity, but specific therapeutic interventions are lacking. Adiponectin is an adipokine with anti-inflammatory activity and is considered a hepatic protector. We aimed to investigate effects of a low-fat diet on the hepatic expression of adiponectin and its receptors in rats with NAFLD. MATERIALS AND METHODS: Sixteen male SD rats were fed a high-fat diet for 8 weeks (HFD1 group) or 16 weeks (HFD2 group) to induce NAFLD, and these rats were compared with rats on a normal diet for 8 weeks (NC1 group) or 16 weeks (NC2 group). Another group of 8 rats was fed an HFD for 8 weeks and then switched to a low-fat diet (DIET group) until the 16th week. The expression of hepatic adiponectin and its receptors was detected by western blotting, immunohistochemistry and RT-qPCR. RESULTS: The NAFLD activity score (NAS) in the HFD groups increased from 3.2 +/- 0.45 (8th week) to 6.2 +/- 0.84 (16th week) (P < 0.001), reflecting the progression in the NAFLD histology. In contrast to the HFD2 group, the low-fat diet ameliorated the steatosis, ballooning degeneration and inflammation. Dietary intervention augmented the expression of adiponectin and its receptors, which was down-regulated in the HFD2 group. CONCLUSIONS: The NAFLD rat model was successfully developed by feeding the animals a high-fat diet. Adiponectin may play a role in the pathogenesis of NAFLD, especially in the progression from steatosis to NASH. The low-fat diet alleviated the histological lesions associated with NAFLD by up-regulating the expression of adiponectin and its receptors. PMID- 25536649 TI - Intrahepatic aneurysmal portohepatic venous shunt: what should be done? PMID- 25536650 TI - Lifestyle changes associated with a new antioxidant formulation in non-alcoholic fatty liver disease: a case series. AB - Non-alcoholic fatty liver disease (NAFLD) is a relevant issue in public health owing to its epidemiological burden. It represents the most common chronic liver disease in the general population and is expected to increase in future as a result of an ageing population. The only currently recommended treatment for NAFLD is lifestyle modification. However, literature reports pre-clinical and clinical studies on the use of antioxidant supplementation in NAFLD. A new antioxidant complex, called Bilirel (BIL) (Pharmaluce, Republic of San Marino), have recently introduced in the Italian market. However no data are reported on his effects on liver steatosis. Here we report on a cases series of seven overweight patients with NAFLD, in which the association of an Italian Mediterranean diet, increased physical activity, and daily administration of two pills of BIL for 6 weeks, have induced the rapid improvement of fatty liver accumulation, glucose and lipid metabolism, and weight reduction. PMID- 25536651 TI - Paradoxical embolization in TIPS: take a closer look to the heart. AB - No definitive indications are provided in the literature for pre-TIPS patient workup, which is often limited to prevent the incidence of refractory hepatic encephalopathy or unacceptable deterioration of liver function. Concerning cardiologic workup, efforts are generally limited at excluding ventricular failure or porto pulmonary hypertension. The cases presented herein focus the attention of the readers on the possible occurrence of post-TIPS paradoxical embolization in the presence of a patent foramen ovale, frequently recognized in adult population. In conclusion, although this complication has been already reported in literature, in the present manuscript we concentrate on possible additional risk factors which may allow to identify a subset of patients with a higher likelihood to experience paradoxical embolization following TIPS. Another important line of information presented herein is the feasibility of percutaneous closure of a patent foramen ovale before TIPS deployment in the presence of portal vein thrombosis and possibly with additional risk factors. PMID- 25536652 TI - Mycobacterium abscessus pulmonary infection during hepatitis C treatment with telaprevir, peginterferon and ribavirin. AB - The first generation protease inhibitors has been the mainstay of hepatitis C treatment for the last couple of years, showing marked improvement in sustained virological response, but also increased side effects. Infection has emerged as a common complication of telaprevir and boceprevir in combination with peginterferon and ribavirin, usually caused by common pathogens. We present the case of a 65 years old man who developed a Mycobacterium abscessus pulmonary infection during treatment with telaprevir, peginterferon and ribavirin. The patient was successfully treated with amikacin, imipenem and chlarithromycin. The present case is relevant for increasing awareness for recognition of opportunistic infections and particularly nontuberculous mycobacterial infections in patients receiving triple therapy for chronic hepatitis C, especially in cirrhotic subjects who develop significant lymphopenia. PMID- 25536653 TI - First confirmed case of native polyomavirus BK nephropathy in a liver transplant recipient seven years post-transplant. AB - Renal dysfunction frequently occurs in liver transplant recipients and is associated with increased morbidity and mortality. BK virus is a human polyoma virus that reactivates during immunocompromised states and is a known cause of renal allograft dysfunction in renal transplant recipients. However, BK nephropathy of native kidneys is rare in non-renal transplant recipients. There is no published data linking BK virus and renal dysfunction in liver transplant recipients. We describe the first confirmed case of native polyomavirus BK nephropathy in a liver transplant recipient. BK nephropathy should be considered in the differential diagnosis of new renal failure in liver transplant recipients. PMID- 25536654 TI - Acute hepatitis E virus infection and association with a subacute thyroiditis. PMID- 25536655 TI - Pathophysiological and pharmacological implications of elucidating the molecular bases of the interaction between HBV and the bile acid transporter NTCP. PMID- 25536656 TI - beta2 adrenergic receptor activation suppresses bone morphogenetic protein (BMP) induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells. AB - beta adrenergic stimulation suppresses bone formation in vivo while its actions in osteoblastic differentiation are still incompletely understood. We therefore examined the effects of beta2 adrenergic stimulation on osteoblast-like MC3T3-E1 cells focusing on BMP-induced alkaline phosphatase expression. Morphologically, isoproterenol treatment suppresses BMP-induced increase in the numbers of alkaline phosphatase-positive small foci in the cultures of MC3T3-E1 cells. Biochemically, isoproterenol treatment suppresses BMP-induced enzymatic activity of alkaline phosphatase in a dose-dependent manner. Isoproterenol suppression of alkaline phosphatase activity is observed even when the cells are treated with high concentrations of BMP. With respect to cell density, isoproterenol treatment tends to suppress BMP-induced increase in alkaline phosphatase expression more in osteoblasts cultured at higher cell density. In terms of treatment protocol, continuous isoproterenol treatment is compared to cyclic treatment. Continuous isoproterenol treatment is more suppressive against BMP-induced increase in alkaline phosphatase expression than cyclic regimen. At molecular level, isoproterenol treatment suppresses BMP-induced enhancement of alkaline phosphatase mRNA expression. Regarding the mode of isoproterenol action, isoproterenol suppresses BMP-induced BRE-luciferase activity. These data indicate that isoproterenol regulates BMP-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells. PMID- 25536658 TI - Nutrition intake and physical activity in a middle school in New York City. AB - PURPOSE: The threat of childhood obesity has never been greater. Behavior changes implemented during childhood and adolescence are believed to be the most successful means of thwarting the progression of this epidemic. The American Academy of Pediatrics has developed a public health campaign that promotes awareness of clinical guidelines for nutrition and physical activity. The campaign is based on a concept developed by the Maine Center for Public Health referred to as "5-2-1-0 Healthy". The simple clear message of this concept outlines steps families can take to help prevent and treat childhood obesity. The purpose of the present study is to determine the current level of compliance and health education needs of a middle school population related to the "5-2-1-0" concept. METHODS: A modified version of the 2010 National Youth Physical Activity and Nutrition Survey (developed by the Centers for Disease Control and Prevention) was distributed to students at a private, nonsectarian, middle school in New York City. The school is located in the borough of Manhattan, but includes youngsters from all five boroughs of the city. The questions were grouped and analyzed according to "5-2-1-0" categories. Surveys were scored, and the association between targeted questionnaire items and demographic variables (i.e., sex and grade) was examined. RESULTS: All 140 students completed the survey, and there was great variability in their responses to both the nutrition and physical activity questions. Of all students, 65% reported eating one cup or more of fruit daily, and 38% reported eating one cup or more of vegetables daily. There was no statistically significant difference reported in consumption of fruits or vegetables by gender or grade. Over 60% of students indicated <2 h of DVD/video or computer/video game time per day, while 10% indicated more than 3 h per day for each. A significant difference existed in the screen time reported between grades (more screen time by the older students) and a statistically significant difference also existed in the amount of physical activity reported by gender and grade (more physical activity by males and younger students). There was no difference in the reported consumption of sugar-sweetened beverages by gender or grade. CONCLUSION: In a cohort of middle school students in New York City, there was great variability in compliance with the principles represented by the "5-2-1 0" concept. Changes in health behaviors were noted as students went from 6th to 7th to 8th grade, with physical activity decreasing and screen time increasing. Consequently, health curriculum topics for middle school students should focus on physical activity and screen time, while continuing to emphasize the need for proper nutrition. PMID- 25536660 TI - Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency. AB - Steroid 17beta-hydroxysteroid dehydrogenase III (17beta-HSD3) deficiency is a rare autosomal recessive disorder that usually presents in patients with a 46,XY karyotype with ambiguous genitalia at birth. The 17beta-HSD3 enzyme, which is encoded by the HSD17B3 gene, converts gonadal delta-4 androstenedione (Delta4) to testosterone (T). Such 17beta-HSD3 enzyme deficiency is expected to lead to an increased ratio of D4 to T when the patient undergoes a human chorionic gonadotropin stimulation (hCG) test. Two patients with 46,XY disorders of sexual differentiation were studied. Serum D4 and T levels were measured by HPLC tandem mass spectrometry. As one of the patients was born to consanguineous parents, we performed single nucleotide polymorphism (SNP) microarray to analyze regions of homozygosity (ROH). The HSD17B3 gene was sequenced using the Sanger method. Contrary to expectations, both patients demonstrated decreased D4/T ratio after hCG stimulation. Initial sequencing results for the androgen receptor or 5alpha reductase were negative for mutations. ROH analysis identified HSD17B3 as a candidate gene that might cause the disease. Sanger sequencing of the HSD17B3 gene confirmed 17beta-HSD3 deficiency in both patients. Serum D4/T ratios are not reliable parameters for the diagnosis of 17beta-HSD3 deficiency. Molecular genetic analysis provides accurate diagnosis. PMID- 25536659 TI - Prevalence of bullying in secondary schools in Port Harcourt. AB - BACKGROUND: School bullying is a global problem involving a high proportion of students worldwide. However, its prevalence and types in secondary schools in Port Harcourt is not yet known. OBJECTIVE: This study aimed to determine the prevalence and types of bullying in secondary schools in Port Harcourt. SUBJECTS: A total of 1160 students from six secondary schools in Port Harcourt comprised the sample. MATERIALS AND METHODS: This was a cross-sectional school-based study conducted in Port Harcourt in March 2014. Two mixed schools, two all-boys schools, and two all-girls schools were selected using purposive sampling technique. Stratified random sampling technique, by class strata (senior secondary 1, 2 and 3) was used to select 1160 students from the six schools. A 22 item self-administered questionnaire adapted from a previous study was modified and used in this study. The questions covered the prevalence, type of bullying, and socio-demographic data. Data were analyzed using SPSS version 20 (IBM SPSS Incorporated, Chicago, IL, USA). RESULTS: About 82.2% reported being victims of bullying, whereas 64.9% reported being bullies. About 9.7% and 11.8% were neither bullies nor bullied, respectively. Bullying was significantly higher in the all boys (90.8%) and all-girls (82.9%) schools than in the mixed schools (73.5%), p=0.000. More males were victims (53.4%) and bullies (53.3%) but more females (55.4%) were bully-victims. The most common (57.5%) type of bullying was physical bullying. CONCLUSION: The rate of bullying was found to be very high in secondary schools in Port Harcourt. PMID- 25536661 TI - Benefit of testosterone in pediatric genital trauma. PMID- 25536657 TI - Macrophages contribute to the cyclic activation of adult hair follicle stem cells. AB - Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer. PMID- 25536662 TI - Carbohydrate-lipid profile and use of metformin with micronized fenofibrate in reducing metabolic consequences of craniopharyngioma treatment in children: single institution experience. AB - AIM: To evaluate auxology and metabolic disturbances in children with craniopharyngioma, and to present observational results of treatment of metabolic sequels with metformin and micronized fenofibrate. METHODS: The studied group comprised 22 children [median age at diagnosis 10.5 (0.17-16.75) years; median follow-up 5.1 years]. Assessment included height standard deviations (SDS), body mass index (BMI) SDS, concentrations of lipids, glucose and insulin (fasting or oral glucose tolerance test) and homeostatic model assessment of insulin resistance (HOMA-IR) index. Ten adolescents with hyperinsulinemia and dyslipidemia received therapy with metformin (500-1500 mg/daily) and micronized fenofibrate (160 mg/daily). RESULTS: At diagnosis, median hSDS was -1.66 (range: 4.08; +0.1). Nine (40.9%) children were growth hormone-treated. There was gradual increase of BMI SDS, 18 (81.8%) patients being overweight at the final assessment. Dyslipidaemia was found in 19 patients (86.4%), hyperinsulinaemia in 11 patients (50%) and elevated HOMA-IR in 15 patients (68.2%). Decrease of triglycerides [median 263.5 (171-362) mg/dL vs. 154 (102-183) mg/dL] and HOMA-IR [8.64 (5.08-12.65) vs. 4.68 (0.7-7.9)] was significant in the group treated with metformin and fenofibrate for 6 months. CONCLUSIONS: Significant auxologic changes and metabolic abnormalities were found in children treated for craniopharyngioma. The use of metformin and fenofibrate seemed to attenuate these disturbances in a short-term observation. PMID- 25536663 TI - Comparative assessment of onion and garlic extracts on endogenous hepatic and renal antioxidant status in rat. AB - BACKGROUND: Despite growing claims of functional health benefits in folkloric medicine, the safety of chronic/elevated intakes of onion and garlic cannot be assumed. Therefore, this study assesses oral administration of varied doses of onion and garlic on some biomarkers of hepatic and renal functions in rats. METHODS: Animals were divided into five groups: control group received vehicle and extract-treated groups received varied doses of onion or garlic extract (0.5 mL and 1.0 mL/100 g bwt/day) for 6 weeks. RESULTS: Both doses of onion caused marked (p<0.05) increase in hepatic and renal levels of glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and marked (p<0.05) decrease in malondialdehyde (MDA). Treatment with low dose of garlic elicited similar trend except in hepatic CAT, renal SOD and GST levels. A high dose of garlic only caused marked (p<0.05) increase in hepatic GST, renal GST, and SOD. Both doses of onion and low dose of garlic significantly (p<0.05) enhanced renal Na+/K+-ATPase activity. Only a high dose of onion caused significant (p<0.05) increase in hepatic aspartate transaminase (AST), alkaline phosphatase (ALP), and decrease in plasma AST activities. CONCLUSIONS: These findings suggest antioxidant enhancing capability for both doses of onion and low dose of garlic, while high dose of garlic elicited pro-oxidant conditions. PMID- 25536664 TI - Evaluation of anti-inflammatory and analgesic activities and the phytochemical study of Astragalus arbusculinus gum in animal models. AB - BACKGROUND: The importance of inflammatory diseases and side effects of conventional drugs necessitate the finding of new anti-inflammatory agents from natural sources. In this study, for the first time, the anti-inflammatory and analgesic effects of the aqueous extract of Astragalus arbusculinus gum were evaluated in animal models. METHODS: Thirty-five male Wistar rats were divided into five groups and pretreated with different doses of A. arbusculinus gum extract before the injection of formalin. Paw edema was measured by a plethysmometer at time 0 and after 8 days and compared to controls. The analgesic effect of the extract was evaluated using the hot-plate test in 42 male albino mice. RESULTS: The extract of A. arbusculinus gum decreased the rat paw edema in a dose-dependent manner. The effect on inflammation of the highest dose of extract was comparable to sodium salicylate. Astragalus arbusculinus gum extract at doses of 300 and 1000 mg/kg showed analgesic effects comparable to sodium salicylate and morphine, respectively. A preliminary phytochemical study and the determination of the total phenolic content of the gum extract were performed for the first time. CONCLUSIONS: The aqueous extract of A. arbusculinus gum reduced the inflammation and pain in a dose-dependent manner and is a good candidate for further studies of safety and efficacy. The clarification of active components of the plant is necessary. PMID- 25536665 TI - Osteoblastic alkaline phosphatase mRNA is stabilized by binding to vimentin intermediary filaments. AB - Vascularization is essential in bone tissue engineering and recent research has focused on interactions between osteoblasts (hOBs) and endothelial cells (ECs). It was shown that cocultivation increases the stability of osteoblastic alkaline phosphatase (ALP) mRNA. We investigated the mechanisms behind this observation, focusing on mRNA binding proteins. Using a luciferase reporter assay, we found that the 3'-untranslated region (UTR) of ALP mRNA is necessary for human umbilical vein endothelial cells (HUVEC)-mediated stabilization of osteoblastic ALP mRNA. Using pulldown experiments and nanoflow-HPLC mass spectrometry, vimentin was identified to bind to the 3'-UTR of ALP mRNA. Validation was performed by Western blotting. Functional experiments inhibiting intermediate filaments with iminodipropionitrile and specific inhibition of vimentin by siRNA transfection showed reduced levels of ALP mRNA and protein. Therefore, ALP mRNA binds to and is stabilized by vimentin. This data add to the understanding of intracellular trafficking of ALP mRNA, its function, and have possible implications in tissue engineering applications. PMID- 25536666 TI - Direct identification of Gram-positive bacteria and resistance determinants from blood cultures using a microarray-based nucleic acid assay: in-depth analysis of microarray data for undetermined results. AB - BACKGROUND: The Verigene Gram-Positive Blood Culture (BC-GP) nucleic acid assay (Nanosphere, Inc., Northbrook, IL, USA) is a newly developed microarray-based test with which 12 Gram-positive bacterial genes and three resistance determinants can be detected using blood culture broths. We evaluated the performance of this assay and investigated the signal characteristics of the microarray images. METHODS: At the evaluation stage, we tested 80 blood cultures that were positive for various bacteria (68 bacteria covered and 12 not covered by the BC-GP panel) collected from the blood of 36 patients and 44 spiked samples. In instances where the automated system failed and errors were called, we manually inspected microarray images, measured the signal intensities of target spots, and reclassified the results. RESULTS: With the manual analysis of the microarray images of 14 samples for which error calls were reported, we could obtain correct identification results for 12 samples without the need for retesting, because strong signals in the target spots were clearly discriminable from background noise. With our interpretation strategy, we could obtain 97.1% sensitivity and 100% specificity for bacterial identification by using the BC-GP assay. The two unidentified bacteria were viridans group streptococci, which produced weaker target signals. During the application stage, among 25 consecutive samples positive for Gram-positive bacteria, we identified two specimens with error calls as Streptococcus spp. by using manual analysis. CONCLUSIONS: With help of the manual review of the microarray images, the BC-GP assay could successfully identify species and resistance markers for many clinically important Gram-positive bacteria. PMID- 25536668 TI - Analytical evaluation of Diazyme procalcitonin (PCT) latex-enhanced immunoturbidimetric assay on Beckman Coulter AU5800. AB - BACKGROUND: This study was aimed to evaluate the analytical performance of the novel Diazyme procalcitonin (PCT) immunoturbidimetric assay on Beckman Coulter AU5800. METHODS: Diazyme PCT is a latex-enhanced immunoturbidimetric assay, developed for use on laboratory instrumentations with capability of reading absorbance at 600 nm. This analytical evaluation included the assessment of limit of blank (LOB), limit of detection (LOD), functional sensitivity, imprecision, linearity, carryover, and method comparison between Diazyme PCT and Kryptor PCT on 129 routine serum inpatient samples. RESULTS: The LOB, LOD, and functional sensitivity of Diazyme PCT were 0.16, 0.26, and 0.28 ng/mL, respectively. The intra- and inter-assay imprecision of Diazyme PCT was between 2.9% and 7.8%. The linearity was excellent in the range of PCT values between 0.16 and 56 ng/mL, and the carryover was negligible (0.02%). A highly significant agreement was found between Kryptor PCT and Diazyme PCT in a range of concentrations between 0.16 and 111 ng/mL (Diazyme PCT=1.10*Kryptor PCT-0.89; r=0.960; p<0.001). The mean bias was 0.48 ng/mL (95% CI, -0.58 to 1.54 ng/mL). The strength of agreement between Kryptor PCT and Diazyme PCT was between 85% and 96% at 0.50, 2.0, and 10 ng/mL cutoffs. CONCLUSIONS: Diazyme PCT appears to be a reliable assay for diagnosis and management of critical care patients susceptible to severe bacterial infections. PMID- 25536667 TI - Compliance of blood sampling procedures with the CLSI H3-A6 guidelines: An observational study by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) working group for the preanalytical phase (WG-PRE). AB - BACKGROUND: An observational study was conducted in 12 European countries by the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Preanalytical Phase (EFLM WG-PRE) to assess the level of compliance with the CLSI H3-A6 guidelines. METHODS: A structured checklist including 29 items was created to assess the compliance of European phlebotomy procedures with the CLSI H3-A6 guideline. A risk occurrence chart of individual phlebotomy steps was created from the observed error frequency and severity of harm of each guideline key issue. The severity of errors occurring during phlebotomy was graded using the risk occurrence chart. RESULTS: Twelve European countries participated with a median of 33 (18-36) audits per country, and a total of 336 audits. The median error rate for the total phlebotomy procedure was 26.9 % (10.6-43.8), indicating a low overall compliance with the recommended CLSI guideline. Patient identification and test tube labelling were identified as the key guideline issues with the highest combination of probability and potential risk of harm. Administrative staff did not adhere to patient identification procedures during phlebotomy, whereas physicians did not adhere to test tube labelling policy. CONCLUSIONS: The level of compliance of phlebotomy procedures with the CLSI H3-A6 guidelines in 12 European countries was found to be unacceptably low. The most critical steps in need of immediate attention in the investigated countries are patient identification and tube labelling. PMID- 25536670 TI - Strong coupling between surface plasmon polaritons and emitters: a review. AB - In this review we look at the concepts and state-of-the-art concerning the strong coupling of surface plasmon-polariton modes to states associated with quantum emitters such as excitons in J-aggregates, dye molecules and quantum dots. We explore the phenomenon of strong coupling with reference to a number of examples involving electromagnetic fields and matter. We then provide a concise description of the relevant background physics of surface plasmon polaritons. An extensive overview of the historical background and a detailed discussion of more recent relevant experimental advances concerning strong coupling between surface plasmon polaritons and quantum emitters is then presented. Three conceptual frameworks are then discussed and compared in depth: classical, semi-classical and fully quantum mechanical; these theoretical frameworks will have relevance to strong coupling beyond that involving surface plasmon polaritons. We conclude our review with a perspective on the future of this rapidly emerging field, one we are sure will grow to encompass more intriguing physics and will develop in scope to be of relevance to other areas of science. PMID- 25536671 TI - Fecal calprotectin: towards a standardized use for inflammatory bowel disease management in routine practice. PMID- 25536669 TI - The effect of recombinant human growth hormone with or without rosiglitazone on hepatic fat content in HIV-1-infected individuals: a randomized clinical trial. AB - BACKGROUND: Hepatic fat is related to insulin resistance (IR) and visceral adipose tissue (VAT) in HIV+ and uninfected individuals. Growth hormone (GH) reduces VAT but increases IR. We evaluated the effects of recombinant human GH (rhGH) and rosiglitazone (Rosi) on hepatic fat in a substudy of a randomized controlled trial. METHODS: HIV+ subjects with abdominal obesity and IR (QUICKI<=0.33) were randomized to rhGH 3 mg daily, Rosi 4 mg twice daily, the combination or double placebo. Hepatic fat was measured by magnetic resonance spectroscopy, visceral fat by MRI and IR by frequently sampled intravenous glucose tolerance tests at baseline and week 12. RESULTS: 31 subjects were studied at both time points. Significant correlations between hepatic fat and VAT (r=0.41; P=0.02) and QUICKI (r=0.39; P<0.05) were seen at baseline. IR rose with rhGH but not Rosi. When rhGH treatment groups were combined, hepatic fat expressed as percentage change decreased significantly (P<0.05) but did not change in Rosi (P=0.71). There were no correlations between changes in hepatic fat and VAT (P=0.4) or QUICKI (P=0.6). In a substudy of 21 subjects, a trend was noticed between changes in hepatic fat and serum insulin-like growth factor-1 (IGF-1; P=0.09). CONCLUSIONS: Hepatic fat correlates significantly with both VAT and IR, but changes in hepatic fat do not correlate with changes in VAT and glucose metabolism. Hepatic fat content is reduced by rhGH but Rosi has no effect. These results suggest an independent effect of GH or IGF-1 on hepatic fat. The study was registered at Clinicaltrials.gov (NCT00130286). PMID- 25536672 TI - Minimal invasive Extra-Corporeal Circulation (MiECC): a revolutionary evolution in perfusion. PMID- 25536673 TI - eComment. Custom-made tissue valve composite tube graft for complex aortic root disease: a safe operative technique. PMID- 25536675 TI - eComment. Current debates on late conversion after endovascular aneurysm repair: a step-by-step discussion. PMID- 25536674 TI - eComment. Further tips on partial sternotomy. PMID- 25536676 TI - eComment. Can video-assisted thoracoscopic surgery or open thoracotomy alter the compliance to adjuvant chemotherapy and the oncologic prognosis of patients with non-small-cell lung cancer? PMID- 25536677 TI - eComment. The Berglin apical stitch: a simple technique to straighten things out in atrial fibrillation surgery? PMID- 25536678 TI - [Usefulness of imaging PET-CT examinations]. PMID- 25536680 TI - [Usefulness of PET-CT in RFA of the lung]. PMID- 25536679 TI - [The role of PET-CT at hospitals forming a regional cancer therapy network]. PMID- 25536681 TI - [C-11 imaging using LSO PET-CT]. PMID- 25536682 TI - [PET diagnosis at the Cancer Prevention and Examination Research Center, National Cancer Center]. PMID- 25536684 TI - [On PET-CT. A preface]. PMID- 25536683 TI - [Gantry-loaded PET-CT apparatus with a combination of 16-row CT and LSO PET]. PMID- 25536685 TI - Ureteroscopy: the first line treatment for distal located ureteral stones smaller than 10 mm. PMID- 25536686 TI - Always be prepared. PMID- 25536687 TI - Serving marginalized communities in Calgary. PMID- 25536688 TI - For that healthy glow..... PMID- 25536690 TI - Novel therapy for celiac disease. PMID- 25536689 TI - Tiny bacteria, big cardiac problems. PMID- 25536691 TI - Your brain on media multi-tasking. PMID- 25536692 TI - NSAID use raises risk of VTE. PMID- 25536693 TI - Allocation concealment in RCTs. PMID- 25536694 TI - Addressing a gap in postpartum care. PMID- 25536695 TI - Matching the right patient to the right care. PMID- 25536696 TI - Nurses heard on care, safe staffing. PMID- 25536697 TI - Ebola response: nurses ask to be informed, involved, equipped. PMID- 25536698 TI - Rethinking chronic care to help clients thrive. PMID- 25536699 TI - Are you prepared for the storm? Type 2 diabetes: fundamentals of treatment. PMID- 25536701 TI - Cannabis, criminal justice and public health. PMID- 25536700 TI - "The North is where I want to be". Interview with Brook Davis. PMID- 25536702 TI - Baby Boomers' subjective life course and its physical health effects: how distinctive is the "forever young" cohort? AB - We consider members of the "forever young" cohort's negotiation of aging by examining how shifts in their views of the life course and their location in it influence their physical health. Using OLS regression (Midlife in the United States, 1995-1996 and 2004-2006; n = 1,257), we compare Early and Late Baby Boomers' subjective life course, measured as age identity and timing of middle age, and its physical health effects with those of an earlier cohort, the Lucky Few. Contrary to expectations, the earlier cohort not only held more elongated conceptions of the life course at Wave 1 but also lengthened them more between waves than did Baby Boomers. Results also failed to support the notion of youthful conceptions having stronger health consequences for Baby Boomers. Examining more cohorts over longer timespans would illuminate how developmental aging processes intersect with sociohistorical contexts to shape the subjective life course and its health consequences. PMID- 25536703 TI - Understanding heterogeneity in adaptation to retirement: a growth mixture modeling approach. AB - Previous research has shown that as people transition to retirement they display heterogeneous growth in outcomes. Typically three subgroups are observed, in which people either increase, decrease, or maintain their scores over time. Extending this research, this study investigates whether subgroups exist independent of the retirement event and compares growth in two outcome measures- retirement adjustment and life satisfaction. Survey data were collected from 360 retirees across three time points. For life satisfaction, growth mixture modeling identified three distinctly growing subgroups. The majority maintained their scores over time, and two smaller groups showed increases and decreases in life satisfaction over time. No subgroups were identified for retirement adjustment. Implications of these results are discussed and suggestions are made for future research. PMID- 25536705 TI - Teenage pregnancy and exclusive breastfeeding rates. AB - BACKGROUND: Teenage pregnancy is an important health issue globally and in Thailand Younger age mothers decide on the breastfeeding practices ofthe first 6 month. OBJECTIVE: To find the rates of 6-month exclusive breastfeeding practices of teenage mothers and compare them with the rates of 6-month exclusive breastfeeding practices in mothers who are 20 years of age or more. MATERIAL AND METHOD: Three thousand five hundred sixty three normal, postpartum women, who delivered without complications at the HRH Princess Maha Chakri Sirindhorn Medical Center in the Nakhon Nayok Province between 2010 and2013 were included in this study. At the second daypostpartum, the data of latch scores and the data of the practice of exclusive breastfeeding were collected Telephone follow-ups on the seventh, fourteenth, and forty-fifth postpartum days and at the second, fourth, and sixth month postpartum month were collected and used for exclusive breastfeeding data following discharge. Demographic data included the maternal age, parity, gestational age, marital status, occupation, religion, route ofdelivery, estimated blood loss, body mass index, nipple length, and the childs birth weight. The collected data was analyzed by the t-test, Chi-square, and odds ratio with 95% confidence interval. RESULTS: The percentage of teenage pregnancies was at 14.8% (527 cases). On postpartum day 2, the percentage of latch scores of 8 or less was 66.4%. At the seventh, fourteenth, and forty-fifth day and at the second, fourth, and sixth months postpartum, the exclusive breastfeeding rates were 88.5, 78.5, 57.6, 43.1, 32.9, and27.0%, respectively. Comparison of the 6-month exclusive breastfeeding rates between teenage mothers and mothers 20 years ofage or older were not statistically significant (p<0.05). CONCLUSION: The 6-month exclusive breastfeeding rate of teenage mothers was at 27.0% and had no significant differences from the rates of mothers 20 years of age or more. PMID- 25536704 TI - Time for living and caring: an intervention to make respite more effective for caregivers. AB - This article presents the rationale for and description of a promising intervention, Time for Living and Caring (TLC), designed to enhance the effectiveness of respite services for family caregivers. It is guided by the theoretical principles of the Selective Optimization with Compensation (SOC) model, which individually coaches caregivers on how to assess their personal circumstances, identify their greatest needs and preferences, and engage in goal setting and attainment strategies to make better use of their respite time. Focusing on respite activities that match caregivers' unique needs is likely to result in improved well-being. We report on a pilot study examining TLC's feasibility and potential benefits and how caregivers viewed their participation. While additional research is needed to test and refine the intervention, we need to find more creative ways to enhance respite services. PMID- 25536706 TI - A comparative study of efficacy and safety of the lyophilized powder alpha erythropoietin and the liquid form alpha-erythropoietin for hemoglobin maintenance in patients with hemodialysis treatment. AB - BACKGROUND: Insufficient production oferythropoietin (EPO) is the primary cause ofanemia in patients with chronic kidney disease (CKD). The EPO treatment is an established treatment for renal anemia. The study investigated the therapeutic outcome between lyophilized powder and liquid form of EPO alpha by intravenous (IV) administration in hemoglobin maintenance of anemic treatment for CKD patients receiving hemodialysis. MATERIAL AND METHOD: Forty patients were randomly assigned to either lyophilized powder of EPO alpha (treatment, n = 21) or liquidform of EPO alpha (control, n = 19) for 12 weeks by lVadministration. The hemoglobin was maintained within the target range of 10. 0 to 12.0 g/dL by adjusting the dosage of EPO. The clinical and biochemical profiles including transferrin saturation andferritin were measured. Adverse events were documented. RESULTS: The mean hemoglobin ofboth groups at baseline was 11.2+/-0.6 g/dL. Mean hemoglobin and mean hematocrit levels at baseline, and follow-up data of both groups were not statistically different. The mean weekly dosage of EPO in the treatment and control groups had no statistical significance within the same group and between groups as well. Stable hemoglobin levels were maintained without EPO dosage adjustment in the majority ofpatients in both groups (treatment group, 90.5%, control group, 94.7%). During the 12-week study period, no serious side effect was detected CONCLUSION: The present study demonstrated that the lyophilizedpowder ofEPO alpha was effective and safe as the standard liquid form of EPO alpha when it was administered by IV route in hemoglobin maintenance of anemia treatment. PMID- 25536707 TI - Comparison on the efficacy and the safety of transradial approach versus conventional transfemoral approach for cardiac catheterization procedures. AB - OBJECTIVE: To compare the efficacy and safety of transradial approach (TR) and conventional transfemoral approach (TF) for cardiac catheterization procedures. MATERIAL AND METHOD: The data were collected retrospectively of all patients that received cardiac catheterization at Thammasat University Cardiac Center between September 1, 2010 and August 31, 2011 (the first year ofTR approach). RESULTS: Cardiac catheterization was performed on 597 patients. TR approach was performed about one-sixth of all procedures compared to conventional TF approach, 93 (15.58%) vs. 504 (84.42%). Safety of TR approach at the beginning was similar to conventional TF approach including in-hospital complication rate 5.4% vs. 4.6%, p = 0.788, volume of contrast media used 90.63+/-66.83 vs. 97.89+/-64.52 milliliters, p = 0.323, radiation exposure defined as median/min-max estimate skin entrance radiation dose 833.35/133.15-8,913.42 vs. 910.00/76.78-13,719.88 mGy, p = 0.599, and dose-area product 63.03/7.87-494.52 vs. 70.85/5.77-829.16 Gy x cm2, p = 0.586. The efficacy defined as procedural success rate was significantly higher in the conventional TF approach 90.3% vs. 97.8%, p = 0.001, as well as the procedural time that showed insignificantly longer 54.03+/-39.40 vs. 47.37?39.86 minutes, p = 0.139. This statistical diference in the procedural success rate was clear only in the first 62 TR. After this learning curve period, the procedural success rate was similar 96.8% vs. 97.6%, p = 0.575. Both the procedural success rate and the procedural time in TR approach showed trend to achieve better outcomes according to the increasing number of TRprocedures; 87.1% vs. 87.1% vs. 96.8%, p = 0.331 and 64.68+/-51.90 vs. 52.45+/-31.94 vs. 44.97+/ 29.04 minutes, p = 0.139 in the first 31 vs. the 32nd to the 62nd, and the 63rd to the 93" cases respectively. CONCLUSION: The safety of the transradial approach for cardiac catheterization procedures was similar to conventional transfemoral approach. The learning curve period was needed but its length is acceptable before the same efficacy rate as the conventional transfemoral procedure was achieved. PMID- 25536708 TI - Management of patients with severe hypertension in emergency department, Maharaj Nakorn Chiang Mai hospital. AB - BACKGROUND: Management of patients with severe hypertension without progressive target organ damage remains controversial. Some guidelines mentioned oral anti hypertensive medication as a treatment to reduce blood pressure in the emergency department, while others recommended against such treatment. OBJECTIVE: To review the management ofpatients with severe hypertension without progressive target organ damage in the emergency department, Maharaj Nakorn Chiang Mai hospital. MATERIAL AND METHOD: In a retrospective descriptive analysis study, medical records ofadult patients diagnosed with severe hypertension without progressive target organ damage between January 2011 and December 2012 were reviewed. Patient demographics, data on management including investigation sent and treatment given were collected. Statistical analysis was done by using descriptive statistics and Kruskal-Wallis one-way analysis of variance test. RESULTS: One hundred fifty one medical records were reviewed. Four oral anti-hypertensive medication were used to reduce blood pressure, Amlodipine, Captopril, Hydralazine, and Nifedipine. There were no significant diference between each medication in terms of their effect on bloodpressure reduction (p = 0.513). No side effect or other complications from the use of oral anti-hypertensive medication were recorded CONCLUSION: The choice of medication used for the treatment of hypertensive urgency ranged from Amlodipine, Captopril, Hydralazine, and Nifedipine, which varied in dosage. However their efficacies were the same when compared with each other and none produced any notable side effects. PMID- 25536710 TI - Recurrence and death from breast cancer after complete treatments: an experience from hospitals in Northern Thailand. AB - OBJECTIVE: To describe the pattern of disease progression and to describe locoregional recurrence, distant recurrence, and death rates in breast cancer patients after complete treatment. MATERIAL AND METHOD: Medical records of women diagnosed with breast cancer at two university affiliated tertiary care hospitals in the Northern Thailand that had complete treatments between 2006 and 2010 were traced. Extracted key information included patient clinical profiles and documented recurrence of cancer The causes of death were verified from breast cancer case registration database, death certificates through The Ministry of Internal Affairs'civil registration, by direct telephone contact, or by distributed prepaid postcards. RESULTS: Medical records of 829 women diagnosed with breast cancer without prior evidence ofdistant metastasis, and had complete recommended treatment were included. Six hundred thirty seven women had not experienced any events up to the end of the follow-up (76.8%). The first occurring events were focused and categorized into three distinct types, locoregional recurrence (n = 83, median follow-up time = 34.2 months), distant recurrence (n = 78, median follow-up time = 35.4 months), and death without any evidences of locoregional or distant recurrences (n = 12, median follow-up time = 36.7 months). Distant recurrence after locoregional recurrence was reported (n = 33). There were 109 patient who had died (breast cancer related death) up to the end of the follow-up (13.2%). The three types of consecutively occurring deaths were death after locoregional recurrence without any distant recurrences (n = 15), death after distant recurrence with locoregional recurrence (n = 21), and death after documenited distant recurrence without any locoregional recurrences (n = 61). CONCLUSION: The trend was that the rate of the first occurring locoregional recurrence was slightly higher than that of distant recurrence, The death rate in patients without any recurrences was much lower than in those experiencing prior recurrences. The rates of disease progression from local recurrence to distant recurrence and to death were approximately 5 to 7 times faster in patients who had experienced earlierprogressions. PMID- 25536709 TI - The study of familial history and associated risks of sexually abused children at Ramathibodi Hospital. AB - BACKGROUND: Nowadays, the incidence of sexual abuse in children is increasing especially in Thailand and the ASEAN countries. However the study of risk factors in family history is limited OBJECTIVE: Assess the significant family background and family history risks of sexually abused children. MATERIAL AND METHOD: This retrospective cross-sectional study used standard questionnaires to collect the general information of children who were sexually abused victims and explore their family history at the Parenting and Family Support Clinic, Department ofPediatrics, Ramathibodi Hospital, Mahidol University between 2011 and 2013. RESULTS: The majority of sexually abused children were aged 13 to 15 years (33 cases, 66%). Twelve children (24%) had underlying substances abuse and mood disorder in parental history, eleven (22%) had fathers with alcoholism problem, nine (18%) had mothers with mood disorder and eight (16%) had both underlying conditions. There were 41 single families (82%). Twenty-nine cases (58%) had conflicting relationship between their parents. The significant risk factors such as baseline children's behaviors, abusers, family status, violent history in family background, underlying substances abused or mood disorder, and baseline relationships in family were studied to develop a decision matrix to see when urgent separation to save the childfrom sexually abuse event is required. The logistic regression was analyzed and demonstrated that parental physical violent history and age group 8 to 12 years were higher odds ratio 19.0 (95% CI: 2.62 137.52, p-value = 0.004), and 19.2 (95% CI: 2.15-171.82, p-value = 0.002) when compared to other groups. CONCLUSION: Basic familial problems were commonlyfound in sexually abused children. Some ofthese factors are significant and can be applied as guidance for safety separation protocol for child safety in case of a sexually abused event. PMID- 25536711 TI - Classification and regression tree analysis for predicting visual outcome after open-globe injuries in Siriraj Hospital. AB - OBJECTIVE: To create a model for predicting visual outcome after open-globe injuries by using data of Siriraj Hospital. MATERIAL AND METHOD: Retrospective data of patients presented with open-globe injuries between January 2007 and December 2010 were used to create prognostic model. Seventeen factors at initialpresentation were collected and evaluated to develop the model by mean of Classification and Regression Tree analysis (CART). The prognostic tree was validated by using the sample ofopen-globe patients who presented between January 2011 and July 2011. RESULTS: The information of 231 eyes from 230 patients was analyzed to create a classification tree model. The calculated model composed of the two greatestpredictivefactors, no light perception (NPL), andpresence of relative afferentpupillary defect (RAPD). No patient with NPL at initial examination had vision at the six-month follow-up period. The other patients could be classified and predicted vision by using the presence of RAPD. CONCLUSION: The classification tree model developed in the present study is easy to calculate and has major significant predictive outcome for the open-globe injured patients. PMID- 25536713 TI - Reduction of spasticity in cerebral palsy by anodal transcranial direct current stimulation. AB - OBJECTIVE: To evaluate the anti-spasticity effects of anodal transcranial direct current stimulation (tDCS) in individuals with spastic cerebral palsy (CP). MATERIAL AND METHOD: Forty-six children and adolescents with cerebral palsy were randomly assigned to either active (1 mA anodal) or sham (placebo) tDCS over the left primary motor cortex (Ml) on five consecutive days. Both group also received routine physical therapy. Measures of spasticity and passive range of motion (PROM) were administered before treatment, immediately after treatment, and at 24 and 48-hours follow-up. RESULTS: Participants assigned to active tDCS treatment evidenced significantly more pre- to immediately post-treatment reductions in spasticity than participants assigned to the sham (p = 0.004, p 0.05 all). MEFV mutation allelic frequency was not different between AS patients and healthy controls after adjusting for mutations studied (34/224 versus 22/200; P > 0.05). CONCLUSION: Although we did not find significant clinical and laboratory differences between MEFV mutation carrier and noncarrier AS patients, further investigations are needed to define the impact of MEFV mutations on AS disease course. PMID- 25536726 TI - A comparison of the generation of free radicals in saliva of active and passive smokers. AB - AIM: To reveal any correlation between cigarette smoke and malondialdehyde (MDA) values in the saliva fluid of subjects who are active smokers or nonsmoking subjects who are exposed to cigarette smoke in their environments. MATERIALS AND METHODS: Saliva samples were taken from 3 groups: a control group (group 1), a group inhaling smoke passively (group 2), and a test group (group 3) smoking 20 cigarettes per day; each group consisted of 20 members, giving a total sample of 60 people, aged 20 to 45 years. MDA, which is an indicator of lipid peroxidation, was measured via the colorimetric method. RESULTS: Salivary MDA levels in smokers were found to be significantly higher compared to the control group and the group of passive smokers (P < 0.05). When compared with the control group, the MDA levels of passive smokers and active smokers were higher; when passive and active smokers were compared, the MDA levels of active smokers were higher. When all 3 groups were compared, the MDA levels in the control group (nonsmokers) were observed to be lower than the MDA level of the other 2 groups. CONCLUSION: It was observed that lipid peroxidation, which is an indicator used to determine oxidative stress, and MDA level, which is a product of this reactive chain, are significantly higher in individuals who are smokers. Such a high level of MDA in passive smokers indicates that smoking also affects nonsmokers negatively. PMID- 25536727 TI - Addition of epirubicin to conventional chemotherapy in patients with advanced ovarian cancer: sequential therapy -a retrospective evaluation. . AB - AIM: To evaluate the effectiveness of the addition of epirubicin to conventional chemotherapy as a first-line therapy for stage III-IV epithelial ovarian cancer. MATERIALS AND METHODS: A total of 132 patients who had undergone primary cytoreductive surgery between January 1998 and March 2003 were enrolled in the study. Twenty-four cases were excluded. Out of the remaining 108 subjects, 35 received epirubicin/paclitaxel/ carboplatin (Group EPC) and 73 were treated with paclitaxel/platinum (cisplatin.or carboplatin) (Group PC). RESULTS: The median follow-up period was 66.5 months. The clinical complete response was 94% in the EPC group and 97% in the PC group. The recurrence rate in the first 6 months after treatment was significantly higher in the PC than the EPC group (47% vs. 23%, P = 0.018). Triplet chemotherapy was not found to improve 2- and 5-year disease-free survival (DFS) statistically. No significant difference in overall survival was observed between the 2 groups (80% vs. 83% at 2 years and 56% vs. 57% at 5 years for the PC and the EPC group, respectively). The main toxicity in both groups was hematological, and it was particularly severe in the EPC group. CONCLUSION: The addition of epirubicin to the standard treatment protocol yielded an improvement in the DFS rate that was not statistically significant and caused a tolerable increase in toxicity. PMID- 25536728 TI - Clinical manifestations, complications, and treatment of brucellosis: evaluation of 72 cases. AB - AIM: Brucellosis is an important disease in developing countries. We aimed to determine the epidemiologic, clinical, and laboratory characteristics of brucellosis, which still has a high morbidity in Turkey. MATERIALS AND METHODS: Seventy-two patients with brucellosis, monitored at our clinic from January 2004 to July 2010, were reviewed retrospectively. RESULTS: The average age was determined to be 44.8 +/- 18 years, and 40 of the patients were female (55.6%). The most frequent transmission route was the use of raw milk and dairy products, in 45 of the patients (62.5%). The most frequent complaints were joint pain, high fever, weakness, low back pain, and gastrointestinal symptoms, whereas the most frequent physical examination findings were fever, osteoarticular involvement, splenomegaly, hepatomegaly, and lymphadenopathy. All of the patients were positive for Rose Bengal testing. The standard tube agglutination titer was 1/160 or higher in 64 (88.9%) patients. Brucella melitensis was isolated from blood cultures of 13 (18.1%) patients and bone marrow cultures of 7 (9.7%) patients. Complications of sacroiliitis in 6 (8.3%), spondylodiscitis in 4 (5.6%), endocarditis in 2 (2.8%), neurobrucellosis in 1 (1.4%), and epididymo-orchitis in 1 (1.4%) of the patients were observed. CONCLUSION: Brucellosis has various clinical presentations. It should be included in the differential diagnosis of high fever and joint pains in endemic countries. PMID- 25536729 TI - Prevalence study of genital tract infections in pregnant women referred to health centers in Iran. AB - AIM: BACKGROUND AND AIM: Pregnancy has its own complications such as premature rupture of membranes, preterm delivery, premature birth, low-birth-weight children, and infection. This study aimed to determine the prevalence rate of reproductive tract infections among pregnant women. MATERIALS AND METHODS: In this cross-sectional study, 85 randomly selected pregnant women referred to the ambulatory care facilities of Ardal County, Iran, were recruited via a systematic classified random sampling. Questionnaires, clinical examination by midwives, and laboratory assessments were used to gather the required data. RESULTS: According to the laboratory tests, 71.76% of samples were infectious. Candida albicans (35.76%), Escherichia coli (17.97%), and Streptococcus (13.06%) were the most observed infections, with a higher prevalence rate of reproductive tract infections during the second half of pregnancy compared to the first half. CONCLUSION: Since the prevalence rate of vaginal infections was high among pregnant women, and apparent symptoms and clinical examinations alone could not be used for diagnosing these infections, considering vaginal tests during pregnancy in additionto other routine tests could be helpful. PMID- 25536730 TI - Comparison of disc and body volumes in degenerated and nondegenerated lumbar discs: a stereological study. AB - AIM: To carry out comparison and correlation analyses of the intervertebral disc (IVD) and vertebral body (VB) volumes in magnetic resonance (MR) images of patients with degenerated and nondegenerated lumbar discs. MATERIALS AND METHODS: MR images were examined retrospectively in 93 patients. Lumbar VB and IVD volumes in T1-T2 weighted sagittal MR images were calculated via the Cavalieri method, a stereological method. Volumetric changes in degenerated and nondegenerated discs were compared. RESULTS: The percentages of degenerated IVDs were 12.9%, 12.9%, 28%, 50.5%, and 52% in discs from levels L1 to L5, respectively. There were no differences in VB volumes between the degenerated and nondegenerated groups for all lumbar vertebra levels. However, significant volumetric decreases were observed in degenerated IVDs for all lumbar vertebra levels, as compared to nondegenerated IVDs. Comparisons of VB volume and IVD volume ratios also revealed decreases, but they were significant only for levels L1 and L4. CONCLUSION: Disc volumes were found to be decreased, although vertebral bodies were not affected in degenerated IVD groups. However, using VB and IVD volume ratios may not always yield reliable results. PMID- 25536731 TI - Expression of NADPH-d in the vagal nuclei of the chronic esophagitis model in rats. AB - AIM: To evaluate the changes in the number of NADPH diaphorase (NADPH-d) stained neurons in the vagal nuclei in a chronic esophagitis model. MATERIALS AND METHODS: There were 3 groups of rats examined: 1) a chronic gastroesophageal reflux rat group, which was created by a partial gastric outlet obstruction; 2) a sham group; and 3) a ranitidine treated group. Serial sections ofbrainstems of all groups were cut and NADPH-d staining, which selectively stains the nitric acid synthase-containing neurons, was done. RESULTS: Histopathological changes due to chronic reflux esophagitis was observed in the reflux group. The ranitidine treatment and sham control groups showed no changes related to esophagitis. The staining in the dorsal motor nucleus of the vagus and nucleus tractus solitarius showed statistically significant differences compared to the control group (P < 0.0001). CONCLUSION: The increased nitric oxide expressions in the dorsal vagal nucleus and nucleus tractus solitarius are most probably due to adaptive changes to disturbed esophageal motility and mucosal damage. PMID- 25536732 TI - The association of nocturia with sleep disorders and metabolic and chronic pulmonary conditions: data derived from the polysomnographic evaluations of 730 patients. AB - AIM: To evaluate the prevalence of nocturia among different degrees of obstructive sleep apnea (OSA) and its association with various clinical conditions. MATERIALS AND METHODS: In 730 OSA patients, the prevalence and frequency of nocturia was determined, and the association of nocturia with clinical and laboratory variables such as the apnea-hypopnea index (AHI), apnea duration, and minimum oxygen saturation and clinical conditions such as diabetes mellitus, coronary heart disease, and chronic obstructive pulmonary disease (COPD) was determined. RESULTS: The overall prevalence of nocturia (>=2 wakes/night) was 50.9%. Prevalences ofnocturia in simple snoring and mild, moderate, and severe OSA patients were 40.6%, 44.4%, 58.6%, and 57.1%, respectively (P < 0.005). The frequency of nocturia significantly increases with the severity of OSA (1.4 +/- 1.0 wakes/night in mild OSA vs. 2.0 ? 1.4 wakes/night in severe OSA, P = 0.001). Age, AHI, average oxygen saturation, and presence of diabetes mellitus, hypertension, and COPD were found to be significant risk factors associated with nocturia (P <0.001). CONCLUSION: The frequency of nocturia increases as the severity of OSA increase. The increased prevalence of nocturia in patients with OSA, diabetes mellitus, hypertension, and COPD indicates the complex physiological background of this bothersome urologic symptom. PMID- 25536734 TI - The place of androgen receptor gene mutation analysis in the molecular diagnosis of prostate cancer and genotype-phenotype relationship. AB - AIM: To determine the relationship between androgen receptor (AR) gene polymorphism and prostate cancer in our society. MATERIALS AND METHODS: Thirty nine patients diagnosed with prostate cancer and 34 benign prostatic hyperplasia (BPH) patients who were diagnosed in 2010 met the study criteria. The inclusion criteria included patients whose diagnosis was confirmed with a biopsy, with the presence of adequate pathologic material for review, between the ages of 40 and 80, and who were healthy men without a family history of prostate cancer. The exclusion criteria excluded men diagnosed with another cancer and those who had kin with a history of prostate cancer. A direct DNA sequencing method was utilized for detection of polymorphisms. RESULTS: CAG repeat length varied from 13 to 28 (mean: 21.67) for the BPH group and 12 to 28 (mean: 21.74) for the prostate cancer group. Prostate-specific antigen (PSA) density and the androgen receptor (AR) CAG repeat had a statistically significant negative correlation in the BPH group. A statistically significant difference was associated between AR CAG repeat and PSA density. CONCLUSION: Randomized prospective studies should be planned with larger patient and control groups and with more variables, which may open new horizons in prostate cancer screening and early detection. PMID- 25536733 TI - A comparison of total thyroidectomies carried out through LigaSure and Harmonic Scalpel: a retrospective study. AB - AIM: Both LigaSure (LS) and Harmonic Scalpel (HS) are new surgical technologies that have been used to secure hemostasis in various fields of surgery. There is little information in the literature about the use of LS and HS in thyroid surgery. The aim of this study was to report our experience with LS and HS in thyroid surgery. MATERIALS AND METHODS: In this nonrandomized retrospective study 326 consecutive patients who underwent primary thyroid surgery were reviewed. HS was used in 136 patients and LS was used in 126 patients. A conventional technique was used in 64 patients. The were 42 male patients (12.9%) and 284 female patients (87.1%); their ages varied between 19 and 72 years (mean 42.8 + 12.4). Data regarding each patient's demographics, thyroid pathology, operation time, and complications were collected throughout the study. RESULTS: The 3 study groups-had similar demographics (age, female/male ratio) and thyroid pathology. Permanent hypocalcemia developed in 2 (1.6%) patients in the patient group operated on through LS, of which 1 was male and the other was female. In the HS group, postoperative hematoma developed in 2 (1.5%) patients. CONCLUSION: The results of this retrospective clinical study showed that LS and HS thyroidectomy can be a useful and fast alternative for conventional thyroidectomy. The main advantage of these devices is that they simplify the procedure and eliminate the need for clips and suture ligations while achieving efficient hemostasis. PMID- 25536735 TI - Thromboelastography in the evaluation of coagulation disorders in patients with sepsis. AB - AIM: Unbalanced hemostasis and disseminated intravenous coagulopathy serve as key participants in organ dysfunction and disability. In this study we evaluated the coagulation profiles of patients diagnosed with systemic inflammatory syndrome (SIRS)-sepsis and multiple organ dysfunction syndrome. We also researched coagulation in sepsis by comparing thromboelastography (TEG) data with those of nonsepsis patients to determine the usefulness of the TEG device. MATERIALS AND METHODS: Data were collected from 55 anesthesiology and surgery intensive care unit (ICU) patients: 21 with SIRS-sepsis (Group S) and 34 patients without SIRS sepsis (Group C). Blood samples were taken upon admission to the ICU (t1) and on day 3 of the ICU stay (t2). TEG data (R = reaction time, K = coagulation time, a = alpha angle, and MA = maximum amplitude) were recorded. TEG parameters were compared with routine coagulation and hemogram studies. RESULTS: The mean R value in Group C was higher than that of Group S at both t1 and t2. Group S had a significantly lower K value and higher alpha angle at t1 compared to Group C (P < 0.05). CONCLUSION: Hypercoagulability was observed in SIRS-sepsis patients in the ICU, as measured with TEG. We believe that TEG will be a useful tool in the evaluation of coagulation disorders developing in septic critically ill patients. PMID- 25536736 TI - Comparison of different ligation techniques in laparoscopic varicocelectomy. AB - AIM: To evaluate the effects of different intracorporeal ligation techniques with titanium clips, Plasma Trisector (Gyrus, USA) (PTG), and surgical silk on bilateral laparoscopic varicocelectomy (LPVx). MATERIALS AND METHODS: Between May 2009 and August 2012, 100 patients who underwent bilateral LPVx were evaluated. The demographic parameters of patients, preoperative radiological findings, semen analysis, operative data, and follow-up were recorded. All of the patients were divided into 3 groups, randomized prospectively. The patients whose veins were ligated by 5-mm titanium clips were included in group I, those whose veins were ligated by PTG were included in group II, and those whose veins were ligated by surgical silk were included in group III. The recorded data of the groups were analyzed. RESULTS: Mean follow-up time was 18.8 + 1.1 months. According to the demographics of age, body mass index, spermiogram, and diameter of veins before surgery, there were no statistical differences between any of the groups (P > 0.05). However, operation time was longer in group III (P < 0.0001), while total numbers ofligated veins did not differ among the groups (P > 0.05). Additionally, hospital stay, oral intake, and complications were not different among the groups (P > 0.05). In follow-up the sperm count analysis was higher than the preoperative count analysis for all of the groups (P < 0.05). CONCLUSION: PTG may provide a shorter operation time than using titanium clips and/or surgical silk in LPVx. Additionally, PTG may increase sperm count with fewer complications than the other ligation techniques in LPVx. Therefore, PTG may be the new candidate electrosurgical standard device for LPVx in the nearby future. PMID- 25536738 TI - Evaluation of 48-week response of treatment-naive chronic hepatitis B patients to 0.5 mg/day entecavir. AB - AIM: The hepatitis B virus (HBV) is an important healthcare problem. Chronic hepatitis B infection may present with a wide range of manifestations from inactive carrier state to cirrhosis and hepatocellular cancer. Therefore, treatment is very important in chronic hepatitis B. In this study, the treatment results of 199 chronic hepatitis B patients taking entecavir 0.5 mg/day for 48 weeks were evaluated. MATERIALS AND METHODS: This study retrospectively evaluated data of 199 treatment-naive chronic hepatitis B patients who were treated with entecavir. RESULTS: Of the 199 treatment-naive chronic hepatitis B patients, 141 (70.9%) were males and 58 (29.1%) were females, and mean age of the whole group was 37.5 +/- 12.1 years. HBeAg was positive in 91 (45.7%) and antiHBe was positive in 108 (54.3%) patients. Mean HBV DNA value was 666,449,365.5 +/- 2,759,013,996.9 IU/mL, mean ALT value was 112.1 +/- 95.7 U/L, and mean AST value was 95.3 _ 71.2 U/L. At week 24 of the treatment, HBV DNA levels were below 50 IU/mL in 56% of the HBeAg-positive and 76% of the HBeAg-negative patients. At week 48 of the treatment, HBV DNA levels were below 50 IU/mL in 79% of the HBeAg positive and 87% of the HBeAg- negative patients. At week 24, ALT had normalized in 72% of the HBeAg-positive and 79% of the HBeAg-negative patients. At week 48, ALT had normalized in 89% of the HBeAg-positive and 88% of the HBeAg-negative patients. AntiHBe seroconversion was seen in 2 of 91 patients (2.2%), but the loss of HBsAg was never observed. CONCLUSION: The 48-week entecavir treatment at a dose of 0.5 mg/day was shown to be effective both for HBeAg-positive and negative patients. PMID- 25536739 TI - New hemostatic agent: the effect of Ankaferd Blood Stopper on healing wounds in experimental skin incision model. AB - AIM: To conduct a histopathological evaluation of the effects of Ankaferd Blood Stopper (ABS) on healing wounds in a rabbit skin incision model. MATERIALS AND METHODS: Incisions were performed on the backs of rabbits. The first incision was allowed to undergo normal secondary healing. ABS (1 mL) was applied to the second incision, which was subsequently allowed to undergo secondary healing. The third incision was sutured. ABS (1 mL) was applied to the fourth incision, which was subsequently sutured. During the wound healing period, the histopathologic signs of ulceration, inflammation, the proliferative phase, and the extent of early remodeling were comparatively evaluated by performing biopsies on days 5, 10, and 30. RESULTS: For all of the ABS-treated wounds, the appearance of the cavities during the early stage and the disappearance of the cavities during the late stage were observed. In addition, on days 5-10, the inflammatory granulation tissue in the ABS-treated wounds was less than in the normal wounds. By day 30, all of the wounds had achieved the same symptomatic state. CONCLUSION: As ABS does not exert any negative effects on wound healing, this agent is a secure and effective method for achieving hemostasis. PMID- 25536737 TI - Epidemiology of organophosphate intoxication and predictors of intermediate syndrome. AB - AIM: To evaluate the usefulness of plasma glucose and serum cholinesterase levels as predictors of organophosphate-induced intermediate syndrome. MATERIALS AND METHODS: Seventy-one organophosphate poisoning patients who were admitted to our emergency department during a 4-year period were evaluated retrospectively. Four patients were excluded from the study due to a lack of medical records. Categorical variables were analyzed using the chi-square test and nonparametric variables were analyzed using the Mann-Whitney U test. RESULTS: Thirty-five (52.2%) patients were male and 32(47.8%) were female. Patients had a mean age of 39.4 +/- 15.9 years and 70.1% of the patients were married. Oral intake (68.7%) was the most common method of intoxication, and attempted suicide (67.2%) was the most common cause. The most common organophosphates were methamidophos (20.8%), dichlorvos (19.4%), parathion (7.5%), and methyl parathion (7.5%). Fifty-seven (85%) patients were treated in the emergency observation unit and 10 (15%) patients were admitted to the intensive care unit. Eleven (16%) patients developed intermediate syndrome and had significantly lower levels of serum cholinesterase (P < 0.01) and higher blood glucose levels (P = 0.037). CONCLUSION: Initial serum cholinesterase and glucose levels measured in the emergency department may be a useful marker in predicting organophosphate-induced intermediate syndrome. PMID- 25536740 TI - Investigation of the effects of magnetic field exposure on febrile seizure latency, seizure duration, and electroencephalographic recordings in a rat febrile convulsion model. AB - AIM: To investigate the effects of a magnetic field (MF) on febrile seizure latency, seizure duration, and electroencephalographic (EEG) recordings in a rat febrile convulsion model. MATERIALS AND METHODS: Thirty-six rats were randomly allocated into 1 of 6 groups: sham group (S), febrile convulsion (FC) group without MF exposure, MF group without FC, group exposed to MF before FC (MF + FC), group exposed to MF after FC (FC + MF), and group exposed to MF before and after FC (MF + FC + MF). The rectal temperature after febrile seizure induction, seizure latency, seizure duration, and EEG recordings were recorded for all animals. RESULTS: Repeated hyperthermic exposure decreased the seizure latency and duration. The effect of the MF was more prominent on seizure duration than on latencies. MF exposure for 10 or 12 days increased seizure latency. MF exposure increased the pathologic theta and delta waves and decreased the beta waves, which are frequently seen in awake animals. CONCLUSION: Our results suggest that MF exposure has a negative effect on brain waves, and this effect becomes more evident with prolonged exposure. On the other hand, MF exposure significantly decreased the convulsion durations. PMID- 25536741 TI - Comparing the fatty acid levels of preterm and term breast milk in Turkish women. AB - AIM: Lipids are the main source of calories and considered very important in infant growth. We aimed to compare fatty acid composition of term and preterm breast milk. This is the first study that compares the fatty acid levels of preterm and term breast milk in Turkish women. MATERIALS AND METHODS: Breast milk samples were obtained from mothers of term (n = 15) and preterm (n = 15) infants on postnatal days 3, 7, and 28. Fatty acid composition of human breast milk was determined longitudinally by gas-chromatography/mass spectrometry. RESULTS: There Were 31 fatty acids measured in the milk samples. In the first month, 17 fatty acid levels had significant differences. In group comparison, some fatty acids (C14:0, C16:0, C18:1 and C20:5) had significantly increased in the preterm group (P = 0.041, P = 0.046, P = 0.027, P = 0.033, respectively), whereas myristoleic acid (C14:1) and eicosanoic acid (C20:0) had significantly increased in the term group (P = 0.015, P = 0.048, respectively). CONCLUSION: Term and preterm milk have different compositions of fatty acids. Breast milk composition changes over time. As a general conclusion, breast milk provides the lipid requirements of infants. PMID- 25536743 TI - Hemodynamic effects of chest-knee position: comparison of perioperative propofol and sevoflurane anesthesia. AB - BACKGROUND/AIM: There are limited data in the literature investigating the effects of anesthetic agents on cardiac output used in the chest-knee position. The aim of this study is to compare the effects of inhalation and total intravenous anesthesia on cardiac output in patients undergoing lumbar discectomy in the chest-knee position. MATERIALS AND METHODS: Forty patients undergoing discectomy in the chest-knee position were allocated to 2 groups. The first group (GrS, n = 20) received sevoflurane after thiopental induction, while the second group (GrP, n = 20) received propofol induction and infusion. Heart rate (HR), mean arterial pressure (MAP), peripheral oxygen saturation, cardiac output (CO), and cardiac index (CI) were recorded. RESULTS: Groups were comparable in terms of HR and MAP. The differences related to anesthetic technique and position were statistically significant within each group. Cardiac output and CI were similar between the groups. Cardiac output and CI of GrP were found to be decreased in the chest-knee position and significantly elevated in the supine position after surgery (P < 0.05). There were significant decreases in the mean CO and CI values recorded after the chest-knee position in GrP. CONCLUSION: Sevoflurane is found to be superior when compared to propofol in patients undergoing surgery in the chest-knee position in terms of perioperative hemodynamic stability. Therefore, sevoflurane may be the anesthetic of choice, especially in patients operated on in the chest-knee position with suspected hemodynamic instability. PMID- 25536742 TI - Anti TNF-alpha therapy might be responsible for an increased incidence of varicocele in patients with ankylosing spondylitis. AB - AIM: To evaluate the effects of anti-tumor necrosis factor-alpha (TNF-alpha) therapy on the frequency of varicocele in patients with ankylosing spondylitis (AS) using color Doppler ultrasound. MATERIALS AND METHODS: The patients were divided into 2 groups: patients with AS who were on anti-TNF-alpha treatment and patients with AS who were not regularly taking any antiinflammatory drugs. Thirty one healthy volunteers were included as controls. RESULTS: Left-sided varicocele was determined in 14 patients of Group 1 (44%), 10 patients of Group 2 (33%), and 7 of the controls (23%). There was a statistically significant difference only between Group 1 and controls (P = 0.009). However, right-sided varicocele was determined in 12 patients of Group 1 (38%), 2 patients of Group 2 (6%), and 2 of the controls (6%) (P = 0.01 vs. Group 2, P = 0.005 vs. controls). CONCLUSION: The present study shows that patients with AS who were taking anti-TNF-a therapy had an increased prevalence of right- sided and bilateral varicocele compared to patients with AS who were not taking any disease-modifying antirheumatic drugs and the healthy control group. PMID- 25536744 TI - Pediatric reference intervals for plasma and urine essential amino acids in a Turkish population. AB - AIM: To establish age- and sex-specific reference intervals for essential amino acids in a healthy Turkish pediatric population. MATERIALS AND METHODS: A total of 945 clinically healthy children (531 boys and 414 girls, ranging in age from birth to 14 years) were enrolled. Plasma and urine amino acids' concentrations were measured by high-performance liquid chromatography. RESULTS: Concentrations of essential amino acids in plasma were higher in girls than in boys in the age groups of 0-1 months and 7-14 years; however, there was no difference in the other age groups. Concentrations of essential amino acids in urine were higher in girls than in boys in the age group of 0-1 months; however, there was no difference in the other age groups. Our results demonstrated the sex-related differences in concentrations ofleucine, isoleucine, valine, phenylalanine, lysine, and histidine in plasma, which increased with age in boys but not in girls. The concentrations of leucine, tryptophan, methionine, and lysine in urine declined with age in girls but not in boys, which were sex-related differences, too. CONCLUSION: We defined essential amino acids' reference intervals in a Turkish pediatric population. PMID- 25536745 TI - Efficacy of resuscitation with Intralipid in a levobupivacaine-induced cardiac arrest model. AB - AIM: Cardiac toxicity due to the administration of local anesthetics may be fatal. In this study, we evaluated the efficacy of a 20% lipid solution combined with epinephrine in a levobupivacaine-induced cardiac arrest model. MATERIALS AND METHODS: A total of 14 New Zealand rabbits were sedated and mechanically ventilated. Asystole was induced with intravenous levobupivacaine injection. The rabbits were randomized into groups receiving the same volume of either 0.9% saline (CR group) or a 20% lipid solution (LE group) along with a 100 MUg/kg epinephrine bolus, which were administered immediately upon asystole. Standard advanced cardiac life support protocols were performed. RESULTS: Four subjects in the LE group as well as 3 subjects in the CR group had a spontaneous recovery (P = 0.592). In the 20th minute after arrest, 3 subjects in the LE group had maintained spontaneous circulation, while there was only 1 subject from the CR group with the same outcome. CONCLUSION: We found that adding a lipid solution to epinephrine for the resuscitation of rabbits that underwent levobupivacaine- induced cardiac arrest increased recovery rates of circulation and therefore the likelihood of survival. Further studies are needed to develop clinical therapies for the systemic toxicity of local anesthetics. PMID- 25536747 TI - Tc-99m MDP bone scintigraphy in the evaluation of the joint damage in asymptomatic alpine ski racers. AB - AIM: To evaluate the role of 99m-technetium methylene diphosphonate (Tc-99m MDP) bone scintigraphy on the detection of joint damage in asymptomatic alpine ski racers. MATERIALS AND METHODS: This study included 20 male asymptomatic alpine ski racers (age range: 18-21 years). None of the skiers had a history of ski crashes. Bone scan findings of the racers were examined with Tc-99m MDP bone scintigraphy during the active racing season and the inactive training season. Planar anterior and posterior images of hip, knee, and ankle joints were obtained 4 h after intravenous injection of 20 mCi Tc-99m MDP. All images were interpreted visually by 2 experienced nuclear medicine physicians. Free regions of interest were drawn on hip, knee, and ankle joints, as well as background regions. Joint to-background ratios were calculated for each joint, and the uptake ratios of both right and left joints during active ski season were compared to those during the inactive training period. RESULTS: Uptake ratios of the right and left hip, knee, and ankle joints were significantly higher during the active racing period than those calculated during the inactive period (P < 0.005). CONCLUSION: Bone scintigraphy may have an important role in detecting joint injuries of hip, knee, and ankle joints in asymptomatic alpine ski racers and can be used successfully when MRI is unavailable. PMID- 25536748 TI - Clinical and prognostic importance of chromosomal abnormalities, Y chromosome microdeletions, and CFTR gene mutations in individuals with azoospermia or severe oligospermia. AB - AIM: To illustrate the importance of genetic screening in the assessment of fertility and the correct diagnosis in patients with azoospermia or severe oligospermia. MATERIALS AND METHODS: This study examined 500 patients with reproductive failure, having fewer than 5 million sperm/mL detected in at least 2 consecutive spermiograms, who presented at a medical genetics polyclinic between 2008 and 2012. Metaphase preparations obtained from cell cultures were stained by trypsin-Giemsa banding. After DNA isolation, Y chromosome loci, including AZFa (SY84, SY86), AZFb (SY127, SY134), AZFc (SY254 SY255), and AZFd, were amplified by polymerase chain reaction using specific primers. Thirty-five patients with congenital unilateral absence of the vas deferens or congenital bilateral absence of the vas deferens (CBAVD) and a positive cystic fibrosis family history were evaluated for cystic fibrosis transmembrane conductance regulator gene mutations. RESULTS: No chromosomal abnormalities were noted in 440 (88%) of the 500 patients, whereas structural or numerical chromosomal abnormalities were detected in 60 patients (12%). Individuals with Y deletions made up 5.6% (n = 28) of the study sample. Three patients with no AZF deletion or chromosomal abnormality, but with CBAVD, were heterozygous for I148T, G1130A, or IVS3 406- 3T>C mutations. CONCLUSION: This study shows that genetic testing can make an important contribution to the treatment of patients planning in vitro fertilization due to azoospermia or severe oligospermia. PMID- 25536746 TI - Epidemiology of uveitis in a referral hospital in Turkey. AB - AIM: To investigate the causes and clinical characteristics of uveitis in patients presenting to a specialized eye hospital in Turkey. MATERIALS AND METHODS: The clinical records of 1028 uveitis patients admitted between 1990 and 2010 were retrospectively reviewed. Age at first presentation, sex, laterality, etiology, associated systemic disease, clinical presentation, and course of the disease were noted. RESULTS: The mean age at presentation was 36.23 +/- 14.9 years. Males constituted 58.2% of patients. Anatomically, anterior uveitis (42%) was most common, followed by posterior uveitis (24.9%), panuveitis (24.7%), and intermediate uveitis (8.4%). The course of the disease was mostly chronic (65.7%). The cases were idiopathic at 25.7% and Behcet's disease (BD) was the most common cause of uveitis (32.2%), followed by ocular toxoplasmosis (7.2%) and herpetic uveitis (6.8%). CONCLUSION: Uveitis tends to affect patients between 20 and 40 years old. BD is the most common cause, leading to male predominance and a higher frequency of a chronic course. PMID- 25536749 TI - The role of CT and MRI in the diagnosis of sigmoid volvulus. PMID- 25536750 TI - [The color test: psychodiagnostic opportunities for the patients presenting with chronic somatic diseases]. AB - The objective of the present study was to estimate the diagnostic potential of the Luscher color test. A total of 1083 patients presenting with chronic somatic diseases were available for the psychodiagnostic examination. It was shown that the color test makes it possible to evaluate clinically significant psychological characteristics as well as dynamics of anxiety and stress-resistance in this group of patients. Specifically, in the cases of chronic somatic diseases, the test can be used as one of the psychodiagnostic methods especially for mass screening and in the situations when the application of the standard questionnaires encounters difficulties (for example, in the patients with disturbed cognitive functions). PMID- 25536751 TI - [The personality structure as a basis for the organization of psychological support in the process of medical rehabilitation of the patients presenting with motor function disorders]. AB - We have analyzed the relationships between personality traits and the quality of life in 95 in-patients with motor function disorders undergoing the rehabilitative treatment. It was shown that the high quality of life in the patients suffering from motor function disorders as a result of an acute cerebral circulation disorder correlated with the positive attitudes towards recovering and stress resistance. In the patients presenting with degenerative-dystrophic diseases of the joints, the high quality of life correlated with the purpose oriented behaviour and discipline expressed as the commitment to the goal. It was suggested based on the results of the study that the correction of the level of situational and trait anxiety should be regarded as the main end-point of the psychological treatment of the patients with acute cerebral circulation disorders, while the patients suffering from degenerative-dystrophic diseases of the joints could benefit from education designed to enhance compliance to the treatment and motivation for recovery. PMID- 25536752 TI - [The technical peculiarities of the application of therapeutic physical exercises for the rehabilitation of the patients presenting with post-infarction cardiosclerosis]. AB - The article reports the results of clinical and physiological studies of 93 patients presenting with post-infarction cardiosclerosis and sings of cerebrovascular disease. The experience with the application of the combined rehabilitative treatment including therapeutic physical exercises is based on the results of the observation of two groups of the patients. Those of the study group performed special physical exercises designed to act on brain hemodynamics. The patients of the control group used traditional therapeutic exercises usually prescribed to those suffering from coronary artery disease. It was shown that the treatment including therapeutic physical exercises offered to the patients of the study group has an advantage of the significant positive impact on haemodynamics and functional activity of the brain; moreover, it reduces the severity of cardio vascular cerebral symptoms and thereby contributes to complete rehabilitation of the patients with post-infarction cardiosclerosis. PMID- 25536753 TI - [Correlation between sympathetic nervous activity of the skin and local temperature of skin projections of the spinal nerves in the course of rehabilitation of the patients presenting with dorsopathies]. AB - We undertook the correlation analysis of the parameters characterizing the intensity of the skin sympathetic reactions and local temperature of skin projections of the spinal nerves in three groups of patients presenting with dorsopathies and differing in terms of sympathetic regulation of the microvasculature. It was shown that the patients of group 1 exhibited positive correlation between the above parameters (preserved vegetative regulation of microcirculation despite the tendency toward its atonic-stagnant disturbances). The patients of group 2 showed negative correlation between these parameters (preserved vegetative regulation of microcirculation despite the tendency toward its spastic-stagnant disturbances). Neither one nor the other type of correlation was documented in the patients of group 3 which suggests the absence of vegetative regulation of the microcirculatory bed. PMID- 25536754 TI - [The experience with the application of the non-medication methods for the treatment of essential arterial hypertension in the adolescents presenting with obstructive sleep apnea/hypopnea syndrome]. AB - The present study was designed to estimate the effectiveness of non-invasive auxiliary lung ventilation under continuous positive airway pressure (CPAP therapy) and phototherapy applied for the treatment of adolescents presenting with essential arterial hypertension and obstructive sleep apnea/hypopnea. It was shown that CPAP therapy decreased the level of arterial pressure (AP) either to normal or to high normal values in accordance with the patients' gender and age. It was confirmed that phototherapy produced beneficial effect on the system of circadian rhythms in the patients with essential hypertension. These findings give reason to recommend the combined application of the above methods for the treatment of adolescents with essential hypertension and obstructive sleep apnea/hypopnea. The proposed treatment makes it possible to decrease arterial pressure due to the correction of obstructive breathing disorders in sleep and to normalize the circadian rhythm system in the adolescents suffering from essential hypertension and obstructive sleep apnea/hypopnea. The clinical application of this method would permit to reduce morbidity, the incidence of disability, and mortality from complications developing in adulthood. PMID- 25536755 TI - [The rehabilitative treatment of chronic pyelonephritis in the children having an environmentally burdened medical history]. AB - The present study involved 40 children aged 7-14 suffering from chronic pyelonephritis and having an environmentally burdened medical history. The combined spa treatment included either traditional peloid therapy applied to the lumbar region or the specially developed treatment using the adaptive-reflexive method that allowed the therapeutic effect to be gradually spread over various reflex zones. Mud applications under the new scheme were shown to be more adequate and sparing because they ensured gradual sequential involvement of different reflex zones that is of special importance for the patients having an environmentally burdened medical history and characterized by the impaired adaptive capacity. The advantage of the proposed peloid-therapeutic modality is confirmed by the reduction in the frequency of the patients' complaints and the more pronounced dynamics of the signs of mikrohematuria, pyuria, and oxaluria combined with the restoration of the anti-crystal-forming urinary activity in response to calcium phosphates in all patients. PMID- 25536756 TI - [The application of the flexion test for the development of the rehabilitation program for the children presenting with cervical spine pathology]. AB - As was proven by clinical studies, the results of the flexion test, a specific technique applied in manual therapy, can be used for differential diagnostics of pathological changes in the cervical spine of dysplastic and "mechanical" origin. This fact is taken into consideration in the elaboration of the prevention and rehabilitation programs. The present report is based on the results of the rehabilitative treatment of the children and young athletes presenting with pathological changes in the cervical spine. PMID- 25536757 TI - [The ultrastructural organization of the liver of rats with experimental hepatitis after drinking mineral water containing humic acids]. AB - We undertook the ultrastructural analysis of liver parenchyma taken from male rats with experimental hepatitis induced by the administration of paracetamol at a dose of 1000 mg per 1 kg body weight either following a course of drinking mineral water containing humic acids at a concentration of 20 mg/sq. decimeter) or 14 days after the termination of the drug action (the after-effect phase). It was shown that the consumption of mineral water during 21 days resulted in the modification of the ultrastructural organization of hepatocytes apparent as the increased amount of cisterns in the granulosa endoplasmic system, glycogen rosettes, and mitochondrial polymorphism. These changes give evidence of the restoration of the energy, glycogen and protein synthesizing functions disturbed by paracetamol administration. The after-effect phase was characterized by the further strengthening of reparative processes and the functional activity of hepatic cells. PMID- 25536758 TI - [The prospects for the development of regenerative physical therapy]. AB - The review is concerned with the investigations into the influence of physiotherapeutic factors on the regeneration of the muscular, nervous, bone, and epidermal tissues; also, it analyses the publications pertaining to the influence of low-intensive physiotherapeutic modalities on the migration rate, proliferative activity, and differentiation of stem cells as well as physiological stability and viability of these cells following their transplantation. The currently available data give evidence of the possibility in principle of the combined application of physiotherapeutic factors and cellular technologies in regenerative medicine and the prospects opening for the development of the new direction of research in modern biomedicine, namely regenerative physical therapy. The importance of interdisciplinary basic and clinical investigations in this direction becomes especially evident in the light of the recent achievements and rapid progress in the development of modern regenerative medicine. PMID- 25536759 TI - [The principal approaches to the treatment of post-stroke shoulder pain syndrome]. AB - Post-stroke pain syndrome is one of the serious complications of stroke preventing the restoration of motor activity, routine everyday and professional independence of the patients. This review is focused on pathogenesis of central and peripheral shoulder pain syndromes on the affected side of the body and the principal approaches to their treatment during the post-stroke recovery period. The paper describes the main manual and robotic methods for the treatment of shoulder pain depending on its pathogenesis and the typical therapeutic protocols. The special emphasis is laid on the necessity of the pathogenetic approach to the pain alleviation as well as clinical significance of the correction of biomechanical disorders in the upper body and the restoration of the functional ability of the upper limbs in the patients presenting with post stroke hemiparesis associated with pain syndrome. PMID- 25536760 TI - [The pathogenetic prerequisites for the application of the general magnetic therapy in the children presenting with cerebral ischemia]. AB - This article presents the analysis of the current literature and the original data of the authors providing the rationale for the use of magnetic therapy for the treatment of the children presenting with cerebral ischemia taking into consideration pathogenesis of this disease. It is demonstrated that the application of the general magnetic field decreases the tone of the cerebral vessels and improves blood flow to the brain which increases resistance to cerebral hypoxia. The results of investigations into the microcirculatory changes and liquor dynamics in conjunction with the ventriculometric measurements give evidence of the effectiveness of the combined treatment of cerebral ischemia making use of general magnetic therapy. PMID- 25536761 TI - [90-year anniversary of the Kuldur health resort]. AB - The article is devoted to the history of creation and development of the Far Eastern health resort Kuldur located in the spurs of the Khingan range at the territory of the Jewish Autonomous Region. The historical sketch spans the period from 1897 to the present time including the phases of the resort activities at different stages of its developments in pre-revolutionary and post-revolutionary Russia (from the epoch of developed socialism to our time). The authors describe the contribution of the personnel of the resort, geologists, scientists of the Khabarovsk Medical Institute and other research institutions to the elucidation of the mechanism of action and therapeutic effectiveness of nitric-siliceous thermal waters. PMID- 25536762 TI - [Mechanisms for regulation of fear conditioning and memory]. AB - Pavlovian fear conditioning is a model of fear learning and memory. The mechanisms regulating fear conditioning and memory have been investigated in humans and rodents. In this paradigm, animals learn and memorize an association between a conditioned stimulus (CS), such as context, and an unconditioned stimulus (US), such as an electrical footshock that induces fear. Fear memory generated though fear conditioning is stabilized via a memory consolidation process. Moreover, recent studies have shown the existence of memory processes that control fear memory following the retrieval of consolidated memory. Indeed, when fear memory is retrieved by re-exposure to the CS, the retrieved memory is re-stabilized via the reconsolidation process. On the other hand, the retrieval of fear memory by prolonged re-exposure to the CS also leads to fear memory extinction, new inhibitory learning against the fear memory, in which animals learn that they do not need to respond to the CS. Importantly, the reinforcement of fear memory after retrieval (i.e., re-experience such as flashbacks or nightmares) has been thought to be associated with the development of emotional disorders such as post-traumatic stress disorder (PTSD). In this review, I summarize recent progress in studies on the mechanism of fear conditioning and memory consolidation, reconsolidation and extinction, and furthermore, introduce our recent establishment of a mouse PTSD model that shows enhancement of fear memory after retrieval. PMID- 25536763 TI - [The therapeutic plasma concentrations of antiparkinson dopamine agonists and their in vitro pharmacology at dopamine receptors]. AB - This review discusses the relationship between therapeutic plasma concentrations of antiparkinson dopamine agonists (rotigotine, pergolide, cabergoline, apomorphine, bromocriptine, ropinirole, pramipexole, and talipexole) and their in vitro pharmacology at dopamine D1, D2 and D3 receptors. A significant correlation was found between therapeutic plasma concentrations of these dopamine agonists and their agonist potencies (EC50) at D2 receptors, although no such correlation existed at D1 or D3 receptors, suggesting that D2 receptors could be the primary and common target for the antiparkinson action of all dopamine agonists. However, D1 receptor stimulation is also important for maintaining swallowing reflex, bladder function and cognition. In particular, continuous D1 and D2 receptor stimulation may be reduced to low levels among Parkinson's disease patients. Our findings revealed therapeutic plasma concentrations of rotigotine were similar to its agonist potencies at both D1 and D2 receptors. Thus, rotigotine may be beneficial for the treatment of Parkinson's disease patients in that this dopamine agonist has the potential of continuous stimulation of both D1 and D2 receptors in the clinical setting. PMID- 25536764 TI - [Characteristics of structure and biological properties of staphylococci isolated from children with HIV-infection]. AB - AIM: Study species composition and factors of pathogenicity of staphylococci isolated from intestine biotope of children with HIV-infection. MATERIALS AND METHODS: 75 strains of staphylococci from HIV-positive and 45 strains from HIV negatfive children were isolated and identified. Factors of specific adhesion, colonization potential, invasion factors and toxin-formation of staphylococci were studied. RESULTS: In HIV-infected children Staphylococcus aureus, Staphylococcus xylosus, Staphylococcus epidermidis dominated. Quantitative level of S. aureus was 1.8 x 10(7) PFU/g. Adhesion, production of hemolysin, DNAse did not differ from the comparison group (p > 0.05). Lipase activity in staphylococci from HIV-infected children was higher than in the control group (p < 0.05). CONCLUSION: The data obtained reveal some mechanisms of development of endogenous infection in HIV-infected children. PMID- 25536765 TI - [Mechanisms of realization of protective effect of miliacin during experimental Salmonella infection: effect of endotoxinemia and cytokine production]. AB - AIM: Evaluate the effect of miliacin on the intensity of endotoxinemia and features of cytokine production in experimental salmonella infection. MATERIALS AND METHODS: The studies were carried out in 128 male mice (CBAxC57Bl6)F1 divided into 4 groups: I--intact; II--infected; III--infected after administration of miliacin solvent: tween-21; IV--infected after administration of miliacin. Determination of the endotoxin in blood plasma was carried out by using chromogenic LAL-test. Cytokine production was studied in splenocyte culture by EIA method. RESULTS: Miliacin reduced the intensity of endotoxinemia in mice of group IV. Salmonella infection increased spontaneous (IFNgamma) and induced (IL 12, IFNgamma, IL-17) cytokine production. Miliacin ensured the most significant increase of spontaneous IL-10, IL-12 and IFNgamma production compared with groups II and III. At the same time it limited the increase of induced IL-17 production compared with groups II and III. CONCLUSION: Protective effect of miliacin is determined by the reduction of endotoxinemia, mobilization of Th-1 response, stimulation of IL-10 production and limitation of IL-17 participation in the development of the inflammatory reaction. PMID- 25536766 TI - [Actual problems of infectious disease control in Russian Federation]. PMID- 25536767 TI - [Frequency of diseases caused by group A streptococci among invasive infections of soft tissues and characteristics of the causative agent]. AB - AIM: Determine frequency of diseases caused by group A streptococci (GAS) among invasive infections of soft tissues; identify emm-types of the isolated streptococci, determine the presence of bacteriophage integrases and toxin genes in their genomes. MATERIALS AND METHODS: 4750 case histories of patients with soft tissue infections of the purulent-surgical department of the 23rd City Clinical Hospital.of Moscow "Medsantrud" in 2008 - 2011 were analyzed. 46 strains of GAS isolated from patients with invasive streptococcus infection (ISI) were studied. GAS identification was carried out by latex-agglutination method. GAS emm-type was determined by molecular-genetic methods, as well as the presence of bacteriophage integrases int2, int3, int4, int5, int6, int7, int49, bacteriophage toxins speA, speI, sla, speC/J, speL, speH, speC, ssa and speB gene present on the chromosomal DNA. RESULTS: 132 cases (2.8%) were attributed to invasive infections. In 46 cases of invasive infections (35%) GAS were isolated. 22 different emm-types of invasive GAS strains were detected. Only speB gene among all the toxin genes (as well as the expression of the gene--SpeB toxin) was detected in all the strains, whereas sla and speI genes were not detected in any of the strains. Genes of the other toxins (ssa, speL, speC, speA, speH, speC/J) occurred in a number of strains. Genes of phage integrases were detected among all the strains however in varying combinations (from 1 to 4 genes). CONCLUSION: Invasive infections caused by GAS are more frequently spread than had been previously assumed and a high degree of genetic heterogeneity of invasive GAS strains was detected. PMID- 25536768 TI - [Comparative analysis of parameters of humoral and cell specific immunity in individuals immunized with a live tularemia vaccine]. AB - AIM: Comparative analysis of parameters of humoral and cell immunity in individuals, vaccinated against tularemia. MATERIALS AND METHODS: Sera and blood samples of 258 immunized individuals were studied by indirect hemagglutination and leukocytolis with tularin reaction. RESULTS: 73% of the examined individuals had both specific antibodies and positive values of cell immunity. The presence of anti-tularemia immunity was registered in 26 of 30 individuals immunized 10 - 20 years ago. However in 76 individuals (26%) we have detected discrepancies of the results of the 2 methods that complicate the evaluation of specific immunity status. As such, the use of only 1 method characterizing either humoral or cell immunity does not give objective information. CONCLUSION: The use of 2 methods directed on detection of both specific antibodies and delayed-type hypersensitivity reaction is reasonable for the increase of validity of results of anti-tularemia immunity status evaluation. Only positive immunologic parameters of both tests confirm the presence of immunity against Francisella tularensjs and the possibility of revaccination period delay. PMID- 25536769 TI - [Grippol, Vaxigrip and influvac vaccines--inductors of innate and adaptive immunity factor genes in human blood cells]. AB - AIM: Study the effect of inactivated influenza vaccines on the activity of innate and adaptive immunity genes (TLR3, TLR4 and B2M), RNA-interference Dicer1-gene, production of cytokines (antiviral IFN type I and II, regulatory IL10, IL17) and pro-inflammatory factors IL1-beta, TNFalpha. MATERIALS AND METHODS: Gene expression was determined by rRT-PCR with authors' primers in human blood cells treated with various doses of the vaccines. Concentration of cytokines by enzyme immunoassay was measured in cultural fluid using "Vector-best" kits. RESULTS: The studied vaccines have characteristic effects on genetic level. Grippol vaccine predominately stimulates TLR4 gene, activates TLR3, B2M and Dicer1 genes. Influvac vaccine mostly induces TLR3 gene and to a lesser extent TLR4 gene, does not influence the expression of B2M gene and inhibits Dicer1 gene. Vaxigrip split vaccine--the most potent stimulator of gene activity at low doses. Its main targets are TLR3 and B2M genes. All the inactivated vaccines--inductors of high level of IFNgamma, low level of TNFalpha and do not induce IL17. Grippol additionally stimulates secretion of IL1-beta, and Vaxigrip - IFNalpha. Subunit vaccines Grippol and Influvac that contain purified influenza virus hemagglutinins induce IL10 synthesis in blood cells. CONCLUSION: Immunogenetic characteristics of the inactivated influenza vaccines administered nowadays are obtained. PMID- 25536770 TI - [Frequency of antibodies against surface and nuclear antigens of hepatitis B virus in population of St. Petersburg in 2013]. AB - AIM: Determine the frequency of antibodies to surface (anti-HBs) and core (anti HBc) antigens of hepatitis B in population of St. Petersburg of various age for evaluation of protective herd immunity against hepatitis B virus (HB). MATERIALS AND METHODS: Blood sera of 970 individuals (491 males, 479 females) of 10 age groups from 0 to 50 years and older were examined for the presence of anti-HBs and anti-HBc IgG by enzyme immunoassay using commercial diagnostic test-systems. RESULTS: In general anti-HBs at the level of 5 mIU/ml and above were detected in 603 of the examined individuals (62.2%). Anti-HBs at the level of 10 mIU/ml and above were detected in 53.9%. The frequency of anti-HBs in protective titers in males and females in general turned out to be similar (52.6% and 55.2%, respectively). Juxtaposition of age-specific parameters of seroprotection and acute HB morbidity in St. Petersburg revealed an inverse correlation of medium strength (r = - 0.54). CONCLUSION: Results of the study confirm high effectiveness of the program of HB vaccine prophylaxis in St. Petersburg and emphasize the necessity of further implementation of broad measures of population immunization against HB. PMID- 25536771 TI - [Mathematic prognosis of cagocel effectiveness for prophylaxis and therapy of influenza]. AB - The possibility of using a mathematic model of influenza epidemic in evaluation of effectiveness of an etiotropic preparation cagocel for prophylaxis and therapy of influenza as well as determination of possible damage from influenza epidemics and outbreaks in major cities of Russia is shown. PMID- 25536772 TI - [Antiviral activity and possible mechanisms of action of moraprenil phosphates during experimental infection caused by herpes simplex type 1 virus]. AB - AIM: Study of antiviral activity of moraprenil phosphates (MPP) against herpes simplex type 1 virus (HSV1) in vitro and during experimental infection caused by HSV1 in mice. MATERIALS AND METHODS: Activity of MPP in vitro was tested by the ability to suppress formation of symplasts in VERO cells infected with HSV1, strain VR-3. A series of MPP that suppress virus-induced symplast-formation by 30 times was selected for in vivo experiments. Anti-viral activity of MPP in vivo was studied in HSV-1 infected mice after administration of either prophylaxis or therapy regimens. RESULTS: MPP at the dose of 20 microg/mice during s/c administration exhibited a pronounced prophylactic-therapeutic effect. Effectiveness of MPP during clinically evident herpes against the background of developing neurologic symptoms was demonstrated for the first time. Visual observation of the mice, that had received MPP as the first clinical symptoms of the disease appeared, has shown that against the background of preparation injection the clinical signs have ceased after 2 - 3 days and did not registered at least for the whole duration of the observation period (14 days). CONCLUSION: Active herpes infection is accompanied by the increase of FoxP3 expression in thymus was shown. Possible mechanisms of anti-viral effect of MPP are discussed. PMID- 25536773 TI - [Content of some pro- and anti-inflammatory cytokines in blood sera of leptospirosis patients]. AB - AIM: Study the content of some pro- and anti-inflammatory cytokines in blood sera of leptospirosis patients in dynamics of infectious process and the role of these cytokines in the disease immunopathogenesis. MATERIALS AND METHODS: The content of cytokines in blood sera was determined by a method based on xMAP technology with a standard panel consisting of 9 analytes: TNF-alpha, MCP-1, IL-8, IL-4, IL 6, IL-10, IL-1Ra, IL-12 (p70), IFN-gamma. RESULTS: A significantly increased level of IL-8, IL-10, TNF-alpha was confirmed and the increased content of MCP-1 in leptospirosis patients compared with practically healthy donors was established for the first time. Correlations between cytokines during leptospirosis were detected. CONCLUSION: The data obtained show that cytokines play an important role in leptospirosis immunopathogenesis. PMID- 25536774 TI - [Effect of Escherichia coli secreted metabolites on functional activity of human neutrophils against the background of estriol effect]. AB - AIM: Study the effect of Escherichia coli acellular metabolites of various phases of development on phagocytic activity of neutrophils against the background of pregnancy hormone effect--estriol (E3). MATERIALS AND METHODS: E. coli K12 (wt) metabolites were selected at the end of adaptation and logarithmic growth phases by filtration after cultivation at 37 degrees C in LB broth. Neutrophils of heparinized venous blood of healthy non-pregnant women (follicular phase, n = 8) were incubated for 1 hour with E3 at 2 ng/ml and 20 ng/ml, then 30 minutes with E. coli metabolites, LB medium or Hanks' solution at 37 degrees C. Phagocytic activity evaluation was carried out by inhibition of bioluminescence of E. coli K12 TG1 lux+. RESULTS: Exometabolites of logarithmic growth phase of E. coli culture inhibited neutrophil phagocytosis after 40 - 60 minutes of incubation in contrast to metabolites of adaptation phase compared with LB medium. Neutrophil cultivation after hormone treatment in LB medium that has the ability to stimulate neutrophil phagocytosis compared with Hanks' solution did not alter their phagocytic activity. However inhibiting effect of E3 at 20 ng/ml on neutrophil phagocytosis compared with control was exhibited in Hanks' solution (at 50 - 60 minutes) and after the effect of E. coli adaptation phase metabolites (at 40 - 60 minutes). CONCLUSION: E3 at the level extrapolated from its level at III trimester of pregnancy could facilitate the reduction of antimicrobial potential of neutrophils at the early stages of growth of pathogenic microorganisms. PMID- 25536775 TI - [Th1/2-balance shift during acute graft-versus-host reaction developing against the background of experimental hyperlipidemia]. AB - AIM: Evaluate the effect of experimental hyperlipidemia on the intensity of development of acute graft-versus-host reaction (GVHR) in mice. MATERIALS AND METHODS: Half-allogenic system C57Bl/6 (C57Bl/6 x DBA/2)F1 was used as a laboratory model of acute GVHR. Experimental hyperlipidemia in mice-recipients was induced by repeated administration of poloxamer 407. RESULTS: Lethality in the group of mice with acute GVHR developing against the background of preceding hyperlipidemia was significantly higher (70% at day 50 of GVHR development) compared with control group with acute GVHR (50% lethality at day 50). Such effect on the degree of severity of acute GVHR induced under the conditions of hyperlipidemia is confirmed by a more pronounced destruction of thymus in mice of the group with previously induced hyperlipidemia. CONCLUSION: Preceding hyperlipidemia induced by administration of poloxamer 407 shifts Th1/2- balance in the development of acute GVHR towards Th1. Mechanisms of this effect and possible role of nuclear LXR receptors in regulation of immune reactions are discussed. PMID- 25536776 TI - [Application of multiplex-PCR for bifidobacteria and propionibacteria genus identification]. AB - AIM: Creation of a PCR test-system for determination of Actinobacteria class bacteria belonging to 2 genera that are the most widely represented among obligate anaerobic microbiota of human intestine: Bifidobacterium and Propionibacterium. MATERIALS AND METHODS: 8 strains of Bifidobacterium spp. and 6 strains of Propionibacterium genus were identified by morphologic, cultural and biochemical properties. Isolation of matrix DNA of the strains for PCR was carried out by "DNA-Express" kit (SPF "Lytech", Russia). Primers for determination of genus membership for obligate anaerobes were developed based on variability of 16S RNA gene by using "Lasergene 7.1" ("DNASTAR, Inc.", USA) program. PCR screening of the isolated DNA was carried out based on "Syntol" LLC primers and reagents. Amplicon detection was carried out by agarose gel electrophoresis. RESULTS: Multiplexing of 2 different primer pairs in a single probe at.68 degrees C annealing temperature for 30 cycles showed the presence of non-specific amplicons that form in samples with bifidobacteria DNA-matrix. The increase of annealing temperature to 70 degrees C and reduction of the number of PCR cycles to 25 resulted in the exclusion of formation of non-specific amplicons. Because the annealing temperature reached the level of values optimal for Taq-polymerase, a 2-phase PCR algorithm could be implemented. This solution allowed reducing the overall time of reaction to 45 minutes. Further increase of annealing temperature to 72 degrees C and reduction of elongation phase up to 15 seconds at 30 PCR cycles did not result in a visible reduction of reaction effectiveness: CONCLUSION: A rapid system for identification of Bifidobacterium and Pronionibacterium genera using a system of 2-phase multiple PCR was developed. The system is part of a screening system for identification of major genera and species of cultured obligate anaerobic bacteria isolated from human intestine biotopes. PMID- 25536777 TI - [Sensitivity to antibacterial preparations of Vibrio cholerae El Tor strains isolated from the environmental objects in Russia in 2005 - 2012]. AB - AIM: Analysis of antibiotic resistance profiles of Vibrio cholerae O1 strains isolated from the environmental objects in the territory of Russia in 2005 - 2012. MATERIALS AND METHODS: Antibiotocograms of 52 strains of V. cholerae were determined by serial dilution method in dense nutrient medium. Interpretation of the results was carried out in accordance with guidelines MI 4.2.2495-09 (2009). RESULTS: All the cultures turned out to be sensitive to tetracyclines, ciprofloxacin, cephalosporins: Isolates from Stavropol region were resistant to furazolidone (33.3%), trimethoprim/sulfamethoxazole (100%). Strains resistant to ampicillin, streptomycin, rifampicin (7%), furazolidone (43%), trimethoprim/sulfamethoxazole (100%) were isolated in Primorsky region. In Irkutsk region and Kalmykia--to furazolidone and trimethoprim/sulfamethoxazole (11 - 89%), ampicillin (8.3 - 11%). Analysis of antibioticograms gives evidence on the occurrence in the studied strains of 1 to 5 r-determinants of antibiotic resistance in various combinations. CONCLUSION: The data obtained give evidence on preservation of the tendency to expand the specter of antibiotic resistance in V. cholerae O1 isolated from environmental objects that necessitates a more rational and effective use of antibacterial preparations, determination of antiobioticogram for every isolated culture, strict bacteriologic control during the course of etiotropic therapy for the prevention of increase of number of resistant strains. PMID- 25536778 TI - [Immunogenic properties of experimental production series of Staphylovac-2 vaccine]. AB - AIM: Study experimental production series of Staphylovac-2 by accumulation of specific IgG and safety. MATERIALS AND METHODS: Experimental production samples of staphylococci vaccines were studied by the accumulation of specific IgG in sera of immunized BALB/c line mice in EIA. Safety was evaluated in tests of acute and chronic toxicity including pathomorphologic and histologic, hematologic and biochemical studies, studies of the effect on central nervous system. RESULTS: A statistically significant (2.6 - 3.0 times) increase of IgG levels in sera of immunized mice compared with control was noted. In the experiments studying acute and chronic toxicity the increase in body mass and mass of internal organs differed from data obtained from control animals at no observation periods. None of the studied methods of safety evaluation showed differences of the studied vaccine series from the control. CONCLUSION: The recommended dose for subcutaneous administration into human of 200 MUg is experimentally justified and could be the basis for carrying out clinical studies of staphylococci vaccines in humans. PMID- 25536779 TI - [Species structure and staphylococci bioprofile characteristics--ausative agents of perinatal infectious-inflammation pathology in children of Orenburg]. AB - AIM: Analysis of taxonomic structure and bioprofile of staphylcocci--causative agents of cutaneous and ophthalmic forms of perinatal infectious-inflammation pathology (IIP) in Orenburg neonates. MATERIALS AND METHODS: Bacteriologic study in 308 neonates with clinical signs of cutaneous and ophthalmic forms of perinatal IIP was carried out with isolation of microorganisms from lesions and their species (genus) identification by generally accepted methods. The presence of hemolytic, anti-lysozyme, activity, ability to form biofilms, resistance to antimicrobial cationic peptides of human leukocytes (intercid) and thrombocytes (trombodefensins), sensitivity to antibiotics were determined in the isolated staphylococci strains. RESULTS: Staphylococci dominated in the structure of causative agents of cutaneous and ophthalmic forms of perinatal IIP (76.2%) and among those coagulase-negative staphylococci had a priority position (82.4 +/- 3.4%). Staphylococci had a distinctive pathogenic potential and frequently had antibiotic resistance. CONCLUSION: Perinatal IIP is examined as a variant of endogenous bacterial infection. The necessity of microbiologic monitoring for development of effective approaches to therapy and prophylaxis of perinatal IIP is justified. PMID- 25536781 TI - [Biological models in studying of staphylococci enterotoxin toxicity]. AB - Enterotoxins--superantigens--are the main toxic agents of staphylococci. Currently, an important role of these proteins is estabished in both toxicity itself--toxic shock and in the development of autoimmune diseases. Enterotoxin studies are carried out in several directions including the search for novel molecular targets, studies in cell tests and establishment of toxicity in animal models. Methods of studying toxicity in animal models: monkeys, mice and rabbits are examined in the review. Methods of animal priming to achieve lethality, features of using various lines of mice during analysis of individual enterotoxins are discussed. Methods of studying enterotoxin-neutralizing compounds in animal models are discussed. PMID- 25536782 TI - [The role of technogenic and biological factors in spread of foodborne bacterial infections]. AB - Epidemiologic aspects of ecology of foodborne infection causative agents that have taken root in contemporary technogenic loci created by humans in urbocenoses which include agrocomplexes of animal breeding, vegetable growing in open and closed ground are discussed. Soil and water sources with a wide transport network where microorganisms dwell in the environment under favorable for vital functions and growth conditions (humus deposits, temperature regimen, optimal pH, associations with hydrobionts, biofilm formation) are potent secondary reservoirs of infection causative agents. Some molecular-genetic mechanisms of polyhostality of Gram negative bacteria and listeria are examined. PMID- 25536780 TI - [Formation of Enterobacter cloacae resistance to disinfectants under the effect of bactericidal concentrations of quaternry ammonium compounds in the experiment]. AB - AIM: Study the possibility of formation of induced resistance of purulent-septic infection (PSI) causative agents against disinfectants (DI) in bactericidal concentrations. MATERIALS AND METHODS: Daily exposure to bactericidal concentrations of preparations from the group of quaternary ammonium compounds (QAC) on Enterobacter cloacae strain that has incomplete sensitivity to the same disinfectants on the same test objects was carried out in experiments on test objects from wood and plastic. Exposure was carried out until the moment of transition from incomplete sensitivity to resistance. RESULTS: E. cloacae strain that initially had incomplete sensitivity to various disinfectants of the QAC group in antibacterial concentrations according to manuals acquires resistance on test objects from wood and plastic after 2 - 12 exposures to the preparations. CONCLUSION: The data obtained give evidence that the resistance of PSI causative agents to disinfectants can take place not only under the influence of low concentrations of the preparations but also during use of disinfectants at bactericidal concentrations. PMID- 25536783 TI - [Antimicrobial compounds of enterococci]. AB - The main studies of a group of antimicrobial compounds produced by Enterococcus genus bacteria: bacteriocins, organic acids, activated oxygen metabolites, enzymes, exopolysaccharides--are described in the review. Data on synergic interaction of these substances in killing of pathogens, formation of active substances from different components as a result of metabolic activity of enterococci are presented. Production of these compounds is a reflection of competitive habitation of bacteria under the conditions of multi-species microbiomes and ensures colonization resistance of host biotopes. A complementation of the group of bacterial antimicrobial compounds by compounds that do not have a direct effect on the growth of microorganisms but suppress pathogenic potential of infectious disease causative agents is assumed. PMID- 25536784 TI - [Effect of citicoline on the development of chronic epileptization of the brain (pentylenetetrazole kindling) and acute seizures reaction of kindled mice C57Bl/6]. AB - In experiments on mice C57Bl/6 was studied effects of citicoline (500 mg/kg, i.p.) on development of chronically epileptization of the brain- pentylenetetrazole (PTZ) kindling (30 mg/kg PTZ, i.p. during 24 days) and on acute generalized seizures (i.v., 1% solution of PTZ with the speed of 0.01 ml/s). It was shown that daily injection of citicoline an hour before the introduction of PTZ had no effect on development of chronically epileptization of the brain --PTZ-kindling (the latency of seizures appearance and their severity). However, citicoIine posses anticonvulsive effects on acute seizures in kindled mice. In animals with increased seizure susceptibility of the brain caused by kindling and severity of seizures 2-3 points injection citicoline after 14 days of kindling had anticonvulsive effect, increasing the threshold clonic seizures. Injection of citicoline during 24 days of kindled animals and severity of seizures 3-5 points caused the increase of thresholds as clonic and tonic phase of seizures with lethal outcome. Thus, the anticonvulsant effect of citicoline more pronounced in the long-term use. PMID- 25536785 TI - [Urgent changes in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in the neocortex of rats with different tolerance to acute hypoxia underwent focal ischemic stroke prefrontal cortex]. AB - Using immunohistochemical method, it was demonstrated that neurons of the cerebral cortex have the capacity to express hypoxia-inducible factor-1 alpha (HIF-1alpha) in normoxia. Intensity of this process is different for rats having unequal tolerance to hypoxia. Basal HIF-1alpha expression in neurons of rats with low-resistance (LR) to hypoxia is higher compared to rats with high-resistance (HR). Bilateral photochemically induced focal ischemic insult in the rat prefrontal cortex completely suppressed HIF-1alpha neuronal expression the in the ischemic zone and only partially--in the area of the penumbra. Neuronal injury was more pronounced in cortex of LR rats compared to HR rats. These findings suggest that functional significance of HIF-1alpha is greater in neurons of the cerebral cortex of LR rats compared to HR rats. PMID- 25536786 TI - [Shifts in subcellular content of blood serum and urine at asthma: animal model, clinic and monitoring data]. AB - We reproduced mouse model of bronchial asthma, evaluated metabolic shifts of serum homeostasis during disease development, and compared these results with the data on metabolic shifts in bronchial asthma patients. In experimental mice pronounced pathological changes in the lungs, considerable lymphocytosis and decrease in neutrophil count were detected. Metabolic shifts were studied using method of laser correlation spectroscopy (LCS) of blood serum and urine. Method of LCS allows determining the dispersion composition of the studied fluid by the relative contribution of particle components into light scattering. The relative content of particles of different size.characterizes the direction of metabolic shifts in the organism. Similar patterns of particle distribution in biological fluids of experimental animals and patients suggest that LCS can be used as an additional method for evaluation of the severity of the disease and efficiency of therapy. PMID- 25536787 TI - [Evaluate the activity of lipid peroxidation in men with obstructive breathing disorders during sleep in different age groups]. AB - The results of research on the state of lipid peroxidation (LPO) and the evaluation of the antioxidant status in 135 men aged 14 to 55 years with obstructive disorders of breathing during sleep (ONDS). The patients were divided into 4 age groups: 14-17 years, 18-22 years, 23-45 years and 46-55 years. Noting the relationship between the duration of hypoxia in ONDS the stages of adaptation to this pathological condition. PMID- 25536788 TI - [Restoration of respiratory function of an organism after cold oppressions without warming]. AB - In experiments on rats studied influence of intravenous introduction NazdTA on respiratory function of rats after the full termination of breath at deep hypothermia. It is shown that such method without warming application it is possible to lower on 1.5-2.0 degrees C a temperature threshold of approach full a cold paralysis of respiratory function of an organism. It confirms the hypothesis put forward earlier about an important role of infringement of balance of ions of calcium in cytoplasm of cells in development of a pathology of an organism at deep hypothermia. The received results can be used at resuscitation of victims accidental hypothermia. PMID- 25536789 TI - [The role of autonomic dysfunction in pathogenesis of irritable bowel syndrome]. AB - This article presents the results of a comparative study of autonomic disorders in patients with differernt types of irritable bowel syndrome (IBS). We used several clinical and instrumental methods, including the Veyn questionnaire, Kerdo autonomic index, skin sympathetic response and heart rate variability analysis. The results show a prevalence of sympathetic tone in all groups of patients (more pronounced in IBS with constipation), as well as an elevated stress index and decreased arterial baroreflex sensitivity. In the IBS with diarrhea group there was a reliable increase of power spectral density alvery low frequency and a lowered respiratory sinus arrhythmia. PMID- 25536790 TI - [The significance of different 5-HT-receptors in regulation of gastrointestinal motility]. AB - Serotonergic mechanisms are involved in many, if not all digestive functions of the gastrointestinal tract. A special role is played by serotoninergic structures in the neuronal control of motor activity. The study of these structures is of particular interest due to the widespread occurrence of irritable bowel syndrome, covering up to 20% of the adult population, which makes the research in this area up to date and in demand. Acute experiments were performed on 102 Wistar rats in 6 series. Experiments were carried out under general anesthesia (Nembutal, 60 mg/kg) and mechanical lung ventilation. Motor responses of the stomach, duodenum and ascending colon were studied to i.a. Serotonin adipate infusion (1 mg/kg) during joint blockade of sympathetic and parasympathetic chains of ANS, as well as on the background of the blockade of various 5-HT-receptors. Infusions of 5-HT blockers reduce the magnitude of motor responses in stomach, duodenum and colon in varying degrees. Based on these data found 5-HT(1b)-receptors are mainly located in enteric neurons. The distribution of 5-HT(2b-4)-receptor is heterogeneous: 5-HT(2b)-receptors are located in enteric neurons of the stomach and intestinal myocytes; 5-HT3-receptors localized in the ganglia supplying the stomach and colon and 5-HT4-receptors are mainly located in the smooth muscle of the stomach, duodenal and ascendent colon enteric neurons. PMID- 25536791 TI - [The opportunity to use combined stem cells transplantation for haemopoesis activation in the old and mature laboratory animals under the conditions of ionizing radiation]. AB - The objective of this work was to study the influence of combined transplantation of stem cells (multypotent mesenchimal stromal and hem poetic stem cells) on the haemopoesis of old and mature laboratory animals under the condition of ionizing radiation. The experiments were conducted on 48 white male mice with the body weight of 30 g, age of 3-4 months, and 48 male mice of 3 years of age and body mass of 50 g. The experiments for obtaining the MMSC and HSC cultures were conducted on 16 laboratory animals: female mice of 3-4 months of age and body mass of 30 g., 18 days gestation period. The control group was formed by the animals not under the ionizing radiation. The experimental group animals got the dose of 4 Gr. These animals also got MMSC and HSC mixture intravenously in the doses of 6 mln. c/kg. and 330 thousand cell/kg prospectively. The control group animals got the 0.9% NaCl - 0.2 ml. intravenously. The infusions were made 1 hour after radiation once. As the result of the experiment it was shown that under physiological conditions combined transplantation brings the erithropoesis activation, under the ionizing radiation conditions it brings the erythroid and granulocytopoesis activation. More over the combined MMSC and HSC transplantation gives cytoprotective action on the myeloid tissue due to decrease of cyto genically changed cells in the mature animals under the condition of ionizing radiation, but in the old animals this effect can be seen even under physiological condition. Conclusions: Combined transplantation of MMSC and GSC can be used in the mature and old laboratory animals under the conditions of ionising radiation for the haemopoesis activation. PMID- 25536792 TI - [The cognitive disorders and raised free-radical activity of a brain of posterity of rats-females with experimental chronic alcoholic pathology of a liver]. AB - It is established, that chronic alcoholic defeat of hepatobiliarity sistems leads to infringement of cognitive functions at posterity. At the given group of animals revealed distress of memory and ability to orientation in space in the conditions of Morris water maze is, the research behavior is oppressed. Besides, the animals, born from mothers with chronic alcoholic defeat of hepatobiliarity systems have raised free-radical activity, which plays an important role in maintenance of adaptive possibilities of a brain. PMID- 25536793 TI - [Influence of calcium and phosphate ions on the adsorption rate of alkaline phosphatase and some of serum proteins on the hydroxyapatite]. AB - Calcium ions accelerate selective adsorption of AP on HAP and phosphate ions inhibit it. Since the biological function of AP is in the synthesis of phosphate ions from organic phosphates, enzyme activity contributes to its adsorption on mineralized tissues HAP, which can be associated with the peculiarities of the action of the enzyme adsorbed compared with dissolved. Apparently, the selective adsorption of enzymes and signaling molecules in the extracellular matrix to produce the microenvironment necessary for cell differentiation and function of tissue. Sorbate composition determines the type of cell differentiation, which, in turn, determines the properties of the synthesized matrix. Thereby circuiting occurs a feedback loop, to maintain homeostasis of tissues. These results can be used to develop a biomimetic material for medicine as well as the fabrication of multilayer coatings with desired properties by means of controlled speed by selectively depositing colloidal particles (nanoparticles). In the case of anisotropic particles the layers it is possible to obtain particles not only one type, but also with their desired orientation in each layer of particles by creating localized sorbent binding sites. PMID- 25536794 TI - [Osteoimmunnology and periodontitis]. AB - Periodontal disease is a pathological condition that involves inflammation of the tooth supporting structures. Accumulated lines of evidence suggest that hyperimmune responses to periodontal bacteria result in the destruction of periodontal connective tissue and alveolar bone. In this review, we discuss several aspects of the immune-inflammatory host response that ultimately results in loss of alveolar bone and stimulates osteoclastogenesis. PMID- 25536795 TI - [Murine peritoneal neutrophil activation upon tungsten nanoparticles exposure in vivo]. AB - Two examples of tungsten carbide nanoparticles (d = 15 nm, 50 nm) and tungsten carbide nanoparticles with 8% cobalt (d = 50 nm) have been found to induce the neutrophil activation 3 h and 36 h after intraperitoneal administration in the doses 0.005; 0.025; 0.05; 0.25; 0.5; 1; 2.5 and 5 microgram per 1 gram body weight to FVB mice. Neutrophil activation was calculated based on the CD11b and S100 antigen expression. Effect of nanoparticles is bimodal for all tested examples. PMID- 25536796 TI - [Regeneration of neurons]. AB - Describes the development of ideas about the regeneration of neurons from the approval "neurons are not restored" to an avalanche stream of messages on neurogenesis. We analysing literature about four ways of neuron regeneration. 1- neurogenesis; 2--intracellular regeneration; 3--BMDC fusion with Purkinje neurons in transgenic experiment; 4--regional cortical cells fusion. In observed some tactical and methodological problems which appears in researches about regeneration. Describes the reasons about the place of these methods of regeneration in modemrnneuroscience. PMID- 25536797 TI - [Pathophysiological aspects of changing of metabolism in patients with severe mechanical trauma]. AB - The review presents contemporary look at the problem of the cascade of pathophysiological reactions in patients with severe mechanical trauma. In the article described in detail changes hormonal and metabolic parameters in this category patients. In severe cases this leads to the development the syndrome of hypermetabolism-hypercatabolizm. Patients with this syndrome have a resistance to the introduction of exogenous nutrients. Syndrome of hypermetabolism hypercatabolizm play a leading role in the pathogenesis of critical condition, it determines the outcome of the disease in general. The article studied in detail the pathogenesis of the processes occurring in critically ill patients, taking into account the pathogenetic mechanism of development are possible solutions to this complex issue. PMID- 25536798 TI - [Theories of immunity: history and development of ideas]. PMID- 25536799 TI - [Method in vivo study of the microcirculation in rat lung using a modified technique]. AB - A modifed technique that allows in vivo study microcirculation in the rat lungs using a special camera. Feature of the method is stable fixation of lung tissue, which prevents its displacement during the study. Imaged surface of the lung tissue (alveoli with surrounding them on all sides capillaries). PMID- 25536800 TI - Cognitive maps discovery--far-reaching implications for contemporary neuroscience. PMID- 25536801 TI - Cyclooxygenase-2 expression in cervical cancer. AB - BACKGROUND/AIM: Cyclooxygenase (COX) or prostaglandin H2 synthase is the first enzyme that catalyzes the first two steps in the biosynthesis of prostaglandins from arachidonic acid. The aim of the study was to determine the expression level of COX-2 in patients with cervical cancer and compare it with that in the control group with no cervical pathology. METHODS: The study included 76 patients divided into two groups: the control group--30 patients without histopathological changes and the group A--46 patients with cervical cancer, FIGO stage IB-IIA. Histopathological and immunohistochemical analyses were performed in these two groups of patients. RESULTS: In the control group, the expression of COX-2 was not confirmed compared to the group A of 26 (56.52%) patients. The expression of COX-2 showed a statistically significant difference in the presence oflymphocytic stromal infiltration (p = 0.0053). The expression of COX-2 was more pronounced in the stromal tissue without lymphocytic infiltration (80% vs. 20%). CONCLUSION: A higher expression of COX-2 in cervical carcinoma without stromal lymphocytic infiltration suggests a possible paradoxical effect of COX-2 in immunosuppression. Frequent COX-2 expression in the subgroup with poor prognostic histological parameters in the group A indicates the importance of COX-2 expression in the carcinogenesis of cervical cancer. PMID- 25536802 TI - Evaluation of conventional and digital radiography capacities for distinguishing dental materials on radiograms depending on the present radiopacifying agent. AB - BACKGROUND/AIM: The radiopacity of an endodontic material can considerably vary as measured on film and a digital sensor. Digital radiography offers numerous advantages over conventional film-based radiography in dental clinical practice regarding both diagnostic capabilities and postintervention procedures. The aim of this study was to investigate the capacity of conventional and charge-conpled device (CCD) based digital radiography to detect material on radiograph depending on the radio-pacifying agent present in the mate- rial. METHODS: Experimental cements were formulated by mixing Portland cement with the following radiopacifying agents: zinc oxide (ZnO), zirconium oxide (ZrO2), titanium dioxide (TiO2), barium sulphate (BaSO4), iodoform (CHI3), bismuth oxide (Bi2O3) and ytterbium trifluoride (YbF3). In addition, 5 endodontic materials comprising Endometh- asone, Diaket, N2, Roth 801 and Acroseal were investigated to serve as control. Per three specimens of each material were radiographed alongside an aluminum step wedge on film (Eastman Kodak Company, Rochester, NY) and a CCD based digital sensor (Trophy Radiologie, Cedex, France). Radiopacity values were calculated by converting the radiographic densities of the specimens expressed as a mean optical densities or mean grey scale values into equivalent thickness of aluminum. RESULTS: Two-way ANOVA detected no significant differences with respect to the imaging system (p > 0.05), but the differences were significant with respect to radiopacifier (p < 0.001) and the interaction of the two factors (p < 0.05). Paired t-test revealed significant differences between the methods used for pure Portland cement, all concentrations of BaSO4 and CHI3, 10% and 20% additions of ZrO2 and Bi2O3 and 10% and 30% additions of YbF3 (p < 0.05). CONCLUSION: The materials which incorporate CHI3 OR BaSO4 as radiopacifying agents are expected to be significantly more radiopaque on a digital sensor than on film. During clinical practice one should concern to the quality of contrast assessment obtained by digital according to conventional radiography. PMID- 25536803 TI - Highly selective vagotomy and gastrojejunostomy in the treatment of peptic ulcer induced gastric outlet obstruction. AB - BACKGROUND/AIM: The incidence of peptic ulcer-induced gastric outlet obstruction is constantly declining. The aim of this study was to present our results in the treatment of gastric outlet obstruction with highly selective vagotomy and gastrojejunostomy. METHODS: This retrospective clinical study included 13 patients with peptic ulcer-induced gastric outlet obstruction operated with higly selective vagotomy and gastrojejunostomy. A 3-year follow-up was conducted including clinical interview and upper gastrointestinal endoscopy on 1 and 3 years after the surgery. RESULTS: The most common preoperative symptom was vomiting (in 92.3% of patients). The mean preoperative body mass index was 16.3 +/- 3.1 kg/m2, with 9 patients classified preoperatively as underweight. There were no intraoperative complications, nor mortality. At a 3-year follow-up there was no ulcer recurrence. Delayed gastric emptying was present in 1, bile reflux in 2, and erosive gastritis in 1 patient. Two patients suffered from mild "dumping" syndrome. CONCLUSION: Higly selective vagotomy combined with gastrojejunostomy is a safe and easily feasible surgical solution of gastric outlet obstruction induced by peptic ulcer. Good functional results and low rate of complications can be expected at a long-term follow-up. PMID- 25536804 TI - Reliability of fine needle aspiration and ex tempore biopsy in the diagnosis of salivary glands lesions. AB - BACKGROUND/AIM: Interpretation of cytological material obtained by fine needle aspiration (FNA) of salivary glands is one of the most challenging areas in cytopathology. FNA is performed easily, it is minimally invasive, inexpensive, fast, reliable and provides valuable information to clinicians about the nature of the lesion and therapeutic modalities. Ex tempore diagnosis, frozen section (FS) is a diagnostic tool that is essential in determining the modalities of surgical treatment of lesions of the salivary glands. Today this method is used in determining the status of resection margins and infiltration of adjacent anatomical structures. The aim of this study was to present our experiences in the application of FNA and FS in the diagnosis of salivary gland lesions and to determine the sensitivity, specificity, predictive value, and diagnostic reliability of these methods. METHODS: The study included 36 patients. In all the patients, cytological analysis was done before surgery and histological analysis of the surgical material. In 23 of the patients the FS diagnostics was done. Then we compared FNA and FS findings with histopathological findings. RESULTS: Correlation of cytological and histological diagnosis showed sensitivity of 83.3%, specificity 96.67%, positive predictive value 83.3%, negative predictive value of 96.77% and diagnostic accuracy of 97.2%. Based on the relationship between FS diagnosis and histopathological diagnosis, the sensitivity was 100%, specificity 96.67%, while positive predictive value and diagnostic accuracy were 100% each. CONCLUSION: The study confirmed that FNA is a sensitive, reliable diagnostic method for differentiation of lesions of the salivary glands. In cases with no posibility to definite differentiation in FNA samples, and with the need to assess the resection margins and invasion of anatomical structures, it is recommended to use FS diagnostics. PMID- 25536805 TI - Cephalometric analysis of the middle part of the face in patients with mandibular prognathism. AB - BACKGROUND/AIM: The middle part of the face, that is the maxilla, has always been mentioned as a possible etiologic factor of skeletal Class III. However, the importance of the relationship of maxillary retroposition towards the cranial base is still unclear, although it has been examined many times. The aim of this study was to conduct cephalometric analysis of the morphology of maxilla, including the whole middle part of the face in patients with divergent and convergent facial types of mandibular prognathism, as well as to determine differences betweeen them. METHODS: Lateral cephalometric teleradiograph images of 90 patients were analyzed at the Dental Clinic of the Military Medical Academy, Belgrade, Serbia. All the patients were male, aged 18-35 years, not previously treated orthodontically. On the basis of dentalskeletal relations of jaws and teeth, the patients were divided into three groups: the group P1 (patients with divergent facial type of mandibular prognathism), P2 (patients with convergent facial type of mandibular pragmathism) and the group E (control group or eugnathic patients). A total of 9 cephalometric parameters related to the middle face were measured and analyzed: the length of the hard palate- SnaSnp, the length of the maxillary corpus--AptmPP, the length of the soft palate, the angle between the hard and soft palate--SnaSnpUt, the angle of inclination of the maxillary alveolar process, the angle of inclination of the upper front teeth, the effective maxillary length--CoA, the posterior maxillary alveolar hyperplasia--U6PP and the angle of maxillary prognathism. RESULTS: The obtained results showed that the CoA, AptmPP and SnaSnp were significally shorter in patients with divergent facial type of mandibular prognathism compared to patients with convergent facial type of the mandibular prognathism and also in both experimental groups of patients compared to the control group. SnaSnp was significantly shorter in patients with divergent facial type of mandibular prognathism compared to the control group, whereas SnaSnp was significantly smaller in patients with convergent facial type of mandibular prognathism compared to the control group. Additionally, there was a pronounced incisor dentoalveolar compensation of skeletal discrepancy in both groups of patients with mandibular prognathism manifested in the form of a significant upper front teeth protrusion, but without significant differences among the groups, while the maxillary retrognathism was present in most patients of both experimental groups. A pronounced UGPP was found only in the patients with divergent type of mandibular prognathism. CONCLUSION: The maxilla is certainly one of the key factors which contributes to making the diagnosis, but primarily to making a plan for mandibular prognathism treatment Accurate assessment of the manifestation of abnormality, localization of skeletal problems and understanding of the biological potential are key factors of the stability of/the results of surgical orthodontic treatment of this abnormality. PMID- 25536806 TI - Computer and experimental analyses of the stress state in the cement hip joint endoprosthesis body. AB - BACKGROUND/AIM: One of the possible complications after implantation of a cement hip-joint endoprosthesis is frac- ture in the endoprosthesis body. Fractures arise from overload or material fatigue of which an implant is made. The purpose of this research was to define the intensity of maximum stress and the positions of a critical cross-section in the endoprosthesis body. METHODS: Unilaterally changing forces which act on the hip joint during walking as well as the loads result in flexible deformations of the endoprosthesis body. Biomechanical analysis of the forces acting on the hip joint determine their direction and intensity, whereas on the basis of Gruen's classification of the endoprosthesis body loosening the level of fixation is established. The bodies of cement hip joint endoprosthesis are made of cobalt-chromium-molybdenum (CoCrMo) alloy, suitable for vacuum casting, are submitted to the analysis. Analysis of the critical stress in the endoprosthesis body was performed on the endoprosthesis body by means of the finite element method. The experimental verification of the obtained results was carried out on the physical prototype under laboratory conditions. RESULTS: Computer analysis, by means of the finite element method, determined the stress state by calculation of the maximum Von Mises stress and critical cross-sections for different angles of the resultant force action. The results obtained by the computer and experimental method correlate and are comparable to the results of similar analyses conducted on various endoprosthesis types. CONCLUSION: The analyses described in the paper make the basis for improving the process designing of hip joint endoprostheses and their customization to each individual patient (custom made). PMID- 25536807 TI - BCL10 aberations and NF-kappa B activation involving p65 are absent or rare in primary gastric MALT lymphoma. AB - BACKGROUND/AIM: Mucosa-associated lymphoid tissue (MALT) lymphoma accounts for 5 17% non-Hodgkin lymphomas (NHL). The molecular pathogenesis of MALT lymphomas is not well-established. The aim of this study was to evaluate immunohistochemically determined nuclear coexpression of BCL10 and NF-kappaB (NF-kappaB) in tumor cells of gastric MALT lymphoma and its impact on the patogenesis and outcome of the disease. METHODS: Medical records of 35 patients with newly diagnosed gastric MALT lymphoma were analyzed and biopsy specimens were immunostained for BCL10 and NF-kappaB expression (p65 subunit). RESULTS: The median age of 35 patients diagnosed with gastric MALT lymphoma was 63.5 years (male/female = 21/14). Symptoms were present in 23/35 (65.7%) patients with the weight loss as the most common symptom. Gastric MALT lymphomas were usually localized in the stomach corpus and corpus and antrum (45.7% and 31.2%, respectively). H. pylon infection was confirmed in 20 out of 30 (66.7%) patients. Treatment options were as follows: immunochemotherapy in 10 (28.5%) patients, surgery in 9 (25.8%) patients, combined surgery and chemotherapy in 14 (40%) patients and supportive measures in 2 (5.7%) patients. Complete remission was achieved in 13 (37.10/) patients and partial remission in two (5.7%/) patients. Sixteen (45.7%/) patients had disease progression (p < 0.001). Cytoplasmatic expression of BCL10 in tumor cells was detected in 19 (54.3%) specimens. Nuclear expression was detected in no specimen. Cytoplasmic expression of NF-kappaB was present in 22 (65.7%) specimens, but nuclear expression was not detected in any specimens. CONCLUSION: Nuclear expressions (activation)of NF-kappaB p65 subunit and BCL10 were not detected in specimens of gastric MALT lymphoma. The correlation of nuclear coexpression of BCL10 and NF-kappaB in gastric MALT lymphoma was not established. These results indicate that other mechanisms and signal pathways are active in lymphogenesis of gastric MALT lymphoma, as that apoptotic inhibition is not the main, nor the only mechanism in tumorogenesis. PMID- 25536808 TI - Surgical treatment and dilemmas in the treatment of basal cell carcinomas with intracranial propagation. AB - BACKGROUND/AIM: Basal cell carcinoma (BCC) is one of the most common malignant skin tumors on the head in 90% of cases and is characterized by a high local infiltrating potential and destructive growth. The aim of this study was to show the characteristics of a correlation between pathohistological types of basal cell carcinoma and the size of this lesion, aggressiveness and infiltration of basal cell carcinoma, and its effect on the course of the therapy. METHODS: We analyzed 27 patients operated on for BCC that affected the scalp and the bone. We described and considered the clinical characteristics (size, depth of invasion), duration and speed of intracranial propagation and then made comparison with the type of BCC. We described the extent of surgical treatment and the width of excision to determine the best course of the treatment. The patients went through examinations during the next three years. RESULTS: According to the histopathological type the most common tumors were: infiltrative (60.2%), noduloinfiltrative (37.2%), and morpheaform (2.6%). Tumors were clinically manifested as ulcerative lesions, ulcus rodens and ulcus terebrans. Tumor diameters ranged from 2 to 25 cm. The depth of intracranial propagation depended on the histological type and tumor size. Most relapses (35%) occurred with morpheaform type of BCC. In 17 of the cases, BCC affected the bone without intracranial propagation. In 10 of the cases, basalioma infiltrated intracranial space--in 8 of the cases it infiltrated the dura and in 6 of the cases the brain parenchyma, of which in two of them, the superior sagittal sinus was affected and had to be surgically tied off. CONCLUSION: The aggressiveness and infiltration of basal cell carcinoma into the brain parenchyma is directly linked to the histological type and the size of the tumor. The larger the basalioma or if histopathological findings confirm morpheaform type of basalioma the larger surrounding healthy tissue, sometimes more than 3 cm in diameter, needs to be removed. In cases of these tumors postoperative radiotherapy is recommended. PMID- 25536809 TI - The importance of sleep apnea index determination using 24 h ECG analysis in patients with heart rhythm disorders. AB - BACKGROUND/AIM: A possible cause of malignant heart rhythm disorders is the syndrome of sleep apnea (periodic cessation of breathing during sleep longer than 10 seconds). Recent 24 h ECG software systems have the option of determination ECG apnea index (AI) based on the change in voltage of QRS complexes. The aim of the study was to determine the significance of AI evaluation in routine 24-hour Holter ECG on a group of 12 patients. METHODS: We presented a total of 12 consecutive patients with previously documented arrhythmias and the history of breathing disorders during night. They were analyzed by 24 h ECG (Medilog AR 12 plus Darwin), that is able to determine AI. RESULTS: We presented a case series of 12 patients, 8 men and 4 women, mean age 58.75 years and the average AI 5.78. In the whole group there was a trend of increasing prevalence of complex rhythm disorders with increasing of AI and increased frequency of arrhythmias in the night phase vs. day phase. CONCLUSION: Determination of AI using routine long term (24 h) ECG analysis is important because sleep apnea can be successfully treated as an etiological or contributing factor of arrhythmias. PMID- 25536810 TI - Health care economics in Serbia: current problems and changes. AB - One of the fundamental rights of every human being is to enjoy "the highest attainable standard of health". Achieving better health requires no only adequate medical knowledge and technologies, laws and social measures in the field of health care, but also sufficient funding for fulfilling people's right to health. However, economic crisis has left every community with limited possibility of investing in health care and forced them to use the available resources more efficiently. This is the reason why health financing policy represents an important and integral part of the health system concerned with how financial resources are generated, allocated and used. Development of new drugs and medical technologies, population aging, increased incidence of chronic diseases as well as the peoples' rising demands from health care providers lead to a constant increase of health system costs worldwide. In these circumstances, countries in transition, like Serbia, face difficult challenges in financing their health systems. Current economic crisis and budget constraints do not allow the Government to simply allocate more public revenues for health and solve the people's expectations by increasing the spending. Instead, Serbia is forced to start reforms to provide a more efficient health system. The reform processes are positioned within the wider context of European integration and public administration reforms. This paper provides a short description of the health care system in Serbia focusing on the healthcare economics and reforms and their influence on financial sustainability. PMID- 25536811 TI - Understanding sensitivity, specificity and predictive values. PMID- 25536812 TI - Syncope as initial symptom of ostial lesion of the left main coronary artery with cardiogenic shock. AB - INTRODUCTION: Syncope represents a relatively atypical symptom of acute coronary syndrome. Syncope itself does not provide enough information to indicate an acute coronary event, especially a lesion of the left main coronary artery, without malignant rhythm and conduction disorders. CASE REPORT: A male patient, aged 63, was admitted to the intensive cardiac care unit because of a short loss of consciousness, in sinus tachycardia, with signs of acute heart failure and being hypotensive. Electrocardiogram showed a possible acute anterior myocardial infarction, followed by cardiogenic shock and emergency coronary angiography (subocclusive ostial lesion of the left main coronary artery) and primary percutaneous coronary intervention with intra-aortic balloon pump therapy was performed. A direct drug eluting stent was implanted with the optimal primary result. CONCLUSION: The prompt diagnosis, especially in such relatively atypical clinical presentation, reperfusion therapy with primary percutaneous coronary intervention in acute myocardial infarction complicated by cardiogenic shock, contribute to the improvement in the survival rate and patient's quality of life. This case report is clinically educative due to relatively atypical presentation and performed interventions. PMID- 25536813 TI - Transluminal Nd:YAG laser embolysis--a reasonable method to reperfuse occluded branch retinal arteries. AB - INTRODUCTION: Central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO) result in partial or complete retinal ischemia and sudden loss of vision; at this moment, there is no effective therapy for CRAO and BRAO. Transluminal Nd:YAG laser embolysis (TYE) represents a therapeutic approach used for retinal vascular occlusive diseases. The main indication is branch retinal artery occlusion with visible embolus; for central retinal artery occlusion this tehnique is hardly applicable. The principle of this method consists of intravascular embolus breakage using the 1064 nm Nd:YAG laser, focused on the embolus surface. CASE REPORT: We presented 5 cases with BRAO, 3 with infero temporal and 2 with supero-temporal BRAO, all of them treated with TYE, with variable results. All the patients had a visible embolus within the BRA, the laser applications being delivered directly to the embolus. CONCLUSION: Despite our short-term experience regarding this therapeutical approach, we can resume that the moment of emboli distruction, as close as possible to the onset of the occlusion, is decisive for regaining vision and that applying the procedure correctly is superior to observation in most cases. Worldwide experience with TYE is still limited, but the technique seems feasible also when treating CRAO caused by visible emboli on the optic disc surface. This most certainly calls for random trials for identifying precisely the role of TYE in treatment of retinal occlusion pathology, though the relatively small number of properly diagnosed cases affects this objective. In all cases, the risks of TYE must be weighed against the possibility of severe and permanent loss of vision secondary to retinal artery occlusions. PMID- 25536815 TI - Dysplasia epiphysealis hemimelica: a case report. AB - INTRODUCTION: Dysplasia epphysealis hemimelica, also known as Trevor's disease, is an extremely rare skeletal developmental disorder of unknown etiology, characterized by an osteocartilaginous outgrowth of one or more epiphyses or of a tarsal bone during childhood. CASE REPORT: We presented a sporadic case of dysplasia Epipysealis hemimelica developed in the talus. A 6-year-old boy complained of swelling of his right ankle joint, with painful and reduced movements. Radiographies suggested excessive overgrowth of the dorsomedial aspect of the talus. The tumor was surgically excised and the gross and histological findings were consistent with those of osteochondroma. CONCLUSION: Dysplasia epphysealis hemimelica is diagnosed by clinical, radiographic and histopathological examination. Early diagnosis is important for the condition to be treated before the deformity becomes disabling. PMID- 25536814 TI - The first case of papillary thyroid carcinoma in an adolescent with congenital dyshormonogenetic hypothyroidism in Serbia. AB - INTRODUCTION: Differentiated thyroid carcinoma (DTC) is a rare childhood malignancy, as it represents 0.3-0.4% of pediatric malignancies. Papillary carcinoma is the most common type of pediatric DTC and it represents about 90% of all DTC patients. Although rare, DTC arising from dyshormonogenetic goiter is the most serious complication of congenital hypothyroidism. CASE REPORT: We presented the development of thyroid papillary carcinoma in a 15-year-old girl diagnosed with congenital dyshormonogenetic hypothyroidism at neonatal age. Considering the early initiation and proper dosage of hormonal substitution, normal levels of thyreotropin and thyroid hormones were achieved quickly and maintained through a follow-up period. The girl remained euthyroid and asymptomatic until 13.8 years of age, when she presented with a large multinodular goiter. The patient underwent total thyroidectomy. Pathological examination revealed intrathyroid microcarcinoma in the right lobe. CONCLUSION: Although differentiated thyroid carcinoma is a rare pediatric malignancy, it is of great importance to have a certain degree of clinical caution and provide a multidisciplinary approach during the follow-up of patients with dyshormonogenetic hypothyroidism. PMID- 25536816 TI - [Genetic transformation of the moss Ceratodon purpureus by novel polycationic carriers of DNA]. AB - There is a big progress in application of genetic engineering for improving the biological properties of different organisms. Viral and non-viral carriers are used for delivery of genetic material into target cells. Nanoscale polymeric materials of natural and synthetic origin are the most promising gene delivery agents. These polymers have demonstrated high efficiency of DNA delivery into the mammalian cells, although they were not very effective in plant cells. Here, the procedure for genetic transformation of Ceratodon purpureus (Hedw.) Brid. moss protoplasts is described. Method is based on the application of novel surface active polymeric carriers of the polyDMAEM structure and controlled length and charge. It allows obtaining more transient and stable moss transformants per microgram of plasmid DNA when compared with known protocol based on using polyethyleneglycol. It is easier, more convenient, and cheaper than the "gene gun" method. Perspectives for further improvement of structure and functional characteristics of novel polymeric carriers are considered for delivery of genetic material into plant cells. PMID- 25536817 TI - [Analysis of nucleotide sequences of cytochrome C oxidase I (CO1) gene of mtDNA of Arctic Liopsetta glacialis and striped Liopsetta pinnifasciata flounder (Pleuronectidae) of the Sea of Okhotsk]. AB - The first data on nucleotide sequences of cytochrome C oxidase I (CO1) gene of Arctic and striped flounders of the Sea of Okhotsk are analyzed. Nucleotide diversity of CO1 gene for 10 individuals of arctic flounder (pi = 0,00370) is slightly less than that for 28 individuals of a striped flounder (pi = 0,00446), caught in the Taui Lip, the Sea of Okhotsk. The size of the disparity index found on variability of nucleotides at individuals of a polar flounder indicates not selective nature of replacements, whereas at individuals of a striped flounder about a third of replacements is selective. The size of nucleotide distinctions between individuals arctic and striped flounders confirms the specific status of these fishes. PMID- 25536818 TI - Conformation of phylogenetic relationship of Penaeidae shrimp based on morphometric and molecular investigations. AB - Understanding of accurate phylogenetic relationship among Penaeidae shrimp is important for academic and fisheries industry. The Morphometric and Randomly amplified polymorphic DNA (RAPD) analysis was used to make the phylogenetic relationsip among 13 Penaeidae shrimp. For morphometric analysis forty variables and total lengths of shrimp were measured for each species, and removed the effect of size variation. The size normalized values obtained was subjected to UPGMA (Unweighted Pair-Group Method with Arithmetic Mean) cluster analysis. For RAPD analysis, the four primers showed reliable differentiation between species, and used correlation coefficient between the DNA banding patterns of 13 Penaeidae species to construct UPGMA dendrogram. Phylogenetic relationship from morphometric and molecular analysis for Penaeidae species found to be congruent. We concluded that as the results from morphometry investigations concur with molecular one, phylogenetic relationship obtained for the studied Penaeidae are considered to be reliable. PMID- 25536819 TI - [ISSR analysis of some species of angustifoliate fescue]. AB - Using ISSR analyses genetic relationships were studied between the populations of the next species of angustifoliate fescue: F. macutrensis, F. rupicola, F. arietina, F. valesiaca, F. pallens, F. psammophila and F. brevipila. High level of ISSR loci polymorphism (average 92.9%) was shown. The species specific amplicon was revealed for F. valesiaca as well as the common fragment was identified for two related species--F. pallens and F. psammophila. On the basis of NJ analyses the differentiation of species was confirmed on such large aggregates as F. glauca agg. and F. valesiaca agg. More clear differentiation of the species was shown for F. glauca agg., while for F. valesiaca agg. we have not found any regularity of genetic relations among the species that represent this aggregate. PMID- 25536820 TI - [Genetic polymorphism of Gentiana lutea L. (Gentianaceae) populations from Chornohora Ridge of Ukrainian Carpathians]. AB - The features of genetic structure and level of diversity were investigated for G. lutea populations from Chornohora Ridge of Ukrainian Carpathians using RAPD- and ISSR-PCR. We have shown a high level of genetic diversity for investigated populations. The differences between populations account for 59-72% of the total genetic variation, whereas intrapopulation polymorphism makes up 28-41%. The relationships among genetic variability level and ecological-geographical conditions as well as biological features of the species were assumed to be possible. The obtained results indicate the genetic isolation of G. lutea Chornohora populations from Ukrainian Carpathians. Pozhyzhevska agropopulation was characterized by a high level of polymorphism that means the possibility to use artificial plantings of the investigated species for its conservation. PMID- 25536821 TI - P element temperature-specific transposition: a model for possible regulation of mobile elements activity by pre-mRNA secondary structure. AB - P element is a DNA transposon, known to spread in genome using transposase activity. Its activity is tissue-specific and normally observed at high temperatures within 24 degrees C to 29 degrees C. Here, we present a predicted RNA secondary structure domain of P element pre-mRNA which could potentially regulate the temperature sensitivity of the P element activity. In canonical P elements, the structure is a small hairpin with double-helical part interrupted by a symmetric loop and a mismatch. In M type P elements, the A.A mismatch is substituted by an A-U base pair, stabilizing the structure. The hairpin structure covers the region involving the IVS-3 5' splice site and both pseudo-splice sites F1 and F2. While the IVS-3 and F1 binding sites of U1 snRNA are located in the double-stranded part of the structure, the F2 site is exposed in the hairpin loop. The formation of this structure may interfere with landing of U1 snRNA on IVS-3 site, while F2 is positioned for the interaction. Alignment of P element sequences supports the proposed existence of the hairpin, showing high similarity for this region. The hairpin structure, stable at low temperatures, may prevent correct IVS-3 splicing. Conversely, temperature-induced destabilization of the hairpin structure may result in the splicing at the proper IVS-3 splice site. Taking into account the increasing amount of data demonstrating the important influence of RNA folding on phenotypes determined by alternative splicing a model for possible regulation of the activity of mobile elements by pre-mRNA secondary structure seems intriguing. PMID- 25536822 TI - [Determination of molecular glioblastoma subclasses on the basis of analysis of gene expression]. AB - Two glioblastoma groups, which are distinguished from each other by expression level of 416 genes (P < 0.05), were determined using a mathematical model of linear Boolean programming on the basis of gene expression data, obtained by microarray analysis of the glioblastomas and available in Gene Expression Omnibus (GEO) data base. The expression level of 15 genes was more than two-fold higher in the first group of glioblastoma (80 samples) in comparison with the second group (144 samples) and 401 genes and--more than two-fold lower as compared to the second group. 10 of 15 genes, which expression level prevailed in the first group, encode the proteins involved in cell cycle regulation and cell proliferation. A significant percentage of 401 genes are the genes that encode proteins involved in the functioning of neural cells and participating in the processes such as synaptic transmission, neurogenesis, the formation of myelin sheath, axon formation. Kohonen map, built on the basis of the data of 15 genes with prevailed expression in the first group and 60 (of4 01) genes, whose expression level elevated in the second group, confirmed the existence of two glioblastoma groups with specific gene expression profiles. Distribution of the glioblastomas into two groups may reflect two pathways of astrocytic glioma development, one of which leads to the formation of tumors with higher levels of gene expression, which protein products are involved in cell cycle regulation and proliferation. On the other hand, the existence of two molecular variants may reflect different states of glioblastoma progression. PMID- 25536823 TI - Combined influence of teichoic acids from Staphylococcus aureus and heterometallik Cu/Cd ethylenediamine complex on peritoneal macrophages and tumor cells. AB - We investigated the effects of teichoic acid (TA) from Staphylococcus aureus Wood 46 on tumor growth and metastasis of the experimental Lewis lung carcinoma (LLC) in mice. Intranasal administration of TA alone aggravated both tumor growth and metastasis, whereas combined administration of TA with a synthetic bimetallic (copper : cadmium) ethylene diamine complex PO244 resulted in pronounced antitumor and antimetastatic effects. The group of animals subjected to the combined treatment with TA and PO244 manifested the highest degree of lymphocyte infiltration into the tumor tissue, compared to the control group and those exposed to TA or PO244 alone. Moreover, the combined treatment negatively affected the adhesive properties of peritoneal macrophages in the LLC bearing mice. Co-cultivation of the isolated macrophages with primary LLC cultures revealed significant (p < 0.05) cytotoxic and cytostatic effects, detected as an increased level of apoptosis and a reduced fraction of replicating cells. PMID- 25536824 TI - [Micronucleus test of human oral buccal epithelium: problems, progress and prospects]. AB - The articles by russian and foreign authors for the period from 2000 to 2012, devoted to the problems of application, analysis and interpretation of the results of micronucleus test in human buccal epithelium has been analyzed in the review. Nuclear abnormality founding in the cells of the oral mucosa has been described. The paper summarizes works devoted to the analysis of the influence of the micronucleus test methods (painting, taking scrapings) to its results. Modern opinions about the factors of different etiology (sex, age, genotype, psycho physiological characteristics, immune status, diseases of different etiology, man made pollution, climatic and geographical conditions, ionizing and nonionizing radiation, chemical compounds (drugs, dietary supplements, androgenic steroids, etc.), dental fillings, occupational exposures, alcohol, using tobacco blends) inducing the estimation of nuclear aberration has been summarized as a scheme. The problems and unresolved issues related to the peculiarities of micronucleus test has been noted. PMID- 25536825 TI - [Patient-centered care: the network]. PMID- 25536826 TI - [Vulnerable older patients in primary care how to identify them? Which ressources to mobilize? ]. AB - Trust is essential to foster and preserve a long-term relationship between primary care physicians and their patients suffering from chronic diseases. However, this relation remains insufficient to successfully manage more complex situations, such as those of older patients with multiple diseases and disability. For the primary care physician, a significant limitation is the time required to plan and coordinate interventions supplied by different health and social care providers. This article describes a structured approach to support primary care physicians in this difficult task and help them to identify vulnerable older patients requiring to mobilize and coordinate health and social care resources. Current and future resources available to family physicians to complete this challenging task are further described. PMID- 25536827 TI - [Pneumonia in the elderly: are there any specificities? ]. AB - Pneumonia is one of the leading causes of death in the elderly. Streptococcus pneumoniae is the leading etiological agent, but the identification of a pathogen remains infrequent despite advances in microbiological methods. Antibiotic resistant organisms should be considered as potential causal agents in recently hospitalized patients and patients with recent antibiotic exposure and influenza during the flu season. The clinical diagnosis is difficult due to frequent atypical presentation. Prognostic scores are not always appropriate to predict the need for hospitalization in very old patients. Studies on the role of low dose chest CT for the diagnosis, management and prevention should help improve the management of this disease in the future. PMID- 25536828 TI - [Hip fracture: call the geriatrician? ]. AB - Hip fracture management by the geriatrician demands a close cooperation with orthopedic surgeons and a interdisciplinary approach with the implementation of protocole-driven care to standardize the care of most patients. From admission to discharge this orthogeriatric management is based on the comprehensive geriatric assessment to reduce the delays in surgery, the occurence of delirium or the most postoperative complications. This collaborative model of care seems to have the potential to improve function, admissions to nursing homes and mortality outcomes compared with usual care of geriatric patient with hip fracture. PMID- 25536829 TI - [Diabetes and dementia: the dangerous liaisons? ]. AB - As population ages, a growing number of older patients present the constellation of diabetes and dementia. Numerous recent studies highlight that diabetes may increase the risk for Alzheimer and vascular dementia. Among patients with previous severe hypoglycemia, that risk may even double. Inversely demented patients have about three times higher risk of hypoglycemia. Given that spiral link between hypoglycemia and dementia, the latter should be considered as a possible complication of diabetes and consistently be screened for among older diabetic patients. Furthermore, the American Diabetes Association and American Geriatric Society consensus recommends a more flexible glycemic treatment goal of AIC among demented patients, with a target range between 8 and 9%. PMID- 25536830 TI - [Constipation in the elderly, which specificities? ]. AB - Although constipation is very common in the geriatric population of both sexes, its importance is often underestimated as older people complain less frequently of rare stools compared to younger adults. The diagnostic approach includes an assessment of risk factors and associated pathologies specific to old age. The initial treatment is conservative, behavioral and pharmacological, in the absence of signs of severity. In case of initial treatment failure, investigations or specialized treatment will depend on individual situations. PMID- 25536831 TI - [Preoperative assessment in elderly patients]. AB - Age-related physiological changes and comorbidities affect older patients' tolerance to surgery. Pre-operative assessment in these patients requires, beside the usual physical evaluation, the systematic screening of common geriatric syndromes. Cognitive, gait and balance, nutritional, and functional impairments, all flag patients at higher risk for per- and postoperative complications. Preoperative assessment is an opportunity to detect these syndromes and propose preventative interventions (physical therapy, nutritional and cognitive support measures) likely to reduce the incidence of postoperative morbidity. PMID- 25536832 TI - [Electives during preclinical medical curriculum: the Geneva experience ]. AB - Electives have come of age in Medical Schools throughout Europe since the Bologna Guidelines were issued. At the Faculty of Medicine of Geneva its importance was recognized early to satisfy the students' curiosity, enlarge their visions, or deepen their knowledge in certain aspects of their curriculum. It was therefore decided to develop a great number of different electives ranging from basic biomedical research to emblematic clinical syndromes and humanitarian medicine for 2nd and 3rd year Bachelor students. The Electives taken have to be validated through specific examinations corresponding to 10% of the yearly ECTS credits. The experience has so far been a success, with high satisfaction as well of the student as of the teacher body. A major challenge for the future will be opening further these Electives to other Faculties and other professions. PMID- 25536833 TI - [Mad cow disease and new form of Creutzfeldt-Jakob disease: state of the art]. PMID- 25536834 TI - [Vacations?]. PMID- 25536836 TI - [Ethics and end of life in France: two scandals and three major stakes]. PMID- 25536835 TI - [What's the best treatment for varicose veins: surgery, sclerotherapy with hydrogel or laser?]. PMID- 25536837 TI - [Postponing gluten consumption delays celiac disease but does not prevent it]. PMID- 25536838 TI - [Ebola: how to repatriate contaminated health care providers?]. PMID- 25536839 TI - [Towards a national cancer registry creation]. PMID- 25536840 TI - [TarMed: The federal administrative tribunal is not taking sides in H+ hospital fees litigation]. PMID- 25536841 TI - [Health: from perfect citizen to concerned citizen]. PMID- 25536842 TI - Effects of age of learning on voice onset time: categorical perception of Swedish stops by near-native L2 speakers. AB - This study examined the effects of age of onset (AO) of L2 acquisition on the categorical perception of the voicing contrast in Swedish word-initial stops varying in voice onset time (VOT). Three voicing continua created on the basis of natural Swedish word pairs with /p-b/, /t-d/, /k-/ in initial position were presented to 41 Spanish early (AO < 12) and late (AO > 12) near-native speakers of L2 Swedish. Fifteen native speakers of Swedish served as controls. Categorizations were influenced by AO and listener status as L1/L2 speaker, in that the late learners deviated the most from native-speaker perception. In addition, only a small minority of the late learners perceived the voicing contrast in a way comparable to native-speaker categorization, while most early L2 learners demonstrated nativelike categorization patterns. However, when the results were combined with the L2 learners' production of Swedish voiceless stops (Stolten, 2005; Stolten, Abrahamsson & Hyltenstam, in press), nativelike production and perception was never found among the late learners, while a majority of the early learners still exhibited nativelike production and perception. It is concluded that, despite their being perceived as mother-tongue speakers of Swedish by native listeners, the late learners do not, after detailed phonetic scrutiny, exhibit a fully nativelike command of Swedish VOT. Consequently, being near-native rather than nativelike speakers of their second language, these individuals do not constitute the evidence necessary to reject the hypothesis of one or several critical (or sensitive) periods for language acquisition. PMID- 25536843 TI - The early phase of /see symbol/ production development in adult Japanese learners of English. AB - Although previous research indicates that Japanese speakers' second language (L2) perception and production of English /see symbol/ may improve with increased L2 experience, relatively little is known about the fine phonetic details of their /see symbol/ productions, especially during the early phase of L2 speech learning. This cross-sectional study examined acoustic properties of word-initial /see symbol/ from 60 Japanese learners with a length of residence of between one month and one year in Canada. Their performance was compared to that of 15 native speakers of English and 15 low-proficiency Japanese learners of English. Formant frequencies (F2 and F3) and F1 transition durations were evaluated under three task conditions--word reading, sentence reading, and timed picture description. Learners with as little as two to three months of residence demonstrated target like F2 frequencies. In addition, increased LOR was predictive of more target like transition durations. Although the learners showed some improvement in F3 as a function of LOR, they did so mainly at a controlled level of speech production. The findings suggest that during the early phase of L2 segmental development, production accuracy is task-dependent and is influenced by the availability of L1 phonetic cues for redeployment in L2. PMID- 25536844 TI - White bear effects in language production: evidence from the prosodic realization of adjectives. AB - A central problem in recent research on speech production concerns the question to what extent speakers adapt their linguistic expressions to the needs of their addressees. It is claimed that speakers sometimes leak information about objects that are only visible for them and not for their listeners. Previous research only takes the occurrence of adjectives as evidence for the leakage of privileged information. The present study hypothesizes that leaked information is also encoded in the prosody of those adjectives. A production experiment elicited adjectives that leak information and adjectives that do not leak information. An acoustic analysis and prominence rating task showed that adjectives that leak information were uttered with a higher pitch and perceived as more prominent compared to adjectives that do not leak information. Furthermore, a guessing task suggested that the adjectives' prosody relates to how listeners infer possible privileged information. PMID- 25536845 TI - Dynamic spectral structure specifies vowels for adults and children. AB - The dynamic specification account of vowel recognition suggests that formant movement between vowel targets and consonant margins is used by listeners to recognize vowels. This study tested that account by measuring contributions to vowel recognition of dynamic (i.e., time-varying) spectral structure and coarticulatory effects on stationary structure. Adults and children (four- and seven-year-olds) were tested with three kinds of consonant-vowel-consonant syllables: (I) unprocessed; (2) sine waves that preserved both stationary coarticulated and dynamic spectral structure; and (3) vocoded signals that primarily preserved that stationary, but not dynamic structure. Sections of two lengths were removed from syllable middles: (I) half the vocalic portion; and (2) all but the first and last three pitch periods. Adults performed accurately with unprocessed and sine-wave signals, as long as half the syllable remained; their recognition was poorer for vocoded signals, but above chance. Seven-year-olds performed more poorly than adults with both sorts of processed signals, but disproportionately worse with vocoded than sine-wave signals. Most four-year-olds were unable to recognize vowels at all with vocoded signals. Conclusions were that both dynamic and stationary coarticulated structures support vowel recognition for adults, but children attend to dynamic spectral structure more strongly because early phonological organization favors whole words. PMID- 25536846 TI - Multiple functional units in the preattentive segmentation of speech in Japanese: evidence from word illusions. AB - We explored the functional units of speech segmentation in Japanese using dichotic presentation and a detection task requiring no intentional sublexical analysis. Indeed, illusory perception of a target word might result from preattentive migration of phonemes, morae, or syllables from one ear to the other. In Experiment I, Japanese listeners detected targets presented in hiragana and/or kanji. Phoneme migrations did occur, suggesting that orthography independent sublexical constituents play some role in segmentation. However, syllable and especially mora migrations were more numerous. This pattern of results was not observed in French speakers (Experiment 2), suggesting that it reflects native segmentation in Japanese. To control for the intervention of kanji representations (many words are written in kanji, and one kanji often corresponds to one syllable), in Experiment 3, Japanese listeners were presented with target loanwords that can be written only in katakana. Again, phoneme migrations occurred, while the first mora and syllable led to similar rates of illusory percepts. No migration occurred for the second, "special" mora (/J/ or/N/), probably because this constitutes the latter part of a heavy syllable. Overall, these findings suggest that multiple units, such as morae, syllables, and even phonemes, function independently of orthographic knowledge in Japanese preattentive speech segmentation. PMID- 25536848 TI - Language familiarity, expectation, and novice musical rhythm production. AB - The music of expert musicians reflects the speech rhythm of their native language. Here, we examine this effect in amateur and novice musicians. English- and French-speaking participants were both instructed to produce simple "English" and "French" tunes using only two keys on a keyboard. All participants later rated the rhythmic variability of English and French speech samples. The rhythmic variability of the "English" and "French" tunes that were produced reflected the perceived rhythmic variability in English and French speech samples. Yet, the pattern was different for English and French participants and did not correspond to the actual measured speech rhythm variability of the speech samples. Surprise recognition tests two weeks later confirmed that the music-speech relationship remained over time. The results show that the relationship between music and speech rhythm is more widespread than previously thought and that musical rhythm production by amateurs and novices is concordant with their rhythmic expectations in the perception of speech. PMID- 25536847 TI - Effects of compatible versus competing rhythmic grouping on errors and timing variability in speech. AB - In typical speech words are grouped into prosodic constituents. This study investigates how such grouping interacts with segmental sequencing patterns in the production of repetitive word sequences. We experimentally manipulated grouping behavior using a rhythmic repetition task to elicit speech for perceptual and acoustic analysis to test the hypothesis that prosodic structure and patterns of segmental alternation can interact in the production planning process. Talkers produced alternating sequences of two words (top cop) and non alternating controls (top top and cop cop), organized into six-word sequences. These sequences were further organized into prosodic groupings of three two-word pairs or two three-word triples by means of visual cues and audible metronome clicks. Results for six speakers showed more speech errors in triples, that is, when pairwise word alternation was mismatched with prosodic subgrouping in triples. This result suggests that the planning process for the segmental units of an utterance interacts with the planning process for the prosodic grouping of its words. It also highlights the importance of extending commonly used experimental speech elicitation methods to include more complex prosodic patterns, in order to evoke the kinds of interaction between prosodic structure and planning that occur in the production of lexical forms in continuous communicative speech. PMID- 25536849 TI - Visual impairment and incident mobility limitations: the health, aging and body composition study. AB - OBJECTIVES: To examine the association between multiple measures of visual impairment (VI) and incident mobility limitations in older adults. DESIGN: Prospective observational cohort study. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Health, Aging and Body Composition study participants aged 70 to 79 without mobility limitations at the Year 3 visit (N = 1,862). MEASUREMENTS: Vision was measured at the Year 3 visit, and VI was defined as distance visual acuity (VA) worse than 20/40, contrast sensitivity (CS) less than 1.55 log Contrast, and stereoacuity (SA) greater than 85 arcsec. Incident persistent walking and stair climbing limitation was defined as two consecutive 6 month reports of any difficulty walking one-quarter of a mile or walking up 10 steps after 1, 3, and 5 years of follow-up. RESULTS: At Year 3 (baseline for these analyses), 7.4% had impaired VA, 27.2% had impaired CS, and 29.2% had impaired SA. At all follow-up times, the incidence of walking and stair climbing limitations was higher in participants with VA, CS, or SA impairment. After 5 years, impaired CS and SA were independently associated with greater risk of walking limitation (hazard ratio (HR)CS = 1.3, 95% confidence interval (CI) = 1.1 1.7; HRSA = 1.3, 95% CI = 1.1-1.6) and stair climbing limitation (HRCS = 1.4, 95% CI = 1.1-1.8; HRSA = 1.3, 95% CI=1.1-1.7). Having impaired CS and SA was associated with greater risk of mobility limitations (HRwalking limitations = 2.0, 95% CI = 1.6-2.5; HRstair limitation = 2.1, 95% CI = 1.6-2.8). CONCLUSION: Multiple aspects of VI may contribute to mobility limitations in older adults. Addressing more than one component of vision may be needed to reduce the effect of vision impairment on functional decline. PMID- 25536850 TI - Detecting a quasi-stable imine species on the reaction pathway of SHV-1 beta lactamase and 6beta-(hydroxymethyl)penicillanic acid sulfone. AB - For the class A beta-lactamase SHV-1, the kinetic and mechanistic properties of the clinically used inhibitor sulbactam are compared with the sulbactam analog substituted in its 6beta position by a CH2OH group (6beta (hydroxymethyl)penicillanic acid). The 6beta substitution improves both in vitro and microbiological inhibitory properties of sulbactam. Base hydrolysis of both compounds was studied by Raman and NMR spectroscopies and showed that lactam ring opening is followed by fragmentation of the dioxothiazolidine ring leading to formation of the iminium ion within 3 min. The iminium ion slowly loses a proton and converts to cis-enamine (which is a beta-aminoacrylate) in 1 h for sulbactam and in 4 h for 6beta-(hydroxymethyl) sulbactam. Rapid mix-rapid freeze Raman spectroscopy was used to follow the reactions between the two sulfones and SHV-1. Within 23 ms, a 10-fold excess of sulbactam was entirely hydrolyzed to give a cis enamine product. In contrast, the 6beta-(hydroxymethyl) sulbactam formed longer lived acyl-enzyme intermediates that are a mixture of imine and enamines. Single crystal Raman studies, soaking in and washing out unreacted substrates, revealed stable populations of imine and trans-enamine acyl enzymes. The corresponding X ray crystallographic data are consonant with the Raman data and also reveal the role played by the 6beta-hydroxymethyl group in retarding hydrolysis of the acyl enzymes. The 6beta-hydroxymethyl group sterically hinders approach of the water molecule as well as restraining the side chain of E166 that facilitates hydrolysis. PMID- 25536852 TI - Jalapinoside, a macrocyclic bisdesmoside from the resin glycosides of Ipomea purga, as a modulator of multidrug resistance in human cancer cells. AB - The first macrocyclic bisdesmoside resin glycoside, jalapinoside (4), was purified by preparative-scale recycling HPLC from the MeOH-soluble extracts of Ipomoea purga roots, the officinal jalap. Purgic acid C (3), a new glycosidic acid of ipurolic acid, was identified as 3-O-beta-d-quinovopyranoside, 11-O-beta d-quinovopyranosyl-(1->2)-O-beta-d-glucopyranosyl-(1->3)-O-[beta-d-fucopyranosyl (1->4)]-O-alpha-l-rhamnopyranosyl-(1->2)-O-beta-d-glucopyranosyl-(1->2)-O-beta-d quinovopyranoside (3S,11S)-dihydroxytetradecanoic acid. The acylating residues of this core were acetic, (+)-(2S)-methylbutanoic, and dodecanoic acids. The site of lactonization was defined as C-3 of the second saccharide moiety. Reversal of multidrug resistance by this noncytotoxic compound was evaluated in vinblastine resistant human breast carcinoma cells. PMID- 25536851 TI - Sexual and reproductive health and rights in changing health systems. AB - Sexual and reproductive health and rights (SRHR) are centrally important to health. However, there have been significant shortcomings in implementing SRHR to date. In the context of health systems reform and universal health coverage/care (UHC), this paper explores the following questions. What do these changes in health systems thinking mean for SRHR and gender equity in health in the context of renewed calls for increased investments in the health of women and girls? Can SRHR be integrated usefully into the call for UHC, and if so how? Can health systems reforms address the continuing sexual and reproductive ill health and violations of sexual and reproductive rights (SRR)? Conversely, can the attention to individual human rights that is intrinsic to the SRHR agenda and its continuing concerns about equality, quality and accountability provide impetus for strengthening the health system? The paper argues that achieving equity on the UHC path will require a combination of system improvements and services that benefit all, together with special attention to those whose needs are great and who are likely to fall behind in the politics of choice and voice (i.e., progressive universalism paying particular attention to gender inequalities). PMID- 25536858 TI - The effect of temperature changes on in vitro slow wave activity in the equine ileum. AB - REASONS FOR PERFORMING STUDY: Slow waves are rhythmic pacemaker currents generated by the gastrointestinal pacemaker cells, the interstitial cells of Cajal, and represent the rate-limiting step for small intestinal smooth muscle contractions. Therefore, factors that affect slow wave activity may also influence contractile activity. It is not known how temperature changes may influence slow wave activity in the horse. This could be of relevance during colic surgery if cooling of exposed intestine resulted in reduced slow wave activity potentially exacerbating post operative ileus. OBJECTIVES: To evaluate the effect of temperature changes on in vitro slow wave activity of normal equine ileum using intracellular recording techniques. STUDY DESIGN: In vitro experimental study. METHODS: A segment of ileum was collected immediately following euthanasia from 9 horses for reasons unrelated to the gastrointestinal tract. Intracellular recordings of membrane potentials were made from individual smooth muscle cells. The temperature of the tissue bath was altered during the course of each experiment across a range of 27-41 degrees C. All data were recorded and stored using a computer-interfaced acquisition system. A software package was used to analyse slow wave frequency, duration, amplitude and resting membrane potential. RESULTS: In all 9 horses, slow wave frequency was highly temperature sensitive and approximately linearly related to the temperature over the range studied, increasing by 0.5 cycles/min for each 1 degrees C increase in temperature (P<0.001). The initial slow wave frequency resumed when the temperature was returned to 37 degrees C. The recovery time appeared to be directly related to the duration for which the temperature had been changed. CONCLUSIONS: Slow wave frequency in the equine ileum is highly temperature sensitive. As post operative ileus is a major cause of morbidity and mortality in the horse, the negative effect of lower temperatures on slow waves, and therefore contractile activity, should be considered. PMID- 25536860 TI - pH-jump induced leucine zipper folding beyond the diffusion limit. AB - The folding of a pH-sensitive leucine zipper, that is, a GCN4 mutant containing eight glutamic acid residues, has been investigated. A pH-jump induced by a caged proton (o-nitrobenzaldehyde, oNBA) is employed to initiate the process, and time resolved IR spectroscopy of the amide I band is used to probe it. The experiment has been carefully designed to minimize the buffer capacity of the sample solution so that a large pH jump can be achieved, leading to a transition from a completely unfolded to a completely folded state with a single laser shot. In order to eliminate the otherwise rate-limiting diffusion-controlled step of the association of two peptides, they have been covalently linked. The results for the folding kinetics of the cross-linked peptide are compared with those of an unlinked peptide, which reveals a detailed picture of the folding mechanism. That is, folding occurs in two steps, one on an ~1-2 MUs time scale leading to a partially folded alpha-helix even in the monomeric case and a second one leading to the final coiled-coil structure on distinctively different time scales of ~30 MUs for the cross-linked peptide and ~200 MUs for the unlinked peptide. By varying the initial pH, it is found that the folding mechanism is consistent with a thermodynamic two-state model, despite the fact that a transient intermediate is observed in the kinetic experiment. PMID- 25536861 TI - Resistance to forced airflow through layers of composting organic material. AB - The objective of this study was to adjust equations to estimate the static pressure gradient of airflow through layers of organic residues submitted to two stages of biochemical degradation, and to evaluate the static pressure drop of airflow thought the material layer. Measurements of static pressure drop in the layers of sugarcane bagasse and coffee husks mixed with poultry litter on day 0 and after 30 days of composting were performed using a prototype with specific airflow rates ranging from 0.02 to 0.13 m(3) s(-1) m(-2). Static pressure gradient and specific airflow rate data were properly fit to the Shedd, Hukill & Ives and Ergun models, which may be used to predict the static pressure gradient of air to be blown through the organic residue layers. However, the Shedd model was that which best represented the phenomenon studied. The static pressure drop of airflow increased as a power of the material layer thickness and showed tendency for decreasing with the biochemical degradation time of the organic material. PMID- 25536859 TI - Crystal structure of an arginase-like protein from Trypanosoma brucei that evolved without a binuclear manganese cluster. AB - The X-ray crystal structure of an arginase-like protein from the parasitic protozoan Trypanosoma brucei, designated TbARG, is reported at 1.80 and 2.38 A resolution in its reduced and oxidized forms, respectively. The oxidized form of TbARG is a disulfide-linked hexamer that retains the overall architecture of a dimer of trimers in the reduced form. Intriguingly, TbARG does not contain metal ions in its putative active site, and amino acid sequence comparisons indicate that all but one of the residues required for coordination to the catalytically obligatory binuclear manganese cluster in other arginases are substituted here with residues incapable of metal ion coordination. Therefore, the structure of TbARG is the first of a member of the arginase/deacetylase superfamily that is not a metalloprotein. Although we show that metal binding activity is easily reconstituted in TbARG by site-directed mutagenesis and confirmed in X-ray crystal structures, it is curious that this protein and its parasitic orthologues evolved away from metal binding function. Knockout of the TbARG gene from the genome demonstrated that its function is not essential to cultured bloodstream form T. brucei, and metabolomics analysis confirmed that the enzyme has no role in the conversion of l-arginine to l-ornithine in these cells. While the molecular function of TbARG remains enigmatic, the fact that the T. brucei genome encodes only this protein and not a functional arginase indicates that the parasite must import l-ornithine from its host to provide a source of substrate for ornithine decarboxylase in the polyamine biosynthetic pathway, an active target for the development of antiparasitic drugs. PMID- 25536862 TI - A simple method for predicting the lower heating value of municipal solid waste in China based on wet physical composition. AB - A rapid and cost-effective prediction method based on wet physical composition has been developed to determine the lower heating value (LHV) of municipal solid waste (MSW) for practical applications in China. The heating values (HVs) of clean combustibles were measured in detail, and the effect of combustibles, food waste, and ash content on HV was studied to develop the model. The weighted average HV can be used to predict the MSW HV with high accuracy. Based on the moisture measurements of each major real combustible and the HV of clean solid waste, a predictive model of the LHV of real MSW was developed. To assess the prediction performance, information was collected on 103 MSW samples from 31 major cities in China from 1994 to 2012. Compared with five predictive models based on the wet physical composition from different regions in the world, the predictive result of the developed model is the most accurate. The prediction performance can be improved further if the MSW is sorted better and if more information is collected on the individual moisture contents of the waste. PMID- 25536863 TI - Effect of mild heat stress on the proliferative and differentiative ability of human mesenchymal stromal cells. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are an attractive candidate for autologous cell therapy, but regenerative potential can be compromised with extensive in vitro cell passaging. Development of viable cell therapies must address the effect of in vitro passaging to maintain overall functionality of expanded MSCs. METHODS: We examined the effect of repeated mild heat shock on the proliferation and differentiation capability of human adipose-derived MSCs. Adipose tissue MSCs were characterized by means of fluorescence activated cell sorting analysis for expression of CD3, CD14, CD19, CD34, CD44, CD45, CD73, CD90 and CD105. Similarly, the expression of SIRT-1, p16(INK4a) and p21 was determined by means of polymerase chain reaction. Measurements of population doubling, doubling time and superoxide dismutase activity were also determined. Differentiation of expanded MSCs into bone and adipose were analyzed qualitatively and quantitatively. RESULTS: The strategy led to an increase in expression of SIRT-1 concomitant with enhanced viability, proliferation and delayed senescence. The stressed MSCs showed better differentiation into osteoblasts and adipocytes. CONCLUSIONS: The results indicate that mild heat shock could be used to maintain MSC proliferative and differentiation potential. PMID- 25536864 TI - Human peripheral blood CD34+ cells attenuate oleic acid-induced acute lung injury in rats. AB - BACKGROUND AIMS: Adult stem cell-based therapy is a promising novel approach for treatment of acute lung injury (ALI). In this study, we evaluated the therapeutic effect of isolated human peripheral blood CD34+ progenitor cells in an ALI rat model, induced by oleic acid (OA) injection. METHODS: Seventy-five adult female rats were used in this study. Group A, control without treatment, and group B, control injected with phosphate-buffered saline, comprised 15 rats each; the remaining 45 rats were injected with OA to induce ALI and were further subdivided into 3 groups: group C (ALI group, 15 rats), group D (ALI and fibroblast group, 15 rats) and group E (ALI and CD34+ cell group, 15 rats). RESULTS: CD34+ cells transplantation in rats with OA-induced lung injury improves the arterial PaO(2) and wet/dry ratio, reduces infiltration of inflammatory cells and decreases lung vascular permeability as determined by reduced intra-alveolar and interstitial patchy congestion and hemorrhage as well as decreased interstitial edema. Additionally, lung inflammation determined by expression of the pro-inflammatory mediators intercellular adhesion molecule 1 and tumor necrosis factor-alpha was attenuated in CD34+ cell-treated rats at 6, 24 and 48 h post-OA challenge compared with non-treated rats. Moreover, the expression of anti-inflammatory molecule interleukin-10 was up-regulated in the lung of OA-induced ALI rats after administration of CD34+ cells. The important finding was that human TNF-alpha induced protein 6 (TSG-6) gene expression was significantly up-regulated in rats treated with CD34+ cells. CONCLUSIONS: The freshly isolated human peripheral blood-derived CD34+ cells may be used as an important source of stem cells that improve ALI. The anti-inflammatory properties of CD34+ cells in the lung are explained, at least in part, by activation of CD34+ cells to express TSG-6. PMID- 25536865 TI - Serum total bilirubin concentration is negatively associated with increasing severity of retinopathy in patients with type 2 diabetes mellitus. AB - AIMS: Serum bilirubin concentration is associated with diabetic retinopathy in patients with type 2 diabetes. This study investigated the relationships between serum bilirubin concentration and the severity of diabetic retinopathy. In addition, the importance of bilirubin was compared with factors that were previously shown to be associated with the incidence of diabetic retinopathy. METHODS: A total of 674 patients with type 2 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy, and according to the severity of retinopathy. Univariate and multivariate analyses were performed to evaluate the association of retinopathy with total bilirubin concentration, duration of diabetes, body mass index, systolic blood pressure, and haemoglobin A1c. RESULTS: Serum total bilirubin concentration was significantly lower in patients with retinopathy than in those without. Patients with severer retinopathy showed lower total bilirubin concentration, longer diabetes duration, and higher systolic blood pressure. These three parameters were independent explanatory factors for diabetic retinopathy. CONCLUSIONS: Total bilirubin concentration is lower in patients with type 2 diabetes complicated with severer retinopathy. Thus, bilirubin might protect against retinopathy in patients with type 2 diabetes. PMID- 25536866 TI - Benefits of timely basal insulin control in patients with type 2 diabetes. AB - Worldwide, both underdiagnosis and undertreatment leave many patients exposed to long periods of hyperglycemia and contribute to irreversible diabetes complications. Early glucose control reduces the risk of both macrovascular and microvascular complications, while tight control late in diabetes has little or no macrovascular benefit. Insulin therapy offers the most potent antihyperglycemic effect of all diabetes agents, and has a unique ability to induce diabetes remission when used to normalize glycemia in newly diagnosed patients. When used as a second-line therapy, basal insulin is more likely to safely and durably maintain A1C levels <=7% than when insulin treatment is delayed. The use of basal insulin analogs is associated with a reduced risk of hypoglycemia and weight gain compared to NPH insulin and pre-mixed insulin. Patient self-titration algorithms can improve glucose control while decreasing the burden on office staff. Finally, recent data suggest that addition of incretin agents to basal insulin may improve glycemic control with very little, if any increased risk of hypoglycemia or weight gain. PMID- 25536867 TI - Serum autotaxin levels correlate with hepatic dysfunction and severity in postoperative biliary atresia. AB - OBJECTIVE: To investigate correlation of serum autotaxin and disease severity in biliary atresia (BA). METHODS: Eighty postoperative BA patients and 15 controls were recruited. Serum autotaxin levels were determined by enzyme-linked immunosorbent assay. RESULTS: BA patients had greater serum autotaxin and liver stiffness than controls. Serum autotaxin and liver stiffness were markedly elevated in BA patients with jaundice compared to those without jaundice. Furthermore, serum autotaxin was correlated with liver stiffness and biochemical parameters in BA. CONCLUSIONS: Elevated serum autotaxin was correlated with hepatic dysfunction in BA. Accordingly, serum autotaxin is a promising biomarker reflecting the severity in BA. PMID- 25536868 TI - Apneic oxygenation was associated with decreased desaturation rates during rapid sequence intubation by an Australian helicopter emergency medicine service. AB - STUDY OBJECTIVE: The Greater Sydney Area Helicopter Emergency Medical Service undertakes in excess of 2,500 physician/paramedic out-of-hospital and interhospital retrievals each year, of which 8% require intubation. Emergency anesthesia of critically ill patients is associated with complications, including hypoxia. In July 2011, the service introduced apneic oxygenation with nasal cannulae to its emergency anesthesia standard operating procedure to reduce rates of desaturation during rapid sequence intubation. We evaluate the association between the introduction of apneic oxygenation and incidence of desaturation during rapid sequence intubation in both out-of-hospital and interhospital retrievals. METHODS: This was a retrospective study of prospectively collected airway registry data. Consecutive patients who underwent rapid sequence intubation by Greater Sydney Area Helicopter Emergency Medical Service personnel between September 2009 and July 2013, spanning the introduction of apneic oxygenation, were included for analysis (n=728). We compared patients who underwent rapid sequence intubation before the service introduced apneic oxygenation (n=310) with those who underwent it after its introduction (n=418). We evaluated the association between the introduction of apneic oxygenation and the incidence of desaturation. RESULTS: During the study period, 9,901 missions were conducted with 728 rapid sequence intubations (310 pre- and 418 postapneic oxygenation). The introduction of apneic oxygenation was followed by a decrease in desaturation rates from 22.6% to 16.5% (difference=6.1%; 95% confidence interval 0.2% to 11.2%). CONCLUSION: Introduction of apneic oxygenation was associated with decreased incidence of desaturation in patients undergoing rapid sequence intubation. PMID- 25536869 TI - Sick kids look sick. PMID- 25536870 TI - Learning to tie well with others: bimanual versus intermanual performance of a highly practised skill. AB - Studies indicate that novices are faster in manual tasks when performing with a partner ('intermanual') than with their own two hands ('bimanual'). The generality of this 'mode effect' was examined using a highly practised bimanual task, shoe tying, at which participants were experts. Speed-variability correlations confirmed participants were bimanually skilled but not intermanually skilled. Contrary to results using novices, intermanual was slower, such that prior skill reverses the effect. Analyses incorporating the similarity of shoe tying strategies across dyads implicated a perceptual rather than shared knowledge/representation basis for intermanual performance. Practice effects indicated that intermanual performance built upon prior bimanual skill, such that novel relative timings between dyads' hands must be acquired. Motor transfer effects provided support for this conclusion. During shoe tying, hands were tightly coupled in the intermanual mode due to the perceptual coupling constraints of intermanual performance. Increased coupling was correlated with slower performance. Implications for real-world tasks (e.g. surgical knot tying) are described. PMID- 25536872 TI - Root-cause failure analysis of photocurrent loss in polythiophene:fullerene-based inverted solar cells. AB - Metal oxide transport layers have played a crucial role in recent progress in organic photovoltaic (OPV) device stability. Here, we measure the stability of inverted and encapsulated polythiophene:fullerene cells with MoO3/Ag/Al composite anode in operational conditions combining solar radiation and 65 degrees C. Performance loss of over 50% in the first 100 h of the aging is dominated by a drop in the short-circuit current (Jsc). We reveal a concurrent loss in reflectance from 85% to 50% above 650 nm, which is below the optical gap of the used photoactive materials, hence, excluding any major degradation in the bulk of this layer. Correlating the responses of aged devices to a series of test structures comprised of ITO/ZnO cathode, MoO3/Ag, and MoO3/Ag/Al anodes and their combinations with the active layer allowed us to identify that the presence of Al causes the reduced reflectance in these devices, independent of the presence of the active layer. Systematic single-stress aging on the test structures further indicates that elevated heat is the cause of the reflectance loss. Cross-section transmission electron microscopy coupled with elemental analysis revealed the unsuspected role of Al; notably, it diffuses through the entire 150 nm thick Ag layer and accumulates at the MoO3/Ag interface. Moreover, XRD analysis of the aged MoO3/Ag/Al anode indicates the formation of Ag2Al alloy. Depth profiling with X-ray photoelectron spectroscopy advanced our understanding by confirming the formation of Ag-Al intermetallic alloy and the presence of oxidized Al only at the MoO3/Ag interface suggesting a concomitant reduction of MoO3 to most probably MoO2. This latter compound is less reflective than MoO3, which can explain the reduced reflectance in aged devices as proven by optical simulations. On the basis of these results, we could estimate that 20% of the loss in Jsc is ascribed to reduction of MoO3 triggered by its direct contact with Al. PMID- 25536873 TI - Evidence-based medicine: what has happened in the past 50 years? AB - Although the phrase 'evidence-based medicine' (EBM) was used for the first time in the medical literature less than 25 years ago, the history of EBM goes back for centuries. What is remarkable is how popular and how globally accepted the EBM movement has become in such a short time. Many famous, past clinicians have played major roles in the disciplines that preceded EBM, particularly 'clinical epidemiology'. It soon became clear to the early EBM champions that 'evidence' was only part of the clinical decision-making process. Consequently, both clinical expertise and the patient's values and preferences were rapidly incorporated into the concept we now know as 'EBM'. The current need for high quality, easily accessible 'evidence-based summaries' for busy clinicians is now apparent, as traditional EBM requires both considerable time and skill. Consequently, there is a progressive move away from the primary literature (such as randomised controlled trials) to systematic reviews and other 'evidence-based summaries'. The future of EBM will almost certainly involve widespread utilisation of 'clinical (computer)-based decision support systems'. PMID- 25536874 TI - Preface to Forum on materials for theranostics. PMID- 25536875 TI - Regenerated silk fibroin films with controllable nanostructure size and secondary structure for drug delivery. AB - The ability of drug release from SF materials was governed largely by their secondary structure. It is known that the breakage degree of the peptide chain during the silk fibroin (SF) dissolution can affect the structure, property, and applications of SF materials. To deeply understand this effect, we designed a reaction system based on CaCl2/H2O/C2H5OH ternary solvent with different ethanol content to obtain the regenerated SF films with different morphologies and secondary structures. The results showed that the globule-like nanostructure was observed in all regenerated SF films, and their size decreased significantly with reducing the ethanol content in the solvent. Correspondingly, the beta-sheet structure content of the SF films increased. In addition, the contact angle and the elongation ratio increased, and water absorption decreased significantly with decreasing the ethanol content in the solvent. The accumulated release percents of doxorubicin from these SF films were significantly different with increasing the time. With smaller nanostructure size and more beta-sheet content, the SF films had a slower drug release at the beginning. This study indicated the importance of the ethanol content in the solvent in controlling the structure and properties of the regenerated SF films, which would improve the application of SF in drug delivery. PMID- 25536876 TI - Stable isotope and chemical compositions of European and Australasian ciders as a guide to authenticity. AB - This paper presents a data set derived from the analysis of bottled and canned ciders that may be used for comparison with suspected counterfeit or substitute products. Isotopic analysis of the solid residues from ciders (predominantly sugar) provided a means to determine the addition of C4 plant sugars. The added sugars were found to comprise cane sugar, high-fructose corn syrup, glucose, or combinations. The majority of ciders from Australia and New Zealand were found to contain significant amounts of added sugar, which provided a limited means to distinguish these ciders from European ciders. The hydrogen and oxygen isotopic compositions of the whole ciders (predominantly water) were shown to be controlled by two factors, the water available to the parent plant and evaporation. Analysis of data derived from both isotopic and chemical analysis of ciders provided a means to discriminate between regions and countries of manufacture. PMID- 25536878 TI - High-level production of creatine amidinohydrolase from Arthrobacter nicotianae 23710 in Escherichia coli. AB - In the present study, the gene encoding creatinase was amplified from Arthrobacter nicotianae 23710 (CICC) and functionally overexpressed in Escherichia coli. By applying a two-stage temperature control strategy, the production of creatinase was increased up to 61.3 U/mL in 3-L fermentor with a high productivity of 6.1 U/mL/h. The recombinant creatinase shows excellent resistance to the chelating agent EDTA, the surfactants (Tween 20, Tween 80, and Triton X-100) and the common preservative NaN3 (20 mM). High-level expression of the recombinant creatinase will contribute to its application in clinical diagnosis of renal function. PMID- 25536877 TI - Combined potentiating action of phytochemical(s) from Cinnamomum tamala and Aloe vera for their anti-diabetic and insulinomimetic effect using in vivo rat and in vitro NIH/3T3 cell culture system. AB - The present investigation was undertaken to analyze the ethanolic extracts of leaves of Cinnamomum tamala and Aloe vera for their anti-diabetic and insulinomimitic effect by determining the levels of blood sugar, glycosylated hemoglobin, and serum lipid profile (total cholesterol, triglycerides, high density lipoprotein (HDL), and low density lipoprotein (LDL)) after daily administration of each alone and in combined at 250 mg/kg in alloxan (ALX) induced diabetic rats. Treatment of diabetic rats with the extracts restored the elevated biochemical parameters significantly. The anti-diabetic effect further potentiated the insulin signaling pathway by co-administration of both extracts. The molecular mechanisms of modulating gene expression and cellular signaling through the insulin receptor were also evaluated on specific targets of the insulin signaling pathway, including insulin receptor substrate (IRS), phosphatidylinositol 3-kinase (PI3-K), AKT, and the glucose transporter (GLUT4) on NIH/3T3 cell line by western blotting, ELISA, semiquantitative RT-PCR, and real-time PCR. The active principle of both extracts revealed insulin mimicking effect as indicated by increased expression of pIRS1 and pAKT in time-dependent manner. There was no significant difference in PI3-K content between unchallenged and challenged groups. Enhanced expression of GLUT-4 transcript further suggested that the Cinnamomum and Aloe phytochemicals could serve as a good adjuvant in the present armamentarium of anti-diabetic drugs by either mimicking or improving insulin action. This study reveals that ethanolic extracts of C. tamala and A. vera have potent therapeutic efficacy and prospect for the development of phytomedicine for diabetes mellitus. PMID- 25536879 TI - Refining Fingermark Development using Diacetylene Copolymers on Difficult Surfaces(.). AB - In further work investigating the intriguing application of diacetylene copolymers in fingermark detection, methods were developed to control (inhibit or enhance) the diacetylene polymerization reaction in fingermarks treated with a mixture of the monomers 2,4-hexadiyne-1,6-bis-(phenylurethane) (HDDPU) and 2,4 hexadiyne-1,6-bis(p-chlorophenylurethane) (HDDCPU) in acetone solution. These methods included the use of a humidity chamber to reduce the amount of background development while promoting development on the fingermark, subjecting developed fingermarks to freezing temperatures and using a solvent to remove unreacted monomer in order to inhibit the polymerization reaction. Developed fingermarks were enhanced by conventional lighting (white light, filtered light) and fast Raman mapping, which was shown to be advantageous over FTIR imaging. This study also demonstrated the applicability of diacetylene copolymer solutions in the covert detection of fingermarks on difficult surfaces. Furthermore, fingermarks were successfully developed with good ridge detail on pig skin (used as a model for human skin, a notoriously difficult surface on which to develop fingermarks). PMID- 25536880 TI - Malleable penile prosthesis is a cost-effective treatment for refractory ischemic priapism. AB - INTRODUCTION: Refractory ischemic priapism (RIP) can be difficult to treat, consuming significant healthcare-related resources. Acute insertion of a malleable penile prosthesis (MPP) has been reported as an effective therapy that treats the priapism and restores sexual function. AIM: We report our 6-year, urban public hospital experience with acute insertion of MPP in patients with RIP. METHODS: We retrospectively reviewed the records of patients receiving MPPs for RIP from 2007 to 2013. Data analyzed included duration of erection, number of emergency room (ER) visits, hospital admissions, days of hospitalization, and postoperative course. Costs were estimated using standard Medicare reimbursement rates. MAIN OUTCOME MEASURE: Healthcare-related costs of treatment of RIP episodes in men presenting to our institution. RESULTS: During the study period, 14 men underwent MPP placement acutely for refractory priapism. Thirteen presented with RIP, and one had stuttering priapism over a 14-day hospitalization. Etiologies included sickle cell anemia (4/13, 29%), medication induced (3/14, 21%), and idiopathic (7/14, 50%). Average preoperative duration of RIP was 82 hours with considerable consumption of health-care resources (average US $83,818 estimated cost, 4 ER visits [range 1-27], 2 hospital admissions [range 1-5], 1.5 shunt procedures [range 1-3], 5 irrigation and drainage procedures using phenylephrine injection [range 2-20], and 5 hospital admission days [range 2-14]). All patients were discharged within 24 hours of MPP surgery. CONCLUSIONS: The management of RIP is associated with multiple ER visits, prolonged hospital admissions, and significant resource utilization. MPP insertion is efficacious for the immediate resolution of refractory priapism, with potential cost and resource benefits. PMID- 25536883 TI - Commentary on 'Colonoscopy screening compliance and outcomes in patients with Lynch syndrome'. PMID- 25536888 TI - EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines. AB - Enterovirus A infections are the primary cause of hand, foot and mouth disease in infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 have emerged as neurotropic viruses responsible for severe neurological complications and a serious public health threat across the Asia-Pacific region. Formalin inactivated EV71 vaccines have elicited protection against EV71 but not against coxsackievirus A16 infections. The development of a bivalent formalin-inactivated EV71/FI coxsackievirus A16 vaccine should be the next step towards that of multivalent hand, foot and mouth disease vaccines which should ultimately include other prevalent pathogenic coxsackieviruses and echovirus 30. This editorial summarizes the major challenges faced by the development of hand, foot and mouth disease vaccines. PMID- 25536881 TI - The fibrate gemfibrozil is a NO- and haem-independent activator of soluble guanylyl cyclase: in vitro studies. AB - BACKGROUND AND PURPOSE: Fibrates are a class of drugs widely used to treat dyslipidaemias. They regulate lipid metabolism and act as PPARalpha agonists. Clinical trials demonstrate that besides changes in lipid profiles, fibrates decrease the incidence of cardiovascular events, with gemfibrozil exhibiting the most pronounced benefit. This study aims to characterize the effect of gemfibrozil on the activity and function of soluble guanylyl cyclase (sGC), the key mediator of NO signalling. EXPERIMENTAL APPROACH: High-throughput screening of a drug library identified gemfibrozil as a direct sGC activator. Activation of sGC is unique to gemfibrozil and is not shared by other fibrates. KEY RESULTS: Gemfibrozil activated purified sGC, induced endothelium-independent relaxation of aortic rings and inhibited platelet aggregation. Gemfibrozil-dependent activation was absent when the sGC haem domain was deleted, but was significantly enhanced when sGC haem was lacking or oxidized. Oxidation of sGC haem enhanced the vasoactive and anti-platelet effects of gemfibrozil. Gemfibrozil competed with the haem-independent sGC activators ataciguat and cinaciguat. Computational modelling predicted that gemfibrozil occupies the space of the haem group and interacts with residues crucial for haem stabilization. This is consistent with structure-activity data which revealed an absolute requirement for gemfibrozil's carboxyl group. CONCLUSIONS AND IMPLICATIONS: These data suggest that in addition to altered lipid and lipoprotein state, the cardiovascular preventive benefits of gemfibrozil may derive from direct activation and protection of sGC function. A sGC-directed action may explain the more pronounced cardiovascular benefit of gemfibrozil observed over other fibrates and some of the described side effects of gemfibrozil. PMID- 25536889 TI - Microfluidic devices for imaging neurological response of Drosophila melanogaster larva to auditory stimulus. AB - Two microfluidic devices (pneumatic chip and FlexiChip) have been developed for immobilization and live-intact fluorescence functional imaging of Drosophila larva's Central Nervous System (CNS) in response to controlled acoustic stimulation. The pneumatic chip is suited for automated loading/unloading and potentially allows high throughput operation for studies with a large number of larvae while the FlexiChip provides a simple and quick manual option for animal loading and is suited for smaller studies. Both chips were capable of significantly reducing the endogenous CNS movement while still allowing the study of sound-stimulated CNS activities of Drosophila 3rd instar larvae using genetically encoded calcium indicator GCaMP5. Temporal effects of sound frequency (50-5000 Hz) and intensity (95-115 dB) on CNS activities were investigated and a peak neuronal response of 200 Hz was identified. Our lab-on-chip devices can not only aid further studies of Drosophila larva's auditory responses but can be also adopted for functional imaging of CNS activities in response to other sensory cues. Auditory stimuli and the corresponding response of the CNS can potentially be used as a tool to study the effect of chemicals on the neurophysiology of this model organism. PMID- 25536891 TI - [The dark side of German child and adolescent psychiatry after World War II - historical reappraisal, responsibility and consequences for the future]. PMID- 25536890 TI - Cutaneous autonomic denervation in Parkinson's disease. AB - Numerous studies have detailed involvement of the peripheral autonomic nervous system (PANS) in Parkinson's disease (PD). We assessed autonomic innervation of dermal annexes through quantitative fluorescence measurement from skin obtained via punch biopsies at distal leg region in PD and control subjects. We defined a ratio between the area corresponding to protein gen product (PGP) immunoreactivity and the area corresponding to blood vessel or sweat gland as a quantitative measure of autonomic innervation. Presence of alpha-synuclein (AS) deposits in dermis and hypodermis was also assessed by immunohistochemistry. Skin biopsies form six PD patients and six healthy controls were studied. Autonomic innervation scores were lower in PD than in controls in both blood vessels and sweat glands. No AS or phosphorylated AS (pAS) immunoreactivity was detected in dermis or hypodermis in any of the studied subjects. The results of this investigation suggest that autonomic innervation of dermal annexes in living patients with PD is reduced compared to controls. AS or pAS deposits were not found in dermis or hypodermis suggesting that distal leg skin study is not useful for in vivo detection of AS in PD. PMID- 25536892 TI - [Relationships between family interactions and pathological internet use in adolescents: an review]. AB - OBJECTIVE: The internet is used intensely by German adolescents for various activities both in school as well as during leisure time. Pathological internet use is currently on the increase in many industrial nations (especially in Asia, North America, and Europe). According to recent epidemiological studies, pathological internet use occurs more frequently in youths than in adults. Several studies have investigated the interdependence of family structures or interactions and pathological adolescent internet use. This article provides an overview of the available research results. METHODS: We conducted a systematic literature search in the bibliographic databases PubMed, PsycINFO, and Psyndex. RESULTS: We identified 15 studies (published in English or German) examining exclusively minor-aged participants. A good family functioning as well as a good communication between parents and adolescents, a positive parent-child relationship, and supportive parental monitoring proved to help prevent pathological adolescent internet use. CONCLUSIONS: The described familial predictors have been replicated in some studies. Implications for future research on this subject are discussed. PMID- 25536893 TI - [Pharmacovigilance in child and adolescent psychiatry]. AB - Rational pharmacotherapy is a challenging task in child and adolescent psychiatry. Increasing prescription numbers contrast with the uncertainties of safety and efficacy issues. The lack of clinical (authorization) trials often implies a non- age-specific use of drugs. However, young patients show particular metabolic conditions and a higher vulnerability for adverse drug reactions. Thus it seems mandatory to create age-specific pharmacological data about efficacy and safety of psychotropic drug use in minors. Legislation authorities became aware of this situation and introduced European and national scientific pharmacovigilance regulations and programmes accordingly in order to continuously evaluate the benefit-risk-ratio, detect, collect, minimize, and prevent adverse effects of drugs by appropriate measures, e.g., therapeutic drug monitoring. In this paper the principles and needs of pharmacovigilance in child and adolescent psychiatry are discussed. Furthermore a large multicenter clinical trial ("TDM VIGIL"), funded by the German Federal Institute for Drugs and Medical Devices, is presented, which appeals to collect epidemiological prescription and safety data of psychotropic drugs in children and adolescents using an internet-based data infrastructure (patient registry). PMID- 25536894 TI - [Body dysmorphic disorder]. AB - Body dysmorphic disorder (BDD) is a relatively common disorder with a point prevalence of 0.7-2.4 %. BDD is characterized by the patient's excessive concern with an imagined or slight defect in physical appearance. BDD usually begins in adolescence. Comorbidity rates and also suicidality rates are high. The course of BDD tends to be chronic. According to the present state of knowledge, cognitive behavioral therapy and pharmacotherapy with selective serotonin reuptake inhibitors are valuable options in the therapy of BDD. The case report describes a recent case of BDD with typical clinical and therapy-related characteristics. The aim of this work is to strengthen the awareness of BDD in clinical practice of child and adolescent psychiatry, facilitating an adequate diagnosis and treatment of the affected individuals. PMID- 25536895 TI - Suicidal behavior in german adolescents. Prevalence and association with depressive and manic symptoms. AB - OBJECTIVE: Research in adults has identified an association between bipolar disorder and suicidal behavior. This relationship, however, has been insufficiently investigated in adolescents to date. METHODS: 1,117 adolescents from 13 German schools (mean age = 14.83, SD = .63; 52.7% females) completed an extended German version of the Center for Epidemiological Studies Depression Scale (CES-D), which assesses depressive and manic symptoms during the last week, as well as the Self-Harm Behavior Questionnaire (SHBQ) for the assessment of lifetime suicidal behavior. RESULTS: In the present sample 39.4% of the girls and 23.1% of the boys reported lifetime suicidal thoughts and 7.1% of the girls as well as 3.9% of the boys a lifetime history of suicide attempts. 18.7% of the adolescent sample revealed elevated symptoms of depression and 9% elevated levels of mania symptoms. Elevated sum scores of depression and mania were associated with a higher number of suicidal ideations and suicide attempts. A block-wise regression analysis revealed that sum scores of depression and mania predicted suicidal ideations best. Concerning suicide attempts, the best predictors were age as well as depression and mania sum scores. CONCLUSIONS: Suicidal behavior was reported more often when adolescents demonstrate symptoms of mania as well as symptoms of depression than when they demonstrate only depressive symptoms. The presence of bipolar symptoms in adolescents should alert clinicians to the heightened possibility of suicidal behavior. PMID- 25536896 TI - [Gender dysphoria in children and adolescents - treatment guidelines and follow up study]. AB - Treatment guidelines for transidentity in children and adolescents are presently under discussion. We present an overview of the various treatment modalities. Further, follow-up data on children and adolescents referred for gender-identity problems are presented. Of the 84 patients seen for the first time more than 3 years before follow-up, 37 mailed in the completed questionnaires. In addition, 33 patients agreed to answer some short follow-up questions. We assessed steps of treatment, gender role, psychopathology, and psychotherapy. We compared differences in psychopathology in patients with vs. without gender role change and in patients with intense vs. less intense psychotherapy. A total of 22 patients had completely changed gender role, and some had started hormonal treatment und sex reassignment surgery. Most patients were satisfied with the treatment results. All patients showed less psychopathology on follow-up, independent of role change or intensity of psychotherapy. In general, the patients reported little psychopathology. Our follow-up results support the present treatment approach. In patients with little psychopathology, low frequency supportive treatment appears sufficient to obtain safe judgement on hormonal of surgical treatment. PMID- 25536897 TI - [A pilot study on the specificity of body image disturbance in anorexia nervosa]. AB - OBJECTIVE: Body image disturbance (BID) is a central feature of anorexia nervosa (AN), but evidence for bodily-related disorders also exists for patients with cystic fibrosis (CF), who are frequently underweight. A comparison of BID in patients with AN, CF and controls serves to clarify the specificity of BID for AN. METHOD: 22 patients with AN, 10 patients with CF, and 23 controls were tested with regard to perceptual and cognitive-affective components of BID. Further data concerning eating-disorder-related psychopathology were assessed. RESULTS: BID occurred in all patients with AN. Patients with CF perceived themselves as thinner than the controls did, and three of them exhibited BID. Patients with AN and CF did not differ regarding body satisfaction, and only controls showed higher satisfaction than patients with CF. Patients with AN and CF differed on desire for thinness, dissatisfaction with their body, and interoceptive awareness, with higher scores occurring in patients with AN. CONCLUSIONS: Our pilot study reveals no severe psychopathology concerning body image in patients with CF. However, we did observe a general body dissatisfaction among these patients, probably associated with their being underweight. BID still seems to be a central diagnostic criterion for AN and should be carefully considered during therapeutic interventions. PMID- 25536900 TI - Growth enhancing effect of exogenous glycine and characterization of its uptake in halotolerant cyanobacterium Aphanothece halophytica. AB - Alkaliphilic halotolerant cyanobacterium Aphanothece halophytica showed optimal growth in the medium containing 0.5 M NaCl. The increase of exogenously added glycine to the medium up to 10 mM significantly promoted cell growth under both normal (0.5 M NaCl) and salt stress (2.0 M NaCl) conditions. Salt stress imposed by either 2.0 or 3.0 M NaCl retarded cell growth; however, exogenously added glycine at 10 mM concentration to salt-stress medium resulted in the reduction of growth inhibition particularly under 3.0 M NaCl condition. The uptake of glycine by intact A. halophytica was shown to exhibit saturation kinetics with an apparent K s of 160 MUM and V max of 3.9 nmol/min/mg protein. The optimal pH for glycine uptake was at pH 8.0. The uptake activity was decreased in the presence of high concentration of NaCl. Both metabolic inhibitors and ionophores decreased glycine uptake in A. halophytica suggesting an energy-dependent glycine uptake. Several neutral amino acids showed considerable inhibition of glycine uptake with higher than 50 % inhibition observed with serine, cysteine and alanine whereas acidic, basic and aromatic amino acids showed only slight inhibition of glycine uptake. PMID- 25536901 TI - Manufacturing and finite element assessment of a novel pressure reducing insole for Diabetic Neuropathic patients. AB - Diabetes is one of the metabolic diseases. Uncontrolled diabetes can lead to diabetic foot ulcers and if it was not treated would lead to amputation. Foot ulcers can be prevented by using suitable insoles which are made of appropriate material and geometrically designed by constituent layers. In this study, single layer and three-layer insoles have been compared during static and dynamic loading. The selected materials were silicone gel (SG), plastazote foam (PLZ), polyfoam (PF) and ethyl vinyl acetate foam (EVA). Four single-layer and 18 combinations of three-layer insoles were selected. Materials behaviors were determined by using a uniaxial pressure test. The description of stress and strain is obtained by using the model of three dimensional nonlinear Finite Element Method (FEM). Then samples were tested by using commercially available plantar pressure measurement system. The FEM results showed that the SG and PLZ insoles are more appropriate compared to single-layer insoles. The combinations of PLZ, SG and EVA (from top to bottom) are recognized as the best between three layer insoles. Also the best three-layer insole is more effective in promoting a favourable stress and strain distribution than single-layer insoles, especially in dynamic mode. According to simulation results, three-layer insole decreases stress concentration by 9%. Also experimental tests showed that using three-layer insole decreases plantar pressure by 63% compared to barefoot condition bare foot. PMID- 25536902 TI - Prokaryotic community structure in deep bedrock aquifers of the Austrian Central Alps. AB - The bacterial and archaeal diversity of deep groundwater systems was investigated based on 16S rRNA-SSCP (single strand conformation polymorphism) fingerprints. The study site included five boreholes along the projected Brenner Base Tunnel in the central Alps of Tyrol, Austria. To obtain representative samples, packer sealed fractures were sampled at specific depths between 105 and 780 m below surface. Sequence analysis of SSCP bands obtained from 13 samples showed that between 29 and 62 % of the phylotypes belonged to a variety of Proteobacteria including representatives of typical freshwater bacteria of the genera Acidovorax, Aquabacterium, and Sphingomonas. Bacteroidetes (especially Flavobacterium), Firmicutes (Acetobacterium), and candidate division OP3-related sequences were observed in the majority of the analysed groundwaters. On average, 14 % of the detected prokaryotic phylotypes were affiliated with Archaea, comprising the phyla Euryarchaeota, Crenarchaeota and Thaumarchaeota. Most of the archaeal sequences showed low similarities to known cultivated species, with exception of two sequences having 98 % similarity to Methanosaeta sp. A considerable number of thaumarchaeal sequences belonged to two groups related to Nitrososphaera and Nitrosopumilus phylotypes. An environmental clustering of the groundwater samples, based on the bacterial and archaeal phylogeny, revealed a clear distribution pattern of the samples (sites and depths) reflecting the hydrochemical characteristics and underlying geologies. PMID- 25536903 TI - Adult care for Duchenne muscular dystrophy in the UK. AB - Survival in Duchenne muscular dystrophy (DMD) has increased in recent years due to iterative improvements in care. We describe the results of the CARE-NMD survey of care practices for adults with DMD in the UK in light of international consensus care guidelines. We also compare the UK experience of adult care with the care available to pediatric patients and adults in other European countries (Germany, Denmark, Bulgaria, Czech Republic, Hungary, and Poland). UK adults experience less comprehensive care compared to children in their access to specialized clinics, frequency of cardiac and respiratory assessments, and access to professional physiotherapy. Access to the latter is especially poor when compared to other European adult cohorts. Although the total number of nights in hospital (planned and unplanned admissions) is lower among UK adults than elsewhere in Western Europe, social inclusion lags behind other Western European countries. We observe that attendance at specialized clinic is associated with more frequent cardiac and respiratory assessments among adults, in line with international best practice. Attendance at such clinics in the UK, though comparable to other countries, is still far from universal. With an increasing adult population living with DMD, and cardiac and respiratory failure the leading causes of death in this population, we suggest the need for an urgent improvement in adult access to specialized clinics and to consistent, comprehensive best practice care. PMID- 25536904 TI - Presumed tuberculous retrobulbar optic neuritis: a diagnosis challenge. PMID- 25536906 TI - Collagen arrangement in space of Disse correlates with fluid flow in normal and cirrhotic rat livers. AB - Little is known about collagen arrangement in the space of Disse was related to the fluid flow both in normal and cirrhotic liver. We examined the changes in the arrangement of type-I collagen in thioacetamide-induced cirrhotic rat livers with immunohistochemistry and SEM after maceration of the noncollagenous tissues with NaOH. The sparse bundles of collagen fibers in the spaces of Disse were mostly elongated fibers with a disorganized arrangement in each nodule. They connected with the broad fibrous septa. Based on a comparison of the architecture of the collagen fibers and the established flow of fluid in the space of Disse, we hypothesize that the fluid in the space of Disse streams along collagen fibers in all directions to broad fibrous septa. The appearance of perinodular plexus in cirrhotic rat livers probably helps to reduce portal hypertension. PMID- 25536905 TI - Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins. AB - We report the case of Niemann-Pick disease type C with extensive phenotypic heterogeneity in two monozygotic twins. One of the twins presented with a history of obsessive-compulsive disorder and slowly progressive inferior limb clumsiness, dysphagia and dysarthria. Neurological examination revealed a broad-based ataxic gait, limb dysmetria, downward vertical gaze palsy, brisk lower limb reflexes and ankle clonus, while neuropsychological assessment revealed global cognitive deficits in multiple domains. Complete neurological and neuropsychological evaluation in the asymptomatic monozygotic twin brother only revealed mild neurological impairment. In the hypothesis of Niemann-Pick disease type C, Filipin test, measurement of plasma oxysterols levels and genetic analysis were carried out in both twins. Filipin staining showed massive intracellular accumulation of non-esterified cholesterol, plasma oxysterols levels were elevated and genetic analysis revealed a homozygous c.2662 C > T (p.P888S) mutation in the NPC1 gene (18q11.2) in both twins. 18F-FDG-PET imaging with single-subject analysis revealed a reduced frontal and temporal glucose metabolism, which correlated with disease progression. This case supports the phenotypic variability of Mendelian inherited disorders in monozygotic twins, likely due to epigenetic differences and post-zygotic mutagenesis. PMID- 25536907 TI - Latino parents' perceptions of weight terminology used in pediatric weight counseling. AB - OBJECTIVE: To identify which English and Spanish terms Latino parents consider motivating, as well as culturally and linguistically appropriate, for provider use during weight counseling of overweight and obese Latino youth. METHODS: Latino parent perceptions of common Spanish and English terms for overweight were discussed with 54 parents in 6 focus groups (3 English, 3 Spanish). Atlas.ti software was used for qualitative analysis. An initial codebook was used to code passages for English and Spanish terminology separately. Subsequent changes to the coded passages and creation of new codes were made by team consensus. RESULTS: "Demasiado peso para su salud" (too much weight for his/her health) was the only phrase for excess weight that was consistently identified as motivating and inoffensive by Spanish-speaking parents. "Sobrepeso" (overweight), a commonly used term among health care providers, was motivating to some parents but offensive to others. English-speaking parents had mixed reactions to "unhealthy weight," "weight problem," and "overweight," finding them motivating, confusing, or insulting. Parents found "fat" "gordo" and "obese" "obeso" consistently offensive. Most participants found growth charts and the term "BMI" confusing. Parents consistently reported that providers could enhance motivation and avoid offending families by linking a child's weight to health risks, particularly diabetes. CONCLUSIONS: "Demasiado peso para su salud" (too much weight for his/her health) was motivating to many Spanish-speaking Latino parents. Among English-speaking Latino parents, no single English term emerged as motivating, well-understood, and inoffensive. Linking a child's excess weight with increased health risks was motivating and valuable to many parents regardless of language spoken. PMID- 25536908 TI - Resolution of protein structure by mass spectrometry. AB - Typically, mass spectrometry is used to identify the peptides present in a complex peptide mixture and subsequently the precursor proteins. As such, mass spectrometry focuses mainly on the primary structure, the (modified) amino acid sequence of peptides and proteins. In contrast, the three-dimensional structure of a protein is typically determined with protein X-ray crystallography or NMR. Despite the close relationship between these two aspects of protein studies (sequence and structure), mass spectrometry and structure determination are not frequently combined. Nevertheless, this combination of approaches, dubbed conformational proteomics, can offer insight into the function, working mechanism, and conformational status of a protein. In this review, we will discuss the developments at the intersection of mass spectrometry-based proteomics and protein structure determination and start from a brief overview of the classic approaches to identify protein structure along with their advantages and disadvantages. We will subsequently discuss the ability of mass spectrometry to overcome some of the hurdles of these classic methods. Finally, we will provide an outlook on the interplay of mass spectrometry and protein structure determination, and highlight several recent experiments in which mass spectrometry was successfully used to either aid or complement structure elucidation. (c) 2014 Wiley Periodicals, Inc. Mass Spec Rev 35:653-665, 2016. PMID- 25536909 TI - In brief: concerns about oseltamivir (Tamiflu). PMID- 25536910 TI - The first 4d/4f single-molecule magnet containing a {Ru(III)2Dy(III)2} core. AB - We report the synthesis, structure and magnetic properties of the first 4d-4f single-molecule magnet. The complex [Ru(III)2Dy(III)2(OMe)2(O2CPh)4(mdea)2(NO3)2] displays a butterfly type core, with an anisotropy barrier of 10.7 cm(-1). Ab initio and DFT calculations provide insight into the observed magnetic behaviour. PMID- 25536911 TI - Macroscopic self-assembly based on complementary interactions between nucleobase pairs. AB - We have created a selective macroscopic self-assembly process by using polymer gels modified with complementary DNA oligonucleotides or nucleobases. The hydrogels modified with complementary DNA oligonucleotides adhered to each other by simple contact. The organogels modified with complementary nucleobases selectively formed macroscopic assemblies by agitation in nonpolar organic solvents. The adhesion strength of each gel was estimated semi-quantitatively by stress-strain measurements. We achieved direct adhesion between macroscopic materials both in water and in organic media, based on complementary hydrogen bonds. PMID- 25536912 TI - Navigating the unknown: shared decision-making in the face of uncertainty. AB - In shared decision-making (SDM), patient and physician deliberate together on the basis of shared evidence, supporting the patient's choice among multiple options, informed by her values and preferences. One factor complicating the implementation of SDM is uncertainty, which has long been recognized in medicine but perhaps not sufficiently addressed in the context of SDM. In order to ensure that SDM can be realistically applied to real-world clinical encounters, the issue of uncertainty should be recognized and explicitly incorporated into SDM strategies. Here we propose practical approaches, based in doctor-patient communication science and bioethics, that may be of help for incorporating the uncertainty factor into SDM in the context of the doctor-patient encounter. We also discuss how decision aids might be more widely applicable through routinely acknowledging the preference sensitivity of decisions and supplementing these tools with a discussion of uncertainty. PMID- 25536913 TI - Inflammatory markers and Lp(a) levels as cardiovascular risk factors in androgenetic alopecia. AB - It is not well-established whether patients with androgenetic alopecia (AGA) show a higher cardiovascular risk and higher prevalence of metabolic syndrome (MS). Therefore, we aimed to analyze the cardiovascular risk and the prevalence of MS by means of a case-control study. We determined lipidic, inflammatory, hormonal and insulin resistance parameters with conventional laboratory methods in 50 male early-onset AGA patients and 50 controls. AGA patients did not show statistical differences for insulin resistance (glucose, insulin, C peptide, HOMA), lipids (total-cholesterol, HDL-cholesterol, tryglicerides) or hormonal parameters (testosterone, free androgen index, sex hormone-binding globulin) P > 0.05, respectively. No differences between groups were observed in prevalence of MS or its components (P > 0.05). AGA patients showed higher levels of fibrinogen, C reactive protein (CRP) and lipoprotein(a) (Lp(a)) (P = 0.016, P = 0.019 and P = 0.032, respectively). In the unadjusted logistic regression analyses, PCR >4 mg/L, fibrinogen >395 mg/dL and Lp(a) >59 mg/dL increased the risk of AGA, but in the adjusted logistic regression analyses, only PCR >4 mg/L and Lp(a) >59 mg/dL independently increased this risk (OR = 5.83, 95% CI 1.33-25.59 P = 0.020; OR = 3.94 CI 95% 1.08-14.43 P = 0.038). The present study indicates that AGA patients do not show differences in either insulin resistance or prevalence of MS. However, AGA patients show a higher cardiovascular risk characterised by an increase in inflammatory parameters and Lp(a) levels. PMID- 25536914 TI - The PMA action via metabolism of uremic erythrocytes. PMID- 25536915 TI - Hemorheologic effects of low intensity endurance training in type 2 diabetic patients: A pilot study. AB - We previously reported that low intensity endurance training in sedentary patients suffering from the metabolic syndrome improves blood rheology, mostly due to a decrease in plasma viscosity correlated with an increase in cardiorespiratory fitness. We investigated whether these findings can be extended to type-2 diabetics. 22 diabetics (11 women and 10 men, age: 52.00 +/- 2.9 yr, BMI: 32.47 +/- 1.17 kg/m(2)) were tested before and after 2 months. Eight of them were trained (2 to 3*45 min/wk) at the power intensity where lipid oxidation reaches a maximum (LIPOX max) and thirteen served as controls. Over this period the only significant hemorheological effect of training was a decrease in RBC aggregation "M" (-1.25 +/- 0.357 p = 0.01) in the trained group. Subjects who lost weight exhibited a decrease in plasma viscosity (from 1.46 +/- 0.013 to 1.38 +/- 0.02 p < 0.01). Changes in waist circumference are associated with changes in hematocrit (r =-0.952 p = 0.01); plasma viscosity (r =-0.91; p = 0.03); RBC aggregation ("M" r = 0.940; p = 0.02). Subjects can also be divided into those who improved their aerobic capacity VO(2max) and those whose VO(2max) decreased or remained unchanged. An increase in VO(2max) is associated with a decrease in whole blood viscosity (r =-0.79 p = 0.06) explained by an improvement in RBC rigidity "Tk" (r =-0.963 p = 0.002). This study suggests that in Type 2 diabetic patients: (a) viscosity factors might be less responsive to training than in non diabetic individuals; (b) visceral fat loss is the main determinant of changes in hematocrit, plasma viscosity and RBC aggregation; PMID- 25536916 TI - Is signal peptide-CUB-EGF domain-containing protein1 a diagnostic biomarker in patients with hypertensive crises. AB - BACKGROUND: Platelet activation might play a significant role in the pathophysiology of cardiovascular and cerebrovascular events in hypertension (HT). Signal peptide-CUB-EGF domain-containing protein1 (SCUBE1), an indicator of platelet activation, is increased in HT. The aim of this study was to investigate the SCUBE1 in patients with hypertensive crises. METHODS: This study included 33 hypertensive urgency (HU) and 39 hypertensive emergency (HI) patients admitted to our emergency department with a diagnosis of hypertensive crisis. Platelet activation was evaluated with biochemical markers such as SCUBE1, soluble CD40L (sCD40L), mean platelet volume, and platelet count. RESULTS: The SCUBE1 values of the HE patients were significantly higher than other groups (1.09 +/- 0.49, 0.71 +/- 0.23 and 0.37 +/- 0.02 ng/dl, respectively; p < 0.01). The sCD40L values were higher in the hypertensive crises compared with the control group (4.16 +/- 1.82, 3.41 +/- 1.76 and 1.76 +/- 0.68 ng/ml, respectively; p < 0.01). More importantly, SCUBE1 had high sensitivity and specificity in the detection of target organ damage. CONCLUSION: In present study showed that SCUBE1 was significantly higher in HE patients. In addition, sCD40L level, presence of diabetes, and systolic blood pressure were independently associated with increased SCUBE1. According to our results, SCUBE1 might be a diagnostic biomarker in hypertensive crisis patients. PMID- 25536917 TI - Down regulation of Jag-1 in VSMCs contributes to impaired angiogenesis under high glucose condition: Experimental study using aortic rings of rats. AB - The major cause of diabetes-related mortality is the complications involving aberrant angiogenesis. To understand the underlying mechanisms of such altered angiogenesis in diabetes, examining the interaction between endothelial cells (ECs) and neighboring smooth muscle cells (VSMCs) rather than mainly focusing on EC might provide us useful information. Thus, in the present study, we examined the effect of high glucose on the expression of Jag1, one of the key trans activating ligands of Notch receptors known to be involved in EC-SMC interaction, as well as angiogenic process, in vascular smooth muscle cells (VSMCs) to elucidate possible role of EC-VSMC interaction in diabetes-related angiopathy. Our data indicate that high glucose condition decreases the expression of Jag1 in VSMCs possibly by increasing Jag1-targeting micro RNAs (miRNAs) such as miR-21, and exogenous Jag1-simulating peptides increase proliferation and migration of ECs under high glucose condition in vitro. Ex vivo study using aortic rings from normal and streptozotocin (STZ)-treated diabetic mouse demonstrated that exogenous Jag1-simulating peptides increases EC sprouting of aortic rings from diabetic mouse under high glucose condition. Our data suggest that EC-VSMC interaction is altered under high glucose condition and restoring EC-VSMC interaction can be a feasible therapeutic target for treating diabetes-related angiopathy. PMID- 25536918 TI - Acute carbon monoxide poisoning alters hemorheological parameters in human. AB - Acute carbon monoxide (CO) poisoning seriously hinders oxygen delivery to tissues. This harmful effect of CO may be aggravated by accompanying changes in the viscosity of blood. We had previously reported increased plasma viscosity in people chronically exposed to CO. This study was planned to test our hypothesis that acute CO poisoning increases blood viscosity. For this purpose four main parameters contributing to blood viscosity - hematocrit, erythrocyte deformability, erythrocyte aggregation and plasma viscosity - were determined in patients with acute CO poisoning and compared with healthy controls. Plasma viscosity and erythrocyte aggregation tendency were lower in the CO group (p < 0.05). Erythrocyte deformability was also lower in CO group (p < 0.05). Our results indicate that acute CO poisoning has diverse effects on hemorheological parameters such as attenuating hematocrit value, plasma viscosity, erythrocyte aggregation tendency and erythrocyte deformability. PMID- 25536919 TI - Early hemorheological changes in a porcine model of intravenously given E. coli induced fulminant sepsis. AB - The pathophysiology of hemorheological and microcirculatory disturbances in septic process -mostly during the early hours- still not clarified in all the details, yet. In anesthetized pigs living E. coli (ATCC 25922 strain) was administered intravenously with an increasing concentration and the animals were observed for 8 hours. Before the intervention and in every 2 hours arterial (cannulated femoral artery) and venous (cannulated external jugular vein) blood samples were collected for hemorheological laboratory tests: blood and plasma viscosity, ESR, leukocyte anti-sedimentation rate, erythrocyte deformability (together with osmoscan parameters) and erythrocyte aggregation (using light transmission and laser back-scattering methods) Control animals were stable over the 8-hour anesthesia, while septic animals died by the 6th hours in a fulminant sepsis. Over the experimental period, the tendency of impairment in erythrocyte deformability (together with osmotic gradient ektacytometry parameters) and the controversial decreasing of erythrocyte aggregation values (declining all aggregation index values, elongating t1/2) were well detected in this porcine model during the early hours (4- 6) of fulminant sepsis. The in vitro effect of these bacteria on erythrocytes' micro-rheological parameter was similar: decreasing red blood cell deformability and lowering aggregation. Further studies are needed to clarify the early micro-rheological changes of bacteremia and the developing sepsis. PMID- 25536920 TI - The effect of leukocyte-reduced platelet-rich plasma on the proliferation of autologous adipose-tissue derived mesenchymal stem cells. AB - Clinical application of platelet-rich plasma (PRP) and stem cells has become more and more important in regenerative medicine during the last decade. However, differences in PRP preparations may contribute to variable PRP compositions with unpredictable effects on a cellular level. In the present study, we modified the centrifugation settings in order to provide a leukocyte-reduced PRP and evaluated the interactions between PRP and adipose-tissue derived mesenchymal stem cells (ASCs).PRP was obtained after modification of three different centrifugation settings and investigated by hemogram analysis, quantification of protein content and growth factor concentration. ASCs were cultured in serum-free alpha-MEM supplemented with autologous 10% or 20% leukocyte-reduced PRP. Cell cycle kinetics of ASCs were analyzed using flow cytometric analyses after 48 hours.Thrombocytes in PRP were concentrated, whereas erythrocytes, and white blood cells (WBC) were reduced, independent of centrifugation settings. Disabling the brake further reduced the number of WBCs. A higher percentage of cells in the S-phase in the presence of 20% PRP in comparison to 10% PRP and 20% fetal calf serum (FCS) advocates the proliferation stimulation of ASCs.These findings clearly demonstrate considerable differences between three PRP separation settings and assist in safeguarding the combination of leukocyte-reduced PRP and stem cells for regenerative therapies. PMID- 25536921 TI - A first-principles study of lithium adsorption on a graphene-fullerene nanohybrid system. AB - The mechanism of Li adsorption on a graphene-fullerene (graphene-C60 ) hybrid system has been investigated using density functional theory (DFT). The adsorption energy for Li atoms on the graphene-C60 hybrid system (-2.285 eV) is found to be higher than that on bare graphene (-1.375 eV), indicating that the Li adsorption on the former system is more stable than on the latter. This is attributed to the high affinity of Li atoms to C60 and the charge redistribution that occurs after graphene is mixed with C60 . The electronic properties of the graphene-C60 system such as band structure, density of states, and charge distribution have been characterized as a function of the number of Li atoms adsorbed in comparison to those of the pure graphene and C60 . Li adsorption is found to preferentially occur on the C60 side due to the high adsorption energy of Li on C60 , which imparts a metallic character to the C60 in the graphene-C60 hybrid system. PMID- 25536922 TI - Endoscopic transnasal approaches to pterygopalatine fossa tumors. AB - BACKGROUND: The pterygopalatine fossa (PPF) is a difficult area to access, as it has been traditionally treated by external approaches. The development of endoscopic transnasal approaches enables surgeons to reach this region through a minimally invasive route, reducing the associated morbidity. METHODS: We conducted a retrospective review of patients with benign and malignant tumors arising in or extending to the PPF, treated from 2000 to 2013 at a single institute, using endoscopic transnasal transmaxillary approaches. RESULTS: Thirty seven consecutive patients with benign (27 cases) and malignant (10 cases) tumors were treated with curative intent. Radical resection was achieved in 36 of 37 patients. No major complications were observed. No local recurrences were observed, with a median follow-up of 38.5 months for malignancies and 60 months for benign tumors. CONCLUSION: The endoscopic transnasal approaches are safe and feasible techniques for the radical resection of selected tumors involving the PPF and should be tailored according to the biology and extension of the lesion. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E214-E220, 2016. PMID- 25536923 TI - Direct synthesis of size-tunable PbS nanocubes and octahedra and the pH effect on crystal shape control. AB - A one-pot synthesis for the growth of PbS nanocubes and octahedra has been developed by heating an aqueous mixture of cetyltrimethylammonium bromide (CTAB), thioacetamide (TAA), lead acetate, and nitric acid at 90 degrees C for 3 h. The method allows for direct large-scale production of small and uniform PbS nanocubes. The PbS cubes and octahedra exhibit different surface properties, as evidenced by zeta potential measurements and stability tests in methyl orange and methylene blue solutions. Examination of the reagent introduction sequence indicates that early or late addition of nitric acid to tune the initial solution pH can strongly influence crystal growth rate and result in the formation of PbS crystals with different sizes and shapes. Remarkably, the use of pre-formed PbS nanocubes for further crystal growth under low TAA concentration can transform the cubes into large octahedra through a series of particle shape evolution. PMID- 25536924 TI - Serum ferritin is associated with progression of peripheral arterial disease in hemodialysis patients. AB - BACKGROUND: Dialysis patients received intravenous iron to treat anemia and had high prevalence of peripheral artery disease (PAD). We hypothesized that high iron status might associate with the progression of PAD among hemodialysis patients. Therefore, we evaluated the relationship between iron status and progression of PAD. METHODS: We measured iron status in 74 hemodialysis patients and studied the association with clinical, biochemical, and vascular parameters including progression of PAD measured by ankle-brachial index (ABI) over 3 years. RESULTS: Mean baseline ABI was 1.03 +/- 0.18. Mean ABI at 3 years was 0.95 +/- 0.20. Mean ?ABI (change in ABI after 3 years) was -0.08 +/- 0.14. Serum ferritin was negatively correlated with baseline ABI (r = -0.232, p = 0.046). After 3 years, ?ABI was negatively associated with 3-year averaged serum ferritin, phosphorus, and calcium-phosphate product (Ca * P) (r = -0.253, p = 0.029; r = 0.278, p = 0.016; r = -0.288, p = 0.013; respectively). After an adjusted model, 3-year averaged serum ferritin and Ca * P remained the significant determinants of ?ABI (beta = -0.234, p = 0.038; beta = -0.271, p = 0.017; respectively). ?ABI was significantly different between 3-year averaged serum ferritin level >=600 and <600 ng/mL (p = 0.032). CONCLUSIONS: In hemodialysis patients, high serum ferritin associates with progression of PAD, especially among those with high Ca x P level. PMID- 25536926 TI - Facile preparation of an immobilized surfactant-free palladium nanocatalyst for metal hydride trapping: a novel sensing platform for TXRF analysis. AB - In this work, a simple route for the synthesis of surfactant-free immobilized palladium nanoparticles (Pd NPs) and their use as effective nanocatalysts for metal hydride decomposition is described. A mixture of ethanol : water was used as the reducing agent. Ethanol was added in a large excess to reduce the ionic Pd and stabilize the obtained Pd NPs. Ethanol is adsorbed on the surface of Pd allowing steric stabilization. Freshly prepared Pd NPs were immobilized onto quartz substrates modified with 3-mercaptopropyltrimethoxysilane. Pd interacts with the thiol group of the alkoxysilane that is adsorbed on the surface of NPs without the dissociation of the S-H bond. Different parameters affecting the synthesis of Pd NPs and their immobilization onto quartz substrates were evaluated. A comprehensive characterization of the synthesized Pd NPs was carried out by transmission electron microscopy (TEM), whereas total reflection X-ray fluorescence (TXRF) spectrometry was applied in order to evaluate their catalytic activity for solid-gas reactions. Immobilized Pd NPs were applied as nanocatalysts for the dissociative chemisorption of arsine at room temperature, yielding the formation of As-Pd bonds. Quartz substrates coated with nanosized Pd could be used as novel sensing platforms for total reflection X-ray fluorescence analysis. Arsenic can be detected in situ in natural water with a limit of detection of 0.08 MUg L(-1). PMID- 25536925 TI - Living on the Societal Edge: India's Transgender Realities. AB - The transgendered people have played an important role in ancient Indian culture over millennia. They were portrayed in famous Hindu religious scriptures such as Ramayana and Mahabharata. They were given imperative roles in the royal courtyards of Mughal emperors. Their downfall came only at the onset of British rule during the eighteenth century when they were blacklisted and treated as criminal elements in society. Only in 2014, India's Supreme Court has made a landmark ruling by declaring that the transgendered people must have access to equal opportunity in society. In spite of this legal recognition, transgenders at large have been forced to live on the fringes of the contemporary Indian society. This article explores their past glories, present struggles and future ambitions in the world's largest democracy. PMID- 25536927 TI - A systematic review on cost effectiveness of HIV prevention interventions in the United States. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) focus on funding HIV prevention interventions likely to have high impact on the HIV epidemic. In its most recent funding announcement to state and local health department grantees, CDC required that health departments allocate the majority of funds to four HIV prevention interventions: HIV testing, prevention with HIV-positives and their partners, condom distribution and policy initiatives. OBJECTIVE: We conducted a systematic review of the published literature to determine the extent of the cost-effectiveness evidence for each of those interventions. METHODOLOGY: We searched for US-based studies published through October 2012. The studies that qualified for inclusion contained original analyses that reported costs per quality-adjusted life-year saved, life-year saved, HIV infection averted, or new HIV diagnosis. For each study, paired reviewers performed a detailed review and data extraction. We reported the number of studies related to each intervention and summarized key cost-effectiveness findings according to intervention type. Costs were converted to 2011 US dollars. RESULTS: Of the 50 articles that met the inclusion criteria, 33 related to HIV testing, 15 assessed prevention with HIV positives and partners, three reported on condom distribution, and one reported on policy initiatives. Methodologies and cost-effectiveness metrics varied across studies and interventions, making them difficult to compare. CONCLUSION: Our review provides an updated summary of the published evidence of cost effectiveness of four key HIV prevention interventions recommended by CDC. With the exception of testing-related interventions, including partner services, where economic evaluations suggest that testing often can be cost effective, more cost effectiveness research is needed to help guide the most efficient use of HIV prevention funds. PMID- 25536928 TI - Potential savings in prescription drug costs for hypertension, hyperlipidemia, and diabetes mellitus by equivalent drug substitution in Austria: a nationwide cohort study. AB - BACKGROUND: Healthcare systems spend considerable proportions of their budgets on pharmaceutical treatment of hypertension, hyperlipidemia, and diabetes mellitus. From data on almost all residents of Austria, a country with mandatory health insurance and universal health coverage, we estimated potential cost savings by substituting prescribed medicines with the cheapest medicines that were of the same chemical substance and strength, and available during the same time. METHODS: Data from 8.3 million persons (98.5 % of the total Austrian insured population) from 2009-2012 were analyzed. Real prescription costs for antihypertensive, lipid-lowering, and hypoglycemic medicines achievable by same substance, same-strength drug substitution were computed for each active ingredient, and per gender and 1-year age category of patients. RESULTS: In 2012, health insurance providers spent 231.3 million, 77.8 million, and 91.9 million for antihypertensive, lipid-lowering, and diabetes medications, of which 52.2 million (22.6 %), 15.9 million (20.5 %), and 4.1 million (4.5 %), respectively, could have been saved by same substance drug substitution. Highest potential savings were calculated for amlodipine (8.0 million, 65.4 %), simvastatin (12.2 million, 59.3 %), and metformin (2.4 million, 54.6 %), respectively. Higher savings for men than for women resulted from differing prescribed cumulative dosages and proportions of patients with co-payment waiver. Potential cost savings in antihypertensive and lipid-lowering drugs increased from 2009-2012. CONCLUSION: Our study highlights the cost-savings potential from arguably the most acceptable of interventions, simply switching to the cheapest available same-substance, same strength product. In 2012, this strategy could have reduced costs for antihypertensive, lipid-lowering, and hypoglycemic treatment by up to 18.0 %. PMID- 25536929 TI - Principal component regression and linear mixed model in association analysis of structured samples: competitors or complements? AB - Genome-wide association studies (GWAS) have been established as a major tool to identify genetic variants associated with complex traits, such as common diseases. However, GWAS may suffer from false positives and false negatives due to confounding population structures, including known or unknown relatedness. Another important issue is unmeasured environmental risk factors. Among many methods for adjusting for population structures, two approaches stand out: one is principal component regression (PCR) based on principal component analysis, which is perhaps the most popular due to its early appearance, simplicity, and general effectiveness; the other is based on a linear mixed model (LMM) that has emerged recently as perhaps the most flexible and effective, especially for samples with complex structures as in model organisms. As shown previously, the PCR approach can be regarded as an approximation to an LMM; such an approximation depends on the number of the top principal components (PCs) used, the choice of which is often difficult in practice. Hence, in the presence of population structure, the LMM appears to outperform the PCR method. However, due to the different treatments of fixed vs. random effects in the two approaches, we show an advantage of PCR over LMM: in the presence of an unknown but spatially confined environmental confounder (e.g., environmental pollution or lifestyle), the PCs may be able to implicitly and effectively adjust for the confounder whereas the LMM cannot. Accordingly, to adjust for both population structures and nongenetic confounders, we propose a hybrid method combining the use and, thus, strengths of PCR and LMM. We use real genotype data and simulated phenotypes to confirm the above points, and establish the superior performance of the hybrid method across all scenarios. PMID- 25536930 TI - The global effect of heat on gene expression in cultured bovine mammary epithelial cells. AB - Heat stress (HS) in hot climates is a major cause that strongly negatively affects milk yield in dairy cattle, leading to immeasurable economic loss. The heat stress response of bovine mammary epithelial cells (BMECs) is one component of the acute systemic response to HS. Gene networks of BMECs respond to environmental heat loads with both intra- and extracellular signals that coordinate cellular and whole-animal metabolism. Our experimental objective was to characterize the direct effects of heat stress on the cultured bovine mammary epithelial cells by microarray analyses. The data identified 2716 differentially expressed genes in 43,000 transcripts which were changed significantly between heat-stressed and normal bovine mammary epithelial cells (fold change >=2, P <= 0.001). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these differentially expressed genes are involved in different pathways that regulate cytoskeleton, cell cycle, and stress response processes. Our study provides an overview of gene expression profile and the interaction between gene expression and heat stress, which will lead to further understanding of the potential effects of heat stress on bovine mammary glands. PMID- 25536931 TI - Small heat shock proteins: big folding machines. AB - The workshop was entitled "The Small HSP World" and had the mission to bring together investigators studying small heat shock proteins (sHSPs). It was held at Le Bonne Entente in Quebec City (Quebec, Canada) from October 2 to October 5 2014. Forty-four scientists from 14 different countries attended this workshop of the Cell Stress Society International (CSSI). The small number of participants stimulated interesting discussions, and the resulting informal atmosphere was appreciated by everybody. This article provides highlights from talks and discussions of the workshop, giving an overview of the latest work on sHSPs. PMID- 25536932 TI - Extracellular vesicles in parasitic diseases. AB - Parasitic diseases affect billions of people and are considered a major public health issue. Close to 400 species are estimated to parasitize humans, of which around 90 are responsible for great clinical burden and mortality rates. Unfortunately, they are largely neglected as they are mainly endemic to poor regions. Of relevance to this review, there is accumulating evidence of the release of extracellular vesicles (EVs) in parasitic diseases, acting both in parasite-parasite inter-communication as well as in parasite-host interactions. EVs participate in the dissemination of the pathogen and play a role in the regulation of the host immune systems. Production of EVs from parasites or parasitized cells has been described for a number of parasitic infections. In this review, we provide the most relevant findings of the involvement of EVs in intercellular communication, modulation of immune responses, involvement in pathology, and their potential as new diagnostic tools and therapeutic agents in some of the major human parasitic pathogens. PMID- 25536933 TI - Effect of storage on physical and functional properties of extracellular vesicles derived from neutrophilic granulocytes. AB - AIM: To carry out a systematic study on the effect of different storage conditions on the number as well as the physical and functional properties of antibacterial extracellular vesicles (EVs) derived from human neutrophilic granulocytes. METHODS: Production of EVs with antibacterial properties was initiated by opsonized Zymosan A particles. The number of released fluorescent EVs was determined by flow cytometry following careful calibration. Physical properties and size of EVs were investigated by flow cytometry, dynamic light scattering and electron microscopy. Functional properties of EVs were tested by bacterial survival assay. RESULTS: Storage at +20 degrees C or +4 degrees C resulted in a significant decrease of EV number and antibacterial effect after 1 day. Storage at -20 degrees C did not influence the EV number up to 28 days, but induced a shift in EV size and almost complete loss of antibacterial function by 28 days. Storage at -80 degrees C had no significant effect either on EV number or size and allowed partial preservation of the antibacterial function up to 28 days. Snap-freezing did not improve the results, whereas the widely used cryoprotectants induced EV lysis. CONCLUSION: Storage significantly alters both the physical and functional properties of EVs even if the number of EVs stays constant. If storage is needed, EVs should be kept at -80 degrees C, preferably not longer than 7 days. For functional tests, freshly prepared EVs are recommended. PMID- 25536934 TI - Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. AB - Secreted membrane-enclosed vesicles, collectively called extracellular vesicles (EVs), which include exosomes, ectosomes, microvesicles, microparticles, apoptotic bodies and other EV subsets, encompass a very rapidly growing scientific field in biology and medicine. Importantly, it is currently technically challenging to obtain a totally pure EV fraction free from non vesicular components for functional studies, and therefore there is a need to establish guidelines for analyses of these vesicles and reporting of scientific studies on EV biology. Here, the International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs. PMID- 25536935 TI - Practical lessons in murine thoracic lymph duct cannulations: observations in female and male mice across four different strains that impact on "cannulatability". AB - Cannulation of the thoracic lymph duct in experimental animals allows direct measurement of the lymphatic exposure of lymph-targeted drugs. When coupled with recent advances in genetically modified and diseased mouse models, this presents further opportunities to define changes in biological processes and disease in response to drug treatment. Although cannulation of the thoracic lymph duct in mice is inherently challenging because of the small size and delicate nature of the duct, it can be further confounded by anatomical variations between animals. In this communication, we present our observations on the anatomical features of the thoracic lymph duct between mice of different strains and genders, and discuss the impact of these features on the "cannulatability" of the duct. We also provide some technical tips to help guide other investigators to deliver higher experimental success rates. PMID- 25536936 TI - Characteristics of Mothers Caring for Children During Episodes of Homelessness. AB - This study provides a description of the physical, psychological, and substance use problems of adult homeless women who are and are not caring for children. We also examined differences in the characteristics of these two groups of women. Interviews were conducted with 148 homeless women from three mid-sized U.S. cities, 24.3 % of whom were caring for at least one child. Our results showed that women caring for children were more likely to be sheltered and have health insurance. Homeless women caring for children and solitary homeless women were generally similar in terms of substance abuse problems. However, rates of Borderline Personality Disorder were higher among women caring for children than among solitary homeless women. Our results are somewhat consistent with previous research, with the exception of substance abuse problems and mental health problems, which were shown to be equally problematic for all women, regardless of current caregiving status. PMID- 25536937 TI - Socio-demographic and Health Behavioral Correlates of Depressive Symptoms among Korean Americans. AB - This study identifies the associations between socio-demographic characteristics and help seeking behaviors for depressive symptoms among adult Korean Americans (KAs). Using survey data from 230 residents of the New York City, Teaneck, New Jersey, and Philadelphia areas, simple and multiple logistic regression analyses were performed to assess the association between depressive symptoms and the covariates. Women were at much lower risk of depressive symptoms than were men, even after adjusting other covariates (OR 0.45, 95% CI 0.21-0.96). Having no health insurance (OR 4.02, 95% CI 1.28-12.61) and having experience in seeking professional help for mental health problems during the last year were significantly associated with depressive symptoms (OR 2.96, 95% CI 1.29-6.80). The findings suggest more attention to the risk of depression of KA men and further efforts on understanding the unique contribution of socio-demographic factors and health-related behaviors on depressive symptoms among KAs. PMID- 25536938 TI - Examining undetermined and accidental deaths as source of 'under-reported suicide' by age and sex in twenty Western countries. AB - OBJECTIVES: 'Undetermined' (UnD) and accidental deaths (AccD) are explored as possible sources of 'under-reported-suicides' (URS) in 20 Western countries. METHODS: WHO mortality rates per million of AccD, UnD and suicides analysed. UnD:suicides ratios of <1:5 calculated as likely URS versus ratios >1:10 unlikely URS and all correlated by sex and age. RESULTS: Male URS likely in 7 countries and in 11 for females. URS in AccD likely in 5 countries for both sexes only UnD and suicide rates the elderly (75+) significantly correlated. CONCLUSION: Strong indication of URS in the UK, Portugal, Switzerland, Sweden, Denmark and Germany with likely URS in AccD in Greece, Portugal, Switzerland and USA. These findings have important implications, indicating that, with the exception of France and Japan, official reported suicide rates contain a degree of under-reporting, and especially for women yet it is essential to have accurate suicide data to ensure adequate service provision. PMID- 25536939 TI - Comparing kept appointment rates when calls are made by physicians versus behavior health technicians in inner city hospital: literature review and cost considerations. AB - Dropping out of scheduled care leads to medication non adherence, increased morbidity, relapse and readmission rates. As part of a performance improvement project to increase attendance rates at our outpatient clinic, psychiatric residents and Behavioral Health Technicians made reminder telephone calls under similar circumstances. We compared follow up appointment rates in the two groups. Our analysis showed that there was no significant difference in the rates of kept appointment overall between the two groups. The important finding is physician time could be better spent in other patient care duties and reminder calls could be delegated to other health staff. PMID- 25536940 TI - Crystalizing the role of traditional healing in an urban Native American health center. AB - A needs assessment surveying American Indians and Alaska Natives (AIs/ANs) at an AI/AN health center in the Midwestern United States was conducted, with an emphasis on traditional Native healing. Data from this study included qualitative material from interviews of community members (N = 27; age 12-82) and service providers (N = 11; age 26-70). Respondents emphasized the path to wellness includes physical, spiritual and mental health and that traditional healing can restore various imbalances. Furthermore, traditional healing was considered a complement to Western medicine. Third, traditional medicine as a tool in healthcare settings was conceptualized on a continuum. PMID- 25536941 TI - Don't Step on the Tiger's Tail: A Mixed Methods Study of the Relationship Between Adult Impact of Childhood Adversity and Use of Coping Strategies. AB - A mixed methods study examined the relationship between childhood adversity (ACE) and coping among individuals grouped by perceived impact of ACE in adulthood. Groups did not differ on mean total ACE scores and total ACE score was not associated with any coping strategy. Differences between groups were found in 6 of 14 coping strategies. Planning and active coping were endorsed the most by both groups, despite their being used in significantly different amounts and in different ways. How individuals with ACE rate its impact in their current lives is a significant factor in the use and meaning of coping strategies. PMID- 25536942 TI - Predictors of Burnout Among Nurses in Taiwan. AB - Nurse burnout is a crucial issue for health care professionals and impacts nurse turnover and nursing shortages. Individual and situational factors are related to nurse burnout with predictors of burnout differing among cultures and health care systems. The predictors of nurse burnout in Asia, particularly Taiwan, are unknown. The purpose of this study was to investigate the predictors of burnout among a national sample of nurses in Taiwan. A secondary data analysis of a nationwide database investigated the predictors of burnout among 1,846 nurses in Taiwan. Hierarchical regression analysis determined the relationship between predictors and burnout. Predictors of Taiwanese nurse burnout were age, physical/psychological symptoms, job satisfaction, work engagement, and work environment. The most significant predictors were physical/psychological symptoms and work engagement. The variables explained 35, 39, and 18 % of the emotional exhaustion, personal accomplishment, and depersonalization variance for 54 % of the total variance of burnout. Individual characteristics and nurse self awareness, especially work, engagement can impact Taiwanese nurses' burnout. Nurse burnout predictors provide administrators with information to develop strategies including education programs and support services to reduce nurse burnout. PMID- 25536943 TI - Attributions of Mental Illness: An Ethnically Diverse Community Perspective. AB - Although the prevalence of mental illness is similar across ethnic groups, a large disparity exists in the utilization of services. Mental health attributions, causal beliefs regarding the etiology of mental illness, may contribute to this disparity. To understand mental health attributions across diverse ethnic backgrounds, we conducted focus groups with African American (n = 8; 24 %), Asian American (n = 6; 18 %), Latino/Hispanic (n = 9; 26 %), and White (n = 11; 32 %) participants. We solicited attributions about 19 mental health disorders, each representing major sub-categories of the DSM-IV. Using a grounded theory approach, participant responses were categorized into 12 themes: Biological, Normalization, Personal Characteristic, Personal Choice, Just World, Spiritual, Family, Social Other, Environment, Trauma, Stress, and Diagnosis. Results indicate that ethnic minorities are more likely than Whites to mention spirituality and normalization causes. Understanding ethnic minority mental health attributions is critical to promote treatment-seeking behaviors and inform culturally responsive community-based mental health services. PMID- 25536944 TI - Implementing the Regional Epidemiological Outcomes Workgroup (REOW) in the State of Oklahoma for Substance Abuse Prevention: An ODMHSAS Project. AB - With substance abuse being a significant problem in Oklahoma, the Oklahoma Department of Mental Health and Substance Abuse Services aimed to address these problems using the Strategic Prevention Framework to empower local communities and to assist in implementing prevention strategies based on epidemiological data by establishing the Regional Epidemiological Outcomes Workgroup (REOW) network. Seventeen REOWs across the state helped identify and use community resources to collect, analyze, and interpret epidemiological data to measure the burden of substance abuse problems and the associated intermediate variables. The REOWs prioritized the needs of each community based on the data, identified the gaps and limitations in available community-level data, and helped find solutions. The REOWs serve as a permanent resource for the communities to establish a sustainable and ongoing monitoring system. With this comprehensive network, prevention providers and coalitions have a partner to assist in strategically allocating resources to address substance abuse and other emerging public health issues. The issues identified among different public health areas can help different community sectors formulate their strategy and address key problems in their areas. The REOW network brings awareness more effectively and efficiently to communities about eminent dangers posed by different health-related problems and behaviors. PMID- 25536946 TI - Tactics of the war on suicide. PMID- 25536945 TI - Patient Management and Psychopharmacological Treatment Associated to Smoking Ban in an Acute Psychiatric Unit. AB - This study investigates differences in terms of clinical and treatment management in psychiatric hospitalization associated to smoking ban. We collected data regarding medication, socio-demographic and admission characteristics from all patients admitted to an acute psychiatric hospital before and after a smoking ban was in force. We also assessed a limited sample of patients before and after the ban regarding nicotine dependence, motivation to quit smoking and attitudes towards the ban. More number of leaves of absence and movement restrictions during the ban period occurred in comparison to the pre-ban period. On the contrary a lack of significant differences in terms of hospital stay (duration, rate of voluntary admissions and voluntary discharges), use of sedatives and doses of antipsychotics was found. A period of adjustment regarding the deal with leave of access and facilitate nicotine replacement treatment may help future psychiatric facilities planning smoking free policies. PMID- 25536948 TI - Thermodynamics versus kinetics in nanosynthesis. AB - One may discover a stone tool by chance but it takes more than luck to make a car or cell phone. With the advance of nanoscience, the synthesis of increasingly sophisticated nanostructures demands a rational design and a systems approach. In this Review, we advocate the distinction between thermodynamically and kinetically controlled scenarios, that is, whether a product forms because it is the most stable state or because the pathway leading to it has the lowest energy barrier. Great endeavours have been made to describe the multiple concurrent processes in typical nanosynthesis phenomena, so that the mechanistic proposals in the literature are brought into a common framework for easy contrast and comparison. PMID- 25536949 TI - Medial meniscus anatomy-from basic science to treatment. AB - This paper focuses on the anatomical attachment of the medial meniscus. Detailed anatomical dissections have been performed and illustrated. Five zones can be distinguished in regard to the meniscus attachments anatomy: zone 1 (of the anterior root), zone 2 (anteromedial zone), zone 3 (the medial zone), zone 4 (the posterior zone) and the zone 5 (of the posterior root). The understanding of the meniscal anatomy is especially crucial for meniscus repair but also for correct fixation of the anterior and posterior horn of the medial meniscus. PMID- 25536950 TI - Validity and reliability of a Dutch version of the Foot and Ankle Ability Measure. AB - PURPOSE: The aim of the study was to develop a Dutch language version of the Foot and Ankle Ability Measure (FAAM) and evaluate its measurement properties according to the consensus-based standards for the selection of health measurement instruments (COSMIN) definitions. METHODS: A forward-backward translation procedure was performed and subsequently the Dutch version of the FAAM was evaluated for its reliability and validity in 369 patients with a variety of foot and ankle complaints. The reliability was assessed by calculating the intraclass correlation coefficients (ICC, test-retest reliability), Cronbach's alpha (internal consistency), the standard error of measurement and the minimal detectable change (MDC). Additionally, this was done for athletes. The construct validity was assessed by the use of Spearman's correlation coefficient between FAAM domains and similar and contradictory domains of the Foot and Ankle Outcome Score, Short Form 36 and the Numeric Rating Scale for pain. RESULTS: The ICC of the subscales ranged from 0.62 to 0.86. Cronbach's alpha's minimum was 0.97. At individual level, the MDC ranged from 23.9 to 44.7 and at group level from 2.77 to 4.32. In the subgroup of athletes, the reliability was higher. The hypothesized correlations of the construct validity were supported by an 80% confirmation rate. CONCLUSION: The Dutch version of the FAAM met adequate measurement properties, although the reliability is not optimal. The FAAM-Sport subscale is more useful in athletes and the FAAM-Sport % seems not to contribute. In athletes with various foot and ankle symptoms, the FAAM can be used for functional assessment and follow-up at group level. For the general population, the FAAM is less appropriate. LEVEL OF EVIDENCE: Diagnostic study, Level I. PMID- 25536951 TI - The "Lever Sign": a new clinical test for the diagnosis of anterior cruciate ligament rupture. AB - PURPOSE: A new clinical test for the diagnosis of ACL rupture is described: the so-called "Lever Sign". This prospective study on four groups of patients divided subjects on the basis of MRI findings (complete or partial ACL lesion) and the clinical phase of the injury (acute or chronic). The hypothesis was that this manual test would be diagnostic for both partial and complete tears of the ACL regardless of the elapsed time from injury. METHODS: A total of 400 patients were evaluated and divided into four, equal-sized groups based on time elapsed from injury and MRI findings: Group A (acute phase with positive MRI for complete ACL rupture), Group B (chronic phase with positive MRI for complete ACL rupture), Group C (acute phase with positive MRI for partial ACL rupture), and Group D (chronic phase with positive MRI for partial ACL rupture). Clinical assessment was performed with the Lachman test, the Anterior Drawer test, the Pivot Shift test, and the Lever Sign test. The Lever Sign test involves placing a fulcrum under the supine patient's calf and applying a downward force to the quadriceps. Depending on whether the ACL is intact or not, the patient's heel will either rise off of the examination table or remain down. Additionally, the Lever Sign test was performed on the un-injured leg of all 400 patients as a control. RESULTS: All tests were nearly 100 % sensitive for patients with chronic, complete tears of the ACL. However, for patients with acute, partial tears, the sensitivity was much lower for the Lachman test (0.42), Anterior Drawer test (0.29), and Pivot Shift test (0.11), but not the Lever Sign test (1.00). CONCLUSION: In general, chronic, complete tears were most successfully diagnosed but acute, partial tears were least successfully diagnosed. The Lever Sign test is more sensitive to correctly diagnosing both acute and partial tears of the ACL compared with other common manual tests. The clinical relevance is that some ACL ruptures may be more accurately diagnosed. PMID- 25536952 TI - The contribution of intraoperative medial compartment stability to post-operative knee flexion angle in unicompartmental knee arthroplasty. AB - PURPOSE: Given the knee kinematics and soft tissue balance in unicompartmental knee arthroplasty (UKA), it was hypothesised that intraoperative medial compartment stability will result in good functional outcome. The purpose of this study was to test the influence of soft tissue balance on post-operative knee flexion in UKA. METHODS: The influence of soft tissue balance on post-operative knee flexion in UKA was first examined retrospectively by using a newly developed tensor device in 30 consecutive patients diagnosed with either isolated medial compartmental osteoarthritis or idiopathic necrosis. The intraoperative component gap of the medial compartment was measured by using the tensor while applying a 20-lb joint distraction force at 0 degrees , 10 degrees , 30 degrees , 45 degrees , 60 degrees , 90 degrees , 120 degrees , and 135 degrees of knee flexion, with calculation of the joint looseness. Correlations between the soft tissue parameters and post-operative knee flexion angles were analysed 1 year after surgery. RESULTS: The post-operative knee flexion angle was negatively correlated with the component gap at 45 degrees , 60 degrees , and 90 degrees of flexion (R = -0.41, P < 0.05; R = -0.44, P < 0.05; and R = -0.44, P < 0.05, respectively). Furthermore, the post-operative knee flexion angle was negatively correlated with joint looseness at 45 degrees , 60 degrees , and 90 degrees of flexion (R = 0.40, P < 0.05; R = -0.41, P < 0.05; and R = -0.36, P < 0.05, respectively). CONCLUSIONS: The intraoperative medial compartment stability of knee flexion in midrange resulted in increasing post-operative knee flexion angle in UKA. Medial soft tissue release should be minimised, and assessment of soft tissue balance using a tensor can be performed to predict the post-operative knee flexion angle during surgery for UKA. LEVEL OF EVIDENCE: III. PMID- 25536953 TI - Regioselective cage opening of La2 @D2 (10611)-C72 with 5,6-diphenyl-3-(2 pyridyl)-1,2,4-triazine. AB - The thermal reaction of the endohedral metallofullerene La2 @D2 (10611)-C72 , which contains two pentalene units at opposite ends of the cage, with 5,6 diphenyl-3-(2-pyridyl)-1,2,4-triazine proceeded selectively to afford only two bisfulleroid isomers. The molecular structure of one isomer was determined using single-crystal X-ray crystallography. The results suggest that the [4+2] cycloaddition was initiated in a highly regioselective manner at the C-C bond connecting two pentagon rings of C72 . Subsequent intramolecular electrocyclization followed by cycloreversion resulted in the formation of an open-cage derivative having three seven-membered ring orifices on the cage and a significantly elongated cage geometry. The reduction potentials of the open-cage derivatives were similar to those of La2 @D2 -C72 whereas the oxidation potentials were shifted more negative than those of La2 @D2 -C72 . These results point out that further oxidation could occur easily in the derivatives. PMID- 25536954 TI - Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma. AB - BACKGROUND: It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas. METHODS: Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design. Abexinostat was administered on days 1 through 5 with 75 mg/m(2) of doxorubicin administered on day 4 of every 21-day cycle until patients developed disease progression or drug intolerance or reached a cumulative lifetime doxorubicin dose of 450 mg/m(2). Granulocyte-colony-stimulating factor (G-CSF) support was provided at physician discretion on arm A and was provided to all participants in arm B. From 3 to 6 participants initially received abexinostat 30 mg/m(2) twice daily, and subsequent cohorts were administered doses of 15 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily. All patients without progressive disease after receiving a cumulative lifetime doxorubicin dose of 450 mg/m(2) were given the option to continue with abexinostat as a single agent until they developed disease progression. RESULTS: In total, 22 participants (10 who had previously experienced tumor growth after doxorubicin therapy) were enrolled (6 in arm A, 14 in arm B), 20 were evaluable for dose-limiting toxicity (DLT), and 17 were evaluable for radiologic response. In arm A, participants received abexinostat 15 mg/m(2) or 30 mg/m(2) twice daily. DLTs of grade 3 and 4 neutropenia were observed in 2 of 3 participants who received abexinostat 30 mg/m(2) twice daily. Neither of those patients received G-CSF prophylaxis. In arm B, participants received abexinostat at doses of 30 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily, all with mandated G-CSF support. Two DLTs were observed at the 60 mg/m(2) twice-daily dose (grade 3 infection, grade 4 thrombocytopenia). The pharmacokinetics of abexinostat were not affected by doxorubicin. HDAC activity, as measured by histone acetylation in peripheral blood mononuclear cells, was maximally inhibited at the abexinostat 30 mg/m(2) twice-daily dose. Of the 17 participants who were evaluable for radiologic response, 1 patient had a partial response, 9 patients had stable disease, and 7 patients had progressive disease as their best response; and 8 patients completed >= 5 cycles. Three of those participants had stable disease as their most recent disease status when the current report was written. Four participants who continued on monotherapy remained in stable disease for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study-related deaths were observed. CONCLUSIONS: The maximum tolerated dose for abexinostat was 45 mg/m(2) twice daily administered on days 1 through 5 when patients received doxorubicin 75 mg/m(2) on day 4 of a 3-week cycle and G CSF support was mandated. Toxicities were manageable, and tumor responses were observed. Additional studies are needed to further define the specific contributions of HDAC inhibition in patients who receive doxorubicin for the treatment of metastatic sarcoma. PMID- 25536955 TI - Prediction of delivery mode by ultrasound-assessed fetal position in nulliparous women with prolonged first stage of labor. AB - OBJECTIVES: To ascertain if fetal head position on transabdominal ultrasound is associated with delivery by Cesarean section in nulliparous women with a prolonged first stage of labor. METHODS: This was a prospective observational study performed at Stavanger University Hospital, Norway, and Addenbrooke's Hospital, Cambridge, UK, between January 2012 and April 2013. Nulliparous pregnant women with a singleton cephalic presentation at term and prolonged labor had fetal head position assessed by ultrasound. The main outcome was Cesarean section vs vaginal delivery, and secondary outcomes were association of fetal head position with operative vaginal delivery and duration of remaining time in labor. RESULTS: Fetal head position was assessed successfully by ultrasound examination in 142/150 (95%) women. In total, 19/50 (38%) women with a fetus in the occiput posterior (OP) position were delivered by Cesarean section compared with 16/92 (17%) women with a fetus in a non-OP position (P = 0.01). On multivariable logistic regression analysis, the OP position predicted delivery by Cesarean section with an odds ratio (OR) of 2.9 (95% CI, 1.3-6.7; P = 0.01) and induction of labor with an OR of 2.4 (95% CI, 1.0-5.6; P = 0.05). Fetal head position was not associated with operative vaginal delivery or with remaining time in labor. The agreement between a digital and an ultrasound assessment of OP position was poor (Cohen's kappa = 0.19; P = 0.18). CONCLUSION: OP fetal head position assessed by transabdominal ultrasound was significantly associated with delivery by Cesarean section. PMID- 25536956 TI - [Original preparations versus generics--latanoprost: how similar is different?]. AB - BACKGROUND: To test the interchangeability of the commercially available (in Germany) latanoprost drugs and their generics respectively, the concentration of the active substance was tested. Guidelines of the European Medicines Agency postulate a sufficient bioequivalence, if the range of the agent is within 80 125% of the original drug. METHODS: All compounds of latanoprost were procured registered. The concentration of latanoprost and benzalkoniumchloride was measured by high-performance liquid chromatography (HPLC) in a validated reference labroratory for 23 generics. In addition, the mean volume of drops and the pH of the formulation were measured. The packaging label and the readability of the enclosed information leaflet were checked. RESULTS: All products contained less than 50 MUg/ml latanoprost. The deviating reduction of the active substance (mean: - 7.39%, +/- 2.8%) was accompanied by fluctions of the eyedrops' mass (mean: 0.03 g, +/- 0.002 g). The concentration of benzalkonium chloride was mostly increased (median: 5.45%, min: - 2.5%, max: 11.5%). The pH of the original drug and the generics (median 6.78, min: 6.62, max: 6.81) was similar to the original drug, but was significantly different from an unpreserved formulation (pH 7.18). Due to type size, the packaging leaflet was illegible for humans with impaired vision. CONCLUSIONS: Before prescribing generics in ophthalmology, different factors have to be considered, which might influence the amount of IOP lowering in effect. In the absence of healthcare research it is still unclear, how different bottle forms of eyedrops--such as appearance (e.g. Cyrillic characters) or pressure point (administration)--reduce the adherence of glaucoma patients. PMID- 25536957 TI - A longitudinal cohort study evaluating the impact of a geriatrician-led residential care outreach service on acute healthcare utilisation. AB - BACKGROUND: over the last decade, high demand for acute healthcare services by long-term residents of residential care facilities (RCFs) has stimulated interest in exploring alternative models of care. The Residential Care Intervention Program in the Elderly (RECIPE) service provides expert outreach services to RCFs residents, interventions include comprehensive care planning, management of inter current illness and rapid access to acute care substitution services. OBJECTIVE: to evaluate whether the RECIPE service decreased acute healthcare utilisation. DESIGN: a retrospective cohort study using interrupted time series analysis to analyse change in acute healthcare utilisation before and after enrolment. SETTING: a 300-bed metropolitan teaching hospital in Australia and 73 RCFs within its catchment. SUBJECTS: there were 1,327 patients enrolled in the service with a median age of 84 years; 61% were female. METHODS: data were collected prospectively on all enrolled patients from 2004 to 2011 and linked to the acute health service administrative data set. Primary outcomes change in admission rates, length of stay and bed days per quarter. RESULTS: in the 2 years prior to enrolment, the mean number of acute care admissions per patient per year was 3.03 (SD 2.9) versus post 2.4 (SD 3.3), the service reducing admissions by 0.13 admissions per patient per quarter (P = 0.046). Prior to enrolment, the mean length of stay was 8.6 (SD 11.0) versus post 3.5 (SD 5.0), a reduction of 1.5 days per patient per quarter (P = 0.003). CONCLUSIONS: this study suggests that an outreach service comprising a geriatrician-led multidisciplinary team can reduce acute hospital utilisation rates. PMID- 25536958 TI - Efficacy of the Levonorgestrel-Releasing Intrauterine System on IVF-ET Outcomes in PCOS With Simple Endometrial Hyperplasia. AB - OBJECTIVE: This study investigated the in vitro fertilization (IVF) outcome of levonorgestrel-releasing intrauterine system (LNG-IUS) pretreatment for simple endometrial hyperplasia (EH) in patients with polycystic ovary syndrome (PCOS) undergoing IVF embryo transfer (IVF-ET). METHODS: One hundred ninety patients with PCOS and simple EH without cytologic atypia were allocated randomly to 2 independent arms, that is, the LNG-IUS group (90 patients) and the non-LNG-IUS group (100 patients). Four hundred fourteen patients with PCOS without endometrial disease comprised the control group. Each patient was reevaluated by transvaginal ultrasonography (TVS) and endometrial biopsy after 6 months. For each patient, IVF outcome measures, such as number of recombinant follicle stimulating hormone, endometrial thickness on human chorionic gonadotropin (HCG) day, hormone levels (progesterone, luetinizing hormone, and serum estradiol) on HCG day, number of oocytes, fertilization rate, clinical pregnancy rate, and miscarriage rate were compared among the 3 groups. RESULTS: In general, the 3 groups did not differ with respect to the main clinical and biochemical data. After 6 months, patients in LNG-IUS group had an EH resolution rate of 87.77%. In the non-LNG-IUS group, the resolution rate was 15.00%, and 3% of these patients showed progression of EH. The clinical pregnancy rates in the non-LNG-IUS group were significantly lower (28.04%) than that in the LNG-IUS group (46.06%) and the control group (44.65%). The miscarriage rate was highest in the non-LNG-IUS group, but no significant difference in miscarriage rate existed among the 3 groups. CONCLUSION: The study illustrates that the LNG-IUS can be safely used for 6 months as a treatment for patients with PCOS and simple EH. Additionally, use of the LNG-IUS can increase the clinical pregnancy rates and implantation rates of patients with PCOS and simple EH who undergo gonadotropin-releasing hormone agonist IVF-ET protocols. PMID- 25536959 TI - Who wants to live forever? Organizational decline in health care. PMID- 25536960 TI - MSF: how a humanitarian charity found itself leading the world's response to Ebola. PMID- 25536961 TI - Variation in photosynthetic performance and hydraulic architecture across European beech (Fagus sylvatica L.) populations supports the case for local adaptation to water stress. AB - The aim of this study was to provide new insights into how intraspecific variability in the response of key functional traits to drought dictates the interplay between gas-exchange parameters and the hydraulic architecture of European beech (Fagus sylvatica L.). Considering the relationships between hydraulic and leaf functional traits, we tested whether local adaptation to water stress occurs in this species. To address these objectives, we conducted a glasshouse experiment in which 2-year-old saplings from six beech populations were subjected to different watering treatments. These populations encompassed central and marginal areas of the range, with variation in macro- and microclimatic water availability. The results highlight subtle but significant differences among populations in their functional response to drought. Interpopulation differences in hydraulic traits suggest that vulnerability to cavitation is higher in populations with higher sensitivity to drought. However, there was no clear relationship between variables related to hydraulic efficiency, such as xylem-specific hydraulic conductivity or stomatal conductance, and those that reflect resistance to xylem cavitation (i.e., Psi(12), the water potential corresponding to a 12% loss of stem hydraulic conductivity). The results suggest that while a trade-off between photosynthetic capacity at the leaf level and hydraulic function of xylem could be established across populations, it functions independently of the compromise between safety and efficiency of the hydraulic system with regard to water use at the interpopulation level. PMID- 25536962 TI - Plant hormone-assisted early family selection in Pinus densiflora via a retrospective approach. AB - In an even-aged pine forest trees can vary considerably in stem size. We examined the basis for this anomaly using a retrospective approach. Twelve open-pollinated families of Pinus densiflora Sieb. et Zucc. were deliberately chosen for their variation in stem volumes at age 32 years. Seedlings obtained from these families were grown to age 6 months under optimal nursery conditions. Endogenous levels of growth hormones (auxin [IAA] and gibberellins [GAs]) and expression of the GA biosynthesis gene, PdGA20ox1, all assessed at age 3 months, were significantly correlated, across family, with seedling stem and/or shoot dry biomass at age 6 months. Retrospective comparisons of seedling growth, seedling stem tissue GA(20) and seedling stem expression levels of PdGA20ox1 were then made, across family, with tree stem growth at age 32 years. Age 6 months length and shoot dry biomass at age 6 months showed positive and significant Pearson's correlations with age 32 years tree stem diameters and a tree stem volume index, as did seedling stem tissue GA(20). Even seedling stem PdGA20ox1 expression levels were positively and near significantly (P = 0.088) correlated with age 32 years tree stem diameters. Auxin and GAs control nursery growth of seedlings at the family level, and this control also extends, for GAs at least, to field growth of older trees. We propose that family differences in PdGA20ox1 gene expression, and thus endogenous GA levels, may explain much of the natural variation seen for tree stem size in even-aged pine forests. If our hypothesis is correct, then the heritable components of variation in tree stem growth capacity should be predictable by hormonal and gene expression profiling. Such profiling, combined with the measurement of seedling phenotypic growth characters, could have the potential to accelerate the early selection of those conifer families that possess traits for inherently rapid stem wood growth. PMID- 25536963 TI - Simulation of the dose rate per activity of beta-emitting radionuclides. AB - The dose rate per activity was simulated for 10 beta-emitting radionuclides and for different activity distributions (point source, areal sources and a semi infinite volume source). The results are given for 7 different distances from the source (from 0.01 to 2 m) for both contributions: the beta- and electron emission, and the X- and gamma-emission. Data are provided for both operational quantities and organ doses: Hp(0.07), Hp(3), Hp(10), Hskin and Hlens. Finally, a software applicaton to interpolate the dose rate per activity due to the beta emission of arbitrary radionuclides is presented and a simple superposition of these data and of gamma-ray dose constants to calculate the total dose rate is described. PMID- 25536964 TI - Development of a software platform for providing environmental monitoring data for the Fukushima Daiichi nuclear accident. AB - In nuclear emergencies, it is especially important to carry out a wide range of environmental monitoring and provide the data immediately so as to understand the current distribution of radionuclides and investigate countermeasures. Therefore, it is indispensable for a nuclear emergency response to establish a system that supports rapid provision of these data. The authors have been developing the software platform by integrating technologies of environmental monitoring, information processing and network communication, based on the experience of the Fukushima Daiichi Nuclear Accident. It was discovered that the platform is effective in reducing the time needed to publish the monitoring data. Reducing the cost and workload for publishing the monitoring data is also important because monitoring should be continued over a few decades in the case of the Fukushima accident. The authors' platform is expected to help to mitigate the problem, too. PMID- 25536965 TI - MACE: mutation-oriented profiling of chemical response and gene expression in cancers. AB - SUMMARY: The mutational status of specific cancer lineages can affect the sensitivity to or resistance against cancer drugs. The MACE database provides web based interactive tools for interpreting large chemical screening and gene expression datasets of cancer cell lines in terms of mutation and lineage categories. GI50 data of chemicals against individual NCI60 cell lines were normalized and organized to statistically identify mutation- or lineage-specific chemical responses. Similarly, DNA microarray data on NCI60 cell lines were processed to analyze mutation- or lineage-specific gene expression signatures. A combined analysis of GI50 and gene expression data to find potential associations between chemicals and genes is also a capability of this system. This database will provide extensive, systematic information to identify lineage- or mutation specific anticancer agents and related gene targets. AVAILABILITY AND IMPLEMENTATION: The MACE web database is available at http://mace.sookmyung.ac.kr/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: yoonsj@sookmyung.ac.kr. PMID- 25536966 TI - Disk-based compression of data from genome sequencing. AB - MOTIVATION: High-coverage sequencing data have significant, yet hard to exploit, redundancy. Most FASTQ compressors cannot efficiently compress the DNA stream of large datasets, since the redundancy between overlapping reads cannot be easily captured in the (relatively small) main memory. More interesting solutions for this problem are disk based, where the better of these two, from Cox et al. (2012), is based on the Burrows-Wheeler transform (BWT) and achieves 0.518 bits per base for a 134.0 Gbp human genome sequencing collection with almost 45-fold coverage. RESULTS: We propose overlapping reads compression with minimizers, a compression algorithm dedicated to sequencing reads (DNA only). Our method makes use of a conceptually simple and easily parallelizable idea of minimizers, to obtain 0.317 bits per base as the compression ratio, allowing to fit the 134.0 Gbp dataset into only 5.31 GB of space. AVAILABILITY AND IMPLEMENTATION: http://sun.aei.polsl.pl/orcom under a free license. CONTACT: sebastian.deorowicz@polsl.pl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25536967 TI - Development of a Quantitative Measure of Holistic Nursing Care. AB - Holistic care has long been a defining attribute of nursing practice. From the earliest years of its formal history, nursing has favored a holistic approach in the care of patients, and such an approach has become more important over time. The expansion of nursing's responsibility in delivering comprehensive primary care, the recognition of the importance of relationship-centered care, and the need for evidence-based legitimation of holistic nursing care and practices to insurance companies, policy-makers, health care providers, and patients highlight the need to examine the holistic properties of nursing care. The Holistic Caring Inventory is a theoretically sound, valid, and reliable tool; however, it does not comprehensively address attributes that have come to define holistic nursing care, necessitating the development of a more current instrument to measure the elements of a holistic perspective in nursing care. The development of a current and more comprehensive measure of holistic nursing care may be critical in demonstrating the importance of a holistic approach to patient care that reflects the principles of relationship-based care, shared decision-making, authentic presence, and pattern recognition. PMID- 25536968 TI - The Dancing Nurses and the Language of the Body: Training Somatic Awareness, Bodily Communication, and Embodied Professional Competence in Nurse Education. AB - At first glance, dance and movement may appear foreign to the idea of nurse education. On closer inspection, it could be high time. The flow of words may stop, but the body is always in movement--always communicating. Still, the language of the body, and certainly movement, is an often overlooked potential in education. This is also true for nurse education: in spite of the often bodily close meetings with vulnerable and crisis-stricken patients. These meetings make great demands on the nurse to both contain own feelings and be able to "read" and understand patients' often only sense-based communication. This dimension of the nursing profession can be overwhelming, touching, and shocking for young nursing students. This research project examines, whether a course composed of theory, dance and movement lessons, and increased focus on the bodily communication between students and patients may be developmental for the nursing students' beginning embodied professionality. Results from the project have innovative educational potentials. They also give concrete indications of how nursing educations can develop new holistic anchored embodied training in a very accessible, as well as essential, ancient, and unavoidably present part of the nursing profession. PMID- 25536969 TI - Correlating pre-operative vitamin D status with post-thyroidectomy hypocalcemia. AB - OBJECTIVE: To examine the relationship between pre-operative vitamin D status and post-thyroidectomy hypocalcemia. METHODS: Retrospective study examining 264 total and completion thyroidectomies conducted between 2007 and 2011. Subjects included had a recorded 25-hydroxyvitamin D (25[OH]D) level within 21 days prior to or 1 day following surgery, did not have a primary parathyroid gland disorder, and were not taking 1,25-dihydroxyvitamin D3 (calcitriol) prior to surgery. Some subjects were repleted with vitamin D pre-operatively if a low 25(OH)D level (typically below 20 ng/mL) was identified. Pre-operative 25(OH)D, concurrent neck dissection, integrity of parathyroid glands, final pathology, postoperative parathyroid hormone (PTH), calcium nadir and repletion, and length of stay were examined. RESULTS: The mean pre-operative 25(OH)D for all subjects was 25 ng/mL, and the overall rate of post-operative hypocalcemia was 37.5%. Lower pre operative 25(OH)D did not predict postoperative hypocalcemia (P = .96); however, it did predict the need for postoperative 1,25-dihydroxyvitamin D3 administration (P = .01). Lower postoperative PTH levels (P = .001) were associated with postoperative hypocalcemia. CONCLUSION: Pre-operative 25(OH)D did not predict a postoperative decrease in serum calcium, although it did predict the need for 1,25-dihydroxyvitamin D3 therapy in hypocalcemic subjects. We recommend that 25(OH)D be assessed and, if indicated, repleted pre-operatively in patients undergoing total thyroidectomy. PMID- 25536970 TI - Opioid endocrinopathy. AB - OBJECTIVE: The use of prescription opioids has increased dramatically over the past 20 years. Opioids appear to affect multiple endocrine pathways leading to abnormal levels of different hormones such as testosterone, cortisol, and prolactin (PRL). In this article, we review the current data regarding opioid effects on the hypothalamus, pituitary, and bone metabolism. METHODS: We conducted a PubMed search for articles regarding opioids and each of the following subjects: testosterone, estrogen, cortisol, thyroid, growth hormone (GH), and bone. Most articles were primary source studies conducted between 1980 and 2014. Articles were included if studies were conducted within the time period, published in English, and available as full-length articles. Case reports were reviewed, but controlled studies were given more weight. RESULTS: Opioids appear to affect each of the pituitary hormone pathways in addition to altering bone metabolism. The most commonly reported and substantial effect was hypogonadism in both sexes; however, suppression of the adrenal axis may be more common than initially thought. Although some studies report a change in thyroid and GH levels, overall effects have not been thoroughly studied. There is some evidence for increased fracture risk, possibly mediated by hypogonadism and fall risk. CONCLUSION: More research is needed to determine which opioids are more likely to cause endocrine dysfunction and which patients need to be screened and treated. Also unknown is the length of time to the development of hormonal changes after starting opioid therapy and if cessation of opioid therapy can normalize hormone levels. PMID- 25536971 TI - Impact of a hypoglycemia reduction bundle and a systems approach to inpatient glycemic management. AB - OBJECTIVE: Uncontrolled hyperglycemia and iatrogenic hypoglycemia represent common and frequently preventable quality and safety issues. We sought to demonstrate the effectiveness of a hypoglycemia reduction bundle, proactive surveillance of glycemic outliers, and an interdisciplinary data-driven approach to glycemic management. METHODS: POPULATION: all hospitalized adult non intensive care unit (non-ICU) patients with hyperglycemia and/or a diagnosis of diabetes admitted to our 550-bed academic center across 5 calendar years (CYs). INTERVENTIONS: hypoglycemia reduction bundle targeting most common remediable contributors to iatrogenic hypoglycemia; clinical decision support in standardized order sets and glucose management pages; measure-vention (daily measurement of glycemic outliers with concurrent intervention by the inpatient diabetes team); educational programs. MEASURES AND ANALYSIS: Pearson chi-square value with relative risks (RRs) and 95% confidence intervals (CIs) were calculated to compare glycemic control, hypoglycemia, and hypoglycemia management parameters across the baseline time period (TP1, CY 2009-2010), transitional (TP2, CY 2011-2012), and mature postintervention phase (TP3, CY 2013). Hypoglycemia defined as blood glucose <70 mg/dL, severe hypoglycemia as <40 mg/dL, and severe hyperglycemia >299 mg/dL. RESULTS: A total of 22,990 non-ICU patients, representing 94,900 patient-days of observation were included over the 5-year study. The RR TP3:TP1 for glycemic excursions was reduced significantly: hypoglycemic stay, 0.71 (95% CI, 0.65 to 0.79); severe hypoglycemic stay, 0.44 (95% CI, 0.34 to 0.58); recurrent hypoglycemic day during stay, 0.78 (95% CI, 0.64 to 0.94); severe hypoglycemic day, 0.48 (95% CI, 0.37 to 0.62); severe hyperglycemic day (>299 mg/dL), 0.76 (95% CI, 0.73 to 0.80). CONCLUSION: Hyperglycemia and hypoglycemia event rates were both improved, with the most marked effect on severe hypoglycemic events. Most of these interventions should be portable to other hospitals. PMID- 25536972 TI - Unique characteristics and outcomes of patients diagnosed with both primary thyroid and primary renal cell carcinoma. AB - OBJECTIVE: Patients with multiple primary malignancies may exhibit unique clinical characteristics that suggest a common predisposition or lead to different disease management. Given the association of primary thyroid (TC) and renal cell carcinoma (RCC), we characterized the clinicopathologic features of patients treated for both malignancies (TC/RCC). METHODS: TC/RCC patients were identified through the institutional tumor registry and using data compiled by retrospective chart review. To compare with broader institutional and national cohorts, we examined patients admitted with TC or RCC institution-wide and reviewed the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for these cancers. RESULTS: Overall, 51% of patients developed TC before RCC, 27% developed RCC before TC, and 22% were diagnosed within 1 year of each other. The mean age at TC diagnosis was 52 +/- 15 (18-77), which was significantly older than institutional TC patients (45 +/- 16.5 years, P<=.0001), and the mean age at RCC diagnosis was 59 +/- 12 (32-79). The TC/RCC cohort had a balanced sex distribution (51% female) compared with the institutional TC group (67% female, P = .0003) and the institutional RCC group (31% female, P<.0001). Similar age and sex ratio differences were seen when compared with SEER cohorts. In the TC/RCC cohort, 43% of patients developed other cancers (52% of females, 33% of males; P = .04); among the females, 45% developed breast cancer. CONCLUSION: Individuals who develop both TC and RCC may represent a unique subset of cancer patients. Further prospective research is warranted to explore the unanticipated association with breast cancer in female patients and to investigate a possible common pathogenesis underlying these malignancies. PMID- 25536973 TI - The classic and nonclassic concenital adrenal hyperplasias. AB - OBJECTIVE: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases. METHODS: Case presentation, discussion of literature, table, and bullet point conclusions. RESULTS: The congenital adrenal hyperplasia (CAH) syndromes are autosomal recessive defects in cortisol biosynthesis. The phenotype of each CAH patient depends on the defective enzyme and the severity of the defect. Clinical manifestations derive from both failure to synthesize hormones distal to the enzymatic block, as well as consequences from cortisol precursor accumulation proximal to the block, often with diversion to other biologically active steroids. The most common form of CAH is 21 hydroxylase deficiency, which occurs in the classic form in 1 in 16,000 newborns and in a milder or nonclassic form in at least 1 in 1,000 people. CONCLUSION: This article reviews the various forms of CAH and pitfalls in the diagnosis and treatment of these conditions. PMID- 25536974 TI - Visual vignette. PMID- 25536975 TI - Genetic basis of bilateral macronodular hyperplasia. AB - OBJECTIVE: To review the genetic basis of bilateral macronodular hyperplasia (BMAH). METHODS: Case presentation, review of literature, table, and bullet point conclusions. RESULTS: BMAH, also known as adrenocorticotropic hormone (ACTH) independent macronodular hyperplasia (AIMH), can cause Cushing syndrome or mild hypercortisolism. Recent studies have demonstrated that hyperplastic tissue reproduces ectopic ACTH, implying that BMAH is the more proper term, as the syndrome is not ACTH-independent. BMAH was thought to be sporadic, but recent data have shown that there is likely a genetic component in the majority of cases. Mutations in ARMC5, a putative suppressor gene, have been found in many familial cases of BMAH and are thought to be responsible for the disorder. As these nodules inefficiently produce cortisol, large nodules are required to produce a clinical syndrome. ARMC5 likely requires a second somatic mutation to become clinically apparent. Clinical manifestations are not generally noted until the fifth to sixth decades of life. CONCLUSION: BMAH is an underrecognized genetic condition that can lead to Cushing syndrome and should be screened for in patients and susceptible family members. PMID- 25536976 TI - Public and mental health. PMID- 25536977 TI - Multivariate analysis of predictors of depression symptomatology after childbirth. AB - BACKGROUND: Risk factors of postpartum depression, although relatively well investigated, remain largely unclear. The aim of this study was to identify the most relevant predictors of postpartum depressive symptomatology that are of clinical importance using the Edinburgh Postnatal Depression Scale (EPDS) 3-5 days and 6 to 9 weeks after childbirth. SUBJECT AND METHODS: In order to explore predictors of depression, 3-5 days after childbirth, 372 participants fulfilled several questionnaires: Edinburgh Postnatal Depression Scale (EPDS), Impact of Events Scale Revised (IES-R), Big Five Inventory, and questions regarding breastfeeding practice as well as social and demographic factors. Six to nine weeks after childbirth, the same participants fulfilled the following questionnaires: IES-R, EPDS and breastfeeding practice questions. RESULTS: On a multivariate level of analysis, the predictors that increased the odds for postnatal depression symptomatology at the first study point were: unsuccessful breast feeding initiation (odds ratio (OR) 2.58; confidence interval (CI) 1.35 4.91) and personality traits neuroticism (OR 1.16; CI 1.07-1.25.). The predictors that increased the odds for depression symptomatology at the second study phase were: fear for labor outcome (OR 2.44; C1.03-5.80) and the baseline EPDS score (OR 3.32; CI 1.31-8.40). The predictor that decreased the odds at the second study phase was the personality trait Openness (OR 0.9; CI 0.86-0.99). CONCLUSIONS: Immediately after childbirth biological and psychological factors seem to be predictive for postpartum symptomatology while later only psychological factors are of greater importance. PMID- 25536978 TI - Depression and auto-aggressiveness in adolescents in Zagreb. AB - BACKGROUND: The aim of the study was to explore the frequency of depression among the general population of adolescents who were high school students in the city of Zagreb. As depression is associated with increased suicidal risk we wanted to check to what extent depression, as an emotional problem among youth, is associated with auto-aggression in the general population of adolescents. SUBJECTS AND METHODS: The study was conducted on a sample of high school students in Zagreb and it included 701 students of both genders aged from 14-19 years of age. To test the depression a Beck Depression Inventory (BDI) was administered for youth between 11-18 years of age (Youth Self Report for ages 11-18). To test auto-aggression a Scale of Auto-destructiveness (SAD) was used. RESULTS: Results obtained by this study show that about 20.7% of high school students have mild and borderline depressive disorders while moderate or severe depression shows about 5% of them, whereby depression is statistically significant among girls who, on average, report more symptoms of depression. It has also been proven a significant impact of depression levels (F (2,423)=35.860, p<0.001) on auto aggression in subjects of both genders. In both genders, moderately depressed show more auto destructiveness than those without depression symptoms (p<0.01). In the group of heavily depressed (n=30), significantly higher self destructiveness is shown by girls (p<0.01). CONCLUSIONS: The data suggest the importance of early recognition, understanding and treatment of depressive symptoms in adolescents in order to reduce the risk of subsequent chronic psychosocial damage. PMID- 25536979 TI - Clinically significant depressive disorder in adolescence; cross-sectional study of two Croatian counties. AB - BACKGROUND: The aim of the study was to determine whether there is a difference in the intensity of depression, suicidality, and expression of clinical features among adolescents in two different regions of Krapina-Zagorje (KZ) and Split Dalmatia (SD). SUBJECTS AND METHODS: The study was designed as a descriptive cross-sectional, the sample consisted of 200 adolescents, 100 from each region, aging 16-18 years, from various high schools. The research was conducted by psychiatrists in Split and Krapina, where school population of Split-Dalmatia County and Krapina-Zagorje County gravitates. For the assessment of depression, the Hamilton rating scale for depression with 21 items was used, which has proven in clinical practice. For the inclusion in the study, among other parameters, participants needed to satisfy the criterion that depression is clinically significant (19 or more points on the HAMD-21). RESULTS: The data obtained points out to statistically significant difference in the intensity of depression between the two regions (p<0.001). There was no difference in suicidal impulses. For the most part, the expression of clinical features between adolescents in these regions showed no significant difference, except that guilt (p=0.001), failing in the work plan and activities (p=0.000) and paranoid ideas (p=0.013) were significantly more expressed in adolescents of Krapina-Zagorje County and sleep disorders (p<0.001) in adolescents of Split-Dalmatia County. CONCLUSIONS: It can be concluded that depression, suicidality and much of the clinical features depend on the developmental age, i.e. the turbulent adolescent development, rather than on regional differences, although, to a lesser extent, the expression of clinical features can be influenced by milieu, lifestyle, family dynamics and educational procedures, which can partially affect the expression of clinical features. PMID- 25536980 TI - Life satisfaction, optimism and social capital as predictors of mental health of the recipients of financial welfare from the state. AB - BACKGROUND: Health is largely influenced by the subjective well-being, optimism, social inclusion and satisfaction with life as well as usually defined variables. The aim of this study was to determine the relationship of dimensions of personality (optimism, control over life), social involvement (social capital) and socio-economic status with health and inequalities in health. SUBJECTS AND METHODS: This study was performed on 1017 respondents which were chosen according to set criteria: middle age, working capability, and, according to the documentation of the Centres for social welfare, the recipients of financial welfare from the state. A questionnaire was created from several existing questionnaires with validated indicators. RESULTS: The results show that 78.1% of respondents were unemployed. Regarding the health males express a higher level of health than female. The presence of a chronic disease was found in 56.6% women and 43.4% men. The predictors of health such as optimism, life satisfaction and locus of control showed that satisfaction with life was expressed by 39.7% respondents. Greater satisfaction with life was seen in females (59.6%). Surprisingly, 47.7% of respondents said they thought they had control over their lives and decisions. Women are statistically more optimistic. Almost 60% of respondents were not satisfied with their lives. CONCLUSIONS: Socially deprived population is mainly unemployed with insufficient resources for living. More burdened and higher risk for future development of the disease was found within this population. Optimism, social inclusion and life satisfaction play a large role, as protective factors in health. The interventions demand a multi disciplinary approach, and, with regard to the sensitivity of the population, the best solution is in their own empowerment, as a protective factor for mental health. PMID- 25536981 TI - Stress, depression and burnout among hospital physicians in Rijeka, Croatia. AB - BACKGROUND: Six years of recent ongoing economic and structural crisis in Croatia have brought to a significant decrease of socioeconomic standard in our country, and had an important impact on the health care system. In this background we examined the prevalence of depression and burnout and their association with work stressors. SUBJECTS AND METHODS: Cross sectional survey was conducted with self reported questionnaires in 459 hospital physicians in Rijeka, Croatia. Physicians were divided into three groups: surgical, nonsurgical and diagnostic group. Socio demographic and work-related characteristics questionnaire, Occupational Stress Assessment Questionnaire (OSAQ), Maslach Burnout Inventory-Human Services Survey (MBI-HSS) and Beck Depression Inventory II (BDI-II) were used. Sperman correlation and logistic regression were calculated to rank association between stressors at work with depression and burnout syndrome. RESULTS: Response rate was 62.3%, (286/459). Every fifth doctor experienced all examined stressors in the workplace as stressful. The prevalence of moderate and severe depression was 12.2%. High levels of emotional exhaustion were 43.6%, depersonalization 33.5%, and lack of personal accomplishment 49.1%. There was no statistical difference in surgical, nonsurgical and diagnostic groups in depression and all domains of MBI HSS. Almost all stressors were correlated with depression and burnout syndrome. Most of the perceived stressors were significant predictors of burnout syndrome and depression. CONCLUSIONS: High levels of burnout domain compared to overall results from similar studies from other countries, placed the results in our sample on the higher end of the range, while results for depression after adjustment with lower cutoff point would be similar to those usually found in research literature. Our study showed that burnout is highly prevalent among Croatian physicians. Target interventions at the workplace should be considered as one of the strategies to reduce negative impact of work stress on physicians' mental health. PMID- 25536982 TI - Characteristics of self-medication for pain relief among first-year health care students in Zagreb, Croatia. AB - BACKGROUND: Taking over the responsibility for one's own health and active participation in eliminating the existing health problems is ever more widespread in the world. Self-medication in the form of using any kind of therapy without previous consultation with medical professionals has been ever more common among student populations in many countries. The aim of this study was to determine the attitudes about self-medication for pain relief and features of self-medication in first-year students of the University of Applied Health Studies in Zagreb. SUBJECTS AND METHODS: The study was conducted using an anonymous questionnaire, which was completed by 389 respondents. RESULTS: Taking painkillers in the past year was reported by 74.6% of respondents, significantly more by female students (80.8%); 62.6% of female students used painkillers once a month versus 45.7% of male students taking analgesics once a year. Ibuprofen was preferred by female students and acetylsalicylic acid by male students. Headache was the most common indication for taking painkillers (76.6%), followed by menstrual discomforts in female students (66.2%) and toothache (28.6%). Significant sex differences were recorded in the choice of drugs, indications for self-medication, and frequency of drug use. There were no differences between study courses. CONCLUSIONS: Appropriate student education and improved information transfer between professionals and students are the key elements to ensure judicious, quality and knowledge based use of drugs among students. PMID- 25536983 TI - Comparison of Psychotropic Drug Prescribing Quality between Zagreb, Croatia and Sarajevo, B&H. AB - BACKGROUND: The purpose of this paper was to compare outpatient consumption and quality of psychotropic drug prescribing between Croatia and Bosnia & Herzegovina 2006-2010. METHODS: Data on drug utilization from Zagreb Municipal Pharmacy and Sarajevo Public Pharmacy were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants per day (DDD/TID) using the WHO Anatomical Therapeutic-Chemical methodology. RESULTS: Total utilization of psychopharmaceuticals increased in both cities; however, it was higher in Zagreb than in Sarajevo throughout the study period. The utilization of psycholeptics increased in Zagreb by 2.4% (from 74.5 to 76.3 DDD/TID) and in Sarajevo by 3.8% (from 62.4 to 64.8 DDD/TID). The utilization of anxiolytics decreased in Zagreb by 2.1% and in Sarajevo by even 18.7%. The utilization of antidepressants increased in both cities with predominance of SSRI over TCA utilization, greater in Sarajevo (96.6%) than in Zagreb (10.2%). The anxiolytic/antidepressant ratio decreased by 11.1% in Zagreb (from 2.87 to 2.55) and by 58.7% in Sarajevo (from 5.66 to 2.34). Outpatient utilization of antipsychotics increased significantly in Sarajevo, predominated by typical ones, whereas in Zagreb the utilization of antipsychotics was stable, predominated by atypical ones. CONCLUSIONS: In Croatia and Bosnia & Herzegovina, there was an obvious tendency to follow western trends in drug prescribing, as demonstrated by the increased use of antidepressants and reduced use of anxiolytics. Despite some improvement observed in the prescribing quality, high use of antipsychotics with dominance of typical antipsychotics in Sarajevo points to the need of prescribing guidelines for antipsychotics. PMID- 25536984 TI - Implementation of the program of preventive examinations at primary health care in the city of Zagreb 2009-2013. AB - BACKGROUND: The program covered all persons who had not been in contact with a physician for two years or had failed to notice symptoms themselves or to timely respond to the symptoms observed. The aim of the present study was to analyze the results of the program and try to draw conclusions regarding the necessity further implementation. SUBJECTS AND METHODS: This paper analyzes data on a cohort of 1375 subjects aged 45+, collected on preventive examinations by family physicians during the 2009-2013 period. RESULTS: Results show 24.4% smokers and 15.5% former smokers. Up to three alcoholic drinks per week consumed 18.5% respondents (27.8% male and 11.2% female). Overweight (body mass index 25-30) was recorded in 50.6% and 38.6%, obesity (body mass index >30) in 30.1% and 29.4%, hypertension in 14.6% and 11.8%, isolated systolic hypertension in 20.5% and 17.4%, and isolated diastolic hypertension in 3.3% and 3.0% of male and female subjects, respectively. Suspicion of one or more newly diagnosed disease was recorded in 52.9% (95% CI 50.2-55.5) of study subjects. Fifty-four subjects (7.4%; 95% CI 5.5-9.3) were suspected to have neoplasm and they were immediately referred for further diagnostic evaluation. CONCLUSIONS: Timely manner suspicion of malignant disease is of crucial influence on the course of treatment and outcome of the disease. The study results confirm the importance of continuing the implementation of prevention programs. PMID- 25536985 TI - School health services in the City of Zagreb - do we meet adolescents' needs? AB - BACKGROUND: School health services (SHS) have in Croatia long tradition, established organizational structure, defined program and educated staff. The program is limited to the preventive activities. The aim of the study was to investigate the satisfaction of the children, school staff and parents with existing school health services in the City of Zagreb. SUBJECT AND METHODS: The structured questionnaire was sent to the primary and secondary schools in the City of Zagreb, which were selected using random sample method. The questionnaires were anonymous and filled in supervised by class masters. In the secondary schools the structure of schooling was respected. Questionnaires were filled by 448 pupils from primary, 551 from secondary schools, by 596 parents and 595 teachers. RESULTS: In primary schools pupils rated SHS more available and accessible, staff complaisant and responsible, counselling being useful and justified, confidentiality respected higher than pupils from secondary schools (p<0.001). Teachers from primary and secondary schools perceived SHS as valuable school partners (88.9% and 82.3%). Teachers from primary and secondary schools (88.9% and 88.1%) and parents (78.3% and 67.5%) stated that SHS could not be replaced by GPs or paediatricians. Primary school pupils felt that most common problems were injuries and vocational counselling, secondary school pupils assessed behavioural and sexual related problems as mostly challenging. Satisfaction with the SHS response to the most challenging problems was rated higher by teachers from primary schools (p<0.001 for learning difficulties, chronic diseases, bullying and vocational counselling), by parents for learning difficulties and vocational counselling, but no significance was found for pupils' satisfactions. CONCLUSION: SHS in Zagreb are recognized as vital and necessary partners for schools, available and accessible for pupils, teachers and parents, especially for primary schools. Counselling is highly rated by all respondents, confidentiality considered as respected, and the problem of the most common challenges as successfully solved. PMID- 25536986 TI - Smoking behaviors and lung cancer epidemiology: a cohort study. AB - BACKGROUND: Lung cancer is the most common cancer in the world. According to the latest available data, in the year 2012 Croatia was among 20 countries with the highest incidence of lung cancer. Although tobacco smoking is a proven cause of lung cancer, recent data show that more than one quarter of adult inhabitants of Croatia are everyday smokers. The purpose of this study was to present epidemiology and treatment modalities of lung cancer in the Department for mediastinal tumors, Clinic for lung diseases Jordanovac, and to make a comparison between the available data from Croatia and the rest of the world. SUBJECTS AND METHODS: The study cohort included 212 newly diagnosed lung cancer patients who had referred to our Department from January 2012 until December 2012. Features such as age, gender, cytology and histology of the tumor, stage at diagnosis and applied therapy were evaluated respectively. RESULTS: Approximately two-thirds of all newly diagnosed lung cancers occurred in men. Out of the study cohort, 12.3% were diagnosed with small cell lung cancer (SCLC) and 87.7% were diagnosed with non-small cell lung cancer (NSCLC). The majority of the patients diagnosed with NSCLC had adenocarcinoma (47.9%), followed by squamous cell carcinoma (33.9%) and large cell carcinoma (15%). Only a small number of patients diagnosed and treated for lung cancer in our Department had never smoked tobacco. The majority of those patients were women and the most common histological type found was adenocarcinoma. CONCLUSION: The number of patients who had potentially operable disease at presentation was around 10%. That is why, in most cases, therapeutic options were confined to palliative chemotherapy or radiotherapy. Attention should be directed to an early detection of lung cancer patients, which could provide better treatment options and improve overall survival. PMID- 25536987 TI - Orofacial injuries reported by professional and non-professional basketball players in zagreb and zagreb county. AB - BACKGROUND: Injuries are common during sport activities, a part of which is also injuries to the stomatognathic system. According to the data from literature orofacial injuries are frequent, but relatively minor. World Dental Federation has listed basketball as a medium-risk sport in sustaining orofacial injuries. The purpose of this investigation was to determine incidence, type and severity of orofacial injuries during basketball and frequents of mouthguard use. SUBJECT AND METHODS: The sample consisted of 195 athletes who actively participate in basketball, 60 amateurs/non-professional and 135 professionals. RESULTS: A total of 2 265 injuries to the stomatognathic system were documented in this research; 200 (8.8%) of those injuries refer to the non-professionals and 2 065 (91.2%) to the professionals. The most common injuries are lacerations and contusions of soft tissue (a total of 2 208 or 97.5%), followed by dental injuries (a total of 57 or 2.5%). Out of all recorded laceration injuries 59.8% lacerations of soft tissue occurred during practice (12.6% amateurs and 87.4% professionals), while 40.2% of them occurred during games (2.5% amateurs and 97.5% professionals). Of a total of 57 dental injuries recorded during an athletes career, in 78.9% it were the professionals who suffered an injury, and in 21.1% of them the amateurs. Out of a total of 195 basketball players only 1% (2 players - one professional and one amateur) frequently used mouthguard during practice and games, while 93.3% of them never tried to wear a mouthguard. Such low percentage of mouthguard use in basketball players reflects poor awareness and education of athletes and coaches, as well as insufficient role of dentists in education. CONCLUSIONS: Orofacial injuries during basketball are not severe (80% lacerations), and therefore do not stimulate the use of a protecting devices even their use will totally diminish this type of injuries. PMID- 25536988 TI - Comparison of two Different Methods (Patient Questionnaire and Medication Possession Ratio - MPR) for Measuring the Chronic Patient's Behavior. AB - BACKGROUND: Medication adherence is the extent to which patients take medications as prescribed by their health care providers. There are a number of approaches to study medication-taking behavior. The aim was to compare two most common methods for measuring adherence: Patient Adherence Questionnaire and Medication Possession Ratio (MPR). They belong to the indirect methods. METHODS: In this article four adherence studies were analysed and the results were compared, two wherein the patient questionnaire was applied and other two with medication possession ratio applied. RESULTS: The obtained results reveal that more than half of respondents (58.9%) experienced constant nonadherence behavior according to the prescribed therapy. The main reason of nonadherence is oblivion, suggesting that it is necessary to pay more attention to this problem. CONCLUSIONS: Nonadherence with therapy has negative consequences on the health of the individual, and an adverse impact on the community health and wealth. Patients should be informed of the importance of regularly taking prescribed therapy. The main problem of long-term therapy is significantly decreased of adherence to medication in a very short time. It is important to stress that almost all the interventions effective for improving patient adherence in long term care are complex and should be repeated after a while. PMID- 25536989 TI - Thirty years of using a series of personality questionnaires constructed by computer. AB - BACKGROUND: The series of personality questionnaires constructed using a computer was created on the basis of cybernetic theories of personality, which presupposes the existence of six conative control systems: a system for the regulation of defense responses, a system for the regulation of attack responses, a system for controlling physiological functions, a system for coordination of regulatory functions, system for integration of regulatory functions and system for regulation of activity. Six personality questionnaires measure the intensity of the following pathological personality tendencies: 1. neurasthenia and anxiety, 2. aggressiveness and impulsiveness, 3. conversive neurotic disorders, 4. psychotic dissociation, 5. psychotic regression and 6. extroversion-introversion. SUBJECTS AND METHODS: The sample consisted of 4368 persons: 3496 subjects without a diagnosis, and 872 patients with a psychiatric diagnosis. Participants had to fill in the six personality questionnaire. Data were collected anonymously, during psychological treatment at the Neuropsychiatric Hospital "Dr. Ivan Barbot" in Popovaca, at the Department of Occupational Medicine and Transport and the Department of Mental Health and Addiction Prevention at Dr. Andrija Stampar Institute of Public Health and for the purpose of selection of candidates for employment in the period from 1984 until today. Basic metric characteristics were determined for all scales. Factor structure of the scales was determined using principal component analysis; as canonical discriminant analysis, polar taxons analysis and canonical correlation analysis are special cases of factor analysis, results of factor analysis were used for further processing. RESULTS: Results from earlier studies are replicated on much larger sample: metric characteristics of scales are very good, as in previous studies, similar structure of polar taxons was found and discrimination between healthy subjects ad those with psychiatric diagnoses was successful. Canonical correlation analysis showed interconnection of reactions on certain scales and extremely complex relationship between them which indirectly confirms the theoretical model on the basis of which the scales are formed. CONCLUSIONS: The usefulness of this scales is confirmed in clinical setting and in selection of candidates for employment. PMID- 25536990 TI - Nursing evaluation of diabetes self-management in tertiary healthcare settings in Croatia. AB - BACKGROUND: Systematic and efficient education on patient self-management behaviour represents one of the key approaches to diabetes treatment. The aim of this paper was to evaluate the current process and content of nursing assessment of illness self-management behaviour in persons with diabetes treated at a tertiary healthcare facility. SUBJECTS AND METHODS: Electronic patient records of N=15,116 persons with type 2 diabetes (51.3% men) who took part in nursing evaluation and education throughout 2011 were collected. The patients' mean age was 65.0+/-11.1 years, with mean diabetes duration of 12.6+/-8.3 years; they were mostly treated with oral anti-diabetic drugs (38.4%) or insulin therapy (38.5%). The likelihood of non-participation in the nursing evaluation was predicted based on a number of patient characteristics using a multivariate logistic regression. RESULTS: The nurses mostly rated the patients' self-management knowledge and real life application of that knowledge as appropriate; however, in a large number of patients, the nursing evaluation was not evidenced in the electronic patient record. Multivariate logistic regression revealed that longer diabetes duration, insulin treatment and better glyceamic control as measured by glycated haemoglobin were associated with a higher likelihood of participating in a nursing evaluation and diabetes re-education. CONCLUSION: Diabetes specialist nurses may use informal criteria when deciding which type 2 diabetes patients to interview about diabetes knowledge and self-care. Participative research on the processes of nurses' decision-making may be needed. PMID- 25536991 TI - The most common factors influencing on quality of life of thyroid cancer patients after thyroid hormone withdrawal. AB - BACKGROUND: The aim of study was to evaluate which factors impact mostly on life quality of patients with differentiated thyroid carcinoma after thyroid hormone withdrawal. SUBJECTS AND METHODS: 150 patients were enrolled in the study by using Quality of life- Thyroid version questionnaire in which they expressed their physical, psychological, social and spiritual well-being. The answers have been interpreted on a scale from 0 to 10. All patients underwent four weeks levothyroxine withdrawal in preparation for I-131 procedures and thyroglobulin testing. RESULTS: Individual statements on the physical subscale showed that patients had most difficulties with fatigue, intolerance to cold and heat, sleep changes and weight gain, but with higher average values than expected. Fatigue was one of the most common physical difficulties. Female patients had significantly more difficulties than male respondents. Five most expressed psychological difficulties have been stress caused by initial diagnosis, followed by stress caused by surgical treatment, fear of metastases, stress caused by initial radioiodine ablation treatment and fear of cancer recurrence. Generally, results revealed troubles mostly in physical symptoms relating to thyroid hormone withdrawal, as well as psychological distress caused by initial diagnosis. Respondents with higher educational level achieved a significantly higher score than less educated patients (p=0.026, Mann-Whitney U test). Illness was very distressing for their families (median value 1, range: 0 to 10) and they reported insufficient support from others (1, range: 0 to 10), but they did not feel isolated. Family and work consequences were less apparent. CONCLUSION: The results of QOL-Thyroid questionnaire help to identify high-risk areas in patients' lives that are negatively affected by hormone withdrawal. Regarding the wide definition of quality of life, a positive impact on patients' recovery could be achieved by directing attention to most expressed difficulties noted in this questionnaire. PMID- 25536992 TI - Dry eye in contact lens wearers as a growing public health problem. AB - BACKGROUND: The aim of this study is to analyze the relationship between the self reported symptoms and objective signs of dry eye disease in long-term rigid gas permeable (RGP) or soft contact lens (SCL) wearers. SUBJECTS AND METHODS: The study included 84 eyes of Caucasian RGP and SCL wearers between the age of 15 and 71 who wore contact lenses on a continuous daily basis for more than 1 year. Symptoms were assessed according to the Ocular Surface Disease Index (OSDI). Clinical assessments included corneal fluorescein staining according to the National Eye Institute (NEI) staining grid and tear film break-up time (TBUT). RESULTS: There were more female (76.19%) than male (23.81%) persons with a higher proportion of RGP wearers among the females (88.89% vs. 11.11%). The mean duration of daily lens wear was 7.71+/-2.72 hours. No RGP wearer in this study had a NEI corneal staining grid score higher than 2. A weak negative correlation was found between daily lens wear duration and TBUT (Pearson's coefficient, r= 0.1467). A strong negative correlation was found between TBUT and OSDI values (r= 0.844). CONCLUSION: The results of the study emphasize the importance of early and accurate diagnosis of dry eye disease for successful long term RGP and SCL contact lens wear. This will hopefully motivate future larger scale investigations on dry eye related problems in contact lens wearers. PMID- 25536993 TI - The profile of scabies patients in Zagreb. AB - BACKGROUND: Scabies is a mandatory notifiable disease according to Croatian law. Due to an increased reports of scabies within a couple of years in Zagreb, we decided to present epidemiological characteristics of patients diagnosed with scabies in Zagreb. SUBJECTS AND METHODS: A retrospective survey was carried out in county Public Health Institute "Dr. Andrija Stampar" in Zagreb and analysis was performed for the period of 2010-2013 upon individual notifications on scabies cases. The patients are presented by sociodemographic data, diagnosis and treatment. RESULTS: In a 4 year period there were 246 scabies cases recorded in Zagreb. Cases have been registered in all quarters of the City. The highest incidence (50/100 000) was recorded in every child age group following by incidence of over 30/100 000 in elderly institutionalized in nursing homes. In almost two thirds of patients management of scabies has not been conducted in accordance to current guidelines. 10% of scabies cases were found in medical health personnel predominantly in those working in nursing homes and psychiatric wards. A small amount of cases 19 (8%) were infected outside Croatia; the majority of these cases 15 (78%) are registered within last two years. CONCLUSION: High percentage of scabies cases registered in nursing homes and psychiatric wards suggests that there is a need of raising awareness on scabies epidemiology and management by public health officers. Due to a higher incidence of scabies in children age, the obligation of medical practitioners is also to emphasize the importance of following treatment guidelines. In order to control scabies cases as well to prevent outbreaks within hospital wards or nursing homes there is an obligation of implementation of strict guidelines regarding treatment of scabies and a public health service referral. PMID- 25536994 TI - Food Safety is an Important Public Health Issue: Chloramphenicol Residues Determination by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) in honey. AB - BACKGROUND: Honey is used for nutritional, medicinal and industrial purposes and antibiotic residues may harm its quality and constitute a danger to human health. The broad spectrum antibiotic chloramphenicol (CAP) was used for curative purposes in veterinary medicine, but is now forbidden in European Union (EU) because of its many serious side effects (e.g. aplastic anaemia, grey syndrome, severe bone marrow depression and hypersensitivity). The aim of this study was to facilitate analyses of the quality and safety of Croatian honey distributed to whole European Union market; an assessment that has not previously been made. SUBJECTS AND METHODS: CAP in honey was qualifying and quantifying by validated liquid chromatography tandem mass spectrometry with negative electrospray ionisation method (LC-MS/MS). The target antibiotic was separated on chromatographic column Zorbax SB C18 (150 mm x 2.1 mm, 3.5 MUm) with a gradient elution using acetonitrile - 0.1% formic acid mobile phase at a flow rate of 0.3 mL/min, with column temperature 35 degrees C for CAP and 5D-CAP as internal standard. Homogenised honey samples were diluted with acetate buffer solution and extracted on Oasis Hydrophilic-Lipophilic-Balanced (HLB) sorbents. The method was used to analyse 280 domestic honey samples collected throughout Croatia between 2005.-2013. RESULTS: Recoveries of the method for real (acacia, chestnut, linden and flower) honey samples were 102% with RSD 8.4%. The value CCalpha and CCbeta were 0.09 and 0.12 MUg/kg, respectively. Results showed only three subsequent positive detections (1.1%) of CAP in honey. CONCLUSIONS: Analysed honey samples from Croatia showed good quality and safety what is the one of the main objective in consumer health policy in EU. PMID- 25536995 TI - Melitococcosis in the republic of croatia. AB - BACKGROUND: Melitococcosis is one of the most widespread zoonoses worldwide. In the period from 2009 to 2013, comprehensive melitococcosis testing was conducted in the Republic of Croatia. METHODS AND RESULTS: During the testing, the Rose Bengal test was applied to 344019 blood samples of sheep and goats, and positive reactions were confirmed in 1143 (0.3%) of samples. The complement fixation test (confirmatory test) was conducted on 43428 samples, with positive reactions confirmed in 768 (1.8%) of samples. The organs and tissues of 336 sheep and goats were inspected bacteriologically, and Brucella sp. was isolated in 15 (4.5%) of samples. Positive serological and bacteriological reactions were confirmed in the Karlovac, Lika-Senj and Split-Dalmatia Counties. Bacteriological and molecular techniques (Bru-up/Bru-low and Bruce-Ladder) in isolates proved the presence of Brucella melitensis biovar 3. CONCLUSION: On the basis of this study, it can be concluded that Croatia has a favourable situation concerning the infection of ruminants with B. melitensis, and that ongoing controls of the disease are necessary. PMID- 25536996 TI - Psychological and somatic health problems in Bosnian refugees: a three year follow-up. AB - BACKGROUND: Aim of this study was to explore association between psychiatric disorders (PTSD and depression) and chronic medical illnesses in a group of Bosnian refugees followed up for three years (1996-1999). SUBJECTS AND METHODS: Study was conducted in refugee camps in Varazdin, Nbaseline=534, Nendpoint=376 (70.4%). The interviews were conducted in Bosnian, data on depression and PTSD were collected using the Hopkins Symptom Checklist-25 and Harvard Trauma Questionnaire, respectively. Medical conditions were self-reported. RESULTS: Most important findings: 1) Half of the sample at both study points reported no psychiatric problems (N=294, 55% vs. N=225, 59%), others suffered from depression (N=99, 18.5% at both times), PTSD (N=30, 5.6% vs. N=15, 4%), and depression + PTSD (N=129, 24.2% vs. N=114, 30.3%); 2) A total of 15 medical conditions were identified, and most frequently present were high blood pressure (N=201, 37.6%) and heart disease (N=167, 31.3%); 3) Occurrence of medical conditions was related to the clinical group - they were more frequent in subjects diagnosed with depression and depression + PTSD, than in those who were asymptomatic or suffering from PTSD only. CONCLUSIONS: Our data indicate the persistence of both psychological and somatic health problems in Bosnian refugees involved in this study over time. Holistic approach and avoiding of mind-body dualism might be beneficial for the care and long-term prognosis of these people. PMID- 25536998 TI - EspR, a regulator of the ESX-1 secretion system in Mycobacterium tuberculosis, is directly regulated by the two-component systems MprAB and PhoPR. AB - The regulatory mechanisms that control the ESX-1 secretion system, a key player in the pathogenesis of Mycobacterium tuberculosis, have not been fully elucidated. However, factors that regulate the ESX-1 substrate EspA usually affect ESX-1 function. Previous studies showed that espA is directly regulated by the nucleoid-associated protein EspR and the two-component system (TCS) MprAB. The PhoPR TCS also activates espA, but the direct target of PhoP was unknown. In this report, we reveal that EspR is directly regulated by MprA and PhoP-Rv, but not by PhoP-Ra. PhoP-Rv and MprA binding sites in the espR promoter were determined by gel-shift and DNase I footprinting assays, which identified a PhoP protected region centred approximately 205 bp before the espR start codon and that encompasses MprA Region-1, one of two MprA-protected regions. MprA Region-2 is located approximately 60 bp downstream of MprA Region-1 and overlaps a known EspR binding site. Nucleotides essential for the binding of PhoP and/or MprA were identified through site-directed DNA mutagenesis. Our studies also indicate that MprA Region-2, but not MprA Region-1/PhoP region, is required for the full expression of espR. Recombinant strains carrying mutations at MprA Region-2 exhibited lower transcription levels for espR, espA and espD, and had reduced EspR and EspA levels in cell lysates. These findings indicate that EspR may mediate the regulatory effect of PhoPR and MprAB, and provide more insight into the mechanisms underlying ESX-1 control. PMID- 25536999 TI - Aspergillus fumigatus transcriptome response to a higher temperature during the earliest steps of germination monitored using a new customized expression microarray. AB - Aspergillus fumigatus is considered to be the most prevalent airborne pathogenic fungus and can cause invasive diseases in immunocompromised patients. It is known that its virulence is multifactorial, although the mechanisms of pathogenicity remain unclear. With the aim of improving our understanding of these mechanisms, we designed a new expression microarray covering the entire genome of A. fumigatus. In this first study, we analysed the transcriptomes of this fungus at the first steps of germination after being grown at 24 and 37 degrees C. The microarray data revealed that 1249 genes were differentially expressed during growth at these two temperatures. According to our results, A. fumigatus modified significantly the expression of genes related to metabolism to adapt to new conditions. The high percentages of genes that encoded hypothetical or unclassified proteins differentially expressed implied that many as yet unknown genes were involved in the establishment of A. fumigatus infection. Furthermore, amongst the genes implicated in virulence upregulated at 37 degrees C on the microarray, we found those that encoded proteins mainly related to allergens (Asp F1, Asp F2 and MnSOD), gliotoxin biosynthesis (GliP and GliZ), nitrogen (NiiA and NiaD) or iron (HapX, SreA, SidD and SidC) metabolism. However, gene expression in iron and nitrogen metabolism might be influenced not only by heat shock, but also by the availability of nutrients in the medium, as shown by the addition of fresh medium. PMID- 25536997 TI - Antibacterial toxin colicin N and phage protein G3p compete with TolB for a binding site on TolA. AB - Most colicins kill Escherichia coli cells by membrane pore formation or nuclease activity and, superficially, the mechanisms are similar: receptor binding, translocon recruitment, periplasmic receptor binding and membrane insertion. However, in detail, they employ a wide variety of molecular interactions that reveal a high degree of evolutionary diversification. Group A colicins bind to members of the TolQRAB complex in the periplasm and heterotrimeric complexes of colicin-TolA-TolB have been observed for both ColA and ColE9. ColN, the smallest and simplest pore-forming colicin, binds only to TolA and we show here that it uses the binding site normally used by TolB, effectively preventing formation of the larger complex used by other colicins. ColN binding to TolA was by beta strand addition with a KD of 1 uM compared with 40 uM for the TolA-TolB interaction. The beta-strand addition and ColN activity could be abolished by single proline point mutations in TolA, which each removed one backbone hydrogen bond. By also blocking TolA-TolB binding these point mutations conferred a complete tol phenotype which destabilized the outer membrane, prevented both ColA and ColE9 activity, and abolished phage protein binding to TolA. These are the only point mutations known to have such pleiotropic effects and showed that the TolA-TolB beta-strand addition is essential for Tol function. The formation of this simple binary ColN-TolA complex provided yet more evidence of a distinct translocation route for ColN and may help to explain the unique toxicity of its N terminal domain. PMID- 25537000 TI - Decrypting the structural, dynamic, and energetic basis of a monomeric kinesin interacting with a tubulin dimer in three ATPase states by all-atom molecular dynamics simulation. AB - We have employed molecular dynamics (MD) simulation to investigate, with atomic details, the structural dynamics and energetics of three major ATPase states (ADP, APO, and ATP state) of a human kinesin-1 monomer in complex with a tubulin dimer. Starting from a recently solved crystal structure of ATP-like kinesin tubulin complex by the Knossow lab, we have used flexible fitting of cryo electron-microscopy maps to construct new structural models of the kinesin tubulin complex in APO and ATP state, and then conducted extensive MD simulations (total 400 ns for each state), followed by flexibility analysis, principal component analysis, hydrogen bond analysis, and binding free energy analysis. Our modeling and simulation have revealed key nucleotide-dependent changes in the structure and flexibility of the nucleotide-binding pocket (featuring a highly flexible and open switch I in APO state) and the tubulin-binding site, and allosterically coupled motions driving the APO to ATP transition. In addition, our binding free energy analysis has identified a set of key residues involved in kinesin-tubulin binding. On the basis of our simulation, we have attempted to address several outstanding issues in kinesin study, including the possible roles of beta-sheet twist and neck linker docking in regulating nucleotide release and binding, the structural mechanism of ADP release, and possible extension and shortening of alpha4 helix during the ATPase cycle. This study has provided a comprehensive structural and dynamic picture of kinesin's major ATPase states, and offered promising targets for future mutational and functional studies to investigate the molecular mechanism of kinesin motors. PMID- 25537001 TI - Salivary and serum leptin concentrations in patients with chronic periodontitis. AB - BACKGROUND: The discovery of leptin has led to the elucidation of a robust physiologic system that not only maintains fat stores but is also an integral part of the host defense mechanism. However, leptin concentrations in the saliva of patients with chronic periodontitis (CP) has not been explored despite the potential role of salivary biomarkers in determining the presence, risk, and progression of periodontal disease. METHODS: Eighty-four participants (44 with generalized severe CP and 40 without periodontitis) were enrolled. For each patient, the values of periodontal parameters were recorded, such as plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (AL), and percentage of sites with bleeding on probing (BOP) and clinical AL >=5 mm. Saliva and serum samples were collected to estimate the leptin concentrations using enzyme-linked immunosorbent assay kits. Statistical analysis was performed using software. RESULTS: Participants with CP demonstrated significantly higher BOP, PI, GI, and percentage of sites with clinical AL >5 mm (P <0.05). Leptin was detectable in all the clinical samples. Salivary leptin concentrations in patients with CP were significantly lower than in healthy volunteers (6,200.61 +/ 2,322.11 versus 8,799.60 +/- 901.70 pg/mL), whereas serum leptin concentrations were significantly higher in patients with CP than in healthy volunteers (11,600.00 +/- 1,705.01 versus 7,616.62 +/- 1,169.83 pg/mL). In addition, the results reflected a significant negative correlation of salivary leptin and a positive correlation of serum leptin with PD (P <0.05). CONCLUSION: The results suggest that leptin concentrations in saliva and serum are significantly altered in CP and relate closely to current disease activity; however, further studies are needed to confirm the findings. PMID- 25537002 TI - Matrix-bound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in tobacco: quantification and evidence for an origin from lignin-incorporated alkaloids. AB - Substantial quantities of the carcinogenic tobacco-specific N-nitrosamine 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (1; NNK) are still found in the mainstream smoke of tobacco exhaustively extracted with water, indicating the presence of an insoluble, matrix-bound form. Soluble and matrix-bound concentrations of 1 in tobacco were determined by applying a new method using sequential aqueous extraction at room temperature and at 130 degrees C. On average, 77% and 53% of the total content of 1 were matrix-bound in air-cured (Burley type) and flue-cured tobaccos, respectively. Thermal release of 1 from its matrix-bound form above ca. 200 degrees C can account for a large fraction of its concentration in cigarette mainstream smoke. An already matrix-bound alkaloid precursor of matrix-bound 1 was identified in vascular tissue of green leaf midribs. The incubation of vascular cell-wall preparations with the lignin precursor coniferyl alcohol and isotopically labeled nicotine or pseudooxynicotine (2) led to the formation of labeled matrix-bound 1 after nitrosation, suggesting that incorporation of nicotine or its oxidized product 2 during lignin polymerization is the origin of the formation of matrix-bound 1. PMID- 25537003 TI - Validity and reliability of rating perceived exertion in women with fibromyalgia: exertion-pain discrimination. AB - The present study aimed (1) to assess the validity and reliability of the Borg category-ratio (CR-10) scale for monitoring exercise intensity in women with fibromyalgia (FM) and (2) to examine whether women with FM can discriminate between perceived exertion and exercise-induced pain. Thirty-three women with FM performed two incremental treadmill tests (1 week separated). Heart rate, oxygen uptake, minute ventilation and respiratory quotient were measured. The ratings of perceived exertion (RPE: CR-10 scale) and exercise-induced pain were obtained at each workload. The Spearman's correlation of RPE with the physiological responses ranged from 0.69 to 0.79. The regression models explained ~50% of the variability of the studied physiological responses. We found "perfect acceptable" agreement in 69% of the observations. Weighted Kappa was 0.66 (95% confidence interval [CI]: 0.59-0.72). There were differences between RPE and pain at workloads 3 (1.50; 95% CI: 0.85-2.16), 4 (2.10; 95% CI: 1.23-2.96), 5 (3.40; 95% CI: 1.29 5.51) and 6 (3.97; 95% CI: 1.61-6.33). The main findings of the present study suggest that the Borg CR-10 scale is valid and moderately reliable for monitoring exercise intensity in women with FM, and these patients were able to discriminate between exertion and exercise-induced pain. PMID- 25537005 TI - Inter-individual postural variability in seated drivers exposed to whole-body vibration. AB - Long-term occupational exposure to whole-body vibration (WBV) is a cause of low back pain for seated drivers. Poor and long-term seated postures are considered as a cofactor in the risk. It depends on the vehicle's ergonomics and tasks. Differences in posture may also be observed between operators doing identical tasks. An experiment has been performed in order to simultaneously measure posture and WBV for 12 drivers in 3 vehicles (loader, dumper and excavator) during controlled tasks. The inter-individual postural variability has been evaluated. The positions and movements of the body were measured with the CUELA system (computer-assisted recording and long-term analysis of musculoskeletal loads). Significant differences were observed between the three vehicles in the WBV, positions and movements of the body. Significant postural differences were observed between drivers (EN 1005-4 2005). Individual strategies for performing a task were also identified. PRACTITIONER SUMMARY: Posture is considered as a cofactor in the risk of low back pain for seated drivers exposed to whole-body vibration. Combined measurements revealed significant postural differences between drivers doing identical tasks. Depending on individual driving strategies, driver's body segments could be significantly deviated from neutral body postures (EN 1005-4 2005). PMID- 25537004 TI - The Paulson-Lichtenberg Frailty Index: evidence for a self-report measure of frailty. AB - OBJECTIVES: This study evaluates the Paulson-Lichtenberg Frailty Index (PLFI), a self-report measure that is based on Fried's well-established frailty phenotype. The PLFI is examined using longitudinal data from the Health and Retirement Study (HRS) database, for which it was developed. METHODS: The sample was drawn from the HRS and included 8844 community-dwelling older adults. Frailty was measured using the PLFI's five-item frailty index (wasting, weakness, slowness, falls, and fatigue). RESULTS: In comparison to intermediate-frail or non-frail respondents, frail respondents were found to be older, more medically compromised, and less independent for activities of daily living (ADLs) and instrumental activities of daily living (IADLs). On average, frail respondents reported worse self-rated health and had fewer years of education. Women, ethnic minorities, and those who were not partnered were also more likely to be frail. Over subsequent years, frail respondents were more likely to be hospitalized, report more loss of independence, and experience higher mortality rates. CONCLUSIONS: The PLFI is a valid tool for assessing frailty in the HRS data set. PMID- 25537006 TI - Correction to "thermodynamic characterization of polypeptide complex coacervation". PMID- 25537007 TI - How great is the threat of chikungunya virus? AB - In the last decade, chikungunya virus has emerged from an obscure arbovirus that caused limited outbreaks of disease in Africa and Asia to the cause of a pandemic affecting millions of people and spanning five continents. Two separate chikungunya virus genotypes have been responsible for outbreaks during this period, including strains adapted to transmission in Aedes albopictus mosquitoes. Further spread of this virus into new regions of the Western Hemisphere is predicted during the present rainy season in the tropics, and recurrent viral introductions and disease outbreaks, as occurred in Reunion in 2010, should be expected. Chikungunya virus no longer simply threatens; it has arrived as a significant, global pathogen. PMID- 25537008 TI - Influence of processing parameters on morphology of polymethoxyflavone in emulsions. AB - Polymethoxyflavones (PMFs) are groups of compounds isolated from citrus peels that have been documented with wide arrays of health-promoting bioactivities. Because of their hydrophobic structure and high melting point, crystallized PMFs usually have poor systemic bioavailability when consumed orally. To improve the oral efficiency of PMFs, a viscoelastic emulsion system was formulated. Because of the crystalline nature, the inclusion of PMFs into the emulsion system faces great challenges in having sufficient loading capacity and stabilities. In this study, the process of optimizing the quality of emulsion-based formulation intended for PMF oral delivery was systematically studied. With alteration of the PMF loading concentration, processing temperature, and pressure, the emulsion with the desired droplet and crystal size can be effectively fabricated. Moreover, storage temperatures significantly influenced the stability of the crystal-containing emulsion system. The results from this study are a good illustration of system optimization and serve as a great reference for future formulation design of other hydrophobic crystalline compounds. PMID- 25537009 TI - Prodromal Alzheimer's disease presenting as cerebral amyloid angiopathy-related inflammation with spontaneous amyloid-related imaging abnormalities and high cerebrospinal fluid anti-Abeta autoantibodies. AB - Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-beta (Abeta) deposition in vessel walls, has been proposed as a spontaneous human model of the amyloid-related imaging abnormalities (ARIA) occurring after anti-Abeta immunotherapy for the treatment of Alzheimer's disease (AD). We describe a case of a patient with biopsy-proven CAA-ri and prodromal AD, confirmed by means of neuropsychological examination after 20 months follow-up, presenting with ARIA and high levels of cerebrospinal fluid anti-Abeta autoantibodies. This case further supports the analogies between the inflammatory response driven by anti-Abeta immunotherapy and that spontaneously occurring in CAA-ri. PMID- 25537010 TI - Mitochondrial lysates induce inflammation and Alzheimer's disease-relevant changes in microglial and neuronal cells. AB - Neuroinflammation occurs in Alzheimer's disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-beta protein promotes inflammation, our understanding of AD neuroinflammation nevertheless remains incomplete. In this study we hypothesized damage-associated molecular pattern (DAMP) molecules arising from mitochondria, intracellular organelles that resemble bacteria, could contribute to AD neuroinflammation. To preliminarily test this possibility, we exposed neuronal and microglial cell lines to enriched mitochondrial lysates. BV2 microglial cells treated with mitochondrial lysates showed decreased TREM2 mRNA, increased TNFalpha mRNA, increased MMP-8 mRNA, increased IL-8 mRNA, redistribution of NFkappaB to the nucleus, and increased p38 MAPK phosphorylation. SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNFalpha mRNA, increased NFkappaB protein, decreased IkappaBalpha protein, increased AbetaPP mRNA, and increased AbetaPP protein. Enriched mitochondrial lysates from SH-SY5Y cells lacking detectable mitochondrial DNA (rho0 cells) failed to induce any of these changes, while mtDNA obtained directly from mitochondria (but not PCR-amplified mtDNA) increased BV2 cell TNFalpha mRNA. These results indicate at least one mitochondrial-derived DAMP molecule, mtDNA, can induce inflammatory changes in microglial and neuronal cell lines. Our data are consistent with the hypothesis that a mitochondrial derived DAMP molecule or molecules could contribute to AD neuroinflammation. PMID- 25537014 TI - Stereological estimation of olfactory receptor neurons in rats. AB - The total number of olfactory receptor neurons (ORNs) in the rat main olfactory epithelium (MOE) was estimated using stereological sampling. Skulls and noses of newborn (postnatal day 0), young adult (8 weeks), and adult (6 months) rats were decalcified, embedded in paraffin, cut into 10-MUm thick sections serially at 100 MUm intervals, and processed for immunohistochemistry for olfactory marker protein (OMP), a specific marker of mature ORNs with fiber connections to the olfactory bulb. The number of OMP (+) receptor neurons was measured using an optical fractionator with stereological software (Stereoinvestigator). The total number of OMP (+) receptor neurons in the unilateral MOE was 0.47 * 10(6) in newborns and 21 * 10(6) in young adults and adults. Our previous study showed that the corresponding unilateral total number of neurons was 5.2 * 10(6) in young adult mice. Accordingly, we concluded that rats had 4 times more OMP (+) receptor neurons than mice at the adult stage and that the number of these neurons increased approximately 45 times between birth and maturity. PMID- 25537012 TI - Diffusion tensor imaging reveals visual pathway damage in patients with mild cognitive impairment and Alzheimer's disease. AB - Visual deficits are commonly seen in patients with Alzheimer's disease (AD), but postmortem histology has not found substantial damage in visual cortex regions, leading to the hypothesis that the visual pathway, from eye to the brain, may be damaged in AD. Diffusion tensor imaging (DTI) has been used to characterize white matter abnormalities. However, there is a lack of data examining the optic nerves and tracts in patients with AD. In this study, we used DTI to analyze the visual pathway in healthy controls, patients with mild cognitive impairment (MCI) and AD using scans provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found significant increases in the total diffusivity and radial diffusivity and reductions in fractional anisotropy in optic nerves among AD patients. Similar but less extensive changes in these metrics were seen in MCI patients as compared to controls. The differences in DTI metrics between groups mirrored changes in the splenium of the corpus callosum, which has commonly been shown to exhibit white matter damage during AD and MCI. Our findings indicate that white matter damage extends to the visual system, and may help explain the visual deficits experienced by AD patients. PMID- 25537015 TI - Long-term alterations in peripheral taste responses to NaCl in adult rats following neonatal chorda tympani transection. AB - The peripheral taste system of the adult rodent is highly resilient against damage, with morphological, behavioral, and functional recovery evident after regeneration of a transected nerve. If chorda tympani transection (CTX) occurs at early postnatal ages however, the nerve fails to regenerate and effects on tongue morphology and behavior are more severe and longer-lasting compared to adult denervation. To examine whether neonatal CTX induces functional changes in intact nerves, whole-nerve electrophysiology was performed on the glossopharyngeal (GL) and chorda tympani (CT) nerves of adult rats that received CTX at P10. Attenuation of NaCl-elicited GL responses were observed in CTX rats 2 months after surgery, with bilateral denervation causing the largest decreases in responses. When assessed 1 year after neonatal CTX, amiloride-sensitive responses to NaCl in the contralateral CT increased while amiloride-insensitive responses decreased. Responses to other tastants were consistent with control animals. This is the first evidence of long-term functional changes to the peripheral taste system after injury in rats fed a normal diet. This study further characterizes the developing peripheral taste system as highly susceptible to change following neural injury. PMID- 25537011 TI - A phase II trial of tideglusib in Alzheimer's disease. AB - BACKGROUND: The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer's disease (AD). OBJECTIVE: To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD. METHODS: Mild to moderate (Mini-Mental State Examination (MMSE) score, 14-26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-beta, and BACE1 in cerebrospinal fluid (CSF) were exploratory endpoints. RESULTS: 306 AD patients were randomized to active (1000 mg QD: n = 86, 1000 mg QOD: n = 90, and 500 mg QD: n = 50) or placebo (n = 85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15, MMSE, and word fluency. Diarrhea (14-18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9 16% in active, 3.5% placebo) were the most frequent adverse events. CONCLUSIONS: Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients. PMID- 25537016 TI - Phenotypic plasticity in a willow leaf beetle depends on host plant species: release and recognition of beetle odors. AB - Aggregation behavior of herbivorous insects is mediated by a wide range of biotic and abiotic factors. It has been suggested that aggregation behavior of the blue willow leaf beetle Phratora vulgatissima is mediated by both host plant odor and by odor released by the beetles. Previous studies show that the beetles respond to plant odors according to their prior host plant experiences. Here, we analyzed the effect of the host plant species on odor released and perceived by adult P. vulgatissima. The major difference between the odor of beetles feeding on salicin rich and salicin-poor host plants was the presence of salicylaldehyde in the odor of the former, where both males and females released this compound. Electrophysiological studies showed that the intensity of responses to single components of odor released by beetles was sex specific and dependent on the host plant species with which the beetles were fed. Finally, behavioral studies revealed that males feeding on salicin-rich willows were attracted by salicylaldehyde, whereas females did not respond behaviorally to this compound, despite showing clear antennal responses to it. Finally, the ecological relevance of the influence of a host plant species on the plasticity of beetle odor chemistry, perception, and behavior is discussed. PMID- 25537017 TI - Leptin's effect on taste bud calcium responses and transmitter secretion. AB - Leptin, a peptide hormone released by adipose tissue, acts on the hypothalamus to control cravings and appetite. Leptin also acts to decrease taste responses to sweet substances, though there is little detailed information regarding where leptin acts in the taste transduction cascade. The present study examined the effects of leptin on sweet-evoked responses and neuro transmitter release from isolated taste buds. Our results indicate that leptin moderately decreased sweet evoked calcium mobilization in isolated mouse taste buds. We also employed Chinese hamster ovary biosensor cells to examine taste transmitter release from isolated taste buds. Leptin reduced ATP and increased serotonin release in response to sweet stimulation. However, leptin has no effect on bitter-evoked transmitter release, further showing that the action of leptin is sweet specific. Our results support those of previous studies, which state that leptin acts on taste tissue via the leptin receptor, most likely on Type II (Receptor) cells, but also possibly on Type III (Presynaptic) cells. PMID- 25537018 TI - Impact of [18F]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma. AB - BACKGROUND: We sought to assess the impact of amino-acid (18)F-fluoro-ethyl tyrosine (FET) positron emission tomography (PET) on the volumetric target definition for radiation therapy of high-grade glioma versus the current standard using MRI alone. Specifically, we investigated the influence of tumor grade, MR defined tumor volume, and the extent of surgical resection on PET positivity. METHODS: Fifty-four consecutive high-grade glioma patients (World Health Organization grades III-IV) with confirmed histology were scanned using FET PET/CT and T1 and T2/fluid attenuated inversion recovery MRI. Gross tumor volume and clinical target volumes (CTVs) were defined in a blinded fashion based on MRI and subsequently PET, and volumetric analysis was performed. The extent of the surgical resection was reviewed using postoperative MRI. RESULTS: Overall, for ~ 90% of the patients, the PET-positive volumes were encompassed by T1 MRI with contrast-defined tumor plus a 20-mm margin. The tumor volume defined by PET was larger for glioma grade IV (P < .001) and smaller for patients with more extensive surgical resection (P = .004). The margin required to be added to the MRI-defined tumor in order to fully encompass the FET-PET positive volume tended to be larger for grade IV tumors (P = .018). CONCLUSION: With an unchanged CTV margin and by including FET-PET for gross tumor volume definition, the CTV will increase moderately for most patients, and quite substantially for a minority of patients. Patients with grade IV glioma were found to be the primary candidates for PET-guided radiation therapy planning. PMID- 25537020 TI - Multifocality in neurofibromatosis type 2. PMID- 25537019 TI - Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. AB - BACKGROUND: Patients with glioblastoma multiforme (GBM) exhibit marked intratumoral and systemic immunosuppression. GBM is heavily infiltrated with monocytic cells. Monocytes contacting GBM cells develop features of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are elevated in GBM patients. Therefore, we hypothesized that circulating MDSC levels could be raised in vivo by increasing glioma-associated macrophages. METHODS: GL261 luciferase glioma was implanted intracranially in C57BL/6 mice with or without additional normal syngeneic CD11b+ monocytes. Tumor growth and intratumoral and systemic MDSC (CD11b+/Gr-1+) levels were determined. Green fluorescent protein (GFP)-transgenic monocytes were coinjected intracranially with GL261-luciferase cells. GFP+ cell frequency among splenic and bone marrow MDSCs was determined. Impact of increased MDSC's on spontaneous immune responses to tumor cells expressing a model antigen (ovalbumin [OVA]) was determined. RESULTS: Tumors grew faster and MDSC's were increased in tumor, spleen, and bone marrow in mice receiving GL261-Luc plus monocytes. Many (30%-50%) systemic MDSC's were GFP+ in mice receiving intracranial tumor plus GFP-transgenic monocytes, suggesting that they originated from glioma-associated monocytes. Tumor-infiltrating OVA-specific CD8+ T cells were markedly reduced in mice receiving GL261-OVA and monocytes compared with mice receiving GL261-OVA alone. CONCLUSIONS: Increasing glioma associated macrophages in intracranial GL261 glioma decreases survival and markedly increases intratumoral and systemic MDSC's, many of which originate directly from glioma-associated macrophages. This is associated with decreased spontaneous immune responses to a model antigen. To our knowledge, this is the first evidence in cancer that systemic MDSC's can arise directly from normal monocytes that have undergone intratumoral immunosuppressive education. PMID- 25537021 TI - Cytogenetic landscape of paired neurospheres and traditional monolayer cultures in pediatric malignant brain tumors. AB - BACKGROUND: New therapeutic targets are needed to eliminate cancer stem cells (CSCs). We hypothesize that direct comparison of paired CSCs and nonstem tumor cells (NSTCs) will facilitate identification of primary "driver" chromosomal aberrations that can serve as diagnostic markers and/or therapeutic targets. METHODS: We applied spectral karyotyping and G-banding to matched pairs of neurospheres (CSC-enriched cultures) and fetal bovine serum-based monolayer cultures (enriched with NSTCs) from 16 patient-derived orthotopic xenograft mouse models, including 9 medulloblastomas (MBs) and 7 high-grade gliomas (HGGs), followed by direct comparison of their numerical and structural abnormalities. RESULTS: Chromosomal aberrations were detected in neurospheres of all 16 models, and 82.0% numerical and 82.4% structural abnormalities were maintained in their matching monolayer cultures. Among the shared abnormalities, recurrent clonal changes were identified including gain of chromosomes 18 and 7 and loss of chromosome 10/10q (5/16 models), isochromosome 17q in 2 MBs, and a new breakpoint of 13q14 in 3 HGGs. Chromothripsis-like evidence was also observed in 3 HGG pairs. Additionally, we noted 20 numerical and 15 structural aberrations that were lost from the neurospheres and found 26 numerical and 23 structural aberrations that were only present in the NSTCs. Compared with MBs, the neurosphere karyotypes of HGG were more complex, with fewer chromosomal aberrations preserved in their matching NSTCs. CONCLUSION: Self-renewing CSCs in MBs and pediatric HGGs harbor recurrent numerical and structural aberrations that were maintained in the matching monolayer cultures. These primary chromosomal changes may represent new markers for anti-CSC therapies. PMID- 25537023 TI - A case example of asphyxia due to occupational exposure to airborne chemicals and review of workplace fatalities. AB - Although worker injury and fatalities have decreased since adoption of the Occupational Safety and Health Act in 1970, it remains an important safety issue. This article describes a 27-year-old white male who died from occupational exposure to airborne chemicals. Several trends in the last several decades, both in the types of injuries and the occupations associated with fatalities, are noted. Additionally, individual risk factors such as age, gender, chronic disease, smoking, and alcohol and drug use are implicated in worker health and safety. The role of the forensic pathologist in the investigation of workplace deaths is highlighted, in addition to the future of occupational safety and current improvements brought about by such incidents. PMID- 25537022 TI - A prospective study of the use and effects of screening mammography in women aged 70 and older. AB - OBJECTIVES: To prospectively examine how age and comorbidity affect screening mammography use, cancer detection, and overall survival. DESIGN: Prospective, with median follow-up of 10.2 years. SETTING: A population-based cohort of Vermont women with data in the Vermont Breast Cancer Surveillance System. PARTICIPANTS: Women aged 70 and older with no history of breast cancer (N = 20,697). MEASUREMENTS: Rates of screening, diagnostic procedure use, and breast cancer diagnosis were examined according to age and comorbidity. The effect of breast cancer on overall survival was assessed in relation to detection mode, tumor characteristics, and treatment. RESULTS: Screening declined 9% per year after age 70 and 18% with each unit increase in comorbidity score, with corresponding increases in clinically detected breast cancer. Invasive cancer was associated with greater overall mortality (screen detected: hazard ratio (HR) = 1.22, 95% confidence interval (CI) = 1.07-1.40; clinically detected: HR = 1.68, 95% CI = 1.43-1.96). The latter HR reflects a much greater absolute risk of death for women in a population with high baseline mortality. Use of breast-conserving surgery as the only treatment for Stage I cancer increased markedly with age and was associated with shorter overall survival than radiation or mastectomy (relative risk = 2.23, 95% CI = 1.42-3.47). CONCLUSION: Lower screening mammography use by older women is associated with more clinically detected breast cancers, which are associated with poorer survival. Treatment received for early stage cancer influences the effect of screening on survival. PMID- 25537024 TI - Paediatric nephrology: the last 50 years. AB - In 1965, the specialty of paediatric nephrology was in its infancy. Following the development of a landmark collaborative research study, the International Study of Kidney Disease in Childhood in the mid-1960s, the first specialist societies were formed: the European Society of Pediatric Nephrology in 1967 and the American Society of Pediatric Nephrology in 1969. The extraordinary improvements in care delivered to children with kidney disease over the past 50 years are too broad to cover in any one paper. They traverse the spectrum of diagnosis, classification, therapeutics, social well-being and transition to adult care. We have selected four case scenarios to highlight these changes in key areas of paediatric nephrology: post-streptococcal glomerulonephritis, nephrotic syndrome, haemolytic uraemic syndrome and neonatal dialysis and childhood transplantation. PMID- 25537027 TI - An optimised injection technique for the navicular bursa that avoids the deep digital flexor tendon. AB - REASONS FOR PERFORMING STUDY: Injection of the navicular bursa is commonly performed from the palmar aspect of the limb, which results in penetration of the deep digital flexor tendon (DDFT). OBJECTIVES: To report a radiographic guided injection from the lateral aspect of the limb that avoids puncture of the DDFT and to assess synovial and soft tissue penetration by the needle. STUDY DESIGN: Prospective clinical and cadaveric study. METHODS: Prospective analysis of cadaver limbs and clinical cases in which the navicular bursa was injected from the lateral aspect. Cadaver limbs were placed in a stand to simulate weight bearing and injection was performed in limbs without synovial distension or with distension of either the distal interphalangeal (DIP) joint, digital flexor tendon sheath (DFTS) or navicular bursa. In cadaver and clinical limbs, contrast was injected and the needle position assessed with radiographs. Cadaver (but not clinical) limbs were also examined using magnetic resonance imaging with the needle in situ. RESULTS: Successful navicular bursal injection was achieved in all limbs (n = 71). Relative risk of DIP joint puncture was 19 times higher (95% confidence interval 1.3-285.4, P<0.001) when the DIP joint was distended (9 of 10 limbs) than in normal limbs (0 of 10 limbs). Relative risk of DFTS puncture was 2.7 times higher (95% confidence interval 1.0-7.2, P = 0.06) when the DFTS was distended (8 of 10 limbs) than in normal limbs (3 of 7 limbs). Synovial fluid was aspirated from 47% of bursae from clinical cases. CONCLUSIONS: The lateral injection technique for the navicular bursa avoids penetration of the DDFT, although risk of synovial penetration must be considered when there is potential DIP joint or DFTS infection. PMID- 25537026 TI - Diagnosis of Glanzmann thrombasthenia by whole blood impedance analyzer (MEA) vs. light transmission aggregometry. AB - BACKGROUND: Glanzmann thrombasthenia (GT) is a rare inherited platelet disorder that is characterized by spontaneous or postprocedural bleeding. The diagnosis of GT depends on identifying the dysfunction of the platelets. AIM: The aim of this study was to compare a whole blood impedance Multiplate analyzer (MEA) with the standard method, light transmission aggregometry (LTA) in diagnosis of GT. METHODS: Fifteen patients with GT were assessed on MEA and LTA using arachidonic acid (ASPI: 15 mm), (TRAP: 1 mm), collagen (100 MUg/mL), ADP (0.2 mm), and ristocetin (Risto: 10 mg/mL). Whole blood samples were collected in sodium citrate and hirudin vacuum, blood collection tubes and tested within 4 h. Platelet-rich plasma was used for LTA using platelet agonists (ristocetin 1.5 mg/mL) (arachidonic acid 0.5 mg/mL) (ADP 2.5 mg/mL) and (collagen 1 mg/mL). RESULTS: The platelet count and PFA-100 results were (average and SD) 319 +/- 93 * 10(9) L and 252 +/- 34 s, respectively. Flow cytometry analysis showed that all samples are positive for CD42a and CD42b, whereas 9/15 samples were negative for CD61 and CD41. The other six patients had either partial or full expression of CD61/CD41. Aggregation analysis using both methods showed that all samples had no aggregation response to any of the agonists used apart from six samples which, using only the MEA, showed minimal aggregation in response to collagen (average = 14.3 +/- 7 MUg, which may suggest ability to detect qualitative abnormality of GPIIb/IIIa). CONCLUSION: These results suggest that the MEA is sensitive for the detection of Glanzmann thrombasthenia. Furthermore, MEA may also be able to differentiate between the subtypes of Glanzmann thrombasthenia. PMID- 25537025 TI - Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity. AB - BACKGROUND AND PURPOSE: In diabetic nephropathy agonism of CB2 receptors reduces albuminuria and podocyte loss; however, the role of CB2 receptors in obesity related nephropathy is unknown. The aim of this study was to determine the role of CB2 receptors in a model of diet-induced obesity (DIO) and characterize the hallmark signs of renal damage in response to agonism (AM1241) and antagonism (AM630) of CB2 receptors. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were fed a high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks. In another cohort, after 9 weeks on a HFD, rats were injected daily with either 3 mg.kg(-1) AM1241, 0.3 mg.kg(-1) AM630 or saline for 6 weeks. KEY RESULTS: Ten weeks on a HFD significantly reduced renal expression of CB2 receptors and renal function. Treatment with AM1241 or AM630 did not reduce weight gain or food consumption in DIO. Despite this, AM1241 significantly reduced systolic BP, peri renal adipose accumulation, plasma leptin, urinary protein, urinary albumin, urinary sodium excretion and the fibrotic markers TGF-beta1, collagen IV and VEGF in kidney lysate. Treatment with AM630 of DIO rats significantly reduced creatinine clearance and increased glomerular area and kidney weight (gross and standardized for body weight). Diastolic BP, glucose tolerance, insulin sensitivity, plasma creatinine, plasma TGF-beta1 and kidney expression of fibronectin and alpha-smooth muscle actin were not altered by either AM1241 or AM630 in DIO. CONCLUSIONS: This study demonstrates that while agonism of CB2 receptors with AM1241 treatment for 6 weeks does not reduce weight gain in obese rats, it leads to improvements in obesity-related renal dysfunction. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc. PMID- 25537029 TI - [Auxetic nuclei in embryonic stem cells]. PMID- 25537028 TI - [Chemical biology: cross-border strategies]. PMID- 25537030 TI - [Neuronal activity influences the development of blood vessels in the brain]. PMID- 25537031 TI - [The revolution of the CRISPR is underway]. PMID- 25537032 TI - [The embryonic DNA damage response: emerging functions of messenger RNA nuclear retention]. PMID- 25537033 TI - [Modulation of permissiveness and antiviral response against hepatitis C virus by interferon lambda-associated polymorphism]. PMID- 25537034 TI - [A novel mouse model to study physiological aging of haematopoietic cells]. PMID- 25537035 TI - [Cancer, reactive oxygen species and chemotherapy-induced peripheral neuropathy]. PMID- 25537036 TI - [Structural insight into negative DNA supercoiling by DNA gyrase, a bacterial type 2A DNA topoisomerase]. PMID- 25537037 TI - [Switch on the light and reactivate the lost memories]. PMID- 25537038 TI - [Mutations in Eml1/EML1 lead to ectopic progenitors and neuronal heterotopia in mouse and human]. PMID- 25537039 TI - [Regenerative medicine of the intervertebral disc: from pathophysiology to clinical application]. AB - A large proportion of low back pain may be explained by intervertebral disc (IVD) degeneration. Currently, the process leading to IVD degeneration highlights the pivotal role of IVD cells. The number of these cells drastically decreases and does not support a spontaneous repair of the tissue. In order to counteract IVD degeneration, regenerative medicine, based on a cell supplementation of the damaged tissue is considered as a promising approach. After a description of IVD physiopathology, we will develop the different strategies based on cell therapy and tissue engineering and currently under investigation to improve altered IVD degeneration. Finally, results from the current pre-clinical and clinical studies will be discussed. PMID- 25537040 TI - [Mitochondrial DNA diseases and therapeutic strategies]. AB - Defects in mitochondrial genome can cause a wide range of clinical disorders, mainly neuromuscular diseases. Various strategies have been proposed to address these pathologies; unfortunately no efficient treatment is currently available. In some cases, defects may be rescued by targeting into mitochondria nuclear DNA expressed counterparts of the affected molecules. Another strategy is based on the induced shift of the heteroplasmy, meaning that wild type and mutated mtDNA can coexist in a single cell. The occurrence and severity of the disease depend on the heteroplasmy level, therefore, several approaches have been recently proposed to selectively reduce the levels of mutant mtDNA. Here we describe the experimental systems used to study the molecular mechanisms of mitochondrial dysfunctions: the respiratory deficient yeast strains, mammalian trans mitochondrial cybrid cells and mice models, and overview the recent advances in development of various therapeutic approaches. PMID- 25537041 TI - [Iron and sulfur in proteins. How does the cell build Fe-S clusters, cofactors essential for life?]. AB - Iron-sulfur clusters (Fe-S) are ubiquitous cofactors present in numerous proteins of most living organisms. By way of an example, the E. coli bacterium synthesizes more that 130 different types of Fe-S proteins. Fe-S proteins are involved in a great diversity of biological processes, ranging from respiration, photosynthesis, central metabolism, to genetic expression and genomic stability. Proteins can acquire spontaneously Fe-S clusters in vitro, but in vivo, dedicated molecular machineries are necessary. Dysfunction of these machineries alters cellular capacities leading to lethality in bacteria and severe pathologies in humans. In this review we will describe how cells make Fe-S clusters and deliver them to clients proteins. The importance of Fe-S clusters homeostasis will be illustrated by reporting a list of cellular dysfunctions associated with mutations altering either Fe-S proteins or Fe-S biogenesis machineries. PMID- 25537042 TI - [Pruritus: considerable progress in pathophysiology]. AB - Pruritus is defined as "an unpleasant sensation that causes the need to scratch". This is not a small pain. It seems that pruriceptors exist but their level of separation from nociceptive receptors is still debated. Pathways of pruritus were identified from the skin (around the dermo-epidermal junction) to the brain. Many mediators are involved in pruritus but there are at least a histaminergic and a non-histaminergic pathway (PAR-2dependent). Similarly to pain, gate control or peripheral and central sensitization mechanisms have been highlighted in pruritus. These pathophysiological advances are important and anticipate therapeutic advances, that will be very useful for the symptomatic treatment of pruritus (poorly efficient at present). PMID- 25537043 TI - [Prediction of the molecular response to pertubations from single cell measurements]. AB - The response of protein signalization networks to perturbations is analysed from single cell measurements. This experimental approach allows characterizing the fluctuations in protein expression levels from cell to cell. The analysis is based on an information theoretic approach grounded in thermodynamics leading to a quantitative version of Le Chatelier principle which allows to predict the molecular response. Two systems are investigated: human macrophages subjected to lipopolysaccharide challenge, analogous to the immune response against Gram negative bacteria and the response of the proteins involved in the mTOR signalizing network of GBM cancer cells to changes in partial oxygen pressure. PMID- 25537044 TI - [Narcolepsy with cataplexy: an autoimmune disease?]. AB - Narcolepsy type 1 (also named narcolepsy-cataplexy or hypocretin deficiency syndrome) is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, plus frequently hypnagogic hallucinations, sleep paralysis and nocturnal sleep disturbances. Narcolepsy type 1 is an immune system-associated disease linked with the destruction of 70.000-90.000 hypocretin neurons notably involved in wakefulness. Among narcoleptic patients, 98% are positive for HLA DQB1*06:02, a HLA class II allele, against 20-25% in general population. Individuals carrying HLA-DQB1*06:02 have an extraordinary risk to develop narcolepsy (odd ratio: 251). Other genes involved in CD4+ T cells and immune system activation as T-cell receptor alpha are also associated with narcolepsy. The development of the disease is linked with environmental factors such as influenza and streptococcal infections. Narcolepsy type 1 incidence also increased in Europe following the use of Pandemrix, a 2009 H1N1 AS03-adjuvanted vaccine manufactured by GlaxoSmithKline. Interestingly, such increase was not observed with Arepanrix, another vaccine developed by GSK very similar to Pandemrix. PMID- 25537045 TI - [High-throughput sequencing: towards a genome-based diagnosis in infectious diseases]. AB - During a pathogen outbreak, the emergency resides in the identification and characterization of the infectious agent. In addition to the traditional phenotypic methods which are still widely used, the molecular biology is nowadays a common approach of clinical microbiology labs and the pathogen can be identified by comparing its molecular fingerprint to a data-bank. High-throughput sequencing should allow overcoming this single identification to exploit the whole information encoded in the pathogen genome. This evolution, supported by an increasing number of proof-of-concept studies, should result in moving from detection through fingerprints to the use of the pathogen whole genome; this forensic profile should allow the adaptation of the treatment to the pathogen specificities. From concept to routine use, many parameters need to be considered to promote high-throughput sequencing as a powerful tool to help physicians and clinicians in microbiological investigations. PMID- 25537046 TI - [Chemical databases and virtual screening]. AB - A prerequisite to any virtual screening is the definition of compound libraries to be screened. As we describe here, various sources are available. The selection of the proper library is usually project-dependent but at least as important as the screening method itself. This review details the main compound libraries that are available for virtual screening and guide the reader to the best possible selection according to its needs. PMID- 25537047 TI - [Chemobiology at happy hour: yeast as a model for pharmacological screening]. AB - Since its discovery and description by Louis Pasteur, the budding yeast Saccharomyces cerevisiae, which was used for thousands of years for alcoholic fermentation and as a leavening agent, has become a popular model system in biology. One of the reasons for this popularity is the strong conservation from yeast to human of most of the pathways controlling cell growth and fate. In addition, at least 30 % of human genes involved in diseases have a functional homolog in yeast. Hence, yeast is now widely used for modelling and deciphering physiopathological mechanisms as well as for developing pharmacological approaches like phenotype-based drug screening. Three examples of such yeast based chemobiological studies are presented. PMID- 25537048 TI - [Nobel Prize in Chemistry 2014 - from microscopy to nanoscopy: a revolution in resolution]. PMID- 25537049 TI - [Compulsive molecular hoarding enables the evolution of protein-coding DNA from non-coding DNA]. AB - It was thought until recently that a new gene could only evolve from a previously existing gene, from recombination of genes, or from horizontal gene transfer. Recently a series of genomic and transcriptomic studies have led to the identification of non-coding DNA as a significant source of protein coding genes. The mechanism, which is probably universal since it has been identified in a wide array of eukaryotes, implies that a gradient of proto-genes, probably established by a balance between selection and genetic drift, exists between coding DNA and non-coding DNA. Therefore genome dynamics could account for the progressive formation of genes "out of the blue" thanks to the interplay of mutation and natural selection. PMID- 25537050 TI - [Single-cell sequencing and tumour heterogeneity]. AB - The heterogeneity of tumours is now beginning to be documented precisely by single-cell new-generation sequencing. Recently published results on breast tumours show that each of the cells analysed displays a unique pattern of point mutations. This extensive genetic diversity is present before any treatment, and is likely to cause resistance to initially successful targeted therapies. PMID- 25537052 TI - Simulated colonoscopy training using a low-cost physical model improves responsiveness of surgery interns. AB - AIM: Surgery residents are required to become proficient in colonoscopy before completing training. The aim of this study was to evaluate the responsiveness of surgery interns to simulated colonoscopy training. METHOD: Interns, defined as postgraduate year 1 residents without exposure to endoscopy, underwent training in a physical model including colonoscopy, synthetic anatomy trays with luminal tattoos and a hybrid simulator. After baseline testing and mentored training, final testing was performed using five predetermined proficiency criteria. Content-valid metrics defined by the extent of departure from clinical reality were evaluated by two blinded assessors. Responsiveness was defined as change in performance over time and assessed comparing baseline testing with nonmentored final testing. RESULTS: Twelve interns (eight male, mean age 26, 80% right handed) performed 48 colonoscopies each over 1 year. Improvement was seen in the overall procedure time (24 min 46 s vs 20 min 54 s; P = 0.03), passing the splenic flexure (20 min 33 s vs 10 min 45 s; P = 0.007), passing the hepatic flexure (23 min 31 s vs 12 min 45 s; P = 0.003), caecal intubation time (23 min 38 s vs 13 min 26 s; P = 0.008), the duration of loss of view of the lumen (75% vs 8.3%; P = 0.023), incomplete colonoscopy (100% vs 33.3%; P = 0.042), colonoscope withdrawal < 6 min (16.7% vs 8.3%; P = 0.052). Tattoo identification time (9 min 16 s vs 12 min 25 s; P = 0.50), colon looped time (2 min 12 s vs 1 min 45 s; P = 0.50) and rate of colon perforation (8.3% vs 8.3%; P = 1) remained unchanged. Interrater reliability was 1.0 for all measures. CONCLUSION: Simulated colonoscopy training in a low-cost physical model improved the performance of surgery interns with decreased procedure time, increased rates of complete colonoscopy and appropriate scope withdrawal. PMID- 25537053 TI - Second derivative of photoplethysmogram. PMID- 25537054 TI - Vascular malformations revisited. AB - Vascular malformations are congenital anomalies that can affect each part of the vasculature. Combined forms are common and they are often part of complex syndromes. Most malformations are diagnosed during infancy, but some get obvious only later in life. The field of vascular malformations is emerging with recently described new entities and treatments. Still, misdiagnosis is common in this field, leading to nosologic confusion and wrong treatment. Clinical evaluation and imaging are the gold standard for diagnostic confirmation. Sclerotherapy and embolization are the main treatment techniques but are also used preoperatively to reduce blood loss and shrink the lesion if surgery is planned. Despite new treatment options, especially if extensive in size or involving vulnerable structures, vascular malformations are still considered chronic diseases and cause significant morbidity. Common understanding and agreement on terminology and a multidisciplinary approach are the basis of successful treatment and long term support for these patients. Continuing research in the field of vascular anomalies will improve knowledge and create further treatment options. PMID- 25537055 TI - Carotid artery disease after head and neck radiotherapy. AB - Radiation induced atherosclerosis of the carotid artery is a clinically relevant late complication after head and neck radiotherapy. Improved long-term survival after multimodality therapy in neck malignancies result in an increased risk of carotid artery disease in patients after radiotherapy (RT). This review focuses on the current knowledge of occlusive carotid disease after head and neck radiotherapy and highlights the exceeding morphologic post-radiation vessel wall pathologies. More severe and extensive carotid artery atherosclerosis with plaque in all segments including the common carotid artery is a frequent finding after RT. Therefore, colour coded duplex ultrasound surveillance in patients after head and neck RT is recommended. Some histopathological studies indicate differences to ?classical? atherosclerosis, and pathogenesis of chronic radiation vasculopathy is still under discussion. PMID- 25537056 TI - Differential impact of diabetes mellitus type II and arterial hypertension on collateral artery growth and concomitant macrophage accumulation. AB - BACKGROUND: Diabetes mellitus type II and arterial hypertension are major risk factors for peripheral arterial disease and have been considered to reduce collateral growth (arteriogenesis). Collateral growth proceeds through different stages. Vascular proliferation and macrophage accumulation are hallmarks of early collateral growth. MATERIAL AND METHODS: We here compare the impact of arterial hypertension and diabetes mellitus type II on collateral proliferation (Brdu incorporation) and macrophage accumulation (ED 2 staining) as well as collateral vessel function (collateral conductance) in a rat model of peripheral vascular disease (femoral artery occlusion), diabetes mellitus type II (Zucker fatty diabetic rats and Zucker lean rat controls) and arterial hypertension (induced via clip placement around the right renal arteriy). We furthermore tested the impact of monocyte chemoattractant protein-1 (MCP-1) on collateral proliferation and macrophage accumulation in these models RESULTS: Diabetic animals showed reduced vascular proliferation and macrophage accumulation, which however did not translate into a change of collateral conductance. Hypertensive animals on the contrary had reduced collateral conductances without altered macrophage accumulation and only a marginal reduction in collateral proliferation. Infusion of MCP-1 only enhanced vascular proliferation in diabetic animals. CONCLUSIONS: These findings illustrate that impaired monocyte/macrophage recruitment is responsible for reduced collateral growth under diabetic conditions but not in arterial hypertension suggesting that diabetes mellitus in particular affects early stages of collateral growth whereas hypertension has its impact on later remodeling stages. Successful pro-arteriogenic treatment strategies in a patient population that presents with diabetes mellitus and arterial hypertension need to address different stages of collateral growth and thus different molecular and cellular targets simultaneously. PMID- 25537057 TI - Postprandial decrease in vascular resistance correlated with change in second derivative of finger plethysmogram in young subjects. AB - BACKGROUND: The second derivative of the finger plethysmogram (SDPTG) comprises five waves termed a to e. The magnitudes of waves b-e are normalized by that of wave a for within- and between-patient comparison. In the present study, affects of meal ingestion for SDPTG in young and elderly subjects are examined. SUBJECTS AND METHODS: Mean arterial pressure and SDPTG before and after meal ingestion in young and elderly subjects were measured. For young subjects, stroke volume and pulse rate were also measured, and the total peripheral resistance (TPR) of the blood vessels was analyzed. Relationship between TPR and the ratio of the peak of SDPTG in young subjects was also analyzed. RESULTS: In young subjects, postprandial d/a was significantly larger and TPR was smaller than before intake and was linearly and significantly correlated with TPR. An increase in the postprandial d/a was also observed in the elderly subjects who were not undergoing hypertension treatment. However, this increase was not observed in elderly subjects who were treated for hypertension. CONCLUSIONS: Change in d/a is considered to be an index of change in TPR. TPR is considered to be decreased by agents for treatment of hypertension, and meal ingestion does not appear to further decrease TPR. These results are considered to be useful for understanding cardiodynamics surrounding meal ingestion. PMID- 25537059 TI - Onychomycosis is associated with subclinical atherosclerosis in patients with diabetes. AB - BACKGROUND: We aimed to investigate the association of toenail onychomycosis with subclinical atherosclerosis in patients with diabetes mellitus. PATIENTS AND METHODS: Consecutive diabetic patients who were seen at our outpatient clinic were enrolled. The carotid intima-media thickness (CIMT) was assessed and toenail onychomycosis was diagnosed with microscopic evaluation. RESULTS: We investigated 127 patients with diabetes melltus type 2. Overall, the prevalence of toenail onychomycosis was 37.8 % (48 of 127). Of the 127 patients, 60 (47.2 %) had subclinical atherosclerosis (CIMT >= 1 mm). Prevalence of male gender (43.3 % vs. 22.4 %, p = 0.012) and onychomycosis (53.3 % vs. 23.9 %, p = 0.001) was significantly higher in patients with subclinical atherosclerosis. Among biochemical parameters, low-density lipoprotein (122 +/- 38 mg/dL vs. 108 +/- 36 mg/dL, p = 0.039) and glycosylated hemoglobin levels (median 8.4 %, IQR: 2.1 % vs. median 7.5 %, IQR: 1.6 %, p = 0.002) were significantly higher in patients with subclinical atherosclerosis. Study groups were similar with respect to all other demographic, clinical, and laboratory parameters. After adjustment for all potential confounders, the presence of onychomycosis was independently associated with subclinical atherosclerosis (OR 2.77, 95 % CI 1.16 to 6.30) in multivariate logistic regression analysis. CONCLUSIONS: Presence of onychomycosis in patients with diabetes is associated with subclinical atherosclerosis. Onychomycosis may be a marker of atherosclerotic arterial involvement. PMID- 25537060 TI - Vein compression syndrome unmasked by intravascular ultrasound guided central vein stenting. PMID- 25537058 TI - Postinterventional microembolism signals detected by transcranial Doppler ultrasound after carotid artery stenting. AB - BACKGROUND: The occurrence of early post-procedural complications after carotid artery stenting (CAS) can be attributed to embolization of thrombus or plaque particles released from the stented segment. Vascular emboli can be non invasively detected by transcranial Doppler ultrasound as microembolic signals (MES). We performed this study to discover factors predicting MES detected by transcranial Doppler (TCD)-monitoring within the early post-interventional phase. PATIENTS AND METHODS: In 134 consecutive patients undergoing CAS, transcranial Doppler monitoring of the ipsilateral middle cerebral artery was performed for MES detection during the first post-interventional hour. To identify clinical, morphologic, and procedure-related parameters likely to predict the occurrence of post-interventional MES a logistic regression analysis was performed. RESULTS: In 134 patients (111 male, mean age 69.7 years) relevant MES were detected in 51 patients (38 %) with a median of 4 MES/h and a maximum of 62 MES/h. Three factors were observed to be associated with increased post-interventional MES-counts. These included symptomatic lesion (p < 0.05), elevated total cholesterol (p < 0.05), and aspirin monotherapy (p < 0.0005). In a binary logistic regression model, dual antiplatelet therapy (OR 5.6, p < 0.0005) and asymptomatic lesions (OR 2.6, p < 0.05) were revealed as independent predictors for the absence of post-interventional MES. CONCLUSIONS: Post-interventional MES were most likely in symptomatic lesions and patients with elevated cholesterol. The absence of an effective dual antiplatelet therapy and symptomatic lesions were revealed as independent predictors for post-interventional MES. An effective pre interventional dual antiplatelet and lipid lowering therapy might improve the safety of CAS. PMID- 25537061 TI - Coexistence of Takayasu?s arteritis and ulcerative colitis. PMID- 25537062 TI - New insights into the mechanism model of endovascular treatment for aortic branch artery pseudoaneurysms with type B intramural hematoma. PMID- 25537064 TI - Phylum-specific regulation of resistomycin production in a Streptomyces sp. via microbial coculture. AB - Actinomycete genomes are encoded with immense potential to produce secondary metabolites, however standard laboratory culture experiments rarely provide the conditions under which associated biosynthetic pathways are expressed. Despite years of research attempting to access these pathways and aside from a few well studied bacterial quorum sensing systems, little is known about the specificity of secondary metabolite regulation in bacteria, such as the conditions under which a bacterium produces an antibiotic and the extent to which it does so in recognition of a particular species in the immediate environment. In the current study, we observed that the cocultivation of a Streptomyces sp. (strain B033) with four pathogenic strains of the phylum Proteobacteria resulted in the production of the antibiotic resistomycin. After further coculture experiments, we determined that Proteobacteria induced the production of resistomycin in B033 at significantly higher rates (65%) than strains from the phyla Firmicutes (5.9%) and Actinobacteria (9.1%), supporting that the regulation of secondary metabolism in bacteria can be dependent on the species present in the immediate environment. These results suggest a lack of promiscuity of antibiotic biosynthetic pathway regulation and indicate that it is feasible to mine existing microbial strain libraries for antibiotics in a phylum-specific manner. PMID- 25537065 TI - The influence of sport goggles on visual target detection in female intercollegiate athletes. AB - The aim of this study was to examine the effects of sport goggles on visual target detection in female intercollegiate athletes. Participants were randomly divided into three groups that varied in goggle use (G) or no goggle use (NG) over a total of three 1-min trials during a visual target detection task. The NG NG-NG group did not wear goggles for any of the trials, whereas the NG-G-NG group wore goggles for the second trial only, and the G-NG-G group wore goggles for the first and third trials. The task consisted of illuminated targets arranged in five concentric rings from central to peripheral visual angles. The effects of sport goggles on response time to detect targets were most evident in the peripheral rings. Those who did not wear sport goggles showed improved performance from the first to second trials. This improvement was impaired, however, in those who wore sport goggles. Moreover, there was a reversal of the performance improvements achieved without goggles in those who wore goggles on the third trial. Together, these findings suggest the sport goggles not only impaired the expected initial performance but also impaired visual target detection after performance improvements were seen. These findings suggest sport goggles may impair detection of peripheral visual stimuli in athletes. PMID- 25537063 TI - Hyperphosphatemic familial tumoral calcinosis: odontostomatologic management and pathological features. AB - BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is to a rare autosomal recessive disorder characterized by cutaneous and sub-cutaneous calcified masses, usually adjacent to large joints. The aim of the current study was to report on the clinico-pathological features of a patient with HFCT, with emphasis on alterations in the jawbones and teeth and the subsequent therapeutic interventions. CASE REPORT: A 13-year-old male patient with HFTC diagnosis came to our attention for dental anomalies and maxillary and mandibular hypoplasia. OPT highlighted multiple impacted teeth, short and bulbous teeth, and pulp chamber and canal obliterations. Lateral cephalometric radiograms pointed out retrusion of both jaws, skeletal class II malocclusion, and deep-bite. He underwent orthopedic, orthodontic, conservative, and surgical treatments, allowing the correction of maxillo-facial and dental abnormalities and dysmorphisms without adverse effects. The surgical samples were sent for conventional and confocal laser scanning microscope (CLSM) histopathological examination, which highlighted several metaplastic micro- and macro calcifications in the soft tissues, and typical islands of homogenous, non tubular, dentino-osteoid calcified structures in dentinal tissues. CONCLUSIONS: The management of maxillo-facial abnormalities in patients affected by HFTC is very difficult and, requires a combined therapeutic approach. To date, very few indications have been published in the literature. PMID- 25537066 TI - Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases. AB - Atherosclerosis is a life-long illness that begins with risk factors, which in turn contribute to the development of subclinical disease, followed by the establishment of overt cardiovascular disease (CVD). Thrombotic-occlusive complications of atherosclerosis are among the most widespread and costly health problems. Oxidized low-density lipoprotein (OxLDL) plays an important role in atherogenesis by promoting an inflammatory environment and lipid deposition in the arterial wall. As cardiovascular events occur in individuals without common risk factors, there is a need for additional tools that may help in CVD risk assessment and management. The use of biomarkers has improved diagnostic, therapeutic and prognostic outcome in cardiovascular medicine. This review elaborates on the value of circulating OxLDL as a biomarker of CVD. Three enzyme linked immunosorbent assays (4E6, DLH3 and E06) using murine monoclonal antibodies for determination of OxLDL blood levels have been developed. However, none of these assays are currently approved for routine clinical practice. We identified studies investigating OxLDL in CVD (measured by 4E6, DLH3 or E06 assay) by searching the PubMed database. Circulating OxLDL was found to be associated with all stages of atherosclerosis, from early atherogenesis to hypertension, coronary and peripheral arterial disease, acute coronary syndromes and ischemic cerebral infarction. The results of studies investigating the usefulness of OxLDL for CVD prediction were also summarized. Furthermore, OxLDL was found to be associated with pathologic conditions linked to CVD, including diabetes mellitus, obesity and metabolic syndrome (MetS). In addition, we have addressed the mechanisms by which OxLDL promotes atherogenesis, and the effects of antiatherogenic treatments on circulating OxLDL. Finally, we highlight the evidence suggesting that lipoprotein (a) [Lp(a)] is the preferential carrier of oxidized phospholipids (OxPL) in human plasma. A strong association between OxPL/apoB level (representing the content of OxPL on apolipoprotein B-100 particles, measured by E06 assay) and Lp(a) has been determined. PMID- 25537067 TI - New synthetic strategies to vitamin D analogues. PMID- 25537068 TI - Development of vitamin D analogs modulating the pocket structure of vitamin D receptor. AB - The first determination of the X-ray crystal structure of the ligand binding domain (LBD) of the vitamin D receptor (VDR) complexed with 1alpha,25 dihydroxyvitamin D3 was reported in 2000. Since then several dozen crystal structures of VDR accommodating various ligands have been presented. Almost all of these complexes display the canonical active conformation observed in the VDR LBD/1alpha,25- dihydroxyvitamin D3 complex, and all have quite similar ligand binding pocket (LBP) architectures. To develop new VDR ligands as therapeutic agents, it is important to separate the various biological activities of 1alpha,25- dihydroxyvitamin D3, such as calcium regulation, cell differentiation and anti-proliferation, and immune modulation. We focused on the structure of the LBP and discovered that vitamin D analogs with a branched side chain induce structural rearrangement of the amino acid residues lining the LBP. These analogs formed an additional cavity in the LBP for accommodation of the side chain and thus altered the structure of the LBP. Interestingly, the ligands showed agonistic, partial agonistic, or antagonistic activity depending upon the structure of the side chain. These results indicate that ligands which alter the pocket structure open a new perspective for the development of VDR ligands exhibiting a specific biological activity. PMID- 25537069 TI - Mine dumps, wheeze, asthma, and rhinoconjunctivitis among adolescents in South Africa: any association? AB - The study investigated the association between community proximity to mine dumps, and current wheeze, rhinoconjunctivitis, and asthma among adolescents. This study was conducted during May-November 2012 around five mine dumps in South Africa. Communities in close proximity to mine dumps had an increased likelihood of current wheeze OR 1.38 (95 % CI: 1.10-1.71), rhinoconjunctivitis OR 1.54 (95 % CI: 1.29-1.82), and a protective association with asthma OR 0.29 (95 % CI: 0.23 0.35). Factors associated with health outcomes included other indoor and outdoor pollution sources. Wheeze and rhinoconjunctivitis appear to be a public health problem in these communities. The findings of this study serve as a base for further detailed epidemiological studies for communities in close proximity to the mine dumps e.g. a planned birth cohort study. PMID- 25537071 TI - Solid lipid nanoparticles co-loaded with simazine and atrazine: preparation, characterization, and evaluation of herbicidal activity. AB - Solid lipid nanoparticles (SLN) containing the herbicides atrazine and simazine were prepared and characterized, and in vitro evaluation was made of the release kinetics, herbicidal activity, and cytotoxicity. The stability of the nanoparticles was investigated over a period of 120 days, via analyses of particle size, zeta potential, polydispersion, pH, and encapsulation efficiency. SLN showed good physicochemical stability and high encapsulation efficiencies. Release kinetics tests showed that use of SLN modified the release profiles of the herbicides in water. Herbicidal activity assays performed with pre- and postemergence treatment of the target species Raphanus raphanistrum showed the effectiveness of the formulations of nanoparticles containing herbicides. Assays with nontarget organisms (Zea mays) showed that the formulations did not affect plant growth. The results of cytotoxicity assays indicated that the presence of SLN acted to reduce the toxicity of the herbicides. The new nanoparticle formulations enable the use of smaller quantities of herbicide and therefore offer a more environmentally friendly method of controlling weeds in agriculture. PMID- 25537070 TI - Anxiety mediates the effect of acute stress on working memory performance when cortisol levels are high: a moderated mediation analysis. AB - BACKGROUND: Anxiety is an aversive emotional state characterized by perceived uncontrollability and hypervigilance to threat that can frequently cause disruptions in higher-order cognitive processes like working memory. The attentional control theory (ACT) predicts that anxiety negatively affects the working memory system. DESIGN: This study tested the association between anxiety and working memory after the addition of stress and measured the glucocorticoid, cortisol. To better understand this relationship, we utilized a moderated mediation model. METHODS: Undergraduate students from a public university (N = 103) self-reported their anxiety levels. Participants first completed a short term memory test. During and after a forehead cold pressor task (stress vs. control procedure) participants completed a working memory test. Salivary cortisol was taken at baseline and after the last working memory test. RESULTS: Overall, acute stress had no effect on working memory. However, we found that anxiety levels mediated the influence of condition (stressed vs. control) on working memory, but only among those individuals who had high cortisol levels after exposure to acute stress, supporting a moderated mediation model. CONCLUSIONS: These results imply that activation of the hypothalamic-pituitary adrenal axis was necessary for working memory impairment in anxious individuals. These results provide support for the ACT. PMID- 25537072 TI - Veterinary drug residues in domestic and imported foods of animal origin in the Republic of Korea. AB - The Korean National Residue Programme comprises three different approaches for evaluating domestic and imported foods of animal origin: monitoring, surveillance/enforcement and an exploratory test programme. Monitoring and surveillance/enforcement testing programmes are routinely implemented by 17 Provincial Veterinary Services for domestic products and regional offices of the Animal and Plant Quarantine Agency (QIA) for imported products. The exploratory project conducted at QIA headquarters is designed to test substances that are not included in monitoring and enforcement testing programmes. Here, we carried out exploratory testing for determining the presence of 42 veterinary drugs that have no established Korean maximum residue limits and analysed their levels simultaneously, in a total of 3108 samples of domestic and imported animal-origin foods. Of the tested drugs, acetylsalicylic, paracetamol, clopidol, diclazuril, amprolium, toltrazuril and its metabolites (toltrazuril sulphone and toltrazuril sulphoxide) and phenylbutazone and its metabolites (oxyphenylbutazone) were detected. PMID- 25537076 TI - Improvement of serum zinc levels in young Japanese women by provision of food information. AB - We investigated whether or not an intervention of providing food information improves serum Zn levels in ninety-two 18-20-year-old Japanese women. The mean serum Zn level of the participants was 73.09 +/- 10.56 (mean +/- SD) MUg/dL, where 79 % of the participants had lower than the reference Zn level (80 MUg/dL) proposed by the Japan Society for Biomedical Research on Trace Elements. Participants were divided into food information (INF) group, supplement (SPL) group, and control (C) group, and their serum Zn levels were measured before and after 2 weeks of intervention. The results showed that changes in serum Zn levels were (expressed in MUg/dL): 71.23 +/- 8.42 to 76.83 +/- 12.22 in INF group (NS; not significant), 72.72 +/- 10.77 to 84.07 +/- 12.03 in SPL group (P < 0.01), and 72.69 +/- 9.46 to 74.52 +/- 11.44 in C group (NS). Percentage of normal subjects in serum Zn level (>79 mg/dL) were significantly increased in INF group (16.7 to 40%, P < 0.05) and SPL group (17.2 to 69%, P < 0.001) by each intervention. Food information only entailed a table of food items with high Zn content (card-type) and Zn intake menu (recipes). The results suggested that providing food information is effective in improving latent low Zn in young Japanese women. PMID- 25537073 TI - Predictors of admission after emergency department discharge in older adults. AB - OBJECTIVES: To identify predictors of hospital inpatient admission of older Medicare beneficiaries after discharge from the emergency department (ED). DESIGN: Retrospective cohort study. SETTING: Nonfederal California hospitals (n = 284). PARTICIPANTS: Visits of Medicare beneficiaries aged 65 and older discharged from California EDs in 2007 (n = 505,315). MEASUREMENTS: Using the California Office of Statewide Health Planning and Development files, predictors of hospital inpatient admission within 7 days of ED discharge in older adults (>=65) with Medicare were evaluated. RESULTS: Hospital inpatient admissions within 7 days of ED discharge occurred in 23,340 (4.6%) visits and were associated with older age (70-74: adjusted odds ratio (AOR) = 1.12, 95% confidence interval (CI) = 1.07 1.17; 75-79: AOR = 1.18, 95% CI = 1.13-1.23; >=80: AOR = 1.4, 95% CI = 1.35 1.46), skilled nursing facility use (AOR = 1.82, 95% CI = 1.72-1.94), leaving the ED against medical advice (AOR = 1.82, 95% CI = 1.67-1.98), and the following diagnoses with the highest odds of admission: end-stage renal disease (AOR = 3.83, 95% CI = 2.42-6.08), chronic renal disease (AOR = 3.19, 95% CI = 2.26 4.49), and congestive heart failure (AOR = 3.01, 95% CI = 2.59-3.50). CONCLUSION: Five percent of older Medicare beneficiaries have a hospital inpatient admission after discharge from the ED. Chronic conditions such as renal disease and heart failure were associated with the greatest odds of admission. PMID- 25537077 TI - Evaluated the levels of lead and cadmium in scalp hair of adolescent boys consuming different smokeless tobacco products with related to controls. AB - The present study was aimed to evaluate the cadmium (Cd) and lead (Pb) levels in the scalp hair samples of adolescent boys age ranged 12-15 years, chewing different smokeless tobacco (SLT) products. For comparative purpose, boys of the same age group who did not consume any SLT products were selected as referents. The concentrations of Cd and Pb in SLT products and the scalp hair samples were measured by electrothermal atomic absorption spectrophotometer (ETAAS) after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked by certified reference materials (CRMs). The difference between experimental and certified values of both elements was not significant (p > 0.05). The resulted data indicated that the adolescent boys who consumed different SLT products have two- to threefold higher levels of Cd and Pb in the scalp hair samples as compared to the referent boys (p < 0.01). The adolescent chewing different SLT products have 82.2-110 and 60.6-94.5% higher levels of Cd and Pb, respectively, in their scalp hair as related to the referents. PMID- 25537078 TI - Fungal associations of basal vascular plants: reopening a closed book? PMID- 25537080 TI - Chemically induced coalescence in droplet-based microfluidics. AB - We present a new microfluidic method to coalesce pairs of surfactant-stabilized water-in-fluorocarbon oil droplets. We achieve this through the local addition of a poor solvent for the surfactant, perfluorobutanol, which induces cohesion between droplet interfaces causing them to merge. The efficiency of this technique is comparable to existing techniques providing an alternative method to coalesce pairs of droplets. PMID- 25537081 TI - Assessing the energy and environmental performance of algae-mediated tertiary treatment of estrogenic compounds. AB - This study uses a systems-level modeling approach to illustrate a novel synergy between municipal wastewater treatment and large-scale algaculture for production of bio-energy, whereby algae-mediated tertiary treatment provides efficient removal of unregulated, strongly estrogenic steroid hormones from the secondary effluent. Laboratory results from previously published studies suggested that algae-mediated treatment could deliver roughly 75-85% removal of a model estrogen (17beta-estradiol) within typical algae pond residence times. As such, experimental results are integrated into a comprehensive life cycle assessment (LCA) framework, to assess the environmental performance of an algae-based tertiary treatment system relative to three conventional tertiary treatments: ozonation, UV irradiation, and adsorption onto granular activated carbon. Results indicate that the algae-mediated tertiary treatment is superior to the selected benchmarks on the basis of raw energy return on investment (EROI) and normalized energy use per mass of estrogenic toxicity removed. It is the only tertiary treatment system that creates more energy than it consumes, and it delivers acceptable effluent quality for nutrient and coliform concentrations while rendering a significant reduction in estrogenic toxicity. These results highlight the dual water and energy sustainability benefits that accrue from the integration of municipal wastewater treatment and large-scale algae farming. PMID- 25537079 TI - A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). AB - BACKGROUND: We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. METHODS: Three dose levels (500, 1,000, and 1,500 ug) of GL-0810 or GL-0817 with adjuvants Montanide (1.2 ml) and GM-CSF (100 ug/m2) were administered subcutaneously q2 weeks for a total of four vaccinations in HPV16 and MAGE-A3 positive RM-SCCHN patients, respectively. RESULTS: Nine and seven patients were enrolled in the HPV16 and MAGE-A3 cohorts, respectively. No dose-limiting toxicities were observed, and toxicity was predominantly local and grade 1 (erythema, pain, and itching at the injection site). In those patients who received all four vaccinations, 80 % (4/5) of the HPV16 cohort and 67 % (4/6) of the MAGE-A3 cohort developed antigen-specific T cell and antibody responses to the vaccine. Significant concordance between T cell and antibody responses was observed for both groups. No clear dose-response correlation was seen. All patients progressed by RECIST at first repeat imaging, except for one patient in the MAGE-A3 500 ug cohort who had stable disease for 10.5 months. The median PFS and OS for the MAGE-A3 cohorts were 79 and 183 days, respectively, and for the HPV16 cohort 80 and 196 days, respectively. CONCLUSIONS: GL-0810 and GL-0817 were well tolerated in patients with RM-SCCHN with T cell and antibody responses observed in the majority of patients who received all four vaccinations. PMID- 25537082 TI - Efficient and practical synthesis of enantioenriched 2,3-dihydropyrroles through gold-catalyzed anti-Markovnikov hydroamination of chiral homopropargyl sulfonamides. AB - A direct gold-catalyzed 5-endo-dig cycloisomerization of chiral homopropargyl sulfonamides has been developed. A range of enantioenriched 2,3-dihydropyrroles are readily accessed by utilizing this approach. Importantly, this gold-catalyzed cycloisomerization reaction proceeds through an anti-Markovnikov addition by using a catalytic base as the additive, which completely suppresses the undesired dimerization. PMID- 25537084 TI - Inflammatory mechanisms of endometritis. AB - Transient post breeding endometritis is a normal physiological reaction in the mare, as it is believed that an inflammatory response is necessary for the effective removal of contaminating bacteria and excess spermatozoa introduced into the uterus. While most mares can clear endometritis within a reasonable amount of time, persistent endometritis caused by either bacteria or spermatozoa can threaten the success of a pregnancy. A subpopulation of mares is susceptible to persistent endometritis, and these mares are a concern in equine reproductive medicine. Research has identified several factors that contribute to susceptibility; however, the exact mechanisms of the progression of the disease are still being elucidated. Current research focuses on endometrial gene expression during endometritis in an attempt to understand the timing of specific inflammatory processes involved with the development of susceptibility to persistent endometritis. With an increased understanding of the mechanisms involved with the disease, current treatments can be improved upon, and new treatments can be developed to target affected pathways. PMID- 25537085 TI - Photoluminescent carbon-nitrogen quantum dots as efficient electrocatalysts for oxygen reduction. AB - Here, we demonstrate novel carbon-nitrogen quantum dots (CNQDs) by the hydrothermal method using melamine and glutaraldehyde. CNQDs are uniformly dispersed with particle diameters of 3-8 nm. These prepared CNQDs show excellent luminescence properties and the photoluminescent quantum yields of CNQDs with 365 nm emission are up to 31%. Interestingly, CNQDs possess the co-existence of both p- and n-type conductivities from the Mott-Schottky relationship. Furthermore, the electrochemical measurements reveal that CNQDs exhibit catalytic activity for the oxygen reduction reaction (ORR). However, the low electrical conductivity affects the ORR electrocatalytic activity. So the catalysis is conducted by chemical coupling of CNQDs on Ag nanoparticles (NPs), the resulting CNQD/Ag NP catalyst is demonstrated to possess superior electrocatalytic ability for the ORR in an alkaline medium. PMID- 25537083 TI - COMPRES: a prospective postmarketing evaluation of the compression anastomosis ring CAR 27(TM) /ColonRing(TM). AB - AIM: Preclinical studies have suggested that nitinol-based compression anastomosis might be a viable solution to anastomotic leak following low anterior resection. A prospective multicentre open label study was therefore designed to evaluate the performance of the ColonRing(TM) in (low) colorectal anastomosis. METHOD: The primary outcome measure was anastomotic leakage. Patients were recruited at 13 different colorectal surgical units in Europe, the United States and Israel. Institutional review board approval was obtained. RESULTS: Between 21 March 2010 and 3 August 2011, 266 patients completed the study protocol. The overall anastomotic leakage rate was 5.3% for all anastomoses, including a rate of 3.1% for low anastomoses. Septic anastomotic complications occurred in 8.3% of all anastomoses and 8.2% of low anastomoses. CONCLUSION: Nitinol compression anastomosis is safe, effective and easy to use and may offer an advantage for low colorectal anastomosis. A prospective randomized trial comparing ColonRing(TM) with conventional stapling is needed. PMID- 25537086 TI - Identification of an Australian-like dicot-infecting mastrevirus in Pakistan. AB - Although members of five distinct viral species in the genus Mastrevirus (family Geminiviridae) infect dicotyledonous plants in Australia, in the remainder of the world, only a single dicot-infecting mastrevirus, chickpea chlorotic dwarf virus (CpCDV) has ever been identified. This virus has been found infecting leguminous hosts in Africa, the Middle East and the Indian subcontinent. To further explore the diversity of CpCDV in Pakistan, ten full mastrevirus genome sequences from chickpea and lentil plants were determined. Eight of these genomes were from previously described CpCDV strains and included the first reported strain D and H isolates in Pakistan. Two other genomes derived from infected chickpea plants are more closely related to dicot-infecting mastreviruses found in Australia than they are to CpCDV. These two divergent genomes shared less than 75 % genome-wide nucleotide sequence identity with other characterised mastreviruses and therefore are likely to belong to a second species of dicot-infecting mastreviruses outside of Australia. We propose naming this species Chickpea yellow dwarf virus. We discuss how the presence of chickpea yellow dwarf virus (CpYDV) in Pakistan weakens the hypothesis that Australia is the geographical origin of the dicot infecting mastreviruses. PMID- 25537087 TI - Non-phytoseiid Mesostigmata within citrus orchards in Florida: species distribution, relative and seasonal abundance within trees, associated vines and ground cover plants and additional collection records of mites in citrus orchards. AB - Seven citrus orchards on reduced- to no-pesticide spray programs in central and south central Florida were sampled for non-phytoseiid mesostigmatid mites. Inner and outer canopy leaves, fruits, twigs and trunk scrapings were sampled monthly between August 1994 and January 1996. Open flowers were sampled in March from five of the sites. A total of 431 samples from one or more of 82 vine or ground cover plants were sampled monthly in five of the seven orchards. Two of the seven orchards (Mixon I and II) were on full herbicide programs and vines and ground cover plants were absent. A total of 2,655 mites (26 species) within the families: Ascidae, Blattisociidae, Laelapidae, Macrochelidae, Melicharidae, Pachylaelapidae and Parasitidae were identified. A total of 685 mites in the genus Asca (nine species: family Ascidae) were collected from within tree samples, 79 from vine or ground cover plants. Six species of Blattisociidae were collected: Aceodromus convolvuli, Blattisocius dentriticus, B. keegani, Cheiroseius sp. near jamaicensis, Lasioseius athiashenriotae and L. dentatus. A total of 485 Blattisociidae were collected from within tree samples compared with 167 from vine or ground cover plants. Low numbers of Laelapidae and Macrochelidae were collected from within tree samples. One Zygoseius furciger (Pachylaelapidae) was collected from Eleusine indica. Four species of Melicharidae were identified from 34 mites collected from within tree samples and 1,190 from vine or ground cover plants: Proctolaelaps lobatus was the most abundant species with 1,177 specimens collected from seven ground cover plants. One Phorytocarpais fimetorum (Parasitidae) was collected from inner leaves and four from twigs. Species of Ascidae, Blattisociidae, Melicharidae, Laelapidae and Pachylaelapidae were collected from 31 of the 82 vine or ground cover plants sampled, representing only a small fraction of the total number of Phytoseiidae collected from the same plants. Including the collection records of Martin Muma prior to 1975, a total of 69 species of Ascidae, Blattisociidae, Laelapidae, Macrochelidae, Melicharidae, Pachylaelapidae and Parasitidae have now been reported from citrus in Florida. PMID- 25537088 TI - SPHK1 inhibitor suppresses cell proliferation and invasion associated with the inhibition of NF-kappaB pathway in hepatocellular carcinoma. AB - Sphingosine kinase 1 (SphK1) is an oncogenic enzyme promoting transformation, proliferation, and angiogenesis of a number of human tumors. However, its effect on hepatocellular carcinoma (HCC) behavior has not been fully clarified. The purpose of this study was to determine the correlation between HCC and SphK1, and to evaluate the effect of SphK1 inhibitor N,N-dimethylsphingosine (DMS) in HCC. The expression of SphK1 was measured in tissue samples from 76 HCC and paired adjacent noncancerous liver tissues (NT) by immunohistochemistry, quantitative real-time PCR, and Western blotting analysis. The effect of DMS was tested on HCC cells by evaluating cell viability in vitro. Transwell cell migration and invasion assay were carried out for functional analysis. Furthermore, Western blotting analysis was performed to examine the impact of DMS on the PI3K/Akt/NF kB signaling. High expression of Sphk1 was observed in 84.21% (64/76) of the HCC versus 15.79% (12/76) of the adjacent non-tumorous liver tissues; the difference of Sphk1 expression between HCC and the adjacent non-tumorous liver tissues was statistically significant (P < 0.001). The results were confirmed by Western blot analyses and quantitative real-time PCR. DMS inhibited the proliferation of SK Hep1 and MHCCLM3 cells which have a relatively high level of SphK1 in a time- and concentration-dependent manner, and the invasion and migration of SK-Hep1 cells were distinctly suppressed after undergoing treatment with DMS. Furthermore, DMS markedly suppressed the expression of phosphorylations of Akt and NF-kappaB in HCC cells. Our data suggest that the pathogenesis of human HCC maybe mediated by Sphk1, and the specific Sphk1 inhibitor DMS can play a therapeutic role in the treatment of HCC and thus, Sphk1 could represent selective targets for the molecularly targeted treatments of HCC. PMID- 25537089 TI - Reactive oxygen species, glutathione, and thioredoxin influence suberoyl bishydroxamic acid-induced apoptosis in A549 lung cancer cells. AB - Suberoyl bishydroxamic acid (SBHA) as a histone deacetylase (HDAC) inhibitor can induce apoptosis through the formation of reactive oxygen species (ROS). However, there is no report about the regulation of ROS and antioxidant enzymes in SBHA treated lung cancer cells. Here, we investigated the toxicological effects of SBHA on the regulations of ROS, glutathione (GSH), and antioxidant enzymes, especially thioredoxin (Trx) in A549 lung cancer cells. SBHA inhibited the growth of A549 cells in time- and dose-dependent manners, and it induced apoptosis which accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim). SBHA significantly increased ROS levels including O2 (*-) level at 72 h whereas it decreased ROS levels at the early time points (30 min to 3 h). SBHA also induced GSH depletion at 24 and 72 h. N-acetyl cysteine (NAC; a well-known antioxidant) prevented apoptotic cell death and GSH depletion via decreasing ROS in SBHA-treated A549 cells. In addition, SBHA changed the levels of antioxidant related proteins, especially Trx1. The expression and activity of Trx1 in A549 cells were reduced by SBHA. While the downregulation of Trx1 enhanced cell death, ROS level, and GSH depletion in SBHA-treated A549 cells, the overexpression of Trx1 decreased ROS level in these cells without the prevention of cell death and GSH depletion. In conclusion, SBHA-induced A549 cell death was influenced by changes in ROS and GSH levels. The basal status of Trx1 among other antioxidant proteins was closely correlated with the survival of A549 cells. PMID- 25537090 TI - Survinin expression in patients with breast cancer during chemotherapy. AB - Breast cancer (BC) is the second most common cancer worldwide and the first among women. If early diagnosed and treated, this disease has a good prognosis. However, it is believed that 90 % of all patients who have had cancer died due to metastatic disease, which highlights the need for a marker which allows the detection of latent cancer cells spread from the primary tumor. The objective of this study was to investigate the expression of survinin in peripheral blood of patients with breast cancer at diagnosis and during chemotherapy aiming correlation with minimal residual disease, clinical and pathological findings. The study included 40 patients with breast cancer and 12 healthy donors as a comparison group. Survinin expression was verified by real-time PCR. For diagnosis, survinin expression cutoff point was 1.05; considering this cutoff point, we obtained a test sensitivity of 85.3 %, specificity of 75.0 %, positive predictive value of 90.6 %, negative predictive value of 64.3 %, and accuracy of 82.6 %. There was statistical significance between groups (patients * control group), presenting to patients a significantly higher value than the control group (p < 0.001). Patients that presented at the diagnosis a survinin gene expression >= 1.05 are 17 times more likely to develop metastatic disease. PMID- 25537091 TI - RA induces differentiation of multipotent P19 cells towards male germ cell. AB - Generating male germ cells in vitro from multipotent stem cells is still a challenge for stem cell biologists. The difficulty is caused by the lack of knowledge about spermatogenesis molecular-controlling mechanisms. In vivo, PGCs differentiate into male germ cells in a very complicated environment through many middle steps. In this study, we use the pluripotent p19 cells to test their responses to different retinoic acid (RA) concentrations by evaluating markers for stem cells (bmp4, egr3), primordial germ cells (ddx4), spermatogonia (c-kit), premeiotic cells (stra8), and male germ cells (dazl and plzf). We have found that cyp26b1, which will catalyze RA, increases dramatically in p19 cells 1 d after RA treatment. Bmp3, egr3, and stra8 are stimulated after 1 d of RA treatment and then recover to normal after 3 d of RA treatment. C-kit keeps being expressed when treated with 10 nM-4 MUM RA. Dazl and plzf are gained after 3 d of stimulation. The morphology of RA (100 nM-4 MUM)-treated cells changes distinctively, and cell colonies are formed. Typical neural cell-like and germ cell-like morphologies appear in the 100 nM and 4 MUM RA groups, respectively. We conclude that 100-500 nM RA can cause responses in p19 cells, but a high concentration of RA (1-4 MUM) can drive these pluripotent cells' differentiation towards male germ cells. However, high concentrations of RA are also toxic. Some colonies that survived from 4 MUM RA begin to express ddx4 and c-kit. Selection of the c-kit(+), dazl(+), and ddx4(+) cells after RA stimulation and creating a special culture medium for their propagation might benefit successful spermatogenesis induction in vitro. PMID- 25537092 TI - Perturbed Development of Striatal Dopamine Transporters in Fatty Versus Lean Zucker Rats: a Follow-up Small Animal PET Study. AB - PURPOSE: Post-synaptic dopamine D2/3 receptors are reduced in animal models of obesity, and in obese humans, concordant with similar findings in habitual drug users. However, corresponding pre-synaptic changes in brain dopamine are less documented in obesity models. Therefore, we used positron emission tomography (PET) with the dopamine transporter (DAT) ligand N-(3-[(18)F]fluoropropyl)-2-beta carbomethoxy-3-beta-(4'-methylphenyl) tropane ([(18)F]FP-CMT) to test the hypothesis that DAT availability is attenuated in adult fatty Zucker (FZ) rats versus lean littermates (LZ). PROCEDURES: Groups of nine FZ and LZ rats were examined by [(18)F]FP-CMT PET at approximately 6 weeks and at 6 months of age. RESULTS: The baseline mean striatal binding potential (BPND) of [(18)F]FP-CMT did not differ between groups (LZ 2.4; FZ 2.5), although FZ rats already had higher body weight and elevated blood triglycerides, cholesterol, and insulin. At follow up, a mixed effects multiple regression model showed that the maturation of DAT availability was attenuated in FZ rats, such that the mean BPND in striatum was 17 % lower (LZ 4.0; FZ 3.3; p = 0.01). Body weight was twofold higher in the adult FZ rats, and triglycerides fourfold increased, but glucose remained normal despite doubling of insulin levels. CONCLUSIONS: Maturation of the striatal dopamine innervation is impaired in this model of obesity/hyperlipidaemia without diabetes, implying an acquired trait of reduced dopamine reuptake capacity. PMID- 25537093 TI - Evaluation of Functionalized Polysaccharide Microparticles Dosimetry for SPECT Imaging Based on Biodistribution Data of Rats. AB - PURPOSE: Technetium-99 m (Tc-99 m)-labelled microparticles, functionalized with fucoidan to present a high affinity for P-Selectin, or [(99m)Tc] MP-fucoidan, were developed as a novel SPECT radiotracer for abdominal aortic aneurysm (AAA). As a prerequisite step forwards a clinical trial, the biodistribution and dosimetry of these [(99m)Tc] MP-fucoidan microparticles were performed in rats in order to estimate the absorbed and effective dose in humans. PROCEDURES: Microparticles with a maximum hydrodynamic diameter of 4 MUm were obtained by crosslinking polysaccharides dextran and pullulan. They were functionalized with fucoidan then radiolabelled with Tc-99 m. A mean labelling efficiency of 92 +/- 1% was measured. [(99m)Tc] MP-fucoidan (43 +/- 2 MBq) was injected to 24 rats via the penis vein. Rats were euthanized at 30, 60, 120 and 240 min after injection (4 rats at each time point). Samples of each organ, as well as the injected microparticle suspensions, were aliquoted for counting. Four animals were sacrificed for blood clearance studies and four were sacrificed for image analysis and quantification of the cortical, medullary, papillary kidney, and pelvis uptake. A compartmental model was realised using SAAM II and organ data were fitted. The area under the curve was then used to compute the residence times in each rat organs and converted to human residence time values. Absorbed and effective human doses in organs were estimated using (1) the OLINDA/EXM 1.1 software with the hermaphroditic mathematical phantoms and (2) the OEDIPE software associated to the MCNPX Monte Carlo code and the ICRP reference computational male and female phantoms, using the updated tissue weighting factors in the ICRP Publication 103. RESULTS: The highest human residence times were found in the liver, kidneys, and urinary bladder wall. The largest doses were found in the kidneys and then in the urinary bladder wall and liver. The human effective doses were 6.06 MUSv/MBq for the hermaphroditic mathematical phantom and 5.95 MUSv/MBq for the ICRP adult reference computational phantom. CONCLUSIONS: Animal-based human dose estimates support a future first-in-human testing of [(99m)Tc] MP-fucoidan following IV injection. PMID- 25537095 TI - Interactions between microemulsion droplets decorated with hydrophobically modified polymers: a small-angle neutron scattering study. AB - The shape and interactions between microemulsion droplets (R = 8.2 nm, polydispersity 20%) either decorated with PEO modified with a single hydrophobic end function (PEO-m: C12H25 - (EO)n, M(PEO) = 5.2 kg/mol), or with telechelic polymers of twice the mass (PEO-2m: C12H25 - (EO)2n - C12H25, M(PEO) = 10.4 kg/mol) have been studied by small-angle neutron scattering (SANS). The results as a function of droplet and polymer concentration have been compared to the reference case of the bare microemulsion which was shown to be unchanged using Porod representations. The interactions between bare and decorated droplets have been analyzed using the structure factor S(q), at first in a model-free way based on its low-q limit S(q -> 0). This analysis provides clear evidence on the concentration-dependent repulsive or attractive nature of the contributions to the pair droplet-droplet pair potential of the polymers. Model pair potentials describing the steric repulsions and attractions by copolymer bridging are used to describe the low-q behavior of the structure factor based on an integral equation approach, giving an estimate of the range and amplitude of the potentials. Moreover, they provide an explanation for the observed transient clustering in terms of a shallow minimum of the total potential, as they establish the respective repulsive and attractive contributions of the polymer molecules. PMID- 25537094 TI - Hierarchical structure in microbial cellulose: what happens during the drying process. AB - We present a time-resolved investigation of the natural drying process of microbial cellulose (MC) by means of simultaneous small-angle neutron scattering (SANS), intermediate-angle neutron scattering (IANS) and weighing techniques. SANS was used to elucidate the microscopic structure of the MC sample. The coherent scattering length density of the water penetrating amorphous domains varied with time during the drying process to give a tunable scattering contrast to the water-resistant cellulose crystallites, thus the contrast variation was automatically performed by simply drying. IANS and weighing techniques were used to follow the macroscopic structural changes of the sample, i.e., the composition variation and the loss of the water. Thus, both the structure and composition changes during the whole drying process were resolved. In particular, the quantitative crosscheck of composition variation by IANS and weighing provides a full description of the drying process. Our results show that: i) The natural drying process could be divided into three time regions: a 3-dimensional shrinkage in region I, a 1-dimensional shrinkage along the thickness of the sample in region II, and completion in region III; ii) the further crystallization and aggregation of the cellulose fibrils are observed in both the rapid drying and natural drying methods, and the rapid drying even induces obvious structural changes in the length scale of 7-125 nm; iii) the amount of "bound water", which is an extremely thin layer of water surrounding the surfaces of cellulose fibrils, was estimated to be ~ 0.35 wt% by the weighing measurement and was verified by the quantitative analysis of SANS results. PMID- 25537096 TI - Peripheral viewing during exposure to a 2D/3D video clip: effects on the human body. AB - OBJECTIVES: Symptoms of three-dimensional (3D) sickness, such as intoxication and eye fatigue, have been observed in subjects viewing 3D films and vary according to the image quality and visual environment. In addition, the influence of stereoscopic vision on the incidence of 3D sickness has not been explored sufficiently. Therefore, it is important to examine the safety of viewing virtual 3D content. METHODS: The present study examines the effects of peripheral vision on reported motion sickness during exposure to 2D/3D video clips for 1 min and for 1 min afterwards in human subjects. Stabilograms were recorded during exposure to video clips with or without visual pursuit of a 3D object and compared, and subjects were administered the simulator sickness questionnaire after stabilometry. RESULTS: There were no significant main effects of solidity of the visual stimulous (2D/3D) and the vision method (visual pursuit/peripheral viewing) in accordance with the two-way analysis of variance of the sway values, although the sway values during the 2D/3D video clips were higher than in control subjects. A consistent trend in the main effect of stability was observed. Further, the sway values changed remarkably after the 3D video clip was viewed peripherally and produced a persistent instability in equilibrium function. The questionnaire findings also significantly changed after the subjects viewed the video clips peripherally. CONCLUSIONS: Subjective exacerbation and deterioration of equilibrium function were observed after peripheral viewing of 3D video clips. This persistent influence may result when subjects view a poorly depicted background element peripherally, which generates depth perception that contradicts daily experience. PMID- 25537097 TI - Burkholderia ginsengiterrae sp. nov. and Burkholderia panaciterrae sp. nov., antagonistic bacteria against root rot pathogen Cylindrocarpon destructans, isolated from ginseng soil. AB - Strain DCY85(T) and DCY85-1(T), isolated from rhizosphere of ginseng, were rod shaped, Gram-reaction-negative, strictly aerobic, catalase positive and oxidase negative. 16S rRNA gene sequence analysis revealed that strain DCY85(T) as well as DCY85-1(T) belonged to the genus Burkholderia and were closely related to Burkholderia fungorum KACC 12023(T) (98.1 and 98.0 % similarity, respectively). The major polar lipids of strain DCY85(T) and DCY85-1(T) were phosphatidylethanolamine, one unidentified aminolipid and two unidentified phospholipids. The major fatty acids of both strains are C16:0, C18:1 omega7c and summed feature 3 (C16:1 omega6c and/or C16:1 omega7c). The predominant isoprenoid quinone of each strain DCY85(T) and DCY85-1(T) was ubiquinone (Q-8) and the G+C content of their genomic DNA was 66.0 and 59.4 mol%, respectively, which fulfill the characteristic range of the genus Burkholderia. The polyamine content of both DCY85(T) and DCY85-1(T) was putrescine. Although both DCY85(T) and DCY85-1(T) have highly similar 16S rRNA and identical RecA and gyrB sequences, they show differences in phenotypic and chemotaxonomic characteristics. DNA-DNA hybridization results proved the consideration of both strains as two different species. Based on the results from our polyphasic characterization, strain DCY85(T) and DCY85-1(T) are considered novel Burkholderia species for which the name Burkholderia ginsengiterrae sp. nov and Burkholderia panaciterrae sp. nov are, respectively, proposed. An emended description of those strains is also proposed. DCY85(T) and DCY85-1(T) showed antagonistic activity against the common root rot pathogen of ginseng, Cylindrocarpon destructans. The proposed type strains are DCY85(T) (KCTC 42054(T) = JCM 19888(T)) and DCY85-1(T) (KCTC 42055(T) = JCM 19889(T)). PMID- 25537098 TI - Growth responses of two tall fescue cultivars to Pb stress and their metal accumulation characteristics. AB - Tall fescue (Festuca arundinacea), a widely planted cool-season turfgrass and forage, is tolerant to heavy metals. However, previous investigation demonstrated that different accessions varied in Pb tolerance. In present study, hydroponic system was used to study the effects of Pb on two tall fescue cultivars, Pb tolerant 'Silverado' and Pb sensitive 'AST7001', respectively. The results indicated that Pb concentration was 14 times lower in shoots of 'Silverado' (1.34 mg g(-1) dry weight) versus 'AST7001' (19.92 mg g(-1) dry weight), although it was higher in roots of 'Silverado' (68.28 mg g(-1) dry weight) versus 'AST7001' (48.7 mg g(-1) dry weight), when subjected to 1,000 mg L(-1) Pb. In both cultivars, Pb caused an induction in malondialdehyde (MDA) content, to a less increase in 'Silerado' than 'AST7001'. Pb treatment decreased significantly soluble protein content in 'AST7001'. By contrast, soluble protein content was increased progressively, and the ratio of variable to maximal chlorophyll fluorescence was not affected in 'Silverado'. Pb treated tall fescue leaves had a greater level of superoxide dismutase (SOD) and guaiacol peroxidase (POD) activity in both cultivars, however, increase was sharp in 'Silverado' plants. The results of Q-PCR analysis for genes encoding antioxidant enzyme were in accordance with that of enzyme activities. The higher Pb tolerance of 'Silverado' might be attributed to lower shoot Pb concentration and MDA content. Meantime, the amount of soluble protein, activity of SOD and POD, as well as the level of up regulation of Cyt Cu/ZnSOD was all higher in 'Silverado' than in 'AST7001'. PMID- 25537100 TI - Introduction to symposium proceedings ?"Applying vitamin A isotope dilution techniques to benefit human nutrition?". PMID- 25537101 TI - Evaluation of the "?Olson equation"?, an isotope dilution method for estimating vitamin A stores. AB - Isotope dilution methods have been successfully used to estimate vitamin A status in human populations as well as to evaluate the impact of vitamin A interventions. The most commonly applied isotope dilution method is the retinol isotope dilution technique, which is based on the 1989 "?Olson equation"? for estimating total body vitamin A stores (sometimes equated to liver vitamin A) after an oral dose of labeled vitamin A. The equation relies on several factors related to absorption and retention of the dose, the equilibration of label in plasma vs. liver, and timing of a blood sample for measurement of labeled vitamin A. Here, the assumptions underlying these factors are discussed, and new results based on applying model-based compartmental analysis [specifically, the Simulation, Analysis and Modeling software (WinSAAM)] to data on retinol kinetics in humans are summarized. A simplification of the Olson equation, in which plasma tracer is measured 3 days after administration of the oral dose and several factors are eliminated, is presented. The potential usefulness of the retinol isotope dilution technique for setting vitamin A requirements and assessing vitamin A status in children, as well as the confounding effects of inflammation and likely variability in vitamin A absorption, are also discussed. PMID- 25537102 TI - Usefulness of vitamin A isotope methods for status assessment: from deficiency through excess. AB - A variety of methods exist to assess vitamin A status of groups and populations. Vitamin A status is usually defined by the liver retinol concentration. Most indicators of status do not measure or estimate liver stores of retinol. Clinical signs only have utility when liver reserves are almost exhausted, and serum retinol concentrations have utility in the zone of overt deficiency. Dose response tests offer more coverage, but cannot distinguish among liver vitamin A stores in the adequate through toxic range. Different countries continue, or are beginning, to add preformed vitamin A to a variety of staple foods through fortification, and vitamin A supplements are still being distributed in many countries, especially to preschool children. Further, provitamin A biofortified crops are currently being released in several countries. Assessing population vitamin A status in response to these interventions needs to move beyond serum retinol concentrations. Indicators that work in the excessive to toxic range of liver reserves are needed. To date, the only indirect indicator that has been validated in this range of liver reserves in animals and humans is the retinol isotope dilution test using deuterium or 13C, which spans the entire liver reserve continuum from deficiency through excess. PMID- 25537099 TI - Daily diary reports of social connection, objective sleep, and the cortisol awakening response during adolescents' first year of college. AB - Poor sleep and alterations in the stress-sensitive hypothalamic-pituitary-adrenal (HPA) axis may be mechanisms through which loneliness impacts adolescents' well being. Few researchers have explored whether daily variation in experiences of social connection predict day-to-day variation in sleep and HPA axis activity among adolescents navigating the college context. Using daily diary reports of social connection, objective measures of sleep (actigraphy), and naturalistic salivary assessment, the present study examined within-person associations between first-year college students' social connection during the day and sleep that night, as well as diurnal cortisol activity the following day. The present study also explored trait-level loneliness as a moderator of these associations after adjusting for baseline loneliness assessed in high school. Seventy-one first-year college students (23% male; M age = 18.85; 52% non-Hispanic White) completed daily diary reports, wore a wrist-based accelerometer (actigraph watch), and provided saliva samples five times daily across three consecutive weekdays. The results from hierarchical linear models indicated that within person increases in daily social connection were significantly associated with longer time spent in bed and more actual time asleep that night only for adolescents high on loneliness. Within-person increases in daily social connection were associated with a greater cortisol awakening response (CAR) the next day, regardless of trait loneliness. These findings illustrate that more daily social connection with others than usual may predict improved sleep quantity for lonely adolescents and a physiological index of anticipating upcoming daily demands (CAR) in general. Future intervention programs might consider including strategies focused on enhancing daily social interactions among adolescents starting college, particularly for lonely adolescents. PMID- 25537103 TI - Vitamin A value of plant food provitamin A - evaluated by the stable isotope technologies. AB - Humans need vitamin A and obtain essential vitamin A by conversion of plant foods rich in provitamin A and/or absorption of preformed vitamin A from foods of animal origin. The determination of the vitamin A value of plant foods rich in provitamin A is important but has challenges. The aim of this paper is to review the progress over last 80 years following the discovery on the conversion of beta carotene to vitamin A and the various techniques including stable isotope technologies that have been developed to determine vitamin A values of plant provitamin A (mainly beta-carotene). These include applications from using radioactive beta-carotene and vitamin A, depletion-repletion with vitamin A and beta-carotene, and measuring postprandial chylomicron fractions after feeding a beta-carotene rich diet, to using stable isotopes as tracers to follow the absorption and conversion of plant food provitamin A carotenoids (mainly beta carotene) in humans. These approaches have greatly promoted our understanding of the absorption and conversion of beta-carotene to vitamin A. Stable isotope labeled plant foods are useful for determining the overall bioavailability of provitamin A carotenoids from specific foods. Locally obtained plant foods can provide vitamin A and prevent deficiency of vitamin A, a remaining worldwide concern. PMID- 25537104 TI - Existing and emerging technologies for measuring stable isotope labelled retinol in biological samples: isotope dilution analysis of body retinol stores. AB - This paper discusses some of the recent improvements in instrumentation used for stable isotope tracer measurements in the context of measuring retinol stores, in vivo. Tracer costs, together with concerns that larger tracer doses may perturb the parameter under study, demand that ever more sensitive mass spectrometric techniques are developed. GCMS is the most widely used technique. It has high sensitivity in terms of sample amount and uses high resolution GC, yet its ability to detect low isotope ratios is limited by background noise. LCMSMS may become more accessible for tracer studies. Its ability to measure low level stable isotope tracers may prove superior to GCMS, but it is isotope ratio MS (IRMS) that has been designed specifically for low level stable isotope analysis through accurate analysis of tracer:tracee ratios (the tracee being the unlabelled species). Compound-specific isotope analysis, where GC is interfaced to IRMS, is gaining popularity. Here, individual 13C-labelled compounds are separated by GC, combusted to CO2 and transferred on-line for ratiometric analysis by IRMS at the ppm level. However, commercially-available 13C-labelled retinol tracers are 2 - 4 times more expensive than deuterated tracers. For 2H labelled compounds, GC-pyrolysis-IRMS has now become more generally available as an operating mode on the same IRMS instrument. Here, individual compounds are separated by GC and pyrolysed to H2 at high temperature for analysis by IRMS. It is predicted that GC-pyrolysis-IRMS will facilitate low level tracer procedures to measure body retinol stores, as has been accomplished in the case of fatty acids and amino acids. Sample size requirements for GC-P-IRMS may exceed those of GCMS, but this paper discusses sample preparation procedures and predicts improvements, particularly in the efficiency of sample introduction. PMID- 25537106 TI - Research recommendations for applying vitamin A-labelled isotope dilution techniques to improve human vitamin A nutrition. AB - The current use of serum retinol concentrations as a measurement of subclinical vitamin A deficiency is unsatisfactory for many reasons. The best technique available for vitamin A status assessment in humans is the measurement of total body pool size. Pool size is measured by the administration of retinol labelled with stable isotopes of carbon or hydrogen that are safe for human subjects, with subsequent measurement of the dilution of the labelled retinol within the body pool. However, the isotope techniques are time-consuming, technically challenging, and relatively expensive. There is also a need to assess different types of tracers and doses, and to establish clear guidelines for the use and interpretation of this method in different populations. Field-friendly improvements are desirable to encourage the application of this technique in developing countries where the need is greatest for monitoring the risk of vitamin A deficiency, the effectiveness of public health interventions, and the potential of hypervitaminosis due to combined supplement and fortification programs. These techniques should be applied to validate other less technical methods of assessing vitamin A deficiency. Another area of public health relevance for this technique is to understand the bioconversion of beta-carotene to vitamin A, and its relation to existing vitamin A status, for future dietary diversification programs. PMID- 25537105 TI - International experiences in assessing vitamin A status and applying the vitamin A-labeled isotope dilution method. AB - Inadequate vitamin A (VA) nutrition continues to be a major problem worldwide, and many interventions being implemented to improve VA status in various populations need to be evaluated. The interpretation of results after an intervention depends greatly on the method selected to assess VA status. To evaluate the effect of an intervention on VA status, researchers in Cameroon, India, Indonesia, Mexico, Senegal and Zambia have used serum retinol as an indicator, and have not always found improvement in response to supplementation. One problem is that homeostatic control of serum retinol may mask positive effects of treatment in that changes in concentration are observed only when status is either moderately to severely depleted or excessive. Because VA is stored mainly in the liver, measurements of hepatic VA stores are the ?gold standard? for assessing VA status. Dose response tests such as the relative dose response (RDR) and the modified relative dose response (MRDR), allow a qualitative assessment of VA liver stores. On the other hand, the use of the vitamin A-labeled isotope dilution (VALID) technique, (using 13C or 2H-labeled retinyl acetate) serves as an indirect method to quantitatively estimate total body and liver VA stores. Countries including Cameroon, China, Ghana, Mexico, Thailand and Zambia are now applying the VALID method to sensitively assess changes in VA status during interventions, or to estimate a population?s dietary requirement for VA. Transition to the use of more sensitive biochemical indicators of VA status such as the VALID technique is needed to effectively assess interventions in populations where mild to moderate VA deficiency is more prevalent than severe deficiency. PMID- 25537108 TI - Expedient metal-free synthesis of 1,3-oxazinen-4-ones. AB - 1,3-Oxazinen-4-ones are medicinally important scaffolds which have traditionally been accessed using a hetero-Diels-Alder approach or more recently using a cobalt catalyzed three-component cycloaddition. Herein we report a novel strategy to access this scaffold which allows for the rapid and high yielding synthesis of 1,3-oxazinen-4-ones under ambient temperature and pressures with improved substrate scope. PMID- 25537109 TI - Anode catalysts for direct methanol fuel cells in acidic media: do we have any alternative for Pt or Pt-Ru? PMID- 25537107 TI - Seizure associated with clozapine: incidence, etiology, and management. AB - Seizures are a known adverse effect of clozapine therapy. The literature varies on incidence rates of seizures, secondary to varying time frames in which each seizure occurred. Tonic-clonic seizures comprise the majority of seizures experienced secondary to clozapine use, but it is imperative to recognize the potential variety of seizure presentation. The exact etiology of clozapine induced seizure is unknown. Conflicting reports regarding total oral dose, serum concentration, dose titration, and concomitant medications make it difficult to identify a single cause contributing to seizure risk. Following seizure occurrence, it may be in the best interests of the patient to continue clozapine treatment. In this clinical situation, the use of an antiepileptic drug (AED) for seizure prophylaxis may be required. The AED of choice appears to be valproate, but several successful case reports also support the use of lamotrigine, gabapentin and topiramate. Well-designed clinical trials regarding clozapine seizure prophylaxis are lacking. Given clozapine's strong evidence for efficacy in the treatment of schizophrenia and schizoaffective disorder, every attempt to manage side effects, including seizure, should be implemented to allow for therapeutic continuation. PMID- 25537110 TI - Pediatric de novo cerebral AVM: report of two cases and review of literature. AB - PURPOSE: Cerebral arteriovenous malformation (AVM) is traditionally thought of as a congenital diagnosis. In recent years, there has been infrequent reports of this neurovascular condition presenting as de novo entities. METHODS: The authors report two cases of pediatric patients who present with de novo cerebral AVMs. In both cases, the patients had magnetic resonance imaging (MRI) of the brain done as part of the work-up for first-onset seizures. At that point in time, the scans were unremarkable. After a latent period of approximately 6 and 9 years respectively, a repeated MRI brain scan showed evidence of de novo AVM for each patient. RESULTS: Both patients did not have radiological evidence of cerebral AVM during their first presentation of seizures. However, a repeated MRI brain scan after a period of 6 and 9 years demonstrated new findings of cerebral AVM for each patient. CONCLUSIONS: Currently, the disease of cerebral de novo AVM remain as an ambiguous condition that is poorly understood. With the advances in molecular diagnostics, there are possibilities of exploring biochemical profiles for better understanding of the origin of cerebral AVMs. However, in the meantime, owing to the unpredictable nature of cerebral AVMs, clinicians should have increased awareness of this unique condition. This is especially important, as definitive treatment is available to prevent devastating neurological sequelae from cerebral AVM rupture. PMID- 25537112 TI - Validation of the SenseWear Armband in different ambient temperatures. AB - This study examines the validity of the SenseWear Armband in different temperatures using the old (SenseWear v2.2) and newest version of the algorithm (SenseWear v5.2) against indirect calorimetry (IC). Thirty-nine male and female students (21.1 +/- 1.41 years) completed an exercise trial in 19 degrees C, 26 degrees C and 33 degrees C consisting of 5 min standing followed by alternating walking/running at 35% and 65% of their maximal oxygen uptake. The accuracy of the algorithms was evaluated by comparing estimated energy expenditure (EE) to IC using a mixed-model design. No difference was reported in EE between the different temperatures for IC. Both algorithms estimated EE significantly higher when exercising at high intensity in 33 degrees C compared to 19 degrees C. Compared to IC, SenseWear v2.2 accurately estimated EE during standing and light intensity exercise but underestimated EE when exercising in a hot environment and at high intensity. SenseWear v5.2 showed a difference when exercising at high intensity in thermoneutral and warm conditions. The new algorithm improved EE estimation in hot environments and at high intensity compared to the old version. However, given the inherent inaccuracy of the EE estimates of SenseWear, greater weight should be given to direct monitor outputs rather than the ability of a monitor to estimate EE precisely. PMID- 25537113 TI - Direct detection of saponins in crude extracts of soapnuts by FTIR. AB - Direct detection of saponins in soapnuts (Sapindus mukorossi) using Fourier transform infrared (FTIR) spectroscopy is investigated in this project. Potassium bromide powder was mixed with extracted powder of soapnuts and compressed to a thin pellet for examination process. The outcome of the FTIR spectra of saponin demonstrated characteristic triterpenoid saponin absorptions of OH, C = O, C-H, and C = C, while the glycoside linkages to the sapogenins were indicated by the absorptions of C-O. The significance of this study is that saponin absorption peaks are directly detectable in crude aqueous and 95% ethanol extracts of soapnuts powder using FTIR spectroscopy, thereby eliminating the need of further expensive and exhaustive purification steps. The extracts of soapnuts were screened for saponins along with controls by phytochemical tests, and advanced spectroscopic techniques such as ultra fast liquid chromatography and ultra performance liquid chromatography quadrupole-time of flight-mass spectrometry were also implemented to validate the saponins. PMID- 25537111 TI - Prenylated flavonoids and resveratrol derivatives isolated from Artocarpus communis with the ability to overcome TRAIL resistance. AB - In a screening program on natural products that can abrogate tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance, four new prenylated flavonoid and resveratrol derivatives (1-4) were isolated from Artocarpus communis, together with eight known prenylflavonoids (5-12). The structures of 1-4 were elucidated spectroscopically. Pannokin D [corrected] (1) (2 MUM) and artonin E (5) (3 MUM) potently exhibited the ability to overcome TRAIL resistance. Artonin E (5) induced caspase-dependent apoptosis in combination with TRAIL, increased caspase 3/7 activity, and enhanced the protein levels of p53 and DR5. Moreover, this substance decreased cell viability in combination with TRAIL and enhanced the protein levels of DR5, and these effects were mediated by increases in the production of ROS (reactive oxygen species). Thus, artonin E (5) was found to induce extrinsic apoptotic cell death by the ROS and p53-mediated up-regulation of DR5 expression in AGS cells. PMID- 25537114 TI - Transfer rates of 19 typical pesticides and the relationship with their physicochemical property. AB - Determining the transfer rate of pesticides during tea brewing is important to identify the potential exposure risks from pesticide residues in tea. In this study, the transfer rates of 19 typical pesticides from tea to brewing were investigated using gas chromatography tandem mass and ultraperformance liquid chromatography tandem mass. The leaching rates of five pesticides (isocarbophos, triazophos, fenvalerate, buprofezin, and pyridaben) during tea brewing were first reported. The pesticides exhibited different transfer rates; however, this result was not related to residual concentrations and tea types. Pesticides with low octanol-water partition coefficients (Logkow) and high water solubility demonstrated high transfer rates. The transfer rates of pesticides with water solubility > 29 mg L(-1) (or <15 mg L(-1)) were >25% (or <10%), and those of pesticides with LogKow < 1.52 (or >2.48) were >65% (or <35%). This result indicates that water solubility at approximately 20 mg L(-1) and LogKow at approximately 2.0 could be the demarcation lines of transfer rate. The results of this study can be used as a guide in the application of pesticides to tea trees and establishment of maximum residue limits of pesticides in tea to reduce pesticide exposure in humans. PMID- 25537115 TI - When does subliminal affective image priming influence the ability of schizophrenic patients to perceive face emotions? AB - BACKGROUND: Deficits in face emotion perception are among the most pervasive aspects of schizophrenia impairments which strongly affects interpersonal communication and social skills. MATERIAL AND METHODS: Schizophrenic patients (PSZ) and healthy control subjects (HCS) performed 2 psychophysical tasks. One, the SAFFIMAP test, was designed to determine the impact of subliminally presented affective or neutral images on the accuracy of face-expression (angry or neutral) perception. In the second test, FEP, subjects saw pictures of face-expression and were asked to rate them as angry, happy, or neutral. The following clinical scales were used to determine the acute symptoms in PSZ: Positive and Negative Syndrome (PANSS), Young Mania Rating (YMRS), Hamilton Depression (HAM-D), and Hamilton Anxiety (HAM-A). RESULTS: On the SAFFIMAP test, different from the HCS group, the PSZ group tended to categorize the neutral expression of test faces as angry and their response to the test-face expression was not influenced by the affective content of the primes. In PSZ, the PANSS-positive score was significantly correlated with correct perception of angry faces for aggressive or pleasant primes. YMRS scores were strongly correlated with PSZ's tendency to recognize angry face expressions when the prime was a pleasant or a neutral image. The HAM-D score was positively correlated with categorizing the test-faces as neutral, regardless of the affective content of the prime or of the test-face expression (angry or neutral). CONCLUSIONS: Despite its exploratory nature, this study provides the first evidence that conscious perception and categorization of facial emotions (neutral or angry) in PSZ is directly affected by their positive or negative symptoms of the disease as defined by their individual scores on the clinical diagnostic scales. PMID- 25537117 TI - Understanding solid-state properties of triglycerides used in pharmaceutical and food microencapsulation. AB - Hydrophobic materials, in particular hydrogenated vegetable oils, HVO, are extensively used as coating materials in food and pharmaceutical systems. Correct application of these coatings requires an evaluation of their behaviour as a function of various parameters such as melting temperature, solubility, concentration and/or pH. The purpose of this study was to assess the physico chemical properties of an HVO in terms of composition, crystallisation, phase transition and polymorphism using a variety of analytical techniques, such as electrospray mass spectrometry (ESI-MS), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). High-resolution ESI-MS allowed establishment of the HVO main composition of long-chain triglycerides (average molecular weight 1183 Da). DSC results showed that thermal history determines the formation of at least two polymorphs of HVO, namely two different crystal forms, assigned as form alpha, melting point (m.p.) 48 degrees C, and form beta', m.p. 60 degrees C. A third polymorph, the more thermodynamically stable beta-form, having a melting point at 62 degrees C, is obtained by solution-mediated re-crystallisation. Phase transformation paths were investigated by isothermal DSC experiments, which evidenced that the alpha-form is kinetically stable at temperatures lower than 25 degrees C. These data are of particular interest in practical applications such as spray freezing or pan coating where significant heat transfer phenomena are involved. PMID- 25537118 TI - Prevalence and development of workplace health promotion in Germany: results of the IAB Establishment Panel 2012. AB - PURPOSE: Based on survey data from the IAB Establishment Panel, the investigation aims to examine the prevalence of workplace health promotion among German establishments and its determinants. METHODS: The IAB Establishment Panel 2012 comprises interviews with 15,556 establishments of all sizes and industrial sectors in Germany. We first present some descriptive statistics and then analyse the determinants of the prevalence of workplace health promotion by means of a probit regression. RESULTS: In 2012, 27 % of the interviewed establishments reported providing workplace health promotion measures on a voluntary basis. 64 % of all employees do work in establishments with workplace health promotion. From 2002 to 2012, the share of establishments with workplace health promotion increased by 8 % points. The strongest increase was observed in establishments in Western Germany and establishments with work councils. Most popular among the measures of workplace health promotion are employee surveys and analysis of the sickness absence. The vast majority of establishments provide only single measures. The econometric analysis shows that industrial sector, size of establishment, expected problems with human resources and the existence of a work council are important factors for workplace health promotion. CONCLUSIONS: Only a minority of establishments are committed to workplace health promotion, while these establishments provide the majority of jobs in Germany. Our analysis displays considerable disparities in terms of prevalence as well as potential for further extensions. This could be taken more into account when discussing innovative approaches of workplace health promotion. PMID- 25537116 TI - Temporal profiles dissociate regional extracellular ethanol versus dopamine concentrations. AB - In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25-30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these "response ratios" differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research. PMID- 25537119 TI - In situ DNA-templated synthesis of silver nanoclusters for ultrasensitive and label-free electrochemical detection of microRNA. AB - On the basis of the use of silver nanoclusters (AgNCs) in situ synthesized by cytosine (C)-rich loop DNA templates as signal amplification labels, the development of a label-free and highly sensitive method for electrochemical detection of microRNA (miRNA-199a) is described. The target miRNA-199a hybridizes with the partial dsDNA probes to initiate the target-assisted polymerization nicking reaction (TAPNR) amplification to produce massive intermediate sequences, which can be captured on the sensing electrode by the self-assembled DNA secondary probes. These surface-captured intermediate sequences further trigger the hybridization chain reaction (HCR) amplification to form dsDNA polymers with numerous C-rich loop DNA templates on the electrode surface. DNA-templated synthesis of AgNCs can be realized by subsequent incubation of the dsDNA polymer modified electrode with AgNO3 and sodium borohydride. With this integrated TAPNR and HCR dual amplification strategy, the amount of in situ synthesized AgNCs is dramatically enhanced, leading to substantially amplified current response for highly sensitive detection of miRNA-199a down to 0.64 fM. In addition, the developed method also shows high selectivity toward the target miRNA-199a. Featured with high sensitivity and label-free capability, the proposed sensing scheme can thus offer new opportunities for achieving sensitive, selective, and simple detection of different types of microRNA targets. PMID- 25537120 TI - Reproductive allocation in plants as affected by elevated carbon dioxide and other environmental changes: a synthesis using meta-analysis and graphical vector analysis. AB - Reproduction is an important life history trait that strongly affects dynamics of plant populations. Although it has been well documented that elevated carbon dioxide (CO2) in the atmosphere greatly enhances biomass production in plants, the overall effect of elevated CO2 on reproductive allocation (RA), i.e., the proportion of biomass allocated to reproductive structures, is little understood. We combined meta-analysis with graphical vector analysis to examine the overall effect of elevated CO2 on RA and how other environmental factors, such as low nutrients, drought and elevated atmospheric ozone (O3), interacted with elevated CO2 in affecting RA in herbaceous plants. Averaged across all species of different functional groups and environmental conditions, elevated CO2 had little effect on RA (-0.9%). RA in plants of different reproductive strategies and functional groups, however, differed in response to elevated CO2. For example, RA in iteroparous wild species decreased by 8%, while RA in iteroparous crops increased significantly (+14%) at elevated CO2. RA was unaffected by CO2 in plants grown with no stress or in low-nutrient soils. RA decreased at elevated CO2 and elevated O3, but increased in response to elevated CO2 in drought stressed plants, suggesting that elevated CO2 could ameliorate the adverse effect of drought on crop production to some extent. Our results demonstrate that elevated CO2 and other global environmental changes have the potential to greatly alter plant community composition through differential effects on RA of different plant species and thus affect the dynamics of natural and agricultural ecosystems in the future. PMID- 25537125 TI - Articulation and oromyofunctional behavior in children seeking orthodontic treatment. AB - OBJECTIVES: The purpose of this controlled study is to document articulation and oromyofunctional behavior in children seeking orthodontic treatment. In addition, relations between malocclusions, articulation, and oromyofunctional behavior are studied. MATERIALS AND METHODS: The study included 56 children seeking orthodontic treatment. The control group, consisting of 54 subjects matched for age and gender, did not undergo orthodontic intervention. To determine the impact of the occlusion on speech, the Oral Health Impact Profile was used. Speech characteristics, intelligibility and several lip and tongue functions were analyzed using consensus evaluations. RESULTS: A significant impact of the occlusion on speech and more articulation disorders for/s,n,l,t/were found in the subjects seeking orthodontic treatment. Several other phenomena were seen more often in this group, namely more impaired lip positioning during swallowing, impaired tongue function at rest, mouth breathing, open mouth posture, lip sucking/biting, anterior tongue position at rest, and tongue thrust. Moreover, all children with a tongue thrust showed an anterior tongue position at rest. CONCLUSIONS: Children seeking orthodontics have articulatory and oromyofunctional disorders. To what extent a combined orthodontic and logopaedic treatment can result in optimal oral health (i.e. perfect dentofacial unit with perfect articulation) is subject for further multidisciplinary research. PMID- 25537128 TI - Cholinesterase Inhibitory Activities of N-Phenylthiazol-2-Amine Derivatives and their Molecular Docking Studies. AB - Alzheimer's disease (AD) is a type of neurodegenerative disorder which is responsible for many cognitive dysfunctions. According to the most accepted cholinergic hypothesis, cholinesterases have a major role in AD symptoms. The use of small molecules as inhibitors is one of the most useful strategies to control AD. In the present work, a series of N-phenylthiazol-2-amine derivatives was screened against acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from horse serum by using Ellman's method, using neostigmine and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors for AChE and BChE activity. N-(2,3 dimethylphenyl)thiazol-2-amine, 3j was found to be the most active inhibitor among the series with IC50 value of 0.009 +/- 0.002 uM and 0.646 +/- 0.012 uM against AChE and BChE, respectively. Molecular docking studies were carried out in order to better understand the ligand binding site interactions. PMID- 25537129 TI - In vitro and in vivo Evaluation of 17-phenylpropylamine/phenoxyethylamine- 17 demethoxygeldanamycins as Potent Hsp90 Inhibitors. AB - A series of 17-phenylpropylamine/phenoxyethylamine-substituted derivatives of geldanamycin (GA) was synthesized and evaluated for the anti-proliferation activity on human cancer cell line MDA-MB-231. All the derivatives exhibited potent cytotoxicity with IC50 values range from 0.35 to 1.03 uM. Among them, 17 (2-phenoxyethylamino)-17-demethoxygeldanamycin (3) was identified as the most potent compound. Hepatotoxicity test in mice demonstrated that the levels of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 3-treated group were lower than that of GA-treated group, indicating that compound 3 was a promising antitumor candidate. Additionally, the Hsp90 inhibitory activity of compound 3 was more active than 17-AAG. Docking and molecular dynamics (MD) refinements of this new series of GA derivatives were also investigated, suggesting a theoretical model between 17- phenylpropylamine/phenoxyethyl-amines and Hsp90. PMID- 25537124 TI - Epidemiology of drug-disease interactions in older veteran nursing home residents. AB - OBJECTIVES: To describe the prevalence of and factors associated with drug disease interactions (DDIs) in older nursing home residents according to the American Geriatrics Society 2012 Beers Criteria. DESIGN: Cross-sectional. SETTING: Fifteen Veterans Affairs Community Living Centers. PARTICIPANTS: Individuals aged 65 and older with a diagnosis of dementia or cognitive impairment, a history of falls or hip fracture, heart failure (HF), a history of peptic ulcer disease (PUD), or Stage IV or V chronic kidney disease (CKD). MEASUREMENTS: Medications that could exacerbate the above conditions (DDIs). RESULTS: Three hundred sixty-one of 696 (51.9%) eligible residents had one or more DDIs. None involved residents with a history of PUD, one involved a resident with CKD, and four occurred in residents with HF. Of 540 residents with dementia or cognitive impairment, 50.7% took a drug that could exacerbate these conditions; the most commonly involved medications were antipsychotics (35.4%) and benzodiazepines (14.4%). Of 267 with a history of falls or hip fracture, 67.8% received an interacting medication, with selective serotonin reuptake inhibitors (33.1%), antipsychotics (30.7%), and anticonvulsants (25.1%) being most commonly involved. Using separate multivariable logistic regression models, factors associated with DDIs in dementia or cognitive impairment and falls or fractures included age 85 and older (adjusted odds ratio (aOR) = 0.38, 95% confidence interval (CI) = 0.24-0.60 and aOR = 0.48, 95% CI = 0.24-0.96, respectively), taking five to eight medications (aOR = 2.06, 95% CI = 1.02-4.16 and aOR = 4.76, 95% CI = 1.68-13.5, respectively), taking nine or more medications (aOR = 1.99, 95% CI = 1.03-3.85 and aOR = 3.68, 95% CI = 1.41-9.61, respectively), and being a long-stay resident (aOR = 1.80, 95% CI = 1.04-3.12 and aOR = 2.35, 95% CI = 1.12-4.91, respectively). CONCLUSION: DDIs were common in older nursing home residents with dementia or cognitive impairment or a history of falls or fractures. PMID- 25537130 TI - Emerging technologies, recent developments, and novel applications for drug metabolite identification. AB - Drug metabolite identification and metabolic characteristics analysis play a crucial role in new drug research and development, because they can lead to varied efficacy, severe adverse reactions, and even toxicity. Classical methodologies for metabolite identification have mainly been based on mass spectrometry (MS) coupled with gas chromatography (GC) or liquid chromatography (LC), and some other techniques are used as complementary approaches, such as nuclear magnetic resonance (NMR). Over the past decade, more and more newly emerging techniques or technologies have been applied to metabolite identification, and are making the procedure easier and more robust, such as LC NMR-MS, ion mobility MS, ambient ionization techniques, and imaging MS. A novel application of drug metabolite identification based on "omics" known as pharmacometabonomics is discussed, which is an interdisciplinary field that combines pre-dose metabolite profiling and chemometrics methods for data analysis and modeling, aiming to predict the responses of individuals to drugs. PMID- 25537132 TI - Combined Effects of Vincristine and Quercetin in Reducing Isoproterenol-Induced Cardiac Necrosis in Rats. AB - Combined effects of vincristine and quercetin in the regulation of isoproterenol (ISO)-induced cardiac necrosis have been evaluated in rats. ISO administration (100 mg/kg, s.c., for two consecutive days) increased the levels of serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), glutamate pyruvate transaminase (SGPT) and cardiac troponin (cTnT) as well as cardiac lipid peroxidation products (malondialdehyde and lipid hydroperoxides). However, it reduced the activities of superoxide dismutase (SOD), catalase and the glutathione peroxidase and the level of reduced glutathione. It also increased the heart rate and ST-segment elevation in ECG. Pretreatment of vincristine (25 MUg/kg) or quercetin (10 mg/kg) alone for 2 weeks ameliorated these cardiotoxic effects partially. However, treatment of both vincristine and quercetin for a similar period reduced the serum CK-MB, LDH, SGPT and cTnT levels near to normal levels in ISO-treated rats. Concomitantly, the test drugs improved the status of antioxidants and decreased the cardiac lipid peroxidation products. Combined treatment of both the drugs also restored the pathological electrocardiographic patterns and reduced the area of myocardial necrosis. Histopathology of heart in ISO-administered rats that received both vincristine and quercetin showed nearly normal myocardium with very little inflammatory infiltration. In conclusion, the present finding appears to be the first one, suggesting a better protection of cardiac tissues by combined treatment of vincristine and quercetin in isoproterenol-induced cardiac toxicity. PMID- 25537133 TI - Probing a chemical compass: novel variants of low-frequency reaction yield detected magnetic resonance. AB - We present a study of a carotenoid-porphyrin-fullerene triad previously shown to function as a chemical compass: the photogenerated carotenoid-fullerene radical pair recombines at a rate sensitive to the orientation of an applied magnetic field. To characterize the system we develop a time-resolved Low-Frequency Reaction Yield Detected Magnetic Resonance (tr-LF-RYDMR) technique; the effect of varying the relative orientation of applied static and 36 MHz oscillating magnetic fields is shown to be strongly dependent on the strength of the oscillating magnetic field. RYDMR is a diagnostic test for involvement of the radical pair mechanism in the magnetic field sensitivity of reaction rates or yields, and has previously been applied in animal behavioural experiments to verify the involvement of radical-pair-based intermediates in the magnetic compass sense of migratory birds. The spectroscopic selection rules governing RYDMR are well understood at microwave frequencies for which the so-called 'high field approximation' is valid, but at lower frequencies different models are required. For example, the breakdown of the rotating frame approximation has recently been investigated, but less attention has so far been given to orientation effects. Here we gain physical insights into the interplay of the different magnetic interactions affecting low-frequency RYDMR experiments performed in the challenging regime in which static and oscillating applied magnetic fields as well as internal electron-nuclear hyperfine interactions are of comparable magnitude. Our observations aid the interpretation of existing RYDMR-based animal behavioural studies and will inform future applications of the technique to verify and characterize further the biological receptors involved in avian magnetoreception. PMID- 25537134 TI - Exploring the Fe(III) binding sites of human serum transferrin with EPR at 275 GHz. AB - We report 275 GHz EPR spectra of human serum transferrin. At this high microwave frequency the zero-field splitting between the magnetic sublevels of the high spin [Formula: see text] sites can be accurately determined. We find the zero field splitting to be a sensitive probe of the structure of the transferrin iron binding sites. Signals arising from iron bound to the transferrin N-lobe can clearly be distinguished from signals from iron bound to the C-lobe. Moreover, our spectra show that the structure of the iron site in the N-lobe is influenced by the presence and conformation of the C-lobe. The spectra of a series of N-lobe mutants altering the second-shell interaction of Arg124 with the synergistic anion carbonate reflect conformational changes induced at the iron site. PMID- 25537135 TI - A multiple path photonic lab on a chip for parallel protein concentration measurements. AB - We propose a PDMS-based photonic system for the accurate measurement of protein concentration with minute amounts of the sample. As opposed to the state of the art approach, in the multiple path photonic lab on a chip (MPHIL), analyte concentration or molar absorptivity is obtained with a single injection step, by performing simultaneous parallel optical measurements varying the optical path length. Also, as opposed to the standard calibration protocol, the MPHIL approach does not require a series of measurements at different concentrations. MPHIL has three main advantages: firstly the possibility of dynamically selecting the path length, always working in the absorbance vs. concentration linear range for each target analyte. Secondly, a dramatic reduction of the total volume of the sample required to obtain statistically reliable results. Thirdly, since only one injection is required, the measurement time is minimized, reducing both contamination and signal drifts. These characteristics are clearly advantageous when compared to commercial micro-spectrophotometers. The MPHIL concept was validated by testing three commercial proteins, lysozyme (HEWL), glucose isomerase (d-xylose-ketol-isomerase, GI) and Aspergillus sp. lipase L (BLL), as well as two proteins expressed and purified for this study, B. cereus formamidase (FASE) and dihydropyrimidinase from S. meliloti CECT41 (DHP). The use of MPHIL is also proposed for any spectrophotometric measurement in the UV-VIS range, as well as for its integration as a concentration measurement platform in more advanced photonic lab on a chip systems. PMID- 25537136 TI - Exploring the potential of using algae in cosmetics. AB - The applications of microalgae in cosmetic products have recently received more attention in the treatment of skin problems, such as aging, tanning and pigment disorders. There are also potential uses in the areas of anti-aging, skin whitening, and pigmentation reduction products. While algae species have already been used in some cosmetic formulations, such as moisturizing and thickening agents, algae remain largely untapped as an asset in this industry due to an apparent lack of utility as a primary active ingredient. This review article focuses on integrating studies on algae pertinent to skin health and beauty, with the purpose of identifying serviceable algae functions in practical cosmetic uses. PMID- 25537131 TI - Advances in receptor conformation research: the quest for functionally selective conformations focusing on the beta2-adrenoceptor. AB - Seven-transmembrane receptors, also called GPCRs, represent the largest class of drug targets. Upon ligand binding, a GPCR undergoes conformational rearrangement and thereby changes its interaction with effector proteins including the cognate G-proteins and the multifunctional adaptor proteins, beta-arrestins. These proteins, by initiating distinct signal transduction mechanisms, mediate one or several functional responses. Recently, the concept of ligand-directed GPCR signalling, also called functional selectivity or biased agonism, has been proposed to explain the phenomenon that chemically diverse ligands exhibit different efficacies towards the different signalling pathways of a single GPCR, and thereby act as functionally selective or 'biased' ligands. Current concepts support the notion that ligand-specific GPCR conformations are the basis of ligand-directed signalling. Multiple studies using fluorescence spectroscopy, X ray crystallography, mass spectroscopy, nuclear magnetic resonance spectroscopy, single-molecule force spectroscopy and other techniques have provided the evidence to support this notion. It is anticipated that these techniques will ultimately help elucidate the structural basis of ligand-directed GPCR signalling at a precision meaningful for structure-based drug design and how a specific ligand molecular structure induces a unique receptor conformation leading to biased signalling. In this review, we will summarize recent advances in experimental techniques applied in the study of functionally selective GPCR conformations and breakthrough data obtained in these studies particularly those of the beta2-adrenoceptor. PMID- 25537137 TI - Integrating an algal beta-carotene hydroxylase gene into a designed carotenoid biosynthesis pathway increases carotenoid production in yeast. AB - The algal beta-carotene hydroxylase gene Crchyb from Chlamydomonas reinhardtii, Czchyb from Chlorella zofingiensis, or Hpchyb from Haematococcus pluvialis and six other carotenoid-synthesis pathway genes were co-integrated into the genome of a yeast host. Each of these three algal genes showed a higher efficiency to convert beta-carotene to downstream carotenoids than the fungal genes from Phaffia rhodozyma. Furthermore, the strain with Hpchyb displayed a higher carotenoid productivity than the strains integrated with Crchyb or Czchyb, indicating that Hpchyb is more efficient than Crchyb and Czchyb. These results suggest that beta-carotene hydroxylase plays a crucial role in the biosynthesis of carotenoids. PMID- 25537138 TI - Extraction of lipids from microalgae using CO2-expanded methanol and liquid CO2. AB - The use of CO2-expanded methanol (cxMeOH) and liquid carbon dioxide (lCO2) is proposed to extract lipids from Botryococcus braunii. When compressed CO2 dissolves in methanol, the solvent expands in volume, decreases in polarity and so increases in its selectivity for biodiesel desirable lipids. Solid phase extraction of the algal extract showed that the cxMeOH extracted 21 mg of biodiesel desirable lipids per mL of organic solvent compared to 3mg/mL using either neat methanol or chloroform/methanol mixture. The non-polar lCO2 showed a high affinity for non-polar lipids. Using lCO2, it is possible to extract up to 10% neutral lipids relative to the mass of dry algae. Unlike extractions using conventional solvents, these new methods require little to no volatile, flammable, or chlorinated organic solvents. PMID- 25537139 TI - Predicting elite Scottish athletes' attitudes towards doping: examining the contribution of achievement goals and motivational climate. AB - Understanding athletes' attitudes to doping continues to be of interest for its potential to contribute to an international anti-doping system. However, little is known about the relationship between elite athletes' attitudes to drug use and potential explanatory factors, including achievement goals and the motivational climate. In addition, despite specific World Anti-Doping Agency Code relating to team sport athletes, little is known about whether sport type (team or individual) is a risk or protective factor in relation to doping. Elite athletes from Scotland (N = 177) completed a survey examining attitudes to performance enhancing drug (PED) use, achievement goal orientations and perceived motivational climate. Athletes were generally against doping for performance enhancement. Hierarchical regression analysis revealed that task and ego goals and mastery motivational climate were predictors of attitudes to PED use (F (4, 171) = 15.81, P < .01). Compared with individual athletes, team athletes were significantly lower in attitude to PED use and ego orientation scores and significantly higher in perceptions of a mastery motivational climate (Wilks' lambda = .76, F = 10.89 (5, 170), P < .01). The study provides insight into how individual and situational factors may act as protective and risk factors in doping in sport. PMID- 25537140 TI - Presence in Mediterranean hotspots and floral symmetry affect speciation and extinction rates in Proteaceae. AB - The Proteaceae is a large angiosperm family displaying the common pattern of uneven distribution of species among genera. Previous studies have shown that this disparity is a result of variation in diversification rates across lineages, but the reasons for this variation are still unclear. Here, we tested the impact of floral symmetry and occurrence in Mediterranean climate regions on speciation and extinction rates in the Proteaceae. A rate shift analysis was conducted on dated genus-level phylogenetic trees of the Proteaceae. Character-dependent analyses were used to test for differences in diversification rates between actinomorphic and zygomorphic lineages and between lineages located within or outside Mediterranean climate regions. The rate shift analysis identified 5-10 major diversification rate shifts in the Proteaceae tree. The character-dependent analyses showed that speciation rates, extinction rates and net diversification rates of the Proteaceae were significantly higher for lineages occurring in Mediterranean hotspots. Higher speciation and extinction rates were also detected for zygomorphic species, but net diversification rates appeared to be similar in actinomorphic and zygomorphic Proteaceae. Presence in Mediterranean hotspots favors Proteaceae diversification. In contrast with observations at the scale of angiosperms, floral symmetry is not a trait that strongly influences their evolutionary success. PMID- 25537141 TI - Idiopathic left upper quadrant omental infarction: diagnosed and managed conservatively in the ED. PMID- 25537142 TI - A Theorem on the Rank of a Product of Matrices with Illustration of Its Use in Goodness of Fit Testing. AB - This paper develops a theorem that facilitates computing the degrees of freedom of Wald-type chi-square tests for moment restrictions when there is rank deficiency of key matrices involved in the definition of the test. An if and only if (iff) condition is developed for a simple rule of difference of ranks to be used when computing the desired degrees of freedom of the test. The theorem is developed exploiting basics tools of matrix algebra. The theorem is shown to play a key role in proving the asymptotic chi-squaredness of a goodness of fit test in moment structure analysis, and in finding the degrees of freedom of this chi square statistic. PMID- 25537143 TI - On the use of partial area under the ROC curve for comparison of two diagnostic tests. AB - Evaluation of diagnostic performance is typically based on the receiver operating characteristic (ROC) curve and the area under the curve (AUC) as its summary index. The partial area under the curve (pAUC) is an alternative index focusing on the range of practical/clinical relevance. One of the problems preventing more frequent use of the pAUC is the perceived loss of efficiency in cases of noncrossing ROC curves. In this paper, we investigated statistical properties of comparisons of two correlated pAUCs. We demonstrated that outside of the classic model there are practically reasonable ROC types for which comparisons of noncrossing concave curves would be more powerful when based on a part of the curve rather than the entire curve. We argue that this phenomenon stems in part from the exclusion of noninformative parts of the ROC curves that resemble straight-lines. We conducted extensive simulation studies in families of binormal, straight-line, and bigamma ROC curves. We demonstrated that comparison of pAUCs is statistically more powerful than comparison of full AUCs when ROC curves are close to a "straight line". For less flat binormal ROC curves an increase in the integration range often leads to a disproportional increase in pAUCs' difference, thereby contributing to an increase in statistical power. Thus, efficiency of differences in pAUCs of noncrossing ROC curves depends on the shape of the curves, and for families of ROC curves that are nearly straight-line shaped, such as bigamma ROC curves, there are multiple practical scenarios in which comparisons of pAUCs are preferable. PMID- 25537144 TI - Neurophysiology: Under pressure. PMID- 25537145 TI - Prefrontal cortex: Dopamine double rules. PMID- 25537148 TI - Inhibitory effects of Guben Yiliu Formula II (II) and its blood activation prescriptions on the growth of MCF-7 human breast cancer xenografts in nude mice. AB - OBJECTIVE: To investigate the inhibitory effects of Guben Yiliu Formula II(II, GFII) and its blood activation prescription (BAP) on the growth of MCF-7 human breast cancer xenografts in nude mice, and explore their mechanisms of action. METHODS: After the establishment of the MCF-7 human breast cancer xenograft model in nude mice, the mice in the GFII and BAP groups were administered with GFII (6.56 g/mL) and BAP (1.65 g/mL) by gavage for 28 days, respectively. The tumor volume and weight were measured twice a week throughout the treatment period. Apoptotic cells were identified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The expression of microtubule associated protein 1 light chain 3 (LC3) was examined by immunohistochemistry, and Western blotting analysis was performed to detect the expression of anti-apoptotic protein Bcl-2 and LC3, as well as the effects on phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. RESULTS: Compared with the control group, the GFII and BAP groups could significantly inhibit the growth of MCF-7 human breast cancer xenografts in nude mice. The expression of Bcl-2 protein was lower in the GFII and BAP than in the control group, whereas both the percentage of apoptotic cells and LC3-II/LC3-I ratio were higher than in the control group. In addition, significantly reduced expression of phospho-Akt, phosphor-mTOR and mTOR were observed in the blood activation group (P<0.05). CONCLUSIONS: To some extent, the GFII and its BAP can exert their inhibitory effect on the growth of MCF-7 human breast cancer xenografts by inducing the cell apoptosis and autophagy. In addition to the induction of cell apoptosis, we also found that the BAP of GFII could induce cell autophagy by inhibiting of PI3K/Akt/mTOR signaling pathway, and then suppress the breast cancer cell growth. PMID- 25537146 TI - TP53 Arg 72Pro and MDM2 SNP309 polymorphisms and colorectal cancer risk: a west Algerian population study. AB - The tumor suppressor gene TP53 and its regulator MDM2 are both key players involved in multiple pathways including apoptosis, cellular transcriptional control and cell cycle regulation. Common germline polymorphisms in these genes may affect colorectal cancer (CRC) susceptibility. An arginine-to-proline substitution at codon 72 in the TP53 gene is reported to decrease apoptotic potential, while a thymine-to-guanine polymorphism at nucleotide 309 (named SNP309) of murine double minute 2 MDM2 gene increases its transcription. These two polymorphisms therefore may be of importance in colorectal carcinogenesis. The relation of these polymorphisms to colorectal cancer in the Algerian population was addressed in this study. DNA samples from 121 controls and 116 cases were genotyped for these two polymorphisms by PCR/RFLP then confirmed by sequencing. Unexpectedly no significant association was found between this potential marker TP53 Arg72Pro and CRC (p > 0.05). However, our findings reveal that individuals with the MDM2 SNP309 GG genotype have a low risk of CRC as compared to the TT genotype (OR = 0.49; 95 % CI: 0.24-0.98, p = 0.04), with more significance for females (OR = 0.16; 95 % CI: 0.06-0.41, p < 0.05). Moreover, no significant association was observed between the combined TP53 and MDM2 genotypes and CRC. Contrary to initial expectations that the GG genotype with high MDM2 levels would increase cancer risk, our results demonstrate that the MDM2 SNP309 GG genotype is associated with decreased risk of colorectal cancer. This is suggesting that other mechanisms independent of increased MDM2 levels can influence cancer susceptibility. PMID- 25537147 TI - Polymorphisms in DNA repair genes and breast cancer risk in Russian population: a case-control study. AB - Genetic variation in DNA repair genes can alter an individual's capacity to repair damaged DNA and influence the risk of cancer. We tested seven polymorphisms in DNA repair genes XRCC1, ERCC2, XRCC3, XRCC2, EXOI and TP53 for a possible association with breast cancer risk in a sample of 672 case and 672 control Russian women. An association was observed for allele A of the polymorphism XRCC1 (R399Q) rs25487 (co-dominant model AA vs. GG: OR 1.76, P = 0.003; additive model OR 1.28, P = 0.005; dominant model: OR 1.29, P = 0.03; recessive model OR 1.63, P = 0.008). Allele T of the polymorphism ERCC2 (D312N) rs1799793 was also associated with breast cancer risk (co-dominant model TT vs. CC: OR 1.43, P = 0.04; additive model OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02), but the association became insignificant after applying Bonferroni correction. No association with breast cancer was found for the remaining SNPs. In summary, our study provides evidence that polymorphisms in DNA repair genes may play a role in susceptibility to breast cancer in the population of ethnical Russians. PMID- 25537149 TI - Study design and implementation for population pharmacokinetics of Chinese medicine: An expert consensus. AB - Although many population pharmacokinetics (PPK) researches have been conducted on chemical drugs, few have been in the field of Chinese medicine (CM). Each ingredient in CMs possesses different pharmacokinetic characteristics, therefore, it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations. To develop an expert consensus on study design and implementation for PPK of CM, in August 2013, 6 experts in the field of PPK, CMs pharmacology, and statistics discussed problems on the PPK research protocol of CMs, and a consensus was reached. The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected. The compositions with definite therapeutic effects were selected as indices, and specific time points and sample sizes were designed according to standard PPK design methods. Target components were tested through various chromatography methods. Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs (which assists in reasonable adjustments on clinical dosage). This consensus specifies the study design and implementation process of PPK. It provides guidance for the following: post-marketing clinical studies, in vivo investigations related to the metabolism in different populations, and development and clinical adjustment of dosages of CMs. PMID- 25537150 TI - Allergic constitution theory of Chinese medicine and its assessment criterion and related studies. AB - Constitution factor plays an important role in the occurrence, development, and transformation of diseases. The occurrence of allergic diseases is mainly caused by the disorganized physiological function and suitability regulation of patients, except for their exposure to outside allergens. Moreover, it represents susceptibility and hypersensitivity to allergens. The current study expresses the concept of allergic constitution from the perspective of Chinese medicine (CM) and presents the criterion of allergic constitution. In addition, the distribution of allergic constitution in population, its factors, and its relation to health-related quality of life (HRQOL) were investigated. The HRQOL scores of allergic constitution were found to be lower than those of the Pinghe constitution. After making a study on the gene expression profile of allergic constitution, the characteristics of up-regulated or down-regulated genes were found. Finally, CM drug was researched and developed to improve allergic constitution. Based on clinical trials and animal experiments, CM is found to have good regulatory effects on allergic constitution. PMID- 25537151 TI - Improvement and application of an acute blood stasis rat model aligned with the 3Rs (reduction, refinement and replacement) of humane animal experimentation. AB - OBJECTIVE: To establish a novel cardiocentesis method for withdrawing venous blood from the right atrium, and to improve an acute blood stasis rat model using an ice bath and epinephrine hydrochloride (Epi) while considering the 3Rs (reduction, refinement, and replacement) of humane animal experimentation. METHODS: An acute blood stasis model was established in male Sprague-Dawley rats by subcutaneous injection (s.c.) Epi (1.2 mg/kg) administration at 0 h, followed by a 5-min exposure to an ice-bath at 2 h and s.c. Epi administration at 4 h. Control rats received physiological saline. Rats were fasted overnight and treated with Angelicae Sinensis Lateralis Radix (ASLR) and Pheretima the following day. Venous blood was collected using our novel cardiocentesis method and used to test whole blood viscosity (WBV), prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen (FIB) content. RESULTS: The rats survived the novel cardiocentesis technique; WBV value returned to normal while hematological parameters such as hemoglobin level and red blood cell count were restored to >94% of the corresponding values in normal rats following a 14 day recovery. Epi (1.2 mg/kg, s.c.) combined with a 5-min exposure to the ice bath replicated the acute blood stasis rat model and was associated with the highest WBV value. In rats showing acute blood stasis, ASLR treatment [4 g/(kg.d) for 8 days] decreased WBV by 9.98%, 11.09%, 9.34%, 9.00%, 7.66%, and 7.03% (P<0.05), while Pheretima treatment [2.6 g/(kg.d), for 8 days] decreased WBV by 25.49%, 25.94%, 16.28%, 17.76%, 11.07%, and 7.89% (P<0.01) at shear rates of 1, 3, 10, 30, 100, and 180 s-1, respectively. Furthermore, Pheretima treatment increased APTT significantly (P<0.01). CONCLUSIONS: We presented a stable, reproducible, and improved acute blood stasis rat model, which could be applied to screen drugs for promoting blood circulation and eliminating blood stasis. PMID- 25537152 TI - Farmers prone to drought risk: why some farmers undertake farm-level risk reduction measures while others not? AB - This research investigates farmers' cognitive perceptions of risk and the behavioral intentions to undertake farm-level risk-reduction measures. It has been observed that people who are susceptible to natural hazards often fail to act, or do very little, to protect their assets or lives. To answer the question of why some people show adaptive behavior while others do not, a socio psychological model of precautionary adaptation based on protection motivation theory and trans-theoretical stage model has been applied for the first time to areas of drought risk in the developing countries cultural context. The applicability of the integrated model is explored by means of a representative sample survey of smallholder farmers in northern Ethiopia. The result of the study showed that there is a statistically significant association between farmer's behavioral intention to undertake farm-level risk-reduction measures and the main important protection motivation model variables. High perceived vulnerability, severity of consequences, self-efficacy, and response efficacy lead to higher levels of behavioral intentions to undertake farm-level risk reduction measures. For farmers in the action stage, self-efficacy and response efficacy were the main motivators of behavioral intention. For farmers in the contemplative stage, self-efficacy and cost appear to be the main motivators for them to act upon risk reduction, while perceived severity of consequences and cost of response actions were found to be important for farmers in the pre contemplative stage. PMID- 25537153 TI - Developing objectives with multiple stakeholders: adaptive management of horseshoe crabs and Red Knots in the Delaware Bay. AB - Structured decision making (SDM) is an increasingly utilized approach and set of tools for addressing complex decisions in environmental management. SDM is a value-focused thinking approach that places paramount importance on first establishing clear management objectives that reflect core values of stakeholders. To be useful for management, objectives must be transparently stated in unambiguous and measurable terms. We used these concepts to develop consensus objectives for the multiple stakeholders of horseshoe crab harvest in Delaware Bay. Participating stakeholders first agreed on a qualitative statement of fundamental objectives, and then worked to convert those objectives to specific and measurable quantities, so that management decisions could be assessed. We used a constraint-based approach where the conservation objectives for Red Knots, a species of migratory shorebird that relies on horseshoe crab eggs as a food resource during migration, constrained the utility of crab harvest. Developing utility functions to effectively reflect the management objectives allowed us to incorporate stakeholder risk aversion even though different stakeholder groups were averse to different or competing risks. While measurable objectives and quantitative utility functions seem scientific, developing these objectives was fundamentally driven by the values of the participating stakeholders. PMID- 25537154 TI - Seasonal and local differences in leaf litter flammability of six Mediterranean tree species. AB - One of the suggested management options for reducing fire danger is the selection of less flammable plant species. Nevertheless, vegetation flammability is both complex and dynamic, making identification of such species challenging. While large efforts have been made to connect plant traits to fire behavior, seasonal changes and within species variability of traits are often neglected. Currently, even the most sophisticated fire danger systems presume that intrinsic characteristics of leaf litter stay unchanged, and plant species flammability lists are often transferred from one area to another. In order to assess if these practices can be improved, we performed a study examining the relationship between morphological characteristics and flammability parameters of leaf litter, thereby taking into account seasonal and local variability. Litter from six Mediterranean tree species was sampled throughout the fire season from three different locations along a climate gradient. Samples were subjected to flammability testing involving an epiradiator operated at 400 degrees C surface temperature with 3 g sample weight. Specific leaf area, fuel moisture content, average area, and average mass of a single particle had significant influences on flammability parameters. Effects of sampling time and location were significant as well. Due to the standardized testing conditions, these effects could be attributed to changes in intrinsic characteristics of the material. As the aforementioned effects were inconsistent and species specific, these results may potentially limit the generalization of species flammability rankings. Further research is necessary in order to evaluate the importance of our findings for fire danger modeling. PMID- 25537155 TI - Public participation in environmental management in China: status quo and mode innovation. AB - Public participation in environmental management is critically important in the development of a healthy environmental governance system. However, public participation has not been well institutionalized in China and the public's role in environmental management is limited. Chinese policy-makers and researchers currently face a dilemma wherein they must determine how to fully and effectively involve the public. This paper aims to contribute an innovative approach that can effectively engage the general public, allowing them to participate more in China's environmental management. In this paper, we first review the current status of environmental management and public participation in China. Based on China's political and socio-cultural-legal dynamics, an Environmental Community Consultative Group (ECCG) was developed to be an innovative means to engage community members. A pilot study of the ECCG was carried out in Yapu village of Changzhou City in Jiangsu Province. The evaluation of the process and outcome of the ECCG showed that the group's effectiveness and influence were significant; the ECCG model was a powerful means by which to promote public environmental awareness, improve public environmental behavior and facilitate public engagement in environmental management. But the ECCG is a small local group that may not function well regarding more complex issues covering a much larger area and has limited impact on environmental policy making. The ECCG experience offers the prospect of grassroots involvement in environmental protection for China's rural areas, while also laying the foundation for further research on community participation in environmental management. PMID- 25537156 TI - Estimating the consequences of fire exclusion for food crop production, soil fertility, and fallow recovery in shifting cultivation landscapes in the humid tropics. AB - In the Congo Basin, smallholder farmers practice slash-and-burn shifting cultivation. Yet, deliberate burning might no longer be sustainable under reduced fallow scenarios. We synthesized data from the Forest Margins Benchmark Area (FMBA), comprising 1.54 million hectares (ha), in southern Cameroon and assessed the impact of fire exclusion on yield, labor inputs, soil fertility, ecosystem carbon stocks, and fallow recovery indicators in two common field types (plantain and maize) under both current and reduced fallow scenarios. While we could not distinguish between impacts of standard farmer burning practice and fire exclusion treatments for the current fallow scenario, we concluded that fire exclusion would lead to higher yields, higher ecosystem carbon stocks as well as potentially faster fallow recovery under the reduced fallow scenario. While its implementation would increase labor requirements, we estimated increased revenues of 421 and 388 US$ ha(-1) for plantain and maize, respectively. Applied to the FMBA, and assuming a 6-year reduced fallow scenario, fire exclusion in plantain fields would potentially retain 240,464 Mg more ecosystem carbon, comprising topsoil carbon plus tree biomass carbon, than standard farmer practice. Results demonstrate a potential "win-win scenario" where yield benefits, albeit modest, and conservation benefits can be obtained simultaneously. This could be considered as a transitional phase towards higher input use and thus higher yielding systems. PMID- 25537157 TI - Wildfire risk assessment in a typical Mediterranean wildland-urban interface of Greece. AB - The purpose of this study was to assess spatial wildfire risk in a typical Mediterranean wildland-urban interface (WUI) in Greece and the potential effect of three different burning condition scenarios on the following four major wildfire risk components: burn probability, conditional flame length, fire size, and source-sink ratio. We applied the Minimum Travel Time fire simulation algorithm using the FlamMap and ArcFuels tools to characterize the potential response of the wildfire risk to a range of different burning scenarios. We created site-specific fuel models of the study area by measuring the field fuel parameters in representative natural fuel complexes, and we determined the spatial extent of the different fuel types and residential structures in the study area using photointerpretation procedures of large scale natural color orthophotographs. The results included simulated spatially explicit fire risk components along with wildfire risk exposure analysis and the expected net value change. Statistical significance differences in simulation outputs between the scenarios were obtained using Tukey's significance test. The results of this study provide valuable information for decision support systems for short-term predictions of wildfire risk potential and inform wildland fire management of typical WUI areas in Greece. PMID- 25537158 TI - High genetic diversity of equine infectious anaemia virus strains from Slovenia revealed upon phylogenetic analysis of the p15 gag gene region. AB - REASONS FOR PERFORMING STUDY: The equine infectious anaemia virus (EIAV), which belongs to the Retroviridae family, infects equids almost worldwide. Every year, sporadic EIAV cases are detected in Slovenia. OBJECTIVES: To characterise the Slovenian EIAV strains in the p15 gag gene region phylogenetically in order to compare the Slovenian EIAV strains with EIAV strains from abroad, especially with the recently published European strains. STUDY DESIGN: Cross-sectional study using material derived from post mortem examination. METHODS: In total, 29 EIAV serologically positive horses from 18 different farms were examined in this study. Primers were designed to amplify the p15 gag gene region. Amplicons of 28 PCRs were subjected to direct DNA sequencing and phylogenetic analysis. RESULTS: Altogether, 28 EIAV sequences were obtained from 17 different farms and were distributed between 4 separate monophyletic groups and 9 branches upon phylogenetic analysis. Among EIAV strains from abroad, the closest relatives to Slovenian EIAV strains were European EIAV strains from Italy. Phylogenetic analysis also showed that some animals from distantly located farms were most probably infected with the same EIAV strains, as well as animals from the same farm and animals from farms located in the same geographical region. CONCLUSIONS: This is the first report of such high genetic diversity of EIAV strains from one country. This led to speculation that there is a potential virus reservoir among the populations of riding horses, horses kept for pleasure and horses for meat production, with some farmers or horse-owners not following legislation, thus enabling the spread of infection with EIAV. The low sensitivity of the agar gel immunodiffusion test may also contribute to the spread of infection with EIAV, because some infected horses might have escaped detection. The results of the phylogenetic analysis also provide additional knowledge about the highly heterogeneous nature of the EIAV genome. PMID- 25537159 TI - A neoadjuvant, randomized, open-label phase II trial of afatinib versus trastuzumab versus lapatinib in patients with locally advanced HER2-positive breast cancer. AB - BACKGROUND: Chemotherapy is standard neoadjuvant treatment of LA BC. Patients with HER2-positive BC require targeted therapy. Trastuzumab and pertuzumab, which target HER2, with chemotherapy are approved as neoadjuvant therapy, however, treatments with different mechanisms of action might provide a broader range of activity. In this study we evaluated the efficacy and safety of the irreversible ErbB family blocker afatinib, versus trastuzumab or lapatinib in the neoadjuvant treatment of HER2-positive, LA BC. PATIENTS AND METHODS: Treatment-naive, HER2 positive BC patients with stage IIIA, B, C or inflammatory disease were randomized 1:1:1 to daily afatinib (50 mg), lapatinib (1500 mg), or weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg/wk) for 6 weeks until surgery or follow-up neoadjuvant treatment. The primary end point was objective response rate according to Response Evaluation Criteria in Solid Tumors (version 1.0). RESULTS: Recruitment was stopped early because of slow patient enrollment; 29 patients were randomized to afatinib (n = 10), lapatinib (n = 8), or trastuzumab (n = 11). Objective response was seen in 8 afatinib-, 6 lapatinib-, and 4 trastuzumab-treated patients. Eleven patients had stable disease (best response); 1 lapatinib- and 1 trastuzumab-treated patient had progressive disease. All 10 afatinib-treated patients experienced drug-related adverse events (commonly diarrhea, dermatitis acneiform, and paronychia) versus 6 of 8 lapatinib- (diarrhea and rash) and 5 of 11 trastuzumab-treated patients (vomiting and arthralgia). CONCLUSION: Afatinib demonstrated clinical activity that compared favorably to trastuzumab and lapatinib for neoadjuvant treatment of HER2-positive BC, with a safety profile consistent with epidermal growth factor receptor tyrosine kinase inhibitors. PMID- 25537160 TI - Antrodan, a beta-glucan obtained from Antrodia cinnamomea mycelia, is beneficial to benign prostate hyperplasia. AB - Benign prostatic hyperplasia (BPH), one of the most common disease usually occurring in men in their 50s, has now become an atypical direct cause of mortality. Currently, phytotherapeutic agents are emerging and are frequently used as a complementary alternative treatment of BPH. beta-glucan has shown a diversity of bioactivities involving anticancer, immunomodulatory and anti inflammatory effects. Antrodia cinnamomea exhibits a diversity of biological activities. Only a few literature references have cited the biomedicinal effects of antrodan, which is a unique beta-glucan present in A. cinnamomea mycelia. We hypothesized that antrodan could be beneficial to BPH. Using the Sprague-Dawley rat model, we performed this present experiment. Results indicated that antrodan alleviated most of the pathophysiological manifestations that can be elicited by BPH, by alleviating the prostatic epithelial hyperplasia and collagen deposition, increasing the total cholesterol biosynthesis and conversion into HDL, and suppressing the production of LDL and ROS and the upregulation of IL-1, COX-2 and CD68. Antrodan also effectively suppressed the serum level testosterone and DHT and downregulated aromatase, estradiol and the expression of the androgen receptor. More importantly, antrodan downregulated N-cadherin and vimentin and upregulated E-cadherin, underlying the effective inhibition on the epithelial mesenchymal transition (EMT). Conclusively, the beta-glucan antrodan present in the A. cinamomea mycelia is beneficial to the BPH therapy. PMID- 25537161 TI - Serum dehydroepiandrosterone sulfate and incident depression in the elderly: the Pro.V.A. study. AB - OBJECTIVE: Dehydroepiandrosterone sulfate (DHEAS) appears to have a protective effect against depression, but contrasting findings are available. Therefore, we investigated whether high serum DHEAS levels were associated with any protective effect on incident depression and incident severe depression in a representative group of elderly men and women. METHODS: In a population-based cohort longitudinal study in the general community, 789 older participants without depression and cognitive impairment at the baseline were included, among 3,099 screened subjects. Serum DHEAS levels were determined based on blood samples; incident depression and severe depression were diagnosed by means of the Geriatric Depression Scale (GDS) and confirmed by geriatricians skilled in psychogeriatric medicine. RESULTS: No baseline differences were found in GDS across age- and gender-specific tertiles of serum DHEAS. Over 4.4 years of follow up, 137 new cases of depression were recorded. Of them, 35 among men and 64 in women were cases of incident severe depression. Cox's regression analysis, adjusted for potential confounders, revealed that higher DHEAS levels were associated with reduced risk of incident depression irrespective of gender (HR: 0.30; 95% CI: 0.09-0.96; Wald chi(2) = 4.09; df = 1; p = 0.04; women: HR: 0.31; 95% CI: 0.14-0.69; Wald chi(2) = 8.37; df = 1; p = 0.004) and of severe incident depression only in men (HR: 0.25; 95% CI: 0.06-0.99; Wald chi(2) = 4.05; df = 1; p = 0.04). CONCLUSION: Higher serum DHEAS levels were found to be significantly protective for the onset of depression irrespective of gender, whereas only in men was this association found also for incident severe depression. PMID- 25537163 TI - Origin of non-spherical particles in the boundary layer over Beijing, China: based on balloon-borne observations. AB - Vertical structures of aerosols from the ground to about 1,000 m altitude in Beijing were measured with a balloon-borne optical particle counter. The results showed that, in hazy days, there were inversions at approximately 500-600 m, below which the particulate matters were well mixed vertically, while the concentration of particles decreased sharply above the mixing layer. Electron microscopic observation of the particles collected with the balloon-borne impactor indicates that the composition of particles is different according to weather conditions in the boundary mixing layer of Beijing city and suggests that dust particles are always dominant in coarse-mode particles. Interestingly, sea salt particles are frequently identified, suggesting the importance of marine air inflow to the Beijing area even in summer. The Ca-rich spherical particles are also frequently identified, suggesting chemical modification of dust particle by NOx or emission of CaO and others from local emission. Additionally, those types of particles showed higher concentration above the mixing layer under the relatively calm weather condition of summer, suggesting the importance of local scale convection found in summer which rapidly transported anthropogenic particles above the mixing layer. Lidar extinction profiles qualitatively have good consistency with the balloon-borne measurements. Attenuation effects of laser pulse intensity are frequently observed due to high concentration of particulate matter in the Beijing atmosphere, and therefore quantitative agreement of lidar return and aerosol concentration can be hardly observed during dusty condition. Comparing the depolarization ratio obtained from the lidar measurements with the balloon-borne measurements, the contribution of the dry sea salt particles, in addition to the dust particles, is suggested as an important factor causing depolarization ratio in the Beijing atmosphere. PMID- 25537162 TI - Concentrations, particle-size distributions, and indoor/outdoor differences of polycyclic aromatic hydrocarbons (PAHs) in a middle school classroom in Xi'an, China. AB - Polycyclic aromatic hydrocarbons (PAHs) attached to particulate matter can affect respiratory health, especially the health of children, but information on the air quality in schools is generally lacking. This study investigated the PAH concentrations in a naturally ventilated classroom in Xi'an, China, from 16 to 31 May 2012. Particulate PAH concentrations were measured for samples collected on five-stage cascade impactors deployed inside the classroom and outside. PM2.5 bound PAH concentrations were 53.2 ng m(-3) indoors and 72.9 ng m(-3) outdoors. PAHs attached to very fine particles (VFPs) accounted for ~70% of the total PAHs. The PAH concentrations indoors were affected by the students' activities, cleaning, and smoking, while outdoors, the main sources were motor vehicle emissions and contaminated road dust. Particle-bound PAHs infiltrated the classroom through open windows, but the activities of the students and staff were also associated with an increase of PAHs attached to particles larger than 1.0 um, most likely through resuspension. Cycles in the sources led to PAH concentrations 2-3 times higher on weekdays compared to weekends, both indoors and outdoors. PAH toxicity risks inside the classroom were substantially lower than those outdoors, and the highest risks were associated with VFPs. PMID- 25537164 TI - Atmospheric particulate matter in proximity to mountaintop coal mines: sources and potential environmental and human health impacts. AB - Mountaintop removal mining (MTM) is a widely used approach to surface coal mining in the US Appalachian region whereby large volumes of coal overburden are excavated using explosives, removed, and transferred to nearby drainages below MTM operations. To investigate the air quality impact of MTM, the geochemical characteristics of atmospheric particulate matter (PM) from five surface mining sites in south central West Virginia, USA, and five in-state study control sites having only underground coal mining or no coal mining whatsoever were determined and compared. Epidemiologic studies show increased rates of cancer, respiratory disease, cardiovascular disease, and overall mortality in Appalachian surface mining areas compared to Appalachian non-mining areas. In the present study, 24-h coarse (>2.5 um) and fine (<=2.5 um) PM samples were collected from two surface mining sites in June 2011 showed pronounced enrichment in elements having a crustal affinity (Ga, Al, Ge, Rb, La, Ce) contributed by local sources, relative to controls. Follow-up sampling in August 2011 lacked this enrichment, suggesting that PM input from local sources is intermittent. Using passive samplers, dry deposition total PM elemental fluxes calculated for three surface mining sites over multi-day intervals between May and August 2012 were 5.8 +/- 1.5 times higher for crustal elements than at controls. Scanning microscopy of 2,249 particles showed that primary aluminosilicate PM was prevalent at surface mining sites compared to secondary PM at controls. Additional testing is needed to establish any link between input of lithogenic PM and disease rates in the study area. PMID- 25537165 TI - Ecological conditions of ponds situated on blast furnace slag deposits located in South Gare Site of Special Scientific Interest (SSSI), Teesside, UK. AB - Slag, a by-product from the iron and steel industry, has a range of applications within construction and is used in wastewater treatment. Historically considered a waste material, little consideration was given to the environmental impacts of its disposal. South Gare (a Site of Special Scientific Interest) located at the mouth of the Tees estuary, UK, formed on slag deposits used to create a sea wall and make the land behind permanent. Over time, ponds formed in depressions with the water chemistry, being significantly impacted by the slag deposits. Calcium levels reached 504 mg/L, nitrate 49.0 mg/L and sulphate 1,698 mg/L. These levels were also reflected in the composition of the sediment. pH (5.10-9.90) and electrical conductivity (2,710-3,598 uS/cm) were variable but often notably high. Pb, Cu and Cd were not present within the water, whilst Zn ranged from 0.027 to 0.37 mg/L. Heavy metal levels were higher in surface sediments. Zinc was most dominant (174.3-1,310.2 mg/L) followed by Pb (9.9-431 mg/L), Cu (8.4-41.8 mg/L) and Cd (0.4-1.1 mg/L). A sediment core provided a historical overview of the ponds. The ponds were unfavourable for aquatic biodiversity and unsuitable for drinking water abstraction. PMID- 25537166 TI - Halide inhibition of the copper-catalysed azide-alkyne cycloaddition. AB - Chloride, bromide and iodide are inhibitors of the copper-catalysed azide-alkyne cycloaddition, with iodide exhibiting the most detrimental effects on rates and yields. A study of this inhibition is presented, along with experimental protocols to accommodate the presence of halides in this widely used reaction. PMID- 25537167 TI - Impact of an online medical internet site on knowledge and practice of health care providers: a mixed methods study of the Spinal Cord Injury Rehabilitation Evidence project. AB - BACKGROUND: It is not known whether ongoing access to a broad-based Internet knowledge resource can influence the practice of health care providers. We undertook a study to evaluate the impact of a Web-based knowledge resource on increasing access to evidence and facilitating best practice of health care providers. OBJECTIVE: The objective of this study was to evaluate (1) the impact of the Spinal Cord Injury Rehabilitation Evidence (SCIRE) project on access to information for health care providers and researchers and (2) how SCIRE influenced health care providers' management of clients. METHODS: A 4-part mixed methods evaluation was undertaken: (1) monitoring website traffic and utilization using Google Analytics, (2) online survey of users who accessed the SCIRE website, (3) online survey of targeted end-users, that is, rehabilitation health care providers known to work with spinal cord injury (SCI) clients, as well as researchers, and (4) focus groups with health care providers who had previously accessed SCIRE. RESULTS: The online format allowed the content for a relatively specialized field to have far reach (eg, 26 countries and over 6500 users per month). The website survey and targeted end-user survey confirmed that health care providers, as well as researchers perceived that the website increased their access to SCI evidence. Access to SCIRE not only improved knowledge of SCI evidence but helped inform changes to the health providers' clinical practice and improved their confidence in treating SCI clients. The SCIRE information directly influenced the health providers' clinical decision making, in terms of choice of intervention, equipment needs, or assessment tool. CONCLUSIONS: A Web-based knowledge resource may be a relatively inexpensive method to increase access to evidence-based information, increase knowledge of the evidence, inform changes to the health providers' practice, and influence their clinical decision making. PMID- 25537169 TI - Chinese students studying at Australian universities with specific reference to nursing students: a narrative literature review. AB - OBJECTIVE: To report the current knowledge on the Chinese nursing students' learning at Australian universities. The intent is to provide educators and researchers with a background to the contexts, the methodologies, the emphases of various relevant studies, and to provide recommendations for future research. BACKGROUND: Attracting international students has become an important part of Australian universities' business and contributes to their cultural diversity. Teaching international students has received considerable attention in the educational research literature. Experiences of international students can vary greatly depending on their country of origin. This paper critically reviews current literature relating to issues for Chinese students and in particular, Chinese nursing students, the biggest single group of international nursing students at Australian universities DESIGN: Narrative literature review. METHOD: A comprehensive search of seven electronic databases for literature between 2003 and 2014 helped to identify qualitative and quantitative studies that addressed issues of Asian international students with English as a second language (ESL) (included nursing students) studying in Australia, New Zealand, the UK, the United States and China. Pertinent websites were also searched. The reference lists and bibliographies of retrieved articles were hand- searched to identify other relevant studies. RESULTS: Fifteen studies met the inclusion criteria for the review. The majority of existing literature claimed that there is a range of challenges confronting international students including Chinese nursing students, in assimilation into their host country. These include issues with English language proficiency, cultural barriers, social problems, different learning styles, academic demands, perceived racism, homesickness, lack of assertiveness and financial problems. CONCLUSION: There is limited research about the Chinese students' study in Australia. In particular, the learning experience of Chinese nursing students has not been fully explored nor understood. This paper highlights the need for further research into the lived learning experience of Chinese nursing students studying at Australian universities. PMID- 25537168 TI - Early formation of the ion-conducting pore in channelrhodopsin-2. AB - Channelrhodopsins (ChRs) are light-gated ion channels that are widely used in optogenetics. They allow precise control of neuronal activity with light, but a detailed understanding of how the channel is gated and the ions are conducted is still lacking. The recent determination of the X-ray structural model in the closed state marks an important milestone. Herein the open state structure is presented and the early formation of the ion conducting pore is elucidated in atomic detail using time-resolved FTIR spectroscopy. Photo-isomerization of the retinal-chromophore causes a downward movement of the highly conserved E90, which opens the pore. Molecular dynamic (MD) simulations show that water molecules invade through this opened pore, Helix 2 tilts and the channel fully opens within ms. Since E90 is a highly conserved residue, the proposed E90-Helix2-tilt (EHT) model might describe a general activation mechanism and provides a new avenue for further mechanistic studies and engineering. PMID- 25537170 TI - The effects of mobile applications in cardiopulmonary assessment education. AB - BACKGROUND: Mobile applications can be used as effective simulations for nursing education. However, little is known regarding the effects of mobile application mediated training on nursing. The aim of this study was to determine the effectiveness of mobile applications by comparing the effectiveness of a high fidelity human patient simulator to that of a mobile application on student learning. METHODS: Following lectures on the lungs and the heart, twenty-two students were separated into two groups to perform a simulation exercise. Then, the students' education effects were evaluated based on their knowledge of lung and heart assessments, their clinical assessment skill, and satisfaction with their education. RESULTS: After four weeks, the mobile application group maintained their knowledge, whereas the high-fidelity human patient simulator group exhibited significantly decreased knowledge of the lung assessment. Knowledge of the heart assessment was significantly increased in both groups. There was no significant difference in clinical assessment skill or educational satisfaction between the groups. CONCLUSIONS: We found that mobile applications provide educational tools similarly effective to a high-fidelity human patient simulator to maintain memory and to teach cardiopulmonary assessment skills. PMID- 25537171 TI - Analysis of organo-chlorine pesticides residue in raw coffee with a modified "quick easy cheap effective rugged and safe" extraction/clean up procedure for reducing the impact of caffeine on the gas chromatography-mass spectrometry measurement. AB - The control of pesticide residues on raw coffee is a task of great importance due to high consumption of this beverage in Italy and in many other countries. High caffeine content can hamper extraction and measurement of any pesticide residue. A tandem extraction protocol has been devised by exploiting the quick easy cheap effective rugged and safe (QuEChERS) scheme for extraction, coupled to a dispersive liquid-liquid micro-extraction (DLLME) in order to drastically reduce caffeine content in the final extract. Gas chromatography-mass spectrometry (GC MS) has been used for quantification of organo-chlorine pesticides in single ion monitoring (SIM) mode. Method has been validated and performances meet the criteria prescribed by European Union regulations. PMID- 25537172 TI - Determination of phthalate esters in cleaning and personal care products by dispersive liquid-liquid microextraction and liquid chromatography-tandem mass spectrometry. AB - Phthalic acid esters (PEs) were preconcentrated from cleaning products, detergents and cosmetics using ultrasound assisted extraction (UAE) in the presence of acetonitrile, and then submitted to dispersive liquid-liquid microextraction (DLLME). For DLLME, 3mL of acetonitrile extract, 150MUL carbon tetrachloride and 10mL aqueous solution were used. The enriched organic phase was evaporated, reconstituted with 25MUL acetonitrile and injected into a liquid chromatograph with a mobile phase (acetonitrile:10mM ammonium acetate, pH 4) under gradient elution. Detection was carried out using both diode-array (DAD) and electrospray-ion trap-tandem mass spectrometry (ESI-IT-MS/MS) in the multiple reaction monitoring mode (MRM) of the positive fragment ions. Quantification was carried out using matrix-matched standards. Detection limits were in the range 0.04-0.45ngmL(-1) for the six PEs considered. The recoveries obtained were in the 84-124% range, with RSDs lower than 10%. Thirty three different cleaning products were analyzed. The most frequently found compound was diethyl phthalate. PMID- 25537173 TI - On-line capillary electrophoresis-based enzymatic methodology for the study of polymer-drug conjugates. AB - This work aims at studying the potentialities of an on-line capillary electrophoresis (CE)-based digestion methodology for evaluating polymer-drug conjugates degradability in the presence of free trypsin (in-solution digestion). A sandwich plugs injection scheme with transverse diffusion of laminar profile (TDLFP) mode was used to achieve on-line digestions. Electrophoretic separation conditions were established using poly-l-Lysine (PLL) as reference substrate. Comparison with off-line digestion was carried out to demonstrate the feasibility of the proposed methodology. The applicability of the on-line CE-based digestion methodology was evaluated for two PLL-drug conjugates and for the four first generations of dendrigraft of lysine (DGL). Different electrophoretic profiles presenting the formation of di, tri, and tetralysine were observed for PLL-drug and DGL. These findings are in good agreement with the nature of the linker used to link the drug to PLL structure and the predicted degradability of DGL. The present on-line methodology applicability was also successfully proven for protein conjugates hydrolysis. In summary, the described methodology provides a powerful tool for the rapid study of biodegradable polymers. PMID- 25537174 TI - Determination triazine pesticides in cereal samples based on single-hole hollow molecularly imprinted microspheres. AB - Single-hole hollow molecularly imprinted microspheres (h-MIMs) were prepared by hard template method and applied to extract six triazine pesticides in cereal samples, followed by HPLC-MS/MS detection. The synthesis mechanism of the h-MIMs has been studied. The h-MIMs exhibited bigger specific surface area and much higher binding capacity than the molecularly imprinted polymers prepared by precipitation polymerization (p-MIPs) and surface polymerization (s-MIPs). Besides, the adsorption rate of h-MIMs to prometryn was significantly higher than that of p-MIPs and s-MIPs. Owing to the hollow structure of the h-MIMs, more binding cavities were located on the inner and outer surfaces of the h-MIMs, which could facilitate the removal of template molecules from the polymers and the rebinding of the target molecules to the polymers. Under the optimal conditions, the detection limits of triazines are in the range of 0.08-0.16ngg( 1). At the spiked level (5ngg(-1)), the recoveries of triazines are in the range of 81+/-4% to 96+/-4%. The proposed method was successfully applied to determine six triazines in five cereal samples. Atrazine was found in two rice samples and a wheat sample with the contents of 5.1, 6.7 and 5.6ngg(-1), respectively. Ametryn and prometryn were found in a maize sample with the contents of 7.6 and 7.3ngg(-1), respectively. PMID- 25537175 TI - Separation of uremic toxins from urine with resorcinarene-based ion chromatography columns. AB - People with chronic kidney disease suffer from uremic toxins which accumulate in their bodies. Detection and quantification of uremic toxins help diagnose kidney problems and start patient care. The aim of this research was to seek a new method to assist this diagnosis by trace level detection and separation of guanidine containing uremic toxins in water and urine. To detect and quantify the uremic toxins, new stationary phases for ion chromatography (IC) columns based on glutamic acid functionalized resorcinarenes bound to divinylbenzene macroporous resin were prepared. The new column packing material afforded separation of the five compounds: guanidinoacetic acid, guanidine, methylguanidine, creatinine, and guanidinobenzoic acid in 30min. Peak resolutions ranged from 7.6 to 1.3. Gradient elutions at ambient temperature with methanesulfonic acid (MSA) solution as eluent resulted in detection levels in water from 10 to 47ppb and in synthetic urine from 28 to 180ppb. Limits of quantification for the analytes using pulsed amperometric detection were 30-160ppb in water and 93-590ppb in urine. Trace levels of creatinine (1ppm) were detected in the urine of a healthy individual using the columns. PMID- 25537176 TI - Silica-based strong anion exchange media for protein purification. AB - The main objective of our research was to develop silica-based, polymer functionalized ion exchange materials for single-use bioprocess applications, with the ultimate goal of achieving maximal binding capacity for target proteins. Herein we report the utilization of Grace((r)) wide pore silica gel and bonding the silica with cationic polymers. The strong anion exchange materials have been prepared by a two-step process involving initial bonding with two trimethoxysilanes and subsequent aqueous solution radical polymerization with quaternary ammonium ion containing monomers and an azo initiator. Using the binding capacities for bovine serum albumin (BSA), a model protein for the evaluation of the new materials, we optimized the processes with regard to the median pore size of the silica gel, as well as polymer composition and ratios, which were determined by reagent ratios and reaction conditions. The products were also characterized by both chemical and physical methods. It has been found that higher binding capacities are associated with lower ligand density and higher molecular weight for the attached polymers, with over 20% higher in both static and dynamic binding capacity values with the same amount of attached polymers. The advantages of a large pore size distribution and optimal median pore size for the base silica are discussed. Optimal pore size range of 500-1500A and distribution of Span 90 for over 1.0 give the highest BSA binding capacities. Silica-based strong anion exchange materials showed excellent flow characteristics when packed into a column and were superior to commercial agarose based strong anion exchange material with respect to dynamic binding capacity, elution of proteins, and baseline separation of a mixture of three model proteins. PMID- 25537178 TI - [Clinical utility of Pourmedia GBS agar on screening for vaginal colonization of Group B Streptococcus]. AB - Group B Streptococcus (GBS) are normal flora of the vagina and intestinal, but if the pregnant woman was infected with GBS in the vagina, miscarriage or premature would occur or the newborn would be developed to severe GBS infection. It is recommended that the inspection of GBS on all pregnant women by Japan Society of Obstetrics and Gynecology (JSOG) and Center for Disease Control and Prevention (CDC). We examined the comparison of detection rate between Pourmedia GBS agar (Eiken Chemical Co., Ltd.) and Nissui Separated Plate Sheep Blood Agar/BTB Lactose Agar medium (Nissui Pharmaceutical Co., Ltd.) on 112 sample. The positive rate of Pourmedia GBS agar was 21.4% (24/112 samples), Whereas Nissui Separated Plate Sheep Blood Agar/BTB Lactose Agar medium was 17.8% (20/112 samples). It was found that the detection rate was improved by using Pourmedia GBS agar on GBS screening test of vaginal swab. PMID- 25537177 TI - Olmesartan improves pulse wave velocity and lowers central systolic blood pressure and ambulatory blood pressure in patients with metabolic syndrome. AB - Ambulatory blood pressure (BP) and central systolic BP (cSBP) are superior to brachial office BP measurements in predicting cardiovascular end organ damage. The authors aimed to analyze the effect of olmesartan 80 mg (OLM 80) vs 20 mg (OLM 20) vs amlodipine 5 mg (AML 5) on central hemodymamics and ambulatory BP in patients with metabolic syndrome (MetS).In a double-blind, three-phase crossover study comprising 69 untreated patients with MetS defined by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults guidelines, the effects of OLM 80 on central hemodynamics (cSBP), central pulse pressure), pulse wave velocity (PWV), and 24-hour ambulatory BP were compared with OLM 20 and AML 5, given for 6 weeks each. In 69 patients (47 men, 22 women) (51.5+/-9.75 years), reduction in cSBP was the highest with OLM 80 and significantly greater than the reduction with AML 5 ( 14.1 mm Hg vs -9.7 mm Hg, P=.0117). All three substances significantly reduced 24 hour ambulatory systolic (OLM 80 and OLM 20 P<.0001; AML 5 P=.0105). BP and 24 hour diastolic BP (OLM 80 and OLM 20 P<.0001; AML 5 P=.0126). PWV was significantly reduced by OLM 80 (-0.58 m/s, P=.0088) and by OLM 20 (-0.48 m/s, P=.0362) but not by AML 5 (-0.28 m/s, P=.2065). For PWV, no significant differences were detected between the three groups. OLM significantly improves arterial stiffness as demonstrated by the reduction in PWV and in cSBP. In addition, 24-hour ambulatory BP was reduced to a greater extent with OLM 80 than with AML 5. PMID- 25537179 TI - [Investigation of the procalcitonin and microbiology test and antibiotics situation from our hospital]. AB - Procalcitonin (PCT) was first described as a sepsis-associated protein in 1993. PCT is increased in the blood at the time of infection by bacteria. Therefore, it is used as an auxiliary indicator of sepsis diagnosis. In addition, PCT is reduced quickly by antibiotics. And use as a stop or change marker is also expected. We have investigated the antimicrobial use and microbial testing of measurement patient and PCT running performance. Number of requests was 3,387 cases (inpatient 2,649 and outpatient 742 cases) for one year. It was subject to the 820 cases that had inspection request to July to October 2012. In 820 cases, 57 cases had exhibited a PCT >0.5 ng/ml and diagnosed with infectious diseases. In 57 cases, 44 cases (77%) were performed microbiology and blood culture. And only blood culture performed in 8 (14%), blood culture and microbiology is not performed for 5 cases (9%), In 21 (40%) cases of 52 cases performed the blood culture shown positive. Detecting bacteria accounted for more than half in 17 cases of Gram-negative bacilli. Also, it had exhibited a systemic inflammatory response syndrome (SIRS) in 18 cases. Antibiotics have been used in all cases regardless of implementation of the microbiology test. If sepsis is suspected, it is necessary for diagnosis is done correctly and quickly. Therefore, PCT has been suggested high usefulness by examining in the hospital. It is required that the reference identification and drug susceptibility results of the pathogenic bacterium combination of microbiology test and the PCT. We considered useful to PCT monitoring that as an indicator of antimicrobial agents change or shorten of antibiotic use period. Future, proactive use of clinical practice is expected. PMID- 25537180 TI - Bioaccumulation kinetics and organ distribution of cadmium and zinc in the freshwater decapod crustacean Macrobrachium australiense. AB - This study used the radioisotopes (109)Cd and (65)Zn to explore the uptake, retention and organ distribution of these nonessential and essential metals from solution by the freshwater decapod crustacean Macrobrachium australiense. Three treatments consisting of cadmium alone, zinc alone, and a mixture of cadmium and zinc were used to determine the differences in uptake and efflux rates of each metal individually and in the metal mixture over a three-week period, followed by depuration for 2 weeks in metal-free water using live-animal gamma-spectrometry. Following exposure, prawns were cryosectioned and the spatial distribution of radionuclides visualized using autoradiography. Metal uptake and efflux rates were the same in the individual and mixed-metal exposures, and efflux rates were close to zero. The majority of cadmium uptake was localized within the gills and hepatopancreas, while zinc accumulated in the antennal gland at concentrations orders of magnitude greater than in other organs. This suggested that M. australiense may process zinc much faster than cadmium by internally transporting the accumulated zinc to the antennal gland. The combination of uptake studies and autoradiography greatly increases our understanding of how metal transport kinetics and internal processing may influence the toxicity of essential and nonessential metals in the environment. PMID- 25537182 TI - Erratum to: Acute liver failure-induced hepatic encephalopathy is associated with changes in microRNA expression profiles in cerebral cortex of the mouse. PMID- 25537181 TI - Regulatory CD8(+)CD122 (+) T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells. AB - Clinical stroke induces inflammatory processes leading to cerebral and splenic injury and profound peripheral immunosuppression. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that transfer of IL-10(+) B-cells reduced infarct volume in male C57BL/6J (wild-type, WT) recipient mice when given 24 h prior to or 4 h after middle cerebral artery occlusion (MCAO). The purpose of this study was to determine if passively transferred IL-10(+) B-cells can exert therapeutic and immunoregulatory effects when injected 24 h after MCAO induction in B-cell sufficient male WT mice. The results demonstrated that IL-10(+) B-cell treated mice had significantly reduced infarct volumes in the ipsilateral cortex and hemisphere and improved neurological deficits vs. Vehicle-treated control mice after 60 min occlusion and 96 h of reperfusion. The MCAO-protected B-cell recipient mice had less splenic atrophy and reduced numbers of activated, inflammatory T-cells, decreased infiltration of T-cells and a less inflammatory milieu in the ischemic hemispheres compared with Vehicle-treated control mice. These immunoregulatory changes occurred in concert with the predominant appearance of IL-10-secreting CD8(+)CD122(+) Treg cells in both the spleen and the MCAO-affected brain hemisphere. This study for the first time demonstrates a major neuroprotective role for IL-10(+) B-cells in treating MCAO in male WT mice at a time point well beyond the ~4 h tPA treatment window, leading to the generation of a dominant IL-10(+)CD8(+)CD122(+) Treg population associated with spleen preservation and reduced CNS inflammation. PMID- 25537183 TI - Nitrite reductase activity of rat and human xanthine oxidase, xanthine dehydrogenase, and aldehyde oxidase: evaluation of their contribution to NO formation in vivo. AB - Nitrite is presently considered a NO "storage form" that can be made available, through its one-electron reduction, to maintain NO formation under hypoxia/anoxia. The molybdoenzymes xanthine oxidase/dehydrogenase (XO/XD) and aldehyde oxidase (AO) are two of the most promising mammalian nitrite reductases, and in this work, we characterized NO formation by rat and human XO/XD and AO. This is the first characterization of human enzymes, and our results support the employment of rat liver enzymes as suitable models of the human counterparts. A comprehensive kinetic characterization of the effect of pH on XO and AO-catalyzed nitrite reduction showed that the enzyme's specificity constant for nitrite increase 8-fold, while the Km(NO2(-)) decrease 6-fold, when the pH decreases from 7.4 to 6.3. These results demonstrate that the ability of XO/AO to trigger NO formation would be greatly enhanced under the acidic conditions characteristic of ischemia. The dioxygen inhibition was quantified, and the Ki(O2) values found (24.3-48.8 MUM) suggest that in vivo NO formation would be fine-tuned by dioxygen availability. The potential in vivo relative physiological relevance of XO/XD/AO dependent pathways of NO formation was evaluated using HepG2 and HMEC cell lines subjected to hypoxia. NO formation by the cells was found to be pH-, nitrite-, and dioxygen-dependent, and the relative contribution of XO/XD plus AO was found to be as high as 50%. Collectively, our results supported the possibility that XO/XD and AO can contribute to NO generation under hypoxia inside a living human cell. Furthermore, the molecular mechanism of XO/AO-catalyzed nitrite reduction was revised. PMID- 25537184 TI - Exercise improves mitochondrial and redox-regulated stress responses in the elderly: better late than never! AB - Ageing is associated with several physiological declines to both the cardiovascular (e.g. reduced aerobic capacity) and musculoskeletal system (muscle function and mass). Ageing may also impair the adaptive response of skeletal muscle mitochondria and redox-regulated stress responses to an acute exercise bout, at least in mice and rodents. This is a functionally important phenomenon, since (1) aberrant mitochondrial and redox homeostasis are implicated in the pathophysiology of musculoskeletal ageing and (2) the response to repeated exercise bouts promotes exercise adaptations and some of these adaptations (e.g. improved aerobic capacity and exercise-induced mitochondrial remodelling) offset age-related physiological decline. Exercise-induced mitochondrial remodelling is mediated by upstream signalling events that converge on downstream transcriptional co-factors and factors that orchestrate a co-ordinated nuclear and mitochondrial transcriptional response associated with mitochondrial remodelling. Recent translational human investigations have demonstrated similar exercise-induced mitochondrial signalling responses in older compared with younger skeletal muscle, regardless of training status. This is consistent with data indicating normative mitochondrial remodelling responses to long-term exercise training in the elderly. Thus, human ageing is not accompanied by diminished mitochondrial plasticity to acute and chronic exercise stimuli, at least for the signalling pathways measured to date. Exercise-induced increases in reactive oxygen and nitrogen species promote an acute redox-regulated stress response that manifests as increased heat shock protein and antioxidant enzyme content. In accordance with previous reports in rodents and mice, it appears that sedentary ageing is associated with a severely attenuated exercise-induced redox stress response that might be related to an absent redox signal. In this regard, regular exercise training affords some protection but does not completely override age-related defects. Despite some failed redox-regulated stress responses, it seems mitochondrial responses to exercise training are intact in skeletal muscle with age and this might underpin the protective effect of exercise training on age-related musculoskeletal decline. Whilst further investigation is required, recent data suggest that it is never too late to begin exercise training and that lifelong training provides protection against several age-related declines at both the molecular (e.g. reduced mitochondrial function) and whole-body level (e.g. aerobic capacity). PMID- 25537185 TI - Identification and validation of vesicant therapeutic targets using a high throughput siRNA screening approach. AB - Sulfur mustard [SM, bis-(2-chloroethyl) sulfide] is a highly reactive bifunctional alkylating agent that has been used as a vesicating agent in warfare scenarios to induce severe lung, skin, and eye injury. SM cutaneous lesions are characterized by both vesication and severe inflammation, but the molecular mechanisms that lead to these signs and symptoms are not well understood. There is a pressing need for effective therapeutics to treat this injury. An understanding of the molecular mechanisms of injury and identification of potential therapeutic targets is necessary for rational therapeutic development. We have applied a high-throughput small interfering RNA (siRNA) screening approach to the problem of SM cutaneous injury in an effort to meet these needs. Our siRNA screening efforts have initially focused on SM-induced inflammation in cutaneous injury since chronic inflammation after exposure appears to play a role in progressive clinical pathology, and intervention may improve clinical outcome. Also, targets that mitigate cellular injury should reduce the inflammatory response. Historical microarray data on this injury were mined for targets and pathways implicated in inflammation, and a siRNA library of 2,017 targets was assembled for screening. Primary screening and library deconvolution were performed using human HaCaT keratinocytes and focused on cell death and inflammatory markers as end points. Using this in vitro approach, we have identified and validated novel targets for the potential treatment of SM-induced cutaneous injury. PMID- 25537186 TI - Acetaminophen hepatotoxicity: an updated review. AB - As the most common cause of acute liver failure (ALF) in the USA and UK, acetaminophen-induced hepatotoxicity remains a significant public health concern and common indication for emergent liver transplantation. This problem is largely attributable to acetaminophen combination products frequently prescribed by physicians and other healthcare professionals, with unintentional and chronic overdose accounting for over 50 % of cases of acetaminophen-related ALF. Treatment with N-acetylcysteine can effectively reduce progression to ALF if given early after an acute overdose; however, liver transplantation is the only routinely used life-saving therapy once ALF has developed. With the rapid course of acetaminophen-related ALF and limited supply of donor livers, early and accurate diagnosis of patients that will require transplantation for survival is crucial. Efforts in developing novel treatments for acetaminophen-induced ALF are directed toward bridging patients to recovery. These include auxiliary, artificial, and bioartificial support systems. This review outlines the most recent developments in diagnosis and management of acetaminophen-induced ALF. PMID- 25537187 TI - Invitation to an open scientific discussion. PMID- 25537188 TI - Comment on Schindler, BK; Weiss, T; Schutze, A; et al. "Occupational exposure of air crews to tricresyl phosphate isomers and organophosphate flame retardants after fume events," Arch Toxicol (2013) 87:645-648. PMID- 25537189 TI - Progress toward the development of in vitro model system for chemical-induced developmental neurotoxicity: potential applicability of stem cells. PMID- 25537190 TI - The mycotoxin patulin reacts with DNA bases with and without previous conjugation to GSH: implication for related alpha,beta-unsaturated carbonyl compounds? AB - The alpha,beta-unsaturated carbonyl group is recognized as alert for mutagenicity, attributed to (1) its direct reaction with DNA, counteractable by glutathione (GSH), and (2) oxidative stress caused indirectly by GSH depletion. Accordingly, the alpha,beta,gamma,delta-unsaturated lactone patulin (PAT), a mycotoxin detected in fruits and products derived thereof, is known to induce gene, chromosome, and genome mutations in vitro, its mutagenicity correlating inversely with intracellular GSH levels. Thus, the reactivity of PAT against DNA bases and nucleosides in the absence and presence of GSH and glutathione S transferases (GSTs) was investigated under cell-free conditions using HPLC mass spectrometry techniques for identification of reaction products. Adduct formation with all four nucleobases as well as with purine base nucleosides occurred even in the presence of GSH, revealing several adducts of PAT, mono- and disubstituted with nucleobases/nucleosides as well as novel GSH-PAT adducts. In addition, novel mixed GSH-PAT-nucleobase adducts were observed. These adducts exhibited a ketohexanoic acid-type structure of the PAT molecule, C6 substituted with GSH and linking C1 of PAT with nitrogens of nucleobases/nucleosides via an amide bond. Formation of GSH-PAT-adenine adducts was not prevented by GSTs, and excess of GSH needed to reduce their formation was higher than for PAT-adenine adducts. The formation of mixed GSH-DNA base adducts has not been described for PAT or any other alpha,beta-unsaturated carbonyl before, although the reaction mechanism seems to be applicable to a variety of alpha,beta-unsaturated carbonyls occurring in food and in the environment. PMID- 25537191 TI - TG-interacting factor mediates arsenic-induced malignant transformation of keratinocytes via c-Src/EGFR/AKT/FOXO3A and redox signalings. AB - Inorganic arsenic is well known as a carcinogen in human beings. Chronic exposure to inorganic arsenic increases risks of developing some cancers and non carcinogenic diseases, such as skin lesions in humans. However, the modes of action are not well elucidated. In the present study, HaCaT cells, an immortalized non-tumorigenic human keratinocyte, were continuously exposed to low dose trivalent arsenic (arsenic trioxide, 0.1 and 0.2 MUM) for at least 4 weeks. We proved that low-dose arsenic could stimulate malignant transformation of HaCaT cells, including increase of cellular proliferation, epithelial-to-mesenchymal transition markers alteration, matrix metalloproteinases activation, invadopodia formation, migration/invasion activities, and anchorage-independent growth. Surprisingly, low-dose arsenic could also transcriptionally increase TG interacting factor (TGIF) expression via c-Src/EGFR/AKT/FOXO3A signaling involving superoxide production from NADPH oxidase. Moreover, stable overexpression of TGIF could also induce malignant transformation of HaCaT cells. Knockdown of TGIF with its specific shRNA abolished the arsenic-induced effects. Taken together, we suggest that TGIF plays an important role in low-dose arsenic induced malignant transformation of HaCaT cells, which is regulated by c Src/EGFR/AKT/FOXO3A pathway and redox signaling. PMID- 25537192 TI - HPLC-SPE-NMR characterization of major metabolites in Salvia fruticosa Mill. extract with antifungal potential: relevance of carnosic acid, carnosol, and hispidulin. AB - Plant pathogenic fungi are considered of significant economic importance for adversely affecting both quantitatively and qualitatively fresh and processed produce. Extracts of Salvia fruticosa were initially screened for their antifungal activity, and the ethyl acetate fraction, being the most active, was further analyzed using HPLC-SPE-NMR hyphenation. The methoxylated flavones hispidulin, salvigenin, and cirsimaritin and the diterpenes carnosic acid, carnosol, and 12-methoxycarnosic acid were identified as the major components of the extract. In addition, the concentration levels of all identified components were determined using q-NMR. The antifungal activity of the crude extract and selected phytochemicals was estimated against the fungal species Aspergillus tubingensis, Botrytis cinerea, and Penicillium digitatum. The estimated MIC and MFC values of the ethyl acetate extract of S. fruticosa, as well as three of its major constituents, carnosic acid, carnosol, and hispidulin, support their antifungal activity, especially against B. cinerea and P. digitatum, suggesting their potential use in food and agricultural systems. PMID- 25537193 TI - A big picture of a small brain. AB - A detailed map of the neurons that carry information away from the mushroom bodies in the brains of fruit flies has improved our understanding of the ways in which experiences can modify behaviour. PMID- 25537194 TI - Titles and abstracts of scientific reports ignore variation among species. AB - An analysis of more than 1000 research articles in biology reveals that the name of the species being studied is not mentioned in the title or abstract of many articles. Consequently, such data are not easily accessible in the PubMed database. These omissions can mislead readers about the true nature of developmental processes and delay the acceptance of valid species differences. To improve the accuracy of the scientific record, I suggest that journals should require that authors include the name of the species being studied in the title or abstract of submitted papers. PMID- 25537196 TI - Threat to fixation at diagnosis and lifetime risk of visual impairment in open angle glaucoma. AB - PURPOSE: To investigate whether threat to fixation (TTF) at diagnosis increases the risk of central vision loss and glaucoma blindness. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 309 patients (309 eyes) with glaucoma were followed up until death; 203 patients (65.7%) had primary open-angle glaucoma, and 106 patients (34.2%) had exfoliation glaucoma. METHODS: Study eyes were divided into 2 groups according to TTF in the first glaucomatous visual field: (1) eyes with TTF, defined as visual field loss (VFL) including >=1 of the 4 innermost points depressed at P < 1% level in 24-2 or 30-2 Humphrey fields; (2) eyes without TTF, defined as VFL only outside the 4 innermost points. Lifetime risk of visual acuity (VA) loss and glaucoma blindness in the 2 groups was compared by logistic regression analysis. A matching technique was used to adjust for differences in disease stage at presentation. The relative influence of TTF on the risk of blindness in the 2 matched groups was analyzed by the Kaplan-Meier method. MAIN OUTCOME MEASURES: Visual acuity <0.3 and blindness from glaucoma (World Health Organization criteria) at last visit. RESULTS: Threat to fixation was detected in 58.9% of the eyes at diagnosis. The frequency of TTF increased with stage of glaucomatous loss: 28.3% in eyes with mean deviation (MD) >-6.00 decibels (dB) versus 95.7% with MD <-20.00 dB. Univariate analysis demonstrated that eyes with TTF at presentation compared with eyes without TTF became blind more often (56/182 [30.8%] vs. 22/127 [17.3%]; P = 0.008) and faster (mean time from diagnosis to blindness, 84.6+/-50.7 vs. 126.7+/-51.4 months; P < 0.002). However, in multivariate analysis, TTF was not an independent risk factor for VA <0.3 (odds ratio, 1.43; 95% confidence interval, 0.75-2.74) or blindness (odds ratio, 1.03; 95% confidence interval, 0.52-2.01). With regard to patient survival time, there were no differences between eyes with TTF and eyes without TTF after adjusting for disparities in disease severity at presentation (P = 0.934). CONCLUSIONS: Including TTF in the assessment of risk for glaucoma blindness did not add any important information when the stage of VFL was taken into account. PMID- 25537195 TI - 3D imaging of Sox2 enhancer clusters in embryonic stem cells. AB - Combinatorial cis-regulatory networks encoded in animal genomes represent the foundational gene expression mechanism for directing cell-fate commitment and maintenance of cell identity by transcription factors (TFs). However, the 3D spatial organization of cis-elements and how such sub-nuclear structures influence TF activity remain poorly understood. Here, we combine lattice light sheet imaging, single-molecule tracking, numerical simulations, and ChIP-exo mapping to localize and functionally probe Sox2 enhancer-organization in living embryonic stem cells. Sox2 enhancers form 3D-clusters that are segregated from heterochromatin but overlap with a subset of Pol II enriched regions. Sox2 searches for specific binding targets via a 3D-diffusion dominant mode when shuttling long-distances between clusters while chromatin-bound states predominate within individual clusters. Thus, enhancer clustering may reduce global search efficiency but enables rapid local fine-tuning of TF search parameters. Our results suggest an integrated model linking cis-element 3D spatial distribution to local-versus-global target search modalities essential for regulating eukaryotic gene transcription. PMID- 25537197 TI - Quality of vision after bilateral multifocal intraocular lens implantation: a randomized trial--AT LISA 809M versus AcrySof ReSTOR SN6AD1. AB - PURPOSE: To compare postoperative visual symptoms and spectacle freedom after bilateral implantation of the AT LISA 809M (Carl Zeiss Meditec, Jena, Germany) versus the AcrySof ReSTOR SN6AD1 (Alcon Laboratories, Irvine, CA) multifocal intraocular lens (IOL). DESIGN: Double-masked, prospective, randomized, controlled clinical trial. PARTICIPANTS: A total of 188 patients undergoing bilateral sequential cataract surgery or bilateral refractive lens exchange. METHODS: Patients were preoperatively randomized (allocation ratio 1:1) to bilateral implantation with the AT LISA 809M IOL or ReSTOR SN6AD1 IOL. Postoperative outcomes were assessed 4 to 8 months after second eye surgery. MAIN OUTCOME MEASURES: The primary outcome was visual symptoms evaluated with the Quality of Vision (QoV) questionnaire. Secondary outcomes included other questionnaire data (CatQuest-9SF, spectacle independence, vision satisfaction, and dysphotopsia) and visual function measures (near, intermediate, and distance visual acuity, binocular reading speed [International Reading Speed Texts], contrast sensitivity, and forward light scatter). Adverse events, including intraoperative and postoperative complications, also were evaluated. RESULTS: There was no significant difference between IOL groups in Rasch-adjusted QoV scores for frequency (P = 0.95), severity (P = 0.56), and bothersomeness (P = 0.34) of visual symptoms; median (interquartile) scores for these QoV subscales were 29 (15-37), 22 (13-27), and 14 (0-29) for the AT LISA 809M IOL group, respectively, and 32 (15-37), 22 (13-30), and 14 (0-29) for the ReSTOR SN6AD1 IOL group, respectively. Halo was the most prominent dysphotopsia symptom, with 6% in both IOL groups reporting halo symptoms as very bothersome. Complete spectacle independence was achieved in 69 of 84 (82.1%) AT LISA 809M recipients and 66 of 85 (77.6%) ReSTOR SN6AD1 recipients (P = 0.57). Preferred reading distance was slightly nearer for the AT LISA 809M IOL. There were no statistically significant differences in any of the other secondary outcome measures. CONCLUSIONS: Visual symptoms were similar after bilateral implantation of the AT LISA 809M and ReSTOR SN6AD1 IOLs. Both these diffractive bifocal IOLs produce high levels of spectacle independence and patient satisfaction. However, a small but clinically significant minority of patients remained symptomatic and dissatisfied with visual results 4 to 8 months after surgery. PMID- 25537199 TI - The longitudinal associations between C-reactive protein and depressive symptoms: evidence from the English Longitudinal Study of Ageing (ELSA). AB - OBJECTIVES: The inflammatory marker C-reactive protein (CRP) is associated with depression. We examined the directional relations between CRP and symptoms of depression among older adults. METHOD: The sample consisted of 3397 participants from the English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. CRP and depressive symptoms were measured at baseline and follow-up. A high CRP level was dichotomized as >3 mg/L. Elevated depressive symptomatology was defined as >=4 using the 8-item Center for Epidemiologic Studies Depression Scale. Logistic regressions computed the association between high CRP levels at baseline with elevated depressive symptoms at follow-up, and vice versa. RESULTS: After adjusting for baseline depressive symptoms, baseline high CRP levels were associated with subsequent elevated symptoms of depression (OR = 1.49; 95% CI, 1.19-1.88). This relationship was no longer significant after simultaneous adjustments for metabolic and health variables. In the other direction, after adjusting for baseline CRP levels, baseline elevated depressive symptoms was not associated with subsequent high CRP levels (OR = 1.12; 95% CI, 0.88-1.42). CONCLUSION: High CRP levels at baseline are related to elevated depressive symptomatology at follow-up due to clinical factors. No association was found in the opposite direction. PMID- 25537198 TI - Oxicams, a class of nonsteroidal anti-inflammatory drugs and beyond. AB - Oxicams are a class of nonsteroidal anti-inflammatory drugs (NSAIDs) structurally related to the enolic acid class of 4-hydroxy-1,2-benzothiazine carboxamides. They are used clinically to treat both acute and chronic inflammation by inhibiting the activity of the two cyclooxygenase (COX) isoforms, COX-1 and COX 2. Oxicams are structurally distinct from all other NSAIDs, exhibiting a novel binding pose in the COX active site. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding while two coordinated water molecules mediate a polar interaction between the oxicam and COX. The rotation of Leu-531 in the complex opens a new pocket, which is not used for binding other NSAIDs to the enzyme. This structure provides the basis for understanding documented structure-activity relationships within the oxicam class. In addition, from the oxicam template, a series of potent microsomal prostaglandin E synthase-1 (mPGES 1) inhibitors represents a new direction for drug development. Here, we review the major route of oxicam synthesis and structure-activity for COX inhibition, as well as recent advances in oxicam-mediated mPGES-1 inhibition. PMID- 25537200 TI - A DNA dot hybridization model for assessment of bacterial bioburden in orthokeratology lens storage cases. AB - PURPOSE: The aim of this study was to evaluate a DNA dot hybridization assay (DHA) for assessing bacterial bioburden in orthokeratology lens (OK) storage cases. METHODS: Forty-one OK wearers participated in this study. The dot hybridization assay was used to assess the bacterial bioburden of OK after removal and 6-hour soaking in a storage case. Signals of the DHA were standardized after gray image transformation. The correlations between the hybridization intensities of three universal bacteria probes (BP1, BP2, and BP3) and bacterial bioburden determined by culture (colony forming units per milliliter) was analyzed by Pearson's correlation coefficient and receiver operating characteristic plots. In addition, three genus-specific probes for Pseudomonas, Acinetobacter, and Klebsiella were used to detect potentially hazardous bacterial contamination regardless of bacterial viability status. RESULTS: Among the three universal probes, there were good correlations between probe BP2 (r2 = 0.31, P = 9.5 * 10(-5)) and probe BP3 (r2 = 0.35, P = 3.1 * 10( 5)) with bacterial bioburden, but no correlation was found between probe BP1 and bacterial bioburden (r2 = 0.04, P = 0.11). In 41 samples, one was Pseudomonas positive by both DHA and culture, while 10 were Pseudomonas-positive by DHA but negative by culture. Furthermore, nine samples tested positive for Acinetobacter (n = 7) and Klebsiella (n = 2) by DHA only. CONCLUSIONS: The dot hybridization assay provides a novel way to assess the bacterial bioburden of OK storage cases. Lens care quality can be assessed with universal bacteria probes, while potentially hazardous bacterial contamination can be traced with genus-specific probes. PMID- 25537201 TI - The prognostic effect of American Joint Committee on Cancer staging and genetic status in patients with choroidal and ciliary body melanoma. AB - PURPOSE: To evaluate the prognostic effect of a combination of American Joint Committee on Cancer (AJCC) staging (7th edition) and genetic status in patients with posterior uveal melanoma. METHODS: A consecutive cohort of 153 patients with posterior uveal melanoma treated at Copenhagen University Hospital from January 1, 2009 through December 31, 2012 was followed until October 2014. Survival, AJCC stage, and cytogenetic data were registered. The AJCC stage was available for all patients, and cytogenetic information for chromosomes 3 and 8 was available for 139 patients. The individual and joint prognostic effects of AJCC staging and cytogenetic changes were evaluated by cumulative incidence curves and Cox proportional hazard models. RESULTS: An overall 5-year survival rate of 62% (95% confidence interval [CI]: 0.50-0.73) was observed. A normal genetic status of chromosomes 3 and 8, as found in 42 patients (30%), minimized the additional prognostic effect of AJCC staging. The frequency of tumors with normal genetic status decreased with increasing AJCC stage. Both AJCC stage III (hazard ratio [HR]: 11.0, 95% CI: 1.4-85.6) and abnormal copy number of chromosomes 3 (HR: 6.3, 95% CI: 1.4-28.3) and 8 (HR: 2.8, 95% CI: 1.03-7.8) were identified as significant predictors of a poor prognosis in the multivariate Cox regression analysis. CONCLUSIONS: Identification of a normal genetic status of chromosomes 3 and 8 minimized the prognostic effect of AJCC staging, while a combination of genetic status and AJCC staging provided the most accurate prediction of survival in patients with an abnormal chromosomal status. PMID- 25537202 TI - Correlation of Pseudomonas aeruginosa genotype with antibiotic susceptibility and clinical features of induced central keratitis. AB - PURPOSE: To determine the association of type III secretion system (T3SS) genotype with antibiotic susceptibility, serotypes, and clinical manifestation of centrally located Pseudomonas aeruginosa keratitis. METHODS: Clinical characteristics of P. aeruginosa keratitis cases from 2001 to 2011 were analyzed. Each strain was serotyped and genotyped for T3SS exotoxin genes. Antibiotic sensitivity and minimum inhibitory concentrations were determined with agar dilution method. Prognostic factors affecting final visual outcomes and time to re-epithelialization were analyzed using linear and Cox regression models. RESULTS: Forty-four invasive and 28 cytotoxic strains were identified. Invasive strains occurred mostly in males (P = 0.03) with older age (P = 0.009) and ocular surgery or trauma history (P = 0.006), poor presenting (P = 0.04) and final (P < 0.0001) best spectacle-corrected visual acuity (BSCVA), and larger infiltration size (P = 0.03). Cytotoxic strains were associated with contact lens wear (P < 0.0001). Poor prognostic factors for final BCVA after adjusting for sex, age, and contact lens wear included invasive strains (P = 0.02), larger infiltration area (P = 0.02), deeper infiltrations (P = 0.02), and presence of hypopyon (P = 0.09). Factors affecting complete re-epithelialization time included invasive strains (P = 0.02), infiltration area (P = 0.01), depth (P = 0.02), and hypopyon (P = 0.03) after adjusting for age and sex. Serotypes 2, 6, and 11 were more commonly found among all isolates. A trend to increased fluroquinolone resistance is noted for invasive strains, although not reaching statistically significant difference. CONCLUSIONS: Cytotoxic strains are associated with contact lens wear while invasive strains are related to poor prognosis and increased resistance to fluoroquinolones. Clinicians should be aware of the two different genotypes of P. aeruginosa affecting prognosis. PMID- 25537203 TI - Loss of thiol repair systems in human cataractous lenses. AB - PURPOSE: The purpose of this study was to investigate the thiol repair systems of thioltransferase (TTase) and thioredoxin (Trx) and oxidation-damaged proteins in human cataractous lenses. METHODS: Cataractous lenses in humans (57-85 years of age) were classified into cortical, nuclear, mixed, mature, and hypermature cataract types by using a lens opacity classification system, and were obtained by extracapsular cataract extraction (ECCE) procedure. Cortical and nuclear cataracts were grouped by decreasing order of visual acuity into optical chart reading (R), counting fingers (CF), hand motion (HM), and light perception (LP). ECCE lens homogenate was analyzed for glutathione (GSH) level and enzyme activities of TTase, glutathione reductase (GR), Trx, and thioredoxin reductase (TR). Cortical and nuclear cataractous lenses (8 of each) with visual acuity better than HM were each dissected into cortical and nuclear portions for measurement of glyceraldehyde 3-phosphate dehydrogenase (G3PD) activity. Clear lenses (in humans 49-71 years of age) were used as control. RESULTS: Compared with control, all cataractous lenses lost more than 80% GSH and 70% GR; TR and Trx activity; and 40% to 70% TTase activity, corroborated with the loss in visual acuity. Among cataracts with R and CF visual acuity, cortical cataract lost more cortical G3PD activity (18% of control) than that of nuclear cataract (50% of control), whereas GSH depletion and TTase inactivation were similar in both cataracts. CONCLUSIONS: Thiol repair systems were damaged in all types of cataracts. Cortical and nuclear cataracts showed differential G3PD inactivation in the cortex, implying those 2 type of cataracts might be formed through different mechanisms. PMID- 25537205 TI - Infantile nystagmus syndrome is associated with inefficiency of goal-directed hand movements. AB - PURPOSE: The effect of infantile nystagmus syndrome (INS) on the efficiency of goal-directed hand movements was examined. METHODS: We recruited 37 children with INS and 65 control subjects with normal vision, aged 4 to 8 years. Participants performed horizontally-oriented, goal-directed cylinder displacements as if they displaced a low-vision aid. The first 10 movements of 20 back-and-forth displacements in a trial were performed between two visually presented target areas, and the second 10 between remembered target locations (not visible). Motor performance was examined in terms of movement time, endpoint accuracy, and a harmonicity index reflecting energetic efficiency. RESULTS: Compared to the control group, the children with INS performed the cylinder displacements more slowly (using more time), less accurately (specifically in small-amplitude movements), and with less harmonic acceleration profiles. Their poor visual acuity proved to correlate with slower and less accurate movements, but did not correlate with harmonicity. When moving between remembered target locations, the performance of children with INS was less accurate than that of the children with normal vision. In both groups, movement speed and harmonicity increased with age to a similar extent. CONCLUSIONS: Collectively, the findings suggest that, in addition to the visuospatial homing-in problems associated with the syndrome, INS is associated with inefficiency of goal-directed hand movements. ( http://www.trialregister.nl number, NTR2380.). PMID- 25537204 TI - Pseudo-fovea formation after gene therapy for RPE65-LCA. AB - PURPOSE: The purpose of this study was to evaluate fixation location and oculomotor characteristics of 15 patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations (RPE65-LCA) who underwent retinal gene therapy. METHODS: Eye movements were quantified under infrared imaging of the retina while the subject fixated on a stationary target. In a subset of patients, letter recognition under retinal imaging was performed. Cortical responses to visual stimulation were measured using functional magnetic resonance imaging (fMRI) in two patients before and after therapy. RESULTS: All patients were able to fixate on a 1 degrees diameter visible target in the dark. The preferred retinal locus of fixation was either at the anatomical fovea or at an extrafoveal locus. There were a wide range of oculomotor abnormalities. Natural history showed little change in oculomotor abnormalities if target illuminance was increased to maintain target visibility as the disease progressed. Eleven of 15 study eyes treated with gene therapy showed no differences from baseline fixation locations or instability over an average of follow-up of 3.5 years. Four of 15 eyes developed new pseudo-foveas in the treated retinal regions 9 to 12 months after therapy that persisted for up to 6 years; patients used their pseudo-foveas for letter identification. fMRI studies demonstrated that preservation of light sensitivity was restricted to the cortical projection zone of the pseudo-foveas. CONCLUSIONS: The slow emergence of pseudo-foveas many months after the initial increases in light sensitivity points to a substantial plasticity of the adult visual system and a complex interaction between it and the progression of underlying retinal disease. The visual significance of pseudo-foveas suggests careful consideration of treatment zones for future gene therapy trials. (ClinicalTrials.gov number, NCT00481546.). PMID- 25537206 TI - Relative roles of luminance and fixation in inducing dissociated vertical divergence. AB - PURPOSE: We evaluated the roles of luminance and fixation in the pathophysiology of dissociated vertical divergence (DVD). METHODS: Vertical eye position was measured in 6 subjects with DVD (ages 11-47 years, 5 females) and 6 controls (ages 16-40 years, 5 females) using video-oculography (VOG) under conditions of change in fixation and luminance. RESULTS: Subjects with DVD showed the following VOG responses. When fixation was precluded with a translucent filter and bright light was shone into one eye to produce a marked binocular luminance disparity, we found some subjects had a small induced vertical divergence causing the illuminated eye to be lower than the nonilluminated eye (mean -1.6 degrees +/- 1.5 degrees , P = 0.06 compared to no vertical divergence using the signed rank test). When fixation was precluded with a translucent filter, while alternate occlusion produced a mild binocular luminance disparity, we found a smaller vertical divergence of the eyes that was not statistically significant (1.2 degrees +/- 2.1 degrees , P = 0.3). When alternate occlusion produced reversal of monocular fixation in the dark (with essentially no change in peripheral luminance disparity), there was a significant vertical divergence movement causing the covered eye to be relatively higher than the uncovered eye (7.2 degrees +/- 3.1 degrees , P = 0.03). The amplitude of this vertical divergence was similar to that measured under conditions of alternate occlusion in a lighted room (where there also was a significant average relative upward movement of the covered eye of 8.1 degrees +/- 2.9 degrees , P = 0.03). Control subjects showed no vertical divergence under any testing conditions. CONCLUSIONS: Dissociated vertical divergence is mediated primarily by changes in fixation and only to a minor degree by binocular luminance disparity. PMID- 25537214 TI - Precision therapy to target apoptosis in prostate cancer. AB - Androgen-independent prostate cancer shows limited response to existing systemic therapies. Recent advances in prostate-selective targeting of small molecule inhibitors and bacterial toxins have created opportunities to design a new generation of therapies for advanced prostate cancer. Yet prioritizing targets for these therapies remain challenging, since multiple mechanisms contribute to the pathophysiology of androgen-independent prostate cancer. This review explores the possibility of targeting the apoptosis regulatory network as most direct approach to efficient treatment of advanced androgen-independent prostate cancer. PMID- 25537213 TI - Characterization of breast cancer DNA content profiles as a prognostic tool. AB - Worldwide, breast cancer in women remains to be the most common malignancy that in a considerable proportion shows the resistance to genotoxic treatments and poor outcome. Chromosomal instability manifested as aneuploidy represents an integral cha-racteristics of the malignant genotype not only because of the selection of mutated aneuploid sub-clones that stipulate the tumor progression, but also because of the reversible endopolyploidy of tumor cells that serves for the endless maintenance of therapy-resistant tumor stem cells. Therefore, cytometric determination of DNA content in tissue samples for detecting malignancy, monitoring responses to therapy, and prognosing disease outcome needs to be revived. Both flow and image cytometry are most frequently used for generation of DNA content profiles (histograms), interpretation of which, however, may have some caveats. This review presents the major characterization criteria and analysis tools for breast cancer DNA histograms. PMID- 25537215 TI - Hypoxia enhances antitumor activity of dichloroacetate. AB - It is known that glycolysis contributes to the survival of tumor cells by providing them with energetic and plastic substrates. Dichloroacetate (DCA) as inhibitor of kinase pyruvate dehydrogenase shifts balance of energy metabolism of tumor cells from aerobic glycolysis towards oxidative phosphorylation. The aim of the study was to investigate cytostatic/cytotoxic effect of DCA on glioma C6 cells at the conditions of different oxygenation of the cell incubation medium. MATERIALS AND METHODS: DCA action on glioma C6 cells was investigated upon the conditions of normoxia, hypoxia (1% of oxygen) and hyperoxia (30% and 95% of oxygen) in vitro. The number and viability of tumor cells were assessed using trypan blue dye-exclusion test. Apoptosis was determined using dye Hoechst 33258. Lactate production by tumor cells was determined by enzymatic method using lactate dehydrogenase. Cell cycle distribution was studied using flow cytometry. Reactive oxygen species (ROS) content was evaluated using 2',7' dichlorofluorescein diacetate. RESULTS: By the data of in vitro cytotoxicity, upon hypoxia IC50 value of DCA was three times lower (p < 0.05) than that upon normoxic conditions (18.2 +/- 3.9 mM vs. 51.2 +/- 8.1 mM). Hypoxia itself enhanced the ROS production in glioma cells by 113.5% (p < 0.05) that correlated with increase of apoptosis by 292% (p < 0.05). In hypoxic glioma C6 cells DCA did not significantly influence the ROS production, but decreased hypoxia-induced apoptosis by 3.5-6.5 times (p < 0.05) and significantly increased cell death rates via necrosis (p < 0.05). In contrast to hypoxia, upon the conditions of hyperoxia IC50 values for DCA did not differ from the corre-sponding values upon the normoxia conditions and at 30% and 95%oxygen content were equal to 35.8 +/- 7.2 mM and 42.3 +/- 5.1 mM respectively. CONCLUSION: According to the obtained results, hypoxia enhances cytostatic/cytotoxic effects of DCA in glioma C6 cells via high level of DCA-induced necrosis of tumor cells and hypoxia-induced ROS hyperproduction. PMID- 25537207 TI - Association of common SIX6 polymorphisms with peripapillary retinal nerve fiber layer thickness: the Singapore Chinese Eye Study. AB - PURPOSE: Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant and peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD OCT) in a population setting. METHODS: Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. Spectral-domain OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip. RESULTS: A total of 2129 eyes from 1243 SCES subjects (mean age: 55.0 +/- 7.4 years) with rs33912345 genotype data and SD-OCT images were included for the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 MUm in RNFL thickness after adjusting for age, sex, genetic principal components, and axial length (P = 0.001). These associations remained similar in 2096 nonglaucoma eyes in which each C allele was associated with a decrease of 1.39 MUm in RNFL thickness (P = 0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 MUm per risk allele, P < 0.001) followed by the inferior RNFL sector (a decrease of 2.24 MUm per risk allele, P = 0.003), while the association did not reach significance in the nasal and temporal sectors. CONCLUSIONS: Nonglaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant. PMID- 25537216 TI - Destabilization of human cell genome under the combined effect of radiation and ascorbic acid. AB - The aim of this study was to investigate peculiarities of ascorbic acid effect on radiation-induced chromosomal aberrations frequency and range in the cultured peripheral blood lymphocytes (PBL) of healthy donors and cancer patients depending on doses of radiation and drug, as well as cells radiosensitivity (in vitro). METHODS: Test system of human PBL, metaphase analysis of chromosomal aberrations. Cells were cultivated according to the standard procedures with some modifications. PBL culture was exposed to x-ray radiation in G0- and G2-phases of cell cycle. Immediately after the irradiation the culture was treated with ascorbic acid in concentrations of 20.0-80.0 ug/ml of blood. RESULTS: Cell culture irradiation in low dose (0.3 Gy) and treatment with ascorbic acid in therapeutic concentration (20.0 MUg/ml of blood) resulted in radioprotective effect, decreasing overall chromosome aberrations frequency as opposed to radiation effects. It has been established that post-irradiation effect of ascorbic acid upon the PBL culture in concentrations of 40.0 and 80.0 MUg/ml, which exceeding therapeutic concentration value 2 and 4 times correspondingly, increased overall chromosome aberrations frequency 1.4 times compared with irradiation effect in a low dose (0.3 Gy). This bears evidence of ascorbic acid co-mutagenic activity in the range of concentrations exceeding therapeutic values. The peak of mitotic activity inhibition was observed at 2.0 Gy irradiation dose. Addition ascorbic acid in therapeutic concentration increased radiation effect this number ~ 2 times (exceeding even intact control value). Compared with G0-phase, co-mutagenic effect of ascorbic acid in G2-phase appears earlier, starting with dose of 1.0 Gy. In the blood lymphocytes of cancer patients, the level of genetic damage was increased 1.7 times after combined treatment with low dose irradiation and ascorbic acid in comparison with irradiation alone which suggest the co-mutagenic instead of radioprotective effect of ascorbic acid. CONCLUSIONS: Genome destabilization enhancement of irradiated in vitro human somatic cells under ascorbic acid effect is due to its co-mutagenic properties. The formation of co-mutagenic effects of ascorbic acid depend on its concentration, irradiation dose and the efficiency of repair processes. Co-mutagenes may pose high carcinogenic hazard at low (above background) radiation levels. PMID- 25537217 TI - Photodynamic responsiveness of human leukemia Jurkat/A4 cells with multidrug resistant phenotype. AB - Photodynamic therapy (PDT) is considered as a possible alternative approach to overcoming multidrug resistance (MDR). Analysis of cross-resistance to PDT in cells with different MDR pathways and resistance levels seems to be advantageous for elucidating the general mechanisms of cancer cell resistance to various treatment modalities. AIM: The aim of the study was to clarify whether the Jurkat/A4 leukemia cells with MDR phenotype are cross-resistant to PDT. METHODS: Human T-cell acute lymphoblastic leukemia line Jurkat and Jurkat/A4 subline with MDR phenotype were used. 5-Aminolevulinic acid (ALA) and Photolon (a complex of chlorine-e6 and polyvinylpyrrolidone; PL) or gold nanocomposite of PL were applied as photosensitizers. The cells were pretreated with photosensitizers and exposed to laser radiation at corresponding wavelengths. The phototoxicity was assessed in trypan blue exclusion test. The hypodiploid cell fraction was analyzed by flow cytometry of propidium iodide-stained cells. Expression of genes related to PDT resistance was analyzed by microarray technique with Affymetrix U133A chips. RESULTS: ALA-mediated PDT resulted in dose-dependent cell death in both lines, the relative photodynamic efficacy in Jurkat/A4 cells being inferior to that in the parental Jurkat cells. There was no correlation between phototoxicity and apoptosis induction both in Jurkat and Jurkat/A4 cells. PL mediated general phototoxicity in Jurkat cells amounted up to 75% at the maximal photosensitizer dose with about 40% of apoptotic death fraction. PL-phototoxicity in Jurkat/A4 cells was considerably lower. In contrast to Jurkat cells, PL-gold composite did not increase the efficacy of photosensitization as compared to free PL in Jurkat/A4 cells. CONCLUSIONS: Multidrug-resistant Jurkat/A4 cells exhibit reduced sensitivity to phototoxic effect in comparison with parental Jurkat cells independently of nature of the photosensitizer being assayed. PMID- 25537218 TI - FGFR3 and TP53 mutations in a prospective cohort of Belarusian bladder cancer patients. AB - AIM: The aim of this study was to determine the frequencies of FGFR3 and TP53 mutations in a prospective cohort of 150 bladder cancer patients and to assess the relationship between their mutational status and clinicopathological variables. MATERIALS AND METHODS: The FGFR3 and TP53 mutations were detected by the SNaPshot method and PCR-single-strand conformational polymorphism analysis followed by DNA sequencing. RESULTS: The activating FGFR3 mutations were found in 71 (47.3%) whereas TP53 mutations were observed in 31 (20.7%) urothelial carcinomas. FGFR3-mutant tumors significantly correlated with lower tumor stage and grade, papillary form of bladder cancer and the absence of metastases while TP53-mutant tumors were strongly associated with higher tumor stage and grade as well as the presence of metastasis. We also found significant inverse correlation between FGFR3 mutations and TP53 alterations in urothelial carcinomas (p=0.03). Four possible genotypes were observed in the whole studied cohort, namely FGFR3mut/TP53wt (41.3%), FGFR3wt/TP53wt (38%), FGFR3wt/TP53mut (14.7%), and FGFR3mut/TP53mut (6%). Tumors with FGFR3wt/TP53wt genotype comprised the subgroup, in which all stages and grades were equally distributed. CONCLUSIONS: Our findings confirm the alternative role of FGFR3 and TP53 mutations in the development of bladder cancer. Together these two genetic markers are attributed to 62% of the tumors studied. Tumors with both wild type genes included urothelial carcinomas of all stages and grades and may develop through another genetic pathway. To elucidate complete molecular profile of bladder tumors further additional studies are needed. PMID- 25537219 TI - Baseline serum levels of multiple cytokines and adhesion molecules in patients with acute myeloid leukemia: results of a pivotal trial. AB - AIM: Evaluation of serum levels of 17 cytokines and 5 adhesion molecules in patients with newly diagnosed acute myeloid leukemia (AML) using biochip array technology. We searched for links between baseline levels and age, hyperleukocytosis, secondary origin of AML, resistance to induction therapy with cytarabine and daunorubicin and standard risk stratification according to cytogenetics and molecular genetics. METHODS: We evaluated the sera of 51 consecutive patients. Serum samples were analyzed by biochip based immunoassays on the Evidence Investigator analyzer. T-tests were used for statistical analysis. RESULTS: We found that higher age is associated with lower levels of interleukin (IL)-12. Patients with secondary disease were older, had higher levels of EGF and IL-7, and lower levels of E-selectin, IL-12 and IL-13. In hyperleukocytosis, the levels of IL-1beta, IL-2, TNF-alpha, VCAM-1, ICAM-1, -E selectin and L-selectin were increased, whereas levels of IFN-gamma and MCP-1 were decreased. In patients who failed to achieve complete remission after induction therapy, we found lower E-selectin and P-selectin levels. High risk patients had lower levels of IFN-gamma. CONCLUSION: Some leukemic cell subpopulations have the ability to produce cytokines that modulate the microenvironment by inducing inflammation. This causes endothelial cells to be activated and overexpress adhesion molecules. Hyperleukocytosis and secondary origin of the disease are the major factors influencing the cytokine and adhesion molecule profile in newly diagnosed AML patients. PMID- 25537220 TI - TP53 codon 72 single nucleotide polymorphism in chronic lymphocytic leukemia. AB - Defects in the tumor suppressor gene TP53 are known to be important in chronic lymphocytic leukemia (CLL) and TP53 inactivation is associated with a particularly aggressive form of the disease. The single nucleotide polymorphism in the TP53 gene at codon 72 (rs1042522), results in amino acid substitution influencing apoptotic potential of TP53 protein. The aim of the study was to evaluate the association of the TP53 codon 72 polymorphism and incidence of TP53 mutations in CLL patients. METHODS: 261 CLL samples were analyzed by polymerase chain reaction and direct sequencing for TP53 mutations and single nucleotide polymorphism. RESULTS: The 72Pro/Pro genotype was associated with an increased incidence of TP53 mutations in previously treated patients (OR = 2.503; 95% CI 1.142-5.487; r = 0.001). CONCLUSION: This study revealed that the TP53 codon 72 polymorphism may be used as a risk factor for incidence of TP53 mutations in CLL. PMID- 25537221 TI - Comprehensive analysis of intratumoral lymphocytes and FOXP3 expression in tumor cells of endometrial cancer. AB - AIM: To study the tumor microenvironment (CD4(+), CD8(+) and FOXP3(+) lymphocytes) and FOXP3 expression by tumor cells and correlation of studied parameters with clinical and morphological characteristics of endometrial adenocarcinomas. MATERIALS AND METHODS: Tumor samples from 40 patients (mean age 56.9 +/- 2.8) with endometrial cancer (EC), who did not receive special treatment before surgery (chemotherapy, radiation therapy and hormontherapy), were investigated. Morphological, immunohistochemical methods as well as methods of mathematical statistics were applied in the study. RESULTS: It has been determined that high quantity of FOXP3(+) tumor cells and intratumoral CD4(+) and CD8(+) T-lymphocytes along with the low content of FOXP3(+)-lymphocytes is typical for the endometrial adenocarcinomas of high differentiation grade (G1). In poorly differentiated (G3) EC an increase of number of FOXP3(+)-lymphocytes and decrease of CD4(+) and CD8(+) lymphocytes in lymphocytic infiltrate have been observed. Moreover, decrease of the content of FOXP3(+) tumor cells has been determined. In EC patients correlation between the following parameters has been detected: proliferative activity and deep invasion of tumor in myometrium (R = 0.74); depth of invasion correlated with the number of the FOXP3(+) tumor cells (R = -0.63) and number of CD4(+) and CD8(+) lymphocytes (R = 0.68 and R = -0.55 respectively) in lymphocytic infiltrate. Thus, results of this study are the evidence of significance of the lymphocytic components of tumor microenvironment and content of FOXP3 expressing tumor cells in EC progression. CONCLUSION: Quantitative changes of tumor microenvironment, such as number of CD4(+), CD8(+) and FOXP3(+) lymphocytes and content of FOXP3(+) tumor cells correlate with biological characteristics of EC. PMID- 25537222 TI - The influence of 5-fluorouracil on activity of thymidine phosphorylase in gastric adenocarcinoma and normal adjacent tissue. AB - The aim of the present study was to evaluate the change of thymidine phosphorylase (TP) activity in gastric adenocarcinoma and adjacent tissue upon the intraarterial administration of 5-fluorouracil (5-FU). Matherials and methods: The specimens of tumor and adjacent tissue were obtained by surgical operation on 36 patients (20 men and 16 women aged from 38 to 82 years) with gastric adenocarcinoma (stages II-IV). 5-FU was administered in the bolus dose to the gastroepiploic artery 2-60 min before the tumor resection. The concentration of 5-FU and activity of TP in both tissues were determined by high performance liquid chromatography method. RESULTS: The concentration of 5-FU was decreased in a time-dependent manner in both tissues, though the interpatient variability of this value was much less in tumor tissue. The activity of TP was decreased with the course of the time after 5-FU administration in tumor and normal adjacent tissue. There were statistically significant differences in the TP activity in both tissues between 2-20 min and 40-60 min after 5-FU injection (p < 0.05). CONCLUSION: 5-FU administration results in the decrease of TP activity in tumor and normal adjacent tissues that might have importance for chemotherapy with fluoropyrimidines. PMID- 25537223 TI - Premorphological alterations in gastric mucosa in patients with gastric cancer: hypoxia level assessed by 31P NMR spectroscopy. AB - The aim of this study was to detect the hypoxic status in adjacent histologically uninvolved gastric mucosa in gastric cancer (GC) patients. PATIENTS AND METHODS: 50 naive patients with primary GC, and one patient with stomach ulcer (gastric mucosa was used as control) were enrolled into the study. The tumor and mucosa samples of stomach (without muscularis and serosa layers) in patients with GC were obtained immediately after operation. Assessment of the hypoxia level has been provided using (31)P NMR spectroscopy in tissue perchloric acid extracts. Mucosa was examined by convenient histological method. Obtained results were analyzed statistically. RESULTS: It was shown that gastric mucosa in 52% of patients with GC is under different levels of hypoxia, among them 23% of mucosa is under severe hypoxia (PME/Pi < 1.0) with average mean of PME/Pi 0.89 +/- 0.04. It was revealed that there are definite associations between the hypoxia in mucosa tissue and pT as well as pN categories and G grade and stage of disease but not with M category. Overall survival of patients with gastric mucosa characterized by severe and mild hypoxia was significantly poorer as compared to that of patients with gastric mucosa with satisfactory oxygenation (p = 0.0035). CONCLUSION: Gastric mucosa uninvolved in tumor process is characterized by hypoxia in 52% of GC patients; severe hypoxia of mucosa was detected in 23% of patients having hypoxic mucosa. It was suggested that biochemical alterations in tissue surrounding tumor node may precede morphological ones. PMID- 25537224 TI - Effect of androgen suppression on bone mineral density in patients with prostate cancer. AB - The androgen-suppressive therapy (AST) in patients with prostate cancer (PC) may dramatically affect the bone mineral density (BMD), which puts patients at risk of severe adverse effects, such as weight-bearing bone fractures. AIM: To study the effect of AST on BMD in patients with non-metastatic hormone-sensitive PC treated with intermittent hormonal therapy, and effect of different total testosterone level on BMD. MATERIALS AND METHODS: From 2011 to 2013 we treated 56 patients with non-metastatic hormone-naive PC. Intermittent hormonal treatment with flutamide at a dose of 250 mg 3 times per day with nine monthly injections of luteinizing gonadotropic releasing hormone (LGnRH) ["treatment" period] followed by period of observance ("no treatment") was administered. We evaluated the BMD of lumbar spine and both proximal thighs by means of dual-energy x-ray densitometry at the end of "treatment" period and at the end of "no treatment" period. RESULTS: During the first treatment period, 44 of 56 patients (78.6%) experienced the reduction in BMD in both lumbar spine and thighs. Total testosterone level in all patients dropped to castration level. During the first period of "no treatment" there was an increase in BMD (p < 0.05) in 30 (68.2%) of 44 patients. The median time to recovery of total testosterone level to the level > 50 ng/dl was 91 days (from 30 to 308 days), and > 100 ng/dl was 110 days (from 49 to 343 days). The changes in BMD positively correlated with the changes in total testosterone level (correlation 0.18 [95% CI, 0.04-0.27], p = 0.009). The decline in total testosterone level in serum was followed by the decline in BMD value in the studied areas, and vice versa. CONCLUSIONS: The changes in BMD positively correlated with changes in total testosterone level. The BMD decreases during the androgen suppression and increases during the pause in the treatment. This demonstrates the benefit of intermittent AST in preventing osteoporosis, pathological bone fractures and possibly, bone metastases. PMID- 25537225 TI - Anatoly I. Bykorez. PMID- 25537226 TI - Hospital readmission and 30-day mortality after surgery for oral cavity cancer: Analysis of 21,681 cases. AB - BACKGROUND: Oral cavity squamous cell cancer (SCC) is treated primarily with surgery. Rates of 30-day hospital readmission and mortality after surgery for oral cavity SCC are unknown. METHODS: We conducted a retrospective analysis of postoperative 30-day unplanned readmission and mortality in patients with oral cavity SCC in the National Cancer Data Base (NCDB). RESULTS: Among 21,681 cases, the 30-day unplanned readmission rate was 3.2%, and the 30-day mortality rate was 1.0%. Male sex (odds ratio [OR] = 1.23; p = .02), stage T3 (OR = 1.55; p = .007), or T4 (OR = 1.52; p = .002), and neck dissection (OR = 1.37; p = .04) were independently associated with readmission. Age 76 to 85 years (OR = 4.80; p < .001), age >85 years (OR = 10.24; p < .001), comorbidity index >=1 (OR = 2.31; p < .001), and stage T3 (OR = 3.02; p < .001) or T4 (OR = 3.24; p < .001) were associated with 30-day mortality. CONCLUSION: Interventions aimed at decreasing hospital readmissions should target high-risk patients identified here. Factors associated with 30-day mortality reflect risk factors for overall mortality. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E221-E226, 2016. PMID- 25537227 TI - Polymer composites for thermoelectric applications. AB - This review covers recently reported polymer composites that show a thermoelectric (TE) effect and thus have potential application as thermoelectric generators and Peltier coolers. The growing need for CO2-minimizing energy sources and thermal management systems makes the development of new TE materials a key challenge for researchers across many fields, particularly in light of the scarcity or toxicity of traditional inorganic TE materials based on Te and Pb. Recent reports of composites with inorganic and organic additives in conjugated and insulating polymer matrices are covered, as well as the techniques needed to fully characterize their TE properties. PMID- 25537229 TI - Graphene oxide supported molybdenum cluster: first heterogenized homogeneous catalyst for the synthesis of dimethylcarbonate from CO2 and methanol. AB - The octahedral molybdenum cluster-based compound, Cs2 Mo6 Br(i) 8 Br(a) 6 was immobilized on graphene oxide (GO) by using a facile approach. High resolution transmission electron microscopy results revealed that molybdenum clusters were uniformly distributed on the GO nanosheets. Cs2 Mo6 Br(i) 8 Br(a) 6 was attached to the GO support via chemical interaction between apical ligands of Mo6 Br(i) 8 Br(a) 6 cluster units and oxygen functionalities of GO, as revealed by XPS studies. The developed material was used for the synthesis of dimethyl carbonate by reduction of carbon dioxide. The synthesized catalyst, that is, GO-Cs2 Mo6 Br(i) 8 Br(a) x , exhibited higher catalytic efficiency than its homogeneous analogue without using dehydrating agent. The catalyst was found to be efficiently recyclable without significant loss of catalytic activity. PMID- 25537228 TI - The emergence of age-dependent social cognitive deficits after generalized insult to the developing brain: a longitudinal prospective analysis using susceptibility weighted imaging. AB - Childhood and adolescence are critical periods for maturation of neurobiological processes that underlie complex social and emotional behavior including Theory of Mind (ToM). While structural correlates of ToM are well described in adults, less is known about the anatomical regions subsuming these skills in the developing brain or the impact of cerebral insult on the acquisition and establishment of high-level social cognitive skills. This study aimed to examine the differential influence of age-at-insult and brain pathology on ToM in a sample of children and adolescents with traumatic brain injury (TBI). Children and adolescents with TBI (n = 112) were categorized according to timing of brain insult: (i) middle childhood (5-9 years; n = 41); (ii) late childhood (10-11 years; n = 39); and (iii) adolescence (12-15 years; n = 32) and group-matched for age, gender, and socioeconomic status to a typically developing (TD) control group (n = 43). Participants underwent magnetic resonance imaging including a susceptibility weighted imaging (SWI) sequence 2-8 weeks postinjury and were assessed on a battery of ToM tasks at 6- and 24-months after injury. Results showed that for adolescents with TBI, social cognitive dysfunction at 6- and 24-months postinjury was associated with diffuse neuropathology and a greater number of lesions detected using SWI. In the late childhood TBI group, we found a time-dependent emergence of social cognitive impairment, linked to diffuse neuropathology. The middle childhood TBI group demonstrated performance unrelated to SWI pathology and comparable to TD controls. Findings indicate that the full extent of social cognitive deficits may not be realized until the associated skills reach maturity. Evidence for brain structure-function relationships suggests that the integrity of an anatomically distributed network of brain regions and their connections is necessary for the acquisition and establishment of high-level social cognitive skills. PMID- 25537230 TI - Characterization of local elastic modulus in confined polymer films via AFM indentation. AB - The properties of polymers near an interface are altered relative to their bulk value due both to chemical interaction and geometric confinement effects. For the past two decades, the dynamics of polymers in confined geometries (thin polymer film or nanocomposites with high-surface area particles) has been studied in detail, allowing progress to be made toward understanding the origin of the dynamic effects near interfaces. Observations of mechanical property enhancements in polymer nanocomposites have been attributed to similar origins. However, the existing measurement methods of these local mechanical properties have resulted in a variety of conflicting results on the change of mechanical properties of confined polymers. Here, an atomic force microscopy (AFM)-based method is demonstrated that directly measures the mechanical properties of polymers adjacent to a substrate with nanometer resolution. This method allows us to consistently observe the gradient in mechanical properties away from a substrate in various materials systems, and paves the way for a unified understanding of thermodynamic and mechanical response of polymers. This gradient is both longer (up to 170 nm) and of higher magnitude (50% increase) than expected from prior results. Through the use of this technique, we will be better able to understand how to design polymer nanocomposites and polymeric structures at the smallest length scale, which affects the fields of structures, electronics, and healthcare. PMID- 25537231 TI - Comparison of essential oil components and in vitro anticancer activity in wild and cultivated Salvia verbenaca. AB - The objectives of our research were to study the chemical composition and the in vitro anticancer effect of the essential oil of Salvia verbenaca growing in natural sites in comparison with those of cultivated (Sc) plants. The oil from wild (Sw) S. verbenaca presented hexadecanoic acid (23.1%) as the main constituent, while the oil from Sc plants contained high quantities of hexahydrofarnesyl acetone (9.7%), scarce in the natural oil (0.7%). The growth inhibitory and proapoptotic effects of the essential oils from Sw and Sc S. verbenaca were evaluated in the human melanoma cell line M14, testing cell vitality, cell membrane integrity, genomic DNA fragmentation and caspase-3 activity. Both the essential oils were able to inhibit the growth of the cancer cells examined inducing also apoptotic cell death, but the essential oil from cultivated samples exhibited the major effects. PMID- 25537232 TI - Histone deacetylase inhibitors in cancer: what have we learned? PMID- 25537233 TI - Oral anticoagulation is frequently discontinued after ablation of paroxysmal atrial fibrillation despite previous stroke: data from the German Ablation Registry. AB - AIMS: Atrial fibrillation (AF) is the most common cause of ischemic stroke. Recent data suggest that AF patients after successful ablation have the same risk for thromboembolic events (TE) as patients without AF. Despite current guideline recommendations it is still under debate if oral anticoagulation (OAC) can be safely discontinued after ablation. We analyzed follow-up (FU) after ablation of paroxysmal AF (PAF) in a high- (previous stroke; group 1) and a low-risk group (no previous stroke; group 2) based on data from the German Ablation Registry to reveal real-life prescription behavior. METHODS: Overall 29 centers in Germany participated by performing AF-ablation. Between April 2008 and April 2011, 83 patients in group 1 and 377 patients in group 2 with a first ablation of PAF were included in the registry. RESULTS: Mean CHA2DS2-VASc-Score was 4.2 +/- 1.4 (group 1) vs. 1.6 +/- 1.2 (group 2) (p < 0.0001). No peri-interventional TE was observed. Arrhythmia recurrence was seen in 47.4 vs. 48.4% (p = 0.79) during a median FU of 489 (453-782) days, resulting in a repeat procedure in 20.0 vs. 20.7% (p = 0.88), respectively. OAC was discontinued in 38.6% in group 1 vs. 66.3% in group 2 (p < 0.0001) during FU. TE during FU occurred more often in group 1 than in group 2 (4.3 vs. 0.3%, p < 0.05). CONCLUSION: Even in patients with previous stroke, OAC was frequently discontinued during FU after PAF ablation in this observational study. However, TE occurred significantly more frequent in these high-risk patients. These data argue against OAC discontinuation after ablation in patients with previous stroke. PMID- 25537235 TI - Assessment of a new instrument for detecting preventable adverse drug reactions. AB - BACKGROUND: Pharmacovigilance centres (PVCs) in the World Health Organization (WHO) Programme for International Drug Monitoring have demonstrated their ability to detect preventable adverse drug reactions (ADRs) in their databases. In this field, there is no gold-standard method for detecting medication errors and evaluating ADR preventability. Therefore, we developed, from existing tools, a preventability assessment method: the 'P Method' (PM). OBJECTIVE: To present the PM and to evaluate its inter-rater reliability. METHODS: The PM includes 20 explicit criteria for assessing ADR preventability. This approach is based on identification of any potentially preventable risk factor that increases the likelihood of ADR occurrence. The outcome of the preventability assessment results in one of three possible scores: 'preventable', 'non-preventable' or 'not assessable'. The PM was tested in a multicentre study involving nine national PVCs. Two experienced reviewers at each participating PVC independently analysed the preventability of 183 ADRs, applying the PM. RESULTS: The overall agreement between all reviewers for assessment of ADR preventability was 'fair', with a kappa value of 0.27 [95 % confidence interval (CI) 0.21-0.40]. The level of agreement between reviewer pairs ranged from 'slight', with a kappa value of 0.12 (95 % CI -0.03 to 0.27), to 'substantial', with a kappa value of 0.69 (95 % CI 0.48-0.89). CONCLUSION: The analysis of the agreements and disagreements between reviewers highlighted where improvements might be made. Given that no standard assessment tool exists in the WHO Programme, the transparency of the assessment process in this method provides a substantial basis for further development and for support in signalling possible preventability. PMID- 25537234 TI - Effect of an educational intervention to improve adverse drug reaction reporting in physicians: a cluster randomized controlled trial. AB - BACKGROUND: The yellow-card scheme continues to be one of the principal methods for signal generation in pharmacovigilance. Nevertheless, under-reporting, one of its disadvantages, delays alert signals and has a negative influence on public health. Educational interventions in pharmacovigilance may have a positive impact on the spontaneous reporting of adverse drug reactions (ADRs). OBJECTIVES: To assess the duration of the effect and effectiveness of an educational intervention in pharmacovigilance designed to improve ADR reporting in a robust pharmacovigilance system. METHODS: A spatial, cluster randomized controlled trial was conducted covering all National Health System physicians in the northwest of Spain and targeting those who were actively engaged in clinical practice (n = 7,498). Of these, 2,120 were assigned in three spatial clusters to the intervention group (six hospitals and 138 primary care centers) and 3,614 in four clusters to the control group (seven hospitals and 267 primary care centers). The educational intervention consisted of two complementary approaches--one active (group sessions), the other passive (educational material, reporting form) implemented from November 2007 to December 2008, with a follow-up period of 8 months. RESULTS: Intervention participation was 53.7 % in a hospital setting and 60.5 % in primary care settings. ADR reporting in the intervention group increased by 65.4 % (95 % confidence interval [CI]: 8.2-153.4) across the follow up. The ADR reporting rate per 1,000 physicians/year in the intervention group rose from 28.1 to 39.6 following the intervention (51.7 and 27.4 in the first and second 4-month period, respectively). For the intervention group, relative risk (RR) was 2.31 (95 % CI: 1.46-3.68) and 1.04 (95 % CI: 0.61-1.77) in the first and second 4-month period, respectively adjusted to baseline values. There was an increase in unexpected ADR reporting (RR 2.06, 95 % CI 1.19-3.55). CONCLUSIONS: Pharmacovigilance educational interventions that have proved effective can be successfully applied in different geographical areas. A high baseline notification rate could account for the educational program having a moderate effect. PMID- 25537237 TI - Impaired executive functioning after left anterior insular stroke: a case report. AB - Given the insular's anatomic complexity and functional interconnectivity, acute lesions may result in varied clinical presentations, including autonomic, somatosensory, perceptual, motor, affective, and cognitive deficits. Although functional neuroimaging studies have demonstrated its role in executive functions, no clinical manifestations have been reported to date. We present the case of a woman with an acute left anterior insular infarction leading to executive (i.e., word and design fluency, mental flexibility, sustained attention, inhibitory control), but not language, visuoperceptual, or memory impairment. This case confirms the left anterior insula's involvement in executive functioning and suggests that an infarction may result in executive impairment. PMID- 25537236 TI - Enhancing bio-hydrogen production from sodium formate by hyperthermophilic archaeon, Thermococcus onnurineus NA1. AB - Hyperthermophilic archaeon, Thermococcus onnurineus NA1 was reported to grow on formate producing hydrogen (H2). In this study, to sustain high H2 production rate and demonstrate the feasibility of mass production of H2, high cell density cultivation of T. onnurineus NA1 on sodium formate was employed under optimized conditions. From batch cultures, it was observed that the salinity of medium, significantly changed by the addition of formate salt and pH-adjusting agent, crucially affected cell growth and H2 production. With salinity carefully controlled between 3.7 and 4.6 %, 400 mM sodium formate was found to be an optimal initial concentration for maximizing cell growth-associated H2 production. Under optimal conditions, the repeated batch culture with cell recycling showed high cell density of OD600 of 1.7 in 3 and 30 L bioreactor, and the volumetric H2 production rate was enhanced up to 235.7 mmol L(-1) h(-1), which is one of the highest values reported to date. PMID- 25537239 TI - Corrigendum. PMID- 25537240 TI - [The expert consensus on cesarean delivery operation (2014)]. PMID- 25537238 TI - Processing past tense in the left cerebellum. AB - We report the case of a patient with ischemic lesion of the left cerebellum, who showed specific deficits in processing past versus future tense of action verbs. These findings confirm, in the presence of cerebellar damage, previous results obtained with transcranial magnetic stimulation in healthy subjects and suggest a specificity of the left cerebellum for preparation of responses to the past tense of action verbs. As part of the procedural brain, the cerebellum could play a role in applying the linguistic rules for selection of morphemes typical of past and future tense formation. PMID- 25537241 TI - [Reduce the rate of cesarean section and promote vaginal delivery: a serious challenge facing in obstetrics]. PMID- 25537242 TI - [Cesarean delivery rate and indications in mainland China: a cross sectional study in 2011]. AB - OBJECTIVE: To estimate cesarean delivery rates and indications by region in mainland China. METHODS: A cross sectional survey of all deliveries in 39 hospitals in 14 provinces of mainland China from January 1 to December 31, 2011 was evaluated for mode of delivery, cesarean delivery rates and indications for delivery. RESULTS: (1) A survey of a total of 112 138 women at delivery with gestations greater than 24 weeks was analyzed. 79 631 and 32 507 deliveries were obtained from the tertiary and secondary hospitals respectively. 90 971 were primipara, 21 167 were multipara. Of these pregnancies, 61 084, 49 734 and 1 320 cases resulted in cesarean delivery, vaginal delivery and operative vaginal delivery respectively, the cesarean delivery rate was 54.472% (61 084/112 138). Among 61 084 women who had cesarean delivery, 14 998 cases of the cesarean deliveries were performed without medical indications, 46 086 cases of the cesarean deliveries had medical indications. The cesarean delivery rate of the tertiary hospitals was 55.927% (44 535/79 631), and was significant higher than that in the secondary hospitals (50.909%, 16 549/32 507; P < 0.01). (2) Overall 24.553 % (14 998/61 084) of cesarean deliveries were performed without medical indications. 19.744% (8 793/44 535) of the cesarean deliveries without medical indications were performed in the tertiary hospitals, and was significant lower than in the secondary hospitals (37.495%, 6 205/16 549;P < 0.01). (3) Maternal request was the most common indication (24.553% of all cesarean deliveries), followed by fetal distress (12.507% , 7 640/61 084), cephalopelvic disproportion (11.787%, 7 200/61 084), previous uterine surgery (10.374%, 6 337/61 084), malpresentation (5.815%, 3 552/61 084), failure to progress (5.710%, 3 488/61 084) and suspected macrosomia (5.594%, 3 417/61 084). CONCLUSIONS: The increasing caesarean section rate in mainland China is explained mainly by the high non indicated caesarean section rate. The main medical indications of the cesarean deliveries included fetal distress, cephalopelvic disproportion, previous uterine surgery, malpresentation and failure to progress. PMID- 25537243 TI - [Investigation on the approach of delivery after previous cesarean section of Xinjiang Uyghur women]. AB - OBJECTIVE: To explore the appropriate approach of delivery after cesarean section of Uyghur women in primary hospitals in Xinjiang Uyghur Autonomous Region. METHODS: A total of 5 154 women delivered in Luopu County People Hospital, Hetian Prefecture, Xinjiang Uyghur Autonomous Region from January 2011 to December 2012. Among them, 178 Uyghur women had cesarean section history. The interval between the previous cesarean section and this delivery varied from 1 year to 17 years. The number of cases attempting vaginal labor and the indications of the previous cesarean section were recorded. The indications for the second cesarean section were analyzed. The gestational weeks at delivery, blood loss in 2 hours after delivery, neonatal birth weight, newborn asphyxia, the rate of postpartum fever (>= 38 degrees C) and hospitalization days were compared between the two approaches of delivery. RESULTS: (1) Among the 178 cases, 119 cases attempted vaginal labor, the rate of attempting vaginal labor was 66.9% (119/178). A total of 113 cases succeeded in vaginal delivery (the vaginal delivery group), with the successful rate of attempting vaginal delivery of 95.0% (113/119), and the successful rate of vaginal delivery was 63.5% (113/178). For those 119 women succeeded in vaginal delivery, the indications of the previous cesarean sections were as following: pregnancy complications (68.1%, 81/119), macrosomia(5.0%, 6/119), dystocia (14.3%, 17/119), pregnancies complicated with other diseases (5.0%, 6/119) and cesarean section on maternal request (7.6%, 9/119). (2) 15 cases in the cesarean section group had postpartum hemorrhage, with the incidence of 13.3% (15/113). The mean total labor time was (507 +/- 182) minutes. 6 cases attempting vaginal delivery failed and turned to cesarean section. (3) 59 cases received the second cesarean section (the cesarean section group). The rate of second cesarean section was 33.1% (59/178). The indications of the second cesarean section were as following: contracted pelvis (5%, 3/59), pregnancy complications (42%, 25/59), macrosomia (20%, 12/59), short interval between the two cesarean sections (<= 2 years); (12%, 7/59) and cesarean section on maternal request (20%, 12/59). (4) Gestational weeks at delivery, rates of newborn asphyxia in the vaginal delivery and cesarean section groups showed no significant statistical difference (P > 0.05). In the vaginal delivery group, the average blood loss in 2 hours after delivery was (259 +/- 213) ml, the rate of postpartum fever was 10.6%, the mean fetal birth weight was (3 272 +/- 477)g and the mean hospitalization was (1.8 +/- 1.6) d. In the cesarean section group, they were (400 +/- 320) ml, 54.2%, (3 539 +/- 500)g and (8.7 +/- 2.2)d, respectively. There was significant statistical difference (P < 0.01) between the two groups. CONCLUSIONS: Vaginal delivery after cesarean section could be attemped in Uyghur pregnant women in Xinjiang primary hospitals, if doctors could choose the indications strictly and monitor closely. These could increase the success rate and safety of vaginal delivery and therefore reduce the cesarean section rate. PMID- 25537244 TI - [Clinical analysis of double-balloon catheter for cervical ripening in 66 cases]. AB - OBJECTIVE: To evaluate the efficacy and safety for cervical ripening by double balloon catheter among full-term pregnancy women underwent labor induction. METHODS: It was a prospective non-randomly controlled research. Totally 128 singleton-pregnancy women in full-term who had to undergo labor induction because of pregnancy complications or comorbidities from August 2011 to April 2013 in Peking University First Hospital were selected as study subjects. Participants were allocated to preinduction cervical ripening with either a double-balloon catheter (66 participants, study group) or prostaglandin vaginal insert (62 participants, control group). Compare the efficacy for cervical ripening and adverse reactions between the two groups. RESULTS: The efficacy for cervical ripening (Bishop scores improved by >= 2) had no significant differences between study and control groups [82% (54/66) compared with 81% (50/62), P > 0.05]. The time interval between intervention and parturiency was significantly higher in the double balloon catheter group than in the prostaglandin vaginal insert group [(24.2 +/- 8.5) compared with (14.5 +/- 8.0) hours, P < 0.05]. The proportion of women who achieved parturiency within 12 hours was significantly lower in the double-balloon catheter group than that in the control group [9% (6/66) compared with 21% (13/62), P < 0.05]. The cesarean section rate showed no significant differences [41% (27/66) compared with 43% (27/62), P > 0.05]. The prevalence of intrauterine infection demonstrated by clinical diagnosis was significantly higher in the double- balloon catheter group [11% (7/66) compared with 6% (4/62), P < 0.05]. The double-balloon catheter group had significantly lower rates of contraction over frequency [0(0/66) compared with 42% (26/62), P < 0.05], hyperthermia [3% (2/66) compared with 19% (12/62), P < 0.05], fetal heart rate abnormalities before removing the device or drug [5% (3/66) compared with 19% (12/62), P < 0.05], as well as precipitate labour [2% (1/66) compared with 16% (10/62), P < 0.05]. CONCLUSIONS: The efficacy of a double- balloon transcervical catheter is similar to that of a prostaglandin vaginal insert. However, the double- balloon catheter cannot significantly reduce the cesarean section rate while it increases the risk of intrauterine infection. The maternal and fetal safety of transcervical catheter is superior to the prostaglandin vaginal insert. In cases of oligohydramnios, fetal growth restriction, pregnancy complicated with asthma, hypertension and scar uterine are in favor of a balloon catheter using for cervical ripening on account of high risk of using prostaglandin. PMID- 25537245 TI - [Precise screening, risk stratification: HPV and prevention of cervical cancer]. PMID- 25537246 TI - [Predictive value of abnormal second-trimester maternal serum triple screening markers for adverse pregnancy outcomes]. AB - OBJECTIVE: To investigate the predictive value of abnormal multiples of the median (MoM) of second trimester maternal serum triple screening (STMSTS) markers for adverse pregnancy outcomes. METHODS: 16 000 singleton pregnancies at 15+0 to 20+5 weeks' gestation who underwent STMSTS between July 2010 and January 2013 in the First Hospital of Jilin University were recruited. Maternal serum AFP, free beta-hCG (F-beta-hCG) and unconjugated estriol (uE3) levels were measured using time- resolved fluoroimmunoassay, and then converted to MoM. LifeCycle 3.2 software was used to calculate risk, and a risk value greater than 1 in 270 or 1 in 350 was considered as high risk for trisomy 21 syndrome (Down syndrome, DS) and trisomy 18 syndrome (Edwards syndrome, ES), respectively. MoM of AFP more than 2.5 was considered high risk for open neural tube defect (ONTD). Amniocentesis and karyotyping, ultrasound screening were advised for high risk women. AFP, F-beta-hCG higher than 2.0 MoM or uE3 lower than 0.5 MoM was considered as abnormal, respectively. The MoM of STMSTS marker between women with adverse pregnancy outcome and with normal outcome was compared. RESULTS: (1) The median MoM of AFP, F-beta-hCG and uE3 was 0.91 MoM, 0.94 MoM and 1.05 MoM, respectively. Of the 16 000 pregnant women, there was no statistical difference in the median MoM of triple screening marker at different weeks of gestation (P > 0.05). The positive rate of DS, ES and ONTD in women <=35 years old (n = 14 972) was 4.03% (603/14 972), 0.36% (54/14 972) and 0.29% (44/14 972) respectively. And in women>35 years old (n = 1 028), the positive rate was 24.51% (252/1 028), 1.95% (20/1 028) and 0.78% (8/1 028), respectively. There was a statistically significant difference of positive rate between the two groups (P < 0.05). (2) 9 cases of DS, 1 case of ES and 1 case of ONTD were found in the high risk group, and 2 cases of DS in the low risk group. The detection rate of DS, ES and ONTD was 9/11, 1/1 and 1/1 respectively; and the positive predictive value was 1.05% (9/855), 1.35% (1/74) and 1.92% (1/52), respectively. (3)The incidence of adverse outcome (group 1) was 1.49 % ( 239/16 000). 7 760 pregnant women in this study were healthy during pregnancy, so were their fetuses (group 2). There were significant differences in the age at delivery, body weight and markers' MoM of STMSTS between the two groups (P < 0.01). (4) In group 1, the rate of abnormal MoM of AFP or F-beta-hCG was 7.95% (19/239) and 23.85% (57/239), and the abnormal rate of MoM of uE3 was 4.18% (10/239). The rate of two abnormal MoM of markers was 5.02% (12/239); the rate that all three MoM were abnormal was 0.84% (2/239). However, in group 2, the rate of two abnormal MoM of markers was 0.14 % ( 11/7 760); and the rate that all three MoM were abnormal was 0. There was a significant difference of abnormal MoM of maternal serum marker between the two groups (P < 0.01). CONCLUSIONS: There is a relationship between abnormal marker of STMSTS and adverse outcomes. STMSTS show a high value in the detection of DS, ES and ONTD. PMID- 25537247 TI - [Effect of pelvic floor muscle training with biofeedback on stress urinary incontinence in postpartum and post-menopausal women]. AB - OBJECTIVE: To investigate the short-term effect of pelvic floor muscle training (PFM) with biofeedback on stress urinary incontinence (SUI) in postpartum and post-menopausal women. METHODS: According to the different period that the SUI occurs, 107 women with SUI were divided into two groups: the group of SUI in postpartum with 60 women, and the group of SUI in post- menopausal with 47 women. PFM with biofeedback was performed on all patients for 8 weeks. One hour pad- weighing test, voiding diary, transperineal three- dimensional ultrasound and female pelvic floor muscle assessment were recorded before and after treatment. RESULTS: There was statistically significant difference in 1 hour pad-weighing test between pre- treatment and post-treatment for the group of SUI in postpartum (the negative, mild, moderate, and severe cases of post-treatment: 21, 24, 14, 1, of pre-treatment: 0, 30, 28, 2; P < 0.05), and the group of SUI in post menopausal (the negative, mild, moderate, and severe cases of post-treatment: 7, 22, 11, 7, of pre-treatment: 0, 14, 25, 8; P < 0.05). The strength of the pelvic floor muscles of type I and type II in two groups after treatment were significantly different from those in pre-treatment (P < 0.01). The efficient rate of improvement in symptoms after treatment in the group of SUI in postpartum was 88% (53/60) and the cure rate was 38% (23/60). While the efficient rate in the group of SUI in post-menopausal women was 64% (30/47) and the cure rate was 15% (7/47). There was statistically significant difference in the development of symptoms in two groups after treatment (P = 0.003). CONCLUSION: PFM with biofeedback is an effective treatment for SUI in postpartum and post-menopausal women, especially for postpartum ones. PMID- 25537248 TI - [Family-based analysis of the adiponectin gene polymorphisms and polycystic ovary syndrome]. AB - OBJECTIVE: To study the association between three single nucleotide polymorphisms (SNP; rs2241766, rs1501299 and rs12495941) variants of the adiponectin gene (ADIPOQ) and polycystic ovary syndrome (PCOS) in PCOS family trios. METHODS: A total of 224 unrelated PCOS probands, their biological parents were recruited. Anthropometric variables such as waist circumference (WC), hip circumference (HC), height and weight were measured in all subjects during the first visit to the outpatient department. Body mass index (BMI) and waist- hip ratio (WHR) were calculated. Serum fasting glucose (FBG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TG), low- density lipoprotein and highdensity lipoprotein cholesterol (HDL) levels were measured. PCOS patients were divided into two groups based on BMI: group A (BMI<25 kg/m2) and group B (BMI >= 25 kg/m2). Parents of PCOS patients were accordingly categorized into group C, D (fathers) and group E, F (mothers). The transmission disequilibrium test (TDT) was used to analyze the association between three SNP of ADIPOQ and PCOS. RESULTS: (1) A significant positive association was detected between SNP rs1501299 and PCOS (chi2 = 7.093, P = 0.008). However we failed to find significant overtransmission of the other two SNP rs2241766 and rs12495941 from parents to PCOS offsprings (chi2 = 1.620, P = 0.203; chi2 = 0.713, P = 0.398). (2) Linkage disequilibrium (LD) was analyzed in the subjects, rs1501299 and rs2241766 were in weak LD (r2 = 0.063, D' = 0.621). (3) The levels of WC, HC, WHR, testosterone, TG, HDL and FINS were significantly differences between obese and lean PCOS patients (P < 0.05). While in fathers we only found WC, HC, TC levels being statistically different (P < 0.05). Mothers of obese PCOS patients had increased levels of FINS compared with mothers of lean PCOS patients (P < 0.05). The genotype frequencies of the three SNP were not different in obese and lean PCOS patients and their parents (P>0.05). CONCLUSIONS: TDT confirms that SNP rs1501299 in the ADIPOQ is significantly associated with the risk of PCOS in the Chinese Han population. The three SNP of the ADIPOQ were not associated with the obesity of PCOS. PMID- 25537249 TI - [Influence of basic thyroid-stimulating hormone levels on outcomes of IVF/ICSI in Qinghai]. AB - OBJECTIVE: To study basic thyroid stimulating hormone (bTSH) levels impact on outcomes of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in Qinghai. METHODS: Totally 282 cases with IVF cycles and 93 cases with ICSI cycles were studied prospectively, according to bTSH level, patients were divided into four groups. Reproduction rate, clinical pregnancy rate, miscarriage rate and live birth rate were studied among four groups. RESULTS: (1) In 375 cases with IVF/ICSI cycles, bTSH was positively correlated with abortion rate (r = 0.42, P = 0.04), but live birth rate and growing rate showed negative correlations with bTSH (r = -0.42, -0.28; P = 0.04, 0.03). bTSH and the number of eggs, the number of fertilized eggs, the number of embryos, biochemical pregnancy rate, and clinical pregnancy rate were no significant correlation (all P > 0.05). (2) Among women at group of <= 1.7, >1.7 and <= 2.5, >2.5 and <= 3.5, >3.5 mU/L, the implantation rates were 28.7%, 27.3%, 37.7% and 19.2%, live birth rates were 80.9%, 75.0%, 82.7%, and 59.8%, abortion rates were 19.0%, 15.0%, 16.7%, 40.1%; they all showed significant difference (all P < 0.05). Abortion rate in women with high bTSH level was higher than that of women with lower bTSH level, however implantation rate, live birth rate in women with high bTSH level were lower. CONCLUSION: When bTSH level is >3.5 mU/L, the abortion rate were increased, but live birth rate, rate of implantation were decreased. PMID- 25537250 TI - [Association between metabolic syndrome and prognosis of endometrioid carcinoma]. AB - OBJECTIVE: To study the association between metabolic syndrome(MS)and prognosis of endometrioid carcinoma. METHODS: A total of 256 patients with endometrioid carcinoma at, Zhejiang Cancer Hospital between January, 2001 and December, 2008 were chosen. The deadline for follow up was December 2008. The general conditions(including age and body mass index), whether coupled with MS and it's risk factors(including waist circumference, fasting plasma glucose, triglycerides, high- density lipoprotein, systolic and diastolic blood pressure) were analyzed. The outcome of 256 patients whether coupled with MS were analyzed using Kaplan-Meier curve. Relative risks were estimated using Cox proportional hazards regression model. RESULTS: A total of 256 cases were followed-up successfully.Sixty-four (33.0%) cases coupled with MS among the 194 patients survived, while thirty-two (51.6%) coupled with MS from 62 cases died, there was significant difference between them(chi2 = 6.953, P = 0.008). The total five-year survival rate was 75.8%, the survival time was (78.0 +/- 3.4) months. The rate and the survival time of patients coupled with MS [66.7%, (67.0 +/- 2.4) months] were significantly lower than those coupled with no MS [81.3%, (85.0 +/- 4.0) months; P < 0.05]. The Cox proportional hazards regression results showed that coupled with MS, body mass index >= 25 kg/m2, waist circumference > 80 cm, abnormol systolic and diastolic blood pressure, abnormal fasting plasma glucose and more than two components of definitions of MS were related to bad prognosis of endometrioid carcinoma (P < 0.05). CONCLUSION: Metabolic syndrome may be lead to a bad prognosis of endometrioid carcinoma. PMID- 25537251 TI - [Analysis of the treatment and prognosis for gestational trophoblastic neoplasia patients with urinary system and adrenal glands metastasis]. AB - OBJECTIVE: To analyze the treatment and prognosis of patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis. METHODS: The treatment and prognoses of 32 patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis from Dec. 1990 to Dec. 2010 at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences were respectively reviewed. RESULTS: Treatment methods: all 32 patients received 9 courses(in average) of a multi- drug chemotherapy in our hospital (range 1-24 coures). Among them, 3 patients with bladder metastasis received intravesical chemotherapy of fluorouracil. 9 patients received surgical treatments in other hospital and 15 patients received surgical treatments while undergoing chemotherapy in our hospital. Treatment results: after the treatments, of the 32 patients, 21 (66%) patients achieved complete remission, 3(9%) exhibited partial remission and 8 (25%) progressed. Seven patients with renal metastasis achieved complete remission. Two patients with adrenal glands metastasis achieved complete remission. Nine patients with urinary bladder metastasis achieved complete remission. Seven patients with ureters metastasis achieved complete remission. Two (10% ) of 21 patients with complete remission relapsed. CONCLUSIONS: Multidrug and multiroute chemotherapy is the main strategy for patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis. The prognoses of patients with renal or adrenal glands metastasis are much worse than those in patients with bladder and ureters metastasis because of concomitant multiogran metastasis. Adequate attention should be given to patients with renal or adrenal glands metastasis. Individual treatment, assisted by surgery when necessary, may be carried out for these patients to achieve a better outcome. PMID- 25537252 TI - [Clinical significance of FIGO 2009 staging I and its prognostic related factors in endometrial carcinoma]. AB - OBJECTIVE: To discuss the clinical significance of Federation International of Gynecology and Obstetrics (FIGO) 2009 staging I and its prognostic related factors in endometrial carcinoma. METHODS: A retrospective analysis was carried out on 233 cases with FIGO 2009 staging I endometrial carcinoma who were admitted to Department of Obstetrics and Gynecology, Peking University People's Hospital from Dec. 1998 to Dec. 2009 and were carried with complete staging operation then compared with FIGO 1988 staging. All follow-up data were complete. RESULTS: Of the 233 cases, including FIGO 1988 staging I a 41 cases, I b 146 cases, I c 29 cases and II a 17 cases. The univariate analysis revealed that there were no significant difference between staging I a and I b group in histological grade, pathological type, intravascular vessel cancer embolus, the expression of ER, PR, postoperative chemotherapy or postoperative chemoradiotherapy (all P > 0.05). The univariate analysis revealed that there were no significant difference between staging I and II a group in histological grade, pathological type, intravascular vessel cancer embolus, the depth of myometrial invasion, the expression of ER and PR postoperative chemotherapy or postoperative chemoradiotherapy (all P > 0.05). CONCLUSION: FIGO 2009 staging I in endometrial carcinoma is more consistent with the patient's clinical status than that in FIGO 1988 stage I and II a. PMID- 25537253 TI - [Expression of Notch1, Jagged1 and NICD in epithelial ovarian carcinomas and a preliminary study on the activity of gamma-secretase in epithelial ovarian carcinoma cell lines]. AB - OBJECTIVE: To study the expression of Notch1, Jagged1 and Notch intracellular domain (NICD)in epithelial ovarian carcinoma tissues and analyze the clinical significance. To explore the activity of gamma-secretase in epithelial ovarian carcinoma cell line SKOV3 and the effect of N-[N-(3, 5-dil uorophenacetyl)-L alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor on the activity of gamma-secretase in SKOV3. METHODS: Immunohistochemistry staining method was performed in 43 patients with epithelial ovarian carcinoma and 11 patients with benign epithelial ovarian tumor to detect the expression of Notch1, Jagged1 and NICD. The differences of expressionof Notch1, Jagged1 and NICD between malignant and benign ovarian tumors was compared and alsoanalyzed the correlation with clinicopathological parameters of ovarian carcinoma. Human serous ovarian cancer cell line SKOV3 and immortalized nontumorigenic ovarian epithelial cell line T29 were incubated in vitro. The activities of gamma secretase in SKOV3 and T29 with dimethyl sulfoxide (DMSO) and DAPT were detected respectively by Gal4-VP16/UAS and dual luciferase reporter assay system. RESULTS: (1) The immunohistochemical composite scores (ICS) of Notch1 in epithelial ovarian carcinoma (6.7 +/- 2.2) were not significantly different with those in benign epithelial ovarian tumor (5.4 +/- 2.7, P = 0.153), while the ICS of Jagged1 and NICD in epithelial ovarian carcinoma (5.3 +/- 2.4, 5.3 +/- 2.3)were higher than those in benign epithelial ovarian tumor (1.6 +/- 1.4, 3.1 +/- 1.7; all P < 0.01). The expression of Notch1, Jagged1 and NICD had no correlation with patients' aged, history of carcinoma, ascites, the level of serum CA125, maximum length of ovarian tumor, Federation International of Gynecology and Obstetrics (FIGO) stage, grade and pathology subtypes (all P > 0.05). The hazard ratio between the high expression of Notch1, Jagged1, or NICD and the moderate to low expression of Notch1, Jagged1, or NICD, and Jagged1 were 0.771, 1.648 and 1.316, respectively (all P > 0.05). The 5-year survival rate and median survival time between the high expression of Notch, Jagged1 or NICD in subgroup and moderate to low expression in subgroup were of no difference (all P > 0.05). The activity of gamma-secretase in SKOV3 was significantly higher than that in T29([ 12.2 +/- 1.4)%, P = 0.019]. (2) After DAPT treated, the relative activity of gamma secretase in SKOV3 (50 umol/L) was declined from (100.0 +/- 5.3)% to(6.6 +/- 0.8)% (P = 0.001). CONCLUSIONS: Jagged1 and NICD in Notch1 pathway may play a key role in the occurrence of ovarian carcinoma. The activity of gamma-secretase in epithelial ovarian carcinoma was higher than that in ovarian epithelial cell which suggest that DAPT, gamma-secretase inhibitor, may become the target of ovarian carcinoma treatment. PMID- 25537255 TI - Solvothermal synthesis of ZnO nanoparticles and anti-infection application in vivo. AB - Zinc oxide nanoparticles (ZnONPs) have been widely studied as the bacteriostatic reagents. However, synthesis of small ZnO nanoparticles with good monodispersion and stability in aqueous solution is still a challenge. Anti-infection research of ZnONPs used as antibacterial agent in vivo is rare. In this paper, a novel, sustainable, and simple method to synthesize ZnO nanoparticles with good monodispersion in aqueous low-temperature conditions and with a small molecule agent is reported. Inhibition zone test and the minimum inhibitory concentration test were performed to examine the antibacterial activity of ZnONPs against bacteria Staphylococcus aureus and Escherichia coli in vitro. For further application in vivo, low cytotoxicity and low acute toxicity in mice of ZnO were demonstrated. Finally, 4 nm ZnONPs combined with poly(vinyl alcohol) gel was used as antibacterial agent in rodent elytritis model, and significant anti-infection effect was proven. In one word, the present research would shed new light on the designing of antibacterial materials like ZnO with promising application in disinfection. PMID- 25537254 TI - Movement restriction does not modulate sensory and perceptual effects of exercise induced arm pain. AB - BACKGROUND: Movement restriction has been proposed as an important modulator of changes in sensory and perceptual function and motor imagery performance that are observed in musculoskeletal pain syndromes. There are no empirical data to support this view. PURPOSE: The primary objective of this experiment was to determine the effects of movement restriction on local and widespread sensory, perceptual and motor imagery changes after exercise-induced muscular pain. Further objectives were to investigate whether changes in sensory perception are correlated with pain intensity and tactile acuity or motor imagery performance. METHODS: In forty healthy volunteers, delayed onset muscle soreness (DOMS) of the non-dominant elbow flexors was induced using eccentric contractions until exhaustion. Participants were then randomised into two groups: a movement restriction group (wearing a sling) or a control group (not wearing a sling). Sensory and perceptual functions were measured using a range of sensory tests and a motor imagery performance task (left/right limb judgements). RESULTS: Movement restriction did not modulate any of the measures. We found concurrent mechanical hypoesthesia (p < 0.01), reduced tactile acuity (p = 0.02) and pressure hyperalgesia (p < 0.01) at the painful side. We found evidence of widespread pressure hyperalgesia. Impaired tactile acuity was associated with a decrease in pain threshold to pressure (r = -0.34, p = 0.03). Motor imagery performance was unchanged (p > 0.35) by pain or movement restriction. CONCLUSION: Short-term movement restriction did not influence local and widespread sensory changes induced by experimentally induced muscular pain. PMID- 25537256 TI - Optimizing early Go/No Go decisions in CNS drug development. AB - Go/No Go decisions concerning development of any single compound determine investment in increasingly costly studies from Phases I-III. Such decisions are problematic for CNS drug development where the variety of molecular targets in the brain have stimulated decades of studies without major therapeutic advances. Many costly studies do not even yield interpretable results as to whether the mechanism being pursued has therapeutic potential. Therefore, both industry and the public sector have implemented a decision making strategy based on whether a compound can test a molecular hypothesis of drug action. One requires, at a minimum, compelling evidence in humans that a compound both interacts with its presumed molecular targets in brain and ideally documents a CNS functional consequence of the interaction prior to efficacy studies. This strategy will much more quickly rule out ineffective mechanisms although it does not address the problem of poorly predictive models of novel CNS drug efficacy. PMID- 25537258 TI - Public Hospital Reform and the Principal Roles of Medical Staff. AB - During the reform of public hospitals, medical staff's enthusiasm and participation must be mobilized. In the positive factors, such as benefit, power, reputation, humanistic concern and satisfaction evaluation, benefit stands at the core position, power and reputation guides the medical staff's enthusiasm, and humanistic concern and satisfaction evaluation guarantees the enthusiasm of medical staff. By the institutionalized settings of benefit, power, reputation, and other factors, medical staffs of Xuzhou Central Hospital have been effectively mobilized, the development of hospital operates well, and the function of ensuring people health level regionally is further developed. PMID- 25537257 TI - Automated pancreatic cyst screening using natural language processing: a new tool in the early detection of pancreatic cancer. AB - INTRODUCTION: As many as 3% of computed tomography (CT) scans detect pancreatic cysts. Because pancreatic cysts are incidental, ubiquitous and poorly understood, follow-up is often not performed. Pancreatic cysts may have a significant malignant potential and their identification represents a 'window of opportunity' for the early detection of pancreatic cancer. The purpose of this study was to implement an automated Natural Language Processing (NLP)-based pancreatic cyst identification system. METHOD: A multidisciplinary team was assembled. NLP-based identification algorithms were developed based on key words commonly used by physicians to describe pancreatic cysts and programmed for automated search of electronic medical records. A pilot study was conducted prospectively in a single institution. RESULTS: From March to September 2013, 566,233 reports belonging to 50,669 patients were analysed. The mean number of patients reported with a pancreatic cyst was 88/month (range 78-98). The mean sensitivity and specificity were 99.9% and 98.8%, respectively. CONCLUSION: NLP is an effective tool to automatically identify patients with pancreatic cysts based on electronic medical records (EMR). This highly accurate system can help capture patients 'at-risk' of pancreatic cancer in a registry. PMID- 25537259 TI - Chronic spinal cord lesions respond positively to tranplants of mesenchymal stem cells. AB - PURPOSE: Despite substantial advances in surgical care and rehabilitation, the consequences of spinal cord injury (SCI) continue to present major challenges. Here we investigate whether transplantation of mesenchymal stem cells (MSCs) in mice during the chronic stage of SCI has benefits in terms of morphological and functional outcomes. METHODS: Mice were subjected to laminectomy at the T9 level, followed by a 1 minute spinal cord compression with a vascular clip. Four weeks later, 8 * 105 MSCs obtained from GFP mice were injected into the injury site. After eight weeks the analyses were performed. RESULTS: The spinal cords of MSC treated animals exhibited better white-matter preservation, greater numbers of fibers, higher levels of trophic factor expression, and better ultrastructural tissue organization. Furthermore, transplanted MSCs were not immunoreactive for neural markers, indicating that these cells mediate functional recovery through a paracrine effect, rather than by transforming into and replacing damaged glia in the spinal cord. MSC-treated mice also showed better functional improvement than control animals. CONCLUSION: We conclude that MSC-based cell therapy, even when applied during the chronic phase of SCI, leads to changes in a number of structural and functional parameters, all of which indicate improved recovery. PMID- 25537260 TI - Evidence-based implementation and increase in the rate of laparoscopic hysterectomy. PMID- 25537262 TI - Structural disordering of de-alloyed Pt bimetallic nanocatalysts: the effect on oxygen reduction reaction activity and stability. AB - Platinum bimetallic alloys are well-known for their ability to catalyze the oxygen reduction reaction (ORR) in proton exchange membrane fuel cells (PEMFCs). Pt(x)Co(1-x) colloidal nanoparticles were synthesized with varying initial Pt : Co ratios, but constant size to investigate how the initial metal composition affects their electrocatalytic performance. The results show that upon contact with acid environment the Co leaches out of the particles leading to almost identical compositions, independent of the initial differences. Surprisingly the data show a clear trend in ORR activity, although the Pt(x)Co(1-x) nanoparticles almost completely de-alloy during acid leaching, i.e. under reaction conditions in a fuel cell. To scrutinize the resulting particle structure after de-alloying we used pair distribution function (PDF) analysis and X-ray diffraction (XRD) gaining insight into the structural disorder and its dependence on the initial metal composition. Our results suggest that not only the ORR activity, but also the corrosion resistance of the synthesized NPs, are dependent on the structural disorder resulting from the de-alloying process. PMID- 25537264 TI - Child and adolescent psychiatry in Austria. PMID- 25537261 TI - The endocannabinoid system in renal cells: regulation of Na(+) transport by CB1 receptors through distinct cell signalling pathways. AB - BACKGROUND AND PURPOSE: The function of the endocannabinoid system (ECS) in renal tissue is not completely understood. Kidney function is closely related to ion reabsorption in the proximal tubule, the nephron segment responsible for the re absorption of 70-80% of the filtrate. We studied the effect of compounds modulating the activity of cannabinoid (CB) receptors on the active re-absorption of Na(+) in LLC-PK1 cells. EXPERIMENTAL APPROACH: Changes in Na(+) /K(+) -ATPase activity were assessed after treatment with WIN55,212-2 (WIN), a non-selective lipid agonist, and haemopressin (HP), an inverse peptide agonist at CB1 receptors. Pharmacological tools were used to investigate the signalling pathways involved in the modulation of Na(+) transport. KEY RESULTS: In addition to CB1 and CB2 receptors and TRPV1 channels, the mRNAs encoding for enzymes of the ECS were also expressed in LLC-PK1. WIN (10(-7) M) and HP (10(-6) M) altered Na(+) re-absorption in LLC-PK1 in a dual manner. They both acutely (after 1 min) increased Na(+) /K(+) -ATPase activity in a TRPV1 antagonist-sensitive way. WIN's stimulating effect persisted for 30 min, and this effect was partially blocked by a CB1 antagonist or a PKC inhibitor. In contrast, HP inhibited Na(+) /K(+) ATPase after 30 min incubation, and this effect was attenuated by a CB1 antagonist or a PKA inhibitor. CONCLUSION AND IMPLICATIONS: The ECS is expressed in LLC-PK1 cells. Both CB1 receptors and TRPV1 channels regulate Na(+) /K(+) ATPase activity in these cells, and are modulated by lipid and peptide CB1 receptor ligands, which act via different signalling pathways. PMID- 25537263 TI - Modelling trajectories of psychosomatic health complaints in children and adolescents: results of the BELLA study. AB - Psychosomatic health complaints (PHC) can significantly impair psychosocial development of children and adolescents and are therefore of considerable interest in health sciences and public health surveillance. Questions addressed the type of function that describes individual trajectories best, potential differences between these, and corresponding predictors from the perspective of both children and their parents. Based on the German population-based and representative BELLA cohort sample, 2,857 children and adolescents between 7 and 17 years of age at baseline were analysed over a period of 3 years with yearly follow-ups using mixed growth curve analyses. PHC were measured in accordance with the health behaviour in school-aged children-symptom checklist. The mean level of PHC was rather low, slightly lower for the parent report than for the self-report and significantly different between subjects. Concerning the parent report, the 2-year course is best described by a slowly increasing linear trend that decelerates somewhat over time. The increasing linear trend was more pronounced in the self-report from 11 to 17 years of age, but was significantly different for each subject and correlated with baseline scores. Trajectories could be explained by known predictors, most importantly by mental health problems of the child or adolescent. The results confirm the findings of previous studies and provide representative data about the individual short-term development of PHC in children and adolescents in Germany. PMID- 25537265 TI - Multivariate meta-analysis helps examine the impact of outcome reporting bias in Cochrane rheumatoid arthritis reviews. AB - OBJECTIVES: Outcome reporting bias (ORB) is a threat to validity of systematic reviews. Multivariate meta-analysis (MVMA) can potentially reduce the impact of ORB when outcomes are correlated. The aim of this study was to assess ORB in Cochrane systematic reviews of rheumatoid arthritis and to demonstrate how MVMA may examine its impact. STUDY DESIGN AND SETTING: Reviews were assessed for ORB in relation to eight outcomes for rheumatoid arthritis using a nine-point classification system. Impact of ORB was assessed by comparing estimates from univariate meta-analysis and MVMA models. RESULTS: ORB assessment was applied in 21 included reviews, and all contained missing data on at least one of the eight outcomes. ORB was highly suspected in 247 (22%) of the 1,118 evaluable outcomes from 155 assessable trials. MVMA and univariate results sometimes differed importantly. The maximum change in treatment effect estimate between MVMA and univariate meta-analysis approach was found to be 176% for one of the outcome considered. CONCLUSION: ORB has the potential to affect the conclusions in meta analyses. This could be avoided if trialists reported on all measured outcomes in full. If missing outcome data are unobtainable, MVMA is useful to examine the impact of missing outcomes and ORB on conclusions. PMID- 25537266 TI - Characterization of syringe-pump-driven induced pressure fluctuations in elastic microchannels. AB - We study pressure and flow-rate fluctuations in microchannels, where the flow rate is supplied by a syringe pump. We demonstrate that the pressure fluctuations are induced by the flow-rate fluctuations coming from mechanical oscillations of the pump motor. Also, we provide a mathematical model of the effect of the frequency of the pump on the normalized amplitude of pressure fluctuations and introduce a dimensionless parameter incorporating pump frequency, channel geometry and mechanical properties that can be used to predict the performance of different microfluidic device configurations. The normalized amplitude of pressure fluctuations decreases as the frequency of the pump increases and the elasticity of the channel material decreases. The mathematical model is verified experimentally over a range of typical operating conditions and possible applications are discussed. PMID- 25537267 TI - Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids. AB - Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9 yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good beta-amyloid (Abeta) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 MUM), affording good neuroprotection against toxic insults such as Abeta1-40 , Abeta1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 MUM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease. PMID- 25537268 TI - Antiproliferative glabretal-type triterpenoids from the root bark of Dictamnus dasycarpus. AB - Four new glabretal-type triterpenoids, dictabretols A-D (1-4), were isolated by activity-guided fractionation from the root bark of Dictamnus dasycarpus T. (Rutaceae) using an in vitro antiproliferative assay on T cells using splenocytes. The structures of these compounds were determined by spectroscopic methods, including 2D NMR experiments. Compounds were evaluated for their immunosuppressive activity on T cells and demonstrated inhibition of proliferation of activated T cells, up to IC50 of 1.5MUM. PMID- 25537269 TI - Synthesis and anti-biofilm activities of dihydro-pyrrol-2-one derivatives on Pseudomonas aeruginosa. AB - Biofilm formation is an important reason for bacterial resistance to antimicrobials. Many compounds with dihydro-pyrrol-2-one (DPO) have antibacterial effects. It is prospective to base on DPO skeleton to design new compounds for biofilm inhibition. DPO was designed by a novel method of tandem cyclization between ethyl glyoxalate and amines, the series of DPO derivatives were synthesized by change of the amines. Their activities were evaluated by the inhibition of biofilm in Pseudomonas aeruginosa. The interaction of DPO derivatives with mannitol dehydrogenase (MDH) or extracellular DNA (eDNA) in the biofilm was simulated by molecular docking to reveal possible mechanism. 19 new DPO derivatives were synthesized and identified, 15 of them had antibacterial activities, but only 5 of them had more than 50% inhibition on biofilm of P. aeruginosa at 50MUg/mL. The MDH activity and eDNA content in biofilm decreased significantly after treatment of the DPO derivatives in concentration dependence. The simulation reveals that strong interaction exists between the five DPO derivatives and MDH or eDNA, which are involved in anti-biofilm mechanism. The synthetic method of DPO derivatives is practical to provide effective anti biofilm agents for P. aeruginosa, and they take effect through inhibition on MDH and eDNA of biofilm. PMID- 25537270 TI - Sulfonamides as multifunctional agents for Alzheimer's disease. AB - Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Abeta self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Abeta self assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD. PMID- 25537271 TI - Synthesis, in vitro antimicrobial and cytotoxic activities of new carbazole derivatives of ursolic acid. AB - A series of new carbazole derivatives of ursolic acid were designed and synthesized in an attempt to develop potent antimicrobial or antitumor agents. Their structures were confirmed by using IR, HRMS and (1)H NMR analysis. All the synthesized compounds were evaluated for their antimicrobial activity against four bacterial and three fungal strains using serial dilution method. Compounds 3a, 3b, 4a, 4b and 5a-f exhibited significant antibacterial activity against at least one tested bacteria with MIC values of 3.9-15.6MUg/ml. In addition, the in vitro cytotoxicity of these compounds were also assayed against two human tumor cell lines (SMMC-7721 and HepG2) using MTT colorimetric method. From the results, compounds 5a-e and 5h displayed pronounced cytotoxic activity with IC50 values below 10MUM. Specially, compound 5e was found to be the most potent compound with IC50 values of 1.08+/-0.22 and 1.26+/-0.17MUM against SMMC-7721 and HepG2 cells, respectively, comparable to those of doxorubicin. In addition, compound 5e showed reduced cytotoxicity against noncancerous LO2 cells with IC50 value of 5.75+/ 0.48MUM. PMID- 25537273 TI - The effect of image quality and forensic expertise in facial image comparisons. AB - Images of perpetrators in surveillance video footage are often used as evidence in court. In this study, identification accuracy was compared for forensic experts and untrained persons in facial image comparisons as well as the impact of image quality. Participants viewed thirty image pairs and were asked to rate the level of support garnered from their observations for concluding whether or not the two images showed the same person. Forensic experts reached their conclusions with significantly fewer errors than did untrained participants. They were also better than novices at determining when two high-quality images depicted the same person. Notably, lower image quality led to more careful conclusions by experts, but not for untrained participants. In summary, the untrained participants had more false negatives and false positives than experts, which in the latter case could lead to a higher risk of an innocent person being convicted for an untrained witness. PMID- 25537272 TI - Structure-based design, synthesis and biological evaluation of novel beta secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand. AB - We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-beta-amino-l alanine as a novel P2 ligand. A number of inhibitors have displayed beta secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki=0.25nM, cellular EC50 of 194nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound beta secretase which revealed critical interactions in the active site. PMID- 25537276 TI - Discussion. PMID- 25537274 TI - Novel role for non-homologous end joining in the formation of double minutes in methotrexate-resistant colon cancer cells. AB - BACKGROUND: Gene amplification is a frequent manifestation of genomic instability that plays a role in tumour progression and development of drug resistance. It is manifested cytogenetically as extrachromosomal double minutes (DMs) or intrachromosomal homogeneously staining regions (HSRs). To better understand the molecular mechanism by which HSRs and DMs are formed and how they relate to the development of methotrexate (MTX) resistance, we used two model systems of MTX resistant HT-29 colon cancer cell lines harbouring amplified DHFR primarily in (i) HSRs and (ii) DMs. RESULTS: In DM-containing cells, we found increased expression of non-homologous end joining (NHEJ) proteins. Depletion or inhibition of DNA-PKcs, a key NHEJ protein, caused decreased DHFR amplification, disappearance of DMs, increased formation of micronuclei or nuclear buds, which correlated with the elimination of DHFR, and increased sensitivity to MTX. These findings indicate for the first time that NHEJ plays a specific role in DM formation, and that increased MTX sensitivity of DM-containing cells depleted of DNA-PKcs results from DHFR elimination. Conversely, in HSR-containing cells, we found no significant change in the expression of NHEJ proteins. Depletion of DNA PKcs had no effect on DHFR amplification and resulted in only a modest increase in sensitivity to MTX. Interestingly, both DM-containing and HSR-containing cells exhibited decreased proliferation upon DNA-PKcs depletion. CONCLUSIONS: We demonstrate a novel specific role for NHEJ in the formation of DMs, but not HSRs, in MTX-resistant cells, and that NHEJ may be targeted for the treatment of MTX resistant colon cancer. PMID- 25537275 TI - Gender differences in health status and adverse outcomes among patients with peripheral arterial disease. AB - BACKGROUND: Few studies have examined gender differences in health status and cardiovascular outcomes in patients with peripheral artery disease (PAD). This study assessed (1) self-reported health status at PAD diagnosis and 12-months later, and explored (2) whether outcomes in women with PAD differ with regard to long-term major adverse events. METHODS AND RESULTS: A total of 816 patients (285 women) with PAD were enrolled from 2 vascular clinics in the Netherlands. Baseline clinical data and subsequent adverse events were recorded and patients completed the Short Form-12 (SF-12, Physical Component Score [PCS] and Mental Component Score [MCS]) upon PAD diagnosis and 12-months later. Women had similar ages and clinical characteristics, but poorer socio-economic status and more depressive symptoms at initial diagnosis, as compared with men. Women also had poorer physical (PCS: 37+/-10 versus 40+/-10, P=0.004) and mental ( MCS: 47+/-12 versus 49+/-11, P=0.005) health status at the time of presentation. At 12-months, women still reported a poorer overall PCS score (41+/-12 versus 46+/-11, P=0.006) and MCS score (42+/-14 versus 49+/-12, P=0.002). Female gender was an independent determinant of a poorer baseline and 12-month PCS and MCS scores. However, there were no significant differences by gender on either mortality (unadjusted hazard ratio [HR]=0.93, 95% CI 0.60;1.44, P=0.74) or major adverse events (unadjusted HR=0.90, 95% CI 0.63;1.29, P=0.57), after a median follow-up of 3.2 years. CONCLUSIONS: Women's physical and mental health status is compromised both at initial PAD diagnosis and at 12-month follow-up, despite experiencing a similar magnitude of change in their health scores throughout the first 12-months after diagnosis. PMID- 25537278 TI - Burnout: evaluation of the efficacy and tolerability of TARGET 1(r) for professional fatigue syndrome (burnout). AB - OBJECTIVE: To study the effect of a dietary supplement (TARGET 1(r): a combination of casozepine, taurine, Eleutherococcus senticosus and extramel) on burnout symptomatology. METHODS: A 12-week, double-blind, randomized, placebo controlled trial was conducted in workers engaged in professional contact with patients, students or clients. All were affected by burnout syndrome based on a score of >=4 on the Burnout Measure Scale (BMS-10). The primary outcome measure was the change in the BMS-10 score; secondary outcome measures included the change in the Maslach's Burnout Inventory scale-Human Service Survey (MBI-HSS) score and the Beck Depression Inventory. Five scores were evaluated. RESULTS: Eighty-seven participants were enrolled in the study: 44 received the active formulation (verum group); 43 received placebo. After 12 weeks' supplementation, the placebo group showed significant improvements in scores for BMS-10, MBI-HSS fatigue and the Beck Depression Inventory, but MBI-HSS depersonalization and task management were not improved; the verum group showed significant improvements in all five scores. The verum group consistently showed significantly greater improvements in scores than the placebo group. CONCLUSIONS: TARGET 1(r) significantly improved the symptoms of burnout after 12 weeks' use. PMID- 25537279 TI - Company's attempt to switch its patients to a new drug is foiled. PMID- 25537277 TI - The contemporary management of renal artery aneurysms. AB - BACKGROUND: Renal artery aneurysms (RAAs) are rare, with little known about their natural history and growth rate or their optimal management. The specific objectives of this study were to (1) define the clinical features of RAAs, including the precise growth rate and risk of rupture, (2) examine the current management and outcomes of RAA treatment using existing guidelines, and (3) examine the appropriateness of current criteria for repair of asymptomatic RAAs. METHODS: A standardized, multi-institutional approach was used to evaluate patients with RAAs at institutions from all regions of the United States. Patient demographics, aneurysm characteristics, aneurysm imaging, conservative and operative management, postoperative complications, and follow-up data were collected. RESULTS: A total of 865 RAAs in 760 patients were identified at 16 institutions. Of these, 75% were asymptomatic; symptomatic patients had difficult to-control hypertension (10%), flank pain (6%), hematuria (4%), and abdominal pain (2%). The RAAs had a mean maximum diameter of 1.5 +/- 0.1 cm. Most were unilateral (96%), on the right side (61%), saccular (87%), and calcified (56%). Elective repair was performed in 213 patients with 241 RAAs, usually for symptoms or size >2 cm; the remaining 547 patients with 624 RAAs were observed. Major operative complications occurred in 10%, including multisystem organ failure, myocardial infarction, and renal failure requiring dialysis. RAA repair for difficult-to-control hypertension cured 32% of patients and improved it in 26%. Three patients had ruptured RAA; all were transferred from other hospitals and underwent emergency repair, with no deaths. Conservatively treated patients were monitored for a mean of 49 months, with no acute complications. Aneurysm growth rate was 0.086 cm/y, with no difference between calcified and noncalcified aneurysms. CONCLUSIONS: This large, contemporary, multi-institutional study demonstrated that asymptomatic RAAs rarely rupture (even when >2 cm), growth rate is 0.086 +/- 0.08 cm/y, and calcification does not protect against enlargement. RAA open repair is associated with significant minor morbidity, but rarely a major morbidity or mortality. Aneurysm repair cured or improved hypertension in >50% of patients whose RAA was identified during the workup for difficult-to control hypertension. PMID- 25537280 TI - Fluorescent in situ hybridization of pre-incubated blood culture material for the rapid diagnosis of histoplasmosis. AB - Fluorescence in situ hybridization (FISH) has been shown to be useful for the detection of Candida and Cryptococcus species in blood culture materials. FISH procedures for the detection of Histoplasma capsulatum var. capsulatum have not been reported so far. This study describes the development and evaluation of fluorescently labeled rRNA-targeting FISH probes to detect and identify H. capsulatum in blood cultures. All three analyzed H. capsulatum reference strains and clinical isolates showed positive signals with the newly designed specific oligonucleotide probes for H. capsulatum, whereas negative reactions were observed for all three nontarget yeast species and the two nontarget bacteria. The assay was also successfully applied for detections of H. capsulatum cells in pre-incubated blood culture samples of patients with clinical suspicion of histoplasmosis (n = 33). The described FISH-based assay was shown to be easy to apply, sensitive, and specific (compared to polymerase chain reaction) for the detection and identification of H. capsulatum in this proof-of-principle analysis. Larger multicentric assessments are recommended for a thorough diagnostic evaluation of the procedure. PMID- 25537282 TI - Cardiovascular fitness is associated with bias between self-reported and objectively measured physical activity. AB - The aim of this research study was to determine whether the level of agreement between self-reported and objective measures of physical activity (PA) is influenced by cardiovascular fitness. Participants (n = 113) completed the Global Physical Activity Questionnaire (GPAQ), a health risk assessment and a sub maximal 12-minute step test. Age-predicted VO2max was used to classify participants as lower fit and higher fit (HF). ActiGraph (GT3X) accelerometers were worn for 7 consecutive days. Matthews cut points were used to calculate minutes of moderate and vigorous PA (MVPA) per week. Bland-Altman plots were used to measure limits of agreement between GPAQ and ActiGraph MVPA. The participants' mean age was 37.9 +/- 12.7 years and more than 60% were categorised as HF (n = 71). Moderate PA was over-reported in 39% of all participants. Most of the over reporters for moderate PA were in the HF group (64.1%). Vigorous PA was over reported by 72.6% of all participants. The discrepancy between self-reported and objective measures of vigorous PA increased with increasing self-reported time spent in vigorous PA. Fitter individuals appear to over-report PA more than lesser fit participants, suggesting that fitness could influence the level of agreement between self-reported and objective measures of PA. PMID- 25537281 TI - Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes. AB - Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 * 10(-) (4). Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P < .05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 * 10(-) (8)). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 * 10(-) (5) to P = 9.40 * 10(-) (8). The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 * 10(-) (17)) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 * 10(-) (11)) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network. PMID- 25537284 TI - Speciation analysis of inorganic antimony in sediment samples from Sao Paulo Estuary, Bahia State, Brazil. AB - This paper proposes an extraction procedure for the speciation analysis of inorganic antimony in sediment samples using slurry sampling and hydride generation atomic absorption spectrometry. The optimization step of extraction of the species was performed employing a full two-level factorial design (2(3)) and a Box-Behnken matrix where the studied factors in both experiments were: extraction temperature, ultrasonic radiation time, and hydrochloric acid concentration. Using the optimized conditions, antimony species can be extracted in closed system using a 6.0 M hydrochloric acid solution at temperature of 70 degrees C and an ultrasonic radiation time of 20 min. The determination of antimony is performed in presence of 2.0 M hydrochloric acid solution using HG AAS by external calibration technique with limits of detection and quantification of 5.6 and 19.0 ng L(-1) and a precision expressed as relative standard deviation of 5.6 % for an antimony solution with concentration of 6.0 MUg L(-1). The accuracy of the method was confirmed by analysis of two certified reference materials of sediments. For a sample mass of sediment of 0.20 g, the limits of detection and quantification obtained were 0.70 and 2.34 ng g(-1), respectively. During speciation analysis, antimony(III) is determined in presence of citrate, while total antimony is quantified after reduction of antimony(V) to antimony(III) using potassium iodide and ascorbic acid. The method was applied for analysis of six sediment samples collected in Sao Paulo Estuary (Bahia State, Brazil). The antimony contents obtained varied from 45.3 to 89.1 ng g(-1) for total antimony and of 17.7 to 31.4 ng g(-1) for antimony(III). These values are agreeing with other data reported by the literature for this element in uncontaminated sediment samples. PMID- 25537283 TI - Potential risk assessment of polybrominated diphenyl ethers (PBDEs) by consuming animal-derived foods collected from interior areas of China. AB - Polybrominated diphenyl ethers (PBDEs) are one class of brominated flame retardants (BFRs). Although studies have reported the occurrence of PBDEs in freshwater fish species from several locations, to our best knowledge, there was no comprehensive data on PBDEs in foods of animal origin, such as pork, egg, and milk samples from interior areas of China, where pork and eggs are the major constituents of diet. The levels of PBDEs (BDE-28, 47, 99, 100, 153, 154, and 183) were determined in samples of animal-derived foods widely consumed by the population of Hubei in east-central China and the middle reaches of the Yangtze River. Two hundred six samples of animal-derived foods were randomly acquired in 17 sites of Hubei in 2010. The highest medium concentration of ?7PBDEs was found in chicken eggs (0.191 ng/g wet weight (ww)), followed by duck eggs (0.176 ng/g ww), pork (0.050 ng/g ww), carps (0.047 ng/g ww), and cow milk (0.013 ng/g ww). The estimated dietary intake of Sigma7PBDEs for a standard adult of 60 kg body weight based on medium and 95th percentile concentrations with consumption of animal-derived foods in Hubei province were 157.5 and 1960.3 pg/kg body weight/day, respectively. Chicken eggs (65.9 %) and pork (23.4 %) were the largest contributors to dietary intake of ?7PBDEs through animal-derived foods. The same PBDE sources were exposed in Hubei province via principal component analysis (PCA), and the particular congener profile in samples of animal-derived foods revealed the possible exposure history of octa-BDEs and penta-BDEs in the local region. The large margins of exposure (MOE) calculated following the European Food Safety Authority (EFSA) approach for three important congeners, BDE 47, BDE-99, and BDE-153, indicated that the estimated dietary exposures were unlikely to be a significant health concern to in Hubei. PMID- 25537285 TI - Effect of sample pretreatment on the fractionation of arsenic in anoxic soils. AB - Using by sequential extraction procedures to obtain the chemical forms of arsenic in soils can provide useful information for the assessment of arsenic mobility and bioavailability in soils. However, sample pretreatments before the extraction probably have some effects on the fractionation of arsenic in soils. Impact of sample pretreatments (freeze-drying, oven-drying, air-drying, and the fresh soil) on the fractionation of arsenic in anoxic soils was investigated in this study. The results show that there are some differences for arsenic fractions in soils between by drying pretreatments and by the fresh soil, indicating that the redistribution among arsenic fractions in anoxic soils occurs after drying pretreatments. The redistribution of arsenic fractions in anoxic soils is ascribed to the oxidation of organic matter and sulfides, the crystallization of iron (hydr)oxides, the ageing process, and the diffusion of arsenic into micropores. The freeze-drying is the best drying method to minimize the effect on the fractionation of arsenic in anoxic soils, while air-drying is the worst one. Drying pretreatments are not recommended for the fractionation of arsenic in anoxic soils with high concentration of iron. PMID- 25537286 TI - Do we underestimate the concentration of estriol in raw municipal wastewater? AB - The main source of natural estrogens to municipal wastewater is human excretions via urine or feces, thus their concentrations in raw wastewater should show positive linear relationship with their human excretions. This study mainly focused on their concentration relationship in raw wastewater. Based on comparison between chemical analyses and predictions through human excretion rates, the observed concentrations of estriol (E 3) in municipal wastewater were found to be noticeably lower than the predicted values. The main cause for the disparity is that substantial conjugated E 3 also exists in raw wastewater. This work suggested that monitoring both E 3 and its conjugates is necessary to get more accurate E 3 removal performance of wastewater treatment plants (WWTPs). PMID- 25537287 TI - Environmental quality indicators and financial development in Malaysia: unity in diversity. AB - Environmental quality indicators are crucial for responsive and cost-effective policies. The objective of the study is to examine the relationship between environmental quality indicators and financial development in Malaysia. For this purpose, the number of environmental quality indicators has been used, i.e., air pollution measured by carbon dioxide emissions, population density per square kilometer of land area, agricultural production measured by cereal production and livestock production, and energy resources considered by energy use and fossil fuel energy consumption, which placed an impact on the financial development of the country. The study used four main financial indicators, i.e., broad money supply (M2), domestic credit provided by the financial sector (DCFS), domestic credit to the private sector (DCPC), and inflation (CPI), which each financial indicator separately estimated with the environmental quality indicators, over a period of 1975-2013. The study used the generalized method of moments (GMM) technique to minimize the simultaneity from the model. The results show that carbon dioxide emissions exert the positive correlation with the M2, DCFC, and DCPC, while there is a negative correlation with the CPI. However, these results have been evaporated from the GMM estimates, where carbon emissions have no significant relationship with any of the four financial indicators in Malaysia. The GMM results show that population density has a negative relationship with the all four financial indicators; however, in case of M2, this relationship is insignificant to explain their result. Cereal production has a positive relationship with the DCPC, while there is a negative relationship with the CPI. Livestock production exerts the positive relationship with the all four financial indicators; however, this relationship with the CPI has a more elastic relationship, while the remaining relationship is less elastic with the three financial indicators in a country. Energy resources comprise energy use and fossil fuel energy consumption, both have distinct results with the financial indicators, as energy demand have a positive and significant relationship with the DCFC, DCPC, and CPI, while fossil fuel energy consumption have a negative relationship with these three financial indicators. The results of the study are of value to both environmentalists and policy makers. PMID- 25537288 TI - Occurrence of organotin compounds in river sediments under the dynamic water level conditions in the Three Gorges Reservoir Area, China. AB - The Three Gorges Project is the largest hydro project in the world, and the water level of the Three Gorges Reservoir (TGR) is dynamic and adjustable with the aim of flood control and electrical power generation. It is necessary to investigate the pollutants and their underlying contamination processes under dynamic water levels to determine their environmental behaviors in the Three Gorges Reservoir Area (TGRA). Here, we report the assessment of organotin compounds (OTs) pollution in the river sediments of the TGRA. Surface sediment samples were collected in the TGRA at low and high water levels. Tributyltin (TBT), triphenyltin (TPhT), and their degradation products in sediments were quantified by gas chromatography-mass spectrometry. Butyltins (BTs) and phenyltins (PhTs) were detected in sediments, and BTs predominated over PhTs in the whole study area under dynamic water level conditions. The concentrations of OTs in sediments varied markedly among locations, and significant concentrations were found in river areas with high levels of boat traffic and wastewater discharge. Sediments at all stations except Cuntan were lightly contaminated with TBT, and total organic carbon (TOC) was a significant factor affecting the fate of TBT in the TGRA. The butyltin and phenyltin degradation indices showed no recent inputs of TBT or TPhT into this region, with the exception of fresh TPhT input at Xiakou Town. Shipping activity, wastewater discharge, and agriculture are the most likely sources of OTs in the TGRA. PMID- 25537291 TI - Reaction to the short communication by Ghose et al. PMID- 25537289 TI - Prevalence, quantification, and typing of human adenoviruses detected in river water in Taiwan. AB - The prevalence of human adenoviruses (HAdV) in river waters was investigated in this study. Water samples were collected from 13 rivers in Taiwan, concentrated, and assessed for the presence of HAdVs using nested polymerase chain reaction (PCR). Human AdV positive samples were then subjected to real-time PCR (qPCR) to quantify the viral genomes and further subjected to primer-based genotyping to identify the various serotypes present. For each water sample, several water quality parameters were evaluated, including heterotrophic plate count, total coliform, Escherichia coli, water temperature, pH, conductivity, and dissolved oxygen. Among the 13 rivers examined, four rivers (30.8 %) were found to contain HAdVs. The major genotype was F species HAdV serotype 41. The mean HAdVs concentrations ranged from 6.10 * 10(2) to 8.51 * 10(2) copies/L. No significant differences were observed between the presence of HAdVs, and all of the water quality parameters evaluated (heterotrophic plate count, total coliform, E. coli, water temperature, pH, conductivity, and dissolved oxygen). Given the potential health risks posed by the presence of enteric viruses in environmental waters, further assessment is desirable with respect to possible sources, virus transport, and survival of viruses in the aquatic environment. PMID- 25537292 TI - Authors' reply. PMID- 25537294 TI - Association of EGF rs4444903 and XPD rs13181 polymorphisms with cutaneous melanoma in Caucasians. AB - Cutaneous melanoma (CM) is a malignant skin cancer with the high incidence in whiteskinned populations. Host genetic factors (such as: genes in nucleotide excision repair system or cell proliferation regulation system) interacted with ultraviolet radiation are potential reasons for CM. Previous studies about associations between CM and the rs4444903 (+61A>G) in the Epidermal growth factor gene (EGF) or rs13181 (+35931 A>C) in the xeroderma pigmentosum group D gene (XPD) have produced inconsistent results. To clarify these associations, metaanalyses of available candidate case-control association studies about Caucasians were performed. Data of each study were gathered according to the "Quality-Evaluation Score" (Ver.1.0). Finally, the meta-analysis with 2167 cases/4211 controls showed that the EGF rs4444903 had no significant association with CM (p>0.05), while the analysis with 3,492 cases/5,381 controls indicated the A allele of XPD rs13181 was significantly associated with CM (odds ratio= 0.93, 95% CI: 0.87-0.99; p=0.019). These results are also supported with linkage disequilibrium (LD) structure analysis. The current meta-analyses results suggest that the XPD gene, but not the EGF gene, has contributed to CM susceptibility, and XPD is a possible drug target. PMID- 25537295 TI - Knowledge about prevention and management of acute diarrhoea among caregivers of children aged under 5 years treated at an emergency department in Pernambuco, Brazil. AB - BACKGROUND: The World Health Organization stresses the need for training families in the adequate management of acute diarrhoea to reduce child mortality and morbidity. This study analysed caregiver knowledge about diarrhoea prevention and management in north-east Brazil. METHODS: Cross-sectional study of 213 children aged under 5 years treated at a public emergency department in Pernambuco, Brazil. Caregiver knowledge was assessed with a questionnaire. RESULTS: Caregivers believed that breastfeeding until age 6 months, not using tap water for food preparation, vaccination against rotavirus and other diseases help prevent diarrhoea. Regarding treatment, caregivers reported taking children to the hospital at the first sign of diarrhoea (57.3%), administering medication (68.1%) and withholding solids (63.7%). Only 40.8% knew how to prepare oral rehydration solution; 78.4% believed it could cure diarrhoea. Only 43.9% of caregivers mentioned one or more signs of dehydration. CONCLUSIONS: Caregivers in this region had limited knowledge of appropriate diarrhoea management. PMID- 25537296 TI - Transport of sick neonates to a tertiary care hospital, South India: condition at arrival and outcome. AB - OBJECTIVE: To describe the transport of sick neonates to a tertiary care hospital and evaluate their condition at arrival and outcome. METHODS: This descriptive study included 303 extramural neonates who were transported to a tertiary care hospital in south India. Demographic parameters, transport details and clinical features at arrival were recorded. All neonates were followed up till discharge or death. Transport and clinical variables were correlated with outcome. RESULTS: Sepsis and birth asphyxia were the major indications for transport. Only 11% were transported by 108 ambulances (free government service). One-fifth of all neonates died and among them 76% were hypothermic and 10% hypoglycemic on admission. Prematurity, pregnancy induced hypertension (PIH), prolonged rupture of membranes (PROM), respiratory distress, grunting, bleeding, abdominal distension and a positive blood culture correlated with a poor outcome. CONCLUSION: Stabilisation prior to transport is essential and the principles of neonatal transportation are independent of distance. Hypothermia and hypoglycaemia should be prevented in neonates during transport as they adversely affect the outcome. PMID- 25537298 TI - Side-to-Side Jejunoileal Bypass Induces Better Glucose-Lowering Effect than End to-Side Jejunoileal Bypass on Nonobese Diabetic Rats. AB - BACKGROUND: Jejunoileal bypass (JIB) can markedly ameliorate diabetes in obese patients and rodents. The aim of this study is to systematically evaluate the role of the operational manner and the retained distal small bowel length in mediating changes in glucose homeostasis after intestinal bypass surgeries in nonobese diabetic rats. METHODS: Streptozotocin-induced diabetic rats underwent side-to-side jejunoileal bypass plus proximal loop ligation (SSJIBL), end-to-side jejunoileal bypass (ESJIB), proximal small bowel resection (PBR), and sham operation. Each operational manner included two subgroups, in which 30 cm (L-30) or 40 cm (L-40) distal small bowel was retained. Main outcome measures were fasting blood glucose levels (FBG), insulin sensitivity, serum insulin, glucagon like peptide-1 (GLP-1), bilirubin (BIL), and total bile acids (TBA) levels. RESULTS: Global food intake in the sham group was higher than in the operation groups, and global body weight and food intake in the SSJIBL group were higher than in the ESJIB and PBR groups. Global body weight and food intake in L-40 group were higher than in L-30 group. The SSJIBL procedure induced better improvement in glucose homeostasis and insulin sensitivity than the ESJIB and PBR procedures, and L-30 group showed better antidiabetic effects than L-40 group. Serum GLP-1, BIL, and TBA levels in SSJIBL group were higher than in ESJIB and PBR groups. CONCLUSIONS: This study shows that side-to-side jejunoileal bypass induced better glucose-lowering effects than end-to-side jejunoileal bypass and proximal small bowel resection, and intestinal bypass surgery that retained shorter distal small bowel yielded better antidiabetic effects. PMID- 25537297 TI - Bariatric Surgery or Non-Surgical Weight Loss for Obstructive Sleep Apnoea? A Systematic Review and Comparison of Meta-analyses. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is a well-recognised complication of obesity. Non-surgical weight loss (medical, behavioural and lifestyle interventions) may improve OSA outcomes, although long-term weight control remains challenging. Bariatric surgery offers a successful strategy for long-term weight loss and symptom resolution. OBJECTIVES: To comparatively appraise bariatric surgery vs. non-surgical weight loss interventions in OSA treatment utilising body mass index (BMI) and apnoea-hypopnoea index (AHI) as objective measures of weight loss and apnoea severity. METHODS: A systematic literature review revealed 19 surgical (n = 525) and 20 non-surgical (n = 825) studies reporting the primary endpoints of BMI and AHI before and after intervention. Data were meta-analysed using random effects modelling. Subgroup analysis, quality scoring and risk of bias were assessed. RESULTS: Surgical patients had a mean pre-intervention BMI of 51.3 and achieved a significant 14 kg/m(2) weighted decrease in BMI (95%CI [11.91, 16.44]), with a 29/h weighted decrease in AHI (95%CI [22.41, 36.74]). Non-surgical patients had a mean pre-intervention BMI of 38.3 and achieved a significant weighted decrease in BMI of 3.1 kg/m(2) (95%CI [2.42, 3.79]), with a weighted decrease in AHI of 11/h (95%CI [7.81, 14.98]). Heterogeneity was high across all outcomes. CONCLUSIONS: Both bariatric surgery and non-surgical weight loss may have significant beneficial effects on OSA through BMI and AHI reduction. However, bariatric surgery may offer markedly greater improvement in BMI and AHI than non-surgical alternatives. Future studies must address the lack of randomised controlled and comparative trials in order to confirm the exact relationship between metabolic surgery and non-surgical weight loss interventions in OSA resolution. PMID- 25537299 TI - Metal-on-metal hip resurfacing: correlation between clinical and radiological assessment, metal ions and ultrasound findings. AB - PURPOSE: We report the clinical, radiological and wear analysis of 52 consecutive MoM hip resurfacings (performed on 49 younger patients) to a mean follow-up of 9.2 years. METHODS: Every patient underwent X-ray and clinical evaluation (HHS). Ultrasonography of the hip was performed in all patients in order to identify possible cystic or solid mass in periprosthetic tissue. In case of mass >20 mm, further MRI was performed to better analyse the characteristics of lesion. RESULTS: Five patients (five hips) had a revision. The overall survival rate was 90.38 %. The average HHS at follow-up examination was 95.5 points. No progressive radiolucent areas and no sclerosis or osteolysis around the implants were found. The US and RMI imaging showed a pseudotumour formation in two patients (correlated with high metal ion levels in blood and urine), both asymptomatic. CONCLUSION: A significant positive correlation between inclination of the acetabular component and serum metal ion levels was found (r = 0.64 and r = 0.62 for cobalt and chromium, respectively). PMID- 25537300 TI - Resilience of Penicillium resedanum LK6 and exogenous gibberellin in improving Capsicum annuum growth under abiotic stresses. AB - Understanding how endophytic fungi mitigate abiotic stresses in plants will be important in a changing global climate. A few endophytes can produce phytohormones, but their ability to induce physiological changes in host plants during extreme environmental conditions are largely unexplored. In the present study, we investigated the ability of Penicillium resedanum LK6 to produce gibberellins and its role in improving the growth of Capsicum annuum L. under salinity, drought, and heat stresses. These effects were compared with exogenous application of gibberellic acid (GA3). Endophyte treatment significantly increased shoot length, biomass, chlorophyll content, and the photosynthesis rate compared with the uninfected control during abiotic stresses. The endophyte and combined endophyte + GA3 treatments significantly ameliorated the negative effects of stresses compared with the control. Stress-responsive endogenous abscisic acid and its encoding genes, such as zeaxanthin epoxidase, 9-cis epoxycarotenoid dioxygenase 3, and ABA aldehyde oxidase 3, were significantly reduced in endophyte-treated plants under stress. Conversely, salicylic acid and biosynthesis-related gene (isochorismate synthase) had constitutive expressions while pathogenesis related (PR1 and PR5) genes showed attenuated responses during endophyte treatment under abiotic stresses. The present findings suggest that endophytes have effects comparable to those of exogenous GA3; both can significantly increase plant growth and yield under changing environmental conditions by reprogramming the host plant's physiological responses. PMID- 25537301 TI - Natural borneol enhances bisdemethoxycurcumin-induced cell cycle arrest in the G2/M phase through up-regulation of intracellular ROS in HepG2 cells. AB - Bisdemethoxycurcumin (BDCur) has been found widely in foods such as cheese, butter, etc., and in curry (powder) as a spice. It has been reported to possess anticancer activity. However, its poor absorption limited its application. Natural borneol (NB) has been used as a promoter of drug absorption and widely used in candies, beverages, baked goods, chewing gum and other foods. Thus, we investigated whether NB could potentiate the cellular uptake of BDCur, and elucidated the molecular mechanisms of their combined inhibitory effects on HepG2 cells. Our results demonstrate that NB significantly enhanced the cellular uptake of BDCur. Induction of cell cycle arrest in HepG2 cells by NB and BDCur in combination was evidenced by accumulation of the G2/M cell population. Further investigation on the molecular mechanism showed that NB and BDCur in combination resulted in a significant decrease in the expression level of Cdc2 and cyclin B. Moreover, studies also found that ROS acted as an upstream mediator in NB/BDCur induced HepG2 cell growth inhibition and led to DNA damage with up-regulation of the expression level of phosphorylated ATM and p53. Our findings suggest that the strategy of using NB and BDCur in combination may have promising potential applications in cancer chemoprevention. PMID- 25537304 TI - Reactivity of inorganic sulfide species toward a heme protein model. AB - The reactivity of inorganic sulfide species toward heme peptides was explored under biorelevant conditions in order to unravel the molecular details of the reactivity of the endogenous hydrogen sulfide toward heme proteins. Unlike ferric porphyrinates, which are reduced by inorganic sulfide, some heme proteins can form stable Fe(III)-sulfide adducts. To isolate the protein factors ruling the redox chemistry, we used as a system model, the undecapeptide microperoxidase (MP11), a heme peptide derived from cytochrome c proteolysis that retains the proximal histidine bound to the Fe(III) atom. Upon addition of gaseous hydrogen sulfide (H2S) at pH 6.8, the UV-vis spectra of MP11 closely resembled those of the low-spin ferric hydroxo complex (only attained at an alkaline pH) and cysteine or alkylthiol derivatives, suggesting that the Fe(III) reduction was prevented. The low-frequency region of the resonance Raman spectrum revealed the presence of an Fe(III)-S band at 366 cm(-1) and the general features of a low spin hexacoordinated heme. Anhydrous sodium sulfide (Na2S) was the source of sulfide of choice for the kinetic evaluation of the process. Theoretical calculations showed no distal stabilization mechanisms for bound sulfide species in MP11, highlighting a key role of the proximal histidine for the stabilization of the Fe(III)-S adducts of heme compounds devoid of distal counterparts, which is significant with regard to the biochemical reactivity of endogenous hydrogen sulfide. PMID- 25537303 TI - Evaluation of the effect of orally administered acid suppressants on intragastric pH in cats. AB - BACKGROUND: Acid suppressant drugs are a mainstay of treatment for cats with gastrointestinal erosion and ulceration. However, clinical studies have not been performed to compare the efficacy of commonly PO administered acid suppressants in cats. HYPOTHESIS/OBJECTIVES: To compare the effect of PO administered famotidine, fractionated omeprazole tablet (fOT), and omeprazole reformulated paste (ORP) on intragastric pH in cats. We hypothesized that both omeprazole formulations would be superior to famotidine and placebo. ANIMALS: Six healthy adult DSH colony cats. METHODS: Utilizing a randomized, 4-way crossover design, cats received 0.88-1.26 mg/kg PO q12h fOT, ORP, famotidine, and placebo (lactose capsules). Intragastric pH monitoring was used to continuously record intragastric pH for 96 hours beginning on day 4 of treatment. Plasma omeprazole concentrations at steady state (day 7) were determined by high performance liquid chromatography (HPLC) with ultraviolet detection. Mean percentage time that intragastric pH was >= 3 and >= 4 were compared among groups using ANOVA with a posthoc Tukey-Kramer test (alpha = 0.05). RESULTS: The mean percentage time +/- SD that intragastric pH was >= 3 was 68.4 +/- 35.0% for fOT, 73.9 +/- 23.2% for ORP, 42.8 +/- 18.6% for famotidine, and 16.0 +/- 14.2% for placebo. Mean +/- SD plasma omeprazole concentrations were similar in cats receiving fOT compared to those receiving ORP and in a range associated with acid suppression reported in other studies. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that both omeprazole formulations provide superior acid suppression in cats compared to famotidine or placebo. Fractionated enteric-coated OT is an effective acid suppressant despite disruption of the enteric coating. PMID- 25537302 TI - Nucleoside diphosphate kinases (NDPKs) in animal development. AB - In textbooks of biochemistry, nucleoside diphosphate conversion to a triphosphate by nucleoside diphosphate 'kinases' (NDPKs, also named NME or NM23 proteins) merits a few lines of text. Yet this essential metabolic function, mediated by a multimeric phosphotransferase protein, has effects that lie beyond a simple housekeeping role. NDPKs attracted more attention when NM23-H1 was identified as the first metastasis suppressor gene. In this review, we examine these NDPK enzymes from a developmental perspective because of the tractable phenotypes found in simple animal models that point to common themes. The data suggest that NDPK enzymes control the availability of surface receptors to regulate cell sensing cues during cell migration. NDPKs regulate different forms of membrane enclosure that engulf dying cells during development. We suggest that NDPK enzymes have been essential for the regulated uptake of objects such as bacteria or micronutrients, and this evolutionarily conserved endocytic function contributes to their activity towards the regulation of metastasis. PMID- 25537307 TI - Abstracts of the Interventionell Radilogisches Olbert Symposium 2015, January 15 17, 2015, Berlin, Germany. PMID- 25537306 TI - Open abdomen with concomitant enteroatmospheric fistula: attempt to rationalize the approach to a surgical nightmare and proposal of a clinical algorithm. PMID- 25537305 TI - Texture analysis of preoperative CT images for prediction of postoperative hepatic insufficiency: a preliminary study. AB - BACKGROUND: Texture analysis is a promising method of analyzing imaging data to potentially enhance diagnostic capability. This approach involves automated measurement of pixel intensity variation that may offer further insight into disease progression than do standard imaging techniques alone. We postulated that postoperative liver insufficiency, a major source of morbidity and mortality, correlates with preoperative heterogeneous parenchymal enhancement that can be quantified with texture analysis of cross-sectional imaging. STUDY DESIGN: A retrospective case-matched study (waiver of informed consent and HIPAA authorization, approved by the Institutional Review Board) was performed comparing patients who underwent major hepatic resection and developed liver insufficiency (n = 12) with a matched group of patients with no postoperative liver insufficiency (n = 24) by procedure, remnant volume, and year of procedure. Texture analysis (with gray-level co-occurrence matrices) was used to quantify the heterogeneity of liver parenchyma on preoperative CT scans. Statistical significance was evaluated using Wilcoxon's signed rank and Pearson's chi-square tests. RESULTS: No statistically significant differences were found between study groups for preoperative patient demographics and clinical characteristics, with the exception of sex (p < 0.05). Two texture features differed significantly between the groups: correlation (linear dependency of gray levels on neighboring pixels) and entropy (randomness of brightness variation) (p < 0.05). CONCLUSIONS: In this preliminary study, the texture of liver parenchyma on preoperative CT was significantly more varied, less symmetric, and less homogeneous in patients with postoperative liver insufficiency. Therefore, texture analysis has the potential to provide an additional means of preoperative risk stratification. PMID- 25537308 TI - Medium-Term Outcomes Following Endovascular Repair of Infrarenal Abdominal Aortic Aneurysms with an Unfavourable Proximal Neck. AB - PURPOSE: The purpose of this study was to evaluate medium-term outcomes following endovascular repair of abdominal aortic aneurysms (EVAR) with unfavourable neck anatomy using stent grafts with a 36 mm or larger proximal diameter. MATERIALS AND METHODS: A retrospective review of 27 patients who underwent elective EVAR between 2006 and 2008 using a stent graft with a 36 mm or larger proximal diameter was carried out. All patients had computed tomography angiography (CTA) for procedure planning, and detailed assessment of the aneurysm neck was performed using a three-dimensional CTA workstation. Patients were followed up with CTA at 3 and 12 months and annual duplex thereafter. RESULTS: The median aneurysm diameter was 7 cm, and the median aneurysm neck diameter was 31 mm. Cook Zenith stent grafts were used in all patients, with a proximal diameter of 36 mm (n = 25) and 40 mm (n = 2). Primary and assisted primary technical success rates were 74 and 93%, respectively. The follow-up period ranged from 62 to 84 months, with a median of 72 months. 15 patients died during follow-up. Two patients died from aortic rupture, and the remaining patients died from cardiac disease (n = 4), chest sepsis (n = 6), cancer (n = 2) and renal failure (n = 1). Complications included type I endoleak (n = 5), limb occlusion (n = 2), limb stenosis (n = 2), limb kinking (n = 1), dissection of an artery (n = 1), occlusion of a femorofemoral cross-over graft (n = 1) and poor attachment of a distal limb (n = 1). CONCLUSIONS: EVAR using stent grafts in the presence of an unfavourable neck has a high risk of complications. Medium-term survival in this group is low but mainly due to patient co-morbidities. PMID- 25537309 TI - Percutaneous Irreversible Electroporation of a Large Centrally Located Hepatocellular Adenoma in a Woman with a Pregnancy Wish. AB - Irreversible electroporation (IRE) is a novel image-guided ablation technique that is rapidly gaining popularity in the treatment of malignant liver tumors located near large vessels or bile ducts. We describe a 28-year-old female patient with a 5 cm large, centrally located hepatocellular adenoma who wished to get pregnant. Regarding the risk of growth and rupture of the adenoma caused by hormonal changes during pregnancy, treatment of the tumor was advised prior to pregnancy. However, due to its central location, the tumor was considered unsuitable for resection and thermal ablation. Percutaneous CT-guided IRE was performed without complications and led to rapid and impressive tumor shrinkage. Subsequent pregnancy and delivery went uncomplicated. This case report suggests that the indication for IRE may extend to the treatment of benign liver tumors that cannot be treated safely otherwise. PMID- 25537310 TI - Radioembolization dosimetry: the road ahead. AB - Methods for calculating the activity to be administered during yttrium-90 radioembolization (RE) are largely based on empirical toxicity and efficacy analyses, rather than dosimetry. At the same time, it is recognized that treatment planning based on proper dosimetry is of vital importance for the optimization of the results of RE. The heterogeneous and often clustered intrahepatic biodistribution of millions of point-source radioactive particles poses a challenge for dosimetry. Several studies found a relationship between absorbed doses and treatment outcome, with regard to both toxicity and efficacy. This should ultimately lead to improved patient selection and individualized treatment planning. New calculation methods and imaging techniques and a new generation of microspheres for image-guided RE will all contribute to these improvements. The aim of this review is to give insight into the latest and most important developments in RE dosimetry and to suggest future directions on patient selection, individualized treatment planning, and study designs. PMID- 25537311 TI - Computed bipolar precordial leads for improved P wave detection. AB - We present an excerpt from a 24-hour 12-lead Holter recording acquired in an 85 year-old man investigated for the Brugada syndrome. The rhythm cannot be determined because no P waves can be discerned due to the high level of noise and to merging of the T and P waves. The P waves, however, are clearly visible and the noise is considerably reduced in bipolar precordial leads computed from the standard unipolar precordial leads. The case demonstrates the potential usefulness of various computed leads for rhythm analysis by detecting P waves that are not visible in the standard leads. PMID- 25537312 TI - The EKG in hypothermia and hyperthermia. AB - Hypothermia and hyperthermia are relatively common clinical conditions that are associated with significant morbidity and mortality, especially if not promptly recognized and treated. Both of these conditions associated with extreme alterations in core body temperatures can be accompanied by alteration in cardiac function, often with manifest EKG changes. However, some of the EKG changes associated with hypothermia and heat stroke are non-specific and lead to diagnostic dilemmas. We here present 2 clinical cases, one each for hypothermia and hyperthermia to describe the EKG changes associated with these clinical conditions. We also present a review of available literature on these subjects. PMID- 25537314 TI - The Long Way From Government Open Data to Mobile Health Apps: Overcoming Institutional Barriers in the US Federal Government. AB - BACKGROUND: Government agencies in the United States are creating mobile health (mHealth) apps as part of recent policy changes initiated by the White House's Digital Government Strategy. OBJECTIVE: The objective of the study was to understand the institutional and managerial barriers for the implementation of mHealth, as well as the resulting adoption pathways of mHealth. METHODS: This article is based on insights derived from qualitative interview data with 35 public managers in charge of promoting the reuse of open data through Challenge.gov, the platform created to run prizes, challenges, and the vetting and implementation of the winning and vendor-created apps. RESULTS: The process of designing apps follows three different pathways: (1) entrepreneurs start to see opportunities for mobile apps, and develop either in-house or contract out to already vetted Web design vendors; (2) a top-down policy mandates agencies to adopt at least two customer-facing mobile apps; and (3) the federal government uses a policy instrument called "Prizes and Challenges", encouraging civic hackers to design health-related mobile apps using open government data from HealthData.gov, in combination with citizen needs. All pathways of the development process incur a set of major obstacles that have to be actively managed before agencies can promote mobile apps on their websites and app stores. CONCLUSIONS: Beyond the cultural paradigm shift to design interactive apps and to open health-related data to the public, the managerial challenges include accessibility, interoperability, security, privacy, and legal concerns using interactive apps tracking citizen. PMID- 25537315 TI - A highly selective copper-indium bimetallic electrocatalyst for the electrochemical reduction of aqueous CO2 to CO. AB - The challenge in the electrochemical reduction of aqueous carbon dioxide is in designing a highly selective, energy-efficient, and non-precious-metal electrocatalyst that minimizes the competitive reduction of proton to form hydrogen during aqueous CO2 conversion. A non-noble metal electrocatalyst based on a copper-indium (Cu-In) alloy that selectively converts CO2 to CO with a low overpotential is reported. The electrochemical deposition of In on rough Cu surfaces led to Cu-In alloy surfaces. DFT calculations showed that the In preferentially located on the edge sites rather than on the corner or flat sites and that the d-electron nature of Cu remained almost intact, but adsorption properties of neighboring Cu was perturbed by the presence of In. This preparation of non-noble metal alloy electrodes for the reduction of CO2 provides guidelines for further improving electrocatalysis. PMID- 25537313 TI - Usability study of the EduMod eLearning Program for contouring nodal stations of the head and neck. AB - PURPOSE: A major strategy for improving radiation oncology education and competence evaluation is to develop eLearning programs that reproduce the real work environment. A valuable measure of the quality of an eLearning program is "usability," which is a multidimensional endpoint defined from the end user's perspective. The gold standard for measuring usability is the Software Usability Measurement Inventory (SUMI). The purpose of this study is to use the SUMI to measure usability of an eLearning course that uses innovative software to teach and test contouring of nodal stations of the head and neck. METHODS AND MATERIALS: This is a prospective institutional review board-approved study in which all participants gave written informed consent. The study population was radiation oncology residents from 8 different programs across the United States. The subjects had to pass all sections of the same 2 eLearning modules and then complete the SUMI usability evaluation instrument. We reached the accrual goal of 25 participants. Usability results for the EduMod eLearning course, "Nodal Stations of the Head and Neck," were compared with a large database of scores of other major software programs. Results were evaluated in 5 domains: Affect, Helpfulness, Control, Learnability, and Global Usability. RESULTS: In all 5 domains, usability scores for the study modules were higher than the database mean and statistically superior in 4 domains. CONCLUSIONS: This is the first study to evaluate usability of an eLearning program related to radiation oncology. Usability of 2 representative modules related to contouring nodal stations of the head and neck was highly favorable, with scores that were superior to the industry standard in multiple domains. These results support the continued development of this type of eLearning program for teaching and testing radiation oncology technical skills. PMID- 25537316 TI - Amyloid-like conformation and interaction for the self-assembly in barnacle underwater cement. AB - Barnacles are unique marine sessile crustaceans and permanently attach to various foreign surfaces during most of their lifespan. The protein complex secreted from their body and used to attach their calcareous shell to almost all surfaces in water has long fascinated us because we have limited technology with which to attach materials in water. Unraveling the mechanism of underwater attachment by barnacles is thus important for interface science, for the understanding of the biology and physiology of barnacles, and for the development of technology to prevent fouling. Previous studies have indicated that the intermolecular interactions optimized by conformations of the adhesive proteins are crucial in the self-assembly and/or curing of the adhesive. This study aimed to identify the possible structural determinants responsible for the self-assembly. Thioflavin T binding screening of peptides designed on the basis of the primary structure of a bulk 52 kDa cement protein indicated the presence of some amyloidogenic motifs in the protein. The conformation of the peptide was transformed to a beta-sheet by an increase in either pH or ionic strength, resulting in its self-assembly. Thioflavin T binding was inhibited by small polyphenolic molecules, suggesting the contribution of aromatic interactions during self-assembly. The occurrence of amyloid-like units in the protein implies that the protein conformation is an important factor contributing to the self-assembly of the cement, the first event of the curing, as the adhesive material is secreted into the seawater out of the animal's body. PMID- 25537318 TI - Ultrasound-guided stellate ganglion blocks combined with pharmacological and occupational therapy in Complex Regional Pain Syndrome (CRPS): a pilot case series ad interim. AB - OBJECTIVE: This preliminary and retrospective pilot case series examines a treatment concept consisting of ultrasound-guided stellate ganglion blocks (SGBs) combined with pharmacological and occupational therapy in patients with complex regional pain syndrome (CRPS) of the hand. Efficacy of combined treatment concepts and safety of ultrasound-guided SGB have not been sufficiently investigated yet. METHODS: A total number of 156 blocks were evaluated in 16 patients with CRPS in a retrospective analysis. All patients received pharmacotherapy and a standard regimen of occupational therapy offered simultaneously to the SGBs. Changes in both spontaneous and evoked pain levels were assessed by numerical pain rating score before and after the last blockade of a series. Side effects were documented. RESULTS: The overall mean pain reduction was 63.2% regarding spontaneous and 45.3% regarding evoked pain. Mild complications, such as hoarseness or dysphagia, occurred in 13.5% of the blocks (21 SGBs). Serious complications, such as plexus paresis or accidental puncture of vessels or other structures, did not occur. Time between symptom onset and start of treatment did not affect the extent of pain reduction. CONCLUSIONS: The combination of ultrasound-guided SGB and simultaneous pharmacological and occupational therapy showed encouraging treatment results under conditions of this pilot case series. Assessment of efficacy of this combined treatment concept and safety of ultrasound-guided SGB require further prospective clinical studies with larger number of participants. PMID- 25537320 TI - Remaining relevant. PMID- 25537321 TI - Artistry of peer review. PMID- 25537322 TI - AORN Surgical Conference & Expo 2015 speaker interviews. PMID- 25537328 TI - Guideline implementation: preoperative patient skin antisepsis. AB - Performing preoperative skin antisepsis to remove soil and microorganisms at the surgical site may help prevent patients from developing a surgical site infection. The updated AORN "Guideline for preoperative skin antisepsis" addresses the topics of preoperative patient bathing and hair removal, selection and application of skin antiseptics, and safe handling, storage, and disposal of skin antiseptics. This article focuses on key points of the guideline to help perioperative personnel develop protocols for patient skin antisepsis. The key points include the need for the patient to take a preoperative bath or shower and the need for perioperative personnel to manage hair at the surgical site, select a safe and effective antiseptic for the individual patient, perform a safe preoperative surgical site prep, and appropriately store skin antiseptics. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 25537329 TI - Symptomatic spinal epidural hematoma after lumbar spine surgery: the importance of diagnostic skills. AB - Symptomatic spinal epidural hematoma (SEH) is a rare but serious complication that may occur after lumbar spine surgery. Prompt recognition of this complication depends on the diagnostic skills of perioperative nursing personnel, particularly postanesthesia care unit nurses. Analysis of a composite of patients undergoing spinal surgery suggests that neurological and functional outcomes of patients with symptomatic lumbar SEH often depend on the time interval between symptom onset and surgical evacuation of the hematoma. Clinicians should consider a diagnosis of symptomatic SEH if there is a change in the patient's neurological status during the first several hours after lumbar spine surgery. Suspicion of postoperative symptomatic SEH should prompt clinicians to notify the responsible surgeon without delay. PMID- 25537330 TI - The efficacy of preemptive analgesia for postoperative pain control: a systematic review of the literature. AB - The purpose of preemptive analgesia is to reduce postoperative pain, contributing to a more comfortable recovery period and reducing the need for narcotic pain control. The efficacy of preemptive analgesia remains controversial. This systematic review of the literature evaluated the efficacy of nonsteroidal anti inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, and gabapentin as preemptive oral analgesics for surgical patients. Included articles were limited to studies of adult patients that compared the difference in postoperative pain between control and treatment groups. Of 40 studies reviewed, 14 met the inclusion criteria, including two on NSAIDs, four on COX-2 inhibitors, and eight on gabapentin. Research was predominantly conducted outside the United States. Gabapentin and COX-2 inhibitors were found to be the most effective preemptive analgesics for postoperative pain control. As part of a collaborative team, perioperative nurses and certified RN anesthetists are responsible for ongoing pain assessment and management for preemptive analgesic interventions. PMID- 25537331 TI - Back to basics: implementing evidence-based practice. AB - As health care transitions from volume-based care to value-based care, it is imperative that perioperative nurses implement evidence-based practices that support effective care. Implementing evidence-based practice is a challenge but improves patient outcomes, standardizes care, and decreases patient care costs. Understanding how care interventions work and how to implement them is important to compete in today's health care market. This "Back to Basics" article discusses how to identify, review, and appraise research; make recommendations to implement new practices; evaluate the outcomes of the implementations; and make necessary changes to facilitate evidence-based practice. PMID- 25537332 TI - Nursing shortages in the OR: solutions for new models of education. AB - The professional literature predicts worldwide perioperative nursing shortages. Compounding this is the absence of perioperative curricula in most nursing programs, which reduces new graduate interest in and awareness of employment opportunities in the OR environment. Educators at a university and a large hospital system formed an innovative partnership to create a pilot undergraduate nursing course to better prepare nurses for the surgical setting. The course was offered in a condensed-semester format and included online activities, simulation experiences, classroom discussions, and clinical experiences in a small group setting. Two of the four nursing students in the course were hired directly into the perioperative setting after graduation, decreasing hospital costs related to recruitment and orientation. The success of the course led to its integration into the undergraduate curriculum, thus providing a valuable elective option for junior and senior nursing students, as well as achieving a new model for perioperative nursing education. PMID- 25537333 TI - Recruiting and retaining Generation Y perioperative nurses. PMID- 25537319 TI - Early origins of chronic obstructive lung diseases across the life course. AB - Chronic obstructive lung diseases, like asthma and chronic obstructive pulmonary disease, have high prevalences and are a major public health concern. Chronic obstructive lung diseases have at least part of their origins in early life. Exposure to an adverse environment during critical periods in early life might lead to permanent developmental adaptations which results in impaired lung growth with smaller airways and lower lung volume, altered immunological responses and related inflammation, and subsequently to increased risks of chronic obstructive lung diseases throughout the life course. Various pathways leading from early life factors to respiratory health outcomes in later life have been studied, including fetal and early infant growth patterns, preterm birth, maternal obesity, diet and smoking, children's diet, allergen exposure and respiratory tract infections, and genetic susceptibility. Data on potential adverse factors in the embryonic and preconception period and respiratory health outcomes are scarce. Also, the underlying mechanisms how specific adverse exposures in the fetal and early postnatal period lead to chronic obstructive lung diseases in later life are not yet fully understood. Current studies suggest that interactions between early environmental exposures and genetic factors such as changes in DNA-methylation and RNA expression patterns may explain the early development of chronic obstructive lung diseases. New well-designed epidemiological studies are needed to identify specific critical periods and to elucidate the mechanisms underlying the development of chronic obstructive lung disease throughout the life course. PMID- 25537334 TI - Communication, teamwork, and trust in an office-based practice. PMID- 25537336 TI - Pathologic mistake. PMID- 25537337 TI - Acute administration of lithium, but not valproate, modulates cognitive judgment bias in rats. AB - RATIONALE AND OBJECTIVES: Both valproic acid (VPA) and lithium (LI) are well established treatments for therapy of intense and sustained mood shifts, which are characteristics of affective disorders, such as bipolar disorder (BP). As mood and cognitive judgment bias have been found to be strongly interrelated, the present study investigated, in an animal model, whether acute treatment with VPA or LI could affect cognitive judgment bias. METHODS: To accomplish this goal, two groups of rats received single injections of either VPA or LI after initial behavioral training and were subsequently tested with the ambiguous-cue interpretation (ACI) test. Both drugs were administered in three doses using the fully randomized Latin square design. RESULTS: VPA (100, 200, and 400 mg/kg) had no significant effect on the interpretation of the ambiguous cue. LI at the lowest dose (10 mg/kg) had no effect; at an intermediate dose (50 mg/kg), it significantly biased animals towards positive interpretation of the ambiguous cue, and at the highest dose (100 mg/kg), it impaired the ability of animals to complete the test. CONCLUSION: To our knowledge, this is the first study demonstrating lithium's effects on increased optimistic judgment bias. Future studies may focus on the ability of putative pharmacotherapies to modify the cognitive judgment bias dimension of patients at risk for bipolar disorder or depression. PMID- 25537339 TI - Performance and microbial community analysis of a pilot-scale UASB for corn ethanol wastewater treatment. AB - The performance and microbial community structure of a pilot-scale upflow anaerobic sludge blanket (UASB) reactor inoculated with flocculent sludge were investigated over 52 days. The characteristics of corn-ethanol wastewater were as follows: CODCr, 1,050-4,970 mg l(-1); ammonia, 14-298 mg l(-1); and alkalinity, 332-2,867 mg l(-1). The UASB could start up smoothly with a hydraulic loading rate lower than 180 l h(-1) and a ratio of volatile fatty acid versus alkalinity between 0.04 and 0.48. The maximum gas production rate was 432 l h(-1) and the highest volumetric loading rate of 7.2 kg m(-3) day(-1) was obtained after 48 days. The 1 mm granules could form a complex network and were composed of many Methanosaeta. Aceticlastic methanogens served as a dominant methanogenic group, which accounted for the relatively high resistance to shock loading. PMID- 25537338 TI - A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid. AB - Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6 methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration-time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect. PMID- 25537340 TI - Graphene oxide - gelatin nanohybrids as functional tools for enhanced Carboplatin activity in neuroblastoma cells. AB - PURPOSE: Preparation of Nanographene oxide (NGO) - Gelatin hybrids for efficient treatment of Neuroblastoma. METHODS: Nanohybrids were prepared via non-covalent interactions. Spectroscopic tools have been used to discriminate the chemical states of NGO prior and after gelatin coating, with UV visible spectroscopy revealing the maximum binding capacity of gelatin to NGO. Raman and X-ray photoelectron spectroscopy (XPS) demonstrated NGO and Gelatin_NGO nanohybrids through a new chemical environments produced after noncovalent interaction. Microscopic analyses, atomic force microscopy (AFM) and scanning electron microscopy (SEM) are used to estimate the thickness of samples and the lateral width in the nanoscale, respectively. RESULTS: The cell viability assay validated Gelatin_NGO nanohybrids as a useful nanocarrier for Carboplatin (CP) release and delivery, without obvious signs of toxicity. The nano-sized NGO (200 nm and 300 nm) did not enable CP to kill the cancer cells efficiently, whilst the CP loaded Gel_NGO 100 nm resulted in a synergistic activity through increasing the local concentration of CP inside the cancer cells. CONCLUSIONS: The nanohybrids provoked high stability and dispersibility in physiological media, as well as enhanced the anticancer activity of the chemotherapy agent Carboplatin (CP) in human neuroblastoma cells. PMID- 25537341 TI - Immunomodulatory effects of a low-dose clarithromycin-based macrolide solution pressurised metered dose inhaler. AB - PURPOSE: The aim of this study was to assess the effects of low-dose clarithromycin, formulated as solution pressurized metered dose inhaler, following deposition on the Calu-3 respiratory epithelial cells. METHODS: Clarithromycin was deposited on the air-interface culture of Calu-3 cells using a modified Andersen cascade impactor. Transport of fluorescein-Na, production of mucus and interleukin-8 release from Calu-3 cells following stimulation with transforming growth factor-beta and treatment with clarithromycin was investigated. RESULTS: The deposition of clarithromycin had significant effect on the permeability of fluorescein-Na, suggesting that the barrier integrity was improved following a short-term treatment with clarithromycin (apparent permeability values were reduced to 3.57 * 10(-9) +/- 2.32 * 10(-9) cm.s(-1), compared to 1.14 * 10(-8) +/- 4.30 * 10(-8) cm.s(-1) for control). Furthermore, the amount of mucus produced was significantly reduced during the course of clarithromycin treatment. The concentration of interleukin-8 secreted from Calu-3 cells following stimulation with transforming growth factor-beta resulted in significantly lower level of interleukin-8 released from the cells pre-treated with clarithromycin (5.2 +/- 0.5 ng.ml(-1) clarithromycin treated vs. 7.7 +/- 0.8 ng.ml(-1) control, respectively). CONCLUSIONS: Our data demonstrate that treatment with clarithromycin decreases the paracellular permeability of epithelial cells, mucus secretion and interleukin-8 release and therefore, inhaled clarithromycin holds potential as an anti-inflammatory therapy. PMID- 25537342 TI - Distinctly Different Glass Transition Behaviors of Trehalose Mixed with Na2HPO 4 or NaH 2PO 4: Evidence for its Molecular Origin. AB - PURPOSE: The present study is aimed at understanding how the interactions between sugar molecules and phosphate ions affect the glass transition temperature of their mixtures, and the implications for pharmaceutical formulations. METHODS: The glass transition temperature (Tg) and the alpha-relaxation temperature (Talpha) of dehydrated trehalose/sodium phosphate mixtures (monobasic or dibasic) were determined by differential scanning calorimetry and dynamic mechanical analysis, respectively. Molecular dynamics simulations were also conducted to investigate the microscopic interactions between sugar molecules and phosphate ions. The hydrogen-bonding characteristics and the self-aggregation features of these mixtures were quantified and compared. RESULTS: Thermal analysis measurements demonstrated that the addition of NaH2PO4 decreased both the glass transition temperature and the alpha-relaxation temperature of the dehydrated trehalose/NaH2PO4 mixture compared to trehalose alone while both Tg and Talpha were increased by adding Na2HPO4 to pure trehalose. The hydrogen-bonding interactions between trehalose and HPO4(2-) were found to be stronger than both the trehalose-trehalose hydrogen bonds and those formed between trehalose and H2PO4(-). The HPO4(2-) ions also aggregated into smaller clusters than H2PO4(-) ions. CONCLUSIONS: The trehalose/Na2HPO4 mixture yielded a higher T g than pure trehalose because marginally self-aggregated HPO4(2-) ions established a strengthened hydrogen-bonding network with trehalose molecules. In contrast H2PO4(-) ions served only as plasticizers, resulting in a lower Tg of the mixtures than trehalose alone, creating large-sized ionic pockets, weakening interactions, and disrupting the original hydrogen-bonding network amongst trehalose molecules. PMID- 25537343 TI - Measuring tissue back-pressure--in vivo injection forces during subcutaneous injection. AB - PURPOSE: Limited information is available on injection forces of parenterals representing the in vivo situation. Scope of the present study was to investigate the contribution of the subcutaneous (sc) tissue layer to injection forces during in vivo injection. METHODS: Gottingen minipigs received injections of isotonic dextran solutions (1-100 mPas) into the plica inguinalis using different injection rates and volumes (0.025-0.2 mL/s and 2.5 vs. 4.5 mL). RESULTS: The contribution of the sc back-pressure to injection forces was found to increase linearly with viscosity and injection rate ranging from 0.6 +/- 0.5 N to 1.0 +/- 0.4 N (1 mPas), 0.7 +/- 0.2 N to 2.4 +/- 1.9 N (10 mPas), and 1.8 +/- 0.6 N to 4.7 +/- 3.3 N (20 mPas) for injection rates of 0.025 to 0.2 mL/s, respectively. Variability increased with viscosity and injection rate. Values are average values from 10 randomized injections. A maximum of 12.9 N was reached for 20 mPas at 0.2 mL/s; 6.9 +/- 0.3 N was determined for 100 mPas at 0.025 mL/s. No difference was found between injection volumes of 2.5 and 4.5 mL. The contribution of the tissue was differentiated from the contribution of the injection device and a local temperature effect. This effect was leading to warming of the (equilibrated) sample in the needle, therefore smaller injection forces than expected compensating tissue resistance to some parts. CONCLUSIONS: When estimating injection forces representative for the in vivo situation, the contribution of the tissue has to be considered as well as local warming of the sample in the needle during injection. PMID- 25537345 TI - Issue editors' notes. PMID- 25537347 TI - Using relational developmental systems theory to link program goals, activities, and outcomes: the sample case of the 4-H Study of Positive Youth Development. AB - In contemporary developmental science, relational development systems models have been used to frame the positive youth development (PYD) perspective, which posits that youth will thrive when there is alignment between their strengths and ecological resources in their context. Evidence from the 4-H Study of PYD indicates that out-of-school-time youth development programs are key ecological resources enhancing youth thriving. This chapter discusses the particular facets of youth development programs (the "Big Three"-positive and sustained adult-youth relationships, skill-building activities, and youth leadership opportunities) involved in promoting youth thriving. The importance of using theory to design and implement programs is also discussed, and challenges of reaching the diversity of American youth with effective programs are noted. PMID- 25537344 TI - Factor structure and clinical utility of the Beck depression inventory in patients with binge eating disorder and obesity. AB - OBJECTIVE: The Beck Depression Inventory (BDI) is often used to assess depression symptoms, but its factor structure and its clinical utility have not been evaluated in patients with binge eating disorder (BED) and obesity. METHODS: A total of 882 treatment-seeking obese patients with BED were administered structured interviews (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders) and completed self-report questionnaires. RESULTS: Exploratory and confirmatory factor analyses supported a brief 16-item BDI version with a three-factor structure (affective, attitudinal and somatic). Both 21- and 16-item versions showed excellent internal consistency (both alpha=0.89) and had significant correlation patterns with different aspects of eating disorder psychopathology; three factors showed significant but variable associations with eating disorder psychopathology. Area under the curves (AUC) for both BDI versions were significant in predicting major depressive disorder (MDD; AUC=0.773 [16-item], 73.5% sensitivity/70.2% specificity, AUC=0.769 [21-item], 79.5% sensitivity/64.1% specificity) and mood disorders (AUC=0.763 [16-item], 67.1% sensitivity/71.5% specificity, AUC=0.769 [21-item], 84.2% sensitivity/55.7% specificity). The 21 item BDI (cutoff score >=16) showed higher negative predictive values (94.0% vs. 93.0% [MDD]; 92.4% vs. 88.3% [mood disorders]) than the brief 16-item BDI (cutoff score >=13). CONCLUSIONS: Both BDI versions demonstrated moderate performance as a screening instrument for MDD/mood disorders in obese patients with BED. Advantages and disadvantages for both versions are discussed. A three-factor structure has potential to inform the conceptualization of depression features. PMID- 25537348 TI - Afterschool quality. AB - This chapter discusses efforts to define and improve the quality of afterschool services, highlighting areas of agreement and identifying leading-edge issues. We conclude that the afterschool field is especially well positioned to deliver high quality services and demonstrate effectiveness at scale because a strong foundation has been built for continuous improvement of service quality. PMID- 25537349 TI - Moving beyond attendance: lessons learned from assessing engagement in afterschool contexts. AB - Youth engagement is the least researched, but potentially most important, aspect of participation in afterschool programs. The level of youth engagement can vary across programs, across youth within a program, and within individual youth over time. Engagement is important for both recruiting and retaining participants, and has been associated with more positive academic outcomes over time. This chapter integrates perspectives from practitioners, researchers, and the school engagement literature. Reasons why engagement is an important dimension of afterschool programming, different methods for assessing engagement, key features of engaging afterschool programs, and implications for practice are also outlined. PMID- 25537350 TI - Growth-promoting relationships with children and youth. AB - At the heart of afterschool programs are the relationships that form between the children and youth who participate in these programs and the adults who lead them. To be effective, adults working in afterschool settings must be able to engage youth in growth-promoting relationships. This article identifies and describes four foundational ways of interacting with youth that foster the development of such relationships-engaging in warm and emotionally supportive connections, providing developmentally appropriate structure and support, cultivating and responding to youth initiative, and scaffolding and propelling youth learning and skill development. PMID- 25537351 TI - Behavior management in afterschool settings. AB - Although behavioral management is one of the most challenging aspects of working in an afterschool setting, staff do not typically receive formal training in evidence-based approaches to handling children's behavior problems. Common approaches to behavioral management such as punishment or time-out are temporary solutions because they do not identify and change the factors causing the problematic behaviors. In some cases, these approaches increase or intensify undesirable behaviors. This chapter discusses one approach to behavioral management-functional behavior assessment-that research proves effective in eliminating or reducing the occurrence of behavior problems in educational settings. PMID- 25537352 TI - Family, school, and community partnerships: practical strategies for afterschool programs. AB - Much attention is given today to the importance of forging family, school, and community partnerships. Growing numbers of schools, many of them with afterschool programs, are dedicating resources to support and sustain relationships with families and community-based organizations. And, among government agencies and the philanthropic sector, there is widespread recognition that schools cannot be successful if they function alone in their quest to educate our nation's children, but must work with families and in the context of the community. Although the field is enjoying unprecedented popularity and many more schools and afterschool programs are partnering with community agencies and organizations, the notion of engaging parents and the community has not yet become an integral part of school reform, and in the afterschool field, practitioners who work at the program level directly with students often struggle with how they can make partnerships a reality. This chapter draws upon lessons learned from the School of the 21st Century (21C) to provide practical strategies for reaching out to and working with families and the community. The School of the 21st Century includes an afterschool component and is one of several national initiatives that use a community school strategy. PMID- 25537353 TI - Cultural competence in afterschool programs. AB - Increasing ethnic diversity among American youth, in combination with funding priorities often targeting underserved populations, has increased the number of diverse youth attending afterschool programs (ASPs). At present, there is little guidance on how to best design ASPs and prepare staff to support the development of these diverse youth. The fields of medicine and education have begun to explore the impact of cultural competence at the organizational, structural, and professional levels to help bridge potential cultural divides. This chapter will briefly review the literature on cultural competence and emerging evidence within ASPs. It will then provide concrete examples of how afterschool programs have infused culturally tailored content and/or staff trainings to build cultural competence. Finally, specific recommendations will be made to serve as a springboard for future research and practice. PMID- 25537354 TI - Evaluating afterschool programs. AB - Well-implemented afterschool programs can promote a range of positive learning and developmental outcomes. However, not all research and evaluation studies have shown the benefits of participation, in part because programs and their evaluation were out of sync. This chapter provides practical guidance on how to foster that alignment between program and evaluation design. It begins with a discussion of why afterschool programs should develop and use a theory of change to guide program development, implementation, and evaluation. It then describes how to develop a logic model to depict program theory. It concludes with an overview of an approach to evaluation that ensures programs use evaluation information to improve and refine programming prior to using information for accountability purposes. PMID- 25537355 TI - Transcriptomic identification and expression of starch and sucrose metabolism genes in the seeds of Chinese chestnut (Castanea mollissima). AB - The Chinese chestnut (Castanea mollissima) seed provides a rich source of carbohydrates as food and feed. However, little is known about starch biosynthesis in the seeds. The objectives of this study were to determine seed composition profiles and identify genes involved in starch and sucrose metabolism. Metabolite analysis showed that starch was the major component and rapidly accumulated during seed endosperm development. Amylopectin was approximately 3-fold of amylose content in chestnut starch. Illumina platform based transcriptome sequencing generated 56671 unigenes in two cDNA libraries from seed endosperms collected at 45 and 75 days after flowering (DAF). A total of 1537 unigenes showed expression differences >=2-fold in the two stages of seeds including 570 up-regulated and 967 down-regulated unigenes. One hundred and fifty-two unigenes were identified as involved in starch and sucrose metabolism, including 1 for glycogenin glucosyltransferase, 4 for adenylate transporter (brittle1-type), 3 for ADP-glucose pyrophosphorylase (AGP, not brittle2- or shrunken2-type), 3 for starch synthase (SS), 2 for starch branching enzyme, 5 for starch debranching enzyme, 11 for sucrose synthase, and 3 for sucrose-phosphate synthase. Among them, 58 unigenes showed a >=2-fold expression difference between the 45 and 75 DAF seeds including 11 up- and 47 down-regulated unigenes. The expression of 21 unigenes putatively coding for major enzymes in starch and sucrose metabolism was validated by qPCR using RNA from five seed stages. Expression profiles and correlation analysis indicated that the mRNA levels of AGP (large and small subunits), granule-bound SS2, and soluble SS1 and SS4 were well-correlated with starch accumulation in the seeds. This study suggests that the starch biosynthesis pathway in Chinese chestnut is similar to that of potato tuber/Arabidopsis leaf and differs from that of maize endosperm. The information provides valuable metabolite and genetic resources for future research in starch and sucrose metabolism in Chinese chestnut tree. PMID- 25537356 TI - Clinical utility gene card for: Cornelia de Lange syndrome. PMID- 25537357 TI - It is time to take timing seriously in clinical genetics. AB - Observations made by molecular techniques on the genome along the individuals' lifetime indicate that the genome in somatic cells displays changes at molecular, cellular, and organismal levels. Timing of genetic events leading to somatic mosaicism and gene expression dynamism results in a highly important variable for comprehending the role of genetics in health and disease. Consideration of time in clinical genetics should be enthusiastically invested into research strategy, interpretation of the results, diagnostic routine, and particularly in ethical discussions. PMID- 25537358 TI - ZNF277 microdeletions, specific language impairment and the meiotic mismatch methylation (3M) hypothesis. PMID- 25537359 TI - Reply to Pembrey et al: 'ZNF277 microdeletions, specific language impairment and the meiotic mismatch methylation (3M) hypothesis'. PMID- 25537361 TI - Consent procedures in pediatric biobanks. AB - The inclusion of children's samples in biobanks brings forward specific ethical issues. Guidelines indicate that children should be involved in the consent procedure. It is, however, unclear how to allocate an appropriate role for children. Knowledge of current practice will be helpful in addressing this issue. Therefore, we conducted an international multiple-case study on the child's role in consent procedures in pediatric biobanks. Four biobanks were included: (1) LifeLines, (2) Prevention and Incidence of Asthma and Mite Allergy (PIAMA), (3) Young-HUNT3 and (4) the Oxford Radcliffe Biobank contribution to the Children's Cancer and Leukaemia Group tissue bank (ORB/CCLG). Four themes linked to the child's role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate. We conclude that biobank characteristics influence the biobank's motives to include children in the consent procedure. Moreover, the motives to include children influence how the children are involved in the consent procedure, and the extent to which children are able to make voluntary decisions as part of the consent procedure. This insight is valuable when designing pediatric biobank governance. PMID- 25537360 TI - The EuroBioBank Network: 10 years of hands-on experience of collaborative, transnational biobanking for rare diseases. AB - The EuroBioBank (EBB) network (www.eurobiobank.org) is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003-2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and 'omics' data, thus challenging the fragmentation of international cooperation on the field. PMID- 25537365 TI - Effect of recombinant human thyroid-stimulating hormone or levothyroxine withdrawal on salivary gland dysfunction after radioactive iodine administration for thyroid remnant ablation. AB - BACKGROUND: The purpose of this study was to examine the incidence of sialadenitis and xerostomia within a year after radioactive iodine administration for thyroid remnant ablation after preparation with recombinant human thyroid stimulating hormone (rhTSH) or levothyroxine (LT4 ) withdrawal. METHODS: The study has included 121 patients, divided into 4 groups: group A (rhTSH = 100 mCi), group B (rhTSH = 70 mCi), group C (LT4 withdrawal = 100 mCi), and group D (LT4 withdrawal = 70 mCi). Study outcomes were Summated Xerostomia Inventory score and number of sialadenitis episodes after radioactive iodine administration. RESULTS: Salivary gland dysfunction was reported in 31% and 12% of patients, at the end of months 1 and 12, respectively. There was significantly lower incidence in groups A and B in comparison with groups C and D (p = .002 and .021, respectively). CONCLUSION: The use of rhTSH for preparation of radioactive iodine ablation as opposed to LT4 withdrawal reduces the incidence of salivary gland dysfunction. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E227-E230, 2016. PMID- 25537362 TI - Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence. AB - Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing. PMID- 25537366 TI - Concise review: growing hearts in the right place: on the design of biomimetic materials for cardiac stem cell differentiation. AB - Tissue engineering aims at recapitulating permissive conditions that enable cells to collaborate and form functional tissues. Applications range from human tissue modeling for diagnostic purposes to therapeutic solutions in regenerative medicine and surgery. Across this spectrum, human stem cells are the active ingredient, expandable virtually indefinitely and with the propensity to generate new tissue. Engaging lineage-specific differentiation requires a precise concerto of key spatial and temporal factors, such as soluble molecules and growth factors, but also physical and mechanical stimuli. These stimuli compete to modulate distinct developmental signaling pathways and ultimately affect the differentiation efficiency. The heart is a chemo-mechano-electrical biological system that behaves as both a sensor and an actuator. It can transduce electrical inputs to generate mechanical contraction and electrical wave propagation. Such a complex organ arises from multipart developmental events that interact with one another to self-regulate. Here, we overview the main events of heart development and the role of mechanical forces in modifying the microenvironment of the progenitor cells. We analyze the cascades regulating cardiac gene activation to illustrate how mechanotransduction is already involved in the most popular protocols for stem cell differentiation (SCD) into cardiomyocytes. We then review how forces are transmitted to embryonic stem cells by cell-substrate or cell-cell communications, and how biomaterials can be designed to mimic these interactions and help reproduce key features of the developmental milieu. Putting this back in a clinical perspective, many challenges need to be overcome before biomaterials based SCD protocols can be scaled up and marketed. PMID- 25537367 TI - Chemistry of diruthenium and dirhodium analogues of pentaborane(9): synthesis and characterization of metal n,s-heterocyclic carbene and B-agostic complexes. AB - Building upon our earlier results on the synthesis of electron-precise transition metal-boron complexes, we continue to investigate the reactivity of pentaborane(9) and tetraborane(10) analogues of ruthenium and rhodium towards thiazolyl and oxazolyl ligands. Thus, mild thermolysis of nido-[(Cp*RuH)2B3H7] (1) with 2-mercaptobenzothiazole (2-mbtz) and 2-mercaptobenzoxazole (2-mboz) led to the isolation of Cp*-based (Cp* = eta(5)-C5Me5) borate complexes 5 a,b [Cp*RuBH3L] (5 a: L = C7H4NS2; 5 b: L = C7H4NOS)) and agostic complexes 7 a,b [Cp*RuBH2(L)2], (7 a: L = C7H4NS2; 7 b: L = C7H4NOS). In a similar fashion, a rhodium analogue of pentaborane(9), nido-[(Cp*Rh)2B3H7] (2) yielded rhodaboratrane [Cp*RhBH(L)2], 10 (L = C7H4NS2). Interestingly, when the reaction was performed with an excess of 2-mbtz, it led to the formation of the first structurally characterized N,S-heterocyclic rhodium-carbene complex [(Cp*Rh)(L2)(1-benzothiazol-2-ylidene)] (11) (L = C7H4NS2). Furthermore, to evaluate the scope of this new route, we extended this chemistry towards the diruthenium analogue of tetraborane(10), arachno-[(Cp*RuCO)2B2H6] (3), in which the metal center possesses different ancillary ligands. PMID- 25537368 TI - Morphological investigation of midblock-sulfonated block ionomers prepared from solvents differing in polarity. AB - Recent developments regarding charged multiblock copolymers that can form physical networks and exhibit robust mechanical properties herald new and exciting opportunities for contemporary technologies requiring amphiphilic attributes. Due to the presence of strong interactions, however, control over the phase behavior of such materials remains challenging, especially since their morphologies can be solvent-templated. In this study, transmission electron microscopy and microtomography are employed to examine the morphological characteristics of midblock-sulfonated pentablock ionomers prepared from solvents differing in polarity. Resultant images confirm that discrete, spherical ion-rich microdomains form in films cast from a relatively nonpolar solvent, whereas an apparently mixed morphology with a continuous ion-rich pathway is generated when the casting solvent is more highly polar. Detailed 3D analysis of the morphological characteristics confirms the coexistence of hexagonally-packed nonpolar cylinders and lamellae, which facilitates the diffusion of ions and/or other polar species through the nanostructured medium. PMID- 25537370 TI - Ascomycotin A, a new citromycetin analogue produced by Ascomycota sp. Ind19F07 isolated from deep sea sediment. AB - A new citromycetin analogue, ascomycotin A (1), together with eight known compounds, wortmannilactone E (2), orcinol (3), orsellinic acid (4), isosclerone (5), (3R,4S)-( - )-4-hydroxymellein (6), diorcinol (7), chaetocyclinone B (8) and 2,5-dimethoxy-3,6-di(p-methoxypheny1)-1,4-benzoquinone (9), was isolated from the fungal strain Ascomycota sp. Ind19F07, which was isolated from the deep sea sediment of the Indian Ocean. The structures of the compounds were established by spectroscopic data including 1D and 2D NMR and HR-ESI-MS. Compounds (1-9) were evaluated for antibacterial activity. PMID- 25537369 TI - Silver-catalyzed arylation of (hetero)arenes by oxidative decarboxylation of aromatic carboxylic acids. AB - A long-standing challenge in Minisci reactions is achieving the arylation of heteroarenes by oxidative decarboxylation of aromatic carboxylic acids. To address this challenge, the silver-catalyzed intermolecular Minisci reaction of aromatic carboxylic acids was developed. With an inexpensive silver salt as a catalyst, this new reaction enables a variety of aromatic carboxylic acids to undergo decarboxylative coupling with electron-deficient arenes or heteroarenes regardless of the position of the substituents on the aromatic carboxylic acid, thus eliminating the need for ortho-substituted aromatic carboxylic acids, which were a limitation of previously reported methods. PMID- 25537371 TI - Effect of vaginal or systemic estrogen on dynamics of collagen assembly in the rat vaginal wall. AB - The objective of this study was to compare the effects of systemic and local estrogen treatment on collagen assembly and biomechanical properties of the vaginal wall. Ovariectomized nulliparous rats were treated with estradiol or conjugated equine estrogens (CEEs) either systemically, vaginal CEE, or vaginal placebo cream for 4 wk. Low-dose local CEE treatment resulted in increased vaginal epithelial thickness and significant vaginal growth without uterine hyperplasia. Furthermore, vaginal wall distensibility increased without compromise of maximal force at failure. Systemic estradiol resulted in modest increases in collagen type I with no change in collagen type III mRNA. Low-dose vaginal treatment, however, resulted in dramatic increases in both collagen subtypes whereas moderate and high dose local therapies were less effective. Consistent with the mRNA results, low-dose vaginal estrogen resulted in increased total and cross-linked collagen content. The inverse relationship between vaginal dose and collagen expression may be explained in part by progressive downregulation of estrogen receptor-alpha mRNA with increasing estrogen dose. We conclude that, in this menopausal rat model, local estrogen treatment increased total and cross-linked collagen content and markedly stimulated collagen mRNA expression in an inverse dose-effect relationship. High-dose vaginal estrogen resulted in downregulation of estrogen receptor-alpha and loss of estrogen induced increases in vaginal collagen. These results may have important clinical implications regarding the use of local vaginal estrogen therapy and its role as an adjunctive treatment in women with loss of vaginal support. PMID- 25537372 TI - Placental growth factor influences maternal cardiovascular adaptation to pregnancy in mice. AB - In healthy human pregnancies, placental growth factor (PGF) concentrations rise in maternal plasma during early gestation, peak over Weeks 26-30, then decline. Because PGF in nongravid subjects participates in protection against and recovery from cardiac pathologies, we asked if PGF contributes to pregnancy-induced maternal cardiovascular adaptations. Cardiovascular function and structure were evaluated in virgin, pregnant, and postpartum C56BL/6-Pgf(-) (/) (-) (Pgf(-) (/) (-)) and C57BL/6-Pgf(+/+) (B6) mice using plethysmography, ultrasound, quantitative PCR, and cardiac and renal histology. Pgf(-/-) females had higher systolic blood pressure in early and late pregnancy but an extended, abnormal midpregnancy interval of depressed systolic pressure. Pgf(-/-) cardiac output was lower than gestation day (gd)-matched B6 after midpregnancy. While Pgf(-) (/) (-) left ventricular mass was greater than B6, only B6 showed the expected gestational gain in left ventricular mass. Expression of vasoactive genes in the left ventricle differed at gd8 with elevated Nos expression in Pgf(-) (/) (-) but not at gd14. By gd16, Pgf(-) (/) (-) kidneys were hypertrophic and had glomerular pathology. This study documents for the first time that PGF is associated with the systemic maternal cardiovascular adaptations to pregnancy. PMID- 25537374 TI - Evidence for an intranasal immune response to human respiratory syncytial virus infection in cynomolgus macaques. AB - There is no large-scale therapy available against human respiratory syncytial virus (hRSV), a major pathogen responsible for acute respiratory diseases. Macaques represent an interesting animal model to evaluate potential treatments because of their genetic, anatomical and immunological proximity with humans. However, the parameters that influence hRSV growth and control in this model are still poorly understood. We have documented in the following study the influence of age as well as repeated infections on the virological, clinical and immunological parameters of this animal model. Following intranasal inoculation, hRSV replicated in the upper respiratory tract for less than 15 days with no clinical signs regardless of age. Interestingly, we observed the induction of a local immune response at the nasal mucosa as assessed by expression profiles of inflammatory and IFN-stimulated genes. Animals also developed specific antibodies and were immune to reinfection. Thus, we showed that even in infant macaques, intranasal hRSV infection induced both local and systemic immune responses to efficiently control the virus. PMID- 25537373 TI - Neutrophil recruitment and activation in decidua with intra-amniotic IL-1beta in the preterm rhesus macaque. AB - Chorioamnionitis, an infection/inflammation of the fetomaternal membranes, is frequently associated with preterm delivery. The mechanisms of inflammation in chorioamnionitis are poorly understood. We hypothesized that neutrophils recruited to the decidua would be the major producers of proinflammatory cytokines. We injected intra-amniotic (IA) interleukin 1beta (IL-1beta) at ~80% gestation in rhesus macaque monkeys, Macaca mulatta, delivered the fetuses surgically 24 h or 72 h after IA injections, and investigated the role of immune cells in the chorion-amnion decidua. IA IL-1beta induced a robust infiltration of neutrophils and significant increases of proinflammatory cytokines in the chorioamnion decidua at 24 h after exposure, with a subsequent decrease at 72 h. Neutrophils in the decidua were the major source of tumor necrosis factor alpha (TNFalpha) and IL-8. Interestingly, IA IL-1beta also induced a significant increase in anti-inflammatory indoleamine 2,3-dioxygenase (IDO) expression in the decidua neutrophils. The frequency of regulatory T cells (Tregs) and FOXP3 mRNA expression in the decidua did not change after IA IL-1beta injection. Collectively, our data demonstrate that in this model of sterile chorioamnionitis, the decidua neutrophils cause the inflammation in the gestational tissues but may also act as regulators to dampen the inflammation. These results help to understand the contribution of neutrophils to the pathogenesis of chorioamnionitis-induced preterm labor. PMID- 25537375 TI - Identification of an avian polyomavirus associated with Adelie penguins (Pygoscelis adeliae). AB - Little is known about viruses associated with Antarctic animals, although they are probably widespread. We recovered a novel polyomavirus from Adelie penguin (Pygoscelis adeliae) faecal matter sampled in a subcolony at Cape Royds, Ross Island, Antarctica. The 4988 nt Adelie penguin polyomavirus (AdPyV) has a typical polyomavirus genome organization with three ORFs that encoded capsid proteins on the one strand and two non-structural protein-coding ORFs on the complementary strand. The genome of AdPyV shared ~60 % pairwise identity with all avipolyomaviruses. Maximum-likelihood phylogenetic analysis of the large T antigen (T-Ag) amino acid sequences showed that the T-Ag of AdPyV clustered with those of avipolyomaviruses, sharing between 48 and 52 % identities. Only three viruses associated with Adelie penguins have been identified at a genomic level, avian influenza virus subtype H11N2 from the Antarctic Peninsula and, respectively, Pygoscelis adeliae papillomavirus and AdPyV from capes Crozier and Royds on Ross Island. PMID- 25537376 TI - Breaking the host range: mandarin fish is susceptible to a vesiculovirus derived from snakehead fish. AB - Members of the genus Vesiculovirus, which belongs to the family Rhabdoviridae, can cause great economic loss in fish culture. In the present report, a vesiculovirus [named snakehead fish vesiculovirus (SHVV)] was isolated from diseased hybrid snakehead fish. SHVV shared 94 % nucleotide sequence identity at the genomic level with Siniperca chuatsi rhabdovirus (SCRV), which infects mandarin fish (S. chuatsi). We showed that SHVV was able to replicate and proliferate well in SSN-1 cells, which originate from striped snakehead fish (Channa striatus). Furthermore, mandarin fish was susceptible to SHVV by bath exposure, as well as by intraperitoneal injection. The infected fish showed typical clinical signs of rhabdovirus infection, including haemorrhage and oedema. Histopathological analysis revealed that extensive inflammation and necrosis were observed in the spleen, kidney, liver, heart and brain of the moribund mandarin fish. These results will shed new light on the epidemic of vesiculovirus infections among fish. PMID- 25537377 TI - The effect of ergonomic laparoscopic tool handle design on performance and efficiency. AB - BACKGROUND: Many factors can affect a surgeon's performance in the operating room; these may include surgeon comfort, ergonomics of tool handle design, and fatigue. A laparoscopic tool handle designed with ergonomic considerations (pistol grip) was tested against a current market tool with a traditional pinch grip handle. The goal of this study is to quantify the impact ergonomic design considerations which have on surgeon performance. We hypothesized that there will be measurable differences between the efficiency while performing FLS surgical trainer tasks when using both tool handle designs in three categories: time to completion, technical skill, and subjective user ratings. METHODS: The pistol grip incorporates an ergonomic interface intended to reduce contact stress points on the hand and fingers, promote a more neutral operating wrist posture, and reduce hand tremor and fatigue. The traditional pinch grip is a laparoscopic tool developed by Stryker Inc. widely used during minimal invasive surgery. Twenty three (13 M, 10 F) participants with no existing upper extremity musculoskeletal disorders or experience performing laparoscopic procedures were selected to perform in this study. During a training session prior to testing, participants performed practice trials in a SAGES FLS trainer with both tools. During data collection, participants performed three evaluation tasks using both handle designs (order was randomized, and each trial completed three times). The tasks consisted of FLS peg transfer, cutting, and suturing tasks. RESULTS: Feedback from test participants indicated that they significantly preferred the ergonomic pistol grip in every category (p < 0.05); most notably, participants experienced greater degrees of discomfort in their hands after using the pinch grip tool. Furthermore, participants completed cutting and peg transfer tasks in a shorter time duration (p < 0.05) with the pistol grip than with the pinch grip design; there was no significant difference between completion times for the suturing task. Finally, there was no significant interaction between tool type and errors made during trials. CONCLUSIONS: There was a significant preference for as well as lower pain experienced during use of the pistol grip tool as seen from the survey feedback. Both evaluation tasks (cutting and peg transfer) were also completed significantly faster with the pistol grip tool. Finally, due to the high degree of variability in the error data, it was not possible to draw any meaningful conclusions about the effect of tool design on the number or degree of errors made. PMID- 25537378 TI - Clinical usefulness of free subcutaneous fat pad for reduction of intraoperative air leakage during thoracoscopic pulmonary resection in lung cancer cases. AB - INTRODUCTION: Intraoperative alveolar air leaks remain a significant problem in thoracoscopic surgery (TS) cases. We examined the usefulness of covering damaged lung tissue with a subcutaneous fat pad for preventing postoperative air leakage in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with NSCLC underwent a thoracoscopic lobectomy or segmentectomy. When alveolar air leakage from the superficial pulmonary parenchyma was found, fibrin glue in combination with an absorbable mesh sheet was applied (S group; n = 100). When leakage originated from deep within the pulmonary parenchyma, a subcutaneous fat pad about 2 * 2 cm in size was harvested from the utility incision and placed on the damaged lung tissue with fibrin glue and sutures (F group; n = 66). Patient characteristics, air leak duration, and chest-tube removal time were analyzed. RESULTS: The homogeneity of each group was consistent, with no statistical differences for age, respiratory function, surgical procedures, pathologic stage, and histological type. The air leak duration was significantly shorter (p = 0.015), and the chest tube was removed significantly earlier (p = 0.002) in patients in the F group. CONCLUSION: Use of a free subcutaneous fat pad during pulmonary resection for TS patients with NSCLC reduced the duration of air leakage and chest tube drainage. The present method is easy, safe, and effective for repairing an air leak from remaining lung tissues in such cases. PMID- 25537379 TI - Management of sessile malignant polyps: is colonoscopic polypectomy enough? AB - BACKGROUND: The role of endoscopy in the management of malignant-pedunculated polyps has been well studied, but endoscopic management of malignant sessile polyps has not. Sometimes patients with malignant sessile polyps have comorbidities that make surgery exceptionally risky, and endoscopy beckons as a definitive management option. The aim of this study is to evaluate the potential role of endoscopy in the management of malignant sessile polyps. METHODS: Patients undergoing colonoscopic polypectomy for malignant sessile polyps by a single endoscopist from 1997 to 2010 were evaluated. Demographic data, clinicopathological variables as well as long-term outcomes were recorded. RESULTS: Sixteen patients had malignant sessile polyps. Six (37.5 %) were male and 10 (62.5 %) were female. Mean age at diagnosis was 72.9 +/- 12.2 years. Six polyps were proximal to the splenic flexure (37.5 %) and 10 (62.5 %) were distal. The mean size of the polyps was 30.5 +/- 15.9 mm. All polyps were removed endoscopically but 7 patients (43.8 %) had formal colectomy following colonoscopic resection. There were no demographic differences between patients with and without surgery. Piecemeal polypectomy was necessary in 8 patients, 4 from the surgery group, and 4 from the endoscopy group. More patients in the surgery group had poorly differentiated cancers (4/6 vs. 0/6) and incomplete margins (5/6 vs. 1/6) and more patients in the endoscopically treated group had serious comorbidity (5/9 vs. 3/7). There was no procedure-related morbidity or mortality. After a mean follow-up of 48.4 +/- 27.2 months, one patient from the polypectomy group patient had a local recurrence and a liver metastasis, after originally declining surgery. In the surgery group, one patient had lung metastasis. The two patients who recurred with distant metastasis died. CONCLUSION: Endoscopic management of sessile colorectal polyps appears to be feasible and safe in patients with well/moderately differentiated cancer and negative margins. Larger studies are needed to confirm these findings. PMID- 25537380 TI - Computer-assessed performance of psychomotor skills in endoscopic otolaryngology surgery: construct validity of the Dundee Endoscopic Psychomotor Otolaryngology Surgery Trainer (DEPOST). AB - BACKGROUND: This study was undertaken to introduce and establish the value of the Dundee Endoscopic Psychomotor Otolaryngology Surgery Trainer (DEPOST) as a customisable, objective real-time scoring system for trainee assessment. The construct validity of the system was assessed by comparing the performance of experienced otolaryngologists with that of otolaryngology trainees, junior doctors and medical students. METHODS: Forty two subjects (13 Consultants, 8 senior trainees, 13 junior trainees and 8 junior doctors/medical students) completed a single test on DEPOST. The test involved using a 30 degrees rigid endoscope and a probe with position sensor, to identify a series of lights in a complex 3-dimensional model. The system scored subjects for time, success rate, and economy of movement (distance travelled). An analysis of variance and correlation analysis were used for the data analysis, with statistical significance set at 0.05. RESULTS: Increasing experience led to significantly improved performance with the DEPOST (p < 0.01). Senior trainees' results were significantly better than those of consultant otolaryngologists in success rate and time (p < 0.05 & p < 0.05). Consultants were the most efficient in their movement (p = 0.051) CONCLUSIONS: The system provides an accurate and customisable assessment of endoscopic skill in otolaryngologists. The DEPOST system has construct validity, with master surgeons and senior trainees completing the tasks more accurately without sacrificing execution time, success rate or efficiency of movement. PMID- 25537381 TI - Single-cycle induction chemotherapy followed by chemoradiotherapy or surgery in patients with head and neck cancer: what are the best predictors of remission and prognosis? AB - BACKGROUND: There is controversy over the concept of function and organ preservation by chemotherapy/chemoradiation instead of surgery in locally advanced cancer of the larynx or pharynx. Tumor response to induction chemotherapy (ICT) can help in choosing between conservative and surgical treatment. This study compared 3 methods of assessing response to ICT: endoscopy, computed tomography, and (18) F-FDG-PET/CT. METHODS: Primary response to 1 cycle of ICT with docetaxel plus platinum was assessed by the aforementioned methods in 62 laryngopharyngeal cancer patients. Endoscopic response was the deciding factor for selecting further treatment: surgery for endoscopic nonresponders (<30% tumor response) versus chemoradiotherapy for endoscopic responders. RESULTS: ICT achieved endoscopic response in 48 of 62 patients (77%). Individual relative residual tumor activity of standardized uptake value (resSUV(max)) in (18)F-FDG PET/CT was a median 0.38 of baseline (0.09-1.71), whereas residual tumor extent in CT (resCT) was 0.75 of baseline (0.32-1.20). Endoscopic responders and nonresponders differed significantly in SUV(max) after ICT (postSUVmax , 6.0 vs 14.5; P < .001), resSUV(max) (0.34 vs 0.81, P < .001), and resCT (0.71 vs 0.87, P = .004), but not in maximum tumor diameter after ICT (14 vs 20 mm, P = .11). resSUV(max) <0.8 and absolute postSUV(max) <10 provided the best discriminatory power for long-term success criteria (tumor-free survival, overall survival). CONCLUSIONS: Metabolic tumor response showed very good correlation with clinical tumor response to ICT. The value of metabolic response detected by (18)F-FDG PET/CT should be explored in a prospective clinical trial. PMID- 25537382 TI - Celebrating the past, looking to the future. PMID- 25537383 TI - SHELXT - integrated space-group and crystal-structure determination. AB - The new computer program SHELXT employs a novel dual-space algorithm to solve the phase problem for single-crystal reflection data expanded to the space group P1. Missing data are taken into account and the resolution extended if necessary. All space groups in the specified Laue group are tested to find which are consistent with the P1 phases. After applying the resulting origin shifts and space-group symmetry, the solutions are subject to further dual-space recycling followed by a peak search and summation of the electron density around each peak. Elements are assigned to give the best fit to the integrated peak densities and if necessary additional elements are considered. An isotropic refinement is followed for non centrosymmetric space groups by the calculation of a Flack parameter and, if appropriate, inversion of the structure. The structure is assembled to maximize its connectivity and centred optimally in the unit cell. SHELXT has already solved many thousand structures with a high success rate, and is optimized for multiprocessor computers. It is, however, unsuitable for severely disordered and twinned structures because it is based on the assumption that the structure consists of atoms. PMID- 25537384 TI - Nuclear-weighted X-ray maximum entropy method - NXMEM. AB - Subtle structural features such as disorder and anharmonic motion may be accurately characterized from nuclear density distributions (NDDs). As a viable alternative to neutron diffraction, this paper introduces a new approach named the nuclear-weighted X-ray maximum entropy method (NXMEM) for reconstructing pseudo NDDs. It calculates an electron-weighted nuclear density distribution (eNDD), exploiting that X-ray diffraction delivers data of superior quality, requires smaller sample volumes and has higher availability. NXMEM is tested on two widely different systems: PbTe and Ba(8)Ga(16)Sn(30). The first compound, PbTe, possesses a deceptively simple crystal structure on the macroscopic level that is unable to account for its excellent thermoelectric properties. The key mechanism involves local distortions, and the capability of NXMEM to probe this intriguing feature is established with simulated powder diffraction data. In the second compound, Ba(8)Ga(16)Sn(30), disorder among the Ba guest atoms is analysed with both experimental and simulated single-crystal diffraction data. In all cases, NXMEM outperforms the maximum entropy method by substantially enhancing the nuclear resolution. The induced improvements correlate with the amount of available data, rendering NXMEM especially powerful for powder and low-resolution single-crystal diffraction. The NXMEM procedure can be implemented in existing software and facilitates widespread characterization of disorder in functional materials. PMID- 25537385 TI - Diffuse multiple scattering. AB - A new form of diffraction lines has been identified, similar to Rutherford, Kikuchi and Kossel lines. This paper highlights some of the properties of these lines and shows how they can be used to eliminate the need for sample/source matching in Lonsdale's triple convergent line method in lattice-parameter determination. PMID- 25537386 TI - Prediction of molecular crystal structures by a crystallographic QM/MM model with full space-group symmetry. AB - A crystallographic quantum-mechanical/molecular-mechanical model (c-QM/MM model) with full space-group symmetry has been developed for molecular crystals. The lattice energy was calculated by quantum-mechanical methods for short-range interactions and force-field methods for long-range interactions. The quantum mechanical calculations covered the interactions within the molecule and the interactions of a reference molecule with each of the surrounding 12-15 molecules. The interactions with all other molecules were treated by force-field methods. In each optimization step the energies in the QM and MM shells were calculated separately as single-point energies; after adding both energy contributions, the crystal structure (including the lattice parameters) was optimized accordingly. The space-group symmetry was maintained throughout. Crystal structures with more than one molecule per asymmetric unit, e.g. structures with Z' = 2, hydrates and solvates, have been optimized as well. Test calculations with different quantum-mechanical methods on nine small organic molecules revealed that the density functional theory methods with dispersion correction using the B97-D functional with 6-31G* basis set in combination with the DREIDING force field reproduced the experimental crystal structures with good accuracy. Subsequently the c-QM/MM method was applied to nine compounds from the CCDC blind tests resulting in good energy rankings and excellent geometric accuracies. PMID- 25537387 TI - From direct-space discrepancy functions to crystallographic least squares. AB - Crystallographic least squares are a fundamental tool for crystal structure analysis. In this paper their properties are derived from functions estimating the degree of similarity between two electron-density maps. The new approach leads also to modifications of the standard least-squares procedures, potentially able to improve their efficiency. The role of the scaling factor between observed and model amplitudes is analysed: the concept of unlocated model is discussed and its scattering contribution is combined with that arising from the located model. Also, the possible use of an ancillary parameter, to be associated with the classical weight related to the variance of the observed amplitudes, is studied. The crystallographic discrepancy factors, basic tools often combined with least squares procedures in phasing approaches, are analysed. The mathematical approach here described includes, as a special case, the so-called vector refinement, used when accurate estimates of the target phases are available. PMID- 25537389 TI - The anatomy of a comprehensive constrained, restrained refinement program for the modern computing environment - Olex2 dissected. AB - This paper describes the mathematical basis for olex2.refine, the new refinement engine which is integrated within the Olex2 program. Precise and clear equations are provided for every computation performed by this engine, including structure factors and their derivatives, constraints, restraints and twinning; a general overview is also given of the different components of the engine and their relation to each other. A framework for adding multiple general constraints with dependencies on common physical parameters is described. Several new restraints on atomic displacement parameters are also presented. PMID- 25537388 TI - Analysis of rapidly synthesized guest-filled porous complexes with synchrotron radiation: practical guidelines for the crystalline sponge method. AB - A detailed set of synthetic and crystallographic guidelines for the crystalline sponge method based upon the analysis of expediently synthesized crystal sponges using third-generation synchrotron radiation are reported. The procedure for the synthesis of the zinc-based metal-organic framework used in initial crystal sponge reports has been modified to yield competent crystals in 3 days instead of 2 weeks. These crystal sponges were tested on some small molecules, with two being unexpectedly difficult cases for analysis with in-house diffractometers in regard to data quality and proper space-group determination. These issues were easily resolved by the use of synchrotron radiation using data-collection times of less than an hour. One of these guests induced a single-crystal-to-single crystal transformation to create a larger unit cell with over 500 non-H atoms in the asymmetric unit. This led to a non-trivial refinement scenario that afforded the best Flack x absolute stereochemical determination parameter to date for these systems. The structures did not require the use of PLATON/SQUEEZE or other solvent-masking programs, and are the highest-quality crystalline sponge systems reported to date where the results are strongly supported by the data. A set of guidelines for the entire crystallographic process were developed through these studies. In particular, the refinement guidelines include strategies to refine the host framework, locate guests and determine occupancies, discussion of the proper use of geometric and anisotropic displacement parameter restraints and constraints, and whether to perform solvent squeezing/masking. The single-crystal to-single-crystal transformation process for the crystal sponges is also discussed. The presented general guidelines will be invaluable for researchers interested in using the crystalline sponge method at in-house diffraction or synchrotron facilities, will facilitate the collection and analysis of reliable high-quality data, and will allow construction of chemically and physically sensible models for guest structural determination. PMID- 25537390 TI - An alternative method for the calculation of joint probability distributions. Application to the expectation of the triplet invariant. AB - This paper presents a completely new method for the calculation of expectations (and thus joint probability distributions) of structure factors or phase invariants. As an example, a first approximation of the expectation of the triplet invariant (up to a constant) is given and a complex number is obtained. Instead of considering the atomic vector positions or reciprocal vectors as the fundamental random variables, the method samples over all functions (distributions) with a given number of atoms and given Patterson function. The aim of this paper was to explore the feasibility of the method, so the easiest problem was chosen: the calculation of the expectation value of the triplet invariant in P1. Calculation of the joint probability distribution of the triplet is not performed here but will be done in the future. PMID- 25537391 TI - High-symmetry embeddings of interpenetrating periodic nets. Essential rings and patterns of catenation. AB - Symmetrical embeddings are given for multiply intergrown sets of some commonly occurring nets such as dia (diamond), qtz (quartz), pcu (net of primitive cubic lattice) and srs (labyrinth net of the G minimal surface). Data are also given for all known pairs of nets which have edge-transitive self-dual tilings. Examples are given for symmetrical polycatenation of the 2-periodic nets sql (square lattice) and hcb (honeycomb). The idea that the rings that are the faces of natural tilings form a complete basis set (essential rings) is explored and patterns of catenation of such rings described. PMID- 25537392 TI - Direct phasing of protein crystals with high solvent content. AB - An iterative transform method is proposed for solving the phase problem in protein crystallography. In each iteration, a weighted average electron-density map is constructed to define an estimated protein mask. Solvent flattening is then imposed through the hybrid input-output algorithm [Fienup (1982). Appl. Opt. 21, 2758-2769]. Starting from random initial phases, after thousands of iterations the mask evolves into the correct shape and the phases converge to the correct values with an average error of 30-40 degrees for high-resolution data for several protein crystals with high solvent content. With the use of non crystallographic symmetry, the method could potentially be extended to phase protein crystals with less than 50% solvent fraction. The new phasing algorithm can supplement and enhance the traditional refinement tools. PMID- 25537393 TI - Symmetry groups associated with tilings on a flat torus. AB - This work investigates symmetry and color symmetry properties of Kepler, Heesch and Laves tilings embedded on a flat torus and their geometric realizations as tilings on a round torus in Euclidean 3-space. The symmetry group of the tiling on the round torus is determined by analyzing relevant symmetries of the planar tiling that are transformed to axial symmetries of the three-dimensional tiling. The focus on studying tilings on a round torus is motivated by applications in the geometric modeling of nanotori and the determination of their symmetry groups. PMID- 25537394 TI - Scanning of two-dimensional space groups. AB - Tables of the scanning of two-dimensional space groups are presented to determine the frieze-group symmetry of lines that transect two-dimensional crystals. It is shown how these tables can be used to predict the (001) projection symmetries of migration-related segments of coincidence site lattice tilt boundaries with [001] tilt axis. PMID- 25537395 TI - Report of the executive committee for 2013. AB - The report of the Executive Committee for 2013 is presented. PMID- 25537396 TI - Mixing of phosphorescent and exciplex emission in efficient organic electroluminescent devices. AB - We fabricated a yellow organic light-emitting diode (OLED) based on the star shaped donor compound tri(9-hexylcarbazol-3-yl)amine, which provides formation of the interface exciplexes with the iridium(III) bis[4,6-difluorophenyl]-pyridinato N,C2']picolinate (FIrpic). The exciplex emission is characterized by a broad band and provides a condition to realize the highly effective white OLED. It consists of a combination of the blue phosphorescent emission from the FIrpic complex and a broad efficient delayed fluorescence induced by thermal activation with additional direct phosphorescence from the triplet exciplex formed at the interface. The fabricated exciplex-type device exhibits a high brightness of 38 000 cd/m(2) and a high external quantum efficiency. PMID- 25537397 TI - Psychological and somatic sequelae of traumatic vaginal delivery: A literature review. AB - This literature review seeks to examine current knowledge of birth trauma associated with major pelvic floor dysfunction by interpreting and critically appraising existing published material. A search of the literature for peer reviewed journal articles was conducted between September and December 2013 of the following databases: PubMed; Wiley Online; MEDLINE; OvidSP; ScienceDirect; MD Consult Australia; Biomed Central; Sage; Cochrane Database of Systematic Reviews. Unpublished interviews from mothers who attended two tertiary teaching hospitals in Sydney, Australia and international Internet blogs/websites were also utilised. Maternal birth trauma seems to be a common cause of pelvic floor dysfunction. Women who have sustained birth trauma to the levator ani muscle or the anal sphincters are often injured more seriously than generally believed. There often is a substantial latency between trauma and the manifestation of symptoms. Urinary and faecal incontinence, prolapse and sexual dysfunction are commonly seen as too embarrassing to discuss with clinicians, and frequently, new mothers have inaccurate recollections of obstetric procedures that occurred without much explanation or explicit consent. Moreover, somatic trauma may contribute to psychological trauma and post-traumatic stress disorder. The link between somatic and psychological trauma is poorly understood. PMID- 25537400 TI - Importance of spontaneous nystagmus detection in the differential diagnosis of acute vertigo. AB - Vertigo is a common cause of emergency department attendance. Detection of spontaneous nystagmus may be a useful sign in distinguishing vestibular neuritis from other vestibular diagnoses. We aimed to assess the contribution of spontaneous nystagmus in the diagnosis of acute vertigo. We enrolled consecutive consenting patients arriving at a single emergency department with acute vertigo. There was no declared protocol for the emergency department staff. A standardized history and examination was conducted by the investigators. Observation for spontaneous nystagmus, its response to visual fixation, and testing the vestibulo ocular reflex with the horizontal head impulse test were the chief examination components. MRI was obtained within 24 hours. Clinical criteria and MRI were used to reach the final diagnosis. The investigators' physical findings and final neurological diagnosis were compared with the initial emergency department examination findings and the referral diagnosis. There were 28 patients, 15 with vestibular neuritis, six with benign paroxysmal positional vertigo, one with stroke, suspected clinically, and three with migraine. In three the diagnosis remained uncertain. Spontaneous nystagmus was seen in all 15 patients with vestibular neuritis, fixation-suppressed in eight of 11 tested for this. The head impulse test was positive in 12 of 15 with vestibular neuritis. The emergency department referral diagnosis was correct in six of 23 patients. The ability to detect spontaneous nystagmus is useful in vestibular diagnosis, both in support of a diagnosis of vestibular neuritis and in avoiding false positive diagnoses of benign paroxysmal positional vertigo. PMID- 25537402 TI - [The rational use of anti-tuberculosis drugs is the cornerstone of controlling the epidemic of drug-resistant tuberculosis]. PMID- 25537398 TI - Impedance analysis of GPCR-mediated changes in endothelial barrier function: overview and fundamental considerations for stable and reproducible measurements. AB - The past 20 years has seen significant growth in using impedance-based assays to understand the molecular underpinning of endothelial and epithelial barrier function in response to physiological agonists and pharmacological and toxicological compounds. Most studies on barrier function use G protein-coupled receptor (GPCR) agonists which couple to fast and transient changes in barrier properties. The power of impedance-based techniques such as electric cell substrate impedance sensing (ECIS) resides in its ability to detect minute changes in cell layer integrity label-free and in real-time ranging from seconds to days. We provide a comprehensive overview of the biophysical principles, applications, and recent developments in impedance-based methodologies. Despite extensive application of impedance analysis in endothelial barrier research, little attention has been paid to data analysis and critical experimental variables, which are both essential for signal stability and reproducibility. We describe the rationale behind common ECIS data presentation and interpretation and illustrate practical guidelines to improve signal intensity by adapting technical parameters such as electrode layout, monitoring frequency, or parameter (resistance versus impedance magnitude). Moreover, we discuss the impact of experimental parameters, including cell source, liquid handling, and agonist preparation on signal intensity and kinetics. Our discussions are supported by experimental data obtained from human microvascular endothelial cells challenged with three GPCR agonists, thrombin, histamine, and sphingosine-1-phosphate. PMID- 25537403 TI - [Focusing on tuberculosis control from a treatment perspective]. PMID- 25537404 TI - [Reevaluation on application of fluoroquinolones in treatment of drug-resistant tuberculosis]. PMID- 25537406 TI - [To explore the treatment of elderly tuberculosis]. PMID- 25537405 TI - [Application of drug injection in treatment of tuberculosis]. PMID- 25537401 TI - One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition. AB - The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer's disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity. PMID- 25537408 TI - [To pay attention to treatment of tuberculosis in special situations]. PMID- 25537407 TI - [How to use rifamycin rationally: the key issue to prevent multidrug-resistant tuberculosis]. PMID- 25537409 TI - [Individual chemotherapy in tuberculosis]. PMID- 25537410 TI - [Interpretation of the clinical significance of interferon-gamma release assays]. PMID- 25537411 TI - [A study on the cooperation between centers for disease control and special tuberculosis hospitals for treatment and management of multi-drug resistant tuberculosis]. AB - OBJECTIVE: To improve the effectiveness of case detection and treatment of multi drug resistant tuberculosis (MDR-TB) by implementing a mechanism of cooperation between hospitals and centers for disease control (CDC). METHODS: Since 1 March 2010, a new mechanism of cooperation between hospitals and CDCs had been established in 5 cities including Daqing, Quzhou, Puyang, Tianjin and Wanzhou in China. Data of MDR-TB case-detection, treatment and economic burdens before the intervention (January 1, 2006-June 30, 2009) and after the intervention (March 1, 2010-February 29, 2012) were collected. Then all data were analyzed by statistical method. RESULTS: After the intervention, samples from 68.4% (5 287/7 733) of smear-positive TB patients in the study regions underwent TB drug resistant testing, and the number of the detected MDR-TB cases were 9.8 times that prior to the intervention. 93.1% (108/116) of the patients incorporated into the treatment of MDR-TB received the standardized initial chemotherapy program, and the number was 7 times that before the intervention. The referral rates after hospital discharge raised from 0% before the intervention to 92.8% after (90/97) the intervention; and 85.7% (83/97) of the patients received treatment and management by CDC. When the 6-month injection ended, MDR-TB patients still under treatment after the intervention were 84.5% (82/97), and those whose sputum culture became negative were 56.7% (55/97). The proportion of patients with self paid and with catastrophic expenditures after the intervention were reduced to 18.0% (1 678/9 324) and 44.7% (17/38) respectively, as compared to 75.4% (7 659/10 158) and 76.7% (23/30) respectively before the intervention. CONCLUSION: To establish a well-performed Hospital-CDC cooperation mechanism could promote the performance of MDR-TB case detection and treatment. PMID- 25537412 TI - [Bronchial glomus tumor: report of 2 cases and review of the literature]. AB - OBJECTIVE: Glomus tumor is a small, predominantly benign tumor, and typically occurs in the soft tissues, rarely in bronchus. The aim of this study was to discuss the clinical manifestation, histology, diagnosis and differential diagnosis of bronchial glomus tumor. METHODS: We studied the histopathological and immunohistochemical results of 2 cases with bronchial glomus tumor. One case was diagnosed by bronchoscopic biopsy, and another by surgery. We searched Wanfang, VIP, CNKI and PubMed database for related articles with key word "bronchial glomus tumor" both in English and in Chinese for literature review. RESULTS: Fiberoptic bronchoscopy demonstrated a bronchial neoplasm in both 2 cases. For Case one, the tumor was pink under fluorescence bronchoscopy, and was histologically composed of groups of nuclear-irregular round cells in interstices, with pale staining plasma and unclear boundary. Immunohistochemically, cytokeratin (CK) was negative, while vimentin and CD34 vascular endothelial cell were positive, smooth muscle actin (SMA) weakly positive, and Synaptophysin partially positive in tumor cells. These results led to the diagnosis of bronchial glomus tumor of right upper lobe bronchus. The tumor of Case two was histologically from the right main bronchus mesechyma, and it invaded into submucosa, but not involving the tracheal cartilage. Histological examination showed groups of medium sized tumor cells with round nuclei, and abundance of interstitial vasculature. No cellular atypia or mitoses were observed. Immunohistochemical staining demonstrated positive reactivity for vimentin, SMA and CD99. Pathological diagnosis was right main bronchus glomus tumor (malignant potential indeterminacy). We identified 16 studies from databases, of which 15 studies including 15 cases (12 males, 3 females) were applicable. Age of onset ranged from 20 to 79 years. The lesion was in the left main bronchus in 8 cases, the right main broncus in 2, the right middle lobe bronchus in 3, and the right upper lobe bronchus in 2 cases. The tumor size ranged from 0.7 to 6.5 cm. Cough, dyspnea with or without fever were observed in 7 patients. Seven cases had blood in phlegm, and 4 patients showed pulmonary atelectasis. All cases showed negative CK staining and positive SMA staining. CONCLUSION: Bronchial glomus tumor usually lacks clinical manifestations, and is often misdiagnosed as bronchial asthma. It can be classified as solid glomus tumor, ball hemangioma, ball vascular leiomyoma by histopathology. Glomus tumors show positive immunohistochemical stainings for vimentin and smooth muscle actin (SMA), and are usually negative for cytokeratin (CK) and epithelial markers. Clinical differential diagnoses such as sclerosing hemangioma, hemangiopericytoma, carcinoid tumor and epithelial tumor should be considered. PMID- 25537413 TI - [Pulmonary cryptococcosis: a retrospective analysis of 65 cases]. AB - OBJECTIVE: To improve understanding of the clinical manifestations and imaging features of pulmonary cryptococcosis. METHODS: The clinical features, imaging characteristics, laboratory examinations, treatment and prognosis of 65 cases of pulmonary cryptococcosis were retrospectively analyzed. The data were collected from Nanjing General Hospital , Suqian Municipal People's Hospital and People's Liberation Army 81 Hospital from January 2001 to March 2013. RESULTS: There were 65 proven cases diagnosed with pulmonary cryptococcosis, including 44 males and 21 females, aged from 12 to 73 years [average (44 +/- 13) years]. The most common clinical symptoms included cough (n = 32), expectoration(n = 20) , fever (n = 16), and chest pain (n = 14), while some patients(n = 18) had no symptoms. Common chest imaging findings included single or multiple masses or nodules (n = 36), patchy infiltrates (n = 19, and mixed lesions (n = 10). Among the 21 cases with cryptococcal capsular polysaccharide antigen detection, 14 were positive. The antigen titre ( >= 1: 8 for positivity) was positively correlated with disease severity and lesion extent. The diagnosis of 45 cases was proven by percutaneous lung biopsy and 3 were diagnosed by bronchoscopic biopsy, while 17 were confirmed by surgery. Among 65 patients, 53 underwent Acute Physiology and Chronic Health EvaluationII (APACHEII) scoring, and 45 had a score of less than 10. Among them, 38 cases acquired complete or partial recovery, 4 were progressive and 3 died. Eight cases had a score of 10 or more, of whom 3 acquired complete or partial recovery, 1 was progressive and 4 died. CONCLUSIONS: The most common clinical manifestations of pulmonary cryptococcosis were cough and expectoration and the most common chest imaging features were masses or nodular shadows. Percutaneous lung biopsy was a commonly used method to diagnose this disease. Cryptococcal capsular polysaccharide antigen detection was helpful for the diagnosis and management with a relatively high sensitivity. Antifungal drug therapy was the major treatment and a few patients may need surgery. The prognosis was better in patients with mild disease. PMID- 25537414 TI - [Assessment of cognition and associated factors in patients with stable chronic obstructive pulmonary disease]. AB - OBJECTIVE: To explore and analyze the cognitive function in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: The cognition differences between patients with COPD and healthy subjects were analyzed by Montreal Cognitive Assessment (MoCA). GOLD grade, PaO2, PaCO2, the education degree and the age were included as associated factors. The correlation between those factors with cognition were analyzed. RESULTS: The MoCA in patients with COPD was 20.6 +/- 2.3, and that in healthy subjects was 25.3 +/- 1.7; the difference between the 2 groups being significant (P < 0.01). The MoCA was 22.4 +/- 0.8 in patients with GOLD grade I disease, 21.7 +/- 1.0 in grade II, 20.2 +/- 1.2 in grade III, and 19.1 +/- 1.20 in grade IV diseases; the difference among the 4 subgroups being significant (F = 31.69, P < 0.05). The MoCA in GOLD grade I was higher than that in GOLD grade II, but the difference did not reach significance (P > 0.05). The MoCA of GOLD grade II was higher than that in GOLD grade III (P < 0.05) , and the MoCA of GOLD grade III was higher than that GOLD grade IV (P < 0.05). The MoCA in non-hypoxemia subgroup and hypoxemia subgroup was 22.2 +/- 1.1 and 19.8 +/- 1.1, respectively (P < 0.05) , while the MoCA in hypercapnia subgroup and non-hypercapnia subgroup was 20.0 +/- 1.3 and 22.3 +/- 1.0 respectively (P < 0.05). By regression analysis, the score of MoCA was correlated positively to education degree (Standard B1 = 0.134, P < 0.01), GOLD grade(Standard B2 = 0.351, P < 0.01) and PaO2(Standard B3 = 0.305, P < 0.01), while the score of MoCA was correlated negatively to age(Standard B4 = -0.146, P < 0.01) and PaCO2(Standard B5 = -0.145, P < 0.01). CONCLUSIONS: The MoCA score in patients with COPD was lower than that in healthy people. Lower MoCA score was found in patients with severe COPD. The MoCA scores in both hypoxemia subgroup and hypercapnia subgroup were lower. The cognitive dysfunction in patients with stable COPD was positively correlated with education degree, GOLD grade, and PaO2, but negatively with age and PaCO2. PMID- 25537415 TI - [Diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration in pulmonary sarcoidosis]. AB - OBJECTIVE: The aim of this study was to observe the diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in sarcoidosis. METHODS: We retrospectively analyzed the diagnostic efficiency of standard bronchoscopy and EBUS-TBNA in all patients diagnosed as sarcoidosis in Peking University First Hospitals between August 2010 and October 2011. The relationship between biopsy puncture numbers and sensitivity was calculated. RESULTS: There were 17 sarcoidosis patients among a total of 107 patients who had received EBUS-TBNA. Forteen patients had a positive TBNA result and the sensitive of EBUS-TBNA was 82%. The sensitivity of standard brochoscopy was 53% and when combined with EBUS-TBNA, the sensitivity increased to 88%. The sensitivity of EBUS-TBNA was associated with the size of lymph nodes. Lymph nodes with a diameter >= 2 cm showed a higher positive rate. Four punctures for 1 lymph node showed a concordance rate of 100% with the final results. CONCLUSIONS: EBUS-TBNA was a safe and effective method in diagnosing pulmonary sarcoidosis. For patients with suspected sarcoidosis EBUS-TBNA should be performed in the largest lymph nodes with at least 4 punctures. PMID- 25537416 TI - [Research progress in tuberculosis infection and iron metabolism]. PMID- 25537417 TI - [Chronic cough hypersensitivity syndrome]. PMID- 25537418 TI - [Application of targeted drugs for chronic thromboembolic pulmonary hypertension]. PMID- 25537419 TI - [The role of hypoxia-in the pathogenesis of ducible factor-1 in pulmonary arterial hypertension]. PMID- 25537420 TI - Correlations of portal pressure in post-cholecystectomy benign biliary stricture. AB - AIM: Presence of portal hypertension (PH) adversely affects perioperative and long-term outcome in patients with post-cholecystectomy benign biliary stricture (PCBBS). Identification of factors related to the development of PH will help to prevent this complication. METHODS: From September 2010 to December 2012, 30 patients with PCBBS were studied prospectively for correlation of portal pressure (PP) with injury repair interval (IRI), biliary pressure (BP), severity of hepatic fibrosis (FS), severity of hepatic inflammation (IS) and obstructive biliary pathology score (OBPS). Appropriate statistical methods employed and P <= 0.05 (two-sided) was considered statistically significant. RESULTS: Mean PP, mean BP and median IRI were 19.4 +/- 4.74 mmHg, 20.1 +/- 3.99 mmHg and 145 days, respectively. Spearman's rank correlation coefficients (P-value) of PP with IRI, FS, IS and OBPS were 0.564 (0.001), 0.502 (0.004), 0.752 (0.0001) and 0.242 (0.19), respectively. Pearson correlation of PP with BP was r = 0.383 (r(2) = 0.146, P = 0.03). Spearman's rank correlation coefficients (P-value) of FS with IS and OBPS were 0.561 (0.003) and 0.371 (0.04), respectively. Spearman's rank correlation coefficient of serum bilirubin with OBPS was 0.550 (P = 0.001). Incidence of PH was 33.3% and mean fall of PP following biliary repair was 6.2 +/ 1.98 mmHg (P < 0.0001). CONCLUSION: PP in patients with PCBBS has a good correlation with IS, and a fair correlation with both FS and IRI whereas PP was not directly related to BP and OBPS; further prospective trials are mandatory to confirm this correlation, and to evaluate mechanism of fall in PP following biliary decompression. PMID- 25537421 TI - HbA1c method evaluation for postmortem samples. AB - Glycated hemoglobin (HbA1c) is used for diagnosis of diabetes and evaluation of the glycemic control of diabetics in clinical medicine. It is also a useful biomarker for analyzing postmortem samples, since it is relatively stable and correlates well with clinical samples. We wanted to evaluate the information provided by HbA1c analysis of postmortem blood samples using a HPLC based, fully automated analyzer. Autopsy data from 55 cases, in which glucose, lactate, ketone bodies, and HbA1c were analyzed as a part of cause of death investigation, were selected for the study. Another set of 71 samples were analyzed in parallel with Mono S HPLC and automated BioRad D-10 HPLC. The results of 64 samples attained using both methods were compared using a Bland-Altman plot. We conclude that HbA1c can be analyzed reliably and cost-effectively from postmortem samples using a fully automated HPLC based analyzer. It is necessary, particularly in ketoacidotic cases, to determine the HbA1c level to help distinguish diabetic ketoacidosis from other causes. PMID- 25537423 TI - Accurate calibration and control of relative humidity close to 100% by X-raying a DOPC multilayer. AB - In this study, we have designed a compact sample chamber that can achieve accurate and continuous control of the relative humidity (RH) in the vicinity of 100%. A 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) multilayer can be used as a humidity sensor by measuring its inter-layer repeat distance (d-spacing) via X ray diffraction. We convert from DOPC d-spacing to RH according to a theory given in the literature and previously measured data of DOPC multilamellar vesicles in polyvinylpyrrolidone (PVP) solutions. This curve can be used for calibration of RH close to 100%, a regime where conventional sensors do not have sufficient accuracy. We demonstrate that this control method can provide RH accuracies of 0.1 to 0.01%, which is a factor of 10-100 improvement compared to existing methods of humidity control. Our method provides fine tuning capability of RH continuously for a single sample, whereas the PVP solution method requires new samples to be made for each PVP concentration. The use of this cell also potentially removes the need for an X-ray or neutron beam to pass through bulk water if one wishes to work close to biologically relevant conditions of nearly 100% RH. PMID- 25537422 TI - Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content. AB - BACKGROUND AND PURPOSE: Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action. EXPERIMENTAL APPROACH: Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. KEY RESULTS: CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21(CIP1/WAF1) . The effect of CaeA on cell proliferation was reversible. CONCLUSIONS AND IMPLICATIONS: CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron. PMID- 25537424 TI - Advances in the therapy of Alzheimer's disease: targeting amyloid beta and tau and perspectives for the future. AB - Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD. PMID- 25537426 TI - Rapid imaging, detection and quantification of Giardia lamblia cysts using mobile phone based fluorescent microscopy and machine learning. AB - Rapid and sensitive detection of waterborne pathogens in drinkable and recreational water sources is crucial for treating and preventing the spread of water related diseases, especially in resource-limited settings. Here we present a field-portable and cost-effective platform for detection and quantification of Giardia lamblia cysts, one of the most common waterborne parasites, which has a thick cell wall that makes it resistant to most water disinfection techniques including chlorination. The platform consists of a smartphone coupled with an opto-mechanical attachment weighing ~205 g, which utilizes a hand-held fluorescence microscope design aligned with the camera unit of the smartphone to image custom-designed disposable water sample cassettes. Each sample cassette is composed of absorbent pads and mechanical filter membranes; a membrane with 8 MUm pore size is used as a porous spacing layer to prevent the backflow of particles to the upper membrane, while the top membrane with 5 MUm pore size is used to capture the individual Giardia cysts that are fluorescently labeled. A fluorescence image of the filter surface (field-of-view: ~0.8 cm(2)) is captured and wirelessly transmitted via the mobile-phone to our servers for rapid processing using a machine learning algorithm that is trained on statistical features of Giardia cysts to automatically detect and count the cysts captured on the membrane. The results are then transmitted back to the mobile-phone in less than 2 minutes and are displayed through a smart application running on the phone. This mobile platform, along with our custom-developed sample preparation protocol, enables analysis of large volumes of water (e.g., 10-20 mL) for automated detection and enumeration of Giardia cysts in ~1 hour, including all the steps of sample preparation and analysis. We evaluated the performance of this approach using flow-cytometer-enumerated Giardia-contaminated water samples, demonstrating an average cyst capture efficiency of ~79% on our filter membrane along with a machine learning based cyst counting sensitivity of ~84%, yielding a limit-of-detection of ~12 cysts per 10 mL. Providing rapid detection and quantification of microorganisms, this field-portable imaging and sensing platform running on a mobile-phone could be useful for water quality monitoring in field and resource-limited settings. PMID- 25537427 TI - Brain tumor pathology. Preface to special issue. PMID- 25537425 TI - Sustained effects of attentional re-training on chocolate consumption. AB - BACKGROUND AND OBJECTIVES: Accumulating evidence shows that cognitive bias modification produces immediate changes in attentional bias for, and consumption of, rewarding substances including food. This study examined the longevity of these attentional bias modification effects. METHODS: A modified dot probe paradigm was used to determine whether alterations in biased attentional processing of food cues, and subsequent effects on consumption, were maintained at 24-h and one-week follow-up. One hundred and forty-nine undergraduate women were trained to direct their attention toward ('attend') or away from ('avoid') food cues (i.e., pictures of chocolate). Within each group, half received a single training session, the other half completed 5 weekly training sessions. RESULTS: Attentional bias for chocolate cues increased in the 'attend' group, and decreased in the 'avoid' group immediately post training. Participants in the 'avoid' group also ate disproportionately less of a chocolate food product in a so-called taste test than did those in the 'attend' group. Importantly, the observed re-training effects were maintained 24 h later and also one week later, but only following multiple training sessions. LIMITATIONS: There are a number of limitations that could be addressed in future research: (a) the inclusion of a no training control group, (b) the inclusion of a suspicion probe to detect awareness of the purpose of the taste test, and (c) the use of different tasks to assess and re-train attentional bias. CONCLUSIONS: The results showed sustained effects of attentional re-training on attentional bias and consumption. They further demonstrate the importance of administering multiple re-training sessions in attentional bias modification protocols. PMID- 25537428 TI - Association between molecular alterations and tumor location and MRI characteristics in anaplastic gliomas. AB - The aim of this study was to determine if molecular alterations are associated with tumor location and radiological characteristics in anaplastic gliomas. We performed a retrospective analysis of 122 anaplastic gliomas for molecular alterations (IDH1/2 mutations, TP53 mutations, and 1p19q co-deletion) to compare MRI features (location and image characteristics). We observed that IDH mutation is strongly associated with frontal location (P = 0.001). However, 13 tumors not located in the cerebral cortex were IDH intact tumors (P < 0.0001). While IDH mutation and TP53 mutation are significantly associated with AA (p < 0.0001), IDH mutation and 1p19q co-deletion were significantly associated with AO/AOA (p < 0.0001). No tumors with IDH mutation and 1p19q co-deletion infiltrated the temporal lobe (P = 0.003). The tumors with 1p19q co-deletion and histologically diagnosed as AO/AOA were associated with contrast enhancement on MR images (p = 0.007, p = 0.002, respectively) and those with TP53 mutation had a weak association with sharp tumor borders (p = 0.043). MRI features might be useful to predict molecular profiles in anaplastic gliomas. PMID- 25537429 TI - The use of thermodynamic and kinetic data in drug discovery: decisive insight or increasing the puzzlement? AB - The prime property to rate the success of hit-to-lead-to-drug optimization in drug discovery is binding affinity. Rational approaches try to relate this property with structure. Affinity can be linked to the thermodynamic property, Gibbs free energy of binding, which itself factorizes into enthalpy and entropy. With respect to kinetic properties, affinity can be associated with the ratio of koff and kon of complex formation. Do these features help to obtain better insight into affinity? The present viewpoint assesses our current understanding of thermodynamics- or kinetics-structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity. PMID- 25537430 TI - 4D co-registration of X-ray and MR-mammograms: initial clinical results and potential incremental diagnostic value. AB - PURPOSE: 4D co-registration of X-ray- and MR-mammograms (XM and MM) is a new method of image fusion. The present study aims to evaluate its clinical feasibility, radiological accuracy, and potential clinical value. METHODS: XM and MM of 25 patients were co-registered. Results were evaluated by a blinded reader. RESULTS: Precision of the 4D co-registration was "very good" (mean-score [ms]=7), and lesions were "easier to delineate" (ms=5). In 88.8%, "relevant additional diagnostic information" was present, accounting for a more "confident diagnosis" in 76% (ms=5). CONCLUSION: 4D co-registration is feasible, accurate, and of potential clinical value. PMID- 25537431 TI - Association of lumbar fractures, abdominal aortic calcification, and osteopenia. AB - PURPOSE: The purpose was to assess if abdominal aortic calcification (AAC) and low bone mineral density (BMD) are associated with fractures on lumbar spine radiographs in trauma patients. METHODS: Retrospectively, 303 consecutive lumbar radiographs were independently reviewed by two radiologists for AAC, low BMD, and traumatic findings. RESULTS: Thirty-one percent of patients had low BMD, 34% had AAC, and 24% had both. Eleven percent of radiographs showed traumatic findings. Seventy-six percent of positive cases had low BMD (P<.001), and 64% had AAC (P<.001). CONCLUSION: A higher index of suspicion for fractures is warranted when AAC and low BMD are present. PMID- 25537432 TI - A patient-specific predictive model increases preoperative templating accuracy in hip arthroplasty. AB - Application of digital radiography during preoperative templating has shown potential to reduce complications in total hip arthroplasty. In this study, we aimed to further improve digital templating by using a predictive model built on patients' specific data. The model was significant in improving the accuracy of templating within +/-1 size of acetabular component (chi(2)(1, N=468)=19.314, P<0.0001, Phi=0.604, and odds-ratio: 7.750 (95% CI 2.740-30.220)). We successfully achieved a 99% accuracy within +/-2 of templated size. Additionally, patient demographics, such as height and weight, have shown significant effects on the predictive model. The outcome of this study may help reducing the costs of health care in the long term by minimizing implant inventory costs. PMID- 25537433 TI - Forensic features of pharmacobezoars. AB - Three cases of pharmacobezoars are reported to demonstrate typical autopsy findings and potential lethal mechanisms: (i) A 32-year-old woman died following an overdose of prescription medications. A gelatinous pharmacobezoar was found forming a cast of her bronchial tree. (ii) A 24-year-old woman also died following an overdose of prescription medications. At autopsy, two pharmacobezoars were present, one within the larynx and another occluding the right main bronchus. Deaths in both cases were attributed to airway occlusion by pharmacobezoars complicating mixed drug toxicity. (iii) A 79-year-old man was found dead in a car. Death was attributed to the combined effects of carbon monoxide and drug toxicity with a large pharmacobezoar lodged within the esophagus. Pharmacobezoars are specific types of bezoars that occur when pharmaceutical materials, such as tablets, suspensions, and/or drug delivery devices, aggregate and contribute to death by occluding airways with tenacious material or by eluting drugs. PMID- 25537434 TI - Community and state systems change associated with the healthy transitions initiative. AB - People engaged in efforts to improve services to emerging adults with serious mental health challenges have reached the conclusion that service change at the program or agency level is not sustainable without related changes at the systems or policy level. This article focuses on one set of efforts to create intentional system change at both the community and state levels. These changes were pursued by states and communities that received grants under the federally funded Healthy Transitions Initiative (HTI), with the aim of creating more effective services for emerging adults with serious mental health conditions. The article reviews the development of a measure to assess systems change efforts at the state and community levels and describes the findings that emerged when the measure was used to assess the change that occurred in the HTI sites over a period of approximately three and a half years. PMID- 25537435 TI - A novel approach to scanning electron microscopy at ambient atmospheric pressure. AB - Scanning electron microscopy (SEM) for observing samples at ambient atmospheric pressure is introduced in this study. An additional specimen chamber with a small window is inserted in the main specimen chamber, and the window is separated with a thin membrane or diaphragm allowing electron beam propagation. Close proximity of the sample to the membrane enables the detection of back-scattered electrons sufficient for imaging. In addition to the empirical imaging data, a probability analysis of the un-scattered fraction of the incident electron beam further supports the feasibility of atmospheric SEM imaging over a controlled membrane sample distance. PMID- 25537436 TI - Child witnesses in the legal system: improving child interviews and understanding juror decisions. PMID- 25537437 TI - Child maltreatment, trauma-related psychopathology, and eyewitness memory in children and adolescents. AB - Two experiments were conducted to examine eyewitness memory in children and adolescents (9- to 15-years-old) with and without known histories of maltreatment (e.g., physical abuse, exposure to domestic violence). In Experiment 1, participants (N = 35) viewed a positive film clip depicting a congenial interaction between family members. In Experiment 2, participants (N = 31) watched a negative film clip in which a family argument was shown. Younger age and higher levels of trauma-related psychopathology significantly predicted commission errors to direct questions when the positive family interaction had been viewed, but not when the negative family interaction had been shown. Maltreatment history was not a significant unique predictor of memory performance for the positive or negative film clip. Implications for a scientific understanding of the effects of child maltreatment on memory are discussed. PMID- 25537438 TI - The emotional child witness: effects on juror decision-making. AB - Despite wide variations in child witness behavior while on the stand, little research has focused on how that behavior influences jurors' perceptions of the child's credibility or the case itself. In the current study, the impact of a child's emotional displays on credibility judgments and verdict preferences was examined in jury-eligible college students and jurors released from jury duty. No significant differences emerged in perceptions or verdicts based on whether a child was shown as crying or not while participants read a transcript of the child's testimony. However, participants who rated the child as more emotional (regardless of whether the image showed a crying child) were more likely to render guilty verdicts, were more certain of guilt, and found the child more credible and the defendant less credible than participants who rated the child as less emotional. Also, when the child was perceived as low in emotion, older children were rated as less credible than younger children. The results have implications for understanding how children's emotional displays and jurors' perceptions of children's emotionality influence decisions in sexual abuse cases. PMID- 25537439 TI - Efficacy of angiotensin-neprilysin inhibition versus enalapril in patient with heart failure with a reduced ejection fraction. PMID- 25537440 TI - The perception of health-related quality of life in colon cancer patients during chemotherapy: differences between men and women. AB - There is a need for more information on the quality of life (QoL) in patients undergoing chemotherapy. We wanted to investigate the perception of health status in colon cancer patients before, 3 and 6 months after chemotherapy. A secondary purpose was to assess the different perceptions of QoL between men and women during and after adjuvant or palliative therapy. We investigated 100 patients throughout chemotherapy for colon cancer. Data were collected through the SF-36 questionnaire. The score of all variables analyzed in the study group was lower than in the control group, which indicates a lower performance status, more marked in the female sex. Patients were then subdivided by the state of disease (localized or metastatic) and the variables, were evaluated before, 3 and 6 months after therapy. In patients treated with adjuvant treatment, there was a worsening of the performance status, followed by an increase after 6 months. We found that after 3 months of therapy, affected male patients perceived more limitations in carrying out their work, other daily activities and social relationships, owing to both their emotional state and their physical health. In metastatic patients the values of the eight variables decreased dramatically after 6 months, indicating a worsening of the QoL. In patients who received adjuvant treatment there was a certain worsening of the health status at 3 months, followed by a general improvement after 6 months. This improvement was not observed in patients undergoing palliative therapy. Several differences were observed between men and women in performance status after treatment. PMID- 25537441 TI - Mental disorders and HIV infection in the emergency department: epidemiology and gender differences. AB - The management of patients with HIV infection who have comorbidity with psychiatric disorders, is a problem that is encountered relatively frequently in Emergency Departments. This retrospective study aims to evaluate the characteristics of HIV-infected patients who have been admitted for mental disorders and other conditions to an Emergency Department (ED) of Sardinia, Italy, in 2013. Regarding the associated psychiatric condition (25.5% of total sample) 46.3% had mood disorders, 38.9% psychotic disorders and 14.8% anxiety disorders, with no significant gender differences (p = 0.329). The analysis of the sample showed drug abuse in 29.2%. A concomitant infection with HBV or HCV was found in the history of almost half of the patients. Only in 24.5% of cases was there a drug treatment in administered urgently, and an admission to hospital was necessary in 34.3% of the total sample of patients. Among the admissions, 70.4% were admitted to a department of infectious diseases, but of these, only 54.4% had at the admission to the ED signs of acute infection. The management of those who had gained access to emergency services required not only the management of acute disease, but also consideration of which would be the most appropriate department to solve the main problem (infection, fever, agitation, decompensated cirrhosis). Poor patient compliance often makes it difficult to manage, as the analysis of the data shows, a relevant percentage of patients appeared to leave before completion. PMID- 25537443 TI - Differences in knee flexion between the Genium and C-Leg microprocessor knees while walking on level ground and ramps. AB - BACKGROUND: Microprocessor knees have improved the gait and functional abilities of persons with transfemoral amputation. The Genium prosthetic knee offers an advanced sensor and control system designed to decrease impairment by: allowing greater stance phase flexion, easing transitions between gait phases, and compensating for changes in terrain. The aim of this study was to determine differences between the knee flexion angle of persons using the Genium knee, the C-Leg knee, and non-amputee controls; and to evaluate the impact the prostheses on gait and level of impairment of the user. METHODS: This study used a randomized experimental crossover of persons with transfemoral amputation using the Genium and C-Leg microprocessor knees (n=25), with an observational sample of non-amputee controls (n=5). Gait analysis by 3D motion tracking of subjects ambulating at different speeds on level ground and on 5 degrees and 10 degrees ramps was completed. FINDINGS: Use of the Genium resulted in a significant increase in peak knee flexion for swing (5 degrees , p<0.01, d=0.34) and stance (2 degrees , p<0.01, d=0.19) phases relative to C-Leg use. There was a high degree of variability between subjects, and significant differences still remain between the Genium group and the control group's knee flexion angles for most speeds and slopes. INTERPRETATION: The Genium knee generally increases flexion in swing and stance, potentially decreasing the level of impairment for persons with transfemoral amputation. This study demonstrates functional differences between the C-Leg and Genium knees to help prosthetists determine if the Genium will provide functional benefits to individual patients. PMID- 25537442 TI - Hemostatic abnormalities in critically ill patients. AB - Hemostatic abnormalities frequently occur in critically ill patients and may vary from prolonged global clotting tests or isolated thrombocytopenia, to composite defects, such as consumption coagulopathies. There are many reasons for a disturbed coagulation in intensive care patients, and each of these underlying syndromes may require specific therapeutic intervention. Hence, an adequate differential diagnosis and initiation of proper (supportive) therapeutic strategies are critical to decrease morbidity and mortality in critically ill patients with hemostatic abnormalities. PMID- 25537444 TI - A seven-gene signature can predict distant recurrence in patients with triple negative breast cancers who receive adjuvant chemotherapy following surgery. AB - The aim of this study was to investigate candidate genes that might function as biomarkers to differentiate triple negative breast cancers (TNBCs) among patients, who received adjuvant chemotherapy after curative surgery. We tested whether the results of a NanoString expression assay that targeted 250 prospectively selected genes and used mRNA extracted from formalin-fixed, paraffin-embedded would predict distant recurrence in patients with TNBC. The levels of expression of seven genes were used in a prospectively defined algorithm to allocate each patient to a risk group (low or high). NanoString expression profiles were obtained for 203 tumor tissue blocks. Increased expressions of the five genes (SMAD2, HRAS, KRT6A, TP63 and ETV6) and decreased expression of the two genes (NFKB1 and MDM4) were associated favorable prognosis and were validated with cross-validation. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low- and high-risk groups according to gene expression signature were 62% [95% confidence interval (CI), 48.6-78.9%] and 85% (95% CI, 79.2-90.7%), respectively. When adjusting for TNM stage, the distant recurrence-free survival (DRFS)s in the low-risk group was significantly longer than that in the high-risk group (p <0.001) for early stage (I and II) and advanced stage (III) tumors. In a multivariate Cox regression model, the gene expression signature provided significant predictive power jointly with the TNM staging system. A seven-gene signature could be used as a prognostic model to predict DRFS in patients with TNBC who received curative surgery followed by adjuvant chemotherapy. PMID- 25537445 TI - Biology and Industrial Applications of Chlorella: Advances and Prospects. AB - Chlorella represents a group of eukaryotic green microalgae that has been receiving increasing scientific and commercial interest. It possesses high photosynthetic ability and is capable of growing robustly under mixotrophic and heterotrophic conditions as well. Chlorella has long been considered as a source of protein and is now industrially produced for human food and animal feed. Chlorella is also rich in oil, an ideal feedstock for biofuels. The exploration of biofuel production by Chlorella is underway. Chlorella has the ability to fix carbon dioxide efficiently and to remove nutrients of nitrogen and phosphorous, making it a good candidate for greenhouse gas biomitigation and wastewater bioremediation. In addition, Chlorella shows potential as an alternative expression host for recombinant protein production, though challenges remain to be addressed. Currently, omics analyses of certain Chlorella strains are being performed, which will help to unravel the biological implications of Chlorella and facilitate the future exploration of industrial applications. PMID- 25537446 TI - Efficient Biocatalytic Synthesis of Chiral Chemicals. AB - Chiral chemicals are a group of important chiral synthons for the synthesis of a series of pharmaceuticals, agrochemicals, and fine chemicals. In past decades, a number of biocatalytic approaches have been developed for the green and effective synthesis of various chiral chemicals. However, the practical application of these biocatalytic processes is still hindered by the lack of highly efficient and robust biocatalysts, which usually results in the low volumetric productivity and high cost of the bioprocesses. Further step forward of biocatalysis in industrial application strongly requires the development of versatile and highly efficient biocatalysts, aiming to increase the process efficiency and facilitate the downstream processing. Recently, the fast growth of genome sequences in the database in post-genomic era offers great opportunities for accessing numerous biocatalysts with practical application potential, and the so-called genome mining approach provides time-effective and highly specific strategy for the fast identification of target enzymes with desired properties and outperforms the traditional screening of soil samples for microbial enzyme producers of interest. A number of biocatalytic processes with industrial application potential were developed thereafter. Further development of protein engineering strategies, process optimization, and cooperative work between biologists, organic chemists, and engineers is expected to make biocatalysis technology the first choice approach for the eco-friendly, highly efficient, and cost-effective synthesis of chiral chemicals in the near future. PMID- 25537448 TI - A sector-based dosimetric analysis of dose heterogeneity in high-dose-rate prostate brachytherapy. AB - PURPOSE: High-dose-rate (HDR) prostate brachytherapy delivers a heterogeneous dose distribution throughout the prostate gland. There is however limited information regarding the spatial distribution of this dose heterogeneity. To this end, we analyzed the magnitude and location of intraprostatic dose heterogeneity in HDR prostate brachytherapy. METHODS AND MATERIALS: Five consecutive prostate cancer patients treated with HDR were analyzed. Based on CT simulation images, each prostate was divided into three sections (apex, base, and mid-gland). These were further subdivided into eight symmetrical sections to give a total of 24 sections. Dose-volume histograms were analyzed from V100-V200% for these 24 sections comparing the means of individual regions, left vs right, apex vs base vs mid-gland, lateral vs medial, and anterior vs posterior. A separate analysis on dose as a function of individual region volume was also performed. RESULTS: Analyses comparing the 24 regions showed a maximum 62% difference (range, 21.9-83.9%) at V130% and 19.9% (1.9-20.8%) at V200%. Seven regions were significantly decreased and one significantly elevated from V130-V180% when compared with the mean. The means for lateral sections were 1.57-fold higher than medial sections from V110-V200% (p < 0.0001). The dose at the base was significantly higher than the rest of the gland from V120-V200 (V150, 35.6 +/- 16.2% vs 20.9 +/- 13.1%, p < 0.0001). CONCLUSIONS: There is significant intra prostatic dose heterogeneity in prostate HDR brachytherapy. This is most notable in the increased dose to base and lateral portions of the gland. Further studies are needed to determine the impact of heterogeneity on clinical outcomes. PMID- 25537449 TI - Intramolecular proton transfer in 2-(2'-hydroxyphenyl)oxazolo[4,5-b]pyridine: evidence for tautomer in the ground state. AB - The intramolecular proton transfer in a newly synthesized molecule, 2-(2' hydroxyphenyl)oxazolo[4,5-b]pyridine (HPOP) is studied using UV-visible absorption, fluorescence emission, fluorescence excitation and time-resolved fluorescence spectroscopy. In the ground state, the molecule exists as cis- and trans-enol in all the solvents. However, in dioxane, alcohols, acetonitrile, dimethylformamide and dimethylsulfoxide the keto tautomer is also observed in the ground state. Dual fluorescence is observed in HPOP where the large Stoke shifted emission is due to emission from the excited-state intramolecular proton transfer product, whereas the other emission is the normal emission from enol form. The fluorescence (both normal and tautomer emission) of HPOP is less than those of corresponding benzoxazole and imidazopyridine derivatives. This reveals that the nonradiative decay becomes more efficient upon substitution of electronegative atom on the charge acceptor group. The pH studies substantiate the conclusion that (unlike in its imidazole analog) the third ground state species is the keto tautomer and not the monoanion. The effect of temperature on cis-enol-trans-enol keto equilibrium and the nonradiative deactivation from the excited state are also investigated. PMID- 25537447 TI - A cell-ECM screening method to predict breast cancer metastasis. AB - Breast cancer preferentially spreads to the bone, brain, liver, and lung. The clinical patterns of this tissue-specific spread (tropism) cannot be explained by blood flow alone, yet our understanding of what mediates tropism to these physically and chemically diverse tissues is limited. While the microenvironment has been recognized as a critical factor in governing metastatic colonization, the role of the extracellular matrix (ECM) in mediating tropism has not been thoroughly explored. We created a simple biomaterial platform with systematic control over the ECM protein density and composition to determine if integrin binding governs how metastatic cells differentiate between secondary tissue sites. Instead of examining individual behaviors, we compiled large patterns of phenotypes associated with adhesion to and migration on these controlled ECMs. In combining this novel analysis with a simple biomaterial platform, we created an in vitro fingerprint that is predictive of in vivo metastasis. This rapid biomaterial screen also provided information on how beta1, alpha2, and alpha6 integrins might mediate metastasis in patients, providing insights beyond a purely genetic analysis. We propose that this approach of screening many cell-ECM interactions, across many different heterogeneous cell lines, is predictive of in vivo behavior, and is much simpler, faster, and more economical than complex 3D environments or mouse models. We also propose that when specifically applied toward the question of tissue tropism in breast cancer, it can be used to provide insight into certain integrin subunits as therapeutic targets. PMID- 25537450 TI - READMIT: a clinical risk index to predict 30-day readmission after discharge from acute psychiatric units. AB - Our aim was to create a clinically useful risk index, administered prior to discharge, for determining the probability of psychiatric readmission within 30 days of hospital discharge for general psychiatric inpatients. We used population level sociodemographic and health administrative data to develop a predictive model for 30-day readmission among adults discharged from an acute psychiatric unit in Ontario, Canada (2008-2011), and converted the final model into a risk index system. We derived the predictive model in one-half of the sample (n = 32,749) and validated it in the other half of the sample (n = 32,750). Variables independently associated with 30-day readmission (forming the mnemonic READMIT) were: (R) Repeat admissions; (E) Emergent admissions (i.e. harm to self/others); (D) Diagnoses (psychosis, bipolar and/or personality disorder), and unplanned Discharge; (M) Medical comorbidity; (I) prior service use Intensity; and (T) Time in hospital. Each 1-point increase in READMIT score (range 0-41) increased the odds of 30-day readmission by 11% (odds ratio 1.11, 95% CI 1.10-1.12). The index had moderate discriminative capacity in both derivation (C-statistic = 0.631) and validation (C-statistic = 0.630) datasets. Determining risk of psychiatric readmission for individual patients is a critical step in efforts to address the potentially avoidable high rate of this negative outcome. The READMIT index provides a framework for identifying patients at high risk of 30-day readmission prior to discharge, and for the development, evaluation and delivery of interventions that can assist with optimizing the transition to community care for patients following psychiatric discharge. PMID- 25537452 TI - Effects of CHO-expressed recombinant lactoferrins on mouse dendritic cell presentation and function. AB - Lactoferrin (LF), a natural iron-binding protein, has previously demonstrated effectiveness in enhancing the Bacillus Calmette-Guerin (BCG) tuberculosis vaccine. This report investigates immune modulatory effects of Chinese hamster ovary (CHO) cell-expressed recombinant mouse and human LFs on mouse bone marrow derived dendritic cells (BMDCs), comparing homologous and heterologous functions. BCG-infected BMDCs were cultured with LF, and examined for class II presentation molecule expression. Culturing of BCG-infected BMDCs with either LF decreased the class II molecule-expressing population. Mouse LF significantly increased the production of IL-12p40, IL-1beta and IL-10, while human LF-treated BMDCs increased only IL-1beta and IL-10. Overlaying naive CD4 T-cells onto BCG-infected BMDCs cultured with mouse LF increased IFN-gamma, whereas the human LF-exposed group increased IFN-gamma and IL-17 from CD4 T cells. Overlay of naive CD8 T cells onto BCG-infected BMDCs treated with mouse LF increased the production of IFN-gamma and IL-17, while similar experiments using human LF only increased IL 17. This report is the first to examine mouse and human recombinant LFs in parallel experiments to assess murine DC function. These results detail the efficacy of the human LF counterpart used in a heterologous system to understand LF-mediated events that confer BCG efficacy against Mycobacterium tuberculosis challenge. PMID- 25537453 TI - Dynamic epigenetic regulation by menin during pancreatic islet tumor formation. AB - The tumor suppressor gene MEN1 is frequently mutated in sporadic pancreatic neuroendocrine tumors (PanNET) and is responsible for the familial multiple endocrine neoplasia type 1 (MEN-1) cancer syndrome. Menin, the protein product of MEN1, associates with the histone methyltransferases (HMT) MLL1 (KMT2A) and MLL4 (KMT2B) to form menin-HMT complexes in both human and mouse model systems. To elucidate the role of methylation of histone H3 at lysine 4 (H3K4) mediated by menin-HMT complexes during PanNET formation, genome-wide histone H3 lysine 4 trimethylation (H3K4me3) signals were mapped in pancreatic islets using unbiased chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). Integrative analysis of gene expression profiles and histone H3K4me3 levels identified a number of transcripts and target genes dependent on menin. In the absence of Men1, histone H3K27me3 levels are enriched, with a concomitant decrease in H3K4me3 within the promoters of these target genes. In particular, expression of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) gene is subject to dynamic epigenetic regulation by Men1-dependent histone modification in a time-dependent manner. Decreased expression of IGF2BP2 in Men1 deficient hyperplastic pancreatic islets is partially reversed by ablation of RBP2 (KDM5A), a histone H3K4-specific demethylase of the jumonji, AT-rich interactive domain 1 (JARID1) family. Taken together, these data demonstrate that loss of Men1 in pancreatic islet cells alters the epigenetic landscape of its target genes. IMPLICATIONS: Epigenetic profiling and gene expression analysis in Men1-deficient pancreatic islet cells reveals vital insight into the molecular events that occur during the progression of pancreatic islet tumorigenesis. PMID- 25537455 TI - Live-cell imaging of endogenous mRNAs with a small molecule. AB - Determination of subcellular localization and dynamics of mRNA is increasingly important to understanding gene expression. A new convenient and versatile method is reported that permits spatiotemporal imaging of specific non-engineered RNAs in living cells. The method uses transfection of a plasmid encoding a gene specific RNA aptamer, combined with a cell-permeable synthetic small molecule, the fluorescence of which is restored only when the RNA aptamer hybridizes with its cognitive mRNA. The method was validated by live-cell imaging of the endogenous mRNA of beta-actin. Application of the technology to mRNAs of a total of 84 human cytoskeletal genes allowed us to observe cellular dynamics of several endogenous mRNAs including arfaptin-2, cortactin, and cytoplasmic FMR1 interacting protein 2. The RNA-imaging technology and its further optimization might permit live-cell imaging of any RNA molecules. PMID- 25537456 TI - Extranodal and nodal diffuse large B cell lymphoma of the head and neck: two different entities? AB - This study analyzes patients with head and neck diffuse large B cell lymphoma (HN DLBCL), focusing on the differences in the biological characteristics and prognosis of lymphomas of nodal and extranodal origin. We have included 72 patients with stage I-II HN-DLBCL who had updated survival information and diagnostic paraffin-embedded tissue blocks available for review. Non-germinal center phenotype (73.7 vs. 32.4 %, P = 0.001) and high level of Bcl-2 expression (78.9 vs. 52.9 %, P = 0.025) were more frequent in nodal than extranodal lymphomas. Univariate analyses indicated that bulky disease, Ann Arbor stage II, high level of Ki-67 expression, and primary nodal disease had adverse effects on complete remission (CR), but these effects were confirmed in a multivariate analysis for primary nodal disease and bulky disease. Patients with primary extranodal lymphoma also had better overall survival (OS) (87.7 vs. 72.5 %, P = 0.04) and event-free survival (EFS) (84 vs. 58.5 %, P = 0.046) than patients with nodal disease, although in the multivariate analysis, only Ann Arbor stage II continued to predict worse OS and EFS, whereas bulky disease was an independent prognostic factor only for EFS. We found significant differences in the biological characteristics and prognosis between primary nodal and extranodal HN DLBCL. PMID- 25537451 TI - Therapies for the bone in mucopolysaccharidoses. AB - Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs. PMID- 25537457 TI - SVM-Based CAC System for B-Mode Kidney Ultrasound Images. AB - The present study proposes a computer-aided classification (CAC) system for three kidney classes, viz. normal, medical renal disease (MRD) and cyst using B-mode ultrasound images. Thirty-five B-mode kidney ultrasound images consisting of 11 normal images, 8 MRD images and 16 cyst images have been used. Regions of interest (ROIs) have been marked by the radiologist from the parenchyma region of the kidney in case of normal and MRD cases and from regions inside lesions for cyst cases. To evaluate the contribution of texture features extracted from de speckled images for the classification task, original images have been pre processed by eight de-speckling methods. Six categories of texture features are extracted. One-against-one multi-class support vector machine (SVM) classifier has been used for the present work. Based on overall classification accuracy (OCA), features from ROIs of original images are concatenated with the features from ROIs of pre-processed images. On the basis of OCA, few feature sets are considered for feature selection. Differential evolution feature selection (DEFS) has been used to select optimal features for the classification task. DEFS process is repeated 30 times to obtain 30 subsets. Run-length matrix features from ROIs of images pre-processed by Lee's sigma concatenated with that of enhanced Lee method have resulted in an average accuracy (in %) and standard deviation of 86.3 +/- 1.6. The results obtained in the study indicate that the performance of the proposed CAC system is promising, and it can be used by the radiologists in routine clinical practice for the classification of renal diseases. PMID- 25537454 TI - Addressing unmet medical needs in type 2 diabetes: a narrative review of drugs under development. AB - The global burden of type 2 diabetes is increasing worldwide, and successful treatment of this disease needs constant provision of new drugs. Twelve classes of antidiabetic drugs are currently available, and many new drugs are under clinical development. These include compounds with known mechanisms of action but unique properties, such as once-weekly DPP4 inhibitors or oral insulin. They also include drugs with new mechanisms of action, the focus of this review. Most of these compounds are in Phase 1 and 2, with only a small number having made it to Phase 3 at this time. The new drug classes described include PPAR agonists/modulators, glucokinase activators, glucagon receptor antagonists, anti inflammatory compounds, G-protein coupled receptor agonists, gastrointestinal peptide agonists other than GLP-1, apical sodium-dependent bile acid transporter (ASBT) inhibitors, SGLT1 and dual SGLT1/SGLT2 inhibitors, and 11beta- HSD1 inhibitors. PMID- 25537458 TI - Ultrasound-Derived Three-Dimensional Printing in Congenital Heart Disease. AB - Three-dimensional printing technology has significant clinical implications for the management of congenital heart disease. Computed tomography and magnetic resonance imaging have been established as imaging tools for the creation of physical three-dimensional models. The potential use of non-invasive bedside imaging techniques such as three-dimensional echocardiography to derive three dimensional printed models can revolutionize the planning of interventions for complex congenital malformations. The feasibility of deriving three-dimensional printing from ultrasound provides an additional cost-effective and patient centered option for interventional cardiologists and surgeons for the management and care of congenital heart disease patients. PMID- 25537459 TI - Elevated systolic blood pressure is associated with increased incidence of chronic kidney disease but not mortality in elderly veterans. AB - The optimal blood pressure to prevent development of chronic kidney disease (CKD) and mortality in the elderly is unclear. Our objective was to determine the effect of differing levels of blood pressure on incidence of CKD and mortality in elderly veterans. This retrospective cohort study included 15,221 individuals >=70 years of age without CKD (outpatient estimated glomular filtration rate >60 mL/min/1.73 m(2)) seen in the primary care clinic in the Veterans Affairs Health Care Upstate New York with Veterans Integrated Service Network 2 between 2001 and 2008. To examine the association of explanatory variables on hazard ratios for outcomes of interest, incident CKD, and death, competing risk analysis (with death as competing risk) was used for the analysis of incident CKD outcome, and time-dependent Cox model with CKD as the time-dependent covariate was used for the analysis of death outcome. The incidence of CKD was 16% over a median follow up of 19 quarters. Compared with reference of systolic blood pressure of 130-139 mm Hg, there was an increased hazard of development of CKD with systolic blood pressure of 140-149 mm Hg or higher. As compared with a reference range of 130 139 mm Hg systolic blood pressure, the relative risk of mortality was higher in the range of 120-129 mm Hg systolic or less. The optimal achieved systolic blood pressure in elderly patients to prevent the development of CKD was <140 mm Hg. However, lowering the systolic blood pressure below 130 mm Hg was associated with increased mortality. PMID- 25537461 TI - SGLT2 inhibitors: their potential reduction in blood pressure. AB - The sodium glucose co-transporter 2 (SGLT2) inhibitors represent a promising treatment option for diabetes and its common comorbidity, hypertension. Emerging data suggests that the SGLT2 inhibitors provide a meaningful reduction in blood pressure, although the precise mechanism of the blood pressure drop remains incompletely elucidated. Based on current data, the blood pressure reduction is partially due to a combination of diuresis, nephron remodeling, reduction in arterial stiffness, and weight loss. While current trials are underway focusing on cardiovascular endpoints, the SGLT2 inhibitors present a novel treatment modality for diabetes and its associated hypertension as well as an opportunity to elucidate the pathophysiology of hypertension in diabetes. PMID- 25537460 TI - Prevalence of angiotensin II type 1 receptor (AT1R)-activating autoantibodies in primary aldosteronism. AB - Autoantibodies to the angiotensin II type 1 receptor (AT1R) have been reported in patients with primary aldosteronism, including aldosterone producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Sera from 25 primary aldosteronism subjects (12 with IAH and 13 with APA) and 15 normotensive control subjects were assayed for AT1R autoantibodies by enzyme-linked immunosorbent assay and an AT1R-transfected cell-based bioassay. Nine of 12 IAH subjects (75%) and six of 13 APA subjects (46%) were positive for AT1R autoantibodies in the bioactivity assay. The mean AT1R autoantibody activity for the IAH and APA subjects was significantly greater than controls (P < .001 and P < .01, respectively), and this in vitro activity was suppressed by the AT1R blocker losartan. None of the controls had significant AT1R autoantibody activity. Enzyme linked immunosorbent assay values were less sensitive but were positive in some subjects with IAH and APA. The mean arterial pressure of these primary aldosteronism subjects correlated modestly with AT1R autoantibody activity. These data confirm the presence of active AT1R autoantibodies in a high percentage of subjects with primary aldosteronism irrespective of their underlying etiology. These observations have both pathophysiological and clinical implications. PMID- 25537462 TI - Plasma visfatin/nicotinamide phosphoribosyltransferase levels in hypertensive elderly - results from the PolSenior substudy. AB - Visfatin/nicotinamide phosphoribosyltransferase (NAMPT), is a 52 kDa adipokine with proinflammatory properties produced mostly by macrophages and adipocytes from visceral adipose tissue. It seems that visfatin/NAMPT plays a role in the pathogenesis of arterial hypertension. As this condition is frequently present in the elderly, the aim of the study was to assess the plasma visfatin/NAMPT levels in normotensive and hypertensive subjects from the Polish elderly population. Visfatin/NAMPT levels were measured by specific enzyme-linked immunosorbent assay method in plasma samples from 2789 elderly subjects (1338 females, 1451 males) without heart failure, the PolSenior study participants, in addition to previously estimated serum concentrations of insulin, glucose, creatinine, C reactive protein, and interleukin-6. Homeostasis model assessment for insulin resistance was calculated and used as a marker of insulin resistance. In the study group, 591 subjects were normotensive, 449 had untreated hypertension, and 1749 had treated hypertension. Plasma visfatin/NAMPT levels were not related to the presence of hypertension or the use of antihypertensive drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. The regression analysis revealed that plasma visfatin/NAMPT concentration variability is increased in subjects with high-sensitivity C-reactive protein concentration above 3 mg/L and with homeostasis model assessment for insulin resistance >=2.5, and decreased in those aged over 80 years. Our study shows that the presence of hypertension is not associated with the plasma levels of visfatin/NAMPT in elderly subjects. Plasma visfatin/NAMPT concentrations positively correlate with inflammation and insulin resistance, and are decreased in the oldest. PMID- 25537463 TI - Improving outcomes in cancer patients on oral anti-cancer medications using a novel mobile phone-based intervention: study design of a randomized controlled trial. AB - BACKGROUND: The widespread and increasing use of oral anti-cancer medications has been ushered in by a rapidly increasing understanding of cancer pathophysiology. Furthermore, their popular ease of administration and potential cost savings has highlighted their central position in the health care system as a whole. These facts have heightened appreciation of the unique challenges associated with the use of oral anti-cancer medications; especially in the long-term use of these medications and the associated side effects that may impede optimal adherence to their use. Therefore, we developed ChemOtheRapy Assistant, CORA, a personalized mobile phone-based self-management application to help cancer patients on oral anti-cancer medications. OBJECTIVE: Our objective is to evaluate the effect of CORA on adherence to oral anti-cancer medications and other clinically relevant outcomes in the management of patients with renal and prostate cancer. METHODS: The study will be implemented as a 2-parallel group randomized controlled trial in 104 patients with renal or prostate cancer on oral anti-cancer medications over a 3-month study period. The intervention group will use CORA in addition to usual care for self-management while the control group will continue care as usual. Medication adherence will be measured objectively by a Medication Event Monitoring System device and is defined as the percentage of prescribed doses taken. We will also assess the effect of the intervention on cancer-related symptoms measured by the MD Anderson Symptom Inventory and unplanned hospital utilizations. Other outcomes that will be measured at study start, midpoint, and endpoint are health-related quality of life, cancer-related fatigue, and anxiety. Group differences in medication adherence will be examined by t tests or by non parametric Mann-Whitney tests if the data are not normally distributed. Logistic regression will be used to identify potential predictors of adherence. RESULTS: We expect to have results for this study before the end of 2016. CONCLUSIONS: This novel mobile phone-enabled, multimodal self-management and educational intervention could lead to improvements in clinical outcomes and serve as a foundation for future mHealth research in improving outcomes for patients on oral anti-cancer medications. PMID- 25537464 TI - The Benefits of Patient Involvement for Translational Research. AB - The question we raise in this paper is, whether patient involvement might be a beneficial way to help determine and achieve the aims of translational (TR) research and, if so, how to proceed. TR is said to ensure a more effective movement ('translation') of basic scientific findings to relevant and useful clinical applications. In view of the fact that patients are supposed to be the primary beneficiaries of such translation and also have relevant knowledge based on their experience, listening to their voice early on in the innovation process might very well increase the effectiveness of the translation. After explaining how the concept of TR emerged and what it entails, this paper shows through a literature review which arguments have been put forward to promote patient involvement in health care research in a more general sense. We examine whether, and if so how, these arguments are relevant for the discourse on TR and we identify pitfalls and dilemmas. Ultimately, we conclude that it may be worthwhile to experiment with patient involvement in TR but that the design of such involvement requires careful consideration. PMID- 25537465 TI - Trial-type probability and task-switching effects on behavioral response characteristics in a mixed saccade task. AB - Eye movement circuitry involved in saccade production offers a model for studying cognitive control: visually guided prosaccades are stimulus-directed responses, while goal-driven antisaccades rely upon more complex control processes to inhibit the prepotent tendency to look toward a cue, transform its spatial location, and generate a volitional saccade in the opposite direction. By manipulating the relative probability of these saccade types, we measured participants' behavioral responses to different levels of implicit trial-type probability and task-switching demands in conditions with relatively long inter trial fixation and trial-type cue lengths. Results indicated that when prosaccades were less probable in a run, more prosaccade errors were generated; however, for antisaccades, trial-type probability had no effect on the percent of correct responses. For reaction times, specifically in runs with a larger probability of antisaccade trials, latencies increased for both anti- and pro saccades. Furthermore, task switching resulted in a lower percentage of correct responses on switched trials, but a prior antisaccade trial led to slower reaction times for both trial types (i.e., a task switch cost for prosaccades and switch benefit for antisaccades). These findings indicate that cognitive control demands and residual inhibition from antisaccades alter performance relative to trial-type probability and task switching within a run, with the prosaccade task showing greater susceptibility to the influence of a large probability of cognitively complex antisaccades. PMID- 25537466 TI - Improved gait adjustments after gait adaptability training are associated with reduced attentional demands in persons with stroke. AB - After stroke, the ability to make step adjustments during walking is reduced and requires more attention, which may cause problems during community walking. The C Mill is an innovative treadmill augmented with visual context (e.g., obstacles and stepping targets), which was designed specifically to practice gait adaptability. The objective of this study was to determine whether C-Mill gait adaptability training can help to improve gait adjustments and associated attentional demands. Sixteen community-ambulating persons in the chronic stage of stroke (age: 54.8 +/- 10.8 years) received ten sessions of C-Mill training within 5-6 weeks. Prior to and after the intervention period, participants performed an obstacle-avoidance task with and without a secondary attention-demanding auditory Stroop task to assess their ability to make gait adjustments (i.e., obstacle avoidance success rates) as well as the associated attentional demands (i.e., Stroop success rates, stratified for pre-crossing, crossing, and post-crossing strides). Obstacle-avoidance success rates improved after C-Mill training from 52.4 +/- 16.3 % at pretest to 77.0 +/- 16.4 % at posttest (p < 0.001). This improvement was accompanied by greater Stroop success rates during the obstacle crossing stride only (pretest: 62.9 +/- 24.9 %, posttest: 77.5 +/- 20.4 %, p = 0.006). The observed improvements in obstacle-avoidance success rates and Stroop success rates were strongly correlated (r = 0.68, p = 0.015). The ability to make gait adjustments and the associated attentional demands can be successfully targeted in persons with stroke using C-Mill training, which suggests that its underlying assumptions regarding motor control are appropriate. This study lends support and guidance for designing a randomized controlled trial to further examine the potential of C-Mill training for improving safe community ambulation after stroke. PMID- 25537467 TI - Retention of proprioceptive recalibration following visuomotor adaptation. AB - We have recently shown that visuomotor adaptation following reaches with a misaligned cursor not only induces changes in an individual's motor output, but their proprioceptive sense of hand position as well. Long-term changes are seen in motor adaptation; however, very little is known about the retention of changes in felt hand position. We sought to evaluate whether this recalibration in proprioception, following visuomotor adaptation, is sufficiently robust to be retained the following day (~24 h later), and if so, to determine its extent. Visuomotor adaptation was induced by having subjects perform reaches to visual targets using a cursor representing their unseen hand, which had been gradually rotated 45 degrees counterclockwise. Motor adaptation and proprioceptive recalibration were determined by assessing subjects' reach aftereffects and changes in hand bias, respectively. We found that subjects adapted their reaches and recalibrated their sense of hand position following training with a misaligned cursor, as shown in Cressman and Henriques (J Neurophysiol 102:3505 3518, 2009). More importantly, subjects who showed proprioceptive recalibration in the direction of motor adaptation on Day 1 did retain changes in felt hand position and motor adaptation on Day 2. These findings suggest that in addition to motor changes, individuals are capable of retaining sensory changes in proprioception up to 24 h later. PMID- 25537468 TI - The effects of warning cues and attention-capturing stimuli on the sustained attention to response task. AB - Performance on the sustained attention to response task (SART) is often characterized by a speed-accuracy trade-off, and SART performance may be influenced by strategic factors (Head and Helton Conscious Cogn 22: 913-919, 2013). Previous research indicates a significant difference between reliable and unreliable warning cues on response times and errors (commission and omission), suggesting that SART tasks are influenced by strategic factors (Helton et al. Conscious Cogn 20: 1732-1737, 2011; Exp Brain Res 209: 401-407, 2011). With regards to warning stimuli, we chose to use cute images (exhibiting infantile features) during a SART, as previous literature indicates cute images cause participants to engage attention. If viewing cute things makes the viewer exert more attention than normal, then exposure to cute stimuli during the SART should improve performance if SART performance is a measure of perceptual coupling. Reliable warning cues were shown to reduce both response time and errors of commission, and increase errors of omission, relative to unreliable warning cues. Cuteness of the warning stimuli, however, had no significant effect on SART performance. These results suggest the importance of strategic factors in SART performance, not increased attention, and add to the growing literature which suggests the SART is not a good measure of sustained attention, vigilance or perceptual coupling. PMID- 25537469 TI - The role of the dorsolateral funiculi in the pain relieving effect of spinal cord stimulation: a study in a rat model of neuropathic pain. AB - Activation of the dorsal columns is relayed to supraspinal centers, involved in pain modulation, probably via the descending fibers in the dorsolateral funiculi (DLF). The present study examines the role of the DLF in the attenuation of pain related signs by spinal cord stimulation (SCS). Several groups of rats were subjected to nerve injury and to chronic bilateral DLF lesions at C5-7 level. In each animal, two sets of miniature electrodes were implanted, a caudal system placed in the dorsal epidural space at low thoracic level and another implanted over the dorsal column nuclei, rostral to the lesions. Stimulation (50 Hz, 0.2 ms; 70 % of motor threshold) was applied for 5 min via either of the electrodes. Behavioral tests were used to assess the effects of SCS on the nerve injury induced mechanical and cold hypersensitivity and heat hyperalgesia. Prior to application of SCS, antagonists to either of GABAA or B, 5-HT1 or 1-2 or alpha/beta-adrenergic receptors were injected i.p. Both stimulations produced comparable decreases (80-90 % of the control) of neuropathic manifestations in rats with intact spinal cords. DLF lesions attenuated the effects of both types of stimulation by about 50 %. Pretreatment with receptor antagonists differentially counteracted the effects of rostral and caudal stimulation; the inhibition with rostral stimulation generally being more prominently influenced. These results provide further support to the notion of important involvement of brainstem pain modulating centers in the effects of SCS. A major component of the inhibitory spinal-supraspinal-spinal loop is mediated by fibers running in the DLF. PMID- 25537470 TI - The role of the viewpoint on body ownership. AB - People are more sensitive to detecting asynchrony between a self-generated movement of the hand and delayed visual feedback when what they see matches the expected "self" perspective rather than an "other" perspective (Hoover and Harris in Exp Brain Res 222:389-397, 2012). We take this as corresponding to the ability to distinguish self from others and call it the "self-advantage": a measure of body ownership. What about views of the body that cannot be seen directly? Here, we assessed the effect of familiarity of the view of the body on the self advantage. Participants performed self-generated hand and head movements viewed directly, in a mirror, and from behind with a variable delay added to the visual feedback. Each view was shown either in the natural perspective or flipped about the vertical or horizontal axes to provide a view from another perspective. Thresholds for detecting a delay in visual feedback were calculated. Dependency of the self-advantage on perspective was most evident for views of the body that are seen most often. Results support the importance of correlating visual feedback with movement information in creating the sense of body ownership. PMID- 25537471 TI - The relationship between aerobic fitness and neural oscillations during visuo spatial attention in young adults. AB - While the cognitive benefits of aerobic fitness have been widely investigated, current findings in young adults remain unclear. Specifically, little is known about how these effects are reflected in the time-frequency domain. This study thus assessed the relationship between aerobic fitness and neural oscillations during visuo-spatial attention. A between-subjects design that included 20 participants with higher aerobic fitness (age = 21.95 +/- 2.24 years; VO2max = 58.98 +/- 6.94 ml/kg/min) and 20 age- and gender-matched lower aerobic fitness participants (age = 23.25 +/- 2.07 years; VO2max = 35.87 +/- 3.41 ml/kg/min) was used to examine the fitness-related differences in performance and neuroelectric indexes during a Posner visuo-spatial attention paradigm. The results demonstrated that high-fitness participants, in comparison with their low-fitness counterparts, showed faster reaction times as well as greater modulation of oscillatory theta and beta power during target processing, regardless of cue types. Moreover, the neurocognitive correlation showed that higher theta power was related to better task performance. Collectively, these findings suggest that aerobic fitness is associated with general enhanced attentional control in relation to visuo-spatial processing, as evidenced through greater motor preparation and in particular the up-regulation of attentional processing in healthy young adults. The present study may contribute to current knowledge by revealing the relationship between aerobic fitness and modulation of brain oscillations. PMID- 25537473 TI - Michael Gross: 25 years of dedication and leadership of JASMS (1990-2015). PMID- 25537472 TI - Effects of support surface stability on feedback control of trunk posture. AB - This study aimed to examine the interactions of visual, vestibular, proprioceptive, and tactile sensory manipulations and sitting on either a stable or an unstable surface on mediolateral (ML) trunk sway. Fifteen individuals were measured. In each trial, subjects sat as quiet as possible, on a stable or unstable surface, with or without each of four sensory manipulations: visual (eyes open/closed), vestibular (left and right galvanic vestibular stimulation alternating at 0.25 Hz), proprioceptive (left and right paraspinal muscle vibration alternating at 0.25 Hz), and tactile (minimal finger contact with object moving in the frontal plane at 0.25 Hz). The root mean square (RMS) and the power at 0.25 Hz (P25) of the ML trunk acceleration were the dependent variables. The latter was analyzed only for the rhythmic sensory manipulations and the reference condition. RMS was always significantly larger on the unstable than the stable surface. Closing the eyes caused a significant increase in RMS, more so on the unstable surface. Vestibular stimulation significantly increased RMS and P25 and more so on the unstable surface. Main effects of the proprioceptive manipulation were significant, but the interactions with surface condition were not. Finally, also tactile manipulation increased RMS and P25, but did not interact with surface condition. Sensory information in feedback control of trunk posture appears to be reweighted depending on stability of the environment. The absolute effects of visual and vestibular manipulations increase on an unstable surface, suggesting a relative decrease in the weights of proprioceptive and tactile information. PMID- 25537478 TI - Diffusely increased bone marrow FDG uptake in recently untreated lymphoma: incidence and relevance. AB - PURPOSE: To determine the incidence of diffusely increased bone marrow (18) F fluoro-2-deoxy-D-glucose (FDG) uptake at positron emission tomography (PET) in recently untreated lymphoma and to assess the frequency of lymphoma-positive bone marrow biopsies (BMBs) in these patients. METHODS: FDG-PET scans of all patients presenting with newly diagnosed or relapsed lymphoma were reviewed. Patients with non-focal diffusely increased bone marrow FDG uptake, who had not received therapy within 3 months, were identified. The incidences of diffusely increased bone marrow FDG uptake and the frequencies of positive posterior iliac crest BMBs among those cases were calculated. RESULTS: The incidences of diffusely increased bone marrow FDG uptake in all lymphomas, and in Hodgkin lymphoma, aggressive non Hodgkin lymphoma (NHL), indolent NHL, and mantle cell NHL separately, were 4.2% (23/542), 9.3% (7/75), 3.4% (8/239), 3.3% (7/214), and 7.1% (1/14), respectively, and frequencies of positive BMBs among these subgroups were 55.0% (11/20), 0.0% (0/7), 83.3% (5/6), 83.3% (5/6), and 100% (1/1), respectively. CONCLUSION: The incidence of diffusely increased bone marrow FDG uptake in recently untreated lymphoma is low, albeit higher in Hodgkin lymphoma than in NHL. BMB in such patients is likely to be negative in Hodgkin lymphoma, but positive in the majority of NHL cases. PMID- 25537479 TI - Endogenous concentrations of biologically relevant metals in rat brain and cochlea determined by inductively coupled plasma mass spectrometry. AB - Manganese (Mn), iron (Fe), copper (Cu), and zinc (Zn) are essential nutrients which aid in the proper functioning of cells, but high concentrations of these metals can be toxic to various organs. Little is known about the endogenous concentrations of these metals in the cochlea, the auditory portion of the inner ear which is extremely small and difficult to access. To fill this gap, a trace quantitative digestion and inductively coupled plasma mass spectrometry method was developed to determine the concentrations of these metals in the stria vascularis, organ of Corti, and spiral ganglion, three critically important parts of the cochlea (<= 1.5 mg); these values were compared to those in specific brain regions (<= 20 mg) of rats. Rats were sacrificed and the cochlea and brain regions were carefully isolated, digested, and analyzed to determine baseline concentrations of Mn, Fe, Cu, and Zn. In the cochlea, Mn, Fe, Cu, and Zn concentrations ranged from 3.2-6, 73-300, non-detect, and 13-200 ug/g respectively. In the brain, Mn, Fe, Cu, and Zn concentrations ranged from 1.3 2.72, 21-120, 5.0-10.6, and 33-47 ug/g respectively. Significant differences (p < 0.05) were observed between the tissue types within the cochlea, and between the cochlea and brain. This validated method provides the first quantitative assessment of these metals in the three key subdivisions of the cochlea compared to the levels in the brain; Mn, Fe, and Zn levels were considerably higher in the cochlea than brain. PMID- 25537480 TI - Kinetic mechanism for the flipping and excision of 1,N(6)-ethenoadenine by AlkA. AB - Escherichia coli 3-methyladenine DNA glycosylase II (AlkA), an adaptive response glycosylase with a broad substrate range, initiates base excision repair by flipping a lesion out of the DNA duplex and hydrolyzing the N-glycosidic bond. We used transient and steady state kinetics to determine the minimal mechanism for recognition and excision of 1,N(6)-ethenoadenine (epsilonA) by AlkA. The natural fluorescence of this endogenously produced lesion allowed us to directly monitor the nucleotide flipping step. We found that AlkA rapidly and reversibly binds and flips out epsilonA prior to N-glycosidic bond hydrolysis, which is the rate limiting step of the reaction. The binding affinity of AlkA for the epsilonA-DNA lesion is only 40-fold tighter than for a nonspecific site and 20-fold weaker than for the abasic DNA site. The mechanism of AlkA-catalyzed excision of epsilonA was compared to that of the human alkyladenine DNA glycosylase (AAG), an independently evolved glycosylase that recognizes many of the same substrates. AlkA and AAG both catalyze N-glycosidic bond hydrolysis to release epsilonA, and their overall rates of reaction are within 2-fold of each other. Nevertheless, we find dramatic differences in the kinetics and thermodynamics for binding to epsilonA-DNA. AlkA catalyzes nucleotide flipping an order of magnitude faster than AAG; however, the equilibrium for flipping is almost 3 orders of magnitude more favorable for AAG than for AlkA. These results illustrate how enzymes that perform the same chemistry can use different substrate recognition strategies to effectively repair DNA damage. PMID- 25537482 TI - Endoscopic transsellar approach to pituitary adenomas with cavernous sinus invasion: Is this just a matter of lateral extension? PMID- 25537483 TI - Synthesis of a carbon-dot-based photoluminescent probe for selective and ultrasensitive detection of Hg(2+) in water and living cells. AB - A nitrogen and sulphur co-doped carbon dot (NSCD) based highly selective photoluminescent probe for mercury detection has been designed. The NSCDs with a PL quantum yield of 69% are easily prepared from a single polymeric molecular precursor. The turn on-off fluorescence change upon mercury addition is attributed to the nonradiative electron transfer from the excited state to the d orbital of the metal ion. The soft-soft acid-base interaction between the sulphur part of the NSCD and Hg(2+) makes the fluorescence probe more specific and selective towards Hg(2+) in contrast to other metal ions. The limit of detection of mercury ions is found to be 0.05 nM. Due to their high photostability, low toxicity and low detection limit, these carbon dots are demonstrated to be excellent probes for the detection of Hg(2+) in the living cell. PMID- 25537481 TI - Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing's disease: results from an open-ended, open-label extension trial. AB - PURPOSE: Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study. METHODS: 162 patients entered the core study. 58 patients who had mean UFC <= ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 MUg bid). Dose titration was permitted according to efficacy or drug-related adverse events. RESULTS: 40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0% (29/58) and 34.5% (20/58) had controlled UFC (UFC <= ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3% (95% CI 40.7-73.9; n = 52) and 62.1% (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received >=1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6%), nausea (48.1%), hyperglycemia (38.9%), and cholelithiasis (31.5%). No new safety issues were identified during the extension. CONCLUSIONS: Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease. PMID- 25537485 TI - Basal insulin secretion, PCL-R and recidivism among impulsive violent alcoholic offenders. AB - Current risk assessment tools have a moderate predicting value for violence. Their power may be enhanced with certain biological indicators, which may serve as predictors of recidivistic violence itself. The aim of our study was to determine the strength of serum insulin levels to predict violence, and compare these results with those from the Revised Psychopathy Checklist (PCL-R). The study population consisted of 105 Finnish alcoholics who were severely violent offenders, recruited from 1991 to 1998. After exclusion, 75 cases were followed until March 2008, or until a new offense was registered. Cox regression analysis was used to evaluate the risk of recidivism. The age and weight adjusted effect of insulin to recidivism risk showed a 7.2% increase for each International Unit (IU), or 19% for the mean difference (2.5IU) between recidivists and non recidivist, which corresponds to a medium effect size (Cohen's d=0.46). Adjusting the insulin model with PCL-R factor 1 enhanced the predictive power slightly. Serum fasting insulin level was equivalent to the PCL-R factor 2 score as a predictor, and better than the total PCL-R score. However, the significance of these results was too low for predicting recidivism in the process of judicial decision-making. PMID- 25537484 TI - Liver growth factor as a tissue regenerating factor in neurodegenerative diseases. AB - Liver growth factor (LGF) is a hepatic mitogen purified by our group in 1986. In the following years we demonstrated its activity both in "in vivo" and "in vitro" systems, stimulating hepatocytes mitogenesis as well as liver regeneration in several models of liver injury. Furthermore, we established its chemical composition (albumin-bilirubin complex) and its mitogenic actions in liver. From 2000 onwards we used LGF as a tissue regenerating factor in several models of extrahepatic diseases. The use of Liver growth factor as a neural tissue regenerator has been recently protected (Patent No US 2014/8,642,551 B2). LGF administration stimulates neurogenesis and neuron survival, promotes migration of newly generated neurons, and induces the outgrowth of striatal dopaminergic terminals in 6-hidroxydopamine-lesioned rats. Furthermore, LGF treatment raises striatal dopamine levels and protects dopaminergic neurons in hemiparkinsonian animals. LGF also stimulates survival of grafted foetal neural stem cells in the damaged striatum, reduces rotational behaviour and improves motor coordination. Interestingly, LGF also exerts a neuroprotective role both in an experimental model of cerebellar ataxia and in a model of Friedrich's ataxia. Microglia seem to be the cellular target of LGF in the CNS. Moreover, the activity of the factor could be mediated by the stimulation of MAPK's signalling pathway and by regulating critical proteins for cell survival, such as Bcl-2 and phospho-CREB. Since the factor shows neuroprotective and neurorestorative effects we propose LGF as a patented novel therapeutic tool that may be useful for the treatment of Parkinson's disease and cerebellar ataxias. Currently, our studies have been extended to other neurological disorders such as Alzheimer's disease (Patent No: US 2014/0113859 A1). PMID- 25537486 TI - Emotion regulation in bipolar disorder: profile and utility in predicting trait mania and depression propensity. AB - Current emotion regulation research in BD has tended to focus on the extent to which patients control their emotions using different cognitive strategies. Fewer studies have investigated whether patients with BD have difficulties in regulating other dimensions of emotion that serve a functional purpose and are thereby more amenable to change. To overcome this paucity of research we utilised a multi-dimensional measure of emotion regulation to characterise the emotion regulation profile of BD, and examine its utility in predicting trait mania and depression propensity. Fifty BD patients and 52 healthy controls completed the Difficulties in Emotion Regulation Scale (DERS) and the General Behaviour Inventory (GBI). Results indicated that patients had difficulties in emotion regulation across a range of dimensions. Impulse control difficulties most parsimoniously predicted trait (hypo)mania propensity in BD patients, whilst poor access to mood regulation strategies predicted depressive propensity. Predictors of the propensity to experience these moods differed in the control group. These findings represent an important step toward informing the development of new treatment strategies to remediate emotion regulation difficulties and improve BD symptomatology. PMID- 25537487 TI - Seasonality and its distinct clinical correlates in bipolar II disorder. AB - Seasonality is one of the key features in subjects with mood disorders and is involved in the multi-faceted nature of the clinical course. However, few studies have explored the clinical implications of seasonality in bipolar disorders. We examined the differential effects of seasonality on clinical variables between bipolar I and II disorder (BD I and II). Seasonality was assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ) in 204 subjects with BD I and 308 with BD II. Following the comparisons between BD I and II groups, clinical characteristics related to seasonality were explored. Next, to predict the presence of seasonality, a logistic regression model was applied. The global seasonality score on the SPAQ was significantly higher in the BD II group than in the BD I group. In the BD I group, seasonality was associated with suicide attempt history. In the BD II group, on the other hand, seasonality was associated with female gender, depressive predominance, and premenstrual dysphoric disorder (PMDD). In the regression models, the presence of PMDD and female gender was significantly associated with seasonality in the BD II group. Our findings suggest that high seasonality tendency, a vulnerability maker for cyclic worsening, may contribute to a differential pattern of clinical characteristics in BD II. PMID- 25537488 TI - Suicidal events among pathological gamblers: the role of comorbidity of axis I and axis II disorders. AB - The risk for suicidal ideation and suicide attempts among pathological gamblers is high compared to the general population. Little is known about the interplay of Axis I and Axis II disorders, severity of gambling disorder, and suicidal ideation and suicide attempts. The study aims to address this linkage. The sampling design of the study "Pathological Gambling and Epidemiology" (PAGE) included four recruitment channels: general population, gambling locations, project telephone hotline, and in-patient treatment for pathological gambling. A total of 442 study participants with lifetime pathological gambling received a clinical interview. The multivariate analysis showed mood disorders (Relative Risk Ratio, RRR=5.14, 95%-Confidence Interval, CI=2.91-9.07), substance use disorders (RRR=1.73, CI=1.02-2.94), and early onset of gambling disorder (RRR=0.96, CI=0.93-0.99) to be associated with suicidal ideation. Suicidal attempts were associated with female sex (RRR=3.58, CI=1.56-8.19), mood disorders (RRR=11.92, CI=4.70-30.26), and Cluster B personality disorders (RRR=2.40, CI=1.13-5.10). Among study participants with suicide attempts, more had a Cluster B personality disorder than among participants with ideation solely (RRR=3.08, CI=1.48-6.40). Among this large mixed sample of pathological gamblers, high proportions of individuals with suicidal events, multi-morbidity on Axis I, and a strong linkage to Cluster B personality disorders were found. PMID- 25537489 TI - Temperament and emotional eating: a crucial relationship in eating disorders. AB - Specific personality traits are related to Eating Disorders (EDs) specific and general psychopathology. Recent studies suggested that Emotional Eating (EE) is a common dimension in all EDs, irrespective of binge eating. The present study was aimed to explore the relationship of temperamental features with EE and eating symptomatology in a sample of EDs patients, adjusting for general psychopathology. One hundred and sixty six female patients were enrolled at the Eating Disorders Outpatient Clinic of the Careggi Teaching-Hospital of Florence. Participants completed the emotional eating scale, the temperament and character inventory, the eating disorder examination questionnaire and the symptom checklist 90-revised. Novelty seeking and self directedness showed significant correlations with EE after adjustment for general psychopathology. Patients with binge eating displayed significant associations between EE and novelty seeking and self directedness. Among patients without binge eating, no significant correlation between EE and temperamental features was observed. Specific temperamental features are associated to EE in EDs. A clear, different pattern of association in patients with different eating attitudes and behavior was found. Considering that treatments of EDs are largely based on psychotherapeutic interventions, focused on emotions and cognitions, the present data provide some hints which could be helpful for the development of more appropriate psychotherapeutic strategies. PMID- 25537490 TI - Ultratrace LC-MS/MS analysis of segmented calf hair for retrospective assessment of time of clenbuterol administration in Agriforensics. AB - In agriforensics, time of administration is often debated when illegal drug residues, such as clenbuterol, are found in frequently traded cattle. In this proof-of-concept work, the feasibility of obtaining retrospective timeline information from segmented calf tail hair analyses has been studied. First, an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) hair analysis method was adapted to accommodate smaller sample sizes and in-house validated. Then, longitudinal 1 cm segments of calf tail hair were analyzed to obtain clenbuterol concentration profiles. The profiles found were in good agreement with calculated, theoretical positions of the clenbuterol residues along the hair. Following assessment of the average growth rate of calf tail hair, time of clenbuterol administration could be retrospectively determined from segmented hair analysis data. The data from the initial animal treatment study (n = 2) suggest that time of treatment can be retrospectively estimated with an error of 3-17 days. PMID- 25537491 TI - In vivo degradation effects of alloy MgNd2 in contact with mucous tissue. AB - Magnesium alloys are currently being investigated for use as resorbable biomaterials. Various applications for magnesium based implant materials have already been presented. Currently, stents and structures that sustain diseased or narrowed vessels seem to be the most promising areas. This study focuses on the use of a magnesium fluoride (MgF2 ) coated magnesium neodymium based alloy (MgNd2 ) and its use as a postsurgery stent material to avoid proliferation in the sinus region. Simple cylindrical shaped specimens were sown to the sinus' mucosa of pigs and left in place for different periods of time to investigate the long-term corrosion resistance of the alloy and its coating during direct contact with physiological tissue. Investigations made within this study explicitly focused on the corrosive behavior of the alloy in the region of a physiological sinus. Thus, losses in mass and volume, and element analyses were considered to obtain information about the specimens' corrosion performance over time. Furthermore, micrographs support the alloy specific corrosion type analyses which focus on grain boundary effects. This study demonstrates the general in vivo applicability of fluoride coated MgNd2 . The progress of corrosion was determined to be adequate and homogeneous over a total period of 180 days. PMID- 25537493 TI - Virology welcomes the new year with good news. PMID- 25537492 TI - Silenced rRNA genes are activated and substitute for partially eliminated active homeologs in the recently formed allotetraploid, Tragopogon mirus (Asteraceae). AB - To study the relationship between uniparental rDNA (encoding 18S, 5.8S and 26S ribosomal RNA) silencing (nucleolar dominance) and rRNA gene dosage, we studied a recently emerged (within the last 80 years) allotetraploid Tragopogon mirus (2n=24), formed from the diploid progenitors T. dubius (2n=12, D-genome donor) and T. porrifolius (2n=12, P-genome donor). Here, we used molecular, cytogenetic and genomic approaches to analyse rRNA gene activity in two sibling T. mirus plants (33A and 33B) with widely different rRNA gene dosages. Plant 33B had ~400 rRNA genes at the D-genome locus, which is typical for T. mirus, accounting for ~25% of total rDNA. We observed characteristic expression dominance of T. dubius origin genes in all organs. Its sister plant 33A harboured a homozygous macrodeletion that reduced the number of T. dubius-origin genes to about 70 copies (~4% of total rDNA). It showed biparental rDNA expression in root, flower and callus, but not in leaf where D-genome rDNA dominance was maintained. There was upregulation of minor rDNA variants in some tissues. The RNA polymerase I promoters of reactivated T. porrifolius-origin rRNA genes showed reduced DNA methylation, mainly at symmetrical CG and CHG nucleotide motifs. We hypothesise that active, decondensed rDNA units are most likely to be deleted via recombination. The silenced homeologs could be used as a 'first reserve' to ameliorate mutational damage and contribute to evolutionary success of polyploids. Deletion and reactivation cycles may lead to bidirectional homogenisation of rRNA arrays in the long term. PMID- 25537494 TI - Increased GIP signaling induces adipose inflammation via a HIF-1alpha-dependent pathway and impairs insulin sensitivity in mice. AB - Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1alpha (HIF-1alpha) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1alpha, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL 6. HIF-1alpha gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1alpha may contribute to this process. PMID- 25537495 TI - Sodium levels of human pancreatic donors are a critical factor for determination of islet efficacy and survival. AB - Organs from hypernatremia (elevated Na+) donors when used for transplantation have had dismal outcomes. However, islet isolation from hypernatremic donors for both transplantation and research applications has not yet been investigated. A retrospective analysis of in vivo and in vitro islet function studies was performed on islets isolated from hypernatremic (serum sodium levels>=160 meq/l) and normal control (serum sodium levels<=155 meq/l) donors. Twelve isolations from 32 hypernatremic and 53 isolations from 222 normal donors were randomly transplanted into diabetic NOD Scid mice. Sodium levels upon pancreas procurement were significantly elevated in the hypernatremia group (163.5+/-0.6 meq/l) compared with the normal control group (145.9+/-0.4 meq/l) (P<0.001). The postculture islet recovery rate was significantly lower in the hypernatremia (59.1+/-3.8%) group compared with the normal (73.6+/-1.8%) group (P=0.005). The duration of hypernatremia was inversely correlated with the recovery rate (r2=0.370, P<0.001). Furthermore, the percentage of successful graft function when transplanted into diabetic NOD Scid mice was significantly lower in the hypernatremia (42%) group compared with the normal control (85%) group (P<0.001). The ability to predict islet graft function posttransplantation using donor sodium levels and duration of hypernatremia was significant (ROC analysis, P=0.022 and 0.042, respectively). In conclusion, duration of donor hypernatremia is associated with reduced islet recovery postculture. The efficacy of islets from hypernatremia donors diminished when transplanted into diabetic recipients. PMID- 25537496 TI - Brief report: the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. AB - Adipocytes (AdCs) and osteoblasts (OBs) are derived from mesenchymal stem cells (MSCs) and differentiation toward either lineage is both mutually exclusive and transcriptionally controlled. Recent studies implicate the mammalian target of rapamycin (mTOR) pathway as important in determining MSC fate, with inhibition of mTOR promoting OB differentiation and suppressing AdC differentiation. mTOR functions within two distinct multiprotein complexes, mTORC1 and mTORC2, each of which contains the unique adaptor protein, raptor or rictor, respectively. While compounds used to study mTOR signaling, such as rapamycin and related analogs, primarily inhibit mTORC1, prolonged exposure can also disrupt mTORC2 function, confounding interpretation of inhibitor studies. As a result, the relative contribution of mTORC1 and mTORC2 to MSC fate determination remains unclear. In this study, we generated primary mouse MSCs deficient in either Rptor (RapKO) or Rictor (RicKO) using the Cre/loxP system. Cre-mediated deletion of Rptor or Rictor resulted in impaired mTORC1 and mTORC2 signaling, respectively. Under lineage-inductive culture conditions, RapKO MSCs displayed a reduced capacity to form lipid-laden AdCs and an increased capacity to form a mineralized matrix. In contrast, RicKO MSCs displayed reduced osteogenic differentiation capacity and enhanced adipogenic differentiation potential. Taken together, our findings reveal distinct roles for mTORC1 and mTORC2 in MSC lineage commitment. PMID- 25537498 TI - Let's start. PMID- 25537497 TI - Ontogenetic changes in cranial vault thickness in a modern sample of Homo sapiens. AB - OBJECTIVES: This work assesses cranial vault thickness (CVT) ontogenetic changes using a computed tomography database to register thickness across multiple regions. METHODS: Vault images of 143 individuals from 0 to 31 years old were analyzed by thickness semiautomatic measurements. For each individual, we obtained a thickness mean measure (TMM) and its coefficient of variation, a measure of endocranial volume (EV), the distribution of relative frequencies of thickness-relative frequency polygon, and a topographic mapping that shows the thickness arrangement through a chromatic scale. Ontogenetic changes of these variables were evaluated by different regression models (TMM vs. age, EV vs. age, TMM vs. EV) and visual comparisons between the age groups. RESULTS: TMM increased during ontogeny until the onset of adulthood without sex differences, but the most accelerated growth rates occur during the first 6 years of postnatal life. TMM variations were associated with EV only in infants and children, but not in later periods. The polygons showed a flattening during ontogeny, probably due to an increase in thickness variation within individuals. However, the adult pattern of thickness arrangement, with the lateral region thinner than the regions near sagittal plane, was detected from infancy. CONCLUSION: The pattern of thickness arrangement is established early in ontogeny but CVT increases and changes in distribution until adolescence. Several factors may influence CVT, such as the brain, muscles, vessels, and sutures. PMID- 25537499 TI - Photochemically induced intramolecular six-electron reductive elimination and oxidative addition of nitric oxide by the nitridoosmate(VIII) anion. AB - UV photolysis of the nitridoosmate(VIII) anion, OsO3 N(-) , in low-temperature frozen matrices results in nitrogen-oxygen bond formation to give the Os(II) nitrosyl complex OsO2 (NO)(-) . Photolysis of the Os(II) nitrosyl product with visible wavelengths results in reversion to the parent Os(VIII) complex. Formally a six-electron reductive elimination and oxidative addition, respectively, this represents the first reported example of such an intramolecular transformation. DFT modelling of this reaction proceeds through a step-wise mechanism taking place through a side-on nitroxyl Os(VI) intermediate, OsO2 (eta(2) -NO)(-) . PMID- 25537500 TI - Deacidification of cranberry juice by electrodialysis with bipolar membranes. AB - Cranberry is recognized for its many benefits on human health; however, its high acidity may be a limiting factor for its consumption. This study aimed to investigate the deacidification of cranberry juice using a two simultaneous step electrodialysis with bipolar membranes (EDBM) process. In step 1 (deacidification), during the 6 h treatment, the pH of the juice increased from 2.47 to 2.71 and a deacidification rate of 22.84% was obtained, whereas in step 2 (pH lowering) the pH of juice 2 was almost stable. Citric, quinic, and malic acid were extracted with a maximum of 25% and were mainly transferred to the KCl 2 fraction. A significant loss of anthocyanins in juice 2 (step 2) was observed, due to their oxidation by oxygen incorporated by the centrifugal pump. This also affected its coloration. The first step of the EDBM process was successful for cranberry juice deacidification and could be improved by increasing the number of membranes stacked. PMID- 25537502 TI - Comparison of different methods for the assessment of the urban heat island in Stuttgart, Germany. AB - This study of the urban heat island (UHI) aims to support planning authorities by going beyond the traditional way of urban heat island studies. Therefore, air temperature as well as the physiologically equivalent temperature (PET) were applied to take into account the effect of the thermal atmosphere on city dwellers. The analysis of the urban heat island phenomenon of Stuttgart, Germany, includes a long-term frequency analysis using data of four urban and one rural meteorological stations. A (high resolution map) of the UHI intensity and PET was created using stepwise multiple linear regression based on data of car traverses as well as spatial data. The mapped conditions were classified according to the long-term frequency analysis. Regarding climate change, the need for adaptation measures as urban greening is obvious. Therefore, a spatial analysis of quantification of two scenarios of a chosen study area was done by the application of a micro-scale model. The nocturnal UHI of Stuttgart is during 15 % stronger than 4 K in the city center during summer when daytime heat stress occurs during 40 %. A typical summer condition is mapped using statistical approach to point out the most strained areas in Stuttgart center and west. According to the model results, the increase in number of trees in a chosen area (Olga hospital) can decrease PET by 0.5 K at 22:00 CET but by maximum 27 K at 14:00 CET. PMID- 25537501 TI - Design of aromatic-containing cell-penetrating peptide mimics with structurally modified pi electronics. AB - Cell-penetrating peptides (CPPs) and their synthetic mimics (CPPMs) represent a class of molecules that facilitate the intracellular delivery of various cargo. Previous studies indicated that the presence of aromatic functionalities improved CPPM activity. Given that aromatic functionalities play prominent roles in membrane biology and participate in various pi interactions, we explored whether these interactions could be optimized for improved CPPM activity. CPPMs were synthesized by ring-opening metathesis polymerization by using monomers that contained aromatic rings substituted with electron-donating and electron withdrawing groups and covered an electrostatic potential range from -29.69 to +15.57 kcal mol(-1) . These groups altered the quadrupole moments of the aromatic systems and were used to test if such structural modifications changed CPPM activity. CPPMs were added to dye-loaded vesicles and the release of carboxyfluorescein was monitored as a function of polymer concentration. Changes in the effective polymer concentration to release 50% of the dye (effective concentration, EC50 ) were monitored. Results from this assay showed that the strength of the electron-donating and electron-withdrawing groups incorporated in the CPPMs did not alter polymer EC50 values or activity. This suggests that other design parameters may have a stronger impact on CPPM activity. In addition, these results indicate that a wide range of aromatic groups can be incorporated without negatively impacting polymer activity. PMID- 25537503 TI - Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A. AB - Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and decrease in AKT phosphorylation. Afatinib suppressed CIP2A at the gene transcription level by reducing the promoter binding activity of Elk-1. Clinical samples showed that higher CIP2A expression predicted a poor prognosis and Elk-1 and CIP2A expressions were highly correlated. In conclusion, afatinib induces apoptosis in NSCLC without EGFR mutations through Elk-1/CIP2A/PP2A/AKT pathway. PMID- 25537504 TI - gamma-H2AX promotes hepatocellular carcinoma angiogenesis via EGFR/HIF 1alpha/VEGF pathways under hypoxic condition. AB - Hepatocellular carcinoma (HCC) is one of the most deadly cancers. Using mRNA microarray analysis, we found that H2AX decreased under hypoxic conditions. Hypoxia is an important physiological and pathological stress that induces H2AX phosphorylation (gamma-H2AX), but the regulatory mechanism of gamma-H2AX remains elusive in the progress of HCC. We report here that increased gamma-H2AX expression in HCC is associated with tumor size, vascular invasion, TNM stage and reduced survival rate after liver transplantation (LT). gamma-H2AX knockdown was able to effectively inhibit VEGF expression in vitro and tumorigenicity and angiogenesis of HCC in vivo. The mechanism of gamma-H2AX on the angiogenic activity of HCC might go through EGFR/HIF-1alpha/VEGF pathways under hypoxic conditions. Combined gamma-H2AX, HIF-1alpha and EGFR has better prognostic value for HCC after LT. This study suggests that gamma-H2AX is associated with angiogenesis of HCC and gamma-H2AX or a combination of gamma-H2AX/EGFR/HIF-1alpha is a novel marker in the prognosis of HCC after LT and a potential therapeutic target. PMID- 25537505 TI - Fibroblast growth factor receptor 1 gene amplification is associated with poor survival in patients with resected esophageal squamous cell carcinoma. AB - To investigate the frequency and the prognostic impact of fibroblast growth factor receptor 1 (FGFR1) gene amplification in 526 curatively resected esophageal squamous cell carcinoma (ESCC). Using fluorescent in situ hybridization, high amplification was defined by an FGFR1/centromer 8 ratio is >= 2.0, or average number of FGFR1 signals/tumor cell nucleus >= 6.0, or percentage of tumor cells containing >= 15 FGFR1 signals or large cluster in >= 10%. Low amplification was defined by >= 5 FGFR1 signals in >= 50%. FGFR2 and FGFR3 mutations were assessed by direct sequencing in 388 cases and no mutation was detected. High and low amplification were detected in 8.6% and 1.1%, respectively. High FGFR1 amplification had significantly shorter disease-free survival (34.0 vs 158.5 months P=0.019) and overall survival (52.2 vs not reached P=0.022) than low/no amplification group. After adjusting for sex, smoking, stage, histology, and adjuvant treatment, high FGFR1 amplification had a greater risk of recurrence (adjusted hazard ratio [AHR], 1.6; P=0.029) and death (AHR, 1.53; P=0.050). High amplification was significantly higher in current smokers than former and never-smokers (Ptrend<0.001) and increased proportional to smoking dosage. High FGFR1 amplification is a frequent oncogenic alteration and an independent poor prognostic factor in resected ESCC. PMID- 25537506 TI - SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice. AB - Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr AKT1), or beta-catenin (DeltaN90-beta-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or DeltaN90 beta-catenin alone as well as co-expression of SKP2 and DeltaN90-beta-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with beta-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo. PMID- 25537507 TI - Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches. AB - The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG 1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells' response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs' combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes. PMID- 25537508 TI - RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR dependent and -independent prostate cancer. AB - Androgen receptor (AR) signaling is essential for the development of prostate cancer. Here, we report that runt-related transcription factor (RUNX1) could be a key molecule for the androgen-dependence of prostate cancer. We found RUNX1 is a target of AR and regulated positively by androgen. Our RUNX1 ChIP-seq analysis indicated that RUNX1 is recruited to AR binding sites by interacting with AR. In androgen-dependent cancer, loss of RUNX1 impairs AR-dependent transcription and cell growth. The RUNX1 promoter is bound by enhancer of zeste homolog 2 (EZH2) and is negatively regulated by histone H3 lysine 27 (K27) trimethylation. Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR independent cells. In clinical prostate cancer samples, the RUNX1 expression level is negatively associated with EZH2 and that RUNX1 loss correlated with poor prognosis. These results indicated the significance of RUNX1 for androgen dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer. PMID- 25537509 TI - New insights into the genetics of glioblastoma multiforme by familial exome sequencing. AB - Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g., PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g., Focal adhesion or ECM receptor interaction) and genomic proximity (e.g., chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease. PMID- 25537511 TI - MicroRNA-26a promotes anoikis in human hepatocellular carcinoma cells by targeting alpha5 integrin. AB - Metastasis is the major reason for the death of patients suffering from malignant diseases such as human hepatocellular carcinoma (HCC). Among the complex metastatic process, resistance to anoikis is one of the most important steps. Previous studies demonstrate that microRNA-26a (miR-26a) is an important tumor suppressor that inhibits the proliferation and invasion of HCC cells by targeting multiple oncogenic proteins. However, whether miR-26a can also influence anoikis has not been well established. Here, we discovered that miR-26a promotes anoikis of HCC cells both in vitro and in vivo. With a combinational analysis of bioinformatics and public clinical databases, we predicted that alpha5 integrin (ITGA5), an integrin family member, is a putative target of miR-26a. Furthermore, we provide experimental evidence to confirm that ITGA5 is a bona fide target of miR-26a. Through gain- and loss-of-function studies, we demonstrate that ITGA5 is a functional target of miR-26a-induced anoikis in HCC cells. Collectively, our findings reveal that miR-26a is a novel player during anoikis and a potential therapeutic target for the treatment of metastatic HCC. PMID- 25537510 TI - Clinically relevant genes and regulatory pathways associated with NRASQ61 mutations in melanoma through an integrative genomics approach. AB - Therapies such as BRAF inhibitors have become standard treatment for melanoma patients whose tumors harbor activating BRAFV600 mutations. However, analogous therapies for inhibiting NRAS mutant signaling have not yet been well established. In this study, we performed an integrative analysis of DNA methylation, gene expression, and microRNA expression data to identify potential regulatory pathways associated with the most common driver mutations in NRAS (Q61K/L/R) through comparison of NRASQ61-mutated melanomas with pan-negative melanomas. Surprisingly, we found dominant hypomethylation (98.03%) in NRASQ61 mutated melanomas. We identified 1,150 and 49 differentially expressed genes and microRNAs, respectively. Integrated functional analyses of alterations in all three data types revealed important signaling pathways associated with NRASQ61 mutations, such as the MAPK pathway, as well as other novel cellular processes, such as axon guidance. Further analysis of the relationship between DNA methylation and gene expression changes revealed 9 hypermethylated and down regulated genes and 112 hypomethylated and up-regulated genes in NRASQ61 melanomas. Finally, we identified 52 downstream regulatory cascades of three hypomethylated and up-regulated genes (PDGFD, ZEB1, and THRB). Collectively, our observation of predominant gene hypomethylation in NRASQ61 melanomas and the identification of NRASQ61-linked pathways will be useful for the development of targeted therapies against melanomas harboring NRASQ61 mutations. PMID- 25537512 TI - FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. AB - Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1 expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of beta-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer. PMID- 25537513 TI - By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy. AB - Basal-like breast cancer is an aggressive tumor subtype with a poor response to conventional therapies. Tumor formation and relapse are sustained by a cell subset of Breast Cancer Stem Cells (BrCSCs). Here we show that miR-100 inhibits maintenance and expansion of BrCSCs in basal-like cancer through Polo-like kinase1 (Plk1) down-regulation. Moreover, miR-100 favors BrCSC differentiation, converting a basal like phenotype into luminal. It induces the expression of a functional estrogen receptor (ER) and renders basal-like BrCSCs responsive to hormonal therapy. The key role played by miR-100 in breast cancer free-survival is confirmed by the analysis of a cohort of patients' tumors, which shows that low expression of miR-100 is a negative prognostic factor and is associated with gene signatures of high grade undifferentiated tumors. Our findings indicate a new possible therapeutic strategy, which could make aggressive breast cancers responsive to standard treatments. PMID- 25537514 TI - The BRCA1/2-directed miRNA signature predicts a good prognosis in ovarian cancer patients with wild-type BRCA1/2. AB - Ovarian cancer patients carrying alterations (i.e., germline mutations, somatic mutations, hypermethylations and/or deletions) of BRCA1 or BRCA2 (BRCA1/2) have a better prognosis than BRCA1/2 alteration non-carriers. However, patients with wild-type BRCA1/2 may also have a favorable prognosis as a result of other mechanisms that remain poorly elucidated, such as the deregulation of miRNAs. We therefore sought to identify BRCA1/2-directed miRNA signatures that have prognostic value in ovarian cancer patients with wild-type BRCA1/2 and study how the deregulation of miRNAs impacts the prognosis of patients treated with platinum-based chemotherapy. By analyzing multidimensional datasets of ovarian cancer patients from the TCGA data portal, we identified three miRNAs (hsa-miR 146a, hsa-miR-148a and hsa-miR-545) that target BRCA1/2 and were associated with overall survival and progression-free survival in patients with wild-type BRCA1/2. By analyzing the expression profiles and Gene Ontology functional enrichment, we found that carriers of BRCA1/2 alterations and patients with miRNA deregulation shared a common mechanism, regulation of the DNA repair-related pathways, that affects the prognosis of ovarian cancer patients. Our work highlights that a proportion of patients with wild-type BRCA1/2 ovarian cancers benefit from platinum-based chemotherapy and that the patients who benefit could be predicted from BRCA1/2-directed miRNA signature. PMID- 25537515 TI - Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers. AB - Acquired resistance to PI3K/mTOR/Akt pathway inhibitors is often associated with compensatory feedback loops involving the activation of oncogenes. Here, we have generated everolimus resistance in ER+ breast cancer cells and in long-term estrogen deprived (LTED) models that mimic progression on anti-estrogens. This allowed us to uncover MYC as a driver of mTOR inhibitor resistance. We demonstrate that both everolimus resistance and acute treatment of everolimus can lead to the upregulation of MYC mRNA, protein expression and, consequently, the enrichment of MYC signatures as revealed by RNA sequencing data. Depletion of MYC resulted in resensitization to everolimus, confirming its functional importance in this setting. Furthermore, ChIP assays demonstrate that MYC upregulation in the everolimus resistant lines is mediated by increased association of the BRD4 transcription factor with the MYC gene. Finally, JQ1, a BRD4 inhibitor combined with everolimus exhibited increased tumor growth inhibition in 3D Matrigel models and an in vivo xenograft model. These data suggest that MYC plays an important role in mediating resistance to everolimus in ER+ and ER+/LTED models. Furthermore, given the regulation ofMYCby BRD4 in this setting, these data have implications for increased therapeutic potential of combining epigenetic agents with mTOR inhibitors to effectively downregulate otherwise difficult to target transcription factors such as MYC. PMID- 25537516 TI - MicroRNA-135b, a HSF1 target, promotes tumor invasion and metastasis by regulating RECK and EVI5 in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) often localize to chromosomal fragile sites and are associated with cancer. In this study, we screened for the aberrant and functional miRNAs in the regions of copy number alterations (CNAs) in hepatocellular carcinoma (HCC), and found that miR-135b was frequently amplified and upregulated in HCC tissues. The expression level of miR-135b was inversely correlated with the occurrence of tumor capsules. In addition, miR-135b promoted HCC cell migration and invasion in vitro and metastasis in vivo. The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and ecotropic viral integration site 5 (EVI5) were identified as the direct and functional targets of miR-135b in HCC. Furthermore, we observed that heat shock transcription factor 1 (HSF1) directly activated miR-135b expression, consequently enhancing HCC cell motility and invasiveness. The newly identified HSF1/miR-135b/RECK&EVI5 axis provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC. PMID- 25537517 TI - Chloride channel-3 promotes tumor metastasis by regulating membrane ruffling and is associated with poor survival. AB - The chloride channel-3 (ClC-3) protein is known to be a component of Cl- channels involved in cell volume regulation or acidification of intracellular vesicles. Here, we report that ClC-3 was highly expressed in the cytoplasm of metastatic carcinomatous cells and accelerated cell migration in vitro and tumor metastasis in vivo. High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients. We found that independent of its volume-activated Cl- channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis. ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control beta1 Integrin recycling. Therefore, cytoplasmic ClC-3 plays an active and key role in tumor metastasis and may be a valuable prognostic biomarker and a therapeutic target to prevent tumor spread. PMID- 25537518 TI - Genetic alterations of histone lysine methyltransferases and their significance in breast cancer. AB - Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer. PMID- 25537521 TI - Fit elderly men can also stand: orthostatic tolerance and autonomic cardiovascular control in elderly endurance athletes. AB - BACKGROUND AND AIMS: Endurance training may reduce orthostatic tolerance. Elderly people are prone to orthostatic intolerance, but the impact of endurance training in old age has been insufficiently explored. METHODS: 54 healthy men; 30 endurance athletes and 24 controls, free from medication and chronic diseases, were subjected to head-up tilt tests: 30o for 10 min and 70o for 40 min. Non invasive recordings of blood pressures, heart rate, stroke volume, end diastolic volume, total peripheral resistance, heart rate variability, blood pressure variability, and baroreflex sensitivity were obtained. We registered terminations of test due to frank syncope or unbearable presyncopal symptoms. RESULTS: Mean age 71 years (range 65-84); athletes had lower body mass index (23.4 versus 24.8, p < 0.05) and lower resting heart rate (50 versus 61, p < 0.01). Blood pressures and total peripheral resistance were equal. End diastolic volume index, baroreflex sensitivity, and heart rate variability were higher among athletes, both HF-RRI (high-frequency variability, reflecting parasympathetic activity) and LF-RRI (low-frequency variability, reflecting both sympathetic and parasympathetic activity). Syncope or presyncopal symptoms occurred in 11 persons, 4 athletes and 7 controls (p = 0.2). Cox Regression analysis showed that higher heart rate at rest was the only variable associated with syncope. DISCUSSION: Orthostatic tolerance was not reduced among elderly endurance athletes. Rather, there was a trend towards better orthostatic tolerance, which might be attributed to stronger parasympathetic cardiovascular control and larger blood volume. CONCLUSIONS: Better orthostatic tolerance might be an additional benefit of physical activity in older age. PMID- 25537520 TI - WW domain-containing oxidoreductase in neuronal injury and neurological diseases. AB - The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain containing oxidoreductase protein. This gene is located on a common fragile site FRA16D. WWOX participates in a variety of cellular events and acts as a transducer in the many signal pathways, including TNF, chemotherapeutic drugs, UV irradiation, Wnt, TGF-beta, C1q, Hyal-2, sex steroid hormones, and others. While transiently overexpressed WWOX restricts relocation of transcription factors to the nucleus for suppressing cancer survival, physiological relevance of this regard in vivo has not been confirmed. Unlike many tumor suppressor genes, mutation of WWOX is rare, raising a question whether WWOX is a driver for cancer initiation. WWOX/Wwox was initially shown to play a crucial role in neural development and in the pathogenesis of Alzheimer's disease and neuronal injury. Later on, WWOX/Wwox was shown to participate in the development of epilepsy, mental retardation, and brain developmental defects in mice, rats and humans. Up to date, most of the research and review articles have focused on the involvement of WWOX in cancer. Here, we review the role of WWOX in neural injury and neurological diseases, and provide perspectives for the WWOX-regulated neurodegeneration. PMID- 25537523 TI - Simultaneous protection of organic p- and n-channels in complementary inverter from aging and bias-stress by DNA-base guanine/Al2O3 double layer. AB - Although organic field-effect transistors (OFETs) have various advantages of lightweight, low-cost, mechanical flexibility, and nowadays even higher mobility than amorphous Si-based FET, stability issue under bias and ambient condition critically hinder its practical application. One of the most detrimental effects on organic layer comes from penetrated atmospheric species such as oxygen and water. To solve such degradation problems, several molecular engineering tactics are introduced: forming a kinetic barrier, lowering the level of molecule orbitals, and increasing the band gap. However, direct passivation of organic channels, the most promising strategy, has not been reported as often as other methods. Here, we resolved the ambient stability issues of p-type (heptazole)/or n-type (PTCDI-C13) OFETs and their bias-stability issues at once, using DNA-base small molecule guanine (C5H5N5O)/Al2O3 bilayer. The guanine protects the organic channels as buffer/and H getter layer between the channels and capping Al2O3, whereas the oxide capping resists ambient molecules. As a result, both p-type and n-type OFETs are simultaneously protected from gate-bias stress and 30 days-long ambient aging, finally demonstrating a highly stable, high-gain complementary type logic inverter. PMID- 25537522 TI - Mindfulness meditation for younger breast cancer survivors: a randomized controlled trial. AB - BACKGROUND: Premenopausal women diagnosed with breast cancer are at risk for psychological and behavioral disturbances after cancer treatment. Targeted interventions are needed to address the needs of this vulnerable group. METHODS: This randomized trial provided the first evaluation of a brief, mindfulness-based intervention for younger breast cancer survivors designed to reduce stress, depression, and inflammatory activity. Women diagnosed with early stage breast cancer at or before age 50 who had completed cancer treatment were randomly assigned to a 6-week Mindful Awareness Practices (MAPS) intervention group (n = 39) or to a wait-list control group (n = 32). Participants completed questionnaires before and after the intervention to assess stress and depressive symptoms (primary outcomes) as well as physical symptoms, cancer-related distress, and positive outcomes. Blood samples were collected to examine genomic and circulating markers of inflammation. Participants also completed questionnaires at a 3-month follow-up assessment. RESULTS: In linear mixed models, the MAPS intervention led to significant reductions in perceived stress (P = .004) and marginal reductions in depressive symptoms (P = .094), as well as significant reductions in proinflammatory gene expression (P = .009) and inflammatory signaling (P = .001) at postintervention. Improvements in secondary outcomes included reduced fatigue, sleep disturbance, and vasomotor symptoms and increased peace and meaning and positive affect (P < .05 for all). Intervention effects on psychological and behavioral measures were not maintained at the 3 month follow-up assessment, although reductions in cancer-related distress were observed at that assessment. CONCLUSIONS: A brief, mindfulness-based intervention demonstrated preliminary short-term efficacy in reducing stress, behavioral symptoms, and proinflammatory signaling in younger breast cancer survivors. PMID- 25537524 TI - Predictors of maternal drinking trajectories before and after pregnancy: evidence from a longitudinal study. AB - BACKGROUND: Little is known about patterns of change in alcohol consumption and predictors of these patterns over the prenatal to postnatal period. AIMS: To determine trajectories of maternal alcohol consumption before and after pregnancy and predictors of these trajectories. MATERIALS AND METHODS: A total of 6597 Australian women were sampled from a longitudinal study. Group-based trajectory modelling was applied to determine drinking trajectories from prepregnancy, early pregnancy, late pregnancy and 6 months after the birth. Predictors associated with drinking trajectories were examined using multinomial logistic regression. RESULTS: Three trajectories of maternal alcohol consumption were identified: abstainers/minimal consumption (53.2%), light consumption (39.4%) and heavy consumption (7.4%). The heavy consumption group substantially reduced their consumption in pregnancy but increased their consumption once the baby was born. Some 80.0% of this group were breastfeeding their babies. The light consumption group had only minor changes in their drinking pattern. Lower family income, being married, high frequency of church attendance, low level of adversity, poor health lifestyle, remaining married to original partner and having many children predicted membership of the abstaining/minimal consumption trajectory. Being unmarried, having only one child, having unhealthy health lifestyle and never going to church predicted membership of the heavy consumption group. CONCLUSION: Women who consume higher levels of alcohol prior to their pregnancy reduce their consumption once pregnant, but tend to increase their alcohol consumption shortly after the birth. A public health campaign dealing with predictors associated with heavier alcohol consumption and safe breastfeeding targetted at these women is needed. PMID- 25537525 TI - Human place and response learning: navigation strategy selection, pupil size and gaze behavior. AB - In this study, we examined the cognitive processes and ocular behavior associated with on-going navigation strategy choice using a route learning paradigm that distinguishes between three different wayfinding strategies: an allocentric place strategy, and the egocentric associative cue and beacon response strategies. Participants approached intersections of a known route from a variety of directions, and were asked to indicate the direction in which the original route continued. Their responses in a subset of these test trials allowed the assessment of strategy choice over the course of six experimental blocks. The behavioral data revealed an initial maladaptive bias for a beacon response strategy, with shifts in favor of the optimal configuration place strategy occurring over the course of the experiment. Response time analysis suggests that the configuration strategy relied on spatial transformations applied to a viewpoint-dependent spatial representation, rather than direct access to an allocentric representation. Furthermore, pupillary measures reflected the employment of place and response strategies throughout the experiment, with increasing use of the more cognitively demanding configuration strategy associated with increases in pupil dilation. During test trials in which known intersections were approached from different directions, visual attention was directed to the landmark encoded during learning as well as the intended movement direction. Interestingly, the encoded landmark did not differ between the three navigation strategies, which is discussed in the context of initial strategy choice and the parallel acquisition of place and response knowledge. PMID- 25537526 TI - Native reading direction influences lateral biases in the perception of shape from shading. AB - Although neurologically normal individuals often exhibit leftward biases of perception and attention, known as pseudoneglect, factors such as lighting, spatial location and native reading direction have been found to modulate these biases. To investigate lighting and spatial biases in left-to-right and right-to left readers search times were measured in a target finding task where lighting and target locations were manipulated. Target search times under upper-left lighting were significantly shorter than lower-left, upper-right and lower-right lighting among left-to-right readers. Right-to-left readers did not display the same leftward bias, even displaying significantly shorter search times under upper-right lighting than those of left-to-right readers. Significantly shorter search times for targets located in the upper-left quadrant (compared to other quadrants) were observed for left-to-right readers, while search times for upper right located targets were significantly shorter for right-to-left readers compared to those of left-to-right readers. Participant scan times of stimuli divided into equal quadrants were monitored by an eye-tracking camera. Both groups displayed greater scan times in upper quadrants. These findings suggest that native reading direction modulates spatial and light perception biases resulting in weaker leftward, or a lack of lateral biases among right-to-left readers. PMID- 25537527 TI - Treatment for a eumycetoma infection caused by Aspergillus in an immunocompromised host: a case report. AB - Eumycetoma is a chronic infection of the skin and subcutaneous tissue caused by filamentous fungi, which usually occurs in tropical or subtropical countries. We report a case of an immunocompromised patient presenting with presumed eumycetoma in the United States and his subsequent treatment with voriconazole. The use of voriconazole and liposomal amphotericin B halted the progression and allowed gradual resolution of the infection. The patient will require close monitoring and long-term therapy with voriconazole to obtain a clinical cure. Voriconazole and liposomal amphotericin B are potential initial treatment options, with long term voriconazole maintenance therapy, for an Aspergillus-induced eumycetoma. PMID- 25537528 TI - The TNFRSF1B rs1061622 polymorphism (p.M196R) is associated with biological drug outcome in Psoriasis patients. AB - Genetic factors are involved not only in the overall risk of suffering psoriasis, but also in their clinical characteristics and eventually in drug outcome. Biological therapies have dramatically improved the prognosis of Psoriasis. However, these treatments are very expensive and patients often exhibit a heterogeneous response that could be partially attributed to their genetic background. Thus, the research for genetic markers in psoriatic patients that could predict a poor response to biological therapies is an important issue. Our aim was to evaluate the effect of DNA variants at the "TNFalpha pathway" that could affect the risk of developing Psoriasis or the response to biological therapies among these patients. The genetic association study included a total of 518 Psoriatic patients and 480 healthy controls. Ninety of these patients received biological treatment and based on the change in the PASI score after 24 weeks were classified as good (PASI score >=75%), intermediate (PASI 50-75), and non-responders (PASI <50). Next generation sequencing (NGS) with semiconductor array technology was used to identify the nucleotide variants in the TNF alpha, TNFRSF1A and TNFRSF1B, and we only found three missense amino acid changes, all in TNFRSF1B. Interestingly, we found a significantly higher frequency of rs1061622 G carriers among CW6-positive patients (p = 0.004; OR = 1.69, 95% CI = 1.18-2.41). Allele G (p.196R) carriers were significantly more frequent in the non-responder group (56%) (p = 0.05). In conclusion, we report a significant association between the TNFRSF1B p.M196R variant and the risk for psoriasis and the response to treatment with anti-TNF or anti-Il-12/Il-23. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs. PMID- 25537529 TI - 4-Dechloro-14-deoxy-oxacyclododecindione and 14-deoxy-oxacylododecindione, two inhibitors of inducible connective tissue growth factor expression from the imperfect fungus Exserohilum rostratum. AB - Connective tissue growth factor (CTGF/CCN2), a member of the CCN superfamily of secreted cysteine-rich glycoproteins, is a central mediator of tissue remodeling and fibrosis. CTGF is suggested to be an important down-stream effector of transforming growth factor-beta (TGF-beta) signaling and has therefore reached considerable pathophysiological relevance because of its involvement in the pathogenesis of fibrotic diseases, atherosclerosis, skin scarring, and other conditions with excess production of connective tissue. In a search for inhibitors of inducible CTGF expression from fungi, two new macrocyclic lactones, namely 4-dechloro-14-deoxy-oxacyclododecindione (1) and 14-deoxy oxacylododecindione, (2) along with the previously described congener oxacyclododecindione (3) were isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1 and 2 turned out to inhibit TGF-beta induced CTGF promoter activity in transiently transfected HepG2 cells in a dose-dependent manner with IC50 values of 1.8 MUM and 336 nM, respectively, and also antagonized TGF-beta induced cellular effects including CTGF mRNA levels, CTGF protein expression and tube formation. PMID- 25537530 TI - Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino benzo[d]isoxazole or 3-aminoindazole scaffold. AB - A series of 3-amino-benzo[d]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds (8d, 8e, 12, 28a-d, 28h and 28i) with IC50s less than 10nM against c Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC50=1.8 nM) and cellular (IC50=0.18 MUM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs. PMID- 25537532 TI - Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase. AB - A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 MUM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31 MUM, SI=48), 3TC (EC50=2.24 MUM, SI>39), DDI (EC50=23.20 MUM, SI>9) and DLV (EC50=0.65 MUM, SI>67), and comparable to AZT (EC50=0.0071 MUM, SI>13144) and EFV (EC50=0.0062 MUM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method. PMID- 25537531 TI - IND-2, a pyrimido[1",2":1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells. AB - Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1",2":1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1 MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1",2":1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer. PMID- 25537534 TI - [Prevention and intervention strategies for hyperbilirubinemia induced brain injury]. PMID- 25537533 TI - Yeast surface display is a novel tool for the rapid immunological characterization of plant-derived food allergens. AB - High-throughput characterization of allergens relies often on phage display technique which is subject to the limitations of a prokaryotic expression system. Substituting the phage display platform with a yeast surface display could lead to fast immunological characterization of allergens with complex structures. Our objective was to evaluate the potential of yeast surface display for characterization of plant-derived food allergens. The coding sequence of mature actinidin (Act d 1) was cloned into pCTCON2 surface display vector. Flow cytometry was used to confirm localization of recombinant Act d 1 on the surface of yeast cells using rabbit polyclonal antisera IgG and IgE from sera of kiwifruit-allergic individuals. Immunological (dot blot, immunoblot ELISA and ELISA inhibition), biochemical (enzymatic activity in gel) and biological (basophil activation) characterization of Act d 1 after solubilization from the yeast cell confirmed that recombinant Act d 1 produced on the surface of yeast cell is similar to its natural counterpart isolated from green kiwifruit. Yeast surface display is a potent technique that enables fast immunochemical characterization of allergens in situ without the need for protein purification and offers an alternative that could lead to improvement of standard immunodiagnostic and immunotherapeutic approaches. PMID- 25537535 TI - [A multicenter study on the surfactant treatment in late-preterm or term infants with respiratory distress syndrome]. AB - OBJECTIVE: To investigate the efficacy and safety of surfactant when it was used to treat late-preterm or term infants with respiratory distress syndrome (RDS). METHOD: Infants who were born at >=34 weeks' gestational age and diagnosed with respiratory distress syndrome, required mechanical ventilation, admitted to 8 tertiary NICUs at <72 hours of age were enrolled. Surfactant was given if the infant required FiO2>=0.4 to maintain PaO2>=50 mmHg(1 mmHg=0.133 kPa) or SpO2>90%. Before and after surfactant treatment, the results of blood gas, ventilator settings, and the incidence of complications were recorded and analyzed. Comparison between continuous variables was made by t-test or one way analysis of variance (ANOVA). Categorical data was analyzed by a 2-tailed Pearson chi2 test. RESULT: Totally 96 infants were enrolled in this prospective study. The mean gestational age was (36.5+/-2.1) weeks. Of whom, 71.9% (n=69) were male, 59.4% (n=57) were late-preterm infants, 62.5% (n=60) were delivered by elective cesarean section. The first dose of surfactant was given at the median age of 13.3 hours with the dosage of (109+/-20) mg/kg. The second dose was given to 10.4% (n=10) infants. Half an hour post surfactant, PaO2/FiO2, OI, A-aDO2, PaO2/PAO2 improved significantly, and lasted for 6 hours. The mean length of hospital stay was (19+/-9) days, median medical cost was (39,000+/-36,000) yuan. Totally 73 cases (76.0%) were discharged after the treatment completed. Compared to small dosage, the improvement of PaO2/FiO2, OI, A-aDO2, PaO2/PAO2 was more significant at 6 hours after relatively large dose (>=100 mg/kg) of surfactant, and the length of mechanical ventilation was shorter. But the length of hospital stay, medical costs, and the incidence of complications was not significantly different between these two dosage groups. CONCLUSION: Surfactant significantly improved the oxygenation in late-preterm or term infants with respiratory distress syndrome. PMID- 25537536 TI - [Survival and mortality rate of extremely preterm and extremely low birth weight infants admitted to neonatology departments]. AB - OBJECTIVE: With the progress of perinatal medicine and neonatal treatment technology, more and more extremely preterm (EP) and extremely low birth weight infant (ELBWI) survived all over the world. But in our country, there is still lack of survival analysis of large sample survey in this field. This study was designed to survey the survival and mortality rate of EP and ELBWI who were admitted to neonatology departments. METHOD: Clinical data of EP and ELBWI, who were discharged from January 1, 2008 to December 31, 2012, were collected retrospectively from twenty tertiary neonatology departments in Guangdong province. Comparisons of cure rate and survival rate were made respectively according to gestational age, birth weight, year of discharge and area of birth. Categorical data were analyzed using the chi-square test, and P<0.05 was considered statistically significant. RESULT: There were 888 cases of EP and ELBWI enrolled in the study totally; 284 cases (32.0%) were discharged of cure, 41 cases (4.6%) were transferred to other hospitals, 178 cases (20.0%) died during hospitalization, and 385 cases (43.4%) were discharged without permission or discharged ahead of schedule. Among these 385 cases, 116 (13.1%) survived and 269 (30.3%) died after discharge. While the period 2011-2012 compared to 2008 2010, the proportion of EP and ELBWI in all discharged infants [0.56% (514/92 298) vs. 0.45% (371/82 834), chi2=10.318, P=0.001] and in preterm infants [2.01% (514/25 629) vs. 1.63% (371/22 716), chi2=9.290, P=0.002] had gone up. The cure rate [37.1% (182/491) vs. 28.7% (102/356), chi2=6.558, P=0.010] and survival rate [50.1% (246/491) vs. 43.3% (154/356), chi2=3.878, P=0.049] had increased too. The overall cure rate and survival rate of EP were 29.7% (140/471) and 38.0% (179/471). And the overall cure rate and survival rate of ELBWI were 31.4% (203/646) and 45.8% (296/646). Along with the increased gestational age and birth weight, the cure rate and survival rate of EP and ELBWI both increased, and mortality rate decreased. The cure rate [44.0% (201/457) vs. 21.3% (83/390), chi2=48.653, P<0.001] and survival rate [51.2% (234/457) vs. 42.6% (166/390), chi2=6.302, P=0.012] between hospitals of Guangzhou and Shenzhen were higher than those of other cities. CONCLUSION: EP and ELBWI slightly increased in neonatology departments. And the cure rate and survival rate of them increased too. They were closely related to gestational age and birth weight. The cure rate and survival rate in the hospitals of Guangzhou and Shenzhen were higher than those of the other areas of Guangdong province. PMID- 25537537 TI - [Clinical analysis of 165 extremely low birth weight infants]. AB - OBJECTIVE: To analyze the clinical features and prognosis of extremely low birth weight infants (ELBWI). METHOD: Data of totally 165 hospitalized ELBWI between August 1st, 2008 and November 30th, 2013 in Hunan Children's Hospital were analyzed. The information of general data and births, prenatal care, delivery room stabilization, transfer information, complications, treatment, outcome and follow up were summarized. RESULT: (1) One hundred and sixty-five ELBWI were involved, their mean gestational age was (28.4+/-2.4) weeks, mean birth weight(910.9+/-93.1) g. (2) Rate of delivery in tertiary hospital was 46.7% (77/165) and prenatal steroids exposure was found in 52.1% (86/165). None of the cases were treated with continuous positive airway pressure (CPAP) in delivery room. (3) Rate of infants who were transfered to the class III b neonatal ward within 12 hours after birth was 58.8% (97/165). (4) The main complications of them included neonatal respiratory distress syndrome(NRDS, 77.0%, 127/165), bronchopulmonary dysplasia (BPD, 70.1%, 75/107), patent ductus arteriosus (PDA, 50.0%, 40/80), preterm retinopathy (ROP, 43.0%, 46/107), sepsis 39.4% (65/165), intraventricular hemorrhage (IVH, 34.8%, 49/141), necrotizing enterocolitis (NEC, 8.0%, 7/88). (5) TREATMENT: 97.6% (161/165) received oxygen therapy and 66.1% (109/165) received mechanical ventilation, 55.2% (91/165) used CPAP. 89.8% (114/127) of the NRDS used PS; 44.0% (33/75) of the BPD used low dose dexamethasone, 32.0% (24/75) used low dose nitric oxide; 60.0% (24/40) of the PDA used medication. 32.6% (15/46) of the ROP received laser photocoagulation. The average time of beginning enteral feeding was 2.0 d, the mean time to achieve full gastrointestinal feeding was 43.4 d. (6) OUTCOME: rate of survival in 165 cases with ELBWI was 51.5% (85/165), treatment was abandoned in 37.6% (62/165), total mortality was 48.5% (80/165). There were significant difference in survival rate between different birth weight group, gestational age group and admission age group (chi2=11.498, 8.789, 13.157, all P<0.05); There was significant difference in rate of giving up treatment between different birth weight and admission age groups (chi2=10.448, 8.259, all P<0.05). The primary cause of death was economic factor and worrying about prognosis. (7) Follow up: rate of neurodevelopmental impairment (NDI) in part of follow up cases was 27.9% (12/43). CONCLUSION: ELBWI have many severe complications and sequelae, which need complex treatment and long hospital stay with a low survival rate. In order to improve the level of treatment, we need to improve the rate of prenatal steroids, carry out intrauterine and postnatal, transport of ELBWI to III b neonatal ward as early and rationally as possible, give professional, sophisticated and integrated treatment technologies as far as possible. PMID- 25537538 TI - [Application of lung recruitment maneuver in preterm infants with respiratory distress syndrome ventilated by proportional assist ventilation]. AB - OBJECTIVE: To understand the effect of lung recruitment maneuver (LRM) with positive end-expiratory pressure (PEEP) on oxygenation and outcomes in preterm infants with respiratory distress syndrome (RDS) ventilated by proportional assist ventilation (PAV). METHOD: From January 2012 to June 2013, thirty neonates with a diagnosis of RDS who required mechanical ventilation were divided randomly into LRM group (n=15, received an LRM and surport by PAV) and control group (n=15, only surport by PAV). There were no statistically significant differences in female (7 vs. 6); gestational age [(29.3+/-1.2) vs. (29.5+/-1.1) weeks]; body weight[(1,319+/-97) vs. (1,295+/-85) g]; Silverman Anderson(SA) score for babies at start of ventilation (7.3+/-1.2 vs. 6.9+/-1.4); initial FiO2 (0.54+/-0.12 vs. 0.50+/-0.10) between the two groups (all P>0.05). LRM entailed increments of 0.2 cmH2O (1 cmH2O=0.098 kPa) PEEP every 5 minutes, until fraction of inspired oxygen (FiO2)=0.25. Then PEEP was reduced and the lung volume was set on the deflation limb of the pressure/volume curve.When saturation of peripheral oxygen fell and FiO2 rose, we reincremented PEEP until SpO2 became stable. The related clinical indicators of the two group were observed. RESULT: The doses of surfactant administered (1.1+/-0.3 vs. 1.5+/-0.5, P=0.027), Lowest FiO2 (0.29+/-0.05 vs. 0.39+/-0.06, P=0.000), time to lowest FiO2[ (103+/-18) vs. (368+/-138) min, P=0.000] and O2 dependency [(7.6+/-1.0) vs.( 8.8+/-1.3) days, P=0.021] in LRM group were lower than that in control group (all P<0.05). The maximum PEEP during the first 12 hours of life [(8.4+/-0.8) vs. (6.8+/-0.8) cmH2O, P=0.000] in LRM group were higher than that in control group (P<0.05). FiO2 levels progressively decreased (F=35.681, P=0.000) and a/AO2 Gradually increased (F=37.654, P=0.000). No adverse events and no significant differences in the outcomes were observed. CONCLUSION: LRM can reduce the doses of pulmonary surfactant administered, time of the respiratory support and the oxygen therapy in preterm children with RDS. PMID- 25537539 TI - [The experts consensus on the management of neonatal hyperbilirubinemia]. PMID- 25537540 TI - [European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants--2013 update]. PMID- 25537541 TI - [Criteria and practical for determination of brain death in children (BQCC version)]. PMID- 25537542 TI - [Anti-vascular endothelial growth factor in the treatment of retinopathy of prematurity: an update]. PMID- 25537519 TI - Classification of current anticancer immunotherapies. AB - During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID- 25537543 TI - [Optimal oxygen saturation in extremely preterm infants]. PMID- 25537544 TI - [The current situation and prospect of pediatric clinical application for transbronchial needle aspiration]. PMID- 25537547 TI - [Factors influencing ventilator weaning and predictive value of weaning criteria in children]. AB - OBJECTIVE: To analyze the factors that influence the outcome of ventilator weaning and the predictive value of ventilator weaning criteria such as PaO2/FiO2, Vt/kg, Cst, RSBI and the changing trend of RSBI [DeltaRSBI = (RSBI2 RSBI1)/RSBI1, RSBI1 and RSBI2 are the start and end of SBT separately] in children. METHOD: One hundred and thirty-two children who were mechanically ventilated over 24 hours were enrolled from April 2012 to October 2013 in Shenzhen Children's Hospital. SIMV+PSV and SBT ventilator mode were used in ventilator weaning according to clinical experience. Age, gender, weight, critical illness score, duration of mechanical ventilation, PICU stays and the causes to mechanical ventilation were taken into account as the effect on the result of ventilator weaning. Using area under ROC curve of the indexes such as PaO2/FiO2, Vt/kg, Cst, RSBI and the DeltaRSBI to evaluate the predictability of children ventilator weaning. RESULT: One hundred and thirty-two children were enrolled and 109 succeeded in ventilator weaning, while 23 failed. Seventy-nine children using SIMV+PSV mode and 64 succeeded in ventilator weaning among them, while 23 failed. The success rate was 81.0%. The remaining 53 children using SBT mode, 45 among them succeeded and 8 failed in ventilator weaning, which success rate was 84.9%. There was no statistically significant difference in ventilator weaning mode(chi2=0.334, P=0.563). Age, gender, weight, critical illness score between the succeeded group and the failed group did not show statistically significant difference (t=-0.661; chi2=1.271; t=-0.749, -0.020; P>0.05), but duration of mechanical ventilation, PICU stays and the causes for mechanical ventilation showed significant difference (t=3.751, 3.701; chi2=11.273, P<0.05). The area under ROC curve of PaO2/FiO2, Vt/kg, Cst and RSBI in SIMV+PSV was 0.506, 0.415,0.557 and 0.512, in SBT was 0.503, 0.653, 0.546 and 0.708 separately. There was no statistically significant difference in the predictors mentioned above (P>0.05). But the area under ROC curve of DeltaRSBI in SBT was 0.814, which was significantly different compared to RSBI in SIMV+PSV (Z=2.966, P<0.05). CONCLUSION: To children who mechanically ventilated for over 24 hours, duration of mechanical ventilation, PICU stays and the causes for mechanical ventilation are the main influencing factors. DeltaRSBI is a better predictor with feasibility and safety, which is also worth generalizing. PMID- 25537546 TI - [Anomalous origin of the left coronary artery from the pulmonary artery in infants: clinical features and the perioperative treatment strategies]. AB - OBJECTIVE: To investigate the clinical features and individualized treatment strategies for infants with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). METHOD: Data of 25 less than 1-year-old infants with ALCAPA who presented at Guangdong Cardiovascular Institute between 2006 and 2013 were retrospectively reviewed. The patients' cardiac function was evaluated with echocardiography during follow-up. RESULT: Most patients presented with symptoms of heart failure, such as tachypnea, diaphoresis, poor feeding, failure to thrive etc. Electrocardiogram showed abnormal q wave in 23 patients and ST-T segment change in 16 patients.Echocardiography showed dilated left ventricle in 25 patients, endocardial hyperplasia in 5 patients, dilated right coronary artery and extensive collateralization between the right and left coronary artery systems in 11 patients. The left ventricular ejection fraction (LVEF) was (45.5+/ 13.9)% (25%-77%). The left ventricular fractional shortening (LVFS) was (22.0+/ 7.3)% (12%-38%). Twenty one patients underwent cardiovascular CT scan. Left coronary artery originated from left posterior sinus in 9 patients, from right posterior sinus in 1 patient, from lower main pulmonary artery in 5 patients, from the bifurcation of main pulmonary artery in 1 patient.Five patients showed ambiguous left coronary artery origination.Sixteen patients were misdiagnosed in other primary or secondary hospitals in 17 patients who were transferred to our tertiary hospital, only 1 case who underwent angiography was diagnosed correctly. Two patients were misdiagnosed in 8 patients first-presented in our hospital. Their diagnoses were corrected after reexamining with echocardiography and cardiovascular CT scan. The preoperative therapies included using inotropic agents, diuretics and vasodilators according to cardiac function. Two patients underwent left coronary artery orifice ligation. Twenty three patients underwent reimplantation of left coronary artery to reconstruct dual coronary system. Patients of NYHA IV with moderate mitral regurgitation (MR) and NYHA III with severe MR underwent mitral annuloplasty. If LVEF was less than 30% after weaning from cardiopulmonary bypass, blood pressure could not be maintained with medication, or lactates increased progressively, extracorporeal membrane oxygenation (ECMO) was demanded. Two patients showed low cardiac output syndrome immediately after surgical procedures, died from refractory ventricular fibrillation even with ECMO.In survived 23 patients during the early stage after surgeries, duration of ventilation was 7-500 hours, 11 of them were supported with ventilator for less than 60 hours. The mean length of hospital stay was (23.4+/-13.9) d (8-65 d). The follow-up duration ranged from 1-91 months (median 28.5 months). One case was lost to follow up. The patient died from infection 3 months after discharge. The cardiac functions of the remaining 22 patients were improved. The size of left ventricle of 14 patients recovered to normal. LVEF increased to the normal level in 20 cases. No patient underwent redo procedure. CONCLUSION: The accurate diagnosis can be made based on history, electrocardiogram, echocardiography and other imaging diagnostic tools.Individualized treatment strategy is helpful for seriously sick infants. Aggressive ECMO support can increase surviving rate for patients with postoperative low cardiac output syndrome. PMID- 25537545 TI - [SLCO1B1c. 521T>C gene polymorphisms are associated with high-dose methotrexate pharmacokinetics and clinical outcome of pediatric acute lymphoblastic leukemia]. AB - OBJECTIVE: To provide guidance for the high-dose methotrexate (HD-MTX) treatment of pediatric acute lymphoblastic leukemia (ALL), and to understand the impact of SLCO1B1c.521T>C (rs4149056) variant on methotrexate (MTX) pharmacokinetics and clinical outcome in children with ALL. METHOD: Eighty-two children with ALL in Division of Hematology of Wuhan Children's Hospital from January 2008 to February 2013 were enrolled. All patients were genotyped for rs4149056 single nucleotide polymorphism (SNP) into wild-type group (TT genotype) and variant group (TC/CC genotype). According to the ALL-BFM 2000 protocol, all patients received intravenous infusion of MTX every ten days at 3 to 5 g/m(2). Leucovorin rescue was performed after 36 hours of the MTX administration and its dose was adjusted according to the MTX plasma concentration at 48 hours. The concentrations of MTX and its metabolite at 24, 48 and 72 h were determined by high performance liquid chromatography with solid phase extraction. Population pharmacokinetic parameters were estimated by the NLME software. The pharmacokinetics, toxicity and leucovorin rescue was compared. The relapse rate within 5 years and event-free survival were followed up. RESULT: Eighty-two pediatric patients were classified into two groups: variant group including 20 TC genotype carriers and one CC genotype carrier, wild-type group included 61 patients with TT genotype. Compared with wild-type group, plasma concentration of MTX at 48 and 72 h increased significantly [48 h: (1.00+/-1.41) vs.(0.34+/-0.17) umol/L, t=2.131, P=0.046; 72 h: (0.31+/-0.26) vs.(0.08+/-0.04) umol/L; t=3.995, P=0.001]. Area under the concentration time curve (AUC48-?) of MTX significantly increased in variant group [(23.18+/-19.91) vs.(5.66+/-2.01) h.umol/L] (t=4.025, P=0.001). Time above the MTX safety threshold (TC>0.1 umol/L) increased significantly in variant group [(95.3+/-22.0) vs.(67.1+/-7.5) h, t=5.880, P<0.001]. Rescue dosage of leucovorin in variant group was higher than that in wild-type group [(312.7+/-287.8) vs.(140.6+/-27.5) mg/m2, t=2.614, P=0.017]. The children carrying rs4149056 C allele suffered from a higher frequency of serious adverse effect [gastrointestinal toxicity: 33% (7/21) vs. 5% (3/61);hepatic toxicity: 24% (5/21) vs. 2% (1/61)]. The difference was statistically significant (chi2=9.275, 8.289, all P<0.05). Hospital stay of variant group was significantly longer than that of wild-type [(4.95+/-1.43) vs. (4.05+/-0.22) d, t=2.881, P=0.009]. The relapse rate within 5 years of variant group and wild-type group were 9% (2/21) and 13% (8/61), respectively. There were no significant differences in the event-free survival between the two groups (chi2=0.001, P=0.971). CONCLUSION: The SLCO1B1 c.521T>C variant was an important determinant of MTX pharmacokinetics. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity and did not affect the long-term clinical outcome. PMID- 25537548 TI - [ASS1 gene mutation in a neonate with citrullinemia type I]. AB - OBJECTIVE: To identify the genetic mutation in ASS1 gene in a Chinese family with citrullinemia typeI, which may provide a basis for the diagnosis and genetic counseling. METHOD: Genomic DNA was isolated from peripheral blood samples of the family members. Mutation analysis of ASS1 gene was carried out by PCR and Sanger sequencing. Biostructural analysis of the mutated ASS1 was completed by Phyre server. RESULT: Double heterozygous mutations in the proband were identified: c.951delT (F317LfsX375) and c.1087C>T (R363W), which were confirmed in the proband's father and mother, respectively. It was found that the c.951delT mutation might change the formation of a dimer or a tetramer and the function of ASS1 protein. CONCLUSION: Double heterozygous mutations for c.951delT and c.1087C>T have been found in a proband with citrullinemia typeI. The c.951delT is a novel mutation in citrullinemia typeI, which may change the configuration of ASS1 protein and result in ASS1 dysfunction. PMID- 25537549 TI - [Analysis of 3 cases with Mycoplasma pneumoniae-associated hemophagocytic syndrome and review of literature]. AB - OBJECTIVE: To analyze the clinical characteristics of Mycoplasma pneumoniae associated hemophagocytic syndrome (MP-HLH). METHOD: A retrospective investigation of the clinical manifestation, laboratory test, imagelogy, clinical course and outcome of 3 cases with MP-HLH seen between June 2013 and July 2013 in Shenzhen Children's Hospital, and review of relevant literature were conducted. RESULT: Of the 3 cases of MP-HLH, 2 were males, one was female, the ages were 1 year, 3 years and 6 years, respectively. They had no underlying disease previously. All the 3 cases had onset of fever, cough as main symptoms. Diagnosis of refractory Mycoplasma pneumoniae pneumonia was made, which was accompanied by decreased neutrophils [(0.08-0.68)*10(9)/L], hemoglobin [(79-103) g/L], platelet [(64-157)*10(9)/L], plasma fibrinogen [(1.3-1.5) g/L], lactate dehydrogenase [(1,170-1,285) U/L] and increased serum ferritin [(936.7-39 789.0) ug/L] in the third week of course. In two cases the T lymphocytes decreased, and the NK cell activity decreased significantly in one. Bone marrow cytology showed prompted bone marrow hyperplasia, and the phenomenon of phagocytosed blood cells. CT scan was performed for all the cases and consolidation with pleural effusion were shown. Two cases were admitted to PICU, and required endotracheal intubation and mechanical ventilation. Flexible bronchoscopy and bronchial lavage were performed and bronchial cast was found in two cases. All of them were treated with macrolide combined with other antibiotics, glucocorticoids and gamma globulin combination therapy, including one case given dexamethasone [10 mg/(m2.d)], cyclosporine[6 mg/(kg.d)], etoposide [150 mg/(m2.d)] chemotherapy. Two cases were cured, and 1 case died. The authors summarized the 18 cases reported in domestic and foreign literature. Foreign children were diagnosed and treated with steroids in 1-2 weeks, and 10 cases were cured, and 2 cases died. They died of massive hemorrhage and meningoencephalitis, and domestic children were diagnosed and treated within two to 4 weeks after onset, 5 cases were cured, one case died of severe pneumonia. CONCLUSION: MP-HLH is a rare disease in children, and had acute onset, rapid progression and high mortality. Early treatment with steroids was associated with a good prognosis, the key to successful treatment is early diagnosis and treatment, avoiding the immune cascade. Too late a diagnosis or development of serious complications may lead to death. PMID- 25537550 TI - [Congenital systemic disseminated fungal infections with gastrointestinal perforation in one case]. PMID- 25537553 TI - Topological states modulation of Bi and Sb thin films by atomic adsorption. AB - Based on first-principles calculations, we systematically investigated the topological surface states of Bi and Sb thin films of 1-5 bilayers in (111) orientation without and with H(F) adsorption, respectively. We find that compared with clean Bi and Sb films, a huge band gap advantageous to observe the quantum spin Hall effect can be opened in chemically decorated bilayer Bi and Sb films, and the quantum phase transition from trivial (non-trivial) to non-trivial (trivial) phase is induced for a three bilayer Bi film and single (four) bilayer Sb film. Surface adsorption is an effective tool to manipulate the geometry, electronic structures and topological properties of film materials. PMID- 25537554 TI - Use of forced vital capacity and forced expiratory volume in 1 second quality criteria for determining a valid test. AB - The 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) spirometry guidelines define valid tests as having three acceptable blows and a repeatable forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The aim of this study was to determine how reviewer and computer determined ATS/ERS quality could affect population reference values for FVC and FEV1. Spirometry results from 7777 normal subjects aged 8-80 years (NHANES (National Health and Nutrition Examination Survey) III) were assigned quality grades A to F for FVC and FEV1 by a computer and one reviewer (reviewer 1). Results from a subgroup of 1466 Caucasian adults (aged 19-80 years ) were reviewed by two additional reviewers. Mean deviations from NHANES III predicted for FVC and FEV1 were examined by quality grade (A to F). Reviewer 1 rejected (D and F grade) 5.2% of the 7777 test sessions and the computer rejected ~16%, primarily due to end-of-test (EOT) failures. Within the subgroup, the computer rejected 11.5% of the results and the three reviewers rejected 3.7-5.9%. Average FEV1 and FVC were minimally influenced by grades A to C allocated by reviewer 1. Quality assessment of individual blows including EOT assessments should primarily be used as an aid to good quality during testing rather than for subsequently disregarding data. Reconsideration of EOT criteria and its application, and improved grading standards and training in over-reading are required. Present EOT criteria results in the exclusion of too many subjects while having minimal impact on predicted values. PMID- 25537552 TI - Autophagy: an emerging therapeutic target in vascular diseases. AB - Autophagy is a cellular catabolic process responsible for the destruction of long lived proteins and organelles via lysosome-dependent pathway. This process is of great importance in maintaining cellular homeostasis, and deregulated autophagy has been implicated in the pathogenesis of a wide range of diseases. A growing body of evidence suggests that autophagy can be activated in vascular disorders such as atherosclerosis. Autophagy occurs under basal conditions and mediates homeostatic functions in cells but in the setting of pathological states up regulated autophagy can exert both protective and detrimental functions. Therefore, the precise role of autophagy and its relationship with the progression of the disease need to be clarified. This review highlights recent findings regarding autophagy activity in vascular cells and its potential contribution to vascular disorders with a focus on atherogenesis. Finally, whether the manipulation of autophagy represents a new therapeutic approach to treat or prevent vascular diseases is also discussed. PMID- 25537555 TI - Asthma medication use during pregnancy, wheeze and estimated exposure to ambient nitrogen dioxide. PMID- 25537556 TI - Inhaled corticosteroids in COPD: the clinical evidence. AB - In this article, we focus on the scientific evidence from randomised trials supporting treatment with inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD), including treatment with combinations of long-acting beta-agonist (LABA) bronchodilators and ICS. Our emphasis is on the methodological strengths and limitations that guide the conclusions that may be drawn. The evidence of benefit of ICS and, therefore, of the LABA/ICS combinations in COPD is limited by major methodological problems. From the data reviewed herein, we conclude that there is no survival benefit independent of the effect of long-acting bronchodilation and no effect on FEV1 decline, and that the possible benefit on reducing severe exacerbations is unclear. Our interpretation of the data is that there are substantial adverse effects from the use of ICS in patients with COPD, most notably severe pneumonia resulting in excess deaths. Currently, the most reliable predictor of response to ICS in COPD is the presence of eosinophilic inflammation in the sputum. There is an urgent need for better markers of benefit and risk that can be tested in randomised trials for use in routine specialist practice. Given the overall safety and effectiveness of long acting bronchodilators in subjects without an asthma component to their COPD, we believe use of such agents without an associated ICS should be favoured. PMID- 25537557 TI - Increased IgA production by B-cells in COPD via lung epithelial interleukin-6 and TACI pathways. AB - Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD). We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured with in vitro-reconstituted airway epithelium. In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas. In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38(+) plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI. These data show that in COPD, the bronchial epithelium imprints B cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF APRIL/TACI pathways, while cigarette smoke partly counteracts this IgA-promoting effect. PMID- 25537558 TI - Computed tomography quantification of airway remodelling in normal ageing subjects: a cross-sectional study. PMID- 25537559 TI - Systematic qualitative review of randomised trials conducted in nonsmall cell lung cancer with a noninferiority or equivalence design. AB - The use of noninferiority randomised trials for patients with advanced non-small cell lung cancer has emerged during the past 10-15 years but has raised some issues related to their justification and methodology. The present systematic review aimed to assess trial characteristics and methodological aspects. All randomised clinical trials with a hypothesis of noninferiority/equivalence, published in English, were identified. Several readers extracted a priori defined methodological information. A qualitative analysis was then performed. We identified 20 randomised clinical trials (three phase II and 17 phase III), 11 of them being conducted in strong collaboration with industry. We highlighted some deficiencies in the reports like the lack of justification for both the noninferiority assumption and the definition of the noninferiority margin, as well as inconsistencies between the results and the authors' conclusions. CONSORT guidelines were better followed for general items than for specific items (p<0.001). Improvement in the reporting of the meth"odology of noninferiority/equivalence trials is needed to avoid misleading interpretation and to allow readers to be fully aware of the assumptions underlying the trial designs. They should be restricted to limited specific situations with a strong justification why a noninferiority hypothesis is acceptable. PMID- 25537560 TI - Prognostic value of right ventricular ejection fraction in pulmonary arterial hypertension. AB - Right ventricle ejection fraction (RVEF) evaluated with magnetic resonance imaging is a strong determinant of patient outcomes in pulmonary arterial hypertension. We evaluated the prognostic value of RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change 3 6 months after initiating pulmonary arterial hypertension-specific therapy. In a prospective cohort of newly diagnosed patients with idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension, RVEF was measured at baseline (n=100) and 3-6 months after initiation of therapy (n=78). After a median follow-up of 4.1 years, 41 deaths occurred, including 35 from cardiovascular causes. Patients with a (median) baseline RVEF >25% had better survival than those with a RVEF <25% using Kaplan-Meier analysis (p=0.010). RVEF at baseline was an independent predictor of all-cause and cardiovascular mortality in adjusted Cox regression model (p=0.002 and p=0.007, respectively; HR 0.93 for both). Patients with stable or increased RVEF at 3-6 months had a trend for improved all-cause survival (HR 2.43, p=0.086) and had less cardiovascular mortality (HR 3.25, p=0.034) than those in whom RVEF decreased despite therapy. RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change in RVEF 3-6 months after therapy initiation independently predict outcomes in patients with pulmonary arterial hypertension. PMID- 25537561 TI - Estimation of post-operative forced expiratory volume by functional respiratory imaging. PMID- 25537562 TI - A systematic review of socioeconomic position in relation to asthma and allergic diseases. AB - The role of socioeconomic position (SEP) in the development of asthma and allergies is unclear, with some pointing to the risks of low SEP and other research pointing in the direction of higher SEP being associated with higher prevalence rates. The aim of this systematic review is to clarify associations between SEP and the prevalence of asthma and allergies. Out of 4407 records identified, 183 were included in the analysis. Low SEP was associated with a higher prevalence of asthma in 63% of the studies. Research on allergies, however, showed a positive association between higher SEP and illness in 66% of studies. Pooled estimates for the odds ratio of disease for the highest compared with the lowest SEP confirmed these results for asthma (unadjusted OR 1.38, 95% CI 1.37-1.39), allergies in general (OR 0.67, 95% CI 0.62-0.72), atopic dermatitis (unadjusted OR 0.72, 95% CI 0.61-0.83) and allergic rhinoconjunctivitis (unadjusted OR 0.52, 95% CI 0.46-0.59). Sensitivity analyses with a subsample of high-quality studies led to the same conclusion. Evidence from this systematic review suggests that asthma is associated with lower SEP, whereas the prevalence of allergies is associated with higher SEP. PMID- 25537563 TI - Severity and outcome of cystic lung disease in women with tuberous sclerosis complex. AB - What are the clinical features, severity, and rate of progression of lung disease in women with tuberous sclerosis and lymphangioleiomyomatosis (LAM) and how do they differ from patients with sporadic LAM? Data from 94 tuberous sclerosis/LAM and 460 sporadic LAM women were compared. 40 tuberous sclerosis/LAM and 40 sporadic LAM patients were age- and lung function-matched, and changes in volume occupied by cysts (cyst score) and pulmonary function occurring over 6.5 years were evaluated. Tuberous sclerosis/LAM patients had better lung function than sporadic LAM patients, but no difference was observed from sporadic LAM patients in yearly rates of change in forced expiratory volume in 1 s (-1.9+/-2.7 versus 1.9+/-1.9% predicted; p=0.302), diffusing capacity of the lung for CO (-2.1+/-2.8 versus -1.9+/-2.7% predicted; p=0.282) or cyst scores (+1.0+/-1.3 versus +1.4+/ 1.7%, p=0.213). However, the proportion of patients with abnormal lung function and higher rates of FEV1 decline was greater in sporadic LAM. Some young tuberous sclerosis/LAM patients (mean age 25.7+/-3 years) progressed rapidly from minimal to severe lung disease. Tuberous sclerosis/LAM patients may experience abrupt declines in lung function. Consequently, women with tuberous sclerosis found to have lung cysts should undergo periodic functional and radiological testing to follow disease progression and determine need for therapy. PMID- 25537564 TI - Prevalence of Birt-Hogg-Dube syndrome in patients with apparently primary spontaneous pneumothorax. PMID- 25537565 TI - Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. AB - We assessed whether intermittent hypoxia, which emulates one of the hallmarks of obstructive sleep apnoea (OSA), leads to altered faecal microbiome in a murine model. In vivo partial pressure of oxygen was measured in colonic faeces during intermittent hypoxia in four anesthetised mice. 10 mice were subjected to a pattern of chronic intermittent hypoxia (20 s at 5% O2 and 40 s at room air for 6 h.day(-1)) for 6 weeks and 10 mice served as normoxic controls. Faecal samples were obtained and microbiome composition was determined by 16S rRNA pyrosequencing and bioinformatic analysis by Quantitative Insights into Microbial Ecology. Intermittent hypoxia exposures translated into hypoxia/re-oxygenation patterns in the faeces proximal to the bowel epithelium (<200 MUm). A significant effect of intermittent hypoxia on global microbial community structure was found. Intermittent hypoxia increased the alpha-diversity (Shannon index, p<0.05) and induced a change in the gut microbiota (ANOSIM analysis of beta-diversity, p<0.05). Specifically, intermittent hypoxia-exposed mice showed a higher abundance of Firmicutes and a smaller abundance of Bacteroidetes and Proteobacteria phyla than controls. Faecal microbiota composition and diversity are altered as a result of intermittent hypoxia realistically mimicking OSA, suggesting the possibility that physiological interplays between host and gut microbiota could be deregulated in OSA. PMID- 25537566 TI - Nonspecific interstitial pneumonia: survival is influenced by the underlying cause. AB - Idiopathic, nonspecific interstitial pneumonia (NSIP) is most often associated with various clinical disorders, including connective tissue diseases (CTDs) and chronic hypersensitivity pneumonitis (cHP). Emerging evidence also suggests that "idiopathic" NSIP may be the lung manifestation of undifferentiated CTD (UCTD). However, whether or not NSIP outcome is influenced by the underlying cause remains uncertain. This retrospective study included 127 biopsy-proven NSIP patients (65 women, mean +/- sd age 55 +/- 12 years). Survivals were estimated using a Kaplan-Meier curve and compared using the log-rank test. Multivariate analyses were based on a Cox model. 15 (11.8%) patients had cHP, 29 (22.8%) had CTD, 32 (25.2%) satisfied the Kinder criteria for UCTD and 51 (40.1%) had idiopathic NSIP. At the end of follow-up (mean +/- sd 64 +/- 54 months), a difference in survival was observed between aetiological groups (p=0.002). Survival was better for UCTD than for idiopathic NSIP (p=0.020) and similar to that observed for CTD. cHP survival tended to be poorer than that of idiopathic NSIP (p=0.087) and was an independent predictor of mortality (hazard ratio 2.17, 95% CI 1.05-4.47; p=0.035). NSIP outcome is influenced by its cause. cHP exhibits the highest mortality. UCTD does not differ from CTD supporting the concept of autoimmune NSIP, with a prognosis that is better than that of idiopathic NSIP. PMID- 25537567 TI - Diagnostic utility and accuracy of rapid on-site evaluation of bronchoscopic brushings. AB - The aim of the study was to determine the accuracy of rapid on-site examinations, performed on transbronchial brushings of peripheral pulmonary lesions, in determining final bronchoscopic diagnosis. In addition to determining if rapid on site examination impacts procedural outcomes. A prospective cohort study of consecutive patients with peripheral pulmonary lesions, which had been located by radial endobronchial ultrasound, was undertaken. Bronchoscopy was terminated if rapid on-site examination demonstrated diagnostic malignant material. Non diagnostic rapid on-site examination resulted in further bronchoscopic sampling, including transbronchial lung biopsy and/or sampling from different locations. 128 peripheral pulmonary lesions were located by endobronchial ultrasound in 118 patients. The final bronchoscopic diagnoses included nonsmall cell lung cancer (n=76), carcinoid (n=3), and metastatic malignancy (n=3). Procedure times were significantly shorter for procedures when rapid on-site examinations demonstrated malignancy compared to those where rapid on-site examination was non-diagnostic (19+/-8 min versus 31+/-11 min, respectively; p<0.0001). In four procedures, initial negative rapid on-site examination results prompted redirection of sampling from alternate bronchial segments, resulting in positive diagnostic tissue being obtained. Positive and negative predictive value of rapid on-site examination for a malignant bronchoscopic diagnosis was 63 (97%) out of 65, and 43 (68%) out of 63, respectively. Rapid on-site examination of brushing specimens has a very high, positive, predictive value for bronchoscopic diagnosis of cancer and shortens the bronchoscopy procedure times. It has the potential to reduce complications, improve cost-effectiveness, and may improve diagnostic performance via live feedback. PMID- 25537568 TI - Scratching the surface of tomorrow's diagnostics: the Editor-in-Chief's opinion at the 15th year of Expert Review of Molecular Diagnostics. AB - Interview with Attila Lorincz by Claire Raison (Commissioning Editor) To mark the beginning of the 15th year of Expert Review of Molecular Diagnostics, the journal's Editor-in-Chief shares his expert knowledge on translational diagnostics, his opinion on recent controversies and his predictions for molecular diagnostics in 2015 and beyond. Attila Lorincz received his doctorate from Trinity College, Dublin, Republic of Ireland, and went on to become a research fellow at the University of California, Santa Barbara, CA, USA. During Professor Lorincz's research on human papillomavirus (HPV), he found several important and novel carcinogenic HPV types and pioneered the use of HPV DNA testing for clinical diagnostics. In 1988, Professor Lorincz's team produced the first HPV test to be FDA-approved for patients and in 2003, for general population cervical precancer screening. Now Professor of Molecular Epidemiology at the Centre for Cancer Prevention, Queen Mary University of London, UK, he and his team are furthering translational research into DNA methylation assays for cancer risk prediction. PMID- 25537569 TI - The cost-effectiveness of point-of-care D-dimer tests compared with a laboratory test to rule out deep venous thrombosis in primary care. AB - OBJECTIVE: Point-of-care (POC) D-dimer tests have been developed to exclude deep venous thrombosis quickly and on the spot, but are known to have lower sensitivity compared with laboratory-based tests. Their cost-effectiveness is still unknown. METHODS: We updated and extended a previously published Markov model to assess the cost-effectiveness of POC D-dimer tests ('Simplify', 'Cardiac', 'Triage' and 'Nycocard') compared with a laboratory-based latex assay to diagnose deep venous thrombosis in primary care. RESULTS: The 'Laboratory' strategy resulted in 6.986 quality-adjusted life years at the cost of ?8354 per patient. All POC D-dimer tests resulted in health outcomes similar to the 'Laboratory' strategy. The 'Simplify' strategy maximized cost savings (-?155 [95% CI: -?246 to -?83]). CONCLUSIONS: POC D-dimer tests yield similar health outcomes as laboratory-based testing procedures but can be performed more easily and at lower costs. Therefore, these tests are an alternative to laboratory-based testing and might be considered for exclusion of deep venous thrombosis in primary care. PMID- 25537570 TI - Posterior component separation with transversus abdominis release successfully addresses recurrent ventral hernias following anterior component separation. AB - PURPOSE: Anterior component separation (ACS) with external oblique release for ventral hernia repair has a recurrence rate up to 32%. Hernia recurrence after prior ACS represents a complex surgical challenge. In this context, we report our experience utilizing posterior component separation with transversus abdominis muscle release (PCS/TAR) and retromuscular mesh reinforcement. METHODS: Patients with a history of recurrent hernia following ACS repaired with PCS/TAR were retrospectively identified from prospective databases collected at two large academic institutions. Patient demographics, hernia characteristics (using CT scan) and outcomes were evaluated. RESULTS: Twenty-nine patients with a history of ACS developed 22 (76%) midline, 3 (10%) lateral and 4 (14%) concomitant recurrences. Contamination was present in 11 (38%) of cases. All were repaired utilizing a PCS/TAR with retromuscular mesh placement (83% synthetic, 17% biologic) and fascial closure. Wound morbidity consisted of 13 (45%) surgical site occurrences including 8 (28%) surgical site infections. Five (17%) patients required 90-day readmission, and two (7%) were related to wound morbidity. One organ space infection with frank spillage of stool resulted in the only instance of mesh excision. This case also represents the only instance of recurrence (3%) with a mean follow-up of 11 (range 3-36) months. CONCLUSION: Patients with a history of an ACS who develop a recurrence represent a challenging clinical scenario with limited options for surgical repair. A PCS/TAR hernia repair achieves acceptable outcomes and may in fact be the best approach available. PMID- 25537571 TI - Single incision laparoscopic totally extraperitoneal hernioplasty (SIL-TEP): experience of 512 procedures. AB - PURPOSE: Reports have been issued recently on single incision laparoscopic hernioplasty, but no large-scale study has been conducted as yet. This study aimed to assess the safety and feasibility of the single incision laparoscopic totally extraperitoneal hernioplasty (SIL-TEP) on a large number of cases. METHODS: 512 SIL-TEPs in 471 patients were performed from June 2010 to January 2014 at Incheon St. Mary's Hospital, The Catholic University of Korea. SIL-TEP was performed using a glove single port device and standard laparoscopic instruments. Short-term outcomes were reviewed. RESULTS: Of the 512 hernias, 329 (64.3 %) were indirect, 144 (28.1 %) were direct, 9 (1.8 %) were femoral, and 30 (5.9 %) were combined. There were 3 (0.6 %) conversions to single or three-port laparoscopic transabdominal preperitoneal hernioplasty. Mean operative time was 41.6 min for unilateral hernias and 65.3 min for bilateral hernias. Postoperative complications occurred in 45 cases (9.6 %); 21 were wound seromas, 5 were hematomas, and 18 were urinary retentions. All were successfully treated conservatively. Mean hospital stay was 1.8 days. CONCLUSION: The SIL-TEP is safe and technically feasible. Additional studies on long-term recurrence rates are needed to confirm the safety of SIL-TEP. PMID- 25537573 TI - Lab on a chip for continuous-flow magnetic cell separation. AB - Separation of cells is a key application area of lab-on-a-chip (LOC) devices. Among the various methods, magnetic separation of cells utilizing microfluidic devices offers the merits of biocompatibility, efficiency, and simplicity. This review discusses the fundamental physics involved in using magnetic force to separate particles, and identifies the optimisation parameters and corresponding methods for increasing the magnetic force. The paper then elaborates the design considerations of LOC devices for continuous-flow magnetic cell separation. Examples from the recently published literature illustrate these state-of-the-art techniques. PMID- 25537572 TI - Occupational mechanical exposures and reoperation after first-time inguinal hernia repair: a prognosis study in a male cohort. AB - PURPOSE: The aim of this study was to evaluate exposure-response relationships between occupational mechanical exposures and risk of reoperation after inguinal hernia repair. METHODS: Using register information, we identified all men born in Denmark 1938-1988, who had their first inguinal hernia repair 1998-2008, and who were 18-65 years old and active in the labour market at the time of surgery. The Danish Hernia Database provided information on repairs and reoperations. We used registered occupational codes and a job exposure matrix based on experts' ratings to estimate total load lifted per day, frequency of heavy lifting, and number of hours per day spent standing/walking. We also obtained register information on sickness absence. Multivariable Cox regression analysis was used. RESULTS: The cohort comprised 34,822 patients. We did not reveal exposure-response relationships between occupational mechanical exposures and the hazard ratio (HR) of reoperation. The percentage of patients with >2 weeks of sickness absence within 8 weeks after surgery increased with total load lifted per day from 15 to 53%. Longer sickness absence was associated with an increased HR of reoperation, but within strata of sickness absence, we found no increase in the HR of reoperation with increasing exposures. CONCLUSION: We did not find indications that the HR of reoperation was related to occupational mechanical exposures, even after accounting for a potential protective effect of sickness absence. Hence, the exposure-related prolonged duration of sickness absence could not be explained by exposure-related complications that led to reoperation. PMID- 25537575 TI - Identification of natural images and computer-generated graphics based on statistical and textural features. AB - To discriminate the acquisition pipelines of digital images, a novel scheme for the identification of natural images and computer-generated graphics is proposed based on statistical and textural features. First, the differences between them are investigated from the view of statistics and texture, and 31 dimensions of feature are acquired for identification. Then, LIBSVM is used for the classification. Finally, the experimental results are presented. The results show that it can achieve an identification accuracy of 97.89% for computer-generated graphics, and an identification accuracy of 97.75% for natural images. The analyses also demonstrate the proposed method has excellent performance, compared with some existing methods based only on statistical features or other features. The method has a great potential to be implemented for the identification of natural images and computer-generated graphics. PMID- 25537574 TI - Correlation of lactate/albumin ratio level to organ failure and mortality in severe sepsis and septic shock. AB - BACKGROUND: This study examines the clinical utility of the increased lactate/albumin ratio as an indicator of multiple-organ dysfunction syndrome (MODS) and mortality in severe sepsis and septic shock. METHODS: We designed a prospective cohort study in an intensive care unit, and 54 patients with severe sepsis or septic shock were included. Data were used to determine a relationship between lactate/albumin ratio and the development of MODS and mortality. These associations were determined by the Mann-Whitney test, multiple logistic regression, plotting the receiver operating characteristic curve and Spearman test. RESULTS: Lactate/albumin ratio level was higher in MODS patients on day 1 (median [interquartile range, or IQR], 2.295 [1.818-3.065]; n = 30, P < .0001) than in those without (median [IQR], 1.550 (1.428-1.685); n = 24), and on day 2, (median [IQR], 1.810 [1.377-2.448]; n = 26, P = .0022) it was higher than in those without (median [IQR], 1.172 (1.129-1.382); n = 23) on day 2. We found that lactate/albumin ratio was an independent predictor of the development of MODS (odds ratio, 5.5; P = .033; 95% confidence interval, 1.1-26.1) during intensive care unit stay. The area under the receiver operating characteristic curve showed that lactate/albumin ratio could predict MODS (0.8458) and mortality (0.8449). Furthermore, the higher the Acute Physiology and Chronic Health Evaluation II score, the more lactate/albumin ratio was discovered on day 1 (r = 0.5315, P < .0001) and day 2 (r = 0.5408, P < .0001), whereas the lower partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio, the more lactate/albumin ratio was illustrated on day 1 (r = -0.5143, P < .0001) and day 2 (r = -0.5420, P < .0001). CONCLUSIONS: Increased lactate/albumin ratio correlates with the development of MODS and mortality in patients with severe sepsis and septic shock. PMID- 25537577 TI - Regional-scale dominance of non-framework building corals on Caribbean reefs affects carbonate production and future reef growth. AB - Coral cover on Caribbean reefs has declined rapidly since the early 1980's. Diseases have been a major driver, decimating communities of framework building Acropora and Orbicella coral species, and reportedly leading to the emergence of novel coral assemblages often dominated by domed and plating species of the genera Agaricia, Porites and Siderastrea. These corals were not historically important Caribbean framework builders, and typically have much smaller stature and lower calcification rates, fuelling concerns over reef carbonate production and growth potential. Using data from 75 reefs from across the Caribbean we quantify: (i) the magnitude of non-framework building coral dominance throughout the region and (ii) the contribution of these corals to contemporary carbonate production. Our data show that live coral cover averages 18.2% across our sites and coral carbonate production 4.1 kg CaCO3 m(-2) yr(-1) . However, non framework building coral species dominate and are major carbonate producers at a high proportion of sites; they are more abundant than Acropora and Orbicella at 73% of sites; contribute an average 68% of the carbonate produced; and produce more than half the carbonate at 79% of sites. Coral cover and carbonate production rate are strongly correlated but, as relative abundance of non framework building corals increases, average carbonate production rates decline. Consequently, the use of coral cover as a predictor of carbonate budget status, without species level production rate data, needs to be treated with caution. Our findings provide compelling evidence for the Caribbean-wide dominance of non framework building coral taxa, and that these species are now major regional carbonate producers. However, because these species typically have lower calcification rates, continued transitions to states dominated by non-framework building coral species will further reduce carbonate production rates below 'predecline' levels, resulting in shifts towards negative carbonate budget states and reducing reef growth potential. PMID- 25537576 TI - Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. AB - Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Delta9-tetrahydrocannabinol (Delta9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Delta9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Delta9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Delta9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Delta9-THC/cannabis in progressive MS. PMID- 25537579 TI - Low-temperature chemical synthesis of high-purity diacylglycerols (DAG) from monoacylglycerols (MAG). AB - A chemical method was developed for low-temperature synthesis of DAG from MAG followed by an easy purification procedure in order to obtain high-purity DAG. Solvent-assisted and solvent-free reaction conditions were used, combined with different catalysts (sodium methoxide, p-toluenesulfonic acid, methanesulfonic acid, and sulfuric acid). All reactions were performed at 35 and 70 degrees C. By increasing both acidity and polarity of the catalyst the equilibrium shifts towards the formation of DAG. When using sulfuric acid in solvent-assisted condition at 70 degrees C, 88% conversion was obtained after 20 min of reaction (77% w/w DAG in the reaction mixture after evaporation of the solvent). After purifying by means of column chromatography, 96% pure DAG were obtained. The overall yield of DAG was 81%. PMID- 25537581 TI - Inelastic X-ray scattering with 0.75 meV resolution at 25.7 keV using a temperature-gradient analyzer. AB - The use of temperature-gradient analyzers for non-resonant high-resolution inelastic X-ray scattering is investigated. The gradient compensates for geometrical broadening of the energy resolution by adjusting the lattice spacing of the analyzer crystal. Applying a ~ 12 mK temperature gradient across a 9.5 cm analyzer, resolutions of 0.75 (2) meV FWHM at 25.7 keV for Si(13 13 13) and 1.25(2) meV at 21.7 keV for Si(11 11 11) were measured, while retaining large (250 mm) clearance between the sample position and detector, and reasonable (9.3 mrad * 8.8 mrad) analyzer acceptance. The temperature control and stability are discussed. PMID- 25537578 TI - Selective magnetic resonance imaging of magnetic nanoparticles by acoustically induced rotary saturation. AB - PURPOSE: The goal of this study was to introduce a new method to selectively detect iron oxide contrast agents using an acoustic wave to perturb the spin locked water signal in the vicinity of the magnetic particles. The acoustic drive can be modulated externally to turn the effect on and off, allowing sensitive and quantitative statistical comparison and removal of confounding image background variations. METHODS: We demonstrated the effect in spin-locking experiments using piezoelectric actuators to generate vibrational displacements of iron oxide samples. We observed a resonant behavior of the signal changes with respect to the acoustic frequency where iron oxide is present. We characterized the effect as a function of actuator displacement and contrast agent concentration. RESULTS: The resonant effect allowed us to generate block-design "modulation response maps" indicating the contrast agent's location, as well as positive contrast images with suppressed background signal. We found that the acoustically induced rotary saturation (AIRS) effect stayed approximately constant across acoustic frequency and behaved monotonically over actuator displacement and contrast agent concentration. CONCLUSION: AIRS is a promising method capable of using acoustic vibrations to modulate the contrast from iron oxide nanoparticles and thus perform selective detection of the contrast agents, potentially enabling more accurate visualization of contrast agents in clinical and research settings. PMID- 25537582 TI - Characterization of a next-generation piezo bimorph X-ray mirror for synchrotron beamlines. AB - Piezo bimorph mirrors are versatile active optics used on many synchrotron beamlines. However, many bimorphs suffer from the 'junction effect': a periodic deformation of the optical surface which causes major aberrations to the reflected X-ray beam. This effect is linked to the construction of such mirrors, where piezo ceramics are glued directly below the thin optical substrate. In order to address this problem, a next-generation bimorph with piezos bonded to the side faces of a monolithic substrate was developed at Thales-SESO and optimized at Diamond Light Source. Using metrology feedback from the Diamond-NOM, the optical slope error was reduced to ~ 0.5 urad r.m.s. for a range of ellipses. To maximize usability, a novel holder was built to accommodate the substrate in any orientation. When replacing a first-generation bimorph on a synchrotron beamline, the new mirror significantly improved the size and shape of the reflected X-ray beam. Most importantly, there was no evidence of the junction effect even after eight months of continuous beamline usage. It is hoped that this new design will reinvigorate the use of active bimorph optics at synchrotron and free-electron laser facilities to manipulate and correct X-ray wavefronts. PMID- 25537583 TI - X-ray focusing scheme with continuously variable lens. AB - A novel hybrid X-ray focusing scheme was developed for operation of the X-ray streak camera at the Advanced Photon Source: an X-ray lens focuses vertically from a long distance of 16 m and produces an extended focus that has a small footprint on an inexpensive sagittal mirror. A patented method is used to continuously adjust the focal length of the lens and compensate for chromatic dispersion in energy scans. PMID- 25537584 TI - Large-acceptance diamond planar refractive lenses manufactured by laser cutting. AB - For the first time, single-crystal diamond planar refractive lenses have been fabricated by laser micromachining in 300 um-thick diamond plates which were grown by chemical vapour deposition. Linear lenses with apertures up to 1 mm and parabola apex radii up to 500 um were manufactured and tested at the ESRF ID06 beamline. The large acceptance of these lenses allows them to be used as beam conditioning elements. Owing to the unsurpassed thermal properties of single crystal diamond, these lenses should be suitable to withstand the extreme flux densities expected at the planned fourth-generation X-ray sources. PMID- 25537585 TI - Cooling dynamics of self-assembled monolayer coating for integrated gold nanocrystals on a glass substrate. AB - Picosecond time-resolved X-ray diffraction has been used to study the nanoscale thermal transportation dynamics of bare gold nanocrystals and thiol-based self assembled monolayer (SAM)-coated integrated gold nanocrystals on a SiO2 glass substrate. A temporal lattice expansion of 0.30-0.33% was observed in the bare and SAM-coated nanocrystals on the glass substrate; the thermal energy inside the gold nanocrystals was transported to the contacted substrate through the gold SiO2 interface. The interfacial thermal conductivity between the single-layered gold nanocrystal film and the SiO2 substrate is estimated to be 45 MW m(-2) K(-1) from the decay of the Au 111 peak shift, which was linearly dependent on the transient temperature. For the SAM-coated gold nanocrystals, the thermal dissipation was faster than that of the bare gold nanocrystal film. The thermal flow from the nanocrystals to the SAM-coated molecules promotes heat dissipation from the laser-heated SAM-coated gold nanocrystals. The thermal transportation of the laser-heated SAM-coated gold nanocrystal film was analyzed using the bidirectional thermal dissipation model. PMID- 25537586 TI - In situ synchrotron X-ray diffraction analysis of deformation behaviour in Ti-Ni based thin films. AB - Deformation mechanisms of as-deposited and post-annealed Ti50.2Ni49.6, Ti50.3Ni46.2Cu3.5 and Ti48.5Ni40.8Cu7.5 thin films were investigated using the in situ synchrotron X-ray diffraction technique. Results showed that initial crystalline phases determined the deformation mechanisms of all the films during tensile loading. For the films dominated by monoclinic martensites (B19'), tensile stress induced the detwinning of <011> type-II twins and resulted in the preferred orientations of (002)B19' parallel to the loading direction (? LD) and (020)B19' perpendicular to the LD (? LD). For the films dominated by austenite (B2), the austenite directly transformed into martensitic variants (B19') with preferred orientations of (002)B19' ? LD and (020)B19' ? LD. For the Ti50.3Ni46.2Cu3.5 and Ti48.1Ni40.8Cu7.5 films, martensitic transformation temperatures decreased apparently after post-annealing because of the large thermal stress generated in the films due to the large differences in thermal expansion coefficients between the film and substrate. PMID- 25537587 TI - Design and development of a controlled pressure/temperature set-up for in situ studies of solid-gas processes and reactions in a synchrotron X-ray powder diffraction station. AB - A novel set-up has been designed and used for synchrotron radiation X-ray high resolution powder diffraction (SR-HRPD) in transmission geometry (spinning capillary) for in situ solid-gas reactions and processes in an isobaric and isothermal environment. The pressure and temperature of the sample are controlled from 10(-3) to 1000 mbar and from 80 to 1000 K, respectively. To test the capacities of this novel experimental set-up, structure deformation in the porous material zeolitic imidazole framework (ZIF-8) by gas adsorption at cryogenic temperature has been studied under isothermal and isobaric conditions. Direct structure deformations by the adsorption of Ar and N2 gases have been observed in situ, demonstrating that this set-up is perfectly suitable for direct structural analysis under in operando conditions. The presented results prove the feasibility of this novel experimental station for the characterization in real time of solid-gas reactions and other solid-gas processes by SR-HRPD. PMID- 25537588 TI - Simultaneous X-ray diffraction and phase-contrast imaging for investigating material deformation mechanisms during high-rate loading. AB - Using a high-speed camera and an intensified charge-coupled device (ICCD), a simultaneous X-ray imaging and diffraction technique has been developed for studying dynamic material behaviors during high-rate tensile loading. A Kolsky tension bar has been used to pull samples at 1000 s(-1) and 5000 s(-1) strain rates for super-elastic equiatomic NiTi and 1100-O series aluminium, respectively. By altering the ICCD gating time, temporal resolutions of 100 ps and 3.37 us have been achieved in capturing the diffraction patterns of interest, thus equating to single-pulse and 22-pulse X-ray exposure. Furthermore, the sample through-thickness deformation process has been simultaneously imaged via phase-contrast imaging. It is also shown that adequate signal-to-noise ratios are achieved for the detected white-beam diffraction patterns, thereby allowing sufficient information to perform quantitative data analysis diffraction via in house software (WBXRD_GUI). Of current interest is the ability to evaluate crystal d-spacing, texture evolution and material phase transitions, all of which will be established from experiments performed at the aforementioned elevated strain-rates. PMID- 25537589 TI - X-ray diffraction strain analysis of a single axial InAs 1-x Px nanowire segment. AB - The spatial strain distribution in and around a single axial InAs 1-x Px hetero segment in an InAs nanowire was analyzed using nano-focused X-ray diffraction. In connection with finite-element-method simulations a detailed quantitative picture of the nanowire's inhomogeneous strain state was achieved. This allows for a detailed understanding of how the variation of the nanowire's and hetero segment's dimensions affect the strain in its core region and in the region close to the nanowire's side facets. Moreover, ensemble-averaging high-resolution diffraction experiments were used to determine statistical information on the distribution of wurtzite and zinc-blende crystal polytypes in the nanowires. PMID- 25537590 TI - Polytypism in GaAs nanowires: determination of the interplanar spacing of wurtzite GaAs by X-ray diffraction. AB - In GaAs nanowires grown along the cubic [111]c direction, zinc blende and wurtzite arrangements have been observed in their stacking sequence, since the energetic barriers for nucleation are typically of similar order of magnitude. It is known that the interplanar spacing of the (111)c Ga (or As) planes in the zinc blende polytype varies slightly from the wurtzite polytype. However, different values have been reported in the literature. Here, the ratio of the interplanar spacing of these polytypes is extracted based on X-ray diffraction measurements for thin GaAs nanowires with a mean diameter of 18-25 nm. The measurements are performed with a nano-focused beam which facilitates the separation of the scattering of nanowires and of parasitic growth. The interplanar spacing of the (111)c Ga (or As) planes in the wurtzite arrangement in GaAs nanowires is observed to be 0.66% +/- 0.02% larger than in the zinc blende arrangement. PMID- 25537591 TI - Monitoring the thin film formation during sputter deposition of vanadium carbide. AB - The thin film formation of magnetron sputtered polycrystalline coatings was monitored by in situ X-ray reflectivity measurements. The measured intensity was analyzed using the Parratt algorithm for time-dependent thin film systems. Guidelines for the on-line interpretation of the data were developed. For thick coatings, the experimental resolution needs to be included in the data evaluation in order to avoid misinterpretations. Based on a simple layer model, the time dependent mean electron density, roughness and growth velocity were extracted from the data. As an example, the method was applied to the hard coating material vanadium carbide. Both instantaneous and slowly varying changes of the coating could be detected. It was shown that the growth velocity is proportional to the DC power. Significant changes of the microstructure induced by the working gas pressure are mainly driven by the chemical composition. PMID- 25537592 TI - Investigation of damaged interior walls using synchrotron-based XPS and XANES. AB - Evidence of internal sulfate attack in field exposure was demonstrated by the damaged interior wall of a three-year-old house situated in Nakhon Ratchasima Province, Thailand. Partial distension of the mortar was clearly observed together with an expansion of a black substance. Removal of the black substance revealed a dense black layer. This layer was only found in the vicinity of the damaged area, suggesting that this black material is possibly involved in the wall cracking. By employing synchrotron-based X-ray photoelectron spectroscopy (XPS) and X-ray absorption near-edge structure (XANES) techniques, the unknown sample was chemically identified. The S 2p and O 1s XPS results mutually indicated the existence of sulfate species in the materials collected from the damaged area. The XANES results indicated the presence of ferrous (II) sulfate, confirming sulfate-induced expansion and cracking. The sulfate attack in the present case appeared to physically affect the structure whereas the chemical integrity at the molecular level of the calcium silicate hydrate phase was retained since there was a lack of spectroscopic evidence for calcium sulfate. It was speculated that internal sulfate probably originated from the contaminated aggregates used during the construction. The current findings would be beneficial for understanding the sulfate-attack mechanism as well as for future prevention against sulfate attack during construction. PMID- 25537593 TI - A portable ultrahigh-vacuum system for advanced synchrotron radiation studies of thin films and nanostructures: EuSi2 nano-islands. AB - A portable ultrahigh-vacuum system optimized for in situ variable-temperature X ray scattering and spectroscopy experiments at synchrotron radiation beamlines was constructed and brought into operation at the synchrotron radiation facility ANKA of the Karlsruhe Institute of Technology, Germany. Here the main features of the new instrument are described and its capabilities demonstrated. The surface morphology, structure and stoichiometry of EuSi2 nano-islands are determined by in situ grazing-incidence small-angle X-ray scattering and X-ray absorption spectroscopy. A size reduction of about a factor of two of the nano-islands due to silicide decomposition and Eu desorption is observed after sample annealing at 1270 K for 30 min. PMID- 25537594 TI - The pH dependence of Am(III) complexation with acetate: an EXAFS study. AB - The complexation of acetate with Am(III) is studied as a function of the pH (1-6) by extended X-ray absorption fine-structure (EXAFS) spectroscopy. The molecular structure of the Am(III)-acetate complexes (coordination numbers, oxygen and carbon distances) is determined from the raw k(3)-weighted Am LIII-edge EXAFS spectra. The results show a continuous shift of Am(III) speciation with increasing pH value towards the complexed species. Furthermore, it is verified that acetate coordinates in a bidentate coordination mode to Am(III) (Am-C distance: 2.82 +/- 0.03 A). The EXAFS data are analyzed by iterative transformation factor analysis to further verify the chemical speciation, which is calculated on the basis of thermodynamic constants, and the used structural model. The experimental results are in very good agreement with the thermodynamic modelling. PMID- 25537595 TI - Structure and effects of annealing in colloidal matrix-free Ge quantum dots. AB - The structure of small (2-5 nm) Ge quantum dots prepared by the colloidal synthesis route is examined. Samples were synthesized using either GeO2 or GeCl4 as precursor. As-prepared samples were further annealed under Ar or H2/Ar atmosphere at different temperatures in order to understand the effect of annealing on their structure. It was found that as-prepared samples possess distinctly different structures depending on their synthesis route as indicated by their long-range ordering. An appreciable amount of oxygen was found to be bound to Ge in samples prepared with GeO2 as a precursor; however, not for GeCl4. Based on combined transmission electron microscope, Raman, X-ray diffraction and X-ray absorption measurements, it is suggested that as-prepared samples are best described by the core-shell model with a small nano-crystalline core and an amorphous outer layer terminated either with oxygen or hydrogen depending on the synthesis route. Annealing in an H2Ar atmosphere leads to sample crystallization and further nanoparticle growth, while at the same time reducing the Ge-O bonding. X-ray diffraction measurements for as-prepared and annealed samples indicate that diamond-type and metastable phases are present. PMID- 25537596 TI - Confocal soft X-ray scanning transmission microscopy: setup, alignment procedure and limitations. AB - Zone-plate-based scanning transmission soft X-ray microspectroscopy (STXM) is a well established technique for high-contrast imaging of sufficiently transparent specimens (e.g. ultrathin biological tissues, polymer materials, archaeometric specimens or magnetic thin films) with spatial resolutions in the regime of 20 nm and high spectroscopic or chemical sensitivity. However, due to the relatively large depth of focus of zone plates, the resolution of STXM along the optical axis so far stays unambiguously behind for thicker X-ray transparent specimens. This challenge can be addressed by the implementation of a second zone plate in the detection pathway of the beam, resulting in a confocal arrangement. Within this paper a first proof-of-principle study for a confocal STXM (cSTXM) and an elaborate alignment procedure in transmission and fluorescence geometry are presented. Based on first confocal soft X-ray micrographs of well known specimens, the advantage and limitation of cSTXM as well as further development potentials for future applications are discussed. PMID- 25537597 TI - X-ray irradiation induces local rearrangement of silica particles in swollen rubber. AB - X-ray photon correlation spectroscopy (XPCS) of swollen rubber containing spherical silica nanoparticles is reported. It is shown that irradiation by intense X-rays leads to the breakdown of cross-links, thereby inducing the local rearrangement of silica nanoparticles. This rearrangement process depends on the cross-link density and is characterized by a compressed exponential relaxation with aging behaviour, which resembles a common feature of complex fluids observed with XPCS. PMID- 25537598 TI - Extended X-ray absorption fine structure and multiple-scattering simulation of nickel dithiolene complexes Ni[S2C2(CF3)2]2(n) (n = -2, -1, 0) and an olefin adduct Ni[S2C2(CF3)2]2(1-hexene). AB - A series of Ni dithiolene complexes Ni[S2C2(CF3)]2(n) (n = -2, -1, 0) (1, 2, 3) and a 1-hexene adduct Ni[S2C2(CF3)2]2(C6H12) (4) have been examined by Ni K-edge X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopies. Ni XANES for 1-3 reveals clear pre-edge features and approximately +0.7 eV shift in the Ni K-edge position for 'one electron' oxidation. EXAFS simulation shows that the Ni-S bond distances for 1, 2 and 3 (2.11-2.16 A) are within the typical values for square planar complexes and decrease by ~ 0.022 A for each 'one-electron' oxidation. The changes in Ni K-edge energy positions and Ni-S distances are consistent with the 'non-innocent' character of the dithiolene ligand. The Ni-C interactions at ~ 3.0 A are analyzed and the multiple-scattering parameters are also determined, leading to a better simulation for the overall EXAFS spectra. The 1-hexene adduct 4 presents no pre edge feature, and its Ni K-edge position shifts by -0.8 eV in comparison with its starting dithiolene complex 3. Consistently, EXAFS also showed that the Ni-S distances in 4 elongate by ~ 0.046 A in comparison with 3. The evidence confirms that the neutral complex is 'reduced' upon addition of olefin, presumably by olefin donating the pi-electron density to the LUMO of 3 as suggested by UV/visible spectroscopy in the literature. PMID- 25537599 TI - Synchrotron radiation computed laminography using an inclined detector. AB - Synchrotron radiation computed laminography (SR-CL) has been in use in three dimensional non-destructive imaging of flat objects for several years. A new set up is proposed based on the traditional SR-CL method but with the detector inclined at the same angle as the sample inclination to collect projections. The results of computer simulations and real-sample experiments demonstrate that reconstructions acquired using an inclined detector are of better quality compared with those acquired using ordinary detecting methods, especially for the situation of few projections and small difference of attenuation ratio of the sample. This method could be applied to obtain high-quality images of weak contrast samples with short measurement time and mild radiation damage. PMID- 25537602 TI - Direct nano-scale patterning of Ag films using hard X-ray induced oxidation. AB - The morphological change of silver nano-particles (AgNPs) exposed to an intense synchrotron X-ray beam was investigated for the purpose of direct nano-scale patterning of metal thin films. AgNPs irradiated by hard X-rays in oxygen ambient were oxidized and migrated out of the illuminated region. The observed X-ray induced oxidation was utilized to fabricate nano-scale metal line patterns using sectioned WSi2/Si multilayers as masks. Lines with a width as small as 21 nm were successfully fabricated on Ag films on silicon nitride. Au/Ag nano-lines were also fabricated using the proposed method. PMID- 25537600 TI - X-ray phase-contrast computed tomography visualizes the microstructure and degradation profile of implanted biodegradable scaffolds after spinal cord injury. AB - Tissue engineering strategies for spinal cord repair are a primary focus of translational medicine after spinal cord injury (SCI). Many tissue engineering strategies employ three-dimensional scaffolds, which are made of biodegradable materials and have microstructure incorporated with viable cells and bioactive molecules to promote new tissue generation and functional recovery after SCI. It is therefore important to develop an imaging system that visualizes both the microstructure of three-dimensional scaffolds and their degradation process after SCI. Here, X-ray phase-contrast computed tomography imaging based on the Talbot grating interferometer is described and it is shown how it can visualize the polyglycolic acid scaffold, including its microfibres, after implantation into the injured spinal cord. Furthermore, X-ray phase-contrast computed tomography images revealed that degradation occurred from the end to the centre of the braided scaffold in the 28 days after implantation into the injured spinal cord. The present report provides the first demonstration of an imaging technique that visualizes both the microstructure and degradation of biodegradable scaffolds in SCI research. X-ray phase-contrast imaging based on the Talbot grating interferometer is a versatile technique that can be used for a broad range of preclinical applications in tissue engineering strategies. PMID- 25537603 TI - Compton scattering imaging of a working battery using synchrotron high-energy X rays. AB - Results of studies on Compton scattering imaging using synchrotron high-energy X rays are reported. The technique is applied to a discharging coin cell, and the intensity of Compton scattered X-rays from the inside of the cell has been measured as a function of position and time. The position-time intensity map captures the migration of lithium ions in the positive electrode and reveals the structural change due to the volume expansion of the electrode. This experiment is a critical step in developing synchrotron-based Compton scattering imaging for electrochemical cells at a product level. PMID- 25537604 TI - Tuning the phase transition of ZnO thin films through lithography: an integrated bottom-up and top-down processing. AB - An innovative approach towards the physico-chemical tailoring of zinc oxide thin films is reported. The films have been deposited by liquid phase using the sol gel method and then exposed to hard X-rays, provided by a synchrotron storage ring, for lithography. The use of surfactant and chelating agents in the sol allows easy-to-pattern films made by an organic-inorganic matrix to be deposited. The exposure to hard X-rays strongly affects the nucleation and growth of crystalline ZnO, triggering the formation of two intermediate phases before obtaining a wurtzite-like structure. At the same time, X-ray lithography allows for a fast patterning of the coatings enabling microfabrication for sensing and arrays technology. PMID- 25537601 TI - Functionalized synchrotron in-line phase-contrast computed tomography: a novel approach for simultaneous quantification of structural alterations and localization of barium-labelled alveolar macrophages within mouse lung samples. AB - Functionalized computed tomography (CT) in combination with labelled cells is virtually non-existent due to the limited sensitivity of X-ray-absorption-based imaging, but would be highly desirable to realise cell tracking studies in entire organisms. In this study we applied in-line free propagation X-ray phase-contrast CT (XPCT) in an allergic asthma mouse model to assess structural changes as well as the biodistribution of barium-labelled macrophages in lung tissue. Alveolar macrophages that were barium-sulfate-loaded and fluorescent-labelled were instilled intratracheally into asthmatic and control mice. Mice were sacrificed after 24 h, lungs were kept in situ, inflated with air and scanned utilizing XPCT at the SYRMEP beamline (Elettra Synchrotron Light Source, Italy). Single-distance phase retrieval was used to generate data sets with ten times greater contrast-to noise ratio than absorption-based CT (in our setup), thus allowing to depict and quantify structural hallmarks of asthmatic lungs such as reduced air volume, obstruction of airways and increased soft-tissue content. Furthermore, we found a higher concentration as well as a specific accumulation of the barium-labelled macrophages in asthmatic lung tissue. It is believe that XPCT will be beneficial in preclinical asthma research for both the assessment of therapeutic response as well as the analysis of the role of the recruitment of macrophages to inflammatory sites. PMID- 25537605 TI - Energy optimization of a regular macromolecular crystallography beamline for ultra-high-resolution crystallography. AB - A practical method for operating existing undulator synchrotron beamlines at photon energies considerably higher than their standard operating range is described and applied at beamline 19-ID of the Structural Biology Center at the Advanced Photon Source enabling operation at 30 keV. Adjustments to the undulator spectrum were critical to enhance the 30 keV flux while reducing the lower- and higher-energy harmonic contamination. A Pd-coated mirror and Al attenuators acted as effective low- and high-bandpass filters. The resulting flux at 30 keV, although significantly lower than with X-ray optics designed and optimized for this energy, allowed for accurate data collection on crystals of the small protein crambin to 0.38 A resolution. PMID- 25537606 TI - The GALAXIES beamline at the SOLEIL synchrotron: inelastic X-ray scattering and photoelectron spectroscopy in the hard X-ray range. AB - The GALAXIES beamline at the SOLEIL synchrotron is dedicated to inelastic X-ray scattering (IXS) and photoelectron spectroscopy (HAXPES) in the 2.3-12 keV hard X ray range. These two techniques offer powerful complementary methods of characterization of materials with bulk sensitivity, chemical and orbital selectivity, resonant enhancement and high resolving power. After a description of the beamline components and endstations, the beamline capabilities are demonstrated through a selection of recent works both in the solid and gas phases and using either IXS or HAXPES approaches. Prospects for studies on liquids are discussed. PMID- 25537607 TI - Upgrade of MacCHESS facility for X-ray scattering of biological macromolecules in solution. AB - X-ray scattering of biological macromolecules in solution is an increasingly popular tool for structural biology and benefits greatly from modern high brightness synchrotron sources. The upgraded MacCHESS BioSAXS station is now located at the 49-pole wiggler beamline G1. The 20-fold improved flux over the previous beamline F2 provides higher sample throughput and autonomous X-ray scattering data collection using a unique SAXS/WAXS dual detectors configuration. This setup achieves a combined q-range from 0.007 to 0.7 A(-1), enabling better characterization of smaller molecules, while opening opportunities for emerging wide-angle scattering methods. In addition, a facility upgrade of the positron storage ring to continuous top-up mode has improved beam stability and eliminated beam drift over the course of typical BioSAXS experiments. Single exposure times have been reduced to 2 s for 3.560 mg ml(-1) lysozyme with an average quality factor I/sigma of 20 in the Guinier region. A novel disposable plastic sample cell design that incorporates lower background X-ray window material provides users with a more pristine sample environment than previously available. Systematic comparisons of common X-ray window materials bonded to the cell have also been extended to the wide-angle regime, offering new insight into best choices for various q-space ranges. In addition, a quantitative assessment of signal-to-noise levels has been performed on the station to allow users to estimate necessary exposure times for obtaining usable signals in the Guinier regime. Users also have access to a new BioSAXS sample preparation laboratory which houses essential wet-chemistry equipment and biophysical instrumentation. User experiments at the upgraded BioSAXS station have been on-going since commissioning of the beamline in Summer 2013. A planned upgrade of the G1 insertion device to an undulator for the Winter 2014 cycle is expected to further improve flux by an order of magnitude. PMID- 25537611 TI - Low-molecular-weight carbon nitrides for solar hydrogen evolution. AB - This work focuses on the control of the polymerization process for melon ("graphitic carbon nitride"), with the aim of improving its photocatalytic activity intrinsically. We demonstrate here that reduction of the synthesis temperature leads to a mixture of the monomer melem and its higher condensates. We show that this mixture can be separated and provide evidence that the higher condensates are isolated oligomers of melem. On evaluating their photocatalytic activity for hydrogen evolution, the oligomers were found to be the most active species, having up to twice the activity of the monomer/oligomer mixture of the as-synthesized material, which in turn has 3 times the activity of the polymer melon, the literature benchmark. These results highlight the role of "defects", i.e., chain terminations, in increasing the catalytic activity of carbon nitrides and at the same time point to the ample potential of intrinsically improving the photocatalytic activity of "carbon nitride", especially through the selective synthesis of the active phase. PMID- 25537608 TI - MX1: a bending-magnet crystallography beamline serving both chemical and macromolecular crystallography communities at the Australian Synchrotron. AB - MX1 is a bending-magnet crystallography beamline at the 3 GeV Australian Synchrotron. The beamline delivers hard X-rays in the energy range from 8 to 18 keV to a focal spot at the sample position of 120 um FWHM. The beamline endstation and ancillary equipment facilitate local and remote access for both chemical and biological macromolecular crystallography. Here, the design of the beamline and endstation are discussed. The beamline has enjoyed a full user program for the last seven years and scientific highlights from the user program are also presented. PMID- 25537612 TI - Male breast uptake in rubidium-82 PET due to spironolactone-induced gynecomastia. PMID- 25537613 TI - Imaging atherosclerotic burden and inflammation: insights into the spectrum of atherosclerotic disease in HIV. PMID- 25537616 TI - One year retrospective anniversary. PMID- 25537614 TI - Prediction of 14-year outcomes in patients with a limited exercise capacity: Utility of dobutamine myocardial perfusion imaging in a high-risk population. AB - OBJECTIVE: Despite multiple studies on the diagnostic and prognostic use of dobutamine myocardial perfusion imaging (MPI), information on its long-term prognostic value is scarce. The aim of this study was to assess the value of this technique for the prediction of very long-term outcome. METHODS: A total of 721 patients with limited exercise capacity underwent dobutamine MPI for the evaluation of suspected or known coronary artery disease. 719 of 721 patients attended follow-up (99.7%). Twenty-eight patients who underwent early coronary revascularization were excluded from analysis. Endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival curves were constructed, and univariate and multivariate analyses were performed to identify predictors of long-term outcome. RESULTS: The mean age of patients was 60 +/- 11 years, and 61% were male. Myocardial perfusion abnormalities were present in 381 patients (55%) and included fixed defects in 190 patients (27%) and reversible defects in 191 patients (28%). During a median follow-up time of 14 years (range 0-16), 295 deaths occurred (43%), of which 158 were cardiac deaths (23%). Nonfatal myocardial infarction occurred in 35 (5%), and late coronary revascularization was performed on 133 patients (19%). An abnormal dobutamine MPI provided significant prognostic information for prediction of cardiac death, hard cardiac events, and MACE, after adjustment for significant clinical variables and stress test variables. CONCLUSIONS: Dobutamine MPI provides incremental prognostic information for the prediction of cardiovascular outcomes in patients with limited exercise capacity. The long-term prognosis of patients with limited exercise capacity who have an abnormal dobutamine MPI is significantly worse than those with a normal MPI. PMID- 25537617 TI - [Spinal anesthesia in high-volume, low-concentration technique for Caesarean sections : Retrospective analysis]. AB - BACKGROUND: Nowadays Caesarean sections are mainly undertaken using spinal anesthesia; therefore, it is important to minimize potential side effects and risks associated with this technique. Currently, many studies have been conducted to optimize the dose of local anesthetics to avoid hypotension, which often occurs during spinal anesthesia. AIM: In a retrospective study design the high volume, low-concentration technique with up to 12 ml isobaric bupivacain 0.1% (1 mg/ml) and sufentanil (1 ug/ml), which has been used at the University Hospital Wurzburg for many years was analyzed with respect to reliability and side effects. The use of this technique so far is unique among university hospitals in Germany. MATERIAL AND METHODS: Of the 1424 anesthesia protocols from 2001 to 2007 a total of 1368 were analyzed. Demographic data and parameters, such as location of puncture, dose and extent of anesthesia, hemodynamic stability and additional medication were recorded. A decrease of systolic blood pressure of more than 20% of the initial value was defined as hypotension. RESULTS: The median volume used for spinal anesthesia was 9 ml, containing 9 mg bupivacaine and 9 ug sufentanil. The rate of hypotension was 48.8 %. No significant differences in hypotension between lower and higher volumes were detectable. In 0.84% (n=12) of the cases the procedure had to be changed to general anesthesia and additional analgesia was administered in 3 cases (0.22%). CONCLUSION: The high-volume, low concentration technique is an effective approach for spinal anesthesia with a small number of cases needing general anesthesia or additional analgesics. The rate of hypotension was moderate compared to other studies; however, because of the retrospective and non-randomized study design the dependence of this rate on dose and given volume should be interpreted with caution. PMID- 25537618 TI - An individual based computational model of intestinal crypt fission and its application to predicting unrestrictive growth of the intestinal epithelium. AB - Intestinal crypt fission is a homeostatic phenomenon, observable in healthy adult mucosa, but which also plays a pathological role as the main mode of growth of some intestinal polyps. Building on our previous individual based model for the small intestinal crypt and on in vitro cultured intestinal organoids, we here model crypt fission as a budding process based on fluid mechanics at the individual cell level and extrapolated predictions for growth of the intestinal epithelium. Budding was always observed in regions of organoids with abundant Paneth cells. Our data support a model in which buds are biomechanically initiated by single stem cells surrounded by Paneth cells which exhibit greater resistance to viscoelastic deformation, a hypothesis supported by atomic force measurements of single cells. Time intervals between consecutive budding events, as simulated by the model and observed in vitro, were 2.84 and 2.62 days, respectively. Predicted cell dynamics was unaffected within the original crypt which retained its full capability of providing cells to the epithelium throughout fission. Mitotic pressure in simulated primary crypts forced upward migration of buds, which simultaneously grew into new protruding crypts at a rate equal to 1.03 days(-1) in simulations and 0.99 days(-1) in cultured organoids. Simulated crypts reached their final size in 4.6 days, and required 6.2 days to migrate to the top of the primary crypt. The growth of the secondary crypt is independent of its migration along the original crypt. Assuming unrestricted crypt fission and multiple budding events, a maximal growth rate of the intestinal epithelium of 0.10 days(-1) is predicted and thus approximately 22 days are required for a 10-fold increase of polyp size. These predictions are in agreement with the time reported to develop macroscopic adenomas in mice after loss of Apc in intestinal stem cells. PMID- 25537620 TI - The embodied brain. AB - In this editorial, I discuss the advantages of interpreting brain data in the context of other bodily systems. I also discuss current research challenges that may greatly benefit from a psychophysiological approach in which multiple methods -both peripheral and central--are used to improve our understanding of brain function, its underlying physiology, and its relationship to psychological constructs. In closing, I summarize the major changes and policy highlights regarding papers published in Psychophysiology. PMID- 25537619 TI - Electrophysiological characterization of adult-onset Niemann-Pick type C disease. AB - In infantile and juvenile Niemann-Pick type C (NPC) disease electrophysiological studies have shown central (CNS) and peripheral (PNS) nervous system abnormalities. However, an extensive electrophysiological evaluation of CNS and PNS in adult form of NPC is still lacking. The aim of the study is to assess in adult-onset NPC disease the involvement of CNS and PNS by a multimodal electrophysiological approach. Three patients affected by adult form of NPC disease underwent electrophysiological evaluation including nerve conduction study (NCS), magnetic motor (MEPs), visual (VEPs), somatosensory (SSEPs) and brainstem auditory (BAEPs) evoked potentials. NCS, MEPs, VEPs and upper limb SSEPs were normal. Lower limb SSEPs were abnormal in all patients and abnormalities were consistent with a length-dependent process affecting the central somatosensory pathway. BAEPs were abnormal in all patients with both peripheral and central impairment of auditory pathway. Our electrophysiological findings suggest that auditory and lower limb somatosensory pathways are constantly affected in adult-onset form of NPC disease. The involvement of PNS, pyramidal, visual and upper limb somatosensory pathways might occur later during the course of disease. PMID- 25537621 TI - Enoch Callaway, III, (1924-2014): a pioneer in biological psychiatry. PMID- 25537622 TI - Co-treatment of chlorpyrifos and lead induce serum lipid disorders in rats: Alleviation by taurine. AB - The aim of this study was to investigate the effects of taurine (TA) on serum lipid profiles following chronic coadministration of chlorpyrifos (CP) and lead acetate (Pb) in male Wistar rats. Fifty rats randomly distributed into five groups served as subjects. Distilled water (DW) was given to DW group, while soya oil (SO; 1 mL kg(-1)) was given to SO group. The TA group was treated with TA (50 mg kg(-1)). The CP + Pb group was administered sequentially with CP (4.25 mg kg( 1); 1/20th median lethal dose (LD50)) and Pb at 233.25 mg kg(-1) (1/20th LD50), while the TA + CP + Pb group received TA (50 mg kg(-1)), CP (4.25 mg kg(-1)), and Pb (233.25 mg kg(-1)) sequentially. The treatments were administered once daily by oral gavage for 16 weeks. The rats were euthanised, and the blood samples were collected at the termination of the study. Sera obtained from the blood samples were analyzed for total cholesterol, high-density lipoprotein cholesterol, triglycerides, and malondialdehyde, and also the activities of serum antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase were analyzed. The low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and atherogenic index were calculated. The results showed that CP and Pb induced alterations in the serum lipid profiles and evoked oxidative stress. TA alleviated the disruptions in the serum lipid profiles of the rats partially by mitigating oxidative stress. It was concluded that TA may be used for prophylaxis against serum lipid disorders in animals that were constantly co exposed to CP and Pb in the environment. PMID- 25537623 TI - Melatonin controlled apoptosis and protected the testes and sperm quality against bisphenol A-induced oxidative toxicity. AB - Epidemiological reports have indicated a correlation between the increasing bisphenol A (BPA) levels in the environment and the incidence of male infertility. In this study, the protective effects of melatonin on BPA-induced oxidative stress and apoptosis were investigated in the rat testes and epididymal sperm. Melatonin (10 mg/kg body weight (bw)) was injected concurrently with BPA (50 mg/kg bw) for 3 and 6 weeks. The administration of BPA significantly increased oxidative stress in the testes and epididymal sperm. This was associated with a decrease in the serum testosterone level as well as sperm quality, chromatin condensation/de-condensation level, and the percentage of haploid germ cells in the semen. BPA administration caused a significant increase in apoptosis accompanied by a decrease in the expression of the antiapoptotic proteins Bcl-2 in the testes and epididymal sperm. The concurrent administration of melatonin decreased oxidative stress by modulating the levels of glutathione, superoxide dismutase, and catalase as well as the malondialdehyde and hydrogen peroxide concentrations in the testes and sperm. Melatonin sustained Bcl-2 expression and controlled apoptosis. Furthermore, melatonin maintained the testosterone levels, ameliorated histopathological changes, increased the percentages of seminal haploid germ cells, and protected sperm chromatin condensation process, indicating appropriate spermatogenesis with production of functional sperm. In conclusion, melatonin protected against BPA-induced apoptosis by controlling Bcl-2 expression and ameliorating oxidative stress in the testes and sperm. Thus, melatonin is a promising pharmacological agent for preventing the potential reproductive toxicity of BPA following occupational or environmental exposures. PMID- 25537624 TI - Mechanism underlying acute lung injury due to sulfur mustard exposure in rats. AB - Sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating the cytotoxic effects of SM are unknown and were investigated in this study. The purpose of this study was to establish a rat model of SM-induced lung injury to observe the resulting changes in the lungs. Male rats (Sprague Dawley) were anesthetized, intratracheally intubated, and exposed to 2 mg/kg of SM by intratracheal instillation. Animals were euthanized 6, 24, 48, and 72 h post-exposure, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including partial bronchiolar epithelium cell shedding, focal ulceration, and an increased amount of inflammatory exudate and number of cells in the alveoli. There was also evidence that the protein content and cell count of BALF peaked at 48 h, and the alveolar septum was widened and filled with lymphocytes. SM exposure also resulted in partial loss of type I alveolar epithelial cell membranes, fuzzy mitochondrial cristae, detachment and dissociation of ribosomes attached to the surface of rough endoplasmic reticulum, cracked, missing, and disorganized microvilli of type II alveolar epithelial cells, and increased apoptotic cells in the alveolar septum. The propylene glycol control group, however, was the same as the normal group. These data demonstrate that the mechanism of a high concentration of SM (2 mg/kg) induced acute lung injury include histologic changes, inflammatory reactions, apoptosis, oxidative stress, and nuclear DNA damage; the degree of injury is time dependent. PMID- 25537625 TI - Postmortem computed tomography angiography, contrast medium administration and toxicological analyses in urine. AB - Postmortem angiography methods that use water soluble or lipid soluble liquid contrast compounds may potentially modify the composition of fluid-based biological samples and thus influence toxicological findings. In this study, we investigated whether toxicological investigations performed in urine collected prior to and post angiography using AngiofilTM mixed with paraffin oil are characterized by different qualitative or quantitative results. In addition, we studied whether diluting samples with 1% and 3% contrast medium solution may modify molecule concentration. A postmortem angiography group consisting of 50 cases and a postmortem group without angiography consisting of 50 cases were formed. In the first group, toxicological investigations were performed in urine samples collected prior to and post angiography as well as in undiluted and diluted samples. In the second group, analyses were performed in undiluted and diluted urine, bile, gastric content, cerebrospinal and pericardial fluids collected during autopsy. The preliminary results indicate that differences may be observed between urine samples collected prior to and post angiography in the number of identified molecules in relation to specific cases. Analyses performed in diluted samples failed to reveal differences that might potentially alter the interpretation of toxicological results in all analyzed specimens for nearly all molecules, except for tetrahydrocannabinol and its metabolites. Though these findings suggest that toxicology might be effectively performed, in very special cases and for a large number of molecules, in biological samples collected after angiography, it remains recommendable to collect biological fluids for toxicology prior to contrast medium injection. PMID- 25537626 TI - Crystalline stereocomplexed polycarbonates: hydrogen-bond-driven interlocked orderly assembly of the opposite enantiomers. AB - Four novel crystalline stereocomplexed polymers are formed by mixing isotactic (R)- and (S)-polycarbonates in 1:1 mass ratio. They show the enhanced thermal stability and new crystalline behavior, significantly distinct from the component enantiomer. Two stereocomplexed CO2 -based polycarbonates from meso-3,4 epoxytetrahydrofuran and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane have high melting temperatures of up to 300 degrees C, about 30 degrees C higher than the individual enantiomers. Isotactic (R)- or (S)-poly(cyclopentene carbonate) and poly(cis-2,3-butene carbonate) are typical amorphous polymeric materials, however, upon mixing both enantiomers together, a strong interlocked interaction between polymer chains of opposite configuration occurs, affording the crystalline stereocomplexes with melting temperatures of about 200 degrees C and 180 degrees C, respectively. A DFT study suggests that the driving force forming the stereocomplex is the hydrogen-bonding between carbonate units of the opposite enantiomers. PMID- 25537627 TI - A phase 1 multiple-dose study of orteronel in Japanese patients with castration resistant prostate cancer. AB - PURPOSE: Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase 1 study in men with progressive and chemotherapy-naive CRPC. Patients received orteronel orally at doses of 200-400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy. RESULTS: Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30%) were hyperlipasemia (47%), hyperamylasemia (40%), and constipation (33%). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200-400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50% reduction from baseline in prostate-specific antigen. CONCLUSIONS: Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone. PMID- 25537628 TI - Detection of Rickettsia felis in Wild Mammals from Three Municipalities in Yucatan, Mexico. AB - The aim of this study was to provide information of the occurrence of Rickettsia felis in wild mammals from three municipalities in Yucatan, Mexico. The reactivity of rodent serum to Rickettsia antigens was detected in 80.9% (17 of 21) samples using immunofluorescence assay. Polymerase chain reaction identified rickettsial DNA in spleens of 43.5% (10 of 23) rodents and 57.1% (4 of 7) opossums. The identification of the rickettsial DNA was confirmed as R. felis by restriction fragment length polymorphism and DNA sequencing. This study comprises the first report of R. felis detection in wild mammals in Yucatan. PMID- 25537629 TI - Seroprevalence of Antibodies to Ross River and Barmah Forest Viruses: Possible Implications for Blood Transfusion Safety After Extreme Weather Events. AB - Climate change is predicted to increase the transmission of many vector-borne pathogens, representing an increasing threat to a safe blood supply. In early 2011, Australia experienced catastrophic rainfall and flooding, coupled with increased arbovirus transmission. We used Ross River (RRV) and Barmah Forest (BFV) viruses as test cases to investigate the potential risk posed to Australia's blood supply after this period of increased rainfall . We estimated the risk of collecting an infected donation as one in 2,500-58,000 for RRV and one in 2,000-28,000 for BFV. Climate change may incrementally increase the arbovirus threat to blood safety. PMID- 25537630 TI - Trends in Ranavirus Prevalence Among Plethodontid Salamanders in the Great Smoky Mountains National Park. AB - Emerging pathogens are a potential contributor to global amphibian declines. Ranaviruses, which infect ectothermic vertebrates and are common in aquatic environments, have been implicated in die-offs of at least 72 amphibian species worldwide. Most studies on the subject have focused on pool-breeding amphibians, and infection trends in other amphibian species assemblages have been understudied. Our primary study objective was to evaluate hypotheses explaining ranavirus prevalence within a lungless salamander assemblage (Family Plethodontidae) in the Great Smoky Mountains National Park, USA. We sampled 566 total plethodontid salamanders representing 14 species at five sites over a 6 year period (2007-2012). We identified ranavirus-positive individuals in 11 of the 14 (78.6%) sampled species, with salamanders in the genus Desmognathus having greatest infection prevalence. Overall, we found the greatest support for site elevation and sampling year determining infection prevalence. We detected the greatest number of infections in 2007 with 82.5% of sampled individuals testing positive for ranavirus, which we attribute to record drought during this year. Infection prevalence remained relatively high in low-elevation sites in 2008 and 2009. Neither body condition nor aquatic dependence was a significant predictor of ranavirus prevalence. Overall, our results indicate that life history differences among species play a minor role determining ranavirus prevalence compared to the larger effects of site elevation and yearly fluctuations (likely due to environmental stressors) during sampling years. PMID- 25537632 TI - Clinical characteristics, treatment patterns and outcomes of Hispanic hypertensive patients. AB - Hispanics are the largest and fastest-growing minority population in the United States, currently comprising about 16.3% (52 million) of the total population. With an increased prevalence of metabolic risk factors in this population, the rate of uncontrolled hypertension (HTN) in Hispanics significantly exceeds the rates observed among non-Hispanic blacks and whites. Unfortunately, data on HTN in Hispanics remains limited due to the under-representation of Hispanics in clinical trials; with most of the data primarily restricted to observational and retrospective subgroup analyses. This article aims to review the available data on prevalence, awareness and control of HTN, risk factors and some of the challenges unique to the Hispanics population. We also discuss treatment strategies derived from large HTN trials that included Hispanics. PMID- 25537633 TI - Application of oncoproteomics to aberrant signalling networks in changing the treatment paradigm in acute lymphoblastic leukaemia. AB - Oncoproteomics is an important innovation in the early diagnosis, management and development of personalized treatment of acute lymphoblastic leukaemia (ALL). As inherent factors are not completely known - e.g. age or family history, radiation exposure, benzene chemical exposure, certain viral exposures such as infection with the human T-cell lymphoma/leukaemia virus-1, as well as some inherited syndromes may raise the risk of ALL - each ALL patient may modify the susceptibility of therapy. Indeed, we consider these unknown inherent factors could be explained via coupling cytogenetics plus proteomics, especially when proteins are the ones which play function within cells. Innovative proteomics to ALL therapy may help to understand the mechanism of drug resistance and toxicities, which in turn will provide some leads to improve ALL management. Most important of these are shotgun proteomic strategies to unravel ALL aberrant signalling networks. Some shotgun proteomic innovations and bioinformatic tools for ALL therapies will be discussed. As network proteins are distinctive characteristics for ALL patients, unrevealed by cytogenetics, those network proteins are currently an important source of novel therapeutic targets that emerge from shotgun proteomics. Indeed, ALL evolution can be studied for each individual patient via oncoproteomics. PMID- 25537634 TI - Characterizing the composition of bone formed during fracture healing using scanning electron microscopy techniques. AB - About 5-10% of all bone fractures suffer from delayed healing, which may lead to non-union. Bone morphogenetic proteins (BMPs) can be used to induce differentiation of osteoblasts and enhance the formation of the bony callus, and bisphosphonates help to retain the newly formed callus. The aim of this study was to investigate if scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) can identify differences in the mineral composition of the newly formed bone compared to cortical bone from a non-fractured control. Moreover, we investigate whether the use of BMPs and bisphosphonates-alone or combined-may have an effect on bone mineralization and composition. Twelve male Sprague-Dawley rats at 9 weeks of age were randomly divided into four groups and treated with (A) saline, (B) BMP-7, (C) bisphosphonates (Zoledronate), and (D) BMP-7 + Zoledronate. The rats were sacrificed after 6 weeks. All samples were imaged using SEM and chemically analyzed with EDS to quantify the amount of C, N, Ca, P, O, Na, and Mg. The Ca/P ratio was the primary outcome. In the fractured samples, two areas of interest were chosen for chemical analysis with EDS: the callus and the cortical bone. In the non-fractured samples, only the cortex was analyzed. Our results showed that the element composition varied to a small extent between the callus and the cortical bone in the fractured bones. However, the Ca/P ratio did not differ significantly, suggesting that the mineralization at all sites is similar 6 weeks post-fracture in this rat model. PMID- 25537635 TI - Human immunodeficiency virus-associated vasculopathy with CNS compartmentalization of HIV-1. PMID- 25537636 TI - Building Baluchitherium and Indricotherium: imperial and international networks in early-twentieth century paleontology. AB - Over the first decades of the twentieth century, the fragmentary remains of a huge prehistoric ungulate were unearthed in scientific expeditions in India, Turkestan and Mongolia. Following channels of formal and informal empire, these were transported to collections in Britain, Russia and the United States. While striking and of immense size, the bones proved extremely difficult to interpret. Alternately naming the creature Paraceratherium, Baluchitherium and Indricotherium, paleontologists Clive Forster-Cooper, Alexei Borissiak and Henry Fairfield Osborn struggled over the reconstruction of this gigantic fossil mammal. However, despite these problems, shared work on the creature served as a focus for collaboration and exchange rather than rivalry between these three scientific communities. Not only did the initial interpretation and analysis depend on pre-existing connections between British and American paleontological institutions, but the need for comparative material, recognition and contacts brought British and American scholars into communication and exchange with their counterparts in the Soviet Union. This article examines these processes. It first uses these excavations as a comparative case-study of different manifestations of colonial science in this period, examining how scholars in the Britain, the Russian Empire and the United States used formal and informal colonial links to Asia to pursue new research. It then moves to examine how the common problem of reconstructing this giant animal drew metropolitan scientific communities together, at least for a time. The construction of the Baluchitherium and Indricotherium illustrates the drives to expand research both imperially and internationally in the early-twentieth century, but also the continual problems in resources, institutionalization, transport and communication that could run up against scientific work. PMID- 25537642 TI - Divergent roles of CXCR3 isoforms in promoting cancer stem-like cell survival and metastasis. AB - There is growing evidence that several chemokine receptors including CXCR3 contribute to metastasis of breast and other cancers, however, in order to target CXCR3 effectively, it is critical to understand the relative contribution of each CXCR3 isoform. Furthermore, the possible contribution of either major CXCR3 isoform (CXCR3-A, CXCR3-B) to cancer stem cell behavior has not been reported. We employed primary invasive ductal carcinomas, a panel of breast cell lines, and a xenograft model of metastatic breast cancer to examine the role of CXCR3 isoforms in the behavior of breast cancer stem-like cells and the contribution of each isoform to metastasis. In primary human breast cancer specimens as well as established breast cancer cell lines, CXCR3-A is more highly expressed than CXCR3 B. Conversely, immortalized normal MCF10A cells express more CXCR3-B relative to CXCR3-A. Overexpression of CXCR3-B in MDA-MB-231 basal-like cells inhibits CXCR3 ligand-stimulated proliferation, which is accompanied by reduced ligand-mediated activation of ERK1/2 and p38 kinases. Likewise, metastatic capacity is reduced in vivo by higher levels of CXCR3-B, and migratory and invasive properties are inhibited in vitro; conversely, silencing of CXCR3-B enhances lung colonization. In contrast to the anti-metastatic and anti-proliferative roles of CXCR3-B in the non-stem cell population, this isoform supports a cancer stem-like cell phenotype. CXCR3-B is markedly elevated in mammosphere-forming parental cells and overexpressing CXCR3-B further enhances mammosphere-forming potential as well as growth in soft agar; stem-like behavior is inhibited in MDA-MB-231shCXCR3-B cells. Targeting of both CXCR3 isoforms may be important to block the stem cell promoting actions of CXCR3-B, while inhibiting the pro-proliferative and metastasis-promoting functions of CXCR3-A. PMID- 25537637 TI - TtOmp85, a beta-barrel assembly protein, functions by barrel augmentation. AB - Outer membrane proteins are vital for Gram-negative bacteria and organisms that inherited organelles from them. Proteins from the Omp85/BamA family conduct the insertion of membrane proteins into the outer membrane. We show that an eight stranded outer membrane beta-barrel protein, TtoA, is inserted and folded into liposomes by an Omp85 homologue. Furthermore, we recorded the channel conductance of this Omp85 protein in black lipid membranes, alone and in the presence of peptides comprising the sequence of the two N-terminal and the two C-terminal beta-strands of TtoA. Only with the latter could a long-living compound channel that exhibits conductance levels higher than those of the Omp85 protein alone be observed. These data support a model in which unfolded outer membrane protein after docking with its C-terminus penetrates into the transmembrane beta-barrel of the Omp85 protein and augments its beta-sheet at the first strand. Augmentation with successive beta-strands leads to a compound, dilated barrel of both proteins. PMID- 25537643 TI - Greater absolute risk for all subtypes of breast cancer in the US than Malaysia. AB - Hormone receptor (HR) negative breast cancers are relatively more common in low risk than high-risk countries and/or populations. However, the absolute variations between these different populations are not well established given the limited number of cancer registries with incidence rate data by breast cancer subtype. We, therefore, used two unique population-based resources with molecular data to compare incidence rates for the 'intrinsic' breast cancer subtypes between a low-risk Asian population in Malaysia and high-risk non-Hispanic white population in the National Cancer Institute's surveillance, epidemiology, and end results 18 registries database (SEER 18). The intrinsic breast cancer subtypes were recapitulated with the joint expression of the HRs (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor-2 (HER2). Invasive breast cancer incidence rates overall were fivefold greater in SEER 18 than in Malaysia. The majority of breast cancers were HR-positive in SEER 18 and HR-negative in Malaysia. Notwithstanding the greater relative distribution for HR negative cancers in Malaysia, there was a greater absolute risk for all subtypes in SEER 18; incidence rates were nearly 7-fold higher for HR-positive and 2-fold higher for HR-negative cancers in SEER 18. Despite the well-established relative breast cancer differences between low-risk and high-risk countries and/or populations, there was a greater absolute risk for HR-positive and HR-negative subtypes in the US than Malaysia. Additional analytical studies are sorely needed to determine the factors responsible for the elevated risk of all subtypes of breast cancer in high-risk countries like the United States. PMID- 25537644 TI - Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. AB - This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade >=3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm. PMID- 25537645 TI - Current status of endoscopic ultrasound for the upper gastrointestinal tract in Asia. AB - We summarize the current status of endoscopic ultrasound (EUS) for the upper gastrointestinal (GI) tract solely in Asia, focusing on the staging of superficial cancers and the diagnosis of submucosal tumors (SMT), by analysis of questionnaire responses and a literature review. EUS for assessing the depth of superficial cancers of the upper GI tract is useful; however, evidence is lacking to support that EUS is superior to other modalities. The current status of EUS varies across different Asian countries, and standardization of the methods used both during the procedure and for depth subclassification is necessary to evaluate the diagnostic accuracy. Although EUS alone is limited in the diagnosis of SMT, EUS-guided fine-needle aspiration is an effective and safe diagnostic tool. Although there is a role for EUS, there are still many limitations both technically and in terms of accessibility. PMID- 25537646 TI - Over-expression of mouse ornithine decarboxylase gene under the control of fruit specific promoter enhances fruit quality in tomato. AB - Diamine putrescine (Put) and polyamines; spermidine (Spd) and spermine (Spm) are essential component of every cell because of their involvement in the regulation of cell division, growth and development. The aim of this study is to enhance the levels of Put during fruit development and see its implications in ripening and quality of tomato fruits. Transgenic tomato plants over-expressing mouse ornithine decarboxylase gene under the control of fruit-specific promoter (2A11) were developed. Transgenic fruits exhibited enhanced levels of Put, Spd and Spm, with a concomitant reduction in ethylene levels, rate of respiration and physiological loss of water. Consequently such fruits displayed significant delay of on-vine ripening and prolonged shelf life over untransformed fruits. The activation of Put biosynthetic pathway at the onset of ripening in transgenic fruits is also consistent with the improvement of qualitative traits such as total soluble solids, titratable acids and total sugars. Such changes were associated with alteration in expression pattern of ripening specific genes. Transgenic fruits were also fortified with important nutraceuticals like lycopene, ascorbate and antioxidants. Therefore, these transgenic tomatoes would be useful for the improvement of tomato cultivars through breeding approaches. PMID- 25537648 TI - An azodye-rhodamine-based fluorescent and colorimetric probe specific for the detection of Pd(2+) in aqueous ethanolic solution: synthesis, XRD characterization, computational studies and imaging in live cells. AB - Azodye-rhodamine hybrid colorimetric fluorescent probe (L) has been designed and synthesized. The structure of L has been established based on single crystal XRD. It has been shown to act as a selective turn-on fluorescent chemosensor for Pd(2+) with >40 fold enhancement by exhibiting red emission among the other 27 cations studied in aqueous ethanol. The coordination features of the species of recognition have been computationally evaluated by DFT methods and found to have a distorted tetrahedral Pd(2+) center in the binding core. The probe (L) has been shown to detect Pd up to 0.45 MUM at pH 7.4. Furthermore, the probe can be used to image Pd(2+) in living cells. PMID- 25537647 TI - Arabidopsis thaliana thymidine kinase 1a is ubiquitously expressed during development and contributes to confer tolerance to genotoxic stress. AB - Thymidine kinase catalyzes the first step in the nucleotide salvage pathway by transferring a phosphate group to a thymidine molecule. In mammals thymidine kinase supplies deoxyribonucleotides for DNA replication and DNA repair, and the expression of the gene is tightly regulated during the cell cycle. Although this gene is phylogenetically conserved in many taxa, its physiological function in plants remains unknown. The genome of the model plant Arabidopsis thaliana has two thymidine kinase genes (AtTK1a and AtTK1b) and microarray data suggest they might have redundant roles. In this study we analyzed the TK1a function by evaluating its expression pattern during development and in response to genotoxic stress. We also studied its role in DNA repair by the characterization of a mutant that contained the T-DNA insertion in the promoter region of the TK1a gene. We found that TK1a is expressed in most tissues during plant development and it was differentially induced by ultraviolet-C radiation because TK1b expression was unaffected. In the mutant, the T-DNA insertion caused a 40 % rise in transcript levels and enzyme activity in Arabidopsis seedlings compared to wild-type plants. This elevation was enough to confer tolerance to ultraviolet-C irradiation in dark conditions, as determined by root growth, and meristem length and structure. TK1a overexpression also provided tolerance to genotoxins that induce double-strand break. Our results suggest that thymidine kinase contributes to several DNA repair pathways by providing deoxythymidine triphosphate that serve as precursors for DNA repair and to balance deoxyribonucleotides pools. PMID- 25537650 TI - Electronic Information Systems Use in Residential Care Facilities: The Differential Effect of Ownership Status and Chain Affiliation. AB - The use of electronic information systems (EISs) including electronic health records continues to increase in all sectors of the health care industry. Research shows that EISs may be useful for improving care delivery and decreasing medical errors. The purpose of this project is twofold: First, we describe the prevalence of EIS use among residential care facilities (RCFs), and second, we explore utilization differences by ownership status and chain affiliation. We anticipate that RCFs that are non-profit and non-chain will use more EIS than other categories of RCFs. Data for this project come from the 2010 National Survey of Residential Care Facilities. The sample consists of 2,300 facilities. Overall use of EIS was greatest among RCFs that are non-profit and chain affiliated. Conversely, the use was lowest among for-profit RCFs that were also non-chain affiliated. This may suggest that these facilities lack the necessary resources or motivation to invest in information systems. PMID- 25537652 TI - Withdrawn: Matched sibling donor hematopoietic stem cell transplant in patients with acquired aplastic anemia. AB - Withdrawn by the publisher. PMID- 25537651 TI - An evaluation of 25 selected ToxCast chemicals in medium-throughput assays to detect genotoxicity. AB - ToxCast is a multiyear effort to develop a cost-effective approach for the US EPA to prioritize chemicals for toxicity testing. Initial evaluation of more than 500 high-throughput (HT) microwell-based assays without metabolic activation showed that most lacked high specificity and sensitivity for detecting genotoxicants. Thus, EPA initiated a pilot project to investigate the use of standard genotoxicity endpoints using medium-throughput genotoxicity (MTG) assays in the context of a large testing program. Twenty-five chemicals were selected from the ToxCast program based in part on their known genotoxicity. The two MTG assays used were the Ames II(TM) assay and 96-well In Vitro MicroFlow((r)) Micronucleus (MN) assay. The Ames II assay showed a reasonable correlation with published Ames test data and industry submissions, though specificity was much better than sensitivity due to restraints on top concentrations as prescribed by ToxCast. Overall concordance was 73% both with and without metabolic activation. The flow MN assay had concordances of 71% and 58% with and without metabolic activation, respectively, when compared to published data and submissions. Importantly, a comparison of results without S9 from the MTG assays to an HT ToxCast p53 activation assay showed a fairly good degree of concordance (67%). The results reported here indicate that assays for genotoxicity endpoints can be conducted in a MT format and have the potential to add to the interpretation of results from large-scale testing programs such as EPA's ToxCast program. Inherent limitations such as the top concentrations used in large scale testing programs are discussed. Environ. Mol. Mutagen. 56:468-476, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25537649 TI - Statin use and decline in gait speed in community-dwelling older adults. AB - OBJECTIVES: To examine the association between statin use and objectively assessed decline in gait speed in community-dwelling older adults. DESIGN: Longitudinal cohort study. SETTING: Health, Aging and Body Composition (Health ABC) Study. PARTICIPANTS: Two thousand five participants aged 70-79 at baseline with medication and gait speed data at 1998-99, 1999-2000, 2001-02, and 2002-03. MEASUREMENTS: The independent variables were any statin use and their standardized daily doses (low, moderate, high) and lipophilicity. The primary outcome measure was decline in gait speed of 0.1 m/s or more in the following year of statin use. Multivariable generalized estimating equations were used, adjusting for demographic characteristics, health-related behaviors, health status, and access to health care. RESULTS: Statin use increased from 16.2% in 1998-99 to 25.6% in 2002-03. The overall proportions of those with decline in gait speed of 0.1 m/s or more increased from 22.2% in 1998 to 23.9% in 2003. Statin use was not associated with decline in gait speed of 0.1 m/s or more (adjusted odds ratio (AOR) = 0.90, 95% confidence interval (CI) = 0.77-1.06). Similar nonsignificant trends were also seen with the use of hydrophilic or lipophilic statins. Users of low-dose statins were found to have a 22% lower risk of decline in gait speed than nonusers (AOR = 0.78, 95% CI = 0.61-0.99), which was mainly driven by the results from 1999-2000 follow-up. CONCLUSION: These results suggest that statin use did not increase decline in gait speed in community-dwelling older adults. PMID- 25537653 TI - Molecular Imaging of Therapeutic Potential of Reporter Probes. AB - Success of medical treatments for any pathological disorders majorly depends on the efficacy of the therapeutic molecules and their delivery to the target sites. Non-invasive molecular imaging technologies have emerged as prime methods for validating both these aspects ranging from preclinical level to clinical application. Reporter genes and the respective reporter probes are essential components of molecular functional imaging that gained wide popularity throughout the world due to easy adaptation, user friendly software and cost-effective experiments. However, to monitor the therapeutic effects, reporter gene-reporter probes (RG-RP) are often combined with separate introductions of therapeutics whose delivery at target sites are not appropriately measured. A small group of reporter genes is associated with probes that behave like a signature as well as a therapeutic molecule thereby having theranostic properties. This Reporter Gene Therapeutic Reporter Probe (RG-TRP) system bears additional advantages over RG-RP system and holds the promise of direct translational applications in humans. This short review focuses on describing the currently available and validated RG-TRP systems, delivery vehicles, associated imaging modalities, applications in various pathological conditions along with the merits and demerits. Identification of new RG-TRP system will open new direction in theranostic imaging with potential human applications. PMID- 25537654 TI - Indoxyl sulfate: a candidate target for the prevention and treatment of cardiovascular disease in chronic kidney disease. AB - The awareness that chronic kidney disease (CKD) is a condition of dramatically increased cardiovascular risk has prompted an intense research activity, aimed at identifying factors that are specifically involved in the development of cardiovascular complications of CKD and that can be delayed or reduced by novel pharmacological approaches. This may be the case with indoxyl sulfate (IS). IS is an endogenous molecule derived from indole, a product of protein metabolism by intestinal bacteria, which acts via the aryl hydrocarbon receptor (AhR). IS accumulates early in CKD and exerts proinflammatory and other detrimental effects on the cardiovascular system, in particular promoting atherosclerosis and atherosclerosis-related arterial remodeling. Furthermore, IS also contributes to renal damage, thereby fueling a vicious circle. Dialysis is poorly effective in removing IS, but its levels can be lowered by preventing the bacterial generation of indole or by absorbing this latter within the intestine. More intriguing, although still theoretical, is the possibility of inhibiting the action of IS at the cell level, by antagonizing the binding to AhR or IS intracellular signaling. Therefore, IS targeting might become an option for reducing the cardiovascular burden of CKD. PMID- 25537655 TI - ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. AB - ATP citrate lyase (ACLY), an important enzyme involved in lipid biogenesis linked with glucose metabolism, catalyzes the conversion of citrate to oxaloacetic acid (OAA) and acetyl-CoA. The obtained acetyl-CoA is required for lipid synthesis during membrane biogenesis, as well as for histone acetylation reactions to regulate the expression of certain proteins in aberrantly proliferating cancer cells. Studies have shown a role for ACLY in tumorigenesis whereby increased levels of the enzyme leads to increased metabolic activity via activation of Akt signaling. Increasing lines of evidence suggest that enzymes involved in lipid biogenesis play a significant role in cancer cell proliferation and progression. In many cancer types such as glioblastoma, colorectal cancer, breast cancer, non small cell lung cancer, hepatocellular carcinoma etc., the level of ACLY has been found to be quite high as compared to normal cells. Cancer cell growth related to overexpression of ACLY can be inhibited by using chemical inhibitors or by the knockdown of ACLY gene. Inhibition of ACLY leads to changes in cancer cell metabolism that promotes tumor growth and proliferation. This review summarizes the role of ACLY in cancer development and its inhibitors in cancer treatment. PMID- 25537656 TI - Evaluation of apparent diffusion coefficient associated with pathological grade of lung carcinoma, before therapy. AB - PURPOSE: To investigate the feasibility and utility of apparent diffusion coefficient (ADC) in predicting the tumor cellular density and grades of lung cancers. MATERIALS AND METHODS: Forty-one consecutive patients (26 men and 15 women; mean age, 59.9 years) with histologically proven lung cancers were enrolled in the study and underwent MR examination. ADC values and tumor cellular density of different histological grades were analyzed. The relationship of the ADC with tumor cellular density and grades were also evaluated. RESULTS: The ADC values of lung cancer in grade III was significantly lower than those in grade I and grade II (P = 0.008 and 0.011, respectively). The cellular density in grade III was significantly higher than other two grades (P = 0.029 and 0.022, respectively). ADC value of lung cancer correlated negatively with grades and tumor cellular density (P = 0.001 and P = 0.001, respectively). According to the ROC analysis, the cutoff value of ADC was 1.175 * 10(-3) mm(2) /s with the optimal sensitivity (88.2%) and specificity (62.5%), respectively. CONCLUSION: ADC measurement of lung cancer was a helpful method to evaluate the pathological grade and tumor cellular density. The quantitative analysis of ADC in conjunction with conventional MR findings could provide more valuable information for the assessment of pulmonary tumor. J PMID- 25537657 TI - Characterization of Fam20C expression in odontogenesis and osteogenesis using transgenic mice. AB - Our previous studies have demonstrated that Fam20C promotes differentiation and mineralization of odontoblasts, ameloblasts, osteoblasts and osteocytes during tooth and bone development. Ablation of the Fam20C gene inhibits bone and tooth growth by increasing fibroblast growth factor 23 in serum and causing hypophosphatemia in conditional knockout mice. However, control and regulation of the expression of Fam20C are still unknown. In this study, we generated a transgenic reporter model which expresses green fluorescence protein (GFP) driven by the Fam20C promoter. Recombineering was used to insert a 16 kb fragment of the mouse Fam20C gene (containing the 15 kb promoter and 1.1 kb of exon 1) into a pBluescript SK vector with the topaz variant of GFP and a bovine growth hormone polyadenylation sequence. GFP expression was subsequently evaluated by histomorphometry on cryosections from E14 to adult mice. Fluorescence was evident in the bone and teeth as early as E17.5. The GFP signal was maintained stably in odontoblasts and osteoblasts until 4 weeks after birth. The expression of GFP was significantly reduced in teeth, alveolar bone and muscle by 8 weeks of age. We also observed colocalization of the GFP signal with the Fam20C antibody in postnatal 1- and 7-day-old animals. Successful generation of Fam20C-GFP transgenic mice will provide a unique model for studying Fam20C gene expression and the biological function of this gene during odontogenesis and osteogenesis. PMID- 25537658 TI - The $64,000 question. PMID- 25537660 TI - Explorative study on quality of life in relation to salivary secretion rate in patients with head and neck cancer treated with radiotherapy. AB - BACKGROUND: Radiotherapy (RT) to the head and neck region often results in oral complications. In this explorative study, the pretreatment and posttreatment (6 months and 12 months) quality of life (QOL) was analyzed for patients with head and neck cancer. The associations between QOL and salivary secretion rates were analyzed. METHODS: In 29 patients (19 men and 10 women; mean age, 59 +/- 8 years), the stimulated whole salivary secretion and buccal minor gland secretion were measured. The patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (EORTC-QLQ C30) and Quality of Life Questionnaire-Core 30 Head and Neck 35-questions (EORTC QLQ-C30-H&N35) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: One year after the completion of RT, patients with hyposalivation (<=0.7 mL/min) reported clinically meaningful, but not statistically significant differences, in cognitive functioning, insomnia, swallowing, social eating, dry mouth, sticky saliva, and use of painkillers. Statistically significant differences were found for emotional functioning, sticky saliva, and dyspnea (p < .05). Thirty-three percent of them had a HADS score suggesting anxiety problems, compared with 8% for those with whole stimulated salivary secretion rates >0.7 mL/min. CONCLUSION: RT in the head and neck region, also using intensity-modulated RT, is associated with many aspects of life, such as cognitive functioning, insomnia, dry mouth, and sticky saliva, especially for those with hyposalivation. PMID- 25537659 TI - Prolonged hypoxia induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair. AB - MSCs encounter extended hypoxia in the wound microenvironment yet little is known about their adaptability to this prolonged hypoxic milieu. In this study, we evaluated the cellular and molecular response of MSCs in extended hypoxia (1% O2 ) versus normoxia (20% O2 ) culture. Prolonged hypoxia induced a switch toward anaerobic glycolysis transcriptome and a dramatic increase in the transcript and protein levels of monocarboxylate transporter-4 (MCT4) in MSCs. To clarify the impact of MCT4 upregulation on MSC biology, we generated MSCs which stably overexpressed MCT4 (MCT4-MSCs) at levels similar to wild-type MSCs following prolonged hypoxic culture. Consistent with its role to efflux lactate to maintain intracellular pH, MCT4-MSCs demonstrated reduced intracellular lactate. To explore the in vivo significance of MCT4 upregulation in MSC therapy, mice were injected intramuscularly following MI with control (GFP)-MSCs, MCT4-MSCs, or MSCs in which MCT4 expression was stably silenced (KDMCT4-MSCs). Overexpression of MCT4 worsened cardiac remodeling and cardiac function whereas silencing of MCT4 significantly improved cardiac function. MCT4-overexpressing MSC secretome induced reactive oxygen species-mediated cardiomyocyte but not fibroblast apoptosis in vitro and in vivo; lactate alone recapitulated the effects of the MCT4-MSC secretome. Our findings suggest that lactate extruded by MCT4 overexpressing MSCs preferentially induced cell death in cardiomyocytes but not in fibroblasts, leading ultimately to a decline in cardiac function and increased scar size. A better understanding of stem cells response to prolonged hypoxic stress and the resultant stem cell-myocyte/fibroblast cross-talk is necessary to optimize MSC-based therapy for cardiac regeneration. PMID- 25537661 TI - Effects of Roux-en-Y gastric bypass surgery on eating behaviour and allopregnanolone levels in obese women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is associated with abnormal eating habits. We examined whether surgical treatment affected allopregnanolone levels and eating behaviour in nine women with PCOS who qualified for Rou-en-Y gastric bypass surgery. Blood samples were obtained to measure sex-hormone-binding globulin, total testosterone, progesterone, and allopregnanolone, and eating behaviour was evaluated using the Three-Factor Eating Questionnaire before surgery and at 6 and 12 months after surgery. Body mass index and total testosterone levels decreased, and progesterone and sex-hormone-binding globulin levels increased after bariatric surgery compared with pre-surgical values. In patients with anovulatory menstrual cycles, both the serum allopregnanolone level and the allopregnanolone/progesterone ratio were unchanged after surgery. The patients had high uncontrolled and emotional eating scores, and low cognitive restraint scores before surgery, and these scores had improved significantly at 6 and 12 months after surgery. The presurgical allopregnanolone levels were significantly correlated with uncontrolled eating. In conclusion, these results suggest that allopregnanolone appear to be part of the mechanism underlying the abnormal eating behaviour of obese PCOS patients by causing the loss of control over food intake. Roux-en-Y gastric bypass surgery can improve eating behaviour and clinical symptoms, and may facilitate weight loss in obese women with PCOS. PMID- 25537663 TI - Insights into the pamamycin biosynthesis. AB - Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate. PMID- 25537662 TI - Protease-activated pore-forming peptides for the treatment and imaging of prostate cancer. AB - A common hallmark of cancers with highly aggressive phenotypes is increased proteolysis in the tumor and the surrounding microenvironment. Prostate cancer has a number of proteases uniquely associated with it that may play various important roles in disease progression. In this report, we utilize the peritumoral proteolytic activity of prostate cancer to activate engineered peptide constructs for the treatment and noninvasive imaging of prostate cancer. Using a modular "propeptide" approach, a cationic diastereomeric pore-forming peptide domain was linked to an inactivating acidic peptide domain. The inactivating acidic peptide domain was engineered to be a cleavable substrate for the secreted serine protease prostate-specific antigen (PSA) or the transmembrane metalloprotease prostate-specific membrane antigen (PSMA). The propeptides were then evaluated in a direct comparison study. Both the PSA and PSMA activated propeptides were found to be cytotoxic to prostate cancer cells in vitro. In vivo, however, treatment of LNCaP and CWR22Rv1 xenografts with the PSMA propeptide resulted in a pronounced cytostatic effect when compared with xenografts treated with the PSA propeptide or the cationic diastereomeric peptide alone. The PSMA activated propeptide also proved to be an effective optical imaging probe in vivo when labeled with a near-infrared fluorophore. These data suggest that protease-activated pore-forming peptides could potentially be used for both imaging and treating prostate cancer. PMID- 25537664 TI - Contribution of phenolic compounds to food flavors: Strecker-type degradation of amines and amino acids produced by o- and p-diphenols. AB - The ability of 20 phenolic derivatives to produce the Strecker-type degradation of phenylalanine and phenylglycine methyl ester was studied to investigate both the direct degradation of amino acids and amines by phenolic compounds in the absence of added oxidants and the effect of the number and positions of hydroxyl groups in the aromatic ring of the phenolic compound in relation to its ability to produce carbonyl derivatives from amino compounds. The obtained results showed that polyphenols can produce the Strecker degradation of amino acids and amines in the absence of added oxidants. The only requisite for producing the reaction is the presence of two hydroxyl groups in ortho or para positions. However, the presence of two hydroxyl groups in meta position in an additional aromatic ring can inhibit the Strecker-degrading ability of the hydroxyl groups in ortho or para positions. A reaction pathway that explains all of these findings is proposed. In addition, the effect of reaction conditions on the obtained reaction yields was studied. Activation energies (Ea) for phenylacetaldehyde formation from phenylalanine in the presence of hydroquinone, 1,2,4-trihydroxybenzene, and benzoquinone were 32.9, 31.5, and 28.8 kJ/mol, respectively. PMID- 25537665 TI - Tris(3,5-dimethylpyrazolyl)methane-based heterobimetallic complexes that contain Zn - and Cd - transition-metal bonds: synthesis, structures, and quantum chemical calculations. AB - Reactions of the tris(3,5-dimethylpyrazolyl)methanide amido complexes [M'{C(3,5 Me2 pz)3 }{N(SiMe3 )2 }] (M'=Mg (1 a), Zn (1 b), Cd (1 c); 3,5-Me2 pz=3,5 dimethylpyrazolyl) with two equivalents of the acidic Group 6 cyclopentadienyl (Cp) tricarbonyl hydrides [MCp(CO)3 H] (M=Cr (2 a), Mo (2 b)) gave different types of heterobimetallic complex. In each case, two reactions took place, namely the conversion of the tris(3,5-dimethylpyrazolyl)methanide ligand (Tpmd*) into the -methane derivative (Tpm*) and the reaction of the acidic hydride M = H bond with the M' = N(SiMe3 )2 moiety. The latter produces HN(SiMe3 )2 as a byproduct. The Group 2 representatives [Mg(Tpm*){MCp(CO)3 }2 (thf)] (3 a/b) form isocarbonyl bridges between the magnesium and chromium/molybdenum centres, whereas direct metal-metal bonds are formed in the case of the ions [Zn(Tpm*){MCp(CO)3 }](+) (4 a/b; [MCp(CO)3 ](-) as the counteranion) and [Cd(Tpm*){MCp(CO)3 }(thf)](+) (5 a/b; [Cd{MCp(CO)3 }3 ](-) as the counteranion). Complexes 4 a and 5 a/b are the first complexes that contain Zn - Cr, Cd - Cr, and Cd - Mo bonds (bond lengths 251.6, 269.8, and 278.9 pm, respectively). Quantum chemical calculations on 4 a/b* (and also on 5 a/b*) provide evidence for an interaction between the metal atoms. PMID- 25537666 TI - Awake postural change to prone in a morbidly obese patient. PMID- 25537667 TI - The stages of consultation-liaison psychiatry. PMID- 25537668 TI - On Becoming a Teacher: Reflections on Teaching and Learning in Psychiatry Residency and Beyond. PMID- 25537669 TI - Surface engineering of reduced graphene oxide for controllable ambipolar flash memories. AB - Tunable charge-trapping behaviors including unipolar charge trapping of one type of charge carrier and ambipolar trapping of both electrons and holes in a complementary manner is highly desirable for low power consumption multibit flash memory design. Here, we adopt a strategy of tuning the Fermi level of reduced graphene oxide (rGO) through self-assembled monolayer (SAM) functionalization and form p-type and n-type doped rGO with a wide range of manipulation on work function. The functionalized rGO can act as charge-trapping layer in ambipolar flash memories, and a dramatic transition of charging behavior from unipolar trapping of electrons to ambipolar trapping and eventually to unipolar trapping of holes was achieved. Adjustable hole/electron injection barriers induce controllable Vth shift in the memory transistor after programming operation. Finally, we transfer the ambipolar memory on flexible substrates and study their charge-trapping properties at various bending cycles. The SAM-functionalized rGO can be a promising candidate for next-generation nonvolatile memories. PMID- 25537670 TI - K-Ras 4A Transcript variant is up-regulated in eutopic endometrium of endometriosis patients during proliferative phase of menstrual cycle. AB - AIMS: K-Ras transcripts comprise two main isoforms: K-Ras 4A and K-Ras 4B, which act differently. The expression of both isoforms was reported in many human tissues. However, K-Ras 4B was the major expressed transcript variant. An increased expression of K-Ras 4B mRNA was reported in eutopic endometrium of endometriosis patients. In this way, we aimed to study the expression of K-Ras 4A transcript in eutopic endometrium related to endometriosis. METHODS: Employing exon4-flanking primers, K-Ras isoforms were simultaneously amplified in a RT-PCR reaction. Quantitative real-time PCR was performed using GAPDH as an internal control. K-Ras 4A transcript expression in eutopic endometrium was analyzed by DeltaDeltaC T method. RESULTS: We identified existence of both of K-Ras 4A and K Ras 4B in eutopic endometrium of patients and controls. Quantitative real-time analysis demonstrated that K-Ras 4A expression was 2.7-fold higher in endometriosis than non-endometriosis eutopic samples. Interestingly, this overexpression mainly occurs through the proliferative phase of menstrual cycle. CONCLUSION: The findings bring to light the eminent role of K-Ras 4A in endometriosis. This splice variant which is known for promoting apoptosis could be an effective factor in balance between proliferation and death of eutopic endometrial cells. PMID- 25537671 TI - Alterations of colonic contractility in an interleukin-10 knockout mouse model of inflammatory bowel disease. AB - BACKGROUND/AIMS: Inflammatory bowel disease is commonly accompanied by colonic dysmotility and causes changes in intestinal smooth muscle contractility. In this study, colonic smooth muscle contractility in a chronic inflammatory condition was investigated using smooth muscle tissues prepared from interleukin-10 knockout (IL-10(-/-)) mice. METHODS: Prepared smooth muscle sections were placed in an organ bath system. Cholinergic and nitrergic neuronal responses were observed using carbachol and electrical field stimulation with L-NG-nitroarginine methyl ester (L-NAME). The expression of interstitial cells of Cajal (ICC) networks, muscarinic receptors, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) was observed via immunofluorescent staining. RESULTS: The spontaneous contractility and expression of ICC networks in the proximal and distal colon was significantly decreased in IL-10(-/-) mice compared to IL-10(+/+) mice. The contractility in response to carbachol was significantly decreased in the proximal colon of IL-10(-/-) mice compared to IL 10(+/+) mice, but no significant difference was found in the distal colon. In addition, the expression of muscarinic receptor type 2 was reduced in the proximal colon of IL-10(-/-) mice. The nictric oxide-mediated relaxation after electrical field stimulation was significantly decreased in the proximal and distal colon of IL-10(-/-) mice. In inflamed colon, the expression of nNOS decreased, whereas the expression of iNOS increased. CONCLUSIONS: These results suggest that damage to the ICC network and NOS system in the proximal and distal colon, as well as damage to the smooth muscle cholinergic receptor in the proximal colon may play an important role in the dysmotility of the inflamed colon. PMID- 25537672 TI - Comparison of High-resolution Anorectal Manometry With Water-perfused Anorectal Manometry. AB - BACKGROUND/AIMS: To date, high-resolution manometry has been used mainly in the study of esophageal motility disorders and has been shown to provide more physiological information than conventional manometry, and is easier to interpret. This study aimed to evaluate the usefulness of high-resolution anorectal manometry (HRARM) compared to water-perfused anorectal manometry. METHODS: Patients who complained of chronic constipation with/without fecal incontinence underwent both water-perfused anorectal manometry and HRARM in a random order on the same day. Resting and squeezing pressures of the anal sphincter, attempted defecation, rectoanal inhibitory reflex, rectoanal contractile reflex, Rao's type of dyssynergia during attempted defecation, anal canal length, defecation dynamic parameters and measurement times for each method were analyzed. RESULTS: Of 14 patients, 7 were female, and the median age was 59 years (range 35-77). Indications for manometry were constipation (n = 8) and constipation with fecal incontinence (n = 6). Resting and squeezing pressures showed that the two methods were strongly correlated (resting pressure: r = 0.746, P = 0.002; squeezing pressure: r = 0.921, P < 0.001). In attempted defection, one equivocal case with water-perfused anorectal manometry was diagnosed type I pelvic floor dyssynergia with HRARM providing detailed pressure changes in internal and external anal spincters, and puborectalis muscle which improved assessment of anorectal disorders. The measurement time for HRARM was significantly shorter than that for water-perfused anorectal manometry (11.3 vs. 23.0 minutes, P < 0.001). CONCLUSIONS: Both water-perfused anorectal manometry and HRARM are well tolerated and reliable methods of evaluating defecation disorders of pelvic floor dysfunction. HRARM is likely to provide better physiological information and to require a shorter measurement time compared to water-perfused anorectal manometry. PMID- 25537673 TI - Development, Translation and Validation of Enhanced Asian Rome III Questionnaires for Diagnosis of Functional Bowel Diseases in Major Asian Languages: A Rome Foundation-Asian Neurogastroenterology and Motility Association Working Team Report. AB - BACKGROUND/AIMS: The development-processes by regional socio-cultural adaptation of an Enhanced Asian Rome III questionnaire (EAR3Q), a cultural adaptation of the Rome III diagnostic questionnaire (R3DQ), and its translation-validation in Asian languages are presented. As English is not the first language for most Asians, translation-validation of EAR3Q is essential. Hence, we aimed to culturally adapt the R3DQ to develop EAR3Q and linguistically validate it to show that the EAR3Q is able to allocate diagnosis according to Rome III criteria. METHODS: After EAR3Q was developed by Asian experts by consensus, it was translated into Chinese, Hindi-Telugu, Indonesian, Korean and Thai, following Rome Foundation guidelines; these were then validated on native subjects (healthy [n = 60], and patients with irritable bowel syndrome [n = 59], functional dyspepsia [n = 53] and functional constipation [n = 61]) diagnosed by clinicians using Rome III criteria, negative alarm features and investigations. RESULTS: Experts noted words for constipation, bloating, fullness and heartburn, posed difficulty. The English back-translated questionnaires demonstrated concordance with the original EAR3Q. Sensitivity and specificity of the questionnaires were high enough to diagnose respective functional gastrointestinal disorders (gold standard: clinical diagnoses) in most except Korean and Indonesian languages. Questionnaires often uncovered overlapping functional gastrointestinal disorders. Test-retest agreement (kappa) values of the translated questionnaires were high (0.700-1.000) except in Korean (0.300-0.500) and Indonesian (0.100-0.400) languages at the initial and 2-week follow-up visit. CONCLUSIONS: Though Chinese, Hindi and Telugu translations were performed well, Korean and Indonesian versions were not. Questionnaires often uncovered overlapping FGIDs, which were quite common. PMID- 25537675 TI - Risk factors for postoperative ileus following orthopedic surgery: the role of chronic constipation. AB - BACKGROUND/AIMS: Distinction is vague between severe constipation and postoperative ileus (POI) in terms of pathogenesis, clinical features, and treatment options. However, no data are available regarding their associations. METHODS: After retrospective review of data from patients who underwent orthopedic surgery during the first 6 months of 2011, a total of 612 patients were included. Severe constipation was defined as symptoms of constipation requiring treatment using at least 2 laxatives from different classes for at least 6 months. POI was defined as paralytic ileus lasting more than 3 days post surgery and associated with 2 or more of the following: (1) nausea/vomiting, (2) inability to tolerate an oral diet over a 24-hour period, and (3) absence of flatus over a 24-hour period. The subjects were divided into non-POI and POI groups, and we com - pared patient-, surgery-, and pharmaceutical-related factors. RESULTS: Thirteen (2.1%) out of 612 experienced POI. In comparisons between the non-POI and POI groups, univariate analysis showed significant differences in the mean age (51.4 vs. 71.6 years), mean body mass index (24.1 vs. 21.8 kg/m(2)), severe constipation (5.8% vs. 76.9%), co-morbidities (33.2% vs. 84.6%), type of orthopedic surgery (spine/hip/limb: 19.4/11.0/65.6% vs. 23.1/61.5/15.4%), and estimated blood loss (50 vs. 300 mL). Multivariate logistic regression analysis, after adjustment for age, body mass index, co-morbidities, type of orthopedic surgery, and estimated blood loss, showed that severe constipation was an independent risk factor for POI (OR 35.23; 95% CI, 7.72 160.82; P < 0.001). CONCLUSIONS: Severe constipation is associated with POI after orthopedic surgery. PMID- 25537674 TI - Change of Fecal Flora and Effectiveness of the Short-term VSL#3 Probiotic Treatment in Patients With Functional Constipation. AB - BACKGROUND/AIMS: We investigated gut flora characteristics in patients with functional constipation (FC) and influences of short-term treatment with VSL#3 probiotic on flora and symptom improvement. METHODS: Thirty patients fulfilling Rome III criteria for FC and 30 controls were enrolled. Fecal samples were obtained before and after VSL#3 intake (one sachet twice daily for 2 weeks) and flora were examined by quantitative real-time polymerase chain reaction (qRT PCR). Symptom changes were also investigated. RESULTS: The fold differences in Bifidobacterium and Bacteroides species were significantly lower in feces from FC, compared to in controls (P = 0.030 and P = 0.021). After taking VSL#3, the fold differences in Lactobacillus, Bifidobacterium and Bacteroides species increased in controls (P = 0.022, P = 0.018, and P = 0.076), but not in FC. Mean Bristol scores and complete spontaneous bowel movements (CSBMs)/week increased significantly in FC after ingesting VSL#3 (both P < 0.001). Relief of subjective CSBM frequency, stool consistency and abdominal bloating were reported in 70%, 60%, and 47% of patients. After VSL#3 cessation, 44.4% of patients with symptom improvement experienced constipation recurrence mostly within one month. CONCLUSIONS: Bifidobacterium and Bacteroides species might be quantitatively altered in FC. A short-term VSL#3 treatment can improve clinical symptoms of FC. Further studies are needed to investigate VSL#3's additional effects beyond altering gut flora to allevate constipation. PMID- 25537676 TI - Predictive factors of response to proton pump inhibitors in korean patients with gastroesophageal reflux disease. AB - BACKGROUND/AIMS: Proton pump inhibitors (PPIs) are widely used in the treatment of gastroesophageal reflux disease (GERD). However, some patients fail to respond to PPI therapy. We investigated the efficacy of response to PPI therapy in patients with GERD symptoms. METHODS: A total of 179 subjects with GERD symptoms were prospectively enrolled and diagnosed with non-erosive reflux disease (NERD, n = 100) and erosive reflux disease (n = 79) by gastroscopy and Bernstein test and/or 24-hour esophageal pH testing. Subjects then received a standard dose of daily PPI therapy for at least 4 weeks. PPI therapy response was evaluated using questionnaires including questions about demographics, GERD symptoms, GERD impact scale, Epworth sleepiness scale, Pittsburgh sleep quality index (PSQI), hospital anxiety and depression scale, and abbreviated version of the World Health Organization quality of life scale. RESULTS: The rates of complete (>= 80%), satisfactory (>= 50%), partial (< 50%), and refractory response in the 179 participants were 41.3%, 30.2%, 18.4%, and 10.1%, respectively. Thus, overall response rate (complete and satisfactory responses) was 71.5%. Multivariate analysis showed body mass index < 23 kg/m(2) (OR, 2.20; 95% CI, 1.12-4.34), higher total PSQI score (OR, 1.20; 95% CI, 1.05-1.35), history of psychotherapy or neuropsychiatric medication (OR, 2.44; 95% CI, 1.23-4.85), and NERD (OR, 3.30; 95% CI, 1.54-7.11) were associated with poor response to PPI therapy. CONCLUSIONS: Psychological factors, sleep dysfunction, body mass index < 23 kg/m(2), and NERD seem to be the major factors that lead to a poor response to PPI treatment in patients with GERD symptoms. PMID- 25537678 TI - The Resveratrol-induced Relaxation of Cholecystokinin Octapeptide- or KCl-induced Tension in Male Guinea Pig Gallbladder Strips Is Mediated Through L-type Ca2+Channels. AB - BACKGROUND/AIMS: Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic compound (stilbene) and a phytoalexin. The purpose of this study was to determine the mechanism which mediated the resveratrol-induced relaxation of cholecystokinin octapeptide- or KCl-induced tension in male guinea pig gallbladder strips. METHODS: Gallbladder strips were prepared and suspended in in vitro chambers filled with Krebs-Henseleit solution. The strips were attached to force displacement transducers, and the changes in tension were recorded on a polygraph. All reagents were added directly into the chambers. RESULTS: To determine if intracellular Ca(2+) release mediated the resveratrol-induced relaxation of cholecystokinin octapeptide-induced tension, 2 aminoethoxydiphenylborane (2-APB) was used. 2-APB significantly (P < 0.01) decreased the amount of RSVL-induced relaxation. To determine if protein kinase A (PKA) mediated the resveratrol-induced relaxation, PKA inhibitor 14-22 amide myristolated (PKA-IM) was used. PKA-IM had no effect on resveratrol-induced relaxation. Neither KT5823, N(G)-methyl-L-arginine acetate salt, a nitric oxide synthase inhibitor, nor fulvestrant had a significant effect on the amount of resveratrol-induced relaxation. Genistein, a protein tyrosine kinase inhibitor, significantly (P < 0.01) increased the RSVL-induced relaxation. To determine if protein kinase C mediated the RSVL-induced relaxation, the protein kinase C inhibitors bisindolymaleimide IV and chelerythrine Cl- were used together, and a significant (P < 0.05) increase in resveratrol-induced relaxation was observed. The pretreatment of the strips with resveratrol significantly (P < 0.001) decreased the amount of KCl- and cholecystokinin octapeptide- induced tension. CONCLUSIONS: Resveratrol-induced relaxation is mediated by its effects on L-type Ca(2+) channels and intracellular Ca(2+) release. PMID- 25537680 TI - Hybrid atrial fibrillation ablation via direct right atrial approach: first-ever case. PMID- 25537681 TI - Human papillomavirus-related high-grade squamous intraepithelial lesions of the esophagus, skin, and cervix in an adolescent lung transplant recipient: a case report and literature review. AB - High-risk (carcinogenic) genotype human papillomavirus (HPV) infections can be associated with significant morbidity in the immunocompromised solid organ transplant (SOT) recipient. Immunosuppression-associated persistent infection can predispose to the development of rapidly progressive high-grade squamous intraepithelial lesions (HSIL) in this population. We present a case report of an adolescent bilateral lung transplant recipient who developed HSIL of the esophagus, cervix, and skin secondary to HPV. This review highlights the unique developmental needs of the sexually active adolescent SOT recipient and reviews guidelines for HPV-related screening and education of this population. PMID- 25537679 TI - Melatonin Attenuates Noise Stress-induced Gastrointestinal Motility Disorder and Gastric Stress Ulcer: Role of Gastrointestinal Hormones and Oxidative Stress in Rats. AB - BACKGROUND/AIMS: There are increasing evidences for gastrointestinal motility disorder (GIMD) and gastric stress ulcer induced by noise stress. The present study was to investigate the reversed effect of melatonin on GIMD and gastric stress ulcer induced by noise stress and potential mechanism. METHODS: Noise stress was induced on rats, and melatonin (15 mg/kg) was administered to rats by intraperitoneal injection. Differences were assessed in gastric residual rate (GRR), small intestine propulsion rate (SPR), Guth injury score, cortisol, gastrointestinal hormones (calcitonin-gene-related peptide and motilin) and oxidative stress markers (superoxide dismutase and malondialde hyde) in blood plasma as well as gastric mucosa homogenate with or without melatonin. The pathological examination of gastric mucosa was also performed. RESULTS: The GRR and SPR were improved by noise stress compared with control (P < 0.05). The pathological examination and Guth injury score revealed gastric stress ulcer. Moreover, the levels of cortisol, motilin and malondialdehyde in blood plasma and ma-londialdehyde in gastric mucosa homogenate were increased by noise stress (P < 0.05). CGRP and superoxide dismutase activ-ity in both of blood plasma and gastric mucosa homogenate were significantly decreased (P< 0.05). Furthermore, melatonin reversed changes in GRR, SPR, pathological examination, Guth injury score, cortisol, motilin, CGRP, superoxide dismutase activity and malondialdehyde (P < 0.05). CONCLUSIONS: Melatonin is effective in reversing the GIMD and gastric stress ulcer induced by noise stress. The underlying mechanism may be involved in oxidative stress and gastrointestinal hormones. PMID- 25537682 TI - Voluntary inhibition of pain avoidance behavior: an fMRI study. AB - Behavioral inhibition has classically been considered to rely upon a neural network centered at the right inferior frontal cortex [rIFC; Aron et al. (8:170 177, 2004; 18:177-185, 2014)]. However, the vast majority of inhibition studies have entailed exogenous stop signals instructing participants to withhold responding. More recent work has begun to examine the neural underpinnings of endogenous inhibition, revealing a distinct cortical basis in the dorsal fronto median cortex [dFMC; Brass and Haggard (27:9141-9145, 2007); Kuhn et al. (30:2834 3843, 2009)]. Yet, contrary to everyday experiences of voluntary behavioral suppression, the paradigms employed to investigate action inhibition have thus far been somewhat artificial, and involve little persuasive motivation to act. Accordingly, the present fMRI study seeks to compare and contrast intentional with instructed inhibition in a novel pain paradigm that recruits 'hot' incentive response systems. Participants received increasing thermal stimulation to their inner wrists, and were required to occasionally withhold their natural impulse to withdraw from the compelling pain sensation at peak temperature, in both instructed and free-choice conditions. Consistent with previous research, we observed inhibition-related activity in the dFMC and the rIFC. However, these regions displayed equivalent activation levels for both inhibition types. These data extend previous research by demonstrating that under ecologically valid conditions with a strong motivation to act, both stopping networks operate in concert to enable suppression of unwanted behavior. PMID- 25537683 TI - An intentional vocalization draws others' attention: a playback experiment with wild chimpanzees. AB - A vital step in the evolution of language is likely to have been when signalers explicitly intended to direct recipients' attention to external objects with the use of referential signals. Although animal signals can direct the attention of others to external events, such as in monkey predator alarm calls, there is little evidence that this is the result of an intention to inform the recipient. Two recent studies, however, indicate that the production of chimpanzee quiet alarm calls, given to snakes, complies with some standard behavioral markers of intentional signaling, such as gaze alternation. But it is currently unknown whether the calls alone direct receivers' attention to the threat. To address this, we carried out a playback experiment with free-ranging chimpanzees in Budongo Forest, Uganda, using a within-subjects design. From a hidden speaker, we broadcast either quiet alarm 'hoos' ('alert hoos') or acoustically distinguishable hoos produced while resting ('rest hoos') and found a significant increase in search behavior after 'alert' compared with 'rest' hoos, with subjects monitoring either the call provider or the area near the call provider. In sum, chimpanzee 'alert hoos' represent a plausible case of an intentionally produced animal vocalization (other studies) that refers recipients to signalers and/or to an external event (this study). PMID- 25537677 TI - Role of Corticotropin-releasing Factor in Gastrointestinal Permeability. AB - The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal microflora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and supersystems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions. PMID- 25537684 TI - 'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models. AB - BACKGROUND AND PURPOSE: Non-competitive drugs that confer allosteric modulation of orthosteric ligand binding are of increasing interest as therapeutic agents. Sought-after advantages include a ceiling level to drug effect and greater receptor-subtype selectivity. It is thus important to determine the mode of interaction of newly identified receptor ligands early in the drug discovery process and binding studies with labelled orthosteric ligands constitute a traditional approach for this. According to the general allosteric ternary complex model, allosteric ligands that exhibit negative cooperativity may generate distinctive 'competition' curves: they will not reach baseline levels and their nadir will increase in par with the orthosteric ligand concentration. This behaviour is often considered a key hallmark of allosteric interactions. EXPERIMENTAL APPROACH: The present study is based on differential equation-based simulations. KEY RESULTS: The differential equation-based simulations revealed that the same 'competition binding' pattern was also obtained when a monovalent ligand binds to one of the target sites of a heterobivalent ligand, even if this process is exempt of allosteric interactions. This pattern was not strictly reciprocal when the binding of each of the ligands was recorded. The prominence of this phenomenon may vary from one heterobivalent ligand to another and we suggest that this phenomenon may take place with ligands that have been proposed to bind according to 'two-domain' and 'charniere' models. CONCLUSIONS AND IMPLICATIONS: The present findings indicate a familiar experimental situation where bivalency may give rise to observations that could inadvertently be interpreted as allosteric binding. Yet, both mechanisms could be differentiated based on alternative experiments and structural considerations. PMID- 25537685 TI - Comparison of objective and subjective refractive surgery screening parameters between regular and high-resolution Scheimpflug imaging devices. AB - PURPOSE: To compare objective and subjective metrics from regular and high resolution Scheimpflug devices (Pentacam) to determine their equivalence and interchangeability for refractive surgery screening. SETTING: Emory Vision at Emory University, Atlanta, Georgia, USA. DESIGN: Retrospective comparative case series. METHODS: Eyes of consecutive screened refractive surgery patients were evaluated with high-resolution and regular Scheimpflug devices. Objective parameters evaluated included keratometry (K) values, central corneal thickness (CCT), and device-generated keratoconus screening indices. Masked expert reviewers subjectively graded images as normal, suspicious, or abnormal. RESULTS: One hundred eyes of 50 patients were evaluated. The mean K values were not significantly different (anterior K: high resolution 1.21 diopters [D] +/- 1.13 (SD) versus regular 1.15 +/- 1.16 D, P = 0.73; posterior K: 0.34 +/- 0.23 D versus regular 0.35 +/- 0.23 D, P = .67). The mean CCT was significantly thinner in the high-resolution group (514.7 +/- 26.6 MUm versus 527.6 +/- 27.6 MUm (P < .0001) with limits of agreement of -12.9 to +17.5 MUm. Most keratoconus screening indices were more suspicious with the high-resolution device than with the regular device except the indices of height asymmetry and height deviation. Subjectively, 60% of cases received the same score, high resolution was more suspicious in 28% of cases, and regular was more suspicious in 12% of cases; there was only slight subjective agreement between technologies (kappa = 0.26 to 0.31). CONCLUSIONS: Regular and high-resolution Scheimpflug imaging devices generated different objective values and significantly different subjective interpretations with poor inter-reviewer agreement. The high-resolution device provided a more conservative overall output. For refractive surgical screening, the 2 devices are not interchangeable. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 25537686 TI - Management of long-standing partially torn and flipped laser in situ keratomileusis flaps. AB - We describe 2 cases of traumatized and torn laser in situ keratomileusis (LASIK) flaps, partially flipped anteriorly or posteriorly, fixed for 8 months or 4 months, and accompanied by epithelial ingrowth. The 2 patients had had uneventful bilateral LASIK 6 years and 1 year before the trauma. In Case 1, the anteriorly flipped flap was removed with transepithelial phototherapeutic keratectomy. Next, mitomycin-C 0.04% was applied for 30 seconds. In Case 2, the portion of the flap that was flipped posteriorly and buried under the remaining intact LASIK flap was restored to its original normal position and epithelial ingrowth was removed mechanically with a microcurette. Irrigation with 20% ethanol was performed to inhibit the recurrence of interfacial epithelial ingrowth. The stretched amniotic membrane overlay over the cornea and sclera was sutured tightly to the episclera as the biologic pressure patch for the inhibition of epithelial re-ingrowth. Good visual acuity was restored in both cases. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25537687 TI - Clostridium difficile infection in Thailand. AB - Clostridium difficile is the aetiological agent in ca. 20% of cases of antimicrobial-associated diarrhoea in hospitalised adults. Diseases caused by this organism range from mild diarrhoea to occasional fatal pseudomembranous colitis. The epidemiology of C. difficile infection (CDI) has changed notably in the past decade, following epidemics in the early 2000s of PCR ribotype (RT) 027 infection in North America and Europe, where there was an increase in disease severity and mortality. Another major event has been the emergence of RT 078, initially as the predominant ribotype in production animals in the USA and Europe, and then in humans in Europe. Although there have been numerous investigations of the epidemiology of CDI in North America and Europe, limited studies have been undertaken elsewhere, particularly in Asia. Antimicrobial exposure remains the major risk factor for CDI. Given the high prevalence of indiscriminate and inappropriate use of antimicrobials in Asia, it is conceivable that CDI is relatively common among humans and animals. This review describes the level of knowledge in Thailand regarding C. difficile detection methods, prevalence and antimicrobial susceptibility profile, as well as the clinical features of, treatment options for and outcomes of the disease. In addition, antimicrobial usage in livestock in Thailand will be reviewed. A literature search yielded 18 studies mentioning C. difficile in Thailand, a greater number than from any other Asian country. It is possible that the situation in Thailand in relation to CDI may mirror the situation in other developing Asians countries. PMID- 25537688 TI - Clinical applications of naturally derived biopolymer-based scaffolds for regenerative medicine. AB - Naturally derived polymeric biomaterials, such as collagens, silks, elastins, alginates, and fibrins are utilized in tissue engineering due to their biocompatibility, bioactivity, and tunable mechanical and degradation kinetics. The use of these natural biopolymers in biomedical applications is advantageous because they do not release cytotoxic degradation products, are often processed using environmentally-friendly aqueous-based methods, and their degradation rates within biological systems can be manipulated by modifying the starting formulation or processing conditions. For these reasons, many recent in vivo investigations and FDA-approval of new biomaterials for clinical use have utilized natural biopolymers as matrices for cell delivery and as scaffolds for cell-free support of native tissues. This review highlights biopolymer-based scaffolds used in clinical applications for the regeneration and repair of native tissues, with a focus on bone, skeletal muscle, peripheral nerve, cardiac muscle, and cornea substitutes. PMID- 25537689 TI - A comparison of human versus virtual interruptions. AB - Although a wealth of research has examined the effects of virtual interruptions, human-initiated interruptions are common in many work settings. An experiment compared performance on a primary data-entry task during human-initiated (human) versus computer-initiated (virtual) interruptions. Participants completed blocks of trials that featured either an interruption from a computer or an interruption from a human experimenter. The timing of the onset of the interruptions was also varied across trials. Human interruptions resulted in much shorter interruption lags. No significant differences were observed for the number of correct responses on the primary task for human versus virtual interruptions, but interruptions that occurred later in the task sequence resulted in fewer mistakes. The social aspect of human interruptions may have attenuated interruption lags in that condition, and it is possible that virtual interruptions may permit people greater temporal flexibility in managing their engagement with interruptions. PMID- 25537690 TI - Erratum to: surgery for thoracic aortic disease in Japan: evolving strategies toward the growing enemies. PMID- 25537691 TI - Plural large floating thrombi in the ascending aorta. AB - Floating thrombi in the ascending aorta are a very rare finding in non aneurysmal, mildly atherosclerotic or normal aortas. We report a case of floating thrombi in a 66-year-old man who was admitted to the hospital with acute chest pain and dyspnea. Enhanced computed tomography showed two large floating thrombi in the ascending aorta, type B aortic dissection, deep venous thrombosis, and pulmonary embolism. A temporary inferior vena cava filter was inserted and the subject underwent an emergency surgical intervention to remove both masses. His postoperative course was uneventful; the etiology of the thrombi is unknown. Lifelong anticoagulation therapy was started and the subject has been stable without recurrence for the last 2 years. PMID- 25537692 TI - The origin of the absorption spectra of porphyrin N- and dithiaporphyrin S-oxides in their neutral and protonated states. AB - meso-Tetraphenylporphyrin N-oxide (1) and meso-tetraphenyl-21,23-dithiaporphyrin S-oxide (3) possess optical spectra that are distinctly different from their parent porphyrins, meso-tetraphenylporphyrin (2) and meso-tetraphenyl-21,23 dithiaporphyrin (4), respectively. The hyperporphyrin spectra were reproduced and classified using TD CAM-B3LYP and SCS-CC2 computational methods. Calculations revealed the electronic and conformational influences of the N- and S-oxide functionalities. While the N-oxide under acidic conditions forms a dication with a UV-vis spectrum that is nearly indistinguishable from that of the diprotonated parent porphyrin, the diprotonated S-oxide possesses a much different UV-vis spectrum from diprotonated parent dithiaporphyrin. A computational study of the protonation events revealed the site and degree of protonation and rationalized the regular and hyperporphyrin UV-vis spectra of the neutral and protonated species, respectively. The study illuminates the electronic effects of the relatively rare modification of the inner porphyrin heteroatoms. It also illustrates a case in which TD CAM-B3LYP reaches its limits to make reliable predictions about the optical properties of a porphyrinoid, making the use of higher methods essential. PMID- 25537693 TI - It is not as simple as boys versus girls: the role of sex differences in pain across the lifespan. PMID- 25537694 TI - Managing chronic pain in survivors of torture. AB - All generalist and specialist clinicians are likely to encounter torture survivors among refugees and asylum seekers. A minority of people survive torture and a smaller minority reach a developed country; those who do tend to be the more resilient and resourceful. They have many health, social and welfare problems; persistent pain in the musculoskeletal system is one of the most common. There is little specific evidence on pain in survivors of torture; the guidelines on interdisciplinary specialist management are applicable. Most of the literature on refugee survivors of torture has an exclusive focus on psychological disorders, with particularly poor understanding of pain problems. This article summarizes the current status of assessment and treatment of pain problems in the torture survivor. PMID- 25537695 TI - Re-branding cannabis: the next generation of chronic pain medicine? AB - The field of pain medicine is at a crossroads given the epidemic of addiction and overdose deaths from prescription opioids. Cannabis and its active ingredients, cannabinoids, are a much safer therapeutic option. Despite being slowed by legal restrictions and stigma, research continues to show that when used appropriately, cannabis is safe and effective for many forms of chronic pain and other conditions, and has no overdose levels. Current literature indicates many chronic pain patients could be treated with cannabis alone or with lower doses of opioids. To make progress, cannabis needs to be re-branded as a legitimate medicine and rescheduled to a more pharmacologically justifiable class of compounds. This paper discusses the data supporting re-branding and rescheduling of cannabis. PMID- 25537696 TI - Pediatric pain management in palliative care. AB - The management of pain in pediatric palliative care (PPC) is essential. Whilst the field of pain management has developed over the years, much of what is done in PPC is based on anecdotal evidence or adult studies. This review explores recent developments in pain management in PPC, in particular the WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. Key issues discussed include the definition, assessment, pharmacological and integrative management of pain, availability of medications, education and research. Whilst advances have been made, including publication of the guidelines, significant gaps exist in terms of the evidence base, education and access to essential medications and both interdisciplinary and international collaboration are required to meet these gaps. PMID- 25537697 TI - Obstructive sleep apnea in adult patients: considerations for anesthesia and acute pain management. AB - Obstructive sleep apnea (OSA) represents a challenge in the perioperative period for both physicians and the health care system alike. A number of studies have associated OSA with increased risk for postoperative complications. This is of particular concern in the face of this disease remaining vastly underdiagnosed. In this context, current guidelines and established concepts such as the use of continuous positive airway pressure or the level of postoperative monitoring, lack strong scientific evidence. Other interventions such as the use neuraxial/regional anesthesia may however offer added benefit. This review aims to address considerations for physicians in charge of OSA patients in the perioperative setting and to give an outlook for current and future research on this topic. PMID- 25537698 TI - Acute pain service: past, present and future. AB - Post surgical pain is a continuing major medical challenge despite all the advances in understanding acute pain and the development of new modalities of pain management. Since 1985 when the first acute pain service (APS) was started, many organizations initiated APS protocols and guidelines and it became mandatory to have an APS in all major acute care centers. This review focuses on the stages of development of APS and the challenges of postoperative pain management to provide optimal analgesia. Further clinical studies are required to determine best medication regimen for post-operative pain management. PMID- 25537699 TI - Inferior Vena Cava Thrombosis Related to Hypothermia Catheter: Report of 20 Consecutive Cases. AB - BACKGROUND: Temperature management using endovascular catheters is an established therapy in neurointensive care. Nonetheless, several case series have reported a high rate of thrombosis related to the use of endovascular hypothermia catheters. METHODS: As a result of a pulmonary embolism that developed in a patient after removing an inferior vena cava hypothermia catheter, we designed a clinical protocol for managing and removing these devices. First, an invasive cavography was performed before the removal of the catheter. If there was a thrombus, a cava vein filter was inserted through jugular access. After that, the catheter was removed. RESULTS: The venography found inferior vena cava thrombi in 18 of 20 consecutive patients. A concomitant ultrasonography study showed vena cava thrombosis in only three patients. A vena cava filter was inserted in all patients where thrombi were found, without any significant complication. Anticoagulation was started in all patients. No symptomatic pulmonary embolism was diagnosed until the time of discharge. CONCLUSIONS: The frequency of thrombosis related to temperature management catheters is extremely high (90 %). Furthermore, ultrasonography has a very low sensibility to detect cava vein thrombosis (16.7 %). The real meaning of our findings is unknown, but other temperature control systems could be a safer option. More studies are needed to confirm our findings. PMID- 25537700 TI - Introduction. PMID- 25537701 TI - (3) Initial evaluation and diabetes management planning. PMID- 25537702 TI - (4) Foundations of care: education, nutrition, physical activity, smoking cessation, psychosocial care, and immunization. PMID- 25537704 TI - (5) Prevention or delay of type 2 diabetes. PMID- 25537705 TI - (6) Glycemic targets. PMID- 25537706 TI - Standards of medical care in diabetes--2015: summary of revisions. PMID- 25537707 TI - (7) Approaches to glycemic treatment. PMID- 25537708 TI - (8) Cardiovascular disease and risk management. PMID- 25537709 TI - (1) Strategies for improving care. PMID- 25537710 TI - (9) Microvascular complications and foot care. PMID- 25537711 TI - (10) Older adults. PMID- 25537712 TI - (11) Children and adolescents. PMID- 25537713 TI - (12) Management of diabetes in pregnancy. PMID- 25537715 TI - (13) Diabetes care in the hospital, nursing home, and skilled nursing facility. PMID- 25537716 TI - (14) Diabetes advocacy. PMID- 25537714 TI - (2) Classification and diagnosis of diabetes. PMID- 25537719 TI - A Substrate Fed-Batch Biphasic Catalysis Process for the Production of Natural Crosslinking Agent Genipin with Fusarium solani ACCC 36223. AB - The natural crosslinking agent genipin has been applied widely in biomedicines and foods nowadays. Because of the special hemiacetal ring structure in its molecule, it can only be prepared by hydrolysis of geniposide according to biocatalysis. In this research, strategies including aqueous-organic biphasic catalysis and substrate fed-batch mode were adopted to improve the biocatalysis process of genipin. A 10 L ethyl acetate-aqueous biphasic system with geniposide fed-batch led to a satisfying genipin yield. With Fusarium solani ACCC 36223, 15.7 g/l genipin in the ethyl acetate phase was obtained, corresponding to space time yields of 0.654 g l(-1) h(-1). PMID- 25537720 TI - Analysis of Heme Biosynthetic Pathways in a Recombinant Escherichia coli. AB - Bacterial heme was produced from a genetic-engineered Escherichia coli via the porphyrin pathway and it was useful as an iron resource for animal feed. The amount of the E. colisynthesized heme, however, was only few milligrams in a culture broth and it was not enough for industrial applications. To analyze heme biosynthetic pathways, an engineered E. coli artificially overexpressing ALA synthase (hemA from Rhodobacter sphaeroides) and pantothenate kinase (coaA gene from self geneome) was constructed as a bacterial heme-producing strain, and both the transcription levels of pathway genes and the intermediates concentrations were determined from batch and continuous cultures. Transcription levels of the pathway genes were not significantly changed among the tested conditions. Intracellular intermediate concentrations indicated that aminolevulinic acid (ALA) and coenzyme A (CoA) were enhanced by the hemA-coaA co-expression. Intracellular coproporphyrinogen I and protoporphyrin IX accumulation suggested that the bottleneck steps in the heme biosynthetic pathway could be the spontaneous conversion of HMB to coproporphyrinogen I and the limited conversion of protoporphyrin IX to heme, respectively. A strategy to increase the conversion of ALA to heme is discussed based on the results. PMID- 25537721 TI - Antimicrobial Peptides (AMPs) with Dual Mechanisms: Membrane Disruption and Apoptosis. AB - Antimicrobial peptides (AMPs) are one of the critical components in host innate immune responses to imbalanced and invading microbial pathogens. Although the antimicrobial activity and mechanism of action have been thoroughly investigated for decades, the exact biological properties of AMPs are still elusive. Most AMPs generally exert the antimicrobial effect by targeting the microbial membrane, such as barrel stave, toroidal, and carpet mechanisms. Thus, the mode of action in model membranes and the discrimination of AMPs to discrepant lipid compositions between mammalian cells and microbial pathogens (cell selectivity) have been studied intensively. However, the latest reports suggest that not only AMPs recently isolated but also well-known membrane-disruptive AMPs play a role in intracellular killing, such as apoptosis induction. In this mini-review, we will review some representative AMPs and their antimicrobial mechanisms and provide new insights into the dual mechanism of AMPs. PMID- 25537722 TI - DnaJ of Streptococcus suis Type 2 Contributes to Cell Adhesion and Thermotolerance. AB - To examine if the molecular chaperone DnaK operon proteins of Streptococcus suis type 2 (SS2) are involved in adhesion to host cells, the abundance values of these proteins from the surface of two SS2 strains of different adhesion capability were compared. Their roles in growth and adhesion to human laryngeal epithelial cell line HEp-2 cells were investigated on SS2 strain HA9801 and its mutants with DnaK operon genes partially knocked-out (PKO mutant) under heat stress. The major difference was that DnaJ was more abundant in strain HA9801 than in strain JX0811. Pretreatment of the bacteria with hyperimmune sera to DnaJ, but not with those to other proteins, could significantly reduce SS2 adhesion to HEp-2 cells. PKO of dnaJ g ene resulted in decreased SS2 growth at 37 degrees C and 42 degrees C, and reduced its adhesion to HEp-2 cells. The wild type strain stressed at 42 degrees C had increased expression of DnaJ on its surface and elevated adhesion to HEp-2 cells, which was also inhibitable by DnaJ specific antiserum. These results indicate that the DnaJ of S. suis type 2 is important not only for thermotolerance but also for adhesion to host cells. Because DnaJ expression is increased upon temperature upshift with increased exposure on the bacterial surface, the febrile conditions of the cases with systemic infections might help facilitate bacterial adhesion to host cells. DnaJ could be one of the potential candidates as a subunit vaccine because of its good immunogenicity. PMID- 25537723 TI - Fungal Growth and Manganese Peroxidase Production in a Deep Tray Solid-State Bioreactor, and In Vitro Decolorization of Poly R-478 by MnP. AB - The growth of Irpex lacteus F17 and manganese peroxidase (MnP) production in a selfdesigned tray bioreactor, operating in solid-state conditions at a laboratory scale, were studied. The bioreactor was divided into three layers by three perforated trays. Agroindustrial residues were used both as the carrier of bound mycelia and as a nutrient medium for the growth of I. lacteus F17. The maximum biomass production in the bioreactor was detected at 60 h of fermentation, which was consistent with the CO2 releasing rate by the fungus. During the stationary phase of fungal growth, the maximum MnP activity was observed, reaching 950 U/l at 84 h. Scanning electron microscopy images clearly showed the growth situation of mycelia on the support matrix. Furthermore, the MnP produced by I. lacteus F17 in the bioreactor was isolated and purified, and the internal peptide sequences were also identified with mass spectrometry. The optimal activity of the enzyme was detected at pH 7 and 25 degrees C, with a long half-life time of 9 days. In addition, the MnP exhibited significant stability within a broad pH range of 4-7 and at temperature up to 55 degrees C. Besides this, the MnP showed the ability to decolorize the polymeric model dye Poly R-478 in vitro. PMID- 25537724 TI - Comparison of primary and secondary breast cancers in adolescents and young adults. AB - BACKGROUND: Breast cancer is one of the most common cancers in adolescent and young adult (AYA) patients (ages 15-39) and may develop de novo or in patients previously treated for cancer. This study compares the demographic, tumor, treatment characteristics, and overall survival (OS) of primary versus secondary (SMN) breast cancer in female AYAs. METHODS: All cases of invasive female AYA breast cancer in the 1998-2010 American College of Surgeons National Cancer Database were divided into 2 cohorts according to primary or secondary occurrence. Comparisons using appropriate statistical methods were performed. RESULTS: Of 106,771 patients, 6241 (5.8%) had experienced a prior, histologically distinct malignancy. Breast SMNs were more likely ER-/PR- (OR, 1.24; 95% CI, 1.15 1.34), <1 cm (OR, 1.86; 95% CI, 1.73-1.99) tumors and present at a lower T, N (OR, 1.43; 95% CI, 1.34-1.52), and summary stage but with more distant metastases (OR, 1.42; 95% CI, 1.21-1.67) compared with primary cancers. Adjusted by stage, SMN patients underwent more total mastectomies and received less chemotherapy, radiation, and hormonal therapy. However, SMN patients received definitive surgical treatment almost twice as fast compared with primary cancers (36.12 vs 67.26 days, P < .001). Patients with SMNs had a significantly decreased 3-year OS (79% vs 88.5%, P < .001), with SMN status an independent risk factor for increased mortality (HR, 1.58; 95% CI, 1.41-1.77). CONCLUSIONS: Nonprimary breast cancer in AYAs has different tumor characteristics, presents at a lower stage, and receives less adjuvant therapy than primary cancers. SMN status is an independent risk factor for decreased OS, with an almost 10% decrease at 3 years. Whether the outcome disparity results from previous cancer treatment or differences in biology, environment, or access to care needs further investigation. PMID- 25537725 TI - Development of 4-hexadecyl-4,7-diaza-1,10-decanedithiol (HDD) kit for the preparation of the liver cancer therapeutic agent Re-188-HDD/lipiodol. AB - INTRODUCTION: A lipiodol solution of (188)Re-4-hexadecyl-2,2,9,9-tetramethyl-4,7 diaza-1,10-decanedithiol (HTDD) has been successfully developed for liver cancer therapy; however, its preparation requires a multi-step synthesis and it is characterized by a low labeling yield. METHODS: We synthesized a new compound, 4 hexadecyl-4,7-diaza-1,10-decanedithioacetate (AHDD), without gem dimethyl groups to address these issues. AHDD was formulated into a kit and was labeled with (188)Re. Biodistribution study was performed using normal BALB/c mice. RESULTS: The kit was labeled with (188)Re with a high efficiency (98.8+/-0.2%). After extraction with lipiodol, the overall yield of (188)Re-HDD/lipiodol was as high as 90.2+/-2.6%. A comparative biodistribution study of (188)Re-HTDD and (188)Re HDD was performed in normal mice after intravenous injection. The lungs were identified as the main uptake site due to capillary-blockage. (188)Re HDD/lipiodol showed a significantly higher lung uptake than that of (188)Re HTDD/lipiodol (p<0.05). CONCLUSION: The newly synthesized (188)Re-HDD/lipiodol showed improved radiolabeling yield and biodistribution results compared to (188)Re-HTDD/lipiodol, and may therefore be more suitable for liver cancer therapy. PMID- 25537726 TI - Characterization of (18)F-dipicolylamine (DPA) derivatives in cells infected with influenza virus. AB - OBJECTIVE: Bis(Zn-dipicolylamine (Zn-DPA)) coordination complexes represent a new class of synthetic small molecules that can target anionic phosphatidylserine (PS) in the apoptotic cells with high affinity and specificity. In this study, we labeled Zn-DPA and Cy7-Zn-DPA with different (18)F-prosthetic groups and characterized their uptake in A549 cells infected with influenza A virus from the 2009 pandemic (H1N1pdm). METHODS: DPA was labeled with N-succinimidyl 4-(18)F fluorobenzoate ((18)F-SFB), 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP), 2 (18)F-Fluoroethyl toslyate ((18)F-FET), and (18)F-aluminum (Al(18)F), respectively. Cy7-DPA was labeled with (18)F-SFB and (18)F-NFP only. The tracers were reconstituted with zinc nitrate before use. Apoptosis in A549 cells was induced by infection with the H1N1pdm virus for 48 h. Three MUCi of each tracer was added to each well and incubated at 37 degrees C. The effect of different prosthetic groups, different MOI, and incubation time on percent cellular uptake was studied. Cell internalization and efflux was evaluated within 2h of incubation. The competitive binding assay was performed with increasing concentration (10(-12)-10(-5)M) of Zn-DPA or Cy7-Zn-DPA prior to the addition of either (18)F-FB-Zn-DPA or (18)F-FB-Cy7-Zn-DPA into each well. IC50 values for the two Zn-DPA analogues were estimated by GraphPad Prism 6.0. RESULTS: Among all the four prosthetic groups, the (18)F-SFB method provided the highest conjugation yield for DPA and the highest uptake ratio between the infection cells and the control when both Zn-DPA and Cy7-Zn-DPA were present in the complex. The uptake ratio was similar for (18)F-FB-Zn-DPA and (18)F-FB-Cy7-Zn-DPA. Uptake of (18)F-FB Zn-DPA and (18)F-FB-Cy7-Zn-DPA was proportional to the degree of apoptosis with a plateau at MOI 3. Uptake of (18)F-FB-Cy7-Zn-DPA also increased over incubation time and reached a plateau at 1h, whereas uptake of (18)F-FB-Zn-DPA did not show any significant change over time. Cell internalization studies showed that more than 70% of (18)F-FB-Zn-DPA remained on the cell surface over a time course of 2 hr in the cell media, but over 90% of (18)F-FB-Cy7-Zn-DPA was internalized within 15 min of incubation. IC50 values were estimated to be 1.5+/-0.3 nM and 26.2+/ 5.1 nM for Zn-DPA and Cy7-Zn-DPA, respectively. CONCLUSIONS: (18)F-SFB was the optimal labeling method for Zn-DPA and Cy7-Zn-DPA with respect to radiochemistry and provided complexes with high target-to-background ratios. (18)F-FB-Zn-DPA and (18)F-FB-Cy7-Zn-DPA appeared to have a completely different internalization mechanism, while Zn-DPA showed higher binding affinity than Cy7-Zn-DPA. Based on these favorable characteristics, (18)F-FB-Zn-DPA and (18)F-FB-Cy7-Zn-DPA should be further evaluated as potential imaging agents for viral infection. PMID- 25537727 TI - In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. AB - INTRODUCTION: The translocator protein 18 kDa (TSPO), a biochemical marker of neuroinflammation, is highly expressed in the brain activated microglia and it is also expressed by peripheral inflammatory cells and normal peripheral tissues. Thus, development of radioligands for the TSPO may contribute to further understanding the in vivo TSPO function in central and peripheral inflammatory processes and other pathologies. Here, we report the biodistribution, the specific binding and the radiometabolites of [(18)F]DPA-714, a promising fluorinated PET radiotracer, in normal mice using a microPET/CT scanner. METHODS: The in vivo biodistribution and kinetics of [(18)F]DPA-714 were measured in mice brain and peripheral tissues. Specific binding to TSPO sites was assessed using pharmacological competitive studies by means of saturation experiments performed by i.v. injection of 1mg/kg of unlabeled DPA-714 or 3mg/kg of unlabeled PK11195. A region of interest analysis was performed to generate time-activity curves in the brain, heart, lung, kidney, spleen and liver. Metabolites assay was performed in the plasma and peripheral organs by radio-HPLC. RESULTS: [(18)F]DPA-714 reached high concentration in lung, heart, kidney and spleen, tissues well known to be rich in TSPO sites. [(18)F]DPA-714 kinetics were faster in the lung and slower in the kidney. Pre-injection of unlabeled DPA-714 or PK11195 inhibited about 80% of [(18)F]DPA-714 uptake in the lung and heart (p<0.0005). The percentage of inhibition in the kidney was lower and achieved at later times only with DPA-714 (p<0.05) but not with PK11195. Sixty minutes after radiotracer injection only unmetabolized radioligand was found in the brain, lung, heart and spleen. CONCLUSION: These results suggest that [(18)F]DPA-714 is a suitable PET ligand for imaging in mice brain and peripheral tissues since it binds with high specificity TSPO binding sites and it is almost unchanged at 60 minutes after radiotracer injection in the brain and TSPO-rich regions. PMID- 25537728 TI - DMP1beta, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer. AB - Our recent work has indicated that the DMP1 locus on 7q21, encoding a haplo insufficient tumour suppressor, is hemizygously deleted at a high frequency in breast cancer. The locus encodes DMP1alpha protein, an activator of the p53 pathway leading to cell cycle arrest and senescence, and two other functionally undefined isoforms, DMP1beta and DMP1gamma. In this study, we show that the DMP1 locus is alternatively spliced in ~30% of breast cancer cases with relatively decreased DMP1alpha and increased DMP1beta expression. RNA-seq analyses of a publicly available database showed significantly increased DMP1beta mRNA in 43 55% of human breast cancers, dependent on histological subtypes. Similarly, DMP1beta protein was found to be overexpressed in ~60% of tumours relative to their surrounding normal tissue. Importantly, alteration of DMP1 splicing and DMP1beta overexpression were associated with poor clinical outcomes of the breast cancer patients, indicating that DMP1beta may have a biological function. Indeed, DMP1beta increased proliferation of non-tumourigenic mammary epithelial cells and knockdown of endogenous DMP1 inhibited breast cancer cell growth. To determine DMP1beta's role in vivo, we established MMTV-DMP1beta transgenic mouse lines. DMP1beta overexpression was sufficient to induce mammary gland hyperplasia and multifocal tumour lesions in mice at 7-18 months of age. The tumours formed were adenosquamous carcinomas with evidence of transdifferentiation and keratinized deposits. Overall, we identify alternative splicing as a mechanism utilized by cancer cells to modulate the DMP1 locus through diminishing DMP1alpha tumour suppressor expression, while simultaneously up-regulating the tumour-promoting DMP1beta isoform. PMID- 25537730 TI - Essential dynamics for the study of microstructures in liquids. AB - Essential Dynamics (ED) is a powerful tool for analyzing molecular dynamics (MD) simulations and it is widely adopted for conformational analysis of large molecular systems such as, for example, proteins and nucleic acids. In this study, we extend the use of ED to the study of clusters of arbitrary size constituted by weakly interacting particles, for example, atomic clusters and supramolecular systems. The key feature of the method we present is the identification of the relevant atomic-molecular clusters to be analyzed by ED for extracting the information of interest. The application of this computational approach allows a straightforward and unbiased conformational study of the local microstructures in liquids, as emerged from semiclassical MD simulations. The good performance of the method is demonstrated by calculating typical observables of liquid water, that is, NMR, NEXAFS O1s, and IR spectra, known to be rather sensitive both to the presence and to the conformational features of hydrogen bonded clusters. PMID- 25537729 TI - Correlates of HIV testing among African American and Latino church congregants: the role of HIV stigmatizing attitudes and discussions about HIV. AB - Faith-based organizations can be key settings in which to reach African Americans and Latinos for HIV prevention, but little is known regarding factors that predict congregants' HIV testing behaviors. We examined the extent to which sociodemographic factors, HIV-related cues to action (e.g., knowing someone who is HIV-positive), and the social climate surrounding HIV (stigma toward a hypothetical HIV-positive congregant, HIV-related discussions at church about abstinence, condoms, and testing) were associated with willingness to be tested in church and with ever having been tested among 1211 African American and Latino congregants. Multivariate analyses indicated that congregants were more open to church-based testing if they were younger and had discussed condoms at church. They were less open if they expressed stigmatizing attitudes toward a hypothetical congregant. Foreign-born Latinos with low English proficiency were more willing to be tested at church than were African Americans. Congregants were more likely to have ever been tested if they were younger, African American, female, or married; if they knew someone who was HIV-positive; and if they had discussed testing and condoms at church. They were less likely if they had discussed abstinence. Open dialogue around HIV may activate congregants to be more receptive to church-based prevention. PMID- 25537731 TI - Evaluation of degradation in DNA from males with a quantitative gender typing, endpoint PCR multiplex. AB - Evidentiary samples submitted to a forensic DNA laboratory occasionally yield DNA that is degraded. Samples of intact chromosomal DNA (both nuclear and mitochondrial) were subjected to a heating protocol to induce DNA degradation. The DNAs were then analyzed using a multiplex PCR assay that amplifies targets of low and high molecular weight on the X/Y and mitochondrial chromosomes. If degradation is random, the amplification of larger DNA targets should be more adversely affected by degradation than smaller targets. In nuclear and mitochondrial DNA from a male donor, exhibiting degradation, DNA quantity estimates based upon higher molecular weight amplicons (HMW) are significantly lower than estimates made using low molecular weight (LMW) Q-TAT amplicons. DNA degradation estimated using this approach correlated well with actual fluorescence associated with HMW and LMW STR alleles amplified from the same genomic DNA templates. Q-TAT is thus useful not only as a quantitation tool, but also as an indicator of template degradation. PMID- 25537732 TI - Acute thrombosis during left main stenting using tap technique in a patient presenting with non-ST-segment elevation acute coronary syndrome. AB - This case reports the sudden development of large burden of thrombi in the left anterior descending coronary artery immediately following distal left main stenting using TAP technique in a middle aged man who presented with non ST segment elevation acute coronary syndrome despite having been administered 7,500 units of unfractionated heparin and being given 325 mg of aspirin and 60 mg of prasugrel prior to the procedure. The thrombi were managed effectively by giving an intra-coronary high bolus dose of tirofiban (25 mcg/kg) without the need for catheter thrombus extraction. Tirofiban intra-venous infusion was maintained for 18 hours, and the patient was discharged in stable condition on the third day. Importantly there is no controlled study on upstream administration of glycoprotein IIb/IIIa inhibitors in addition to the newer more potent anti platelet agents in patients with unprotected distal left main disease presenting with non ST-segment elevation acute coronary syndrome, nor is there any data on safety and efficacy of mandatory usage of injectable anti-platelet agents at the start of a procedure in a catheterization laboratory in such a setting. PMID- 25537733 TI - Controversy between anesthesiologists and obstetricians on the labour ward: the Delphi method is used as a consensus-building technique. AB - PURPOSE: Obstetricians and anesthesiologists may interpret medical evidence differently, which could potentially generate conflict and compromise patient care. We sought to identify the most important controversial topics involving obstetricians and anesthesiologists on the labour ward that had the potential to affect patient outcome. METHODS: We conducted a consensus-building study based on the Delphi technique. A panel of experts comprised of obstetric anesthesiologists and obstetricians responded to a series of four parallel sequential questionnaires interspersed with feedback. The first round consisted of an open questionnaire: Which topics in patient management would rouse a difference of opinion between anesthesiologists and obstetricians that may interfere with patient outcome, and why? The second round sought agreement on the topics, and the third round sought to rank the topics, and their underlying reasons, that scored at least 60% agreement. The final round allowed each discipline insight into the controversies gathered by the other discipline. RESULTS: Ten anesthesiologists and ten obstetricians participated in the study. Anesthesiologists identified twice as many controversial topics as the obstetricians (six vs three, respectively). The obstetricians agreed with all topics identified by the anesthesiologists, but agreed with only five of the 18 (28%) reasons to support them. Anesthesiologists agreed with all topics raised by the obstetricians, but agreed with only three of the six (50%) reasons to support them. CONCLUSIONS: Both the obstetricians and the anesthesiologists identified several controversial topics that may influence clinical practice on the labour ward. This information could serve as the basis to develop educational programs and strategies to improve communication between the two disciplines. PMID- 25537734 TI - Transtracheal ultrasound for verification of endotracheal tube placement: a systematic review and meta-analysis. AB - PURPOSE: Early confirmation of endotracheal tube placement is of paramount importance to prevent hypoxia and its catastrophic consequences. Despite certain limitations, capnography is considered the gold standard to evaluate the proper placement of an endotracheal tube. Ultrasound is a novel tool with some definitive advantages over capnography. It enables a real-time view and can be performed quickly; furthermore, it is independent of pulmonary blood flow and does not require lung ventilation. In this review, we aimed to evaluate the diagnostic accuracy of transtracheal ultrasound in detecting endotracheal intubation. SOURCE: We completed an extensive search of MEDLINE(r), EMBASETM, The Cochrane Library, KoreaMed, LILACS, OpenGrey, and the World Health Organization International Clinical Trials Registry from their inception to September 4, 2014. The studies that met the inclusion criteria were pooled and a meta-analysis was conducted. PRINCIPAL FINDINGS: Eleven studies and 969 intubations were included in the final analysis. Eight studies and 713 intubations were performed in emergency situations and the others were carried out in elective situations. Transtracheal ultrasonography's pooled sensitivity and specificity with 95% confidence intervals (CIs) were 0.98 (95% CI 0.97 to 0.99) and 0.98 (95% CI 0.95 to 0.99), respectively. In emergency scenarios, transtracheal ultrasonography showed an aggregate sensitivity and specificity of 0.98 (95% CI 0.97 to 0.99) and 0.94 (95% CI 0.86 to 0.98), respectively. CONCLUSION: Transtracheal ultrasound is a useful tool to confirm endotracheal intubation with an acceptable degree of sensitivity and specificity. It can be used in emergency situations as a preliminary test before final confirmation by capnography. PMID- 25537735 TI - Interrelationship of preoperative anemia, intraoperative anemia, and red blood cell transfusion as potentially modifiable risk factors for acute kidney injury in cardiac surgery: a historical multicentre cohort study. AB - PURPOSE: Acute kidney injury (AKI) is a potentially serious complication of cardiac surgery. Anemia and red blood cell (RBC) transfusion have individually been identified as potentially modifiable risk factors, but their interrelationship with AKI has not been clearly defined. The purpose of this study was to explore the interrelationship of preoperative anemia, intraoperative anemia, and RBC transfusion on the day of surgery with AKI in cardiac surgery. METHODS: This historical cohort study included 16 hospitals, each contributing data on approximately 100 consecutive patients who underwent cardiac surgery with cardiopulmonary bypass. Acute kidney injury was defined as a > 50% increase in creatinine levels during the first postoperative week. Multivariable regression was used to identify the interrelationship between preoperative anemia (hemoglobin < 130 g.L(-1) in males and < 120 g.L(-1) in females), intraoperative anemia (hemoglobin < 80 g.L(-1) during cardiopulmonary bypass), RBC transfusion on the day of surgery, and their interaction terms, after adjusting for site and baseline AKI risk. RESULTS: Of the 1,444 patients included in the study, 541 (37%) had preoperative anemia, 501 (35%) developed intraoperative anemia, 619 (43%) received RBC transfusions, and 238 (16%) developed AKI. After risk adjustment, an individual with the combination of these three risk factors had a 2.6-fold (95% confidence interval 2.0 to 3.3) increase in the relative risk of AKI over an individual with none of these risk factors. CONCLUSIONS: Preoperative anemia, intraoperative anemia, and RBC transfusion on the day of surgery are interrelated risk factors for AKI after cardiac surgery. Targeting these risk factors may reduce the burden of AKI. PMID- 25537736 TI - A randomized comparison between the i-gelTM and the air-QTM supraglottic airways when used by anesthesiology trainees as conduits for tracheal intubation in children. AB - PURPOSE: Supraglottic airways are commonly used as conduits for fibreoptic bronchoscopy (FOB)-guided intubation in pediatric patients. We hypothesized that anesthesiology trainees with limited prior experience with FOB-guided intubation through a supraglottic airway in children would intubate the trachea faster through the air-QTM supraglottic airway than through the i-gelTM. METHODS: Ninety six children aged one month to six years were randomized to receive either the i gel or air-Q for FOB-guided tracheal intubation by anesthesiology trainees. Time for successful tracheal intubation was the primary endpoint. Secondary endpoints included: time for device insertion, number of attempts for successful device insertion, airway leak pressures, FOB grade of laryngeal view, total number of attempts for tracheal intubation, time for removal of the device after tracheal intubation, and associated complications. RESULTS: The median (interquartile range [IQR]) times to successful tracheal intubation for the air-Q (62.5 [47.9 77] sec) and the i-gel (55.9 [48.5-81.8] sec) were not significantly different (median difference 6.6 sec; 95% confidence interval [CI] -13.3 to 8.7; P = 0.53). The median (IQR) time to insertion for the air-Q (16.7 [14.4-20.0] sec) was shorter than for the i-gel (19.6 [16.7-23.0] sec) (median difference 2.9 sec; 95% CI 0.8 to 4.7; P = 0.005). There were no differences between devices with respect to airway leak pressures, success rates, and time to removal. Compared with the air-Q, the i-gel was associated with more problems during device removal after tracheal intubation, including breakage of the tracheal tube pilot balloon (n = 0 vs n = 13, respectively; P < 0.001), inadvertent extubation (n = 1 vs n = 5, respectively; P < 0.001), and difficulty controlling the tracheal tube (n = 0 vs n = 21, respectively; P < 0.001). CONCLUSIONS: Contrary to our hypothesis, both the air-Q and i-gel supraglottic airways served as effective conduits for FOB guided tracheal intubation in children when performed by trainees with limited prior experience. The i-gel, however, was associated with more problems during device removal following tracheal intubation. This study was registered at http://clinicaltrials.gov/show/NCT02189590 . PMID- 25537737 TI - Sensitivity and specificity of the animal fluency test for predicting postoperative delirium. AB - BACKGROUND: Preoperative cognitive impairment is a major risk factor for postoperative delirium. We therefore investigated the prognostic significance and feasibility of administering a brief cognitive screen before surgery. METHODS: Patients > 65 yr of age undergoing hip, knee, or spine surgery were enrolled. A 60-sec cognitive screen, the animal fluency test (AFT), was administered preoperatively. Postoperative delirium was measured using a chart-based tool previously validated using criteria from the Confusion Assessment Method. RESULTS: Of the 362 patients satisfying the inclusion/exclusion criteria, 199 (55%) underwent the AFT. Among them, 57 patients (29%) had an AFT score < 15, and 38 patients (19%, 95% confidence interval [CI]: 14 to 25%) developed postoperative delirium as measured by chart review. Patients with scores of < 15 were more likely to develop postoperative delirium than those who scored >= 15 (54% vs 5%, P < 0.01). A multiple logistic regression, with postoperative delirium as the dependent variable, identified an AFT score of < 15 (odds ratio 20.1, 95% CI: 7.9 to 51.4) and high American Society of Anesthesiologists classification (odds ratio 3.5, 95% CI: 1.3 to 9.2) as independent predictors. CONCLUSIONS: The AFT is a potentially useful brief cognitive screen for identifying patients at risk of developing postoperative delirium. Limited participation by eligible participants in this study, however, raises questions about how useful and feasible systematic administration of the test is. Large studies using prospective measurement of postoperative delirium are indicated to validate our results. PMID- 25537739 TI - Effects of sport expertise on representational momentum during timing control. AB - Sports involving fast visual perception require players to compensate for delays in neural processing of visual information. Memory for the final position of a moving object is distorted forward along its path of motion (i.e., "representational momentum," RM). This cognitive extrapolation of visual perception might compensate for the neural delay in interacting appropriately with a moving object. The present study examined whether experienced batters cognitively extrapolate the location of a fast-moving object and whether this extrapolation is associated with coincident timing control. Nine expert and nine novice baseball players performed a prediction motion task in which a target moved from one end of a straight 400-cm track at a constant velocity. In half of the trials, vision was suddenly occluded when the target reached the 200-cm point (occlusion condition). Participants had to press a button concurrently with the target arrival at the end of the track and verbally report their subjective assessment of the first target-occluded position. Experts showed larger RM magnitude (cognitive extrapolation) than did novices in the occlusion condition. RM magnitude and timing errors were strongly correlated in the fast velocity condition in both experts and novices, whereas in the slow velocity condition, a significant correlation appeared only in experts. This suggests that experts can cognitively extrapolate the location of a moving object according to their anticipation and, as a result, potentially circumvent neural processing delays. This process might be used to control response timing when interacting with moving objects. PMID- 25537740 TI - Does semantic preactivation reduce inattentional blindness? AB - We are susceptible to failures of awareness if a stimulus occurs unexpectedly and our attention is focused elsewhere. Such inattentional blindness is modulated by various parameters, including stimulus attributes, the observer's cognitive resources, and the observer's attentional set regarding the primary task. In three behavioral experiments with a total of 360 participants, we investigated whether mere semantic preactivation of the color of an unexpected object can reduce inattentional blindness. Neither explicitly mentioning the color several times before the occurrence of the unexpected stimulus nor priming the color more implicitly via color-related concepts could significantly reduce the susceptibility to inattentional blindness. Even putting the specific color concept in the main focus of the primary task did not lead to reduced inattentional blindness. Thus, we have shown that the failure to consciously perceive unexpected objects was not moderated by semantic preactivation of the objects' most prominent feature: its color. We suggest that this finding reflects the rather general principle that preactivations that are not motivationally relevant for one's current selection goals do not suffice to make an unexpected object overcome the threshold of awareness. PMID- 25537738 TI - Smoking-associated risks of conventional adenomas and serrated polyps in the colorectum. AB - PURPOSE: Prior studies suggest cigarette smoking is associated with 1.5- to twofold increased risk of colorectal adenomas and possibly a higher risk of serrated polyps. Further clarification of risk differences between adenomas and serrated polyps is needed with regard to co-occurrence and polyp location. METHODS: We conducted a combined analysis of conventional adenoma and serrated polyp occurrence using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. All participants had >=1 adenomas removed at baseline and were followed for up to 4 years. Smoking habits and other lifestyle factors were collected at baseline using questionnaires. We used generalized linear regression to estimate risk ratios and 95 % confidence intervals. RESULTS: Smokers were at slightly increased risk of adenomas compared to never smokers [current: RR 1.29 (95 % CI 1.11-1.49) and former: RR 1.18 (1.05 1.32)]. Smoking was associated with greater risk of serrated polyps [current: RR 2.01 (1.66-2.44); former: RR 1.42 (1.20-1.68)], particularly in the left colorectum. Associations between current smoking and occurrence of serrated polyps only [RR 2.33 (1.76-3.07)] and both adenomas and serrated polyps [RR 2.27 (1.68-3.06)] were more pronounced than for adenomas only [RR 1.31 (1.08-1.58)]. Results were similar for other smoking variables and did not differ by gender or for advanced adenomas. CONCLUSIONS: Cigarette smoking has only a weak association with adenomas, but is associated with a significantly increased risk of serrated polyps, particularly in the left colorectum. Since a minority of left-sided serrated polyps is thought to have malignant potential, the role of smoking in initiation phases of carcinogenesis is uncertain. PMID- 25537741 TI - Parathyroid carcinoma presenting with pathologic fracture: case report and review of the literature. AB - BACKGROUND: Parathyroid carcinoma is a rare neoplasm representing <1% of primary hyperparathyroidism cases. It is often not diagnosed until surgical exploration as a preoperative diagnosis is often not possible. Thus, preoperative staging for most patients is not feasible and this may compromise the treatment strategy. METHODS AND RESULTS: We report a case of a 29-year-old man presenting with avulsion fracture of the right elbow after a trivial fall. Neck exploration revealed an enlarged left lobe focally adherent to the larynx and trachea. Final pathology revealed parathyroid carcinoma with focally positive margin at the site of tracheal invasion. CONCLUSION: Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. The etiology of parathyroid carcinoma is usually obscured, and the initial operation offers the best chance for cure. PMID- 25537743 TI - Sex differences in renal and metabolic responses to a high-fructose diet in mice. AB - High fructose intake has been associated with increased incidences of renal disease and hypertension, among other pathologies. Most fructose is cleared by the portal system and metabolized in the liver; however, systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high-fructose diet in mice. Two-month-old male and female C57BL6/129/SV mice (n = 6 mice per sex per treatment) were randomized to receive control or high-fructose (65% by weight) diets as pelleted chow ad libitum for 3 mo. Fructose feeding did not significantly affect body weight but led to a 19% and 10% increase in kidney weight in male and female mice, respectively. In male mice, fructose increased the expression (~50%) of renal cortical proteins involved in metabolism, including glucose transporter 5 (facilitative fructose transporter), ketohexokinase, and the insulin receptor (beta-subunit). Female mice had lower basal levels of glucose transporter 5, which were unresponsive to fructose. However, female mice had increased urine volume and plasma K(+) and decreased plasma Na(+) with fructose, whereas male mice were less affected. Likewise, female mice showed a two- to threefold reduction in the expression Na(+)-K(+)-2Cl(-) cotransporter 2 in the thick ascending limb and aquaporin-2 in the collecting duct with fructose relative to female control mice, whereas male mice had no change. Overall, our results support greater proximal metabolism of fructose in male animals and greater distal tubule/collecting duct (electrolyte homeostasis) alterations in female animals. These sex differences may be important determinants of the specific nature of pathologies that develop in association with high fructose consumption. PMID- 25537742 TI - Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors. AB - Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR)4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-alpha, transforming growth factor (TGF)-beta1, and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-alpha and TGF beta1 levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4(+) immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO induced fibrosis. There was also reduced total kidney TGF-beta1, which correlated with reduced Smad activation and alpha-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-beta1 and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis. PMID- 25537746 TI - [Oswald Schwarz: a pioneer in psychosomatic urology and sexual medicine]. AB - Oswald Schwarz, a urologist from Vienna, was a scholar of Anton Ritter von Frisch and Hans Rubritius. As a physician during World War I, he was confronted with numerous bullet wounds to the spinal cord. In 1919, he completed his professorial thesis"Bladder dysfunction as a result of bullet wounds to the spinal cord". Oswald Schwarz was known as a committed surgeon. As an urologist he also treated patients with sexual dysfunction. Besides his practical and scientific urology related work, he was also interested in psychology and philosophy. He held lectures on both subjects earning himself the nickname, the Urosoph. In the 1920s, Oswald Schwarz belonged to the inner circle of Alfred Adler, the founder of Individual Psychology, and was editor of the first psychosomatic textbook published in German, "Psychological origin and psychotherapy of physical symptoms" (1925). In addition, Schwarz wrote numerous articles and several books on sexual medicine. He also made many valuable contributions to the development of medical anthropology. Altogether, his work includes over 130 publications. Faced with the rise of fascism and National Socialism in Europe, Oswald Schwarz, who was of Jewish origin, emigrated to England in 1934. There he died in 1949. Unfortunately his scientific work has largely been forgotten. The aim of the following article is to remind us of his important contributions to the field. PMID- 25537744 TI - Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in Pkd2. AB - Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-beta and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-beta, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney. PMID- 25537745 TI - Effect of prenatal programming and postnatal rearing on glomerular filtration rate in adult rats. AB - The present study examined whether a prenatal low-protein diet programs a decrease in glomerular filtration rate (GFR) and an increase in systolic blood pressure (BP). In addition, we examined whether altering the postnatal nutritional environment of nursing neonatal rats affected GFR and BP when rats were studied as adults. Pregnant rats were fed a normal (20%) protein diet or a low-protein diet (6%) during the last half of pregnancy until birth, when rats were fed a 20% protein diet. Mature adult rats from the prenatal low-protein group had systolic hypertension and a GFR of 0.38 +/- 0.03 versus 0.57 +/- 0.05 ml.min(-1).100 g body wt(-1) in the 20% group (P < 0.01). In cross-fostering experiments, mothers continued on the same prenatal diet until weaning. Prenatal 6% protein rats cross-fostered to a 20% mother on day 1 of life had a GFR of 0.53 +/- 0.05 ml.min(-1).100 g body wt(-1), which was not different than the 20% group cross-fostered to a different 20% mother (0.45 +/- 0.04 ml.min(-1).100 g body wt( 1)). BP in the 6% to 20% group was comparable with the 20% to 20% group. Offspring of rats fed either 20% or 6% protein diets during pregnancy and cross fostered to a 6% mother had elevated BP but a comparable GFR normalized to body weight as the 20% to 20% control group. Thus, a prenatal low-protein diet causes hypertension and a reduction in GFR in mature adult offspring, which can be modified by postnatal rearing. PMID- 25537747 TI - [Urotechnology: a new interdisciplinary platform for promoting and managing of technical innovations in urology]. AB - The innovative power in medical engineering and technology development requires a close cooperation between universities and non-university research institutions and a collaboration with industrial partners. German knowledge in the fields of video and micro-optics, microsystem technology and of informational technology and software applications seem to be highly competitive at international level. Germany's previous leadership in the development of technical equipment will be challenged by today's requirements and difficulties in medical engineering. Research and expenses demands for the development of novel medical instruments, products and applications will increase continuously. Transparency and coordinated collaboration between universities and industrial partners will contribute to a substantial improvement in surgical therapy. Medical technology of the future, including urotechnology, requires professional structures and coordination and will have to be based on evidence. PMID- 25537748 TI - Anthropogenic impacts on meiobenthic Ostracoda (Crustacea) in the moderately polluted Kasado Bay, Seto Inland Sea, Japan, over the past 70 years. AB - Two sediment cores were obtained from Kasado Bay, a moderate-polluted enclosed bay in Japan, to examine anthropogenic impacts on Ostracoda over the past ca. 70 years. We analyzed ostracode abundance and diversity, grain size, and CHN, and used (210)Pb and (137)Cs as the dating method. The present study showed that cross-plot comparisons of ostracode abundance and each environmental factor, based on sediment core data, could be used to identify ostracode species as indicators for anthropogenic influences. Ostracode abundance reflected mainly the changes that had occurred in total organic carbon content in sediments related to eutrophication, but heavy metal concentration did not directly influence several ostracode abundance in the bay. Environmental deterioration because of eutrophication started in the 1960s. The regulations regarding the chemical oxygen demand in waters introduced in the 1980s probably influence ostracode abundance for certain species in this period. Currently, Kasado Bay is not experiencing severe degradation. PMID- 25537749 TI - Weak acid extractable metals in Bramble Bay, Queensland, Australia: temporal behaviour, enrichment and source apportionment. AB - Sediment samples were taken from six sampling sites in Bramble Bay, Queensland, Australia between February and November in 2012. They were analysed for a range of heavy metals including Al, Fe, Mn, Ti, Ce, Th, U, V, Cr, Co, Ni, Cu, Zn, As, Cd, Sb, Te, Hg, Tl and Pb. Fraction analysis, Enrichment Factors and Principal Component Analysis-Absolute Principal Component Scores (PCA-APCS) were carried out in order to assess metal pollution, potential bioavailability and source apportionment. Cr and Ni exceeded the Australian Interim Sediment Quality Guidelines at some sampling sites, while Hg was found to be the most enriched metal. Fraction analysis identified increased weak acid soluble Hg and Cd during the sampling period. Source apportionment via PCA-APCS found four sources of metals pollution, namely, marine sediments, shipping, antifouling coatings and a mixed source. These sources need to be considered in any metal pollution control measure within Bramble Bay. PMID- 25537750 TI - Primary mediastinal lymphoma: diagnosis and treatment options. AB - Primary mediastinal large B-cell lymphoma (PMBCL) is a unique B-cell lymphoma variant that arises from a putative thymic medulla B cell. It constitutes 2-4% of non-Hodgkin lymphomas and occurs most frequently in young females. PMBCL is characterized by a diffuse proliferation of medium-to-large B cells associated with sclerosis. Molecular analysis shows that PMBCL is a distinct entity compared to other types of diffuse large B-cell lymphomas. PMBCL is characterized by a locally invasive anterior mediastinal bulky mass. The combination of rituximab with CHOP/CHOP-like regimens followed by mediastinal radiation therapy (RT) is associated with a 5-year progression-free survival of 75-85%. However, the role of consolidation RT still remains uncertain. More intensive regimens, such as DA EPOCH-R without mediastinal RT, have shown very promising results. The conclusive role of PET-CT scan requires prospective studies and there is hope that this may allow to de-escalate RT and accordingly yield reliable prognostic information. PMID- 25537751 TI - Co-Prescribing of Potentially Interacting Drugs during Warfarin Therapy - A Population-Based Register Study. AB - We analysed the occurrence of co-prescribing of potentially interacting drugs during warfarin therapy in the community-dwelling population of Finland. We identified drugs having interaction potential with warfarin using the Swedish Finnish INteraction X-referencing drug-drug interaction database (SFINX) and obtained data on drug purchases from the nationwide Prescription Register. We defined warfarin users as persons purchasing warfarin in 2010 (n = 148,536) and followed them from their first prescription in 2010 until the end of the calendar year. Co-prescribing was defined as at least 1-day overlap between warfarin and interacting drug episodes. In addition, we identified persons who initiated warfarin therapy between 1 January 2007 and 30 September 2010 (n = 110,299) and followed these incident users for a 3-month period since warfarin initiation. Overall, 74.4% of warfarin users were co-prescribed interacting drugs. Co prescribing covered 46.4% of the total person-years of warfarin exposure. Interacting drugs that should be avoided with warfarin were co-prescribed for 13.4% of warfarin users. The majority of the co-prescriptions were for drugs that are not contraindicated during warfarin therapy but require special consideration. Among incident users, 57.1% purchased potentially interacting drugs during the 3-month period after initiation, while 9.0% purchased interacting drugs that should be avoided with warfarin. To conclude, the occurrence of co-prescribing of potentially interacting drugs was high during warfarin therapy. Our findings highlight the importance of close monitoring of warfarin therapy and the need for further studies on the clinical consequences of co-prescribing of interacting drugs with warfarin. PMID- 25537752 TI - Timing of examinations affects school performance differently in early and late chronotypes. AB - Circadian clocks of adolescents typically run late-including sleep times-yet adolescents generally are expected at school early in the morning. Due to this mismatch between internal (circadian) and external (social) times, adolescents suffer from chronic sleep deficiency, which, in turn, affects academic performance negatively. This constellation affects students' future career prospects. Our study correlates chronotype and examination performance. In total, 4734 grades were collected from 741 Dutch high school students (ages 11-18 years) who had completed the Munich ChronoType Questionnaire to estimate their internal time. Overall, the lowest grades were obtained by students who were very late chronotypes (MSFsc > 5.31 h) or slept very short on schooldays (SDw < 7.03 h). The effect of chronotype on examination performance depended on the time of day that examinations were taken. Opposed to late types, early chronotypes obtained significantly higher grades during the early (0815-0945 h) and late (1000-1215 h) morning. This group difference in grades disappeared in the early afternoon (1245 1500 h). Late types also obtained lower grades than early types when tested at the same internal time (hours after MSFsc), which may reflect general attention and learning disadvantages of late chronotypes during the early morning. Our results support delaying high school starting times as well as scheduling examinations in the early afternoon to avoid discrimination of late chronotypes and to give all high school students equal academic opportunities. PMID- 25537753 TI - Tailored selection of study individuals to be sequenced in order to improve the accuracy of genotype imputation. AB - The addition of sequence data from own-study individuals to genotypes from external data repositories, for example, the HapMap, has been shown to improve the accuracy of imputed genotypes. Early approaches for reference panel selection favored individuals who best reflect recombination patterns in the study population. By contrast, a maximization of genetic diversity in the reference panel has been recently proposed. We investigate here a novel strategy to select individuals for sequencing that relies on the characterization of the ancestral kernel of the study population. The simulated study scenarios consisted of several combinations of subpopulations from HapMap. HapMap individuals who did not belong to the study population constituted an external reference panel which was complemented with the sequences of study individuals selected according to different strategies. In addition to a random choice, individuals with the largest statistical depth according to the first genetic principal components were selected. In all simulated scenarios the integration of sequences from own study individuals increased imputation accuracy. The selection of individuals based on the statistical depth resulted in the highest imputation accuracy for European and Asian study scenarios, whereas random selection performed best for an African-study scenario. Present findings indicate that there is no universal 'best strategy' to select individuals for sequencing. We propose to use the methodology described in the manuscript to assess the advantage of focusing on the ancestral kernel under own study characteristics (study size, genetic diversity, availability and properties of external reference panels, frequency of imputed variants...). PMID- 25537756 TI - Controlled self-assembly of organic composite microdisks for efficient output coupling of whispering-gallery-mode lasers. AB - Flexible microdisk whispering-gallery-mode (WGM) resonators with high quality factors were achieved through the controlled assembly of organic materials with an emulsion-solvent-evaporation method. The high material compatibility of the assembled microdisks enabled us to realize low-threshold WGM lasers by doping with organic dyes as gain media. Furthermore, the emulsion-assisted self-assembly provided a strategy for the one-step fabrication of microwire-waveguide-connected microdisk heterostructures, which can be utilized for the efficient output of the isotropic WGM lasers from the coupled waveguides. We hope that these results will pave an avenue for the construction of new types of flexible WGM-based components for photonic integration. PMID- 25537755 TI - The combination of artificial neural networks and synchrotron radiation-based infrared micro-spectroscopy for a study on the protein composition of human glial tumors. AB - Protein-related changes associated with the development of human brain gliomas are of increasing interest in modern neuro-oncology. It is due to the fact that they might make some of these tumors highly aggressive and difficult to treat. This paper presents a methodology for protein-based analysis of human brain gliomas using synchrotron radiation based Fourier transform infrared spectroscopy (SRFTIR) coupled with artificial neural networks (ANNs). The main goal of this study was to optimize a set of ANNs to predict the secondary structure of proteins (alpha-helices, beta-sheets, beta-turns, bends, random coils) in brain gliomas, based on the amide I-II spectral range. All networks were tested and optimized to reach the standard error of prediction (SEP) lower than 5%. The results indicate that protein-related changes are associated with a tumor's malignancy grade. Particularly, the content of alpha helices increases with increasing malignancy grade, while the content of beta sheets decreases. We also found that proteomic information could be a useful marker to distinguish either between low and high grade tumors or between oligodendroglial- and astrocyte derived ones. This demonstrates the applicability of FTIR coupled with ANNs to provide clinically relevant information. PMID- 25537754 TI - Trends in the selection of insecticide resistance in Anopheles gambiae s.l. mosquitoes in northwest Tanzania during a community randomized trial of longlasting insecticidal nets and indoor residual spraying. AB - Anopheles gambiae s.l. (Diptera: Culicidae) in Muleba, Tanzania has developed high levels of resistance to most insecticides currently advocated for malaria control. The kdr mutation has almost reached fixation in An. gambiae s.s. in Muleba. This change has the potential to jeopardize malaria control interventions carried out in the region. Trends in insecticide resistance were monitored in two intervention villages using World Health Organization (WHO) susceptibility test kits. Additional mechanisms contributing to observed phenotypic resistance were investigated using Centers for Disease Control (CDC) bottle bioassays with piperonylbutoxide (PBO) and S,S,S-tributyl phosphorotrithioate (DEF) synergists. Resistance genotyping for kdr and Ace-1 alleles was conducted using quantitative polymerase chain reaction (qPCR). In both study villages, high phenotypic resistance to several pyrethroids and DDT was observed, with mortality in the range of 12-23%. There was a sharp decrease in mortality in An. gambiae s.l. exposed to bendiocarb (carbamate) from 84% in November 2011 to 31% in December 2012 after two rounds of bendiocarb-based indoor residual spraying (IRS). Anopheles gambiae s.l. remained susceptible to pirimiphos-methyl (organophosphate). Bendiocarb-based IRS did not lead to the reversion of pyrethroid resistance. There was no evidence for selection for Ace-1 resistance alleles. The need to investigate the operational impact of the observed resistance selection on the effectiveness of longlasting insecticidal nets and IRS for malaria control is urgent. PMID- 25537757 TI - Late Manifestation of Struma Peritonei and Widespread Functioning Lesions in the Setting of Struma Ovarii Simulating Highly Differentiated Follicular Carcinoma. AB - Malignant transformation of struma ovarii is a rare event observed in about 5% of cases. We present here an unusual case that closely simulated highly differentiated follicular carcinoma, an entity with a relatively similar appearance to malignant struma ovarii. In our case, peritoneal and systemic dissemination occurred 18 y after excision of struma ovarii, which had been reported as histopathologically benign. There were 3 noteworthy features in the case: the highly functioning nature of the lesions (evidenced by a low level of thyroid-stimulating hormone even without thyroxine suppression); the low to minimal (18)F-FDG avidity of the foci, which reiterates the well-differentiated nature of these lesions, as expected in highly differentiated follicular carcinoma; and prominent involvement of rare sites such as spleen and liver, in addition to usual sites such as lungs, peritoneum, and bilateral adnexae. PMID- 25537758 TI - The Appearance of Maffucci Syndrome on 18F-FDG PET/CT. AB - Maffucci syndrome is a rare condition with multiple enchondromas and hemangiomas. Fewer than 200 cases have been reported in the United States. There is a high predilection for neoplastic changes, and PET/CT has an important role in detecting these changes. PMID- 25537759 TI - Liver uptake on bone scanning: a diagnostic algorithm. AB - In this report, we present a case of liver uptake seen on a bone scan that was due to diffuse metastatic disease from breast carcinoma. We discuss possible etiologies for the uptake and offer an algorithm to narrow the differential diagnosis. PMID- 25537760 TI - An anthropomorphic phantom study of brain dopamine transporter SPECT images obtained using different SPECT/CT devices and collimators. AB - The aim of this study was to evaluate differences in dopamine transporter SPECT images among different SPECT/CT devices and to determine the most appropriate region of interest (ROI) for semiquantitative evaluation. METHODS: An anthropomorphic striatal phantom was filled with (123)I solutions of different striatum-to-background radioactivity ratios. Data were acquired using 2 SPECT/CT devices equipped with low- to medium-energy general-purpose and low-energy high resolution (LEHR) collimators. The SPECT images were reconstructed by filtered backprojection with both attenuation and scatter correction and then were analyzed using specific binding ratio (SBR). The most appropriate of 7 ROI types was determined, and we then compared the linearity and recovery of SBR among the different SPECT/CT devices and collimators. RESULTS: The linearity of SBR was excellent for all types of ROIs. The ROI contouring the striatum based on the CT images showed the best recovery of SBR using mean activity in the striatal ROI (SBRmean) (47.8%). For this ROI, the recovery of SBRmean for SPECT/CT with a LEHR collimator with thick septa and a long hole length was 61.6%-significantly higher than that of other devices. CONCLUSION: The ROI contouring the striatum based on CT images was considered appropriate for evaluating dopamine transporter SPECT/CT. Among the different SPECT/CT devices, an LEHR collimator designed for (123I)I imaging is recommended. PMID- 25537761 TI - Assessment of 99mTc-succimer residual activity using inert nonreactive syringes. AB - It has been widely reported that (99m)Tc-succimer adsorbs to plastic syringes significantly (up to 50%), often resulting in a lower administered dose than intended or inaccurate dosing. This adsorption rate is especially problematic in the pediatric population. To improve (99m)Tc-succimer dosing, we compared the adsorption of (99m)Tc-succimer with 2 types of syringes: silicone-coated syringes with nonlatex rubber on the plunger and inert nonreactive syringes with no silicone coating and no rubber on the plunger. METHODS: (99m)Tc-succimer kits were compounded according to the manufacturer's instructions. (99m)Tc-succimer doses (37-185 MBq) were drawn into 3-mL (silicone-coated or inert nonreactive) syringes in a 1-mL volume. Thirty min, 1 h, 2 h, and 4 h later, the syringes were assayed in a dose calibrator and assayed again after being emptied and rinsed with saline. In addition, we examined the data collected from 129 (99m)Tc succimer doses administered in a pediatric department, in which 52 were dispensed in silicone-coated syringes and 77 were dispensed in inert nonreactive syringes. The doses were assayed immediately before and after injection. The syringes were flushed with normal saline. RESULTS: The labeling efficiency of the (99m)Tc succimer kits was more than 95%. Residual activity left in the inert nonreactive syringes was 0.73% (SD, +/-0.18%), which was significantly lower than the activity left in the silicone-coated syringes, 20.9% (SD, +/-5.6%; P < 0.0001). The extent of adsorption did not change significantly between 30 min and 4 h of incubation. The clinical data showed that the residual activity was 30.6% (SD, +/ 12.5%) from doses dispensed in silicone-coated syringes and 6.38% (SD, +/-2.95%) from doses dispensed in inert nonreactive syringes (P < 0.001). CONCLUSION: The inert nonreactive syringes had significantly less residual of (99m)Tc-succimer than silicone-based syringes, making it possible to accurately administer calculated doses of (99m)Tc-succimer to pediatric patients. PMID- 25537762 TI - Interesting Layering of Excreted 18F-FDG in the Urinary Bladder in Patients with Urinary Tract Infection and Distended Bladder. AB - Settling of (18)F-FDG in the bladder is often noted on whole-body PET/CT images, but this phenomenon has never received any careful attention and the mechanism has been unclear. The 2 patients described in this report, one with a T1 pathologic fracture and another with widespread bone and lymph node metastases from an unknown primary tumor, underwent PET/CT. Both had urinary tract infection and a distended bladder during scanning. The interesting layering of (18)F-FDG in the urinary bladder was observed in both patients. The presence of this phenomenon demands careful evaluation of the urine by the clinician, and the mechanism is hypothesized to be slow (18)F-FDG excretion in patients with a distended urinary bladder, resulting in delayed mixing with urine. In addition, urinary tract infection may be a potential cause. Images showing this interesting layering should be interpreted with care. PMID- 25537763 TI - Assessment of L-lactatemia as a predictor of respiratory disease recognition and severity in feedlot steers. AB - The bovine respiratory disease complex (BRD) is a major health issue in feedlot cattle and one of the primary reasons for antimicrobial use in the North American feedlot industry. The purpose of the present study was to assess blood L-lactate levels of feedlot steers at high risk of developing BRD during the early feeding period. Blood samples were obtained at initial processing and again after BRD confirmation (using bronchial lavage or thoracic ultrasound exam). The study involved 232 recently weaned steers received at a single research feedlot that were processed without metaphylactic antimicrobial treatment. Blood samples were obtained for determination of L-lactatemia and temperament scores (very quiet or stoic [score 1], average [score 2] and very excited [score 3]) were systematically assigned at initial processing. A subsample of calves that were later confirmed as cases of BRD were sampled at first pull (day 0), and at subsequent observation points on days 3, 6, 9 and 15 following initial BRD diagnosis for blood lactate determination as a potential indicator of subsequent death. The clinical BRD cumulative incidence in the cohort was 38% (87/232). Temperament was associated with the probability of becoming a BRD case during the early feeding period. Stoic or very excited calves showed 2.2 times higher odds (95%CI: 1.3, 3.8) of becoming BRD cases compared to calves with average temperament. The impact of L-lactatemia differed by temperament strata. In calves with a temperament score of 2 (average temperament) every 1-log unit increase of lactatemia at processing resulted in 1.9 times higher odds (95% CI: 1.2, 3.1) of becoming a BRD case; this relationship was not significant in calves with a score of either 1 or 3. Twenty-nine confirmed BRD cases were studied for the dynamic lactate assessment analysis. L-lactate at first pull was not significantly different between survivors (median 3.3mmol/L; range 0.8-7.8mmol/L) and non survivors (median 2.7mmol/L; range: 1.6-5.4mmol/L) steers. However, the dynamic assessment of L-lactatemia was associated with the hazard of death using Cox proportional hazard survival analysis. A 1-log increase of lactatemia increased the hazard of dying prior to the next observation by a factor of 36.5 (95% CI: 3.5-381.6). For calves showing a normal temperament score (i.e. temperament score of 2), a misclassification cost term analysis was conducted to identify potential L-lactate test thresholds for identifying future BRD steers. When planned test usage was for informing decision of administering or not a metaphylactic treatment at processing, experts agreed that false-negative (not treating a calf that would have benefit from treatment) to false-positive (wrongfully treating a calf that would have remained healthy) health costs ratio ranged from 8:1 to 20:1. In this situation, a threshold of 5mmol/L would have best informed treatment decision. When using L-lactate for informing the type of antimicrobial used at processing, false-negative to false-positive health costs ratio ranging from 1:1 to 3:1 could be expected and, again, a L-lactate threshold of 5.0mmol/L would have minimized the costs associated with calves' misclassification and could be used to identify calves that would benefit from a more efficient metaphylactic treatment. This study provides an interesting perspective on the potential application of chute-side markers or diagnostic tests to stratify the risk of future pull for BRD in cattle during processing in order to adapt antimicrobial treatments accordingly. PMID- 25537764 TI - A case of bronze turkey twins developing from hatching. AB - A double-yolked egg that was laid by an 11-month-old bronze turkey hen on 2 April, 2013 was reported. The presented case of developing turkey twin embryos is the first ever described case for this species. The egg weighed 125 g and had 74.6 mm in length and 53.0 mm in width. The embryos died between the 23rd and 24th day of incubation. Both twin 1 and twin 2 were fully developed with body weights of: 37.7 g and 40.3 g, respectively. The likely causes of death include inappropriate arrangement of embryos and insufficient gas exchange in the last period of incubation. The embryos were arranged along the long axis of the egg, one underneath the other, and were closely adhering to one another. The twins were different in plumage pigmentation. In twin 1, a spontaneous mutation of plumage pigmentation (B) was observed, whereas twin 2 showed appropriate pigmentation (b+) in respect to parents. PMID- 25537766 TI - Erratum to: Association between the functional ITGAM rs1143679 G/A polymorphism and systemic lupus erythematosus/lupus nephritis or rheumatoid arthritis: an update meta-analysis. PMID- 25537765 TI - A novel regulator of human villous trophoblast fusion: the Kruppel-like factor 6. AB - Cell-cell fusion is an essential event during life. Throughout human pregnancy, the syncytiotrophoblast (STB) layer of the placenta is formed by continuous fusion of the underlying villous cytotrophoblasts, thus maintaining placental functionality. Defects in this process are associated with pathologies like pre eclampsia and intrauterine growth restriction. Kruppel-like factor 6 (KLF6) is a transcription factor highly expressed in human and murine placenta. However, KLF6 functions in trophoblast cells remain largely unexplored. The aim of this work was to address the role of KLF6 during STB formation. KLF6 knockdown through small interfering RNA experiments hindered cell-cell fusion revealed by immunofluorescence microscopy in human primary villous cytotrophoblast as well as in the human placental-derived BeWo cell line. Furthermore, KLF6 silencing led to a decrease in the expression of the fusogenic protein Syncytin-1 and the cell cycle regulator p21 CIP1/WAF1: measured by quantitative RT-PCR and western blot assays. On the contrary, transcript levels of genes that encode for proteins involved in STB formation such as Syncytin-1, Syncytin-2, Connexin-43 and Zonula Occludens-1 increased when KLF6 was overexpressed in differentiating villous cytotrophoblasts and in non-fusing placental-derived JEG-3 cells. Interestingly, the expression of two trophoblast biochemical differentiation markers, betahCG and PSG3, were not reduced after KLF6 silencing in differentiating trophoblast cells. Present results support the notion that KLF6 is a relevant participant in cytotrophoblast fusion. PMID- 25537767 TI - A high-power ultrasonic microreactor and its application in gas-liquid mass transfer intensification. AB - The combination of ultrasound and microreactor is an emerging and promising area, but the report of designing high-power ultrasonic microreactor (USMR) is still limited. This work presents a robust, high-power and highly efficient USMR by directly coupling a microreactor plate with a Langevin-type transducer. The USMR is designed as a longitudinal half wavelength resonator, for which the antinode plane of the highest sound intensity is located at the microreactor. According to one dimension design theory, numerical simulation and impedance analysis, a USMR with a maximum power of 100 W and a resonance frequency of 20 kHz was built. The strong and uniform sound field in the USMR was then applied to intensify gas liquid mass transfer of slug flow in a microfluidic channel. Non-inertial cavitation with multiple surface wave oscillation was excited on the slug bubbles, enhancing the overall mass transfer coefficient by 3.3-5.7 times. PMID- 25537768 TI - Malaria detection using inertial microfluidics. AB - Diagnosis of malaria at the early stage of infection is challenging due to the difficulty in detecting low abundance parasites from blood. Molecular methods such as real-time polymerase chain reaction (qPCR) can be especially useful for detecting low parasitemia levels due to their high sensitivity and their ability to recognize different malarial species and strains. Unfortunately, the accuracy of qPCR-based malaria detection can be compromised by many factors, including the limited specificity of primers, presence of PCR inhibitors in blood serum and DNA contamination from nucleated blood cells. Here, we use a label-free, shear modulated inertial microfluidic system to enrich malaria parasites from blood so as to facilitate a more reliable and specific PCR-based malaria detection. This technique capitalizes on cell focusing behaviors in high aspect ratio microchannels coupled with pinched flow dynamics to isolate ring-stage malaria parasites from lysed blood containing white blood cells (WBCs). In this high aspect ratio (ratio of the channel height to the width) platform, the high shear rate along the channel width causes the dispersed WBCs at the inlet to migrate and align into two streams near the channel sidewalls while the malaria parasites remain unfocused. Sensitive detection of parasites at spiked densities ranging from 10(3) to 10(4)Plasmodium falciparum parasites per mL (~2-10 per MUL) has been demonstrated; they have also been quantified in whole blood using qPCR. This is approximately 100-fold more sensitive than the gold standard conventional microscopy analysis of thick blood smears. The simplicity of this device makes it ideal for integration with an automatic system for ultra-fast and accurate detection despite low levels of parasitemia. It can also help in malaria screening and elimination efforts. PMID- 25537769 TI - Similar outcomes among general medicine patients discharged on weekends. AB - BACKGROUND: Hospitals reduce staffing levels and services on weekends. This raises the question of whether weekend discharges may be inadequately prepared and thus at higher risk for adverse events postdischarge. OBJECTIVE: To compare death or nonelective readmission rates 30 days after weekend versus weekday discharge. DESIGN: Retrospective cohort. SETTING: All teaching hospitals in Alberta, Canada. PATIENTS: General internal medicine (GIM) discharges (only 1 per patient). MEASUREMENTS: Analyses were adjusted for demographics, comorbidity, and length of stay based on a previously validated index. RESULTS: Of 7991 patients (mean age, 62.1 years; 51.9% male; mean Charlson 2.56; 57.5% LACE >=10) discharged from 7 teaching hospitals, 1146 (14.3%) were discharged on a weekend. Although they had substantially shorter lengths of stay (5.64 days, 95% confidence interval [CI]: 5.35-5.93 vs 7.86 days, 95% CI: 7.71-8.00, adjusted P value < 0.0001) and were less likely to be discharged with homecare support (10.9% vs 19.3%) or to long-term care facilities (3.1% vs 7.8%), patients discharged on weekends exhibited similar rates of death or readmission at 30 days compared to those discharged on weekdays (10.6% vs 13.2%, adjusted odds ratio [aOR]: 0.94, 95% CI: 0.77-1.16), even among the 4591 patients deemed to be at high risk for postdischarge events based on LACE (length of hospital stay, acuity of admission, comorbidity burden quantified using the Charlson Comorbidity Index, and emergency department visits in the 6 months prior to admission) score >=10 (16.8% vs 16.5% for weekday discharges, aOR: 1.09 [95% CI: 0.85-1.41]). CONCLUSIONS: GIM patients discharged from teaching hospitals on weekends have shorter lengths of stay and exhibit similar postdischarge outcomes as patients discharged on weekdays. PMID- 25537770 TI - Targeting cancer stem cells as a therapeutic approach in liver cancer. AB - Cancer stem cells (CSCs) are a subset of cells within tumours that have the ability to selfrenew, differentiate and resist both chemotherapy and radiotherapy. Evidence has emerged in recent years to support liver cancer stem cells (LCSCs) as the key tumour initiating cells and major drivers of tumour progression in hepatocellular carcinoma (HCC). Currently the major approaches to targeting LCSCs are ablating the expression of LCSC markers, disruption of key LCSCs signaling pathways, micro-RNA or siRNA targeting, inducing differentiation of LCSCs and the disruption of chemoresistance of LCSCs. However, complex crosstalk amongst gene regulatory pathways in LCSCs provides a major barrier in implementing these approaches in a clinical setting. Given these findings a deeper understanding of the pathways that mediate LCSC tumourigenesis is imperative for developing new therapeutic strategies for HCC and to improve clinical outcomes. PMID- 25537771 TI - Targeting angiogenic genes as a therapeutic approach for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a complex liver disease with limited treatment options and often resulting in a poor prognosis. The development of HCC depends on the formation of new blood vessels and it demonstrates hypervascularity and invasive property to the surrounding vasculature clinically. A complex network of growth factors acting on both tumor cells and endothelial cells mediates the angiogenesis in HCC. It is an attractive approach to inhibit the angiogenic processes as the treatment of HCC and therefore, anti-angiogenic TKIs were developed to inhibit the vessel formation in the tumors. However, it is currently perceived that the efficacy of these anti-angiogenic TKIs has reached plateau, and it is necessary to develop novel agents with non-TKI mechanism to inhibit the angiogenic targets. With the better understanding of molecular mechanisms that govern angiogenesis, as well as the advancement in biomedical engineering, new approaches of gene therapy have brought hopes for therapeutic intervention in HCC. Gene therapy is based on the transfer of genetic material to the patients with the aim to modify or correct the malignancy from its molecular basis. In this article, we will discuss the conventional anti-angiogenic therapies and the gene therapy approaches in HCC. The therapeutic potential of gene therapy for HCC treatment has been demonstrated and further development of anti-angiogenic may result in new treatment option for HCC patients. PMID- 25537772 TI - Modulation of Notch signaling as a therapeutic approach for liver cancer. AB - Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Aberrant Notch signaling has been mechanistically linked to cancer development including liver cancer. The two principal types of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC). HCCs comprise over 80% of all liver cancers and are the 6(th) most common malignancy worldwide. Hepatocellular carcinoma is also a cancer with an extremely poor prognosis, being the 3(rd) commonest cause of cancer-related mortality. Accumulating evidence indicates that the role of Notch signaling in liver cancer is more complex than once thought and is dependent on the expression of specific Notch signaling components and the complex crosstalk with other signaling pathways. Currently there are a variety of gene therapy based approaches used to target Notch signaling in preclinical studies to successfully treat liver cancer including neutralizing antibodies, siRNA, shRNA and miRNA. The use of targeted anti-Notch therapy in the clinic to treat liver cancer will require considerable refinement of our current knowledge on the regulation of Notch signaling components and their effects in both normal and malignant liver cells in order to target specific Notch subunits which are critical to liver cancer tumorigenesis but not to the homeostasis of normal cells. Using this approach will reduce the major side effects, which are frequently seen in patients treated with GSIs to inhibit the entire Notch signaling pathway. Here our understanding of Notch signaling is reviewed, highlighting its function in liver cancer initiation, progress and opportunities for liver cancer therapies. PMID- 25537774 TI - Exosomes: a role for naturally occurring nanovesicles in cancer growth, diagnosis and treatment. AB - Exosomes are 30-100 nm bodies secreted from almost all types of cells into the extracellular spaces. They enclose in their lumen active genetic information in the form of messenger RNA (mRNA), micro RNA (miRNA), DNA and active peptides that are representative of the parental cell and can be isolated from different body fluids. Exosomes can participate in inter-cellular communication by trafficking molecules to their target cells. Because they can stably carry cargo including miRNA, mRNA, and proteins and can pass through stringent biological barriers (e.g., blood brain barrier) without eliciting an immune response, they are considered as an ideal acellular vehicle for drug delivery. In this review, we describe the structure and biogenesis of exosomes and new directions related to their role in diagnosis and treatment of diseases, especially for cancer. We also discuss potential challenges associated with exosomes that should be addressed before exosome-based therapy can be applied to clinical settings. PMID- 25537773 TI - miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir. AB - miR-122, a completely conserved liver-specific miRNA in vertebrates, is essential for the maintenance of liver homeostasis. This 22 nucleotide RNA regulates diverse functions such as cholesterol, glucose and iron homeostasis, lipid metabolism and infection of hepatitis C virus (HCV) and of the parasitic protozoa, Leishmania donovani. It is the first miRNA that underwent successful clinical trials in HCV infected patients. In contrast, miR-122 expression is reduced in nonalcoholic steatohepatitis (NASH) patients, and in a subset of hepatocellular carcinoma (HCC) patients including hepatitis B virus (HBV) positive patients with highly invasive and metastatic cancer. Studies in mice genetically depleted of miR-122 have highlighted its critical role in liver biology. These mice progressively develop steatohepatitis, fibrosis and hepatocellular cancer, establishing it as a bona fide tumor suppressor. Additionally, delivery of miR-122 using a viral vector or liposomal nanoparticles resulted in liver tumor suppression in animal models. These results suggest miR 122 supplementation might be beneficial in NASH or HBV positive HCC patients. Furthermore, circulating miR-122 has emerged as a sensitive biomarker for liver injury. The ability of miR-122 to promote differentiation of embryonic and adult stem cells to hepatocyte-like cells in vitro suggests its potential role in driving the hepatic differentiation program. In this review, we will discuss the role of miR-122 in liver physiology and the deleterious consequences of its loss of function, its role as a sensitive biomarker for liver injury and therapeutic target. Development of novel technologies for targeted delivery of miR-122 to tumor cells and for direct monitoring of miR-122 in biological fluids is urgently needed for translating the basic research to the bedside. This review focuses on miR-122, the most abundant hepatic miRNA, in the context of liver health and diseases. PMID- 25537775 TI - Current status of gene therapy for hepatocellular carcinoma, with a focus on gene delivery approaches. AB - Hepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality rates, especially in East Asia. Gene therapy is a potential approach for treating HCC. An efficient and safe gene delivery method is a crucial factor for HCC gene therapy. In recent years, gene delivery systems, including viral and non-viral gene vectors, bacteria, and physical methods, have undergone substantial development. Among them, various non-viral vectors have been studied widely and in detail because they are relatively safe and have a high capacity. In this review, we focus on current and emerging HCC delivery techniques and address the challenges involved in the use and improvement of non-viral vectors. PMID- 25537776 TI - Combined therapy for gastrointestinal carcinomas: exploiting synergies between gene therapy and classical chemo-radiotherapy. AB - Surgical resection is the only curative option for patients with gastrointestinal carcinomas. Unfortunately, the majority of patients are diagnosed in advanced stages when surgery is not possible. Moreover, the incidence and mortality for certain type of tumors such as hepatocellular carcinoma or pancreatic cancer are steadily increasing worldwide. In spite of the advances in the development of molecular targeted therapies for cancer, the impact on patient survival has been rather limited. It is unlikely that individual agents would be ultimately successful as monotherapy. There is a growing area of research focused on the combination of classical chemotherapy (e.g. cyclophosphamide, gemcitabine, paclitaxel and doxorubicin) with radiotherapy and/or gene therapy strategies. Combined approaches seem to be required due to multiple resistance mechanisms that tumors utilize to limit the activity of chemotherapeutic agents (e.g. the occurrence of multidrug resistance or epigenetic alterations), evade immune responses (e.g. induction of regulatory T cells or myeloid-derived suppressor cells) and to generate resistance against anti-angiogenesis or to radiotherapy by, for example, the induction of hypoxia-inducible factor 1. In addition, new studies suggest that combination of low dose of conventional chemotherapy and gene therapy could allow the development of synergic mechanisms able to achieve significant therapeutic effects against diverse tumors. Although cancer gene therapy is not yet available in clinical practice, advances being recently made look promising, especially when it was applied in combination with standard chemo or radiotherapy protocols. PMID- 25537777 TI - Aptamer-mediated cancer gene therapy. AB - Cancer as a genetic disorder is one of the leading causes of death worldwide. Conventional anticancer options such as chemo- and/or radio-therapy have their own drawbacks and could not provide a cure in most cases at present. More effective therapeutic strategies with less side effects are urgently needed. Aptamers, also known as chemical antibodies, are single strand DNA or RNA molecules that can bind to their target molecules with high affinity and specificity. Such site-specific binding ability of aptamers facilitates the delivery and interaction of exogenous nucleic acids with diseased genes. Thus, aptamer-guided gene therapy has emerged as a promising anticancer strategy in addition to the classic treatment regimen. Aptamers can directly deliver anti cancer nucleic acids, e.g. small interfering RNA, micro RNA, antimicroRNA and small hairpin RNA, to cancer cells or function as a targeting ligand to guide nanoparticles containing therapeutic nucleic acids. This review focuses on recent progress in aptamer-mediated gene therapy for the treatment of hepatocellular carcinoma and other types of cancers, shedding light on the potential of this novel approach of targeted cancer gene therapy. PMID- 25537778 TI - Apoptosis-induction is a novel therapeutic strategy for gastrointestinal and liver cancers. AB - Gastrointestinal and liver cancers are among the most frequently encountered cancers worldwide. Though great strides have been made in improving the early detection and overall patient survival in the last decade, the currently available treatment approaches remain suboptimal due to drug resistance and side effects. Apoptosis is the most desirable type of programmed cell death in cancer therapy. By eliminating unnecessary and unwanted cells, apoptosis plays a critical role in development, physiology and homeostasis. Recent studies have shown that apoptosis-inducing therapy is a safe and effective anti-cancer approach, which thus may become one of the most important areas in cancer treatment. In this review, the authors provide an overview on the apoptosis system in multicellular organisms and summarize the recent advances of apoptosis inducing therapeutic strategy for gastrointestinal and liver cancers. PMID- 25537779 TI - Krebs cycle metabolon: structural evidence of substrate channeling revealed by cross-linking and mass spectrometry. AB - It has been hypothesized that the high metabolic flux in the mitochondria is due to the self-assembly of enzyme supercomplexes (called metabolons) that channel substrates from one enzyme to another, but there has been no experimental confirmation of this structure or the channeling. A structural investigation of enzyme organization within the Krebs cycle metabolon was accomplished by in vivo cross-linking and mass spectrometry. Eight Krebs cycle enzyme components were isolated upon chemical fixation, and interfacial residues between mitochondrial malate dehydrogenase, citrate synthase, and aconitase were identified. Using constraint protein docking, a low-resolution structure for the three-enzyme complex was achieved, as well as the two-fold symmetric octamer. Surface analysis showed formation of electrostatic channeling upon protein-protein association, which is the first structural evidence of substrate channeling in the Krebs cycle metabolon. PMID- 25537780 TI - Awareness and control of hypertension in Bangladesh: follow-up of a hypertensive cohort. AB - OBJECTIVES: To assess the effect of awareness and advice to seek care on blood pressure (BP) control among patients with hypertension in Bangladesh. DESIGN: Longitudinal study. SETTING: The study was carried out in icddr,b surveillance sites at rural Matlab in Chandpur district and semi-urban Kamalapur in Dhaka, Bangladesh. PARTICIPANTS: Randomly selected men and non-pregnant women aged 20 years or older without any acute illness or history of any vascular events such as stroke or acute myocardial infarction. MAIN OUTCOME MEASURE: Hypertension was defined as systolic BP (SBP) >=140 and/or diastolic BP (DBP) >=90 mm Hg or as self-reported hypertension under medication. We advised patients to seek care from a qualified provider and to adopt a healthy lifestyle. We compared changes in BP from baseline to follow-up at around 6 months. RESULTS: Overall, 17.1% (n=287) of participants had hypertension at baseline with significantly higher prevalence in the semi-urban than in the rural population (23.6% vs 10.8%; p<0.001); half were unaware of their condition. At follow-up, 83% (n=204) reported a visit to any healthcare provider. In the semi-urban area, a higher proportion of patients visited medically qualified practitioners than in the rural area (76.7% vs 36.6%, p<0.000). SBP (-3.3+/-20.7 mm Hg; p<0.01) and DBP ( 2.0+/-13.0 mm Hg; p<0.02) were lower at follow-up. Those who visited medically qualified practitioners had significant SBP (-3.9+/-22.4 mm Hg; p<0.03) and DBP ( 2.7+/-14.1 mm Hg; p<0.02) reduction. BP reduction did not reach statistical significance among those visiting a pharmacist or their village doctors. Overall, half of the patients with hypertension achieved the BP control goal (BP<140/90 mm Hg). CONCLUSIONS: Awareness and simple health messages increase provider visit, reduce blood pressure and improve BP control in hypertensive Bangladeshis. Longer term follow-up is required to verify the sustainability. PMID- 25537782 TI - A usability study of two formats of a shortened systematic review for clinicians. AB - OBJECTIVE: The aim of this study was to evaluate the usability of two formats of a shortened systematic review for clinicians. MATERIALS AND METHODS: Usability of the prototypes was assessed using three cycles of iterative testing. 10 participants were asked to complete tasks of locating information or items within two prototypes and 'think aloud' while being audio taped. Interviews were also audio recorded and participants completed a systematic usability scale. RESULTS: Revisions were made between each iteration in order to address issues identified by participants. Finding information relating to the number of studies in the meta-analysis, and locating the number of studies in the entire systematic review were revealed as areas needing attention during the usability evaluation. CONCLUSIONS: Iterative testing combined with a multifaceted approach to usability testing offered essential insight into aspects of the prototypes that required modifications. Alterations were made in order to create finalised versions of the two shortened systematic review formats. PMID- 25537781 TI - Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors versus intermediate-acting insulin for adults with type 2 diabetes mellitus (T2DM) and poor glycaemic control despite treatment with two oral agents. SETTING: Studies were multicentre and multinational. PARTICIPANTS: Ten studies including 2967 patients with T2DM. INTERVENTIONS: Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness. RESULTS: 10 randomised clinical trials with 2967 patients were included after screening 5831 titles and abstracts, and 180 full-text articles. DPP-4 inhibitors significantly reduced HbA1c versus placebo in network meta-analysis (NMA; mean difference (MD) -0.62%, 95% CI -0.93% to 0.33%) and meta-analysis (MD -0.61%, 95% CI -0.81% to -0.41%), respectively. Significant differences in HbA1c were not observed for neutral protamine Hagedorn (NPH) insulin versus placebo and DPP-4 inhibitors versus NPH insulin in NMA. In meta-analysis, no significant differences were observed between DPP-4 inhibitors and placebo for severe hypoglycaemia, weight gain, cardiovascular disease, overall harms, treatment-related harms and mortality, although patients receiving DPP-4 inhibitors experienced less infections (relative risk 0.72, 95% CI 0.57 to 0.91). CONCLUSIONS: DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors. TRIAL REGISTRATION NUMBER: PROSPERO # CRD42013003624. PMID- 25537783 TI - The association between neighbourhood greenspace and type 2 diabetes in a large cross-sectional study. AB - OBJECTIVE: To investigate the relationship between neighbourhood greenspace and type 2 diabetes. DESIGN: Cross-sectional. SETTING: 3 diabetes screening studies conducted in Leicestershire, UK in 2004-2011. The percentage of greenspace in the participant's home neighbourhood (3 km radius around home postcode) was obtained from a Land Cover Map. Demographic and biomedical variables were measured at screening. PARTICIPANTS: 10,476 individuals (6200 from general population; 4276 from high-risk population) aged 20-75 years (mean 59 years); 47% female; 21% non white ethnicity. MAIN OUTCOME MEASURE: Screen-detected type 2 diabetes (WHO 2011 criteria). RESULTS: Increased neighbourhood greenspace was associated with significantly lower levels of screen-detected type 2 diabetes. The ORs (95% CI) for screen-detected type 2 diabetes were 0.97 (0.80 to 1.17), 0.78 (0.62 to 0.98) and 0.67 (0.49 to 0.93) for increasing quartiles of neighbourhood greenspace compared with the lowest quartile after adjusting for ethnicity, age, sex, area social deprivation score and urban/rural status (Ptrend=0.01). This association remained on further adjustment for body mass index, physical activity, fasting glucose, 2 h glucose and cholesterol (OR (95% CI) for highest vs lowest quartile: 0.53 (0.35 to 0.82); Ptrend=0.01). CONCLUSIONS: Neighbourhood greenspace was inversely associated with screen-detected type 2 diabetes, highlighting a potential area for targeted screening as well as a possible public health area for diabetes prevention. However, none of the risk factors that we considered appeared to explain this association, and thus further research is required to elicit underlying mechanisms. TRIAL REGISTRATION NUMBER: This study uses data from three studies (NCT00318032, NCT00677937, NCT00941954). PMID- 25537784 TI - Acupuncture at Houxi (SI 3) acupoint for acute neck pain caused by stiff neck: study protocol for a pilot randomised controlled trial. AB - INTRODUCTION: The use of acupuncture has been suggested for the treatment of acute neck pain caused by stiff neck in China. However, current evidence is insufficient to draw any conclusions about its efficacy. Therefore this pilot study was designed to evaluate the feasibility and efficacy of acupuncture at the Houxi (SI3) acupoint for treatment of acute neck pain. METHODS/ANALYSIS: This pilot study will be a two-parallel-group, assessor-blinded, randomised controlled trial. Thirty-six stiff neck participants with acute neck pain will be recruited and randomly divided into two groups in a 1:1 ratio. Participants in the control group will receive massage on the local neck region (5 min each session, three times a day for 3 days). In addition to massage, patients in the treatment group will receive acupuncture (one session a day for 3 days). Measures will be taken at 0, 3 and 15 days. The primary outcome is the Northwick Park Neck Pain Questionnaire (NPQ). The secondary outcome is the Short Form of the McGill Pain Questionnaire (SF-MPQ). ETHICS/DISSEMINATION: The protocol for this pilot randomised clinical trial has undergone ethics scrutiny and been approved by the ethics review boards of the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine (Permission number: HZYLL201303502). The findings of this study will provide important clinical evidence on the feasibility and efficacy of acupuncture treatment for stiff neck patients with acute neck pain. In addition, it will explore the feasibility of further acupuncture research. TRIAL REGISTRATION NUMBER: ChiCTR-TRC-13003911. PMID- 25537785 TI - A cross-sectional exploration of the clinical characteristics of disengaged (NEET) young people in primary mental healthcare. AB - OBJECTIVE: Youth with mental health problems often have difficulties engaging in education and employment. In Australia, youth mental health services have been widely established with a key aim of improving role functioning; however, there is little knowledge of those who are not engaged in employment, education or training (NEET) and the factors which may influence this. This study aimed to examine NEET status and its correlates in a sample of such youth. DESIGN: Cross sectional data from a longitudinal cohort study. SETTING: Between January 2011 and August 2012, young people presenting to one of the four primary mental health centres in Sydney or Melbourne were invited to participate. PARTICIPANTS: Young adults (N=696) aged between 15 and 25 years (M=19.0, SD=2.8), 68% female, 58% (n=404) attended headspace in Sydney. MEASURES: Individuals 'Not in any type of Education, Employment or Training' in the past month were categorised as NEET. Demographic, psychological and clinical factors alongside disability and functioning were assessed using clinical interview and self-report. RESULTS: A total of 19% (n=130/696) were NEET. NEETs were more likely to be male, older, have a history of criminal charges, risky cannabis use, higher level of depression, poorer social functioning, greater disability and economic hardship, and a more advanced stage of mental illness than those engaged in education, training or work. Demographics such as postsecondary education, immigrant background and indigenous background, were not significantly associated with NEET status in this sample. CONCLUSIONS: One in five young people seeking help for mental health problems were not in any form of education, employment and training. The commonly observed risk factors did not appear to influence this association, instead, behavioural factors such as criminal offending and cannabis use appeared to require targeted intervention. PMID- 25537786 TI - Exploring cardiovascular health: the Healthy Life in Suriname (HELISUR) study. A protocol of a cross-sectional study. AB - INTRODUCTION: Obesity, hypertension and diabetes are on a dramatic rise in low income and middle-income countries, and this foretells an overwhelming increase in chronic disease burden from cardiovascular disease. Therefore, rapid action should be taken through preventive population-based programmes. However, in these regions, data on the population distribution of cardiovascular risk factors, and of intermediate and final end points for cardiovascular disease are scarce. The Healthy Life in Suriname (HELISUR) study is a cardiovascular population study in Suriname, which is part of the Caribbean Community. The HELISUR study is dedicated to provide data on risk factors and prevalent cardiovascular disease in the multiethnic population, which is mainly of African and Asian descent. METHODS AND ANALYSIS: In a cross-sectional, observational population-based setting, a random representative sample of 1800 citizens aged between 18 and 70 years will be selected using a cluster household sampling method. Self-reported demographic, socioeconomic and (cardiovascular) health-related data will be collected. Physical examination will include the assessment of cardiovascular risk factors and prevalent cardiovascular disease. In addition, we will study cardiovascular haemodynamics non-invasively, as a novel intermediate outcome. Finally, fasting blood and overnight urine samples will be collected to monitor cardiometabolic risk factors. The main outcome will be descriptive in reporting the prevalence of risk factors and measures of (sub) clinical end organ damage, stratified for ethnicity and sex-age groups. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the State Secretary of Health. Data analysis and manuscript submission are scheduled for 2016. Findings will be disseminated in peer-reviewed journals, and at national, regional and international scientific meetings. Importantly, data will be presented to Surinamese policymakers and healthcare workers, to develop preventive strategies to combat the rapid rise of cardiovascular disease. PMID- 25537788 TI - Acupuncture for postoperative pain in laparoscopic surgery: a systematic review protocol. AB - INTRODUCTION: This review aims to evaluate the effectiveness and safety of acupuncture for patients with postoperative pain after laparoscopic surgery. METHODS AND ANALYSIS: We will search the following databases from their inception to October 2014: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), three Chinese databases (China National Knowledge Infrastructure (CNKI), the Chongqing VIP Chinese Science and Technology Periodical Database (VIP) and the Wanfang database), one Japanese database (Japan Science and Technology Information Aggregator, Electronic (J-STAGE)) and eight Korean databases (Korean Association of Medical Journal Edition, Korean Medical Database, Korean Studies Information Service System, National Discovery for Science Leaders, Database Periodical Information Academic, Korean National Assembly Digital Library, Oriental Medicine Advanced Searching Integrated System and Korean Traditional Knowledge Portal). All randomised controlled trials of acupuncture for postoperative pain after laparoscopic surgery will be considered for inclusion. The risk of bias and reporting quality will be assessed using the Cochrane risk of bias tool, the Consolidated Standards of Reporting Trials (CONSORT) and the revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). The risk ratio for dichotomous data and mean difference or standard mean difference for continuous data will be calculated with 95% CIs. DISSEMINATION: The results of this review will be disseminated through peer-reviewed publication or conference presentation. Our findings will summarise the current evidence of acupuncture to treat postoperative pain after laparoscopic surgery, and may provide important guidance for acupuncture usage after laparoscopic surgery for clinicians and patients. TRIAL REGISTRATION NUMBER: PROSPERO 2014: CRD42014010825. PMID- 25537789 TI - The Optimizing Patient Transfers, Impacting Medical Quality, andImproving Symptoms:Transforming Institutional Care approach: preliminary data from the implementation of a Centers for Medicare and Medicaid Services nursing facility demonstration project. AB - The Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) project aims to reduce avoidable hospitalizations of long-stay residents enrolled in 19 central Indiana nursing facilities. This clinical demonstration project, funded by the Centers for Medicare and Medicaid Services Innovations Center, places a registered nurse in each nursing facility to implement an evidence-based quality improvement program with clinical support from nurse practitioners. A description of the model is presented, and early implementation experiences during the first year of the project are reported. Important elements include better medical care through implementation of Interventions to Reduce Acute Care Transfers tools and chronic care management, enhanced transitional care, and better palliative care with a focus on systematic advance care planning. There were 4,035 long-stay residents in 19 facilities enrolled in OPTIMISTIC between February 2013 and January 2014. Root-cause analyses were performed for all 910 acute transfers of these long stay residents. Of these transfers, the project RN evaluated 29% as avoidable (57% were not avoidable and 15% were missing), and opportunities for quality improvement were identified in 54% of transfers. Lessons learned in early implementation included defining new clinical roles, integrating into nursing facility culture, managing competing facility priorities, communicating with multiple stakeholders, and developing a system for collecting and managing data. The success of the overall initiative will be measured primarily according to reduction in avoidable hospitalizations of long-stay nursing facility residents. PMID- 25537787 TI - A Frailty Instrument for primary care for those aged 75 years or more: findings from the Survey of Health, Ageing and Retirement in Europe, a longitudinal population-based cohort study (SHARE-FI75+). AB - OBJECTIVE: To create and validate a frailty assessment tool for community dwelling adults aged >=75 years. DESIGN: Longitudinal, population-based study. SETTING: The Survey of Health, Ageing and Retirement in Europe (SHARE). PARTICIPANTS: 4001 women and 3057 men aged >=75 years from the second wave of SHARE. 3325 women and 2587 men had complete information for the frailty indicators: fatigue, low appetite, weakness, observed gait (walking without help, walking with help, chairbound/bedbound, unobserved) and low physical activity. MAIN OUTCOME MEASURES: The internal validity of the frailty indicators was tested with latent class analysis, by modelling an underlying variable with three ordered categories. The predictive validity of the frailty classification was tested against 2-year mortality and 4-year disability. The mortality prediction of SHARE-FI75+ was compared with that of previously operationalised frailty scales in SHARE (SHARE-FI, 70-item index, phenotype, FRAIL). RESULTS: In both genders, all frailty indicators significantly aggregated into a three-category ordinal latent variable. After adjusting for baseline age, comorbidity and basic activities of daily living (BADL) disability, the frail had an OR for 2-year mortality of 2.2 (95% CI 1.2 to 3.8) in women and 4.2 (2.6 to 6.8) in men. The mortality prediction of SHARE-FI75+ was similar to that of the other SHARE frailty scales. By wave 4, 49% of frail women (78 of 159) had at least one more limitation with BADL (compared with 18% of non-frail, 125 of 684; p<0.001); in men, these proportions were 39% (26 of 66) and 18% (110 of 621), respectively (p<0.001). A calculator is supplied for point-of-care use, which automatically replicates the frailty classification for any given measurements. CONCLUSIONS: SHARE-FI75+ could help frailty case finding in primary care and provide a focus for personalised community interventions. Further validation in trials and clinical programmes is needed. PMID- 25537790 TI - A conservative isoleucine to leucine mutation causes major rearrangements and cold sensitivity in KlenTaq1 DNA polymerase. AB - Assembly of polymerase chain reactions at room temperature can sometimes lead to low yields or unintentional products due to mispriming. Mutation of isoleucine 707 to leucine in DNA polymerase I from Thermus aquaticus substantially decreases its activity at room temperature without compromising its ability to amplify DNA. To understand why a conservative change to the enzyme over 20 A from the active site can have a large impact on its activity at low temperature, we solved the X ray crystal structure of the large (5'-to-3' exonuclease-deleted) fragment of Taq DNA polymerase containing the cold-sensitive mutation in the ternary (E-DNA ddNTP) and binary (E-DNA) complexes. The I707L KlenTaq1 ternary complex was identical to the wild-type in the closed conformation except for the mutation and a rotamer change in nearby phenylalanine 749, suggesting that the enzyme should remain active. However, soaking out of the nucleotide substrate at low temperature results in an altered binary complex made possible by the rotamer change at F749 near the tip of the polymerase O-helix. Surprisingly, two adenosines in the 5'-template overhang fill the vacated active site by stacking with the primer strand, thereby blocking the active site at low temperature. Replacement of the two overhanging adenosines with pyrimidines substantially increased activity at room temperature by keeping the template overhang out of the active site, confirming the importance of base stacking. These results explain the cold-sensitive phenotype of the I707L mutation in KlenTaq1 and serve as an example of a large conformational change affected by a conservative mutation. PMID- 25537791 TI - Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27. AB - We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence. PMID- 25537792 TI - Cost of unintended pregnancy in Norway: a role for long-acting reversible contraception. AB - OBJECTIVES: The objective of this study was to quantify the cost burden of unintended pregnancies (UPs) in Norway, and to estimate the proportion of costs due to imperfect contraceptive adherence. Potential cost savings that could arise from increased uptake of long-acting reversible contraception (LARC) were also investigated. METHODS: An economic model was constructed to estimate the total number of UPs and associated costs in women aged 15-24 years. Adherence-related UP was estimated using 'perfect use' and 'typical use' contraceptive failure rates. Potential savings from increased use of LARC were projected by comparing current costs to projected costs following a 5% increase in LARC uptake. RESULTS: Total costs from UP in women aged 15-24 years were estimated to be 164 million Norwegian Kroner (NOK), of which 81.7% were projected to be due to imperfect contraceptive adherence. A 5% increase in LARC uptake was estimated to generate cost savings of NOK 7.2 million in this group. CONCLUSIONS: The cost of UP in Norway is substantial, with a large proportion of this cost arising from imperfect contraceptive adherence. Increased LARC uptake may reduce the UP incidence and generate cost savings for both the health care payer and contraceptive user. PMID- 25537793 TI - New apoptosis-inducing sesquiterpenoids from the mycelial culture of Chinese edible fungus Pleurotus cystidiosus. AB - Two new bisabolane-type sesquiterpenoids, pleuroton A (1) and pleuroton B (2), and three clitocybulol derivatives, clitocybulol D (3), clitocybulol E (4), and clitocybulol F (5), were obtained from the mycelial culture of edible fungus Pleurotus cystidiosus O. K. Mill by repeated column chromatography over RP-18, Sephadex LH-20, and silica gel. Their structures were determined according to nuclear magnetic resonance data, high-resolution electron impact mass spectrometry, and circular dichroism spectra. These new sesquiterpenoids exhibited significant cytotoxicity against two human prostate cancer DU-145 and C42B cells in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The median inhibitory concentration (IC50) of compounds 1, 2, 3, 4, and 5 was 174, 28, 233, 162, and 179 nM, respectively, against the DU-145 cell and was 104, 52, 163, 120, and 119 nM, respectively, against the C42B cell. Especially, pleuroton B (2) exhibited the strongest cytotoxity among these sesquiterpenoids, which was confirmed by the colony formation assay. Furthermore, pleuroton B (2) could trigger the apoptosis of DU-145 cells through the detection of apoptosis cells using annexin V-FITC staining by flow cytometry, the observation of condensed nuclei in the apoptosis cells, and the western blot analysis for the expression of apoptosis-related proteins Bcl-2, Bak, and Bax. Analysis of structure-activity relationships of these sesquiterpenoids revealed that the unusual functional moiety of pleuroton B should contribute to its significant bioactivity. These results display the pharmacological potential of P. cystidiosus. PMID- 25537794 TI - Heart failure prognosis and management in over-80-year-old patients: data from a French national observational retrospective cohort. AB - PURPOSE: The aim of the study was to assess the impact of clinical characteristics and management on the mid- to long-term follow-up prognosis of unselected over-80-year-old patients hospitalized for a first heart failure (HF) episode in a real-life setting. Despite the increasing proportion of HF patients over 80 years of age, the latter remain a poorly studied population. METHODS: Analysis was based on the EGB ("Echantillon Generaliste des Beneficiaires") database. A cohort comprising 1825 adult patients with a first admission for HF between 2009 and 2011 was created and followed until June 2013 for survival analysis. RESULTS: Over-80-year-old patients represented 53 % of this cohort, with a median follow-up of 18.6 (3.3-29.5) months. Only 5 % of patients over 80 years received an optimal treatment at discharge [combination of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta blockers (BB), and mineralocorticoid receptor antagonists (MRA)]. During the follow-up period, only BB prescription levels (p = 0.02) increased. In over-80 year-olds, in-hospital mortality was 12 % (range, 10-14) and survival was 62.8 % (59.6-65.7) and 48.7 % (45.4-51.9) at 12 and 24 months, respectively. On multivariate analysis, dyslipidemia [0.74 (0.58-0.94), p = 0.02], vitamin K antagonists [0.55 (0.44-0.69), p < 0.001], ACEi/ARB + BB + MRA [0.56 (0.32-0.96), p = 0.04], and ACEi/ARB + BB [0.57 (0.45-0.72), p < 0.001] were associated with improved survival, conversely to cardiogenic shock [3.37 (1.90-5.98), p < 0.001], denutrition [1.61 (1.24-2.09), p < 0.001], and age over 90 [1.35 (1.09-1.67), p = 0.01]. CONCLUSIONS: These real-life HF data provide insight into prognostic factors and demonstrate that over-80-year-old HF patients displaying several comorbidities are poorly managed, despite the confirmed clinical benefit of HF drugs. PMID- 25537795 TI - Selective Interference Targeting of Lnk in Umbilical Cord-Derived Late Endothelial Progenitor Cells Improves Vascular Repair, Following Hind Limb Ischemic Injury, via Regulation of JAK2/STAT3 Signaling. AB - The Lnk adaptor protein is a strong negative regulator that affects self-renewal of hematopoietic stem cells and vascular repair in injured tissues. However, the signaling mechanisms through which these proteins influence the vascular regeneration function of endothelial progenitor cells (EPCs) remain unknown. In this study, we investigated the effect of Lnk-targeted small interfering RNA (si lnk) on the clonogenic proliferative potential and vascular regenerative function of EPCs and the activation of the JAK/STAT3 signaling pathway. Treatment with stem cell factor (SCF) increased the clonogenic proliferation of si-lnk EPCs. Importantly, activation of the JAK2/STAT3 pathway was enhanced in SCF-sensitized si-lnk EPCs. In a hind limb model of ischemia, transplantation of si-lnk EPCs increased the blood flow ratio, capillary density, proliferation, and survival of transplanted cells, and the secretion of pivotal angiogenic cytokines at ischemic sites. These results provide strong evidence that si-lnk regulates the clonogenic proliferative potential of EPCs through the activation of the JAK2/STAT3 signaling pathway, thereby accelerating angiogenesis and promoting repair in injured hind limb ischemia. Stem Cells 2014;33:1490-1500. PMID- 25537796 TI - Interleukin-4 -589C/T Polymorphism is Associated with Increased Pediatric Asthma Risk: A Meta-Analysis. AB - IL4 -589C/T polymorphism has been implicated in susceptibility to pediatric asthma risk. Several studies investigated the association of this polymorphism with pediatric asthma in different populations. However, the results were contradictory. A meta-analysis was conducted to assess the association between IL4 -589C/T polymorphism and pediatric asthma risk. Databases including Pubmed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Wangfang were searched to find relevant studies. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. A significant association was found between IL4 -589C/T polymorphism and pediatric asthma risk (OR=1.53, 95% CI 1.27-1.85). In the subgroup analyses by ethnicity, the significant association was found among Caucasians (OR=1.70, 95% CI 1.38-2.09) and Asians (OR=1.58, 95% CI 1.23-2.04). Our results suggested that IL4 -589C/T polymorphism conferred a risk factor of pediatric asthma. PMID- 25537797 TI - Comparison of the effects of aerobic conditioning before and after pulmonary allergic inflammation. AB - The aim of this study is to compare the effects of aerobic conditioning (AC) before (ACBS) and after (ACAS) allergic sensitization. BALB/c mice were divided into two main groups: ACBS and ACAS. Each groups was divided into subgroups: control (nonsensitized/nontrained), AC (nonsensitized/trained), ovalbumin (OVA) (sensitized/nontrained), AC+OVA (trained/sensitized), and OVA+AC (sensitized/trained). Sensitization was induced using OVA and AC performed in treadmill (moderate intensity). We examined IgE and IgG1 levels, eosinophil counting, expression of Th1 (interleukin (IL)-2, IFN-alpha) and Th2 cytokines (IL 4, IL-5, IL-13), IL-10, vascular endothelial growth factor (VEGF), and airway remodeling. IgE and IgG1 were decreased only when exercise was performed before sensitization (ACBS); however, there was a decrease of eosinophils, Th2 cytokines, VEGF, and airway remodeling and increase in IL-10 in either ACBS or ACAS groups. Our results demonstrate that aerobic conditioning reduces Th2 response before and after sensitization by increasing IL-10 while the production of anaphylactic antibodies is reduced only when exercise is performed before sensitization. PMID- 25537798 TI - Mesenteric lymph duct drainage attenuates acute lung injury in rats with severe intraperitoneal infection. AB - The purpose of this study is to investigate the hypothesis that the mesenteric lymphatic system plays an important role in acute lung injury in a rat model induced by severe intraperitoneal infection. Male Wistar rats weighing 250~300 g were randomly divided into 3 groups and subjected to sham operation, intraperitoneal infection, or mesenteric lymphatic drainage. The activity of diamine oxidase (DAO) and myeloperoxidase (MPO) were measured by enzymatic assay. The endotoxin levels in plasma, lymph, and bronchoalveolar lavage fluid (BALF) were evaluated using the limulus amoebocyte lysate reagent. The cytokines, adhesion factors, chemokines, and inflammatory factors were detected by ELISA. TLR-4, NF-kB, and IRAK-4 were analyzed by Western blotting. Compared with sham operated rats, rats with intraperitoneal infection had increased MPO and decreased DAO activity in intestinal tissues. Mesenteric lymph drainage reduced the alterations in MPO and DAO activity induced by intraperitoneal infection. The MPO activity in pulmonary tissue and the permeability of pulmonary blood vessels were also increased, which were partially reversed by mesenteric lymph drainage. The endotoxin levels in lymphatic fluid and alveolar perfusion fluid were elevated after intraperitoneal infection but decreased to control levels after lymph drainage. No alterations in the levels of plasma endotoxin were observed. The number of neutrophils was increased in BALF and lymph in the infected rats, and was also reduced after drainage. Lymph drainage also decreased the levels of inflammatory cytokines, chemokines, and adhesion factors in the plasma, lymph, and BALF, as well as the levels of TLR-4, NF-kB, and IRAK-4 in pulmonary and intestinal tissues. The mesenteric lymphatic system is the main pathway involved in early lung injury caused by severe intraperitoneal infection, in which activation of the TLR-4 signal pathway may play a role. PMID- 25537799 TI - Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation. AB - Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS. PMID- 25537800 TI - beta-Cyclodextrin functionalized magnetic mesoporous silica colloid for cholesterol separation. AB - Although cholesterol plays significant biochemical function in the human body, excess of it leads to various disorders, and thus, its control/separation is important in medical science and food industries. However, efficient and selective separation of cholesterol is challenging because cholesterol often exists in microheterogeneous or insoluble forms in remote organ and exists with other chemicals/biochemicals. Here, we have described a colloidal magnetic mesoporous silica (MMS)-based approach for efficient separation of cholesterol in different forms. MMS is functionalized with beta-cyclodextrin for selective binding with cholesterol via host-guest interaction. The colloidal form of MMS offers effective interaction with cholesterol of any form, and magnetic property of MMS offers easier separation of bound cholesterol. Functionalized MMS is efficient in separating cholesterol crystals, water-insoluble cholesterol, and the microheterogeneous form of cholesterol from milk or a cellular environment. Developed material can be used to remove cholesterol from a complex bioenvironment and extended for large-scale cholesterol separation from food. PMID- 25537806 TI - Lateral Opening-wedge Distal Femoral Osteotomy: Pain Relief, Functional Improvement, and Survivorship at 5 Years. AB - BACKGROUND: Distal femoral varus osteotomy may be used to treat valgus knee malalignment or to protect a knee compartment in which cartilage restoration surgery (such as osteochondral or meniscus allografting) has been performed. Medial closing-wedge osteotomy has demonstrated good success in treatment of osteoarthritis in published series, but few studies have evaluated distal femoral lateral opening-wedge osteotomy in terms of correction of deformity, pain and function, and survivorship. QUESTIONS/PURPOSES: (1) Does lateral opening-wedge osteotomy lead to accurate correction? (2) What pain and function levels do patients experience after lateral opening-wedge osteotomy? (3) What are the nonunion, complication, and reoperation rates after lateral opening-wedge osteotomy? METHODS: Between 2000 and 2010, we performed 40 distal femoral osteotomies. Two knees (two patients) underwent a medial closing-wedge osteotomy and were excluded from the present study. Thirty-eight knees (97%) in 36 patients were lateral opening-wedge varus-producing osteotomies; of those, 31 knees (82%) in 30 patients had followup at a minimum of 2 years (mean, 5 years; SD, 2; range, 2-12 years) and comprised the study population. The indications for osteotomy included symptomatic lateral compartment arthritis with clinical valgus deformity or a cartilage or meniscal defect in the lateral compartment with clinical valgus alignment. The study population was stratified into two groups based on reason for osteotomy: patients with isolated symptomatic lateral compartment arthritis (arthritis group; 19 knees [61%]) and patients who underwent joint preservation procedures including osteochondral allograft transplantation or meniscal allograft transplantation (joint preservation group; 12 knees [39%]). Data collection from our institution's osteotomy database included patient demographics, lower extremity coronal alignment, and operative details. Pain and function were measured preoperatively and postoperatively using the International Knee Documentation Committee (IKDC) score. Time to radiographic union, complications, and reoperations were recorded. RESULTS: Twenty-one of 31 knees had postoperative radiographic data available for review. Of these, seven of 15 knees in the arthritis group and three of six knees in the joint preservation group were within the correction goal of +/- 3 degrees from neutral mechanical alignment. In the arthritis group, the mean IKDC total score improved from 47 (SD, 15) preoperatively to 67 (SD, 10) postoperatively. In the joint preservation group, the mean IKDC total score improved from 36 (SD, 12) preoperatively to 62 (SD, 18) postoperatively. One nonunion occurred in the arthritis group. No postoperative complications were experienced. Ten knees in the arthritis group and six knees in the joint preservation group had additional surgery after the osteotomy, consisting primarily of hardware removal, arthroscopy for cartilage related conditions, or conversion to arthroplasty. Survivorship at 5 years, with conversion to arthroplasty as the endpoint, was 74% in the arthritis group and 92% in the joint preservation group. CONCLUSIONS: Lateral opening-wedge distal femoral osteotomy was less accurate in correction of valgus deformity than expected, but the procedure was associated with improved knee pain and function scores. Our clinical and radiographic results are comparable to published series evaluating medial closing-wedge distal femoral osteotomy. Achieving our desired correction of +/- 3 degrees from neutral alignment was clinically difficult. An improved method of preoperative templating and refinement of the intraoperative technique may improve this. Future studies with more patients and longer followup will provide clarity on this topic. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25537807 TI - Sex Differences in Cartilage Topography and Orientation of the Developing Acetabulum: Implications for Hip Preservation Surgery. AB - BACKGROUND: Increased attention is being placed on hip preservation surgery in the early adolescent. An understanding of three-dimensional (3-D) acetabular development as children approach maturity is essential. Changes in acetabular orientation and cartilage topography have not previously been quantified as the adolescent acetabulum completes development. QUESTIONS/PURPOSES: We used a novel 3-D CT analysis of acetabular development in children and adolescents to determine (1) if there were sex-specific differences in the growth rate or surface area of the acetabular articular cartilage; (2) if there were sex specific differences in acetabular version or tilt; and (3) whether the amount of version and tilt present correlated with acetabular coverage. METHODS: We assessed acetabular morphology in 157 patients (314 hips); 71 patients were male and 86 were female. Patient ages ranged from 8 years to 17 years. A 3-D surface reconstruction of each pelvis was created from CT data using MIMICs software. Custom MATLAB software was used to obtain data from the 3-D reconstructions. We calculated articular surface area, acetabular version, and acetabular tilt as well as novel measurements of acetabular morphology, which we termed "coverage angles." These were measured in a radial fashion in all regions of the acetabulum. Data were organized into three age groups: 8 to 10 years old, 10 to 13 years old, and 13 to 17 years old. RESULTS: Male patients had less acetabular anteversion in all three age groups, including at maturity (7 degrees versus 13 degrees , p<0.001; 10 degrees versus 17 degrees , p<0.001; 14 degrees versus 20 degrees , p<0.001). Males had less acetabular tilt in all three age groups (32 degrees versus 34 degrees , p=0.03; 34 degrees versus 38 degrees , p<0.001; 39 degrees versus 41 degrees , p=0.023). Increases in anteversion correlated with increased posterior coverage angles (r=0.805; p<0.001). Increases in tilt were correlated with increases in superior coverage angles (r=0.797; p<0.001). The posterosuperior regions of the acetabulum were the last to develop and this process occurred earlier in females compared with males. Articular surface area increased from 18 (8-10 years) to 24 cm(2) (13-17 years) in males and from 17 (8 10 years) to 21 cm(2) (13-17 years) in females. [corrected]. Articular surface area was higher in males beginning in the 10- to 13-year-old age group (p=0.001). CONCLUSIONS: Using a novel technique to analyze acetabular morphology, we found that acetabular development occurs earlier in females than males. The posterosuperior region of the acetabulum is the final region to develop. The articular cartilage surface area and articular cartilage coverage of the femoral head are increasing in addition to total coverage of the femoral head during the final stages of acetabular development. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25537808 TI - Retrieval analysis of sequentially annealed highly crosslinked polyethylene used in total hip arthroplasty. AB - BACKGROUND: First-generation annealed and second-generation sequentially annealed, highly crosslinked polyethylenes (HXLPEs) have documented reduced clinical wear rates in their first decade of clinical use compared with conventional gamma inert-sterilized polyethylene. However, for both types of annealed HXLPE formulations, little is known about their reasons for revision, their in vivo oxidative stability, and their resistance to mechanical degradation. QUESTIONS/PURPOSES: We asked whether retrieved sequentially annealed HLXPE acetabular liners exhibited: (1) similar reasons for revision; (2) lower oxidation; (3) improved resistance to wear and degradation of mechanical properties; and (4) improved resistance to macroscopic evidence of rim damage when compared with acetabular liners fabricated from single-dose annealed HXLPE. METHODS: One hundred eighty-five revised acetabular liners in two cohorts (annealed and sequentially annealed) were collected in a multicenter retrieval program between 2000 and 2013. We controlled for implantation time between the two cohorts by excluding annealed liners with a greater implantation time than the longest term sequentially annealed retrieval (5 years); the mean implantation time (+/- SD) for the annealed components was 2.2 +/- 1.4 years, and for the sequentially annealed liners, it was 1.2 +/- 1.2 years. Reasons for revision were assessed based on medical records, radiographs, and examinations of the retrieved components. Oxidation was measured at the bearing surface, the backside surface, the locking mechanism, and the rim using Fourier transform infrared spectroscopy (ASTM F2102). Penetration was measured directly using a micrometer (accuracy: 0.001 mm). Mechanical behavior (ultimate load) was measured at the superior and inferior bearing surfaces using the small punch test (ASTM F2183). We used nonparametric statistical testing to analyze for differences in oxidation, penetration rates, and ultimate load when adjusting for HXLPE formulation as a function of implantation time. RESULTS: The acetabular liners in both cohorts were revised most frequently for instability, loosening, and infection. Oxidation indices (OIs) of the sequentially annealed liners were lower than annealed liners at the bearing surface (mean OI difference = 0.3; p < 0.001), the backside surface (mean OI difference = 0.2; p < 0.001), and the rim (mean OI difference = 2.6; p < 0.001). No differences were detected in linear penetration rates between the cohorts (p = 0.10). Ultimate strength at the bearing surface of the HLXPE was not different between sequentially annealed and annealed cohorts (p = 0.72). CONCLUSIONS: We observed evidence of in vivo oxidation in retrieved annealed and, to a lesser extent, retrieved sequentially annealed acetabular liners. However, we observed no association between the levels of oxidation and clinical performance of the liners. CLINICAL RELEVANCE: The findings of this study document the oxidative and mechanical behavior of sequentially annealed HXLPE. The reduced oxidation levels in sequentially annealed liners support the hypothesis that annealing in sequential steps eliminates more free radicals. However, as a result of the short-term followup, analysis of longer-term retrievals is warranted. PMID- 25537809 TI - CORR Insights (r): Intramedullary nailing of femoral diaphyseal metastases: is it necessary to protect the femoral neck? PMID- 25537810 TI - CORR Insights((r)): Time Seeing a Hand Surgeon Is Not Associated With Patient Satisfaction. PMID- 25537811 TI - Letter to the editor: editor's spotlight/take 5: Is single-stage revision according to a strict protocol effective in treatment of chronic knee arthroplasty infections. PMID- 25537812 TI - CORR Insights (r): What clinimetric evidence exists for using hip-specific patient-reported outcome measures in pediatric hip impingement? PMID- 25537813 TI - Redescription of the hyoid apparatus and associated musculature in the extant coelacanth Latimeria chalumnae: functional implications for feeding. AB - The coelacanth Latimeria is the only extant vertebrate in which the neurocranium is divided into an anterior and a posterior portion which articulate by means of an intracranial joint. This articulation is thought to allow an elevation of the snout up to 20-degree angle, which is supposed to enhance mouth gape and velocity, in turn allowing for a powerful suction. Several functional models have been proposed to explain the skull movement in Latimeria, but they disagree on the mechanisms responsible for mandibular depression and intracranial elevation, and more precisely on the role and mobility of the hyoid apparatus during these processes. We here show that the m. coracomandibularis spans ventrally to the palate-mandible joint, and is likely involved in mandibular depression. The hyoid apparatus is sheathed by several layers of ligaments, rendering extensive movements of the hyoid bones in the anteroposterior direction unlikely. Together with the manipulation of the 3D virtual model of the skull, these observations suggest that the hyoid arch is less mobile than previously proposed, and that the movements proposed in previous models are unlikely. In the light of our new observations, we suggest that the mechanisms proposed for explaining the intracranial elevation are incomplete. Moreover, we suggest that the extensive movements of the hyoid arch elements, which were thought to accompany intracranial elevation, are unlikely. In the absence of intracranial elevation, we propose that the movements of the hyoid mainly take place in the transverse plane, allowing the lateral expansion of the orobranchial chamber. PMID- 25537815 TI - Synthesis and platinum complexes of an alane-appended 1,1' bis(phosphino)ferrocene ligand. AB - An aryldimethylalane-appended analogue of 1,1'-bis(diphenylphosphino)ferrocene, FcPPAl, was prepared, and reaction with [Pt(nb)3 ] (nb=norbornene) afforded [Pt(eta(2) -nb)(FcPPAl)] (1). Heating a solution of 1 to 80 degrees C resulted in crystallization of [{Pt(FcPPAl)}2 ] (2), whereas treatment of 1 with C2 H4 , C2 Ph2 , H2 , or CO provided [PtL(FcPPAl)] [L=C2 H4 (3), C2 Ph2 (4)], [PtH2 (FcPPAl)] (5), and [Pt(CO)(FcPPAl)] (6). In all complexes, the FcPPAl ligand is coordinated through both phosphines and the alane. Whereas 2 adopts a T-shaped geometry at platinum, 3-5 are square-pyramidal, and 6 is distorted square-planar. The hydride and carbonyl complexes feature unusual multicenter bonding involving platinum, aluminum, and a hydride or carbonyl ligand. PMID- 25537814 TI - Lessons from writing sessions: a school-based randomized trial with adolescent orphans in Rwanda. AB - BACKGROUND: Treatments for adolescents affected by long-term loss in low- and middle-income countries are lacking. As school-based interventions are cost efficient and easy to disseminate, an evaluation of this treatment setting for adolescents is worthwhile. OBJECTIVE: Examining the effect of a school-based unstructured emotional writing intervention (sensu Pennebaker, group 1) about the loss of a parent to reduce adaptation problems to loss, compared to writing about a hobby (group 2), and non-writing (group 3). METHOD: We randomly assigned 14-18 year-old Rwandan orphans to one of the three conditions (n=23 per condition). Before and after the intervention, subjects completed the Prolonged Grief Questionnaire for Adolescents and the Mini International Neuropsychiatric Interview for Children and Adolescents, Part A, on depression as self-report measures of long-term effects of early parental loss. RESULTS: Repeated measures analyses of variance showed no differential effect for any of the three conditions but revealed a significant effect of time at posttest regarding grief severity. Reduction of grief symptoms was significantly higher in subjects with elevated grief. Depressive symptoms showed no significant change from pre- to posttest in the emotional writing condition, whereas they significantly decreased in the control condition. CONCLUSIONS: RESULTS imply that unstructured, brief emotional writing might not be indicated in adolescents affected by early parental loss who show severe and long-term distress; a more structured approach seems recommendable. PMID- 25537816 TI - Nasal endoscopy and paranasal sinus computerised tomography (CT) findings in an Irish cystic fibrosis adult patient group. AB - Cystic fibrosis (CF) is a common inherited disorder in Caucasians in Ireland having the highest reported incidence. CF has well-recognised clinical sequelae in several physiological systems. Its' impact on the sinonasal system is less well established. We evaluated symptoms, endoscopic and computerised tomographic (CT) findings in an Irish adult CF group with the aim of characterising the relationship between these clinical features in an Irish CF group. Adult CF patients attending a specialist clinic underwent prospective evaluation of sinonasal symptoms using a specifically designed questionnaire. They subsequently underwent nasoendoscopy and CT scanning of their paranasal sinuses. Abnormalities identified were quantified using established radiological (Lund-Mackay) and endoscopic (Lund-Kennedy) scoring systems. The relationship between symptoms of chronic rhinosinusitis (CRS), endoscopic findings and CT abnormalities were then compared. Sixty-three CF patients (n = 63) were studied. 29 patients had a CT scan. Thirty-three CF patients (52%) had no symptoms of CRS. Fifty CF patients (80% of CF group) had evidence of CRS on nasoendoscopy including thirteen patients (20%) with nasal polyposis. 98% of patients scanned have positive findings on CT scan. There was no significant difference between symptomatic and asymptomatic CF groups with respect to their Lund-Kennedy endoscopic score or their Lund-Mackay CT score. 86% demonstrated one or more hypoplastic sinus. There was no increased incidence of hypoplastic sinuses amongst Deltaf508 homozygotes than other mutation groups. PMID- 25537817 TI - Ipsilateral cochlear implantation in patients with sporadic vestibular schwannoma in the only or best hearing ear and in patients with NF2. AB - The aim of this study was to evaluate the cochlear implant (CI) performances in neurofibromatosis type 2 (NF2) patients with bilateral vestibular schwannoma (VS) and in patients with sporadic VS in the only or better hearing ear. All patients with bilateral VS or sporadic VS in the only or better hearing ear who underwent cochlear implantation, either simultaneous to VS surgery or staged after treatment for VS, in the tumor side were chosen for the study. Postimplantation audiometric scores (sound detection, closed-set and open-set discrimination scores) and device use patterns were the main outcome measures. 15 patients were implanted. Eight patients (53 %) were NF2 and seven patients had VS in the only or better hearing ear. One patient was explanted for cerebrospinal fluid leak. In the CI-only condition, the other 14 patients obtained sound detection, 64 % of them achieving open-set discrimination (mean 70 +/- 38 %) and 85 % achieving closed-set discrimination (mean 41 +/- 33 %). At the last follow-up 10 patients (67 %) were using the CI. Cochlear implantation provides hearing in particular cases of patients with bilateral VS or VS in the only or better hearing ear. As long as anatomic preservation of the cochlear nerve is achieved, cochlear implantation may offer improvement in communication skills for most patients. PMID- 25537818 TI - Long-term outcomes of observation for clinically negative central compartment lymph nodes in papillary thyroid carcinoma. AB - The treatment strategy for clinically negative lymph nodes of papillary thyroid carcinoma is controversial. We report the long-term outcomes of a series of cases treated with thyroidectomy without prophylactic central neck dissection. We reviewed 1,397 cases with papillary thyroid carcinoma treated at our institution between 1991 and 2000. One hundred and seventy-two newly diagnosed cases underwent observation for cN0 central neck lymph nodes. Regional recurrence of the ipsilateral side including central compartment and the lateral neck which needs reoperation was considered as key point for analysis. With a mean follow-up of 96.4 months (34-204 months), the overall 10-year disease-specific and recurrence-free survival rates were 99 and 86 %, respectively. The recurrence and reoperation rates of the central compartment were 3 % (5/172) and 4 % (7/172), respectively. Univariate analysis showed that extrathyroidal extension was associated with regional recurrence (99 vs. 82 %; p = 0.002). Central compartment observation is safe in cN0 cases with papillary thyroid carcinoma, particularly in those without extrathyroidal extension. PMID- 25537819 TI - Functional computed tomography scanning for evaluating fusion status after anterior cervical decompression fusion. AB - INTRODUCTION: Nonunion is a major complication of anterior cervical fusion that causes poor outcomes and occasionally requires additional operative intervention. The purpose of this study is to evaluate the accuracy of functional computed tomography (CT) scanning for determining fusion status after anterior cervical fusion by comparing with functional radiographs. MATERIALS AND METHODS: The fusion status in 59 patients treated by anterior cervical fusion was assessed by functional radiography and functional CT scanning at 6 and 12 months after surgery. Fusion rates and clinical symptoms were evaluated. Fusion on functional radiography was defined as less than 2 mm of motion between adjacent spinous processes and a particular bony trabeculation on functional CT; fusion was defined as nonexistence of a clear zone or a gas pattern and a particular bone connection on reconstructed sagittal-view images. RESULTS: Functional radiographs demonstrated solid fusion in 83.9% at 6 months and 91.1% at 12 months postoperatively; functional CT showed solid fusion in 55.3 and 78.6%, respectively. The fusion rate detected on functional CT images was significantly lower than that on functional radiographs at each period. At 6 months postoperatively, patients with incomplete union on functional CT were more likely to have neck pain than those who had complete union on functional CT. (46.2 vs 13.3%, P < 0.05) CONCLUSION: Functional CT can detect nonunion more clearly than functional radiography. At 6 months postoperatively, patients with incomplete union on functional CT images were likely to have more neck pain. Functional CT may allow accurate detection of symptomatic nonunion after anterior cervical fusion. PMID- 25537820 TI - Musculoskeletal: what's different in children? Fall, right hand braces fall, pain in forearm and wrist. PMID- 25537822 TI - Can threshold for MPO by flow cytometry be reduced in classifying acute leukaemia? A comparison of flow cytometric and cytochemical myeloperoxidase using different flow cytometric cut-offs. AB - Objectives Myeloperoxidase (MPO) detection either by enzyme cytochemistry (cMPO) or flow cytometry (fMPO) plays a major role in acute leukaemia (AL) diagnosis as per World Health Organization (WHO) 2008 classification. Although 3% cMPO was recommended as positivity, no specific cut-off had been mentioned by WHO for fMPO. Various authors recommend different cut-offs ranging from 3 to 28% for fMPO. The aim of this study was to analyse fMPO cut-offs ranging from 3 to 10% in classifying AL and to assess whether a new cut-off could be suggested. Methods Totally, 216 cases of AL were retrospectively analysed for fMPO ranging from 3 to 10% and compared with gold standard. Presence of cMPO (>=3%) and/or expression of two or more pan-myeloid markers (CD13, CD33, and CD117) in the absence of CD19 and CD3 were kept as gold standard for diagnosis of acute myeloid leukaemia (AML). Results Sensitivities for classifying AL as AML/mixed phenotypic acute leukaemia (MPAL) at 3, 5.4, and 10% were 98.3, 98.3, and 96.6%, respectively, whereas specificities at this cut-off were 22.2, 91, and 71%, respectively. Discussion Only few studies have been done in this aspect to define a consistent cut-off for fMPO for proper classification of acute leukaemias. This was one of the largest and few studies available till date in this regard. Conclusion The newer cut-off for fMPO (5.4%) emerged out from our study with best sensitivity and specificity for accurately classifying AL cases into acute lymphoblastic leukaemia, AML, and MPAL. PMID- 25537821 TI - Complications of minimally invasive procedures of the abdomen and pelvis: a comprehensive update on the clinical and imaging features. AB - Minimally invasive gastrointestinal, genitourinary, and gynecological procedures are widely used in the clinical practice for diagnostic and therapeutic purposes. Complications both minor and major are not uncommon with these procedures. Imaging plays an important role in the detection and optimal management of these complications. Familiarity with the clinical and imaging features of these complications by radiologists can help in their timely detection. PMID- 25537824 TI - Retraction. Fenofibrate improves the impaired endothelial progenitor cell function through inhibiting eNOS uncoupling in diabetic mice. PMID- 25537823 TI - Reliability of magnetic resonance elastography using multislice two-dimensional spin-echo echo-planar imaging (SE-EPI) and three-dimensional inversion reconstruction for assessing renal stiffness. AB - BACKGROUND: To evaluate the reliability of MRE using a spin-echo echo-planar imaging (SE-EPI) renal MRE technique in healthy volunteers. METHODS: Institutional review board approved prospective study in which all participants provided written informed consent. Sixteen healthy volunteers comprising seven males and nine females with a median age of 35 years (age range: 23 to 59 years) were included. Coronal 90 Hz and 60 Hz MRE acquisitions were performed twice within a 30-min interval between examinations. Renal MRE reliability was assessed by (i) test-retest repeatability, and (ii) inter-rater agreement between two independent readers. The MRE-measured averaged renal stiffness values were evaluated using: intraclass correlation coefficient (ICC), Bland-Altman and the within-subject coefficient of variation (COV). RESULTS: For test-retest repeatability, Bland-Altman showed a mean stiffness difference between examinations of 0.07 kPa (95% limits of agreement: -1.41, 1.54) at 90 Hz and 0.01 kPa (95% limits of agreement: -0.51, 0.53) at 60 Hz. Coefficient of repeatability was 1.47 kPa and 0.52 kPa at 90 Hz and 60 Hz, respectively. The within-subject COV was 13.6% and 7.7% at 90 Hz and 60 Hz, respectively. ICC values were 0.922 and 0.907 for test-retest repeatability and 0.998 and 0.989 for inter-rater agreement, respectively (P < 0.001). CONCLUSION: SE-EPI renal MRE is a reliable technique. PMID- 25537825 TI - Themed section. PMID- 25537826 TI - The extent of changes in the membranous urethra angle is associated with the outcome of retrourethral transobturator sling procedure. AB - PURPOSE: To evaluate the outcome of the retrourethral transobturator sling (RTS) by functional magnetic resonance imaging (MRI) and to identify parameters associated with sling failure. METHODS: Of thirty recruited men with postprostatectomy stress urinary incontinence (SUI), 26 consecutively underwent functional MRI before sling procedure and 12 months thereafter in a prospective clinical cohort observational study. Periurethral/urethral fibrosis and sling visualization were evaluated on static sequences. The angle of the membranous urethra, position of the bladder neck and external urethral sphincter were assessed during Valsalva's maneuver and voiding. Sling success was defined as no or one dry "security" pad. RESULTS: The success and failure rates were 58 % (15/26 patients) and 42 % (11/26 patients), respectively. The sling leads to reduction in the membranous urethra angle during Valsalva's maneuver (39.55 degrees vs. 36.82 degrees , p = 0.025) and voiding (38.25 degrees vs. 34.83 degrees , p = 0.001) and elevation of the external urethral sphincter (2.9 vs. 4.8 mm, p = 0.017). Preoperative wider angle of the membranous urethra was significantly correlated with severe preoperative incontinence. Sling failure (p = 0.001) and severe preoperative incontinence (p = 0.001) were significantly related to only small changes of the membranous urethra angle. The interrater and intrarater reliability for membranous urethra angle was excellent (intraclass correlation coefficient >=0.75). CONCLUSIONS: The RTS leads to reduction in the membranous urethra angle. The extent of the changes in the membranous urethra angle is associated with RTS outcome. Functional MRI is a reliable noninvasive visualization tool of interactions between the sling and pelvic floor for further research on the complex nature of postprostatectomy SUI. PMID- 25537827 TI - Secondary hyperparathyroidism is associated with pulmonary hypertension in older patients with chronic kidney disease and proteinuria. AB - PURPOSE: Hyperparathyroidism is associated with pulmonary vascular calcification and pulmonary hypertension (PH) in a chronic kidney failure dog model, and increased prevalence of PH and a PH-hyperparathyroidism relationship in pre dialysis chronic kidney disease (CKD) and hemodialysis patients are reported. This study investigated the prevalence of PH and relationships between PH and metabolic abnormalities in patients with stage 1-4 proteinuria CKD. METHODS: One hundred and ninety patients (mean age 61 +/- 17.4, 116 males) with proteinuria CKD and no coronary diseases, congestive heart failure, smoking history, and pulmonary diseases were enrolled. Estimated glomerular filtration rate was 39.7 +/- 23 ml/min. CKD etiology was diabetes mellitus in 52 (27.3 %), chronic glomerulonephritis or tubulointerstitial nephritis in 56 (29.4 %), hypertension in 36 (19 %), and other etiologies (nephrolithiasis, obstructive nephropathy, and amyloidosis) in 46 (25.3 %) patients. Echocardiography was performed, and systolic pulmonary artery pressure (PAP) and left ventricular ejection fraction were determined. Laboratory tests examined lipid parameters, serum albumin, urea, creatinine, calcium, phosphorus, C-reactive protein, parathyroid hormone, ferritin, and hemoglobin levels. RESULTS: PH (PAP >35 mmHg) was detected in 68 patients (35.9 %). Patients with PH were older (68 +/- 12.3 vs. 52.1 +/- 16.7, p = 0.03), had lower ejection fractions (51.3 +/- 13.4 vs. 60.8 +/- 9.1 %, p = 0.003), lower hemoglobin (11.3 +/- 1.5 vs. 12.1 +/- 1.9, p = 0.05), and higher parathyroid hormone (218 +/- 159.3 vs. 127.7 +/- 67.4 pg/ml, p = 0.05) levels. The remaining parameters were similar between groups. CONCLUSIONS: Older age, lower ejection fraction, and secondary hyperparathyroidism may contribute to PH in stage 1-4 proteinuria CKD. PMID- 25537828 TI - Early stages of bone fracture healing: formation of a fibrin-collagen scaffold in the fracture hematoma. AB - This work is concerned with the sequence of events taking place during the first stages of bone fracture healing, from bone breakup until the formation of early fibrous callus (EFC). The latter provides a scaffold over which subsequent remodeling processes will eventually result in successful bone repair. Specifically, some mathematical models are proposed to estimate the time required for (1) the formation immediately after fracture of a fibrin clot, described in terms of a phase transition in a polymerization process, and (2) the onset of EFC which is produced when fibroblasts arising from differentiation of chemotactically recruited mesenchymal stem cells remodel a previous fibrin clot by releasing a collagen matrix over it. An attempt has been made to keep models as simple as possible, so that a explicit dependence of the estimates obtained on relevant biochemical parameters involved is obtained. PMID- 25537829 TI - Allergic Fungal Sinusitis. AB - A 42 year old male presents with worsening pain and an increase in thick chronic drainage of the left sinus. Image studies show complete opacification of the left frontal sinus, left sphenoid sinus, and the left maxillary sinus. The patient was taken to the operating room and tissue for microscopic evaluation was obtained. The microscopic findings were classic for allergic fungal sinusitis: areas of alternating mucinous material and inflammatory cell debris and abundant Charcot Leyden crystals. Cultures were performed and the patient began steroid therapy and desensitization therapy. PMID- 25537830 TI - Eagle's Syndrome. AB - Eagle's Syndrome (ES) refers to a symptomatic anomaly due to elongation of the styloid process or mineralization of the styloid complex. If not diagnosed timely and treated properly, elongation of the styloid process or the hyper mineralization of the stylohyoid ligament may eventually lead to complete ossification of the stylohyoid complex. Non-specific head and neck symptoms of the ES may pose diagnostic challenges to the clinician. Therefore it is crucial to include ES among differential diagnosis when evaluating patients with similar head and neck symptoms. Once the diagnosis is confirmed, treatment plan should be tailored in accordance with the individual requirements of the case and performed without delay. Both pharmacological and surgical methods have been described for the treatment of the patients with ES. However for those who suffer from persistent symptoms, surgical removal of the elongated styloid process is the treatment of choice and can be done with an intraoral or an extraoral approach. The aim of this work is to present unusual clinical symptoms and radiologic findings of ES due to complete ossification of the stylohyoid complex. The importance of a correct diagnosis and appropriate treatment are highlighted. PMID- 25537831 TI - The lipooligosaccharide-modifying enzyme LptA enhances gonococcal defence against human neutrophils. AB - Infection with Neisseria gonorrhoeae (Gc) is marked by an influx of neutrophils to the site of infection. Despite a robust immune response, viable Gc can be recovered from neutrophil-rich gonorrhoeal secretions. Gc enzymatically modifies the lipid A portion of lipooligosaccharide by the addition of phosphoethanolamine to the phosphate group at the 4' position. Loss of lipooligosaccharide phosphoethanolamine transferase A (LptA), the enzyme catalysing this reaction, increases bacterial sensitivity to killing by human complement and cationic antimicrobial peptides. Here, we investigated the importance of LptA for interactions between Gc and human neutrophils. We found that lptA mutant Gc was significantly more sensitive to killing by human neutrophils. Three mechanisms underlie the increased sensitivity of lptA mutant Gc to neutrophils. (i) lptA mutant Gc is more likely to reside in mature phagolysosomes than LptA-expressing bacteria. (ii) lptA mutant Gc is more sensitive to killing by components found in neutrophil granules, including CAP37/azurocidin, human neutrophil peptide 1 and the serine protease cathepsin G. (iii) lptA mutant Gc is more susceptible to killing by antimicrobial components that are exocytosed from neutrophils, including those decorating neutrophil extracellular traps. By increasing the resistance of Gc to the bactericidal activity of neutrophils, LptA-catalysed modification of lipooligosaccharide enhances survival of Gc from the human inflammatory response during acute gonorrhoea. PMID- 25537832 TI - Self-illuminative cascade-reaction-driven anticancer therapeutic cassettes made of cooperatively interactive nanocomplexes. AB - Therapeutic options based on near-infrared (NIR) wavelengths have attracted attention owing to in vivo lowest-background interventions and the development of several nano-architectures with localized surface plasmon resonance. Because of their limited tissue penetration, the clinical use of NIR light-driven treatments is not widespread; this technology is inapplicable to infection sites in the deeper areas of internal tissues. In this study, we demonstrate a self illuminative therapeutic cassette able to exert anticancer effects via a series of enzymatic, chemical, and optical cooperative cascade reactions. It consists of (1) NIR-illuminative nanocomplexes and (2) NIR-sensitive therapeutic cassettes, which demonstrate a 60% chemically-induced killing effect in a prostate cancer model without external NIR irradiation. This technology can also be actively exploited as an imaging agent due to adaptation of a self-illuminating nanocomplex. Consequently, these novel therapeutic cassettes, which work not only as a powerful internal NIR stimulant, but also as a biological imaging platform, provide a new rational design concept for biomedical use. PMID- 25537833 TI - Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. AB - AIMS/HYPOTHESIS: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity. METHODS: Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2alpha mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. RESULTS: We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinase-eukaryotic translation factor 2alpha activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21 null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. CONCLUSIONS/INTERPRETATION: Our results suggest that FGF21 plays an important role in the adaptive response to ER stress- or obesity-induced hepatic metabolic stress. PMID- 25537834 TI - Targeting 12-lipoxygenase as a novel strategy to combat the effects of inflammation on beta cells in diabetes. AB - Inflammation is a pathological feature of the pancreatic islet in type 1 and 2 diabetes, contributing to islet endocrine cell failure and the onset of hyperglycaemia in both diseases. Indeed, numerous immune targets have recently been found to be altered in type 2 diabetes, but few have yet to be translated to the clinic. Taylor-Fishwick and colleagues aimed to change this by performing proof-of-concept studies investigating the efficacy of small molecule inhibitors of 12-lipoxygenase in rodent and human beta cells exposed to proinflammatory cytokines. The results of these studies, published in this issue of Diabetologia (DOI: 10.1007/s00125-014-3452-0), build on a wealth of preclinical data that have implicated 12-lipoxygenase in rodent models of type 1 and 2 diabetes. While there remain some unanswered mechanistic questions regarding how cytokines regulate 12 lipoxygenase activation and the downstream consequences of activation, it is hoped that future studies with newly identified selective inhibitors may overcome the in vitro limitations of this study and allow for the eventual clinical translation of these highly interesting findings. PMID- 25537835 TI - Pharmacokinetics of diluted (U20) insulin aspart compared with standard (U100) in children aged 3-6 years with type 1 diabetes during closed-loop insulin delivery: a randomised clinical trial. AB - AIMS/HYPOTHESIS: The aim of this study was to compare the pharmacokinetics of two different concentrations of insulin aspart (B28Asp human insulin) in children aged 3-6 years with type 1 diabetes. METHODS: Young children with type 1 diabetes underwent an open-label, randomised, two-period crossover study in a clinical research facility, 2-6 weeks apart. In random order, diluted (1:5 dilution with saline [154 mmol/l NaCl]; 20 U/ml) or standard strength (100 U/ml) insulin aspart was administered via an insulin pump as a meal bolus and then overnight by closed loop insulin delivery as determined by a model predictive algorithm. Plasma insulin was measured every 30-60 min from 17:00 hours on day 1 to 8:00 hours on day 2. We measured the time-to-peak insulin concentration (tmax), insulin metabolic clearance rate (MCR(I)) and background insulin concentration (ins(c)) using compartmental modelling. RESULTS: Eleven children (six male; age range 3.75 6.96 years, HbA1c 7.6% +/- 1.3% [60 +/- 14 mmol/mol], BMI standard deviation score 1.0 +/- 0.8, duration of diabetes 2.2 +/- 1.0 years, total daily dose 12.9 [10.6-16.5] U, fasting C-peptide concentration 5 [5-17.1] pmol/l; mean +/- SD or median [interquartile range]) participated in the study. No differences between standard and diluted insulin were observed in terms of t max (59.2 +/- 14.4 vs 61.6 +/- 8.7) min for standard vs diluted, p = 0.59; MCR I (1.98 * 10(-2) +/- 0.99 * 10(-2) vs 1.89 * 10(-2) +/- 0.82 * 10(-2) 1/kg/min, p = 0.47), and ins c (34 [1-72] vs 23 [3-65] pmol/l, p = 0.66). However, t max showed less intersubject variability following administration of diluted aspart (SD 14.4 vs 8.7 min, p = 0.047). CONCLUSIONS/INTERPRETATION: Diluting insulin aspart does not change its pharmacokinetics. However, it may result in less variable absorption and could be used in young children with type 1 diabetes undergoing closed-loop insulin delivery. TRIAL REGISTRATION: Clinicaltrials.gov NCT01557634. FUNDING: FUNDING was provided by the JDRF, 7th Framework Programme of the European Union, Wellcome Trust Strategic Award and the National Institute for Health Research Cambridge Biomedical Research Centre. PMID- 25537837 TI - Purification of human induced pluripotent stem cell-derived neural precursors using magnetic activated cell sorting. AB - Neural precursor (NP) cells derived from human induced pluripotent stem cells (hiPSCs), and their neuronal progeny, will play an important role in disease modeling, drug screening tests, central nervous system development studies, and may even become valuable for regenerative medicine treatments. Nonetheless, it is challenging to obtain homogeneous and synchronously differentiated NP populations from hiPSCs, and after neural commitment many pluripotent stem cells remain in the differentiated cultures. Here, we describe an efficient and simple protocol to differentiate hiPSC-derived NPs in 12 days, and we include a final purification stage where Tra-1-60+ pluripotent stem cells (PSCs) are removed using magnetic activated cell sorting (MACS), leaving the NP population nearly free of PSCs. PMID- 25537836 TI - Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. AB - BACKGROUND: Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in patient with head and neck cancer. The objective of the current study was to evaluate the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of patients with head and neck cancer who received concurrent chemoradiotherapy. METHODS: Patients who had head and neck cancer diagnosed between 2000 and 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared with a noncancer population. RESULTS: Of 3513 patients with head and neck cancer, 801 developed aspiration pneumonia at a median of 5 months after initiating treatment. The 1-year and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8%, respectively, for patients with head and neck cancer and 3.6% and 8.7%, respectively, for noncancer controls. Among the patients with cancer, multivariate analysis identified independent risk factors (P < .05) for aspiration pneumonia, including hypopharyngeal and nasopharyngeal tumors, male gender, older age, increased comorbidity, no surgery before radiation, and care received at a teaching hospital. Among the patients with cancer who experienced aspiration pneumonia, 674 (84%) were hospitalized; and, of these, 301 (45%) were admitted to an intensive care unit. The 30-day mortality rate after hospitalization for aspiration pneumonia was 32.5%. Aspiration pneumonia was associated with a 42% increased risk of death (hazard ratio, 1.42; P < .001) after controlling for confounders. CONCLUSIONS: The current results indicated that nearly 25% of elderly patients will develop aspiration pneumonia within 5 years after receiving chemoradiotherapy for head and neck cancer. A better understanding of mitigating factors will help identify patients who are at risk for this potentially lethal complication. PMID- 25537838 TI - The suspension culture of undifferentiated human pluripotent stem cells using spinner flasks. AB - Suspension cell culture systems with superior scalability, controllability, and monitoring options are an attractive alternative to static adherent culture methods for expansion and production of human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs). In this chapter, we describe a scalable suspension culture system using serum-free, feeder-free, matrix-free, and defined culture conditions with spinner flasks for hPSC maintenance and expansion. This suspension culture system provides an efficient and GMP-compatible process for large-scale manufacture of hPSCs. PMID- 25537839 TI - Therapeutic mesenchymal stromal cells: where we are headed. AB - With a range of therapeutic uses, from diabetes and Crohn's disease to wound repair, interest in the function, characterization, and expansion of mesenchymal stromal cells (MSCs) is growing rapidly. When considering the therapeutic use of MSCs, one must take into account a multitude of options including the ideal source of MSCs, the ideal donor, and the best means of expansion. Here we discuss different sources of MSCs, including cord blood, bone marrow, and adipose tissue, the option of using autologous and allogeneic donors, and finally we discuss GMP applicable expansion protocols aimed at expanding MSCs for clinical use. PMID- 25537840 TI - The fate of redundant cues: Further analysis of the redundancy effect. AB - Pearce, Dopson, Haselgrove, and Esber (Journal of Experimental Psychology: Animal Behavior Processes, 38, 167-179, 2012) conducted a series of experiments with rats and pigeons in which the conditioned responding elicited by two types of redundant cue was compared. One of these redundant cues was a blocked cue X from A+ AX+ training, whereas the other was cue Y from a simple discrimination BY+ CY . Greater conditioned responding was elicited by X than by Y; we refer to this difference as the redundancy effect. To test an explanation of this effect in terms of comparator theory (Denniston, Savastano, & Miller, 2001), a single group of rats in Experiment 1 received training of the form A+ AX+ BY+ CY-, followed by an A- Y+ discrimination. Responding to the individual cues was tested both before and after the latter discrimination. In addition to a replication of the redundancy effect during the earlier test, we observed stronger responding to B than to X, both during the earlier test and, in contradiction of the theory, after the A- Y+ discrimination. In Experiment 2, a blocking group received A+ AX+, a continuous group received AX+ BX-, and a partial group received AX+/- BX+/ training. Subsequent tests with X again demonstrated the redundancy effect, but also revealed a stronger response in the partial than in the continuous group. This pattern of results is difficult to explain with error-correction theories that assume that stimuli compete for associative strength during conditioning. We suggest, instead, that the influence of a redundant cue is determined by its relationship with the event with which it is paired, and by the attention it is paid. PMID- 25537841 TI - Comparison of spatial learning in the partially baited radial-arm maze task between commonly used rat strains: Wistar, Spargue-Dawley, Long-Evans, and outcrossed Wistar/Sprague-Dawley. AB - Strain-related differences in animals' cognitive ability affect the outcomes of experiments and may be responsible for discrepant results obtained by different research groups. Therefore, behavioral phenotyping of laboratory animals belonging to different strains is important. The aim of the present study was to compare the variation in allothetic visuospatial learning in most commonly used laboratory rat strains: inbred Wistar (W) and Sprague-Dawley (SD), outcrossed Wistar/Sprague-Dawley (W/SD), and outbred Long Evans (LE) rats. All rats were trained to the arbitrary performance criterion of 83 % correct responses in the partially baited 12-arm radial maze allowing for simultaneous evaluation of both working and reference memory. In the present study, testing albino versus pigmented and inbred versus outcrossed rats revealed significant strain-dependent differences with the inbred SD rats manifesting lower performance on all learning measures compared to other strains. On the other hand, the outcrossed W/SD rats showed a lower frequency of reference memory errors and faster rate of task acquisition compared to both LE and W rats, with W rats showing a lower frequency of working memory errors compared to other strains. In conclusion, albinism apparently did not reduce the animals' performance in the allothetic visuospatial learning task, while outcrossing improved the spatial learning. A differential effect of strain on the contribution of each error type to the animals' overall performance was observed. The strain-dependent differences were more pronounced between subpopulations of learning-deficient individuals ("poor" learners), and generally the reference memory errors contributed more to the final behavioral output than did the working memory errors. PMID- 25537842 TI - The ambiguousness of 3D. PMID- 25537843 TI - Reversible photoswitching of RNA hybridization at room temperature with an azobenzene C-nucleoside. AB - Photoregulation of RNA remains a challenging task as the introduction of a photoswitch entails changes in the shape and the stability of the duplex that strongly depend on the chosen linker strategy. Herein, the influence of a novel nucleosidic linker moiety on the photoregulation efficiency of azobenzene is investigated. To this purpose, two azobenzene C-nucleosides were stereoselectively synthesized, characterized, and incorporated into RNA oligonucleotides. Spectroscopic characterization revealed a reversible and fast switching process, even at 20 degrees C, and a high thermal stability of the respective cis isomers. The photoregulation efficiency of RNA duplexes upon trans to-cis isomerization was investigated by using melting point studies and compared with the known D-threoninol-based azobenzene system, revealing a photoswitching amplitude of the new residues exceeding 90 % even at room temperature. Structural changes in the duplexes upon photoisomerization were investigated by using MM/MD calculations. The excellent photoswitching performance at room temperature and the high thermal stability make these new azobenzene residues promising candidates for in-vivo and nanoarchitecture photoregulation applications of RNA. PMID- 25537845 TI - Commentary: Reproductive health and rights in Brazil 20 years post-International Conference on Population and Development. PMID- 25537846 TI - Notice of retraction. PMID- 25537844 TI - Guidance on platelet transfusion for patients with hypoproliferative thrombocytopenia. AB - Patients with hypoproliferative thrombocytopenia are at an increased risk for hemorrhage and alloimmunization to platelets. Updated guidance for optimizing platelet transfusion therapy is needed as data from recent pivotal trials have the potential to change practice. This guideline, developed by a large international panel using a systematic search strategy and standardized methods to develop recommendations, incorporates recent trials not available when previous guidelines were developed. We found that prophylactic platelet transfusion for platelet counts less than or equal to 10 * 10(9)/L is the optimal approach to decrease the risk of hemorrhage for patients requiring chemotherapy or undergoing allogeneic or autologous transplantation. A low dose of platelets (1.41 * 10(11)/m2) is hemostatically as effective as higher dose of platelets but requires more frequent platelet transfusions suggesting that low-dose platelets may be used in hospitalized patients. For outpatients, a median dose (2.4 * 10(11)/m2) may be more cost-effective to prevent clinic visits only to receive a transfusion. In terms of platelet products, whole blood-derived platelet concentrates can be used interchangeably with apheresis platelets, and ABO compatible platelet should be given to improve platelet increments and decrease the rate of refractoriness to platelet transfusion. For RhD-negative female children or women of child-bearing potential who have received RhD-positive platelets, Rh immunoglobulin should probably be given to prevent immunization to the RhD antigen. Providing platelet support for the alloimmunized refractory patients with ABO-matched and HLA-selected or crossmatched products is of some benefit, yet the degree of benefit needs to be assessed in the era of leukoreduction. PMID- 25537847 TI - Differential diagnosis of liver tumours using intraoperative real-time tissue elastography. AB - BACKGROUND: Real-time tissue elastography is an innovative tool that informs the surgeon about tissue elasticity by applying the principle of ultrasonography. The aim of this study was to investigate the accuracy of intraoperative real-time tissue elastography (IORTE) for the detection and characterization of liver tumours. METHODS: Between October 2010 and November 2011, IORTE was performed for liver lesions after the completion of routine B-mode intraoperative ultrasonography (IOUS). The elasticity images of all tumours, except those of cysts, were classified into six categories according to modified criteria (types 1-6), according to the degree of strain contrast with the surrounding liver. The concordance of IORTE with pathological examination of the tumour, B-mode IOUS and clinical diagnosis after follow-up was assessed. RESULTS: Images were obtained from 92 hepatocellular carcinomas (HCCs), 92 adenocarcinomas, 19 other malignant tumours and 18 benign tumours in 158 patients. Using a minilinear probe, 73 of 88 HCCs were classified as having a 'HCC pattern' (type 3, 4 or 5), resulting in a sensitivity of 83.0 per cent, a specificity of 67.2 per cent and an accuracy of 73.7 per cent. Some 66 of 90 adenocarcinomas were classified as 'adenocarcinoma pattern' (type 6), resulting in a sensitivity of 73.3 per cent, specificity of 95.1 per cent and accuracy of 85.9 per cent. IORTE detected seven new lesions (8 per cent). CONCLUSION: IORTE is useful for the detection and characterization of liver tumours. PMID- 25537848 TI - Thermoelectric effect in Aharonov-Bohm structures. AB - The thermoelectric effects of a single Aharonov-Bohm (SAB) ring and coupled double Aharonov-Bohm (DAB) rings have been investigated on a theoretical basis, taking into account the contributions of both electrons and phonons to the transport process by using the nonequilibrium Green's function technique. The thermoelectric figure of merit of the coupled DAB rings cannot be predicted directly by combining the values of two SAB ring systems due to the contribution of electron-phonon interaction to coupling between the two sites connecting the rings. We find that thermoelectric efficiency can be optimized by modulating the phases of the magnetic flux threading the two rings. PMID- 25537850 TI - Photoresponsive ionic liquid crystals based on azobenzene guanidinium salts. AB - The use of non-ionic LC phases as anisotropic matrices for E/Z-isomerization of azo-guest molecules is often restricted due to limited solubilities and demixing effects. In this study we therefore employed an ionic liquid crystal (ILC) matrix to follow the photo-induced E/Z-isomerization of ionic mesogenic azobenzene guanidinium guests. The latter were prepared from 4-hydroxy-4' (octyloxy)azobenzene, which was first treated with N-(bromoalkyl)phthalimides to introduce the spacer with varying chain length. Removal of phthalimide and final reaction with a formamidinium salt linked the ionic head group to the photoisomerizable azobenzene unit. Investigation of the mesomorphic behaviour revealed for all azobenzene ILCs smectic A mesophases with high translational order parameters and partial bilayers, as could be stated by layer spacing d. Similar packing behaviour was found for the solid state by X-ray crystal structure analysis. E/Z-isomerization of azobenzene ILCs which were completely miscible with the ionic LC phase of C12MIM-Br as anisotropic host was induced by irradiation with UV light and the reisomerization observed by time-resolved UV Vis spectroscopy. For comparison, water was used as isotropic host. Z/E reisomerization activation energies exhibited similar values of 97-100 kJ mol(-1) irrespective of spacer lengths and the type of host. The results demonstrate that a proper match of steric requirements of host and guest as well as layer spacings are needed for a decreased activation energy. PMID- 25537851 TI - Role of M2-like macrophage recruitment during angiogenic growth factor therapy. AB - Therapeutic angiogenesis has yet to fulfill its promise for the clinical treatment of ischemic diseases. Given the impact of macrophages during pathophysiological angiogenesis, we asked whether macrophages may similarly modulate vascular responses to targeted angiogenic therapies. Mouse matrigel plug assay and rat myocardial infarction (MI) model were used to assess angiogenic therapy with either VEGF-A or FGF-2 with HGF (F+H) delivered locally via albumin alginate microcapsules. The infiltration of classical M1-type and alternative M2 like macrophages was assessed. Clodronate was used to prevent macrophage recruitment, and the VEGFR2 blocking antibody, DC101, to prevent VEGF-A signaling. At 3 weeks after matrigel implantation, the combination therapy (F+H) led to increased total, and specifically M2-like, macrophage infiltration versus control and VEGF-A plugs, correlating with the angiogenic response. In contrast, VEGF-A preferential recruited M1-type macrophages. In agreement with a direct role of M2-like macrophages in F+H-induced vessel growth, clodronate radically decreased angiogenesis. Further, DC101 reduced F+H-induced angiogenesis, without altering macrophage infiltration, revealing macrophage-derived VEGF-A as a crucial determinant of tissue responsiveness. Similarly, increased cardiac M2 like macrophage infiltration was found following F+H therapy post-MI, with strong correlation between macrophage levels and angiogenic and arteriogenic responses. In conclusion, M2-like macrophages play a decisive role, linked to VEGF-A production, in regulation of tissue responsiveness to angiogenic therapies including the combination of F+H. Our data suggest that future attempts at therapeutic revascularization in ischemic patients might benefit from coupling targeted growth factor delivery with either direct or indirect approaches to recruit pro-angiogenic macrophages in order to maximize therapeutic angiogenic/arteriogenic responses. PMID- 25537849 TI - Mutational escape of CD8+ T cell epitopes: implications for prevention and therapy of persistent hepatitis virus infections. AB - Over the past two decades, much has been learned about how human viruses evade T cell immunity to establish persistent infection. The lessons are particularly relevant to two hepatotropic viruses, HBV and HCV, that are very significant global public health problems. Although HCV and HBV are very different, the natural history of persistent infections with these viruses in humans shares some common features including failure of T cell immunity. During recent years, large sequence studies of HCV have characterized intra-host evolution as well as sequence diversity between hosts in great detail. Combined with studies of CD8+ T cell phenotype and function, it is now apparent that the T cell response shapes viral evolution. In turn, HCV sequence diversity influences the quality of the CD8+ T cell response and thus infection outcome. Here, we review published studies of CD8+ T cell selection pressure and mutational escape of the virus. Potential consequences for therapeutic strategies to restore T cell immunity against persistent human viruses, most notably HBV, are discussed. PMID- 25537853 TI - Exploring abortion attitudes of US adolescents and young adults using social media. AB - OBJECTIVES: To explore the use of social media for recruitment of adolescents and young adults in the United States and to describe how they learn and feel about abortion. STUDY DESIGN: Americans 13-29years of age were recruited through web based social media to complete an online survey about sex and pregnancy-related decision making, including abortion. Descriptive statistics were used to compare the study population's demographics and prevalence of sexual experience to national databases [US Census and National Survey of Family Growth (NSFG)] and to describe abortion attitudes and related topics. RESULTS: Survey completion rate was 78% and 996 participants' responses were analyzed. The study population appeared diverse with respect to gender, ethnicity, race and geographic distribution with some similarities to the US Census and was sexually active at an earlier age compared to the NSFG. While the majority of participants supported abortion (74%), acceptance of abortion for themselves or their partners varied based on circumstances. The media were the most popular sources of information for learning about sex and abortion (73% and 68%, respectively). Parents had the most influence on individuals' abortion stances compared to other sources. CONCLUSIONS: Social media recruitment, compared to traditional methods, has the potential to reach a geographically, ethnically and racially diverse group of young people to study sensitive topics in an economical and expedient fashion. Similar to the general population, the study population's abortion views fell on a spectrum with overall supportive attitudes toward abortion. The media served as common sources of information for learning about both sex and abortion. IMPLICATIONS: Web-based social media offer a novel recruiting strategy to study sensitive topics such as abortion attitudes among difficult-to-reach populations such as adolescents and young adults. The presented findings begin characterizing young people's abortion attitudes, offering a foundation for more in-depth research. PMID- 25537854 TI - A novel method for the photographic recovery of fingermark impressions from ammunition cases using digital imaging. AB - The photographic preservation of fingermark impression evidence found on ammunition cases remains problematic due to the cylindrical shape of the deposition substrate preventing complete capture of the impression in a single image. A novel method was developed for the photographic recovery of fingermarks from curved surfaces using digital imaging. The process involves the digital construction of a complete impression image made from several different images captured from multiple camera perspectives. Fingermark impressions deposited onto 9-mm and 0.22-caliber brass cartridge cases and a plastic 12-gauge shotgun shell were tested using various image parameters, including digital stitching method, number of images per 360 degrees rotation of shell, image cropping, and overlap. The results suggest that this method may be successfully used to recover fingermark impression evidence from the surfaces of ammunition cases or other similar cylindrical surfaces. PMID- 25537852 TI - Salsolinol, an endogenous compound triggers a two-phase opposing action in the central nervous system. AB - Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), an endogenous compound present in the brain, was suspected of participation in the etiopathogenesis of Parkinson's disease, the most common serious movement disorder worldwide. In this study, we evaluated the effect of different (50, 100, and 500 uM) concentrations of salsolinol on markers of glutamate-induced apoptotic and neurotoxic cell damage, such as caspase-3 activity, lactate dehydrogenase (LDH) release, and the loss of mitochondrial membrane potential. Biochemical data were complemented with the cellular analysis, including Hoechst 33342 and calcein AM staining, to visualize apoptotic DNA-fragmentation and to assess cell survival, respectively. The assessment of all investigated parameters was performed in primary cultures of rat or mouse hippocampal and striatum cells. Our study showed that salsolinol had biphasic effects, namely, at lower concentrations (50 and 100 uM), it demonstrated a distinct neuroprotective activity, whereas in the highest one (500 uM) caused neurotoxic effect. Salsolinol in concentrations of 50 and 100 uM significantly antagonized the pro apoptotic and neurotoxic effects caused by 1 mM glutamate. Salsolinol diminished the number of bright fragmented nuclei with condensed chromatin and increased cell survival in Hoechst 33342 and calcein AM staining in hippocampal cultures. Additionally, in the low 50 uM concentration, it produced a significant inhibition of glutamate-induced loss of membrane mitochondrial potential. Only the highest concentration of salsolinol (500 uM) enhanced the glutamate excitotoxicity. Ex vivo studies indicated that both acute and chronic administration of salsolinol did not affect the dopamine metabolism, its striatal concentration or alpha-synuclein and tyrosine hydroxylase protein level in the rat substantia nigra and striatum. Summarizing, the present studies exclude possibility that salsolinol under physiological conditions could be an endogenous factor involved in the neurogenerative processes; conversely, it can exert a protective action on nerve cells in the brain. These findings may have important implications for the development of the new strategies to treat or prevent neural degeneration. PMID- 25537855 TI - A new enabling proteomics methodology to investigate membrane associated proteins from parasitic nematodes: case study using ivermectin resistant and ivermectin susceptible isolates of Caenorhabditis elegans and Haemonchus contortus. AB - The mechanisms involved in anthelmintic resistance (AR) are complex but a greater understanding of AR management is essential for effective and sustainable control of parasitic helminth worms in livestock. Current tests to measure AR are time consuming and can be technically problematic, gold standard diagnostics are therefore urgently required to assist in combatting the threat from drug resistant parasites. For anthelmintics such as ivermectin (IVM), target proteins may be present in the cellular membrane. As proteins usually act in complexes and not in isolation, AR may develop and be measurable in the target associated proteins present in the parasite membrane. The model nematode Caenorhabditis elegans was used to develop a sub-proteomic assay to measure protein expression differences, between IVM resistant and IVM susceptible isolates in the presence and absence of drug challenge. Evaluation of detergents including CHAPS, ASB-14, C7BzO, Triton *100 and TBP (tributyl phosphine) determined optimal conditions for the resolution of membrane proteins in Two Dimensional Gel Electrophoresis (2DE). These sub-proteomic methodologies were then translated and evaluated using IVM susceptible and IVM-resistant Haemonchus contortus; a pathogenic blood feeding parasitic nematode which is of global importance in livestock health, welfare and productivity. We have demonstrated the successful resolution of membrane associated proteins from both C. elegans and H. contortus isolates, using a combination of CHAPS and the zwitterionic amphiphilic surfactant ASB-14 to further support the detection of markers for AR. PMID- 25537856 TI - Intensity-modulated radiotherapy for early-stage glottic cancer. AB - BACKGROUND: The purpose of this study was to report on treatment outcome of intensity-modulated radiotherapy (IMRT) for early-stage (cT1-2 cN0 M0) squamous cell carcinoma of the glottis, as compared with patients treated with conventional radiotherapy. METHODS: Between November 2007 and December 2011, 40 consecutive patients were treated with IMRT with daily cone-beam CT position verification. The median prescription to the planning target volume (PTV) was 63 Gy/28 fractions and 67.5 Gy/30 fractions for T1 and T2 tumors, respectively. The historical control comprised 81 consecutive patients treated with conventional radiotherapy to total doses of 66 Gy/33 fractions (66 patients) and 70 Gy/35 fractions (15 patients) for T1 and T2 tumors, respectively. RESULTS: The median follow-up of living patients was 3.8 years (range, 1.0-5.0 years) in the IMRT group and 9.0 years, (range, 5.2-12.7 years) in the conventional group. Five-year actuarial local control was equal compared to the conventional group: 83% versus 74% (p = .64). Five-year actuarial ultimate local control was 100% in the IMRT group and 95% in the conventional group (p = .17). Five-year actuarial overall and disease-specific survival was 85% after IMRT versus 65% after conventional radiotherapy (p = .15) and 97% versus 89% (p = .31), respectively. Incidence and severity of acute dermatitis was significantly less during IMRT than in the control group (p < .001). Two patients receiving IMRT had late grade 3 hoarseness. CONCLUSION: IMRT is as efficient as conventional radiotherapy in terms of disease control and overall survival. It has the potential to reduce toxicity as compared to conventional radiotherapy. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E179-E184, 2016. PMID- 25537857 TI - Diagnosis and Management of Scrotal Superficial Angiomyxoma With the Aid of a Scrotoscope: Case Report and Literature Review. PMID- 25537859 TI - Life of T follicular helper cells. AB - Antibodies are powerful defense tools against pathogens but may cause autoimmune diseases when erroneously directed toward self-antigens. Thus, antibody producing cells are carefully selected, refined, and expanded in a highly regulated microenvironment (germinal center) in the peripheral lymphoid organs. A subset of T cells termed T follicular helper cells (Tfh) play a central role in instructing B cells to form a repertoire of antibody producing cells that provide life-long supply of high affinity, pathogen-specific antibodies. Therefore, understanding how Tfh cells arise and how they facilitate B cell selection and differentiation during germinal center reaction is critical to improve vaccines and better treat autoimmune diseases. In this review, I will summarise recent findings on molecular and cellular mechanisms underlying Tfh generation and function with an emphasis on T cell costimulation. PMID- 25537860 TI - NELL2 function in the protection of cells against endoplasmic reticulum stress. AB - Continuous intra- and extracellular stresses induce disorder of Ca(2+) homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This anti-apoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti- and pro-apoptotic proteins and on the protection from ER stress-induced cell death. PMID- 25537861 TI - Structural features of beta2 adrenergic receptor: crystal structures and beyond. AB - The beta2-adrenergic receptor (beta2AR) family, which is the largest family of cell surface receptors in humans. Extra attention has been focused on the human GPCRs because they have been studied as important protein targets for pharmaceutical drug development. In fact, approximately 40% of marketed drugs directly work on GPCRs. GPCRs respond to various extracellular stimuli, such as sensory signals, neurotransmitters, chemokines, and hormones, to induce structural changes at the cytoplasmic surface, activating downstream signaling pathways, primarily through interactions with heterotrimeric G proteins or through G-protein independent pathways, such as arrestin. Most GPCRs, except for rhodhopsin, which contains covalently linked 11 cis-retinal, bind to diffusible ligands, having various conformational states between inactive and active structures. The first human GPCR structure was determined using an inverse agonist bound beta2AR in 2007 and since then, more than 20 distinct GPCR structures have been solved. However, most GPCR structures were solved as inactive forms, and an agonist bound fully active structure is still hard to obtain. In a structural point of view, beta2AR is relatively well studied since its fully active structure as a complex with G protein as well as several inactive structures are available. The structural comparison of inactive and active states gives an important clue in understanding the activation mechanism of beta2AR. In this review, structural features of inactive and active states of beta2AR, the interaction of beta2AR with heterotrimeric G protein, and the comparison with beta1AR will be discussed. PMID- 25537865 TI - Reporting of randomized controlled trials in andrology journals: a quality assessment. AB - INTRODUCTION: Quality assessment of randomized controlled trials (RCTs) is important to prevent the adoption of findings of low-quality trials into clinical practice. AIM: The aim of this study was to analyze the quality of studies reporting RCTs in andrology journals (The Journal of Sexual Medicine [JSM], the Asian Journal of Andrology [AJA], the Journal of Andrology [JOA], the International Journal of Andrology [IJA]). METHODS: A quality assessment was conducted on all studies identified as RCTs published in andrology journals (JSM, AJA, JOA, IJA) until 2011. The review period was divided into three terms: early, mid, and late each journal. MAIN OUTCOME MEASURES: The Jadad scale, van Tulder scale, and the Cochrane Collaboration Risk of Bias Tool (CCRBT) were employed. The RCTs were also categorized by country of origin, the inclusion of institutional review board (IRB) approval, funding, and blindness. RESULTS: There were1,954 original articles published in the JSM, 893 articles in the AJA, 2,527 articles in the JOA, and 2,086 articles in the IJA for the review period. There were 172 studies reporting on RCTs in the JSM, 33 RCTs in the AJA, 63 RCTs in the JOA, and 29 RCTs in the IJA. No significant increase in Jadad or van Tulder scale scores were found over time, nor were there any significant changes in the number of high-quality articles as assessed by CCRBT. However, significant differences in quality analysis were found according to blinding, funding, and IRB approval. CONCLUSION: The number of original articles and RCTs in andrology increased over time. However, the ratio of RCTs to original articles as well as RCT quality was statistically insignificant. It would be required for the researchers to focus efforts in performing high-quality studies to ensure appropriate randomization, reviews by IRB, financial support, and inclusion of allocation concealment during study performance. PMID- 25537866 TI - Investigating differences in the root to shoot transfer and xylem sap solubility of organic compounds between zucchini, squash and soybean using a pressure chamber method. AB - A pressure chamber method was used to examine differences in the root to shoot transfer and xylem sap solubility of caffeine (log Kow=-0.07), triclocarban (log Kow=3.5-4.2) and endosulfan (log Kow=3.8-4.8) for zucchini (cucurbita pepo ssp pepo), squash (cucurbita pepo ssp ovifera), and soybean (glycine max L.). Transpiration stream concentration factors (TSCF) for caffeine (TSCF=0.8) were statistically equivalent for all plant species. However, for the more hydrophobic endosulfan and triclocarban, the TSCF values for zucchini (TSCF=0.6 and 0.4, respectively) were 3 and 10 times greater than the soybean and squash (TSCF=0.2 and 0.05, respectively). The difference in TSCF values was examined by comparing the measured solubilities of caffeine, endosulfan and triclocarban in deionized water to those in soybean and zucchini xylem saps using a modified shake flask method. The measured solubility of organic contaminants in xylem sap has not previously been reported. Caffeine solubilities in the xylem saps of soybean and zucchini were statistically equal to deionized water (21500mgL(-1)) while endosulfan and triclocarban solubilities in the zucchini xylem sap were significantly greater (0.43 and 0.21mgL(-1), respectively) than that of the soybean xylem sap (0.31 and 0.11mgL(-1), respectively) and deionized water (0.34 and 0.11mgL(-1), respectively). This suggests that the enhanced root to shoot transfer of hydrophobic organics reported for zucchini is partly due to increased solubility in the xylem sap. Further xylem sap characterization is needed to determine the mechanism of solubility enhancement. PMID- 25537862 TI - Raloxifene induces autophagy-dependent cell death in breast cancer cells via the activation of AMP-activated protein kinase. AB - Raloxifene is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor (ER), and exhibits potent anti-tumor and autophagy-inducing effects in breast cancer cells. However, the mechanism of raloxifene-induced cell death and autophagy is not well-established. So, we analyzed mechanism underlying death and autophagy induced by raloxifene in MCF-7 breast cancer cells. Treatment with raloxifene significantly induced death in MCF-7 cells. Raloxifene accumulated GFP-LC3 puncta and increased the level of autophagic marker proteins, such as LC3-II, BECN1, and ATG12-ATG5 conjugates, indicating activated autophagy. Raloxifene also increased autophagic flux indicators, the cleavage of GFP from GFP-LC3 and only red fluorescence-positive puncta in mRFP-GFP-LC3-expressing cells. An autophagy inhibitor, 3-methyladenine (3-MA), suppressed the level of LC3-II and blocked the formation of GFP-LC3 puncta. Moreover, siRNA targeting BECN1 markedly reversed cell death and the level of LC3-II increased by raloxifene. Besides, raloxifene-induced cell death was not related to cleavage of caspases-7, -9, and PARP. These results indicate that raloxifene activates autophagy-dependent cell death but not apoptosis. Interestingly, raloxifene decreased the level of intracellular adenosine triphosphate (ATP) and activated the AMPK/ULK1 pathway. However it was not suppressed the AKT/mTOR pathway. Addition of ATP decreased the phosphorylation of AMPK as well as the accumulation of LC3-II, finally attenuating raloxifene-induced cell death. Our current study demonstrates that raloxifene induces autophagy via the activation of AMPK by sensing decreases in ATP, and that the overactivation of autophagy promotes cell death and thereby mediates the anti-cancer effects of raloxifene in breast cancer cells. PMID- 25537867 TI - Increased numbers of peripheral blood CD34+ cells in dogs with canine atopic dermatitis. AB - BACKGROUND: The bone marrow may be involved in human atopic diseases, as shown by the release of CD34+ cells into the peripheral blood. HYPOTHESIS/OBJECTIVES: The aim was to determine the numbers of CD34+ cells in atopic dogs. ANIMALS: The following three groups of dogs were studied: 27 dogs with nonfood-induced atopic dermatitis (NFICAD); 16 dogs with nonallergic inflammatory diseases; and 13 healthy control dogs. METHODS: Dogs with NFICAD were selected after fulfilment of Favrot's criteria and exclusion of other pruritic dermatoses, including flea infestation and adverse reaction to foods. The Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03 and a Visual Analog Scale (VAS) score for pruritus were used to quantify clinical signs. A phycoerythrin-conjugated anticanine CD34 antibody was used to stain peripheral blood CD34+ cells, and these were enumerated using a flow cytometer. The CD34+ cell counts were compared between groups and tested (in the NFICAD group) for correlation with the severity of clinical signs. RESULTS: The numbers of peripheral CD34+ cells in dogs with NFICAD (median 1.7) were statistically higher than in dogs with other nonallergic inflammatory diseases (median 1.0; P = 0.01) and healthy control dogs (median 0.9; P = 0.009). In dogs with NFICAD, there was no correlation between CD34+ cell numbers and CADESI-03 scores or owner-assessed pruritus (VAS score). CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this study suggest the possible involvement of CD34+ cells in dogs with NFICAD. The role of CD34+ cells in the aetiopathogenesis of canine atopic dermatitis remains to be determined. PMID- 25537869 TI - Avoid haste in defining human muscular sarcocystosis. PMID- 25537871 TI - Editorial commentary: dead or alive: can viability staining predict response to tuberculosis treatment? PMID- 25537872 TI - Editorial commentary: severe infections in patients with chronic granulomatous disease. PMID- 25537870 TI - Clinical evaluation of tuberculosis viability microscopy for assessing treatment response. AB - BACKGROUND: It is difficult to determine whether early tuberculosis treatment is effective in reducing the infectiousness of patients' sputum, because culture takes weeks and conventional acid-fast sputum microscopy and molecular tests cannot differentiate live from dead tuberculosis. METHODS: To assess treatment response, sputum samples (n=124) from unselected patients (n=35) with sputum microscopy-positive tuberculosis were tested pretreatment and after 3, 6, and 9 days of empiric first-line therapy. Tuberculosis quantitative viability microscopy with fluorescein diacetate, quantitative culture, and acid-fast auramine microscopy were all performed in triplicate. RESULTS: Tuberculosis quantitative viability microscopy predicted quantitative culture results such that 76% of results agreed within +/-1 logarithm (rS=0.85; P<.0001). In 31 patients with non-multidrug-resistant (MDR) tuberculosis, viability and quantitative culture results approximately halved (both 0.27 log reduction, P<.001) daily. For patients with non-MDR tuberculosis and available data, by treatment day 9 there was a >10-fold reduction in viability in 100% (24/24) of cases and quantitative culture in 95% (19/20) of cases. Four other patients subsequently found to have MDR tuberculosis had no significant changes in viability (P=.4) or quantitative culture (P=.6) results during early treatment. The change in viability and quantitative culture results during early treatment differed significantly between patients with non-MDR tuberculosis and those with MDR tuberculosis (both P<.001). Acid-fast microscopy results changed little during early treatment, and this change was similar for non-MDR tuberculosis vs MDR tuberculosis (P=.6). CONCLUSIONS: Tuberculosis quantitative viability microscopy is a simple test that within 1 hour predicted quantitative culture results that became available weeks later, rapidly indicating whether patients were responding to tuberculosis therapy. PMID- 25537873 TI - Therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness. AB - BACKGROUND: Onchocerca volvulus and lymphatic filariae, causing river blindness and elephantiasis, depend on endosymbiotic Wolbachia bacteria for growth, development, fertility, and survival. Clinical trials have shown that doxycycline treatment eliminates Wolbachia, causing long-term sterilization of adult female filariae and effecting potent macrofilaricidal activity. The continual reinfection by drug-naive worms that occurs in these trial settings dilutes observable anti-Wolbachia and antifilarial effects, making it difficult to estimate therapeutic efficacy and compare different doxycycline regimens, evaluated at different times after treatment. METHODS: A meta-analytical modeling framework is developed to link all usable data collected from clinical trials measuring the Wolbachia status and viability of individual female adult worms collected at various times after treatment with 4, 5, or 6 weeks of daily 100 or 200 mg oral doxycycline. The framework is used to estimate efficacy parameters that are not directly measurable as trial outcomes. RESULTS: The estimated efficacy of doxycycline (the maximum proportional reduction in the percentage of adult female O. volvulus positive for Wolbachia) is 91%-94% on average, irrespective of the treatment regimen. Efficacy is >95% in the majority of trial participants. The life span of Wolbachia-depleted worms is reduced by 70%-80%, from approximately 10 years to 2-3 years. CONCLUSIONS: The efficacy parameters are pertinent to the prospects of using doxycycline on a "test and treat" basis for onchocerciasis control and confirm doxycycline as a potent macrofilaricidal therapy. The modeling approach is more generally relevant to the design and evaluation of clinical trials for antifilarial drugs conducted in endemic settings. PMID- 25537874 TI - Reply to Italiano et al. PMID- 25537875 TI - Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort and response of azithromycin failures to alternative antibiotic regimens. AB - BACKGROUND: Our aim was to determine the efficacy of 1 g azithromycin and alternative antibiotic regimens in a prospective cohort of Mycoplasma genitalium infected participants, and factors associated with azithromycin failure. METHODS: Consecutive eligible M. genitalium-infected men and women attending the Melbourne Sexual Health Centre between July 2012 and June 2013 were treated with 1 g of azithromycin and retested by polymerase chain reaction (PCR) on days 14 and 28. Cure was defined as PCR negative on day 28. Cases failing azithromycin were treated with moxifloxacin, and those failing moxifloxacin were treated with pristinamycin. Pre- and posttreatment samples were assessed for macrolide resistance mutations (MRMs) by high-resolution melt analysis. Mycoplasma genitalium samples from cases failing moxifloxacin were sequenced for fluoroquinolone resistance mutations. Multivariable analysis was used to examine associations with azithromycin failure. RESULTS: Of 155 participants treated with 1 g azithromycin, 95 (61% [95% confidence interval {CI}, 53%-69%]) were cured. Pretreatment MRM was detected in 56 (36% [95% CI, 28%-43%]) participants, and strongly associated with treatment failure (87% [95% CI, 76%-94%]; adjusted odds ratio, 47.0 [95% CI, 17.1-129.0]). All 11 participants who had MRM detected in posttreatment samples failed azithromycin. Moxifloxacin was effective in 53(88% [95% CI, 78%-94%]) of 60 cases failing azithromycin; all failures had gyrA and parC mutations detected in pretreatment samples. Six of 7 patients failing moxifloxacin treatment received pristinamycin, and all were PCR negative 28 days after pristinamycin treatment. CONCLUSIONS: We report a high azithromycin failure rate (39%) in an M. genitalium-infected cohort in association with high levels of pretreatment macrolide resistance. Moxifloxacin failure occurred in 12% of patients who received moxifloxacin; all had pretreatment fluoroquinolone mutations detected. Pristinamycin was highly effective in treating macrolide- and quinolone-resistant strains. PMID- 25537876 TI - Common severe infections in chronic granulomatous disease. AB - BACKGROUND: Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades. METHODS: All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus. RESULTS: Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%). Gastrointestinal complications were not associated with either infection or mortality. CONCLUSIONS: Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality. PMID- 25537877 TI - Prevention of colonization and infection by Klebsiella pneumoniae carbapenemase producing enterobacteriaceae in long-term acute-care hospitals. AB - BACKGROUND: Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae (hereafter "KPC") are an increasing threat to healthcare institutions. Long-term acute-care hospitals (LTACHs) have especially high prevalence of KPC. METHODS: Using a stepped-wedge design, we tested whether a bundled intervention (screening patients for KPC rectal colonization upon admission and every other week; contact isolation and geographic separation of KPC-positive patients in ward cohorts or single rooms; bathing all patients daily with chlorhexidine gluconate; and healthcare-worker education and adherence monitoring) would reduce colonization and infection due to KPC in 4 LTACHs with high endemic KPC prevalence. The study was conducted between 1 February 2010 and 30 June 2013; 3894 patients were enrolled during the preintervention period (lasting from 16 to 29 months), and 2951 patients were enrolled during the intervention period (lasting from 12 to 19 months). RESULTS: KPC colonization prevalence was stable during preintervention (average, 45.8%; 95% confidence interval [CI], 42.1%-49.5%), declined early during intervention, then reached a plateau (34.3%; 95% CI, 32.4%-36.2%; P<.001 for exponential decline). During intervention, KPC admission prevalence remained high (average, 20.6%, 95% CI, 19.1%-22.3%). The incidence rate of KPC colonization fell during intervention, from 4 to 2 acquisitions per 100 patient weeks (P=.004 for linear decline). Compared to preintervention, average rates of clinical outcomes declined during intervention: KPC in any clinical culture (3.7 to 2.5/1000 patient-days; P=.001), KPC bacteremia (0.9 to 0.4/1000 patient-days; P=.008), all-cause bacteremia (11.2 to 7.6/1000 patient-days; P=.006) and blood culture contamination (4.9 to 2.3/1000 patient-days; P=.03). CONCLUSIONS: A bundled intervention was associated with clinically important and statistically significant reductions in KPC colonization, KPC infection, all-cause bacteremia, and blood culture contamination in a high-risk LTACH population. PMID- 25537878 TI - Molecular assessment of artemisinin resistance markers, polymorphisms in the k13 propeller, and a multidrug-resistance gene in the eastern and western border areas of Myanmar. AB - BACKGROUND: As K13 propeller mutations have been recently reported to serve as molecular markers, assessment of K13 propeller polymorphisms in multidrug resistant gene in isolates from Myanmar, especially the eastern and western border areas, is crucial if we are to understand the spread of artemisinin resistance. METHODS: A 3-day surveillance study was conducted in the eastern and western border areas in Myanmar, and K13 propeller and Plasmodium falciparum multidrug resistance-associated protein 1 (pfmrp1) mutations were analyzed. RESULTS: Among the 1761 suspected malaria cases screened, a total of 42 uncomplicated falciparum cases from the eastern border and 49 from the western border were subjected to 3 days of surveillance after artemether-lumefantrine treatment. No parasitemic case showing positivity on day 3 was noted from the western border, but 26.2% (11/42) of cases were positive in the eastern border. Although we found no marked difference in the prevalence of the pfmrp1 mutation in the eastern and western borders (36% vs 31%, respectively), K13 mutations were more frequent in the eastern border area (where the 3-day persistent cases were detected; 48% vs 14%). C580Y, M476I, A481V, N458Y, R539T, and R516Y accounted for 68.9% of all K13 mutations significantly associated with day 3 parasitaemia. CONCLUSIONS: The K13 mutations were significantly associated with day 3 parasitaemia, emphasizing the importance of K13 surveillance. The low prevalence of K13 mutations and the absence of day 3 parasitaemic cases indicate that artemisinin resistance may not have spread to the western Myanmar border region. Although analysis of multiple K13 mutations is challenging, it should be done at various sentinel sites in Myanmar. PMID- 25537879 TI - From ESKAPE to ESCAPE, from KPC to CCC. PMID- 25537881 TI - Three-part differential of unlabeled leukocytes with a compact lens-free imaging flow cytometer. AB - A compelling clinical need exists for inexpensive, portable haematology analyzers that can be utilized at the point-of-care in emergency settings or in resource limited settings. Development of a label-free, microfluidic blood analysis platform is the first step towards such a miniaturized, cost-effective system. Here we assemble a compact lens-free in-line holographic microscope and employ it to image blood cells flowing in a microfluidic chip, using a high-speed camera and stroboscopic illumination. Numerical reconstruction of the captured holograms allows classification of unlabeled leukocytes into three main subtypes: lymphocytes, monocytes and granulocytes. A scale-space recognition analysis to evaluate cellular size and internal complexity is also developed and used to build a 3-part leukocyte differential. The lens-free image-based classification is compared to the 3-part white blood cell differential generated by using a conventional analyzer on the same blood sample and is found to be in good agreement with it. PMID- 25537882 TI - In the realms of future: new frontiers of 'techno-oncology' as a platform for global improvement in the outcomes of childhood cancer. AB - The survival outcome of childhood cancers in developing nations has failed to keep pace with that of developed nations. Technological advances offer a unique and radical opportunity to develop programs and strategies to improve outcomes of childhood cancer globally. The novel field of 'techno-oncology' has a broad scope and the potential to phenomenally impact, revamp and model the care of pediatric cancer patients in the developing world. Many frontiers and opportunities in the area remain to be explored as well as many challenges to be surmounted. PMID- 25537883 TI - Quantitative proteomic analysis reveals heat stress-induced injury in rat small intestine via activation of the MAPK and NF-kappaB signaling pathways. AB - The intestinal epithelium plays a critical role in absorbing nutrients and maintaining the integrity of the gut barrier. Extreme heat stress induces damage to the intestinal epithelium. However, the protein expression changes and the mechanism behind this damage remain poorly understood. In this study, morphological observation showed that heat stress induced desquamation of intestinal epithelial cells, and destruction of intestinal microvilli and mitochondria. Heat stress-induced changes in the intestinal proteome were quantified using the iTRAQ method followed by mass spectrometry and software analysis. A total of 1689 proteins were identified in rat intestine tissue, of which 41 showed significantly altered expression between the heat stressed and control groups. However, these proteins with significant alterations were involved in biological processes such as cellular assembly and organization, developmental disorder, organismal injury and abnormalities, and inflammation. We found that members of the MAPK and NF-kappaB signaling pathways act as hub proteins in the network interaction analysis. Furthermore, western blot analysis verified that the MAPK and NF-kappaB signaling pathways were activated by heat stress as expected. This study suggests that heat stress induces cell cytoskeleton reorganization and an inflammatory response, and the activation of the MAPK and NF-kappaB signaling pathways, which may ultimately contribute to intestinal injury. PMID- 25537884 TI - Global analysis of methylation profiles from high resolution CpG data. AB - New high throughput technologies are now enabling simultaneous epigenetic profiling of DNA methylation at hundreds of thousands of CpGs across the genome. A problem of considerable practical interest is identification of large scale, global changes in methylation that are associated with environmental variables, clinical outcomes, or other experimental conditions. However, there has been little statistical research on methods for global methylation analysis using technologies with individual CpG resolution. To address this critical gap in the literature, we develop a new strategy for global analysis of methylation profiles using a functional regression approach wherein we approximate either the density or the cumulative distribution function (CDF) of the methylation values for each individual using B-spline basis functions. The spline coefficients for each individual are allowed to summarize the individual's overall methylation profile. We then test for association between the overall distribution and a continuous or dichotomous outcome variable using a variance component score test that naturally accommodates the correlation between spline coefficients. Simulations indicate that our proposed approach has desirable power while protecting type I error. The method was applied to detect methylation differences, both genome wide and at LINE1 elements, between the blood samples from rheumatoid arthritis patients and healthy controls and to detect the epigenetic changes of human hepatocarcinogenesis in the context of alcohol abuse and hepatitis C virus infection. A free implementation of our methods in the R language is available in the Global Analysis of Methylation Profiles (GAMP) package at http://research.fhcrc.org/wu/en.html. PMID- 25537885 TI - Transgenic rice expressing a codon-modified synthetic CP4-EPSPS confers tolerance to broad-spectrum herbicide, glyphosate. AB - KEY MESSAGE: Highly tolerant herbicide-resistant transgenic rice was developed by expressing codon-modified synthetic CP4--EPSPS. The transformants could tolerate up to 1% commercial glyphosate and has the potential to be used for DSR (direct seeded rice). Weed infestation is one of the major biotic stress factors that is responsible for yield loss in direct-seeded rice (DSR). Herbicide-resistant rice has potential to improve the efficiency of weed management under DSR. Hence, the popular indica rice cultivar IR64, was genetically modified using Agrobacterium mediated transformation with a codon-optimized CP4-EPSPS (5-enolpyruvylshikimate 3-phosphate synthase) gene, with N-terminal chloroplast targeting peptide from Petunia hybrida. Integration of the transgenes in the selected rice plants was confirmed by Southern hybridization and expression by Northern and herbicide tolerance assays. Transgenic plants showed EPSPS enzyme activity even at high concentrations of glyphosate, compared to untransformed control plants. T0, T1 and T2 lines were tested by herbicide bioassay and it was confirmed that the transgenic rice could tolerate up to 1% of commercial Roundup, which is five times more in dose used to kill weeds under field condition. All together, the transgenic rice plants developed in the present study could be used efficiently to overcome weed menace. PMID- 25537887 TI - Code stroke: multicenter experience with in-hospital stroke alerts. AB - Between 2.2% and 17% of all strokes have symptom onset during hospitalization in a patient originally admitted for another diagnosis or procedure. A response system to rapidly evaluate inpatients with acute neurologic symptoms facilitates evaluation and treatment of stroke developing during hospitalization. The National Stroke Association implemented an in-hospital stroke quality-improvement initiative from July 2010 to June 2011 in 6 certified stroke centers from Michigan, South Carolina, Pennsylvania, Colorado, Washington, and North Carolina. Three hundred ninety-three in-hospital stroke alerts were examined over a 1-year period. Of the alerts, 42.5% were for ischemic stroke, 8.7% probable or possible TIA, 2.8% intracranial hemorrhage, and 46.1% were stroke mimics. The most common stroke mimics were seizure, hypotension, and delirium. Participating hospitals had an alarm rate for diagnoses other than acute cerebrovascular events ranging from 28.0% to 66.7%. Of 194 in-hospital stroke/transient ischemic attack cases, 8.2% received intravenous thrombolysis alone, 10.3% received intra arterial/mechanical thrombolysis alone, and 1% received both. No patient with a stroke mimic received thrombolysis. Our findings suggest that in-hospital response teams need to be prepared to respond to a range of acute medical conditions other than ischemic stroke. PMID- 25537886 TI - Mass spectrometric measurement of neuropeptide secretion in the crab, Cancer borealis, by in vivo microdialysis. AB - Neuropeptides (NPs), a unique and highly important class of signaling molecules across the animal kingdom, have been extensively characterized in the neuronal tissues of various crustaceans. Because many NPs are released into circulating fluid (hemolymph) and travel to distant sites in order to exhibit physiological effects, it is important to measure the secretion of these NPs from living animals. In this study, we report on extensive characterization of NPs released in the crab Cancer borealis by utilizing in vivo microdialysis to sample NPs from the hemolymph. We determined the necessary duration for collection of microdialysis samples, enabling more comprehensive identification of NP content while maintaining the temporal resolution of sampling. Analysis of in vivo microdialysates using a hybrid quadrupole-OrbitrapTM Q-Exactive mass spectrometer revealed that more than 50 neuropeptides from 9 peptide families-including the allatostatin, RFamide, orcokinin, tachykinin-related peptide and RYamide families - were released into the circulatory system. The presence of these peptides both in neuronal tissues as well as in hemolymph indicates their putative hormonal roles, a finding that merits further investigation. Preliminary quantitative measurement of these identified NPs suggested several potential candidates that maybe associated with the circadian rhythm in Cancer borealis. PMID- 25537888 TI - [u-opioid receptors in the central nucleus of the amygdala regulate food rather than water intake in rats]. AB - OBJECTIVE: To investigate the effect of u-opioid receptors (u-ORs) in the central nucleus of the amygdala (CeA) on feeding and drinking behaviors in rats and evaluate the role of glutamate signaling in opioid-mediated ingestive behaviors. METHODS: Stainless steel cannulas were implanted in the unilateral CeA for microinjection of different doses of the selective u-OR agonist DAMGO in satiated or water-deprived male SD rats. The subsequent food intake or water intake of the rats was measured at 60, 120, and 240 min after the injection. The rats receiving microinjections of naloxone (NTX, a nonselective opioid antagonist) or D-AP-5 (a selective N-methyl-D-aspartic acid-type glutamate receptor antagonist) prior to DAMGO microinjection were tested for food intake at 60, 120, and 240 min after the injections. RESULTS: Injections of DAMGO (1-4 nmol in 0.5 ul) into the CeA significantly increased food intake in satiated rats, but did not affect water intake in rats with water deprivation. NTX (26.5 nmol in 0.5 ul) injected into the CeA antagonized DAMGO-induced feeding but D-AP-5 (6.3-25.4 nmol in 0.5 ul) injections did not produce such an effect. CONCLUSION: u-ORs in the CeA regulate food intake rather than water intake in rats, and the orexigenic role of u-ORs is not dependent on the activation of the NMDA receptors in the CeA. PMID- 25537889 TI - [Lentivirus-mediated interference of E3 ubiquitin ligase RNF31 inhibits tumor necrosis factor-alpha-induced activation of nuclear factor-kappaB pathway]. AB - OBJECTIVE: To study the effect of E3 ubiquitin ligase RNF31 knockdown on nuclear factor-kappaB (NF-kappaB) pathway activation and cell apoptosis. METHODS: Human RNF31 siRNA sequences were cloned into the lentiviral vector pGreenPuro and transiently transfected in HEK293T cells to screen the most effective fragments, which were co-transfected along with the packaging plasmids PMD and SPA in 293T cells. The cell supernatant was collected at 24 h and 48 h after the transfection and the viral titers were determined with flow cytometry. Real-time PCR and Western blotting were used to evaluate the effect of RNF31 knockdown on the expression of NF-kappaB downstream target genes and IkappaBalpha activity; the changes of NF-kappaB pathway transcriptional activity were assessed with dual luciferase reporter gene. Hochest dying was used to examine the influence of RNF31 down-regulation on cell apoptosis. RESULTS: RNF31 knockdown mediated by the lentiviral vector pGreenPuro-RNF31 suppressed the transcriptional activity of NF kappaB and the downstream target genes in HEK293 cells stimulated with TNF-alpha. RNF31 knockdown also resulted in suppression of NF-kappaB-stimulated expression of pIkappaBalpha and in increased apoptosis of cells stimulated with TNF-alpha for 24 h. CONCLUSION: RNF31 down-regulation inhibits NF-kappaB pathway activation induced by TNF-alpha. PMID- 25537890 TI - [Establishment of a canine WRD cell line with stable p53 knockdown by lentivirus mediated p53 silencing]. AB - OBJECTIVE: To establish a canine cell line with p53 gene knockdown by lentivirus- mediated RNA interference (RNAi). METHODS: Four pairs of oligonucleotide sequences of p53 gene were synthesized and cloned into the pGMLV-SC5 RNAi vector. Following confirmation by PCR and DNA sequencing, the recombinant pGMLV-p53 plasmids and packaging mix vectors were packaged into mature lentivirus to infect 293T cells. The supernatant of the infected cells was harvested to infect WRD cells, in which p53 expression was detected using Western blotting and real-time PCR. The lentivirus with the strongest p53- silencing effect was packaged for infecting WRD cells at the optimal multiplicity of infection (MOI) to establish a stably infected cell line (WRD/p53-) screened using puromycin. RESULTS: The lentivirus carrying p53 shRNA was constructed successfully and a virus titer of 1 * 109 TU/ml. The 4 pGMLV-p53 plasmids all produced strong p53 interference affects, and pGMLV- p53A1 with the strongest effect. The stably infected cells line WRD/p53- was established successfully using pGMLV-p53A1 plasmid. CONCLUSION: The canine cell line WRD/p53- with stable lentivirus-mediated p53 silencing has been established successfully. PMID- 25537891 TI - [Modulatory effect of neurokinin-1 and non-N-methyl-D-aspartate receptors on cardiosomatic reflex in rat spinal cord]. AB - OBJECTIVE: To investigate the role of neurokinin-1 (NK1) receptor and non-N methyl-D-aspartate (non-NMDA) receptor in modulating the cardiosomatic reflex in the spinal cord of rat. METHODS: The effects of intrathecal injection of NK1 receptor agonist Sar-SP and antagonist CP-96345 and non-NMDA receptor agonist NMDA and antagonist 6, 7-dinitro-1,4-dihydro-quinoxaline-2,3-dione (DNQX) on the cardiosomatic reflex were observed in rats. The changes of the cardiosomatic reflex were monitored by observing the electromyogram (EMG) responses of the dorsal spinotrapezius muscle to intrapericardial bradykinin (BK) injection. RESULTS: Intrathecal injection of Sar-SP significantly facilitated EMG responses to intrapericardial BK injection (P<0.05), which was completely blocked by intrathecal injection of NK1 antagonist CP-96345. Similarly, intrathecal injection of NMDA obviously facilitated the EMG responses (P<0.05), which was partially reversed by intrathecal injection of non-NMDA receptor antagonist DNQX. Intrathecal injection of Sar-SP along with NMDA significantly increased EMG as compared with single administration of Sar-SP or NMDA (P<0.05). CONCLUSION: The spinal cord levels of NK1 receptor and non-NMDA receptor are involved in the modulation of the cardiosomatic reflex in rats. PMID- 25537892 TI - [Establishment of a method for detecting peripheral blood circulating brain microvascular endothelial cells, a novel biomarker for blood-brain barrier injury]. AB - OBJECTIVE: To establish a method for detecting circulating brain microvascular endothelial cells (cBMECs), a novel biomarker of blood-brain barrier (BBB) injury. METHODS: Blood samples were collected from 33 patients with AIDS encephalitis and 13 healthy subjects for detection of cBMECs, cECs and EPCs using magnetic affinity isolation and immune identification technology. RESULTS: The numbers of cBMECs, cECs and EPCs were significantly higher in the AIDS patients than in the control subjects (t=4.298, P<0.01; t=4.886, P<0.01; t=4.889, P<0.01). An significant association was also noted between HIV load and cBMEC number (r=0.928, P<0.01). CONCLUSION: We have successfully established a method for detecting peripheral blood cBMECs, which can be of important value in non invasive assessment of BBB injury. PMID- 25537893 TI - [Alternative polyadenylation site analysis of tumor-related genes based on 3'RACE in gastric cancer cells]. AB - OBJECTIVE: To analyze the alteration in alternative polyadenylation (APA) sites of tumor-related genes in gastric cancer cells. METHODS: We used 3'RACE to capture the APA sites of two tumor-related genes (HSP90alpha and SEC11A) in gastric cancer cell lines MKN45, MKN28 and AGS, and compared the results with annotated poly(A) sites in UCSC database. RESULTS: We found new APA sites in the two tumor-related genes in gastric cancer cells to produce new mRNA isoforms with different 3'UTRs. CONCLUSIONS: There are new mRNA isoforms of HSP90alpha and SEC11A derived from ATA in gastric cancer cells, which provides new insights into the mechanisms of gastric tumorigenesis. PMID- 25537894 TI - [Lentivirus-mediated shRNA interference of Cx26 suppresses epithelial mesenchymal transition and invasion of highly invasive hepatocellular carcinoma cells in vitro]. AB - OBJECTIVE: To explore the effect of lentivirus-mediated shRNA interference of Cx26 on epithelial-mesenchymal transition (EMT) and invasion of highly invasive human hepatocellular carcinoma cells in vitro. METHODS: SK-Hep-1 cells were infected with the lentivirus for delivering Cx26 shRNA, and the stably transfected cells were selected by puromycin. The interference efficiency of shRNA-Cx26 was assessed with real-time PCR and Western blotting. The morphological changes of the transfected SK-Hep-1 cells were observed microscopically, and the protein expressions of E-cadherin and vimentin were detected using Western blotting. The effect of Cx26 interference on the invasiveness of SK-Hep-1 cells was determined by Transwell invasion assay. RESULTS: Compared with SK-Hep-1 cells infected with empty EGFP vector and uninfected cells, the cells transfected with shRNA-Cx26 showed significantly reduced mRNA and protein expressions of Cx26 (P<0.01), which resulted in obvious morphological conversion from mesenchymal cells to epithelial cells. shRNA-Cx26 transfected cells showed significantly increased E-cadherin protein expression (P<0.01) but decreased vimentin expression (P<0.01) with obviously attenuated invasive ability in vitro (P<0.01). CONCLUSION: Targeted down-regulation of Cx26 expression can inhibit the EMT and invasion of SK-Hep-1 cells in vitro. PMID- 25537895 TI - [Effect of miR-92b on migration, adhesion and invasion of human gastric cancer cell line SGC7901]. AB - OBJECTIVE: To investigate the effect of miR-92b on the migration, adhesion and invasion of gastric cancer cell line SGC7901. METHODS: The miR-92b inhibitor and mimics were transiently transfected in SGC7901 cells. The changes in the migration, adhesion and invasion of the transfected cells were tested with wound healing assay, Transwell migration assay, matrigel adhesion and Transwell invasion assay. The cellular expression of E-cadherin, vimentin, Akt and p-Akt were analyzed by Western blotting. RESULTS: The migration, adhesion and invasion assays showed that transfection with the inhibitor of miR-92b obviously decreased the numbers of gastric cancer cells. The expression of E-cadherin, AKT, and pAKT increased and vimentin decreased significantly in the cells transfected with the inhibitor of miR-92b. Transfection with the mimics of miR-92b produced opposite effects in SGC7901 cells. CONCLUSION: miR-92b promotes the migration, adhesion and invasion of human gastric cancer cell line SGC7901 by mediating epithelial mesenchymal transition, and may accelerate tumor cell metastasis via signaling pathways other than PI3K/Akt pathway. PMID- 25537896 TI - [Expression of phosphorylated caspase-8 in non-small cell lung cancer and the clinical implications]. AB - OBJECTIVE: To investigate the clinical significance of phosphorylated caspase-8 by Src in patients with operable non-small cell lung cancer. METHODS: Src and caspase-8 expressions were tested using immunohistochemistry in non-small cell lung cancer tissues and control lung tissues. The expression of phosphorylated caspase-8 at 380 tyrosine by Src was detected using Western blotting. The disease free survival (DFS) of patients positive and negative for phosphorylated caspase 8 was analyzed with Kaplan-Meire survival curve. RESULTS: No significant difference was found in the positivity rate of caspase-8 or Src between the cancer tissues and control lung tissues (76.3% vs 83.3%, P>0.05; 70.1% vs 66.4%, P>0.05). All the patients with Casp8- and Src-positive cancers were positive for phosphoryalted caspase-8, whose expression rate was significantly higher in the cancer tissues than in the paired control lung tissues (52.4% vs 7.1%, P<0.05). The 2-year DFS was significantly higher in patients negative for phosphorylated caspase-8 than in the positive patients (32.0% vs 60.3%, P<0.05). CONCLUSION: Phosphorylated caspase-8 may serve as a predictor for a poorer DFS in patients with operable non-small cell lung cancer. PMID- 25537898 TI - [Impact of recipient/donor killer cell immunoglobulin-like receptor gene mismatch on outcomes of renal transplant]. AB - OBJECTIVE: To explore the impact of killer cell immunoglobulin-like receptor (KIR) gene mismatch on the outcomes of renal transplantation. METHODS: We collected the data from 111 donor-recipient pairs of kidney transplant and analyzed the status of KIR gene matching, acute rejection (AR), and 1-year and 3 year survival of the recipients who were followed continuously for over 37 months. RESULTS: Seventeen KIR genes were expressed in both recipient and donor groups, and the frequency of KIR3DS1 was significantly higher in the recipients than in the donors (38.75% vs 24.66%, OR=2.17, chi2 = 3.94, P<0.05). The average rate of donor-recipient KIR matching was 82.53%. The donor-recipient KIR2DS1 matching rate was significantly higher in AR group than in no-AR group (85.00% vs 54.95%, chi2 = 6.19, P<0.05). The rate of donor-recipient KIR AB-AB genotype was significantly higher in AR group than in no-AR group (33.33% vs 8.00%, P<0.05). The 1- and 3-year survival rates was 94.59% and 82.88% in these recipients, respectively. The frequency of donor KIR-AB genotpye was significantly higher in recipients with poor outcomes (57.89% vs 29.63%, chi2 = 8.19, P<0.05); the frequency of both donor and recipient KIR-AB genotype was also significantly higher in recipients with poor prognoses (36.84% vs 9.78%, chi2 = 14.87, P<0.05). CONCLUSIONS: KIR3DS1 may be the susceptible gene associated with uremia. A KIR-AB genotype of either the donor or the recipient can increase the risk of AR and reduce the 1- and 3-year survival rate. This finding can be of ethically importance in choosing a living related donor. PMID- 25537897 TI - [Effects of Biejiajian Pills on Wnt signal pathway signal molecules beta catenin/TCF4 complex activities and downstream proteins cyclin D1 and MMP-2 in hepatocellular carcinoma cells]. AB - OBJECTIVE: To study the effect of Biejiajian Pills on Wnt signal pathway and the mechanisms underlying its action to suppress the invasiveness of hepatocellular carcinoma. METHODS: HepG2 cells cultured in the serum of rats fed with Biejiajian Pills for 48 h were examined for beta-catenin expression using immunofluorescence, beta-catenin/TCF4 complex activity with luciferase, and expressions of the downstream proteins cyclin D1 and MMP-2 using qRT-PCR. RESULTS: Biejiajian Pills-treated sera significantly reduced the expressions of cytoplasmic and nuclear beta-catenin protein, cyclin D1 and MMP-2 proteins and lowered the activities of beta-catenin/TCF4 complex. CONCLUSION: Biejiajian Pills may serve as a potential anti-tumor agent, whose effect might be mediated by inhibiting the Wnt/beta-catenin pathway. PMID- 25537899 TI - [Neural stem cell-specific peroxisome proliferator-activated receptor gamma knockout mice: breeding and genetic identification]. AB - OBJECTIVE: To breed neual stem cell-specific peroxisome proliferator-activated receptor gamma (PPARgamma) knockout mice. METHODS: Two transgenic mouse models, namely B6.PPARgammaloxp/loxp and B6.Nestin-Cre were interbred, and the first- generation offsprings were backcrossed with B6.PPARgammaloxp/loxp to obtain the second-generation mice. Genomic DNA was extracted from the second-generation mice for PCR to amplify the loxp and Cre gene fragments followed by agarose gel electrophoresis to verify their sizes. The mice with the PPARgammaloxp/loxp.Nestin-Cre (KO) genotype were selected as the neural stem cell specific knockout PPARgamma mice, with B6.PPARgammaloxp/loxp (loxp) mice as the control. Tissue samples were collected from specific regions of the mouse brain and peripheral tissue for detecting the expression of PPARgamma mRNA using RT-PCR and real-time quantitative PCR. RESULTS AND CONCLUSION: Genotyping results showed PPARgammaloxp and Cre bands in the knockout mice, which showed obviously decreased mRNA expression of PPARgamma, suggesting successful establishment of neural stem cell-specific PPARgamma knockout mice. The two transgenic mice we used were fertile, and their breeding pattern followed the laws of Mendelian inheritance. PMID- 25537900 TI - [Association of myocardial bridge in the left anterior descending coronary with coronary atherosclerosis proximal to the bridge site in diabetic patients]. AB - OBJECTIVE: To investigate whether myocardial bridging (MB) is an independent risk factor for coronary atherosclerosis proximal to the bridge site in the left anterior descending coronary artery (LAD) in diabetic patients. METHODS: From March 2011 to December 2012, 9862 patients with suspected coronary disease underwent coronary computed tomography angiography (CCTA) using a dual-source CT scanner. The baseline clinical characteristics (age, gender, smoking history, presence of hypertension, dyslipidemia, diabetes mellitus, family history of heart attack and body mass index) and the results of CCTA were reviewed. Two radiologists evaluated the MB and coronary atherosclerosis stenosis (CAS) over 50% in the LAD and made a diagnosis by consensus. Significant independent risk factors for CAS were investigated by logistic regression analysis. RESULTS: Of the 2345 patients identified to have diabetes mellitus, 1373 had MB, among whom 827 had coronary atherosclerosis proximal to the bridge site; 972 of the diabetic patients were free of MB, among whom 254 had coronary atherosclerosis at the equivalent site. None of the patients had CAS in the tunneled segment. After adjusted for clinical data, logistic regression analysis showed that MB in the LAD was significantly correlated with coronary atherosclerosis in the proximal LAD in diabetic patient (OR=3.91) and non-diabetic patients (OR=2.69) (P<0.05). CONCLUSION: In diabetic patients, atherosclerosis occurred frequently in the segment proximal to MB in the LAD, and MB in the mid-LAD is an independent risk factor for CAS in the proximal LAD. PMID- 25537901 TI - [Expression of Mus81 gene in Chinese Han patients with colorectal cancer and its clinical significance]. AB - OBJECTIVE: To explore the expression pattern of Mus81 gene in Chinese Han patients with colorectal cancer and analyze its correlation with the clinicopathological parameters and the tumor markers. METHODS: Mus81 expression was detected using nested quantitative real-time PCR in the colorectal cancer tissues and corresponding adjacent normal tissues from 43 Chinese Han patients. The correlations of Mus81 expression profile with the clinicopathological parameters and common tumor markers were evaluated. RESULTS: Mus81 expression level was significantly lower in the colorectal cancer tissues than in the corresponding adjacent normal tissues (114.6 +/- 68.0 vs 202.5 +/- 109.0, P<0.001). Of the 43 patients, 32 (74.4%) showed down-regulated Mus81 expression, which correlated significantly with distant metastasis (P=0.043), high TNM stage (P=0.022) and high P53 protein expression (P=0.011) of the tumor. CONCLUSION: Down-regulation of Mus81 in colorectal cancer is correlated with tumor metastasis and progression, suggesting the value of Mus81 as a potential marker for colorectal cancer in Chinese Han patients. PMID- 25537902 TI - [Expression of chemokine receptor CXCR7 in gastric cancer tissues and cell lines]. AB - OBJECTIVE: To investigate the expression status of CXCR7 in gastric cancer tissues and cell lines. METHODS: The expression status of CXCR7 was detected in 35 primary gastric cancer tissues and matched adjacent tissues by immunohistochemistry and RT-PCR. The correlation of CXCR7 expression with the clinicopathological parameters and risk factors of gastric cancer was analyzed. The expression of CXCR7 in gastric cell lines (HGC-27, MGC-803, BGC-823, SGC-7901 and MKN-28) was also detected by immunofluorescence assay. RESULTS: The expression of CXCR7 was significantly higher in gastric cancer tissues than in adjacent tissues (P<0.01). CXCR7 expression was not correlated with age, gender, smoking history, Helicobacter pylori infection, tumor location or the pathological type, but showed a higher expression level in patients with a alcohol-drinking history than in those without (P<0.05). CXCR7 was expressed with variable intensities in the 5 gastric cancer cell lines without correlation with the degrees of cell differentiation; its expression was the highest in SGC-7901 cells, a moderately differentiated human gastric adenocarcinoma cell line. CONCLUSIONS: CXCR7 is highly expressed in gastric cancer tissues with variable intensities in 5 gastric cancer cell lines, suggesting its important role in gastric cancer progression. PMID- 25537903 TI - [Comparison of the expression profiles of cell death factors in articular cartilage between Kashin-Beck disease and osteoarthritis]. AB - OBJECTIVE: To compare the expressions of programmed cell death 5 (PDCD5) and early growth response protein-1 (EGR-1) in the articular cartilage between Kashin Beck disease (KBD) and primary osteoarthritis and the roles of these factors in KBD cartilage. METHODS: Cartilage specimens were collected from 10 confirmed KBD patients, 15 osteoarthritic patients and 6 healthy subjects. The expression levels of PDCD5 and EGR-1 in the cartilage were detected by immunohistochemistry staining, and the positive chondrocyte counts were recorded in the different layers of KBD and OA cartilages. RESULTS: The KBD cartilages contained a significantly higher percentage of PDCD5-positive chondrocytes in the middle layer [(41.35 +/- 2.97)%] than OA cartilages [(26.48 +/- 2.04)%, P=0.001] and normal cartilages [(19.02 +/- 1.88)%, P=0.000] with also obvious PDCD5 over expression in the deeper layer compared to OA (P=0.000) and normal cartilages (P=0.029), but PDCD5 expression in the superficial layer of the cartilages showed no significant difference among the 3 groups(P>0.05). The average EGR-1 positivity rate in the superficial layer of the cartilage was significantly higher in KBD patients than in OA patients (P=0.000) and healthy controls (P=0.000), but in the middle layer, its positivity rate in KBD patients was higher than that in the normal control (P=0.017) but lower than that of OA cartilage (P=0.002); EGR-1 expression in the deeper layer was comparable in KBD and OA cartilages but both was higher than that in normal cartilages. PDCD5 and EGR-1 expressions were not correlated in either KBD or normal cartilages, but were positively correlated in the superficial layer of OA cartilages. CONCLUSIONS: KBD cartilages show a significantly increased PDCD5 expression in the deeper layer and enhanced EGR-1 expression in both superficial and deeper layers, suggesting the involvement of PDCD5 and EGR-1 in the pathogenesis of KBD. PMID- 25537904 TI - [Detection of transforming growth factor-beta1 in colorectal cancer and its clinical significance]. AB - OBJECTIVE: To investigate the role of transforming growth factor beta1 (TGF beta1) in patients with colorectal cancer. METHODS: Fresh peripheral blood were obtained from 50 patients (before surgery and at least one week after surgery) and 25 healthy donors in the morning. Fresh colorectal cancer tissues and the adjacent tissues (at least 5 cm from the tumor site) were obtained from patients undergoing tumor resection. The expression levels of TGF-beta1 in the blood and tissue specimens were determined using ELISA. RESULTS: The plasma levels of TGF beta1 in patients with colorectal cancer were significantly higher than those in the healthy donors, and decreased after the surgery (P<0.05). The tumor tissues expressed higher levels of TGF-beta1 than the adjacent tissues from both CEA negative and -positive patients. The plasma level of TGF-beta1 in the patients were positively correlated with the tumor size and clinical tumor stage (P<0.05). CONCLUSION: TGF-beta1 combined with CEA can provide important information for the diagnosis, prognostic assessment and prediction of recurrence in patients with colorectal cancer, and may provide new insights for anti-TGF-beta1-based tumor immune therapeutic strategies. PMID- 25537905 TI - [Analysis of risk factors of nonspecific low back pain in a community population: a case-control study]. AB - OBJECTIVE: To analyze the risk factors of nonspecific low back pain in community populations. METHODS: Two community populations were investigated using questionnaires in this case-control study. The questionnaire was designed to collect data including age, gender, body weight, marriage, education, income, occupation, labor intensity, smoking, alcohol drinking and social mental status. The subjects with low back pain constituted the case group and those without low back pain served as the control group, and the data was analyzed by a Logistic regression model. RESULTS: A total of 1747 community residents participated in this survey, among whom 398 subjects had low back pain and 1126 subjects without low back pain were selected as the control group. Of all the latent risk factors of low back pain in Logistic regression model, gender was the most relevant factor (OR=3.5522) followed by education (OR=1.958), labor intensity (OR=1.956), marital status (OR=1.612), vibration source exposure (OR=1.491), BMI (OR=1.127) and age (OR=1.060). CONCLUSION: Gender, education, labor intensity, marriage, vibration source exposure and BMI are risk factors of nonspecific low back pain in community populations, and exercises and mental status can be protective factors against low back pain. PMID- 25537906 TI - [A quick solution for lumbar vertebra CT values in different ages and its clinical significance]. AB - OBJECTIVE: To investigate the relationship between the mean CT value and bone density value and explore a rapid and accurate image segmentation method for lumbar CT values in different age groups. METHODS: We randomly collected thin lumbar spine CT scan data from 202 patients stratified by gender and age (at the interval of 10 years). The data of each group were imported into Mimics 14.0 software to obtain independent Mask files using the new image segmentation method. The Mask files were used to fill the empty space and calculate mean, maximum, and minimum CT values. RESULTS: In the age groups of 21-30, 31-40, 41 50, 51-60, and 61-70 years, the male subjects had mean CT values of 424.94 +/- 52.23 Hu, 405.59 +/- 53.60 Hu, 361.76 +/- 53.50 Hu, 344.17 +/- 47.76 Hu, and 332.88 +/- 58.33 Hu, respectively; the values in the female group were 439.89 +/- 50.99 Hu, 448.06 +/- 65.89 Hu, 421.43 +/- 54.74 Hu, 369.07 +/- 78.27 Hu, and 304.98 +/- 55.05 Hu, respectively. The mean CT value in men aged 61-70 years was significantly lower than the values in men below 50 years (P<0.05), but comparable with that in those aged 51-60 years (P>0.05); The mean CT value was significantly lower in women aged 51-70 years groups than in those aged below 50 years (P<0.05). CONCLUSIONS: The mean CT values are correlated with the bone density values. The new image segmentation method allows rapid and accurate acquisition of the CT values in the regions of interest. The lumbar mean CT values tend to decrease with age. PMID- 25537907 TI - [Changes of endoplasmic reticulum stress- and apoptosis-related factors in rat cerebral cortex following controlled hypotension]. AB - OBJECTIVE: To investigate the changes of endoplasmic reticulum stress (ERS)- and apoptosis-related factors in rat cerebral cortex following controlled hypotension. METHODS: Twenty-four healthy male SD rats were randomly divided into 4 equal groups, including a sham hypotension group (group A) and 3 hypotension groups with the mean arterial pressure maintained for 60 min at 70 mmHg (group B), 50 mmHg (group) and 30 mmHg (group D) with sodium nitroprusside and esmolol. All the rats received an equal volume of fluid infusion. Twelve hours after controlled hypotension, the rats were sacrificed to examine the protein expressions of Bax, Bcl-2, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12 in the cortex with Western blotting. GRP78 mRNA expression was measured by RT-PCR, and the cell apoptosis was evaluated by TUNEL staining. RESULTS: Compared with those in group A, GRP78 mRNA and protein expressions of GRP78, CHOP, caspase-12 related with ERS increased significantly in groups C and D (P<0.05), especially in group D (P<0.05), but not in group B (P>0.05). Apoptotic cells and Bax expression increased and Bcl-2 expression decreased significantly in groups C and D (P<0.05), but not in group B (P>0.05); such changes were more prominent in group D than in group C (P<0.05). CONCLUSION: Mild controlled hypotension (70 mmHg) does not induce neuronal injury in rat cerebral cortex, but severe hypertension (lower than 50 mmHg) can cause neuronal ERS and apoptosis. PMID- 25537908 TI - [Role of Treg/Th17 cells and related cytokines in Graves' ophthalmopathy]. AB - OBJECTIVE: To explore the role of CD4+ CD25+ Foxp3+ Treg/CD4+ IL-17A(+)Th17 cells and the related cytokines in Graves' ophthalmopathy. METHODS: Based on clinical activity scores (CAS), we divided patients with untreated Graves' ophthal- mopathy into active group (AGO group with CAS >= 3 (15 cases) and non-active group (NGO group) with CAS<3 (15 cases), with another 15 patients with untreated Graves' disease free of eye symptoms (GD group) and 15 normal subjects as controls. Peripheral venous blood Treg/Th17 cell ratio was determined using flow cytometry. RT-PCR was used to detect the mRNA expression levels of Treg-specific transcription factor Foxp3 and Th17-specific transcription factor RORgammat. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of Th17 cell-related cytokines (IL-17A, IL-23, and IL-6) and Treg-related cytokines (TGF-beta, IL-10, and IL-35). RESULTS: Compared with the normal subjects, the patients in GD, NGO, AGO groups all showed significantly increased Th17 cell count (P<0.05), which was the highest in AGO group. RT-PCR results revealed significantly increased RORgammat in GD, NGO, and AGO groups, also the highest in AGO group. Serum IL-17A, IL-23, and IL-6 levels all showed significant increments in GD, NGO, and AGO groups (P<0.05), especially in AGO group. Among the Treg related cytokines, TGF-beta and IL-35 levels decreased (P<0.05) but IL-10 increased significantly (P<0.05) in GD, NGO, AGO groups. CONCLUSION: Decreased immunosuppressive capacity of Treg cells can be an important factor in the pathogenesis of Graves' ophthalmopathy. Th17 cells may also participate in the occurrence and progression of Graves' ophthalmopathy and can serve along with related cytokines as novel indicators of the disease activity. Impaired Treg/Th17 balance may importantly contribute to the occurrence of Graves' ophthalmopathy. PMID- 25537909 TI - [Value of VEGF-C, VEGF-D and VEGFR-3 levels combined with serum TSH in diagnosis of papillary thyroid carcinoma]. AB - OBJECTIVE: To investigate serum vascular endothelial growth factor-C (VEGF-C), VEGF-D and VEGFR-3 levels in patients with papillary thyroid carcinoma (PTC) and analyze their relation with the clinicopathological and thyroid function of the patients. METHODS: Serum samples and the data of thyroid function were collected from 55 patients with PTC and 24 with benign thyroid tumor (BT). ELISA was used to detect VEGF-C/D and VEGFR-3 concentration in the serum samples and their relation with the thyroid function was analyzed. RESULTS: The VEGF-C and VEGFR-3 levels were significantly higher in PTC group than in BT group (P<0.05), but VEGF D level was comparable between them (P>0.05). In PTC patients, the elevation of serum VEGF-C and VEGFR-3 levels was associated with an advanced clinical stage (III-IV), elevated thyroid-stimulating hormone (TSH) level, an age over 45 years, and a tumor diameter exceeding 2 cm (P<0.05 or P<0.01). Patients with lymph node metastasis had significantly higher VEGF-C level but lower VEGF-3 level than those without metastasis regardless of gender. Serum VEGF-D level was higher in PTC patients with lymph node metastasis (P<0.05) and elevated TSH level (P<0.01) without association with the clinical stage, tumor diameter, age, or gender. The area under ROC curve (AUC) of serum VEGF-C, VEGFR-3 and TSH was 0.803, 0.734 and 0.707 respectively (P<0.01), and that of VEGF-D was 0.556 (P>0.05); when combined, serum VEGF-C, VEGFR-3 and TSH showed an AUC of 0.862 (P<0.01). CONCLUSION: Detecting serum VEGF-C and VEGFR-3 levels combined with TSH may enhance the early diagnosis rate of papillary thyroid carcinoma. PMID- 25537910 TI - [Clinical efficacy of transperitoneal verus retroperitoneal laparoscopic partial nephrectomy for renal tumors with R. E. N. A. L score over 7]. AB - OBJECTIVE: To compare the safety, feasibility and efficacy of transperitoneal and retroperitoneal laparoscopic partial nephrectomy (LPN) in the treatment of renal tumors with R. E. N. A. L score more than 7. METHODS: The clinical data were collected from 62 patients undergoing transperitoneal LPN (32 cases) and retroperitoneal LPN (30 cases) for a complex renal mass (R.E.N.A.L. score>=7) between January 2012 and March 2014. The surgical and early postoperative outcomes and complications were analyzed to evaluate the efficacy of the treatments. The mean operative time, estimated blood loss, warm ischemia time, surgical complications, blood transfusion rate, tolerating regular diet time, postoperative hospital stay and surgical margin were compared between the two groups. RESULTS: The operations were completed successfully in all cases except for 1 case in transperitoneal group and 3 in retroperitoneal group that required conversion to open surgery. No significant differences were found in age, body mass index, ASA score, Charlson comorbidity index, tumor size or R.E.N.A.L. nephrometry score (P>0.05), nor in estimated blood loss, warm ischemia time, intraoperative complication, blood transfusion rate or surgical margin between the two groups (P>0.05, respectively). The transperitoneal LPN group had a shorter mean operative time than retroperitoneal LPN group (210.4?59.2 vs 252?58.3 min, P<0.05) but showed longer tolerating regular diet time (47?10 h vs 23?6 h, P<0.05) and postoperative hospital stay time (8.4?1.9 days vs 6.5?1.6 days, P<0.05). CONCLUSION: Both transperitoneal LPN and retroperitoneal LPN are safe, feasible and effective for surgical management of complex localized tumors, but the transperitoneal procedure offers larger operative space with better exposure; the retroperitoneal procedure better promotes postoperative recovery of the patients. PMID- 25537911 TI - [Epidemiology of dengue fever in China since 1978]. AB - Since 1978, dengue fever occurred endemically and epidemically every 4 to 7 years in China, affecting commonly people aged between 20 and 60 years with similar incidences in males and females. Four serotypes of dengue virus have been identified in China, with DENV-1 as the predominant serotype. The incidence of dengue fever became gradually decreased after 1997 but increased significantly in the recent two years, especially in 2014, where, up to November, a total of 44894 cases had been reported in Guangdong Province. In this review, the authors summarize the epidemiology, geographical and population distribution of dengue fever in China since 1978 and analyze the factors contributing to the outbreak in 2014. PMID- 25537912 TI - [Cell-specific roles of domains I and II of HCV 5'untranslated region in the translation initiation activity]. AB - OBJECTIVE: To investigate the roles of Domain I and Domain II of hepatitis C virus (HCV) 5' untranslated region (UTR) in the translation initiation activity of HCV 5'UTR in different host cell lines. METHODS: The eukaryotic expression plasmid pCMVNCRLuc (pCN1), in which full-length HCV 5'UTR regulates firefly luciferase expression, was modified by deleting Domain I and the downstream single-stranded sequence (43 bp in total) from the UTR (pCNl-d2), Domain I with the downstream single-stranded sequence and Domain II (118 bp in total) from the UTR (pCNl-d3), or the total UTR (pCNl-d5). The modified plasmids were transfected via liposome into different cell lines with pRL-TK plasmid co-transfected as the normalization control. At 36 h after the transfection, the total cellular RNA was harvested for semi-quantitative RT-PCR, and the relative expression activities of luciferase were assayed with a dual luciferase reporter gene assay system. The translation initiation activities of the truncated HCV 5'UTRs in different translation systems were analyzed. RESULTS: Deletion of Domain I and the downstream single-stranded sequence caused no significant changes of the translational activity of HCV 5'UTR in Hela or C6 cells, but decreased the translational activity by 46% in L-02 cells and increased the translational activity by 46% in 293T cells. Deletion of both Domain I and Domain II resulted in decreased translational activity of HCV 5'UTR by 51% in HeLa cells, but increased the translational activity by 40% in L-02 cells, 60% in C6 cells and 135% in 293T cells. CONCLUSIONS: Domain I and Domain II of HCV 5'UTR perform cell type-specific roles in HCV IRES-driven translation initiation. PMID- 25537913 TI - [Design, synthesis and biological activity assessment of phenoxybutyric acid derivatives as nonsteroidal 5alpha-reductase inhibitors]. AB - OBJEVTIVE: To synthesize phenoxybutyric acid derivatives as 5alpha-reductase inhibitors and test their biological activities in vitro. METHODS: Eight analogues as nonsteroidal 5alpha-reductase inhibitors were designed and synthesized by substitution reaction of 6-(4-phenyl-piperazine-1-yl)-3(2H) pyridazinone with phenoxybutyric acid derivatives. RESULTS AND CONCLUSION: The structures of the compounds were characterized by 1H-NMR and MS. Biological evaluation indicated that 7 out of the 8 compounds exhibited moderate 5alpha reductase inhibitory activities, especially the compounds A1 and A7 with inhibition rates reaching 12.50% and 19.64% at the concentration of 3.3 * 10-5 mol/L, respectively. PMID- 25537914 TI - [Effect of mean arterial pressure on arterial to end-tidal CO2partial pressure difference during one-lung ventilation]. AB - OBJECTIVE: To study the effect of different mean arterial pressures (MAP) on arterial to end-tidal CO2partial pressure difference [(Pa-et)CO2] and the intrapulmonary shunt (Qs/Qt) in patients undergoing thoracic surgery during one lung ventilation (OLV). METHODS: Forty-two patients undergoing right-sided pulmonary lobectomy were allocated into group A with fluctuation of MAP (at 20 min after OLV) within +/- 10% of the baseline (n=22) and group B with lowered MAP by 30% of the baseline (n=20). Arterial and venous blood gas analyses were recorded to calculate [(Pa-et)CO2] and Qs/Qt at 20 min after induction with two lung ventilation (T1), 20 min after OLV (T2), 30 min after recovery of normal blood pressure (T3), and 20 min after recovery of two-lung ventilation (T4). RESULTS: PetCO2and PaCO2were well correlated during two-lung ventilation and OLV in group A (P<0.05). In group B, [(Pa-et)CO2] at T2was significantly higher than that in group A, but PetCO2was still correlated with PaCO2(P<0.05). Qs/Qt increased more obviously in group B than in group A in T2(P<0.05). Bo obvious correlation was found between the [(Pa-et)CO2] and Qs/Qt during OLV. CONCLUSION: PetCO2reflects the dynamic changes of PaCO2under normal blood pressure during OLV. In the hypotension period, when [(Pa-et)CO2] increases and the correlation coefficient between PetCO2and PaCO2lowers, PetCO2may not accurately reflect the changes of PaCO2and blood gas analysis is warranted. PMID- 25537915 TI - [Expressions of Bim and ERKs in multidrug-resistant hepatic carcinoma cells]. AB - OBJECTIVE: To investigate the expressions of extracellular signal-regulated kinase (ERK) and the BH3-only subgroup of Bcl-2 related proteins (Bim) in multidrug-resistant hepatocellular carcinoma (HCC) cells and their association with drug resistance in the cells. METHODS: The multdrug-resistant HepG-2 cell line was established by treatment with gradually increasing doses of ADM. CCK-8 assay was used to determine the drug sensitivity of the cells, and the expressions of MRP-1, P-gp, ERK1, ERK2, ERK5, and Bim were detected with Western blot. Bim mRNA expression level was measured using quantitative real-time PCR. RESULTS: The drug resistance indices to ADM, 5-FU and CDDP was 6.8, 4.10, and 4.5 in HepG-2/ADM cells, respectively. The drug-resistantcells showed marked up regulation of MRP-1, P-gp, ERK1, ERK2 and ERK5 with down-regulated phosphorylated ERK2 protein expression but no significant changes in phosphorylated ERK1 protein expression to result in a decreased ratio of P-ERK1/2 and P-ERK1/2. Bim mRNA and protein expressions were both decreased in HepG-2/ADM cells. CONCLUSION: ERK and Bim are related to multidrug resistance in HepG-2/ADM cells. PMID- 25537916 TI - [Therapeutic window of mycophenolate mofetil for preventing acute graft rejection following renal transplantation]. AB - OBJECTIVE: To determine the optimal dose range (therapeutic window) of mycophenolate mofetil (MMF) for preventing acute graft rejection following renal transplantation. METHODS: The trough concentration of MMF (MPA-C0) at 12 h after oral administration of the drug (two doses daily given at an interval of 12 h) was monitored in 110 renal transplant recipients within a month, in 2-3 months, and over 4 months after the transplantation using EMIT method. The occurrence of acute graft rejection and drug toxicity were observed in all the patients during the one-year follow-up. RESULTS: s The incidence of acute graft rejection after transplantation was 13.64% (15/110) in these patients. Drug toxicity and complications occurred in 32.73% (36/110) of the patients, including 12 cases with reduced white blood cell counts, 10 with MMF cid-associated diarrhea, 10 with infection, 4 with liver function damage. Acute rejection was successfully reversed after methylprednisolone treatment and drug toxicity was managed by corresponding treatment and adjustment of MMF dose. No deaths or graft removal occurred in these patients. The ROC curve showed that a MPA-C0 of 1.40-2.80 mg/L was optimal in preventing acute rejection after the transplantation and reducing adverse drug effects. CONCLUSION: Monitoring MPA-C0 and individualized MMF dosing help to prevent acute graft rejection, reducing drug toxicity and complications, and improving graft survival rate after renal transplantation. PMID- 25537917 TI - [Efficacy of oral bosentan for treatment of congenital heart disease-associated pulmonary arterial hypertension]. AB - OBJECTIVE: To investigate the effect of oral bosentan in the treatment of congenital heart disease-associated pulmonary arterial hypertension. METHODS: 24 patients with congenital heart disease-associated pulmonary arterial hypertension, including 4 receiving heart surgery and 20 with surgical contraindications, were enrolled in this study. All the patients were given oral bosentan and followed up regularly for analyzing the outcomes and side effects. RESULTS: One patient was lost to follow up and one patient died. Systolic pulmonary artery pressure showed no significant changes at 2 (93.6 +/- 17.2 mmHg) and 4 months (85.7 +/- 25.5 mmHg) of bosentan treatment compared to that before the medication (97.8 +/- 14.9 mmHg) (P=0.096), but decreased significantly after a 6-month therapy (80.9 +/- 25.0 mmHg, P=0.029). The 6-minute walking distance increased significantly after a 2, 4, and 6-month therapy [(488 +/- 98.8, 496.3 +/- 89.0, and 491.3 +/- 114.2 m, respectively; P=0.004, 0.003, and 0.004 vs the distance before medication (317.0 +/- 134.1)]. The New York heart functional classification was improved significantly after a 2, 4, and 6-month therapy [(2.0 +/- 0.5, 1.8 +/- 0.4, and 1.7 +/- 0.5, respectively; P<0.001 vs pre-medication score (2.9 +/- 0.5)). Hepatic and renal function remained normal, and ALT and AST showed no significant variations during the medication (P>0.05). CONCLUSION: Oral bosentan can effectively relieve the symptoms, decrease pulmonary artery hypertension, and improve exercise tolerance and cardiac function classification in patients with pulmonary artery hypertension associated with congenital heart disease with good safety and mild side effects. PMID- 25537918 TI - [Research progress of Wnt/beta-catenin signaling pathway in prevention and treatment of gastric cancer]. AB - The mechanism underlying the occurrence and development of gastric cancer is complex. Abnormal activation of cell signaling pathways play a vital role in the occurrence and development of cancer. The Wnt/beta-catenin signaling pathway participates in gastric cancer cell proliferation, invasion and metastasis and effectively induces drug resistance of the gastric cancer cells; it is also the key signal to mediate gastric carcinogenesis. Disturbances of Wnt/beta-catenin signaling pathway can inhibit the growth, invasion and metastasis of gastric cancer and increase the sensitivity of the cancer cells to chemotherapeutic drugs. The authors reviewed the research progress of the role of Wnt/beta-catenin signaling pathway in the occurrence and development of gastric cancer and discussed the prospective of preventing gastric cancer by interfering with Wnt/beta-catenin signaling pathway. PMID- 25537920 TI - Synthesis of air-stable, volatile uranium(IV) and (VI) compounds and their gas phase conversion to uranium oxide films. AB - Four air-stable, volatile uranium heteroarylalkenolates have been synthesized and characterized by three synthetic approaches and their gas phase deposition to uranium oxide films has been examined. PMID- 25537919 TI - Significant unmet oral health needs of homebound elderly adults. AB - OBJECTIVES: To assess the oral health status, use of dental care, and dental needs of homebound elderly adults and to determine whether medical diagnoses or demographic factors influenced perceived oral health. DESIGN: Cross-sectional analysis. SETTING: Participants' homes in New York City. PARTICIPANTS: Homebound elderly adults (N = 125). MEASUREMENTS: A trained dental research team conducted a comprehensive clinical examination in participants' homes and completed a dental use and needs survey and the Geriatric Oral Health Assessment Index. RESULTS: Participants who reported a high level of unmet oral health needs were more likely to be nonwhite, although this effect was not significant in multivariate analysis. Individual medical diagnoses and the presence of multiple comorbidities were not associated with unmet oral health needs. CONCLUSION: The oral health status of homebound elderly adults was poor regardless of their medical diagnoses. High unmet oral health needs combined with strong desire to receive dental care suggests there is a need to improve access to dental care for this growing population. In addition to improving awareness of geriatricians and primary care providers who care for homebound individuals, the medical community must partner with the dental community to develop home-based programs for older adults. PMID- 25537921 TI - Human exposure risks for metals in soil near a coal-fired power-generating plant. AB - Coal-fired thermal power stations (TPSs) may contaminate the surrounding soil and could lead to pollution levels that can affect human health. Soil samples collected from the immediate vicinity of a TPS were analysed for heavy metals. TPS soils were enriched with arsenic (As), strontium (Sr), copper (Cu), mercury (Hg), barium (Ba), vanadium (V), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), and nickel (Ni). Enrichment factor, principal component, and cluster analyses suggest that As, Cd, Co, Cr, and Hg in TPS soils originated from the TPS, whereas Pb and Zn were from vehicular/traffic-related emissions. The human exposure risk assessment based on different exposure pathways showed that the hazard index (HI) was <1.0 for all of the elements. The relative exposure risk was greater for toddlers. Although the overall risk was within the acceptable limit of 1.00, the HIs of Co (0.15) and Cr (0.082) were close to the threshold limits, which over the long-term may pose a health risk. PMID- 25537922 TI - Screening the toxicity and biodegradability of petroleum hydrocarbons by a rapid colorimetric method. AB - Crude oil and petroleum products have a wide variety of hazardous components with high toxicity and low biodegradability. Certain dyes change their colors by intercepting electron transfer reactions during the transformation processes. This study applied resazurin and 2,6-dichlorophenol-indophenol indicators for a rapid screening biodegradation capability and toxicity response to various petroleum products such as motor oil, diesel, gasoline, and phenol. Colorimetry tests were performed in test tubes, and the absorbance values were measured over time. We observed different discoloration profiles after degradation tests using Bacillus subtilis inoculum. Phytotoxicity assays were also performed to compare colorimetric screening assays with a conventional toxicity testing with plants (seed germination). The results indicated that biotransformation of oils can increase its overall toxicity. Intermediate byproducts can be formed through biodegradation and thereby increase the toxicity of oils. The assessment of acute toxicity has shown that phenol is extremely toxic to petroleum-biodegrading microbial communities. Low molecular-weight gasoline was considered biodegradable, but it also exhibited a high acute toxic effect, mainly due to its high solubility and the presence of more volatile compounds that can penetrate cells and potentially damage cellular structures. PMID- 25537923 TI - Prospectively Isolated Human Bone Marrow Cell-Derived MSCs Support Primitive Human CD34-Negative Hematopoietic Stem Cells. AB - Hematopoietic stem cells (HSCs) are maintained in a specialized bone marrow (BM) niche, which consists of osteoblasts, endothelial cells, and a variety of mesenchymal stem/stromal cells (MSCs). However, precisely what types of MSCs support human HSCs in the BM remain to be elucidated because of their heterogeneity. In this study, we succeeded in prospectively isolating/establishing three types of MSCs from human BM-derived lineage- and CD45-negative cells, according to their cell surface expression of CD271 and stage-specific embryonic antigen (SSEA)-4. Among them, the MSCs established from the Lineage(-) CD45(-) CD271(+) SSEA-4(+) fraction (DP MSC) could differentiate into osteoblasts and chondrocytes, but they lacked adipogenic differentiation potential. The DP MSCs expressed significantly higher levels of well characterized HSC-supportive genes, including IGF-2, Wnt3a, Jagged1, TGFbeta3, nestin, CXCL12, and Foxc1, compared with other MSCs. Interestingly, these osteo chondrogenic DP MSCs possessed the ability to support cord blood-derived primitive human CD34-negative severe combined immunodeficiency-repopulating cells. The HSC-supportive actions of DP MSCs were partially carried out by soluble factors, including IGF-2, Wnt3a, and Jagged1. Moreover, contact between DP MSCs and CD34-positive (CD34(+) ) as well as CD34-negative (CD34(-) ) HSCs was important for the support/maintenance of the CD34(+/-) HSCs in vitro. These data suggest that DP MSCs might play an important role in the maintenance of human primitive HSCs in the BM niche. Therefore, the establishment of DP MSCs provides a new tool for the elucidation of the human HSC/niche interaction in vitro as well as in vivo. PMID- 25537924 TI - Meaning in life in chronic pain patients over time: associations with pain experience and psychological well-being. AB - We explored the relationship between meaning in life and adjustment to chronic pain in a three-wave, 2 year, longitudinal study of 273 Belgian chronic pain patients. We examined the directionality of the relationships among the meaning in life dimensions (Presence of Meaning and Search for Meaning) and indicators of adjustment (depressive symptoms, life satisfaction, pain intensity, and pain medication use). We found that Presence of Meaning was an important predictor of well-being. Secondly, we used a typological methodology to distinguish meaning in life profiles, and the relationship of individual meaning in life profiles with indicators of adjustment. Five meaning in life profiles emerged: High Presence High Search, High Presence Low Search, Moderate Presence Moderate Search, Low Presence Low Search, and Low Presence High Search. Each meaning in life profile was associated with a unique adjustment outcome. Profiles that scored high on Presence of Meaning showed more optimal adjustment. The profiles showed little change over time and did not moderate the development of adjustment indicators, except for life satisfaction. Practical implications and suggestions for future research are discussed. PMID- 25537925 TI - Highly-active antiretroviral therapy and oral opportunistic microorganisms in HIV positive individuals of Thailand. AB - AIM: Oral mucosal lesions and opportunistic microorganisms in HIV-positive Thais treated with highly-active antiretroviral therapy (HAART) for more than 5 years were investigated. METHODS: A total of 221 HIV-infected patients, comprising 148 HIV patients undergoing HAART for more than 5 years, 20 non-HAART HIV patients, 53 vertically-transmitted (VT) HAART HIV patients, and 30 HIV-negative controls, were examined for CD4+ counts, viral load, saliva secretion rate, and oral mucosal lesions. Samples from the tongue, gingival crevices, and mucosal lesions when present were cultured for the amounts of Candida, staphylococci, enterococci, and aerobic Gram-negative bacilli. RESULTS: HAART (including HIV-VT) maintained oral microbial homeostasis predominated by alpha-hemolytic streptococci similar to the non-HIV controls and with a low prevalence of mucosal lesions. The HAART group had a reduced saliva secretion rate. The frequency and load of opportunistic microorganisms in the HAART group were similar to the non HAART group, which was significantly higher than the HIV-negative controls. Candida spp. was found significantly more frequently on the tongue in HIV infected individuals with CD4+ counts <500 cells/mm(3). CONCLUSION: Although we did not find lower levels of mucosal lesions among HAART compared to non-HAART individuals, HAART therapy could prolong the time before opportunistic oral pathogens overwhelm the commensal members of oral microbiota. PMID- 25537930 TI - Prevalence and clinical correlates of drooling in Parkinson disease: a study on 518 Chinese patients. AB - BACKGROUND: The prevalence and clinical correlates of drooling in Chinese patients with Parkinson disease (PD) are unknown. METHODS: A cross-sectional analysis of 518 Chinese patients with PD was conducted. Assessments included Unified PD Rating Scale (UPDRS), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), PD Questionnaire-39 (PDQ 39), Frontal assessment battery (FAB) and Montreal Cognitive Assessment (MoCA). RESULTS: Two hundred and seventy-three PD patients (52.7%) reported drooling (droolers). Drooling occurred more frequently in the late-onset PD patients than the early-onset PD patients (p < 0.05). Droolers had higher levodopa equivalent daily doses, higher incidences of dysarthria, dysphagia and fluctuation, higher scores for the UPDRS part III, NMSS, HAMD and HAMA, and higher scores for the mobility, activities of daily life, stigma and communication subdomains of the PDQ-39 than the non-droolers (p < 0.05). The percentage of benzhexol use in the non-droolers was significantly higher than the droolers (p < 0.05). The FAB and MoCA scores between the droolers and non-droolers were not different. The binary logistic regression analysis indicated that dysarthria, dysphagia, benzhexol use, and a lower score for the naming domain of the MoCA were associated with drooling. CONCLUSIONS: Drooling is a relatively common disabling symptom in Chinese PD patients. Patients with dysarthria, dysphagia and naming disorder are likely to experience drooling. Drooling is not correlated with disease duration and motor severity of PD. PMID- 25537932 TI - Analysis of clinical factors related to the efficacy of shoulder arthroscopic synovectomy plus capsular release in patients with rheumatoid arthritis. AB - Shoulder synovectomy is a well-known surgical treatment for rheumatoid arthritis. However, synovectomy alone is insufficient for improving range of motion clinically. We investigated the clinical factors related to the efficacy of shoulder synovectomy performed with capsular release in patients with rheumatoid arthritis. Fifty-four shoulders of 54 patients (12 males, 42 females; mean age 53.3 years) with rheumatoid arthritis were treated by synovectomy plus capsular release. The patients had a mean disease duration of 8.33 years, a mean follow-up period of 5.02 years, and 66.7% received biological treatment. The disease activity score 28 using C-reactive protein, range of motion of the shoulder, and Japanese Orthopaedic Association (JOA) score assessment were used to investigate clinical factors, analyzed by multiple regression analysis, associated with improved outcome. The average disease activity score 28 using C-reactive protein and JOA score improved significantly from 4.29 and 36.7 to 3.11 and 84.6, respectively, with the restoration of range of motion. Multiple regression analysis showed that disease duration and prednisolone were significantly associated with flexion degree and JOA score. Larsen grade and JOA score were not correlated significantly. There was no significant difference in the JOA score between the groups with or without biological medicinal treatment. Shoulder arthroscopic synovectomy performed with capsular release with or without biological treatment effectively improved function. Short disease duration and low prednisolone dose in rheumatoid arthritis were important for prediction of efficacy. PMID- 25537933 TI - Medium-term comparison of results in obese patients and non-obese hip prostheses with Metha(r) short stem. AB - INTRODUCTION: Total hip arthroplasty is one of the most successful orthopedic surgeries in terms of results. However, the prevalence of obesity has nearly doubled between 1980 and 2008. There is limited and controversial data on hip replacement results in obese patients. The Metha(r) prosthesis, introduced in 2004, is a short stem midway between devices maintaining the femoral neck and metaphyseal implants. The purpose of this study was to evaluate the influence of obesity on clinical and radiological results at medium term. MATERIALS AND METHODS: Eighty-two patients were retrospectively divided into two cohorts based on their BMI. Mean BMI were, respectively, 35.22 kg/m2 in the obese group [30.02 57.79] and 26.15 [23.25-28.72] in the other cohort. Follow-up were 47.16 [26.10 74.33] and 54.06 [28.17-77.73]. The mean ages at surgery were 55 years [39.8 67.8] and 54 [31.3-70.4]. We used self-assessment questionnaires WOMAC and Oxford; two clinical scores Harris Hip Score and Postel-Merle d'Aubigne. ARA score was used for osseointegration evaluation. RESULTS: Operative times were comparable. The self-assessment questionnaires and clinical scores showed significant poorer results in the obese cohort. HHS were 87.54 [56-100] and 92.49 [25-100]. However, the clinical improvement obtained between pre- and postoperative was identical in both groups: 52 [19-73] and 52 [-6 to 90]. Radiological ARA scores were good or excellent for 97.56 and 92.68%. Survival analysis was comparable with more than 0.96 at 50 months follow-up. CONCLUSION: The Metha(r) prosthesis can be implanted at the forefront of primary total hip arthroplasty in normal subjects as well as in obese subjects. However, we cannot yet claim we will reach the same durability we experience with standard prostheses. PMID- 25537935 TI - Pudendal nerve exposure and preservation in low rectal surgery by using transvaginal access. PMID- 25537934 TI - Serum surfactant protein D (SP-D) is a prognostic marker of poor outcome in patients with A/H1N1 virus infection. AB - INTRODUCTION: Surfactant protein D (SP-D) plays an important role in the innate responses against pathogens and its production is altered in lung disorders. METHODS: We studied the circulating levels of SP-D in 37 patients with acute respiratory distress syndrome due to the A/H1N1 virus infection and in 40 healthy controls. Cox logistic regression models were constructed to explore the association of SP-D levels and risk of death. RESULTS: Mortality rate after a 28 day was 32.42 %. Significant higher levels of SP-D were detected in A/H1N1 patients with fatal outcome (p < 0.05). After adjusting for confounding variables, levels of SP-D >=250 ng/mL were associated with increased the risk of death (HR = 8.27, 95 % CI 1.1-64.1, p = 0.043). CONCLUSIONS: Our results revealed that higher circulating levels of SP-D are associated with higher mortality risk in critically ill A/H1N1 patients. SP-D might be a predictive factor of poor outcomes in viral pneumonia. PMID- 25537936 TI - Utilisation and costs of nursing agencies in the South African public health sector, 2005-2010. AB - BACKGROUND: Globally, insufficient information exists on the costs of nursing agencies, which are temporary employment service providers that supply nurses to health establishments and/or private individuals. OBJECTIVE: The aim of the study was to determine the utilisation and direct costs of nursing agencies in the South African public health sector. DESIGN: A survey of all nine provincial health departments was conducted to determine utilisation and management of nursing agencies. The costs of nursing agencies were assumed to be equivalent to expenditure. Provincial health expenditure was obtained for five financial years (2005/6-2009/10) from the national Basic Accounting System database, and analysed using Microsoft Excel. Each of the 166,466 expenditure line items was coded. The total personnel and nursing agency expenditure was calculated for each financial year and for each province. Nursing agency expenditure as a percentage of the total personnel expenditure was then calculated. The nursing agency expenditure for South Africa is the total of all provincial expenditure. The 2009/10 annual government salary scales for different categories of nurses were used to calculate the number of permanent nurses who could have been employed in lieu of agency expenditure. All expenditure is expressed in South African rands (R; US$1 ~ R7, 2010 prices). RESULTS: Only five provinces reported utilisation of nursing agencies, but all provinces showed agency expenditure. In the 2009/10 financial year, R1.49 billion (US$212.64 million) was spent on nursing agencies in the public health sector. In the same year, agency expenditure ranged from a low of R36.45 million (US$5.20 million) in Mpumalanga Province (mixed urban-rural) to a high of R356.43 million (US$50.92 million) in the Eastern Cape Province (mixed urban-rural). Agency expenditure as a percentage of personnel expenditure ranged from 0.96% in KwaZulu-Natal Province (mixed urban-rural) to 11.96% in the Northern Cape Province (rural). In that financial year, a total of 5369 registered nurses could have been employed in lieu of nursing agency expenditure. CONCLUSIONS: The study findings should inform workforce planning in South Africa. There is a need for uniform policies and improved management of commercial nursing agencies in the public health sector. PMID- 25537937 TI - Using diaries to explore the work experiences of primary health care nursing managers in two South African provinces. AB - BACKGROUND: South Africa is on the brink of another wave of major health system reforms that underscore the centrality of primary health care (PHC). Nursing managers will play a critical role in these reforms. OBJECTIVE: The aim of the study was to explore the work experiences of PHC clinic nursing managers through the use of reflective diaries, a method hitherto under-utilised in health systems research in low- and middle-income countries. DESIGN: During 2012, a sub-set of 22 PHC nursing managers was selected randomly from a larger nurses' survey in two South African provinces. After informed consent, participants were requested to keep individual diaries for a period of 6 weeks, using a clear set of diary entry guidelines. Reminders consisted of weekly short message service reminders and telephone calls. Diary entries were analysed using thematic content analysis. A diary feedback meeting was held with all the participants to validate the findings. RESULTS: Fifteen diaries were received, representing a 68% response rate. The majority of respondents (14/15) were female, each with between 5 and 15 years of nursing experience. Most participants made their diary entries at home. Diaries proved to be cathartic for individual nursing managers. Although inter related and not mutually exclusive, the main themes that emerged from the diary analysis were health system deficiencies; human resource challenges; unsupportive management environment; leadership and governance; and the emotional impact of clinic management. CONCLUSIONS: Diaries are an innovative method of capturing the work experiences of managers at the PHC level, as they allow for confidentiality and anonymity, often not possible with other qualitative research methods. The expressed concerns of nursing managers must be addressed to ensure the success of South Africa's health sector reforms, particularly at the PHC level. PMID- 25537938 TI - Contestations and complexities of nurses' participation in policy-making in South Africa. AB - BACKGROUND: There has been increased emphasis globally on nurses' involvement in health policy and systems development. However, there has been limited scholarly attention on nurses' participation in policy-making in South Africa. OBJECTIVE: This paper analyses the dynamics, strengths, and weaknesses of nurses' participation in four national health workforce policies: the 2008 Nursing Strategy, revision of the Scope of Practice for nurses, the new Framework for Nursing Qualifications, and the Occupation-Specific Dispensation (OSD) remuneration policy. DESIGN: Using a policy analysis framework, we conducted in depth interviews with 28 key informants and 73 frontline nurses in four South African provinces. Thematic content analysis was done using the Atlas.ti software. RESULTS: The study found that nurses' participation in policy-making is both contested and complex. The contestation relates to the extent and nature of nurses' participation in nursing policies. There was a disjuncture between nursing leadership and frontline nurses in their levels of awareness of the four policies. The latter group was generally unaware of these policies with the exception of the OSD remuneration policy as it affected them directly. There was also limited consensus on which nursing group legitimately represented nursing issues in the policy arena. Shifting power relationships influenced who participated, how the participation happened, and the degree to which nurses' views and inputs were considered and incorporated. CONCLUSIONS: The South African health system presents major opportunities for nurses to influence and direct policies that affect them. This will require a combination of proactive leadership, health policy capacity and skills development among nurses, and strong support from the national nursing association. PMID- 25537939 TI - Does moonlighting influence South African nurses' intention to leave their primary jobs? AB - BACKGROUND: Staff retention and turnover have risen in prominence in the global discourse on the health workforce. Moonlighting, having a second job in addition to a primary job, has not featured in debates on turnover. OBJECTIVE: This paper examines whether moonlighting is a determinant of South African nurses' intention to leave their primary jobs. DESIGN: During 2010, a one-stage cluster random sample of 80 hospitals was selected in four South African provinces. On the survey day, all nurses working in critical care, theatre, emergency, maternity, and general medical and surgical wards completed a self-administered questionnaire after giving informed consent. In addition to demographic information and information on moonlighting, the questionnaire obtained information on the participants' intention to leave their primary jobs in the 12 months following the survey. A weighted analysis of the survey data was done using STATA((r)) 13. RESULTS: Survey participants (n=3,784) were predominantly middle-aged with a mean age of 41.5 (SD+/-10.4) years. Almost one-third of survey participants (30.9%) indicated that they planned to leave their jobs within 12 months. Intention to leave was higher among the moonlighters (39.5%) compared to non-moonlighters (27.9%; p<0.001). Predictors of intention to leave in a multiple logistic regression were moonlighting in the preceding year, nursing category, sector of primary employment, period working at the primary job, and number of children. The odds of intention to leave was 1.40 (95% CI: 1.16-1.69) times higher for moonlighters than for non-moonlighters. The odds ratio of intention to leave was 0.53 (95% CI: 0.42-0.66) for nursing assistants compared to professional nurses and 2.09 (95% CI: 1.49-2.94) for nurses working for a commercial nursing agency compared to those working in the public sector. CONCLUSIONS: Moonlighting is a predictor of intention to leave. Both individual and organisational strategies are needed to manage moonlighting and to enhance retention among South African nurses. PMID- 25537940 TI - Development and community-based validation of the IDEA study Instrumental Activities of Daily Living (IDEA-IADL) questionnaire. AB - BACKGROUND: The dementia diagnosis gap in sub-Saharan Africa (SSA) is large, partly due to difficulties in assessing function, an essential step in diagnosis. OBJECTIVES: As part of the Identification and Intervention for Dementia in Elderly Africans (IDEA) study, to develop, pilot, and validate an Instrumental Activities of Daily Living (IADL) questionnaire for use in a rural Tanzanian population to assist in the identification of people with dementia alongside cognitive screening. DESIGN: The questionnaire was developed at a workshop for rural primary healthcare workers, based on culturally appropriate roles and usual activities of elderly people in this community. It was piloted in 52 individuals under follow-up from a dementia prevalence study. Validation subsequently took place during a community dementia-screening programme. Construct validation against gold standard clinical dementia diagnosis using DSM-IV criteria was carried out on a stratified sample of the cohort and validity assessed using area under the receiver operating characteristic (AUROC) curve analysis. RESULTS: An 11-item questionnaire (IDEA-IADL) was developed after pilot testing. During formal validation on 130 community-dwelling elderly people who presented for screening, the AUROC curve was 0.896 for DSM-IV dementia when used in isolation and 0.937 when used in conjunction with the IDEA cognitive screen, previously validated in Tanzania. The internal consistency was 0.959. Performance on the IDEA-IADL was not biased with regard to age, gender or education level. CONCLUSIONS: The IDEA-IADL questionnaire appears to be a useful aid to dementia screening in this setting. Further validation in other healthcare settings in SSA is required. PMID- 25537941 TI - Nursing education reform in South Africa--lessons from a policy analysis study. AB - BACKGROUND: Nursing education reform is identified as an important strategy for enhancing health workforce performance, and thereby improving the functioning of health systems. Globally, a predominant trend in such reform is towards greater professionalisation and university-based education. Related nursing education reform in South Africa culminated in a new Framework for Nursing Qualifications in 2013. OBJECTIVE: We undertook a policy analysis study of the development of the new Nursing Qualifications Framework in South Africa. DESIGN: We used a policy analysis framework derived from Walt and Gilson that interrogated the context, content, actors, and processes of policy development and implementation. Following informed consent, in-depth interviews were conducted with 28 key informants from national and provincial government; the South African Nursing Council; the national nursing association; nursing academics, managers, and educators; and other nursing organisations. The interviews were complemented with a review of relevant legislation and policy documents. Documents and interview transcripts were coded thematically using Atlas-ti software. RESULTS: The revision of nursing qualifications was part of the post-apartheid transformation of nursing, but was also influenced by changes in the education sector. The policy process took more than 10 years to complete and the final Regulations were promulgated in 2013. The two most important changes are the requirement for a baccalaureate degree to qualify as a professional nurse and abolishing the enrolled nurse with 2 years training in favour of a staff nurse with a 3-year college diploma. Respondents criticised slow progress, weak governance by the Nursing Council and the Department of Health, limited planning for implementation, and the inappropriateness of the proposals for South Africa. CONCLUSIONS: The study found significant weaknesses in the policy capacity of the main institutions responsible for the leadership and governance of nursing in South Africa, which will need to be addressed if important nursing education reforms are to be realised. PMID- 25537943 TI - Factors predictive of concomitant injuries among children and adolescents undergoing anterior cruciate ligament surgery. AB - BACKGROUND: The timing of treatment for pediatric anterior cruciate ligament (ACL) injuries remains controversial. The risks of delaying reconstruction and the differences between age groups are poorly defined. PURPOSE: To investigate factors that contribute to the prevalence and severity of concomitant chondral and meniscal injuries among patients aged 14 to 19 years versus those aged <=14 years at the time of ACL reconstruction. The hypothesis was that concomitant injuries would be more prevalent in older versus younger subjects. Also, a delay in surgery would be predictive of the presence and severity of concomitant knee injuries requiring additional operative procedures. STUDY METHODS: Cohort study; Level of evidence, 3. METHODS: All subjects who underwent primary ACL reconstruction at a single tertiary pediatric hospital between 2005 and 2012 were retrospectively reviewed. The location, severity, and treatment of all concomitant knee injuries were recorded. Chi-square tests were used to compare the prevalence of chondral and meniscal injuries in the older (age, 14-19 years; n = 165) versus younger (age, <=14 years; n = 66) cohorts. A multivariable logistic regression analysis was used to identify factors related to the presence of a concomitant injury that required additional treatment. Kaplan-Meier analyses were used to explore the relation between time to surgery and meniscal injury severity. RESULTS: There was a significant relationship between time to surgery and the development of an irreparable meniscal injury (P < .05 for all) in both the younger and older groups. Time to surgery correlated with severity of chondral injury in the younger cohort (P = .0343) but not in the older cohort (P = .8877). In the younger cohort, only a delay in surgery >3 months (odds ratio [OR] = 4.8; 95% CI, 1.7-14.4; P = .0027) was significantly predictive of the presence of an injury that required additional operative procedures. In the older patients, a return to activity before surgery (OR = 3.8; 95% CI, 1.52-11.9; P = .0034) and obesity (OR = 2.5; 95% CI, 1.1-7.4; P = .0381) were significantly predictive of an injury that required additional operative procedures. CONCLUSION: Compared with younger subjects, the prevalence of concomitant knee injuries as well as the need for additional operative procedures was greater among older subjects. A delay to surgery correlated with increased severity of injury among both older and younger populations. A delay in surgery >3 months was the strongest predictor of the development of a concomitant injury in the younger cohort. A return to activity and obesity were significantly related to the presence of a concomitant knee injury in the older cohort. PMID- 25537945 TI - Serum ionised calcium as a prognostic risk factor in the clinical course of pancreatitis in cats. AB - OBJECTIVES: The aims of the study were to assess the possible effects of sex, age and breed on the evolution of pancreatitis, and to understand if low values of serum ionised calcium ([Ca(2+)i]) can be considered as a prognostic risk factor for determining the clinical course of the disease. METHODS: A sample of 24 cats (n = 24) with pancreatitis was used and grouped according to the disease progress into two groups: (i) non-fatal (NF) for those that recovered and (ii) fatal (F) for those that died. Quantification of [Ca(2+)i] and feline pancreatic lipase (fPL) was carried out for each patient at two different times: T1 (day of diagnosis) and T2 (day of recovery or death). For statistical analysis, P values < 0.05 were considered significant. RESULTS: At T1, 58.3% of patients presented with hypocalcaemia, 33.3% with normocalcaemia and 8.3% with hypercalcaemia. The [Ca(2+)i] mean values were higher in the F group than in NF. At T2, 75.0% of patients showed normocalcaemia and 25.0% hypocalcaemia. The mean value of [Ca(2+)i] for F at T2 was 0.88 +/- 0.23 mmol/l, whereas for NF it was 1.10 +/- 0.11 mmol/l. There was no sex or age predisposition for disease development, but a breed effect was noted (domestic shorthair cats were more prone to developing pancreatitis). CONCLUSIONS AND RELEVANCE: The results suggest that hypocalcaemia is common in patients with pancreatitis and that [Ca(2+)i] may be used as a prognostic risk factor for predicting the clinical course of the disease, with values ? 1 mmol/l corresponding to a poor prognosis. PMID- 25537944 TI - In utero localized diffusion MRI of the embryonic mouse brain microstructure and injury. AB - PURPOSE: To develop an in vivo diffusion magnetic resonance imaging (dMRI) technique to study embryonic mouse brain structure and injury. MATERIALS AND METHODS: Pregnant CD-1 mice were examined on embryonic day 17 on an 11.7T scanner. Spatially selective excitation pulses were used to achieve localized imaging of individual mouse brains, in combination with a 3D fast imaging sequence to acquire dMRI at 0.16-0.2 mm isotropic resolution. Subject motions were corrected by navigator echoes and image registration. Further acceleration was achieved by simultaneous imaging of two embryos in an interleaved fashion. We applied this technique to detect embryonic brain injury in a mouse model of intrauterine inflammation. RESULTS: With the localized imaging technique, we achieved in utero high-resolution T2 -weighted and dMRI of the embryonic mouse brain for the first time. Early embryonic brain structures were delineated from diffusion tensor images, and major white matter tracts were reconstructed in 3D. Comparison with ex vivo data showed significant changes in the apparent diffusion coefficient (ADC), but mostly unchanged fractional anisotropy. In the inflammation-affected embryonic brains, ADC in the cortical regions was reduced at 6 hours after the injury, potentially caused by cellular edema. CONCLUSION: The feasibility of in utero dMRI of embryonic mouse brains was demonstrated. The technique is important for noninvasive monitoring of embryonic mouse brain microstructure and injury. PMID- 25537946 TI - Morphometric description of the feline radius and ulna generated from computed tomography. AB - OBJECTIVES: This study aimed to describe the length, internal and external diameters, cancellous bone volume and extent, and cortical thickness at predetermined locations in the radius and ulna of a cohort of skeletally mature, disease-free feline cadavers using radiography and computed tomography (CT). METHODS: Five feline cadavers were used (mean weight 3.31 kg, range 2.55-4.24 kg). Antebrachii (n = 10) were radiographed to confirm skeletal maturity and normal radiographic appearance prior to CT. Reconstructed CT images were used to measure bone length, cortical thickness, internal and external diameters, and cancellous extent. Cancellous bone volume was calculated automatically using OsiriX after manual segmentation (350-850 Hounsfield units window) from axial CT slices. RESULTS: CT images were used to measure bone length, cortical thickness, internal and external diameters, and cancellous extent and volume. Mean radial length was 95.89 mm (95% confidence interval [CI] 88.52-103.26 mm) and mean ulna length was 114.67 mm (95% CI 105.53-123.81 mm). The olecranon had the largest mean cancellous bone volume (94.16 mm(3); 95% CI 72.09-116.23 mm(3)) and it extended a mean of 13.12 mm (95% CI 11.73-14.51 mm) distally. The radius at the level of the trochlea and the ulna at the level of the coronoid processes had the largest external diameters, respectively. The medullary canal narrowed at the level of the coronoid processes and became cranially eccentric at the proximal third of the diaphysis. The cranial cortex at the level of the coronoid processes and the caudal cortex of the olecranon were markedly thicker than other cortices at those levels. CONCLUSIONS AND RELEVANCE: Morphometry of the feline antebrachium was described using CT, and should be a useful reference for future research investigations and clinical applications. PMID- 25537942 TI - Multirater agreement of the causes of anterior cruciate ligament reconstruction failure: a radiographic and video analysis of the MARS cohort. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction failure occurs in up to 10% of cases. Technical errors are considered the most common cause of graft failure despite the absence of validated studies. Limited data are available regarding the agreement among orthopaedic surgeons regarding the causes of primary ACL reconstruction failure and accuracy of graft tunnel placement. HYPOTHESIS: Experienced knee surgeons have a high level of interobserver reliability in the agreement about the causes of primary ACL reconstruction failure, anatomic graft characteristics, and tunnel placement. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Twenty cases of revision ACL reconstruction were randomly selected from the Multicenter ACL Revision Study (MARS) database. Each case included the patient's history, standardized radiographs, and a concise 30-second arthroscopic video taken at the time of revision demonstrating the graft remnant and location of the tunnel apertures. All 20 cases were reviewed by 10 MARS surgeons not involved with the primary surgery. Each surgeon completed a 2-part questionnaire dealing with each surgeon's training and practice, as well as the placement of the femoral and tibial tunnels, condition of the primary graft, and the surgeon's opinion as to the causes of graft failure. Interrater agreement was determined for each question with the kappa coefficient and the prevalence-adjusted, bias-adjusted kappa (PABAK). RESULTS: The 10 reviewers have been in practice an average of 14 years and have performed at least 25 ACL reconstructions per year, and 9 were fellowship trained in sports medicine. There was wide variability in agreement among knee experts as to the specific causes of ACL graft failure. When participants were specifically asked about technical error as the cause for failure, interobserver agreement was only slight (PABAK = 0.26). There was fair overall agreement on ideal femoral tunnel placement (PABAK = 0.55) but only slight agreement on whether a femoral tunnel was too anterior (PABAK = 0.24) and fair agreement on whether it was too vertical (PABAK = 0.46). There was poor overall agreement for ideal tibial tunnel placement (PABAK = 0.17). CONCLUSION: This study suggests that more objective criteria are needed to accurately determine the causes of primary ACL graft failure as well as the ideal femoral and tibial tunnel placement in patients undergoing revision ACL reconstruction. PMID- 25537947 TI - Soybean actin-depolymerizing factor 2 interacts with Soybean mosaic virus-encoded P3 protein. AB - Soybean mosaic virus (SMV), a member of the Potyvirus genus, is one of the most prevalent and devastating viral pathogens in soybean-growing regions worldwide. It is generally accepted that symptom development of a viral plant disease results from molecular interactions between the virus and its host plant. P3 protein is the most variable polyprotein in potyviruses, which potentially plays an important role in the process of the evolution of virus type specialization. However, P3 not only plays a major role in virus replication and movement, but it is also responsible for symptom development in SMV-infected plants. This study provides evidence that actin-depolymerizing factor 2 (designated as ADF2) of soybean interacts with SMV P3 via a two-hybrid yeast system by screening a soybean cDNA library. Bimolecular fluorescence complementation assay further confirmed the interaction, which occurred in both the cytomembrane and cytoskeleton of Nicotiana benthamiana cells. The results support the hypothesis that SMV P3 might have a role in virus movement within cells. PMID- 25537949 TI - Three gene products of a begomovirus-betasatellite complex restore expression of a transcriptionally silenced green fluorescent protein transgene in Nicotiana benthamiana. AB - Single-stranded DNA geminiviruses replicate via double-stranded DNA intermediates forming mini-chromosomes that are targets for transcriptional gene silencing (TGS) in plants. The ability of the cotton leaf curl Kokhran virus (CLCuKoV) cotton leaf curl Multan betasatellite (CLCuMuB) proteins, replication-associated protein (Rep), transcriptional activator protein (TrAP), C4, V2 and betaC1, to suppress TGS was investigated by using the Nicotiana benthamiana line 16-TGS (16 TGS) harbouring a transcriptionally silenced green fluorescent protein (GFP) transgene. Inoculation of 16-TGS plants with a recombinant potato virus X vector carrying Rep, TrAP or betaC1 resulted in re-expression of GFP. Northern blot analysis confirmed that the observed GFP fluorescence was associated with GFP mRNA accumulation. These results indicated that Rep, TrAP and betaC1 proteins of CLCuKoV-CLCuMuB can re-activate the expression of a transcriptionally silenced GFP transgene in N. benthamiana. Although Rep, TrAP, or betaC1 proteins have, for other begomoviruses or begomoviruses-betasatellites, been previously shown to have TGS suppressor activity, this is the first report demonstrating that a single begomovirus-betasatellite complex encodes three suppressors of TGS. PMID- 25537950 TI - Detection and differentiation of Japanese encephalitis virus genotype I and genotype III by reverse transcription loop-mediated isothermal amplification combined with restriction fragment length polymorphism. AB - Japanese encephalitis (JE), which is a mosquito-borne arboviral infection, is the leading cause of viral encephalitis in Asian countries. The causative agent of JE is Japanese encephalitis virus (JEV), in which the predominant genotype has changed from genotype III (G III) to genotype I (G I). However, a method for the rapid differentiation between JEV G I and G III remains unavailable. This study aimed to establish a rapid JEV genotyping method using reverse transcription loop mediated isothermal amplification (RT-LAMP). An Spe I site, which was located in the target sequence (C gene) of JEV G III strains but not in JEV G I strains, was selected as the RT-LAMP target. After testing 64 specimens, results showed that RT-LAMP can detect and differentiate JEV G I and G III specifically. Thus, a novel RT-LAMP system for the rapid detection and differentiation of JEV G I and G III was developed successfully. PMID- 25537948 TI - Recombination among human non-polio enteroviruses: implications for epidemiology and evolution. AB - Human enteroviruses (EV) belong to the Picornaviridae family and are among the most common viruses infecting humans. They consist of up to 100 immunologically and genetically distinct types: polioviruses, coxsackieviruses A and B, echoviruses, and the more recently characterized 43 EV types. Frequent recombinations and mutations in enteroviruses have been recognized as the main mechanisms for the observed high rate of evolution, thus enabling them to rapidly respond and adapt to new environmental challenges. The first signs of genetic exchanges between enteroviruses came from polioviruses many years ago, and since then recombination has been recognized, along with mutations, as the main cause for reversion of vaccine strains to neurovirulence. More recently, non-polio enteroviruses became the focus of many studies, where recombination was recognized as a frequent event and was correlated with the appearance of new enterovirus lineages and types. The accumulation of multiple inter- and intra typic recombination events could also explain the series of successive emergences and disappearances of specific enterovirus types that could in turn explain the epidemic profile of circulation of several types. This review focuses on recombination among human non-polio enteroviruses from all four species (EV-A, EV B, EV-C, and EV-D) and discusses the recombination effects on enterovirus epidemiology and evolution. PMID- 25537951 TI - First hepatitis B virus full-length genomic study among blood donors from Argentina: unexpected mutations in the circulating subgenotypes' proteins. AB - Hepatitis B virus (HBV) is a worldwide public health concern. The circulation of strains carrying mutations in the viral proteins implies both clinical and therapeutics challenges. HBV complete genomes (HBV-CGs) were reported from injecting drug users and HBV chronically infected patients from Argentina including Amerindians-although no studies were conducted in blood donors. Here, we described HBV-CG sequences from the latter population. Some of the HBV sequences classified as B2 and C2 subgenotypes clustering together with Asian isolates, while others, such as D3, F1b, and F4, were homologous to European and Latin America sequences. New substitutions for all analyzed open reading frames and changes in the HBsAg hydrophobicity profiles were detected. Several HBV-CG subgenotypes are described for the first time in this population. Mutations observed in X, PreS, and P proteins have been associated with advanced liver disease, hepatocellular carcinoma, and/or natural resistance to nucleos(t)ide antiviral treatment. It deserves to be highlighted that these substitutions were detected in a population without epidemiological risk factors for viral infection, and most importantly, without any previous antiviral treatment (natural resistance). Regarding the remaining mutations, further research is warranted in order to determine their clinical and therapeutics relevance. PMID- 25537952 TI - Working memory and intraindividual variability in processing speed: A lifespan developmental and individual-differences study. AB - Working memory (WM) and intraindividual variability (IIV) in processing speed are both hypothesized to reflect general attentional processes. In the present study, we aimed at exploring the relationship between WM capacity and IIV in reaction times (RTs) and its possible variation with development across the lifespan. Two WM tasks and six RT tasks of varying complexity were analyzed in a sample of 539 participants, consisting of five age groups: two groups of children (9-10 and 11 12 years of age), one group of young adults, and two groups of older adults (59 69 and 70-89 years of age). Two approaches were adopted. First, low-span and high span individuals were identified, and analyses of variance were conducted comparing these two groups within each age group and for each RT task. The results consistently showed a span effect in the youngest children and oldest adults: High-span individuals were significantly faster and less variable than low-span individuals. In contrast, in young adults no difference was observed between high- and low-span individuals, whether in terms of their means or IIV. Second, multivariate analyses were conducted on the entire set of tasks, to determine whether IIV in RTs brought different information than the mean RT. The results showed that, although very strongly correlated, the mean and IIV in speed should be kept separate in terms of how they account for individual differences in WM. Overall, our results support the assumption of a link between WM capacity and IIV in RT, more strongly so in childhood and older adulthood. PMID- 25537953 TI - The influence of graphotactic knowledge on adults' learning of spelling. AB - Three experiments investigated whether and how the learning of spelling by French university students is influenced by the graphotactic legitimacy of the spellings. Participants were exposed to three types of novel spellings: AB, which do not contain doublets (e.g., guprane); AAB, with a doublet before a single consonant, which is legitimate in French (e.g., gupprane); and ABB, with a doublet after a single consonant, which is illegitimate (e.g., guprrane). In Experiment 1, the nonwords were embedded within texts that participants read for meaning. In Experiment 2, participants read the nonwords in isolation, with or without instruction to memorize their spellings; they copied the nonwords in Experiment 3. In all of these conditions, AB and AAB spellings were learned more readily than ABB spellings. Although participants were highly knowledgeable about the illegitimacy of ABB spellings, the orthographic distinctiveness of these spellings did not make them easier to recall than legitimate spellings. When recalling ABB spellings, participants sometimes made transposition errors, doubling the wrong consonant of a cluster (e.g., spelling gupprane instead of guprrane). Participants almost never transposed the doubling for AAB items. Transposition errors, biased in the direction of replacing illegitimate with legitimate orthographic patterns, show that graphotactic knowledge influences memory for specific items. An analysis of the spellings produced in the copy phase and final recall test of Experiment 3 further suggests that transposition errors resulted not so much from reconstructive processes at the time of recall but from reconstructive processes or inefficient encoding at earlier points. PMID- 25537954 TI - Phonological similarity and orthographic similarity affect probed serial recall of Chinese characters. AB - The previous literature on working memory (WM) has indicated that verbal materials are dominantly retained in phonological representations, whereas other linguistic information (e.g., orthography, semantics) only contributes to verbal WM minimally, if not negligibly. Although accumulating evidence has suggested that multiple linguistic components jointly support verbal WM, the visual/orthographic contribution has rarely been addressed in alphabetic languages, possibly due to the difficulty of dissociating the effects of word forms from the effects of their pronunciations in relatively shallow orthography. In the present study, we examined whether the orthographic representations of Chinese characters support the retention of verbal materials in this language of deep orthography. In Experiments 1a and 2, we independently manipulated the phonological and orthographic similarity of horizontal and vertical characters, respectively, and found that participants' accuracy of probed serial recall was reduced by both similar pronunciations and shared phonetic radicals in the to-be remembered stimuli. Moreover, Experiment 1b showed that only the effect of phonological, but not that of orthographic, similarity was affected by concurrent articulatory suppression. Taken together, the present results indicate the indispensable contribution of orthographic representations to verbal WM of Chinese characters, and suggest that the linguistic characteristics of a specific language not only determine long-term linguistic-processing mechanisms, but also delineate the organization of verbal WM for that language. PMID- 25537955 TI - Too much information: visual research ethics in the age of wearable cameras. AB - When everything you see is data, what ethical principles apply? This paper argues that first-person digital recording technologies challenge traditional institutional approaches to research ethics, but that this makes ethics governance more important, not less so. We review evolving ethical concerns across four fields: Visual ethics; ubiquitous computing; mobile health; and grey literature from applied or market research. Collectively, these bodies of literature identify new challenges to traditional notions of informed consent, anonymity, confidentiality, privacy, beneficence and maleficence. Challenges come from the ever-increasing power, breadth and multi-functional integration of recording technologies, and the ubiquity and normalization of their use by participants. Some authors argue that these evolving relationships mean that institutional ethics governance procedures are irrelevant or no longer apply. By contrast, we argue that the fundamental principles of research ethics frameworks have become even more important for the protection of research participants, and that institutional frameworks need to adapt to keep pace with the ever-increasing power of recording technologies and the consequent risks to privacy. We conclude with four recommendations for efforts to ensure that contemporary visual recording research is held appropriately accountable to ethical standards: (i) minimizing the detail, scope, integration and retention of captured data, and limiting its accessibility; (ii) formulating an approach to ethics that takes in both the 'common rule' approaches privileging anonymity and confidentiality together with principles of contextual judgement and consent as an ongoing process; (iii) developing stronger ethical regulation of research outside academia; (iv) engaging the public and research participants in the development of ethical guidelines. PMID- 25537956 TI - Perils and potentials in qualitative psychology. AB - Famously, Ebbinghaus declared that psychology has a long past, but only a short history. Psychology, as something implicit to human conduct, is as old as the human race, but the science, as an explicit investigative reflection upon that conduct, is a recent invention. Within the short history of psychology, we find an even shorter history of qualitative psychology specifically. Although most founding fathers (Freud, Piaget, Bartlett etc.) worked as "qualitative psychologists", they found no need to thematize their methods of inquiry in this manner. Since around 1980, however, a field has established itself that can be called qualitative psychology. In this paper, I discuss how this field can move sensibly into the future, and I highlight two perils and two potentials. The perils stem from neo-positivism and a threatening "McDonaldization" of qualitative research, while the potentials are related to proliferation of new forms of inquiry and a transcending of disciplinary boundaries. PMID- 25537959 TI - The importance of usage guidance from anesthesiologists when disseminating video laryngoscopes throughout emergency departments and intensive care units. PMID- 25537957 TI - Bariatric surgery improves histological features of nonalcoholic fatty liver disease and liver fibrosis. AB - Nonalcoholic fatty liver disease (NAFLD) is prevalent in obese patients. We sought to determine the effects of bariatric surgery on the histological features of NAFLD. Two blinded pathologists graded liver biopsies done during bariatric procedures and subsequent operations in 160 patients using the Brunt classification. Data are mean +/- SD. Interval between biopsies was 31 +/- 26 months. Initial biopsies demonstrated steatosis 77 %, lobular inflammation 39 %, and chronic portal inflammation 56 %. Steatohepatitis was present in 27 %. Grade 2-3 fibrosis was present in 27 %, and cirrhosis was present in one patient. On post-bariatric biopsy, steatosis resolved in 75 %, lobular inflammation resolved in 75 %, chronic portal inflammation resolved in 49 %, and steatohepatitis resolved in 90 %. Fibrosis of any grade resolved in 53 % and improved in another 3 % of patients. Grade 2 fibrosis resolved in 58 %, improved in 3 %, and did not worsen in 11 %. Bridging fibrosis resolved in 29 %, improved in 29 %, and did not worsen in 29 %. Bariatric surgery is associated with resolution of steatosis or steatohepatitis in the majority of patients. More importantly, grade 2 or 3 (bridging) fibrosis is resolved or improved in 60 % of patients. Bariatric surgery should be considered as a treatment of NAFLD in severely obese patients. PMID- 25537958 TI - Performance of digital screening mammography among older women in the United States. AB - BACKGROUND: Although healthy women aged 65 years have a life expectancy of 20 years, there is a paucity of data on the performance of digital screening mammography among these women. The authors examined the performance and outcomes of digital screening mammography among a national group of women aged >=65 years. METHODS: From Breast Cancer Surveillance Consortium data for the years 2005 to 2011, the authors included 296,496 full-field digital screening mammograms among 133,042 women ages >=65 years without a history of breast cancer. Sensitivity, specificity, positive predictive value (PPV1 ), recall rates, and 95% confidence intervals (95% CIs) were calculated across the spectrum of age and breast density. Multivariate logistic regression was used to compare mammography accuracy, cancer-detection rates (CDRs), and tumor characteristics by age and breast density. RESULTS: Multivariate analyses revealed a significant decrease in the recall rate with age (P for linear trend [Ptrend ] < .001) and significant increases in specificity, PPV1 , and CDR with age (Ptrend < .001, Ptrend < .001, and Ptrend = .01, respectively). Sensitivity did not vary significantly with age. Among women with cancer, the proportion with invasive disease increased with age from 76% at ages 65 to 74 years to 81% at ages >=80 years. There was a higher proportion of late stage cancers and positive lymph nodes among women ages 65 to 74 years compared with women in the older age groups. CONCLUSIONS: The specificity, PPV1 , recall rate, and CDR of digital screening mammography improved with increased age. In addition, as age increased, the proportion of women with invasive versus ductal carcinoma in situ rose, whereas the proportion of women with positive lymph nodes decreased. PMID- 25537961 TI - Nucleos(t)ide analogues associated with a reduced risk of hepatocellular carcinoma in hepatitis B patients: a population-based cohort study. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a major complication of hepatitis B virus (HBV) infection. This study investigated the association between nucleos(t)ide analogue (NA) use and the risk of HCC and mortality in HBV carriers on the basis of the Taiwan National Health Insurance Database. METHODS: In all, 1544 HBV carriers taking NAs (treated cohort) who were identified between October 1, 2003 and December 31, 2011 were examined for their risk of HCC and mortality; 1544 patients not receiving NA treatment (untreated cohort) were selected via propensity score matching as the comparison group. The risks of first tumor occurrence and mortality were compared. RESULTS: The treated cohort had a significantly lower HCC occurrence rate (6.0%; 95% confidence interval [CI], 4.4% 7.9%) in comparison with the untreated cohort (8.5%; 95% CI, 6.6%-10.6%; P = .0025). The overall mortality rates for the treated and untreated cohorts were 6.9% (95% CI, 5.3%-8.7%) and 9.4% (95% CI, 7.7%-11.3%), respectively (P = .0003). After adjustments for competing confounders, Cox regression analyses showed that NA use significantly reduced the risk of HCC (hazard ratio [HR], 0.64; 95% CI, 0.45-0.93; P = .017) and overall mortality (HR, 0.58; 95% CI, 0.43-0.79; P < .001). There was a dose-response relationship between NA use and the risk of HCC in the treated cohort. With respect to no NA use, the adjusted HRs were 0.93 (95% CI, 0.58-1.48), 0.67 (95% CI, 0.42-1.06), and 0.35 (95% CI, 0.17-0.70) for 90 to 365, 366 to 730, and >730 cumulative defined daily doses of NAs, respectively. CONCLUSIONS: NA use reduced the risk of HCC and overall mortality in HBV carriers. PMID- 25537962 TI - Total synthesis and absolute configuration assignment of MRSA active garcinol and isogarcinol. AB - A short total synthesis of (+/-)-garcinol and (+/-)-isogarcinol, two endo-type B PPAPs with reported activity against methiciline resistant Staphylococcus aureus (MRSA), is presented. The separation of framework-constructing from framework decorating steps and the application of two highly regio- and stereoselective Pd catalysed allylations, that is, the Pd-catalysed decarboxylative Tsuji-Trost allylation and the diastereoselective Pd-catalysed allyl-allyl cross-coupling, are key elements that allowed the total synthesis to be accomplished within 13 steps starting from acetylacetone. After separation of the enantiomers the absolute configurations of the four natural products (i.e., (-)-garcinol, (+) guttiferone E (i.e., ent-garcinol), (-)-isogarcinol, and (+)-isoxanthochymol (i.e., ent-isogarcinol)) were assigned based on ECD spectroscopy. PMID- 25537960 TI - Neuronal analysis and behaviour in prenatally gamma-irradiated rats. AB - The intrauterinal development in mammals represents a very sensitive period of life in relation to many environmental factors, including ionizing radiation (IR). The developing nervous system is particularly vulnerable to IR, and the consequences of exposure are of importance because of its potential health risks. The aim of our work was to assess whether prenatal irradiation of rats on the 17th day of embryonic development with a dose of 1 Gy would affect the formation of new cells and the number of mature neurons in the hippocampus and the selected forms of behaviour in the postnatal period. Male progeny of irradiated and control females was tested at ages of 3 weeks, 2 and 3 months. The number of mitotically active cells in the gyrus dentatus (GD) of the hippocampus was significantly reduced in irradiated rats aged 3 weeks. In irradiated rats aged 2 months, a significant reduction of mature neurons in CA1 area and in GD of the hippocampus was observed. The IR negatively influenced the spatial memory in Morris water maze, significantly decreased the exploratory behaviour and increased the anxiety-like behaviour in elevated plus-maze in rats aged 2 months. No significant differences were observed in animals aged 3 months compared with controls of the same age. A significant correlation between the number of mature neurons in the hilus and of the cognitive performances was found. Our results show that a low dose of radiation applied during the sensitive phase of brain development can influence the level of neurogenesis in the subgranular zone of GD and cause an impairment of the postnatal development of mental functions. PMID- 25537964 TI - First-principles study of the lattice instabilities in Mn2NiX (X = Al, Ga, In, Sn) magnetic shape memory alloys. AB - Using first-principles based density functional theory, we have investigated the structural instabilities in the austenite phases of Mn(2)NiX (X = Al, Ga, In, Sn) magnetic shape memory alloys. A complete softening is observed in the acoustic TA(2) branches for all the materials along [xixi0] directions leading to instability in the austenite structure which effectively stabilizes into martensitic structure. The reasons behind this softening are traced back to the repulsion from the optical T(2g) branches and to the nesting features in the Fermi surfaces. The vibrational density of states, the force constants and the elastic moduli are also computed and analyzed, which reconfirm the underlying mechanism behind the instabilities. The results indicate that the phonon anomalies are related to the occurrence of possible pre-martensitic phases which can be quite complex. PMID- 25537963 TI - Visceral and subcutaneous fat as new independent predictive factors of survival in locally advanced gastric carcinoma patients treated with neo-adjuvant chemotherapy. AB - PURPOSE: Abdominal adipose distribution may be associated with tumor growth, but its impact on gastric carcinoma survival after neo-adjuvant therapies is uncertain. This retrospective study was to determine the association linking BMI and CT-measured fat parameters to the survival in advanced gastric cancer patients who underwent preoperative chemotherapy. METHODS: Eighty-four consecutive patients with locally advanced gastric cancer who received neo adjuvant chemotherapy and following gastrectomy were identified between January 2005 and June 2008. CT parameters were measured retrospectively on the CT images obtained before chemotherapy initiation. Subcutaneous fat thicknesses of the anterior, lateral, and posterior abdominal wall (ASFT, LSFT, and PSFT) represented subcutaneous fat. Intraperitoneal fat thickness (IFT) and retro-renal fat thickness represented visceral fat. Association linking BMI and CT factors to overall survival was evaluated with survival analysis. RESULTS: ASFT and PSFT above the median value (i.e., high ASFT and PSFT) were associated with longer OS (P = 0.001; 0.003). Conversely, high IFT and high IFT/PSFT were associated with shorter OS (P = 0.003; 0.003) and DFS (P < 0.001; 0.004). By multivariate analysis, high IFT and PSFT were independently associated with OS (HR 2.94, 95% CI 1.54-5.60; 0.38, 95% CI 0.21-0.71) and DFS (HR 3.28, 95% CI 1.55-6.93; 0.42, 95% CI 0.21-0.82). BMI was not significant for OS and DFS. CONCLUSIONS: This study provided the first evidence that IFT, ASFT, and PSFT measured before neo adjuvant chemotherapy were likely to be useful predictive biomarkers for survival of advanced gastric cancer patients. PMID- 25537966 TI - Switching nuclearity and Co(II) content through stoichiometry adjustment: {Co(II)6Co(III)3} and {Co(II)Co4(III)} mixed valent complexes and a study of their magnetic properties. AB - We are reporting two new mixed valent Co(ii)/Co(iii) polynuclear complexes, {Co(II)6Co(III)3} and {Co(II)Co(III)4}, bearing different amount of Co(ii) ions in their cores, through the employment of the multidentate triethanolamine (teaH3) ligand in different stoichiometric ratios. We present a complete picture of the magnetic behaviour of both complexes through a combined usage of the susceptibility, magnetization and X-band EPR data as well as broken-symmetry DFT calculations. Compound shows an atypical spin-only behaviour, probably due to the presence of four and five coordinated Co(ii) sites as well as highly distorted six coordinated Co(ii) ions, promoting a high degree of orbital contribution quenching. Through the usage of a simplified exchange coupling scheme and relying on DFT based magneto-structural correlation we have been able to explain the observed diamagnetic ground state. Concerning compound , DC magnetic data supported by X-band EPR measurements suggest the existence of anisotropy with a zero-field splitting parameter D, at least in the range of 2-10 cm(-1). In agreement with this description, a slow relaxation of magnetization is observed after applying a small external magnetic field, under AC measurements. Field and temperature dependence of the characteristic relaxation time establishes a thermal barrier for magnetization reversal of about 25 cm(-1), which is in good agreement with the energy splitting of the |+/-1/2> and |+/-3/2> doublets established from static magnetic measurements. PMID- 25537965 TI - Approval and potential use of over-the-counter HIV self-tests: the opinion of participants in a street based HIV rapid testing program in Spain. AB - HIV self-testing, not yet available in Spain, is a strategy thought to be able to increase the number of people tested and testing frequency. 3,373 attenders of a street-based HIV rapid-testing program gave their opinion on authorizing over-the counter self-tests and a potentially shorter lead time if self-tests were available. 88.0 % of participants were in favor of authorization, 9.2 % had no clear opinion and 2.8 % were against. 54.6 % of men who have sex with men (MSM), 38.4 % of men who have sex with women and 36.3 % of women acknowledged a potential for lead time reduction. Potential lead time was associated with being >=35 years, having a university degree, never injected drugs, previous HIV tests and being concerned about an HIV positive result, and in MSM, also having >=5 partners. Self-testing seems a promising strategy for Spain: its authorization is supported by nearly all potential users and almost three quarters of MSM would have opted to advance their current testing if self-tests were available. PMID- 25537968 TI - Anatomic characteristics of the dural sheath of the trigeminal nerve. AB - BACKGROUND: The purpose of this study was to clarify the anatomic characteristics and discuss the clinical implications of the dural sheath of the trigeminal nerve, especially its compartmentalization. METHODS: The dural sheath of the trigeminal nerve was microsurgically dissected in 8 formalin-fixed adult cadaver heads (16 sides). RESULTS: The dural sheath of the trigeminal nerve is meningeal dura in origin and composed of Meckel's cave and the peripheral sheaths. The peripheral sheath is a direct continuation of Meckel's cave, but separated from the latter by a cribriform area from where the nerve rootlets pass through. Within the peripheral sheaths, there are a few septa, which are frequently interrupted by connections among nerve rootlets. CONCLUSION: The cribriform area of Meckel's cave, which divides the dural sheath of the trigeminal nerve into 2 distinct compartments, may play an important role in tumor growth and surgical planning. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E185-E188, 2016. PMID- 25537967 TI - Inflammatory bowel disease-the role of cross-sectional imaging techniques in the investigation of the small bowel. AB - BACKGROUND: The diagnosis of inflammatory bowel disease (IBD) in children and adolescents is based on the integration of clinical, biological, endoscopic, histological and radiological data. METHODS: The most important part of the diagnosis is the histology, which is acquired by endoscopy. Imaging of the small bowel has changed in recent years, but the imaging goals are primarily to determine the extent of small bowel involvement, assess complications and define candidates for surgery. Imaging techniques are divided into conventional and cross-sectional ones. RESULTS: The spectrum of imaging findings of cross sectional techniques is discussed, emphasising the advantages and limitations of each technique, acknowledging the specificities of the paediatric population. Cross-sectional techniques have advanced the ability to diagnose and monitor inflammatory disease of the small bowel. CONCLUSION: MR enterography is the technique of choice in children with known IBD, for the investigation of the small bowel and the whole GI tract. US should be the first choice examination in children with suspected IBD, while CT should be reserved for cases in which MRI is contraindicated or in acute emergency situations when US is inadequate. TEACHING POINTS: * Cross-sectional imaging of the small bowel is essential in paediatric IBD. * Endoscopy is unable to assess extramural disease and examine the entire small bowel. * US should be the first choice examination in children with suspected IBD. * MR enterography is the technique of choice in children with known IBD. * There are still controversies regarding the prediction of disease activity or fibrosis. PMID- 25537970 TI - Comparative proteomic analysis of rat left ventricle in a subtotal nephrectomy model. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy that leads to increased cardiovascular morbidity and mortality. To date, use of the renin-angiotensin-aldosterone system blockade has been the main treatment modality. However, renin-angiotensin-aldosterone system blockade by the angiotensin converting enzyme inhibitors (ACEi) can only partially reverse the cardiac hypertrophy without having a significant impact on all-cause mortality as evidenced by meta-analyses from clinical trials. It is imperative to elucidate the molecular pathogenesis of CKD-related cardiomyopathy for potential targets in further treatment. METHODS: Male Sprague-Dawley rats that underwent subtotal nephrectomy (SNX) rats were established as the CKD model. A hemodynamic study was used to evaluate the left ventricle (LV) structural and functional alterations. We used proteomic techniques to profile the LV protein changes among sham operated rats, SNX rats, and SNX rats with 6 months of ACEi enalapril interventions. The differentially expressed proteins were further annotated by functional and network analyses. RESULTS: As compared to the sham-operated rats, the SNX rats had 25 upregulated and 46 decreased protein expression. The top canonical pathways identified by ingenuity pathway analysis for the CKD cardiomyopathy were mitochondrial dysfunction, oxidative phosphorylation, fatty acid beta oxidation, protein ubiquitination, and ketolysis. The most relevant functions extracted from these networks contained 27 and 23 focused proteins, respectively. They were related to cellular assembly and organization, RNA posttranscriptional modification, and protein synthesis. After ACEi intervention for 6 weeks, the residual canonical pathways identified by ingenuity pathway analysis that mediated the CKD-related cardiomyopathy were mitochondrial dysfunction, ketolysis, phenylalanine degradation IV, and putrescine degradation III. There were decreased Sirt3 and SNRNP, and increased monoamine oxidase and SAHH expression in the LV of SNX rats that could not be reversed by the ACEi. CONCLUSION: Our studies provide a repertoire of potential biomarkers related to cardiac hypertrophy in CKD. There are still residual disturbed molecules/pathways despite ACEi intervention. Further studies are warranted to investigate these potential novel targets to alleviate CKD-related cardiomyopathy. PMID- 25537971 TI - Flexible and stretchable micromagnet arrays for tunable biointerfacing. AB - A process to surface pattern polydimethylsiloxane (PDMS) with ferromagnetic structures of varying sizes (micrometer to millimeter) and thicknesses (>70 MUm) is developed. Their flexibility and magnetic reach are utilized to confer dynamic, additive properties to a variety of substrates, such as coverslips and Eppendorf tubes. It is found that these substrates can generate additional modes of magnetic droplet manipulation, and can tunably steer magnetic-cell organization. PMID- 25537972 TI - Development of disulfiram-loaded poly(lactic-co-glycolic acid) wafers for the localised treatment of glioblastoma multiforme: a comparison of manufacturing techniques. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumour in adults with a very poor prognosis. This paper describes the development of disulfiram (DSF)-loaded biodegradable wafers manufactured using three standard techniques: compression, solvent casting and heat compression moulding. The paper demonstrates that neither technique has an adverse effect on the stability of the DSF within the wafers. However, the solvent casting technique results in an interaction between the poly(lactic-co-glycolic acid) (PLGA) and the DSF. The physical state of the DSF within the wafers was dependent on the manufacturing technique, with the DSF in the wafers manufactured by compression or solvent casting retaining between 40% and 98% crystallinity, whereas the DSF in the wafers manufactured using heat compression moulding was completely amorphous. Release of DSF from the wafers is dependent on the degradation of the PLGA, the manufacturing technique used, and the DSF loading. DSF in the compressed and heat compression moulded wafers had a similar cytotoxicity against a GBM cell line compared with the unprocessed DSF control. However, the cytotoxicity of the DSF in the solvent-casted wafers was significantly lower than the unprocessed DSF. PMID- 25537973 TI - Cigarette smoke-induced MMP2 and MMP9 secretion from aortic vascular smooth cells is mediated via the Jak/Stat pathway. AB - It is hypothesized that cigarette smoke may increase MMP2 and MMP9 secretion through Jak/Stat pathway in the aorta, thereby facilitating abdominal aortic aneurysm (AAA) formation/progression in smokers. We observed through zymograms that treatment of male rat aortic vascular smooth muscle cells (RASMC) with an aqueous extract of cigarette smoke (CSE) for 24 hours resulted in a significant increase in pro-MMP9 (P = .005) and a modest increase in pro-MMP2 (P = .055) production. Western blot with protein extracts from CSE-treated RASMC showed up regulation of pStat3, pJak2, and T-Jak2 and unchanged levels of T-Stat3. Transfection of RASMC with small interfering RNAs for Jak2, Stat3, or both Jak2 and Stat3 significantly reduced pro-MMP9 (P < .005) and pro-MMP2 (P < .05) in medium of CSE-treated RASMC compared with control small interfering RNA transfected cells. Immunoprecipitation with total Jak2 antibody showed increased pStat3 and T-Stat3 in the cytoplasm and nucleus of CSE-treated RASMC. Immunofluorescence revealed increased presence of pJak2, T-Jak2, pStat3, and T Stat3 in the cytoplasm and nucleus of the CSE-treated cells. Treatment of control human tissues with CSE resulted in pro-MMP9 secretion and up-regulation of the Jak/Stat proteins. In addition, AAA tissues showed more pJak2 and pStat3 than control human tissues. Therefore, inhibiting the Jak/Stat pathway could be a potential therapeutic approach in the treatment of AAA. PMID- 25537974 TI - Microvessel density, lymphovascular density, and lymphovascular invasion in primary cutaneous melanoma-correlation with histopathologic prognosticators and BRAF status. AB - The relationship between microvessel density (MVD), lymphovascular density (LVD), and lymphovascular invasion (LVI) in primary cutaneous melanoma (PCM) remains unclear. Given this, a total of 102 PCMs were assessed for MVD (vascular endothelial growth factor receptor 2 and Endocan), LVD (D2-40), and LVI (immunostaining with D2-40/S-100 and hematoxylin and eosin); tumoral S-100A13, vascular endothelial growth factor receptor 2, and Endocan; and BRAF status. LVD was associated with MVD (P = .01). MVD was higher in PCMs with depth greater than or equal to 2 mm and ulceration (P = .04, .05), whereas LVD was higher in PCMs with depth greater than or equal to 2 mm and mitoses (P = .03, .02). After adjusting for MVD and LVD, only ulceration was associated with LVI (P < .02). A BRAF mutation was seen in 30.4% cases, and when present, both LVD and host response (P = .0008 and .04, respectively) were significantly associated with MVD. Immunostaining with S-100A13 was noted in 99% of cases and a significant association noted only with ulceration (P = .05). Immunostaining increased LVI positivity (46.5% versus 4.9% by hematoxylin and eosin, P < .0001). MVD and LVD are not associated with LVI, appear to be closely related with each other, and are associated with select markers of poor prognosticative value. The association between a host response and LVD and MVD in PCMs with a BRAF mutation suggests that they exhibit potential for strategizing immunotherapies. PMID- 25537975 TI - Fatal aortic pseudoaneurysm from disseminated Mycobacterium kansasii infection: case report. AB - Mycobacterium kansasii is a photochromogenic, slow-growing mycobacterium species that can cause pulmonary infection in patients with predisposing lung diseases, as well as extrapulmonary or disseminated disease in immunosuppressed patients. We describe a patient with a myelodysplastic syndrome, disseminated M kansasii infection, and ruptured aortic aneurysm. He had a recent diagnosis of mycobacterium cavitary lung lesions and was transferred to our facility for possible surgical intervention of an aortic aneurysm. Few hours after admission, the patient suddenly collapsed and died despite resuscitation efforts. A complete autopsy was performed and showed ruptured ascending aortic pseudoaneurysm with hemopericardium, disseminated necrotizing and nonnecrotizing granulomas with acid fast bacilli in the aortic wall, lungs, heart, liver, spleen, and kidneys. Further genetic studies were consistent with monocytopenia and mycobacterial infection syndrome. PMID- 25537977 TI - Influence of field strength, coil type and image resolution on assessment of synovitis by unenhanced MRI--a comparison with contrast-enhanced MRI. AB - OBJECTIVES: To explore if the reliability of synovitis assessment by unenhanced MRI is influenced by different MRI field-strengths, coil types and image resolutions in RA patients. METHODS: Forty-one RA patients and 12 healthy controls underwent hand MRI (wrist and 2(nd)--5(th) metacarpophalangeal joints) at 4 different field-strengths (0.23 T/0.6 T/1.5 T/3.0 T) on the same day. Seven protocols using a STIR sequence with different field-strengths, coils (flex coils/dedicated phased-array extremity coils) and resolution were applied and scored blindly for synovitis (OMERACT-RAMRIS method). A 1.5 T post-contrast T1 weighted sequence was used as gold standard reference. RESULTS: Fair-good agreement (ICC=0.38--0.72) between the standard reference and the different STIR protocols (best agreement with extremity coil and small voxel size at 1.5 T). The accuracy for presence/absence of synovitis was very high per person (0.80--1.0), and moderate-high per joint (0.63--0.85), whereas exact agreements on scores were moderate (0.50--0.66). The intrareader agreement (15 patients and 3 controls) on presence/absence of synovitis was very high (0.87--1.0). CONCLUSIONS: Unenhanced MRI using STIR sequence is only moderately reliable for assessing hand synovitis in RA, when contrast-enhanced MRI is considered the gold standard reference. Contrast injection, field strength and coil type influence synovitis assessment, and should be considered before performing MRI in clinical trials and practice. KEY POINTS: * STIR is only moderately reliable for synovitis assessment, compared with post-contrast-T1-w. * Contrast injection, field strength, and coil type influence synovitis assessment. * Contrast injection is recommended for reliable and reproducible hand synovitis assessment. PMID- 25537978 TI - A multicentre retrospective study of transcatheter angiographic embolization in the treatment of delayed haemorrhage after percutaneous nephrolithotomy. AB - OBJECTIVE: The objective is to determine the timing and indications of transcatheter angiographic embolization (TAE) for delayed haemorrhage after percutaneous nephrolithotomy (PCNL). METHODS: The medical records of 144 patients who underwent arteriography and TAE for delayed post-PCNL haemorrhage at five university hospitals between January 2005 and December 2012 were reviewed retrospectively. RESULTS: The mean time to the onset of post-PCNL haemorrhage was 10.5 days (2 - 30 days). Clinical presentation included sudden onset bleeding in 51 patients (35.4 %), intermittent bleeding in 67 patients (46. 5 %), and continuous slow bleeding in 26 patients (18.1 %). Hemodynamic instability occurred in 32 patients (22.2 %). The mean haemoglobin decrease from the first post-PCNL day to the day of TAE was 49.5 g/L (31.0 - 79.0 g/L). Renal arteriography showed pseudoaneurysms in 69 (47.9 %) patients, arteriovenous fistulas in 28 (19.4 %) patients, mixed arterial and arteriovenous lesions in 17 (11.8 %) patients, arterial lacerations in 23 (16.0 %) patients, and negative angiographic finding in seven (4.9 %) patients. TAE was successful in stopping bleeding in all 137 patients with vascular lesions. There were no major complications associated with TAE. CONCLUSIONS: TAE should be the recommended treatment for delayed post-PCNL haemorrhage in patients with hemodynamic instability and/or corrected haemoglobin decrease >30 g/L following conservative management. KEY POINTS: * Delayed haemorrhage after percutaneous nephrolithotomy occurs more than 24 hours postoperatively. * Angio-embolization is a safe and effective treatment for delayed post-PCNL haemorrhage. * Angio-embolization can treat hemodynamic instability and/or corrected haemoglobin decrease >30 g/L. PMID- 25537979 TI - The diagnostic value of Gd-EOB-DTPA-MRI for the diagnosis of focal nodular hyperplasia: a systematic review and meta-analysis. AB - OBJECTIVE: We aimed to systematically review the gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI) findings of focal nodular hyperplasia (FNH) and its diagnostic value. METHODS: A thorough literature search was conducted in Ovid-MEDLINE and EMBASE databases to identify studies evaluating Gd-EOB-DTPA-MRI findings of FNH. To evaluate the frequency of characteristic imaging findings on Gd-EOB-DTPA-MRI, pooled proportions of high/iso signal intensity (SI) on the hepatobiliary phase (HBP), arterial enhancement, high/iso SI on the portal-venous phase (PVP) or equilibrium phase (EP), and the central scar were calculated. Meta analysis was performed to evaluate the diagnostic accuracy of high/iso SI on HBP for distinguishing FNH from hepatocellular adenoma. RESULTS: A review of 96 articles identified ten eligible articles with 304 patients with FNHs for meta analysis. Pooled proportion of the Gd-EOB-DTPA-MRI findings showed that high/iso SI on the HBP, arterial enhancement, and high/iso SI on the PVP/EP were observed in 93% (95% CI, 90-97%), 99% (95% CI, 97-100%), and 97% (95% CI, 95-99%) of FNHs, respectively, while a central scar was observed in 61% of FNHs (95% CI, 47-74%). High/iso SI on the HBP was highly accurate for distinguishing FNH from hepatocellular adenoma, with a summary sensitivity of 93.9% (95% CI, 89.1-97.1%) and a specificity of 95.3% (95% CI, 88.4-98.7%). CONCLUSIONS: High/iso SI on the HBP of Gd-EOB-DTPA-MRI is characteristic and a prevalent finding of FNHs and can be helpful in the management of patients with FNH. KEY POINTS: * The vast majority (94-97 %) of FNHs show high/iso SI on HBP. * High/iso SI on HBP was accurate for distinguishing FNH from hepatocellular adenoma. * HBP of Gd-EOB-DTPA MRI can reduce unnecessary biopsies for the diagnosis of FNHs. PMID- 25537981 TI - Supporting colleagues to improve care: educating for quality improvement. AB - Clinicians at the front line of healthcare delivery are very well positioned to identify and improve the system in which they work. Training curricula, however, have not always equipped them with the skills or knowledge to implement change. This article looks at educational approaches to support clinicians to be actively involved with quality improvement (QI). It looks at the role of doctors in postgraduate training (DrPGT) and their educational supervisors and builds on the topics discussed throughout the 'EQUIPPED' article series. Factors for success of a QI education programme and practical ideas for overcoming barriers to supporting clinicians in QI are discussed. We present examples of educational initiatives and a framework for evaluating such programmes, and we examine the role of faculty development to help inspire and support colleagues to improve care. PMID- 25537980 TI - Dual energy computed tomography quantification of carotid plaques calcification: comparison between monochromatic and polychromatic energies with pathology correlation. AB - PURPOSE: We compared carotid plaque calcification detection sensitivity and apparent cross-sectional area on CT as a function of CT beam energy using conventional CT techniques and virtual mono-energetic CT images generated from dual-energy acquisitions. METHODS & MATERIALS: Five ex-vivo carotid endarterectomy (CEA) specimens were imaged with dual-energy computed tomography. Virtual monochromatic spectrum (VMS) CT images were reconstructed at energies between 40-140 keV. The same specimens were imaged using conventional polyenergetic spectrum (PS) CT with peak beam energies 80, 100, 120, and 140 kVp. The histological calcium areas on each corresponding CEA specimen were traced manually on digitized images of Toluidine-Blue/Basic-Fuchsin stained plastic sections. RESULTS: 40 keV VMS CT images provided high detection sensitivity (97 %) similar to conventional PS CT images (~96 %). The calcification size measured on CT decreased systematically with increasing CT beam energy; the rate of change was larger for the VMS images than for PS images. CONCLUSION: From a single dual energy CT, multiple VMS-CT images can be generated, yielding equivalent detection sensitivity and size correlations as conventional PS-CT in CEA calcification imaging. VMS-CT at 80-100 keV provided the most accurate estimates of calcification size, as compared to histology, but detection sensitivity was reduced for smaller calcifications on these images. KEY POINTS: * Calcifications depicted at 80-100 keV were most similar to the histology standard. * Conventional polychromatic images demonstrated excellent correlation with plaque size at pathology. * Conventional polychromatic images systematically overestimate plaque size. * Plaque calcifications can be missed on high energy monochromatic images. PMID- 25537982 TI - Open season: select the best 'beast' for each skin lesion. AB - Animal bites can cause skin lesions that suggest other conditions, and therefore diagnosis can be a challenge. Four cases of skin injuries caused by arthropods are presented below. PMID- 25537984 TI - The effect of hydrogenation on the growth of carbon nanospheres and their performance as anode materials for rechargeable lithium-ion batteries. AB - Hydrogenated carbon nanomaterials exhibit many advantages in both mechanical and electrochemical properties, and thus have a wide range of potential applications. However, methods to control the hydrogenation and the effect of hydrogenation on the microstructure and properties of the produced nanomaterials have rarely been studied. Here we report the synthesis of hydrogenated carbon nanospheres (HCNSs) with different degrees of hydrogenation by a facile solvothermal method, in which C2H3Cl3/C2H4Cl2 was used as the carbon precursor and potassium as the reductant. The hydrogenation level of the obtained nanospheres depends on the reaction temperature and higher temperature leads to lower hydrogenation due to the fact that the breaking of C-H bonds requires more external energy. The reaction temperature also affects the diameter of the HCNSs and larger spheres are produced at higher temperatures. More importantly, the size and the degree of hydrogenation are both critical factors for determining the electrochemical properties of the HCNSs. The nanospheres synthesized at 100 degrees C have a smaller size and a higher hydrogenation degree and show a capacity of 821 mA h g( 1) after 50 cycles, which is significantly higher than that of the HCNSs produced at 150 degrees C (450 mA h g(-1)). Our study opens a possible way for obtaining high-performance anode materials for rechargeable lithium-ion batteries. PMID- 25537983 TI - Integrative analysis of micro-RNA, gene expression, and survival of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM), the most common type of malignant brain tumor, is highly fatal. Limited understanding of its rapid progression necessitates additional approaches that integrate what is known about the genomics of this cancer. Using a discovery set (n = 348) and a validation set (n = 174) of GBM patients, we performed genome-wide analyses that integrated mRNA and micro-RNA expression data from GBM as well as associated survival information, assessing coordinated variability in each as this reflects their known mechanistic functions. Cox proportional hazards models were used for the survival analyses, and nonparametric permutation tests were performed for the micro-RNAs to investigate the association between the number of associated genes and its prognostication. We also utilized mediation analyses for micro-RNA-gene pairs to identify their mediation effects. Genome-wide analyses revealed a novel pattern: micro-RNAs related to more gene expressions are more likely to be associated with GBM survival (P = 4.8 * 10(-5)). Genome-wide mediation analyses for the 32,660 micro-RNA-gene pairs with strong association (false discovery rate [FDR] < 0.01%) identified 51 validated pairs with significant mediation effect. Of the 51 pairs, miR-223 had 16 mediation genes. These 16 mediation genes of miR-223 were also highly associated with various other micro-RNAs and mediated their prognostic effects as well. We further constructed a gene signature using the 16 genes, which was highly associated with GBM survival in both the discovery and validation sets (P = 9.8 * 10(-6)). This comprehensive study discovered mediation effects of micro-RNA to gene expression and GBM survival and provided a new analytic framework for integrative genomics. PMID- 25537985 TI - SIFT-MS and FA-MS methods for ambient gas phase analysis: developments and applications in the UK. AB - Selected ion flow tube mass spectrometry, SIFT-MS, a relatively new gas/vapour phase analytical method, is derived from the much earlier selected ion flow tube, SIFT, used for the study of gas phase ion-molecule reactions. Both the SIFT and SIFT-MS techniques were conceived and developed in the UK, the former at Birmingham University, the latter at Keele University along with the complementary flowing afterglow mass spectrometry, FA-MS, technique. The focus of this short review is largely to describe the origins, developments and, most importantly, the unique features of SIFT-MS as an analytical tool for ambient analysis and to indicate its growing use to analyse humid air, especially exhaled breath, its unique place as a on-line, real time analytical method and its growing use and applications as a non-invasive diagnostic in clinical diagnosis and therapeutic monitoring, principally within several UK universities and hospitals, and briefly in the wider world. A few case studies are outlined that show the potential of SIFT-MS and FA-MS in the detection and quantification of metabolites in exhaled breath as a step towards recognising pathophysiology indicative of disease and the presence of bacterial and fungal infection of the airways and lungs. Particular cases include the detection of Pseudomonas aeruginosa infection of the airways of patients with cystic fibrosis (SIFT-MS) and the measurement of total body water in patients with chronic kidney disease (FA-MS). The growing exploitation of SIFT-MS in other areas of research and commerce are briefly listed to show the wide utility of this unique UK-developed analytical method, and future prospects and developments are alluded to. PMID- 25537986 TI - A monolithic glass chip for active single-cell sorting based on mechanical phenotyping. AB - The mechanical properties of biological cells have long been considered as inherent markers of biological function and disease. However, the screening and active sorting of heterogeneous populations based on serial single-cell mechanical measurements has not been demonstrated. Here we present a novel monolithic glass chip for combined fluorescence detection and mechanical phenotyping using an optical stretcher. A new design and manufacturing process, involving the bonding of two asymmetrically etched glass plates, combines exact optical fiber alignment, low laser damage threshold and high imaging quality with the possibility of several microfluidic inlet and outlet channels. We show the utility of such a custom-built optical stretcher glass chip by measuring and sorting single cells in a heterogeneous population based on their different mechanical properties and verify sorting accuracy by simultaneous fluorescence detection. This offers new possibilities of exact characterization and sorting of small populations based on rheological properties for biological and biomedical applications. PMID- 25537987 TI - High rates of Native Hawaiian and older Japanese adults hospitalized with dementia in Hawai'i. AB - Data on dementia in Native Hawaiians and many Asian subgroups in the United States are limited. Inpatients with dementia have higher costs, longer stays, and higher mortality than those without dementia. This study compared rates of inpatients with a dementia diagnosis for disaggregated Asian and Pacific Islanders (Native Hawaiian, Chinese, Japanese, Filipino) with those of whites according to age (18-59, 60-69, 70-79, 80-89, <=90) for all adults hospitalized in Hawai'i between December 2006 and December 2010; 13,465 inpatients with a dementia diagnosis were identified using International Classification of Diseases, Ninth Revision, codes. Rates were calculated using population size denominators derived from the U.S. Census. In all age categories, Native Hawaiians had the highest unadjusted rates of inpatients with dementia and were more likely to have a dementia diagnosis at discharge at younger ages than other racial and ethnic groups. In adjusted models (controlling for sex, residence location, and insurer), Native Hawaiian inpatients aged 18 to 59 (aRR = 1.50, 95% CI = 0.84-2.69), 60 to 69 (aRR = 2.53, 95% CI = 1.74-3.68), 70 to 79 (aRR = 2.19, 95% CI = 1.78-2.69), and 80 to 89 (aRR = 2.53, 95% CI = 1.24-1.71) were significantly more likely to have dementia than whites, as were Japanese aged 70 to 79 (aRR = 1.30, 95% CI = 1.01-1.67), 80 to 89 (aRR = 1.29, 95% CI = 1.05 1.57), and 90 and older (aRR = 1.51, 95% CI = 1.24-1.85). Japanese aged 18 to 59 had were significantly less likely to have dementia than whites (aRR = 0.40, 95% CI = 0.17-0.94). These patterns have important public health and clinical care implications for Native Hawaiians and older Japanese populations. Future studies should consider whether preventable medical risk, caregiving, socioeconomic conditions, genetic disposition, or a combination of these factors are responsible for these findings. PMID- 25537988 TI - Measuring tumor metabolism by 18F-FDG PET predicts outcome in a multicenter study: a step off in the right direction. PMID- 25537989 TI - PET/CT with 18F-FDG- and 18F-FBEM-labeled leukocytes for metabolic activity and leukocyte recruitment monitoring in a mouse model of pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is characterized by a progressive and irreversible respiratory failure. Validated noninvasive methods able to assess disease activity are essential for prognostic purposes as well as for the evaluation of emerging antifibrotic treatments. METHODS: C57BL/6 mice were used in a murine model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (control mice were instilled with a saline solution). At different times after instillation, PET/CT with (18)F-FDG- or (18)F-4-fluorobenzamido-N-ethylamino maleimide ((18)F-FBEM)-labeled leukocytes was performed to assess metabolic activity and leukocyte recruitment, respectively. RESULTS: In bleomycin-treated mice, a higher metabolic activity was measured on (18)F-FDG PET/CT scans from day 7 to day 24 after instillation, with a peak of activity measured at day 14. Of note, lung mean standardized uptake values correlated with bleomycin doses, histologic score of fibrosis, lung hydroxyproline content, and weight loss. Moreover, during the inflammatory phase of the model (day 7), but not the fibrotic phase (day 23), bleomycin-treated mice presented with an enhanced leukocyte recruitment as assessed by (18)F-FBEM-labeled leukocyte PET/CT. Autoradiographic analysis of lung sections and CD45 immunostaining confirm the higher and early recruitment of leukocytes in bleomycin-treated mice, compared with control mice. CONCLUSION: (18)F-FDG- and (18)F-FBEM-labeled leukocyte PET/CT enable monitoring of metabolic activity and leukocyte recruitment in a mouse model of pulmonary fibrosis. Implications for preclinical evaluation of antifibrotic therapy are expected. PMID- 25537990 TI - Prognostic significance of dynamic 18F-FET PET in newly diagnosed astrocytic high grade glioma. AB - Despite advances in diagnosis and the use of different therapeutic regimens in astrocytic high-grade glioma (HGG), the prognosis for patients remains grim. Additional pretherapeutic information is needed to tailor management. To gain additional prognostic information at primary diagnosis, we investigated the value of dynamic O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET. METHODS: We retrospectively evaluated 121 patients who had a primary diagnosis of astrocytic HGG (51 World Health Organization [WHO] grade III; 70 WHO IV) and underwent dynamic (18)F-FET PET before histopathologic assessment. We assessed static parameters (maximal and mean tumoral standardized uptake value corrected for mean background activity in the contralateral hemisphere [SUV(max)/BG and SUV(mean)/BG, respectively], biologic tumor volume) and dynamic time-activity curves, including minimal time to peak (TTP(min)). The prognostic influence of PET parameters and other clinical parameters on progression-free and overall survival was evaluated using uni- and multivariate Cox regression and Kaplan Meier survival estimates. RESULTS: In the group overall, median progression-free survival and overall survival were 12.2 and 21.9 mo. SUV(max)/BG, SUV(mean)/BG, and biologic tumor volume were significantly higher in WHO IV than in WHO III gliomas; median TTP(min) was 12.5 min in both groups. On univariate analysis, the factors age, WHO grade, O6-methylguanine-DNA methyltransferase promoter methylation status, contrast enhancement, initial treatment, and TTP(min) showed prognostic significance, with WHO grade, O6-methylguanine-DNA methyltransferase status, age, and TTP(min) remaining significant in the multivariate analysis. WHO grade and TTP(min) reached a similar fit for the prognostic evaluation. The prognosis of WHO III astrocytoma with an early TTP(min) of 12.5 min or less did not differ significantly from that of glioblastoma. CONCLUSION: Early TTP(min) is associated with worse outcome in patients with newly diagnosed astrocytic HGG. In the preoperative setting, TTP(min) can be a valuable noninvasive prognostic marker with comparable significance to WHO grade. Additionally, TTP(min) can help identify highly aggressive WHO III astrocytoma tumors and may help in adjusting standard treatment toward an individualized, risk-adapted therapy regime. PMID- 25537991 TI - Diversification of 99Mo/99mTc separation: non-fission reactor production of 99Mo as a strategy for enhancing 99mTc availability. AB - This paper discusses the benefits of obtaining (99m)Tc from non-fission reactor produced low-specific-activity (99)Mo. This scenario is based on establishing a diversified chain of facilities for the distribution of (99m)Tc separated from reactor-produced (99)Mo by (n,gamma) activation of natural or enriched Mo. Such facilities have expected lower investments than required for the proposed chain of cyclotrons for the production of (99m)Tc. Facilities can receive and process reactor-irradiated Mo targets then used for extraction of (99m)Tc over a period of 2 wk, with 3 extractions on the same day. Estimates suggest that a center receiving 1.85 TBq (50 Ci) of (99)Mo once every 4 d can provide 1.48-3.33 TBq (40 90 Ci) of (99m)Tc daily. This model can use research reactors operating in the United States to supply current (99)Mo needs by applying natural (nat)Mo targets. (99)Mo production capacity can be enhanced by using (98)Mo-enriched targets. The proposed model reduces the loss of (99)Mo by decay and avoids proliferation as well as waste management issues associated with fission-produced (99)Mo. PMID- 25537992 TI - Does the MTHFR C677T gene polymorphism indicate cardiovascular disease risk in type 2 diabetes mellitus patients? AB - OBJECTIVE: Diabetes mellitus is a major risk factor for cardiovascular disease (CVD). We investigated the relationship among biochemical and cardiac risk parameters with the methylenetetrahydrofolate reductase (MTHFR) C677T genotype in type 2 diabetes mellitus (T2DM) patients. METHODS: One hundred seven T2DM subjects with severe CVD diagnosed by angiography were included consecutively in this cross-sectional study. Biochemical and clinical parameters were obtained from patients who were not positive for nephropathy and retinopathy. MTHFR C677T genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Normally and abnormally distributed continuous variables were analyzed using student t- and Mann-Whitney U tests. Categorical variables were analyzed using chi-square test. RESULTS: In the study, 31 T2DM subjects had the CC (29.0%), 62 had the CT (57.9%), and 14 had the TT (13.1%) genotypes. There were no significant differences between subjects with wild-type (677CC) and with mutant (677CT+677TT) alleles in terms of diabetes duration, visceral fat area, total cholesterol, triglyceride, fasting plasma glucose, systolic blood pressure, diastolic blood pressure, high-sensitivity C reactive protein, homocysteine (Hcy), and carotid intima-media thickness values. CONCLUSION: This study suggests that MTHFR gene polymorphisms can not be used as a marker for the assessment of cardiovascular risk in T2DM patients. PMID- 25537993 TI - Coronary slow flow: Benign or ominous? AB - OBJECTIVE: Coronary slow flow phenomenon has been arbitrarily defined as delayed coronary blood flow in the absence of obstructive coronary artery disease. The present study sought to investigate the clinical features, natural history, and outcomes of affected patients. METHODS: In this prospective cross-sectional study, 217 consecutive patients who had undergone coronary angiography and showed features of coronary slow flow phenomenon were evaluated for demographic and coronary risk factor profile, as well as clinical outcomes, at baseline and following treatment. RESULTS: The study population consisted of 165 (76%) males and 52 (24%) females. The mean age of patients was 52.6+/-10 years. Mean ejection fraction was 48.2+/-5.4, 39.3% had diabetes, 43.3% had hypertension, 49.8% was a cigarette smoker, 41.9% had dyslipidemia, and 15% had a familial history of cardiac disease. Forty-nine percent was detected to have abnormal hsCRP levels. The most prevalent presenting complaint was atypical chest pain. Fifty-four percent of patients had slow blood flow in all three vessels. Thirty-six people had undergone repeat coronary angiography in a follow-up period of 5-7 years due to persisting or worsening clinical symptoms, of whom 6 (16.6%) showed significant coronary artery stenosis. Eight (22.2%) had mild CAD, and the rest still showed coronary slow flow without significant stenosis. The most common complaint during follow-up and after initiation of medical therapy was nonanginal chest pain. CONCLUSION: Patients with coronary slow flow phenomenon are predisposed to atherosclerosis and obstructive coronary artery disease. Therefore, this pathology should not be considered as a totally benign condition. Primary and secondary cardiovasculature preventive measures should be constituted and seem worthwhile in this patient population. PMID- 25537994 TI - Right ventricular function in hypertrophic cardiomyopathy: A speckle tracking echocardiography study. AB - OBJECTIVE: The aim of this study was to explore right ventricular (RV) mechanical function in patients with hypertrophic cardiomyopathy (HCM) by 2-D speckle tracking echocardiography (2-D-STE). METHODS: Forty-three patients with HCM (mean age 48, 17 females) and 40 healthy subjects were consecutively included in this cross-sectional study. The diagnosis of HCM was based on the presence of typical clinical, electrocardiographic (ECG), and echocardiographic features. Patients with LV systolic impairment, significant valvular disease, history of coronary artery disease, hypertension, malignancy, and chronic obstructive pulmonary disease were excluded. Right and left ventricular (LV) function was assessed by tissue Doppler imaging (TDI) and 2-D-STE. Hypertrophic cardiomyopathy patients were divided into two groups according to ACC/ESC guidelines (LVOT gradient below and above 30 mm Hg). Student t-test was used to compare differences between groups. Non-parametric tests (Mann-Whitney U) were used in cases of abnormal distribution. RESULTS: Hypertrophic cardiomyopathy patients had a significantly larger right atrium and RV diameters compared to controls. Mean pulmonary artery pressures (mPAB) were significantly higher in HCM patients (19.01+/-13.09 mm Hg vs. 8.40+/-4.50 mm Hg; p<0.001). Although RV Sm measurements were similar, RV strain measurements (-28.51+/-5.36% vs. -32.06+/-7.65%; p=0.016) were significantly lower in HCM patients. Left ventricular global longitudinal, radial, and circumferential strain values were also significantly different between the two groups (-20.50+/-3.58% vs. -24.12+/-3.40%; p<0.001, 38.18+/ 12.67% vs. 44.80+/-10.15%; p=0.012, -21.94+/-4.28% vs. -23.91+/-3.95%; p=0.036 consecutively). Rotational movement of LV in each apical, mid-, and basal left ventricular segment was determined, and only mid-ventricular rotation of the HCM patients was more clockwise (-1.71+/-2.16 degrees vs. 0.04+/-1.72 degrees ; p<0.001). Although mPAP measurements were higher in HCM patients with significant LVOT obstruction (21.52+/-13.26 mm Hg vs. 12.31+/-10.53 mm Hg; p=0.049), none of the other TDI or 2-D-STE parameters was significantly different between groups. CONCLUSION: Speckle tracking echocardiography-derived right ventricular systolic function is impaired in HCM patients when compared with healthy subjects. However, RV systolic function is not affected form LVOT obstruction and left ventricular rotation dynamics in HCM patients. PMID- 25537995 TI - Coronary sinus dilatation is a sign of impaired right ventricular function in patients with heart failure. AB - OBJECTIVE: The coronary sinus (CS) has been largely ignored by physicians due to a lack of adequate data about the importance of CS enlargement in patients with heart failure (HF). We aimed to assess whether CS dilatation develops in patients with HF and to demonstrate its relation with global myocardial function of the right ventricle (RV). METHODS: In this cross-sectional study, 45 healthy subjects and 95 HF patients exhibiting left ventricular systolic dysfunction on echocardiographic examination (EF <45%) secondary to ischemic (n=56) or idiopathic dilated cardiomyopathy (DCM) (n=39) were enrolled. Patients with severe renal dysfunction and/or valve disease were excluded. CS was measured by echocardiography from the posterior atrioventricular groove in the apical four chamber view. The RV myocardial performance index (MPI), which reflects both systolic and diastolic function of the ventricle, was detected using tissue Doppler imaging, and patients with an RV MPI >0.55 were defined as having impaired RV myocardial function. ANOVA, Kruskal-Wallis, Pearson's correlation, and multivariate logistic regression analyses were used for the statistical analysis. RESULTS: The CS and RV MPI values were significantly greater both in patients with ischemic and idiopathic DCM than in controls (8.79+/-1.7 mm and 8.33+/-2.1 mm vs. 5.74+/-0.6 mm, and 0.64+/-0.07 and 0.62+/-0.08 vs. 0.43+/-0.02; p<0.001 for both, respectively). For the prediction of HF patients with impaired RV function, the cut-off value for the diameter of the CS was 7.35 mm, with a sensitivity of 83% and a specificity of 79%. CONCLUSION: The CS diameter can be used as a novel echocardiographic marker that provides information about impaired RV function in patients with HF. PMID- 25537996 TI - Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction. AB - OBJECTIVE: Isolated ventricular noncompaction is a rare primary genetic cardiomyopathy characterized by persistent embryonic myocardial morphology without any other cardiac anomalies. Arrhythmias are frequently present, including both tachyarrhythmia and conduction disturbance. Our study aimed to describe the electrocardiographic findings and to correlate them with the clinical presentation and cardiac magnetic resonance imaging findings. METHODS: We retrospectively reviewed 24 patients diagnosed with isolated ventricular noncompaction (IVNC) by cardiac magnetic resonance imaging. Correlations were investigated between arrhythmias and the site of ventricular noncompaction, number of noncompacted segments, presence of fibrosis, and left ventricular dysfunction. RESULTS: The mean age was 42.7+/-13.1 years. Patients were first presented with heart failure in 41.7% and arrhythmia in 45.8%. Electrocardiogram was abnormal in 91.6% of patients; the most common anomaly was left bundle branch block (LBBB) (41.7%), followed by supraventricular arrhythmias (29.1%), repolarization abnormalities (29.1%), and ventricular tachycardia (20.8%). A normal left ventricular systolic function was frequently observed in patients who first presented with rhythm disorders than heart failure (p=0.008). There was also a delayed diagnosis of IVNC when presented with arrhythmia versus heart failure (p=0.02). We found no correlation between arrhythmias and the noncompaction site or fibrosis, except for LBBB, which was associated to left ventricle lateral wall involvement (p=0.028). No correlation between systolic dysfunction and the number of noncompacted segments, fibrosis, or arrhythmia was demonstrated. CONCLUSION: While electrocardiographic abnormalities are frequent in isolated ventricular noncompaction, no specific patterns were identified. More large studies are needed for stratification of arrhythmic risk of this highly arrhythmogenic substrate. PMID- 25537997 TI - Mitral annular plane systolic excursion in the assessment of left ventricular diastolic dysfunction in obese adults. AB - OBJECTIVE: Mitral annular plane systolic excursion (MAPSE) is a simple way to assess left ventricle (LV) function. MAPSE is also correlated to parameters, illustrating the close relation between systolic and diastolic function of LV. In this study, we evaluated whether MAPSE could help us in the determination the LV diastolic dysfunction (DD) in obese adults. METHODS: Our study was a prospective cross-sectional study. Obese patients who were referred from the endocrinology clinic were enrolled into this study. The participants included 40 obese patients with early-stage DD (grade I and II) and 40 obese patients with normal diastolic function, with an equal number of males and females. The patients with DD were further divided into Obese DD+I, who had grade I DD, and Obese DD+II, who had grade II DD. Student t-test, Mann-Whitney U test, one-way analysis of variance, ROC curve analysis, and pairwise comparisons of the ROC curves were used for statistical analysis. RESULTS: MAPSE was different in all groups, with the lowest value in the Obese DD+II group (p<0.001). E/Em ratio was also different among all groups and was highest in the Obese DD+II group (p<0.001). Furthermore, MAPSE was negatively correlated with E/Em ratio (r=-0.368, p=0.020). The optimal threshold point of MAPSE in the diagnosis of left ventricle diastolic dysfunction (LVDD) was <=1.45 cm, with 92.5% sensitivity (95% CI 79.6-98.4) and 77.5% specificity (95% CI 61.5-89.2) in the ROC curve analysis. There was no difference in the pairwise comparisons of the ROC curves of MAPSE and E/Em ratio in the diagnosis of DD [area under the ROC curve 0.902 (0.033) vs. 0.927 (0.027); p=0.54]. CONCLUSION: Consequently, we found significantly a close relationship between MAPSE with conventional echocardiographic parameters, especially with E/Em, in the detection of left ventricle diastolic dysfunction (LVDD) in obese adults with normal LV ejection fraction. We think that MAPSE is a simple, easily acquired and less time consuming measurement and may help us in the stratification of LVDD in obese adults. PMID- 25537998 TI - The relationship between atrial electromechanical delay and left atrial mechanical function in stroke patients. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between atrial electromechanical delay (EMD) measured with tissue Doppler imaging (TDI) and left atrial (LA) mechanical functions in patients with ischemic stroke and compare them with healthy controls. METHODS: Thirty patients with ischemic stroke were enrolled into this cross-sectional, observational study. The control group consisted of 35 age- and gender-matched apparently healthy individuals patients. Acute cerebral infarcts of probable embolic origin were diagnosed via imaging and were confirmed by a neurologist. Echocardiographically, time intervals from the beginning of P wave to beginning of A wave from the lateral and septal mitral and right ventricular tricuspid annuli in TDI were recorded. The differences between these intervals gave the mechanical delays (inter- and intra-atrial). Left atrial (LA) volumes were measured using the biplane area-length method, and LA mechanical function parameters were calculated. Statistical analysis was performed using student's t-test, chi-squared test, and Pearson's test. RESULTS: The laboratory and clinical characteristics were similar in the two groups. Increased left atrial EMD (21.36+/-10.38 ms versus 11.74+/-6.06 ms, p<0.001), right atrial EMD (13.66+/-8.62 ms versus 9.66+/-6.81 ms, p=0.040), and interatrial EMD (35.03+/-9.95 ms versus 21.40+/-8.47 ms, p<0.001) were observed in stroke patients as compared to controls. Active LA emptying volume and fraction and passive LA emptying volumes and fraction were similar between controls and stroke patients. Total LA emptying volumes were significantly increased in stroke patients as compared to healthy controls (33.19+/-11.99 mL/m2 versus 27.48+/-7.08 mL/m2, p=0.021). CONCLUSION: According to the results of our study, interatrial electromechanical delay may be a new predictor for ischemic stroke. PMID- 25537999 TI - Comparison of estimated GFR equations based on serum cystatin C alone and in combination with serum creatinine in patients with coronary artery disease. AB - OBJECTIVE: Several new equations (GFRCKD-EPI-cr, GFRCKD-EPI-CysC, GFRCKD-EPI Cr+CysC) are used for the calculation of estimated GFR (eGFR) to evaluate renal function. These equations explicitly demonstrate the association of coronary artery disease (CAD) and severe renal impairment cases. However, these equations are considered insufficient to explain the relation with normal or mildly impaired eGFR and CAD. Our hypothesis was to indicate the inversely proportional relationship of eGFR values, calculated by the different equations, with the presence of CAD in patients with normal or mildly impaired renal function. METHODS: Eighty-eight patients who underwent elective coronary angiographic intervention were enrolled into the study. The study population was divided into two groups based on angiographic documents: patients with normal coronary arteries (CAD-) and patients with CAD (CAD +). These patients were stable and decided to implement angiography for the purpose of suspicion about CAD and control. Since it is thought that eGFR equations based on creatinine are inadequate to determine chronic kidney disease (CKD) and overestimate CKD diagnosis, cystatin C-based equations are considered an alternative. Due to the potential effects of inflammatory events of the markers used in equations, patients with diabetes mellitus, severe CKD, and inflammatory bowel disease were excluded from the study. RESULTS: The average age of all participants was 51.93+/ 9.31 (32-65 years); 80.7% (n=71) was male. A statistical difference was found between the CAD (-) group and the CAD (+) group in terms of the variables of age (45.46+/-8.48 vs. 54.95+/-8.11, p<0.001), gender (67.9% vs. 86.7%, male, p=0.037), cystatin C values (1.37+/-0.34 vs. 0.85+/-0.39, p<0.001), and GFR equations defined by the Chronic Kidney Disease Epidemiology: GFRCKD-EPI-cr (85.86+/-14.20 vs. 79.45+/-10.25, p=0.018), GFRCKD-EPI-CysC (58.61+/-21.87 vs. 100.82+/-32.00, p<0.001), and GFRCKD-EPI Cr+CysC (68.29+/-13.49 vs. 90.75+/ 18.34, p<0.001). After adjustment of the variables in multiple regression analyses, only age (OR, 1.199; 95% CI, 1.077 to 1.335, p=0.001), gender (OR, 8.252; 95% CI, 0.223 to 55.659, p=0.030), and the GFRCKD-EPI-CysC equation (OR, 1.059; 95% CI, 1.028 to 1.090, p<0.001) were detected as predictors for presence of CAD. CONCLUSION: GFR equations based on cystatin C or combined with creatinine may have superiority to GFR equations based on creatinine alone in CAD patients. However, the impact of different variables on the GFRCKD-EPI-CysC equation should not be ignored in specific groups, such as CAD. PMID- 25538001 TI - Cooperative Lewis pairs based on late transition metals: activation of small molecules by platinum(0) and B(C6 F5 )3. AB - A Lewis basic platinum(0)-CO complex supported by a diphosphine ligand and B(C6 F5 )3 act cooperatively, in a manner reminiscent of a frustrated Lewis pair, to activate small molecules such as hydrogen, CO2 , and ethene. This cooperative Lewis pair facilitates the coupling of CO and ethene in a new way. PMID- 25538000 TI - The relationship of plasma catestatin concentrations with metabolic and vascular parameters in untreated hypertensive patients: Influence on high-density lipoprotein cholesterol. AB - OBJECTIVE: Catestatin has several cardiovascular actions, in addition to diminished sympatho-adrenal flow. Decreased plasma catestatin levels may reflect a predisposition for the development of hypertension and metabolic disorders. We planned to investigate the possible roles of catestatin in untreated hypertensive patients. As a secondary objective, we compared catestatin concentrations of healthy subjects with those of hypertensive patients in order to understand whether catestatin is increased reactively or diminished at onset. METHODS: Our study was cross-sectional and observational. The patient group, comprising 109 consecutive untreated hypertensive patients without additional systemic or coronary heart disease, underwent evaluations of plasma catestatin, waist circumference, lipid parameters, left ventricular mass, carotid intima-media thickness, and flow-mediated dilation of the brachial artery. Additionally, we measured catestatin concentrations of 38 apparently healthy subjects without any disease using a commercial enzyme-linked immunosorbent assay kit. RESULTS: We documented increased catestatin concentrations in previously untreated hypertensive patients compared to healthy controls (2.27+/-0.83 vs. 1.92+/-0.49 ng/mL, p=0.004). However, this association became insignificant after adjustments for age, gender, height, and weight. Within the patient group, catestatin levels were significantly higher in females. Among all study parameters, age, high density lipoprotein cholesterol (HDL-C) correlated positively to plasma catestatin, whereas triglycerides, hemoglobin, and left ventricular mass correlated negatively to plasma catestatin. We could not detect an association between vascular parameters and catestatin. Catestatin levels were significantly elevated with increasing HDL-C (1.91+/-0.37, 2.26+/-0.79, and 3.1+/-1.23 ng/mL in patients with HDL-C <40, 40-60, and >60 mg/dL, respectively). Multiple linear regression analysis revealed age (beta: 0.201, p=0.041) and HDL-C (beta: 0.390, p<0.001) as independent correlates of plasma catestatin concentration. Additionally, male gender (beta:-0.330, p=0.001) and plasma catestatin (beta: 0.299, p=0.002) were significantly associated with HDL-C concentrations. CONCLUSION: We documented that plasma catestatin is an independent predictor of high-density lipoprotein cholesterol. In addition to antihypertensive effects, catestatin appears to be related to improved lipid and metabolic profiles. Coexistence of low catestatin levels with low HDL-C may provide a probable mechanism for the predictive value of low HDL-C for increased hypertension and cardiovascular events. PMID- 25538002 TI - Calculation of the infrared spectra of proteins. AB - The CHARMM22 force field with associated partial charges is used to calculate the infrared spectra of a number of small proteins and some larger biothreat proteins. The calculated high-frequency region, from about 2,500 to 3,500 cm(-1), is dominated by stretching modes of hydrogen bonded to other atoms, and is very similar in all proteins. There is a peak at 3,430 cm(-1) whose intensity is predicted by these calculations to be a direct measure of arginine content. The calculated low-frequency THz region, up to 300 cm(-1), is also very similar in all the proteins and just reflects the vibrational density of states in agreement with experimental results. Calculations show that the intermediate-frequency region between 500 and 1,200 cm(-1) shows the greatest difference between individual proteins and is also the least affected by water absorption. However, to match experimental measurements in the amide region, it was necessary to reduce the hydrogen partial charges. PMID- 25538003 TI - A Pilot Study of Changes in Environmental Knowledge and Behaviors among Head Start Employees and Parents Following Environmental Health Training in Webb County, TX. AB - Head Start centers in Webb County, Texas primarily serve low-income Hispanic families disproportionately affected by environmental exposures. A total of 560 parents and employees attended environmental trainings. Pre- and post-assessments measured whether the trainings were effective at improving related knowledge and behaviors. A total of 152 parents and 94 employees signed consent forms. Only the 64 parents and 50 employees who completed all questionnaires were included in the data analysis. Paired t tests and McNemar tests found significant improvements in knowledge and behaviors related to multiple environmental topics (p < 0.05). Mean scores out of eleven for knowledge before and immediately after were 9.69 (95 % CI 9.44, 9.94) and 10.58 (95 % CI 10.42, 10.74), respectively. Mean scores out of ten for behavior before and 1 month after training were 8.00 (95 % CI 7.71, 8.29) and 9.29 (95 % CI 9.10, 9.48), respectively. This pilot study found improved knowledge and behaviors following environmental health training. PMID- 25538004 TI - Health Risk Behaviors by Length of Time in the United States Among High School Students in Five Sites. AB - One in five public school students is from an immigrant-headed household. We used Youth Risk Behavior Survey data from one state and four large urban school districts to examine whether length of time living in the US was associated with health risk behaviors. Logistic regression models, using weighted data, controlled for sex, race/ethnicity, and grade. Compared to US natives, not having always lived in the US was correlated with lower risk for some behaviors (e.g., current marijuana use and alcohol use) among high school students, but higher risk for other behaviors (e.g., attempted suicide, physical inactivity). Many findings were inconsistent across the study sites. Interventions that specifically target recently-arrived school-aged youth to prevent behaviors that put health and safety at risk, may result in the best outcomes for immigrant youth. Care should be taken to understand the specific health risks present in different immigrant communities. PMID- 25538005 TI - Automated analysis of multi-channel EEG in preterm infants. AB - OBJECTIVE: To develop and validate two automatic methods for the detection of burst and interburst periods in preterm eight-channel electroencephalographs (EEG). To perform a detailed analysis of interobserver agreement on burst and interburst periods and use this as a benchmark for the performance of the automatic methods. To examine mathematical features of the EEG signal and their potential correlation with gestational age. METHODS: Multi-channel EEG from 36 infants, born at less than 30 weeks gestation was utilised, with a 10 min artifact-free epoch selected for each subject. Three independent expert observers annotated all EEG activity bursts in the dataset. Two automatic algorithms for burst/interburst detection were applied to the EEG data and their performances were analysed and compared with interobserver agreement. A total of 12 mathematical features of the EEG signal were calculated and correlated with gestational age. RESULTS: The mean interobserver agreement was found to be 77% while mean algorithm/observer agreement was 81%. Six of the mathematical features calculated (spectral entropy, Higuchi fractal dimension, spectral edge frequency, variance, extrema median and Hilberts transform amplitude) were found to have significant correlation with gestational age. CONCLUSIONS: Automatic detection of burst/interburst periods has been performed in multi-channel EEG of 36 preterm infants. The algorithm agreement with expert observers is found to be on a par with interobserver agreement. Mathematical features of EEG have been calculated which show significant correlation with gestational age. SIGNIFICANCE: Automatic analysis of preterm multi-channel EEG is possible. The methods described here have the potential to be incorporated into a fully automatic system to quantitatively assess brain maturity from preterm EEG. PMID- 25538008 TI - Management of cerebral arteriovenous malformations with associated aneurysms: a proposed multimodality treatment algorithm. PMID- 25538007 TI - Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis. AB - Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline. PMID- 25538009 TI - Spatiotemporal consistency of local neural activities: A new imaging measure for functional MRI data. AB - PURPOSE: To characterize the local consistency by integrating temporal and spatial information in the local region using functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: One simulation was implemented to explain the definition of FOur-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA). Then three experiments included resting state data (33 subjects), resting state reproducibility data (16 subjects), and event state data (motor execution task, 26 subjects) were designed. Finally, FOCA were respectively analyzed using statistical analysis methods, such as one-sample t test and paired t-test, etc. RESULTS: During resting state (Experiment 1), the FOCA values (P < 0.05, family-wise error [FWE] corrected, voxel size >621 mm(3) ) were found to be distinct at the bilateral inferior frontal gyrus, middle frontal gyrus, angular gyrus, and precuneus/cuneus. In Experiment 2 (reproducibility), a high degree of consistency within subjects (correlation ~0.8) and between subjects (correlation ~0.6) of FOCA were obtained. Comparing event with resting state in Experiment 3, enhanced FOCA (P < 0.05, FWE-corrected, voxel size >621 mm(3) ) was observed mainly in the precentral gyrus and lingual gyrus. CONCLUSION: These findings suggest that FOCA has the potential to provide further information that will help to better understand brain function in neural imaging. PMID- 25538010 TI - Interleukin-18 bioactivity and dose: data interpretation at a crossroads. PMID- 25538011 TI - Author response: interleukin-18 bioactivity and dose: data interpretation at a crossroads. PMID- 25538012 TI - Heritability of corneal shape in twin study. PMID- 25538013 TI - Potential benefits of mathematical models to predict endothelial cell density following penetrating keratoplasty. PMID- 25538014 TI - A novel pediatric treatment intensity score: development and feasibility in heart failure patients with ventricular assist devices. AB - BACKGROUND: The evolution of pharmacologic therapies and mechanical support including ventricular assist devices (VADs) has broadened the scope of care available to children with advanced heart failure. At the present time, there are only limited means of quantifying disease severity or the concomitant morbidity for this population. This study describes the development of a novel pediatric treatment intensity score (TIS), designed to quantify the burden of illness and clinical trajectory in children on VAD support. METHODS: There were 5 clinical domains assessed: nutrition, respiratory support, activity level, cardiovascular medications, and care environment. A scale was developed through expert consensus. Higher scores indicate greater morbidity as reflected by intensity of medical management. To evaluate feasibility and face validity, the TIS was applied retrospectively to a subset of pediatric inpatients with VADs. The Bland Altman method was used to assess limits of agreement. RESULTS: The study comprised 39 patients with 42 implantations. Bland-Altman interobserver and intraobserver comparisons showed good agreement (mean differences in scores of 0.02, limits of agreement +/-0.12). Trends in TIS were concordant with the overall clinical impression of improvement. Scores remained >=0.6 preceding VAD implantation and peaked at 0.71 3 days after VAD implantation. CONCLUSIONS: We describe a pediatric VAD scoring tool, to assess global patient morbidity and clinical recovery. We demonstrate feasibility of using this TIS in a test population of inpatients on VAD support. PMID- 25538015 TI - The contribution of Micro-CT to the evaluation of trabecular bone at the posterior part of the auricular surface in men. AB - AIM: Using multi-slice computed tomography (MSCT), Barrier et al. described the disappearance at the posterior auricular surface of a "central line" (CL) and "juxtalinear cells" (JLCs) belonging to a trabecular bundle, and a trabecular density gradient around the CL that decreased with age. The aim of our study was to use micro-CT to test these findings, referring to the concept of Ascadi and Nemeskeri. METHODOLOGY: The coxal bones of fifteen males were used; age was known. CLs were identified on MSCT-sections using Barrier's method (64 detectors, 0.6 mm slice thickness, 0.1 mm overlap) with two different software programs (Synapse(r), Amira(r)). Then, CLs were researched on microCT slices (pixel size: 36 MUm). Three volumes of interest were defined (around, above, and below CL), and 3D morphometric parameters of the trabecular microarchitecture (particularly BV/TV and DA) were calculated. Two-tailed statistical analyses were performed attempting to correlate these parameters with age at death. RESULTS: CLs and JLCs were observed on micro-CT slices, but with moderate agreement between both imaging techniques. Their presence was not correlated with the age of the subjects. Around the CL, BV/TV decreased significantly with age; DA was negatively correlated with BV/TV and had a tendency to increase with age. Between areas above and below the CL, there was a BV/TV gradient and both BV/TVs decreased in parallel with age. CONCLUSION: Our findings regarding the contribution of micro-CT to the evaluation of trabecular bone could be a promising research approach for application in a larger study population. PMID- 25538016 TI - A survey of etiologic hypotheses among testicular cancer researchers. AB - Basic research results can provide new ideas and hypotheses to be examined in epidemiological studies. We conducted a survey among testicular cancer researchers on hypotheses concerning the etiology of this malignancy. All researchers on the mailing list of Copenhagen Testis Cancer Workshops and corresponding authors of PubMed-indexed articles identified by the search term 'testicular cancer' and published within 10 years (in total 2750 recipients) were invited to respond to an e-mail-based survey. Participants of the 8th Copenhagen Testis Cancer Workshop in May 2014 were subsequently asked to rate the plausibility of the suggested etiologic hypotheses on a scale of 1 (very implausible) to 10 (very plausible). This report describes the methodology of the survey, the score distributions by individual hypotheses, hypothesis group, and the participants' major research fields, and discuss the hypotheses that scored as most plausible. We also present plans for improving the survey that may be repeated at a next international meeting of experts in testicular cancer. Overall 52 of 99 (53%) registered participants of the 8th Copenhagen Testis Cancer Workshop submitted the plausibility rating form. Fourteen of 27 hypotheses were related to exposures during pregnancy. Hypotheses with the highest mean plausibility ratings were either related to pre-natal exposures or exposures that might have an effect during pregnancy and in post-natal life. The results of the survey may be helpful for triggering more specific etiologic hypotheses that include factors related to endocrine disruption, DNA damage, inflammation, and nutrition during pregnancy. The survey results may stimulate a multidisciplinary discussion about new etiologic hypotheses of testicular cancer. PMID- 25538017 TI - Quality of life and satisfaction among prostate cancer patients followed in a dedicated survivorship clinic. AB - BACKGROUND: Integrating quality-of-life (QOL) outcomes into clinics may assist providers in identifying and responding to problems experienced by cancer survivors. To date, however, patient-reported outcomes (PROs) such as QOL are used infrequently to guide care. We integrated QOL assessments into a prostate cancer survivorship clinic and compared recovery and satisfaction among men managed in the survivorship clinic with those followed with more routine care. METHODS: We conducted a before-after study comparing 235 men treated surgically for prostate cancer who received routine follow-up care with 102 men managed in a survivorship clinic characterized by point-of-care QOL reporting and integration of QOL scores (EPIC) following radical prostatectomy. We then assessed baseline and postprostatectomy QOL at 6 and 12 months, as well as patient satisfaction, and compared outcomes between groups. RESULTS: Although baseline QOL was comparable, scores were generally higher among the survivorship group at 6 months and 1 year compared with those followed with routine care. In particular, sexual function scores were significantly higher among patients managed in the survivorship clinic (52.2 vs 33.6 at 1 year, P < .01). Satisfaction scores were consistently higher in the survivorship clinic group compared with the routine care group (all P < .05). CONCLUSIONS: Patient QOL and satisfaction were higher among men managed in a survivorship program, suggesting that disease-specific survivorship clinics that integrate QOL reporting into care pathways may yield better outcomes compared with less tailored approaches to patient care following cancer therapy. PMID- 25538018 TI - Prevalence and determinants of chronic obstructive pulmonary disease in HIV infected patients in an African country with low level of tobacco smoking. AB - BACKGROUND: Little is known on the association between HIV infection and chronic obstructive pulmonary disease (COPD) in sub-Saharan Africa. We assessed the prevalence and investigated the determinants of COPD according to HIV status in a reference centre for HIV and tuberculosis (TB) management in Cameroon. METHODS: This case-control study involved 461 HIV-positive patients aged >18 years (cases) receiving care at the Yaounde Jamot Hospital (YJH) between November 2012 and February 2013, and in 461 age- and sex-matched HIV negative controls selected from the community through a multilevel stratified sampling. Logistic regression models were used to investigate the determinants of COPD. RESULTS: Each study group included 312 (67.7%) women. The mean age (standard deviation) was 42.6 (10.1) years in HIV positive group and 42.6 (10.2) years in HIV negative group. HIV infection was positively associated with COPD defined by the lower limit of normal FEV1/FVC ratio. In multivariable adjusted logistic regression, history of pulmonary TB, chronic respiratory symptoms and lower body mass index (BMI) were the main determinants of COPD in HIV infected patients (on antiretrovirals or not) regardless of the definition of COPD. CONCLUSIONS: HIV infection is possibly a risk factor for COPD in this setting. The careful investigation of the determinants of COPD during routine diagnosis and care of people with HIV infection can aid the detection, further investigation, and improvement of the management of this group of patients. PMID- 25538020 TI - Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic alpha alkylidene beta-oxo imides with ynamides. AB - Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic alpha alkylidene beta-oxo imides with ynamides are described. The high reactivity of the cyclic alpha-alkylidene beta-oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at low temperature. The X-ray crystallographic analysis of the product suggests that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic alpha-alkylidene beta-oxo imide coordinates with Cu(II) through the two imide carbonyls. The imide group in the product can be transformed to amide, nitrile, and ester groups; moreover, it is removable. PMID- 25538021 TI - Experimental climate warming alters aspen and birch phytochemistry and performance traits for an outbreak insect herbivore. AB - Climate change and insect outbreaks are key factors contributing to regional and global patterns of increased tree mortality. While links between these environmental stressors have been established, our understanding of the mechanisms by which elevated temperature may affect tree-insect interactions is limited. Using a forest warming mesocosm, we investigated the influence of elevated temperature on phytochemistry, tree resistance traits, and insect performance. Specifically, we examined warming effects on forest tent caterpillar (Malacosoma disstria) and host trees aspen (Populus tremuloides) and birch (Betula papyrifera). Trees were grown under one of three temperature treatments (ambient, +1.7 degrees C, +3.4 degrees C) in a multiyear open-air warming experiment. In the third and fourth years of warming (2011, 2012), we assessed foliar nutrients and defense chemistry. Elevated temperatures altered foliar nitrogen, carbohydrates, lignin, and condensed tannins, with differences in responses between species and years. In 2012, we performed bioassays using a common environment approach to evaluate plant-mediated indirect warming effects on larval performance. Warming resulted in decreased food conversion efficiency and increased consumption, ultimately with minimal effect on larval development and biomass. These changes suggest that insects exhibited compensatory feeding due to reduced host quality. Within the context of observed phytochemical variation, primary metabolites were stronger predictors of insect performance than secondary metabolites. Between-year differences in phytochemical shifts corresponded with substantially different weather conditions during these two years. By sampling across years within an ecologically realistic and environmentally open setting, our study demonstrates that plant and insect responses to warming can be temporally variable and context dependent. Results indicate that elevated temperatures can alter phytochemistry, tree resistance traits, and herbivore feeding, but that annual weather variability may modulate warming effects leading to uncertain consequences for plant-insect interactions with projected climate change. PMID- 25538019 TI - Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. AB - BACKGROUND: This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). METHODS: A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT. RESULTS: The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade >= 2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months 16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections. CONCLUSIONS: Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy. PMID- 25538022 TI - Histopathological and ultrastructural studies of a Henneguya species (Myxozoa: Myxosporea) infesting the intestine of Clarias gariepinus from Benin (West Africa). AB - Fish culture is the best alternative to fill the gap between natural fish catches and estimated needs of populations in animal protein consumption. In West Africa, this goal required to have suitable fishes for aquaculture which are Clariidae and Tilapia. Clarias gariepinus (Clariidae) fetches a higher price than tilapias as it can be sold alive at the market but a high infestation by Henneguya leads to decrease this commercial value. Those reasons lead us to perform studies on seasonal variations, histopathological aspects and life cycle of Henneguya sp. infecting the intestine of C. gariepinus using light and electron microscope. From November 2011 to December 2012, 339 specimens were collected from Oueme River (Benin) and examined. An overall prevalence of 7.37 % was recorded for plasmodia of Henneguya sp. Parasite occurrence did not vary significantly between seasons (chi(2) = 12.235; df = 3; p > 0.05), nor sexes (chi(2) = 2.992; df = 7; p > 0.05) while differences were significant between classes of weight (chi(2) = 39.929; df = 5; p < 0.05). The highest prevalence was recorded in host ranging from 300 to 374 g. Histopathological analysis showed that the mass continuous development of the plasmodium produced thickening of the intestine wall and compressed neighboring tissues and destroyed villi and smooth muscle layers. The stages of the parasite development including sporogenesis, capsulogenesis, and valvogenesis were asynchronous. Investigations are still running by molecular approaches in order to identify accurately this species. PMID- 25538023 TI - Morphological and phylogenetic analysis of Nosema sp. HR (Microsporidia, Nosematidae): a new microsporidian pathogen of Histia rhodope Cramer (Lepidoptera, Zygaenidae). AB - A new microsporidium was isolated from Histia rhodope Cramer (Lepidoptera, Zygaenidae), a pest of Bischofia javanica BL. in China. The morphology and molecular systematic of this novel microsporidian isolate had been described in this study. The spores were long oval and measured 3.1 * 1.9 MUm on fresh smears. Ultrastructure of the spores was characteristic for the genus Nosema: 14-15 polar filament coils, posterior vacuole, and a diplokaryon. The sequenced rRNA gene of this isolate is 4309 bp long. The organization of the rRNA gene is 5'-LSU rRNA ITS-SSU rRNA-IGS-5S-3', which is similar to that of other Nosema species (such as Nosema bombycis). Phylogenetic analysis based on LSU rRNA gene and SSU rRNA gene both revealed that this novel micorsporidian which isolated from H. rhodope had close relationship to the genus Nosema. Additionally, this isolate can also cause systemic infection of Bombyx mori. So, we should pay attention not only to N. bombycis, but also to other microsporidian (such as Nosema sp. HR) in sericulture in the future. PMID- 25538024 TI - Surface resonances in electron reflection from overlayers. AB - Electron scattering by oxygen monolayers on the Ru(0 0 0 1) surface is studied both experimentally and theoretically. Sharp transmission resonances at low energies are revealed and established to originate from critical points of a special kind in the complex band structure of the substrate. Electron reflection from the clean and oxidized Ru(0 0 0 1) is measured for kinetic energies up to 40 eV at normal incidence for oxygen coverages of 1/4, 1/2, 3/4, and one monolayer. The reflection spectra R(E) are analyzed using a Bloch-waves based ab initio scattering theory. In addition to the substrate-induced resonances the reconstructed (2 * 1) and (2 * 2) surfaces show surface resonances due to pre emergent secondary diffraction beams. The R(E) spectra are shown to give unambiguous evidence of the hcp stacking of the oxygen layer. PMID- 25538025 TI - Constrained off-line synthesis approach of model predictive control for networked control systems with network-induced delays. AB - This paper investigates the off-line synthesis approach of model predictive control (MPC) for a class of networked control systems (NCSs) with network induced delays. A new augmented model which can be readily applied to time varying control law, is proposed to describe the NCS where bounded deterministic network-induced delays may occur in both sensor to controller (S-A) and controller to actuator (C-A) links. Based on this augmented model, a sufficient condition of the closed-loop stability is derived by applying the Lyapunov method. The off-line synthesis approach of model predictive control is addressed using the stability results of the system, which explicitly considers the satisfaction of input and state constraints. Numerical example is given to illustrate the effectiveness of the proposed method. PMID- 25538026 TI - Evaluation of the floating time of a corpse found in a marine environment using the barnacle Lepas anatifera L. (Crustacea: Cirripedia: Pedunculata). AB - Human activities involving water may result in a crime scene. Typically, death may be due to natural causes, homicide, or mass disasters. Decomposition in water is a complex process where many factors may interplay. Human remains in water are subject to many potential interactions, depending upon the remains themselves, the type of water and the characteristics of the water. A number of studies are focused on the decomposition process of the corpse in water, on the identification of the post mortem submersion interval (PMSI) and on the diagnosis of drowning, but very few studies consider the fate of floating remains in any aquatic environment. The following case describes a corpse found on a shore of the Tyrrhenian Sea (South West of Italy, Calabria Region). The corpse and the soles of his shoes were colonized by the barnacle Lepas anatifera L. (Crustacea: Cirripedia: Pedunculata). The analyses of the barnacles present on the corpse aided in the evaluation of the floating time of the corpse which assisted in estimating the minimum time since death. PMID- 25538027 TI - Treatment outcomes of intensity-modulated radiotherapy versus 3D conformal radiotherapy for patients with maxillary sinus cancer in the postoperative setting. AB - BACKGROUND: In this study, we compared the treatment outcomes of postoperative 3D conformal radiotherapy (RT) and intensity-modulated radiotherapy (IMRT) for patients with maxillary sinus carcinoma. METHODS: Fifty-four patients underwent surgery and postoperative RT, of whom 27 (50%) had squamous cell carcinoma and 14 (26%) had adenoid cystic carcinoma. Nineteen patients (35%) were treated with IMRT and 35 patients (65%) received 3D conformal RT. The median radiation dose for 3D conformal RT and IMRT were 62.1 and 63 Gy, respectively. RESULTS: IMRT produced significantly superior radiation dose distribution to planning target volumes (PTVs) than 3D conformal RT. Over a median follow-up of 60 months, IMRT provided better 3-year locoregional recurrence-free survival (89.2% vs 59.5%; p = .035) and distant metastasis-free survival (94.7% vs 55.3%; p = .042) rates than 3D conformal RT. CONCLUSION: Postoperative IMRT for patients with maxillary sinus carcinoma resulted in excellent disease control, and should be considered as the first treatment option in these cases. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E207-E213, 2016. PMID- 25538028 TI - Molecular size and electronic structure combined effects on the electrogenerated chemiluminescence of sulfurated pyrene-cored dendrimers. AB - The electrochemistry, photophysics, and electrochemically generated chemiluminescence (ECL) of a family of polysulfurated dendrimers with a pyrene core have been thoroughly investigated and complemented by theoretical calculations. The redox and luminescence properties of dendrimers are dependent on the generation number. From low to higher generation it is both easier to reduce and oxidize them and the emission efficiency increases along the family, with respect to the polysulfurated pyrene core. The analysis of such data evidences that the formation of the singlet excited state by cation-anion annihilation is an energy-deficient process and, thus, the ECL has been justified through the triplet-triplet annihilation pathway. The study of the dynamics of the ECL emission was achieved both experimentally and theoretically by molecular mechanics and quantum chemical calculations. It has allowed rationalization of a possible mechanism and the experimental dependence of the transient ECL on the dendrimer generation. The theoretically calculated Marcus electron-transfer rate constant compares very well with that obtained by the finite element simulation of the whole ECL mechanism. This highlights the role played by the thioether dendrons in modulating the redox and photophysical properties, responsible for the occurrence and dynamics of the electron transfer involved in the ECL. Thus, the combination of experimental and computational results allows understanding of the dendrimer size dependence of the ECL transient signal as a result of factors affecting the annihilation electron transfer. PMID- 25538029 TI - Using lysine-reactive fluorescent dye for surface characterization of a mAb. AB - The biopharmaceutical industry increasingly demands thorough characterization of protein conformation and conformational dynamics to ensure product quality and consistency. Here, we present a chromatography-based method that is able to characterize protein conformation and conformational dynamics at peptide level resolution in a high-throughput manner. The surface lysine residues of the protein were labeled with a fluorescent dye prior to enzyme digestion. The resulting peptide maps were monitored by fluorescence detection where fluorescence peak area indicates higher solvent accessibility at a specific site. The peptides of reactivity difference and the extent of the difference can be detected by HPLC with fluorescent detector alone, whereas the identity of these peptides can then be determined by mass spectrometry if desired. We first demonstrated this method is suitable for probing protein surface/conformation by studying the effect of deglycosylation on a recombinant mAb, IgG 1. We then applied our method to study the interaction of the mAb with a common excipient, polysorbate-20 (PS-20). The presence of PS-20 increased the fluorescent labeling of several lysine residues on the mAb. This result provides a first insight into PS20-mAb interaction at peptide level resolution. PMID- 25538030 TI - Role of factor V Leiden polymorphism or G20210A prothrombin variant in patients with sudden sensorineural hearing loss: a meta-analysis of the literature. PMID- 25538031 TI - The effect of clinical decision support on adherence to thrombosis prophylaxis guidelines in medical patients; a single center experience. AB - INTRODUCTION: Venous thromboembolism (VTE) is an underestimated health problem. The administration of low molecular weight heparins (LMWH) to the appropriate patients dramatically decreases VTE incidence. Clinical decision support (CDS) might contribute to thrombosis prophylaxis guideline adherence. METHODS: A computerized integrated risk score program was used to estimate VTE and bleeding risk of nonsurgical patients. A VTE risk score of >=4 resulted in an advice to administer LMWH. We selected 64 medical patients before the introduction of CDS (T0) and 64 patients after the introduction (T1). We compared guideline compliance between these groups using chi(2) tests. RESULTS: No difference between groups was found; Adherence to the guidelines at T0 was 59.4%, the same percentage of 59.4% was found at T1. To evaluate the effect of the introduction of CDS in terms of under and overtreatment we compared the prevalence of over and under treatment at T1 and T0. The OR for receiving under treatment at T1 compared to T0 is 0.48 (95% CI: 0.18-1.30), p = 0.14. The OR for overtreatment at T1 compared to T0 is 1.66 (95% CI: 0.74-3.73), p = 0.22 CONCLUSION: We found no improvement in guideline adherence towards anti thrombotic prophylaxis in medical patients after the introduction of CDS in this pilot study. There was however a non-significant shift towards over treatment. Possible explanations for these results are the increased awareness of the risk for thromboembolism induced by the study, suboptimal use of CDS and deviation from CDS advice caused by patient's preferences. PMID- 25538032 TI - Submembranous recruitment of creatine kinase B supports formation of dynamic actin-based protrusions of macrophages and relies on its C-terminal flexible loop. AB - Subcellular partitioning of creatine kinase contributes to the formation of patterns in intracellular ATP distribution and the fuelling of cellular processes with a high and sudden energy demand. We have previously shown that brain-type creatine kinase (CK-B) accumulates at the phagocytic cup in macrophages where it is involved in the compartmentalized generation of ATP for actin remodeling. Here, we report that CK-B catalytic activity also helps in the formation of protrusive ruffle structures which are actin-dependent and abundant on the surface of both unstimulated and LPS-activated macrophages. Recruitment of CK-B to these structures occurred transiently and inhibition of the enzyme's catalytic activity with cyclocreatine led to a general smoothening of surface morphology as visualized by scanning electron microscopy. Comparison of the dynamics of distribution of YFP-tagged CK-mutants and isoforms by live imaging revealed that amino acid residues in the C-terminal segment (aa positions 323-330) that forms one of the protein's two mobile loops are involved in partitioning over inner regions of the cytosol and nearby sites where membrane protrusions occur during induction of phagocytic cup formation. Although wt CK-B, muscle-type CK (CK-M), and a catalytically dead CK-B-E232Q mutant with intact loop region were normally recruited from the cytosolic pool, no dynamic transition to the phagocytic cup area was seen for the CK-homologue arginine kinase and a CK-B-D326A mutant protein. Bioinformatics analysis helped us to predict that conformational flexibility of the C-terminal loop, independent of conformational changes induced by substrate binding or catalytic activity, is likely involved in exposing the enzyme for binding at or near the sites of membrane protrusion formation. PMID- 25538034 TI - Complete effect-profile assessment in association studies with multiple genetic and multiple environmental factors. AB - Studying complex diseases in the post genome-wide association studies (GWAS) era has led to developing methods that consider factor-sets rather than individual genetic/environmental factors (i.e., Multi-G-Multi-E studies), and mining for potential gene-environment (G*E) interactions has proven to be an invaluable aid in both discovery and deciphering underlying biological mechanisms. Current approaches for examining effect profiles in Multi-G-Multi-E analyses are either underpowered due to large degrees of freedom, ill-suited for detecting G*E interactions due to imprecise modeling of the G and E effects, or lack of capacity for modeling interactions between two factor-sets (e.g., existing methods focus primarily on a single E factor). In this work, we illustrate the issues encountered in constructing kernels for investigating interactions between two factor-sets, and propose a simple yet intuitive solution to construct the G*E kernel that retains the ease-of-interpretation of classic regression. We also construct a series of kernel machine (KM) score tests to evaluate the complete effect profile (i.e., the G, E, and G*E effects individually or in combination). We show, via simulations and a data application, that the proposed KM methods outperform the classic and PC regressions across a range of scenarios, including varying effect size, effect structure, and interaction complexity. The largest power gain was observed when the underlying effect structure involved complex G*E interactions; however, the proposed methods have consistent, powerful performance when the effect profile is simple or complex, suggesting that the proposed method could be a useful tool for exploratory or confirmatory G*E analysis. PMID- 25538035 TI - Highly diastereoselective and enantioselective olefin cyclopropanation using engineered myoglobin-based catalysts. AB - Using rational design, an engineered myoglobin-based catalyst capable of catalyzing the cyclopropanation of aryl-substituted olefins with catalytic proficiency (up to 46,800 turnovers) and excellent diastereo- and enantioselectivity (98-99.9%) was developed. This transformation could be carried out in the presence of up to 20 g L(-1) olefin substrate with no loss in diastereo- and/or enantioselectivity. Mutagenesis and mechanistic studies support a cyclopropanation mechanism mediated by an electrophilic, heme-bound carbene species and a model is provided to rationalize the stereopreference of the protein catalyst. This work shows that myoglobin constitutes a promising and robust scaffold for the development of biocatalysts with carbene-transfer reactivity. PMID- 25538036 TI - Illness uncertainty in breast cancer patients: validation of the 5-item short form of the Mishel Uncertainty in Illness Scale. AB - PURPOSE: Several studies have shown that uncertainty about disease and fear of disease progression affects psychosocial adjustment and quality of life. The purpose of this study was to validate a Norwegian short version of the "The Mishel Uncertainty in Illness Scale" (SF-MUIS) and to examine the impact of uncertainty in illness in breast cancer patients. METHOD AND SAMPLE: 209 patients in breast cancer treatment completed questionnaires for SF-MUIS, Hospital Anxiety and Depression Scale (HADS), the Functional Assessment of Cancer Therapy-Breast (FACT-ES), and eight questions concerning quality of the patient information provided (IQP). Relationship between scores on uncertainty in illness and anxiety, depression, social support, emotional well-being, the quality of patient information provided, and age were studied by multiple regression analyses. RESULTS: Ordinal coefficient alpha for the Norwegian version of SF-MUIS was 0.70. Scores on SF-MUIS correlated significantly with scores on HADS (P = 0.001), FACT ES (P = 0.001), and IQP (P = 0.001) indicating good convergent validity. The patients reported a moderate degree of uncertainty in illness. However, those who had been diagnosed with breast cancer for a year, reported higher scores than those newly diagnosed (P=<0.0001). Information provided was the sole significant predictor of illness uncertainty (P=<0.0001). CONCLUSION: The results of the present study confirm that the Norwegian version of the SF-MUIS is a suitable tool for assessment of uncertainty in breast cancer patients, who reported a moderate degree of uncertainty in illness. PMID- 25538037 TI - Quantitative liver tumor blood volume measurements by a C-arm CT post-processing software before and after hepatic arterial embolization therapy: comparison with MDCT perfusion. AB - PURPOSE: We aimed to determine whether the C-arm computed tomography (CT) blood volume (BV) imaging of hepatic tumors performed with a new prototype software is capable of measuring the BV changes in response to hepatic arterial treatments and to validate these quantitative measurements with commercially available multidetector computed tomography (MDCT) perfusion software. METHODS: A total of 34 patients with hepatic tumors who underwent either radioembolization (RE, n=21) or transarterial chemoembolization (TACE, n=13) were included in the study. Using a prototype software by Siemens Healthcare, 74 C-arm CT BV measurements were obtained in both pre- and postembolization settings (three patients had additional BV measurements before and after work-up angiography for RE). Ten of 34 patients underwent MDCT perfusion study before embolization, enabling comparison of BV measurements using C-arm CT versus MDCT methods. RESULTS: The mean BV of 14 tumor lesions in 10 patients on MDCT perfusion was highly correlated with the BV values on C-arm CT (r=0.97, P < 0.01). The BV values obtained by C-arm CT decreased from 140.6+/-28.3 mL/1000 mL to 45.9+/-23.5 mL/1000 mL after TACE (66.37% reduction) and from 175.6+/-29.4 mL/1000 mL to 84.1+/-22.5 mL/1000 mL after RE (53.75% reduction). DISCUSSION: Quantitative BV measurement with C-arm CT is well-correlated with MDCT BV measurements, and it is a promising tool to monitor perfusion changes during hepatic arterial embolization. PMID- 25538038 TI - Hysterosalpingography and ultrasonography findings of female genital tuberculosis. AB - Genital tuberculosis (TB) is an important cause of female infertility in the world, especially in developing countries. Majority of infertility cases are due to involvement of the fallopian tubes (92%-100%), endometrial cavity (50%), and ovaries (10%-30%); cervical and vulvovaginal TB are uncommon. Genital TB has characteristic radiological appearances based on the stage of the disease process (acute inflammatory or chronic fibrotic) and the organ of involvement. Hysterosalpingography (HSG) and ultrasonography (US) remain the main imaging modalities used in the diagnosis of genital TB. HSG is the primary modality for evaluating uterine, fallopian tube, and peritubal involvement and also helps in evaluating tubal patency. US, on the other hand, allows simultaneous evaluation of ovarian and extrapelvic involvement. PMID- 25538040 TI - A Regulatory Network Involving beta-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling. AB - The mechanisms underlying disparate roles of the canonical Wnt signaling pathway in maintaining self-renewal or inducing differentiation and lineage specification in embryonic stem cells (ESCs) are not clear. In this study, we provide the first demonstration that self-renewal versus differentiation of human ESCs (hESCs) in response to Wnt signaling is predominantly determined by a two-layer regulatory circuit involving beta-catenin, E-cadherin, PI3K/Akt, and Slug in a time dependent manner. Short-term upregulation of beta-catenin does not lead to the activation of T-cell factor (TCF)-eGFP Wnt reporter in hESCs. Instead, it enhances E-cadherin expression on the cell membrane, thereby enhancing hESC self renewal through E-cadherin-associated PI3K/Akt signaling. Conversely, long-term Wnt activation or loss of E-cadherin intracellular beta-catenin binding domain induces TCF-eGFP activity and promotes hESC differentiation through beta-catenin induced upregulation of Slug. Enhanced expression of Slug leads to a further reduction of E-cadherin that serves as a beta-catenin "sink" sequestering free cytoplasmic beta-catenin. The formation of such a framework reinforces hESCs to switch from a state of temporal self-renewal associated with short-term Wnt/beta catenin activation to definitive differentiation. Stem Cells 2015;33:1419-1433. PMID- 25538042 TI - Expression of executioner procaspases and their activation by a procaspase activating compound in chronic lymphocytic leukemia cells. AB - Intrinsic and extrinsic apoptotic pathways converge to activate common downstream executioner caspases (caspase-3, -6, and -7), resulting in cell death. In chronic lymphocytic leukemia (CLL), neoplastic B cells evade apoptosis owing to the overexpression of survival proteins. We hypothesized that direct activation of procaspases could bypass the apoptosis resistance induced by the upstream prosurvival proteins. The procaspase-activating compounds (PAC-1), including B PAC-1 (L14R8), convert inactive executioner procaspases to their active cleaved forms by chelation of labile zinc ions. Both at transcript and protein levels, primary CLL cells express high levels of latent procaspases (3, -7, and -9). B PAC-1 treatment induced CLL lymphocyte death which was higher than that in normal peripheral blood mononuclear cells or B cells, and was independent of prognostic markers and microenvironmental factors. Mechanistically, B-PAC-1 treatment activated executioner procaspases and not other Zn-dependent enzymes. Exogenous zinc completely, and pancaspase inhibitors partially, reversed B-PAC-1-induced apoptosis, elucidating the zinc-mediated mechanism of action. The cell demise relied on the presence of caspase-3/7 but not caspase-8 or Bax/Bak proteins. B PAC-1 in combination with an inhibitor of apoptosis protein antagonist (Smac066) synergistically induced apoptosis in CLL samples. Our investigations demonstrated that direct activation of executioner procaspases via B-PAC-1 treatment bypasses apoptosis resistance and is a novel approach for CLL therapeutics. PMID- 25538041 TI - Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia. AB - Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL rearranged leukemia. PMID- 25538044 TI - The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis. AB - The interaction between thrombopoietin (THPO) and its receptor c-Mpl regulates downstream cytokine signaling and platelet homeostasis. Hereditary mutations of c Mpl can either result in loss-of-function and thrombocytopenia or in gain-of function and thrombocythemia (HT), and are important models to analyze the mechanism of c-Mpl activity. We have analyzed the effect of the c-Mpl P106L gain of-function and the nearby loss-of-function R102P and F104S mutations, which cause HT or thrombocytopenia, respectively, on posttranslational processing, intracellular trafficking, cell surface expression, and cell proliferation. In contrast to R102P and F104S, the P106L mutant confers cytokine-independent growth and stimulates downstream signaling after THPO treatment in Ba/F3 cells. Despite their opposite function, R102P and P106L, both lead to abnormal subcellular receptor distribution, lack of membrane localization, impaired glycosylation, and elevated THPO serum levels in effected patients. These findings indicate that the activation of downstream signaling by c-Mpl P106L does not require correct processing, trafficking, and cell surface expression of c-Mpl, whereas the negative feedback loop controlling THPO serum levels requires cell surface expression of the receptor. Thus, we propose that the P106L mutation functionally separates the activity of c-Mpl in downstream signaling from that in maintaining platelet homeostasis. PMID- 25538043 TI - P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation. AB - The small GTPase Rac is required for neutrophil recruitment during inflammation, but its guanine-nucleotide exchange factor (GEF) activators seem dispensable for this process, which led us to investigate the possibility of cooperation between Rac-GEF families. Thioglycollate-induced neutrophil recruitment into the peritoneum was more severely impaired in P-Rex1(-/-) Vav1(-/-) (P1V1) or P-Rex1( /-) Vav3(-/-) (P1V3) mice than in P-Rex null or Vav null mice, suggesting cooperation between P-Rex and Vav Rac-GEFs in this process. Neutrophil transmigration and airway infiltration were all but lost in P1V1 and P1V3 mice during lipopolysaccharide (LPS)-induced pulmonary inflammation, with altered intercellular adhesion molecule 1-dependent slow neutrophil rolling and strongly reduced L- and E-selectin-dependent adhesion in airway postcapillary venules. Analysis of adhesion molecule expression, neutrophil adhesion, spreading, and migration suggested that these defects were only partially neutrophil-intrinsic and were not obviously involving vascular endothelial cells. Instead, P1V1 and P1V3 platelets recapitulated the impairment of LPS-induced intravascular neutrophil adhesion and recruitment, showing P-Rex and Vav expression in platelets to be crucial. Similarly, during ovalbumin-induced allergic inflammation, pulmonary recruitment of P1V1 and P1V3 eosinophils, monocytes, and lymphocytes was compromised in a platelet-dependent manner, and airway inflammation was essentially abolished, resulting in improved airway responsiveness. Therefore, platelet P-Rex and Vav family Rac-GEFs play important proinflammatory roles in leukocyte recruitment. PMID- 25538046 TI - Supramolecular control of spin exchange in a spin-labelled [2]rotaxane incorporating a tetrathiafulvalene unit. AB - The EPR properties of a novel triradical obtained by single-electron oxidation of a nitroxide-spin-labelled rotaxane containing a tetrathiafulvalene unit and cyclobis(paraquat-p-phenylene) ring is reported. Rotaxanation is proved to have a dramatic effect on through-space magnetic interactions between radical fragments. Analysis of the EPR spectra by a three-jump model, allowed us to obtain structural information on the interlocked structure. PMID- 25538045 TI - Sp1/Sp3 transcription factors regulate hallmarks of megakaryocyte maturation and platelet formation and function. AB - Sp1 and Sp3 belong to the specificity proteins (Sp)/Kruppel-like transcription factor family. They are closely related, ubiquitously expressed, and recognize G rich DNA motifs. They are thought to regulate generic processes such as cell cycle and growth control, metabolic pathways, and apoptosis. Ablation of Sp1 or Sp3 in mice is lethal, and combined haploinsufficiency results in hematopoietic defects during the fetal stages. Here, we show that in adult mice, conditional pan-hematopoietic (Mx1-Cre) ablation of either Sp1 or Sp3 has minimal impact on hematopoiesis, whereas the simultaneous loss of Sp1 and Sp3 results in severe macrothrombocytopenia. This occurs in a cell-autonomous manner as shown by megakaryocyte-specific (Pf4-Cre) double-knockout mice. We employed flow cytometry, cell culture, and electron microscopy and show that although megakaryocyte numbers are normal in bone marrow and spleen, they display a less compact demarcation membrane system and a striking inability to form proplatelets. Through megakaryocyte transcriptomics and platelet proteomics, we identified several cytoskeleton-related proteins and downstream effector kinases, including Mylk, that were downregulated upon Sp1/Sp3 depletion, providing an explanation for the observed defects in megakaryopoiesis. Supporting this notion, selective Mylk inhibition by ML7 affected proplatelet formation and stabilization and resulted in defective ITAM receptor-mediated platelet aggregation. PMID- 25538047 TI - Growth, structure and morphology of epitaxial Fe(0 0 1) films on GaAs(0 0 1)c(4 * 4). AB - We studied epitaxy, growth, structure and morphology of thin Fe(0 0 1) films on the As-rich GaAs(0 0 1)-c(4 * 4) surface, deposited by molecular beam epitaxy at growth temperatures between room temperature and 250 degrees C. Electron and x ray diffraction (XRD) techniques evidence epitaxial growth with Fe(0 0 1)[1 0 0] ? GaAs(0 0 1)[1 0 0]. The residual strain derived from the XRD results is consistent with recent stress measurements. Cross-sectional transmission electron microscopy reveals an abrupt interface for room-temperature films and the formation of a ~10 nm thick crystalline Fe-Ga-As intermediate layer at 250 degrees C. The dependence of the surface morphology on growth temperature and annealing evidences a kinetic roughening of the Fe surface at growth temperatures of 100-200 degrees C due to the presence of step-edge barriers. PMID- 25538048 TI - Interplay of hole transfer and host-guest interaction in a molecular dyad and triad: ensemble and single-molecule spectroscopy and sensing applications. AB - A new molecular dyad consisting of a Cy5 chromophore and ferrocene (Fc) and a triad consisting of Cy5, Fc, and beta-cyclodextrin (CD) are synthesized and their photophysical properties investigated at both the ensemble and single-molecule levels. Hole transfer efficiency from Cy5 to Fc in the dyad is reduced upon addition of CD. This is due to an increase in the Cy5-Fc separation (r) when the Fc is encapsulated in the macrocyclic host. On the other hand, the triad adopts either a Fc-CD inclusion complex conformation in which hole transfer quenching of the Cy5 by Fc is minimal or a quasi-static conformation with short r and rapid charge transfer. Single-molecule fluorescence measurements reveal that r is lengthened when the triad molecules are deposited on a glass substrate. By combining intramolecular charge transfer and competitive supramolecular interaction, the triad acts as an efficient chemical sensor to detect different bioactive analytes such as amantadine hydrochloride and sodium lithocholate in aqueous solution and synthetic urine. PMID- 25538049 TI - Interrelations between siblings and parents in families living with children with cancer. AB - Having a child diagnosed with cancer is a stressful event for the family. This exploratory multimethod study utilized both quantitative and qualitative multiinformant methodologies to investigate the relationships between parental family functioning and siblings' health-related quality of life (HRQOL) and to describe interrelations between the experiences of parents and siblings of children with childhood cancer. A total of 14 Japanese families participated in the quantitative study, and 4 families of the 14 participated in the qualitative study. In-depth, semistructured interviews revealed three family-unit stages during the time course of the ill child's treatment that included particular parent-sibling interrelations. We also found strong correlation between parental family functioning and siblings' HRQOL in the quantitative study. The results suggest the importance of family nursing interventions directed to individual family members and the family unit that focus on strengthening the parent-sibling relationship and supporting families who are experiencing childhood cancer. PMID- 25538050 TI - Progressively engaging: constructing nurse, patient, and family relationships in acute care settings. AB - In this grounded theory study, informed by symbolic interactionism, we explain how nurses, patients, and family members construct relationships in acute care settings, including managing effects of work environments. We recruited participants from 10 acute care units across four community hospitals in a Western Canadian city. From 33 hr of participant observation and 40 interviews with 13 nurses, 17 patients, and 10 family members, we constructed the basic social-psychological process of progressively engaging. Nurses, patients, and family members approached constructing relationships through levels of engagement, ranging from perspectives about "just doing the job" to "doing the job with heart." Progressively engaging involved three stages: focusing on tasks, getting acquainted, and building rapport. Workplace conditions and personal factors contributed or detracted from participants' movement through the stages of the process; with higher levels of engagement, participants experienced greater satisfaction and cooperation. Progressively engaging provides direction for how all participants in care can invest in relationships. PMID- 25538051 TI - The 5th China-France International Symposium 2013. PMID- 25538052 TI - Stem cells and applications: a survey. AB - Since the 1960s and the therapeutic use of hematopoietic stem cells of bone marrow origin, there has been increasing interest in the study of undifferentiated progenitors that have ability to proliferate and differentiate in different tissues. Different stem cells (SC) with different potential can be isolated and characterised. Despite the promise of embryonic stem cells, in many cases, adult stem cells provide a more interesting approach to clinical applications. It is undeniable that mesenchymal stem cells (MSC) from bone marrow, adipose tissue or MSC of Wharton Jelly, which have limited potential, are of interest for clinical applications in regenerative medicine because they are easily separated and prepared and no ethical problems are involved in their use.During the last 10 years, these multipotent cells have generated considerable interest and in particular have been shown to escape allogeneic immune response and be capable of immunomodulatory activity. These properties may be of a great interest for regenerative medicine. Different clinical applications are under study (cardiac insufficiency, atherosclerosis, stroke, bone, cartilage, diabetes, ophthalmology, urology, liver, organ's reconstruction...). PMID- 25538053 TI - Validation of a single-platform method for hematopoietic CD34+ stem cells enumeration according to accreditation procedure. AB - INTRODUCTION: Stem cells for autologous and allogenic transplantation are obtained from several sources including bone marrow, peripheral blood or cord blood. Accurate enumeration of viable CD34+ hematopoietic stem cells (HSC) is routinely used in clinical settings, especially to monitor progenitor cell mobilization and apheresis. The number of viable CD34+ HSC has also been shown to be the most critical factor in haematopoietic engraftment. The International Society for Cellular Therapy actually recommends the use of single-platform flow cytometry system using 7-AAD as a viability dye. AIM: In a way to move routine analysis from a BD FACSCaliburTM instrument to a BD FACSCantoTM II, according to ISO 15189 standard guidelines, we define laboratory performance data of the BDTM Stem Cell Enumeration (SCE) kit on a CE-IVD system including a BD FACSCanto II flow cytometer and the BD FACSCantoTM Clinical Software. InterQCTM software, a real time internet laboratory QC management system developed by VitroTM and distributed by Becton DickinsonTM, was also tested to monitor daily QC data, to define the internal laboratory statistics and to compare them to external laboratories. METHODS: Precision was evaluated with BDTM Stem Cell Control (high and low) results and the InterQC software, an internet laboratory QC management system by Vitro. This last one drew Levey-Jennings curves and generated numeral statistical parameters allowing detection of potential changes in the system performances as well as interlaboratory comparisons. Repeatability, linearity and lower limits of detection were obtained with routine samples from different origins. Agreement evaluation between BD FACSCanto II system versus BD FACSCalibur system was tested on fresh peripheral blood, freeze-thawed apheresis, fresh bone marrow and fresh cord blood samples. RESULTS: Instrument's measure and staining repeatability clearly evidenced acceptable variability on the different samples tested. Intra- and inter-laboratory CV in CD34+ cell absolute count are consistent and reproducible. Linearity analysis, established between 2 and 329 cells/MUl showed a linear relation between expected counts and measured counts (R2=0.97). Linear regression and Bland-Altman representations showed an excellent correlation on samples from different sources between the two systems and allowed the transfer of routine analysis from BD FACSCalibur to BD FACSCanto II. CONCLUSIONS: The BD SCE kit provides an accurate measure of the CD34 HSC, and can be used in daily routine to optimize the enumeration of hematopoietic CD34+ stem cells by flow cytometry. Moreover, the InterQC system seems to be a very useful tool for laboratory daily quality monitoring and thus for accreditation. PMID- 25538054 TI - Toward an understanding of mechanism of aging-induced oxidative stress in human mesenchymal stem cells. AB - Under physiological conditions, there is a production of limited range of free radicals. However, when the cellular antioxidant defence systems, overwhelm and fail to reverse back the free radicals to their normal basal levels, there is a creation of a condition of redox disequilibrium termed "oxidative stress", which is implicated in a very wide spectrum of genetic, metabolic, and cellular responses. The excess of free radicals can, cause unfavourable molecular alterations to biomolecules through oxidation of lipids, proteins, RNA and DNA, that can in turn lead to mutagenesis, carcinogenesis, and aging. Mesenchymal stem cells (MSCs) have been proven to be a promising source of cells for regenerative medicine, and to be useful in the treatment of pathologies in which tissue damage is linked to oxidative stress. Moreover, MSCs appeared to efficiently manage oxidative stress and to be more resistant to oxidative insult than normal somatic cells, making them an interesting and testable model for the role of oxidative stress in the aging process. In addition, aging is accompanied by a progressive decline in stem cell function, resulting in less effective tissue homeostasis and repair. Also, there is an obvious link between intracellular reactive oxygen species levels and cellular senescence. To date, few studies have investigated the promotion of aging by oxidative stress on human MSCs, and the mechanism by which oxidative stress induce stem cell aging is poorly understood. In this context, the aim of this review is to gain insight the current knowledge about the molecular mechanisms of aging-induced oxidative stress in human MSCs. PMID- 25538055 TI - Structure, physical properties, hemocompatibility and cytocompatibility of starch/zein composites. AB - A series of composite films were prepared from glycerol-plasticized starch and zein by intensive mixing and hot press. The structure and physical properties of the starch/zein (SZ) composite films were characterized by scanning electron microscope (SEM), optical microscopy and water contract angle testing. The hemocompatibility and cytocompatibility of SZ films were evaluated by plasma recalcification time, hemolysis assay and cell culture experiment. SEM and optical observation showed that starch and zein domains can be differed in the films and in a two phase separation status. Glycerol affects the surface hydrophilicity/hydrophobicity of the films. The hemocompatibility and cytocompatibility evaluation showed that SZ composites are anticoagulant materials with no hemolysis and low cytotoxicity. The SZ composites maybe have potentials for applications as biomaterials. PMID- 25538056 TI - Cellulose/soy protein isolate composite membranes: evaluations of in vitro cytocompatibility with Schwann cells and in vivo toxicity to animals. AB - OBJECTIVE: To evaluate the in vitro cytocompatibility of cellulose/soy protein isolate composite membranes (CSM) with Schwann cells and in vivo toxicity to animals. METHODS: A series of cellulose/soy protein isolate composite membranes (CSM) were prepared by blending, solution casting and coagulation process. The cytocompatibility of the CSM to Schwann cells were evaluated by MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and by direct cells culture of Schwann cells on the surfaces of the CSM, respectively. The in vivo toxicity of the CSM to animals were also evaluated by acute toxicity testing, skin sensitization testing, pyrogen testing and intracutaneous stimulation testing, respectively, according to the ISO 10993 standard. RESULTS: The MTT assay showed that the cell viability of Schwann cells cultured in extracts from the CSM was higher than that from the neat cellulose membrane without containing SPI component. The direct cells culture indicated that the Schwann cells could attach and grow well on the surface of the CSM and the incorporation of SPI into cellulose contributed to improvement of cell adhesion and proliferation. The evaluations of in vivo biological safety suggested that the CSM showed no acute toxicity, no skin sensitization and no intracutaneous stimulation to the experimental animals. CONCLUSION: The CSM had in vitro cytocompatibility with Schwann cells and biological safety to animals, suggesting potential for the applications as nerve conduit for the repair of nerve defect. PMID- 25538057 TI - Construction of biocompatible porous tissue scaffold from the decellularized umbilical artery. AB - The scaffolds prepared from the tissue decellularization conserve the porous 3-D structure and provide an optimal matrix for the tissue regeneration. Since decade, the enzymatic digestion, chemical reagent treatment and mechanical actions such as eversion and abrasion have been used to remove the cells from the intact matrix. In this study, we optimized an enzymatic method to decellularize the umbilical artery to construct a 3-D porous scaffold which is suitable for the culture of mesenchymal stem cells (MSCs). The scaffold maintained the interconnected porous structure. It remained the similar high water content 95.3 +/- 1% compared to 94.9 +/- 0.6% in the intact umbilical artery (p>0.05). The decellularization process decreased the stress from 0.24 +/- 0.05 mPa to 0.15 +/- 0.06 mPa (p<0.05). However the decellularization did not change the strain of the artery (45 +/- 15% vs. 53 +/- 10%, p>0.05). When the scaffold was transplanted to the subcutaneous tissue in the wild type mice, there were less T cells appeared in the surrounding tissue which meant the decreased the immunogenicity by decellularization. This scaffold also supported the adhesion and proliferation of the MSCs. In this study, we constructed a biological compatible porous scaffold from the decellularized umbilical artery which may provide a suitable scaffold for cell-matrix interaction studies and for tissue engineering. PMID- 25538058 TI - Stem cells as a new treatment for peripheral artery disease: hype or hope? The point of view of a vascular surgeon. AB - Because many of patients with peripheral arterial disease are not eligible for direct or conventional revascularization procedures, because stem cell therapy is being investigated as to its possible role in the treatment of limb ischemia, there is a need to evaluate this treatment and his true application. On the basis of experimental data, preliminary clinical studies have established the safety and feasibility of stem cells implantation in case of critical limb ischemia. Forthcoming large studies, especially randomized placebo controlled double blind studies, related to the optimal cell type, dosage, administration route, will consolidate this evidence and establish mid and long term effectiveness. PMID- 25538059 TI - Nanostructured thick 3D nanofibrous scaffold can induce bone. AB - Designing unique nanostructured biomimetic materials is a new challenge in modern regenerative medicine. In order to develop functional substitutes for damaged organs or tissues, several methods have been used to create implants able to regenerate robust and durable bone. Electrospinning produces nonwoven scaffolds based on polymer nanofibers mimicking the fibrillar organization of bone extracellular matrix. Here, we describe a biomimetic 3D thick nanofibrous scaffold obtained by electrospinning of the biodegradable, bioresorbable and FDA approved polymer, poly(epsilon-caprolactone). Such scaffold presents a thickness reaching one centimeter. We report here the demonstration that the designed nanostructured implant is able to induce in vivo bone regeneration. PMID- 25538060 TI - A simple two dimensional culture method to study the hypertrophic differentiation of rat articular chondrocytes. AB - OBJECTIVES: Chondrocytes hypertrophy is a physiological process observed in endochondral ossification during development until adolescence in human. It can also be observed during pathophysiological conditions such as osteoarthritis. Hypertrophic chondrocytes synthesise collagen X and express matrix metalloproteinase 13 and alkaline phosphatase. The cellular models available to study this process are either not convenient, they might lead to a rapid dedifferentiation of chondrocytes, or they are far from the physiological conditions. The objective of this study was to design an user-friendly 2D-primary cell culture of young articular chondrocytes of rat able to follow the terminal differentiation process. EXPERIMENTAL DESIGN: After confluence, chondrocytes were cultured according to 4 differentiation protocols. Protocol 1 contained DMEM/F12 supplemented with 10% foetal bovine serum (FBS) and 2 MUg/ml insulin. Protocol 2 contained alpha-MEM supplemented with 5% FBS and 2 MUg/ml insulin. Protocol 3 contained 2% FBS and 2 MUg/ml insulin. Protocol 4 contained DMEM/F12 supplemented with 2% FBS in absence or in presence of 2 MUg/ml insulin and 37.5 MUg/ml ascorbate. The cell morphology was observed by phase-contrast microscopy and the expression of markers specific of mature and hypertrophic chondrocytes were assessed by RT-qPCR. RESULTS: The effect of a decrease in nutrient quality of the culture medium after confluence was tested using protocols 1, 2 and 3. Protocol 1 did not allow the maintenance of chondrocyte phenotype more than one week, because cells became fibroblastic. A decrease in Sox9 mRNA expression, in collagen II/collagen I and in aggrecan/versican mRNA ratios was also found with protocol 1. Protocol 3 was the best when compared with protocols 1 and 2. It allowed chondrocytes to adopt a hypertrophic morphology. Cells also expressed the collagen X specific hypertrophic marker, and presented an increase in collagen II/I and aggrecan/versican ratios after 15 days of culture post-confluence. The effect of the insulin/ascorbate supplementation was studied using protocol 4. The insulin/ascorbate supplementation allowed an earlier chondrocytes conversion to terminal differentiation with a prolonged effect till 3 weeks post-confluence, compared to control without insulin/ascorbate. Finally, the profile of chondrocyte differentiation was checked during 5 successive sub-cultures. Only the first passage could be used to study hypertrophy. CONCLUSION: A convenient protocol to study chondrocyte hypertrophy is proposed. Protocol 4 offers the possibility to study this differentiation phenotype which is crucial for the development of articular diseases such as osteoarthritis. Our model could also be used in tissue engineering for cartilage repair strategies in which hypertrophic differentiation of chondrocyte should be avoided. PMID- 25538061 TI - Identification of two populations of osteoarthritic osteoblasts according to the 1,25[OH]2 vitamin D3 potency to stimulate osteocalcin. AB - INTRODUCTION: Few studies have tried to discriminate a differential behavior between osteoarthritic (OA) osteoblasts (Obs). Based on osteocalcin level, we aimed, in the present study, to evaluate the capacity of OA Obs for producing molecules of the Wnt/beta-catenin signaling pathway. METHODS: Human primary OA Obs (n=11) were exposed or not to 50 nM of 1,25 dihydroxyvitamin D3 (VitD3) for 24 h. Osteocalcin (OCN), TGF-beta1, Dickkopf-related protein 2 (DKK2), R-spondin 2 (Rspo2), Wnt5b, and low density lipoprotein related-receptor 1 (LRP1) were evaluated by real time RT-PCR. RESULTS: All samples responded to VitD3 as validated by the increase in OCN expression. However two populations of Obs were discriminated; one called "high responders" whose OCN stimulation was higher than 100 fold (mean 881 fold, p<0.01, n=5) and the second one whose stimulation was inferior to 100 fold (mean 47 fold, p<0.01, n=6), namely "low responders". In fact, high responders have a weaker basal expression of OCN. With regards to these two cell populations and in absence of VitD3 challenge, the expression level of TGF-beta1 (15 fold, p<0.001), DKK2 (2.5 fold, p<0.002) and Wnt5b (5.5 fold, p<0.003) was higher in "high responders", meanwhile Rspo2 and LRP1 expression was unchanged. VitD3 exacerbated this pattern but corrected OCN expression and favored Wnt agonist expression. CONCLUSION: We identified 2 populations of OA Obs according to the OCN expression under the control of VitD3. In addition under basal conditions, these 2 populations expressed differently TGF beta1, Wnt5b, DKK2, suggesting a heterogeneous differentiation and phenotype in Obs among OA patients. PMID- 25538062 TI - Bone defects and future regenerative nanomedicine approach using stem cells in the mutant Tabby mouse model. AB - X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) is associated to a large spectrum of ectodermal and extra-ectodermal symptoms, especially craniofacial bone morphological, structural and metabolic anomalies. This skeletal phenotype described in affected patients and in the Ta mutant mouse model leads to craniofacial dysmorphies, endosseous implants and jaw bone grafts complications. Bone tissue bioengineering based on the use of PCL synthetic nanofibrous membrane and BMP nanoreservoirs appears as an original and promising approach to prevent such complications in the context of dysfunctional bone. Use of osteoblasts or stem cells seeded biomembranes appears as another strategy developed on the Tabby (Ta) model of XLHED. The Ta mouse experimental model is used to study the jaw bone response during the post-operative period after bone lesion and placement of synthetic PCL membrane functionalized with nanoreservoirs embedding different BMPs dimers or seeded with living cells. PMID- 25538063 TI - Fabrication, characterization and cell cultures on a novel chitosan scaffold. AB - Chitosan has been used as scaffolds with various methods of fabrication including expensive commercial available ones for tissue engineering. The objective of this study is to assemble our novel method of chitosan scaffold fabrication in economical and uncomplicated way that suitable for dental pulp stem cell (DPSC) and stem cells of human exfoliated deciduous teeth (SHED). Chitosan scaffolds (2% and 3%) were fabricated in an uncomplicated procedure, including centrifugation and freeze-drying steps. The chitosan scaffolds were compared and the pore size, swelling and degradation were assessed. In addition, the cytocompatibility was assessed of chitosan scaffolds seeded with DPSC and SHED. The pore size of 2% and 3% chitosan scaffolds were similar being 188.71 +/- 51.90 MUm and 195.30 +/- 67.21 MUm, respectively. Swelling ratios of 3% chitosan scaffolds were significantly lower than those of 2% chitosan scaffolds. Dimension of scaffolds changed in first 5 minutes. After that, those scaffolds could maintain their dimension. Chitosan scaffolds degraded as from day 7. No differences were found between 2% and 3% chitosan scaffolds. The scaffolds were shown to be non-toxic and to promote DPSCs and SHED growth. The viability of DPSCs and SHED on 2% scaffolds proved to be higher than that of the 3% scaffold group. This study suggested that chitosan scaffolds fabricated with our novel method were suitable for the growth and survival of DPSC and SHED. PMID- 25538064 TI - Application potential of mesenchymal stem cells derived from Wharton's jelly in liver tissue engineering. AB - The shortage of organ resource has been limiting the application of liver transplantation. Bioartificial liver construction is increasingly focused as a replacement treatment. To product a bioartificial liver, three elements must be considered: seeding cells, scaffold and bioreactor. Recent studies have shown that several methods can successfully differentiate MSC (mesenchymal stem cells) derived from Wharton's jelly into hepatocyte, such as stimulating MSC by cytokines and growth factors, direct and indirect co-culture MSC with hepatocytes, or promote MSC differentiation by 3-dimensional matrix. In some cases, differentiation of MSC into hepatocytes can also be an alternative approach for whole organ transplantation in treatment of acute and chronic liver diseases. In this review, the characterization of MSC from Wharton's jelly, their potential of application in liver tissue engineering on base of decellularized scaffold, their status of banking and their preclinical work performed will be discussed. PMID- 25538065 TI - Differentiation of human umbilical cord-derived mesenchymal stem cells into hepatocytes in vitro. AB - OBJECTIVE: The stem cell based therapy is a potential alternative to liver transplantation. The aim of the study is to investigate the hepatocytic differentiation ability of human umbilical cord derived mesenchymal stem cells (HUC-MSCs) in vitro. METHODS: The HUC-MSCs were isolated from Wharton's jelly of human umbilical cord. The cells were identified by assessing the stem cell markers. The HUC-MSCs were characterized by multipotency of differentiation. We modified the hepatogenic differentiation protocol and examine the function of differentiated cell by Periodic acid-Schiff (PAS) staining and Low-Density Lipoprotein (LDL) uptake. The protein expressions of Total protein (TP), Albumin (ALB), Globulin (GLB), Urea (BUN) and alpha-fetoprotein (AFP) were also detected. RESULTS: The cells of the hepatogenic differentiation group showed the function of hepatocyte. Protein expressions of TP, ALB, GLB BUN and AFP improve that the HUC-MSCs are able to different into the functional hepatogenic-like cell. CONCLUSION: The above founding indicated that the HUC-MSCs are able to different into the functional hepatogenic-like cell by present method. PMID- 25538066 TI - An approach to preparing decellularized whole liver organ scaffold in rat. AB - OBJECTIVES: In present study, we plan to produce a decellularization protocol from rat liver to generate a three-dimensional whole organ scaffold. METHODS: A combination of 1% SDS and 1% tritonX-100 were used orderly to decellularize rat livers. After about 6 h of interactive antegrade/retrograde perfusion, a decellularized whole translucent liver scaffold with integrated blood vessel networks was generated. The decellularized livers are charactered by light microscopy, scanning electron microscopy, and biochemical analysis (DNA quantification) for preservation of the three-dimension of extracellular matrix architecture. RESULTS: The decellularization protocol was verified by observation of the whole translucent liver organ with intact vascular trees under macroscopy, in conjunction with the hematoxylin-eosin staining that showed no cells or nuclear material remained. Additionally, the Masson's stain indicted that the extracellular proteins were well kept and scanning electron microscopy (SEM) revealed a preserved decellularized matrix architecture. Compared to normal livers, DNA in the decellularized livers was quantified less than 10% at the same mass. CONCLUSIONS: The current method of decellularization protocol was feasible, simple and quick, and was verified by an absence of residual cells. The decellularized extracellular matrix had preserved integrate vascular network and a three-dimensional architecture. PMID- 25538067 TI - Bone marrow mesenchymal stem cells suppress ascitogenous hepatoma progression in BALB/c mouse through reducing myeloid-derived suppressor cells. AB - Bone marrow mesenchymal stem cells (BMSCs) and myeloid-derived suppressor cells (MDSCs) can be mobilized from bone marrow (BM) into blood stream and home in tumor stroma, where they either help or hinder tumor growth. The issue of whether BMSCs could affect MDSCs in ascitogenous hepatoma BALB/c mice, thus influencing their functional activity, remains unclear. In this study, we demonstrated that after transfusion into ascitogenous hepatoma BALB/c mice, the homing fraction of BMSCs in BM was 2%-5% in 24-72 h and the percentage of Gr-1+CD11b+ MDSCs was downregulated in peripheral blood (PB) and BM. Meanwhile, IFN-gamma+ T lymphocytes in PB increased. As a result of such immunoregulation, BMSCs treatment caused a delayed tumor growth and a prolonged survival in H22 ascitogenous hepatoma model. Because the proliferation of H22 cells was not affected by in vitro coculture with BMSCs, this observation is likely due to a systemic suppressive effect on the host MDSCs. We also demonstrated that BMSCs inhibited the induction and proliferation of MDSCs from hematopoietic stem cells (HSCs) in an in vitro tumor conditioned medium. Thus, our findings show for the first time that BMSCs are potentially inhibitor during MDSCs induction and proliferation and that when injected intravenously into tumor bearing mice they might be effective antitumor agents suitable for cancer therapy. PMID- 25538068 TI - Angelica sinensis and osteoarthritis: a natural therapeutic link? AB - The dried root of Angelica sinensis is widely used in Chinese traditional medicine for its beneficial effects against several diseases, including osteoarthritis. In order to understand the mechanism of action, two main components of the plant, the phytochemical, sodium ferulate, and a polysaccharidic fraction have been tested on osteoarthritis animal models or in human chondrocytes stimulated by the pro-inflammatory cytokine, Interleukine 1beta. The results showed that sodium ferulate exhibited marked anti-inflammatory and anti-apoptotic properties by inhibiting the TNF/TNFR signal transduction pathway. On the other hand, the polysaccharidic fraction which contains a mixture of various carbohydrates was found to promote proteoglycan biosynthesis in cartilage matrix by stimulating the activity of the UDP-glycosyltransferases that synthesize the chondroitin sulfate chains of aggrecans. It is suggested that the combined action of sodium ferulate and polysaccharidic fraction would prevent cartilage destruction in osteoarthritis and favor cartilage repair. PMID- 25538069 TI - Percutaneous autologous bone marrow injection for treatment of delayed and non union of long bone: a retrospective study of 45 cases. AB - BACKGROUND: Non-union of long bones is still a current problem in traumatology. Although corticocancellous bone autograft remains the usual procedure for the treatment of non-union, innovative therapies such as, percutaneous autologous concentrated bone marrow grafting (PABMG), are now appearing. MATERIAL AND METHODS: Over a period of 8 years, 45 non-union of long bones were treated by PABMG in the Department of Orthopaedic and Traumatologic Surgery (University Hospital of Nancy, France): 26 tibiae, 16 femurs, 3 humeri. Efficiency was evaluated by clinical criteria: full weight-bearing without pain, absence of motion at non-union site, and radiological criteria: healing of 3 corticales out of 4. RESULTS: Eighteen out of 28 non-unions at the tibia were healed (69%), 10 at the femur (63%), but none was noticed at the humerus. Some pejorative prognosis factors were noted such as: tobacco, alcohol abuse, diabetes and history of infection at the fracture site. An earlier grafting improved the success rate. The number of CFU-F (Colony Forming Unit Fibroblastic) affected the healing time more than the healing rate. CONCLUSION: The procedure, even though a little invasive, enables the healing of non-union in two out of three cases with less morbidity than conventional procedures. This procedure fits perfectly into the therapeutic arsenal of non-union. PMID- 25538070 TI - Cultured blood versus donated blood: long-run perspectives of the economy of blood. AB - Recent advances of fundamental research on the in vitro generation of red blood cells (RBCs) from hematopoietic stem cells in the laboratory open new possibilities of the utilization of cultured RBCs in transfusion medicine. We study the economic challenge of the setup and development of the mass industrial production of RBCs in mature transfusion organizations. We argue that: (i) RBC manufacturing could be set up and developed in the short-medium run for the treatment of the small proportion of transfused patients who have a rare blood type or are alloimmunized against blood antigens; (ii) manufactured RBCs could substitute for donated RBCs in the long run if the physical productivity of RBC engineering technology approaches that of bone marrow. PMID- 25538071 TI - Efficient and elaborate treatment of hand fractures. PMID- 25538072 TI - Fracture-dislocations of the carpometacarpal joints of the ring and little finger. AB - We report the functional and radiographic results of 16 patients with fracture dislocations of the ring and little finger carpometacarpal joints and 23 cases with fracture-dislocations of only the little finger carpometacarpal joint treated between 2006 and 2012. The above two cohort populations of patients were treated with either open reduction and pin fixation or closed reduction and pin fixation. These patients were followed for a mean of 13 months (range 9 to 48). The DASH scores for patients with fracture-dislocations of the ring and little finger carpometacarpal joints were 6.0 and of the little finger carpometacarpal joint 7.2. We found no functional differences in term of DASH scores after treatment between patients with fracture-dislocations of only the little finger carpometacarpal joint and both the ring and little finger carpometacarpal joints. PMID- 25538073 TI - Overview of indications, preferred methods and technical tips for hand fractures from around the world. AB - This article presents techniques used by six senior surgeons from different parts of the world. Our commentaries on treating hand fractures are included, together with the methods we use. While non-operative treatment is appropriate and effective for the majority of the hand fractures (including those many practitioners currently treat surgically), we describe how we try to manage difficult cases with less invasive surgical methods. We recommend simple, efficient, non-operative or less invasive operative methods for almost all fractures, except for some open or very complex injuries. PMID- 25538074 TI - Re: Gulabi D, Cecen GS, Bekler HI, Saglam F and Tanju N. A study of 60 patients with percutaneous trigger finger releases: clinical and ultrasonographic findings. J Hand Surg Eur. 2014, 39: 699-703. PMID- 25538075 TI - Goubau et al. The wrist hyperflexion and abduction of the thumb (WHAT) test: a more specific and sensitive test to diagnose de Quervain tenosynovitis than the Eichhoff's Test. J Hand Surg Eur. 2014, 39: 286-92. PMID- 25538076 TI - Re: Goutos et al. Extravasation injuries: a review. J Hand Surg Eur. 2014, 39: 808-18. PMID- 25538078 TI - Over a quarter of Salmonella cases in English children are caused by pet reptiles, study finds. PMID- 25538081 TI - Fear of a family member in childhood is associated with use of prescription psychotropic drugs when older, study shows. PMID- 25538079 TI - Systematic identification of signaling pathways with potential to confer anticancer drug resistance. AB - Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a gamma-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts. PMID- 25538080 TI - RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. AB - Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2) associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance. PMID- 25538082 TI - Quality improvement in the national cancer institute community cancer centers program: the quality oncology practice initiative experience. AB - PURPOSE: The National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) began in 2007; it is a network of community-based hospitals funded by the NCI. Quality of care is an NCCCP priority, with participation in the American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) playing a fundamental role in quality assessment and quality improvement (QI) projects. Using QOPI methodology, performance on quality measures was analyzed two times per year over a 3-year period to enhance our implementation of quality standards at NCCCP hospitals. METHODS: A data-sharing agreement allowed individual-practice QOPI data to be electronically sent to the NCI. Aggregated data with the other NCCCP QOPI participants were presented to the network via Webinars. The NCCCP Quality of Care Subcommittee selected areas in which to focus subsequent QI efforts, and high-performing practices shared voluntarily their QI best practices with the network. RESULTS: QOPI results were compiled semiannually between fall 2010 and fall 2013. The network concentrated on measures with a quality score of <= 0.75 and planned voluntary group-wide QI interventions. We identified 13 measures in which the NCCCP fell at or below the designated quality score in fall 2010. After implementing a variety of QI initiatives, the network registered improvements in all parameters except one (use of treatment summaries). CONCLUSION: Using the NCCCP as a paradigm, QOPI metrics provide a useful platform for group-wide measurement of quality performance. In addition, these measurements can be used to assess the effectiveness of QI initiatives. PMID- 25538083 TI - In response to S.A. Glied. PMID- 25538084 TI - Correcting misperceptions related to chemotherapy drug shortages in the United States. PMID- 25538085 TI - In response to "surviving surveys". PMID- 25538086 TI - Prognostic performance of a high-sensitivity assay for cardiac troponin I after non-ST elevation acute coronary syndrome: Analysis from MERLIN-TIMI 36. AB - BACKGROUND: Newer troponin assays offer the ability to quantify circulating troponin levels at an order of magnitude lower than contemporary assays, fueling continued debate over the prognostic implications of very low-level increases in concentration. We evaluated the prognostic implications of low-level increases in cardiac troponin I (cTnI) using an investigational single-molecule high sensitivity assay in patients with acute coronary syndrome (ACS). METHODS: We measured cTnI using both a high-sensitivity troponin I (hsTnI) assay (Erenna, Singulex, 99(th) percentile 9 pg/ml) and a current generation sensitive assay (TnI-Ultra, Siemens, 99(th) percentile 40 pg/ml) at baseline in 1807 patients with non-ST elevation ACS and compared their prognostic ability for adverse cardiovascular events at 30 days and one year. RESULTS: Among patients with TnI Ultra<99(th) percentile, patients with elevated hsTnI (>= 9 pg/ml) had a significantly higher risk than patients with hsTnI<9 pg/ml: cardiovascular death (CVD) or myocardial infarction (MI) at one year (7.0% vs 3.8%; p<0.001, hazard ratio (HR) 2.05, confidence interval (CI) 1.23-3.41); including a higher risk of CVD (3.5% vs 1.5%, p<0.001) and MI (5.0% vs 2.8%, p<0.001) individually. This higher risk of CVD/MI was independent of clinical risk stratification using the TIMI Risk Score (adj. HR 1.76, CI 1.05-2.90). Moreover, hsTnI showed a trend toward a gradient of risk even below the hsTnI 99 percentile. CONCLUSIONS: Low level cardiac troponin detected using a single-molecule technique, below the cutpoint of a contemporary sensitive assay, identified a significant gradient of risk. These findings support the prognostic relevance of low-level cardiac troponin elevation with increasingly sensitive assays in patients with ACS. PMID- 25538087 TI - Salivary microRNAs show potential as a noninvasive biomarker for detecting resectable pancreatic cancer. AB - Early surgery is vital in the treatment of pancreatic cancer, which is often fatal. However, there is currently no useful noninvasive biomarker to screen for pancreatic cancer. Studies have documented that many salivary molecules can be used to detect systemic diseases. We investigated whether salivary miRNAs are useful biomarkers for detecting resectable pancreatic cancer. Using an Agilent microarray, salivary miRNAs were profiled from saliva samples of 8 patients with resectable pancreatic cancer and 8 healthy controls. Candidate biomarkers identified in the profiles were subjected to validation using quantitative PCR and an independent sample set of 40 patients with pancreatic cancer, 20 with benign pancreatic tumors (BPT), and 40 healthy controls. The validated salivary miRNA biomarkers were evaluated within three discriminatory categories: pancreatic cancer versus healthy control, pancreatic cancer versus BPT, and pancreatic cancer versus noncancer (healthy control + BPT). miR-3679-5p showed significant downregulation in the pancreatic cancer group within the three categories (P = 0.008, 0.007, and 0.002, respectively), whereas miR-940 showed significant upregulation in pancreatic cancer (P = 0.006, 0.004, and 0.0001, respectively). Logistic regression models combining the two salivary miRNAs were able to distinguish resectable pancreatic cancer within the three categories, showing sensitivities of 72.5%, 62.5%, and 70.0% and specificities of 70.0%, 80.0%, and 70.0%, respectively. Salivary miR-3679-5p and miR-940 possess good discriminatory power to detect resectable pancreatic cancer, with reasonable specificity and sensitivity. This report provides a new method for the early detection of pancreatic cancer and other systemic diseases by assessing salivary miRNAs. PMID- 25538089 TI - Infective endarteritis associated with aortic dissection underlying bacterial meningitis. PMID- 25538090 TI - Aborted cardiac death in a previously healthy young adult: coronary angiography and cardiac computed tomography reveal an unexpected diagnosis. PMID- 25538091 TI - Primary cardiac sarcoma: a rare disease with rapid progression. PMID- 25538088 TI - Spectrin repeat containing nuclear envelope 1 and forkhead box protein E1 are promising markers for the detection of colorectal cancer in blood. AB - Identifying biomarkers in body fluids may improve the noninvasive detection of colorectal cancer. Previously, we identified N-Myc downstream-regulated gene 4 (NDRG4) and GATA binding protein 5 (GATA5) methylation as promising biomarkers for colorectal cancer in stool DNA. Here, we examined the utility of NDRG4, GATA5, and two additional markers [Forkhead box protein E1 (FOXE1) and spectrin repeat containing nuclear envelope 1 (SYNE1)] promoter methylation as biomarkers in plasma DNA. Quantitative methylation-specific PCR was performed on plasma DNA from 220 patients with colorectal cancer and 684 noncancer controls, divided in a training set and a test set. Receiver operating characteristic analysis was performed to measure the area under the curve of GATA5, NDRG4, SYNE1, and FOXE1 methylation. Functional assays were performed in SYNE1 and FOXE1 stably transfected cell lines. The sensitivity of NDRG4, GATA5, FOXE1, and SYNE1 methylation in all stages of colorectal cancer (154 cases, 444 controls) was 27% [95% confidence interval (CI), 20%-34%), 18% (95% CI, 12%-24%), 46% (95% CI, 38% 54%), and 47% (95% CI, 39%-55%), with a specificity of 95% (95% CI, 93%-97%), 99% (95% CI, 98%-100%), 93% (95% CI, 91%-95%), and 96% (95% CI, 94%-98%), respectively. Combining SYNE1 and FOXE1, increased the sensitivity to 56% (95% CI, 48%-64%), while the specificity decreased to 90% (95% CI, 87%-93%) in the training set and to 58% sensitivity (95% CI, 46%-70%) and 91% specificity (95% CI, 80%-100%) in a test set (66 cases, 240 controls). SYNE1 overexpression showed no major differences in cell proliferation, migration, and invasion compared with controls. Overexpression of FOXE1 significantly decreased the number of colonies in SW480 and HCT116 cell lines. Overall, our data suggest that SYNE1 and FOXE1 are promising markers for colorectal cancer detection. PMID- 25538092 TI - Chest X-ray in cardiac illness: a tale of four decades. PMID- 25538094 TI - Operation Gritrock: Christmas bulletin from UK army medics in Sierra Leone. PMID- 25538093 TI - Diagnosis and treatment response evaluation of cardiac sarcoidosis using positron emission tomography/magnetic resonance imaging. PMID- 25538095 TI - Message from the Editor-in-Chief. PMID- 25538099 TI - Overdominance effect of the bovine ghrelin receptor (GHSR1a)-DelR242 locus on growth in Japanese Shorthorn weaner bulls: heterozygote advantage in bull selection and molecular mechanisms. AB - Ghrelin and the ghrelin receptor (GHSR1a) are involved in growth hormone secretion, food intake, and several other important functions. Ghrelin acts on GHSR1a and induces signal transduction via the Galphaq subunit. In our previous study, we identified the DelR242 (3R) allele, a truncated 3-arginine residue (3R) [major type: 4 arginine residues (4R)] of the third intracellular loop of GHSR1a, with a high frequency in Japanese Shorthorn bulls (0.43) but with a low frequency in other cattle breeds (0.00-0.09). To further investigate the reasons for the higher frequency of the 3R allele, we performed several experiments. In this study, we found a significant sex difference in the frequency of the 3R allele. Statistical analysis revealed a significant overdominance effect of the DelR242 locus on growth in Japanese Shorthorn weaner bulls. However, additive/dominance/overdominance effects of the 3R allele on carcass traits in adult steers and dams were not significant. The mode of the overdominance effect was estimated to be solely controlled by the single DelR242 locus without any other linked loci using linkage disequilibrium analysis in GHSR1a. These results indicated that 4R/3R heterozygotes had a selective advantage in weaner bulls because of their higher average daily gain than homozygotes. We discussed possible molecular mechanisms involved in the overdominance effect of the DelR242 locus on these traits in weaner bulls using a structural model of the complex consisting of a GHSR1a dimer and Galphaq. PMID- 25538100 TI - Abiotic and biotic stressors causing equivalent mortality induce highly variable transcriptional responses in the soybean aphid. AB - Environmental stress affects basic organismal functioning and can cause physiological, developmental, and reproductive impairment. However, in many nonmodel organisms, the core molecular stress response remains poorly characterized and the extent to which stress-induced transcriptional changes differ across qualitatively different stress types is largely unexplored. The current study examines the molecular stress response of the soybean aphid (Aphis glycines) using RNA sequencing and compares transcriptional responses to multiple stressors (heat, starvation, and plant defenses) at a standardized stress level (27% adult mortality). Stress-induced transcriptional changes showed remarkable variation, with starvation, heat, and plant defensive stress altering the expression of 3985, 510, and 12 genes, respectively. Molecular responses showed little overlap across all three stressors. However, a common transcriptional stress response was identified under heat and starvation, involved with up regulation of glycogen biosynthesis and molecular chaperones and down-regulation of bacterial endosymbiont cellular and insect cuticular components. Stressor specific responses indicated heat affected expression of heat shock proteins and cuticular components, whereas starvation altered a diverse set of genes involved in primary metabolism, oxidative reductive processes, nucleosome and histone assembly, and the regulation of DNA repair and replication. Exposure to host plant defenses elicited the weakest response, of which half of the genes were of unknown function. This study highlights the need for standardizing stress levels when comparing across stress types and provides a basis for understanding the role of general vs. stressor specific molecular responses in aphids. PMID- 25538101 TI - Genetic dissection of internode length above the uppermost ear in four RIL populations of maize (Zea mays L.). AB - The internode length above the uppermost ear (ILAU) is an important influencing factor for canopy architecture in maize. Analyzing the genetic characteristics of internode length is critical for improving plant population structure and increasing photosynthetic efficiency. However, the genetic control of ILAU has not been determined. In this study, quantitative trait loci (QTL) for internode length at five positions above the uppermost ear were identified using four sets of recombinant inbred line (RIL) populations in three environments. Genetic maps and initial QTL were integrated using meta-analyses across the four populations. Seventy QTL were identified: 16 in population 1; 14 in population 2; 25 in population 3; and 15 in population 4. Individual effects ranged from 5.36% to 26.85% of phenotypic variation, with 27 QTL >10%. In addition, the following common QTL were identified across two populations: one common QTL for the internode length of all five positions; one common QTL for the internode length of three positions; and one common QTL for the internode length of one position. In addition, four common QTL for the internode length of four positions were identified in one population. The results indicated that the ILAU at different positions above the uppermost ear could be affected by one or several of the same QTL. The traits may also be regulated by many different QTL. Of the 70 initial QTL, 46 were integrated in 14 meta-QTL (mQTLs) by meta-analysis, and 17 of the 27 initial QTL with R(2) >10% were integrated in 7 mQTLs. Four of the key mQTLs (mQTL2-2, mQTL3-2, mQTL5-1, mQTL5-2, and mQTL9) in which the initial QTL displayed R(2) >10% included four to 11 initial QTL for an internode length of four to five positions from one or two populations. These results may provide useful information for marker-assisted selection to improve canopy architecture. PMID- 25538102 TI - Threshold models for genome-enabled prediction of ordinal categorical traits in plant breeding. AB - Categorical scores for disease susceptibility or resistance often are recorded in plant breeding. The aim of this study was to introduce genomic models for analyzing ordinal characters and to assess the predictive ability of genomic predictions for ordered categorical phenotypes using a threshold model counterpart of the Genomic Best Linear Unbiased Predictor (i.e., TGBLUP). The threshold model was used to relate a hypothetical underlying scale to the outward categorical response. We present an empirical application where a total of nine models, five without interaction and four with genomic * environment interaction (G*E) and genomic additive * additive * environment interaction (G*G*E), were used. We assessed the proposed models using data consisting of 278 maize lines genotyped with 46,347 single-nucleotide polymorphisms and evaluated for disease resistance [with ordinal scores from 1 (no disease) to 5 (complete infection)] in three environments (Colombia, Zimbabwe, and Mexico). Models with G*E captured a sizeable proportion of the total variability, which indicates the importance of introducing interaction to improve prediction accuracy. Relative to models based on main effects only, the models that included G*E achieved 9-14% gains in prediction accuracy; adding additive * additive interactions did not increase prediction accuracy consistently across locations. PMID- 25538103 TI - Ectopic expression screen identifies genes affecting Drosophila mesoderm development including the HSPG Trol. AB - Gastrulation of the embryo involves coordinate cell movements likely supported by multiple signaling pathways, adhesion molecules, and extracellular matrix components. Fibroblast growth factors (FGFs) have a major role in Drosophila melanogaster mesoderm migration; however, few other inputs are known and the mechanism supporting cell movement is unclear. To provide insight, we performed an ectopic expression screen to identify secreted or membrane-associated molecules that act to support mesoderm migration. Twenty-four UAS insertions were identified that cause lethality when expressed in either the mesoderm (Twi-Gal4) or the ectoderm (69B-Gal4). The list was narrowed to a subset of 10 genes that were shown to exhibit loss-of-function mutant phenotypes specifically affecting mesoderm migration. These include the FGF ligand Pyramus, alpha-integrins, E cadherin, Cueball, EGFR, JAK/STAT signaling components, as well as the heparan sulfate proteoglycan (HSPG) Terribly reduced optic lobes (Trol). Trol encodes the ortholog of mammalian HSPG Perlecan, a demonstrated FGF signaling cofactor. Here, we examine the role of Trol in Drosophila mesoderm migration and compare and contrast its role with that of Syndecan (Sdc), another HSPG previously implicated in this process. Embryos mutant for Trol or Sdc were obtained and analyzed. Our data support the view that both HSPGs function to support FGF-dependent processes in the early embryo as they share phenotypes with FGF mutants: Trol in terms of effects on mesoderm migration and caudal visceral mesoderm (CVM) migration and Sdc in terms of dorsal mesoderm specification. The differential roles uncovered for these two HSPGs suggest that HSPG cofactor choice may modify FGF-signaling outputs. PMID- 25538104 TI - Fexofenadine regulates nuclear factor-kappaB signaling and endoplasmic reticulum stress in intestinal epithelial cells and ameliorates acute and chronic colitis in mice. AB - The aim of this study was to evaluate the effect of fexofenadine on intestinal inflammation. HCT116 and COLO205 cells were pretreated with fexofenadine and then stimulated with tumor necrosis factor (TNF)-alpha. Interleukin (IL)-8 expression was determined by real-time reverse-transcription polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. DNA-binding activity of nuclear factor kappaB was assessed by electrophoretic mobility shift assay. The molecular markers of endoplasmic reticulum (ER) stress were evaluated by Western blot analysis and PCR. In the acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days with or without fexofenadine. IL-10(-/-) mice were used to evaluate the effect of fexofenadine on chronic colitis. Fexofenadine significantly inhibited the upregulated expression of IL-8 in HCT116 and COLO205 cells stimulated with TNF-alpha. Fexofenadine suppressed nuclear factor-kappaB DNA-binding activity. C/EBP homologous protein mRNA expression was enhanced in the presence of TNF-alpha, and it was dampened by pretreatment of fexofenadine. In addition, the induction of ER stress markers caspase-12 and p-eukaryotic initiation factor 2 (eIF2)-alpha was significantly suppressed by the pretreatment of fexofenadine. Administration of fexofenadine significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IkappaB kinase activation was significantly decreased in fexofenadine-pretreated mice. Finally, fexofenadine significantly reduced the severity of colitis and the immunoreactivity of caspase-12 and p-eIF2-alpha in IL-10(-/-) mice as compared with controls. These results suggest that fexofenadine is a potential therapeutic agent for the treatment of inflammatory bowel disease. PMID- 25538107 TI - Personal breathalysers may give false reassurance to drivers, research shows. PMID- 25538106 TI - Alteration patterns of brain glucose metabolism: comparisons of healthy controls, subjective memory impairment and mild cognitive impairment. AB - BACKGROUND: Some groups have focused on the detection and management of subjective memory impairment (SMI) as the stage that precedes mild cognitive impairment (MCI). However, there have been few clinical studies that have examined biomarkers of SMI to date. PURPOSE: To investigate the differences in glucose metabolism as a prodromal marker of dementia in patients with SMI, MCI, and healthy controls using brain F-18 fluoro-2-deoxyglucose positron emission tomography (FDG-PET). MATERIAL AND METHODS: Sixty-eight consecutive patients with SMI, 47 patients with MCI, and 42 age-matched healthy subjects were recruited. All subjects underwent FDG-PET and detailed neuropsychological testing. FDG-PET images were analyzed using the statistical parametric mapping (SPM) program. RESULTS: FDG-PET analysis showed glucose hypometabolism in the periventricular regions of patients with SMI and in the parietal, precentral frontal, and periventricular regions of patients with MCI compared with healthy controls. Interestingly, hypometabolism on FDG-PET was noted in the parietal and precentral frontal regions in MCI patients compared to SMI patients. CONCLUSION: The results suggest that hypometabolism in the periventricular regions as seen on FDG-PET may play a role as a predictive biomarker of pre-dementia, and the extension of reduced glucose metabolism into parietal regions likely reflects progression of cognitive deterioration. PMID- 25538105 TI - A novel carboline derivative inhibits nitric oxide formation in macrophages independent of effects on tumor necrosis factor alpha and interleukin-1beta expression. AB - Neuropathic pain is a maladaptive immune response to peripheral nerve injury that causes a chronic painful condition refractory to most analgesics. Nitric oxide (NO), which is produced by nitric oxide synthases (NOSs), has been implicated as a key factor in the pathogenesis of neuropathic pain. beta-Carbolines are a large group of natural and synthetic indole alkaloids, some of which block activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), a predominant transcriptional regulator of NOS expression. Here, we characterize the inhibitory effects of a novel 6-chloro-8-(glycinyl)-amino-beta-carboline (8 Gly carb) on NO formation and NF-kappaB activation in macrophages. 8-Gly carb was significantly more potent than the NOS inhibitor NG-nitro-L-arginine methyl ester in inhibiting constitutive and inducible NO formation in primary rat macrophages. 8-Gly carb interfered with NF-kappaB-mediated gene expression in differentiated THP1-XBlue cells, a human NF-kappaB reporter macrophage cell line, but only at concentrations severalfold higher than needed to significantly inhibit NO production. 8-Gly carb also had no effect on tumor necrosis factor alpha (TNFalpha)-induced phosphorylation of the p38 mitogen-activated protein kinase in differentiated THP1 cells, and did not inhibit lipopolysaccharide- or TNFalpha stimulated expression of TNFalpha and interleukin-1beta. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of NOS, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible NO formation independent of NF-kappaB activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain mediated by macrophage-derived NO without interfering with cytokine expression required for neural recovery following peripheral nerve injury. PMID- 25538108 TI - Producing patient-avatar identification in animation video information on spinal anesthesia by different narrative strategies. AB - Visual approaches to health information reduce complexity and may bridge challenges in health literacy. But the mechanisms and meanings of using animated video in communication with patients undergoing surgery are not well described. By comparing two versions of a two-dimensional animated video on spinal anesthesia, this study tested the patient-avatar identification within two different narrative models. To explore the perspectives of total hip arthroplasty, we employed qualitative methods of interviews and ethnographic observation. The animated presentation of the spinal anesthesia procedure was immediately recognized by all participants as reflecting their experience of the procedure independent of the narrative form. The avatar gender did not affect this identification. We found no preference for either narrative form. This study supports the potential of animation video in health informatics as a didactic model for qualifying patient behavior. Animation video creates a high degree of identification that may work to reduce pre-surgical anxiety. PMID- 25538109 TI - Are carbon and nitrogen exchange between fungi and the orchid Goodyera repens affected by irradiance? AB - BACKGROUND AND AIMS: The green orchid Goodyera repens has been shown to transfer carbon to its mycorrhizal partner, and this flux may therefore be affected by light availability. This study aimed to test whether the C and N exchange between plant and fungus is dependent on light availability, and in addition addressed the question of whether flowering and/or fruiting individuals of G. repens compensate for changes in leaf chlorophyll concentration with changes in C and N flows from fungus to plant. METHODS: The natural abundances of stable isotopes of plant C and N were used to infer changes in fluxes between orchid and fungus across natural gradients of irradiance at five sites. Mycorrhizal fungi in the roots of G. repens were identified by molecular analyses. Chlorophyll concentrations in the leaves of the orchid and of reference plants were measured directly in the field. KEY RESULTS: Leaf delta(13)C values of G. repens responded to changes in light availability in a similar manner to autotrophic reference plants, and different mycorrhizal fungal associations also did not affect the isotope abundance patterns of the orchid. Flowering/fruiting individuals had lower leaf total N and chlorophyll concentrations, which is most probably explained by N investments to form flowers, seeds and shoot. CONCLUSIONS: The results indicate that mycorrhizal physiology is relatively fixed in G. repens, and changes in the amount and direction of C flow between plant and fungus were not observed to depend on light availability. The orchid may instead react to low light sites through increased clonal growth. The orchid does not compensate for low leaf total N and chlorophyll concentrations by using a (13)C- and (15)N enriched fungal source. PMID- 25538110 TI - Arachis batizocoi: a study of its relationship to cultivated peanut (A. hypogaea) and its potential for introgression of wild genes into the peanut crop using induced allotetraploids. AB - BACKGROUND AND AIMS: Arachis batizocoi is a wild relative of cultivated peanut (A. hypogaea), an allotetraploid with an AABB genome. Arachis batizocoi was once considered the ancestral donor of the peanut B genome, but cytogenetics and DNA phylogenies have indicated a new genome classification, 'K'. These observations seem inconsistent with genetic studies and breeding that have shown that A. batizocoi can behave as a B genome. METHODS: The genetic behaviour, genome composition and phylogenetic position of A. batizocoi were studied using controlled hybridizations, induced tetraploidy, whole-genome in situ fluorescent hybridization (GISH) and molecular phylogenetics. KEY RESULTS: Sterile diploid hybrids containing AK genomes were obtained using A. batizocoi and the A genome species A. duranensis, A. stenosperma, A. correntina or A. villosa. From these, three types of AAKK allotetraploids were obtained, each in multiple independent polyploidy events. Induced allotetraploids were vigorous and fertile, and were hybridized to A. hypogaea to produce F1 hybrids. Even with the same parental combination, fertility of these F1 hybrids varied greatly, suggesting the influence of stochastic genetic or epigenetic events. Interestingly, hybrids with A. hypogaea ssp. hypogaea were significantly more fertile than those with the subspecies fastigiata. GISH in cultivated * induced allotetraploids hybrids (harbouring AABK genomes) and a molecular phylogeny using 16 intron sequences showed that the K genome is distinct, but more closely related to the B than to the A genome. CONCLUSIONS: The K genome of A. batizocoi is more related to B than to the A genome, but is distinct. As such, when incorporated in an induced allotetraploid (AAKK) it can behave as a B genome in crosses with peanut. However, the fertility of hybrids and their progeny depends upon the compatibility of the A genome interactions. The genetic distinctness of A. batizocoi makes it an important source of allelic diversity in itself, especially in crosses involving A. hypogaea ssp. hypogaea. PMID- 25538111 TI - Aphid-repellent pheromone E-beta-farnesene is generated in transgenic Arabidopsis thaliana over-expressing farnesyl diphosphate synthase2. AB - BACKGROUND AND AIMS: Plant-synthesized sesquiterpenes play a pivotal role in chemotactic interactions with insects. Biosynthesis of functionally diverse sesquiterpenes is dependent on the availability of a pool of the precursor farnesyldiphosphate (FDP). In Arabidopsis thaliana, FPS2, encoding cytosolic farnesyldiphosphate synthase, is implicated in the synthesis of cytosolic FDP, but it is not known whether enhanced levels of FDP have a commensurate effect on sesquiterpene-mediated defence responses. This study examined transgenic arabidopsis plants generated to over-express FPS2 in order to determine if any effects could be observed in the response of aphids, Myzus persicae. METHODS: Transgenic arabidopsis plants were generated to over-express FPS2 to produce FPS2 in either the cytosol or the chloroplasts. Morphochemical analyses of the transgenic plants were carried out to detremine growth responses of roots and shoots, and for GC-MS profiling of sesquiterpenes. Aphid response to hyrdo distillate extracts and head-space volatiles from transgenic plants was assessed using a bioassay. KEY RESULTS: Either over-expression of FPS2 in the cytosol or targetting of its translated product to chlorplasts resulted in stimulatory growth responses of transgenic arabidopsis at early and late developmental stages. GC-MS analysis of hydro-distillate extracts from aerial parts of the plants revealed biosynthesis of several novel sesquiterpenes, including E-beta farnesene, an alarm pheromone of aphids. Both entrapped volatiles and hydro distillate extracts of the transgenic leaves triggered agitation in aphids, which was related to both time and dose of exposure. CONCLUSIONS: Over-expression of FPS2 in the cytosol and targeting of its translated product to chloroplasts in arabidopsis led to synthesis of several novel sesquiterpenes, including E-beta farnesene, and induced alarm responses in M. persicae. The results suggest a potential for engineering aphid-resistant strains of arabidopsis. PMID- 25538113 TI - Predicting species' tolerance to salinity and alkalinity using distribution data and geochemical modelling: a case study using Australian grasses. AB - BACKGROUND AND AIMS: Salt tolerance has evolved many times independently in different plant groups. One possible explanation for this pattern is that it builds upon a general suite of stress-tolerance traits. If this is the case, then we might expect a correlation between salt tolerance and other tolerances to different environmental stresses. This association has been hypothesized for salt and alkalinity tolerance. However, a major limitation in investigating large scale patterns of these tolerances is that lists of known tolerant species are incomplete. This study explores whether species' salt and alkalinity tolerance can be predicted using geochemical modelling for Australian grasses. The correlation between taxa found in conditions of high predicted salinity and alkalinity is then assessed. METHODS: Extensive occurrence data for Australian grasses is used together with geochemical modelling to predict values of pH and electrical conductivity to which species are exposed in their natural distributions. Using parametric and phylogeny-corrected tests, the geochemical predictions are evaluated using a list of known halophytes as a control, and it is determined whether taxa that occur in conditions of high predicted salinity are also found in conditions of high predicted alkalinity. KEY RESULTS: It is shown that genera containing known halophytes have higher predicted salinity conditions than those not containing known halophytes. Additionally, taxa occurring in high predicted salinity tend to also occur in high predicted alkalinity. CONCLUSIONS: Geochemical modelling using species' occurrence data is a potentially useful approach to predict species' relative natural tolerance to challenging environmental conditions. The findings also demonstrate a correlation between salinity tolerance and alkalinity tolerance. Further investigations can consider the phylogenetic distribution of specific traits involved in these ecophysiological strategies, ideally by incorporating more complete, finer-scale geochemical information, as well as laboratory experiments. PMID- 25538112 TI - Zinc induces distinct changes in the metabolism of reactive oxygen and nitrogen species (ROS and RNS) in the roots of two Brassica species with different sensitivity to zinc stress. AB - BACKGROUND AND AIMS: Zinc (Zn) is an essential micronutrient naturally present in soils, but anthropogenic activities can lead to accumulation in the environment and resulting damage to plants. Heavy metals such as Zn can induce oxidative stress and the generation of reactive oxygen and nitrogen species (ROS and RNS), which can reduce growth and yield in crop plants. This study assesses the interplay of these two families of molecules in order to evaluate the responses in roots of two Brassica species under high concentrations of Zn. METHODS: Nine day-old hydroponically grown Brassica juncea (Indian mustard) and B. napus (oilseed rape) seedlings were treated with ZnSO4 (0, 50, 150 and 300 um) for 7 d. Stress intensity was assessed through analyses of cell wall damage and cell viability. Biochemical and cellular techniques were used to measure key components of the metabolism of ROS and RNS including lipid peroxidation, enzymatic antioxidants, protein nitration and content of superoxide radical ([Formula: see text]), nitric oxide (NO) and peroxynitrite (ONOO(-)). KEY RESULTS: Analysis of morphological root damage and alterations of microelement homeostasis indicate that B. juncea is more tolerant to Zn stress than B. napus. ROS and RNS parameters suggest that the oxidative components are predominant compared with the nitrosative components in the root system of both species. CONCLUSIONS: The results indicate a clear relationship between ROS and RNS metabolism as a mechanism of response against stress caused by an excess of Zn. The oxidative stress components seem to be more dominant than the elements of the nitrosative stress in the root system of these two Brassica species. PMID- 25538114 TI - Variation in pollen limitation and floral parasitism across a mating system transition in a Pacific coastal dune plant: evolutionary causes or ecological consequences? AB - BACKGROUND AND AIMS: Evolutionary transitions from outcrossing to self fertilization are thought to occur because selfing provides reproductive assurance when pollinators or mates are scarce, but they could also occur via selection to reduce floral vulnerability to herbivores. This study investigated geographic covariation between floral morphology, fruit set, pollen limitation and florivory across the geographic range of Camissoniopsis cheiranthifolia, a Pacific coastal dune endemic that varies strikingly in flower size and mating system. METHODS: Fruit set was quantified in 75 populations, and in 41 of these floral herbivory by larvae of a specialized moth (Mompha sp.) that consumes anthers in developing buds was also quantified. Experimental pollen supplementation was performed to quantify pollen limitation in three large flowered, outcrossing and two small-flowered, selfing populations. These parameters were also compared between large- and small-flowered phenotypes within three mixed populations. KEY RESULTS: Fruit set was much lower in large-flowered populations, and also much lower among large- than small-flowered plants within populations. Pollen supplementation increased per flower seed production in large flowered but not small-flowered populations, but fruit set was not pollen limited. Hence inadequate pollination cannot account for the low fruit set of large-flowered plants. Floral herbivory was much more frequent in large-flowered populations and correlated negatively with fruit set. However, florivores did not preferentially attack large-flowered plants in three large-flowered populations or in two of three mixed populations. CONCLUSIONS: Selfing alleviated pollen limitation of seeds per fruit, but florivory better explains the marked variation in fruit set. Although florivory was more frequent in large-flowered populations, large-flowered individuals were not generally more vulnerable within populations. Rather than a causative selective factor, reduced florivory in small-flowered, selfing populations is probably an ecological consequence of mating system differentiation, with potentially significant effects on population demography and biotic interactions. PMID- 25538115 TI - A reference genetic linkage map of apomictic Hieracium species based on expressed markers derived from developing ovule transcripts. AB - BACKGROUND AND AIMS: Apomixis in plants generates clonal progeny with a maternal genotype through asexual seed formation. Hieracium subgenus Pilosella (Asteraceae) contains polyploid, highly heterozygous apomictic and sexual species. Within apomictic Hieracium, dominant genetic loci independently regulate the qualitative developmental components of apomixis. In H. praealtum, LOSS OF APOMEIOSIS (LOA) enables formation of embryo sacs without meiosis and LOSS OF PARTHENOGENESIS (LOP) enables fertilization-independent seed formation. A locus required for fertilization-independent endosperm formation (AutE) has been identified in H. piloselloides. Additional quantitative loci appear to influence the penetrance of the qualitative loci, although the controlling genes remain unknown. This study aimed to develop the first genetic linkage maps for sexual and apomictic Hieracium species using simple sequence repeat (SSR) markers derived from expressed transcripts within the developing ovaries. METHODS: RNA from microdissected Hieracium ovule cell types and ovaries was sequenced and SSRs were identified. Two different F1 mapping populations were created to overcome difficulties associated with genome complexity and asexual reproduction. SSR markers were analysed within each mapping population to generate draft linkage maps for apomictic and sexual Hieracium species. KEY RESULTS: A collection of 14 684 Hieracium expressed SSR markers were developed and linkage maps were constructed for Hieracium species using a subset of the SSR markers. Both the LOA and LOP loci were successfully assigned to linkage groups; however, AutE could not be mapped using the current populations. Comparisons with lettuce (Lactuca sativa) revealed partial macrosynteny between the two Asteraceae species. CONCLUSIONS: A collection of SSR markers and draft linkage maps were developed for two apomictic and one sexual Hieracium species. These maps will support cloning of controlling genes at LOA and LOP loci in Hieracium and should also assist with identification of quantitative loci that affect the expressivity of apomixis. Future work will focus on mapping AutE using alternative populations. PMID- 25538116 TI - Pore size regulates operating stomatal conductance, while stomatal densities drive the partitioning of conductance between leaf sides. AB - BACKGROUND AND AIMS: Leaf gas exchange is influenced by stomatal size, density, distribution between the leaf adaxial and abaxial sides, as well as by pore dimensions. This study aims to quantify which of these traits mainly underlie genetic differences in operating stomatal conductance (gs) and addresses possible links between anatomical traits and regulation of pore width. METHODS: Stomatal responsiveness to desiccation, gs-related anatomical traits of each leaf side and estimated gs (based on these traits) were determined for 54 introgression lines (ILs) generated by introgressing segments of Solanum pennelli into the S. lycopersicum 'M82'. A quantitative trait locus (QTL) analysis for stomatal traits was also performed. KEY RESULTS: A wide genetic variation in stomatal responsiveness to desiccation was observed, a large part of which was explained by stomatal length. Operating gs ranged over a factor of five between ILs. The pore area per stomatal area varied 8-fold among ILs (2-16 %), and was the main determinant of differences in operating gs between ILs. Operating gs was primarily positioned on the abaxial surface (60-83 %), due to higher abaxial stomatal density and, secondarily, to larger abaxial pore area. An analysis revealed 64 QTLs for stomatal traits in the ILs, most of which were in the direction of S. pennellii. CONCLUSIONS: The data indicate that operating and maximum gs of non-stressed leaves maintained under stable conditions deviate considerably (by 45-91 %), because stomatal size inadequately reflects operating pore area (R(2) = 0.46). Furthermore, it was found that variation between ILs in both stomatal sensitivity to desiccation and operating gs is associated with features of individual stoma. In contrast, genotypic variation in gs partitioning depends on the distribution of stomata between the leaf adaxial and abaxial epidermis. PMID- 25538118 TI - Intimate Partner Violence Between Male Iraq and Afghanistan Veterans and Their Female Partners Who Seek Couples Therapy. AB - The current study has three aims: (1) to describe the frequency, gender differences, and agreement in couples' reports of male-to-female and female-to male intimate partner violence (IPV) reported by male veterans and their female partners who were seeking couples therapy; (2) to describe the pattern of violence reported by these couples (e.g., one-sided, mutual) and determine if frequency of violence varied based on patterns; and (3) to examine whether frequency of violence or pattern of violence were associated with veteran diagnosis of posttraumatic stress disorder (PTSD). One hundred heterosexual couples (male Iraq/Afghanistan veteran, female civilian) seeking couples therapy at a Veterans Affairs (VA) clinic completed self-report measures of violence in their relationship. Almost all couples reported verbal aggression. Men reported perpetrating more frequent sexual coercion, and women reported perpetrating more frequent physical aggression. Correspondence in partners' reports of violence varied based on type of violence from high correspondence on verbal aggression to low correspondence on sexual coercion. Three patterns of violence were identified: verbally aggressive (n = 45), one-sided physically aggressive (n = 27), and mutually physically aggressive (n = 26). Mutually physically aggressive couples generally reported the most frequent violence. Frequency and pattern of violence were not associated with veteran diagnosis of PTSD. Findings underscore the need for clinicians to assess both partners for violence perpetration and the need for effective prevention strategies and treatments for IPV among veterans. PMID- 25538117 TI - Expansion of first-in-class drug candidates that sequester toxic all-trans retinal and prevent light-induced retinal degeneration. AB - All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all trans-retinal by drugs containing a primary amine group. We identified the first in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation. PMID- 25538119 TI - College Students' Definitions of Intimate Partner Violence: A Comparative Study of Three Chinese Societies. AB - Although a large number of studies have been conducted worldwide to examine various aspects of intimate partner violence (IPV), comparative study of people's views on such violence in Chinese societies has been scarce. Using survey data collected from more than 850 college students in China, Hong Kong, and Taiwan, this study specifically assessed the impact of attitudes toward gender role and violence, personal and vicarious experience, demographic characteristics, and locality on students' definitions of IPV. The Taiwanese students were most likely to define a broader range of abusive behavior as IPV, followed by Hong Kong and Beijing students. Gender role and violence attitudes appeared to be most important predictors of IPV definitions. College students who supported the notion of male dominance were more likely to have a narrower definition of IPV, whereas those who viewed domestic violence as crime were more inclined to have a broader definition of IPV. Implications for future research and policy were discussed. PMID- 25538120 TI - Longitudinal Relationships of Social Reactions, PTSD, and Revictimization in Sexual Assault Survivors. AB - Sexual assault survivors receive various positive and negative social reactions to assault disclosures, yet little is known about the directionality of associations of social reactions to posttraumatic stress disorder (PTSD) symptoms over time. Data from a large, diverse sample of women who had experienced adult sexual assault was analyzed with hierarchical linear modeling (HLM) to examine how negative and positive reactions relate to PTSD symptoms over 3 years and to test the hypothesis that the relationship between negative social reactions and PTSD symptoms is reciprocal. We found that, as predicted, social reactions predicted subsequent PTSD symptoms, and in turn PTSD symptoms predicted subsequent social reactions. We also investigated the role of sexual revictimization by comparing women who suffered (vs. not) additional sexual victimization during the course of our study. Revictimized women had greater PTSD symptoms and more negative social reactions, but associations of social reactions with PTSD symptoms did not vary according to revictimization status. Implications for practice and suggestions for future research are discussed. PMID- 25538121 TI - The Effects of Cumulative Violence Clusters on Young Mothers' School Participation: Examining Attention and Behavior Problems as Mediators. AB - Using a cluster analysis approach with a sample of 205 young mothers recruited from community sites in an urban Midwestern setting, we examined the effects of cumulative violence exposure (community violence exposure, witnessing intimate partner violence, physical abuse by a caregiver, and sexual victimization, all with onset prior to age 13) on school participation, as mediated by attention and behavior problems in school. We identified five clusters of cumulative exposure, and found that the HiAll cluster (high levels of exposure to all four types) consistently fared the worst, with significantly higher attention and behavior problems, and lower school participation, in comparison with the LoAll cluster (low levels of exposure to all types). Behavior problems were a significant mediator of the effects of cumulative violence exposure on school participation, but attention problems were not. PMID- 25538122 TI - Backlash for Breaking Racial and Ethnic Breaking Stereotypes: Adolescent School Victimization Across Contexts. AB - This research examines if and how social and cultural stereotypes insulate or aggravate the risk for adolescent victimization and partially explain racial and ethnic disparities with being a victim of violence at school. Analyses that draw on the Educational Longitudinal Study of 2002 and use multilevel analytical techniques suggest important results. Most notably, increased educational achievement, academic involvement, and having White American friendships are potential victimization risk factors for Black/African American and Latino American adolescents at urban and/or suburban schools. In addition to discussing the findings, this study underscores the importance of investigating the complexities associated with race and ethnicity when addressing adolescent victimization. PMID- 25538124 TI - What Atul Gawande teaches us about dying. PMID- 25538123 TI - Negotiating access to a diagnosis of dementia: Implications for policies in health and social care. AB - The 'Pathways to Diagnosis' study captured the experience of the prediagnosis period of Alzheimer's disease and related dementias through indepth interviews with 29 persons with dementia and 34 of their family caregivers across four sites: anglophones in Calgary, francophones in Ottawa, Chinese-Canadians in Greater Vancouver and Indo-Canadians in Toronto. In this cross-site analysis, we use the 'Candidacy' framework to comprehensively explore the challenges to securing a diagnosis of dementia in Canada and to develop relevant health and social policy. Candidacy views eligibility for appropriate medical care as a process of joint negotiation between individuals and health services, which can be understood relative to seven dimensions: identification of need, navigation, appearances at services, adjudication by providers, acceptance of/resistance to offers, permeability of services and local conditions. Interviewees experienced challenges relative to each of the seven dimensions and these varied in form and emphasis across the four ethno-linguistic groups. PMID- 25538125 TI - Venous thromboembolism in orthopaedic trauma. AB - Patients who sustain orthopaedic trauma are at risk for developing deep venous thrombosis and symptomatic pulmonary emboli. The prevention of venous thromboembolism has moved to the forefront of patient safety initiatives, resulting in the formation of various guidelines to assist the practitioner. Recommendations for venous thromboembolism prophylaxis in the orthopaedic trauma patient exist, but there is insufficient evidence in the literature to make strong recommendations regarding type and duration of prophylaxis. The associated morbidity of chemical anticoagulants used in the orthopaedic trauma patient must also be taken into consideration, specifically the increased risk of bleeding. Mechanical prophylaxis is used in place of, or in addition to, these medications in certain situations. New, potentially superior anticoagulants have been developed but are still understudied. Larger studies are needed to further define the type and duration of deep venous thrombosis prophylaxis in the orthopaedic trauma patient. PMID- 25538127 TI - A comparison of the lateral decubitus and beach-chair positions for shoulder surgery: advantages and complications. AB - Arthroscopic or open shoulder surgery can be performed using the lateral decubitus or beach-chair position. Advantages of the lateral decubitus position include better visualization and instrument access for certain procedures and decreased risk for cerebral hypoperfusion. Complications associated with this position include traction injuries, resulting in neurapraxia, thromboembolic events, difficulty with airway management, and the potential need to convert to an anterior open approach. One advantage of the beach-chair position is easier setup from a supine to upright position, which allows the surgeon the option to convert to an open procedure if necessary. Although rare, patients in this position may experience cerebral hypoperfusion and complications that range from cranial nerve injury to infarction. Other complications related to this position include cervical traction neurapraxia, blindness, and cardiac and embolic events. The surgeon must be cognizant of the complications associated with both positions and take extra care in the initial patient setup and coordination with the anesthesiologist to minimize the risk of complications and morbidity. PMID- 25538126 TI - Mimickers of lumbar radiculopathy. AB - Orthopaedic surgeons frequently treat patients who report pain that radiates from the back into the lower extremity. Although the most common etiology is either a herniated disk or spinal stenosis, a myriad of pathologies can mimic the symptoms of radiculopathy, resulting in differences in the clinical presentation and the workup. Therefore, the clinician must be able to distinguish the signs and symptoms of lumbar radiculopathy from pathologies that may have a similar presentation. Being cognizant of these other possible conditions enables the physician to consider a breadth of alternative diagnoses when a patient presents with radiating lower extremity pain. PMID- 25538128 TI - Methicillin-resistant staphylococcus aureus bone and joint infections in children. AB - Methicillin-resistant Staphylococcus aureus has been a clinically significant pathogen in orthopaedics for more than a decade. Research shows that these infections are more virulent and that treatment requires greater use of hospital resources. A multidisciplinary approach involving emergency department physicians, radiologists, interventional radiologists, MRI technicians, pediatricians, infectious disease specialists, anesthesiologists, and orthopaedic surgeons is necessary to optimize outcomes and minimize costs. Early use of MRI helps delineate the extent of infection, aids in the consideration of surgery, and provides valuable information for surgical planning. Healthcare providers need to stay vigilant during the course of the disease to detect other sites of infection or complications of methicillin-resistant S aureus, such as deep vein thrombosis and septic pulmonary emboli. Patients with infections near growth centers require long-term monitoring to ensure the absence of growth disturbances. Physicians should help educate patients and families on prevention strategies and be aware of guidelines for students to return to school and athletes to return to play. PMID- 25538129 TI - Management of metastatic cervical spine tumors. AB - The skeletal system is the third most common site of metastases after the lung and liver. Within the skeletal system, the vertebral column is the most common site of metastases, and 8% to 15% of vertebral metastases are in the cervical spine, consisting, anatomically and biomechanically, of the occipitocervical junction, subaxial spine, and cervicothoracic junction. The vertebral body is more commonly affected than the posterior elements. Nonsurgical management techniques include radiation therapy (stereotactic and conventional), bracing, and chemotherapy. Surgical techniques include percutaneous methods, such as vertebroplasty, and palliative methods, such as decompression and stabilization. Surgical approach depends on the location of the tumor and the goals of the surgery. Appropriate patient selection can lead to successful surgical outcomes by restoring spinal stability and improving quality of life. PMID- 25538130 TI - Human and other mammalian bite injuries of the hand: evaluation and management. AB - The hand is the most common site for bite injuries. Because of specific characteristics of hand anatomy, bite mechanics, and organisms found in human and animal saliva, even small wounds can lead to aggressive infections. Failure to recognize and treat hand bites can result in significant morbidity. Human and animal bites most commonly lead to polymicrobial bacterial infections with a mixture of aerobic and anaerobic organisms. Pasteurella species are commonly found in dog and cat bite wounds, and Eikenella is characteristic of human wounds. Staphylococcus, Streptococcus, and anaerobic bacterial species are common to all mammals. Although public health measures in developed countries have been highly effective at reducing rabies transmission, dog bites remain the most common source of rabies infection worldwide. Human bites can transmit HIV, hepatitis B, or hepatitis C, especially when contaminated blood is exposed to an open wound. Appropriate management of any mammal bite requires recognition, early wound cleansing, evaluation of injured structures, and infection prophylaxis. Structural repair is performed as indicated by the severity and contamination of the injury, and wounds may require delayed closure. Wound infections typically require debridement, empiric antibiotics, and delayed repair or reconstruction. PMID- 25538131 TI - Entrapment neuropathy about the foot and ankle: an update. AB - Occurrences of entrapment neuropathies of the lower extremity are relatively infrequent; therefore, these conditions may be underappreciated and difficult to diagnose. Understanding the anatomy of the peripheral nerves and their potential entrapment sites is essential. A detailed physical examination and judicious use of imaging modalities are also vital when establishing a diagnosis. Once an accurate diagnosis is obtained, treatment is aimed at reducing external pressure, minimizing inflammation, correcting any causative foot and ankle deformities, and ultimately releasing any constrictive tissues. PMID- 25538132 TI - Wnt signaling: an emerging target for bone regeneration. PMID- 25538135 TI - Poverty, development and cardiovascular trials: more questions than answers? PMID- 25538134 TI - Impact of Human Development Index on the profile and outcomes of patients with acute coronary syndrome. AB - OBJECTIVE: To study the impact of national economic and human development status on patient profiles and outcomes in the setting of acute coronary syndrome (ACS). METHODS: We conducted a retrospective analysis of the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial (TRILOGY ACS) population (51 countries; 9301 patients). Outcome measures compared baseline characteristics and clinical outcomes through 30 months by 2010 country-level United Nations Human Development Indices (HDIs) and per-capita gross national income. RESULTS: TRILOGY ACS enrolled 3659 patients from 27 very-high HDI countries, 3744 from 18 high-HDI countries and 1898 from 6 medium-HDI countries. Baseline characteristics of groups varied significantly, with the medium-HDI group having a lower mean age (63.0 years, vs 65.0 and 68.0 years for high-HDI and very-high HDI, respectively; p<0.001), lower baseline Global Registry of Acute Coronary Events risk score and lower rate of non-ST segment elevation myocardial infarction (58.0%, vs 62.2% and 83.9% among high-HDI and very-high HDI, respectively). Medium-HDI and high-HDI patients had lower unadjusted 30-month rates for the composite of cardiovascular death/myocardial infarction/stroke (17.6%, 16.9% and 23.1% for medium-HDI, high-HDI and very-high HDI, respectively); this difference disappeared after adjusting for baseline characteristics. Adjusted HRs for the composite endpoint were lower in lower income/middle-income countries vs upper-income/middle-income (0.791(95% CI 0.632 to 0.990)) and high-income countries (0.756 (95% CI 0.616 to 0.928)), with differences largely attributable to myocardial infarction rates. CONCLUSIONS: Clinical patient profiles differed substantially by country HDI groupings. Lower unadjusted event rates in medium-HDI countries may be explained by younger age and lower comorbidity burden among these countries' patients. This heterogeneity in patient recruitment across country HDI groupings may have important implications for future global ACS trial design. TRIAL REGISTRATION NUMBER: NCT00699998. PMID- 25538133 TI - WWOX: a fragile tumor suppressor. AB - WWOX, the WW domain-containing oxidoreductase gene at chromosome region 16q23.3 q24.1, spanning chromosomal fragile site FRA16D, encodes the 46 kDa Wwox protein, a tumor suppressor that is lost or reduced in expression in a wide variety of cancers, including breast, prostate, ovarian, and lung. The function of Wwox as a tumor suppressor implies that it serves a function in the prevention of carcinogenesis. Indeed, in vitro studies show that Wwox protein interacts with many binding partners to regulate cellular apoptosis, proliferation, and/or maturation. It has been reported that newborn Wwox knockout mice exhibit nascent osteosarcomas while Wwox(+/-) mice exhibit increased incidence of spontaneous and induced tumors. Furthermore, absence or reduction of Wwox expression in mouse xenograft models results in increased tumorigenesis, which can be rescued by Wwox re-expression, though there is not universal agreement among investigators regarding the role of Wwox loss in these experimental models. Despite this proposed tumor suppressor function, the overlap of the human WWOX locus with FRA16D sensitizes the gene to protein-inactivating deletions caused by replication stress. The high frequency of deletions within the WWOX locus in cancers of various types, without the hallmark protein inactivation-associated mutations of "classical" tumor suppressors, has led to the proposal that WWOX deletions in cancers are passenger events that occur in early cancer progenitor cells due to fragility of the genetic locus, rather than driver events which provide the cancer cell a selective advantage. Recently, a proposed epigenetic cause of chromosomal fragility has suggested a novel mechanism for early fragile site instability and has implications regarding the involvement of tumor suppressor genes at chromosomal fragile sites in cancer. In this review, we provide an overview of the evidence for WWOX as a tumor suppressor gene and put this into the context of fragility associated with the FRA16D locus. PMID- 25538136 TI - Viewpoint: adaptation of vascular surgery in the interventional era. PMID- 25538137 TI - Viewpoint: transitions in cardiac surgery and interventional cardiology...team mates or rivals? PMID- 25538138 TI - Loss of growth homeostasis by genetic decoupling of cell division from biomass growth: implication for size control mechanisms. AB - Growing cells adjust their division time with biomass accumulation to maintain growth homeostasis. Size control mechanisms, such as the size checkpoint, provide an inherent coupling of growth and division by gating certain cell cycle transitions based on cell size. We describe genetic manipulations that decouple cell division from cell size, leading to the loss of growth homeostasis, with cells becoming progressively smaller or progressively larger until arresting. This was achieved by modulating glucose influx independently of external glucose. Division rate followed glucose influx, while volume growth was largely defined by external glucose. Therefore, the coordination of size and division observed in wild-type cells reflects tuning of two parallel processes, which is only refined by an inherent feedback-dependent coupling. We present a class of size control models explaining the observed breakdowns of growth homeostasis. PMID- 25538139 TI - Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation. AB - Ribosome profiling data report on the distribution of translating ribosomes, at steady-state, with codon-level resolution. We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast. We show that neither elongation rate nor translational efficiency is improved by experimental manipulation of the abundance or body sequence of the rare AGG tRNA. Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start. This suggests that correlation between codon bias and efficiency arises as selection for codons to utilize translation machinery efficiently in highly translated genes. We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation. PMID- 25538141 TI - Coming out during adolescence: Perceived parents' reactions and internalized sexual stigma. AB - Disclosing sexual orientation to parents is a challenging developmental task for lesbian and gay adolescents. The aim of the study is to investigate parental negative reaction to coming out, which is associated with high levels of internalized sexual stigma and psychological problems. Participants' perceptions of their parents' reactions, age at coming out, gender, parental political orientation and religiosity, family functioning, and internalized sexual stigma were assessed in 150 Italian homosexual adolescents. Findings confirm that negative parental reactions are connected to poor family functioning and strong beliefs in traditional values. Path analysis results identified that negative reaction to coming out mediates the effect between a more rigid family functioning and internalized sexual stigma. Implications for clinical and social fields are discussed. PMID- 25538142 TI - Prevalence of chest symptoms amongst brick kiln migrant workers and care seeking behaviour: a study from South India. AB - BACKGROUND: Early detection and treatment of tuberculosis (TB) have been key principles of TB control. However, this can be a challenge with 'hard to reach' populations such as migrants. Brick kiln workers are one such group of migrants who are exposed to smoke, heat and dust from brick kilns which are one of the major causes of respiratory illnesses. METHODOLOGY: A cross-sectional community based study was carried out in Thiruvallur, Tamil Nadu, South India, from August 2011 to June 2012. A total of 4002 individuals from 55 brick kiln chambers were interviewed to determine the prevalence of chest symptoms and care seeking behaviour patterns. RESULTS: Three hundred and seventy-seven (9.4%) chest symptomatics were identified. The most significant variables associated with chest symptoms were illiteracy, alcohol abuse and heavy smoking. Of the chest symptomatics identified, 50.4% took action to get relief from their symptoms. The duration of over 6-month stay in the chamber was significantly associated with taking action (OR, 5.5, 95% CI: 2.3, 13.3). CONCLUSIONS: The TB control programme needs to further explore how to extend its services to such 'hard to reach' groups. Active case finding to ensure early diagnosis and treatment initiation amongst such groups needs consideration. PMID- 25538140 TI - ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma. AB - Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach, we performed two parallel shRNA screens using a kinome library to identify genes whose inhibition sensitizes to BRAF or ERK inhibitor treatment. By integrating our functional genomic and (phospho)proteomic data, we identified ROCK1 as a potential drug target for BRAF mutant melanoma. ROCK1 silencing increased melanoma cell elimination when combined with BRAF or ERK inhibitor treatment. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro. These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies. PMID- 25538143 TI - Sedentary behavior and prevalent diabetes in Non-Latino Whites, Non-Latino Blacks and Latinos: findings from the National Health Interview Survey. AB - BACKGROUND: Sedentary behavior is associated with type II diabetes, though little is known about prevalence of this behavior across racial/ethnic groups or how it may contribute to disparities in diabetes prevalence. In this study, we examined the association between sedentary behavior and diabetes in a diverse data set, and explored whether differences in sedentary behavior across racial/ethnic groups could contribute to disparities in diabetes. METHODS: Participants were 27 141 adults from the 2010 US National Health Interview Survey. Logistic regression was used to assess associations between self-reported, non-occupational sitting time, race/ethnicity and physician diagnosis of type II diabetes. RESULTS: In fully adjusted models, each hour of daily sitting was associated with 4% increased odds of diabetes (P < 0.01). Odds of diabetes were nearly double in Latinos (odds ratio [OR] = 1.83, confidence interval [CI] = 1.59-2.13) and Blacks (OR = 1.83, CI = 1.59-2.11) after adjusting for demographics and lifestyle factors. However, Blacks reported only slightly more sitting than Whites, and Latinos reported significantly less. Further adjustment for sitting hours in multivariate models did not attenuate disparities and slightly increased odds for Latinos (OR = 2.03, CI = 1.74-2.36). CONCLUSIONS: Sitting appears to be an independent risk factor for diabetes across racial/ethnic groups, though it does not appear to account for disparities in diabetes. PMID- 25538144 TI - What is the impact of reporting guidelines on Public Health journals in Europe? The case of STROBE, CONSORT and PRISMA. AB - BACKGROUND: The aim was to evaluate the use of PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), CONSORT (Consolidated Standards of Reporting Trials) and STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) methods in reviews, clinical trials and observational studies, respectively, which were published in European journals within the field of Public Health (PH). METHODS: Papers published between 2010 and 2013 in seven PH journals were evaluated. The presence of the words PRISMA, STROBE and CONSORT was considered in the search criteria. RESULTS: In total, 2355 of 3456 retrieved articles were included: 1.5% appeared to follow the guidelines. The boundaries within which the criteria were applied are 0-100% for CONSORT, 0-0.6% for STROBE and 0-37% for PRISMA. CONCLUSIONS: A strong heterogeneity in the application of guideline statements was observed. A common agreement among journals regarding research-reporting methodologies could improve the quality of PH research publishing. PMID- 25538145 TI - Opportunities for reducing morbidity and mortality due to leading cancers in a developing country. AB - BACKGROUND: Malignancies are a leading cause of chronic non-communicable disease deaths in Jamaica. However, little or no data is available on integration of cancer screening guidelines in clinics. METHODS: A cross-sectional survey of 88 consecutive patients with diabetes mellitus (DM) and/or hypertension (HTN) was conducted at major health centers in Jamaica between September and December 2011. RESULTS: Eighty percent respondents were women; 20% were men. The mean age was 57 years old. Forty persons (45.5%) had high cholesterol, 62 (71%) had DM and 62 (71%) had HTN. Of 66 women, 27% reported never having a pap smear and 66% had no pap smear within the last 12 months. 49% women over 40 years never had a mammogram and 74% did not have a mammogram in the last 12 months. Among men over 40 years old, at least 25% never had a prostate examination and 19% never had a prostate-specific antigen blood test. Most participants (>90%) received counseling about diet and exercise, but self-reported compliance with recommendations was low. CONCLUSIONS: Cancer screening among chronic disease patients is suboptimal in our population. Improved implementation of guidelines for cancer in chronic disease clinics have the potential to impact on morbidity and mortality. PMID- 25538146 TI - Authors' reply to comments made about our article 'Food for thought'. PMID- 25538147 TI - Reversal of glucose intolerance in rat offspring exposed to ethanol before birth through reduction of nuclear skeletal muscle HDAC expression by the bile acid TUDCA. AB - Prenatal ethanol exposure causes cellular stress, insulin resistance, and glucose intolerance in adult offspring, with increased gluconeogenesis and reduced muscle glucose transporter-4 (glut4) expression. Impaired insulin activation of Akt and nuclear translocation of histone deacetylases (HDACs) in the liver partly explain increased gluconeogenesis. The mechanism for the reduced glut4 is unknown. Pregnant rats were gavaged with ethanol over the last week of gestation and adult female offspring were studied. Some ethanol exposed offspring was treated with tauroursodeoxycholic acid (TUDCA) for 3 weeks. All these rats underwent intraperitoneal glucose tolerance and insulin tolerance tests. The expression of glut4, HDACs, and markers of endoplasmic reticulum (ER) unfolded protein response (XBP1, CHOP, ATF6) was examined in the gastrocnemius muscle fractions, and in C2C12 muscle cells cultured with ethanol, TUDCA, and HDAC inhibitors. Non-TUDCA treated rats exposed to prenatal ethanol were insulin resistant and glucose intolerant with reduced muscle glut4 expression, increased ER marker expression, and increased nuclear HDACs, whereas TUDCA-treated rats had normal insulin sensitivity and glucose tolerance with normal glut4 expression, ER marker expression, and HDAC levels. In C2C12 cells, ethanol reduced glut4 expression, but increased ER makers. While TUDCA restored glut4 and ER markers to control levels and HDAC inhibition rescued glut4 expression, HDAC inhibition had no effect on ER markers. The increase in nuclear HDAC levels consequent to prenatal ethanol exposure reduces glut4 expression in adult rat offspring, and this HDAC effect is independent of ER unfolded protein response. HDAC inhibition by TUDCA restores glut4 expression, with improvement in insulin sensitivity and glucose tolerance. PMID- 25538148 TI - Altering the redox state of skeletal muscle by glutathione depletion increases the exercise-activation of PGC-1alpha. AB - We investigated the relationship between markers of mitochondrial biogenesis, cell signaling, and antioxidant enzymes by depleting skeletal muscle glutathione with diethyl maleate (DEM) which resulted in a demonstrable increase in oxidative stress during exercise. Animals were divided into six groups: (1) sedentary control rats; (2) sedentary rats + DEM; (3) exercise control rats euthanized immediately after exercise; (4) exercise rats + DEM; (5) exercise control rats euthanized 4 h after exercise; and (6) exercise rats + DEM euthanized 4 h after exercise. Exercising animals ran on the treadmill at a 10% gradient at 20 m/min for the first 30 min. The speed was then increased every 10 min by 1.6 m/min until exhaustion. There was a reduction in total glutathione in the skeletal muscle of DEM treated animals compared to the control animals (P < 0.05). Within the control group, total glutathione was higher in the sedentary group compared to after exercise (P < 0.05). DEM treatment also significantly increased oxidative stress, as measured by increased plasma F2-isoprostanes (P < 0.05). Exercising animals given DEM showed a significantly greater increase in peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA compared to the control animals that were exercised (P < 0.05). This study provides novel evidence that by lowering the endogenous antioxidant glutathione in skeletal muscle and inducing oxidative stress through exercise, PGC-1alpha gene expression was augmented. These findings further highlight the important role of exercise induced oxidative stress in the regulation of mitochondrial biogenesis. PMID- 25538149 TI - Endogenous angiotensins and catecholamines do not reduce skin blood flow or prevent hypotension in preterm piglets. AB - Endocrine control of cardiovascular function is probably immature in the preterm infant; thus, it may contribute to the relative ineffectiveness of current adrenergic treatments for preterm cardiovascular compromise. This study aimed to determine the cardiovascular and hormonal responses to stress in the preterm piglet. Piglets were delivered by cesarean section either preterm (97 of 115 days) or at term (113 days). An additional group of preterm piglets received maternal glucocorticoids as used clinically. Piglets were sedated and underwent hypoxia (4% FiO2 for 20 min) to stimulate a cardiovascular response. Arterial blood pressure, skin blood flow, heart rate and plasma levels of epinephrine, norepinephrine, angiotensin II (Ang II), angiotensin-(1-7) (Ang-(1-7)), and cortisol were measured. Term piglets responded to hypoxia with vasoconstriction; preterm piglets had a lesser response. Preterm piglets had lower blood pressures throughout, with a delayed blood pressure response to the hypoxic stress compared with term piglets. This immature response occurred despite similar high levels of circulating catecholamines, and higher levels of Ang II compared with term animals. Prenatal exposure to glucocorticoids increased the ratio of Ang-(1 7):Ang II. Preterm piglets, in contrast to term piglets, had no increase in cortisol levels in response to hypoxia. Preterm piglets have immature physiological responses to a hypoxic stress but no deficit of circulating catecholamines. Reduced vasoconstriction in preterm piglets could result from vasodilator actions of Ang II. In glucocorticoid exposed preterm piglets, further inhibition of vasoconstriction may occur because of an increased conversion of Ang II to Ang-(1-7). PMID- 25538151 TI - What coauthors wish lead authors knew. PMID- 25538150 TI - The incidence and prevalence of comorbid gastrointestinal, musculoskeletal, ocular, pulmonary, and renal disorders in multiple sclerosis: a systematic review. AB - BACKGROUND: As new disease-modifying therapies emerge a better knowledge of the risk of comorbid disease in multiple sclerosis (MS) is needed. OBJECTIVE: To estimate the incidence and prevalence of comorbid gastrointestinal, musculoskeletal, ocular, pulmonary, and renal disorders in MS. METHODS: We systematically reviewed the world literature by searching PUBMED, EMBASE, SCOPUS, the Web of Knowledge, and reference lists of retrieved articles. For selected articles, one reviewer abstracted data using a standardized form. The abstraction was verified by a second reviewer. The quality of all selected studies was assessed. For population-based studies we quantitatively assessed studies using the I2 statistic, and conducted random effects meta-analyses. RESULTS: Study designs were heterogeneous with respect to populations, case definitions, and methods of ascertainment. Incidence of the studied comorbidities was rarely reported. Irritable bowel syndrome and chronic lung disease had a prevalence of more than 10% in the MS population. Irritable bowel syndrome, fibromyalgia, cataracts and glaucoma were more common than expected in the MS population. CONCLUSION: Although they have been the subject of less study than other comorbidities, irritable bowel syndrome, arthritis, and chronic lung disease are common in the MS population and occur more often than expected when compared to the general population. PMID- 25538152 TI - Effects of Community Exercise Therapy on Metabolic, Brain, Physical, and Cognitive Function Following Stroke: A Randomized Controlled Pilot Trial. AB - BACKGROUND: Exercise therapy could potentially modify metabolic risk factors and brain physiology alongside improving function post stroke. OBJECTIVE: To explore the short-term metabolic, brain, cognitive, and functional effects of exercise following stroke. METHODS: A total of 40 participants (>50 years, >6 months post stroke, independently mobile) were recruited to a single-blind, parallel, randomized controlled trial of community-based exercise (19 weeks, 3 times/wk, "exercise" group) or stretching ("control" group). Primary outcome measures were glucose control and cerebral blood flow. Secondary outcome measures were cardiorespiratory fitness, blood pressure, lipid profile, body composition, cerebral tissue atrophy and regional brain metabolism, and physical and cognitive function. RESULTS: Exercise did not change glucose control (homeostasis model assessment 1.5 +/- 0.8 to 1.5 +/- 0.7 vs 1.6 +/- 0.8 to 1.7 +/- 0.7, P = .97; CI = -0.5 to 0.49). Medial temporal lobe tissue blood flow increased with exercise (38 +/- 8 to 42 +/- 10 mL/100 g/min; P < .05; CI = 9.0 to 0.1) without any change in gray matter tissue volume. There was no change in medial temporal lobe tissue blood flow in the control group (41 +/- 8 to 40 +/- 7 mL/100 g/min; P = .13; CI = -3.6 to 6.7) but significant gray matter atrophy. Cardiorespiratory fitness, diastolic blood pressure, high-density lipoprotein cholesterol, physical function, and cognition also improved with exercise. CONCLUSION: Exercise therapy improves short-term metabolic, brain, physical, and cognitive function, without changes in glucose control following stroke. The long-term impact of exercise on stroke recurrence, cardiovascular health, and disability should now be explored. PMID- 25538153 TI - Fibroblast growth factor 21 protects the heart from oxidative stress. AB - AIMS: Oxidative stress mediated by reactive oxygen species (ROS) plays a striking role in the pathogenesis of heart failure, and antioxidants have been shown to attenuate cardiac remodelling in experimental models of cardiac damage. We recently showed that fibroblast growth factor 21 (Fgf21) is produced by the heart and exerts protective effects, preventing cardiac hypertrophy development. The aim of the study was to determine the effects of Fgf21 during oxidative stress signalling in the heart. METHODS AND RESULTS: Fgf21 treatment in cardiomyocytes in culture induced the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3) and superoxide dismutase-2 (Sod2) and reduced ROS production. In keeping with this, expression of antioxidant genes in response to lipopolysaccharide (LPS)-induced stimulation of pro-inflammatory pathways or isoproterenol-induced cardiac hypertrophy in the heart was reduced in Fgf21-null mice. Moreover, we found that Fgf21 is expressed in and released by cardiomyocytes in response to LPS, and its expression is under the control of the Sirt1 (sirtuin-1) pathway. This Fgf21 released by cardiomyocytes acts in an autocrine manner to protect cells against oxidative stress. Finally, failing human hearts showed up regulation of Fgf21, Ucp3, and Sod2, confirming the association between Fgf21 induction and the control of cardiac oxidative stress pathways. CONCLUSION: Our data indicate that Fgf21 regulates genes involved in antioxidant pathways in an autocrine manner, thus preventing ROS production in cardiac cells. Therefore, Fgf21 acts as an antioxidant factor in the heart, preventing induction of pro oxidative pathways by inflammatory or hypertrophic conditions. PMID- 25538154 TI - Akt activation by PHLPP1 ablation prevents pathological hypertrophy by promoting angiogenesis. PMID- 25538155 TI - Essential role for TMEM100 in vascular integrity but limited contributions to the pathogenesis of hereditary haemorrhagic telangiectasia. AB - AIMS: TMEM100 was previously identified as a downstream target of activin receptor-like kinase 1 (ALK1; ACVRL1) signalling. Mutations on ALK1 cause hereditary haemorrhagic telangiectasia (HHT), a vascular disorder characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). The aims of this study are to investigate the in vivo role of TMEM100 at various developmental and adult stages and to determine the extent to which TMEM100 contributed to the development of AVMs as a key downstream effector of ALK1. METHODS AND RESULTS: Blood vasculature in Tmem100-null embryos and inducible Tmem100-null neonatal and adult mice was examined. We found that TMEM100 deficiency resulted in cardiovascular defects at embryonic stage; dilated vessels, hyperbranching, and increased number of filopodia in the retinal vasculature at neonatal stage; and various vascular abnormalities, including internal haemorrhage, arteriovenous shunts, and weakening of vasculature with abnormal elastin layers at adult stage. However, arteriovenous shunts in adult mutant mice appeared to be underdeveloped without typical tortuosity of vessels associated with AVMs. We uncovered that the expression of genes encoding cell adhesion and extracellular matrix proteins was significantly affected in lungs of adult mutant mice. Especially Mfap4, which is associated with elastin fibre formation, was mostly down-regulated. CONCLUSION: These results demonstrate that TMEM100 has essential functions for the maintenance of vascular integrity as well as the formation of blood vessels. Our results also indicate that down-regulation of Tmem100 is not the central mechanism of HHT pathogenesis, but it may contribute to the development of vascular pathology of HHT by weakening vascular integrity. PMID- 25538157 TI - Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation. AB - AIMS: In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. METHODS AND RESULTS: We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. CONCLUSION: Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications. PMID- 25538156 TI - Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release. AB - AIMS: Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study. METHODS AND RESULTS: We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice. CONCLUSIONS: Thus, our study offers the first evidence that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy. PMID- 25538158 TI - Pro: Should we move to more frequent haemodialysis schedules? AB - Most end-stage renal disease patients on maintenance haemodialysis follow the typical schedule of three sessions per week, and thus remain outside dialysis for two short intervals (~2 days in duration) and for a longer interval (~3 days) at the end of each week. This pattern was historically enforced more due to calendar logistics and less due to factors related to health and disease. Therefore, it is long hypothesized that the intermittent nature of haemodialysis and the consequent shifts and fluctuations in volume status and metabolic parameters during the dialysis-free periods may pre-dispose patients to several complications. Recent large-scale observational studies in haemodialysis patients link the first week-day (including the last hours of the long interval and the subsequent dialysis session) with increased risk of cardiovascular morbidity and mortality. Previous observational studies support that enhanced-frequency home haemodialysis is associated with reduced risk of all-cause mortality, while randomized studies suggest that short-daily or alternate-day in-centre haemodialysis offer improvements in left ventricular hypertrophy, blood pressure, phosphorous homeostasis and other intermediate end points when compared with conventional thrice-weekly in-centre haemodialysis. This article summarizes available evidence relating long inter-dialytic intervals with elevated cardiovascular risk, potential mechanisms for this association and the main benefits of more frequent dialytic modalities. PMID- 25538160 TI - Should we extend the application of more frequent dialysis schedules? A 'yes' and a hopeful 'no'. AB - Observational studies associate long dialysis intervals with an excess risk for mortality and cardiovascular disease hospitalizations. The application alternate day dialysis is an appealing possibility to reduce the cardiovascular burden of long dialysis intervals and a small pilot study demonstrated that this regimen allows safe reduction of dry body weight, BP and left ventricular mass index. However, the actual impact of alternate day hemodialysis and of frequent hemodialysis in general on survival remains unknown. Frequent dialysis schedules may increase the risk of arteriovenous fistula problems and the burden of disease and eventually reduce treatment adherence. Furthermore we cannot safely exclude that more frequent dialysis regimens may be harmful. On the other hand increasing the duration of dialysis and/or frequency of hemodialysis in patients with refractory fluid overload, uncontrolled hypertension, hyperphosphatemia, malnutrition or cardiovascular disease is of unquestionable benefit in these problematic patients.Thus the moderators conclusion to the question being asked is a yes and a hopeful "no". Whenever and wherever possible we should pro actively apply more frequent dialysis regimens, starting with the alternate day approach, in problematic patients. However, extensive application of frequent hemodialysis schedules is by now unjustified. Evidence that these regimens are beneficial mainly derives from observational studies and the possibility that frequent schedules are harmful cannot be excluded. A clinical trial is needed. PMID- 25538159 TI - Con: Frequent haemodialysis for all chronic haemodialysis patients. AB - Frequent haemodialysis (HD) regimens have been proposed with the aim to improve survival and other important patient outcomes. They indeed avoid the long interdialytic interval and have been associated with some proven benefits, i.e. an improvement in blood pressure and phosphataemia control, a reduction in left ventricular mass and lower ultrafiltration rates. However, the actual impact of frequent HD regimens on survival is, at best, inconclusive and, at worse, harmful, and remains uncertain regarding nutritional status and anaemia control. Moreover, the higher rates of vascular access complications and more rapid development of anuria with frequent HD regimens are worrying. Frequent HD also considerably increases the burden for patients and their caregivers, logistics and costs, especially with in-centre frequent schedules. In our opinion, before increasing HD frequency, a number of underused strategies summarized in our review and able to improve patient tolerance and/or HD dose should be tested first, taking into account patient's characteristics and life expectancy. Frequent HD schedules should be reserved for selected cases, only after all other available options have failed. PMID- 25538161 TI - Cell cycle control in the kidney. AB - Proper control of the cell cycle is mandatory during homeostasis and disease. The balance of p53 and MDM2 integrates numerous signalling pathways to regulate the cell cycle, which is executed by multiple proteins including the cyclins, cyclin kinases and cyclin kinase inhibitors. Mutations or environmental factors that affect cell cycle control can lead to inappropriate hyperplasia or cancer as well as to cell loss and tissue atrophy. Normal kidney function is maintained largely by post-mitotic quiescent cells in the G0 phase with a low turnover. Early cell cycle activation during kidney injury contributes to cell death via mitotic catastrophe, i.e. death via mitosis, e.g. of cell with significant DNA damage. At later stages, cell cycle entry supports tissue regeneration and functional reconstitution via cell hypertrophy and/or cell proliferation. It is of note that so-called proliferation markers such as Ki67, PCNA or BrdU identify only cell cycle entry without telling whether this results in cell hypertrophy, cell division or mitotic catastrophe. With this in mind, some established concepts on kidney injury and regeneration are to be re-evaluated. Here, we discuss the components and functional roles of p53/MDM2-mediated cell cycle regulation in kidney homeostasis and disease. PMID- 25538162 TI - A case of rectal adenocarcinoma presented with palatine tonsil metastasis. AB - The most common metastatic sites of colorectal cancer are liver, lung, peritoneum and lymph nodes. Metastasis of colorectal carcinoma to palatine tonsil is rarely seen. To our knowledge, only 11 patients were documented in English literature. Atypical metastases can sometimes lead to misdiagnosis. Precise diagnosis of atypical metastases requires a careful physical examination, good imaging method and comprehensive pathological evaluation. Here, we report a case of rectal adenocarcinoma presented with palatine tonsil metastasis. PMID- 25538163 TI - To create a cleanroom controlled environment using a mobile air decontamination unit for the preparation of antineoplastic drugs. AB - OBJECTIVES: To use a mobile air decontamination unit (MADU) for a microbial destruction and decreased particle burden making a cleanroom controlled environment in a Centralized Chemotherapy Preparation Unit (CCPU). Good manufacturing practices (GMP) in France specify that the ambient air in the vicinity of a class III biosafety cabinet (isolator) complies with air cleanliness ISO 8 level in CCPU. This guideline has a significant impact because implementing a dedicated air handling unit (AHU) brings some engineering constraints and generates substantial additional costs. METHODS: Authors have previously studied some technical and economical aspects to evaluate the feasibility of the MADU option. RESULTS: Using a MADU was the chosen option. Qualification of the CCPU showed that results were in compliance with the French GMP. After one year of use, the efficiency of the MADU was confirmed. According to these results, using a MADU constitutes a beneficial option for CCPU previously equipped with an isolator when compared to renovation work involving a standard built-in AHU. PMID- 25538164 TI - Acquisition of high-level mupirocin resistance in CoNS following nasal decolonization with mupirocin. AB - OBJECTIVES: The association between mupirocin use and plasmid-based high-level resistance development mediated through mupA in CoNS has not been quantified. We determined acquisition of mupirocin resistance in Staphylococcus aureus and CoNS in surgery patients treated peri-operatively with mupirocin. PATIENTS AND METHODS: Patients admitted for surgery were treated with nasal mupirocin ointment and chlorhexidine soap for 5 days, irrespective of S. aureus carrier status. Nasal swabs were obtained before decolonization (T1) and 4 days after surgery (T2) and were inoculated onto agars containing 8 mg/L mupirocin. Staphylococci were identified by MALDI-TOF MS and mupirocin resistance was confirmed by Etest. RESULTS: Among 1578 surgical patients, 936 (59%) had nasal swabs obtained at T1 and T2; 192 (21%) patients carried mupirocin-resistant CoNS at T1 and 406 (43%) at T2 (P<0.001). Of 744 patients not colonized at T1, 277 acquired resistance (37%), corresponding to an acquisition rate of 7.4/100 patient days at risk. In all, 588 (97%) of 607 mupirocin-resistant CoNS had an MIC >256 mg/L (high level) and 381 of 383 (99.5%) were mupA positive. No acquisition of mupirocin resistance was observed in S. aureus. CONCLUSIONS: Acquisition of mupirocin resistance following decolonization was widespread in CoNS and absent in S. aureus. As almost all isolates harboured the mupA gene, monitoring resistance development in S. aureus when decolonization strategies containing mupirocin are used is recommended. PMID- 25538165 TI - Antibiotic policies in acute English NHS trusts: implementation of 'Start Smart Then Focus' and relationship with Clostridium difficile infection rates. AB - OBJECTIVES: The objective of this study was to establish how antibiotic prescribing policies at National Health Service (NHS) hospitals match the England Department of Health 'Start Smart-Then Focus' recommendations and relate to Clostridium difficile infection (CDI) rates. METHODS: Antibiotic pharmacists were surveyed regarding recommendations for empirical treatment of common syndromes ('Start Smart') and antimicrobial prescription reviews ('Focus') at their hospital trusts. If no response was provided, policy data were sought from trust websites and the MicroGuide app (Horizon Strategic Partners, UK). Empirical treatment recommendations were categorized as broad spectrum (a beta-lactam penicillin/beta-lactamase inhibitor, cephalosporin, quinolone or carbapenem) or narrow spectrum. CDI rates were gathered from the national mandatory surveillance system. RESULTS: Data were obtained for 105/145 English acute hospital trusts (72%). beta-Lactam/beta-lactamase inhibitor combinations were recommended extensively. Only for severe community-acquired pneumonia and pyelonephritis were narrow-spectrum agents recommended first line at a substantial number of trusts [42/105 (40%) and 50/105 (48%), respectively]. Policies commonly recommended dual therapy with aminoglycosides and beta-lactams for abdominal sepsis [40/93 trusts (43%)] and undifferentiated severe sepsis [54/94 trusts (57%)]. Most policies recommended treating for >= 7 days for most indications. Nearly all policies [100/105 trusts (95%)] recommended antimicrobial prescription reviews, but only 46/96 respondents (48%) reported monitoring compliance. Independent predictors of higher CDI rates were recommending a broad-spectrum regimen for community acquired pneumonia (P=0.06) and, counterintuitively, a recommended treatment duration of <48 h for nosocomial pneumonia (P=0.01). CONCLUSIONS: Hospital antibiotic policies in the NHS 'Start Smart' by recommending broad-spectrum antibiotics for empirical therapy, but this may have the unintended potential to increase the use of broad-spectrum antibiotics and risk of CDI unless better mechanisms are in place to improve 'Focus'. PMID- 25538166 TI - Atherogenic properties of lipoproteins in HIV patients starting atazanavir/ritonavir or darunavir/ritonavir: a substudy of the ATADAR randomized study. AB - OBJECTIVES: To assess LDL subfraction phenotype and lipoprotein-associated phospholipase A2 (Lp-PLA2) in naive HIV-infected patients starting atazanavir/ritonavir or darunavir/ritonavir plus tenofovir/emtricitabine. METHODS: This was a substudy of a multicentre randomized study. Standard lipid parameters, LDL subfraction phenotype (by gradient gel electrophoresis) and Lp PLA2 activity (by 2-thio-PAF) were measured at baseline and weeks 24 and 48. Multivariate regression analysis was performed. Results are expressed as the median (IQR). RESULTS: Eighty-six (atazanavir/ritonavir, n=45; darunavir/ritonavir, n=41) patients were included: age 36 (31-41) years; 89% men; CD4 319 (183-425) cells/mm(3); and Framingham score 1% (0%-2%). No differences in demographics or lipid measurements were found at baseline. At week 48, a mild but significant increase in total cholesterol and HDL-cholesterol was observed in both arms, whereas LDL cholesterol increased only in the darunavir/ritonavir arm and triglycerides only in the atazanavir/ritonavir arm. The apolipoprotein A I/apolipoprotein B ratio increased only in the atazanavir/ritonavir arm. At week 48, the LDL subfraction phenotype improved in the darunavir/ritonavir arm (increase in LDL particle size and in large LDL particles), whereas it worsened in the atazanavir/ritonavir arm (increase in small and dense LDL particles, shift to a greater prevalence of phenotype B); the worsening was related to the greater increase in triglycerides in the atazanavir/ritonavir arm. No changes in total Lp PLA2 activity or relative distribution in LDL or HDL particles were found at week 48 in either arm. CONCLUSIONS: In contrast with what occurred in the atazanavir/ritonavir arm, the LDL subfraction phenotype improved with darunavir/ritonavir at week 48. This difference was associated with a lower impact on plasma triglycerides with darunavir/ritonavir. PMID- 25538167 TI - Specific antifungal susceptibility profiles of opportunists in the Fusarium fujikuroi complex. AB - OBJECTIVES: The aim of the present study was to evaluate and assess the in vitro activity of eight drugs, including the new azole isavuconazole, against 81 strains representing 13 species of the Fusarium fujikuroi species complex. METHODS: A total of 81 Fusarium spp. isolates, within the F. fujikuroi species complex, were identified by molecular methods and tested according to CLSI M38 A2. Eight antifungal compounds, including the new azole isavuconazole, were tested. Isolates were selected to represent the widest variety of geographical regions and to include clinical as well as environmental strains. RESULTS: Susceptibility profiles differed between and within species, with Fusarium verticillioides showing the lowest MICs and Fusarium nygamai the highest MICs. Amphotericin B was the most active drug, followed by voriconazole, posaconazole, isavuconazole and natamycin. The remaining antifungals (fluconazole, itraconazole and micafungin) showed poor activity with MIC/minimum effective concentration values of >= 32, >= 16 and >8 mg/L, respectively. CONCLUSIONS: Resistance patterns in the F. fujikuroi species complex are species specific and therefore identification down to species level is important for the choice of antifungal treatment. PMID- 25538168 TI - Utility of a newly developed Mueller-Hinton E agar for the detection of MRSA carrying the novel mecA homologue mecC. PMID- 25538169 TI - Outpatient parenteral antimicrobial therapy and antimicrobial stewardship: challenges and checklists. AB - Outpatient parenteral antimicrobial therapy (OPAT) has become, for many countries, an established form of healthcare delivery. At the same time, there have been calls to ensure the prudent use of the existing antimicrobial armamentarium. For OPAT, this presents a dilemma. On one hand, stewardship principles look for the most effective agent with minimal collateral effects. In OPAT, whilst the aims of the service are similar, convenience of dosing to optimize early hospital discharge or admission avoidance may take precedence over an agent's spectrum of activity. This brief article aims to highlight the importance and explore the challenges of antimicrobial stewardship in the context of OPAT. Within the UK, the safe and effective use of antimicrobials is modelled around the IDSA/Society for Healthcare Epidemiology of America stewardship practice guidelines with local customization where appropriate. Current UK stewardship practice principles were compared with published good practice recommendations for OPAT to identify how OPAT could support the broader antimicrobial stewardship agenda. It is essential that antimicrobial stewardship teams should understand the challenges faced in the non-inpatient setting and the potential benefits/lower risks associated with avoided admission or shortened hospital stay in this population. Within its limitations, OPAT should practise stewardship principles, including optimization of intravenous to oral switch and the reporting of outcomes, healthcare-associated infections and re-admission rates. OPAT should report to the antimicrobial stewardship team. Ideally the OPAT team should be formally represented within the stewardship framework. A checklist has been proposed to aid OPAT services in ensuring they meet their stewardship agenda. PMID- 25538170 TI - MDR ST2179-CTX-M-15 Escherichia coli co-producing RmtD and AAC(6')-Ib-cr in a horse with extraintestinal infection, Brazil. PMID- 25538171 TI - Surrogate end points for overall survival. Festina lente (more haste, less speed). PMID- 25538172 TI - Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use. AB - BACKGROUND: The neutrophil-lymphocyte ratio (NLR), proposed as an indicator of cancer-related inflammation, has known prognostic value in prostate cancer. We examine its association with survival (OS) and response in patients treated with second-line chemotherapy. METHODS: We analysed patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the TROPIC trial, evaluating cabazitaxel versus mitoxantrone. Cox regression models were used to investigate the association of baseline NLR (BLNLR) with OS and the significance of a change in NLR count with treatment. Logistic regression models were used to determine the association of BLNLR counts with prostate specific antigen (PSA) and RECIST responses. The optimal NLR cut-off was established based on the concordance index of different values. RESULTS: Data from 755, 654 and 405 patients was available for OS, PSA and RECIST response analysis respectively. Median OS was 14.0 months [95% confidence interval (CI) 13.2-14.8]. Median NLR was 2.9 (IQR: 1.9-5.1). BLNLR was associated with survival (HR 1.5, 95% CI 1.1 2.1, P = 0.011) in multivariable analysis (MVA) independently of variables included in the Halabi nomogram, treatment arm and corticosteroid use. The optimal cut-off for a dichotomous NLR was selected at 3.0 based on its higher c index related to survival. BLNLR >=3.0 was associated with lower PSA response (40.1% versus 59.9%; P < 0.001) and RECIST response (7.7% versus 15.6%, P = 0.022) in MVA. Conversion from high (>=3) to low (<3) NLR was associated with improved survival (HR 0.66; 95% CI 0.51-0.85; P = 0.001) and higher PSA response rates (66.4% versus 33.6%; P = 0.000). Use of corticosteroids at baseline did not modify the association between NLR and survival. CONCLUSIONS: NLR is a valid prognostic biomarker in CRPC and is associated with survival, PSA and RECIST responses in patients treated with second-line chemotherapy. Changes in NLR counts with treatment may indicate benefit. NLR prognostic value is independent of prior use of corticosteroids. CLINICALTRIALSGOV: NCT00417079. PMID- 25538173 TI - Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. AB - BACKGROUND: For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5 fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting. PATIENTS AND METHODS: OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as >=1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis. RESULTS: In patients assigned to bevacizumab FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX 6. Median progression-free survival (PFS) was 18.6 (95% CI 12.9-22.3) months and 11.5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively). CONCLUSIONS: Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab FOLFOXIRI. CLINICALTRIALSGOV: NCT00778102. PMID- 25538174 TI - A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small cell lung cancer. AB - BACKGROUND: It is unclear whether treating brain metastasis before starting systemic chemotherapy can improve survival compared with upfront chemotherapy in non-small-cell lung cancer (NSCLC) with asymptomatic cerebral oligo-metastases. PATIENTS AND METHODS: We undertook a randomized, controlled trial of 105 patients with one to four brain metastases, admitted to Samsung Medical Center between 2008 and 2013. Patients were randomly assigned to receive stereotactic radiosurgery (SRS) (49 patients) followed by chemotherapy or upfront chemotherapy (49 patients). The primary end point was overall survival (OS) and secondary end points included central nervous system (CNS) progression-free survival, progression to symptomatic brain metastasis and brain functional outcome. RESULTS: The median age was 58 years (range, 29-85) with ECOG 0-1 performance status, and 40% of patients were never smokers. Most patients had adenocarcinoma, and about half of patients had only one brain metastasis, while the rest had multiple cerebral metastases. The median OS time was 14.6 months [95% confidence interval (CI), 9.2-20.0] in the SRS group and 15.3 months (95% CI, 7.2-23.4) for the upfront chemotherapy group (P = 0.418). There was no significant difference in time to CNS disease progression [median, 9.4 months (SRS) versus 6.6 months (upfront chemotherapy), P = 0.248]. Symptomatic progression of brain metastases was observed more frequently in the upfront chemotherapy group (26.5%) than the SRS group (18.4%) but without statistical significance. CONCLUSIONS: Although this study included smaller sample size than initially anticipated due to early termination, SRS followed by chemotherapy did not improve OS in oligo-brain metastases NSCLC patients compared with upfront chemotherapy. Further study with large number of patients should be needed to confirm the use of upfront chemotherapy alone in this subgroup of patients. CLINICAL TRIALS NUMBER: NCT01301560. PMID- 25538175 TI - Impact of centralization on aCGH-based genomic profiles for precision medicine in oncology. AB - BACKGROUND: Comparative genomic hybridization (CGH) arrays are increasingly used in personalized medicine programs to identify gene copy number aberrations (CNAs) that may be used to guide clinical decisions made during molecular tumor boards. However, analytical processes such as the centralization step may profoundly affect CGH array results and therefore may adversely affect outcomes in the precision medicine context. PATIENTS AND METHODS: The effect of three different centralization methods: median, maximum peak, alternative peak, were evaluated on three datasets: (i) the NCI60 cell lines panel, (ii) the Cancer Cell Line Encyclopedia (CCLE) panel, and (iii) the patients enrolled in prospective molecular screening trials (SAFIR-01 n = 283, MOSCATO-01 n = 309), and compared with karyotyping, drug sensitivity, and patient-drug matching, respectively. RESULTS: Using the NCI60 cell lines panel, the profiles generated by the alternative peak method were significantly closer to the cell karyotypes than those generated by the other centralization strategies (P < 0.05). Using the CCLE dataset, selected genes (ERBB2, EGFR) were better or equally correlated to the IC50 of their companion drug (lapatinib, erlotinib), when applying the alternative centralization. Finally, focusing on 24 actionable genes, we observed as many as 7.1% (SAFIR-01) and 6.8% (MOSCATO-01) of patients originally not oriented to a specific treatment, but who could have been proposed a treatment based on the alternative peak centralization method. CONCLUSION: The centralization method substantially affects the call detection of CGH profiles and may thus impact precision medicine approaches. Among the three methods described, the alternative peak method addresses limitations associated with existing approaches. PMID- 25538176 TI - Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. AB - BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. PATIENTS AND METHODS: This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3 year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naive' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692. PMID- 25538177 TI - Low-dose aspirin use and the risk of ovarian cancer in Denmark. AB - BACKGROUND: A comprehensive body of evidence has shown that aspirin has cancer preventive effects, particularly against gastrointestinal cancer, but its effects on the risk of ovarian cancer are less well established. This nationwide case control study examined the association between low-dose aspirin and the risk of ovarian cancer. PATIENTS AND METHODS: We identified all patients in the Danish Cancer Registry aged 30-84 years old with a histologically verified first diagnosis of epithelial ovarian cancer during 2000-2011. Each patient was sex- and age-matched to 15 population controls using risk-set sampling. Prescription use, comorbidity, reproductive history, and demographic characteristics data were obtained from nationwide registries. The use of low-dose (75-150 mg) aspirin was defined according to the dose as well as the duration and consistency of use. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between low-dose aspirin use and the risk of epithelial ovarian cancer, both overall and for specific histological types. RESULTS: For 4103 ovarian cancer cases and 58 706 population controls, the adjusted OR for epithelial ovarian cancer associated with ever use (>=2 prescriptions) of low-dose aspirin was 0.94 (95% CI 0.85-1.05). ORs for epithelial ovarian cancer were lower with the use of 150 mg aspirin tablets (OR = 0.82; 95% CI 0.68-0.99) and with long-term use (>=5 years) of low-dose aspirin (OR = 0.77; 95% CI 0.55-1.08). Continuous long-term use of low-dose aspirin, defined as close consecutive prescriptions, was associated with a further reduction in OR (0.56; 95% CI 0.32-0.97). For histological types of epithelial ovarian cancer, the strongest inverse associations with low-dose aspirin use were seen for mucinous and endometrioid tumours. CONCLUSION: This nationwide case control study indicates that low-dose aspirin use may be associated with a reduced risk of epithelial ovarian cancer. PMID- 25538179 TI - Oxy-RVAD: rescue in pulmonary complications after LVAD implantation. AB - Pulmonary complications after left ventricular assist device (LVAD) implantation seldom occur; however, if present, they may prove catastrophic. An Oxy-RVAD (oxygenator in right VAD circuit) is a lifesaving technique in such cases and allows freedom of introducing and removing an oxygenator into the RVAD circuit without opening the chest and competing with LVAD flow. PMID- 25538180 TI - Heart failure: the epidemic of the new century. PMID- 25538178 TI - A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study. AB - BACKGROUND: The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC. PATIENTS AND METHODS: Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m(2) was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes. RESULTS: A total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72-155), 114 (91-193) and 148 (71-225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm). CONCLUSIONS: Vandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs. CLINICAL TRIAL NUMBER: NCT00753675. PMID- 25538181 TI - The emergence of cardiovascular imaging as a subspecialty and individualized treatment of coronary artery disease: two related trends. PMID- 25538182 TI - A hopefully not too long goodbye. PMID- 25538185 TI - DNA methylation in maize: toto, i've a feeling we're not in Arabidopsis anymore. PMID- 25538183 TI - Proteasome-mediated degradation of FRIGIDA modulates flowering time in Arabidopsis during vernalization. AB - Winter-annual accessions of Arabidopsis thaliana require either exposure to cold stress or vernalization to initiate flowering via FRIGIDA (FRI). FRI acts as a scaffold protein to recruit several chromatin modifiers that epigenetically modify flowering genes. Here, we report that proteasome-mediated FRI degradation regulates flowering during vernalization in Arabidopsis. Our genetic and biochemical experiments demonstrate that FRI directly interacts with the BTB (Bric-a-Brac/Tramtrack/Broad Complex) proteins LIGHT-RESPONSE BTB1 (LRB1) and LRB2 as well as the CULLIN3A (CUL3A) ubiquitin-E3 ligase in vitro and in vivo, leading to proteasomal degradation of FRI during vernalization. The degradation of FRI is accompanied by an increase in the levels of the long noncoding RNA ColdAIR, which reduces the level of histone H3Lys4 trimethylation (H3K4me3) in FLOWERING LOCUS C chromatin to promote flowering. Furthermore, we found that the cold-induced WRKY34 transcription factor binds to the W-box in the promoter region of CUL3A to modulate CUL3A expression. Deficiency of WRKY34 suppressed CUL3A transcription to enhance FRI protein stability and led to late flowering after vernalization. Conversely, overexpression of WRK34 promoted FRI degradation and early flowering through inducing CUL3A accumulation. Together, these data suggest that WRKY34-induced and CUL3A-dependent proteolysis of FRI modulate flowering in response to vernalization. PMID- 25538184 TI - The Arabidopsis abiotic stress-induced TSPO-related protein reduces cell-surface expression of the aquaporin PIP2;7 through protein-protein interactions and autophagic degradation. AB - The Arabidopsis thaliana multi-stress regulator TSPO is transiently induced by abiotic stresses. The final destination of this polytopic membrane protein is the Golgi apparatus, where its accumulation is strictly regulated, and TSPO is downregulated through a selective autophagic pathway. TSPO-related proteins regulate the physiology of the cell by generating functional protein complexes. A split-ubiquitin screen for potential TSPO interacting partners uncovered a plasma membrane aquaporin, PIP2;7. Pull-down assays and fluorescence imaging approaches revealed that TSPO physically interacts with PIP2;7 at the endoplasmic reticulum and Golgi membranes in planta. Intriguingly, constitutive expression of fluorescently tagged PIP2;7 in TSPO-overexpressing transgenic lines resulted in patchy distribution of the fluorescence, reminiscent of the pattern of constitutively expressed yellow fluorescent protein-TSPO in Arabidopsis. Mutational stabilization of TSPO or pharmacological inhibition of the autophagic pathway affected concomitantly the detected levels of PIP2;7, suggesting that the complex containing both proteins is degraded through the autophagic pathway. Coexpression of TSPO and PIP2;7 resulted in decreased levels of PIP2;7 in the plasma membrane and abolished the membrane water permeability mediated by transgenic PIP2;7. Taken together, these data support a physiological role for TSPO in regulating the cell-surface expression of PIP2;7 during abiotic stress conditions through protein-protein interaction and demonstrate an aquaporin regulatory mechanism involving TSPO. PMID- 25538187 TI - Examining the molecular basis of heterophylly in North American lake cress. PMID- 25538188 TI - Career intentions and choices of paediatricians entering training in the UK. AB - INTRODUCTION: The paediatric workforce has grown substantially in recent years. Roles have changed considerably with the introduction of working time legislation and a move towards a trained doctor solution. By gaining a better understanding of paediatric trainees' career intentions, this study aims to assess whether the right workforce is being trained to meet the future demand for paediatric services in the UK. METHOD: A survey was sent to paediatric specialist trainees, when they were expected to have completed their 1st year of Specialty Training or Fixed Term Specialty Training Appointments, in 2009 (part 1). A second survey was sent to the same cohort when they were expected to have completed their 3rd year in 2011 (part 2). RESULTS: In part 1 of the survey, the response rate was 79.1%. In part 2 the response rate was 80.5%. Of those who had responded to part 1, 87.4% also responded to part 2. The attrition rate of trainees leaving the paediatric training scheme between the 1st year and 3rd year of training was 15%. Of those still training in paediatrics after the 3rd year, 38.7% intended to be subspecialty paediatricians, 25.7% general paediatricians, 5.4% community paediatricians and 3.5% academic paediatricians. 26% were undecided and 0.6% did not intend to follow a career in paediatrics at all. The proportion of trainees who were undecided about their career intentions had risen substantially from 7.7% after the 1st year. There was a decrease in trainees' confidence in obtaining a consultant post between the 1st year and the 3rd year. CONCLUSIONS: Workforce planning is a complex task and this study shows that trainees will change their career plans while progressing through their run-through programmes. A better understanding of these factors will enable the Royal College of Paediatrics and Chld Health to deliver the right workforce for the UK. PMID- 25538186 TI - Stress-induced chloroplast degradation in Arabidopsis is regulated via a process independent of autophagy and senescence-associated vacuoles. AB - Two well-known pathways for the degradation of chloroplast proteins are via autophagy and senescence-associated vacuoles. Here, we describe a third pathway that was activated by senescence- and abiotic stress-induced expression of Arabidopsis thaliana CV (for chloroplast vesiculation). After targeting to the chloroplast, CV destabilized the chloroplast, inducing the formation of vesicles. CV-containing vesicles carrying stromal proteins, envelope membrane proteins, and thylakoid membrane proteins were released from the chloroplasts and mobilized to the vacuole for proteolysis. Overexpression of CV caused chloroplast degradation and premature leaf senescence, whereas silencing CV delayed chloroplast turnover and senescence induced by abiotic stress. Transgenic CV-silenced plants displayed enhanced tolerance to drought, salinity, and oxidative stress. Immunoprecipitation and bimolecular fluorescence complementation assays demonstrated that CV interacted with photosystem II subunit PsbO1 in vivo through a C-terminal domain that is highly conserved in the plant kingdom. Collectively, our work indicated that CV plays a crucial role in stress-induced chloroplast disruption and mediates a third pathway for chloroplast degradation. From a biotechnological perspective, silencing of CV offers a suitable strategy for the generation of transgenic crops with increased tolerance to abiotic stress. PMID- 25538189 TI - Reptile-associated salmonellosis in children aged under 5 years in South West England. AB - OBJECTIVE: To determine the proportion of Salmonella cases in children aged <5 years that were reptile-associated salmonellosis (RAS) and to compare the severity of illness. DESIGN: To analyse all cases of salmonellosis reported to public health authorities in children aged under 5 years in the South West of the UK from January 2010 to December 2013 for reptile exposure, age, serotype, hospitalisation and invasive disease. RESULTS: 48 of 175 (27%) Salmonella cases had exposure to reptiles. The median age of RAS cases was significantly lower than non-RAS cases (0.5 vs 1.0 year). RAS cases were 2.5 times more likely to be hospitalised (23/48) compared with non-RAS cases (25/127; p=0.0002). This trend continued in cases aged under 12 months, with significantly more RAS cases hospitalised (19/38) than non-RAS cases (8/42; p=0.003). Significantly more RAS cases had invasive disease (8/48: 5 bacteraemia, 2 meningitis, 1 colitis) than non-RAS cases (4/127: 3 bacteraemia, 1 meningitis). CONCLUSIONS: Reptile exposure was found in over a quarter of all reported Salmonella cases in children under 5 years of age. RAS is associated with young age, hospitalisation and invasive disease. PMID- 25538190 TI - High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis. AB - Osteomyelitis is a difficult-to-eradicate bone infection typically caused by Staphylococcus aureus. In this study, we investigated the in vivo transcriptional adaptation of S. aureus during bone infection. To this end, we determined the transcriptome of S. aureus during the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed by S. aureus during acute or chronic in vivo infection than under in vitro growth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level, sarA and -R and saeR and -S as well as the small RNA RsaC were predominantly expressed by S. aureus during in vivo infection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed by S. aureus during the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of these in vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis, S. aureus induced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however, S. aureus switched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies of S. aureus during chronic infection could lead to more effective treatments. IMPORTANCE: The key to the survival success of pathogens during an infection is their capacity to rapidly adjust to the host environment and to evade the host defenses. Understanding how a pathogen redirects and fine-tunes its gene expression in response to the challenges of infection is central to the development of more efficient anti-infective therapies. Osteomyelitis is a debilitating infection of the bone predominantly caused by S. aureus. In this study, we evaluated the transcriptional response of S. aureus during bone infection. Our results indicate that S. aureus reprograms its genetic repertoire during the acute phase of infection to adapt to nutrient availability and to replicate within the host. During the chronic phase, S. aureus upregulates a survival genetic program activated in response to nutrient starvation. Thus, we have uncovered key survival pathways of S. aureus during acute and chronic osteomyelitis that can be used as therapeutic targets. PMID- 25538191 TI - Phylodynamic analysis of clinical and environmental Vibrio cholerae isolates from Haiti reveals diversification driven by positive selection. AB - Phylodynamic analysis of genome-wide single-nucleotide polymorphism (SNP) data is a powerful tool to investigate underlying evolutionary processes of bacterial epidemics. The method was applied to investigate a collection of 65 clinical and environmental isolates of Vibrio cholerae from Haiti collected between 2010 and 2012. Characterization of isolates recovered from environmental samples identified a total of four toxigenic V. cholerae O1 isolates, four non-O1/O139 isolates, and a novel nontoxigenic V. cholerae O1 isolate with the classical tcpA gene. Phylogenies of strains were inferred from genome-wide SNPs using coalescent based demographic models within a Bayesian framework. A close phylogenetic relationship between clinical and environmental toxigenic V. cholerae O1 strains was observed. As cholera spread throughout Haiti between October 2010 and August 2012, the population size initially increased and then fluctuated over time. Selection analysis along internal branches of the phylogeny showed a steady accumulation of synonymous substitutions and a progressive increase of nonsynonymous substitutions over time, suggesting diversification likely was driven by positive selection. Short-term accumulation of nonsynonymous substitutions driven by selection may have significant implications for virulence, transmission dynamics, and even vaccine efficacy. IMPORTANCE: Cholera, a dehydrating diarrheal disease caused by toxigenic strains of the bacterium Vibrio cholerae, emerged in 2010 in Haiti, a country where there were no available records on cholera over the past 100 years. While devastating in terms of morbidity and mortality, the outbreak provided a unique opportunity to study the evolutionary dynamics of V. cholerae and its environmental presence. The present study expands on previous work and provides an in-depth phylodynamic analysis inferred from genome-wide single nucleotide polymorphisms of clinical and environmental strains from dispersed geographic settings in Haiti over a 2 year period. Our results indicate that even during such a short time scale, V. cholerae in Haiti has undergone evolution and diversification driven by positive selection, which may have implications for understanding the global clinical and epidemiological patterns of the disease. Furthermore, the continued presence of the epidemic strain in Haitian aquatic environments has implications for transmission. PMID- 25538192 TI - Regulation of the arginine deiminase system by ArgR2 interferes with arginine metabolism and fitness of Streptococcus pneumoniae. AB - Streptococcus pneumoniae is auxotrophic for arginine, and molecular analysis of the pneumococcal genome showed that the gene encoding an arginine-ornithine antiporter (ArcD) is organized in a cluster together with the arcABC genes encoding the arginine deiminase system (ADS) of pneumococci. The ADS consists of the arginine deiminase (AD), the catabolic ornithine carbamoyltransferase (cOCT), and the carbamate kinase (CK). Pneumococcal genomes contain three ArgR-type regulators (ArgR1, ArgR2, and AhrC) that are supposed to be involved in the regulation of arginine metabolism. Here, we identified ArgR2 of TIGR4 as the regulator of the ADS and ArcD. ArgR2 binds to promoter sequences of the arc operon, and the deficiency of ArgR2 in TIGR4 abrogates expression of the ADS, including the arginine-ornithine antiporter ArcD. Intranasal infection of mice and real-time bioimaging revealed that deletion of the arcABCDT genes attenuates TIGR4. However, the acute-pneumonia model and coinfection experiments indicated that the arginine-ornithine antiporter ArcD is essential to maintain fitness, while the deficiency of ADS enzymes has a minor impact on pneumococcal fitness under in vivo conditions. Strikingly, argR2 mutant TIGR4 outcompeted the wild type in the respiratory tract, suggesting an increase in fitness and further regulatory functions of ArgR2. In contrast to TIGR4, other pneumococci, such as D39, lacking expression of ArgR2, constitutively express the ADS with a truncated nonfunctional AD. On the basis of these results, we propose that the arginine ornithine antiporter is essential to maintain pneumococcal fitness and that the genes of the ADS cluster are positively regulated in a strain-specific manner by ArgR2. IMPORTANCE: Pneumococci are the major etiologic agents of community acquired pneumonia, causing more than 1.5 million deaths annually worldwide. These versatile pathogens are highly adapted to the nutrients provided by the host niches encountered. Physiological fitness is of major importance for colonization of the nasopharyngeal cavity and dissemination during invasive infections. This work identifies the regulator ArgR2 as the activator of the S. pneumoniae TIGR4 ADS and the arginine-ornithine transporter ArcD, which is needed for uptake of the essential amino acid arginine. Although ArgR2 activates ArcD expression and uptake of arginine is required to maintain pneumococcal fitness, the deficiency of ArgR2 increases TIGR4 virulence under in vivo conditions, suggesting that other factors regulated by ArgR2 counterbalance the reduced uptake of arginine by ArcD. Thus, this work illustrates that the physiological homeostasis of pneumococci is complex and that ArgR2 plays a key role in maintaining bacterial fitness. PMID- 25538193 TI - A Ralstonia solanacearum type III effector directs the production of the plant signal metabolite trehalose-6-phosphate. AB - The plant pathogen Ralstonia solanacearum possesses two genes encoding a trehalose-6-phosphate synthase (TPS), an enzyme of the trehalose biosynthetic pathway. One of these genes, named ripTPS, was found to encode a protein with an additional N-terminal domain which directs its translocation into host plant cells through the type 3 secretion system. RipTPS is a conserved effector in the R. solanacearum species complex, and homologues were also detected in other bacterial plant pathogens. Functional analysis of RipTPS demonstrated that this type 3 effector synthesizes trehalose-6-phosphate and identified residues essential for this enzymatic activity. Although trehalose-6-phosphate is a key signal molecule in plants that regulates sugar status and carbon assimilation, the disruption of ripTPS did not alter the virulence of R. solanacearum on plants. However, heterologous expression assays showed that this effector specifically elicits a hypersensitive-like response on tobacco that is independent of its enzymatic activity and is triggered by the C-terminal half of the protein. Recognition of this effector by the plant immune system is suggestive of a role during the infectious process. IMPORTANCE: Ralstonia solanacearum, the causal agent of bacterial wilt disease, infects more than two hundred plant species, including economically important crops. The type III secretion system plays a major role in the pathogenicity of this bacterium, and approximately 70 effector proteins have been shown to be translocated into host plant cells. This study provides the first description of a type III effector endowed with a trehalose-6-phosphate synthase enzymatic activity and illustrates a new mechanism by which the bacteria may manipulate the plant metabolism upon infection. In recent years, trehalose-6-phosphate has emerged as an essential signal molecule in plants, connecting plant metabolism and development. The finding that a bacterial pathogen could induce the production of trehalose-6 phosphate in plant cells further highlights the importance of this metabolite in multiple aspects of the molecular physiology of plants. PMID- 25538194 TI - ADP-ribosylation of NLRP3 by Mycoplasma pneumoniae CARDS toxin regulates inflammasome activity. AB - The inflammasome is a major regulator of inflammation through its activation of procaspase-1, which cleaves prointerleukin-1beta (pro-IL-1beta) into its mature form. IL-1beta is a critical proinflammatory cytokine that dictates the severity of inflammation associated with a wide spectrum of inflammatory diseases. NLRP3 is a key component of the inflammasome complex, and multiple signals and stimuli trigger formation of the NLRP3 inflammasome complex. In the current study, we uncovered a yet unknown mechanism of NLRP3 inflammasome activation by a pathogen derived factor. We show that the unique bacterial ADP-ribosylating and vacuolating toxin produced by Mycoplasma pneumoniae and designated community acquired respiratory distress syndrome (CARDS) toxin activates the NLRP3 inflammasome by colocalizing with the NLRP3 inflammasome and catalyzing the ADP ribosylation of NLRP3. Mutant full-length CARDS toxin lacking ADP ribosyltransferase (ADPRT) activity and truncated CARDS toxins unable to bind to macrophages and be internalized failed to activate the NLRP3 inflammasome. These studies demonstrate that CARDS toxin-mediated ADP-ribosylation constitutes an important posttranslational modification of NLRP3, that ADPRT activity of CARDS toxin is essential for NLRP3 inflammasome activation, and that posttranslational ADPRT-mediated modification of the inflammasome is a newly discovered mechanism for inflammasome activation with subsequent release of IL-1beta and associated pathologies. IMPORTANCE: Inflammation is a fundamental innate immune response to environmental factors, including infections. The inflammasome represents a multiprotein complex that regulates inflammation via its ability to activate specific proinflammatory cytokines, resulting in an effective host protective response. However, excessive release of proinflammatory cytokines can occur following infection that skews the host response to "hyperinflammation" with exaggerated tissue damage. Mycoplasma pneumoniae, a common bacterial airway pathogen, possesses a unique protein toxin with ADP-ribosyltransferase and vacuolating properties capable of reproducing the robust inflammation and cytopathology associated with mycoplasma infection. Here, we show that the toxin uniquely activates the NLRP3 inflammasome by colocalizing with and ADP ribosylating NLRP3, possibly leading to "hyperinflammation" and thus uncovering a novel target for therapeutic intervention. PMID- 25538195 TI - Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B. AB - Several recent studies have converged upon the innate immune DNA cytosine deaminase APOBEC3B (A3B) as a significant source of genomic uracil lesions and mutagenesis in multiple human cancers, including those of the breast, head/neck, cervix, bladder, lung, ovary, and other tissues. A3B is upregulated in these tumor types relative to normal tissues, but the mechanism is unclear. Because A3B also has antiviral activity in multiple systems and is a member of the broader innate immune response, we tested the hypothesis that human papillomavirus (HPV) infection causes A3B upregulation. We found that A3B mRNA expression and enzymatic activity were upregulated following transfection of a high-risk HPV genome and that this effect was abrogated by inactivation of E6. Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause A3B upregulation, and a panel of high-risk E6 proteins triggered higher A3B levels than did a panel of low-risk or noncancer E6 proteins. Knockdown experiments in HPV-positive cell lines showed that endogenous E6 is required for A3B upregulation. Analyses of publicly available head/neck cancer data further support this relationship, as A3B levels are higher in HPV-positive cancers than in HPV-negative cancers. Taken together with the established role for high-risk E6 in functional inactivation of TP53 and published positive correlations in breast cancer between A3B upregulation and genetic inactivation of TP53, our studies suggest a model in which high-risk HPV E6, possibly through functional inactivation of TP53, causes derepression of A3B gene transcription. This would lead to a mutator phenotype that explains the observed cytosine mutation biases in HPV-positive head/neck and cervical cancers. IMPORTANCE: The innate immune DNA cytosine deaminase APOBEC3B (A3B) accounts for a large proportion of somatic mutations in cervical and head/neck cancers, but nothing is known about the mechanism responsible for its upregulation in these tumor types. Almost all cervical carcinomas and large proportions of head/neck tumors are caused by human papillomavirus (HPV) infection. Here, we establish a mechanistic link between HPV infection and A3B upregulation. The E6 oncoprotein of high-risk, but not low risk, HPV types triggers A3B upregulation, supporting a model in which TP53 inactivation causes a derepression of A3B gene transcription and elevated A3B enzyme levels. This virus-induced mutator phenotype provides a mechanistic explanation for A3B signature mutations observed in HPV-positive head/neck and cervical carcinomas and may also help to account for the preferential cancer predisposition caused by high-risk HPV isolates. PMID- 25538198 TI - Reliability and limitations of automated arrhythmia detection in telemetric monitoring after stroke. AB - BACKGROUND AND PURPOSE: Guidelines recommend continuous ECG monitoring in patients with cerebrovascular events. Studies on intensive care units (ICU) demonstrated high sensitivity but high rates of false alarms of monitoring systems resulting in desensitization of medical personnel potentially endangering patient safety. Data on patients with acute stroke are lacking. METHODS: One hundred fifty-one consecutive patients with acute cerebrovascular events were prospectively included. Automatically identified arrhythmia events were analyzed by manual ECG analysis. Muting of alarms was registered. Sensitivity was evaluated by beat-to-beat analysis of the entire recorded ECG data in a subset of patients. Ethics approval was obtained by University of Erlangen-Nuremberg. RESULTS: A total of 4809.5 hours of ECG registration and 22 509 alarms were analyzed. The automated detection algorithm missed no events but the overall rate of false alarms was 27.4%. Only 0.6% of all alarms indicated acute life threatening events and 91.4% of these alarms were incorrect. Transient muting of acoustic alarms was observed in 20.5% patients. CONCLUSIONS: Continuous ECG monitoring using automated arrhythmia detection is highly sensitive in acute stroke. However, high rates of false alarms and alarms without direct therapeutic consequence cause desensitization of personnel. Therefore, acoustic alarms may be limited to life-threatening events but standardized manual evaluation of all alarms should complement automated systems to identify clinically relevant arrhythmias. PMID- 25538197 TI - Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery. AB - OBJECTIVES: Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR). METHODS: In a multicentre double-blind randomized controlled trial of patients with AS undergoing AVR +/- coronary artery bypass graft surgery, patients were randomized to preoperative oral therapy with either perhexiline or placebo. The primary end point was incidence of inotrope use to improve haemodynamic performance due to a low cardiac output state during the first 6 h of reperfusion, judged by a blinded end points committee. Secondary outcome measures included haemodynamic measurements, electrocardiographic and biochemical markers of new myocardial injury and clinical safety outcome measures. RESULTS: The trial was halted early on the advice of the Data Safety and Monitoring Board. Sixty-two patients were randomized to perhexiline and 65 to placebo. Of these, 112 (54 perhexiline and 48 placebo) patients received the intervention, remained in the trial at the time of the operation and were analysed. Of 110 patients who achieved the primary end point, 30 patients (16 perhexiline and 14 placebo) had inotropes started appropriately; there was no difference in the incidence of inotrope usage OR of 1.65 [confidence interval (CI): 0.67-4.06] P = 0.28. There was no difference in myocardial injury as evidenced by electrocardiogram odds ratio (OR) of 0.36 (CI: 0.07-1.97) P = 0.24 or postoperative troponin release. Gross secondary outcome measures were comparable between the groups. CONCLUSIONS: Perhexiline as a metabolic modulator to enhance standard myocardial protection does not provide an additional benefit in haemodynamic performance or attenuate myocardial injury in the hypertrophied heart secondary to AS. The role of perhexiline in cardiac surgery is limited. PMID- 25538196 TI - The Vibrio cholerae VprA-VprB two-component system controls virulence through endotoxin modification. AB - The bacterial cell surface is the first structure the host immune system targets to prevent infection. Cationic antimicrobial peptides of the innate immune system bind to the membrane of Gram-negative pathogens via conserved, surface-exposed lipopolysaccharide (LPS) molecules. We recently reported that modern strains of the global intestinal pathogen Vibrio cholerae modify the anionic lipid A domain of LPS with a novel moiety, amino acids. Remarkably, glycine or diglycine addition to lipid A alters the surface charge of the bacteria to help evade the cationic antimicrobial peptide polymyxin. However, the regulatory mechanisms of lipid A modification in V. cholerae are unknown. Here, we identify a novel two component system that regulates lipid A glycine modification by responding to important biological cues associated with pathogenesis, including bile, mildly acidic pH, and cationic antimicrobial peptides. The histidine kinase Vc1319 (VprB) and the response regulator Vc1320 (VprA) respond to these signals and are required for the expression of the almEFG operon that encodes the genes essential for glycine modification of lipid A. Importantly, both the newly identified two component system and the lipid A modification machinery are required for colonization of the mammalian host. This study demonstrates how V. cholerae uses a previously unknown regulatory network, independent of well-studied V. cholerae virulence factors and regulators, to respond to the host environment and cause infection. IMPORTANCE: Vibrio cholerae, the etiological agent of cholera disease, infects millions of people every year. V. cholerae El Tor and classical biotypes have been responsible for all cholera pandemics. The El Tor biotype responsible for the current seventh pandemic has displaced the classical biotype worldwide and is highly resistant to cationic antimicrobial peptides, like polymyxin B. This resistance arises from the attachment of one or two glycine residues to the lipid A domain of lipopolysaccharide, a major surface component of Gram-negative bacteria. Here, we identify the VprAB two-component system that regulates the charge of the bacterial surface by directly controlling the expression of genes required for glycine addition to lipid A. The VprAB-dependent lipid A modification confers polymyxin B resistance and contributes significantly to pathogenesis. This finding is relevant for understanding how Vibrio cholerae has evolved mechanisms to facilitate the evasion of the host immune system and increase bacterial fitness. PMID- 25538199 TI - Alberta stroke program early computed tomographic scoring performance in a series of patients undergoing computed tomography and MRI: reader agreement, modality agreement, and outcome prediction. AB - BACKGROUND AND PURPOSE: In this study, we compare the performance of pretreatment Alberta Stroke Program Early Computed Tomographic scoring (ASPECTS) using noncontrast CT (NCCT) and MRI in a large endovascular therapy cohort. METHODS: Prospectively enrolled patients underwent baseline NCCT and MRI and started endovascular therapy within 12 hours of stroke onset. Inclusion criteria for this analysis were evaluable pretreatment NCCT, diffusion-weighted MRI (DWI), and 90 day modified Rankin Scale scores. Two expert readers graded ischemic change on NCCT and DWI using the ASPECTS. ASPECTS scores were analyzed with the full scale or were trichotomized (0-4 versus 5-7 versus 8-10) or dichotomized (0-7 versus 8 10). Good functional outcome was defined as a 90-day modified Rankin Scale score of 0 to 2. RESULTS: Seventy-four patients fulfilled our study criteria. The full scale inter-rater agreement for CT-ASPECTS and DWI-ASPECTS was 0.579 and 0.867, respectively. DWI-ASPECTS correlated with functional outcome (P=0.004), whereas CT-ASPECTS did not (P=0.534). Both DWI-ASPECTS and CT-ASPECTS correlated with DWI volume. The receiver operating characteristic analysis revealed that DWI-ASPECTS outperformed both CT-ASPECTS and the time interval between symptom onset and start of the procedure for predicting good functional outcome (modified Rankin Scale score, <=2) and DWI volume >=70 mL. CONCLUSION: Inter-rater agreement for DWI-ASPECTS was superior to that for CT-ASPECTS. DWI-ASPECTS outperformed NCCT ASPECTS for predicting functional outcome at 90 days. PMID- 25538200 TI - Chronic ischemia alters brain microstructural integrity and cognitive performance in adult moyamoya disease. AB - BACKGROUND AND PURPOSE: The mechanisms underlying frontal lobe dysfunction in moyamoya disease (MMD) are unknown. We aimed to determine whether chronic ischemia induces subtle microstructural brain changes in adult MMD and evaluated the association of changes with neuropsychological performance. METHODS: MRI, including 3-dimensional T1-weighted imaging and diffusion tensor imaging, was performed in 23 adult patients with MMD and 23 age-matched controls and gray matter density and major diffusion tensor imaging indices were compared between them; any alterations in the patients were tested for associations with age, ischemic symptoms, hemodynamic compromise, and neuropsychological performance. RESULTS: Decrease in gray matter density, associated with hemodynamic compromise (P<0.05), was observed in the posterior cingulate cortex of patients with MMD. Widespread reduction in fractional anisotropy and increases in radial diffusivity and mean diffusivity in some areas were also observed in bilateral cerebral white matter. The fractional anisotropy (r=0.54; P<0.0001) and radial diffusivity (r= 0.41; P<0.01) of white matter significantly associated with gray matter density of the cingulate cortex. The mean fractional anisotropy of the white matter tracts of the lateral prefrontal, cingulate, and inferior parietal regions were significantly associated with processing speed, executive function/attention, and working memory. CONCLUSIONS: In adult MMD, there were more white matter abnormalities than gray matter changes. Disruption of white matter may play a pivotal role in the development of cognitive dysfunction. PMID- 25538202 TI - Comparing National Institutes of Health Stroke Scale among a stroke team and helicopter emergency medical service providers. AB - BACKGROUND AND PURPOSE: The use of tissue-type plasminogen activator is limited to a maximum of 4.5 hours after symptom-onset. Endovascular recanalization may improve outcomes for large-vessel occlusions (LVO), but efficacy decreases with time from symptom-onset. A National Institutes of Health Stroke Scale (NIHSS) score >=12 is predictive of LVOs and could be used to triage patients if appropriately used by prehospital providers. The NIHSS has been considered too complex and has not been validated in the prehospital setting. METHODS: We reviewed all patients with ischemic stroke transported by helicopter emergency medical services (HEMS) to a single comprehensive stroke center in 2010. HEMS NIHSS were compared with in-hospital stroke team physician scores. NIHSS was categorized based on 3 clinically relevant groupings and ability to predict LVO was investigated. RESULTS: Three-hundred five patients met inclusion criteria, 68.9% having LVO. Moderate agreement existed between HEMS and physicians (72.1%; kappa=0.571). Interclass correlation was 0.879 (95% confidence interval, 0.849 0.904). Excluding patients with tissue-type plasminogen activator before HEMS transport, there were 216 patients and good agreement (82.7%; kappa=0.619). Among patients presenting within 8 hours postonset and NIHSS>=12, HEMS had a sensitivity of 55.9% and positive predictive value of 83.7% in predicting LVO. CONCLUSIONS: HEMS providers can administer NIHSS with moderate to good agreement with the receiving stroke team. The use of the NIHSS in HEMS may identify patients with LVO and inform triage decisions for patients ineligible for tissue type plasminogen activator. PMID- 25538201 TI - Effect of a broad-specificity chemokine-binding protein on brain leukocyte infiltration and infarct development. AB - BACKGROUND AND PURPOSE: Expression of numerous chemokine-related genes is increased in the brain after ischemic stroke. Here, we tested whether post-stroke administration of a chemokine-binding protein (CBP), derived from the parapoxvirus bovine papular stomatitis virus, might reduce infiltration of leukocytes into the brain and consequently limit infarct development. METHODS: The binding spectrum of the CBP was evaluated in chemokine ELISAs, and binding affinity was determined using surface plasmon resonance. Focal stroke was induced in C57Bl/6 mice by middle cerebral artery occlusion for 1 hour followed by reperfusion for 23 or 47 hours. Mice were treated intravenously with either bovine serum albumin (10 MUg) or CBP (10 MUg) at the commencement of reperfusion. At 24 or 48 hours, we assessed plasma levels of the chemokines CCL2/MCP-1 and CXCL2/MIP-2, as well as neurological deficit, brain leukocyte infiltration, and infarct volume. RESULTS: The CBP interacted with a broad spectrum of CC, CXC, and XC chemokines and bound CCL2/MCP-1 and CXCL2/MIP-2 with high affinity (pM range). Stroke markedly increased plasma levels of CCL2/MCP-1 and CXCL2/MIP-2, as well as numbers of microglia and infiltrating leukocytes in the brain. Increases in plasma chemokines were blocked in mice treated with CBP, in which there was reduced neurological deficit, fewer brain-infiltrating leukocytes, and ~50% smaller infarcts at 24 hours compared with bovine serum albumin-treated mice. However, CBP treatment was no longer protective at 48 hours. CONCLUSIONS: Post stroke administration of CBP can reduce plasma chemokine levels in association with temporary atten uation of brain inflammation and infarct volume development. PMID- 25538203 TI - Activation of the high-mobility group box 1 protein-receptor for advanced glycation end-products signaling pathway in rats during neurogenesis after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote neurogenesis that supports functional recovery. How HMGB1 regulates or participates in this process is unclear, as are the pattern recognition receptors and signaling pathways involved. METHODS: ICH was induced by injection of collagenase in Sprague-Dawley rats, which were treated 3 days later with saline, with the HMGB1 inhibitor ethyl pyruvate or with FPS-ZM1, an antagonist of the receptor for advanced glycation end-products. A Sham group was treated with saline solution instead of collagenase and then treated 3 days later with saline again or with ethyl pyruvate or N-benzyl-4 chloro-N-cyclohexylbenzamide (FPS-ZM1). Expression of the following proteins was measured by Western blot, immunohistochemistry, or immunofluorescence: HMGB1, receptor for advanced glycation end-products, toll-like receptor (TLR)-2, TLR4, brain-derived neurotrophic factor, and matrix metalloproteinase-9. The number of cells positive for 5-bromo-2-deoxyuridine or doublecortin was determined by immunohistochemistry and immunofluorescence. RESULTS: Levels of HMGB1, receptor for advanced glycation end-products, TLR4, TLR2, brain-derived neurotrophic factor, and matrix metalloproteinase-9 were significantly higher 14 days after ICH than at baseline, as were the numbers of 5-bromo-2-deoxyuridine- or doublecortin-positive cells. At the same time, HMGB1 moved from the nucleus into the cytoplasm. Administering ethyl pyruvate significantly reduced all these ICH induced increases, except the increase in TLR4 and TLR2. Administering FPS-ZM1 reduced the ICH-induced increases in the expression of brain-derived neurotrophic factor and matrix metalloproteinase-9 and in the numbers of 5-bromo-2 deoxyuridine- or doublecortin-positive cells. CONCLUSIONS: These findings suggest that HMGB1 acts via the receptor for advanced glycation end-products signaling pathway to promote neurogenesis in later phases of ICH. PMID- 25538204 TI - Changes in functional outcome over the first year after stroke: an observational study from the Swedish stroke register. AB - BACKGROUND AND PURPOSE: Large longitudinal studies on stroke outcome are scarce. The aim of this study was to analyze predictors and changes in functional outcome during the first year poststroke. METHODS: Data on patients who were independent in activities of daily living (ADL) and hospitalized for acute stroke in 2008 to 2010 were obtained from the Swedish Stroke Register. Case fatality was assessed by linkage to the Swedish Population Register. ADL was defined by independence or dependence in dressing, toileting, and indoor mobility and assessed at 3 and 12 months. Predictors of ADL dependency were assessed through multivariate analysis. RESULTS: In total, 64 746 patients were included. Case fatality at 3 months was 13.1% (men 11.6% versus women 14.8%; P<0.0001) and at 12 months 18.2% (men 16.4% versus women 20.3%; P<0,0001). In the 35 064 followed-up survivors, ADL dependency rates at 3 and 12 months were 16.2% (men 15.9% versus women 19.2%; P<0.0001) and 28.3% (men 22.7% versus women 34.9%, P<0.0001), respectively. Factors predicting deterioration to ADL dependency between 3 and 12 months were female sex (relative risk [RR]=1.56; 95% confidence interval [CI], 1.50-1.70), diabetes mellitus (RR=1.50; 95% CI, 1.05-1.60), comatose at admittance (RR=2.34; 95% CI, 1.79-3.05), previous stroke (RR=1.52; 95% CI, 1.43-1.61), hemorrhagic or unspecified stroke (RR=1.14; 95% CI, 1.05-1.25), and atrial fibrillation (RR= 1.11; 95% CI, 1.04-1.17). CONCLUSIONS: Transition from ADL independence to dependence was observed in a high proportion of patients between 3 and 12 months, challenging the common belief that functioning after stroke is stable beyond 3 months. Deterioration occurred more commonly in women, among whom 1/6 converted to dependency. PMID- 25538205 TI - Progress in aldosteronism: a review of the prevalence of primary aldosteronism in pre-hypertension and hypertension. AB - Primary aldosteronism (PA) secondary to excessive and/or autonomous aldosterone secretion from the renin-angiotensin system accounts for ~10% of cases of hypertension and is primarily caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenomas (APAs). Although the diagnosis has traditionally been supported by low serum potassium levels, normokalaemic and even normotensive forms of PA have been identified expanding further the clinical phenotype. Moreover, recent evidence has shown that serum aldosterone correlates with increased blood pressure (BP) in the general population and even moderately raised aldosterone levels are linked to increased cardiovascular morbidity and mortality. In addition, aldosterone antagonists are effective in BP control even in patients without evidence of dysregulated aldosterone secretion. These findings indicate a higher prevalence of aldosterone excess among hypertensive patients than previously considered that could be attributed to disease heterogeneity, aldosterone level fluctuations related to an ACTH effect or inadequate sensitivity of current diagnostic means to identify apparent aldosterone excess. In addition, functioning aberrant receptors expressed in the adrenal tissue have been found in a subset of PA cases that could also be related to its pathogenesis. Recently a number of specific genetic alterations, mainly involving ion homeostasis across the membrane of zona glomerulosa, have been detected in ~50% of patients with APAs. Although specific genotype/phenotype correlations have not been clearly identified, differential expression of these genetic alterations could also account for the wide clinical phenotype, variations in disease prevalence and performance of diagnostic tests. In the present review, we critically analyse the current means used to diagnose PA along with the role that ACTH, aberrant receptor expression and genetic alterations may exert, and provide evidence for an increased prevalence of aldosterone dysregulation in patients with essential hypertension and pre-hypertension. PMID- 25538206 TI - Long-term results of the surgical management of insulinoma patients with MEN1: a Groupe d'etude des Tumeurs Endocrines (GTE) retrospective study. AB - OBJECTIVE: Management of insulinomas in the context of MEN1 remains poorly studied. The aim of this study was to evaluate long-term results of various surgical approaches in a large cohort of insulinoma-MEN1 patients. DESIGN AND METHODS: Consecutive insulinoma-MEN1 patients operated on for a nonmetastatic insulinoma between 1957 and 2010 were retrospectively selected from the MEN1 database of the French Endocrine Tumor Group. The type of surgery was categorized as distal pancreatectomy (DP), total pancreatectomy/cephalic duodenopancreatectomy (TP/CDP), or enucleation (E). Primary endpoint was time until recurrence of hypoglycemia after initial surgery. Secondary endpoints were post-operative complications. RESULTS: The study included 73 patients (median age=28 years). Surgical procedures were DP (n=46), TP/CDP (n=9), or E (n=18). After a median post-operative follow-up of 9.0 years (inter-quartile range (IQR): 2.5-16.5 years), 60/73 patients (82.2%) remained hypoglycemia free. E and TP/CDP were associated with a higher risk of recurrent hypoglycemia episodes (unadjusted hazard ratio: 6.18 ((95% CI: 1.54-24.8); P=0.010) for E vs DP and 9.51 ((95% CI: 1.85-48.8); P=0.007) for TP/CDP vs DP. After adjustment for International Union against Cancer pTNM classification, enucleation remained significantly associated with a higher probability of recurrence. Long-term complications had occurred in 20 (43.5%) patients with DP, five (55.6%) with TP/CDP, but in none of the patients who have undergone E (P=0.002). CONCLUSION: In the French Endocrine database, DP is associated with a lower risk for recurrent hypoglycemia episodes. Due to lower morbidity, E alone might be considered as an alternative. PMID- 25538208 TI - Monocyte fate in atherosclerosis. AB - Monocytes and their descendant macrophages are essential to the development and exacerbation of atherosclerosis, a lipid-driven inflammatory disease. Lipid-laden macrophages, known as foam cells, reside in early lesions and advanced atheromata. Our understanding of how monocytes accumulate in the growing lesion, differentiate, ingest lipids, and contribute to disease has advanced substantially over the last several years. These cells' remarkable phenotypic and functional complexity is a therapeutic opportunity: in the future, treatment and prevention of cardiovascular disease and its complications may involve specific targeting of atherogenic monocytes/macrophages and their products. PMID- 25538207 TI - Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. AB - OBJECTIVE: Vascular and valvular calcifications are pathological processes regulated by resident cells, and depending on a complex interplay between calcification promoters and inhibitors, resembling skeletal metabolism. Here, we study the role of the vitamin K-dependent Gla-rich protein (GRP) in vascular and valvular calcification processes. APPROACH AND RESULTS: Immunohistochemistry and quantitative polymerase chain reaction showed that GRP expression and accumulation are upregulated with calcification simultaneously with osteocalcin and matrix Gla protein (MGP). Using conformation-specific antibodies, both gamma carboxylated GRP and undercarboxylated GRP species were found accumulated at the sites of mineral deposits, whereas undercarboxylated GRP was predominant in calcified aortic valve disease valvular interstitial cells. Mineral-bound GRP, MGP, and fetuin-A were identified by mass spectrometry. Using an ex vivo model of vascular calcification, gamma-carboxylated GRP but not undercarboxylated GRP was shown to inhibit calcification and osteochondrogenic differentiation through alpha-smooth muscle actin upregulation and osteopontin downregulation. Immunoprecipitation assays showed that GRP is part of an MGP-fetuin-A complex at the sites of valvular calcification. Moreover, extracellular vesicles released from normal vascular smooth muscle cells are loaded with GRP, MGP, and fetuin-A, whereas under calcifying conditions, released extracellular vesicles show increased calcium loading and GRP and MGP depletion. CONCLUSIONS: GRP is an inhibitor of vascular and valvular calcification involved in calcium homeostasis. Its function might be associated with prevention of calcium-induced signaling pathways and direct mineral binding to inhibit crystal formation/maturation. Our data show that GRP is a new player in mineralization competence of extracellular vesicles possibly associated with the fetuin-A-MGP calcification inhibitory system. GRP activity was found to be dependent on its gamma-carboxylation status, with potential clinical relevance. PMID- 25538209 TI - CRISPR-Cas9 genome editing of a single regulatory element nearly abolishes target gene expression in mice--brief report. AB - OBJECTIVE: To ascertain the importance of a single regulatory element in the control of Cnn1 expression using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) genome editing. APPROACH AND RESULTS: The CRISPR/Cas9 system was used to produce 3 of 18 founder mice carrying point mutations in an intronic CArG box of the smooth muscle cell restricted Cnn1 gene. Each founder was bred for germline transmission of the mutant CArG box and littermate interbreeding to generate homozygous mutant (Cnn1(DeltaCArG/DeltaCArG)) mice. Quantitative reverse transcription polymerase chain reaction, Western blotting, and confocal immunofluorescence microscopy showed dramatic reductions in Cnn1 mRNA and CNN1 protein expression in Cnn1(DeltaCArG/DeltaCArG) mice with no change in other smooth muscle cell restricted genes and little evidence of off-target edits elsewhere in the genome. In vivo chromatin immunoprecipitation assay revealed a sharp decrease in binding of serum response factor to the mutant CArG box. Loss of CNN1 expression was coincident with an increase in Ki-67 positive cells in the normal vessel wall. CONCLUSIONS: CRISPR/Cas9 genome editing of a single CArG box nearly abolishes Cnn1 expression in vivo and evokes increases in smooth muscle cell DNA synthesis. This facile genome editing system paves the way for a new generation of studies designed to test the importance of individual regulatory elements in living animals, including regulatory variants in conserved sequence blocks linked to human disease. PMID- 25538210 TI - Comparing cystic fibrosis outcomes across the pond. PMID- 25538211 TI - Adrenal tumours: how to establish malignancy. AB - Adrenal masses are commonly found in the course of abdominal investigations and present diagnostic challenges. The foremost issue is whether the mass is the cause of the symptoms being investigated. Additional important clinical questions are: (1) is the adrenal mass benign or malignant and (2) whether the adrenal mass is functional or non-functional? We present a case of a 48-year-old man with severe abdominal pain. Imaging revealed a very large adrenal mass. Differential diagnostic procedures were performed and a diagnosis of primary adrenal lymphoma, an extremely rare cause of adrenal malignancy, was made. He proceeded to chemotherapy with cyclical cyclophosphamide, doxorubicin, etoposide and prednisolone, in addition to rituximab. This case illustrates the importance of establishing the nature of adrenal masses, to rapidly facilitate appropriate treatment. PMID- 25538212 TI - Sclerosing osteomyelitis of Garre: management of femoral pain by intramedullary nailing. AB - We describe a case of chronic sclerosing osteomyelitis of Garre in a 50-year-old woman occurring in her right femur and presenting with uncontrolled pain. The patient was initially treated with intramedullary reaming of the femur, but 3 years later re-presented with similar symptoms. This required further reaming and intramedullary nailing, achieving good clinical outcomes and lasting pain relief at 8-year follow-up. PMID- 25538213 TI - Compartment syndrome resulting from undetected ulnar artery injury in the absence of a forearm fracture. AB - A 6-year-old boy presented following a transient crush injury to his forearm. He displayed mild abrasions but no laceration or associated fractures. The injury resulted in traumatic rupture of the ulnar artery, which caused a large forearm haematoma and an acute forearm compartment syndrome. Prompt clinical diagnosis and operative intervention were required to prevent disastrous consequences. PMID- 25538214 TI - Internal hernia in late pregnancy after laparoscopic Roux-en-Y gastric bypass. AB - A 27-year-old patient in late pregnancy presented to the department of obstetrics with crampy abdominal pain located in the right flank, 3 years after a laparoscopic Roux-en-Y gastric bypass. Clinical investigation showed tenderness on palpation in the upper abdomen without signs of peritonitis. The cardiotocogram and blood tests were normal. The ultrasound showed a hydronephrosis on the right side, and a pigtail catheter was inserted. The abdominal symptoms did not abate and the abdominal surgeon was consulted 36 hours after admission. Diagnostic laparoscopy was performed promptly because of high suspicion of internal hernia (IH). Laparoscopy showed IH at the mesojejunal intermesenteric defect with a herniated common channel and volvulus of the anastomosis. Conversion to open reduction and complete closure with non absorbable interrupted sutures was performed. Small bowel resection was avoided. The patient was discharged 10 days after the operation and a healthy boy was born 4 weeks later. PMID- 25538215 TI - Chronic meningitis with intracranial hypertension and bilateral neuroretinitis following Mycoplasma pneumoniae infection. AB - A previously well 12-year-old boy presented with a 2-week history of headache, nausea, vomiting and left-sided weakness. He subsequently developed meningism, right abducens nerve palsy, persistent papilloedema and reduced visual acuity in association with a bilateral macular star, consistent with neuroretinitis. Cerebrospinal fluid (CSF) examination indicated chronic meningitis and serological testing confirmed recent Mycoplasma pneumoniae infection, although PCR in CSF was negative. He was treated for aseptic meningitis with ceftriaxone, aciclovir, azithromycin and acetazolamide for intracranial hypertension, with gradual improvement in clinical condition and visual acuity over several weeks. This is the first report of M. pneumoniae chronic meningitis further complicated with bilateral neuroretinitis and intracranial hypertension. Evidence of central nervous system inflammation in the absence of direct infection suggests an immune mediated pathophysiology. Although the use of macrolides with antibiotic and immunomodulatory activity might be beneficial, it was not possible to ascertain whether it influenced clinical recovery in this case. PMID- 25538216 TI - Long-term repetitive transcranial magnetic stimulation therapy: new research questions arising from one tinnitus case? AB - Tinnitus may become refractory to treatment and disabling. Brain transcranial magnetic stimulation (TMS) has shown promise as a therapy, but has been employed primarily short-term. We treated a patient with 5 weeks of weekly repetitive TMS (rTMS), followed by 6 months of monthly rTMS. He was a 75-year-old dentist with chronic tinnitus from occupational noise exposure. Physical examination and MRIs of the auditory canals and brain had revealed no lesions. The patient showed a general gradual, progressive improvement on per cent of severe tinnitus diary days (from baseline 100% to 33%), tinnitus handicap inventory (from baseline score 70 to 18), and mini-tinnitus questionnaire (from baseline score 17 to 6). No changes occurred in serial audiograms. Transient adverse events were a headache during stimulation, and dizziness 30 min after treatment. Implications and questions for future non-invasive neuromodulation clinical research raised by our case are discussed. PMID- 25538217 TI - Granulocytic sarcoma in a patient with chronic myeloid leukaemia in complete haematological, cytogenetic and molecular remission. AB - Granulocytic sarcoma, also known as myeloid sarcoma, is an extramedullary tumour composed of immature myeloid cells. Granulocytic sarcoma is typically found in patients with acute myeloid leukaemia, accelerated phase or blast crisis of chronic myeloid leukaemia, myelodysplastic syndrome, or as an isolated event without bone marrow involvement. We present a case of granulocytic sarcoma in a patient with chronic myeloid leukaemia in the setting of complete haematological, molecular and cytogenetic remission. Our patient was first treated with imatinib for chronic-phase chronic myeloid leukaemia. After maintaining remission for 42 months, he developed a granulocytic sarcoma in his spine. In this case report, we describe our case, along with the three other cases reported in the literature. In addition to being a rare diagnosis, this case demonstrates the importance of being vigilant in diagnosing the cause of back pain and atypical symptoms in patients with a history of leukaemia. PMID- 25538218 TI - A 'silent', new polymorphism of factor H and apparent de novo atypical haemolytic uraemic syndrome after kidney transplantation. AB - The pathophysiology of atypical haemolytic-uraemic syndrome (aHUS) occurring de novo after renal transplantation may include genetic mutations of regulators of complement activation, but they are still rarely determined. A 41-year-old female renal transplant recipient presented two very different episodes of thrombotic microangiopathy. The first episode was associated with antibody-mediated rejection and the second was an isolated, acute aHUS, successfully treated with eculizumab. The diagnosis included a genetic analysis and we found a synonymous variant in the Complement Factor H (CFH) gene, c2634C>T (p.His878=) and low factor H (FH) activity during both events. In conclusion, the diagnosis of aHUS should be considered when TMA is associated with an AMR episode. In this setting, a silent polymorphism of factor H may be responsible for these rare cases of "de novo" aHUS after transplantation. PMID- 25538219 TI - Childhood hypopigmented mycosis fungoides: a commonly delayed diagnosis. AB - Primary cutaneous lymphomas (PCLs) are exceedingly rare in children and adolescents, with mycosis fungoides (MF) being the most frequent PCL diagnosed in childhood. There are numerous unusual clinical variants of MF, including the hypopigmented type form (HMF). HMF is exceptional overall, but comparatively common among children. We present an 8-year-old boy with a 3-year history of progressive, generalised, scaly, hypopigmented round patches and few erythematous papules. He was first diagnosed with pityriasis alba (PA), and moisturisers were prescribed with no improvement. Skin biopsy showed typical features of MF, and the patient was successfully treated with narrowband ultraviolet B. HMF may simulate atopic dermatitis, PA, pityriasis lichenoides, tinea versicolour, vitiligo, postinflammatory hypopigmentation or leprosy. Therefore, persistent and unusual hypopigmented lesions should be biopsied to rule out this rare variant of MF. PMID- 25538221 TI - Assessment of cardiomyocyte contraction in human-induced pluripotent stem cell derived cardiomyocytes. AB - Functional changes to cardiomyocytes are a common cause of attrition in preclinical and clinical drug development. Current approaches to assess cardiomyocyte contractility in vitro are limited to low-throughput methods not amenable to early drug discovery. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) were used to assess their suitability to detect drug induced changes in cardiomyocyte contraction. Application of field stimulation and measurement of cardiac contraction (IonOptix edge detection) and Ca(2+) transients confirmed hiPS-CMs to be a suitable model to investigate drug-induced changes in cardiomyocyte contractility. Using a live cell, fast kinetic fluorescent assay with a Ca(2+) sensitive dye to test 31 inotropic and 20 non inotropic compounds in vivo, we report that hiPS-CMs provide a high-throughput experimental model to detect changes in cardiomyocyte contraction that is applicable to early drug discovery with a sensitivity and specificity of 87% and 70%, respectively. Moreover, our data provide evidence of the detection of this liability at therapeutically relevant concentrations with throughput amenable to influencing chemical design in drug discovery. Measurement of multiple parameters of the Ca(2+) transient in addition to the number of Ca(2+) transients offered no insight into the mechanism of cardiomyocyte contraction. PMID- 25538220 TI - USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses. AB - Reversible protein ubiquitylation plays important roles in various processes including DNA repair. Here, we identify the deubiquitylase USP45 as a critical DNA repair regulator. USP45 associates with ERCC1, a subunit of the DNA repair endonuclease XPF-ERCC1, via a short acidic motif outside of the USP45 catalytic domain. Wild-type USP45, but not a USP45 mutant defective in ERCC1 binding, efficiently deubiquitylates ERCC1 in vitro, and the levels of ubiquitylated ERCC1 are markedly enhanced in USP45 knockout cells. Cells lacking USP45 are hypersensitive specifically to UV irradiation and DNA interstrand cross-links, similar to cells lacking ERCC1. Furthermore, the repair of UV-induced DNA damage is markedly reduced in USP45-deficient cells. ERCC1 translocation to DNA damage induced subnuclear foci is markedly impaired in USP45 knockout cells, possibly accounting for defective DNA repair. Finally, USP45 localises to sites of DNA damage in a manner dependent on its deubiquitylase activity, but independent of its ability to bind ERCC1-XPF. Together, these results establish USP45 as a new regulator of XPF-ERCC1 crucial for efficient DNA repair. PMID- 25538223 TI - Photo Quiz: Fungal sinusitis in a 75-year-old neutropenic cancer patient. PMID- 25538222 TI - Association between alendronate and atypical femur fractures: a meta-analysis. AB - Alendronate (ALN) is a commonly used drug for the treatment of osteoporosis. Atypical femur fractures (AFFs) have been associated with long-term use of ALN and have recently become the subject of considerable attention as ALN use increases. This meta-analysis aimed to determine the relationship between ALN and AFF. The Embase, PubMed, and Cochrane library databases were searched for relevant studies published before November 6, 2014. Studies clearly reporting the relationship between ALN and AFF were selected for our analysis. From these results, the relationship between ALN and AFF was analyzed. Weighted mean differences were calculated using a random-effects model. Five studies were included in this meta-analysis. The results revealed that the use of ALN will not increase the risk of AFF in short term (P>0.05), but there will be a risk of AFF (P<0.05) with long-term (>5 years) use of ALN. These findings indicate that long term use of ALN is a risk factor for AFF and that more attention should be paid to the clinical applications of ALN. PMID- 25538225 TI - Intraindividual variation and short-term temporal trend in DNA methylation of human blood. AB - BACKGROUND: Between- and within-person variation in DNA methylation levels are important parameters to be considered in epigenome-wide association studies. Temporal change is one source of within-person variation in DNA methylation that has been linked to aging and disease. METHODS: We analyzed CpG-site-specific intraindividual variation and short-term temporal trend in leukocyte DNA methylation among 24 healthy Chinese women, with blood samples drawn at study entry and after 9 months. Illumina HumanMethylation450 BeadChip was used to measure methylation. Intraclass correlation coefficients (ICC) and trend estimates were summarized by genomic location and probe type. RESULTS: The median ICC was 0.36 across nonsex chromosomes and 0.80 on the X chromosome. There was little difference in ICC profiles by genomic region and probe type. Among CpG loci with high variability between participants, more than 99% had ICC > 0.8. Statistically significant trend was observed in 10.9% CpG loci before adjustment for cell-type composition and in 3.4% loci after adjustment. CONCLUSIONS: For CpG loci differentially methylated across subjects, methylation levels can be reliably assessed with one blood sample. More samples per subject are needed for low-variability and unmethylated loci. Temporal changes are largely driven by changes in cell-type composition of blood samples, but temporal trend unrelated to cell types is detected in a small percentage of CpG sites. IMPACT: This study shows that one measurement can reliably assess methylation of differentially methylated CpG loci. Cancer Epidemiol Biomarkers Prev; 24(3); 490-7. (c)2014 AACR. PMID- 25538228 TI - Pediatric cardiac surgery: the long view. PMID- 25538226 TI - A pooled analysis of cigarette smoking and risk of multiple myeloma from the international multiple myeloma consortium. AB - BACKGROUND: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates. METHODS: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center. RESULTS: Neither ever smokers (OR, 0.95; 95% CI, 0.87-1.05), current smokers (OR, 0.82; 95% CI, 0.73-0.93), nor former smokers (OR, 1.03; 95% CI, 0.92-1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups. CONCLUSION: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma. IMPACT: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. Cancer Epidemiol Biomarkers Prev; 24(3); 631-4. (c)2014 AACR. PMID- 25538229 TI - Progress in late results among pediatric cardiac surgery patients: a population based 6-decade study with 98% follow-up. AB - BACKGROUND: Surgical treatment of congenital cardiac defects in Finland started >60 years ago. We analyzed the survival of all the pediatric cardiac surgery patients operated on before 2010. METHODS AND RESULTS: Data were obtained retrospectively from a pediatric cardiac surgery database. Patient status was received from the Finnish Population Registry. Survival was determined with the Kaplan-Meier method, and the survival rate was compared with a sex- and age matched general population. Between 1953 and 2009, 13 876 cardiac operations were performed on 10 964 pediatric patients in Finland. Follow-up coverage was 98%. The 60-year survival for the entire study was 70% versus 86% for the general population. The number and proportion of severe cardiac defects increased in the 2000s. The long-term survival of patients with severe defects improved significantly across decades. For instance, the 22-year survival rate of patients with transposition of the great arteries operated on in 1953 to 1989 and in 1990 to 2009 improved from 71% to 93% (hazard ratio for death, 0.29; 95% confidence interval, 0.17-0.49; P<0.0001), respectively. The mean patient age at operation decreased from 8.9 to 2.2 years (95% confidence interval, 6.2-7.1; P<0.0001). The early mortality of patients decreased from a maximum of 7% in the 1970s to 3% in the 2000s (95% confidence interval, 0.05-0.08; P<0.0001). CONCLUSIONS: Patients are diagnosed and treated at an increasingly younger age. Advanced diagnostics, surgical methods, and postoperative intensive care have led to substantial improvements in both early and late results among pediatric cardiac surgery patients. PMID- 25538227 TI - Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia. AB - BACKGROUND: Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. METHODS AND RESULTS: Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A2B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia. CONCLUSIONS: We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets. PMID- 25538230 TI - Achievements in congenital heart defect surgery: a prospective, 40-year study of 7038 patients. AB - BACKGROUND: This article presents an update of the results achieved by modern surgery in congenital heart defects (CHDs) over the past 40 years regarding survival and the need for reoperations, especially focusing on the results from the past 2 decades. METHODS AND RESULTS: From 1971 to 2011, all 7038 patients <16 years of age undergoing surgical treatment for CHD at Rikshospitalet (Oslo, Norway) were enrolled prospectively. CHD diagnosis, date, and type of all operations were recorded, as was all-cause mortality until December 31, 2012. CHDs were classified as simple (3751/7038=53.2%), complex (2918/7038=41.5%), or miscellaneous (369/7037=5.2%). Parallel to a marked, sequential increase in operations for complex defects, median age at first operation decreased from 1.6 years in 1971 to 1979 to 0.19 years in 2000 to 2011. In total, 1033 died before January 1, 2013. Cumulative survival until 16 years of age in complex CHD operated on in 1971 to 1989 versus 1990 to 2011 was 62.4% versus 86.9% (P<0.0001). In the comparison of patients operated on in 2000 to 2004 versus 2005 to 2011, 1-year survival was 90.7% versus 96.5% (P=0.003), and 5-year cumulative survival was 88.8% versus 95.0% (P=0.0003). In simple versus complex defects, 434 (11.6%) versus 985 (33.8%) patients needed at least 1 reoperation before 16 years of age. In complex defects, 5-year cumulative freedom of reoperation among patients operated on in 1990 to 1999 versus 2000 to 2011 was 66% versus 73% (P=0.0001). CONCLUSIONS: Highly significant, sequential improvements in survival and reductions in reoperations after CHD surgery were seen. A future challenge is to find methods to reduce the need for reoperations and further reduce long-term mortality. PMID- 25538231 TI - Silencing of long noncoding RNA MALAT1 by miR-101 and miR-217 inhibits proliferation, migration, and invasion of esophageal squamous cell carcinoma cells. AB - MALAT1, a highly conserved long noncoding RNA, is deregulated in several types of cancers. However, its role in esophageal squamous cell carcinoma (ESCC) and its posttranscriptional regulation remain poorly understood. In this study we provide first evidences that a posttranscriptional regulation mechanism of MALAT1 by miR 101 and miR-217 exists in ESCC cells. This posttranscriptional silencing of MALAT1 could significantly suppress the proliferation of ESCC cells through the arrest of G2/M cell cycle, which may be due to MALAT1-mediated up-regulation of p21 and p27 expression and the inhibition of B-MYB expression. Moreover, we also found the abilities of migration and invasion of ESCC cells were inhibited after overexpression of miR-101, miR-217, or MALAT1 siRNA. This might be attributed to the deregulation of downstream genes of MALAT1, such as MIA2, HNF4G, ROBO1, CCT4, and CTHRC1. A significant negative correlation exists between miR-101 or miR-217 and MALAT1 in 42 pairs of ESCC tissue samples and adjacent normal tissues. Mice xenograft data also support the tumor suppressor role of both miRNAs in ESCCs. PMID- 25538232 TI - Mechanistic insights into PTS2-mediated peroxisomal protein import: the co receptor PEX5L drastically increases the interaction strength between the cargo protein and the receptor PEX7. AB - The destination of peroxisomal matrix proteins is encoded by short peptide sequences, which have been characterized as peroxisomal targeting signals (PTS) residing either at the C terminus (PTS1) or close to the N terminus (PTS2). PTS2 carrying proteins interact with their cognate receptor protein PEX7 that mediates their transport to peroxisomes by a concerted action with a co-receptor protein, which in mammals is the PTS1 receptor PEX5L. Using a modified version of the mammalian two-hybrid assay, we demonstrate that the interaction strength between cargo and PEX7 is drastically increased in the presence of the co-receptor PEX5L. In addition, cargo binding is a prerequisite for the interaction between PEX7 and PEX5L and ectopic overexpression of PTS2-carrying cargo protein drastically increases the formation of PEX7-PEX5L complexes in this assay. Consistently, we find that the peroxisomal transfer of PEX7 depends on cargo binding and that ectopic overexpression of cargo protein stimulates this process. Thus, the sequential formation of a highly stable trimeric complex involving cargo protein, PEX7 and PEX5L stabilizes cargo binding and is a prerequisite for PTS2-mediated peroxisomal import. PMID- 25538233 TI - Cleavage of Mer tyrosine kinase (MerTK) from the cell surface contributes to the regulation of retinal phagocytosis. AB - Phagocytosis of apoptotic cells by macrophages and spent photoreceptor outer segments (POS) by retinal pigment epithelial (RPE) cells requires several proteins, including MerTK receptors and associated Gas6 and protein S ligands. In the retina, POS phagocytosis is rhythmic, and MerTK is activated promptly after light onset via the alphavbeta5 integrin receptor and its ligand MFG-E8, thus generating a phagocytic peak. The phagocytic burst is limited in time, suggesting a down-regulation mechanism that limits its duration. Our previous data showed that MerTK helps control POS binding of integrin receptors at the RPE cell surface as a negative feedback loop. Our present results show that a soluble form of MerTK (sMerTK) is released in the conditioned media of RPE-J cells during phagocytosis and in the interphotoreceptor matrix of the mouse retina during the morning phagocytic peak. In contrast to macrophages, the two cognate MerTK ligands have an opposite effect on phagocytosis and sMerTK release, whereas the integrin ligand MFG-E8 markedly increases both phagocytosis and sMerTK levels. sMerTK acts as a decoy receptor blocking the effect of both MerTK ligands. Interestingly, stimulation of sMerTK release decreases POS binding. Conversely, blocking MerTK cleavage increased mostly POS binding by RPE cells. Therefore, our data suggest that MerTK cleavage contributes to the acute regulation of RPE phagocytosis by limiting POS binding to the cell surface. PMID- 25538234 TI - Protein-tyrosine phosphatase Shp2 positively regulates macrophage oxidative burst. AB - Macrophages are vital to innate immunity and express pattern recognition receptors and integrins for the rapid detection of invading pathogens. Stimulation of Dectin-1 and complement receptor 3 (CR3) activates Erk- and Akt dependent production of reactive oxygen species (ROS). Shp2, a protein-tyrosine phosphatase encoded by Ptpn11, promotes activation of Ras-Erk and PI3K-Akt and is crucial for hematopoietic cell function; however, no studies have examined Shp2 function in particulate-stimulated ROS production. Maximal Dectin-1-stimulated ROS production corresponded kinetically to maximal Shp2 and Erk phosphorylation. Bone marrow-derived macrophages (BMMs) from mice with a conditionally deleted allele of Ptpn11 (Shp2(flox/flox);Mx1Cre+) produced significantly lower ROS levels compared with control BMMs. Although YFP-tagged phosphatase dead Shp2 C463A was strongly recruited to the early phagosome, its expression inhibited Dectin-1- and CR3-stimulated phospho-Erk and ROS levels, placing Shp2 phosphatase function and Erk activation upstream of ROS production. Further, BMMs expressing gain of function Shp2-D61Y or Shp2-E76K and peritoneal exudate macrophages from Shp2D61Y/+;Mx1Cre+ mice produced significantly elevated levels of Dectin-1- and CR3-stimulated ROS, which was reduced by pharmacologic inhibition of Erk. SIRPalpha (signal regulatory protein alpha) is a myeloid inhibitory immunoreceptor that requires tyrosine phosphorylation to exert its inhibitory effect. YFP-Shp2C463A-expressing cells have elevated phospho-SIRPalpha levels and an increased Shp2-SIRPalpha interaction compared with YFP-WT Shp2-expressing cells. Collectively, these findings indicate that Shp2 phosphatase function positively regulates Dectin-1- and CR3-stimulated ROS production in macrophages by dephosphorylating and thus mitigating the inhibitory function of SIRPalpha and by promoting Erk activation. PMID- 25538235 TI - Metformin activates AMP-activated protein kinase by promoting formation of the alphabetagamma heterotrimeric complex. AB - Metformin is the most widely prescribed oral anti-diabetic agent. Recently, we have shown that low metformin concentrations found in the portal vein suppress glucose production in hepatocytes through activation of AMPK. Moreover, low concentrations of metformin were found to activate AMPK by increasing the phosphorylation of AMPKalpha at Thr-172. However, the mechanism underlying the increase in AMPKalpha phosphorylation at Thr-172 and activation by metformin remains unknown. In the current study, we find that low concentrations of metformin promote the formation of the AMPK alphabetagamma complex, resulting in an increase in net phosphorylation of the AMPK alpha catalytic subunit at Thr-172 by augmenting phosphorylation by LKB1 and antagonizing dephosphorylation by PP2C. PMID- 25538236 TI - Salinomycin and other polyether ionophores are a new class of antiscarring agent. AB - Although scarring is a component of wound healing, excessive scar formation is a debilitating condition that results in pain, loss of tissue function, and even death. Many tissues, including the lungs, heart, skin, and eyes, can develop excessive scar tissue as a result of tissue injury, chronic inflammation, or autoimmune disease. Unfortunately, there are few, if any, effective treatments to prevent excess scarring, and new treatment strategies are needed. Using HEK293FT cells stably transfected with a TGFbeta-dependent luciferase reporter, we performed a small molecule screen to identify novel compounds with antiscarring activity. We discovered that the polyether ionophore salinomycin potently inhibited the formation of scar-forming myofibroblasts. Salinomycin (250 nm) blocked TGFbeta-dependent expression of the cardinal myofibroblast products alpha smooth muscle actin, calponin, and collagen in primary human fibroblasts without causing cell death. Salinomycin blocked phosphorylation and activation of TAK1 and p38, two proteins fundamentally involved in signaling myofibroblast and scar formation. Expression of constitutively active mitogen activated kinase kinase 6, which activates p38 MAPK, attenuated the ability of salinomycin to block myofibroblast formation, demonstrating that salinomycin targets the p38 kinase pathway to disrupt TGFbeta signaling. These data identify salinomycin and other polyether ionophores as novel potential antiscarring therapeutics. PMID- 25538237 TI - IgLON cell adhesion molecules are shed from the cell surface of cortical neurons to promote neuronal growth. AB - Matrix metalloproteinases and a disintegrin and metalloproteinases are members of the zinc endopeptidases, which cleave components of the extracellular matrix as well as cell surface proteins resulting in degradation or release of biologically active fragments. Surface ectodomain shedding affects numerous biological processes, including survival, axon outgrowth, axon guidance, and synaptogenesis. In this study, we evaluated the role of metalloproteinases in regulating cortical neurite growth. We found that treatment of mature cortical neurons with pan metalloproteinase inhibitors or with tissue inhibitors of metalloproteinase-3 reduced neurite outgrowth. Through mass spectrometry, we characterized the metalloproteinase-sensitive cell surface proteome of mature cortical neurons. Members of the IgLON family of glycosylphosphatidylinositol-anchored neural cell adhesion molecules were identified and validated as proteins that were shed from the surface of mature cortical neurons in a metalloproteinase-dependent manner. Introduction of two members of the IgLON family, neurotrimin and NEGR1, in early embryonic neurons was sufficient to confer sensitivity to metalloproteinase inhibitors in neurite outgrowth assays. Outgrowth experiments on immobilized IgLON proteins revealed a role for all IgLON family members in promoting neurite extension from cortical neurons. Together, our findings support a role for metalloproteinase-dependent shedding of IgLON family members in regulating neurite outgrowth from mature cortical neurons. PMID- 25538238 TI - Differential effects on light chain amyloid formation depend on mutations and type of glycosaminoglycans. AB - Amyloid light chain (AL) amyloidosis is a protein misfolding disease where immunoglobulin light chains sample partially folded states that lead to misfolding and amyloid formation, resulting in organ dysfunction and death. In vivo, amyloid deposits are found in the extracellular space and involve a variety of accessory molecules, such as glycosaminoglycans, one of the main components of the extracellular matrix. Glycosaminoglycans are a group of negatively charged heteropolysaccharides composed of repeating disaccharide units. In this study, we investigated the effect of glycosaminoglycans on the kinetics of amyloid fibril formation of three AL cardiac amyloidosis light chains. These proteins have similar thermodynamic stability but exhibit different kinetics of fibril formation. We also studied single restorative and reciprocal mutants and wild type germ line control protein. We found that the type of glycosaminoglycan has a different effect on the kinetics of fibril formation, and this effect seems to be associated with the natural propensity of each AL protein to form fibrils. Heparan sulfate accelerated AL-12, AL-09, kappaI Y87H, and AL-103 H92D fibril formation; delayed fibril formation for AL-103; and did not promote any fibril formation for AL-12 R65S, AL-103 delP95aIns, or kappaI O18/O8. Chondroitin sulfate A, on the other hand, showed a strong fibril formation inhibition for all proteins. We propose that heparan sulfate facilitates the formation of transient amyloidogenic conformations of AL light chains, thereby promoting amyloid formation, whereas chondroitin sulfate A kinetically traps partially unfolded intermediates, and further fibril elongation into fibrils is inhibited, resulting in formation/accumulation of oligomeric/protofibrillar aggregates. PMID- 25538239 TI - Dimeric quaternary structure of human laforin. AB - The phosphatase laforin removes phosphate groups from glycogen during biosynthetic activity. Loss-of-function mutations in the gene encoding laforin is the predominant cause of Lafora disease, a fatal form of progressive myoclonic epilepsy. Here, we used hybrid structural methods to determine the molecular architecture of human laforin. We found that laforin adopts a dimeric quaternary structure, topologically similar to the prototypical dual specificity phosphatase VH1. The interface between the laforin carbohydrate-binding module and the dual specificity phosphatase domain generates an intimate substrate-binding crevice that allows for recognition and dephosphorylation of phosphomonoesters of glucose. We identify novel molecular determinants in the laforin active site that help decipher the mechanism of glucan phosphatase activity. PMID- 25538240 TI - Germ line variants of human N-methylpurine DNA glycosylase show impaired DNA repair activity and facilitate 1,N6-ethenoadenine-induced mutations. AB - Human N-methylpurine DNA glycosylase (hMPG) initiates base excision repair of a number of structurally diverse purine bases including 1,N(6)-ethenoadenine, hypoxanthine, and alkylation adducts in DNA. Genetic studies discovered at least eight validated non-synonymous single nucleotide polymorphisms (nsSNPs) of the hMPG gene in human populations that result in specific single amino acid substitutions. In this study, we tested the functional consequences of these nsSNPs of hMPG. Our results showed that two specific arginine residues, Arg-141 and Arg-120, are important for the activity of hMPG as the germ line variants R120C and R141Q had reduced enzymatic activity in vitro as well as in mammalian cells. Expression of these two variants in mammalian cells lacking endogenous MPG also showed an increase in mutations and sensitivity to an alkylating agent compared with the WT hMPG. Real time binding experiments by surface plasmon resonance spectroscopy suggested that these variants have substantial reduction in the equilibrium dissociation constant of binding (KD) of hMPG toward 1,N(6) ethenoadenine-containing oligonucleotide (epsilonA-DNA). Pre-steady-state kinetic studies showed that the substitutions at arginine residues affected the turnover of the enzyme significantly under multiple turnover condition. Surface plasmon resonance spectroscopy further showed that both variants had significantly decreased nonspecific (undamaged) DNA binding. Molecular modeling suggested that R141Q substitution may have resulted in a direct loss of the salt bridge between epsilonA-DNA and hMPG, whereas R120C substitution redistributed, at a distance, the interactions among residues in the catalytic pocket. Together our results suggest that individuals carrying R120C and R141Q MPG variants may be at risk for genomic instability and associated diseases as a consequence. PMID- 25538241 TI - Regulation of gene transcription by voltage-gated L-type calcium channel, Cav1.3. AB - Cav1.3 L-type Ca(2+) channel is known to be highly expressed in neurons and neuroendocrine cells. However, we have previously demonstrated that the Cav1.3 channel is also expressed in atria and pacemaking cells in the heart. The significance of the tissue-specific expression of the channel is underpinned by our previous demonstration of atrial fibrillation in a Cav1.3 null mutant mouse model. Indeed, a recent study has confirmed the critical roles of Cav1.3 in the human heart (Baig, S. M., Koschak, A., Lieb, A., Gebhart, M., Dafinger, C., Nurnberg, G., Ali, A., Ahmad, I., Sinnegger-Brauns, M. J., Brandt, N., Engel, J., Mangoni, M. E., Farooq, M., Khan, H. U., Nurnberg, P., Striessnig, J., and Bolz, H. J. (2011) Nat. Neurosci. 14, 77-84). These studies suggest that detailed knowledge of Cav1.3 may have broad therapeutic ramifications in the treatment of cardiac arrhythmias. Here, we tested the hypothesis that there is a functional cross-talk between the Cav1.3 channel and a small conductance Ca(2+)-activated K(+) channel (SK2), which we have documented to be highly expressed in human and mouse atrial myocytes. Specifically, we tested the hypothesis that the C terminus of Cav1.3 may translocate to the nucleus where it functions as a transcriptional factor. Here, we reported for the first time that the C terminus of Cav1.3 translocates to the nucleus where it functions as a transcriptional regulator to modulate the function of Ca(2+)-activated K(+) channels in atrial myocytes. Nuclear translocation of the C-terminal domain of Cav1.3 is directly regulated by intracellular Ca(2+). Utilizing a Cav1.3 null mutant mouse model, we demonstrate that ablation of Cav1.3 results in a decrease in the protein expression of myosin light chain 2, which interacts and increases the membrane localization of SK2 channels. PMID- 25538242 TI - Yeast DNA polymerase epsilon catalytic core and holoenzyme have comparable catalytic rates. AB - The holoenzyme of yeast DNA polymerase epsilon (Pol epsilon) consists of four subunits: Pol2, Dpb2, Dpb3, and Dpb4. A protease-sensitive site results in an N terminal proteolytic fragment of Pol2, called Pol2core, that consists of the catalytic core of Pol epsilon and retains both polymerase and exonuclease activities. Pre-steady-state kinetics showed that the exonuclease rates on single stranded, double-stranded, and mismatched DNA were comparable between Pol epsilon and Pol2core. Single-turnover pre-steady-state kinetics also showed that the kpol of Pol epsilon and Pol2core were comparable when preloading the polymerase onto the primer-template before adding Mg(2+) and dTTP. However, a global fit of the data over six sequential nucleotide incorporations revealed that the overall polymerization rate and processivity were higher for Pol epsilon than for Pol2core. The largest difference between Pol epsilon and Pol2core was observed when challenged for the formation of a ternary complex and incorporation of the first nucleotide. Pol epsilon needed less than 1 s to incorporate a nucleotide, but several seconds passed before Pol2core incorporated detectable levels of the first nucleotide. We conclude that the accessory subunits and the C terminus of Pol2 do not influence the catalytic rate of Pol epsilon but facilitate the loading and incorporation of the first nucleotide by Pol epsilon. PMID- 25538243 TI - Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells. AB - Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. PMID- 25538245 TI - Structural basis for replication origin unwinding by an initiator primase of plasmid ColE2-P9: duplex DNA unwinding by a single protein. AB - Duplex DNA is generally unwound by protein oligomers prior to replication. The Rep protein of plasmid ColE2-P9 (34 kDa) is an essential initiator for plasmid DNA replication. This protein binds the replication origin (Ori) in a sequence specific manner as a monomer and unwinds DNA. Here we present the crystal structure of the DNA-binding domain of Rep (E2Rep-DBD) in complex with Ori DNA. The structure unveils the basis for Ori-specific recognition by the E2Rep-DBD and also reveals that it unwinds DNA by the concerted actions of its three contiguous structural modules. The structure also shows that the functionally unknown PriCT domain, which forms a compact module, plays a central role in DNA unwinding. The conservation of the PriCT domain in the C termini of some archaeo-eukaryotic primases indicates that it probably plays a similar role in these proteins. Thus, this is the first report providing the structural basis for the functional importance of the conserved PriCT domain and also reveals a novel mechanism for DNA unwinding by a single protein. PMID- 25538246 TI - Transcriptional activation is a conserved feature of the early embryonic factor Zelda that requires a cluster of four zinc fingers for DNA binding and a low complexity activation domain. AB - Delayed transcriptional activation of the zygotic genome is a nearly universal phenomenon in metazoans. Immediately following fertilization, development is controlled by maternally deposited products, and it is not until later stages that widespread activation of the zygotic genome occurs. Although the mechanisms driving this genome activation are currently unknown, the transcriptional activator Zelda (ZLD) has been shown to be instrumental in driving this process in Drosophila melanogaster. Here we define functional domains of ZLD required for both DNA binding and transcriptional activation. We show that the C-terminal cluster of four zinc fingers mediates binding to TAGteam DNA elements in the promoters of early expressed genes. All four zinc fingers are required for this activity, and splice isoforms lacking three of the four zinc fingers fail to activate transcription. These truncated splice isoforms dominantly suppress activation by the full-length, embryonically expressed isoform. We map the transcriptional activation domain of ZLD to a central region characterized by low complexity. Despite relatively little sequence conservation within this domain, ZLD orthologs from Drosophila virilis, Anopheles gambiae, and Nasonia vitripennis activate transcription in D. melanogaster cells. Transcriptional activation by these ZLD orthologs suggests that ZLD functions through conserved interactions with a protein cofactor(s). We have identified distinct DNA-binding and activation domains within the critical transcription factor ZLD that controls the initial activation of the zygotic genome. PMID- 25538244 TI - Generation and characterization of small single domain antibodies inhibiting human tumor necrosis factor receptor 1. AB - The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named "TNF Receptor-One Silencer" (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin alpha/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients. PMID- 25538247 TI - Interactions with the bifunctional interface of the transcriptional coactivator DCoH1 are kinetically regulated. AB - Pterin-4a-carbinolamine dehydratase (PCD) is a highly conserved enzyme that evolved a second, unrelated function in mammals, as a transcriptional coactivator. As a coactivator, PCD is known as DCoH or dimerization cofactor of the transcription factor HNF-1. These two activities are associated with a change in oligomeric state: from two dimers interacting as an enzyme in the cytoplasm to a dimer interacting with a dimer of HNF-1 in the nucleus. The same interface of DCoH forms both complexes. To determine how DCoH partitions between its two functions, we studied the folding and stability of the DCoH homotetramer. We show that the DCoH1 homotetramer is kinetically trapped, meaning once it forms it will not dissociate to interact with HNF-1. In contrast, DCoH2, a paralog of DCoH1, unfolds within hours. A simple mutation in the interface of DCoH2 from Ser-51 to Thr, as found in DCoH1, increases the kinetic stability by 9 orders of magnitude, to tau(1/2) ~ 2 million years. This suggests that the DCoH1.HNF-1 complex must co fold to interact. We conclude that simple mutations can dramatically affect the dissociation kinetics of a complex. Residue 51 represents a "kinetic hot spot" instead of a "thermodynamic hot spot." Kinetic regulation allows PCD to adopt two distinct functions. Mutations in DCoH1 associated with diabetes affect both functions of DCoH1, perhaps by disrupting the balance between the two DCoH complexes. PMID- 25538248 TI - The Transcriptional Repressor ZNF503/Zeppo2 Promotes Mammary Epithelial Cell Proliferation and Enhances Cell Invasion. AB - The NET (nocA, Nlz, elB, TLP-1) subfamily of zinc finger proteins is an important mediator during developmental processes. The evolutionary conserved zinc finger protein ZNF503/Zeppo2 (zinc finger elbow-related proline domain protein 2, Zpo2) plays critical roles during embryogenesis. We found that Zpo2 is expressed in adult tissue and examined its function. We found that ZPO2 is a nuclearly targeted transcriptional repressor that is expressed in mammary epithelial cells. Elevated Zpo2 levels increase mammary epithelial cell proliferation. Zpo2 promotes cellular invasion through down-regulation of E-cadherin and regulates the invasive phenotype in a RAC1-dependent manner. We detect elevated Zpo2 expression during breast cancer progression in a MMTV-PyMT transgenic mouse model. Tumor transplant experiments indicated that overexpression of Zpo2 in MMTV PyMT mammary tumor cell lines enhances lung metastasis. Our findings suggest that Zpo2 plays a significant role in mammary gland homeostasis and that deregulation of Zpo2 may promote breast cancer development. PMID- 25538249 TI - pH-dependent binding engineering reveals an FcRn affinity threshold that governs IgG recycling. AB - The Fc domain of IgG has been the target of multiple mutational studies aimed at altering the pH-dependent IgG/FcRn interaction to modulate IgG pharmacokinetics. These studies have yielded antibody variants with disparate pharmacokinetic characteristics, ranging from extended in vivo half-life to those exhibiting extremely rapid clearance. To better understand pH-dependent binding parameters that govern these outcomes and limit FcRn-mediated half-life extension, we generated a panel of novel Fc variants with high affinity binding at acidic pH that vary in pH 7.4 affinities and assessed pharmacokinetic outcomes. Pharmacokinetic studies in human FcRn transgenic mice and cynomolgus monkeys showed that multiple variants with increased FcRn affinities at acidic pH exhibited extended serum half-lives relative to the parental IgG. Importantly, the results reveal an underappreciated affinity threshold of neutral pH binding that determines IgG recycling efficiency. Variants with pH 7.4 FcRn affinities below this threshold recycle efficiently and can exhibit increased serum persistence. Increasing neutral pH FcRn affinity beyond this threshold reduced serum persistence by offsetting the benefits of increased pH 6.0 binding. Ultra high affinity binding to FcRn at both acidic and neutral pH leads to rapid serum clearance. PMID- 25538251 TI - Nonstatistical 13C distribution during carbon transfer from glucose to ethanol during fermentation is determined by the catabolic pathway exploited. AB - During the anaerobic fermentation of glucose to ethanol, the three micro organisms Saccharomyces cerevisiae, Zymomonas mobilis, and Leuconostoc mesenteroides exploit, respectively, the Embden-Meyerhof-Parnas, the Entner Doudoroff, and the reductive pentose phosphate pathways. Thus, the atoms incorporated into ethanol do not have the same affiliation to the atomic positions in glucose. The isotopic fractionation occurring in each pathway at both the methylene and methyl positions of ethanol has been investigated by isotopic quantitative (13)C NMR spectrometry with the aim of observing whether an isotope redistribution characteristic of the enzymes active in each pathway can be measured. First, it is found that each pathway has a unique isotope redistribution signature. Second, for the methylene group, a significant apparent kinetic isotope effect is only found in the reductive pentose phosphate pathway. Third, the apparent kinetic isotope effects related to the methyl group are more pronounced than for the methylene group. These findings can (i) be related to known kinetic isotope effects of some of the enzymes concerned and (ii) give indicators as to which steps in the pathways are likely to be influencing the final isotopic composition in the ethanol. PMID- 25538250 TI - Osteoblast menin regulates bone mass in vivo. AB - Menin, the product of the multiple endocrine neoplasia type 1 (Men1) tumor suppressor gene, mediates the cell proliferation and differentiation actions of transforming growth factor-beta (TGF-beta) ligand family members. In vitro, menin modulates osteoblastogenesis and osteoblast differentiation promoted and sustained by bone morphogenetic protein-2 (BMP-2) and TGF-beta, respectively. To examine the in vivo function of menin in bone, we conditionally inactivated Men1 in mature osteoblasts by crossing osteocalcin (OC)-Cre mice with floxed Men1 (Men1(f/f)) mice to generate mice lacking menin in differentiating osteoblasts (OC-Cre;Men1(f/f) mice). These mice displayed significant reduction in bone mineral density, trabecular bone volume, and cortical bone thickness compared with control littermates. Osteoblast and osteoclast number as well as mineral apposition rate were significantly reduced, whereas osteocyte number was increased. Primary calvarial osteoblasts proliferated more quickly but had deficient mineral apposition and alkaline phosphatase activity. Although the mRNA expression of osteoblast marker and cyclin-dependent kinase inhibitor genes were all reduced, that of cyclin-dependent kinase, osteocyte marker, and pro-apoptotic genes were increased in isolated Men1 knock-out osteoblasts compared with controls. In contrast to the knock-out mice, transgenic mice overexpressing a human menin cDNA in osteoblasts driven by the 2.3-kb Col1a1 promoter, showed a gain of bone mass relative to control littermates. Osteoblast number and mineral apposition rate were significantly increased in the Col1a1-Menin-Tg mice. Therefore, osteoblast menin plays a key role in bone development, remodeling, and maintenance. PMID- 25538253 TI - Preservation of the donor heart: from basic science to clinical studies. AB - The methods of donor heart preservation are aimed at minimizing graft dysfunction caused by ischaemia-reperfusion injury (IRI) which inevitably occurs during the ex vivo transport interval. At present, the standard technique of heart preservation is cardiac arrest followed by static cold storage in a crystalloid heart preservation solution (HPS). This technique ensures an acceptable level of heart protection against IRI for <6 h. In clinical trials, comparable levels of myocardial protection against IRI were provided by various HPSs. The growing shortage of donor hearts is one of the major factors stimulating the development of new techniques of heart preservation. Here, we summarize new HPS formulations and provide a focus for optimization of the composition of existing HPSs. Such methods of donor heart preservation as machine perfusion, preservation at sub zero temperature and oxygen persufflation are also discussed. Furthermore, we review experimental data showing that pre- and post-conditioning of the cardiac graft can improve its function when used in combination with cold storage. The evidence on the feasibility of cardiac donation after circulatory death, as well as the techniques of heart reconditioning after a period of warm ischaemia, is presented. The implementation of new techniques of donor heart preservation may contribute to the use of hearts from extended criteria donors, thereby expanding the total donor pool. PMID- 25538252 TI - Minimally invasive thoracoscopic ligation of a persistent left superior vena cava. AB - Persistent left superior vena cava draining into the left atrium is a rare congenital venous anomaly, which remains asymptomatic and therefore undetected in most cases. Paradoxical embolization caused by right-to-left shunt is a severe complication and requires surgical correction. We describe the first thoracoscopic approach for ligation of a persistent left superior vena cava even though our patient had severe kyphoscoliosis because of Klippel-Feil syndrome. PMID- 25538254 TI - Acute on chronic pulmonary autograft dissection. AB - We report a case of combined acute and chronic dissection limited to the pulmonary autograft 10 years after a Ross procedure, managed by replacement with a stentless porcine bioprosthesis. Implications for timing and technique of reintervention for pulmonary autograft dilatation are discussed. PMID- 25538255 TI - Probe optimization for sequencing by ligation. AB - Sequencing by ligation (SBL) is a straightforward enzymatic method for interrogating DNA sequence, in which the ligation efficiency and specificity of each probe play an essential role. Here, the number of labelled dyes in the probe, probe length and probe constituent were investigated to optimize the ligation efficiency and specificity. First, the performance of double- and single labelled fluorescent probes in SBL was evaluated. The experimental results showed that double-labelled fluorescent probes could yield a remarkable increase in the fluorescence intensities and avoid higher background compared with single labelled fluorescent probes. Second, probes between 7- and 9-mers in length were designed to uniform Tm difference. We hoped the uniformed probes with smaller Tm difference could improve the ligation efficiency. However, 8-mer probes with larger Tm difference showed stronger fluorescence intensities. Third, we evaluated whether probes containing deoxyinosines either in the 5' or the 3' end had influence on the ligation efficiency. Consequently, probes containing deoxyinosines at the 5' termini might decrease the ligation efficiency, and the accumulation of 3' terminal deoxyinosines in the sequencing primers was likely to reduce the fluorescence intensity and the ligation efficiency, which was inconsistent with the traditional viewpoint. The optimized probes will improve the ligation efficiency and accuracy in SBL. PMID- 25538256 TI - Childhood adversities predict strongly the use of psychotropic drugs in adulthood: a population-based cohort study of 24,284 Finns. AB - BACKGROUND: Exposure to adverse childhood experiences has been shown to be associated with negative health outcomes including mental health problems, but only a few studies with register-based data have used psychotropic drugs as an outcome variable. The purpose of this study is to examine whether adverse emotional childhood experiences, such as serious conflicts in the family and frequent fear of a family member, predict the use of psychotropic drugs in adulthood. In addition, the association of a child-parent relationship during childhood with the use of psychotropic drugs is studied. METHODS: The participants of the population-based Health and Social Support Study (24,284 working aged Finns) were followed up for 9 years. The information on childhood experiences and child-parent relationships was obtained from the questionnaires in 1998 and 2003. The number of psychotropic purchases (antipsychotics, drugs for bipolar disorder, antidepressants, anxiolytics, hypnotics and sedatives) was obtained from the National-Drug-Prescription-Register. Logistic and multinomial regression models were used. RESULTS: A graded association between childhood adversities and the use of psychotropic drugs was found, even after adjustments for occupational training, work status, recent life events and health behaviour. Frequent fear of a family member showed the strongest association: the OR for multiple use of antidepressants was 3.08 (95% CI 2.72 to 3.49) and 2.69 (2.27 to 3.20) for multiple use of anxiolytics. Use of psychotropic drugs was clearly increased among those with poor child-parent relationship and multiple childhood adversities. CONCLUSIONS: The results highlight the effect of environmental factors during childhood on mental health and the need for early recognition of families at risk. PMID- 25538257 TI - Multidimensional approaches for studying plant defence against insects: from ecology to omics and synthetic biology. AB - The biggest challenge for modern biology is to integrate multidisciplinary approaches towards understanding the organizational and functional complexity of biological systems at different hierarchies, starting from the subcellular molecular mechanisms (microscopic) to the functional interactions of ecological communities (macroscopic). The plant-insect interaction is a good model for this purpose with the availability of an enormous amount of information at the molecular and the ecosystem levels. Changing global climatic conditions are abruptly resetting plant-insect interactions. Integration of discretely located heterogeneous information from the ecosystem to genes and pathways will be an advantage to understand the complexity of plant-insect interactions. This review will present the recent developments in omics-based high-throughput experimental approaches, with particular emphasis on studying plant defence responses against insect attack. The review highlights the importance of using integrative systems approaches to study plant-insect interactions from the macroscopic to the microscopic level. We analyse the current efforts in generating, integrating and modelling multiomics data to understand plant-insect interaction at a systems level. As a future prospect, we highlight the growing interest in utilizing the synthetic biology platform for engineering insect-resistant plants. PMID- 25538258 TI - Angiogenic cytokines are antibody targets during graft-versus-leukemia reactions. AB - PURPOSE: The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed patients with advanced myelodysplasia (MDS) and acute myelogenous leukemia (AML) who received an autologous, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT). EXPERIMENTAL DESIGN: A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were used to characterize sera obtained longitudinally from 15 patients with AML/MDS who were vaccinated early after allogeneic HSCT. RESULTS: A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival. CONCLUSIONS: These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with natural killer cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias. PMID- 25538259 TI - Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. AB - PURPOSE: The BEVERLY-2 single-arm phase II trial assessed the efficacy and safety of combining neoadjuvant chemotherapy with bevacizumab and trastuzumab for the treatment of HER2-positive inflammatory breast cancer (IBC). Here, we report the results of a preplanned survival analysis at 3 years of follow-up, along with the association between outcome and circulating biomarkers and pathologic complete response (pCR). EXPERIMENTAL DESIGN: Patients received fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, trastuzumab, and bevacizumab (cycles 5-8) before surgery, followed by trastuzumab and bevacizumab for 30 weeks after surgery. Circulating tumor cell (CTC) and endothelial cell (CEC) counts were assessed at baseline, cycle 5, preoperative, postoperative, and at 1 year. RESULTS: Fifty-two patients were included. The 3-year disease-free survival (DFS) rate was 68% and overall survival (OS) rate was 90%. pCR (centrally reviewed) was strongly associated with 3-year DFS [80% and 53% in patients with/without pCR, respectively (P = 0.03)]. CTC detection also independently predicted 3-year DFS [81% vs. 43% for patients with <1 vs. >=1 CTC/7.5 mL at baseline (P = 0.01)]. Patients with no CTCs detected at baseline and with pCR had a high 3-year DFS (95%). CEC changes during treatment had no prognostic value. CONCLUSIONS: Our study suggests that the prognosis of IBC relies on more than the achievement of pCR and highlights the role of early hematogenous tumor dissemination as assessed by CTCs. Combining these two prognostic factors isolates a subgroup of IBC with excellent survival when treated with bevacizumab- and trastuzumab-containing regimens. PMID- 25538260 TI - Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice. AB - PURPOSE: Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC. EXPERIMENTAL DESIGN: Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8(-/-)) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS induced colitis and tumors. RESULTS: AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8(-/-) mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8(-/-) mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8(-/ ) mice than in wild-type mice. Palpable masses were seen in the AKR1B8(-/-) mice only, not in wild-type. CONCLUSIONS: AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases. PMID- 25538261 TI - Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer. AB - PURPOSE: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer. EXPERIMENTAL DESIGN: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV associated epigenetic alterations. RESULTS: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi signature is a better predictor of survival than HPV status alone. CONCLUSIONS: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies. PMID- 25538262 TI - Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. AB - PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier. RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. CONCLUSION: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given. PMID- 25538263 TI - Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. AB - PURPOSE: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by IHC was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. RESULTS: HS data were available from 453 of 1,110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS = 0). Patients with HS > 55 (n = 59, 13%) had significantly shorter overall survival (OS) than those with HS <= 55 in both pazopanib and sunitinib arms (median 15.1 vs. 35.6 and 15.3 vs. 27.8 months, respectively, P = 0.03). In both arms, median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS <= 55 and CD8-positive T-cell counts <= 300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. CONCLUSIONS: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8 positive T-cell counts, were associated with shorter survival in patients with metastatic RCC receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC. PMID- 25538265 TI - Electronic medical record-based performance improvement project to document and reduce excessive cardiac troponin testing. AB - BACKGROUND: We assessed the utilization rationale behind provider ordering of cardiac troponin I (cTnI) testing for the diagnosis of myocardial infarction after implementation of a hospital-wide serial order protocol. METHODS: During 2 months in 2013, any request for additional cTnI testing within 30 days of the initial serial cTnI order prompted an electronic health record best practice alert (BPA), which included clinical decision support that could be bypassed by giving a clinical indication. cTnI orders were not limited (timing, number), and upon BPA, trigger data was collected for clinical indications and actions, patient stay (duration, location), International Classification of Diseases, Revision 9 diagnosis, cTnI orders, and timing of cTnI measurements. RESULTS: The BPA was triggered 1477 times by 423 providers who cared for 702 patients. There were a mean of 3.6 cTnI results per patient, 2.1 BPAs per patient, and 1.2 visits per patient. Providers (42% of whom were residents) acknowledged and overrode the BPA 97% of the time. In response to the BPA, 65% of providers selected a prepared rationale: 64% acute coronary syndrome/ST-elevation myocardial infarction/non-ST elevation myocardial infarction; 30% demand ischemia; and 6% non-ACS myocardial necrosis. Of the remaining 35% of providers, 71% listed no rationale for their additional cTnI orders. Of patients with a BPA, 93% had non-ACS-related primary International Classification of Diseases, Revision 9 diagnosis, and 58% of the time, patients' cTnI results never increased during their stay. In 53% of cases, BPAs were generated by a request for an additional cTnI series when <2 results were available. CONCLUSIONS: Providers largely ignored the BPA that warned of potential overutilization of cTnI testing independent of diagnosis, including ACS. PMID- 25538266 TI - The statement that some ochratoxins are ". . .classified as human carcinogens" is not accurate. PMID- 25538264 TI - A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. AB - PURPOSE: Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, the application of this approach to the treatment of other solid tumors has been limited. The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70% to 80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial using the adoptive transfer of autologous peripheral blood mononuclear cells that were retrovirally transduced with an NY-ESO-1-reactive T-cell receptor (TCR) to heavily pretreated patients bearing these metastatic cancers. EXPERIMENTAL DESIGN: HLA-*0201 patients with metastatic synovial cell sarcoma or melanoma refractory to standard treatments and whose cancers expressed NY-ESO-1 received autologous TCR-transduced T cells following a lymphodepleting preparative chemotherapy. Response rates using Response Evaluation Criteria in Solid Tumors (RECIST), as well as immunologic correlates of response, are presented in this report. RESULTS: Eleven of 18 patients with NY-ESO-1(+) synovial cell sarcomas (61%) and 11 of 20 patients with NY-ESO-1(+) melanomas (55%) who received autologous T cells transduced with an NY ESO-1-reactive TCR demonstrated objective clinical responses. The estimated overall 3- and 5-year survival rates for patients with synovial cell sarcoma were 38% and 14%, respectively, whereas the corresponding estimated survival rates for patients with melanoma were both 33%. CONCLUSIONS: The adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA A*0201 restricted NY-ESO-1 epitope can be an effective therapy for some patients bearing synovial cell sarcomas and melanomas that are refractory to other treatments. PMID- 25538267 TI - Data sharing in toxicology: beyond show and tell. PMID- 25538268 TI - Staying on target with continuous dialysis. PMID- 25538269 TI - Reductions in red blood cell 2,3-diphosphoglycerate concentration during continuous renal replacment therapy. AB - BACKGROUND AND OBJECTIVES: Hypophosphatemia is a frequent complication during continuous renal replacement therapy (CRRT), a dialytic technique used to treat AKI in critically ill patients. This study sought to confirm that phosphate depletion during CRRT may decrease red blood cell (RBC) concentration of 2,3 diphosphoglycerate (2,3-DPG), a crucial allosteric effector of hemoglobin's (Hgb's) affinity for oxygen, thereby leading to impaired oxygen delivery to peripheral tissues. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Phosphate mass balance studies were performed in 20 patients with severe AKI through collection of CRRT effluent. RBC concentrations of 2,3-DPG, venous blood gas pH, and oxygen partial pressure required for 50% hemoglobin saturation (P50) were measured at CRRT initiation and days 2, 4, and 7. Similar measurements were obtained on days 0 and 2 in a reference group of 10 postsurgical patients, most of whom did not have AKI. Associations of 2,3-DPG with laboratory parameters and clinical outcomes were examined using mixed-effects and Cox regression models. RESULTS: Mean 2,3-DPG levels decreased from a mean (+/-SD) of 13.4+/-3.4 umol/g Hgb to 11.0+/-3.1 umol/g Hgb after 2 days of CRRT (P<0.001). Mean hemoglobin saturation P50 levels decreased from 29.7+/-4.4 mmHg to 26.7+/-4.0 mmHg (P<0.001). No significant change was seen in the reference group. 2,3-DPG levels after 2 days of CRRT were not significantly lower than those in the reference group on day 2. Among patients receiving CRRT, 2,3-DPG decreased by 0.53 umol/g Hgb per 1 g phosphate removed (95% confidence interval 0.38 to 0.68 umol/g Hgb; P<0.001). Greater reductions in 2,3-DPG were associated with higher risk for death (hazard ratio, 1.43; 95% confidence interval, 1.09 to 1.88; P=0.01). CONCLUSIONS: CRRT induced phosphate depletion is associated with measurable reductions in RBC 2,3 DPG concentration and a shift in the O2:Hgb affinity curve even in the absence of overt hypophosphatemia. 2,3-DPG reductions may be associated with higher risk for in-hospital death and represent a potentially avoidable complication of CRRT. PMID- 25538270 TI - Quantitative and Qualitative Antibody Responses to Immunization With the Pneumococcal Polysaccharide Vaccine in HIV-Infected Patients After Initiation of Antiretroviral Treatment: Results From a Randomized Clinical Trial. AB - BACKGROUND: Pneumococcal vaccination is recommended for human immunodeficiency virus-infected (HIV+) persons; the best timing for immunization with respect to initiation of antiretroviral therapy (ART) is unknown. METHODS: Double-blind, placebo-controlled trial in HIV+ with CD4(+) T cells/uL (CD4) >= 200 randomized to receive the 23-valent pneumococcal polysaccharide vaccine (PPV23) or placebo at enrollment, followed by placebo or PPV23, respectively, 9-12 months later (after >=6 months of ART). Capsular polysaccharide-specific immunoglobin (Ig) G and IgM levels to serotypes 1, 3, 4, 6B, and 23F, and opsonophagocytic killing activity (OPA) to serotypes 6B and 23F were evaluated 1 month postvaccination. RESULTS: One hundred seven subjects were enrolled, 72 (67.3%) were evaluable (36/group). Both groups had significant increases in pre- to 1-month postvaccination IgG levels, but negligible to IgM, and significant increases in OPA titers to serotype 6B but not to 23F. There were no significant differences between groups in serotype-specific IgM or IgG levels or OPA titers. For the combined groups, there was a significant correlation between serotype-specific IgG and OPA titers to 23F but not to 6B. There was no correlation between CD4, viral load and IgG responses. CONCLUSIONS: In HIV+ with CD4 >= 200, delaying PPV23 until >=6 months of ART does not improve responses and may lead to missed opportunities for immunization. PMID- 25538272 TI - Involvement of nitric oxide in the mitochondrial action of efavirenz: a differential effect on neurons and glial cells. AB - The anti-human immunodeficiency virus (HIV) drug efavirenz (EFV) alters mitochondrial function in cultured neurons and glial cells. Nitric oxide (NO) is a mediator of mitochondrial dysfunction associated with HIV central nervous system symptoms. We show that EFV promotes inducible nitric oxide synthase (iNOS) expression in cultured glial cells and generated NO undermines their mitochondrial function, as inhibition of NOS partially reverses this effect. EFV inhibits mitochondrial Complex I in both neurons and glia; however, when the latter cells are treated for longer periods, other mitochondrial complexes are also affected in accordance with the increased NO production. These findings shed light on the mechanisms responsible for the frequent EFV-associated neurotoxicity. PMID- 25538271 TI - Salmonella-induced Diarrhea Occurs in the Absence of IL-8 Receptor (CXCR2) Dependent Neutrophilic Inflammation. AB - BACKGROUND: Gastroenteritis is the most common manifestation of nontyphoidal Salmonella enterica infections, but little is known about the pathogenesis of diarrhea in this infection METHODS: To determine whether polymorphonuclear neutrophils (PMNs) are required for diarrhea for Salmonella colitis, we infected kanamycin-pretreated interleukin 8R (IL-8R) mutant mice and controls, both with nonmutant Slc11a1 (Nramp1, ItyR). We compared the 2 mouse strains for increases in fecal water content (diarrhea) 3 days after infection, changes in expression of ion transporters in colonic epithelial cells, proliferation of epithelial cells, and severity of infection as measured by colony-forming units (CFUs). RESULTS: The IL-8R knockout mice had fewer PMNs in the colon but the other variables we measured were unaffected except for an increase in CFUs in the colon. The pathologic changes in the cecum were similar in both groups except for the lack of PMNs in the IL-8R knockout mice. There was minimal damage to the colon more distally. CONCLUSIONS: In the early stage of Salmonella colitis, PMNs are not required for diarrhea or for the decrease in expression of colonic epithelial cell apical ion transporters. They contribute to defense against infection in the cecum but not extracolonically at this stage of Salmonella colitis. PMID- 25538273 TI - Early Antiretroviral Therapy in South African Children Reduces HIV-1-Infected Cells and Cell-Associated HIV-1 RNA in Blood Mononuclear Cells. AB - We measured cell-associated human immunodeficiency virus (HIV)-1 DNA (CAD) and RNA (CAR) and plasma HIV-1 RNA in blood samples from 20 children in the Children with HIV Early Antiretroviral (CHER) cohort after 7-8 years of suppressive combination antiretroviral therapy (cART). Children who initiated cART early (<2 months; n = 12) had lower HIV-1 CAD (median, 48 vs 216; P < .01) and CAR (median, 5 vs 436; P < .01) per million peripheral blood mononuclear cells than children who started later (>= 2 months; n = 8). Plasma HIV-1 RNA levels were not significantly lower in early-treated children (0.5 vs 1.2 copies/mL; P = .16). Early treatment at <2 months of age reduces the number of HIV-infected cells and HIV CAR. PMID- 25538274 TI - Sphingosine-1-phosphate Receptor Agonism Reduces Bordetella pertussis-mediated Lung Pathology. AB - Recent pertussis resurgence represents a major public health concern. Currently, there are no effective treatments for critical pertussis in infants. Recent data have demonstrated the potential of sphingosine-1-phosphate receptor (S1PR) agonism in the treatment of infectious diseases. We used the murine Bordetella pertussis model to test the hypothesis that treatment with S1PR agonist AAL-R reduces pulmonary inflammation during infection. AAL-R treatment resulted in reduced expression of inflammatory cytokines and chemokines and attenuated lung pathology in infected mice. These results demonstrate a role for sphingosine-1 phosphate (S1P) signaling in B. pertussis-mediated pathology and highlight the possibility of host-targeted therapy for pertussis. PMID- 25538275 TI - Striking Divergence in Toxoplasma ROP16 Nucleotide Sequences From Human and Meat Samples. AB - BACKGROUND: ROP16 is a protein kinase of Toxoplasma gondii identified in the mouse model as a virulent marker, but it is unknown whether this finding is relevant in human toxoplasmosis. METHODS: We obtained the Toxoplasma ROP16 locus DNA sequence in samples from 12 patients with ocular toxoplasmosis, 1 sample from a patient with congenital toxoplasmosis, 22 samples from soldiers operating in the jungle, 2 samples from urban soldiers, and 10 samples from meat for human consumption. An enzyme-linked immunosorbent assay specific for antibodies against the ROP16 mouse-virulent peptide was performed in 46 serum specimens from patients with ocular toxoplasmosis and in 28 serum specimens from patients with chronic asymptomatic infection, of whom 19 had congenital infection and 11 had toxoplasmic lymphadenitis. RESULTS: We found a striking divergence of the ROP16 nucleotide sequences. Ten of 12 sequences (83.3%) from patients with ocular toxoplasmosis clustered with those of mouse-virulent strains, whereas 7 of 7 ROP16 sequences (100%) from meat were clustered with those of mouse-avirulent strains. Only 11 of 104 serum specimens (10.5%) had specific antibodies against the mouse-virulent peptide, and there was no association between clinical forms and positive results of serological assays. CONCLUSIONS: The majority of ROP16 nucleotide sequences from Colombian patients with ocular toxoplasmosis belonged to the group of mouse-virulent strains. PMID- 25538276 TI - Medroxyprogesterone Acetate Regulates HIV-1 Uptake and Transcytosis but Not Replication in Primary Genital Epithelial Cells, Resulting in Enhanced T-Cell Infection. AB - Although clinical and experimental evidence indicates that female sex hormones and hormonal contraceptives regulate susceptibility to human immunodeficiency virus type 1 (HIV-1) infection, the underlying mechanism remains unknown. Genital epithelial cells (GECs) are the first cells to encounter HIV during sexual transmission and their interaction with HIV may determine the outcome of exposure. This is the first report that HIV uptake by GECs increased significantly in the presence of the hormonal contraceptive medroxyprogesterone acetate (MPA) and progesterone and that uptake occurred primarily via endocytosis. No productive infection was detected, but endocytosed virus was released into apical and basolateral compartments. Significantly higher viral transcytosis was observed in the presence of MPA. In GEC and T-cell cocultures, maximum viral replication in T cells was observed in the presence of MPA, which also broadly upregulated chemokine production by GECs. These results suggest that MPA may play a significant role in regulating susceptibility to HIV. PMID- 25538277 TI - Safety and Immunogenicity of Cell Culture-Derived A/H3N2 Variant Influenza Vaccines: A Phase I Randomized, Observer-Blind, Dose-Ranging Study. AB - BACKGROUND: A/H3N2 variant (H3N2v) influenza may sustain human-to-human transmission, and an available candidate vaccine would be important. METHODS: In this phase I, randomized, observer-blind, dose-ranging study, 627 healthy subjects >= 3 years of age were randomized to receive 2 vaccinations with H3N2c cell-culture-derived vaccine doses containing 3.75 ug, 7.5 ug, or 15 ug hemagglutinin antigen of H3N2v with or without MF59 (registered trademark of Novartis AG) adjuvant (an oil-in-water emulsion). This paper reports Day 43 planned interim data. RESULTS: Single MF59-adjuvanted H3N2c doses elicited immune responses in almost all subjects regardless of antigen and adjuvant dose; the Center for Biologics Evaluation Research and Review (CBER) licensure criteria were met for all groups. Subjects with prevaccination hemagglutination inhibition titers <10 and children 3-<9 years achieve CBER criteria only after receiving 2 doses of nonadjuvanted H3N2c vaccine. Highest antibody titers were observed in the 7.5 ug + 0.25 mL MF59 groups in all age cohorts. MF59-adjuvanted H3N2c vaccines showed the highest rates of solicited local and systemic events, predominately mild or moderate. CONCLUSIONS: A single dose of H3N2c vaccine may be immunogenic and supports further development of MF59-adjuvanted H3N2c vaccines, especially for pediatric populations. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT01855945 (http://clinicaltrials.gov/ct2/show/NCT01855945). PMID- 25538279 TI - Mineralocorticoid receptors: an appealing target to treat coronary microvascular dysfunction in diabetes. PMID- 25538280 TI - Glucose-dependent Foxo1 switch in healing wounds: a shred of hope for diabetic ulcers? PMID- 25538281 TI - Hidden complexities in the measurement of fructosyl-lysine and advanced glycation end products for risk prediction of vascular complications of diabetes. PMID- 25538285 TI - The split-brain: rooting consciousness in biology. PMID- 25538286 TI - Inner workings: Discovering the split mind. PMID- 25538288 TI - Insight into the role of chlorhexidine in Delftia acidovorans biofilm formation. PMID- 25538289 TI - Simple solutions reflect misunderstanding of animal antibiotic use. PMID- 25538290 TI - Reply to "Simple solutions reflect misunderstanding of animal antibiotic use". PMID- 25538292 TI - Acupuncture for knee osteoarthritis: study by Hinman et al represents missed opportunities. PMID- 25538293 TI - An observational study on the costs and consequences of acupuncture for the management of chronic low back pain in Korean patients. AB - OBJECTIVES: To investigate the consequences and costs of acupuncture in general medical practice for patients with chronic low back pain (CLBP) in Korea. METHODS: A multicentre observational study was performed. Outpatients with CLBP who received at least one acupuncture session in a Korean Medicine clinic during the study period were included and followed up for 3 months. All patients received regular acupuncture treatments in accordance with the doctors' discretion. The consequences in terms of effects included condition-specific outcomes and preference-based outcome. For cost analysis, the cumulative resource use for direct medical costs at each research clinic during the study period and direct patient data using the self-reported healthcare utilisation questionnaires were used. RESULTS: A total of 157 patients were eligible to participate and 105 were finally included. Significant improvements in condition-specific and preference-based measures were observed after acupuncture treatment. An average of approximately $146 (L93) per patient was reported for direct medical costs in each clinic for 1 month and $231 (L148) for 3 months. Other medical expenses related to CLBP were reduced during this period. CONCLUSIONS: The use of acupuncture to manage CLBP in general clinical practice in Korea inexpensively improved pain, functional disability and quality of life. The study results are meaningful and consistent with the results of previous trials performed in other European countries but the power of the study is not strong, having major design weaknesses. A large-scale cohort or registry based on practice may be helpful to strengthen the evidence of the cost-effectiveness of acupuncture. PMID- 25538295 TI - New evidence on the origin of carnivorous plants. PMID- 25538298 TI - Precisely cyclic sand: self-organization of periodically sheared frictional grains. AB - The disordered static structure and chaotic dynamics of frictional granular matter has occupied scientists for centuries, yet there are few organizational principles or guiding rules for this highly hysteretic, dissipative material. We show that cyclic shear of a granular material leads to dynamic self-organization into several phases with different spatial and temporal order. Using numerical simulations, we present a phase diagram in strain-friction space that shows chaotic dispersion, crystal formation, vortex patterns, and most unusually a disordered phase in which each particle precisely retraces its unique path. However, the system is not reversible. Rather, the trajectory of each particle, and the entire frictional, many-degrees-of-freedom system, organizes itself into a limit cycle absorbing state. Of particular note is that fact that the cyclic states are spatially disordered, whereas the ordered states are chaotic. PMID- 25538299 TI - Adaptor-mediated Lon proteolysis restricts Bacillus subtilis hyperflagellation. AB - The Lon AAA+ protease is a highly conserved intracellular protease that is considered an anticancer target in eukaryotic cells and a crucial virulence regulator in bacteria. Lon degrades both damaged, misfolded proteins and specific native regulators, but how Lon discriminates among a large pool of candidate targets remains unclear. Here we report that Bacillus subtilis LonA specifically degrades the master regulator of flagellar biosynthesis SwrA governed by the adaptor protein swarming motility inhibitor A (SmiA). SmiA-dependent LonA proteolysis is abrogated upon microbe-substrate contact causing SwrA protein levels to increase and elevate flagellar density above a critical threshold for swarming motility atop solid surfaces. Surface contact-dependent cellular differentiation in bacteria is rapid, and regulated proteolysis may be a general mechanism of transducing surface stimuli. PMID- 25538300 TI - High-pressure superconducting phase diagram of 6Li: isotope effects in dense lithium. AB - We measured the superconducting transition temperature of (6)Li between 16 and 26 GPa, and report the lightest system to exhibit superconductivity to date. The superconducting phase diagram of (6)Li is compared with that of (7)Li through simultaneous measurement in a diamond anvil cell (DAC). Below 21 GPa, Li exhibits a direct (the superconducting coefficient, alpha, T(c) ?proportional M(-alpha), is positive), but unusually large isotope effect, whereas between 21 and 26 GPa, lithium shows an inverse superconducting isotope effect. The unusual dependence of the superconducting phase diagram of lithium on its atomic mass opens up the question of whether the lattice quantum dynamic effects dominate the low temperature properties of dense lithium. PMID- 25538304 TI - How many scientific papers are not original? PMID- 25538301 TI - ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons. AB - ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin remodeling proteins and primarily functions at heterochromatic loci via its recognition of "repressive" histone modifications [e.g., histone H3 lysine 9 tri methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX's ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this "methyl/phos" switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction. PMID- 25538305 TI - Reply to Simon and Reed: Independent and converging results rule out historic disturbance and confirm age constraints for Barrier Canyon rock art. PMID- 25538306 TI - Incorrect representation of Barrier Canyon rock art site's history and other factors invalidate reported dates. PMID- 25538307 TI - Alteration of substrate specificity of alanine dehydrogenase. AB - The l-alanine dehydrogenase (AlaDH) has a natural history that suggests it would not be a promising candidate for expansion of substrate specificity by protein engineering: it is the only amino acid dehydrogenase in its fold family, it has no sequence or structural similarity to any known amino acid dehydrogenase, and it has a strong preference for l-alanine over all other substrates. By contrast, engineering of the amino acid dehydrogenase superfamily members has produced catalysts with expanded substrate specificity; yet, this enzyme family already contains members that accept a broad range of substrates. To test whether the natural history of an enzyme is a predictor of its innate evolvability, directed evolution was carried out on AlaDH. A single mutation identified through molecular modeling, F94S, introduced into the AlaDH from Mycobacterium tuberculosis (MtAlaDH) completely alters its substrate specificity pattern, enabling activity toward a range of larger amino acids. Saturation mutagenesis libraries in this mutant background additionally identified a double mutant (F94S/Y117L) showing improved activity toward hydrophobic amino acids. The catalytic efficiencies achieved in AlaDH are comparable with those that resulted from similar efforts in the amino acid dehydrogenase superfamily and demonstrate the evolvability of MtAlaDH specificity toward other amino acid substrates. PMID- 25538309 TI - Trends in the evidence level for the American Diabetes Association's "Standards of Medical Care in Diabetes" from 2005 to 2014. PMID- 25538310 TI - Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. PMID- 25538312 TI - Insights into the role of the microbiome in obesity and type 2 diabetes. AB - The worldwide prevalence of obesity and type 2 diabetes mellitus (T2DM) continues to rise at an alarming pace. Recently the potential role of the gut microbiome in these metabolic disorders has been identified. Obesity is associated with changes in the composition of the intestinal microbiota, and the obese microbiome seems to be more efficient in harvesting energy from the diet. Lean male donor fecal microbiota transplantation (FMT) in males with metabolic syndrome resulted in a significant improvement in insulin sensitivity in conjunction with an increased intestinal microbial diversity, including a distinct increase in butyrate producing bacterial strains. Such differences in gut microbiota composition might function as early diagnostic markers for the development of T2DM in high-risk patients. Products of intestinal microbes such as butyrate may induce beneficial metabolic effects through enhancement of mitochondrial activity, prevention of metabolic endotoxemia, and activation of intestinal gluconeogenesis via different routes of gene expression and hormone regulation. Future research should focus on whether bacterial products (like butyrate) have the same effects as the intestinal bacteria that produce it, in order to ultimately pave the way for more successful interventions for obesity and T2DM. The rapid development of the currently available techniques, including use of fecal transplantations, has already shown promising results, so there is hope for novel therapies based on the microbiota in the future. PMID- 25538311 TI - BMI cut points to identify at-risk Asian Americans for type 2 diabetes screening. PMID- 25538313 TI - Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? Yes, they continue to serve us well! AB - Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestyle modification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the point narrative presented below, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the following counterpoint narrative, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable. PMID- 25538314 TI - Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? No, it's time to move on! AB - Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestyle modification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the preceding point narrative, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the counterpoint narrative below, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable. PMID- 25538315 TI - Statement of principle. PMID- 25538317 TI - Treatment of recent-onset type 1 diabetic patients with DiaPep277: results of a double-blind, placebo-controlled, randomized phase 3 trial. Diabetes Care 2014;37:1392-1400. DOI: 10.2337/dc13-1391. PMID- 25538318 TI - Evaluation of long-term treatment effect in a type 1 diabetes intervention trial: differences after stimulation with glucagon or a mixed meal. Diabetes Care 2014;37:1384-1391. DOI: 10.2337/dc13-1392. PMID- 25538320 TI - Glycemic variability is associated with quality of life and treatment satisfaction in patients with type 1 diabetes. PMID- 25538321 TI - Corneal confocal microscopy shows an improvement in small-fiber neuropathy in subjects with type 1 diabetes on continuous subcutaneous insulin infusion compared with multiple daily injection. PMID- 25538322 TI - Medalists with extreme duration of type 1 diabetes exhibit only mild diastolic dysfunction and myocardial fibrosis. PMID- 25538323 TI - Effect of exogenous intravenous administrations of GLP-1 and/or GIP on circulating pro-atrial natriuretic peptide in subjects with different stages of glucose tolerance. PMID- 25538324 TI - Role of endothelial dysfunction and arterial stiffness in the development of diabetic retinopathy. PMID- 25538325 TI - Clinical trials and evolving regulatory science in India. PMID- 25538327 TI - Postgraduate pharmacology curriculum in medical institutions in India: time for need-based appraisal and modifications. AB - The need to revise the curriculum for the postgraduate course (M.D.) in Pharmacology has been perceived by the academicians in India since quite some time. The changing professional requirements of the graduating students, the current scenario vis a vis animal experimentation and the emphasis of the Medical Council of India on a competency based curriculum has triggered this felt need. In spite of the fact that most medical institutions and universities in India offer postgraduate courses in pharmacology, the curriculum lacks uniformity with extreme variations observed at some places. This article attempts to analyze the existing curricula in pharmacology in India and suggest modifications that could be recommended to the suitable regulatory bodies for implementation. A revision of objectives in the three domains of learning, development of skills that help develop suitable competencies, adoption of teaching learning methods in addition to the conventional methods, and a rethink on the assessment methods have been recommended. Development and validation of alternatives skill-based modules in lieu of animal experiments are recommended. Additional skills like medical writing and communication skills, professionalism and ethics, multi and inter disciplinary integration and collaboration and a wider exposure of students to the pharmaceutical, academic, regulatory and research institutions for onsite learning were also recommended to fulfill their future career requirements. PMID- 25538326 TI - Endocan: a novel circulating proteoglycan. AB - Endocan is a novel endothelium derived soluble dermatan sulfate proteoglycan. It has the property of binding to a wide range of bioactive molecules associated with cellular signaling and adhesion and thus regulating proliferation, differentiation, migration, and adhesion of different cell types in health and disease. An increase in tissue expression or serum level of endocan reflects endothelial activation and neovascularization which are prominent pathophysiological changes associated with inflammation and tumor progression. Consequently, endocan has been used as a blood-based and tissue-based biomarker for various cancers and inflammation and has shown promising results. PMID- 25538328 TI - Colchicine in prevention of atrial fibrillation following cardiac surgery: systematic review and meta-analysis. AB - OBJECTIVES: Inflammation is one of the predictors of atrial fibrillation (AF) following surgical or interventional cardiac procedures. Recent evidence suggests that colchicine may represent a new strategy to prevent AF following cardiac procedures. This study aims to assess the antiinflammatory efficacy of colchicine in prevention of early AF event (EAFE). MATERIALS AND METHODS: We reviewed all available studies that assessed the effectiveness of colchicine therapy on the occurrence of AF in patients undergoing cardiac procedures. Meta-analysis was performed by random effect inverse variance-weighted method by entering AF events and the total population from each study. RESULTS: After thorough review of the databases, we found three studies comparing colchicine and placebo which had EAFE as the outcome. Of 584 patients, 286 patients were on colchicine and 298 on placebo. All the three studies were randomized. After pooled analysis, colchicine was associated with significant reduction in AF events compared to placebo (odds ratio = 0.44 [0.29, 0.66], P < 0.001). There was no statistical heterogeneity between included studies (chi(2) = 0.45, P = 0.80, I(2) = 0%). CONCLUSION: Colchicine may prove beneficial in the prevention of AF following cardiac surgery. Further research is warranted. PMID- 25538329 TI - Study on the impact of lead acetate pollutant on immunotoxicity produced by thiamethoxam pesticide. AB - OBJECTIVE: The curtailed knowledge about neonicotinoids that it has low affinity for vertebrate relative to insect nicotinic receptors is a major factor for its widespread use assuming that it is much safer than the previous generation insecticides. But literature regarding effect of thiamethoxam (second generation neonicotinoid)on immune system is not available. Also, there might be chances of interaction of heavy persistent metals in the water table with these pesticides. So, this study was undertaken with the objective to find immunotoxic alterations of lead acetate after exposure with thiamethoxam in animal model. MATERIALS AND METHODS: For this albino mice were randomly divided into 6 groups (numbered I to VI) each containing 6 mice. Animals of groups I and II were administered 87.1 mg/kg b.w.(body weight) and 43.5 mg/kg b.w. respectively of thiamethoxam. Group III animals, lead acetate was administered orally and IV and V mice were administered combination of lead acetate and thiamethoxam at higher and lower dose level for 28 days. The group VI was control group. On 29(th) day and humoral and cell mediated immune responses, TLC (Total leukocyte count), DLC (Differential leukocyte count), serum total protein, globulin and albumin, and histopathological studies were conducted. RESULT: The result obtained clearly indicated that on oral administration of thiamethoxam immunotoxicity was induced in mice in dose related manner. Lead acetate when administered for 28 days showed immunotoxic potential. Thiamethoxam and lead acetate when administered together did not lead to any new altered immunotoxic response but additive toxic effects of both were observed. PMID- 25538330 TI - Evaluation of silodosin in comparison to tamsulosin in benign prostatic hyperplasia: a randomized controlled trial. AB - OBJECTIVES: Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms in elderly men. Selective alfa1-adrenergic antagonists are now first-line drugs in the medical management of BPH. We conducted a single blind, parallel group, randomized, controlled trial to compare the effectiveness and safety of the new alfa1-blocker silodosin versus the established drug tamsulosin in symptomatic BPH. MATERIALS AND METHODS: Ambulatory male BPH patients, aged above 50 years, were recruited on the basis of International Prostate Symptom Score (IPSS). Subjects were randomized in 1:1 ratio to receive either tamsulosin 0.4 mg controlled release or silodosin 8 mg once daily after dinner for 12 weeks. Primary outcome measure was reduction in IPSS. Proportion of subjects who achieved IPSS <8, change in prostate size as assessed by ultrasonography and changes in peak urine flow rate and allied uroflowmetry parameters, were secondary effectiveness variables. Treatment emergent adverse events were recorded. RESULTS: Data of 53 subjects - 26 on silodosin and 27 on tamsulosin were analyzed. Final IPSS at 12-week was significantly less than baseline for both groups. However, groups remained comparable in terms of IPSS at all visits. There was a significant impact on sexual function (assessed by IPSS sexual function score) in silodosin arm compared with tamsulosin. Prostate size and uroflowmetry parameters did not change. Both treatments were well-tolerated. Retrograde ejaculation was encountered only with silodosin and postural hypotension only with tamsulosin. CONCLUSIONS: Silodosin is comparable to tamsulosin in the treatment of BPH in Indian men. However, retrograde ejaculation may be troublesome for sexually active patients. PMID- 25538331 TI - Protective effect of L-arginine on gentamicin-induced nephrotoxicity in rats. AB - INTRODUCTION: L-arginine has a protective effect on gentamicin-induced renal failure and it may decrease the tubular reabsorption of another cationic substance, gentamicin due to its cationic structure. The aim of this study is to compare the possible protective effects of L-arginine and its inactive isomer D arginine on gentamicin-induced nephrotoxicity in rats. MATERIALS AND METHODS: Wistar albino rats were housed in metabolic cages and assigned to six groups as: control group, gentamicin (100 mg/kg), gentamicin + L-arginine (2 g/l), gentamicin + D-arginine (2 g/l), gentamicin + L-arginine + Nv-nitro-L-arginine methyl ester (L-NAME) (100 mg/l) and gentamicin + D-arginine + L-NAME. Gentamicin was administered by subcutaneous injections and the other drugs were added in drinking water for seven consecutive days. The animals were killed by decapitation and intracardiac blood and urine samples were obtained on the seventh day. Blood urea nitrogen, serum creatinine, sodium, potassium, urine gamma glutamyl transferase, creatinine, sodium, potassium and gentamicin levels were measured using High Performance Liquid Chromatography (HPLC) technique. RESULTS: Gentamicin treated group had significant increase in blood urea nitrogen, serum creatinine, fractional Na excretion and urine gamma glutamyl transferase levels, and significant decrease in creatinine clearance compared to the control group. L-arginine and D-arginine reversed these findings. L-NAME abolished the nephroprotective effect of L-arginine. The urinary levels of gentamicin were significantly increased in rats treated with L-arginine or D arginine compared to those treated with gentamicin. L-arginine and D-arginine reversed the advanced degenerative changes due to gentamicin administration in histopathological examination. CONCLUSION: Our study revealed the protective effect of L-arginine on gentamicin-induced nephrotoxicity, the contribution of the cationic feature of L-arginine, and the major role of NO in this protective effect. PMID- 25538332 TI - Optimal single-dose epidural neostigmine for postoperative analgesia after partial hepatectomy. AB - OBJECTIVE: Neostigmine can produce analgesia by acting on the spinal cord. This study was to determine the optimal single-dose of epidural neostigmine for postoperative analgesia after partial hepatectomy. PATIENTS AND METHODS: Twenty six patients undergoing elective partial hepatectomy under general anesthesia combined with epidural block were studied. The dose of epidural neostigmine was determined using Dixon's up-and-down method, starting from neostigmine 100 MUg with an interval of 25 MUg. Thirty minutes after skin incision, a predetermined dose of neostigmine was injected via the epidural catheter. Each patient received 0.125% bupivacaine and fentanyl 2 MUg/ml for patient controlled epidural analgesia (PCEA) after the operation. Assessment of analgesia quality was performed at 8 h and 24 h after the operation. RESULTS: The ED50 of epidural neostigmine in combination with PCEA for satisfactory analgesia was 226.78 +/- 33.20 MUg. Probit analysis showed that the ED50 and ED95 of epidural neostigmine were 228.63 MUg (95% CI = 197.95-299.77 MUg) and 300.12 MUg (95% CI = 259.44 741.65 MUg), respectively. CONCLUSION: The ED50 and ED95 of epidural neostigmine in combination with PCEA for satisfactory analgesia after partial hepatectomy were 228.63 MUg (95% CI = 197.95-299.77 MUg) and 300.12 MUg (95% CI = 259.44 741.65 MUg). PMID- 25538333 TI - Neuroprotective effect of Feronia limonia on ischemia reperfusion induced brain injury in rats. AB - OBJECTIVES: Brain stroke is a leading cause of death without effective treatment. Feronia limonia have potent antioxidant activity and can be proved as neuroprotective against ischemia-reperfusion induced brain injury. MATERIALS AND METHODS: We studied the effect of methanolic extract of F. limonia fruit (250 mg/kg, 500 mg/kg body weight, p.o.) and Vitamin E as reference standard drug on 30 min induced ischemia, followed by reperfusion by testing the neurobehavioral tests such as neurodeficit score, rota rod test, hanging wire test, beam walk test and elevated plus maze. The biochemical parameters, which were measured in animals brain were catalase, superoxide dismutase (SOD), malondialdehyde and nitric oxide in control and treated rats. RESULTS: The methanolic extract of F. limonia fruit (250 mg/kg, 500 mg/kg body weight, p.o.) treated groups showed a statistically significant improvement in the neurobehavioral parameters such as motor performance (neurological status, significant increase in grasping ability, forelimb strength improvement in balance and co-ordination). The biochemical parameters in the brains of rats showed a significant reduction in the total nitrite (P < 0.01) and lipid peroxidation (P < 0.01), also a significant enhanced activity of enzymatic antioxidants such as catalase (P < 0.01) and SOD (P < 0.05). CONCLUSION: These observations suggest the neuroprotective and antioxidant activity of F. limonia and Vitamin E on ischemia reperfusion induced brain injury and may require further evaluation. PMID- 25538334 TI - The effect of progesterone on systemic inflammation and oxidative stress in the rat model of sepsis. AB - OBJECTIVES: To explore the protective effect of progesterone on inflammation and oxidative stress in a rat model of sepsis created by cecal ligation and puncture (CLP). MATERIALS AND METHODS: Rats were randomly divided into 4 groups: Overiectomy group (OVX), sham operated (control), sepsis (CLP) group and progesterone-treated CLP group (CLP+ progesterone). The rats in CLP+ progesterone group received intraperitoneal progesterone (2 mg/kg). Cardiac blood samples were obtained for the measurement levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Tissue samples, including liver, kidney and uterus of rats were prepared to determine activities of myeloperoxidase (MPO), glutathione peroxidase (GPx) and levels of malondialdehyde (MDA). RESULTS: Increased serum IL 6 and TNF-alpha levels were found in the CLP group in comparison with the control group (P = 0.01, P = 0.02; respectively). In CLP+ progesterone group, mean MDA concentration of kidney tissue was significantly lower than in CLP group (P = 0.003). Liver MDA concentration of the CLP+ progesterone group was not significantly different from that of the control group. While there were no significant differences among groups regarding liver MPO; in the CLP group, MPO activity in kidney (P = 0.02) and uterine tissues (P = 0.03) were found to be significantly higher compared to the control group. In CLP+ progesterone group, mean MPO activities of all tissues were not different than those of control group. The uterine tissue GPx activity in the CLP+ progesterone group was not statistically significantly different from control group. CONCLUSIONS: We suggest that progesterone ameliorates sepsis syndrome by reduction of the inflammatory cytokines IL-6 and TNF-alpha, and by restoration of antioxidant enzyme activities in some tissues. PMID- 25538336 TI - Effects of tanshinone IIA on the transforming growth factor beta1/Smad signaling pathway in rat cardiac fibroblasts. AB - OBJECTIVES: This study explores the mechanism of tanshinone IIA (TSN)-mediated inhibition of myocardial fibrosis by investigating the effect of TSN on transforming growth factor beta1 (TGFbeta1) signal transduction in rat cardiac fibroblasts (CFs). MATERIALS AND METHODS: CFs were isolated from neonatal Sprague Dawley rats by trypsin digestion and differential adhesion and stimulated with 5 ng/mL TGFbeta1 and TSN (10(-6), 10(-5), or 10(-4) mol/L). The expression of fibronectin (FN) mRNA in the CFs was determined using reverse transcriptase polymerase chain reaction and the protein expression of FN and Smads in CFs was detected using Western blot. The intracellular expression and localization of Smads in the CFs were analyzed using immunocytochemistry. RESULTS: TGFbeta1 induced the expression of FN and Smads in a time-dependent manner. At the end of the culture treatment, the mRNA expression of FN and the expression of phosphorylated Smad2/3 (p-Smad2/3) increased significantly (P < 0.01). TSN pretreatment (10(-5) and 10(-4) mol/L) reduced the expression of FN and p-Smad2/3 (P < 0.01) following TGFbeta1 stimulation and led to a significant decrease in the nuclear staining intensity and a positive rate of p-Smad2/3 (P < 0.05 and P < 0.01, respectively). CONCLUSION: The inhibitory effect of TSN on myocardial fibrosis may be associated with its inhibition of TGFbeta1-induced Smad2/3 phosphorylation and p-Smad2/3 nuclear translocation, which blocks the TGFbeta1/Smad signaling pathway in CFs. PMID- 25538335 TI - Effect of coenzyme Q10 alone and its combination with metformin on streptozotocin nicotinamide-induced diabetic nephropathy in rats. AB - OBJECTIVES: This study was aimed to investigate the therapeutic potential of coenzyme Q10 and its combination with metformin on streptozotocin (STZ) nicotinamide-induced diabetic nephropathy (DN). MATERIALS AND METHODS: Type 2 diabetes in rats was induced with STZ-nicotinamide. The diabetic rats were treated with coenzyme Q10 (10 mg/kg, p.o.) alone or coenzyme Q10 + metformin. Various parameters of renal function tests such as serum creatinine, urea, uric acid, and markers of oxidative stress such as renal malondialdehyde (MDA) level, superoxide dismutase (SOD), and catalase (CAT) activities were measured. Tumor necrosis factor-alpha (TNF-alpha), myeloperoxidase (MPO) activity, transforming growth factor-beta (TGF-beta), and nitrite content were estimated in renal tissues. All treated animal were subjected to histopathological changes of kidney. RESULT: Diabetic rats showed a significant reduction in renal function, which was reflected with an increase in serum urea, serum creatinine, uric acid. In addition, STZ-nicotinamide caused renal tubular damage with a higher MDA level, depletion of SOD and CAT activity and glutathione (GSH) level. Moreover, TNF-alpha, MPO activity, TGF-beta, and nitrite content were significantly increased in diabetic rats, while treatment with coenzyme Q10 or metformin or their combination ameliorate STZ-nicotinamide induced renal damage due to improvement in renal function, oxidative stress, suppression of TNF-alpha, MPO activity, TGF-beta and nitrite content along with histopathological changes. CONCLUSIONS: This finding suggests that the treatment with coenzyme Q10 or metformin showed significant renoprotective effect against STZ-nicotinamide induced DN. However, concomitant administration of both showed a better renoprotective effect than coenzyme Q10 or metformin alone treatment. PMID- 25538337 TI - Effect of combination of ketanserin and escitalopram on behavioral anomalies after olfactory bulbectomy: prediction of quick onset of antidepressant action. AB - OBJECTIVES: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant drugs. The addition of low dose of 5-hydroxytryptamine type 2A enhances the therapeutic effect of SSRIs. The purpose of the present studies was to test the effects of combined treatment of a low dose of ketanserin (KET) and escitalopram (ESC) on behavioral anomalies occurring after olfactory bulbectomy (OBX). MATERIALS AND METHODS: Chronic Depression was induced by OBX as shown in behavioral tests such as Open field, social interaction, and hyperemotionality tests. Acute and chronic treatment effect of KET, ESC, and combination was administered to the OBX rats. RESULTS: Chronic (14 days) treatment with KET (1 mg/kg) or ESC (10 mg/kg) alleviated the behavioral anomalies of olfactory bulbectomized rats in modified open field exploration, social interaction, hyperemotionality. When KET treatment was combined with ESC, a short duration regimen (7 days) was sufficient to reverse the bulbectomy induced anomalies. CONCLUSION: The combination therapy as a likely strategy to achieve an early-onset of antidepressant action. PMID- 25538339 TI - Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy. AB - Methotrexate (MTX) is one of the most commonly used medicines in the treatment of psoriatic arthritis. The drug can produce steatosis and cirrhosis. Autoimmune hepatitis is a rare and serious adverse effect. We describe the case of a 53-year old woman who developed autoimmune hepatitis after a long-term use of MTX for psoriatic arthritis. Hepatitis was completely resolved 4 months after stopping this drug. The pathophysiologic mechanisms of a drug-induced autoimmunity are unclear and complex. This report confirms the need to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis. PMID- 25538338 TI - Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits. AB - OBJECTIVES: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. MATERIALS AND METHODS: Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. RESULTS: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. CONCLUSION: Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection. PMID- 25538341 TI - Linezolid induced black hairy tongue. AB - Black hairy tongue (BHT) also called as lingua villosa nigra, is a self limiting benign condition characterized by hypertrophy and elongation of filiform papillae of tongue with brown or black discoloration. Smoking, poor oral hygiene, xerostomia, using peroxide containing mouth washes, substance abuse and drugs (steroids, methyldopa, olanzapine, etc) are the predisposing factors. However its occurrence in relation to linezolid ingestion among south Indians has not been reported in PubMed database. Here we report a case, where significant association of linezolid intake with BHT was found in a 10-year-old boy, who was treated with tablet linezolid for post surgical infection of left side radial neck fracture. This case is reported for the rarity of occurrence with linezolid therapy. According to Naranjo adverse drug reaction (ADR) causality scale, the association of BHT due to linezolid in our case was probable. PMID- 25538340 TI - Hypoglycemia - a rare complication of carbamazepine overdose. AB - Carbamazepine overdose usually presents with neurological manifestations such as ataxia, seizures and altered sensorium or cardiac manifestations that include tachycardia, hypotension and ventricular extra-systoles. We report a patient with carbamazepine overdose who manifested recurrent hypoglycemia on the third and fourth day following ingestion that resolved with supportive therapy. PMID- 25538342 TI - A case of etizolam dependence. AB - Etizolam is a thienodiazepine anxiolytic which is said to have lower dependence potential than other benzodiazepines. We report a case of etizolam dependence in a young male with social anxiety disorder and moderate depression. This case report highlights the fact that the same caution be exercised while prescribing etizolam with respect to its potential to cause dependence as with any other benzodiazepine. PMID- 25538343 TI - Duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics. AB - Hyponatremia is a known adverse effect of duloxetine, and it can lead to potentially life-threatening complications. Administration of thiazide diuretics also has been the cause of hyponatremia. We report a case of duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics. An 86-year old woman treated with the trichlormethiazide was admitted for vertebral compression fracture with disorientation and nausea on the 6(th) day of treatment with duloxetine. Laboratory findings revealed hyponatremia, hypo-osmolality, concentrated urine, and increased urine sodium. Syndrome of inappropriate antidiuretic hormone was considered, therefore, duloxetine, and trichlormethiazide was discontinued and treated with fluid restriction, furosemide and sodium chloride administered orally. Disorientation and nausea were improved after correction of hyponatremia. Health care practitioners should be aware of the possibility of duloxetine-induced hyponatremia, particularly in patients treated with thiazide diuretics. PMID- 25538344 TI - Venlafaxine induced akathisia: a case report. AB - Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used for the management of depression and anxiety disorders. The drug has been rarely reported to be associated with the development of akathisia. A review of the literature revealed only three such case reports. In this report we present the case of a middle-aged female, who developed akathisia while receiving venlafaxine (225 mg/day). The patient was suffering from recurrent depressive disorder and Crohn's disease. She was earlier treated with Cap venlafaxine up to 75 mg/day, but had a relapse of depressive symptoms when an attempt was made to taper off venlafaxine. When she presented to us, her depressive symptoms amounted to severe depression without psychotic symptoms. In view of the past response to venlafaxine, she was restarted on venlafaxine, but did not achieve remission of symptoms with the earlier dose and hence, venlafaxine was increased up to 225 mg/day. Within 48 h of increasing venlafaxine to 225 mg/day, she developed akathisia, which subsided after stopping venlafaxine. PMID- 25538347 TI - Ayurvedic education: Where to go from here? PMID- 25538346 TI - Redundant publication: expect the unexpected. PMID- 25538348 TI - Standardization of Rajanyadi curna: An ayurvedic preparation. AB - BACKGROUND: Rajanyadi curna (RC) is an ayurvedic classical preparation used in the treatment of digestive disorders, fever, jaundice, anemia, and asthma. We seek to standardize this drug to ensure its quality. OBJECTIVE: The current investigation was aimed at the preparation of curna in three batches so as to standardize it. MATERIALS AND METHODS: The curna was prepared in-house in three different batches according to directions given in The Ayurvedic Formulary of India. The curna was evaluated based on organoleptic characters, physical characteristics, and physico-chemical parameters. High performance thin layer chromatography was carried out for the quantification of curcumin. RESULTS: The parameters were found to be comparable and sufficient for the evaluation of the curna. CONCLUSION: Ayurvedic medicine, RC has been standardized using the various parameters and can be incorporated while developing the pharmacopoeial standards. PMID- 25538350 TI - Detoxification of Croton tiglium L. seeds by Ayurvedic process of Sodhana. AB - OBJECTIVE: Croton tiglium seeds, known as Jamalgota in Hindi, Marathi, and Urdu is well-known for its toxicity (severe purgative action). In Ayurvedic texts, the plant is known as Kumbhini and is used for the treatment of constipation after Sodhana (detoxification process) of the seeds with Godugdha (cow milk). MATERIAL AND METHODS: In the present study, C. tiglium seeds were purified with cow milk as reported in Ayurvedic classics. Phorbol esters equivalent to phorbol-12 myristate-13-acetate (PMA) and crotonic acid contents were quantified by high performance liquid chromatography method in the seeds of C. tiglium before and after the purification process. RESULTS: The content of the phorbol ester equivalent to PMA in unpurified and purified sample was found to be 5.2 mg/100 g and 1.8 mg/100 g of dried seeds of C. tiglium, respectively. The quantity of crotonic acid in unpurified seeds of C. tiglium was found to be 0.102 mg/100 g of dried seeds while it was absent in the purified seed extract of C. tiglium. CONCLUSION: The toxicity of C. tiglium seeds may be due to the presence of phorbol esters and crotonic acid along with other constituents. These constituents are oil soluble and may be removed by cow milk during the process of Sodhana. Reduction in the level of these constituents after the purification decreases the toxicity of C. tiglium seeds. Reduction in the oily content from the seeds of C. tiglium during the purification process is also supported by the results obtained from the physiochemical parameters. PMID- 25538349 TI - Chemical composition and antimicrobial activity of the essential oil of Ocimum basilicum L. (sweet basil) from Western Ghats of North West Karnataka, India. AB - CONTEXT: Ocimum basilicum L. (Lamiaceae) commonly known as sweet basil, has been used as a traditional medicinal plant for the treatment of headaches, coughs, diarrhea, constipation, warts, worms, and kidney malfunctions. MATERIALS AND METHODS: The essential oil of the flowering aerial parts of O. basilicum growing in the Western Ghats region of North West Karnataka, India, was obtained by hydro distillation and analyzed by gas chromatography equipped with flame ionization detector and gas chromatography coupled to mass spectrometry (GC-MS). The oil was tested against six Gram-positive, eight Gram-negative bacteria, and three fungi by the tube-dilution method at a concentration range of 5.00-0.009 mg/mL. RESULTS: Twenty-five constituents were identified in the essential oil of O. basilicum. The major constituents were identified as methyl eugenol (39.3%) and methyl chavicol (38.3%), accounting for 98.6% of the total oil. The oil was found to be active against Gram-positive, Gram-negative bacteria, and fungi with minimal bactericidal concentration values in the range of 0.143 +/- 0.031 to 0.572 +/- 0.127 mg/mL, 0.781 +/- 0.382 to 1.875 +/- 0.684 mg/mL, and 0.312 +/- 0.171 to 0.442 +/- 0.207 mg/mL, respectively. CONCLUSION: The essential oil of O. basilicum of this region contains methyl eugenol/methyl chavicol chemotype and has bactericidal properties. PMID- 25538351 TI - In vitro thrombolytic potential of root extracts of four medicinal plants available in Bangladesh. AB - CONTEXT: Thrombus formation inside the blood vessels obstructs blood flow through the circulatory system leading hypertension, stroke to the heart, anoxia, and so on. Thrombolytic drugs are widely used for the management of cerebral venous sinus thrombosis patients, but they have certain limitations. Medicinal plants and their components possessing antithrombotic activity have been reported before. However, plants that could be used for thrombolysis has not been reported so far. AIMS: This study's aim was to evaluate the thrombolytic potential of selected plants' root extracts. SETTINGS AND DESIGN: Plants were collected, dried, powdered and extracted by methanol and then fractionated by n-hexane for getting the sample root extracts. Venous blood samples were drawn from 10 healthy volunteers for the purposes of investigation. SUBJECTS AND METHODS: An in vitro thrombolytic model was used to check the clot lysis potential of four n-hexane soluble roots extracts viz., Acacia nilotica, Justicia adhatoda, Azadirachta indica, and Lagerstroemia speciosa along with streptokinase as a positive control and saline water as a negative control. STATISTICAL ANALYSIS USED: Dunnett t-test analysis was performed using SPSS is a statistical analysis program developed by IBM Corporation, USA. on Windows. RESULTS: Using an in vitro thrombolytic model, A. nilotica, L. speciosa, A. indica, and J. adhatoda at 5 mg extract/ml NaCl solution concentration showed 15.1%, 15.49%, 21.26%, and 19.63% clot lysis activity respectively. The reference streptokinase showed 47.21%, and 24.73% clot lysis for 30,000 IU and 15,000 IU concentrations, respectively whereas 0.9% normal saline showed 5.35% clot lysis. CONCLUSIONS: The selected extracts of the plant roots possess marked thrombolytic properties that could lyse blood clots in vitro; however, in vivo clot dissolving properties and active components responsible for clot lysis are yet to be discovered. PMID- 25538352 TI - Physicochemical standardization, HPTLC profiling, and biological evaluation of Asvagandhadyarista: A comparative study of three famous commercial brands. AB - BACKGROUND: Asvagandhadyarista is a polyherbal formulation that is available commercially as an over the counter drug. There are three famous brands that are available in the market. However, there are no comparative reports on the physicochemical, chromatographic, and biological profiles of Asvagandhadyarista manufactured by these famous companies. AIMS: The present study deals with the physicochemical standardization, high performance thin layer chromatography (HPTLC) profiling, and biological evaluation of Asvagandhadyarista. MATERIALS AND METHODS: Asvagandhadyarista manufactured by three leading companies were purchased from Jalandhar, Punjab. The physicochemical standardization of the samples was carried out in accordance with the Ayurvedic Pharmacopoeia of India (API). Authentified Eisenia foetida were procured from Ujjwal Ujala Vermiculture Group, Amritsar. The anthelmintic activity, 1,1-diphenyl-2-picrylhydrazyl scavenging, and hydrogen peroxide scavenging ability of Asvagandhadyarista was determined. STATISTICAL ANALYSIS USED: The data of anthelmintic activity were expressed as mean +/- standard error of the mean of six earthworms in each group. The statistical analysis was carried out using one-way analysis of variance, followed by Dunnet t-test. The difference in values at P < 0.05 was considered to be statistically significant. RESULTS: Most of the physicochemical standardization parameters mentioned as per the API were found to be within limit. HPTLC profiling showed the presence of withanolide D in commercial samples. Out of three commercial brands, ASA-DAB was the most active as compared to the ASA-BDN and ASA-AVP at the concentration of 200 mg/ml for anthelmintic activity against E. foetida. ASA-DAB showed the best antioxidant activity in both the in vitro assay at the concentration of 100 MUg/ml. CONCLUSIONS: The ability of this formulation to scavenge free radicals supports its medical claim of antistress formulation. The anthelmintic potential of this formulation helps us conclude that it can also be considered as a general tonic because it provides relief from helminths. PMID- 25538353 TI - A combined administration of Aragvadadi kasayam and Syrup Talekt induced skin rashes. AB - It is a common notion among people in India that herbal or Ayurvedic products are safe and do not produce any adverse effect. This is not true since Ayurveda has evaded many adverse effects which occur by combination of herbs. This axiom is potentiated by our report that occurs in the form of skin rashes. A 20-year-old South Indian female of Pittakapha prakrti (constitution) after beginning therapy with Aragvadadi kasayam (ARK) (poly-herbal formulation) and Syrup Talekt (poly herbal patent formulation) for the treatment of recurrent incidence of abscess. Rash disappeared after stopping the suspected drug and treatment with Vibhitaki kasayam (decoction of Terminilia bellarica) and Satadhauta ghrtam. Possible and probable (score 6) were the causality according to WHO-Uppsala Monitoring Centre and Naranjo's Adverse Drug Reaction Probability Scale and grouped under type-B reaction. To the best of our knowledge, this is the first case of skin rashes which seen after administration of ARK and Syrup Talekt. This report highlights the need of implementation of pharmacovigilance center in the hospital level and additional research in the field of skin toxicity of ARK and Syrup Talekt. PMID- 25538354 TI - A unique nonsurgical management of internal hemorrhoids by Jimutaka Lepa. AB - This is the era of fast foods. Irregularity in food timing, improper diet, and mental stress coupled with a sedentary life disturb the digestive system resulting in increased incidence of hemorrhoids. In the present report, we present two cases of intero-external hemorrhoids. Case 1: A 30-year old young male approached with intero-external hemorrhoid at 11 O'clock position as a primary. Case 2: A 41-year-old female visited with second degree intero-external hemorrhoid at 11 O'clock position. Hemorrhoids present in these patients can be considered as Kaphaja Arsa. These cases were diagnosed by per rectal digital and proctoscopic examinations by ayurvedic proctologists. In both cases, application of Jimutaka Lepa was done under local anesthesia administered using lignocaine 2% with adrenaline. This was followed by manual anal dilatation. Jimutaka Lepa was applied to the internal hemorrhoids (Arsa). Changes were observed in the form of edema, ulcer in 3-4 days and sloughing out of the pile mass up to 5-7 days. Subsequently fibrosis of hemorrhoidal masses started after 7 days. Jimutaka Lepa shows a significant effect in obliterating the hemorrhoidal mass within a month of application. The patients were followed-up regularly with proctoscopic examination in each visit and did not reveal any evidence of recurrence of the hemorrhoids. PMID- 25538355 TI - Management of rare, low anal anterior fistula exception to Goodsall's rule with Ksarasutra. AB - Anal fistula (bhagandara) is a chronic inflammatory condition, a tubular structure opening in the ano-rectal canal at one end and surface of perineum/peri anal skin on the other end. Typically, fistula has two openings, one internal and other external associated with chronic on/off pus discharge on/off pain, pruritis and sometimes passing of stool from external opening. This affects predominantly male patients due to various etiologies viz., repeated peri-anal infections, Crohn's disease, HIV infection, etc., Complex and atypical variety is encountered in very few patients, which require special treatment for cure. The condition poses difficulty for a surgeon in treating due to issues like patient hesitation, trouble in preparing ksarasutra, natural and routine infection with urine, stool etc., and dearth of surgical experts and technique. We would like to report a complex and atypical, single case of anterior, low anal fistula with tract reaching to median raphe of scrotum, which was managed successfully by limited application of ksarasutra. PMID- 25538356 TI - Rasa Nirdharana (assessment of taste) of Leonotis nepetifolia (L.) R. Br.: A preliminary study in healthy volunteers. AB - BACKGROUND: Rasa (a concept corresponding to taste) is the only perceivable parameter for drug identification in Ayurveda. The Ayurvedic pharmacological principles such as guna (quality), virya (potency) and vipaka (effect of biotransformation) are inferred based on the identified Rasa of a drug. All these principles together predict the probable spectrum of drug action in Ayurveda. It is mandatory to screen a drug in the Ayurvedic pharmacological perspective to incorporate it into Ayurvedic materia medica. AIM: To assess the rasa of a non classical herb, Leonotis nepetifolia (L.).R.Br. based on the laksanas (characteristics) described in Ayurvedic texts for the identification of individual rasa. SETTINGS AND DESIGN: The study was conducted at the Department of Dravyaguna, Institute for Post Graduate Teaching and Reaseach in Ayurveda, Gujarat Ayurved University, Jamnagar. MATERIALS AND METHODS: The whole plant powder (3g) of Leonotisnepetifolia was administered to 50 participants (trained Ayurvedic physicians) and their responses after intake of the drug were elicited using a structured questionnaire. RESULTS AND CONCLUSION: On analyzing the data it was found that Leonotis nepetifolia possess predominantly tikta rasa (bitter taste) followed by Kasaya rasa (astringent taste). Recent researches and ethnomedicinal claims on Leonotis nepetifolia stand comparable with the pharmacological activities attributed to tikta and Kasaya rasa in Ayurvedic classics. Rasa nirdharana can be one of the preliminary steps to initiate the process of screening of an unknown drug along the lines of Ayurvedic pharmacology specially because rasa is the only perceivable parameter. According to Ayurveda, rasa of a dravya has a bearing on its karma (pharmacological action) and the identification of rasa could be one of the subjective means for inferring pancabhautika constitution of a substance which in turn could help in tentatively inferring guna, virya and vipaka of the dravya. This paper demonstrates how a simple method can be used without any instruments to do a preliminary assessment of the rasa or taste of a plant. PMID- 25538357 TI - Honey and bee venom in dermatology: A novel possible alternative or complimentary therapy for psoriasis vulgaris. PMID- 25538358 TI - Remarks on "Tinospora cordifolia: One plant, many roles". PMID- 25538359 TI - The surgical waiting time initiative: A review of the Nigerian situation. AB - The concept of surgical waiting time initiative (SWAT) was introduced in developed countries to reduce elective surgery waiting lists and increase efficiency of care. It was supplemented by increasing popularity of day surgery, which shortens elective waiting lists and minimises cancellations. It is established in Western countries, but not in developing countries like Nigeria where it is still evolving. A search was carried out in Pub Med, Google, African journals online (AJOL), Athens and Ovid for relevant publications on elective surgery waiting list in Nigeria, published in English language. Words include waiting/wait time, waiting time initiative, time to surgery, waiting for operations, waiting for intervention, waiting for procedures and time before surgery in Nigeria. A total of 37 articles published from Nigeria in relation to various waiting times were found from the search and fulfilled the inclusion criteria. Among them, 11 publications (29.7%) were related to emergency surgery waiting times, 10 (27%) were related to clinic waiting times, 9 (24.3%) were related to day case surgery, 2 (5.5%) were related to investigation waiting times and only 5 (13.5%) articles were specifically published on elective surgery waiting times. A total of 9 articles (24.5%) were published from obstetrics and gynaecology (OG), 7 (19%) from general surgery, 5 (13.5%) from public health, 3 (8%) from orthopaedics, 3 (8%) from general practice (GP), 3 (8%) from paediatrics/paediatric surgery, 2 (5.5%) from ophthalmology, 1 (2.7%) from ear, nose and throat (ENT), 1 (2.7%) from plastic surgery, 1 (2.7%) from urology and only 1 (2.7%) article was published from dental/maxillofacial surgery. Waiting times mean different things to different health practitioners in Nigeria. There were only 5/37 articles (13.5%) specifically related to elective surgery waiting times in Nigerian hospitals, which show that the concept of the SWAT is still evolving in Nigeria. Of the 37, 11 (24.5%) publications were from obstetrics and gynaecology (O & G) alone, but these were mostly related to emergency antenatal care rather than surgery. Therefore, more research and initiative needs to be undertaken from all the surgical sub-specialties in order to disseminate this concept of SWAT towards early diagnosis and treatment of elective life threatening conditions, as well as effective patient care. Adopting this concept will help healthcare managers and policy makers to stream line and ring face resources to cater for non-urgent or semi-urgent cases presenting to our hospitals in Nigeria. PMID- 25538360 TI - Motorcycle-related injuries at a university teaching hospital in north central Nigeria. AB - BACKGROUND: Motorcycle-related injuries lead to considerable morbidity and mortality. The aim of this study is to determine the pattern and outcome of motorcycle-related injuries at Benue State University Teaching Hospital, Makurdi, Nigeria. PATIENTS AND METHODS: Case records of all patients who presented to the accident and emergency department with motorcycle-related injuries between July 2012 and June 2013 were analysed for age, gender, injury host status (i.e. rider, pillion or pedestrian), nature of collision (motorcycle versus other vehicles, motorcycle versus motorcycle, motorcycle versus pedestrian or lone riders), body region injured, injury severity score (ISS) at arrival, length of hospital stay (LOS) and mortality. RESULTS: Seventy - nine patients with motorcycle-related injuries were included in the study. They consisted of 63 males (61.8%) and 16 females (15.7%). The age range was 5-65 years with a mean of 32.4 +/- 14.0. Motorcycle versus vehicle collisions were the most common mechanism of injury (n = 46, 58.2%). Musculoskeletal injuries constituted the most common injuries sustained (n = 50, 47.6%) and the tibia was the most frequently fractured bone (n = 14, 35.9%). The majority of patients (57.0%) sustained mild/moderate injuries (ISS <= 15). There was no statistically significant difference between the sexes for sustaining mild/moderate injuries or severe/profound injuries (P > 0.05). Mortality rate was 6.3% with head injuries being involved in all cases. CONCLUSION: Young males were mostly injured in motorcycle-related trauma. Musculoskeletal injuries were the most common injuries sustained and head injuries were involved in all the deaths. Enforcement of motorcycle crash bars and helmet usage is recommended. PMID- 25538361 TI - Aqueous seed extract of Cola nitida rubra reduces serum reproductive hormone concentrations and sperm count in adult male albino Wistar rats. AB - BACKGROUND: Following the high rate of consumption of Cola nitida (cola nut) among the male population in Nigeria, this study seeks to determine the effects of consumption of Cola nitida on serum reproductive hormones and sperm count, which are major determinants of male fertility. MATERIALS AND METHODS: Thirty-two male albino wistar rats weighing 180-220 g were used for this study and were divided into 4 groups of eight animals each. Group 1 served as control, group 2 received 2 mg/kg Cola nitida extract (Test 1), group 3 received 6 mg/kg Cola nitida extract (Test 2) and group 4 received 10 mg/kg Cola nitida extract (Test 3). After 6 weeks of treatment, reproductive hormonal assay was carried out using the rat serum. Epididymal spermatozoa were collected and sperm count determined. RESULTS: Serum concentrations of luteinizing hormone (LH) and testosterone were significantly (P < 0.05) reduced in test 2 and 3, compared with control. Sperm count was significantly lower in test group 1 (P < 0.05), 2 (P < 0.001) and 3 (P < 0.001) compared with control, with test 3 significantly (P < 0.05) lower compared with test 1. There was no significant difference in testicular and epididymis weight in the different experimental groups studied. CONCLUSION: Aqueous seed extract of Cola nitida rubra resulted in reduced serum reproductive hormone concentrations and sperm count in male wistar rats, and may therefore be detrimental to reproductive health, hence the need for regulation of its consumption. PMID- 25538362 TI - Prevalence and socio-demographic risk factors associated with psychoactive substance use in psychiatric out-patients of a tertiary hospital in Nigeria. AB - BACKGROUND: The co-morbidity of psychoactive substance use and other mental disorders is a major challenge to the management of both conditions in several parts of the world. There is relative dearth of information on co-morbidity and its predictors in Nigeria. This study determined the prevalence and socio demographic risk factors associated with psychoactive substance use in the psychiatric out-patients of a tertiary hospital in Nigeria. STUDY DESIGN: A cross sectional study. MATERIALS AND METHODS: From routine clinic visits over a 4-month period, each consecutive 4(th) adult patients (>18 years) who had previously attended the clinic at least for 1 year, completed a socio-demographic and semi structured drug use questionnaires and interview with the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) to generate substance use diagnosis. Data was analysed using the statistical package for social sciences (SPSS), version 16. Level of significance was set at P < 0.05. RESULTS: The lifetime prevalence for the use of substance was 29.3%, while that for multiple substances was 17.7%. The most commonly used substances were alcohol, cannabis and tobacco and they were also the ones mostly used in combination with one or the other. A total of 10.1% of the patients had a psychoactive substance use disorder. Being male, married with at least primary education and unemployed were significant risk factors for substance use. CONCLUSION: Psychoactive substance is common among the psychiatric outpatients of the hospital with males, those with formal education, the married and unemployed being at high risk of substance use. PMID- 25538363 TI - Correlation between maternal weight and insulin resistance in second half of pregnancy. AB - BACKGROUND: In pregnancy, routine measurement of maternal weight gives a crude assessment of maternal and foetal well-being. Excess weight gain in pregnancy is related to increased risk for gestational diabetes mellitus (GDM), hypertension in pregnancy and foetal macrosomia. In the Nigerian context, lack of knowledge of pre-pregnancy weight coupled with late booking of women in pregnancy hinders accurate assessment of weight gain in pregnancy. The absolute maternal weight is often used as surrogate. This study evaluates the relationship between absolute weight in the second half of pregnancy and insulin resistance. PATIENTS AND METHODS: The weight of hundred pregnant women was measured between 24 to 32 weeks of pregnancy and their insulin resistance was measured using Homeostatic Model Assessment (HOMA-IR) from fasting serum glucose and fasting serum insulin. RESULTS: Twenty-six women had weight >=95 kg and 74 women had weight of <95 kg. There was a significant positive correlation between weight and HOMA-IR (r = 0.248), fasting glucose (r = 0.198), and fasting insulin (r = 0.228), (P < 0.05). The mean weight, HOMA-IR, fasting glucose and fasting insulin were higher in women with weight >=95 kg compared to those with less weight. Also maternal weight >= 95 kg was associated with severe insulin resistance, (Odds Ratio = 3.1). CONCLUSION: Absolute weight in pregnancy correlates well with insulin resistance. Women having weight >=95 kg between 24-32 weeks of gestation were more likely to have severe insulin resistance with implications for increased risk of GDM and other complications. PMID- 25538364 TI - Assessment of Snoring and obstructive sleep apnoea in a Nigerian university: Association with cardiovascular risk factors. AB - BACKGROUND: Snoring remains under diagnosed in general population. It however has significant morbidity and mortality risk factors with multiple effects on the cardiovascular system. The Berlin questionnaire is a worldwide validated instrument to identify those at increased risk for obstructive sleep apnoea (OSA). MATERIALS AND METHODS: In all, 206 workers of LAUTECH were invited to participate in the study. The Berlin questionnaire was used for this study. It was a cross-sectional study. Socio-demographic and clinical data were taken with a data form. Statistical Package for the Social Sciences software (SPSS 17.0) was used for statistical analysis. P < 0.05 was taken as statistically significant value. RESULTS: The study participants consisted of 96 males (46.6%) and 110 (53.4%) females. The mean age was 45.3 +/- 7.9 years. The mean body mass index was 28.5 +/- 6.0 kg/m2. The frequency of occurrence of snoring was 91 (44.2%) including 50 males (54.9% and 41 females (37.3 %, P <0.05). Using the Berlin score, 63 (30.6%) including 34 females (30.9%) were assessed to be at high risk for OSA. Snorers were more likely to be at higher risk of OSA compared to non snorers: odd risk was 113.8, relative risk was 3.3. Snoring was most likely to be associated with obesity, elevated blood pressure and male gender in this study. CONCLUSION: We concluded that snoring and high risk for sleep apnoea is common among this unselected University population and they are closely related to many conventional cardiovascular risk factors. Appropriate interventional strategies are indicated to reduce the burden of the increased morbidity and mortality associated with sleep apnoea in our population. PMID- 25538365 TI - Medical treatment of allergy in children with recurrent or chronic sinusitis. AB - BACKGROUND: Diagnosis and treatment of chronic and recurrent sinusitis in children is of potential importance and many factors can havean influence on it. This study assessed the chronic and recurrent sinusitis and affecting factors, as well as the role of allergy in its course and treatment in children. MATERIALS AND METHODS: A total of 106 children with the diagnosis of chronic or recurrent sinusitis, referred to specialty clinics of otolaryngology and allergy of Tabriz Children Educational-Medical centres since 2010 to 2012, were enrolled. The history and physicalexamination findings were recorded for all patients and allergy Prick test was done for all. Response to treatment was evaluated during the follow-up visits. RESULTS: The mean age of studied patients was 6.5 +/- 2.9 years. Of all the patients, 54 (50.9%) were male and 52 (49.1%) were female. Skin Prick test was positive in 69.8%. Response to treatment was seen in 86.8% of the patients while 7.5% did not have any favourable outcome. Anti-allergic treatment caused better outcomes in patients with positive Skin Prick test than those with negative results. CONCLUSION: The prevalence of allergic disease in children with chronic or recurrent sinusitis is considerable and anti-allergic treatments can result infavourable therapeutic outcomes in children with sinusitis, especially with positive skin prick test results. PMID- 25538366 TI - Predictors of malaria in febrile children in Sokoto, Nigeria. AB - BACKGROUND: Presumptive diagnosis of malaria is widespread, even where microscopy is available. As fever is very nonspecific, this often leads to over diagnosis, drug wastage and loss of opportunity to consider alternative causes of fever, hence the need to improve on the clinical diagnosis of malaria. MATERIALS AND METHODS: In a prospective cross-sectional comparative study, we examined 45 potential predictors of uncomplicated malaria in 800 febrile children (0-12 years) in Sokoto, Nigeria. We developed a clinical algorithm for malaria diagnosis and compared it with a validated algorithm, Olaleye's model. RESULTS: Malaria was confirmed in 445 (56%). In univariate analysis, 13 clinical variables were associated with malaria. In multivariate analysis, vomiting (odds ratio, OR 2.6), temperature >= 38.5 degrees C (OR 2.2), myalgia (OR 1.8), weakness (OR 1.9), throat pain (OR 1.8) and absence of lung crepitations (OR 5.6) were independently associated with malaria. In children over age 3 years, any 3 predictors had a sensitivity of 82% and specificity of 47% for malaria. An Olaleye score >= 5 had a sensitivity of 62% and a specificity of 51%. CONCLUSION: In hyperendemic areas, the sensitivity of our algorithm may permit presumptive diagnosis of malaria in children. Algorithm positive cases can be presumptively treated, and negative cases can undergo parasitological testing to determine need for treatment. PMID- 25538367 TI - Oral self-care practices among university students in Port Harcourt, Rivers State. AB - BACKGROUND: The maintenance of optimum oral health is dependent on the efficacy of oral self-care. The objective of the present study was to evaluate oral self care practices and knowledge among non-medical students at the University of Port Harcourt, Rivers State Nigeria. MATERIALS AND METHODS: The cross-sectional survey was conducted among undergraduate students at the University of Port Harcourt Nigeria, in January, 2014. Self-administered questionnaire elicited information on demography, frequency of tooth brushing, type of tooth brush, use of dental floss and previous visit to the dentist. RESULTS: A total of 360 young adults, 188 males and 172 females, aged 18-33 years participated in the study. Brushing habits of the study population was at least once a day (90%). Approximately half (52.5 %) of the samples used medium-sized bristles and about 28.8% of the students replaced their toothbrush every 3 months. Regarding oral hygiene aids, few students, 5.8% and 4.2% used dental floss and mouthwash, respectively, as oral cleaning aid. Most of the students (71.6%) had never visited the dentist, 18.1% visited due to dental pain and 8.1% for extraction. Regarding knowledge on oral hygiene practice, approximately 60% of students knew that we have to brush our teeth twice daily, 31% knew we need to visit the dentist twice a year and only 18% knew what was dental floss. CONCLUSION: Oral hygiene practices among the students were poor. Therefore, oral health education and promotion is required to improve oral hygiene practices and health among young adults and the general population. PMID- 25538368 TI - Effects of high versus low-dose atorvastatin on high sensitive C-reactive protein in acute coronary syndrome. AB - BACKGROUND: Cardiovascular disease is the leading cause of mortality. The previous findings which suggest the reduction in C-reactive protein (CRP) levels by statin encouraged us to conduct the present study in which we tested the effects of atorvastatin, on levels of hs-CRP in a prospective randomised clinical trial study on patients with acute coronary syndrome. MATERIALS AND METHODS: Present prospective randomised clinical trial study conducted on 180 patients who had developed coronary artery disease and presented in emergency departments of Educational-Medical centers of Tabriz University of Medical Sciences. The patients were divided randomly into two groups and then two therapeutic protocols were given to them. One group medicated by high-dose atorvastatin (40 mg) and the other group received low-dose atorvastatin (20 mg). All variables were collected by questionnaires and were analyzed. RESULTS: There were 180 patients consisted of 34 females and 56 males in low-dose atorvastatin group (L-DA group), and 30 females and 60 males in high-dose atorvastatin group (H-DA group) (P = 0.533). In this study atorvastatin in high doses decreased hs-CRP levels about 40% and in low doses it only caused decrease of 13.3%, and significant correlation was observed between two groups (Paired Sample T-test) (P = 0.001). Also atorvastatin in high doses decreased LDL levels about 23% and in low doses it only decreased 10%, and significant correlation was observed between two groups (Paired Sample T test) (P = 0.001). Atorvastatin in high doses decreased HDL levels about 9% and in low doses it only decreased 6%, and again significant correlation was observed between two groups (P = 0.009). CONCLUSION: The present study confirms the novel observation that atorvastatin therapy results in a significant reduction in hs CRP levels. PMID- 25538369 TI - Human papilloma virus 16/18 genotypes in patients with squamous cell carcinoma of cervix in northeast Iran. AB - BACKGROUND: A relation has been established between infection with high-risk types of human papilloma virus (HPV) and development of cervical cancer. To estimate the risk of HPV infection for cervical malignancies, we conducted a case control study in northeast Iran. MATERIALS AND METHODS: This study was carried out on 123 paraffin embedded blocks with exact diagnosis of squamous cell carcinoma (SCC). A total of 100 cervical tissue specimens with normal histopathology product of hysterectomy were also used as control. Both groups were tested for the presence of HPV DNA and HPV 16/18 subtypes using PCR assay. RESULTS: Large non-keratinising subtype of cervical carcinoma was the most frequent one (62.6%), followed by keratinising and small cell subtypes (27% and 10%, respectively). Overall prevalence of HPV infection in SCC of cervix was 34.2% (42 out of 123 cases). HPV 16 was the most common type in this group (21 cases, 17.1%), followed by HPV 18 (16 cases, 13%) and other subtypes (5 cases, 4.1%). In this study, overall prevalence of HPV infection in control group was 12% (including 3% HPV 16; 5% HPV 18 and 4% other subtypes). CONCLUSION: Although association of HPV 16/18 and SCC of cervix was relatively higher than control group, compared with the previous study, the association between cervical SCC and HPV infection was significantly lower in our study; and possibly, the other risk factors play a major role in carcinogenesis of cervical carcinoma in this region. PMID- 25538370 TI - Synopsis of non-communicable diseases in children admitted to the paediatric ward of the university of Nigeria teaching hospital (UNTH) Enugu, Nigeria: A ten year review. AB - BACKGROUND: Non-communicable diseases are increasing worldwide due to rapidly changing lifestyles and socio-economic status. It is contributing significantly to the global burden of diseases. OBJECTIVE: To determine the pattern of non communicable diseases in children admitted into the Paediatrics ward in a tertiary health centre in Enugu. MATERIALS AND METHODS: A review of admissions into the Paediatrics ward of the University of Nigeria Teaching Hospital Enugu, between January 1999 and December 2008 was done using the registry of admission and discharge. RESULTS: The age range of patients admitted during the period was 2 months to 18 years (mean 5.27 +/- 5.42 years). There were 1173 (59.6%) males and 796 (40.4%) females. Disorders of the haematological system accounted for 514 (23.3%) of the non-communicable diseases among the admissions, malignancies accounted for 424 (19.2%) among the admissions, whereas the renal, central nervous, and cardiovascular systems were involved in 282 (12.8%), 274 (12.4%), and 241 (10.9%) patients, respectively. There were 274 (12.4%) deaths and 1667 (75.5%) discharges while 38 (1.7%) were discharged against medical advice. Data on 221(10.2%) of the patients were reported missing. Malignancies contributed to 75 (27.3%) of the deaths, haematological disorders accounted for 44 (16%) whereas renal disorders and nutritional disorders contributed to 43 (15.7%) and 41 (15%) of the deaths, respectively. CONCLUSION: Non-communicable diseases affect children in our environment and contribute to morbidity and mortality in children. Strategies to prevent these diseases should be encouraged in order to avert the challenges of double burden of the diseases in children. PMID- 25538371 TI - Crystalluria in HIV/AIDS patients on highly active anti-retroviral therapy in the Kumasi metropolis; a cross sectional study. AB - BACKGROUND: Crystalluria is associated with some highly active anti-retroviral therapies (HAART's) used in the management of HIV/AIDS. AIMS: This study used light microscopy to establish the prevalence of crystalluria among HIV/AIDS patients on HAART and identified the routine crystals present in their urine. MATERIALS AND METHODS: In this simple randomised cross-sectional study, 200 HIV/AIDS participants, comprising 150 on HAART and 50 HAART-naive were recruited from the HIV clinic at the Komfo Anokye Teaching Hospital (KATH). Urine and blood samples were collected, for urinalysis and the determination of the CD4 count, respectively. A well-structured pre-tested questionnaire was used to obtain socio demographic data and clinical history of the participants. RESULTS: The prevalence of crystalluria was higher among HIV-infected persons on HAART than those not on HAART (6.7% vs 4%; P = 0.733). Calcium oxalate and triple phosphate crystals were the crystal types present in their urine (3.5% and 2.5%, respectively) and was present only in HIV subjects on first line of treatment (without protease inhibitors). Participants aged between 40-50 years and those with hypersthenuria and acidic urine had the highest amount of crystalluria (41.6%, 83.3%, and 58.3%, respectively). CONCLUSION: HAART is associated with crystalluria in HIV patients. Light microscopy will be of disgnostic value in resource limited settings. PMID- 25538372 TI - Comparison of microalbuminuria among treatment naive HIV sero-positive and negative adult clients in Faith Alive Foundation Hospital, Jos. AB - BACKGROUND: This study is to determine microalbuminuria in human immunodeficiency virus (HIV) infected patients before commencement of highly active anti retroviral treatment (HAART). PATIENTS AND METHODS: Consecutive patients with the HIV infection seen in the HIV counselling and testing (HCT) unit of the Faith Alive Foundation Hospital, Jos, and a similar group of healthy uninfected patients were evaluated for renal disease: Urinary albumin and urinary creatinine were analysed. RESULTS: Of the 200 patients with HIV infection and 100 uninfected controls studied, increased urinary albumin excretion (UAE) was present in 39 (19.5%) of the subjects and 5.0 (5.0%) of controls. The difference between the mean values for the UAE for both subjects and controls [182.3 +/- 54.3 and 163.9 +/- 39.3 mg/l, respectively (P = 0.006)] was statistically significant. On the other hand the urinary creatinine for both the subjects and controls [11.7 +/- 5.2 and 12.0 +/- 4.8 mmol/L, respectively (P = 0.6)] was not statistically significant. The difference between the mean urinary albumin/creatinine ratio (UACR) for both subjects and controls [1.8 +/- 1.2 mg/mmol and 1.4 +/- 0.4 mg/mmol respectively (P = 0.001)] was statistically significant. CONCLUSION/RECOMMENDATION: Increase UAE is a common complication of HIV infection due to a number of factors other than HAART. Early screening for renal disease using microalbuminuria is very useful since the use of medications such as angiotensin converting enzyme inhibitors, which could help reverse progression to end-stage renal disease. PMID- 25538373 TI - National health insurance scheme: How receptive are the private healthcare practitioners in a local government area of Lagos state. AB - BACKGROUND: National Health Insurance Scheme (NHIS) is one of the health financing options adopted by Nigeria for improved healthcare access especially to the low income earners. One of the key operators of the scheme is the health care providers, thus their uptake of the scheme is fundamental to the survival of the scheme. The study reviewed the uptake of the NHIS by private health care providers in a Local Government Area in Lagos State. OBJECTIVE: To assess the uptake of the NHIS by private healthcare practitioners. MATERIALS AND METHODS: This descriptive cross-sectional study recruited 180 private healthcare providers selected by multistage sampling technique with a response rate of 88.9%. RESULT: Awareness, knowledge and uptake of NHIS were 156 (97.5%), 110 (66.8%) and 97 (60.6%), respectively. Half of the respondents 82 (51.3%) were dissatisfied with the operations of the scheme. Major reasons were failure of entitlement payment by Health Maintenance Organisations 13 (81.3%) and their incurring losses in participating in the scheme 8(50%). There was a significant association between awareness, level of education, knowledge of NHIS and registration into scheme by the respondents P-value < 0.05. CONCLUSIONS: Awareness and knowledge of NHIS were commendable among the private health care providers. Six out of 10 had registered with the NHIS but half of the respondents 82 (51.3%) were dissatisfied with the scheme and 83 (57.2%) regretted participating in the scheme. There is need to improve payment modalities and ensure strict adherence to laid down policies. PMID- 25538374 TI - Syndrome of myelinated retinal nerve fibres, myopia, amblyopia and strabismus in a Nigerian. AB - Myelinated retinal nerve fibres (MRNF) are rare congenital anomalies. They may present in a syndrome characterised by ipsilateral myelinated retinal nerve fibres, myopia and amblyopia. We report a case of this rare condition with unilateral extensive MRNF, axial myopia, amblyopia and strabismus in a Nigerian girl. PMID- 25538375 TI - How tertiary hospitals can strengthen primary health care in Nigeria. PMID- 25538376 TI - Claim Construction Cannot Save a Modified Gene Invention Claimed with a Scientifically Debatable Biological Mechanism: A Lesson from Bayer CropScience AG v. Dow AgroSciences LLC, 728 F.3d 1324 (Fed. Cir. 2013). PMID- 25538377 TI - The History of Technology Assessment and Comparative Effectiveness Research for Drugs and Medical Devices and the Role of the Federal Government. PMID- 25538378 TI - Prognostic value of plasma pentraxin-3 levels in patients with stable coronary artery disease after drug-eluting stent implantation. AB - Pentraxin-3 (PTX3) is an inflammatory marker thought to be more specific to cardiovascular inflammation than C-reactive protein (CRP). Our aim was to assess the prognostic value of PTX3 in patients with stable coronary artery disease (CAD) after drug eluting stent (DES) implantation. Plasma PTX3 levels were measured before percutaneous coronary intervention (PCI) and at 24 h post-PCI in 596 consecutive patients with stable CAD. Patients were followed up for a median of 3 years (range 1-5) for major adverse cardiovascular events (MACEs). We found that the post-PCI plasma PTX3 levels were significantly higher at 24 h after PCI than pre-PCI, patients with MACEs had higher post-PCI PTX3 levels compared with MACEs-free patients, patients with higher post-PCI PTX3 levels (median > 4.384 ng/mL) had a higher risk for MACEs than those with PTX3 < 4.384 ng/mL, and post PCI PTX3, cTnI, multiple stents, and age but not high-sensitivity CRP (hsCRP) were independently associated with the prevalence of MACEs after DES implantation. The present study shows that post-PCI PTX3 may be a more reliable inflammatory predictor of long-term MACEs in patients with stable CAD undergoing DES implantation than CRP. Measurement of post-PCI PTX3 levels could provide a rationale for risk stratification of patients with stable CAD after DES implantation. PMID- 25538379 TI - Flow cytometric immunophenotyping and cell block immunocytochemistry in the diagnosis of primary Non-Hodgkin's Lymphoma by fine-needle aspiration: Experience from a tertiary care center. AB - BACKGROUND: Accurate diagnosis of Non-Hodgkin's Lymphoma (NHL) on fine-needle aspiration (FNA) specimen is challenging and requires ancillary testing. AIM: The feasibility of flow cytometric immunophenotyping (FCI) along with cell block immunocytochemistry (CB-ICC) as adjunct techniques in the diagnosis of NHL as per the current World Health Organization (WHO) classification was evaluated. MATERIALS AND METHODS: All cases of suspected lymphoma underwent FNA, and the sample was triaged for light microscopic evaluation, FCI, and CB-ICC, and each case was classified as per the current WHO classification. RESULTS: A total of 65 cases was analyzed which included 40 B-cell, 21 T-cell, and 4 unclassifiable lymphomas. Of 61 cases, FCI alone was contributory in 74% (45/61) cases whereas CB-ICC alone was contributory in 65.5% (40/61) cases in typing the lymphoma. In 11.4% (7/61) cases, the lymphoma could not be classified by either technique. Thus, in a total of 88.5% (54/61) cases a combination of FCI and CB-ICC from FNA enabled a diagnosis of lymphoma with its subtyping. CONCLUSION: Flow cytometric immunophenotyping and ICC on CBs are feasible on FNA material and are very useful in a suspected case of NHL especially when a biopsy may not be possible or feasible. PMID- 25538380 TI - Evaluation of ploidy status using DNA-image cytometry of exfoliated mucosal cells in oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is one of the potentially malignant disorders (PMDs) with a malignancy rate of 0.2-2%. Aneuploidy is considered to be one of the important markers for malignant transformation and DNA-image cytometry (DIC) has been successfully employed in oral mucosal PMDs and also in tumors of the cervix, lung and biliary tract. AIMS: In this study, we intend to assess the ploidy status of exfoliated cells in OLP using DIC. MATERIALS AND METHODS: Exfoliated cells from 48 patients with different subtypes of OLP (reticular, plaque type, erosive and atrophic) and 10 controls were stained using Feulgen reaction and assessed for integrated optical density using image analysis software and the ploidy status was assessed. RESULTS: All the patients in the control group and most of the patients (93.5%) who had reticular or plaque type of OLP (29 out of 31) exhibited diploid nuclei in the smears, whereas 11 patients who had erosive or atrophic types of OLP showed aneuploid nuclei. CONCLUSIONS: The patients with erosive or atrophic types of OLP are at more risk and assessment of ploidy status by exfoliative cytology can be used as an adjuvant for diagnosis. PMID- 25538381 TI - Diagnostic utility of bronchoalveolar lavage. AB - INTRODUCTION: Bronchoalveolar lavage (BAL) is a diagnostic procedure by which cells and other components from bronchial and alveolar spaces are obtained for various studies. One of the main advantages of BAL is that it can be done as a day care procedure. Material obtained by BAL can give a definite diagnosis in conditions such as infections and malignancies. AIMS: The aims and objective of this study were to assess the utility of BAL as a diagnostic tool to determine the diagnostic accuracy of the material obtained from BAL in various infections and neoplastic lesions to study the limitations of BAL in certain lung disorders. MATERIALS AND METHODS: This study was done in a tertiary care center in Hyderabad. Bronchoscopy was done as an outpatient procedure and lavage fluid obtained analyzed. This is a prospective study done from January 2012 to Jun 2013. Ninety-one BALs were analyzed for total and differential count, microbiological examination and cytological evaluation. Cases selected included nonresolving pneumonias, diffuse lung infiltrates, infiltrates in immunosuppressed hosts and ventilator-associated pneumonias. RESULTS: Bronchoalveolar lavage was done in 91 cases over a period of 11/2 years. Definite diagnosis was not given in 7 cases. Four cases were inadequate. Tuberculosis was diagnosed in 22 cases, fungal infections in 7 cases. Thirty-eight cases of bacterial pneumonias were diagnosed, Klebsiella was the most common organism. Malignancy was diagnosed in 13 cases. CONCLUSION: Definite diagnosis can be made in tuberculosis, fungal infections, bacterial pneumonias and in malignancies. PMID- 25538383 TI - Correlation between cytological and histopathological examination of the endometrium in abnormal uterine bleeding. AB - BACKGROUND: Abnormal uterine bleeding (AUB) is a common problem for which women seek gynecological consultation. Endometrial aspiration cytology (EAC) is an acceptable and valuable diagnostic procedure for screening the endometrial status. MATERIALS AND METHODS: Endometrial aspiration using a menstrual regulation (MR) syringe and a 4 mm Karman's cannula was performed just prior to D and C in 100 women presenting with AUB. Smears were reviewed for cytomorphological findings and were correlated with the histopathological findings. These findings were categorized as benign endometrium, endometrial hyperplasia, malignancy and inadequate smears. RESULTS: Age of the patients ranged from 19 to 70 years. In our study, the accuracy in diagnosing benign conditions of endometrium, hyperplasia, and malignancy on aspiration cytology were 93.88%, 96.94% and 96.84%, respectively. CONCLUSIONS: Endometrial aspiration is an effective, useful and a minimally invasive procedure. With an experienced cytologist, it can be used routinely for the primary investigation of women with AUB, provided all the points of discrepancies are taken care of. PMID- 25538382 TI - Nuclear morphometric and morphological analysis of exfoliated buccal and tongue dorsum cells in type-1 diabetic patients. AB - BACKGROUND: Diabetes mellitus type 1 that results from immunologically mediated damage to the beta-cells in the pancreas. Diabetes mellitus is characterized by recurrent or persistent hyperglycemia. Hyperglycemia can be associated with salivary gland dysfunction and alterations in the oral epithelial cells. AIM: The aim of this study was to evaluate the qualitative and quantitative changes in buccal and tongue dorsum epithelial cells using an exfoliative cytology method in type 1 diabetic patients. MATERIALS AND METHODS: We performed light microscopic analysis of the buccal and tongue dorsum smears in thirty type 1 diabetic patients and thirty healthy individuals. The oral smears were stained using Papanicolaou method for cytological examination and nuclear morphometric analysis. In each case, the mean nuclear area, perimeter, length, breadth, and roundness factor were evaluated in each smear using the image analysis software (Q Win, LeicaTM). RESULTS: The nuclear area, length, breadth, and perimeters were significantly higher in the diabetic group from tongue dorsum smear than that of the control group (P < 0.05). In the cytological examination, karyorrhexis karyolysis-karyopyknosis, binucleation, nuclear membrane irregularity, cytoplasmic polymorphism, perinuclear halo were observed in oral smears with type 1 diabetic patients. Binucleation (P = 0.002) and nuclear membrane irregularity (P = 0.024) were significantly more common in buccal smears of diabetic group. Furthermore, the sensitivity of buccal mucosa was significantly higher in the diabetic group (P = 0.006). CONCLUSION: The light microscopic and nuclear morphometric study indicates that type 1 diabetes can produce morphological and nuclear morphometric changes in the oral mucosa that are noticeable with exfoliative cytology. PMID- 25538384 TI - Correlation of eosinophilic structures with detection of acid-fast bacilli in fine needle aspiration smears from tuberculous lymph nodes: Is eosinophilic structure the missing link in spectrum of tuberculous lesion? AB - BACKGROUND: Acid-fast bacilli (AFB) is not seen in all necrotic tuberculous lesions. If the subset of tuberculous lesions which yield positive result for AFB can be identified, it would save on time and manpower besides optimizing use of resources. A prospective study was undertaken to assess if presence of eosinophilic structures (ESs) in necrotic tuberculous lesions correlated with the presence of AFB. MATERIALS AND METHODS: Patients referred for fine needle aspiration cytology for evaluation of lymphadenopathy between July 2012 and June 2013 were analyzed. The hematoxylin and eosin and May-Grunwald-Giemsa stained slides were screened for epithelioid cell granuloma, ES and necrosis and Ziehl Neelsen stained smears for AFB. RESULT: One hundred and eight tuberculous lymph nodes yielded necrotic material on aspiration. Four cytologic pictures were seen: (a) ES(+) AFB(+) in 58.33%, (b) ES(+) AFB(-) in 20.37%, (c) ES(-) AFB(+) in 9.26% (d) ES(-) AFB(-) in 12.04% cases. Overall AFB was found in 67.59% cases, out of which 58.33% correlated with the presence of ES while 9.26% were seen in smears without ES. CONCLUSION: Presence of ESs should be included in the morphological description of tuberculous lesions. In the absence of granulomas, they indicate tuberculous nature of the lesion. Presence of ES mandates a search for AFB as probability of finding AFB is high in such lesions. Significance of ES lies in their presence and not in their absence. Eosinophilic structures appear to be the missing link in the spectrum of tuberculous lesion. PMID- 25538385 TI - Efficacy of rapid, economical, acetic acid, Papanicolaou stain in cervical smears as an alternative to conventional Papanicolaou stain. AB - BACKGROUND: Papanicolaou (Pap) stain has been used over the years for cervical cytology screening. However; it utilizes a considerable amount of alcohol which is expensive and difficult to procure. In one of the modifications, ethyl alcohol is replaced by 1% acetic acid and is termed as rapid, economical, acetic acid Papanicolaou (REAP) stain. It is cost effective, easily available and provides a suitable and rapid staining alternative. AIM: This study was undertaken to assess the efficacy of REAP stain as an alternative method to conventional Pap stain. MATERIALS AND METHODS: This study was done over a period of 18 months in a tertiary care hospital. Two sets of cervical smears were prepared of which one was stained with conventional Pap stain, and other was stained with REAP stain. The smears were examined for cytomorphological parameters and were evaluated using a modification of parameters given by Ng et al. RESULTS: A total of 737 smears were examined in duplicate. Most of the conventional Pap smears showed excellent preservation (91.6%) with very few showing optimal (7.6%) and sub optimal staining (0.8%). In contrast to this excellent preservation was seen in just 33.6% of the REAP stained smears with majority showing optimal and sub optimal preservation (46.5% and 20% respectively). The P value was statistically significant (<0.0001) depicting inferior staining quality of REAP stain. CONCLUSION: Rapid, economical, acetic acid Papanicolaou stain undoubtly is a simple, fast and cost effective stain which can be adopted mainly in resource limited settings, but cannot be utilized for research purpose in a tertiary care setup due to poor preservation of the staining quality. PMID- 25538387 TI - Ameloblastoma: Cytopathologic profile of 12 cases and literature review. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) has been used as a diagnostic tool in evaluating suspected lesions. It shows a high diagnostic accuracy for diagnosing salivary gland lesions. AIM: The aim of this study was to highlight FNAC as an effective diagnostic tool in the presumptive diagnosis of ameloblastoma. MATERIALS AND METHODS: A total of 12 cases of ameloblastoma sampled by FNAC retrieved from the archives of the Oral Pathology Department were retrospectively studied. The smears were alcohol-fixed and stained with hematoxylin and eosin. All the 12 cases of FNAC had subsequent corresponding surgical incisional biopsy or excision specimens. RESULTS: Cytologically, seven cases were diagnosed as benign odontogenic tumor more in favor of ameloblastoma. All the 12 fine-needle aspiration cases were given a histopathologic work-up and diagnosed as ameloblastomas. Of these, the seven cytologically diagnosed benign odontogenic lesions were also confirmed to be ameloblastoma by both incisional biopsy as well as surgical excision. CONCLUSION: It was deduced from the above results that FNAC helps potentially in diagnosing ameloblastoma. PMID- 25538386 TI - Solitary bone plasmacytoma: An interesting case report with unusual clinico cytological features. AB - Solitary bone plasmacytoma (SBP) is a rare entity characterized by localized proliferation of monoclonal plasma cells primarily occurring in the axial skeleton without systemic involvement. Involvement of the distal extremity is unusual. In the absence of typical clinical presentation, diagnosis may not be suspected clinico-radiologically; hence, fine-needle aspiration cytology may help in early and definitive diagnosis, hastening meticulous diagnostic workup and appropriate management of these patients. Intracytoplasmic crystalline inclusions (CI) have been reported in multiple myeloma and lymphoproliferative disorders. The present case highlights unusual clinico-cytological features of SBP with primary involvement of humerus, progression to tibia, and presence of extracellular and intracytoplasmic CI in plasma cells, a morphologic finding not reported in SBP earlier. PMID- 25538388 TI - Direct sampling of metastatic ovarian carcinoma masquerading as endocervical adenocarcinoma in liquid-based cytology cervical sample. AB - Cervical sample is routinely taken to identify squamous dysplastic lesions of the cervix. Glandular lesions are far less commonly reported on cervical samples. The most common glandular lesion reported on cervical smear is endocervical adenocarcinoma, followed by endometrial adenocarcinoma. Direct sampling by Cervex brush is possible even in endometrial adenocarcinoma, if the tumor directly involves lower uterine segment/endocervical canal. Metastases to cervix are rare but have occasionally been reported in previous reports. We wish to highlight in this case, metastatic ovarian carcinoma directly sampled in cervical liquid-based cytology (LBC) sample, which mimicked cytomorphologically a well-differentiated endocervical adenocarcinoma. To the best of our knowledge, a similar case has not been previously published in SurePath LBC sample. PMID- 25538389 TI - Lymphadenopathic form of solid variant of alveolar rhabdomyosarcoma: A rare case report. AB - Lymph node enlargement due to metastatic rhabdomyosarcoma, without an obvious primary tumor, is rare. We report a fine-needle aspiration diagnosed and histopathologically confirmed case of solid variant of alveolar rhabdomyosarcoma in a 13-year-old female. She presented with right cervical lymphadenopathy, followed by a diffuse swelling in right forearm 2 months later. PMID- 25538390 TI - Fine-needle aspiration cytology of chondroid syringoma of fore arm: Report of a rare case. AB - Chondroid syringoma is a rare benign adnexal tumor of sweat glands with microscopic resemblance to the salivary gland pleomorphic adenoma. Cytology is rarely utilized for preoperative assessment of these slow-growing, small, nodular lesions. Definitive cytological diagnosis is also quite difficult, and majority of the aspirates are evaluated as benign adnexal tumors leading to mandatory histopathological examination for pinpoint diagnosis. Here, we report a case of chondroid syringoma of forearm, which was diagnosed by cytology and also confirmed after histopathological examination. Pinpoint cytological diagnosis can help early formulation of necessary management protocol. PMID- 25538391 TI - Incidental diagnosis of filariasis in association with carcinoma of gall bladder: Report of a case evidenced on ultrasound-guided fine-needle aspiration cytology with review of the literature. AB - Lymphatic filariasis is endemic in India and South-East Asia. Detection of microfilaria is infrequently reported during cytological evaluation of various lesions or body cavity fluids. Microfilariae in cytological smears of few benign and malignant neoplasms have also been reported. Here we present a very rare case of presence of microfilariae in a smear from ultrasound guided fine-needle aspiration of gallbladder adenocarcinoma. The present patient is probably the second reported case in the literature harboring occult filariasis in association with gallbladder carcinoma. Though it is a chance finding, cytology can be an effective tool for detection of asymptomatic filariasis helping to pave the way of disease eradication. PMID- 25538392 TI - Penile neurilemmoma: Utility of fine-needle aspiration cytology in diagnosis of a rare entity. AB - Subcutaneous lesions in the penis are of rare occurrence and encompass benign as well as malignant tumors. These include lipomas, leiomyomas, neurilemmomas and their malignant counterparts. A surgical excision at this site carries the risk of postoperative penile curvature and erectile dysfunction. We report a rare case of penile neurilemmoma which presented as a subcutaneous nodule on the dorsal surface of the penis. A fine-needle aspiration was performed which aided in the preoperative diagnosis and guided the extent of excision. We report this case to highlight the importance of needle aspiration as a simple outdoor procedure for penile lesions which can aid surgical approach and postoperative outcome. PMID- 25538393 TI - Fine-needle aspiration cytology of recurrent Merkel cell carcinoma of eye-brow. PMID- 25538394 TI - Scrape cytology in localized oral mucosal leishmaniasis. PMID- 25538395 TI - Aspergillus involving submandibular salivary gland: An unusual presentation. PMID- 25538396 TI - Timing of surgery following chemoradiotherapy in rectal Cancer. PMID- 25538397 TI - Emerging role of circulating tumor cells in cancer management. PMID- 25538398 TI - Indian Council of Medical Research consensus document for the management of gastric cancer. AB - The document is based on consensus among the experts and best available evidence pertaining to Indian population and is meant for practice in India.Evaluation of a patient with newly diagnosed gastric cancer should include essential tests: A standard white light endoscopy with multiple biopsies from the tumor for confirmation of the diagnosis, a computed tomography (CT) scan (multi-detector or helical) of the abdomen and pelvis for staging with a CT chest or chest X-ray, and complete blood counts, renal and liver function tests. Endoscopic ultrasonography/ magnetic resonance imaging/positron emission tomography-CT is not recommended for all patients.For early stage disease (IA/B, N0), surgery alone is recommended. The need for adjuvant treatment would be guided by the histopathological analysis of the resected specimen.For locally advanced stage (IB, N(+) to IIIC), neoadjuvant chemotherapy may be considered to downstage the disease followed by surgery. This may be followed by adjuvant chemotherapy (as part of the peri-operative chemotherapy regimen)Patients with stage IV/metastatic disease must be assessed for chemotherapy versus best supportive care on an individual basis.Clinical examination including history and physical examination are recommended at each follow-up visit, with a yearly CT scan of the chest, abdomen, and pelvis.HER2 testing should be considered in patients with metastatic disease.5-FU may be replaced with capecitabine if patients do not have gastric outlet obstruction. Cisplatin may be replaced with oxaliplatin in the regimens. PMID- 25538400 TI - Lung cancer screening: Is there a future? AB - Lung cancer is the leading cause of cancer death worldwide with an average rate of 40-100/100,000 depending on the level of deprivation, and the rates are higher in smokers. The National Lung Screening Trial using three consecutive annual low dose computed tomography scans is the first and largest screening study to show clear evidence of a significant reduction in lung cancer mortality in selected high-risk subjects. The many on-going European screening studies will generate information on the groups of subjects that may or may not benefit from screening (demographics, pack-years smoked, length of smoking, number of years from quitting etc.) and the required frequency and duration of the intervention. Smoking cessation remains the most important tool for general improvement in health outcomes and in particular lung cancer prevention. Early intervention for investigations of symptoms that are considered mild or common could also change the outcome. Doctors and patients must become increasingly aware that these common symptoms are also potentially symptoms of lung cancer and are not 'normal' even in smokers. PMID- 25538399 TI - Indian Council of Medical Research consensus document for the management of gastrointestinal stromal tumors. AB - This consensus statement was produced along with the gastric cancer discussions as stomach is the most common site for gastrointestinal stromal tumor (GIST). The recommendations apply to treatment of GIST.Evaluation of a patient with newly diagnosed GIST should include essential tests: A standard white light endoscopy with 6-8 biopsies (c-KIT testing on immunohistochemistry) from the tumor for confirmation of the diagnosis, a computed tomography (CT) scan (multi-detector or helical) of the abdomen and pelvis for staging with a CT chest or chest X-ray, and complete blood counts, renal function tests and liver function tests. Endoscopic ultrasonography (EUS)/magnetic resonance imaging (MRI)/positron emission tomography (PET)-CT are not recommended for all patients.For localized and resectable disease, surgery is recommended. The need for adjuvant treatment with imatinib would be guided by the risk stratification on the histopathological analysis of the resected specimen.For localized but borderline resectable tumors, upfront surgery may be considered only if complications due to the tumor are present such as major bleeding or gastric outlet obstruction. In all other patients, neoadjuvant imatinib should be considered to downstage the disease followed by surgery (with a curative intent, if feasible) in those with stable or partial response. This may be followed by adjuvant imatinib. In those patients with a poor response, further imatinib with dose escalation or sunitinib may be considered.Patients with metastatic disease must be assessed for treatment with imatinib as first-line therapy followed by sunitinib as second-line therapy versus best supportive care on an individual basis. PMID- 25538401 TI - Anti-angiogenic therapies for advanced esophago-gastric cancer. AB - Neo-vascularization is a vital process for tumor growth and development which involves the interaction between tumor cells and stromal endothelial cells through several growth factors and membranous receptors which ultimately activate pro-angiogenic intracellular signaling pathways. Inhibition of angiogenesis has become a standard treatment option for several tumor types including colorectal cancer, glioblastoma and ovarian cancer. In gastric cancer, the therapeutic role of anti-angiogenic agents is more controversial. Bevacizumab and ramucirumab, two monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, have been demonstrated antitumor activity in patients with tumors of the stomach or esophagogastric junction. However, especially for bevacizumab, this antitumor activity has not consistently translated into a survival advantage over standard treatment in randomized trials. In this article, we provide an overview of the role of angiogenesis in gastric cancer and discuss the results of clinical trials that investigated safety and effectiveness of antiangiogenic therapies in this disease. A review of the literature has been done using PubMed, ClinicalTrials.gov website and the ASCO Annual Meeting Library. PMID- 25538402 TI - Down-staging following neoadjuvant chemo-radiotherapy for locally advanced rectal cancer: Does timing of surgery really matter? AB - BACKGROUND: Neoadjuvant chemoradiotherapy (NACTRT) improves local recurrence rate in locally advanced (LA) rectal cancer with no survival benefit. Pathological complete response (pCR) post-NACTRT is associated with improved outcome. Debate is ongoing as to when would be the opportune time to operate. AIM: To determine if greater down-staging can be achieved by a longer time interval from NACTRT to surgery (tumor regression score [TRS]) and whether this would impact sphincter saving surgery rates and early relapse rates. MATERIALS AND METHODS: A retrospective analysis of a prospectively maintained database of patients with LA rectal adenocarcinoma treated from January 2012 to August 2013 was carried out. One hundred and ten patients who completed NACTRT (50 Gy/25 fractions with capecitabine 825 mg/m(2) twice daily) followed by surgical resection were included. For response evaluation patients were divided into two groups, Group 1 (TRS <=60 days, n = 42) and 2 (TRS >60 days, n = 68). Tumor down-staging, pCR rate, tumor regression grade (TRG) post-NACTRT and relapse rates were correlated with TRS. RESULTS: Of 110 patients (median age: 49 years (21-73), 71% males; 18 (16.5%) with signet ring histology) 96% patients underwent an R0 resection. Post NACTRT, CR was attained in 5 (4.5%), partial response in 98 (89%) and stable disease in 7 (6.4%) patients. Median time from completion of NACTRT to surgery was 64.5 days (6-474). Median lymph nodes harvested were 10 (1-50). Overall, 22 (20%) patients achieved pCR. 26 (62%) patients in Group 1 compared to 36 (53%) in Group 2 underwent sphincter sparing surgery (SSS) (P = 0.357). Six patients (14%) in Group 1 and 16 (24%) in Group 2 achieved pCR (P = 0.24). Median TRG in both groups was three. CONCLUSION: Timing of surgery following NACTRT for LA rectal cancer does not influence pathological response, ability to perform SSS or disease-free survival. There is no incremental benefit of delaying the surgery though this needs to be confirmed in a prospective randomized trial. PMID- 25538403 TI - Morphometric evaluation and clinical correlations in pediatric malignant small round cell tumors. AB - AIMS: Nuclear size increases in malignant tumors and reflects DNA content, ploidy and proliferation index. Present study investigated if the nuclear morphometry could differentiate histomorphologically similar paediatric malignant small round cell tumors on hematoxylin and eosin stained sections for diagnostics in a resource poor setting. SETTINGS AND DESIGN: All the consecutive malignant pediatric tumors received in Pathology Department from other faculties of King George's Medical University and also those referred directly to Pathology Department from other hospitals of city/other cities during 3 years period were recorded. MATERIALS AND METHODS: Morphometric analysis was done in 22 confirmed (by higher ancillary techniques) but histomorphologically difficult to differentiate round cell tumors. All sections were analyzed by cell images from six different areas, using Leica Q win 500 images software. RESULTS: Nuclear measurements were obtained for retinoblastoma (RB) (nine cases), neuroblastoma (five cases), Wilms tumor (WT) (three cases), rhabdomyosarcoma (three cases), malignant hemangiopericytoma (one case) and non-Hodgkin lymphoma (one case). Among the RBs, maximum mean nuclear area percent (24.93) was seen in a case with nerve involvement and metastasis, followed by cases with only nerve involvement (21.60) and smallest area (16.57) was in non-nerve involving, nonmetastatic cases. All five cases of neuroblastoma had almost similar mean nuclear area percent (18.05-18.29). WT case with metastasis had higher nuclear area (21.25) than nonmetastatic (19.47). Amongst all the tumors, minimum value (14.93) was seen in malignant hemangiopericytoma. CONCLUSION: Morphometric evaluation in paediatric malignant round cell tumors have generated useful data, and needs further multicentric confirmation for implementation. PMID- 25538404 TI - Hairy cell leukemia: A decade long experience of North Indian Hematology Center. AB - INTRODUCTION: Hairy cell leukemia is a rare chronic B-cell disorder that follows an indolent but progressive course. This disorder is characterized by pancytopenia, splenomegaly, bone marrow fibrosis and the presence of atypical lymphoid cells with hairy projections in peripheral blood, bone marrow and spleen. Treatment is mainly with nucleoside analog cladribine, which induces complete remission in up to 85% cases. MATERIALS AND METHODS: This is a retrospective analysis of Hairy cell Leukemia cases diagnosed and treated in the Department of Hematology, All India Institute of Medical Sciences, New Delhi between 2002 and 2013. Various parameters such as clinical features, laboratory parameters including complete blood cell count, bone marrow findings, cytochemistry, immunophenotyping by flowcytometry or immunohistochemistry, treatment protocol and complications secondary to treatment and relapse were reviewed. RESULTS: A total of 35 cases were diagnosed during this period of 12 years of which 27 received cladribine and went in to remission. Median follow-up duration was 26 months. 5 (18%) cases had a relapse and all relapsed cases achieved second remission with cladribine; however, there was no case of second malignancy in our cohort. CONCLUSION: Cladribine has emerged as the treatment of choice for hairy cell leukemia given that the overwhelming majority of patients achieve long-lasting complete remissions. Upon relapse, these patients could be successfully salvaged with cladribine retreatment. PMID- 25538405 TI - Thiopurine methyltransferase polymorphisms in children with acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. 6-mercaptopurine (6-MP) and methotrexate are backbone drugs for maintenance phase of treatment. Purine Analogs 6-MP/6-thioguanine/azathiopurine are metabolized to its inactive form by the enzyme thiopurine methyltransferase (TPMT). Ninety percent of the population harbor wild type on both alleles (TPMT wild/wild), 10% are heterozygous, that is, one allele is mutant (TPMT wild/mutant) and 0.3% are homozygous, that is, both allele are mutant (TPMT mutant/mutant). In heterozygous and homozygous variant, activity of enzyme is low, leading to a higher incidence of toxicity (myelosuppression). AIM: The primary objective was to access the polymorphism of the enzyme, TPMT, in Children with ALL. Secondary objective was to correlate TPMT genotype with 6-MP toxicities. MATERIALS AND METHODS: Seventy-two children with newly diagnosed ALL during first maintenance phase were serially enrolled after obtaining consent. Five ml of peripheral blood was drawn and DNA extracted. TPMT 2 polymorphisms were performed using Allele specific polymerase chain reaction (PCR) and TPMT 3B and 3C are performed by PCR-restriction fragment length polymorphism. RESULTS: Sixty-nine children of 72 (95.8%) were wild for TPMT polymorphism and 3 (4.2%) were heterozygous for TPMT. Among the heterozygous variant one each (33.3%) were heterozygous for 2A, 3A, 3C. Febrile neutropenia was the most common toxicity in both wild and heterozygous group. CONCLUSION: The frequency of TPMT polymorphisms in children with ALL is 4.2%. Heterozygous variant is this study are one each (33%) of 2A, 3A, 3C. PMID- 25538406 TI - Immediate treatment effects of high-dose methotrexate and cranial irradiation on neuropsychological functions of children treated for acute lymphoblastic leukemia at a regional cancer center. AB - CONTEXT: Overall cure rates for pediatric acute lymphoblastic leukemia (ALL) have improved; however, the neuropsychological sequelae of ALL treatment have not been adequately documented in India. AIMS: The present study assesses the immediate effects of ALL treatment on neuropsychological functioning, at the Regional Cancer Center in Chennai, South India. MATERIALS AND METHODS: Newly diagnosed with ALL patients (n = 24) (aged 6-15 years; 13M:11F) registered between March 2008 and February 2009 were included. Patients who had received high-dose methotrexate (HD-MTX) and cranial radiotherapy (CRT) as part of their treatment were enrolled for the study. Neurocognitive assessments were done to assess various functions such as performance intelligence, visuo-perception, visuo spatial, perceptual organization, processing speed, planning, working memory, and immediate verbal memory (IVM) (Malin's intelligence scale); verbal fluency (ideation fluency test) and verbal attention (vigilance test). Three assessments were done during induction (baseline), after re-induction phase (second) and during the maintenance phase (third). RESULTS: The patients performed significantly worse in the third assessment (mean duration from diagnosis 17.48 months) on performance intelligence quotient (PIQ), visuo-perception, visuo spatial, processing speed, planning, IVM, verbal attention, and verbal fluency (P < 0.05), there were no significant changes observed in visuo-perceptual organization and working memory (P > 0.05). Significant difference was observed between age groups 6 and 10 (41.7%) and 11-15 years (58.3%) in perceptual organization, verbal fluency, and verbal attention (P < 0.05) and no gender difference was observed across the three assessments (P > 0.05). CONCLUSIONS: Combining HD MTX and CRT had an immediate effect on neuropsychological sequelae among the children with ALL, however, long-term evaluation is recommended to study the long-term effects. PMID- 25538407 TI - National cancer control and registration program in India. PMID- 25538408 TI - Critical care of elderly in India: Coming of age? PMID- 25538409 TI - Endotoxin hemadsorption in septic shock. PMID- 25538410 TI - Do we need a protocol for weaning patients from noninvasive ventilation? PMID- 25538411 TI - Griggs percutaneous tracheostomy without bronchoscopic guidance is a safe method: A case series of 300 patients in a tertiary care Intensive Care Unit. AB - INTRODUCTION: Percutaneous tracheostomy (PCT) is being increasingly done by intensivists for critical care unit patients requiring either prolonged ventilation and/or for airway protection.[1] Bronchoscopic guidance considered a gold standard,[23] is not always possible due to logistic reasons and ventilation issues. We share our experience of Griggs PCT technique without bronchoscopic guidance with simple modifications to ensure safe execution of the procedure. OBJECTIVE: The purpose of this study was to evaluate the safety issues and complications of PCT without bronchoscopic guidance in a multi-disciplinary tertiary Intensive Care Unit (ICU). MATERIALS AND METHODS: A retrospective review of consecutive PCTs performed in our ICU between August 2010 and December 2013 by Griggs guide wire dilating forceps technique without bronchoscopic guidance is being presented. It is done by withdrawing endotracheal tube with inflated cuff while monitoring expired tidal volume on ventilator and ensuring the free mobility of guide wire during each step of the procedure, thereby ensuring a safe placement of the tracheostomy tube (TT) in trachea. RESULTS: Analysis of 300 PCTs showed 26 patients (8.6%) had complications including 2 (0.6%) patients deteriorated neurologically and 2 (0.6%) deaths observed within 24 h following procedure. The median operating time was 3.5 min (range, 2.5-8 min). There were no TT placement problems in any case. CONCLUSION: Percutaneous tracheostomy can be safely performed without bronchoscopic guidance by adhering to simple steps as described. PMID- 25538412 TI - Alteco endotoxin hemoadsorption in Gram-negative septic shock patients. AB - BACKGROUND AND AIMS: Severe sepsis and septic shock are common causes of mortality and morbidity in an intensive care unit setting. Endotoxin, derived from the outer membranes of Gram-negative bacteria, is considered a major factor in the pathogenesis of sepsis. This study investigated the effect of Alteco endotoxin hemoadsorption device on Gram-negative septic shock patients. MATERIALS AND METHODS: An open, controlled, prospective, randomized, single-center trial was conducted between February 2010 and June 2012. Patients with septic shock due to intra-abdominal sepsis were randomized to either conventional therapy (n = 8) or conventional therapy plus two 2-hourly sessions of Alteco endotoxin hemoadsorption (n = 7). Primary endpoint was the Sequential Organ Failure Assessment (SOFA) score changes from 0 to 72 h. Secondary end points included vasopressor requirement, PaO2/FiO2 ratio (PFR), length of stay (LOS), and 28-day mortality. RESULTS: This study was terminated early as interim analysis showed a low probability of significant findings. No significant difference was noted between the two groups with respect to change in SOFA score, vasopressor score, PFR, LOS, and 28-day mortality. Side-effect was minimal. CONCLUSIONS: We could not identify any clinical benefit on the addition of Alteco endotoxin hemoadsorption to conventional therapy in patients who suffered from intra abdominal sepsis with shock. The side effect profile of this novel device was acceptable. PMID- 25538413 TI - Do Intensive Care Unit treatment modalities predict mortality in geriatric patients: An observational study from an Indian Intensive Care Unit. AB - BACKGROUND: Ageing being a global phenomenon, increasing number of elderly patients are admitted to Intensive Care Units (ICU). Hence, there is a need for continued research on outcomes of ICU treatment in the elderly. OBJECTIVES: Examine age-related difference in outcomes of geriatric ICU patients. Analyze ICU treatment modalities predicting mortality in patients >65 years of age. MATERIALS AND METHODS: A retrospective observational study was conducted in 2317 patients admitted in a multi-specialty ICU of a tertiary care hospital over 2-year study period from January 1, 2011 to December 31, 2012. A clinical database was collected which included age, sex, specialty under which admitted, APACHE-II and SOFA scores, patient outcome, average length of ICU stay, and the treatment modalities used in ICU including mechanical ventilation, inotropes, hemodialysis, and tracheostomy. Patients were divided into two groups: <65 years (Control group) and >65 years (Geriatric age group). RESULTS: The observed overall ICU mortality rate in the study population was 19.6%; no statistical difference was observed between the control and geriatric age group in overall mortality (P > 0.05). Mechanical ventilation (P = 0.003, odds ratio [OR] =0.573, 95% confidence interval [CI] =0.390-0.843) and use of inotropes (P = 0.018, OR = 0.661, 95% CI = 0.456-0.958) were found to be predictors of mortality in elderly population. On multivariate analysis, inotropic support was found to be an independent ICU treatment modality predicting mortality in the geriatric age group (beta coefficient = 1.221, P = 0.000). CONCLUSION: Intensive Care Unit mortality rates increased in the geriatric population requiring mechanical ventilation and inotropes during ICU stay. Only inotropic support could be identified as independent risk factor for mortality. PMID- 25538414 TI - Drug-induced anaphylactic reactions in Indian population: A systematic review. AB - BACKGROUND: Epidemiological data on drug-induced anaphylactic reactions are limited in India and are largely depending on studies from developed countries. AIM: The aim was to analyze the published studies of drug-induced anaphylaxis reported from India in relation with causative drugs and other clinical characteristics. MATERIALS AND METHODS: The electronic databases were searched for Indian publications from 1998 to 2013 describing anaphylactic reactions. The information was collected for demographics, set up in which anaphylaxis occurred, causative drugs, incubation period, clinical features, associated allergic conditions, past reactions, co-morbid conditions, skin testing, IgE assays, therapeutic intervention and mortality. Reactions were analyzed for severity, causality, and preventability. Data were extracted and summarized by absolute numbers, mean (95% confidence interval [CI]), percentages and odds ratio (OR) (95% CI). RESULTS: From 3839 retrieved references, 52 references describing 54 reactions were included. The mean age was 35.31 (95% CI: 30.52-40.10) years. Total female patients were 61.11%. Majority reactions were developed in perioperative conditions (53.70%), ward (20.37%) and home (11.11%). The major incriminated groups were antimicrobials (18.52%), nonsteroidal antiinflammatory drugs-(NSAIDs) (12.96%) and neuromuscular blockers (12.96%). Common causative drugs were diclofenac (11.11%), atracurium (7.41%) and beta-lactams (5.96%). Cardiovascular (98.15%) and respiratory (81.48%) symptoms dominated the presentation. Skin tests and IgE assays were performed in 37.03% and 18.52% cases, respectively. The fatal cases were associated with complications (OR =5.04; 95% CI: 1.41-17.92), cerebral hypoxic damage (OR =6.80; 95% CI: 2.14 21.58) and preventable reactions (OR =14.33; 95% CI: 2.33-87.97). CONCLUSION: Antimicrobials, NSAIDs, and neuromuscular blockers are common causative groups. The most fatal cases can be prevented by avoiding allergen drugs. PMID- 25538416 TI - Challenges in management of blast injuries in Intensive Care Unit: Case series and review. AB - Blast injuries are rare, but life-threatening medical emergencies. We report the clinical presentation and management of four bomb blast victims admitted in Intensive Care Unit of Trauma center of our hospital in 2011. Three of them had lung injury; hemothorax (2) and pneumothorax (1). Traumatic brain injury was present in only one. Long bone fractures were present in all the victims. Presence of multiple shrapnels was a universal finding. Two blast victims died (day 7 and day 9); cause of death was multi-organ failure and septic shock. Issues relating to complexity of injuries, complications, management, and outcome are discussed. PMID- 25538415 TI - The benefits of tight glycemic control in critical illness: Sweeter than assumed? AB - Hyperglycemia has long been observed amongst critically ill patients and associated with increased mortality and morbidity. Tight glycemic control (TGC) is the clinical practice of controlling blood glucose (BG) down to the "normal" 4.4-6.1 mmol/L range of a healthy adult, aiming to avoid any potential deleterious effects of hyperglycemia. The ground-breaking Leuven trials reported a mortality benefit of approximately 10% when using this technique, which led many to endorse its benefits. In stark contrast, the multi-center normoglycemia in intensive care evaluation-survival using glucose algorithm regulation (NICE SUGAR) trial, not only failed to replicate this outcome, but showed TGC appeared to be harmful. This review attempts to re-analyze the current literature and suggests that hope for a benefit from TGC should not be so hastily abandoned. Inconsistencies in study design make a like-for-like comparison of the Leuven and NICE-SUGAR trials challenging. Inadequate measures preventing hypoglycemic events are likely to have contributed to the increased mortality observed in the NICE SUGAR treatment group. New technologies, including predictive models, are being developed to improve the safety of TGC, primarily by minimizing hypoglycemia. Intensive Care Units which are unequipped in trained staff and monitoring capacity would be unwise to attempt TGC, especially considering its yet undefined benefit and the deleterious nature of hypoglycemia. International recommendations now advise clinicians to ensure critically ill patients maintain a BG of <10 mmol/L. Despite encouraging evidence, currently we can only speculate and remain optimistic that the benefit of TGC in clinical practice is sweeter than assumed. PMID- 25538417 TI - Potassium permanganate toxicity: A rare case with difficult airway management and hepatic damage. AB - Potassium permanganate (KMnO4) is rarely used for suicidal attempt. Its ingestion can lead to local as well as systemic toxicities due to coagulation necrosis and damage, caused by free radicals of permanganate. We recently managed a case of suicidal ingestion of KMnO4 in a lethal dose. She had significant narrowing of upper airway leading to difficult intubation as well as hepatic dysfunction and coagulopathy as systemic manifestation. We suggest to keep ourselves ready to handle difficult airway with the aid of fiber optic bronchoscope or surgical airway management in such patients. Upper gastrointestinal (GI) endoscopy should be done at the earliest to determine the extent of upper GI injury and further nutrition planning. PMID- 25538418 TI - Use of a novel hemoadsorption device for cytokine removal as adjuvant therapy in a patient with septic shock with multi-organ dysfunction: A case study. AB - CytoSorb((r)) (CytoSorbents Corporation, USA) is a novel sorbent hemoadsorption device for cytokine removal. The aim of this study was to examine the clinical use of CytoSorb((r)) in the management of patient with septic shock. We used this device as an adjuvant to stabilize a young patient with multi-organ failure and severe sepsis with septic shock. A 36-year-old female patient was hospitalized with the complaints of malaise, general body ache, and breathing difficulty and had a medical history of diabetes mellitus type II, hypertension, obstructive sleep apnea, hypothyroidism and morbid obesity. She was diagnosed to have septic shock with multi-organ dysfunction (MODS) and a low perfusion state. CytoSorb((r)) hemoadsorption column was used as an attempt at blood purification. Acute physiology and chronic health evaluation score, MODS score, and sequential organ failure assessment score were measured before and after the device application. CytoSorb application as an adjuvant therapy could be considered in septic shock. PMID- 25538420 TI - Prospective cohort versus retrospective cohort studies to estimate incidence. PMID- 25538419 TI - Acute airway obstruction due to spontaneous intrathyroid hemorrhage precipitated by anticoagulation therapy. AB - Acute airway compromise due to hemorrhage in of thyroid gland is a rare life hreating condition. The increasing use of anticoagulants for various reasons is likely increased the occurrence of this this complication. We describe an elderly patient on anticoagulation for atrial fibrillation, which developed swelling on the right side of neck causing acute airway obstruction requiring emergency intubation for airway protection. Computed tomographic scan showed massive intrathyroid hemorrhage along with substernal extension. She had supratherapeutic INR which was appropriately corrected emergently. She underwent resection of the thyroid gland which showed multinodular goiter without any evidence of malignancy. Our case illustrates the rare but lethal bleeding complication of anticoagulants in critical anatomical area and we request physicians should be wary of similar conditions. PMID- 25538421 TI - Evaluation of BACTECTM blood culture system for culture of normally sterile body fluids. PMID- 25538422 TI - N-acetylcystein in dengue hepatitis. PMID- 25538423 TI - Coiling of central venous catheter in right internal jugular vein. PMID- 25538424 TI - A case of guidewire embolism during central venous catheterization: Better safe than sorry! PMID- 25538425 TI - Correlation of end-tidal and arterial carbon-dioxide levels in critically Ill neonates and children. PMID- 25538426 TI - Successful management of acute kidney injury in severe acute pancreatitis with intra-abdominal hypertension using peritoneal dialysis. PMID- 25538427 TI - Age-related joint space narrowing independent of the development of osteoarthritis of the shoulder. AB - PURPOSE: It is commonly accepted that the glenohumeral joint space remains unchanged until the onset of osteoarthritis, at which point progressive degenerative changes, and joint space narrowing occur. The aim of this study was to evaluate the radiographic width of the glenohumeral joint space in patients of different ages: Those with otherwise normal radiographs, those with a history of instability, those with calcific tendonitis, and those with a radiologic diagnosis of osteoarthritis. MATERIALS AND METHODS: In this retrospective study, two independent investigators measured the glenohumeral joint width on true anteroposterior and axillary views of standardized shoulder radiographs taken from 2002 to 2009. The digital image resolution was 0.01 mm. Group I comprised 60 patients with normal shoulder radiographs, Group II comprised 53 patients with instability but normal radiographs, Group III comprised 109 patients with radiologically proven calcific tendonitis, and Group IV comprised 120 patients with manifest osteoarthritis. RESULTS: The interobserver reliability (r) was 0.621-0.862. The mean joint space width was significantly different among Groups I-IV (central anteroposterior: 4.28 +/- 0.75 mm, 3.12 +/- 0.73 mm, 2.87 +/- 0.80 mm, and 1.47 +/- 1.07 mm, respectively; P = 0.001; central axillary: 6.12 +/- 1.09 mm, 3.92 +/- 0.77 mm, 3.34 +/- 0.84 mm, and 1.08 +/- 1.12 mm, respectively; P = 0.001). There was a significant negative correlation between the joint space width and age at all measured levels in both projections (P < 0.001). CONCLUSIONS: The glenohumeral joint space width decreases with increasing age beginning in early adulthood, and this effect is enhanced by osteoarthritis. LEVEL OF EVIDENCE: Level II, retrospective study. PMID- 25538428 TI - Arthroscopic double row cuff repair with suture-bridging and autologous conditioned plasma injection: Functional and structural results. AB - PURPOSE: The double row cuff repair with suture bridging is commonly used for arthroscopic rotator cuff repair (RCR). Despite its biomechanical qualities, the rate of iterative tears with this technique is important. The aim of our study was to evaluate the effect of autologous conditioned plasma (ACP) on functional results and on the rate of iterative tears after RCR by suture bridging. MATERIALS AND METHODS: A consecutive series of 65 patients who underwent arthroscopic double-row suture bridge (Speed-Bridge, Arthrex) primary cuff repair of symptomatic full-thickness supraspinatus tear (retraction <3 in the Patte classification) were evaluated. Mean patient age was 60 (+/-8). The supraspinatus was repaired by knot-less bridging (SwiveLock, Arthrex) with suture tape material. 2 homogenous groups were created (A: 33 patients, B: 32 patients). In group A, all patients received, besides the cuff repair, an intra-tendinous ACP injection. Constant scores and Simple Shoulder Tests (SST) were measured pre operatively and after a minimum follow-up period of 12 months post-operatively. Structural integrity of the repairs was evaluated by MRI according to the Sugaya classification. Sugaya >4 were considered as iterative tears. RESULTS: Mean follow-up was 19 months (+/-42) in the 2 groups. The mean quantity of ACP injected was 6ml. (+/-1.5) and no specific complication of the injection was found. Mean preoperative Constant-Murley scores were 41,2 (+/-7,7) and 38 (+/ 11)in group B. Mean normalized Constant-Murley score increased from 41 points (+/ 7) pre-operatively to 70 points (+/-8) post-operatively in group A and from 38 points (+/-11) to 73 points (+/-11) in group B. There were no significative differences between the two groups (P > 0.05). In group A, 31 repairs were Sugaya 1-3 (94%), vs. 30 in group B (93%), and 1 was type 4 in group A (5%) vs. 2 in group B (8%). CONCLUSION: In both groups, RCR with suture bridging gave successful functional outcomes, with a low rate of iterative tear. In this preliminary study, the adjuvant effect of ACP injections could not be showed on both functional and structural results. Longer follow-up is needed to evaluate potential differences. PMID- 25538429 TI - Assessment of function in patients with rotator cuff tears: Functional test versus self-reported questionnaire. AB - PURPOSE: The rotator cuff tears (RCT) are a well-known cause of shoulder pain and loss of upper extremity function. The purpose of this study was to evaluate the upper extremity function using two different methods in patients with RCT and to determine the parameters that influence the upper extremity function. MATERIALS AND METHODS: A sample of 38 patients (27-76 years; 10 men and 28 women) who were diagnosed with a chronic full-thickness RCT, confirmed by magnetic resonance imaging (MRI), was studied. Upper extremity function was determined using Western Ontario Rotator Cuff Index (WORC) and 9 Hole Peg Test (9PEG). Other assessments included active range of motion (ROM), muscle strength, shoulder pain, and scapular dyskinesis. RESULTS: There was a weak association between WORC scores and 9PEG. A statistically significant, negative relationship was found between 9PEG and ROM in supination, as well as muscle strength of shoulder extensors, adductors, internal and external rotators. CONCLUSIONS: In addition to the weak association between WORC and 9PEG, the difference between the parameters related to each method suggests that they should not be used interchangeably to determine the upper extremity function. We recommend the utilization of 9PEG instead of WORC in assessing the upper extremity function in the setting of loss of muscle strength. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 25538430 TI - Intra-articular infiltration therapy for patients with glenohumeral osteoarthritis: A systematic review of the literature. AB - BACKGROUND: Conservative treatments are especially in patients with glenohumeral osteoarthritis (GH-OA) important, since shoulder arthroplasty has its limitations. In this systematic review, we will evaluate the current evidence regarding the efficacy of intra-articular (IA) infiltration treatment options in patients with GH-OA. MATERIALS AND METHODS: The following databases are searched: Pubmed/Medline, Cochrane Clinical Trial Register, Embase and the WHO clinical trial register. All IA injection products used for the treatment of shoulder OA in humans are included. RESULTS: A total of 8 studies could be included in this review. Hyaluronic acid (HA) showed effect sizes of 2.07, 2.02 and 2.11 at 6, 12 and 26 weeks follow-up, respectively. Placebo (1.60, 1.82 and 1.68) also showed stable effect sizes at the same time points. The efficacy of corticosteroids (CS) decreased rapidly at follow-up (1.08, 0.43 and 0.19). Although statistical significant, the maximum difference in effect sizes between HA and placebo was only 0.43 with absolute values between 2.0 and 6.4 on a 100-point visual analogue score for pain. CONCLUSION: IA treatment with HA has a good efficacy at follow-up compared to baseline. However, the difference in efficacy between HA and placebo never reaches the minimal clinically important difference at any of the follow-up points. We are not able to give clear recommendations for the use of IA CS injections in patients with GH-OA. In future research, we recommend focusing on sufficiently powered randomized trials to compare the efficacies of HA, CS, placebo and other IA treatment options in patients with GH-OA. PMID- 25538431 TI - Association between screw prominence and vascular complications after clavicle fixation. AB - CONTEXT: Fixation of clavicle fractures has become more common to prevent symptomatic malunion and nonunion. The subclavian and axillary vessels are in close proximity to the medial two-thirds of the clavicle, placing them at risk from prominent metalware. Injury to these major vessels has the potential to be life or limb-threatening. Despite this anatomical risk, iatrogenic vascular injury associated with clavicle fixation is rare. AIMS: The aim of this study was to identify risk factors associated with modern fixation techniques in reported cases of vascular injury after clavicle fixation. MATERIALS AND METHODS: A literature search was performed, and all identified cases of iatrogenic vascular injury associated with prominent clavicle fixation were analyzed. Clinical details, the total length of the prominent screws and the distance that they protruded from the far cortex were recorded. RESULTS: Five cases were identified; there were four pseudoaneurysms and one arteriovenous fistula. The total length of the offending screw was identifiable in two cases, measuring 26 and 30 mm. The length of screw prominence was identifiable in 3 cases (8, 10 and 10 mm). The pseudoaneurysms presented at 2-10 years following clavicle fixation. Three of these cases developed limb-threatening ischemia. CONCLUSIONS: Vascular complications associated with clavicle fixation are uncommon but potentially limb threatening. Several associated factors are identified. The authors provide a number of detailed recommendations aimed at preventing these complications. PMID- 25538433 TI - Risk assessment and prevention of complications in aesthetic surgery. PMID- 25538432 TI - Iliac crest allograft glenoid reconstruction for recurrent anterior shoulder instability in athletes: Surgical technique and results. AB - Performing a labral repair alone in patients with recurrent anterior instability and a large glenoid defect has led to poor outcomes. We present a technique involving the use of the iliac crest allograft inserted into the glenoid defect in athletes with recurrent anterior shoulder instability and large bony defects of the glenoid (>25% of glenoid diameter). All athletes with recurrent anterior shoulder instability and a large glenoid defect that underwent open anterior shoulder stabilization and glenoid reconstruction with the iliac crest allograft were followed over a 4-year period. Preoperatively, a detailed history and physical exam were obtained along with standard radiographs and magnetic resonance imaging of the affected shoulder. All patients also completed the Simple Shoulder Test (SST) and American Shoulder and Elbow Surgeons (ASES) evaluation forms preoperatively. A computed tomography scan was obtained postoperatively to assess osseous union of the graft and the patient again went through a physical exam in addition to completing the SST, ASES, and Western Ontario Shoulder Instability Index (WOSI) forms. 10 patients (9 males, 1 female) were followed for an average of 16 months (4-36 months) and had a mean age of 24.4 years. All patients exhibited a negative apprehension/relocation test and full shoulder strength at final follow-up. Eight of 10 patients had achieved osseous union at 6 months (80.0%). ASES scores improved from 64.3 to 97.8, and SST scores improved from 66.7 to 100. Average postoperative WOSI scores were 93.8%. The use of the iliac crest allograft provides a safe and clinically useful alternative compared to previously described procedures for recurrent shoulder instability in the face of glenoid deficiency. PMID- 25538434 TI - Basal cell carcinoma of the outer nose: overview on surgical techniques and analysis of 312 patients. AB - BACKGROUND: Basal cell carcinoma of the nose is common, with a potential of local recurrence and high-risk features. MATERIALS AND METHODS: We provide a review on anatomy of the nose, tumour surgery and defect closure on the nose. We analysed our own patients with nasal BCC of a 24 months period. RESULTS: We identified 321 patients with nasal BCC. There was a predominance of female patients of 1.2 to 1. The mean age was 74.8 years. Slow Mohs technique was employed for all tumours until 3D tumour-free margins were achieved. That resulted on average in 1.8 +/- 0.7 Mohs stages. The most common histologic types were solitary (n = 182), morpheic (79), and micronodular (20), Perineural infiltration was evident in 56 tumours. Primary closure after mobilisation of soft tissue was possible in 105 BCCs. Advancement flaps were used in 91 tumours, rotation flaps in 47, transposition flaps in 34 tumours, and combined procedures in 6 cases. In 36 patients full-thickness skin grafting was performed. In two patients healing by second intention was preferred. Partial flap loss was seen in four patients (1.4%). All of them had significant underlying pathologies. None of the tumours treated showed a relapse during the observation time. However, this is a limitation of the present study since follow-up was on average only 10 months. CONCLUSIONS: BCCs of the nose are common. Only 3D-controlled micrographic surgery (Mohs or slow Mohs) guarantee a high rate of complete tumour removal and a very low risk of recurrence. PMID- 25538435 TI - Adjuvant Narrow Band UVB Improves the Efficacy of Oral Azithromycin for the Treatment of Moderate to Severe Inflammatory Facial Acne Vulgaris. AB - BACKGROUND: Acne vulgaris (AV) is a common inflammatory disease of the pilosebaceous unit. A variety of treatment modalities are available for the treatment of AV. Among the available options, oral azithromycin is popularly prescribed for its proven anti-inflammatory effects. Narrow band UVB (NBUVB) also has a potent anti-inflammatory action. Concomitant use of both modalities may result in a synergistic therapeutic response; however, the combined efficacy has not yet been evaluated for the treatment of inflammatory AV. OBJECTIVE: The aim of this study was to compare the efficacy of oral azithromycin plus NBUVB (peak 311 nm) to oral azithromycin alone for the treatment of moderate to severe inflammatory AV. MATERIALS AND METHODS: A randomized, open-label, clinical trial was conducted over 4 weeks. Subjects were randomized into two groups. Group 1 received 500 mg of oral azithromycin three times per week. Group 2 received 500 mg of oral azithromycin plus NBUVB three and two times per week, respectively. Concomitant topical or oral AV treatments were not permitted during the treatment period. Response to treatment was measured by photographic records at the primary endpoint (2 weeks) and at the end of treatment. RESULTS: One hundred and four subjects were enrolled in the trial; 94 subjects completed the treatment period of the study. Group 2 demonstrated significant clinical improvement of the inflammatory papular lesions (88.55%) compared with group 1 (70.34%) at the end of treatment (P = 0.002). The clinical response of pustular (P = 0.562), nodular (P = 0.711) and cystic (P = 0.682) lesions did not significantly differ between the two treatment groups. Interestingly, response to treatment in group 2 had a significant anatomical predilection for the forehead (P = 0.023). There was no side-effect except erythema, which subsided within 1-2 days. CONCLUSION: NBUVB plus oral azithromycin is more effective than oral azithromycin alone for treating papular lesions of inflammatory AV. NBUVB is certainly a viable adjunct in acne therapy. PMID- 25538436 TI - A Retrospective Study of Marjolin's Ulcer Over an Eleven Year Period. AB - BACKGROUND: Marjolin's ulcer is a rare aggressive cutaneous malignancy occurring in previously occurred wounds. The most common aetiology is a burn wound involving extremities and squamous cell carcinoma is the most common variant. MATERIALS AND METHODS: A retrospective analyses of medical records of patients treated in a single unit with a diagnosis of Marjolin's ulcer was performed. RESULTS: During the study period, 14 patients were treated. Four patients had lymph node metastases and one had pulmonary metastases at the time of presentation. Seven patients underwent wide excision with reconstruction and seven underwent amputation or disarticulation because of advanced malignancy. During the follow up two patients developed local recurrence and one developed pulmonary metastases. Both the patients with pulmonary metastases had Marjolin's ulcer of trunk. CONCLUSION: Marjolin's ulcer occurs more commonly in the extremities. Distant metastases occur commonly in patients with ulcers on the of trunk. PMID- 25538437 TI - The rhombic bilobed flap, a simple, geometrically designed flap. AB - We describe a combination of the common rhomboid flap and bilobed flap and provide an example of its use. The rhombic bilobed flap is simple to use and is associated with fewer complications, such as pin-cushioning and standing cone deformities, while minimizing the risk of skin necrosis and tension on the flap. PMID- 25538438 TI - Anoscrotal median raphe sinus in a child. AB - Anoscrotal median raphe sinus is an extremely rare entity in children. We report a pediatric patient and describe the management of this condition. PMID- 25538439 TI - Gauze strip tourniquet for nail surgery. AB - All nail surgical procedures require the use of a tourniquet. The nail bed, being a very vascular structure, needs to be exsanguinated at the start and then a tourniquet needs to be tied at the base. A number of tourniquets have been described, including a Foley's catheter, a Penrose drain, a rubber strip or a rubber band. The present article explains the use of the easily available, improvised, gauze strip tourniquet. This does not require much special preparation, is easily autoclavable, perfect for single use and can achieve exsanguination as well as tightening as a single step. This technique does not require much learning and is easily reproducible in almost all surgical setups. PMID- 25538440 TI - Essential Requirements to Setting up an Aesthetic Practice. AB - Aesthetic dermatology is becoming a vital and popular branch of medicine. This article aims to guide dermatologists to set up a professional and ethical aesthetic practice. Dermatologists should have an integrated practice of clinical dermatology, dermatosurgery and cosmetic dermatology. Ethical practice is the gold standard for any medical field, especially with dermatologists, who should avoid doing unnecessary procedures. Proper patient counselling and addressing the patients' concerns is imperative. PMID- 25538441 TI - A rare case of synchronous saree cancer. AB - Skin cancers are rather uncommon malignancies comprising less than 1% of all the cancers in India. Saree cancer is a rare type of squamous cell carcinoma (SCC). Saree and dhoti are traditional male and female costumes respectively, which is unique to the Indian subcontinent. Constant wear of this clothing tightly around the waist results in changes in pigmentation and scaling of the skin, acanthosis, scar and ulceration and subsequent, gradual malignant changes. The process of repeated trauma over a long time and consequent interference with the healing process may rationalise the reason for malignant transformation. Few papers have been published on saree cancer, in main stream medical journals. We are presenting a rare case of saree cancer in a 68-year-old woman, with two distant bilateral ulceroproliferative growths in loin (Synchronous), along the waistline, which showed well-differentiated SCC on biopsy. Wide excision with rhomboid transposition flap was done bilaterally. PMID- 25538442 TI - Facial fat necrosis following autologous fat transfer and its management. AB - Autologous fat transfer (AFT) is an increasingly popular cosmetic procedure practiced by dermatologic surgeons worldwide. As this is an office based procedure performed under local or tumescent anaesthesia with fat transferred within the same individual and limited associated down time its is considered relatively safe and risk free in the cosmetic surgery arena. We describe a case of AFT related fat necrosis causing significant facial dysmorphia and psychosocial distress. We also discuss the benefits and risks of AFT highlighting common causes of fat graft failure. PMID- 25538443 TI - Mutaf triangular flap technique in the repair of infraorbital skin losses: report of 5 cases. PMID- 25538444 TI - Side-effects from follicular unit extraction in hair transplantation. PMID- 25538445 TI - Unusual location of glomus tumour on the right ring finger. PMID- 25538446 TI - Large skin tags on the thigh. PMID- 25538447 TI - Re: superficial large Basal cell carcinoma over the face, reconstructed by v-y plasty. PMID- 25538448 TI - Re: utility of gel nails. PMID- 25538449 TI - Creating recipient sites using custom cut razor blades in hair transplantation. PMID- 25538450 TI - State of the globe: time to revisit kikuchi fujimoto disease. PMID- 25538451 TI - Antimicrobial susceptibility patterns of leading bacterial pathogens isolated from laboratory confirmed blood stream infections in a multi-specialty sanatorium. AB - OBJECTIVE: Dealing with severe blood stream infections (BSI) is one of the intractable conditions in hospitals. The empirical treatment given remains pertinent in determining patient outcome, which becomes evidence based when substantiated by knowledge of susceptibility patterns of prevalent pathogenic organisms in the set up. This study was undertaken to determine the occurrence, species prevalence, and antibiotic susceptibility pattern of laboratory confirmed BSI (LCBSI) in patients admitted to our multi-specialty sanatorium. MATERIALS AND METHODS: Eight hundred and forty-six blood samples from 829 patients suspected of having BSI were cultured as per standard microbiological procedures. Antimicrobial susceptibility testing was done for bacterial isolates from positive blood cultures. RESULTS: Sixty (7.2%) cases were established as LCBSI. A total of eight pathogenic bacterial genera were identified and their antimicrobial susceptibility pattern was noted. Staphylococcus spp. were most prevalent (33%), followed by Klebsiella pneumoniae (20%), Escherichia coli (13%), Acinetobacter spp. (13%), Enterococcus spp. (12%), Pseudomonas aeruginosa (3%), Proteus spp. (2%), and Citrobacter spp. (2%). CONCLUSIONS: The study shows the prevalence of common bacterial pathogens causing BSI and their susceptibility patterns. Such studies provide benefit of instantaneous choice of antibiotic therapy aiming at improved patient management and reduced drug resistance. PMID- 25538452 TI - Kikuchi-fujimoto disease: clinical and laboratory characteristics and outcome. AB - INTRODUCTION: Kikuchi-Fujimoto disease is an uncommon disorder with worldwide distribution, characterized by fever and benign enlargement of the lymph nodes, primarily affecting young adults. Awareness about this disorder may help prevent misdiagnosis and inappropriate investigations and treatment. The objective of the study was to evaluate the clinical and laboratory characteristics of histopathologically confirmed cases of Kikuchi's disease from a tertiary care center in southern India. MATERIALS AND METHODS: Retrospective analysis of all adult patients with histopathologically confirmed Kikuchi's disease from January 2007 to December 2011 in a 2700-bed teaching hospital in South India was done. The clinical and laboratory characteristics and outcome were analyzed. RESULTS: There were 22 histopathologically confirmed cases of Kikuchi's disease over the 5 year period of this study. The mean age of the subjects' was 29.7 years (SD 8.11) and majority were women (Male: female- 1:3.4). Apart from enlarged cervical lymph nodes, prolonged fever was the most common presenting complaint (77.3%). The major laboratory features included anemia (54.5%), increased erythrocyte sedimentation rate (31.8%), elevated alanine aminotransferase (27.2%) and elevated lactate dehydrogenase (LDH) (31.8%). CONCLUSION: Even though rare, Kikuchi's disease should be considered in the differential diagnosis of young individuals, especially women, presenting with lymphadenopathy and prolonged fever. Establishing the diagnosis histopathologically is essential to avoid inappropriate investigations and therapy. PMID- 25538453 TI - Resazurin tube method: rapid, simple, and inexpensive method for detection of drug resistance in the clinical isolates of mycobacterium tuberculosis. AB - BACKGROUND: Tuberculosis (TB) remains a serious public health problem worldwide. The emergence of drug resistance and multidrug resistance (MDR) has become the main threat to TB treatment and control programs. Rapid detection is critical for the effective treatment of patients. In recent times, a new method using the colorimetric indicator resazurin has been proposed for drug susceptibility of Mycobacterium tuberculosis. MATERIALS AND METHODS: In this study, the resazurin reduction assay was adapted to screw cap tubes. Using the Resazurin Tube Method (RTM), a total of 100 clinical isolates were tested against Rifampicin (RIF) and Isoniazide (INH). By visual reading, the minimum inhibitory concentrations (MICs) were obtained after eight days. The results obtained were compared with the gold standard proportion method. RESULTS: Excellent results were obtained for RTM with a sensitivity of 100% for both RIF and INH, with a specificity of 98.7 and 95.3%, respectively. Kappa is the measure of agreement between the RTM and proportion method (PM) for RIF and INH, which was found to be 0.972 and 0.935 for RIF and INH, respectively. CONCLUSION: The RTM appears to be a reliable method for the rapid and simultaneous detection of MDR-TB and drug susceptibility testing (DST) of M. tuberculosis. It is simple, inexpensive, and with no biohazard risk involved. PMID- 25538454 TI - Virulence markers of vancomycin resistant enterococci isolated from infected and colonized patients. AB - BACKGROUND: The aim of study was to find out the potential pathogenic role of virulence factors elaborated by strains of vancomycin resistant enterococci (VRE) isolated from clinical samples and VRE colonizing the gastrointestinal tract of hospitalized patients. MATERIALS AND METHODS: Enterococci were isolated from various clinical samples and also from fecal specimens of colonized patients at the time of admission, after 48 h and after 5 days of admission. Various virulence determinants were detected by phenotypic tests. Vancomycin susceptibility in enterococci was detected by disc diffusion and agar screen method. Minimum inhibitory concentration was determined by agar dilution method. RESULTS: Out of all the clinical and fecal samples processed, 12.0% isolates were either vancomycin resistant or vancomycin intermediate. Hemagglutinating activity against rabbit red blood cells was seen with 27.8% and 25.0% of clinical and fecal strains, respectively. Slime layer formation was seen with fecal VRE strains (37.5%) when compared to clinical VRE (27.8%). Among the clinical VRE strains the most prolific biofilm producers were Enterococcus. fecalis (92.9%) when compared to Enterococcus. faecium (52.9%). Biofilm formation/(presence of adhesions) was also seen in (29.2%) of the fecal VREs. In wound infection production of gelatinase, deoxyribonuclease (DNase), and caseinase (70.0% each) were the major virulence factors. The predominant virulence factors seen in the blood stream infection were adhesin, and hemolysin (44.4% each) and in catheter induced infection were DNase and adhesins (75.0% each). Adhesin (29.2%), slime layer (37.6%), DNAse (33.3%), gelatinase (25.0%), lipase (20.8%) and caseinase (16.6%) and hemolysin (8.3%) were produced the fecal isolates. CONCLUSION: An association between adhesin (as detected by biofilm formation) and urinary tract infection, adhesion and hemolysin with BSI, as also between DNase gelatinase & caseinase with wound infection was noted. PMID- 25538456 TI - Toxoplasmosis of spinal cord in acquired immunodeficiency syndrome patient presenting as paraparesis: a rare entity. AB - Although brain has been the most common site for toxoplasma infection in acquired immunodeficiency syndrome patients, involvement of spinal cord by toxoplasma has been rarely found. Spinal cord toxoplasmosis can present as acute onset weakness in both lower limbs associated with sensory and bladder dysfunction. A presumptive diagnosis can be made in patients with CD4 count <100/mm(3) based on a positive serum Toxoplasma gondii IgG antibodies, no recent prophylaxis against toxoplasmosis, intramedullary ring enhancing lesion in spinal cord supported by similar lesions in brain parenchyma. Institutions of antitoxoplasma treatment in such patients result in prompt clinical response and therefore avoiding the need of unnecessary invasive diagnostic tests. Here, we report a case of toxoplasmic myelitis in immunocompromised patient presenting as myelopathy who showed significant clinical improvement after starting antitoxoplasma treatment. Hence toxoplasmic myelitis should be considered in toxoplasma seropositive immunocompromised patients presenting as myelopathy and imaging studies showing ring enhancing intramedullary lesion. PMID- 25538457 TI - Antimicrobial Resistance in Pseudomonas sp. Causing Infections in Trauma Patients: A 6 Year Experience from a South Asian Country. AB - Drug resistance to Pseudomonas sp. has spread to such a level irrespective of the type of patients, that its pattern of distribution and antibiotic resistance needs to be studied in detail, especially in trauma patients and hence the study. A 6 year study was carried out among trauma patients to see the trend and type of resistance prevalent in the apex hospital for trauma care in India among nonduplicate isolates where multidrug-resistance (MDR), cross-resistance and pan drug resistance in Pseudomonas sp. were analyzed. Of the total 2,269 isolates obtained, the species, which was maximally isolated was Pseudomonas aeruginosa (2,224, 98%). The highest level of resistance was seen in tetracycline (2,166, 95.5%, P < 0.001) and chloramphenicol (2,160, 95.2%, P < 0.001) and least in meropenem (1,739, 76.7%, P < 0.003). Of the total, 1,692 (74.6%) isolates were MDR in which P. aeruginosa (75%) were maximum. MDR Pseudomonas is slowing increasing since the beginning of the study period. Of 1,797 imipenem-resistant P. aeruginosa isolated during the study period, 1,763 (98%) showed resistance to ciprofloxacin or levofloxacin, suggesting that cross-resistance may have developed for imipenem due to prior use of fluoroquinolones. Antibiotic resistance in Pseudomonas sp. is fast becoming a problem in trauma patients, especially in those who requires prolong hospital stay, which calls for proper antimicrobial stewardship. PMID- 25538455 TI - The emergence of ebola as a global health security threat: from 'lessons learned' to coordinated multilateral containment efforts. AB - First reported in remote villages of Africa in the 1970s, the Ebolavirus was originally believed to be transmitted to people from wild animals. Ebolavirus (EBOV) causes a severe, frequently fatal hemorrhagic syndrome in humans. Each outbreak of the Ebolavirus over the last three decades has perpetuated fear and economic turmoil among the local and regional populations in Africa. Until now it has been considered a tragic malady confined largely to the isolated regions of the African continent, but it is no longer so. The frequency of outbreaks has increased since the 1970s. The 2014 Ebola outbreak in Western Africa has been the most severe in history and was declared a public health emergency by the World Health Organization. Given the widespread use of modern transportation and global travel, the EBOV is now a risk to the entire Global Village, with intercontinental transmission only an airplane flight away. Clinically, symptoms typically appear after an incubation period of approximately 11 days. A flu-like syndrome can progress to full hemorrhagic fever with multiorgan failure, and frequently, death. Diagnosis is confirmed by detection of viral antigens or Ribonucleic acid (RNA) in the blood or other body fluids. Although historically the mortality of this infection exceeded 80%, modern medicine and public health measures have been able to lower this figure and reduce the impact of EBOV on individuals and communities. The treatment involves early, aggressive supportive care with rehydration. Core interventions, including contact tracing, preventive initiatives, active surveillance, effective isolation and quarantine procedures, and timely response to patients, are essential for a successful outbreak control. These measures, combined with public health education, point-of-care diagnostics, promising new vaccine and pharmaceutical efforts, and coordinated efforts of the international community, give new hope to the Global effort to eliminate Ebola as a public health threat. Here we present a review of EBOV infection in an effort to further educate medical and political communities on what the Ebolavirus disease entails, and what efforts are recommended to treat, isolate, and eventually eliminate it. PMID- 25538458 TI - Changing bacteriological profile and mortality trends in community acquired pneumonia. AB - There are very few and conflicting Indian data regarding the bacteriological etiology of community acquired pneumonia (CAP). Adding to this agony, there is no credible data from the eastern part of India. This is a cross-sectional study and descriptive in nature over a period of 1-year. Of the 464 cases of the study population, we could isolate aerobic bacteria in 149 patients (32.1%). Streptococcus pneumoniae has been identified as the most common organism causing CAP (68/149). Gram-negative bacilli (GNB) as a group exceeded marginally over S. pneumoniae (69/149). Among GNB, Pseudomonas aeruginosa was the most common organism (31/69), followed by Klebsiella pneumoniae (29/69). Staphylococcus aureus was identified in (12/149) cases. Co-amoxyclav is still the most sensitive drug for S. pneumoniae. P. aeruginosa was most sensitive to imipenam followed by piperacillin-tazobactam. PMID- 25538459 TI - Soft Tissue and Wound Infections Due to Enterococcus spp. Among Hospitalized Trauma Patients in a Developing Country. AB - Soft tissue and wound infections due to Enterococcus spp. are increasing worldwide with current need to understand the epidemiology of the Enterococcal infections of wounds. Hence, we have looked into the distribution of Enterococcus spp. responsible for causing wound and soft tissue infections among trauma patients, its antibiotic resistance pattern and how it affects the length of hospital stay and mortality. A laboratory cum clinical-based study was performed over a period of 3 years at a level I trauma center in New Delhi, India. Patients with Enterococcal wound and soft tissue infections were identified using the hospital data base, their incidence of soft tissue/wound infections calculated, drug resistance pattern and their possible risk factors as well as outcomes analyzed. A total of 86 non-repetitive Enterococcus spp. was isolated of which E. faecium were maximally isolated 48 (56%). High level of resistance was seen to gentamicin HLAR in all the species of Enterococcus causing infections whereas a low level resistance to vancomycin and teicoplanin was observed among the isolates. Longer hospital stay, repeated surgical procedure, prior antibiotic therapy and ICU stay were observed to associate with increased morbidity (P < 0.05) and hence, more chances of infections with VRE among the trauma patients. The overall rate of wound and soft tissue infections with Enterococcus sp. was 8.6 per 1,000 admissions during the study period. Enterococcal wound infection is much prevalent in trauma care facilities especially in the ICUs. Here, a microbiologist can act as a sentinel, help in empirical therapeutic decisions and also in preventing such infections. PMID- 25538460 TI - Fecal Carriage of Escherichia coli from Pediatric Patients with Diarrhea and Asymptomatic Healthy Individuals. PMID- 25538461 TI - Anti-nuclear antibody expression in severe scrub typhus infection: preliminary observations. PMID- 25538462 TI - The HIV Associated Type 2 Diabetes. PMID- 25538463 TI - Fever and cervical lymphadenopathy in a young female; thinking beyond tuberculosis. PMID- 25538464 TI - Quality of prescribing for hypertension and bronchial asthma at a tertiary health care facility, India using Prescription Quality Index tool. AB - OBJECTIVE: Several tools have been introduced to evaluate the quality of prescribing. The aim of this study was to determine the quality of prescribing in hypertension and bronchial asthma in tertiary health care (THC) setting using the new Prescription Quality Index (PQI) tool and to assess the reliability of this tool. METHODS: A prospective cross-sectional study was carried out for 2 months in order to assess the quality of prescribing of antihypertensive and antiasthmatic drugs using recently described PQI at THC facility. Patients with hypertension and bronchial asthma, attending out-patient departments of internal medicine and pulmonary medicine respectively for at least 3 months were included. Complete medical history and prescriptions received were noted. Total and criteria wise PQI scores were derived for each prescription. Prescriptions were categorized as poor, medium and high quality based on total PQI scores. RESULTS: A total of 222 patients were included. Mean age was 56 +/- 15.1 years (range 4-87 years) with 67 (30.2%) patients above 65 years of age. Mean total PQI score was 32.1 +/- 5.1. Of 222 prescriptions, 103 (46.4%) prescriptions were of high quality with PQI score >=34. Quality of prescribing did not differ between hypertension and bronchial asthma (P > 0.05). The value of Cronbach's alpha for the entire 22 criteria of PQI was 0.71. CONCLUSION: As evaluated by PQI tool, the quality of prescribing for hypertension and bronchial asthma is good in about 47% of prescriptions at THC facility. PQI is valid for measuring prescribing quality in these chronic diseases in Indian setting. PMID- 25538465 TI - Development and validation of reversed-phase high-performance liquid chromatography method for estimation of rizatriptan benzoate in oral strip formulations. AB - AIM: A simple, accurate, precise, and reproducible reversed-phase high performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of rizatriptan benzoate in oral strip formulations. METHODOLOGY: Separation was achieved under optimized chromatographic condition on a Hiper C18 column (250 mm * 4.6 mm, 5 m) using Shimadzu HPLC. The mobile phase consisted of phosphate buffer (20 mM pH adjusted to 3.2 +/- 0.005 with ortho phosphoric acid): Methanol in the ratio of 70:30 v/v with isocratic elution at a flow rate of 1 ml/min at ambient temperature was performed. The detection was carried out at 225 nm using photodiode array detector. The method was validated as per Q1A (R2) guidelines and suitability of developed method was ascertained by using optimized oral strip formulation. RESULTS: The retention time of rizatriptan benzoate was found to be 5.17 min, and the calibration curve was linear in the concentration range of 0.20-20 mg/mL (r (2)= 0.9998). The limit of detection and the limit of quantitation were found to be 0.016 mg/mL and 0.0528 mg/mL, respectively. Method validation parameters were found to be within the specified limits. The percentage drug content of oral strips formulation was found to be 98.96 +/- 1.37. CONCLUSION: The proposed HPLC method may be used efficiently for routine and quality control analysis of rizatriptan benzoate in pharmaceutical formulations. PMID- 25538466 TI - Evaluating sanitization of toothbrushes using ultra violet rays and 0.2% chlorhexidine solution: A comparative clinical study. AB - BACKGROUND: Toothbrushes may play a significant role in plaque control. Toothbrushes should be correctly stored, disinfected and changed at regular intervals. OBJECTIVE: The purpose of this study was to evaluate the efficacy of 0.2% chlorhexidine (CHX) gluconate solution and ultra violet (UV) toothbrush sanitizer for toothbrush disinfection. MATERIALS AND METHODS: Fresh tooth brushes were distributed to fifteen study subjects, who were selected randomly and who met the study criteria. All the study participants were asked to brush their teeth with the tooth brush provided. No special instructions were given regarding the brushing techniques. Toothbrushes were collected after 7 days. All tooth brushes were randomly allocated to three groups. Tooth brushes were subjected to microbial analysis and total bacterial count was assessed. Tooth brushes allocated to Group I were soaked in 2% CHX mouthwash for 12 h, Group II were kept in UV-light toothbrush holder for 7 min, and Group III were soaked in normal saline for 12 h. All the toothbrushes were subjected for microbial analysis and mean bacterial count was determined. RESULTS: There was a statistically significant difference between mean colony-forming unit count pre-sanitization and post-sanitization in all the groups, using 0.2% CHX gluconate, UV rays and normal saline (P < 0.007). However, the mean bacterial count reduced drastically after the treatment with UV rays (P = 0.001). CONCLUSIONS: CHX, UV rays and normal saline are effective in a reduction of bacterial count on toothbrushes. UV rays treatment was more effective, when compared to CHX and normal saline. PMID- 25538467 TI - Knowledge about the availability of the pharmacist in the Nuclear Medicine Department: A questionnaire-based study among health-care professionals. AB - OBJECTIVE: The objective of this study was to analyze the knowledge about the availability of the pharmacist in the nuclear medicine department among health care professionals through a prospective cohort study. METHODS: A total of 741 health-care professionals participated in the study by answering 10 simple questions about the role of the pharmacist in the nuclear medicine department and the availability of pharmacist in the nuclear medicine department. An online questionnaire system was used to conduct the study, and participants were invited to participate through personal communications and by promoting the study through social websites including Facebook, LinkedIn and Google (including Gmail and Google+). The study was conducted between April 2013 and March 2014 using the http://www.freeonlinesurveys.com/Webserver. Finally, the data provided by 621 participants was analyzed. Group frequency analysis was performed using Statistical Package for the Social Sciences (SPSS) version 16 (SPSS Inc. USA). RESULTS: The participants were from Malaysia, India, Pakistan, Sri Lanka, Bangladesh, UAE and Nepal. In total, 312 (50.2%) female health-care professionals and 309 (49.8%) male health-care professionals participated in the study. Of the 621 participants, 390 were working in hospitals, and 231 were not working in hospitals. Of the participants who were working in hospitals, 57.6% were pharmacists. The proportion of study participants who were aware of nuclear pharmacists was 55.39%. Awareness about the role of the pharmacist in nuclear medicine was poor. CONCLUSION: The role of the pharmacist in a nuclear medicine unit needs to be highlighted and promoted among health-care professionals and hence that the nuclear medicine team can provide better pharmaceutical care. PMID- 25538468 TI - Comparative evaluation of subgingivally delivered chlorhexidine varnish and chlorhexidine gel in reducing microbial count after mechanical periodontal therapy. AB - CONTEXT: Antimicrobial efficacy of subgingival chlorhexidine (CHX) application using two different vehicles of delivery. AIMS: The aim was to evaluate the efficacy of CHX varnish and gel as an adjunct to scaling and root planing (SRP) in reducing microbial count within moderate to deep periodontal pockets. SETTINGS AND DESIGN: Experimental parallel mouth study. SUBJECTS AND METHODS: A total of 30 subjects between the age groups 25 and 55 years having moderate to severe periodontitis, with pocket depth >= 5 mm were selected for the study. The selected patients were randomized into three groups of 10 each. Subjects in Group 1 received SRP followed by subgingival application of CHX varnish, subjects in Group 2 received SRP followed by subgingival application of CHX gel, subjects in Group 3 received SRP alone. Subgingival plaque samples were collected to estimate mean motile and nonmotile microbial counts using dark field microscopy at baseline, 1 week, 1 month, and 3 months. RESULTS: After 3 months, there was statistically significant reduction in nonmotile microbial count in all the three groups. Motile microbial count was significantly reduced in all the three groups till 1 month from baseline. Only subjects in Group 1 who received subgingival CHXvarnish after SRP showed a significant reduction in motile microbial count till 3 months from baseline. CONCLUSIONS: Subgingival application of highly concentrated CHX varnish following SRP is beneficial in reducing microbial count in moderate to deep periodontal pockets. PMID- 25538469 TI - Healing of burn wounds by topical treatment: A randomized controlled comparison between silver sulfadiazine and nano-crystalline silver. AB - BACKGROUND: Silver sulfadiazine (SSD) has been the standard topical antimicrobial for burn wounds for decades. Recently, nanometer-sized silver particles are available which have high surface to volume ratio and remain effective even at a very low concentration and minimizes the chance for tissue toxicity due to silver. Hence, we conducted a randomized controlled trial to compare the effectiveness of topical SSD and nano-crystalline silver (AgNP) hydrogel in burn wounds management. MATERIALS AND METHODS: Study was conducted in the Burn Unit of IPGME&R & SSKM Hospital Calcutta, from January 2011 to August 2012. Patients with 2 degrees burn injury were randomly allocated to SSD and AgNP treatment group. Clinical assessments of burn wound were done on every week till 4(th) week and on completion of treatment. RESULTS: Data for evaluation were obtained for 54 patients on SSD (2 degrees deep-dermal cases 27) and 52 (2 degrees deep-dermal cases 31) on AgNP treatment. Healing status of 2 degrees deep-dermal burns was more satisfactory for AgNP group than SSD treatment at 4 weeks. Among patients receiving AgNP, 80.6% showed at least 50% healing of 2 degrees deep-dermal wounds compared to 48.1% on SSD at 4 weeks (P = 0.001). The figures for complete healing at 4 weeks were, respectively, 4% and 0% (P = 0.116). CONCLUSIONS: AgNP can be an effective and superior alternative to SSD for burn wounds, particularly 2 degrees deep-dermal burns. Healing can be expected, in general, in 6 to 8 weeks time, depending upon the extent of body surface involvement. PMID- 25538470 TI - In vitro antibacterial activity of Camellia sinensis extract against cariogenic microorganisms. AB - CONTEXT: Dental caries, a ubiquitous multifactorial infectious disease, is primarily caused by microorganisms like Streptococcus mutans and Lactobacillus acidophilus. Use of antimicrobials is an important strategy to curb cariogenic microorganisms. AIM: The aim was to evaluate the in vitro antimicrobial activity of C. sinensis extract on S. mutans and L. acidophilus. STUDY SETTING AND DESIGN: Experimental design, in vitro study, lab setting. MATERIALS AND METHODS: Aqueous, acetone and ethanolic extracts of C. sinensis were subjected to antioxidant analysis. The ethanolic extract was used for assessment of antimicrobial properties. Ethanolic green tea extract at ten different concentrations and 0.2% chlorhexidine was used. Microbiological investigations were carried out to determine the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and zone of Inhibition of the test and control agents against S. mutans and L. acidophilus. STATISTICAL ANALYSIS: Kruskall-Wallis and Mann Whitney U-test. RESULTS: MIC of green tea extract on S. mutans and L. acidophilus was found to be 0.2% and 0.3% respectively, MBC was found to be 0.8% and 0.9%, respectively. The mean zone of inhibition for 30 MUl containing 300 MUg of ethanolic extract of green tea and control against S. mutans were 18.33 mm and 14.67 mm, respectively. The mean zone of inhibition for 30 MUl containing 300 MUg of ethanolic extract of green tea and control against L. acidophilus were 12.67 mm and 7.33 mm, respectively. CONCLUSION: Green tea has antibacterial activity against predominant cariogenic bacteria namely S. mutans and L. acidophilus. PMID- 25538471 TI - A new venture with sclerotherapy in an oral vascular lesion. AB - Vascular malformations are one of the most common lesions of the oral cavity. The lesion may be a congenital malformation observed in neonates or arteriovenous malformation observed in adults. Various surgical and medical managements are possible for vascular lesions which include surgical excision, laser therapy, cryotherapy, selective embolization, intralesional sclerosing agents, beta blockers and steroid therapy. Here we report a case of oral vascular lesion where intralesional injection with 30 mg/ml of sodium tetradecyl sulfate (STS) was given, which resulted in local complications with severe inflammatory response including pain, swelling, and surface ulceration that remained for 2 weeks. Sclerotherapy with STS still remain an effective agent in treating benign oral vascular lesions and provides alternative or support for surgical methods. Sometimes it can lead to undesirable complications like allergic reactions, local inflammatory response, etc. PMID- 25538472 TI - Prescribing pattern of interns: Time for new interventions. PMID- 25538473 TI - Functional capacity and its associated factors in the elderly with low back pain. AB - OBJECTIVE: To assess the level of functional capacity in subjects aged 60 years and older, who have lower back pain, and its association with demographic, socioeconomic, work-related, lifestyle-related and disease mentioned variables. METHODS: A cross-sectional study was conducted with 246 elderly registered at the Family Health Strategy of Vila Sao Paulo, Bauru,SP, Brazil, who reported lower back pain and were sampled by a two-stage cluster technique. The subjects were interviewed at home by using a multidimensional instrument (demographic; socioeconomic aspects; life style; work characterization; disease mentioned), and also the IPAQ, the Nordic and the Roland Morris questionnaires. A bivariate and multivariate descriptive logistic regression analysis was carried out. RESULTS: The prevalence of lower back pain in men was of 25.1% and in women it was of 35.1%. The mean score in the functional capacity assessment was 10.46 +/- 5.62. A fraction of 67.5% of the elderly demonstrated an inappropriate functional capacity. The age group from 70 to 80 years old, the subjects reporting three or more diseases and the sedentary group presented an independent association with inappropriate functional capacity. CONCLUSION: The older, sedentary subjects and who reported more than three diseases presented low functional capacity. Level of Evidence III, Cross Sectioning. PMID- 25538474 TI - Fracture of distal humerus: MIPO technique with visualization of the radial nerve. AB - OBJECTIVES: To evaluate the outcomes in patients treated for humerus distal third fractures with MIPO technique and visualization of the radial nerve by an accessory approach, in those without radial palsy before surgery. METHODS: The patients were treated with MIPO technique. The visualization and isolation of the radial nerve was done by an approach between the brachialis and the brachiorradialis, with an oblique incision, in the lateral side of the arm. MEPS was used to evaluate the elbow function. RESULTS: Seven patients were evaluated with a mean age of 29.8 years old. The average follow up was 29.85 months. The radial neuropraxis after surgery occurred in three patients. The sensorial recovery occurred after 3.16 months on average and also of the motor function, after 5.33 months on average, in all patients. We achieved fracture consolidation in all patients (M=4.22 months). The averages for flexion-extension and prono supination were 112.85 degrees and 145 degrees , respectively. The MEPS average score was 86.42. There was no case of infection. CONCLUSION: This approach allowed excluding a radial nerve interposition on site of the fracture and/or under the plate, showing a high level of consolidation of the fracture and a good evolution of the range of movement of the elbow. Level of Evidence IV, Case Series. PMID- 25538475 TI - Trapezius muscle transfer for external shoulder rotation: anatomical study. AB - OBJECTIVE: To compare the viability of transferring the lower and transverse trapezius to the greater tuberosity using three different techniques. METHODS: Twelve shoulders from six cadavers were used. The primary outcome was to assess the suture viability of the trapezius muscle transfer to the greater tuberosity in the insertion topography of the infraspinatus, with the arm adducted during internal rotation (hand on the abdomen) and maximum scapular retraction. Three transfers were applied to each shoulder: the lower and transverse trapezius distal insertion (Group 1); lower trapezius alone (Group 2); and lower trapezius insertion and origin (Group 3). Accessory nerve integrity was assessed before and after transfers. RESULTS: Sutures were viable in 42% (5/12) and 58% (7/12) on Groups 1 and 3, respectively, with no statistically significant difference (Fisher's test, p=0.558); Group 3 exhibited frequent neurologic injury (11/12). Group 2 was the least successful; the tendon did not reach the greater tuberosity, and no sutures were viable. CONCLUSION: Groups 1 and 3 exhibited the best nongrafting suture viability to the greater tuberosity; however, Group 3 was associated to frequent spinal accessory nerve injury. Level of Evidence IV, Anatomical Study. PMID- 25538476 TI - GCT: What happened after 10 years of curettage and cement? Retrospective study of 46 cases. AB - OBJECTIVE: To compare the functional outcome of patients with and without arthrosis, and to determine whether the development of arthrosis is related to the distance of the tumor from the subchondral bone. METHODS: Forty six patients treated for Giant-cell tumor (GCT) between 1975 and 1999 met inclusion criteria. GCT was diagnosed by percutaneous biopsy and confirmed after resection, in all cases. Campanacci's and Kellgren's classification, the distance of the cement to the articular surface and MSTS score were obtained throughout the sample. RESULTS: The distance of the cement to the subchondral bone was associated with greater risk of developing arthrosis, but there was no difference in MSTS scores between patients with or without arthrosis. CONCLUSION: We found that the distance from the cement to the subchondral bone has a prognostic value regarding future arthrosis, but it does not impact on the functional outcome. Level of Evidence IV, Therapeutic Study. PMID- 25538477 TI - Height of the foot longitudinal arch and anterior cruciate ligament injuries. AB - OBJECTIVE: To evaluate the association between the height of the medial longitudinal arch of the foot and non-contact injuries of the anterior cruciate ligament. METHODS: One hundred and five patients were included in this case control study. The case group consisted of 52 patients with non-contact injury of the anterior cruciate ligament. Fifty-three individuals with no history of symptoms regarding to feet or knees comprised the control group. An anthropometric assessment of the bony arch index was performed, which consisted of measuring the ratio of the height between the navicular bone to the ground and the distance from the most posterior support point of the calcaneus to the first metatarsal-phalangeal joint. Gender, height, weight, body mass index and the frequency of sports practice were also evaluated. RESULTS: Subjects in the case group had significantly higher medial longitudinal arches than individuals in the control group. CONCLUSION: Individuals with rupture of the anterior cruciate ligament had higher arches than the corresponding controls, suggesting an association between a high medial longitudinal arch of the foot and injury of the anterior cruciate ligament. Level of Evidence III, Case-Control Study. PMID- 25538478 TI - Outcome comparison of Lisfranc injuries treated through dorsal plate fixation versus screw fixation. AB - OBJECTIVE: The objective of this prospective study was to test whether the treatment of Lisfranc injuries with open reduction and dorsal plate fixation would have the same or better functional outcomes as treatment with standard trans-articular screw fixation. METHODS: Sixty patients with primarily isolated Lisfranc joint injury were treated by open reduction and dorsal plate fixation or standard screw fixation. The patients were followed on average for 31 months. Evaluation was performed with patients' chief complaint, clinical examination, radiography, and AOFAS Midfoot Scale. RESULTS: Thirty two patients were treated with open reduction and dorsal plate fixation, and twenty eight patients were treated with open reduction and screw fixation. After two years follow-up, the mean AOFAS Midfoot score was 83.1 points in the dorsal plate fixation group and 78.5 points in the screw fixation group (p<0.01). Of the dorsal plate fixation group, radiographic analysis revealed anatomic reduction in twenty-nine patients (90.6%, 29/32) and nonanatomic reduction in three patients. Of the screw fixation group, radiographic analysis revealed anatomic reduction in twenty-three patients and nonanatomic reduction in five patients (82.1%, 23/28). CONCLUSIONS: Open reduction and dorsal plate fixation for a dislocated Lisfranc injury do have better short and median term outcome and a lower reoperation rate than standard screw ORIF. In our experience, we recommend using dorsal plate in ORIF on dislocated Lisfranc injuries. Level of Evidence II, Prospective Comparative Study. PMID- 25538479 TI - Epidemiology of sports injuries on collegiate athletes at a single center. AB - OBJECTIVE: To evaluate the incidence of sports injuries in college athletes from the same institution from 1993 to 2013. METHODS: Athletes from 13 modalities were interviewed about the presence and type of injury, type of treatment and time of withdrawal, based on the questionnaire "Injury Surveillance System" (ISS). Data were analyzed with graphs and tables of injury prevalence by gender, age, site of injury and modality. We also analyzed the average time of withdrawal of athletes, returning to sports practice and new lesions. RESULTS: It was observed that 49.91% of the athletes showed some type of injury, with similar incidence between genders; the most frequent injuries were the anterior cruciate ligament (ACL) and the ankle sprain; the average withdrawal time was 11 weeks. ACL was the injury with greater impact on college sports career, especially given the time of withdrawal. CONCLUSION: The most frequent injury, ACL, occurred most frequently in indoor sports such as handball and volleyball and had the highest number of cases treated with surgery and a longer average withdrawal time. More studies are needed to create a larger database in order to schedule preventive measures for amateur athletes. Level IV of Evidence, Epidemiological Study. PMID- 25538480 TI - Evaluation of Q angle in differents static postures. AB - OBJECTIVE: To compare the value of Q angle in different positions, in the external and internal rotations of lower limbs. METHODS: This is a descriptive cross-sectional study. We have evaluated 62 volunteers, 32 women and 30 men in the following positions: supine positions with parallel feet, supine with abduction (external rotation of lower limbs), and standing position with parallel feet and with external rotation. All the participants were sedentary and without previous history of acute injury or complaints regarding lower limbs. In order to calculate the Q angle we used computerized biophotogrammetry through ALC image 2.1((r)) program. RESULTS: The results of the comparisons showed significant difference between the standing position with feet parallel and orthostatic positions with abductees feet on the left side for both genders (p = 0.000). We also found a significant difference between supine and standing position with abducted feet and with feet parallel on the left side (p = 0.046) in females. CONCLUSION: From these results, we can conclude that there are significant differences in the standing position with abducted feet and parallel to the left leg, and symmetry between the lower limbs independent of rotation of limbs in the supine posture. Level of Evidence II, Diagnostic Studies Investigating a Diagnostic Test. PMID- 25538481 TI - Outcomes in orthopedics and traumatology: translating research into practice. AB - Clinical research is focused in generating evidence that is feasible to be applicable to practitioners. However, translating research-focused evidence into practice may be challenging and often misleading. This article aims is to pinpoint these challenges and suggest some methodological safeguards, taking platelet-rich plasma therapies and knee osteochondral injuries as examples. Studies and systematic reviews involving the following concepts will be investigated: clinically relevant outcomes, systematic errors on sample calculation, internal and external validity. Relevant studies on platelet-rich plasma for muscle-tendon lesions and updates on osteochondral lesions treatment were included in this analysis. Authors and clinicians should consider these concepts for the implementation and application of dissemination of the best evidence. Research results should be challenged by a weighted analysis of its methodological soundness and applicability. Level of Evidence V, Therapeutic Studies - Investigating the Results of Treatment. PMID- 25538482 TI - Effects of exercise on pain of musculoskeletal disorders: a systematic review. AB - Work related musculoskeletal disorders are a major concern for public health and pain is the most important symptom. The aim of this study was to verify the effectiveness of workplace exercises to control musculoskeletal pain and its frequency, intensity, duration and type of exercises used. The search was conducted systematically in Medline, Pubmed, Embase, Bireme, Web of Knowledge and Pedro databases. The keywords "workplace", "exercise" and "musculoskeletal disorders" were used combined. Randomized control trials which performed worksite exercises were selected and the studies were assessed by their methodological soundness. Ten articles were selected which investigated the resistance training, cardio respiratory exercises, Pilates, stretching, postural orientation and exercises for relaxation. Workplace resistance training performed at 70-85% RM, three times a week for 20 minutes promotes reduction of the pain in shoulders, wrists, cervical, dorsal and lumbar spine. However, there is no consensus regarding the total duration of the intervention for the decrease of musculoskeletal pain in these regions. Level of Evidence I, Therapeutic Studies Investigating the Results of Treatment, Systematic Review of RCTs (Randomized and Controlled Clinical Studies). PMID- 25538483 TI - Excellence is the Enemy of Good. PMID- 25538484 TI - Comparison of the Relative Renal Function Calculated with 99mTc Diethylenetriaminepentaacetic Acid and 99mTc-Dimercaptosuccinic Acid in Children. AB - The aim was to compare the relative renal functions measured with technetium-99m dimercaptosuccinic acid (99mTc-DMSA) and technetium-99m diethylenetriaminepentaacetic acid (99mTc-DTPA) in children with renal diseases. Relative renal function of 128 children who applied to three hospitals from 2009 to 2011 were analyzed retrospectively. The mean value measured with 99mTc-DTPA and 99mTc-DMSA were 51.58 +/- 14.95 and 51.96 +/- 14.99 for the right kidney, 47.87 +/- 15.27 and 47.94 +/- 15.17 for the left kidney, respectively. A significant positive correlation was found between the relative renal functions (r = 0.963, P < 0.001). In Bland-Altman plots, the mean difference between two methods was 0.7 and the correlation limits were between 10.1 and-10.8. As a result, although 99mTc-DMSA is accepted as the most reliable method for the determination of relative renal function, 99mTc-DTPA can be another choice for the calculation of relative renal function without a complementary DMSA scan particularly in pediatric patients who require renogram curve and GFR calculations. PMID- 25538485 TI - Synthesis of (99m)TcN-clinafloxacin Dithiocarbamate Complex and Comparative Radiobiological Evaluation in Staphylococcus aureus Infected Mice. AB - Clinafloxacin dithiocarbamate (CNND) preparation and radiolabeling through [(99m)Tc = N](2+) core with the gamma (gamma) emitter ((99m)Tc) was assessed. The potentiality of the (99m)Tc(V) = N-CNND complex was investigated as perspective a Staphylococcus aureus (S.a.) in vivo infection radiotracer in terms of radiochemical stability in normal saline (n.s.), human serum (h.s.), binding efficacy with live and heat killed S.a. and biodistribution in female nude mice model (FNMD). More than 90% stability was observed in n.s. for 4 h with the highest yield of 98.70 +/- 0.26% at 30 min after reconstitution. In h.s., the (99m)Tc(V) = N-CNND complex was found stable up to 16 h with 15.35% side products. Maximum in vitro binding (68.75 +/- 0.80%, 90 min) with S.a. was observed after 90 min of incubation. In FNMD, (infected with live strain) approximately six-fold higher uptakes was noted in the infected to inflamed and normal muscles. The higher stability in n.s., h.s., higher S.a. (live) up take with specific and targeted in vivo distribution confirmed potentiality of the (99m)Tc(V) = N-CNND complex as perspective S.a. in vivo infection radiotracer. PMID- 25538486 TI - (99m)Tc Diethylenetriaminepentacetic Acid Angiotension-coverting Enzyme Inhibitor Renography as Screening Test for Renovascular Hypertension in Unilateral Small Kidney: A Prospective Study. AB - To know the probability of renal artery stenosis (RAS) in unilateral small kidney and function of the unilateral small kidney, which includes glomerular filtration rate, differential function, uptake, Tmax by (99m)Tc diethylenetriaminepentacetic acid (DTPA) base and (99m)Tc DTPA angiotensin converting enzyme (ACE) inhibition scan. All our patients were subjected to (99m)Tc DTPA ACE inhibition renal scintigraphy. All the patients underwent either computed tomography (CT) angiography and magnetic resonance (MR) angiography was done in those patients in which kidney function test was deranged. Renal angiography was subsequently performed in cases with the suggestion of RAS on CT or MR angiography. The quantitative data was expressed as the arithmetic mean, standard deviation and percentages. The intergroup comparisons for parametric data were done by Student's t-test, whereas non-parametric data was compared with Mann-Whitney U test. The intergroup comparisons were made by paired t-test and Wilcoxon sign rank test. P <0.05 was considered to be significant, and data was analyzed by Statistical package for social sciences(SPSS-20) software. Out of 47 patients, 25 patients were in the low probability group out of which none was positive for RAS on CT/MR angiography. Out of 47 patients, 12 were in the intermediate group out of which none was positive for RAS. Ten, out of 47 patients were suspected of high probability for RAS by ACE inhibition scan out of which 4 were positive for RAS by CT/MR angiography including one with bilateral RAS. (99m)Tc DTPA angiotension-coverting enzyme inhibitor renography is a safe, non-invasive, sensitive, specific, and cost-effective test for excluding renovascular hypertension in patients who have normal or nearly normal renal function in unilateral small kidney. PMID- 25538487 TI - Role of scintimammography in assessing the response of neoadjuvant chemotherapy in locally advanced breast cancer. AB - Locally advanced breast cancer (LABC) is a common cancer in the developing countries. Neoadjuvant chemotherapy (NACT) is a very important step in the treatment of such tumors and hence that the disease can be down staged and made amenable for surgery. All the tumors do not respond to the therapy equally. Hence, it becomes very important to predict the response of chemotherapy in such cases. This study evaluated the role of scintimammography in assessing the response to NACT in 23 patients with LABC. Histologically proven 23 patients of LABC were recruited in this study. Prechemotherapy tumor size was measured clinically in all patients and technitium (Tc)-99m sestamibi test was performed before NACT for each patient. Early (10 min) and delayed (2 h) image of the breast were acquired in anterior and lateral views after Tc-99m sestamibi intravenous injections and wash out rate (WOR) was computed. After 3-4 cycles of chemotherapy, surgery in the form of modified radical mastectomy was performed in 20 out of 23 patients (3 patients lost to follow-up) with pathologic evaluation of the residual tumor size. The pretherapy Tc-99m sestamibi WOR ranged from 8.3% to 68% with mean +/- SD of 34.5% +/-16.5%. The prechemotherapy Tc-99m sestamibi study predicted chemoresistance (WOR >45%) in 6 out of 20 patients and no chemoresistance (WOR <45%) in 14 out of 20 patients. When the WOR cut-off was set at >45%, the predictivity of the test was indicated by sensitivity of 91.7%, specificity of 62.5%, positive predictive value of 78.6%, and negative predictive value of 82.3% with a likelihood ratio of 0.1. Tc-99m sestamibi WOR is a reliable test for predicting tumor response to NACT. WOR >45% is highly predictive of chemoresistance with likelihood ratio of 0.1 than WOR <45% being predictive of chemoresponsiveness. PMID- 25538488 TI - The Accuracy of Integrated [(18)F] Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography in Detection of Pelvic and Para-aortic Nodal Metastasis in Patients with High Risk Endometrial Cancer. AB - Lymph nodal (LN) metastasis is the most important prognostic factor in high-risk endometrial cancer. However, the benefit of routine lymphadenectomy in endometrial cancer is controversial. This study was conducted to assess the accuracy of [(18)F] fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F] FDG-PET/CT) in detection of pelvic and para-aortic nodal metastases in high-risk endometrial cancer. 20 patients with high-risk endometrial carcinoma underwent [(18)F] FDG-PET/CT followed by total abdominal hysterectomy, bilateral salpingo-oophorectomy and systematic pelvic lymphadenectomy with or without para-aortic lymphadenectomy. The findings on histopathology were compared with [(18)F] FDG-PET/CT findings to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [(18)F] FDG-PET/CT. The pelvic nodal findings were analyzed on a patient and nodal chain based criteria. The para-aortic nodal findings were reported separately. Histopathology documented nodal involvement in two patients (10%). For detection of pelvic nodes, on a patient based analysis, [(18)F] FDG-PET/CT had a sensitivity of 100%, specificity of 61.11%, PPV of 22.22%, NPV of 100% and accuracy of 65% and on a nodal chain based analysis, [(18)F] FDG-PET/CT had a sensitivity of 100%, specificity of 80%, PPV of 20%, NPV of 100%, and accuracy of 80.95%. For detection of para-aortic nodes, [(18)F] FDG PET/CT had sensitivity of 100%, specificity of 66.67%, PPV of 20%, NPV of 100%, and accuracy of 69.23%. Although [(18)F] FDG-PET/CT has high sensitivity for detection of LN metastasis in endometrial carcinoma, it had moderate accuracy and high false positivity. However, the high NPV is important in selecting patients in whom lymphadenectomy may be omitted. PMID- 25538489 TI - Correlative (99m)tc-labeled tropane derivative single photon emission computer tomography and clinical assessment in the staging of Parkinson disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a selective loss of dopamine in the striatum. Problems remain in the accurate diagnosis of PD. The diagnosis of idiopathic PD is based on the interpretation of clinical signs and symptoms could be incorrect at the time of initial presentation. In vivo imaging of the dopaminergic system has the potential to improve the diagnosis of PD in its early stages. The imaging of dopamine transporter (DAT) with (99m)Tc-labeled tropane derivative (TRODAT-1) single photon emission computer tomography/computer tomography (SPECT/CT) has been proposed to be a valuable and feasible means of assessment of the integrity of dopamine neurons. The purpose of this study was to investigate the potential usefulness of (99m)Tc-TRODAT-1 imaging in the evaluation of patients with PD and classify into different stages of the disease. SPECT imaging with (99m)Tc-TRODAT 1 was conducted in 16 consecutive PD patients (9 men; 7 women) and in 6 age matched healthy volunteers (4 men; 2 women). The images were obtained 3 h after the intra-venous injection of the tracer. Specific uptake in the striatum and its sub-regions, including the putamen and caudate nucleus was calculated and the ratios of specific striatal binding to nonspecific occipital binding were calculated. ANOVA with Dunnett C post-hoc analysis was conducted using SPSS 20. A stepwise reduction in specific striatal uptake of (99m)Tc-TRODAT-1 with increasing disease severity between healthy control versus Stage I versus Stage II versus Stage III was found in PD patients (i.e., 3.77 vs. 2.56 vs. 1.57 vs. 0.63, P < 0.05). The changes were magnified by measurement of specific putaminal uptake (1.43 vs. 0.79 vs. 0.54 vs. 0.19, P < 0.05) and specific caudate uptake (1.90 vs. 1.47 vs. 0.73 vs. 0.27, P < 0.05). No remarkable adverse reactions were found in either healthy volunteers or PD patients during or after imaging. (99m)Tc-TRODAT-1 is accurate and widely available for the assessment of DAT activity, which might shed light on the integrity of the presynaptic nigrostriatal function. Our preliminary study results confirm the potential of using (99m)Tc-TRODAT-1 for DAT measurement, which is clinically important for the staging of PD. PMID- 25538490 TI - A Comparison between Quantitative Gated Myocardial Perfusion Scintigraphy and Strain Echocardiography as Indicators of Ventricular Functions in Patients with Anterior Myocardial Infarction. AB - The purpose of this study is to compare the strain echocardiographic and scintigraphic parameters for evaluating of the left ventricular (LV) functions in patients with anterior myocardial infarction (MI). Fifty-four patients (male/female: 36/18; mean age 62 +/- 13 years) with anterior MI were prospectively enrolled. All patients were performed gated myocardial perfusion scintigraphy gated single-photon emission computed tomography (GSPECT) and echocardiography (EC). GSPECT data were processed and analyzed using 4D-MSPECT (4DM, Invia Medical Imaging Solutions, Ann Arbor, MI, USA). The echocardiographic strain (S) and strain rate (SR) values were calculated. The results obtained by these techniques were compared each other. A total of 918 segments of LV wall were evaluated. In all patients, 385 segments were automatically scored as normokinetic, 206 as hypokinetic, 122 as akinetic, 205 as dyskinetic and 300 as normal thickening, 348 as decrease thickening and 270 as no thickening. The means of S and SR values in thickening and motion score groups according to GSPECT were statistically different from each other (P < 0.001). There was a negative significant correlation between LV wall thickening sum score and S and SR and between LV wall motion sum score and S and SR (P < 0.001). There was a good correlation between GSPECT and echocardiographic LV-ejection fraction (r = 0.7, P < 0.001). GSPECT and strain EC are similar in quantitative grading of the severity of regional and global myocardial dysfunction in patients with anterior MI and these techniques provide valuable diagnostic information. PMID- 25538491 TI - False Negative (99m)Tc-Hydroxymethane Diphosphonate Three-phase Bone Scintigraphy and (99m)Tc-besilesomab Scan in Detecting Tibia Osteomyelitis Concomitant with Necrotizing Fasciitis. AB - We described a case of 51-year-old female patient presented with a right calf necrotising fasciitis (NF) where osteomyelitis (OM) was suspected. (99m)Tc hydroxymethane diphosphonate three-phase bone scintigraphy and (99m)Tc besilosomab scan failed to demonstrate classical features of OM. The final diagnosis was only made by isolating Acinetobacter sp. in both intra-operative bone and tissue cultures from below-knee amputation. As conclusions, the detection of lower limb OM by (99m)Tc-besilosomab scan is not easy when there is concurrence overlying NF. The unusual three-phase bone scan finding of pericortical accumulation of tracer as an early sign of OM is highlighted in this case. PMID- 25538492 TI - (99m)Tc DTPA renogram indentifies Bochdalek hernia with an intra thoracic kidney as its content. AB - Congenital diaphragmatic hernia (CDH) is a rare anomaly with reported incidence of 1 in 16,000 and is associated with herniation of stomach, intestinal loops, spleen, and kidney through a chest wall defect. We report a case of 1-year-old male child with history of recurrent fever and non-visualization of left kidney on ultrasonogram. Patient was referred to us to look for ectopic left kidney.(99m)Tc-diethylenetriaminepentaacetic acid renogram was performed. An ectopically placed intrathoracic left kidney was identified. Subsequently a chest X-ray was done that showed bowel loops and diagnosis of CDH was confirmed. The patient underwent thoracoscopic repair of CDH and hernial contents were found to be left kidney, intestinal loops and spleen. PMID- 25538493 TI - Looking outside the "cardiac" box: incidental detection of a metastatic lung tumor on cardiac position emission tomography/computed tomography. AB - Incidental extracardiac findings are not uncommon in patients undergoing cardiac positron emission tomography/computed tomography (PET/CT) and some of these findings can have significant clinical impact. We report a case of a 74-year-old man who presented with dyspnea and left sided chest pain. 82-rubidium PET/CT imaging showed normal myocardial perfusion. Review of the low dose CT scan performed for attenuation correction purposes (CTAC) incidentally revealed a 4 cm mass in the left lung, which was histologically shown to be a squamous cell carcinoma. A subsequent staging CT showed chest wall metastases and rib destruction in the upper left thorax, which were outside the image reconstruction field of view of the CTAC. This report illustrates the importance of vigilant review of all acquired images by the PET/CT reader to look for extracardiac abnormalities that may explain symptoms in the absence of coronary artery disease. It also raises the question as to whether a larger field of CT image acquisition should be routinely performed to scan the entire chest during cardiac PET/CT imaging. However, the latter needs to be weighed against the increase in patient dose, which we estimated to be an additional 15%. PMID- 25538494 TI - Gallium-68 DOTA-TATE Positron Emission Tomography/Computed Tomography: Scintigraphic Changes of Adrenal Glands Following Management of Ectopic Cushing's Syndrome by Steroidogenesis Inhibitors. AB - In the era of emerging functional imaging techniques, an understanding of the effects of hormonal therapies on the scintigraphic appearance of endocrine organs is desirable to minimize the erroneous scan interpretation. The mechanisms by which changes in the scintigraphic appearance of endocrine organs occur however sometimes remain ambiguous. This case demonstrates the gallium-68 (Ga-68) DOTA TATE positron emission tomography/computed tomography (CT) appearance of adrenal glands following management with steroidogenesis inhibitors. The potential mechanisms underlying this change are discussed. A 17-year-old boy with adrenocorticotropic hormone (ACTH) dependent Cushing's syndrome secondary to ectopic ACTH secretion underwent pre- and post-metyrapone and dexamethasone treatment Ga-68 DOTA-TATE scans 4 months apart. Pretreatment, both adrenals demonstrated normal symmetrical prominent Ga-68 DOTA-TATE uptake and normal CT appearance. The posttherapy scan revealed marked symmetrical suppression of Ga-68 DOTA-TATE uptake, but with bilateral adrenal hypertrophy on CT. PMID- 25538495 TI - Occult Prostate Cancer Detected with 18F-Fluorocholine Positron Emission Tomography/Computed Tomography. AB - We present a case of a 63-year-old gentleman, who had an initial negative prostate needle biopsy, but persistently elevated prostate-specific antigen levels. An magnetic resonance imaging study of the prostate failed to demonstrate the presence of malignancy. 18F-fluorocholine positron emission tomography/computed tomography (PET/CT) was then acquired which revealed suspicious prostate lesions. These were confirmed by subsequent surgery and histology to represent prostatic carcinoma. PMID- 25538496 TI - Bone metastases treatment by sm-153 oxabifore in combination with monoclonal antibody denosumab (xgeva). PMID- 25538497 TI - Sipple syndrome with pregnancy: Anesthetic and obstetrical implications. PMID- 25538498 TI - General anesthesia for the heaviest man in the world. AB - The prevalence of obesity has increased greatly over the last 20 years, resulting in an increase in the number of bariatric and nonbariatric surgeries in this population. We present the case of a 20-year-old male, weighing 610 kg (1345 lb), and believed to be the heaviest living man in the world. After 4 months of rigorous in-hospital weight reduction, now weighing 510 kg (1125 lb), he underwent a laparoscopic gastric sleeve procedure under general anesthesia. This report describes the management of his anesthetic and exemplifies the challenges associated with this patient population. PMID- 25538499 TI - Management of anesthesia in unspecified extra-adrenal pheochromocytoma patient who used beta-blocker. AB - An operation was planned for a female patient aged 59 for intra-abdominal mass. The patient was using nebivolol for hypertension. Blood pressure (BP) of the patient was raised to 200/130 mmHg during anesthesia induction. BP was gradually reduced by remifentanil infusion. Following the manipulation of the mass, BP began to increase (225/160 mmHg), thus nitroglycerin and followed nitroprusside infusion was started. Propofol (200 + 200 mg) and furosemide (20 mg) were administered intravenously. BP suddenly dropped (90/60 mmHg) following the removal of the mass, nitroglycerine, and nitroprusside infusions were stopped; remifentanil dose was decreased and fluid was quickly infused. The patient was uneventually recovered. Vanilmandelic acid level was higher in the patient and pheochromocytoma was considered. PMID- 25538500 TI - Locked-in syndrome caused by the pressure exerted by the sound gun. AB - A 19-year-old male patient who wounded himself with a gun in the cranial region had a Glasgow coma scale of 3E. At posttraumatic day 7, locked-in syndrome was considered upon detection of vertical eye movements, meaningful winks, and quadriplegia. Apart from the classical view, computed tomography (CT) and postmortem examination of the brain showed an infarct area in the cerebellum. However, vertebrobasilar artery system was normal. In this case report, we would like to present that unlike cases with ischemia, specific CT findings may not be evident in posttraumatic cases and ischemia may occur in the cerebellum as a result of the pressure exerted by a sound gun. PMID- 25538501 TI - Accidental placement of central venous catheter in lung parenchyma causing hydrothorax. AB - Central venous catheterization is associated with its share of complications. Most of these complications can be avoided and treated by appropriate patient selection, careful insertion technique and vigilance following catheter insertion. We report a patient presenting with unilateral hydrothorax due malposition of central venous catheter in lung parenchyma. Prompt recognition of complication and its treatment remedied the situation. PMID- 25538502 TI - Could pregabalin premedication predispose to perioperative atrial fibrillation in patients with sepsis? PMID- 25538503 TI - Sudden and sustained elevation of bispectral index due to electromyographic interference during closed circuit inhalational anesthesia. PMID- 25538504 TI - Near fatal bradycardia during cesarean section under spinal anesthesia: "High spinal" may not be only risk factor. PMID- 25538506 TI - Classical is not that simple: Lesson from trigeminal neuralgia. PMID- 25538505 TI - Artery of Percheron infarct: An unusual cause for non-awakening from anesthesia. PMID- 25538507 TI - An unusual mid-shaft spinal needle defect detected accidentally. PMID- 25538508 TI - Hemiplegic migraine: An atypical presentation of Moyamoya disease. PMID- 25538509 TI - Pneumothorax following flexible fiberoptic bronchoscopy: A rare occurrence. PMID- 25538510 TI - Ultrasound guided nerve block in successful anesthetic management of an achondroplasic dwarf with severe kyphoscoliosis. PMID- 25538511 TI - Anesthetic management of pediatric with congenital heart disease with pulmonary hypertension. PMID- 25538512 TI - Anesthetic management of a case of spontaneous rupture of diaphragm. PMID- 25538513 TI - Novel technique in placement of transesophageal echocardiography probe in neurosurgical procedures. PMID- 25538514 TI - Topical airway anesthesia for awake fiberoptic intubation: Comparison between airway nerve blocks and nebulized lignocaine by ultrasonic nebulizer. AB - OVERVIEW: Awake fiberoptic bronchoscope (FOB) guided intubation is the gold standard of airway management in patients with cervical spine injury. It is essential to sufficiently anesthetize the upper airway before the performance of awake FOB guided intubation in order to ensure patient comfort and cooperation. This randomized controlled study was performed to compare two methods of airway anesthesia, namely ultrasonic nebulization of local anesthetic and performance of airway blocks. MATERIALS AND METHODS: A total of 50 adult patients with cervical spine injury were randomly allocated into two groups. Group L received airway anesthesia through ultrasonic nebulization of 10 ml of 4% lignocaine and Group NB received airway blocks (bilateral superior laryngeal and transtracheal recurrent laryngeal) each with 2 ml of 2% lignocaine and viscous lignocaine gargles. FOB guided orotracheal intubation was then performed. Hemodynamic variables at baseline and during the procedure, patient recall, vocal cord visibility, ease of intubation, coughing/gagging episodes, and signs of lignocaine toxicity were noted. RESULTS: The observations did not reveal any significant differences in demographics or hemodynamic parameters at any time during the study. However, the time taken for intubation was significantly lower in Group NB as compared with the Group L. Group L had an increased number of coughing/gagging episodes as compared with Group NB. Vocal cord visibility and ease of intubation were better in patients who received airway blocks and hence the amount of supplemental lignocaine used was less in this group. Overall patient comfort was better in Group NB with fewer incidences of unpleasant recalls as compared with Group L. CONCLUSION: Upper airway blocks provide better quality of anesthesia than lignocaine nebulization as assessed by patient recall of procedure, coughing/gagging episodes, ease of intubation, vocal cord visibility, and time taken to intubate. PMID- 25538515 TI - Between pain and pleasure: Pregnant women's knowledge and preferences for pain relief in labor, a pilot study from Zaria, Northern Nigeria. AB - BACKGROUND: Pain relief in labor remains a hot topic and these debates get louder by the day as more women become aware of their rights to better quality of care in labor. This study was conceived in a background where the practice of pain relief in labor is evolving and where women are seeking to fulfill their need for pain-free labor. OBJECTIVE: To investigate the knowledge, utilization and preferences of methods of pain relief in labor by expectant mothers in order to design a labor analgesia program. MATERIALS AND METHODS: A questionnaire-based descriptive study involving 124 antenatal clients in a teaching hospital over a 1 week period. Descriptive statistics were carried out using SPSS for windows version 17. RESULTS: The mean age of clients was 28.8 years (standard deviation = 5.17) with median parity of two and mean gestational age was 31.5 weeks. Majority of the respondents (47.9%) were of Hausa/Fulani ethnicity and 97.6% had primary school level education. Majority (87.3%) had heard about pain relief methods with the hospital being the source in 79% of cases. The most common method ever heard about was epidural analgesia (69.4%). Only 4% (n = 5) of respondents remembered ever using any form of pain relief agent in labor, of which three received parenteral opioids. In their current pregnancies, 45.2% consented to the use of pain relief in labor; of which, epidural analgesia was preferred by 92.9% (n = 52). Fear of adverse effects on self and infants were cited as reasons for non consent by some respondents while others had no reason. CONCLUSION: The study reveals a high awareness of pain relief methods which is not matched by utilization and low knowledge about side-effects, although fear of side-effects is a factor for under-utilization. There is a need to educate adequately as well provide high quality pain relief services in labor in order to dispel with myths, misconceptions and fears associated with the use of methods of pain relief in labor. PMID- 25538516 TI - A cadaveric study comparing the three approaches for ulnar nerve block at wrist. AB - BACKGROUND: Ulnar nerve blockade as a component of wrist block is a promising technique for adequate anesthesia and analgesia for different surgeries of the hand. Due to anatomical variations in the location of ulnar nerve under the flexor carpi ulnaris (FCU) a technique with good results and minimal complications are required. AIM: The aim of the following study is to compare the three techniques (volar, transtendinous volar [TTV] and ulnar) for ulnar nerve block at the wrist in human cadaveric wrists. MATERIALS AND METHODS: Our study was conducted using 40 cadaver wrists. After inserting standard hypodermic needles by three techniques for ulnar nerve blockade at the wrist, a detailed dissection of FCU was done. The mean distance from the tip of the needle to ulnar artery/nerve and number of instances in which the ulnar artery/nerve pierced were observed. RESULTS: Inter-group statistical significance was observed in measurement of the mean distance (mm) from the tip of the needle to the ulnar artery (volar [0.92 +/- 0.11], TTV [3.96 +/- 0.14] and ulnar [7.14 +/- 0.08] approaches) and ulnar nerve (volar/TTV/ulnar approaches were 0.71 +/- 0.12/3.61 +/- 0.10/6.31 +/- 0.49, respectively) (P = 0.001). Inadvertent intra arterial/intraneural injections was seen with volar approach in 14 (35%) and 16 (40%) of the cadaveric wrists respectively, statistically significant with transtendinous and ulnar techniques of ulnar nerve block. CONCLUSION: TTV approach could be a better technique of choice for ulnar nerve blockade at the wrist because of its ease to practice, safer profile and minimum chances of inadvertent intra-arterial/intraneural injection with adequate anesthesia/analgesia. PMID- 25538517 TI - Critical care issues in solid organ injury: Review and experience in a tertiary trauma center. AB - BACKGROUND AND AIM: Solid organ (spleen and liver) injuries are dreaded by both surgeons and anesthesiologists because of associated high morbidity and mortality. The purpose of this review is to describe our experience of critical care concerns in solid organ injury, which otherwise has been poorly addressed in the literature. MATERIALS AND METHODS: Retrospective cohort of solid organ injury (spleen and liver) patients was done from January 2010 to December 2011 in tertiary level trauma Center. RESULTS: Out of 624 abdominal trauma patients, a total of 212 patients (70%) were admitted in intensive care unit (ICU). Their ages ranged from 6 to 74 years (median 24 years). Nearly 89% patients in liver trauma and 84% patients in splenic trauma were male. Mechanism of injury was blunt abdominal trauma in 96% patients and the most common associated injury was chest trauma. Average injury severity score, sequential organ failure assessment, lactate on admission was 16.84, 4.34 and 3.42 mmol/L and that of dying patient were 29.70, 7.73 and 5.09 mmol/L, respectively. Overall mortality of ICU admitted solid organ injury was 15.55%. Major issues of concern in splenic injury were hemorrhagic shock, overwhelming post-splenectomy infection and post-splenectomy vaccination. Issues raised in liver injury are damage control surgery, deadly triad, thromboelastography guided transfusion protocols and hemostatic agents. CONCLUSIONS: A protocol-based and multidisciplinary approach in high dependency unit can significantly reduce morbidity and mortality in patients with solid organ injury. PMID- 25538519 TI - Labor pain relief for parturients: We can do better. PMID- 25538518 TI - Patient-controlled sedation with propofol/remifentanil versus propofol/alfentanil for patients undergoing outpatient colonoscopy, a randomized, controlled double blind study. AB - CONTEXT: Many techniques are used for sedation of colonoscopies. Patient controlled sedation (PCS) is utilizing many drugs or drug combinations. AIMS: The aim of this study is to compare the safety and feasibility of propofol/remifentanil versus propofol/alfentanil given to sedate patients undergoing outpatient colonoscopies through a patient-controlled technique. SETTINGS AND DESIGN: Controlled randomized and double-blind study. MATERIALS AND METHODS: A total of 80 patients were randomly divided into two groups; PA group received a combination of propofol/alfentanil and PR group received propofol/remifentanil combination. Patients were monitored for heart rate (HR), blood pressure (BP), oxygen saturation, and Ramsay sedation scale (RSS). Times of the following events were recorded; initiation of sedation, insertion and removal of the colonoscope, recovery and discharge. Five intervals were calculated; time to sedation, procedure time, postprocedure time, procedure room time, and postanesthesia care unit (PACU) time. Endoscopist and patient satisfaction scores were obtained. STATISTICAL ANALYSIS USED: Unpaired Student's t-test was used to compare between the two groups. Paired Student's t-test was used to compare baseline readings with readings after 30 min of sedation in the same group when needed. RESULTS: Both groups showed slowing of the HR and decrease in mean arterial BP. HR and mean arterial BP were significantly lower 5 and 10 min after initiation of sedation in PR group when compared with PA group. Both HR and mean arterial BP returned to presedation readings 30 min after initiation of sedation in PR group but not in PA group. No differences between the two groups concerning oxygen saturation, RSS, endoscopist and patient satisfaction scores. Postprocedure and PACU times were significantly prolonged in PA group. CONCLUSION: PCS with either remifentanil/propofol or alfentanil/propofol for patients undergoing outpatient colonoscopy is safe and feasible. Remifentanil/proofol has more beneficial advantages in this setting secondary to its more rapid clearance. PMID- 25538520 TI - Identification of epidural space using loss of resistance syringe, infusion drip, and balloon technique: A comparative study. AB - BACKGROUND AND OBJECTIVE: There are various techniques to identify epidural space but superiority of one technique over other has not been adequately studied. We conducted a study to Compare and evaluate the three techniques for epidural space localization that is, loss of resistance (LOR) syringe technique, balloon technique and drip infusion technique. MATERIALS AND METHODS: Seventy-five patients of either sex, belonging to American Society of Anesthesiologists physical status Class 1 or 2, between 20 and 50 years of age, scheduled to undergo lower abdominal and lower limb surgeries were randomly allocated to one of the three groups (n = 25 each) depending upon epidural space localization. In Group I, epidural space localization was done with LOR syringe technique. In Group II Balloon technique and in Group III drip infusion technique was used. Distance of the epidural space from skin, number of attempts, time taken for epidural space localization and quality of the block were the parameter recorded during the study. RESULTS: First attempt success rate for epidural space localization was highest in Group III (100%). The mean time taken for epidural space localization was least in Group III, and when compared with other groups it was found to be statistically significant with P = 0.016. Number of attempt for space localization and success rate of the block was better in the majority of patients of Group III, but the difference was found to be statistically nonsignificant. Complication rate was almost negligible in all three techniques. CONCLUSION: We conclude that the time taken to localize the epidural space was least in drip infusion technique. As for number of attempts, quality of the block and complications is concerned, all the three techniques are comparable. PMID- 25538521 TI - Five-year experience with the peri-operative goal directed management for surgical repair of traumatic aortic injury in the eastern province, Saudi Arabia. AB - CONTEXT: Traumatic aortic injury (TAI) accounts for 1/3 of all trauma victims. AIM: We aimed to investigate the efficacy of the adopted standardized immediate pre-operative and intra-operative hemodynamic goal directed control, anesthetic technique and organs protection on the morbidity and mortality in patients presented with TAI. SETTINGS AND DESIGN: An observational retrospective study at a single university teaching hospital. MATERIALS AND METHODS: Following ethical approval, we recruited the data of 44 patients admitted to the King Fahd Hospital of the University, Al Khobar, Saudi Arabia, with formal confirmation of diagnosis of blunt TAI during a 5-year period from February 2008 to April 2013 from the hospital medical records. STATISTICAL ANALYSIS: descriptive analysis. RESULTS: A total of 44 victims (41 men, median (range) age 29 (22-34) years) with TAI who underwent surgical repair were recruited. Median (range) post-operative chest tube output was 700 (200-1100) ml necessitated transfusion in 5 (11.4%) of cases. Post-operative complications included transient renal failure (13.6%), pneumonia (6.8%), acute lung injury/distress syndrome (20.5%), sepsis (4.5%), wound infection (47.7%) and air leak (6.8%). No patient developed end stage renal failure or spinal cord injury. Median intensive care unit stay was 6 (4-30) days and in-hospital mortality was 9.1%. CONCLUSION: We found that the implementation of a standardized early goal directed hemodynamic control for the peri-operative management of patients with TAI reduces the post-operative morbidity and mortality after surgical repair. PMID- 25538522 TI - Comparison of serum triglyceride levels with propofol in long chain triglyceride and propofol in medium and long chain triglyceride after short term anesthesia in pediatric patients. AB - BACKGROUND: Significant increase in serum triglyceride (ST) concentration have been described in adult population after prolonged administration of propofol formulation containing long chain triglyceride (LCT). Though, medium chain triglyceride-LCT (MCT-LCT) propofol when compared with LCT propofol for long-term sedation in adults resulted in identical triglyceride levels, the elimination of triglyceride was faster in patients administered MCT-LCT propofol. MATERIALS AND METHODS: A total of 40 children were randomized into two groups of 20 each; Group I were induced with 1% LCT propofol (3 mg/kg) and Group II with 1% medium and LCT propofol and maintained with descalating dose of 20.15 and 10 mg/kg/h at 10 min intervals. Blood samples for ST concentration were obtained before induction of anesthesia, at the end of propofol infusion and 4 h after terminating propofol infusion. RESULTS: ST levels were raised significantly above the basal values in both the groups but the rise was significantly higher in Group I (P < 0.05). Four hours after stopping propofol infusion the triglyceride levels were similar to the basal values in Group II, whereas in Group I the values were significantly greater than the baseline (P < 0.05) as well as those of Group II (P < 0.05). No clinically significant adverse effect of hypertriglyceridemia was observed. CONCLUSION: Even short term anesthesia with LCT and MCT-LCT propofol (1%) leads to elevated ST levels. The increase in ST levels is less with MCT-LCT propofol and elimination of triglyceride is also rapid after terminating MCT-LCT propofol infusion. PMID- 25538523 TI - Effect of clonidine versus dexmedetomidine on pain control after laparoscopic gastric sleeve: A prospective, randomized, double-blinded study. AB - BACKGROUND: The use of opioids in surgeries for morbidly obese patients could cause respiratory depression. Therefore, alternative analgesics are needed to improve anesthetic management for obese patients. The objective of this study was to compare the effect of dexmedetomidine and clonidine on pain as well as analgesic consumption at 24 h postoperatively in patients undergoing laparoscopic gastric sleeve. The secondary objective was to compare patients' and surgeons' satisfaction. MATERIALS AND METHODS: A total of 60 obese and morbidly obese patients scheduled to undergo laparoscopic gastric sleeve were randomly assigned into two groups. 10 min after induction of general anesthesia, one group received 0.8-1.2 MUg/kg/30 min intravenous (IV) clonidine through 500 mL lactated Ringer's solution and placebo (normal saline solution) through syringe pump. The second group received IV dexmedetomidine through syringe pump at a rate 0.5-0.8 MUg/kg/h and placebo through 500 mL lactated Ringer's solution. Data on pain, analgesic consumption, and return to normal activity in addition to patients' and surgeons' satisfaction were collected. RESULTS: Both groups were similar with respect to demographic and intraoperative hemodynamic characteristics. Fentanyl consumption, surgery duration and hospital stay were similar for the two groups. Pain scores on walking were significantly lower in the clonidine group at 12 h postoperatively (P = 0.014) compared with dexmedetomidine group. The number of patients who consumed pethidine was significantly lower in the clonidine group at 12 h postoperatively (P = 0.045). CONCLUSION: This study concluded that clonidine and dexmedetomidine yielded similar outcomes with a difference in pain and analgesic consumption at 12 h postoperatively. PMID- 25538524 TI - Evidence-based approaches toward reducing cancellations on the day of surgery. PMID- 25538525 TI - Randomized controlled trial to evaluate intraocular pressure following sub Tenon's local anesthesia for cataract surgery: With and without hyaluronidase added to anesthetic solution. AB - AIM: To evaluate effect on intraocular pressure (IOP) during sub-Tenon's local anesthesia (LA) during cataract surgery with 4 ml of anesthetic injected without and with addition of hyluronidase to anesthetic solution. MATERIALS AND METHODS: This randomized controlled study included 65 eyes of 65 patients undergoing phacoemulsification and lens implant for cataract. The patients were randomized to a standardized procedure of administration of 4 ml of sub-Tenon's LA without and with addition of 15 IU/ml hylaluronidase to 2% lidocaine (control group and intervention group respectively). IOP measurements were carried out immediately prior to and at 2, 5, and 10 and 15 min after sub-Tenon's injection using a hand held tonometer (Tonopen). RESULTS: All patients achieved satisfactory akinesia and complete analgesia during surgery. The mean age of patients in control group was 59.56 +/- 14.3 years, and 61.77 +/- 11.91 years in intervention group (P = 0.507). The mean preinjection and 15 min IOP was 19.16 +/- 4.39 and 20.21 +/- 5.49 mm Hg, respectively in control group (P = 0.220); and 19.81 +/- 3.8 and 19.68 +/- 5.19 mmHg respectively in intervention group (P = 0.911). No statistical difference from baseline was detected between preinjection and at 2, 5, 10, and 15 min after injection in control (P = 0.124, 0.310, 0.804, 0.220, respectively) and intervention group (P = 0.367, 0.879, 0.765, 0.911 respectively). CONCLUSION: No significant rise in IOP occurs following injection of sub-Tenon's LA, when up to 4 ml of anesthetic is injected. The addition of hyaluronidase to 2% lignocaine has no beneficial lowering effect on IOP in sub Tenon's LA. Hence, the practice of addition of this agent may not be necessary during cataract surgery. PMID- 25538526 TI - Postoperative nausea and vomiting prophylaxis: A comparative study of ondansetron, granisetron and granisetron and dexamethasone combination after modified radical mastectomy. AB - BACKGROUND: Post-operative nausea and vomiting (PONV) is commonly seen after modified radical mastectomy (MRM). In this randomized double-blind prospective study we compared the efficacy of ondansetron, granisetron and granisetron and dexamethasone combination for prevention of PONV following MRM in female patients. MATERIALS AND METHODS: A total of 75 patients (20-60 years of age) undergoing elective MRM were randomly allocated to one of the three groups of 25 patients each. Group O received ondansetron 4 mg, Group G received granisetron 40 mcg/kg and group granisetron and dexamethasone (G + D) received granisetron 40 mcg/kg + dexamethasone 8 mg prior to induction. All episodes of PONV within 24 h after induction of anesthesia were recorded. STATISTICAL ANALYSIS: Statistical analysis was done using Kruskal-Wallis test (nonparametric ANOVA). RESULTS: The incidence of complete response (no PONV, no rescue medication) was 96% with G+D, as compared with 86% with granisetron and 4% with ondansetron during 0-3h after surgery which was clinically significant (P < 0.05). Similarly clinically significant response was seen during 3-6, 6-9, 9-12 and 12-24 h of surgery. CONCLUSION: Granisetron and dexamethasone combination is more effective for prevention of PONV in comparison to individual ondansetron and granisetron in MRM. PMID- 25538527 TI - Effect of dexmedetomidine as adjuvant in ropivacaine-induced supraclavicular brachial plexus block: A prospective, double-blinded and randomized controlled study. AB - BACKGROUND AND AIMS: Different additives have been used to prolong brachial plexus block. We evaluated the effect of adding dexmedetomidine to ropivacaine for supraclavicular brachial plexus blockade. The primary endpoints were the onset and duration of sensory and motor block and duration of analgesia. MATERIALS AND METHODS: A total of 84 patients (20-50 years) posted for elective forearm and hand surgery under supraclavicular brachial plexus block were divided into two equal groups (Group R and RD) in a randomized, double-blind fashion. In group RD (n = 42) 30 ml 0.5% ropivacaine +1 ml (100 MUg) of dexmedetomidine and group R (n = 42) 30 ml 0.5% ropivacaine +1 ml normal saline were administered in supraclavicular block. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative visual analog scale (VAS), hemodynamics and side-effects were recorded for each patient. RESULTS: Though with similar demographic profile in both groups, sensory and motor block in group RD (P < 0.05) was earlier than group R. Sensory and motor block duration and time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in group RD (P < 0.05) than group R. Post-operative VAS value at 12 h were significantly lower in group RD (P < 0.05). Intra-operative hemodynamics were significantly lower in group RD (P < 0.05) without any appreciable side-effects. CONCLUSION: It can be concluded that adding dexmedetomidine to supraclavicular brachial plexus block increases the sensory and motor block duration and time to first analgesic use, and decreases total analgesic use with no side-effects. PMID- 25538528 TI - The efficacy of adding dexamethasone, midazolam, or epinephrine to 0.5% bupivacaine in supraclavicular brachial plexus block. AB - AIMS: The aim was to assess the effectiveness of adding either dexamethasone or midazolam in comparison with epinephrine addition to 0.5% bupivacaine in supraclavicular brachial plexus block. SETTINGS AND DESIGN: This is a prospective randomized controlled observer-blinded study. SUBJECTS AND METHODS: This study was carried out in Tanta University Hospital on 60 patients of both sexes; American Society of Anesthesiologists physical Status I and II, age range from 18 to 45 years undergo elective surgery to upper limb. All patients were anesthetized with ultrasound guided supraclavicular brachial plexus block and randomly divided into three groups (each group 20 patients) Group E (epinephrine): 30 mL bupivacaine 0.5%with 1:200,000 epinephrine (5 MUg/mL). Group D (dexamethasone): 30 mL bupivacaine 0.5% and dexamethasone 8 mg. Group M (midazolam): 30 ml bupivacaine 0.5% and midazolam 50 MUg/kg. The primary outcome measures were onset and duration of sensory and motor block and time to first analgesic request. STATISTICAL ANALYSIS USED: The windows version of SPSS 11.0.1 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Data were presented in form of mean +/- standard deviation multiple analysis of variance (ANOVA) was used to compare the three groups and Scheffe test was used after ANOVA. Power of significance P < 0.05 was considered to be statistically significant. RESULTS: Onset of sensory and motor block was significantly rapid (P < 0.05) in Groups D and M in comparison with Group E. Time of administration of rescue analgesic, duration of sensory and motor block showed significant increase (P < 0.05) in Group D in comparison with Group M which showed significant increase (P < 0.05) in comparison with Group E. CONCLUSIONS: In comparison with epinephrine and midazolam addition of dexamethasone to bupivacaine had rapid onset of block and longer time to first analgesic request with fewer side effects. PMID- 25538529 TI - A 5-year observational study of cancellations in the operating room: Does the introduction of preoperative preparation have an impact? AB - BACKGROUND: Preoperative preparation (assessment) of patients reduces cancellations on the day of surgery. A Center for Reviews and Dissemination review (2007) concluded "the evidence was weak and it was uncertain that preassessment reduced cancellations." The aim of this study was to observe the impact of a preoperative preparation clinic on cancellations of operating room cases on the day of surgery, and in particular on those causes of cancellation on the day of surgery which were expected to be affected by preoperative preparation. MATERIALS AND METHODS: Observational study conducted in a 194 bed District General Hospital in the United Kingdom from April 1, 2006 to March 31, 2011. 42,082 operating room cases were scheduled for operation during this period. Surgical sessions which did not require anesthetic input were excluded. Contemporaneous data were collected and analyzed on a monthly basis, and also grouped by year over a 5-year period. The cancellations on the day of surgery were divided into two groups: Those considered to be affected by preoperative preparation and those which were not. Comparisons were made between these two groups and between individual reasons for cancellation. RESULTS: A total of 28,928 cases met the inclusion criteria. The clinic introduction reduced cancellations considered to be affected by preoperative preparation from 462 to 177 (78% and 42% total cancellations, respectively) (P < 0.001). There was a decrease in cancellations due to patients who did not arrive (P < 0.001) and medical reasons (P < 0.001), but an increase in the number of cancellations by the patients themselves (P = 0.002). Cancellations due to lack of beds and "other" reasons both increased (P < 0.001) across the study period. CONCLUSIONS: This study suggests that the introduction of preoperative preparation clinics for patients reduces cancellations on the day of surgery. PMID- 25538530 TI - Hospital acquired blood stream infection as an adverse outcome for patients admitted to hospital with other principle diagnosis. AB - BACKGROUND: Hospital acquired infections (HAI) have emerged as an important public health problem and are a leading cause of morbidity and mortality worldwide. They affect both developed and resource-poor countries and constitute a significant burden both for the patient and for the health care system. Specific objectives in this study are assessment of HAI rate among patients admitted with other principle diagnosis, to identifying the causative agents of hospital acquired infections and to identify some possible risk factors associated with each type of infection, both health related and non-health related. PATIENTS AND METHODS: The study was done on selected diagnosis groups during year 2010. The infections were found among 250 patients (43.6% males) have been exposed to episodes of infections. Median age of patients was 56. Data were abstracted from the archived patients' files in medical record department using the annually infection control log-book prepared by the infection control department. The Data collected were demographic information about the patients (age and sex), clinical condition (diagnosis and the length of hospital stay) and possible risk factors for infection as smoking, diabetes mellitus, hypertension and exposure to invasive devices or exposure to surgical procedures. RESULTS: Liver diseases 22.8%, cardiac diseases 22.8%, Gastro-Intestinal System diseases 20%, urinary system diseases 13.6%, and endocrinal disorder 13.6% Prostate gland diseases 7.2%. Episodes of infections caused by 9 types of organisms divided into 47.2% for blood stream infection and 52.8% for other types. 66% acquired blood stream infection were exposed to central venous line. CONCLUSION: Most common type of HAIs was blood stream infections. Liver, cardiac diseases and gastro intestinal diseased patients show more proportion of HAIs while urinary system and prostate disease patients show less proportion of HAIs. Gram negative bacilli were the most common organisms found in our study (60%). PMID- 25538532 TI - Successful management of difficult airway in an adult patient of Goldenhar syndrome. AB - The present case emphasizes on the increasing difficulty in management of patients with Goldenhar syndrome as they age. Fiberoptic intubation using high dose dexmedetomidine along with local anesthetics is a safe technique for securing the airway in a difficult situation, even if the patient dose not cooperates for awake procedure. A16-year-old Goldenhar patient with multiple facial deformities was scheduled for correction of hollowness of right cheek and was successfully managed with high dose dexmedetomidine infusion along with local anesthetics to facilitate fiberoptic intubation with no untoward side-effects. PMID- 25538531 TI - Neonatal pain management. AB - The past 2-3 decades have seen dramatic changes in the approach to pain management in the neonate. These practices started with refuting previously held misconceptions regarding nociception in preterm infants. Although neonates were initially thought to have limited response to painful stimuli, it was demonstrated that the developmental immaturity of the central nervous system makes the neonate more likely to feel pain. It was further demonstrated that untreated pain can have long-lasting physiologic and neurodevelopmental consequences. These concerns have resulted in a significant emphasis on improving and optimizing the techniques of analgesia for neonates and infants. The following article will review techniques for pain assessment, prevention, and treatment in this population with a specific focus on acute pain related to medical and surgical conditions. PMID- 25538533 TI - Data collection and data sharing - the holy gral of transfusion medicine and modern bioscience. PMID- 25538534 TI - DGTI Register of Rare Donors. AB - For patients with antibodies against the most common blood groups a rapid and efficient supply of compatible erythrocyte concentrates is self-evident. But typically we have to make the greatest effort providing blood for these patients, which have made antibodies against common blood groups. There are however patients with antibodies against rare blood group antigens that need special blood. The supply of such blood can be very difficult and mostly time-consuming. For this reason we set up a database of blood donors with rare blood groups. Since 2005 the BTS SRC Berne Ltd. has run this database on behalf of the Swiss BTS SRC. After a reorganization and extension of the database, conducted during 2011/2012, the data file was renamed 'DGTI Register of Rare Donors' and is now run under the patronage of the German Society for Transfusion Medicine and Immunohematology (DGTI). PMID- 25538535 TI - REGGI and the American Rare Donor Program. AB - The American Rare Donor Program (ARDP) was formed in 1998 to provide rare blood units for patients in need. Members of the program identify rare donors and submit donor information for entrance into a database, REGGI. Information on patients in need of rare blood is also submitted and entered into REGGI. REGGI serves to match phenotypes of registered donors with patients having the respective antibodies. A search process for available units ensues, and blood is provided to the patient. This report provides information on REGGI and its use in the ARDP. PMID- 25538536 TI - BGMUT Database of Allelic Variants of Genes Encoding Human Blood Group Antigens. AB - The Blood group antigen Gene MUTation (BGMUT) database documents variations in genes of human blood group systems. In March 2014, the database, accessible at www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut, listed 1,545 alleles of 44 genes of 34 blood group systems. Besides allelic information, the BGMUT resource also presents comprehensive and current information on blood group systems. This review describes the database and notes its utility for the transfusion medicine and human genetics communities. PMID- 25538537 TI - Allele frequencies database. AB - This review describes a database for the collection, archiving, sorting, searching and display of gene and allele frequencies for immunogenetic genes. PMID- 25538538 TI - The Rhesus Site. AB - The Rhesus Site is a resource for information of the 'Rhesus' blood group. It is intended for specialists and non-specialists. The website details research in the field relevant for transfusion medicine, immunohematology, and molecular research. Link areas guide to important publications and to methodological resources for Rhesus. Many data originally presented at The Rhesus Site have been formally published later. The 'RhesusBase' section represents the largest database for RHD alleles; the 'RhesusSurveillance' section details the results of the largest prospective observational study on anti-D immunization events in D positive patients. Visitors to the website are encouraged to explore the intricacies of the most complex blood group gene locus. PMID- 25538539 TI - All Information Is Not Equal: Using the Literature Databases PubMed and The Cochrane Library for Identifying the Evidence on Granulocyte Transfusion Therapy. AB - To be able to take well-informed decisions or carry out sound research, clinicians and researchers alike require specific information seeking skills matching their respective information needs. Biomedical information is traditionally available via different literature databases. This article gives an introduction to two diverging sources, PubMed (23 million references) and The Cochrane Library (800,000 references), both of which offer sophisticated instruments for searching an increasing amount of medical publications of varied quality and ambition. Whereas PubMed as an unfiltered source of primary literature comprises all different kinds of publication types occurring in academic journals, The Cochrane Library is a pre-filtered source which offers access to either synthesized publication types or critically appraised and carefully selected references. A search approach has to be carried out deliberately and requires a good knowledge on the scope and features of the databases as well as on the ability to build a search strategy in a structured way. We present a specific and a sensitive search approach, making use of both databases within two application case scenarios in order to identify the evidence on granulocyte transfusions for infections in adult patients with neutropenia. PMID- 25538540 TI - Two Novel alpha 1,2-Fucosyltransferase Alleles in an H-Deficient Phenotype Individual. AB - BACKGROUND: Abnormal alpha1,2-fucosyltransferase activity due to gene mutation results in decreased synthesis of H antigen and leads to an H-deficient phenotype. Here we studied the underlying molecular mechanisms in 7 Chinese blood donors with the H-deficient phenotype. METHODS: Red blood cell typing was performed using standard serologic tests, and ABO genotype was analyzed using ABO polymerase chain reaction with sequence-specific primer tests. The coding sequence of the FUT1 gene was amplified using the specific primers. The FUT1 alleles were identified by a pCRII-TOPO carrier for TOPO TA cloning sequencing. RESULTS: The H-deficient phenotype frequency was estimated to be approximately 1/30,000 (6/159,515) in the Chinese Han population. The FUT1 gene mutation was demonstrated in 6 Chinese blood donors with the H-deficient phenotype. In only 1 case, no mutation was detected. Novel FUT1 alleles were found in 1 donor. One of these novel FUT1 alleles showed nucleotide 35C>T and 748C>T site mutations that resulted in amino acid substitution of Ala to Val and Trp to Arg at positions 11 and 250, respectively. Another novel FUT1 allele had a nucleotide 655G>C site mutation, causing amino acid substitution of Leu to Val at position 219. CONCLUSIONS: Two novel FUT1 alleles, 35T+748T and 655C, were identified that may greatly diminish the activity of alpha1,2-fucosyltransferase and result in the H deficient phenotype. PMID- 25538541 TI - Long-Term Treatment and Transfusion of Normal Blood Components Following Tolerance Induction in Patients with Anti-IgA Anaphylactic Reactions. AB - BACKGROUND: In general, patients with significant anti-Ig-A do not tolerate intravenous (i.v.) administration of normal blood products. Here, we present our experiences in the induction of immune tolerance (IIT) and long-term treatment in a series of such patients affected in such a way. The question whether blood components from IgA-deficient donors are required will be discussed. METHODS: Ten adult patients (4 females and 6 males; age ranging from 36 to 75 years) with anti IgA were included in this study. All patients required long-term treatment with blood components. One patient had IgA deficiency and paroxysmal nocturnal hemoglobinuria (PNH), and all other patients had common variable immunodeficiency (CVID). The particle gel immunoassay was used for the detection of anti-IgA. Immune tolerance to IgA was induced by controlled subcutaneous (s.c.) and/or i.v. infusions of IgG preparations. RESULTS: Prior to IIT, anti-IgA was detectable in plasma samples of all patients and significantly diminished or abolished by controlled s.c. and/or i.v. infusions of IgG. Multiple transfusions with normal blood components could be repeatedly performed with the patient suffering from PNH without any complications. As long as i.v. IgG (IVIgG) infusions were consequently administered as individually required (intervals 2-8 weeks), none of the patients developed reactions during observation (up to 10 years). However, interruption of treatment and re-exposure to IVIgG resulted in adverse reactions. CONCLUSION: Patients with significant anti-IgA can be safely desensitized and tolerate long-term IgG substitutions independent of the IgA concentration of the used blood component. PMID- 25538542 TI - Unexpected Hypotensive Events during Preparatory Plasmaphereses. PMID- 25538543 TI - An acoustic gap between the NICU and womb: a potential risk for compromised neuroplasticity of the auditory system in preterm infants. AB - The intrauterine environment allows the fetus to begin hearing low-frequency sounds in a protected fashion, ensuring initial optimal development of the peripheral and central auditory system. However, the auditory nursery provided by the womb vanishes once the preterm newborn enters the high-frequency (HF) noisy environment of the neonatal intensive care unit (NICU). The present article draws a concerning line between auditory system development and HF noise in the NICU, which we argue is not necessarily conducive to fostering this development. Overexposure to HF noise during critical periods disrupts the functional organization of auditory cortical circuits. As a result, we theorize that the ability to tune out noise and extract acoustic information in a noisy environment may be impaired, leading to increased risks for a variety of auditory, language, and attention disorders. Additionally, HF noise in the NICU often masks human speech sounds, further limiting quality exposure to linguistic stimuli. Understanding the impact of the sound environment on the developing auditory system is an important first step in meeting the developmental demands of preterm newborns undergoing intensive care. PMID- 25538544 TI - Cognitive state monitoring and the design of adaptive instruction in digital environments: lessons learned from cognitive workload assessment using a passive brain-computer interface approach. AB - According to Cognitive Load Theory (CLT), one of the crucial factors for successful learning is the type and amount of working-memory load (WML) learners experience while studying instructional materials. Optimal learning conditions are characterized by providing challenges for learners without inducing cognitive over- or underload. Thus, presenting instruction in a way that WML is constantly held within an optimal range with regard to learners' working-memory capacity might be a good method to provide these optimal conditions. The current paper elaborates how digital learning environments, which achieve this goal can be developed by combining approaches from Cognitive Psychology, Neuroscience, and Computer Science. One of the biggest obstacles that needs to be overcome is the lack of an unobtrusive method of continuously assessing learners' WML in real time. We propose to solve this problem by applying passive Brain-Computer Interface (BCI) approaches to realistic learning scenarios in digital environments. In this paper we discuss the methodological and theoretical prospects and pitfalls of this approach based on results from the literature and from our own research. We present a strategy on how several inherent challenges of applying BCIs to WML and learning can be met by refining the psychological constructs behind WML, by exploring their neural signatures, by using these insights for sophisticated task designs, and by optimizing algorithms for analyzing electroencephalography (EEG) data. Based on this strategy we applied machine-learning algorithms for cross-task classifications of different levels of WML to tasks that involve studying realistic instructional materials. We obtained very promising results that yield several recommendations for future work. PMID- 25538546 TI - ERP correlates of word production predictors in picture naming: a trial by trial multiple regression analysis from stimulus onset to response. AB - A major effort in cognitive neuroscience of language is to define the temporal and spatial characteristics of the core cognitive processes involved in word production. One approach consists in studying the effects of linguistic and pre linguistic variables in picture naming tasks. So far, studies have analyzed event related potentials (ERPs) during word production by examining one or two variables with factorial designs. Here we extended this approach by investigating simultaneously the effects of multiple theoretical relevant predictors in a picture naming task. High density EEG was recorded on 31 participants during overt naming of 100 pictures. ERPs were extracted on a trial by trial basis from picture onset to 100 ms before the onset of articulation. Mixed-effects regression models were conducted to examine which variables affected production latencies and the duration of periods of stable electrophysiological patterns (topographic maps). Results revealed an effect of a pre-linguistic variable, visual complexity, on an early period of stable electric field at scalp, from 140 to 180 ms after picture presentation, a result consistent with the proposal that this time period is associated with visual object recognition processes. Three other variables, word Age of Acquisition, Name Agreement, and Image Agreement influenced response latencies and modulated ERPs from ~380 ms to the end of the analyzed period. These results demonstrate that a topographic analysis fitted into the single trial ERPs and covering the entire processing period allows one to associate the cost generated by psycholinguistic variables to the duration of specific stable electrophysiological processes and to pinpoint the precise time course of multiple word production predictors at once. PMID- 25538545 TI - Functional and molecular neuroimaging of menopause and hormone replacement therapy. AB - The level of gonadal hormones to which the female brain is exposed considerably changes across the menopausal transition, which in turn, is likely to be of great relevance for neurodegenerative diseases and psychiatric disorders. However, the neurobiological consequences of these hormone fluctuations and of hormone replacement therapy in the menopause have only begun to be understood. The present review summarizes the findings of thirty-five studies of human brain function, including functional magnetic resonance imaging, positron and single photon computed emission tomography studies, in peri- and postmenopausal women treated with estrogen, or estrogen-progestagen replacement therapy. Seven studies using gonadotropin-releasing hormone agonist intervention as a model of hormonal withdrawal are also included. Cognitive paradigms are employed by the majority of studies evaluating the effect of unopposed estrogen or estrogen-progestagen treatment on peri- and postmenopausal women's brain. In randomized-controlled trials, estrogen treatment enhances activation of fronto-cingulate regions during cognitive functioning, though in many cases no difference in cognitive performance was present. Progestagens seems to counteract the effects of estrogens. Findings on cognitive functioning during acute ovarian hormone withdrawal suggest a decrease in activation of the left inferior frontal gyrus, thus essentially corroborating the findings in postmenopausal women. Studies of the cholinergic and serotonergic systems indicate these systems as biological mediators of hormonal influences on the brain. More, hormonal replacement appears to increase cerebral blood flow in several cortical regions. On the other hand, studies on emotion processing in postmenopausal women are lacking. These results call for well-powered randomized-controlled multi-modal prospective neuroimaging studies as well as investigation on the related molecular mechanisms of effects of menopausal hormonal variations on the brain. PMID- 25538547 TI - Relating hearing loss and executive functions to hearing aid users' preference for, and speech recognition with, different combinations of binaural noise reduction and microphone directionality. AB - Knowledge of how executive functions relate to preferred hearing aid (HA) processing is sparse and seemingly inconsistent with related knowledge for speech recognition outcomes. This study thus aimed to find out if (1) performance on a measure of reading span (RS) is related to preferred binaural noise reduction (NR) strength, (2) similar relations exist for two different, non-verbal measures of executive function, (3) pure-tone average hearing loss (PTA), signal-to-noise ratio (SNR), and microphone directionality (DIR) also influence preferred NR strength, and (4) preference and speech recognition outcomes are similar. Sixty elderly HA users took part. Six HA conditions consisting of omnidirectional or cardioid microphones followed by inactive, moderate, or strong binaural NR as well as linear amplification were tested. Outcome was assessed at fixed SNRs using headphone simulations of a frontal target talker in a busy cafeteria. Analyses showed positive effects of active NR and DIR on preference, and negative and positive effects of, respectively, strong NR and DIR on speech recognition. Also, while moderate NR was the most preferred NR setting overall, preference for strong NR increased with SNR. No relation between RS and preference was found. However, larger PTA was related to weaker preference for inactive NR and stronger preference for strong NR for both microphone modes. Equivalent (but weaker) relations between worse performance on one non-verbal measure of executive function and the HA conditions without DIR were found. For speech recognition, there were relations between HA condition, PTA, and RS, but their pattern differed from that for preference. Altogether, these results indicate that, while moderate NR works well in general, a notable proportion of HA users prefer stronger NR. Furthermore, PTA and executive functions can account for some of the variability in preference for, and speech recognition with, different binaural NR and DIR settings. PMID- 25538548 TI - Age-related decreased inhibitory vs. excitatory gene expression in the adult autistic brain. AB - Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted behavior and interests. A disruption in the balance of excitatory and inhibitory neurotransmission has been hypothesized to underlie these disorders. Here we demonstrate that genes of both pathways are affected by ASD, and that gene expression of inhibitory and excitatory genes is altered in the cerebral cortex of adult but not younger autistic individuals. We have developed a measure for the difference in the level of excitation and inhibition based on gene expression and observe that in this measure inhibition is decreased relative to excitation in adult ASD compared to control. This difference was undetectable in young autistic brains. Given that many psychiatric features of autism are already present at an early age, this suggests that the observed imbalance in gene expression is an aging phenomenon in ASD rather than its underlying cause. PMID- 25538549 TI - Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia. AB - Negative symptoms (e.g., decreased spontaneity, social withdrawal, blunt affect) and disturbances of cognitive function (e.g., several types of memory, attention, processing speed, executive function, fluency) provide a major determinant of long-term outcome in patients with schizophrenia. Specifically, motivation deficits, a type of negative symptoms, have been attracting interest as (1) a moderator of cognitive performance in schizophrenia and related disorders, and (2) a modulating factor of cognitive enhancers/remediation. These considerations suggest the need to clarify neurobiological substrates regulating motivation. Genetic studies indicate a role for the monoamine systems in motivation and key cognitive domains. For example, polymorphism of genes encoding catecholamine-O methyltransferase, an enzyme catabolizing dopamine (DA), affects performance on tests of working memory and executive function in a phenotype (schizophrenia vs. healthy controls)-dependent fashion. On the other hand, motivation to maximize rewards has been shown to be influenced by other genes encoding DA-related substrates, such as DARPP-32 and DA-D2 receptors. Serotonin (5-HT) receptors may also play a significant role in cognitive and motivational disabilities in psychoses and mood disorders. For example, mutant mice over-expressing D2 receptors in the striatum, an animal model of schizophrenia, exhibit both decreased willingness to work for reward and up-regulation of 5-HT2C receptors. Taken together, genetic predisposition related to 5-HT receptors may mediate the diversity of incentive motivation that is impaired in patients receiving biological and/or psychosocial treatments. Thus, research into genetic and neurobiological measures of motivation, in association with 5-HT receptors, is likely to facilitate intervention into patients seeking better social consequences. PMID- 25538550 TI - Brain dynamics that correlate with effects of learning on auditory distance perception. AB - Accuracy in auditory distance perception can improve with practice and varies for sounds differing in familiarity. Here, listeners were trained to judge the distances of English, Bengali, and backwards speech sources pre-recorded at near (2-m) and far (30-m) distances. Listeners' accuracy was tested before and after training. Improvements from pre-test to post-test were greater for forward speech, demonstrating a learning advantage for forward speech sounds. Independent component (IC) processes identified in electroencephalographic (EEG) data collected during pre- and post-testing revealed three clusters of ICs across subjects with stimulus-locked spectral perturbations related to learning and accuracy. One cluster exhibited a transient stimulus-locked increase in 4-8 Hz power (theta event-related synchronization; ERS) that was smaller after training and largest for backwards speech. For a left temporal cluster, 8-12 Hz decreases in power (alpha event-related desynchronization; ERD) were greatest for English speech and less prominent after training. In contrast, a cluster of IC processes centered at or near anterior portions of the medial frontal cortex showed learning-related enhancement of sustained increases in 10-16 Hz power (upper alpha/low-beta ERS). The degree of this enhancement was positively correlated with the degree of behavioral improvements. Results suggest that neural dynamics in non-auditory cortical areas support distance judgments. Further, frontal cortical networks associated with attentional and/or working memory processes appear to play a role in perceptual learning for source distance. PMID- 25538551 TI - The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases. AB - DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC) modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC), which is formed by oxidation of 5mC by ten-eleven translocation (TET) enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS). The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA), Huntington's disease (HD), and Parkinson's disease (PD). PMID- 25538553 TI - Cardiovascular state changes in simulated work environments. AB - The usefulness of cardiovascular measures as indicators of changes in cognitive workload has been addressed in several studies. In this paper the question is explored whether cardiovascular patterns in heart rate, blood pressure, baroreflex sensitivity and HRV that are found are consistent within and between two simulated working environments. Two studies, were performed, both with 21 participants: one in an ambulance dispatch simulation and one in a driving simulator. In the ambulance dispatcher task an initial strong increase in blood pressure is followed by a moderate on-going increase in blood pressure during the next hour of task performance. This pattern is accompanied by a strong increase in baroreflex sensitivity while heart rate decreases. In the driving simulator study, blood pressure initially increases but decreases almost to baseline level in the next hour. This pattern is accompanied by a decrease in baroreflex sensitivity, while heart rate decreases. Results of both studies are interpreted in terms of autonomic control (related to both sympathetic and para-sympathetic effects), using a simplified simulation of a baroreflex regulation model. Interpretation of the results leads to the conclusion that the cardiovascular response patterns in both tasks are a combination of an initial defensive reaction, in combination with compensatory blood pressure control. The level of compensatory blood pressure control, however, is quite different for the two tasks. This helps to understand the differences in response patterns between the two studies in this paper and may be helpful as well for understanding differences in cardiovascular response patterns in general. A substantial part of the effects observed during task performance are regulatory effects and are not always directly related to workload manipulations. Making this distinction may also contribute to the understanding of differences in cardiovascular response patterns during cognitive workload. PMID- 25538552 TI - Energy substrates that fuel fast neuronal network oscillations. AB - Fast neuronal network oscillations in the gamma-frequency band (30--100 Hz) provide a fundamental mechanism of complex neuronal information processing in the hippocampus and neocortex of mammals. Gamma oscillations have been implicated in higher brain functions such as sensory perception, motor activity, and memory formation. The oscillations emerge from precise synapse interactions between excitatory principal neurons such as pyramidal cells and inhibitory GABAergic interneurons, and they are associated with high energy expenditure. However, both energy substrates and metabolic pathways that are capable to power cortical gamma oscillations have been less defined. Here, we investigated the energy sources fueling persistent gamma oscillations in the CA3 subfield of organotypic hippocampal slice cultures of the rat. This preparation permits superior oxygen supply as well as fast application of glucose, glycolytic metabolites or drugs such as glycogen phosphorylase inhibitor during extracellular recordings of the local field potential. Our findings are: (i) gamma oscillations persist in the presence of glucose (10 mmol/L) for greater than 60 min in slice cultures while (ii) lowering glucose levels (2.5 mmol/L) significantly reduces the amplitude of the oscillation. (iii) Gamma oscillations are absent at low concentration of lactate (2 mmol/L). (iv) Gamma oscillations persist at high concentration (20 mmol/L) of either lactate or pyruvate, albeit showing significant reductions in the amplitude. (v) The breakdown of glycogen significantly delays the decay of gamma oscillations during glucose deprivation. However, when glucose is present, the turnover of glycogen is not essential to sustain gamma oscillations. Our study shows that fast neuronal network oscillations can be fueled by different energy-rich substrates, with glucose being most effective. PMID- 25538554 TI - GASICA: generic automated stress induction and control application design of an application for controlling the stress state. AB - In a multitude of research and therapy paradigms it is relevant to know, and desirably to control, the stress state of a patient or participant. Examples include research paradigms in which the stress state is the dependent or independent variable, or therapy paradigms where this state indicates the boundaries of the therapy. To our knowledge, no application currently exists that focuses specifically on the automated control of the stress state while at the same time being generic enough to be used in various therapy and research purposes. Therefore, we introduce GASICA, an application aimed at the automated control of the stress state in a multitude of therapy and research paradigms. The application consists of three components: a digital stressor game, a set of measurement devices, and a feedback model. These three components form a closed loop (called a biocybernetic loop by Pope et al. (1995) and Fairclough (2009) that continuously presents an acute psychological stressor, measures several physiological responses to this stressor, and adjusts the stressor intensity based on these measurements by means of the feedback model, hereby aiming to control the stress state. In this manner GASICA presents multidimensional and ecological valid stressors, whilst continuously in control of the form and intensity of the presented stressors, aiming at the automated control of the stress state. Furthermore, the application is designed as a modular open-source application to easily implement different therapy and research tasks using a high level programming interface and configuration file, and allows for the addition of (existing) measurement equipment, making it usable for various paradigms. PMID- 25538555 TI - How to be patient. The ability to wait for a reward depends on menstrual cycle phase and feedback-related activity. AB - Dopamine (DA) plays a major role in reinforcement learning with increases promoting reward sensitivity (Go learning) while decreases facilitate the avoidance of negative outcomes (NoGo learning). This is also reflected in adaptations of response time: higher levels of DA enhance speeding up to get a reward, whereas lower levels favor slowing down. The steroid hormones estradiol and progesterone have been shown to modulate dopaminergic tone. Here, we tested 14 women twice during their menstrual cycle, during the follicular (FP) and the luteal phase (LP), applying functional magnetic resonance imaging while they performed a feedback learning task. Subsequent behavioral testing assessed response time preferences with a clock task, in which subjects had to explore the optimal response time (RT) to maximize reward. In the FP subjects displayed a greater learning-related change of their RT than during the LP, when they were required to slow down. Final RTs in the slow condition were also predicted by feedback-related brain activation, but only in the FP. Increased activation of the inferior frontal junction and rostral cingulate zone was thereby predictive of slower and thus better adapted final RTs. Conversely, final RT was faster and less optimal for reward maximization if activation in the ventromedial prefrontal cortex was enhanced. These findings show that hormonal shifts across the menstrual cycle affect adaptation of response speed during reward acquisition with higher RT adjustment in the FP in the condition that requires slowing down. Since high estradiol levels during the FP increase synaptic DA levels, this conforms well to our hypothesis that estradiol supports Go learning at the expense of NoGo learning. Brain-behavior correlations further indicated that the compensatory capacity to counteract the follicular Go bias may be linked to the ability to more effectively monitor action outcomes and suppress bottom-up reward desiring during feedback processing. PMID- 25538556 TI - A systematic framework for functional connectivity measures. AB - Various methods have been proposed to characterize the functional connectivity between nodes in a network measured with different modalities (electrophysiology, functional magnetic resonance imaging etc.). Since different measures of functional connectivity yield different results for the same dataset, it is important to assess when and how they can be used. In this work, we provide a systematic framework for evaluating the performance of a large range of functional connectivity measures-based upon a comprehensive portfolio of models generating measurable responses. Specifically, we benchmarked 42 methods using 10,000 simulated datasets from 5 different types of generative models with different connectivity structures. Since all functional connectivity methods require the setting of some parameters (window size and number, model order etc.), we first optimized these parameters using performance criteria based upon (threshold free) ROC analysis. We then evaluated the performance of the methods on data simulated with different types of models. Finally, we assessed the performance of the methods against different levels of signal-to-noise ratios and network configurations. A MATLAB toolbox is provided to perform such analyses using other methods and simulated datasets. PMID- 25538557 TI - The mitochondrial L-lactate dehydrogenase affair. PMID- 25538559 TI - Rapid regulation of microRNA following induction of long-term potentiation in vivo. AB - Coordinated regulation of gene expression is essential for consolidation of the memory mechanism, long-term potentiation (LTP). Triggering of LTP by N-methyl-D aspartate receptor (NMDAR) activation rapidly activates constitutive and inducible transcription factors, which promote expression of genes responsible for LTP maintenance. As microRNA (miRNA) coordinate expression of genes related through seed sites, we hypothesize that miRNA contribute to the regulation of the LTP-induced gene response. MiRNA function primarily as negative regulators of gene expression. As LTP induction promotes a generalized rapid up-regulation of gene expression, we predicted a complementary rapid down-regulation of miRNA levels. Accordingly, we carried out global miRNA expression profiling in the rat dentate gyrus 20 min post-LTP induction in vivo. Consistent with our hypothesis, we found a large number of differentially expressed miRNA, the majority down regulated. Detailed analysis of miR-34a-5p and miR-132-3p revealed this down regulation was transient and NMDAR-dependent, whereby block of NMDARs released an activity-associated inhibitory mechanism. Furthermore, down-regulation of mature miR-34a-5p and miR-132-3p occurred solely by post-transcriptional mechanisms, occurring despite an associated up-regulation of the pri-miR-132 transcript. To understand how down-regulation of miR-34a-5p and miR-132-3p intersects with the molecular events occurring following LTP, we used bioinformatics to identify potential targets. Previously validated targets included the key LTP-regulated genes Arc and glutamate receptor subunits. Predicted targets included the LTP linked kinase, Mapk1, and neuropil-associated transcripts Hn1 and Klhl11, which were validated using luciferase reporter assays. Furthermore, we found that the level of p42-Mapk1, the protein encoded by the Mapk1 transcript, was up-regulated following LTP. Together, these data support the interpretation that miRNA, in particular miR-34a-5p and miR-132-3p, make a surprisingly rapid contribution to synaptic plasticity via dis-inhibition of translation of key plasticity-related molecules. PMID- 25538558 TI - Monitoring activity in neural circuits with genetically encoded indicators. AB - Recent developments in genetically encoded indicators of neural activity (GINAs) have greatly advanced the field of systems neuroscience. As they are encoded by DNA, GINAs can be targeted to genetically defined cellular populations. Combined with fluorescence microscopy, most notably multi-photon imaging, GINAs allow chronic simultaneous optical recordings from large populations of neurons or glial cells in awake, behaving mammals, particularly rodents. This large-scale recording of neural activity at multiple temporal and spatial scales has greatly advanced our understanding of the dynamics of neural circuitry underlying behavior-a critical first step toward understanding the complexities of brain function, such as sensorimotor integration and learning. Here, we summarize the recent development and applications of the major classes of GINAs. In particular, we take an in-depth look at the design of available GINA families with a particular focus on genetically encoded calcium indicators (GCaMPs), sensors probing synaptic activity, and genetically encoded voltage indicators. Using the family of the GCaMP as an example, we review established sensor optimization pipelines. We also discuss practical considerations for end users of GINAs about experimental methods including approaches for gene delivery, imaging system requirements, and data analysis techniques. With the growing toolbox of GINAs and with new microscopy techniques pushing beyond their current limits, the age of light can finally achieve the goal of broad and dense sampling of neuronal activity across time and brain structures to obtain a dynamic picture of brain function. PMID- 25538560 TI - Visualization of cyclic nucleotide dynamics in neurons. AB - The second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) transduce many neuromodulatory signals from hormones and neurotransmitters into specific functional outputs. Their production, degradation and signaling are spatiotemporally regulated to achieve high specificity in signal transduction. The development of genetically encodable fluorescent biosensors has provided researchers with useful tools to study these versatile second messengers and their downstream effectors with unparalleled spatial and temporal resolution in cultured cells and living animals. In this review, we introduce the general design of these fluorescent biosensors and describe several of them in more detail. Then we discuss a few examples of using cyclic nucleotide fluorescent biosensors to study regulation of neuronal function and finish with a discussion of advances in the field. Although there has been significant progress made in understanding how the specific signaling of cyclic nucleotide second messengers is achieved, the mechanistic details in complex cell types like neurons are only just beginning to surface. Current and future fluorescent protein reporters will be essential to elucidate the role of cyclic nucleotide signaling dynamics in the functions of individual neurons and their networks. PMID- 25538561 TI - Spontaneous vesicle recycling in the synaptic bouton. AB - The trigger for synaptic vesicle exocytosis is Ca(2+), which enters the synaptic bouton following action potential stimulation. However, spontaneous release of neurotransmitter also occurs in the absence of stimulation in virtually all synaptic boutons. It has long been thought that this represents exocytosis driven by fluctuations in local Ca(2+) levels. The vesicles responding to these fluctuations are thought to be the same ones that release upon stimulation, albeit potentially triggered by different Ca(2+) sensors. This view has been challenged by several recent works, which have suggested that spontaneous release is driven by a separate pool of synaptic vesicles. Numerous articles appeared during the last few years in support of each of these hypotheses, and it has been challenging to bring them into accord. We speculate here on the origins of this controversy, and propose a solution that is related to developmental effects. Constitutive membrane traffic, needed for the biogenesis of vesicles and synapses, is responsible for high levels of spontaneous membrane fusion in young neurons, probably independent of Ca(2+). The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs) rather than bona fide synaptic vesicles. In mature neurons, constitutive traffic is much dampened, and the few remaining spontaneous release events probably represent bona fide spontaneously releasing synaptic vesicles (SRSVs) responding to Ca(2+) fluctuations, along with a handful of CRVs that participate in synaptic vesicle turnover. PMID- 25538562 TI - Granulocyte colony-stimulating factor (G-CSF) treatment in combination with transplantation of bone marrow cells is not superior to G-CSF treatment alone after cortical stroke in spontaneously hypertensive rats. AB - Granulocyte-colony stimulating factor (G-CSF) and bone marrow derived mononuclear cells (BM-MNCs) have both been shown to improve functional outcome following experimental stroke. These effects are associated with increased angiogenesis and neurogenesis. In the present study, we aimed to determine synergistic effects of G-CSF and BM-NMC treatment on long-term structural and functional recovery after photothrombotic stroke. To model the etiology of stroke more closely, we used spontaneously hypertensive (SH) rats in our experiment. Bone marrow derived mononuclear cells transplantation was initiated 1 h after the onset of photothrombotic stroke. Repeated G-CSF treatment commenced immediately after BM MNC treatment followed by daily injections for five consecutive days. The primary endpoint was functional outcome after ischemia. Secondary endpoints included analysis of neurogenesis and angiogenesis as well as determination of infarct size. Granulocyte-colony stimulating factor treated rats, either in combination with BM-MNC or alone showed improved somatosensory but not gross motor function following ischemia. No beneficial effect of BM-MNC monotherapy was found. Infarct volumes were comparable in all groups. In contrast to previous studies, which used healthy animals, post-stroke neurogenesis and angiogenesis were not enhanced by G-CSF. In conclusion, the combination of G-CSF and BM-MNC was not more effective than G-CSF alone. The reduced efficacy of G-CSF treatment and the absence of any beneficial effect of BM-MNC transplantation might be attributed to hypertension-related morbidity. PMID- 25538563 TI - Extracellular Na(+) levels regulate formation and activity of the NaX/alpha1 Na(+)/K(+)-ATPase complex in neuronal cells. AB - MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of extracellular sodium concentration ([Na(+)]out). The mechanism underlying Na(+)-sensing involves Na(+)-flow through the NaX channel, directly regulated by the Na(+)/K(+)-ATPase alpha1-isoform which controls Na(+) influx by modulating channel permeability. Together, these two partners form a complex involved in the regulation of intracellular sodium ([Na(+)]in). Here we aim to determine whether environmental changes in Na(+) could actively modulate the NaX/Na(+)/K(+)-ATPase complex activity. We investigated the complex activity using patch-clamp recordings from rat MnPO neurons and Neuro2a cells. When the rats were fed with a high-salt-diet, or the [Na(+)] in the culture medium was increased, the activity of the complex was up-regulated. In contrast, drop in environmental [Na(+)] decreased the activity of the complex. Interestingly under hypernatremic condition, the colocalization rate and protein level of both partners were up-regulated. Under hyponatremic condition, only NaX protein expression was increased and the level of NaX/Na(+)/K(+)-ATPase remained unaltered. This unbalance between NaX and Na(+)/K(+)-ATPase pump proportion would induce a bigger portion of Na(+)/K(+)-ATPase-control-free NaX channel. Thus, we suggest that hypernatremic environment increases NaX/Na(+)/K(+)-ATPase alpha1 isoform activity by increasing the number of both partners and their colocalization rate, whereas hyponatremic environment down-regulates complex activity via a decrease in the relative number of NaX channels controlled by the pump. PMID- 25538567 TI - 2015: which new directions for Alzheimer's disease? PMID- 25538566 TI - Global SUMOylation is a molecular mechanism underlying hypothermia-induced ischemic tolerance. AB - The molecular mechanisms underlying hypothermic neuroprotection have yet to be fully elucidated. Herein we demonstrate that global SUMOylation, a form of post translational modification with the Small Ubiquitin-like MOdifer, participates in the multimodal molecular induction of hypothermia-induced ischemic tolerance. Mild (32 degrees C) to moderate (28 degrees C) hypothermic treatment(s) during OGD (oxygen-glucose-deprivation) or ROG (restoration of oxygen/glucose) increased global SUMO-conjugation levels and protected cells (both SHSY5Y and E18 rat cortical neurons) from OGD and ROG-induced cell death. Hypothermic exposure either before or after permanent middle cerebral artery occlusion (pMCAO) surgery in wild type mice increased global SUMO-conjugation levels in the brain and in so doing protected these animals from pMCAO-induced ischemic damage. Of note, hypothermic exposure did not provide an additional increase in protection from pMCAO-induced ischemic brain damage in Ubc9 transgenic (Ubc9 Tg) mice, which overexpress the sole E2 SUMO conjugating enzyme and thereby display elevated basal levels of global SUMOylation under normothermic conditions. Such evidence suggests that increases in global SUMOylation are critical and may account for a substantial part of the observed increase in cellular tolerance to brain ischemia caused via hypothermia. PMID- 25538565 TI - GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics. AB - Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the delta, epsilon, and rho2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A gamma1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior. PMID- 25538564 TI - Convergence of circuit dysfunction in ASD: a common bridge between diverse genetic and environmental risk factors and common clinical electrophysiology. AB - Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD). Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents). Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD. PMID- 25538568 TI - The neuroimmune-neuroplasticity interface and brain pathology. PMID- 25538569 TI - Statistical analysis and data mining of digital reconstructions of dendritic morphologies. AB - Neuronal morphology is diverse among animal species, developmental stages, brain regions, and cell types. The geometry of individual neurons also varies substantially even within the same cell class. Moreover, specific histological, imaging, and reconstruction methodologies can differentially affect morphometric measures. The quantitative characterization of neuronal arbors is necessary for in-depth understanding of the structure-function relationship in nervous systems. The large collection of community-contributed digitally reconstructed neurons available at NeuroMorpho.Org constitutes a "big data" research opportunity for neuroscience discovery beyond the approaches typically pursued in single laboratories. To illustrate these potential and related challenges, we present a database-wide statistical analysis of dendritic arbors enabling the quantification of major morphological similarities and differences across broadly adopted metadata categories. Furthermore, we adopt a complementary unsupervised approach based on clustering and dimensionality reduction to identify the main morphological parameters leading to the most statistically informative structural classification. We find that specific combinations of measures related to branching density, overall size, tortuosity, bifurcation angles, arbor flatness, and topological asymmetry can capture anatomically and functionally relevant features of dendritic trees. The reported results only represent a small fraction of the relationships available for data exploration and hypothesis testing enabled by sharing of digital morphological reconstructions. PMID- 25538571 TI - DiI tracing of the hypothalamic projection systems during perinatal development. AB - The hypothalamus is the higher neuroendocrine center of the brain and therefore possesses numerous intrinsic axonal connections and is connected by afferent and efferent fiber systems with other brain structures. These projection systems have been described in detail in the adult but data on their early development is sparse. Here I review studies of the time schedule and features of the development of the major hypothalamic axonal systems. In general, anterograde tracing experiments have been used to analyze short distance projections from the arcuate and anteroventral periventricular nuclei (Pe), while hypothalamic projections to the posterior and intermediate pituitary lobes (IL) and median eminence, mammillary body tracts and reciprocal septohypothalamic connections have been described with retrograde tracing. The available data demonstrate that hypothalamic connections develop with a high degree of spatial and temporal specificity, innervating each target with a unique developmental schedule which in many cases can be correlated with the functional maturity of the projection system. PMID- 25538572 TI - Activity-dependent expression of neuronal PAS domain-containing protein 4 (npas4a) in the developing zebrafish brain. AB - In rodents, the Npas4 gene has recently been identified as being an important regulator of synaptic plasticity and memory. Homologs of Npas4 have been found in invertebrate species though their functions appear to be too divergent for them to be studied as a proxy for the mammalian proteins. The aim of this study, therefore, was to ascertain the suitability of the zebrafish as a model organism for investigating the function of Npas4 genes. We show here that the expression and regulation of the zebrafish Npas4 homolog, npas4a, is remarkably similar to that of the rodent Npas4 genes. As in mammals, expression of the zebrafish npas4a gene is restricted to the brain where it is up-regulated in response to neuronal activity. Furthermore, we also show that knockdown of npas4a during embryonic development results in a number of forebrain-specific defects including increased apoptosis and misexpression of the forebrain marker genes dlx1a and shha. Our work demonstrates that the zebrafish is a suitable model organism for investigating the role of the npas4a gene and one that is likely to provide valuable insights into the function of the mammalian homologs. Furthermore, our findings highlight a potential role for npas4a in forebrain development. PMID- 25538570 TI - Barriers in the brain: resolving dendritic spine morphology and compartmentalization. AB - Dendritic spines are micron-sized protrusions that harbor the majority of excitatory synapses in the central nervous system. The head of the spine is connected to the dendritic shaft by a 50-400 nm thin membrane tube, called the spine neck, which has been hypothesized to confine biochemical and electric signals within the spine compartment. Such compartmentalization could minimize interspinal crosstalk and thereby support spine-specific synapse plasticity. However, to what extent compartmentalization is governed by spine morphology, and in particular the diameter of the spine neck, has remained unresolved. Here, we review recent advances in tool development - both experimental and theoretical - that facilitate studying the role of the spine neck in compartmentalization. Special emphasis is given to recent advances in microscopy methods and quantitative modeling applications as we discuss compartmentalization of biochemical signals, membrane receptors and electrical signals in spines. Multidisciplinary approaches should help to answer how dendritic spine architecture affects the cellular and molecular processes required for synapse maintenance and modulation. PMID- 25538573 TI - Cognitive enhancement kept within contexts: neuroethics and informed public policy. AB - Neurothics has far greater responsibilities than merely noting potential human enhancements arriving from novel brain-centered biotechnologies and tracking their implications for ethics and civic life. Neuroethics must utilize the best cognitive and neuroscientific knowledge to shape incisive discussions about what could possibly count as enhancement in the first place, and what should count as genuinely "cognitive" enhancement. Where cognitive processing and the mental life is concerned, the lived context of psychological performance is paramount. Starting with an enhancement to the mental abilities of an individual, only performances on real-world exercises can determine what has actually been cognitively improved. And what can concretely counts as some specific sort of cognitive improvement is largely determined by the classificatory frameworks of cultures, not brain scans or laboratory experiments. Additionally, where the public must ultimately evaluate and judge the worthiness of individual performance enhancements, we mustn't presume that public approval towards enhancers will somehow automatically arrive without due regard to civic ideals such as the common good or social justice. In the absence of any nuanced appreciation for the control which performance contexts and public contexts exert over what "cognitive" enhancements could actually be, enthusiastic promoters of cognitive enhancement can all too easily depict safe and effective brain modifications as surely good for us and for society. These enthusiasts are not unaware of oft-heard observations about serious hurdles for reliable enhancement from neurophysiological modifications. Yet those observations are far more common than penetrating investigations into the implications to those hurdles for a sound public understanding of cognitive enhancement, and a wise policy review over cognitive enhancement. We offer some crucial recommendations for undertaking such investigations, so that cognitive enhancers that truly deserve public approval can be better identified. PMID- 25538575 TI - Educating the blind brain: a panorama of neural bases of vision and of training programs in organic neurovisual deficits. AB - Vision is a complex function, which is achieved by movements of the eyes to properly foveate targets at any location in 3D space and to continuously refresh neural information in the different visual pathways. The visual system involves five main routes originating in the retinas but varying in their destination within the brain: the occipital cortex, but also the superior colliculus (SC), the pretectum, the supra-chiasmatic nucleus, the nucleus of the optic tract and terminal dorsal, medial and lateral nuclei. Visual pathway architecture obeys systematization in sagittal and transversal planes so that visual information from left/right and upper/lower hemi-retinas, corresponding respectively to right/left and lower/upper visual fields, is processed ipsilaterally and ipsialtitudinally to hemi-retinas in left/right hemispheres and upper/lower fibers. Organic neurovisual deficits may occur at any level of this circuitry from the optic nerve to subcortical and cortical destinations, resulting in low or high-level visual deficits. In this didactic review article, we provide a panorama of the neural bases of eye movements and visual systems, and of related neurovisual deficits. Additionally, we briefly review the different schools of rehabilitation of organic neurovisual deficits, and show that whatever the emphasis is put on action or perception, benefits may be observed at both motor and perceptual levels. Given the extent of its neural bases in the brain, vision in its motor and perceptual aspects is also a useful tool to assess and modulate central nervous system (CNS) in general. PMID- 25538577 TI - Initiation of voluntary movements at free will and ongoing 0.1-Hz BOLD oscillations in the insula-a pilot study. AB - Recently we hypothesized that the intention to initiate a voluntary movement at free will may be related to the dynamics of hemodynamic variables, which may be supported by the intertwining of networks for the timing of voluntary movements and the control of cardiovascular variables in the insula. In the present study voluntary movements of 3 healthy subjects were analyzed using fMRI scans at 1.83 s intervals along with the time course of slow hemodynamic changes in sensorimotor networks. For the analyses of BOLD time courses the Wavelet transform coherence (WTC) and calculation of phase-locking values were used. Analyzed was the frequency band between 0.07 and 0.13 Hz in the supplementary motor area (SMA) and insula, two widely separated regions co-active in motor behavior. BOLD signals displayed slow fluctuations, concentrated around 0.1 Hz whereby the intrinsic oscillations in the insula preceded those in the SMA by 0.5 1 s. These preliminary results suggest that slow hemodynamic changes in SMA and insula may condition the initiation of a voluntary movement at free will. PMID- 25538576 TI - Content congruency and its interplay with temporal synchrony modulate integration between rhythmic audiovisual streams. AB - Both lower-level stimulus factors (e.g., temporal proximity) and higher-level cognitive factors (e.g., content congruency) are known to influence multisensory integration. The former can direct attention in a converging manner, and the latter can indicate whether information from the two modalities belongs together. The present research investigated whether and how these two factors interacted in the perception of rhythmic, audiovisual (AV) streams derived from a human movement scenario. Congruency here was based on sensorimotor correspondence pertaining to rhythm perception. Participants attended to bimodal stimuli consisting of a humanlike figure moving regularly to a sequence of auditory beat, and detected a possible auditory temporal deviant. The figure moved either downwards (congruently) or upwards (incongruently) to the downbeat, while in both situations the movement was either synchronous with the beat, or lagging behind it. Greater cross-modal binding was expected to hinder deviant detection. Results revealed poorer detection for congruent than for incongruent streams, suggesting stronger integration in the former. False alarms increased in asynchronous stimuli only for congruent streams, indicating greater tendency for deviant report due to visual capture of asynchronous auditory events. In addition, a greater increase in perceived synchrony was associated with a greater reduction in false alarms for congruent streams, while the pattern was reversed for incongruent ones. These results demonstrate that content congruency as a top-down factor not only promotes integration, but also modulates bottom-up effects of synchrony. Results are also discussed regarding how theories of integration and attentional entrainment may be combined in the context of rhythmic multisensory stimuli. PMID- 25538574 TI - Optogenetic dissection of medial prefrontal cortex circuitry. AB - The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders. PMID- 25538578 TI - Virtual multiple errands test (VMET): a virtual reality-based tool to detect early executive functions deficit in Parkinson's disease. AB - INTRODUCTION: Several recent studies have pointed out that early impairment of executive functions (EFs) in Parkinson's Disease (PD) may be a crucial marker to detect patients at risk for developing dementia. The main objective of this study was to compare the performances of PD patients with mild cognitive impairment (PD MCI) with PD patients with normal cognition (PD-NC) and a control group (CG) using a traditional assessment of EFs and the Virtual Multiple Errands Test (VMET), a virtual reality (VR)-based tool. In order to understand which subcomponents of EFs are early impaired, this experimental study aimed to investigate specifically which instrument best discriminates among these three groups. MATERIALS AND METHODS: The study included three groups of 15 individuals each (for a total of 45 participants): 15 PD-NC; 15 PD-MCI, and 15 cognitively healthy individuals (CG). To assess the global neuropsychological functioning and the EFs, several tests (including the Mini Mental State Examination (MMSE), Clock Drawing Test, and Tower of London test) were administered to the participants. The VMET was used for a more ecologically valid neuropsychological evaluation of EFs. RESULTS: Findings revealed significant differences in the VMET scores between the PD-NC patients vs. the controls. In particular, patients made more errors in the tasks of the VMET, and showed a poorer ability to use effective strategies to complete the tasks. This VMET result seems to be more sensitive in the early detection of executive deficits because these two groups did not differ in the traditional assessment of EFs (neuropsychological battery). CONCLUSION: This study offers initial evidence that a more ecologically valid evaluation of EFs is more likely to lead to detection of subtle executive deficits. PMID- 25538581 TI - The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation. AB - The subthalamic nucleus (STN) belongs to the basal ganglia and is the current target for the surgical treatment of neurological and psychiatric disorders such as Parkinson's Disease (PD) and obsessive compulsive disorders (OCD), but also a proposed site for the treatment of addiction. It is therefore very important to understand its functions in order to anticipate and prevent possible side-effects in the patients. Although the involvement of the STN is well documented in motor, cognitive and motivational processes, less is known regarding emotional processes. Here we have investigated the direct consequences of STN inactivation by excitotoxic lesions on emotional processing and reinforcement in the rat. We have used various behavioral procedures to assess affect for neutral, positive and negative reinforcers in STN lesioned rats. STN lesions reduced affective responses for positive (sweet solutions) and negative (electric foot shock, Lithium Chloride-induced sickness) reinforcers while they had no effect on responses for a more neutral reinforcer (novelty induced place preference (NIPP)). Furthermore, when given the choice between saccharine, a sweet but non caloric solution, and glucose, a more bland but caloric solution, in contrast to sham animals that preferred saccharine, STN lesioned animals preferred glucose over saccharine. Taken altogether these results reveal that STN plays a critical role in emotional processing. These results, in line with some clinical observations in PD patients subjected to STN surgery, suggest possible emotional side-effects of treatments targeting the STN. They also suggest that the increased motivation for sucrose previously reported cannot be due to increased pleasure, but could be responsible for the decreased motivation for cocaine reported after STN inactivation. PMID- 25538580 TI - Motor imagery in unipolar major depression. AB - BACKGROUND: Motor imagery is a potential tool to investigate action representation, as it can provide insights into the processes of action planning and preparation. Recent studies suggest that depressed patients present specific impairment in mental rotation. The present study was designed to investigate the influence of unipolar depression on motor imagery ability. METHODS: Fourteen right-handed patients meeting DSM-IV criteria for unipolar depression were compared to 14 matched healthy controls. Imagery ability was accessed by the timing correspondence between executed and imagined movements during a pointing task, involving strong spatiotemporal constraints (speed/accuracy trade-off paradigm). RESULTS: Compared to controls, depressed patients showed marked motor slowing on both actual and imagined movements. Furthermore, we observed greater temporal discrepancies between actual and mental movements in depressed patients than in healthy controls. Lastly, depressed patients modulated, to some extent, mental movement durations according to the difficulty of the task, but this modulation was not as strong as that of healthy subjects. CONCLUSION: These results suggest that unipolar depression significantly affects the higher stages of action planning and point out a selective decline of motor prediction. PMID- 25538582 TI - Relationships between brain-derived neurotrophic factor, clinical symptoms, and decision-making in chronic schizophrenia: data from the Iowa Gambling Task. AB - The levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with schizophrenia and correlate with impairments in cognitive function. However, no study has investigated the relationship between the serum BDNF levels and decision-making. We compared patients with schizophrenia to healthy controls with respect to their decision-making ability and serum BDNF levels. Eighty-six chronic schizophrenia patients and 51 healthy controls participated in this study. We controlled for gender, age, and estimated intelligence quotient (IQ), and we investigated the differences in decision making performance on the Iowa Gambling Task (IGT) between the schizophrenia patient and control groups. We also compared the IGT scores, the serum BDNF levels, and the clinical symptoms between the groups. The IGT scores of the schizophrenia patients were lower than those of the controls. A negative correlation was detected between the mean net scores on the trials in the final two blocks and the serum BDNF levels (p < 0.05). Multiple regression analysis revealed that depressive symptoms and the serum BDNF levels were significantly associated with the mean net scores on the trials in the final two blocks. Based on these results, impaired sensitivity to both reward and punishment is associated with depressive symptoms and reduced serum BDNF levels in chronic schizophrenia patients and may be related to their poor performance on the IGT. PMID- 25538579 TI - Are Extremes of Consumption in Eating Disorders Related to an Altered Balance between Reward and Inhibition? AB - The primary defining characteristic of a diagnosis of an eating disorder (ED) is the "disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food" (DSM V; American Psychiatric Association, 2013). There is a spectrum, ranging from those who severely restrict eating and become emaciated on one end to those who binge and overconsume, usually accompanied by some form of compensatory behaviors, on the other. How can we understand reasons for such extremes of food consummatory behaviors? Recent work on obesity and substance use disorders has identified behaviors and neural pathways that play a powerful role in human consummatory behaviors. That is, corticostriatal limbic and dorsal cognitive neural circuitry can make drugs and food rewarding, but also engage self-control mechanisms that may inhibit their use. Importantly, there is considerable evidence that alterations of these systems also occur in ED. This paper explores the hypothesis that an altered balance of reward and inhibition contributes to altered extremes of response to salient stimuli, such as food. We will review recent studies that show altered sensitivity to reward and punishment in ED, with evidence of altered activity in corticostriatal and insula processes with respect to monetary gains or losses, and tastes of palatable foods. We will also discuss evidence for a spectrum of extremes of inhibition and dysregulation behaviors in ED supported by studies suggesting that this is related to top-down self-control mechanisms. The lack of a mechanistic understanding of ED has thwarted efforts for evidence-based approaches to develop interventions. Understanding how ED behavior is encoded in neural circuits would provide a foundation for developing more specific and effective treatment approaches. PMID- 25538583 TI - Lateralization of music processing with noises in the auditory cortex: an fNIRS study. AB - The present study is to determine the effects of background noise on the hemispheric lateralization in music processing by exposing 14 subjects to four different auditory environments: music segments only, noise segments only, music + noise segments, and the entire music interfered by noise segments. The hemodynamic responses in both hemispheres caused by the perception of music in 10 different conditions were measured using functional near-infrared spectroscopy. As a feature to distinguish stimulus-evoked hemodynamics, the difference between the mean and the minimum value of the hemodynamic response for a given stimulus was used. The right-hemispheric lateralization in music processing was about 75% (instead of continuous music, only music segments were heard). If the stimuli were only noises, the lateralization was about 65%. But, if the music was mixed with noises, the right-hemispheric lateralization has increased. Particularly, if the noise was a little bit lower than the music (i.e., music level 10~15%, noise level 10%), the entire subjects showed the right-hemispheric lateralization: This is due to the subjects' effort to hear the music in the presence of noises. However, too much noise has reduced the subjects' discerning efforts. PMID- 25538584 TI - Beyond the computational-representational brain: why affective neuroscience tells us attitudes must be explained on multiple levels. PMID- 25538586 TI - Distinct neuronal populations in the basal forebrain encode motivational salience and movement. AB - Basal forebrain (BF) is one of the largest cortically-projecting neuromodulatory systems in the mammalian brain, and plays a key role in attention, arousal, learning and memory. The cortically projecting BF neurons, comprised of mainly magnocellular cholinergic and GABAergic neurons, are widely distributed across several brain regions that spatially overlap with the ventral striatopallidal system at the ventral pallidum (VP). As a first step toward untangling the respective functions of spatially overlapping BF and VP systems, the goal of this study was to comprehensively characterize the behavioral correlates and physiological properties of heterogeneous neuronal populations in the BF region. We found that, while rats performed a reward-biased simple reaction time task, distinct neuronal populations encode either motivational salience or movement information. The motivational salience of attended stimuli is encoded by phasic bursting activity of a large population of slow-firing neurons that have large, broad, and complex action potential waveforms. In contrast, two other separate groups of neurons encode movement-related information, and respectively increase and decrease firing rates while rats maintained fixation. These two groups of neurons mostly have higher firing rates and small, narrow action potential waveforms. These results support the conclusion that multiple neurophysiologically distinct neuronal populations in the BF region operate independently of each other as parallel functional circuits. These observations also caution against interpreting neuronal activity in this region as a homogeneous population reflecting the function of either BF or VP alone. We suggest that salience- and movement-related neuronal populations likely correspond to BF corticopetal neurons and VP neurons, respectively. PMID- 25538585 TI - Self-regulation of frontal-midline theta facilitates memory updating and mental set shifting. AB - Frontal-midline (fm) theta oscillations as measured via the electroencephalogram (EEG) have been suggested as neural "working language" of executive functioning. Their power has been shown to increase when cognitive processing or task performance is enhanced. Thus, the question arises whether learning to increase fm-theta amplitudes would functionally impact the behavioral performance in tasks probing executive functions (EFs). Here, the effects of neurofeedback (NF), a learning method to self-up-regulate fm-theta over fm electrodes, on the four most representative EFs, memory updating, set shifting, conflict monitoring, and motor inhibition are presented. Before beginning and after completing an individualized, eight-session gap-spaced NF intervention, the three-back, letter/number task-switching, Stroop, and stop-signal tasks were tested while measuring the EEG. Self-determined up-regulation of fm-theta and its putative role for executive functioning were compared to an active control group, the so called pseudo-neurofeedback group. Task-related fm-theta activity after training differed significantly between groups. More importantly, though, after NF significantly enhanced behavioral performance was observed. The training group showed higher accuracy scores in the three-back task and reduced mixing and shifting costs in letter/number task-switching. However, this specific protocol type did not affect performance in tasks probing conflict monitoring and motor inhibition. Thus, our results suggest a modulation of proactive but not reactive mechanisms of cognitive control. Furthermore, task-related EEG changes show a distinct pattern for fm-theta after training between the NF and the pseudo neurofeedback group, which indicates that NF training indeed tackles EFs networks. In sum, the modulation of fm-theta via NF may serve as potent treatment approach for executive dysfunctions. PMID- 25538587 TI - Discrimination of fearful and angry emotional voices in sleeping human neonates: a study of the mismatch brain responses. AB - Appropriate processing of human voices with different threat-related emotions is of evolutionarily adaptive value for the survival of individuals. Nevertheless, it is still not clear whether the sensitivity to threat-related information is present at birth. Using an odd-ball paradigm, the current study investigated the neural correlates underlying automatic processing of emotional voices of fear and anger in sleeping neonates. Event-related potential data showed that the fronto central scalp distribution of the neonatal brain could discriminate fearful voices from angry voices; the mismatch response (MMR) was larger in response to the deviant stimuli of anger, compared with the standard stimuli of fear. Furthermore, this fear-anger MMR discrimination was observed only when neonates were in active sleep state. Although the neonates' sensitivity to threat-related voices is not likely associated with a conceptual understanding of fearful and angry emotions, this special discrimination in early life may provide a foundation for later emotion and social cognition development. PMID- 25538588 TI - Variation in the oxytocin receptor gene is associated with behavioral and neural correlates of empathic accuracy. AB - The neuromodulators oxytocin and serotonin have been implicated in regulating affective processes underlying empathy. Understanding this dependency, however, has been limited by a lack of objective metrics for measuring empathic performance. Here we employ a novel psychophysical method for measuring empathic performance that quantitatively measures the ability of subjects to decode the experience of another person's pain. In 50 female subjects, we acquired functional magnetic resonance imaging data as they were exposed to a target subject experiencing variable degrees of pain, whilst performing an irrelevant attention-demanding task. We investigated the effect of variation in the oxytocin receptor gene (OXTR) and the serotonin transporter gene (SLC6A4) on the psychophysical and neurometric variability associated with empathic performance. The OXTR rs2268498 and rs53576 polymorphisms, but not the SLC6A4 5-HTTLPR, were associated with significant differences in empathic accuracy, with CC- and AA carriers, respectively, displaying higher empathic accuracy. For OXTR rs2268498 there was also a genotype difference in the correlation between empathic accuracy and activity in the superior temporal sulcus (STS). In OXTR rs2268498 CC carriers, high empathic accuracy was associated with stronger responsiveness of the right STS to the observed pain. Together, the results show that genetic variation in the OXTR has significant influence on empathic accuracy and that this may be linked to variable responsivity of the STS. PMID- 25538589 TI - Compassion meditators show less anger, less punishment, and more compensation of victims in response to fairness violations. AB - Fairness violations elicit powerful behavioral and affective responses. Indeed, people are willing to incur costs to sanction unfair behavior. Here we study the possible impact of long-term mental training in socio-affective capacities such as compassion on altruistic punishment and compensatory behavior in economic games. To this end we recruited a group of long-term meditation practitioners (LTPs) who had engaged in an average of 40 K h of mental training exercises including compassion-related meditation, along with a group of meditation-naive controls. Participants played several adaptations of the dictator game in which they had the opportunity to punish the dictator both when they were the recipients of the dictator's offer and when they were third-party witnesses to the dictator's treatment of an anonymous second player. Compared to controls, LTPs were less likely to punish when they were the victims of fairness violations. However, both groups punished equivalently when they witnessed others receiving unfair treatment. In post-task questionnaires, controls reported significantly more anger in response to unfair offers than LTPs, although fairness judgments did not differ between groups. These data suggest that because the LTPs were less angered by unfair treatment of themselves, they punished that behavior less. However, when they witnessed the unfair treatment of others, they engaged in norm-reinforcing punishment. Finally, when participants played an additional game which included the opportunity to recompense victims, LTPs were more likely to do so. Together these data point to differential approaches to justice whereby LTPs engaged less in vengeful, retributive justice and focused more on norm reinforcement and the restoration of equity. These differences suggest that social preferences are plastic and that altruistic responses to unfairness may be shaped by the prolonged cultivation of prosocial motivation, altruism, and compassion. PMID- 25538592 TI - Sport neuroscience revisited (?): a commentary. PMID- 25538591 TI - Learned self-regulation of the lesioned brain with epidural electrocorticography. AB - INTRODUCTION: Different techniques for neurofeedback of voluntary brain activations are currently being explored for clinical application in brain disorders. One of the most frequently used approaches is the self-regulation of oscillatory signals recorded with electroencephalography (EEG). Many patients are, however, unable to achieve sufficient voluntary control of brain activity. This could be due to the specific anatomical and physiological changes of the patient's brain after the lesion, as well as to methodological issues related to the technique chosen for recording brain signals. METHODS: A patient with an extended ischemic lesion of the cortex did not gain volitional control of sensorimotor oscillations when using a standard EEG-based approach. We provided him with neurofeedback of his brain activity from the epidural space by electrocorticography (ECoG). RESULTS: Ipsilesional epidural recordings of field potentials facilitated self-regulation of brain oscillations in an online closed loop paradigm and allowed reliable neurofeedback training for a period of 4 weeks. CONCLUSION: Epidural implants may decode and train brain activity even when the cortical physiology is distorted following severe brain injury. Such practice would allow for reinforcement learning of preserved neural networks and may well provide restorative tools for those patients who are severely afflicted. PMID- 25538590 TI - Differences in brain circuitry for appetitive and reactive aggression as revealed by realistic auditory scripts. AB - Aggressive behavior is thought to divide into two motivational elements: The first being a self-defensively motivated aggression against threat and a second, hedonically motivated "appetitive" aggression. Appetitive aggression is the less understood of the two, often only researched within abnormal psychology. Our approach is to understand it as a universal and adaptive response, and examine the functional neural activity of ordinary men (N = 50) presented with an imaginative listening task involving a murderer describing a kill. We manipulated motivational context in a between-subjects design to evoke appetitive or reactive aggression, against a neutral control, measuring activity with Magnetoencephalography (MEG). Results show differences in left frontal regions in delta (2-5 Hz) and alpha band (8-12 Hz) for aggressive conditions and right parietal delta activity differentiating appetitive and reactive aggression. These results validate the distinction of reward-driven appetitive aggression from reactive aggression in ordinary populations at the level of functional neural brain circuitry. PMID- 25538594 TI - Sensory abnormalities in focal hand dystonia and non-invasive brain stimulation. AB - It has been proposed that synchronous and convergent afferent input arising from repetitive motor tasks may play an important role in driving the maladaptive cortical plasticity seen in focal hand dystonia (FHD). This hypothesis receives support from several sources. First, it has been reported that in subjects with FHD, paired associative stimulation produces an abnormal increase in corticospinal excitability, which was not confined to stimulated muscles. These findings provide support for the role of excessive plasticity in FHD. Second, the genetic contribution to the dystonias is increasingly recognized indicating that repetitive, stereotyped afferent inputs may lead to late-onset dystonia, such as FHD, more rapidly in genetically susceptible individuals. It can be postulated, according to the two factor hypothesis that dystonia is triggered and maintained by the concurrence of environmental factors such as repetitive training and subtle abnormal mechanisms of plasticity within somatosensory loop. In the present review, we examine the contribution of sensory-motor integration in the pathophysiology of primary dystonia. In addition, we will discuss the role of non invasive brain stimulation as therapeutic approach in FHD. PMID- 25538593 TI - Technology-aided programs for post-coma patients emerged from or in a minimally conscious state. AB - Post-coma persons in a minimally conscious state (MCS) or emerged/emerging from such state (E-MCS), who are affected by extensive motor impairment and lack of speech, may develop an active role and interact with their environment with the help of technology-aided intervention programs. Although a number of studies have been conducted in this area during the last few years, new evidence about the efficacy of those programs is warranted. These three studies were an effort in that direction. Study I assessed a technology-aided program to enable six MCS participants to access preferred environmental stimulation independently. Studies II and III assessed technology-aided programs to enable six E-MCS participants to make choices. In Study II, three of those participants were led to choose among leisure and social stimuli, and caregiver interventions automatically presented to them. In Study III, the remaining three participants were led to choose (a) among general stimulus/intervention options (e.g., songs, video-recordings of family members, and caregiver interventions); and then (b) among variants of those options. The results of all three studies were largely positive with substantial increases of independent stimulation access for the participants of Study I and independent choice behavior for the participants of Studies II and III. The results were analyzed in relation to previous data and in terms of their implications for daily contexts working with MCS and E-MCS persons affected by multiple disabilities. PMID- 25538595 TI - Quantification of gait changes in subjects with visual height intolerance when exposed to heights. AB - INTRODUCTION: Visual height intolerance (vHI) manifests as instability at heights with apprehension of losing balance or falling. We investigated contributions of visual feedback and attention on gait performance of subjects with vHI. MATERIALS AND METHODS: Sixteen subjects with vHI walked over a gait mat (GAITRite(r)) on a 15-m-high balcony and at ground-level. Subjects walked at different speeds (slow, preferred, fast), during changes of the visual input (gaze straight/up/down; eyes open/closed), and while doing a cognitive task. An rmANOVA with the factors "height situation" and "gait condition" was performed. Subjects were also asked to estimate the height of the balcony over ground level. The individual estimates were used for correlations with the gait parameters. RESULTS: Study participants walked slower at heights, with reduced cadence and stride length. The double support phases were increased (all p < 0.01), which correlated with the estimated height of the balcony (R (2) = 0.453, p < 0.05). These changes were still present when walking with upward gaze or closure of the eyes. Under the conditions walking and looking down to the floor of the balcony, during dual-task and fast walking, there were no differences between the gait performance on the balcony and at ground-level. DISCUSSION: The found gait changes are features of a cautious gait control. Internal, cognitive models with anxiety play an important role for vHI; gait was similarly affected when the visual perception of the depth was prevented. Improvement by dual task at heights may be associated by a reduction of the anxiety level. CONCLUSION: It is conceivable that mental distraction by dual task or increasing the walking speed might be useful recommendations to reduce the imbalance during locomotion in subjects susceptible to vHI. PMID- 25538596 TI - Viewing photos and reading nouns of natural graspable objects similarly modulate motor responses. AB - It is well known that the observation of graspable objects recruits the same motor representations involved in their actual manipulation. Recent evidence suggests that the presentation of nouns referring to graspable objects may exert similar effects. So far, however, it is not clear to what extent the modulation of the motor system during object observation overlaps with that related to noun processing. To address this issue, 2 behavioral experiments were carried out using a go-no go paradigm. Healthy participants were presented with photos and nouns of graspable and non-graspable natural objects. Also scrambled images and pseudowords obtained from the original stimuli were used. At a go-signal onset (150 ms after stimulus presentation) participants had to press a key when the stimulus referred to a real object, using their right (Experiment 1) or left (Experiment 2) hand, and refrain from responding when a scrambled image or a pseudoword was presented. Slower responses were found for both photos and nouns of graspable objects as compared to non-graspable objects, independent of the responding hand. These findings suggest that processing seen graspable objects and written nouns referring to graspable objects similarly modulates the motor system. PMID- 25538597 TI - Neurobiological foundations of multisensory integration in people with autism spectrum disorders: the role of the medial prefrontal cortex. AB - This review aims to relate the sensory processing problems in people with autism spectrum disorders (ASD), especially multisensory integration (MSI), to the role of the medial prefrontal cortex (mPFC) by exploring neuroanatomical findings; brain connectivity and Default Network (DN); global or locally directed attention; and temporal multisensory binding. The mPFC is part of the brain's DN, which is deactivated when attention is focused on a particular task and activated on rest when spontaneous cognition emerges. In those with ASD, it is hypoactive and the higher the social impairment the greater the atypical activity. With an immature DN, cross-modal integration is impaired, resulting in a collection of disconnected fragments instead of a coherent global perception. The deficit in MSI may lie in the temporal synchronization of neural networks. The time interval in which the stimulation of one sensory channel could influence another would be higher, preventing integration in the typical shorter time range. Thus, the underconnectivity between distant brain areas would be involved in top-down information processes (relying on global integration of data from different sources) and would enhance low level perception processes such as over focused attention to sensory details. PMID- 25538598 TI - Non-physical practice improves task performance in an unstable, perturbed environment: motor imagery and observational balance training. AB - For consciously performed motor tasks executed in a defined and constant way, both motor imagery (MI) and action observation (AO) have been shown to promote motor learning. It is not known whether these forms of non-physical training also improve motor actions when these actions have to be variably applied in an unstable and unpredictable environment. The present study therefore investigated the influence of MI balance training (MI_BT) and a balance training combining AO and MI (AO+MI_BT) on postural control of undisturbed and disturbed upright stance on unstable ground. As spinal reflex excitability after classical (i.e., physical) balance training (BT) is generally decreased, we tested whether non physical BT also has an impact on spinal reflex circuits. Thirty-six participants were randomly allocated into an MI_BT group, in which participants imagined postural exercises, an AO+MI_BT group, in which participants observed videos of other people performing balance exercises and imagined being the person in the video, and a non-active control group (CON). Before and after 4 weeks of non physical training, balance performance was assessed on a free-moving platform during stance without perturbation and during perturbed stance. Soleus H-reflexes were recorded during stable and unstable stance. The post-measurement revealed significantly decreased postural sway during undisturbed and disturbed stance after both MI_BT and AO+MI_BT. Spinal reflex excitability remained unchanged. This is the first study showing that non-physical training (MI_BT and AO+MI_BT) not only promotes motor learning of "rigid" postural tasks but also improves performance of highly variable and unpredictable balance actions. These findings may be relevant to improve postural control and thus reduce the risk of falls in temporarily immobilized patients. PMID- 25538600 TI - Luminance gradient configuration determines perceived lightness in a simple geometric illusion. AB - Accurate perception of surface reflectance poses a significant computational problem for the visual system. The amount of light reflected by a surface is affected by a combination of factors including the surface's reflectance properties and illumination conditions. The latter are not limited by the strength of the illuminant but also include the relative placement of the light illuminating the surface, the orientation of the surface and its 3d shape, all of which result in a pattern of luminance gradients across the surface. In this study we explore how luminance gradients contribute to lightness perception. We introduce a novel, simple lightness illusion. It consists of six separate checks, organized in rows of two. Each check has a negative luminance gradient across it. The top and the bottom rows are the same: with the darker check on the left, and the lighter check on the right. Two checks in the middle row are identical; however, the check on the right appears darker than the check on the left. As there are no shared borders between the checks, simultaneous contrast cannot explain the effect. However, there are multiple possible explanations including spatial filtering (Blakeslee and McCourt, 2004) or some higher-order mechanism such as perceptual grouping or amodal completion. Here, we explore these possibilities by manipulating the luminance configurations and the gradient slopes of the checks. PMID- 25538599 TI - Children with low working memory and children with ADHD: same or different? AB - The purpose of this study was to compare working memory (WM), executive function, academic ability, and problem classroom behaviors in children aged 8-11 years who were either identified via routine screening as having low WM, or had been diagnosed with ADHD. Standardized assessments of WM, executive function and reading and mathematics were administered to 83 children with ADHD, 50 children with low WM and 50 typically developing children. Teachers rated problem behaviors on checklists measuring attention, hyperactivity/impulsivity, oppositional behavior, and difficulties associated with executive function in the classroom. The ADHD and low WM groups had highly similar WM and executive function profiles, but were distinguished in two key respects: children with ADHD had higher levels of rated and observed impulsive behavior, and children with low WM had slower response times. Possible mechanisms for these common and distinct deficits are discussed. PMID- 25538602 TI - Contribution of a luminance-dependent S-cone mechanism to non-assimilative color spreading in the watercolor configuration. AB - In the watercolor configuration composed of wavy double contours, both assimilative and non-assimilative color spreading have been demonstrated depending on the luminance conditions of the inner and outer contours (IC and OC, respectively). This study investigated how the induced color in the watercolor configuration was modulated by combinations of the IC and the OC color, particularly addressing non-assimilative color spreading. In two experiments, the IC color was fixed to a certain color and combined with various colors selected from a hue circle centered at the background white color. Color spreading was quantified with a chromatic cancelation technique. Results showed that both the magnitude and the apparent hue of the color spreading were largely changed with the luminance condition. When the IC contrast (Weber contrast of the IC to the background luminance) was smaller in size than the OC contrast (higher IC luminance condition), the color spreading was assimilative. When the luminance condition was reversed and the IC contrast was greater than the OC contrast (lower IC luminance condition), the color spreading was non-assimilative and yellowish. When the color spreading was analyzed in terms of cone-opponent excitations, the results were consistent with the interpretation that the color spreading is explainable by a combination of chromatic diffusion from the IC and chromatically opponent induction from the OC. The color spreading in the higher IC luminance condition mainly reflected the chromatic diffusion by both (L-M) and S cone-opponent mechanisms. The non-assimilative color spreading in the lower IC luminance condition mostly reflected S-cone mediated opponent induction and the contribution of -S inducing mechanisms was differentially large. These findings provided several constraints on possible visual mechanisms underlying the watercolor effect. PMID- 25538603 TI - The influence of oculomotor tasks on postural control in dyslexic children. AB - Dual task is known to affect postural stability in children. We explored the effect of visual tasks on postural control in thirty dyslexic children. A selected group of thirty chronological age-matched non-dyslexic children (mean age: 9.92 +/- 0.35 years) and a group of thirty reading age-matched non-dyslexic children (mean reading age: 7.90 +/- 0.25 years) were chosen for comparison. All children underwent ophthalmologic and optometric evaluation. Eye movements were recorded by a video-oculography system (EyeBrain(r) T2) and postural sway was recorded simultaneously by a force platform (TechnoConept(r)). All children performed fixations, pursuits, pro- and anti-saccades tasks. Dyslexic children showed significantly poor near fusional vergence ranges (convergence and divergence) with respect to the non-dyslexic children groups. During the postural task, quality of fixation and anti-saccade performance in dyslexic children were significantly worse compared to the two non-dyslexic children groups. In contrast, the number of catch-up saccades during pursuits and the latency of pro- and anti-saccades were similar in the three groups of children examined. Concerning postural quality, dyslexic children were more unstable than chronological age-matched non-dyslexic children group. For all three groups of children tested we also observed that executing saccades (pro- and anti-saccades) reduced postural values significantly in comparison with fixation and pursuit tasks. The impairment in convergence and divergence fusional capabilities could be due to an immaturity in cortical structures controlling the vergence system. The poor oculomotor performance reported in dyslexic children suggested a deficit in allocating visual attention and their postural instability observed is in line with the cerebellar impairment previously reported in dyslexic children. Finally, pro- or anti-saccades reduce postural values compared to fixation and pursuit tasks in all groups of children tested, suggesting a different influence of visual tasks on postural control according to their attentional demand. PMID- 25538605 TI - On the use of cues to assess attention in dyslexia. PMID- 25538601 TI - Top-down influences on ambiguous perception: the role of stable and transient states of the observer. AB - The world as it appears to the viewer is the result of a complex process of inference performed by the brain. The validity of this apparently counter intuitive assertion becomes evident whenever we face noisy, feeble or ambiguous visual stimulation: in these conditions, the state of the observer may play a decisive role in determining what is currently perceived. On this background, ambiguous perception and its amenability to top-down influences can be employed as an empirical paradigm to explore the principles of perception. Here we offer an overview of both classical and recent contributions on how stable and transient states of the observer can impact ambiguous perception. As to the influence of the stable states of the observer, we show that what is currently perceived can be influenced (1) by cognitive and affective aspects, such as meaning, prior knowledge, motivation, and emotional content and (2) by individual differences, such as gender, handedness, genetic inheritance, clinical conditions, and personality traits and by (3) learning and conditioning. As to the impact of transient states of the observer, we outline the effects of (4) attention and (5) voluntary control, which have attracted much empirical work along the history of ambiguous perception. In the huge literature on the topic we trace a difference between the observer's ability to control dominance (i.e., the maintenance of a specific percept in visual awareness) and reversal rate (i.e., the switching between two alternative percepts). Other transient states of the observer that have more recently drawn researchers' attention regard (6) the effects of imagery and visual working memory. (7) Furthermore, we describe the transient effects of prior history of perceptual dominance. (8) Finally, we address the currently available computational models of ambiguous perception and how they can take into account the crucial share played by the state of the observer in perceiving ambiguous displays. PMID- 25538604 TI - Action verbs are processed differently in metaphorical and literal sentences depending on the semantic match of visual primes. AB - Language comprehension requires rapid and flexible access to information stored in long-term memory, likely influenced by activation of rich world knowledge and by brain systems that support the processing of sensorimotor content. We hypothesized that while literal language about biological motion might rely on neurocognitive representations of biological motion specific to the details of the actions described, metaphors rely on more generic representations of motion. In a priming and self-paced reading paradigm, participants saw video clips or images of (a) an intact point-light walker or (b) a scrambled control and read sentences containing literal or metaphoric uses of biological motion verbs either closely or distantly related to the depicted action (walking). We predicted that reading times for literal and metaphorical sentences would show differential sensitivity to the match between the verb and the visual prime. In Experiment 1, we observed interactions between the prime type (walker or scrambled video) and the verb type (close or distant match) for both literal and metaphorical sentences, but with strikingly different patterns. We found no difference in the verb region of literal sentences for Close-Match verbs after walker or scrambled motion primes, but Distant-Match verbs were read more quickly following walker primes. For metaphorical sentences, the results were roughly reversed, with Distant-Match verbs being read more slowly following a walker compared to scrambled motion. In Experiment 2, we observed a similar pattern following still image primes, though critical interactions emerged later in the sentence. We interpret these findings as evidence for shared recruitment of cognitive and neural mechanisms for processing visual and verbal biological motion information. Metaphoric language using biological motion verbs may recruit neurocognitive mechanisms similar to those used in processing literal language but be represented in a less-specific way. PMID- 25538606 TI - Constrained spherical deconvolution analysis of the limbic network in human, with emphasis on a direct cerebello-limbic pathway. AB - The limbic system is part of an intricate network which is involved in several functions like memory and emotion. Traditionally the role of the cerebellum was considered mainly associated to motion control; however several evidences are raising about a role of the cerebellum in learning skills, emotions control, mnemonic and behavioral processes involving also connections with limbic system. In 15 normal subjects we studied limbic connections by probabilistic Constrained Spherical Deconvolution (CSD) tractography. The main result of our work was to prove for the first time in human brain the existence of a direct cerebello limbic pathway which was previously hypothesized but never demonstrated. We also extended our analysis to the other limbic connections including cingulate fasciculus, inferior longitudinal fasciculus, uncinated fasciculus, anterior thalamic connections and fornix. Although these pathways have been already described in the tractographic literature we provided reconstruction, quantitative analysis and Fractional Anisotropy (FA) right-left symmetry comparison using probabilistic CSD tractography that is known to provide a potential improvement compared to previously used Diffusion Tensor Imaging (DTI) techniques. The demonstration of the existence of cerebello-limbic pathway could constitute an important step in the knowledge of the anatomic substrate of non motor cerebellar functions. Finally the CSD statistical data about limbic connections in healthy subjects could be potentially useful in the diagnosis of pathological disorders damaging this system. PMID- 25538607 TI - Automatic processing of abstract musical tonality. AB - Music perception builds on expectancy in harmony, melody, and rhythm. Neural responses to the violations of such expectations are observed in event-related potentials (ERPs) measured using electroencephalography. Most previous ERP studies demonstrating sensitivity to musical violations used stimuli that were temporally regular and musically structured, with less-frequent deviant events that differed from a specific expectation in some feature such as pitch, harmony, or rhythm. Here, we asked whether expectancies about Western musical scale are strong enough to elicit ERP deviance components. Specifically, we explored whether pitches inconsistent with an established scale context elicit deviant components even though equally rare pitches that fit into the established context do not, and even when their timing is unpredictable. We used Markov chains to create temporally irregular pseudo-random sequences of notes chosen from one of two diatonic scales. The Markov pitch-transition probabilities resulted in sequences that favored notes within the scale, but that lacked clear melodic, harmonic, or rhythmic structure. At the random positions, the sequence contained probe tones that were either within the established scale or were out of key. Our subjects ignored the note sequences, watching a self-selected silent movie with subtitles. Compared to the in-key probes, the out-of-key probes elicited a significantly larger P2 ERP component. Results show that random note sequences establish expectations of the "first-order" statistical property of musical key, even in listeners not actively monitoring the sequences. PMID- 25538609 TI - The anodal tDCS over the left posterior parietal cortex enhances attention toward a focus word in a sentence. AB - The posterior parietal cortex (PPC) has two attentional functions: top-down attentional control and stimulus-driven attentional processing. Using the focused version of the reading span test (RST), in which the target word to be remembered is the critical word for comprehending a sentence (focused word) or a non-focused word, we examined the effect of tDCS on resolution of distractor interference by the focused word in the non-focus condition (top-down attentional control) and on augmented/shrunk attentional capture by the focused word in both the focus and non-focus conditions (stimulus-driven attentional processing). Participants were divided into two groups: anodal tDCS (atDCS) and cathodal tDCS (ctDCS). Online stimulation was given while participants performed the RST. A post-hoc recognition task was also administered in which three kinds of words were presented: target words in the RST, distractor words in the RST, and novel words. atDCS augmented the effect of the focused word by increasing differences in performance between the focus and non-focus conditions. Such an effect was not observed in the ctDCS group. As for the recognition task, atDCS again produced the augmented effect of the focused words in the distractor recognition. On the other hand, ctDCS brought less recognition of non-focused target words in comparison to sham. The results indicate that atDCS promotes stimulus-driven attentional processing, possibly by affecting neural firing in the inferior parietal regions. In contrast, ctDCS appears to prevent retrieval of less important information from episodic memory, which may require top-down attentional processing. PMID- 25538608 TI - Executive function and self-regulated exergaming adherence among older adults. AB - The rise in dementia and the evidence of cognitive benefits of exercise for the older adult population together make salient the research into variables affecting cognitive benefit and exercise behavior. One promising avenue for increasing exercise participation has been the introduction of exergaming, a type of exercise that works in combination with virtual reality to enhance both the exercise experience and health outcomes. Past research has revealed that executive function (EF) was related to greater use of self-regulatory strategies, which in turn was related to greater adherence to exercise following an intervention (McAuley et al., 2011). Best et al. (2014) found improvement in EF related to adherence to exercise post- intervention. Anderson-Hanley et al. (2012) found that for older adults aerobic exergaming yielded greater cognitive benefit than traditional exercise alone; however, questions remain as to the possible impact of greater cognitive benefit and other factors on participants' involvement in exercise following the end of an intervention. The current study presents follow-up data exploring the relationship between EF, self-regulation, and exercise behavior in the post-intervention (naturalistic) period. Herein, it was predicted that higher EF at the start of the naturalistic window, would predict subsequent exercise with an exergame. Contrary to expectations, results suggest that those with poorer EF are likely to exergame more frequently. The results of this study contradict previous literature, but suggest an interesting relationship between EF, self-regulation, and exercise behaviors when exergaming is employed, particularly with older adults with some cognitive decline. We hypothesize that other factors may be at work, perhaps expectation of cognitive benefit might act as a unique motivator. PMID- 25538610 TI - Neuroscience perspectives on security. PMID- 25538611 TI - Hemispheric bases for emotion and memory. PMID- 25538613 TI - Emulated muscle spindle and spiking afferents validates VLSI neuromorphic hardware as a testbed for sensorimotor function and disease. AB - The lack of multi-scale empirical measurements (e.g., recording simultaneously from neurons, muscles, whole body, etc.) complicates understanding of sensorimotor function in humans. This is particularly true for the understanding of development during childhood, which requires evaluation of measurements over many years. We have developed a synthetic platform for emulating multi-scale activity of the vertebrate sensorimotor system. Our design benefits from Very Large Scale Integrated-circuit (VLSI) technology to provide considerable scalability and high-speed, as much as 365* faster than real-time. An essential component of our design is the proprioceptive sensor, or muscle spindle. Here we demonstrate an accurate and extremely fast emulation of a muscle spindle and its spiking afferents, which are computationally expensive but fundamental for reflex functions. We implemented a well-known rate-based model of the spindle (Mileusnic et al., 2006) and a simplified spiking sensory neuron model using the Izhikevich approximation to the Hodgkin-Huxley model. The resulting behavior of our afferent sensory system is qualitatively compatible with classic cat soleus recording (Crowe and Matthews, 1964b; Matthews, 1964, 1972). Our results suggest that this simplified structure of the spindle and afferent neuron is sufficient to produce physiologically-realistic behavior. The VLSI technology allows us to accelerate this behavior beyond 365* real-time. Our goal is to use this testbed for predicting years of disease progression with only a few days of emulation. This is the first hardware emulation of the spindle afferent system, and it may have application not only for emulation of human health and disease, but also for the construction of compliant neuromorphic robotic systems. PMID- 25538612 TI - Proprioceptive dysfunction in focal dystonia: from experimental evidence to rehabilitation strategies. AB - Dystonia has historically been considered a disorder of the basal ganglia, mainly affecting planning and execution of voluntary movements. This notion comes from the observation that most lesions responsible for secondary dystonia involve the basal ganglia. However, what emerges from recent research is that dystonia is linked to the dysfunction of a complex neural network that comprises basal ganglia-thalamic-frontal cortex, but also the inferior parietal cortex and the cerebellum. While dystonia is clearly a motor problem, it turned out that sensory aspects are also fundamental, especially those related to proprioception. We outline experimental evidence for proprioceptive dysfunction in focal dystonia from intrinsic sensory abnormalities to impaired sensorimotor integration, which is the process by which sensory information is used to plan and execute volitional movements. Particularly, we will focus on proprioceptive aspects of dystonia, including: (i) processing of vibratory input, (ii) temporal discrimination of two passive movements, (iii) multimodal integration of visual tactile and proprioceptive inputs, and (iv) motor control in the absence of visual feedback. We suggest that these investigations contribute not only to a better understanding of dystonia pathophysiology, but also to develop rehabilitation strategies aimed at facilitating the processing of proprioceptive input. PMID- 25538614 TI - Toward embodied artificial cognition: TIME is on my side. PMID- 25538615 TI - Detection of bacterial antigens and Alzheimer's disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of Chlamydia pneumoniae. AB - Pathology consistent with that observed in Alzheimer's disease (AD) has previously been documented following intranasal infection of normal wild-type mice with Chlamydia pneumoniae (Cpn) isolated from an AD brain (96-41). In the current study, BALB/c mice were intranasally infected with a laboratory strain of Cpn, AR-39, and brain and olfactory bulbs were obtained at 1-4 months post infection (pi). Immunohistochemistry for amyloid beta or Cpn antigens was performed on sections from brains of infected or mock-infected mice. Chlamydia specific immunolabeling was identified in olfactory bulb tissues and in cerebrum of AR-39 infected mice. The Cpn specific labeling was most prominent at 1 month pi and the greatest burden of amyloid deposition was noted at 2 months pi, whereas both decreased at 3 and 4 months. Viable Cpn was recovered from olfactory bulbs of 3 of 3 experimentally infected mice at 1 and 3 months pi, and in 2 of 3 mice at 4 months pi. In contrast, in cortical tissues of infected mice at 1 and 4 months pi no viable organism was obtained. At 3 months pi, only 1 of 3 mice had a measurable burden of viable Cpn from the cortical tissues. Mock-infected mice (0 of 3) had no detectable Cpn in either olfactory bulbs or cortical tissues. These data indicate that the AR-39 isolate of Cpn establishes a limited infection predominantly in the olfactory bulbs of BALB/c mice. Although infection with the laboratory strain of Cpn promotes deposition of amyloid beta, this appears to resolve following reduction of the Cpn antigen burden over time. Our data suggest that infection with the AR-39 laboratory isolate of Cpn results in a different course of amyloid beta deposition and ultimate resolution than that observed following infection with the human AD-brain Cpn isolate, 96-41. These data further support that there may be differences, possibly in virulence factors, between Cpn isolates in the generation of sustainable AD pathology. PMID- 25538617 TI - The effect of functional hearing loss and age on long- and short-term visuospatial memory: evidence from the UK biobank resource. AB - The UK Biobank offers cross-sectional epidemiological data collected on >500,000 individuals in the UK between 40 and 70 years of age. Using the UK Biobank data, the aim of this study was to investigate the effects of functional hearing loss and hearing aid usage on visuospatial memory function. This selection of variables resulted in a sub-sample of 138,098 participants after discarding extreme values. A digit triplets functional hearing test was used to divide the participants into three groups: poor, insufficient and normal hearers. We found negative relationships between functional hearing loss and both visuospatial working memory (i.e., a card pair matching task) and visuospatial, episodic long term memory (i.e., a prospective memory task), with the strongest association for episodic long-term memory. The use of hearing aids showed a small positive effect for working memory performance for the poor hearers, but did not have any influence on episodic long-term memory. Age also showed strong main effects for both memory tasks and interacted with gender and education for the long-term memory task. Broader theoretical implications based on a memory systems approach will be discussed and compared to theoretical alternatives. PMID- 25538619 TI - Glutathione depletion in survival and apoptotic pathways. PMID- 25538621 TI - Pharmacoeconomic studies in Nepal: the need of the hour. PMID- 25538620 TI - Strategy for communicating benefit-risk decisions: a comparison of regulatory agencies' publicly available documents. AB - The assessment report formats of four major regulatory reference agencies, US Food and Drug Administration, European Medicines Agency, Health Canada, and Australia's Therapeutic Goods Administration were compared to a benefit-risk (BR) documentation template developed by the Centre for Innovation in Regulatory Science and a four-member Consortium on Benefit-Risk Assessment. A case study was also conducted using a US FDA Medical Review, the European Public Assessment Report and Australia's Public Assessment Report for the same product. Compared with the BR Template, existing regulatory report formats are inadequate regarding the listing of benefits and risks, the assigning of relative importance and values, visualization and the utilization of a detailed, systematic, standardized structure. The BR Template is based on the principles of BR assessment common to major regulatory agencies. Given that there are minimal differences among the existing regulatory report formats, it is timely to consider the feasibility of a universal template. PMID- 25538618 TI - Toll-like receptors in systemic lupus erythematosus: potential for personalized treatment. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. The symptoms of SLE, progression of pathology and the array of autoantibodies present in the serum differ significantly from patient to patient, which calls for a personalized approach to treatment. SLE is polygenic and strongly influenced by gender, ethnicity, and environmental factors. Data from genome-wide association studies suggests that polymorphisms in as many as 100 genes contribute to SLE susceptibility. Recent research has focused on genes associated with Toll-like receptors (TLRs), type I interferons, immune regulation pathways, and immune complex clearance. TLR7 and TLR9 have been extensively studied using lupus-prone mouse models. In multiple systems overexpression of TLR7 drives disease progression but interestingly, a loss of TLR9 results in an almost identical phenotype. While TLR7 overexpression has been linked to human SLE, the possible role of TLR9 in human disease remains elusive. In the present review, we focus on TLR polymorphisms and TLR expression in SLE patients and discuss their potential as biomarkers for individualized treatment. PMID- 25538622 TI - A mathematics for medicine: The Network Effect. AB - The theory of medicine and its complement systems biology are intended to explain the workings of the large number of mutually interdependent complex physiologic networks in the human body and to apply that understanding to maintaining the functions for which nature designed them. Therefore, when what had originally been made as a simplifying assumption or a working hypothesis becomes foundational to understanding the operation of physiologic networks it is in the best interests of science to replace or at least update that assumption. The replacement process requires, among other things, an evaluation of how the new hypothesis affects modern day understanding of medical science. This paper identifies linear dynamics and Normal statistics as being such arcane assumptions and explores some implications of their retirement. Specifically we explore replacing Normal with fractal statistics and examine how the latter are related to non-linear dynamics and chaos theory. The observed ubiquity of inverse power laws in physiology entails the need for a new calculus, one that describes the dynamics of fractional phenomena and captures the fractal properties of the statistics of physiological time series. We identify these properties as a necessary consequence of the complexity resulting from the network dynamics and refer to them collectively as The Network Effect. PMID- 25538616 TI - Buying time: a rationale for examining the use of circadian rhythm and sleep interventions to delay progression of mild cognitive impairment to Alzheimer's disease. AB - As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia's annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer's disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Abeta), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD-though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-epsilon4 is proinflammatory and individuals with this genotype accumulate more Abeta, are at high risk of developing AD, and almost half of all AD patients have at least one epsilon4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Abeta clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the epsilon4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia. PMID- 25538623 TI - Utilizing past and present mouse systems to engineer more relevant pancreatic cancer models. AB - The study of pancreatic cancer has prompted the development of numerous mouse models that aim to recapitulate the phenotypic and mechanistic features of this deadly malignancy. This review accomplishes two tasks. First, it provides an overview of the models that have been used as representations of both the neoplastic and carcinoma phenotypes. Second, it presents new modeling schemes that ultimately will serve to more faithfully capture the temporal and spatial progression of the human disease, providing platforms for improved understanding of the role of non-epithelial compartments in disease etiology as well as evaluating therapeutic approaches. PMID- 25538626 TI - Syncope: epidemiology, etiology, and prognosis. AB - Syncope is a common medical problem, with a frequency between 15% and 39%. In the general population, the annual number episodes are 18.1-39.7 per 1000 patients, with similar incidence between genders. The first report of the incidence of syncope is 6.2 per 1000 person-years. However, there is a significant increase in the incidence of syncope after 70 years of age with rate annual 19.5 per thousand individuals after 80 years. It presents a recurrence rate of 35% and 29% of physical injury. Among the causes of syncope, the mediated neural reflex, known as neurocardiogenic or vasovagal syncope, is the most frequent. The others are of cardiac origin, orthostatic hypotension, carotid sinus hypersensitivity, neurological and endocrinological causes and psychiatric disorders. The diagnosis of syncope can be made by clinical method associated with the electrocardiogram in up 50% of patients. Its prognosis is determined by the underlying etiology specifically the presence and severity of cardiac disease. The annual mortality can reach between 18 and 33% if cardiac cause, and between 0 and 12% if the non cardiac cause. Thus, it is imperative to identify its cause and risk stratification for positive impact in reducing morbidity and mortality. PMID- 25538624 TI - Characterization of heme binding to recombinant alpha1-microglobulin. AB - BACKGROUND: Alpha-1-microglobulin (A1M), a small lipocalin protein found in plasma and tissues, has been identified as a heme and radical scavenger that may participate in the mitigation of toxicities caused by degradation of hemoglobin. The objective of this work was to investigate heme interactions with A1M in vitro using various analytical techniques and to optimize analytical methodology suitable for rapid evaluation of the ligand binding properties of recombinant A1M versions. METHODS: To examine heme binding properties of A1M we utilized UV/Vis absorption spectroscopy, visible circular dichroism (CD), catalase-like activity, migration shift electrophoresis, and surface plasmon resonance (SPR), which was specifically developed for the assessment of His-tagged A1M. RESULTS: The results of this study confirm that A1M is a heme binding protein that can accommodate heme at more than one binding site and/or in coordination with different amino acid residues depending upon heme concentration and ligand-to-protein molar ratio. UV/Vis titration of A1M with heme revealed an unusually large bathochromic shift, up to 38 nm, observed for heme binding to a primary binding site. UV/Vis spectroscopy, visible CD and catalase-like activity suggested that heme is accommodated inside His-tagged (tgA1M) and tagless A1M (ntA1M) in a rather similar fashion although the His-tag is very likely involved into coordination with iron of the heme molecule. SPR data indicated kinetic rate constants and equilibrium binding constants with KD values in a MUM range. CONCLUSIONS: This study provided experimental evidence of the A1M heme binding properties by aid of different techniques and suggested an analytical methodology for a rapid evaluation of ligand-binding properties of recombinant A1M versions, also suitable for other His-tagged proteins. PMID- 25538625 TI - Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior. AB - In most tissues, the function of Ca(2+)- and voltage-gated K(+) (BK) channels is modified in response to ethanol concentrations reached in human blood during alcohol intoxication. In general, modification of BK current from ethanol-naive preparations in response to brief ethanol exposure results from changes in channel open probability without modification of unitary conductance or change in BK protein levels in the membrane. Protracted and/or repeated ethanol exposure, however, may evoke changes in BK expression. The final ethanol effect on BK open probability leading to either BK current potentiation or BK current reduction is determined by an orchestration of molecular factors, including levels of activating ligand (Ca(2+) i), BK subunit composition and post-translational modifications, and the channel's lipid microenvironment. These factors seem to allosterically regulate a direct interaction between ethanol and a recognition pocket of discrete dimensions recently mapped to the channel-forming (slo1) subunit. Type of ethanol exposure also plays a role in the final BK response to the drug: in several central nervous system regions (e.g., striatum, primary sensory neurons, and supraoptic nucleus), acute exposure to ethanol reduces neuronal excitability by enhancing BK activity. In contrast, protracted or repetitive ethanol administration may alter BK subunit composition and membrane expression, rendering the BK complex insensitive to further ethanol exposure. In neurohypophyseal axon terminals, ethanol potentiation of BK channel activity leads to a reduction in neuropeptide release. In vascular smooth muscle, however, ethanol inhibition of BK current leads to cell contraction and vascular constriction. PMID- 25538627 TI - Petrosal ganglion: a more complex role than originally imagined. AB - The petrosal ganglion (PG) is a peripheral sensory ganglion, composed of pseudomonopolar sensory neurons that innervate the posterior third of the tongue and the carotid sinus and body. According to their electrical properties PG neurons can be ascribed to one of two categories: (i) neurons with action potentials presenting an inflection (hump) on its repolarizing phase and (ii) neurons with fast and brisk action potentials. Although there is some correlation between the electrophysiological properties and the sensory modality of the neurons in some species, no general pattern can be easily recognized. On the other hand, petrosal neurons projecting to the carotid body are activated by several transmitters, with acetylcholine and ATP being the most conspicuous in most species. Petrosal neurons are completely surrounded by a multi-cellular sheet of glial (satellite) cells that prevents the formation of chemical or electrical synapses between neurons. Thus, PG neurons are regarded as mere wires that communicate the periphery (i.e., carotid body) and the central nervous system. However, it has been shown that in other sensory ganglia satellite glial cells and their neighboring neurons can interact, partly by the release of chemical neuro-glio transmitters. This intercellular communication can potentially modulate the excitatory status of sensory neurons and thus the afferent discharge. In this mini review, we will briefly summarize the general properties of PG neurons and the current knowledge about the glial-neuron communication in sensory neurons and how this phenomenon could be important in the chemical sensory processing generated in the carotid body. PMID- 25538628 TI - New avenues for regulation of lipid metabolism by thyroid hormones and analogs. AB - Weight loss due to negative energy balance is a goal in counteracting obesity and type 2 diabetes mellitus. The thyroid is known to be an important regulator of energy metabolism through the action of thyroid hormones (THs). The classic, active TH, 3,5,3'-triiodo-L-thyronine (T3) acts predominantly by binding to nuclear receptors termed TH receptors (TRs), that recognize TH response elements (TREs) on the DNA, and so regulate transcription. T3 also acts through "non genomic" pathways that do not necessarily involve TRs. Lipid-lowering therapies have been suggested to have potential benefits, however, the establishment of comprehensive therapeutic strategies is still awaited. One drawback of using T3 in counteracting obesity has been the occurrence of heart rhythm disturbances. These are mediated through one TR, termed TRalpha. The end of the previous century saw the exploration of TH mimetics that specifically bind to TR beta in order to prevent cardiac disturbances, and TH derivatives such as 3,5-diiodo-L thyronine (T2), that possess interesting biological activities. Several TH derivatives and functional analogs have low affinity for the TRs, and are suggested to act predominantly through non-genomic pathways. All this has opened new perspectives in thyroid physiology and TH derivative usage as anti-obesity therapies. This review addresses the pros and cons of these compounds, in light of their effects on energy balance regulation and on lipid/cholesterol metabolism. PMID- 25538629 TI - The large conductance Ca(2+) -activated K(+) (BKCa) channel regulates cell proliferation in SH-SY5Y neuroblastoma cells by activating the staurosporine sensitive protein kinases. AB - Here we investigated on the role of the calcium activated K(+)-channels(BKCa) on the regulation of the neuronal viability. Recordings of the K(+)-channel current were performed using patch-clamp technique in human neuroblastoma cells (SH-SY5Y) in parallel with measurements of the cell viability in the absence or presence of the BKCa channel blockers iberiotoxin(IbTX) and tetraethylammonium (TEA) and the BKCa channel opener NS1619. Protein kinase C/A (PKC, PKA) activities in the cell lysate were investigated in the presence/absence of drugs. The whole-cell K(+) current showed a slope conductance calculated at negative membrane potentials of 126.3 pS and 1.717 nS(n = 46) following depolarization. The intercept of the I/V curve was -33 mV. IbTX(10(-8) - 4 * 10(-7) M) reduced the K(+)-current at +30 mV with an IC50 of 1.85 * 10(-7) M and an Imax of -46% (slope = 2.198) (n = 21). NS1619(10-100 * 10(-6) M) enhanced the K(+)-current of +141% (n = 6), at -10 mV(Vm). TEA(10(-5)-10(-3) M) reduced the K(+)-current with an IC50 of 3.54 * 10( 5) M and an Imax of -90% (slope = 0.95) (n = 5). A concentration-dependent increase of cell proliferation was observed with TEA showing a maximal proliferative effect(MPE) of +38% (10(-4) M). IbTX showed an MPE of +42% at 10( 8) M concentration, reducing it at higher concentrations. The MPE of the NS1619(100 * 10(-6) M) was +42%. The PKC inhibitor staurosporine (0.2-2 * 10(-6) M) antagonized the proliferative actions of IbTX and TEA. IbTX (10 * 10(-9) M), TEA (100 * 10(-6) M), and the NS1619 significantly enhanced the PKC and PKA activities in the cell lysate with respect to the controls. These results suggest that BKCa channel regulates proliferation of the SH-SY5Y cells through PKC and PKA protein kinases. PMID- 25538631 TI - Long-Term Heavy Ketamine Use is Associated with Spatial Memory Impairment and Altered Hippocampal Activation. AB - Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users. PMID- 25538630 TI - Hormonal regulation of the hypothalamic melanocortin system. AB - Regulation of energy homeostasis is fundamental for life. In animal species and humans, the Central Nervous System (CNS) plays a critical role in such regulation by integrating peripheral signals and modulating behavior and the activity of peripheral organs. A precise interplay between CNS and peripheral signals is necessary for the regulation of food intake and energy expenditure in the maintenance of energy balance. Within the CNS, the hypothalamus is a critical center for monitoring, processing and responding to peripheral signals, including hormones such as ghrelin, leptin, and insulin. Once in the brain, peripheral signals regulate neuronal systems involved in the modulation of energy homeostasis. The main hypothalamic neuronal circuit in the regulation of energy metabolism is the melanocortin system. This review will give a summary of the most recent discoveries on the hormonal regulation of the hypothalamic melanocortin system in the control of energy homeostasis. PMID- 25538633 TI - Functional and structural alterations in the cingulate motor area relate to decreased fronto-striatal coupling in major depressive disorder with psychomotor disturbances. AB - Psychomotor disturbances are a classic feature of major depressive disorders. These can manifest as lack of facial expressions and decreased speech production, reduced body posture and mobility, and slowed voluntary movement. The neural correlates of psychomotor disturbances in depression are poorly understood but it has been suggested that outputs from the cingulate motor area (CMA) to striatal motor regions, including the putamen, could be involved. We used functional and structural magnetic resonance imaging to conduct a region-of-interest analysis to test the hypotheses that neural activation patterns related to motor production and gray matter volumes in the CMA would be different between depressed subjects displaying psychomotor disturbances (n = 13) and matched healthy controls (n = 13). In addition, we conducted a psychophysiological interaction analysis to assess the functional coupling related to self-paced finger-tapping between the caudal CMA and the posterior putamen in patients compared to controls. We found a cluster of increased neural activation, adjacent to a cluster of decreased gray matter volume in the caudal CMA in patients compared to controls. The functional coupling between the left caudal CMA and the left putamen during finger-tapping task performance was additionally decreased in patients compared to controls. In addition, the strength of the functional coupling between the left caudal CMA and the left putamen was negatively correlated with the severity of psychomotor disturbances in the patient group. In conclusion, we found converging evidence for involvement of the caudal CMA and putamen in the generation of psychomotor disturbances in depression. PMID- 25538635 TI - ASPIRE Model for Treating Cannabis and Other Substance Use Disorders: A Novel Personalized-Medicine Framework. PMID- 25538634 TI - Reducing the symptomatology of panic disorder: the effects of a yoga program alone and in combination with cognitive-behavioral therapy. AB - INTRODUCTION: Yoga is a holistic system of different mind-body practices that can be used to improve mental and physical health. It has been shown to reduce perceived stress and anxiety as well as improve mood and quality of life. Research documenting the therapeutic benefits of yoga has grown progressively for the past decades and now includes controlled trials on a variety of mental health conditions such as depression, anxiety, and panic disorder. OBJECTIVES: The primary goal of this study was to investigate the effects of yoga in patients suffering from panic disorder. We aimed at observing the efficacy of yoga techniques on reducing the symptomatology of panic disorder (anxiety and agoraphobia), compared to a combined intervention of yoga and psychotherapy. METHOD: Twenty subjects previously diagnosed with panic disorder were selected. Subjects were randomly assigned to both experimental groups: Group 1 (G1-Yoga: 10 subjects) attended yoga classes and Group 2 (G2-CBT + Yoga: 10 subjects) participated in a combined intervention of yoga practice followed by a cognitive behavioral therapy (CBT) session. Both interventions occurred weekly for 100 min and lasted 2 months. Subjects were evaluated two times during the study: pre-test and post-test. Psychometric tools included the Beck Anxiety Inventory (BAI), Hamilton Anxiety Rating Scale (HAM-A), The Panic Beliefs Inventory (PBI), and Body Sensations Questionnaire (BSQ). RESULTS: Statistical analysis showed significant reductions in anxiety levels associated with panic disorder (G1: BAI p = 0.035, HAM-A - p = 0.000; G2: BAI - p = 0.002, HAM-A - p = 0.000), panic related beliefs (G1: PBI - p = 0.000; G2: PBI - p = 0.000) and panic-related body sensations (G1: BSQ - p = 0.000; G2: BSQ - p = 0.000) both in G1 and G2. However, the combination of yoga and CBT (G2) showed even further reductions in all observed parameters (mean values). CONCLUSION: This study observed significant improvement in panic symptomatology following both the practice of yoga and the combination of yoga and psychotherapy. While contemplative techniques such as yoga promote a general change in dealing with private events, CBT teaches how to modify irrational beliefs and specific cognitive distortions. The results observed in G2 might indicate that the techniques complemented each other, increasing the intervention efficacy. These findings are in agreement with many investigations found in the literature which observed improvements in different mental health parameters after the practice of contemplative techniques alone or combined to psychotherapy. Future research joining psychological and physiological variables could help better elucidate the mechanisms through which mind-body practices work to improve mental health. PMID- 25538632 TI - The kappa opioid receptor: from addiction to depression, and back. AB - Comorbidity is a major issue in psychiatry that notably associates with more severe symptoms, longer illness duration, and higher service utilization. Therefore, identifying key clusters of comorbidity and exploring the underlying pathophysiological mechanisms represent important steps toward improving mental health care. In the present review, we focus on the frequent association between addiction and depression. In particular, we summarize the large body of evidence from preclinical models indicating that the kappa opioid receptor (KOR), a member of the opioid neuromodulatory system, represents a central player in the regulation of both reward and mood processes. Current data suggest that the KOR modulates overlapping neuronal networks linking brainstem monoaminergic nuclei with forebrain limbic structures. Rewarding properties of both drugs of abuse and natural stimuli, as well as the neurobiological effects of stressful experiences, strongly interact at the level of KOR signaling. In addiction models, activity of the KOR is potentiated by stressors and critically controls drug-seeking and relapse. In depression paradigms, KOR signaling is responsive to a variety of stressors, and mediates despair-like responses. Altogether, the KOR represents a prototypical substrate of comorbidity, whereby life experiences converge upon common brain mechanisms to trigger behavioral dysregulation and increased risk for distinct but interacting psychopathologies. PMID- 25538638 TI - An investigation into prospective memory in children with developmental dyslexia. AB - Developmental dyslexia hinders reading and writing acquisition of around 5-10% of the children all over the world. However, little is known about role of prospective memory among dyslexics. Prospective memory is realization of delayed intention. Realization of delayed intention requires self initiated process. The present study explored the role of memory (prospective and retrospective memory), meta-memory and attention among dyslexic's children. One hundred and fifteen children (51 dyslexics and 64 normal controls) participated in the study. Prospective and retrospective memory questionnaire, everyday attention questionnaire and meta-memory were administered on children. Analysis of variance was used to analyses the data. All the main effects were significant. Some interactions were also found to be significant. Results suggest that dyslexic's performance on memory (prospective and retrospective memory) was worse than normal control. Meta-memory influences both dyslexics and normal control on prospective and retrospective memory. However, meta-memory affected dyslexics much more than normal control group. Similarly, significant differential effects were observed for simple, difficult and mixed attentional condition among between dyslexics and normal control. Dyslexic's performance was deteriorated as compared to normal control group. The findings of the study are discussed in the light of the existing literature. PMID- 25538637 TI - Adaptive learning in a compartmental model of visual cortex-how feedback enables stable category learning and refinement. AB - The categorization of real world objects is often reflected in the similarity of their visual appearances. Such categories of objects do not necessarily form disjunct sets of objects, neither semantically nor visually. The relationship between categories can often be described in terms of a hierarchical structure. For instance, tigers and leopards build two separate mammalian categories, both of which are subcategories of the category Felidae. In the last decades, the unsupervised learning of categories of visual input stimuli has been addressed by numerous approaches in machine learning as well as in computational neuroscience. However, the question of what kind of mechanisms might be involved in the process of subcategory learning, or category refinement, remains a topic of active investigation. We propose a recurrent computational network architecture for the unsupervised learning of categorial and subcategorial visual input representations. During learning, the connection strengths of bottom-up weights from input to higher-level category representations are adapted according to the input activity distribution. In a similar manner, top-down weights learn to encode the characteristics of a specific stimulus category. Feedforward and feedback learning in combination realize an associative memory mechanism, enabling the selective top-down propagation of a category's feedback weight distribution. We suggest that the difference between the expected input encoded in the projective field of a category node and the current input pattern controls the amplification of feedforward-driven representations. Large enough differences trigger the recruitment of new representational resources and the establishment of additional (sub-) category representations. We demonstrate the temporal evolution of such learning and show how the proposed combination of an associative memory with a modulatory feedback integration successfully establishes category and subcategory representations. PMID- 25538639 TI - Next-generation leadership development in family businesses: the critical roles of shared vision and family climate. AB - The multigenerational survival rate for family-owned businesses is not good. Lack of a shared vision for the family enterprise and weak next-generation leadership are often cited as two of the leading reasons for the failure of family firms to successfully transition from one generation of family ownership to the next. The climate of the business-owning family has also been suggested as important to the performance of the family enterprise. Despite these commonly held tenets, there is a lack of rigorous quantitative research that explores the relationships among these three factors. To address this gap, a quantitative study of 100 next generation family firm leaders and 350 family and non-family leaders and employees with whom they work was conducted. The results demonstrate that a shared vision for the family business has a strong effect on the leadership effectiveness of next-generation family leaders and a moderate effect on the degree to which they are positively engaged with their work. The findings also show that two dimensions of family climate significantly influence the likelihood that a shared vision for the family firm has been created. Open communication in the family is positively related to the presence of a shared vision for the business. Intergenerational authority, which refers to a senior generation that exercises unquestioned authority and sets the rules, is negatively related to the presence of a shared vision. Surprisingly, a third dimension of family climate, cognitive cohesion, which includes shared values in the family, had no relationship with the degree to which there was a shared vision for the family business. The implications for family business owners is that they would be wise to spend as much time on fostering a positive family climate characterized by open communication as they do on creating and executing a successful business strategy if their goal is to pass the business from one generation of family owners to the next. PMID- 25538640 TI - Young children's difficulties in switching from rhythm production to temporal interval production (>1 s). AB - This study examined the young children's abilities to switch from rhythm production, with short inter-tap intervals (ITIs), to temporal interval production, with long ITI (>1 s), in a sensorimotor synchronization task. Children aged 3- and 5-year-olds were given six sessions of synchronization. In a control group, they had to synchronize their ITI to an inter-stimulus interval (ISI) of 4 s. In the experimental group, they must progressively increase their ITI for one session to the next (from 0.4 to 4.0-s ISI). Our results showed that the 5-year-olds produced longer ITI that the 3-year-olds in synchronization. However, the value of ITI in the 5-year-olds never exceeded 1.5 s, with more variable ITI in the control than in the experimental group. In addition, at 5 years, boys had more difficulties than girls in changing their tapping rhythm. These results suggest a temporal window in sensorimotor synchronization, beyond which the rhythm is lost and the synchronization becomes difficult. PMID- 25538641 TI - Bilingual education searching for promising didactic proposals. PMID- 25538636 TI - A clinical review of the treatment of catatonia. AB - Catatonia is a severe motor syndrome with an estimated prevalence among psychiatric inpatients of about 10%. At times, it is life-threatening especially in its malignant form when complicated by fever and autonomic disturbances. Catatonia can accompany many different psychiatric illnesses and somatic diseases. In order to recognize the catatonic syndrome, apart from thorough and repeated observation, a clinical examination is needed. A screening instrument, such as the Bush-Francis Catatonia Rating Scale, can guide the clinician through the neuropsychiatric examination. Although severe and life-threatening, catatonia has a good prognosis. Research on the treatment of catatonia is scarce, but there is overwhelming clinical evidence of the efficacy of benzodiazepines, such as lorazepam, and electroconvulsive therapy. PMID- 25538642 TI - Time-varying boundaries for diffusion models of decision making and response time. AB - Diffusion models are widely-used and successful accounts of the time course of two-choice decision making. Most diffusion models assume constant boundaries, which are the threshold levels of evidence that must be sampled from a stimulus to reach a decision. We summarize theoretical results from statistics that relate distributions of decisions and response times to diffusion models with time varying boundaries. We then develop a computational method for finding time varying boundaries from empirical data, and apply our new method to two problems. The first problem involves finding the time-varying boundaries that make diffusion models equivalent to the alternative sequential sampling class of accumulator models. The second problem involves finding the time-varying boundaries, at the individual level, that best fit empirical data for perceptual stimuli that provide equal evidence for both decision alternatives. We discuss the theoretical and modeling implications of using time-varying boundaries in diffusion models, as well as the limitations and potential of our approach to their inference. PMID- 25538643 TI - Cross-cultural differences in crossmodal correspondences between basic tastes and visual features. AB - We report a cross-cultural study designed to investigate crossmodal correspondences between a variety of visual features (11 colors, 15 shapes, and 2 textures) and the five basic taste terms (bitter, salty, sour, sweet, and umami). A total of 452 participants from China, India, Malaysia, and the USA viewed color patches, shapes, and textures online and had to choose the taste term that best matched the image and then rate their confidence in their choice. Across the four groups of participants, the results revealed a number of crossmodal correspondences between certain colors/shapes and bitter, sour, and sweet tastes. Crossmodal correspondences were also documented between the color white and smooth/rough textures on the one hand and the salt taste on the other. Cross cultural differences were observed in the correspondences between certain colors, shapes, and one of the textures and the taste terms. The taste-patterns shown by the participants from the four countries tested in the present study are quite different from one another, and these differences cannot easily be attributed merely to whether a country is Eastern or Western. These findings therefore highlight the impact of cultural background on crossmodal correspondences. As such, they raise a number of interesting questions regarding the neural mechanisms underlying crossmodal correspondences. PMID- 25538645 TI - Phonetic compliance: a proof-of-concept study. AB - In this paper, we introduce the concept of "phonetic compliance," which is defined as the intrinsic individual ability to produce speech sounds that are unusual in the native language, and constitutes a part of the ability to acquire L2 phonetics and phonology. We argue that phonetic compliance represents a systematic source of variance that needs to be accounted for if one wants to improve the control over the independent variables manipulated in SLA experimental studies. We then present the results of a two-fold proof-of-concept study aimed at testing the feasibility of assessing phonetic compliance in terms of gradient. In study 1, a pilot data collection paradigm is implemented on an occasional sample of 10 native French speakers engaged in two reproduction tasks involving respectively vowels and aspirated stops, and data are analyzed using descriptive statistics. In study 2, complementary data including L1-typical realizations are collected, resulting in the development of a first set of indicators that may be useful to appropriately assess, and further refine the concept of, phonetic compliance. Based on a critical analysis of the contributions and limitations of the proof-of-concept study, general discussion formulates the guidelines for the following stages of development of a reliable and valid test of phonetic compliance. PMID- 25538644 TI - Behavioral and ERP measures of attentional bias to threat in the dot-probe task: poor reliability and lack of correlation with anxiety. AB - The dot-probe task is often considered a gold standard in the field for investigating attentional bias to threat. However, serious issues with the task have been raised. Specifically, a number of studies have demonstrated that the traditional reaction time (RT) measure of attentional bias to threat in the dot probe task has poor internal reliability and poor test-retest reliability. In addition, although threatening stimuli capture attention in other paradigms, attentional bias to threat has not usually been found in typical research participants in the dot-probe task. However, when attention is measured in the dot-probe task with the N2pc component of the event-related potential waveform, substantial attentional orienting to threat is observed, and the internal reliability is moderate. To provide a rigorous comparison of the reliability of this N2pc measure and the conventional behavioral measure, as well as to examine the relationship of these measures to anxiety, the present study examined the N2pc in conjunction with RT in the dot-probe task in a large sample of participants (N = 96). As in previous studies, RT showed no bias to threatening images across the sample and exhibited poor internal reliability. Moreover, this measure did not relate to trait anxiety. By contrast, the N2pc revealed a significant initial shift of attention to threat, and this measure was internally reliable. However, the N2pc was not correlated with trait anxiety, indicating that it does not provide a meaningful index of individual differences in anxiety in the dot-probe task. Together, these results indicate a serious need to develop new tasks and methods to more reliably investigate attentional bias to threat and its relationship to anxiety in both clinical and non-clinical populations. PMID- 25538646 TI - Insights into the neural mechanisms underlying hand praxis: implications for the neurocognitive rehabilitation of apraxia. PMID- 25538647 TI - Attentional control mediates the relationship between social anhedonia and social impairment. AB - Social anhedonia (SA), a trait-like disinterest in social contact and diminished capacity to experience pleasure from social interactions, is consistently associated with social impairments in both healthy and clinical populations. However, the mechanisms underlying the relationship between SA and social impairment are poorly understood. Attentional control, selecting and focusing on relevant information and inhibiting irrelevant, may be one such mechanism. We examined individual differences in SA, attentional control, and social impairment in 108 healthy adults. High SA related to low attentional control and high social impairment. Moreover, attentional control mediated the relationship between SA and social impairment, establishing attentional control as one mechanism underlying aberrations in the fundamental human need for social contact. Although both attentional deficits and social impairment have been separately noted in SA, the relationship between SA, attentional control and social impairment in this non-clinical sample reflects a novel contribution. PMID- 25538648 TI - A psychologically-based taxonomy of misdirection. AB - Magicians use misdirection to prevent you from realizing the methods used to create a magical effect, thereby allowing you to experience an apparently impossible event. Magicians have acquired much knowledge about misdirection, and have suggested several taxonomies of misdirection. These describe many of the fundamental principles in misdirection, focusing on how misdirection is achieved by magicians. In this article we review the strengths and weaknesses of past taxonomies, and argue that a more natural way of making sense of misdirection is to focus on the perceptual and cognitive mechanisms involved. Our psychologically based taxonomy has three basic categories, corresponding to the types of psychological mechanisms affected: perception, memory, and reasoning. Each of these categories is then divided into subcategories based on the mechanisms that control these effects. This new taxonomy can help organize magicians' knowledge of misdirection in a meaningful way, and facilitate the dialog between magicians and scientists. PMID- 25538649 TI - Inner experience in the scanner: can high fidelity apprehensions of inner experience be integrated with fMRI? AB - To provide full accounts of human experience and behavior, research in cognitive neuroscience must be linked to inner experience, but introspective reports of inner experience have often been found to be unreliable. The present case study aimed at providing proof of principle that introspection using one method, descriptive experience sampling (DES), can be reliably integrated with fMRI. A participant was trained in the DES method, followed by nine sessions of sampling within an MRI scanner. During moments where the DES interview revealed ongoing inner speaking, fMRI data reliably showed activation in classic speech processing areas including left inferior frontal gyrus. Further, the fMRI data validated the participant's DES observations of the experiential distinction between inner speaking and innerly hearing her own voice. These results highlight the precision and validity of the DES method as a technique of exploring inner experience and the utility of combining such methods with fMRI. PMID- 25538650 TI - Is tool-making knowledge robust over time and across problems? AB - In three studies, we explored the retention and transfer of tool-making knowledge, learnt from an adult demonstration, to other temporal and task contexts. All studies used a variation of a task in which children had to make a hook tool to retrieve a bucket from a tall transparent tube. Children who failed to innovate the hook tool independently saw a demonstration. In Study 1, we tested children aged 4-6 years (N = 53) who had seen the original demonstration 3 months earlier. Performance was excellent at the second time, indicating that children's knowledge was retained over the 3 month period. In Studies 2 and 3 we explored transfer of the new knowledge to other tasks. In Study 2, children were given two variants of the apparatus that differed in surface characteristics (e.g., shape and color). Participants generalized their knowledge to these new apparatuses even though the new pipecleaner also differed in size and color. Five to 6-year-olds (N = 22) almost always transferred their knowledge to problems where the same tool had to be made. Younger, 3- to 5-year-olds' (N = 46), performance was more variable. In Study 3, 4- to 7-year-olds (N = 146) saw a demonstration of hook making with a pipecleaner, but then had to make a tool by combining pieces of wooden dowel (or vice versa: original training on dowel, transfer to pipecleaner). Children did not transfer their tool-making knowledge to the new material. Children retained tool-making knowledge over time and transferred their knowledge to new situations in which they needed to make a similar tool from similar materials, but not different materials. We concluded that children's ability to use tool-making knowledge in novel situations is likely to depend on memory and analogical reasoning, with the latter continuing to develop during middle childhood. PMID- 25538651 TI - Consciousness doesn't overflow cognition. PMID- 25538652 TI - Personal vision: enhancing work engagement and the retention of women in the engineering profession. AB - This study examines how personal vision enhances work engagement and the retention of women in the engineering profession. Using a mixed method approach to understand the factors related to the retention of women in the engineering profession, we first interviewed women who persisted and women who opted out of the profession (Buse and Bilimoria, 2014). In these rich stories, we found that women who persisted had a personal vision that included their profession, and that this personal vision enabled them to overcome the bias, barriers and discrimination in the engineering workplace. To validate this finding on a larger population, we developed a scale to measure one's personal vision conceptualized as the ideal self (Boyatzis and Akrivou, 2006). The measure was tested in a pilot study and then used in a study of 495 women with engineering degrees. The findings validate that the ideal self is comprised of self-efficacy, hope, optimism and core identity. For these women, the ideal self directly impacts work engagement and work engagement directly impacts career commitment to engineering. The findings add to extant theory related to the role of personal vision and intentional change theory. From a practical perspective, these findings will aid efforts to retain women in engineering and other STEM professions. PMID- 25538653 TI - Improving visual functions in adult amblyopia with combined perceptual training and transcranial random noise stimulation (tRNS): a pilot study. AB - Amblyopia is a visual disorder due to an abnormal pattern of functional connectivity of the visual cortex and characterized by several visual deficits of spatial vision including impairments of visual acuity (VA) and of the contrast sensitivity function (CSF). Despite being a developmental disorder caused by reduced visual stimulation during early life (critical period), several studies have shown that extensive visual perceptual training can improve VA and CSF in people with amblyopia even in adulthood. With the present study we assessed whether a much shorter perceptual training regime, in association with high frequency transcranial electrical stimulation (hf-tRNS), was able to improve visual functions in a group of adult participants with amblyopia. Results show that, in comparison with previous studies where a large number sessions with a similar training regime were used (Polat et al., 2004), here just eight sessions of training in contrast detection under lateral masking conditions combined with hf-tRNS, were able to substantially improve VA and CSF in adults with amblyopia. PMID- 25538655 TI - Contingency and congruency switch in the congruency sequence effect: a reply to Blais, Stefanidi, and Brewer (2014). PMID- 25538654 TI - The undervalued self: social class and self-evaluation. AB - Social class ranks people on the social ladder of society, and in this research we examine how perceptions of economic standing shape the way that individuals evaluate the self. Given that reminders of one's own subordinate status in society are an indicator of how society values the self in comparison to others, we predicted that chronic lower perceptions of economic standing vis-a-vis others would explain associations between objective social class and negative self evaluation, whereas situation-specific reminders of low economic standing would elicit negative self-evaluations, particularly in those from lower-class backgrounds. In Study 1, perceptions of social class rank accounted for the positive relationship between objective material resource measures of social class and self-esteem. In Study 2, lower-class individuals who received a low (versus equal) share of economic resources in an economic game scenario reported more negative self-conscious emotions-a correlate of negative self-evaluation relative to upper-class individuals. Discussion focused on the implications of this research for understanding class-based cultural models of the self, and for how social class shapes self-evaluations chronically. PMID- 25538656 TI - Modulation of manual preference induced by lateralized practice diffuses over distinct motor tasks: age-related effects. AB - In this study we investigated the effect of use of the non-preferred left hand to practice different motor tasks on manual preference in children and adults. Manual preference was evaluated before, immediately after and 20 days following practice. Evaluation was made with tasks of distinct levels of complexity requiring reaching and manipulation of cards at different eccentricities in the workspace. Results showed that left hand use in adults induced increased preference of that hand at the central position when performing the simple task, while left hand use by the children induced increased preference of the left hand at the rightmost positions in the performance of the complex task. These effects were retained over the rest period following practice. Kinematic analysis showed that left hand use during practice did not lead to modification of intermanual performance asymmetry. These results indicate that modulation of manual preference was a consequence of higher frequency of use of the left hand during practice rather than of change in motor performance. Findings presented here support the conceptualization that confidence on successful performance when using a particular limb generates a bias in hand selection, which diffuses over distinct motor tasks. PMID- 25538658 TI - It's a kind of magic-what self-reports can reveal about the phenomenology of insight problem solving. AB - Magic tricks usually remain a mystery to the observer. For the sake of science, we offered participants the opportunity to discover the magician's secret method by repeatedly presenting the same trick and asking them to find out how the trick worked. In the context of insightful problem solving, the present work investigated the emotions that participants experience upon solving a magic trick. We assumed that these emotions form the typical "Aha! experience" that accompanies insightful solutions to difficult problems. We aimed to show that Aha! experiences can be triggered by magic tricks and to systematically explore the phenomenology of the Aha! experience by breaking it down into five previously postulated dimensions. 34 video clips of different magic tricks were presented up to three times to 50 participants who had to find out how the trick was accomplished, and to indicate whether they had experienced an Aha! during the solving process. Participants then performed a comprehensive quantitative and qualitative assessment of their Aha! experiences which was repeated after 14 days to control for its reliability. 41% of all suggested solutions were accompanied by an Aha! experience. The quantitative assessment remained stable across time in all five dimensions. Happiness was rated as the most important dimension. This primacy of positive emotions was also reflected in participants' qualitative self reports which contained more emotional than cognitive aspects. Implementing magic tricks as problem solving task, we could show that strong Aha! experiences can be triggered if a trick is solved. We could at least partially capture the phenomenology of Aha! by identifying one prevailing aspect (positive emotions), a new aspect (release of tension upon gaining insight into a magic trick) and one less important aspect (impasse). PMID- 25538659 TI - Influence of context-sensitive rules on the formation of orthographic representations in Spanish dyslexic children. AB - Spanish-speaking developmental dyslexics are mainly characterized by poor reading fluency. One reason for this lack of fluency could be a difficulty in creating and accessing lexical representations, because, as the self-teaching theory suggest, it is necessary to develop orthographic representations to use direct reading (Share, 1995). It is possible that this difficulty to acquire orthographic representations can be specifically related to words that contain context-sensitive graphemes, since it has been demonstrated that reading is affected by this kind of graphemes (Barca et al., 2007). In order to test this possibility we compared a group of dyslexic children with a group of normal readers (9-13 years), in a task of repeated reading. Pseudo-words (half short and half long) with simple and contextual dependent rules were used. The length effect reduction on the reading speed, after repeated exposure, was considered an indicator of orthographic representation development, as the length effect is strong when reading unknown words, but absent when reading familiar words. The results show that dyslexic children have difficulties in developing orthographic representations, not only with context-sensitive graphemes, but also with simple graphemes. In contrast to the control children, in the dyslexic group differences between reading times for short and long stimuli remained without significant changes after six presentations. Besides, this happened with sensitive context rules and also with simple grapheme-phoneme conversion rules. On the other hand, response and articulation times were greatly affected by length in dyslexic children, indicating the use of serial reading. Results suggest that the problems related to storing orthographic representations could be caused by a learning deficit, independently of whether the word contained context-sensitive rules or not. PMID- 25538657 TI - For your eyes only: effect of confederate's eye level on reach-to-grasp action. AB - Previous studies have shown that the spatio-temporal parameters of reach-to-grasp movement are influenced by the social context in which the motor action is performed. In particular, when interacting with a confederate, movements are slower, with longer initiation times and more ample trajectories, which has been interpreted as implicit communicative information emerging through voluntary movement to catch the partner's attention and optimize cooperation (Quesque et al., 2013). Because gaze is a crucial component of social interactions, the present study evaluated the role of a confederate's eye level on the social modulation of trajectory curvature. An actor and a partner facing each other took part in a cooperative task consisting, for one of them, of grasping and moving a wooden dowel under time constraints. Before this Main action, the actor performed a Preparatory action, which consisted of placing the wooden dowel on a central marking. The partner's eye level was unnoticeably varied using an adjustable seat that matched or was higher than the actor's seat. Our data confirmed the previous effects of social intention on motor responses. Furthermore, we observed an effect of the partner's eye level on the Preparatory action, leading the actors to exaggerate unconsciously the trajectory curvature in relation to their partner's eye level. No interaction was found between the actor's social intention and their partner's eye level. These results suggest that other bodies are implicitly taken into account when a reach-to-grasp movement is produced in a social context. PMID- 25538660 TI - ISPC effect is not observed when the word comes too late: a time course analysis. AB - The item-specific proportion congruency (ISPC) effect is demonstrated by a smaller Stroop effect observed for mostly incongruent items compared to mostly congruent items. Currently, there is a continuing debate on whether conflict driven item-specific control processes or stimulus-response contingency learning account for the ISPC effect. In the present study, we conducted two experiments to investigate the time course of the ISPC effect with a stimulus onset asynchrony (SOA) manipulation. Both negative and positive SOAs were used in order to manipulate the contingency learning between the word and the color dimensions. We also combined this SOA manipulation with a set size manipulation (Bugg and Hutchison, 2013) to moderate the contribution of contingency learning and item specific processes to the observed ISPC effect. We expected that the change in the magnitude of the ISPC effect as a result of SOA would follow different patterns for the 2-item and 4-item set conditions. Results showed that the SOA manipulation influenced the ISPC effect. Specifically, when the word followed the color with a 200 ms delay, the observed ISPC effect was smaller, if at all present, than the ISPC effects in other negative and positive SOA conditions, regardless of set size. In conclusion, our results showed that the ISPC effect was not observed if the word arrived too late. We also conducted additional awareness and RT distribution analyses (delta plots) to further investigate the ISPC effect. These analyses showed that a higher percentage of participants were aware of the ISPC manipulation in the 2-item set condition compared to the 4-item set condition. Delta plots revealed that the ISPC effect was smaller for fastest responses and increased as the responses got slower. PMID- 25538661 TI - Spatial navigation, episodic memory, episodic future thinking, and theory of mind in children with autism spectrum disorder: evidence for impairments in mental simulation? AB - This study explored spatial navigation alongside several other cognitive abilities that are thought to share common underlying neurocognitive mechanisms (e.g., the capacity for self-projection, scene construction, or mental simulation), and which we hypothesized may be impaired in autism spectrum disorder (ASD). Twenty intellectually high-functioning children with ASD (with a mean age of ~8 years) were compared to 20 sex, age, IQ, and language ability matched typically developing children on a series of tasks to assess spatial navigation, episodic memory, episodic future thinking (also known as episodic foresight or prospection), theory of mind (ToM), relational memory, and central coherence. This is the first study to explore these abilities concurrently within the same sample. Spatial navigation was assessed using the "memory island" task, which involves finding objects within a realistic, computer simulated, three dimensional environment. Episodic memory and episodic future thinking were assessed using a past and future event description task. ToM was assessed using the "animations" task, in which children were asked to describe the interactions between two animated triangles. Relational memory was assessed using a recognition task involving memory for items (line drawings), patterned backgrounds, or combinations of items and backgrounds. Central coherence was assessed by exploring differences in performance across segmented and unsegmented versions of block design. Children with ASD were found to show impairments in spatial navigation, episodic memory, episodic future thinking, and central coherence, but not ToM or relational memory. Among children with ASD, spatial navigation was found to be significantly negatively related to the number of repetitive behaviors. In other words, children who showed more repetitive behaviors showed poorer spatial navigation. The theoretical and practical implications of the results are discussed. PMID- 25538663 TI - A cluster randomized control field trial of the ABRACADABRA web-based reading technology: replication and extension of basic findings. AB - The present paper reports a cluster randomized control trial evaluation of teaching using ABRACADABRA (ABRA), an evidence-based and web-based literacy intervention (http://abralite.concordia.ca) with 107 kindergarten and 96 grade 1 children in 24 classes (12 intervention 12 control classes) from all 12 elementary schools in one school district in Canada. Children in the intervention condition received 10-12 h of whole class instruction using ABRA between pre- and post-test. Hierarchical linear modeling of post-test results showed significant gains in letter-sound knowledge for intervention classrooms over control classrooms. In addition, medium effect sizes were evident for three of five outcome measures favoring the intervention: letter-sound knowledge (d= +0.66), phonological blending (d = +0.52), and word reading (d = +0.52), over effect sizes for regular teaching. It is concluded that regular teaching with ABRA technology adds significantly to literacy in the early elementary years. PMID- 25538662 TI - The medium helps the message: Early sensitivity to auditory fluency in children's endorsement of statements. AB - Recently, a growing number of studies have investigated the cues used by children to selectively accept testimony. In parallel, several studies with adults have shown that the fluency with which information is provided influences message evaluation: adults evaluate fluent information as more credible than dysfluent information. It is therefore plausible that the fluency of a message could also influence children's endorsement of statements. Three experiments were designed to test this hypothesis with 3- to 5-year-olds where the auditory fluency of a message was manipulated by adding different levels of noise to recorded statements. The results show that 4 and 5-year-old children, but not 3-year-olds, are more likely to endorse a fluent statement than a dysfluent one. The present study constitutes a first attempt to show that fluency, i.e., ease of processing, is recruited as a cue to guide epistemic decision in children. An interpretation of the age difference based on the way cues are processed by younger children is suggested. PMID- 25538664 TI - Bilinguals implicitly name objects in both their languages: an ERP study. AB - Upon being presented with a familiar name-known image, monolingual infants and adults implicitly generate the image's label (Meyer et al., 2007; Mani and Plunkett, 2010, 2011; Mani et al., 2012a). Although the cross-linguistic influences on overt bilingual production are well studied (for a summary see Colome and Miozzo, 2010), evidence that bilinguals implicitly generate the label for familiar objects in both languages remains mixed. For example, bilinguals implicitly generate picture labels in both of their languages, but only when tested in L2 and not L1 (Wu and Thierry, 2011) or when immersed in their L2 (Spivey and Marian, 1999; Marian and Spivey, 2003a,b) but not when immersed in their L1 (Weber and Cutler, 2004). The current study tests whether bilinguals implicitly generate picture labels in both of their languages when tested in their L1 with a cross-modal ERP priming paradigm. The results extend previous findings by showing that not just do bilinguals implicitly generate the labels for visually fixated images in both of their languages when immersed in their L1, but also that these implicitly generated labels in one language can prime recognition of subsequently presented auditory targets across languages (i.e., L2 L1). The current study provides support for cascaded models of lexical access during speech production, as well as a new priming paradigm for the study of bilingual language processing. PMID- 25538665 TI - Variability and systematic differences in normal, protan, and deutan color naming. AB - The congenital color vision deficient (CVD) generally demonstrates difficulties in color naming tasks. In our study we investigated color naming properties and uncertainties of a relatively large group of red-green CVDs using quasi monochromatic stimuli and seven basic color terms. The results show a large variability in color naming for the CVD when contrasted to normal color vision and similar alterations when comparing protans to deutans. Statistically significant differences were found in specific wavelength ranges between the tested groups. In general, protans and deutans have shown better color naming ability than expected, which suggests the use of non-chromatic visual cues. PMID- 25538666 TI - A structured approach to a diagnostic of collective practices. AB - "How social norms change" is not only a theoretical question but also an empirical one. Many organizations have implemented programs to abandon harmful social norms. These programs are standardly monitored and evaluated with a set of empirical tools. While monitoring and evaluation (M&E) of changes in objective outcomes and behaviors is well-developed, we will argue that M&E of changes in the wide range of beliefs and preferences important to social norms is still problematic. In this paper, we first present a theoretical framework and then show how it should guide social norms measurement. As a case study, we focus on the harmful practice of child marriage. We show how an operational theory of social norms can guide the design of surveys, experiments, and vignettes. We use examples from existing research to illustrate how to study social norms change. PMID- 25538668 TI - Is thinking really aversive? A commentary on Wilson et al.'s "Just think: the challenges of the disengaged mind". PMID- 25538667 TI - Helping traumatized people survive: a psychoanalytic intervention in a contaminated site. AB - Psychoanalytic literature on extreme traumatization usually distinguishes between natural catastrophes and man-made catastrophes. While the first ones are usually sensed as nature's ferocity, fate, or God's will, the second ones are experienced as a volountary and violent attack aimed at disrupting other human beings. In this paper we focus on man-made disasters caused by a profit-driven logic. When traumatization is due to irresponsible actions perpetrated by the owners of the major economic resource of a community, it deeply affects the identity of the group, entailing the loss of basic trust and lively parts of the Self. In such a situation, where the whole community is severely traumatized, psychoanalytic group therapy seems to be the most suitable setting: it allows to place the historization of the event and the creation of multiple narratives of somato psychic suffering. Trust and faith are two crucial factors in the encounter with patients lacking a sense of vitality. The working through of each one through the group field is an essential forerunner to the construction of a recovered sense of faith and reliability that precedes the onset of a true new-beginning. PMID- 25538669 TI - Would you fund this movie? A reply to Fox et al. (2014). PMID- 25538670 TI - Estimating the divergence point: a novel distributional analysis procedure for determining the onset of the influence of experimental variables. AB - The divergence point analysis procedure is aimed at obtaining an estimate of the onset of the influence of an experimental variable on response latencies (e.g., fixation duration, reaction time). The procedure involves generating survival curves for two conditions, and using a bootstrapping technique to estimate the timing of the earliest discernible divergence between curves. In the present paper, several key extensions for this procedure were proposed and evaluated by conducting simulations and by reanalyzing data from previous studies. Our findings indicate that the modified versions of the procedure performed substantially better than the original procedure under conditions of low experimental power. Furthermore, unlike the original procedure, the modified procedures provided divergence point estimates for individual participants and permitted testing the significance of the difference between estimates across conditions. The advantages of the modified procedures are illustrated, the theoretical and methodological implications are discussed, and promising future directions are outlined. PMID- 25538671 TI - Bringing back the body into the mind: gestures enhance word learning in foreign language. AB - Foreign language education in the twenty-first century still teaches vocabulary mainly through reading and listening activities. This is due to the link between teaching practice and traditional philosophy of language, where language is considered to be an abstract phenomenon of the mind. However, a number of studies have shown that accompanying words or phrases of a foreign language with gestures leads to better memory results. In this paper, I review behavioral research on the positive effects of gestures on memory. Then I move to the factors that have been addressed as contributing to the effect, and I embed the reviewed evidence in the theoretical framework of embodiment. Finally, I argue that gestures accompanying foreign language vocabulary learning create embodied representations of those words. I conclude by advocating the use of gestures in future language education as a learning tool that enhances the mind. PMID- 25538672 TI - Subject-Motion Correction in HARDI Acquisitions: Choices and Consequences. AB - Diffusion-weighted imaging (DWI) is known to be prone to artifacts related to motion originating from subject movement, cardiac pulsation, and breathing, but also to mechanical issues such as table vibrations. Given the necessity for rigorous quality control and motion correction, users are often left to use simple heuristics to select correction schemes, which involves simple qualitative viewing of the set of DWI data, or the selection of transformation parameter thresholds for detection of motion outliers. The scientific community offers strong theoretical and experimental work on noise reduction and orientation distribution function (ODF) reconstruction techniques for HARDI data, where post acquisition motion correction is widely performed, e.g., using the open-source DTIprep software (1), FSL (the FMRIB Software Library) (2), or TORTOISE (3). Nonetheless, effects and consequences of the selection of motion correction schemes on the final analysis, and the eventual risk of introducing confounding factors when comparing populations, are much less known and far beyond simple intuitive guessing. Hence, standard users lack clear guidelines and recommendations in practical settings. This paper reports a comprehensive evaluation framework to systematically assess the outcome of different motion correction choices commonly used by the scientific community on different DWI derived measures. We make use of human brain HARDI data from a well-controlled motion experiment to simulate various degrees of motion corruption and noise contamination. Choices for correction include exclusion/scrubbing or registration of motion corrupted directions with different choices of interpolation, as well as the option of interpolation of all directions. The comparative evaluation is based on a study of the impact of motion correction using four metrics that quantify (1) similarity of fiber orientation distribution functions (fODFs), (2) deviation of local fiber orientations, (3) global brain connectivity via graph diffusion distance (GDD), and (4) the reproducibility of prominent and anatomically defined fiber tracts. Effects of various motion correction choices are systematically explored and illustrated, leading to a general conclusion of discouraging users from setting ad hoc thresholds on the estimated motion parameters beyond which volumes are claimed to be corrupted. PMID- 25538674 TI - Impact of Severe Extracranial ICA Stenosis on MRI Perfusion and Diffusion Parameters in Acute Ischemic Stroke. AB - PURPOSE: The aim of this study was to investigate the impact of a coexisting internal carotid artery (ICA) stenosis on lesion volumes as well as diffusion and perfusion parameters in acute ischemic stroke resulting from middle cerebral artery (MCA) occlusion. MATERIAL AND METHODS: Magnetic resonance imaging data of 32 patients with MCA occlusion with or without additional ICA stenosis imaged within 4.5 h of symptom onset were analyzed. Both groups consisted of 16 patients. Acute diffusion lesions were semi-automatically segmented in apparent diffusion coefficient (ADC) MRI datasets. Perfusion maps of cerebral blood volume (CBV), cerebral blood flow, mean transit time and T max were calculated using perfusion-weighted MRI datasets. Tissue-at-risk (TAR) volumes were generated by subtracting the ADC lesion from the hypoperfusion lesion defined by T max >6 s. Median ADC and perfusion parameter values were extracted separately for the diffusion lesion and TAR and used for statistical analysis. RESULTS: No significant differences were found between the groups regarding the diffusion lesion and TAR volumes. Statistical analysis of diffusion and perfusion parameters revealed CBV as the only parameter with a significant difference (p = 0.009) contributing a small effect (eta(2) = 0.11) to the group comparison with higher CBV values for the patient group with a coexisting ICA stenosis, while no significant effects were found for the other diffusion and perfusion parameters analyzed. CONCLUSION: The results of this study suggest that a coexisting ICA stenosis does not have a strong effect on tissue status or perfusion parameters in acute stroke patients except for a moderate elevation of CBV. This may reflect improved collateral circulation or ischemic preconditioning in patients with a pre-existing proximal stenosis balancing impaired perfusion from the stenosis. PMID- 25538673 TI - Pedunculopontine Nucleus Stimulation: Where are We Now and What Needs to be Done to Move the Field Forward? AB - Falls and gait impairment in Parkinson's Disease (PD) is a leading cause of morbidity and mortality, significantly impacting quality of life and contributing heavily to disability. Thus far axial symptoms, such as postural instability and gait freezing, have been refractory to current treatment approaches and remain a critical unmet need. There has been increased excitement surrounding the surgical targeting of the pedunculopontine nucleus (PPN) for addressing axial symptoms in PD. The PPN and cuneate nucleus comprise the mesencephalic locomotor region, and electrophysiologic studies in animal models and human imaging studies have revealed a key role for the PPN in gait and postural control, underscoring a potential role for DBS surgery. Previous limited studies of PPN deep brain stimulation (DBS) in treating gait symptoms have had mixed clinical outcomes, likely reflect targeting variability and the inherent challenges of targeting a small brainstem structure that is both anatomically and neurochemically heterogeneous. Diffusion tractography shows promise for more accurate targeting and standardization of results. Due to the limited experience with PPN DBS, several unresolved questions remain about targeting and programing. At present, it is unclear if there is incremental benefit with bilateral versus unilateral targeting of PPN or whether PPN targeting should be performed as an adjunct to one of the more traditional targets. The PPN also modulates non-motor functions including REM sleep, cognition, mood, attention, arousal, and these observations will require long-term monitoring to fully characterize potential side effects and benefits. Surgical targeting of the PPN is feasible and shows promise for addressing axial symptoms in PD but may require further refinements in targeting, improved imaging, and better lead design to fully realize benefits. This review summarizes the current knowledge of PPN as a DBS target and areas that need to be addressed to advance the field. PMID- 25538675 TI - The Two Visual Systems Hypothesis: New Challenges and Insights from Visual form Agnosic Patient DF. AB - Patient DF, who developed visual form agnosia following carbon monoxide poisoning, is still able to use vision to adjust the configuration of her grasping hand to the geometry of a goal object. This striking dissociation between perception and action in DF provided a key piece of evidence for the formulation of Goodale and Milner's Two Visual Systems Hypothesis (TVSH). According to the TVSH, the ventral stream plays a critical role in constructing our visual percepts, whereas the dorsal stream mediates the visual control of action, such as visually guided grasping. In this review, we discuss recent studies of DF that provide new insights into the functional organization of the dorsal and ventral streams. We confirm recent evidence that DF has dorsal as well as ventral brain damage - and that her dorsal-stream lesions and surrounding atrophy have increased in size since her first published brain scan. We argue that the damage to DF's dorsal stream explains her deficits in directing actions at targets in the periphery. We then focus on DF's ability to accurately adjust her in-flight hand aperture to changes in the width of goal objects (grip scaling) whose dimensions she cannot explicitly report. An examination of several studies of DF's grip scaling under natural conditions reveals a modest though significant deficit. Importantly, however, she continues to show a robust dissociation between form vision for perception and form vision-for-action. We also review recent studies that explore the role of online visual feedback and terminal haptic feedback in the programming and control of her grasping. These studies make it clear that DF is no more reliant on visual or haptic feedback than are neurologically intact individuals. In short, we argue that her ability to grasp objects depends on visual feedforward processing carried out by visuomotor networks in her dorsal stream that function in the much the same way as they do in neurologically intact individuals. PMID- 25538676 TI - Current treatment options in vestibular migraine. AB - Approximately 1% of the general population in western industrialized countries suffers from vestibular migraine. However, it remains widely unknown and often under diagnosed despite the recently published diagnostic criteria for vestibular migraine. Treatment trials that specialize on vestibular migraine are scarce and systematic randomized controlled clinical trials are now only emerging. This review summarizes the knowledge on the currently available treatment options that were tested specifically for vestibular migraine and gives an evidence-based, informed treatment recommendation with all its limitations. To date only two randomized controlled treatment trials provide limited evidence for the use of rizatriptan and zolmitriptan for the treatment of vestibular migraine attacks because of methodological shortcomings. There is an ongoing multicenter randomized placebo-controlled trial testing metoprolol 95 mg vs. placebo (PROVEMIG-trial). Therefore, the therapeutic recommendations for the prophylactic treatment of vestibular migraine are currently widely based on the guidelines of migraine with and without aura as well as expert opinion. PMID- 25538679 TI - A critical role for network structure in seizure onset: a computational modeling approach. AB - Recent clinical work has implicated network structure as critically important in the initiation of seizures in people with idiopathic generalized epilepsies. In line with this idea, functional networks derived from the electroencephalogram (EEG) at rest have been shown to be significantly different in people with generalized epilepsy compared to controls. In particular, the mean node degree of networks from the epilepsy cohort was found to be statistically significantly higher than those of controls. However, the mechanisms by which these network differences can support recurrent transitions into seizures remain unclear. In this study, we use a computational model of the transition into seizure dynamics to explore the dynamic consequences of these differences in functional networks. We demonstrate that networks with higher mean node degree are more prone to generating seizure dynamics in the model and therefore suggest a mechanism by which increased mean node degree of brain networks can cause heightened ictogenicity. PMID- 25538680 TI - The mobilization of aluminum into the biosphere. PMID- 25538681 TI - Proteomic Analysis of Pig (Sus scrofa) Olfactory Soluble Proteome Reveals O Linked-N-Acetylglucosaminylation of Secreted Odorant-Binding Proteins. AB - The diversity of olfactory binding proteins (OBPs) is a key point to understand their role in molecular olfaction. Since only few different sequences were characterized in each mammalian species, they have been considered as passive carriers of odors and pheromones. We have explored the soluble proteome of pig nasal mucus, taking benefit of the powerful tools of proteomics. Combining two dimensional electrophoresis, mass spectrometry, and western-blot with specific antibodies, our analyses revealed for the first time that the pig nasal mucus is mainly composed of secreted OBP isoforms, some of them being potentially modified by O-GlcNAcylation. An ortholog gene of the glycosyltransferase responsible of the O-GlcNAc linking on extracellular proteins in Drosophila and Mouse (EOGT) was amplified from tissues of pigs of different ages and sex. The sequence was used in a phylogenetic analysis, which evidenced conservation of EOGT in insect and mammalian models studied in molecular olfaction. Extracellular O-GlcNAcylation of secreted OBPs could finely modulate their binding specificities to odors and pheromones. This constitutes a new mechanism for extracellular signaling by OBPs, suggesting that they act as the first step of odor discrimination. PMID- 25538678 TI - The piriform cortex and human focal epilepsy. AB - It is surprising that the piriform cortex, when compared to the hippocampus, has been given relatively little significance in human epilepsy. Like the hippocampus, it has a phylogenetically preserved three-layered cortex that is vulnerable to excitotoxic injury, has broad connections to both limbic and cortical areas, and is highly epileptogenic - being critical to the kindling process. The well-known phenomenon of early olfactory auras in temporal lobe epilepsy highlights its clinical relevance in human beings. Perhaps because it is anatomically indistinct and difficult to approach surgically, as it clasps the middle cerebral artery, it has, until now, been understandably neglected. In this review, we emphasize how its unique anatomical and functional properties, as primary olfactory cortex, predispose it to involvement in focal epilepsy. From recent convergent findings in human neuroimaging, clinical epileptology, and experimental animal models, we make the case that the piriform cortex is likely to play a facilitating and amplifying role in human focal epileptogenesis, and may influence progression to epileptic intractability. PMID- 25538683 TI - Obesity-induced inflammation and insulin resistance. PMID- 25538677 TI - What are the Best Animal Models for Testing Early Intervention in Cerebral Palsy? AB - Interventions to treat cerebral palsy should be initiated as soon as possible in order to restore the nervous system to the correct developmental trajectory. One drawback to this approach is that interventions have to undergo exceptionally rigorous assessment for both safety and efficacy prior to use in infants. Part of this process should involve research using animals but how good are our animal models? Part of the problem is that cerebral palsy is an umbrella term that covers a number of conditions. There are also many causal pathways to cerebral palsy, such as periventricular white matter injury in premature babies, perinatal infarcts of the middle cerebral artery, or generalized anoxia at the time of birth, indeed multiple causes, including intra-uterine infection or a genetic predisposition to infarction, may need to interact to produce a clinically significant injury. In this review, we consider which animal models best reproduce certain aspects of the condition, and the extent to which the multifactorial nature of cerebral palsy has been modeled. The degree to which the corticospinal system of various animal models human corticospinal system function and development is also explored. Where attempts have already been made to test early intervention in animal models, the outcomes are evaluated in light of the suitability of the model. PMID- 25538682 TI - RFamide Peptides in Early Vertebrate Development. AB - RFamides (RFa) are neuropeptides involved in many different physiological processes in vertebrates, such as reproductive behavior, pubertal activation of the reproductive endocrine axis, control of feeding behavior, and pain modulation. As research has focused mostly on their role in adult vertebrates, the possible roles of these peptides during development are poorly understood. However, the few studies that exist show that RFa are expressed early in development in different vertebrate classes, perhaps mostly associated with the central nervous system. Interestingly, the related peptide family of FMRFa has been shown to be important for brain development in invertebrates. In a teleost, the Japanese medaka, knockdown of genes in the Kiss system indicates that Kiss ligands and receptors are vital for brain development, but few other functional studies exist. Here, we review the literature of RFa in early vertebrate development, including the possible functional roles these peptides may play. PMID- 25538684 TI - A new method to investigate how mechanical loading of osteocytes controls osteoblasts. AB - Mechanical loading, a potent stimulator of bone formation, is governed by osteocyte regulation of osteoblasts. We developed a three-dimensional (3D) in vitro co-culture system to investigate the effect of loading on osteocyte osteoblast interactions. MLO-Y4 cells were embedded in type I collagen gels and MC3T3-E1(14) or MG63 cells layered on top. Ethidium homodimer staining of 3D co cultures showed 100% osteoblasts and 86% osteocytes were viable after 7 days. Microscopy revealed osteoblasts and osteocytes maintain their respective ovoid/pyriform and dendritic morphologies in 3D co-cultures. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) of messenger ribonucleic acid (mRNA) extracted separately from osteoblasts and osteocytes, showed that podoplanin (E11), osteocalcin, and runt-related transcription factor 2 mRNAs were expressed in both cell types. Type I collagen (Col1a1) mRNA expression was higher in osteoblasts (P < 0.001), whereas, alkaline phosphatase mRNA was higher in osteocytes (P = 0.001). Immunohistochemistry revealed osteoblasts and osteocytes express E11, type I pro-collagen, and connexin 43 proteins. In preliminary experiments to assess osteogenic responses, co-cultures were treated with human recombinant bone morphogenetic protein 2 (BMP-2) or mechanical loading using a custom built loading device. BMP-2 treatment significantly increased osteoblast Col1a1 mRNA synthesis (P = 0.031) in MLO Y4/MG63 co-cultures after 5 days treatment. A 16-well silicone plate, loaded (5 min, 10 Hz, 2.5 N) to induce 4000-4500 MUepsilon cyclic compression within gels increased prostaglandin E2 (PGE2) release 0.5 h post-load in MLO-Y4 cells pre cultured in 3D collagen gels for 48, 72 h, or 7 days. Mechanical loading of 3D co cultures increased type I pro-collagen release 1 and 5 days later. These methods reveal a new osteocyte-osteoblast co-culture model that may be useful for investigating mechanically induced osteocyte control of osteoblast bone formation. PMID- 25538685 TI - Humanin and age-related diseases: a new link? AB - Humanin (HN) is 24-amino acid mitochondria-associated peptide. Since its initial discovery over a decade ago, a role for HN has been reported in many biological processes such as apoptosis, cell survival, substrate metabolism, inflammatory response, and response to stressors such as oxidative stress, ischemia, and starvation. HN and its potent analogs have been shown to have beneficial effects in many age-related diseases including Alzheimer's disease, stroke, diabetes, myocardial ischemia and reperfusion, atherosclerosis, amyotrophic lateral sclerosis, and certain types of cancer both in vitro and in vivo. More recently, an association between HN levels, growth hormone/insulin-like growth factor-1 (GH/IGF axis), and life span was demonstrated using various mouse models with mutations in the GH/IGF axis. The goal of this review is to summarize the current understanding of the role of HN in aging and age-related diseases. PMID- 25538687 TI - In vitro antagonistic activity, plant growth promoting traits and phylogenetic affiliation of rhizobacteria associated with wild plants grown in arid soil. AB - The role of plant growth-promoting rhizobacteria (PGPR) in adaptation of plants in extreme environments is not yet completely understood. For this study native bacteria were isolated from rhizospeheric arid soils and evaluated for both growth-promoting abilities and antagonistic potential against phytopathogenic fungi and nematodes. The phylogentic affiliation of these representative isolates was also characterized. Rhizobacteria associated with 11 wild plant species from the arid soil of Almadinah Almunawarah, Kingdom of Saudi Arabia (KSA) were investigated. From a total of 531 isolates, only 66 bacterial isolates were selected based on their ability to inhibit Fusarium oxysporum, and Sclerotinia sclerotiorum. The selected isolates were screened in vitro for activities related to plant nutrition and plant growth regulation as well as for antifungal and nematicidal traits. Isolated bacteria were found to exhibit capabilities in fix atmospheric nitrogen, produce ammonia, indoleacetic acid (IAA), siderophores, solubilize phosphate and zinc, and showed an antagonistic potential against some phytopathogenic fungi and one nematode species (Meloidogyne incognita) to various extent. Isolates were ranked by their potential ability to function as PGPR. The 66 isolates were genotyped using amplified rDNA restriction analysis (ARDRA) and 16S rRNA gene sequence analysis. The taxonomic composition of the representative genotypes from both rhizosphere and rhizoplane comprised Bacillus, Enterobacter and Pseudomonas. Out of the 10 genotypes, three strains designated as PHP03, CCP05, and TAP02 might be regarded as novel strains based on their low similarity percentages and high bootstrap values. The present study clearly identified specific traits in the isolated rhizobacteria, which make them good candidates as PGPR and might contribute to plant adaption to arid environments. Application of such results in agricultural fields may improve and enhance plant growth in arid soils. PMID- 25538686 TI - Microbial experimental evolution as a novel research approach in the Vibrionaceae and squid-Vibrio symbiosis. AB - The Vibrionaceae are a genetically and metabolically diverse family living in aquatic habitats with a great propensity toward developing interactions with eukaryotic microbial and multicellular hosts (as either commensals, pathogens, and mutualists). The Vibrionaceae frequently possess a life history cycle where bacteria are attached to a host in one phase and then another where they are free from their host as either part of the bacterioplankton or adhered to solid substrates such as marine sediment, riverbeds, lakebeds, or floating particulate debris. These two stages in their life history exert quite distinct and separate selection pressures. When bound to solid substrates or to host cells, the Vibrionaceae can also exist as complex biofilms. The association between bioluminescent Vibrio spp. and sepiolid squids (Cephalopoda: Sepiolidae) is an experimentally tractable model to study bacteria and animal host interactions, since the symbionts and squid hosts can be maintained in the laboratory independently of one another. The bacteria can be grown in pure culture and the squid hosts raised gnotobiotically with sterile light organs. The partnership between free-living Vibrio symbionts and axenic squid hatchlings emerging from eggs must be renewed every generation of the cephalopod host. Thus, symbiotic bacteria and animal host can each be studied alone and together in union. Despite virtues provided by the Vibrionaceae and sepiolid squid-Vibrio symbiosis, these assets to evolutionary biology have yet to be fully utilized for microbial experimental evolution. Experimental evolution studies already completed are reviewed, along with exploratory topics for future study. PMID- 25538688 TI - Emergence of a novel subpopulation of CC398 Staphylococcus aureus infecting animals is a serious hazard for humans. AB - Until recently, Staphylococcus aureus from clonal complex (CC)398 were mostly described as colonizing asymptomatic raised pigs and pig-farmers. Currently, the epidemiology of the CC398 lineage is becoming more complex. CC398 human-adapted isolates are increasingly being identified in bloodstream infections in humans living in animal-free environments. In addition, CC398 isolates are increasingly responsible for invasive infections in various animals. CC398 isolates that colonize asymptomatic pigs and the isolates that infect humans living in animal free environments (human-adapted isolates) both lack several clinically important S. aureus-associated virulence factors but differ on the basis of their prophage content. Recent findings have provided insight into the influence of a phiMR11 like helper prophage on the ability of CC398 isolates to infect humans. To assess the recent spread of the CC398 lineage to various animal species and to investigate the links between the phiMR11-like prophage and the emergence of CC398 isolates infecting animals, we studied 277 isolates causing infections in unrelated animals. The prevalence of CC398 isolates increased significantly between 2007 and 2013 (p < 0.001); 31.8% of the animal isolates harbored the phiMR11-like prophage. High-density DNA microarray experiments with 37 representative infected-animal isolates positive for phiMR11-like DNA established that most infected-animal isolates carried many genetic elements related to antimicrobial resistance and virulence genes, and a phi3 prophage encoding immune modulating proteins and associated with animal-to-human jumps. Our findings suggest recent clonal expansion and dissemination of a new subpopulation of CC398 isolates, responsible for invasive infections in various animals, with a considerable potential to colonize and infect humans, probably greater than that of human-adapted CC398 isolates, justifying active surveillance. PMID- 25538689 TI - Two TIR-like domain containing proteins in a newly emerging zoonotic Staphylococcus aureus strain sequence type 398 are potential virulence factors by impacting on the host innate immune response. AB - Staphylococcus aureus, sequence type (ST) 398, is an emerging pathogen and the leading cause of livestock-associated methicillin-resistant S. aureus infections in Europe and North America. This strain is characterized by high promiscuity in terms of host-species and also lacks several traditional S. aureus virulence factors. This does not, however, explain the apparent ease with which it crosses species-barriers. Recently, TIR-domain containing proteins (Tcps) which inhibit the innate immune response were identified in some Gram-negative bacteria. Here we report the presence of two proteins, S. aureus TIR-like Protein 1 (SaTlp1) and S. aureus TIR-like Protein 2 (SaTlp2), expressed by ST398 which contain domain of unknown function 1863 (DUF1863), similar to the Toll/IL-1 receptor (TIR) domain. In contrast to the Tcps in Gram-negative bacteria, our data suggest that SaTlp1 and SaTlp2 increase activation of the transcription factor NF-kappaB as well as downstream pro-inflammatory cytokines and immune effectors. To assess the role of both proteins as potential virulence factors knock-out mutants were created. These showed a slightly enhanced survival rate in a murine infectious model compared to the wild-type strain at one dose. Our data suggest that both proteins may act as factors contributing to the enhanced ability of ST398 to cross species barriers. PMID- 25538692 TI - Antifungal amphiphilic aminoglycoside K20: bioactivities and mechanism of action. AB - K20 is a novel amphiphilic antifungal aminoglycoside that is synthetically derived from the antibiotic kanamycin A. Reported here are investigations of K20's antimicrobial activities, cytotoxicity, and fungicidal mechanism of action. In vitro growth inhibitory activities against a variety of human and plant pathogenic yeasts, filamentous fungi, and bacteria were determined using microbroth dilution assays and time-kill curve analyses, and hemolytic and animal cell cytotoxic activities were determined. Effects on Cryptococcus neoformans H 99 infectivity were determined with a preventive murine lung infection model. The antifungal mechanism of action was studied using intact fungal cells, yeast lipid mutants, and small unilamellar lipid vesicles. K20 exhibited broad-spectrum in vitro antifungal activities but not antibacterial activities. Pulmonary, single dose-administration of K20 reduced C. neoformans lung infection rates 4-fold compared to controls. Hemolysis and half-maximal cytotoxicities of mammalian cells occurred at concentrations that were 10 to 32-fold higher than fungicidal MICs. With fluorescein isothiocyanate (FITC), 20-25 mg/L K20 caused staining of >95% of C. neoformans and Fusarium graminearum cells and at 31.3 mg/L caused rapid leakage (30-80% in 15 min) of calcein from preloaded small unilamellar lipid vesicles. K20 appears to be a broad-spectrum fungicide, capable of reducing the infectivity of C. neoformans, and exhibits low hemolytic activity and mammalian cell toxicity. It perturbs the plasma membrane by mechanisms that are lipid modulated. K20 is a novel amphiphilic aminoglycoside amenable to scalable production and a potential lead antifungal for therapeutic and crop protection applications. PMID- 25538690 TI - Multitasking SecB chaperones in bacteria. AB - Protein export in bacteria is facilitated by the canonical SecB chaperone, which binds to unfolded precursor proteins, maintains them in a translocation competent state and specifically cooperates with the translocase motor SecA to ensure their proper targeting to the Sec translocon at the cytoplasmic membrane. Besides its key contribution to the Sec pathway, SecB chaperone tasking is critical for the secretion of the Sec-independent heme-binding protein HasA and actively contributes to the cellular network of chaperones that control general proteostasis in Escherichia coli, as judged by the significant interplay found between SecB and the trigger factor, DnaK and GroEL chaperones. Although SecB is mainly a proteobacterial chaperone associated with the presence of an outer membrane and outer membrane proteins, secB-like genes are also found in Gram positive bacteria as well as in certain phages and plasmids, thus suggesting alternative functions. In addition, a SecB-like protein is also present in the major human pathogen Mycobacterium tuberculosis where it specifically controls a stress-responsive toxin-antitoxin system. This review focuses on such very diverse chaperone functions of SecB, both in E. coli and in other unrelated bacteria. PMID- 25538693 TI - Combining flagellin and human beta-defensin-3 to combat bacterial infections. AB - The discovery and therapeutic use of antibiotics made a major contribution to the reduction of human morbidity and mortality. However, the growing resistance to antibiotics has become a matter of huge concern. In this study we aimed to develop an innovative approach to treat bacterial infections utilizing two components: the human antibacterial peptide beta-defensin-3 (BD3) and the bacterial protein flagellin (F). This combination was designed to provide an efficient weapon against bacterial infections with the peptide killing the bacteria directly, while the flagellin protein triggers the immune system and acts against bacteria escaping from the peptide's action. We designed, expressed and purified the fusion protein flagellin BD3 (FBD3) and its two components, the F protein and the native BD3 peptide. FBD3 fusion protein and native BD3 peptide had antibacterial activity in vitro against various bacterial strains. FBD3 and F proteins could also recognize their receptor expressed on target cells and stimulated secretion of IL-8. In addition, F and FBD3 proteins had a partial protective effect in mice infected by pathogenic Escherichia coli bacteria that cause a lethal disease. Moreover, we were able to show partial protection of mice infected with E. coli using a flagellin sequence from Salmonella. We also explored flagellin's basic mechanisms of action, focusing on its effects on CD4+ T cells from healthy donors. We found that F stimulation caused an increase in the mRNA levels of the Th1 response cytokines IL12A and IFNgamma. In addition, F stimulation affected its own receptor. PMID- 25538691 TI - Fine scale spatial variability of microbial pesticide degradation in soil: scales, controlling factors, and implications. AB - Pesticide biodegradation is a soil microbial function of critical importance for modern agriculture and its environmental impact. While it was once assumed that this activity was homogeneously distributed at the field scale, mounting evidence indicates that this is rarely the case. Here, we critically examine the literature on spatial variability of pesticide biodegradation in agricultural soil. We discuss the motivations, methods, and main findings of the primary literature. We found significant diversity in the approaches used to describe and quantify spatial heterogeneity, which complicates inter-studies comparisons. However, it is clear that the presence and activity of pesticide degraders is often highly spatially variable with coefficients of variation often exceeding 50% and frequently displays non-random spatial patterns. A few controlling factors have tentatively been identified across pesticide classes: they include some soil characteristics (pH) and some agricultural management practices (pesticide application, tillage), while other potential controlling factors have more conflicting effects depending on the site or the pesticide. Evidence demonstrating the importance of spatial heterogeneity on the fate of pesticides in soil has been difficult to obtain but modeling and experimental systems that do not include soil's full complexity reveal that this heterogeneity must be considered to improve prediction of pesticide biodegradation rates or of leaching risks. Overall, studying the spatial heterogeneity of pesticide biodegradation is a relatively new field at the interface of agronomy, microbial ecology, and geosciences and a wealth of novel data is being collected from these different disciplinary perspectives. We make suggestions on possible avenues to take full advantage of these investigations for a better understanding and prediction of the fate of pesticides in soil. PMID- 25538694 TI - Systematic genomic analysis reveals the complementary aerobic and anaerobic respiration capacities of the human gut microbiota. AB - Because of the specific anatomical and physiological properties of the human intestine, a specific oxygen gradient builds up within this organ that influences the intestinal microbiota. The intestinal microbiome has been intensively studied in recent years, and certain respiratory substrates used by gut inhabiting microbes have been shown to play a crucial role in human health. Unfortunately, a systematic analysis has not been previously performed to determine the respiratory capabilities of human gut microbes (HGM). Here, we analyzed the distribution of aerobic and anaerobic respiratory reductases in 254 HGM genomes. In addition to the annotation of known enzymes, we also predicted a novel microaerobic reductase and novel thiosulfate reductase. Based on this comprehensive assessment of respiratory reductases in the HGM, we proposed a number of exchange pathways among different bacteria involved in the reduction of various nitrogen oxides. The results significantly expanded our knowledge of HGM metabolism and interactions in bacterial communities. PMID- 25538696 TI - Mycorrhizal-induced calmodulin mediated changes in antioxidant enzymes and growth response of drought-stressed trifoliate orange. AB - Trifoliate orange [Poncirus trifoliata (L) Raf.] is considered highly arbuscular mycorrhizal (AM) dependent for growth responses through a series of signal transductions in form of various physiological responses. The proposed study was carried out to evaluate the effect of an AM fungus (Funneliformis mosseae) on growth, antioxidant enzyme (catalase, CAT; superoxide dismutase, SOD) activities, leaf relative water content (RWC), calmodulin (CaM), superoxide anion ([Formula: see text]), and hydrogen peroxide (H2O2) concentrations in leaves of the plants exposed to both well-watered (WW) and drought stress (DS) conditions. A 58-day of DS significantly decreased mycorrhizal colonization by 60% than WW. Compared to non-AM seedlings, AM seedlings displayed significantly higher shoot morphological properties (plant height, stem diameter, and leaf number), biomass production (shoot and root fresh weight) and leaf RWC, regardless of soil water status. AM inoculation significantly increased CaM and soluble protein concentrations and CAT activity, whereas significantly decreased [Formula: see text] and H2O2 concentration under both WW and DS conditions. The AM seedlings also exhibited significantly higher Cu/Zn-SOD and Mn-SOD activities than the non-AM seedlings under DS but not under WW, which are triggered by higher CaM levels in AM plants on the basis of correlation studies. Further, the negative correlation of Cu/Zn SOD and Mn-SOD activities with [Formula: see text] and H2O2 concentration showed the DS-induced ROS scavenging ability of CaM mediated SODs under mycorrhization. Our results demonstrated that AM-inoculation elevated the synthesis of CaM in leaves and up-regulated activities of the antioxidant enzymes, thereby, repairing the possible oxidative damage to plants by lowering the ROS accumulation under DS condition. PMID- 25538695 TI - Functional validation of putative toxin-antitoxin genes from the Gram-positive pathogen Streptococcus pneumoniae: phd-doc is the fourth bona-fide operon. AB - Bacterial toxin-antitoxin (TAs) loci usually consist of two genes organized as an operon, where their products are bound together and inert under normal conditions. However, under stressful circumstances the antitoxin, which is more labile, will be degraded more rapidly, thereby unleashing its cognate toxin to act on the cell. This, in turn, causes cell stasis or cell death, depending on the type of TAs and/or time of toxin exposure. Previously based on in silico analyses, we proposed that Streptococcus pneumoniae, a pathogenic Gram-positive bacterium, may harbor between 4 and 10 putative TA loci depending on the strains. Here we have chosen the pneumococcal strain Hungary(19A)-6 which contains all possible 10 TA loci. In addition to the three well-characterized operons, namely relBE2, yefM-yoeB, and pezAT, we show here the functionality of a fourth operon that encodes the pneumococcal equivalent of the phd-doc TA. Transcriptional fusions with gene encoding Green Fluorescent Protein showed that the promoter was slightly repressed by the Phd antitoxin, and exhibited almost background values when both Phd-Doc were expressed together. These findings demonstrate that phd doc shows the negative self-regulatory features typical for an authentic TA. Further, we also show that the previously proposed TAs XreA-Ant and Bro-XreB, although they exhibit a genetic organization resembling those of typical TAs, did not appear to confer a functional behavior corresponding to bona fide TAs. In addition, we have also discovered new interesting bioinformatics results for the known pneumococcal TAs RelBE2 and PezAT. A global analysis of the four identified toxins-antitoxins in the pneumococcal genomes (PezAT, RelBE2, YefM-YoeB, and Phd Doc) showed that RelBE2 and Phd-Doc are the most conserved ones. Further, there was good correlation among TA types, clonal complexes and sequence types in the 48 pneumococcal strains analyzed. PMID- 25538697 TI - Bioactive compounds produced by gut microbial tannase: implications for colorectal cancer development. AB - The microorganisms in the human gastrointestinal tract have a profound influence on the transformation of food into metabolites which can impact human health. Gallic acid (GA) and pyrogallol (PG) are bioactive compounds displaying diverse biological properties, including carcinogenic inhibiting activities. However, its concentration in fruits and vegetables is generally low. These metabolites can be also generated as final products of tannin metabolism by microbes endowed with tannase, which opens up the possibility of their anti-cancer potential being increased. Patients with colorectal cancer (CRC) display an imbalanced gut microbiota respect to healthy population. The recent use of next generation sequencing technologies has greatly improved knowledge of the identity of bacterial species that colonize non-tumorous and tumorous tissues of CRC patients. This information provides a unique opportunity to shed light on the role played by gut microorganisms in the different stages of this disease. We here review the recently published gut microbiome associated to CRC patients and highlight tannase as an underlying gene function of bacterial species that selectively colonize tumorous tissues, but not adjacent non-malignant tissues. Given the anti-carcinogenic roles of GA and PG produced by gut tannin-degrading bacteria, we provide an overview of the possible consequences of this intriguing coincidence for CRC development. PMID- 25538698 TI - Nucleotide sequence of conjugative prophage Phi1207.3 (formerly Tn1207.3) carrying the mef(A)/msr(D) genes for efflux resistance to macrolides in Streptococcus pyogenes. AB - Genetic element Phi1207.3 (formerly Tn1207.3) is a prophage of Streptococcus pyogenes which carries the macrolide efflux resistance genes mef(A)/msr(D) and is capable of conjugal transfer among streptococci. Complete nucleotide sequence showed that Phi1207.3 is 52,491 bp in length and contained 58 open reading frames (ORFs). A manual homology-based annotation with functional prediction of the hypothetical gene product was possible only for 34 out of 58 ORFs. Phi1207.3 codes for two different C-methylation systems, several phage structural genes, a lysis cassette (composed by a holin and a peptidoglycan hydrolase), and three site-specific resolvases of the serine recombinase family. PMID- 25538699 TI - Bacterial communities in the rumen of Holstein heifers differ when fed orchardgrass as pasture vs. hay. AB - The rich and diverse microbiota of the rumen provides ruminant animals the capacity to utilize highly fibrous feedstuffs as their energy source, but there is surprisingly little information on the composition of the microbiome of ruminants fed all-forage diets, despite the importance of such agricultural production systems worldwide. In three 28-day periods, three ruminally-cannulated Holstein heifers sequentially grazed orchardgrass pasture (OP), then were fed orchardgrass hay (OH), then returned to OP. These heifers displayed greater shifts in ruminal bacterial community composition (determined by automated ribosomal intergenic spacer analysis and by pyrotag sequencing of 16S rRNA genes) than did two other heifers maintained 84 d on the same OP. Phyla Firmicutes and Bacteroidetes dominated all ruminal samples, and quantitative PCR indicated that members of the genus Prevotella averaged 23% of the 16S rRNA gene copies, well below levels previously reported with cows fed total mixed rations. Differences in bacterial community composition and ruminal volatile fatty acid (VFA) profiles were observed between the OP and OH despite similarities in gross chemical composition. Compared to OP, feeding OH increased the molar proportion of ruminal acetate (P = 0.02) and decreased the proportion of ruminal butyrate (P < 0.01), branched-chain VFA (P < 0.01) and the relative population size of the abundant genus Butyrivibrio (P < 0.001), as determined by pyrotag sequencing. Despite the low numbers of animals examined, the observed changes in VFA profile in the rumens of heifers on OP vs. OH are consistent with the shifts in Butyrivibrio abundance and its known physiology as a butyrate producer that ferments both carbohydrates and proteins. PMID- 25538701 TI - Prevalence and detection of Stenotrophomonas maltophilia carrying metallo-beta lactamase blaL1 in Beijing, China. AB - Intrinsic beta-lactam resistance in Stenotrophomonas maltophilia is caused by bla L1 and/or bla L2, a kind of metallo-beta-lactamase with a broad substrate spectrum including carbapenems. A rapid and sensitive molecular method for the detection of bla L1 in clinical samples is needed to guide therapeutic treatment. In present study, we first described a loop-mediated isothermal amplification (LAMP) method for the rapid detection of bla L1 in clinical samples by using two methods including a chromogenic method using calcein/Mn(2+) complex and the real time turbidity monitoring to assess the reaction. Then dissemination of L1 producing S. maltophilia was investigated from ICU patients in three top hospital in Beijing, China. The results showed that both methods detected the target DNA within 60 min under isothermal conditions (65 degrees C). The detection limit of LAMP was 3.79 pg/MUl DNA, and its sensitivity 100-fold greater than that of conventional PCR. All 21 test strains except for S. maltophilia were negative for bla L1, indicative of the high-specificity of the primers for the bla L1. A total of 22 L1-positive isolates were identified for LAMP-based surveillance of bla L1 from 105 ICU patients with clinically suspected multi-resistant infections. The sequences of these bla L1 genes were conservative with only a few sites mutated, and the strains had highly resistant to beta-lactam antibiotics. The MLST recovered that 22 strains belonged to seven different S. maltophilia sequence types (STs). Furthermore, co-occurrence of bla L1 and bla L2 genes were detected in all of isolates. Strikingly, S. maltophilia DCPS-01 was recovered to contain bla L1, bla L2, and bla NDM-1 genes, possessing an ability to hydrolyse all beta lactams antibiotics. Our data showed the diversity types of S. maltophilia carrying bla L1 and co-occurrence of many resistant genes in the clinical strains signal an ongoing and fast evolution of S. maltophilia resulting from their wide spread in the respiratory infections, and therefore will be difficult to control. PMID- 25538702 TI - Phototrophic Fe(II)-oxidation in the chemocline of a ferruginous meromictic lake. AB - Precambrian Banded Iron Formation (BIF) deposition was conventionally attributed to the precipitation of iron-oxides resulting from the abiotic reaction of ferrous iron (Fe(II)) with photosynthetically produced oxygen. Earliest traces of oxygen date from 2.7 Ga, thus raising questions as to what may have caused BIF precipitation before oxygenic photosynthesis evolved. The discovery of anoxygenic phototrophic bacteria thriving through the oxidation of Fe(II) has provided support for a biological origin for some BIFs, but despite reports suggesting that anoxygenic phototrophs may oxidize Fe(II) in the environment, a model ecosystem of an ancient ocean where they are demonstrably active was lacking. Here we show that anoxygenic phototrophic bacteria contribute to Fe(II) oxidation in the water column of the ferruginous sulfate-poor, meromictic lake La Cruz (Spain). We observed in-situ photoferrotrophic activity through stimulation of phototrophic carbon uptake in the presence of Fe(II), and determined light dependent Fe(II)-oxidation by the natural chemocline microbiota. Moreover, a photoferrotrophic bacterium most closely related to Chlorobium ferrooxidans was enriched from the ferruginous water column. Our study for the first time demonstrates a direct link between anoxygenic photoferrotrophy and the anoxic precipitation of Fe(III)-oxides in a ferruginous water column, providing a plausible mechanism for the bacterial origin of BIFs before the advent of free oxygen. However, photoferrotrophs represent only a minor fraction of the anoxygenic phototrophic community with the majority apparently thriving by sulfur cycling, despite the very low sulfur content in the ferruginous chemocline of Lake La Cruz. PMID- 25538700 TI - Modeling HCV disease in animals: virology, immunology and pathogenesis of HCV and GBV-B infections. AB - Hepatitis C virus (HCV) infection has become a global public health burden costing billions of dollars in health care annually. Even with rapidly advancing scientific technologies this disease still poses a significant threat due to a lack of vaccines and affordable treatment options. The immune correlates of protection and predisposing factors toward chronicity remain major obstacles to development of HCV vaccines and immunotherapeutics due, at least in part, to lack of a tangible infection animal model. This review discusses the currently available animal models for HCV disease with a primary focus on GB virus B (GBV B) infection of New World primates that recapitulates the dual Hepacivirus phenotypes of acute viral clearance and chronic pathologic disease. HCV and GBV-B are also closely phylogenetically related and advances in characterization of the immune systems of New World primates have already led to the use of this model for drug testing and vaccine trials. Herein, we discuss the benefits and caveats of the GBV-B infection model and discuss potential avenues for future development of novel vaccines and immunotherapies. PMID- 25538703 TI - Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4(+) T-lymphocytes. AB - Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated. We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4(+) T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4(+) immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4(+) T-cell model was constructed and simulated under CAV1 (+/+), CAV1 (+/ ), and CAV1 (-/-) conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4(+) T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4(+) T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia. PMID- 25538705 TI - Macrophage: SHIP of Immunity. PMID- 25538704 TI - Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4. AB - T-cell co-receptor cytotoxic T-cell antigen-4 (CTLA-4) is a critical inhibitory regulator of T-cell immunity and antibody blockade of the co-receptor has been shown to be effective in tumor immunotherapy. Paradoxically, the majority of CTLA 4 is located in intracellular compartments from where it is transported to the cell surface and rapidly internalized. The intracellular trafficking pathways that control transport of the co-receptor to the cell surface ensures the appropriate balance of negative and positive signaling for a productive immune response with minimal autoimmune disorders. It will also influence the degree of inhibition and the potency of antibody checkpoint blockade in cancer immunotherapy. Current evidence indicates that the mechanisms of CTLA-4 transport to the cell surface and its residency are multifactorial involving a combination of immune cell-specific adapters such as TRIM and LAX, the small GTPase Rab8 as well as generic components such as ARF-1, phospholipase D, and the heterotetrameric AP1/2 complex. This review covers the recent developments in our understanding of the processes that control the expression of this important co inhibitory receptor for the modulation of T-cell immunity. Interference with the processes that regulate CTLA-4 surface expression could provide an alternate therapeutic approach in the treatment of cancer and autoimmunity. PMID- 25538707 TI - Comparative evaluation of heterologous production systems for recombinant pulmonary surfactant protein D. AB - Commercial surfactant products derived from animal lungs are used for the treatment of respiratory diseases in premature neonates. These products contain lipids and the hydrophobic surfactant proteins B and C, which help to lower the surface tension in the lungs. Surfactant products are less effective when pulmonary diseases involve inflammatory complications because two hydrophilic surfactant proteins (A and D) are lost during the extraction process, yet surfactant protein D (SP-D) is a component of the innate immune system that helps to reduce lung inflammation. The performance of surfactant products could, therefore, be improved by supplementing them with an additional source of SP-D. Recombinant SP-D (rSP-D) is produced in mammalian cells and bacteria (Escherichia coli), and also experimentally in the yeast Pichia pastoris. Mammalian cells produce full-size SP-D, but the yields are low and the cost of production is high. In contrast, bacteria produce a truncated form of SP-D, which is active in vitro and in vivo, and higher yields can be achieved at a lower cost. We compare the efficiency of production of rSP-D in terms of the total yields achieved in each system and the amount of SP-D needed to meet the global demand for the treatment of pulmonary diseases, using respiratory distress syndrome as a case study. PMID- 25538708 TI - The Maternal Serological Response to Intrauterine Ureaplasma sp. Infection and Prediction of Risk of Pre-Term Birth. AB - Pre-term birth (PTB) associated with intrauterine infection and inflammation (IUI) is the major cause of early PTB less than 32 weeks of gestation. Ureaplasma spp. are common commensals of the urogenital tract in pregnancy and are the most commonly identified microorganisms in amniotic fluid of pre-term pregnancies. While we have an understanding of the causal relationship between intra-amniotic infection, inflammation and PTB, we are still unable to explain why vaginal Ureaplasma sp. colonization is tolerated in some women but causes PTB in others. It is now known that placental tissues are frequently colonized by bacteria even in apparently healthy pregnancies delivered at term; usually this occurs in the absence of a significant local inflammatory response. It appears, therefore, that the site, nature, and magnitude of the immune response to infiltrating microorganisms are key in determining pregnancy outcome. Some evidence exists that the maternal serological response to Ureaplasma sp. colonization may be predictive of adverse pregnancy outcome, although issues such as the importance of virulence factors (serovars) and the timing, magnitude, and functional consequences of the immune response await clarification. This mini-review discusses the evidence linking the maternal immune response to risk of PTB and the potential applications of maternal serological analysis for predicting obstetric outcome. PMID- 25538709 TI - Epigenetic regulation of monoallelic rearrangement (allelic exclusion) of antigen receptor genes. AB - While most genes in the mammalian genome are transcribed from both parental chromosomes in cells where they are expressed, approximately 10% of genes are expressed monoallelically, so that any given cell will express either the paternal or maternal allele, but not both. The antigen receptor genes in B and T cells are well-studied examples of a gene family, which is expressed in a monoallelic manner, in a process coined "allelic exclusion." During lymphocyte development, only one allele of each antigen receptor undergoes V(D)J rearrangement at a time, and once productive rearrangement is sensed, rearrangement of the second allele is prevented. In this mini review, we discuss the epigenetic processes, including asynchronous replication, nuclear localization, chromatin condensation, histone modifications, and DNA methylation, which appear to regulate the primary rearrangement of a single allele, while blocking the rearrangement of the second allele. PMID- 25538706 TI - Plasticity of gammadelta T Cells: Impact on the Anti-Tumor Response. AB - The tumor immune microenvironment contributes to tumor initiation, progression, and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of gamma and delta chains (gammadelta T cells) are of particular interest. gammadelta T cells can contribute to the immune response against many tumor types (lymphoma, myeloma, melanoma, breast, colon, lung, ovary, and prostate cancer) directly through their cytotoxic activity and indirectly by stimulating or regulating the biological functions of other cell types required for the initiation and establishment of the anti-tumor immune response, such as dendritic cells and cytotoxic CD8+ T cells. However, the notion that tumor infiltrating gammadelta T cells are a good prognostic marker in cancer was recently challenged by studies showing that the presence of these cells in the tumor microenvironment was associated with poor prognosis in both breast and colon cancer. These findings suggest that gammadelta T cells may also display pro tumor activities. Indeed, breast tumor-infiltrating gammadelta T cells could exert an immunosuppressive activity by negatively regulating dendritic cell maturation. Furthermore, recent studies demonstrated that signals from the microenvironment, particularly cytokines, can confer some plasticity to gammadelta T cells and promote their differentiation into gammadelta T cells with regulatory functions. This review focuses on the current knowledge on the functional plasticity of gammadelta T cells and its effect on their anti-tumor activities. It also discusses the putative mechanisms underlying gammadelta T cell expansion, differentiation, and recruitment in the tumor microenvironment. PMID- 25538711 TI - Identification of the IgG1 Induction Factor (Interleukin 4). PMID- 25538710 TI - Immunoglobulin replacement therapy in secondary hypogammaglobulinemia. AB - Immunoglobulin (Ig) replacement therapy dramatically changed the clinical course of primary hypogammaglobulinemias, significantly reducing the incidence of infectious events. Over the last two decades its use has been extended to secondary antibody deficiencies, particularly those related to hematological disorders as lymphoproliferative diseases (LPDs) and multiple myeloma. In these malignancies, hypogammaglobulinemia can be an intrinsic aspect of the disease or follow chemo-immunotherapy regimens, including anti-CD20 treatment. Other than in LPDs the broadening use of immunotherapy (e.g., rituximab) and immune-suppressive therapy (steroids, sulfasalazine, and mycophenolate mofetil) has extended the occurrence of iatrogenic hypogammaglobulinemia. In particular, in both autoimmune diseases and solid organ transplantation Ig replacement therapy has been shown to reduce the rate of infectious events. Here, we review the existing literature about Ig replacement therapy in secondary hypogammaglobulinemia, with special regard for subcutaneous administration route, a safe, effective, and well tolerated treatment approach, currently well established in primary immunodeficiencies and secondary hypogammaglobulinemias. PMID- 25538712 TI - Genetic introgression of ethylene-suppressed transgenic tomatoes with higher polyamines trait overcomes many unintended effects due to reduced ethylene on the primary metabolome. AB - Ethylene regulates a myriad physiological and biochemical processes in ripening fruits and is accepted as the ripening hormone for the climacteric fruits. However, its effects on metabolome and resulting fruit quality are not yet fully understood, particularly when some of the ripening-associated biochemical changes are independent of ethylene action. We have generated a homozygous transgenic tomato genotype (2AS-AS) that exhibits reduced ethylene production as a result of impaired expression of 1-aminocyclopropane-1-carboxylate synthase 2 gene by its antisense RNA and had a longer shelf life. Double transgenic hybrid (2AS-AS * 579HO) developed through a genetic cross between 2AS-AS and 579HO (Mehta et al., 2002) lines resulted in significantly higher ethylene production than either the WT or 2AS-AS fruit. To determine the effects of reduced ethylene and introgression of higher polyamines' trait, the metabolic profiles of ripening fruits from WT (556AZ), 2AS-AS, and 2AS-AS * 579HO lines were determined using (1)H-NMR spectroscopy. The levels of Glu, Asp, AMP, Adenosine, Nucl1, and Nucl2 increased during ripening of the WT fruit. The increases in Glu, Asp, and AMP levels were attenuated in 2AS-AS fruit but recovered in the double hybrid with higher ethylene and polyamine levels. The ripening-associated decreases in Ala, Tyr, Val, Ile, Phe, malate, and myo-inositol levels in the 2AS-AS line were not reversed in the double hybrid line suggesting a developmental/ripening regulated accumulation of these metabolites independent of ethylene. Significant increases in the levels of fumarate, formate, choline, Nucl1, and Nucl2 at most stages of ripening fruit were found in the double transgenic line due to introgression with higher-polyamines trait. Taken together these results show that the ripening associated metabolic changes are both ethylene dependent and independent, and that the fruit metabolome is under the control of multiple regulators, including ethylene and polyamines. PMID- 25538714 TI - Heterogeneity in pineapple fruit quality results from plant heterogeneity at flower induction. AB - Heterogeneity in fruit quality constitutes a major constraint in agri-food chains. In this paper the sources of the heterogeneity in pineapple in the field were studied in four experiments in commercial pineapple fields. The aims were to determine (a) whether differences in pineapple fruit quality among individual fruits are associated with differences in vigor of the individual plants within the crop at the time of artificial flower induction; and (b) whether the side shoots produced by the plant during the generative phase account for the fruit quality heterogeneity. Two pineapple cultivars were considered: cv. Sugarloaf and cv. Smooth Cayenne. Plant vigor at the time of artificial flower induction was measured by three variates: the number of functional leaves, the D-leaf length and their cross product. Fruit quality attributes measured at harvest time included external attributes (weight and height of fruit, infructescence and crown) and internal quality attributes [total soluble solids (TSS), pH, translucent flesh]. Results showed that the heterogeneity in fruit weight was a consequence of the heterogeneity in vigor of the plants at the moment of flower induction; that effect was mainly on the infructescence weight and less or not on the crown weight. The associations between plant vigor variates at flower induction and the internal quality attributes of the fruit were poor and/or not consistent across experiments. The weight of the slips (side shoots) explained part of the heterogeneity in fruit weight, infructescence weight and fruit height in cv. Sugarloaf. Possibilities for reducing the variation in fruit quality by precise cultural practices are discussed. PMID- 25538713 TI - VitisCyc: a metabolic pathway knowledgebase for grapevine (Vitis vinifera). AB - We have developed VitisCyc, a grapevine-specific metabolic pathway database that allows researchers to (i) search and browse the database for its various components such as metabolic pathways, reactions, compounds, genes and proteins, (ii) compare grapevine metabolic networks with other publicly available plant metabolic networks, and (iii) upload, visualize and analyze high-throughput data such as transcriptomes, proteomes, metabolomes etc. using OMICs-Viewer tool. VitisCyc is based on the genome sequence of the nearly homozygous genotype PN40024 of Vitis vinifera "Pinot Noir" cultivar with 12X v1 annotations and was built on BioCyc platform using Pathway Tools software and MetaCyc reference database. Furthermore, VitisCyc was enriched for plant-specific pathways and grape-specific metabolites, reactions and pathways. Currently VitisCyc harbors 68 super pathways, 362 biosynthesis pathways, 118 catabolic pathways, 5 detoxification pathways, 36 energy related pathways and 6 transport pathways, 10,908 enzymes, 2912 enzymatic reactions, 31 transport reactions and 2024 compounds. VitisCyc, as a community resource, can aid in the discovery of candidate genes and pathways that are regulated during plant growth and development, and in response to biotic and abiotic stress signals generated from a plant's immediate environment. VitisCyc version 3.18 is available online at http://pathways.cgrb.oregonstate.edu. PMID- 25538715 TI - Cellular dynamics during early barley pollen embryogenesis revealed by time-lapse imaging. AB - Plants display a remarkable capacity for cellular totipotency. An intriguing and useful example is that immature pollen cultured in vitro can pass through embryogenic development to form haploid or doubled haploid plants. However, a lack of understanding the initial mechanisms of pollen embryogenesis hampers the improvement and more effective and widespread employment of haploid technology in plant research and breeding. To investigate the cellular dynamics during the onset of pollen embryogenesis, we used time-lapse imaging along with transgenic barley expressing nuclear localized Green Fluorescent Protein. The results enabled us to identify nine distinct embryogenic and non-embryogenic types of pollen response to the culture conditions. Cell proliferation in embryogenic pollen normally started via a first symmetric mitosis (54.3% of pollen observed) and only rarely did so via asymmetric pollen mitosis I (4.3% of pollen observed). In the latter case, proliferation generally originated from the vegetative-like cell, albeit the division of the generative-like cell was observed in few types of pollen. Under the culture conditions used, fusion of cell nuclei was the only mechanism of genome duplication observed. PMID- 25538716 TI - Genetic mapping of legume orthologs reveals high conservation of synteny between lentil species and the sequenced genomes of Medicago and chickpea. AB - Lentil (Lens culinaris Medik.) is a global food crop with increasing importance for food security in south Asia and other regions. Lens ervoides, a wild relative of cultivated lentil, is an important source of agronomic trait variation. Lens is a member of the galegoid clade of the Papilionoideae family, which includes other important dietary legumes such as chickpea (Cicer arietinum) and pea (Pisum sativum), and the sequenced model legume Medicago truncatula. Understanding the genetic structure of Lens spp. in relation to more fully sequenced legumes would allow leveraging of genomic resources. A set of 1107 TOG-based amplicons were identified in L. ervoides and a subset thereof used to design SNP markers for mapping. A map of L. ervoides consisting of 377 SNP markers spread across seven linkage groups was developed using a GoldenGate genotyping array and single SNP marker assays. Comparison with maps of M. truncatula and L. culinaris documented considerable shared synteny and led to the identification of a few major translocations and a major inversion that distinguish Lens from M. truncatula, as well as a translocation that distinguishes L. culinaris from L. ervoides. The identification of chromosome-level differences among Lens spp. will aid in the understanding of introgression of genes from L. ervoides into cultivated L. culinaris, furthering genetic research and breeding applications in lentil. PMID- 25538717 TI - Assessing the transcriptional regulation of L-cysteine desulfhydrase 1 in Arabidopsis thaliana. AB - Hydrogen sulfide is an important signaling molecule that functions as a physiological gasotransmitter of comparable importance to NO and CO in mammalian systems. In plants, numerous studies have shown that sulfide increases tolerance/resistance to stress conditions and regulates essential processes. The endogenous production of hydrogen sulfide in the cytosol of Arabidopsis thaliana occurs by the enzymatic desulfuration of L-cysteine, which is catalyzed by the L cysteine desulfhydrase enzyme DES1. To define the functional role of DES1 and the role that the sulfide molecule may play in the regulation of physiological processes in plants, we studied the localization of the expression of this gene at the tissue level. Transcriptional data reveal that DES1 is expressed at all developmental stages and is more abundant at the seedling stage and in mature plants. At the tissue level, we analyzed the expression of a GFP reporter gene fused to promoter of DES1. The GFP fluorescent signal was detected in the cytosol of both epidermal and mesophyll cells, including the guard cells. GFP fluorescence was highly abundant around the hydathode pores and inside the trichomes. In mature plants, fluorescence was detected in floral tissues; a strong GFP signal was detected in sepals, petals, and pistils. When siliques were examined, the highest GFP fluorescence was observed at the bases of the siliques and the seeds. The location of GFP expression, together with the identification of regulatory elements within the DES1 promoter, suggests that DES1 is hormonally regulated. An increase in DES1 expression in response to ABA was recently demonstrated; in the present work, we observe that in vitro auxin treatment significantly repressed the expression of DES1. PMID- 25538719 TI - The role of ethylene and ROS in salinity, heavy metal, and flooding responses in rice. AB - Plant growth and developmental processes as well as abiotic and biotic stress adaptations are regulated by small endogenous signaling molecules. Among these, phytohormones such as the gaseous alkene ethylene and reactive oxygen species (ROS) play an important role in mediating numerous specific growth or cell death responses. While apoplastic ROS are generated by plasma membrane-located respiratory burst oxidase homolog proteins, intracellular ROS are produced mainly in electron transfer chains of mitochondria and chloroplasts. Ethylene accumulates in plants due to physical entrapment or by enhanced ethylene biosynthesis. A major crop that must endure high salt and heavy metal concentrations upon flooding in regions of Asia is rice. Ethylene and ROS have been identified as the major signals that mediate salinity, chromium, and flooding stress in rice. This mini review focuses on (i) what is known about ethylene and ROS level control during these abiotic stresses in rice, (ii) how the two signals mediate growth or death processes, and (iii) feedback mechanisms that in turn regulate ethylene and ROS signaling. PMID- 25538720 TI - Current perspectives in proteomic analysis of abiotic stress in Grapevines. AB - Grapes are an important crop plant which forms the basis of a globally important industry. Grape and wine production is particularly vulnerable to environmental and climatic fluctuations, which makes it essential for us to develop a greater understanding of the molecular level responses of grape plants to various abiotic stresses. The completion of the initial grape genome sequence in 2007 has led to a significant increase in research on grapes using proteomics approaches. In this article, we discuss some of the current research on abiotic stress in grapevines, in the context of abiotic stress research in other plant species. We also highlight some of the current limitations in grapevine proteomics and identify areas with promising scope for potential future research. PMID- 25538722 TI - Effect of alternating day and night temperature on short day-induced bud set and subsequent bud burst in long days in Norway spruce. AB - Young seedlings of the conifer Norway spruce exhibit short day (SD)-induced cessation of apical growth and bud set. Although different, constant temperatures under SD are known to modulate timing of bud set and depth of dormancy with development of deeper dormancy under higher compared to lower temperature, systematic studies of effects of alternating day (DT) and night temperatures (NT) are limited. To shed light on this, seedlings of different provenances of Norway spruce were exposed to a wide range of DT-NT combinations during bud development, followed by transfer to forcing conditions of long days (LD) and 18 degrees C, directly or after different periods of chilling. Although no specific effect of alternating DT/NT was found, the results demonstrate that the effects of DT under SD on bud set and subsequent bud break are significantly modified by NT in a complex way. The effects on bud break persisted after chilling. Since time to bud set correlated with the daily mean temperature under SD at DTs of 18 and 21 degrees C, but not a DT of 15 degrees C, time to bud set apparently also depend on the specific DT, implying that the effect of NT depends on the actual DT. Although higher temperature under SD generally results in later bud break after transfer to forcing conditions, the fastest bud flush was observed at intermediate NTs. This might be due to a bud break-hastening chilling effect of intermediate compared to higher temperatures, and delayed bud development to a stage where bud burst can occur, under lower temperatures. Also, time to bud burst in un-chilled seedlings decreased with increasing SD-duration, suggesting that bud development must reach a certain stage before the processes leading to bud burst are initiated. The present results also indicate that low temperature during bud development had a larger effect on the most southern compared to the most northern provenance studied. Decreasing time to bud burst was observed with increasing northern latitude of origin in un-chilled as well as chilled plants. In conclusion, being a highly temperature-dependent process, bud development is strongly delayed by low temperature, and the effects of DT is significantly modified by NT in a complex manner. PMID- 25538718 TI - Wheat proteomics: proteome modulation and abiotic stress acclimation. AB - Cellular mechanisms of stress sensing and signaling represent the initial plant responses to adverse conditions. The development of high-throughput "Omics" techniques has initiated a new era of the study of plant molecular strategies for adapting to environmental changes. However, the elucidation of stress adaptation mechanisms in plants requires the accurate isolation and characterization of stress-responsive proteins. Because the functional part of the genome, namely the proteins and their post-translational modifications, are critical for plant stress responses, proteomic studies provide comprehensive information about the fine-tuning of cellular pathways that primarily involved in stress mitigation. This review summarizes the major proteomic findings related to alterations in the wheat proteomic profile in response to abiotic stresses. Moreover, the strengths and weaknesses of different sample preparation techniques, including subcellular protein extraction protocols, are discussed in detail. The continued development of proteomic approaches in combination with rapidly evolving bioinformatics tools and interactive databases will facilitate understanding of the plant mechanisms underlying stress tolerance. PMID- 25538721 TI - Membrane transporters and drought resistance - a complex issue. AB - Land plants have evolved complex adaptation strategies to survive changes in water status in the environment. Understanding the molecular nature of such adaptive changes allows the development of rapid innovations to improve crop performance. Plant membrane transport systems play a significant role when adjusting to water scarcity. Here we put proteins participating in transmembrane allocations of various molecules in the context of stomatal, cuticular, and root responses, representing a part of the drought resistance strategy. Their role in the transport of signaling molecules, ions or osmolytes is summarized and the challenge of the forthcoming research, resulting from the recent discoveries, is highlighted. PMID- 25538723 TI - Strategies for transferring resistance into wheat: from wide crosses to GM cassettes. AB - The domestication of wheat in the Fertile Crescent 10,000 years ago led to a genetic bottleneck. Modern agriculture has further narrowed the genetic base by introducing extreme levels of uniformity on a vast spatial and temporal scale. This reduction in genetic complexity renders the crop vulnerable to new and emerging pests and pathogens. The wild relatives of wheat represent an important source of genetic variation for disease resistance. For nearly a century farmers, breeders, and cytogeneticists have sought to access this variation for crop improvement. Several barriers restricting interspecies hybridization and introgression have been overcome, providing the opportunity to tap an extensive reservoir of genetic diversity. Resistance has been introgressed into wheat from at least 52 species from 13 genera, demonstrating the remarkable plasticity of the wheat genome and the importance of such natural variation in wheat breeding. Two main problems hinder the effective deployment of introgressed resistance genes for crop improvement: (1) the simultaneous introduction of genetically linked deleterious traits and (2) the rapid breakdown of resistance when deployed individually. In this review, we discuss how recent advances in molecular genomics are providing new opportunities to overcome these problems. PMID- 25538724 TI - Forage polyphenol oxidase and ruminant livestock nutrition. AB - Polyphenol oxidase (PPO) is predominately associated with the detrimental effect of browning fruit and vegetables, however, interest within PPO containing forage crops (crops to be fed to animals) has grown since the browning reaction was associated with reduced nitrogen (N) losses in silo and the rumen. The reduction in protein breakdown in silo of red clover (high PPO forage) increased the quality of protein, improving N-use efficiency [feed N into product N (e.g., Milk): NUE] when fed to ruminants. A further benefit of red clover silage feeding is a significant reduction in lipolysis (cleaving of glycerol-based lipid) in silo and an increase in the deposition of beneficial C18 polyunsaturated fatty acid (PUFA) in animal products, which has also been linked to PPO activity. PPOs protection of plant protein and glycerol based-PUFA in silo is related to the deactivation of plant proteases and lipases. This deactivation occurs through PPO catalyzing the conversion of diphenols to quinones which bind with cellular nucleophiles such as protein reforming a protein-bound phenol (PBP). If the protein is an enzyme (e.g., protease or lipase) the complexing denatures the enzyme. However, PPO is inactive in the anaerobic rumen and therefore any subsequent protection of plant protein and glycerol based-PUFA in the rumen must be as a result of events that occurred to the forage pre-ingestion. Reduced activity of plant proteases and lipases would have little effect on NUE and glycerol based-PUFA in the rumen due to the greater concentration of rumen microbial proteases and lipases. The mechanism for PPOs protection of plant protein in the rumen is a consequence of complexing plant protein, rather than protease deactivation per se. These complexed proteins reduce protein digestibility in the rumen and subsequently increase undegraded dietary protein flow to the small intestine. The mechanism for protecting glycerol-based PUFA has yet to be fully elucidated but may be associated with entrapment within PBP reducing access to microbial lipases or differences in rumen digestion kinetics of the forage and therefore not related to PPO activity. PMID- 25538726 TI - Subjective cognitive impairment subjects in our clinical practice. AB - BACKGROUND: The clinical challenge in subjective cognitive impairment (SCI) is to identify which individuals will present cognitive decline. We created a statistical model to determine which variables contribute to SCI and mild cognitive impairment (MCI) versus Alzheimer's disease (AD) diagnoses. METHODS: A total of 993 subjects diagnosed at a memory clinic (2007-2009) were included retrospectively: 433 with SCI, 373 with MCI and 187 with AD. Descriptive statistics were provided. A logistic regression model analyzed the likelihood of SCI and MCI patients being diagnosed with AD, using age, gender, Mini-Mental State Examination score, the ratio of beta-amyloid 42 divided by total tau, and phosphorylated tau as independent variables. RESULTS: The SCI subjects were younger (57.8 +/- 8 years) than the MCI (64.2 +/- 10.6 years) and AD subjects (70.1 +/- 9.7 years). They were more educated, had less medial temporal lobe atrophy (MTA) and frequently normal cerebrospinal fluid biomarkers. Apolipoprotein E4/E4 homozygotes and apolipoprotein E3/E4 heterozygotes were significantly less frequent in the SCI group (6 and 36%) than in the AD group (28 and 51%). Within the regression model, cardiovascular risk factors, confluent white matter lesions, MTA and central atrophy increased the AD likelihood for SCI subjects. CONCLUSIONS: SCI patients form a distinct group. In our model, factors suggesting cardiovascular risk, MTA and central atrophy increased the AD likelihood for SCI subjects. PMID- 25538725 TI - Salicylic acid signal transduction: the initiation of biosynthesis, perception and transcriptional reprogramming. AB - The phytohormone salicylic acid (SA) is a small phenolic compound that regulates diverse physiological processes, in particular plant resistance against pathogens. Understanding SA-mediated signaling has been a major focus of plant research. Pathogen-induced SA is mainly synthesized via the isochorismate pathway in chloroplasts, with ICS1 (ISOCHORISMATE SYNTHASE 1) being a critical enzyme. Calcium signaling regulates activities of a subset of transcription factors thereby activating nuclear ICS1 expression. The produced SA triggers extensive transcriptional reprogramming in which NPR1 (NON-EXPRESSOR of PATHOGENESIS RELATED GENES 1) functions as the central coactivator of TGA transcription factors. Recently, two alternative but not exclusive models for SA perception mechanisms were proposed. The first model is that NPR1 homologs, NPR3 and NPR4, perceive SA thereby regulating NPR1 protein accumulation. The second model describes that NPR1 itself perceives SA, triggering an NPR1 conformational change thereby activating SA-mediated transcription. Besides the direct SA binding, NPR1 is also regulated by SA-mediated redox changes and phosphorylation. Emerging evidence show that pathogen virulence effectors target SA signaling, further strengthening the importance of SA-mediated immunity. PMID- 25538727 TI - The Pattern of Brain Amyloid Load in Posterior Cortical Atrophy Using (18)F-AV45: Is Amyloid the Principal Actor in the Disease? AB - BACKGROUND: Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuoperceptual dysfunction and praxis declines. This syndrome is related to a number of underlying diseases, including, in most cases, Alzheimer's disease (AD). The aim of this study was to compare the amyloid load with (18)F AV45 positron emission tomography (PET) between PCA and AD subjects. METHODS: We performed (18)F-AV45 PET, cerebrospinal fluid (CSF) biomarker analysis and a neuropsychological assessment in 11 PCA patients and 12 AD patients. RESULTS: The global and regional (18)F-AV45 uptake was similar in the PCA and AD groups. No significant correlation was observed between global (18)F-AV45 uptake and CSF biomarkers or between regional (18)F-AV45 uptake and cognitive and affective symptoms. CONCLUSION: This (18)F-AV45 PET amyloid imaging study showed no specific regional pattern of cortical (18)F-AV45 binding in PCA patients. These results confirm that a distinct clinical phenotype in amnestic AD and PCA is not related to amyloid distribution. PMID- 25538728 TI - Are There Any Connections between Language Deficits and Cognitive Slowing in Alzheimer's Disease? AB - BACKGROUND: Speech disorders already occur in the early phases of Alzheimer's disease (AD). As a possible cause, problems of executive processes are discussed. Cognitive slowing is also repeatedly addressed. AIMS: Are there any connections between cognitive slowing and speech disorders in AD? And is there a relationship between cognitive slowing and executive processes? METHODS: The data of 72 healthy controls and 52 AD patients were examined with regard to their language performance and their response times in a computerized Stroop paradigm. RESULTS: The AD patients showed significantly worse results in all language tests as well as much longer reaction times in all Stroop conditions, especially in the interference condition (Stroop 3). Speech errors and response times correlated with severity (MMSE), and the speech errors correlated with the reaction times in Stroop 3 (interference condition, which reflects the processing time of executive processes). CONCLUSION: The most interesting question now is: How are language processing and executive processing time (Stroop 3) related? PMID- 25538729 TI - Influence of the rs1080985 Single Nucleotide Polymorphism of the CYP2D6 Gene and APOE Polymorphism on the Response to Donepezil Treatment in Patients with Alzheimer's Disease in China. AB - BACKGROUND/AIM: Recent data have indicated that the rs1080985 single nucleotide polymorphism (SNP) of the cytochrome P450 (CYP) 2D6 and the common apolipoprotein E (APOE) gene may affect the response to donepezil in patients with Alzheimer's disease (AD). We investigated this association in Chinese patients with mild-to moderate AD. METHODS: In this prospective cohort study, analyses of CYP2D6 and APOE were conducted in 208 native Chinese patients with mild-to-moderate AD. All patients were treated with donepezil 5 mg/day for 6 months, and the response to treatment was assessed using the Mini-Mental State Examination. RESULTS: No significant differences between responders (68.9%) and nonresponders (31.1%) to donepezil treatment (6 months' duration) were observed in the distribution of the CYP2D6 rs1080985 SNP, common APOE polymorphism or a combination of the two. CONCLUSIONS: Our results suggest that neither the CYP2D6 nor the APOE polymorphism influences the 6-month response to donepezil treatment in a Chinese population with AD. PMID- 25538731 TI - The disparity mutagenesis model predicts rescue of living things from catastrophic errors. AB - In animals including humans, mutation rates per generation exceed a perceived threshold, and excess mutations increase genetic load. Despite this, animals have survived without extinction. This is a perplexing problem for animal and human genetics, arising at the end of the last century, and to date still does not have a fully satisfactory explanation. Shortly after we proposed the disparity theory of evolution in 1992, the disparity mutagenesis model was proposed, which forms the basis for an explanation for an acceleration of evolution and species survival. This model predicts a significant increase of the mutation threshold values if the fidelity difference in replication between the lagging and leading strands is high enough. When applied to biological evolution, the model predicts that living things, including humans, might overcome the lethal effect of accumulated deleterious mutations and be able to survive. Artificially derived mutator strains of microorganisms, in which an enhanced lagging-strand-biased mutagenesis was introduced, showed unexpectedly high adaptability to severe environments. The implications of the striking behaviors shown by these disparity mutators will be discussed in relation to how living things with high mutation rates can avoid the self-defeating risk of excess mutations. PMID- 25538733 TI - An appraisal of RECQ1 expression in cancer progression. AB - RECQ1 is the most abundant member of the human RecQ family of DNA helicases genetically linked with cancer predisposition syndromes and well known for their functions in genome stability maintenance through DNA repair. Despite being the first discovered RecQ homolog in humans, biological functions of RECQ1 have remained largely underappreciated and its relevance to cellular transformation is yet unclear. RECQ1 is overexpressed and amplified in many clinical cancer samples. In silico evaluation of RECQ1 mRNA expression across the NCI-60 cancer cell lines predicts an association of RECQ1 with cancer cell migration, invasion, and metastasis. Consistent with this, latest work implicates RECQ1 in regulation of gene expression, especially of those associated with cancer progression. Functionally, silencing RECQ1 expression significantly reduces cell proliferation, migration, and invasion. Collectively, these results propose that discerning the role of RECQ1 in conferring proliferative and invasive phenotype to cancer cells could be useful in developing therapeutic strategies to block primary tumor progression and metastasis. PMID- 25538732 TI - Multiple functions of DDX3 RNA helicase in gene regulation, tumorigenesis, and viral infection. AB - The DEAD-box RNA helicase DDX3 is a multifunctional protein involved in all aspects of RNA metabolism, including transcription, splicing, mRNA nuclear export, translation, RNA decay and ribosome biogenesis. In addition, DDX3 is also implicated in cell cycle regulation, apoptosis, Wnt-beta-catenin signaling, tumorigenesis, and viral infection. Notably, recent studies suggest that DDX3 is a component of anti-viral innate immune signaling pathways. Indeed, DDX3 contributes to enhance the induction of anti-viral mediators, interferon (IFN) regulatory factor 3 and type I IFN. However, DDX3 seems to be an important target for several viruses, such as human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV), hepatitis B virus (HBV), and poxvirus. DDX3 interacts with HIV-1 Rev or HCV Core protein and modulates its function. At least, DDX3 is required for both HIV-1 and HCV replication. Therefore, DDX3 could be a novel therapeutic target for the development of drug against HIV-1 and HCV. PMID- 25538730 TI - Phospholipase A2 - nexus of aging, oxidative stress, neuronal excitability, and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment. AB - The aging brain undergoes a range of changes varying from subtle structural and physiological changes causing only minor functional decline under healthy normal aging conditions, to severe cognitive or neurological impairment associated with extensive loss of neurons and circuits due to age-associated neurodegenerative disease conditions. Understanding how biological aging processes affect the brain and how they contribute to the onset and progress of age-associated neurodegenerative diseases is a core research goal in contemporary neuroscience. This review focuses on the idea that changes in intrinsic neuronal electrical excitability associated with (per)oxidation of membrane lipids and activation of phospholipase A2 (PLA2) enzymes are an important mechanism of learning and memory failure under normal aging conditions. Specifically, in the context of this special issue on the biology of cognitive aging we portray the opportunities offered by the identifiable neurons and behaviorally characterized neural circuits of the freshwater snail Lymnaea stagnalis in neuronal aging research and recapitulate recent insights indicating a key role of lipid peroxidation-induced PLA2 as instruments of aging, oxidative stress and inflammation in age-associated neuronal and memory impairment in this model system. The findings are discussed in view of accumulating evidence suggesting involvement of analogous mechanisms in the etiology of age-associated dysfunction and disease of the human and mammalian brain. PMID- 25538735 TI - Locus heterogeneity disease genes encode proteins with high interconnectivity in the human protein interaction network. AB - Mutations in genes potentially lead to a number of genetic diseases with differing severity. These disease genes have been the focus of research in recent years showing that the disease gene population as a whole is not homogeneous, and can be categorized according to their interactions. Locus heterogeneity describes a single disorder caused by mutations in different genes each acting individually to cause the same disease. Using datasets of experimentally derived human disease genes and protein interactions, we created a protein interaction network to investigate the relationships between the products of genes associated with a disease displaying locus heterogeneity, and use network parameters to suggest properties that distinguish these disease genes from the overall disease gene population. Through the manual curation of known causative genes of 100 diseases displaying locus heterogeneity and 397 single-gene Mendelian disorders, we use network parameters to show that our locus heterogeneity network displays distinct properties from the global disease network and a Mendelian network. Using the global human proteome, through random simulation of the network we show that heterogeneous genes display significant interconnectivity. Further topological analysis of this network revealed clustering of locus heterogeneity genes that cause identical disorders, indicating that these disease genes are involved in similar biological processes. We then use this information to suggest additional genes that may contribute to diseases with locus heterogeneity. PMID- 25538734 TI - MBD2 and MBD3: elusive functions and mechanisms. AB - Deoxyribonucleic acid methylation is a long known epigenetic mark involved in many biological processes and the 'readers' of this mark belong to several distinct protein families that 'read' and 'translate' the methylation mark into a function. Methyl-CpG binding domain proteins belong to one of these families that are associated with transcriptional activation/repression, regulation of chromatin structure, pluripotency, development, and differentiation. Discovered decades ago, the systematic determination of the genomic binding sites of these readers and their epigenome make-up at a genome-wide level revealed the tip of the functional iceberg. This review focuses on two members of the methyl binding proteins, namely MBD2 and MBD3 that reside in very similar complexes, yet appear to have very different biological roles. We provide a comprehensive comparison of their genome-wide binding features and emerging roles in gene regulation. PMID- 25538737 TI - Down-regulation of Homer1b/c expression protects cultured neurons after traumatic injury. AB - Activation of metabotropic glutamate receptor 1a aggravates traumatic brain injury. The constitutively expressed protein Homer1b/c participates in delivering and anchoring metabotropic glutamate receptors in neurons. Here, we aimed to verify whether down-regulation of Homer1b/c by RNA interference could protect cultured rat cortical neurons from traumatic injury. We showed that 36 hours after transfection of Homer1b/c small interfering RNA, metabotropic glutamate receptor 1a was present only in the neuronal cytoplasm, but not in the dendrites. Calcium fluorescence intensity was also decreased significantly. Moreover, lactate dehydrogenase concentration was significantly decreased in Homer1b/c small interfering RNA-transfected cells compared with that in untransfected and control small interfering RNA-transfected cells 24 hours after traumatic neuronal injury. Our findings indicate that down-regulation of Homer1b/c could reduce metabotropic glutamate receptor 1a transfer from the cell body to the dendrite, relieve calcium overload, and protect neurons from traumatic injury. PMID- 25538736 TI - Enteric glia mediate neuronal outgrowth through release of neurotrophic factors. AB - Previous studies have shown that transplanted enteric glia enhance axonal regeneration, reduce tissue damage, and promote functional recovery following spinal cord injury. However, the mechanisms by which enteric glia mediate these beneficial effects are unknown. Neurotrophic factors can promote neuronal differentiation, survival and neurite extension. We hypothesized that enteric glia may exert their protective effects against spinal cord injury partially through the secretion of neurotrophic factors. In the present study, we demonstrated that primary enteric glia cells release nerve growth factor, brain derived neurotrophic factor and glial cell line-derived neurotrophic factor over time with their concentrations reaching approximately 250, 100 and 50 pg/mL of culture medium respectively after 48 hours. The biological relevance of this secretion was assessed by incubating dissociated dorsal root ganglion neuronal cultures in enteric glia-conditioned medium with and/or without neutralizing antibodies to each of these proteins and evaluating the differences in neurite growth. We discovered that conditioned medium enhances neurite outgrowth in dorsal root ganglion neurons. Even though there was no detectable amount of neurotrophin-3 secretion using ELISA analysis, the neurite outgrowth effect can be attenuated by the antibody-mediated neutralization of each of the aforementioned neurotrophic factors. Therefore, enteric glia secrete nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and neurotrophin-3 into their surrounding environment in concentrations that can cause a biological effect. PMID- 25538738 TI - Protein hairy enhancer of split-1 expression during differentiation of muscle derived stem cells into neuron-like cells. AB - Muscle-derived stem cells were isolated from the skeletal muscle of Sprague Dawley neonatal rats aged 3 days old. Cells at passage 5 were incubated in Dulbecco's modified Eagle's medium supplemented with 10% (v/v) fetal bovine serum, 20 MUg/L nerve growth factor, 20 MUg/L basic fibroblast growth factor and 1% (v/v) penicillin for 6 days. Cells presented with long processes, similar to nerve cells. Connections were formed between cell processes. Immunocytochemical staining with neuron specific enolase verified that cells differentiated into neuron-like cells. Immunofluorescence cytochemistry and western blot results revealed that the expression of protein hairy enhancer of split-1 was significantly reduced. These results indicate that low expression of protein hairy enhancer of split-1 participates in the differentiation of muscle-derived stem cells into neuron-like cells. PMID- 25538739 TI - Telencephalin protects PAJU cells from amyloid beta protein-induced apoptosis by activating the ezrin/radixin/moesin protein family/phosphatidylinositol-3 kinase/protein kinase B pathway. AB - Telencephalin is a neural glycoprotein that reduces apoptosis induced by amyloid beta protein in the human neural tumor cell line PAJU. In this study, we examined the role of the ezrin/radixin/moesin protein family/phosphatidylinositol-3 kinase/protein kinase B pathway in this process. Western blot analysis demonstrated that telencephalin, phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B were not expressed in PAJU cells transfected with empty plasmid, while they were expressed in PAJU cells transfected with a telencephalin expression plasmid. After treatment with 1.0 nM amyloid beta protein 42, expression of telencephalin and phosphorylated phosphatidylinositol-3-kinase/protein kinase B in the transfected cells gradually diminished, while levels of phosphorylated ezrin/radixin/moesin increased. In addition, the high levels of telencephalin, phosphorylated ezrin/radixin/moesin and phosphatidylinositol-3-kinase/protein kinase B expression in PAJU cells transfected with a telencephalin expression plasmid could be suppressed by the phosphatidylinositol-3-kinase inhibitor LY294002. These findings indicate that telencephalin activates the ezrin/radixin/moesin family/phosphatidylinositol-3 kinase/protein kinase B pathway and protects PAJU cells from amyloid beta protein induced apoptosis. PMID- 25538740 TI - Brain cell apoptosis and enhancement of nervous excitability in pregnant rats with high plasma levels of homocysteine. AB - Hyperhomocysteinemia is an important risk factor for preeclampsia-eclampsia. This study established a pregnant rat model of hyperhomocysteinemia, in which blood plasma homocysteine concentrations were twice or three times greater than that of normal pregnant rats. TUNEL revealed an increase in the number of apoptotic cells in the frontal cortex of pregnant rats with hyperhomocysteinemia. In addition, immunohistochemical staining detected activated nuclear factor-kappaB-positve cells in the frontal cortex. Reverse transcription-PCR detected that mRNA expression of the anti-apoptotic gene bcl-2 diminished in the frontal cortex. In situ hybridization and western blotting revealed that N-methyl-D-aspartate receptor 1 mRNA and protein expression was upregulated in the frontal cortex and hippocampus. These results indicate that hyperhomocysteinemia can induce brain cell apoptosis, increase nerve excitability, and promote the occurrence of preeclampsia in pregnant rats. PMID- 25538742 TI - A plastic stabilizer dibutyltin dilaurate induces subchronic neurotoxicity in rats. AB - Dibutyltin dilaurate functions as a stabilizer for polyvinyl chloride. In this study, experimental rats were intragastrically administered 5, 10, or 20 mg/kg dibutyltin dilaurate to model sub-chronic poisoning. After exposure, our results showed the activities of superoxide dismutase and glutathione peroxidase decreased in rat brain tissue, while the malondialdehyde and nitric oxide content, as well as nitric oxide synthase activity in rat brain tissue increased. The cell cycle in the right parietal cortex was disordered and the rate of apoptosis increased. DNA damage was aggravated in the cerebral cortex, and the ultrastructure of the right parietal cortex tissues was altered. The above changes became more apparent with exposure to increasing doses of dibutyltin dilaurate. Our experimental findings confirmed the neurotoxicity of dibutyltin dilaurate in rat brain tissues, and demonstrated that the poisoning was dose dependent. PMID- 25538741 TI - Microstructural changes in memory and reticular formation neural pathway after simple concussion. AB - Patients with concussion often present with temporary disturbance of consciousness. The microstructural and functional changes in the brain associated with concussion, as well as the relationship with transient cognitive disorders, are currently unclear. In the present study, a rabbit model of simple concussion was established. Magnetic resonance-diffusion tensor imaging results revealed that the corona radiata and midbrain exhibited significantly decreased fractional anisotropy values in the neural pathways associated with memory and the reticular formation. In addition, the apparent diffusion coefficient values were significantly increased following injury compared with those before injury. Following a 1-hour period of quiet rest, the fractional anisotropy values significantly increased, and apparent diffusion coefficient values significantly decreased, returning to normal pre-injury levels. In contrast, the fractional anisotropy values and apparent diffusion coefficient values in the corpus callosum, thalamus and hippocampus showed no statistical significant alterations following injury. These findings indicate that the neural pathways associated with memory and the reticular formation pathway exhibit reversible microstructural white matter changes when concussion occurs, and these changes are exhibited to a different extent in different regions. PMID- 25538743 TI - Expression of Clock genes in the pineal glands of newborn rats with hypoxic ischemic encephalopathy. AB - Clock genes are involved in circadian rhythm regulation, and surviving newborns with hypoxic-ischemic encephalopathy may present with sleep-wake cycle reversal. This study aimed to determine the expression of the clock genes Clock and Bmal1, in the pineal gland of rats with hypoxic-ischemic brain damage. Results showed that levels of Clock mRNA were not significantly changed within 48 hours after cerebral hypoxia and ischemia. Expression levels of CLOCK and BMAL1 protein were significantly higher after 48 hours. The levels of Bmal1 mRNA reached a peak at 36 hours, but were significantly reduced at 48 hours. Experimental findings indicate that Clock and Bmal1 genes were indeed expressed in the pineal glands of neonatal rats. At the initial stage (within 36 hours) of hypoxic-ischemic brain damage, only slight changes in the expression levels of these two genes were detected, followed by significant changes at 36-48 hours. These changes may be associated with circadian rhythm disorder induced by hypoxic-ischemic brain damage. PMID- 25538745 TI - Peripheral nerve regeneration research: Why is it getting so "cool"? PMID- 25538744 TI - Could androgens maintain specific domains of mental health in aging men by preserving hippocampal neurogenesis? AB - Interest surrounds the role of sex-hormones in regulating brain function outside of reproductive behaviour. Declining androgen production in aging males has been associated with cognitive impairment, depression and increased risk of developing Alzheimer's disease. Indication for testosterone replacement therapy is based on biochemically determined low circulating testosterone combined with manifest symptoms. However, which aspects of age-related cognitive decline are attributable to low circulating testosterone remain ambiguous. Studies examining cognition in aging men receiving testosterone replacement therapy have yielded equivocal results. The exact role of testosterone in maintaining cognitive function and the underlying neural mechanisms are largely unknown, though it would appear to be domain specific. Clarity in this area will provide clinical direction toward addressing an increasing healthcare burden of mental health decline coincident with increasing longevity. The premise that androgens contribute to maintaining aspects of mental health in aging men by preserving hippocampal neurogenesis will be used as a forum in this review to discuss current knowledge and the need for further studies to better define testosterone replacement strategies for aging male health. PMID- 25538746 TI - Use of hybrid chitosan membranes and human mesenchymal stem cells from the Wharton jelly of umbilical cord for promoting nerve regeneration in an axonotmesis rat model. AB - Many studies have been dedicated to the development of scaffolds for improving post-traumatic nerve regeneration. The goal of this study was to assess the effect on nerve regeneration, associating a hybrid chitosan membrane with non differentiated human mesenchymal stem cells isolated from Wharton's jelly of umbilical cord, in peripheral nerve reconstruction after crush injury. Chromosome analysis on human mesenchymal stem cell line from Wharton's jelly was carried out and no structural alterations were found in metaphase. Chitosan membranes were previously tested in vitro, to assess their ability in supporting human mesenchymal stem cell survival, expansion, and differentiation. For the in vivo testing, Sasco Sprague adult rats were divided in 4 groups of 6 or 7 animals each: Group 1, sciatic axonotmesis injury without any other intervention (Group 1 Crush); Group 2, the axonotmesis lesion of 3 mm was infiltrated with a suspension of 1 250-1 500 human mesenchymal stem cells (total volume of 50 MUL) (Group 2 CrushCell); Group 3, axonotmesis lesion of 3 mm was enwrapped with a chitosan type III membrane covered with a monolayer of non-differentiated human mesenchymal stem cells (Group 3-CrushChitIIICell) and Group 4, axonotmesis lesion of 3 mm was enwrapped with a chitosan type III membrane (Group 4-CrushChitIII). Motor and sensory functional recovery was evaluated throughout a healing period of 12 weeks using sciatic functional index, static sciatic index, extensor postural thrust, and withdrawal reflex latency. Stereological analysis was carried out on regenerated nerve fibers. Results showed that infiltration of human mesenchymal stem cells, or the combination of chitosan membrane enwrapment and human mesenchymal stem cell enrichment after nerve crush injury provide a slight advantage to post-traumatic nerve regeneration. Results obtained with chitosan type III membrane alone confirmed that they significantly improve post traumatic axonal regrowth and may represent a very promising clinical tool in peripheral nerve reconstructive surgery. Yet, umbilical cord human mesenchymal stem cells, that can be expanded in culture and induced to form several different types of cells, may prove, in future experiments, to be a new source of cells for cell therapy, including targets such as peripheral nerve and muscle. PMID- 25538747 TI - Role of inflammatory cytokines in peripheral nerve injury. AB - Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery. The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration. Cytokines can be divided into pro- and anti-inflammatory cytokines that upregulate and downregulate, respectively, the production of inflammatory mediators. While pro inflammatory cytokines are expressed in the first phase of Wallerian degeneration and promote the recruitment of macrophages, anti-inflammatory cytokines are expressed after this recruitment and downregulate the production of all cytokines, thus determining the end of the process. In this review, we describe the major inflammatory cytokines involved in Wallerian degeneration and the early phases of nerve regeneration. In particular, we focus on interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-beta, interleukin-10 and transforming growth factor-beta. PMID- 25538749 TI - Direct muscle neurotization after end-to end and end-to-side neurorrhaphy: An experimental study in the rat forelimb model. AB - The need for the continuous research of new tools for improving motor function recovery after nerve injury is justified by the still often unsatisfactory clinical outcome in these patients. It has been previously shown that the combined use of two reconstructive techniques, namely end-to-side neurorrhaphy and direct muscle neurotization in the rat hindlimb model, can lead to good results in terms of skeletal muscle reinnervation. Here we show that, in the rat forelimb model, the combined use of direct muscle neurotization with either end to-end or end-to-side neurorrhaphy to reinnervate the denervated flexor digitorum muscles, leads to muscle atrophy prevention over a long postoperative time lapse (10 months). By contrast, very little motor recovery (in case of end-to-end neurorrhaphy) and almost no motor recovery (in case of end-to-side neurorrhaphy) were observed in the grasping activity controlled by flexor digitorum muscles. It can thus be concluded that, at least in the rat, direct muscle neurotization after both end-to-end and end-to-side neurorrhaphy represents a good strategy for preventing denervation-related muscle atrophy but not for regaining the lost motor function. PMID- 25538748 TI - Emerging issues in peripheral nerve repair. AB - It is today widely acknowledged that nerve repair is now more than a matter of perfect microsurgical reconstruction only and that, to further improve clinical outcome, the involvement of different scientific disciplines is required. This evolving reconstructive/regenerative approach is based on the interdisciplinary and integrated pillars of tissue engineering such as reconstructive microsurgery, transplantation and biomaterials. In this paper, some of the most promising innovations for the tissue engineering of nerves, emerging from basic science investigation, are critically overviewed with special focus on those approaches that appear today to be more suitable for clinical translation. PMID- 25538750 TI - Sensory reinnervation of free flaps in reconstruction of the breast and the upper and lower extremities. AB - There is long-standing debate about sensate versus non-sensate free microvascular flaps among microsurgeons. The principle of connecting not only the vascular supply, but also sensitive nerves, in free tissue transfer is attractive. However, increased operating time and partial spontaneous innervation led to the common decision to restrict microsurgical tissue transfer to the vascular anastomosis and to leave the nerves "untreated". Nevertheless, in special cases such as breast reconstruction or extremity reconstruction, the question about sensory nerve coaptation of the flaps remains open. We present our experience with free microvascular tissue transfer for breast and extremity reconstruction and compare the data with previous literature and conclude that most free flap surgeries do not benefit from nerve coaptation. PMID- 25538751 TI - Platelet-rich plasma gel in combination with Schwann cells for repair of sciatic nerve injury. AB - Bone marrow mesenchymal stem cells were isolated from New Zealand white rabbits, culture-expanded and differentiated into Schwann cell-like cells. Autologous platelet-rich plasma and Schwann cell-like cells were mixed in suspension at a density of 1 * 10(6) cells/mL, prior to introduction into a poly (lactic-co glycolic acid) conduit. Fabricated tissue-engineered nerves were implanted into rabbits to bridge 10 mm sciatic nerve defects (platelet-rich plasma group). Controls were established using fibrin as the seeding matrix for Schwann cell like cells at identical density to construct tissue-engineered nerves (fibrin group). Twelve weeks after implantation, toluidine blue staining and scanning electron microscopy were used to demonstrate an increase in the number of regenerating nerve fibers and thickness of the myelin sheath in the platelet-rich plasma group compared with the fibrin group. Fluoro-gold retrograde labeling revealed that the number of Fluoro-gold-positive neurons in the dorsal root ganglion and the spinal cord anterior horn was greater in the platelet-rich plasma group than in the fibrin group. Electrophysiological examination confirmed that compound muscle action potential and nerve conduction velocity were superior in the platelet-rich plasma group compared with the fibrin group. These results indicate that autologous platelet-rich plasma gel can effectively serve as a seeding matrix for Schwann cell-like cells to construct tissue-engineered nerves to promote peripheral nerve regeneration. PMID- 25538752 TI - Chemoattractive capacity of different lengths of nerve fragments bridging regeneration chambers for the repair of sciatic nerve defects. AB - A preliminary study by our research group showed that 6-mm-long regeneration chamber bridging is equivalent to autologous nerve transplantation for the repair of 12-mm nerve defects. In this study, we compared the efficacy of different lengths (6, 8, 10 mm) of nerve fragments bridging 6-mm regeneration chambers for the repair of 12-mm-long nerve defects. At 16 weeks after the regeneration chamber was implanted, the number, diameter and myelin sheath thickness of the regenerated nerve fibers, as well as the conduction velocity of the sciatic nerve and gastrocnemius muscle wet weight ratio, were similar to that observed with autologous nerve transplantation. Our results demonstrate that 6-, 8- and 10-mm long nerve fragments bridging 6-mm regeneration chambers effectively repair 12-mm long nerve defects. Because the chemoattractive capacity is not affected by the length of the nerve fragment, we suggest adopting 6-mm-long nerve fragments for the repair of peripheral nerve defects. PMID- 25538753 TI - Stress and strain analysis on the anastomosis site sutured with either epineurial or perineurial sutures after simulation of sciatic nerve injury. AB - The magnitude of tensile stress and tensile strain at an anastomosis site under physiological stress is an important factor for the success of anastomosis following suturing in peripheral nerve injury treatment. Sciatic nerves from fresh adult cadavers were used to create models of sciatic nerve injury. The denervated specimens underwent epineurial and perineurial suturing. The elastic modulus (40.96 +/- 2.59 MPa) and Poisson ratio (0.37 +/- 0.02) of the normal sciatic nerve were measured by strain electrical measurement. A resistance strain gauge was pasted on the front, back, left, and right of the edge of the anastomosis site after suturing. Strain electrical measurement results showed that the stress and strain values of the sciatic nerve following perineurial suturing were lower than those following epineurial suturing. Scanning electron microscopy revealed that the sciatic nerve fibers were disordered following epineurial compared with perineurial suturing. These results indicate that the effect of perineurial suturing in sciatic nerve injury repair is better than that of epineurial suturing. PMID- 25538754 TI - Heme oxygenase-1 inhibits neuropathic pain in rats with diabetic mellitus. AB - A diabetes mellitus model was established through single intraperitoneal injection of streptozotocin into rats. Seven days later, model rats were intraperitoneally administered zinc protoporphyrin, a heme oxygenase-1 inducer, and cobalt protoporphyrin, a heme oxygenase-1 inhibitor, once every two days, for 5 successive weeks. After administration, the paw withdrawal mechanical threshold of diabetic mellitus rats significantly decreased, the myelin sheath of the sciatic nerve thickened or showed vacuole defects, the number of spinal dorsal horn neurons reduced, some neurons degenerated and were necrotic, and heme oxygenase-1 was visible in the cytoplasm of spinal dorsal horn neurons. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling demonstrated that the number of apoptotic neurons increased, which could be inhibited by cobalt protoporphyrin, however, zinc protoporphyrin led to an opposite effect. Our experimental findings indicate that heme oxygenase-1 attenuates neuropathic pain in diabetic mellitus rats through amelioration of peripheral neuropathy and inhibition of spinal dorsal horn neuron apoptosis. PMID- 25538755 TI - X-ray repair cross-complementing gene 1 Arg399Gln polymorphism and glioma risk among Asians: A meta-analysis based on 2 326 cases and 3 610 controls. AB - OBJECTIVE: Previous reports have demonstrated that X-ray repair cross complementing gene 1 (XRCC1) Arg399Gln polymorphism is a possible risk factor for several cancers. Published data on the association of XRCC1 Arg399Gln polymorphism with glioma susceptibility have generated conflicting results. This study is designed to precisely estimate the relationship. DATA RETRIEVAL: A computer-based online retrieval of Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure was performed to search papers regarding association of XRCC1 Arg399Gln polymorphisms with glioma published up to April 2012. SELECTION CRITERIA: Two investigators selected data independently. Meta analysis was then performed for the selected studies using STATA 11.0 software after strict selection. Heterogeneity test, sensitivity analysis and publication bias assessments were then conducted. MAIN OUTCOME MEASURES: Association of XRCC1 Arg399Gln polymorphism with glioma risk. RESULTS: A total of nine case-controlled studies comprising 2 326 cases and 3 610 controls were selected for final analysis. The overall data failed to indicate a significant association of XRCC1 Arg399Gln polymorphism with glioma risk (Gln/Gln vs. Arg/Arg: odds ratio (OR) = 1.11; 95% confidence interval (CI) = 0.94-1.31; dominant model: OR = 1.06; 95%CI = 0.95-1.18; recessive model: OR = 1.04; 95%CI = 0.81-1.34). However, subgroup analysis regarding ethnicity showed an increased risk among Asians (Gln/Gln vs. Arg/Arg: OR = 1.70; 95%CI = 1.17-2.46; dominant model: OR = 1.40; 95%CI = 1.10-1.78; recessive model: OR = 1.46; 95%CI = 1.04 2.05) but not Caucasians or mixed ethnicities. CONCLUSION: XRCC1 Arg399Gln polymorphism might modify the susceptibility to glioma among Asians but not Caucasians. Further large and well-designed studies are needed to confirm this conclusion. PMID- 25538756 TI - Osthole improves synaptic plasticity in the hippocampus and cognitive function of Alzheimer's disease rats via regulating glutamate. AB - Osthole, an effective monomer in Chinese medicinal herbs, can cross the blood brain barrier and protect against brain injury, with few toxic effects. In this study, a rat model of Alzheimer's disease was established after intracerebroventricular injection of beta-amyloid peptide (25-35). Subsequently, the rats were intraperitoneally treated with osthole (12.5 or 25.0 mg/kg) for 14 successive days. Results showed that osthole treatment significantly improved cognitive impairment and protected hippocampal neurons of Alzheimer's disease rats. Also, osthole treatment alleviated suppressed long-term potentiation in the hippocampus of Alzheimer's disease rats. In these osthole-treated Alzheimer's disease rats, the level of glutamate decreased, but there was no significant change in gamma-amino-butyric acid. These experimental findings suggest that osthole can improve learning and memory impairment, and increase synaptic plasticity in Alzheimer's disease rats. These effects of osthole may be because of its regulation of central glutamate and gamma-amino-butyric acid levels. PMID- 25538757 TI - Oxymatrine reduces neuroinflammation in rat brain: A signaling pathway. AB - Cerebral neuroinflammation models were established by injecting 10 MUg lipopolysaccharide into the hippocampus of male Sprague-Dawley rats. The rats were treated with an intraperitoneal injection of 120, 90, or 60 mg/kg oxymatrine daily for three days prior to the lipopolysaccharide injection. Twenty-four hours after model induction, the hippocampus was analyzed by real-time quantitative PCR, and the cerebral cortex was analyzed by enzyme-linked immunosorbent assay and western blot assay. The results of the enzyme-linked immunosorbent assay and the real-time quantitative PCR showed that the secretion and mRNA expression of the pro-inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha were significantly decreased in the hippocampus and cerebral cortex of model rats treated with oxymatrine. Western blot assay and real-time quantitative PCR analysis indicated that toll-like receptor 4 mRNA and protein expression were significantly decreased in the groups receiving different doses of oxymatrine. Additionally, 120 and 90 mg/kg oxymatrine were shown to reduce protein levels of nuclear factor-kappaB p65 in the nucleus and of phosphorylated IkappaBalpha in the cytoplasm of brain cells, as detected by western blot assay. Experimental findings indicate that oxymatrine may inhibit neuroinflammation in rat brain via downregulating the expression of molecules in the toll-like receptor 4/nuclear factor-kappaB signaling pathway. PMID- 25538758 TI - Ginsenoside Rb1 relieves glucose fluctuation-induced oxidative stress and apoptosis in Schwann cells. AB - Cultured Schwann cells were treated with 5.6 mM and 50 mM glucose alternating every 8 hours to simulate intermittent high glucose. The present study analyzed the neuroprotective effects of 1, 10 and 100 MUM ginsenoside Rb1 on oxidative damage and apoptosis in Schwann cells induced by intermittent high glucose. Flow cytometry demonstrated that ginsenoside Rb1 reduced intermittent high glucose mediated reactive oxygen species production. Enzyme linked immunosorbent assay showed that 8-hydroxy-2-deoxy guanosine levels in Schwann cells decreased following ginsenoside Rb1 treatment. Quantitative real-time reverse transcription PCR and western blot assay results revealed that ginsenoside Rb1 inhibited intermittent high glucose-upregulated Bax expression, but antagonized intermittent high glucose-downregulated Bcl-2 expression in Schwann cells. These effects were most pronounced with 100 MUM ginsenoside Rb1. These results indicate that ginsenoside Rb1 inhibits intermittent high glucose-induced oxidative stress and apoptosis in Schwann cells. PMID- 25538759 TI - Expressions of apoptosis-related proteins in rats with focal cerebral ischemia after Angong Niuhuang sticker point application. AB - In this study, we extracted and purified components in the Angong Niuhuang pill. Then we applied transdermal enhancers to Angong Niuhuang stickers by modern technology. The Angong Niuhuang sticker includes extracts from curcuma, berberine hydrochloride, baicalin, geniposide, borneol, and musk. Angong Niuhuang stickers at different point application doses (1.35, 2.7, and 5.4 g/kg) were administered to Dazhui (DU14), Qihai (RN6) and Mingmen (DU4). Rats in the different dose point application and acupuncture groups were continuously administered for 7 days. Then a middle cerebral artery occlusion model was prepared for simulating human cerebral ischemia. Twelve hours later, expressions of Bcl-2, Bax and p53 protein in hippocampal CA1 were detected with immunohistochemistry. The expression level of Bcl-2, an anti-apoptotic protein, significantly increased in the high-, medium and low-dose point application groups and the acupuncture group, while the expression of the pro-apoptotic proteins, Bax and p53, significantly decreased compared with the middle cerebral artery occlusion rats; and the Bcl-2/Bax ratio was significantly increased. The difference was noticeable for the high-dose point application group, which showed statistical difference compared with the low-dose point application group and the acupuncture group. Our experimental findings indicate that point application with Angong Niuhuang stickers promotes the expression of Bcl-2, and inhibits the expressions of Bax and p53 in the hippocampal CA1 area of rats after focal cerebral ischemia. Thus, point application of Angong Niuhang stickers protects brain tissues from cerebral ischemia. PMID- 25538761 TI - Activated and deactivated functional brain areas in the Deqi state: A functional MRI study. AB - We compared the activities of functional regions of the brain in the Deqi versus non-Deqi state, as reported by physicians and subjects during acupuncture. Twelve healthy volunteers received sham and true needling at the Waiguan (TE5) acupoint. Real-time cerebral functional MRI showed that compared with non-sensation after sham needling, true needling activated Brodmann areas 3, 6, 8, 9, 10, 11, 13, 20, 21, 37, 39, 40, 43, and 47, the head of the caudate nucleus, the parahippocampal gyrus, thalamus and red nucleus. True needling also deactivated Brodmann areas 1, 2, 3, 4, 5, 6, 7, 9, 10, 18, 24, 31, 40 and 46. PMID- 25538762 TI - Effects of pre-moxibustion at Zusanli (ST36) on heat shock protein 70 expression in rats with gastric mucosal lesions after neurotomy. AB - Studies have shown that pre-moxibustion protects the gastric mucosa by up regulating the expression of heat shock protein 70. However, the signaling pathway underlying this effect remains unclear. Rats were intragastrically administered absolute alcohol, causing obvious lesion of the gastric mucosa. Following pre-moxibustion at Zusanli (ST36) for 8 days, the ulcer index decreased to different degrees. The results of an enzyme linked immunosorbent assay and western blotting showed significant upregulation of heat shock protein 70 expression in the gastric mucosa and serum. None out of transection of the spinal cord, damage to the nucleus of the solitary tract, neurotomy of the vagal nerve and neurotomy of the common peroneal nerve affected the decrease in ulcer index or the increase in heat shock protein 70 expression in serum after pre moxibustion at Zusanli, and heat shock protein 70 expression was obviously decreased in the gastric mucosa. These findings suggest that pre-moxibustion at Zusanli can protect the gastric mucosa against lesioning, and that the mechanism underlying this effect involves its induction of heat shock protein 70 expression. Neural pathways participate in the regulatory effects of moxibustion on heat shock protein 70 expression in the gastric mucosa. PMID- 25538760 TI - Tea polyphenols increase X-ray repair cross-complementing protein 1 and apurinic/apyrimidinic endonuclease/redox factor-1 expression in the hippocampus of rats during cerebral ischemia/reperfusion injury. AB - Recent studies have shown that tea polyphenols can cross the blood-brain barrier, inhibit apoptosis and play a neuroprotective role against cerebral ischemia. Furthermore, tea polyphenols can decrease DNA damage caused by free radicals. We hypothesized that tea polyphenols repair DNA damage and inhibit neuronal apoptosis during global cerebral ischemia/reperfusion. To test this hypothesis, we employed a rat model of global cerebral ischemia/reperfusion. We demonstrated that intraperitoneal injection of tea polyphenols immediately after reperfusion significantly reduced apoptosis in the hippocampal CA1 region; this effect started 6 hours following reperfusion. Immunohistochemical staining showed that tea polyphenols could reverse the ischemia/reperfusion-induced reduction in the expression of DNA repair proteins, X-ray repair cross-complementing protein 1 and apurinic/apyrimidinic endonuclease/redox factor-1 starting at 2 hours. Both effects lasted at least 72 hours. These experimental findings suggest that tea polyphenols promote DNA damage repair and protect against apoptosis in the brain. PMID- 25538763 TI - Genetic association of urokinase-type plasminogen activator gene rs2227564 site polymorphism with sporadic Alzheimer's disease in the Han Chinese population. AB - A missense C/T polymorphism in exon 6 (the NCBI rsID is rs2227564) of the urokinase-type plasminogen activator gene has been identified as a possible hot spot for Alzheimer's disease risk. The present study analyzed urokinase-type plasminogen gene polymorphisms of rs2227564 with sporadic Alzheimer's disease by PCR-restriction fragment length polymorphism. Results showed that CC, CT and TT genotype distribution frequencies had significant differences between sporadic Alzheimer's disease patients and healthy controls. In-depth analysis of the association between urokinase-type plasminogen gene rs2227564 polymorphisms and sporadic Alzheimer's disease indicated that people with the C-positive genotype CC + CT were at a higher risk for developing sporadic Alzheimer's disease. These results support the contribution of the polymorphisms of rs2227564 in the urokinase-type plasminogen gene to the pathogenesis of sporadic Alzheimer's disease in the Han Chinese population. PMID- 25538764 TI - Is the C677T polymorphism in methylenetetrahydrofolate reductase gene or plasma homocysteine a risk factor for diabetic peripheral neuropathy in Chinese individuals? AB - The present study enrolled 251 diabetic patients, including 101 with neuropathy and 150 without neuropathy. Of the 150 patients, 100 had no complications, such as retinopathy, nephropathy, or neuropathy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to identify methylenetetrahydrofolate reductase gene variants. Plasma homocysteine levels were also measured. Homocysteine levels and the frequency of hyperhomocysteinemia were significantly higher in patients with diabetic peripheral neuropathy compared with diabetic patients without neuropathy (P < 0.05). In logistic regression analysis with neuropathy as the dependent variable, the frequency of C677T in methylenetetrahydrofolate reductase was significantly higher in patients with diabetic peripheral neuropathy compared with patients without diabetic complications. Homocysteine levels were significantly higher in patients with diabetic peripheral neuropathy carrying the 677T allele and low folic acid levels. In conclusion, hyperhomocysteinemia is an independent risk factor for diabetic neuropathy in Chinese patients with diabetes. The C677T polymorphism in methylenetetrahydrofolate reductase and low folic acid levels may be risk factors for diabetic peripheral neuropathy in Chinese patients with diabetes. PMID- 25538765 TI - Neuroimaging diagnosis for cerebral infarction: An 8-year bibliometric analysis. AB - OBJECTIVE: To identify global research trends in neuroimaging diagnosis for cerebral infarction using a bibliometric analysis of the Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of data retrieval for neuroimaging diagnosis for cerebral infarction containing the key words "CT, magnetic resonance imaging, MRI, transcranial Doppler, transvaginal color Doppler, digital subtraction angiography, and cerebral infarction" using the Web of Science. SELECTION CRITERIA: Inclusion criteria were: (a) peer-reviewed articles on neuroimaging diagnosis for cerebral infarction which were published and indexed in the Web of Science; (b) original research articles and reviews; and (c) publication between 2004-2011. Exclusion criteria were: (a) articles that required manual searching or telephone access; and (b) corrected papers or book chapters. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) top cited publications; (5) distribution according to journals; and (6) comparison of study results on neuroimaging diagnosis for cerebral infarction. RESULTS: Imaging has become the predominant method used in diagnosing cerebral infarction. The most frequently used clinical imaging methods were digital subtraction angiography, CT, MRI, and transcranial color Doppler examination. Digital subtraction angiography is used as the gold standard. However, it is a costly and time consuming invasive diagnosis that requires some radiation exposure, and is poorly accepted by patients. As such, it is mostly adopted in interventional therapy in the clinic. CT is now accepted as a rapid, simple, and reliable non-invasive method for use in diagnosis of cerebrovascular disease and preoperative appraisal. Ultrasonic Doppler can be used to reflect the hardness of the vascular wall and the nature of the plaque more clearly than CT and MRI. CONCLUSION: At present, there is no unified standard of classification of cerebral infarction imaging. Detection of clinical super-acute cerebral infarction remains controversial due to its changes on imaging, lack of specificity, and its similarity to a space-occupying lesion. Neuroimaging diagnosis for cerebral infarction remains a highly active area of research and development. PMID- 25538766 TI - Poisoning after ingestion of pufferfish in Brazil: report of 11 cases. AB - In this brief communication the authors report eleven cases of human poisoning caused by ingestion of pufferfish meat. Three patients (two children and one adult) were seriously affected. The circumstances that precipitated the poisoning are discussed as well as the clinical aspects observed. No deaths were registered and the patients did not present sequelae after the episode. PMID- 25538768 TI - Rail mounted gantry crane scheduling optimization in railway container terminal based on hybrid handling mode. AB - Rail mounted gantry crane (RMGC) scheduling is important in reducing makespan of handling operation and improving container handling efficiency. In this paper, we present an RMGC scheduling optimization model, whose objective is to determine an optimization handling sequence in order to minimize RMGC idle load time in handling tasks. An ant colony optimization is proposed to obtain near optimal solutions. Computational experiments on a specific railway container terminal are conducted to illustrate the proposed model and solution algorithm. The results show that the proposed method is effective in reducing the idle load time of RMGC. PMID- 25538767 TI - Analysis of vehicle-following heterogeneity using self-organizing feature maps. AB - A self-organizing feature map (SOM) was used to represent vehicle-following and to analyze the heterogeneities in vehicle-following behavior. The SOM was constructed in such a way that the prototype vectors represented vehicle following stimuli (the follower's velocity, relative velocity, and gap) while the output signals represented the response (the follower's acceleration). Vehicle trajectories collected at a northbound segment of Interstate 80 Freeway at Emeryville, CA, were used to train the SOM. The trajectory information of two selected pairs of passenger cars was then fed into the trained SOM to identify similar stimuli experienced by the followers. The observed responses, when the stimuli were classified by the SOM into the same category, were compared to discover the interdriver heterogeneity. The acceleration profile of another passenger car was analyzed in the same fashion to observe the interdriver heterogeneity. The distribution of responses derived from data sets of car following-car and car-following-truck, respectively, was compared to ascertain inter-vehicle-type heterogeneity. PMID- 25538769 TI - Risk of Type 2 Diabetes among Osteoarthritis Patients in a Prospective Longitudinal Study. AB - Objectives. Our aim was to determine the risk of diabetes among osteoarthritis (OA) cases in a prospective longitudinal study. Methods. Administrative health records of 577,601 randomly selected individuals from British Columbia, Canada, from 1991 to 2009, were analyzed. OA and diabetes cases were identified by checking physician's visits and hospital records. From 1991 to 1996 we documented 19,143 existing OA cases and selected one non-OA individual matched by age, sex, and year of administrative records. Poisson regression and Cox proportional hazards models were fitted to estimate the effects after adjusting for available sociodemographic and medical factors. Results. At baseline, the mean age of OA cases was 61 years and 60.5% were women. Over 12 years of mean follow-up, the incidence rate (95% CI) of diabetes was 11.2 (10.90-11.50) per 1000 person years. Adjusted RRs (95% CI) for diabetes were 1.27 (1.15-1.41), 1.21 (1.08-1.35), 1.16 (1.04-1.28), and 0.99 (0.86-1.14) for younger women (age 20-64 years), older women (age >= 65 years), younger men, and older men, respectively. Conclusion. Younger adults and older women with OA have increased risks of developing diabetes compared to their age-sex matched non-OA counterparts. Further studies are needed to confirm these results and to elucidate the potential mechanisms. PMID- 25538771 TI - A new acupuncture method for management of irritable bowel syndrome: A randomized double blind clinical trial. AB - BACKGROUND: Irritable bowel syndrome (IBS) is gastrointestinal functional disorder which is multifactorial with unknown etiology. There are several modalities for treatment of it. Acupuncture is increasingly used in numerous diseases, also in gastrointestinal disorders like IBS. The purpose of the study was to assess the effects of catgut embedding acupuncture in improving of IBS. MATERIALS AND METHODS: A randomized double blind sham control clinical trial was designed. A total of 60 IBS patients assigned to three separated groups. The first group received clofac as drug only group (DO). The second one received catgut embedding acupuncture in special point (AP) and the last group received sham acupuncture (SA). Symptoms, pain, depression and anxiety assessed before and after two weeks at the end of study. RESULTS: There was statistically significant difference between AP and SA and DO in constipation and bloating. Differences that were statistically significant favored acupuncture on pain (F = 6.409, P = 0.003), and depression (F = 6.735, P = 0.002) as the other outcomes. The average (standard deviation (SD)) of weight loss was 2 kg (0.88) in acupuncture group. CONCLUSION: Our finding showed a significant positive associated between acupuncture and IBS. Catgut embedding acupuncture is a new method which can eliminated IBS symptoms and can use as alternative therapeutic method for improvement of IBS. PMID- 25538770 TI - Practice variation in the management of first trimester miscarriage in the Netherlands: a nationwide survey. AB - Objectives. To survey practice variation in the management of first trimester miscarriage in The Netherlands. Methods. We sent an online questionnaire to gynecologists in eight academic, 37 nonacademic teaching, and 47 nonteaching hospitals. Main outcome measures were availability of a local protocol; estimated number of patients treated with curettage, misoprostol, or expectant management; misoprostol regimen; and estimated number of curettages performed after initial misoprostol treatment. Outcomes were compared to the results of a previous nationwide survey. Results. The response rate was 100%. A miscarriage protocol was present in all academic hospitals, 68% of nonacademic teaching hospitals, and 38% of nonteaching hospitals (P = 0.008). Misoprostol was first-choice treatment for 41% of patients in academic hospitals versus 34% and 27% in teaching-and nonteaching hospitals (P = 0.045). There were 23 different misoprostol regimens. Curettage was first-choice treatment in 29% of patients in academic hospitals versus 46% and 50% in nonacademic teaching or nonteaching hospitals (P = 0.007). In 30% of patients, initial misoprostol treatment was followed by curettage. Conclusions. Although the percentage of gynaecologists who are aware of the availability of misoprostol for miscarriage treatment has doubled to almost 100% since 2005, practice variation is still large. This practice variation underlines the need for a national guideline. PMID- 25538772 TI - Can methylene blue dye be used as an alternative to patent blue dye to find the sentinel lymph node in breast cancer surgery? AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is standard care to evaluate axillary involvement in early breast cancer. It has fewer complications than complete lymph node dissection; however, using blue dye in SLNB is controversial. We have evaluated the detection rate and local complications associated with methylene blue dye (MBD) used in SLNB in early breast cancer patients and compared these results to patent blue dye (PBD). MATERIALS AND METHODS: In a cohort prospective study, 312 patients with early breast cancer without axillary lymph node involvement were divided into two groups according to dye type. All of the patients received radiotracer and one type of blue dye. We filled out a checklist for the patients that contained demographic data, size of tumor, stage, detection of sentinel lymph node, and complications and then analyzed the data. RESULTS: Demographic and histopathologic characteristics were not significantly different in both groups. Mean (standard deviation [SD]) tumor size in all patients was 2.4 (0.8) cm. Detection rate in the MBD group was 77.5% with dye alone and 94.2% with dye and radioisotope; and in the PBD group it was 80.1% and 92.9% respectively (P > 0.05). We had blue discoloration of the skin in 23.7% in the PBD and 14.1% in the MBD group (P < 0.05) local inflammation was detected in one patient in the PBD and five in the MBD group (P < 0.05). Skin necrosis and systemic complications were not observed. CONCLUSION: Methylene blue has an acceptable detection rate, which may be a good alternative in SLNB. Complication such as blue discoloration of the skin was also lower with MBD. PMID- 25538773 TI - Role of protein phosphatases inhibitors on the histamine release and the functional desensitization in human lung mast cells. AB - BACKGROUND: The beta2-adrenoceptor agonist, isoprenaline, is an effective inhibitor of histamine release from human lung mast cells (HLMC). Since phosphorylations of the beta2-adrenoceptors are probably important in inducing desensitization, we sought to investigate the importance of phosphorylation events by targeting protein phosphatases (PPs) in mast cells. To this end, the effects of the inhibitor of on the functional desensitization of beta adrenoceptor-mediated responses in mast cells were investigated. MATERIALS AND METHODS: In this study the effects of PP inhibitors on the inhibition of histamine release from HLMC, on beta-agonists in mast cells and on desensitization were investigated. RESULTS: Long-term exposure of mast cells to both isoprenaline and salbutamol substantially reduced the extent to which isoprenaline inhibited histamine release. Pretreatments of up to 24 h with inhibitors alone had no effect on immunoglobulin E-mediated histamine release. Shorter (<=4 h) pretreatments had little effect on the activity of isoprenaline and salbutamol to inhibit histamine release from mast cells. CONCLUSION: Collectively, these data suggest that PP has an important role in regulating mast cell beta2-adrenoceptors. PMID- 25538774 TI - Domestic and peridomestic risk factors associated with transmission of cutaneous leishmaniasis in three hypo endemic, endemic, and hyper endemic areas: A randomized epidemiological study. AB - BACKGROUND: Leishmaniasis is an infection caused by leishmania protozoa. Knowledge about health effects associated with environment situation and human behavior in national and local levels seems to be very necessary. MATERIALS AND METHODS: This cross-sectional case-control study was carried out in three adjacent counties of Isfahan province in Iran. Data were collected by face-to face interviewing and recorded structured questionnaire. Statistical analysis was performed using Chi-square test and logistic. P < 0.05 was considered as significant. RESULTS: The economic level had significant association with cutaneous leishmaniasis (CL) transmission (P < 0.05). However, there was no significant association between existence of food storage and transmission of CL. We, however, found significant reduction of CL transmission following use of insect control measures (P < 0.05). The odds ratio for peridomestic transmission was 0.420 for houses that weren't round with any old or ruined houses. CONCLUSION: We conclude that among aforementioned risk factors, the impact of peridomestic factors is stronger in CL transmission when compared with domestic and behavioral factors. PMID- 25538775 TI - The effect of sumac (Rhus coriaria L.) powder on insulin resistance, malondialdehyde, high sensitive C-reactive protein and paraoxonase 1 activity in type 2 diabetic patients. AB - BACKGROUND: Sumac (Rhus coriaria L.) has been used in traditional treatment of some diseases. The aim of this study was to determine the effect of sumac (R. coriaria L.) powder on insulin resistance (IR), malondialdehyde (MDA), high sensitive C-reactive protein (hs-CRP), and paraoxonase 1 (PON1) activity in type 2 diabetic patients. MATERIALS AND METHODS: A double-blind randomized placebo controlled trial on 41 type 2 diabetic volunteers was conducted. Participants randomly assigned into 3 g per day sumac powder (n = 22) or placebo (n = 19) groups for 3 months. IR was assessed using the homeostatic model assessment of IR (HOMA-IR), which including measurement of insulin by immunoassay method and measurement of glucose by enzymatic method. MDA and PON1 activity were measured colorimetrically, hs-CRP turbidimetrically. RESULTS: There were a significant increase in PON1 activity (from 84.72 +/- 30.59 to 92.91 +/- 32.63) and significant decrease in insulin (from 7.09 +/- 4.28 to 5.32 +/- 3.22), HOMA-IR (from 2.56 +/- 1.58 to 1.67 +/- 0.94), MDA (from 2.71 +/- 0.73 to 1.97 +/- 0.49), and also hs-CRP (from 18.49 +/- 16.96 to 15.89 +/- 16.70) in the sumac group at the end of study compared with initial values (P < 0.05). Furthermore, there were significant differences in MDA and PON1 between the two groups at the end of the study (P < 0.05). Furthermore, the mean of differences of insulin, HOMA-IR, MDA, hs-CRP and PON1 activity between groups were significant (P < 0.05). CONCLUSION: We concluded that daily intake of 3 g sumac for 3 months may be beneficial for diabetic patients to make them less susceptible to cardiovascular disease. PMID- 25538776 TI - Blood lead level in opium dependents and its association with anemia: A cross sectional study from the capital of Iran. AB - BACKGROUND: Opium dependence is one of the most challenging health problems in the developing countries as well as Iran. Among several health problems due to opium dependence, there are limited reports indicating the presence of lead in opium. The aim of this study is to investigate the blood lead level (BLL) in oral and inhalational opium dependents and its association with anemia. MATERIALS AND METHODS: A cross-sectional study was done among 86 opium dependent patients who were referred to five large detoxification centers in Tehran city and 48 healthy individuals. BLL was assessed using the atomic absorption spectrometry technique. Multivariate analysis of variance and binary logistic regression analysis were performed for statistical assessment using SPSS version 18 for Windows. RESULTS: The highest BLL was detected in oral opium dependent group (mean = 11.75, standard deviation (SD) = 6.06) in comparison to inhalational opium dependent group (mean = 7.07, SD = 3.61) and healthy control group (mean = 6.05, SD = 1.83). Anemia was detected in 38% of oral-opium dependent and 43% of inhalational opium dependent group. Age (odds ratio (OR): 1.06, 95% confidence interval (CI): 1.03-1.09) and opium dependence (OR: 3.59, 95% CI: 1.69-7.59) were significant predictors of anemia in these patients (P < 0.001). CONCLUSION: The results of this study confirmed the higher BLL in opium dependents, especially with an oral form of consumption. PMID- 25538777 TI - What's the role of perceived social support and coping styles in depression and anxiety? AB - BACKGROUND: Due to the excessive and pathologic effects of depression and anxiety, it is important to identify the role of protective factors, such as effective coping and social support. This study examined the associations between perceived social support and coping styles with depression and anxiety levels. MATERIALS AND METHODS: This cross sectional study was part of the Study on the Epidemiology of Psychological, Alimentary Health and Nutrition project. A total 4658 individuals aged >=20 years was selected by cluster random sampling. Subjects completed questionnaires, which were used to describe perceived social support, coping styles, depression and anxiety. t-test, Chi-square test, pearson's correlation and Logistic regression analysis were used in data analyses. RESULTS: The results of Logistic regression analysis showed after adjusting demographic characteristics for odd ratio of anxiety, active copings such as positive re-interpretation and growth with odds ratios; 95% confidence interval: 0.82 (0.76, 0.89), problem engagement (0.92 [0.87, 0.97]), acceptance (0.82 [0.74, 0.92]) and also among perceived social supports, family (0.77 [0.71, 0.84]) and others (0.84 [0.76, 0.91]) were protective. In addition to, for odd ratio of depression, active copings such as positive re-interpretation and growth (0.74 [0.69, 0.79]), problem engagement (0.89 [0.86, 0.93]), and support seeking (0.96 [0.93, 0.99]) and all of social support types (family [0.75 (0.70, 0.80)], friends [0.90 (0.85, 0.95)] and others [0.80 (0.75, 0.86)]) were protective. Avoidance was risk factor for both of anxiety (1.19 [1.12, 1.27]) and depression (1.22 [1.16, 1.29]). CONCLUSION: This study shows active coping styles and perceived social supports particularly positive re-interpretation and family social support are protective factors for depression and anxiety. PMID- 25538778 TI - The effect of biofeedback therapy on dyssynergic constipation in patients with or without Irritable Bowel Syndrome. AB - BACKGROUND: The Rome II and III diagnostic criteria for dyssynergic defecation recommended the exclusion of irritable bowel syndrome (IBS). This study determined the effect of biofeedback therapy on dyssynergic constipation in patients with or without IBS. MATERIALS AND METHODS: This study was a nonrandomized, single blinded, semi experimental study. Dyssynergic defecation patients with and without IBS were asked to undergo biofeedback therapy 8 sessions. The defecation dynamics and balloon expulsion time were evaluated before, at the end and 1 month after the biofeedback therapy. IBS symptoms were graded using a 4-point Likert scale. Mann-Whitney U-test, Wilcoxon test and Friedman test were applied to analyze data using SPSS software package (SPSS Inc., Chicago, IL, USA). RESULTS: After the biofeedback therapy, the IBS symptoms have been decreased significantly (the median of 2 before and 1 after therapy, P < 0.01). The biofeedback therapy significantly decreased the anismus index in IBS group by the mean of 0.75 +/- 0.31, 0.28 +/- 0.07 and 0.28 +/- 0.06 in three phases, respectively. Similar results were found in non-IBS patients (the mean of 0.74 +/- 0.32, 0.28 +/- 0.08, 0.27 +/- 0.08 in three phases, respectively). The symptoms of constipation (sensation of incomplete evacuation, difficult and painful defecation), defecation facilitative manual maneuver frequency, pelvic floor muscles resting amplitude and strain amplitude decreased and squeezing amplitude improved significantly after biofeedback therapy in both groups with and without IBS (P < 0.001). There were not significant differences between patients with and without IBS (P > 0.05) with respect to outcome. No complication was observed in treatment groups. CONCLUSION: Dyssynergic constipation patients with and without IBS will likely benefit from biofeedback therapy. PMID- 25538779 TI - Recurrence rate of repaired hard palate oronasal fistula with conchal cartilage graft. AB - BACKGROUND: After cleft palate repair, oronasal fistula (ONF) formation is one of the considerable and troublesome complications. Conchal cartilage graft is one option that can be used in recurrent fistula correction. The aim of the current study is investigating the recurrence rate of the hard palate ONF or ONF at the junction of hard and soft palate after utilizing conchal cartilage graft and comparing this rate with other methods. MATERIALS AND METHODS: In this observational prospective study, 29 patients suffering from ONF with small, medium and large sizes who were referring to Alzahra university hospital, Isfahan, Iran and Fateme Zahra university hospital, Tehran, Iran between November 2011 and November 2012 were enrolled. All patients had midline cleft palate, 29.6% of them had cleft lip too that was repaired previously. All patients were followed-up for 2 years (every 2 months) after repair. RESULTS: The mean (range) age of studied samples was 10.7 (2-23) years. 16 patients (55.7%) were female, and reminders were male. During 2 years followup, we detected recurrence of ONF in 6 patients (20.68%) and the success rate was 79.32%. The recurrence rate, after applying the current approach, among who experienced the several times of recurrence was significantly higher than among those who experienced first time of recurrence (33.3% vs. 7.1%; P < 0.001). The mean [+/-SD] age of failed and successfully repaired patients were 11.3 (+/-4.5) and 8.4 (+/-5.25) years, respectively (P > 0.1). CONCLUSION: Using of conchal cartilage graft for recurrent ONF with <=1 cm was safe and efficacious, in ONF >1 cm conchal cartilage graft can be used as a primary method and if recurrence occurred chooses other complex procedure. PMID- 25538780 TI - Role of electrophysiological study in patients with syncope and bundle branch block. AB - BACKGROUND: The finding of bundle branch block (BBB) in patients with syncope suggests that paroxysmal atrioventricular block (AVB) or ventricular tachyarrhythmia (VT) may be the cause of syncope. Guidelines for cardiac pacing and cardiac resynchronization therapy have been recommended to perform electrophysiological study (EPS) for confirming main cause of syncope. Therefore, the aim of our study was to evaluate the role of EPS in patients with syncope and BBB. MATERIALS AND METHODS: We evaluated 133 patients (mean age 63 +/- 13.8 years) with past history of syncope and BBB from April 2002 to December 2010 who referred to Arrhythmia clinic in two tertiary care centers. All patients underwent EPS on admission time. The frequency distributions of AVB and VT in patients were determined. RESULTS: Left bundle branch block was diagnosed in 184 (82.1%) patients. 133 of them had preserved left ventricular ejection fraction (LVEF >=45%) that in 91 (68.4%) of those, EPS finding was normal. In 41 (30.8%) patients AVB was reported. In 2 (1.5%) patients VT and atrioventricular nodal reentrant tachycardia were seen. Coronary artery disease was more common in patients with AVB and abnormal EPS finding (P = 0.02). CONCLUSION: Ventricular tachyarrhythmia was a rare electrophysiological finding in those with syncope, bifascicular block, and preserved LVEF. Considering cost-effect benefit, pacemaker or implantable loop recorder implantation is suggested; however, EPS may not be necessary to perform before permanent pacemaker implantation. PMID- 25538781 TI - The injection rate of intravenous midazolam significantly influences the occurrence of paradoxical reaction in pediatric patients. AB - BACKGROUND: Paradoxical reactions to benzodiazepines including restlessness, anxiety and sometimes violent behavior sometimes occur. Most of the known predicting factors of disinhibitory reactions such as age, gender, genetic or the psychological background are not modifiable. This study was conducted to evaluate the effect of rate of midazolam administration, as a controllable factor, on the occurrence of paradoxical reaction to midazolam (PRM) in pediatric patients. MATERIALS AND METHODS: In a randomized, double-blind clinical trial 98 American Society of Anesthesiologists physical status I, II, aged from 6 months to 6 years, and undergoing elective surgery, were enrolled in the study. Patients were randomly allocated to receive midazolam 0.1 mg/kg as a 0.1% solution at an injection rate of 0.2 ml/s or 1 ml/s. The occurrence of PRM was compared between the two groups with Chi-square test. RESULTS: The occurrence of PRM in the rapid injection group was significantly higher than the slow injection group (20.4% vs. 4.1%, P < 0.05, relative risk CI: 95% 6.03 (1.24-29.4)). CONCLUSION: Slow intravenous administration of midazolam significantly reduces the occurrence of paradoxical reactions and should be respected in premedication of pediatric patients. PMID- 25538782 TI - Neonatal outcomes in women with gestational diabetes mellitus treated with metformin in compare with insulin: A randomized clinical trial. AB - BACKGROUND: The objective of this study was to compare neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with either metformin or insulin. MATERIALS AND METHODS: A randomized clinical trial carried out on year 2011 on 109 women with GDM who did not adequately control by dietary measures. They received metformin 500 mg once or twice daily or insulin 0.2 IU/kg/day initially. The dose was titrated to achieve target blood glucose values. Neonatal outcomes such as hypoglycemia, birth weight, Apgar score, umbilical artery pH, and hyperbilirubinemia in the 50 women who remained exclusively on metformin were compared with 50 women who treated with insulin. RESULTS: Two groups were similar in mean fasting blood sugar (P = 0.7) and postprandial measurements (P = 0.8) throughout GDM treatment. Pregnancy complications or preterm labor were not different significantly between two groups. Considering neonatal outcomes between insulin and metformin groups, such as hypoglycemia (2 [4%] and 0 [0%], respectively), birth weight (3342 +/- 506 mg and 3176 +/- 438 mg, respectively), 5(th) min Apgar score <7 (no one in either group), umbilical artery pH <7.05 (no one in either group) and hyperbilirubinemia (1 [2%] and 0 [0%], respectively), no significant statistical differences were seen. CONCLUSION: Based on these preliminary data, considering neonatal outcomes, metformin appears to be a safe as insulin in the treatment of GDM. PMID- 25538783 TI - Topiramate augmentation in refractory obsessive-compulsive disorder: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: This study aimed to assess the efficacy of topiramate, a glutamate modulating agent, in patients with treatment-resistant obsessive-compulsive disorder (OCD) as an adjunct to serotonin reuptake inhibitors (SRIs). MATERIALS AND METHODS: Thirty-eight patients with refractory OCD, were randomly assigned to receive topiramate or placebo. This study was designed as a 12 weeks, double blind, placebo-controlled trial. Primary outcome measures were the change in Yale Brown Obsessive-Compulsive Scale (Y-BOCS) score and the rate of treatment response in each group at the study end point. Treatment response was considered as 25% or more reduction in Y-BOCS score. RESULTS: A total of 13 patients in the topiramate group and 14 ones in the placebo group completed the trial. Topiramate assigned patients showed significantly improved mean Y-BOCS score over time (P < 0.001). Although differences between two groups were significant in the Y-BOCS score at the first 2 months (P = 0.01), this was not significant at the end of the study (P = 0.10). Changes of Clinical Global Impression (CGI)-Severity of Illness Scale score and CGI-Improvement Scale score were not significantly different between two groups (P > 0.05). Treatment response was almost significantly different in the topiramate group comparing placebo group (P = 0.054). Mean topiramate dosage was 137.5 mg/day (range, 100-200). CONCLUSION: This study didn't show efficacy of topiramate as an agent to augment SRIs in treatment-resistant OCD patients. PMID- 25538784 TI - Effects of whole-body vibration training on fibrinolytic and coagulative factors in healthy young men. AB - BACKGROUND: The aim was to evaluate effects of 5-week whole body vibration (WBV) training with different amplitudes and progressive frequencies on fibrinolytic/coagulative factors. MATERIALS AND METHODS: 25 subjects were divided randomly in high or low-amplitude vibration, and control groups. Training consisted of 5-week WBV with amplitudes 4 or 2 mm. Plasma samples were analyzed before and after training. Statistical analysis was done using one-way analysis of variance and Wilcoxon signed ranked test. P <0.05 was considered significant. RESULTS: High-amplitude vibration caused an increase in tissue plasminogen activator (tPA) (P = 0.028) (pretest: 1744.61 +/- 707.95; posttest: 2313.63 +/- 997.19 pg/ml), and decrease in plasminogen activator inhibitor-1 (PAI-1) (P = 0.033) (pretest: 97.94 +/- 34.37; posttest: 85.12 +/- 36.92 ng/ml). Fibrinogen and plasminogen were not changed significantly. Low-amplitude vibration caused an increase in tPA (P = 0.006) (pretest: 2208.18 +/- 1280.37; posttest: 3492.72 +/- 3549.22 pg/ml). PAI-1, fibrinogen and plasminogen were not changed significantly. There were no significant differences between groups. CONCLUSION: Amplitude of vibrations in WBV training may affect fibrinolytic factors. PMID- 25538785 TI - Is Ramadan fasting related to health outcomes? A review on the related evidence. AB - BACKGROUND: Fasting during Ramadan is an Islamic rule. Although previous review studies have assessed the impact of Ramadan on cardiovascular risk factors, athlete performance, diabetes and transplantation, in this study we have appraised some on these reviews by focusing on limitations and also, we have reviewed more recently published study and several recent studies, which are not reviewed till now. MATERIALS AND METHODS: In this article, we reviewed recently conducted studies in regarding the impact of Ramadan fasting on weight, lipid profile, diabetes, immune system and gestation. MEDLINE (http://www.pubmed.com) was searched by using "Ramadan" as keyword and the most recent articles in mentioned topics since 2009 until February 2014 were selected. RESULTS: Although weight has been decreased during Ramadan in the most studies, weight regain is prevalent during the following months. Meta-analysis of pre-Ramadan lipid profile in comparison to post-Ramadan values had been showed that total cholesterol and triglyceride were decreased in men and high-density lipoprotein was increased among women. In regarding diabetes and fasting, diabetic patients should be aware that medical, nutritional and physical activity consulting is necessary for individuals with diabetes who want to fast during Ramadan. Although published studies show that Ramadan fasting had no serious adverse effect on offspring, it is strongly recommended that pregnant women avoid fasting because of the limitations of studies. The effect of fasting during Ramadan on the immune system is favorable. Ramadan fasting has no impact on kidney function and urine component. CONCLUSION: Studies showed that Ramadan fasting has health protective effects. More precise studies should be conducted for more reliable conclusion. PMID- 25538787 TI - Vasculitis and long standing ankylosing spondylitis in a patient with familial Mediterranean fever. AB - Coexistence of familial Mediterranean fever (FMF) and other inflammatory disorders has been frequently reported, but no specific underlying factor has been identified. We report a patient with FMF who is presented with long-standing ankylosing spondylitis (AS) and cutaneous leukocytoklastic vasculitis (LV) of the lower limbs. It is the first report on combination of FMF with AS and LV. The Mediterranean Fever (MEFV) gene mutation of heterozygote (R202Q/R726A) and HLA B27 are detected in this case, and are believed to form genetic susceptibility to LV. PMID- 25538788 TI - Simultaneous radical cystectomy and colorectal cancer resection for synchronous muscle invasive bladder cancer and cT3 colorectal cancer: Our initial experience in five patients. AB - To review cases of simultaneous radical cystectomy and colorectal cancer (CRC) resection for synchronous carcinoma of bladder and colorectum. Between May 1997 and September 2010, five patients were diagnosed with synchronous bladder cancer and CRCs. The primary colorectal tumors included three sigmoid cancers, one ascending colon cancer and one rectal cancer. All patients underwent simultaneous radical cystectomy and CRC resection. Pathologic types were confirmed by the biopsies of cystoscopy and colonoscopy. All patients were performed synchronous radical cystectomy and CRC resection. Four of them received adjuvant chemotherapies for CRC. Two of them died of liver metastasis 32.8 months and 13 months after surgery. Although patients with synchronous carcinoma of bladder and colorectum are rare, the Urologist should be alerted to this possibility when evaluating patients for the initially presenting symptoms and/or detected tumors. The simultaneous surgery is technically feasible for the selected patients. PMID- 25538789 TI - Appendiceal knotting causing small bowel strangulation. AB - Small bowel obstruction is a common cause of an emergency admission in the surgical wards. Acute appendicitis presenting with small bowel obstruction due to appendiceal knotting is a very rare and unsuspected condition in an emergency scenario. We report a case of acute small bowel obstruction in a 26-year-old male who, on exploration was found to have small bowel strangulation due to appendiceal knotting. Though rare, the possibilities of such a diagnosis should be kept in mind in patients with small bowel obstruction with no known identifiable etiology. PMID- 25538790 TI - The deficits of matrigel plug assay. PMID- 25538786 TI - Controlling childhood obesity: A systematic review on strategies and challenges. AB - BACKGROUND: Childhood obesity is a global health problem with short- and long term health consequences. This systematic review presents a summary of the experiences on different family-, school-, and clinic-based interventions. MATERIALS AND METHODS: Electronic search was conducted in MEDLINE, PubMed, ISI Web of Science, and Scopus scientific databases. We included those studies conducted among obese individuals aged up to 18 years. Our search yielded 105 relevant papers, 70 of them were conducted as high quality clinical trials. RESULTS: Our findings propose that school-based programs can have long-term effects in a large target group. This can be related to this fact that children spend a considerable part of their time in school, and adopt some parts of lifestyle there. They have remarkable consequences on health behaviors, but as there are some common limitations, their effects on anthropometric measures are not clear. Due to the crucial role of parents in development of children's behaviors, family-based interventions are reported to have successful effects in some aspects; but selection bias and high dropout rate can confound their results. Clinic-based interventions revealed favorable effects. They include dietary or other lifestyle changes like increasing physical activity or behavior therapy. It seems that a comprehensive intervention including diet and exercise are more practical. When they have different designs, results are controversial. CONCLUSION: We suggest that among different types of interventional programs, a multidisciplinary approach in schools in which children's family are involved, can be the best and most sustainable approach for management of childhood obesity. PMID- 25538791 TI - Effects of danshen ethanol extract on the pharmacokinetics of fexofenadine in healthy volunteers. AB - This study investigated the effect of multidose administration of danshen ethanol extract on fexofenadine pharmacokinetics in healthy volunteers. A sequential, open-label, two-period pharmacokinetic interaction design was used. 12 healthy male volunteers received a single oral dose of fexofenadine (60 mg) followed by danshen ethanol extract (1 g orally, three times a day) for 10 days, after which they received 1 g of the danshen extract with fexofenadine (60 mg) on the last day. The plasma concentrations of fexofenadine was measured by LC-MS/MS. After 10 days of the danshen extract administration, the mean AUC and C max? of the fexofenadine was decreased by 37.2% and 27.4% compared with the control, respectively. The mean clearance of fexofenadine was increased by 104.9%. The in vitro study showed that tanshinone IIA and cryptotanshinone could induce MDR1 mRNA. This study showed that multidose administration of danshen ethanol extract could increase oral clearance of fexofenadine. The increased oral clearance of fexofenadine is attributable to induction of intestinal P-glycoprotein. PMID- 25538792 TI - Cholecystectomy for acute cholecystitis. How time-critical are the so called "golden 72 hours"? Or better "golden 24 hours" and "silver 25-72 hour"? A case control study. AB - INTRODUCTION: Early cholecystectomy within 72 hours has been shown to be superior to late or delayed cholecystectomy with regard to outcome and cost of treatment. Recently, immediate cholecystectomy within 24 hours of onset of symptom was proposed as standard procedure for the management of fit patients presenting with acute cholecystitis. We sort to find out if there are any differences in surgical outcomes between patients managed within 24 h and those managed 25-72 h following symptom begin for acute cholecystitis. PATIENTS AND METHODS: A retrospective analysis was performed. The outcomes of patients undergoing laparoscopic cholecystectomy within 24 h were compared to those of patients managed 25-72 h following symptom onset for acute cholecystitis. RESULTS: 35 patients managed 25 72 h following begin of symptoms were matched with 35 patients with similar baseline features, medical comorbidities and disease severity managed within 24 hours of symptom onset. There were no significant differences in the duration of surgery, postoperative complications, rate of conversion and length of hospital stay. CONCLUSION: Immediate laparoscopic cholecystectomy for acute cholecystitis within 24 hour of symptom onset is not superior to surgery 25-72 hour after symptoms begin. Laparoscopic cholecystectomy for acute cholecystitis therefore can be safely performed anytime within the golden 72 h. PMID- 25538793 TI - Genes on B chromosomes of vertebrates. AB - BACKGROUND: There is a growing body of evidence that B chromosomes, once regarded as totally heterochromatic and genetically inert, harbor multiple segmental duplications containing clusters of ribosomal RNA genes, processed pseudogenes and protein-coding genes. Application of novel molecular approaches further supports complex composition and possible phenotypic effects of B chromosomes. RESULTS: Here we review recent findings of gene-carrying genomic segments on B chromosomes from different vertebrate groups. We demonstrate that the genetic content of B chromosomes is highly heterogeneous and some B chromosomes contain multiple large duplications derived from various chromosomes of the standard karyotype. Although B chromosomes seem to be mostly homologous to each other within a species, their genetic content differs between species. There are indications that some genomic regions are more likely to be located on B chromosomes. CONCLUSIONS: The discovery of multiple autosomal genes on B chromosomes opens a new discussion about their possible effects ranging from sex determination to fitness and adaptation, their complex interactions with host genome and role in evolution. PMID- 25538795 TI - The impact of workforce redesign policies on role boundaries in 'generalist' podiatry practice: expert views within the professional body. AB - BACKGROUND: Demographic changes and a predicted rise in the prevalence of chronic illness have led to a range of health policies in the UK (and elsewhere) focused on workforce flexibility and extended roles for the allied health professions. Whilst much academic attention has been paid to extended specialised roles for allied health professionals such as podiatrists, little work has addressed the likely impact of these policy changes on non-specialist, 'generalist' podiatry practice. This study aimed to explore expert professional views on the impact of role flexibility on generalist podiatry practice. METHODS: Expert podiatry practitioners drawn from within the professional body, the Society of Chiropodists and Podiatrists/College of Podiatry were recruited to 3 focus groups and 4 individual semi structured interviews and the data subject to a thematic analysis. RESULTS: Three key themes emerged, reflecting concerns about the future of generalist podiatry practice in the NHS, a perceived likelihood that generalist care will move inexorably towards private sector provision, and a growth in support worker grades undermining the position of generalist practice in the mainstream health division of labour. Up skilling generalist practitioners was viewed as the strongest defence against marginalisation. CONCLUSIONS: An emphasis on enhanced and specialised roles in podiatry by NHS commissioners and profession alike may threaten the sustainability of generalist podiatry provision in the state funded NHS. Non-specialist general podiatry may increasingly become the province of the private sector. PMID- 25538796 TI - Investigating Women's Experiences of Asthma Care in Pregnancy: A Qualitative Study. AB - Background : Most asthmatic women have normal pregnancies and complications are infrequent when their asthma is well-controlled. Symptom control and medical treatment are concerning to pregnant asthma suffers, as is the impact that their illness and treatment might have on their unborn baby. The aim was to investigate in a qualitative study the thoughts and feelings of women's experiences of asthma in pregnancy. Twenty-two women with asthma who had a pregnancy within two years were asked to participate. Seven women were interviewed when data saturation was achieved. Interviews were transcribed and analysed using the 'Framework' Method, independently analysed by two researchers and consensus reached concerning the construction of themes. The key themes that emerged were Asthma and pregnancy; Pregnancy and post-natal experiences; and Health professionals. These findings are globally interesting because of the prevalence of maternal asthma and they illustrate participants' experiences concerning their asthma care and their views on its improvement. Pregnant asthmatic women have concerns about their care and treatment which might be alleviated by outreach, joint working between respiratory doctors and nurse specialists, midwives and General Practice nurses. Targeted educational activities could form a part of this care delivery. PMID- 25538794 TI - An integrated transcriptome and expressed variant analysis of sepsis survival and death. AB - BACKGROUND: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. METHODS: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes. RESULTS: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. CONCLUSIONS: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005. PMID- 25538798 TI - Classical signs and appearances in pediatric neuroradiology: a pictorial review. AB - Radiological practice includes classification of illnesses with similar characteristics through recognizable signs. In this report, twenty-eight important and frequently seen neuroradiological signs in childhood are presented and described using X-rays, computed tomography (CT), magnetic resonance (MR) images, illustrations and photographs. PMID- 25538797 TI - Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine. AB - Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different disciplines including hepatologists, gastroenterologists, medical and surgical oncologists, liver transplant teams, interventional radiologists and radiation oncologists. The article concludes with a review providing an outlook and recommendations for the application of MGT to enhance the medical management of HCC through PPPM. PMID- 25538799 TI - Preface to Special Topic: Selected Papers from the Advances in Microfluidics and Nanofluidics 2014 Conference in Honor of Professor Hsueh-Chia Chang's 60th Birthday. PMID- 25538800 TI - Quantifying spatio-temporal dynamics of biomarker pre-concentration and depletion in microfluidic systems by intensity threshold analysis. AB - Microfluidic systems are commonly applied towards pre-concentration of biomarkers for enhancing detection sensitivity. Quantitative information on the spatial and temporal dynamics of pre-concentration, such as its position, extent, and time evolution are essential towards sensor design for coupling pre-concentration to detection. Current quantification methodologies are based on the time evolution of fluorescence signals from biomarkers within a statically defined region of interest, which does not offer information on the spatial dynamics of pre concentration and leads to significant errors when the pre-concentration zone is delocalized or exhibits wide variations in size, shape, and position over time under the force field. We present a dynamic methodology for quantifying the region of interest by using a statistical description of particle distribution across the device geometry to determine the intensity thresholds for particle pre concentration. This method is applied to study the delocalized pre-concentration dynamics under an electrokinetic force balance driven by negative dielectrophoresis, for aligning the pre-concentration and detection regions of neuropeptide Y, and for quantifying the polarizability dispersion of silica nano colloids with frequency of the force field. We envision the application of this automated methodology on data from 2D images and 3D Z-stacks for quantifying pre concentration dynamics over delocalized regions as a function of the force field. PMID- 25538801 TI - An on-chip study on the influence of geometrical confinement and chemical gradient on cell polarity. AB - Cell polarity plays key roles in tissue development, regeneration, and pathological processes. However, how the cells establish and maintain polarity is still obscure so far. In this study, by employing microfluidic techniques, we explored the influence of geometrical confinement and chemical stimulation on the cell polarity and their interplay. We found that teardrop shape-induced anterior/posterior polarization of cells displayed homogeneous distribution of epidermal growth factor receptor, and the polarity could be maintained in a uniform epidermal growth factor (EGF) solution, but be broken by a reverse gradient of EGF, implying different mechanism of geometrical and chemical cue induced cell polarity. Further studies indicated that a teardrop pattern could cause polarized distribution of microtubule-organization center and nucleus-Golgi complex, and this polarity was weakened when the cells were released from the confinement. Our study provides the evidence regarding the difference between geometrical and chemical cue-induced cell polarity and would be useful for understanding relationship between polarity and directional migration of cells. PMID- 25538802 TI - Fabrication and characterization of sub-100/10 nm planar nanofluidic channels by triple thermal oxidation and silicon-glass anodic bonding. AB - We reported the fabrication and characterization of nanofluidic channels by Triple Thermal Oxidation and Silicon-Glass Anodic Bonding. Planar nanochannels with depths from sub-100 nm down to sub-10 nm were realized by this method. A theoretical model was developed to precisely predict the depth of nanochannels. The depth and uniformity of nanochannels showed good stability during anodic bonding. This method is promising for various nanofluidic studies, such as nanofluidic electrokinetics, biomolecule manipulation, and energy conversion. PMID- 25538803 TI - An enzyme-linked immunosorbent assay on a centrifugal platform using magnetic beads. AB - An automated, disk-based, enzyme-linked immunosorbent assay (ELISA) system is presented in this work. Magnetic beads were used as the antibody carriers to improve the assay sensitivity and shorten the reaction time. The magnetic module integrated on the system is capable of controlling the magnetic beads to either move in the incubation stage or immobilize at a specific location during washing stage. This controlling mechanism utilizes a passive controlling approach so that it can be performed through disk spinning without the need of active control from external devices. The movement of the magnetic beads was investigated and the optimal rotational speed was found to be related to the ratio of the processing time to the cycle time of the magnetic beads. Comparing to ELISA conducted on microtiter plates, similar test results could be achieved by the disk-based ELISA but the entire protocol can be finished automatically within 45 min with much less reagent consumption. PMID- 25538804 TI - Advances in three-dimensional rapid prototyping of microfluidic devices for biological applications. AB - The capability of 3D printing technologies for direct production of complex 3D structures in a single step has recently attracted an ever increasing interest within the field of microfluidics. Recently, ultrafast lasers have also allowed developing new methods for production of internal microfluidic channels within the bulk of glass and polymer materials by direct internal 3D laser writing. This review critically summarizes the latest advances in the production of microfluidic 3D structures by using 3D printing technologies and direct internal 3D laser writing fabrication methods. Current applications of these rapid prototyped microfluidic platforms in biology will be also discussed. These include imaging of cells and living organisms, electrochemical detection of viruses and neurotransmitters, and studies in drug transport and induced-release of adenosine triphosphate from erythrocytes. PMID- 25538805 TI - Microfluidic platform integrated with worm-counting setup for assessing manganese toxicity. AB - We reported a new microfluidic system integrated with worm responders for evaluating the environmental manganese toxicity. The micro device consists of worm loading units, worm observing chambers, and a radial concentration gradient generator (CGG). Eight T-shape worm loading units of the micro device were used to load the exact number of worms into the corresponding eight chambers with the assistance of worm responders and doorsills. The worm responder, as a key component, was employed for performing automated worm-counting assay through electric impedance sensing. This label-free and non-invasive worm-counting technique was applied to the microsystem for the first time. In addition, the disk-shaped CGG can generate a range of stepwise concentrations of the appointed chemical automatically and simultaneously. Due to the scalable architecture of radial CGG, it has the potential to increase the throughput of the assay. Dopaminergic (DAergic) neurotoxicity of manganese on C. elegans was quantitatively assessed via the observation of green fluorescence protein-tagged DAergic neurons of the strain BZ555 on-chip. In addition, oxidative stress triggered by manganese was evaluated by the quantitative fluorescence intensity of the strain CL2166. By scoring the survival ratio and stroke frequency of worms, we characterized the dose- and time-dependent mobility defects of the manganese-exposed worms. Furthermore, we applied the microsystem to investigate the effect of natural antioxidants to protect manganese-induced toxicity. PMID- 25538806 TI - Hydrodynamic resistance and mobility of deformable objects in microfluidic channels. AB - This work reports experimental and theoretical studies of hydrodynamic behaviour of deformable objects such as droplets and cells in a microchannel. Effects of mechanical properties including size and viscosity of these objects on their deformability, mobility, and induced hydrodynamic resistance are investigated. The experimental results revealed that the deformability of droplets, which is quantified in terms of deformability index (D.I.), depends on the droplet-to channel size ratio [Formula: see text] and droplet-to-medium viscosity ratio [Formula: see text]. Using a large set of experimental data, for the first time, we provide a mathematical formula that correlates induced hydrodynamic resistance of a single droplet [Formula: see text] with the droplet size [Formula: see text] and viscosity [Formula: see text]. A simple theoretical model is developed to obtain closed form expressions for droplet mobility [Formula: see text] and [Formula: see text]. The predictions of the theoretical model successfully confront the experimental results in terms of the droplet mobility [Formula: see text] and induced hydrodynamic resistance [Formula: see text]. Numerical simulations are carried out using volume-of-fluid model to predict droplet generation and deformation of droplets of different size ratio [Formula: see text] and viscosity ratio [Formula: see text], which compare well with that obtained from the experiments. In a novel effort, we performed experiments to measure the bulk induced hydrodynamic resistance [Formula: see text] of different biological cells (yeast, L6, and HEK 293). The results reveal that the bulk induced hydrodynamic resistance [Formula: see text] is related to the cell concentration and apparent viscosity of the cells. PMID- 25538807 TI - Microfluidic generation of droplet interface bilayer networks incorporating real time size sorting in linear and non-linear configurations. AB - In this study, a novel droplet based microfluidic method for the generation of different sized droplet interface bilayers is reported. A microfluidic platform was designed, which allows the generation and packing of picoliter lipid coated water droplets. Droplets were generated by hydrodynamic focusing coupled with selective transport along grooves according to their size. A trapping structure at the end of the groove and a fine control of the flow pressures allowed for the droplets to be successfully trapped and aligned on demand. This technology facilitates the fine control of droplet size production as well as the generation of extended networks from a variety of lipids including 1,2-diphytanoyl-sn glycero-3-phosphocholine and 1,2-dioleoyl-sn-glycero-3-phosphocholine in linear and non-linear configurations, which is vital to the application of Droplet Interface Bilayers to biological network construction on-chip. PMID- 25538808 TI - Improving the binding efficiency of quartz crystal microbalance biosensors by applying the electrothermal effect. AB - A quartz crystal microbalance (QCM) serving as a biosensor to detect the target biomolecules (analytes) often suffers from the time consuming process, especially in the case of diffusion-limited reaction. In this experimental work, we modify the reaction chamber of a conventional QCM by integrating into the multi microelectrodes to produce electrothermal vortex flow which can efficiently drive the analytes moving toward the sensor surface, where the analytes were captured by the immobilized ligands. The microelectrodes are placed on the top surface of the chamber opposite to the sensor, which is located on the bottom of the chamber. Besides, the height of reaction chamber is reduced to assure that the suspended analytes in the fluid can be effectively drived to the sensor surface by induced electrothermal vortex flow, and also the sample costs are saved. A series of frequency shift measurements associated with the adding mass due to the specific binding of the analytes in the fluid flow and the immobilized ligands on the QCM sensor surface are performed with or without applying electrothermal effect (ETE). The experimental results show that electrothermal vortex flow does effectively accelerate the specific binding and make the frequency shift measurement more sensible. In addition, the images of the binding surfaces of the sensors with or without applying electrothermal effect are taken through the scanning electron microscopy. By comparing the images, it also clearly indicates that ETE does raise the specific binding of the analytes and ligands and efficiently improves the performance of the QCM sensor. PMID- 25538809 TI - Rapid microfluidic solid-phase extraction system for hyper-methylated DNA enrichment and epigenetic analysis. AB - Genetic sequence and hyper-methylation profile information from the promoter regions of tumor suppressor genes are important for cancer disease investigation. Since hyper-methylated DNA (hm-DNA) is typically present in ultra-low concentrations in biological samples, such as stool, urine, and saliva, sample enrichment and amplification is typically required before detection. We present a rapid microfluidic solid phase extraction (MUSPE) system for the capture and elution of low concentrations of hm-DNA (<=1 ng ml(-1)), based on a protein-DNA capture surface, into small volumes using a passive microfluidic lab-on-a-chip platform. All assay steps have been qualitatively characterized using a real-time surface plasmon resonance (SPR) biosensor, and quantitatively characterized using fluorescence spectroscopy. The hm-DNA capture/elution process requires less than 5 min with an efficiency of 71% using a 25 MUl elution volume and 92% efficiency using a 100 MUl elution volume. PMID- 25538810 TI - A novel microfluidic flow focusing method. AB - A new microfluidic method that allows hydrodynamic focusing in a microchannel with two sheath flows is demonstrated. The microchannel network consists of a T shaped main channel and two T-shaped branch channels. The flows of the sample stream and the sheath streams in the microchannel are generated by electroosmotic flow-induced pressure gradients. In comparison with other flow focusing methods, this novel method does not expose the sample to electrical field, and does not need any external pumps, tubing, and valves. PMID- 25538811 TI - Continuous removal of glycerol from frozen-thawed red blood cells in a microfluidic membrane device. AB - Cryopreservation of human red blood cells (RBCs) in the presence of 40% glycerol allows a shelf-life of 10 years, as opposed to only 6 weeks for refrigerated RBCs. Nonetheless, cryopreserved blood is rarely used in clinical therapy, in part because of the requirement for a time-consuming (~1 h) post-thaw wash process to remove glycerol before the product can be used for transfusion. The current deglycerolization process involves a series of saline washes in an automated centrifuge, which gradually removes glycerol from the cells in order to prevent osmotic damage. We recently demonstrated that glycerol can be extracted in as little as 3 min without excessive osmotic damage if the composition of the extracellular solution is precisely controlled. Here, we explore the potential for carrying out rapid glycerol extraction using a membrane-based microfluidic device, with the ultimate goal of enabling inline washing of cryopreserved blood. To assist in experimental design and device optimization, we developed a mass transfer model that allows prediction of glycerol removal, as well as the resulting cell volume changes. Experimental measurements of solution composition and hemolysis at the device outlet are in reasonable agreement with model predictions, and our results demonstrate that it is possible to reduce the glycerol concentration by more than 50% in a single device without excessive hemolysis. Based on these promising results, we present a design for a multistage process that is predicted to safely remove glycerol from cryopreserved blood in less than 3 min. PMID- 25538812 TI - Computational investigations of the mixing performance inside liquid slugs generated by a microfluidic T-junction. AB - Droplet-based microfluidics has gained extensive research interest as it overcomes several challenges confronted by conventional single-phase microfluidics. The mixing performance inside droplets/slugs is critical in many applications such as advanced material syntheses and in situ kinetic measurements. In order to understand the effects of operating conditions on the mixing performance inside liquid slugs generated by a microfluidic T-junction, we have adopted the volume of fluid method coupled with the species transport model to study and quantify the mixing efficiencies inside slugs. Our simulation results demonstrate that an efficient mixing process is achieved by the intimate collaboration of the twirling effect and the recirculating flow. Only if the reagents are distributed transversely by the twirling effect, the recirculating flow can bring in convection mechanism thus facilitating mixing. By comparing the mixing performance inside slugs at various operating conditions, we find that slug size plays the key role in influencing the mixing performance as it determines the amount of fluid to be distributed by the twirling effect. For the cases where short slugs are generated, the mixing process is governed by the fast convection mechanism because the twirling effect can distribute the fluid to the flow path of the recirculating flow effectively. For cases with long slugs, the mixing process is dominated by the slow diffusion mechanism since the twirling effect is insufficient to distribute the large amount of fluid. In addition, our results show that increasing the operating velocity has limited effects on improving the mixing performance. This study provides the insight of the mixing process and may benefit the design and operations of droplet-based microfluidics. PMID- 25538813 TI - Optofluidic microvalve-on-a-chip with a surface plasmon-enhanced fiber optic microheater. AB - We present an optofluidic microvalve utilizing an embedded, surface plasmon enhanced fiber optic microheater. The fiber optic microheater is formed by depositing a titanium thin film on the roughened end-face of a silica optical fiber that serves as a waveguide to deliver laser light to the titanium film. The nanoscale roughness at the titanium-silica interface enables strong light absorption enhancement in the titanium film through excitation of localized surface plasmons as well as facilitates bubble nucleation. Our experimental results show that due to the unique design of the fiber optic heater, the threshold laser power required to generate a bubble is greatly reduced and the bubble growth rate is significantly increased. By using the microvalve, stable vapor bubble generation in the microchannel is demonstrated, which does not require complex optical focusing and alignment. The generated vapor bubble is shown to successfully block a liquid flow channel with a size of 125 MUm * 125 MUm and a flow rate of ~10 MUl/min at ~120 mW laser power. PMID- 25538814 TI - Fabrication of rigid microstructures with thiol-ene-based soft lithography for continuous-flow cell lysis. AB - In this work, we introduce a method for the soft-lithography-based fabrication of rigid microstructures and a new, simple bonding technique for use as a continuous flow cell lysis device. While on-chip cell lysis techniques have been reported previously, these techniques generally require a long on-chip residence time, and thus cannot be performed in a rapid, continuous-flow manner. Microstructured microfluidic devices can perform mechanical lysis of cells, enabling continuous flow lysis; however, rigid silicon-based devices require complex and expensive fabrication of each device, while polydimethylsiloxane (PMDS), the most common material used for soft lithography fabrication, is not rigid and expands under the pressures required, resulting in poor lysis performance. Here, we demonstrate the fabrication of microfluidic microstructures from off-stoichiometry thiol-ene (OSTE) polymer using soft-lithography replica molding combined with a post assembly cure for easy bonding. With finite element simulations, we show that the rigid microstructures generate an energy dissipation rate of nearly 10(7), which is sufficient for continuous-flow cell lysis. Correspondingly, with the OSTE device we achieve lysis of highly deformable MDA-MB-231 breast cancer cells at a rate of 85%, while a comparable PDMS device leads to a lysis rate of only 40%. PMID- 25538815 TI - Acupuncture: An Alternative Therapy in Dentistry and Its Possible Applications. AB - Background: Traditional Chinese acupuncture has a history of more than 2500 years and is one of the best-known complementary and alternative therapies. Acupuncture stimulates the nervous system and alters the processing and perception of pain signals and also releases natural painkillers, such as endorphins and serotonin in the nervous system. Acupuncture's successful use for various dental conditions has been proven. Thus, it is important for the dental clinicians to be familiar with the applications of acupuncture for dental disorders. Objective: One aim of this article is to review related articles in the literature that have focused on acupuncture and its applications in dentistry. Another aim is to provide a quick sketch of acupuncture use in dentistry for dental clinicians. Materials and Methods: A detailed search was performed to identify systematic reviews and research articles, using PUBMED and the Cochrane Database of Systematic Reviews. Language was restricted to English. Key search terms were acupuncture in dentistry, myofacial pain, temporomandibular disorders, xerostomia, dental pain and gag reflex. Results: All of the current the authors independently extracted data for analysis and review. Two independent reviewers screened the titles and abstracts of all the articles for eligibility. When the reviewers noted that an abstract or title of an article indicated that the article was potentially useful, full copies were retrieved. Ultimately, 40 articles underwent full-text review. Conclusions: The research to date certainly offers valid applications of acupuncture in dentistry. Meanwhile, practical strategies with the highest success rates are needed to use in further interventions. PMID- 25538818 TI - Delay of Fibrinolysis in ST- Elevation Myocardial Infarction: Results of an Investigation Conducted in a Single Center in Sousse Tunisia. AB - BACKGROUND: The aim of our study was to assess the delay of fibrinolysis in ST elevation myocardial infarction (STEMI) in our region and to identify characteristics associated with prolonged delay. PATIENTS AND METHODS: We analyzed clinical characteristics of a prospective cohort of unselected patients admitted for (STEMI). The study was conducted over three years 2007-2009 and 250 patients were included in a single center without capability of percutaneous coronary intervention. RESULTS: The mean age of our patients was 58+/-13, 7 years. Ninety percent of our patients consult directly the emergency department and 61, (5%) of them were admitted within first 6 hours of onset of symptoms. Median time to reperfusion was 46 min. Predictor of this long delay to initiate fibrinolysis were inter-department decision OR 6; 95% CI 3,48-10,34, diabetes OR 2,25; 95% CI 1,28-3,96 age >58,4 years OR 1,97; 95% CI 1,19-3,25 and transfer from regional hospital to our center OR 1,78; 95% 1,03-3.07. CONCLUSION: These results suggest that improvement in organization health care system can shorten delay to fibrinolysis in a center without percutaneous coronary intervention capability. PMID- 25538817 TI - Exercise-induced neuroprotection of hippocampus in APP/PS1 transgenic mice via upregulation of mitochondrial 8-oxoguanine DNA glycosylase. AB - Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-beta (Abeta) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Abeta-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD related mitochondrial dysfunction and phenotypic deterioration. PMID- 25538816 TI - Relevance of the glutathione system in temporal lobe epilepsy: evidence in human and experimental models. AB - Oxidative stress, which is a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with diseases that are systemic as well as diseases that affect the central nervous system. Epilepsy is a chronic neurological disorder, and temporal lobe epilepsy represents an estimated 40% of all epilepsy cases. Currently, evidence from human and experimental models supports the involvement of oxidative stress during seizures and in the epileptogenesis process. Hence, the aim of this review was to provide information that facilitates the processing of this evidence and investigate the therapeutic impact of the biochemical status for this specific pathology. PMID- 25538819 TI - Assessment of heart rate turbulence in hypertensive patients: rationale, perspectives, and insight into autonomic nervous system dysfunction. AB - BACKGROUND: Heart rhythm turbulence is classically impaired in patients with previous myocardial infarction and congestive heart failure and is poorly investigated in patients with essential hypertension. OBJECTIVE: To evaluate heart rhythm turbulence parameters (turbulence onset, (TO); turbulence slope, (TS) in a series of hypertensive patients while gaining insight into autonomic nervous system dysfunction. SETTING AND DESIGN: University hospital, cross sectional monocentric study. MATERIALS AND METHODS: Heart rhythm turbulence was assessed in 50 hypertensive (case group) and 40 normotensive patients (control group). RESULTS: TO and TS were found independently correlated with hypertension. The mean TO was found at -1.64% +/- 2.85% in the normotensive patients compared to 1.21% +/- 1.95% in the hypertensive patients; the mean TS was found at 4.29 +/ 3.18 ms/RR in the normotensive patients compared to 2.27 +/- 0.93 ms/RR in the hypertensive patients. Hypertension has a predictive value on heart rhythm turbulence impairment (OR 4.99, 95% CI 1.28-19.41, P = 0.02). Insights into the role of autonomic nervous system dysfunction for the management of hypertensive patients and prevention of malignant ventricular arrhythmia are presented and discussed with regard to heart rhythm turbulence. CONCLUSION: Essential hypertension is correlated with blunted heart rhythm turbulence parameters. PMID- 25538820 TI - Cardioprotective effects of ghrelin in heart failure: from gut to heart. AB - Chronic heart failure (CHF) is a major cause of morbidity and mortality. Cardioprotective effects of ghrelin, especially in its acylated form have been demonstrated in heart failure (HF) models and exploratory human clinical studies. Hence, it has been proposed for the treatment of HF. However, the underlying mechanism of its protective effects against HF remains unclear. Future researches are needed to evaluate the efficacy of Ghrelin as a new biomarker and prognostic tool and for exploring its therapeutic potential in patients suffering from CHF. PMID- 25538821 TI - First Degree Heart Block with Multi-focal Atrial Ectopics in an Adolescent Girl Due to Hypomagnesemia. AB - Nutritional deficiencies are common in adolescent children and include deficiencies of both micro- and macronutrients. Magnesium is an important mineral that is essential for maintenance of numerous electrophysiological and biochemical processes in the body. We report an adolescent girl who developed an episode of syncope with first degree heart block on electrocardiography and run of multifocal atrial ectopics on 24 h holter monitoring. Serum magnesium was found to be low with decreased urinary magnesium excretion. There were no other electrolyte abnormalities. Structural heart disease was ruled out by a normal echocardiogram. The rhythm changes were attributable to nutritional hypomagnesemia and were promptly reversed on correcting the hypomagnesemia. PMID- 25538822 TI - Spontaneous coronary artery dissection and acute myocardial infarction after cesarean section in a postpartum woman with untreated dyslipidemia. AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial infarction (AMI). We are presenting a case of a young woman with a history of untreated dyslipidemia presented with AMI secondary to left anterior descending coronary artery dissection during postpartum period. Physicians should be aware of this rare etiology of AMI which occurs during pregnancy and postpartum, since early diagnosis and treatment play a key role in saving both the mother and the baby. It is important to screen for other possible causes such as collagen vascular diseases, blunt injury to the chest, or cocaine abuse. PMID- 25538823 TI - Diffuse pulmonary hemorrhage after fibrinolytic therapy for acute myocardial infarction in a cocaine abuser patient. AB - We report a 45-year-old man with antroseptal myocardial infarction who developed bilateral basal alveolar infiltrates after initiating the fibrinolytic therapy. Although thrombolytic therapy with streptokinase is generally used in the course of acute myocardial infarction and has diminished morbidity and mortality, pulmonary hemorrhage is an uncommon, but a potentially life-threatening complication that should be regarded as one of the differential diagnoses of pulmonary infiltrates or dropping hemoglobin with no apparent bleeding site. PMID- 25538824 TI - Assessment of carotid body tumor and its association with tetralogy of fallot: effect of the chronic hypoxia. AB - This is a rare combined presentation of Tetralogy of Fallot and carotid body tumor (CBT). Hypotheses and further discussion provides data for the development of CBT as a response to chronic hypoxemia. This present study demonstrates and discusses such an occurrence. PMID- 25538825 TI - Giant pulmonary artery aneurysm in a patient with rheumatic mitral stenosis. AB - Pulmonary artery (PA) aneurysm is a rare condition, frequently associated with pulmonary hypertension. However, the evolution and treatment of this pathology is still not clear. We report a case of a 45-year-old female patient with giant PA aneurysm associated with rheumatic mitral stenosis and severe pulmonary arterial hypertension. The patient had undergone balloon mitral valvotomy around 7 years back; aneurysm was first identified 3 years back during routine follow-up. The PA aneurysm size, however, had remained almost unchanged with associated severe pulmonary regurgitation. Surgical correction was advised but denied by the patient. To our knowledge, this is the first case report of such a large PA aneurysm in association with rheumatic heart disease. Although medical therapy for pulmonary hypertension was started, surgical correction of the aneurysm was advised in order to prevent the future complications. PMID- 25538826 TI - Xanthomas and hypercholoesterolemia. PMID- 25538827 TI - The visual aspect of medicine. PMID- 25538828 TI - The medieval origins of the concept of hypertension. AB - Despite the well-known history of hypertension research in the modern era, like many other cardiovascular concepts, main points in the medieval concept of this disease and its early management methods remain obscure. This article attempts to make a brief review on the medieval origin of the concept of this disease from the Hidayat of Al-Akhawayni (?-983 AD). This article has reviewed the chapter of "Fi al-Imtela" (About the Fullness) from the Hidbetayat al-Muta'allimin fi al Tibb (The Students' Handbook of Medicine) of Al-Akhawayni. The definition, symptoms and treatments presented for the Imtela are compared with the current knowledge on hypertension. Akhawayni believed that Imtela could result from the excessive amount of blood within the blood vessels. It can manifest with symptoms including the presence of a pulsus magnus, sleepiness, weakness, dyspnea, facial blushing, engorgement of the vessels, thick urine, vascular rupture, and hemorrhagic stroke. He also suggested some ways to manage al-Imtela'. These include recommendations of changes in lifestyle (staying away from anger and sexual intercourse) and dietary program for patients (avoiding the consumption of wine, meat, and pastries, reducing the volume of food in a meal, maintaining a low-energy diet and the dietary usage of spinach and vinegar). Al-Akhawayni's description of "Imtela," despite of its numerous differences with current knowledge of hypertension, can be considered as medieval origin of the concept of hypertension. PMID- 25538829 TI - A Systematic Review on Exposure to Toxic and Essential Elements through Black Tea Consumption in Iran: Could It be a Major Risk for Human Health? AB - BACKGROUND: Tea is the most popular nonalcoholic beverage worldwide. In recent years, some Iranian studies have shown the occurrence of toxic elements in fresh or dried tea leaves as well as in brewed tea. The present study aimed to ascertain the health risks associated with exposure to toxic and essential element through black tea consumption in Iran by systematically reviewing the accredited articles in the field. METHODS: In order to obtain the relevant articles and academic databases, the search engines covering the specific disciplines were searched for the keywords, including tea, elements, heavy metals and determination. Having provided the complete list of sound articles, being conducted in Iran was considered as the inclusion criteria. Exclusion criteria were established as failure to provide information on the validity parameters and accuracy in the analytical methods. Choosing well conducted, reliable studies, analytical results for the concentration of each element in black tea were utilized in the determination of the hazard quotient (HQ) for the given element and the hazard index (HI) was then determined for all of the elements in each study. RESULTS: Among the total studies, two were considered to be reliable. Aluminum was found to be the most abundant element in black tea marketed in Iran. Although the HQ for manganese was the highest among the studied elements, HQ and HI values for both toxic elements and essential elements were calculated as less than 1. CONCLUSIONS: The hazard of excessive element intake through black tea consumption should be considered as negligible in Iran. However, related risk for manganese appeared to be more than toxic metals. PMID- 25538830 TI - Lack of nephroprotective efficacy of althaea officinalis flower extract against gentamicin renal toxicity in male rats. AB - BACKGROUND: Gentamicin (GM) is used as antibiotic for Gram-negative infections, but its administration is limited due to a side-effect of nephrotoxicity. It was attempted to investigate the effect of Althaea officinalis flower extract (AOFE) against nephrotoxicity induced by GM in male rats. METHODS: 30-year-old male Wistar rats were divided into five groups. Group 1 as a negative control group received AOFE 250 mg/kg/day. Groups 2-5 received saline, AOFE 50 mg/kg/day, AOFE 250 mg/kg/day, and AOFE 500 mg/kg/day for 9 days, respectively, and GM (100 mg/kg/day) was added from the 3(rd) day on. At the end of the experiment, blood samples were obtained, animals were sacrificed, and the kidneys were removed immediately. RESULTS: Gentamicin (in group 2) significantly increased serum levels of blood urea nitrogen and creatinine as well as the pathological damage score (P < 0.05) when compared with group 1. Low dose of AOFE did not decrease the nephrotoxicity induced by GM while the high dose of AOFE aggravated renal toxicity (P < 0.05). CONCLUSIONS: Although AOFE acts as an antioxidant, at the doses used in the current study did not ameliorate nephrotoxicity induced by GM. PMID- 25538831 TI - Tobacco use, Alcohol Consumption and Self-rated Oral Health among Nigerian Prison Officials. AB - BACKGROUND: The oral health condition and lifestyle in term of tobacco use and alcohol consumption of custodian of prisons have been left unstudied. The purpose of this study was to determine the prevalence of tobacco use, alcohol consumption and self-rated oral health among Nigerian prison officials. METHODS: This cross sectional study was conducted among prison officials working in Abuja, Nassarawa and Kano prison yards between March and June 2011 using 28-item self-administered questionnaire as a tool of data collection. The questionnaire elicited information on demography, self-rated oral health, oral health behaviors, oral health conditions, tobacco use, pattern and quit attempts, alcohol consumption, type and pattern. RESULTS: The participants were aged between 20 and 51 years, with a mean age of 32.25 +/- 6.13 years. The majority of the participants were males (66.4%), Christians (76.7%), junior officials (78.1%) and of Northern origin (50.7%). A total of 50 (34.2%) of the participants indicated that they were tobacco users and 39 (78.0%) indulged in cigarette smoking only. Of the study participants, 67 (45.9%) indicated they consume alcohol, beer majorly and gin rarely with 23 (34.3%) consuming it excessively. The dominant tooth cleaning device utilized by the participants was toothbrush and toothpaste, and 65 (44.5%) had visited the dentists with the majority of the visit done >5 years ago. About one-third 57 (39.0%) reported experiencing one or more forms of oral disease. However, it was only 17 (11.6%) of them that rated their oral health poor/fair, and the determinants of self-rated oral health were age, rank, and oral health condition. CONCLUSIONS: Data from this survey revealed that the majority of the participants rated their oral health as good/excellent. The prevalence of tobacco use and alcohol consumption among prison officials was higher than reported values among the general population in Nigeria. This indicates that more surveillance and intervention studies are needed to evaluate the best way to control tobacco use and alcohol consumption among prison officials in Nigeria. PMID- 25538832 TI - Geographic Health's Way to Prevention of Diseases: A Case Study on Arsenic Spatial Dispersion and Dyspnea in Isfahan Province. AB - BACKGROUND: As geographic science discusses the analysis of environment, human beings and their mutual relations, thus the field of medical geography consists of being inspired from the relations between these two factors, analyzing environmental factors, their identification them and the state of their effects on human health, as well as determining the location of these factors. Some hazards that threat human health are the results of environmental factors and the relevant pollutions. Some important categories of diseases including (Shortness of Breath or, Dyspnea) have considerable differences in various places, as observed in their spatial prevalence and distribution maps. METHODS: The record of patients with Dyspnea diseases were prepared for this descriptive research, for the period of 2009-2011, from the provincial health center, with the questionnaires were excluded patients with a family history of disease and the spatial diagram for disease prevalence was drawn according to the prepared data. The arsenic geographical distribution diagram in Isfahan province was also prepared and then the relation between an element of Arsenic in the province and the Dyspnea diseases were analyzed. RESULTS: The analyses showed that the highest rate of Arsenic is entered the soil via fertilizers to come eventually into the food cycle of humans. By analyzing the amount of used fertilizers in Isfahan province and the dispersion diagram of Arsenic in Isfahan province, it was found that the highest frequency of Arsenic is in places having agricultural base. The spatial dispersion of Dyspnea diseases also showed that the spreading of Dyspnea diseases is greater in places with higher scale of Arsenic. CONCLUSIONS: This study is a logical justification between the two diagrams to confirm the hypothesis regarding the effect of arsenic on Dyspnea. PMID- 25538833 TI - Conversion from radiologically isolated syndrome to multiple sclerosis. AB - BACKGROUND: The aim of this study was to estimate the conversion rate from radiologically isolated syndrome (RIS) to definite multiple sclerosis (MS). METHODS: During a mean (standard deviation [SD]) follow-up period of 17.4 (5.4) (range 8-29) months, 25 subjects with RIS and without neurological symptom aged 22-45 year from a single-center have been examined for the occurrence of definite MS. The mean (SD) age of participants was 35.1 (6.2) years at first brain magnetic resonance imaging (MRI). The definite MS were assessed using the revised McDonald's criteria (2010). RESULTS: Six of 25 patients developed clinical symptom consistent with criteria for definite MS. The conversion rate from RIS to definite MS was 1.5 (95% confidence interval [CI] 0.54, 3.17) per 100 person months based on 480 person-months of follow-up. Multivariate analysis revealed that presence of contrast-enhancing lesions on the initial MRI was marginally significantly associated with MS (hazard ratio 1.83, 95% CI 0.98, 3.45, P = 0.060). CONCLUSIONS: This is the first estimate of conversion rate from RIS to definite MS in Iran. The conversion rates from RIS to definite MS in these participants are high and intensive follow-up and intervention strategies are recommended for these high-risk individuals. A larger study is warranted to assess this risk in greater detail. PMID- 25538834 TI - The Effect of Neutral Oligosaccharides on Reducing the Incidence of Necrotizing Enterocolitis in Preterm infants: A Randomized Clinical Trial. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most destructive diseases associated with conditions of neonatal prematurity. Supplementation with enteral prebiotics may reduce the incidence of NEC, especially in infants who fed exclusively with breast-milk. Therefore, we compared the efficacy and safety of enteral supplementation of a prebiotic mixture (short chain galacto oligosaccharides/long chain fructo-oligosaccharides [SCGOS/LCFOS]) versus no intervention on incidence of NEC in preterm infants. METHODS: In a single-center randomized control trial 75 preterm infants (birth weight [BW] <=1500 g, gestational age <=34 weeks and were not fed with formula) on 30 ml/kg/day volume of breast-milk were randomly allocated to have enteral supplementation with a prebiotic mixture (SCGOS/LCFOS; 9:1) or not receive any prebiotic. The incidence of suspected NEC, feeding intolerance, time to full enteral feeds, duration of hospitalization were investigated. RESULTS: Differences in demographic characteristics were not statistically important. SCGOS/LCFOS mixture significantly reduced the incidence of suspected NEC, (1 [4.0%] vs. 11 [22.0%]; hazard ratio: 0.49 [95% confidence interval: 0.29-0.84]; P = 0.002), and time to full enteral feeds (11 [7-21] vs. 14 [8-36] days; P - 0.02]. Also duration of hospitalization was meaningfully shorter in the prebiotic group (16 [9-45] vs. 25 [11-80]; P - 0.004]. Prebiotic oligosaccharides were well tolerated by very low BW (VLBW) infants. CONCLUSIONS: Enteral supplementation with prebiotic significantly reduced the incidence of NEC in VLBW infants who were fed exclusively breast-milk. This finding suggests that it might have been the complete removal of formula which caused a synergistic effect between nonhuman neutral oligosaccharides (prebiotic) and human oligosaccharides. PMID- 25538835 TI - Dropouts and social determinants of health; policy for the prevention of school dropout, qualitative study of the causes and interventions. AB - BACKGROUND: Indicators of the level of education are the most important parameters influencing each country's development. Social indicators considered to be a determinant of one's health consists of two constituents namely; (1) Rate of students enrolled in elementary, guidance, secondary and higher education and (2) the rate of adult literacy. This study is aimed to evaluate the situation of school dropouts in Iran, their causes, and appropriate interventions. METHODS: Data were collected through literature review (including published researches and analysis of documents), focus group discussions with the presence of experts from (Department of Community Health, Academy of Medical Sciences) and interviews with stakeholders then these data were classified and presented in three sections namely; current situation, causes and solutions. RESULTS: Results showed that Iran's current situation in terms of school dropouts is unsatisfactory in comparison to developed countries and in some countries in the region. Influencing factors for school dropouts were classified into (1) Individual factors such as intellectual disability and behavioral disorders (2) group factors such as peer groups, family problems and children's reduced interests in school and (3) major factors such as educational system and the changes of value, economic, cultural, and political issues. CONCLUSIONS: The present study, with the presentation of statistical documents specifically of the current problem of school dropouts in all levels of the Iranian society has been determined and aside from identifying the causes and factors affecting school dropouts, provision of strategies in three levels of prevention to combat this problem has been addressed. PMID- 25538836 TI - Effect of Low-fat Milk Consumption Compared to Apple Juice and Water on the Energy Intake Among 10-12-Year-Old Obese Boys: A Three-way Cross-over Clinical Trial. AB - BACKGROUND: Appetite lowering characteristics of dairy have attracted scientists to look for its effect on energy intake particularly among children. In the present study, we tried to assess the effect of low-fat milk on total and short term energy intake among obese boys in a randomized three-way cross-over clinical trial. METHODS: A total of 34 obese 10-12-year-old boys were randomized to consume three beverages (low-fat milk, apple juice, or water) with a fixed energy breakfast for two consecutive days, 1 week apart. Ad libitum lunch was provided for subjects 5 h later. The energy intake from breakfast till lunch and total energy intake on intervention days, and 2 days after intervention were compared. Generalized linear model repeated measures procedure in which test beverages were considered as repeated factors. RESULTS: Energy intake from breakfast till lunch was lower when low-fat milk consumption was included in the breakfast compared with water and apple juice (adjusted mean +/- standard error: Low-fat milk = 1484.33 +/- 15.30 Kcal, apple juice = 1543.39 +/- 20.70 Kcal, water = 1606.6 +/- 19.94 Kcal; P < 0.05). The energy intake on a day before interventions, total energy intake on intervention days, and 2 days after intervention was not statistically different between intervention periods (P > 0.05). CONCLUSIONS: One serving of low-fat milk might affect the energy intake in a short-term period. The possible effect of frequent consumption of dairy products on long-term energy intake among children is needed to be examined. PMID- 25538838 TI - Preventive effect of central administration of venlafaxine on morphine physical dependence, nociception, and blood cortisol level in rat. AB - BACKGROUND: Chronic abuse of opiates induces dependency, but the neurobiological mechanisms of this event remain unclear. The aim of this study was to evaluate the effects of intracerebroventricular of venlafaxine on the morphine dependence and pain perception. METHODS: A total of 80 adult male rats were divided into two major groups: (1) 40 of them was divided into groups of positive control (morphine dependent) negative control (received saline) and morphine dependent groups under treatment by central administration of venlafaxine at various dosages (25, 50, or 100 MUg), after drug treatment total withdrawal index (TWI), latency time of withdrawal syndrome expression and blood cortisol as marker of anxiety were measured and compared with positive control and negative control. (2) Forty rats were grouped in control; indometacin treated (5 mg/kg) and grouped which received central administration of venlafaxine at three doses (25, 50, or 100 MUg) and then pain perception and expression was assessed in the writhing test (acetic acid induced abdominal constriction), tail flick, and hot plate test. RESULTS: Central administration of three doses (25, 50, or 100 MUg,) of venlafaxine attenuates TWI to 47 +/- 1.2, 38 +/- 1.5, and 23 +/- 1.1 and decrease blood cortisol level to 14 +/- 1, 13.75 +/- 0.5, and 12.5 +/- 0.8, this decreases was significant in comparison with the positive control group (P < 0.05). Central administration of venlafaxine at mentioned doses significantly attenuates pain response with 37%, 24%, and 20% inhibition in writhing test, 69%, 34%, and 23% inhibition in hot plate test, and 29%, 23%, and 15% inhibition in tail flick test in comparison with control group (P < 0.05). CONCLUSIONS: This study suggested that central administration of venlafaxine attenuated morphine withdrawal index and can be effective in modulation of pain that was induced by morphine dependency. PMID- 25538839 TI - The effect of quality of care on cardiovascular risk factors in newly diagnosed diabetic patients. AB - BACKGROUND: In this study, we evaluated the quality of care and control of cardiovascular risk factors in newly diagnosed diabetic patients, identified during diabetes screening program, 1 year after diagnosis. METHODS: In this prospective study, 83 newly diagnosed diabetic patients identified at screening in Isfahan, were studied. Height, weight, blood pressure, plasma glucose, lipids, and hemoglobin A1c (HbA1c) of these patients were measured 2 times, first at the time of diagnosis and then 1 year later, and the results were compared between two groups, with and without regular course of treatment. RESULTS: Nearly 46.99% and 53.1% of the studied patients have regular and irregular course of treatment. After 1 year, significant improvement in the mean of plasma glucose, cholesterol, triglyceride, low density lipoprotein (LDL), high density lipoprotein and HbA1c was seen in patients with regular course of treatment except for blood pressure (P < 0.05). Frequency of controlled cardiovascular risk factors including fasting plasma glucose, HbA1c, cholesterol and LDL was significantly improved in patients with regular course of treatment (P < 0.05). Mentioned changes were not seen in patients with irregular course of treatment. CONCLUSIONS: The findings of the current study demonstrated that though diabetes screening program result in earlier diagnosis of patients with type 2 diabetes, but it seems that regular follow-up and proper management of newly diagnosed patients is crucial for appropriate glycemic and metabolic control and preventing its related micro and macrovascular complication. PMID- 25538837 TI - Cardiovascular Risk Factors and Nutritional Intake are not Associated with Ultrasound-defined Increased Carotid Intima Media Thickness in Individuals Without a History of Cardiovascular Events. AB - BACKGROUND: Carotid ultrasound appears to be useful in the assessment of cardiovascular risk. In this study, we have assessed the carotid intima-media thickness (CIMT) in a group of individuals without a history of cardiovascular events. METHODS: A sample of 431subjects (189 [43.9%] males and 242 [56.1%] females) was obtained from an urban population using a stratified-cluster method in Mashhad stroke and heart atherosclerosis disorder study. None of the subjects had a history of the cardiovascular event. Carotid artery duplex ultrasound was used to determine the CIMT in all subjects, and to identify those with an abnormal value (CIMT [+]; i.e., CIMT >= 0.8 mm). Dietary intake of participants was assessed using a questionnaire for 24-h dietary recall. The relationship between anthropometric, biochemical and dietary data and CIMT were assessed. RESULTS: The mean age of subjects was 48.7 +/- 8.0 years. Of the 431 patients, 118 (27.4%) were found to be CIMT (+). Of the cardiovascular parameters assessed, only age (odds ratio [OR] [95% confidence interval (CI)], 1.11 [0.56-4.34]; P < 0.01) and male gender (OR [95% CI], 1.14 [0.63-2.23]; P < 0.05) were significant independent predictors of ultrasound defined CIMT. Crude and total energy adjusted intake were not associated with the presence of CIMT (+). CONCLUSIONS: It appears that within a relatively young Iranian population of individuals without a history of cardiovascular event, the presence of CIMT (+) defined by duplex ultrasound cut-off value of >=0.8 mm, did not associate with several modifiable cardiovascular risk factors or measures of dietary intake. PMID- 25538840 TI - Burden of obstructive lung disease study in tehran: research design and lung spirometry protocol. AB - BACKGROUND: Chronic obstructive pulmonary diseases (COPD) are planned to rank fifth in burden of disease and third with respect to mortality by 2020. Carrying out research regarding different aspects of COPD is mentioned as important health priorities by academic institutions and governments. The burden of lung disease (BOLD) Initiative was designed a decade ago to develop robust models that can be used to estimate the prevalence and current and future economic burden of COPD. The goal of the present project is to describe the prevalence and determining the causes and risk factors of COPD in the population of Tehran city. METHODS: This cross-sectional study follows a stratified cluster sampling strategy with proportional allocation within strata. The target population is all noninstitutionalized inhabitants, aged 18-40 in one group and over 40 in another, who inhabit in Tehran city. The stratification of the sample according to the 22 municipal districts of Tehran is incorporated in the sampling process. Proportional to the number of households in the 22 districts, the appropriate number of clusters is weighted according to each district. For each cluster, a team of three members approaches the index household, which is specified through the aforementioned random selection of clusters, and continues the enumeration in 10 neighbor households in a systematic manner. RESULTS: As a study protocol, there are no specific results to present; our purpose is to share our design with the scientific body. CONCLUSIONS: We expect that findings from the BOLD study in Tehran will show the status of COPD and its causes in the community. PMID- 25538841 TI - Obstructive sleep apnea and postoperative complications in patients undergoing coronary artery bypass graft surgery: a need for preventive strategies. AB - BACKGROUND: Obstructive sleep apnea (OSA) is very frequent and often unrecognized in surgical patients. OSA is associated with perioperative complications. We evaluated the effects of OSA on postoperative complications and hospital outcomes in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: Candidates of elective CABG were evaluated by the Berlin questionnaire for OSA. After surgery, patients were assessed for postoperative complications, re admission to the Intensive Care Unit (ICU), duration of intubation, re intubation, days spent in the ICU and the hospital. RESULTS: We studied 61 patients who underwent CABG from which 25 (40.9%) patients had OSA. Patients with OSA had higher body mass index (29.5 +/- 3.9 vs. 26.0 +/- 3.7 kg/m(2), P = 0.003) and higher frequency of hypertension (68.0% vs. 30.5%, P = 0.003), dyslipidemia (36.0% vs. 5.5%, P = 0.004), and pulmonary disease (16.0 vs. 2.7%, P = 0.08). Regarding the surgical outcomes, OSA patients had longer intubation duration (0.75 +/- 0.60 vs. 0.41 +/- 0.56 days, P = 0.03). CONCLUSIONS: Obstructive sleep apnea is frequent, but unrecognized among patients undergoing CABG. In these patients, OSA is associated with prolonged intubation duration. Preventing these problems may be possible by early diagnosis and management of OSA in cardiac surgery patients. Further studies with larger sample of patients and longer follow-ups are required in this regard. PMID- 25538843 TI - Blood glucose and cholesterol concentrations in a mediterranean rural population of andros island, Greece. AB - BACKGROUND: This study conducted as part of a screening program for the promotion of community health in the primary care setting of Ormos Korthi in Andros, Greece. The objective of this study was to identify the levels of glucose and total cholesterol in individuals without major cardiovascular problems in order to identify cases of undetected dyslipidemia and high blood glucose levels, in a rural population located in the southern part of Andros Island, Greece. METHODS: In total, 242 individuals (152 women, mean age 65.1 +/- 12.3 and range 33-91 years) were examined for the determination of serum glucose and total cholesterol levels. Participants were arbitrarily divided into 5 age groups and statistical differences between groups investigated. RESULTS: The mean serum glucose level was 125.1 +/- 42.4 mg/dl and the mean total serum cholesterol level was 225.2 +/- 44.9 mg/dl. Statistical differences were not observed between the age groups in either the glucose or cholesterol levels. Difference between men and women was not significant regarding glucose levels while women had significantly elevated levels of total cholesterol (P < 0.01). Age was significantly correlated with glucose, but statistical analysis did not show significant correlation between age and total cholesterol levels. CONCLUSIONS: The present study confirms that dyslipidemia and high blood glucose levels are prevalent among the rural populations of Greece and therefore informative campaigns and structured screening programs are required to promote preventive health care. PMID- 25538842 TI - New insight into fat, muscle and bone relationship in women: determining the threshold at which body fat assumes negative relationship with bone mineral density. AB - BACKGROUND: The aim was to investigate the relationships among lean mass (LM), fat mass (FM), and bone mineral density (BMD) in women stratified by body mass index (BMI) (BMI - normal-weight, overweight, obese) and to determine threshold at which body fat assumes negative relationship with BMD. METHODS: This was a cross-sectional study in 471 healthy Caucasian women, aged 18-67 years. BMD, LM, and FM were measured using dual-energy X-ray absorptiometry. Analysis of variance with Bonferroni corrections was used to test the BMI group differences. Linear regression was used to examine independent contributions of LM and FM on BMD of various skeletal sites (controlling for age and height). In overweight/obese women PROC LOESS plots were used to determine the inflection points at which either LM or FM relationship with BMD changes direction. Separate analyses in pre and post-menopausal women were conducted as well. RESULTS: Spine and femoral neck BMD were not different among three BMI groups while total body, femur and radius BMD were statistically different (the highest in the obese group). Linear regression revealed that LM had significant positive association with BMD of various skeletal sites in all groups. FM showed a negative association with BMD of femoral neck and femur in normal-weight and spine in overweight women, but a positive association with radius in obese women. Inflection points showed that body fat between 33% and 38% assumed negative relationship with BMD for most skeletal sites in overweight and obese women. CONCLUSIONS: Although LM has strong positive relationship with BMD, FM above 33% in overweight/obese women is negatively related to BMD of most skeletal sites. Therefore, overweight/obesity after certain amount of FM, may not be a protective factor against osteoporosis in females. For clinical practice in women, it is important to maintain LM and keep FM accrual below ~30% body fat to maintain good skeletal health. PMID- 25538844 TI - Do medical students prefer a career in community medicine? AB - BACKGROUND: Inadequate attention to management and institutional reforms is an important barrier to achieving universal health coverage. Skilled and motivated public health managers in adequate numbers are an important requirement to overcome this hurdle. However, what are the career choices of medical students? Are they interested in Community Medicine and Public Health? To document the career choices of MBBS students and their perceptions toward Community Medicine as a career option. METHODS: A cross sectional survey was carried out among 226 MBBS students (III, V and VII semesters) studying in a tertiary care teaching hospital of South India during July-October 2011. A pre-tested semi-structured questionnaire was used, and information was collected on socio-demographic variables, choice of specialty and reasons for preference. Qualitative content analysis of student feedback was done by categorization and interpretation of data in terms of common themes. RESULTS: Of the 226 available students, 204 (90.3%) students returned the completely filled questionnaires. Of them, 101 (49.5%) were girls. The mean (standard deviation) age of the participants was 20.13 (+/-1.3) years. Almost all (92.1%) wanted to pursue post-graduation in India and Internal medicine was the most preferred career choice (30.9%). The qualitative responses for opinion about Community Medicine as a career choice were interpreted under two themes; those that were favorable and those not so favorable. CONCLUSIONS: There is limited preference for Community Medicine as a career choice. curriculum modification and explanation of career path after post graduation in Community Medicine will help to generate interest in the subject. PMID- 25538846 TI - Diet and food in Iranian traditional medicine: hints for further research. PMID- 25538845 TI - Combating Iron Deficiency Anemia among School Going Adolescent Girls in a Hilly State of North India: Effectiveness of Intermittent Versus Daily Administration of Iron Folic Acid Tablets. AB - BACKGROUND: National surveys in India have documented an increasing number of adolescent girls suffering from anemia. Efforts to build iron stores in adolescent girls will help them improve their prepregnancy hemoglobin level. To assess the effectiveness of school-based supervised weekly, bi-weekly, and daily regimen of iron folic tablets in the treatment of anemia among adolescent girls. METHODS: This randomized clinical trial included 331 anemic school going adolescent girls of Shimla district of North India. Study subjects were randomized to once weekly, bi-weekly, and daily iron folic acid regimen group. An intent-to-treat approach was used to analyze the change in hemoglobin level and serum ferritin levels at the end of the trial period. RESULTS: The rate of change of hemoglobin and serum ferritin levels from baseline to the end of the intervention was found to be similar in all the three groups (P = 0.64 and 0.98 for change in hemoglobin and serum ferritin). Bi-weekly treatment regimen results in comparatively more increase in hemoglobin levels (3.1 g/dl) as compared to once weekly (2.4 g/dl) and daily groups (2.3 g/dl) (ANOVA F statistics = 6.08, P = 0.003). Among the study subjects who reported side effects, more were from daily regimen group (55%) as compared to intermittent regimen group (25% in bi weekly group; 18% in weekly group; P < 0.001). CONCLUSIONS: In Shimla hills of North India, school-based intermittent iron-folic acid therapy is a feasible and effective intervention for increasing hemoglobin and serum ferritin levels of anemic adolescent girls. PMID- 25538847 TI - Comment on: Relationship of Serum Magnesium and Vitamin D Levels in a Nationally representative Sample of Iranian Adolescents: The CASPIAN-III Study. PMID- 25538848 TI - Job satisfaction of primary health care providers: experience from an institution in lima, peru. PMID- 25538849 TI - Analysis of Current Status and Strategies of Retinopathy of Prematurity Screening during 6 Years in Local Regions of China: Implication and Caution. AB - Purpose. To understand the current status of retinopathy of prematurity (ROP) screening in a province of North China. Methods. We retrospectively analyzed 5651 cases with ROP screening in the Provincial Screening Center of Hebei Province from January 2008 to December 2013. Results. 14.98% of all ROP patients and 1.56% of severe ROP patients required treatment. All the severe ROP patients met the criteria of screening. Severe ROP patients were detected at recommended initial screening time (4-6 weeks after birth). The frequency of other ocular diseases was 8.03%, in which the main disease was fundus hemorrhage. In 2665 more mature and unqualified infants, only 2 retinoblastoma and 2 familial exudative vitreoretinopathy were detected, which indicates the advantage of early diagnosis and treatment based on fundus examination. Conclusions. It is suggested that the standard of GA < 32 weeks and/or BW < 1800 g could be served as the screening criteria in the local region for ROP screening. 4 weeks after birth is the most appropriate time for initial screening. PMID- 25538850 TI - An in vitro analysis of the effects of intravenous lipid emulsion on free and total local anaesthetic concentrations in human blood and plasma. AB - Background. Intravenous lipid emulsion (ILE) is recommended as a "rescue" treatment for local anaesthetic (LA) toxicity. A purported mechanism of action suggests that lipophilic LAs are sequestered into an intravascular "lipid-sink," thus reducing free drug concentration. There is limited data available correlating the effects of ILE on LAs. Aims. To compare the in vitro effect of ILE on LA concentrations in human blood/plasma and to correlate this reduction to LA lipophilicity. Method. One of four LAs (bupivacaine-most lipophilic-4 mg/L, ropivacaine-6 mg/L, lignocaine-14 mg/L, and prilocaine-least lipophilic-7 mg/L) was spiked into plasma or whole blood. ILE or control-buffer was added. Plasma was centrifuged to separate ILE and total-LA concentration assayed from the lipid free fraction. Whole blood underwent equilibrium dialysis and free-LA concentration was measured. Percent reduction in LA concentration from control was compared between the LAs and correlated with lipophilicity. Results. ILE caused a significant reduction in total and free bupivacaine concentration compared with the other LAs. Ropivacaine had the least reduction in concentration, despite a lipophilicity similar to bupivacaine. The reduction in LA concentration correlated to increasing lipophilicity when ropivacaine was excluded from analysis. Conclusion. In this first in vitro model assessing both free- and total-LA concentrations exposed to ILE in human blood/plasma, ILE effect was linearly correlated with increasing lipophilicity for all but ropivacaine. PMID- 25538851 TI - Comment on "short-term efficacy of ultramicronized palmitoylethanolamide in peripheral neuropathic pain". PMID- 25538853 TI - Effect of Task Specific Exercises, Gait Training, and Visual Biofeedback on Equinovarus Gait among Individuals with Stroke: Randomized Controlled Study. AB - Background and Purpose. Equinovarus foot is a common sign after stroke. The aim of this study is to investigate the effect of task specific exercises, gait training, and visual biofeedback on correcting equinovarus gait among individuals with stroke. Subjects and Methods. Sixteen subjects with ischemic stroke were randomly assigned to two equal groups (G1 and G2). All the patients were at stage 4 of motor recovery of foot according to Chedoke-McMaster Stroke Assessment without any cognitive dysfunction. E-med pedography was used to measure contact time, as well as force underneath hind and forefoot during walking. Outcome measures were collected before randomization, one week after the last session, and four weeks later. Participants in G1 received task specific exercises, gait training, and visual biofeedback and a traditional physical therapy program was applied for participants in G2 for 8 weeks. Results. Significant improvement was observed among G1 patients (P <= 0.05) which lasts one month after therapy termination. On the other hand, there were no significant differences between measurements of the participants in G2. Between groups comparison also revealed a significant improvement in G1 with long lasting effect. Conclusion. The results of this study showed a positive long lasting effect of the task specific exercises, gait training, and visual biofeedback on equinovarus gait pattern among individuals with stroke. PMID- 25538854 TI - Primary headache in yemen: prevalence and common medications used. AB - Background and Objective. Primary headaches is a major medical concern in certain Arabic countries, for example Oman, Jordan, and Qatar. This study was aimed at increasing understanding of the prevalence of headache in Arabic countries and identifying common medications used for treatment because of the lack of research done in this field in Yemen. Methods. This is a cross-sectional observational study conducted by recruiting case-series of adults and elderly who have primary headache within the age group from 18 to 85 years. 12640 subjects received a simple explanation for the aim of the study as ethical issue. The subjects were allowed to complete a self-conducted screening questionnaire. The data were diagnosed according to the International Headache Society's diagnostic criteria (2004). Results. The results showed that 76.5% of the primary headache is prevalent at least once per year, 27.1% of the tension type headache (TTH) was the maximum percentage of type of headache, and 14.48% of the migraine headache (MH) was the minimum percentage. On the other hand, the relationship between the primary headache and age of subjects was statistically significant (P < 0.05), while between primary headache and sex was not (P > 0.05). In addition, 70.15% of the subjects said that headache attacks affected their activity of daily livings (ADL). 62.26% of the subjects used the medications without medical advice regarding their headache. 37.73% of the subjects relied on medical professionals (physicians and pharmacist) regarding analgesics use. The most common agent used among the medications was paracetamol (38.4%). Others included ibuprofen, aspirin, diclofenac sodium, naproxen, mefenamic acid, ergotamine and (11.45%) were unknown agents. Conclusion. We concluded that absence of health attention from the Yemeni Community and education from the health system in the country regarding analgesics use and their potential risk led to abuse of such medications and could be a reason beyond high prevalence of headache in Yemen. PMID- 25538855 TI - What happens in a 5-year follow-up of benign thyroid nodules. AB - To determine an optimal time for follow-up of benign thyroid nodules, we retrospectively evaluated 249 euthyroid patients with uni-multinodular goiter, who underwent annual visit, and significant events that occurred in 5 years' time were registered. A significant event (appearance of new nodule, increase of nodule diameter >50%, appearance of compressive symptoms, thyroidectomy, repetition of FNA on the same nodule, and execution of FNA on new nodule) occurred in 26.1% of patients, with more than one event occurring in the same patient in 27.7% of cases. The majority of events (71.9%) were observed at 24- and 36-month follow-up visit. These results suggest that a patient diagnosed with benign nodular goiter may be safely followed-up at a 2-3-year interval time. PMID- 25538852 TI - Biomarkers to improve diagnosis and monitoring of obstructive sleep apnea syndrome: current status and future perspectives. AB - Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent episodes of upper airway collapse associated with oxygen desaturation and sleep disruption. It is proposed that these periodic changes lead to molecular variations that can be detected by assessing serum biomarkers. Studies have identified inflammatory, oxidative, and metabolic perturbations attributable to sleep-disordered breathing. Given that OSAS is associated with increased cardiovascular and cerebrovascular morbidity, the ideal biomarker should enable timely recognition with the possibility of intervention. There is accumulating data on the utility of serum biomarkers for the evaluation of disease severity, prognosis, and response to treatment. However, current knowledge is limited by data collection techniques, disease complexity, and potential confounding factors. The current paper reviews the literature on the use of serum biomarkers in OSAS. It is concluded that the ideal serum biomarker still needs to be discovered, while caution is needed in the interpretation of hitherto available results. PMID- 25538856 TI - Effect of Centella asiatica Leaf Extract on the Dietary Supplementation in Transgenic Drosophila Model of Parkinson's Disease. AB - The role of Centella asiatica L. leaf extract was studied on the transgenic Drosophila model flies expressing normal human alpha synuclein (h-alphaS) in the neurons. The leaf extract was prepared in acetone and was subjected to GC-MS analysis. C. asiatica extract at final concentration of 0.25, 0.50, and 1.0 MUL/mL was mixed with the diet and the flies were allowed feeding on it for 24 days. The effect of extract was studied on the climbing ability, activity pattern, lipid peroxidation, protein carbonyl content, glutathione content, and glutathione-S-transferase activity in the brains of transgenic Drosophila. The exposure of extract to PD model flies results in a significant delay in the loss of climbing ability and activity pattern and reduced the oxidative stress (P < 0.05) in the brains of PD flies as compared to untreated PD flies. The results suggest that C. asiatica leaf extract is potent in reducing the PD symptoms in transgenic Drosophila model of Parkinson's disease. PMID- 25538857 TI - Determination of sunset yellow and tartrazine in food samples by combining ionic liquid-based aqueous two-phase system with high performance liquid chromatography. AB - We proposed a simple and effective method, by coupling ionic liquid-based aqueous two-phase systems (IL-ATPSs) with high performance liquid chromatography (HPLC), for the analysis of determining tartrazine and sunset yellow in food samples. Under the optimized conditions, IL-ATPSs generated an extraction efficiency of 99% for both analytes, which could then be directly analyzed by HPLC without further treatment. Calibration plots were linear in the range of 0.01-50.0 MUg/mL for both Ta and SY. The limits of detection were 5.2 ng/mL for Ta and 6.9 ng/mL for SY. This method proves successful for the separation/analysis of tartrazine and sunset yellow in soft drink sample, candy sample, and instant powder drink and leads to consistent results as obtained from the Chinese national standard method. PMID- 25538858 TI - Pathophysiology of Hereditary Angioedema. AB - The genetic deficiency of the C1 inhibitor is responsible for hereditary angioedema (HAE), which is a disease transmitted as an autosomal dominant trait. More than 200 point mutations in the C1 inhibitor gene have been found to be associated with HAE. Patients with this disease suffer from recurrent angioedema, which is mediated by bradykinin derived from activation of the contact system. This system is physiologically controlled at several steps by the C1 inhibitor. In this review, we describe known mechanisms for the development of angioedema in patients with C1 inhibitor deficiency. PMID- 25538859 TI - Critical Review of Clinical Practice Guidelines for Fertility Preservation in Teenagers and Young Adults with Cancer. AB - Purpose: The 5-year survival of teenagers and young adults (TYAs; 13-24 years old) with cancer has continued to rise, but as a result more patients experience late effects of treatment, such as infertility. Advice regarding fertility preservation in relation to cancer is provided in numerous clinical practice guidelines, but the rigor of their development is unclear. Methods: A systematic search was undertaken for clinical practice guidelines regarding fertility preservation in TYAs with cancer. All guidelines were reviewed according to the Appraisal of Guidelines for Research and Evaluation (AGREE-II) criteria. Five out of 13 identified guidelines scored over 75% in the "rigor of development" section and were further appraised. Content, scope, and consistencies between recommendations were also examined. Results: All five of the reviewed guidelines encouraged oncologists to have discussions with their patients about potential fertility issues associated with treatment and available fertility preservation methods. The cryopreservation of sperm, oocytes, and embryos were all recommended as first-line interventions in postpubertal patients. Recommendations surrounding pre- or peripubescent adolescents were few, with many techniques only recommended as part of a clinical trial. The risk of subfertility associated with different treatment regimens was poorly described. Conclusions: The methodology and development of guidelines describing fertility preservation in TYA cancer patients varied greatly. Methodological quality did not clearly influence key recommendations. Those involved with the development of guidelines are encouraged to clearly define their development methods to allow users to be confident of the quality. PMID- 25538860 TI - The Association Between Testis Cancer and Semen Abnormalities Before Orchiectomy: A Systematic Review. AB - Purpose: Testicular germ cell tumors (TGCT) are the most common solid organ malignancy in young men. It is a largely curable disease, so the extent to which it affects quality of life-including male fertility-is important. Abnormal semen analysis is highly predictive of male infertility. We conducted a systematic review of published studies that reported pre-orchiectomy semen parameters (as a surrogate for fertility) in TGCT patients to evaluate the association between TGCT and semen abnormalities before orchiectomy. Methods: We conducted a systematic review of peer-reviewed publications reporting semen parameters before orchiectomy in adult patients diagnosed with TGCT. Further, we assessed the association between TGCT and semen abnormalities that may lead to infertility. Results: We applied MeSH search terms to four online databases (PubMed, Cochrane Reviews, Web of Science, and Ovid), resulting in 701 potentially relevant citations. After conducting a three-stage screening process, six articles were included in the systematic review. For each study, the participants' data and the study's quality and risk of bias were assessed and described. All studies showed semen abnormalities-including count, motility, and morphology-in men with TGCT prior to orchiectomy. Conclusions: TGCT is associated with semen abnormalities before orchiectomy. This review shows an increase in abnormal semen parameters among men with TGCT even outside the treatment effects of orchiectomy, radiation, or chemotherapy. To improve long-term quality of life, these findings should be considered when counseling patients on future fertility and sperm banking during discussions about treatment and prognosis for TGCT. PMID- 25538862 TI - Colorectal Cancer Incidence Among Young Adults in California. AB - Purpose: Colorectal cancer (CRC) incidence has decreased over the past three decades, due largely to screening efforts. Relatively little is known about CRC incidence among the young adult (YA) population ages 20-39, as screening typically commences at age 50 for average-risk individuals. We examined CRC incidence with a focus on YAs in order to identify high-risk subgroups. Methods: We analyzed 231,544 incident CRC cases from 1988-2009 (including 5617 YAs 20-39 years of age) from the California Cancer Registry. We assessed age-specific incidence rates by race/ethnicity, gender, and colorectal tumor location, and calculated the biannual percent change (BAPC) to monitor change in incidence over the 22-year study period. Results: The absolute incidence of CRC per 100,000 was low among YAs 20-29 and 30-39 years old (ranging from 0.7 per 100,000 among Hispanic and African American females aged 20-29 up to 5.0 per 100,000 among Asian/Pacific Islander males aged 30-39). However, we observed increasing CRC incidence rates over time among both males and females in the YA population, particularly for distal colon cancer in Hispanic females aged 20-29 (BAPC=+15.9%; p<0.042). Conclusion: The absolute incidence of CRC remains far lower for YAs than among adults aged 50 and over. However, CRC incidence is increasing among young adults, in contrast to the decreasing rates observed for adults in the screened population (aged 50 and above). More research is needed to better characterize YAs at increased risk for CRC. PMID- 25538861 TI - Management of Concurrent Pregnancy and Acute Lymphoblastic Malignancy in Teenaged Patients: Two Illustrative Cases and Review of the Literature. AB - The usual age range of acute lymphoblastic malignancies (acute lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma) includes teenagers and young adults (<22 years of age) and coincides with the age of fertility. Concurrence of acute lymphoblastic malignancy with pregnancy is therefore most likely to happen during the younger childbearing ages. However, the therapeutic challenges posed by the dual diagnosis of lymphoblastic malignancy and pregnancy have not specifically been studied in the context of age, and management guidelines for pregnant young patients are lacking. Inconsistency in defining the legal decision making rights of pregnant teenaged patients adds a further level of complexity in this age group. Management of this challenging combination in the young patient therefore entails unique ethical considerations. Here we present two illustrative cases of teenage pregnancy complicated by acute lymphoblastic malignancy, review the available literature, and offer suggestions for the therapeutic management of such cases in adolescent and young adult patients. Importantly, practical management recommendations are provided in the context of clinical ethics principles that are universally applicable, including in developing countries, where the highest incidence of adolescent pregnancies has been documented. PMID- 25538863 TI - Cocaine Shifts the Estrus Cycle Out of Phase and Caffeine Restores It. AB - Background: Sex differences in cocaine abuse are well established. Females have a higher sensitivity and thus higher vulnerability to cocaine abuse compared to males. There are many studies showing that sensitivity to cocaine reward varies during the estrus cycle. Methods: Vaginal smears were examined through a DIFF staining kit and viewed through a microscope to determine the estrus cycle stage. Smears were taken immediately before and after cocaine and/or caffeine injections. Furthermore, we suggest a new tool to analyze the estrus cycle by using electrical resistance of the vaginal mucosa. Results: In the present study, we discovered that cocaine directly induced changes in the estrus cycle. Interestingly, caffeine did not affect the estrus cycle and nor did the combination of cocaine and caffeine. We observed that caffeine blocked the cocaine-induced estrus cycle changes using conventional exfoliate cytology. Therefore, caffeine may have neuroprotective properties on the changes induced by cocaine. Conclusion: These phase changes in the estrus cycle may be the underlying cause of sex differences in cocaine addiction that can be blocked by caffeine. Thus, we propose a valuable insight into sex differences in cocaine abuse and reveal a possible treatment with antagonizing the adenosine system. PMID- 25538864 TI - Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A1 and A2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats. AB - Background: Caffeine is the most widely consumed psychoactive substance in the world, even during pregnancy. Its stimulatory effects are mainly due to antagonism of adenosine actions by blocking adenosine A1 and A2A receptors. Previous studies have shown that caffeine can cross the placenta and therefore modulate these receptors not only in the fetal brain but also in the heart. Methods: In the present work, the effect of caffeine chronically consumed during pregnancy on A1 and A2A receptors in Wistar rat heart, from both mothers and their fetuses, were studied using radioligand binding, Western-blotting, and adenylyl cyclase activity assays, as well as reverse transcription polymerase chain reaction. Results: Caffeine did not significantly alter A1R neither at protein nor at gene expression level in both the maternal and fetal heart. On the contrary, A2AR significantly decreased in the maternal heart, although mRNA was not affected. Gi and Gs proteins were also preserved. Finally, A1R-mediated inhibition of adenylyl cyclase activity did not change in the maternal heart, but A2AR mediated stimulation of this enzymatic activity significantly decreased according to the detected loss of this receptor. Conclusions: Opposite to the downregulation and desensitization of the A1R/AC pathway previously reported in the brain, these results show that this pathway is not affected in rat heart after caffeine exposure during pregnancy. In addition, A2AR is downregulated and desensitized in the maternal heart, suggesting a differential modulation of these receptor-mediated pathways by caffeine. PMID- 25538865 TI - The microbes we eat: abundance and taxonomy of microbes consumed in a day's worth of meals for three diet types. AB - Far more attention has been paid to the microbes in our feces than the microbes in our food. Research efforts dedicated to the microbes that we eat have historically been focused on a fairly narrow range of species, namely those which cause disease and those which are thought to confer some "probiotic" health benefit. Little is known about the effects of ingested microbial communities that are present in typical American diets, and even the basic questions of which microbes, how many of them, and how much they vary from diet to diet and meal to meal, have not been answered. We characterized the microbiota of three different dietary patterns in order to estimate: the average total amount of daily microbes ingested via food and beverages, and their composition in three daily meal plans representing three different dietary patterns. The three dietary patterns analyzed were: (1) the Average American (AMERICAN): focused on convenience foods, (2) USDA recommended (USDA): emphasizing fruits and vegetables, lean meat, dairy, and whole grains, and (3) Vegan (VEGAN): excluding all animal products. Meals were prepared in a home kitchen or purchased at restaurants and blended, followed by microbial analysis including aerobic, anaerobic, yeast and mold plate counts as well as 16S rRNA PCR survey analysis. Based on plate counts, the USDA meal plan had the highest total amount of microbes at 1.3 * 10(9) CFU per day, followed by the VEGAN meal plan and the AMERICAN meal plan at 6 * 10(6) and 1.4 * 10(6) CFU per day respectively. There was no significant difference in diversity among the three dietary patterns. Individual meals clustered based on taxonomic composition independent of dietary pattern. For example, meals that were abundant in Lactic Acid Bacteria were from all three dietary patterns. Some taxonomic groups were correlated with the nutritional content of the meals. Predictive metagenome analysis using PICRUSt indicated differences in some functional KEGG categories across the three dietary patterns and for meals clustered based on whether they were raw or cooked. Further studies are needed to determine the impact of ingested microbes on the intestinal microbiota, the extent of variation across foods, meals and diets, and the extent to which dietary microbes may impact human health. The answers to these questions will reveal whether dietary microbes, beyond probiotics taken as supplements-i.e., ingested with food-are important contributors to the composition, inter-individual variation, and function of our gut microbiota. PMID- 25538866 TI - The relative importance of DNA methylation and Dnmt2-mediated epigenetic regulation on Wolbachia densities and cytoplasmic incompatibility. AB - Wolbachia pipientis is a worldwide bacterial parasite of arthropods that infects germline cells and manipulates host reproduction to increase the ratio of infected females, the transmitting sex of the bacteria. The most common reproductive manipulation, cytoplasmic incompatibility (CI), is expressed as embryonic death in crosses between infected males and uninfected females. Specifically, Wolbachia modify developing sperm in the testes by unknown means to cause a post-fertilization disruption of the sperm chromatin that incapacitates the first mitosis of the embryo. As these Wolbachia-induced changes are stable, reversible, and affect the host cell cycle machinery including DNA replication and chromosome segregation, we hypothesized that the host methylation pathway is targeted for modulation during cytoplasmic incompatibility because it accounts for all of these traits. Here we show that infection of the testes is associated with a 55% increase of host DNA methylation in Drosophila melanogaster, but methylation of the paternal genome does not correlate with penetrance of CI. Overexpression and knock out of the Drosophila DNA methyltransferase Dnmt2 neither induces nor increases CI. Instead, overexpression decreases Wolbachia titers in host testes by approximately 17%, leading to a similar reduction in CI levels. Finally, strength of CI induced by several different strains of Wolbachia does not correlate with levels of DNA methylation in the host testes. We conclude that DNA methylation mediated by Drosophila's only known methyltransferase is not required for the transgenerational sperm modification that causes CI. PMID- 25538868 TI - Optimization in the utility maximization framework for conservation planning: a comparison of solution procedures in a study of multifunctional agriculture. AB - Quantitative methods of spatial conservation prioritization have traditionally been applied to issues in conservation biology and reserve design, though their use in other types of natural resource management is growing. The utility maximization problem is one form of a covering problem where multiple criteria can represent the expected social benefits of conservation action. This approach allows flexibility with a problem formulation that is more general than typical reserve design problems, though the solution methods are very similar. However, few studies have addressed optimization in utility maximization problems for conservation planning, and the effect of solution procedure is largely unquantified. Therefore, this study mapped five criteria describing elements of multifunctional agriculture to determine a hypothetical conservation resource allocation plan for agricultural land conservation in the Central Valley of CA, USA. We compared solution procedures within the utility maximization framework to determine the difference between an open source integer programming approach and a greedy heuristic, and find gains from optimization of up to 12%. We also model land availability for conservation action as a stochastic process and determine the decline in total utility compared to the globally optimal set using both solution algorithms. Our results are comparable to other studies illustrating the benefits of optimization for different conservation planning problems, and highlight the importance of maximizing the effectiveness of limited funding for conservation and natural resource management. PMID- 25538867 TI - Arterial spin labeling versus BOLD in direct challenge and drug-task interaction pharmacological fMRI. AB - A carefully controlled study allowed us to compare the sensitivity of ASL (arterial spin labeling) and BOLD (blood oxygen level dependent) fMRI for detecting the effects of the adenosine A2a antagonist tozadenant in Parkinson disease. The study compared the effect of drug directly or the interaction of the drug with a cognitive task. Only ASL detected the direct effect of tozadenant. BOLD was more sensitive to the cognitive task, which (unlike most drugs) allows on-off comparisons over short periods of time. Neither ASL nor BOLD could detect a cognitive-pharmacological interaction. These results are consistent with the known relative advantages of each fMRI method, and suggest that for drug development, directly imaging pharmacodynamic effects with ASL may have advantages over cognitive-pharmacological interaction BOLD, which has hitherto been the more common approach to pharmacological fMRI. PMID- 25538870 TI - Spatial variation in the littoral vertebrate community of a reservoir relative to physical and biological gradients. AB - Reservoirs possess gradients in conditions and resources along their long (deep shallow) axis, but the response of littoral vertebrates (fish and turtles) to these gradients is poorly understood. We have quantified the littoral vertebrate communities throughout a small reservoir in Southeastern Ohio during July and August using traps, and related community composition to environmental variables using NMDS ordination. Ordination revealed that fish and turtles were broadly separated in ordination space, and three distinctly different environmental gradients were significantly associated with the underlying observed species abundances. Observed turtle abundance was explained by measurements of bathymetry, turbidity, and benthic resources, but none of these environmental variables were a reliable predictor of observed fish abundance. Temperature was a poor predictor of observed abundance for both fish and turtles independently, but when fish and turtles were considered together, it became apparent that there were cold areas of the reservoir where observed fish and turtle abundances were different than in other areas of the reservoir. These results suggest that the predictor (environmental) variables we used were appropriate for investigating turtle ecology in reservoirs, but that observed fish abundance is mediated by factors that were not modeled. The efficacy of using traps, the ecological implications of considering fish and turtles together as sympatric and potentially competing species, and directions for future study are discussed. PMID- 25538869 TI - Franz Josef Land: extreme northern outpost for Arctic fishes. AB - The remote Franz Josef Land (FJL) Archipelago is the most northerly land in Eurasia and its fish fauna, particularly in nearshore habitats, has been poorly studied. An interdisciplinary expedition to FJL in summer 2013 used scuba, seines, and plankton nets to comprehensively study the nearshore fish fauna of the archipelago. We present some of the first underwater images for many of these species in their natural habitats. In addition, deep water drop cameras were deployed between 32 and 392 m to document the fish fauna and their associated habitats at deeper depths. Due to its high latitude (79 degrees -82 degrees N), extensive ice cover, and low water temperatures (<0 degrees C much of the year), the fish diversity at FJL is low compared to other areas of the Barents Sea. Sixteen species of fishes from seven families were documented on the expedition, including two species previously unknown to the region. One Greenland shark, Somniosus microcephalus (Somniosidae), ca. 2 m in length, was recorded by drop camera near Hayes Island at 211 m, and Esipov's pout, Gymnelus esipovi (Zoarcidae), was collected at Wilton Island at 15 m in a kelp forest. Including the tape-body pout, Gymnelus taeniatus, described earlier from the sub-littoral zone of Kuhn Island, 17 fish species are now known from FJL's nearshore waters. Species endemic to the Arctic accounted for 75% of the nearshore species observed, followed by species with wider ranges. A total of 43 species from 15 families are known from FJL with the majority of the records from offshore trawl surveys between 110 and 620 m. Resident species have mainly high Arctic distributions, while transient species visit the archipelago to feed (e.g., Greenland shark), and others are brought by currents as larvae and later migrate to spawn grounds in the south (e.g., Atlantic cod Gadus morhua, Capelin Mallotus villosus, Beaked redfish Sebastes mentella). Another species group includes warmer-water fishes that are rare waifs (e.g., Glacier lanternfish Benthosema glaciale, White barracudina Arctozenus rissoi). The rapid warming of the Arctic will likely result in significant changes to the entire ecosystem and this study therefore serves as an important baseline for the nearshore fish assemblages in this unique and fragile region. PMID- 25538871 TI - Comparative analysis of early ontogeny in Bursatella leachii and Aplysia californica. AB - Opisthobranch molluscs exhibit fascinating body plans associated with the evolution of shell loss in multiple lineages. Sea hares in particular are interesting because Aplysia californica is a well-studied model organism that offers a large suite of genetic tools. Bursatella leachii is a related tropical sea hare that lacks a shell as an adult and therefore lends itself to comparative analysis with A. californica. We have established an enhanced culturing procedure for B. leachii in husbandry that enabled the study of shell formation and loss in this lineage with respect to A. californica life staging. PMID- 25538872 TI - Marinobacter hydrocarbonoclasticus NY-4, a novel denitrifying, moderately halophilic marine bacterium. AB - The isolation and characterization of a novel halophilic denitrifying marine bacterium is described. The halophilic bacterium, designated as NY-4, was isolated from soil in Yancheng City, China, and identified as Marinobacter hydrocarbonoclasticus by 16S rRNA gene sequence phylogenetic analysis. This organism can grow in NaCl concentrations ranging from 20 to 120 g/L. Optimum growth occurs at 80 g/L NaCl and pH 8.0. The organism can grow on a broad range of carbon sources and demonstrated efficient denitrifying ability (94.2% of nitrate removal and 80.9% of total nitrogen removal in 48 h). During denitrification by NY-4, no NO2 (-)-N was accumulated, N2 was the only gaseous product and no harmful N2O was produced. Because of its rapid denitrification ability, broad carbon use range and ability to grow under high salinity and pH conditions, NY-4 holds promise for the treatment of saline waste waters. PMID- 25538873 TI - Anemia and growth. PMID- 25538874 TI - Determinants, consequences and prevention of childhood overweight and obesity: An Indian context. AB - The prevalence of obesity in adolescents and children has risen to alarming levels globally, and this has serious public health consequences. Sedentary lifestyle and consumption of calorie-dense foods of low nutritional value are speculated to be two of the most important etiological factors responsible for escalating rate of childhood overweight in developing nations. To tackle the childhood obesity epidemic we require comprehensive multidisciplinary evidence based interventions. Some suggested strategies for childhood obesity prevention and management include increasing physical activity, reducing sedentary time including television viewing, personalized nutrition plans for very obese kids, co-curriculum health education which should be implemented in schools and counseling for children and their parents. In developing countries like India we will need practical and cost-effective community-based strategies with appropriate policy changes in order to curb the escalating epidemic of childhood obesity. PMID- 25538875 TI - Endocrine check-up in adolescents and indications for referral: A guide for health care providers. AB - The American Academy of Pediatrics recommends that young people between the ages of 11 and 21 years should be seen annually by their pediatricians, since annual checkups can be an important opportunity for health evaluation and anticipatory guidance. Parents of infants and young children are accustomed to regularly visiting a pediatrician for their child's checkups. Unfortunately, when children reach the teen years, these annual checkups may decrease in frequency. In routine check-ups and medical office visits, particular attention should be paid to the possibility of a developmental or endocrine disorder. Early diagnosis and treatment may prevent medical complications in adulthood and foster age appropriate development. Our purpose is to acquaint readers with the concept, based on current scientific understanding, that some endocrine disorders may be associated with a wide range of deleterious health consequences including an increased risk of hypertension and hyperlipidemia, increased risk of coronary artery disease, type 2 diabetes, significant anxiety and lack of self-esteem. Understanding the milestones and developmental stages of adolescence is essential for pediatricians and all other health providers who care for adolescents. Treating adolescents involves knowledge of a variety of medical, social and legal information; in addition, close working relationships must be established within the adolescent's network to create an effective care system. In summary, we underline the importance of a periodic endocrine checkup in adolescents in order to identify endocrine problems early and develop an approach to treatment for those patients who need help during this time. Indications for endocrine referral for professional and other healthcare providers are also included. These lists are clearly not intended to be comprehensive, but will hopefully serve as a guide for specific clinical circumstances. PMID- 25538876 TI - Nutrition and pubertal development. AB - Nutrition is one of the most important factors affecting pubertal development. Puberty entails a progressive nonlinear process starting from prepubescent to full sexual maturity through the interaction and cooperation of biological, physical, and psychological changes. Consuming an adequate and balanced healthy diet during all phases of growth (infancy, childhood and puberty) appears necessary both for proper growth and normal pubertal development. Girls begin puberty at an earlier age compared to past decades. Excessive eating of many processed, high-fat foods, may be the cause of this phenomenon. Overweight or obese children are more likely to enter puberty early. Some evidence suggests that obesity can accelerate the onset of puberty in girls and may delay the onset of puberty in boys. Moreover, the progression of puberty is affected by nutrition. On the other hand, puberty triggers a growth spurt, which increases nutritional needs including macro and micronutrients. Increased caloric, protein, iron, calcium, zinc and folate needs have to be provided during this critical period of rapid growth. Severe primary or secondary malnutrition also can delay the onset and progression of puberty. The higher incidence of anorexia nervosa and bulimia in adolescents imposes a nutritional risk on pubertal development. Moreover, many environmental endocrine disruptors (EDs) have been identified that can significantly impair the normal course of puberty. This mini-review sums up some important findings in this important complex that link nutrition and pubertal development. PMID- 25538877 TI - Twins and endocrinology. AB - Twins are two independent babies delivered during the same pregnancy and are divided as monozygotic or dizygotic based on their origin. Dizygotic twins are similar to two siblings and have different genetic information. In contrary, monozygotic twins have a similar genetic identity and provide a unique opportunity to evaluate the contribution of genetic and environmental factors of the disease. The endocrine and metabolic disorders affect a large number of the population including the twins. Diabetes, obesity, and autoimmune thyroid disease are the most common endocrine disorders in general practice. It is essential to understand the genetic basis of endocrine disorders for therapy, prognostication and risk assessment for future generations. In this article, we review the endocrine disorders in relation to their occurrence in monozygotic twins to highlight the genetic and environmental contribution. PMID- 25538879 TI - Pediatric diabetes: Potential for insulin degludec. PMID- 25538878 TI - Advances in pubertal growth and factors influencing it: Can we increase pubertal growth? AB - Puberty is a period of development characterized by partially concurrent changes which includes growth acceleration, alteration in body composition and appearance of secondary sex characteristics. Puberty is characterized by an acceleration and then deceleration in skeletal growth. The initiation, duration and amount of growth vary considerably during the growth spurt. Pubertal growth and biological maturation are dynamic processes regulated by a variety of genetic and environmental factors. Changes in skeletal maturation and bone mineral accretion concomitant with the stage of pubertal development constitute essential components in the evaluation of growth during this pubertal period. Genetic, endocrine and nutritional factors and ethnicity contribute variably to the amount of growth gained during this important period of rapid changes. Many studies investigated the possibility of increasing pubertal growth to gain taller final adult height in adolescents with idiopathic short stature (ISS). The pattern of pubertal growth, its relation to sex maturity rating and factors affecting them has been addressed in this review. The results of different trials to increase final adult height of adolescents using different hormones have been summarized. These data enables Endocrinologists to give in-depth explanations to patients and families about the efficacy and clinical significance as well as the safety of using these therapies in the treatment of adolescents with ISS. PMID- 25538880 TI - Hand X-ray in pediatric endocrinology: Skeletal age assessment and beyond. AB - Skeletal age assessment (SAA) is a clinical procedure which is used in determining the SA of children and adolescents. Bone development is influenced by a number of factors, including nutrition, hormonal secretions, and genetics. There are several factors to be borne in mind when using methods of assessing skeletal maturity. These include: Variability among methods, degree of variability in the estimation of skeletal maturation, sources of low accuracy, and dispersion of the values of skeletal maturation. Currently, the main clinical methods for SAA are the Greulich and Pyle (GP) and Tanner and Whitehouse (TW) methods. The GP method has the advantage of being quick and easy to use. A well trained radiologist takes few minutes to determine the bone age (BA) from a single hand radiograph. The method of TW, however, seems to be more reliable than the GP method. In recent years, the increasing speed in computer sciences and reduction of their cost has given the opportunity to create and use computerized BA estimation system. Despite the fact that the number of automated systems for BAA have increased, most are still within the experimental phase. The use of automated BA determination system, cleared for clinical use in Europe (BoneXpert), has been validated for various ethnicities and children with endocrine disorders. Ultrasound imaging has some limitations that include operator dependence, lower intra-rater and inter-rater reliability of assessment and difficulties with standardization of documentation and imaging transfer. Magnetic resonance imaging (MRI) is noninvasive alternative tool for SA assessment in children. However, few studies have been reported on this topic, and further research is needed to evaluate the reliability and validity of MRI BAAs. In conclusion, at present radiographic methods for the assessment of BA remain the gold standards. Whatever method one adopts, it is essential to minimize the causes of imprecision by taking care to consider the quality of the X-ray. Moreover, it is imperative to assume a correct hand positioning because poor positioning can change the appearance of some bones. It is also preferable to employ scoring methods to these techniques and percentiles rather than BA in years and months. In addition, the possible differences in maturation among different population should be kept in mind. PMID- 25538881 TI - Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations. AB - OBJECTIVES: The objective was to seek evidence on the prevalence and consequences of heterozygous CYP21A2 mutations in girls, adolescent, and adult females with clinical manifestation of androgen excess. PATIENTS AND METHODS: The study included 64 girls diagnosed with premature adrenarche (PA) in childhood and 141 females with clinical hyperandrogenemia manifested in adolescence or adulthood. Direct DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to identify mutations in the CYP21A2 gene. RESULTS: (1) Thirty four patients were diagnosed with nonclassical-congenital adrenal hyperplasia (NC CAH) based on the 17-hydroxyprogesterone (17-OHP) levels and the presence of two mutations in CYP21A2 and therefore were excluded from the study, 66 were found to be heterozygotes and finally 105 had no identifiable mutations. The most frequent mutations among the carriers were the mild p.Val281 Leu and p.Qln318stop. Higher levels of mean stimulated 17-OHP were found in the carriers of the p.Val281 Leu. (2) A notable increased allelic frequency for the known p.Asn493 Ser polymorphism was observed in the pool of females with hyperandrogenemia in whom no mutation was identified. (3) In girls, who presented early with PA, 26.6% were diagnosed with NC-CAH and carried two mutations, 28.7% were identified as heterozygotes 43.7% had no identifiable genetic defect in the translated region of the CYP21A2 gene. On the contrary, in the group of 141 females with late onset hyperandrogenemia, the presence of 2 mutations was detected in 12%, 1 mutation in 33.4% and no mutation in 54.6%. CONCLUSIONS: The carrier status for 21-OHD, may be an important factor in the variable phenotype of hyperandrogenism and may be a contributing factor for the early manifestation of the disease. PMID- 25538882 TI - Does priming with sex steroids improve the diagnosis of normal growth hormone secretion in short children? AB - INTRODUCTION: There is still controversy for priming with sex steroid before growth hormone (GH) testing. OBJECTIVE: We studied GH response to stimulation in 92 children >9 years with idiopathic short stature (height standard deviation score [HtSDS]-2). They were divided randomly into two groups. Children in Group 1 (n = 50) were primed with premarin in girls and testosterone in boys and those in Group 2 were not primed (n = 42). All children were tested using standard clonidine test and their serum insulin-like growth factor-I concentration (IGF I). Additionally the growth and GH-IGF-I data of the two groups of children were compared with those for 32 short children (HtSDS <-2) below the age 9 years who were non-primed before GH testing (Group 3). RESULTS: Neither GH peak response to provocation nor IGF-I concentrations differed between the two groups with and without priming. DISCUSSION: Taking a cut-level of 7 ng/ml for normal GH response to clonidine, priming with sex steroids did not significantly increase the percentage of patients with normal GH response (52%) versus nonpriming (47%). IGF I level did not show any significant difference among the two studied groups >9 years. The peak GH response to clonidine provocation test did not differ before (n = 42) versus after 9 years (n = 32) of age. CONCLUSIONS: In this randomized study priming with sex steroids before GH testing did not significantly increase the yield of diagnosing short patients with normal GH secretion. In addition, GH response to provocation did not vary significantly between young (<9 years) and old (>9 years) short children. PMID- 25538883 TI - Onset of menstrual cycle and menses features among secondary school girls in Italy: A questionnaire study on 3,783 students. AB - PREMISE: Healthcare professionals need updated information about what is the range of "normal" variation of menstrual cycle features to support young girls and their parents in managing reproductive health, and to detect diseases early. MATERIALS AND METHODS: This cross-sectional study aimed to provide an updated picture of age at menarche and main menstrual cycle characteristics and complaints in an Italian population-based sample of 3,783 adolescents attending secondary school. Girls filled in a self-administered anonymous questionnaire including questions about demography, anthropometry, smoking and drinking habits, use of contraceptive, socioeconomic status, age at menarche, menstrual pattern, and physical/psychological menstrual complaints. Mean age at menarche and prevalence of polymenorrhea (cycle length < 21 days), oligomenorrhea (cycle length > 35 days), irregularity, dysmenorrhea, and of physical/psychological complaints were computed. Factors associated with age at menarche and menstrual disturbances were explored by using multiple logistic models. RESULTS: The girls' mean age was 17.1 years (SD 1.4 years) and the mean age at menarche was 12.4 years (SD 1.3 years); menarche occurred with two monthly peaks of frequency in July-September and in December-January (P < 0.0001). Age at menarche was significantly associated with geographic genetics (as expressed by parents' birth area), mother's menarcheal age, BMI, family size, and age at data collection. The prevalence of polymenorrhea was about 2.5%, oligomenorrhea was declared by 3.7%, irregular length by 8.3%, while long bleeding (>6 days) was shown in 19.6% of girls. Gynecological age was significantly associated with cycle length (P < 0.0001) with long cycles becoming more regular within the fourth year after menarche, while frequency of polymenorrhea stabilized after the second gynecological year. Oligomenorrhea and irregularity were both significantly associated with long menstrual bleeding (adjusted OR = 2.36; 95% CI = 1.55-3.60, and adjusted OR = 2.59; 95% CI = 1.95-3.44, respectively). CONCLUSIONS: The findings of the study support the levelling-off of secular trend in menarche anticipation in Italy and confirm the timing in menstrual cycle regularization. The study provides updated epidemiological data on frequency of menstrual abnormalities to help reproductive health professionals in managing adolescent gynecology. PMID- 25538885 TI - Linear growth and endocrine function in children with ataxia telangiectasia. AB - INTRODUCTION: Ataxia telangiectasia (AT) is a rare, genetic, primary immune deficiency disease characterized by immunodeficiency and neurological manifestations, with an increased tendency to infection, malignancy, and autoimmune diseases. Both growth delay and endocrine abnormalities are occasionally reported in these patients. PATIENTS AND METHODS: We studied growth parameters height (Ht), weight, body mass index (BMI) and calculated the Ht standard deviation scores (HtSDS) of 13 patients (age 7.7 +/- 3.5 years-age range: 3-14.5 years) with AT in relation to their mid-parental Ht SDS (MPHtSDS). We measured their serum calcium (Ca), phosphorus (PO4), alkaline phosphatase, alanine transferase (ALT), serum ferritin, creatinine and albumin concentrations. Endocrine investigations included the assessment of serum free thyroxine (FT4), thyrotropin (TSH), insulin-like growth factor-I (IGF-I) and morning cortisol. Complete blood count and serum immunoglobulins (IgG, IgM and IgA antibodies) were also measured. Growth data were correlated to hormonal and immune data. RESULTS: About 31% of patients with AT had short stature (HtSDS <-2). However, their MPHtSDS denoted that their short stature was familial because four out of 13 had MPHtSDS <-2. They had low BMI, and two of them had low serum albumin and IGF-I, denoting malnutrition or disturbed growth hormone secretion. Elevated serum ALT and ferritin in some patients suggest immune-related inflammation in the liver. 30% of patients had high TSH, two of them had low FT4 diagnosing overt (15%) and sub-clinical (15%) hypothyroidism. Anti-thyroid peroxidase antibodies were high in two out of 13 patients denoting immune-related thyroid aggression. Eight out of 13 patients had Vitamin D deficiency (<20 ng/ml) however, their serum Ca and PO4 levels were in the normal range. One adolescent girl (14.5 years) had hyper gonadotropic hypogonadism (low estradiol and high follicle stimulating hormone). All patients had normal 8 AM cortisol and renal function. None of the growth parameters were correlated with the IgG, IgM or IgA levels. IN SUMMARY: Patients with AT had a high prevalence of growth retardation and endocrine dysfunction in the form of low IGF-I, overt and subclinical hypothyroidism and hypogonadism. Physicians should be aware of these possible endocrinopathies for an early diagnosis and proper treatment. PMID- 25538884 TI - Vitamin D deficiency in adolescents. AB - The prevalence of severe vitamin D deficiency (VDD) in adolescents is variable but considerably high in many countries, especially in Middle-east and Southeast Asia. Different factors attribute to this deficiency including lack of sunlight exposure due to cultural dress codes and veiling or due to pigmented skin, and less time spent outdoors, because of hot weather, and lower vitamin D intake. A potent adaptation process significantly modifies the clinical presentation and therefore clinical presentations may be subtle and go unnoticed, thus making true prevalence studies difficult. Adolescents with severe VDD may present with vague manifestations including pain in weight-bearing joints, back, thighs and/or calves, difficulty in walking and/or climbing stairs, or running and muscle cramps. Adaptation includes increased parathormone (PTH) and deceased insulin like growth factor-I (IGF-I) secretion. PTH enhances the tubular reabsorption of Ca and stimulates the kidneys to produce 1, 25-(OH) 2D3 that increases intestinal calcium absorption and dissolves the mineralized collagen matrix in bone, causing osteopenia and osteoporosis to provide enough Ca to prevent hypocalcaemia. Decreased insulin like growth factor-I (IGF-I) delays bone growth to economize calcium consumption. Radiological changes are not uncommon and include osteoporosis/osteopenia affecting long bones as well as vertebrae and ribs, bone cysts, decalcification of the metaphysis of the long bones and pseudo fractures. In severe cases pathological fractures and deformities may occur. Vitamin D treatment of adolescents with VDD differs considerably in different studies and proved to be effective in treating all clinical, biochemical, and radiological manifestations. Different treatment regiments for VDD have been discussed and presented in this mini-review for practical use. Adequate vitamin D replacement after treating VDD, improving calcium intake (milk and dairy products), encouraging adequate exposure to the sun and possible enrichment of the stable food with vitamin D in areas with high prevalence of VDD are important measures to prevent the harmful consequences of VDD. PMID- 25538886 TI - Agenesis and not ectopia is common in North Indian children with thyroid dysgenesis. AB - CONTEXT: Ectopic Thyroid Gland (ETG) is known to be the most common form of thyroid dysgenesis in children with permanent congenital hypothyroidism (CH). Recent reports indicate that agenesis or hypoplasia of thyroid gland may be commoner as compared to ETG in thyroid dysgenesis (TD). There is limited information available on the proportion of different variants of TD in Indian children. AIM: To characterize the different TD variants in a cohort of North Indian children with TD. SETTINGS AND DESIGN: Endocrinology Unit of a large Multispecialty Pediatrics Center located in North India. Retrospective review of clinical records of children with CH due to TD diagnosed between April 2004 and March 2014. RESULTS: Diagnoses of TD in 94 children (48 boys and 46 girls) were based on combined scanning with high-resolution ultrasonography, and technetium 99m pertechnetate thyroid scintigraphy. Thyroid agenesis, ectopia and hypoplasia were diagnosed in 74 (78.7%), 14 (14.8%) and 6 (6.4%) patients respectively. The mean initial serum total T4 and thyroid stimulating hormone concentrations at diagnosis were 3.03 +/- 2.88 MUg/dL (range 0.01-8.9) and 284.52 +/- 300.67 mIU/L (range 10.03-1159.0) respectively. Patients with ETG were older at the time of diagnosis as compared to patients with hypoplasia or ectopia. The mean duration of follow-up was 3.7 +/- 2.85 years (range 3 months-10 years). CONCLUSIONS: Thyroid agenesis was the most common form of TD in our children with permanent CH. Hypoplasia and ectopia were uncommon. Female preponderance, noted in many previous reports, was not seen in our patients with TD. PMID- 25538888 TI - Toward an improved understanding of the ionizing radiation induced DNA damage/response networks in human malignancies. PMID- 25538887 TI - Promising targets and current clinical trials in metastatic squamous cell lung cancer. AB - Squamous cancer of the lung (SQCC), although no longer the premier variant of non small cell lung cancer, continues to impose a heavy world-wide burden. Advanced SQCC has enjoyed little of the recent progress benefiting patients with adenocarcinoma of the lung, but that has now begun to change. This article reviews the underlying molecular pathology of SQCC, as well as potential new targets and the corresponding novel targeted agents; included are some of which may soon be approvable in this notoriously hard-to-treat indication. PMID- 25538889 TI - Altered Transcriptional Control Networks with Trans-Differentiation of Isogenic Mutant-KRas NSCLC Models. AB - BACKGROUND: The capacity of cancer cells to undergo epithelial mesenchymal trans differentiation has been implicated as a factor driving metastasis, through the acquisition of enhanced migratory/invasive cell programs and the engagement of anti-apoptotic mechanisms promoting drug and radiation resistance. Our aim was to define molecular signaling changes associated with mesenchymal trans differentiation in two KRas mutant NSCLC models. We focused on central transcription and epigenetic regulators predicted to be important for mesenchymal cell survival. EXPERIMENTAL DESIGN: We have modeled trans-differentiation and cancer stemness in inducible isogenic mutant-KRas H358 and A549 non-small cell lung cell backgrounds. As expected, our models show mesenchymal-like tumor cells acquire novel mechanisms of cellular signaling not apparent in their epithelial counterparts. We employed large-scale quantitative phosphoproteomic, proteomic, protein-protein interaction, RNA-Seq, and network function prediction approaches to dissect the molecular events associated with the establishment and maintenance of the mesenchymal state. RESULTS: Gene-set enrichment and pathway prediction indicated BMI1, KDM5B, RUNX2, MYC/MAX, NFkappaB, LEF1, and HIF1 target networks were significantly enriched in the trans-differentiation of H358 and A549 NSCLC models. Physical overlaps between multiple networks implicate NR4A1 as an overlapping control between TCF and NFkappaB pathways. Enrichment correlations also indicated marked decrease in cell cycling, which occurred early in the EMT process. RNA abundance time course studies also indicated early expression of epigenetic and chromatin regulators within 8-24 h, including CITED4, RUNX3, CMBX1, and SIRT4. CONCLUSION: Multiple transcription and epigenetic pathways where altered between epithelial and mesenchymal tumor cell states, notably the polycomb repressive complex-1, HP1gamma, and BAF/Swi-Snf. Network analysis suggests redundancy in the activation and inhibition of pathway regulators, notably factors controlling epithelial cell state. Through large-scale transcriptional and epigenetic cell reprograming, mesenchymal trans differentiation can promote diversification of signaling networks potentially important in resistance to cancer therapies. PMID- 25538890 TI - Non-canonical notch signaling in cancer and immunity. AB - Canonical Notch signaling is initiated by gamma-secretase-mediated cleavage of the Notch receptor, leading to the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-Jkappa, resulting in the activation of downstream target genes. While canonical Notch signaling is well known to play an active role in several steps during development as well in multiple cell fate decisions, recent evidence from both invertebrate and vertebrate systems indicates that non-canonical, RBP-Jkappa-independent signaling is important in several cellular processes including oncogenesis and activation of T lymphocytes. These observations raise the possibility that, through an understanding of non-canonical Notch signaling, novel strategies for inhibiting Notch signaling may prove useful in the design of therapies targeted to block aberrant Notch activity. In this mini-review, we will examine the current data demonstrating a non-canonical role for Notch signaling in both cancer and the immune system and suggest a better understanding of non-canonical signaling may reveal novel strategies to block Notch signaling in disease. PMID- 25538891 TI - Cardiovascular toxicities from systemic breast cancer therapy. AB - Cardiovascular toxicity is unfortunately a potential short- or long-term sequela of breast cancer therapy. Both conventional chemotherapeutic agents such as anthracyclines and newer targeted agents such as trastuzumab can cause varying degrees of cardiac dysfunction. Type I cardiac toxicity is dose-dependent and irreversible, whereas Type II is not dose-dependent and is generally reversible with cessation of the drug. In this review, we discuss what is currently known about the cardiovascular effects of systemic breast cancer treatments, with a focus on the putative mechanisms of toxicity, the role of biomarkers, and potential methods of preventing and minimizing cardiovascular complications. PMID- 25538894 TI - EGFR Mutation Positive Stage IV Non-Small-Cell Lung Cancer: Treatment Beyond Progression. AB - Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men and women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10-15% in Western countries, epidermal growth factor receptor (EGFR) mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper, we present three patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing. PMID- 25538893 TI - Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate during pathological conditions such as cancer and are associated with a poor clinical outcome. MDSC expansion hampers the host anti-tumor immune response by inhibition of T cell proliferation, cytokine secretion, and recruitment of regulatory T cells. In addition, MDSC exert non-immunological functions including the promotion of angiogenesis, tumor invasion, and metastasis. Recent years, MDSC are considered as a potential target in solid tumors and hematological malignancies to enhance the effects of currently used immune modulating agents. This review focuses on the characteristics, distribution, functions, cell-cell interactions, and targeting of MDSC in hematological malignancies including multiple myeloma, lymphoma, and leukemia. PMID- 25538892 TI - Myeloid-derived suppressor cells in multiple myeloma: pre-clinical research and translational opportunities. AB - Immunosuppressive cells have been reported to play an important role in tumor progression mainly because of their capability to promote immune-escape, angiogenesis, and metastasis. Among them, myeloid-derived suppressor cells (MDSCs) have been recently identified as immature myeloid cells, induced by tumor associated inflammation, able to impair both innate and adaptive immunity. While murine MDSCs are usually identified by the expression of CD11b and Gr1, human MDSCs represent a more heterogeneous population characterized by the expression of CD33 and CD11b, low or no HLA-DR, and variable CD14 and CD15. In particular, the last two may alternatively identify monocyte-like or granulocyte-like MDSC subsets with different immunosuppressive properties. Recently, a substantial increase of MDSCs has been found in peripheral blood and bone marrow (BM) of multiple myeloma (MM) patients with a role in disease progression and/or drug resistance. Pre-clinical models recapitulating the complexity of the MM-related BM microenvironment (BMM) are major tools for the study of the interactions between MM cells and cells of the BMM (including MDSCs) and for the development of new agents targeting MM-associated immune-suppressive cells. This review will focus on current strategies for human MDSCs generation and investigation of their immunosuppressive function in vitro and in vivo, taking into account the relevant relationship occurring within the MM-BMM. We will then provide trends in MDSC associated research and suggest potential application for the treatment of MM. PMID- 25538895 TI - Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity. AB - Compared to the overwhelming amount of literature describing how epithelial-to mesenchymal transition (EMT)-inducing transcription factors orchestrate cellular plasticity in embryogenesis and epithelial cells, the functions of these factors in non-epithelial contexts, such as melanoma, are less clear. Melanoma is an aggressive tumor arising from melanocytes, endowed with unique features of cellular plasticity. The reversible phenotype-switching between differentiated and invasive phenotypes is increasingly appreciated as a mechanism accounting for heterogeneity in melanoma and is driven by oncogenic signaling and environmental cues. This phenotypic switch is coupled with an intriguing and somewhat counterintuitive signaling switch of EMT-inducing transcription factors. In contrast to carcinomas, different EMT-inducing transcription factors have antagonizing effects in melanoma. Balancing between these different EMT transcription factors is likely the key to successful metastatic spread of melanoma. PMID- 25538896 TI - Structure and function of thyroid hormone plasma membrane transporters. AB - Thyroid hormones (TH) cross the plasma membrane with the help of transporter proteins. As charged amino acid derivatives, TH cannot simply diffuse across a lipid bilayer membrane, despite their notorious hydrophobicity. The identification of monocarboxylate transporter 8 (MCT8, SLC16A2) as a specific and very active TH transporter paved the way to the finding that mutations in the MCT8 gene cause a syndrome of psychomotor retardation in humans. The purpose of this review is to introduce the current model of transmembrane transport and highlight the diversity of TH transmembrane transporters. The interactions of TH with plasma transfer proteins, T3 receptors, and deiodinase are summarized. It is shown that proteins may bind TH owing to their hydrophobic character in hydrophobic cavities and/or by specific polar interaction with the phenolic hydroxyl, the aminopropionic acid moiety, and by weak polar interactions with the iodine atoms. These findings are compared with our understanding of how TH transporters interact with substrate. The presumed effects of mutations in MCT8 on protein folding and transport function are explained in light of the available homology model. PMID- 25538898 TI - Spontaneous abortion, stillbirth and hyperthyroidism: a danish population-based study. AB - OBJECTIVES: Pregnancy loss in women suffering from hyperthyroidism has been described in case reports, but the risk of pregnancy loss caused by maternal hyperthyroidism in a population is unknown. We aimed to evaluate the association between maternal hyperthyroidism and pregnancy loss in a population-based cohort study. STUDY DESIGN: All pregnancies in Denmark from 1997 to 2008 leading to hospital visits (n = 1,062,862) were identified in nationwide registers together with information on maternal hyperthyroidism for up to 2 years after the pregnancy [hospital diagnosis/prescription of antithyroid drug (ATD)]. The Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence interval (CI) for spontaneous abortion (gestational age <22 weeks) and stillbirth (>=22 weeks), reference: no maternal thyroid dysfunction. RESULTS: When maternal hyperthyroidism was diagnosed before/during the pregnancy (n = 5,229), spontaneous abortion occurred more often both in women treated before the pregnancy alone [aHR 1.28 (95% CI 1.18-1.40)] and in women treated with ATD in early pregnancy [1.18 (1.07-1.31)]. When maternal hyperthyroidism was diagnosed and treated for the first time in the 2-year period after the pregnancy (n = 2,361), there was a high risk that the pregnancy under study had terminated with a stillbirth [2.12 (1.30-3.47)]. CONCLUSIONS: Both early (spontaneous abortion) and late (stillbirth) pregnancy loss were more common in women suffering from hyperthyroidism. Inadequately treated hyperthyroidism in early pregnancy may have been involved in spontaneous abortion, and undetected high maternal thyroid hormone levels present in late pregnancy may have attributed to an increased risk of stillbirth. PMID- 25538897 TI - Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup. AB - A thyroid incidentaloma is an unexpected, asymptomatic thyroid tumor fortuitously discovered during the investigation of an unrelated condition. The prevalence rate is 67% with ultrasonography (US) imaging, 15% with computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, and 1-2% with fluorodeoxyglucose (FDG) positron emission tomography. In the absence of a history of external beam radiation or familial medullary thyroid cancer, the risk of malignancy ranges between 5 and 13% when discovered with US, CT or MRI, but is much higher if based on focal FDG uptake (30%). All patients with a thyroid incidentaloma, independent of the mode of detection, should undergo a dedicated neck US with risk stratification: US imaging allows a quantitative risk stratification of malignancy in thyroid nodules, named 'reporting system' or 'TIRADs' (thyroid imaging reporting and data system). The reported sensitivity ranges from 87 to 95% for the detection of carcinomas and the negative predictive value from 88 to 99.8%. We suggest that the indications for fine-needle aspiration be based mainly on size and US risk stratification. However, the diagnosis and workup of thyroid incidentalomas leads to superfluous surgery for benign conditions, and excess diagnosis and treatment of papillary microcarcinomas, the vast majority of which would cause no harm. Recognizing this must form the basis of any decision as to supplementary investigations and whether to offer therapy, in a close dialogue between patient and physician. The current use of minimally invasive nonsurgical ablation options, as alternatives to surgery, is highlighted. PMID- 25538899 TI - Anxiety and depression are more prevalent in patients with graves' disease than in patients with nodular goitre. AB - BACKGROUND AND OBJECTIVE: Graves' disease has been associated with an increased psychiatric morbidity. It is unclarified whether this relates to Graves' disease or chronic disease per se. The aim of our study was to estimate the prevalence of anxiety and depression symptoms in patients with Graves' disease compared to patients with another chronic thyroid disease, nodular goitre, and to investigate determinants of anxiety and depression in Graves' disease. METHODS: 157 cross sectionally sampled patients with Graves' disease, 17 newly diagnosed, 140 treated, and 251 controls with nodular goitre completed the Hospital Anxiety and Depression Scale (HADS). The differences in the mean HADS scores between the groups were analysed using multiple linear regression, controlling for socio demographic variables. HADS scores were also analysed dichotomized: a score >10 indicating probable 'anxiety'/probable 'depression'. Determinants of anxiety and depression symptoms in Graves' disease were examined using multiple linear regression. RESULTS: In Graves' disease levels of anxiety (p = 0.008) and depression (p = 0.014) were significantly higher than in controls. The prevalence of depression was 10% in Graves' disease versus 4% in nodular goitre (p = 0.038), anxiety was 18 versus 13% (p = 0.131). Symptoms of anxiety (p = 0.04) and depression (p = 0.01) increased with comorbidity. Anxiety symptoms increased with duration of Graves' disease (p = 0.04). Neither thyroid function nor autoantibody levels were associated with anxiety and depression symptoms. CONCLUSIONS: Anxiety and depression symptoms were more severe in Graves' disease than in nodular goitre. Symptoms were positively correlated to comorbidity and duration of Graves' disease but neither to thyroid function nor thyroid autoimmunity. PMID- 25538900 TI - Challenges in the evaluation of urinary iodine status in pregnancy: the importance of iodine supplement intake and time of sampling. AB - OBJECTIVES: Median urinary iodine concentration (UIC) is the recommended method to evaluate iodine status in pregnancy, but several factors may challenge the interpretation of the results. We evaluated UIC in pregnant women according to (1) sampling in the hospital versus at home, (2) time of the most recent iodine supplement intake prior to sampling, and (3) members of their household. STUDY DESIGN: Danish cross-sectional study in the year 2012. Pregnant women (n = 158), their male partners (n = 157) and children (n = 51) provided a questionnaire with detailed information on iodine supplement intake and a spot urine sample obtained in the hospital and/or at home for measurement of UIC and urinary creatinine concentration. RESULTS: In the pregnant women providing a urine sample both in the hospital and at home (n = 66), individual UIC (p = 0.002) and urinary creatinine concentration (p = 0.042), but not estimated 24-hour urinary iodine excretion (p = 0.79), were higher when sampling was at home. Median UIC was dependent on the time of the most recent iodine supplement intake prior to sampling [same day (n = 79): 150 ug/l (95% CI 131-181 ug/l), the day before (n = 51): 105 ug/l (78-131 ug/l), several days ago/non-user (n = 28): 70 ug/l (56-94 ug/l), p < 0.001]. The pattern was similar in the male partners. Apart from a more frequent iodine supplement intake in pregnancy (87.3% vs. partners 15.9%), no systematic differences were observed in urinary measurements between the pregnant women and their partners. CONCLUSIONS: Time of spot urine sampling and time span from iodine supplement intake to spot urine sampling should be considered when evaluating urinary iodine status in pregnancy. PMID- 25538901 TI - Environmental, lifestyle, and anthropometric risk factors for differentiated thyroid cancer in cuba: a case-control study. AB - BACKGROUND: The incidence of differentiated thyroid carcinoma (DTC) is low in people of African origin and higher in populations living on islands, but there is no well-established explanation for these differences. Cuba is a multiethnic nation with people of African and Spanish descent. Until now, no study on the risk factors of DTC has focused on the Cuban population. Our aim is to establish the role of environmental and lifestyle factors and to relate anthropometric measurements to the risk of developing DTC in Cuba. METHODS: We performed a case control study of 203 DTC patients treated in two hospitals in Havana and 212 controls living in the area covered by these hospitals (i.e. parts of Havana and the municipality of Jaruco). Risk factors were analyzed using conditional logistic regression. RESULTS: As has been shown by other studies, we found that non-African ethnicity, never smoking, parity, and high body mass index are risk factors significantly associated with DTC, whereas a history of exposure to ionizing radiation and level of education were not significantly related with disease development. Being rhesus factor-positive, having a personal history of benign thyroid disorder, agricultural occupation, and consumption of artesian well water were also associated with a significantly increased risk of developing DTC. CONCLUSIONS: The original findings reported here concern the risk of DTC that was associated with non-African ethnicity, positive rhesus factor, farming, and drinking water from an artesian well. PMID- 25538903 TI - Small lymphocytic lymphoma of the thyroid mimicking plasmacytoma. AB - Primary thyroid gland lymphomas (PTLs) typically occur in middle-to older-aged individuals in the setting of lymphocytic thyroiditis with a predilection for females. Diffuse large B-cell lymphoma is the most frequent histologic subtype of thyroid lymphomas. Small lymphocytic lymphoma (SLL) belongs to the least common subtypes of thyroid lymphoma. It is often associated with the involvement of lymph nodes, bone marrow, spleen, liver and, extremely rarely, other organs. PTLs with plasmacytic differentiation or extensive infiltration by plasma cells have been observed in marginal zone B-cell lymphomas in the thyroid but have never been described in a setting of SLL. Here, we present a case of primary SLL of the thyroid mimicking extramedullary plasmacytoma on fine-needle aspiration cytology. PMID- 25538902 TI - Evolution of differentiated thyroid cancer: a decade of thyroidectomies in a single institution. AB - BACKGROUND: Numerous studies have shown an increase in the incidence of thyroid cancer (TC) in recent years. OBJECTIVES: In this paper, we reviewed the incidence of TC in a series of patients undergoing thyroid surgery at a single institution over a 10-year period. PATIENTS AND METHODS: The cohorts were divided into two periods (2001-2005 and 2006-2010) with the purpose of comparing various clinicopathologic variables. RESULTS: A total of 1,263 patients were included. A significant increase in the number of malignancies was shown in the second period, namely 90 cases in 2001-2005 (15.2% of all interventions) compared to 163 cases in 2006-2010 (24.3%) (p < 0.001). These differences were attributed to an increase in papillary thyroid carcinoma (PTC), as there were 66 PTC cases in the first period (11.13% of thyroidectomies performed) compared to 129 cases in the second period (19.25%). There were no clinicohistological differences among PTC cases in these two periods. CONCLUSIONS: Over the last decade, there has been an increase in the incidence of TC in patients undergoing thyroid surgery. This increase is exclusively due to increases in PTC. Our study verifies the existence of this trend in our geographical area, similar to that noted in other parts of the world. PMID- 25538904 TI - Myasthenic Crisis Manifesting as Postoperative Respiratory Failure following Resection of Unsuspected Intrathoracic Thymic T-Cell Lymphoma during Thyroidectomy for an Adjacent Large Retrosternal Goiter. AB - A middle-aged female with a goiter of 10 years' duration presented with progressive pressure symptoms, nocturnal choking and dyspnea on exertion for 5 months. Physical examination demonstrated a large simple multinodular goiter. Imaging revealed a deep retrosternal goiter extending below the tracheal bifurcation with marked tracheal deviation. Total thyroidectomy was carried out via a cervical approach and a median sternotomy. Extubation was not possible, and the patient had to be kept intubated. She then went into a myasthenic crisis. Initial ventilatory support was followed by intravenous immunoglobulin, steroids and pyridostigmine. The patient had complete remission and was asymptomatic 18 months later. Histopathology showed a T-cell-rich thymoma in addition to a nodular colloid goiter. PMID- 25538905 TI - Playing hide-and-seek with host macrophages through the use of mycobacterial cell envelope phthiocerol dimycocerosates and phenolic glycolipids. AB - Mycobacterial pathogens, including Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), have evolved a remarkable ability to evade the immune system in order to survive and to colonize the host. Among the most important evasion strategies is the capacity of these bacilli to parasitize host macrophages, since these are major effector cells against intracellular pathogens that can be used as long-term cellular reservoirs. Mycobacterial pathogens employ an array of virulence factors that manipulate macrophage function to survive and establish infection. Until recently, however, the role of mycobacterial cell envelope lipids as virulence factors in macrophage subversion has remained elusive. Here, we will address exclusively the proposed role for phthiocerol dimycocerosates (DIM) in the modulation of the resident macrophage response and that of phenolic glycolipids (PGL) in the regulation of the recruitment and phenotype of incoming macrophage precursors to the site of infection. We will provide a unique perspective of potential additional functions for these lipids, and highlight obstacles and opportunities to further understand their role in the pathogenesis of TB and other mycobacterial diseases. PMID- 25538906 TI - Does disk space degeneration according to Los Angeles and Modic scales have relation with recurrent disk herniation? AB - BACKGROUND: After single disk herniation operation, about 5-20% recurrences may occur. Different etiology may affect the prevalence of recurrence. Disk degeneration according to Modic and Los Angles scales could affect recurrence rate. This study wants to show the relationship between disk space degeneration according to these scales on severity, time, and prevalence of disk herniation recurrence. MATERIALS AND METHODS: Thirty-four patients presented with radicular pain (with or without back pain) and history of lumbar disk surgery was included in this prospective study. Pre- and postoperative T2-weighted sagittal magnetic resonance imaging (MRI) compared for Modic and Los Angeles disk degeneration grading, then, data analysis on SPSS (version 20) software, paired t-test, and others. RESULTS: The result of study shows for first operation that grade (II) Los Angeles is the most common, but, for second procedure grade (IV) was less common and the mostly decreased (from 14.7 to 9.2%). In addition, Wilcoxon test shows no change of Los Angeles grading for both first and second surgery (P = 0.06). Whereas; based on Modic criteria grading was different from first operation, in other words, grade (I) (41.2%) in first operation was changed to 20.6% in second operation (P = 0.007). CONCLUSION: Our study showed that the Los Angeles criterion is more practical and useful for prediction of recurrence and in the patients with Los Angles grade III and IV and grade II and III on Modic scale, the chance of recurrence is less than patients with lower grades. PMID- 25538907 TI - Corneal haze and visual outcome after collagen crosslinking for keratoconus: A comparison between total epithelium off and partial epithelial removal methods. AB - BACKGROUND: Keratoconus is an asymmetric, bilateral, progressive noninflammatory ectasia of the cornea that affects approximately 1 in 2000 of the general population. This may cause a significant negative impact on quality of life. Corneal collagen crosslinking (CXL) is one of the recently introduced methods that have been used to decrease the progression of keratoconus, in particular, as well as other corneal-thinning processes. MATERIALS AND METHODS: A total of 44 keratoconic eyes of 22 patients were enrolled in this randomized prospective study, after obtaining informed consent. In the first group, the corneal epithelium were totally removed and in the second group, the central 3 mm of epithelium was kept intact and partial removal was performed. After collagen crosslinking in both groups, comprehensive ophthalmologic examination was performed on all patients before and 6 months after the surgery. This article is registered at www.clinicaltrial.gov with registration number NCT01809977. RESULTS: The difference between the two groups was not statistically significant regarding postoperative corneal haziness, refraction, and visual acuity (P > 0.05). However, comparison of pre- and postoperative parameters within each group revealed that total removal of the cornea has resulted in significant improvement of K-max (P value: 0.01) and Q-value (P value: 0.009); while eyes in partial removal group had better improvement of corrected vision (P value: 0.006). Both methods had significant and similar increase in optical corneal density (P < 0.0001). CONCLUSION: In our study, keeping the central corneal epithelium intact was not beneficial for decreasing corneal haziness, however, this method caused better improvement in corrected vision. Total epithelium off technique resulted in better improvement of K-max and Q-value. PMID- 25538908 TI - Effect of acute hypoxia on CXCR4 gene expression in C57BL/6 mouse bone marrow derived mesenchymal stem cells. AB - BACKGROUND: One of the most important stimuli in stem cell biology is oxygen. Chemokine receptor 4 (CXCR4) plays a crucial role in the migration and homing of stem cells. In this study, mesenchymal stem cells (MSCs) were exposed to 1% oxygen to investigate the effect of acute hypoxia on CXCR4 gene expression. MATERIALS AND METHODS: MSCs were isolated from C57BL/6 mouse bone marrow and were identified and expanded in normoxic culture. Cells were incubated at 37 degrees C under 1% hypoxic conditions for periods of 4, 8, 16, 24, and 48 h. After hypoxia preconditioning, the cells were placed in normoxic condition for 8 h to achieve cellular hypoxia-reoxygenation. To assess the level of CXCR4 gene expression, real-time quantitative reverse transcription-polymerase chain reaction was carried out for each group. RESULTS: Data from statistical analysis illustrated that exposure of MSCs to acute hypoxic condition down-regulates CXCR4 expression with the maximum under-expression observed in 4 h (0.91 +/- 0.107) and 8 h (50 +/ 2.98) groups. Moreover, the relative gene expression of CXCR4 was decreased after hypoxia-reoxygenation by more than 80% in 4 h (0.136 +/- 0.018) and 24 h (12.77 +/- 0.707) groups. CONCLUSION: The results suggest that CXCR4 expression in MSCs decreases upon acute hypoxic stress. Furthermore, hypoxia-reoxygenated MSCs showed decreased expression of CXCR4, compared to cells subjected to acute hypoxia. This difference could have resulted from the cells being compatible with low oxygen metabolism. In summary, before the therapeutic application of MSCs, it should be regarded as a necessity to optimize the oxygen concentration in these cells, as it is a critical factor in modulating CXCR4 expression. PMID- 25538909 TI - Correlation of serum neutrophil gelatinase associated lipocalin with disease severity in hypertensive disorders of pregnancy. AB - BACKGROUND: Vascular endothelial dysfunction is considered central to the pathogenesis of hypertensive disorders of pregnancy (HDP). Serum level of neutrophil gelatinase-associated lipocalin (NGAL) is closely related to endothelial injury. The aim of this study was to examine the correlation of serum NGAL with disease severity in HDP. MATERIALS AND METHODS: This prospective case control study was carried out for one year. After informed consent, ethical clearance, total 1,850 pregnant women were screened. Analysis was performed on 142 cases of HDP and 31 healthy controls. Quantitative measurement of serum NGAL levels was done by the enzyme linked immunosorbent assay (ELISA) technique, by using sandwich ELISA kit. RESULTS: Mean serum NGAL value in patients with oliguria was significantly higher when compared with non-oliguric patients (P < 0.001). Serum NGAL had a positive correlation with systolic blood pressure (r ~ 0.5973), diastolic blood pressure (r ~ 0.6195), blood urea (r ~ 0.4392), serum creatinine (r ~ 0.6112), serum uric acid (r ~ 0.3878). Sensitivity and specificity of serum NGAL using a cut-off value of 545 pg/ml, for the diagnosis of HDP, was 97.89% and 93.55% respectively, using 95% confidence interval. CONCLUSION: Between the two groups, we found that serum NGAL had a positive correlation with disease severity and better sensitivity and specificity in the evaluation of HDP. PMID- 25538911 TI - Primary actinomycosis of hand. AB - Actinomycosis is a chronic granulomatous suppurative disease having the propensity for extension to the contagious tissue with the formation of multiple discharging sinus tracts. Primary actinomycosis of extremity is a very uncommon clinical entity and is commonly considered as a soft-tissue infection. We report here, a case of primary actinomycosis of the upper extremity in a 24-year-old male who was treated successfully with surgical excision and extended period of antimicrobial treatment. PMID- 25538910 TI - Some side effects and effcts on physical activity of second-generation antipsychotics: A study in children and adolescents. AB - BACKGROUND: This study was designed to investigate the metabolic adverse effects (AEs) of second-generation antipsychotics (SGAs) and their relationship with physical activity and non-metabolic AE in children and adolescents. MATERIALS AND METHODS: After exclusion of patients with metabolic syndrome, 62 patients (34 children, 28 adolescents) of both genders who were candidates for SGA therapy were selected. Metabolic parameters included fasting blood glucose (FBG), triglyceride (TG), blood pressure (BP), and waist circumference (WC); non metabolic AEs and physical activity were evaluated at baseline, 1 month, and 3 months after starting the treatment. RESULTS: Mean of post-treatment FBG and TG were significantly higher than the baseline values (P < 0.0001). Compared to the baseline value, significantly more patients developed abnormally high (AbH) FBG at the end point (P = 0.02). There was no significant difference in the frequency of patients with AbH-FBG either at the baseline or at the end point (P > 0.05). The frequency of patients with AbH-TG at the end point was not significantly higher than those with baseline AbH-TG (P = 0.10). Although no patient was obese at baseline, 11 (18%) patients developed abdominal obesity at the end point (P < 0.0001). There was no significant difference in the frequency of non-metabolic AE (P > 0.05). There was no significant correlation between metabolic and non metabolic AE (P > 0.05). Frequency of inactive patients was significantly more than the baseline value (P-0.008), and abdominal obesity was significantly more prevalent in less active participants (P = 0.03). CONCLUSION: The present study showed the AE of SGA on FBG and TG, but no effect on BP and WC. We also found that children are more prone to develop abnormally high FBG. PMID- 25538912 TI - Study of association between promoter tumor necrosing factor alpha gene polymorphisms in -850T/C, -863 A/C, and endometriosis. AB - BACKGROUND: The purpose of this study was to determine whether variability in gene encoding for promoter of tumor necrosis factor participates to women differences in susceptibility to endometriosis. MATERIALS AND METHODS: The study involved 130 women; 65 endometriotic and 65 healthy control women. The blood samples were genotyped for -850 T/C and -863 C/A polymorphisms in TNF alpha gene promoter. Chi-square, odd ratio, and confidence interval 95% were used to evaluate genotypes and allele frequency differences between two groups. RESULTS: No significant differences in genotypes distribution of -850 T/C (P = 0.32) and 863 C/A (P = 0.34) polymorphisms were obtained between two groups. CONCLUSION: According to this study, these two polymorphisms have no risk or protective factor to develop endometriosis. PMID- 25538913 TI - Percutaneous nephrolithotomy: Effect of unilateral procedure on contralateral kidney function. AB - BACKGROUND: Although long-term effects of percutaneous nephrolithotomy (PCNL) on renal function and structure have been evaluated, knowledge regarding the immediate effects of surgery on renal function is limited. We conducted this study to evaluate the impact of unilateral PCNL on bilateral renal function during immediate post-operative period. MATERIALS AND METHODS: From April to September 2012, 40 eligible patients were enrolled in this study and underwent unilateral PCNL. During the post-operative period, creatinine clearances (CrCl) of treated and untreated sides were estimated separately and pattern of changes in bilateral renal function following this procedure was evaluated. RESULTS: Following the operation, CrCl of both kidneys showed a similar pattern of changes, of course more dramatic on treated side. We observed progressive decline in CrCl of both sides followed by bilateral improvement in renal function toward pre-operative values. CONCLUSIONS: During the early post-operative period following unilateral PCNL, both kidneys experienced a temporary drop in function warranting more intensive post-operative care. PMID- 25538914 TI - Infective endocarditis in children: A 5 year experience from Al-Zahra Hospital, Isfahan, Iran. AB - BACKGROUND: Considering that there are no regional published data regarding the epidemiologic findings of infective endocarditis (IE) in children, in this study we reviewed the epidemiologic and clinical features and treatment and outcome of children diagnosed with IE at Al-Zahra hospital over a 5-year period. MATERIALS AND METHODS: In this retrospective study, medical records of patients (<18 years old) admitted from March 2006 to March 2011 in Al-Zahra Hospital (Pediatrics Infectious or Cardiology Departments) reviewed. The medical files reviewed regarding demographic, clinical, diagnostic (laboratory, microbiological and echocardiographic details) and treatment and outcome details. Obtained data were recorded in a questionnaire. The diagnosis of IE was determined based on Duke criteria. RESULTS: In this study, 17 patients fulfill the Duke criteria for definite or the possible IE. The most common causes of IE was non-cyanotic heart disease (ventricular septal defect and AS; 64.8%). From cyanotic hearth disease, Tetralogy of Fallot (TOF) was the most frequent causes (11.8%). In this study, 41% of patients with IE aged < 2 years and 70% aged < 6 years. In this study, 76.5% of patients had a history of congenital heart disease or cardiac surgery. Blood cultures were positive in 10 patients (58.8%). Coagulase-negative staphylococci (23.5%) and Staphylococcus aureus (11.7%) were the most common organisms that cause IE. CONCLUSION: It seems that in order to provide a regional comprehensive guideline for appropriate management and prevention of IE related complications further advanced studies with larger sample size and evaluation is recommended. PMID- 25538915 TI - Impact of sperm chromatin evaluation on fertilization rate in intracytoplasmic sperm injection. AB - BACKGROUND: Sperm DNA in human beings and most vertebrates is packed by protamines into highly compact form of chromatin. There are many staining methods to assess sperm chromatin. Three different methods of staining were used simultaneously in this study and the goal was to determine which of these sperm tests has a relation with fertilization rate in intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: Thirty couples who referred to Yamagata University Hospital (Yamagata, Japan) for ICSI were included in this study. The greater part of semen was prepared for ICSI. The remaining part was used for staining with aniline blue, acridine orange, and chromomycin A3 (CMA3). For evaluation of abnormal morphology and abnormality of head, Papanicolaou-stained smears were used. The analysis of data was done using Spearman coefficient of correlation and logistic regression model. Receiver operator characteristic (ROC) curve was used for discrimination of CMA3 staining power to identify ICSI rates. RESULTS: Percentage of CMA3 positivity, unlike those of aniline blue and acridine orange, showed significant negative correlation with fertilization rate. Moreover, the percentage of CMA3 positivity showed a positive correlation with the percentage of abnormal morphology and abnormality of head. By dividing patients into CMA3 <48% and CMA3> 48% groups, the area under the curve was 0.646. CONCLUSIONS: CMA3 staining (protamine deficiency) could be considered as a useful tool for evaluation of male fertility prior to infertility treatment. PMID- 25538916 TI - Focal hot spot induced by a central subclavian line on bone scan. AB - The diagnostic accuracy of nuclear medicine reporting can be improved by awareness of these instrument-related artifacts. Both awareness and experience are also important when it comes to detecting and identifying normal (and abnormal) variants. We present a case of hot spot on the upper right chest in the region of right subclavicular region resulting from injection of radiotracer from central subclavian line. A 52-year-old woman with a history of left breast cancer and recent bone pain was referred to our nuclear medicine department for skeletal survey. Anterior views of chest show a focus of increased radiotracer uptake corresponding to anterior arch of one of the right second rib. The nuclear physician reported it as a focal rib bony lesion and recommended radiological evaluation. As technician later explained, physicians realized that injection site was a central subclavian line on the right side and hot spot on that region is due to injection site. The appearance of both skeletal and soft-tissue uptake depends heavily on imaging technique (such as the route of radiotracer administration) and the interpreting physicians should be aware of the impact of technical factors on image quality. PMID- 25538917 TI - Effects of biosurfactant produced by Lactobacillus casei on gtfB, gtfC, and ftf gene expression level in S. mutans by real-time RT-PCR. AB - BACKGROUND: The Streptococci are the pioneer strains in plaque formation and Streptococcus mutans are the main etiological agent of dental plaque and caries. In general, biofilm formation is a step-wise process, which begins by adhesion of planktonic cells to the surfaces. Evidences show that expression of glucosyltransferase B and C (gtfB and gtfC) and fructosyltransferase (ftf) genes play critical role in initial adhesion of S. mutans to the tooth surface which results in formation of dental plaques and consequently caries and other periodontal disease. MATERIALS AND METHODS: The aim of this study was to determine the effect of biosurfactants produced by a probiotic strain; Lactobacillus casei (ATCC39392) on gene expression profile of gftB/C and tft of S. mutans (ATCC35668) using quantitative real-time PCR. RESULTS: The application of the prepared biosurfactant caused dramatic down regulation of all the three genes under study. The reduction in gene expression was statistically highly significant (for gtfB, P > 0.0002; for gtfC, P > 0.0063, and for ftf, P > 0.0057). CONCLUSION: Considerable downregulation of all three genes in the presence of the prepared biosurfactant comparing to untreated controls is indicative of successful inhibition of influential genes in bacterial adhesion phenomena. In view of the importance of glucosyltransferase gene products for S.mutans attachment to the tooth surface which is the initial important step in biofilm production and dental caries, further research in this field may lead to an applicable alternative for successful with least adverse side effects in dental caries prevention. PMID- 25538918 TI - Effect of ketamine as an adjuvant in ultrasound-guided supraclavicular brachial plexus block: A double-blind randomized clinical trial study. AB - BACKGROUND: Supraclavicular brachial plexus block is one of the most effective anesthetic procedures in operations for the upper extremity. Ketamine has been reported to enhance the analgesic effects of local anesthetics. We have conducted this study to assess whether coadministration of ketamine can prolong the local analgesic effect of lidocaine in the supraclavicular brachial plexus block for patients undergoing elective upper extremity surgery. MATERIALS AND METHODS: Sixty adult patients undergoing elective surgery of the elbow, forearm, wrist or hand were randomly allocated in two groups of 30 patients each. Group 1 (ketamine group) received 5 mg/kg lidocaine 1.5% plus 2 mg/kg ketamine, Group 2 (control group) received 5 mg/kg lidocaine 1.5% and saline. The outcome measures included severity of pain by using visual analog scale (VAS, 0 = no pain 10 cm = the most severe pain), time of first request for analgesia, and total dose of postoperative opioid administration. The data was analyzed using the chi(2) test, student's t-test, Kaplan-Meier survival analysis, and Multivariate analysis tests. RESULTS: Patients in the control group had a higher VAS than patients who received ketamine, at all time points during the first 24 hours after surgery (all P < 0.05). The time of first request for analgesia in the ketamine group was significantly more than in the control group (8.93 +/- 1.0 vs. 7.30 +/- 1.9, respectively, P < 0.001). CONCLUSION: The addition of ketamine to lidocaine in the ultrasound-guided brachial plexus block could decrease the postoperative pain and need for analgesic. Therefore, it could be considered as an option in the brachial plexus block to enhance the analgesic action of lidocaine. PMID- 25538919 TI - The epidemiological aspects of congenital heart disease in central and southern district of Iran. AB - BACKGROUND: Congenital heart disease (CHD) is a major health problem and its prevalence is different around the world. The aim of study was determination of the epidemiological aspects of CHD in central and southern district of Iran. MATERIALS AND METHODS: In this descriptive and analytical study, 3714 medical records were evaluated from March 21, 2001 to December 18, 2011. Medical records of inpatients from angiography and outpatients in the Heart Clinic of Afshar hospital (a referral hospital in center and south of Iran) were the source of information. Types of CHD and demographic data including age, sex and residential location are collected. The data were analyzed by SPSS (version 17) software. Chi square and Fisher's exact tests were used to compare variables between groups. RESULTS: At the study, the mean age of the patients at diagnosis time was 8.8 +/- 11.6 year (at the range of one day to 76 years with median of 4 years). The percentage of females and males was 54.2 (n: 2014) and 43.8 (n: 1627), respectively. The chi-square test showed that there was significant difference in frequency of CHDs between females and males (P value < 0.0001). Ventricular septal defect (VSD) was found to be the most frequent of CHDs (27%). Patent ductus arteriosus (PDA) (16.8%), atrial septal defect (ASD) (15.8%), pulmonary stenosis (PS) (11%) and Tetralogy of Fallot (TOF) (8.9%) were more prevalent in CHDs after VSD. CONCLUSIONS: The frequency of CHDs in female was more than male and VSD, PDA, ASD, PS, and TOF were most common in CHDs, respectively. PMID- 25538920 TI - Awareness and apgar score in elective Cesarean section under general anesthesia with propofol or Isoflurane: A prospective, randomized, double-blinded clinical trial study. AB - BACKGROUND: Awareness is a postoperative recall of events experienced under general anesthesia. In this study, we compared the incidence of awareness between two routine methods used, inhalation (Isoflurane) and intravenous protocol (Propofol), in elective Cesarean section, and also evaluated the effect of these two different methods on the apgar score of newborns. MATERIALS AND METHODS: In this prospective, clinical trial study, 90 pregnant women candidates for elective Cesarean section were randomly enrolled, after taking written consent. Induction of anesthesia in both groups was provided by propofol and succinylcholine in the same manner, and maintenance of anesthesia in Group 1 was provided by propofol 100 MUg/kg/minute and in Group 2 with isoflurane 1 MAC, to maintain the bispectral index (BIS) between 45 and 60. Blood pressure, heart rate, electrocardiography (ECG), and also Etco2 and o2sat were recorded throughout the surgery and finally analyzed and compared. RESULTS: From 90 patients, four cases of confirmed awareness were found in the propofol group and three cases in the Isoflurane group (8/9% vs. 6/7%), but the apgar scores were comparable between the two groups. Meanwhile there were no significant differences between the two groups in basic information, neonatal apgar scores, hemodynamic changes, and BIS, Electromyography (EMG), and signal quality index (SQI) values. CONCLUSION: According to the patient's state, diagnosis of the anesthesiologist, and other criteria like price and its availability, we could use these drugs in general anesthesia during Cesarean section, although it is recommended that more studies be done to compare the effect of these two drugs in larger groups. PMID- 25538921 TI - Chromium level in prediction of diabetes in pre-diabetic patients. AB - BACKGROUND: Chromium supplementations (Cr) have been shown to exert beneficial effects in the management of type-2 diabetes. Prevalence of Cr deficiency in pre diabetic patients is not well-understood, therefore, the aim of this study was to evaluate the extent of this prevalence. MATERIALS AND METHODS: In this cross sectional descriptive study, 132 pre-diabetic patients were recruited. The participants were randomly selected from those who referred to the Shariati Hospital in Isfahan, Iran. Blood samples are collected for measurement of Cr, insulin, fasting blood sugar (FBS), and two-hour post-load plasma glucose. The body mass index (BMI) was calculated. Determination of Cr was carried out by atomic absorption spectrometry. RESULTS: Thirty-four (31.5%) patients had Cr deficiency and 74 (68.5%) patients had normal Cr. There was no significant difference between sex, age groups (<50 years and >=50 years) and between patients with and without a family history of diabetes in both the groups. No significant differences in age, BMI, FBS or insulin were observed between two groups. In the group with a normal level of Cr, there was a significant reversed correlation between the Cr level and age, but no significant correlation existed between the Cr level and other factors in both groups. CONCLUSION: The levels of Cr deficiency are relatively common in patients with pre-diabetes, and it is necessary to screen patients with diabetes and pre-diabetes according to the American Diabetes Association guidelines, with regard to the Cr level and action should be taken to eliminate the Cr deficiency in these patients. PMID- 25538922 TI - Seroprevalence of toxoplasma-specific antibodies in patients suspected to have active toxoplasmosis: A cross-sectional survey. AB - BACKGROUND: The aim of this study was to investigate the presence and distribution of anti-toxoplasma-specific IgM and IgG tantibodies in patients suspected to have toxoplasmosis and investigate for any association between IgM and IgG antibodies and some toxoplasmosis risk factors as well. MATERIALS AND METHODS: In a comparative cross-sectional study, 70 patients suspected to had active toxoplasmosis and 30 control volunteers, who gave informed consent, entered the study. In each group, patient age, sex, signs of appearance, education level, residency status (urban / rural), occupation, frequency of toxoplasma-specific IgG and IgM antibodies, abortion history, and some risk factors (Direct cat exposure, Occupational exposure to raw meat, and Raw vegetable consumption) were recorded. The enzyme-linked immunosorbent assay (ELISA) kits (EUROIMMUN((r)), United Kingdom) were used for the evaluation of anti-toxoplasma IgG and IgM antibodies according to the manufacturer's instructions. All analyses were done using SPSS-20. RESULTS: The frequency of toxoplasma-specific IgG and IgM antibodies like: Direct cat exposures, Occupational exposure to raw meat, and Raw vegetable consumption were not statistically significant between the two groups (P > 0.05). The history of previous abortions in women in the toxoplasmosis-suspected group was significantly higher than that in the controls (31.4% versus 6.7%; P = 0.009). CONCLUSION: The frequency of specific IgM and IgG antibodies in toxoplasmosis suspected in the toxoplasmosis and control groups was not statistically significant. PMID- 25538923 TI - Association of neck circumference as an indicator of upper body obesity with cardio-metabolic risk factors among first degree relatives of diabetes patients. AB - BACKGROUND: The aim of the present study was to determine the relation between neck circumferences (NC), as an indicator of upper body obesity, with anthropometric and cardio-metabolic factors among the first degree relatives of diabetes patients. MATERIALS AND METHODS: This cross-sectional study was performed on first degree relatives of diabetes patients (n = 213). Weight, height, waist circumference (WC), hip circumference (HC), systolic blood pressure (SBP), diastolic blood pressure (DBP) and NC were measured. Laboratory data included oral glucose tolerance test (OGTT) results, high density lipoprotein (HDL), low density lipoprotein, triglyceride (TG) and total cholesterol. RESULTS: There was no difference in NC among different results of OGTT in men or women. Factors including weight, body mass index (BMI), WC and HC were strongly associated with NC in both genders (r = 0.420-0.711). NC was weakly associated with SBP in women (r = 0.195) and moderately with DBP in men (r = 0.314). Regarding lipid profile, HDL and TG were associated with NC only in women (r = 0.268-0.325). CONCLUSIONS: NC has a significant correlation with gender and anthropometric variables including BMI, weight and waist and HCs in both men and women but it does not differ significantly in patients with different status in OGTT. PMID- 25538924 TI - Genetic association of rs1520333 G/A polymorphism in the IL7 gene with multiple sclerosis susceptibility in Isfahan population. AB - BACKGROUND: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease in which the insulating membrane of central nervous system is damaged. The etiology of MS includes both genetic and environmental causes. A Genome - Wide Association Study (GWAS) recognized genetic single nucleotide polymorphisms (SNP) linked with MS predisposition among which immunologically related genes are considerably over signified. The purpose of the present study is to explore the association of rs1520333 C/T polymorphism in the IL7 gene variants with the risk of MS in a subset of Iranian population. MATERIALS AND METHODS: In this case - control study, 110 cases with MS and 110 controls were contributed. DNA was extracted from blood samples and to amplify the fragment of interest contain rs1520333 SNP, polymerase chain reaction - restriction fragment length polymorphism method was implemented for genotyping of the DNA samples with a specific restriction enzyme (MwoI). SPSS for Windows software (version 18.0; SPSS, Chicago, IL, USA) was used for statistical analysis. RESULT: We demonstrated the important association between G allele [odds ratio (OR) =1.6614, confidence interval (CI) =1.12-2.47, P = 0.0124] and GG genotype (OR = 7.45, 95% CI = 2.13-25.97, P 0.0016) of the rs1520333 SNP for susceptibility to MS after adjustment for age, and gender. OR adjusted for age, gender, and body mass index has displayed similar outcomes. CONCLUSION: These results indicate that the rs1520333 SNP is a significant susceptibility gene variant for development of MS in the Iranian population. Nevertheless, functional studies are required to completely elucidate how this SNP contributed to MS pathogenesis. PMID- 25538925 TI - Emergence of travel: Associated dengue fever in a non-endemic, hilly state. AB - BACKGROUND: We assessed the occurrence of dengue fever in association with travel in a non-endemic hilly region. The clinical presentation and laboratory parameters of febrile patients with a travel history to an endemic region were studied, and the role of the laboratory in the diagnosis was affirmed. MATERIALS AND METHODS: Febrile patients presenting with clinical features defining dengue with a history of travel to an endemic area constituted the study group. Serum samples were tested for dengue-specific NS1 antigen and IgM, IgG antibodies. The demographic data were retrieved from the hospital information system. A hematological and biochemical workup was done and the results analyzed using percentage, proportion, mean, and median. RESULTS: Out of 189 febrile patients, 58 were reactive to serological tests for dengue, with 47 (81%) males. The presenting features were chills and rigors, myalgia, cough, sweating, and vomiting. Thrombocytopenia (74.35%), lymphopenia (52.94%), and leucopenia (47.05%) were present in early disease, with AST >34 IU/L in 58.97% of the patients. The NS1 antigen was detectable between three and seven days of fever and the IgM antibodies after five days. The positivities to only NS1, both NS1 and IgM, and IgM alone were 60.34, 27.58, and 10.34%, respectively, and the median duration of fever was five, seven, and ten days, respectively. One case of dengue hemorrhagic fever and one of probable secondary dengue infection with detectable IgG were encountered. CONCLUSION: Dengue fever remains unsuspected in febrile cases in non-endemic regions. History of travel is an essential criterion to suspect dengue. A non-specific clinical presentation eludes diagnosis. Serological tests for antigen and antibodies, and hematological and biochemical markers are vital for distinguishing the diagnosis. PMID- 25538926 TI - Placenta increta as an important cause of uterine mass after first-trimester Curettage (case report). AB - Placenta increta during the first trimester of pregnancy is very rare. This report describes two cases of placenta increta that caused prolonged vaginal bleeding after a first-trimester abortion. We were encountered two cases of placenta increta in October 2012 and May 2013. Case I: A 35-year-old patient with continues vaginal bleeding from 2 months after curettage due to missed abortion in the first trimester. The uterus was large, the human chorionic gonadotropin (BHCG) level was 112 mUI/mL and ultrasound showed an echogenic mass in the lower segment of the uterine cavity. She was a candidate for curettage but received hysterectomy because of massive vaginal bleeding. Pathology reported placenta increta. Case II: A 32-year-old patient in the 12th week of gestation with missed abortion. After 6 weeks from curettage, she returned with continues vaginal bleeding, BHCG = 55 mUI/mL and sonography showing mixed echo lesion in the uterine cavity like hydatiform mole. Total abdominal hysterectomy was performed. Pathology reported placenta increta. In patients with a history of recent first trimester abortion presenting with prolonged vaginal bleeding, uterine mass and low-level BHCG, a diagnosis of abnormal placentaion should be kept in mind. PMID- 25538927 TI - Dermatophytes contamination of wrestling mats in sport centers of Isfahan, Iran. PMID- 25538929 TI - Association between fetal weight and amniotic fluid index in women of Central India. AB - BACKGROUND: The placenta is important for fetal growth and well-being. Defective placentation and impaired placental circulation may result in anomalies in fetal growth. Placental volume in the second trimester appears to be closely related to the neonatal weight. The association of body weight with urine output has been observed in human neonates. Our goal is to assess the association of the amniotic fluid index (AFI) with the estimated fetal weight (EFW). MATERIALS AND METHODS: Thirteen hundred and ninety-three pregnant women were prospectively studied by means of an ultrasound over a 12-month period. The fetal weight (FW) was estimated using a combination of fetal parameters - bi-parietal diameter, fetal trunk cross-sectional area, and femur length. AFI was assessed using the four quadrant method. The level of statistical significance was set at P <= 0.05. RESULTS: There was no statistically significant association between AFI and EFW (P > 0.05; r = 0.413). We also did not find a significant association between AFI and EFW for all subdivisions of gestation age, except in the 24 - 28 weeks and 29 - 32 weeks' groups. CONCLUSION: The FW calculations and amniotic index show a variation in values in late pregnancy. There does not appear to be a linear association between the ultrasound estimate of FW and the amniotic index. The implication of this is that the fetal size need not be taken into cognizance when alterations in amniotic fluid values are noted. PMID- 25538928 TI - The cumulative incidence of conventional risk factors of cardiovascular disease and their population attributable risk in an Iranian population: The Isfahan Cohort Study. AB - BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death in Iran. The present study evaluated the 7-year incidence of CVD risk factors among the participants of Isfahan cohort study (ICS). MATERIALS AND METHODS: ICS was a longitudinal study on adults over 35 years of age from the urban and rural areas in three counties in central Iran. Data on clinical examination and blood measurements were collected in 2001. Subjects were followed and similar data were collected in 2007. Cumulative incidence was calculated through dividing new cases of each risk factor by the population free of that risk factor at baseline. Incidence proportion was determined for major CVD risk factors including hypertension (HTN), hypercholesterolemia (HC), hypertriglyceridemia (HTg), obesity, diabetes mellitus (DM), metabolic syndrome (MetS), and smoking. RESULTS: A total number of 6323 adults free of CVDs were recruited. After 7 years of follow-up, 3283 individuals were re-evaluated in 2007. The participants' age was 49.2 +/- 10.3 years in 2001 (mean +/- SD). The 7-year cumulative incidence of HTN, HC, HTg, overweight, obesity, DM, MetS, and smoking was 22.8%, 37.4%, 28.0%, 26.3%, 7.4%, 9.5%, 23.9%, and 5.9% in men and 22.2%, 55.4%, 33.5%, 35.0%, 18.8%, 11.3%, 36.1%, and 0.7% in women, respectively. Among those with overweight or obesity, 14.7% of men and 7.9% of women decreased their weight up to the normal level. CONCLUSIONS: The present study revealed a high incidence of CVD risk factors especially dyslipidemia, obesity, MetS and HTN. Therefore, the application of life-style modification interventions seems necessary. PMID- 25538930 TI - Association of depression with type 2 diabetes and relevant factors. AB - BACKGROUND: Based on the high prevalence of diabetes and depression in Rasht, we conducted a study to evaluate the prevalence of depression in type 2 diabetic patients, and its association with glycemic control, chronic complications, and some clinical and paraclinical parameters in this northern state of Iran. MATERIALS AND METHODS: Beck depression inventory was used for evaluating depression on 90 type 2 diabetics and 90 healthy controls selected. Information on demographic and clinical and paraclinical characteristics was collected by interviews and from medical records. RESULTS: This cross-sectional study was performed on 90 type 2 diabetic patients (63 female and 27 male with a mean age of 54.17 +/- 10.57 years) and 90 healthy matched controls. Overall, depression was significantly more prevalent in case group [37.8% vs. 16%, odds ratio (OR) = 3.29, P = 0.001]. The prevalence of depression in diabetic women was significantly higher than nondiabetic ones (39.7% vs. 15%, P = 0.002). We could not find any significant correlation between depression and positive family history of depression, duration of diabetes, HBA1c level, and body mass index. The prevalence of depression was prominently more in diabetic patients with retinopathy than in those without this complication (55.6% vs. 24%, P = 0.015). Logistic regression analysis indicated that diabetes itself was the only significant determinant of having depression (OR = 3.29, P = 0.005, 95% confidence interval: 0.118-0.667). CONCLUSION: There was a prominent prevalence of depression in type 2 diabetics overall. Depression was not correlated with duration of diabetes and glycemic control. There was a significant association between depression and retinopathy in diabetic patients. Diabetes itself was the only significant determinant of having depression after matching with other variables. PMID- 25538931 TI - Stakeholder perspectives on barriers for healthy living for low-income african american families. AB - BACKGROUND: Childhood obesity is a growing problem for children in the United States, especially for children from low-income, African American families. OBJECTIVE: The purpose of this qualitative study was to understand facilitators and barriers to engaging in healthy lifestyles faced by low-income African American children and their families. METHODS: This qualitative study used semi structured focus group interviews with eight African American children clinically identified as overweight or obese (BMI >= 85) and their parents. An expert panel provided insights in developing culturally appropriate intervention strategies. RESULTS: Child and parent focus group analysis revealed 11 barriers and no definitive facilitators for healthy eating and lifestyles. Parents reported confusion regarding what constitutes nutritional eating, varying needs of family members in terms of issues with weight, and difficulty in engaging the family in appropriate and safe physical activities; to name a few themes. Community experts independently suggested that nutritional information is confusing and, often, contradictory. Additionally, they recommended simple messaging and practical interventions such as helping with shopping lists, meal planning, and identifying simple and inexpensive physical activities. CONCLUSION: Childhood obesity in the context of low-resource families is a complex problem with no simple solutions. Culturally sensitive and family informed interventions are needed to support low income African American families in dealing with childhood obesity. PMID- 25538932 TI - Pediatric infectious diseases: getting research evidence into practice and generation of new evidence. PMID- 25538934 TI - Cardiac tumors: a brief commentary. AB - Patients with cardiac tumors may present with cardiovascular related or constitutional symptoms, but more often than not a cardiac mass is discovered incidentally during an imaging examination performed for an unrelated indication. Cardiac myxoma is generally considered to be a surgical emergency. Echocardiography, including the transesophageal approach, is the most important means of diagnosis; computed tomography and magnetic resonance imaging. The clinical presentation has changed, and the management of cardiac myxoma now needs to be reviewed. PMID- 25538933 TI - Challenges and considerations in optimizing ovarian stimulation protocols in oncofertility patients. AB - The scope of cancer treatment in women of childbearing age has changed in the last decade. Fertility preservation is no longer an afterthought but central to multi-disciplinary cancer treatment planning and should be addressed due to the cytotoxic effects of cancer therapy. However, oncology patients present as a unique treatment challenge as the physician must balance the urgency of fertility preservation with the risks of delaying cancer therapy. Controlled ovarian stimulation (COS) is routinely applied in assisted reproductive technology but can be contraindicated in women with estrogen-receptor-positive tumors. This paper reviews some of the challenges to consider when using COS and newer stimulation protocols to minimize risks and optimize outcomes in oncofertility patients. PMID- 25538936 TI - Results of the META-Health Study Suggest Pathways by Which Vitamin D Affect Obesity and Cardiovascular Risk through Adiponectin Levels may Require Further Characterization in Subgroups. PMID- 25538935 TI - A Retrospective Analysis of Pediatric Cases Handled by the MSF Tele-Expertise System. AB - We conducted a retrospective analysis of all pediatric cases referred by Medecins Sans Frontieres (MSF) field doctors via the MSF telemedicine system during a 4 year period from April 2010. A total of 467 pediatric cases were submitted, representing approximately 40% of all telemedicine cases. The median age of the patients was 4 years. The median response time (i.e., the interval between the case being submitted and the first response from a specialist) was 13 h (interquartile range 4-32 h). We selected a random sample of 12 pediatric cases in each of four age categories for detailed analysis by an experienced MSF pediatrician. In the 48 randomly selected cases, the mean rating for the quality of information provided by the referrer was 2.8 (on a scale from 1 = very poor to 5 = very good), and the mean rating for the appropriateness of the response was 3.3 (same scale). More than two-thirds of the responses were considered to be useful to the patient, and approximately three-quarters were considered to be useful to the medical team. The usefulness of the responses tended to be higher for the medical team than for the patient, and there was some evidence that usefulness to both groups was lower in newborns and adolescent patients. The telemedicine system allows the quality of the medical support given to medical teams in the field to be controlled objectively as there is a record of all cases and answers. Telemedicine has an important role in supporting the aims of medical humanitarian organizations such as MSF. PMID- 25538938 TI - African-American Fathers' Perspectives on Their Children's Health Education: A Qualitative, Exploratory Study. AB - PURPOSE: To investigate African-American fathers' (AAF) perceptions regarding the applicability and need for their involvement as a health connection for their children and describe how participating fathers' behavior was affected by their attitudes, knowledge, and perceptions of their influence on their children's health. METHODS: This exploratory study gathered data via semi-structured focus groups (n = 3) and thematically analyzed it utilizing a grounded theory approach. Participants included AAF (n = 20) with a mean age of 37 years (SD 11.79), with at least one child between 6 and 18 years old. RESULTS: Four major themes were revealed: (1) appropriate health education for participants' children (should first and foremost be delivered by parents); (2) participants' paternal health related guidance approach (reactive, rather than proactive); (3) participants' perceived influences on health-related communication with their children (gender roles, efficacy constraints); and (4) paternal definitions of health (most often associated with diet). CONCLUSION: Understanding AAFs' perceived and desired role in their children's health edification can inform initiatives that actively engage these men, and nurture their level of involvement, to promote positive health behaviors among their children; this is necessary to realize their potential to actively improve the health of their children, families, and communities. PMID- 25538937 TI - Emergence of west nile virus lineage 2 in europe: a review on the introduction and spread of a mosquito-borne disease. AB - West Nile virus (WNV) is transmitted by mosquitoes and causes fever and encephalitis in humans, equines, and occasionally wild birds. The virus was first isolated in sub-Saharan Africa where it is endemic. WNV lineage 1 has been responsible for repeated disease outbreaks in the countries of the Mediterranean basin over the past 50 years. This lineage was also introduced into North America in 1999 causing widespread human, equine, and avian mortality. WNV lineage 2, the first WNV lineage to be isolated, was believed to be restricted to sub-Saharan Africa causing a relatively mild fever in humans. However, in 2004, an investigation in Hungary of a case of encephalitis in a wild goshawk (Accipiter gentiles) resulted in the isolation of WNV lineage 2. During the summer of 2004, and in subsequent years, the virus appeared to spread locally throughout Hungary and into neighboring Austria. Subsequently, WNV lineage 2 emerged in Greece in 2010 and in Italy in 2011, involving outbreaks on the Italian mainland and Sardinia. Further spread through the Balkan countries is also suspected. Whole genome sequencing has confirmed that the virus responsible for the outbreaks in Greece and Italy was almost identical to that isolated in Hungary. However, unlike the outbreaks in Hungary, the burden of disease in Mediterranean countries has fallen upon the human population with numerous cases of West Nile fever and a relatively higher mortality rate than in previous outbreaks. The emergence of WNV lineage 2 in Europe, its over-wintering and subsequent spread over large distances illustrates the repeated threat of emerging mosquito-borne diseases. This article will review the emergence of WNV lineage 2 in Europe; consider the pathways for virus spread and the public health implications for the continent. PMID- 25538940 TI - Uncovering RNA Editing Sites in Long Non-Coding RNAs. AB - RNA editing is an important co/post-transcriptional molecular process able to modify RNAs by nucleotide insertions/deletions or substitutions. In human, the most common RNA editing event involves the deamination of adenosine (A) into inosine (I) through the adenosine deaminase acting on RNA proteins. Although A-to I editing can occur in both coding and non-coding RNAs, recent findings, based on RNA-seq experiments, have clearly demonstrated that a large fraction of RNA editing events alter non-coding RNAs sequences including untranslated regions of mRNAs, introns, long non-coding RNAs (lncRNAs), and low molecular weight RNAs (tRNA, miRNAs, and others). An accurate detection of A-to-I events occurring in non-coding RNAs is of utmost importance to clarify yet unknown functional roles of RNA editing in the context of gene expression regulation and maintenance of cell homeostasis. In the last few years, massive transcriptome sequencing has been employed to identify putative RNA editing changes at genome scale. Despite several efforts, the computational prediction of A-to-I sites in complete eukaryotic genomes is yet a challenging task. We have recently developed a software package, called REDItools, in order to simplify the detection of RNA editing events from deep sequencing data. In the present work, we show the potential of our tools in recovering A-to-I candidates from RNA-Seq experiments as well as guidelines to improve the RNA editing detection in non-coding RNAs, with specific attention to the lncRNAs. PMID- 25538939 TI - Improving collaboration by standardization efforts in systems biology. AB - Collaborative genome-scale reconstruction endeavors of metabolic networks would not be possible without a common, standardized formal representation of these systems. The ability to precisely define biological building blocks together with their dynamic behavior has even been considered a prerequisite for upcoming synthetic biology approaches. Driven by the requirements of such ambitious research goals, standardization itself has become an active field of research on nearly all levels of granularity in biology. In addition to the originally envisaged exchange of computational models and tool interoperability, new standards have been suggested for an unambiguous graphical display of biological phenomena, to annotate, archive, as well as to rank models, and to describe execution and the outcomes of simulation experiments. The spectrum now even covers the interaction of entire neurons in the brain, three-dimensional motions, and the description of pharmacometric studies. Thereby, the mathematical description of systems and approaches for their (repeated) simulation are clearly separated from each other and also from their graphical representation. Minimum information definitions constitute guidelines and common operation protocols in order to ensure reproducibility of findings and a unified knowledge representation. Central database infrastructures have been established that provide the scientific community with persistent links from model annotations to online resources. A rich variety of open-source software tools thrives for all data formats, often supporting a multitude of programing languages. Regular meetings and workshops of developers and users lead to continuous improvement and ongoing development of these standardization efforts. This article gives a brief overview about the current state of the growing number of operation protocols, mark-up languages, graphical descriptions, and fundamental software support with relevance to systems biology. PMID- 25538942 TI - Sulfa drugs as inhibitors of carbonic anhydrase: new targets for the old drugs. AB - Sulfa drugs are well-known antibacterial agents containing N-substituted sulfonamide group on para position of aniline ring (NH2RSO2NHR'). In this study 2,4-dichloro-1,3,5-triazine derivatives of sulfa drugs, sulfamerazine (1b), sulfaquinoxaline (2b), sulfadiazine (3b), sulfadimidine (4b), and sulfachloropyrazine (5b) (1a-5a) were synthesized and characterized. Their carbonic anhydrase inhibition activity was evaluated against bovine cytosolic carbonic anhydrase isozyme II (bCA II). For the sake of comparison the CA inhibition activity of the parent sulfa drugs (1b-5b) was also evaluated. A significant increase in CA inhibition activity of sulfa drugs was observed upon substitution with 2,4-dichloro-1,3,5-triazine moiety. Molecular docking studies were carried out to highlight binding site interactions. ADME properties were calculated to evaluate drug likeness of the compounds. PMID- 25538943 TI - Differences in anatomy and kinematics in Asian and Caucasian TKA patients: influence on implant positioning and subsequent loading conditions in mobile bearing knees. AB - The objective of our study was to determine the mechanical stress conditions under tibiofemoral loading with an overlay of knee kinematics in deep flexion on two different mobile bearing designs in comparison to in vivo failure modes. This study investigates the seldom but severe complication of fatigue failure of polyethylene components at mobile bearing total knee arthroplasty designs. Assuming a combination of a floor-based lifestyle and tibial malrotation as a possible reason for a higher failure rate in Asian countries we developed a simplified finite element model considering a tibiofemoral roll-back angle of 22 degrees and the range of rotational motion of a clinically established floating platform design (e.motion FP) at a knee flexion angle of 120 degrees in order to compare our results to failure modes found in retrieved implants. Compared to the failure mode observed in the clinical retrievals the locations of the occurring stress maxima as well as the tensile stress distribution show analogies. From our observations, we conclude that the newly introduced finite element model with an overlay of deep knee flexion (lateral roll-back) and considerable internally rotated tibia implant positioning is an appropriate analysis for knee design optimizations and a suitable method to predict clinical failure modes. PMID- 25538944 TI - The efficacy of Jing Wan Hong ointment for nerve injury diabetic foot ulcer and its mechanisms. AB - Jing Wan Hong ointment contains 30 kinds of Chinese herbs, with functions of activating blood circulation to disperse blood stasis, clearing heat, eliminating dampness, and reducing swelling by detoxification. Therefore, Jing Wan Hong ointment may facilitate the healing of ulcers. The aim of this study was to evaluate the efficacy and mechanisms of Jing Wan Hong ointment for healing diabetic foot ulceration in Wistar rats induced by streptozotocin and sciatic nerve damage. The results showed that Jing Wan Hong ointment had a marked effect on foot ulcers in diabetic rats induced by initial nerve injury. These effects were manifested by reducing the foot ulcer size and Wagner grade after seven days of treatment. The diabetic rats with foot ulcers were almost healed after 21 days of treatment. Moreover, the mechanisms of this effect seem to be dependent on increased expression of PDGF mRNA, but there was no influence on the expression of TGF-beta, VEGF, and FLT-1 mRNA. PMID- 25538946 TI - Characteristics of Lake Chad level variability and links to ENSO, precipitation, and river discharge. AB - This study used trend, correlation, and wavelet analysis to characterize Lake Chad (LC) level fluctuations, river discharge, El Nino Southern Oscillation (ENSO), and precipitation regimes and their interrelationships. Linear correlation results indicate a negative association between ENSO and LC level, river discharge and precipitation. Trend analysis shows increasing precipitation in the Lake Chad Basin (LCB) but decreasing LC level. The mode of interannual variability in LC level, rainfall, and ENSO analyzed using wavelet analysis is dominated by 3-4-year periods. Results show that variability in ENSO could explain only 31% and 13% of variations in LC level at Kindjeria and precipitation in the northern LCB, respectively. The wavelet transform coherency (WTC) between LC level of the southern pool at Kalom and ENSO is statistically significant at the 95% confidence level and phase-locked, implying a cause-and-effect association. These strong coherencies coincide with the La Nina years with the exception of 1997-1998 El Nino events. The WTC shows strong covariance between increasing precipitation and LC level in the northern pool at a 2- to 4-year band and 3- to 4-year band localized from 1996 to 2010. Implications for water resource planning and management are discussed. PMID- 25538941 TI - Synthetic biology outside the cell: linking computational tools to cell-free systems. AB - As mathematical models become more commonly integrated into the study of biology, a common language for describing biological processes is manifesting. Many tools have emerged for the simulation of in vivo synthetic biological systems, with only a few examples of prominent work done on predicting the dynamics of cell free synthetic systems. At the same time, experimental biologists have begun to study dynamics of in vitro systems encapsulated by amphiphilic molecules, opening the door for the development of a new generation of biomimetic systems. In this review, we explore both in vivo and in vitro models of biochemical networks with a special focus on tools that could be applied to the construction of cell-free expression systems. We believe that quantitative studies of complex cellular mechanisms and pathways in synthetic systems can yield important insights into what makes cells different from conventional chemical systems. PMID- 25538945 TI - ErbB4 as a potential molecular target in the treatment of esophageal squamous cell cancers. AB - ErbB4 is an important member of ErbB subfamily of tyrosine kinases receptor with overexpression in several tumors; however its biological role in esophageal cancer is poorly understood till date. The main objective of this study was to examine whether miRNA-140-5p could target and control ErbB4 expression at transcriptional level. The ErbB4 expressions in different cell lines were evaluated by western blotting and luciferase assay. Moreover, cell proliferation, apoptosis, and cell invasion studies were investigated using MTT, flow cytometry, and transwell assays. miRNA-140-5p remarkably downregulated the ErbB4 expression in EC9706 and TE-1A cell lines. Furthermore, miRNA-140-5p transfected cell significantly controlled the cell proliferation and enhanced the apoptosis of multiple cells. Additionally, miRNA-140-5p had marked effect on the DNA synthesis and caspase 3/7 activity in comparison to control cells. Specifically, miRNA-140 5p inhibited/repressed the cancer cell invasion and migration in a sign to have important biological role in esophageal carcinomas. Taken together, miRNA-140-5p could act as a potential molecular target in ErbB4 overexpressing ESCC cell lines paving the way for effective esophageal cancer treatment. PMID- 25538948 TI - Integrating SOMs and a Bayesian classifier for segmenting diseased plants in uncontrolled environments. AB - This work presents a methodology that integrates a nonsupervised learning approach (self-organizing map (SOM)) and a supervised one (a Bayesian classifier) for segmenting diseased plants that grow in uncontrolled environments such as greenhouses, wherein the lack of control of illumination and presence of background bring about serious drawbacks. During the training phase two SOMs are used: one that creates color groups of images, which are classified into two groups using K-means and labeled as vegetation and nonvegetation by using rules, and a second SOM that corrects classification errors made by the first SOM. Two color histograms are generated from the two color classes and used to estimate the conditional probabilities of the Bayesian classifier. During the testing phase an input image is segmented by the Bayesian classifier and then it is converted into a binary image, wherein contours are extracted and analyzed to recover diseased areas that were incorrectly classified as nonvegetation. The experimental results using the proposed methodology showed better performance than two of the most used color index methods. PMID- 25538949 TI - Identification and validation of a new male sex-specific ISSR marker in pointed gourd (Trichosanthes dioica Roxb.). AB - The aim of the present study was to develop a genetic sex marker for the pointed gourd (Trichosanthes dioica Roxb.) to allow gender determination at any stage in the life cycle. Screening of genomic DNA with intersimple sequence repeat (ISSR) primers was used to discover sex-specific touch-down polymerase chain reaction (Td-PCR) amplification products. Using pooled DNA from male and female genotypes and 42 ISSR primers, a putative male specific marker (~550 bp) was identified. DNA marker specific to male is an indication of existence of nonepigenetic factors involved in gender development in pointed gourd. The ISSR technique has proved to be a reliable technique in gender determination of pointed gourd genotypes at the seedling phenophase. The sex marker developed here could also be used as a starting material towards sequence characterization of sex linked genes for better understanding the developmental as well as evolutionary pathways in sexual dimorphism. PMID- 25538950 TI - Computed tomographic image analysis based on FEM performance comparison of segmentation on knee joint reconstruction. AB - The demand for an accurate and accessible image segmentation to generate 3D models from CT scan data has been increasing as such models are required in many areas of orthopedics. In this paper, to find the optimal image segmentation to create a 3D model of the knee CT data, we compared and validated segmentation algorithms based on both objective comparisons and finite element (FE) analysis. For comparison purposes, we used 1 model reconstructed in accordance with the instructions of a clinical professional and 3 models reconstructed using image processing algorithms (Sobel operator, Laplacian of Gaussian operator, and Canny edge detection). Comparison was performed by inspecting intermodel morphological deviations with the iterative closest point (ICP) algorithm, and FE analysis was performed to examine the effects of the segmentation algorithm on the results of the knee joint movement analysis. PMID- 25538951 TI - Break-before-make CMOS inverter for power-efficient delay implementation. AB - A modified static CMOS inverter with two inputs and two outputs is proposed to reduce short-circuit current in order to increment delay and reduce power overhead where slow operation is required. The circuit is based on bidirectional delay element connected in series with the PMOS and NMOS switching transistors. It provides differences in the dynamic response so that the direct-path current in the next stage is reduced. The switching transistors are never ON at the same time. Characteristics of various delay element implementations are presented and verified by circuit simulations. Global optimization procedure is used to obtain the most power-efficient transistor sizing. The performance of the modified CMOS inverter chain is compared to standard implementation for various delays. The energy (charge) per delay is reduced up to 40%. The use of the proposed delay element is demonstrated by implementing a low-power delay line and a leading-edge detector cell. PMID- 25538947 TI - Cross-sectional investigation of HEMS activities in Europe: a feasibility study. AB - OBJECTIVES: To gather information on helicopter emergency medical services (HEMSs) activities across Europe. METHODS: Cross-sectional data-collection on daily (15 November 2013) activities of a sample of European HEMSs. A web-based questionnaire with both open and closed questions was used, developed by experts of the European Prehospital Research Alliance (EUPHOREA). RESULTS: We invited 143 bases from 11 countries; 85 (60%) reported base characteristics only and 73 (51%) sample-day data too. The variety of base characteristics was enormous; that is, the target population ranged from 94.000 to 4.500.000. Of 158 requested primary missions, 62 (0.82 per base) resulted in landing. Cardiac aetiology (36%) and trauma (36%) prevailed, mostly of life-threatening severity (43%, 0.64 per mission). Had HEMS been not dispatched, patients would have been attended by another physician in 67% of cases, by paramedics in 24%, and by nurses in 9%. On board physicians estimated to have caused a major decrease of death risk in 47% of missions, possible decrease in 22%, minor benefit in 17%, no benefit in 11%, and damage in 3%. Earlier treatment and faster transport to hospital were the main reasons for benefit. The most frequent therapeutic procedure was drug administration (78% of missions); endotracheal intubation occurred in 25% of missions and was an option hardly offered by ground crews. CONCLUSIONS: The study proved feasible, establishing an embryonic network of European HEMS. The participation rate was low and limits the generalizability of the results. Fortunately, because of its cross-sectional characteristics and the handy availability of the web platform, the study is easily repeatable with an enhanced network. PMID- 25538952 TI - Expression, purification, and functional analysis of novel RelE operon from X. nematophila. AB - Bacterial toxin-antitoxin (TA) complexes induce programmed cell death and also function to relieve cell from stress by various response mechanisms. Escherichia coli RelB-RelE TA complex consists of a RelE toxin functionally counteracted by RelB antitoxin. In the present study, a novel homolog of RelE toxin designated as Xn-relE toxin from Xenorhabdus nematophila possessing its own antitoxin designated as Xn-relEAT has been identified. Expression and purification of recombinant proteins under native conditions with GST and Ni-NTA chromatography prove the existence of novel TA module. The expression of recombinant Xn-relE under tightly regulated ara promoter in E. coli Top 10 cells confirms its toxic nature in endogenous toxicity assay. The neutralization activity in endogenous toxicity assay by Xn-relEAT antitoxin confirms its antidote nature when studying the whole TA operon under ara regulated promoter. This study promotes newly discovered TA module to be regarded as important as other proteins of type II toxin-antitoxin system. PMID- 25538953 TI - Influence of weight gain rate on early life nutritional status and body composition of children. AB - OBJECTIVE: To evaluate the influence of the weight gain rate at 4-6 months on nutritional status and body composition in children between 4 and 7 years of age. METHODS: Retrospective cohort study, sample of 257 children. Data collection was performed in two stages, with the first relating to retrospective data of weight gain from birth to the first 4-6 months of life in the patient records. Measurements of weight, height, waist circumference, and body composition in children between ages 4 and 7 years were obtained. Nutritional status was assessed by the BMI/age. Control variables, such as pregnancy, breastfeeding, lifestyle, and sociodemographics, were studied. Descriptive analysis and multiple linear regression were performed. RESULTS: In the nutritional status assessment, the prevalence of overweight observed was 24.9%. After adjusting for control variables, it was found that the increase of the WGR at 4-6 months of age explained the occurrence of higher BMI/age, percentage of total body fat, body fat percentage in the android region, and waist circumference in children between 4 and 7 years of age. CONCLUSION: The increase of the WGR in the first months of life can lead to the occurrence of higher values of parameters of nutritional status and body composition in later life. PMID- 25538955 TI - Supervised wavelet method to predict patient survival from gene expression data. AB - In microarray studies, the number of samples is relatively small compared to the number of genes per sample. An important aspect of microarray studies is the prediction of patient survival based on their gene expression profile. This naturally calls for the use of a dimension reduction procedure together with the survival prediction model. In this study, a new method based on combining wavelet approximation coefficients and Cox regression was presented. The proposed method was compared with supervised principal component and supervised partial least squares methods. The different fitted Cox models based on supervised wavelet approximation coefficients, the top number of supervised principal components, and partial least squares components were applied to the data. The results showed that the prediction performance of the Cox model based on supervised wavelet feature extraction was superior to the supervised principal components and partial least squares components. The results suggested the possibility of developing new tools based on wavelets for the dimensionally reduction of microarray data sets in the context of survival analysis. PMID- 25538956 TI - Fast motion deblurring using sensor-aided motion trajectory estimation. AB - This paper presents an image deblurring algorithm to remove motion blur using analysis of motion trajectories and local statistics based on inertial sensors. The proposed method estimates a point-spread-function (PSF) of motion blur by accumulating reweighted projections of the trajectory. A motion blurred image is then adaptively restored using the estimated PSF and spatially varying activity map to reduce both restoration artifacts and noise amplification. Experimental results demonstrate that the proposed method outperforms existing PSF estimation based motion deconvolution methods in the sense of both objective and subjective performance measures. The proposed algorithm can be employed in various imaging devices because of its efficient implementation without an iterative computational structure. PMID- 25538954 TI - A comparison in mechanical properties of cermets of calcium silicate with Ti-55Ni and Ti-6Al-4V alloys for hard tissues replacement. AB - This study investigated the impact of calcium silicate (CS) content on composition, compressive mechanical properties, and hardness of CS cermets with Ti-55Ni and Ti-6Al-4V alloys sintered at 1200 degrees C. The powder metallurgy route was exploited to prepare the cermets. New phases of materials of Ni16Ti6Si7, CaTiO3, and Ni31Si12 appeared in cermet of Ti-55Ni with CS and in cermet of Ti-6Al-4V with CS, the new phases Ti5Si3, Ti2O, and CaTiO3, which were emerged during sintering at different CS content (wt%). The minimum shrinkage and density were observed in both groups of cermets for the 50 and 100 wt% CS content, respectively. The cermets with 40 wt% of CS had minimum compressive Young's modulus. The minimum of compressive strength and strain percentage at maximum load were revealed in cermets with 50 and 40 wt% of CS with Ti-55Ni and Ti-6Al-4V cermets, respectively. The cermets with 80 and 90 wt% of CS showed more plasticity than the pure CS. It concluded that the composition and mechanical properties of sintered cermets of Ti-55Ni and Ti-6Al-4V with CS significantly depend on the CS content in raw cermet materials. Thus, the different mechanical properties of the cermets can be used as potential materials for different hard tissues replacements. PMID- 25538957 TI - Collaborative and multilingual approach to learn database topics using concept maps. AB - Authors report on a study using the concept mapping technique in computer engineering education for learning theoretical introductory database topics. In addition, the learning of multilingual technical terminology by means of the collaborative drawing of a concept map is also pursued in this experiment. The main characteristics of a study carried out in the database subject at the University of the Basque Country during the 2011/2012 course are described. This study contributes to the field of concept mapping as these kinds of cognitive tools have proved to be valid to support learning in computer engineering education. It contributes to the field of computer engineering education, providing a technique that can be incorporated with several educational purposes within the discipline. Results reveal the potential that a collaborative concept map editor offers to fulfil the above mentioned objectives. PMID- 25538958 TI - Confirmatory factor analysis of the Malay version comprehensive feeding practices questionnaire tested among mothers of primary school children in Malaysia. AB - Comprehensive feeding practices questionnaire (CFPQ) is an instrument specifically developed to evaluate parental feeding practices. It has been confirmed among children in America and applied to populations in France, Norway, and New Zealand. In order to extend the application of CFPQ, we conducted a factor structure validation of the translated version of CFPQ (CFPQ-M) using confirmatory factor analysis among mothers of primary school children (N = 397) in Malaysia. Several items were modified for cultural adaptation. Of 49 items, 39 items with loading factors >0.40 were retained in the final model. The confirmatory factor analysis revealed that the final model (twelve-factor model with 39 items and 2 error covariances) displayed the best fit for our sample (Chi square = 1147; df = 634; P < 0.05; CFI = 0.900; RMSEA = 0.045; SRMR = 0.0058). The instrument with some modifications was confirmed among mothers of school children in Malaysia. The present study extends the usability of the CFPQ and enables researchers and parents to better understand the relationships between parental feeding practices and related problems such as childhood obesity. PMID- 25538959 TI - Ultrasound thickness of bladder wall in continent and incontinent women and its correlation with cystometry. AB - OBJECTIVE: To compare bladder wall thickness in two kinds of urinary incontinent women-stress urinary incontinence (SUI) and overactive bladder (OAB) with urodynamic detrusor overactivity (DO), and to compare them with continent patients by ultrasound, also, correlate with cystometric results in incontinent women. METHODS: 91 women were divided into the following groups: continent (n = 31), SUI (n = 30), and DO (n = 30) groups after clinical evaluation and urodynamic test (only in incontinent women). Transvaginal ultrasound was performed to the bladder wall thickness (BWT) measurement. The mean of BWT was calculated and data were analyzed with ANOVA and Turkey's multiple comparison tests. Pearson's correlation coefficient (r) was used to compare two variables. Receiver operating characteristic (ROC) curve was performed to study BWT as a diagnostic parameter. RESULTS: BWT in DO group was significantly higher than that in the other groups (P < 0.005). A moderate positive correlation was found between BWT and maximum bladder pressure during involuntary bladder contraction. There was no difference in BWT between SUI and continent groups. DO group had lower first desire to void and cystometric capacity. Maximum bladder pressure at detrusor contraction had a moderate positive correlation with BWT. The ROC revealed an area under the curve of 0.962 (95% CI, 0.90-1.01). CONCLUSIONS: DO patients have increased bladder wall thickness, lower first desire to void, and lower cystometric capacity. There was a moderate correlation between BWT and maximum bladder pressure during involuntary bladder contraction. PMID- 25538960 TI - Cholesterol-lowering potentials of lactic acid bacteria based on bile-salt hydrolase activity and effect of potent strains on cholesterol metabolism in vitro and in vivo. AB - This study collected different probiotic isolates from animal and plant sources to evaluate the bile-salt hydrolase activity of probiotics in vitro. The deconjugation potential of bile acid was determined using high-performance liquid chromatography. HepG2 cells were cultured with probiotic strains with high BSH activity. The triglyceride (TG) and apolipoprotein B (apo B) secretion by HepG2 cells were evaluated. Our results show that the BSH activity and bile-acid deconjugation abilities of Pediococcus acidilactici NBHK002, Bifidobacterium adolescentis NBHK006, Lactobacillus rhamnosus NBHK007, and Lactobacillus acidophilus NBHK008 were higher than those of the other probiotic strains. The cholesterol concentration in cholesterol micelles was reduced within 24 h. NBHK007 reduced the TG secretion by 100% after 48 h of incubation. NBHK002, NBHK006, and NBHK007 could reduce apo B secretion by 33%, 38%, and 39%, respectively, after 24 h of incubation. The product PROBIO S-23 produced a greater decrease in the total concentration of cholesterol, low-density lipoprotein, TG, and thiobarbituric acid reactive substance in the serum or livers of hamsters with hypercholesterolemia compared with that of hamsters fed with a high-fat and high-cholesterol diet. These results show that the three probiotic strains of lactic acid bacteria are better candidates for reducing the risk of cardiovascular disease. PMID- 25538961 TI - Salicylanilide diethyl phosphates as potential inhibitors of some mycobacterial enzymes. AB - Antimycobacterially active salicylanilide diethyl phosphates were evaluated to identify their potential drug target(s) for the inhibition of several mycobacterial enzymes, including isocitrate lyase, L-alanine dehydrogenase (MtAlaDH), lysine epsilon-aminotransferase, chorismate mutase, and pantothenate synthetase. The enzymes are related to the nongrowing state of Mycobacterium tuberculosis. Salicylanilide diethyl phosphates represent new candidates with significant inhibitory activity especially against L-alanine dehydrogenase. The most active MtAlaDH inhibitor, 5-chloro-2-[(3-chlorophenyl)carbamoyl]phenyl diethyl phosphate, has an IC50 of 4.96 uM and the best docking results. Other mycobacterial enzymes were mostly inhibited by some derivatives but at higher concentrations; isocitrate lyase showed the highest resistance to salicylanilide diethyl phosphates. PMID- 25538962 TI - Artificial neural network modelling of photodegradation in suspension of manganese doped zinc oxide nanoparticles under visible-light irradiation. AB - The artificial neural network (ANN) modeling of m-cresol photodegradation was carried out for determination of the optimum and importance values of the effective variables to achieve the maximum efficiency. The photodegradation was carried out in the suspension of synthesized manganese doped ZnO nanoparticles under visible-light irradiation. The input considered effective variables of the photodegradation were irradiation time, pH, photocatalyst amount, and concentration of m-cresol while the efficiency was the only response as output. The performed experiments were designed into three data sets such as training, testing, and validation that were randomly splitted by the software's option. To obtain the optimum topologies, ANN was trained by quick propagation (QP), Incremental Back Propagation (IBP), Batch Back Propagation (BBP), and Levenberg Marquardt (LM) algorithms for testing data set. The topologies were determined by the indicator of minimized root mean squared error (RMSE) for each algorithm. According to the indicator, the QP-4-8-1, IBP-4-15-1, BBP-4-6-1, and LM-4-10-1 were selected as the optimized topologies. Among the topologies, QP-4-8-1 has presented the minimum RMSE and absolute average deviation as well as maximum R squared. Therefore, QP-4-8-1 was selected as final model for validation test and navigation of the process. The model was used for determination of the optimum values of the effective variables by a few three-dimensional plots. The optimum points of the variables were confirmed by further validated experiments. Moreover, the model predicted the relative importance of the variables which showed none of them was neglectable in this work. PMID- 25538963 TI - Quality of life, disability, well-being, and coping strategies in patients undergoing neurosurgical procedures: preoperative results in an Italian sample. AB - BACKGROUND: The aim of this paper is to present the preliminary results of QoL, well-being, disability, and coping strategies of patients before neurosurgical procedure. METHODS: We analysed data on preoperative quality of life (EUROHIS QoL), disability (WHODAS-II), well-being (PGWB-S), coping strategies (Brief COPE), and functional status (KPS score) of a sample of patients with brain tumours and cerebrovascular and spinal degenerative disease admitted to Neurological Institute Carlo Besta. Statistical analysis was performed to illustrate the distribution of sociodemographic and clinical data, to compare mean test scores to the respective normative samples, and to investigate the differences between diagnoses, the correlation between tests, and the predictive power of sociodemographic and clinical variables of QoL. RESULTS: 198 patients were included in the study. PGWB-S and EUROHIS-QoL scores were significantly lower than normative population. Patients with spinal diseases reported higher scores in WHODAS-II compared with oncological and cerebrovascular groups. Finally sociodemographic and clinical variables were significant predictors of EUROHIS QoL, in particular PGWB-S and WHODAS-II. CONCLUSION: Our preliminary results show that preoperatory period is critical and the evaluation of coping strategies, quality of life, disability, and well-being is useful to plan tailored intervention and for a better management of each patient. PMID- 25538965 TI - Cadmium and lead in blood cockle (Anadara granosa) from Asajaya, Sarawak, Malaysia. AB - The concentrations were ranged from 1.35 +/- 0.16 to 2.22 +/- 0.34 ug/g (dry weight) and 2.65 +/- 0.34 to 4.36 +/- 0.53 ug/g (dry weight) for Cd and Pb, respectively, in blood cockle Anadara granosa from four sites of Sabang River, namely, Kampung Sambir, Kampung Tambirat, Beliong Temple, and Kampung Tanjung Apong, which are located at Asajaya, Sarawak, Malaysia. All values exceeded safety limits set by Malaysian Food Regulation (1985). It may be the cause of serious human health problems after long term consumption. Thus, consumer should have consciousness about such type of seafood from mentioned sites and need further investigation. PMID- 25538964 TI - Scaling-stimulated salivary antioxidant changes and oral-health behavior in an evaluation of periodontal treatment outcomes. AB - AIM: Our goal was to investigate associations among scaling-stimulated changes in salivary antioxidants, oral-health-related behaviors and attitudes, and periodontal treatment outcomes. MATERIALS AND METHODS: Thirty periodontitis patients with at least 6 pockets with pocket depths of >5 mm and more than 16 functional teeth were enrolled in the study. Patients were divided into three groups: an abandoned group (AB group), a nonprogress outcome group (NP group), and an effective treatment group (ET group). Nonstimulated saliva was collected before and after scaling were received to determine superoxide dismutase (SOD) and the total antioxidant capacity (TAOC). RESULTS: Salivary SOD following scaling significantly increased from 83.09 to 194.30 U/g protein in patients who had irregular dental visit patterns (<1 visit per year). After scaling, the TAOC was significantly higher in patients who had regular dental visits than in patients who had irregular dental visits (3.52 versus 0.70 mmole/g protein, P < 0.01). The scaling-stimulated increase in SOD was related to a higher severity of periodontitis in the NP group, while the scaling-stimulated increase in the TAOC was inversely related to the severity of periodontitis in the AB group. CONCLUSIONS: These results demonstrate the importance of scaling-stimulated salivary antioxidants as prognostic biomarkers of periodontal treatment. PMID- 25538967 TI - Understanding critical disability studies. PMID- 25538968 TI - The Author Response. PMID- 25538966 TI - Clinical application of partial splenic embolization. AB - Partial splenic embolization (PSE) is one of the intra-arterial therapeutic approaches of diseases. With the development of interventional radiology, the applications of PSE in clinical practice are greatly extended, while various materials are developed for embolization use. Common indications of PSE include hypersplenism with portal hypertension, hereditary spherocytosis, thalassemia, autoimmune hemolytic anemia, splenic trauma, idiopathic thrombocytopenic purpura, splenic hemangioma, and liver cancer. It is also performed to exclude splenic artery aneurysms from the parent vessel lumen and prevent aneurysm rupture, to treat splenic artery steal syndrome and improve liver perfusion in liver transplant recipients, and to administer targeted treatment to areas of neoplastic disease in the splenic parenchyma. Indicators of the therapeutic effect evaluation of PSE comprise blood routine test, changes in hemodynamics and in splenic volume. Major complications of PSE include the pulmonary complications, severe infection, damages of renal and liver function, and portal vein thrombosis. The limitations of PSE exist mainly in the difficulties in selecting the arteries to embolize and in evaluating the embolized volume. PMID- 25538969 TI - Author response. PMID- 25538970 TI - Retraction notice to: Clinical significance of the best response during repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma [J. Hepatol. 2014;60:1212-1218]. PMID- 25538971 TI - Authors' reply. PMID- 25538972 TI - Label-free evanescent microscopy for membrane nano-tomography in living cells. AB - We show that through-the-objective evanescent microscopy (epi-EM) is a powerful technique to image membranes in living cells. Readily implementable on a standard inverted microscope, this technique enables full-field and real-time tracking of membrane processes without labeling and thus signal fading. In addition, we demonstrate that the membrane/interface distance can be retrieved with 10 nm precision using a multilayer Fresnel model. We apply this nano-axial tomography of living cell membranes to retrieve quantitative information on membrane invagination dynamics. PMID- 25538973 TI - Spectroscopic biofeedback on cutaneous carotenoids as part of a prevention program could be effective to raise health awareness in adolescents. AB - The cutaneous carotenoid concentration correlates with the overall antioxidant status of a person and can be seen as biomarker for nutrition and lifestyle. 50 high school students were spectroscopically measured for their cutaneous carotenoid concentrations initially in a static phase, followed by an intervention phase with biofeedback of their measured values, living a healthy lifestyle and on healthy food this time. The volunteers showed higher carotenoid concentrations than found in previous studies. A significant correlation of healthy lifestyle habits and a high antioxidant status could be determined. Subjects improved their nutritional habits and significantly increased their carotenoid concentration during intervention. Follow-up five months later showed a consolidation of the increase. The investigations show that a healthy diet and a well-balanced lifestyle correlate with a high cutaneous antioxidant concentration and that spectroscopic biofeedback measurement of cutaneous carotenoids as part of an integrated prevention program is a feasible and effective means to raise the health awareness in adolescents. PMID- 25538974 TI - [Limit risk of facial paralysis - parotid surgery]. PMID- 25538975 TI - [Dysphagia after radiotherapy - cervical esophagostomy can help]. PMID- 25538976 TI - In memoriam: Mervyn Susser, MB, BCh, DPH. PMID- 25538977 TI - [The digital operating theatre]. PMID- 25538978 TI - 30th anniversary of ALTEX. PMID- 25538979 TI - Image of the month: Esophageal squamous papilloma. PMID- 25538980 TI - Obinutuzumab (Gazyva) for chronic lymphocytic leukemia. PMID- 25538981 TI - Pembrolizumab (Keytruda) for metastatic melanoma. PMID- 25538982 TI - Use of the Xpert MTB/RIF assay in the diagnosis of tuberculous meningitis: a cautionary note. PMID- 25538983 TI - Hydroxyethyl starches in severe burns. PMID- 25538984 TI - Professional competence- adding reflective elements to case reports. PMID- 25538985 TI - The 'Marketplace' - a novel conference teaching and learning model. PMID- 25538986 TI - Ebola: SA has no outbreak 'laurels' to rest on. PMID- 25538987 TI - Dismal obs/gynae training contributing to maternal deaths- Motsoaledi. PMID- 25538988 TI - New partnership stands to save millions of mothers and children. PMID- 25538989 TI - BHF and government: 'I'll change if you'll change. PMID- 25538990 TI - Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. AB - Background: To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression. Methods: Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling.Patients were randomized to 8 weeks of quetiapine extended release(XR) 300 mg daily monotherapy or placebo.The primary out come measure was changed from baseline to Week 8 in MADRS total score. Results: Quetiapine XR 300 mg once daily(N=133)showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1(p<0.001)through to Week 8 (p<0.001).Mean change in MADRS total score at Week 8 was 17.4 in the quetiapine XR group and -11.9 in the placebo group(p<0.001). Response (>= 50% reduction in MADRS total score)and remission (MADRS total score <=12)rates at Week 8 were significantly higher with quetiapine XR compared with placebo (p<0.001 and p<0.05, respectively).Quetiapine XR improved core symptoms of depression. The most common adverse events associated with quetiapine XR were dry mouth, somnolence,and sedation. Greater weight gain was observed inpatients on quetiapine XR relative to placebo. Limitations: Fewer patients with bipolar II disorder included, only one fixed dose tested and the lack of an active comparator. Conclusions: Quetiapine XR(300 mg)once daily monotherapy was significantly more effective than placebo for treating episodes of depression in bipolar I disorder, throughout the 8-week study,with significance observed as early as Day 7.Adverse events were consistent with the known effects of quetiapine. PMID- 25538991 TI - [Conventional certain safety margin captures the prostate after partial prostatectomy]. PMID- 25538992 TI - [Radiation therapy (4 Gy vs. 24 Gy) in patients with indolent non-Hodgkins lymphoma: Results of the FORT Study]. PMID- 25538993 TI - Atopic dermatitis. PMID- 25538994 TI - Aetiopathogenesis of atopic dermatitis. AB - The aetiopathogenesis of atopic dermatitis (AD) is complex and during recent years much has been learnt regarding the genetic predisposition to the development of this condition and how its interaction with the environment influences clinical manifestations. AD is not a simple condition. An inherited stratum corneum barrier defect, transepidermal water loss, early antigen exposure through the skin and over-hygienic care of the young child seem to be the major drivers in the manifestation of the disease. Many other, more specific, environmental factors may influence the clinical picture in individual patients; some of these have an allergic basis, while others do not. In this article, the terminology used in this issue of CME is explained, the evidence for the different aetiopathological factors is presented and the factors that worsen or improve AD are listed. PMID- 25538995 TI - Revised guidance on meningitis outbreak response in sub-Saharan Africa. PMID- 25538996 TI - Monthly report on dracunculiasis cases, January-October 2014. PMID- 25538997 TI - Behavioural neurogenetics. Preface. PMID- 25538998 TI - Tribute to Professor Sun Shiquan (1927-2012). PMID- 25538999 TI - Preface. PMID- 25539000 TI - Cortisol secretion from incidentally discovered adrenal adenomas has been described as autonomous. PMID- 25539001 TI - Letter to the editor response. PMID- 25539002 TI - Ca2+ signalling in plant immune response: from pattern recognition receptors to Ca2+ decoding mechanisms. AB - Ca2+ is a ubiquitous second messenger for cellular signalling in various stresses and developmental processes. Here, we summarize current developments in the roles of Ca2+ during plant immunity responses. We discuss the early perception events preceding and necessary for triggering cellular Ca2+ fluxes, the potential Ca2+ permeable channels, the decoding of Ca2+ signals predominantly via Ca2+-dependent phosphorylation events and transcriptional reprogramming. To highlight the complexity of the cellular signal network, we briefly touch on the interplay between Ca2+-dependent signalling and selected major signalling mechanisms--with special emphasis on reactive oxygen species at local and systemic levels. PMID- 25539003 TI - Reprogramming of plant cells by filamentous plant-colonizing microbes. AB - Although phylogenetically unrelated, filamentous oomycetes and fungi establish similar structures to colonize plants and they represent economically the most important microbial threat to crop production. In mutualistic interactions established by root-colonizing fungi, clear differences to pathogens can be seen, but there is mounting evidence that their infection strategies and molecular interactions have certain common features. To infect the host, fungi and oomycetes employ similar strategies to circumvent plant innate immunity. This process involves the suppression of basal defence responses which are triggered by the perception of conserved molecular patterns. To establish biotrophy, effector proteins are secreted from mutualistic and pathogenic microbes to the host tissue, where they play central roles in the modulation of host immunity and metabolic reprogramming of colonized host tissues. This review article discusses key effector mechanisms of filamentous pathogens and mutualists, how they modulate their host targets and the fundamental differences or parallels between these different interactions. The orchestration of effector actions during plant infection and the importance of their localization within host tissues are also discussed. PMID- 25539004 TI - TAL effectors--pathogen strategies and plant resistance engineering. AB - Transcription activator-like effectors (TALEs) from plant pathogenic Xanthomonas spp. and the related RipTALs from Ralstonia solanacearum are DNA-binding proteins with a modular DNA-binding domain. This domain is both predictable and programmable, which simplifies elucidation of TALE function in planta and facilitates generation of DNA-binding modules with desired specificity for biotechnological approaches. Recently identified TALE host target genes that either promote or stop bacterial disease provide new insights into how expression of TALE genes affects the plant-pathogen interaction. Since its elucidation the TALE code has been continuously refined and now provides a mature tool that, in combination with transcriptome profiling, allows rapid isolation of novel TALE target genes. The TALE code is also the basis for synthetic promoter-traps that mediate recognition of TALE or RipTAL proteins in engineered plants. In this review, we will summarize recent findings in plant-focused TALE research. In addition, we will provide an outline of the newly established gene isolation approach for TALE or RipTAL host target genes with an emphasis on potential pitfalls. PMID- 25539006 TI - Torque loss under mechanical cycling of long-span zirconia and titanium-cemented and screw-retained implant-supported CAD/CAM frameworks. AB - OBJECTIVES: This study evaluated the screw joint stability after cyclic loading of implant-supported titanium and zirconia CAD/CAM frameworks for fixed dental prostheses (FDPs) with different retention methods. MATERIAL AND METHODS: Twenty four one-piece frameworks supported by six threaded implants placed in the maxilla were fabricated using a CAD/CAM technique (NeoShape). Dry-pressed porcelain crowns were luted to the frameworks to standardize the specimens. The specimens were then divided into four groups (n = 6) according to framework material (titanium or zirconia) and retention method for the prosthesis (cement- or screw-retained): G1, Ti-cemented; G2, Ti-screw-retained; G3, Zr-cemented; and G4, Zr-screw-retained. A digital torque ratchet was used to assess the initial preload removal torque. Torque was then reapplied and the specimens were submitted to a 200 N cyclic load, at a frequency of 2 Hz, underwater in controlled temperature of 37 degrees , and for 1 * 106 cycles. An opposing lower dental arch was fabricated using bis-acrylic resin to simulate occlusal contacts in centric. After cyclic loading, postload removal torque was measured. Preload and postload torque loss was expressed as a percentage of the initial load. Data were submitted to a linear mixed-effects model for statistical significance (alpha = 0.05) to evaluate the effect of cyclic loading in the screw torque loss used with frameworks of different materials and retention methods. RESULTS: Significant screw torque loss (%) was found for the tested groups (before/after cyclic loading, respectively): G1 (39.77/61.83), G2 (37.57/50.96), G3 (34.87/54.10), and G4 (47.56/73.50) (P < 0.05). CONCLUSIONS: The screw removal torque was significantly reduced for all groups in this study after cyclic loading the specimens. Screw-retained zirconia specimens presented the highest torque loss before and after the cyclic loadings compared with the other specimens that were tested. PMID- 25539005 TI - The floral morphospace--a modern comparative approach to study angiosperm evolution. AB - Morphospaces are mathematical representations used for studying the evolution of morphological diversity and for the evaluation of evolved shapes among theoretically possible ones. Although widely used in zoology, they--with few exceptions--have been disregarded in plant science and in particular in the study of broad-scale patterns of floral structure and evolution. Here we provide basic information on the morphospace approach; we review earlier morphospace applications in plant science; and as a practical example, we construct and analyze a floral morphospace. Morphospaces are usually visualized with the help of ordination methods such as principal component analysis (PCA) or nonmetric multidimensional scaling (NMDS). The results of these analyses are then coupled with disparity indices that describe the spread of taxa in the space. We discuss these methods and apply modern statistical tools to the first and only angiosperm wide floral morphospace published by Stebbins in 1951. Despite the incompleteness of Stebbins' original dataset, our analyses highlight major, angiosperm-wide trends in the diversity of flower morphology and thereby demonstrate the power of this previously neglected approach in plant science. PMID- 25539007 TI - Differences in degradation behavior of two non-cross-linked collagen barrier membranes: an in vitro and in vivo study. AB - OBJECTIVES: Collagen barrier membranes are used in guided bone regeneration/guided tissue regeneration because of their excellent bio- and cytocompatibility. However, they are considered to have limitations in clinical outcome because of rapid and unpredictable degradation profiles. The aim of this study was to investigate the degradation behavior of two porcine-based, non-cross linked collagen membranes in vitro and in vivo. MATERIALS AND METHODS: RemaixTM (RX; Matricel GmbH, Herzogenrath, Germany) and Bio-Gide(r) (BG; Geistlich Pharma AG, Wolhusen, Switzerland) membranes were characterized by testing mechanical strength, denaturation temperature, enzymatic degradation and hydroxyproline content in vitro (n = 5 up to 16). Thereafter, both membranes were implanted subcutaneously in rats (n = 20) for up to 20 weeks to investigate tissue compatibility with respect to membrane thickness. RESULTS: BG contained a significant higher hydroxyproline content compared with RX, but RX showed a higher stress at break (dry: 11.4 (SD 2.9) vs. 5.5 (SD 1.5) N/mm(2)), higher suture retention (wet: 5.6 (SD 1.3) vs. 2.7 (SD 0.7) N), increased denaturation temperature (55.1 (SD 1) vs. 49.4 (SD 0.6) degrees C) and an almost twofold reduction in degradation rate (15.6% (SEM 1.3)/h vs. 24.8% (SEM 2.9)/h) in vitro. In the rat model, both membranes showed excellent tissue compatibility without signs of inflammatory reactions. Shortly after implantation, RX and BG showed moderate infiltration of mononuclear cells that appeared not to be influenced by the surface texture of the membranes. In the histomorphometric analysis, both membranes showed significant different thickness over the 20 weeks period (P = 0.0002). Although the thickness remained almost stable during the first 9 weeks after implantation, after 20 weeks, the thickness of RX decreased only slightly, whereas BG showed a thickness loss of around 50% and stronger degradation than RX. Therefore, the higher stability of RX against biodegradation found in vitro was confirmed in the animal study. CONCLUSION: This study shows differences in the biodegradation characteristics of two non-cross-linked collagen membranes in vitro and in vivo. Whether the higher stability of RX is of clinical relevance should be analyzed in future clinical investigations. PMID- 25539008 TI - Cell-mediated BMP-2 release from a novel dual-drug delivery system promotes bone formation. AB - OBJECTIVES: In this study, a novel biomimetic calcium phosphate bone substitute (BioCaP) is introduced as a dual-drug release system with two drug/protein delivery modes: protein is incorporated into (i) the interior of BioCaP (an internal depot); and (ii) a superficial calcium phosphate coating on BioCaP (a surface-coated depot). Our aim is to investigate each of the two delivery modes of BioCaP. Our hypotheses are that (i) both of the drug delivery modes, in in vitro as well as in vivo environment, can achieve a sustained cell-mediated protein release; and (ii) BioCaP with these two delivery modes with incorporated bone morphogenetic protein-2 (BMP-2) promotes bone formation. MATERIALS AND METHODS: Tablets of BioCaP were prepared with different carrying modes using bovine serum albumin (BSA) as model protein. The release of this protein was analysed (n = 6 per group). Granules of BioCaP with different carrying modes of BMP-2 were implanted subcutaneously in rats (n = 6 animals per group). Samples were collected after 5 weeks for histomorphometric analysis. RESULTS: In vitro data showed that the internal and surface-coated depots of BSA resulted in a sustained osteoclast-mediated release, while the adsorbed BSA was rapidly released, and this release was not affected by osteoclasts. In vivo data showed that the volume densities of bone, bone marrow, and blood vessels were significantly higher in samples where BMP-2 was incorporated internally or in the coating compared with granules with adsorbed growth factor. Osteoclast-like cells were associated with the granules, and resorption lacunae were frequently observed. CONCLUSION: It is shown that different modes of incorporation of BMP-2 on and in BioCaP granules have a beneficial effect on the formation of ectopic bone. This dual-drug release system makes BioCaP granule a promising tool for delivering multiple therapeutic agents for different clinical applications. PMID- 25539009 TI - Biomedical ITC convergence engineering. PMID- 25539010 TI - Histiocytic clearance of neoplastic cells in acute promyelocytic leukemia. PMID- 25539011 TI - Reply to the letter to the editor: the case for duplicate meta-analyses of patent foramen ovale closure in patients with cryptogenic stroke: more a ripple than a tsunami. PMID- 25539012 TI - Reply: To PMID 24247272. PMID- 25539013 TI - Controlling the mechanism of phase transformation of colloidal In2O3 nanocrystals. AB - Controlling the crystal structure of transparent metal oxides is essential for tailoring the properties of these polymorphic materials to specific applications. The structural control is usually done via solid state phase transformation at high temperature or pressure. Here, we report the kinetic study of in situ phase transformation of In2O3 nanocrystals from metastable rhombohedral phase to stable cubic phase during their colloidal synthesis. By examining the phase content as a function of time using the model fitting approach, we identified two distinct coexisting mechanisms, surface and interface nucleation. It is shown that the mechanism of phase transformation can be controlled systematically through modulation of temperature and precursor to solvent ratio. The increase in both of these parameters leads to gradual change from surface to interface nucleation, which is associated with the increased probability of nanocrystal contact formation in the solution phase. The activation energy for surface nucleation is found to be 144 +/- 30 kJ/mol, very similar to that for interface nucleation. Despite the comparable activation energy, interface nucleation dominates at higher temperatures due to increased nanocrystal interactions. The results of this work demonstrate enhanced control over polymorphic nanocrystal systems and contribute to further understanding of the kinetic processes at the nanoscale, including nucleation, crystallization, and biomineralization. PMID- 25539014 TI - Translocation and induced permeability of random amphiphilic copolymers interacting with lipid bilayer membranes. AB - We investigate adsorption and passive translocation of random amphiphilic copolymers interacting with a self-assembled lipid bilayer membrane. By using the bond fluctuation model with explicit solvent, we consider random copolymers under variation of the fraction, H, of hydrophobic sites and chain length. Our results indicate a point of balanced hydrophobicity, where a slight excess of hydrophobic monomers compensates an additional insertion barrier due to the self-organized packing of the bilayer. Close to balanced hydrophobicity, we observe translocation events of shorter polymers through the membrane. Compared to homopolymers, surface localization of amphiphilic polymers is considerably increased due to the polar nature of the molecules with respect to the amphiphilic environment, and translocations are suppressed for longer chains. Close to balanced hydrophobicity, the polymer induces dynamic and static perturbations in the bilayer, and permeability with respect to solvent is significantly increased around the copolymer. We discuss how to design membrane active copolymers with a desired emphasis on either translocation or permeabilization based on a systematic sequence analysis. Our results indicate that alternating copolymers with an optimal block size smaller than the lipid size maximize perturbation of the bilayer, whereas for passive translocation, the limit of small block size or homopolymers with balanced hydrophobicity are most relevant. PMID- 25539015 TI - Exploring architecture of xyloglucan cellulose nanocrystal complexes through enzyme susceptibility at different adsorption regimes. AB - Xyloglucan (XG) is believed to act as a cementing material that contributes to the cross-linking and mechanical properties of the cellulose framework in plant cell walls. XG can adsorb to the cellulose nanocrystal (CNC) surface in vitro in order to simulate this in vivo relationship. The target of our work was to investigate the sorption behavior of tamarind seed XG on CNC extracted from cotton linters at different XG/CNC concentration ratios, that is, different adsorption regimes regarding the XG-CNC complex organization and the enzymatic susceptibility of XG. First, we determined the adsorption isotherm. Second, XG CNC complexes were enzymatically hydrolyzed using a xyloglucan-specific endoglucanase in order to quantify the different XG fractions involved in binding to CNC and to determine adsorption regimes, that is, presence of loops, tails, and trains. Finally, the architecture of the XG-CNC complex was investigated by transmission electron microscopy imaging of negatively stained XG-CNC suspensions and XG immunolabeled suspensions at different XG/CNC concentration ratios, both before and after xyloglucanase hydrolysis process. This study revealed that an increasing XG/CNC concentration ratio led to a change in the XG binding organization to CNC. At low XG/CNC concentration ratios, almost all XG chains were bound as trains to the CNC surface. In contrast, at increasing XG/CNC concentration ratios, the proportion of loops and tails increases. The organization change induces CNC aggregation to form a cellulose/XG network at low XG/CNC regimes, whereas CNC remains in the form of individual particles at higher XG/CNC regimes. Results are discussed both regarding the biological role of XG in plant cell walls and in the perspective of designing new biobased materials. PMID- 25539016 TI - Carbene-dichlorosilylene stabilized phosphinidenes exhibiting strong intramolecular charge transfer transition. AB - The unstable species dichlorosilylene was previously stabilized by carbene. The lone pair of electrons on the silicon atom of (carbene)SiCl2 can form a coordinate bond with metal-carbonyls. Herein we report that (carbene)SiCl2 can stabilize a phosphinidene (Ar-P, a carbone analogue) with the general formula carbene->SiCl2->P-Ar (carbene = cyclic alkyl(amino) carbene (cAAC; 2) and N heterocyclic carbene (NHC; 3)). Compounds 2 and 3 are stable, isolable, and storable at 0 degrees C (2) to room temperature (3) under an inert atmosphere. The crystals of 2 and 3 are dark blue and red, respectively. The intense blue color of 2 arises due to the strong intramolecular charge transfer (ICT) transition from piSi?P->pi*cAAC. The electronic structure and bonding of 2, 3 were studied by theoretical calculations. The HOMO of the molecule is located on the piSi?P bond, while the LUMO is located at the carbene moiety (cAAC or NHC). The dramatic change in color of these compounds from red (3, NHC) to blue (2, cAAC) is ascribed to the difference in energy of the LUMO within the carbenes (cAAC/NHC) due to a lower lying LUMO of cAAC. PMID- 25539017 TI - Assembly of metal-organic frameworks based on 3,3',5,5'-azobenzene tetracarboxylic acid: photoluminescences, magnetic properties, and gas separations. AB - We systematically studied the solvothermal reactions of transition-metal ions and H4abtc ligand and successfully isolated five metal-organic frameworks with various characterized tools, which are formulated as {[Mn2(abtc)(DMA)2.75].1.25(DMA)}n (1), {[NH2(CH3)2][Co3(COOH)2.5(abtc)(H2O)2]2.H2O}n (2), {[Zn3(abtc)1.5(DMF)3].1.75(DMF)}n (3), {[Zn2(abtc)(H2O)0.75(DMA)0.5].3(DMA).(H2O)}n (4), and {[Cd2(abtc)(DMA)2].2(DMA)}n (5), (H4abtc = 3,3',5,5'-azobenzenetetracarboxylic acid, DMF = N,N dimethylformamide, and DMA = N,N-dimethylacetamide). 1-5 all consist of {Mn(CO2)4}-type clusters and H4abtc ligands; however, they exhibit four distinct architectures resulting from different coordinated modes of H4abtc ligand. A pair of Mn(2+)ions in 1 forms a {Mn2(CO2)4} cluster, which further results in the "PtS"-type three-dimensional (3D) framework. In 2, three independent Co(2+) ions are bridged by COOH(-) groups to afford a {Co3} core, and {Co3} cores are connected by abtc(2-) to generate a "ZSW1"-type topology. Two types of {Zn2(CO2)4} secondary building units in 3 linked by abtc(2-) give the 3D "NbO" type cage. When DMF is replaced by DMA and CH3OH, the scarce "nou"-type topology of 4 is obtained. And 5 is isomorphous to 1. Photoluminescence properties of 1-5 were characterized. Magnetic measurements demonstrate that dominant antiferromagnetic interactions exist in 1 and 2. In addition, 3 exhibits significant adsorption capability of CO2 and highly selective sorption of CO2 over N2. PMID- 25539018 TI - Linking health information seeking to behavioral outcomes: antecedents and outcomes of childhood vaccination information seeking in South Korea. AB - Although research on health information has made significant progress in identifying the antecedents of individuals' information-seeking behavior in the context of the United States, the results have not been generalizable to the contexts of many other countries. Moreover, little is known about how one's information-seeking behavior is connected to actual behavioral outcomes relevant to the search action. The authors conducted an online survey with a stratified random sample of 1,004 mothers to examine the applicability of the comprehensive model of health information seeking in predicting the use of diverse childhood vaccination information sources in South Korea, and to investigate associations between the mothers' engagement with specific vaccine information sources and behavioral intention to immunize their children. Findings indicated that the hierarchical structure and the role of predictors within the comprehensive model of health information seeking provided a valid framework in the context of vaccine information seeking in Korea. In addition, the authors found negative associations between the use of certain types of information sources and mothers' intention to vaccinate. This suggests that the dissemination of critical health information through a variety of available sources does not automatically lead to prudent behavioral decisions when the specific characteristics of the different sources are not considered. PMID- 25539019 TI - SEX DIFFERENCES IN SCORES on THE DRAW-A-PERSON TEST ACROSS CHILDHOOD: DO THEY RELATE TO GRAPHIC FLUENCY? AB - Girls are said to outperform boys in the human figure drawing, but some disagreement exists among studies regarding such sex differences, and the reasons for these sex differences are unclear. The study examined how sex, age, and graphic fluency affect scores at the human figure drawing in large sample of children aged five to 12 years. To that end, the Draw-a-Person Test was administered to 336 boys and girls from kindergarten to Grade 6, using Goodenough's scoring method. Graphic fluency was measured using Torrance's Parallel Lines Test. Results showed a sex by age interaction on scores at the Draw-a-Person test, with girls outperforming boys at Grades 3 and 6. Split-sample regression analyses indicated that for boys both age and graphic fluency were relevant predictors for scores on the Draw-a-Person test; by contrast, for girls age, but not fluency, predicted the drawing scores. It was concluded that graphic fluency differently affected boys' and girls' scores. PMID- 25539020 TI - Effects of coloured lighting on the perception of interior spaces. AB - Use of coloured lighting in interior spaces has become prevalent in recent years. Considerable importance is ascribed to coloured lighting in interior and lighting design. The effects of colour on the perception of interior spaces have been studied as surface colour; but here, the effects of three different types of chromatic light were investigated. The lighting differed in colour (red, green and white) and perceptions of interior space were assessed. 97 participants (59 women, 38 men; M age = 21.4 yr.) evaluated the experiment room on a questionnaire assessing eight evaluative factors: Pleasantness, Arousal, Aesthetics, Usefulness, Comfort, Spaciousness, Colour, and Lighting quality. Perceptions of the room differed by colour of lighting for some of the evaluative factors, but there was no sex difference in perceptions. Interior spaces may be perceived as equally pleasant under white, green and red lighting. Under white lighting a space is perceived as more useful, spacious, clear, and luminous. Green lighting would make the same effect. Green and white lighting were perceived equally comfortable in an interior space. Chromatic coloured lighting was perceived to be more aesthetic than white lighting. The results support previous findings for some evaluative factors, but differed for others. PMID- 25539021 TI - Growth of close-packed semiconducting single-walled carbon nanotube arrays using oxygen-deficient TiO2 nanoparticles as catalysts. AB - For the application of single-walled carbon nanotubes (SWNTs) in nanoelectronic devices, techniques to obtain horizontally aligned semiconducting SWNTs (s-SWNTs) with higher densities are still in their infancy. We reported herein a rational approach for the preferential growth of densely packed and well-aligned s-SWNTs arrays using oxygen-deficient TiO2 nanoparticles as catalysts. Using this approach, a suitable concentration of oxygen vacancies in TiO2 nanoparticles could form by optimizing the flow rate of hydrogen and carbon sources during the process of SWNT growth, and then horizontally aligned SWNTs with the density of ~ 10 tubes/MUm and the s-SWNT percentage above 95% were successfully obtained on ST cut quartz substrates. Theoretical calculations indicated that TiO2 nanoparticles with a certain concentration of oxygen vacancies have a lower formation energy between s-SWNT than metallic SWNT (m-SWNT), thus realizing the preferential growth of s-SWNT arrays. Furthermore, this method can also be extended to other semiconductor oxide nanoparticles (i.e., ZnO, ZrO2 and Cr2O3) for the selective growth of s-SWNTs, showing clear potential to the future applications in nanoelectronics. PMID- 25539022 TI - Electrocatalytic proton reduction by dimeric nickel complex of a sterically demanding pincer-type NS2 aminobis(thiophenolate) ligand. AB - Basic methanolysis of a sterically hindered aminobis(S-arylthiocarbamate) affords a novel aminobis(thiophenolate) pincer-type ligand NS22-; the in situ generated dianion reacts cleanly with Ni2+ and Zn2+ resulting in dimeric complexes with bridging thiophenolate ligands, as determined spectroscopically and by X-ray crystallography. The C2-symmetric [Ni(NS2)]2 dimer (1) has a square planar coordination geometry around the Ni2+ ions, while the [Zn(NS2)]2 analogue (2) is characterized by a distorted tetrahedral geometry around each independent Zn2+ ion. Addition of the neutral monodentate donor L = 2,6-xylylisocyanide to [Ni(NS2)]2 affords the monomeric complex [LNi(NS2)] (3), which is characterized in the solid state by a square planar geometry with the isocyanide donor trans to the tertiary amine of NS2. The pincer NS2 ligand provides redox plasticity to 1, manifested in the accessibility of the putative Ni+Ni+ and Ni3+Ni3+ dimeric complexes, based on comparative cyclic voltammetry studies with 2 and 3. The redox properties of 1 endow it with hydrogenase-type activity, as evidenced in the electrocatalytic reduction of protons in a mixed aqueous/organic phase, as well as the oxidation of hydrides from NaBH(OAc)3. Both 1 and 3 are resilient under protic and oxidative conditions, as evidenced in reactivity tests monitored by UV-vis spectroscopy. PMID- 25539023 TI - Cost-effectiveness of asthma therapy: a comprehensive review. AB - BACKGROUND: Asthma has an important impact in terms of both direct and indirect costs. In Europe, the disease costs ? 19 000 million a year. Moreover, the cost is greater among patients with severe uncontrolled asthma and is even higher when the work productivity is also taken into account. Improved control of the disease results in cost savings. In this context, cost-effectiveness and cost-utility studies offer important information for clinicians in deciding the best treatment options for asthmatic patients and contribute to ensure an efficient use of the available healthcare resources. METHODS: An English and Spanish literature search using electronic search engines (PubMed and EMBASE) was conducted in peer-review journals, from 2009 to June 2014. In order to perform the search for the most suitable and representative articles, key words were selected ("asthma", "cost effectiveness", "cost-utility", "QALY", "cost-benefit", "economic impact of asthma" "healthcare cost", "asthma treatment" and "work productivity with asthma"). RESULTS: Two-hundred forty-three titles and abstracts were identified by the primary literature search. The full text of the potentially 76 eligible papers was reviewed, and 22 articles were qualified to be finally included. CONCLUSIONS: This article provides a comprehensive review on the evidence of cost effectiveness of asthma treatments derived from the published literature and offers an overall summary of the socioeconomic burden of asthma and its relationship with the degree of disease control. Management alternatives, such as the use of combination therapy with ICS/LABA or omalizumab, when administered according to their current therapeutic indications, have been shown to be cost effective. PMID- 25539024 TI - Early-life antibiotic use is associated with wheezing among children with high atopic risk: a prospective European study. AB - BACKGROUND: Little is known about the relationship between antibiotic use and asthma in the children with a higher risk of allergic sensitization. We examine the association between the use of specific therapeutic antibiotics in the first year of life and development of wheezing by 36 months among children with a higher risk of allergic sensitization. METHODS: A multi-center prospective cohort study was conducted among children at high risk for allergic sensitization. A validated questionnaire was used to prospectively collect information on antibiotic use and potential risk factors for wheezing from parents or guardians of 606 children from three European countries at 6, 12, 24 and 36 months of age. Multivariate linear and logistic regression models were used to adjust for potential confounders and effect modifiers and to estimate the association of antibiotic use with the development of early childhood wheezing. RESULTS: Of the antibiotics assessed, only macrolide use in the first year of life was associated with increasing risk for wheezing by 36 months, after adjusting for gender, socioeconomic status, breast feeding >6 months, tobacco smoke exposure, family history of asthma, and respiratory infection (RR = 1.09; 95% CI 1.05-1.13). To avoid a bias by indication, we analyzed children with and without respiratory infection separately. Similar associations were observed for macrolides use in children who had no respiratory infection. CONCLUSIONS: In European children with a familial risk for allergic sensitization, we found a positive association between macrolide use in the first year of life and wheezing until 36 months old which was independent of the effect of respiratory infection. PMID- 25539025 TI - Psychopathology in difficult asthma. AB - OBJECTIVE: Within the asthma population, difficult asthma (DA) is a severe condition in which patients present with frequent exacerbations, hospitalizations and emergency room visits. The identification and treatment of psychopathology is included in the management of DA. Psychopathology is supposed to predispose patients to DA or vice versa; psychopathology may develop as a consequence of DA. We reviewed the available literature on empirical findings regarding psychopathology in adult patients with DA. METHODS: Studies in English language journals using MEDLINE, Cochrane and PsycINFO databases, were retrieved by an electronic search published from 1990 till July 2014. RESULTS: Literature on psychopathology in DA is scarce. The search identified 16 articles of which only 6 articles were specifically about psychopathology in adult patients with DA. Almost half of the patients with DA had evidence of psychopathology at both syndrome and symptom level. Moreover, psychopathology appeared to be related to frequent exacerbations in patients with DA. CONCLUSIONS: This literature review suggests a high prevalence of psychopathology of patients with DA, although it remains unclear whether psychopathology occurs more often in DA compared to "stable asthma". More research is needed on a possible role of psychopathology on clinical signs and symptoms in DA. PMID- 25539026 TI - Evaluation of a statewide medical home program on children and young adults with asthma. AB - OBJECTIVE: Asthma, the most common chronic condition among children, accounts for significant healthcare utilization and impact on quality of life. Care coordination in a medical home is considered standard practice, but has not been rigorously evaluated. METHODS: We initiated this pilot study of children/young adults with asthma (n = 967), ages: birth to 24 years, receiving care from a subset of pediatric practices (n = 20) participating in the Pennsylvania Medical Home Initiative, Educating Practices in Community-Integrated Care (92 practices statewide). We hypothesized children and youth with asthma receiving care coordination in the context of a formal medical home program would experience favorable associations with healthcare utilization and quality of life measures. RESULTS: A total of 9240 care coordination encounters for this cohort of children/youth occurred over 100 days. The average length of care coordination encounter was 20.7 minutes. The most common care coordination activity was referral management (21%) and the care coordinator in the practice most often contacted parent/family and specialists (75%). Children with more severe asthma had more hospitalizations and emergency department (ED) visits than children with less severe asthma. There was a significant decrease in school absences, ED visits and acute care visits for children/youth with asthma with increasing length of time in a medical home program (p < 0.05). CONCLUSION: Care coordination for children/youth with asthma is feasible and may yield improvements in healthcare utilization, expenditures and quality of life. Larger scale implementation of care coordination and medical home models for children/youth with asthma and other diagnoses are warranted. PMID- 25539027 TI - Novel strategies to enhance lateral flow immunoassay sensitivity for detecting foodborne pathogens. AB - Food contaminated by foodborne pathogens causes diseases, affects individuals, and even kills those affected individuals. As such, rapid and sensitive detection methods should be developed to screen pathogens in food. One current detection method is lateral flow immunoassay, an efficient technique because of several advantages, including rapidity, simplicity, stability, portability, and sensitivity. This review presents the format and principle of lateral flow immunoassay strip and the development of conventional lateral flow immunoassay for detecting foodborne pathogens. Furthermore, novel strategies that can be applied to enhance the sensitivity of lateral flow immunoassay to detect foodborne pathogens are presented; these strategies include innovating new label application, designing new formats of lateral flow immunoassay, combining with other methods, and developing signal amplification systems. With these advancements, detection sensitivity and detection time can be greatly improved. PMID- 25539029 TI - Synthesis of a pillar[5]arene-based [2]rotaxane with two equivalent stations via copper(I)-catalyzed alkyne-azide cycloaddition. AB - A one-pot synthesis of pillar[5]arene-based [2]rotaxanes containing one and two stations by copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction is reported. In situ formation of the two stations by two stepwise CuAAC reactions allows for the synthesis of a [2]rotaxane containing two stations with equal energy levels that exhibit shuttling of the pillar[5]arene wheel. PMID- 25539028 TI - The importance of ensemble averaging in enzyme kinetics. AB - CONSPECTUS: The active site of an enzyme is surrounded by a fluctuating environment of protein and solvent conformational states, and a realistic calculation of chemical reaction rates and kinetic isotope effects of enzyme catalyzed reactions must take account of this environmental diversity. Ensemble averaged variational transition state theory with multidimensional tunneling (EA VTST/MT) was developed as a way to carry out such calculations. This theory incorporates ensemble averaging, quantized vibrational energies, energy, tunneling, and recrossing of transition state dividing surfaces in a systematic way. It has been applied successfully to a number of hydrogen-, proton-, and hydride-transfer reactions. The theory also exposes the set of effects that should be considered in reliable rate constants calculations. We first review the basic theory and the steps in the calculation. A key role is played by the generalized free energy of activation profile, which is obtained by quantizing the classical potential of mean force as a function of a reaction coordinate because the one-way flux through the transition state dividing surface can be written in terms of the generalized free energy of activation. A recrossing transmission coefficient accounts for the difference between the one-way flux through the chosen transition state dividing surface and the net flux, and a tunneling transmission coefficient converts classical motion along the reaction coordinate to quantum mechanical motion. The tunneling calculation is multidimensional, accounting for the change in vibrational frequencies along the tunneling path and shortening of the tunneling path with respect to the minimum energy path (MEP), as promoted by reaction-path curvature. The generalized free energy of activation and the transmission coefficients both involve averaging over an ensemble of reaction paths and conformations, and this includes the coupling of protein motions to the rearrangement of chemical bonds in a statistical mechanically correct way. The standard deviations of the transmissions coefficients provide information on the diversity of the distribution of reaction paths, barriers, and protein conformations along the members of an ensemble of reaction paths passing through the transition state. We first illustrate the theory by discussing the application to both wild-type and mutant Escherichia coli dihydrofolate reductase and hyperthermophilic Thermotoga maritima dihydrofolate reductase (DHFR); DHFR is of special interest because the protein conformational changes have been widely studied. Then we present shorter discussions of several other applications of EA-VTST/MT to transfer of protons, hydrogen atoms, and hydride ions and their deuterated analogs. Systems discussed include hydride transfer in alcohol dehydrogenase, xylose isomerase, and thymidylate synthase, proton transfer in methylamine dehydrogenase, hydrogen atom transfer in methylmalonyl-CoA mutase, and nucleophilic substitution in haloalkane dehalogenase and two-dimensional potentials of mean force for potentially coupled proton and hydride transfer in the beta-oxidation of butyryl-coenzyme A catalyzed by short-chain acyl-CoA dehydrogenase and in the pyruvate to lactate transformation catalyzed by lactate dehydrogenase. PMID- 25539030 TI - Hydrothermal growth of hierarchical Ni3S2 and Co3S4 on a reduced graphene oxide hydrogel@Ni foam: a high-energy-density aqueous asymmetric supercapacitor. AB - Ni foam@reduced graphene oxide (rGO) hydrogel-Ni3S2 and Ni foam@rGO hydrogel Co3S4 composites have been successfully synthesized with the aid of a two-step hydrothermal protocol, where the rGO hydrogel is sandwiched between the metal sulfide and Ni foam substrate. Sonochemical deposition of exfoliated rGO on Ni foam with subsequent hydrothermal treatment results in the formation of a rGO hydrogel-coated Ni foam. Then second-time hydrothermal treatment of the dried Ni@rGO substrate with corresponding metal nitrate and sodium sulfide results in individual uniform growth of porous Ni3S2 nanorods and a Co3S4 self-assembled nanosheet on a Ni@rGO substrate. Both Ni@rGO-Ni3S2 and Ni@rGO-Co3S4 have been electrochemically characterized in a 6 M KOH electrolyte, exhibiting high specific capacitance values of 987.8 and 1369 F/g, respectively, at 1.5 A/g accompanied by the respective outstanding cycle stability of 97.9% and 96.6% at 12 A/g over 3000 charge-discharge cycles. An advanced aqueous asymmetric (AAS) supercapacitor has been fabricated by exploiting the as-prepared Ni@rGO-Co3S4 as a positive electrode and Ni@rGO-Ni3S2 as a negative electrode. The as-fabricated AAS has shown promising energy densities of 55.16 and 24.84 Wh/kg at high power densities of 975 and 13000 W/kg, respectively, along with an excellent cycle stability of 96.2% specific capacitance retention over 3000 charge-discharge cycles at 12 A/g. The enhanced specific capacitance, stupendous cycle stability, elevated energy density, and a power density as an AAS of these electrode materials indicate that it could be a potential candidate in the field of supercapacitors. PMID- 25539031 TI - Two-dimensional material confined water. AB - CONSPECTUS: The interface between water and other materials under ambient conditions is of fundamental importance due to its relevance in daily life and a broad range of scientific research. The structural and dynamic properties of water at an interface have been proven to be significantly difference than those of bulk water. However, the exact nature of these interfacial water adlayers at ambient conditions is still under debate. Recent scanning probe microscopy (SPM) experiments, where two-dimensional (2D) materials as ultrathin coatings are utilized to assist the visualization of interfacial water adlayers, have made remarkable progress on interfacial water and started to clarify some of these fundamental scientific questions. In this Account, we review the recently conducted research exploring the properties of confined water between 2D materials and various surfaces under ambient conditions. Initially, we review the earlier studies of water adsorbed on hydrophilic substrates under ambient conditions in the absence of 2D coating materials, which shows the direct microscopic results. Subsequently, we focus on the studies of water adlayer growth at both hydrophilic and hydrophobic substrates in the presence of 2D coating materials. Ice-like water adlayers confined between hydrophobic graphene and hydrophilic substrates can be directly observed in detail by SPM. It was found that the packing structure of the water adlayer was determined by the hydrophilic substrates, while the orientation of intercalation water domains was directed by the graphene coating. In contrast to hydrophilic substrates, liquid like nanodroplets confined between hydrophobic graphene and hydrophobic substrates appear close to step edges and atomic-scale surface defects, indicating that atomic-scale surface defects play significant roles in determining the adsorption of water on hydrophobic substrates. In addition, we also review the phenomena of confined water between 2D hydrophilic MoS2 and the hydrophilic substrate. Finally, we further discuss researchers taking advantage of 2D graphene coatings to stabilize confined water nanodroplets to manipulate nanofluidics through applying an external force by using novel SPM techniques. Moreover, for future technology application purposes, the doping effect of confined water is also discussed. The use of 2D materials as ultrathin coatings to investigate the properties of confined water under ambient conditions is developing and recognized as a profound approach to gain fundamental knowledge of water. This ideal model system will provide new opportunities in various research fields. PMID- 25539032 TI - High-performance liquid chromatography separation of cis-trans anthocyanin isomers from wild Lycium ruthenicum Murr. employing a mixed-mode reversed phase/strong anion-exchange stationary phase. AB - The cis-trans isomerism is a common phenomenon for acylated anthocyanins. Nevertheless, few studies reported effective methods for the preparation of isomeric anthocyanins from natural products. In this work, a high-performance liquid chromatography (HPLC) method was developed to efficiently purify anthocyanin isomers from Lycium ruthenicum Murr. based on a mixed-mode reversed phase/strong anion-exchange column (named XCharge C8SAX). Four commercially available columns were evaluated with a pair of isomeric anthocyanins, and the results demonstrated that the XCharge C8SAX column exhibited improved selectivity and column efficiency for the isomers. The chromatographic parameters, including pH, organic content, and ionic strength, were investigated. Optimal separation quality for the anthocyanin isomers was achieved on the XCharge C8SAX column. Six pure anthocyanins, including two pairs of cis-trans isomeric anthocyanins with one new anthocyanin, were purified from L. ruthenicum and identified. All of the results indicated that this method is an effective way to separate anthocyanins, especially for cis-trans isomers. PMID- 25539033 TI - Alleviative effect of quercetin on rat testis against arsenic: a histological and biochemical study. AB - The preventive effect of quercetin on arsenic stimulated reproductive ailments in male Sprague Dawely (SD) rats was investigated. Twenty rats were divided into four groups. The first group served as a control and was provided tap water. The second group of rats was treated with sodium arsenite at the dose of 50 ppm in drinking water. The third group served as a positive control and received an oral dose of quercetin (50 mg/kg). In the fourth group, quercetin (50 mg/kg) was co administered orally with arsenic (50 ppm in drinking water). All the treatments were carried out for 49 days. Arsenic treatment resulted in adverse morphological and histopathological changes in testis of rats including reduced epithelial height and tubular diameter, and increased luminal diameter. In contrast, these adverse effects of arsenic were eliminated by co-administration of quercetin. Additionally arsenic treatment significantly increased testicular thiobarbituric acid reactive substance (TBARS) levels while catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), and glutathione reductase (GSR) activities, and plasma and intra-testicular testosterone concentrations, were decreased significantly. Lipid peroxidation (LPO) was significantly suppressed and depleted antioxidant defense mechanism was restored by the quercetin co-treatment. Also quercetin treatment resulted in a marked increase in plasma and testicular testosterone concentrations. On the basis of these findings, it was concluded that quercetin may be used as a potential therapeutic drug against arsenic induced reproductive toxicity. PMID- 25539034 TI - An Intensive Locomotor Training Paradigm Improves Neuropathic Pain following Spinal Cord Compression Injury in Rats. AB - Spinal cord injury (SCI) is often associated with both locomotor deficits and sensory dysfunction, including debilitating neuropathic pain. Unfortunately, current conventional pharmacological, physiological, or psychological treatments provide only marginal relief for more than two-thirds of patients, highlighting the need for improved treatment options. Locomotor training is often prescribed as an adjunct therapy for peripheral neuropathic pain but is rarely used to treat central neuropathic pain. The goal of this study was to evaluate the potential anti-nociceptive benefits of intensive locomotor training (ILT) on neuropathic pain consequent to traumatic SCI. Using a rodent SCI model for central neuropathic pain, ILT was initiated either 5 d after injury prior to development of neuropathic pain symptoms (the "prevention" group) or delayed until pain symptoms fully developed (~3 weeks post-injury, the "reversal" group). The training protocol consisted of 5 d/week of a ramping protocol that started with 11 m/min for 5 min and increased in speed (+1 m/min/week) and time (1-4 minutes/week) to a maximum of two 20-min sessions/d at 15 m/min by the fourth week of training. ILT prevented and reversed the development of heat hyperalgesia and cold allodynia, as well as reversed developed tactile allodynia, suggesting analgesic benefits not seen with moderate levels of locomotor training. Further, the analgesic benefits of ILT persisted for several weeks once training had been stopped. The unique ability of an ILT protocol to produce robust and sustained anti-nociceptive effects, as assessed by three distinct outcome measures for below-level SCI neuropathic pain, suggests that this adjunct therapeutic approach has great promise in a comprehensive treatment strategy for SCI pain. PMID- 25539035 TI - Overexpression of the Circadian Clock Gene Rev-erbalpha Affects Murine Bone Mesenchymal Stem Cell Proliferation and Osteogenesis. AB - Bone mesenchymal stem cell (BMSC) age-related changes include decreased osteogenesis and increased adipogenesis. Rev-erbalpha and the Wnt/beta-catenin signaling pathway were known to play important roles in BMSC aging. In this study, we have aimed to elucidate whether Rev-erbalpha and Wnt/beta-catenin signaling interact during BMSC proliferation and osteogenesis. Our results showed that Rev-erbalpha expression gradually dropped during BMSC osteogenesis, and overexpression of Rev-erbalpha in BMSCs inhibited cell proliferation and osteogenesis. The inhibition of cell proliferation induced by Rev-erbalpha overexpression was partially reversed when Wnt/beta-catenin signaling was activated. These results suggested that Rev-erbalpha could promote BMSC aging and may be the negative regulator during the late stage of osteogenesis. The clock gene Rev-erbalpha and Wnt/beta-catenin signaling interact in the regulation of cell proliferation. PMID- 25539036 TI - An fMRI study of differences in brain activity among elite, expert, and novice archers at the moment of optimal aiming. AB - OBJECTIVE: We investigated brain activity in elite, expert, and novice archers during a simulated archery aiming task to determine whether neural correlates of performance differ by skill level. BACKGROUND: Success in shooting sports depends on complex mental routines just before the shot, when the brain prepares to execute the movement. METHODS: During functional magnetic resonance imaging, 40 elite, expert, or novice archers aimed at a simulated 70-meter-distant target and pushed a button when they mentally released the bowstring. RESULTS: At the moment of optimal aiming, the elite and expert archers relied primarily on a dorsal pathway, with greatest activity in the occipital lobe, temporoparietal lobe, and dorsolateral pre-motor cortex. The elites showed activity in the supplementary motor area, temporoparietal area, and cerebellar dentate, while the experts showed activity only in the superior frontal area. The novices showed concurrent activity in not only the dorsolateral pre-motor cortex but also the ventral pathways linked to the ventrolateral pre-motor cortex. The novices exhibited broad activity in the superior frontal area, inferior frontal area, ventral prefrontal cortex, primary motor cortex, superior parietal lobule, and primary somatosensory cortex. CONCLUSIONS: The more localized neural activity of elite and expert archers than novices permits greater efficiency in the complex processes subserved by these regions. The elite group's high activity in the cerebellar dentate indicates that the cerebellum is involved in automating simultaneous movements by integrating the sensorimotor memory enabled by greater expertise in self-paced aiming tasks. A companion article comments on and generalizes our findings. PMID- 25539037 TI - Neural processes distinguishing elite from expert and novice athletes. AB - This commentary builds on a companion article in which Kim et al compare brain activation in elite, expert, and novice archers during a simulated target aiming task (Kim et al. 2014. Cogn Behav Neurol. 27:173-182). With the archery study as our starting point, we address 4 neural processes that may be responsible in general for elite athletes' superior performance over experts and novices: neural efficiency, cortical expansion, specialized processes, and internal models. In Kim et al's study, the elite archers' brains showed more activity in the supplementary motor area and the cerebellum than those of the novices and experts, and showed minimal widespread activity, especially in frontal areas involved with executive control. Kim et al's results are consistent with the idea of specialized neural processes that help coordinate motor planning and control. As athletes become more skilled, these processes may mediate the reduction in widespread activity in regions mapping executive control, and may produce a shift toward more automated processing. Kim et al's finding that activity in the cerebellum rose with increasing skill is consistent both with expansion of the finger representational area in the cerebellum and with internal models that simulate how archers manipulate the bow and arrow when aiming. Kim et al prepare the way for testing of neuromodulation techniques to improve athletic performance, refine highly technical job skills, and rehabilitate patients. PMID- 25539038 TI - Highly variable blood pressure as a predictor of poor cognitive outcome in patients with acute lacunar infarction. AB - OBJECTIVE AND BACKGROUND: Many patients develop cognitive impairment after an acute stroke. It is not clear whether blood pressure variability is a prognostic factor for cognitive impairment. We aimed to determine the association between blood pressure variability on hospital admission and cognitive outcome in patients with acute lacunar infarction. METHODS: We performed a retrospective analysis on 22 men and 14 women (mean age, 61.8 years) who had completed a cognitive evaluation 3 months after onset of an acute lacunar infarction. The patients had no previous functional disability or dementia, stenosis in major cerebral arteries, cardiac embolic sources, or infarct in strategic territories for cognition. We used standard deviation and coefficient of variance as parameters of blood pressure variability, and each cognitive function test z score as an outcome parameter. We performed linear regression analysis to assess the relationship between blood pressure variability and cognition, adjusted for vascular risk factors, severity of neurologic deficits, and mean blood pressure. RESULTS: High variability of both systolic and diastolic blood pressure was significantly associated with low z scores on the Controlled Oral Word Association Test and the Digit Symbol Coding test (P<0.01). High variability of diastolic blood pressure was significantly associated with low z scores on the Korean Mini-Mental State Examination and Seoul Verbal Learning Test delayed recall (P<0.01). CONCLUSIONS: Highly variable blood pressure on admission for acute lacunar infarction may predict poor cognitive outcomes, especially frontal lobe dysfunction. PMID- 25539039 TI - Psychosocial factors and antiepileptic drug use related to delayed diagnosis of refractory psychogenic nonepileptic seizures. AB - OBJECTIVE: We analyzed clinical and psychosocial factors in patients with refractory psychogenic nonepileptic seizures, seeking characteristics that could hasten diagnosis. BACKGROUND: Psychogenic nonepileptic seizures remain a diagnostic challenge. Prognosis is best if patients are treated within 2 years of symptom onset. Psychosocial factors have been shown to provide important information for differential diagnosis. METHODS: Over a year and 1132 consecutive patients, our hospital's Epilepsy Unit suspected 93 patients of having psychogenic nonepileptic seizures and confirmed refractory psychogenic nonepileptic seizures in 67. We referred these patients to our psychiatric consultation unit for detailed diagnostic interviews, and 53 of the patients followed through. Two months after the psychiatric evaluation we gave them a psychiatric intervention, explaining the diagnosis and treating their comorbidities. We also tracked the patients' use of antiepileptic drugs for 3 months, from just before the psychiatric evaluation until a month after they started the intervention. RESULTS: Women, patients with an inadequate primary support group, and patients who had tried many antiepileptic drugs were most likely to have their diagnosis of psychogenic nonepileptic seizures delayed by >2 years after onset. A stepwise logistic regression showed that the 2 best predictors of late diagnosis were lack of availability of a primary support group and patients trying many antiepileptic drugs. CONCLUSIONS: Clinicians evaluating patients with questionable seizures should raise their suspicion of psychogenic nonepileptic seizures especially in female patients with an insufficient primary support group and a history of taking multiple antiepileptic drugs. PMID- 25539041 TI - Need for early diagnosis of mental and mobility changes in Wernicke encephalopathy. AB - Korsakoff syndrome is a chronic form of amnesia resulting from thiamine deficiency. The syndrome can develop from unrecognized or undertreated Wernicke encephalopathy. The intra-individual course of Wernicke-Korsakoff syndrome has not been studied extensively, nor has the temporal progression of gait disturbances and other symptoms of Wernicke encephalopathy. Here we present the detailed history of a patient whose acute symptoms of Wernicke encephalopathy were far from stable. We follow his mobility changes and the shifts in his mental status from global confusion and impaired consciousness to more selective cognitive deficits. His Wernicke encephalopathy was missed and left untreated, being labeled as "probable" Korsakoff syndrome. Patients with a history of self neglect and alcohol abuse, at risk of or suffering with Wernicke encephalopathy, should receive immediate and adequate vitamin replacement. Self-neglecting alcoholics who are bedridden may have severe illness and probably active Wernicke encephalopathy. In these patients, mobility changes, delirium, or impaired consciousness can be an expression of Wernicke encephalopathy, and should be treated to prevent further damage from the neurologic complications of thiamine deficiency. PMID- 25539042 TI - Topiramate improves psychiatric symptoms in a patient with Lewy body dementia. AB - Many patients with Lewy body dementia develop visual hallucinations and other psychiatric symptoms. These patients are hypersensitive to antipsychotic drugs. Although patients tolerate atypical better than typical antipsychotics, both types can cause major extrapyramidal side effects. The anticonvulsant mood stabilizer topiramate, which does not cause parkinsonism, has been used as adjuvant therapy for both the positive and negative symptoms of schizophrenia; these symptoms can resemble those of Lewy body dementia. This report documents a 65-year-old woman with a 3-year history of progressive dementia that over the past 2 years had become complicated by severe extrapyramidal symptoms and agitated hallucinations. Her hallucinations became daily and were disrupting to her family. She was given a clinical diagnosis of Lewy body dementia after imaging and laboratory studies ruled out other etiologies. Treatment with olanzapine relieved her psychotic symptoms but caused severe dystonias, daily myoclonic jerks, and tremors. Stopping the olanzapine and starting topiramate 25 mg daily eliminated the hallucinations and agitation without worsening her extrapyramidal side effects. However, the topiramate was stopped because the patient reportedly developed anorexia and significant weight loss. Her hallucinations returned. When topiramate was reinstated at 12.5 mg a day, her agitation resolved, although her hallucinations continued. After 6 months on this dose, her agitation was still fairly well controlled without serious side effects or worsening of her parkinsonian symptoms. PMID- 25539040 TI - White matter disease contributes to apathy and disinhibition in behavioral variant frontotemporal dementia. AB - OBJECTIVE: To relate changes in fractional anisotropy associated with behavioral variant frontotemporal dementia to measures of apathy and disinhibition. BACKGROUND: Apathy and disinhibition are the 2 most common behavioral features of behavioral variant frontotemporal dementia, and these symptoms are associated with accelerated patient decline and caregiver stress. However, little is known about how white matter disease contributes to these symptoms. METHODS: We collected neuropsychiatric data, volumetric magnetic resonance imaging, and diffusion-weighted imaging in 11 patients who met published criteria for behavioral variant frontotemporal dementia and had an autopsy-validated cerebrospinal fluid profile consistent with frontotemporal lobar degeneration. We also collected imaging data on 34 healthy seniors for analyses defining regions of disease in the patients. We calculated and analyzed fractional anisotropy with a white matter tract-specific method. This approach uses anatomically guided data reduction to increase sensitivity, and localizes results within canonically defined tracts. We used nonparametric, cluster-based statistical analysis to relate fractional anisotropy to neuropsychiatric measures of apathy and disinhibition. RESULTS: The patients with behavioral variant frontotemporal dementia had widespread reductions in fractional anisotropy in anterior portions of frontal and temporal white matter, compared to the controls. Fractional anisotropy correlated with apathy in the left uncinate fasciculus and with disinhibition in the right corona radiata. CONCLUSIONS: In patients with behavioral variant frontotemporal dementia, apathy and disinhibition are associated with distinct regions of white matter disease. The implicated fiber tracts likely support frontotemporal networks that are involved in goal-directed behavior. PMID- 25539043 TI - Sodium channel blockers: a patent review (2010 - 2014). AB - INTRODUCTION: Abnormal activity of voltage-gated sodium channels (VGSCs) is related to several pathological processes, including cardiac arrhythmias, epilepsy, cancer, neurodegenerative diseases, spasticity, chronic and neuropathic pain. As such VGSCs are considered important therapeutic targets. AREAS COVERED: This review summarized > 30 patents on sodium channel blockers, having beneficial effects on a number of diseases. Pubmed, http://www.sciencedirect.com/ , SciFinder Scholar, http://ep.espacenet.com/ were used as sources for this review and patents filed 2010 and July 2014 were examined. EXPERT OPINION: Over the past 4 years we assisted to a continuous effort in the discovery of new sodium channel blockers by a large number of pharmaceutical companies. All the different chemical classes presented, and here analyzed, could represent an important breakout but, the lack of precise structural information, with the incompleteness of the biological data hampered the possibility to understand the real 'state of the art' of any of these inventions. Upon analysis of a number of patents in this review, it remains clear that the major hurdle faced by the discovery teams is the ability to develop subtype selective compounds. The development of subtype selective blockers could, in theory, lead to more effective and better tolerated compounds. PMID- 25539044 TI - Common and unique representations in pFC for face and place attractiveness. AB - Although previous neuroimaging research has identified overlapping correlates of subjective value across different reward types in the ventromedial pFC (vmPFC), it is not clear whether this "common currency" evaluative signal extends to the aesthetic domain. To examine this issue, we scanned human participants with fMRI while they made attractiveness judgments of faces and places-two stimulus categories that are associated with different underlying rewards, have very different visual properties, and are rarely compared with each other. We found overlapping signals for face and place attractiveness in the vmPFC, consistent with the idea that this region codes a signal for value that applies across disparate reward types and across both economic and aesthetic judgments. However, we also identified a subregion of vmPFC within which activity patterns for face and place attractiveness were distinguishable, suggesting that some category specific attractiveness information is retained in this region. Finally, we observed two separate functional regions in lateral OFC: one region that exhibited a category-unique response to face attractiveness and another region that responded strongly to faces but was insensitive to their value. Our results suggest that vmPFC supports a common mechanism for reward evaluation while also retaining a degree of category-specific information, whereas lateral OFC may be involved in basic reward processing that is specific to only some stimulus categories. PMID- 25539045 TI - Making cognitive latent variables manifest: distinct neural networks for fluid reasoning and processing speed. AB - Cognitive psychologists posit several specific cognitive abilities that are measured with sets of cognitive tasks. Tasks that purportedly tap a specific underlying cognitive ability are strongly correlated with one another, whereas performances on tasks that tap different cognitive abilities are less strongly correlated. For these reasons, latent variables are often considered optimal for describing individual differences in cognitive abilities. Although latent variables cannot be directly observed, all cognitive tasks representing a specific latent ability should have a common neural underpinning. Here, we show that cognitive tasks representing one ability (i.e., either perceptual speed or fluid reasoning) had a neural activation pattern distinct from that of tasks in the other ability. One hundred six participants between the ages of 20 and 77 years were imaged in an fMRI scanner while performing six cognitive tasks, three representing each cognitive ability. Consistent with prior research, behavioral performance on these six tasks clustered into the two abilities based on their patterns of individual differences and tasks postulated to represent one ability showed higher similarity across individuals than tasks postulated to represent a different ability. This finding was extended in the current report to the spatial resemblance of the task-related activation patterns: The topographic similarity of the mean activation maps for tasks postulated to reflect the same reference ability was higher than for tasks postulated to reflect a different reference ability. Furthermore, for any task pairing, behavioral and topographic similarities of underlying activation patterns are strongly linked. These findings suggest that differences in the strengths of correlations between various cognitive tasks may be because of the degree of overlap in the neural structures that are active when the tasks are being performed. Thus, the latent variable postulated to account for correlations at a behavioral level may reflect topographic similarities in the neural activation across different brain regions. PMID- 25539047 TI - Modularly evolved 2-aminoDMAP/squaramides as highly active bifunctional organocatalysts in Michael addition. AB - We report a new family of chiral bifunctional acid/base type organocatalysts, 2 aminoDMAP/Squaramides, which are proved to be highly active (1 mol % cat. loading) promoters in conjugate addition of dibenzoylmethane to various trans beta-nitroalkenes. Steric demand of the catalysts was clearly seen by a set-by set modulation of the squaramide unit through electronic and steric factors. The synergistic cooperation of 2-aminoDMAP "superbase" and sterically encumbered squaramide (H-bond donor) enabled complete conversion of a range of reactants into corresponding Michael adducts in a couple of hours with exquisite selectivities (up to 98% ee). PMID- 25539048 TI - Dynamically achieved active site precision in enzyme catalysis. AB - CONSPECTUS: The grand challenge in enzymology is to define and understand all of the parameters that contribute to enzymes' enormous rate accelerations. The property of hydrogen tunneling in enzyme reactions has moved the focus of research away from an exclusive focus on transition state stabilization toward the importance of the motions of the heavy atoms of the protein, a role for reduced barrier width in catalysis, and the sampling of a protein conformational landscape to achieve a family of protein substates that optimize enzyme-substrate interactions and beyond. This Account focuses on a thermophilic alcohol dehydrogenase for which the chemical step of hydride transfer is rate determining across a wide range of experimental conditions. The properties of the chemical coordinate have been probed using kinetic isotope effects, indicating a transition in behavior below 30 degrees C that distinguishes nonoptimal from optimal C-H activation. Further, the introduction of single site mutants has the impact of either enhancing or eliminating the temperature dependent transition in catalysis. Biophysical probes, which include time dependent hydrogen/deuterium exchange and fluorescent lifetimes and Stokes shifts, have also been pursued. These studies allow the correlation of spatially resolved transitions in protein motions with catalysis. It is now possible to define a long-range network of protein motions in ht-ADH that extends from a dimer interface to the substrate binding domain across to the cofactor binding domain, over a distance of ca. 30 A. The ongoing challenge to obtaining spatial and temporal resolution of catalysis-linked protein motions is discussed. PMID- 25539049 TI - Immunohistochemical distribution of leptin in kidney tissues of melatonin treated diabetic rats. AB - We examined using immunohistochemistry the distribution of leptin in kidney tissues of melatonin treated, streptozotocin (STZ) diabetic rats. The animals were divided into five groups: control, sham, melatonin-treated, diabetic and melatonin-treated diabetic. Kidney sections were prepared and stained with hematoxylin and eosin, and Crossman's triple staining for histological examination. The immunohistochemical localization of leptin in the kidney tissue was determined using the streptavidin-biotin-peroxidase method. We determined that on days 7 and 14, the leptin immunoreactivity of the diabetic and melatonin treated diabetic groups was weaker than for the other groups. Weak immunoreactivity was found in the proximal and distal tubules of the kidney in the diabetic and melatonin-treated diabetic groups on days 7 and 14, and strong immunoreactivity was found in the control, sham and melatonin groups. Melatonin application had no significant effect on leptin production in the kidney tissues of diabetic rats. PMID- 25539046 TI - Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems. AB - INTRODUCTION: Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. AREAS COVERED: This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. EXPERT OPINION: We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse. PMID- 25539050 TI - Neurotoxic effects of local anesthetics on the mouse neuroblastoma NB2a cell line. AB - Local anesthetics are used clinically for peripheral nerve blocks, epidural anesthesia, spinal anesthesia and pain management; large concentrations, continuous application and long exposure time can cause neurotoxicity. The mechanism of neurotoxicity caused by local anesthetics is unclear. Neurite outgrowth and apoptosis can be used to evaluate neurotoxic effects. Mouse neuroblastoma cells were induced to differentiate and generate neurites in the presence of local anesthetics. The culture medium was removed and replaced with serum-free medium plus 20 MUl combinations of epidermal growth factor and fibroblast growth factor containing tetracaine, prilocaine, lidocaine or procaine at concentrations of 1, 10, 25, or 100 MUl prior to neurite measurement. Cell viability, iNOS, eNOS and apoptosis were evaluated. Local anesthetics produced toxic effects by neurite inhibition at low concentrations and by apoptosis at high concentrations. There was an inverse relation between local anesthetic concentrations and cell viability. Comparison of different local anesthetics showed toxicity, as assessed by cell viability and apoptotic potency, in the following order: tetracaine > prilocaine > lidocaine > procaine. Procaine was the least neurotoxic local anesthetic and because it is short-acting, may be preferred for pain prevention during short procedures. PMID- 25539051 TI - A histochemical comparison of methyl green-pyronin, and hematoxylin and eosin for detecting apoptotic cells in oral squamous cell carcinoma, oral leukoplakia, oral submucous fibrosis and normal oral mucosa. AB - Analysis of apoptotic cells in oral pathological states could be useful for determining the rates of tissue turnover, which would help determine prognosis. The use of histochemical stains such as hematoxylin and eosin (H & E) and methyl green-pyronin (MGP) can provide a simple and cost-effective method for detecting apoptotic cells. We compared the efficacy of MGP and H & E for detecting apoptotic cells in oral squamous cell carcinoma (OSCC), oral leukoplakia (OL), oral submucous fibrosis (OSMF) and normal oral mucosa (NOM). Ten cases each of OSCC, OSMF, OL and NOM were retrieved from the archives and two serial sections were stained, one with H & E and the other with MGP. Apoptotic cells were identified at 100 x magnification and the apoptotic index was calculated. Apoptotic cells were distinguished more readily in MGP stained sections than in those stained with H & E. Also, the apoptotic cell count was greater in OSCC compared to OL, OSMF and NOM. We concluded that MGP staining can be used as a routine, cost-effective method for detecting apoptotic cells. PMID- 25539052 TI - Hematospermia due to clopidogrel: the unknown side effect. PMID- 25539053 TI - Pharmacokinetics of recombinant and plasma-derived factor IX products in pediatric patients with severe hemophilia B. PMID- 25539054 TI - Portal, but not peripheral, blood D-dimer level may help to differentiate malignant from benign pancreatic tumors. PMID- 25539055 TI - The impact of economic and noneconomic exchange on physicians' organizational attitudes: The moderating effects of the Chief Medical Officer. AB - BACKGROUND: Hospital-physician relationships are critical to hospitals' organizational success. A distinction can be drawn between economic and noneconomic physician-hospital exchange. Physician senior leadership could be an important component of managerial strategies aimed at optimizing hospital physician relationships. PURPOSE: The purpose of this study was to investigate the moderating role of the quality of exchange with the Chief Medical Officer (CMO) in the relationship between economic and noneconomic exchange and physicians' key organizational attitudes. METHODOLOGY: Self-employed physicians practicing at six Belgian hospitals were surveyed. Economic exchange was conceptualized by the concepts of distributive and procedural justice, whereas noneconomic exchange was conceptualized by the concepts of administrative and professional psychological contract. Our outcomes comprise three key organizational attitudes identified in the literature (job satisfaction, affective organizational commitment, and intention to leave). The moderating role of leader-member exchange with the CMO in these relationships was assessed. FINDINGS: Our results showed a relationship between both psychological contract breach and organizational justice and physicians' organizational attitudes. The quality of exchange with the CMO buffered the negative effect of psychological contract breach and reinforced the positive effects of organizational justice with respect to physicians' organizational attitudes. PRACTICE IMPLICATIONS: Our results demonstrate that both economic and noneconomic aspects are important when considering physicians' key organizational attitudes. The reciprocity dynamic between physician and hospital can be enhanced by high-quality exchange with the CMO. PMID- 25539056 TI - The experience of Patient Aligned Care Team (PACT) members. AB - BACKGROUND: In April 2010, the Veterans Health Administration (VHA) launched the Patient Aligned Care Team (PACT) initiative to implement a patient-centered medical home (PCMH) model. Few evaluations have addressed the effects of PCMH on health care professionals' experiences. PURPOSES: The aim of this study was to contribute to evaluation of the PACT initiative and the broader literature on PCMH by assessing respondents' experiences of implementing a PCMH model and becoming a teamlet. METHODOLOGY/APPROACH: A retrospective qualitative analysis of open-text responses in a survey fielded to all VHA Primary Care personnel (VHA Primary Care physicians, nurse practitioners, physician assistants, nurse care managers, clinical associates, and administrative clerks) in May and June 2012 (approximately 2 years into the 5-year planned implementation of PACT) using deductive and inductive content analysis. The main measures were two open response fields: "Is there anything else you would like us to relay to the VA leadership in Central Office?" and "Do you have any other comments or feedback on PACT?" The data consisted of free text responses of 3,868 survey participants who provided text for one or both of the open-response fields. FINDINGS: Although respondents viewed PACT positively as a model and reported it improved relationships with patients and increased patient satisfaction, they described multiple barriers to achieving functioning teamlets and unintended consequences, including reduced time with patients, increased participant burnout, and decreased team efficacy because of low-performing team members. A central theme related to staffing being insufficient for the new model. PRACTICE IMPLICATIONS: Insufficient staffing of PCMH teams is a critical barrier to realizing the benefits of the new model. Frontline staff have concrete recommendations for other problems, such as using back-up teams to cover during absences, but that will require providing more opportunities for feedback from staff to be heard. PMID- 25539057 TI - Effects of organizational context on Lean implementation in five hospital systems. AB - BACKGROUND: Despite broad agreement among researchers about the value of examining how context shapes implementation of improvement programs and projects, limited attention has been paid to contextual effects on implementation of Lean. PURPOSE: To help reduce gaps in knowledge of effects of intraorganizational context, we researched Lean implementation initiatives in five organizations and examined 12 of their Lean rapid improvement projects. All projects aimed at improving clinical care delivery. METHODOLOGY/APPROACH: On the basis of the literature on Lean, innovation, and quality improvement, we developed a framework of factors likely to affect Lean implementation and outcomes. Drawing on the framework, we conducted semistructured interviews and applied qualitative codes to the transcribed interviews. Available documents, data, and observations supplemented the interviews. We constructed case studies of Lean implementation in each organization, compared implementation across organizations, and compared the 12 projects. FINDINGS: Intraorganizational characteristics affecting organization-wide Lean initiatives and often also shaping project outcomes included CEO commitment to Lean and active support for it, prior organizational capacity for quality improvement-based performance improvement, alignment of the Lean initiative with the organizational mission, dedication of resources and experts to Lean, staff training before and during projects, establishment of measurable and relevant project targets, planning of project sequences that enhance staff capabilities and commitment without overburdening them, and ensuring communication between project members and other affected staff. Dependence of projects on inputs of new information technology was a barrier to project success. Incremental implementation of Lean produced reported improvements in operational efficiency and occasionally in care quality. However, even under the relatively favorable circumstances prevailing in our study sites, incremental implementation did not readily change organizational culture. PRACTICE IMPLICATIONS: This study should alert researchers, managers, and teachers of management to ways that contexts shape Lean implementation and may affect other types of process redesign and quality improvement. PMID- 25539058 TI - Rolling with the punches: examining the socialization experiences of kinesiology doctoral students. AB - PURPOSE: An increasing body of literature examines the socialization experiences of graduate students on a myriad of topics across academic disciplines. However, relatively absent from these discussions are the perspectives of kinesiology doctoral students. Using Weidman, Twale, and Stein's framework for graduate and professional student socialization, this research examined the doctoral education and socialization perspectives of 12 kinesiology students at 3 research institutions. METHOD: A phenomenological case-study approach incorporating interviews, both individual and focus group, and journals served to obtain participants' perspectives. Traditional data analysis, coding, thematic category development, and interpretation techniques were used. RESULTS: Participants provided critical experiences, enlightening perspectives, and specific recommendations regarding their socialization into the kinesiology academic field and profession. Four major thematic categories were derived from the data: (a) transition, when participants highlighted professional, academic, or personal shifts in perspectives occurring during studies; (b) negotiation, when participants pointed out experiences when significant consideration was given to the consequences, risk, and rewards of formal and informal interactions with peers, faculty, and administrators; (c) balance, during which participants described their struggles and successes with meeting academic, professional, and personal obligations; and (d) support, when participants identified emotional, financial, and professional resources that impacted their socialization. CONCLUSIONS: The authenticity and sameness of the participants' experiences call for further scrutiny and discussion of kinesiology doctoral student socialization policies and practices. Suggestions for future research and administrative initiatives are discussed. PMID- 25539059 TI - Reconstruction of fluorescence molecular tomography via a nonmonotone spectral projected gradient pursuit method. AB - Fluorescence molecular tomography (FMT) is a promising imaging technique in preclinical research, enabling three-dimensional location of the specific tumor position for small animal imaging. However, FMT presents a challenging inverse problem that is quite ill-posed and ill-conditioned. Thus, the reconstruction of FMT faces various challenges in its robustness and efficiency. We present an FMT reconstruction method based on nonmonotone spectral projected gradient pursuit (NSPGP) with /1-norm optimization. At each iteration, a spectral gradient projection method approximately minimizes a least-squares problem with an explicit one-norm constraint. A nonmonotone line search strategy is utilized to get the appropriate updating direction, which guarantees global convergence. Additionally, the Barzilai-Borwein step length is applied to build the optimal step length, further improving the convergence speed of the proposed method. Several numerical simulation studies, including multisource cases as well as comparative analyses, have been performed to evaluate the performance of the proposed method. The results indicate that the proposed NSPGP method is able to ensure the accuracy, robustness, and efficiency of FMT reconstruction. Furthermore, an in vivo experiment based on a heterogeneous mouse model was conducted, and the results demonstrated that the proposed method held the potential for practical applications of FMT. PMID- 25539060 TI - Imaging of skin birefringence for human scar assessment using polarization sensitive optical coherence tomography aided by vascular masking. AB - We demonstrate the in vivo assessment of human scars by parametric imaging of birefringence using polarization-sensitive optical coherence tomography (PS-OCT). Such in vivo assessment is subject to artifacts in the detected birefringence caused by scattering from blood vessels. To reduce these artifacts, we preprocessed the PS-OCT data using a vascular masking technique. The birefringence of the remaining tissue regions was then automatically quantified. Results from the scars and contralateral or adjacent normal skin of 13 patients show a correspondence of birefringence with scar type: the ratio of birefringence of hypertrophic scars to corresponding normal skin is 2.2 +/- 0.2 (mean +/- standard deviation ), while the ratio of birefringence of normotrophic scars to normal skin is 1.1 +/- 0.4 . This method represents a new clinically applicable means for objective, quantitative human scar assessment. PMID- 25539061 TI - Confocal Raman microscopic investigation of the effectiveness of penetration enhancers for procaine delivery to the skin. AB - A methodology that employs confocal Raman microscopy (CRM) on ex vivo skin samples is proposed for the investigation of drug content and distribution in the skin. To this end, the influence of the penetration enhancers propylene glycol and polyoxyethylene-23-lauryl ether on the penetration and permeation of procaine as a model substance was investigated. The drug content of skin samples that had been incubated with semisolid formulations containing one of these enhancers was examined after skin segmentation. The experiments showed that propylene glycol did not affect the procaine content that was delivered to the skin, whereas polyoxyethylene-23-lauryl ether led to higher procaine contents and deeper penetration. Neither substance was found to influence the permeation rate of procaine. It is thereby shown that CRM can provide additional information on drug penetration and permeation. Furthermore, the method was found to enhance the depth from which Raman spectra can be collected and to improve the depth resolution compared to previously proposed methods. PMID- 25539062 TI - Combined lineage mapping and gene expression profiling of embryonic brain patterning using ultrashort pulse microscopy and image registration. AB - During embryogenesis, presumptive brain compartments are patterned by dynamic networks of gene expression. The spatiotemporal dynamics of these networks, however, have not been characterized with sufficient resolution for us to understand the regulatory logic resulting in morphogenetic cellular behaviors that give the brain its shape. We have developed a new, integrated approach using ultrashort pulse microscopy [a high-resolution, two-photon fluorescence (2PF) optical coherence microscopy (OCM) platform using 10-fs pulses] and image registration to study brain patterning and morphogenesis in zebrafish embryos. As a demonstration, we used time-lapse 2PF to capture midbrain-hindbrain boundary morphogenesis and a wnt1 lineage map from embryos during brain segmentation. We then performed in situ hybridization to deposit NBT/BCIP, where wnt1 remained actively expressed, and reimaged the embryos with combined 2PF-OCM. When we merged these datasets using morphological landmark registration, we found that the mechanism of boundary formation differs along the dorsoventral axis. Dorsally, boundary sharpening is dominated by changes in gene expression, while ventrally, sharpening may be accomplished by lineage sorting. We conclude that the integrated visualization of lineage reporter and gene expression domains simultaneously with brain morphology will be useful for understanding how changes in gene expression give rise to proper brain compartmentalization and structure. PMID- 25539064 TI - Atrial fibrillation: a moving target. AB - Present atrial fibrillation research focuses on three different fields of interest: Basic research to gain a better understanding of the mechanisms leading to atrial fibrillation, epidemiological studies to learn about the time course, the risk factors and the complications of atrial fibrillation, and clinical trials to further improve existing treatment strategies and develop new ones. The focus of this manuscript was the mechanisms, the epidemiology, the diagnosis and the treatment of the arrhythmia per se. Therefore, the field of prevention of stroke and systemic embolism is mostly excluded for the purpose of this article. PMID- 25539063 TI - Partial laryngeal surgery in recurrent carcinoma. AB - With the growing acceptance of nonsurgical therapies for laryngeal squamous cell carcinomas (LSCCs), it has become important to delineate surgical salvage strategies for disease recurrences. Total laryngectomy is often recommended, but appropriately selected laryngeal recurrences may be treated successfully with partial laryngeal surgery: laryngeal function can be preserved with oncological efficacy. The main available studies dealing with partial laryngeal surgery in recurrent carcinoma were critically reviewed. The most appealing feature of salvage transoral laser surgery (TLS) is the opportunity to make tumor-tailored excisions without any reconstructive limitations and retaining the option to switch to open partial laryngectomy. A recent detailed review of 11 series found a pooled local control rate of 57% after a first TLS procedure. Supracricoid laryngectomy (SCL) seems to achieve good local control rates in selected cases of recurrent supraglottic-glottic carcinoma: one review considering seven series calculated that 85% of the patients treated with salvage SCL after radiotherapy experienced no local recurrence; and total laryngectomy after failure of salvage SCL afforded an overall local control rate of 65%. Neck dissection is mandatory in all cases of local LSCC recurrence with evidence of neck metastases, and routine elective neck dissection is recommended for recurrent supraglottic and transglottic cancers. PMID- 25539065 TI - Novel readout method for molecular diagnostic assays based on optical measurements of magnetic nanobead dynamics. AB - We demonstrate detection of DNA coils formed from a Vibrio cholerae DNA target at picomolar concentrations using a novel optomagnetic approach exploiting the dynamic behavior and optical anisotropy of magnetic nanobead (MNB) assemblies. We establish that the complex second harmonic optical transmission spectra of MNB suspensions measured upon application of a weak uniaxial AC magnetic field correlate well with the rotation dynamics of the individual MNBs. Adding a target analyte to the solution leads to the formation of permanent MNB clusters, namely, to the suppression of the dynamic MNB behavior. We prove that the optical transmission spectra are highly sensitive to the formation of permanent MNB clusters and, thereby to the target analyte concentration. As a specific clinically relevant diagnostic case, we detect DNA coils formed via padlock probe recognition and isothermal rolling circle amplification and benchmark against a commercial equipment. The results demonstrate the fast optomagnetic readout of rolling circle products from bacterial DNA utilizing the dynamic properties of MNBs in a miniaturized and low-cost platform requiring only a transparent window in the chip. PMID- 25539066 TI - The lack of consensus in management of malignant struma ovarii. AB - Struma ovarii is a rare variant of teratoma characterized by the presence of thyroid tissue in more than 50%. Malignant transformation is rare (less than 5%) and the criteria to classify this condition have changed over time. Nowadays it must fulfill the histological categories of differentiated thyroid carcinoma. Its treatment is controversial and there is no unanimous management. We present three cases of women with malignant struma ovarii, diagnosed by the surgical specimen. PMID- 25539067 TI - Endoscopic endonasal transmaxillary transpterygoid approach to meckel cave: anatomical study and preliminary clinical results. AB - OBJECTIVE: Tumors involving Meckel cave (MC) always present challenges to neurosurgeons. We performed an investigation of the anatomical characteristics of the endoscopic endonasal transmaxillary transpterygoid approach to MC as an alternative to routine transcranial approaches and further confirmed its efficacy in the clinical setting. METHODS: Five adult fresh head specimens (10 sides) were studied to identify crucial anatomical landmarks and quantify the anatomical structures involved in the endoscopic endonasal transmaxillary transpterygoid approach. Two patients with a tumor involving the left MC were treated using the endoscopic endonasal transmaxillary transpterygoid approach. RESULTS: The distance from the columella nasi to the choana, the sphenoid ostium, the anterior aperture of the palatosphenoidal canal (PSC), the sphenopalatine foramen, and the anterior aperture of the vidian canal (VC) was 66.5 +/- 3.3 mm, 61.2 +/- 1.6 mm, 64.6 +/- 1.4 mm, 62.8 +/- 2.3 mm, and 75.4 +/- 3.3 mm, respectively. The distance from the anterior aperture of the VC to the anterior aperture of the PSC and the foramen rotundum (FR) was 2.1 +/- 0.7 mm and 7.5 +/- 0.7 mm, respectively; the length of the PSC and the VC was 6.4 +/- 0.5 mm and 13.3 +/- 1.2 mm, respectively. The landmarks of this route included the PSC, the VC, and the paraclival carotid prominence (CP). Subtotal resection and gross total resection were achieved in the first and second patients, respectively. CONCLUSION: The anatomical landmarks of the endoscopic endonasal transmaxillary transpterygoid route are useful for clinical application. The endoscopic endonasal transmaxillary transpterygoid approach is an effective and minimally invasive route for certain tumors involving MC. Identifying the anatomical landmarks including the PSC, the VC, the FR, and the CP is crucial for safe manipulation. PMID- 25539068 TI - A selective carotid artery shunting for carotid endarterectomy: prospective MR DWI monitoring of embolization in a group of 754 patients. AB - BACKGROUND: Intraoperative use of the intraluminal shunt may reduce the risk of a stroke by reducing cerebral blood flow compromise, but it may also increase the risk of atherosclerotic arterial wall damage with subsequent stroke during carotid endarterectomy (CEA). There is still no evidence to support routine or selective shunting. MATERIAL AND METHODS: A total of 754 CEAs were performed in a prospective study from 2005 to 2011 at our department. All procedures were done under regional anesthesia with selective carotid artery shunting according to neurologic status after internal carotid artery clamping. Magnetic resonance (MR) evaluation of brain parenchyma using diffusion-weighed imaging (DWI) sequence was performed upon hospital admission and 24 hours after the surgical procedure. Acute new MR DWI lesions were evaluated according to the classification published by Szabo et al. A routine neurologic evaluation was recorded as well. RESULTS: The intraluminal shunt was used in 46 of 754 patients (6.1%). A new ischemic lesion was detected in 45 patients (6%). Most of these lesions were neurologically asymptomatic (80%). A new lesion on MR DWI in the subgroup of shunted patients was detected in 15 cases (32.6%) and in the subgroup of nonshunted patients in 30 cases (4.2%). Most of these lesions were due to embolization or hypoperfusion during shunt insertion. CONCLUSION: Use of the intraluminal shunt was the most important risk factor for the new MR DWI lesion in the entire group of CEAs. Results support the strategy of a selective use of intraluminal shunts. PMID- 25539069 TI - The Impact of a Standardized Sodium Protocol on Incidence and Outcome of Dysnatremias in Neurocritical Care. AB - BACKGROUND: Dysnatremias are common and prognostically serious in neurocritical care. We studied whether a standardized sodium protocol would improve our neurocritical care of dysnatremias. METHODS: A 5-year prospective study of a standardized sodium protocol for 1,560 patients admitted with various brain diseases in an adult neurologic-neurosurgical intensive care unit (NNICU) was compared with a 5-year retrospective analysis of 1,440 patients without the sodium protocol. Hyponatremia was defined as serum sodium (SNa(+)) < 135 mmol/L and hypernatremia SNa(+ )> 150 mmol/L. The sodium protocol involved measuring SNa(+), serum, and urine osmolality, measured and calculated renal function parameters, fluid intake 40 mL/kg weight/day without hypotonic saline, thiazide, and desmopressin acetate in all normonatremic NNICU patients. RESULTS: In the protocol study, hyponatremia occurred slightly less often (15.7 versus 16.3% of patients; p = 0.684), hypernatremia was significantly higher (respectively 8.5% versus 5.2% of patients; p < 0.001), and no differences were noted in hypo/hypernatremia (p = 0.483). There were no differences in the incidence of hypo-osmolal hyponatremia (respectively 3.5% versus 3.5% of patients; p = 0.987), cerebral salt wasting (CSW; respectively 1.7% versus 1.7% of patients; p = 0.883), syndrome of inappropriate secretion of antidiuretic hormone (SIADH; respectively 0.1% versus 0.3% of patients; p = 0.152), central diabetes insipidus (CDI; respectively 1.0% versus 0.6% of patients; p = 0.149). In hyponatremia there were no differences in the Glasgow Coma Scale (GCS) score upon onset of hyponatremia (p = 0.294), NNICU mortality (respectively 1.0% versus 0.4% patients; p = 0.074), and bad outcome upon discharge from NNICU (respectively 5.1% versus 6.5% of patients; p = 0.101), but in hypernatremia GCS score upon onset (p < 0.001), mortality (respectively 2.8% versus 1.0%; p < 0.001), and bad outcome from NNICU (respectively 6.7% versus 2.7% patients; p < 0.001) were significantly higher. Multivariate logistic regression analysis showed that hypernatremia, compared with hyponatremia, was a significant predictor of mortality during NNICU stay (respectively odds ratio [OR]: 1.14; p = 0.003 versus OR; 5.3; p = 0.002). CONCLUSIONS: The standard sodium protocol lowered the frequency of SIADH, which was encountered in only one patient over 5 years. However, it did not significantly reduce the incidence and improve the outcome of hyponatremia. Hypernatremia occurred more often and had a higher mortality and worse outcome than hyponatremia, but these patients were neurologically worse upon its onset. The prospective study confirmed that CSW, SIADH, and CDI were not common in our neurocritical care. PMID- 25539070 TI - Surgical management of eloquent supratentorial low-grade gliomas with special emphasis on intraoperative imaging. AB - OBJECTIVE: Eloquent diffuse low-grade gliomas (LGGs) threaten patients' neurologic function and are also associated with inferior survival. Many neurosurgeons still refrain from early resection due to the fear of iatrogenic neurologic injury. However, the perceived safety of expectant management strategies may soon be overshadowed by the progressive deficits of tumor growth in eloquent regions. It is also known that radical and successful surgery prolongs progression-free survival, overall survival, and may reduce seizure burden and also potentially neurocognitive functions. Thus early successful surgery with preservation of function has a significant impact on patients' health. In modern neurosurgery, safe resection is often possible with detailed knowledge of anatomy and function together with the active use of various intraoperative surgical tools. We present illustrative cases of eloquent LGGs treated with different intraoperative tools. METHODS: An introduction to important intraoperative tools in LGG surgery is provided by experts in the field and described in five cases viewed in the context of the recent LGG literature. RESULTS: We present five cases with presumed eloquently located LGGs where extensive resection was offered using different intraoperative techniques. The clinical and radiologic outcomes are described. CONCLUSIONS: Correct use of intraoperative tools together with the surgeon's knowledge of anatomy and function will provide good functional and oncologic results in eloquently located LGGs. Watchful waiting or deferral of surgery due to tumor location (i.e., claiming inoperability) is very rarely good practice. PMID- 25539071 TI - Biomaterials-based nanofiber scaffold: targeted and controlled carrier for cell and drug delivery. AB - Nanofiber scaffold formulations (diameter less than 1000 nm) were successfully used to deliver the drug/cell/gene into the body organs through different routes for an effective treatment of various diseases. Various fabrication methods like drawing, template synthesis, fiber-mesh, phase separation, fiber-bonding, self assembly, melt-blown, and electrospinning are successfully used for fabrication of nanofibers. These formulations are widely used in various fields such as tissue engineering, drug delivery, cosmetics, as filter media, protective clothing, wound dressing, homeostatic, sensor devices, etc. The present review gives a detailed account on the need of the nanofiber scaffold formulation development along with the biomaterials and techniques implemented for fabrication of the same against innumerable diseases. At present, there is a huge extent of research being performed worldwide on all aspects of biomolecules delivery. The unique characteristics of nanofibers such as higher loading efficiency, superior mechanical performance (stiffness and tensile strength), controlled release behavior, and excellent stability helps in the delivery of plasmid DNA, large protein drugs, genetic materials, and autologous stem-cell to the target site in the future. PMID- 25539072 TI - Fangchinoline as a kinase inhibitor targets FAK and suppresses FAK-mediated signaling pathway in A549. AB - BACKGROUND: Fangchinoline as a novel anti-tumor agent has been paid attention in several types of cancers cells except lung cancer. Here we have investigated the effect of fangchinoline on A549 cells and its underlying mechanism. PURPOSE: The purpose of this work was to study the effect of fangchinoline on A549 cells. METHODS: Four lung cancer cell lines (A549, NCI-H292, NCI-H446, and NCI-H460) were exposed to varying concentrations (10-40 MUmol/l) of fangchinoline to observe the effect of fangchinoline on the four lung cancer cell lines and to observe the changes of the lung cancer cell on proliferation, apoptosis, and invasion. RESULTS: Fangchinoline effectively suppressed proliferation and invasion of A549 cell line but not NCI-H292, NCI-H446, and NCI-H460 cell lines by inhibiting the phosphorylation of FAK (Tyr397) and its downstream pathways, due to the significant differences of Fak expression between A549 and the other three cell lines. And all FAK-paxillin/MMP2/MMP9 pathway, FAK-Akt pathway, and FAK-MEK ERK1/2 pathway could be inhibited by fangchinoline. DISCUSSION: Fangchinoline effectively suppressed proliferation and invasion of A549 cell line by inhibiting the phosphorylation of FAK (Tyr397) and its downstream pathways. CONCLUSION: Fangchinoline could inhibit the phosphorylation of FAK(p-Tyr397), at least partially. Fangchinoline as a kinase inhibitor targets FAK and suppresses FAK mediated signaling pathway and inhibits the growth and the invasion in tumor cells which highly expressed FAK such as A549 cell line. PMID- 25539073 TI - Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment. AB - This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression. PMID- 25539074 TI - Anti-tumor activity of paclitaxel through dual-targeting lipoprotein-mimicking nanocarrier. AB - In the present study, we devised a strategy that paclitaxel (PTX) with lipid and octadecylamine were prepared to lipid nanoparticle (PTX-LNP) with positive charge, folic acid-modified bovine serum albumin (FB)-coated surface of PTX-LNP through electrostatic attraction and generated the lipoprotein-mimicking nanocomplex (FB-PTX-LNP) for dual-targeting therapy. Bovine serum albumin (BSA) was used as the protein model due to its specific targeting to tumor by increased transendothelial gp60-mediated transport and increased intratumoral accumulation as a result of the secreted protein, acidic and rich in cysteine (SPARC)-albumin interaction. The further conjugating folic acid to BSA achieved the dual active targeting. In vitro cytotoxicity tests suggested FB-PTX-LNP and BSA-PTX-LNP exhibited significantly higher cytotoxic activity against MCF-7 and HepG2 cells compared to PTX-LNP. The cellular uptake experiments indicated that FB-coumarin-6 LNP modified with dual-targeting had a faster and greater cellular uptake when compared to BSA-coumarin-6-LNP and coumarin-6-LNP by MCF-7 cells. Thus, both BSA and FA did play roles in in vitro cytotoxicity and cellular uptake. Furthermore, the targeting ability and therapeutic efficacy of FB-PTX-LNP were assessed in vivo. FB-PTX-LNP produced very marked targeting ability and anti-tumor activity in MDA-MB-231 tumor-bearing mice. These results indicate the protein-lipid nanocomplex FB-PTX-LNP is a potential nanocarrier for Paclitaxel dual-targeting to tumor. PMID- 25539075 TI - Triblock polymeric micelles as carriers for anti-inflammatory drug delivery. AB - This study evaluated the properties of poly(ethylene oxide)-b-poly(n-butyl acrylate)-b-poly(acrylic acid) (PEO-PnBA-PAA) polymeric micelles as carriers for anti-inflammatory drugs (prednisolone and budesonide). The micelles comprising a hydrophobic PnBA core and a PEO/PAA corona showed average diameter less than 40 nm. The size of the drug-loaded micelles did not change during eight hours into media that mimic physiological fluids indicating high colloidal stability. The calculation of Flory-Huggins parameter showed greater compatibility between budesonide and micellar core suggesting its location in the micellar core, whereas prednisolone was located also into the interface layer. This observation correlated further with slower release of budesonide, especially in acid medium (pH = 1.2). The inclusion of budesonide into micelles showed significant protective effect against the cytotoxic damage induced by the co-cultivation of differentiated human EOL-1 and HT-29 cells. This study revealed the capacity of PEO-PnBA-PAA terpolymer as carrier of nanosized micelles suitable for oral delivery of anti-inflammatory drugs. PMID- 25539076 TI - Invasive treatments for complex regional pain syndrome in children and adolescents: a scoping review. AB - This review aimed to synthesize the current evidence on the effectiveness of invasive treatments for complex regional pain syndrome in children and adolescents. Studies on children and adolescents with complex regional pain syndrome that evaluated the effects of invasive treatment were identified in PubMed (search March 2013). Thirty-six studies met the inclusion criteria. Articles reported on a total of 173 children and adolescents with complex regional pain syndrome. Generally, many studies lack methodological quality. The invasive treatments applied most often were singular sympathetic blocks, followed by epidural catheters and continuous sympathetic blocks. Rarely, spinal cord stimulation and pain-directed surgeries were reported. An individual patient frequently received more than one invasive procedure. Concerning outcome, for approximately all patients, an improvement in pain and functional disability was reported. However, these outcomes were seldom assessed with validated tools. In conclusion, the evidence level for invasive therapies in the treatment of complex regional pain syndrome in children and adolescents is weak. PMID- 25539077 TI - The monuments men: in the history of anesthesia, too. AB - A 2014 American-German war movie directed by and starring George Clooney (Actor, Screenwriter, Film Director, and Producer; Los Angeles, California and Laglio, Italy) (1961-current) popularized the work of a special United States Army unit devoted to the rescue of art treasures stolen or hidden by the Nazis during World War II. A similar story occurred in Paris to a curious little monument closely linked to the history of Anesthesia. This happened about 70 years ago, in December 1944. PMID- 25539078 TI - Monumental efforts: perspiring professionals, conspiring tradesmen ... inspiring you? PMID- 25539081 TI - Introduction to the review papers series on novelties and state of the art in pediatric surgical oncology. PMID- 25539080 TI - How Common Is Airflow Limitation in Patients With Emphysema on CT Scan of the Chest? AB - BACKGROUND: COPD has traditionally been defined by the presence of irreversible airflow limitation on spirometry using either the GOLD (Global Initiative for Chronic Obstructive Lung Disease) or American Thoracic Society/European Respiratory Society criteria (lower limit of normal [LLN]). We have observed that some patients with clinical COPD and emphysema on chest CT scan have no obstruction on spirometry. The purpose of this study was to assess the prevalence of obstruction by GOLD and LLN criteria in patients with emphysema on CT scan and determine which radiographic criteria were associated with a clinical diagnosis of COPD. METHODS: We retrospectively analyzed the clinical records and spirometry of all patients who had radiographically defined emphysema on chest CT scans completed at the University of Vermont in 2011. We compared spirometric criteria and CT scan factors with the presence of clinical COPD based on chart review. RESULTS: We identified 274 patients with CT scan-defined emphysema. GOLD criteria detected obstruction in 228 patients (83%), and LLN detected obstruction in 206 patients (75%). However, GOLD failed to correctly identify 19 patients (6.9%) and LLN failed to identify 38 patients (13.9%) (average 10.4%) who had radiographic emphysema and a clinical diagnosis of COPD. Obese patients had a lower prevalence of obstruction whether classified by LLN or GOLD. Among patients with spirometric obstruction, there were greater degrees of emphysema and more severely increased airway wall thickness. Factors that were independently associated with clinical COPD were lower FVC % predicted, lower FEV1/FVC ratio, and increasing airway wall thickness. CONCLUSIONS: Spirometry missed 10.4% of patients with clinical COPD who have significant emphysema on chest CT scan. PMID- 25539082 TI - Natural history of typical pulmonary carcinoid tumors: a comparison of nonsurgical and surgical treatment. AB - BACKGROUND: The natural history of typical pulmonary carcinoid tumors has not been described and has important implications for counseling elderly patients or patients with high operative-risk about surgical resection. METHODS: Data from the Surveillance, Epidemiology, and End Results Program were used to identify 4,111 patients with biopsy specimen-proven lymph node-negative typical carcinoid tumor of the lung between 1988 and 2010; 306 had no resection, 929 underwent sublobar resection, and 2,876 underwent lobectomy. Overall survival and disease specific survival (DSS) were analyzed using Kaplan-Meier plots. Multivariate analysis was used to determine predictors of survival. RESULTS: Five-year overall survival in patients who underwent lobectomy, sublobar resection, or no surgery was 93%, 92%, and 69%, respectively (P < .0001); 5-year DSS was 97%, 98%, and 88%, respectively (P < .0001). Among T1 tumors, DSS was 98% for patients who underwent lobectomy and sublobar resection and 92% for no surgery; among T2 tumors, DSS was 97%, 100%, and 87%, respectively, and among T3 and T4 tumors, it was 96%, 100%, and 75%, respectively. On multivariate analysis, nonoperative management was associated with an increased risk for disease-specific mortality compared with lobectomy (hazard ratio, 2.14; 95% CI, 1.35-3.40; P = .0013). CONCLUSIONS: In this population-based cohort, surgical resection of lymph node negative carcinoid tumors is associated with a survival advantage over nonoperative treatment. However, the DSS at 5 years was still high without any treatment, suggesting that observation of asymptomatic peripheral typical carcinoid tumors or endoscopic management of symptomatic central carcinoid tumors may be considered in patients at high risk for surgical resection. PMID- 25539083 TI - Evolution of the snake body form reveals homoplasy in amniote Hox gene function. AB - Hox genes regulate regionalization of the axial skeleton in vertebrates, and changes in their expression have been proposed to be a fundamental mechanism driving the evolution of new body forms. The origin of the snake-like body form, with its deregionalized pre-cloacal axial skeleton, has been explained as either homogenization of Hox gene expression domains, or retention of standard vertebrate Hox domains with alteration of downstream expression that suppresses development of distinct regions. Both models assume a highly regionalized ancestor, but the extent of deregionalization of the primaxial domain (vertebrae, dorsal ribs) of the skeleton in snake-like body forms has never been analysed. Here we combine geometric morphometrics and maximum-likelihood analysis to show that the pre-cloacal primaxial domain of elongate, limb-reduced lizards and snakes is not deregionalized compared with limbed taxa, and that the phylogenetic structure of primaxial morphology in reptiles does not support a loss of regionalization in the evolution of snakes. We demonstrate that morphometric regional boundaries correspond to mapped gene expression domains in snakes, suggesting that their primaxial domain is patterned by a normally functional Hox code. Comparison of primaxial osteology in fossil and modern amniotes with Hox gene distributions within Amniota indicates that a functional, sequentially expressed Hox code patterned a subtle morphological gradient along the anterior posterior axis in stem members of amniote clades and extant lizards, including snakes. The highly regionalized skeletons of extant archosaurs and mammals result from independent evolution in the Hox code and do not represent ancestral conditions for clades with snake-like body forms. The developmental origin of snakes is best explained by decoupling of the primaxial and abaxial domains and by increases in somite number, not by changes in the function of primaxial Hox genes. PMID- 25539084 TI - Tel1(ATM)-mediated interference suppresses clustered meiotic double-strand-break formation. AB - Meiotic recombination is a critical step in gametogenesis for many organisms, enabling the creation of genetically diverse haploid gametes. In each meiotic cell, recombination is initiated by numerous DNA double-strand breaks (DSBs) created by Spo11, the evolutionarily conserved topoisomerase-like protein, but how these DSBs are distributed relatively uniformly across the four chromatids that make up each chromosome pair is poorly understood. Here we employ Saccharomyces cerevisiae to demonstrate distance-dependent DSB interference in cis (in which the occurrence of a DSB suppresses adjacent DSB formation)--a process that is mediated by the conserved DNA damage response kinase, Tel1(ATM). The inhibitory function of Tel1 acts on a relatively local scale, while over large distances DSBs have a tendency to form independently of one another even in the presence of Tel1. Notably, over very short distances, loss of Tel1 activity causes DSBs to cluster within discrete zones of concerted DSB activity. Our observations support a hierarchical view of recombination initiation where Tel1(ATM) prevents clusters of DSBs, and further suppresses DSBs within the surrounding chromosomal region. Such collective negative regulation will help to ensure that recombination events are dispersed evenly and arranged optimally for genetic exchange and efficient chromosome segregation. PMID- 25539085 TI - A spin-down clock for cool stars from observations of a 2.5-billion-year-old cluster. AB - The ages of the most common stars--low-mass (cool) stars like the Sun, and smaller--are difficult to derive because traditional dating methods use stellar properties that either change little as the stars age or are hard to measure. The rotation rates of all cool stars decrease substantially with time as the stars steadily lose their angular momenta. If properly calibrated, rotation therefore can act as a reliable determinant of their ages based on the method of gyrochronology. To calibrate gyrochronology, the relationship between rotation period and age must be determined for cool stars of different masses, which is best accomplished with rotation period measurements for stars in clusters with well-known ages. Hitherto, such measurements have been possible only in clusters with ages of less than about one billion years, and gyrochronology ages for older stars have been inferred from model predictions. Here we report rotation period measurements for 30 cool stars in the 2.5-billion-year-old cluster NGC 6819. The periods reveal a well-defined relationship between rotation period and stellar mass at the cluster age, suggesting that ages with a precision of order 10 per cent can be derived for large numbers of cool Galactic field stars. PMID- 25539087 TI - Homing properties of mesenchymal stromal cells. AB - A large number of clinical trials are underway to assess the therapeutic potential of mesenchymal stromal cells. This is based on preclinical observations that point to the probable efficacy of these cells. Very little is known however about the homing mechanisms of these cells to sites of injury and inflammation. This is important if one is to enhance this process to improve the therapeutic outcome. We have addressed this issue by highlighting what is known and through an analogy with leukocyte homing, and have identified possible areas of future research. PMID- 25539088 TI - Child and family characteristics associated with age of diagnosis of an autism spectrum disorder in a tertiary care setting. AB - OBJECTIVE: To identify child and family characteristics associated with age of diagnosis of autism spectrum disorder (ASD) in a tertiary care setting using objective, standardized assessments ensuring diagnostic validity and timing. METHODS: The authors conducted a chart review of children who received their initial ASD diagnosis from 2007 to 2011. Child variables included gender, birth order, cognitive functioning, and for children <=36 months, language and adaptive assessments. Family variables included insurance, maternal age, maternal education, sibling or family member with ASD, and number of children in the house. Primary outcome was age of ASD diagnosis. The authors ran multiple regression models evaluating the impact of child and family variables on the total sample and on the subsample of children <=36 months. RESULTS: Median age of diagnosis was 2.9 years (range, 15 mo-13.8 yr; n = 591). In the total sample, significant predictors of earlier age of diagnosis were later birth order, higher maternal education, fewer children in the house, and a sibling with ASD. In a separate analysis of children <=36 months of age (n = 315) with additional data for language and adaptive assessments, significant predictors of younger age of diagnosis were higher cognitive and adaptive functioning, lower receptive and expressive language, and having a sibling with ASD. CONCLUSIONS: This study suggests that both family and child characteristics play an important role in the early identification of ASD and that predictive variables may vary based on a child's age. Future research should help to elucidate this finding so that screening measures and policies aimed at early identification can target the most predictive factors. PMID- 25539086 TI - Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. AB - The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies. PMID- 25539089 TI - A comparison of observers' and self-report pain ratings for children with cerebral palsy. AB - OBJECTIVES: This study aimed to examine (1) the relationship between children's self-reports of pain and their different care providers' pain ratings, (2) the relationship between different care providers' ratings of pain in children with cerebral palsy (CP), and (3) whether the child's level of disability influences care providers' pain ratings. METHODS: Sixty-three children with CP were separated into 2 groups according to whether they were able to pass a self-report training task. Pain was rated using a Numerical Rating Scale and the Non Communicating Children's Pain Checklist-Postoperative Version (NCCPC-PV). Children were observed during their regular physiotherapy sessions at 3 separate time segments (Baseline, Stretch Procedure, and Recovery). RESULTS: As anticipated, results showed that all observers reported significantly higher pain scores during a physiotherapy stretching procedure than the baseline and recovery segments. Observers' NCCPC-PV scores were significantly higher during the stretch procedure for the children who did not pass the self-report training task. Findings also indicated that parents tended to report significantly lower pain scores compared with both their children and other observers. CONCLUSIONS: The findings bring into question the accuracy of single-observer pain ratings for children with CP and possess implications for the management of pain in children with CP. PMID- 25539090 TI - Distress regulation in infancy: attachment and temperament in the context of acute pain. AB - OBJECTIVE: The relationship between attachment, temperamental fear, and pain related distress was examined in a sample of 130 caregiver-infant dyads to explore the differential susceptibility hypothesis. METHOD: Infant distress was measured during routine immunization at 12 months, and attachment and temperamental fear were measured at 12 to 18 months (meanage = 13.74, SD = 1.35) using the Strange Situation Procedure and parent-rated Infant Behavior Questionnaire-Revised, respectively. RESULTS: Immediately before immunization, avoidant infants exhibited significantly less distress than secure infants. Temperamental fear moderated the relationship between attachment and regulation; under conditions of high temperamental fear, avoidant infants regulated distress more slowly than secure infants, whereas under conditions of low temperamental fear, secure infants regulated distress more slowly than avoidant and disorganized infants. CONCLUSION: The findings suggest that attachment interacts with extremes in temperamental fear to produce differences in the regulation of distress. The results partially support the differential susceptibility hypothesis. PMID- 25539091 TI - Autism associated with early institutionalization, high intelligence, and naturalistic behavior therapy in a 7-year-old boy. AB - CASE: Paul is a 7-year-old boy with a history of cerebral palsy and left-side weakness secondary to perinatal injury. He was adopted to the United States at 19 months from a baby home in Eastern Europe, where the caregiver to child ratio was 7:1. Paul spent most of his early developmental period in a crib. On adoption, he was nonverbal and nonambulatory, but these skills developed within 1 year. Paul was noted at 4 years of age to be struggling socially and also to exhibit restricted interests (e.g., memorizing maps and world leaders). He was referred for neuropsychological testing at age 5 and was found to have cognitive skills in the gifted range (verbal intelligence quotient, IQ =143; 99.8%) but exhibited markedly reduced social reciprocity with high levels of restricted interests and repetitive behaviors, leading to a diagnosis of autism spectrum disorder (ASD) in the context of early institutionalization. Given his cooperative and attentive presentation, high IQ, and ability to imitate, Floortime, a more naturalistic behavioral therapy for ASD, was recommended rather than traditional applied behavior analysis, which is more commonly available in the region. In addition, Paul was provided with group speech and language therapy with a social/pragmatic focus. After 1 year, Paul's socialization improved but he struggled to initiate interactions and maintain friendships. He focused instead on his restricted interests and played alone. After 2 years of intervention, Paul presents as highly sociable with well-sustained eye gaze, interactive play, and successful friendships. Still, without direction and structure, Paul will happily draw maps for hours at a time. He is hyperlexic and working far above grade level across subjects. His mother now questions--is this still truly institutional autism or is he simply too intelligent to relate to same-age peers? PMID- 25539092 TI - Patterns of use and expenses associated with mail-service pharmacy in adults with diabetes. AB - OBJECTIVES: To identify socioeconomic factors associated with mail-service pharmacy use and compare the differences in disease-specific prescription medication and medical utilization expenses in a nationally representative sample of adults with diabetes. DESIGN: A retrospective, longitudinal, cross-sectional study. SETTING: United States in 2006-11. PARTICIPANTS: Medical Expenditure Panel Survey household component (MEPS-HC) participants aged 18 years or older diagnosed with diabetes and prescribed antidiabetic medications. MAIN OUTCOME MEASURES: Likelihood of mail-service pharmacy use, diabetes-related medical utilization, and medication expenses. RESULTS: Among 4,430 eligible participants identified in the 2006-11 surveys, representing more than 83 million U.S. individuals, nearly 13% of the participants obtained two-thirds or more of their antidiabetic medications via mail service predominantly. Mail-service pharmacy users were older, had high school or college degrees, had higher incomes, and were more likely to be covered by private insurance. There were no significant differences in diabetes-related medical utilization and drug expenses between the two groups. CONCLUSION: Besides pharmacy benefit design, sociodemographic and economic factors influenced drug dispensing channel use (mail service versus community pharmacy). No significant differences in diabetes-related drug and medical expenses between mail-service and community pharmacy users were observed. PMID- 25539093 TI - Environmental considerations on solar disinfection of wastewater and the subsequent bacterial (re)growth. AB - In this work, solar disinfection of wastewater was studied, focusing on the effect of selected environmental variables, namely light intensity, continuous/intermittent light delivery, and post-irradiation storage as well as dilution in lake water. These variables were studied for their effect on the disinfection efficiency and on post-irradiation survival/regrowth in undiluted wastewater and in wastewater diluted in lake water at different dilution rates. The bacterial inactivation curves were studied, and distinct kinetic phases were identified and interpreted. The dose primarily influenced the demonstration of phases and total inactivation times, independently of the irradiance. Intermittent illumination unevenly prolonged the required exposure time and highlighted the need for extended illumination times when unstable weather conditions are expected. Post-irradiation survival/regrowth in undiluted wastewater showed three distinct kinetic profiles, with transitions among them largely determined by the applied light dose. Lower doses resulted in similar inactivation profiles to the higher ones, when irradiation was followed by prolonged storage at high dilution rates in lake water. The studied factors show significant design and operation implications for solar wastewater applications based on local environmental conditions and water receptor restrictions. PMID- 25539094 TI - Self-measurement of upper extremity volume in women post-breast cancer: reliability and validity study. AB - BACKGROUND: Secondary lymphedema is a chronic swelling of the upper limb that may occur after treatment for breast cancer. During the acute phase, intensive treatment with a therapist is provided, while during the maintenance phase the patient needs to detect any re-swelling by self-examination. OBJECTIVE: To assess the test-retest reliability and the concurrent validity of self-measurement upper limb volume among women post-breast cancer. DESIGN: A cross-sectional study of 17 women post-breast cancer that experience a period of intensive unilateral upper limb lymphedema treatment in the past. METHODS: On day 1 and day 10 at the clinic, the physiotherapist measured the volume of the upper limbs with the water displacement method (i.e. the "gold standard" for volume measure) as well as with the more common method of plastic tape. The participants performed self measurement twice with the paper tape under the supervision of a physiotherapist in the clinic. After a week the participants performed self-measurement at home with the paper tape. RESULTS: The intra-class correlations measures indicated excellent values for the self-measure tape measurements on the operated side (0.97-0.99) as well as on the opposite arm (0.96-0.99). The self-measurement revealed a moderate association with the criterion measure, the water displacement (rp 0.59-0.68, (p < 0.05)), and strong concurrent validity with therapist tape measurements (rp 0.88-0.95, (p < 0.05)). CONCLUSIONS: Women post breast cancer can self-measure upper limb volume using a paper tape which is both, reliable and valid. PMID- 25539095 TI - Patients' and therapists' perception of change following physiotherapy in an orthopedic hospital's outpatient clinic. AB - OBJECTIVE: The aims of this observational, prospective cohort study were to: assess the patients' and therapists' perception of change after physiotherapy in an orthopedic hospital's outpatient clinic; relate these retrospective assessments to a serial assessment of pain; and study the influence of patient characteristics on the perceived change. METHODS: 161 patients of the outpatient clinic participated. The main outcome measures were the patient global impression of change (PGIC) and the clinical global impression of change (CGIC) after physiotherapy. The visual analogue scale was used as serial assessment. RESULTS: The PGIC indicated improvement in 128 patients (80%) and the CGIC in 117 patients (73%). The correlation between PGIC and CGIC was good (rS = 0.71, p < 0.001). The perceived change correlated little to baseline pain (PGIC: rS = 0.24, p = 0.004; CGIC: rS = 0.18, p = 0.024) and change in pain due to physiotherapy (PGIC: rS = 0.22, p = 0.004; CGIC: rS = -0.31, p < 0.001). The logistic regression model revealed a significant influence of the patients' education level and the number of problems on the PGIC and the CGIC. CONCLUSIONS: The addition of at least one GPC scale might be valuable in evaluating the outcome in physical therapy, which requires little time and thus may be ideal for a clinical setting. Patients' and therapists' perception of change is significantly influenced by the patients' education level and the number of problems, which might be of relevance when choosing adequate treatment strategies. PMID- 25539096 TI - Validity and reliability of Turkish version of the Pain Attitudes and Beliefs Scale for Physiotherapists. AB - BACKGROUND: The initial purpose of this study was to perform a linguistic and cultural translation of the Pain Attitudes and Beliefs Scale for Physiotherapists into the Turkish language. Following the translation process the primary purpose of the study was to examine the validity and reliability of the Turkish version of Pain Attitudes and Beliefs Scale for Physiotherapists. MATERIALS AND METHODS: A survey study design was used. The Turkish version of Pain Attitudes and Beliefs Scale for Physiotherapists was developed. A pilot test was performed and a final version was completed. Participants were recruited to examine the reliability and validity of the new instrument. Participants received an online survey package with the PABS-PT-TR and Turkish Version of the Tampa Scale for Kinesiophobia. RESULTS: A total of 51 physiotherapists (response rate 60.7%) completed the PABS PT-TR and Turkish Version of the Tampa Scale for Kinesiophobia and 28 physiotherapists completed the retest. Factor analysis was conducted to determine the construct of the scale. Two factors emerged: one focused on biomedical orientation and the second on biopsychosocial orientation. The test-retest reliability (ICC) for the biomedical scale was 0.81 (95% CI = 0.60-0.91) and 0.82 (95% CI = 0.61-0.91) for the biopsychosocial scale. Internal consistency for the "biomedical" scale was Cronbach's alpha = 0.72 and alpha = 0.59 for the biopsychosocial scale. When the relationship between PABS-PT-TR and TSK was investigated, r value was 0.39 (p < 0.05) indicating fair convergent validity. These results indicated that the PABS-PT-TR shows construct validity. CONCLUSION: The PABS-PT-TR appears to have good test-retest reliability, acceptable to good internal consistency, and acceptable construct validity. PMID- 25539097 TI - The clinical relevance of timed motor performance in children with Duchenne muscular dystrophy. AB - BACKGROUND: The measurement of time and compensatory movements for functional tasks is not frequently used to evaluate children with Duchenne muscular dystrophy (DMD). As muscle weakness progresses, new synergies (compensatory movements) are selected to perform the tasks, demanding higher times. OBJECTIVES: The present study aimed to describe the timed motor performance of rising from the floor to standing, sitting down on the floor from standing, climbing up four steps and climbing down four steps 18 and 6 months prior to gait loss and to investigate possible relationships between these timed performances, the compensatory movements and the Vignos Scale (VS) scores. METHOD: Fourteen children with DMD (mean age: 9.6) were videotaped performing the tasks. Spearman correlation tests investigated the relationships between the times, compensatory movements (scored by FES-DMD) and VS. RESULTS: The timed performance and the compensatory movements for rising from the floor, climbing up and climbing down steps varied broadly and were correlated to each other among patients with DMD at 18 and 6 months prior to gait loss. The relationship was not found for sitting on the floor. The timed performance and compensatory movements for climbing up and down steps also correlated to the VS. CONCLUSION: Rising from the floor, climbing up, and climbing down steps have some components in common, such as the demand for muscle strength and the recruitment of compensatory muscle synergies, as DMD progresses. To sit down on the floor, some children let themselves fall, resulting in a faster performance, but more compensatory movements. PMID- 25539103 TI - Very complicated math--reconfiguring organ allocation. PMID- 25539104 TI - Transplantation traffic--geography as destiny for transplant candidates. PMID- 25539105 TI - Transparency and the European Medicines Agency--sharing of clinical trial data. PMID- 25539107 TI - Images in clinical medicine. Epiphrenic diverticulum. PMID- 25539106 TI - Esophageal carcinoma. PMID- 25539108 TI - Case records of the Massachusetts General Hospital. Case 40-2014. A 57-year-old man with inguinal pain, lymphadenopathy, and HIV infection. PMID- 25539109 TI - Microbiota, antibiotics, and obesity. PMID- 25539110 TI - Ultrasonography vs. CT for suspected nephrolithiasis. PMID- 25539111 TI - Ultrasonography vs. CT for suspected nephrolithiasis. PMID- 25539112 TI - Ultrasonography vs. CT for suspected nephrolithiasis. PMID- 25539113 TI - Ultrasonography vs. CT for suspected nephrolithiasis. PMID- 25539114 TI - Immunotherapy for tuberculous pericarditis. PMID- 25539115 TI - Immunotherapy for tuberculous pericarditis. PMID- 25539116 TI - Immunotherapy for tuberculous pericarditis. PMID- 25539117 TI - Immunotherapy for tuberculous pericarditis. PMID- 25539118 TI - Immunotherapy for tuberculous pericarditis. PMID- 25539119 TI - Immunotherapy for tuberculous pericarditis. PMID- 25539121 TI - Microcytic anemia. PMID- 25539120 TI - Microcytic anemia. PMID- 25539122 TI - Microcytic anemia. PMID- 25539123 TI - Microcytic anemia. PMID- 25539124 TI - Remission of recalcitrant dermatomyositis treated with ruxolitinib. PMID- 25539125 TI - Images in clinical medicine. Cervical aortic arch. PMID- 25539126 TI - Childhood asthma: causes, risks, and protective factors; a role of innate immunity. AB - Childhood asthma is an umbrella of multifactorial diseases with similar clinical features such as mast cell and eosinophil infiltration causing airway hyper responsiveness, inflammation, and airway obstruction. There are various factors that are implicated in childhood asthma pathogenesis. A combined contribution of genetic predisposition, environmental insults, and epigenetic changes account for polarisation of the immune system towards T helper (Th) type 2 cell responses that include production of pro-inflammatory cytokines, IgE, and eosinophil infiltrates, shown to associate with asthma. Environmental cues in prenatal, perinatal, and early childhood seem to determine development of asthma incidence or protection against it. Mode of birth delivery, use of antibiotics, oxidative stress, exposure to tobacco smoke and an industrialised lifestyle are significant contributors to childhood asthma exacerbation. Environmental stimuli such as exposure to maternal antibodies through breast milk, and certain early infections favour Th1 cell responses, leading to the production of anti-inflammatory cytokines that protect from asthma. Aside from the Th cell responses the role of innate immunity in the context of alveolar macrophages, dendritic cells, and surfactant protein A (SP-A) and SP-D is discussed. SP-A and SP-D enhance pathogen phagocytosis and cytokine production by alveolar macrophages, bind and clear pathogens, and interact with dendritic cells to mediate adaptive immunity responses. Further study of the interactions between genetic variants of genes of interest (SP-A and SP-D) and the environment may provide valuable knowledge about the underlying mechanisms of various interactions that differentially affect asthma susceptibility, disease severity, and reveal potential points for therapeutic interventions. PMID- 25539127 TI - Improving children's menus in community restaurants: best food for families, infants, and toddlers (Best Food FITS) intervention, South Central Texas, 2010 2014. AB - BACKGROUND: Approximately 32% of US children are overweight or obese. Restaurant and fast food meals contribute 18% of daily calories for children and adolescents aged 2 to 18 years. Changing children's menus may improve their diets. This case study describes Best Food for Families, Infants, and Toddlers (Best Food FITS), a community-based intervention designed to address childhood obesity. The objective of this study was to improve San Marcos children's access to healthy diets through partnerships with local restaurants, removing sugar-sweetened beverages, decreasing the number of energy-dense entrees, and increasing fruit and vegetable offerings on restaurant menus. COMMUNITY CONTEXT: San Marcos, Texas, the fastest growing US city, has more restaurants and fewer grocery stores than other Texas cities. San Marcos's population is diverse; 37.8% of residents and 70.3% of children are Hispanic. Overweight and obesity rates among school children exceed 50%; 40.3% of children live below the poverty level. METHODS: This project received funding from the Texas Department of State Health Services Nutrition, Physical Activity, and Obesity Prevention Program to develop Best Food FITS. The case study consisted of developing a brand, engaging community stakeholders, reviewing existing children's menus in local restaurants, administering owner manager surveys, collaborating with restaurants to improve menus, and assessing the process and outcomes of the intervention. OUTCOME: Best Food FITS regularly participated in citywide health events and funded the construction of a teaching kitchen in a new community building where regular nutrition classes are held. Sixteen independent restaurants and 1 chain restaurant implemented new menus. INTERPRETATION: Improving menus in restaurants can be a simple step toward changing children's food habits. The approach taken in this case study can be adapted to other communities. Minimal funding would be needed to facilitate development of promotional items to support brand recognition. PMID- 25539128 TI - Relationship between social support and body mass index among overweight and obese African American women in the rural deep South, 2011-2013. AB - INTRODUCTION: African American women in the Deep South of the United States are disproportionately obese, a condition strongly influenced by their social environment. The objective of this study was to characterize the prevalence of social support from family and friends for healthy eating and exercise in rural communities. METHODS: This study is an analysis of a subgroup (N = 195) of overweight and obese African American women from a larger ongoing weight loss trial (N = 409) in rural communities of the Alabama Black Belt and Mississippi Delta. The Social Support and Eating Habits Survey and Social Support and Exercise Survey were used to measure support from family and friends for healthy eating and exercise, respectively. Linear regression was conducted to determine the association between social support factors and body mass index (BMI). RESULTS: Concurrently prevalent in our sample were encouraging support for healthy eating (family, median,14.0; range, 5.0-25.0; friends, median, 13.0; range 5.0-25.0) and discouraging support for healthy eating (family, median, 12.0; range, 5.0-25.0; friends, median, 11.0; range, 5.0-25.0). Median scores for support for exercise received in the form of participation from family and friends were 24.0 (range 10.0-48.0) and 24.0 (range 10.0-50.0), respectively. The median score for support for exercise in the form of rewards and punishment from family was 3.0 (range, 3.0-11.0). Social support factors were not associated with BMI. CONCLUSION: Overweight and obese African American women in the rural Deep South experience minimal social support from family and friends for healthy eating and exercise. Given the evidence that social support promotes healthy behaviors, additional research on ways to increase support from family and friends is warranted. PMID- 25539129 TI - The impact of a state-sponsored mass media campaign on use of telephone quitline and web-based cessation services. AB - INTRODUCTION: Most US smokers do not use evidence-based interventions as part of their quit attempts. Quitlines and Web-based treatments may contribute to reductions in population-level tobacco use if successfully promoted. Currently, few states implement sustained media campaigns to promote services and increase adult smoking cessation. This study examines the effects of Florida's tobacco cessation media campaign and a nationally funded media campaign on telephone quitline and Web-based registrations for cessation services from November 2010 through September 2013. METHODS: We conducted multivariable analyses of weekly media-market-level target rating points (TRPs) and weekly registrations for cessation services through the Florida Quitline (1-877-U-CAN-NOW) or its Web based cessation service, Web Coach (www.quitnow.net/florida). RESULTS: During 35 months, 141,221 tobacco users registered for cessation services through the Florida Quitline, and 53,513 registered through Web Coach. An increase in 100 weekly TRPs was associated with an increase of 7 weekly Florida Quitline registrants (beta = 6.8, P < .001) and 2 Web Coach registrants (beta = 1.7, P = .003) in an average media market. An increase in TRPs affected registrants from multiple demographic subgroups similarly. When state and national media campaigns aired simultaneously, approximately one-fifth of Florida's Quitline registrants came from the nationally advertised portal (1-800-QUIT-NOW). CONCLUSION: Sustained, state-sponsored media can increase the number of registrants to telephone quitlines and Web-based cessation services. Federally funded media campaigns can further increase the reach of state-sponsored cessation services. PMID- 25539131 TI - Room temperature synthesis of covalent-organic framework films through vapor assisted conversion. AB - We describe the facile synthesis of several two-dimensional covalent-organic frameworks (2D COFs) as films by vapor-assisted conversion at room temperature. High-quality films of benzodithiophene-containing BDT-COF and COF-5 with tunable thickness were synthesized under different conditions on various substrates. BDT COF films of several micrometer thickness exhibit mesoporosity as well as textural porosity, whereas thinner BDT-COF films materialize as a cohesive dense layer. In addition, we studied the formation of COF-5 films with different solvent mixture compositions serving as vapor source. Room temperature vapor assisted conversion is an excellent method to form COF films of fragile precursors and on sensitive substrates. PMID- 25539130 TI - Importance of nutrition visits after gastric bypass surgery for American veterans, San Francisco, 2004-2010. AB - INTRODUCTION: Nutrition counseling is important for veterans undergoing gastric bypass surgery. The aim of this study was to explore the relationship between the number of nutrition visits a patient attended and change in body mass index (BMI) after gastric bypass surgery for the veteran population. METHODS: A retrospective study examined veterans (N = 79) who underwent Roux-en-Y gastric bypass surgery from June 2004 through July 2010. Spearman's correlation and multivariate regression analysis were used to analyze data. RESULTS: A significant correlation was found between the number of postoperative nutrition visits and the change in postsurgery BMI at 2 years (Spearman's rho = 0.21; P = .017). After adjusting for age, sex, and race, the association between postsurgery nutrition visits and BMI change persisted (beta = 0.255; 95% confidence interval, 0.015-0.581; P = .039). CONCLUSION: Veterans with more nutrition visits following Roux-en-Y gastric bypass surgery experienced greater declines in BMI. This finding underscores the importance of the dietitian on the bariatric surgery team. PMID- 25539132 TI - Novel insights into the inhibitory mechanism of kaempferol on xanthine oxidase. AB - Xanthine oxidase (XO), a key enzyme in purine catabolism, is widely distributed in human tissues. It can catalyze xanthine to generate uric acid and cause hyperuricemia and gout. Inhibition kinetics assay showed that kaempferol inhibited XO activity reversibly in a competitive manner. Strong fluorescence quenching and conformational changes of XO were found due to the formation of a kaempferol-XO complex, which was driven mainly by hydrophobic forces. The molecular docking further revealed that kaempferol inserted into the hydrophobic cavity of XO to interact with some amino acid residues. The main inhibition mechanism of kaempferol on XO activity may be due to the insertion of kaempferol into the active site of XO occupying the catalytic center of the enzyme to avoid the entrance of the substrate and inducing conformational changes of XO. In addition, luteolin exhibited a stronger synergistic effect with kaempferol than did morin at the lower concentration. PMID- 25539133 TI - QM/MM simulations of amyloid-beta 42 degradation by IDE in the presence and absence of ATP. AB - The ability of the insulin-degrading enzyme (IDE) to degrade amyloid-beta 42 (Abeta42), a process regulated by ATP, has been studied as an alternative path in the development of drugs against Alzheimer's disease. In this study, we calculated the potential of mean force for the degradation of Abeta42 by IDE in the presence and absence of ATP by umbrella sampling with hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, using the SCC-DFTB QM Hamiltonian and Amber ff99SB force field. Results indicate that the reaction occurs in two steps: The first step is characterized by the formation of the intermediate. The second step is characterized by breaking the peptide bond of the substrate, the latter being the rate-determining step. In our simulations, the activation energy barrier in the absence of ATP is 15 +/- 2 kcal mol(-1), which is 7 kcal mol(-1) lower than in the presence of ATP, indicating that the presence of the nucleotide decreases the reaction rate by about 10(5) times. PMID- 25539134 TI - Direct momentum-resolved observation of one-dimensional confinement of externally doped electrons within a single subnanometer-scale wire. AB - Cutting-edge research in the band engineering of nanowires at the ultimate fine scale is related to the minimum scale of nanowire-based devices. The fundamental issue at the subnanometer scale is whether angle-resolved photoemission spectroscopy (ARPES) can be used to directly measure the momentum-resolved electronic structure of a single wire because of the difficulty associated with assembling single wire into an ordered array for such measurements. Here, we demonstrated that the one-dimensional (1D) confinement of electrons, which are transferred from external dopants, within a single subnanometer-scale wire (subnanowire) could be directly measured using ARPES. Convincing evidence of 1D electron confinement was obtained using two different gold subnanowires with characteristic single metallic bands that were alternately and spontaneously ordered on a stepped silicon template, Si(553). Noble metal atoms were adsorbed at room temperature onto the gold subnanowires while the overall structure of the wires was maintained. Only one type of gold subnanowire could be controlled using external noble metal dopants without transforming the metallic band of the other type of gold subnanowires. This result was confirmed by scanning tunnelling microscopy experiments and first-principles calculations. The selective control clearly showed that externally doped electrons could be confined within a single gold subnanowire. This experimental evidence was used to further investigate the effects of the disorder induced by external dopants on a single subnanowire using ARPES. PMID- 25539135 TI - Novel dispersive micro-solid-phase extraction combined with ultrahigh-performance liquid chromatography-high-resolution mass spectrometry to determine morpholine residues in citrus and apples. AB - This paper presents a new analytical method for the determination of morpholine residues in citrus and apples using a novel dispersive micro-solid-phase extraction (DMSPE), followed by ultrahigh-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Samples were extracted with 1% formic acid in acetonitrile/water (1:1, v/v) and then cleaned up using the DMSPE procedure. Morpholine from the extract was adsorbed to a polymer cation exchange sorbent and eluted with ammonium hydroxide/acetonitrile (3:97, v/v) through a 1 mL syringe with a 0.22 MUm nylon syringe filter. All of the samples were analyzed by UHPLC-HRMS/MS on a Waters Acquity BEH hydrophilic interaction chromatography column using 0.1% formic acid and 4 mM ammonium formate in water/acetonitrile as the mobile phase with gradient elution. The method showed good linearity (R(2) > 0.999) in the range of 1-100 MUg/L for the analyte. The limit of detection and limit of quantitation values of morpholine were 2 and 5 MUg/kg, respectively. The average recoveries of morpholine from the citrus and apple samples spiked at three different concentrations (5, 20, and 100 MUg/kg) were in a range from 78.4 to 102.7%. PMID- 25539136 TI - Reversible C-C bond activation enables stereocontrol in Rh-catalyzed carbonylative cycloadditions of aminocyclopropanes. AB - Upon exposure to neutral or cationic Rh(I)-catalyst systems, amino-substituted cyclopropanes undergo carbonylative cycloaddition with tethered alkenes to provide stereochemically complex N-heterocyclic scaffolds. These processes rely upon the generation and trapping of rhodacyclopentanone intermediates, which arise by regioselective, Cbz-directed insertion of Rh and CO into one of the two proximal aminocyclopropane C-C bonds. For cyclizations using cationic Rh(I) systems, synthetic and mechanistic studies indicate that rhodacyclopentanone formation is reversible and that the alkene insertion step determines product diastereoselectivity. This regime facilitates high levels of stereocontrol with respect to substituents on the alkene tether. The option of generating rhodacyclopentanones dynamically provides a new facet to a growing area of catalysis and may find use as a (stereo)control strategy in other processes. PMID- 25539138 TI - Effectiveness of an asthma integrated care program on asthma control and adherence to inhaled corticosteroids. AB - OBJECTIVE: To measure the effectiveness of an integrated care program for individuals with asthma aged 12-45 years, on asthma control and adherence to inhaled corticosteroids (ICS). METHODS: Researchers used a theoretical model to develop the program and assessed effectiveness at 12 months, using a pragmatic controlled clinical trial design. Forty-two community pharmacists in Quebec, Canada recruited participants with either uncontrolled or mild-to-severe asthma. One group was exposed to the program; another received usual care. Asthma control was measured with the Asthma Control Questionnaire; ICS adherence was assessed with the Morisky medication adherence scale and the medication possession ratio. Program effectiveness was assessed with an intention-to-treat approach using multivariate generalized estimating equation models. RESULTS: Among 108 exposed and 241 non-exposed, 52.2% had controlled asthma at baseline. At 12-months, asthma control had improved in both groups but the interaction between study groups and time was not significant (p = 0.09). The proportion of participants with good ICS adherence was low at baseline. Exposed participants showed improvement in adherence and the interaction between study groups and time was significant (p = 0.02). CONCLUSION: An integrated intervention, with healthcare professionals collaborating to optimize asthma control, can improve ICS adherence. PMID- 25539140 TI - Hydroxylamine diffusion can enhance N2O emissions in nitrifying biofilms: a modeling study. AB - Wastewater treatment plants can be significant sources of nitrous oxide (N2O), a potent greenhouse gas. However, little is known about N2O emissions from biofilm processes. We adapted an existing suspended-growth mathematical model to explore N2O emissions from nitrifying biofilms. The model included N2O formation by ammonia-oxidizing bacteria (AOB) via the hydroxylamine and the nitrifier denitrification pathways. Our model suggested that N2O emissions from nitrifying biofilms could be significantly greater than from suspended growth systems under similar conditions. The main cause was the formation and diffusion of hydroxylamine, an AOB nitrification intermediate, from the aerobic to the anoxic regions of the biofilm. In the anoxic regions, hydroxylamine oxidation by AOB provided reducing equivalents used solely for nitrite reduction to N2O, since there was no competition with oxygen. For a continuous system, very high and very low dissolved oxygen (DO) concentrations resulted in lower emissions, while intermediate values led to higher emissions. Higher bulk ammonia concentrations and greater biofilm thicknesses increased emissions. The model effectively predicted N2O emissions from an actual pilot-scale granular sludge reactor for sidestream nitritation, but significantly underestimated the emissions when the NH2OH diffusion coefficient was assumed to be minimal. This numerical study suggests an unexpected and important role of hydroxylamine in N2O emission in biofilms. PMID- 25539137 TI - Factors associated with poor control of 9/11-related asthma 10-11 years after the 2001 World Trade Center terrorist attacks. AB - OBJECTIVE: To identify key factors associated with poor asthma control among adults in the World Trade Center (WTC) Health Registry, a longitudinal study of rescue/recovery workers and community members who were directly exposed to the 2001 WTC terrorist attacks and their aftermath. METHODS: We studied incident asthma diagnosed by a physician from 12 September 2001 through 31 December 2003 among participants aged >=18 on 11 September 2001, as reported on an enrollment (2003-2004) or follow-up questionnaire. Based on modified National Asthma Education and Prevention Program criteria, asthma was considered controlled, poorly-controlled, or very poorly-controlled at the time of a 2011-2012 follow-up questionnaire. Probable post-traumatic stress disorder, depression, and generalized anxiety disorder were defined using validated scales. Self-reported gastroesophageal reflux symptoms (GERS) and obstructive sleep apnea (OSA) were obtained from questionnaire responses. Multinomial logistic regression was used to examine factors associated with poor or very poor asthma control. RESULTS: Among 2445 participants, 33.7% had poorly-controlled symptoms and 34.6% had very poorly-controlled symptoms in 2011-2012. Accounting for factors including age, education, body mass index, and smoking, there was a dose-response relationship between the number of mental health conditions and poorer asthma control. Participants with three mental health conditions had five times the odds of poor control and 13 times the odds of very poor control compared to participants without mental health comorbidities. GERS and OSA were significantly associated with poor or very poor control. CONCLUSIONS: Rates of poor asthma control were very high in this group with post-9/11 diagnosed asthma. Comprehensive care of 9/11-related asthma should include management of mental and physical health comorbidities. PMID- 25539141 TI - Large-scale solvent driven actuation of polyelectrolyte multilayers based on modulation of dynamic secondary interactions. AB - Polyelectrolyte multilayers (PEMs), assembled from weak polyelectrolytes, have often been proposed for use as smart or responsive materials. However, such response to chemical stimuli has been limited to aqueous environments with variations in ionic strength or pH. In this work, a large in magnitude and reversible transition in both the swelling/shrinking and the viscoelastic behavior of branched polyethylenimine/poly(acrylic acid) multilayers was realized in response to exposure with various polar organic solvents (e.g., ethanol, dimethyl sulfoxide, and tetrahydrofuran). The swelling of the PEM decreases with an addition of organic content in the organic solvent/water mixture, and the film contracts without dissolution in pure organic solvent. This large response is due to both the change in dielectric constant of the medium surrounding the film as well as an increase in hydrophobic interactions within the film. The deswelling and shrinking behavior in organic solvent significantly enhances its elasticity, resulting in a stepwise transition from an initially liquid-like film swollen in pure water to a rigid solid in pure organic solvents. This unique and recoverable transition in the swelling/shrinking behaviors and the rheological performances of weak polyelectrolyte multilayer film in organic solvents is much larger than changes due to ionic strength or pH, and it enables large scale actuation of a freestanding PEM. The current study opens a critical pathway toward the development of smart artificial materials. PMID- 25539139 TI - Cardiac function in types II and III spinal muscular atrophy: should we change standards of care? AB - OBJECTIVE: In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. PATIENTS AND METHODS: We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2-74 years). Of them, 82 also had echocardiography. RESULTS: None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. CONCLUSIONS: Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care. PMID- 25539142 TI - Traceless directing groups in radical cascades: from oligoalkynes to fused helicenes without tethered initiators. AB - We report the first example of a traceless directing group in a radical cascade. The chemo- and regioselectivity of the initial attack in skipped oligoalkynes is controlled by propargyl OR moiety. Radical translocations lead to the boomerang return of the radical center to the site of initial attack where it assists the elimination of the directing functionality via beta-scission in the last step of the cascade. The Bu3Sn moiety continues further via facile reactions with electrophiles as well as Stille and Suzuki cross-coupling reactions. This selective radical transformation opens a new approach for the controlled transformation of skipped oligoalkynes into polycyclic ribbons of tunable dimensions. PMID- 25539143 TI - LC-MS/MS improves screening towards 21-hydroxylase deficiency. AB - Basal serum 17OHP measurement remains the first screening step for nonclassic congenital adrenal hyperplasia (NCCAH) and the accuracy of the test is of high value. The aim of this study was to compare the accuracy of immunoassays to LC MS/MS in the assessment of serum 17OHP and androgens concentration in women with hyperandrogenism and controls. 17OHP, total testosterone, androstendione and DHEA S were measured in 39 women with clinically and/or biochemically evident hyperandrogenism and in 29 age-matched controls without clinical hyperandrogenism. 17OHP and androgens were measured by immunoassays and by LC MS/MS. In patients group median 17OHP level measured by immunoassays was significantly higher compared to LC-MS/MS (5.49 nmol/l-ELISA NovaTec(r) and 3.57 nmol/l-ELISA DRG(r) versus 1.56 nmol/l-LC-MS/MS p < 0.0001) as well as in the control group (2.58 nmol/l-ELISA DRG(r) versus 1.14 nmol/l-LC-MS/MS p < 0.0001). Additional, unnecessary diagnostic procedures explaining elevated 17OHP level were undertaken in 85% of patients when NovaTec(r) test was used, in 50% when ELISA DRG(r) and in none when LC-MS/MS method was applied. Total testosterone, androstendione and DHEA-S concentrations in the patients and the controls assessed by the immunoassays were also significantly higher compared to LC-MS/MS. LC-MS/MS is more reliable diagnostic tool in the measurement of serum 17OHP and androgens concentrations compared to immunoassays in women with hyperandrogenism. PMID- 25539144 TI - The dynamical nature of enzymatic catalysis. AB - CONSPECTUS: As is well-known, enzymes are proteins designed to accelerate specific life essential chemical reactions by many orders of magnitude. A folded protein is a highly dynamical entity, best described as a hierarchy or ensemble of interconverting conformations on all time scales from femtoseconds to minutes. We are just beginning to learn what role these dynamics play in the mechanism of chemical catalysis by enzymes due to extraordinary difficulties in characterizing the conformational space, that is, the energy landscape, of a folded protein. It seems clear now that their role is crucially important. Here we discuss approaches, based on vibrational spectroscopies of various sorts, that can reveal the energy landscape of an enzyme-substrate (Michaelis) complex and decipher which part of the typically very complicated landscape is relevant to catalysis. Vibrational spectroscopy is quite sensitive to small changes in bond order and bond length, with a resolution of 0.01 A or less. It is this sensitivity that is crucial to its ability to discern bond reactivity. Using isotope edited IR approaches, we have studied in detail the role of conformational heterogeneity and dynamics in the catalysis of hydride transfer by LDH (lactate dehydrogenase). Upon the binding of substrate, the LDH.substrate system undergoes a search through conformational space to find a range of reactive conformations over the microsecond to millisecond time scale. The ligand is shuttled to the active site via first forming a weakly bound enzyme.ligand complex, probably consisting of several heterogeneous structures. This complex undergoes numerous conformational changes spread throughout the protein that shuttle the enzyme.substrate complex to a range of conformations where the substrate is tightly bound. This ensemble of conformations all have a propensity toward chemistry, but some are much more facile for carrying out chemistry than others. The search for these tightly bound states is clearly directed by the forces that the protein can bring to bear, very much akin to the folding process to form native protein in the first place. In fact, the conformational subspace of reactive conformations of the Michaelis complex can be described as a "collapse" of reactive substates compared with that found in solution, toward a much smaller and much more reactive set. These studies reveal how dynamic disorder in the protein structure can modulate the on enzyme reactivity. It is very difficult to account for how the dynamical nature of the ground state of the Michaelis complex modulates function by transition state concepts since dynamical disorder is not a starting feature of the theory. We find that dynamical disorder may well play a larger or similar sized role in the measured Gibbs free energy of a reaction compared with the actual energy barrier involved in the chemical event. Our findings are broadly compatible with qualitative concepts of evolutionary adaptation of function such as adaptation to varying thermal environments. Our work suggests a methodology to determine the important dynamics of the Michaelis complex. PMID- 25539145 TI - Small angle neutron scattering studies on the internal structure of poly(lactide co-glycolide)-block-poly(ethylene glycol) nanoparticles as drug delivery vehicles. AB - Poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) nanoparticles are commonly used as drug carriers in controlled drug release and targeting. To achieve predictable and clinically relevant volumes of drug distribution, nanoparticle size, surface charge, and especially composition and structure must be controlled. Understanding the internal structures within the particles is fundamentally important to explain differences in drug loading and variations in drug release rate. We prepared nanoparticles from ester-terminated PLGA-PEG polymers via nanoprecipitation, and studied the effects of altering the solvent water miscibility (THF, acetone, and acetonitrile). Morphology, size, polydispersity, and zeta-potential of PLGA-PEG nanoparticles were characterized. Small angle neutron scattering measurements and fitted models revealed the internal nanoparticle structure: PLGA blocks of 7-9 nm are encapsulated inside a fairly dense PEG/water network in a fractal geometry. Particles with a larger PLGA block volume and higher PEG volume fraction in the particle interior result in greater retention of the hydrophilic anticancer drug carboplatin. PMID- 25539147 TI - Minicircle DNA vectors for gene therapy: advances and applications. AB - INTRODUCTION: Nucleic-acid-based biopharmaceuticals enclose a remarkable potential for treating debilitating or life-threatening diseases that currently remain incurable. This promising area of research envisages the creation of state of-the-art DNA vaccines, pluripotent cells or gene-based therapies, which can be used to overcome current issues. To achieve this goal, DNA minicircles are emerging as ideal nonviral vectors due to their safety and persistent transgene expression in either quiescent or actively dividing cells. AREAS COVERED: This review focuses on the characteristics of minicircle DNA (mcDNA) technology and the current advances in their production. The possible modifications to further improve minicircle efficacy are also emphasized and discussed in light of recent advances. As a final point, the main therapeutic applications of mcDNA are summarized, with a special focus on pluripotent stem cells production and cancer therapy. EXPERT OPINION: Achieving in-target and persistent transgene expression is a challenging issue that is of critical importance for a successful therapeutic outcome. The use of miniaturized mcDNA cassettes with additional modifications that increase and prolong expression may contribute to an improved generation of biopharmaceuticals. The unique features of mcDNA render it an attractive alternative to overcome current technical issues and to bridge the significant gap that exists between basic research and clinical applications. PMID- 25539146 TI - Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. AB - BACKGROUND: Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases. METHODS: We identified a family with pulmonary fibrosis, idiopathic infertility, and short telomeres. RESULTS: Exome sequencing of blood-derived DNA revealed two mutations in the telomere-binding protein TINF2. The first was a 15-base-pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele, indicating that the deletion seen in the blood was acquired and may have a protective advantage because it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to that described for Fanconi anemia. No mutations were identified in over 40 uncharacterized pulmonary fibrosis probands suggesting that mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of TERT and TR mutation carriers (five of 45). CONCLUSIONS: Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis and suggest that infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes. PMID- 25539148 TI - Successful treatment of Candida osteoarticular infections with limited duration of antifungal therapy and orthopedic surgical intervention. AB - BACKGROUND: Current guidelines for treatment of Candida osteoarticular infections (COAIs) recommend a prolonged course of antifungal therapy (AFT) of 6-12 months. Based upon strategies developed at the Hospital for Special Surgery (HSS), we hypothesized that the duration of antifungal therapy may be substantially reduced for management of COAI. METHODS: This was a retrospective chart review of cases of COAI treated at the HSS for the past 14 years. COAI was documented by open biopsy and direct culture in all cases. The mean (95% confidence interval, CI) duration of documented follow-up was 39 (16-61) months. RESULTS: Among the 23 cases of COAI, the median age was 62 years (range 22-83 years) with 61% having no underlying condition. Orthopedic appliances, including joint prostheses and fracture hardware, were present in 74% of cases. All patients had COAI as the first proven site of candidiasis. Candida albicans and Candida parapsilosis were the most common species. Hip, knee, foot, and ankle were the most common sites. All patients received aggressive surgical intervention followed by AFT administered for a mean (95% CI) duration of 45 (38-83) days. Systemic AFT consisted principally of fluconazole alone (65%) or in combination with other agents (26%). Adjunctive intraoperative amphotericin B irrigation was used in 35%. Among eight cases of CAOI that required placement of a new prosthetic joint, all were successfully treated. There were no microbiologic failures. CONCLUSIONS: Candida osteoarticular infections may be successfully treated with substantially limited durations of AFT when combined with a thorough surgical approach. PMID- 25539151 TI - The self-reported use of research in clinical practice: a survey of occupational therapists in Sweden. AB - BACKGROUND: Today, healthcare providers and occupational therapists are increasingly required to rely on evidence-based practices. In both outpatient and inpatient settings, the use of research-based practices can be identified using the Research Utilization Measure questionnaire. AIM: This study explores how occupational therapists in Sweden perceive research utilization. METHOD: The Research Utilization Measure was sent to 807 randomly selected occupational therapists in Sweden, and the response rate was 59% (n = 472). RESULTS: The majority of respondents (56%, n = 256) reported use of research-based knowledge in their practice "very or rather often", although 49% (n = 225) of the therapists noted that they "very seldom or never" discussed research findings with their managers. Differences in answers for most items were related to degree of education and length of experience. Occupational therapists with higher education levels more often reported use of research in their clinical practice and therapists with greater experience less often reported use of research in their clinical practice. CONCLUSION: Education seems to influence the degree to which occupational therapists rely on research to inform their practices. A future challenge for managers and occupational therapists is to create strategic discussions on how to implement treatment that is based on current research. PMID- 25539150 TI - Temporal and embryonic lineage-dependent regulation of human vascular SMC development by NOTCH3. AB - Vascular smooth muscle cells (SMCs), which arise from multiple embryonic progenitors, have unique lineage-specific properties and this diversity may contribute to spatial patterns of vascular diseases. We developed in vitro methods to generate distinct vascular SMC subtypes from human pluripotent stem cells, allowing us to explore their intrinsic differences and the mechanisms involved in SMC development. Since Notch signaling is thought to be one of the several key regulators of SMC differentiation and function, we profiled the expression of Notch receptors, ligands, and downstream elements during the development of origin-specific SMC subtypes. NOTCH3 expression in our in vitro model varied in a lineage- and developmental stage-specific manner so that the highest expression in mature SMCs was in those derived from paraxial mesoderm (PM). This pattern was consistent with the high expression level of NOTCH3 observed in the 8-9 week human fetal descending aorta, which is populated by SMCs of PM origin. Silencing NOTCH3 in mature SMCs in vitro reduced SMC markers in cells of PM origin preferentially. Conversely, during early development, NOTCH3 was highly expressed in vitro in SMCs of neuroectoderm (NE) origin. Inhibition of NOTCH3 in early development resulted in a significant downregulation of specific SMC markers exclusively in the NE lineage. Corresponding to this prediction, the Notch3-null mouse showed reduced expression of Acta2 in the neural crest-derived SMCs of the aortic arch. Thus, Notch3 signaling emerges as one of the key regulators of vascular SMC differentiation and maturation in vitro and in vivo in a lineage- and temporal-dependent manner. PMID- 25539152 TI - Role of substrate dynamics in protein prenylation reactions. AB - CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions will facilitate the design of novel catalysts that can produce high quality compounds that can be employed, for example, as fuels and life saving drugs. We have used molecular dynamics (MD) methods and combined quantum mechanical/molecular mechanical (QM/MM) methods to study a series of proteins either whose substrates are too far away from the catalytic center or whose experimentally resolved substrate binding modes cannot explain the observed product distribution. In particular, we describe studies of farnesyl transferase (FTase) where the farnesyl pyrophosphate (FPP) substrate is ~8 A from the zinc bound peptide in the active site of FTase. Using MD and QM/MM studies, we explain how the FPP substrate spans the gulf between it and the active site, and we have elucidated the nature of the transition state (TS) and offered an alternate explanation of experimentally observed kinetic isotope effects (KIEs). Our second story focuses on the nature of substrate dynamics in the aromatic prenyltransferase (APTase) protein NphB and how substrate dynamics affects the observed product distribution. Through the examples chosen we show the power of MD and QM/MM methods to provide unique insights into how protein substrate dynamics affects catalytic efficiency. We also illustrate how complex these reactions are and highlight the challenges faced when attempting to design de novo catalysts. While the methods used in our previous studies provided useful insights, several clear challenges still remain. In particular, we have utilized a semiempirical QM model (self-consistent charge density functional tight binding, SCC-DFTB) in our QM/MM studies since the problems we were addressing required extensive sampling. For the problems illustrated, this approach performed admirably (we estimate for these systems an uncertainty of ~2 kcal/mol), but it is still a semiempirical model, and studies of this type would benefit greatly from more accurate ab initio or DFT models. However, the challenge with these methods is to reach the level of sampling needed to study systems where large conformational changes happen in the many nanoseconds to microsecond time regimes. Hence, how to couple expensive and accurate QM methods with sophisticated sampling algorithms is an important future challenge especially when large-scale studies of catalyst design become of interest. The use of MD and QM/MM models to elucidate enzyme catalytic pathways and to design novel catalytic agents is in its infancy but shows tremendous promise. While this Account summarizes where we have been, we also discuss briefly future directions that improve our fundamental ability to understand enzyme catalysis. PMID- 25539153 TI - Theoretical and Experimental Photoelectron Spectroscopy Characterization of the Ground State of Thymine Cation. AB - We report on the vibronic structure of the ground state X(2)A" of the thymine cation, which has been measured using a threshold photoelectron photoion coincidence technique and vacuum ultraviolet synchrotron radiation. The threshold photoelectron spectrum, recorded over ~0.7 eV above the ionization potential (i.e., covering the whole ground state of the cation) shows rich vibrational structure that has been assigned with the help of calculated anharmonic modes of the ground electronic cation state at the PBE0/aug-cc-pVDZ level of theory. The adiabatic ionization energy has been experimentally determined as AIE = 8.913 +/- 0.005 eV, in very good agreement with previous high resolution results. The corresponding theoretical value of AIE = 8.917 eV has been calculated in this work with the explicitly correlated method/basis set (R)CCSD(T)-F12/cc-pVTZ-F12, which validates the theoretical approach and benchmarks its accuracy for future studies of medium-sized biological molecules. PMID- 25539154 TI - Preparation and in vitro-in vivo evaluation of surface-modified poly(lactide-co glycolide) nanoparticles as controlled release carriers for flutamide delivery. AB - This investigation explores the use of methoxy polyethylene glycol (mPEG) functionalised poly(D,L-lactide-co-glycolide) (PLGA) nanocrystals of flutamide (FLT) with enhanced solubility, bioavailability and blood circulation time for targeting prostate cancer. FLT had Log P 3.27, short half life 5-6 h, low water solubility, permeability and bioavailability with extensive first-pass metabolism. FLT-loaded nanocrystals were prepared using nanoprecipitation method with surface coating by mPEG and characterised through differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray powder diffraction, scanning electronic microscopy, particle size, zeta potential, percent entrapment efficiency (% EE), in vitro dissolution, haemolysis, sterility, bioavailability and stability studies. The percent cumulative drug release and % EE of optimised formulation was found to be 95.21 +/- 1.18 and 88.36 +/- 1.20, respectively, for 48 h. In addition, FLT-loaded PEGylated PLGA nanocrystals exhibited significantly delayed blood clearance with drug level of about 766.71 ng/mL at 48 h. In conclusion, PEGylated PLGA FLT nanocrystals could be demonstrated as a novel approach to enhance solubility, bioavailability and blood circulation time. PMID- 25539155 TI - Pendant alkyl and aryl groups on tin control complex geometry and reactivity with H2/D2 in Pt(SnR3)2(CNBu(t))2 (R = Bu(t), Pr(i), Ph, mesityl). AB - The complex Pt(SnBu(t)3)2(CNBu(t))2(H)2, 1, was obtained from the reaction of Pt(COD)2 and Bu(t)3SnH, followed by addition of CNBu(t). The two hydride ligands in 1 can be eliminated, both in solution and in the solid state, to yield Pt(SnBu(t)3)2(CNBu(t))2, 2. Addition of hydrogen to 2 at room temperature in solution and in the solid state regenerates 1. Complex 2 catalyzes H2-D2 exchange in solution to give HD. The proposed mechanism of exchange involves reductive elimination of Bu(t)3SnH from 1 to afford vacant sites on the Pt center, thus facilitating the exchange process. This is supported by isolation and characterization of Pt(SnMes3)(SnBu(t)3)(CNBu(t))2, 3, when the addition of H2 to 2 was carried out in the presence of free ligand Mes3SnH (Mes = 2,4,6-Me3C6H2). Complex Pt(SnMes3)2(CNBu(t))2, 5, can be prepared from the reaction of Pt(COD)2 with Mes3SnH and CNBu(t). The exchange reaction of 2 with Ph3SnH gave Pt(SnPh3)3(CNBu(t))2(H), 6, wherein both SnBu(t)3 ligands are replaced by SnPh3. Complex 6 decomposes in air to form square planar Pt(SnPh3)2(CNBu(t))2, 7. The complex Pt(SnPr(i)3)2(CNBu(t))2, 8, was also prepared. Out of the four analogous complexes Pt(SnR3)2(CNBu(t))2 (R = Bu(t), Mes, Ph, or Pr(i)), only the Bu(t) analogue does both H2 activation and H2-D2 exchange. This is due to steric effects imparted by the bulky Bu(t) groups that distort the geometry of the complex considerably from planarity. The reaction of Pt(COD)2 with Bu(t)3SnH and CO gas afforded trans-Pt(SnBu(t)3)2(CO)2, 9. Compound 9 can be converted to 2 by replacement of the CO ligands with CNBu(t) via the intermediate Pt(SnBu(t)3)2(CNBu(t))2(CO), 10. PMID- 25539157 TI - Anticoagulant therapy in atrial fibrillation: vitamin K antagonists or novel oral anticoagulant drugs? PMID- 25539158 TI - Pitfalls of the interpretation of myocardial infarction data in patients on dabigatran treatment. PMID- 25539159 TI - Is positive troponin a hype in myopericarditis: should emergency room risk stratification criteria be revisited? PMID- 25539160 TI - What we do not know about the role of colchicine in pericarditis in 2014. PMID- 25539161 TI - The complete sequence of the mitochondrial genome of Luchuan pig (Sus scrofa). AB - Luchuan pig is one of the famous native breeds in China. In this study, we report the complete mitochondrial genome sequence of Luchuan pig for the first time, which is determined through the PCR-based method. The total length of the mitogenome is 16,710 bp with the base composition of 34.67% A, 13.33% G, 25.82% T and 26.18% C, and an A + T (60.48%)-rich feature is detected, which contains 1 control region (D-loop region), 2 ribosomal RNA genes, 13 PCGs and 22 tRNA genes. The complete mitochondrial genome of Luchuan pig provides an important data in genetic mechanism and the evolution genomes. PMID- 25539163 TI - Mechanism of photocatalytic hydrogen generation by a polypyridyl-based cobalt catalyst in aqueous solution. AB - The mechanism of photocatalytic hydrogen production was studied with a three component system consisting of fac-[Re(py)(CO)3bipy](+) (py = pyridine, bipy = 2,2'-bipyridine) as photosensitizer, [Co(TPY-OH)(OH2)](2+) (TPY-OH = 2-bis(2 pyridyl)(hydroxy)methyl-6-pyridylpyridine), a polypyridyl-based cobalt complex, as water reduction catalyst (WRC), and triethanolamine (TEOA) as sacrificial electron donor in aqueous solution. A detailed mechanistic picture is provided, which covers all processes from excited state quenching on the time scale of a few nanoseconds to hydrogen release taking place between seconds and minutes at moderately basic reaction conditions. Altogether these processes span 9 orders of magnitude in time. The following reaction sequence was found to be the dominant pathway for hydrogen generation: After reductive quenching by TEOA, the reduced photosensitizer (PS) transfers an electron to the Co(II)-WRC. Protonation of Co(I) yields Co(III)H which is reduced in the presence of excess Co(I). Co(II)H releases hydrogen after a second protonation step, which is detected time resolved by a clark-type hydrogen electrode. Aside from these productive steps, the role of side and back reactions involving TEOA-derived species is assessed, which is particularly relevant in laser flash photolysis measurements with significantly larger transient concentrations of reactive species as compared to continuous photolysis experiments. Most notable is an equilibrium reaction involving Co(I), which is explained by a nucleophilic addition of Co(I) to the oxidation product of TEOA, an electrophilic iminium ion. Quantum chemical calculations indicate that the reaction is energetically feasible. The calculated spectra of the adduct are consistent with the spectroscopic observations. PMID- 25539162 TI - Oxidised phospholipids as biomarkers in human disease. AB - Oxidised phospholipids (OxPLs) are generated from (poly)unsaturated diacyl- and alk(en)ylacyl glycerophospholipids under conditions of oxidative stress. OxPLs exert a wide variety of biological effects on diverse cell types in vitro and in vivo and are thought to play a role in the development of several chronic diseases including atherosclerosis, a classical lipid-associated and inflammatory disorder. OxPLs are recognised as culprit molecular components responsible for the pathophysiological actions of oxidised low-density lipoproteins. There is growing interest in the potential use of OxPLs as biomarkers of human pathologies. Here we offer a brief overview of current detection methods and knowledge on relationships between levels of circulating OxPLs and disease progression, with particular emphasis on cardiovascular disease. PMID- 25539164 TI - Effects of physiologic mechanical stimulation on embryonic chick cardiomyocytes using a microfluidic cardiac cell culture model. AB - Hemodynamic mechanical cues play a critical role in the early development and functional maturation of cardiomyocytes (CM). Therefore, tissue engineering approaches that incorporate immature CM into functional cardiac tissues capable of recovering or replacing damaged cardiac muscle require physiologically relevant environments to provide the appropriate mechanical cues. The goal of this work is to better understand the subcellular responses of immature cardiomyocytes using an in vitro cardiac cell culture model that realistically mimics in vivo mechanical conditions, including cyclical fluid flows, chamber pressures, and tissue strains that could be experienced by implanted cardiac tissues. Cardiomyocytes were cultured in a novel microfluidic cardiac cell culture model (CCCM) to achieve accurate replication of the mechanical cues experienced by ventricular CM. Day 10 chick embryonic ventricular CM (3.5 * 10(4) cell clusters per cell chamber) were cultured for 4 days in the CCCM under cyclic mechanical stimulation (10 mmHg, 8-15% stretch, 2 Hz frequency) and ventricular cells from the same embryo were cultured in a static condition for 4 days as controls. Additionally, ventricular cell suspensions and ventricular tissue from day 16 chick embryo were collected and analyzed for comparison with CCCM cultured CM. The gene expressions and protein synthesis of calcium handling proteins decreased significantly during the isolation process. Mechanical stimulation of the cultured CM using the CCCM resulted in an augmentation of gene expression and protein synthesis of calcium handling proteins compared to the 2D constructs cultured in the static conditions. Further, the CCCM conditioned 2D constructs have a higher beat rate and contractility response to isoproterenol. These results demonstrate that early mechanical stimulation of embryonic cardiac tissue is necessary for tissue proliferation and for protein synthesis of the calcium handling constituents required for tissue contractility. Thus, physiologic mechanical conditioning may be essential for generating functional cardiac patches for replacement of injured cardiac tissue. PMID- 25539165 TI - Evaluation of a Community-Based Exercise Program for Breast Cancer Patients Undergoing Treatment. AB - BACKGROUND: Exercise is important during treatment for breast cancer to alleviate the usual declines in physical and emotional health and overall health-related quality of life (HRQL). OBJECTIVE: This study evaluated the effectiveness, safety, and enjoyment of a community exercise program for breast cancer patients who were currently undergoing or within 3 months of completing chemotherapy or radiation treatment. METHODS: Breast cancer patients Engaging in Activity while Undergoing Treatment (BEAUTY) is a 12-week program of resistance, aerobic, and flexibility exercise. Participants completed pre and post fitness assessments, and questionnaires to measure HRQL, fatigue, cognitive function, and depressive symptoms. Participants had access to group exercise classes and were provided a home-based exercise program. RESULTS: Participants (n = 80) were middle aged (mean age, 50.3 [SD, 9.0] years), and the majority were diagnosed with stage II breast cancer (53.8%). From baseline to 12 weeks, resting heart rate (mean [INCREMENT], +4.15 beats/min) and body mass index increased slightly (mean [INCREMENT], +0.47 kg/m). No clinically significant changes in HRQL or other psychosocial questionnaires, but social well-being decreased (t77 = 3.83, P = .000) slightly, and emotional well-being improved (t77 = -2.15, P = .034). Participants attended an average of 7.5 (SD, 6.5) classes; feedback about the program was positive, and no exercise-related injuries were reported. CONCLUSIONS: The BEAUTY program was feasible and effective in managing chemotherapy and radiation treatment-related declines in physical fitness and HRQL. IMPLICATIONS FOR PRACTICE: This study supports the need to integrate exercise programming as part of treatment plans for breast cancer patients. PMID- 25539166 TI - Self-reported Pain in Adolescents With Leukemia or a Brain Tumor: A Systematic Review. AB - BACKGROUND: Given the changes adolescents experience in psychosocial domains as they transition from childhood to young adulthood, the experience of cancer at this time of life is likely to differ in regard to symptom manifestation and relative distress. OBJECTIVE: The purpose of this systematic review is to examine self-reported pain among adolescents diagnosed with leukemia or a brain tumor. METHODS: Electronic searches of MEDLINE, PubMed, and the Cochrane Database of Systematic Reviews since inception to May 2014 were conducted. Search terms included pain; a second term including adolescent, juvenile, youth, child, or childhood; and a third term including cancer, leukemia, or brain tumor. Adolescents were defined as being 10 to 19 years of age. RESULTS: A total of 30 articles met inclusion criteria. Pain was reported associated with the cancer itself, with treatments, and with procedures and was assessed via a variety of measures and methods. Pain was also found to persist long after treatment completion. CONCLUSION: Pain is a frequently reported symptom among adolescents with leukemia or a brain tumor. More consistent inclusion of established measures across studies could increase the availability of data suitable for meta-analyses while also providing information on which aspects of the pain experience are understudied. IMPLICATIONS FOR PRACTICE: Rigorous assessment of pain should be conducted from diagnosis throughout the cancer continuum into long-term survivorship or end of life, with particular attention paid to before and after treatment procedures. Improved pain management incorporating behavioral and/or pharmacological strategies may result in improved quality of life for adolescents with cancer. PMID- 25539167 TI - Effects of autonomy-supportive and controlling styles on situational self determined motivation: some unexpected results of the commitment procedure. AB - Distinct and simultaneous effects of autonomy-supportive and controlling styles, usually considered as mutually exclusive, on situational self-determined motivation are tested. In Study 1, economics students (N = 100; 57 men, 43 women; M age = 21.5 yr.) were randomly assigned to one of the four experimental conditions (high vs. low) of autonomy supportive and/or controlling behaviors during a task. Results supported the independence of those constructs. An unexpected effect in regards to Self-determination Theory was found in the Low autonomy - High control condition in which self-determined motivation was observed. The interpretation for this specific condition, an effect due to the attempt to reduce cognitive dissonance triggered by the commitment procedure, was tested. In Study 2, sport students (N = 80, 44 men, 36 women; M age = 19.2 yr.) were randomly assigned to one of the three experimental conditions: No commitment, Commitment plus self-affirmation, and Commitment without self affirmation. Results supported Study 1's interpretation: motivation was lower when participants were recruited without a commitment procedure or when they were invited to self-affirm than when participants recruited with a commitment procedure. PMID- 25539168 TI - Using Kollar's solution-focused pastoral counseling for bereaved clients: the process of empowerment from clients' perception. AB - The purpose of this study was to investigate how bereaved clients recovered from grief and loss after receiving Kollar's solution-focused pastoral counseling (KSFPC) from a perspective of empowerment. Ten Taiwanese Christian clients (3 men, 7 women; M age = 42.5 yr., SD = 8.5), who had experienced a significant loss of a loved one within the past two years, were recruited from churches in northern Taiwan, forming a convenience sample. The clients, based on their time availability, were randomly assigned to one of the two pastoral counselors and had four KSFPC sessions. The grounded theory procedure was adopted for qualitative data analysis. Four prominent categories emerged from the open-ended questions, in-depth interviews, and interactive counseling notes, including First Encounter with Solution-focused Pastoral Counseling (SFPC), Transitional Life Re Decision-Making Process, Reflections and Changes, and New Participatory Competencies, within which 12 axial categories and 42 meaning units were identified. The results support the use of KSFPC to empower clients' competence in recovery from grief and loss. Implications for future research and KSFPC practice are suggested. PMID- 25539169 TI - A study of intelligence in Oman. AB - There have been two studies of the Coloured Progressive Matrices and the Standard Progressive Matrices in Oman, giving British IQs of 87 and 81, respectively. The present paper reports results for the Advanced Progressive Matrices to ascertain how far these are consistent with the previous studies. The Advanced Progressive Matrices was standardized in Oman in 2009-10 on a sample of 2,467 Grade 11 and 12 students (M age = 17.13 yr., SD = 1.01, range = 16-18). The sample obtained a mean score of 12.2, equivalent to a British IQ of 88, consistent with the results of the two previous studies. PMID- 25539170 TI - Validity and reliability evidence of the TOCA-C in a sample of Greek students. AB - Validity and reliability evidence of the Teacher Observation of Classroom Adaptation-Checklist (TOCA-C) was examined in 186 Greek students through exploratory factor analysis, divergent and concurrent validity, internal consistency, and test-retest reliability. The TOCA-C showed a high internal consistency for the three factors of Concentration Problems, Disruptive/Aggressive Behaviour, and Prosocial Behaviour (alphas = .89-.96), and acceptable two-week test-retest reliability. The three-factor solution explained 74.50% of the total variance. Regarding divergent validity, a significant Sex * Disability interaction was evident for Disruptive Behaviour, with women scoring higher in 'special' and lower in 'general' schools compared to men. Main effects were significant across disability, but not across sex. Correlations with the Strengths and Difficulties Questionnaire suggested convergent and divergent validity evidence. The TOCA-C should be useful in testing Greek students with and without disabilities. PMID- 25539171 TI - Cognitive dysfunction in fibromyalgia: slow access to the mental lexicon. AB - Lexical access speed, the time needed for the brain to access the catalogue of words in long-term memory, is assumed to provide a foundation for a broad array of cognitive operations. It was hypothesized that deficits in lexical speed are likely to play a central role in deficiencies in cognitive performance of patients with fibromyalgia, who as a group show deficits in lexical speed. This was tested in a sample of 209 patients with fibromyalgia and in 72 control patients with memory deficits. Participants completed the Stroop word-naming measure of lexical access speed and 12 neurocognitive measures. Deficit in lexical access speed occurred at approximately twice the frequency (48.3% vs 25.0%) in fibromyalgia. The average delay in speed of lexical access was 171 msec. in fibromyalgia and 163 msec. in controls. Those with deficits in lexical access speed displayed deficiencies on 10 of 12 cognitive measures in the fibromyalgia group, and on 8 of 12 cognitive measures in the control group. The premise that lexical access speed is disproportionately present in fibromyalgia and serves as a foundation for a wide array of cognitive operations is supported. PMID- 25539172 TI - Analog study investigating diary assessments of rewards and punishments for emotional states. AB - Behavioral Activation is a treatment for depression relying on rewards from activities; but it is possible that the effects of punishments should also be considered, as should its generalizability to the healthy population. Effect of rewards and punishments on emotional states and depression were investigated by using the daily diary method. Participants (7 men, 21 women; M age = 19.4 yr.) recorded their daily activities and the intensity of rewards and punishments accompanying each activity for one week. Positive and negative affects of participants were assessed using the Japanese version of the Positive Affect and Negative Affect Schedule. Multiple regression analysis indicated that both rewards and punishments predicted depressive symptoms. Moreover, rewards (but not punishments) predicted positive affect, whereas punishments predicted negative affects (and rewards did not). These preliminary results suggest that the effects of both rewards and punishments given for activities should be considered in models of behavioral activation. PMID- 25539173 TI - Leader-follower value congruence in social responsibility and ethical satisfaction: a polynomial regression analysis. AB - This paper presents empirical research into the relationship between leader follower value congruence in social responsibility and the level of ethical satisfaction for employees in the workplace. 163 dyads were analyzed, each consisting of a team leader and an employee working at a large manufacturing company in South Korea. Following current methodological recommendations for congruence research, polynomial regression and response surface modeling methodologies were used to determine the effects of value congruence. Results indicate that leader-follower value congruence in social responsibility was positively related to the ethical satisfaction of employees. Furthermore, employees' ethical satisfaction was stronger when aligned with a leader with high social responsibility. The theoretical and practical implications are discussed. PMID- 25539174 TI - The moderating role of alienation on the relation between social dominance orientation, right-wing authoritarianism, and person-organization fit. AB - Right-Wing Authoritarianism and Social Dominance Orientation have been found to be related with Person-Organization fit. This study examined whether alienation also plays a role in the relation between Person-Organization fit and these two socio-political attitudes. Measures of Right-Wing Authoritarianism, Social Dominance Orientation, alienation, and Person-Organization fit were given to a sample of Officer Cadets (N = 99; M age = 22.8 yr., SD = 5.4). The findings suggest that when individuals felt alienated, Social Dominance Orientation and Right-Wing Authoritarianism were not related to Person-Organization fit. When alienation was low, Social Dominance Orientation and Right-Wing Authoritarianism interacted to predict Person-Organization fit. Therefore, feelings of alienation can influence the perception of fit within an organization and the relation between perception of fit with Social Dominance Orientation and Right-Wing Authoritarianism. PMID- 25539175 TI - The lure technique: replication and refinement in a field setting. AB - Many techniques designed to gain compliance to a request are presented in the social psychological literature. However, the lure technique has received little attention from scientists. This technique, also called bait-and-switch, is used to influence people's choices and involves three stages: (1) individuals are led to make a rewarding decision to carry out a given behavior; (2) they are informed of the impossibility of carrying out this behavior; (3) a new but less rewarding decision is proposed. Only one formal study has been published on this technique, which failed to control two key methodological factors: the status of the participants and the solicitor, and the delay between the initial decision and the target request. These two factors were controlled in this study. Outside a French campus, 40 female students in the 18-22 age range were solicited by a student to participate in a pleasant experiment for which they would be remunerated. One minute after accepting, they were informed that the number of participants was reached, and they were no longer needed. The solicitor then proposed a different task that was less interesting and not remunerated. Greater compliance with the final request was found in the lure condition (70%) than in the control condition (35%) in which the final request was addressed immediately. The results confirm the effectiveness of the lure technique to increase compliance and show that its effectiveness is not dependent on the solicitor's status. PMID- 25539176 TI - Self-compassion and life satisfaction in gay men. AB - Studies have shown that gay men are at increased risk for anxiety and depression due to social oppression; research suggests that self-compassion is positively associated with life-satisfaction and emotional resilience. In a sample of 68 gay men (M age = 39.7 yr., SD = 16.3), the influence of self-compassion on satisfaction with life was examined while controlling for age, income, and openness about sexual orientation. Analysis of the data revealed that self compassion was a significant predictor of satisfaction with life. Implications of this finding were discussed. PMID- 25539177 TI - Musical key perception in relation to color. AB - A link between musical keys and colors is common among musicians, although there has never been any agreement about which color matches which key. This study tested two alternative key-color associations: E is red and Eb is green, or vice versa. 21 participants (10 men, 11 women; M age = 20 yr., SD = 3.3) with absolute pitch listened to melodies beginning with an anacrusis and a perfect cadence which were played through in C major. Then the melodies began in another key, while four or two colored squares were displayed (in Experiments 1 and 2, respectively). Participants were asked to chose the color which best matched the quality of the new key. The results showed strong support for the E red / Eb green linkage. PMID- 25539178 TI - Short form of Spanish version of the WISC-IV for intelligence assessment in elementary school children. AB - In educational settings, quick assessments of intelligence are often required to screen children with potential special needs. The WISC-IV is administered individually and takes between one and two hours to complete. Given its widespread use in Spain, a short-form of the Spanish version is likely to be of use to professionals. The goal of this research was to develop a short form of the WISC-IV that can be performed in approximately half an hour. Data obtained in 100 elementary school children were analyzed following the criteria of Resnick and Entin (1971) . The results showed that the most accurate estimation of intelligence was achieved with a combination of the Vocabulary, Block Design, Letter-Number Sequencing, and Coding subtests. PMID- 25539179 TI - Propargyl 1,2-orthoesters for a catalytic and stereoselective synthesis of pyrimidine nucleosides. AB - Pyrimidine nucleosides are synthesized by using propargyl 1,2-orthoesters and Au(III) salt as a catalyst. Strategically positioned 1,2-orthoesters are found to yield only 1,2-trans nucleosides and enable preparation of 2'-OH containing pyrimidine nucleosides. The glycosyl donor employed in this study is stable and easily accessible. The identified high-yielding protocol is mild, diastereoselective, and catalytic. PMID- 25539180 TI - The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients. AB - Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with mono- or poly-therapy of carbamazepine, valproic acid, or phenytoin. The treated epileptic patients were divided into 2 main groups according to the seizure frequency: controlled seizure patients GII (n = 30) and uncontrolled seizure patients GIII (n = 30). GII included the GIIA subgroup (n = 15) which had been seizure free for more than 12 months and the GIIB subgroup (n = 15) which had been seizure free for a period from 6 to12 months. GIII included GIIIA (n = 15) and GIIIB (n = 15) for patients which had a seizure frequency of less than and more than four times/month, respectively. In comparison to the control group (GI), the levels of nitric oxide (NO) and malondialdehyde/creatinine ratio were significantly increased in GIIB, GIIIA, and GIIIB, while vitamins A and E levels were significantly decreased in GIIIB. Serum NO levels had significant negative correlations with serum vitamin E in the GIIA and GIIB groups, and with vitamin A in the GIIIA and GIIIB groups. However, serum NO had positive correlation with urinary MDA/Cr ratio. The imbalance between free radical generation and antioxidant system in epileptic patients may be a factor in seizure frequency. PMID- 25539182 TI - Isolation and structural characterization of geminal di(iodozincio)methane complexes stabilized with nitrogen ligands. AB - Treatment of gem-di(iodozincio)methane with pyridine or diamine derivatives resulted in the isolation of a storable gem-di(iodozincio)methane species. Use of the sterically bulky bipyridine ligand gave a gem-di(iodozincio)methane complex, which allowed the first X-ray structural analysis of such species. This work represents a rare example of the isolation of an organometallic reactive species in Schlenk equilibrium and thus provides new insight into the design of efficient and storable organometallic reagents. The isolated gem-di(iodozincio)methane complexes serve as effective methylene dianion synthons for olefination of carbonyl compounds. PMID- 25539181 TI - Expression levels of microRNA-199 and hypoxia-inducible factor-1 alpha in brain tissue of patients with intractable epilepsy. AB - OBJECTIVES: During the last decade, experimental evidence has demonstrated an important role of hypoxia, which leads to neuronal cell death and angiogenesis, in the mechanisms of seizure precipitation and recurrence. MicroRNA-199 targets hypoxia-inducible factor-1alpha (HIF-1alpha), which has recently been implicated in the pathophysiology of the hypoxic state and brain injury. However, little is known about the roles of MicroRNA-199 and HIF-1alpha in the human epileptogenic process. DESIGN AND METHODS: In this study, we investigated the expression of miR 199a-5p, miR-199b-5p and HIF-1alpha using real-time PCR, immunohistochemistry and western blots in the temporal neocortex of twenty four patients with intractable epilepsy and twelve control subjects. RESULTS: Compared with the control group, the expression of miR-199a-5p and miR-199b-5p was significantly lower in epileptic brain tissues (p < 0.05). The levels of HIF-1alpha mRNA and protein were highly up-regulated in epileptic brain tissues compared with those of control subjects (p < 0.05). CONCLUSION: These data suggest that the abnormal expression of miR-199 and HIF-1alpha in epileptic brain tissue may be involved in the pathophysiology of human epilepsy and that the expression of HIF-1alpha may be regulated by miR-199. These findings may provide new insights into the treatment of epilepsy. PMID- 25539183 TI - Is consistency a domain-general individual differences characteristic? AB - We explored randomness in responding in two ways across six experiments. First, we predicted that people would differ from each other in randomness in a stable way when tested in the same domain across two sessions; people who responded more randomly in a particular domain in one session also should respond more randomly in a second session whereas people who responded less randomly in one session also should respond less randomly in a second session. Second, we predicted that there would be some domain general randomness; people's randomness in one domain should predict their randomness in another domain. We used consistency coefficients across blocks of a session as an inverse measure of randomness and found (a) consistency coefficients correlated across sessions within the same domain and (b) consistency coefficients in one domain correlated with consistency coefficients in other domains. PMID- 25539184 TI - Unique contributions of metacognition and cognition to depressive symptoms. AB - This study attempts to examine the unique contributions of "cognitions" or "metacognitions" to depressive symptoms while controlling for their intercorrelations and comorbid anxiety. Two-hundred-and-fifty-one university students participated in the study. Two complementary hierarchical multiple regression analyses were performed, in which symptoms of depression were regressed on the dysfunctional attitudes (DAS-24 subscales) and metacognition scales (Negative Beliefs about Rumination Scale [NBRS] and Positive Beliefs about Rumination Scale [PBRS]). Results showed that both NBRS and PBRS individually explained a significant amount of variance in depressive symptoms above and beyond dysfunctional schemata while controlling for anxiety. Although dysfunctional attitudes as a set significantly predicted depressive symptoms after anxiety and metacognitions were controlled for, they were weaker than metacognitive variables and none of the DAS-24 subscales contributed individually. Metacognitive beliefs about ruminations appeared to contribute more to depressive symptoms than dysfunctional beliefs in the "cognitive" domain. PMID- 25539185 TI - Determinants on the quality of social networks among Hong Kong Chinese. AB - The aim of the present study is to examine prospectively the quality of social networks of Hong Kong Chinese adults. A randomized household survey was employed. A total of 1170 Hong Kong Chinese respondents were recruited to the study. Participants ranged in age from 18 to 79 years, 43% of respondents were male. Findings revealed a negative association between familial trust and social network size. Network trust, social identification, and structural networks were all found to be positively associated with social network size and perceived respect from social network. The importance of family and the prioritization of the needs of the family over individual needs has implications on social network size and formation for Hong Kong Chinese individuals. More research is needed to further examine the importance of familial relationships and the prioritization of family and the impact this has on social network development and maintenance among Hong Kong Chinese. PMID- 25539186 TI - Causal inference from descriptions of experimental and non-experimental research: public understanding of correlation-versus-causation. AB - The human tendency to conflate correlation with causation has been lamented by various scientists (Kida, 2006; Stanovich, 2009), and vivid examples of it can be found in both the media and peer-reviewed literature. However, there is little systematic data on the extent to which individuals conflate correlation with causation. In three experiments, we presented people with one of four research vignettes generated from the combination of two independent variables: whether the vignette described an experimental or non-experimental design, and whether it revealed a positive or negative association. Upon reading their vignette, participants selected inferences that could be drawn from the findings. Participants drew causal inferences from non-experimental vignettes as often as they did from experimental vignettes, and more frequently for causal statements and directions of association that fit with intuitive notions than for those that did not. We discuss our findings in relation to other biases in human thinking. PMID- 25539187 TI - Determination of scattering in intraocular lenses by spectrophotometric measurements. AB - This study presents a method for measuring scattering in explanted intraocular lenses (IOLs). Currently, determining scattering in IOLs is usually performed by Scheimpflug cameras and the results are expressed in the units used by this apparatus. The method we propose uses a spectrophotometer and this makes it possible to measure the total transmission of the IOL by using an integrating sphere; the direct transmission is determined by the double-beam mode. The difference between these two transmissions gives a value of the scattering in percentage values of light lost. In addition, by obtaining the spectral transmission curve, information about the most scattered wavelengths is also obtained. The IOL power introduces errors when directly measured, particularly with high powers. This problem can be overcome if a tailor-made cuvette is used that shortens the distance between the IOL and the condensing lens of the spectrophotometer when the IOL powers are below 24 diopters. We checked the effectiveness of this method by measuring the scattering of three explanted IOLs from cornea donors. This method, however, does not make it possible to ascertain whether the scattering measured is caused by surface light scattering or internal light scattering. PMID- 25539188 TI - Is 18F-fluorodeoxyglucose positron emission tomography/computed tomography helpful in the decision-making process for neck dissection in patients with T1-T2 lingual cancer? AB - CONCLUSION: The usefulness of addition of positron emission tomography/computed tomography (PET/CT) in decisions as to whether to perform neck dissection in patients with T1-T2 lingual squamous cell carcinoma (SCC) might be limited, but adding the condition of lymph nodes with a maximum standardized uptake value (SUVmax) >4.5 to existing criteria would be helpful. OBJECTIVES: The purpose of this study was to investigate the usefulness of PET/CT for performing neck dissection in patients with T1-T2 lingual SCC. METHODS: This retrospective review surveyed 19 patients with T1-T2 lingual SCC who underwent neck dissection after meeting one or more of the following criteria: (1) clinically positive nodes; (2) >4 mm thickness; (3) >= 3 cm longest diameter of the primary tumor. Focal 18F fluorodeoxyglucose (FDG) uptake was considered to indicate PET-positive nodes (PET + Ns). The relation between pathologically positive nodes (p + Ns) and PET + Ns was estimated. RESULTS: There were 14 PET + Ns at 12 of 66 levels (18%) in 8 of the 19 (42%) patients. There were also 6 p + Ns (1%) among 412 nodes at 5 cervical lymph node levels (8%) in 5 patients (26%). The sensitivity and specificity for PET/CT were 80% and 64%, respectively. The SUVmax was measured, and receiver operating characteristic (ROC) analysis was undertaken to obtain better accuracy. The sensitivity and specificity were 60% and 100% when the SUVmax cut-off value was set at 4.5. PMID- 25539189 TI - Design of stable beta-hairpin mimetics through backbone disulfide bonds. AB - The synthesis and utilization of novel thiostatines (beta-SH-substituted gamma amino acids) in the design of backbone-disulfide-stabilized beta-hairpin mimetics, solution conformations of hybrid beta-hairpins and Cys-disulfide stabilized alpha-peptide analogue, their thiol exchange, and proteolytic stability are investigated. The results suggest that thiostatines can be used to design proteolytically stable water-soluble beta-hairpin mimetics without deviating from overall beta-hairpin conformation. PMID- 25539190 TI - Metabolic endotoxaemia--a potential novel link between ovarian inflammation and impaired progesterone production. AB - INTRODUCTION: Medical conditions such as obesity and inflammatory bowel disease are associated with impaired luteal function, menstrual disturbance and infertility. It is proposed that the disturbance in gut wall integrity ("leaky gut") seen in these conditions may result in the passage of bacterial endotoxin (LPS) from the colonic lumen into the circulation that may initiate inflammation in the ovary and subsequently impair hormone production. METHODS: Quantify the association between systemic levels of LBP, a marker of endotoxin exposure, and levels of inflammation in the ovary (follicular fluid IL-6), plus steroid hormone production in 45 women undergoing IVF treatment. RESULTS: Endotoxaemia (LBP) were positively correlated with plasma CRP and inflammation within the ovary (follicular fluid IL-6). Furthermore, endotoxaemia was negatively correlated with progesterone production. CONCLUSION: The observed correlations, together with previously published animal studies linking endotoxin exposure to impaired luteal function, suggest that the translocation of bacterial endotoxin from the gut lumen into the circulation has the potential to interfere with progesterone production and result in luteal deficiency. PMID- 25539191 TI - Oral administration of surfactant protein-a reduces pathology in an experimental model of necrotizing enterocolitis. AB - OBJECTIVES: Necrotizing enterocolitis (NEC) frequently results in significant morbidity and mortality in premature infants. Others reported that mice deficient in pulmonary surfactant protein-A (SP-A) born and raised in a nonhygienic environment succumb to significant gastrointestinal tract pathology, and enteral administration of purified SP-A significantly reduced mortality. We hypothesized that oral administration of purified SP-A can ameliorate pathology in an experimental model of neonatal NEC. METHODS: Experimental NEC was induced in newborn Sprague-Dawley rat pups by daily formula gavage and intermittent exposure to hypoxia. Purified human SP-A (5 MUg/day) was administered by oral gavage. After 4 days, surviving pups were sacrificed, and intestinal pathology was assessed by histological examination of distal terminal ileal sections. Intestinal levels of inflammatory cytokines (IL-1beta, IFN-gamma, and TNF-alpha) were assessed by enzyme-linked immunosorbent assay and levels of Toll-like receptor 4 (TLR4) by Western analysis. RESULTS: Sixty-one percent of the gavaged rat pups that survived to day 4 met the criteria for experimental NEC after hypoxia, whereas treatment with SP-A significantly reduced mortality and assessment of NEC. Intestinal levels of proinflammatory cytokines were significantly increased in pups exposed to hypoxia. Administration of SP-A to pups exposed to hypoxia significantly reduced IL-1beta and TNF-alpha levels, but had little effect on elevated levels of IFN-gamma. SP-A treatment of hypoxia exposed pups significantly reduced expression of intestinal TLR4, key in NEC pathogenesis. CONCLUSIONS: In a rat model of experimental neonatal NEC, oral administration of SP-A reduces intestinal levels of proinflammatory cytokines and TLR4 protein and ameliorates adverse outcomes associated with gastrointestinal pathologies. PMID- 25539193 TI - Acute upper gastrointestinal bleeding in childhood: development of the Sheffield scoring system to predict need for endoscopic therapy. AB - BACKGROUND/AIMS: Upper gastrointestinal bleeding (UGIB) is a rare and potentially life-threatening condition in childhood. In adults with UGIB, validated scoring systems exist, but these are not applicable to children. The aim of this study was to construct a clinical scoring system to accurately predict the need for endoscopic haemostatic intervention. METHODS: A retrospective data collection occurred during a 3-year period at a tertiary children's hospital. A total of 69 patients who had had endoscopic assessment were divided into group 1 (no intervention required) and group 2 (intervention required). A wide range of clinical parameters were collated including preexisting conditions, melaena, haematemesis and degree, transfusion requirement, parameters of hypovolaemia, presenting haemoglobin (Hb), Hb drop during 24 hours, platelet count, coagulation indices, liver function tests, and urea/electrolytes. RESULTS: Parameters that reached statistical significance for endoscopic intervention (group 1 vs group 2) were the presence of significant preexisting condition, melaena, large haematemesis, heart rate (HR) >20 mean HR for age, prolonged capillary refill time (CRT), Hb drop of >20 g/L, need for fluid bolus, need for blood transfusion (Hb < 80 g/L), and need for other blood products. Using these parameters, a number of scoring models were tested, and the most predictive resulted in a scoring system constructed with a total of 24 and a cutoff for intervention of 8. According to this design, there were 4 false-negatives in the interventional group with 3 false-positives in the noninterventional group. This resulted in a positive predictive value (PPV) of 91.18% (95% confidence interval [CI] 76.3 98.04), negative predictive value (NPV) of 88.57% (95% CI 73.24-96.73), sensitivity of 88.7% (95% CI 73.24-96.73), and specificity of 91.18% (95% CI 76.3 98.04). CONCLUSIONS: In our study population, we were able to formulate a scoring system with reasonable PPV and NPV to predict the need for endoscopic intervention in acute UGIB in children. Prospective evaluation is now required. PMID- 25539192 TI - MMPs-2 and -14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy. AB - OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic, antigen-mediated disease in children and adults associated with substantial esophageal remodeling and fibrosis. The expression of the remodeling-associated matrix metalloproteinases (MMPs) has not been previously detailed in EoE. METHODS: MMP-2 and -14 expression and cellular localization were assessed using real-time quantitative polymerase chain reaction and immunohistochemistry/immunofluorescence in EoE fibroblasts, active and inactive pediatric EoE biopsies, and nondiseased control biopsies. The effect of transforming growth factor (TGF)-beta1 treatment on MMP-2 expression in cultured esophageal epithelial (HET1A) cells was analyzed. RESULTS: MMP-2 and -14 mRNA were expressed in EoE fibroblasts and biopsies. Proliferating epithelial cells produced MMP-14 more abundantly in EoE than in controls (P < 0.001) and the degree of epithelial MMP-14 expression correlated positively with basal zone hyperplasia (r = 0.65, P = 0.002). EoE lamina propria had higher numbers of MMP-2 and -14-positive cells (906 +/- 167 and 701 +/- 93 cells/mm2) as compared with controls (258 +/- 93 cells/mm2, P < 0.01 and 232 +/- 54 cells/mm2, P < 0.01), and MMP-14 expression correlated with the severity of fibrosis. Following therapy with topical corticosteroids, MMP-14 and -2 were significantly diminished (P < 0.01). TGF-beta1 increased the expression and secretion of MMP-2 from esophageal epithelial HET1A cells. CONCLUSIONS: MMP-2 and -14 are elevated in pediatric patients with EoE and significantly decrease following topical corticosteroid therapy. TGF-beta1 increases MMP-2 in esophageal epithelial cells. This alludes to previously unappreciated role for MMPs in EoE-associated esophageal remodeling and a potential positive feedback loop via TGF-beta1. PMID- 25539194 TI - Fermentation pattern of infant formulas containing different prebiotics. AB - Prebiotics play a role in the development of intestinal flora. When exposed to unabsorbed food, such as prebiotic carbohydrates, intestinal bacteria produce hydrogen. Increases in hydrogen may signify a slower rate of fermentation or digestion. In this blinded, crossover study, infants (n = 13) consumed formula containing either 4 g/L galactooligosaccharide (GOS) or 4 g/L polydextrose (PDX) + GOS, and breath hydrogen was measured. Breath hydrogen was higher in the PDX/GOS group versus GOS alone (mean +/- standard error, 25.35 +/- 2.87 ppm vs 13.69 +/- 2.87 ppm, P = 0.0001). These results indicate that the formula with PDX/GOS may have undergone slower digestion. PMID- 25539195 TI - Profound Anemia in a Child Secondary to Salmonella Enteritis. PMID- 25539196 TI - Intestinal inflammation and impact on growth in children with cystic fibrosis. AB - OBJECTIVE: The aim of the study was to evaluate and compare faecal markers of intestinal inflammation in children with cystic fibrosis (CF), and determine whether intestinal inflammation adversely affects the nutritional phenotype. METHODS: Faecal samples for markers of intestinal inflammation, calprotectin, S100A12, and osteoprotegerin, were collected from children with CF, healthy controls (HCs), and Crohn disease (CD). Associations between inflammatory markers and clinical and nutritional indices were determined in subjects with CF. RESULTS: Twenty-eight children with CF (mean [standard deviation (SD)] 8.4 [3.3] years old, 22 pancreatic insufficient [PI]), 47 HC, and 30 CD were recruited. Mean (SD) faecal calprotectin in CF (94.3 [100.6] mg/kg) was greater than HC (26.7 [15.4] mg/kg, P < 0.0001), but lower than CD (2133 [2781] mg/kg, P = 0.0003). Abnormal faecal calprotectin was found in subjects only with PI (17/22 (77%), P = 0.001). There was no difference in faecal mean (SD) S100A12 (0.8 [0.9] vs 1.5 [2.2] mg/kg, P = 0.14) and osteoprotegerin concentrations (72.7 [52.2] vs 62.5 [0.0] pg/mL, P = 0.2) between CF and HC. Patients with CD had significantly elevated S100A12 and osteoprotegerin compared with CF and HC. Faecal calprotectin inversely correlated with both weight (r = -0.5, P = 0.003) and height z scores (r = -0.6, P = 0.002) in CF. CONCLUSIONS: The pattern of intestinal inflammation in CF is unique and distinct from inflammatory bowel disease, with elevated faecal calprotectin but normal faecal S100A12 and osteoprotegerin concentrations. The severity of intestinal inflammation, based on faecal calprotectin, significantly correlates with poor growth. PMID- 25539197 TI - Acute cholecystitis: When to operate and how to do it safely. PMID- 25539199 TI - Clearly defining pediatric massive transfusion: cutting through the fog and friction with combat data. AB - BACKGROUND: Massive transfusion (MT) in pediatric patients remains poorly defined. Using the largest existing registry of transfused pediatric trauma patients, we sought a data-driven MT threshold. METHODS: The Department of Defense Trauma Registry was queried from 2001 to 2013 for pediatric trauma patients (<18 years). Burns, drowning, isolated head injury, and missing Injury Severity Score (ISS) were excluded. MT was evaluated as a weight-based volume of all blood products transfused in the first 24 hours. Mortality at 24 hours and in the hospital was calculated for increasing transfusion volumes. Sensitivity and specificity curves for predicting mortality were used to identify an optimal MT threshold. Patients above and below this threshold (MT+ and MT-, respectively) were compared. RESULTS: The Department of Defense Trauma Registry yielded 4,990 combat-injured pediatric trauma patients, of whom 1,113 were transfused and constituted the study cohort. Sensitivity and specificity for 24-hour and in hospital mortality were optimal at 40.1-mL/kg and 38.6-mL/kg total blood products in the first 24 hours, respectively. With the use of a pragmatic threshold of 40 mL/kg, patients were divided into MT+ (n = 443) and MT- (n = 670). MT+ patients were more often in shock (68.1% vs. 47.0%, p < 0.001), hypothermic (13.0% vs. 3.4%, p < 0.001), coagulopathic (45.0% vs. 29.6%, p < 0.001), and thrombocytopenic (10.6% vs. 5.0%, p = 0.002) on presentation. MT+ patients had a higher ISS, more mechanical ventilator days, and longer intensive care unit and hospital stay. MT+ was independently associated with an increased 24-hour mortality (odds ratio, 2.50; 95% confidence interval, 1.28-4.88; p = 0.007) and in-hospital mortality (odds ratio, 2.58; 95% confidence interval, 1.70-3.92; p < 0.001). CONCLUSION: Based on this large cohort of transfused combat-injured pediatric patients, a threshold of 40 mL/kg of all blood products given at any time in the first 24 hours reliably identifies critically injured children at high risk for early and in-hospital death. This evidence-based definition will provide a consistent framework for future research and protocol development in pediatric resuscitation. LEVEL OF EVIDENCE: Diagnostic study, level II. Prognostic/epidemiologic study, level III. PMID- 25539198 TI - A protocol for the management of adhesive small bowel obstruction. AB - BACKGROUND: Differentiating between partial adhesive small bowel obstruction (aSBO) likely to resolve with medical management and complete obstruction requiring operative intervention remains elusive. We implemented a standardized protocol for the management of aSBO and reviewed our experience retrospectively. METHODS: Patients with symptoms of aSBO were admitted for intravenous fluid resuscitation, bowel rest, nasogastric tube decompression, and abdominal examinations every 4 hours. Laboratory values and a computed tomography scan of the abdomen and pelvis with intravenous contrast were obtained. Patients with peritonitis or computed tomography scan findings suggesting bowel compromise were taken to the operating room for exploration following resuscitation. All other patients received 80 mL of Gastroview (GV) and 40 mL of sterile water via nasogastric tube. Abdominal plain films were obtained at 4, 8, 12, and 24 hours. If contrast did not reach the colon within 24 hours, then operative intervention was performed. RESULTS: Over 1 year, 91 patients were admitted with aSBO. Sixty three patients received GV, of whom 51% underwent surgery. Twenty-four patients went directly to the operating room because of clinical or imaging findings suggesting bowel ischemia. Average time to surgery was within 1 day for the no-GV group and 2 days for the GV group. Patients passing GV to the colon within 5 hours of administration had a 90% rate of resolution of obstruction. There was a direct relationship between the duration of time before passing GV to the colon and hospital length of stay (HLOS) (r = 0.459). Patients who received GV and did not require surgery had lower HLOS (3 days vs. 11 days, p < 0.0001). CONCLUSION: The GV protocol facilitated early recognition of complete obstruction. Administration of GV had diagnostic and therapeutic value and did not increase HLOS, morbidity, or mortality. LEVEL OF EVIDENCE: Therapeutic study, level V. Epidemiologic study, level V. PMID- 25539200 TI - Obesity and clotting: Body mass index independently contributes to hypercoagulability after injury. AB - BACKGROUND: Although obese patients have high thrombosis rates following injury, the role of obesity in coagulation after trauma remains unknown. We hypothesized that body mass index (BMI) is independently associated with increased measures of hypercoagulability longitudinally after injury. METHODS: Data were prospectively collected for 377 consecutive highest-level trauma activation patients with a BMI of 18.5 kg/m2 or greater. Standard coagulation measures, citrated kaolin and functional fibrinogen thromboelastography, as well as clotting factors were measured at 0 hour to 120 hours. BMI categories were defined as normal weight (18.5-24.99 kg/m2), overweight (25-29.99 kg/m2), and obese (>=30 kg/m2). RESULTS: The 377 patients were mostly male (81%) and had blunt injury (61%), with a median BMI of 25.8 kg/m2. Of the patients, 42% were normal weight (median BMI, 22.5 kg/m2). There were no differences in age, sex, Injury Severity Score (ISS), or base deficit between groups. There were no differences in admission international normalized ratio/partial thromboplastin time or factors II, V, VII, VIII, and X; antithrombin III; or protein C. However, obese patients had higher admission platelet counts (303 * 109/L vs. 269 * 109/L, p = 0.004), lower D-dimer (1.88 MUg/mL vs. 4.00 MUg/mL, p = 0.004), and a trend toward higher factor IX (134% vs. 119% activity, p = 0.042) compared with normal weight patients. Measured by thromboelastography, clot strength (maximum amplitude) and functional fibrinogen level (FLEV) were also higher on admission for obese patients (maximum amplitude, 65.7 mm vs. 63.4 mm, p = 0.016; FLEV, 407 mg/dL vs. 351 mg/dL, p = 0.008). In multiple linear regression, the relationship of BMI to clot strength, FLEV, and factor IX persisted through 24 hours. Similarly, the relationship of BMI and platelet count persisted through 120 hours (all p < 0.05). In multiple logistic regression, for every 5-kg/m2 increase in BMI, there was an 85% increase in odds of thromboembolic complication (odds ratio, 1.85; 95% confidence interval, 1.13 3.08; p = 0.017). CONCLUSION: Obese trauma patients are hypercoagulable compared with their similarly injured normal-weight counterparts, which persists longitudinally after injury. The significance of this hypercoagulability requires elucidation for guidance of anticoagulation in this at-risk group. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 25539201 TI - Does resuscitation with plasma increase the risk of venous thromboembolism? AB - BACKGROUND: Resuscitation with blood products improves survival in patients with traumatic hemorrhage. However, the risk of venous thromboembolic (VTE) complications associated with fresh frozen plasma (FFP) resuscitation is unknown. We hypothesized that a higher ratio of FFP to packed red blood cells (PRBCs) given during acute resuscitation increases the risk of VTE independent of severity of injury and shock. METHODS: The records of patients admitted from April 2007 to December 2011 who had surveillance lower extremity duplex ultrasounds were retrospectively reviewed. Patients who received at least 1 U of PRBCs within 24 hours of admission were included. Patients who died without VTE were excluded. The relationship between FFP and VTE was evaluated using logistic regression. RESULTS: A total of 381 patients met inclusion criteria, of whom 77 (20.2%) developed VTE. In patients who required less than 4 U of PRBCs, increasing units of FFP were associated with an increasing risk for VTE, with each unit of FFP having an adjusted odds ratio of 1.27 (95% confidence interval, 1.04-1.54, p = 0.015). Conversely, in patients who required four or greater units of PRBCs, FFP in equal or greater ratios than PRBCs was not associated with VTE. CONCLUSION: Each unit of FFP increased VTE risk by 25% in patients who required less than 4 U of PRBCs. In patients who required 4 U or greater PRBCs, FFP administration conferred no increased risk of VTE. This suggests that FFP should be used cautiously when early hemodynamic stability can be achieved with less than 4 U of PRBCs. LEVEL OF EVIDENCE: Care management study, level III. PMID- 25539202 TI - Damage-control techniques in the management of severe lung trauma. AB - BACKGROUND: Damage control (DC) has improved survival from severe abdominal and extremity injuries. The data on the surgical strategies and outcomes in patients managed with DC for severe thoracic injuries are scarce. METHODS: This is a retrospective review of patients treated with DC for thoracic/pulmonary complex trauma at two Level I trauma centers from 2006 to 2010. Subjects 14 years and older were included. Demographics, trauma characteristics, surgical techniques, and resuscitation strategies were reviewed. RESULTS: A total of 840 trauma thoracotomies were performed. DC thoracotomy (DCT) was performed in 31 patients (3.7%). Pulmonary trauma was found in 25 of them. The median age was 28 years (interquartile range [IQR], 20-34 years), Revised Trauma Score (RTS) was 7.11 (IQR, 5.44-7.55), and Injury Severity Score (ISS) was 26 (IQR, 25-41). Nineteen patients had gunshot wounds, four had stab wounds, and two had blunt trauma.Pulmonary trauma was managed by pneumorrhaphy in 3, tractotomy in 12, wedge resection in 1, and packing as primary treatment in 8 patients. Clamping of the pulmonary hilum was used as a last resource in seven patients. Five patients returned to the intensive care unit with the pulmonary hilum occluded by a vascular clamp or an en masse ligature. These patients underwent a deferred resection within 16 hours to 90 hours after the initial DCT. Four of them survived.Bleeding from other intrathoracic sources was found in 20 patients: major vessels in nine, heart in three, and thoracic wall in nine.DCT mortality in pulmonary trauma was 6 (24%) of 25 because of coagulopathy, or persistent bleeding in 5 patients and multiorgan failure in 1 patient. CONCLUSION: This series describes our experience with DCT in severe lung trauma. We describe pulmonary hilum clamping and deferred lung resection as a viable surgical alternative for major pulmonary injuries and the use of packing as a definitive method for hemorrhage control. LEVEL OF EVIDENCE: Epidemiologic study, level V. PMID- 25539203 TI - A pharmacologic approach to vagal nerve stimulation prevents mesenteric lymph toxicity after hemorrhagic shock. AB - BACKGROUND: Electrical stimulation of the vagus nerve (VN) prevents gut and lung inflammation and mesenteric lymph (ML) toxicity in animal models of injury. We have previously shown that treatment with CPSI-121, a guanylhydrazone-derived compound, prevents gut barrier failure after burn injury. While the structure of CPSI-121 predicts that it will activate parasympathetic signaling, its ability to stimulate the VN is unknown. The aims of this study were to (1) measure the ability of CPSI-121 to induce VN activity, (2) determine whether CPSI-121 causes significant hemodynamic effects, and (3) further define the potential for CPSI 121 to limit the systemic inflammatory response to injury. METHODS: Male Sprague Dawley rats were given 1-mg/kg CPSI-121 intravenously while blood pressure, heart rate, and efferent VN electrical activity were recorded. Rats were also assigned to sham or trauma/hemorrhagic shock (T/HS). T/HS was induced by laparotomy and 60 minutes of HS (mean arterial pressure, 35 mm Hg) followed by fluid resuscitation. A separate cohort of animals received CPSI-121 after the HS phase. Gut and lung tissues were harvested for histologic analysis. Lung wet-dry ratios were also evaluated. The ability of ML to prime neutrophils was assessed by measuring in vitro oxidative burst using flow cytometry. RESULTS: Blood pressure was not altered after treatment with CPSI-121, while heart rate decreased only slightly. Recording of efferent VN electrical activity revealed an increase in discharge rate after administration of CPSI-121. T/HS caused gut and lung injury, which were prevented in animals treated with CPSI-121 (p < 0.05). Treatment with CPSI 121 following T/HS attenuated neutrophil priming after exposure to ML (p < 0.05). CONCLUSION: CPSI-121 causes efferent VN output and limits shock-induced gut and lung injury as well as ML toxicity. CPSI-121 is a candidate pharmacologic approach to VN stimulation aimed at limiting the inflammatory response in patients following T/HS. PMID- 25539205 TI - Outcomes after emergency general surgery at teaching versus nonteaching hospitals. AB - BACKGROUND: Previous analyses demonstrate teaching hospitals to have worse outcomes raising concerns for quality of care. The purpose of this study was to compare outcomes between teaching and nonteaching hospitals for emergency surgical conditions in a national sample. METHODS: The Nationwide Inpatient Sample (2005-2011) was queried for patients with emergency general surgery (EGS) conditions as determined by the American Association for Surgery of Trauma. Outcomes of in-hospital mortality, major complications, length of stay (LOS) and hospital cost were compared between patients presenting to teaching versus nonteaching hospitals. Propensity scores were used to match both groups on demographics, clinical diagnosis, comorbidities, and disease severity. Multivariate regression analyses were performed further adjusting for hospital level factors including EGS volume. Small effect estimates were further tested using standardized differences. RESULTS: A total of 3,707,465 patients from 3,163 centers were included. A majority of patients (59%) (n = 2,187,107) were treated at nonteaching hospitals. After propensity score matching and adjustment, teaching hospitals had a slightly higher odds likelihood of mortality (odds ratio, 1.04; 95% confidence interval, 1.02-1.06), slightly lower rate of major complications (odds ratio, 0.99; 95% confidence interval, 0.98-0.99), slightly decreased LOS (5.03 days [4.98-5.09] vs. 5.22 days [5.16-5.29]), and slightly higher hospital costs [$12,846 [$12,827-$12,865] vs. $12,304 [12,290-12,318]). Although these differences were statistically significant at p < 0.05, the absolute difference was very small. Further testing of these effect estimates using standardized differences revealed an insignificant difference of 0.5% for mortality, 0.4% for major complications, 0.2% for LOS, and 3.1% for hospital cost. CONCLUSION: National estimates of outcomes for EGS conditions demonstrate comparable results between teaching and nonteaching hospitals. Concerns regarding quality of care and higher costs at teaching hospitals may be unfounded. Further research to test for differences by specific EGS conditions, operative management, and hospital costs are warranted. PMID- 25539206 TI - Regional collaborative quality improvement for trauma reduces complications and costs. AB - BACKGROUND: Although evidence suggests that quality improvement to reduce complications for trauma patients should decrease costs, studies have not addressed this question directly. In Michigan, trauma centers and a private payer have created a regional collaborative quality initiative (CQI). This CQI program began as a pilot in 2008 and expanded to a formal statewide program in 2010. We examined the relationship between outcomes and expenditures for trauma patients treated in collaborative participant and nonparticipant hospitals. METHODS: Payer claims and collaborative registry data were analyzed for 30-day episode payments and serious complications in patients admitted with trauma diagnoses. Patients were categorized as treated in hospitals that had different CQI status: (1) never participated (Never-CQI); (2) collaborative participant, but patient treated before CQI initiation (Pre-CQI); or (3) active collaborative participant (Post CQI). DRG International Classification of Diseases--9th Rev. codes were crosswalked to Abbreviated Injury Scale (AIS) 2005 codes. Episode payment data were risk adjusted (age, sex, comorbidities, type/severity of injury, and year of treatment), and price was standardized. Outcome data were risk adjusted. A serious complication consisted of one or more of the following occurrences: acute lung injury/adult respiratory distress syndrome, acute kidney injury, cardiac arrest with cardiopulmonary resuscitation, decubitus ulcer, deep vein thrombosis, enterocutaneous fistula, extremity compartment syndrome, mortality, myocardial infarction, pneumonia, pulmonary embolism, severe sepsis, stroke/cerebral vascular accident, unplanned intubation, or unplanned return to operating room. RESULTS: The risk-adjusted rate of serious complications declined from 14.9% to 9.1% (p < 0.001) in participating hospitals (Post-CQI, n = 26). Average episode payments decreased by $2,720 (from $36,043 to $33,323, p = 0.08) among patients treated in Post-CQI centers, whereas patients treated at Never-CQI institutions had a significant year-to-year increase in payments (from $23,547 to $28,446, p < 0.001). A savings of $6.5 million in total episode payments from 2010 to 2011 was achieved for payer-covered Post-CQI treated patients. CONCLUSION: This study confirms our hypothesis that participation in a regional CQI program improves outcomes and reduces costs for trauma patients. Support of a regional CQI for trauma represents an effective investment to achieve health care value. LEVEL OF EVIDENCE: Economic/value-based evaluation, level III. PMID- 25539207 TI - Radiation fear: Impact on compliance with trauma imaging guidelines in the pregnant patient. AB - BACKGROUND: The Royal Melbourne Hospital is a Level 1 adult trauma center, and due to its colocation with The Royal Women's Hospital, it functions as the state's major obstetric trauma center. Obstetric trauma guidelines have been established to facilitate management of pregnant patients, yet adherence to these recommendations has not been evaluated. The aim of this study was to assess compliance with recommended imaging guidelines in obstetric trauma patients. METHODS: The prospectively collated trauma registry at Royal Melbourne Hospital was used to identify obstetric trauma presentations to the emergency department from January to December 2012. Demographics, mechanism of injury, clinical examination findings, and the use of diagnostic radiology were collected to determine adherence to recommended imaging guidelines. RESULTS: Of 74 obstetric trauma patients, the most common mechanisms of injury were motor vehicle collisions (81%), assaults (8%), and falls (7%). Despite the mechanism and severity of injury, 29 patients (39%) did not undergo imaging during their initial emergency department assessment. All of the remaining 45 patients (61%) were imaged as part of their assessment; however, plain x-rays were often used to avoid imaging with computed tomography.Of the 32 patients identified with a high risk mechanism, chest x-ray was used in 84.4%, pelvic x-ray in 28.1%, and computed tomography-angiography in 34.4%. In the high-risk mechanism group, the compliance rate with guidelines was only 18.8% (6 patients had the recommended radiologic assessment). CONCLUSION: Concerns about fetal radiation have resulted in a low compliance rate with recommended trauma guidelines at our institution. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 25539204 TI - Variations in the implementation of acute care surgery: results from a national survey of university-affiliated hospitals. AB - BACKGROUND: To date, no studies have reported nationwide adoption of acute care surgery (ACS) or identified structural and/or process variations for the care of emergency general surgery (EGS) patients within such models. METHODS: We surveyed surgeons responsible for EGS coverage at University Health Systems Consortium hospitals using an eight-page postal/e-mail questionnaire querying respondents on hospital and EGS structure/process measures. Survey responses were analyzed using descriptive statistics, univariate comparisons, and multivariable regression models. RESULTS: Of 319 potential respondents, 258 (81%) completed the surveys. A total of 81 hospitals (31%) had implemented ACS, while 134 (52%) had a traditional general surgeon on-call (GSOC) model. Thirty-eight hospitals (15%) had another model (hybrid). Larger-bed, university-based, teaching hospitals with Level 1 trauma center verification status located in urban areas were more likely to have adopted ACS. In multivariable modeling, hospital type, setting, and trauma center verification predicted ACS implementation. EGS processes of care varied, with 28% of the GSOC hospitals having block time versus 67% of the ACS hospitals (p < 0.0001), 45% of the GSOC hospitals providing ICU [intensive care unit] care to EGS patients in a surgical/trauma ICU versus 93% of the ACS hospitals (p < 0.0001), 5.7 +/- 3.2 surgeons sharing call at GSOC hospitals versus 7.9 +/- 2.3 surgeons at ACS hospitals (p < 0.0001), and 13% of the GSOC hospitals requiring in-house EGS call versus 75% of the ACS hospitals (p < 0.0001). Among ACS hospitals, there were variations in patient cohorting (EGS patients alone, 25%; EGS + trauma, 21%; EGS + elective, 17%; and EGS + trauma + elective, 30%), data collection (26% had prospective EGS registries), patient hand-offs (56% had attending surgeon presence), and call responsibilities (averaging 4.8 +/- 1.3 calls per month, with 60% providing extra call stipend and 40% with no postcall clinical duties). CONCLUSION: The potential of the ACS on the national crisis in access to EGS care is not fully met. Variations in EGS processes of care among adopters of ACS suggest that standardized criteria for ACS implementation, much like trauma center verification criteria, may be beneficial. PMID- 25539208 TI - Estrogen modulates intestinal mucus physiochemical properties and protects against oxidant injury. AB - BACKGROUND: The intestinal epithelial barrier and the intestinal mucus layer may be protective against trauma/hemorrhage shock-induced injury in females. This effect is related to estradiol (E2) concentrations and varies with the menstrual cycle. We examined the ability of E2 to impact the physiochemical properties of intestinal mucus and to protect against oxidant-related injury to the mucus and underlying intestinal epithelial barrier in an in vitro model. METHODS: Non-mucus producing (HT29) and mucus-producing (HT29-MTX) intestinal epithelial cells (IECs) were exposed to E2 or no E2 for 3 days and then grown to confluence on transwell plates. Nonadherent and adherent mucus content was indexed by analysis of mucin using an enzyme-linked immunosorbent assay and mucus viscosity (cp) and elasticity (G') were determined by rheometry. In additional experiments, IEC groups were exposed to hydrogen peroxide and IEC apoptosis as well as permeability (fluorescein isothiocyanate-dextran) and oxidative damage determined by measuring lipid hydroperoxide and protein carbonyl content. RESULTS: There were nearly 50% increases in the mucin content of both the nonadherent and adherent mucus layer(s) in HT29-MTX cells exposed to estrogen. Estrogen treatment also resulted in a twofold and eightfold increase in mucus viscosity and elasticity versus HT29-MTX cells with no estrogen exposure, respectively. Oxygen radical damage to the mucus layer caused by H2O2 was significantly reduced by E2 compared with HT29-MTX + H2O2 without estrogen. Estrogen treatment resulted in significant reductions in both apoptosis and permeability seen after H2O2 challenge. CONCLUSION: The results of this study suggest that sex differences in gut barrier function following trauma/hemorrhage shock may in part be related to differences in intestinal mucus content and the resultant physiochemical and oxidant-resistant properties of the mucus layer. PMID- 25539209 TI - Successful laparoscopic cholecystectomy after percutaneous cholecystostomy tube placement. AB - BACKGROUND: Interval cholecystectomy (IC) after percutaneous cholecystostomy tube (PCT) placement is the definitive treatment for cholecystitis in patients who are operative candidates after optimization of medical comorbidities. It is not clear, however, which patients will be able to have a laparoscopic IC after PCT placement. We aimed to identify factors associated with successful laparoscopic IC in these patients. METHODS: This is a retrospective review of patients who had a PCT from 2009 to 2011. Patient's baseline demographics, clinical data, and outcomes were analyzed. Univariable and multivariable comparisons were performed between patients who did and did not undergo IC. A subgroup analysis of patients who had laparoscopic IC and open IC was performed. Data are presented as percentages, medians with interquartile ranges (IQRs), or odds ratios with 95% confidence interval as appropriate. RESULTS: A total of 245 patients had PCT placement, with a median age of 71 years (IQR, 59-80 years); 63% were male, of whom 72 (29%) underwent IC. The median time from PCT placement to IC was 55 days (IQR, 42-75 days). IC patients had a lower Charlson Comorbidity Index (5 [4-6] vs. 6 [4-8], p = 0.005) at the time of PCT placement. When controlling for other factors, lower Charlson Comorbidity Index and fewer previous abdominal operations were associated with performance of IC. Laparoscopic surgery was planned for 89% of the patients and completed successfully in 78%. The only factor associated with successful laparoscopic IC was fewer previous abdominal operations. CONCLUSION: Patients who have been medically optimized following PCT can undergo laparoscopic IC with a high rate of success. The degree of illness at the time of PCT placement did not seem to influence the rate of success of laparoscopic IC. LEVEL OF EVIDENCE: Therapeutic/care management study, level III. PMID- 25539210 TI - Early surgical intervention for blunt bowel injury: the Bowel Injury Prediction Score (BIPS). AB - BACKGROUND: Computed tomography (CT) scan of the abdomen has been used for 30 years to evaluate the stable blunt trauma patient. However, the early diagnosis of blunt hollow viscus injury (BHVI) remains a challenge. Delayed diagnosis and intervention of BHVI lead to significant morbidity and mortality. This study aimed to identify a combination of radiographic and clinical variables present at admission that could lead to earlier surgical intervention for BHVI. METHODS: Significant predictors were identified through a retrospective review of all blunt trauma patients admitted to a Level 1 trauma center from 2005 to 2010 with an admission CT of the abdomen/pelvis and diagnosed with any mesenteric injury. The Bowel Injury Prediction Score (BIPS) was calculated based on the following three elements with a point given for each outcome: white blood cell count of 17.0 or greater, abdominal tenderness, and CT scan grade for mesenteric injury of 4 or higher. RESULTS: A total of 18,927 blunt trauma patients were admitted during the study period. Of these, 380 had a mesenteric injury, 110 met inclusion criteria, 60 had a surgical intervention, and 43 had BHVI. Of the 110 study patients, 43 (39%) had an immediate operation, 17 (16%) had a delayed operation (>4 hours), and 50 (46%) had no surgical intervention. The median BIPS for the immediate and delayed group was 2, while for the no-surgery group, the score was 0. Patients with a BIPS of 2 or greater were 19 times more likely to have a BHVI than patients with a BIPS of less than 2 (odds ratio, 19.2; 95% confidence interval, 6.78-54.36; p < 0.001). CONCLUSION: Three predictors (admission CT scan grade of mesenteric injury, white blood cell count, and abdominal tenderness) were used to create a new bowel injury score, with a score of 2 or greater being strongly associated with BHVI. Prospective validation of these retrospective findings is warranted to fully assess the accuracy of the BIPS. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 25539211 TI - Identification of diverticulitis patients at high risk for recurrence and poor outcomes. AB - BACKGROUND: Currently, the indications for elective surgery for patients who have recovered from an acute diverticulitis (AD) are controversial. We examined the natural history of AD in New York and identified risk factors for recurrent admissions and poor outcome to create a simple model to produce risk stratification groups. Poor outcome was defined as complicated disease, emergency surgery, or mortality during any recurrent admission. METHODS: Data on adult diverticulitis admissions between 1985 and 2006 were extracted from the state discharge database; recurrences were monitored using unique identifiers. Survivors of nonoperative management who did not undergo subsequent elective surgery were considered eligible for recurrence. Clinical variables from the first admission with significant association with poor outcomes or recurrence were identified using multivariable analysis and were used to create risk stratification groups. RESULTS: A total of 237,879 individuals were identified. Of the 181,115 patients eligible for recurrence after one admission, 8.7% recurred; of the patients eligible for recurrence after two admissions, 23.2% recurred. Complicated AD or abscess and age less than 50 years allowed the creation of discrete risk groups for both recurrence and poor outcome. CONCLUSION: The majority of patients (91.3%) had no further admissions for AD. However, patients admitted for recurrence were increasingly likely to require subsequent admissions. Patients with complicated AD at the first admission, specifically abscess, had a high risk of recurrence and poor outcome and should be offered surgery. Younger patients also had higher recurrence and poor outcomes. We provide a risk stratification model to help identify patients at high risk for recurrence and poor outcome. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic/prognostic study, level III. PMID- 25539212 TI - The modern acute care surgeon: characterization of an evolving surgical niche. AB - BACKGROUND: Trauma and emergency surgery continues to evolve as a surgical niche. The simple fact that The Journal of Trauma is now entitled The Journal of Trauma and Acute Care Surgery captures this reality. We sought to characterize the niche that trauma and emergency surgeons have occupied during the maturation of the acute care surgery model. METHODS: We analyzed the University Health System Consortium-Association of American Medical Colleges Faculty Practice Solutions Center database for the years 2007 to 2012 for specific current procedural terminology (CPT) codes. This database includes coding and billing data for more than 90 academic medical centers throughout the United States. We analyzed frequency counts and work relative value units (wRVUs) generated for specific codes to characterize the average trauma and emergency surgeon's work experience over time. RESULTS: We found that acute care surgeons generated 42.4% of wRVUs from procedural work and 57.6% from cognitive work. For cognitive work, critical care services generated the most wRVUs per year (25.2% of total), and subsequent hospital care was the most frequently performed activity (1,236.6 codes generated per year). For procedural work, laparoscopic cholecystectomies produced the most wRVUs per year (2.4% of total), and placement of a nontunneled catheter was the most frequently performed procedure (42.2 times per year). The average acute care surgeon performed the following numbers of procedures per year: 29.6 cholecystectomies and 20.0 appendectomies; 7.7 wound vacuum device changes; 5.9 implantation of mesh procedures; 4.9 splenectomies and 0.4 splenorrhaphies; 2.6 perirectal abscess drainage procedures; less than one component separation fascial hernia repair; and less than one video-assisted thoracic surgery. CONCLUSION: The modern acute care surgeon is a hybrid of critical care medicine physician and ever-evolving surgical interventionist. Acute care surgeons continue to do traditional trauma work while increasingly performing acute care surgeries. The work of acute care surgeons serves a growing role and fills a valuable niche in our health care system. PMID- 25539213 TI - The benefit of neck computed tomography compared with its harm (risk of cancer). AB - BACKGROUND: The purpose of this study was to compare the benefit of neck computed tomography (CT) of identifying important cervical spine injuries (CSIs) with its harm of radiation exposure and cancer risk. METHODS: A PubMed search for published studies relating to CSI in trauma, cervical spine imaging, CT, and cancer risk was conducted. Article abstracts were reviewed, and selected published studies relating to the study objective were retrieved. RESULTS: Of 100,000 trauma patients, neck CT scans were obtained in 3,767 to 26,785 patients. Of 100,000 patients with trauma on whom a neck CT scan was performed, a CSI was identified in 2,470 to 33,898 patients. Clinically important CSI ranged from 4,724 to 27,119 per 100,000 CT scans. For every 100,000 neck CT scans performed, additional cancer cases occur in a low end estimate of a thyroid cancer cases to a high end estimate of 100 male and 700 female cancer cases. In females, cancer risks are higher than in males, and these are closer to, but still less than, the incidence of clinically important CSI found by CT. CONCLUSION: CT's benefit of identifying important CSIs in the published studies exceeds its cancer harm risk. However, at their extremes, the numbers are disturbingly close. Limiting neck CT scanning to a higher-risk group would increase the gap between benefit and harm, whereas performing CT routinely on low-risk cases approaches a point where its harm equals or exceeds its benefit. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 25539214 TI - Nonoperative management of hemodynamically unstable abdominal trauma patients with angioembolization and resuscitative endovascular balloon occlusion of the aorta. AB - BACKGROUND: Many hemodynamically stable patients with blunt abdominal solid organ injuries are successfully managed nonoperatively, while unstable patients often require urgent laparotomy. Recently, therapeutic angioembolization has been used in the treatment of intra-abdominal hemorrhage in hemodynamically unstable patients. We undertook this study to review a series of hemodynamically unstable patients with abdominal solid organ injuries managed nonoperatively with angioembolization and resuscitative endovascular balloon occlusion of the aorta. METHODS: The institutional review board approved this study. All patients were appropriately resuscitated with transfusions, and angiography was performed after computed tomography. Resuscitative endovascular balloon occlusion of the aorta was performed before computed tomography in all patients. RESULTS: Seven patients underwent resuscitative endovascular balloon occlusion of the aorta following severe blunt abdominal trauma. The 28-day survival rate was 86% (6 of 7). There were no complications related to the procedure. CONCLUSION: We describe the first clinical series of hemodynamically unstable patients with abdominal solid organ injury treated nonoperatively with angioembolization and resuscitative endovascular balloon occlusion of the aorta. Survival rate was 86%, supporting the need for further study of this modality as an adjunct to the nonoperative management of patients with severe traumatic injuries. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 25539215 TI - Evaluation and management of blunt traumatic aortic injury: a practice management guideline from the Eastern Association for the Surgery of Trauma. AB - BACKGROUND: Blunt traumatic aortic injury (BTAI) is the second most common cause of death in trauma patients. Eighty percent of patients with BTAI will die before reaching a trauma center. The issues of how to diagnose, treat, and manage BTAI were first addressed by the Eastern Association for the Surgery of Trauma (EAST) in the practice management guidelines on this topic published in 2000. Since that time, there have been advances in the management of BTAI. As a result, the EAST guidelines committee decided to develop updated guidelines for this topic using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework recently adopted by EAST. METHODS: A systematic review of the MEDLINE database using PubMed was performed. The search retrieved English language articles regarding BTAI from 1998 to 2013. Letters to the editor, case reports, book chapters, and review articles were excluded. Topics of investigation included imaging to diagnose BTAI, type of operative repair, and timing of operative repair. RESULTS: Sixty articles were identified. Of these, 51 articles were selected to construct the guidelines. CONCLUSION: There have been changes in practice since the publication of the previous guidelines in 2000. Computed tomography of the chest with intravenous contrast is strongly recommended to diagnose clinically significant BTAI. Endovascular repair is strongly recommended for patients without contraindications. Delayed repair of BTAI is suggested, with the stipulation that effective blood pressure control must be used in these patients. PMID- 25539216 TI - An evidence-based review: distracted driver. AB - BACKGROUND: Cell phone use and texting are prevalent within society and have thus pervaded the driving population. This technology is a growing concern within the confines of distracted driving, as all diversions from attention to the road have been shown to increase the risk of crashes. Adolescent, inexperienced drivers, who have the greatest prevalence of texting while driving, are at a particularly higher risk of crashes because of distraction. METHODS: Members of the Injury Control Violence Prevention Committee of the Eastern Association for the Surgery of Trauma performed a PubMed search of articles related to distracted driving and cell phone use as a distractor of driving between 2000 and 2013. RESULTS: A total of 19 articles were found to merit inclusion as evidence in the evidence-based review. These articles provided evidence regarding the relationship between distracted driving and crashes, cell phone use contributing to automobile accidents, and/or the relationship between driver experience and automobile accidents. (Adjust methods/results sections to the number of articles that correctly corresponds to the number of references, as well as the methodology for reference inclusion.) CONCLUSION: Based on the evidence reviewed, we can recommend the following. All drivers should minimize all in-vehicle distractions while on the road. All drivers should not text or use any touch messaging system (including the use of social media sites such as Facebook and Twitter) while driving. Younger, inexperienced drivers should especially not use cell phones, texting, or any touch messaging system while driving because they pose an increased risk for death and injury caused by distractions while driving. PMID- 25539217 TI - Traumatic intra-abdominal hemorrhage control: has current technology tipped the balance toward a role for prehospital intervention? AB - BACKGROUND: The identification and control of traumatic hemorrhage from the torso remains a major challenge and carries a significant mortality despite the reduction of transfer times. This review examines the current technologies that are available for abdominal hemorrhage control within the prehospital setting and evaluates their effectiveness. METHODS: A systematic search of online databases was undertaken. Where appropriate, evidence was highlighted using the Oxford levels of clinical evidence. The primary outcome assessed was mortality, and secondary outcomes included blood loss and complications associated with each technique. RESULTS: Of 89 studies, 34 met the inclusion criteria, of which 29 were preclinical in vivo trials and 5 were clinical. Techniques were subdivided into mechanical compression, endovascular control, and energy-based hemostatic devices. Gas insufflation and manual pressure techniques had no associated mortalities. There was one mortality with high intensity focused ultrasound. The intra-abdominal infiltration of foam treatment had 64% and the resuscitative endovascular balloon occlusion of the aorta had 74% mortality risk reduction. In the majority of cases, morbidity and blood loss associated with each interventional procedure were less than their respective controls. CONCLUSION: Mortality from traumatic intra-abdominal hemorrhage could be reduced through early intervention at the scene by emerging technology. Manual pressure or the resuscitative endovascular balloon occlusion of the aorta techniques have demonstrated clinical effectiveness for the control of major vessel bleeding, although complications need to be carefully considered before advocating clinical use. At present, fast transfer to the trauma center remains paramount. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 25539218 TI - Impact of prehospital transfer strategies in major trauma and head injury: systematic review, meta-analysis, and recommendations for study design. AB - BACKGROUND: It is unclear whether trauma patients should be transferred initially to a trauma center or local hospital. METHODS: A systematic review and meta analysis assessed the evidence for direct transport to specialist centers (SCs) versus initial stabilization at non-SCs (NSCs) for major trauma or moderate-to severe head injury. Nine databases were searched from 1988 to 2012. Limitations in the study design informed recommendations for future studies. RESULTS: Of 19 major trauma studies, five (n = 19,910) included patients not transferred to SCs and adjusted for case mix. Meta-analysis showed no difference in mortality for initial triage to NSCs versus SCs (odds ratio [OR] 1.03; 95% confidence interval [CI], 0.85-1.23). Within studies excluding patients not transferred to SCs, unadjusted analyses of mortality nonsignificantly favored transfer via NSCs (16 studies; n = 37,079; OR, 0.83; 95% CI, 0.68-1.01), whereas adjusted analysis nonsignificantly favored direct triage to SCs (9 studies; n = 34,266; OR, 1.18; 95% CI, 0.96-1.44). Of 11 head injury studies, all excluded patients not transferred to SCs and half were in remote locations. There was no significant mortality difference between initial triage to NSCs versus SCs within adjusted analyses (3 studies; n = 1,507; OR, 0.74; 95% CI, 0.31-1.79) or unadjusted analyses (10 studies; n = 3,671; OR, 0.87; 95% CI, 0.62-1.23). CONCLUSION: This systematic review demonstrated no difference in outcomes for direct transport to a trauma center versus initial triage to a local hospital. Many studies had significant limitations in the design, and heterogeneity was high. Recommendations for future studies include the following: (i) inclusion of patients not transferred to SCs and those dying during transport; (ii) clear description of centers plus transport distances/times; (iii) adjustments for case mix; and (iv) assessment of morbidity and mortality. LEVEL OF EVIDENCE: Systematic review, level IV. PMID- 25539219 TI - Improvised tourniquets: Obsolete or obligatory? PMID- 25539221 TI - Refining the operative curriculum of the acute care surgery fellowship. PMID- 25539222 TI - Central pressurized cadaver model (CPCM) for resuscitative endovascular balloon occlusion of the aorta (REBOA) training and device testing. PMID- 25539223 TI - On-demand three-dimensional printing of surgical supplies in conflict zones. PMID- 25539220 TI - Clinical evidence of inflammation driving secondary brain injury: a systematic review. AB - BACKGROUND: Despite advances in both prevention and treatment, traumatic brain injury (TBI) remains one of the most burdensome diseases; 2% of the US population currently lives with disabilities resulting from TBI. Recent advances in the understanding of inflammation and its impact on the pathophysiology of trauma have increased the interest in inflammation as a possible mediator in TBI outcome. OBJECTIVES: The goal of this systematic review is to address the question: "What is the evidence in humans that inflammation is linked to secondary brain injury?" As the experimental evidence has been well described elsewhere, this review will focus on the clinical evidence for inflammation as a mechanism of secondary brain injury. DATA SOURCES: Medline database (1996-Week 1 June 2014), Pubmed and Google Scholar databases were queried for relevant studies. STUDY ELIGIBILITY CRITERIA: Studies were eligible if participants were adults and/or children who sustained moderate or severe TBI in the acute phase of injury, published in English. Studies published in the last decade (since 2004) were preferentially included. Trials could be observational or interventional in nature. APPRAISAL AND SYNTHESIS METHODS: To address the quality of the studies retrieved, we applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria to assess the limitations of the included studies. RESULTS: Trauma initiates local central nervous system as well as systemic immune activation. Numerous observational studies describe elevation of pro-inflammatory cytokines that are associated with important clinical variables including neurologic outcome and mortality. A small number of clinical trials have included immunomodulating strategies, but no intervention to date has proven effective in improving outcomes after TBI. LIMITATIONS: Inclusion of studies not initially retrieved by the search terms may have biased our results. Additionally, some reports may have been inadvertently excluded due to use of non-search term key words. Conclusions and Implications of Key Findings Clinical evidence of inflammation causing secondary brain injury in humans is gaining momentum. While inflammation is certainly present, it is not clear from the literature at what juncture inflammation becomes maladaptive, promoting secondary injury rather than facilitating repairand identifying patients with maladaptive inflammation (neuro inflammation, systemic, or both) after TBI remains elusive. Direct agonism/antagonism represents an exciting target for future study. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 25539224 TI - Pelvic and lower extremity injuries in Homer's Iliad: a review of the literature. AB - The Iliad, composed approximately in the middle of the eighth century bc, constitutes the leading and oldest known example of heroic epic. The Homeric epic presents the conflicts that took place during the last year of the 10-year lasting Trojan War, offering a realistic description of battle wounds. We studied the text of The Iliad in ancient Greek and in the translations in modern Greek and English and searched for all recorded injuries to the pelvis and lower extremities. A total of 16 traumatic injuries of pelvis and lower extremities were described, including 7 fatal wounds, while in 9 cases, the outcome was unknown.The Iliad remains the oldest record of Greek medicine and a unique source of surgical history. To study the vividly reported events is a great experience, particularly for a surgeon. PMID- 25539225 TI - A case of profound pneumatosis intestinalis in a patient with recent polytrauma. PMID- 25539228 TI - Reviewer development: new initiatives. PMID- 25539229 TI - The role of early postmortem CT in the evaluation of support-line misplacement in patients with severe trauma. AB - OBJECTIVE: The purpose of this study was to retrospectively assess the role of early postmortem CT in evaluating support-line misplacement to improve future treatment in the trauma setting. MATERIALS AND METHODS: We included all postmortem CT examinations that were performed for trauma patients within the 1st hour after declaration of death in our tertiary medical center between August 1, 2008, and August 31, 2013. Correct placement of the following support lines was evaluated: endotracheal tubes (ETTs), chest drains, central venous catheters (CVCs), and nasogastric tubes (NGTs). Prehospital resuscitation efforts were started in all cases. RESULTS: Early postmortem CT was performed on average 22 minutes after declaration of death in 25 consecutive patients with severe trauma. Overall, 14 subjects (56%) had suboptimal or misplaced support lines. Of ETTs inserted into 18 trauma victims; three (17%) were mislaid in the right main bronchus and five (28%) were near or at the level of the carina. Of chest drains inserted into 13 subjects, 10 were suboptimally positioned (77%). Of CVCs inserted into eight subjects (seven femoral and one brachiocephalic), one femoral CVC (13%) was malpositioned in the soft tissues of the pelvis. Of NGTs inserted in five trauma victims, one was folded within the pharynx. CONCLUSION: Early postmortem CT for patients who have experienced severe poly-trauma can be of important educational value to radiologists and the trauma teams, providing immediate feedback regarding the location of the support lines and possibly contributing to improved training and command of the learning curve by medical staff. PMID- 25539230 TI - Pairwise comparison versus Likert scale for biomedical image assessment. AB - OBJECTIVE: Biomedical imaging research relies heavily on the subjective and semi quantitative reader analysis of images. Current methods are limited by interreader variability and fixed upper and lower limits. The purpose of this study was to compare the performance of two assessment methods, pairwise comparison and Likert scale, for improved analysis of biomedical images. MATERIALS AND METHODS: A set of 10 images with varying degrees of image sharpness was created by digitally blurring a normal clinical chest radiograph. Readers assessed the degree of image sharpness using two different methods: pairwise comparison and a 10-point Likert scale. Reader agreement with actual chest radiograph sharpness was calculated for each method by use of the Lin concordance correlation coefficient (CCC). RESULTS: Reader accuracy was highest for pairwise comparison (CCC, 1.0) and ranked Likert (CCC, 0.99) scores and lowest for nonranked Likert scores (CCC, 0.83). Accuracy improved slightly when readers repeated their assessments (CCC, 0.87) or had reference images available (CCC, 0.91). CONCLUSION: Pairwise comparison and ranked Likert scores yield more accurate reader assessments than nonranked Likert scores. PMID- 25539232 TI - Nasopharyngeal carcinoma patients with retropharyngeal lymph node metastases: a minimum axial diameter of 6 mm is a more accurate prognostic predictor than 5 mm. AB - OBJECTIVE: The criteria for the diagnosis of metastatic retropharyngeal lymph nodes (RLNs) have not yet been resolved and are not included in the current edition of the American Joint Committee on Cancer (AJCC) staging system (seventh edition) for the staging of nasopharyngeal carcinoma (NPC). The aim of this study was to use MRI to identify an RLN size criterion that can accurately predict prognosis in patients with NPC. MATERIALS AND METHODS: Eight hundred seventeen patients with newly diagnosed localized NPC were identified. All of the patients underwent MRI before treatment with definitive radiation therapy. All the MRI studies and medical records were reviewed retrospectively. Overall survival (OS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS) were assessed using SPSS software (version 17.0). RESULTS: RLN size cutoffs of >= 5 mm and of >= 6 mm were used. There was no significant difference in OS (p = 0.216), DMFS (p = 0.081), or LRFS (p = 0.067) in patients with RLNs >= 5 mm and in those with RLNs < 5 mm. When 6 mm was used as a size cutoff, significant differences in OS (p = 0.000) and DMFS (p = 0.001) were identified; there was no significant difference observed for LRFS (p = 0.380). CONCLUSION: A minimum axial RLN diameter of 6 mm was a more accurate prognostic predictor in NPC patients with RLN metastases than 5 mm. PMID- 25539231 TI - Trends in lumbar puncture over 2 decades: a dramatic shift to radiology. AB - OBJECTIVE: The purpose of this study is to evaluate national trends in lumbar puncture (LP) procedures and the relative roles of specialty groups providing this service. MATERIALS AND METHODS: Aggregated claims data for LPs were extracted from Medicare Physician Supplier Procedure Summary master files annually from 1991 through 2011. LP procedure volumes by specialty group and place of service were studied. RESULTS: Between 1991 and 2011, the overall numbers of LP procedures increased, with a slight increase in diagnostic LP procedures (90,460 vs 90,785) and a marked increase in therapeutic LP procedures (2868 vs 6461) in Medicare fee-for-service beneficiaries. Although radiologists performed 11.3% (n = 10,533) of all LP procedures in 1991, they performed 46.6% (n = 45,338) in 2011. For diagnostic LPs, radiology (11.4% [n = 10,272] in 1991 and 48.0% [n = 43,601] in 2011) now exceeds emergency medicine, neurosciences, and all others as the dominant provider group. For therapeutic LP procedures, radiology now performs the second greatest number of LP procedures (9.0% [n = 261] in 1991 and 26.9% [n = 1737] in 2011). Although volumes remain small (< 10% of all procedures), midlevel practitioners have experienced over 100-fold growth for most services. The inpatient hospital setting remains the dominant site of service (71,385 in 1991 vs 44,817 in 2011: -37%), followed by procedures performed in the emergency department (297 in 1991 vs 26,117 in 2011: 8794%). CONCLUSION: Over the last 2 decades, LP procedures on Medicare beneficiaries have increased, with radiology now the dominant overall provider. Although this trend may have relatively negative financial implications for radiology practices in current fee-for-service payment models, it has the potential to cement radiology's more central position through direct involvement in patient care in emerging accountable care organizations. PMID- 25539233 TI - Journal Club: Head CT scans in the emergency department for syncope and dizziness. AB - OBJECTIVE: The purpose of this study was to determine the yield of acutely abnormal findings on head CT scans in patients presenting to the emergency department with dizziness, near-syncope, or syncope and to determine the clinical factors that potentially predicted acutely abnormal head CT findings and hospital admission. MATERIALS AND METHODS: We retrospectively reviewed the electronic medical records of all patients presenting to an HMO emergency department between July 1, 2012, and December 31, 2012, who underwent head CT for a primary complaint of dizziness, syncope, or near-syncope. The primary outcomes were head CT scans with acutely abnormal findings and hospital admission. Binary logistic regression was used to assess the association between clinical variables and acute head CT findings and between clinical variables and hospital admission. RESULTS: Of the 253 patients who presented with dizziness, 7.1% had head CT scans with acutely abnormal findings, and 18.6% were admitted. Of the 236 patients who presented with syncope or near-syncope, 6.4% had head CT scans with acutely abnormal findings, and 39.8% were admitted. The following three clinical factors were found to be significantly correlated with acutely abnormal head CT findings: a focal neurologic deficit (p = 0.003), age greater than 60 years (p = 0.011), and acute head trauma (p = 0.026). CONCLUSION: Our results suggest that most patients presenting with syncope or dizziness to the emergency department may not benefit from head CT unless they are older, have a focal neurologic deficit, or have a history of recent head trauma. PMID- 25539234 TI - CT-guided fine-needle aspiration and core needle biopsies of pulmonary lesions: a single-center experience with 750 biopsies in Japan. AB - OBJECTIVE: CT-guided lung biopsy is a well-established diagnostic method for pulmonary lesions. The aim of our study was to evaluate the diagnostic outcomes and safety profile of conventional CT-guided lung biopsies. MATERIALS AND METHODS: We retrospectively analyzed the results of CT-guided lung biopsies for 750 patients to determine the diagnostic accuracy, complication rates, and independent risk factors for diagnostic failure and severe pneumothorax. RESULTS: Diagnostic accuracy was 92.9%. Independent risk factors for diagnostic failure were malignant lesions (odds ratio [OR], 4.20; 95% CI, 1.66-14.1; p = 0.001), lesions in the lower lobe (OR, 2.01; 95% CI, 1.17-3.47; p = 0.011), lesions 2.0 cm or smaller (OR, 2.87; 95% CI, 1.59-5.48; p < 0.001), and the presence of pneumothorax during the procedure (OR, 2.18; 95% CI, 1.27-3.78; p = 0.004). Pneumothorax requiring drainage occurred in 7% of patients. Independent risk factors for pneumothorax requiring drainage were age of 73 years or older (OR, 2.19; 95% CI, 1.21-4.05; p = 0.009), the presence of emphysema (OR, 4.29; 95% CI, 2.05-8.82; p < 0.001), benign lesions (OR, 2.33; 95% CI, 1.20-4.40; p = 0.012), supine positioning of the patient (OR, 2.61; 95% CI, 1.44-4.84; p = 0.001), and length from the pleura to the lesion of 1.5 cm or greater (OR, 3.08; 95% CI, 1.63 6.17; p < 0.001). CONCLUSION: CT-guided lung biopsy has a high diagnostic accuracy. Complication rates were acceptable and comparable to those of previous studies. PMID- 25539235 TI - Mediastinal lymph nodes and pulmonary nodules in children: MDCT findings in a cohort of healthy subjects. AB - OBJECTIVE: Existing data are very limited on incidentally detected pulmonary nodules or mediastinal lymph nodes in healthy children who undergo chest MDCT. We aimed to evaluate the prevalence, distribution, and average dimensions of these occasional findings in a cohort of otherwise healthy patients. MATERIALS AND METHODS: Two radiologists reviewed in consensus the scans of patients referred for chest MDCT during the preoperative workup for pectus carinatum or pectus excavatum treatments. Exclusion criteria included the presence of any documented malignancy (by date of MDCT or during the 2 years after the examination), history of recent infections, or trauma. Patients' records were assessed after 2 years for the development of any malignancy. RESULTS: A total of 99 individuals (63 boys, 36 girls; mean age, 13.5 years; range, 4-18 years) who fulfilled the study criteria were evaluated. The presence of at least one pulmonary nodule was observed in 75% of the patients, with a mean diameter of 2.8 mm. Of a total number of 225 pulmonary nodules, only 24 (10.7%) were calcified. Mediastinal lymph nodes were also identified in 81% of the cases, with a maximum diameter of 7 mm (smallest axis). CONCLUSION: The presence of pulmonary nodules or mediastinal lymph nodes on the basis of preoperative chest MDCT scans in healthy children is frequent. Given that 95% of the nodules and 100% of the lymph nodes measured less than 6 mm and 7 mm, respectively, we conclude that incidental findings under these limits are very unlikely to be pathologic. PMID- 25539236 TI - Clinicoradiologic evidence of pulmonary lymphatic spread in adult patients with tuberculosis. AB - OBJECTIVE: The purpose of this study is to evaluate the prevalence and clinicoradiologic characteristics of pulmonary tuberculosis with lymphatic involvement. MATERIALS AND METHODS: A total of 126 adults with active tuberculosis who underwent CT were enrolled. A retrospective investigation of CT images focused on the presence of perilymphatic micronodules, as well as other CT features of active tuberculosis. We selected two groups of patients with micronodules according to distribution (perilymphatic vs centrilobular). We compared clinical and CT findings between the two groups. RESULTS: Fifteen patients were excluded because of coexisting pulmonary disease. Among 111 patients, the prevalence of perilymphatic micronodules, galaxy or cluster signs, and interlobular septal thickening was 64 (58%), 18 (16%), and 30 (27%), respectively. Of 106 patients with micronodules, 37 and 40 were classified into the perilymphatic and centrilobular groups, respectively. Compared with the centrilobular group, the perilymphatic group had statistically significantly lower frequencies of positive acid-fast bacilli smears (32% vs 70%), consolidation (70% vs 98%), and cavitation (30% vs 60%). However, frequencies of interlobular septal thickening (41% vs 18%), galaxy or cluster signs (30% vs 0%), and pleural effusion (43% vs 20%) were statistically significantly higher in the perilymphatic group. CONCLUSION: CT findings representing pulmonary perilymphatic involvement are relatively common in adults with tuberculosis. These findings may represent lymphatic spread of tuberculosis and provide an explanation for the unusual CT features of pulmonary tuberculosis mimicking sarcoidosis and the low detection of Mycobacterium tuberculosis in patients with micronodules. PMID- 25539237 TI - Fluoroscopic evaluation of oropharyngeal dysphagia: anatomic, technical, and common etiologic factors. AB - OBJECTIVE: The purposes of this article are to review the anatomy of the upper gastrointestinal tract; review techniques and contrast agents used in the fluoroscopic examination of the oropharynx and hypopharynx; provide a pictorial review of some important causes of oropharyngeal dysphagia; and link these causes to key findings in the clinical history to assist in establishing a clinical diagnosis. CONCLUSION: Many important causes and presentations of oropharyngeal dysphagia are sometimes overlooked during conventional upper gastrointestinal studies. Videofluoroscopic evaluation for assessment of both structural abnormalities and motility disorders of the oropharynx by use of various compositions of barium contrast medium is the standard of practice. Using best practices radiographic techniques and having knowledge of swallowing mechanisms and various diseases are important for assessment of dysphagia. Dynamic fluoroscopic imaging remains an essential tool for assessing functional disorders of swallowing. Detailed videofluoroscopic assessment can guide treatment decisions with the goal of decreasing the secondary complications of dysphagia. PMID- 25539238 TI - Diffusion-weighted imaging of the liver in patients with chronic liver disease: comparison of monopolar and bipolar diffusion gradients for image quality and lesion detection. AB - OBJECTIVE: The objective of our study was to compare diffusion-weighted imaging (DWI) sequences using a bipolar versus a monopolar single-shot echo-planar imaging (EPI) gradient design for image quality and for lesion detection and characterization in patients with liver disease. MATERIALS AND METHODS: In this retrospective study, 77 patients with chronic liver disease who underwent MRI including bipolar and monopolar DWI at 1.5 T were assessed. Two independent observers reviewed the DWI studies for image quality and the detection and characterization of liver lesions. The reference standard for diagnosis was established by consensus review of two different observers using imaging characteristics on conventional MRI sequences, lesion stability over time, pathologic correlation, or a combination of these findings. The estimated signal to-noise ratio (SNR) of liver parenchyma and apparent diffusion coefficients (ADCs) of the liver and lesions were calculated for both sequences. ROC analysis was conducted to evaluate the performance of ADC for the diagnosis of hepatocellular carcinoma (HCC). RESULTS: Eighty-five lesions, 50 HCCs and 35 benign lesions, were detected with the reference standard in 38 patients. There was equivalent image quality for the bipolar and monopolar sequences (p = 0.24 0.42). The HCC detection rate for observers 1 and 2 was slightly better with bipolar DWI (50.0% and 52.0%, respectively) compared with monopolar DWI (44.0% and 46.0%); however, this difference did not reach statistical significance. The estimated SNR was higher with the monopolar sequence than with the bipolar sequence (p <= 0.001). The AUC for the ROC curve was 0.691 for bipolar DWI and 0.649 for monopolar DWI when ADC was used for the characterization of HCC, which is not a statistically significant difference (p = 0.59). CONCLUSION: The higher estimated SNR yielded by the monopolar DWI sequence did not translate into better HCC detection compared with the bipolar DWI sequence. ADC has a limited role for HCC characterization in patients with liver disease. PMID- 25539239 TI - Feasibility of 5-minute delayed transition phase imaging with 30 degrees flip angle in gadoxetic acid-enhanced 3D gradient-echo MRI of liver, compared with 20 minute delayed hepatocyte phase MRI with standard 10 degrees flip angle. AB - OBJECTIVE: The purpose of this study was to compare 5-minute delayed transitional phase imaging using a 30 degrees flip angle (hereafter, 5 min-FA30) and 20 minute hepatocyte phase imaging using a 10 degrees flip angle (hereafter, 20 min FA10) in gadoxetic acid-enhanced MRI for focal hepatic lesion detection and lesion-to-liver contrast-to-noise ratio (CNR), and to determine whether 5 min FA30 could replace 20 min-FA10 with a 15-minute time saving. MATERIALS AND METHODS: One hundred sixteen patients with 282 focal hepatic lesions (size range, 0.2-12.5 cm; malignant, n = 146; benign, n = 136) underwent gadoxetic acid enhanced MRI with 5 min-FA30 and 20 min-FA10 with a 3D T1-weighted gradient-echo sequence. Three radiologists independently assessed the presence of focal hepatic lesions using a 4-point scale, and detection sensitivity of focal hepatic lesions was calculated. Lesion-to-liver CNRs were calculated and compared in two image groups. RESULTS: There was no significant difference in detection sensitivity of focal hepatic lesions for all three readers between 5 min-FA30 (mean, 95.4%) and 20 min-FA10 (mean, 95.6%), irrespective of lesion size or malignancy. The mean CNR on 5 min-FA30 (167.9 +/- 84.1) was significantly higher than that on 20 min FA10 (160.2 +/- 79.5). However, the mean CNR difference between the two image groups was relatively small (7.8 +/- 41.9). CONCLUSION: Compared with 20 min FA10, 5 min-FA30 provided higher CNR and similar sensitivity. These findings indicate that 5 min-FA30 could replace 20-min delayed hepatocyte phase imaging using a 10 degrees flip angle with similar diagnostic performance and 15 minutes of time saving. PMID- 25539240 TI - Colonic distention at CT colonography: randomized evaluation of both IV hyoscine butylbromide and automated carbon dioxide insufflation. AB - OBJECTIVE: The purpose of this article is to evaluate the efficacy of IV hyoscine butylbromide as a bowel relaxant and automated carbon dioxide insufflation in CT colonography in terms of colonic distention and perceived burden. SUBJECTS AND METHODS; Two hundred twenty-four participants were randomly allocated to one of four groups: control (no bowel relaxant and IV saline placebo before CT colonography with manual carbon dioxide insufflation), hyoscine butylbromide (IV hyoscine butylbromide before examination with manual carbon dioxide insufflation), automated (no bowel relaxant before examination with automated carbon dioxide insufflation), and combined (hyoscine butylbromide before examination with automated carbon dioxide insufflation). The degree of colonic distention on a 4-point scale, examination time, and participants' satisfaction, as measured by their responses to a questionnaire, were assessed. RESULTS: The mean distention grades of all the colonic segments and both positions were 3.22 in the control group, 3.28 in the hyoscine butylbromide group, 3.77 in the automated group, and 3.74 in the combined group. Compared with manual carbon dioxide insufflation, automated carbon dioxide insufflation significantly improved the clinical adequacy of colonic distention and shortened examination time. No statistically significant difference was seen in the clinical adequacy of distention between participants who received hyoscine butylbromide and those who did not, or in examination time. Overall, the participants' experiences were not different. CONCLUSION: Colonic distention was statistically significantly improved by automated carbon dioxide insufflation, but not by the administration of hyoscine butylbromide. The participants' tolerance was similar in each group. PMID- 25539241 TI - Evaluation of MRI-TRUS fusion versus cognitive registration accuracy for MRI targeted, TRUS-guided prostate biopsy. AB - OBJECTIVE: The purpose of this article is to compare transrectal ultrasound (TRUS) biopsy accuracies of operators with different levels of prostate MRI experience using cognitive registration versus MRI-TRUS fusion to assess the preferred method of TRUS prostate biopsy for MRI-identified lesions. SUBJECTS AND METHODS; One hundred patients from a prospective prostate MRI-TRUS fusion biopsy study were reviewed to identify all patients with clinically significant prostate adenocarcinoma (PCA) detected on MRI-targeted biopsy. Twenty-five PCA tumors were incorporated into a validated TRUS prostate biopsy simulator. Three prostate biopsy experts, each with different levels of experience in prostate MRI and MRI TRUS fusion biopsy, performed a total of 225 simulated targeted biopsies on the MRI lesions as well as regional biopsy targets. Simulated biopsies performed using cognitive registration with 2D TRUS and 3D TRUS were compared with biopsies performed under MRI-TRUS fusion. RESULTS: Two-dimensional and 3D TRUS sampled only 48% and 45% of clinically significant PCA MRI lesions, respectively, compared with 100% with MRI-TRUS fusion. Lesion sampling accuracy did not statistically significantly vary according to operator experience or tumor volume. MRI-TRUS fusion-naive operators showed consistent errors in targeting of the apex, midgland, and anterior targets, suggesting that there is biased error in cognitive registration. The MRI-TRUS fusion expert correctly targeted the prostate apex; however, his midgland and anterior mistargeting was similar to that of the less-experienced operators. CONCLUSION: MRI-targeted TRUS-guided prostate biopsy using cognitive registration appears to be inferior to MRI-TRUS fusion, with fewer than 50% of clinically significant PCA lesions successfully sampled. No statistically significant difference in biopsy accuracy was seen according to operator experience with prostate MRI or MRI-TRUS fusion. PMID- 25539243 TI - Renal perfusional cortex volume for arterial input function measured by semiautomatic segmentation technique using MDCT angiographic data with 0.5-mm collimation. AB - OBJECTIVE: The purpose of this study was to evaluate the usefulness of renal perfusional cortex volume for arterial input function. MATERIALS AND METHODS: This retrospective study included 45 potential kidney donors--33 patients with aortic dissection and 12 patients with renovascular hypertension--who underwent both MDCT angiography with 0.5-mm collimation and renal (99m)Tc diethylenetriamine pentaacetic acid (DTPA) scanning using the modified Gates method. Each perfusional cortex volume for the arterial input function and parenchymal volume was measured by semiautomatic segmentation using the region growing technique. Linear regression analysis and correlation coefficients were used to assess the impact of the cortical volume, parenchymal volume, and renal scanning glomerular filtration rate (GFR) on estimated GFR (eGFR) using a modified Modification of Diet in Renal Disease (MDRD) equation. RESULTS: The correlation coefficient was higher for the total renal DTPA GFR adjusted for body surface area, weight-adjusted perfusion cortex volume, and adjusted total parenchyma volume in rank (r = 0.712, 0.642, 0.510, respectively, p< 0.0001 for each). The coefficient of the right renal perfusional cortex volume percent with a mean value of 52.1% +/- 10.1% was 0.826 (p < 0.0001) for the right renal DTPA GFR percent with a mean value of 51.0% +/- 12.1% (range, 22.0-89.5%), although the value for the right renal parenchymal volume percent with a mean value of 49.5% +/- 5.5% was 0.764 (p < 0.0001). CONCLUSION: Weight-adjusted perfusional cortex volume for arterial input function can be measured clinically and may replace renal DTPA scanning using the modified Gates method. PMID- 25539242 TI - Feasibility of discriminating uric acid from non-uric acid renal stones using consecutive spatially registered low- and high-energy scans obtained on a conventional CT scanner. AB - OBJECTIVE: The objective of our study was to show the feasibility of distinguishing between uric acid (UA) and non-UA renal stones using two consecutive spatially registered low- and high-energy scans acquired on a conventional CT system. SUBJECTS AND METHODS: A total of 33 patients undergoing clinically indicated dual-source dual-energy CT examinations to differentiate UA from non-UA renal stones were enrolled in this study. Immediately after patients underwent clinically indicated dual-source dual-energy CT, two consecutive scans (one at 80 kV and one at 140 kV) were obtained on a conventional CT scanner over the region limited to the stones identified on the dual-source scans. After 3D deformable registration of the 80- and 140-kV images, UA and non-UA stones were identified using commercial software. The sensitivity, specificity, and accuracy of stone classification were calculated using the dual-source results as the reference standard. RESULTS: A total of 469 stones were identified in the dual source examinations (26 UA and 443 non-UA stones). The average in-plane stone diameter was 4.4 +/- 2.5 (SD) mm (range, 2.0-18.9 mm). The overall sensitivity, specificity, and accuracy for identifying UA stones were 73.1%, 90.1%, and 89.1%, respectively. The sensitivity, specificity, and accuracy were 94.7%, 96.9%, and 96.8% for stones 3 mm or larger (n = 341 [19 UA and 322 non-UA]). CONCLUSION: Accurate differentiation of UA from non-UA renal stones is feasible using two consecutively acquired and spatially registered conventional CT scans. PMID- 25539244 TI - Practice and quality improvement: successful implementation of TeamSTEPPS tools into an academic interventional ultrasound practice. AB - OBJECTIVE: The goal of this study was to implement an evidence-based teamwork system to improve communication and teamwork skills among health care professionals (TeamSTEPPS) into an academic interventional ultrasound program and to assess safety and team-work climate across team members both before and after implementation. MATERIALS AND METHODS: Members of a change team (including master trainers) selected specific tools available within TeamSTEPPS to implement into an academic interventional ultrasound service. Tools selected were based on preimplementation survey data obtained from team members (n = 64: 11 attending faculty physicians, 12 clinical abdominal imaging fellows or residents, 17 sonographers, 19 nurses, and five technologist aides or administrative personnel). The survey included teamwork climate and safety climate domains from the Safety Attitudes Questionnaire. Four months after implementation, respondents were resurveyed and post-implementation data were collected. RESULTS: Teamwork climate scores improved from a mean of 67.9 (SD, 12.8) before implementation to a mean of 87.8 (SD, 14.1) after implementation (t = -7.6; p < 0.001). Safety climate scores improved from a mean of 76.5 (SD, 12.8) before implementation to a mean of 88.3 (SD, 13.4) after implementation (t = -4.6; p < 0.001). In particular, teamwork items about "input being well received" and "speaking up" were the most responsive to the intervention. CONCLUSION: The implementation of TeamSTEPPS tools was associated with statistically significant improvements in safety and teamwork metrics in an academic interventional ultrasound practice. The most notable improvements were seen in communication among team members and role clarification. We think that this model, which has been successfully implemented in many nonradiologic areas in medical care, is also applicable in imaging practice. PMID- 25539245 TI - Health literacy and online educational resources: an opportunity to educate patients. AB - OBJECTIVE: Given the increasing accessibility of material on the Internet and the use of these materials by patients as a source of health care information, the purpose of this study was to quantitatively evaluate the level of readability of resources made available on the European Society of Radiology website to determine whether these materials meet the health literacy needs of the general public as set forth by guidelines of the U.S. National Institutes of Health (NIH) and the American Medical Association (AMA). MATERIALS AND METHODS: All 41 patient education articles created by the European Society of Radiology (ESR) were downloaded and analyzed with the following 10 quantitative readability scales: the Coleman-Liau Index, Flesch-Kincaid Grade Level, Flesch Reading Ease, FORCAST Formula, Fry Graph, Gunning Fog Index, New Dale-Chall, New Fog Count, Raygor Reading Estimate, and the Simple Measure of Gobbledygook. RESULTS: The 41 articles were written collectively at a mean grade level of 13.0 +/- 1.6 with a range from 10.8 to 17.2. For full understanding of the material, 73.2% of the articles required the reading comprehension level of, at minimum, a high school graduate (12th grade). CONCLUSION: The patient education resources on the ESR website are written at a comprehension level well above that of the average Internet viewer. The resources fail to meet the NIH and AMA guidelines that patient education material be written between the third and seventh grade levels. Recasting these resources in a simpler format would probably lead to greater comprehension by ESR website viewers. PMID- 25539246 TI - Lens dose in routine head CT: comparison of different optimization methods with anthropomorphic phantoms. AB - OBJECTIVE: The purpose of this study was to study different optimization methods for reducing eye lens dose in head CT. MATERIALS AND METHODS: Two anthropomorphic phantoms were scanned with a routine head CT protocol for evaluation of the brain that included bismuth shielding, gantry tilting, organ-based tube current modulation, or combinations of these techniques. Highsensitivity metal oxide semiconductor field effect transistor dosimeters were used to measure local equivalent doses in the head region. The relative changes in image noise and contrast were determined by ROI analysis. RESULTS: The mean absorbed lens doses varied from 4.9 to 19.7 mGy and from 10.8 to 16.9 mGy in the two phantoms. The most efficient method for reducing lens dose was gantry tilting, which left the lenses outside the primary radiation beam, resulting in an approximately 75% decrease in lens dose. Image noise decreased, especially in the anterior part of the brain. The use of organ-based tube current modulation resulted in an approximately 30% decrease in lens dose. However, image noise increased as much as 30% in the posterior and central parts of the brain. With bismuth shields, it was possible to reduce lens dose as much as 25%. CONCLUSION: Our results indicate that gantry tilt, when possible, is an effective method for reducing exposure of the eye lenses in CT of the brain without compromising image quality. Measurements in two different phantoms showed how patient geometry affects the optimization. When lenses can only partially be cropped outside the primary beam, organ-based tube current modulation or bismuth shields can be useful in lens dose reduction. PMID- 25539247 TI - Radiation risks: what is to be done? AB - OBJECTIVE: What is currently known about radiologic risks is reviewed, policies that should be adopted based on our current knowledge are proposed, and how these policies can be applied to adequately protect patients in everyday clinical practice is described. CONCLUSION: All activities in life (e.g., driving automobiles) are associated with risks, and medical imaging is no different, so the most important message to convey to patients is whether a proposed examination is worthwhile. Our collective goal should be ensuring that all radiologic examinations are justified and are as low as reasonably achievable (ALARA), which maximizes the benefits of medical imaging for our patients. PMID- 25539248 TI - Necrotizing fasciitis and its mimics: what radiologists need to know. AB - OBJECTIVE: The purpose of this article is to review the imaging features of necrotizing fasciitis and its potential mimics. Key imaging features are emphasized to enable accurate and efficient interpretation of variables that are essential in appropriate management. CONCLUSION: Necrotizing fasciitis is a medical emergency with potential lethal outcome. Dissecting gas along fascial planes in the absence of penetrating trauma (including iatrogenic) is essentially pathognomonic. However, the lack of soft-tissue emphysema does not exclude the diagnosis. Mimics of necrotizing fasciitis include nonnecrotizing fasciitis (eosinophilic, paraneoplastic, inflammatory (lupus myofasciitis, Churg-Strauss, nodular, or proliferative), myositis, neoplasm, myonecrosis, inflammatory myopathy, and compartment syndrome. Necrotizing fasciitis is a clinical diagnosis, and imaging can reveal nonspecific or negative findings (particularly during the early course of disease). One should be familiar with salient clinical and imaging findings of necrotizing fasciitis to facilitate a more rapid and accurate diagnosis and be aware that its diagnosis necessitates immediate discussion with the referring physician. PMID- 25539250 TI - Efficacy of ultrasound-guided percutaneous needle treatment of calcific tendinitis. AB - OBJECTIVE: The purpose of this study was to conduct a systematic review of the efficacy of ultrasound-guided needle lavage in treating calcific tendinitis. MATERIALS AND METHODS: Two independent assessors searched medical databases and screened studies for eligibility. RESULTS: Eleven articles were included. Heterogeneity among included studies precluded meta-analysis. Results of randomized controlled trials suggested no difference in pain relief between needle lavage and other interventions, but the studies were of low quality. CONCLUSION: Additional high-quality evidence is required to determine the relative efficacy of ultrasound-guided needle lavage in the management of calcific tendinitis of the rotator cuff. PMID- 25539249 TI - Metal artifact reduction with MAVRIC SL at 3-T MRI in patients with hip arthroplasty. AB - OBJECTIVE: The objective of our study was to compare the multiacquisition variable-resonance image combination selective (MAVRIC SL) sequence with the 2D fast spin-echo (FSE) sequence for metal artifact reduction on 3-T MRI in patients with hip arthroplasty (HA). MATERIALS AND METHODS: Matched 2D FSE and MAVRIC SL images of 21 hips (19 patients with HA) were included in the study group. Paired image sets, composed of 13 coronal and 12 axial slices (total, 25 image sets), of the 21 hips were evaluated. For quantitative analysis, the artifact area was measured at the level of the hip and femur. For qualitative analysis, two musculoskeletal radiologists independently compared paired 2D FSE and MAVRIC SL sets in terms of artifacts, depiction of anatomic detail, level of diagnostic confidence, and detection of abnormal findings. RESULTS: The measured artifact area was significantly smaller (p < 0.05) on MAVRIC SL than 2D FSE at both the level of hip (59.9% reduction with MAVRIC SL) and femur (31.3% reduction with MAVRIC SL). The artifact score was also significantly decreased (p < 0.0001) with MAVRIC SL compared with 2D FSE for both reviewers. The hip joint capsule and the muscle and tendon attachment sites of the obturator externus and iliopsoas muscles were better depicted with MAVRIC SL than 2D FSE (p < 0.0125). Abnormal findings were significantly better shown on MAVRIC SL imaging compared with 2D FSE imaging (p < 0.0001). CONCLUSION: The MAVRIC SL sequence can significantly reduce metal artifact on 3-T MRI compared with the 2D FSE sequence and can increase diagnostic confidence of 3-T MRI in patients with total HA. PMID- 25539251 TI - Pediatric bone sarcoma: diagnostic performance of 18F-FDG PET/CT versus conventional imaging for initial staging and follow-up. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic performance of (18)F-FDG PET/CT and conventional imaging for staging and follow-up of pediatric osteosarcoma and skeletal Ewing sarcoma. MATERIALS AND METHODS: We calculated sensitivity, specificity, and accuracy of PET/CT and conventional imaging (CT, MRI, bone scanning) for sites of disease and number of lesions. Diagnostic benefit, defined as better characterization of lesions, was evaluated on a per scan basis, comparing PET/CT and conventional imaging. RESULTS: A total of 412 lesions were characterized by imaging in 64 patients (20, osteosarcoma; 44, Ewing sarcoma). For osteosarcoma patients PET/CT was available only at follow-up, where it proved more accurate than conventional imaging for the detection of bone lesions (accuracy, 95% vs 67% for CT and 86% for MRI) and complementary to CT in evaluating lung nodules (sensitivity, 84% vs 94%; specificity, 79% vs 71%) with diagnostic benefit in 18% of examinations. In patients with Ewing sarcoma, PET/CT tended to perform better during follow-up than at initial staging (accuracy, 85% vs 69%). For lung findings, PET/CT was more specific than CT but was less sensitive. The diagnostic benefit of PET/CT was greater at staging (28%) than during followup (9%). On a per-patient basis, PET/CT provided diagnostic benefit in 21 of 44 patients with Ewing sarcoma and nine of 20 patients with osteosarcoma at least once during clinical management. CONCLUSION: FDG PET/CT provides diagnostic benefit in Ewing sarcoma and osteosarcoma, with the exception of small lung nodules. Prospective studies are needed to define the best imaging algorithm and combination of tests in the staging and follow-up of patients with pediatric bone sarcoma. PMID- 25539252 TI - Comparison of Insall-Salvati ratios in children with an acute anterior cruciate ligament tear and a matched control population. AB - OBJECTIVE: An anterior cruciate ligament (ACL) injury is an increasingly recognized cause of knee pain in young patients and in athletes in particular and can be detected non-invasively with MRI. Anecdotal information suggests that patella alta may be more common in the setting of this injury, but no study has documented this phenomenon. This study sought to test whether an ACL tear is associated with an increased Insall-Salvati ratio suggestive of patella alta. MATERIALS AND METHODS: Measurements of patellar height, patellar tendon length, and the Insall-Salvati ratio obtained from MRI of the knee were compared for 34 children with an arthroscopically proven ACL tear (mean age +/- SD, 12.4 +/- 1.4 years) and 36 control subjects with normal knee examinations (12.8 +/- 2.1 years); these measurements were performed independently by two observers. RESULTS: Patellar tendon length (47.6 +/- 6.6 mm vs 40.4 +/- 5.7 mm) and patellar position calculated as the Insall-Salvati ratio (1.16 +/- 0.16 vs 0.99 +/- 0.14) were significantly greater in the knees with an ACL injury than in those without an internal injury, respectively, on MRI (p < 0.001). Patella length was not significantly different between the two groups (patients vs control subjects, 41.1 +/- 4.2 mm vs 40.6 +/- 2.7 mm, respectively; p = 0.523). There was good to excellent interobserver and intraobserver correlation for all measurements. CONCLUSION: There is a significant association between an ACL tear and increased patellar tendon length with a greater Insall-Salvati ratio. The mechanism for this finding is unclear, but this association provides support to suggest relative patella alta may be a risk factor for ACL injuries in pediatric patients. PMID- 25539254 TI - Diagnostic yield of sonography in infants with suspected hip dysplasia: diagnostic thinking efficiency and therapeutic efficiency. AB - OBJECTIVE: The purpose of this study is to determine the impact of sonographic information on surgeons' diagnostic thinking and decision making in the management of infants with a possible diagnosis of developmental dysplasia of the hip (DDH). SUBJECTS AND METHODS: Five experienced orthopedic surgeons examined 66 hips of infants who were referred for a possible diagnosis of DDH and reported for each hip a confidence level about the diagnosis of DDH using a visual analog scale (VAS) before and after hip sonography was obtained. In addition, they reported a management plan. We determined the efficiency in diagnostic thinking by calculating the mean gain in diagnostic confidence as the percentage change in VAS scores and the impact of sonography on the management plan (therapeutic efficiency). RESULTS: Sonography led to a change in diagnosis in 52% (34/66) of hips. The management plan changed in 32% (21/66) of hips. The mean gain in reported diagnostic confidence was 19.4% (95% CI, 17.3-21.5%), but it was 46.0% (95% CI, 30.5-60.8%) in cases where the management changed as a result of sonography (difference, 37.7%; p < 0.0001). The greatest yield of sonography was found in hips showing limited abduction. Sonography obviated further follow-up in 23% (15/66) of cases. CONCLUSION: Sonography refined the diagnostic thinking of clinicians and led to a change in diagnosis in 52% of cases. Management plans changed in 32% of cases. PMID- 25539253 TI - Simplifying size-specific radiation dose estimates in pediatric CT. AB - OBJECTIVE: Size-specific dose estimates (SSDEs) require manual measurement of torso diameters for individual patients--anteroposterior (hereafter, D(AP)), lateral (hereafter, D(LAT)), and effective (hereafter, D(E))--which can be tedious in clinical settings. We aimed to determine whether body weight can be used as a surrogate for measuring diameter in children. MATERIALS AND METHODS: D(AP) and D(LAT) were measured in 522 consecutive CT examinations (chest, 187 and abdomen-pelvis, 335) performed in 483 (+/- SD) children (13 +/- 7 years). Effective diameter (D(E1)) was calculated as the square root of the product of D(AP) and D(LAT). A second measurement of effective diameter (D(E2)) was obtained using automated software. Correlation coefficients between patient body weight, age, and diameter were measured in addition to 95% prediction interval analysis for diameters corresponding to body weight. RESULTS: Median body weight was 51 kg, and mean D(AP), D(LAT), D(E1), and D(E2) were 207.1 +/- 50.8 mm, 289.8 +/- 72.6 mm, 243.3 +/- 62.0 mm, and 233.6 +/- 55.4 mm, respectively. Overall body weight had a strong correlation with diameter (0.88, 0.85, 0.86, and 0.93 respectively; all p < 0.0001). SSDE measured using body weight was statistically not different than SSDE measured using effective diameters (p = 0.9). Children weighing less than 27 kg and between 46 and 100 kg had statistically significant correlations with torso diameters, whereas only anteroposterior and effective diameters were correlated with children weighing between 27 and 45 kg. Children less than 4 years old had strong correlation with all diameters. Adolescents (15 18 years) did not have statistically significant correlation with any of the diameters. CONCLUSION: Body weight, instead of body diameter, can be used as a surrogate to estimate size-specific dose in children, making dose estimation clinically simpler and more rapid. PMID- 25539255 TI - An international multicenter comparison of time-SLIP unenhanced MR angiography and contrast-enhanced CT angiography for assessing renal artery stenosis: the renal artery contrast-free trial. AB - OBJECTIVE: The unenhanced MR angiography (MRA) technique time-spatial labeling inversion pulse (time-SLIP) may provide a safe alternative for evaluating the renal arteries for stenosis. This international multicenter trial tested the hypothesis that time-SLIP unenhanced MRA is accurate and robust for assessing the renal arteries for stenosis in comparison with contrast-enhanced CT angiography (CTA). SUBJECTS AND METHODS: Four centers (United States, Europe, Asia) enrolled 75 patients (average age +/- SD, 58 +/- 13 years; 41 [55%] men and 34 [45%] women). Each patient underwent abdominal contrast-enhanced CTA and abdominal unenhanced MRA using time-SLIP with balanced steady-state free precession. All images were visually assessed for quality (arterial signal intensity) and for the absence or presence of renal artery stenosis (<= 50% or > 50% stenosis, respectively). In addition, for arteries with any visible disease, the severity of the stenosis was quantified. Two blinded readers evaluated each study. No arteries were excluded from analysis. RESULTS: Unenhanced MRA image quality was excellent for 56 of 75 patients (75%) and good for 16 of 75 patients (21%). CTA was used as the reference standard and showed that 23 of 161 renal arteries (14.3%) had stenosis > 50%. Unenhanced MRA correctly classified 17 of the 23 renal arteries with > 50% stenosis and correctly classified 128 of the 138 renal arteries as not having disease (<= 50% stenosis) to yield a sensitivity of 74%, specificity of 93%, and accuracy of 90% (chi(2) = 0.56; p = 0.45, no statistically significant difference). Of the 16 misclassified arteries, only three had a clinically relevant misclassification (CTA >= 70% stenosis and unenhanced MRA <= 50% stenosis or unenhanced MRA >= 70% stenosis and CTA <= 50% stenosis). On average, measured stenotic severity (n = 28 arteries) was similar for unenhanced MRA (64% +/- 17%) and CTA (62% +/- 16%) (p = 0.51). CONCLUSION: Compared with contrast-enhanced CTA, the unenhanced MRA technique time-SLIP shows promise for assessing the renal arteries for stenosis. The unenhanced MRA technique time-SLIP may provide a safe alternative for evaluating the renal arteries for stenosis. PMID- 25539256 TI - Utility of 99mTc-human serum albumin diethylenetriamine pentaacetic acid SPECT for evaluating endoleak after endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: The purpose of this study was to assess the utility of (99m)Tc-human serum albumin diethylenetriamine pentaacetic acid ((99m)Tc-HSAD) SPECT in the detection of endoleaks after endovascular abdominal aortic aneurysm repair. SUBJECTS AND METHODS: Fifteen patients (11 men, four women) with aneurysm sac expansion of 5 mm or greater after endovascular abdominal aortic aneurysm repair underwent three-phase CT, (99m)Tc-HSAD SPECT, and CT during aortography. Sensitivity calculations for three-phase CT and (99m)Tc-HSAD SPECT were performed with CT during aortography as the reference standard. The volume of each endoleak was measured with CT during aortography. Seven subjects underwent embolization with N-butyl cyanoacrylate (NBCA)-Lipiodol (ethiodized oil, Guerbet and metallic coils. Three-phase CT and (99m)Tc-HSAD SPECT were repeated after embolization to assess their efficacy. RESULTS: Endoleaks were interpreted as perigraft radioisotope accumulation in 12 patients (80.0%) on (99m)Tc-HSAD SPECT images, in 13 patients (86.7%) on three-phase CT images, and in 15 patients (100%) on CT during aortography. The mean endoleak volume visualized with (99m)Tc-HSAD SPECT was 8.37 cm(3) (range, 5.2-15.1 cm(3)), and the volume not visualized was 3.47 cm(3) (2.5-4.6 cm(3)), a statistically significant difference (p = 0.019). In two patients, (99m)Tc-HSAD SPECT depicted endoleaks evident at delayed phase CT during aortography but not at three-phase CT, suggesting they were slow-filling endoleaks. Accumulation of (99m)Tc-HSAD corresponding to endoleaks disappeared after embolization, but CT evaluation of embolization was impeded by artifacts of NBCA-Lipiodol and metallic coils. CONCLUSION: Technetium-99m-labeled HSAD SPECT proved less sensitive than three-phase CT but depicted endoleaks with volumes 5.2 cm(3) or greater as perigraft radioisotope accumulation. Slow-filling endoleaks can be visualized with (99m)Tc-HSAD SPECT, which can be used to evaluate the efficacy of embolization. PMID- 25539257 TI - Microwave ablation of hepatic tumors abutting the diaphragm is safe and effective. AB - OBJECTIVE: The purpose of this study was to evaluate the incidence of clinically significant diaphragmatic injuries and local tumor progression after microwave ablation of hepatic tumors abutting the diaphragm. MATERIALS AND METHODS: This retrospective study included 55 peripheral hepatic tumors abutting the diaphragm treated by microwave ablation versus a control group of 15 centrally located tumors. Treated tumors were further subdivided according to the use of artificial ascites (fluid vs no fluid) and whether instilled fluid achieved displacement of the liver surface away from the diaphragm (displaced vs nondisplaced). Measurements of tumor size, distance to the diaphragm, ablation zone size, displacement distance, length of the ablation zone along the liver capsule, diaphragm thickness, diaphragmatic hernia, and local tumor progression were made on pre- and postablation CT and MRI. The electronic medical record was reviewed for patient self-reported pain scores and other symptoms. Data were analyzed by use of the Kruskal-Wallis and Fisher exact tests. RESULTS: There were no cases of diaphragmatic hernia in peripheral or central tumors. Postablation diaphragm thickness was higher in peripheral hepatic tumors than in control tumors. Peripheral tumors had an overall higher incidence of postprocedure shoulder pain (18% vs 0%) and local tumor progression (5.5% vs 0%) compared with control tumors, but these differences did not achieve statistical significance (p = 0.2 and p = 1, respectively). CONCLUSION: Our study shows that microwave ablation of peridiaphragmatic hepatic tumors is safe, without incidence of diaphragmatic hernia, and can be performed with a low rate of local tumor progression. PMID- 25539258 TI - Mucocele-like lesions in the breast diagnosed with percutaneous biopsy: is surgical excision necessary? AB - OBJECTIVE: The purpose of this study was to determine the frequencies of atypia and cancer at excisional biopsy of lesions with a diagnosis of mucocele-like lesion (MLL) at percutaneous breast biopsy. MATERIALS AND METHODS: Retrospective review of 9286 lesions subjected to percutaneous imaging-guided biopsy identified MLLs in 35 (0.38%) patients. Medical records, imaging studies, and histologic results were reviewed. RESULTS: Of the 35 patients with core biopsy findings of MLL, 27 underwent stereotactic core needle biopsy (19 with microcalcifications, five with calcifications with an associated mass, and three with only a mass), and eight underwent ultrasound-guided core needle biopsy (four with a solid mass, three with a complex cystic mass). At core biopsy, 12 of 35 (34%) MLLs were associated with atypia (10 cases of atypical ductal hyperplasia, two of flat epithelial atypia), and 23 of 35 (66%) were benign MLL only. All 12 MLLs associated with atypia and 12 of 23 benign MLLs were surgically excised. Eleven patients did not undergo surgery, five of whom were lost to follow-up. One of the 12 (3% of the 35) MLLs associated with atypia was upgraded to DCIS. None were upgraded to invasive cancer. None of the benign MLLs were upgraded to malignancy, and findings at excision of four of the 23 (17%) benign MLLs led to a change in diagnosis to a high-risk lesion (three atypical ductal hyperplasia, one atypical lobular hyperplasia). CONCLUSION: MLL is a rare diagnosis but is encountered in large-volume breast practices. The findings are nonspecific with a range of imaging appearances. No imaging test is reliable for differentiating MLL from other suspicious lesions or lesions with associated atypia. Surgery is clearly warranted for MLL associated with atypia at core needle biopsy because it may be upgraded to malignancy upon excision. However, if the presence of atypia at excision of benign MLL will change clinical management, then benign MLL at core needle biopsy warrants surgical excision in some cases. In patients whose treatment will not change if atypia is found at excision, close surveillance with short-interval follow-up is a reasonable alternative. PMID- 25539259 TI - Breast MRI-detected cystic apocrine metaplasia: imaging features with microvessel analysis and histologic correlation. AB - OBJECTIVE: The purpose of this article is to characterize the histologic vascular features and distinguishing MRI features of cystic apocrine metaplasia to better understand imaging-pathology concordance. MATERIALS AND METHODS: Retrospective review of 261 consecutive MRI-guided biopsy cases was performed. Pathology results were reviewed for all biopsies; cystic apocrine metaplasia was identified as the predominant finding in 19 cases (7%). CD31 immunohistochemistry was subsequently performed on the most representative block of cystic apocrine metaplasia, and microvasculature was evaluated using computer-assisted image analysis. The contrast-enhanced MRI examinations correlating with the cystic apocrine metaplasia cases were independently reviewed by two radiologists specializing in breast imaging; lesions were analyzed for morphologic, kinetic, and T2 characteristics. RESULTS: On MRI review, 17 of 19 (89%) lesions were 10 mm or smaller. Washout kinetics were present in 11 of 19 (58%) lesions, and 14 of 19 (74%) lesions were at least partially hyperintense on T2-weighted sequences relative to adjacent glandular tissue. Cystic apocrine metaplasia had a higher percentage area (mean, 4.1%) of CD31-immunostained microvessels compared with background fibroglandular tissue (mean, 1.2%). CONCLUSION: Cystic apocrine metaplasia should be considered in the differential diagnosis of a T2 hyperintense enhancing focus or subcentimeter smoothly marginated mass, even if associated with washout kinetics. Cystic apocrine metaplasia contains a statistically significant increase in microvessel area compared with background fibroglandular tissue and fat and, therefore, may be considered a concordant result for this set of imaging findings. PMID- 25539261 TI - Diagnostic reference levels. PMID- 25539260 TI - Nonmass enhancement on breast MRI: review of patterns with radiologic-pathologic correlation and discussion of management. AB - OBJECTIVE: The purpose of this article is to review the varied appearances and associated diagnoses of nonmass enhancement on breast MRI with radiologic pathologic correlation. CONCLUSION: Knowledge of the distribution and internal characteristics of these findings is helpful to determine when core needle biopsy is indicated. Correlating imaging with pathologic findings is critical in making appropriate recommendations regarding clinical management. PMID- 25539262 TI - Cardiac MRI and CT: differentiation of normal ostium and intraseptal course from slitlike ostium and interarterial course in anomalous left coronary artery in children. AB - OBJECTIVE: Anomalous left coronary artery from the inappropriate aortic sinus with intraseptal course is generally benign but can be confused on imaging studies with the potentially lethal interarterial, intramural anomalous left coronary artery. The purpose of this study was to assess normal ostial morphologic features and intraseptal course using cardiac MRI and CT in pediatric patients with intraseptal anomalous left coronary artery. MATERIALS AND METHODS: A retrospective review was conducted of the medical records of 14 children with the diagnosis of intraseptal anomalous left coronary artery between November 2009 and March 2013. Coronary artery origin and course were evaluated with cardiac MRI or CT, and 3D assessment of coronary ostial morphologic features was performed with virtual angioscopy. RESULTS: The patient ages ranged from 5 to 18 years at diagnosis; 10 (71.4%) were boys. The right and left coronary origins were the right sinus of Valsalva as a common origin (n = 9) or a single coronary artery (n = 5). Anomalous intraseptal left main coronary was found in 13 patients, and one patient had anomalous left anterior descending with retroaortic circumflex coronary artery. Anomalous coronary ostia were round and without stenosis in all studies. The anomalous vessel was identified with echocardiography, but the anomalous left coronary artery was not delineated, and a normal ostium was not adequately portrayed in any instance. CONCLUSION: By use of cardiac MRI and CT, the anomalous course of round coronary ostia was confirmed and visualized in a pediatric cohort with intraseptal anomalous left coronary artery. The data provide the basis for understanding the benign clinical course and showing that surgery is unnecessary for this coronary anomaly. PMID- 25539264 TI - MEDIOCOLEGAL--Malpractice and ethical issues in radiology. PMID- 25539265 TI - Chest CT findings in MERS. PMID- 25539263 TI - CT perfusion as an imaging biomarker in monitoring response to neoadjuvant bevacizumab and radiation in soft-tissue sarcomas: comparison with tumor morphology, circulating and tumor biomarkers, and gene expression. AB - OBJECTIVE: The purpose of this study was to evaluate the role of CT perfusion in monitoring response to neoadjuvant antiangiogenic and radiation therapy in resectable soft-tissue sarcomas and correlate the findings with tumor size, circulating and tumor biomarkers, and gene expression. SUBJECTS AND METHODS: This phase II clinical trial included 20 patients (13 men and 7 women; mean age, 55 years) with soft-tissue sarcomas who were undergoing treatment with the antiangiogenic drug bevacizumab followed by bevacizumab, radiation, and surgical resection. The patients underwent CT perfusion and diagnostic contrast-enhanced CT at baseline, at 2 weeks after bevacizumab therapy, and after completion of bevacizumab and radiation therapy. Multiple CT perfusion parameters (blood flow, blood volume, mean transit time, and permeability) were correlated with tumor size, circulating and tumor biomarkers, and gene expression. RESULTS: Two weeks after bevacizumab therapy, there was substantial fall in blood volume (31.9% reduction, p = 0.01) with more pronounced reduction in blood flow, blood volume, and permeability after treatment completion (53-64% reduction in blood flow, blood volume, and permeability; p = 0.001), whereas tumor size showed no significant change (p = 0.34). Tumors with higher baseline blood volume and lower baseline tumor size showed superior response to bevacizumab and radiation (p = 0.05). There was also an increase in median plasma vascular endothelial growth factor and placental-derived growth factor concentration after bevacizumab therapy paralleled by a decrease in tumor perfusion depicted by CT perfusion, although this was not statistically significant (p = 0.4). The baseline tumor microvessel density (MVD) correlated with blood flow (p = 0.04). At least 20 different genes were differentially expressed in tumors with higher and lower baseline perfusion. CONCLUSION: CT perfusion is more sensitive than tumor size for monitoring early and late response to bevacizumab and radiation therapy. CT perfusion parameters correlate with MVD, and the gene expression levels of baseline tumors could potentially predict treatment response. PMID- 25539266 TI - Reply to "Chest CT findings in MERS". PMID- 25539267 TI - Usefulness of CT in differentiating lymphoid thymic hyperplasia from true thymic hyperplasia: added value of thymic measurements and CT attenuation. PMID- 25539268 TI - Reply to "Usefulness of CT in differentiating lymphoid thymic hyperplasia from true thymic hyperplasia: added value of thymic measurements and CT attenuation". PMID- 25539269 TI - A practical review of the muscles of facial mimicry with special emphasis on the superficial musculoaponeurotic system. AB - OBJECTIVE: In this article, we elaborate a practical approach to superficial facial anatomy enabling easy identification of the facial mimic muscles by classifying them according to their shared common insertion sites. CONCLUSION: The facial mimic muscles are often difficult to identify on imaging. By tracing them from their common group insertion sites back to their individual origins as well as understanding key anatomic relationships, radiologists can more accurately identify these muscles. PMID- 25539270 TI - Comprehensive assessment of radiation dose estimates for the CORE320 study. AB - OBJECTIVE. The purpose of this study was to comprehensively study estimated radiation doses for subjects included in the main analysis of the Combined Non invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) study ( ClinicalTrials.gov identifier NCT00934037), a clinical trial comparing combined CT angiography (CTA) and perfusion CT with the reference standard catheter angiography plus myocardial perfusion SPECT. SUBJECTS AND METHODS. Prospectively acquired data on 381 CORE320 subjects were analyzed in four groups of testing related to radiation exposure. Radiation dose estimates were compared between modalities for combined CTA and perfusion CT with respect to covariates known to influence radiation exposure and for the main clinical outcomes defined by the trial. The final analysis assessed variations in radiation dose with respect to several factors inherent to the trial. RESULTS. The mean radiation dose estimate for the combined CTA and perfusion CT protocol (8.63 mSv) was significantly (p < 0.0001 for both) less than the average dose delivered from SPECT (10.48 mSv) and the average dose from diagnostic catheter angiography (11.63 mSv). There was no significant difference in estimated CTA perfusion CT radiation dose for subjects who had false-positive or false-negative results in the CORE320 main analyses in a comparison with subjects for whom the CTA-perfusion CT findings were in accordance with the reference standard SPECT plus catheter angiographic findings. CONCLUSION. Radiation dose estimates from CORE320 support clinical implementation of a combined CT protocol for assessing coronary anatomy and myocardial perfusion. PMID- 25539272 TI - Tube potential and CT radiation dose optimization. AB - OBJECTIVE: This article describes tube potential and its effect on image quality and radiation dose for CT in different body regions and clinical indications. CONCLUSION: Tube potential is an important scanning parameter for radiation dose optimization. Reduction of tube potential results in increased image contrast of iodine-enhanced CT as well as increased image noise. PMID- 25539271 TI - Impact of the time interval between MDCT imaging and surgery on the accuracy of identifying metastatic disease in patients with pancreatic cancer. AB - OBJECTIVE: Pancreatic adenocarcinoma is a rapidly progressive malignancy characterized by its tendency for early metastatic spread. MDCT is the primary diagnostic modality for the preoperative staging of patients with pancreatic cancer, with an accuracy established in multiple studies. However, for a variety of reasons, there is often a prolonged interval between staging MDCT and the surgical intervention. This study examines the relationship between the interval between imaging and surgery and the accuracy of MDCT in determining the presence or absence of metastatic disease at surgery in patients with pancreatic cancer. MATERIALS AND METHODS: Patients were identified who had undergone surgery for pancreatic cancer at our institution with a dedicated preoperative pancreas protocol MDCT performed in our department. Findings from the preoperative MDCT report were correlated with the operative findings, as well as the time between imaging and surgery. RESULTS: Two hundred ninety-two MDCT scans were performed on 256 patients who underwent exploration for pancreatic adenocarcinoma. The patients had a median age of 67 years (range, 30-95 years), and 51.6% (132/256) were male. The median time between MDCT and surgical exploration was 15.5 days (range, 1-198 days). MDCT correctly predicted the absence of metastatic disease at surgery in 233 of 274 (85.0%) studies. MDCT was more accurate in predicting the absence of metastatic disease if the study was performed within 25 days of surgery than it was if the study was performed within more than 25 days of surgery (89.3% vs 77.0%; p = 0.0097). Furthermore, regression models showed that the negative predictive value of a given MDCT significantly decreased after approximately 4 weeks. CONCLUSION: MDCT is an accurate method to stage patients with pancreatic cancer, but its accuracy in excluding distant metastatic disease depreciates over time. Patients should undergo a repeat MDCT within 25 days of any planned definitive operative intervention for pancreatic cancer to avoid unexpectedly finding metastatic disease at surgery. PMID- 25539274 TI - Imbalance of opinions expressed on Twitter relating to CT radiation risk: an opportunity for increased radiologist representation. AB - OBJECTIVE: The purpose of this study was to assess perspectives and information relating to CT radiation risk on Twitter, a popular microblogging social network. MATERIALS AND METHODS: Publicly available posts on Twitter ("tweets") containing both the words "CT" and "radiation" were identified from the 1st week of each month in 2013. Type of user posting and source of linked articles were recorded. Two reviewers assessed the content of tweets and links regarding CT's benefit-to risk ratio (favorable, unfavorable, etc.). RESULTS: Six hundred twenty-one relevant tweets were tweeted by 557 unique users, of whom 90 (16%) were physicians (17 of these were radiologists), 30 (5%) were medical practices or hospitals, 34 (6%) were patients, 8 (1%) were physicists or technologists, and 395 (71%) were other types of users. Two hundred twenty-seven tweets included user commentary regarding CT's benefit-to-risk ratio, of which 134 (59%) were unfavorable or concerned, 65 (29%) were neutral, 22 (10%) were informative regarding CT dose reduction strategies, and only 6 (3%) were favorable. Four hundred seventy-two tweets (76%) included links to a total of 99 unique articles, of which 25 (25%) were unfavorable or concerned, 10 (10%) were favorable, 25 (25%) were neutral, and 39 (39%) were informative regarding CT dose reduction. Article types were non-peer-reviewed medical sources (n = 50), lay press (n = 15), peer-reviewed medical journals (n = 13), blogs (n = 12), advertisements (n = 5), and informational websites (n = 4). CONCLUSION: The large majority of content on Twitter was either unfavorable or concerned regarding CT radiation risk. Most articles were not peer-reviewed and were posted by nonphysicians; posts by physicians were largely by nonradiologists. More active engagement on Twitter by radiologists and physicists and increased dissemination of peer-reviewed articles may achieve a more balanced representation and alleviate concerns regarding CT radiation risk on social networks. PMID- 25539273 TI - Periprostatic fat thickness on MRI: correlation with Gleason score in prostate cancer. AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate the relationship between periprostatic fat thickness on MRI and Gleason score of prostate cancer using radical prostatectomy as the reference standard. MATERIALS AND METHODS: This study included 190 patients (mean age [+/- SD], 66.9 +/- 7.0 years) who underwent MRI before radical prostatectomy. Two radiologists measured the subcutaneous and periprostatic fat thickness on midsagittal T2-weighted MR images as the shortest perpendicular distance from the pubic symphysis to the skin and prostate, respectively. Subcutaneous and periprostatic fat along with age, height, weight, body mass index, and prostate-specific antigen (PSA) were correlated with Gleason score by using Pearson (r) or Spearman (rho) correlation coefficients and compared between low- (Gleason score = 6) and high- (>= 7) grade prostate cancer by using univariate and multivariate logistic regression analyses. RESULTS: The mean subcutaneous and periprostatic fat thicknesses were 24.0 +/- 8.4 mm and 5.0 +/- 2.0 mm, respectively. The Gleason score was significantly correlated with age (rho = 0.181, p = 0.012), PSA (rho = 0.345, p < 0.001), and periprostatic fat thickness (rho = 0.228, p = 0.002). Multivariate analysis revealed that age, height, PSA level, and periprostatic fat thickness (odds ratio, 1.331; 95% CI, 1.063-1.666) were independently predictive of high grade (p <= 0.013) disease. CONCLUSION: Periprostatic fat thickness on MRI showed a mild to modest but significant correlation with Gleason score of prostate cancer with radical prostatectomy as the reference standard and was an independent predictive factor for high-grade prostate cancer. PMID- 25539275 TI - Increased rates of authorship in radiology publications: a bibliometric analysis of 142,576 articles published worldwide by radiologists between 1991 and 2012. AB - OBJECTIVE; There is evidence in academic medicine that the number of authors per paper has increased over time. The goal of this study was to quantitatively analyze authorship trends in the field of radiology over 20 years. MATERIALS AND METHODS: A search of the National Library of Medicine MEDLINE database was conducted to identify articles published by radiology departments between 1991 and 2012. Country of origin, article study design, and journal impact factor were recorded. The increase in number of authors per paper was assessed by linear and nonlinear regression. Pearson correlation was used to assess the relation between journal impact factor and number of authors. RESULTS: A total of 142,576 articles and 699,257 authors were identified during the study period. The mean number of authors per paper displayed linear growth from 3.9 to 5.7 (p < 0.0001). The proportion of single authors declined from 11% in 1991 to 4.4% in 2012. The number of clinical trials increased in a linear pattern, review articles in an exponential pattern, and case reports in a logistic pattern (p < 0.0001 for each). Countries with the highest number of authors per paper were Japan, Italy, and Germany. The number of articles funded by the U.S. National Institutes of Health (NIH) displayed exponential growth and of non-NIH-funded articles displayed linear growth (p < 0.0001 for each). A negligible relation was observed between journal impact factor and number of authors (Pearson r = 0.1066). CONCLUSION: Radiology has had a steady increase in mean number of authors per paper since the early 1990s that has varied by study design. The increase is probably multi-factorial and includes components of author inflation and increasing complexity of research. Findings support the need for reemphasis of authorship criteria to preserve authorship value and accountability. PMID- 25539276 TI - Computer-assisted virtual autopsy using surgical navigation techniques. AB - OBJECTIVE; Virtual autopsy methods, such as postmortem CT and MRI, are increasingly being used in forensic medicine. Forensic investigators with little to no training in diagnostic radiology and medical laypeople such as state's attorneys often find it difficult to understand the anatomic orientation of axial postmortem CT images. We present a computer-assisted system that permits postmortem CT datasets to be quickly and intuitively resliced in real time at the body to narrow the gap between radiologic imaging and autopsy. CONCLUSION: Our system is a potentially valuable tool for planning autopsies, showing findings to medical laypeople, and teaching CT anatomy, thus further closing the gap between radiology and forensic pathology. PMID- 25539277 TI - MRI and surgical findings in deltoid ligament tears. AB - OBJECTIVE: The objectives of our study were to determine the accuracy of new MRI criteria in detecting tears of the superficial deltoid ligament of the ankle, the accuracy of established criteria for detecting deep deltoid ligament tears, the most common location of super-ficial deltoid ligament tears, and the frequency of other injuries associated with deltoid tears. MATERIALS AND METHODS: A chart review yielded 89 cases over a 3-year interval in which ankle MRI was followed by open or arthroscopic surgery and the surgical report described findings in the deltoid ligament. One case was excluded because the MRI study was technically inadequate. MRI and surgical reports were then compared for the presence and location of deltoid ligament tears. RESULTS: MRI findings of focal detachment of the superficial deltoid origin or detachment of the fascial sleeve of the medial malleolus yielded a sensitivity for superficial deltoid ligament tears of 83.3% (45/54) and specificity of 93.9% (31/33). Eight of nine prospectively missed tears were visible on retrospective review. All superficial deltoid tears involved the origin of the ligament from the medial malleolus, and six involved mid or distal bundles of the superficial deltoid as well. MRI findings of discontinuity or nonvisualization of discrete fibers yielded a sensitivity for deep deltoid ligament tears of 96.3% (26/27) and specificity of 97.9% (46/47). CONCLUSION: MRI has a high accuracy for deltoid ligament tears in consecutive cases prospectively evaluated by musculoskeletal radiologists. The location of superficial deltoid ligament tears differed in our series from findings previously reported in the imaging literature. PMID- 25539278 TI - Accuracy of 3-T MR arthrography versus conventional 3-T MRI of elbow tendons and ligaments compared with surgery. AB - OBJECTIVE: MR arthrography of the elbow has been found to be useful in the diagnosis of fullversus partial-thickness tears of the collateral ligaments. This article assesses the accuracy of 3-T MR arthrography of the elbow versus conventional 3-T MRI of the elbow, compared with surgery. MATERIALS AND METHODS: Seventy-nine consecutive conventional elbow MRI and MR arthrography examinations performed on the same patients who went on to surgery were retrospectively read in consensus by two musculoskeletal radiologists. Full- or partial-thickness tears of the collateral ligaments and full-thickness tears of the extensor and flexor tendons were assessed. RESULTS: In 54 patients, the diagnoses made on MRI and MR arthrogram examinations were the same. In 16 patients, MR arthrogram examinations revealed additional findings that were not clearly seen on conventional MRI examinations. There were six full-thickness extensor tendon tears, seven radial collateral ligament tears, and three partial-thickness ulnar collateral ligament tears seen on MR arthrography that were not well seen on conventional MRI. In nine patients, MR arthrogram showed ligaments and tendons to be intact that appeared torn on conventional MRI. There were six ulnar collateral ligaments and three common flexor tendons found to be intact on MR arthrography examination that appeared to be torn on conventional MRI. All MR arthrography findings were confirmed at surgery. CONCLUSION: MR arthrography is more accurate than conventional MRI of the elbow at 3 T. In 16 cases, MR arthrography showed tendons and ligaments to be torn that appeared intact on conventional MRI. In nine cases, MR arthrography showed intact tendons and ligaments that appeared to be torn on conventional MRI. These nine cases are most likely the result of the tears healing, with fibrous tissue allowing the tendon and ligament tissues to coapt. PMID- 25539279 TI - Brain FDG PET and the diagnosis of dementia. AB - OBJECTIVE: We review the role of brain FDG PET in the diagnosis of Alzheimer disease, frontotemporal dementia, dementia with Lewy bodies, and vascular dementia. Characteristic spatial patterns of brain metabolism on FDG PET can help differentiate various subtypes of dementia. CONCLUSION: In patients with different subtypes of dementia, FDG PET/CT shows distinct spatial patterns of metabolism in the brain and can help clinicians to make a reasonably accurate and early diagnosis for appropriate management or prognosis. PMID- 25539280 TI - Pediatric CT dose reduction for suspected appendicitis: a practice quality improvement project using artificial Gaussian noise--part 1, computer simulations. AB - OBJECTIVE: The purpose of this study was to develop a departmental practice quality improvement project to systematically reduce CT doses for the evaluation of suspected pediatric appendicitis by introducing computer-generated gaussian noise. MATERIALS AND METHODS: Two hundred MDCT abdominopelvic examinations of patients younger than 20 years performed with girth-based scanning parameters for suspected appendicitis were reviewed. Two judges selected 45 examinations in which the diagnosis of appendicitis was excluded (14, appendix not visualized; 31, normal appendix visualized). Gaussian noise was introduced into axial image series, creating five additional series acquired at 25-76% of the original dose. Two readers reviewed 270 image series for appendix visualization (4-point Likert scale and arrow localization). Volume CT dose index (CTDIvol) and size-specific dose estimate (SSDE) were calculated by use of patient girth. Confidence ratings and localization accuracy were analyzed with mixed models and nonparametric bootstrap analysis at a 0.05 significance level. RESULTS: The mean baseline SSDE for the 45 patients was 16 mGy (95% CI, 12-20 mGy), and the corresponding CTDIvol was 10 mGy (95% CI, 4-16 mGy). Changes in correct appendix localization frequencies were minor. There was no substantial trend with decreasing simulated dose level (p = 0.46). Confidence ratings decreased with increasing dose reduction (p = 0.007). The average decreases were -0.27 for the 25% simulated dose (p = 0.01), -0.17 for 33% (p = 0.03), and -0.03 for 43% (p = 0.65). CONCLUSION: Pediatric abdominal MDCT can be performed with 43% of the original dose (SSDE, 7 mGy; CTDIvol, 4.3 mGy) without substantially affecting visualization of a normal appendix. PMID- 25539281 TI - Improving health literacy: use of an informational brochure improves parents' understanding of their child's fluoroscopic examination. AB - OBJECTIVE: The purpose of this study was to determine parents' knowledge about pediatric fluoroscopic procedures and potential risk from ionizing radiation before and after being given an informational brochure. SUBJECTS AND METHODS: We reviewed responses from 120 randomly selected participants who were parents or guardians of pediatric patients undergoing diagnostic fluoroscopic examinations. A questionnaire assessed participants' knowledge of the procedure, radiation exposure, and whether their child had a prior examination before and after receiving an informational brochure. In a feedback survey, participants rated the brochure. A repeated measures mixed model was used to evaluate the effect of the brochure on the participants' knowledge. RESULTS: Participant demographics were women (79%), English speaking (99%), white (90%), and education higher than 12th grade (76%). The median age of patients undergoing the fluoroscopic examination was 4 years. Participant knowledge increased (p < 0.0001) between pre- and postbrochure (least-squares means) for those without a previous examination from 38.3 to 63.4 (total test score) and from 46.3 to 61.8 for those with a prior examination. The proportion of correct answers was higher (p < 0.0001) postbrochure compared with pre-brochure in areas of examination name (99% vs 93%), procedure details (97% vs 87%); use of radiation (100% vs 68%), and radiation dose comparison (79% vs 25%). Overall, 99% (119/120) rated the brochure "good" or "great" (p < 0.0001). CONCLUSION: An informational brochure given to participants before their child's fluoroscopic procedure improved their knowledge of the examination and radiation exposure. No participants refused their child's examination. PMID- 25539283 TI - Effects of improving teachers' content knowledge on teaching and student learning in physical education. AB - PURPOSE: The purpose of this study was to examine the efficacy of a content knowledge (CK) workshop on the enacted pedagogical content knowledge (PCK) of teachers and in turn the effects on student learning. METHOD: A quasiexperimental design was used to examine 4 questions: (a) How does student learning differ as a function of PCK? (b) How does teachers' selection of tasks differ in teaching as a function of CK? (c) How does teachers' representation of tasks differ in teaching as a function of CK? (d) How does teachers' adaptation of tasks differ in teaching as a function of CK? In examining student learning, 2 statistical analyses were employed using correct trials and incorrect trials as dependent measures, respectively. Analyses of variance were conducted examining the effects of the intervention on students' percentage of correct or incorrect trials. The analyses consisted of independent variables, including teachers as a block, treatment, class nested within conditions, gender, skill levels, and 2-way interactions among treatment conditions, gender, and skill levels. RESULTS: A statistically significant effect was reported for both analyses. Effect sizes were .63 and .67, indicating a moderate-to-high practical difference between groups in favor of the experimental condition. Large effect size differences (>2.0) were found for teacher PCK behaviors. There were no interaction effects. CONCLUSION: Our findings show that the enacted PCK of a teacher can be changed from immature to mature as a function of learning CK and that this change has a significant and meaningful impact on student learning. PMID- 25539282 TI - Advances in pharmacotherapy for opioid-induced constipation - a systematic review. AB - INTRODUCTION: Opioid-induced constipation (OIC) is one of the most frequent and burdening adverse events (AE) of opioid therapy. This systematic review aimed to evaluate efficacy and safety of drugs in randomized controlled trials (RCTs) with adult OIC patients. AREAS COVERED: Efficacy assessment focused on objective outcome measures (OOMs): bowel movement (BM) frequency, BM within 4 h and time to first BM. Twenty-one studies examining seven drugs were identified. Methylnaltrexone showed improvements in all three OOMs. RCTs in naloxone and alvimopan tended to be effective for BM frequency measures. Naloxegol (>= 12.5 mg) improved all OOMs. Though effectiveness of lubiprostone was demonstrated for all OOMs, group differences were small to moderate. CB-5945 and prucalopride tended to increase BM frequency, especially for 0.1 mg twice daily and 4 mg daily, respectively. Besides nausea and diarrhea, abdominal pain was the most frequent AE for all drugs (risk ratio, range: 1.52 - 5.06) except for alvimopan. Treatment-related serious AEs were slightly higher for alvimopan (cardiac events) and prucalopride (severe abdominal pain, headache). Pain scores for placebo and intervention groups were similar for all drugs. EXPERT OPINION: Finding a consensus definition and inclusion criteria for OIC plus a rational balance between efficacy and AEs of drugs remain future challenges. PMID- 25539284 TI - Novel investigational therapeutics for panic disorder. AB - INTRODUCTION: Panic disorder (PD) is a common disabling anxiety disorder associated with relevant social costs. Effective anti-panic medications exist but have several drawbacks. From a clinical perspective, there is still a strong unmet need for more effective, faster acting and more tolerable therapeutic treatments. AREAS COVERED: The authors review the available results on novel mechanism-based anti-panic drugs that are under investigation in animal studies up to Phase II studies. The preclinical studies investigated include: the modulators of the glutamate/orexin/cannabinoid systems, corticotrophin-releasing factor 1 (CRF1)/arginine vasopressine V1B/angiotensin II receptor antagonists and neuropeptide S. The Phase I/II studies investigated include: the modulators of the glutamate system, isoxazoline derivative, translocator protein (18 kDa) ligands and CRF1/neurokinin receptor antagonists. EXPERT OPINION: There has been little progress in recent times. However, glutamate- and orexin-related molecular targets may represent very promising opportunities for treating panic attacks. Very preliminary findings suggest that the antagonists of CRF1 and A-II receptors may have anti-panic properties. However, new medications for PD are far from being implemented in clinical use. The reasons are multiple, including: the heterogeneity of the disorder, the translational validity of animal models and the insufficient use of biomarkers in preclinical/clinical studies. Nevertheless, biomarker-based strategies, pharmacogenomics, 'personalized psychiatry' and the NIH's Research Domain Criteria approach could help to remove those obstacles limiting drug development. PMID- 25539286 TI - Advancing sexual health through human rights: the role of the law. AB - Since the International Conference on Population and Development, definitions of sexuality and sexual health have been greatly elaborated alongside widely accepted recognition that sexual health requires respect, protection and fulfilment of human rights. Considerable progress has also been made in enacting or changing laws that affect sexuality and sexual health, in line with human rights standards. These measures include legal guarantees against non discrimination and violence, decriminalisation of consensual sexual conduct and guaranteeing availability, accessibility, acceptability and quality of sexual health information and services to all. Such legal actions have had positive effects on health and specifically on sexual health, particularly for marginalised populations. Yet in all regions of the world, laws still exist which jeopardise health, including sexual health, and violate human rights. In order to ensure accountability for the rights and health of their populations, states have an obligation to bring their laws into line with international, regional and national human rights standards. These rights-based legal guarantees, while insufficient alone, are essential for effective systems of accountability, achieving positive sexual health outcomes and the respect and protection of human rights. PMID- 25539287 TI - Changes in the content of free and conjugated polyamines during Lettuce (Lactuca sativa) growth. AB - Polyamines (PAs) in plant foods are relevant due to the association of these bioactive nutrients with health and disease. The scope of the present study was to monitor the content of free, conjugated, and total (free + conjugated) putrescine (Put), spermidine (Spd), and spermine (Spm) at five stages of lettuce growth in three different greenhouses. The daily intake of PAs from lettuce consumption was estimated since its consumption represents about 7.2% of vegetables intake. Results showed that the content of free Put, Spd, and Spm decreased during plant growth, while the content of conjugated Put, Spd, and Spm increased. Nevertheless, the total PA content remained fairly constant. Significant differences were observed in the PAs content in lettuces grown in different greenhouses. The conjugated fraction of PAs in mature lettuces has an important contribution to the total PAs and will certainly influence the bioavailability and/or bioactivity of dietary polyamines. PMID- 25539285 TI - Serum Bilirubin and Disease Progression in Mild COPD. AB - BACKGROUND: COPD is a chronic inflammatory disorder associated with oxidative stress. Serum bilirubin has potent antioxidant actions, and higher concentrations have been shown to protect against oxidative stress. The relation between serum bilirubin and COPD progression is unknown. METHODS: Serum bilirubin was measured in 4,680 smokers aged 35 to 60 years old with mild to moderate airflow limitation. The relationship of serum bilirubin to postbronchodilator FEV1 and rate of FEV1 decline over 3 to 9 years was determined using regression modeling. Total and disease-specific mortality were also ascertained. RESULTS: Serum bilirubin was positively related to FEV1 (P < .001). Serum bilirubin was also negatively related to the annual decline in FEV1 when adjusted for baseline demographics, pack-years smoked, and baseline measures of lung function (P = .01). Additionally, serum bilirubin was negatively associated with risk of death from coronary heart disease (P = .03); however, the relationships between bilirubin and other mortality end points were not statistically significant (P > .05). CONCLUSIONS: Bilirubin is inversely related to COPD disease severity and progression. Higher serum bilirubin concentration was associated with a higher FEV1 and less annual decline in FEV1. Bilirubin was also associated with less coronary heart disease mortality. These data support the hypothesis that bilirubin has a protective effect on COPD disease progression, possibly through its antioxidant actions. Bilirubin may prove useful as an easily accessible and readily available blood-based COPD biomarker. PMID- 25539288 TI - Extended-release and long-acting opioids for chronic pain management. PMID- 25539289 TI - General pharmacology of long-acting, extended-release, and sustained-release opioids for the treatment of chronic nonmalignant pain. PMID- 25539290 TI - Specific pharmacology of long-acting, extended-release, and sustained-release opioids for the treatment of chronic nonmalignant pain. PMID- 25539291 TI - Case studies of long-acting, extended-release, and sustained-release opioids for the treatment of chronic nonmalignant pain. PMID- 25539292 TI - Predicting and managing donor-site wound complications in abdominally based free flap breast reconstruction: improved outcomes with early reoperative closure. AB - BACKGROUND: The purpose of this study was to (1) determine risk factors predictive of delayed abdominal healing; (2) determine characteristics that perpetuate progression to chronic abdominal wounds and describe the resultant morbidity; and (3) identify outcomes and cost following two treatment strategies conservative wound care and early reoperative primary closure. METHODS: Patients were identified from a database of abdominally based free flaps performed from January of 2005 through July of 2012. RESULTS: One thousand two hundred eighteen abdominal donor sites were reviewed, and 167 cases (13.7 percent) of delayed abdominal wound healing were identified. Obesity (p < 0.0001), smoking (p = 0.043), bilateral reconstruction (p = 0.006), preoperative chemotherapy (p = 0.006), and abdominal mesh (p = 0.028) were independently associated with delayed healing. Initiation of chemotherapy p < 0.0001), wet-to-dry wound care (p = 0.001), negative-pressure wound therapy (p = 0.002), and flap type (p = 0.047) were predictive of chronic wounds, and such wounds generated higher rates of hospital readmission (p = 0.009), mesh complications (p < 0.001), and hernia/bulge (p = 0.006). Patients who underwent delayed primary wound closure were more likely to have a well-healed abdomen within 1 month (90.9 percent versus 24.2 percent; p < 0.0001), resulting in lower cost, fewer hospital readmissions, lower rates of scar revision, and lower rates of mesh complications/hernia/bulge. CONCLUSIONS: Chronic abdominal wounds were associated with abdominal wall sequelae, including hernia. Early reoperative primary wound closure has been successfully and selectively implemented, resulting in improved patient outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25539294 TI - The short-scar periareolar inferior pedicle reduction technique in severe mammary hypertrophy. AB - BACKGROUND: Reduction mammaplasty in severe mammary hypertrophy is challenging to even the very experienced plastic surgeon. Extremely long pedicles threaten blood supply, and the severely stretched skin envelope is difficult to effectively shape and reduce. In this setting, free-nipple techniques and inverted-T pattern skin resections are often used. METHODS: A retrospective review of 88 consecutive patients undergoing breast reduction with the removal of at least 1000 g of tissue in at least one breast over a 17-year period was performed. Patient demographics, comorbidities, and complications were noted during routine postoperative care. RESULTS: One hundred forty breasts in 88 patients were noted to meet the study criteria. The mean body mass index of the patients was 37 kg/m (range, 24 to 57 kg/m), and 89 percent of the patients were categorized as obese. The mean volume of resection was 1336 g (range, 1000 to 3144 g). Mean follow-up was 10 months (range, 1 to 96 months). There was a 16.4 percent incidence of minor delayed healing along with a 2.9 percent incidence of partial areolar necrosis, which was treated conservatively and allowed to heal by secondary intention. There was a 5.7 percent reoperation rate related to excisional biopsy of fat necrosis in 4.3 percent and revision of periareolar scar in 1.4 percent. CONCLUSION: Combining an inferior pedicle approach with a circumvertical skin pattern in the setting of severe mammary hypertrophy is a safe and effective technique for breast reduction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539293 TI - Poly implant prothese asymmetrical anatomical breast implants: a product recall study. AB - BACKGROUND: In 2010 high rupture rates were unexpectedly found among prostheses produced by the French manufacturer Poly Implant Prothese. Since then, several studies have been performed concerning the round implants, but there are still few data available on anatomical implants. METHODS: From 2003 to 2006 Poly Implant Prothese implants were employed at the authors' institute for immediate or delayed reconstruction after mastectomy. All implants were anatomical and asymmetrical. In November of 2010, the authors began offering free consultation with a plastic surgeon and radiologist. Demographic data, type of reconstruction, implant lifespan, indications for implant removal, and rupture rate were recorded. RESULTS: A total of 578 women underwent postmastectomy immediate or delayed reconstruction with 658 Poly Implant Prothese implants from 2003 to 2006 at the authors' institute. The authors explanted 409 of 443 prostheses, and 34 were explanted at other centers. Eighty-nine patients died and 120 are alive with the implants in place. The mean implant lifespan was 57.5 months, 76 ruptured implants were explanted (18.5 percent), and in 22 cases (5.4 percent), leakage of silicone gel was detected. CONCLUSIONS: Poly Implant Prothese implant failure is to be ascribed to shell structure, although the primary safety issue concerned the gel (an industrial-grade and low-cohesive silicone). These issues produce the known rupture rates in the manufacturer's round implants. The authors' use of only anatomical and asymmetrical implants, with their more cohesive silicone gel and more rigid shell allowing a stable form and projection along with a natural feel and touch, probably reduces the rupture rate and silicone spread, although these events remain unacceptably high compared with similar products of other brands. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539295 TI - Which breast is the best? Successful autologous or alloplastic breast reconstruction: patient-reported quality-of-life outcomes. AB - BACKGROUND: Breast reconstruction is an appropriate option offered to women who are diagnosed with breast cancer or gene mutations. It may be accomplished with implants or autologous procedures. This cross-sectional study evaluated the satisfaction and quality of life in addition to complications and secondary corrections in women after successful autologous or alloplastic (implant) breast reconstruction. METHODS: Women were included after successful breast reconstruction. The BREAST-Q instrument and standardized questionnaires on depression, recurrence concerns, and anxiety were sent by mail to the participants. In addition, data were collected on complications and secondary corrections. Multiple regression analysis and chi-square tests were applied to evaluate differences between the autologous breast reconstruction group (n = 47) and the implant breast reconstruction group (n = 45). RESULTS: Women with a successful autologous reconstruction were significantly more satisfied with their reconstructed breasts than women with successful alloplastic breast reconstruction as measured with the BREAST-Q satisfaction with breasts module (p = 0.023). More women with an autologous breast reconstruction required secondary correction than women with an implant breast reconstruction (p = 0.012). Other findings did not differ between the two groups. CONCLUSIONS: Autologous breast reconstruction leads to more satisfaction than does implant breast reconstruction, notwithstanding that women with an autologous breast reconstruction more often required a secondary correction. The study found no ideal breast reconstruction suitable for all patients. However, this study may inform patients and medical teams in making decisions about breast reconstruction. This pilot study indicated several questions that we plan to further investigate in a larger prospective study. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25539296 TI - Changes in use of autologous and prosthetic postmastectomy reconstruction after medicaid expansion in New York state. AB - BACKGROUND: With Medicaid expansion beginning in 2014, it is important to understand the effects of access to reconstructive services for new beneficiaries. The authors assessed changes in use of breast cancer reconstruction for Medicaid beneficiaries after expansion in New York State in 2001. METHODS: The authors used the State Inpatient Database for New York (1998 to 2006) for all patients aged 19 to 64 years who underwent breast reconstruction. An interrupted time series design with linear regression modeling evaluated the effect of Medicaid expansion on the proportion of breast reconstruction patients that were Medicaid beneficiaries. RESULTS: The proportion of breast reconstructions provided to Medicaid beneficiaries increased by 0.28 percent per quarter after expansion (p < 0.001), resulting in a 5.5 percent increase above predicted trajectory without expansion. This corresponds to a population-adjusted increase of 1.8 Medicaid cases per 1 million population per quarter. On subgroup analysis, there was no significant increase in the proportion of autologous reconstructions (p = 0.4); however, the proportion of prosthetic reconstructions for Medicaid beneficiaries had a significant increase of 0.41 percent per quarter (p < 0.001), resulting in a 7.5 percent cumulative increase. This indicates that 135 additional prosthetic reconstruction operations were provided to Medicaid beneficiaries within 5 years of expansion. CONCLUSIONS: Surgeons increased the volume of breast reconstructions provided to Medicaid beneficiaries after expansion. However, there are disparities between autologous and prosthetic reconstruction. If Medicaid expansion is to provide comprehensive care, with adequate access to all reconstructive options, these disparities must be addressed. PMID- 25539297 TI - Tuberous breast deformity: classification and treatment strategy for improving consistency in aesthetic correction. AB - BACKGROUND: Tuberous breast deformity is a common congenital anomaly with varying degrees of constriction, hypoplasia, skin deficiency, areolar herniation, and asymmetry that poses challenges to consistency in aesthetic correction. In this study, the authors classify tuberous breast deformities, and evaluate their techniques used for treatment. METHODS: Twenty-six patients (51 breasts) treated from 2008 to 2012 were included. Mean patient age was 25 years (range, 18 to 39 years). Cases were classified using a three-tier system. A periareolar approach and glandular scoring maneuvers were used in all cases. Prosthetic placement (implant or tissue expander) was subpectoral (dual-plane) in all cases. The selection of one- versus two-stage correction and mastopexy techniques is presented with reference to the specific deformities in each tier. RESULTS: Mean follow-up was 22 months (range, 8 to 37 months). Twelve type I, 26 type II, and 13 type III deformities were treated. Periareolar incisions only were used in two (4 percent). Circumareolar mastopexy was used in 49 (96 percent), and vertical mastopexy was used in four (8 percent). One-stage correction was achieved in 47 (92 percent); four (8 percent) were treated in two stages with tissue expansion. The global complication rate for all patients in this study is 7.8 percent-two breasts (3.9 percent) had capsular contracture, and two (3.9 percent) had postoperative malposition. CONCLUSION: The authors' experience demonstrates that satisfactory results can be obtained with appropriate classification and treatment of tuberous breast deformity with periareolar access, glandular scoring, subpectoral implant placement, and mastopexy techniques tailored to the specific deformity type. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539298 TI - Outcomes in primary breast augmentation: a single surgeon's review of 1539 consecutive cases. AB - BACKGROUND: The use of implants in aesthetic breast surgery may lead to complications resulting in the need for reoperation. This study examines outcomes following breast augmentation in a single surgeon's practice and investigates the effect of implant selection and surgical technique on complications and reoperations. METHODS: A retrospective review of a single surgeon's prospectively maintained database over 15 years was performed. All primary bilateral breast augmentation patients were included. Implant characteristics-including implant type, fill, shape, surface, and projection; incision type; and pocket location were collected. Complications and reasons for reoperation were analyzed using survival analysis. RESULTS: One thousand five hundred thirty-nine patients with 3078 implants were included. Implant types included 596 shaped textured gel, 515 round smooth saline, 192 round textured gel, and 236 round smooth gel implants. Follow-up ranged from 0 to 155 months (average, 18 months). Total complication and reoperation rates were 6.8 and 7.7 percent, respectively. Inframammary incisions and the use of shaped textured gel implants were associated with lower rates of complications. The use of a dual-plane II or III pocket, and implant volumes over 400 cc, were associated with higher rates of complications. Full projection round implants had rates of complications and reoperations equivalent to those of moderate-projection devices. Both textured shaped gel implants and a subpectoral pocket location were associated with the lowest rates of capsular contracture. CONCLUSION: This large series of breast implant patients demonstrates that both implant- and technique-related factors may influence complications and reoperations in breast implant surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539299 TI - Medial thigh lift in the massive weight loss population: outcomes and complications. AB - BACKGROUND: Complication profiles of medial thighplasty in the massive weight loss population are not well described. The authors present their experience with these procedures in the massive weight loss population. METHODS: Thighplasty patients from 2003 to 2012 were assessed. Variables included age, sex, body mass index, method of weight loss, comorbidities, and smoking status. Outcomes included seroma, dehiscence, infection, hematoma, edema, and revision. Statistical analysis was performed as appropriate. RESULTS: One hundred six subjects (90 women and 16 men) underwent thighplasty. Fourteen patients underwent horizontal thighplasty, with a complication rate of 43 percent; 24 underwent short-scar thighplasty, with a complication rate of 67 percent; and 68 underwent full-length vertical thighplasty, with a complication rate of 74 percent. Seventy two subjects (68 percent) had at least one complication. Complications included dehiscence (51 percent), seroma (25 percent), infection (16 percent), and hematoma (6 percent). Overall, 25 patients (23 percent) developed edema, which did not resolve in two patients by 12 months. Hypertension was significantly associated with postoperative seroma (p = 0.02). Age (p = 0.01), hypothyroidism (p = 0.01), and liposuction outside the area of resection (p = 0.025) were associated with postoperative infections. A full-length vertical incision was associated with increased lower extremity edema (p = 0.007). CONCLUSIONS: Medial thighplasty has a high rate of minor wound healing problems. Full-length vertical thighplasty is associated with prolonged edema. Concomitant liposuction may also increase complications. Patients should be counseled appropriately about the potential for minor wound healing problems. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25539300 TI - The pythagorean theorem as a tool for preoperative planning of a concealed scar in augmentation mammaplasty with round implants. AB - SUMMARY: The inframammary incision is the most versatile and popular approach in breast augmentation. For an optimal aesthetic result, the incision site should be chosen in such a way that the scar is carefully hidden in the (new) inframammary fold. Based on an assumption of the senior author (B.v.d.L.) that the Pythagorean theorem (alpha + beta = gamma) is suited to describe the ratios of implant and incision location variables, the authors developed an almost perfect roadmap for accurate determination of the right incision location in augmentation mammaplasty with round implants through the inframammary incision. The authors plenary judged the photographs of 263 augmented breasts whether the scar of the augmentation mammaplasty was located in the neo-inframammary fold. In all cases, the Pythagorean theorem was used to determine the exact location of the site of incision. In only four of the 263 augmented breasts (1.5 percent), the position of the scar was a little below the neo-inframammary fold and thereby visible with the patient in the upright position. A scar correction to reposition the scar into the inframammary fold was performed in one patient on one breast by means of additional skin excision above the scar; in the two other cases, the scar was accepted by the patients as being not too bothersome. The Pythagorean theorem is an effective method for determining the right incision site in augmentation mammaplasty with round implants through an inframammary approach. PMID- 25539301 TI - Textured silicone breast implant use in primary augmentation: core data update and review. AB - Evolution of silicone breast implant design has focused primarily on advances in implant fill, surface texture, and shape. Fifth-generation, shaped, form-stable, silicone breast implants from all three major implant manufacturers are now approved for use by the U.S. Food and Drug Administration in the United States. As part of this approval, the U.S. Food and Drug Administration mandated Core Study follow-up of silicone implants for 10 years after premarket approval. An updated and comprehensive collection of Core data from all three manufacturers is presented in this review. In addition, cause and rates of capsular contracture, seroma, rippling, and malposition are discussed. New concepts such as tissue friction coefficient are discussed that may influence outcome after primary breast augmentation. The theoretical advantages and disadvantages of the various textured surfaces ranging from microtexturing to macrotexturing are presented in relation to breast tissue incorporation. PMID- 25539302 TI - Alternatively activated M2 macrophages improve autologous Fat Graft survival in a mouse model through induction of angiogenesis. AB - BACKGROUND: Variability in graft retention with subsequent undercorrection remains a significant limitation of autologous fat grafting. The authors evaluated whether graft retention in a mouse model could be improved via graft supplementation with alternatively activated M2 macrophages, cells known to play a critical role in tissue repair. METHODS: Grafts from C57BL/6 mouse inguinal fat pads were supplemented with M2 macrophages generated by intraperitoneal Brewer's thioglycollate injection and in vitro culture. Grafts with saline or M2 macrophages were injected under recipient mouse scalps and assessed by serial micro-computed tomographic analysis. Explanted grafts underwent immunohistochemical and flow cytometric analyses. M2 culture supernatants were added to stromal vascular fraction adipose-derived stem cells to assess adipogenic gene expression induction. RESULTS: One month after graft injection, no significant difference was noted between M2 macrophage-supplemented (105 +/- 7.0 mm) and control graft volumes (72 +/- 22 mm). By 3 months after injection, M2 macrophage-supplemented grafts remained stable, whereas controls experienced further volume loss (103 +/- 8 mm versus 39.4 +/- 15 mm; p = 0.015). Presence of macrophages in supplemented grafts was confirmed by flow cytometry. M2 macrophage supplemented grafts exhibited a 157 percent increase in vascular density compared with controls (p < 0.05). Induction of adipogenic C/EBPalpha gene expression was observed with M2 supernatants addition to stromal vascular fraction adipose derived stem cells. CONCLUSIONS: M2 macrophages improve autologous fat graft volume retention by stimulating angiogenesis. These findings provide proof-of principle for development of fat grafting techniques that harness reparative properties of M2 macrophages. PMID- 25539303 TI - Topical delivery of ultrahigh concentrations of gentamicin is highly effective in reducing bacterial levels in infected porcine full-thickness wounds. AB - BACKGROUND: Injury to the skin can predispose individuals to invasive infection. The standard of care for infected wounds is treatment with intravenous antibiotics. However, antibiotics delivered intravenously may have poor tissue penetration and be dose limited by systemic side effects. Topical delivery of antibiotics reduces systemic complications and delivers increased drug concentrations directly to the wound. METHODS: Porcine full-thickness wounds infected with Staphylococcus aureus were treated with ultrahigh concentrations (over 1000 times the minimum inhibitory concentration) of gentamicin using an incubator-like wound healing platform. The aim of the present study was to evaluate clearance of infection and reduction in inflammation following treatment. Gentamicin cytotoxicity was evaluated by in vitro assays. RESULTS: Application of 2000 MUg/ml gentamicin decreased bacterial counts in wound tissue from 7.2 +/- 0.3 log colony-forming units/g to 2.6 +/- 0.6 log colony-forming units/g in 6 hours, with no reduction observed in saline controls (p < 0.005). Bacterial counts in wound fluid decreased from 5.7 +/- 0.9 log colony-forming units/ml to 0.0 +/- 0 log colony-forming units/ml in 1 hour, with no reduction observed in saline controls (p < 0.005). Levels of interleukin-1beta were significantly reduced in gentamicin-treated wounds compared with saline controls (p < 0.005). In vitro, keratinocyte migration and proliferation were reduced at gentamicin concentrations between 100 and 1000 MUg/ml. CONCLUSIONS: Topical delivery of ultrahigh concentrations of gentamicin rapidly decontaminates acutely infected wounds and maintains safe systemic levels. Treatment of infected wounds using the proposed methodology protects the wound and establishes a favorable baseline for subsequent treatment. PMID- 25539304 TI - Surgical treatment of distal digit amputation: success in distal digit replantation is not dependent on venous anastomosis. AB - BACKGROUND: Although digit amputation at or distal to the distal interphalangeal joint is a common injury, it remains a challenging problem to restore digital length and pulp because of the lack of healthy vessels and the absence of proper vascular size for reanastomosis. The purpose of the present study was to review the authors' clinical experience with distal digital replantation and to test the hypothesis that success in distal digit replantation is not dependent on venous anastomosis. METHODS: Twenty-eight patients with 31 complete distal digit amputations were included in the study. Data regarding patient demographic, replantation technique, and surgical outcome were analyzed. RESULTS: Sixteen digits were replanted with arterial and venous anastomoses (group A). Eleven digits were replanted with only arterial anastomosis (group B). Composite grafting was performed in four digits without vascular anastomosis (group C). The success rates in group A and group B were 81.3 and 81.8 percent, respectively. None of the composite grafts survived. Fisher's exact test was used for statistical analysis. Although group C has the lowest survival rate (p < 0.05), the differences between the survival rates in group A and group B (p > 0.05) were insignificant. CONCLUSIONS: The overall success rate of distal digit replantations in the authors' series was 81 percent, and there were no differences in the survival rates between replantations with and without venous anastomosis. Finally, the authors conclude that success in distal digit replantation is not dependent on venous anastomosis and suggest that replantation should be encouraged in complete distal digital amputation, even without venous anastomosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25539305 TI - The effect of residency and fellowship type on hand surgery clinical practice patterns. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education requires accredited fellowship programs to exhibit proficiency in six broadly defined domains; however, core competencies specifically mandated for hand surgery training have yet to be established. Several studies have demonstrated significant disparities in exposure to essential skills and knowledge between orthopedic surgery- and plastic surgery-based hand surgery fellowship programs. To determine whether significant discrepancies also exist after fellowship between hand surgeons trained in orthopedic surgery and those trained in plastic surgery, clinical practice patterns were evaluated. METHODS: A 20-question survey was created and distributed electronically to American Society for Surgery of the Hand and American Association for Hand Surgery members. Responses were compared using descriptive statistics. RESULTS: Nine hundred eighty-two hand surgeons (76 percent orthopedic and 24 percent plastic) responded, representing a 39 percent response rate. Most plastic surgery hand practices were academic-based (41 percent), whereas orthopedic practices were private (67 percent). More orthopedic hand surgeons worked in multipractitioner practices than plastic surgeons (54 percent versus 30 percent; p < 0.0001). Orthopedic hand surgeons performed a higher percentage of hand cases in their practice facilities (86 percent versus 71 percent; p < 0.0001). Plastic surgeons performed more congenital hand (56 percent versus 35 percent; p < 0.05) and digital replantation cases (53 percent versus 22 percent; p < 0.05) but treated significantly fewer open reduction and internal fixation distal radius fractures. CONCLUSIONS: Orthopedic and plastic surgery hand surgeons differ significantly in their clinical practice patterns. Differences in clinical exposure during training are reflected in practice and persist over time. Referral patterns and practice situations are also contributors to ultimate practice patterns. PMID- 25539306 TI - Comparative effectiveness studies examining patient-reported outcomes among children with cleft lip and/or palate: a systematic review. AB - BACKGROUND: Health care policy makers are increasingly encouraging comparative effectiveness research. Little is known regarding comparative studies among children with cleft lip and/or palate. Cleft lip and/or palate profoundly influences self-perception and social functioning, and patient-reported outcomes provide a unique perspective on the success of reconstruction. The purpose of this study was to systematically review the literature regarding patient-reported outcomes among patients with cleft lip and/or palate. METHODS: The authors reviewed articles from MEDLINE, Embase, and PsycInfo that examined the use of patient-reported outcome instruments for cleft lip and/or palate. Studies of patients with cleft lip and/or palate across any age that described the use of patient-completed measures in patient and control populations were included. A research librarian confirmed the search, and two independent, blinded reviewers performed full-text review. RESULTS: The authors identified 1979 articles and selected 30 for inclusion. Forty-two different assessment tools were used to analyze factors such as self-esteem, behavior, and social support. The Strengths and Difficulties Questionnaire was most commonly used (n = 7), followed by the Childhood Experience Questionnaire (n = 5), and the Satisfaction with Appearance survey (n = 4). Barriers to analysis included lack of standardization of survey administration, effect of publication bias, and variations in patient populations between individual studies. CONCLUSIONS: Comparative studies of patient-reported outcomes among patients with cleft lip and/or palate are infrequent. Many instruments exist to measure patient-reported outcomes in this population, but no specific standard exists. Identifying efficient and targeted forms of instrument selection and administration will enhance comparative studies among children with cleft lip and/or palate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, III. PMID- 25539307 TI - Parental health and social support in the first trimester of pregnancy and the risk of oral clefts: a questionnaire-based, case-control study. AB - BACKGROUND: Nonsyndromic oral clefts are complex in cause and have multiple genetic and environmental risk factors. This retrospective, questionnaire-based, case-control study investigated the relationship between oral clefts and parental mental and physical health and social support. METHODS: Three hundred forty-seven parents of children with nonsyndromic oral clefts and 420 controls were included. Maternal and paternal health during the first trimester was assessed using interviews and questionnaires modeled from the Cornell Medical Index and the Social Support Rating Scale. Case-control analyses were performed using t tests, chi-square tests, and logistic regression. RESULTS: Parental age, household income, and subsisting on farming were significantly different for cases and controls. The Cornell Medical Index for cases was significantly worse compared with controls for physical and psychological health. Logistic regression showed that nine factors were significantly associated with oral clefts: paternal respiratory health (OR, 1.56; p = 0.03), maternal gastrointestinal health (OR, 1.71; p < 0.01), maternal musculoskeletal health (OR, 1.50; p < 0.01), paternal nervous system health (OR, 2.82; p < 0.01), maternal frequency of illness (OR, 2.21; p = 0.01), maternal diseases (OR, 2.44; p < 0.01), maternal health habits (OR, 1.73; p < 0.01), paternal feelings of inadequacy (OR, 2.28; p = 0.03), and maternal anger (OR, 2.28; p < 0.01) in the first trimester. Weaker social support from the community was associated with oral clefts (p < 0.01). CONCLUSION: Maternal and paternal health and social support may affect a family's risk of having a child with a cleft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25539309 TI - Armadillo cranioplasty for expansion and remodeling in craniosynostosis. AB - Craniosynostosis is typically treated in the first year of life, when osteogenic potential is high and residual obligate skull defects heal. Delayed reconstruction can result in persistent skull defects because of diminished osteogenic potential. Adequately expanding the cranium yet minimizing residual skull defects in older patients presents a conundrum. Although secondary cranioplasty can be performed, primary cortical bone coverage is preferred. The authors present a technique of cranial expansion by sliding stairstep osteotomies, thus preventing residual skull defects when treating craniosynostosis at an advanced age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539308 TI - A critical evaluation of long-term aesthetic outcomes of fronto-orbital advancement and cranial vault remodeling in nonsyndromic unicoronal craniosynostosis. AB - BACKGROUND: This study reports long-term aesthetic outcomes with fronto-orbital advancement and cranial vault remodeling in treating unicoronal synostosis over a 35-year period. METHODS: Retrospective review was performed on patients with isolated unicoronal synostosis from 1977 to 2012. Demographic, preoperative phenotypic, and long-term aesthetic outcomes data were analyzed with chi-squared and Fisher's exact test for categorical data and Wilcoxon rank-sum and Kruskal Wallis rank for continuous data. RESULTS: A total of 238 patients were treated; 207 met inclusion criteria. None underwent secondary intervention for intracranial pressure. At definitive intervention, there 96 (55 percent) Whitaker class I patients, 11 (6 percent) class II, 62 (35 percent) class III, and six (3 percent) class IV. Nasal root deviation and occipital bossing each conferred an increased risk of Whitaker class III/IV [OR, 4.4 (1.4 to 13.9), p = 0.011; OR, 2.6 (1.0 to 6.8), p = 0.049]. Patients who underwent bilateral cranial vault remodeling with extended unilateral bandeau were less likely Whitaker class III/IV at latest follow-up compared with those undergoing strictly unilateral procedures [OR, 0.2 (0.1 to 0.7), p = 0.011]. Overcorrection resulted in decreased risk of temporal hollowing [OR, 0.3 (0.1 to 1.0), p = 0.05]. Patients with 5 years or more of follow-up were more likely to develop supraorbital retrusion [OR, 7.2 (2.2 to 23.4), p = 0.001] and temporal hollowing [OR, 3.7 (1.5 to 9.6), p = 0.006] and have Whitaker class III/IV outcomes [OR, 4.9 (1.8 to 12.8), p = 0.001]. CONCLUSION: Traditional fronto-orbital advancement and cranial vault remodeling appears to mitigate risk of intracranial pressure but may lead to aesthetic shortcomings as patients mature, namely fronto-orbital retrusion and temporal hollowing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539310 TI - Cost analysis of conventional face reconstruction versus face transplantation for large tissue defects. AB - BACKGROUND: Large facial tissue defects are traditionally treated with staged conventional reconstruction. Facial allograft transplantation has emerged as a treatment modality. Facial allografts are procured from a dead donor and transplanted to the recipient. Recipients are then subjected to lifelong global immunosuppression to prevent immunologic rejection. This study analyzes the cost of facial allograft transplantation in comparison with conventional reconstruction. METHODS: Hospital billing records from facial allograft transplantation (2009 to 2011) and conventional reconstruction (2000 to 2010) patients were compiled. Comparative 1-year costs were calculated, segregated by physician, hospital, and hospital's department costs. Because most conventional reconstruction patients had smaller facial deficits than their facial allograft transplantation counterparts, regression models were used to estimate costs of conventional reconstruction for full facial defects, mirroring the facial transplantation cohort. All costs were adjusted using the medical consumer price index. RESULTS: One-year costs for facial allograft transplantation were significantly higher than those for conventional reconstruction (mean/median, $337,360/$313,068 versus $70,230/$64,451, respectively). One-year costs for a hypothetical full-face conventional reconstruction were $184,061 (95 percent CI, $89,358 to $278,763). The per-patient cost in a hypothetical cohort of conventional reconstruction patients with deficits identical to four facial allograft transplantation recipients was $155,475 (95 percent CI, $69,021 to $241,929). CONCLUSIONS: Initial cost comparison portrays facial allograft transplantation as significantly more costly than conventional reconstruction. However, after adjustments for case severity, the cost profiles are similar. Gains in efficiency and experience are expected to lower costs. Additional unmeasured benefits may also positively influence the cost-to-benefit ratio of facial allograft transplantation. PMID- 25539312 TI - Discussion: reverse lymphatic mapping: a new technique for maximizing safety in vascularized lymph node transfer. PMID- 25539311 TI - Simultaneous prosthetic mesh abdominal wall reconstruction with abdominoplasty for ventral hernia and severe rectus diastasis repairs. AB - BACKGROUND: Standard abdominoplasty rectus plication techniques may not suffice for severe cases of rectus diastasis. In the authors' experience, prosthetic mesh facilitates the repair of severe rectus diastasis with or without concomitant ventral hernias. METHODS: A retrospective review of all abdominal wall surgery patients treated in the past 8 years by the senior author (G.A.D.) was performed. Patients with abdominoplasty and either rectus diastasis repair with mesh or a combined ventral hernia repair were analyzed. RESULTS: Thirty-two patients, 29 women and three men, underwent mesh-reinforced midline repair with horizontal or vertical abdominoplasty. Patient characteristics included the following: mean age, 53 years; mean body mass index, 26 kg/m; average width of diastasis or hernia, 6.7 cm; and average surgery time, 151 minutes. There were no surgical site infections and two surgical-site occurrences-two seromas treated with drainage in the office. After an average of 471 days' follow-up, none of the patients had recurrence of a bulge or a hernia. CONCLUSIONS: For patients with significant rectus diastasis, with or without concomitant hernias, the described mesh repair is both safe and durable. Although this operation requires additional dissection and placement of prosthetic mesh in the retrorectus plane, it may be safely combined with standard horizontal or vertical abdominoplasty skin excision techniques to provide an aesthetically pleasing overall result. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539313 TI - Emerging paradigms in perioperative management for microsurgical free tissue transfer: review of the literature and evidence-based guidelines. AB - BACKGROUND: Microsurgical free tissue transfer has become an increasingly valuable technique in reconstructive surgery. However, there is a paucity of evidence-based guidelines to direct management. A systematic review was performed to define strategies to optimize perioperative management. METHODS: A systematic review of the literature was performed using key search terms. Strategies to guide patient management were identified, classified according to level of evidence, and used to devise recommendations in seven categories: patient temperature, anesthesia, fluid administration/blood transfusion, vasodilators, vasopressors, and anticoagulation. RESULTS: A total of 106 articles were selected and reviewed. High-level evidence was identified to guide practices in several key areas, including patient temperature, fluid management, vasopressor use, anticoagulation, and analgesic use. CONCLUSIONS: Current practices remain exceedingly diverse. Key strategies to improve patient outcomes can be defined from the available literature. Key evidence-based guidelines included that normothermia should be maintained perioperatively to improve outcomes (level of evidence 2b), and volume replacement should be maintained between 3.5 and 6.0 ml/kg per hour (level of evidence 2b). Vasopressors do not harm outcomes and may improve flap flow (level of evidence 1b), with most evidence supporting the use of norepinephrine over other vasopressors (level of evidence 1b). Dextran should be avoided (level of evidence 1b), and pump systems for local anesthetic infusion are beneficial following free flap breast reconstruction (level of evidence 1b). Further prospective studies will improve the quality of available evidence. PMID- 25539314 TI - The certificate of added qualifications in microsurgery: consideration for subspecialty certification in microvascular surgery in the United States. PMID- 25539316 TI - Discussion: clinicians performing cosmetic surgery in the community: a nationwide analysis of physician certification. PMID- 25539317 TI - The role of estrogen in the modulation of autologous fat graft outcomes. AB - BACKGROUND: Autologous fat grafting is a widely used procedure, yet the mechanisms that regulate graft outcomes are poorly understood. Estrogen signaling is a potent regulator of lipid handling, inflammation, fibrosis, and adipocyte progenitor recruitment in adipose tissues. To date, no studies have investigated the effect of circulating estrogens on fat graft outcomes. METHODS: Immunosuppressed (Nu/Nu) mice underwent ovariectomy or sham surgery. Forty-five days later, half the mice (donors) were killed, and adipose tissue was taken and transplanted into the remaining cohort (recipients). Forty-five days after transplantation, grafts were dissected, weighed, and assessed for expression of vascular endothelial growth factor, estrogen receptor-alpha, and vascular density. RESULTS: Grafts harvested from and transplanted into sham environments are smaller but more highly vascularized compared with ovariectomy environments. The estrogenic effects on grafts are more critical at the site of the donor tissue than the recipient. Finally, expression of estrogen receptor-alpha in the grafted tissue correlates with the observed graft characteristics, which is altered by both the donor and recipient environments. CONCLUSIONS: Circulating estrogens have significant effects on fat graft outcomes, primarily at the site of the donor tissue. As there are well-established depot-specific estrogenic responses, the choice of adipose depot used as a donor for fat grafting may affect outcomes. In addition, outcomes may be confounded by the patient's hormonal status. Understanding the mechanisms by which estrogen signaling regulates graft outcomes is important in refining this commonly used clinical procedure. PMID- 25539318 TI - Lack of activation of telomere maintenance mechanisms in human adipose stromal cells derived from fatty portion of lipoaspirates. AB - BACKGROUND: Significant improvement in the understanding of mesenchymal stem cell biology paved the way to their clinical use. Human lipoaspirates derived from mesenchymal stem cells (adipose-derived stem cells) continue to draw the attention of researchers in the field of basic and applied research due to their regenerative, reparative, angiogenic, antiapoptotic, and immunosuppressive properties, all of which collectively point out their therapeutic potential. There is still, however, a need for further investigation to improve the knowledge of stem cell biology, to broaden their field of use, and to enhance their therapeutic effectiveness. METHODS: The authors characterized human adipose derived stem cells at different in vitro culture time points in terms of immunophenotype, multilineage differentiation, long-term survival with self renewal capacity, and presence of telomere maintenance mechanisms (telomerase activity and alternative lengthening of telomere) for excluding their eventual susceptibility to malignant transformation. RESULTS: Adipose-derived stem cells were isolated from the abdomen and peritrochanteric region of 31 female donors, propagated, and monitored in vitro for several passages. The outgrown cells shared the biological properties of mesenchymal stem cells, with adherence to plastic, expression of the typical surface markers, and induction of adipogenic, osteogenic, and chondrogenic differentiation. Telomerase activity and alternative lengthening of telomere mechanisms at different passages of cultures were not evidenced. CONCLUSION: The results support the concept that in vitro expanded adipose-derived stem cells obtained from fat tissue are not susceptible to developing one of the hallmarks of malignant transformation and can be considered amenable for cell therapy approaches. PMID- 25539319 TI - Deferoxamine mitigates radiation-induced tissue injury in a rat irradiated TRAM flap model. AB - BACKGROUND: Radiation therapy results in permanent damage to the microvasculature, leading to dermal damage and inelasticity in normal tissues. Deferoxamine is a U.S. Food and Drug Administration-approved iron-chelating medication that has also been shown to increase angiogenesis. The authors hypothesize that the application of deferoxamine will result in increased vascularity and improved tissue elasticity in a rat irradiated transverse rectus abdominis musculocutaneous flap model. METHODS: Fifteen rats underwent a transverse rectus abdominis myocutaneous flap and were randomized to three groups: control, radiation therapy, and radiation therapy plus deferoxamine. The flaps in the radiation therapy and radiation therapy plus deferoxamine groups were irradiated with 35 Gy in a single dose. Four weeks after irradiation, rats in the radiation therapy plus deferoxamine group were treated with deferoxamine. Flaps were imaged with micro-computed tomographic angiography. Flap creep and stress relaxation were assessed using a tensiometer. Hematoxylin and eosin, picrosirius red, and Verhoeff-van Gieson staining was performed. RESULTS: Irradiated flaps demonstrated gross stigmata of cutaneous radiation injury within 4 weeks. Histologically, the epidermis in the radiation therapy flaps was found to be thicker than in the radiation therapy plus deferoxamine and control flaps (p < 0.001). Micro-computed tomographic angiography demonstrated a statistically significant (p < 0.05) increase in vascularity in the radiation therapy plus deferoxamine flaps compared with radiation therapy alone. The creep curve was indicative of increased elasticity in the radiation therapy plus deferoxamine flaps compared with radiation therapy flaps. CONCLUSION: Deferoxamine appears to mitigate radiation-induced hypovascularity and improve tissue elasticity in a rat model of soft-tissue reconstruction. PMID- 25539320 TI - Optimal axon counts for brachial plexus nerve transfers to restore elbow flexion. AB - BACKGROUND: Nerve transfer surgery has revolutionized the management of traumatic brachial plexus injures. However, the optimal size ratio of donor to recipient nerve has yet to be elucidated. The authors investigated the axon count ratios of ulnar and median fascicular transfers to restore elbow flexion. The authors hypothesized that donor nerve axon counts would be correlated with historical success of various nerve transfers used to restore elbow flexion. METHODS: Ten cadaveric specimens were used for a histomorphologic analysis of fascicular nerve transfers. Review of previously published axon counts and clinical results following transfer to the musculocutaneous nerve to restore elbow flexion was performed for the following donor nerves: medial pectoral, spinal accessory, intercostal, thoracodorsal, ulnar, and median fascicular. RESULTS: The average number of fascicles identified was 7.9 in the ulnar nerve and 8.0 in the median nerve. The mean fascicular axon count was 1318 for the ulnar nerve and 1860 for the median nerve. Mean recipient nerve axon count was 1826 for the musculocutaneous biceps branch and 1840 for the brachialis branch. A significant correlation between axon count and clinical results of transfers to restore elbow flexion was observed. Donor-to-recipient nerve axon count ratios below 0.7:1 were associated with a decreased likelihood of a successful outcome. CONCLUSIONS: In nerve transfers to restore elbow flexion, an appropriate size match between donor and recipient nerves appears to be a factor affecting clinical success. These data support a donor-to-recipient axon count ratio greater than 0.7:1 as the goal for brachial plexus nerve transfers to restore elbow flexion. PMID- 25539321 TI - Lateral incisor agenesis predicts maxillary hypoplasia and Le Fort I advancement surgery in cleft patients. AB - BACKGROUND: Severe maxillary hypoplasia in cleft patients is caused by a combination of pathogenic and iatrogenic factors. In this work, the authors investigated anatomical deficiencies in dentition for predicting Le Fort I maxillary advancement surgery for severe maxillary hypoplasia in cleft patients. METHODS: Cleft lip-cleft palate and cleft palate patients older than 14 years of age were reviewed for demographics, dental anomalies, and Le Fort I advancement. Chi-square tests, t tests, and multivariate logistic regression analyses were performed to delineate the contribution of quantity and position of dental agenesis to maxillary advancement surgery. RESULTS: In the 114 patients reviewed (mean age, 19.2 years), 64.0 percent were male patients, 71.9 percent had dental agenesis, and 59.6 percent required Le Fort I advancement. In patients who did not exhibit dental agenesis, 18.8 percent required Le Fort I advancement compared with 74.4 percent of patients with dental agenesis (p < 0.0001). Le Fort I advancement surgery was increased to 76.3 percent when dental agenesis was at the lateral incisor position (p < 0.0001) and 86.4 percent when patients were missing two or more teeth (p < 0.0001). Both sella-to-nasion-to-A point angle (p = 0.003) and A point-to-nasion-to-B point angle (p = 0.04) measurements were decreased in patients missing dentition at the lateral incisor position. Adjusting for multiple missing teeth and orthodontic compensations, multivariate logistic regression analyses demonstrated that lateral incisor agenesis is an independent predictor for Le Fort I advancement surgery (OR, 4.4; 95 percent CI, 1.42 to 13.64; p = 0.01). CONCLUSIONS: Lateral incisor agenesis correlated to maxillary hypoplasia and independently predicted the need for Le Fort I advancement in cleft patients, potentially as an anatomical readout of intrinsic growth deficiency. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25539322 TI - Clarifying the relationships among the different features of the OMENS+ classification in craniofacial microsomia. AB - BACKGROUND: The OMENS+ classification is commonly used to describe the phenotypically diverse craniofacial features of craniofacial microsomia. The purpose of this study was to evaluate associations among the individual components of the OMENS+ criteria. METHODS: An institutional review board approved retrospective chart review was performed for patients who presented with a diagnosis of unilateral or bilateral craniofacial microsomia to the craniofacial clinic from January of 1990 to December of 2012. Demographic, diagnosis, classification, treatment, and radiographic data were abstracted for all patients who met inclusion criteria. Associations and correlations were evaluated using the Spearman rank test and a logistic regression model. RESULTS: One hundred five patients (61 male and 44 female) with craniofacial microsomia met inclusion criteria. Eighty-one patients (77.1 percent) had unilateral microsomia and 24 (22.9 percent) had bilateral microsomia. Twenty-eight patients (26.7 percent) had macrostomia. Correlations were all significantly interrelated (p = 0.000 to p = 00.018) between the degree of orbital, mandibular, and soft tissue deformities. Moreover, the severity of ear deformity and facial nerve involvement were also significantly correlated (p = 0.008). Between these two groupings, there was a significant correlation between soft-tissue deficiency and nerve involvement (p = 0.010). Macrostomia was associated with the individual components of the group orbit (p = 0.008), mandible (p = 0.000), and soft tissue (p = 0.005). CONCLUSIONS: The association between structures using the OMENS+ classification may be caused by their branchial arch origin. Structures mainly developed from the first branchial arch (orbit, mandible, and soft tissue) are associated in degree of severity, as are the structures mainly derived from the second branchial arch (facial nerve and ear). CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25539323 TI - Vascularized proximal fibular epiphyseal transfer for Bayne and Klug type III radial longitudinal deficiency in children. AB - BACKGROUND: Treatment of Bayne and Klug type III radial longitudinal deficiency with fibular epiphyseal transplantation in children has had limited success to date. The purpose of this investigation was to review the authors' results of microvascular epiphyseal transplantation for radial longitudinal deficiency. METHODS: Between 2007 and 2009, four children with a mean age of 4.3 years (range, 3.3 to 5.8 years) who had a type III radial longitudinal deficiency underwent microsurgical reconstruction of the distal radius with vascularized proximal fibular transplantation, including the physis, partial superior tibiofibular joint, and a variable length of the diaphysis. All of the grafts were supplied by the inferior lateral genicular artery. In all patients, the range of motion of the digits, wrist, forearm, and elbow; the length of the forearm; and the deviation of the wrist were evaluated. RESULTS: The mean duration of follow-up was 42 months (range, 24 to 65 months). All four transfers survived and united with the host bone within 3 months postoperatively. An average correction of 28 degrees in the hand-forearm angle was obtained. Forearm length was 67.9 percent that of the normal side on average at the final follow up. The overall range of wrist motion was approximately 55 percent that of the contralateral extremity. No major complications were observed. CONCLUSIONS: Vascularized proximal fibular epiphyseal transfer, based on the inferior lateral genicular artery, is a technically feasible method for treatment of type III radial longitudinal deficiency, which maintains hand-forearm alignment, provides excellent function, and minimizes the length discrepancy between the distal radius and ulna. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25539324 TI - Eyelid transplantation: lessons from a total face transplant and the importance of blink. AB - BACKGROUND: Despite inclusion of periorbital structures in facial transplants, critical assessment of posttransplantation short- and long-term periorbital function has not been reported. The purpose of this article is to report recovery of ocular and periorbital function, with critical appraisal of posttransplant blink in the setting of revision surgery. METHODS: Prospective ocular and periorbital functional assessments were completed at multiple time points in a patient undergoing facial transplantation and subsequent revision operations. Function was evaluated using clinical ocular examinations, visual acuity assessments, photography, and video at various intervals from preoperative baseline to 13.5 months after transplantation. During this period, revision operations involving periorbital structures were performed at 6 and 9 months after transplantation. RESULTS: Before transplantation, volitional blink was 100 percent in both eyes. Involuntary blink was 40 percent in the right eye and 90 percent in the left eye, with occasional full closure. Following face transplantation, voluntary blink was preserved, partial skin sensation was present, and involuntary blink improved to 70 percent in the right eye and 100 percent in the left eye. Following revision surgery, visual acuity and voluntary and involuntary blink were impaired. By 7.5 months after revision, improvement comparable to the pretransplantation assessment was observed. CONCLUSIONS: Adherence to principles of blink preservation is critical in periorbital transplantation. Involuntary blink is essential for preserving vision, and can be improved after transplantation. Revision surgery may temporarily impair advances made with initial allotransplantation. A comprehensive understanding of ocular biomechanics and function is invaluable to the reconstructive surgeon performing facial transplantation involving periorbital structures and posttransplant revision operations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 25539325 TI - Perineal flap reconstruction following oncologic anorectal extirpation: an outcomes assessment. AB - BACKGROUND: The poorly healing perineal wound is a significant complication of abdominoperineal resection. The authors examined criteria for immediate flap coverage of the perineum and long-term cross-sectional surgical outcomes. METHODS: Patients who underwent abdominoperineal resection or pelvic exenteration for anorectal cancer were retrospectively analyzed. Demographic characteristics, premorbid and oncologic data, surgical treatment, reconstruction method, and recovery were recorded. Outcomes of successful wound healing, surgical complications necessitating intervention (admission or return to the operating room), and progression to chronic wounds were assessed. RESULTS: The authors identified 214 patients who underwent this procedure from 1995 to 2013. Forty seven patients received pedicled flaps and had higher rates of recurrence and reoperation, active smoking, Crohn disease, human immunodeficiency virus, and anal cancers, and had higher American Joint Committee on Cancer tumor stages. Thirty-day complication rates were equivalent in the two groups. There were no complete flap losses or reconstructive failures. Perineal wound complication rates were marginally but not significantly higher in the flap group (55 percent versus 41 percent; p = 0.088). Infectious complications, readmissions for antibiotics, and operative revision were more frequent in the flap cohort. A larger proportion of the primary closure cohort developed chronic draining perineal wounds (23.3 versus 8.5 percent; p = 0.025). CONCLUSIONS: Immediate flap coverage of the perineum was less likely to progress to a chronic draining wound, but had higher local infectious complication rates. The authors attribute this to increased comorbidity in the selected patient population, reflecting the surgical decision making in approaching these high-risk closures and ascertainment bias in diagnosis of infectious complications with multidisciplinary examination. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25539326 TI - Segmental anatomy of the vastus lateralis: guidelines for muscle-sparing flap harvest. AB - BACKGROUND: The vastus lateralis muscle is a versatile donor site for pedicled and free flaps that, despite great potential, remains unpopular. Although the muscle is classically described as a single belly, evidence exists for a more complex morphology. The aim of this study was to investigate the segmental anatomy of the vastus lateralis muscle and the feasibility of selective flap harvest. METHODS: Ten cadaveric lower limbs were investigated. Muscular partitions were identified according to morphologic architecture, vascular supply, and nerve supply; guidelines for selective flap harvest were described. Twenty-three segmental vastus lateralis (n = 14) or chimeric anterolateral thigh vastus lateralis flaps (n = 9) were raised based on neurovascular segmental supply, and used as noninnervated free flaps for reconstruction of moderate and large defects of the head and neck, trunk, or lower limbs. Intraoperative electrostimulation was used to confirm segmental innervation. Lower limb function was evaluated through the Lower Extremity Functional Scale. RESULTS: The authors clearly identified three anatomical partitions, which receive a constant segmental neurovascular supply, and two aponeuroses. The authors successfully applied the proposed guidelines for flap harvesting to all 23 patients. Intraoperative electrostimulation confirmed functional integrity of both the flap and the spared partitions. All muscle flaps survived. Donor-site morbidity was negligible, with comparable mean preoperative and postoperative Lower Extremity Functional Scale values (67.7 versus 67.4; p > 0.05). CONCLUSIONS: This study provides detailed knowledge on the morphologic and neurovascular anatomy of the vastus lateralis muscle, which supports the authors' guidelines for selective flap harvesting. The technique described is safe and minimizes surgical damage. PMID- 25539327 TI - Discussion: does the use of biopatch devices at drain sites reduce perioperative infectious complications in patients undergoing immediate tissue expander breast reconstruction? PMID- 25539328 TI - Nerve entrapment: update. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the pathophysiology of chronic nerve compression. 2. Describe the evaluation of a patient presenting with compression neuropathy. 3. Discuss the current controversies in the management of compression neuropathies. 4. Describe the treatment of common compression neuropathies, including carpal and cubital tunnel syndromes. SUMMARY: Nerve entrapment syndromes are common in the general population, and are managed by a wide variety of medical and surgical specialists. A thorough understanding of the pathophysiology of nerve compression and appropriate clinical workup are critical in the overall management of these conditions. There remain several topics of controversy regarding the surgical management of nerve entrapment syndromes, including multiple points of nerve compression, carpal tunnel release under local anesthesia, open versus endoscopic decompression surgery, the "best" operation for primary cubital tunnel surgery, and revision decompression surgery. This article attempts to provide a concise summary of the advances in the basic and clinical science of peripheral nerve entrapment. PMID- 25539329 TI - Comparison of clinical outcomes and patient satisfaction in immediate single stage versus two-stage implant-based breast reconstruction. AB - BACKGROUND: The purpose of this study was to assess the outcomes of immediate, single-stage, implant-based reconstruction compared with traditional, two-stage reconstruction (i.e., tissue expander placement followed by exchange to implant). METHODS: A retrospective review of consecutive patients who underwent immediate unilateral or bilateral breast reconstruction over an 8-year period was performed. The primary predictor variable was method of reconstruction (single stage versus two-stage). Outcome measures were postoperative complication rates, revision rates, and BREAST-Q patient satisfaction scores. Descriptive, bivariate, and multiple regression statistics were computed. RESULTS: The study sample consisted of 346 subjects who underwent reconstruction of 582 breasts (166 single stage and 416 two-stage reconstructions). Complication rates between the single stage and two-stage groups were similar for minor infections, major infections, hematoma formation, seroma formation, minor necrosis, and major necrosis (p >= 0.20). In a multiple logistic regression model, subjects undergoing single-stage reconstruction were found to be 87 percent more likely to require revision necessitating an additional operation (p = 0.005). In an adjusted regression model, subjects undergoing two-stage reconstruction had higher BREAST-Q scores for satisfaction with medical and office staff (p <= 0.02). Subjects undergoing single-stage reconstruction had higher sexual well-being satisfaction scores. CONCLUSIONS: There is no significant difference in complication rates between single-stage versus two-stage implant-based breast reconstructions. Although single-stage reconstruction is associated with higher sexual well-being satisfaction, it is more than 80 percent more likely to require additional operative revisions. Two-stage reconstruction is associated with significantly higher satisfaction with the medical and office staff. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25539330 TI - The breast reconstruction evaluation of acellular dermal matrix as a sling trial (BREASTrial): design and methods of a prospective randomized trial. AB - BACKGROUND: Recent literature has focused on the advantages and disadvantages of using acellular dermal matrix in breast reconstruction. Many of the reported data are from low level-of-evidence studies, leaving many questions incompletely answered. The present randomized trial provides high-level data on the incidence and severity of complications in acellular dermal matrix breast reconstruction between two commonly used types of acellular dermal matrix. METHODS: A prospective randomized trial was conducted to compare outcomes of immediate staged tissue expander breast reconstruction using either AlloDerm or DermaMatrix. The impact of body mass index, smoking, diabetes, mastectomy type, radiation therapy, and chemotherapy on outcomes was analyzed. Acellular dermal matrix biointegration was analyzed clinically and histologically. Patient satisfaction was assessed by means of preoperative and postoperative surveys. Logistic regression models were used to identify predictors of complications. RESULTS: This article reports on the study design, surgical technique, patient characteristics, and preoperative survey results, with outcomes data in a separate report. After 2.5 years, we successfully enrolled and randomized 128 patients (199 breasts). The majority of patients were healthy nonsmokers, with 41 percent of patients receiving radiation therapy and 49 percent receiving chemotherapy. Half of the mastectomies were prophylactic, with nipple-sparing mastectomy common in both cancer and prophylactic cases. Preoperative survey results indicate that patients were satisfied with their premastectomy breast reconstruction education. CONCLUSION: Results from the Breast Reconstruction Evaluation Using Acellular Dermal Matrix as a Sling Trial will assist plastic surgeons in making evidence-based decisions regarding acellular dermal matrix assisted tissue expander breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25539331 TI - Structure and establishing validity in survey research. AB - Survey research is a commonly used research tool used to gather opinions regarding emerging technologies and current practices. As randomized clinical trials rose to prominence, the Consolidated Standards of Reporting Trials Study Group created a checklist of items necessary for the complete and transparent reporting of randomized clinical trials. Similar checklists have been created for a variety of research methodologies. Notably missing is a checklist for the reporting of survey studies. This article examines the conduct of survey research publications and proposes a checklist to evaluate the validity of survey studies published in Plastic and Reconstructive Surgery. PMID- 25539332 TI - iPad integration in plastic surgical training: optimizing clinical efficiency, education, and compliance with the health insurance portability and accountability act. AB - The authors share their experience with the issuance of iPads to all residents, faculty, and physician extenders in their plastic surgical division. They found that these devices (1) optimized compliance with the Health Insurance Portability and Accountability Act by eliminating the use of paper service lists; (2) improved clinical efficiency; and (3) promoted resident education. They believe the use of these devices in residency is cost-effective when considering mitigating patient privacy risk and enriching educational value. PMID- 25539333 TI - Comprehensive analysis of donor-site morbidity in abdominally based free flap reconstruction. PMID- 25539334 TI - Reply: comprehensive analysis of donor-site morbidity in abdominally based free flap breast reconstruction. PMID- 25539335 TI - Studies in fat grafting: part I. Effects of injection technique on in vitro fat viability and in vivo volume retention. PMID- 25539336 TI - Evidence-based medicine: flexor tendon repair. PMID- 25539337 TI - Fat grafting to the hand in patients with raynaud phenomenon: a novel therapeutic modality. PMID- 25539338 TI - Reply: fat grafting to the hand in patients with raynaud phenomenon: a novel therapeutic modality. PMID- 25539339 TI - Vascularization of the dorsal base of the second metacarpal bone: implications for a reverse second dorsal metacarpal artery flap. PMID- 25539340 TI - Reply: vascularization of the dorsal base of the second metacarpal bone: implications for a reverse second metacarpal dorsal artery flap. PMID- 25539341 TI - The assassination of John F. Kennedy: revisiting the medical data. PMID- 25539342 TI - Association between agent orange exposure and nonmelanotic invasive skin cancer: a pilot study. PMID- 25539343 TI - Reply: association between agent orange exposure and nonmelanotic invasive skin cancer: a pilot study. PMID- 25539344 TI - The twenty-first century hospital: checklists, compliance, and disruption. PMID- 25539345 TI - Tissue-engineered breast reconstruction: bridging the gap toward large-volume tissue engineering in humans. PMID- 25539346 TI - Acute hypertensive crisis secondary to pheochromocytoma during elective cosmetic surgery. PMID- 25539347 TI - Prevention of bone adherence to an oscillating burr. PMID- 25539348 TI - Suction drain-assisted split-thickness skin grafting: a simple procedure to improve skin graft take. PMID- 25539349 TI - The BREASTrial: stage I. Outcomes from the time of tissue expander and acellular dermal matrix placement to definitive reconstruction. AB - BACKGROUND: Use of acellular dermal matrix in tissue expander breast reconstruction has become a popular adjunct to the total submuscular technique. The question remains as to which matrix, if any, is ideal for breast reconstruction. METHODS: A randomized trial was conducted to analyze outcomes of immediate staged tissue expander breast reconstruction using either AlloDerm or DermaMatrix. The impact of obesity, radiation, and chemotherapy on complications and biointegration of matrix was investigated. The trial was divided into three stages, with stage I results reported here. RESULTS: One hundred twenty-eight patients (199 breasts) were randomized equally over 2.5 years. Most patients were white, healthy nonsmokers. The overall complication rate was 36.2 percent; half of the complications were minor. The AlloDerm and DermaMatrix groups had similar rates of complications (33.6 percent versus 38.8 percent; p = 0.52), consisting mostly of skin necrosis (17.8 percent versus 21.4 percent; p = 0.66) and infections (13.9 percent versus 16.3 percent; p = 0.29), both of which led to tissue expander losses (5 percent versus 11.2 percent; p = 0.11). The AlloDerm group required less time for completion of expansion (42 days versus 70 days; p < 0.001). Obesity was associated with poor matrix biointegration and a longer drain time, both of which were associated with higher complication rates. CONCLUSION: The Breast Reconstruction Evaluation Using Acellular Dermal Matrix as a Sling Trial is the largest randomized trial to date in matrix breast reconstruction and emphasizes the importance of careful patient and allograft selection to minimize complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25539351 TI - Infection in face-lift surgery: an evidence-based approach to infection prevention. AB - BACKGROUND: Complications in face-lift surgery are rare but can present a difficult experience for the patient and surgeon. It is the objective of this review to evaluate the clinical efficacy of routine perioperative safety measures in preventing surgical-site infection in face-lift surgery. METHODS: A review of the literature was performed to assess the correlation of preoperative decolonization, prophylactic antibiotic use, perioperative hypothermia, body mass index, and smoking status with the incidence of surgical-site infection in cosmetic surgery, especially pertaining to face-lift surgery. RESULTS: Studies supporting safe practice in cosmetic surgery and "clean" procedures are analyzed and discussed. CONCLUSION: This article provides the current evidence on perioperative safety measures and recommendations regarding the prevention of infection in cosmetic surgery, especially in face-lift surgery. PMID- 25539352 TI - Quality-of-Life assessment after medial thighplasty in patients following massive weight loss. AB - BACKGROUND: The improvement of medial thighplasty techniques has greatly reduced the morbidity of these interventions and participated in their democratization among surgeons and patients. The aim of this study was to evaluate the beneficial effect of medial thighplasty on quality of life in patients following massive weight loss. METHODS: The quality of life following massive weight loss after diet or bariatric surgery of 21 patients was measured using the Moorehead-Ardelt Quality of Life Questionnaire. Patients who underwent medial thighplasty following a percentage of weight loss greater than 20 percent of the body weight were included. RESULTS: The mean age of the patients was 49.9 +/- 8.7 years. The average pre-medial thighplasty body mass index was 28.4 +/- 4.8 kg/m and the average weight loss before surgery was 46 +/- 17.1 kg. In our study, medial thighplasty improved the quality of life of patients (mean quality-of-life scores, 1.49 +/- 1.3; e.g., self-esteem, physical status, social life, and improved labor conditions of patients). However, the quality of the sex life of the patient was not improved by this operation. No difference was found in quality-of-life results between patients according to the number of months since they had undergone surgery (p = 0.7252). CONCLUSIONS: Medial thighplasty improves the aesthetic and functional outcome of the thigh. The authors report, for the first time, that medial thighplasty improves quality of life of patients with massive weight loss. With the worldwide development of obesity, this study demonstrated that the operation should be widely proposed to patients with massive weight loss to improve quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 25539353 TI - Liposuction-assisted medial brachioplasty after massive weight loss: an efficient procedure with a high functional benefit. AB - BACKGROUND: Brachioplasty frequently offers functional benefits but results in poor aesthetic scars and a relatively high complication rate. The authors describe the complications and risk factors inherent in liposuction-assisted medial brachioplasty and assess patient satisfaction with the functional and aesthetic benefits. METHODS: A 5-year retrospective study was performed that included all patients who underwent liposuction-assisted medial brachioplasty. Complications were reviewed and analyzed by aesthetic and nonaesthetic categories, and patient satisfaction was rated. RESULTS: Sixty-six patients were included (mean age, 44.4 years). The average body mass index was 30.2 kg/m; mean weight reduction was 50.72 kg. Thirty-seven patients (56.1 percent) developed at least one complication, including six (9.1 percent) with a nonaesthetic complication versus 31 (47.0 percent) with an aesthetic complication. Complications were significantly associated with a longer operative time (p = 0.015), 233 minutes in the complication group versus 164 minutes in the no complication group. Fifty-three patients answered the questionnaire. Forty-six (86.8 percent) stated that they would undergo this intervention again. Overall satisfaction was reported as excellent for 12 patients (22.6 percent) and pleasing for 24 (45.3 percent). All patients rated the functional outcome superior or equal to the aesthetic outcome. Quality of life was estimated to be better after than before the intervention for 41 patients (77.4 percent). CONCLUSIONS: Liposuction-assisted medial brachioplasty is a safe and efficient technique. It offers a functional benefit with a low nonaesthetic complication rate. Despite the inherent scars, the majority of patients would undergo this intervention again because of an important satisfaction rate and improvement in quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25539350 TI - The impact of chemotherapy and radiation therapy on the remodeling of acellular dermal matrices in staged, prosthetic breast reconstruction. AB - BACKGROUND: An acellular dermal matrix will typically incorporate, in time, with the overlying mastectomy skin flap. This remodeling process may be adversely impacted in patients who require chemotherapy and radiation, which influence neovascularization and cellular proliferation. METHODS: Multiple biopsy specimens were procured from 86 women (n = 94 breasts) undergoing exchange of a tissue expander for a breast implant. These were divided by biopsy location: submuscular capsule (control) as well as superiorly, centrally, and inferiorly along the paramedian acellular dermis. Specimens were assessed for cellular infiltration, cell type, fibrous encapsulation, scaffold degradation, extracellular matrix deposition, neovascularization, mean composite remodeling score, and type I and III collagen. Patients were compared based on five oncologic treatment groups: no adjuvant therapy (untreated), neoadjuvant chemotherapy with or without radiation, and chemotherapy with or without radiation. RESULTS: Biopsy specimens were procured 45 to 1805 days after implantation and demonstrated a significant reduction in type I collagen over time. Chemotherapy adversely impacted fibrous encapsulation (p = 0.03). Chemotherapy with or without radiation adversely impacted type I collagen (p = 0.02), cellular infiltration (p < 0.01), extracellular matrix deposition (p < 0.04), and neovascularization (p < 0.01). Radiation exacerbated the adverse impact of chemotherapy for several remodeling parameters. Neoadjuvant chemotherapy also caused a reduction in type I (p = 0.01) and III collagen (p = 0.05), extracellular matrix deposition (p = 0.03), and scaffold degradation (p = 0.02). CONCLUSION: Chemotherapy and radiation therapy limit acellular dermal matrix remodeling. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25539354 TI - Does the use of compression garments increase venous stasis in the common femoral vein? AB - BACKGROUND: Abdominoplasty is one of the most frequently performed procedures in plastic surgery. The impact of deep venous thrombosis and pulmonary embolism after this operation is well described and is a feared complication. Most plastic surgeons recommend the use of compression garment after this procedure. The purpose of this study was to evaluate the venous changes at the common femoral vein induced by the use compression garments. METHODS: Fifteen female volunteers with no history of abdominal surgery were selected. Doppler examination was used to evaluate maximum and average flow speed and the vessel perimeter, area, and diameter of the common femoral vein of the patients using no garments and using a compressive garment and a Velcro binder in the supine position. Also patients were evaluated in the Fowler position. The t test was used to compare the parameters among all situations. The level of significance was stated as 0.05 (5 percent). RESULTS: The use of both garments increased venous flow stasis, and there were no significant differences between them. Also, it has been demonstrated that the Fowler position can worsen venous stasis. Therefore, the use of compressive garments can increase femoral vein stasis. CONCLUSIONS: The use of compressive garments promotes venous stasis. There was no difference in stasis reduction when using the two different types of garments. The Fowler position increases venous stasis compared with the supine position. PMID- 25539355 TI - Clinicians performing cosmetic surgery in the community: a nationwide analysis of physician certification. AB - BACKGROUND: Practitioners who are not board-certified by the American Board of Plastic Surgery are practicing cosmetic surgery. The extent of this issue across the United States has yet to be examined in detail. METHODS: A systematic search using Google was performed to evaluate the qualifications of clinicians marketing themselves as plastic surgeons. For every U.S. state, the following searches were performed: [state] plastic surgery, [state] cosmetic surgery, and [state] aesthetic surgery. The first 50 Web sites returned for each search were visited and scrutinized using the American Society of Plastic Surgeons and American Board of Plastic Surgery Web sites. RESULTS: In total, 7500 Web sites were visited, yielding 2396 board-certified plastic surgeons (77.9 percent of all practitioners). There were 284 board-certified ear, nose, and throat surgeons, 61 (21.5 percent) of whom practice outside their scope; 106 board-certified general surgeons, 100 (94.3 percent) of whom practice outside their scope; 104 board certified oral and maxillofacial surgery surgeons, 68 (65.4 percent) of whom practice outside their scope; 70 board-certified ophthalmologists/oculoplastic surgeons, 49 (70 percent) of whom practice outside their scope; and 74 board certified dermatologists, 36 (48.6 percent) of whom practice outside their scope. There were also 16 internal medicine doctors, 13 obstetrics and gynecology physicians, six emergency medicine physicians, three pediatricians, two urologists, two anesthesiologists, and finally one phlebotomist; all of these practitioners practice outside their scope as defined by Accreditation Council for Graduate Medical Education core competencies. CONCLUSIONS: Many clinicians performing cosmetic surgery are not board-certified. This finding has important implications for patient safety. PMID- 25539356 TI - Discussion: clinicians performing cosmetic surgery in the community: a nationwide analysis of physician certification. PMID- 25539357 TI - Does the use of biopatch devices at drain sites reduce perioperative infectious complications in patients undergoing immediate tissue expander breast reconstruction? AB - BACKGROUND: To decrease the rate of infectious complications, surgeons have begun to use Biopatch (Ethicon, Somerville, N.J.) disks at drain exit sites. The authors investigated whether use of a Biopatch disk could convey a reduction in perioperative infections in patients undergoing immediate tissue expander breast reconstruction. METHODS: A retrospective review was conducted of all patients undergoing tissue expander/implant breast reconstruction from November of 2010 to November of 2012 at a single institution. Breasts were divided into two cohorts: controls with traditional adhesive dressings and those with Biopatch disks at drain sites. Breasts were compared based on demographics, complications, drain duration, and antibiotic type. RESULTS: A total of 1211 breasts met inclusion criteria. The control group (November of 2010 to October of 2011) included 606 breasts. The Biopatch cohort (November of 2011 to October of 2012) included 605 breasts. When comparing breasts with disks to controls, there were no statistical differences in overall infection (6.2 versus 7.4 percent; p = 0.4235), major infection (4.0 versus 4.3 percent; p = 0.8853), need for explantation (2.2 versus 1.8 percent; p = 0.5372), and mastectomy skin flap necrosis (12.6 versus 14.6 percent; p = 0.3148). However, age greater than 50 years, diabetes mellitus, hypertension, hypercholesterolemia, obesity, history of prior breast irradiation, and mastectomy skin flap necrosis were independent predictors of infectious complications. CONCLUSIONS: Biopatch disks do not reduce the rate infectious complications in patients undergoing immediate tissue expander breast reconstruction. Other conventional risks, including medical comorbidities, obesity, and mastectomy skin flap necrosis, remain significantly associated with infectious complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25539359 TI - The state of radiation therapy in the state of Israel. PMID- 25539358 TI - Clinical pharmacists supporting patients with diabetes and/or hyperlipidemia in a military medical home. AB - OBJECTIVE: To evaluate the effect of clinical pharmacists embedded in primary care at a military facility by reviewing laboratory assessments following pharmacist management of referred patients with diabetes and hyperlipidemia. METHODS: Electronic medical records of patients who were referred to clinical pharmacists for control of diabetes and/or hyperlipidemia were reviewed for those with at least two encounters during a 6-month period with baseline and follow-up laboratory assessments. As appropriate to patient diagnoses, glycosylated hemoglobin (A1C), low density lipoprotein cholesterol (LDL-C), triglycerides (TGs), and body mass index (BMI) were included in assessments. Paired t tests were used to determine the statistical significance of mean changes between the beginning and end of the 6-month period. RESULTS: In the cohort of patients with diabetes (n = 46), mean A1C decrease over 6 months was 0.9 points (P = 0.004). In the cohort of patients with hyperlipidemia (n = 15), mean LDL-C decrease was 20 mg/dL (P = 0.004). Changes in mean LDL-C, TGs, and BMIs were observed in each group but were not statistically significant. CONCLUSION: Although small sample sizes limited statistical power in this analysis, results suggest that referral of ambulatory patients to a clinical pharmacist in a military medical home for diabetes and/or hyperlipidemia improved care management. PMID- 25539360 TI - Radiation dose in non-small cell lung cancer: too much of a good thing? PMID- 25539361 TI - Revisiting the Sustainable Growth Rate "hole": sources of healthcare cost stabilization in 2010-2012. PMID- 25539362 TI - Is financial literacy necessary for radiation oncology residents? PMID- 25539363 TI - A report on quality and safety education for radiation oncology residents. PMID- 25539364 TI - Whole-breast radiation therapy: the long and short of it. PMID- 25539365 TI - Adoption of hypofractionated radiation therapy for breast cancer after publication of randomized trials. AB - PURPOSE: Large randomized trials have established the noninferiority of shorter courses of "hypofractionated" radiation therapy (RT) to the whole breast compared to conventional courses using smaller daily doses in the adjuvant treatment of selected breast cancer patients undergoing lumpectomy. Hypofractionation is more convenient and less costly. Therefore, we sought to determine uptake of hypofractionated breast RT over time. METHODS AND MATERIALS: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, we identified 16,096 women with node-negative breast cancer and 4269 with ductal carcinoma in situ (DCIS) who received lumpectomy followed by more than 12 fractions of RT between 2004 and 2010. Based on Medicare claims, we determined the number of RT treatments given and grouped patients into those receiving hypofractionation (13 24) or those receiving conventional fractionation (>=25). We also determined RT technique (intensity modulated RT or not) using Medicare claims. We evaluated patterns and correlates of hypofractionation receipt using bivariate and multivariable analyses. RESULTS: Hypofractionation use was similar in patients with DCIS and those with invasive disease. Overall, the use of hypofractionation increased from 3.8% in 2006 to 5.4% in 2007, to 9.4% in 2008, and to 13.6% in 2009 and 2010. Multivariable analysis showed increased use of hypofractionation in recent years and in patients with older age, smaller tumors, increased comorbidity, higher regional education, and Western SEER regions. However, even in patients over the age of 80, the hypofractionation rate in 2009 to 2010 was only 25%. Use of intensity modulated RT (IMRT) also increased over time (from 9.4% in 2004 to 22.7% in 2009-2010) and did not vary significantly between patients receiving hypofractionation and those receiving traditional fractionation. CONCLUSIONS: Hypofractionation use increased among low-risk older US breast cancer patients with publication and maturation of evidence from randomized trials, but overall use of this cost-saving approach remained low. This contrasts with the more rapid rate of adoption of IMRT in the same time period, a costly innovation supported by less strong evidence of benefit. PMID- 25539366 TI - Choosing wisely? Patterns and correlates of the use of hypofractionated whole breast radiation therapy in the state of Michigan. AB - PURPOSE: Given evidence from randomized trials that have established the non inferiority of more convenient and less costly courses of hypofractionated radiotherapy to the whole breast in selected breast cancer patients who receive lumpectomy, we sought to investigate the use of hypofractionated radiation therapy and factors associated with its use in a consortium of radiation oncology practices in Michigan. We sought to determine the extent to which variation in use occurs at the physician or practice level versus the extent to which use reflects individualization based on potentially relevant patient characteristics (such as habitus, age, chemotherapy receipt, or laterality). METHODS AND MATERIALS: We evaluated associations between receipt of hypofractionated radiation therapy and various patient, provider, and practice characteristics in a multilevel model. RESULTS: Of 1477 patients who received lumpectomy and whole breast radiation therapy and were registered by the Michigan Radiation Oncology Quality Consortium (MROQC) from October 2011 to December 2013, 913 had T1-2, N0 breast cancer. Of these 913, 283 (31%) received hypofractionated radiation therapy. Among the 13 practices, hypofractionated radiation therapy use ranged from 2% to 80%. On multilevel analysis, 51% of the variation in the rate of hypofractionation was attributable to the practice level, 21% to the provider level, and 28% to the patient level. On multivariable analysis, hypofractionation was more likely in patients who were older (odds ratio [OR] 2.16 for age >=50 years, P=.007), less likely in those with larger body habitus (OR 0.52 if separation between tangent entry and exit >=25 cm, P=.002), and more likely without chemotherapy receipt (OR 3.82, P<.001). Hypofractionation use was not higher in the last 6 months analyzed: 79 of 252 (31%) from June 2013 to December 2013 and 204 of 661 (31%) from October 2011 to May 2013 (P=.9). CONCLUSIONS: Hypofractionated regimens of whole-breast radiation therapy have been variably administered in the adjuvant setting in Michigan after the publication of long term trial results and consensus guidelines. Most of this variability is explained at the practice and provider level rather than by patient-level features, although care is being individualized to some degree. PMID- 25539368 TI - A dose-response analysis of biochemical control outcomes after (125)I monotherapy for patients with favorable-risk prostate cancer. AB - PURPOSE: To define the optimal dose for (125)I prostate implants by correlating postimplantation dosimetry findings with biochemical failure and toxicity. METHODS AND MATERIALS: Between 2003 and 2009, 683 patients with prostate cancer were treated with (125)I prostate brachytherapy without supplemental external beam radiation therapy and were followed up for a median time of 80 months. Implant dose was defined as the D90 (the minimal dose received by 90% of the prostate) on postoperative day 1 and 1 month after implantation. Therefore, 2 dosimetric variables (day 1 D90 and day 30 D90) were analyzed for each patient. We investigated the dose effects on biochemical control and toxicity. RESULTS: The 7-year biochemical failure-free survival (BFFS) rate for the group overall was 96.4% according to the Phoenix definition. A multivariate analysis found day 1 D90 and day 30 D90 to be the most significant factors affecting BFFS. The cutoff points for day 1 D90 and day 30 D90, calculated from ROC curves, were 163 Gy and 175 Gy, respectively. By use of univariate analysis, various dosimetric cutoff points for day 30 D90 were tested. We found that day 30 D90 cutoff points from 130 to 180 Gy appeared to be good for the entire cohort. Greater D90s were associated with an increase in late genitourinary or gastrointestinal toxicity >= grade 2, but the increase was not statistically significant. CONCLUSIONS: Improvements in BFFS rates were seen with increasing D90 levels. Day 30 D90 doses of 130 to 180 Gy were found to serve as cutoff levels. For low-risk and low-tier intermediate-risk prostate cancer patients, high prostate D90s, even with doses exceeding 180 Gy, achieve better treatment results and are feasible. PMID- 25539367 TI - [18F]-Fluoromisonidazole positron emission tomography/computed tomography visualization of tumor hypoxia in patients with chordoma of the mobile and sacrococcygeal spine. AB - PURPOSE: To investigate [18F]-fluoromisonidazole positron emission tomography/computed tomography (FMISO-PET/CT) detection of targetable hypoxic subvolumes (HSVs) in chordoma of the mobile or sacrococcygeal spine. METHODS AND MATERIALS: A prospective, pilot study of 20 patients with primary or locally recurrent chordoma of the mobile or sacrococcygeal spine treated with proton or combined proton/photon radiation therapy (RT) with or without surgery was completed. The FMISO-PET/CT was performed before RT and after 19.8-34.2 GyRBE (relative biologic effectiveness). Gross tumor volumes were delineated and HSVs defined including voxels with standardized uptake values >=1.4 times the muscle mean. Clinical characteristics and treatments received were compared between patients with and without HSVs. RESULTS: The FMISO-PET/CT detected HSVs in 12 of 20 patients (60%). Baseline and interval HSV spatial concordance varied (0%-94%). Eight HSVs were sufficiently large (>=5 cm(3)) to potentially allow an intensity modulated proton therapy boost. Patients with HSVs had significantly larger gross tumor volumes (median 410.0 cm(3) vs 63.4 cm(3); P=.02) and were significantly more likely to have stage T2 tumors (5 of 12 vs 0 of 8; P=.04). After a median follow-up of 1.8 years (range, 0.2-4.4 years), a local recurrence has yet to be observed. Three patients developed metastatic disease, 2 with HSVs. CONCLUSIONS: Detection of targetable HSVs by FMISO-PET/CT within patients undergoing RT with or without surgery for treatment of chordoma of the mobile and sacrococcygeal spine is feasible. The study's inability to attribute interval HSV changes to treatment, rapidly changing hypoxic physiology, or imaging inconsistencies is a limitation. Further study of double-baseline FMISO-PET/CT and hypoxia-directed RT dose escalation, particularly in patients at high risk for local recurrence, is warranted. PMID- 25539369 TI - Mucosal melanoma of the head and neck: a systematic review of the literature. AB - Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN. PMID- 25539370 TI - Comprehensive craniospinal radiation for controlling central nervous system leukemia. AB - PURPOSE: To determine the benefit of radiation therapy (RT) in resolution of neurologic symptoms and deficits and whether the type of RT fields influences central nervous system (CNS) control in adults with CNS leukemia. METHODS AND MATERIALS: A total of 163 adults from 1996 to 2012 were retrospectively analyzed. Potential associations between use of radiation and outcome were investigated by univariate and multivariate analysis. RESULTS: The median survival time was 3.8 months after RT. Common presenting symptoms were headache in 79 patients (49%), cranial nerve VII deficit in 46 (28%), and cranial nerve II deficit in 44 (27%). RT was delivered to the base of skull in 48 patients (29%), to the whole brain (WB) in 67 (41%), and to the craniospinal axis (CS) in 48 (29%). Among 149 patients with a total of 233 deficits, resolution was observed in 34 deficits (15%), improvement in 126 deficits (54%), stability in 34 deficits (15%), and progression in 39 deficits (17%). The 12-month CNS progression-free survival was 77% among those receiving CS/WB and 51% among those receiving base of skull RT (P=.02). On multivariate analysis, patients who did not undergo stem cell transplantation after RT and base of skull RT were associated with worse CNS progression-free survival. CONCLUSIONS: Improvement or resolution of symptoms occurred in two thirds of deficits after RT. Comprehensive radiation to the WB or CS seems to offer a better outcome, especially in isolated CNS involvement. PMID- 25539371 TI - A decade of comparative dose planning studies for early-stage Hodgkin lymphoma: what can we learn? AB - During the past 4 decades, the treatment of Hodgkin lymphoma has changed dramatically, and combined modality treatment is now considered the standard of care for patients with early-stage disease. However, the risk of late effects has led to concerns regarding the use of radiation therapy, especially in young patients with a long life expectancy. In this study, we review the current evidence for modern radiation therapy planning and delivery techniques in the treatment of early-stage Hodgkin lymphoma with a focus on a reduced delivered dose, a reduced irradiated volume, and a more conformal dose distribution. Although studies are difficult to compare because of differences in field technique, prescribed dose, target volumes, patient population, and reported dosimetric and plan evaluation parameters, modern radiation therapy significantly reduces exposure to normal tissues and thereby the estimated risk of late effects. However, there is no such thing as a single best modern delivery technique when multiple organs at risk are considered simultaneously because of the heterogeneity in patient anatomy and disease location, and the choice of radiation therapy technique should be made individually for each patient. PMID- 25539372 TI - Predicting outcome in patients with rhabdomyosarcoma: role of [(18)f]fluorodeoxyglucose positron emission tomography. AB - PURPOSE: To evaluate whether [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) response of the primary tumor after induction chemotherapy predicts outcomes in rhabdomyosarcoma (RMS). METHODS AND MATERIALS: After excluding those with initial tumor resection, 107 patients who underwent FDG-PET after induction chemotherapy at Memorial Sloan Kettering Cancer Center from 2002 to 2013 were reviewed. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated according to FDG-PET response and maximum standardized uptake value (SUV) at baseline (PET1/SUV1), after induction chemotherapy (PET2/SUV2), and after local therapy (PET3/SUV3). Receiver operator characteristic curves were used to determine the optimal cutoff for dichotomization of SUV1 and SUV2 values. RESULTS: The SUV1 (<9.5 vs >=9.5) was predictive of PFS (P=.02) and OS (P=.02), but not LC. After 12 weeks (median) of induction chemotherapy, 45 patients had negative PET2 scans and 62 had positive scans: 3-year PFS was 72% versus 44%, respectively (P=.01). The SUV2 (<1.5 vs >=1.5) was similarly predictive of PFS (P=.005) and was associated with LC (P=.02) and OS (P=.03). A positive PET3 scan was predictive of worse PFS (P=.0009), LC (P=.05), and OS (P=.03). CONCLUSIONS: [(18)F]fluorodeoxyglucose positron emission tomography is an early indicator of outcomes in patients with RMS. Future prospective trials may incorporate FDG-PET response data for risk adapted therapy and early assessment of new treatment regimens. PMID- 25539373 TI - Preclinical evaluation of bioabsorbable polyglycolic acid spacer for particle therapy. AB - PURPOSE: To evaluate the efficacy and safety of a polyglycolic acid (PGA) spacer through physical and animal experiments. METHODS AND MATERIALS: The spacer was produced with surgical suture material made of PGA, forming a 3-dimensional nonwoven fabric. For evaluation or physical experiments, 150-MeV proton or 320 MeV carbon-ion beams were used to generate 60-mm width of spread-out Bragg peak. For animal experiments, the abdomens of C57BL/6 mice, with or without the inserted PGA spacers, were irradiated with 20 Gy of carbon-ion beam (290 MeV) using the spread-out Bragg peak. Body weight changes over time were scored, and radiation damage to the intestine was investigated using hematoxylin and eosin stain. Blood samples were also evaluated 24 days after the irradiation. Long-term thickness retention and safety were evaluated using crab-eating macaques. RESULTS: No chemical or structural changes after 100 Gy of proton or carbon-ion irradiation were observed in the PGA spacer. Water equivalency of the PGA spacer was equal to the water thickness under wet condition. During 24 days' observation after 20 Gy of carbon-ion irradiation, the body weights of mice with the PGA spacer were relatively unchanged, whereas significant weight loss was observed in those mice without the PGA spacer (P<.05). In mice with the PGA spacer, villus and crypt structure were preserved after irradiation. No inflammatory reactions or liver or renal dysfunctions due to placement of the PGA spacer were observed. In the abdomen of crab-eating macaques, thickness of the PGA spacer was maintained 8 weeks after placement. CONCLUSIONS: The absorbable PGA spacer had water-equivalent, bio-compatible, and thickness-retaining properties. Although further evaluation is warranted in a clinical setting, the PGA spacer may be effective to stop proton or carbon-ion beams and to separate normal tissues from the radiation field. PMID- 25539375 TI - In regard to Fokas et al. PMID- 25539374 TI - Global harmonization of quality assurance naming conventions in radiation therapy clinical trials. AB - PURPOSE: To review the various radiation therapy quality assurance (RTQA) procedures used by the Global Clinical Trials RTQA Harmonization Group (GHG) steering committee members and present the harmonized RTQA naming conventions by amalgamating procedures with similar objectives. METHODS AND MATERIALS: A survey of the GHG steering committee members' RTQA procedures, their goals, and naming conventions was conducted. The RTQA procedures were classified as baseline, preaccrual, and prospective/retrospective data capture and analysis. After all the procedures were accumulated and described, extensive discussions took place to come to harmonized RTQA procedures and names. RESULTS: The RTQA procedures implemented within a trial by the GHG steering committee members vary in quantity, timing, name, and compliance criteria. The procedures of each member are based on perceived chances of noncompliance, so that the quality of radiation therapy planning and treatment does not negatively influence the trial measured outcomes. A comparison of these procedures demonstrated similarities among the goals of the various methods, but the naming given to each differed. After thorough discussions, the GHG steering committee members amalgamated the 27 RTQA procedures to 10 harmonized ones with corresponding names: facility questionnaire, beam output audit, benchmark case, dummy run, complex treatment dosimetry check, virtual phantom, individual case review, review of patients' treatment records, and protocol compliance and dosimetry site visit. CONCLUSIONS: Harmonized RTQA harmonized naming conventions, which can be used in all future clinical trials involving radiation therapy, have been established. Harmonized procedures will facilitate future intergroup trial collaboration and help to ensure comparable RTQA between international trials, which enables meta-analyses and reduces RTQA workload for intergroup studies. PMID- 25539376 TI - In regard to Olson et al and Ellsworth et al. PMID- 25539377 TI - In reply to Weiss et al. PMID- 25539378 TI - In regard to Zietman. PMID- 25539379 TI - In reply to Raju. PMID- 25539392 TI - Regioselective gold-catalyzed oxidative C-N bond formation. AB - A novel protocol for the regioselective intermolecular amination of various arenes has been developed. By using an I(III) oxidant in the presence of a Au(I) catalyst, a direct and novel route for regioselectively accessing a variety of substituted aniline moieties has been achieved with yields as high as 90%. Mechanistic insight suggests that regioselectivity can be predicted based on electrophilic aromatic metalation patterns. PMID- 25539393 TI - Label-free measurement of amyloid elongation by suspended microchannel resonators. AB - Protein aggregation is a widely studied phenomenon that is associated with many human diseases and with the degradation of biotechnological products. Here, we establish a new label-free method for characterizing the aggregation kinetics of proteins into amyloid fibrils by suspended microchannel resonators (SMR). SMR devices are unique in their ability to provide mass-based measurements under reaction-limited conditions in a 10 pL volume. To demonstrate the method, insulin seed fibrils of defined length, characterized by atomic force microscopy (AFM) and transmission electron microscopy (TEM), were covalently immobilized inside microchannels embedded within a micromechanical resonator, and the elongation of these fibrils under a continuous flow of monomer solution (rate ~1 nL/s) was measured by monitoring the resonance frequency shift. The kinetics for concentrations below ~0.6 mg/mL fits well with an irreversible bimolecular binding model with the rate constant kon = (1.2 +/- 0.1) * 10(3) M(-1) s(-1). Rate saturation occurred at higher concentrations. The nonlinear on-rate for monomer concentrations from 0 to 6 mg/mL and for temperatures from 20 to 42 degrees C fit well globally with an energy landscape model characterized by a single activation barrier. Finally, elongation rates were studied under different solution conditions and in the presence of a small molecule inhibitor of amyloid growth. Due to the low volume requirements, high precision, and speed of SMR measurements, the method may become a valuable new tool in the screening for inhibitors and the study of fundamental biophysical mechanisms of protein aggregation processes. PMID- 25539394 TI - In vitro bioaccessibility of carotenoids, flavonoids, and vitamin C from differently processed oranges and orange juices [Citrus sinensis (L.) Osbeck]. AB - Carotenoid, flavonoid, and vitamin C concentrations were determined in fresh orange segments and a puree-like homogenate derived thereof, as well as freshly squeezed, flash-pasteurized, and pasteurized juices. Lutein and beta cryptoxanthin were slightly degraded during dejuicing, whereas beta-carotene levels were retained. Vitamin C levels remained unaffected, whereas flavonoid levels decreased 8-fold upon juice extraction, most likely due to the removal of flavonoid-rich albedo and juice vesicles. Likewise, the presence of such fibrous matrix compounds during in vitro digestion was assumed to significantly lower the total bioaccessibility (BA) of all carotenoids from fresh fruit segments (12%) as compared to juices (29-30%). Mechanical disruption of orange segments prior to digestion did not alter carotenoid BA, whereas pasteurization of the freshly squeezed juice slightly increased BA by 9-11%. In addition to carotenoid BA, the stabilities of hesperidin, narirutin, and vitamin C including dehydroascorbic acid during in vitro digestion were monitored, and applied analytical methods were briefly validated. PMID- 25539397 TI - Mexican-American caregivers' perceptions about asthma management: a photovoice study. AB - OBJECTIVE: The purpose of this study is to report how photovoice was used to (1) ascertain Mexican-American caregiver perspectives about asthma management, and (2) engage caregivers in dissemination. METHODS: Eleven Mexican-American caregivers of children with asthma were recruited and given cameras to photograph what helped or hindered their ability to care for their child. Participants prioritized which images to share, discussed the images with the group, and wrote accompanying titles and captions in four photovoice sessions. Sessions were in Spanish and occurred in a community setting. Participants presented their work to peers and community members. Identified issues were subsequently categorized by investigators according to the four components of asthma care. RESULTS: Participants prioritized 32 phototexts, the majority of which (n = 20, 63%) reflected activities associated with environmental control. Caregivers highlighted asthma triggers, and suggested ways to maintain indoor air quality (IAQ) through home cleaning. The need for policies that enforce smoking bans in shared housing and public places was identified as an important strategy to improve outdoor air quality. "Education for a Partnership in Asthma Care" was represented in six (19%) phototexts. Five phototexts (16%) represented "Assessment and Monitoring". Only one phototext (3.13%) primarily represented "Medications". CONCLUSIONS: Results support the need for active partnerships between caregivers and providers. Photographs can serve as the basis for reciprocal education between patient and provider, especially in the area of environmental triggers. Provider visits should include assessment, strategies and resources to maximize IAQ. Photovoice facilitates caregivers' ability to advocate for improved asthma management and health equity. PMID- 25539396 TI - Illness representations and cultural practices play a role in patient-centered care in childhood asthma: experiences of Mexican mothers. AB - OBJECTIVE: Patients' cultural health beliefs and behaviors may conflict with biomedical healthcare values and practices potentially leading to non-adherence with asthma treatment regimens. To optimize shared decision-making, healthcare providers should understand and be sensitive to these cultural beliefs and behaviors and negotiate an asthma management plan acceptable to parents. The purpose of this study was to obtain the perspective of Mexican mothers regarding (1) their experiences of living with a child with asthma, (2) their understanding of the nature of asthma, and (3) how their cultural beliefs influence asthma management. METHODS: A qualitative, phenomenological study design was employed to assess mothers' lived experiences with and perceptions of their child's asthma. Individual in-depth interviews were conducted with a purposeful sample of 20 Mexican mothers of children ages 5-17 years with asthma. An inductive, theory driven, phenomenological analysis approach was used to elicit thematic findings. RESULTS: Mothers expressed a symptomatic perception of asthma and limited understanding of the disease. Most believe the disease is present only when their child is symptomatic. Many are surprised and puzzled by the unpredictability of their child's asthma attacks, which they report as sometimes "silent". The inconsistency of triggers also leads to frustration and worry, which may reflect their concerns around daily controller medication use and preference for alternative illness management strategies. CONCLUSIONS: Our clinical encounters should be refocused to better understand the context of these families' lives and the cultural lens through which they view their child's asthma. PMID- 25539398 TI - Managing chronic rhinosinusitis and respiratory disease: a qualitative study of triggers and interactions. AB - OBJECTIVE: The aim of this analysis is to explore views of patients with chronic rhinosinusitis (CRS) about of the aetiology of their respiratory symptoms and the relationship between upper and lower respiratory symptoms. METHODS: This study is part of a larger mixed methods study investigating the epidemiology of CRS, which comprises a questionnaire study of patients with CRS and controls and a qualitative study of 21 patients with CRS. Semi structured qualitative interviews were undertaken with these patients; 11 males and 10 females. Twelve patients had asthma. Patients were recruited with a tertiary outpatient rhinology clinic. Interviews were transcribed verbatim and analysed using thematic analysis, using Nvivo software (QSR International, Melbourne, Australia). Several important and recurring themes were highlighted. RESULTS: Patients described many perceived triggering factors and an interaction between upper and lower respiratory tract symptoms. They felt that their symptoms could be managed more holistically. CONCLUSIONS: Concerns about triggers of respiratory symptoms and interactions between upper and lower respiratory symptoms are of significant concern to patients. These should be appropriately managed and acknowledged in formal treatment pathways, for example, through the use of combined ENT/respiratory clinics. PMID- 25539399 TI - Bedroom air quality and vacuuming frequency are associated with repeat child asthma hospital admissions. AB - OBJECTIVE: Indoor environment factors have been associated with risk of asthma exacerbations in children but little is known about their role on asthma hospital readmissions. As children in Western societies continually spend more time indoors, understanding the influence of these factors on asthma exacerbation is important. We examined the role of indoor environmental and lifestyle characteristics on child asthma readmissions. METHODS: A hospital-based case control study recruited 22 children readmitted for asthma and 22 controls not readmitted for asthma. Logistic regression models were used to examine the association between aeroallergens and fungi in the bedroom and indoor lifestyle characteristics factors for asthma readmissions. To determine the best possible set of predictors among a large set of risk factors, we used random forests (RF) techniques. RESULTS: Higher levels of airborne Cladosporium and yeast in the child's bedroom increased risk of readmission (OR = 1.68, 95% CI 1.04-2.72 and OR = 1.52, 95% CI 0.99-2.34, respectively). Carpeted floors in the bedroom and synthetic doonas were also associated with increase in asthma readmissions (OR = 4.07, 95% CI 1.03-16.06 and OR = 14.6, 95% CI 1.26-169.4, respectively). In the home, frequent vacuuming using bagged cleaners increased risk of asthma readmission OR = 15.7 (95% CI 2.82-87.2). CONCLUSIONS: Factors in the child's bedroom play an important role in increasing the risk of asthma hospital readmissions. These findings have major clinical implications as the identified potential risk factors may be modifiable. Further epidemiological studies with larger samples are necessary to evaluate these associations further. PMID- 25539400 TI - Wear and loosening in total knee arthroplasty: a quick review. AB - Wear and osteolysis are common problems that often require revision surgery following total knee arthroplasty (TKA). Wear rates can be reduced through proper implant positioning and the use of modern, highly cross-linked polyethylene liners. More research is needed to identify medications that could prevent or treat the bone loss associated with osteolysis. Bone defects resulting from osteolysis can be managed with a variety of bone-preserving strategies and often require the use of structural augmentation, either in the form of bulk allografts or metal augments. Recently, porous metal augments such as tantalum cones have gained popularity among surgeons performing revision TKA for osteolytic bone defects with promising early clinical results. A megaprosthesis with a rotating hinge device may be used in salvage cases for severe bone deficiencies. PMID- 25539401 TI - Tuning of multiple luminescence outputs and white-light emission from a single gelator molecule through an ESIPT coupled AIEE process. AB - A unique example of an ESIPT coupled AIEE process, associated with a single molecule (1), is utilized for generating multiple luminescent colors (blue-green white-yellow). The J-aggregated state of 1 forms a luminescent gel in THF and this luminescent property is retained even in the solid state. PMID- 25539402 TI - Ruthenium(II) and osmium(II) mixed chelates based on pyrenyl-pyridylimidazole and 2,2'-bipyridine ligands as efficient DNA intercalators and anion sensors. AB - We report herein the synthesis and characterization of two monometallic ruthenium(II) and osmium(II) complexes of composition [(bpy)2M(HImzPPy)] (ClO4)2 derived from pyrenylimidazole-10-pyridin-2-yl-9H-9,11-diazacyclopenta[e]pyrene (HImzPPy) and 2,2'-bipyridine (bpy) ligands. X-ray crystallographic study shows that both crystals belong to the triclinic system having space group P1. The photophysical properties of 1 and 2 in acetonitrile indicate that the metal-to ligand charge-transfer excited state is mainly centered in the [M(bpy)2](2+) moiety of the complexes and slightly affected by the extended conjugation of the pyrenylimidazole moiety. Both complexes display one-electron reversible metal centered oxidative processes and a number of quasi-reversible reductive processes. The binding affinities of the complexes toward calf-thymus DNA (CT DNA) were thoroughly studied through different methods such as absorption, emission, excited-state lifetime, circular dichroism, and thermal denaturation of DNA and a relative DNA binding study using ethidium bromide. All of these experiments account for the intercalative nature of both 1 and 2 toward CT-DNA as well as their light-switch behavior. The anion recognition study through different spectroscopic techniques reveals that both complexes act as "turn-on" luminescence sensors for H2PO4(-) and "turn-off" sensors toward F(-) and AcO(-). The imidazole N-H proton of the receptors gets deprotonated with the excessive addition of F(-) and AcO(-), while it interacts with H2PO4(-) through hydrogen bonding interaction. Theoretical calculations (DFT and TD-DFT) were also performed to understand the photophysical properties of the metalloreceptors. PMID- 25539405 TI - Rational design of Bi2Te3 polycrystalline whiskers for thermoelectric applications. AB - Bi2Te3 polycrystalline whiskers consisting of interconnected nanoplates have been synthesized through chemical transformation from In2Te3 polycrystalline whisker templates assembled by nanoparticles. The synthesized Bi2Te3 whiskers preserve the original one-dimensional morphology of the In2Te3, while the In2Te3 nanoparticles can be transformed into the Bi2Te3 thin nanoplates, accompanied by the formation of high-density interfaces between nanoplates. The hot-pressed nanostructures consolidated from Bi2Te3 polycrystalline whiskers at 400 degrees C demonstrate a promising figure of merit (ZT) of 0.71 at 400 K, which can be attributed to their low thermal conductivity and relatively high electrical conductivity. The small nanoparticles inherited from the polycrystalline whiskers and high-density nanoparticle interfaces in the hot-pressed nanostructures contribute to the significant reduction of thermal conductivity. This study provides a rational chemical transformation approach to design and synthesize polycrystalline microstructures for enhanced thermoelectric performances. PMID- 25539406 TI - Synthesis of highly twisted and fully pi-conjugated porphyrinic oligomers. AB - Highly twisted pi-conjugated molecules have been attractive but challenging targets. We report here an efficient synthesis of highly twisted diporphyrins with 126 degrees and 136 degrees twist angles that involves an oxidative fusion reaction of planar aminoporphyrin precursors at room temperature. Repeated amination-oxidative fusion sequences provide a unidirectionally twisted tetramer. The twisting angle of the tetramer is 298 degrees . PMID- 25539403 TI - Spirodi(iminohydantoin) products from oxidation of 2'-deoxyguanosine in the presence of NH4Cl in nucleoside and oligodeoxynucleotide contexts. AB - Upon oxidation of the heterocyclic ring in 2'-deoxyguanosine (dG), the initial electrophilic intermediate displays a wide range of reactivities with nucleophiles leading to many downstream products. In the present study, the product profiles were mapped when aqueous solutions of dG were allowed to react with NH4Cl in the presence of the photooxidants riboflavin and Rose Bengal as well as the diffusible one-electron oxidant Na2IrCl6. Product characterization identified the 2'-deoxyribonucleosides of spiroiminodihydantoin, 5 guanidinohydantoin, and oxazolone resulting from H2O as the nucleophile. When NH3 was the nucleophile, a set of constitutional isomers that are diastereotopic were also observed, giving characteristic masses of dG + 31. ESI(+)-MS/MS of these NH3 adducts identified them to be spirocycles with substitution of either the C5 or C8 carbonyl with an amine. The NH3 adducts exhibit acid-catalyzed hydrolysis to spiroiminodihydantoin. Quantification of the NH3 and H2O adducts resulting from oxidation of dG in the nucleoside, single-stranded, and duplex oligodeoxynucleotide contexts were monitored allowing mechanisms for product formation to be proposed. These data also provide a cautionary note to those who purify their oligonucleotide samples with ammonium salts before oxidation because this will lead to unwanted side reactions in which ammonia participates in product formation. PMID- 25539407 TI - History of biochemical pregnancy was associated with the subsequent reproductive failure among women with recurrent spontaneous abortion. AB - The aim of this study was to evaluate whether the presence of history of biochemical pregnancy (BP) was associated with clinical characteristics and the subsequent pregnancy outcome among women with recurrent spontaneous abortion (RSA). One-hundred and seventy-five RSA women with two or more clinical pregnancy losses were enrolled. The clinical characteristics were compared between 164 women with history of 0-1 BP (Group A) and 11 women with two or more BP (Group B). The frequency of previous pregnancy loss and history of in vitro fertilization and embryo transfer in Group B was higher than that in Group A; while frequency of secondary RSA in Group B was lower than Group A. The subsequent pregnancy outcome was assessed prospectively; and live-birth rate in Group A (72.9%) was higher (p < 0.05) than that in Group B (41.7%). The incidence of reproductive failure (58.3%, p < 0.05) and spontaneous abortion with normal chromosome (25.0%, p = 0.050) in Group B was higher than those (27.1 and 5.9%, respectively) in Group A. RSA women with two or more BP had higher risk of reproductive failure and spontaneous abortion with normal chromosome together with lower chance of live-birth. The results of the present study involve important information and are helpful for clinical practitioners. PMID- 25539408 TI - Neonatal outcomes in very preterm singleton infants conceived using assisted reproductive technologies. AB - OBJECTIVE: To compare neonatal mortality, severe morbidities and hospital length of stay in very preterm singleton infants conceived using assisted reproductive technologies (ARTs) or spontaneously (SP). STUDY DESIGN: Singleton infants born at 23 to 32 weeks gestation during 2010-2012 were retrospectively identified from the Canadian Neonatal Network database. A composite outcome indicating a mortality or severe morbidity (grade >= 3 intraventricular hemorrhage, periventricular leukomalacia, stage >= 3 retinopathy of prematurity, bronchopulmonary dysplasia, or stage >= 2 necrotizing enterocolitis) was compared between ART and SP infants using multivariable logistic regression. Length of stay was examined in multivariable time-to-event analyses adjusting for competing risk of mortality. RESULTS: Eligible subjects included 346 (4.4%) ART and 7,578 (95.6%) SP infants. ART mothers were older, with fewer single parents, higher rates of nulliparity, diabetes, hypertension, antenatal corticosteroids, and prenatal care, but less smoking and substance use than SP mothers. No significant differences were detected in the composite outcome (odds ratio: 0.79; 95% confidence interval: 0.54-1.17) or length of stay (hazard ratio: 0.84; 95% confidence interval: 0.63-1.12) between ART and SP infants after adjustment for potential confounders and risk factors. CONCLUSION: Among singleton infants born very preterm, mode of conception is not associated with overall mortality/morbidity or length of stay. PMID- 25539409 TI - Time from uterine incision to delivery and hypoxic neonatal outcomes. AB - OBJECTIVE: The objective of this study was to estimate the association between time from uterine incision to delivery and hypoxic neonatal outcomes in nonanomalous term infants. METHODS: All women undergoing in-labor term cesarean deliveries (CDs) in the first 2 years of an ongoing prospective cohort study were included. The primary exposure was time in seconds from uterine incision to delivery. The primary outcome was a composite of hypoxia-associated neonatal outcomes, defined as at least one of: seizures, hypoxic ischemic encephalopathy, need for hypothermia treatment, and death within 7 days. RESULTS: Of 812 patients who underwent in-labor CD, the composite hypoxia outcome occurred in 18 (2.2%) neonates. There was no significant difference in the rate of hypoxic morbidity with increasing increments of 60 seconds from uterine incision to delivery (p = 0.35). There was a significantly increased risk of hypoxic morbidity in those delivered in the highest quintile (>240 seconds) compared with those in the lowest quintile (<= 60 seconds) in cesareans performed for an indication other than nonreassuring fetal status (relative risk, 5.58; 95% confidence interval, 1.30-23.91). CONCLUSION: Overall, duration from uterine incision to delivery for in-labor cesareans of nonanomalous term infants was not associated with an increase in risk of hypoxia-associated morbidities. PMID- 25539410 TI - Syphilis treatment in the presence of HIV: the debate goes on. AB - PURPOSE OF REVIEW: Benzathine Penicillin G has been used to treat syphilis for over 50 years; however, the precise regimen of penicillin for treatment of syphilis in HIV-positive individuals remains a hot topic of debate. Although international guidelines recommend the same treatment for syphilis, regardless of HIV status, there are inconsistencies in prescribing practices among clinicians. RECENT FINDINGS: Two previous systematic reviews have found limited evidence for enhanced treatment of syphilis in the presence of HIV. However, a growing body of literature indicates that the rate of asymptomatic neurosyphilis may be higher in HIV, and that syphilis infection is associated with poorer long-term neurocognitive outcomes. A number of retrospective studies propose that serological response may be slower, or serological failure may be higher, among HIV-positive individuals, but these studies are limited by high loss to follow up, high reinfection rates and a focus on serological rather than clinical response. Beyond penicillin, some evidence suggests equivalence of macrolides, cephalosporins and doxycycline, although macrolide resistance is an increasing concern. SUMMARY: Until a prospective, randomized study is conducted, inconsistency with treatment will continue. We offer a pragmatic approach to recognizing patients who may require further investigation or neuropenetrative antibiotic treatment. PMID- 25539413 TI - Visible-light-initiated thiol-acrylate photopolymerization of heparin-based hydrogels. AB - An in situ heparin-based forming hydrogel that cures under visible-light is formulated using eosin Y as a photoinitiator with triethanolamine as an electron donor to initiate reaction of thiolated-heparin with acrylate-ended poly(ethylene glycol). Formulations and irradiation conditions are presented for control of heparin content (1.6 to 3.3% w/v), modulus (100-10,000 Pa), and gelation time (30 600 s). Encapsulation of 3T3 fibroblasts in the hydrogel gave over 96% viability for all conditions examined. In vitro characterization of epidermal growth factor released from the hydrogel confirmed that the growth factor remains bioactive. The ability to deliver growth factors, fast gelation kinetics under visible light, and independent control of physical and biochemical properties makes this system a promising candidate for use in regenerative medicine. In particular, irradiation conditions that achieve gelation in 150s are compatible with the stringent light exposure limits of the retina, which affords a wide safety margin for use with other tissues. PMID- 25539411 TI - Innate immunity and genetic determinants of urinary tract infection susceptibility. AB - PURPOSE OF REVIEW: Urinary tract infections (UTIs) are common, dangerous and interesting. Susceptible individuals experience multiple, often clustered episodes, and in a subset of patients, infections progress to acute pyelonephritis (APN), sometimes accompanied by uro-sepsis. Others develop asymptomatic bacteriuria (ABU). Here, we review the molecular basis for these differences, with the intention to distinguish exaggerated host responses that drive disease from attenuated responses that favour protection and to highlight the genetic basis for these extremes, based on knock-out mice and clinical studies. RECENT FINDINGS: The susceptibility to UTI is controlled by specific innate immune signalling and by promoter polymorphisms and transcription factors that modulate the expression of genes controlling these pathways. Gene deletions that disturb innate immune activation either favour asymptomatic bacteriuria or create acute morbidity and disease. Promoter polymorphisms and transcription factor variants affecting those genes are associated with susceptibility in UTI prone patients. SUMMARY: It is time to start using genetics in UTI-prone patients, to improve diagnosis and to assess the risk for chronic sequels such as renal malfunction, hypertension, spontaneous abortions, dialysis and transplantation. Furthermore, the majority of UTI patients do not need follow-up, but for lack of molecular markers, they are unnecessarily investigated. PMID- 25539414 TI - Current opinion on bevacizumab on endometrial cancer treatment. AB - INTRODUCTION: Advanced or recurrent endometrial cancer is still a challenge for clinicians as it has a poor prognosis despite treatment efforts. Thus, there is an urgent need for new agents with activity in this subset of patients. The increased knowledge of the molecular aspects of endometrial carcinogenesis has led to the development of molecular targeted therapies and in particular anti angiogenic drugs. One of the most promising of these agents is bevacizumab , a recombinant humanized immunoglobulin monoclonal antibody to VEGF. AREAS COVERED: The objective of this paper is to discuss the role of angiogenesis in endometrial cancer and analyze the rational of bevacizumab use, alone or in combination with other therapies, in endometrial cancer patients. We reviewed the most important preclinical and clinical studies published on this topic up to March 2014. EXPERT OPINION: Bevacizumab in combination with others targeted therapies, chemotherapy or radiotherapy demonstrated promising anti-tumor activity. Despite the good oncological outcomes of these recent clinical experiences, caution must be used in light of significant toxicity reported in this subset of heavily pre-treated patients. The identification of biomarkers able to predict either the efficacy or toxicity of anti-angiogenic drugs is a compelling need. PMID- 25539416 TI - Impact of gender difference in hospital outcomes following percutaneous coronary intervention. Results of the Belgian Working Group on Interventional Cardiology (BWGIC) registry. AB - AIMS: To determine whether there are gender-based differences in in-hospital outcomes among patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: We studied a large cohort using clinical data from a registry of 130,985 PCI procedures in Belgium, from January 2006 to February 2011. Compared to males, females were significantly older (70.3 vs. 64.8 years), and were more frequently diabetic or hypertensive. Men smoked more and more frequently had previous myocardial infarction (MI), previous PCI or previous coronary artery bypass graft (CABG) surgery. Coronary artery disease (CAD) was less severe in women, and PCI to the left anterior descending artery was more common in female patients. Unadjusted in-hospital mortality rates were higher in females versus males (2.5% for women and 1.6% for men, p<0.0001). After multivariable analysis, female gender remained an independent predictor of mortality (odds ratio 1.35, 95% CI: 1.22-1.49, p<0.0001). CONCLUSIONS: Gender based differences in hospital mortality rates after PCI were observed in this large registry. Female sex remained an independent predictor of mortality after multivariable adjustment. PMID- 25539415 TI - Keep on moving: discovering and perturbing the conformational dynamics of enzymes. AB - CONSPECTUS: Because living organisms are in constant motion, the word "dynamics" can hold many meanings to biologists. Here we focus specifically on the conformational changes that occur in proteins and how studying these protein dynamics may provide insights into enzymatic catalysis. Advances in integrating techniques such as X-ray crystallography, nuclear magnetic resonance, and electron cryomicroscopy (cryo EM) allow us to model the dominant structures and exchange rates for many proteins and protein complexes. For proteins amenable to atomic resolution techniques, the major questions shift from simply describing the motions to discovering their role in function. Concurrently, there is an increasing need for using perturbations to test predictive models of dynamics function relationships. Examples are the catalytic cycles of dihydrofolate reductase (DHFR) and cyclophilin A (CypA). In DHFR, mutations that alter the ability of the active site to sample productive higher energy states on the millisecond time scale reduce the rate of hydride transfer significantly. Recently identified rescue mutations restore function, but the mechanism by which they do so remains unclear. The exact role of any changes in the dynamics remains an open question. For CypA, a network of side chains that exchange between two conformations is critical for catalysis. Mutations that lock the network in one state also reduce catalytic activity. A further understanding of enzyme dynamics of well-studied enzymes such as dihydrofolate reductase and cyclophilin A will lead to improvement in ability to modulate the functions of computationally designed enzymes and large macromolecular machines. In designed enzymes, directed evolution experiments increase catalytic rates. Detailed X-ray studies suggest that these mutations likely limit the conformational space explored by residues in the active site. For proteins where atomic resolution information is currently inaccessible, other techniques such as cryo-EM and high-resolution single molecule microscopy continue to advance. Understanding the conformational dynamics of larger systems such as protein machines will likely become more accessible and provide new opportunities to rationally modulate protein function. PMID- 25539417 TI - Impact of left ventricular function and transaortic gradient on outcomes from transcatheter aortic valve implantation: data from the UK TAVI Registry. AB - AIMS: Aortic valve surgery in the presence of reduced ejection fraction (EF) or low transaortic gradient is associated with adverse outcome. Low gradient (LG) may be associated with reduced EF, known as low EF-low gradient (LEF-LG), or "paradoxically" low with normal EF (P-LG). Our aim was to investigate the impact of EF and transaortic gradient on outcome following transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: We retrospectively analysed the UK TAVI Registry from 2007 to 2011 (n=2,535 consecutive patients, mean age 81.3+/-7.5, logistic EuroSCORE 21.8+/-14). Thirty-day mortality was 7.8%, low EF (<50%) was present in 39%, low gradient (<64 mmHg) was present in 27%, LEF-LG in 15% and P LG in 12% of patients, respectively. LEF-LG patients had the highest risk profile vs. the other groups (EuroSCORE 30+/-16 vs. 20+/-12, p<0.001). Neither EF nor gradient impacted on procedural outcome or 30-day mortality. Mortality at two years was significantly higher in LEF-LG patients (34.7%), whereas, in patients with low EF/high gradient (27.8%) or normal EF/low gradient (23%), mortality was not significantly different from that of normal EF/high gradient (23%) patients. LEF-LG independently predicted reduced survival, HR 1.7 (1.4-2.1). CONCLUSIONS: Neither low EF nor low gradient affected procedural success or 30-day mortality. Long-term survival was reduced in LEF-LG patients but not in those with low EF and high gradient or P-LG with normal EF. PMID- 25539420 TI - Conductive nanocomposites based on polystyrene microspheres and silver nanowires by latex blending. AB - Metallic nanowires with excellent electrical conductivity and high aspect ratio are critical in the preparation of conductive polymer nanocomposites. In this work, highly conductive polystyrene/silver nanowire (PS/AgNW) nanocomposites were prepared by latex blending, and their electrical and rheological properties were investigated. A high yield of long and thin AgNWs was synthesized with the polyol method. AgNWs were incorporated with highly monodisperse PS microspheres to produce polymer nanocomposites with a nanowire network structure providing electrical pathways. An electrically conductive network of AgNWs was obtained at an electrical percolation threshold of 0.49 vol % AgNW, and an electrical conductivity of 10(2) S/m was obtained at 1 vol %. The dynamic rheological properties evaluated at 1 vol % also confirmed that the AgNWs were physically connected to one another at this concentration. PMID- 25539419 TI - Reliability of home respiratory polygraphy for the diagnosis of sleep apnea in children. AB - OBJECTIVE: The objective of this study was to evaluate the diagnostic reliability of home respiratory polygraphy (HRP) in children with a clinical suspicion of OSA hypopnea syndrome (OSAS). METHODS: A prospective blind evaluation was performed. Children between the ages of 2 to 14 years with clinical suspicion of OSAS who were referred to the Sleep Unit were included. An initial HRP followed by a later date, same night, in-laboratory overnight respiratory polygraphy and polysomnography (PSG) in the sleep laboratory were performed. The apnea-hypopnea index (AHI)-HRP was compared with AHI-PSG, and therapeutic decisions based on AHI HRP and AHI-PSG were analyzed using intraclass correlation coefficients, Bland Altman plots, and receiver operator curves (ROCs). RESULTS: Twenty-seven boys and 23 girls, with a mean age of 5.3 +/- 2.5 years, were studied, and 66% were diagnosed with OSAS based on a PSG-defined obstructive respiratory disturbance index >= 3/h total sleep time. Based on the availability of concurrent HRP-PSG recordings, the optimal AHI-HRP corresponding to the PSG-defined OSAS criterion was established as >= 5.6/h The latter exhibited a sensitivity of 90.9% (95% CI, 79.6%-100%) and a specificity of 94.1% (95% CI, 80%-100%). CONCLUSIONS: HRP recordings emerge as a potentially useful and reliable approach for the diagnosis of OSAS in children. However, more research is required for the diagnosis of mild OSAS using HRP in children. PMID- 25539418 TI - Five-year clinical outcome of the Nobori drug-eluting coronary stent system in the treatment of patients with coronary artery disease: final results of the NOBORI 1 trial. AB - AIMS: To assess the safety and performance of the Nobori drug-eluting stent with biodegradable polymer versus the TAXUS drug-eluting stent with permanent polymer, in the treatment of patients with de novo coronary artery lesions. METHODS AND RESULTS: NOBORI 1 was a multicentre, randomised (2:1), prospective, controlled, clinical trial which enrolled 363 patients (238 Nobori and 125 TAXUS) with up to two de novo lesions in two epicardial vessels. The primary endpoint was in-stent late loss at nine months, while secondary endpoints included safety and efficacy up to five years. At five years, clinical data were available for 350 patients (96%). There were no differences in the composite of death and myocardial infarction (10.9% vs. 11.2%) and target lesion failure (9.2% and 10.4%), while ischaemia- and non-ischaemia-driven target lesion revascularisations were less frequent in the Nobori (6.3%) than in the TAXUS arm (16.0%). The rates of stent thrombosis (definite and probable according to the ARC definitions) were 0.0% and 3.2%, in the Nobori and TAXUS stents, respectively (p=0.014). CONCLUSIONS: Five years after implantation, the Nobori DES resulted in durable treatment effects with very low TLR and no stent thrombosis. The study was not powered to assess the differences in clinical endpoints. These data are hypothesis-generating. PMID- 25539422 TI - Integration of adult patients with phenylketonuria into professional life: long term follow-up of 27 patients in a single centre in Switzerland. AB - BACKGROUND: Neonatal screening and treatment of phenylketonuria (PKU) prevent the development of neurocognitive impairment. The degree of dysfunction may be related to metabolic control and responsible for a hampered school career. METHODS: This was a retrospective study from a single metabolic unit of a Swiss University Hospital. The time point of diagnosis and all Phenylalanin (Phe) concentrations during the follow-up were recorded. The primary outcome was integration into professional life defined as no professional studies versus accomplished apprenticeship versus high school diploma/university. Phe levels were correlated with professional outcome. The control group consisted of the patients' healthy parents and siblings. RESULTS: A total of 27 patients (13 females, 14 males) were included in the study. The mean (SD) follow-up period was 25.1 (7.6) years. The control group consisted of 57 subjects. Overall, 23 patients were diagnosed by neonatal screening, and 4 patients were diagnosed later. All 4 were in the non-professional study group. Compared with the controls there were significantly more patients in the non-professional study group (26% vs 9%, p <0.05) and significantly less in the accomplished apprenticeship group (59% vs 82%; p <0.04). After exclusion of the patients with late diagnosis no significant differences were found with regard to the professional integration between patients and controls. Significant differences in Phe-levels between the three groups could be documented between 2-10 years of age with the highest levels in the non-professional study followed by the accomplished apprenticeship and the high school diploma group (p <0.01). CONCLUSION: Patients who are diagnosed by neonatal screening and are consequently cared for are able to accomplish an apprenticeship or a high school diploma. PMID- 25539423 TI - Strategies for the hyperpolarization of acetonitrile and related ligands by SABRE. AB - We report on a strategy for using SABRE (signal amplification by reversible exchange) for polarizing (1)H and (13)C nuclei of weakly interacting ligands which possess biologically relevant and nonaromatic motifs. We first demonstrate this via the polarization of acetonitrile, using Ir(IMes)(COD)Cl as the catalyst precursor, and confirm that the route to hyperpolarization transfer is via the J coupling network. We extend this work to the polarization of propionitrile, benzylnitrile, benzonitrile, and trans-3-hexenedinitrile in order to assess its generality. In the (1)H NMR spectrum, the signal for acetonitrile is enhanced 8 fold over its thermal counterpart when [Ir(H)2(IMes)(MeCN)3](+) is the catalyst. Upon addition of pyridine or pyridine-d5, the active catalyst changes to [Ir(H)2(IMes)(py)2(MeCN)](+) and the resulting acetonitrile (1)H signal enhancement increases to 20- and 60-fold, respectively. In (13)C NMR studies, polarization transfers optimally to the quaternary (13)C nucleus of MeCN while the methyl (13)C is hardly polarized. Transfer to (13)C is shown to occur first via the (1)H-(1)H coupling between the hydrides and the methyl protons and then via either the (2)J or (1)J couplings to the respective (13)Cs, of which the (2)J route is more efficient. These experimental results are rationalized through a theoretical treatment which shows excellent agreement with experiment. In the case of MeCN, longitudinal two-spin orders between pairs of (1)H nuclei in the three-spin methyl group are created. Two-spin order states, between the (1)H and (13)C nuclei, are also created, and their existence is confirmed for Me(13)CN in both the (1)H and (13)C NMR spectra using the Only Parahydrogen Spectroscopy protocol. PMID- 25539424 TI - Drug-loaded PLGA-mPEG microparticles as treatment for atopic dermatitis-like skin lesions in BALB/c mice model. AB - This study evaluated the feasibility of mizolastine-loaded microparticles as therapy for atopic dermatitis. Microparticles have been researched for decades as a controlled-release drug delivery system, but seldom been used as treatment for skin disease. In this research, we induced dermatitis in BALB/c mice model by repeated topical application of dinitrofluorobenzene and compared the mizolastine microparticles injection and daily mizolastine injection treatment. The results showed that the mizolastine microparticles treatments significantly inhibited ear thickness and dermatitis index in dermatitis model compared with the dermatitis mice without treatment, showing a similar curative effect compared with daily mizolastine injection treatment, and the improvement continued for several days. Inflammatory cells infiltration into the ears and the plasma level of immunoglobulin E were also suppressed by mizolastine microparticles according to the histopathology analysis. In conclusion, the results suggested that drug loaded microparticles could be a proper candidate for the treatment of skin diseases. PMID- 25539425 TI - A nice reminder from a former patient to consider hemochromatosis as a cause of arthritis. PMID- 25539426 TI - Clinical and pathological study on patients with primary antineutrophil cytoplasmic autoantibody-associated vasculitis with renal immune complex deposition. AB - BACKGROUND: Traditionally, antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is histologically characterized by pauci-immune glomerulonephritis. However, more and more literature has reported immune complex (IC) deposits to be found in renal specimen from patients with AAV. The role that these IC deposits play in the development of AAV, as well as their clinical and pathological significance, is worthy of studying. OBJECTIVES: The objective of this study was to analyze the clinical and pathological characteristics of Chinese patients with AAV having renal IC deposition. METHODS: A retrospective study was performed on 34 patients with AAV in Shanghai Ruijin Hospital with renal IC deposition. Clinical and pathological data were collected and studied and compared with other 76 AAV patients having classic pauci-immune glomerulonephritis. RESULTS: Thirty-four patients were enrolled in this study, with a mean age of 56.4 +/- 16.4 years and a male-female ratio of 1:1.3 (19/15). Twenty-seven patients (79.4%) had impaired renal function, with an average serum creatinine of 4.4 +/- 3.2 mg/dL. C3 (82.4%) and immunoglobulin M (50%) were the most common IC deposits observed in the kidneys. During the follow-up (median, 39 months), 6 patients (17.7%) died, and 11 (32.4%) finally progressed to end-stage renal disease despite immunosuppressive therapy. Compared with patients having classic pauci-immune glomerulonephritis, patients with renal IC deposits had similar clinical and laboratory features except for more proteinuria (2374 +/- 2221 vs 1444 +/- 1956 mg/24 h, P = 0.002), a higher prevalence of nephrotic syndrome (30.3% vs 9.6%, P = 0.007) and hypocomplementemia (86.8 +/- 33.1 vs 110 +/- 45.5 mg/dL, P = 0.029), and also a higher risk for progressing to end-stage renal disease (32.4% vs 13.1%, P = 0.018). CONCLUSIONS: Patients with AAV with renal IC deposition might have a worse renal prognosis than those having classic pauci-immune glomerulonephritis. PMID- 25539427 TI - Immunology for rheumatology residents: working toward a Canadian national curriculum consensus. AB - BACKGROUND: Immunologic mechanisms play an integral role in understanding the pathogenesis and management of rheumatic conditions. Currently, there is limited access to formal instruction in immunology for rheumatology trainees across Canada. AIM: The aims of this study were (1) to describe current immunology curricula among adult rheumatology training programs across Canada and (2) to compare the perceived learning needs of rheumatology trainees from the perspective of program directors and trainees to help develop a focused nationwide immunology curriculum. METHODS: Rheumatology trainees and program directors from adult rheumatology programs across Canada completed an online questionnaire and were asked to rank a comprehensive list of immunology topics. A modified Delphi approach was implemented to obtain consensus on immunology topics. RESULTS: Only 42% of program directors and 31% of trainees felt the current method of teaching immunology was effective. Results illustrate concordance between program directors and trainees for the highest-ranked immunology topics including innate immunity, adaptive immunity, and cells and tissues of the immune system. However, there was discordance among other topics, such as diagnostic laboratory immunology and therapeutics. CONCLUSIONS: There is a need to improve immunology teaching in rheumatology training programs. Results show high concordance between the basic immunology topics. This study provides the groundwork for development of future immunology curricula. PMID- 25539428 TI - Frequency of radiologic procedures in patients with rheumatoid arthritis. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) undergo radiologic investigations for disease and comorbidity evaluation. The actual use of radiologic imaging in RA is unknown. METHODS: Using the Rochester Epidemiology Project medical record linkage system, adult patients from previously assembled population-based cohorts of Olmsted County, Minnesota, residents who fulfilled the 1987 American College of Rheumatology criteria for RA in 1988 to 2007 and comparator subjects without RA of similar age and gender were studied. Data on all radiologic procedures performed were collected. RESULTS: The study included 650 patients with RA and 650 patients without RA. Patients with RA had significantly more radiographs of the chest (rate ratio [RR], 1.33; 95% confidence interval [CI], 1.28-31.38), upper extremity (RR, 2.97; 95% CI, 2.80 83.17), lower extremity (RR, 2.05; 95% CI, 1.94-102.16), spine (RR, 1.46; 95% CI, 1.35-41.59), and hip, pelvis, or sacroiliac joints (RR, 1.14; 95% CI, 1.03 11.26), as well as bone radionuclide (RR, 1.90; 95% CI, 1.50-52.44) and dual energy x-ray absorptiometry imaging (RR, 1.77; 95% CI, 1.59-61.98) compared with patients without RA. Among patients with RA, having a positive rheumatoid factor was associated with an increased likelihood of undergoing radiologic procedures (RR, 1.05; 95% CI, 1.02-11.07). Women with RA underwent more imaging procedures than men (RR, 1.20; 95% CI, 1.16-21.23). CONCLUSIONS: Patients with RA undergo more radiologic procedures than patients without RA. Among patients with RA, women and patients with a positive rheumatoid factor have more radiologic procedures. The utilization of radiography is likely a reflection of overall disease burden. Despite some guidelines, routine hand wrist radiographs were not obtained with regularity; "overuse" is unlikely. PMID- 25539429 TI - Refractory sarcoid arthritis in World Trade Center-exposed New York City firefighters: a case series. AB - OBJECTIVE: The objective of this study was to describe cases of sarcoid arthritis in firefighters from the Fire Department of the City of New York (FDNY) who worked at the World Trade Center (WTC) site. METHODS: All WTC-exposed FDNY firefighters with sarcoidosis and related chronic inflammatory arthritis (n = 11) are followed jointly by the FDNY-WTC Health Program and the Rheumatology Division at the Hospital for Special Surgery. Diagnoses of sarcoidosis were based on clinical, radiographic, and pathological criteria. Patient characteristics, WTC exposure information, smoking status, date of diagnosis, and pulmonary findings were obtained from FDNY-WTC database. Joint manifestations (symptoms and duration, distribution of joints involved), radiographic findings, and treatment responses were obtained from chart review. RESULTS: Nine of 60 FDNY firefighters who developed sarcoidosis since 9/11/2001 presented with polyarticular arthritis. Two others diagnosed pre-9/11/2001 developed sarcoid arthritis after WTC exposure. All 11 were never cigarette smokers, and all performed rescue/recovery at the WTC site within 3 days of the attacks. All had biopsy-proven pulmonary sarcoidosis, and all required additional disease-modifying antirheumatic drugs for adequate control (stepwise progression from hydroxychloroquine to methotrexate to anti-tumor necrosis factor alpha agents) of their joint manifestations. CONCLUSIONS: Chronic inflammatory polyarthritis appears to be an important manifestation of sarcoidosis in FDNY firefighters with sarcoidosis and WTC exposure. Their arthritis is chronic and, unlike arthritis in non-WTC-exposed sarcoid patients, inadequately responsive to conventional oral disease-modifying antirheumatic drugs, often requiring anti-tumor necrosis factor alpha agents. Further studies are needed to determine the generalizability of these findings to other groups with varying levels of WTC exposure or with other occupational/environmental exposures. PMID- 25539430 TI - Long-term real-life experience with rituximab in adult Finnish patients with rheumatoid arthritis refractory or with contraindication to anti-tumor necrosis factor drugs. AB - OBJECTIVE: The objective of this study was to evaluate the long-term safety and efficacy of repeated rituximab (RTX) infusions in the treatment of rheumatoid arthritis in daily clinical practice in Finland. METHODS: Data were collected from the medical records of a total of 151 patients with rheumatoid arthritis treated with RTX and followed up for at least 12 months after the treatment onset. Change in the 28-joint Disease Activity Score (DAS28), European League Against Rheumatism response criteria and proportions of patients reaching disease remission (DAS28 < 2.6) or low disease activity (DAS28 < 3.2) were used to assess the clinical response. RESULTS: Of the 151 patients 128 received 2 courses, 76 received 3 courses, and 42 received 4 courses of RTX. The mean time to retreatment for the first 4 courses varied between 11 and 13 months. Median DAS28 decreased from 5.4 (0.5-8.6) to 3.3 (0.6-6.6) after the first course. After the second treatment course, the DAS28 was 3.1 (range, 0.1-6.5). The median precourse baseline DAS28 before the second and third courses were 4.6 (range, 1.7-7.8) and 4.24 (range, 1.7-7.2), respectively. The number of previously failed tumor necrosis factor inhibitors did not predict response to RTX in this patient cohort with extensive use of previous disease-modifying antirheumatic drugs (median = 6). CONCLUSIONS: The treatment as-needed regimen used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. A regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity. PMID- 25539431 TI - Refractory primary Sjogren syndrome successfully treated with bortezomib. AB - Primary Sjogren syndrome (PSS) is a chronic autoimmune disease characterized by sicca complex and various systemic manifestations. Although it is well accepted to use corticosteroids for the treatment of systemic manifestations, there is scarce information available regarding the use of targeted therapy for refractory cases. We describe a case of a severe PSS patient refractory to conventional treatment with a response to bortezomib, a proteasome inhibitor commonly used for the treatment of multiple myeloma. Bortezomib administration resulted in a notable improvement of the general symptoms, particularly fatigue, and a decrease in serum globulin levels as well as in serum viscosity. Hyperglobulinemic purpura disappeared, and prednisone tapering succeeded. Because of chronicity, no clinical changes were observed in sicca symptoms. As far as we know, this is the first report on the use of bortezomib in a refractory case of PSS. PMID- 25539432 TI - Three cases of reactive arthritis secondary to lymphogranuloma venereum. AB - We describe 3 cases of sexually acquired reactive arthritis following rectal lymphogranuloma venereum (LGV) infection in London men who have sex with men. While sexually acquired reactive arthritis is well recognized following urogenital Chlamydia trachomatis infections, the association with rectal infection by LGV-associated serovars of C. trachomatis has been seldom reported, and thus the organism might not be sought by clinicians. The recognition of the various clinical syndromes of LGV by all clinicians, including rheumatologists, is essential given the endemicity of LGV in European men who have sex with men. PMID- 25539433 TI - Use of intravenous immunoglobulin in patients with active vasculitis associated with concomitant infection. PMID- 25539434 TI - Pilot open observations on doxycycline treatment for erosive osteoarthritis of the hand. PMID- 25539435 TI - Cat-scratch fever and lymphadenopathy in a rheumatoid arthritis patient on tocilizumab. PMID- 25539437 TI - Cardiac tamponade in a patient with mixed connective tissue disease. PMID- 25539439 TI - Protracted superficial granulomatosis with polyangiitis: a therapeutic challenge. PMID- 25539438 TI - Multiple thrombi in a man with Behcet disease. PMID- 25539440 TI - Spinal epidural abscess following minimally invasive dental examination in a rheumatoid arthritis patient receiving methotrexate, glucocorticoids, and anti tumor necrosis factor therapy. PMID- 25539441 TI - A case of rheumatoid arthritis with Felty syndrome complicated by late-onset ankylosing spondylitis and psoriatic arthritis: a potpourri of rheumatic diseases. PMID- 25539442 TI - Role of dynamics in enzyme catalysis: substantial versus semantic controversies. AB - CONSPECTUS: The role of the enzyme's dynamic motions in catalysis is at the center of heated contemporary debates among both theoreticians and experimentalists. Resolving these apparent disputes is of both intellectual and practical importance: incorporation of enzyme dynamics could be critical for any calculation of enzymatic function and may have profound implications for structure-based drug design and the design of biomimetic catalysts. Analysis of the literature suggests that while part of the dispute may reflect substantial differences between theoretical approaches, much of the debate is semantic. For example, the term "protein dynamics" is often used by some researchers when addressing motions that are in thermal equilibrium with their environment, while other researchers only use this term for nonequilibrium events. The last cases are those in which thermal energy is "stored" in a specific protein mode and "used" for catalysis before it can dissipate to its environment (i.e., "nonstatistical dynamics"). This terminology issue aside, a debate has arisen among theoreticians around the roles of nonstatistical vs statistical dynamics in catalysis. However, the author knows of no experimental findings available today that examined this question in enzyme catalyzed reactions. Another source of perhaps nonsubstantial argument might stem from the varying time scales of enzymatic motions, which range from seconds to femtoseconds. Motions at different time scales play different roles in the many events along the catalytic cascade (reactant binding, reprotonation of reactants, structural rearrangement toward the transition state, product release, etc.). In several cases, when various experimental tools have been used to probe catalytic events at differing time scales, illusory contradictions seem to have emerged. In this Account, recent attempts to sort the merits of those questions are discussed along with possible future directions. A possible summary of current studies could be that enzyme, substrate, and solvent dynamics contribute to enzyme catalyzed reactions in several ways: first via mutual "induced-fit" shifting of their conformational ensemble upon binding; then via thermal search of the conformational space toward the reaction's transition-state (TS) and the rare event of the barrier crossing toward products, which is likely to be on faster time scales then the first and following events; and finally via the dynamics associated with products release, which are rate-limiting for many enzymatic reactions. From a chemical perspective, close to the TS, enzymatic systems seem to stiffen, restricting motions orthogonal to the chemical coordinate and enabling dynamics along the reaction coordinate to occur selectively. Studies of how enzymes evolved to support those efficient dynamics at various time scales are still in their infancy, and further experiments and calculations are needed to reveal these phenomena in both enzymes and uncatalyzed reactions. PMID- 25539443 TI - Five-year follow-up using a prostate stent as fiducial in image-guided radiotherapy of prostate cancer. AB - PURPOSE: To report results from the five-year follow-up on a previously reported study using image-guided radiotherapy (IGRT) of localized or locally advanced prostate cancer (PC) and a removable prostate stent as fiducial. MATERIAL AND METHODS: Patients with local or locally advanced PC were treated using five-field 3D conformal radiotherapy (3DRT). The clinical target volumes (CTV) were treated to 78 Gy in 39 fractions using daily on-line image guidance (IG). Late genito urinary (GU) and gastro-intestinal (GI) toxicities were scored using the radiotherapy oncology group (RTOG) score and the common toxicity score of adverse events (CTC) score. Urinary symptoms were also scored using the international prostate symptom score (IPSS). RESULTS: Median observation time was 5.4 year. Sixty-two of the 90 patients from the original study cohort were eligible for toxicity assessment. Overall survival, cancer-specific survival and biochemical freedom from failure were 85%, 96% and 80%, respectively at five years after radiotherapy. Late toxicity GU and GI RTOG scores>=2 were 5% and 0%. Comparing pre- and post-radiotherapy IPSS scores indicate that development in urinary symptoms after radiotherapy may be complex. CONCLUSIONS: Prostate image-guided radiotherapy using a prostate stent demonstrated survival data comparable with recently published data. GU and GI toxicities at five-year follow-up were low and comparable to the lowest toxicity rates reported. These findings support that the precision of the prostate stent technique is at least as good as other techniques. IPSS revealed a complex development in urinary symptoms after radiotherapy. PMID- 25539444 TI - The proposed rule for U.S. clinical trial registration and results submission. PMID- 25539445 TI - Ebola in West Africa at one year--from ignorance to fear to roadblocks. PMID- 25539447 TI - Ebola in Freetown area, Sierra Leone--a case study of 581 patients. PMID- 25539448 TI - Controlled folding of graphene: GraFold printing. AB - We have used elastomeric stamps with periodically varying adhesive properties to introduce structure and print folded graphene films. The structure of the induced folds is investigated with scanning probe techniques, high-resolution electron microscopy, and tip-enhanced Raman spectroscopy. Furthermore, a finite element model is developed to show the fold formation process. Terahertz spectroscopy reveals induced anisotropy of carrier mobility along, and perpendicular to, the graphene folds. Graphene fold printing is a new technique which allows for significant modification of the properties of 2D materials without damaging or chemically modifying them. PMID- 25539446 TI - West African Ebola epidemic after one year--slowing but not yet under control. PMID- 25539449 TI - New Al-MOFs based on sulfonyldibenzoate ions: a rare example of intralayer porosity. AB - A new sulfone-functionalized metal-organic framework [Al(OH)(SDBA)].0.25DMF, denoted CAU-11, was synthesized using a V-shaped linker molecule 4,4' sulfonyldibenzoic acid (H2SDBA). The crystal structure was solved from synchrotron X-ray powder diffraction data. Chains of trans corner-sharing AlO6 octahedra are interconnected by the carboxylate groups to form layers (ABAB stacking). Within the layers, hydrophobic lozenge-shaped pores with a diameter of 6.4 * 7.1 A(2) are present inducing permanent porosity (aBET = 350 m(2) g(-1) and Vmicro = 0.17 cm(3) g(-1)). With the application of HT-methods (HT = high throughput), the isoreticular carboxylate functionalized compound [Al(OH)(H2DPSTC)].0.5H2O (CAU-11-COOH) was synthesized using the linker molecule 3,3',4,4'-diphenylsulfonetetracarboxylic dianhydride (DPSDA), which hydrolyzes under the reaction conditions. Due to the additional noncoordinating carboxylic acid groups the pores are hydrophilic. Changing the molar ratio of Al(3+) to linker lead to the discovery of a second new compound [Al2(OH)2(DPSTC)(H2O)2].0.5H2O (CAU-12). In CAU-12 the linker molecule is fully deprotonated which leads to different connectivity compared to the structure of CAU-11-COOH. Thermal activation of CAU-12 leads to dehydration and transformation of the structure to [Al2(OH)2(DPSTC)].nH2O (CAU-12-dehy). Coordinated water molecules were removed, and the coordination site is replaced by the previously noncoordinating O atom of the adjacent carboxylate group. The SO2-groups point into the pores resulting in a highly hydrophobic three-dimensional framework. The compounds exhibit high thermal stability in air at least up to 420 degrees C. Synthesis of CAU-11 can be easily scaled up in very high yields (98%). PMID- 25539452 TI - The clinical utility of multimodal MR image-guided needle biopsy in cerebral gliomas. AB - PURPOSE: Our aim was to evaluate the diagnostic value of multimodal Magnetic Resonance (MR) Image in the stereotactic biopsy of cerebral gliomas, and investigate its implications. MATERIALS AND METHODS: Twenty-four patients with cerebral gliomas underwent (1)H Magnetic Resonance Spectroscopy ((1)H-MRS)- and intraoperative Magnetic Resonance Imaging (iMRI)-supported stereotactic biopsy, and 23 patients underwent only the preoperative MRI-guided biopsy. The diagnostic yield, morbidity and mortality rates were analyzed. In addition, 20 patients underwent subsequent tumor resection, thus the diagnostic accuracy of the biopsy was further evaluated. RESULTS: The diagnostic accuracies of biopsies evaluated by tumor resection in the trial groups were better than control groups (92.3% and 42.9%, respectively, p = 0.031). The diagnostic yield in the trial groups was better than the control groups, but the difference was not statistically significant (100% and 82.6%, respectively, p = 0.05). The morbidity and mortality rates were similar in both groups. CONCLUSIONS: Multimodal MR image-guided glioma biopsy is practical and valuable. This technique can increase the diagnostic accuracy in the stereotactic biopsy of cerebral gliomas. Besides, it is likely to increase the diagnostic yield but requires further validation. PMID- 25539454 TI - Coexistence of high-T(c) ferromagnetism and n-type electrical conductivity in FeBi2Se4. AB - The discovery of n-type ferromagnetic semiconductors (n-FMSs) exhibiting high electrical conductivity and Curie temperature (Tc) above 300 K would dramatically improve semiconductor spintronics and pave the way for the fabrication of spin based semiconducting devices. However, the realization of high-Tc n-FMSs and p FMSs in conventional high-symmetry semiconductors has proven extremely difficult due to the strongly coupled and interacting magnetic and semiconducting sublattices. Here we show that decoupling the two functional sublattices in the low-symmetry semiconductor FeBi2Se4 enables unprecedented coexistence of high n type electrical conduction and ferromagnetism with Tc ~ 450 K. The structure of FeBi2Se4 consists of well-ordered magnetic sublattices built of [FenSe4n+2]infinity single-chain edge-sharing octahedra, coherently embedded within the three-dimensional Bi-rich semiconducting framework. Magnetotransport data reveal a negative magnetoresistance, indicating spin-polarization of itinerant conducting electrons. These findings demonstrate that decoupling magnetic and semiconducting sublattices allows access to high-Tc n- and p-FMSs as well as helps unveil the mechanism of carrier-mediated ferromagnetism in spintronic materials. PMID- 25539453 TI - Cardiac CaMKIIdelta splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart. AB - BACKGROUND: Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca(2+)/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. METHODS AND RESULTS: Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca(2+)-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 +/- 18 vs 548 +/- 9, s, p<0.05), yet had augmented P-CaMKII (2.69 +/- 0.30 vs 1.50 +/- 0.14, rel. units, p<0.05) and downstream phosphorylation of phospholamban (1.71 +/- 0.42 vs 0.90 +/- 0.10, p<0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca(2+)-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIdeltaB and CaMKIIdeltaC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. CONCLUSIONS: This study provides new mechanistic evidence that CaMKIIdelta splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIdeltaB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid. PMID- 25539455 TI - In vitro/in vivo investigations to examine the gender differences in the pharmacokinetics of novel oral Janus kinase (JAK) inhibitor ASP015K and sulfate metabolite M2 in rats. AB - 1. Although marked gender differences have been reported for the exposure level of the sulfate metabolite M2 of ASP015K in rats, no such differences have been reported for the unchanged drug. To clarify the cause of these pharmacokinetic gender differences, we investigated the in vitro hepatic sulfation, glucuronidation, and cytochrome P450 (CYP) metabolism of ASP015K in rat liver cytosols or rat liver microsomes. Further, in vivo excretion and metabolic profiles were investigated using rat urine, bile, and feces post-ASP015K administration. 2. In vitro metabolism study using liver cytosols clearly suggested that the gender differences in the M2 exposure were mainly attributed to the female-predominant ASP015K metabolism mediated by sulfotransferase (SULT). Metabolic profiles in urine and bile from male rats suggested that the major elimination pathway of ASP015K is glucuronidation in rats. No remarkable gender differences in the in vitro glucuronidation were observed. 3. The contribution of the sulfation pathway to the clearance of ASP015K was markedly lower than that of the glucuronidation pathway in both male and female rats. These results might explain why gender differences were not marked for ASP015K exposure but were for M2. PMID- 25539456 TI - Key determinants of the circulatory exposure of organic anions: differences in hepatic uptake between multidrug resistance-associated protein 2 (Mrp2)-deficient rats and wild-type rats. AB - 1. Raloxifene-6-glucuronide (R6G) is a substrate of rat multidrug resistance associated protein 2 (Mrp2), a transporter responsible for biliary excretion of organic anions. 2. Pharmacokinetic modeling of R6G in Eisai hyperbilirubinemic rats (EHBRs), hereditary Mrp2-deficient rats, and wild-type Sprague-Dawley rats (SDRs) indicated that reduction in not only biliary excretion but also hepatic uptake of R6G influenced low clearance in EHBRs. 3. An integration plot study demonstrated that the hepatic uptake of R6G was 66% lower in EHBRs than that in SDRs. A reduction was observed for the other Mrp2 substrate Valsartan (95% lower) but not for estradiol-17beta-glucuronide (E217betaG). This variation may be associated with the difference in substrate specificity of transporters and/or inhibition of hepatic uptake of organic anions by endogenous substances such as bilirubin glucuronides. 4. In conclusion, incidental alteration of the hepatic uptake of organic anions should be considered as an explanation of their enhanced systemic exposure in EHBRs. PMID- 25539457 TI - Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats. AB - 1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained >=3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates. PMID- 25539458 TI - Characterization of bovine phenol sulfotransferases: evidence of a major role for SULT1B1 in the liver. AB - 1. Cattle are an important component of the human food chain. Drugs used either legally or illegally in cattle may therefore enter the food chain and it is thus important to understand pathways of drug metabolism in this species, including sulfation catalyzed by the sulfotransferases (SULTs). 2. In this study, we have analyzed the sulfation of 4-nitrophenol and other compounds in male and female bovine liver and characterized recombinant bovine SULT isoforms 1A1 and 1B1 expressed in Escherichia coli. 3. We found that, in contrast to most other mammalian species, the major phenol sulfotransferase SULT1A1 is not expressed in bovine liver. Rather SULT1B1 seems to be a major form in both male and female bovine liver. 4. We also identified kinetic differences between bovine and human SULT1A1 and, using the human SULT1A1 crystal structure, identified two amino acid positions in the active site of bovine SULT1A1 (Ile89Val and Phe247Val) that may be responsible for these differences. PMID- 25539459 TI - Swiss clinical practice guidelines on field cancerization of the skin. AB - Actinic keratosis (AK) affects millions of people worldwide, and its prevalence continues to increase. AK lesions are caused by chronic ultraviolet radiation exposure, and the presence of two or more AK lesions along with photodamage should raise the consideration of a diagnosis of field cancerization. Effective treatment of individual lesions as well as field cancerization is essential for good long-term outcomes. The Swiss Registry of Actinic Keratosis Treatment (REAKT) Working Group has developed clinical practice guidelines for the treatment of field cancerization in patients who present with AK. These guidelines are intended to serve as a resource for physicians as to the most appropriate treatment and management of AK and field cancerization based on current evidence and the combined practical experience of the authors. Treatment of AK and field cancerization should be driven by consideration of relevant patient, disease, and treatment factors, and appropriate treatment decisions will differ from patient to patient. Prevention measures and screening recommendations are discussed, and special considerations related to management of immunocompromised patients are provided. PMID- 25539460 TI - CD4+CD45RO+CD25-/lowCD127+: CD4+CD45RO+CD25hiCD127-/low Ratio in Peripheral Blood: A Useful Biomarker to Detect Cardiac Allograft Vasculopathy in Heart Transplanted Patients. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major limitation in long term graft survival after heart transplantation (HTx). Its prediction and detection at an early stage is a challenge because an accurate, minimally invasive blood test is lacking. The aim of this study was to analyze the relationship of Tact (CD4CD45ROCD25-CD127) cells, Th1 cells, and thymus-derived regulatory (Treg) (CD4CD45ROCD25CD127) cells in peripheral blood with the development of CAV in HTx patients. METHODS: First, we performed a cross sectional study in 29 patients at least 2 years after HTx, 17 with CAV and 12 without CAV. We then prospectively followed a group of 38 patients for 2 years immediately after HTx surgery. In both groups, we analyzed the relationship between CAV and the effector-to-regulatory T cell ratio. RESULTS: In the cross sectional study, patients with CAV showed statistically significant higher values of Th1-to-FoxP3Treg and Tact-to-CD127Treg ratios than non-CAV patients, with P less than 0.01 and P less than 0.001, respectively. Receiver operating characteristic curve analysis showed that the Tact:CD127Treg ratio was a potential biomarker of CAV, clearly discriminating CAV and non-CAV patients (area under curve [AUC] = 0.955; P = 0.001). In the prospective part of the study, we monitored the Th1:FoxP3Treg and Tact:CD127Treg ratios using the best tradeoff between anterior receiver operating characteristic sensitivity and specificity as a cutoff. Changes in the Tact:CD127Treg ratio were detected earlier than changes in the Th1:FoxP3Treg ratio. Both ratios were higher in HTx patients with CAV. CONCLUSION: The Tact-to-Treg ratio is a valuable follow-up marker to detect HTx patients at risk of developing CAV. PMID- 25539461 TI - Lactic acidosis after cardiac transplantation: foe or common innocent bystander? AB - BACKGROUND: Lactic acidosis (LA) frequently occurs after heart transplantation (HTx). It is hypothesized to be related to inotropic support or metabolic derangements from chronic heart failure. As such, restoring hemodynamic stability with mechanical circulatory support before HTx should mitigate this problem. Our aim was to evaluate the incidence and outcomes of LA after HTx. METHODS: We evaluated HTx recipients January 2000 to May 2011. Post-HTx outcomes included graft dysfunction, length of intensive care unit stay, length of hospital stay, inotropic support, and survival. RESULTS: Of 143 eligible patients, 98.6% had LA, 67% severe, after HTx. Data were analyzed based on the severity of LA. Time to peak lactate, intensive care unit stay, length of hospital stay, peak glucose, inotropic dose, graft dysfunction, and survival after HTx were similar between groups. Statistically significant differences included pretransplant support (25.6% mechanical circulatory support in nonsevere vs. 44.9% severe LA), hospitalization at the time of HTx (37.2% vs. 21.4%), glucose at the time of peak lactate (182.88 +/- 69.80 vs. 221.31 +/- 56.91), ischemic time (187.4 +/- 63.1 vs. 215.5 +/- 68.1), and duration of inotrope. CONCLUSION: Severe LA is common after HTx, though it appears to be transient and benign. Mechanical circulatory support after HTx does not prevent LA. High lactate levels are associated with longer ischemic times, longer duration of inotrope, and correspond with higher glucose levels. The underlying mechanism is yet to be satisfactorily elucidated. PMID- 25539462 TI - Optimizing pancreas transplantation outcomes in obese recipients. AB - BACKGROUND: Pancreas transplant recipient obesity has been associated with increased risk of perioperative complications, graft failure, and death. The imperative to maximize organ utility must be balanced against the need to maintain equity of access, including for the increasing number of obese diabetic patients. METHODS: We compared the outcomes of pancreas transplant recipients with body mass index (BMI) greater than 30 kg/m(2) (n=60, mean +/- SD BMI 32.1 +/ 1.7 kg/m(2)) to those with BMI less than 30 kg/m(2) (n=308, mean +/- SD BMI 24.5 +/- 2.7 kg/m(2)) between 1996 and 2013. RESULTS: There were no differences in the pretransplant recipient or donor characteristics apart from BMI. The BMI greater than 30 group were more likely to suffer a rejection episode (43% vs. 29%; P = 0.03). The median time to first rejection was shorter (1 vs. 6 months; P = 0.04), and wound infection was more common in the BMI greater than 30 group (P = 0.03). There was no difference in the rate of patient, pancreas, or kidney graft survival or difference in graft function between the two groups. CONCLUSION: The obese recipients in this study were in the lower range of the obese category. Although there was an increased risk of rejection and wound infection in the obese group, there was no difference in patient or graft survival. This finding, when compared with previous reports, may be related to stringent recipient selection and posttransplant care particularly with respect to cardiovascular disease. PMID- 25539463 TI - Luminal injection of hydrogen-rich solution attenuates intestinal ischemia reperfusion injury in rats. AB - BACKGROUND: Luminal preservation of the intestine is an attractive method to locally mitigate preservation injury and ischemic-reperfusion injury in small bowel transplantation (SBT) because this method has a potential to maintain the intestinal graft integrity. Hydrogen is noted as an antioxidant material by reducing hydroxyl radicals. We hypothesized that hydrogen-containing solution can be an optimum material for luminal preservation method in SBT. METHODS: Ischemic reperfusion was induced in Lewis rats by occlusion of the supramesenteric artery and vein for 90 min. Experimental protocols were divided into four groups: sham operation group, no luminal injection (control) group, luminal injection of 5% glucose saline (GS) solution group, and luminal injection of hydrogen-rich GS (HRGS) group. Two milliliters of experimental solution was locally injected into the lumen of the intestine before declamping of vessels. Oxidative stress markers, proinflammatory cytokines, apoptosis in the crypt cells, and morphologic changes of the intestine were assessed. RESULTS: The production of malondialdehyde and 8-hydroxydeoxyguanosine, as oxidative stress markers, were markedly suppressed in HRGS group. The level of proinflammatory cytokines, such as inducible nitric oxide synthase and interleukin-6, was significantly inhibited in HRGS group. Crypt apoptosis was also significantly suppressed in HRGS group. Histopathologically, integrity of villus in intestine was maintained in HRGS group in comparison to the other groups. CONCLUSION: Luminal injection of hydrogen-rich solution can reduce oxidative stress and consequently ameliorate ischemic-reperfusion injury. Hydrogen-containing solution can be a novel and promising luminal preservation material in SBT. PMID- 25539464 TI - Steroid-free Liver Transplantation Using Rabbit Antithymocyte Globulin Induction in 500 Consecutive Patients. AB - BACKGROUND: We have previously documented the efficacy of a steroid-free immunosuppression protocol using rabbit antithymocyte globulin (RATG) induction in orthotopic liver transplantation (OLT) with tacrolimus minimization. The purpose of this report is to demonstrate the benefits of this protocol in a large cohort of patients. METHODS: We evaluated outcomes of 500 consecutive OLT recipients who received RATG induction and a single dose of solumedrol given before the first dose of RATG. Mycophenolate mofetil was initiated postoperatively with delayed initiation of tacrolimus. Sirolimus replaced tacrolimus if serum creatinine remained above 2.0 mg/dL by day 7. Patients were weaned to tacrolimus or sirolimus monotherapy at 3 months. Mean model for end stage liver disease (MELD) at transplantation was 22 +/- 6. RESULTS: Forty-four percent of patients had hepatitis C. Posttransplant creatinine was highest at 1 month (1.43 +/- 0.95 mg/dL) and improved to 1.26 +/- 0.60 mg/dL (P < 0.05) at 2.5 years. Glomerular filtration rate was lowest at 1 month (65.6 +/- 30.0) and improved by 1 year (72.7 +/- 28.2, P < 0.01). Tacrolimus was initiated at 4.79 +/ 13.3 days with a level of 4.95 +/- 2.45 ng/mL at 1 year. One-year patient and graft survival were 92.8% and 89.6%, respectively, with a 3-year patient survival of 82.9%. Rejection occurred in 114 (22.8%) patients, 33 (6.6%) patients requiring steroids. Univariate and multivariate Cox proportional hazard analyses were performed to evaluate the effects of donor and recipient characteristics on patient and graft survivals. Pretransplant creatinine was consistently a statistically significant predictor for patient and graft survival. CONCLUSION: This is the largest reported series of OLT recipients using a steroid-free protocol with RATG induction demonstrating excellent outcomes, low complication rates, and preservation of renal function. PMID- 25539465 TI - Risk factors of metabolic disorders after liver transplantation: an analysis of data from fasted patients. AB - BACKGROUND: Metabolic disorders are common complications after orthotopic liver transplantation (OLT) and may lead to increased morbidity and mortality. METHODS: Fasting glucose and lipid metabolism, and body weight of 81 patients undergoing primary OLT were prospectively analyzed. Patients were investigated preoperatively, on postoperative days 1, 3, 5, 10, 14, 28 as well as 6 months and 1 year after OLT. Data of nonfasted patients were excluded from the analysis. Standardized definitions and classifications for diabetes mellitus (DM), body mass index (BMI), and dyslipidemia were used. RESULTS: Prevalence of new-onset diabetes after transplantation was 9.3%, and obesity was its only independent risk factor (odds ratio [OR], 16.5). Preoperative impaired glucose homeostasis (OR, 10.8) and initial poor graft function (OR, 6.89) were independent risk factors for postoperative DM. Maximum prevalence of hypertriglyceridemia and hypercholesterolemia was found on postoperative day 10 and 6 months post-OLT, respectively. Risk factors for hypercholesterolemia at 1 year were patient age (OR, 1.17) and postoperative renal dysfunction (OR, 16.33). Higher preoperative BMI was a risk factor for postoperative hypertriglyceridemia (OR, 1.17). Overall body weight and BMI significantly decreased over 1 year (P < 0.05). Prevalence of obesity was 22.2% before and 20.9% after OLT. CONCLUSION: For the first time, initial poor graft function was identified as a risk factor for post-OLT DM. By ruling out any exogenous factors influencing metabolism, we believe we were able to show the true prevalence of metabolic disorders and therefore provided a valuable contribution to the identification of potential risk factors. PMID- 25539466 TI - Peak panel reactive antibody, cancer, graft, and patient outcomes in kidney transplant recipients. AB - BACKGROUND: High levels of pretransplant panel reactive antibodies (PRA) are known to be associated with detrimental effects on graft outcomes, but the association between pretransplant PRA levels and long-term patient outcomes is unclear. METHODS: Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the risk of rejection, graft failure, mortality and cancer in kidney transplant recipients with varying peak PRA levels. RESULTS: In 7,118 kidney transplant recipients between 1997 and 2009, there were a total of 3,171 (44.6%), 3,306 (46.4%), 323 (4.5%), and 318 (4.5%) recipients with peak PRA levels of 0%, 1% to 50%, 51% to 80%, and greater than 80%, respectively. Compared to recipients with 0% peak PRA level, recipients with peak PRA levels greater than 80% were at increased risk of acute rejection (odds ratio, 1.81, 95% confidence interval [95% CI], 1.30-2.35; P < 0.001), death censored graft failure (hazard ratio [HR], 2.06; 95% CI, 1.46-2.91; P < 0.001), all-cause mortality (HR, 1.56; 95% CI, 1.15-2.11; P < 0.001) and cancer (HR, 1.94; 95% CI, 1.26-2.97; P = 0.002) in the adjusted models independent of human leukocyte antigen mismatches and initial immunosuppression. CONCLUSION: Highly sensitized kidney transplant recipients with peak PRA greater than 80% had a greater risk of rejection, graft failure, cancer and death independent of age and time on dialysis. Strategies to reduce transplant waiting time and avoidance of sensitization in all potential transplant candidates are imperative to improve the overall graft and patient survival. PMID- 25539467 TI - Corticosteroid-free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial. AB - BACKGROUND: Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828-836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term. METHODS: Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model. RESULTS: Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (-0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected. CONCLUSION: Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children. PMID- 25539468 TI - Role of innate and acquired immune mechanisms in clinical intestinal transplant rejection. AB - BACKGROUND: Long-term outcomes of intestinal transplantation are limited by infection and rejection. To understand the underlying immune mechanisms, graft infiltrating and peripheral blood cells were analyzed using multiple ex vivo assays in intestinal transplantation recipients. METHODS: Infiltrating cells from rejected (graft enterectomy for rejection) and accepted or quiescent (stoma closure in stable transplant recipients) grafts were isolated and phenotypically characterized as to subsets and Toll-like receptor expressions as well as functionally tested for antimicrobial and antidonor immune responses. Multiparameter antidonor immunity was also assessed serially in the peripheral blood. RESULTS: The graft infiltrating lymphocytes were mostly of recipient origin in all patients tested. In rejecting grafts, the predominant populations were TcRalphabeta(+)CD3(+)CD8(+) T cells, and CD14(+) monocytes that coexpressed Toll-like receptor-2, receptor-3, receptor-4, receptor-5, and receptor-9, suggesting innate immune activation. In quiescent allografts the major cell subsets were CD13(+)CD14(-) monocytes and CD4(+)CD25(+) T cells with possible regulatory functions. Infiltrating cells from rejected but not quiescent grafts proliferated in response to enteric bacterial and donor antigens as well as killed donor targets. Serial follow-up of peripheral blood indicated donor specific posttransplant unresponsiveness in micro-cell-mediated lympholysis (m CML) and mixed lymphocyte reaction (MLR) in recipients with quiescent grafts, but not in recipients with multiple rejection episodes. Enzyme-Linked ImmunoSpot assays yielded parallel results: granzyme-B with micro-cell-mediated lympholysis and interferon-gamma with MLR tests. CONCLUSION: These results were consistent with the notion that rejection was associated with innate and acquired antimicrobial and antidonor immune reactivity and that patients with stable grafts were free from these deleterious effects. PMID- 25539469 TI - Renal allograft loss caused by cardiorenal syndrome: frequency and diagnosis. AB - BACKGROUND: Scientific interest in cardiorenal syndrome (CRS) affecting the native kidneys is increasing. In contrast, no relevant literature exists on CRS after kidney transplantation. METHODS: Prompted by the clinical course of a renal allograft recipient, who lost his graft because of CRS, we systematically investigated the frequency, the clinical appearance, the underlying cardiac pathophysiology, and the renal pathology of patients with graft loss caused by CRS between 2006 and 2011 at our center. RESULTS: We identified seven cases of graft loss caused by CRS, six cases of CRS type II, and one case of CRS type I. The proportion of death-censored graft losses caused by CRS was 4.6% (7/152 patients). Median graft survival after diagnosis was 6 (1-62) months. Clinically, all patients suffered from repeated episodes of decreasing renal function together with severe volume overload necessitating multiple hospitalizations (range, 23-308 days) and ultrafiltration treatments (range, 4-45). Cardiac investigation revealed a combination of left heart failure, right heart failure and moderate-to-severe tricuspid regurgitation in 5/6 CRS type II patients. Renal allograft pathology showed the same pattern of tubular injury in all biopsy specimens: microvesicular tubular epithelial cytoplasmatic vacuolization and luminal dilatation with flattening of the epithelium. CONCLUSION: We propose that the diagnosis of CRS after renal transplantation should be based on the following triad: (i) otherwise unexplained decrease of renal function together with severe volume overload; (ii) functionally relevant heart disease, predominantly left heart failure in combination with right heart failure, and tricuspid regurgitation; and (iii) a typical histopathologic pattern of tubular injury. PMID- 25539470 TI - Carreira alkynylations with paraformaldehyde. a mild and convenient protocol for the hydroxymethylation of complex base-sensitive terminal acetylenes via alkynylzinc triflates. AB - A new synthetic protocol for the hydroxymethylation of terminal acetylenes is described that involves stoichiometric Carreira alkynylation with solid paraformaldehyde (HO[CH2O]nH) in PhMe at 60 degrees C. Significantly, the method can be successfully applied on acetylenes that possess base-sensitive ester functionality and heterocyclic rings that readily undergo metalation. While N methylephedrine (NME) is generally the best Zn(OTf)2-coordinating ligand for promoting hydroxymethylation, TMEDA can serve as a replacement. PMID- 25539471 TI - Comparative analysis of lipotoxicity induced by endocrine, pharmacological, and innate immune stimuli in rat basophilic leukemia cells. AB - Cellular lipotoxicity manifests as the steatotic accumulation of lipid droplets or lipid bodies, and/or induction of phospholipidosis. Lipotoxicity can be induced by hyperinsulinemia/nutrient overload, cationic amphiphilic drugs (CAD), and innate immunological stimuli, all of which are stimuli relevant to mast cell physiology. Hyper-accumulation of mast cell lipid bodies in response to hyperinsulinemia has been documented, but lipotoxicity in response to CAD or innate immunologic stimuli has not been analysed comparatively. Moreover, gaps in our understanding of this steatosis remain, specifically as to whether hyperinsulinemia-driven steatosis in these cells attains lipotoxic levels or is accompanied by phospholipidosis. To compare endocrine, pharmacological, and innate immunological stimuli for their ability to induce steatosis and phospholipidosis in a rat basophilic leukemia mast cell model (RBL2H3), differential fluorescence microscopy staining and quantitation of phospholipidosis and steatosis in the RBL2H3 cell line was examined. The three classes of stimuli differentially induced phospholipidosis and steatosis. PPARgamma up-regulation was not uniformly associated with the expansion of the lipid body population. Fluorescence imaging of lipid-enriched structures generated in response to lipotoxic cationic amphiphilic drugs, chronic insulin exposure, and TLR2/4 ligands revealed differential staining patterns when visualized using lipophilic dyes. It is concluded that lipotoxicity-inducing pathways in this model mast cell system are diverse, and include steatotic responses to an endocrine stimulus, as well as phospholipidosis responses to cationic lipophilic drugs not previously described in this cell type. PMID- 25539472 TI - Cytotoxic and antioxidant properties of phenolic compounds from Tagetes patula flower. AB - CONTEXT: Tagetes patula Linn. (Asteraceae) (French Marigold) flowers are used by local practitioners for cancer treatment; however, it lacks scientific justification. OBJECTIVE: Identification of bioactive compounds in T. patula flower for cytotoxic and growth inhibition in human cancer cell lines along with its antioxidant properties using chemical and cell based systems. MATERIALS AND METHODS: The T. patula flower methanol extract, its seven fractions, and three phenolic compounds including methyl protocatechuate (1), patuletin (2), and patulitrin (3) were evaluated using sulforhodamine-B assay against HeLa, HT-144, NCI-H460, MCF-7, PC-3, and SF-268 human cancer cell lines. In parallel, antioxidant activity was evaluated using chemical (DPPH(.), deoxyribose, and lipid peroxidation assays) and cell-based chemiluminescence systems (human neutrophils and mice macrophages). RESULTS: The methanol extract and ethyl acetate insoluble fraction exhibited cytotoxic and growth inhibitory effects against HeLa in which 2 exhibited highest cell growth inhibition (GI50: 0.6 +/- 0.1 ug/ml) and cytotoxicity (LC50: 2.5 +/- 0.1 ug/ml). It also scavenged LOO(.) (IC50: 6.5 +/- 0.7 ug/ml) and [Formula: see text] (IC50: 27.5 +/- 1.3 MUg/ml) in chemical systems and human neutrophils, respectively. However, 1 preferably scavenged H2O2-Cl(-) (IC50: 0.5 +/- 0.01 MUg/ml) in mice macrophages. DISCUSSION AND CONCLUSION: Compound 2 from T. patula flower exhibited both growth inhibitory and cytotoxic properties while 1 and 3 were only growth inhibitory against HeLa. 1-3 also displayed antioxidant properties implying its probable role in growth inhibition/cytotoxic action. The present study provides scientific evidence for the use of T. patula flower in cancer treatment by traditional healer. PMID- 25539473 TI - Using network science in the language sciences and clinic. AB - A number of variables-word frequency, word length-have long been known to influence language processing. This study briefly reviews the effects in speech perception and production of two more recently examined variables: phonotactic probability and neighbourhood density. It then describes a new approach to study language, network science, which is an interdisciplinary field drawing from mathematics, computer science, physics and other disciplines. In this approach, nodes represent individual entities in a system (i.e. phonological word-forms in the lexicon), links between nodes represent relationships between nodes (i.e. phonological neighbours) and various measures enable researchers to assess the micro-level (i.e. the individual word), the macro-level (i.e. characteristics about the whole system) and the meso-level (i.e. how an individual fits into smaller sub-groups in the larger system). Although research on individual lexical characteristics such as word-frequency has increased understanding of language processing, these measures only assess the "micro-level". Using network science, researchers can examine words at various levels in the system and how each word relates to the many other words stored in the lexicon. Several new findings using the network science approach are summarized to illustrate how this approach can be used to advance basic research as well as clinical practice. PMID- 25539474 TI - Learning from input and memory evolution: points of vulnerability on a pathway to mastery in word learning. AB - Word learning consists of at least two neurocognitive processes: learning from input during training and memory evolution during gaps between training sessions. Fine-grained analysis of word learning by normal adults provides evidence that learning from input is swift and stable, whereas memory evolution is a point of potential vulnerability on the pathway to mastery. Moreover, success during learning from input is linked to positive outcomes from memory evolution. These two neurocognitive processes can be overlaid on to components of clinical treatment with within-session variables (i.e. dose form and dose) potentially linked to learning from input and between-session variables (i.e. dose frequency) linked to memory evolution. Collecting data at the beginning and end of a treatment session can be used to identify the point of vulnerability in word learning for a given client and the appropriate treatment component can then be adjusted to improve the client's word learning. Two clinical cases are provided to illustrate this approach. PMID- 25539475 TI - Efficacy and safety of prucalopride in adults and children with chronic constipation. AB - INTRODUCTION: Chronic constipation (CC) is a debilitating condition with high prevalence rates both in children and adults. Despite the broad range of medical and pharmaceutical treatments, the bowel function does not restore in a fair amount of patients. Prucalopride is a first-in-class selective, high affinity serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist promoting gastro intestinal prokinetic activity and has been evaluated for the treatment of CC. AREAS COVERED: A PubMed search (1965 - 2014) using the following terms alone or in combination: prucalopride, 5-HT4, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, human ether-a-go-go related gene (hERG), arrhythmia, potassium current, elderly, children. EXPERT OPINION: Prucalopride, a highly selective 5-HT4 receptor agonist, stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency, reducing constipation-related symptoms and improving quality of life (QoL). The safety and tolerability have been proven to be excellent. More research would be preferable on the effect of prucalopride on men, children and in other gastrointestinal motility disorders. PMID- 25539476 TI - Elite female athletes' ventilatory compensation to decreased inspired O2 during the wingate test. AB - PURPOSE: The purpose of this study was to determine if anaerobic performance as measured by the Wingate is decremented in elite female athletes when fraction of inspired oxygen is decreased from 20.9% to 10%. METHOD: Nine collegiate female soccer players (Mweight = 63.2 +/- 10 kg, Mheight = 164 +/- 4.7 cm, Mage = 18.6 +/- 0.5 year) performed 1 Wingate test under each condition separated by at least 24 hr. Oxygen consumption was measured breath by breath using a Sensor-Medics metabolic cart. Postexercise blood lactates were measured using the finger-stick method. During normoxic and hypoxic (10% inspired oxygen [O2]) conditions, participants inhaled air from a 300-L weather balloon during the 30-s test. RESULTS: Peak power, minimum power, average power, postexercise blood lactate, preexercise and postexercise blood O2 saturation, and total O2 consumed during exercise and during recovery were not statistically different between conditions. However, the Fatigue Index and peak ventilation were significantly greater during hypoxia than normoxia (35 +/- 11% vs. 27 +/- 9% & 91.6 +/- 14.2 L/min vs. 75.2 +/ 11.1 L/min, respectively, p < .05, Cohen's d = - 0.80 and - 1.29, respectively). Ventilation was elevated during hypoxia within 5 s of beginning the Wingate and remained elevated throughout exercise. This increased ventilation was sufficient to maintain oxygen consumption during exercise. CONCLUSION: Under hypoxic conditions, the ventilatory response to the Wingate test is perhaps more important than aerobic capacity per se in determining whether or not Wingate performance is decremented. PMID- 25539477 TI - Motor Performance as Predictor of Physical Activity in Children: The CHAMPS Study DK. AB - PURPOSE: Physical activity (PA) is associated with several health benefits in children, and PA habits developed in childhood tend to persist into adulthood. PA may be the foundation of a healthy lifestyle, and motor performance has been shown to be positively associated with PA in cross-sectional studies. The purpose of this study was to explore the longitudinal relation between motor performance and PA in a 3-yr follow-up study. METHODS: Longitudinal analyses were performed using data from 673 participants (44% boys, 6-12 yr old) who had been included in the Childhood Health Activity and Motor Performance School study-DK. Baseline motor performance tests consisted of vertical jump, shuttle run, hand grip strength, backward balance, precision throw, and cardiovascular fitness. Composite z-scores were generated to express health-related fitness and performance-related fitness. PA was measured by accelerometer at baseline and at 3-yr follow-up and was expressed as a percentage of time in moderate-to-vigorous PA. RESULTS: Cardiovascular fitness, vertical jump, health-related fitness, and performance-related fitness showed significant positive associations with 3-yr follow-up measures of PA in both sexes. Furthermore, shuttle run showed significant inverse associations with follow-up measures of PA for both sexes. CONCLUSIONS: Cardiorespiratory fitness, shuttle run, vertical jump, health related fitness, and performance-related fitness were significantly associated with time spent in moderate-to-vigorous PA at 3-yr follow-up. The clinical relevance of the results indicates that cardiorespiratory fitness and shuttle run in childhood may be important determinants of PA in adolescence. PMID- 25539478 TI - Neuromuscular Exercise post Partial Medial Meniscectomy: Randomized Controlled Trial. AB - PURPOSE: This study aimed to evaluate the effects of a 12-wk, home-based, physiotherapist-guided neuromuscular exercise program on the knee adduction moment (an indicator of mediolateral knee load distribution) in people with a medial arthroscopic partial meniscectomy (APM) within the past 3-12 months. METHODS: An assessor-blinded, randomized controlled trial including people age 30 50 yr with no to mild pain after medial APM was conducted. Participants were randomly allocated to either a 12-wk neuromuscular exercise program that targeted neutral lower limb alignment or a control group with no exercise. The exercise program included eight individual sessions with one of seven physiotherapists in private clinics, together with home exercises. Primary outcomes were the peak external knee adduction moment during normal-paced walking and during one-leg sit to-stand. Secondary outcomes included additional measures of knee joint load distribution, patient-reported outcomes, maximal knee and hip muscle strength, and physical function measures. RESULTS: Of 62 randomized participants, 60 (97%) completed the trial. There were no significant between-group differences in the change in peak knee adduction moment during normal-paced walking (mean difference (95% confidence interval), 0.22 (-0.11 to 0.55) N.m/body weight * height %, P =0.19) or during one-leg sit-to-stand (-0.01 (-0.33 to 0.31) N.m/body weight * height %, P = 0.95). There were also no significant between-group differences for any of the secondary outcomes. CONCLUSIONS: In patients 3-12 months after a medial APM, a neuromuscular exercise program did not alter the peak knee adduction moment, a key predictor of osteoarthritis structural disease progression. (Australia and New Zealand Clinical Trials Registry, #ACTRN12612000542897.). PMID- 25539480 TI - Effect of Training Intensity on Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Training intensity may play a key role in magnifying the protective effect of physical exercise against nonalcoholic fatty liver disease (NAFLD). PURPOSE: This study aimed to test the hypothesis that vigorous-intensity and interval training is as effective as moderate-intensity and continuous exercise training on NAFLD in high-fat diet (HFD)-induced obese mice. METHODS: C57BL/6 mice (N = 40) were fed a standard-chow diet (n = 10) or HFD (n = 30) for 16 wk. After the initial 8-wk dietary treatments, HFD mice were further divided into HFD only (n = 10), HFD plus vigorous-intensity and interval treadmill running (VIT) (n = 10), and HFD plus moderate-intensity and continuous treadmill running (MIT) (n = 10) for the remaining 8-wk period. RESULTS: Chronic exposure to HFD resulted in hepatic steatosis in conjunction with an obese and impaired glucose tolerance condition characterized by dyslipidemia, hyperinsulinemia elevated markers for the liver damage, and hypoadiponectinemia. Although VIT and MIT alleviated the NAFLD conditions, the former was more effective at alleviating hepatic steatosis than the latter. The intensity-dependent benefit of exercise training against hepatic steatosis was associated with greater activation of VIT on hepatic AMP mediated protein kinase in conjunction with greater suppressive effect of VIT on hypoadiponectinemia, downregulation of the Adiponectin receptor 2 signaling pathway, and upregulation of the NF-kappaB signaling pathway in the liver. CONCLUSIONS: The current findings suggest that VIT is an alternative way of exercise training to combat hepatic steatosis associated with an obese and impaired glucose tolerance phenotype. PMID- 25539481 TI - The behavioural pharmacology of the basal ganglia: in memory of Lex Cools. PMID- 25539479 TI - Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle. AB - INTRODUCTION: Loss of mitochondrial competency is associated with several chronic illnesses. Therefore, strategies that maintain or increase mitochondrial function will likely be of benefit in numerous clinical settings. Endurance exercise has long been known to increase mitochondrial function in the skeletal muscle. Comparatively little is known regarding the effect of resistance exercise training (RET) on skeletal muscle mitochondrial respiratory function. PURPOSE: The purpose of the current study was to determine the effect of chronic resistance training on skeletal muscle mitochondrial respiratory capacity and function. METHODS: Here, we studied the effect of a 12-wk RET program on skeletal muscle mitochondrial function in 11 young healthy men. Muscle biopsies were collected before and after the 12-wk training program, and mitochondrial respiratory capacity was determined in permeabilized myofibers by high-resolution respirometry. RESULTS: RET increased lean body mass and quadriceps muscle strength by 4% and 15%, respectively (P < 0.001). Coupled mitochondrial respiration supported by complex I, and complex I and II substrates increased by 2- and 1.4-fold, respectively (P < 0.01). The ratio of coupled complex I supported respiration to maximal respiration increased with RET (P < 0.05), as did complex I protein abundance (P < 0.05), whereas the substrate control ratio for succinate was reduced after RET (P < 0.001). Transcripts responsible for proteins critical to electron transfer and NAD production increased with training (P < 0.05), whereas transcripts involved in mitochondrial biogenesis were unaltered. CONCLUSIONS: Collectively, 12 wk of RET resulted in qualitative and quantitative changes in skeletal muscle mitochondrial respiration. This adaptation was accompanied by modest changes in mitochondrial proteins and transcript expression. RET seems to be a means to augment the respiratory capacity and intrinsic function of skeletal muscle mitochondria. PMID- 25539482 TI - Synthesis and characterization of monodispersed beta-Ga2O3 nanospheres via morphology controlled Ga4(OH)10SO4 precursors. AB - To our best knowledge, monodispersed beta-Ga2O3 nanospheres were successfully synthesized for first time via morphology-controlled gallium precursors using the forced hydrolysis method, followed by thermal calcination processes. The morphology and particle sizes of the gallium precursors were strongly dependent on the varying (R = SO4(2-)/NO3(-)) concentration ratios. As R decreased, the size of the prepared gallium precursors decreased and morphology was altered from sphere to rod. The synthesized S2 (R = 0.33) consists of uniform and monodispersed amorphous nanospheres with diameters of about 200 nm. The monodispersed beta-Ga2O3 nanospheres were synthesized using thermal calcination processes at various temperatures ranging from 500 to 1000 degrees C. Monodispersed beta-Ga2O3 nanospheres (200 nm) consist of small particles of approximately 10-20 nm with rough surface at 1000 degrees C for 1 h. The UV (375 nm) and broad blue (400-450 nm) emission indicate recombination via a self trapped exciton and the defect band emission. Our approach described here is to show the exploration of beta-Ga2O3 nanospheres as an automatic dispersion, three dimensional support for fabrication of hierarchical materials, which is potentially important for a broad range of optoelectronic applications. PMID- 25539485 TI - Improving trauma care for pregnant patients at the LAC+USC Medical Center by conducting regular multidisciplinary drills. PMID- 25539484 TI - Clinical characteristics of IgA nephropathy associated with low complement 4 levels. AB - OBJECTIVE: C4 deficiency is the most commonly inherited immune disorder in human. The present study investigated the characteristics of the IgAN patients with low serum C4 levels. METHODS: We performed a prospective observational study. Clinical as well as histopathologic parameters were assessed. A Kaplan-Meier survival analysis was performed concerning the primary outcome defined as the serum creatinine increased 1.5-fold from baseline. The prognostic significances of clinical and histopathologic parameters were determined using Cox proportional hazards models. RESULTS: Five-hundred twelve biopsy proven IgAN cases were available for analysis with a median follow-up of 38.4 months. Ninety-nine cases (19.34%) presented with low C4 levels (LowC4 group) and the other 413 cases did not (NlowC4 group). At the time of renal biopsy, renal injury was lighter in the LowC4 group compared with the NlowC4 group. Renal C4 deposition was significantly decreased while IgM deposition was increased in the LowC4 group. A correlation analysis shows that lower C4 levels were associated with better renal presentations at biopsy. However, the risk of developing the primary outcome was significantly greater in those with low C4 levels. Specifically, during the follow-up period, the risk of developing primary outcome was nearly ten folds higher in those with low C4, compared to those without low C4. CONCLUSION: There is a high prevalence of low C4 levels in IgAN patients. These patients with low C4 levels exhibited better renal presentations at the time of renal biopsy, whereas might be associated with a poor prognosis. PMID- 25539483 TI - Understanding why patients with COPD get readmitted: a large national study to delineate the Medicare population for the readmissions penalty expansion. AB - BACKGROUND: The Hospital Readmissions Reduction Program (HRRP) penalizes hospitals for 30-day readmissions and was extended to COPD in October 2014. There is limited evidence available on readmission risk factors and reasons for readmission to guide hospitals in initiating programs to reduce COPD readmissions. METHODS: Medicare claims data from 2006 to 2010 in seven states were analyzed, with an index admission for COPD defined by discharge International Classification of Diseases, Ninth Revision, codes as stipulated in the HRRP guidelines. Rates of index COPD admission and readmission, patient demographics, readmission diagnoses, and use of post-acute care (PAC) were investigated. RESULTS: Over the study period, there were 26,798,404 inpatient admissions, of which 3.5% were index COPD admissions. At 30 days, 20.2% were readmitted to the hospital. Respiratory-related diseases accounted for only one half of the reasons for readmission, and COPD was the most common diagnosis, explaining 27.6% of all readmissions. Patients discharged home without home care were more likely to be readmitted for COPD than patients discharged to PAC (31.1% vs 18.8%, P < .001). Readmitted beneficiaries were more likely to be dually enrolled in Medicare and Medicaid (30.6% vs 25.4%, P < .001), have a longer median length of stay (5 days vs 4 days, P < .0001), and have more comorbidities (P < .001). CONCLUSIONS: Medicare patients with COPD exacerbations are usually not readmitted for COPD, and these reasons differ depending on PAC use. Readmitted patients are more likely to be dually enrolled in Medicare and Medicaid, suggesting that the addition of COPD to the readmissions penalty may further worsen the disproportionately high penalties seen in safety net hospitals. PMID- 25539486 TI - Transformational quality in Kaiser Permanente Northern California. AB - The evolving nature of health care related to optimizing the quality of patient care while increasing efficiencies presents an opportunity to redesign roles within hospital quality departments to meet these upcoming challenges. Specifically, passage of the Patient Protection and Affordable Care Act and creation of Accountable Care Organizations will require hospitals to carefully monitor patient care outcomes as well as continually seek to improve their processes. An approach used by the Kaiser Permanente Northern California Regional Quality and Regulatory Services Department assisted the 21 hospitals of Kaiser Permanente Northern California to improve quality-of-care outcomes, establish effective assessment teams, and create infrastructure for sustainability. Leadership by a centralized internal consulting group used a model that weighs risk and opportunity against cost and outcomes to support strategic planning as projects and initiatives developed, rather than after they were initiated. This model can assist other organizations in maximizing cost-efficient and -effective performance improvement approaches to clinical and operational excellence. PMID- 25539487 TI - Reducing pharmacy wait time to promote customer service: a follow-up study. AB - PURPOSE: The present study had 3 objectives: (1) to evaluate the effects of 2 different interventions (feedback regarding customer satisfaction with wait time and combined feedback and goal setting) on wait time in a hospital outpatient pharmacy; (2) to assess the extent to which the previously applied interventions maintained their effects; and (3) to evaluate the differences between the effects of the original study and those of the present follow-up study. SUBJECTS AND METHODS: Participants were 10 employees (4 pharmacists and 6 technicians) of an outpatient pharmacy. Wait times and customer satisfaction ratings were collected for "waiting customers." An ABCB within-subjects design was used to assess the effects of the interventions on both wait time and customer satisfaction, where A was the baseline (no feedback and no goal setting); B was the customer satisfaction feedback; and C was the customer satisfaction feedback, the wait time feedback, and the goal setting for wait time reduction. RESULTS AND CONCLUSIONS: Wait time decreased after baseline when the combined intervention was introduced, and wait time increased with the reintroduction of satisfaction feedback (alone). The results of the replication study confirm the pattern of the results of the original study and demonstrate high sensitivity of levels of customer satisfaction with wait time. The most impressive result of the replication is the nearly 2-year maintenance of lower wait time between the end of the original study and the beginning (baseline) of the replication. PMID- 25539488 TI - Sustaining improvement? The 20-year Jonkoping quality improvement program revisited. AB - BACKGROUND: There is scarce evidence of organization-wide and sustained impact of quality improvement (QI) programs in health care. For 20 years, the Jonkoping County Council's (Sweden) ambitious program has attracted attention from practitioners and researchers alike. METHODS: This is a follow-up case of a 2006 study of Jonkoping's improvement program, triangulating data from 20 semi structured interviews, observation and secondary analysis of internal performance data. RESULTS: In 2010, clinical outcomes had clearly improved in 2 departments (pediatrics, intensive care), while process improvements were evident in many departments. In an overall index of the 20 Swedish county councils' performance, Jonkoping had improved its ranking since 2006 to lead in 2010. Five key issues shaped Jonkoping's improvement program since 2006: a rigorously managed succession of chief executive officer; adept management of a changing external context; clear strategic direction relating to integration; a broadened conceptualization of "quality" (incorporating clinical effectiveness, patient safety, and patient experience); and continuing investment in QI education and research. Physician involvement in formal QI initiatives had increased since 2006 but remained a challenge in 2010. A new clinical information system was being deployed but had not yet met expectations. CONCLUSIONS: This study suggests that ambitious approaches can carry health care organizations beyond the sustainability threshold. PMID- 25539489 TI - Patient-centered care in diagnostic radiology: lessons learned from patient interviews prior to musculoskeletal magnetic resonance imaging. AB - BACKGROUND: Since most radiologists do not meet with patients, questionnaires often substitute for face-to-face interviews to collect patients' history. We report the effect of direct radiologist-patient interviews on the quality of patient history recorded for musculoskeletal magnetic resonance imaging. METHODS: Magnetic resonance imaging questionnaires completed by outpatients were separated into 2 cohorts: (1) imaging center (IC) forms with no radiologist interviews; (2) hospital (H) forms with radiologist-patient interviews. Three blinded radiologists independently scored each questionnaire for quality on a 5-point scale. A separate quantitative analysis was also performed. The unpaired t test, Fischer exact test, and chi2 test were used to compare the cohorts. RESULTS: The mean score of the H cohort among reviewers was superior to the IC cohort: 3.79 (+/-0.98) versus 3.04 (+/-1.00), P < .0001. Each reviewer also independently found the H cohort to be of higher quality for patient history, P < .0001. For the IC cohort, 7.8% of questionnaires did not report a single symptom versus 0.0% in the H cohort, P = .0331. Also, the IC cohort recorded symptoms in 2 or less words more often than the H cohort, P < .0001. CONCLUSION: Brief radiologist patient interviews are superior for obtaining a higher quality of patient history for musculoskeletal MRI than patient questionnaires alone. PMID- 25539490 TI - A multidisciplinary care pathway significantly increases the number of early morning discharges in a large academic medical center. AB - In an environment where there is increased demand for hospital beds, it is important that inpatient flow from admission to treatment to discharge is optimized. Among the many drivers that impact efficient patient throughput is an effective and timely discharge process. Early morning discharge helps align inpatient capacity with clinical demand, thereby avoiding gridlock that adversely affects scheduled surgical procedures, diagnostic procedures, and therapies. At our large, academic medical center, we hypothesized that an interdisciplinary approach to scheduled discharge order entry would increase the percentage of discharges occurring before 11:00 AM and improve overall discharge time. The pilot study involved moving rate-limiting steps to earlier in the discharge process, specifically medication reconciliation to the night before discharge and "discharge to home" order entry before 9:00 AM the morning of discharge. The baseline rate of discharges before 11:00 AM was 8% and significantly increased to 11% after the intervention (P = .02). Moreover, in the subset of patients (21%) for whom early medication reconciliation and discharge to home order entry were both executed, the percentage of patient discharges occurring before 11:00 AM increased to 29.7%, with an associated average discharge time of more than 3 hours earlier. No patient harm events were associated with this pilot project. There was no significant change in length of stay, and 30-day readmission rate improved significantly from 13.8% to 10.3% (P = .002). Our study demonstrates that a multidisciplinary approach using prescribed order entry and medication reconciliation is a low cost, safe, and effective way to increase early morning discharges and improve patient flow for large hospitals with high volumes of scheduled patient admissions. PMID- 25539491 TI - Hospitals as learning organizations: fostering innovation through interactive learning. AB - The article aims to provide an analytical understanding of hospitals as "learning organizations." It further analyzes the development of learning organizations as a way to enhance innovation and performance in the hospital sector. The article pulls together primary data on organizational flexibility, innovation, and performance from 95 administrators from hospital boards in Portugal, collected through a survey, interviews with hospital's boards, and a nominal group technique with a panel of experts on health systems. Results show that a combination of several organizational traits of the learning organization enhances its capacity for innovation development. The logistic model presented reveals that hospitals classified as "advanced learning organizations" have 5 times more chance of developing innovation than "basic learning organizations." Empirical findings further pointed out incentives, standards, and measurement requirements as key elements for integration of service delivery systems and expansion of the current capacity for structured and real-time learning in the hospital sector. The major implication arising from this study is that policy needs to combine instruments that promote innovation opportunities and incentives, with instruments stimulating the further development of the core components of learning organizations. Such a combination of policy instruments has the potential to ensure a wide external cooperation through a learning infrastructure. PMID- 25539495 TI - Barriers and facilitators to recovering from e-prescribing errors in community pharmacies. AB - OBJECTIVE: To explore barriers and facilitators to recovery from e-prescribing errors in community pharmacies and to explore practical solutions for work system redesign to ensure successful recovery from errors. DESIGN: Cross-sectional qualitative design using direct observations, interviews, and focus groups. SETTING: Five community pharmacies in Wisconsin. PARTICIPANTS: 13 pharmacists and 14 pharmacy technicians. INTERVENTIONS: Observational field notes and transcribed interviews and focus groups were subjected to thematic analysis guided by the Systems Engineering Initiative for Patient Safety (SEIPS) work system and patient safety model. MAIN OUTCOME MEASURES: Barriers and facilitators to recovering from e-prescription errors in community pharmacies. RESULTS: Organizational factors, such as communication, training, teamwork, and staffing levels, play an important role in recovering from e-prescription errors. Other factors that could positively or negatively affect recovery of e-prescription errors include level of experience, knowledge of the pharmacy personnel, availability or usability of tools and technology, interruptions and time pressure when performing tasks, and noise in the physical environment. CONCLUSION: The SEIPS model sheds light on key factors that may influence recovery from e-prescribing errors in pharmacies, including the environment, teamwork, communication, technology, tasks, and other organizational variables. To be successful in recovering from e-prescribing errors, pharmacies must provide the appropriate working conditions that support recovery from errors. PMID- 25539500 TI - A vector reconstruction based clustering algorithm particularly for large-scale text collection. AB - Along with the fast evolvement of internet technology, internet users have to face the large amount of textual data every day. Apparently, organizing texts into categories can help users dig the useful information from large-scale text collection. Clustering is one of the most promising tools for categorizing texts due to its unsupervised characteristic. Unfortunately, most of traditional clustering algorithms lose their high qualities on large-scale text collection, which mainly attributes to the high-dimensional vector space and semantic similarity among texts. To effectively and efficiently cluster large-scale text collection, this paper puts forward a vector reconstruction based clustering algorithm. Only the features that can represent the cluster are preserved in cluster's representative vector. This algorithm alternately repeats two sub processes until it converges. One process is partial tuning sub-process, where feature's weight is fine-tuned by iterative process similar to self-organizing mapping (SOM) algorithm. To accelerate clustering velocity, an intersection based similarity measurement and its corresponding neuron adjustment function are proposed and implemented in this sub-process. The other process is overall tuning sub-process, where the features are reallocated among different clusters. In this sub-process, the features useless to represent the cluster are removed from cluster's representative vector. Experimental results on the three text collections (including two small-scale and one large-scale text collections) demonstrate that our algorithm obtains high-quality performances on both small scale and large-scale text collections. PMID- 25539497 TI - Geometry sensing through POR1 regulates Rac1 activity controlling early osteoblast differentiation in response to nanofiber diameter. AB - Bone grafting procedures in the United States rely heavily upon autografts and allografts, which are donor-dependent, cause donor site pain, and can transmit disease. Synthetic bone grafts can reduce these risks; however, synthetics lack the bone differentiating (osteoinductive) abilities of auto- and allografts. Achieving innate osteoinductive properties of synthetics through surface modifications is currently under investigation. This study focuses on nanofibers, with emphasis on how fiber diameter and the potential curvature sensor POR1 affect the activation of the signaling molecules Rac1 and Arf1, and leading to expression of alkaline phosphatase (ALP), an osteoinductive marker. Diameters of 0.1, 0.3, and 1.0 MUm were compared against a flat control. The highest level of Rac1 activation was achieved on the smallest fibers (0.1 MUm), a trend that was lost in POR1 knockdowns. This supports the hypothesis that on small nanofibers, POR1 favorably binds to highly curved cell membranes, which allows Rac1 to subsequently dissociate and activate. When the curvature is insufficient to bind POR1, POR1 binds to inactive Rac1 and competitively inhibits its activation. Arf1 activation followed an opposite trend, with the largest nanofibers exhibiting the highest activity. This trend reinforces the known interaction between Rac1 and Arf1 through the GIT-PIX complex, an Arf1 GAP and Rac1 GEF, respectively. Large, (1.0 MUm), nanofibers demonstrated the highest ALP activity, indicating that ALP expression is inversely dependent on Rac1 activation. Knockdown of POR1 resulted in increased ALP activity across the substrates but without regard to the curvature sensing trend seen previously. Thus, POR1 senses curvature and increases Rac1 activity, which negatively regulates bone differentiation. PMID- 25539501 TI - Carrier-mediated cocaine transport at the blood-brain barrier as a putative mechanism in addiction liability. AB - BACKGROUND: The rate of entry of cocaine into the brain is a critical factor that influences neuronal plasticity and the development of cocaine addiction. Until now, passive diffusion has been considered the unique mechanism known by which cocaine crosses the blood-brain barrier. METHODS: We reassessed mechanisms of transport of cocaine at the blood-brain barrier using a human cerebral capillary endothelial cell line (hCMEC/D3) and in situ mouse carotid perfusion. RESULTS: Both in vivo and in vitro cocaine transport studies demonstrated the coexistence of a carrier-mediated process with passive diffusion. At pharmacological exposure level, passive diffusion of cocaine accounted for only 22.5% of the total cocaine influx in mice and 5.9% in hCMEC/D3 cells, whereas the carrier-mediated influx rate was 3.4 times greater than its passive diffusion rate in vivo. The functional identification of this carrier-mediated transport demonstrated the involvement of a proton antiporter that shared the properties of the previously characterized clonidine and nicotine transporter. The functionnal characterization suggests that the solute carrier (SLC) transporters Oct (Slc22a1 3), Mate (Slc47a1) and Octn (Slc22a4-5) are not involved in the cocaine transport in vivo and in vitro. Diphenhydramine, heroin, tramadol, cocaethylene, and norcocaine all strongly inhibited cocaine transport, unlike benzoylecgonine. Trans-stimulation studies indicated that diphenhydramine, nicotine, 3,4 methylenedioxyamphetamine (ecstasy) and the cathinone compound 3,4 methylenedioxypyrovalerone (MDPV) were also substrates of the cocaine transporter. CONCLUSIONS: Cocaine transport at the BBB involves a proton antiporter flux that is quantitatively much more important than its passive diffusion. The molecular identification and characterization of this transporter will provide new tools to understand its role in addictive mechanisms. PMID- 25539502 TI - Lipopolysaccharide-induced depressive-like behavior is associated with alpha1 adrenoceptor dependent downregulation of the membrane GluR1 subunit in the mouse medial prefrontal cortex and ventral tegmental area. AB - BACKGROUND: Chronic stress-induced depressive-like behavior is relevant to inflammatory immune activation. However, the neurobiological alterations in the brain following the central inflammatory immune activation remain elusive. METHODS: Therefore, we investigated the neurobiological alterations during depressive-like behavior induced in mice by systemic administration of lipopolysaccharide (LPS; 1.2 mg/kg administered twice at a 30-min interval via intraperitoneal injection). RESULTS: At 24 h after the second administration of LPS, an increased immobility time in the tail suspension test and the forced swimming test were observed, as well as reduced sucrose preference. Protein levels of the AMPA receptor GluR1 were significantly decreased at the plasma membrane in the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA), while levels of the GluR2 were increased at the plasma membrane in the nucleus accumbens (NAc) at 24h after LPS. However, total GluR1 and GluR2 protein levels in the mPFC, VTA, and NAc were not affected by LPS. Moreover, LPS facilitated release of noradrenaline in the mPFC and VTA, but not in the NAc. Consistently, systemic administration of prazosin, an alpha1-adrenoceptor antagonist, blocked the LPS-induced downregulation of the membrane GluR1 subunit in both the mPFC and VTA and also blocked the upregulation of the membrane GluR2 subunit in the NAc. Intracerebroventricular administration of prazosin 30 min before LPS injection abrogated the LPS-induced depressive-like behaviors. In opposition, administration of propranolol, a beta-adrenoceptor antagonist, did not affect the LPS-induced downregulation of GluR1, the upregulation of GluR2, or the depressive like behavior. CONCLUSIONS: These results suggest that LPS-activated alpha1 adrenoceptor-induced downregulation of membrane GluR1 in the mPFC and VTA is associated with inflammation-induced depressive-like behavior. PMID- 25539503 TI - Dopamine and glutamate interaction mediates reinstatement of drug-seeking behavior by stimulation of the ventral subiculum. AB - BACKGROUND: Drug addiction is a chronic brain disease characterized by recurrent episodes of relapse to drug-seeking/-taking behaviors. The ventral subiculum, the primary output of the hippocampus, plays a critical role in mediating drug seeking behavior. METHODS: A d-amphetamine intravenous self-administration rat model was employed along with focal electrical stimulation of the ventral subiculum (20 Hz/200 pulses) to examine its role in reinstatement of drug-seeking behavior. Dopamine efflux in the nucleus accumbens was measured by in vivo microdialysis and subsequent HPLC-ED analyses. Pharmacological antagonism of dopamine and ionotropic glutamate receptors locally within the nucleus accumbens was employed to assess the role of glutamate and dopamine in reinstatement of drug-seeking behavior induced by stimulation of the ventral subiculum. RESULTS: Here, we demonstrate that reinstatement of drug-seeking behavior following extinction of d-amphetamine self-administration by rats was induced by electrical stimulation in the ventral subiculum but not the cortex. This reinstatement was accompanied by a significant increase in dopamine efflux in the nucleus accumbens and was disrupted by microinfusion of a dopamine D1 or D2 antagonist into the nucleus accumbens. Inhibition of N-methyl-D-aspartate or non- N-methyl-D aspartate receptors had no effect on the reinstatement induced by ventral subiculum stimulation, whereas co-infusion of D1 and N-methyl-D-aspartate antagonists at formerly ineffective doses prevented drug-seeking behavior. CONCLUSIONS: These data support the hypothesis that dopamine/glutamate interactions within the ventral striatum related to memory processes are involved in relapse to addictive behavior. PMID- 25539504 TI - Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function. AB - BACKGROUND: Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. METHODS: In the present study, we used a self administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. RESULTS: Systemic oxytocin dose-dependently reduced cocaine self administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal regulated kinase-independent manner. CONCLUSIONS: These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions. PMID- 25539505 TI - Targeted multiplexed selected reaction monitoring analysis evaluates protein expression changes of molecular risk factors for major psychiatric disorders. AB - BACKGROUND: Extensive research efforts have generated genomic, transcriptomic, proteomic, and functional data hoping to elucidate psychiatric pathophysiology. Selected reaction monitoring, a recently developed targeted proteomic mass spectrometric approach, has made it possible to evaluate previous findings and hypotheses with high sensitivity, reproducibility, and quantitative accuracy. METHODS: Here, we have developed a labelled multiplexed selected reaction monitoring assay, comprising 56 proteins previously implicated in the aetiology of major psychiatric disorders, including cell type markers or targets and effectors of known psychopharmacological interventions. We analyzed postmortem anterior prefrontal cortex (Brodmann area 10) tissue of patients diagnosed with schizophrenia (n=22), bipolar disorder (n=23), and major depressive disorder with (n=11) and without (n=11) psychotic features compared with healthy controls (n=22). RESULTS: Results agreed with several previous studies, with the finding of alterations of Wnt-signalling and glutamate receptor abundance predominately in bipolar disorder and abnormalities in energy metabolism across the neuropsychiatric disease spectrum. Calcium signalling was predominantly affected in schizophrenia and affective psychosis. Interestingly, we were able to show a decrease of all 4 tested oligodendrocyte specific proteins (MOG, MBP, MYPR, CNPase) in bipolar disorder and to a lesser extent in schizophrenia and affective psychosis. Finally, we provide new evidence linking ankyrin 3 specifically to affective psychosis and the 22q11.2 deletion syndrome-associated protein septin 5 to schizophrenia. CONCLUSIONS: Our study highlights the potential of selected reaction monitoring to evaluate the protein abundance levels of candidate markers of neuropsychiatric spectrum disorders, providing a high throughput multiplex platform for validation of putative disease markers and drug targets. PMID- 25539506 TI - Monocyte and lymphocyte activation in bipolar disorder: a new piece in the puzzle of immune dysfunction in mood disorders. AB - BACKGROUND: This study tested the hypothesis that the low-grade inflammation presented in patients with bipolar disorder (BD) is associated with expansion of activated T cells, and this activated state may be due to a lack of peripheral regulatory cells. METHODS: Specifically, we investigated the distribution of monocytes and lymphocyte subsets, and investigated Th1/Th2/Th17 cytokines in plasma by flow cytometry. Twenty-one BD type I patients and 21 age- and sex matched controls were recruited for this study. RESULTS: BD patients had increased proportions of monocytes (CD14+). Regarding lymphocyte populations, BD patients presented reduced proportions of T cells (CD3+) and cytotoxic T cells (CD3+CD8+). BD patients also exhibited a higher percentage of activated T CD4+CD25+ cells, and a lower percentage of IL-10 expressing Treg cells. CONCLUSIONS: Our data shed some light into the underlying mechanisms involved with the chronic low-grade inflammatory profile described in BD patients. PMID- 25539507 TI - Cerebrospinal fluid neuropeptide Y levels in major depression and reported childhood trauma. AB - BACKGROUND: Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants. METHODS: In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY-like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers. RESULTS: Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group (p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma (p = 0.001) may be indicative of an intact but insufficient NPY-related stress response. CONCLUSIONS: We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences. PMID- 25539508 TI - Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex. AB - BACKGROUND: Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. METHODS: We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. RESULTS: Although acute cocaine (10 mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20 mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10 mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3. CONCLUSIONS: These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas. PMID- 25539509 TI - PTSD-like memory generated through enhanced noradrenergic activity is mitigated by a dual step pharmacological intervention targeting its reconsolidation. AB - BACKGROUND: Traumatic memories have been resilient to therapeutic approaches targeting their permanent attenuation. One of the potentially promising pharmacological strategies under investigation is the search for safe reconsolidation blockers. However, preclinical studies focusing on this matter have scarcely addressed abnormal aversive memories and related outcomes. METHODS: By mimicking the enhanced noradrenergic activity reported after traumatic events in humans, here we sought to generate a suitable condition to establish whether some clinically approved drugs able to disrupt the reconsolidation of conditioned fear memories in rodents would still be effective. RESULTS: We report that the alpha2-adrenoceptor antagonist yohimbine was able to induce an inability to restrict behavioral (fear) and cardiovascular (increased systolic blood pressure) responses to the paired context when administered immediately after acquisition, but not 6h later, indicating the formation of a generalized fear memory, which endured for over 29 days and was less susceptible to suppression by extinction. It was also resistant to reconsolidation disruption by the alpha2-adrenoceptor agonist clonidine or cannabidiol, the major non-psychotomimetic component of Cannabis sativa. Since signaling at N-methyl-D-aspartate (NMDA) receptors is important for memory labilization and because a dysfunctional memory may be less labile than is necessary to trigger reconsolidation on its brief retrieval and reactivation, we then investigated and demonstrated that pre-retrieval administration of the partial NMDA agonist D-cycloserine allowed the disrupting effects of clonidine and cannabidiol on reconsolidation. CONCLUSIONS: These findings highlight the effectiveness of a dual-step pharmacological intervention to mitigate an aberrant and enduring aversive memory similar to that underlying the post-traumatic stress disorder. PMID- 25539510 TI - BDNF release is required for the behavioral actions of ketamine. AB - BACKGROUND: Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate alpha-amino-3-hydroxy 5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC). METHODS: Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine. RESULTS: The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs. CONCLUSIONS: Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant. PMID- 25539513 TI - Comparison between bottom-up and top-down approaches in the estimation of measurement uncertainty. AB - BACKGROUND: Measurement uncertainty is a metrological concept to quantify the variability of measurement results. There are two approaches to estimate measurement uncertainty. In this study, we sought to provide practical and detailed examples of the two approaches and compare the bottom-up and top-down approaches to estimating measurement uncertainty. METHODS: We estimated measurement uncertainty of the concentration of glucose according to CLSI EP29-A guideline. Two different approaches were used. First, we performed a bottom-up approach. We identified the sources of uncertainty and made an uncertainty budget and assessed the measurement functions. We determined the uncertainties of each element and combined them. Second, we performed a top-down approach using internal quality control (IQC) data for 6 months. Then, we estimated and corrected systematic bias using certified reference material of glucose (NIST SRM 965b). RESULTS: The expanded uncertainties at the low glucose concentration (5.57 mmol/L) by the bottom-up approach and top-down approaches were +/-0.18 mmol/L and +/-0.17 mmol/L, respectively (all k=2). Those at the high glucose concentration (12.77 mmol/L) by the bottom-up and top-down approaches were +/-0.34 mmol/L and +/-0.36 mmol/L, respectively (all k=2). CONCLUSIONS: We presented practical and detailed examples for estimating measurement uncertainty by the two approaches. The uncertainties by the bottom-up approach were quite similar to those by the top-down approach. Thus, we demonstrated that the two approaches were approximately equivalent and interchangeable and concluded that clinical laboratories could determine measurement uncertainty by the simpler top-down approach. PMID- 25539511 TI - Increasing endocannabinoid levels in the ventral pallidum restore aberrant dopamine neuron activity in the subchronic PCP rodent model of schizophrenia. AB - BACKGROUND: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. METHODS: Using in vivo extracellular recordings in chloral hydrate-anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. RESULTS: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. CONCLUSIONS: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID- 25539514 TI - AM Last Page. The "Pillars" of Curriculum Reform. PMID- 25539512 TI - Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder. AB - BACKGROUND: A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine's antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine's antidepressant efficacy. METHODS: Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100 200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17). RESULTS: FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9). CONCLUSIONS: Ketamine's extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials. PMID- 25539515 TI - A national study of medical students' attitudes toward self-prescribing and responsibility to report impaired colleagues. AB - PURPOSE: The authors investigated medical students' attitudes about appropriate prescribing behaviors, their personal responsibility to report impaired colleagues, and what factors may influence these beliefs. METHOD: The authors conducted a cross-sectional study of U.S. medical students in 2012 to assess attitudes about appropriate prescribing behaviors and responsibility to report impaired colleagues, and to explore relationships between prescribing beliefs and burnout, depression, and alcohol abuse/dependence. Chi-square test and multivariate logistic regression were performed. RESULTS: Of 12,500 medical students invited to participate, 4,402 (35%) completed surveys. Believing it is appropriate to prescribe an antidepressant to self or spouse was rare (<10%) in comparison with believing it is appropriate to prescribe an antibiotic for oneself (34.5%) or a spouse (57.7%).In multivariate analysis, students with burnout were more likely to agree that each of the inappropriate prescribing behaviors was acceptable (ORs 1.15-1.51). Students with burnout were less likely to believe they had a personal responsibility to report colleagues with impairment due to alcohol or substance use (OR 0.87). Students personally experiencing symptoms of depression were less likely to believe medical students should report colleagues impaired by mental health problems (OR 0.72). Similarly, students with alcohol abuse/dependence were less likely to believe they had a duty to report colleagues impaired by alcohol/substance use (OR 0.55). CONCLUSIONS: Suboptimal attitudes about prescribing and personal responsibility to report impaired colleagues are common among medical students. Suboptimal attitudes are associated with personal distress, further evidence of a link between personal distress and professionalism. PMID- 25539516 TI - Transforming educational accountability in medical ethics and humanities education toward professionalism. AB - Effectively developing professionalism requires a programmatic view on how medical ethics and humanities should be incorporated into an educational continuum that begins in premedical studies, stretches across medical school and residency, and is sustained throughout one's practice. The Project to Rebalance and Integrate Medical Education National Conference on Medical Ethics and Humanities in Medical Education (May 2012) invited representatives from the three major medical education and accreditation organizations to engage with an expert panel of nationally known medical educators in ethics, history, literature, and the visual arts. This article, based on the views of these representatives and their respondents, offers a future-tense account of how professionalism can be incorporated into medical education.The themes that are emphasized herein include the need to respond to four issues. The first theme highlights how ethics and humanities can provide a response to the dissonance that occurs in current health care delivery. The second theme focuses on how to facilitate preprofessional readiness for applicants through reform of the medical school admission process. The third theme emphasizes the importance of integrating ethics and humanities into the medical school administrative structure. The fourth theme underscores how outcomes-based assessment should reflect developmental milestones for professional attributes and conduct. The participants emphasized that ethics and humanities-based knowledge, skills, and conduct that promote professionalism should be taught with accountability, flexibility, and the premise that all these traits are essential to the formation of a modern professional physician. PMID- 25539517 TI - Toward a better understanding of gender-based performance in the obstetrics and gynecology clerkship: women outscore men on the NBME subject examination at one medical school. AB - PURPOSE: To better understand why women outperform men in the obstetrics and gynecology (Ob/Gyn) clerkship. METHOD: The authors conducted a retrospective cohort study of students who rotated in the Ob/Gyn clerkship from 2008 to 2011 and graduated by May 2012 from the Icahn School of Medicine at Mount Sinai in New York City. They compared female and male students' performance on preclerkship standardized tests (the Medical College Admission Test [MCAT] and United States Medical Licensing Examination [USMLE] Step 1) and on Ob/Gyn clerkship components (clinical skills achievement, oral and written case presentations, clinical evaluations, and National Board of Medical Examiners [NBME] subject examination). RESULTS: The study included 163 (53.4%) women and 142 (46.6%) men. Among students who took the MCAT, women scored lower than men with a mean (standard deviation) of 33.2 (3.2) versus 34.6 (3.3) (P=.001). Similarly, among all students, women scored lower than men on the USMLE Step 1: 227 (19.1) versus 232.5 (18.8) (P=.012). There were no significant gender differences on most clerkship components. However, women scored higher than men on the Ob/Gyn NBME subject examination: 78.0 (7.5) versus 74.8 (8.4) (P=.001). Consequently, female students achieved higher overall clerkship scores than men: 88.5 (5.6) versus 87.1 (5.1) (P=.024). Analysis of covariance confirmed that gender is associated with NBME subject examination score (P<.001). CONCLUSIONS: Women outscored men on the NBME subject examination in Ob/Gyn and thereby outperformed men in the Ob/Gyn clerkship. PMID- 25539520 TI - Transcatheter aortic valve replacement indications should be expanded to lower risk and younger patients. PMID- 25539518 TI - A comparison of Web-based and small-group palliative and end-of-life care curricula: a quasi-randomized controlled study at one institution. AB - PURPOSE: Few studies have compared the effect of Web-based eLearning versus small group learning on medical student outcomes. Palliative and end-of-life (PEOL) education is ideal for this comparison, given uneven access to PEOL experts and content nationally. METHOD: In 2010, the authors enrolled all third-year medical students at the University of California, Davis School of Medicine into a quasi randomized controlled trial of Web-based interactive education (eDoctoring) compared with small-group education (Doctoring) on PEOL clinical content over two months. Students participated in three 3-hour PEOL sessions with similar content. Outcomes included a 24-item PEOL-specific self-efficacy scale with three domains (diagnosis/treatment [Cronbach alpha=0.92; CI: 0.91-0.93], communication/prognosis [alpha=0.95; CI: 0.93-0.96], and social impact/self-care [alpha=0.91; CI: 0.88-0.92]); 8 knowledge items; 10 curricular advantage/disadvantages; and curricular satisfaction (both students and faculty). RESULTS: Students were randomly assigned to Web-based eDoctoring (n=48) or small group Doctoring (n=71) curricula. Self-efficacy and knowledge improved equivalently between groups (e.g., prognosis self-efficacy, 19%; knowledge, 10% 42%). Student and faculty ratings of the Web-based eDoctoring curriculum and the small-group Doctoring curriculum were equivalent for most goals, and overall satisfaction was equivalent for each, with a trend toward decreased eDoctoring student satisfaction. CONCLUSIONS: Findings showed equivalent gains in self efficacy and knowledge between students participating in a Web-based PEOL curriculum in comparison with students learning similar content in a small-group format. Web-based curricula can standardize content presentation when local teaching expertise is limited, but it may lead to decreased user satisfaction. PMID- 25539519 TI - Primary care workforce shortages and career recommendations from practicing clinicians. AB - PURPOSE: The success of efforts to bolster the primary care workforce rests in part on how these clinicians view their professions and their willingness to recommend their careers to others. The authors sought to examine career and job satisfaction, perceptions of workforce shortages, and willingness to make career recommendations among primary care physicians (PCPs) and primary care nurse practitioners (PCNPs). METHOD: In 2012, the authors mailed a national survey concerning the issues above to 1,914 randomly chosen clinicians found on national databases: 957 PCPs and 957 PCNPs. RESULTS: A total of 972 eligible clinicians (505 PCPs, 467 PCNPs) returned the survey. Using standard opinion research procedures, the authors estimated there were approximately 1,589 eligible clinicians in their sample (response rate, 61.2%). PCNPs and PCPs were more likely to recommend a career as a PCNP than as a PCP, despite the perception among all clinicians of a serious shortage of PCPs nationally and in their own communities. This finding held among PCNPs who reported low workplace autonomy and among PCPs reporting that they were satisfied with their own careers. CONCLUSIONS: Efforts to solve the primary care workforce shortage that ignore the significant dissatisfaction of PCPs with their own careers are unlikely to be successful. Simply adding training slots and increasing reimbursement rates will do little to solve the problem if PCPs continue to view their own careers as ones they cannot recommend to others. PMID- 25539521 TI - Transcatheter aortic valve replacement indications should not be expanded to lower-risk and younger patients. PMID- 25539523 TI - ECG response: December 23/30, 2014. PMID- 25539522 TI - Duration of anticoagulation for venous thromboembolic events. PMID- 25539524 TI - Blood balloon induced by an atrial myxoma in the heart. PMID- 25539525 TI - Ex vivo coronary angiographic evaluation of a beating donor heart. PMID- 25539526 TI - Letter by Qureshi et al regarding article, "Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis". PMID- 25539531 TI - New Jersey's public cord blood stem cell bank: seventeen years of growth & transformation. PMID- 25539527 TI - Response to letter regarding article, "Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis". PMID- 25539532 TI - Taking the pressure off diabetic wound care. PMID- 25539533 TI - Universal hepatitis C screening and surgeon safety. PMID- 25539534 TI - Universal hepatitis C screening and surgeon safety. Author's response. PMID- 25539535 TI - Comparison of high-resolution melting analysis to denaturing high performance liquid chromatography in the detection of point mutations in MEFV, F5, and F2 genes. AB - BACKGROUND/AIM: Sensitive and cost-effective detection of point mutations is important in genetics research. Denaturing high-performance liquid chromatography (DHPLC) is known to be one of the most sensitive techniques for point mutation detection. A more recent technique, high-resolution melting (HRM), is based on the melting behavior of PCR products. In this study, the efficiency and sensitivity of HRM and DHPLC for the detection of MEFV, F5, and F2 gene point mutations were evaluated. MATERIALS AND METHODS: We studied 15 patients with MEFV mutations (E148Q, M680I, M694V, or V726A), 7 patients with the F51691G>A mutation, and 12 patients with the F220210G>A mutation. All mutations were screened by HRM and DHPLC. RESULTS: All mutations were successfully detected by HRM. However, only 4 (MEFVE148Q and M680I, F51691G>A, and F220210G>A) of 6 mutations were successfully detected with DHPLC. CONCLUSION: Our study showed that HRM is more sensitive than DHPLC for detection of the studied point mutations. PMID- 25539536 TI - Effects of some of the regional Turkish fermented foods and medications on respiratory alcohol levels. AB - BACKGROUND/AIM: Alcohols are used in many areas like medicine and industry. They may be naturally found in some fruits and vegetables secondary to fermentation. According to the traffic law in Turkey, professional drivers are prohibited from driving while they are under the influence of alcohol; nonprofessional drivers are allowed to drive vehicles with a blood alcohol level of up to 50 mg/dL. The aim of this research is to determine whether or not consumed medicine or fermented, nonalcoholic beverages cause false positive results in breathalyzer tests. MATERIALS AND METHODS: In this research, we used nonalcoholic fermented foods and 6 medicines. After the use of these materials, we measured breath alcohol level at 1, 3, 5, 15, and 30 min with a breathalyzer. RESULTS: False positive results were obtained only with Disinol and cologne. Other drugs and nutrients did not cause any false positivity in breathalyzer tests. CONCLUSION: At the end of the research, we observed that some substances caused false positive results, even if people did not use any alcohol. If there is any suspicion of the measured values, then measurements should be repeated. If a person cannot be sure of the reliability of the breathalyzer measurements, the person should consult other centers without losing time. PMID- 25539537 TI - Evaluation and comparison of alpha- and beta-amanitin toxicity on MCF-7 cell line. AB - BACKGROUND/AIM: Alpha- and beta-amanitins are the main toxins of the poisonous Amanita phalloides mushroom. Although there are many studies available concerning alpha-amanitin, there are limited data about beta-amanitin in the literature. Therefore, this study is aimed at comparing the toxic effects of alpha- and beta amanitin on the MCF-7 cell line. MATERIALS AND METHODS: The alpha- and beta amanitins used for this research were purified from Amanita phalloides by preparative high-performance liquid chromatography. The MCF-7 breast cancer cell line was used, and specific concentrations of the toxins (100, 10, 1, 0.1, and 0.01 MUg/mL) were applied to the cells. The MTT test was performed to determine the level of toxicity, and the quantity of protein in the cell was measured using the biuret test. RESULTS: The aLpha-amanitin showed a higher toxicity at 36 h, while the highest inhibition of protein synthesis by the beta-amanitin was observed at 24 h. CONCLUSION: It was shown that the beta-amanitin may be responsible for toxicity, like alpha-amanitin, in Amanita phalloides mushroom poisoning. The early inhibition of protein synthesis for beta-amanitin might be useful for future experiments and research. PMID- 25539538 TI - The effect of Malaysian honey and its major components on the proliferation of cultured fibroblasts. AB - BACKGROUND/AIM: To examine, for the first time, the effect of a selected Malaysian honey and its major components on the proliferation of cultured fibroblasts. MATERIALS AND METHODS: Honey and some of its components, which include the sugars, the proteins, the hydrogen peroxide produced, and the phenolics, were exposed to cultured fibroblasts. The MTT colorimetric assay was used to assess cell viability and proliferation. RESULTS: The stimulatory effect of honey on fibroblast proliferation was observed to be time- and dose-dependent. The continuous production of hydrogen peroxide by the honey-glucose oxidase system also acts to stimulate cell proliferation in a time- and dose-dependent manner. The presence of phenolics with antioxidant properties, on the other hand, renders protection to the cells against the toxic effect of hydrogen peroxide. However, the presence of a growth factor-like substance in honey could not be ascertained. CONCLUSION: For the first time, honey and its major components were shown to exert stimulatory effects on cultured fibroblasts. Honey is therefore potentially useful in medicinal practices. PMID- 25539539 TI - Molecular discrimination of Echinococcus granulosus and Echinococcus multilocularis by sequencing and a new PCR-RFLP method with the potential use for other Echinococcus species. AB - BACKGROUND/AIM: To develop a novel polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol using a new genomic marker sequence and a novel set of restriction enzymes in order to detect and discriminate 2 Echinococcus species, E. granulosus and E. multilocularis, found in formalin fixed paraffin-embedded (FFPE) human tissues. MATERIALS AND METHODS: DNA was isolated from 11 FFPE human tissue samples positive for cystic echinococcosis or alveolar echinococcosis. A mitochondrial genomic marker region was amplified and sequenced using a novel primer pair and a new PCR-RFLP protocol was developed for the detection and discrimination of E. granulosus and E. multilocularis using a set of restriction enzymes including AccI, MboI, MboII, and TsoI. RESULTS: The selected marker region was amplified using DNA isolated from FFPE human tissue samples positive for cystic echinococcosis or alveolar echinococcosis and the discrimination of E. granulosus and E. multilocularis was accomplished by use of the novel PCR-RFLP method. CONCLUSION: In this PCR-RFLP protocol, use of any single restriction enzyme is enough for the discrimination of E. granulosus and E. multilocularis. The PCR-RFLP protocol can be potentially used for the discrimination of 5 other Echinococcus species: E. oligarthus, E. shiquicus, E. ortleppi, E. canadensis, and E. vogeli. PMID- 25539540 TI - Effects of ozone therapy and taurine on ischemia/reperfusion-induced testicular injury in a rat testicular torsion model. AB - BACKGROUND/AIM: To investigate the effect of ozone and/or taurine treatment comparatively on testicular damage due to ischemia/ reperfusion (I/R) injury in an experimental torsion model in rats. MATERIALS AND METHODS: Adult Wistar rats with and without torsion/detorsion were used. In order to monitor the effect of ozone and/or taurine treatment on testicular damage due to I/R injury, following histopathological investigation apoptotic indexes were scored by TUNEL method. Moreover, tumor necrosis factor receptor 1 (TNFR1), caspase 3, caspase 8, endothelial nitric oxide synthase (eNOS), tumor necrosis factor alpha (TNFalpha), and cytochrome C immunostainings were performed and the levels of malondialdehyde, glutathione peroxidase, superoxide dismutase, catalase, total sulfhydryl, and nitric oxide were determined in the testicular tissue. RESULTS: Intraperitoneal ozone and/or taurine treatment prevented both histopathological damage and increase in the apoptotic index. Torsion did not exert an effect on the levels of TNFalpha and cytochrome C. Ozone and/or taurine treatment prevented increases in TNFR1, caspase 3, and caspase 8. The level of oxidative stress markers was unchanged. The increases in NO level and eNOS expression were prevented by ozone and/or taurine treatment in I/R groups. CONCLUSION: Using ozone therapy and/or taurine before reperfusion may be a solution for germ cell degeneration resulting from testicular torsion and related infertility. PMID- 25539541 TI - Normal M mode values in healthy Turkish children. AB - AIM: Evaluation of cardiac structures requires a large study group for accurate data on normal values. The aim of the study was to obtain normal M mode echocardiographic values in a substantial sample of healthy term neonates and children to develop centile charts. MATERIALS AND METHODS: Data were obtained over 2 years from a single center in Turkey, from 1200 healthy infants and children aged 1 day to 17 years. Using echocardiographic investigation, measurements were obtained of the following: left ventricular dimension at end diastole and end systole; thickness of interventricular septum and posterior wall of the left ventricle; aortic and pulmonary root diameter; and left atrial dimension. The influence of systematic errors as statistical noise in this large sample was decreased using third- degree polynomial curves. RESULTS: Measurements are presented graphically as curved lines of centiles with respect to body weight for healthy term neonates and children. The values showed a good correlation with body weight and allowed the construction of percentile curves (5%, 25%, 50%, 75%, and 95%). Higher values were observed in boys during adolescence. CONCLUSION: The presented charts and tables make it possible to judge the echocardiographic measurements of a particular patient as normal or abnormal. PMID- 25539542 TI - Is the diagnosis and treatment of childhood acute bacterial meningitis in Turkey evidence-based? AB - BACKGROUND/AIM: Evidence-based guidance is likely to significantly improve patient care. We aimed to characterize the adequacy of standard diagnostic methods and treatment in children with acute bacterial meningitis (ABM) in Turkey. MATERIALS AND METHODS: We conducted a retrospective study among children 1 month to 5 years old hospitalized with ABM in Istanbul. The World Health Organization case definition and laboratory criteria were used for diagnosis. RESULTS: Of the 283 cases, 250 were probable and 33 (11.2%) were confirmed as bacterial meningitis. The majority of patients (92%) were treated at 9 governmental hospitals and the remaining 21 at 2 university hospitals. Blood culture, cerebrospinal fluid (CSF) culture, and CSF Gram smear examinations were performed in 68%, 87%, and 13% of the cases, respectively. A third-generation cephalosporin, alone or in combination with other antibiotics, was the drug of choice in 90% of cases. Dexamethasone was given as adjunctive therapy in 43%. Initial antibiotics were modified during the course of treatment for 43 patients, with culture-confirmed indications for only 5 of them. CONCLUSION: Recommended laboratory tests including blood culture and CSF Gram smears were insufficiently performed. Appropriate antibiotics were used in the majority of cases. Better identification of the causative pathogens will improve stewardship of antimicrobial therapy. PMID- 25539543 TI - Early extracorporeal life support experiences in 2 tertiary pediatric intensive care units in Turkey. AB - BACKGROUND/AIM: Extracorporeal membrane oxygenation (ECMO) is a unique life support modality offered to patients unresponsive to optimal medical therapy. The aim of this study was to evaluate early experiences with ECMO support in 2 tertiary Turkish pediatric intensive care units (PICUs). MATERIALS AND METHODS: We retrospectively evaluated a total of 10 ECMO-supported patients between March 2012 and March 2013 in Marmara and Ege University Hospital PICUs. We reported data regarding demographics, laboratory and diagnostic information, and the clinical course of the patients. RESULTS: The study consisted of 6 males and 4 females from 5 months to 14 years of age (mean age: 0.5 +/- 5.01 years) supported with ECMO. Out of the 10 patients, 8 were on venovenous ECMO for respiratory failure and 2 received venoarterial ECMO for cardiac failure. Mean ECMO and intensive care duration was 11.1 +/- 7.3 days and 23.5 +/- 17.8 days, respectively. Bleeding was the most common complication (60%). Forty percent of the patients were weaned from ECMO, among which 50% were discharged in good health without sequelae. CONCLUSION: Initial experiences build the learning curve of institutions, and our early results are encouraging. Giving time to heal to the right patient at the right time is the key to success. PMID- 25539544 TI - Association between the apelin rs2235306 gene polymorphism and metabolic syndrome. AB - AIM: The rs2235306 of apelin polymorphism has been shown to be associated with fasting plasma glucose levels and hypertension. The present study aimed to investigate the impact of the apelin rs2235306 gene polymorphism on the risk of metabolic syndrome (MeS) in a sample of the Iranian population. MATERIALS AND METHODS: This population-based cross-sectional study was performed on 151 subjects with MeS and 149 without MeS, as defined by ATPIII criteria. Apelin rs2235306 polymorphism detection was done using the tetra amplification refractory mutation system-polymerase chain reaction. Because the apelin gene is located on the X chromosome, statistical analyses were conducted in a sex specific manner. RESULTS: Our findings proposed that the apelin rs2235306 polymorphism was not associated with MeS susceptibility in the codominant, dominant, and recessive inheritance models tested (OR = 0.93, 95% CI = 0.51-1.71 for TC vs. TT; OR = 2.39, 95% CI = 0.70-8.16 CC vs. TT; OR = 1.09, 95% CI = 0.62 1.93 for TC+CC vs. TT; and OR = 2.45, 95% CI = 0.73-8.21 for CC vs. TT+TC). We found that the apelin TC+CC genotypes were associated with lower HDL-cholesterol in women without MeS. CONCLUSION: Our findings indicated no association between the apelin rs2235306 polymorphism and MeS. However, the results suggest that healthy females carrying apelin TC+CC genotypes have lower HDL-cholesterol in comparison with those carrying TT, which remains to be confirmed. PMID- 25539545 TI - Insulin-like growth factor 1, liver enzymes, and insulin resistance in patients with PCOS and hirsutism. AB - AIM: Hyperinsulinemia and insulin resistance are commonly seen in patients with hirsutism and polycystic ovary syndrome (PCOS), and are associated with cardiovascular disease risk. However, it is not yet known whether insulin-like growth factor I (IGF-I) and alanine transaminase (ALT) produced by the liver play roles in hyperinsulinemia and subclinical atherosclerotic process in patients with PCOS and idiopathic hirsutism (IH). MATERIALS AND METHODS: This was a prospective case-controlled study. The study population consisted of 25 reproductive-age PCOS women, 33 women with IH, and 25 control subjects. RESULTS: Mean IGF-I levels and median ALT levels were higher in patients with IH and PCOS than controls, but these differences were not statistically significant. The participants who had a homeostasis model assessment insulin resistance index (HOMA-IR) greater than 2.7 had significantly higher IGF-1 and ALT levels. ALT levels were positively correlated with body mass index, FG, insulin and HOMA-IR. CONCLUSION: The study illustrated that IGF-1 and ALT levels were significantly higher in patients with increased insulin resistance. Due to short disease duration in younger participants, we did not observe any correlation between IGF 1 and hyperinsulinemia. These findings suggest that increased hepatic production of IGF-I and ALT might be an early indicator of insulin resistance in hirsutism. PMID- 25539546 TI - Endothelial dysfunction and insulin resistance in young women with polycystic ovarian syndrome. AB - BACKGROUND/AIM: To evaluate whether there is a correlation between insulin resistance and nitric oxide-related endothelial dysfunction in patients with polycystic ovarian syndrome (PCOS). MATERIALS AND METHODS: The study was conducted with 25 young women with PCOS and 25 young healthy women, between 18 and 35 years of age. Plasma asymmetric dimethylarginine (ADMA) levels, serum nitric oxide (NO) levels, and homeostatic model assessment of insulin resistance (HOMA-IR) rates were measured in both the patient and control groups. RESULTS: Plasma ADMA levels were significantly higher in PCOS patients than in the controls (P = 0.001). Serum NO levels were significantly lower in patients than in the controls (P = 0.008). The HOMA-IR rates, accepted as an insulin resistance parameter, were significantly higher in patients than in the controls (P = 0.001). CONCLUSION: Results of the present study indicate that, independent of age, body mass index, and blood lipid profile, there is significant insulin resistance in PCOS patients. However, no correlation was found between HOMA-IR as an insulin resistance determinant and altered ADMA and NO levels. This finding may indicate that there are additional mechanisms of cardiovascular risks in PCOS patients other than insulin resistance. PMID- 25539547 TI - Investigating the effects of negative-calorie diet compared with low-calorie diet under exercise conditions on weight loss and lipid profile in overweight/obese middle-aged and older men. AB - BACKGROUND/AIM: Negative-calorie diets (NCDs) are among the popular dieting guides for weight loss; however, there is still little knowledge about this method. The present study aimed to determine the effects of a NCD supplemented with exercise on weight loss and lipid profile, and to compare its efficiency with low-calorie diets (LCDs) with exercise among elderly adult men with abnormal weight gain. MATERIALS AND METHODS: Participants included sedentary men (aged 45 75 years) who were overweight or obese (n = 37). They were randomly divided into 2 groups: a group with a NCD and exercise, and a group with a LCD with exercise. Of all 37 participants, 30 completed the treatment. Weight assessment parameters, including changes in weight and body composition and blood sample tests, were performed before and 3 months after intervention. RESULTS: All parameters decreased significantly in both groups. Elevation in high-density lipoprotein (HDL) cholesterol levels (P < 0.001) was different between the 2 groups. The decline in the total cholesterol to HDL cholesterol ratio was greater in the LCD than the NCD group. CONCLUSION: Contrary to expectations, both weight-loss diets were equally efficacious. PMID- 25539548 TI - Pittsburgh Sleep Quality Index scores and their relationship with body measurements in late menopause patients. AB - BACKGROUND/AIM: With an increase in life expectancy, women live about one-third of their lives in the postmenopausal period. Our aim was to investigate the findings regarding quality of sleep and sleep apnea in postmenopausal women and research the relationship between sleep complaints and body measurements. MATERIALS AND METHODS: The Pittsburgh Sleep Quality Index (PSQI) was administered to all participants and their height, weight, and neck circumferences were measured. RESULTS: A total of 206 patients (mean age: 61.4 +/- 8.8 years) were included. Their mean weight gain after menopause was 8.1 +/- 12.8 kg, and their mean neck circumference and body mass index was 39.7 +/- 2.6 cm and 33.4 +/- 2.1, respectively. The rate of patients who snored each night increased from 3.4% to 13.2% (P = 0.000) after menopause. The rate of self-reported poor sleep quality was found in 57.8% of patients according to the PSQI global score (>=5). The prevalence of sleep medication usage increased from 5.8% to 11.2% with menopause. Although body measurements were a little lower in patients with a total PSQI score of less than 5, this difference was insignificant. CONCLUSION: The prevalence of self-reported poor sleep quality was high in the postmenopausal period and the prevalence of snoring increased significantly with weight gain after menopause. PMID- 25539549 TI - Airway inflammation and tiotropium treatment in stable COPD patients. AB - BACKGROUND/AIM: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lung associated with progressive airflow limitation. The aim of this study is to assess the influence of tiotropium treatment on airway inflammation and symptoms in stable COPD patients. MATERIALS AND METHODS: Inflammatory markers were measured in the expired breath condensate fluid (EBC) before starting tiotropium treatment and at the end of the first month. RESULTS: Twenty-two patients (81% men) with a mean age of 65.4 +/- 10.1 years completed the study. The mean nitrotyrosine and 8-isoprostane levels for oxidative stress markers in EBC before and after treatment were 4.5 +/- 2.3, 3.5 +/- 1.9 pg/mL (P = 0.06) and 7.3 +/- 10.8, 8.1 +/- 11.7 pg/mL (P = 0.28), respectively. The mean interleukin-6 and tumor necrosis factor-alpha levels for inflammation markers in EBC before and after treatment were 1.03 +/- 1.1, 0.77 +/- 0.8 pg/mL (P = 0.41) and 27.8 +/- 2.6, 29.2 +/- 5.7 pg/mL (P = 0.36) respectively. The mean symptom scores decreased significantly with tiotropium and a mean increase of 124.6 +/- 0.86 mL was observed in a lung function test (FEV1). CONCLUSION: Although a 4 week treatment with tiotropium did not modify any of the inflammatory or oxidative stress markers in EBC fluid, tiotropium treatment helps to control symptoms in COPD. PMID- 25539550 TI - Leptin and leptin receptor polymorphisms are related to body mass index in a Turkish population. AB - BACKGROUND/AIM: Leptin is a hormone that is known to be related to weight gain and obesity. The soluble leptin receptor has been found in plasma as an important determinant of leptin sensitivity. In this study, our goal was to investigate the association between leptin levels and leptin receptor polymorphisms in a Turkish population. MATERIALS AND METHODS: The sample pool of this study consisted of 202 subjects. G2548A variant in the promoter region of the leptin gene and Q223R polymorphism of the leptin receptor gene were evaluated by using PCR-RFLP. Leptin levels were determined by ELISA. RESULTS: Leptin levels were significantly higher in subjects with the A allele than in subjects without the A allele. Leptin receptor levels were lower in subjects with the AA genotype than in those with the AG genotype. There was a higher prevalence of the leptin-2548 AA genotype among subjects with a BMI >= 25 kg/m2 than in those with a BMI < 25 kg/m2. CONCLUSION: The leptin-2548A allele might be a predisposing factor for obesity. PMID- 25539551 TI - The effect of dietary salt restriction on hypertension in peritoneal dialysis patients. AB - BACKGROUND/AIM: To investigate the effect of dietary salt restriction on blood pressure levels, total sodium removal, and hydration status of peritoneal dialysis (PD) patients. MATERIALS AND METHODS: Thirty-one stable PD patients who consulted a renal dietitian monthly for dietary recommendations, including restricted salt intake <5 g/day, and education about hypertension and hypervolemia were included in this study. Baseline and third month clinical and laboratory findings, bioelectrical impedance analysis results, and urinary and peritoneal sodium removal values were recorded. RESULTS: The mean age of the patients was 47.6 years and the mean time on PD was 39.6 months. The mean total sodium removal decreased slightly from 139.4 +/- 69.1 to 136.2 +/- 64.8 mmol/day (P > 0.05) for the whole sample, and from 164.3 +/- 70.9 to 154.2 +/- 72.3 mmol/day (P > 0.05) for the hypertensive subgroup (n: 17). Systolic blood pressure (from 134.3 +/- 20.1 to 127.2 +/- 19.5 mmHg, P: 0.01), diastolic blood pressure (from 83.2 +/- 12.0 to 77.4 +/- 10.5 mmHg, P: 0.01) and total body water (from 39.2 +/- 10.9 to 38.3 +/- 9.3 L, P: 0.04) decreased significantly. CONCLUSION: We demonstrated that even a little reduction in daily dietary sodium intake caused significant decreases in blood pressure levels and fluid overload. PMID- 25539552 TI - The relation between Helicobacter pylori and ulcerative colitis. AB - BACKGROUND/AIM: Besides some genetic explanations of the native course of ulcerative colitis (UC), the most attributable factors are pathogenic bacterial agents. There are some conflicting data about the relationship between Helicobacter pylori and the rate of UC in the literature. Therefore, we aimed to investigate the rate of H. pylori in UC patients. MATERIALS AND METHODS: Forty nine individuals diagnosed with UC who had undergone upper gastrointestinal tract endoscopy for different reasons were included in the study. The presence of H. pylori in the stomach was checked by histopathological examination. RESULTS: H. pylori positivity was present in 57.1% of patients with UC. Interestingly, H. pylori positivity was lower (11.1%) in pancolitis patients compared to those presenting with more limited illnesses. There were no relationships among the severity of the underlying disease, medication already used, and H. pylori positivity rate. CONCLUSION: The extension of UC is important for the positivity rate of H. pylori. It could not be determined whether the low positivity of H. pylori in extended UC cases was due to immunosuppressive drugs or to the UC itself. PMID- 25539553 TI - Seroprevalences and associated risk factors of hepatitis B and C in adults. AB - BACKGROUND/AIM: Chronic hepatitis due to hepatitis B and hepatitis C virus infections is the most common cause of chronic liver disease. In this study we aimed to find out seroprevalences and associated risk factors of hepatitis B and C in adults in Duzce. MATERIALS AND METHODS: The sample of study was determined with a cluster-type sampling method. The study included 1321 people, consisting of 667 women and 654 men who were 18 years or older. A questionnaire about demographic information and risk factors was applied. RESULTS: Seroprevalences of HBsAg, anti-HBs, and anti-HCV were 4.8%, 9.4%, and 0.7%, respectively. HBsAg seroprevalences were found to be statistically higher in the dental visit group (8.9% versus 4.0%, P = 0.002) and in people living within the same house with hepatitis B carriers (11.5% versus 4.6%, P = 0.036). Living in Duzce during the 1999 earthquake and staying in prefabricated houses after the earthquake were not risk factors of HBsAg carriage. CONCLUSION: HBsAg and anti-HCV seroprevalences in Duzce were in parallel with the previous data from Turkey and a low ratio of anti HBs appeared. Identifying risk groups with large epidemiological screening studies and vaccination of nonimmune people are essential. PMID- 25539554 TI - The correlation of ECHO findings of right cardiac pathologies with BNP, uric acid, and CRP in OSAS. AB - BACKGROUND/AIM: Right cardiac pathologies develop in patients with obstructive sleep apnea syndrome (OSAS) and in most patients there are no symptoms in the early stages of right cardiac disorders. We aimed to evaluate a possible relationship between B-type natriuretic peptide (BNP), blood uric acid, C reactive protein (CRP), and the right cardiac pathologies in patients with OSAS, and the role of these parameters in the management of patients with OSAS. MATERIALS AND METHODS: A total of 98 subjects, 31 (31.6%) controls and 67 (68.4%) with OSAS, were included in the study. All the subjects underwent polysomnography, and standard and tissue Doppler echocardiography (ECHO) examinations. BNP, CRP, and blood uric acid levels were measured in all patients. RESULTS: Upon evaluating the relationship between BNP and ECHO parameters, BNP levels were found to positively correlate with such ECHO parameters as pulmonary artery pressure. As for the association between CRP and ECHO findings, RV diameter exhibited a statistically significant positive correlation with them. Moreover, uric acid was found to statistically correlate positively with right atrium dimensions. CONCLUSION: BNP, CRP, and blood uric acid levels can be used as adjunctive parameters in the early diagnosis and follow-up of right heart pathologies in patients with OSAS. PMID- 25539555 TI - Polymorphisms in MMP-2 and TIMP-2 in Turkish patients with prostate cancer. AB - AIM: Prostate cancer is the most commonly diagnosed malignancy and the second most common cause of cancer deaths in the Western male population. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) modulate the remodeling of the extracellular matrix (ECM). The imbalance between MMPs and TIMPs may lead to an emergence of pathological processes such as cancer. In this study, the association between TIMP-2 (-418 G/C) and MMP-2 (-1306 C/T) polymorphisms and prostate cancer in the Turkish population was investigated. MATERIALS AND METHODS: Sixty-one prostate cancer patients and 46 healthy subjects were included in the study. DNA was isolated from 2 mL of peripheral blood taken from subjects, and genotypes were analyzed by the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: The TIMP-2 -418 (GC) genotype was found in 15 cases (32.6%) in the control group and in 9 cases (14.8%) in the patients group, and statistical significance was determined (P = 0.037, OR = 0.346). The MMP-2 -1306 (CT) genotype was found 2.17 times more in the patient group than in the control group (P = 0.149, OR = 2.17). CONCLUSION: Our results show that the TIMP-2 -418 (GC) genotype had a putative protective effect against prostate cancer. PMID- 25539557 TI - Hormone replacement therapy-related changes in the early postmenopausal period (critical window): an in vivo brain proton magnetic resonance spectroscopy study. AB - AIM: Findings from clinical studies in postmenopausal women with late initiation of hormone replacement therapy (HRT) that test whether HRT protects cognitive functions in women are inconsistent. The aim of this study was to investigate the effects of HRT on brain metabolite ratios when initiated in the early postmenopausal period (critical window). MATERIALS AND METHODS: Proton magnetic resonance spectrometry (1H MRS) was performed in 4 brain regions of 47 healthy postmenopausal women (21 received HRT, 26 did not). The subjects were aged between 45 and 65 years. The duration of HRT ranged from 1 to 12 years (mean: 6.3 years). The duration of menopause was 2-12 years (mean: 6.1 years) for HRT users and 1-20 years (mean: 7.8 years) for non-HRT users. Metabolite ratios [N-acetyl aspartate/choline (NAA/Cho), NAA/creatine (Cr), and Cho/Cr] were evaluated. RESULTS: Cho/Cr ratios were significantly increased and NAA/Cho ratios significantly decreased in all 4 regions in the HRT user group compared to the other group after elimination of the effects of age and menopause duration. Regression analysis revealed an association only between NAA/Cho and duration of menopause. CONCLUSION: HRT-related changes in metabolite ratios are found in all brain regions. Decreased NAA/Cho and increased Cho/Cr levels do not support the neuroprotective role of HRT in the critical window. PMID- 25539556 TI - Does lymph node involvement affect the patterns of recurrence in stage IB cervical cancer? AB - BACKGROUND/AIM: To investigate the variations in the recurrence patterns of stage IB cervical cancer according to lymph node involvement. MATERIALS AND METHODS: We reviewed the medical records of 170 patients who had undergone type III radical hysterectomy and systematic lymphadenectomy from 1993 to 2007. RESULTS: Among the patients in the study group, 115 did not have lymph node metastases, whereas 55 did. A total of 27 patients developed recurrences. Twelve were in the lymph node negative group, and 15 were in the lymph node-positive group. The recurrence rate was higher in lymph node-positive group (27.3% versus 10.4%, P = 0.011). The recurrence pattern was not affected by lymph node involvement. However, distant recurrence was more common in the lymph node-positive group (53.3% versus 25%, P = 0.137). Additionally, distant failure was observed only in the patients in the lymph node-negative group who received adjuvant radiotherapy. In this group, 3 patients who did not receive adjuvant radiotherapy developed recurrences only in the pelvic region. CONCLUSION: The presence of lymph node involvement in stage IB cervical cancer does not affect the site of recurrence. However, distant recurrence was more frequent in the lymph node-positive group. PMID- 25539558 TI - A case-control study of the factors affecting male infertility. AB - BACKGROUND/AIM: Infertility is defined as the inability to conceive after at least 1 year of unprotected intercourse. In about one third of infertile couples, a male factor is the primary problem. Thus, the present study aimed to determine the most common risk factors for male infertility in Iranian men. MATERIALS AND METHODS: This case-control study included 268 men attending an infertility clinic in Shiraz, Iran. In this study, 161 fertile men were compared with 108 infertile ones regarding risk factors such as smoking habits, drug consumption, hernia, varicocele, job, and BMI. The data were analyzed using logistic regression analysis and t-test. RESULTS: The mean age of the fertile and infertile participants was 37.5 +/- 7 and 36.3 +/- 10, respectively. Our findings demonstrated a statistically significant relationship between male infertility and hernia, varicocele, taking ranitidine, job, and BMI. With an increase of 1 cigarette per day, there was a 1% decrease in the motility of the sperm. Moreover, with an increase of 1 year of cigarette smoking, 800,000 sperm are lost. CONCLUSION: The results revealed varicocele and hernia as the most common risk factors in men attending the infertility clinics in Shiraz. In addition, strenuous work could cause testicular injury. PMID- 25539559 TI - Surgery for intractable temporal lobe epilepsy: experience of a single institution. AB - BACKGROUND/AIM: In the treatment of epilepsy, encouraging results have been achieved with surgical treatment, especially for temporal lobe epilepsy (TLE). Drug resistance must be diagnosed as early as possible, because the ensuing seizures can be eliminated surgically via temporal lobe surgery in a high percentage (70%-90%) of patients. In this study we share our experience, in a single institution, of surgical treatment of intractable TLE. MATERIALS AND METHODS: Between March 2006 and November 2010 we performed 127 corticoamygdalohippocampectomy (CAH) procedures. All CAH surgical procedures were done as described by Niemeyer's technique. Resection lengths were 4-4.5 cm from the temporal pole. RESULTS: At the end of 24 months, 79.7% (n = 94) patients were still on antiepileptic medications, with 55 of them on a decreased number or dose of drugs, and 20.3 (n = 24) patients were antiepileptic drug-free. Postoperative Engel's classes were 1, 2, and 3 in 87.2%, 5.08%, and 7.6%, respectively. There was no mortality in follow-up, and dysphasia in 1 patient (0.84%) was the only morbidity. CONCLUSION: In our series we found that the outcome of surgery is associated with careful patient selection, which requires a detailed investigation of the patients. Our final conclusion is that outcome scores are independent of age, pathology, or sex but are dependent on correct patient selection. PMID- 25539560 TI - Effects of conservative therapy applied before arthroscopic subacromial decompression on the clinical outcome in patients with stage 2 shoulder impingement syndrome. AB - BACKGROUND/AIM: To investigate the effects of conservative therapy applied before arthroscopic subacromial decompression on the clinical outcome in patients with stage 2 shoulder impingement syndrome. MATERIALS AND METHODS: Sixty-eight patients having stage 2 shoulder impingement syndrome and treated with arthroscopic subacromial decompression were included in the study. We divided these patients into 2 groups, whereby 32 (47%) patients received conservative therapy before arthroscopic subacromial decompression and 36 (53%) patients did not receive conservative therapy. We compared both groups in terms of the the Constant, UCLA, and VAS scores for shoulder pain before and after arthroscopic subacromial decompression. RESULTS: Constant, UCLA, and VAS scores were statistically significantly improved in both groups after arthroscopic subacromial decompression (P <0.001). Constant, UCLA, and VAS scores before arthroscopic subacromial decompression were statistically better in Group 1 than in Group 2 (P < 0.001). No statistically significant difference was found between the groups in terms of Constant, UCLA, and VAS scores after arthroscopic subacromial decompression (P > 0.05). CONCLUSION: Conservative therapy applied in patients with stage 2 shoulder impingement syndrome before arthroscopic subacromial decompression does not have a positive contribution on the clinical outcome after arthroscopic subacromial decompression. PMID- 25539562 TI - Review of clinical experience with acute cholecystitis on the development of subsequent gallstone-related complications. AB - BACKGROUND/AIM: Recently, surgery during admission has been advocated for acute cholecystitis, rather than delayed surgery after conservative treatment. This study was designed to perform early surgeries and analyze the criteria used for conservative management followed by delayed surgery. MATERIALS AND METHODS: After implementation of a study with the aim of performing early surgery, a retrospective review using a prospective database during the period of June 2009 to June 2011 was established. Early surgery during index hospitalization was offered to all patients, except those having criteria for conservative management. RESULTS: There were 118 patients admitted for acute cholecystitis. Early and delayed surgeries were performed for 18 (15%) and 23 (20%) patients, respectively. Percutaneous cholecystostomy was performed for 10 (8%) patients with a success rate of 90% and significantly higher length of hospital stay (P = 0.001). Gallstone-related complications developed in 33 (28%) patients, causing significantly higher readmission rates (P = 0.001). Ofthe patients, 34 (29%) were neither operated on nor had complications. The subsequent cholecystectomy rate was calculated as 35%. The overall mortality rate was 1.7% for all groups. CONCLUSION: Although surgical treatment of acute cholecystitis, either by early or delayed surgery, has some specific morbidity and mortality, it should be kept in mind that conservative treatment modalities have a higher rate of recurrences and subsequent complications, which all cause additional morbidity and mortality in patients. PMID- 25539561 TI - Expression and clinical implications of P53, P63, and P73 protein in malignant tumor of the parotid gland. AB - BACKGROUND/AIM: To investigate the expression of P53, P63, and P73 proteins in malignant parotid gland tumors and adjacent nonneoplastic tissues and the association between the 3 proteins and their clinical characteristics. MATERIALS AND METHODS: A total of 40 pairs of paraffin-embedded malignant parotid gland tumors and adjacent nonneoplastic tissues were collected. We detected P53, P63, and P73 protein expression by immunohistochemistry. Statistical analysis was performed by using the chi-square test. RESULTS: P53, P63, and P73 protein expression in malignant parotid gland tumors was higher than their expression in adjacent nonneoplastic tissue (P = 0.030, 0.001, and 0.001, respectively). Expression of P53, P63, and P73 proteins was not associated with age, sex, or lymph node metastasis (P > 0.05). Expression of P53 and P73 proteins, instead of the P63 protein, was correlated to the degree of malignancy (P = 0.026 and 0.018, respectively). There was no significant difference among the P53, P73, and P63 proteins in malignant parotid gland tumors (P > 0.05). In the follow-up, only one patient died of colon cancer. CONCLUSION: Our results suggest that the P53, P63, and P73 proteins may play a role in the development of malignant parotid gland tumors and provide data for their diagnosis. PMID- 25539563 TI - Comparative study of photodynamic therapy monotherapy versus triple management in age-related macular degeneration. AB - AIM: To compare the effectiveness of photodynamic therapy (PDT) and PDT combined with intravitreal triamcinolone (IVTA) and vascular endothelial growth factor inhibition (anti-VEGF) in age-related macular degeneration (AMD). MATERIALS AND METHODS: Eighty eyes of 80 patients diagnosed with choroidal neovascularization (CNV) caused by AMD were included in the study. PDT was carried out on 40 eyes in group I, and PDT combined with 4 mg IVTA and anti-VEGF (1.25 mg bevacizumab in 20 eyes, 0.3 mg pegaptanib sodium in 20 eyes) was carried out in group II. The primary efficacy endpoint was the mean change from baseline visual acuity at month 12. RESULTS: Mean follow-up was 14.2 +/- 2.18 months in group I and 12.45 +/- 2.82 months in group II. In group I there was a 2.88 logMAR line decrease and 1.95 logMAR line increase in group II in vision between pretreatment and 12th month measurements (P < 0.05). Mean PDT session was 2.00 in group I and the mean combined treatment session was 1.15 in group II in the 12th month. CONCLUSION: Combination of IVTA and anti-VEGF with PDT is more effective and safer than PDT monotherapy in the treatment of CNV secondary to AMD. Combination treatment decreases the frequency and number of treatment sessions for an improved visual prognosis. PMID- 25539564 TI - Early surgical results of a 23-gauge trocar combined with a one-directional valve system in primary and secondary pars plana vitrectomy. AB - BACKGROUND/AIM: To elucidate the early surgical advantages of a 23-gauge trocar combined with a one-directional valve system in transconjunctival pars plana vitrectomies. MATERIALS AND METHODS: Early surgical results of 432 eyes of 432 patients (190 female and 242 male) who underwent 23-gauge (23G) transconjunctival sutureless vitrectomies (TSV) were evaluated. Sixty-three patients out of 432 underwent a second operation, 29 of them underwent silicone oil extraction, and 34 had phacoemulsification surgery with the help of vitreous infusion. If any sign of leakage was observed after the withdrawal of the cannulae, a suture was applied at the conjunctiva-scleral opening site. RESULTS: A total of 21 (4.8%) patients in the first operation and 7 (11.1%) cases in the second operation needed suture in at least 1 sclerotomy site. No one had intraoperative hypotony. On postoperative day 1, 37 initial surgery patients and 3 second TSV patients had hypotony; all of them resolved spontaneously 1 week after surgery. No one developed choroidal effusions or detachment. Intraocular pressure spikes more than 22 mmHg in day 1 occurred in 18 eyes after initial TSV; 6 of them had gas and 4 eyes had silicone tamponade. CONCLUSION: 23G TSV is an effective and safe procedure for both first vitreoretinal surgery and second intraocular surgeries in eyes that had TSV previously. PMID- 25539565 TI - Calcifying fibrous pseudotumor of lungs. AB - Calcified fibrous pseudotumors can generally be detected as solitary masses in various regions of the body, and were first described in 1988. In this case report, we discuss an adult patient whose tumor was localized in the lung, which has not been reported in the literature before. PMID- 25539567 TI - Polypharmacy and falls in older people: Balancing evidence-based medicine against falls risk. AB - The term polypharmacy has negative connotations due to its association with adverse drug reactions and falls. This spectrum of adverse events widens when polypharmacy occurs among the already vulnerable geriatric population. To date, there is no consensus definition of polypharmacy, and diverse definitions have been used by various researchers, the most common being the consumption of multiple number of medications. Taking multiple medications is considered a risk factor for falls through the adverse effects of drug-drug or drug-disease interactions. Falls studies have determined that taking >= 4 drugs is associated with an increased incidence of falls, recurrent falls, and injurious falls. In light of existing evidence, careful and regular medication reviews are advised to reduce the effect of polypharmacy on falls. However, intervention studies on medication reviews and their effectiveness on falls reduction have been scarce. This article reviews and discusses the evidence behind polypharmacy and its association with falls among older individuals, and highlights important areas for future research. PMID- 25539566 TI - CAGE-defined promoter regions of the genes implicated in Rett Syndrome. AB - BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes. RESULTS: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum. CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome. PMID- 25539568 TI - Sub-genomic selection patterns as a signature of breeding in the allopolyploid Brassica napus genome. AB - BACKGROUND: High-density single-nucleotide polymorphism (SNP) genotyping arrays are a powerful tool for genome-wide association studies and can give valuable insight into patterns of population structure and linkage disequilibrium (LD). In this study we used the Brassica 60kSNP Illumina consortium genotyping array to assess the influence of selection and breeding for important agronomic traits on LD and haplotype structure in a diverse panel of 203 Chinese semi-winter rapeseed (Brassica napus) breeding lines. RESULTS: Population structure and principal coordinate analysis, using a subset of the SNPs, revealed diversification into three subpopulations and one mixed population, reflecting targeted introgressions from external gene pools during breeding. Pairwise LD analysis within the A- and C-subgenomes of allopolyploid B. napus revealed that mean LD, at a threshold of r2=0.1, decayed on average around ten times more rapidly in the A-subgenome (0.25 0.30 Mb) than in the C-subgenome (2.00-2.50 Mb). A total of 3,097 conserved haplotype blocks were detected over a total length of 182.49 Mb (15.17% of the genome). The mean size of haplotype blocks was considerably longer in the C subgenome (102.85 Kb) than in the A-subgenome (33.51 Kb), and extremely large conserved haplotype blocks were found on a number of C-genome chromosomes. Comparative sequence analysis revealed conserved blocks containing homoloeogous quantitative trait loci (QTL) for seed erucic acid and glucosinolate content, two key seed quality traits under strong agronomic selection. Interestingly, C subgenome QTL were associated with considerably greater conservation of LD than their corresponding A-subgenome homoeologues. CONCLUSIONS: The data we present in this paper provide evidence for strong selection of large chromosome regions associated with important rapeseed seed quality traits conferred by C-subgenome QTL. This implies that an increase in genetic diversity and recombination within the C-genome is particularly important for breeding. The resolution of genome wide association studies is also expected to vary greatly across different genome regions. PMID- 25539569 TI - Does the Swedish Interactive Threshold Algorithm (SITA) accurately map visual field loss attributed to vigabatrin? AB - BACKGROUND: Vigabatrin (VGB) is an anti-epileptic medication which has been linked to peripheral constriction of the visual field. Documenting the natural history associated with continued VGB exposure is important when making decisions about the risk and benefits associated with the treatment. Due to its speed the Swedish Interactive Threshold Algorithm (SITA) has become the algorithm of choice when carrying out Full Threshold automated static perimetry. SITA uses prior distributions of normal and glaucomatous visual field behaviour to estimate threshold sensitivity. As the abnormal model is based on glaucomatous behaviour this algorithm has not been validated for VGB recipients. We aim to assess the clinical utility of the SITA algorithm for accurately mapping VGB attributed field loss. METHODS: The sample comprised one randomly selected eye of 16 patients diagnosed with epilepsy, exposed to VGB therapy. A clinical diagnosis of VGB attributed visual field loss was documented in 44% of the group. The mean age was 39.3 years +/- 14.5 years and the mean deviation was -4.76 dB +/-4.34 dB. Each patient was examined with the Full Threshold, SITA Standard and SITA Fast algorithm. RESULTS: SITA Standard was on average approximately twice as fast (7.6 minutes) and SITA Fast approximately 3 times as fast (4.7 minutes) as examinations completed using the Full Threshold algorithm (15.8 minutes). In the clinical environment, the visual field outcome with both SITA algorithms was equivalent to visual field examination using the Full Threshold algorithm in terms of visual inspection of the grey scale plots , defect area and defect severity. CONCLUSIONS: Our research shows that both SITA algorithms are able to accurately map visual field loss attributed to VGB. As patients diagnosed with epilepsy are often vulnerable to fatigue, the time saving offered by SITA Fast means that this algorithm has a significant advantage for use with VGB recipients. PMID- 25539570 TI - Electrocatalytic assay for monitoring methylglyoxal-mediated protein glycation. AB - Protein glycation is a complex process that plays an important role in diabetes mellitus, aging, and the regulation of protein function in general. As a result, current methodological research on proteins is focused on the development of novel approaches for investigating glycation and the possibility of monitoring its modulation and selective inhibition. In this paper, a first sensing strategy for protein glycation is proposed, based on protein electroactivity measurement. Concretely, the label-free method proposed is based on the application of a constant-current chronopotentiometric stripping (CPS) analysis at Hg-containing electrodes. The glycation process was monitored as the decrease in the electrocatalytic protein signal, peak H, observed at highly negative potentials at around -1.8 V (vs Ag/AgCl3 M KCl), which was previously ascribed to a catalytic hydrogen evolution reaction (CHER). Using this method, a model protein bovine serum albumin was investigated over 3 days of incubation with the glycation agent methylglyoxal in the absence or presence of the glycation inhibitor aminoguanidine (pimagedine). The electrochemical methodology presented here could open up new possibilities in research on protein glycation and oxidative modification. The methodology developed also provides a new option for the analysis of protein intermolecular interactions using electrochemical sensors, which was demonstrated by the application of a silver solid amalgam electrode (AgSAE) for monitoring the glycation process in samples of bovine serum albumin, human serum albumin, and lysozyme. PMID- 25539572 TI - Advances in the management of childhood portal hypertension. AB - Portal hypertension is one of the most serious complications of childhood liver disease, and variceal bleeding is the most feared complication. Most portal hypertension results from cirrhosis but extra hepatic portal vein obstruction is the single commonest cause. Upper gastrointestinal endoscopy endoscopy remains necessary to diagnose gastro-esophageal varices. Families of children with portal hypertension should be provided with written instructions in case of gastrointestinal bleeding. Children with large varices should be considered for primary prophylaxis on a case-by-case basis. The preferred method is variceal band ligation. Children with acute bleeding should be admitted to hospital and treated with antibiotics and pharmacotherapy before urgent therapeutic endoscopy. All children who have bled should then receive secondary prophylaxis. The preferred method is variceal band ligation and as yet there is little evidence to support the use of beta-blockers. Children with extrahepatic portal vein obstruction should be assessed for suitability of mesoportal bypass. PMID- 25539573 TI - Renal vein thrombosis in the post-partum period: a case report. AB - INTRODUCTION: Physiological hypercoagulability is a known condition in pregnancy designed to limit the risk of bleeding; it may exceptionally be complicated by thrombosis of the renal vein. To the best of our knowledge, this is the third case of renal venous infarction reported in the literature. CASE PRESENTATION: We report the case of a 43-year-old Caucasian woman, a mother of three sons who presented with left flank pain and hematuria. The clinical investigations did not find any other cause for her thrombophilia. CONCLUSIONS: Clinical onset is not specific, so it is important to evoke the diagnosis in the context of pregnancy; computed tomography angiography is the investigation of choice to set the diagnosis. It is important to know that anticoagulation therapy must be initiated as soon as possible. PMID- 25539571 TI - Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2). AB - BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013). PMID- 25539575 TI - Differential effects of extracellular vesicles secreted by mesenchymal stem cells from different sources on glioblastoma cells. AB - BACKGROUND: Malignant glial tumors, including glioblastoma multiforme, account for 15 - 20% of pediatric CNS malignancies. They are most resistant to therapy and are associated with a poor prognosis. OBJECTIVE: Given the ability of mesenchymal stem cells (MSCs) to affect glioma growth, we investigated the effects of extracellular vesicles (EVs) derived from MSCs on U87MG glioblastoma cells line. METHODS: EVs were isolated from culture media of MSCs from different sources, including bone marrow (BM), umbilical cord (UC) and adipose tissue (AT) and added to U87MG culture. The internalization and the effects of BM-, UC- and AT-MSC-EVs on proliferation and apoptosis of tumor cells were evaluated. RESULTS: Both confocal microscopy and FACS analysis showed internalization of EVs into tumor cells. BM- and UC-MSC-EVs decreased cell proliferation, while an opposite effect was observed with AT-MSC-EVs. Moreover, both BM- and UC-MSC-EVs induced apoptosis of glioblastoma cells, while AT-MSC-EVs had no effect. Loading UC-MSC EVs with Vincristine further increased cytotoxicity when compared both to the free drug and to untreated EVs. CONCLUSIONS: Different effects of MSC-EVs on cancer cells were observed depending on their tissue of origin. Moreover, MSC-EVs can deliver antiblastic drugs to glioblastoma cells. PMID- 25539574 TI - Ability of naringenin, a bioflavonoid, to activate M-type potassium current in motor neuron-like cells and to increase BKCa-channel activity in HEK293T cells transfected with alpha-hSlo subunit. AB - BACKGROUND: Naringenin (NGEN) is a citrus bioflavonoid known to have beneficial health properties; however, the ionic mechanism of its actions remains largely unclear. In this study, we attempted to evaluate the possible effects of NGEN on K(+) currents in NSC-34 neuronal cells and in HEK293T cells expressing alpha hSlo. RESULTS: NGEN increased M-type K(+) current (I(K(M))) in a concentration dependent manner with an EC50 value of 9.8 MUM in NSC-34 cells. NGEN shifted the activation curve of I(K(M)) conductance to the more negative potentials. In cell attached recordings, NGEN or flupirtine enhanced the activity of M-type K(+) (K(M)) channels with no changes in single-channel amplitude. NGEN (10 MUM) had minimal effect on erg-mediated K(+) currents. Under cell-attached voltage-clamp recordings, NGEN decreased the frequency of spontaneous action currents and further application of linopirdine can reverse NGEN-induced inhibition of firing. In HEK293T cells expressing alpha-hSlo, this compound increased the amplitude of Ca(2+)-activated K(+) current (I(K(Ca))). Under inside-out recordings, NGEN applied to the intracellular side of the detached patch enhanced the activity of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels. Moreover, from the study of a modeled neuron, burst firing of simulated action potentials (APs) was reduced in the presence of the increased conductances of both K(M) and K(Ca) channels. Fast-slow analysis of AP bursting from this model also revealed that as the conductances of both K(M) and BK(Ca) channels were increased by two-fold, the voltage nullcline was shifted in an upward direction accompanied by the compression of burst trajectory. CONCLUSIONS: The present results demonstrate that activation of both K(M) and BK(Ca) channels caused by NGEN might combine to influence neuronal activity if similar channels were functionally co-expressed in central neurons in vivo. PMID- 25539576 TI - Chemical composition, antinociceptive, anti-inflammatory and redox properties in vitro of the essential oil from Remirea maritima Aubl. (Cyperaceae). AB - BACKGROUND: The present study was carried out to evaluate antioxidant, antinociceptive and anti-inflammatory activities of essential oil from R. maritima (RMO) in experimental protocols. METHODS: The essential oil from the roots and rhizomes of RMO were obtained by hydrodistillation using a Clevenger apparatus, and analyzed by gas chromatography/mass spectrometry (GC/MS). Here, we evaluated free radical scavenging activities and antioxidant potential of RMO using in vitro assays for scavenging activity against hydroxyl radicals, hydrogen peroxide, superoxide radicals, and nitric oxide. The total reactive antioxidant potential (TRAP) and total antioxidant reactivity (TAR) indexes and in vitro lipoperoxidation were also evaluated. The ability of RMO to prevent lipid peroxidation was measured by quantifying thiobarbituric acid-reactive substances (TBARS). NO radical generated at physiological pH was found to be inhibited by RMO, that showed scavenging effect upon SNP-induced NO production at all concentrations. Antinociceptive and anti-inflammatory properties were evaluated by acetic acid writhing reflex, Formalin-induced nociception and Carrageenan induced edema test. RESULTS: The majors compounds identified was remirol (43.2%), cyperene (13.8%), iso-evodionol (5.8%), cyperotundone (5.7%), caryophyllene oxide (4.9%), and rotundene (4.6%). At the TRAP assay, RMO concentration of 1 mg.mL(-1) showed anti-oxidant effects and at concentration of 1 and 10 ng.mL(-1) RMO showed pro-oxidant effect. RMO at 1 mg.mL(-1) also showed significant anti-oxidant capacity in TAR measurement. Concentrations of RMO from 1 ng.mL(-1) to 100 MUg.mL(-1) enhanced the AAPH-induced lipoperoxidation. RMO reduced deoxyribose oxidative damage, induced by the Fenton reaction induction system, at concentrations from 1 ng.mL(-1) to 100 MUg.mL(-1). We observed that RMO caused a significant increase in rate of adrenaline auto-oxidation. On the other hand RMO did not present any scavenging effect in H2O2 formation in vitro. The results of this study revealed that RMO has both peripheral and central analgesic properties. The RMO, all doses, orally (p.o.) administered significantly inhibited (p < 0.05, p < 0.01 and p < 0.001) the acetic acid-induced writhings and two phases of formalin-induced nociception in mice. CONCLUSION: The RMO demonstrated antioxidant and analgesic profile which may be related to the composition of the oil. PMID- 25539577 TI - Low calpain-9 is associated with adverse disease-specific survival following endocrine therapy in breast cancer. AB - BACKGROUND: The calpains are intracellular cysteine proteases that function in a variety of important cellular functions, including signalling, motility, apoptosis and survival. In breast cancer high calpain-1 and calpain-2 expression has been associated with adverse clinical outcome. Calpain-9 was thought to be exclusively expressed in the digestive tract; however recent studies have shown that this protein is also expressed in breast tissue. METHODS: We investigated the expression of calpain-9 in a large cohort of early stage breast cancer patients (n = 783) using immunohistochemistry on a tissue microarray. Patients had long-term follow-up information available for analysis. RESULTS: Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014). Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013). Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003). CONCLUSIONS: This study suggests that calpain-9 may play a role in breast cancer and that low expression is associated with poorer patient clinical outcome following endocrine therapy. Validation studies are warranted as determining expression of calpain-9 may provide important prognostic information. PMID- 25539578 TI - Paternal X inactivation does not correlate with X chromosome evolutionary strata in marsupials. AB - BACKGROUND: X chromosome inactivation is the transcriptional silencing of one X chromosome in the somatic cells of female mammals. In eutherian mammals (e.g. humans) one of the two X chromosomes is randomly chosen for silencing, with about 15% (usually in younger evolutionary strata of the X chromosome) of genes escaping this silencing. In contrast, in the distantly related marsupial mammals the paternally derived X is silenced, although not as completely as the eutherian X. A chromosome wide examination of X inactivation, using RNA-seq, was recently undertaken in grey short-tailed opossum (Monodelphis domestica) brain and extraembryonic tissues. However, no such study has been conduced in Australian marsupials, which diverged from their American cousins ~80 million years ago, leaving a large gap in our understanding of marsupial X inactivation. RESULTS: We used RNA-seq data from blood or liver of a family (mother, father and daughter) of tammar wallabies (Macropus eugenii), which in conjunction with available genome sequence from the mother and father, permitted genotyping of 42 expressed heterozygous SNPs on the daughter's X. These 42 SNPs represented 34 X loci, of which 68% (23 of the 34) were confirmed as inactivated on the paternally derived X in the daughter's liver; the remaining 11 X loci escaped inactivation. Seven of the wallaby loci sampled were part of the old X evolutionary stratum, of which three escaped inactivation. Three loci were classified as part of the newer X stratum, of which two escaped inactivation. A meta-analysis of previously published opossum X inactivation data revealed that 5 of 52 genes in the old X stratum escaped inactivation. CONCLUSIONS: We demonstrate that chromosome wide inactivation of the paternal X is common to an Australian marsupial representative, but that there is more escape from inactivation than reported for opossum (32% v 14%). We also provide evidence that, unlike the human X chromosome, the location of loci within the oldest evolutionary stratum on the marsupial X does not correlate with their probability of escape from inactivation. PMID- 25539579 TI - Modeling skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol compounds with quantum mechanistic properties. AB - BACKGROUND: Advanced structure-activity relationship (SAR) modeling can be used as an alternative tool for identification of skin sensitizers and in improvement of the medical diagnosis and more effective practical measures to reduce the causative chemical exposures. It can also circumvent ethical concern of using animals in toxicological tests, and reduce time and cost. Compounds with aniline or phenol moieties represent two large classes of frequently skin sensitizing chemicals but exhibiting very variable, and difficult to predict, potency. The mechanisms of action are not well-understood. METHODS: A group of mechanistically hard-to-be-classified aniline and phenol chemicals were collected. An in silico model was established by statistical analysis of quantum descriptors for the determination of the relationship between their chemical structures and skin sensitization potential. The sensitization mechanisms were investigated based on the features of the established model. Then the model was utilized to analyze a subset of FDA approved drugs containing aniline and/or phenol groups for prediction of their skin sensitization potential. RESULTS AND DISCUSSION: A linear discriminant model using the energy of the highest occupied molecular orbital (epsilonHOMO) as the descriptor yielded high prediction accuracy. The contribution of epsilonHOMO as a major determinant may suggest that autoxidation or free radical binding could be involved. The model was further applied to predict allergic potential of a subset of FDA approved drugs containing aniline and/or phenol moiety. The predictions imply that similar mechanisms (autoxidation or free radical binding) may also play a role in the skin sensitization caused by these drugs. CONCLUSIONS: An accurate and simple quantum mechanistic model has been developed to predict the skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol chemicals. The model could be useful for the skin sensitization potential predictions of a subset of FDA approved drugs. PMID- 25539580 TI - Assessing the application of non-pharmacological interventions for people with dementia in German nursing homes: feasibility and content validity of the dementia care questionnaire (DemCare-Q). AB - BACKGROUND: Non-pharmacological interventions are guideline-recommended as initial treatment for people with dementia in nursing homes. In Germany, there is no instrument available to collect standardized data on the application of all of these interventions; an investigation of their use in large-scale samples is not currently possible. This article describes the development and initial testing of a questionnaire (Dementia Care Questionnaire (DemCare-Q)) to assess provided non pharmacological interventions in residents with dementia in nursing homes that can be completed by nurses. METHODS: The questionnaire development comprised the following steps to achieve content validity and feasibility: a structured content analysis of the German guideline for the care of people with dementia and challenging behavior in nursing homes and a systematic literature review of projects that implemented these; quantitative expert ratings and calculation of content validity indices; qualitative pre-test with future users using cognitive techniques; quantitative pre-test using frequency analysis of item non-response. RESULTS: The developed questionnaire covers seven dementia-specific non pharmacological interventions in nursing homes. Problematic items could be improved by revising them successively, bringing forth a feasible and content valid version of the DemCare-Q. The DemCare-Q enables researchers to collect data on the application of dementia interventions in German nursing homes in large scale studies. CONCLUSION: A literature review, expert rating and multi-method pre-test are important steps of questionnaire development. The applied methods ensure content validity and the practicability of the instrument. The publication of this process enhances the transparency of questionnaire design and supports researchers in solving problems in developing questions to assess the application of interventions. Since these are initial steps of questionnaire development, further testing of its reliability is needed. PMID- 25539581 TI - The context of violent disagreements between parents: a qualitative analysis from parents' reports. AB - BACKGROUND: Intimate partner violence (IPV) is a prevalent public health problem that affects millions of families. Much of what is known about IPV comes from quantitative studies that often "count" acts of IPV without exploring in depth the circumstances surrounding the violence, thereby leaving critical questions unanswered; existing qualitative studies tend to focus solely on women's perspectives. There is a dearth of dyadic qualitative research exploring the context of IPV in families with children, thus hindering the development of effective interventions for families experiencing IPV. METHODS: Seven heterosexual couples were recruited from a University-based family therapy clinic to participate in qualitative interviews. Couples were eligible if they had experienced severe verbal or any physical aggression during the past 4 months; had >= one child living in the household; were English-speaking; and were >= 18. Each individual was interviewed separately. Key topics explored included specific types of violence used by men and women; primary triggers and the context surrounding aggressive disagreements; degree to which the child(ren) were exposed; and perceived consequences for adults and children. RESULTS: All couples listed household responsibilities and parenting as key IPV triggers. Couples with infants reported that parenting disagreements were particularly heated, with women using aggression due to frustration about their partners' lack of support. Couples also described substance use, wanting to be heard, and prior violence histories as triggers or as the background context for IPV episodes. Children were present during IPV and often intervened in conflicts involving severe violence. Parents' perceptions of the effects of IPV on their children ranged from minimal to major emotional distress, with men describing more significant impact than women. CONCLUSIONS: When describing acute triggers, parents most commonly mentioned that arguments were instigated by concerns about the division of household labor and parenting, a finding that may have significant implications for intervention development; this was particularly notable for parents of infants. Our findings emphasize the need for innovative programs that help parents cope with the stresses of raising a family as well as programs that directly address the consequences of IPV for children. PMID- 25539582 TI - The Dutch Obesity Intervention in Teenagers (DOiT) cluster controlled implementation trial: intervention effects and mediators and moderators of adiposity and energy balance-related behaviours. AB - BACKGROUND: The Dutch Obesity Intervention in Teenagers (DOiT) programme is an evidence-based obesity prevention programme tailored to adolescents attending the first two years of prevocational education in the Netherlands. The initial programme showed promising results during an effectiveness trial. The programme was adapted and prepared for nationwide dissemination. To gain more insight into the process of translating evidence-based approaches into 'real world' (i.e., 'natural') conditions, our research aims were to evaluate the impact of the DOiT implementation programme on adolescents' adiposity and energy balance-related behaviours during natural dissemination and to explore the mediating and moderating factors underlying the DOiT intervention effects. METHODS: We conducted a cluster-controlled implementation trial with 20 voluntary intervention schools (n=1002 adolescents) and 9 comparable control schools (n = 484 adolescents). We measured adolescents' body height and weight, skinfold thicknesses, and waist circumference. We assessed adolescents' dietary and physical activity behaviours by means of self-report. Data were collected at baseline and at 20-months follow-up. We used multivariable multilevel linear or logistic regression analyses to evaluate the intervention effects and to test the hypothesised behavioural mediating factors. We checked for potential effect modification by gender, ethnicity and education level. RESULTS: We found no significant intervention effects on any of the adiposity measures or behavioural outcomes. Furthermore, we found no mediating effects by any of the hypothesised behavioural mediators. Stratified analyses for gender showed that the intervention was effective in reducing sugar-containing beverage consumption in girls (B = -188.2 ml/day; 95% CI = -344.0; -32.3). In boys, we found a significant positive intervention effect on breakfast frequency (B = 0.29 days/week; 95% CI = 0.01; 0.58). Stratified analyses for education level showed an adverse intervention effect (B = 0.09; 95% CI = 0.02; 0.16) on BMI z-scores for adolescents attending the vocational education track. CONCLUSIONS: Although not successful in changing adolescents' adiposity, the DOiT-implementation programme had some beneficial effects on specific obesity-related behaviours in subgroups. This study underlines the difficulty of translating intervention effectiveness in controlled settings to real world contexts. Adaptations to the implementation strategy are needed in order to promote implementation as intended by the teachers. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92755979. PMID- 25539583 TI - Whole genome amplification approach reveals novel polyhydroxyalkanoate synthases (PhaCs) from Japan Trench and Nankai Trough seawater. AB - BACKGROUND: Special features of the Japanese ocean include its ranges of latitude and depth. This study is the first to examine the diversity of Class I and II PHA synthases (PhaC) in DNA samples from pelagic seawater taken from the Japan Trench and Nankai Trough from a range of depths from 24 m to 5373 m. PhaC is the key enzyme in microorganisms that determines the types of monomer units that are polymerized into polyhydroxyalkanoate (PHA) and thus affects the physicochemical properties of this thermoplastic polymer. Complete putative PhaC sequences were determined via genome walking, and the activities of newly discovered PhaCs were evaluated in a heterologous host. RESULTS: A total of 76 putative phaC PCR fragments were amplified from the whole genome amplified seawater DNA. Of these 55 clones contained conserved PhaC domains and were classified into 20 genetic groups depending on their sequence similarity. Eleven genetic groups have undisclosed PhaC activity based on their distinct phylogenetic lineages from known PHA producers. Three complete DNA coding sequences were determined by IAN PCR, and one PhaC was able to produce poly(3-hydroxybutyrate) in recombinant Cupriavidus necator PHB-4 (PHB-negative mutant). CONCLUSIONS: A new functional PhaC that has close identity to Marinobacter sp. was discovered in this study. Phylogenetic classification for all the phaC genes isolated from uncultured bacteria has revealed that seawater and other environmental resources harbor a great diversity of PhaCs with activities that have not yet been investigated. Functional evaluation of these in silico-based PhaCs via genome walking has provided new insights into the polymerizing ability of these enzymes. PMID- 25539585 TI - Babesiosis in China, an emerging threat. PMID- 25539584 TI - Liver ENPP1 protein increases with remission of type 2 diabetes after gastric bypass surgery. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive disease resulting from increasing insulin resistance and reduced pancreatic beta-cell insulin secretion. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibits insulin signalling and may contribute to the pathogenesis of T2DM. Others have found elevated ENPP1 levels in muscle, fat, and skin tissues from insulin resistant individuals, but similar data on liver ENPP1 is lacking. The purpose of this study was to compare expression and protein concentrations of ENPP1 in liver between patients with and without T2DM. METHODS: Roux-en-Y gastric bypass surgery (RYGB) results in remission of insulin resistance and T2DM thus presenting an opportunity to examine some critical aspects of these conditions. We measured liver ENPP1 gene and protein expression in individuals with or without T2DM at RYGB and on average 17 (+/-5.6) months later. RESULTS: We found liver ENPP1 protein abundance was lower in individuals with T2DM than in those with normal glucose tolerance, and increased after RYGB surgery in those individuals who had remission of T2DM. ENPP1 positively correlated with insulin sensitivity at the liver (as measured by HOMA-IR), which is contrary to what others have reported in other insulin target tissues. CONCLUSIONS: Liver ENPP1 expression in T2DM is the reverse of that expected based on expression in other tissues and is likely due to the unique role the liver has in insulin clearance. The work presented here adds another dimension to the role of ENPP1, and supports the hypothesis that ENPP1 may act as a natural modulator of insulin signalling in the liver. PMID- 25539586 TI - Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial. AB - BACKGROUND: Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia. METHODS: In this international, randomised, controlled, double-blind, phase 3, non inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV acute community-acquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5-7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8-15 days after last dose of study drug) in the clinically evaluable population. Non inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of -10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838. FINDINGS: Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9.9%, 95% CI 2.8-17.1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data. INTERPRETATION: Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III-IV community acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population. FUNDING: AstraZeneca. PMID- 25539587 TI - Time to reconsider how we do antibiotic therapy trials. PMID- 25539589 TI - Erratum to: Nonmedical prescription drug use among US young adults by educational attainment. PMID- 25539588 TI - Epidemiological, clinical, and laboratory characteristics of 48 cases of "Babesia venatorum" infection in China: a descriptive study. AB - BACKGROUND: Human babesiosis is an emerging zoonosis. "Babesia venatorum" has been identified in only four asplenic men and a child so far. We aimed to describe the epidemiological, clinical, and laboratory characteristics of a series of cases with "B venatorum" infection identified in a sentinel hospital in China. METHODS: We recruited participants with a recent tick bite at Mudanjiang Forestry Central Hospital, Heilongjiang province, China. Cases were diagnosed through PCR followed by sequencing, microscopic identification, or isolation by animal inoculation, or both. FINDINGS: 48 individuals (30 women or girls; median age 45 years, range 7 months to 75 years) with "B venatorum" infection were identified. 32 of these individuals were confirmed cases and 16 were probable cases. None of the 48 cases had received a blood transfusion or had a splenectomy. Geographically, cases were distributed diffusely throughout the hospital catchment area. Of the 32 confirmed cases, 21 (66%) presented with a fever, 13 (41%) with a headache, 12 (38%) with myalgia or arthralgia, and three (9%) with chills. 14 (44%) patients had fatigue, eight (25%) had dizziness, and eight (25%) had hypersomnia. Six (19%) patients had an erythematous non-pruritic rash around the tick-bite site and two (6%) had lymphadenopathy. Seven (22%) and four (13%) patients had anaemia and thrombocytopenia, respectively, and seven (50%) of 14 patients with confirmed infection had increased hepatic transaminase concentrations. In the confirmed cases, concentrations of intercellular adhesion molecule 3 (p<0.001), P-selectin (p<0.05), and platelet endothelial cell adhesion molecule 1 (p<0.001) were significantly reduced, whereas tumour necrosis factor alpha (p<0.01) and vascular cell adhesion molecule 1 (p<0.001) were significantly increased. INTERPRETATION: "B venatorum" infection should be included in the differential diagnosis of patients with a tick-exposure history in areas where this pathogen has previously been identified in ticks or people. FUNDING: Natural Science Foundation of China and Mega-Project for Infectious Diseases. PMID- 25539590 TI - Asian Americans and European Americans' stigma levels in response to biological and social explanations of depression. AB - INTRODUCTION: Mental illness stigma is prevalent among Asian Americans, and it is a key barrier that prevents them from seeking psychological services. Limited studies have experimentally examined how Asian Americans respond to biological and social explanations of mental illness. Understanding how to educate and communicate about mental illness effectively is crucial in increasing service utilization among Asian Americans. PURPOSE: To assess how genetic, neurobiological, and social explanations for the onset of depression affects Asian American and European American's mental illness stigma. METHODS: 231 Asian Americans and 206 European Americans read about an individual with major depression and were randomly assigned to be informed that the cause was either genetic, neurobiological, social, or unknown. Various stigma outcomes, including social distance, fear, and depression duration were assessed. RESULTS: Consistent with prior research, Asian Americans had higher baseline levels of stigma compared to European Americans. Greater social essentialist beliefs predicted positive stigma outcomes for Asian Americans, such as a greater willingness to be near, help, and hire someone with depression, but genetic essentialist beliefs predicted negative stigma outcomes, such as fear. In addition, a social explanation for the etiology of depression led to lower stigma outcomes for Asian Americans; it decreased their fear of someone with depression and increased the perception that depression is treatable. For European Americans, both genetic and social essentialist beliefs predicted a greater perception of depression treatability. CONCLUSION: Although genetics do play a role in the development of depression, emphasizing a social explanation for the origin of depression may help reduce stigma for Asian Americans. PMID- 25539592 TI - Insights from systems pharmacology into cardiovascular drug discovery and therapy. AB - BACKGROUND: Given the complex nature of cardiovascular disease (CVD), information derived from a systems-level will allow us to fully interrogate features of CVD to better understand disease pathogenesis and to identify new drug targets. RESULTS: Here, we describe a systematic assessment of the multi-layer interactions underlying cardiovascular drugs, targets, genes and disorders to reveal comprehensive insights into cardiovascular systems biology and pharmacology. We have identified 206 effect-mediating drug targets, which are modulated by 254 unique drugs, of which, 43% display activities across different protein families (sequence similarity < 30%), highlighting the fact that multitarget therapy is suitable for CVD. Although there is little overlap between cardiovascular protein targets and disease genes, the two groups have similar pleiotropy and intimate relationships in the human disease gene-gene and cellular networks, supporting their similar characteristics in disease development and response to therapy. We also characterize the relationships between different cardiovascular disorders, which reveal that they share more etiological commonalities with each other rooted in the global disease-disease networks. Furthermore, the disease modular analysis demonstrates apparent molecular connection between 227 cardiovascular disease pairs. CONCLUSIONS: All these provide important consensus as to the cause, prevention, and treatment of various CVD disorders from systems-level perspective. PMID- 25539591 TI - Early risk factors for adult bipolar disorder in adolescents with mood disorders: a 15-year follow-up of a community sample. AB - BACKGROUND: We aimed to outline the early risk factors for adult bipolar disorder (BPD) in adolescents with mood disorders. METHODS: Adolescents (16-17 years old) with mood disorders (n = 287; 90 participants with hypomania spectrum episodes and 197 with major depressive disorder [MDD]) were identified from a community sample. Fifteen years later (at 30-33 years of age), mood episodes were assessed (n = 194). The risk of developing BPD (n = 22), compared with MDD (n = 104) or no mood episodes in adulthood (n = 68), was estimated via logistic regression. Adolescent mood symptoms, non-mood disorders, and family characteristics were assessed as potential risk factors. RESULTS: Among the adolescents with mood disorders, a family history of BPD was the strongest predictor of developing BPD compared with having no mood episodes in adulthood (OR = 5.94; 95% CI = 1.11 31.73), whereas disruptive disorders significantly increased the risk of developing BPD compared with developing MDD (OR = 2.94; CI = 1.06-8.12). The risk that adolescents with MDD would develop adult BPD, versus having no mood episodes in adulthood, was elevated among those with an early disruptive disorder (OR = 3.62; CI = 1.09-12.07) or multiple somatic symptoms (OR = 6.60; CI = 1.70-25.67). Only disruptive disorders significantly predicted adult BPD among adolescents with MDD versus continued MDD in adulthood (OR = 3.59; CI = 1.17-10.97). Only a few adolescents with hypomania spectrum episodes continued to have BPD as adults, and anxiety disorders appeared to increase this risk. CONCLUSIONS: Although most of the identified potential risk factors are likely general predictors of continued mood disorders, disruptive disorders emerged as specific predictors of developing adult BPD among adolescents with MDD. PMID- 25539593 TI - Friend retrovirus drives cytotoxic effectors through Toll-like receptor 3. AB - BACKGROUND: Pathogen recognition drives host defense towards viral infections. Specific groups rather than single members of the protein family of pattern recognition receptors (PRRs) such as membrane spanning Toll-like receptors (TLRs) and cytosolic helicases might mediate sensing of replication intermediates of a specific virus species. TLR7 mediates host sensing of retroviruses and could significantly influence retrovirus-specific antibody responses. However, the origin of efficient cell-mediated immunity towards retroviruses is unknown. Double-stranded RNA intermediates produced during retroviral replication are good candidates for immune stimulatory viral products. Thus, we considered TLR3 as primer of cell-mediated immunity against retroviruses in vivo. RESULTS: Infection of mice deficient in TLR3 (TLR3(-/-)) with Friend retrovirus (FV) complex revealed higher viral loads during acute retroviral infection compared to wild type mice. TLR3(-/-) mice exhibited significantly lower expression levels of type I interferons (IFNs) and IFN-stimulated genes like Pkr or Ifi44, as well as reduced numbers of activated myeloid dendritic cells (DCs) (CD86(+) and MHC II(+)). DCs generated from FV-infected TLR3(-/-) mice were less capable of priming virus-specific CD8(+) T cell proliferation. Moreover, cytotoxicity of natural killer (NK) cells as well as CD8(+) T cells were reduced in vitro and in vivo, respectively, in FV-infected TLR3(-/-) mice. CONCLUSIONS: TLR3 mediates antiretroviral cytotoxic NK cell and CD8(+) T cell activity in vivo. Our findings qualify TLR3 as target of immune therapy against retroviral infections. PMID- 25539594 TI - Peer Experiences in Short-Term Residential Treatment: Individual and Group Moderated Prediction of Behavioral Responses to Peers and Adults. AB - This research examined the independent and interactional contributions of peer experiences and group aggression to youth behavioral adjustment in short-term residential treatment. Participants were 219 youth (M age = 12.70, SD = 2.76; 71 % male) nested in 28 same-age, same-sex treatment groups. Sociometric interviews assessed social preference and victimization. Daily behavioral observations by staff assessed overall levels of treatment group aggression, as well as aggressive, withdrawn, and prosocial responses to specific social events. End-of summer behavioral responses (to all events; to peers; to adults) were predicted, controlling for initial levels of these responses. Social preference predicted higher end-of-summer prosocial responses, and victimization predicted lower prosocial and higher withdrawn responses. Each interacted with group aggression in some analyses, with more positive peer experiences only predicting more favorable responses in groups that were low or average in aggression. Interactant specific analyses revealed that some of these associations were broad, whereas others applied only to adults. For example, group aggression moderated the association between social preference and aggressive responses to adults but not peers. Gender differences were also interactant-specific. Results highlight the importance of peer experiences in group treatment and underscore the value of both aggregation and disaggregation over interactants in analyses of behavioral adjustment. PMID- 25539595 TI - Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations. AB - BACKGROUND: Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell. METHOD: To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML. To further study the transcriptional alterations of HOX genes in hematopoiesis, we also analyzed gene expression of epigenetic modifiers in the subpopluations of healthy BM and leukemic cells. RESULTS: Unsupervised hierarchical clustering divided the AMLs into five clusters characterized by the presence of prevalent molecular genetic aberrations. Notably, the impact of genotype on HOX gene expression was significantly more pronounced than that of the differentiation stage of the blasts. This driving role of molecular aberrations was best exemplified by the repressive effect of the PML-RARa fusion gene on HOX gene expression, regardless of the presence of the FLT3/ITD mutation. Furthermore, HOX gene expression was positively correlated with mRNA levels of histone demethylases (JMJD3 and UTX) and negatively correlated with gene expression of DNA methyltranferases. No such relationships were observed in subpopulations of healthy BM cells. CONCLUSION: Our results demonstrate that specific molecular genetic aberrations, rather than differentiation per se, underlie the observed differences in HOX gene expression in AML. Moreover, the observed correlations between epigenetic modifiers and HOX expression that are specific to malignant hematopoiesis, suggest their potential causal relationships. PMID- 25539596 TI - On the beginning of mortality acceleration. AB - Physiological senescence is characterized by the increasing limitation of capabilities of an organism resulting from the progressive accumulation of molecular damage, which at group (cohort) level translates into, among other things, an increase in mortality risks with age. Physiological senescence is generally thought to begin at birth, if not earlier, but models of demographic aging (i.e., an increase in mortality risks) normally start at considerably later ages. This apparent inconsistency can be solved by assuming the existence of two mortality regimes: "latent" and "manifest" aging. Up to a certain age, there is only latent aging: physiological senescence occurs, but its low level does not trigger any measurable increase in mortality. Past a certain level (and age), molecular damage is such that mortality risks start to increase. We first discuss why this transition from latent to manifest aging should exist at all, and then we turn to the empirical estimation of the corresponding threshold age by applying Bai's approach to the estimation of breakpoints in time series. Our analysis, which covers several cohorts born between 1850 and 1938 in 14 of the countries included in the Human Mortality Database, indicates that an age at the onset of manifest aging can be identified. However, it has not remained constant: it has declined from about 43 and 47 years, respectively, for males and females at the beginning of the period (cohorts born in 1850-1869) to about 31 for both males and females toward its end (cohorts born in 1920-1938). A discussion of why this may have happened ensues. PMID- 25539597 TI - Treatment dismantling pilot study to identify the active ingredients in personalized feedback interventions for hazardous alcohol use: randomized controlled trial. AB - BACKGROUND: There is a considerable body of evidence supporting the effectiveness of personalized feedback interventions for hazardous alcohol use-whether delivered face-to-face, by postal mail, or over the Internet (probably now the primary mode of delivery). The Check Your Drinking Screener (CYD; see www.CheckYourDrinking.net) is one such intervention. OBJECTIVES: The current treatment dismantling study assessed which components of personalized feedback interventions were effective in motivating change in drinking. Specifically, the major objective of this project was to conduct a randomized controlled trial (RCT) comparing the impact of the normative feedback and other personalized feedback components of the CYD intervention in the general population. METHODS: Participants were recruited to take part in an RCT and received either the complete CYD final report, just the normative feedback sections of the CYD, just the personalized feedback components of the CYD, or were assigned to a no intervention control group. Participants were followed-up at 3 months to assess changes in alcohol consumption. RESULTS: A total of 741 hazardous drinking participants were recruited for the trial, of which 73 percent provided follow-up data. Analyses using an intent-to-treat approach found some evidence for the impact of the personalized feedback components of the CYD in reducing alcohol consumption on the variables, number of drinks in a week and AUDIT-C (p = .028 and .047 respectively; no impact on highest number of drinks on one occasion; p = .594). However, there was no significant evidence of the impact of the normative feedback components (all p > .3). CONCLUSIONS: Personalized feedback elements alone could provide an active intervention for hazardous drinkers, particularly in situations where normative feedback information was not available. TRIALS REGISTRATION: ClinicalTrials.gov NCT01608763. PMID- 25539598 TI - Cloning of a novel thermostable glucoamylase from thermophilic fungus Rhizomucor pusillus and high-level co-expression with alpha-amylase in Pichia pastoris. AB - BACKGROUND: Fungal amylase, mainly constitute of fungal alpha-amylase and glucoamylase, are utilized in a broad range of industries, such as starch hydrolysis, food and brewing. Although various amylases have been found in fungi, the amylases from Aspergillus dominate the commercial application. One of main problems exist with regard to these commercial use of amylases is relatively low thermal and acid stability. In order to maximize the efficiency of starch process, developing fungal amylases with increased thermostability and acid stability has been attracting researchers' interest continually. Besides, synergetic action of glucoamylase and alpha-amylase could facilitate the degradation of starch. And co-expressing glucoamylase with alpha-amylase in one host could avoid the need to ferment repeatedly and improves cost-effectiveness of the process. RESULTS: A novel fungal glucoamylase (RpGla) gene encoding a putative protein of 512 amino acid residues was cloned from Rhizomucor pusillus. BLAST analysis revealed that RpGla shared highest identity of 51% with the Rhizopus oryzae glucoamylase (ABB77799.1). The fungal glucoamylase RpGla was expressed in Pichia pastoris (KM71/9KGla) with maximum activity of 1237 U ml(-1). The optimum pH and temperature of RpGla were pH 4.0 and 70 degrees C, respectively. Fungal alpha-amylase (RpAmy) gene was also cloned from R. pusillus and transformed into KM71/9KGla, resulted in recombinant yeast KM71/9KGla ZalphaAmy harboring the RpGla and RpAmy genes simultaneously. The maximum saccharogenic activity of KM71/9KGla-ZalphaAmy was 2218 U ml(-1), which improved 79% compared to KM71/9KGla. Soluble starch hydrolyzed by purified RpGla achieved 43% glucose and 34% maltose. Higher productivity was achieved with a final yield of 48% glucose and 47% maltose catalyzed by purified enzyme preparation produced by KM71/9KGla-ZalphaAmy. CONCLUSIONS: A novel fungal glucoamylase and fungal alpha-amylase genes were cloned from Rhizomucor pusillus. The two enzymes showed good thermostability and acid stability, and similar biochemical properties facilitated synergetic action of the two enzymes. A dramatic improvement was seen in amylase activity through co-expressing RpGla with RpAmy in Pichia pastoris. This is the first report of improving activity through co-expression glucoamylase with alpha-amylase in P. pastoris. Besides, fungal glucoamylase and alpha-amylase from R. pusillus were shown as promising candidates for further application in starch hydrolysis. PMID- 25539599 TI - Association of von Willebrand factor blood levels with exercise hypertension. AB - PURPOSE: A hypertensive response to moderate intensity exercise (HRE) is associated with increased cardiovascular risk. The mechanisms of an HRE are unclear, although previous studies suggest this may be due to haemostatic and/or haemodynamic factors. We investigated the relationships between an HRE with haemostatic and hemodynamic indices. METHODS: Sixty-four participants (57 +/- 10 years, 71 % male) with indication for exercise stress testing underwent cardiovascular assessment at rest and during moderate intensity exercise, from which 20 participants developed an HRE (defined as moderate exercise systolic BP >= 170 mmHg/men and >= 160 mmHg/women). Rest, exercise and post-exercise blood samples were analysed for haemostatic markers, including von Willebrand factor (vWf), and haemodynamic measures of brachial and central blood pressure (BP), aortic stiffness and systemic vascular resistance index (SVRi). RESULTS: HRE participants had higher rest vWf compared with normotensive response to exercise (NRE) participants (1,927 mU/mL, 95 % CI 1,240-2,615, vs. 1,129 mU/mL, 95 % CI 871-1,386; p = 0.016). vWf levels significantly decreased from rest to post exercise in HRE participants (p = 0.005), whereas vWf levels significantly increased from rest to exercise in NRE participants (p = 0.030). HRE participants also had increased triglycerides, rest BP, aortic stiffness and exercise SVRi (p < 0.05 for all). Rest vWf predicted exercise brachial systolic BP (beta = 0.220, p = 0.043; adjusted R (2) = 0.451, p < 0.001) independent of age, sex, body mass index, triglycerides, rest brachial systolic BP and aortic stiffness. CONCLUSIONS: Increased rest blood levels of vWf are independently associated with moderate intensity exercise systolic BP. These findings implicate abnormalities in haemostasis as a possible factor contributing to HRE at moderate intensity. PMID- 25539600 TI - Image-guided radiation therapy using surgical clips for localization of colonic metastasis from thyroid cancer. AB - A 67-year old man with a history of papillary thyroid cancer (PTC) presented with metastatic disease to the left colon in the form of a 6.1x1.0 cm bleeding, ulcerated mass. Radiopaque surgical clips were used as fiducial markers to localize the gross tumor volume (GTV) as well as the corresponding clinical target volume (CTV) and planning target volume (PTV). Daily cone beam computed tomography (CBCT) image guidance was utilized to verify the tumor position. Inter and intrafraction movement of the tumor mass was assessed. Gastrointestinal bleeding was controlled using palliative image-guided radiation therapy (IGRT). PMID- 25539601 TI - Comparing satisfaction and burnout between caseload and standard care midwives: findings from two cross-sectional surveys conducted in Victoria, Australia. AB - BACKGROUND: Caseload midwifery reduces childbirth interventions and increases women's satisfaction with care. It is therefore important to understand the impact of caseload midwifery on midwives working in and alongside the model. While some studies have reported higher satisfaction for caseload compared with standard care midwives, others have suggested a need to explore midwives' work life balance as well as potential for stress and burnout. This study explored midwives' attitudes to their professional role, and also measured burnout in caseload midwives compared to standard care midwives at two sites in Victoria, Australia with newly introduced caseload midwifery models. METHODS: All midwives providing maternity care at the study sites were sent questionnaires at the commencement of the caseload midwifery model and two years later. Data items included the Midwifery Process Questionnaire (MPQ) to examine midwives' attitude to their professional role, the Copenhagen Burnout Inventory (CBI) to measure burnout, and questions about midwives' views of caseload work. Data were pooled for the two sites and comparisons made between caseload and standard care midwives. The MPQ and CBI data were summarised as individual and group means. RESULTS: Twenty caseload midwives (88%) and 130 standard care midwives (41%) responded at baseline and 22 caseload midwives (95%) and 133 standard care midwives (45%) at two years. Caseload and standard care midwives were initially similar across all measures except client-related burnout, which was lower for caseload midwives (12.3 vs 22.4, p = 0.02). After two years, compared to midwives in standard care, caseload midwives had higher mean scores in professional satisfaction (1.08 vs 0.76, p = 0.01), professional support (1.06 vs 0.11, p <0.01) and client interaction (1.4 vs 0.09, p <0.01) and lower scores for personal burnout (35.7 vs 47.7, p < 0.01), work-related burnout (27.3 vs 42.7, p <0.01), and client-related burnout (11.3 vs 21.4, p < 0.01). CONCLUSION: Caseload midwifery was associated with lower burnout scores and higher professional satisfaction. Further research should focus on understanding the key features of the caseload model that are related to these outcomes to help build a picture of what is required to ensure the long-term sustainability of the model. PMID- 25539602 TI - The economic burden of pulmonary arterial hypertension (PAH) in the US on payers and patients. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare condition that can ultimately lead to right heart failure and death. In this study we estimated the health care costs and resource utilization associated with PAH in a large US managed care health plan. METHODS: Subjects with claims-based evidence of PAH from 1/1/2004 to 6/30/2010 (identification period) were selected. To be included in the final PAH study sample, subjects were required to have >=2 claims with a primary PH diagnosis; >=2 claims with a PAH related-diagnosis (connective tissue diseases, congenital heart diseases, portal hypertension); and >=1 claim with evidence of a PAH-indicated medication. The earliest date of a claim with evidence of PAH-indicated medication during the identification period was set as the index date. Health care costs and resource utilization were compared between an annualized baseline period and a 12 month follow-up period. RESULTS: 504 PAH subjects were selected for the final study cohort. Estimated average total health care costs were approximately 16% lower in the follow-up period compared to the baseline period (follow-up costs = $98,243 [SD = 110,615] vs. baseline costs = $116,681 [SD = 368,094], p < 0.001), but substantively high in each period relative to costs reported for other chronic diseases. Pharmacy costs were significantly higher in the follow-up period vs. the baseline period, ($38,514 [SD = 34,817] vs. $6,440 [SD = 12,186], p < 0.001) but medical costs were significantly lower in the follow-up vs. baseline ($59,729 [SD = 106,683] vs. $110,241 [SD = 368,725], p < 0.001). These costs were mirrored in health-care resource utilization estimates. The average counts of ambulatory visits and inpatient stays were lower in the follow-up vs. the baseline (both p < 0.001). Results varied in exploratory analyses when less restrictive subject identification algorithms were used. CONCLUSIONS: Subjects with evidence of PAH had substantively high health care costs. Medical costs appeared to decrease following PAH medication use, but with a concomitant increase in pharmacy costs. PMID- 25539604 TI - Location! The unanswered question in right ventricular pacing. PMID- 25539603 TI - Longitudinal observation, evaluation and interpretation of coping with mental (emotional) health in low vision rehabilitation using the Dutch ICF Activity Inventory. AB - BACKGROUND: Since there is evidence that mental health aspects (such as depression) may inhibit an optimal rehabilitation outcome, there is growing interest in the psychosocial aspects of vision loss as part of rehabilitation. The purpose of this study is to provide more insight into the construct validity and (longitudinal) interpretation of goals related to 'Coping with mental (emotional) health aspects' which are part of the recently developed 'Dutch ICF Activity Inventory (D-AI). Moreover, the data allowed to provide some insight in the outcome in this domain in relation to rehabilitation programs followed in Dutch Multidisciplinary Rehabilitation Centers at baseline and follow-up. METHODS: In a cohort of 241 visually impaired persons, the D-AI was assessed at baseline (enrollment), 4 and 12 months, The importance and difficulty of the D-AI goals 'Handle feelings', 'Acceptance', and 'Feeling fit' and difficulty scores of underlying tasks were further analyzed, together with similar or related standardized questionnaires. At baseline, Spearman correlations were determined between D-AI goals and task and additional questionnaires to investigate the construct validity. Corrected and uncorrected linear mixed models were used to determine longitudinal rehabilitation outcomes in relation to rehabilitation programs followed. RESULTS: Baseline correlations indicated that the difficulty of tasks and the umbrella goal 'Acceptance' were not similar. Longitudinal analyses provided insight in some subtle differences in concepts measured at the goal and task level of the D-AI, as well as similar validated questionnaires. After correcting for confounding variables, none of the underlying task difficulty scales changed over time. For goal difficulty scores only 'Acceptance' was reported to be significantly less difficult at 4 and 12 months follow-up. Importance scores of goals were stable from baseline to follow-up. CONCLUSION: With respect to the constructs measured, results support the formulation of the new goal question 'Emotional life' which replaces the goals 'Handle feelings' and 'Acceptance'. Results indicate that MRCs should pay more attention to problems related to mental health. They have started to use the D-AI as it seems a promising tool to investigate and evaluate rehabilitation needs (including those related to mental health) over time and to clearly define rehabilitation goals from the very start. PMID- 25539605 TI - The heart of darkness. PMID- 25539606 TI - [XAF1 inhibits cell proliferation and induces apoptosis in human lung adenocarcinoma cell line A549 in vitro]. AB - BACKGROUND AND OBJECTIVE: XAF1 is a factor necessary to inhibit tumor cell growth. Low XAF1 expression is associated with various tumor cells. The aim of this study is to investigate the effect and the mechanism of adenovirus vector Ad5/F35 mediated X-linked inhibitor of apoptosis protein associated factor-1 (XAF1) on the inhibition of cell proliferation and the induction of apoptosis of human lung adenocarcinoma cell A549. METHODS: Recombinant virus Ad5/F35-XAF1 and controlled virus Ad5/F35-NULL exhibited different multiplicities of infection (MOI) at the same time. mRNA and protein expressions of XAF1 were determined by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. Cell proliferation was observed by methyl thiazolyl tetrazolium (MTT) assay, and cell apoptosis was analyzed by FACS with Annexin V-FITC/PI double staining. The expressions of apoptosis-associated proteins, such as PARP, Caspase-3, and Caspase-8, were also determined by Western blot. RESULTS: mRNA and protein expressions of XAF1 were significantly increased in human lung adenocarcinoma cell A549 after this cell was transfected with Ad5/F35-XAF1 for 48 h; these expressions were higher than those of the controlled group Ad5/F35-NULL. Cell proliferation was inhibited and apoptosis was induced in a dose-dependent manner in the Ad5/F35-XAF1 group. After Ad5/F35-XAF1 transfection was performed, the cleavage of apoptosis-associated proteins, such as PARP, Caspase-3, and Caspase-8, was activated. CONCLUSIONS: Restored XAF1 expression inhibits cell proliferation and induces cell apoptosis in human lung adenocarcinoma cell line A549. Furthermore, XAF1 may activate associated apoptotic signaling pathways in A549 cell line. PMID- 25539607 TI - [Effect of EGFR-TKI on lymphangiogenesis of lung cancer with EGFR mutation]. AB - BACKGROUND AND OBJECTIVE: This study aims to explore the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) on the lymphangiogenesis of lung cancer with EGFR mutation, as well as to determine the function of EGFR targeted therapy in relation to the inhibition of lymphangiogenesis during lung cancer treatment. METHODS: The EGFR double mutant lung cancer cell line NCI-H1975 is used to construct lung cancer xenograft models. The models are divided into two groups: the solvent control group and the EGFR-TKI treatment group. Each group includes five mice. The inhibitory effect of EGFR-TKI on the growth of transplanted tumors was observed. Immunohistochemical method and lymphatic endothelium specific antibody D2-40 were used in the experiment to observe the influence of EGFR-TKI on lymphangiogenesis in lung cancer. RESULTS: The weight and relative volume of tumors in the EGFR-TKI treated group were less than those in the solvent control group. The average lymphatic vessel density of EGFR-TKI-treated mice was 6.44 per case. This value was 10.70 per case in the solvent control group. Lower density of lymphangiogenesis was found in the EGFR-TKI treated group (P=0.023). The area and longest diameter of neonatal lymphatic vessel of the EGFR-TKI treated group were less than those of the solvent control group. Moreover, EGFR-TKI exhibited no significant effect on the invasion of tumor cells into the lymphatic vessel (P=0.519). CONCLUSIONS: EGFR-TKI can inhibit lymphangiogenesis in EGFR mutant lung cancer while suppressing vessel diameter and expansion area. PMID- 25539608 TI - [Fourth-line and beyond therapy in advanced non-small cell lung cancer: a retrospective analysis]. AB - BACKGROUND AND OBJECTIVE: A common consensus has been reached regarding first- and second-line therapies for advanced non-small cell lung cancer (NSCLC). The newest guideline from National Comprehensive Cancer Network (NCCN) also provides recommendations for third-line therapy. This study focused on fourth-line and enhanced treatments for advanced NSCLC. Treatment results and impact factors were analyzed and discussed. METHODS: A total of 140 patients with advanced NSCLC were selected and their data were analyzed. Response rate, survival rate, and prognostic factors were evaluated. RESULTS: Among the 140 patients, 12.9% (18 cases) showed partial response, 25.7% (36 cases) suffered from a stable disease, and 38.6% (54 cases) exhibited a disease control rate. Median overall survival (OS) and fourth-line therapy OS were 31 months and 10.1 months, respectively. The median progression free survival (PFS) of fourth-line therapy was 2.6 months. Univariate and multivariate analyses indicated different therapy regimens and suggested whether or not patients should undergo follow-up treatments. These parameters were independent prognostic factors of the OS of the fourth-line therapy; by contrast, no independent impact factor of PFS was found. Chemotherapy resulted in better median OS in fourth-line therapy than in targeted therapy (11.7 months vs 7.1 months, P=0.013). Considering the median OS of fourth-line therapy, we observed that single agent therapy did not significantly differ from double agent therapy; likewise, we found that first-time usage did not significantly differ from multiple usage of epidermal growth factor receptor tyrosine kinase inhibitor. CONCLUSIONS: Fourth-line therapy is recommended to increase the survival of advanced NSCLC patients. Nevertheless, the role of fourth-line therapy in advanced NSCLC should be further assessed in clinical trials. PMID- 25539609 TI - [Clinical study of intra-operative computed tomography guided localization with a hook-wire system for small ground glass opacities in minimally invasive resection]. AB - BACKGROUND AND OBJECTIVE: Localization of pulmonary ground glass small nodule is the technical difficulty of minimally invasive operation resection. The aim of this study is to evaluate the value of intraoperative computed tomography (CT) guided localization using a hook-wire system for small ground glass opacity (GGO) in minimally invasive resection, as well as to discuss the necessity and feasibility of surgical resection of small GGOs (<10 mm) through a minimally invasive approach. METHODS: The records of 32 patients with 41 small GGOs who underwent intraoperative CT-guided double-thorn hook wire localization prior to video-assisted thoracoscopic wedge resection from October 2009 to October 2013 were retrospectively reviewed. All patients received video-assisted thoracoscopic surgery (VATS) within 10 min after wire localization. The efficacy of intraoperative localization was evaluated in terms of procedure time, VATS success rate, and associated complications of localization. RESULTS: A total of 32 patients (15 males and 17 females) underwent 41 VATS resections, with 2 simultaneous nodule resections performed in 3 patients, 3 lesion resections in 1 patient, and 5 lesions in a patient. Nodule diameters ranged from 2 mm-10 mm (mean: 5 mm). The distance of lung lesions from the nearest pleural surfaces ranged within 5 mm-24 mm (mean: 12.5 mm). All resections of lesions guided by the inserted hook wires were successfully performed by VATS (100% success rate). The mean procedure time for the CT-guided hook wire localization was 8.4 min (range: 4 min-18 min). The mean procedure time for VATS was 32 min (range: 14 min-98 min). The median hospital time was 8 d (range: 5 d-14 d). Results of pathological examination revealed 28 primary lung cancers, 9 atypical adenomatous hyperplasia, and 4 nonspecific chronic inflammations. No major complication related to the intraoperative hook wire localization and VATS was noted. CONCLUSIONS: Intraoperative CT-guided hook wire localization is useful, particularly in small GGO localization in VATS wedge resection and has a significantly low rate of minor complications. Lung GGOs carry a 90% risk of malignancy. Aggressive surgical resection of these GGOs is necessary and feasible through the guidance of intraoperative CT localization technique. PMID- 25539610 TI - [Current status of targeted therapy for anaplastic lymphoma kinase in non-small cell lung cancer]. AB - The rate of the anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) tissues is 3%-5%. The first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. A randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients demonstrated durable responses and well tolerance in the majority of ALK-positive NSCLC patients treated with crizotinib. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802), and AP26113, and new agents shock protein 90 inhibitors. This review aims to present the current knowledge on this fusion gene, the treatment advances, and novel drug clinical trials in ALK rearranged NSCLC. PMID- 25539611 TI - [Status and advances of RGD molecular imaging in lung cancer]. AB - Lung cancer has been one of the most common and the highest mortality rates malignant tumors at home and abroad. Sustained angiogenesis was not only the characteristic of malignant tumors, but also the foundation of tumor proliferation, invasion, recurrence and metastasis, it was also one of the hot spots of treatments in lung cancer biology currently. Integrins played an important part in tumor angiogenesis. Arg-Gly-Asp (RGD) peptides could combine with integrins specifically, and the application of radionuclide-labeled RGD molecular probes enabled imaging of tumor blood vessels to reflect its changes. The lung cancer imaging of RGD peptides at home and abroad in recent years was reviewed in this article. PMID- 25539612 TI - [Advance in microRNAs and EGFR-TKIs secondary resistance research in non-small cell lung cancer]. AB - In recent years, in non-small cell lung cancer (NSCLC) targeted therapy, especially in patients with epidermal growth factor receptor (EGFR) mutations, EGFR-tyrosine kinase inhibitors (TKI) more and more come into the clinical treatment, but EGFR-TKI resistance not only influence the drug sensitivity, appear even disease progression, become the main bottleneck of its curative effect. MicroRNAs (miRNAs) is a non coding RNA and protein involved in regulating gene expression in the transcription level. Recent studies found that miRNAs involved in EGFR-TKIs resistance, which affect the sensitivity of tumor cells to treatment. In this paper, we reviewed briefly advance in miRNAs and EGFR-TKIs secondary resistance research in NSCLC. PMID- 25539613 TI - [Research progress of nutrition support for patients with lung cancer during chemotherapy]. AB - Primary lung cancer is one of the most common malignancies. Nowadays, both its morbidity and mortality rank first, patients with lung cancer are often goes with some affiliating symptoms such as malnutrition and weight loss. The side effects of cytotoxicity during chemotherapy may lead to further deteriorate of the nutritional status and worsen the anti-tumor therapy's efficacy and the patients' quality of life. With the development of palliative treatment and the higher request of patients for quality of life, nutritional support will be an important adjunctive treatment to maintain a good nutritional status and enhance the patients' immunity during chemotherapy. It will play an active role in improving tolerability of chemotherapy and prognosis for patients with lung cancer. Here is a review about research progress of nutrition support treatment during chemotherapy for the patients with lung cancer. PMID- 25539614 TI - [Advances of lentiviral vectors]. AB - Lentiviral vectors are currently very effective tools in molecular and cell experiment. Lentiviral vector, a kind of retroviral vectors, has a number of unique advantages in target gene transferation, for example, the ability of transfection to the dividing or nondividing cells, its high efficiency of transfection and a capacity of large target gene fragments. This paper describes the sources of lentiviral vectors, molecular characteristics, research progress, etc. PMID- 25539615 TI - [Advances in treatment of brain metastases from primary non-small cell lung cancer]. AB - Metastatic tumors involving the brain are an important complication in the overall management of non-small cell lung cancers. Surgery and radiation remain the cornerstones of the therapy, however, the burgeoning knowledge of tumor biology has facilitated the entry of systemically administered therapies into the clinic. This review mainly summarizes the current applications of these data to surgery, radiation therapy, chemotherapy and targeted therapy. PMID- 25539616 TI - [Status of perioperative airway management in patients with chronic obstructive pulmonary disease and lung cancer]. AB - The close association between chronic obstructive pulmonary disease (COPD) and lung cancer has long been known. New evidence suggests that there is an inverse relationship between the severity of pulmonary function and the risk of surgery in patients with lung cancer, COPD may play a key role in the incidence of postoperative pulmonary complications (PPC) and improving pulmonary function with perioperation airway management has been suggested as a possible preventive PPC. This review describes the current understanding and clinical application of perioperation airway management in lung cancer patients with COPD. We summarized that: (1) The necessity of perioperation airway management; (2) The status and characteristic of inhaled drug in perioperation airway management; (3) The clinical value in improving pulmonary function of perioperation airway management; (4) The optimum population of peri-operation airway management; (5) The problem of perioperation airway management. PMID- 25539617 TI - A clinicopathological study of renal biopsies from 288 elderly patients: analysis based on 4,185 cases. AB - PURPOSE: To investigate the clinical characteristics and histopathological features of kidney disease in elderly patients. METHODS: We retrospectively analyzed the results of 4,185 consecutive renal biopsies, and 288 patients aged >60 years at the Second Hospital of Jilin University from January 1998 to December 2013 were finally included. All patients had been clinically and histologically diagnosed with kidney disease. RESULTS: Nephrotic syndrome was the main clinical indication for biopsy. Twenty-four patients (8.33 %) experienced a minor complication related to their biopsy procedure. Among patients diagnosed as primary glomerulonephritis (GN), membranous nephropathy (MN) was the most frequent subclassification (24.7 %), followed by mesangioproliferative glomerulonephritis (MsPGN, 11.1 %) and IgA nephropathy (IgAN, 8.0 %). Amyloidosis (8.7 %) was the most common secondary GN, followed by antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune GN (5.2 %) and diabetic nephropathy (DN, 3.8 %). Based on renal biopsies results, 143/288 patients received immunosuppressive therapy and showed an overall remission rate (complete plus partial remissions) of 74.1 %. Among 71 MN patients, 29 patients received steroids plus cyclophosphamide and showed a remission rate of 79.3 %, while 42 patients received steroids and tacrolimus and showed a remission rate of 90.5 %. Among 25 patients with amyloidosis, 22 cases received melphalan plus dexamethasone and showed a remission rate of 40.9 %, while three patients received vincristine, adriamycin, and dexamethasone and showed a remission rate of 66.7 %. CONCLUSION: Making an accurate pathologic diagnosis by renal biopsy is crucial for selecting the proper treatment for elderly patients with kidney disease. PMID- 25539618 TI - Glucose challenge test (50-g GCT) in detection of glucose metabolism disorders in peritoneal dialysis patients: preliminary study. AB - BACKGROUND: The aim was to evaluate the clinical utility of the oral glucose tolerance screening test (50-g GCT--glucose challenge test) for the detection of glucose metabolism disorders (GMD) in peritoneal dialysis (PD) patients with normal fasting glucose levels. METHODS: The 50-g GCT was performed in 20 prevalent patients without history of diabetes before PD treatment onset, who had been on dialysis for a median time of 15.34 months. In addition, other indicators of glucose metabolism were measured: C-peptide, fasting insulin serum concentration, and the glycated hemoglobin level (HbA1c). The patients were prospectively followed for a median time of 25.8 months. RESULTS: 50-g GCT revealed GMD in 15 studied patients (75%)--impaired glucose tolerance in 11 patients (55%) and diabetes mellitus in four patients (20%). HbA1c and insulin resistance, estimated by homeostasis model assessment, were elevated in two (10%) and seven (35%) patients, respectively. In patients with GMD, dietetic and pharmacologic interventions were performed. When the 50-g GCT was repeated at the end of the observation period, 12 (60%) patients reported GMD, with no case of diabetes. CONCLUSION: 50-g GCT appears to be a simple and practical tool for the detection of GMD in PD patients with normal fasting glucose. Timely therapeutic intervention can effectively inhibit the progression of glucose intolerance during PD treatment. PMID- 25539619 TI - Mechanism underlying an elevated serum bile acid level in chronic renal failure patients. AB - INTRODUCTION: Bile acids play an important role in the digestion of dietary lipids. Bile acid metabolism is regulated by the digestive system. The kidney is an important organ of the urinary system and is believed to play a minor role in bile acid excretion; however, many recent studies have reported an increased serum bile acid level and alterations in bile acid homeostasis in both clinical and animal model studies on chronic renal failure. The existing research findings on the mechanisms underlying this phenomenon were mostly derived from animal model studies, but clinical investigations have been limited. MATERIALS AND METHODS: Kidney tissues and serum and urine samples from CRF patients and normal controls were studied. RESULTS: We found increased serum bile acid levels and decreased urine bile acid output levels in chronic renal failure patients. Mesangial cell and endothelial cell proliferation, glomerular sclerosis, renal interstitial fibrosis, and intrarenal vascular sclerosis were observed based on hematoxylin-eosin and Masson trichrome staining pathology analysis. Scatter diagram and Pearson correlation analysis showed that in chronic renal failure patients, the estimated glomerular filtration rate and serum bile acid level were interrelated. Reverse transcription polymerase chain reaction and Western blotting results indicated that reabsorption and secretion of bile acid at the apical surface of the proximal renal tubular did not contribute to the elevated serum BA level. CONCLUSION: The increase in plasma bile acid is due to decreased bile acid filtration through the kidneys in CRF patients. PMID- 25539620 TI - Altered snowfall and soil disturbance influence the early life stage transitions and recruitment of a native and invasive grass in a cold desert. AB - Climate change effects on plants are expected to be primarily mediated through early life stage transitions. Snowfall variability, in particular, may have profound impacts on seedling recruitment, structuring plant populations and communities, especially in mid-latitude systems. These water-limited and frequently invaded environments experience tremendous variation in snowfall, and species in these systems must contend with harsh winter conditions and frequent disturbance. In this study, we examined the mechanisms driving the effects of snowpack depth and soil disturbance on the germination, emergence, and establishment of the native Pseudoroegnaria spicata and the invasive Bromus tectorum, two grass species that are widely distributed across the cold deserts of North America. The absence of snow in winter exposed seeds to an increased frequency and intensity of freeze-thaw cycles and greater fungal pathogen infection. A shallower snowpack promoted the formation of a frozen surface crust, reducing the emergence of both species (more so for P. spicata). Conversely, a deeper snowpack recharged the soil and improved seedling establishment of both species by creating higher and more stable levels of soil moisture availability following spring thaw. Across several snow treatments, experimental disturbance served to decrease the cumulative survival of both species. Furthermore, we observed that, regardless of snowpack treatment, most seed mortality (70-80%) occurred between seed germination and seedling emergence (November-March), suggesting that other wintertime factors or just winter conditions in general limited survival. Our results suggest that snowpack variation and legacy effects of the snowpack influence emergence and establishment but might not facilitate invasion of cold deserts. PMID- 25539621 TI - How is acceptance of the brain disease model of addiction related to Australians' attitudes towards addicted individuals and treatments for addiction? AB - BACKGROUND: We investigated whether beliefs about addiction being a 'disease' or 'brain disease', and holding certain beliefs about addiction aetiology, are associated with public views about addicted persons and support for different types of treatment, coerced treatment and punishment for addiction. METHODS: Data were collected as part of the 2012 Queensland Social Survey, a computer assisted telephone interview of 1263 residents of Queensland, Australia. Participants were presented with scenarios of two addicted males, one who was addicted to heroin and the other addicted to alcohol. Participants were then asked a series of questions for both characters. RESULTS: There was widespread support for all treatment modalities (alcohol: 80.8-98.0%, heroin: 89.9-97.2%). There was less support for coerced treatment for alcohol than heroin addiction (alcohol: 41%, heroin: 71%, chi(2) = 273.90, p < 0.001). Being 35 years of age or older (alcohol: OR = 0.58 (0.37-0.91), heroin: OR = 0.49 (0.28-0.85)) and having 15 or more years of education (alcohol: OR = 0.60 (0.44-0.81), heroin: 0.55 (0.40 0.75)) predicted less support for coerced treatment. 31.7% of respondents agreed heroin use should be punished by imprisonment and being 35 years of age or older (OR = 0.51 (0.33-0.80)) predicted lack of support. The sample agreed that an alcohol or heroin dependent person would suffer career damage (alcohol: 96.2%, heroin: 98.9%), marriage breakdown (alcohol: 92.2%, heroin: 97.3%) and get in trouble with the law (alcohol: 92.3%, heroin: 98.9%). Respondents expressed more comfort with encountering alcohol rather than heroin addicted persons in the workplace or at a dinner party. Beliefs that addiction was a 'brain disease' or a 'disease' did not predict any of these attitudes. Beliefs about addiction aetiology were inconsistent predictors of outcomes measured. CONCLUSIONS: Age and educational attainment were the most consistent predictors of stigmatising beliefs and beliefs about coercion and punishment. Beliefs that addiction is a 'disease' or a 'brain disease' were not associated with an overall reduction in beliefs about stigma, coercion or punishment. Beliefs in different causes of addiction were not consistent predictors of beliefs about stigma, coercion or punishment. PMID- 25539622 TI - Admission glucose and left ventricular systolic function in non-diabetic patients with acute myocardial infarction. AB - Carbohydrate metabolism disorder in patients hospitalized due to acute ST-segment elevation myocardial infarction (STEMI) is associated with poor outcome. The association is even stronger in non-diabetic patients compared to the diabetics. Poor outcome of patients with elevated parameters of carbohydrate metabolism may be associated with negative impact of these disorders on left ventricular (LV) function. The aim of the study was to determine the impact of admission glycemia on LV systolic function in acute phase and 6 months after myocardial infarction in STEMI patients treated with primary angioplasty, without carbohydrate disorders. The study group consisted of 52 patients (9 female, 43 male) aged 35 74 years, admitted to the Department of Cardiology and Internal Medicine, Collegium Medicum in Bydgoszcz, due to the first STEMI treated with primary coronary angioplasty with stent implantation, without diabetes in anamnesis and carbohydrate metabolism disorders diagnosed during hospitalization. Echocardiography was performed in all patients in acute phase and 6 months after MI. Plasma glucose were measured at hospital admission. In the subgroup with glycemia >=7.1 mmol/l, in comparison to patients with glycemia <7.1 mmol/l, significantly lower ejection fraction (EF) was observed in acute phase of MI (44.4 +/- 5.4 vs. 47.8 +/- 6.3 %, p = 0.04) and trend to lower EF 6 months after MI [47.2 +/- 6.5 vs. 50.3 +/- 6.3 %, p = 0.08 (ns)]. Higher admission glycemia in patients with STEMI and without carbohydrate metabolism disturbances, may be a marker of poorer prognosis resulting from lower LV ejection fraction in the acute phase and in the long-term follow-up. PMID- 25539623 TI - Gender differences in sensitivity of acetylcholine and ergonovine to coronary spasm provocation test. AB - We examined the sex difference concerning the coronary artery response between ACh and ER in this study. We already reported the difference of coronary response between acetylcholine (ACh) and ergonovine (ER). We performed both ACh and ER tests of 461 patients (male 294 patients, female 167 patients, mean age 64.4 +/- 11.3 years) during 23 years. Positive coronary spasm was defined as >99 % transient luminal narrowing with usual chest pain and/or ischemic ECG changes. Firstly, ACh was administered in incremental doses of 20/50/(80) MUg into the RCA and 20/50/100/(200) MUg into the LCA over 20 s. Secondly, ER was administered in a total dose of 40 MUg into the RCA and of 64 MUg into the LCA over 2-4 min. Intracoronary injection of ACh and ER provoked spasm in 221 patients consisting of 160 male patients and 61 female patients. In female patients, the spasm provoked by ACh was almost perfect except in two patients (59 patients, 96.7 %), while ER provoked spasm in only 20 patients (32.8 %). In male patients, provoked spasm by ACh (129 patients, 80.6 %) was significantly higher than ER (97 patients, 60.6 %). As a spasm provocation test, ACh is more sensitive than ER in both sexes and especially in females. We may select two pharmacological agents by sex differences to provoke coronary artery spasm in the cardiac catheterization laboratory in the future. PMID- 25539625 TI - Areas of the visual field important during reading in patients with glaucoma. AB - PURPOSE: To determine the areas of the binocular visual field (VF) associated with reading speed in glaucomatous patients with preserved visual acuity (VA). MATERIALS AND METHODS: Fifty-four patients with glaucoma (mean age +/- standard deviation 70 +/- 8 years) and 38 visually healthy controls (mean age 66 +/- 9 years) had silent reading speeds measured using non-scrolling text on a computer setup. Participants completed three cognitive tests and tests of visual function, including the Humphrey 24-2 threshold VF test in each eye; the results were combined to produce binocular integrated VFs (IVFs). Regression analyses using the control group to correct for cognitive test scores, age and VA were conducted to obtain the IVF mean deviation (MD) and total deviation (TD) value from each IVF test location. Concordance between reading speed and TD, assessed using R (2) statistics, was ranked in order of importance to explore the parts of the IVF most likely to be linked with reading speed. RESULTS: No significant association between IVF MD value and reading speed was observed (p = 0.38). Ranking individual thresholds indicated that the inferior left section of the IVF was most likely to be associated with reading speed. CONCLUSIONS: Certain regions of the binocular VF impairment may be associated with reading performance even in patients with preserved VA. The inferior left region of patient IVFs may be important for changing lines during reading. PMID- 25539624 TI - Correlations of the changes in bioptic findings with echocardiographic, clinical and laboratory parameters in patients with inflammatory cardiomyopathy. AB - Patients with myocarditis and left ventricular (LV) dysfunction may improve after standard heart failure therapy. This improvement seems to be related to retreat of myocardial inflammation. The aim of the present study was to assess changes in clinical, echocardiographic and some laboratory parameters and to correlate them with changes in the number of inflammatory infiltrating cells in endomyocardial biopsy (EMB) samples during the 6-month follow-up, and to define predictors of LV function improvement among baseline parameters. Forty patients with biopsy-proven myocarditis and impaired LV function (LV ejection fraction-LVEF <40 %) with heart failure symptoms <= 6 months were evaluated. Myocarditis was defined as the presence of >14 mononuclear leukocytes/mm(2) and/or >7 T-lymphocytes/mm(2) in the baseline EMB. The EMB, echocardiography and clinical evaluation were repeated after 6 months of standard heart failure therapy. LVEF improved on average from 25 +/- 9 to 42 +/- 12 % (p < 0.001); LV end-systolic volume and LV end-diastolic volume (LVEDV) decreased from 158 +/- 61 to 111 +/- 58 ml and from 211 +/- 69 to 178 +/- 63 ml (both p < 0.001). NYHA class decreased from 2.6 +/- 0.5 to 1.6 +/- 0.6 (p < 0.001) and NTproBNP from 2892 +/- 3227 to 851 +/- 1835 ug/ml (p < 0.001). A decrease in the number of infiltrating leukocytes (CD45+/LCA+) from 23 +/- 15 to 13 +/- 8 cells/mm(2) and in the number of infiltrating T lymphocytes (CD3+) from 7 +/- 5 to 4 +/- 3 cells/mm(2) (both p < 0.001) was observed. The decline in the number of infiltrating CD45+ cells significantly correlated with the change in LVEF (R = -0.43; p = 0.006), LVEDV (R = 0.39; p = 0.012), NYHA classification (R = 0.35; p = 0.025), and NTproBNP (R = 0.33; p = 0.045). The decrease in the number of CD3+ cells correlated with the change of systolic and diastolic diameters of the left ventricle (R = -0.33; p = 0.038 and R = -0.45; p = 0.003) and with the change in LVEDV (R = -0.43; p = 0.006). Tricuspid annular plane systolic excursion (TAPSE) (OR 0.61; p = 0.005) and early transmitral diastolic flow velocity (E wave) (OR 0.89; p = 0.002) were identified as predictors of LVEF improvement. Improvements in clinical status, LV function and NTproBNP levels correlated with decrease in the number of infiltrating inflammatory cells. TAPSE and E wave velocity were significant predictors of improvement in multivariate regression. Our observations suggest that contemporary guidelines-based therapy of heart failure is an effective treatment option in patients with recent onset biopsy-proven inflammatory cardiomyopathy. PMID- 25539627 TI - Serum free indoxyl sulfate associated with in-stent restenosis after coronary artery stentings. AB - Uremic toxins, including P-cresyl sulfate (PCS) and indoxyl sulfate (IS), have been found to participate in the process of atherosclerosis and patient mortality. We aim to discover if uremic toxins are related to in-stent restenosis in patients with coronary artery disease after stent implantation. We enrolled 214 patients who received coronary angioplasty with stenting and follow-up angiography between November 1995 and June 2011 with a total of 293 lesions divided into bare metal stent (BMS) or drug-eluting stent (DES) groups. Patients' basic information and total and free form IS and PCS were used to correlate with the late loss (LL) and loss index (LI). Significantly higher LL and LI in the BMS group compared with the DES group (1.10 vs. 0.45 mm, p < 0.001, and 0.46 vs. 0.19, p < 0.001, respectively). The unadjusted correlation revealed a positive relationship between log-normalized free IS and LL, LI in the DES group (p = 0.001). After adjustment for multiple variables, the log-normalized free IS still presented as an independent predictor for the LL and LI (p = 0.012 and p = 0.031). Free IS is an independent predictor for coronary restenosis in patients receiving DES implantations. However, among patients undergoing BMS stentings, uremic toxin is not a predictor of the intracoronary restenosis. PMID- 25539626 TI - Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. PMID- 25539628 TI - Clozapine-Induced Cardiotoxicity: Role of Oxidative Stress, Tumour Necrosis Factor Alpha and NF-kappabeta. AB - Safety concerns have been raised about clozapine-induced cardiotoxicity particularly in young patients. The exact mechanism of clozapine cardiotoxicity has not yet been thoroughly studied. This study aimed to investigate the possible mechanisms of clozapine-induced cardiotoxicity in a rat model. Young male Wistar rats were treated with clozapine (10, 15 and 25 mg/kg/day, i.p.) for 21 days. Haemodynamic and echocardiographic studies were performed for assessment of cardiac functions. Heart sections were studied histopathologically and immunohistochemically. Serum and cardiac markers of cardiotoxicity, oxidative stress, inflammation and apoptosis were evaluated. Heart sections of clozapine treated animals showed increased cardiac inflammation that correlated with the clozapine dose. Serum levels of CK-MB and LDH levels increased, as did cardiac levels of TNF-alpha, MDA, NO, myeloperoxidase, 8-OHdG, caspase-3 and NF-kappaB p65. In contrast, GSH levels and GSH-Px activity decreased. Furthermore, immunohistochemical examination of the heart sections showed positive immunostaining for both 3-nitrotyrosine and caspase-3 in all clozapine-treated groups. Clozapine, particularly in relatively high doses, has a clear cardiotoxic effect. This cardiotoxicity is accompanied by increased myocardial oxidative stress, inflammatory cytokines, DNA damage and apoptosis with attenuation in antioxidant defences, thus explaining the previously reported myocarditis and pericarditis during clozapine therapy in clinical studies. PMID- 25539629 TI - Systematic exploration of autonomous modules in noisy microRNA-target networks for testing the generality of the ceRNA hypothesis. AB - BACKGROUND: In the competing endogenous RNA (ceRNA) hypothesis, different transcripts communicate through a competition for their common targeting microRNAs (miRNAs). Individual examples have clearly shown the functional importance of ceRNA in gene regulation and cancer biology. It remains unclear to what extent gene expression levels are regulated by ceRNA in general. One major hurdle to studying this problem is the intertwined connections in miRNA-target networks, which makes it difficult to isolate the effects of individual miRNAs. RESULTS: Here we propose computational methods for decomposing a complex miRNA target network into largely autonomous modules called microRNA-target biclusters (MTBs). Each MTB contains a relatively small number of densely connected miRNAs and mRNAs with few connections to other miRNAs and mRNAs. Each MTB can thus be individually analyzed with minimal crosstalk with other MTBs. Our approach differs from previous methods for finding modules in miRNA-target networks by not making any pre-assumptions about expression patterns, thereby providing objective information for testing the ceRNA hypothesis. We show that the expression levels of miRNAs and mRNAs in an MTB are significantly more anti-correlated than random miRNA-mRNA pairs and other validated and predicted miRNA-target pairs, demonstrating the biological relevance of MTBs. We further show that there is widespread correlation of expression between mRNAs in same MTBs under a wide variety of parameter settings, and the correlation remains even when co regulatory effects are controlled for, which suggests potential widespread expression buffering between these mRNAs, which is consistent with the ceRNA hypothesis. Lastly, we also propose a potential use of MTBs in functional annotation of miRNAs. CONCLUSIONS: MTBs can be used to help identify autonomous miRNA-target modules for testing the generality of the ceRNA hypothesis experimentally. The identified modules can also be used to test other properties of miRNA-target networks in general. PMID- 25539630 TI - A qualitative study of the anticipated barriers and facilitators to the implementation of a lifestyle intervention in the Dutch construction industry. AB - BACKGROUND: Lifestyle interventions have proven effective for lowering a cardiovascular risk profile by improving lifestyle behaviors, blood glucose and blood cholesterol levels. However, implementation of lifestyle interventions is often met with barriers. This qualitative study sought to determine anticipated barriers and facilitators to the nationwide implementation of an effective lifestyle intervention in the construction industry in the Netherlands. METHODS: Prior to implementation, focus groups were held with 8 lifestyle counselors and semi-structured interviews with 20 employees of the construction industry, 4 occupational physicians, 4 medical assistants, and 1 manager of an occupational health service. The transcripts were coded by two coders and analyzed by constant comparison. RESULTS: Hypothetical employee willingness to sign up for the intervention was facilitated by a high level of perceived risk, perceived added value of the intervention, and perceived social support. It was hampered by a preference for independence and perceived interference with their work. All professionals named a lack of time as an anticipated barrier to implementation. Lifestyle counselors suggested several strategies to improve the proficiency of their counseling technique, such as training in small groups and a continuous stream of employee referrals. Occupational physicians thought they would be hampered in screening employees and referring them to a lifestyle counselor by the perception that addressing employee lifestyles was not their task, and by a counter-productive relationship with other stakeholders. The manager addressed financial incentives and a good intervention fit with the current approach of the OHS. CONCLUSION: The findings suggest that employees can be motivated to sign up for a lifestyle intervention by tailoring the implementation strategy to various subgroups within the target group. Occupational physicians can be motivated to refer employees for the intervention by making a referral personally and professionally rewarding. PMID- 25539632 TI - Crucial resources to strengthen the desire to live: Experiences of suicidal patients. AB - BACKGROUND: Suicidality is a life-and-death struggle in deep loneliness and psychological pain. There is a lack of knowledge about what could help the suicidal patients' struggle for continued life. The aim of this study was to develop a deeper understanding of suicidal patients in the aftermath of suicidal attempts. The research question was 'What resources in the person himself or herself and his or her surroundings are crucial in a suicidal crisis to maintaining the will to live and hope for life'? METHODOLOGY: The study has a hermeneutic approach and an explorative design. Data were collected using semi structured interviews with 10 participants: men and women 21-52 years of age. The context was two emergency psychiatric units and one crisis resolution team. ETHICAL CONSIDERATIONS: The participants signed an informed consent before the interviews were conducted. FINDINGS: This article presents three themes: (a) becoming aware of the desire to live, (b) an experience of connectedness and (c) someone who cares. DISCUSSION: The suicidal person's awareness of wishes, dreams, hopes and will, but also of their feelings in the aftermath of the suicide attempt, seemed to play a crucial role in a suicidal crisis. Experiences of connectedness remind the person of the responsibility in his or her own life and in the lives of others and seemed to strengthen the urge to go on. Private and professional relationships seem to be crucial in stimulating the desire and hope to go on living. CONCLUSION: Becoming aware of the desire to live, being connected to others and experiencing someone who cares is necessary for life. Both private and professional networks seemed to be important resources that could remind the suicidal person of his or her own dignity as part of being human. PMID- 25539631 TI - Genomic prediction of genetic merit using LD-based haplotypes in the Nordic Holstein population. AB - BACKGROUND: A haplotype approach to genomic prediction using high density data in dairy cattle as an alternative to single-marker methods is presented. With the assumption that haplotypes are in stronger linkage disequilibrium (LD) with quantitative trait loci (QTL) than single markers, this study focuses on the use of haplotype blocks (haploblocks) as explanatory variables for genomic prediction. Haploblocks were built based on the LD between markers, which allowed variable reduction. The haploblocks were then used to predict three economically important traits (milk protein, fertility and mastitis) in the Nordic Holstein population. RESULTS: The haploblock approach improved prediction accuracy compared with the commonly used individual single nucleotide polymorphism (SNP) approach. Furthermore, using an average LD threshold to define the haploblocks (LD>=0.45 between any two markers) increased the prediction accuracies for all three traits, although the improvement was most significant for milk protein (up to 3.1% improvement in prediction accuracy, compared with the individual SNP approach). Hotelling's t-tests were performed, confirming the improvement in prediction accuracy for milk protein. Because the phenotypic values were in the form of de-regressed proofs, the improved accuracy for milk protein may be due to higher reliability of the data for this trait compared with the reliability of the mastitis and fertility data. Comparisons between best linear unbiased prediction (BLUP) and Bayesian mixture models also indicated that the Bayesian model produced the most accurate predictions in every scenario for the milk protein trait, and in some scenarios for fertility. CONCLUSIONS: The haploblock approach to genomic prediction is a promising method for genomic selection in animal breeding. Building haploblocks based on LD reduced the number of variables without the loss of information. This method may play an important role in the future genomic prediction involving while genome sequences. PMID- 25539633 TI - Narrativizing Nursing Students' Experiences With Medical Errors During Clinicals. AB - The ways providers story their mistake experiences help to explain how providers understand medical errors and how they communicate about those errors. Communication scholars have slowly begun to explore the communicative nature of medical error experiences, with communication research becoming more abundant over the past few years. Missing from this discussion is how students in health professions, in this case nursing students, tell medical errors narratives and how the stories help them determine how to respond to mistakes. In this article, we explore how nursing students narrativize their medical errors experiences during clinicals. Qualitative interviews were conducted with 68 nursing students. The interviews were transcribed and resulted in a total of 1,261 single-spaced pages of data. We found that nursing students told three different narratives: (a) the "save the day" narrative, (b) the "silence" narrative, and (c) the "not always right" narrative. Finally, we discuss the implications of these narratives and their impact on nursing education. PMID- 25539634 TI - Approval of antiobesity drug is "major regression for patients' safety," says health watchdog. PMID- 25539636 TI - An improved inverse PCR protocol for the generation of T-vectors. PMID- 25539635 TI - Bias analyses of preclinical and clinical D2 dopamine ligands: studies with immediate and complex signaling pathways. AB - G protein-coupled receptors (GPCRs) often activate multiple signaling pathways, and ligands may evoke functional responses through individual pathways. These unique responses provide opportunities for biased or functionally selective ligands to preferentially modulate one signaling pathway over another. Studies with several GPCRs have suggested that selective activation of signaling pathways downstream of a GPCR may lead to safer and more effective drug therapies. The dopamine D2 receptor (D2R) is one of the main drug targets in the therapies for Parkinson's disease and schizophrenia. Recent studies suggest that selective modulation of individual signaling pathways downstream of the D2R may lead to safer antipsychotic drugs. In the present study, immediate effectors of the D2R (i.e., Galphai/o, Gbetagamma, beta-arrestin recruitment) and more complex signaling pathways (i.e., extracellular signal-regulated kinase phosphorylation, heterologous sensitization, and dynamic mass redistribution) were examined in response to a series of D2R ligands. This was accomplished using Chinese hamster ovary cells stably expressing the human D2L dopamine receptor in the PathHunter beta-Arrestin GPCR Assay Platform. The use of a uniform cellular background was designed to eliminate potential confounds associated with cell-to-cell variability, including expression levels of receptor as well as other components of signal transduction, including G protein subunits. Several well characterized and clinically relevant D2R ligands were evaluated across each signaling pathway in this cellular model. The most commonly used methods to measure ligand bias were compared. Functional selectivity analyses were also used as tools to explore the relative contribution of immediate D2R effectors for the activation of more complex signaling pathways. PMID- 25539637 TI - Characteristics associated with willingness to participate in a randomized controlled behavioral clinical trial using home-based personal computers and a webcam. AB - BACKGROUND: Trials aimed at preventing cognitive decline through cognitive stimulation among those with normal cognition or mild cognitive impairment are of significant importance in delaying the onset of dementia and reducing dementia prevalence. One challenge in these prevention trials is sample recruitment bias. Those willing to volunteer for these trials could be socially active, in relatively good health, and have high educational levels and cognitive function. These participants' characteristics could reduce the generalizability of study results and, more importantly, mask trial effects. We developed a randomized controlled trial to examine whether conversation-based cognitive stimulation delivered through personal computers, a webcam and the internet would have a positive effect on cognitive function among older adults with normal cognition or mild cognitive impairment. To examine the selectivity of samples, we conducted a mass mail-in survey distribution among community-dwelling older adults, assessing factors associated with a willingness to participate in the trial. METHODS: Two thousand mail-in surveys were distributed to retirement communities in order to collect data on demographics, the nature and frequency of social activities, personal computer use and additional health-related variables, and interest in the prevention study. We also asked for their contact information if they were interested in being contacted as potential participants in the trial. RESULTS: Of 1,102 surveys returned (55.1% response rate), 983 surveys had complete data for all the variables of interest. Among them, 309 showed interest in the study and provided their contact information (operationally defined as the committed with interest group), 74 provided contact information without interest in the study (committed without interest group), 66 showed interest, but provided no contact information (interest only group), and 534 showed no interest and provided no contact information (no interest group). Compared with the no interest group, the committed with interest group were more likely to be personal computer users (odds ratio (OR) = 2.78), physically active (OR = 1.03) and had higher levels of loneliness (OR = 1.16). CONCLUSION: Increasing potential participants' familiarity with a personal computer and the internet before trial recruitment could increase participation rates and improve the generalizability of future studies of this type. TRIAL REGISTRATION: The trial was registered on 29 March 2012 at ClinicalTirals.gov (ID number NCT01571427). PMID- 25539638 TI - Respiratory tract isolation of Mycobacterium europaeum following influenza infection in an immunocompromised patient: a case report. AB - INTRODUCTION: Mycobacterium europaeum, a slow-growing nontuberculous mycobacteria belonging to the Mycobacterium simiae complex, was described after the seminal characterization of five isolates collected from three sputum specimens and a jaw gland biopsy in Italy, Greece and Sweden. Five respiratory tract isolates were further reported in Iran. Here, we report the first isolation of M. europaeum in France, in the respiratory tract of a patient co-infected with human immunodeficiency virus and hepatitis C virus. CASE PRESENTATION: A 49-year-old Caucasian woman with a 26-year history of human immunodeficiency virus-hepatitis C virus co-infection was admitted for significant influenza-like syndrome in a context of repetitive exacerbations of chronic obstructive pulmonary disease. Significant biological parameters included lymphocytes of 1.6G/L including 237/mm3 T4 lymphocytes, a human immunodeficiency virus viral load of 1.6 log and a hepatitis C virus viral load of 6 log. Reverse-transcriptase polymerase chain reaction of her nasopharyngeal aspiration confirmed influenza A H1N1. Three sputum specimens lacked acid-fast bacilli but one grew mycobacteria identified by using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry as M. europaeum with a 1.56 log score. A 1,482-bp 16S ribosomal ribonucleic acid gene sequence yielded 99% similarity with both Mycobacterium parascrofulaceum ATCC BAA-614 and M. europaeum DSM 45397T and partial rpoB polymerase chain reaction-sequencing yielded a 725-bp sequence exhibiting 100% similarity with M. europaeum strain DSM 45397T. CONCLUSIONS: We report the first isolation of M. europaeum in France, in the respiratory tract of a patient co infected with human immunodeficiency virus and hepatitis C virus. M. europaeum warrants further attention in immunosuppressed patients with influenza, using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry and rpoB partial sequencing as tools for its accurate identification. PMID- 25539639 TI - Community knowledge and practices regarding malaria and long-lasting insecticidal nets during malaria elimination programme in an endemic area in Iran. AB - BACKGROUND: Since malaria is one of the foremost public health problems in Iran, a malaria elimination phase has been initiated and application of long-lasting insecticidal nets (LLINs) is an important strategy for control. Success and effectiveness of this community based strategy largely dependent on proper use of LLINs. In this context, to determine the community's knowledge and practices about malaria and LLINs, a study was conducted in Rudan County, one of the important malaria endemic areas in southeast of Iran. METHODS: In this cross sectional study, 400 households in four villages were selected by cluster randomly sampling method. Community knowledge and practices about malaria and LLINs including symptoms and transmission of malaria and washing, drying and using of bed nets were investigated using pre-tested structured questionnaires. The data were analysed using SPSS.16 software. RESULTS: In this study nearly 89% of the respondents knew at least one symptom of malaria and 86.8% considered malaria as an important disease. The majority of respondents (77.8%) believed that malaria transmits through mosquito bite and 72.5% mentioned stagnated water as a potential mosquito breeding place. About 46% of respondents mentioned the community health worker as the main source of their information about malaria. Approximately 44.8% of studied population washed the LLINs once in six months and 92% of them mentioned that they dry the bed nets in direct sunlight. While 94% of households reported they received one or more LLINs by government and 60.8% of respondents mentioned that LLINs were the main protective measure against malaria, only 18.5% of households slept under bed nets the night before the survey, this use rate is lower than the targeted coverage (80%) which is recommended by World Health Organization. CONCLUSION: Although, majority of studied population were aware of the symptoms and cause of malaria, a majority had misconceptions about LLINs. Therefore, appropriate educational intervention by trained health workers should be developed for a behaviour change and motivating people to use LLINs which would improve malaria elimination programme. PMID- 25539641 TI - NOS2 and CCL27: clinical implications for psoriasis and eczema diagnosis and management. AB - Chronic inflammatory skin diseases such as psoriasis and eczema are a major medical challenge. Development of highly specific therapies for both conditions is opposed by the lack of translation of basic knowledge into biomarkers for clinical use. Furthermore, to distinguish psoriasis from eczema might be difficult occasionally, but specific and costly therapies would not be efficient in misdiagnosed patients. In the era of high-throughput 'omics'-technologies, comparing the molecular signature of psoriasis and eczema is a promising approach to gain insight into their complex pathogeneses and develop new diagnostic and therapeutic strategies. Investigating patients affected by both psoriasis and eczema simultaneously, we recently constructed a disease classifier consisting of only two genes (NOS2 and CCL27) that reliably predicts the correct diagnosis even in clinically unclear cases. When such easy-to-handle approaches are combined with individual therapeutic response, we might reach the ultimate goal of personalized medicine in inflammatory skin diseases in near future. PMID- 25539640 TI - Noise alters guinea pig's blood-labyrinth barrier ultrastructure and permeability along with a decrease of cochlear Claudin-5 and Occludin. AB - BACKGROUND: Noise exposure (NE) is a severe modern health hazard that induces hearing impairment. However, the noise-induced ultrastructural changes of blood labyrinth barrier (BLB) and the potential involvements of tight junction proteins (TJP) remain inconclusive. We investigated the effects of NE on not only the ultrastructure of cochlea and permeability of BLB but also the expression of TJP within the guinea pig cochlea. RESULTS: Male albino guinea pigs were exposed to white noise for 4 h or 2 consecutive days (115 dB sound pressure level, 6 hours per day) and the hearing impairments and light microscopic change of BLB were evaluated with auditory brainstem responses (ABR) and the cochlear sensory epithelia surface preparation, respectively. The cochlear ultrastructure and BLB permeability after NE 2d were revealed with transmission electron microscope (TEM) and lanthanum nitrate-tracing techniques, respectively. The potential alterations of TJPs Claudin-5 and Occludin were quantified with immunohistochemistry and western blot. NE induced significant hearing impairment and NE 2d contributed to significant outer hair cell (OHC) loss that is most severe in the first row of outer hair cells. Furthermore, the loosen TJ and an obvious leakage of lanthanum nitrate particles beneath the basal lamina were revealed with TEM. Moreover, a dose-dependent decrease of Claudin-5 and Occludin was observed in the cochlea after NE. CONCLUSIONS: All these findings suggest that both decrease of Claudin-5 and Occludin and increased BLB permeability are involved in the pathologic process of noise-induced hearing impairment; however, the causal relationship and underlying mechanisms should be further investigated. PMID- 25539642 TI - Characterization of hypersensitivity reactions reported among Andrographis paniculata users in Thailand using Health Product Vigilance Center (HPVC) database. AB - BACKGROUND: Andrographis paniculata (andrographis) is one of the herbal products that are widely used for various indications. Hypersensitivity reactions have been reported among subjects receiving Andrographis paniculata in Thailand. Understanding of characteristics of patients, adverse events, and clinical outcomes is essential for ensuring population safety.This study aimed to describe the characteristics of hypersensitivity reactions reported in patients receiving andrographis containing products in Thailand using national pharmacovigilance database. METHODS: Thai Vigibase data from February 2001 to December 2012 involving andrographis products were used. This database includes the reports submitted through the spontaneous reporting system and intensive monitoring programmes. The database contained patient characteristic, adverse events associated with andrographis products, and details on seriousness, causality, and clinical outcomes. Case reports were included for final analysis if they met the inclusion criteria; 1) reports with andrographis being the only suspected cause, 2) reports with terms consistent with the constellation of hypersensitivity reactions, and 3) reports with terms considered critical terms according to WHO criteria. Descriptive statistics were used. RESULTS: A total of 248 case reports of andrographis-associated adverse events were identified. Only 106 case reports specified andrographis herbal product as the only suspected drug and reported at least one term consistent with constellation of hypersensitivity reactions. Most case reports (89%) came from spontaneous reporting system with no previously documented history of drug allergy (88%). Of these, 18 case reports were classified as serious with 16 cases requiring hospitalization. For final assessment, the case reports with terms consistent with constellation of hypersensitivity reactions and critical terms were included. Thirteen case reports met such criteria including anaphylactic shock (n = 5), anaphylactic reaction (n = 4) and angioedema (n = 4). Time to development of symptoms ranged from 5 minutes to 1 day. The doses of andrographis used varied from 352 mg to 1,750 mg. Causality assessment of 13 case reports were certain (n = 3), probable (n = 8) and possible (n = 2). CONCLUSIONS: Our findings suggested that hypersensitivity reactions have been reported among patients receiving Andrographis paniculata. Healthcare professionals should be aware of this potential risk. Further investigation of the causal relationship is needed; meanwhile including hypersensitivity reactions for andrographis product labeling should be considered. PMID- 25539643 TI - If not dieting, how to lose weight? Tips and tricks for a better global and cardiovascular health. AB - Weight loss is a popular topic and may be of serious concern for many patients. Even with the abundant literature on obesity and cardiometabolic risk, it is always challenging to demystify and reinforce the determinants of safe approaches to lose weight. Measures of central obesity are essential to characterize the patient's adiposity distribution and should be part of the routine medical examination. Beyond this, screening for fasting lipids and glucose are important for the assessment of the cardiometabolic risk which may lead to increased cardiovascular morbidity and mortality. Differences in adiposity as well as in weight loss exist between sexes and should be taken into consideration. Rather than avoiding some food or following certain type of diet, any planned weight loss interventions should promote lifestyle and environmental modifications with healthy eating and appropriate physical activity. With clear objectives, this appears to be the best way in order to achieve weight loss goals permanently. PMID- 25539644 TI - Deregulation of microRNAs Let-7a and miR-21 mediate aberrant STAT3 signaling during human papillomavirus-induced cervical carcinogenesis: role of E6 oncoprotein. AB - BACKGROUND: Aberrantly expressed and constitutively active STAT3 signaling plays a pivotal role in initiation and progression of human papillomavirus-induced cervical carcinogenesis. However, the underlying mechanism(s) responsible for pleiotropic effects of STAT3 signaling is poorly understood. In view of emerging regulatory role of microRNAs, Let-7a and miR-21 that may interact with STAT3 signaling and/or its downstream effectors, present study was designed in HPV16 positive cervical cancer cells to assess the functional contribution of these miRs in STAT3 signaling in cervical cancer. METHODS: Functional silencing of STAT3 signaling and HPV16 oncoprotein expression in SiHa cells was done by STAT3 specific and 16 E6 siRNAs. Pharmacological intervention of STAT3 was done using specific inhibitors like curcumin and stattic. Loss-of-function study of miR-21 using miR-21 inhibitor and gain-of-function study of let-7a was done using let-7a mimic in SiHa cells. RESULTS: Functional silencing of STAT3 signaling in SiHa cells by STAT3-specific siRNA resulted in a dose-dependent decrease in cellular miR-21 level. Pharmacological intervention of STAT3 using specific inhibitors like curcumin and Stattic that abrogated STAT3 activation resulted in loss of cellular miR-21 pool. Contrary to this, specific targeting of miR-21 using miR-21 inhibitor resulted in an increased level of PTEN, a negative regulator of STAT3, and reduced active pSTAT3 level. Besides miR-21, restoration of cellular Let-7a using chemically synthesized Let-7a mimic reduced overall STAT3 level. Abrogation of HPV oncoprotein E6 by specific siRNA resulted in increased Let-7a but loss of miR-21 and a correspondingly reduced pSTAT3/STAT3 and elevated the level of cellular PTEN. CONCLUSIONS: Our results demonstrate existence of a functional loop involving Let-7a, STAT3 and miR-21 which were found potentially regulated by viral oncoprotein E6. IMPLICATIONS: miR-21 and Let-7a along with STAT3 may prove useful targets for pharmacological intervention for management of cervical cancer. PMID- 25539645 TI - Correlation between sequence divergence and polymorphism reveals similar evolutionary mechanisms acting across multiple timescales in a rapidly evolving plastid genome. AB - BACKGROUND: Although the plastid genome is highly conserved across most angiosperms, multiple lineages have increased rates of structural rearrangement and nucleotide substitution. These lineages exhibit an excess of nonsynonymous substitutions (i.e., elevated dN/dS ratios) in similar subsets of plastid genes, suggesting that similar mechanisms may be leading to relaxed and/or positive selection on these genes. However, little is known regarding whether these mechanisms continue to shape sequence diversity at the intraspecific level. RESULTS: We examined patterns of interspecific divergence and intraspecific polymorphism in the plastid genome of Campanulastrum americanum, and across plastid genes found a significant correlation between dN/dS and pN/pS (i.e., the within-species equivalent of dN/dS). A number of genes including ycf1, ycf2, clpP, and ribosomal protein genes exhibited high dN/dS ratios. McDonald-Kreitman tests detected little evidence for positive selection acting on these genes, likely due to the presence of substantial intraspecific divergence. CONCLUSIONS: These results suggest that mechanisms leading to increased nucleotide substitution rates in the plastid genome are continuing to act at the intraspecific level. Accelerated plastid genome evolution may increase the likelihood of intraspecific cytonuclear genetic incompatibilities, and thereby contribute to the early stages of the speciation process. PMID- 25539646 TI - Two-year follow-up of the Collision Auto Repair Safety Study (CARSS). AB - This paper presents an evaluation of the sustainability of health and safety improvements in small auto collision shops 1 year after the implementation of a year-long targeted intervention. During the first year (active phase), owners received quarterly phone calls, written reminders, safety newsletters, and access to online services and in-person assistance with creating safety programs and respirator fit testing. During the second year (passive phase), owners received up to three postcard reminders regarding the availability of free health and safety resources. Forty-five shops received an evaluation at baseline and at the end of the first year (Y1). Of these, 33 were evaluated at the end of the second year (Y2), using the same 92-item assessment tool. At Y1, investigators found that between 70 and 81% of the evaluated items were adequate in each business (mean = 73% items, SD = 11%). At Y2, between 63 and 89% of items were deemed adequate (mean = 73% items, SD = 9.5%). Three safety areas demonstrated statistically significant (P < 0.05) changes: compressed gasses (8% improvement), personal protective equipment (7% improvement), and respiratory protection (6% decline). The number of postcard reminders sent to each business did not affect the degree to which shops maintained safety improvements made during the first year of the intervention. However, businesses that received more postcards were more likely to request assistance services than those receiving fewer. PMID- 25539647 TI - Characterization of exposure to carbon nanotubes in an industrial setting. AB - While production and use of carbon nanotubes (CNTs) is increasing, workers exposure to CNTs is expected to increase as well, with inhalation being potentially the main pathway for uptake. However, there have been few studies reporting results about workers' personal exposure to CNTs. In this study, worker exposure to single-walled CNTs (SWCNTs) during the production of conductive films in a modern up-scaling factory was assessed. Particulate matter concentrations (2.5-10 MUm) and concentrations of CO and CO2 were monitored by using real-time instruments. Workers' exposure levels to SWCNTs were qualitatively estimated by analyzing particle samples by transmission electron microscopy (TEM). TEM samples identified high aspect ratio (length/width > 500) SWCNTs in workplace air. SWCNT concentrations estimated from micrographs varied during normal operation, reactor use without local exhaust ventilation (LEV), and cleaning between 1.7*10(-3), 5.6 and 6.0*10(-3) SWCNT cm(-3), respectively. However, during cleaning it was unclear whether the SWCNTs originated from the cleaning itself or from other reactor openings. We were unable to quantify the SWCNT emissions with online particle instrumentation due to the SWCNT low concentrations compared to background particle concentrations, which were on average 2.6+/-1.1*10(3)cm(-3). However, CO concentrations were verified as a good indicator of fugitive emissions of SWCNTs. During normal operation, exposure levels were well below proposed limit values (1.0*10(-2) fibers cm(-3) and 1 ug m(-3)) when LEV was used. Based on the results in this study, the analysis of TEM grids seems to be the only direct method to detect SWCNTs in workplace air. PMID- 25539650 TI - Incidental aortic valve myxoma: tumour excision and aortic valve repair. PMID- 25539649 TI - Virtual-assisted lung mapping: outcome of 100 consecutive cases in a single institute. AB - OBJECTIVES: We developed virtual-assisted lung mapping (VAL-MAP), a bronchoscopic multispot dye-marking technique using three dimensional (3D) virtual imaging, for precise thoracoscopic sublobar lung resection with safe surgical margins. We herein review the results of 100 consecutive cases of VAL-MAP in our institute to identify types of tumours or resections that benefit from VAL-MAP. METHODS: Markings were bronchoscopically made within 2 days preoperatively using virtual 3D images. Post-VAL-MAP computer tomography (CT) scans localizing the actual markings were reconstructed into 3D images for intraoperative navigation. All data on patients, markings and outcomes were prospectively collected, and the contribution of VAL-MAP to the operation was graded by the surgeon. RESULTS: Resections of 156 lung lesions in 100 consecutive patients were planned from July 2012 to March 2014. The lesion diameter was 8.3 +/- 4.9 (range, 2-24) mm. The total number of actually conducted markings was 380 (3.83 +/- 1.07 markings/patient). Eighty-four lesions were resected by 71 wedge resections using 158 markings (2.1 +/- 0.1/resection; range, 1-3). Seventy lesions were resected by 63 segmentectomies using 224 markings (3.6 +/- 0.1/resection; range, 2-6). Markings were identifiable on post-VAL-MAP CT mostly as ground-glass opacities (87.7%) and/or bronchial dilatation (56.1%). During the operation, 357 of 380 markings (93.9%) were visible on the pleural surface and significantly associated with marking visibility on CT. Multiple markings that were complementary to one another appeared to have contributed to the high rate of successful resection (99.3%) with satisfactory resection margins. The contribution of VAL-MAP to the operation as graded by surgeons demonstrated that VAL-MAP is most effective during wedge resection or complex segmentectomy for hardly palpable, small tumours, while VAL-MAP still plays an important role in simple segmentectomy or resection of palpable tumours by providing higher confidence levels to surgeons during the operation. Minor pneumothoraces were found on post-VAL-MAP CT images in 4 patients without symptoms or a need for treatment. CONCLUSIONS: The present study further demonstrated the efficacy and safety of VAL-MAP. VAL-MAP is likely to benefit a broader range of patients than are conventional marking techniques by assisting with both accurate tumour identification and precise determination of resection lines. PMID- 25539648 TI - Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial. AB - BACKGROUND: Safety of tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) has been studied more extensively among HIV-infected patients than among HIV uninfected people. Using data from a pre-exposure trial - FEM-PrEP -, we determined the cumulative probabilities of grade 1+ ALT, AST and creatinine and grade 2+ phosphorus toxicities; ALT/AST toxicities by baseline hepatitis B status; and change in mean creatinine, phosphorus, ALT and AST levels controlling for TDF-FTC adherence. METHODS AND FINDINGS: FEM-PrEP was a randomized, blinded, placebo-controlled trial of daily TDF-FTC among women in Africa. Enrolled women were in general good health, HIV antibody negative, 18 to 35 years old, hepatitis B surface antigen negative, and had normal hepatic and renal function at baseline. AST, ALT, phosphorus and serum creatinine were measured regularly throughout the trial. TDF-FTC concentrations were measured to assess adherence to TDF-FTC. The cumulative probabilities of grade 1+ creatininemia and grade 2+ phosphatemia toxicities were not statistically different between TDF-FTC and placebo arms. The cumulative probabilities of grade 1+ ALT and AST toxicities were higher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both). The proportions of grade 1+ and grade 2+ ALT or AST toxicities were significantly higher in participants who were hepatitis B virus surface antibody (HBsAb) positive than in those who were HBsAb-negative. Women with good adherence had higher mean change from baseline to week 4 in their AST levels (2.90 (0.37, 5.42); p = 0.025) than women with less than good adherence. CONCLUSIONS: We did not observe a significant relationship between randomization to TDF-FTC and creatinine or phosphorus toxicities. Women randomized to TDF-FTC had higher rates of mild to moderate ALT/AST toxicities, especially women with prior hepatitis B virus exposure. We also observed a significant increase in AST from baseline to week 4 among women who had higher adherence to TDF-FTC during that interval. TRIAL REGISTER: #NCT00625404, February 19, 2008. PMID- 25539651 TI - Amino acid substitutions in hemagglutinin of the 2009 pandemic influenza A(H1N1) viruses that might affect the viral antigenicity. AB - BACKGROUND: During 2009 to 2012, Thailand had encountered 4 distinctive waves of the 2009 pandemic influenza A(H1N1) (H1N1pdm) outbreaks. Considering the RNA nature of the influenza viral genome, a mutation in hemagglutinin (HA) gene which led to change in antigenicity of the strains circulating during those epidemic periods is anticipated. It is also uncertain whether the A/California/07/2009 (H1N1) (CA/07) vaccine strain still confers protective immunity against those evolved viruses, the causative agents of the later epidemic waves. METHODS: HA gene segments of 10 H1N1pdm isolates obtained during 2009 to 2012 were sequenced and phylogenetically analysed using ClustalW and MEGA5 programs. A total of 124 convalescent serum samples collected from patients naturally infected during 3 epidemic waves were employed as tools to investigate for antigenic change in HA of these 10 circulating H1N1pdm viruses by hemagglutination inhibition (HI) assay. RESULTS: A phylogenetic analysis showed that the 10 virus isolates were grouped into 4 clusters corresponding to the time of 4 consecutive outbreaks. An accumulation of amino acid substitutions in HA was observed in viruses derived from the late epidemic waves. Significantly lower antibody titers were observed when CA/07 was tested against convalescent sera collected from the 3 waves (p<0.05) compared to most of Thai isolates; and significantly lower antibody titers were also obtained when virus isolates, retrieved from the third epidemic wave were tested against convalescent sera collected during the first and second wave. These results were suggestive of change in antigenicity of the evolved viruses. Our results also showed some mutation position residing outside the previously reported antigenic site that may involve in an alteration of the viral antigenicity. CONCLUSIONS: Our study demonstrated that convalescent sera collected from individuals naturally infected with H1N1pdm virus were successfully used to reveal a statistically significant change in antibody titers against the currently evolved H1N1pdm viruses as determined by HI assay. Nevertheless, the antibody titers of individual serum against various viruses were less than 4-folded difference as compared to that against the CA/07 vaccine strain. Therefore, CA/07 is still a potent vaccine strain for those evolved H1N1pdm viruses. PMID- 25539653 TI - Novel approach to inpatient glucometric monitoring and variability in a community hospital setting. AB - Hyperglycemia and glucose variability in the hospital environment are associated with higher rates of complications, longer lengths of stay, and mortality. Standardized metrics are needed to assess the efficacy and safety of glucose management interventions. Glucometric data were collected from 2024 inpatients in a San Diego hospital between 2009 and 2011. As a complementary measure of glucose control, individual patient excursion rates were calculated using counts of distinct excursions from normal to critical glucose ranges >180 or <70 mg/dL. Prediction models for excursion rates were devised, based on patient demographic and clinical characteristics. Patients were predominantly male (51.2%), Caucasian (86.0%), and elderly (median age 72 years). Obesity was prevalent: 32% were overweight and 33% were obese. Median length of hospitalization was 5.0 days (range, 0.8-139.4 days). Unadjusted rate of excursions >180 mg/dL was 0.456 per 24 hours. The proportion of zero excursions decreased as severity of illness decreased, but was unrelated to age. Excursion rates were slightly smaller for major and extreme severity of illness compared to mild or moderate illness severity. Excursion rates did not vary in a monotone fashion with age, although the general pattern reflected a reduction in excursion rates from the first age quartile (19 to 59) through the last age quartile (83 to 100). Using the Akaike information criterion, zero-inflated negative binomial models were identified as appropriate for analyzing glucose excursion rates. Systematic approaches to glucose reporting and management in the hospital environment offer "windows of opportunity" to improve diabetes care. PMID- 25539652 TI - Accuracy of Intra-arterial and Subcutaneous Continuous Glucose Monitoring in Postoperative Cardiac Surgery Patients in the ICU. AB - BACKGROUND: The GluCath(r) intra-arterial continuous glucose monitoring (IA-CGM) system uses a novel quenched chemical fluorescence sensing mechanism to optically measure blood glucose when deployed in the radial artery. The aim of this study was to compare the accuracy of the IA-CGM and the FreeStyle Navigator(r) subcutaneous continuous glucose monitoring (SC-CGM) system with standard care. METHODS: After admission to the intensive care unit (ICU), the IA-CGM was inserted via a 20 gauge radial arterial study catheter and the SC-CGM was placed at the abdominal wall of postoperative cardiac surgery patients with an expected ICU length of stay > 24 hours. Each device was calibrated according to manufacturer instructions. Glucose values of both CGM systems were blinded for the clinical staff. Reference blood glucose samples were collected from the study catheter every 1-2 hours for at least 24 hours and analyzed on a Radiometer ABL blood gas analyzer. RESULTS: The IA-CGM and SC-CGM sensors were successfully inserted in 8 subjects. Accuracy assessment was performed with 183 paired points: 85.8% of the IA-CGM measurements and 84.2% of the SC-CGM measurements met ISO 15197:2003 glucometer criteria (within 20%) across a 79-248 mg/dl (4.4-13.8 mmol/L) glucose range. Overall +/- SD mean absolute relative difference was 12.3 +/- 11.3% for IA-CGM and 11.1 +/- 8.3% for SC-CGM (difference -1.2%, 95% CI -3.3 to 0.8; P = .24). CONCLUSIONS: The IA-CGM system directly measured arterial blood glucose and did not interfere with clinical care. However, accuracy was similar to that of the less invasive SC-CGM device. PMID- 25539654 TI - Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial. AB - BACKGROUND: This study evaluated the effects of aclidinium bromide, a long-acting muscarinic antagonist indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD), on exercise endurance, dyspnea, lung hyperinflation, and physical activity. METHODS: In this randomized, double-blind, crossover study, patients with stable COPD and moderate-to-severe airflow limitation received aclidinium 400 MUg twice daily or placebo via Genuair(r)/Pressair((r)a) for 3 weeks (2-week washout between treatment periods). The primary endpoint was change from baseline to Week 3 in endurance time, measured by constant work rate cycle ergometry testing at 75% peak incremental work rate. Changes from baseline in intensity of exertional dyspnea (Borg CR10 Scale(r)) and trough inspiratory capacity were secondary endpoints. Additional endpoints included changes from baseline in other spirometric, plethysmographic, and physical activity (assessed by objective accelerometer measurement) parameters. Efficacy endpoints were analyzed using an analysis of covariance model. RESULTS: In total, 112 patients were randomized and treated (mean age 60.3 years; mean post-bronchodilator forced expiratory volume in 1 s 1.7 L [56.7% predicted]; mean endurance time 485.7 s). After 3 weeks, endurance time was significantly increased with aclidinium versus placebo (treatment difference 58.5 s; p < 0.05). At Week 3, aclidinium significantly reduced dyspnea intensity at isotime during exercise (treatment difference -0.63; p < 0.05) and improved trough inspiratory capacity (treatment difference 78 mL; p < 0.05) versus placebo. Significant improvements in spirometric, plethysmographic, and some physical activity parameters were observed with aclidinium versus placebo. CONCLUSIONS: These results suggest that aclidinium significantly improves exercise endurance, exertional dyspnea, hyperinflation, and physical activity in patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01471171; URL: http://www.clinicaltrials.gov. PMID- 25539655 TI - Global transcriptome analysis of Mesorhizobium alhagi CCNWXJ12-2 under salt stress. AB - BACKGROUND: Mesorhizobium alhagi CCNWXJ12-2 is a alpha-proteobacterium which could be able to fix nitrogen in the nodules formed with Alhagi sparsifolia in northwest of China. Desiccation and high salinity are the two major environmental problems faced by M. alhagi CCNWXJ12-2. In order to identify genes involved in salt-stress adaption, a global transcriptional analysis of M. alhagi CCNWXJ12-2 growing under salt-free and high salt conditions was carried out. The next generation sequencing technology, RNA-Seq, was used to obtain the transcription profiles. RESULTS: We have compared the transcriptome of M. alhagi growing in TY medium under high salt conditions (0.4 M NaCl) with salt free conditions as a control. A total of 1,849 differentially expressed genes (fold change ? 2) were identified and 933 genes were downregulated while 916 genes were upregulated under high salt condition. Except for the upregulation of some genes proven to be involved in salt resistance, we found that the expression levels of protein secretion systems were changed under high salt condition and the expression levels of some heat shock proteins were reduced by salt stress. Notably, a gene encoding YadA domain-containing protein (yadA), a gene encoding trimethylamine methyltransferase (mttB) and a gene encoding formate--tetrahydrofolate ligase (fhs) were highly upregulated. Growth analysis of the three gene knockout mutants under salt stress demonstrated that yadA was involved in salt resistance while the other two were not. CONCLUSIONS: To our knowledge, this is the first report about transcriptome analysis of a rhizobia using RNA-Seq to elucidate the salt resistance mechanism. Our results showed the complex mechanism of bacterial adaption to salt stress and it was a systematic work for bacteria to cope with the high salinity environmental problems. Therefore, these results could be helpful for further investigation of the bacterial salt resistance mechanism. PMID- 25539656 TI - The EPIYA-ABCC motif pattern in CagA of Helicobacter pylori is associated with peptic ulcer and gastric cancer in Mexican population. AB - BACKGROUND: Helicobacter pylori chronic infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. Cytotoxin-associated gene A (cagA) positive H. pylori strains increase the risk of gastric pathology. The carcinogenic potential of CagA is linked to its polymorphic EPIYA motif variants. The goals of this study were to investigate the frequency of cagA-positive Helicobacter pylori in Mexican patients with gastric pathologies and to assess the association of cagA EPIYA motif patterns with peptic ulcer and gastric cancer. METHODS: A total of 499 patients were studied; of these, 402 had chronic gastritis, 77 had peptic ulcer, and 20 had gastric cancer. H. pylori DNA, cagA, and the EPIYA motifs were detected in total DNA from gastric biopsies by PCR. The type and number of EPIYA segments were determined by the electrophoretic patterns. To confirm the PCR results, 20 amplicons of the cagA 3' variable region were sequenced, and analyzed in silico, and the amino acid sequence was predicted with MEGA software, version 5. The odds ratio (OR) was calculated to determine the associations between the EPIYA motif type and gastric pathology and between the number of EPIYA-C segments and peptic ulcers and gastric cancer. RESULTS: H. pylori DNA was found in 287 (57.5%) of the 499 patients, and 214 (74%) of these patients were cagA-positive. The frequency of cagA-positive H. pylori was 74.6% (164/220) in chronic gastritis patients, 73.6% (39/53) in peptic ulcer patients, and 78.6% (11/14) in gastric cancer patients. The EPIYA-ABC pattern was more frequently observed in chronic gastritis patients (79.3%, 130/164), while the EPIYA-ABCC sequence was more frequently observed in peptic ulcer (64.1%, 25/39) and gastric cancer patients (54.5%, 6/11). However, the risks of peptic ulcer (OR = 7.0, 95% CI = 3.3-15.1; p < 0.001) and gastric cancer (OR = 5.9, 95% CI = 1.5 22.1) were significantly increased in individuals who harbored the EPIYA-ABCC cagA gene pattern. CONCLUSIONS: cagA-positive H. pylori is highly prevalent in southern Mexico, and all CagA variants were of the western type. The cagA alleles that code for EPIYA-ABCC motif patterns are associated with peptic ulcers and gastric cancer. PMID- 25539657 TI - Validation of an FBA model for Pichia pastoris in chemostat cultures. AB - BACKGROUND: Constraint-based metabolic models and flux balance analysis (FBA) have been extensively used in the last years to investigate the behavior of cells and also as basis for different industrial applications. In this context, this work provides a validation of a small-sized FBA model of the yeast Pichia pastoris. Our main objective is testing how accurate is the hypothesis of maximum growth to predict the behavior of P. pastoris in a range of experimental environments. RESULTS: A constraint-based model of P. pastoris was previously validated using metabolic flux analysis (MFA). In this paper we have verified the model ability to predict the cells behavior in different conditions without introducing measurements, experimental parameters, or any additional constraint, just by assuming that cells will make the best use of the available resources to maximize its growth. In particular, we have tested FBA model ability to: (a) predict growth yields over single substrates (glucose, glycerol, and methanol); (b) predict growth rate, substrate uptakes, respiration rates, and by-product formation in scenarios where different substrates are available (glucose, glycerol, methanol, or mixes of methanol and glycerol); (c) predict the different behaviors of P. pastoris cultures in aerobic and hypoxic conditions for each single substrate. In every case, experimental data from literature are used as validation. CONCLUSIONS: We conclude that our predictions based on growth maximisation are reasonably accurate, but still far from perfect. The deviations are significant in scenarios where P. pastoris grows on methanol, suggesting that the hypothesis of maximum growth could be not dominating in these situations. However, predictions are much better when glycerol or glucose are used as substrates. In these scenarios, even if our FBA model is small and imposes a strong assumption regarding how cells will regulate their metabolic fluxes, it provides reasonably good predictions in terms of growth, substrate preference, product formation, and respiration rates. PMID- 25539659 TI - Utility of peak inspiratory flow in managing subglottic stenosis. AB - OBJECTIVES: To identify the utility of peak inspiratory flow (PIF) in the assessment and management of subglottic stenosis through correlation of clinical presentation with PIF. STUDY DESIGN: Case report. METHODS: Review of the clinical course of a 31-year-old woman with the diagnosis of granulomatosis with polyangiitis. Repeated PIF measurements at clinic visits were obtained over a 30 month follow-up. RESULTS: Twenty-seven PIF measurements were obtained at 31 otolaryngology clinic visits. Correlations were identified between low PIF measurements with the clinical symptom shortness of breath (2.04+/-0.38 L/s, n=10), clinically recorded stridor at rest (1.64+/-0.41 L/s, n=3), and urgent operative intervention (1.60+/-0.23 L/s, n=5). Correlations were identified between high PIF measurement with patient report of normal breathing (3.07+/-0.35 L/s, n=16) and clinical observation of absence of stridor at rest (2.81+/-0.32 L/s, n=23). There was a statistically significant difference in the patient's PIF values with patient-documented shortness of breath vs no shortness of breath (P=.001) and clinician-noted stridor vs no stridor (P=.017). CONCLUSION: Peak inspiratory flow measurements correlate with degree of airway compromise and are helpful to monitor the degree of airway obstruction and document response to treatment. PMID- 25539658 TI - Validity of subjective versus objective quality of life assessment in people with schizophrenia. AB - BACKGROUND: Quality of life (QoL) is considered an important outcome in health research. It can be rated by the patient, or by an external assessor. We wished to identify the predictors of any discrepancies between these two approaches in people with schizophrenia. METHODS: Patients with DSM schizophrenia and related disorders (N = 80) completed both patient-rated (Lancashire Quality of Life Profile; LQOLP) and assessor-rated (Heinrich's Quality of Life Scale; QLS) measures of QoL. RESULTS: Patient-rated (LQOLP) and assessor-rated (QLS) measures showed a modest correlation (r = 0.38). In a regression analysis, independent predictors of subjectively-rated QoL being higher than objectively-assessed QoL in the same patient, were low insight score (BIS), negative symptoms (PANSS), absence of depression (CDSS), and less positive attitude toward prescribed treatment (DAI). CONCLUSIONS: In people with schizophrenia, scores on objectively and subjectively-rated measures of quality of life can differ markedly. When comparing subjective to objective assessments, patients with depressive symptoms will value their QoL lower, and those with low insight will value their QoL higher. This has important implications for the utility and interpretation of QoL measures in schizophrenia. PMID- 25539660 TI - Predictors of quality of life improvement in allergic rhinitis patients after sublingual immunotherapy. AB - OBJECTIVES: Sublingual immunotherapy (SLIT) has been described as a significant intervention in the treatment of allergic rhinitis (AR). However, factors that may predict treatment outcomes with respect to quality of life (QoL) results and mainly the role of olfactory function are still being underestimated. In this study, we investigated determinants that best predict treatment outcomes for QoL, exploring mainly the role of olfaction. METHODS: One hundred forty-five patients following SLIT, 45 placebo-controls, and 48 healthy subjects were studied. Olfactory function was objectively evaluated using "Sniffin' Sticks" test pre- and post-cessation of SLIT. Three categories of validated QoL questionnaires were filled out by all subjects: questionnaire specific for olfaction (Questionnaire of Olfactory Deficits), questionnaires for assessing psychology (Beck Depression Inventory, Zung Depression Scale, State & Trait Anxiety Inventory), general Short Form-36 health survey. RESULTS: Statistically significant improvement of olfactory function by 11.1% and of all QoL questionnaires results (all P<.001) was observed on final evaluation. Anosmia, asthma history, and the severity of symptoms-expressed by the Total Symptoms Score-were proven independent determinants of clinically significant improvement in patients' QoL. CONCLUSIONS: Several factors were found that may predict QoL outcomes in AR patients following SLIT. PMID- 25539661 TI - How reliable are sino-nasal cell lines for studying the pathophysiology of chronic rhinosinusitis? AB - BACKGROUND: Well-characterized cell lines represent useful scientific tools to study the pathophysiology of human disease. Chronic rhinosinusitis (CRS) is a very common condition, though the number of CRS cell lines is limited, as are data showing how closely they resemble primary cells. METHODOLOGY: Searches for available human cell lines were performed using the American Type Culture Collection (ATCC) and European Collection of Cell Cultures (ECACC). Identified cells were cultured and characterized with tinctorial and immunohistochemical staining and ELISA to assess their response to common, disease-relevant inflammatory stimuli. Carefully phenotyped CRS patients were recruited with informed consent. Primary nasal epithelial cell (PNEC) brushings were harvested, cultured, and compared to the available cell lines. RESULTS: Searches identified 1 relevant CRS sino-nasal cell line, RPMI 2650. Cultured PNECs showed strong expression of epithelial markers while being negative for mesenchymal markers. However, RPMI 2650 cells show an atypical mixed epithelial/mesenchymal phenotype. When stimulated by pro-inflammatory ligands, PNECs responded in a dose-dependent manner, whereas RPMI 2650 cells showed limited response. CONCLUSIONS: The number and availability of cell lines to study the pathophysiology of CRS greatly underrepresent the disease burden. Additionally, the sole commercially available cell line appears to have a different phenotype and behavior to primary patient derived cells. The development of further reproducible cell lines would be beneficial in our understanding of CRS. PMID- 25539662 TI - No transmission of hepatitis E virus in pigs fed diets containing commercial spray-dried porcine plasma: a retrospective study of samples from several swine trials. AB - BACKGROUND: Hepatitis E virus (HEV) has been reported in the human population and pigs are a recognized reservoir for HEV and a possible source of HEV transmission to humans. Spray-dried porcine plasma (SDPP) is an ingredient commonly used in feed for pigs around the world. Even though processing conditions used to produce SDPP should be adequate to inactivate HEV, it was of interest to analyze commercial SDPP samples for presence of genome and antibodies (AB) against HEV and to retrospectively analyze serum samples collected from pigs used in past experiments that had been fed diets containing either 0% or 8% SDPP to detect potential transmission of HEV as determined by seroconversion. RESULTS: Eighty five commercial SDPP samples were analyzed by ELISA and 100% of them contained AB against HEV, while 22.4% (11 of 49 samples analyzed) were positive for HEV RNA. Frozen sera samples (n = 140) collected from 70 pigs used in past experiments that had been fed diets containing either 0% or 8% commercial SDPP was analyzed by ELISA for AB against HEV. Age of pigs at sera sampling ranged from 3 to 15 weeks and feeding duration of diets ranged from approximately 4 to 9 weeks. One lot of SDPP used in one experiment was analyzed and confirmed to contain HEV RNA. Regardless of the diet fed, some sera samples collected at the beginning of an experiment contained AB titer against HEV. These sera samples were collected from weaned pigs prior to feeding of the experimental diets and the HEV titer was probably from maternal origin. However, by the end of the experiments, HEV titer was not detected or had declined by more than 50% of the initial titer concentration. CONCLUSIONS: To our knowledge, this is the first study reporting presence of HEV AB titer and RNA in SDPP. Retrospective analysis of serum collected from pigs fed diets with SDPP revealed no indication of seroconversion to HEV. The results indicate that feeding SDPP in diets for pigs does not represent a risk of transmitting HEV, even though HEV genome may be detected in SDPP. PMID- 25539664 TI - Developmental hypothyroidism abolishes bilateral differences in sonic hedgehog gene control in the rat hippocampal dentate gyrus. AB - Both developmental and adult-stage hypothyroidism disrupt rat hippocampal neurogenesis. We previously showed that exposing mouse offspring to manganese permanently disrupts hippocampal neurogenesis and abolishes the asymmetric distribution of cells expressing Mid1, a molecule regulated by sonic hedgehog (Shh) signaling. The present study examined the involvement of Shh signaling on the disruption of hippocampal neurogenesis in rats with hypothyroidism. Pregnant rats were treated with methimazole (MMI) at 0 or 200 ppm in the drinking water from gestation day 10-21 days after delivery (developmental hypothyroidism). Adult male rats were treated with MMI in the same manner from postnatal day (PND) 46 to PND 77 (adult-stage hypothyroidism). Developmental hypothyroidism reduced the number of Mid1(+) cells within the subgranular zone of the dentate gyrus of offspring on PND 21, and consequently abolished the normal asymmetric predominance of Mid1(+) cells on the right side through the adult stage. In control animals, Shh was expressed in a subpopulation of hilar neurons, showing asymmetric distribution with left side predominance on PND 21; however, this asymmetry did not continue through the adult stage. Developmental hypothyroidism increased Shh(+) neurons bilaterally and abolished the asymmetric distribution pattern on PND 21. Adult hypothyroidism also disrupted the asymmetric distribution of Mid1(+) cells but did not affect the distribution of Shh(+) hilar neurons. The results suggest that the hippocampal neurogenesis disruption seen in hypothyroidism involves changes in asymmetric Shh(+) neuron distribution in developmental hypothyroidism and altered Mid1 expression in both developmental and adult-stage hypothyroidism. PMID- 25539663 TI - Parathyroid hormone-related protein serves as a prognostic indicator in oral squamous cell carcinoma. AB - BACKGROUND: In our previous study, parathyroid hormone-like hormone (PTHLH) which encodes parathyroid hormone-related protein (PTHrP) was revealed to be up regulated in oral squamous cell carcinoma (OSCC) compared with paired apparently normal surgical margins using microarray method. However, the function and prognostic indicators of PTHLH/PTHrP in OSCC remain obscure. METHODS: The mRNA levels of PTHLH and its protein levels were investigated in 9 OSCC cell lines and in 36 paired OSCC specimens by real-time PCR and western blotting. The biological function of PTHLH/PTHrP was investigated using small interfering RNA (siRNA) in 3 OSCC cell lines, and immunohistochemistry was used to estimate the prognostic value of PTHrP in 101 patients with head and neck squamous cell carcinoma (HNSCC), including OSCC and oropharyngeal squamous cell carcinoma. Cell cycle was tested by flow cytometry and cell cycle related genes were investigated by western blotting and immunocytochemistry assay. RESULTS: This study showed that the mRNA and protein levels of PTHLH in 9 OSCC cell lines were much higher than that in normal epithelial cells (P < 0.0001). In 36 paired OSCC tissues, PTHLH mRNA expressions were found higher in 32 OSCC tissues than that of paired apparently normal surgical margins (P = 0.0001). The results revealed that the down-regulation of PTHLH/PTHrP by siRNAs could reduce cell proliferation and inhibit plate and soft agar colony formation as well as affect the cell cycle of OSCC cells. The key proteins related to the cell cycle were changed by anti-PTHLH siRNA. The results showed that cyclin D1 and CDK4 expressions were significantly reduced in the cells transfected with anti-PTHLH siRNA. On the other hand, the expression of p21 was increased. The results also showed that high PTHrP level was associated with poor pathologic differentiation (P = 0.0001) and poor prognosis (P = 0.0003) in patients with HNSCC. CONCLUSIONS: This study suggests that PTHLH/PTHrP is up-regulated in OSCCs. Therefore, PTHLH/PTHrP could play a role in the pathogenesis of OSCC by affecting cell proliferation and cell cycle, and the protein levels of PTHrP might serve as a prognostic indicator for evaluating patients with HNSCCs. PMID- 25539666 TI - Self-assembled nanocomposite film with tunable enhanced fluorescence for the detection of DNA. AB - In this study, a simple and environmentally friendly, silver nanocomposite film was prepared via the in situ reduction of silver ions in self-assembled chitosan (CS)/sodium alginate film matrixes. Negatively charged DNA containing the fluorescent intercalator acriflavine (Acf) was assembled on the surface of the silver nanocomposite film, to facilitate the detection of DNA. A tunable fluorescence enhancement was achieved for the Acf in the silver nanocomposite film simply by changing the thickness of the interlayer between the DNA and the silver nanocomposite film. Using the interlayer prepared by an assembly of poly(acrylic acid) and CS, a significant enhancement in the fluorescence of Acf was obtained. Owing to the ability of Acf to intercalate into DNA, this hybrid system with an enhanced Acf fluorescence could be used to monitor the template independent DNA elongation process in a facile, high-efficiency, label-free fashion. PMID- 25539665 TI - Persistence of furan-induced epigenetic aberrations in the livers of F344 rats. AB - Furan is a heterocyclic organic compound produced in the chemical manufacturing industry and also found in a broad range of food products, including infant formulas and baby foods. Previous reports have indicated that the adverse biological effects of furan, including its liver tumorigenicity, may be associated with epigenetic abnormalities. In the present study, we investigated the persistence of epigenetic alterations in rat liver. Male F344 rats were treated by gavage 5 days per week with 8 mg furan/kg body weight (bw)/day for 90 days. After the last treatment, rats were divided randomly into 4 groups; 1 group of rats was sacrificed 24 h after the last treatment, whereas other groups were maintained without further furan treatment for an additional 90, 180, or 360 days. Treatment with furan for 90 days resulted in alterations in histone lysine methylation and acetylation, induction of base-excision DNA repair genes, suggesting oxidative damage to DNA, and changes in the gene expression in the livers. A majority of these furan-induced molecular changes was transient and disappeared after the cessation of furan treatment. In contrast, histone H3 lysine 9 and H3 lysine 56 showed a sustained and time-depended decrease in acetylation, which was associated with formation of heterochromatin and altered gene expression. These results indicate that furan-induced adverse effects may be mechanistically related to sustained changes in histone lysine acetylation that compromise the ability of cells to maintain and control properly the expression of genetic information. PMID- 25539667 TI - Controlling cancer cell fate using localized biocatalytic self-assembly of an aromatic carbohydrate amphiphile. AB - We report on a simple carbohydrate amphiphile able to self-assemble into nanofibers upon enzymatic dephosphorylation. The self-assembly can be triggered by alkaline phosphatase (ALP) in solution or in situ by the ALP produced by osteosarcoma cell line, SaOs2. In the latter case, assembly and localized gelation occurs mainly on the cell surface. The gelation of the pericellular environment induces a reduction of the SaOs2 metabolic activity at an initial stage (<=7 h) that results in cell death at longer exposure periods (>=24 h). We show that this effect depends on the phosphatase concentration, and thus, it is cell-selective with prechondrocytes ATDC5 (that express ~15-20 times lower ALP activity compared to SaOs2) not being affected at concentrations <=1 mM. These results demonstrate that simple carbohydrate derivatives can be used in an antiosteosarcoma strategy with limited impact on the surrounding healthy cells/tissues. PMID- 25539669 TI - Determinants and consequences of short birth interval in rural Bangladesh: a cross-sectional study. AB - BACKGROUND: Short birth intervals are known to have negative effects on pregnancy outcomes. We analysed data from a large population surveillance system in rural Bangladesh to identify predictors of short birth interval and determine consequences of short intervals on pregnancy outcomes. METHODS: The study was conducted in three districts of Bangladesh - Bogra, Moulavibazar and Faridpur (population 282,643, 54,668 women of reproductive age). We used data between January 2010 and June 2011 from a key informant surveillance system that recorded all births, deaths and stillbirths. Short birth interval was defined as an interval between consecutive births of less than 33 months. Initially, risk factors of a short birth interval were determined using a multivariate mixed effects logistic regression model. Independent risk factors were selected using a priori knowledge from literature review. An adjusted mixed effects logistic regression model was then used to determine the effect of up to 21-, 21-32-, 33 44- and 45-month and higher birth-to-birth intervals on pregnancy outcomes controlling for confounders selected through a directed acyclic graph. RESULTS: We analysed 5,571 second or higher order deliveries. Average birth interval was 55 months and 1368/5571 women (24.6%) had a short birth interval (<33 months). Younger women (AOR 1.11 95% CI 1.08-1.15 per year increase in age), women who started their reproductive life later (AOR 0.95, 0.92-0.98 per year) and those who achieve higher order parities were less likely to experience short birth intervals (AOR 0.28, 0.19-0.41 parity 4 compared to 1). Women who were socioeconomically disadvantaged were more likely to experience a short birth interval (AOR 1.42, 1.22-1.65) and a previous adverse outcome was an important determinant of interval (AOR 2.10, 1.83-2.40). Very short birth intervals of less than 21 months were associated with increased stillbirth rate (AOR 2.13, 95% CI 1.28-3.53) and neonatal mortality (AOR 2.28 95% CI 1.28-4.05). CONCLUSIONS: Birth spacing remains a reproductive health problem in Bangladesh. Disadvantaged women are more likely to experience short birth intervals and to have increased perinatal deaths. Research into causal pathways and strategies to improve spacing between pregnancies should be intensified. PMID- 25539670 TI - Assessment of a couples HIV counseling and testing program for pregnant women and their partners in antenatal care (ANC) in 7 provinces, Thailand. AB - BACKGROUND: Couples HIV testing and counseling (CHTC) at antenatal care (ANC) settings allows pregnant women to learn the HIV status of themselves and their partners. Couples can make decisions together to prevent HIV transmission. In Thailand, men were tested at ANC settings only if their pregnant partners were HIV positive. A CHTC program based in ANC settings was developed and implemented at 16 pilot hospitals in 7 provinces during 2009-2010. METHODS: Cross-sectional data were collected using standard data collection forms from all pregnant women and accompanying partners who presented at first ANC visit at 16 hospitals. CHTC data for women and partners were analyzed to determine service uptake and HIV test results among couples. In-depth interviews were conducted among hospital staff of participating hospitals during field supervision visits to assess feasibility and acceptability of CHTC services. RESULTS: During October 2009 April 2010, 4,524 women initiating ANC were enrolled. Of these, 2,435 (54%) women came for ANC alone; 2,089 (46%) came with partners. Among men presenting with partners, 2,003 (96%) received couples counseling. Of these, 1,723 (86%) men and all pregnant women accepted HIV testing. Among 1,723 couples testing for HIV, 1,604 (93%) returned for test results. Of these, 1,567 (98%) were concordant negative, 6 (0.4%) were concordant positive and 17 (1%) were HIV discordant (7 male+/female- and 10 male-/female+). Nine of ten (90%) executive hospital staff reported high acceptability of CHTC services. CONCLUSIONS: CHTC implemented in ANC settings helps identify more HIV-positive men whose partners were negative than previous practice, with high acceptability among hospital staff. PMID- 25539671 TI - Evaluation of a skin self examination attitude scale using an item response theory model approach. AB - INTRODUCTION: The Skin Self-Examination Attitude Scale (SSEAS) is a brief measure that allows for the assessment of attitudes in relation to skin self-examination. This study evaluated the psychometric properties of the SSEAS using Item Response Theory (IRT) methods in a large sample of men >= 50 years in Queensland, Australia. METHODS: A sample of 831 men (420 intervention and 411 control) completed a telephone assessment at the 13-month follow-up of a randomized controlled trial of a video-based intervention to improve skin self-examination (SSE) behaviour. Descriptive statistics (mean, standard deviation, item-total correlations, and Cronbach's alpha) were compiled and difficulty parameters were computed with Winsteps using the polytomous Rasch Rating Scale Model (RRSM). An item person (Wright) map of the SSEAS was examined for content coverage and item targeting. RESULTS: The SSEAS have good psychometric properties including good internal consistency (Cronbach's alpha = 0.80), fit with the model and no evidence for differential item functioning (DIF) due to experimental trial grouping was detected. CONCLUSIONS: The present study confirms the SSEA scale as a brief, useful and reliable tool for assessing attitudes towards skin self examination in a population of men 50 years or older in Queensland, Australia. The 8-item scale shows unidimensionality, allowing levels of SSE attitude, and the item difficulties, to be ranked on a single continuous scale. In terms of clinical practice, it is very important to assess skin cancer self-examination attitude to identify people who may need a more extensive intervention to allow early detection of skin cancer. PMID- 25539673 TI - Motilin-induced gastric contractions signal hunger in man. AB - RATIONALE: Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. OBJECTIVES: To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. FINDINGS: In fasting healthy volunteers, mean hunger ratings during a gastric (62.5+/-7.5) but not a duodenal (40.4+/-5.4) phase III were higher (p<0.0005) than during phase I (27.4+/-4.7) and phase II (37+/-4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2+/-7 to 61.7+/-8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (beta=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. CONCLUSIONS: Motilin-induced gastric phase III is a hunger signal from GIT in man. PMID- 25539674 TI - Early effect of screening programmes on incidence and mortality rates of colorectal cancer. PMID- 25539672 TI - Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry. AB - BACKGROUND: Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. METHODS: We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008-2010 and 2011-2013). Durability of successful treatment and progression to OAC were also evaluated. RESULTS: 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). CONCLUSIONS: Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2-4% at 1 year in these high risk patients. TRIAL REGISTRATION NUMBER: ISRCTN93069556. PMID- 25539676 TI - [Pathophysiology of urticaria]. AB - Urticaria is a dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major mediator responsible for urticaria is histamine. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. It is a common practice to distinguish immunological and nonimmunological urticaria. Immunological urticaria is a hypersensitivity reaction mediated by antibodies and/or T-cells that results in mast cell activation. Although immunoglobulin (Ig) E-mediated type I hypersensitivity (HS) was long postulated to be the major immunological pathway associated with mast cell activation, interaction between IgEbound mast cells and allergens is unlikely to be the mechanism by which urticaria develops in most patients. It is now well established that urticaria may result from the binding of IgG auto antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50 % of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment. PMID- 25539675 TI - A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. AB - BACKGROUND AND AIMS: Helicobacter pylori is the causative agent of gastric diseases and the main risk factor in the development of gastric adenocarcinoma. In vitro studies with this bacterial pathogen largely rely on the use of transformed cell lines as infection model. However, this approach is intrinsically artificial and especially inappropriate when it comes to investigating the mechanisms of cancerogenesis. Moreover, common cell lines are often defective in crucial signalling pathways relevant to infection and cancer. A long-lived primary cell system would be preferable in order to better approximate the human in vivo situation. METHODS: Gastric glands were isolated from healthy human stomach tissue and grown in Matrigel containing media supplemented with various growth factors, developmental regulators and apoptosis inhibitors to generate long-lasting normal epithelial cell cultures. RESULTS: Culture conditions were developed which support the formation and quasi indefinite growth of three dimensional (3D) spheroids derived from various sites of the human stomach. Spheroids could be differentiated to gastric organoids after withdrawal of Wnt3A and R-spondin1 from the medium. The 3D cultures exhibit typical morphological features of human stomach tissue. Transfer of sheared spheroids into 2D culture led to the formation of dense planar cultures of polarised epithelial cells serving as a suitable in vitro model of H. pylori infection. CONCLUSIONS: A robust and quasi-immortal 3D organoid model has been established, which is considered instrumental for future research aimed to understand the underlying mechanisms of infection, mucosal immunity and cancer of the human stomach. PMID- 25539677 TI - [Interest of allergy tests in urticaria]. AB - Urticaria is a common skin disease that may affect 20 % of the general population. Most of the time, urticaria is an acute disorder that rarely can be chronic. The difficulty in urticaria is not the clinical diagnosis because the rash is characteristic, but the underlying causes and treatment that result. Urticaria is a benign disease when chronic and potentially dangerous when acute and associated with allergy. This allergy risk, needs an allergy exploration, based on skin tests and / or specific IgE assays. Because allergy is unusual in chronic urticaria, no allergy tests should be performed. By contrast, these tests must be undertaken in case of acute urticaria with a strong suspicion of IgE mediated reaction because of the risk of severe anaphylaxis in case of allergenic re-exposure. PMID- 25539678 TI - [Inducible urticaria and chronic spontaneous urticaria]. AB - In the recently published 2013 revision of the guidelines of urticaria, chronic urticaria (CU) gathers chronic spontaneous urticaria (CSU) and inducible urticaria (IU), and excludes pseudourticarial rashes with more than 24h-lasting rash or more than 72h-lasting angioedema. Activity and psychosocial impact of the disease must be measured with validated scores such as Urticaria and Angioedema Activity Scores, Urticaria Control Test, CU-Q2OL, AE-QOL. Although an allergic cause is generaly absent in CU, pathomecanisms remain elusive even since the well known role of mast cell degranulation and the presence of autoantibodies anti FcRepsilonI or anti-IgE. Coagulation pathways may be involved, at least as an amplifying phenomenon. Mean duration of CU is 1 to 4 years, but many patients still have symptoms after 10 years, some predictive factors being known as severity, angioedema, a positive autologous serum test, inducible urticaria. Recommended routine diagnosic tests are validated provocation tests for IU (and cryoproteins for cold urticaria), blood cell count and CRP for CSU, since a thorough history and a normal detailed physical examination should avoid unnecessary tests. Management of CU has been improved by the off-label use of increased dosages of second generation anti- H1 antihistamines, but a subsequent therapeutic intensification may be necessary in some cases. Educational program may prevent this intensification. Independent studies evaluating available molecules are needed, along with more fundamental research studies. PMID- 25539679 TI - [Systemic urticaria in 2014]. AB - Systemic urticaria are defined as urticaria, most often chronic, associated with systemic diseases. At present time, urticarial vasculitis and neutrophilic urticarial dermatosis associated to autoinflammatory syndromes are not considered to be subtypes of chronic spontaneous urticaria due to their distinctly clinical and histological characteristics as well different pathomechanisms. Sometimes, chronic urticaria is associated to thyroid autoimmunity. However, the majority of cases of chronic spontaneous urticaria have no discernible cause and further investigations are not necessary, as already suggested by some authors and French consensus conference more than 10 years ago. PMID- 25539680 TI - [Angioedema and urticaria]. AB - Angioedema (AE) is the clinical expression of urticaria (U) which occurs when urticaria is located within the subcutis. It is a syndrome characterized by a sudden and limited subcutaneous and/or submucous swelling. The updated classification of urticaria distinguishes acute and chronic urticaria. Chronic urticaria is spontaneous (CSU) or inducible (CIU). Angioedema in chronic urticaria is rarely allergic, but most of the time caused by a non-specific histamine release from activated mast-cell (non IgE mediated reaction). Angioedemas are recurrent, concomitant or not with wheals. They appear skin coloured, sometimes slightly rosy, non-inflammatory, and more painful than itchy. They are transient, ephemeral, migrant, last most of the time a few hours (< 24 or 48h) and disappear without after-effects. They are considered "deep urticaria" and wheals "superficial urticaria". When AE or wheals last more than 6 weeks (with or without free intermission), it is called chronic urticaria. Angioedema can be elicited or worsened by physical factors (cold urticaria, exercise, heat, solar, vibratory, aquagenic, delayed pressure urticaria...) and /or drugs (as aspirin, nonsteroid anti-inflammatory drugs, morphine, antibiotics...). The treatment of histaminergic angioedemas of chronic urticaria is based on modern second generation antihistamines (anti H1). In allergic acute urticaria only, additional treatment for anaphylaxis can be used if needed (grade 2 to 4). In chronic urticaria, steroids should be avoided : they can make symptoms worse and long-lasting because of corticosteroid dependence. PMID- 25539681 TI - Freiburg Questionnaire of linguistic pragmatics (FQLP): psychometric properties based on a psychiatric sample. AB - BACKGROUND: Asperger's Syndrome (AS) is an autism spectrum disorder that is characterized by significant difficulties in social interaction and nonverbal communication, and restricted and repetitive patterns of behavior and interests. Difficulties with respect to pragmatic speech, reading emotional and social cues, differentiating between fact and fiction, and taking into account the influence of context on a statement are commonly described features. However, hitherto established questionnaires did not focus on these symptoms. METHODS: In this study we present a short (11 questions) questionnaire which focuses on self-rated pragmatic speech abilities, the Freiburg Questionnaire of linguistic pragmatics (FQLP). Psychometric properties of the questionnaire were explored in a sample of 57 patients with Asperger's Syndrome, 66 patients with other psychiatric disorders, and a convenience sample of 56 people. RESULTS: Reliability analysis showed a high Cronbach's alpha. Strong correlations could be demonstrated for the FQLP with the Autism Quotient and the Empathy Quotient. Concerning divergent validity a moderate correlation was found between the FQLP and self-rated symptoms of personality disorders. No significant correlation was found between the FQLP and the vocabulary skills. The receiver operating characteristics curve showed an excellent diagnostic accuracy of the FQLP (.97). CONCLUSIONS: As the control group consisted of people without mental disorder and patients with different psychiatric disorders, the results indicate that the construct examined by the FQLP is quite specific to the peculiarities of AS. The FQLP is a reliable, brief and valid instrument. First results regarding sensitivity and specificity are highly promising. PMID- 25539684 TI - Are special read alignment strategies necessary and cost-effective when handling sequencing reads from patient-derived tumor xenografts? AB - BACKGROUND: Patient-derived tumor xenografts in mice are widely used in cancer research and have become important in developing personalized therapies. When these xenografts are subject to DNA sequencing, the samples could contain various amounts of mouse DNA. It has been unclear how the mouse reads would affect data analyses. We conducted comprehensive simulations to compare three alignment strategies at different mutation rates, read lengths, sequencing error rates, human-mouse mixing ratios and sequenced regions. We also sequenced a nasopharyngeal carcinoma xenograft and a cell line to test how the strategies work on real data. RESULTS: We found the "filtering" and "combined reference" strategies performed better than aligning reads directly to human reference in terms of alignment and variant calling accuracies. The combined reference strategy was particularly good at reducing false negative variants calls without significantly increasing the false positive rate. In some scenarios the performance gain of these two special handling strategies was too small for special handling to be cost-effective, but it was found crucial when false non synonymous SNVs should be minimized, especially in exome sequencing. CONCLUSIONS: Our study systematically analyzes the effects of mouse contamination in the sequencing data of human-in-mouse xenografts. Our findings provide information for designing data analysis pipelines for these data. PMID- 25539683 TI - Life as an evacuee after the Fukushima Daiichi nuclear power plant accident is a cause of polycythemia: the Fukushima Health Management Survey. AB - BACKGROUND: The Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster forced people to evacuate their hometowns. Many evacuees from the government-designated evacuation zone were forced to change their lifestyle, diet, exercise, and other personal habits. The Comprehensive Health Check (CHC), 1 of 4 detailed surveys of The Fukushima Health Management Survey (FHMS), was implemented to support the prevention of lifestyle-related disease. The aim of this study was to analyze changes in red blood cell count (RBC), hemoglobin (Hb) levels, and hematocrit (Ht) levels by comparing data from the medical health checkup before and after the disaster in individuals who were 40 years old or older. METHODS: Subjects in this study were Japanese men and women living in the vicinity of the Fukushima Daiichi Nuclear Power Plant in Fukushima prefecture. Annual health checkups with a focus on metabolic syndrome for insured persons/dependents aged 40 or older by Health Care Insurers have been conducted since 2008. All analyses in this study were limited to men and women aged 40-90 years. Changes in RBC, Hb levels, Ht levels, and prevalence of polycythemia before and after the disaster were compared. RESULTS: First, RBC, Hb, and Ht significantly increased in both men and women evacuees. The evacuation was significantly associated with increased Hb levels after adjustment for age, gender, smoking status, excess ethanol intake, BMI, and baseline Hb level (beta = 0.16, p < 0.001). Furthermore, the prevalence of polycythemia stratified by smoking status or obesity also increased in the evacuee group. CONCLUSIONS: To our knowledge, this is the first report revealing that the evacuation was associated with the risk of polycythemia. This information could be very important for periodic health checkup and lifestyle recommendations for evacuees in the future. PMID- 25539685 TI - A model of multisecond timing behaviour under peak-interval procedures. AB - In this study, the authors developed a fundamental theory of interval timing behaviour, inspired by the learning-to-time (LeT) model and the scalar expectancy theory (SET) model, and based on quantitative analyses of such timing behaviour. Our experiments used the peak-interval procedure with rats. The proposed model of timing behaviour comprises clocks, a regulator, a mixer, a response, and memory. Using our model, we calculated the basic clock speeds indicated by the subjects' behaviour under such peak procedures. In this model, the scalar property can be defined as a kind of transposition, which can then be measured quantitatively. The Akaike information criterion (AIC) values indicated that the current model fit the data slightly better than did the SET model. Our model may therefore provide a useful addition to SET for the analysis of timing behaviour. PMID- 25539682 TI - The use of genome wide association methods to investigate pathogenicity, population structure and serovar in Haemophilus parasuis. AB - BACKGROUND: Haemophilus parasuis is the etiologic agent of Glasser's disease in pigs and causes devastating losses to the farming industry. Whilst some hyper virulent isolates have been described, the relationship between genetics and disease outcome has been only partially established. In particular, there is weak correlation between serovar and disease phenotype. We sequenced the genomes of 212 isolates of H. parasuis and have used this to describe the pan-genome and to correlate this with clinical and carrier status, as well as with serotype. RESULTS: Recombination and population structure analyses identified five groups with very high rates of recombination, separated into two clades of H. parasuis with no signs of recombination between them. We used genome-wide association methods including discriminant analysis of principal components (DAPC) and generalised linear modelling (glm) to look for genetic determinants of this population partition, serovar and pathogenicity. We were able to identify genes from the accessory genome that were significantly associated with phenotypes such as potential serovar specific genes including capsule genes, and 48 putative virulence factors that were significantly different between the clinical and non clinical isolates. We also show that the presence of many previously suggested virulence factors is not an appropriate marker of virulence. CONCLUSIONS: These genes will inform the generation of new molecular diagnostics and vaccines, and refinement of existing typing schemes and show the importance of the accessory genome of a diverse species when investigating the relationship between genotypes and phenotypes. PMID- 25539686 TI - Real-time sonoelastography as novel follow-up method in Achilles tendon surgery. AB - PURPOSE: To evaluate the sonoelastographic features of Achilles tendon healing after percutaneous treatment using real-time sonoelastography, a new tool able to quantify deformation in biological tissues. METHODS: Patients with atraumatic Achilles tendon ruptures, treated with a percutaneous technique, were assessed. Sonoelastographic evaluations were performed at the myotendinous junction, tendon body/lesion site and osteotendinous junction, both for the operated and contralateral side, at 40 days, 6 months and 1 year after surgery. Using standard regions of interest, the "strain index" (SI) was calculated as an indicator of tendon elasticity. Clinical outcomes were assessed by the ATRS questionnaire at 6 months and 1 year post-operatively and correlated with sonoelastographic findings. Sixty healthy tendons from 30 volunteers were used to provide a healthy control range. RESULTS: Twenty-five patients were recruited for this study. The SI in treated tendons showed progressive stiffening over time, especially at myotendinous junction and at the site of the sutured lesion, resulting in significantly higher stiffness than both the contralateral tendon and healthy volunteers. Peak thickness of treated tendons occurred at 6 months, with a tendency to reduce at 1 year, while never achieving a normal physiological state. Greatest remodelling was seen at the lesion site. The contralateral tendon showed significant thickening at the myotendinous and osteotendinous junctions. The SI of the contralateral tendon was found to be stiffer than physiological values found in the control group. ATRS score improved significantly between 6 months and 1 year, being negatively correlated with the SI (p < 0.001). CONCLUSION: RTSE showed that operatively treated Achilles tendons become progressively stiffer during follow-up, while the ATRS score improved. From a biomechanical point of view, at 1 year after surgery Achilles tendons did not show a "restitutio ad integrum". Real-time sonoelastography provides more qualitative and quantitative details in the diagnostics and follow-up of Achilles tendon conditions as the post-operative evolution of the repairing tissue. LEVEL OF EVIDENCE: Diagnostic and therapeutic study, Level III. PMID- 25539688 TI - Is it meaningful to compare the difference in condyle widths between men and women? PMID- 25539687 TI - Stress distribution of the patellofemoral joint in the anatomic V-shape and curved dome-shape femoral component: a comparison of resurfaced and unresurfaced patellae. AB - PURPOSE: Whether to resurface the patella in knee replacement remains a controversial issue. The geometrical design of the trochlear groove in the femoral component could play an important role in determining the stress distribution on the patellofemoral joint, but this has not been sufficiently reported on. This study attempted to determine the effect of implant design on contact mechanics by means of a finite element method. METHODS: Two designs, an anatomical V-shape design (VSD) and a dome-shape design (DSD), for the anterior trochlear surface in a contemporary femoral component were chosen for examining the contact characteristics. The use and absence of patella resurfacing was simulated. The stress and strain distribution on the patellar bone and the polyethylene component were calculated for comparison. RESULTS: Without patellar resurfacing, the maximal compressive strain in the patellar bone in the VSD model was about 20 % lower than the DSD model. On the other hand, with resurfacing, the maximal strain for the VSD model was 13.3 % greater than for DSD. Uneven stress distribution at the bone-implant interface was also noted for the two designs. CONCLUSION: The femoral component with a V-shape trochlear groove reduced the compressive strain on the unresurfaced patella. If resurfacing the patella, the femoral component with a curved domed-shape design might reduce the strain in the remaining patellar bone. Uneven stress could occur at the bone-implant interface, so design modifications for improving fixation strength and medialization of the patellar button would be helpful in reducing the risk of peg fracture or loosening. LEVEL OF EVIDENCE: III. PMID- 25539689 TI - Surgeons' perceptions of transanal endoscopic microsurgery using minilaparoscopic instruments in a simulator: the thinner the better. AB - BACKGROUND: Several issues have limited the widespread adoption of transanal endoscopic microsurgery (TEM). The need for specialized equipment and the steep learning curve represent one of them. To operate on within a 4-cm diameter, rectoscope represents a major technical challenge. However, minilaparoscopic surgery has been introduced to reduce invasiveness and abdominal wall trauma. In TEM, instrument miniaturization may lead to technique optimization. We hypothesized that visualization and maneuverability during TEM performed with 3 mm minilaparoscopic instruments would be superior to TEM performed with conventional 5-mm instruments. METHODS: Eighteen general and colorectal surgeons with experience with TEM under ten cases were recruited. Two tasks should be accomplished using the TEO((r))-Neoderma simulator. First, using conventional 5 mm TEO((r)) curved-tip instruments, a "polypoid lesion" should be excised. Next, closure of the "rectal" defect should be undertaken. In the second part, the same participants repeated the same excision/closure tasks using 3-mm minilaparoscopic instruments. After tasks conclusion, participants fulfilled an evaluation questionnaire with seven questions regarding visualization and maneuverability when using 3-mm compared to 5-mm instruments. RESULTS: For each one of the seven questions in the questionnaire, the score results were significantly higher for the 3-mm instruments indicating that performance with the 3-mm minilaparoscopic instruments in the TEO simulator was in all cases between "better than expected" and "much better than expected." Appropriateness of the diameter of the minilaparoscopic instruments was the best evaluated parameter. The question addressing the ease of performing the tasks in the simulator presented the lowest mean score. CONCLUSIONS: The perceptions of participating surgeons indicated that there is better visualization and maneuverability during basic transanal endoscopic microsurgery tasks conducted in a simulator using 3-mm minilaparoscopic instruments when compared to conventional 5-mm instruments. PMID- 25539690 TI - Development of an arm support system to improve ergonomics in laparoscopic surgery: study design and provisional results. AB - BACKGROUND: Laparoscopic surgery (LS) induces physical stress to the surgeon that is associated with an increased prevalence of musculoskeletal pain and injury in the shoulder-neck region. The aim of this research project is to develop an arm support system (ASsyst) that reduces physical stress and is applicable to various laparoscopic interventions and operation room settings. METHODS: A systematic approach to develop an ASsyst started in October 2012 consisting of five consecutive steps. In step 1, 14 laparoscopic interventions were observed using subjective and objective measures to determine key indicators for the conception of an ASsyst in LS. In step 2, an expert workshop was held to find and evaluate solutions to generate concepts for a support system based on the results of step 1 and general methods. During the third step, prototypes of ASsyst were tested in an experimental setting. Steps 4 and 5 are currently in process and include the final development of the ASsyst using the most promising concept for the evaluation during simulated LS. RESULTS: Increased levels of physical stress were found in LS. Asymmetric strains were common. Three prototypes of ASsyst emerged from step 1 and 2. These prototypes were a cable construction with a noose for the lower arm, a support from below the elbow and a pneumatic vest supporting the upper arm. The experimental testing of these prototypes demonstrated reduced physical stress when compared to the unsupported environment. The support from below the elbow seemed to be the most practical in terms of implementation in various operation room settings and acceptance by surgeons. Step 4 and 5 are still in process. CONCLUSIONS: Ergonomic problems have been identified in LS that could be addressed by an ASsyst. The concept of supporting the elbow from below has been found to be the most promising approach. PMID- 25539691 TI - Early post-operative weight loss after laparoscopic sleeve gastrectomy correlates with the volume of the excised stomach and not with that of the sleeve! Preliminary data from a multi-detector computed tomography-based study. AB - BACKGROUND: Pre- and post-operative stomach volumes can be important determinants for effectiveness of laparoscopic sleeve gastrectomy (LSG) in causing weight loss. There is little existing data on the volumes of stomach preoperatively and that excised during LSG. This study was designed to evaluate the change in gastric volume after LSG using multi-detector CT and to correlate it with early post-operative weight loss. METHODS: Twenty consecutive patients with BMI >= 40 kg/m(2) and medical comorbidities underwent LSG between October 2011 and October 2013 and were analysed prospectively. The pre-operative stomach volume was measured by MDCT done 1-3 days before the surgery. LSG was performed in the standard manner using a 36F bougie. The volume of excised stomach was measured by distending the specimen with saline. MDCT of the upper abdomen was repeated 3 months postoperatively to calculate the gastric sleeve volume. Weight loss and resolution of comorbidities were documented. RESULTS: The mean pre-operative weight of patients was 123.90 kg, and the mean pre-operative stomach volume on MDCT was 1,067 ml. The stomach volume on pre-operative MDCT correlated with pre operative weight and BMI. The mean volume of the excised stomach was 859 ml when measured by distension of the specimen and 850 ml on MDCT. After 3 months post surgery, the mean volume of gastric sleeve on MDCT was 217 ml, and the mean weight of the patients was 101.22 kg. The volume of the excised stomach calculated by MDCT correlated with the weight loss achieved 3 months postoperatively. However, no correlation was seen between the gastric sleeve volume 3 months postoperatively and weight loss during this period. CONCLUSIONS: MDCT is a good method to measure gastric volume before and after LSG. Early post operative weight loss (3 months) correlates well with the volume of the excised stomach but not with that of the gastric sleeve. PMID- 25539692 TI - Comprehensive complication index for NOTES procedures: results from a randomized controlled trial and comparison to published NOTES complication data. AB - OBJECTIVE: This investigation uses the comprehensive complication index (CCI) to compare complications after natural orifice transluminal endoscopic surgery (NOTES) procedures. BACKGROUND: NOTES procedures are developed to miniaturize surgical trauma. NOTES publications inconsistently report complications. The CCI improves reporting of complications. METHODS: The CCI is calculated using complication data from a single center, double blind, randomized controlled trial comparing transvaginal [transvaginal cholecystectomy (TVC), N = 41] and conventional laparoscopic cholecystectomy (CLC, N = 51). Complications are assessed using the classification of surgical complications (CSC). Two different scenarios are applied to the CSC for definition of complications with an emphasis on minor complications. CSC data are fed into the free online CCI-calculator. The CCIs from complication data from other NOTES reports are calculated accordingly and compared to our results. RESULTS: The CCI allows easy indexing of complications with or without a CSC table. For scenario I, the mean CCI of CLC versus TVC is 3.3 (+/- 6.3; SD) versus 3.5 (+/- 6.4; n.s.) and for scenario II it is 7.6 (+/- 6.4) versus 6.5 (+/- 7.0; n.s.). The difference of the mean between the two scenarios is highly significant (p < 0.000). The mean CCIs of both groups and scenarios are below the CCI of 8.7 for a grade I CSC complication. Similar calculation of CCIs from other NOTES publications yields mean CCIs below 8.7 for the surgical procedures reported. CONCLUSION: The CCI results in a single, easily comparable complication index for surgical procedures whereas the CSC yields tabular results. A significant difference in interpretation occurs with variation in definition of complications. Average CCIs below a value of 10 describe low complication rates. Authors need to describe their definition of complications if using the CSC and the CCI. More emphasis should be given to reporting of minor complications. The use of the CCI for NOTES procedures will enable international comparison. PMID- 25539693 TI - Surgeons and non-surgeons prefer haptic feedback of instrument vibrations during robotic surgery. AB - BACKGROUND: Clinical robotic surgery systems do not currently provide haptic feedback because surgical instrument interactions are difficult to measure and display. Our laboratory recently developed a technology that allows surgeons to feel and/or hear the high-frequency vibrations of robotic instruments as they interact with patient tissue and other tools. Until now, this type of feedback had not been carefully evaluated by users. METHODS: We conducted two human subject studies to discover whether surgeons and non-surgeons value the addition of vibration feedback from surgical instruments during robotic surgery. In the first experiment, 10 surgeons and 10 non-surgeons (n = 20) used an augmented Intuitive da Vinci Standard robot to repeatedly perform up to four dry-lab tasks both with and without haptic and audio feedback. In the second experiment, 68 surgeons and 26 non-surgeons (n = 94) tested the same robot at a surgical conference: each participant spent approximately 5 min performing one or two tasks. RESULTS: Almost all subjects in both experiments (95 and 98 %, respectively) preferred receiving feedback of tool vibrations, and all subjects in the second experiment thought it would be useful for surgeons to have the option of such feedback. About half of the subjects (50, 60 %) preferred haptic and audio feedback together, and almost all the rest (45, 35 %) preferred haptic feedback alone. Subjects stated that the feedback made them more aware of tool contacts and did not interfere with use of the robot. There were no significant differences between the responses of different subject populations for any questions in either experiment. CONCLUSIONS: This study illustrates that both surgeons and non-surgeons prefer instrument vibration feedback during robotic surgery. Some participants found audio feedback useful but most preferred haptic feedback overall. This strong preference for tool vibration feedback indicates that this technology provides valuable tactile information to the surgeon. PMID- 25539694 TI - Total inverse transgastric resection with transoral specimen removal. AB - BACKGROUND: Laparoscopic local excision is accepted for gastrointestinal stromal tumors (GIST) and benign lesions of the stomach. Yet, tumors at the gastroesophageal junction, on the posterior wall, or in the distal antrum are difficult to approach. Such tumors often must be exposed via gastrotomy or using a rendezvous maneuver. Our method of total intragastric laparoscopic resection using 'pneumogastrum', rigid laparoscope, and conventional laparoscopic instruments is described in an intuitive video. METHODS: Two cases of total inverse transgastric resection involved resection of a submucosal GIST, one at the front wall of the cardia and the other on the posterior wall of the antrum. The third case required excision of a large prepyloric cystic lesion leading to a gastric outlet stenosis. After insertion of three trocars under laparoscopic control, a further trocar was introduced into the stomach and 'pneumogastrum' was established. Two additional 5-mm trocars were intragastrally placed. Intragastric endoscopy with a rigid optic provided an excellent view. The tumor was exposed resected with a linear stapler. The specimen was inserted into an Endo PouchTM which was sutured to an orally inserted gastric tube. The Endo PouchTM was gently pulled transorally. After removal of the intragastric trocars, the entrance points were laparoscopically closed. RESULTS: From the first and second cases, we retrieved GIST tumors. In the third case, we retrieved a gastritis cystica profunda. Postoperative course was uneventful. CONCLUSIONS: Gastric GIST should be resected laparoscopically if negative margins are safely achieved regardless of its size. Tumors at the frontwall and exophytic backwall GIST are addressed by laparoscopic wedge resection. Tumors at the gastrojejunal junction, in the prepyloric region, and fundus as well as submucous GIST of the gastric backwall are best approached by intragastric laparoscopic resection. Transoral specimen retrieval is an interesting option in smaller tumors. PMID- 25539695 TI - Efficacy of peroral endoscopic myotomy (POEM) in the treatment of achalasia: a systematic review and meta-analysis. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) is an evolving therapeutic modality for achalasia. We aim to determine efficacy of POEM for the treatment of achalasia and compare it with laparoscopic Heller's myotomy (LHM). MATERIALS AND METHODS: Systematic review and meta-analyses was conducted on 19 studies using POEM for achalasia. Pubmed, Medline, Cochrane, and Ovid databases, were searched using the terms 'achalasia', 'POEM', 'peroral endoscopic myotomy', 'per oral endoscopic myotomy', and 'per-oral endoscopic myotomy'. Reduction in Eckhart's score and lower esophageal sphincter (LES) pressure were the main outcome measures. RESULTS: A total of 1,045 patients underwent POEM in 29 studies. Ninety patients undergoing POEM was compared with 160 undergoing LHM in five studies. Nineteen and 14 studies, respectively, evaluated for Eckhart's score and LES pressure. There was significant reduction in Eckhart's score and LES pressure with effect sizes of -7.95 (p < 0.0001) and -7.28 (p < 0.0001), respectively. There was significant heterogeneity among the studies [(Q = 83.06; I (2) = 78.33 %; p < 0.0001) for Eckhart's score and (Q = 61.44; I (2) = 75.68 %; p < 0.0001) for LES pressure]. There were no differences between POEM and LHM in reduction in Eckhart's score, post-operative pain scores and analgesic requirements, length of hospital stay, adverse events, and symptomatic gastroesophageal reflux/reflux esophagitis. Operative time was significantly lower for POEM. CONCLUSIONS: POEM is effective for achalasia and has similar outcomes as LHM. Multicenter randomized trials need to be conducted to further compare the efficacy and safety of POEM between treatment naive achalasia patients and those who failed treatment. PMID- 25539697 TI - Deliberate practice enhances quality of laparoscopic surgical performance in a randomized controlled trial: from arrested development to expert performance. AB - BACKGROUND: This study investigated whether deliberate practice leads to an increase in surgical quality in virtual reality (VR) laparoscopic cholecystectomies (LC). Previous research has suggested that sustained DP is effective in surgical training. METHODS: Fourteen residents were randomized into deliberate practice (n = 7) or control training (n = 7). Both groups performed ten sessions of two VR LCs. Each session, the DP group was assigned 30 min of DP activities in between LCs while the control group viewed educational videos or read journal articles. Performance was assessed on speed and dexterity; quality was rated with global (GRS) and procedure-specific (PSRS) rating scales. All participants then performed five porcine LCs. RESULTS: Both groups improved over 20 VR LCs in time, dexterity, and global rating scales (all p < 0.05). After 20 LCs, there were no differences in speed or dexterity between groups. The DP group achieved higher quality of VR surgical performance than control for GRS (26 vs. 20, p = 0.001) and PSRS (18 vs. 15, p = 0.001). For VR cases, DP subjects plateaued at GRS = 25 after ten cases and control group at GRS = 20 after five cases. At completion of VR training, 100 % of the DP group reached target quality of performance (GRS >= 21) compared with 30 % in the control group. There were no significant differences for improvements in time or dexterity over five porcine LCs. CONCLUSION: This study suggests that DP leads to higher quality performance in VR LC than standard training alone. Standard training may leave individuals in a state of "arrested development" compared with DP. PMID- 25539696 TI - Laparoscopic surgery minimizes the release of circulating tumor cells compared to open surgery for hepatocellular carcinoma. AB - BACKGROUND: The aim of this study was to determine whether tumor manipulation enhances cancer cell release from the primary tumor in HCC patients and which surgical approach, open surgery or laparoscopic resection, is superior with respect to preventing tumor cells from scattering in the blood. METHODS: A total of 26 HCC patients were prospectively randomized to receive either open surgery (n = 14) or laparoscopic surgery (n = 12). Blood samples were obtained at three time points: preoperative, postoperative, and 24 h after surgery. The CD45( )/CD44(+)/CD90(+) cells were obtained and counted using quantitative flow cytometry. The serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF-alpha) were also compared between the two groups. RESULTS: There was no significant difference between the laparoscopic and open groups in terms of patient characteristics. The levels of CCSCs increased immediately after surgical manipulation, and the laparoscopy group released fewer tumor cells into the blood stream. The amount of CCSCs in both groups decreased to reach a similar level 24 h after surgery. Both IL-6 and IL-8 increased after surgery, and the mean postoperative increases in IL-6 and IL-8 serum levels were significantly less in the laparoscopic group than in the open group. The TNF alpha levels showed no differences at any time point. CONCLUSIONS: Our results showed that patients with laparoscopic surgery have lower IL-6, IL-8 secretion and less CTCs, which may suggest an advantage by restricting CTCs release and a preserved immune response. Further studies are needed to investigate the relationship between the number of CCSCs after surgery and long-term survival rates. PMID- 25539698 TI - Variation of outcome and charges in operative management for diverticulitis. AB - BACKGROUND: Outcomes after surgery for diverticulitis are of continued interest to improve quality of care. The aim of this study was to assess variations in mortality, length of stay, and patient charges between geographic regions of the United States. METHODS: A retrospective analysis of the Nationwide Inpatient Sample database was performed. Adults with diverticulitis who underwent laparoscopic or open segmental colectomy were identified using ICD-9 codes. Subset analyses were performed by state and then compared. Outcomes included mortality, length of stay (LOS), and total charges. Results were adjusted for age, race, gender, findings of peritonitis, stoma placement, Charlson comorbidity index, and insurance status on multivariate analysis. RESULTS: 148,874 patients underwent segmental colectomy for diverticulitis from 1998 to 2010. Using California as the comparison state and after adjusting for covariates, in hospital mortality was significantly higher in the State of New York (OR 1.32; 95 % CI 1.13-1.55; P < 0.05) and Mississippi (OR 2.84; 95 % CI 1.24-6.51, P < 0.02). Wisconsin had a significant lower mortality rate (OR 0.74; 95 % CI 0.59-0.94, P < 0.01). LOS was 1.4 days longer in New York and 0.54 days shorter in Wisconsin than in California (P < 0.01). Patients with age >40 years, findings of peritonitis, and without private insurance had higher in-hospital mortality and longer length of stay. Average hospital charges differed dramatically between the states in the observation period. The highest hospital charges occurred in California, Nebraska, and Nevada while lowest occurred in Maryland, Wisconsin and Utah. CONCLUSIONS: Patients who undergo surgical treatment for diverticulitis in the United States have high geographic variation in mortality, LOS, and hospital charges despite adjusting for demographic and socioeconomic factors. Further analysis should be performed to identify the causes of outlier regions, with the goal of improving and standardizing best practices. PMID- 25539699 TI - Case files of the Harvard medical toxicology fellowship: valacyclovir neurotoxicity and unintentional overdose. PMID- 25539700 TI - Mitral valve replacement after failed MitraClipTM therapy: report of two cases. AB - We report 2 cases of patients who were successfully treated surgically for remaining or recurrent mitral regurgitation after MitraClip (Abbott Vascular, Santa Clara, CA, USA) implantation. In one patient, intervention with MitraClip was indicated because of the extremely poor heart function and poor general status of the patient. However, the severe mitral insufficiency remained after the MitraClip treatment and valve replacement was required. In the other high risk patient, severe mitral regurgitation recurred 3 years after a successful MitraClip treatment due to infective endocarditis. Our experience suggests that some patients who are considered "high-risk" before MitraClip treatment might be reasonable candidates for a straight forward mitral valve surgery, even in the re intervention setting. We conclude that patients considered for MitraClip implantation should undergo detailed risk stratification, because we have to keep in mind that after failed clip implantation the perioperative risk increases and the chance of mitral repair decreases. PMID- 25539702 TI - Hand suture versus stapler for closure of loop ileostomy--a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: The aims of this study are to compare the 30-day rate of bowel obstruction for stapled vs. handsewn closure of loop ileostomy, and to further assess efficacy and safety for each technique by secondary endpoints such as operative time, rates of anastomotic leakage, and other post-operative complications within 30 days. METHODS: A systematic literature search (MEDLINE, The Cochrane Library, EMBASE and ISI Web of Science) was performed to identify randomized controlled trials (RCTs) comparing stapled and handsewn closure of loop ileostomy after low anterior resection. Random effects meta-analyses were calculated and presented as risk ratio (RR) and mean difference (MD) with corresponding 95 % confidence intervals. RESULTS: Forty publications were retrieved and 4 RCTs (649 patients) were included. There was methodological and clinical heterogeneity of included trials, but statistical heterogeneity was low for most endpoints. Stapler use significantly reduced the rate of bowel obstruction compared to hand-sewn closure (RR 0.53 [0.32, 0.88]; P = 0.01). The operation time was significantly lower for stapling compared to hand suture (MD 15.5 min [-18.4, 12.6]; P < 0.001). All other secondary outcomes did not show significant differences. CONCLUSIONS: This meta-analysis shows superiority of stapled closure of loop ileostomy compared to handsewn closure in terms of bowel obstruction rate and mean operation time. Other relevant complications such as anastomotic leakage are equivalent. Even so, both techniques are options with opposing advantages and disadvantages. PMID- 25539704 TI - Sorafenib-associated facial acneiform eruption. AB - INTRODUCTION: Sorafenib is an oral multikinase inhibitor that targets tumor cell angiogenesis and proliferation. Drug-associated cutaneous adverse events, such as alopecia and hand-foot skin reaction, occur frequently. Sorafenib-related side effects affecting hair, nails, and skin are summarized and the characteristics of sorafenib-treated patients who developed acneiform facial lesions are reviewed to present the clinical features of these individuals. CASE REPORT: A man with sorafenib-associated facial acneiform lesions mimicking those of chloracne is described. DISCUSSION: PubMed was used to search the following terms, separately and in combination: acne, acneiform eruption, chloracne, cutaneous adverse events, hepatocellular carcinoma, renal cell carcinoma, skin side effects, and sorafenib. Inclusion criteria for selecting papers to be reviewed included case reports and studies that described cutaneous and mucosal adverse side effects associated with sorafenib. All papers fulfilling inclusion criteria were reviewed and relevant manuscripts, along with their reference citations, were evaluated. Five patients-a woman with liver epithelioid hemangioendothelioma, three men with metastatic renal cell carcinoma, and a man with hepatocellular carcinoma-have developed sorafenib-associated facial acneiform eruption. The eruption typically occurred after 4 weeks of treatment at a dose of 400 mg twice daily. The lesions presented as either papules and pustules (2 patients) or, similar in appearance and distribution to chloracne, only open and closed comedones (3 patients). The sorafenib-associated facial acneiform eruption partially improved after initiating topical antibiotics, keratolytics, and/or retinoids; however, progressive improvement or resolution occurred after lowering the daily dose or discontinuation of sorafenib. CONCLUSIONS: Sorafenib-associated facial acneiform eruption is a rarely occurring cutaneous adverse event that has only been observed in five individuals. The skin lesions usually presented after 4 weeks of sorafenib (at a dose of 400 mg twice daily) treatment. The morphology and distribution of the lesions mimicked those of chloracne in three of the patients. Two of the patients also had other drug-related skin side effects. Topical acne directed therapy was only partially effective in clearing the lesions; lowering the dose or discontinuation of sorafenib resulted in progressive improvement or resolution of the facial acneiform eruption. PMID- 25539701 TI - Atrial fibrillation and long-term sports practice: epidemiology and mechanisms. AB - BACKGROUND: Lone atrial fibrillation (AF) is the most common arrhythmia of the heart and is considered to have a higher prevalence in athletes, especially in endurance sports. METHODS: We conducted an extensive literature research in pubmed using the key words s ports and atrial fibrillation. RESULTS: The majority of studies have methodological limitations due to different inclusion criteria, such as age, type of sport, training level as well as statistical bias. The inconsistency of data is reflected by the considerable range of AF occurrence, spanning from 0.3 to 12.8 %. CONCLUSIONS: We consider it reasonable to separate a study population into sedentary individuals, leisure time sportsmen/women and elite athletes. A distinction between the categories may be achieved through a combination of exercise history, capacity (e.g. MET hours/week, e.g. VO2max) and competitive results. Since there is a large span in the analyzed age groups (24 84 years), we claim that the focus should be laid upon the 45- to 65-year-olds due to a sound detection rate of true positives. Finally, we discuss ways to increase the detection rate of paroxysmal AF and comment on new therapeutic options. PMID- 25539705 TI - Silver nanoparticles impact phototrophic biofilm communities to a considerably higher degree than ionic silver. AB - Due to the significant increase in nanoparticle production and especially that of silver nanoparticles over the past decade, the toxicity of silver in both ionic (Ag(+)) and nanoparticulate (AgNPs) form must be studied in detail in order to understand their impact on natural ecosystems. A comparative study of the effect of AgNPs and ionic silver on two independent phototrophic biofilms was conducted in a rotating annular bioreactor (RAB) operating under constant conditions. The concentration of dissolved silver in the inlet solution was progressively increased every 4 days of exposure, from 0.1 to 100 MUg L(-1). In the course of the 40-day experiment, biofilm samples were collected to determine the evolution of biomass, chlorophyll-a, as well as photosynthetic and heterotrophic enzymatic activities in response to silver addition. Analysis of both dissolved and particulate silver allowed quantification of the distribution coefficient and uptake rate constants. The presence of both AgNPs and Ag(+) produced significant changes in the biofilm structure, decreasing the relative percentage of Diatomophyceae and Cyanophyceae and increasing the relative percentage of Chlorophyceae. The accumulation capacity of the phototrophic biofilm with respect to ionic silver and the corresponding distribution coefficients were an order of magnitude higher than those of the phototrophic biofilm with respect to AgNPs. Higher levels of AgNPs decreased the biomass from 8.6 +/- 0.2 mg cm(-2) for 0-10 MUg L(-1) AgNPs to 6.0 +/- 0.1 mg cm(-2) for 100 MUg L(-1) added AgNPs, whereas ionic silver did not have any toxic effect on the biofilm growth up to 100 MUg L( 1) of added Ag(+). At the same time, AgNPs did not significantly affect the photosynthetic activity of the biofilm surface communities compared to Ag(+). It can thus be hypothesized that negatively charged AgNPs may travel through the biofilm water channels, thereby affecting the whole biofilm structure. In contrast, positively charged Ag(+) is bound at the cell surfaces and EPS, thus blocking its further flux within the biofilm layers. On the whole, the phototrophic biofilm demonstrated significant capacities to accumulate silver within the surface layers. The main mechanism to avoid the toxic effects is metal complexation with exopolysaccharides and accumulation within cell walls, especially pronounced under Ag(+) stress. The significant AgNPs and Ag(+) uptake capacities of phototrophic biofilm make it a highly resistant ecosystem in silver polluted river waters. PMID- 25539707 TI - Coronary Revascularization Improves QT Dispersion in Patients with Chronic Coronary Artery Total Occlusion. AB - As an important parameter of cardiac functions, QT interval is usually irregular in patients with chronic coronary artery total occlusion (CTO). We sought to determine the effect of coronary revascularization (CRV) on QT interval dispersion in patients with CTO. To this end, we used electrocardiogram of 12 leads to record changes in the QT interval dispersion in 22 patients with CTO treated with percutaneous coronary intervention (PCI) and 24 patients treated with coronary artery bypass grafting (CABG). Our data showed that QTd and QTcd diminished markedly (P < 0.01) after PCI or CABG. No significant difference was observed between the postoperative groups (P > 0.05) or between PCI and CABG groups. We concluded that CRV could diminish QTd and QTcd in patients with CTO with no distinguishable differences with PCI and CABG procedures. Therefore, CRV can revitalize the existing functional myocardium and resume the myocardial electrophysiological functions in patients with CTO. PMID- 25539703 TI - Acute acalculous cholecystitis in the critically ill: risk factors and surgical strategies. AB - PURPOSE: Acute acalculous cholecystitis (AAC) is characterized by severe gallbladder inflammation without cystic duct obstruction. Critical illness and neurological deficits are often associated with AAC, and early radiologic imaging is necessary for the detection and timely treatment of AAC. In critically ill patients, effective surgical management is difficult. This review examines the three common surgical treatments for AAC (open cholecystectomy (OC), laparoscopic cholecystectomy (LC), or percutaneous cholecystostomy (PC)), their prevalence in current literature, and the perioperative outcomes of these different approaches using a large retrospective database. MATERIALS AND METHODS: This review examined literature gathered from PubMed and Google Scholar to select more than 50 sources with data pertinent to AAC; of which 20 are described in a summary table. Outcomes from our previous research and several updated results were obtained from the University HealthSystem Consortium (UHC) database. RESULTS: LC has proven effective in treating AAC when the risks of general anesthesia and the chance for conversion to OC are low. In critically ill patients with multiple comorbidities, PC or OC may be the only available options. Data in the literature and an examination of outcomes within a national database indicate that for severely ill patients, PC may be safer and met with better outcomes than OC for the healthier set of AAC patients. CONCLUSIONS: We suggest a three-pronged approach to surgical resolution of AAC. Patients that are healthy enough to tolerate LC should undergo LC early in the course of the disease. In critically ill patients, patients with multiple comorbidities, a high conversion risk, or who are poor surgical candidates, PC may be the safest and most successful intervention. PMID- 25539706 TI - Leaching of lead from new unplasticized polyvinyl chloride (uPVC) pipes into drinking water. AB - Unplasticized polyvinyl chloride (uPVC) pipes have been used in the premise plumbing system due to their high strength, long-term durability, and low cost. uPVC pipes, however, may contain lead due to the use of lead compounds as the stabilizer during the manufacturing process. The release of lead from three locally purchased uPVC pipes was investigated in this study. The effects of various water quality parameters including pH value, temperature, and type of disinfectant on the rate of lead release were examined. The elemental mapping obtained using scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) confirmed the presence of lead on the inner surfaces of the uPVC pipes and their surface lead weight percentages were determined. The leachable lead concentration for each pipe was determined using high strength acidic EDTA solutions (pH 4, EDTA = 100 mg/L). Lead leaching experiments using tap water and reconstituted tape water under static conditions showed that the rate of lead release increased with the decreasing pH value and increasing temperature. In the presence of monochloramine, lead release was faster than that in the presence of free chlorine. PMID- 25539708 TI - Epigallocatechin-3-gallate Sensitizes Human 786-O Renal Cell Carcinoma Cells to TRAIL-Induced Apoptosis. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent. Epigallocatechin-3-gallate (EGCG) is a polyphenolic constituent of green tea. In this study, potentiating effect of EGCG on TRAIL-induced apoptosis human renal carcinoma cell line 786-O which is relatively resistant to TRAIL was examined, and the possible mechanism was investigated. Here, we show that co-treatment with EGCG and TRAIL induced significantly more profound apoptosis in 786-O cells. Treatment of 786-O cells with EGCG and TRAIL downregulated c-FLIP, Mcl-1, and Bcl-2 proteins in a caspase-dependent pathway. Moreover, we found that pretreatment with NAC markedly inhibited the expression levels of c-FLIP, Mcl-1, and Bcl-2 downregulated by the combinatory treatment, suggesting that the regulating effect of EGCG on these above apoptosis-relevant molecules was partially mediated by generation of ROS. Taken together, the present study demonstrates that EGCG sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis by downregulation of c-FLIP, Mcl-1, and Bcl-2. PMID- 25539709 TI - A constitutive modeling interpretation of the relationship among carotid artery stiffness, blood pressure, and age in hypertensive subjects. AB - Aging has a profound influence on arterial wall structure and function. We have previously reported the relationship among pulse wave velocity, age, and blood pressure in hypertensive subjects. In the present study, we aimed for a quantitative interpretation of the observed changes in wall behavior with age using a constitutive modeling approach. We implemented a model of arterial wall biomechanics and fitted this to the group-averaged pressure-area (P-A) relationship of the "young" subgroup of our study population. Using this model as our take-off point, we assessed which parameters had to be changed to let the model describe the "old" subgroup's P-A relationship. We allowed elastin stiffness and collagen recruitment parameters to vary and adjusted residual stress parameters according to published age-related changes. We required wall stress to be homogeneously distributed over the arterial wall and assumed wall stress normalization with age by keeping average "old" wall stress at the "young" level. Additionally, we required axial force to remain constant over the cardiac cycle. Our simulations showed an age-related shift in pressure-load bearing from elastin to collagen, caused by a decrease in elastin stiffness and a considerable increase in collagen recruitment. Correspondingly, simulated diameter and wall thickness increased by about 20 and 17%, respectively. The latter compared well with a measured thickness increase of 21%. We conclude that the physiologically realistic changes in constitutive properties we found under physiological constraints with respect to wall stress could well explain the influence of aging in the stiffness-pressure-age pattern observed. PMID- 25539710 TI - Mitochondria-derived ROS bursts disturb Ca2+ cycling and induce abnormal automaticity in guinea pig cardiomyocytes: a theoretical study. AB - Mitochondria are in close proximity to the redox-sensitive sarcoplasmic reticulum (SR) Ca(2+) release [ryanodine receptors (RyRs)] and uptake [Ca(2+)-ATPase (SERCA)] channels. Thus mitochondria-derived reactive oxygen species (mdROS) could play a crucial role in modulating Ca(2+) cycling in the cardiomyocytes. However, whether mdROS-mediated Ca(2+) dysregulation translates to abnormal electrical activities under pathological conditions, and if yes what are the underlying ionic mechanisms, have not been fully elucidated. We hypothesize that pathological mdROS induce Ca(2+) elevation by modulating SR Ca(2+) handling, which activates other Ca(2+) channels and further exacerbates Ca(2+) dysregulation, leading to abnormal action potential (AP). We also propose that the morphologies of elicited AP abnormality rely on the time of mdROS induction, interaction between mitochondria and SR, and intensity of mitochondrial oxidative stress. To test the hypotheses, we developed a multiscale guinea pig cardiomyocyte model that incorporates excitation-contraction coupling, local Ca(2+) control, mitochondrial energetics, and ROS-induced ROS release. This model, for the first time, includes mitochondria-SR microdomain and modulations of mdROS on RyR and SERCA activities. Simulations show that mdROS bursts increase cytosolic Ca(2+) by stimulating RyRs and inhibiting SERCA, which activates the Na(+)/Ca(2+) exchanger, Ca(2+)-sensitive nonspecific cationic channels, and Ca(2+)-induced Ca(2+) release, eliciting abnormal AP. The morphologies of AP abnormality are largely influenced by the time interval among mdROS burst induction and AP firing, dosage and diffusion of mdROS, and SR-mitochondria distance. This study defines the role of mdROS in Ca(2+) overload-mediated cardiac arrhythmogenesis and underscores the importance of considering mitochondrial targets in designing new antiarrhythmic therapies. PMID- 25539711 TI - TNF-alpha increases endothelial progenitor cell adhesion to the endothelium by increasing bond expression and affinity. AB - Endothelial progenitor cells (EPCs) are a rare population of cells that participate in angiogenesis. To effectively use EPCs for regenerative therapy, the mechanisms by which they participate in tissue repair must be elucidated. This study focused on the process by which activated EPCs bind to a target tissue. It has been demonstrated that EPCs can bind to endothelial cells (ECs) through the tumore necrosis factor-alpha (TNF-alpha)-regulated vascular cell adhesion molecule 1/very-late antigen 4 (VLA4) interaction. VLA4 can bind in a high or low affinity state, a process that is difficult to experimentally isolate from bond expression upregulation. To separate these processes, a new parallel plate flow chamber was built, a detachment assay was developed, and a mathematical model was created that was designed to analyze the detachment assay results. The mathematical model was developed to predict the relative expression of EPC/EC bonds made for a given bond affinity distribution. EPCs treated with TNF-alpha/vehicle were allowed to bind to TNF-alpha/vehicle-treated ECs in vitro. Bound cells were subjected to laminar flow, and the cellular adherence was quantified as a function of shear stress. Experimental data were fit to the mathematical model using changes in bond expression or affinity as the only free parameter. It was found that TNF-alpha treatment of ECs increased adhesion through bond upregulation, whereas TNF-alpha treatment of EPCs increased adhesion by increasing bond affinity. These data suggest that injured tissue could potentially increase recruitment of EPCs for tissue regeneration via the secretion of TNF-alpha. PMID- 25539712 TI - Muscle metaboreflex activation during dynamic exercise evokes epinephrine release resulting in beta2-mediated vasodilation. AB - Muscle metaboreflex-induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies, we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia) a small but significant increase in vascular conductance occurred within the nonischemic areas (calculated as cardiac output minus hindlimb blood flow and termed nonischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex-induced release of epinephrine, resulting in beta2-mediated dilation. We measured NIVC and arterial plasma epinephrine levels in chronically instrumented dogs during rest, mild exercise (3.2 km/h), and MMA before and after beta-blockade (propranolol; 2 mg/kg), alpha1 blockade (prazosin; 50 MUg/kg), and alpha1 + beta-blockade. Both epinephrine and NIVC increased significantly from exercise to MMA: 81.9 +/- 18.6 to 141.3 +/- 22.8 pg/ml and 33.8 +/- 1.5 to 37.6 +/- 1.6 ml.min(-1).mmHg(-1), respectively. These metaboreflex-induced increases in NIVC were abolished after beta-blockade (27.6 +/- 1.8 to 27.5 +/- 1.7 ml.min(-1).mmHg(-1)) and potentiated after alpha1 blockade (36.6 +/- 2.0 to 49.7 +/- 2.9 ml.min(-1).mmHg(-1)), while alpha1 + beta blockade also abolished any vasodilation (33.7 +/- 2.9 to 30.4 +/- 1.9 ml.min( 1).mmHg(-1)). We conclude that MMA during mild dynamic exercise induces epinephrine release causing beta2-mediated vasodilation. PMID- 25539713 TI - Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. AB - Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P < 0.05). During the normoxic dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP (P < 0.05). The AT1aR CIH group showed significant decreases in FosB/DeltaFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/DeltaFosB expression in forebrain autonomic nuclei associated with CIH. PMID- 25539715 TI - Polyorchidism: two case reports and a review of the literature. AB - INTRODUCTION: Polyorchidism is a very rare anomaly that is defined by the presence of more than two testes. Although its presentation is primarily as triorchidism, cases of four testes have also been reported in the literature. CASE PRESENTATION: In this report, we describe color Doppler ultrasound findings in two cases. Patient 1 was a 37-year-old Arabic man with a scrotal mass and a double testicle in the right hemiscrotum visualized by ultrasound. Patient 2 was an 11-year-old Arabic boy with an inguinal mass resulted to be an additional testicle in the inguinal canal. The echogenic texture and vascular flow of supernumerary testicles in question were similar to those of the normal testicles; however, their size was smaller. After 3 years of follow-up, the tertiary testes in the two patients remained stable in both size and echogenicity. CONCLUSION: Ultrasound plays a crucial role in the evaluation of masses. Notably, inguinal or scrotal masses should not always be considered as lymph nodes or tumors. Indeed, a radiologist should always keep polyorchidism in mind when such masses are encountered. PMID- 25539716 TI - Adiposity markers and risk of coronary heart disease in patients with type 2 diabetes mellitus. AB - BACKGROUND: This cross-sectional study aimed to evaluating the association between body adiposity markers and high-risk of coronary heart disease (CHD) in patients with type 2 diabetes. METHODS: Recent adiposity markers [waist-to-height ratio, conicity index (C-index) and body adiposity index] and traditional markers [BMI, waist circumference and waist-to-hip ratio (WHR)] were measured. The 10 year risk of fatal CHD was estimated according to UKPDS risk engine scores. Patients were divided into high (CHD risk >=20%; n = 99) or low-moderate (CHD risk <20%; n = 321) risk groups. Multiple logistic regression models were performed to analyze associations between CHD risk (outcome) and adiposity markers. RESULTS: A total of 420 patients with type 2 diabetes (61.9 +/- 9.5 years; 53.5% females; HbA1c 7.6 +/- 1.6%) were evaluated. The high risk group had greater proportions of elevated C-index and BMI values than patients with low moderate risk. No between-group differences in other adiposity markers were observed. In multiple logistic regression models, only C-index values >=1.35 were associated with CHD risk >20% (OR = 1.69; 95% CI 1.03-2.78; P = 0.039) after adjusting for confounders (sedentary lifestyle, diabetic nephropathy, serum creatinine, and diabetes duration). The association between WHR and CHD risk did not hold in this sample. CONCLUSIONS: The C-index was the body adiposity marker best associated with high risk of fatal CHD in these patients with type 2 diabetes. PMID- 25539718 TI - The expression of epidermal growth factor-like domain 7 regulated by oxygen tension via hypoxia inducible factor (HIF)-1alpha activity. AB - OBJECTIVE: Hypoxia inducible factor-1alpha (HIF-1alpha) regulates many genes involved in angiogenesis during embryonic development. Epidermal growth factor like domain 7 (Egfl7) is a specific marker for human arterial endothelial cells that are in an activated state of proliferation, migration, and remodeling. This study evaluates the intricate relationship between HIF-1alpha and Egfl7 under both hyperoxia and hypoxia states. METHODS: The neonatal mice were exposed to either hyperoxia or hypoxia in order to detect the pulmonary and cardiac Egfl7 messenger RNA (mRNA) or protein expression regulated by oxygen tension in vivo by reverse transcriptase polymerase chain reaction or immunohistochemistry staining. Egfl7 expression in HIF-1alpha null pulmonary endothelial cells in hypoxia conditions and effects of overexpression or knockdown of HIF-1alpha on Egfl7 expression in human umbilical vein endothelial cells would be clarified in vitro by reverse transcriptase polymerase chain reaction and Western blot, respectively. RESULTS: Hyperoxia exposure significantly reduced Egfl7 expression in neonatal mice lungs by 36% compared with age-matched normoxia control mice (P < 0.05, n = 6). The pulmonary Egfl7 transcription levels were increased by 1.7- and 1.9-fold in 24 hours and by day 8 in hypoxia groups compared with the normoxia control values (P < 0.05, n = 6). The cardiac Egfl7 mRNA expression was significantly increased by 4.5-fold in the day 8 group compared with the normoxia control values (P < 0.05, n = 6). The expression of Egfl7 decreased significantly in the HIF-1alpha(-/-) endothelial cells (ECs), which was only 26% of wild-type HIF-1alpha(+/+) ECs (P < 0.05, n = 3). Hypoxia caused a mild but significant increase of Egfl7 expression in HIF-1alpha(+/+) ECs (P < 0.05). In vitro, overexpression of HIF-1alpha enhanced Egfl7 expression, whereas knockdown of HIF 1alpha reduced Egfl7 expression. CONCLUSIONS: Overexpression of HIF-1alpha enhanced Egfl7 expression, whereas knockdown of HIF-1alpha reduced Egfl7 expression. Egfl7 could be a HIF-1alpha responsive gene regulated by oxygen tension. PMID- 25539717 TI - Quantitative detection of free 24S-hydroxycholesterol, and 27-hydroxycholesterol from human serum. AB - BACKGROUND: Cholesterol metabolism is important for the maintenance of myelin and neuronal membranes in the central nervous system. Blood concentrations of the brain specific cholesterol metabolite 24S-hydroxysterol to the peripheral metabolite 27-hydroxycholesterol may be useful surrogate markers for neurodegenerative diseases including Alzheimer's disease, Huntington's disease, HIV-Associated Neurocognitive Disorders, and Multiple Sclerosis. However, current methods to isolate hydroxycholesterols are labor intensive, prone to produce variable extraction efficiencies and do not discriminate between free and esterfied forms of hydroxycholesterols. Since free hydroxycholesterols are the biologically active form of these sterols, separating free from esterfied forms may provide a sensitive measure to identify disease-associated differences in brain sterol metabolism. RESULTS: We found that average human serum concentrations were 12.3 +/- 4.79 ng/ml for free 24(s)-hydroxycholesterol and 17.7 +/- 8.5 ng/ml for 27-hydroxycholesterol. CONCLUSION: Serum measurements of these biologically active oxysterols may be useful surrogate measures for brain health in a variety of neurodegenerative conditions. PMID- 25539719 TI - New frontiers in oncology: biosimilar monoclonal antibodies for the treatment of breast cancer. AB - Trastuzumab is a highly successful monoclonal antibody (mAb) that has been used primarily for the treatment of HER2-positive breast cancer. Because of its success and its impending patent expiry in Europe in 2014, a number of copy versions of trastuzumab have been developed and are currently undergoing a comparability exercise for marketing authorization. Although biosimilar products have been approved in Europe since 2006, including two biosimilar mAbs of infliximab approved in 2013, the use of mAbs such as trastuzumab in the cancer setting has raised a number of new concerns. The requirements for the approval of biosimilar mAbs published by the EMA will be discussed and examined in the context of trastuzumab biosimilars to highlight potential controversies. PMID- 25539714 TI - Identifying continence options after stroke (ICONS): a cluster randomised controlled feasibility trial. AB - BACKGROUND: Urinary incontinence (UI) affects half of patients hospitalised after stroke and is often poorly managed. Cochrane systematic reviews have shown some positive impact of conservative interventions (such as bladder training) in reducing UI, but their effectiveness has not been demonstrated with stroke patients. METHODS: We conducted a cluster randomised controlled feasibility trial of a systematic voiding programme (SVP) for the management of UI after stroke. Stroke services were randomised to receive SVP (n = 4), SVP plus supported implementation (SVP+, n = 4), or usual care (UC, n = 4).Feasibility outcomes were participant recruitment and retention. The main effectiveness outcome was presence or absence of UI at six and 12 weeks post-stroke. Additional effectiveness outcomes included were the effect of the intervention on different types of UI, continence status at discharge, UI severity, functional ability, quality of life, and death. RESULTS: It was possible to recruit patients (413; 164 SVP, 125 SVP+, and 124 UC) and participant retention was acceptable (85% and 88% at six and 12 weeks, respectively). There was no suggestion of a beneficial effect on the main outcome at six (SVP versus UC: odds ratio (OR) 0.94, 95% CI: 0.46 to 1.94; SVP+ versus UC: OR: 0.62, 95% CI: 0.28 to 1.37) or 12 weeks (SVP versus UC: OR: 1.02, 95% CI: 0.54 to 1.93; SVP+ versus UC: OR: 1.06, 95% CI: 0.54 to 2.09).No secondary outcomes showed a strong suggestion of clinically meaningful improvement in SVP and/or SVP+ arms relative to UC at six or 12 weeks. However, at 12 weeks both intervention arms had higher estimated odds of continence than UC for patients with urge incontinence. CONCLUSIONS: The trial has met feasibility outcomes of participant recruitment and retention. It was not powered to demonstrate effectiveness, but there is some evidence of a potential reduction in the odds of specific types of incontinence. A full trial should now be considered. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN08609907, date of registration: 7 July 2010. PMID- 25539720 TI - Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) extract on human cancer cells. AB - BACKGROUND: Annona muricata (A. muricata) is widely distributed in Asia, Africa and South America. Different parts of this plant are used to treat several diseases in Cameroon. The aim of this study is to determine the in vitro anti proliferative effects and apoptotic events of A. muricata extracts on HL-60 cells as well as to quantify its phenols content. METHODS: The cell viability was measured by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay while the changes in morphology of HL-60 cells, membrane mitochondrial potential (MMP) and the cell cycle were used for assessment apoptosis induction. RESULTS: The results show that the concentration of phenols, flavonoids and flavonols in the extracts varied depending on the part of the plant. All the extracts tested inhibited the proliferation of HL-60 cells in a concentration dependent manner with IC50 varied from 6-49 MUg/mL. The growth inhibition of the cells by extracts was associated with the disruption of MMP, reactive oxygen species (ROS) generation and the G0/G1 cell arrest. CONCLUSION: These findings suggest that the extracts from A. muricata have strong antiproliferation potential and can induce apoptosis through loss of MMP and G0/G1 phase cell arrest. PMID- 25539721 TI - Liposomal delivery of nucleic acid-based anticancer therapeutics: BP-100-1.01. AB - INTRODUCTION: Antisense oligonucleotides, siRNA, anti-microRNA are designed to selectively bind to target mRNAs, and silence disease-causing or -associated proteins. The clinical development of nucleic acid drugs has been limited by their poor bioavailability. AREAS COVERED: This review article examines the strategies that have been utilized to improve the bioavailability of nucleic acids. The chemical modifications made to nucleic acids that have improved their resistance against nuclease degradation are briefly discussed. The design of cationic and neutral lipid nanoparticles that enable the systemic delivery of nucleic acids in vivo is reviewed, and the proof-of-concept evidence that intravenous administration of nucleic acids incorporated into lipid nanoparticles leads to decreased expression of target genes in humans. Preclinical results of the neutral BP-100-1.01 nanoparticle are highlighted. EXPERT OPINION: To further improve the clinical potential of nucleic acid cancer drugs, we predict research on the next generation of lipid nanoparticles will focus on: i) enhancing nucleic acid delivery to poorly vascularized tumors, as well as tumors behind the blood brain barrier; and ii) improving the accessibility of nucleic acids to the cytoplasm by enhancing endosomal escape of nucleic acids and/or reducing exocytosis of nucleic acids to the external milieu. PMID- 25539722 TI - Functional annotation of the Ophiostoma novo-ulmi genome: insights into the phytopathogenicity of the fungal agent of Dutch elm disease. AB - The ascomycete fungus Ophiostoma novo-ulmi is responsible for the pandemic of Dutch elm disease that has been ravaging Europe and North America for 50 years. We proceeded to annotate the genome of the O. novo-ulmi strain H327 that was sequenced in 2012. The 31.784-Mb nuclear genome (50.1% GC) is organized into 8 chromosomes containing a total of 8,640 protein-coding genes that we validated with RNA sequencing analysis. Approximately 53% of these genes have their closest match to Grosmannia clavigera kw1407, followed by 36% in other close Sordariomycetes, 5% in other Pezizomycotina, and surprisingly few (5%) orphans. A relatively small portion (~3.4%) of the genome is occupied by repeat sequences; however, the mechanism of repeat-induced point mutation appears active in this genome. Approximately 76% of the proteins could be assigned functions using Gene Ontology analysis; we identified 311 carbohydrate-active enzymes, 48 cytochrome P450s, and 1,731 proteins potentially involved in pathogen-host interaction, along with 7 clusters of fungal secondary metabolites. Complementary mating-type locus sequencing, mating tests, and culturing in the presence of elm terpenes were conducted. Our analysis identified a specific genetic arsenal impacting the sexual and vegetative growth, phytopathogenicity, and signaling/plant-defense degradation relationship between O. novo-ulmi and its elm host and insect vectors. PMID- 25539723 TI - Octocoral mitochondrial genomes provide insights into the phylogenetic history of gene order rearrangements, order reversals, and cnidarian phylogenetics. AB - We use full mitochondrial genomes to test the robustness of the phylogeny of the Octocorallia, to determine the evolutionary pathway for the five known mitochondrial gene rearrangements in octocorals, and to test the suitability of using mitochondrial genomes for higher taxonomic-level phylogenetic reconstructions. Our phylogeny supports three major divisions within the Octocorallia and show that Paragorgiidae is paraphyletic, with Sibogagorgia forming a sister branch to the Coralliidae. Furthermore, Sibogagorgia cauliflora has what is presumed to be the ancestral gene order in octocorals, but the presence of a pair of inverted repeat sequences suggest that this gene order was not conserved but rather evolved back to this apparent ancestral state. Based on this we recommend the resurrection of the family Sibogagorgiidae to fix the paraphyly of the Paragorgiidae. This is the first study to show that in the Octocorallia, mitochondrial gene orders have evolved back to an ancestral state after going through a gene rearrangement, with at least one of the gene orders evolving independently in different lineages. A number of studies have used gene boundaries to determine the type of mitochondrial gene arrangement present. However, our findings suggest that this method known as gene junction screening may miss evolutionary reversals. Additionally, substitution saturation analysis demonstrates that while whole mitochondrial genomes can be used effectively for phylogenetic analyses within Octocorallia, their utility at higher taxonomic levels within Cnidaria is inadequate. Therefore for phylogenetic reconstruction at taxonomic levels higher than subclass within the Cnidaria, nuclear genes will be required, even when whole mitochondrial genomes are available. PMID- 25539724 TI - More than skin deep: functional genomic basis for resistance to amphibian chytridiomycosis. AB - The amphibian-killing chytrid fungus Batrachochytrium dendrobatidis (Bd) is one of the most generalist pathogens known, capable of infecting hundreds of species globally and causing widespread population declines and extinctions. However, some host species are seemingly unaffected by Bd, tolerating or clearing infections without clinical signs of disease. Variation in host immune responses is commonly evoked for these resistant or tolerant species, yet to date, we have no direct comparison of amphibian species responses to infection at the level of gene expression. In this study, we challenged four Central American frog species that vary in Bd susceptibility, with a sympatric virulent strain of the pathogen. We compared skin and spleen orthologous gene expression using differential expression tests and coexpression gene network analyses. We found that resistant species have reduced skin inflammatory responses and increased expression of genes involved in skin integrity. In contrast, only highly susceptible species exhibited suppression of splenic T-cell genes. We conclude that resistance to chytridiomycosis may be related to a species' ability to escape the immunosuppressive activity of the fungus. Moreover, our results indicate that within-species differences in splenic proteolytic enzyme gene expression may contribute to intraspecific variation in survival. This first comparison of amphibian functional immunogenomic architecture in response to Bd provides insights into key genetic mechanisms underlying variation in disease outcomes among amphibian species. PMID- 25539725 TI - Evolution of spatially coexpressed families of type-2 vomeronasal receptors in rodents. AB - The vomeronasal organ (VNO) is an olfactory structure for the detection of pheromones. VNO neurons express three groups of unrelated G-protein-coupled receptors. Type-2 vomeronasal receptors (V2Rs) are specifically localized in the basal neurons of the VNO and are believed to sense protein pheromones eliciting specific reproductive behaviors. In murine species, V2Rs are organized into four families. Family-ABD V2Rs are expressed monogenically and coexpress with family-C V2Rs of either subfamily C1 (V2RC1) or subfamily C2 (V2RC2), according to a coordinate temporal diagram. Neurons expressing the phylogenetically ancient V2RC1 coexpress family-BD V2Rs or a specific group of subfamily-A V2Rs (V2RA8 10), whereas a second neuronal subset (V2RC2-positive) coexpresses a recently expanded group of five subfamily-A V2Rs (V2RA1-5) along with vomeronasal-specific Major Histocompatibility Complex molecules (H2-Mv). Through database mining and Sanger sequencing, we have analyzed the onset, diversification, and expansion of the V2R-families throughout the phylogeny of Rodentia. Our results suggest that the separation of V2RC1 and V2RC2 occurred in a Cricetidae ancestor in coincidence with the evolution of the H2-Mv genes; this phylogenetic event did not correspond with the origin of the coexpressing V2RA1-5 genes, which dates back to an ancestral myomorphan lineage. Interestingly, the evolution of receptors within the V2RA1-5 group may be implicated in the origin and diversification of some of the V2R putative cognate ligands, the exocrine secreting peptides. The establishment of V2RC2, which probably reflects the complex expansion and diversification of family-A V2Rs, generated receptors that have probably acquired a more subtle functional specificity. PMID- 25539727 TI - A neutrality test for detecting selection on DNA methylation using single methylation polymorphism frequency spectrum. AB - Inheritable epigenetic mutations (epimutations) can contribute to transmittable phenotypic variation. Thus, epimutations can be subject to natural selection and impact the fitness and evolution of organisms. Based on the framework of the modified Tajima's D test for DNA mutations, we developed a neutrality test with the statistic "D(m)" to detect selection forces on DNA methylation mutations using single methylation polymorphisms. With computer simulation and empirical data analysis, we compared the D(m) test with the original and modified Tajima's D tests and demonstrated that the D(m) test is suitable for detecting selection on epimutations and outperforms original/modified Tajima's D tests. Due to the higher resetting rate of epimutations, the interpretation of D(m) on epimutations and Tajima's D test on DNA mutations could be different in inferring natural selection. Analyses using simulated and empirical genome-wide polymorphism data suggested that genes under genetic and epigenetic selections behaved differently. We applied the D(m) test to recently originated Arabidopsis and human genes, and showed that newly evolved genes contain higher level of rare epialleles, suggesting that epimutation may play a role in origination and evolution of genes and genomes. Overall, we demonstrate the utility of the D(m) test to detect whether the loci are under selection regarding DNA methylation. Our analytical metrics and methodology could contribute to our understanding of evolutionary processes of genes and genomes in the field of epigenetics. The Perl script for the "D(m)" test is available at http://fanlab.wayne.edu/ (last accessed December 18, 2014). PMID- 25539726 TI - Mutation rate, spectrum, topology, and context-dependency in the DNA mismatch repair-deficient Pseudomonas fluorescens ATCC948. AB - High levels of genetic diversity exist among natural isolates of the bacterium Pseudomonas fluorescens, and are especially elevated around the replication terminus of the genome, where strain-specific genes are found. In an effort to understand the role of genetic variation in the evolution of Pseudomonas, we analyzed 31,106 base substitutions from 45 mutation accumulation lines of P. fluorescens ATCC948, naturally deficient for mismatch repair, yielding a base substitution mutation rate of 2.34 * 10(-8) per site per generation (SE: 0.01 * 10(-8)) and a small-insertion-deletion mutation rate of 1.65 * 10(-9) per site per generation (SE: 0.03 * 10(-9)). We find that the spectrum of mutations in prophage regions, which often contain virulence factors and antibiotic resistance, is highly similar to that in the intergenic regions of the host genome. Our results show that the mutation rate varies around the chromosome, with the lowest mutation rate found near the origin of replication. Consistent with observations from other studies, we find that site-specific mutation rates are heavily influenced by the immediately flanking nucleotides, indicating that mutations are context dependent. PMID- 25539728 TI - Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia. AB - BACKGROUND: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype. METHODS: To inhibit endogenous FoxO DNA binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later. RESULTS: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL 6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPbeta target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model. CONCLUSIONS: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting. PMID- 25539729 TI - Seasonality in the migration and establishment of H3N2 Influenza lineages with epidemic growth and decline. AB - BACKGROUND: Influenza A/H3N2 has been circulating in humans since 1968, causing considerable morbidity and mortality. Although H3N2 incidence is highly seasonal, how such seasonality contributes to global phylogeographic migration dynamics has not yet been established. In this study, we incorporate time-varying migration rates in a Bayesian MCMC framework. We focus on migration within China, and to and from North-America as case studies, then expand the analysis to global communities. RESULTS: Incorporating seasonally varying migration rates improves the modeling of migration in our regional case studies, and also in a global context. In our global model, windows of increased immigration map to the seasonal timing of epidemic spread, while windows of increased emigration map to epidemic decline. Seasonal patterns also correlate with the probability that local lineages go extinct and fail to contribute to long term viral evolution, as measured through the trunk of the phylogeny. However, the fraction of the trunk in each community was found to be better determined by its overall human population size. CONCLUSIONS: Seasonal migration and rapid turnover within regions is sustained by the invasion of 'fertile epidemic grounds' at the end of older epidemics. Thus, the current emphasis on connectivity, including air travel, should be complemented with a better understanding of the conditions and timing required for successful establishment. Models which account for migration seasonality will improve our understanding of the seasonal drivers of influenza, enhance epidemiological predictions, and ameliorate vaccine updating by identifying strains that not only escape immunity but also have the seasonal opportunity to establish and spread. Further work is also needed on additional conditions that contribute to the persistence and long term evolution of influenza within the human population, such as spatial heterogeneity with respect to climate and seasonality. PMID- 25539731 TI - Hodgkin's lymphoma: better outcomes with fewer drugs? PMID- 25539730 TI - Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. AB - BACKGROUND: The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma. METHODS: In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366. FINDINGS: Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of 11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0.1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin. INTERPRETATION: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT. FUNDING: Deutsche Krebshilfe and Swiss State Secretariat for Education and Research. PMID- 25539733 TI - The validation of Fibit ZipTM physical activity monitor as a measure of free living physical activity. AB - BACKGROUND: The new generation of activity monitors allow users to upload their data to the internet and review progress. The aim of this study is to validate the Fitbit Zip as a measure of free-living physical activity. FINDINGS: Participants wore a Fitbit Zip, ActiGraph GT3X accelerometer and a Yamax CW700 pedometer for seven days. Participants were asked their opinion on the utility of the Fitbit Zip. Validity was assessed by comparing the output using Spearman's rank correlation coefficients, Wilcoxon signed rank tests and Bland-Altman plots. 59.5% (25/47) of the cohort were female. There was a high correlation in steps/day between the Fitbit Zip and the two reference devices (r = 0.91, p < 0.001). No statistically significant difference between the Fitbit and Yamax steps/day was observed (Median (IQR) 7477 (3597) vs 6774 (3851); p = 0.11). The Fitbit measured significantly more steps/day than the Actigraph (7477 (3597) vs 6774 (3851); p < 0.001). Bland-Altman plots revealed no systematic differences between the devices. CONCLUSIONS: Given the high level of correlation and no apparent systematic biases in the Bland Altman plots, the use of Fitbit Zip as a measure of physical activity. However the Fitbit Zip recorded a significantly higher number of steps per day than the Actigraph. PMID- 25539732 TI - Heterogeneity of PIK3CA mutational status at the single cell level in circulating tumor cells from metastatic breast cancer patients. AB - Circulating Tumor Cells (CTCs) represent a "liquid biopsy of the tumor" which might allow real-time monitoring of cancer biology and therapies in individual patients. CTCs are extremely rare in the blood stream and their analysis is technically challenging. The CellSearch((r)) system provides the enumeration of CTCs with prognostic significance in patients with metastatic breast cancer (mBC), but it does not allow their molecular characterization, which might be useful to identify therapeutically relevant targets for individualized treatment. Combining the CellSearch((r)) and DEPArrayTM technologies allows the recovery of single CTCs as a pure sample for molecular analysis. The purpose of the study was to investigate the heterogeneity of PIK3CA mutational status within single CTCs isolated from individual mBC patients. CTCs were enriched and enumerated by CellSearch((r)) in blood samples collected from 39 mBC patients. In 20 out of 39 patients enriched samples with >=5 CTCs were sorted using DEParrayTM to isolate single CTCs or pools of CTCs to be submitted to Whole Genome Amplification (WGA) before sequencing analysis. In 18 out of 20 patients, it was possible to perform PIK3CA sequencing on exons 9 and 20. Twelve subjects were wild type (wt) for the PIK3CA gene. PIK3CA status could also be assessed in pools of CTCs in seven of these patients, with consistent wt status found. Six patients (33%) had a PIK3CA mutation identified. In 2 of the six patients, molecular heterogeneity was detected when mutational analysis was performed on more than one single CTC, including one patient with loss of heterozygosity on both single and pooled CTCs, and one patient with three different PIK3CA variants on single CTCs but PIK3CA wt status on pooled CTC samples. In six out of the 18 cases PIK3CA status was also evaluable on a primary tumor sample. In one of the six cases a discordance in PIK3CA status between the primary (wild-type) and the matched CTC (exon 20 mutation) was observed. This study demonstrates the feasibility of a non-invasive approach based on the liquid biopsy in mBC patients. Moreover, our data suggest the importance of characterizing CTCs at the single cell level in order to investigate the molecular heterogeneity within cells from the same patient. PMID- 25539734 TI - Development of an outcome prediction tool for patients considering a total knee replacement--the Knee Outcome Prediction Study (KOPS). AB - BACKGROUND: Knee osteoarthritis affects 10% of the UK population over 55 years, resulting in pain and decreased quality of life. Knee replacement surgery has a proven benefit, with over 85,000 performed each year in the UK; however, approximately 17% of people are dissatisfied after surgery. Consequently, some Primary Care Trusts have reduced the funding available for knee replacements.Most previous work has focused on the effect of different prostheses and treatment protocols on patient's outcome. However, this has been unable to account for all the variability and there is growing evidence that patient factors may significantly affect outcome. How to identify these at risk patients has been identified as a research priority by the National Institute of Clinical Excellence, the British Orthopedic Association, and the National Joint Registry.The aim of this study is to develop a clinically appropriate outcome prediction tool based on measurable predictors affecting outcome. METHODS/DESIGN: We propose a prospective cohort study, designed to develop and validate an outcome prediction tool based on patient factors.Six hundred patients who are scheduled for total knee replacement secondary to primary osteoarthritis will be recruited before surgery from all six hospitals (NHS and private) that provide total knee replacements to the population of Coventry and Warwickshire (UK). Patients will complete a baseline assessment of patient factors before their operation and will be followed up at 6 and 12 months post surgery. DISCUSSION: A clinically appropriate outcome prediction tool will allow patients to make a more informed decision regarding surgery. Aligning patient expectations with a realistic prediction of outcome should improve satisfaction. Ultimately, this project is likely to inform national policy making and regional service provision. PMID- 25539736 TI - Clinical value of wireless pH-monitoring of gastro-esophageal reflux in children before and after proton pump inhibitors. AB - BACKGROUND: Wireless pH-monitoring is an accurate method for diagnosing adults with gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the use of the Bravo capsule on children investigated for GERD in terms of safety, tolerability and feasibility before and after administration of proton pump inhibitors. METHODS: A Bravo capsule was inserted during upper endoscopy under general anaesthesia or deep sedation with propofol. 48-hour pH-metry was performed in 106 children (50 males, 56 females) at the median age of 11 years (range 17 months-18 years). On the second day of investigation, proton pump inhibitor (PPI) was given at a mean dose of 1.6 mg/kg (SD +/-0.6 mg). The definition of GERD was set to a reflux index (RI) of >=5% and DeMeester score (DMS) >=14.7. RESULTS: Application of the capsule was successful in 103 of the 106 children (97.2%) and interpretable in 99 of these 103 (96.1%). 49 of the children with interpretable results (49.5%) had GERD according to RI, while 51 (56.7%) had GERD according to DMS. After PPI was given on day 2, RI decreased from a median of 4.9% (range 0.3-63.4%) to 2.2% (0-58.0%), while DMS decreased from a median of 17.6 (range 2.2-207.6) to 8.2 (0.3-178.6), respectively (p < 0.0001). No severe adverse events were reported. CONCLUSION: Wireless pH-metry is a safe and tolerable method when investigating children for GERD. PPI given on the second day of assessment provides additional information on response to treatment suggesting that pH-metry preferably should be extended to 48 hours. PMID- 25539735 TI - Inhibition of store-operated calcium entry in microglia by helminth factors: implications for immune suppression in neurocysticercosis. AB - BACKGROUND: Neurocysticercosis (NCC) is a disease of the central nervous system (CNS) caused by the cestode Taenia solium. The infection exhibits a long asymptomatic phase, typically lasting 3 to 5 years, before the onset of the symptomatic phase. The severity of the symptoms is thought to be associated with the intensity of the inflammatory response elicited by the degenerating parasite. In contrast, the asymptomatic phase shows an absence of brain inflammation, which is presumably due to immunosuppressive effects of the live parasites. However, the host factors and/or pathways involved in inhibiting inflammation remain largely unknown. Recently, using an animal model of NCC in which mice were intracranially inoculated with a related helminth parasite, Mesocestoides corti, we reported that Toll-like receptor (TLR)-associated signaling contributes to the development of the inflammatory response. As microglia shape the initial innate immune response in the CNS, we hypothesized that the negative regulation of a TLR induced inflammatory pathway in microglia may be a novel helminth-associated immunosuppressive mechanism in NCC. METHODS AND RESULTS: Here we report that helminth soluble factors (HSFs) from Mesocestoides corti inhibited TLR ligation induced production of inflammatory cytokines in primary microglia. This was correlated with an inhibition of TLR-initiated upregulation of both phosphorylation and acetylation of the nuclear factor kappaB (NF-kappaB) p65 subunit, as well as phosphorylation of JNK and ERK1/2. As Ca2+ influx due to store-operated Ca2+ entry (SOCE) has been implicated in induction of downstream signaling, we tested the inhibitory effect of HSFs on agonist-induced Ca2+ influx and specific Ca2+ channel activation. We discovered that HSFs abolished the lipopolysaccharide (LPS)- or thapsigargin (Tg)-induced increase in intracellular Ca2+ accumulation by blocking the ER store release and SOCE. Moreover, electrophysiological recordings demonstrated HSF-mediated inhibition of LPS- or Tg-induced SOCE currents through both TRPC1 and ORAI1 Ca2+ channels on plasma membrane. This was correlated with a decrease in the TRPC1-STIM1 and ORAI1-STIM1 clustering at the plasma membrane that is essential for sustained Ca2+ entry through these channels. CONCLUSION: Inhibition of TRPC1 and ORAI1 Ca2+ channel mediated activation of NF-kappaB and MAPK pathways in microglia is likely a novel helminth-induced immunosuppressive mechanism that controls initiation of inflammatory response in the CNS. PMID- 25539737 TI - Altered motility of Caulobacter Crescentus in viscous and viscoelastic media. AB - BACKGROUND: Motility of flagellated bacteria depends crucially on their organelles such as flagella and pili, as well as physical properties of the external medium, such as viscosity and matrix elasticity. We studied the motility of wild-type and two mutant strains of Caulobacter crescentus swarmer cells in two different types of media: a viscous and hyperosmotic glycerol-growth medium mixture and a viscoelastic growth medium, containing polyethylene glycol or polyethylene oxide of different defined sizes. RESULTS: For all three strains in the medium containing glycerol, we found linear drops in percentage of motile cells and decreases in speed of those that remained motile to be inversely proportional to viscosity. The majority of immobilized cells lost viability, evidenced by their membrane leakage. In the viscoelastic media, we found less loss of motility and attenuated decrease of swimming speed at shear viscosity values comparable to the viscous medium. In both types of media, we found more severe loss in percentage of motile cells of wild-type than the mutants without pili, indicating that the interference of pili with flagellated motility is aggravated by increased viscosity. However, we found no difference in swimming speed among all three strains under all test conditions for the cells that remained motile. Finally, the viscoelastic medium caused no significant change in intervals between flagellar motor switches unless the motor stalled. CONCLUSION: Hyperosmotic effect causes loss of motility and cell death. Addition of polymers into the cell medium also causes loss of motility due to increased shear viscosity, but the majority of immobilized bacteria remain viable. Both viscous and viscoelastic media alter the motility of flagellated bacteria without affecting the internal regulation of their motor switching behavior. PMID- 25539738 TI - Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas. AB - BACKGROUND: Clinically nonfunctional pituitary adenomas (NFPAs) without any clinical elevation of hormone and with a difficulty in its early-stage diagnosis are highly heterogeneous with different hormone expressions in NFPA tissues, including luteinizing hormone (LH)-positive, follicle-stimulating hormone (FSH) positive, LH/FSH-positive, and negative (NF). Elucidation of molecular mechanisms and discovery of biomarkers common and specific to those different subtypes of NFPAs will benefit NFPA patients in early-stage diagnosis and individualized treatment. METHODS: Two-dimensional gel electrophoresis (2DGE) and PDQuest image analyses were used to compare proteomes of different NFPA subtypes (NF-, LH-, FSH , and LH/FSH-positive) relative to control pituitaries (Con). Differentially expressed proteins (DEPs) were characterized with mass spectrometry (MS). Each set of DEPs in four NFPA subtypes was evaluated with overlap analysis and signaling pathway network analysis with comparison to determine any DEP and pathway network that are common and specific to each NFPA subtype. RESULTS: A total of 93 differential protein-spots were determined with comparison of each NFPA type (NF-, LH-, FSH-, and LH/FSH-positive) versus control pituitaries. A total of 76 protein-spots were MS-identified (59 DEPs in NF vs. Con; 65 DEPs in LH vs. Con; 63 DEPs in FSH vs. Con; and 55 DEPs in LH/FSH vs. Con). A set of DEPs and pathway network data were common and specific to each NFPA subtype. Four important common pathway systems included MAPK-signaling abnormality, oxidative stress, mitochondrial dysfunction, and cell-cycle dysregulation. However, these pathway systems were, in fact, different among four NFPA subtypes with different protein-expression levels of most of nodes, different protein profiles, and different pathway network profiles. CONCLUSIONS: These result data demonstrate that common and specific DEPs and pathway networks exist in four NFPA subtypes, and clarify proteome heterogeneity of four NFPA subtypes. Those findings will help to elucidate molecular mechanisms of NFPAs, and discover protein biomarkers to effectively manage NFPA patients towards personalized medicine. PMID- 25539739 TI - Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis. AB - BACKGROUND: In view of previous conflicting findings, this meta-analysis was performed to comprehensively determine the overall strength of associations between brain-derived neurotrophic factor (BDNF) genetic polymorphism Val66Met and susceptibility to bipolar disorders (BPD). METHODS: Literatures published and cited in Pubmed and Wanfang Data was searched with terms of 'Val66Met', 'G196A', 'rs6265', 'BDNF', 'association', and 'bipolar disorder' up to March 2014. All original case-control association studies were meta-analyzed with a pooled OR to estimate the risk and 95% confidence interval (CI) to reflect the magnitude of variance. RESULTS: Twenty-one case-control association studies met our criteria for the meta-analysis. Overall, there was no significant difference in allelic distribution of Val66Met polymorphism between patients and controls with a pooled OR = 1.03 (95% CI 0.98, 1.08) although there was a trend towards association between Val66Met polymorphism and BPD in Caucasians with an OR of 1.08 (95% CI 1.00, 1.16). However, subgroup analyses showed that there was a significant association of Val allele with decreased disease susceptibility for bipolar disorder type II with a pooled OR of 0.88 (95% CI 0.78, 0.99). CONCLUSIONS: There is no compelling evidence to supportVal66Met polymorphism in BDNF gene playing an important role in the susceptibility to BPD across different ethnicities. PMID- 25539740 TI - Sampling variability between two mid-turbinate swabs of the same patient has implications for influenza viral load monitoring. AB - BACKGROUND: With the clinical development of several antiviral intervention strategies for influenza, it becomes crucial to explore viral load shedding in the nasal cavity as a biomarker for treatment success, but also to explore sampling strategies for sensible and reliable virus collection. FINDINGS: In this study, 244 patients suffering from Influenza like Illness and/or acute respiratory tract infection were enrolled. Sampling was done using mid-turbinate flocked swabs and two swabs per patient were collected (one swab per nostril). The influenza A viral loads of two mid-turbinate flocked swabs (one for each nostril) per patient were compared and we have also assessed whether normalization for human cellular DNA in the swabs could be useful. The Influenza mid-turbinate nasal swab testing resulted in considerable sampling variability that could not be normalized against co-isolated human cellular DNA. CONCLUSIONS: Influenza viral load monitoring in nasal swabs could be very valuable as virological endpoints in clinical trials to monitor treatment efficacy, in analogy to HIV, HBV & HCV viral load monitoring. However, the differences between left and right nostrils, as observed in this study, highlight the importance of proper sampling and the need for standardized sampling procedures. PMID- 25539741 TI - Functionalization of alkyne-terminated thermally hydrocarbonized porous silicon nanoparticles with targeting peptides and antifouling polymers: effect on the human plasma protein adsorption. AB - Porous silicon (PSi) nanomaterials combine a high drug loading capacity and tunable surface chemistry with various surface modifications to meet the requirements for biomedical applications. In this work, alkyne-terminated thermally hydrocarbonized porous silicon (THCPSi) nanoparticles were fabricated and postmodified using five bioactive molecules (targeting peptides and antifouling polymers) via a single-step click chemistry to modulate the bioactivity of the THCPSi nanoparticles, such as enhancing the cellular uptake and reducing the plasma protein association. The size of the nanoparticles after modification was increased from 176 to 180-220 nm. Dextran 40 kDa modified THCPSi nanoparticles showed the highest stability in aqueous buffer. Both peptide- and polymer-functionalized THCPSi nanoparticles showed an extensive cellular uptake which was dependent on the functionalized moieties presented on the surface of the nanoparticles. The plasma protein adsorption study showed that the surface modification with different peptides or polymers induced different protein association profiles. Dextran 40 kDa functionalized THCPSi nanoparticles presented the least protein association. Overall, these results demonstrate that the "click" conjugation of the biomolecules onto the alkyne-terminated THCPSi nanoparticles is a versatile and simple approach to modulate the surface chemistry, which has high potential for biomedical applications. PMID- 25539744 TI - Highly strained nonclassical nanotube end-caps. A single-step solution synthesis from strain-free, non-macrocyclic precursors. AB - Nonclassical nanotube end-caps have been constructed from strain-free heterocyclic precursors using a one-step synthetic procedure, involving multiple nickel-mediated Ullmann couplings. These systems consist of tubular macrocyclic sections that are tightly capped on one side with a bridging benzene ring, forming deep, chemically accessible cavities. The end-caps are characterized by exceptionally high internal strain energies reaching 144 kcal/mol. The optical absorption and emission properties of these molecules show a marked dependence on conjugation length and geometrical factors. The mechanism of end-cap formation, investigated using DFT calculations, relies on precise timing of transmetalation and reductive elimination events. PMID- 25539743 TI - Dynamic change of glomerular filtration rate in the early stage is associated with kidney allograft status: a preliminary report. AB - BACKGROUND: This study aimed to investigate the relationship between the dynamic changes of estimated glomerular filtration rate (eGFR) in the early stage post renal transplantation and renal allograft dysfunction. METHODS: We selected 9 patients with interstitial fibrosis and tubular atrophy (IF/TA) and 11 patients with stable renal function based on the Banff 2007 classification system. Pathology of the patients was evidenced with renal biopsy results. Glomerular filtration rate (GFR) was calculated continuously for 14 days post transplantation by using an estimated GFR (eGFR) formula adjusted into Chinese. Linear regression was employed, and eGFR slopes were compared. Prisoners or organs from prisoners were not used in this study. RESULTS AND CONCLUSION: The eGFR slope in the IF/TA group was significantly higher than that in the stable group (P < 0.01), and a cut-off value of 5.11 mL/min/1.73 m(2)/d was a reliable clinical value in a receiver operating characteristic (ROC) curve. On the basis of the ROC area under the curve, predictive accuracy of the eGFR slope was excellent (0.848). In conclusion, the eGFR in IF/TA increased faster within a period of 14 days post-transplantation, suggesting that reperfusion in the early stage may damage the glomerular filtration membrane to some extent. Furthermore, reperfusion might adversely affect long-term renal allograft survival. PMID- 25539742 TI - Y-box binding protein 1 enhances DNA topoisomerase 1 activity and sensitivity to camptothecin via direct interaction. AB - BACKGROUND: The Y-box binding protein 1 (YB-1) possesses pleiotropic functions through its interactions with various cellular proteins, and its high expression levels make it a potential useful prognostic biomarker for cancer cells. Eukaryotic DNA topoisomerases, such as DNA topoisomerase 1 (TOPO1) and DNA topoisomerase 2 (TOPO2), are the essential DNA metabolism regulators that usually overexpressed in cancer cells, and multiple proteins have been reported to regulate the enzyme activity and the clinical efficacy of their inhibitors. The present study unraveled the interaction of YB-1 with TOPO1, and further investigated the related function and potential mechanisms during the interaction. METHODS: The direct association of TOPO1 with specific domain of YB 1 was explored by co-immunoprecipitation and GST pull-down assays. The interaction function was further clarified by DNA relaxation assays, co immunoprecipitation and WST-8 assays with in vitro gain- and loss- of function models. RESULTS: We found that YB-1 interacts directly with TOPO1 (but not with TOPO2) and promotes TOPO1 catalytic activity. Interactions between YB-1 and TOPO1 increased when cancer cells were treated with the TOPO1 inhibitor, camptothecin (CPT), but not with the TOPO2 inhibitor, adriamycin (ADM). Furthermore, we found that the interaction is prevented by pretreatment with the antioxidant agent, N acetyl cysteine, and that YB-1 downregulation renders cells resistant to CPT. CONCLUSIONS: Our findings suggest that nuclear YB-1 serves as an intracellular promoter of TOPO1 catalytic activity that enhances CPT sensitivity through its direct interaction with TOPO1. PMID- 25539745 TI - A comparison of smartphones to paper-based questionnaires for routine influenza sentinel surveillance, Kenya, 2011-2012. AB - BACKGROUND: For disease surveillance, manual data collection using paper-based questionnaires can be time consuming and prone to errors. We introduced smartphone data collection to replace paper-based data collection for an influenza sentinel surveillance system in four hospitals in Kenya. We compared the quality, cost and timeliness of data collection between the smartphone data collection system and the paper-based system. METHODS: Since 2006, the Kenya Ministry of Health (MoH) with technical support from the Kenya Medical Research Institute/Centers for Disease Control and Prevention (KEMRI/CDC) conducted hospital-based sentinel surveillance for influenza in Kenya. In May 2011, the MOH replaced paper-based collection with an electronic data collection system using Field Adapted Survey Toolkit (FAST) on HTC Touch Pro2 smartphones at four sentinel sites. We compared 880 paper-based questionnaires dated Jan 2010-Jun 2011 and 880 smartphone questionnaires dated May 2011-Jun 2012 from the four surveillance sites. For each site, we compared the quality, cost and timeliness of each data collection system. RESULTS: Incomplete records were more likely seen in data collected using pen-and-paper compared to data collected using smartphones (adjusted incidence rate ratio (aIRR) 7, 95% CI: 4.4-10.3). Errors and inconsistent answers were also more likely to be seen in data collected using pen-and-paper compared to data collected using smartphones (aIRR: 25, 95% CI: 12.5-51.8). Smartphone data was uploaded into the database in a median time of 7 days while paper-based data took a median of 21 days to be entered (p < 0.01). It cost USD 1,501 (9.4%) more to establish the smartphone data collection system ($17,500) than the pen-and-paper system (USD $15,999). During two years, however, the smartphone data collection system was $3,801 (7%) less expensive to operate ($50,200) when compared to pen-and-paper system ($54,001). CONCLUSIONS: Compared to paper-based data collection, an electronic data collection system produced fewer incomplete data, fewer errors and inconsistent responses and delivered data faster. Although start-up costs were higher, the overall costs of establishing and running the electronic data collection system were lower compared to paper based data collection system. Electronic data collection using smartphones has potential to improve timeliness, data integrity and reduce costs. PMID- 25539747 TI - Comprehensive report of an Enterococcus cecorum infection in a broiler flock in Northern Germany. AB - BACKGROUND: Enterococcus cecorum is considered as an emerging pathogen in poultry and can cause substantial losses in broiler flocks. Femoral head necrosis and spondylitis were described as the main pathological changes in infected chickens. Nevertheless, little is known about the pathogenesis of Enterococcus cecorum infection in broilers. This report shows for the first time the whole course of disease over an entire growing period including repeated necropsies and subsequent microbiological investigations. CASE PRESENTATION: In a flock of 18200 broilers, a decrease in flock uniformity was detected from 14 days post hatch onwards with affected chickens showing lameness and an increase in flock mortality up to 7.22% at day 33 post hatch. In the first 3 weeks post hatch, pericarditis and hepatitis were found as the main pathological changes in 27.6% and 9.8% of the examined broilers respectively. Femoral head necrosis and vertebral osteomyelitis were detected in the last week of the growing period with 10.3% and 2.3% respectively. Heart, liver, spleen, yolk sac and vertebral column of 59 broilers with pathological changes were subjected to bacteriological analysis. Enterococcus cecorum was isolated from 23 birds (39%), the first broiler was already positive at day 3 post hatch in the yolk sac. Additionally, 9.75% of the broilers were rejected at the slaughterhouse primarily because of pathological changes. The investigated broiler cycle had by far the best footpad score compared to 7 cycles before and 4 cycles after the Enterococcus cecorum infection at the same farm. CONCLUSIONS: Bacteraemia and generalized infection appear to be important steps in the pathogenesis of Enterococcus cecorum infection in broilers. Furthermore, this disease causes economic losses for the farmer not only due to an increase in flock mortality, but probably also through substantially higher condemnation rates at the slaughterhouse. It was speculated that the broilers were infected via the respiratory tract as this flock had lower footpad scores likely the result of drier litter. The latter may have led to higher dust concentrations and thus airborne Enterococcus cecorum. PMID- 25539746 TI - Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study. AB - BACKGROUND: The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project "Functional and Molecular Characterization of Patients with Inherited Platelet Disorders" under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis. PATIENTS/METHODS: Subjects were patients from a prospective cohort of individuals referred for clinical suspicion of IPDs as well as healthy controls. Functional studies included light transmission aggregation, flow cytometry, and when indicated, Western-blot analysis of platelet glycoproteins, and clot retraction analysis. Genetic analysis was mainly performed by sequencing of coding regions and proximal regulatory regions of the genes of interest. RESULTS: Of the 70 cases referred for study, we functionally and molecularly characterized 12 patients with Glanzmann Thrombasthenia, 8 patients with Bernard Soulier syndrome, and 8 with other forms of IPDs. Twelve novel mutations were identified among these patients. The systematic study of patients revealed that almost one-third of patients had been previously misdiagnosed. CONCLUSIONS: Our study provides a global picture of the current limitations and access to the diagnosis of IPDs, identifies and confirms new genetic variants that cause these disorders, and emphasizes the need of creating reference centers that can help health care providers in the recognition of these defects. PMID- 25539748 TI - Development and psychometric validation of the Chinese version of Skindex-29 and Skindex-16. AB - BACKGROUND: Dermatological disease significantly affects patient's health-related quality of life (HrQoL). Skindex is one of the most frequently used dermatology specific HrQoL measures. Currently no Chinese version of Skindex is available. The aim of this study was to translate and culturally adapt Skindex-29 and Skindex-16 into Chinese, and to evaluate their reliability and validity. METHODS: Translation and cultural adaption were performed following guidelines for cross cultural adaption of health-related quality of life measures. Subsequently, a cross-sectional study was conducted in which patients with dermatological disease (n = 225) were enrolled. The Chinese version of Skindex-29 and Skindex-16 and Dermatology Life Quality Index (DLQI) were completed. Reliability was evaluated with internal consistency using Cronbach's alpha. Validity was evaluated using known-groups validity, convergent validity and factor structure validity. RESULTS: There were both seven items of Skindex-29 and Skindex-16 requiring a second forward- and backward- translation to achieve the final satisfactory Chinese version. The internal consistency reliability was high (range of Cronbach's alpha for the scales of Skindex-29 0.85-0.97, Skindex-16 0.86-0.96). Known-group validity was demonstrated by higher scores from patients with inflammatory dermatosis than from patients with isolated skin lesions (P < 0.05). Evidence of factor structure validity of the Skindex-29 and Skindex-16 was demonstrated by both exploratory factor analysis that accounted for 68.66% and 77.78% of the total variance, respectively, and confirmatory factor analysis with acceptable fitness into the expected three-factor structure. CONCLUSION: This study has developed semantically equivalent translations of Skindex-29 and Skindex-16 into Chinese. The evaluation of the instruments' psychometric properties shows they have substantial evidence of reliability and validity for use as HrQoL instruments in Chinese patients with dermatological disease. PMID- 25539749 TI - Dietary intake in 6-year-old children from southern Poland: part 2--vitamin and mineral intakes. AB - BACKGROUND: Studies on vitamin and mineral intakes in children are very important: firstly because of the high prevalence of diet-related diseases and secondly because of the widespread consumption of highly processed foods which are characterised by high energy content and low density of essential nutrients. Therefore, the purpose of this study was to analyse vitamin and mineral intakes in 6-year-old children from southern Poland. METHODS: Vitamin and mineral intakes were estimated from a three-day food record in 120 children, 64 girls and 56 boys, aged 6 years. Nutrient densities were estimated as amounts per 1000 kcal (4185 kJ) of energy intake. Statistical analysis was carried out by means of the IBM SPSS Statistics computer programme, version 19. The studied population was divided according to gender. RESULTS: Intakes of folic acid (MUg/1000 kcal) and vitamin C (mg, mg/1000 kcal) were significantly higher in girls. Nutrient densities for all vitamins were higher in girls, however, these results did not reach statistical significance. Intake of vitamin D was lower than EAR in all of the studied children. Intakes of sodium (mg) and zinc (mg) were significantly higher in boys. Intakes of the remaining minerals were higher in boys, however, these findings did not reach statistical significance. Nutrient densities for all minerals, except for sodium, zinc and manganese, were higher in girls. All of the studied children had sodium intakes above UL. CONCLUSIONS: Inadequate intakes of vitamin D, calcium and potassium in the studied 6-year-olds along with excessive sodium intake are the risk factors for developing osteoporosis and hypertension. To prevent these diseases in the studied children, educational programmes for both preschool staff and parents should be worked out and implemented. PMID- 25539750 TI - TREC-IN: gene knock-in genetic tool for genomes cloned in yeast. AB - BACKGROUND: With the development of several new technologies using synthetic biology, it is possible to engineer genetically intractable organisms including Mycoplasma mycoides subspecies capri (Mmc), by cloning the intact bacterial genome in yeast, using the host yeast's genetic tools to modify the cloned genome, and subsequently transplanting the modified genome into a recipient cell to obtain mutant cells encoded by the modified genome. The recently described tandem repeat coupled with endonuclease cleavage (TREC) method has been successfully used to generate seamless deletions and point mutations in the mycoplasma genome using the yeast DNA repair machinery. But, attempts to knock-in genes in some cases have encountered a high background of transformation due to maintenance of unwanted circularization of the transforming DNA, which contains possible autonomously replicating sequence (ARS) activity. To overcome this issue, we incorporated a split marker system into the TREC method, enabling seamless gene knock-in with high efficiency. The modified method is called TREC assisted gene knock-in (TREC-IN). Since a gene to be knocked-in is delivered by a truncated non-functional marker, the background caused by an incomplete integration is essentially eliminated. RESULTS: In this paper, we demonstrate applications of the TREC-IN method in gene complementation and genome minimization studies in Mmc. In the first example, the Mmc dnaA gene was seamlessly replaced by an orthologous gene, which shares a high degree of identity at the nucleotide level with the original Mmc gene, with high efficiency and low background. In the minimization example, we replaced an essential gene back into the genome that was present in the middle of a cluster of non-essential genes, while deleting the non-essential gene cluster, again with low backgrounds of transformation and high efficiency. CONCLUSION: Although we have demonstrated the feasibility of TREC-IN in gene complementation and genome minimization studies in Mmc, the applicability of TREC-IN ranges widely. This method proves to be a valuable genetic tool that can be extended for genomic engineering in other genetically intractable organisms, where it may be implemented in elucidating specific metabolic pathways and in rationale vaccine design. PMID- 25539751 TI - [What's new in clinical dermatology?]. AB - Dermatoses have been better characterized as hypochromic vitiligo in subjects with dark skin or the acquired racquet nails associated with hyperparathyroidism. The innate immunity has a central role in the new classification of auto inflammatory diseases, neutrophilic dermatoses, neutrophilic urticaria or pseudo neutrophilic urticaria. Comorbidities have been studied e.g. cardiovascular co morbidities for psoriasis, IBD associated with hidradenitis suppurativa or neurological disorders associated with pemphigoid. Bullous pemphigoid could be renamed as cutaneous pemphigoid, it can be induced by drugs especially gliptins. Genetic predispositions are analyzed in auto inflammatory diseases, psoriasis (HLA), drug eruptions (HLA or cytokines). Telaprevir often induces rashes, which can be severe but other treatments against hepatitis C as interferon can also induce debilitating rashes, some eligible for drug tolerance induction. European guidelines for the definition, classification, diagnosis of chronic spontaneous urticaria have been published. Severe cutaneous adverse drug reactions may be associated with severe systemic symptoms such as organ involvement in AGEP or the occurrence of a shock in DRESS. Allover Europe, there is now an epidemic of contact allergies to methylisothiazolinone (MIT), contained in cosmetics, wet wipes but also in paints. MIT should be tested at 2.000 ppm in water, included in the standard series for patch tests. Its role has to be evoked in any case localized on the face or hand, airborne or generalized eczema. Among infectious diseases, skin manifestations due to Parvovirus have been specified, a febrile rash can be related to dengue infection or to Zika virus. PMID- 25539752 TI - [What's new in instrumental dermatology?]. AB - This "What's new in instrumental dermatology" focuses on cutaneous oncologic surgery, base on a review of the 2012-2014 literature. First, the ability of dermatologists to make a good "oncologic reading of tumors" is the key of radical surgical treatment. Advantages and disadvantages of the biopsy are discussed. Then, the second message is the management of anticoagulants, that should not be interrupted for skin surgery. Despite recommendations, this practice is not followed in 40% of cases; this point is critical because bleeding complications are minor compared to potential morbidity of thrombotic events when stopping these medications. Regarding infection, nasal carriage of Staphylococcus aureus is identified as a risk factor for wound infection. A preoperative shower with chlorhexidine and mupirocin topical decolonization of nostril reduces this risk. Surgical techniques are trying to reach minimalism, by reducing undermining and scarring. On the trunk, using deep slow resorbable sutures improve scarring. In addition using adhesive sutures (strip) reduce the wideness of scar. On the face, the lower third of the nose is the most challenging because of the free edges, which are deformable. In this location bilobed or trilobed transposition flap offer the advantage of remaining in the nasal aesthetic unit and not disturbing the free edges of the nasal orifices. Regarding scarring, early hypertrophic scar is now well defined and linked with transposition flaps of the nasal region. An early treatment with intralesional corticosteroid injection appears to be effective. Finally, the biological mechanism of the effectiveness of compression in the prevention and treatment of dystrophic scar is now clear. The mechanotransduction explain how a mechanical stress of the skin activates biological cell pathways, which regulate the quality of collagen synthesis and the arrangement of skin fibrosis. PMID- 25539753 TI - [What's new in internal medicine?]. AB - This article focuses on current trends in various autoimmune diseases of interest for the dermatologist. In the antiphospholipid syndrome, many news: better characterization of the severe disease, involvement of the mTOR pathway in the vasculopathy-induced renal disease, and diversification of the therapeutic approaches: use of mTOR inhibitors and several biologics, new various antiplatelet and anticoagulants. In dermatomyositis, new autoantibodies are better characterized with a good correlation with clinical disease; the results of a large study on genetic predisposition to the disease are available. There are also some therapeutic innovations in systemic sclerosis: benefit of rituximab that seems well tolerated, the results of a large controlled European study about aggressive immunoablative chemotherapy followed by autologous stem cells have just been published, intralesional stem cells injections in the fingers of sclerodactylic patients. Finally, news in celiac disease that is constantly increasing and whose mild forms often have cutaneous manifestations, leading to diagnosis. PMID- 25539754 TI - [What's new in paediatric dermatology?]. AB - Regular analysis of the major journals in dermatology and paediatrics has been used to select forty articles which are representative of the past year in paediatric dermatology. This selection is not exhaustive but rather reflects the interests of the author and also the dominant topics in paediatric dermatology in 2013-2014. PMID- 25539755 TI - [What's new in skin cancers?]. AB - The present "what's new in oncology in 2014?" is in keeping with data reported in the past years. Indeed, metastatic melanoma still keeps the lion's share. The results of the combinations schedules with BRAF and MEK inhibitors showed an improvement in progression-free survival. Otherwise, resistance mechanisms to MAPKinase pathway inhibitors are of interest worldwide. Nevertheless, more fundamental and transversal researches are currently being investigated than validated schedules in daily clinical practice. Following anti-CTLA-4 drugs, second-generation immunotherapies, including anti-PD1 and PD-L1 molecules, confirmed their results in extended cohorts. In the setting of localized melanoma, the final results from MLST-1, Morton's study, regarding the sentinel node procedure versus observation alone, prompted a new enhancement in the sentinel node controversy. From another point of view, "what is not new in oncology in 2014?" In this area, the absence of original investigations on the primary melanoma detection in France and the absence of innovations in the adjuvant treatment of melanoma after surgery should be mentioned. While recent revolutionary drugs, i.e. targeted therapies and immunotherapies, will know advances under the resistance pressure in a near future, a revolution is still awaited in melanoma earlier stages. PMID- 25539756 TI - [What's new in dermatological therapy?]. AB - This non-exhaustive review focuses on publications that have been the subject of randomized controlled trials. It will also include results from research that may lead to new therapeutic perspectives. The selected articles were published between October 2013 and September 2014. The vast majority of them were dedicated to the treatment of psoriasis (anti-TNF, ustekinumab, antibodies against IL-17 or its receptors, anti-IL-23, anti-CD6 and ponesimod). Selected papers will also address the following diseases: atopic dermatitis, urticaria, acne, bullous diseases, alopecia areata, skin infections, acne rosacea and leg ulcers. PMID- 25539757 TI - Lack of efficacy of psychological and pharmacological treatments of disorders of eating behavior: neurobiological background. AB - BACKGROUND: Treatments of eating disorders result too often in partial psychological and physical remission, chronicization, dropout, relapse and death, with no fully known explanations for this failure. In order to clarify this problem, we conducted three studies to identify the biochemical background of cognitive-behavioural psychotherapy (CBT), individual psychology brief psychotherapy (IBPP), and psychotherapy-pharmacotherapy with CBT + olanzapine in anorexics (AN) and bulimics (BN) by measuring the levels of plasma homovanillic acid (HVA) for dopamine secretion, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) for noradrenalin secretion, and platelet [3H]-Paroxetin-binding Bmax and Kd for serotonin transporter function. The data were then compared with psychopathological and physical alterations. METHODS: Study 1 investigated the effects of 4 months of CBT on plasma HVA, MHPG and [3H]-Par-binding in 14 AN restricted, 14 AN-bingeing/purging, and 22 BN inpatients. Study 2 investigated the effects of 4 months of IBPP on plasma HVA in 15 AN and 17 BN outpatients. Study 3 investigated the effect of 3 months of CBT + olanzapine (5 mg/day) in 30 AN outpatients. The data were analyzed using one-way ANOVA for repeated measures for the changes between basal and post-treatment biological and psychological parameters, two-way ANOVA for repeated measures for the differences in the psychobiological data in the 3 groups, Spearman's test for the correlations between basal and final changes in the psychological and biological scores. RESULTS: Study 1 revealed significant amelioration of the psychopathology in the AN and BN patients, no effects on HVA, MHPG or Paroxetin binding Kd, and a significant increase in Par-binding Bmax only in the BN patients. Study 2 revealed a significant effect of IBPP on psychopathology in the AN and BN patients, and a significant increase in HVA only in the BN patients. Study 3 revealed a significant positive effect of CBT + olanzapine therapy on the psychopathology and increased HVA values. No correlations were observed in the 3 groups between biological and psychological effects of the three treatments. CONCLUSIONS: Our data advance suggestions on the mechanism of action of the three therapies; however, the lack of correlations between biochemical and psychological effects casts doubt on their significance. Clinical Trials.gov. Identifier NCT01990755 . PMID- 25539758 TI - Associations of neighborhood area level deprivation with the metabolic syndrome and inflammation among middle- and older- age adults. AB - BACKGROUND: The study examines the association of neighborhood socioeconomic deprivation and metabolic syndrome with inflammation. METHODS: The analysis included 19, 079 black and white participants from the REasons for Geographic And Racial Differences in Stroke Study who were age > 45 years at baseline. Logistic regression examined whether neighborhood deprivation was associated with increased odds of METS and CRP-MetS. RESULTS: Among black adults, residing in the most deprived neighborhoods was associated with increased odds of obesity (p < .01), lower HDL (p < .001), high blood pressure (p < .01), elevated fasting glucose (p < .001), inflammation (p < .01), and CRP-MetS (p < .001). Among white adults, neighborhood deprivation was associated with higher waist circumference (p < .001), lower HDL (p < .001), higher triglycerides (p < .01), higher glucose (p < .001), higher BMI (p < .0001), higher blood pressure (p = .01), METS (p < .001), inflammation (p < .01) and CRP-MetS (p < .001). CONCLUSIONS: These findings highlight the role of neighborhood socioeconomic deprivation on METS and CRP-MetS for black and white adults. Interventions tailored to address the contextual effects of deprived neighborhoods may reduce the observed neighborhood disparities. PMID- 25539761 TI - Erratum to: How can psychological science inform research about genetic counseling for clinical genomic sequencing? AB - Erratum to: J Genet Counsel DOI 10.1007/s10897-014-9804-6. Grant support from the Clinical Sequencing Exploratory Research program of the National Human Genome Research Institute was awarded to James P. Evans, Jonathan S. Berg, and Gail E. Henderson for the NCGENES Study (NIH #U01 HG006487). The authors and publisher regret the omission from the original article. PMID- 25539760 TI - Changes in activity of metabolic and regulatory pathways during germination of S. coelicolor. AB - BACKGROUND: Bacterial spore germination is a developmental process during which all required metabolic pathways are restored to transfer cells from their dormant state into vegetative growth. Streptomyces are soil dwelling filamentous bacteria with complex life cycle, studied mostly for they ability to synthesize secondary metabolites including antibiotics. RESULTS: Here, we present a systematic approach that analyzes gene expression data obtained from 13 time points taken over 5.5 h of Streptomyces germination. Genes whose expression was significantly enhanced/diminished during the time-course were identified, and classified to metabolic and regulatory pathways. The classification into metabolic pathways revealed timing of the activation of specific pathways during the course of germination. The analysis also identified remarkable changes in the expression of specific sigma factors over the course of germination. Based on our knowledge of the targets of these factors, we speculate on their possible roles during germination. Among the factors whose expression was enhanced during the initial part of germination, SigE is though to manage cell wall reconstruction, SigR controls protein re-aggregation, and others (SigH, SigB, SigI, SigJ) control osmotic and oxidative stress responses. CONCLUSIONS: From the results, we conclude that most of the metabolic pathway mRNAs required for the initial phases of germination were synthesized during the sporulation process and stably conserved in the spore. After rehydration in growth medium, the stored mRNAs are being degraded and resynthesized during first hour. From the analysis of sigma factors we conclude that conditions favoring germination evoke stress-like cell responses. PMID- 25539759 TI - Influence of family members on utilization of maternal health care services among teen and adult pregnant women in Kathmandu, Nepal: a cross sectional study. AB - BACKGROUND: In some developing countries a woman's decision to utilize maternal health care services is not made by the woman herself but by other family members. The perception of family members regarding who is the most influential person for making the decision to utilize these services is inconclusive. Hence, this study aimed to determine the perceived influential person on utilization of antenatal care (ANC) and delivery care services among teen, young adult and adult pregnant women from the perspective of the woman themselves, their husband and their mother-in-law, identify the factors associated with the woman being the most influential person, and assess the level of agreement between the woman's and her husband's response to the woman being the most influential person. METHODS: A cross-sectional study was conducted at Paropakar Maternity and Women's Hospital and Tribhuvan University Teaching Hospital. Purposive sampling technique was used to select 315 women of which 105 were from each age group and their accompanied husbands (n = 315) and mothers-in-law (n = 315). The proportion of perceived influential person and mean priority score of the perceived influence with its 95% confidence interval was calculated. The factors associated with the woman perceived as the most influential person were analyzed by multivariate logistic regression model. The agreement was analyzed using kappa statistic. RESULTS: Among teens and young adults and their husband and mother-in-law, the woman's husband was perceived as the most influential person. Among adults, the most influential person for ANC was the woman herself but for delivery care was the woman's husband. A woman of adult age, having a non-indigenous ethnicity or who was not referred was more likely to perceive herself as the most influential person in the decision to utilize delivery care. A fair to poor level of agreement was found on the perception of the most influential person for ANC and delivery care utilization. CONCLUSIONS: Both women and their husbands influenced the decision to utilize ANC and delivery care but husbands were more influential, especially in teens and young adults. Thus, husband's involvement is crucial as a strategy to improve maternal health care utilization in Nepal. PMID- 25539762 TI - Effects of seven-day diazepam administration on resting-state functional connectivity in healthy volunteers: a randomized, double-blind study. AB - RATIONALE: Benzodiazepines, such as diazepam, are anxiolytic-sedative drugs, used for the treatment of several different disorders. The pharmacological mechanism of action of benzodiazepines is well understood; however, it remains unclear which neural networks and systems are involved in translating these neurochemical actions into their therapeutic effects. OBJECTIVES: The objective of this study was to investigate the effects of 7-day diazepam administration compared to placebo on resting-state functional connectivity in healthy adults independent of any task. METHODS: Thirty-four healthy participants were randomly assigned to receive either diazepam (N = 17) or placebo (15 mg daily for 7 days) and underwent resting-state functional magnetic resonance acquisition. Model-free data analysis was performed using independent component analysis and dual regression. RESULTS: Consistent with previous research, 11 resting-state networks were identified. Increased connectivity in response to diazepam administration was found in the medial visual network and middle/inferior temporal network. Diazepam did not cause any decreases in functional connectivity. CONCLUSIONS: Diazepam administration increases functional connectivity in areas of emotional processing independent of any task. Diazepam also enhanced functional connectivity in the medial visual system, which is a brain region rich in GABAA receptors, and shows high binding of GABAergic drugs. These increases in functional connectivity are characteristic of CNS depressants. PMID- 25539763 TI - ALCAM is indirectly modulated by miR-125b in MCF7 cells. AB - MicroRNA (miRNA) deregulation is associated with various cancers. Among an expanding list of cancer-related miRNAs, deregulation of miR-125b has been well documented in many cancers including breast. Based on current knowledge, miR-125b is considered to be a tumor suppressor in breast cancers. While important messenger RNA (mRNA) targets have been defined for miR-125b, here, we aimed to further investigate direct/indirect consequences of miR-125b expression in breast cancer cells by using a transcriptome approach. Upon miR-125b expression, a total of 138 cancer-related genes were found to be differentially expressed in breast cancer cells. While only a few of these were predicted to be direct mRNA targets, majority of the gene expression changes were potentially downstream and indirect effects of miR-125b expression. Among these, activated leukocyte antigen molecule (ALCAM) mRNA and protein levels were found to be highly significantly increased upon miR-125b expression. Given the tumor suppressor role of miR-125b in our model system, upon silencing of ALCAM expression, cell proliferation rate re increased in miR-125b-expressing cells. While ALCAM's possible context-dependent roles are not clear in breast cancer, a diverse expression pattern of ALCAM mRNA was detected in a panel of breast cancer patient samples. Differentially expressed/regulated cancer-related genes upon miR-125b expression along with the significant increase of ALCAM are of future interest to understand how deregulated expression of miR-125b may have a tumor suppressor role in breast and other cancers. PMID- 25539764 TI - The Oswestry Spinal Risk Index (OSRI): an external validation study. AB - PURPOSE: The Oswestry Spinal Risk Index (OSRI) was recently reported as an adjunct in the management of metastatic spinal disease. Based on the tumour type and a general condition score, survivorship is predicted. We aimed to externally validate this new score. METHODS: We assessed the survivorship of 121 patients identified from a prospectively collated database in the National Spinal Injuries Unit in the Republic of Ireland. Actual survivorship was calculated according to the tumour subtype and general conditioning, according to the Karnofsky Performance Score (OSRI = Primary Tumour Pathology + (2-General Conditioning Score)). Our results were then compared to those previously published. RESULTS: 45.5 % were female (n = 55). The mean age at presentation was 61.5 years (range 23-85). Breast and prostate cancers were the most frequent diseases encountered. The actual survival in our cohort closely mirrored the predicted survival, according to the equation used to calculate the OSRI with an overall strong correlation found (r = 0.798, p = 0.001). CONCLUSION: We found that the OSRI is a simple to use scoring system. We found a strong correlation in our results with the predicted survivorship based on the OSRI. The OSRI can be used as a useful adjunct in the management of patient with metastatic disease of the spine. PMID- 25539766 TI - Defecation patterns in infants: a prospective cohort study. AB - INTRODUCTION: Data regarding prevalence and natural history of infant dyschezia, defined by the Rome III criteria as straining and crying for at least 10 min before successful passage of soft stools, are lacking. OBJECTIVE: We aimed to investigate prevalence and natural history of infant dyschezia. STUDY DESIGN: In 2003, 124 youth healthcare doctors participated in a national study on defecation patterns of infants. Using standardised questionnaires and bowel diaries, these were recorded of infants aged 1, 3 and 9 months old. RESULTS: Out of 1292 infants, 46.4% had no gastrointestinal complaints. At 1 and 3 months old, 3.9% and 0.9% infants, respectively, fulfilled the Rome III criteria for infant dyschezia. However, at the same time points, parents of 17.3% and 6.5% of infants, respectively, reported symptoms preceding defecation while not strictly fulfilling the Rome III criteria ('modified Rome III criteria'). Dyschezia-like symptoms (Rome III criteria) were also reported in 0.9% of 9-month-old infants, with 5.7% having symptoms (modified Rome III criteria). Only 3/61 (4.9%) Rome III dyschezia infants and 1/306 (0.3%) infants with modified Rome III criteria at 1 or 3 months had symptoms fitting the diagnosis of infant functional constipation at 9 months old. CONCLUSIONS: The present definition of infant dyschezia seems too strict. We propose to widen the definition in terms of symptoms as well as age in order to better fit the appreciation of the parents. The prevalence of infant dyschezia declines with age. There seems to be no relation to the development of functional constipation. PMID- 25539767 TI - The posterior medial blind spot of the distal tibia: implications for surgical fixation. AB - The distal tibial blind spot represents an area where improperly measured long screws may pose a risk to surrounding anatomic structures and is not well visualized on AP, mortise, and lateral radiographs. Awareness of this area as well as the use of a 45 degrees external rotation oblique view when placing fixation in this area may prevent iatrogenic injury. LEVELS OF EVIDENCE: Level V, Expert Opinion. PMID- 25539768 TI - DCDB 2.0: a major update of the drug combination database. AB - Experience in clinical practice and research in systems pharmacology suggested the limitations of the current one-drug-one-target paradigm in new drug discovery. Single-target drugs may not always produce desired physiological effects on the entire biological system, even if they have successfully regulated the activities of their designated targets. On the other hand, multicomponent therapy, in which two or more agents simultaneously interact with multiple targets, has attracted growing attention. Many drug combinations consisting of multiple agents have already entered clinical practice, especially in treating complex and refractory diseases. Drug combination database (DCDB), launched in 2010, is the first available database that collects and organizes information on drug combinations, with an aim to facilitate systems-oriented new drug discovery. Here, we report the second major release of DCDB (Version 2.0), which includes 866 new drug combinations (1363 in total), consisting of 904 distinctive components. These drug combinations are curated from ~140,000 clinical studies and the food and drug administration (FDA) electronic orange book. In this update, DCDB collects 237 unsuccessful drug combinations, which may provide a contrast for systematic discovery of the patterns in successful drug combinations. Database URL: http://www.cls.zju.edu.cn/dcdb/ PMID- 25539769 TI - C-Reactive Protein Levels Among U.S. Adults Exposed to Parental Incarceration. AB - Previous studies have linked childhood adversity to low-grade inflammation via C reactive protein (CRP) levels. This study analyzed the association between low grade inflammation and prior biological parental incarceration. Data from the National Longitudinal Study of Adolescent to Adult Health (1994-2008) were analyzed using multinomial logistic regression models. Measures included high sensitivity (hs)-CRP (<3 mg/L = reference, 3-10 mg/L = low-grade inflammation, and >10 mg/L = acute inflammation), parent incarceration occurring in the child's lifetime, and frequency and timing of incarceration with respect to child's age (0-18 years or >18 years vs. never) of incarceration. Analyses were stratified by child's gender. Final sample sizes were n = 5,396 males and n = 6,447 females for maternal incarceration and n = 4,956 males and n = 5,860 females for paternal incarceration. In models with and without potential mediators, females whose fathers were ever incarcerated were more likely to have hs-CRP levels of 3-10 mg/L than females whose fathers were never incarcerated (adjusted odds ratio [AOR]: 1.44, 95% confidence interval [CI]: [1.09, 1.91]). Additionally, daughter's age (<18 years; AOR: 1.48, 95% CI: [1.11, 1.97]) and frequency of father's incarceration were significant (AOR: 1.24, 95% CI: [1.04, 1.49]). No mediating effects were observed. Males whose fathers were incarcerated when they were >=18 years were less likely to have hs-CRP levels of 3-10 mg/L than those whose father was never incarcerated; the association was nonsignificant in the mediated model. Further investigation is needed on the physiological effects of exposure to parental incarceration and interventions to support children. PMID- 25539771 TI - The use of proportion by young domestic chicks (Gallus gallus). AB - We investigated whether 4-day-old domestic chicks can discriminate proportions. Chicks were trained to respond, via food reinforcement, to one of the two stimuli, each characterized by different proportions of red and green areas (1/4 vs. 3/4). In Experiment 1, chicks approached the proportion associated with food, even if at test the spatial dispositions of the two areas were novel. In Experiment 2, chicks responded on the basis of proportion even when the testing stimuli were of enlarged dimensions, creating a conflict between the absolute positive area experienced during training and the relative proportion of the two areas. However, chicks could have responded on the basis of the overall colour (red or green) of the figures rather than proportion per se. To control for this objection, in Experiment 3, we used new pairs of testing stimuli, each depicting a different number of small squares on a white background (i.e. 1 green and 3 red vs. 3 green and 1 red or 5 green and 15 red vs. 5 red and 15 green). Chicks were again able to respond to the correct proportion, showing they discriminated on the basis of proportion of continuous quantities and not on the basis of the prevalent colour or on the absolute amount of it. Data indicate that chicks can track continuous quantities through various manipulations, suggesting that proportions are information that can be processed by very young animals. PMID- 25539770 TI - Serum Polyunsaturated Fatty Acids and Endometriosis. AB - Polyunsaturated fatty acids (PUFAs) are fatty acids containing 2 or more double bonds, and they are classified by the location of the last double bond. Omega 3 (n-3) and omega 6 (n-6) PUFAs are obtained through food sources including fatty fish and seed/vegetable oils, respectively, and they are important to a number of physiologic processes including inflammation. Previous work demonstrates suppressive effects of n-3 PUFAs on endometriotic lesions in animal models and decreased risk of endometriosis among women with high n-3 PUFA intake. Thus, we sought to determine the relationship between circulating levels of PUFAs and endometriosis in women. To do this, we performed a cross-sectional study of serum PUFAs and clinical data from 205 women undergoing in vitro fertilization (IVF). Serum PUFAs were measured using liquid chromatography coupled to tandem mass spectroscopy and included n-3 PUFAs such as alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid and n-6 PUFAs such as linoleic acid and arachidonic acid. Multivariable logistic regression was used to determine relationships between specific and total serum PUFAs and patient history of endometriosis. Women with high serum EPA levels were 82% less likely to have endometriosis compared to women with low EPA levels (odds ratio = 0.18, 95% confidence interval 0.04-0.78). PMID- 25539772 TI - Wild vervet monkeys copy alternative methods for opening an artificial fruit. AB - Experimental studies of animal social learning in the wild remain rare, especially those that employ the most discriminating tests in which alternative means to complete naturalistic tasks are seeded in different groups. We applied this approach to wild vervet monkeys (Chlorocebus aethiops) using an artificial fruit ('vervetable') opened by either lifting a door panel or sliding it left or right. In one group, a trained model lifted the door, and in two others, the model slid it either left or right. Members of each group then watched their model before being given access to multiple baited vervetables with all opening techniques possible. Thirteen of these monkeys opened vervetables, displaying a significant tendency to use the seeded technique on their first opening and over the course of the experiment. The option preferred in these monkeys' first successful manipulation session was also highly correlated with the proportional frequency of the option they had previously witnessed. The social learning effects thus documented go beyond mere stimulus enhancement insofar as the same door knob was grasped for either technique. Results thus suggest that through imitation, emulation or both, new foraging techniques will spread across groups of wild vervet monkeys to create incipient foraging traditions. PMID- 25539773 TI - Veteran status and paid sex among American men: results from three national surveys. AB - Surprisingly little population-based, social scientific research directly examines the association between veteran status and ever paying for sex although there are theoretical reasons to expect that such an association might emerge across the life course. In this article, we examined the relationship between veteran status and ever paying for sex among American men who turned 18 years old between 1922 and 2010 using data from three independent national samples: Wave 1 of the 2005-2006 National Social Life, Health, and Aging Project (NSHAP); the 1992 National Health and Social Life Survey (NHSLS); and pooled data from the 1991, 1993, 1994, and 2010 General Social Survey (GSS). In all three datasets, we found that veterans were significantly more likely than non-veterans to report ever having paid for sex: rates across the three sub-studies ranged from 10.86 to 14.57 % among non-veterans and from 25.27 to 33.92 % among veterans. In multivariate models that controlled for demographic and early-life factors to the extent possible with available data, the odds of ever paying for sex were estimated to be 2.25-3.10 times higher among veterans than among non-veterans. In a supplemental analysis using data from the GSS, we found that longer duration of service was associated with an increased odds of ever paying for sex. While these results do not demonstrate a causal relationship between serving in the military and ever paying for sex, the strength and consistency of the findings provide compelling evidence of an association that is worthy of further theorizing and empirical investigation. There is considerable room for advancing knowledge related to the influence of military service on the initiation, maintenance, frequency, and timing of paid sexual relationships in relation to other life events. PMID- 25539774 TI - Mexican-American Adolescents' Gender-Typed Characteristics: The Role of Sibling and Friend Characteristics. AB - This study examined the role of sibling and friend characteristics in Mexican American youth's gender-typed characteristics (i.e., attitudes, interests, and leisure activities) in early versus middle adolescence using a sibling design. Mexican-American 7th graders (M = 12.51 years; SD = .58) and their older siblings (M = 15.48 years; SD = 1.57) from 246 families participated in home interviews and a series of seven nightly phone calls. Results revealed that younger/early adolescent siblings reported more traditional gender role attitudes than their older/middle adolescent siblings and older brothers were more traditional in their attitudes than older sisters. When comparing siblings' gender-typed interests and leisure activities, boys reported more masculine orientations than girls and girls reported more feminine orientations than boys. Older brothers' gender-typed characteristics were associated with the amount of time spent with and gender characteristics of their friendship group, but for younger brothers, sibling characteristics were associated with their gender-typed characteristics. In contrast, both sibling and friendship characteristics were significantly associated with older and younger sisters' gender-typed characteristics. The discussion addressed the different correlates of older and younger sisters' and brothers' gender-typed characteristics. PMID- 25539775 TI - In the grey zone between epilepsy and schizophrenia: alterations in group II metabotropic glutamate receptors. AB - Glutamate is the major excitatory neurotransmitter in the brain. The glutamate system plays an important role in the formation of synapses during brain development and synaptic plasticity. Dysfunctions in glutamate regulation may lead to hyperexcitatory neuronal networks and neurotoxicity. Glutamate excess is possibly of great importance in the pathophysiology of several neurological and psychiatric disorders such as epilepsy and schizophrenia. Interestingly, cross talk between these disorders has been well documented: psychiatric comorbidities are frequent in epilepsy and temporal lobe epilepsy is one of the highest risk factors for developing psychosis. Therefore, dysfunctions in glutamatergic neurotransmission might constitute a common pathological mechanism. A major negative feedback system is regulated by the presynaptic group II metabotropic glutamate (mGlu) receptors including mGlu2/3 receptors. These receptors are predominantly localised extrasynaptically in basal ganglia and limbic structures. Hence, mGlu2/3 receptors are an interesting target for the treatment of disorders like epilepsy and schizophrenia. A dysfunction in the glutamate system may be associated with alterations in mGlu2/3 receptor expression. In this review, we describe the localization of mGlu2/3 receptors in the healthy brain of mice, rats and humans. Secondly, changes in mGlu2/3 receptor density of the brain regions affected in epilepsy and schizophrenia are summarised. Increased mGlu2/3 receptor density might represent a compensatory mechanism of the brain to regulate elevated glutamate levels, while reduced mGlu2/3 receptor density in some brain regions may further contribute to the aberrant hyperexcitability. Further research considering the mGlu2/3 receptor can contribute significantly to the understanding of the etiological and therapeutic role of group II mGlu receptor in epilepsy, epilepsy with psychosis and schizophrenia. PMID- 25539777 TI - Reappearance of Bitot's spots after complete resolution in children between 1 and 5 years of age. AB - There is limited data on proportion of Bitot's spots (BS), which could reappear after receiving mega dose of Vitamin A (MDVA), and their complete resolution. A prospective, community-based, cohort study with 12 months follow-up was conducted among children (1-5 years) with BS at a district from North India. On diagnosis, 200,000 IU of vitamin A was administered on the same day, then after 4 weeks and subsequently after 6 months. Out of 262 children with BS, 157 (59.9%, 95% CI: 54.1-65.9) children had shown resolution of BS after the MDVA supplementation. Out of 157 children, 97 (61.8%, 95% CI: 54.2-69.4) had reappearance of BS after complete resolution. Kaplan-Meir analysis found that median duration of reappearance of BS was 5 months (95% CI: 3.8-6.2) after their complete resolution. The reappearance of BS after administration of two MDVA within 12 months suggests that children with possibly adequate serum retinol level status may have reappearance of BS. PMID- 25539776 TI - The potassium current carried by TREK-1 channels in rat cardiac ventricular muscle. AB - We studied the potassium current flowing through TREK-1 channels in rat cardiac ventricular myocytes. We separated the TREK-1 current from other current components by blocking most other channels with a blocker cocktail. We tried to inhibit the TREK-1 current by activating protein kinase A (PKA) with a mixture of forskolin and isobutyl-methylxanthine (IBMX). Activation of PKA blocked an outwardly rectifying current component at membrane potentials positive to -40 mV. At 37 degrees C, application of forskolin plus IBMX reduced the steady-state outward current measured at positive voltages by about 52 %. Application of the potassium channel blockers quinidine or tetrahexylammonium also reduced the steady-state outward current by about 50 %. Taken together, our results suggest that the increase in temperature from 22 to 37 degrees C increased the TREK-1 current by a factor of at least 5 and that the average density of the TREK-1 current in rat cardiomyocytes at 37 degrees C is about 1.5 pA/pF at +30 mV. The contribution of TREK-1 to the action potential was assessed by using a dynamic patch clamp technique. After subtraction of simulated TREK-1 currents, action potential duration at 50 or 90 % repolarisation was increased by about 12 %, indicating that TREK-1 may be functionally important in rat ventricular muscle. During sympathetic stimulation, inhibition of TREK-1 channels via PKA is expected to prolong the action potential primarily in subendocardial myocytes; this may decrease the transmural dispersion of repolarisation and thus may serve to prevent the occurrence of arrhythmias. PMID- 25539778 TI - Harlequin ichthyosis in an infant born to a father with eczema. AB - Harlequin ichthyosis is characterized by thickening of the layer of the skin which contains keratin. Eczema is a chronic relapsing skin disorder which is also associated with disrupted epidermal barrier. We report the case of a 6-hour-old male patient who was brought to the neonatal intensive care unit of our hospital with crusting skin lesions all over the body, presence of a severe ectropion and deranged electrolytes. A diagnosis of harlequin ichthyosis was made, and the neonate was managed accordingly. However, the infant eventually expired on the seventh day of life. The infant's father was a patient of eczema with a chronic relapsing course and was on oral steroid therapy. As per our knowledge, this is the first reported case of an infant with harlequin ichthyosis born to a father suffering from eczema. The similarities in the pathogenesis of the two diseases and the genetic mutation of filaggrin might suggest an association between the two conditions. Harlequin ichthyosis can hence be looked out for in infants born of parents with eczema. PMID- 25539781 TI - A Single Session of Repetitive Transcranial Magnetic Stimulation Over the Dorsolateral Prefrontal Cortex in Patients With Unresponsive Wakefulness Syndrome: Preliminary Results. AB - BACKGROUND: The level of consciousness is regulated by the activation of the frontal parietal network since a disruption within this interregional cortical connectivity is associated with a consciousness breakdown. OBJECTIVE: The primary aim of the present study was to examine the feasibility and the safety of a single session of repetitive transcranial magnetic stimulation (rTMS), delivered over the dorsolateral prefrontal cortex (DLPFC), in patients with unresponsive wakefulness syndrome (UWS). As a secondary aim, we investigated the efficacy of rTMS over DLPFC on cortico-cortical connectivity as tested with paired-pulse and dual-coil TMS techniques. METHODS: We enrolled 10 healthy and 10 postanoxic UWS subjects. After clinical assessment, subjects underwent a single/paired pulse TMS paradigm evaluating the inhibitory and facilitatory intracortical circuits. In addition, several interregional interactions between primary motor, dorsal and ventral premotor, supplementary motor, and posterior parietal cortex areas were investigated by means of dual-coil TMS technique. These parameters were evaluated at baseline, immediately after, and 60 minutes after a protocol of 10-Hz rTMS delivered at the level of the DLPFC. RESULTS: rTMS over DLPFC did not cause any adverse events. We showed that rTMS over DLPFC did not induce, at group level, any clinical improvement or intra-/intercortical connectivity changes. Interestingly, in 3 patients rTMS induced a significant, although transient, clinical improvement associated with a short-lasting reshaping of brain connectivity. CONCLUSIONS: We demonstrated that a single session of 10-Hz rTMS over the right DLPFC may transiently improve consciousness and partially restore the connectivity within several cortical areas in some patients with UWS. PMID- 25539780 TI - Effectiveness of new legislation on partial sickness benefit on work participation: a quasi-experiment in Finland. AB - OBJECTIVES: To examine the effect of the new legislation on partial sickness benefit on subsequent work participation of Finns with long-term sickness absence. Additionally, we investigated whether the effect differed by sex, age or diagnostic category. DESIGN: A register-based quasi-experimental study compared the intervention (partial sick leave) group with the comparison (full sick leave) group regarding their pre-post differences in the outcome. The preintervention and postintervention period each consisted of 365 days. SETTING: Nationwide, individual-level data on the beneficiaries of partial or full sickness benefit in 2008 were obtained from national sickness insurance, pension and earnings registers. PARTICIPANTS: 1738 persons in the intervention and 56,754 persons in the comparison group. OUTCOME: Work participation, measured as the proportion (%) of time within 365 days when participants were gainfully employed and did not receive either partial or full ill-health-related or unemployment benefits. RESULTS: Although work participation declined in both groups, the decline was 5% (absolute difference-in-differences) smaller in the intervention than in the comparison group, with a minor sex difference. The beneficial effect of partial sick leave was seen especially among those aged 45-54 (5%) and 55-65 (6%) and in mental disorders (13%). When the groups were rendered more exchangeable (propensity score matching on age, sex, diagnostic category, income, occupation, insurance district, work participation, sickness absence, rehabilitation periods and unemployment, prior to intervention and their interaction terms), the effects on work participation were doubled and seen in all age groups and in other diagnostic categories than traumas. CONCLUSIONS: The results suggest that the new legislation has potential to increase work participation of the population with long-term sickness absence in Finland. If applied in a larger scale, partial sick leave may turn out to be a useful tool in reducing withdrawal of workers from the labour market due to health reasons. PMID- 25539779 TI - Deliberative democracy and cancer screening consent: a randomised control trial of the effect of a community jury on men's knowledge about and intentions to participate in PSA screening. AB - OBJECTIVE: Prostate-specific antigen (PSA) screening is controversial. A community jury allows presentation of complex information and may clarify how participants view screening after being well-informed. We examined whether participating in a community jury had an effect on men's knowledge about and their intention to participate in PSA screening. DESIGN: Random allocation to either a 2-day community jury or a control group, with preassessment, postassessment and 3-month follow-up assessment. SETTING: Participants from the Gold Coast (Australia) recruited via radio, newspaper and community meetings. PARTICIPANTS: Twenty-six men aged 50-70 years with no previous diagnosis of prostate cancer. INTERVENTION: The control group (n=14) received factsheets on PSA screening. Community jury participants (n=12) received the same factsheets and further information about screening for prostate cancer. In addition, three experts presented information on PSA screening: a neutral scientific advisor provided background information, one expert emphasised the potential benefits of screening and another expert emphasised the potential harms. Participants discussed information, asked questions to the experts and deliberated on personal and policy decisions. MAIN OUTCOME AND MEASURES: Our primary outcome was change in individual intention to have a PSA screening test. We also assessed knowledge about screening for prostate cancer. RESULTS: Analyses were conducted using intention-to-treat. Immediately after the jury, the community jury group had less intention-to-screen for prostate cancer than men in the control group (effect size=-0.6 SD, p=0.05). This was sustained at 3-month follow-up. Community jury men also correctly identified PSA test accuracy and considered themselves more informed (effect size=1.2 SD, p<0.001). CONCLUSIONS: Evidence-informed deliberation of the harms and benefits of PSA screening effects men's individual choice to be screened for prostate cancer. Community juries may be a valid method for eliciting target group input to policy decisions. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12612001079831). PMID- 25539782 TI - Virtual Reality-Based Training to Improve Obstacle-Crossing Performance and Dynamic Balance in Patients With Parkinson's Disease. AB - BACKGROUND: Obstacle crossing is a balance-challenging task and can cause falls in people with Parkinson's disease (PD). However, programs for people with PD that effectively target obstacle crossing and dynamic balance have not been established. OBJECTIVE: To examine the effects of virtual reality-based exercise on obstacle crossing performance and dynamic balance in participants with PD. METHODS: Thirty-six participants with a diagnosis of PD (Hoehn and Yahr score ranging 1 to 3) were randomly assigned to one of three groups. In the exercise groups, participants received virtual reality-based Wii Fit exercise (VRWii group) or traditional exercise (TE group) for 45 minutes, followed by 15 minutes of treadmill training in each session for a total of 12 sessions over 6 weeks. Participants in the control group received no structured exercise program. Primary outcomes included obstacle crossing performance (crossing velocity, stride length, and vertical toe obstacle clearance) and dynamic balance (maximal excursion, movement velocity, and directional control measured by the limits-of stability test). Secondary outcomes included sensory organization test (SOT), Parkinson's Disease Questionnaire (PDQ39), fall efficacy scale (FES-I), and timed up and go test (TUG). All outcomes were assessed at baseline, after training, and at 1-month follow-up. RESULTS: The VRWii group showed greater improvement in obstacle crossing velocity, crossing stride length, dynamic balance, SOT, TUG, FES-I, and PDQ39 than the control group. VRWii training also resulted in greater improvement in movement velocity of limits-of-stability test than TE training. CONCLUSIONS: VRWii training significantly improved obstacle crossing performance and dynamic balance, supporting implementation of VRWii training in participants with PD. PMID- 25539784 TI - Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements. AB - BACKGROUND: Hyponatremia is a common electrolyte disorder. Multiple organizations have published guidance documents to assist clinicians in managing hyponatremia. We aimed to explore the scope, content, and consistency of these documents. METHODS: We searched MEDLINE, EMBASE, and websites of guideline organizations and professional societies to September 2014 without language restriction for Clinical Practice Guidelines (defined as any document providing guidance informed by systematic literature review) and Consensus Statements (any other guidance document) developed specifically to guide differential diagnosis or treatment of hyponatremia. Four reviewers appraised guideline quality using the 23-item AGREE II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Total scores were calculated as standardized averages by domain. RESULTS: We found ten guidance documents; five clinical practice guidelines and five consensus statements. Overall, quality was mixed: two clinical practice guidelines attained an average score of >50% for all of the domains, three rated the evidence in a systematic way and two graded strength of the recommendations. All five consensus statements received AGREE scores below 60% for each of the specific domains.The guidance documents varied widely in scope. All dealt with therapy and seven included recommendations on diagnosis, using serum osmolality to confirm hypotonic hyponatremia, and volume status, urinary sodium concentration, and urinary osmolality for further classification of the hyponatremia. They differed, however, in classification thresholds, what additional tests to consider, and when to initiate diagnostic work-up. Eight guidance documents advocated hypertonic NaCl in severely symptomatic, acute onset (<48 h) hyponatremia. In chronic (>48 h) or asymptomatic cases, recommended treatments were NaCl 0.9%, fluid restriction, and cause-specific therapy for hypovolemic, euvolemic, and hypervolemic hyponatremia, respectively. Eight guidance documents recommended limits for speed of increase of sodium concentration, but these varied between 8 and 12 mmol/L per 24 h. Inconsistencies also existed in the recommended dose of NaCl, its initial infusion speed, and which second line interventions to consider. CONCLUSIONS: Current guidance documents on the assessment and treatment of hyponatremia vary in methodological rigor and recommendations are not always consistent. PMID- 25539783 TI - Mismatch between perceived and objectively measured land use mix and street connectivity: associations with neighborhood walking. AB - Studies on the mismatch between objective and perceived measures of walkability and walking provide insights into targeting interventions. These studies focused on those living in more walkable environments, but perceiving them as less walkable. However, it is equally important to understand how the other mismatch (living in less walkable areas, but perceiving them as walkable) is related to walking. This study examined how the mismatch between perceived and objective walkability measures (i.e., living in less walkable areas, but perceiving them as walkable, and living in more walkable areas, but perceiving them as less walkable) was associated with walking. Baseline data from adult participants (n = 1466) of the RESIDential Environment Project (Perth, Australia in 2004-06) collected self-report neighborhood walking for recreation and transport in a usual week and participants' perceptions of street connectivity and land use mix in their neighborhood. The exposure was the mismatch between objective and perceived measures of these. Multilevel logistic regression examined associations of walking with the mismatch between perceived and objective walkability measures. Perceiving high walkable attributes as low walkable was associated with lower levels of walking, while perceiving a low walkable attribute as walkable was associated with higher levels of walking. Walking interventions must create more pedestrian-friendly environments as well as target residents' perceptions. PMID- 25539785 TI - Prevalence and prognostic value of right ventricular dysfunction in severe aortic stenosis. AB - AIMS: Systolic pulmonary artery pressure (sPAP) is a well-known outcome predictor in patients with valvular heart disease. Limited data are available regarding the evaluation of right ventricular (RV) performance, particularly in patients with aortic stenosis (AS). The aim of this study was to evaluate the prevalence, determinants, and prognostic significance of RV dysfunction in severe AS independently from the strategy of treatment chosen. METHODS AND RESULTS: Two hundred patients (mean age: 79.9 +/- 8.8 years) with severe AS underwent two dimensional and speckle tracking echocardiography for the evaluation of left ventricular (LV) and RV functions, aortic valve gradients, and sPAP. A tricuspid annular plane systolic excursion (TAPSE) <=17 mm defined RV dysfunction. RV dysfunction was detected in 48 patients (24%). At multivariable regression analysis, LV global longitudinal strain (r = -0.29, P = 0.001), mean aortic gradient (r = 0.25, P = 0.002), and LV ejection fraction (r = 0.18, P = 0.02) were well correlated with TAPSE. After a median 16-month follow-up, cardiovascular death occurred in 17 patients. At multivariate Cox regression analysis, biventricular dysfunction (TAPSE <=17 mm and LVEF <=50%) emerged as the strongest predictor of prognosis (hazard ratio 4.08, 95% confidence interval 1.36 12.22; P = 0.012). CONCLUSIONS: RV dysfunction is common in AS patients, and this finding can likely be accounted for by the RV-LV interdependence. Given that biventricular function impairment was a strong predictor of mortality in our population, we suggest that RV dysfunction should be systematically looked for in AS patients. PMID- 25539787 TI - Upgrading physical activity counselling in primary care in the Netherlands. AB - The systematic development of a counselling protocol in primary care combined with a monitoring and feedback tool to support chronically ill patients to achieve a more active lifestyle. An iterative user-centred design method was used to develop a counselling protocol: the Self-management Support Programme (SSP). The needs and preferences of future users of this protocol were identified by analysing the literature, through qualitative research, and by consulting an expert panel. The counselling protocol is based on the Five A's model. Practice nurses apply motivational interviewing, risk communication and goal setting to support self-management of patients in planning how to achieve a more active lifestyle. The protocol consists of a limited number of behaviour change consultations intertwined with interaction with and responses from the It's LiFe! monitoring and feedback tool. This tool provides feedback on patients' physical activity levels via an app on their smartphone. A summary of these levels is automatically sent to the general practice so that practice nurses can respond to this information. A SSP to stimulate physical activity was defined based on user requirements of care providers and patients, followed by a review by a panel of experts. By following this user-centred approach, the organization of care was carefully taken into account, which has led to a practical and affordable protocol for physical activity counselling combined with mobile technology. PMID- 25539788 TI - Alcohol-branded merchandise: association with Australian adolescents' drinking and parent attitudes. AB - There is growing evidence that young people own alcohol-branded merchandise (ABM), and that ownership influences their drinking intentions and behaviours. However, there is a paucity of research on parents' knowledge or attitudes in relation to ownership of ABM. Study 1 (n = 210) identified high levels of ownership of ABM and associations between ABM and drinking attitudes and behaviours. In Study 2, focus groups with Australian parents found that they were aware of ABM-and many had items of ABM in their home-but they had generally not engaged in consideration of the potential impact on their children. They clearly perceived ABM as advertising and, on reflection, acknowledged that this form of marketing may influence children's decisions about drinking. There is a need to raise parental awareness of the effects of ABM and to endeavour to reduce children's exposure to this influential form of alcohol marketing. PMID- 25539786 TI - Gender differences in the prevalence, severity, and composition of coronary artery disease in the young: a study of 1635 individuals undergoing coronary CT angiography from the prospective, multinational confirm registry. AB - OBJECTIVE: Prior studies examining coronary atherosclerosis in the young have been limited by retrospective analyses in small cohorts. We examined the relationship between cardiovascular risk factors (RFs) and prevalence and severity of coronary atherosclerosis in a large, prospective, multinational registry of consecutive young individuals undergoing coronary computerized tomographic angiography (CCTA). METHOD AND RESULTS: Of 27 125 patients undergoing CCTA, 1635 young (<45 years) individuals without known coronary artery disease (CAD) or coronary anomalies were identified. Coronary plaque was assessed for any CAD, obstructive CAD (>=50% stenosis), and presence of calcified plaque (CP) and non-calcified plaque (NCP). Among 1635 subjects (70% men, age 38 +/- 6 years), any CAD, obstructive CAD, CP, and NCP were observed in 19, 4, 5, and 8%, respectively. Compared with women, men demonstrated higher rates of any CAD (21 vs. 12%, P < 0.001), CP (6 vs. 3%, P = 0.01), and NCP (9 vs. 5%, P = 0.008), although no difference was observed for rates of obstructive CAD (5 vs. 4%, P = 0.46). Any CAD, obstructive CAD, and NCP were higher for young individuals with diabetes, hypertension, dyslipidaemia, current smoking, or family history of CAD; while only diabetes and dyslipidaemia were associated with CP. Increasing cardiovascular RFs was associated with a greater prevalence and extent and severity of CAD, with individuals with 0, 1, 2, >=3 RFs manifesting a dose response increase in any CAD (P < 0.001, for trend), obstructive CAD (P < 0.001, for trend), NCP (P < 0.001, for trend), and CP (P < 0.001, for trend). In multivariable analysis adjusting for sex and cardiovascular RFs, male sex was the strongest predictor for any CAD (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.43-2.66, P < 0.001), CP (OR = 1.46, 95% CI = 1.08-1.98, P = 0.01), and NCP (OR = 1.33, 95% CI = 1.06-1.67, P = 0.01); family history of CAD was the strongest predictor for obstructive CAD (OR = 2.71, 95% CI = 1.65-4.45, P < 0.001). CONCLUSION: Any and obstructive CAD is present in 1 in 5 and 1 in 20 young individuals, respectively, with family history associated with the greatest risk of obstructive CAD. PMID- 25539789 TI - Cervical Ectropion and Intra-Uterine Contraceptive Device (IUCD): a five-year retrospective study of family planning clients of a tertiary health institution in Lagos Nigeria. AB - BACKGROUND: Cervical ectropion (also known as cervical erosion) is a common finding on routine pelvic examination during the fertile years. The decision to treat or not remains controversial. According to studies in support of routine treatment of cervical erosion, there is a possible relationship between squamous metaplasia and squamous cell carcinoma of the cervix. To determine the prevalence of cervical ectropion and associated risk factors among clients with intra uterine contraceptive devices (IUCDs) attending a family planning clinic of a tertiary health institution in Lagos, Nigeria. METHODS: A 5-year retrospective study was conducted by assessing existing clinic records from years 2007-2011. Clients with IUCDs undergo routine pelvic examination during check-up visits. A total of 628 clients' records were seen within the stated time frame. This study was approved by the ethical committee of the Lagos State University Teaching Hospital (LASUTH) and the collected data were analyzed using SPSS version 19.0. RESULTS: The mean age of the IUCD users was 34.7+/-6.52 years, while 517 (82.3%) had secondary education. On routine pelvic examination, seventy-nine clients (12.6%) had cervical ectropion. Thirty-nine (6.2%) clients had presented with a history of abnormal vaginal bleeding while 12.1% had vaginal discharge. Treatments offered to cases of cervical ectropion include cervical painting with gentian violet (89.9%) and antibiotics prescription (58.2%). On bivariate analysis, previous hormonal contraceptive use (P=0.041) and vaginal discharge (P<0.001) were significantly associated with developing cervical ectropion. Clients with ectropion were significantly more likely to receive prescriptions for antibiotics (P<0.001). CONCLUSION: Less than one fifth of the clients had cervical erosion. However, routine pelvic examination could aid the detection and control of latent reproductive health problems such as cervical ectropion which may require further investigations for example, pap smears, to exclude potentially lethal conditions and to determine appropriate treatment modality. PMID- 25539790 TI - Goserelin plus endocrine treatments maintained long-term clinical benefit in a male patient with advanced breast cancer. AB - BACKGROUND: Goserelin plus aromatase inhibitors (AI) have already been used in male advanced breast cancer, but the cases that fulvestrantin male breast cancer are rare. CASE PRESENTATION: Here we report a case of long-term (3 years) response to Goserelin plus continuing endocrine treatments given for a male advanced breast cancer. The patient prolongs his life with high life quality, and has more time with his family. CONCLUSION: Goserelin plus endocrine treatments may benefit male breast cancer. PMID- 25539791 TI - A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia. AB - BACKGROUND: Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia. METHODS: Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461. RESULTS: Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023. CONCLUSION: LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed. CLINICAL TRIALS REGISTRATION: A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT01086748. PMID- 25539792 TI - Detailed statistical analysis plan for the pulmonary protection trial. AB - BACKGROUND: Pulmonary dysfunction complicates cardiac surgery that includes cardiopulmonary bypass. The pulmonary protection trial evaluates effect of pulmonary perfusion on pulmonary function in patients suffering from chronic obstructive pulmonary disease. This paper presents the statistical plan for the main publication to avoid risk of outcome reporting bias, selective reporting, and data-driven results as an update to the published design and method for the trial. RESULTS: The pulmonary protection trial is a randomized, parallel group clinical trial that assesses the effect of pulmonary perfusion with oxygenated blood or CustodiolTM HTK (histidine-tryptophan-ketoglutarate) solution versus no pulmonary perfusion in 90 chronic obstructive pulmonary disease patients. Patients, the statistician, and the conclusion drawers are blinded to intervention allocation. The primary outcome is the oxygenation index from 10 to 15 minutes after the end of cardiopulmonary bypass until 24 hours thereafter. Secondary outcome measures are oral tracheal intubation time, days alive outside the intensive care unit, days alive outside the hospital, and 30- and 90-day mortality, and one or more of the following selected serious adverse events: pneumothorax or pleural effusion requiring drainage, major bleeding, reoperation, severe infection, cerebral event, hyperkaliemia, acute myocardial infarction, cardiac arrhythmia, renal replacement therapy, and readmission for a respiratory related problem. CONCLUSIONS: The pulmonary protection trial investigates the effect of pulmonary perfusion during cardiopulmonary bypass in chronic obstructive pulmonary disease patients. A preserved oxygenation index following pulmonary perfusion may indicate an effect and inspire to a multicenter confirmatory trial to assess a more clinically relevant outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01614951, registered on 6 June 2012. PMID- 25539793 TI - Cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills: A comparative study. AB - This study aimed to evaluate the associated cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills (COCPs) via determination of lipids profiles, Castelli index I, leptin, adiponectin, and resistin concentrations as cardiovascular risk factors. In this cross-sectional study, the study groups consisted of control group that represented by 30 healthy married women who were not on any contraceptive mean or any hormonal therapy and had normal menstrual cycles, group two consisted of 30 women who were users of Levonorgesterl 0.15 mg plus Ethinylestradiol 0.03 mg as 21 days cycle, group three consisted of 30 women who were users of Gestodene 0.075 mg plus Ethinylestradiol 0.03 mg as 21 days cycle, and group four consisted of 30 women who were users of Drospirenone 3 mg plus Ethinylestradiol 0.03 mg as 21 days cycle. One-way analysis of variance followed by LSD post hoc test was used for comparison of variables. P value <0.05 was considered to be significant. The comparison of the studied groups revealed that COCPs containing levonorgestrel plus ethinylestradiol resulted in significantly lower adiponectin level, and significantly higher leptin and resistin levels with more atherogenic lipid profile presented by significantly higher LDL-C, significantly lower HDL-C concentrations, and significantly higher atherogenic index. Formulation containing ethinylestradiol combined with gestodene neither altered adipose tissue function nor showed deleterious effect on lipid panel. Formulation containing ethinylestradiol combined with drospirenone resulted in significantly higher HDL-C and adiponectin concentrations. In conclusion, the uptake of COCPs containing levonorgestrel plus ethinylestradiol is associated with high cardiovascular risk since this formulation showed significantly lower adiponectin concentration, significantly higher leptin, resistin, and atherogenic index as compared to other studied groups. By contrast, the formulations containing ethinylestradiol combined with third generation progestin gestodene or fourth generation progestin drospirenone are associated with low cardiovascular risk since they neither altered adipose tissue function nor impaired lipoprotein metabolism as experienced by their favorable effect on leptin, adiponectin, and resistin, with non-changed atherogenic index, higher HDL-C levels and lower LDL-C levels as compared to levonorgestrel plus ethinylestradiol formulation. PMID- 25539794 TI - Renal tubular markers in pregnant women with and without gestational diabetes mellitus: a pilot study. PMID- 25539795 TI - Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy. AB - To assess if anti-mullerian hormone (AMH) concentrations decrease during the third trimester of pregnancy and puerperium and whether this is correlated to gestational diabetes mellitus (GDM). AMH serum concentrations were determined by ELISA, with lowest detection limit of 0.08 ng/ml, during the third trimester of pregnancy and puerperium in 34 patients with GDM and in 32 healthy control pregnant women. Three blood samples were collected at 28-32, 34-36 weeks' gestation and 40 days after delivery, respectively. No differences in AMH concentration between GDM and healthy pregnant women were found at any follow-up time. On the contrary, significant differences in delta AMH values between the first and the second sample (p < 0.0001), the second and the third sample (p < 0.0001), and the first and the third sample (p = 0.004) were found in both groups. The multivariate analysis showed that maternal age was not correlated to delta AMH variations. The analysis of AMH concentrations did not show a significant relationship with body mass index-variation, newborn and placental weight, and GDM, while only maternal age was significantly correlated with AMH concentrations in all blood samples. A significant decrease in AMH values was observed during the third trimester of pregnancy and this was independent on maternal age. GDM does not seem to influence the AMH concentrations during pregnancy and after delivery. PMID- 25539796 TI - Silencing of omega-5 gliadins in transgenic wheat eliminates a major source of environmental variability and improves dough mixing properties of flour. AB - BACKGROUND: The end-use quality of wheat flour varies as a result of the growth conditions of the plant. Among the wheat gluten proteins, the omega-5 gliadins have been identified as a major source of environmental variability, increasing in proportion in grain from plants that receive fertilizer or are subjected to high temperatures during grain development. The omega-5 gliadins also have been associated with the food allergy wheat-dependent exercise-induced anaphylaxis (WDEIA). Recently, transgenic lines with reduced levels of omega-5 gliadins were developed using RNA interference (RNAi). These lines make it possible to determine whether changes in the levels of omega-5 gliadins in response to environmental conditions and agronomic inputs may be responsible for changes in flour end-use quality. RESULTS: Two transgenic wheat lines and a non-transgenic control were grown under a controlled temperature regimen with or without post anthesis fertilizer and the protein composition of the resulting flour was analyzed by quantitative two-dimensional gel electrophoresis (2-DE). In one transgenic line, all 2-DE spots identified as omega-5 gliadins were substantially reduced without effects on other proteins. In the other transgenic line, the omega-5 gliadins were absent and there was a partial reduction in the levels of the omega-1,2 gliadins and the omega-1,2 chain-terminating gliadins as well as small changes in several other proteins. With the exception of the omega gliadins, the non-transgenic control and the transgenic plants showed similar responses to the fertilizer treatment. Protein contents of flour were determined by the fertilizer regimen and were similar in control and transgenic samples produced under each regimen while both mixing time and mixing tolerance were improved in flour from transgenic lines when plants received post-anthesis fertilizer. CONCLUSIONS: The data indicate that omega-5 gliadins have a negative effect on flour quality and suggest that changes in quality with the growth environment may be due in part to alterations in the levels of the omega gliadins. Because a known food allergen and one of the major sources of environmentally-induced variation in wheat flour protein composition has been eliminated, the transgenic lines may yield flour with both improved end-use quality and more consistent functionality when grown in different locations. PMID- 25539797 TI - Chronic noncancer pain management in primary care: family medicine physicians' risk assessment of opioid misuse. AB - OBJECTIVE: The majority of patients with chronic noncancer pain (CNCP) are managed in the primary care settings. The primary care family physician (PCFP) generally has limited time, training, or access to resources to effectively evaluate and treat these patients, particularly when there is the added potential liability of prescribing opioids. The aim of this study is to make a favorable change in PCFPs' knowledge, attitudes, and practices about opioid use in CNCP via education on assessment of the risk of opioid misuse. MATERIALS AND METHODS: The universe of this cross-sectional study comprised 36 family physicians working at Family Health Centers affiliated to Antalya Provincial Directorate of Health who volunteered to participate in the study. Initially, a survey on patients risk assessment was performed in both intervention and control groups; whereas the intervention group received education on assessment of the risk of opioid misuse, the control group did not. The survey was repeated after 6 months and the intervention group underwent a core examination. Data obtained were analyzed with Statistical Package for the Social Sciences 18.0 statistics program. Intervention and control groups were compared. Additionally, pre- and post-education results of the intervention group were also compared. RESULTS: About 61.1% of family physicians reported concern and hesitation in prescribing opioids due to known risks, such as overdose, addiction, dependence, or diversion, and agreed that family physicians should apply risk assessment before opioid use in CNCP. Only 16.6% of PCFP reported that risk assessment is not so necessary, whereas 22.2% of PCFP were undecided. Although 47.2% of the family physicians expressed a willingness to apply risk assessment before starting opioids, the rate of eagerness increased markedly to 77.7% after the education, but the rate of increase in practicing was not statistically significant. CONCLUSION: Knowledge and competency of the family physicians in managing CNCP were improved as was expected. Although the rate of eagerness about risk assessment of opioid misuse was increased, expected increase in the rate of using risk assessment was not achieved. Further studies are needed to identify the reasons of the difficulties on changing the attitudes and practices of primary care physicians about this subject. PMID- 25539798 TI - A balance of quality care and patient satisfaction. PMID- 25539800 TI - Tigecycline : a critical safety review. AB - INTRODUCTION: The emergence of multidrug-resistant (MDR) infections has been extensively observed worldwide and has become a priority issue over past decade. Tigecycline , a broad spectrum antibiotic covering against many MDR organisms, has been widely used. However, recent meta-analysis studies have raised a concern for its efficacy and safety. Reviewing tigecycline safety data would enhance the appropriate use of this medication. AREAS COVERED: This article reviews the safety profile of tigecycline, including its side effects and drug interactions. EXPERT OPINION: The increased mortality associated with tigecycline is not yet well understood. Based on current evidence, alternative options must be prioritized over tigecycline if available. When tigecycline use is warranted, vigilant observation to identify any breakthrough infections and careful monitoring of progression of the original infection are highly recommended. Considering a second agent (either for synergism or enhancing coverage) may be required. PMID- 25539799 TI - An implementation framework for the feedback of individual research results and incidental findings in research. AB - BACKGROUND: This article outlines procedures for the feedback of individual research data to participants. This feedback framework was developed in the context of a personalized medicine research project in Canada. Researchers in this domain have an ethical obligation to return individual research results and/or material incidental findings that are clinically significant, valid and actionable to participants. Communication of individual research data must proceed in an ethical and efficient manner. Feedback involves three procedural steps: assessing the health relevance of a finding, re-identifying the affected participant, and communicating the finding. Re-identification requires researchers to break the code in place to protect participant identities. Coding systems replace personal identifiers with a numerical code. Double coding systems provide added privacy protection by separating research data from personal identifying data with a third "linkage" database. A trusted and independent intermediary, the "keyholder", controls access to this linkage database. DISCUSSION: Procedural guidelines for the return of individual research results and incidental findings are lacking. This article outlines a procedural framework for the three steps of feedback: assessment, re-identification, and communication. This framework clarifies the roles of the researcher, Research Ethics Board, and keyholder in the process. The framework also addresses challenges posed by coding systems. Breaking the code involves privacy risks and should only be carried out in clearly defined circumstances. Where a double coding system is used, the keyholder plays an important role in balancing the benefits of individual feedback with the privacy risks of re-identification. Feedback policies should explicitly outline procedures for the assessment of findings, and the re-identification and contact of participants. The responsibilities of researchers, the Research Ethics Board, and the keyholder must be clearly defined. We provide general guidelines for keyholders involved in feedback. We also recommend that Research Ethics Boards should not be directly involved in the assessment of individual findings. Hospitals should instead establish formal, interdisciplinary clinical advisory committees to help researchers determine whether or not an uncertain finding should be returned. PMID- 25539801 TI - Visual improvement following glaucoma surgery: a case report. AB - BACKGROUND: Glaucoma is a progressive optic neuropathy and a leading cause of blindness. Neural losses from glaucoma are irreversible, and so the aim of glaucoma treatment is to slow progression and minimize the risk of further damage. Functional improvement with treatment is not expected. We report the case of a patient who experienced a significant improvement in vision following glaucoma surgery and review the literature regarding this phenomenon. CASE PRESENTATION: A 64-year old male presented with a 13-month history of gradual vision loss in the right eye to the extent that he could only perceive hand movements. His intraocular pressure (IOP) measured 50 mmHg and he was found to have advanced primary open angle glaucoma. Medical treatment was commenced and he underwent a successful right Mitomycin C-augmented trabeculectomy. Unexpectedly he experienced marked improvement in vision post-operatively, with improvements maintained through six months of follow-up. At his most recent visit visual acuity was 6/18 in the affected eye. Although the mechanism of improved vision cannot be proven it is likely that successful lowering of IOP resulted in some reversal of retinal ganglion cell dysfunction. Important factors may have included his relatively young age, high IOP and short duration of symptoms. CONCLUSION: Although rare, functional improvements may occur following trabeculectomy. Glaucoma surgery should be offered early to those with advanced disease, and considered even in those with reduced visual acuity. PMID- 25539802 TI - Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner. AB - BACKGROUND: The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression. RESULTS: We genotyped 65 single nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p = 4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p = 7.06e 31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies. CONCLUSIONS: ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements. PMID- 25539803 TI - Cross-talk between the inflammatory response, sympathetic activation and pulmonary infection in the ischemic stroke. AB - The immune system response and inflammation play a key role in brain injury during and after a stroke. The acute immune response is responsible for secondary brain tissue damage immediately after the stroke, followed by immunosuppression due to sympathetic nervous system activation. The latter increases risk of infection complications, such as pneumonia. The pneumonia-related inflammatory state can release a bystander autoimmune response against central nervous system antigens, thereby initiating a vicious circle. The aim of this review is to summarize the relationship between ischemic stroke, sympathetic nervous system activation and pulmonary infection. PMID- 25539804 TI - Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease. AB - Prion disease is a unique category of illness, affecting both animals and humans, in which the underlying pathogenesis is related to a conformational change of a normal, self-protein called PrP(C) (C for cellular) to a pathological and infectious conformer known as PrP(Sc) (Sc for scrapie). Bovine spongiform encephalopathy (BSE), a prion disease believed to have arisen from feeding cattle with prion contaminated meat and bone meal products, crossed the species barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionosis has an effective treatment. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. In the current study, white-tailed deer were orally inoculated with attenuated Salmonella expressing PrP, while control deer were orally inoculated with vehicle attenuated Salmonella. Once a mucosal response was established, the vaccinated animals were boosted orally and locally by application of polymerized recombinant PrP onto the tonsils and rectal mucosa. The vaccinated and control animals were then challenged orally with CWD-infected brain homogenate. Three years post CWD oral challenge all control deer developed clinical CWD (median survival 602 days), while among the vaccinated there was a significant prolongation of the incubation period (median survival 909 days; p=0.012 by Weibull regression analysis) and one deer has remained CWD free both clinically and by RAMALT and tonsil biopsies. This negative vaccinate has the highest titers of IgA in saliva and systemic IgG against PrP. Western blots showed that immunoglobulins from this vaccinate react to PrP(CWD). We document the first partially successful vaccination for a prion disease in a species naturally at risk. PMID- 25539805 TI - The 'Switch' study protocol: a randomised-controlled trial of switching to an alternative tumour-necrosis factor (TNF)-inhibitor drug or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-inhibitor drug. AB - BACKGROUND: Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 1% of the UK adult population. Patients suffer considerable pain, stiffness and swelling and can sustain various degrees of joint destruction, deformity, and significant functional decline. In addition, the economic burden due to hospitalisation and loss of employment is considerable, with over 50% of patients being work-disabled within 10 years of diagnosis. Despite several biologic disease modifying anti-rheumatic drugs (bDMARD) now available, there is a lack of data to guide biologic sequencing. In the UK, second-line biologic treatment is restricted to a single option, rituximab. The aim of the SWITCH trial is to establish whether an alternative mechanism-TNF-inhibitor (TNFi) or abatacept are as effective as rituximab in patients with RA who have failed an initial TNFi drug. METHODS/DESIGN: SWITCH is a pragmatic, phase IV, multi-centre, parallel-group design, open-label, randomised, controlled trial (RCT) comparing alternative-mechanism-TNFi and abatacept with rituximab in patients with RA who have failed an initial TNFi drug. Participants are randomised in a 1:1:1 ratio to receive alternative mechanism TNFi, (monoclonal antibodies: infliximab, adalimumab, certolizumab or golimumab or the receptor fusion protein, etanercept), abatacept or rituximab during the interventional phase (from randomisation up to week 48). Participants are subsequently followed up to a maximum of 96 weeks, which constitutes the observational phase. The primary objective is to establish whether an alternative mechanism-TNFi or abatacept are non-inferior to rituximab in terms of disease response at 24 weeks post randomisation. The secondary objectives include the comparison of alternative-mechanism-TNFi and abatacept to rituximab in terms of disease response, quality of life, toxicity, safety and structural and bone density outcomes over a 12-month period (48 weeks) and to evaluate the cost effectiveness of switching patients to alternative active therapies compared to current practice. DISCUSSION: SWITCH is a well-designed trial in this therapeutic area that aims to develop a rational treatment algorithm to potentially inform personalised treatment regimens (as opposed to switching all patients to only one available (and possibly unsuccessful) therapy), which may lead to long-term improved patient outcomes and gains in population health. TRIAL REGISTRATION: UKCRN Portfolio ID: 12343; ISRCTN89222125 ; NCT01295151. PMID- 25539806 TI - Regulatory elements involved in the expression of competence genes in naturally transformable Vibrio cholerae. AB - BACKGROUND: The human pathogen Vibrio cholerae normally enters the developmental program of natural competence for transformation after colonizing chitinous surfaces. Natural competence is regulated by at least three pathways in this organism: chitin sensing/degradation, quorum sensing and carbon catabolite repression (CCR). The cyclic adenosine monophosphate (cAMP) receptor protein CRP, which is the global regulator of CCR, binds to regulatory DNA elements called CRP sites when in complex with cAMP. Previous studies in Haemophilus influenzae suggested that the CRP protein binds competence-specific CRP-S sites under competence-inducing conditions, most likely in concert with the master regulator of transformation Sxy/TfoX. RESULTS: In this study, we investigated the regulation of the competence genes qstR and comEA as an example of the complex process that controls competence gene activation in V. cholerae. We identified previously unrecognized putative CRP-S sites upstream of both genes. Deletion of these motifs significantly impaired natural transformability. Moreover, site directed mutagenesis of these sites resulted in altered gene expression. This altered gene expression also correlated directly with protein levels, bacterial capacity for DNA uptake, and natural transformability. CONCLUSIONS: Based on the data provided in this study we suggest that the identified sites are important for the expression of the competence genes qstR and comEA and therefore for natural transformability of V. cholerae even though the motifs might not reflect bona fide CRP-S sites. PMID- 25539807 TI - SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay. AB - BACKGROUND: Molecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity (LOH), which can indicate the presence of a homozygous mutation or uniparental disomy. Since these abnormalities can be associated with ID and/or MCA, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection has not been established. METHODS: We selected 21 children affected with ID, with or without congenital malformations, for whom standard genetic analyses failed to provide a diagnosis. We performed high-resolution SNP array analysis with four platforms (Affymetrix Genome-Wide Human SNP Array 6.0, Affymetrix Cytogenetics Whole-Genome 2.7 M array, Illumina HumanOmni1-Quad BeadChip, and Illumina HumanCytoSNP-12 DNA Analysis BeadChip) on whole-blood samples obtained from children and their parents to detect pathogenic CNVs and LOHs, and compared the results with those obtained on a moderate resolution array-based comparative genomic hybridization platform (NimbleGen CGX-12 Cytogenetics Array), already used in the clinical setting. RESULTS: We identified a total of four pathogenic CNVs in three patients, and all arrays successfully detected them. With the SNP arrays, we also identified a LOH containing a gene associated with a recessive disorder consistent with the patient's phenotype (i.e., an informative LOH) in four children (including two siblings). A homozygous mutation within the informative LOH was found in three of these patients. Therefore, we were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs. CONCLUSIONS: This study shows the clinical usefulness of SNP arrays in children with ID, since they successfully detect pathogenic CNVs, identify informative LOHs that can lead to the diagnosis of a recessive disorder. It also highlights some challenges associated with the use of SNP arrays in a clinical laboratory. PMID- 25539808 TI - Alterations in white matter fractional anisotropy in subsyndromal perimenopausal depression. AB - BACKGROUND: Subsyndromal depression (SSD) is considered as a predictor for future depressive disorders, however whether white matter abnormalities are involved in the high-susceptibility of women to depressive disorders during perimenopause is unknown. The purpose of this study was to investigate fractional anisotropy (FA) in the white matter of the whole brain in perimenopausal women with SSD using diffusion tensor imaging (DTI). METHODS: In a cross-sectional study, 24 perimenopausal women with SSD and 24 other age-, education-, and body mass index matched healthy women underwent DTI. A voxel-based analysis was used to elucidate regional FA changes at a voxel threshold of p < 0.001 with an extent threshold of k > 127 voxels (p < 0.05, AlphaSim correction). Subsequently, correlation analyses were performed between mean FA values in significant brain regions and plasma estradiol level. RESULTS: Compared to healthy controls, women with SSD exhibited significantly lower FA values in the left insula, while higher FA values were observed in the left ventral lateral thalamus and left and right brainstem in the midbrain. In subjects with SSD, the mean FA value in the left insula was positively correlated to plasma estradiol levels (r = 0.453, p = 0.026) (uncorrected). CONCLUSIONS: Our findings indicate altered microstructures in white matter of the insula and subcortical regions may be associated with the high susceptibility of perimenopausal women to depressive disorders. Estrogen may modulate the white matter microstructure of the insula. PMID- 25539809 TI - In vitro investigation of silica nanoparticle uptake into human endothelial cells under physiological cyclic stretch. AB - BACKGROUND: In general the prediction of the toxicity and therapeutic efficacy of engineered nanoparticles in humans is initially determined using in vitro static cell culture assays. However, such test systems may not be sufficient for testing nanoparticles intended for intravenous application. Once injected, these nanoparticles are caught up in the blood stream in vivo and are therefore in continuous movement. Physical forces such as shear stress and cyclic stretch caused by the pulsatile blood flow are known to change the phenotype of endothelial cells which line the luminal side of the vasculature and thus may be able to affect cell-nanoparticle interactions. METHODS: In this study we investigated the uptake of amorphous silica nanoparticles in primary endothelial cells (HUVEC) cultured under physiological cyclic stretch conditions (1 Hz, 5% stretch) and compared this to cells in a standard static cell culture system. The toxicity of varying concentrations was assessed using cell viability and cytotoxicity studies. Nanoparticles were also characterized for the induction of an inflammatory response. Changes to cell morphology was evaluated in cells by examining actin and PECAM staining patterns and the amounts of nanoparticles taken up under the different culture conditions by evaluation of intracellular fluorescence. The expression profile of 26 stress-related was determined by microarray analysis. RESULTS: The results show that cytotoxicity to endothelial cells caused by silica nanoparticles is not significantly altered under stretch compared to static culture conditions. Nevertheless, cells cultured under stretch internalize fewer nanoparticles. The data indicate that the decrease of nanoparticle content in stretched cells was not due to the induction of cell stress, inflammation processes or an enhanced exocytosis but rather a result of decreased endocytosis. CONCLUSIONS: In conclusion, this study shows that while the toxic impact of silica nanoparticles is not altered by stretch this dynamic model demonstrates altered cellular uptake of nanoparticles under physiologically relevant in vitro cell culture models. In particular for the development of nanoparticles for biomedical applications such improved in vitro cell culture models may play a pivotal role in the reduction of animal experiments and development costs. PMID- 25539810 TI - Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. AB - Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from 45 patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic and functional signatures in vivo in purified human T cells and monocytes. Therapy-induced changes are more prominent in T cells than in monocytes and involve largely nonoverlapping changes in coding genes, including alternatively spliced transcripts and noncoding RNAs. Pathway analysis revealed that CTLA-4 blockade induces a proliferative signature predominantly in a subset of transitional memory T cells, whereas PD-1 blockade instead leads to changes in genes implicated in cytolysis and NK cell function. Combination blockade leads to nonoverlapping changes in gene expression, including proliferation-associated and chemokine genes. These therapies also have differential effects on plasma levels of CXCL10, soluble IL-2R, and IL-1alpha. Importantly, PD-1 receptor occupancy following anti-PD-1 therapy may be incomplete in the tumor T cells even in the setting of complete receptor occupancy in circulating T cells. These data demonstrate that, despite shared property of checkpoint blockade, Abs against PD-1, CTLA-4 alone, or in combination have distinct immunologic effects in vivo. Improved understanding of pharmacodynamic effects of these agents in patients will support rational development of immune-based combinations against cancer. PMID- 25539811 TI - Chronic morphine-induced microRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6. AB - Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects including immunosuppression. However, the mechanisms are unclear. TLRs and acetylcholine are widely expressed in the immune and nervous systems, and play critical roles in immune responses. In this article, we show that morphine suppresses the innate immunity in microglia and bone marrow-derived macrophages through differential regulation of TLRs and acetylcholinesterase. Either morphine or inhibition of acetylcholine significantly promotes upregulation of microRNA 124 (miR-124) in microglia, bone marrow-derived macrophages, and the mouse brain, where miR-124 mediates morphine inhibition of the innate immunity by directly targeting a subunit of NF-kappaB p65 and TNFR-associated factor 6 (TRAF6). Furthermore, transcription factors AP-1 and CREB inhibited miR-124, whereas p65 bound directly to promoters of miR-124, thereby enhancing miR-124 transcription. Moreover, acute morphine treatment transiently upregulated the expression of p65 and phospho-p65 in both nucleus and cytoplasm priming the expression of miR-124, whereas long exposure of morphine maintained miR-124 expression, which inhibited p65- and TRAF6-dependent TLR signaling. These data suggest that modulation of miRs is capable of preventing opioid-induced damage to microglia. PMID- 25539812 TI - TSLP expression: analysis with a ZsGreen TSLP reporter mouse. AB - Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays a central role in induction of allergic inflammatory responses. Its principal targets have been reported to be dendritic cells and/or CD4 T cells; epithelial cells are a principal source. We report in this study the development of a reporter mouse (TSLP-ZsG) in which a ZsGreen (ZsG)-encoding construct has been inserted by recombineering into a bacterial artificial chromosome immediately at the translation initiating ATG of TSLP. The expression of ZsG by mice transgenic for the recombinant BAC appears to be a faithful surrogate for TSLP expression, particularly in keratinocytes and medullary thymic epithelial cells. Limited ZsG and TSLP mRNA was observed in bone marrow-derived mast cells, basophils, and dendritic cells. Using the TSLP-ZsG reporter mouse, we show that TNF-alpha and IL 4/IL-13 are potent inducers of TSLP expression by keratinocytes and that local activation of Th2 and Th1 cells induces keratinocyte TSLP expression. We suggest that the capacity of TSLP to both induce Th2 differentiation and to be induced by activated Th2 cells raises the possibility that TSLP may be involved in a positive feedback loop to enhance allergic inflammatory conditions. PMID- 25539813 TI - Phosphatidylinositol 4-phosphate 5-kinase alpha and Vav1 mutual cooperation in CD28-mediated actin remodeling and signaling functions. AB - Phosphatidylinositol 4,5-biphosphate (PIP2) is a cell membrane phosphoinositide crucial for cell signaling and activation. Indeed, PIP2 is a pivotal source for second messenger generation and controlling the activity of several proteins regulating cytoskeleton reorganization. Despite its critical role in T cell activation, the molecular mechanisms regulating PIP2 turnover remain largely unknown. In human primary CD4(+) T lymphocytes, we have recently demonstrated that CD28 costimulatory receptor is crucial for regulating PIP2 turnover by allowing the recruitment and activation of the lipid kinase phosphatidylinositol 4-phosphate 5-kinase (PIP5Kalpha). We also identified PIP5Kalpha as a key modulator of CD28 costimulatory signals leading to the efficient T cell activation. In this study, we extend these data by demonstrating that PIP5Kalpha recruitment and activation is essential for CD28-mediated cytoskeleton rearrangement necessary for organizing a complete signaling compartment leading to downstream signaling functions. We also identified Vav1 as the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kalpha, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions. PMID- 25539814 TI - Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. AB - Asthma is a chronic inflammatory disease that fails to resolve. Recently, a key role for type 2 innate lymphoid cells (ILC2s) was linked to asthma pathogenesis; however, mechanisms for ILC2 regulation remain to be determined. In this study, metabololipidomics of murine lungs identified temporal changes in endogenous maresin 1 (MaR1) during self-limited allergic inflammation. Exogenous MaR1 reduced lung inflammation and ILC2 expression of IL-5 and IL-13 and increased amphiregulin. MaR1 augmented de novo generation of regulatory T cells (Tregs), which interacted with ILC2s to markedly suppress cytokine production in a TGF beta-dependent manner. Ab-mediated depletion of Tregs interrupted MaR1 control of ILC2 expression of IL-13 in vivo. Together, the findings uncover Tregs as potent regulators of ILC2 activation; MaR1 targets Tregs and ILC2s to restrain allergic lung inflammation, suggesting MaR1 as the basis for a new proresolving therapeutic approach to asthma and other chronic inflammatory diseases. PMID- 25539815 TI - CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor. AB - Ag receptors used for cancer immunotherapy are often directed against tumor associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor associated Ag that shows low expression in many normal tissues. Transfer of MDM2 TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR engineered CD8(+) T cells and can be readily generated with the same TCR. PMID- 25539817 TI - Cutting edge: critical role for C5aRs in the development of septic lymphopenia in mice. AB - In the early stages of sepsis, lymphocytes undergo apoptosis, resulting in lymphopenia and immunosuppression. The trigger for septic lymphopenia is unknown. Using the polymicrobial model of murine sepsis, we investigated the role of C5a receptors in septic lymphopenia. In wild-type mice, cecal ligation and puncture resulted in splenocyte apoptosis and significant lymphopenia after 3 d, which was not observed in C5aR1(-/-) or C5aR2(-/-) mice. Our data show that mouse neutrophils exposed to recombinant mouse C5a cause release of histones in a dose dependent and time-dependent manner. Histone levels in spleen were significantly elevated following cecal ligation and puncture but were reduced by the absence of C5aR1. Histones induced significant lymphocyte apoptosis in vitro. Ab-mediated neutralization of histones prevented the development of lymphopenia in sepsis. Together, these results describe a new pathway of septic lymphopenia involving complement and extracellular histones. Targeting of this pathway may have therapeutic benefit for patients with sepsis or other serious illness. PMID- 25539816 TI - CD8+ T cells complement antibodies in protecting against yellow fever virus. AB - The attenuated yellow fever (YF) vaccine (YF-17D) was developed in the 1930s, yet little is known about the protective mechanisms underlying its efficiency. In this study, we analyzed the relative contribution of cell-mediated and humoral immunity to the vaccine-induced protection in a murine model of YF-17D infection. Using different strains of knockout mice, we found that CD4(+) T cells, B cells, and Abs are required for full clinical protection of vaccinated mice, whereas CD8(+) T cells are dispensable for long-term survival after intracerebral challenge. However, by analyzing the immune response inside the infected CNS, we observed an accelerated T cell influx into the brain after intracerebral challenge of vaccinated mice, and this T cell recruitment correlated with improved virus control in the brain. Using mice deficient in B cells we found that, in the absence of Abs, YF vaccination can still induce some antiviral protection, and in vivo depletion of CD8(+) T cells from these animals revealed a pivotal role for CD8(+) T cells in controlling virus replication in the absence of a humoral response. Finally, we demonstrated that effector CD8(+) T cells also contribute to viral control in the presence of circulating YF-specific Abs. To our knowledge, this is the first time that YF-specific CD8(+) T cells have been demonstrated to possess antiviral activity in vivo. PMID- 25539819 TI - A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphylatoxin C5a. AB - Polymorphonuclear neutrophilic granulocytes (PMN) as cellular components of innate immunity play a crucial role in the defense against systemic Candida albicans infection. To analyze stimuli that are required for PMN activity during C. albicans infection in a situation similar to in vivo, we used a human whole blood infection model. In this model, PMN activation 10 min after C. albicans infection was largely dependent on the anaphylatoxin C5a. Most importantly, C5a enabled blood PMN to overcome filament-restricted recognition of C. albicans and allowed efficient elimination of nonfilamentous C. albicans cph1Delta/efg1Delta from blood. Major PMN effector mechanisms, including oxidative burst, release of secondary granule contents and initial fungal phagocytosis could be prevented by blocking C5a receptor signaling. Identical effects were achieved using a humanized Ab specifically targeting human C5a. Phagocytosis of C. albicans 10 min postinfection was mediated by C5a-dependent enhancement of CD11b surface expression on PMN, thus establishing the C5a-C5aR-CD11b axis as a major modulator of early anti-Candida immune responses in human blood. In contrast, phagocytosis of C. albicans by PMN 60 min postinfection occurred almost independently of C5a and mainly contributed to activation of phagocytically active PMN at later time points. Our results show that C5a is a critical mediator in human blood during C. albicans infection. PMID- 25539818 TI - Radiation exposure induces inflammasome pathway activation in immune cells. AB - Radiation exposure induces cell and tissue damage, causing local and systemic inflammatory responses. Because the inflammasome pathway is triggered by cell death and danger-associated molecular patterns, we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase-1 detection in cells. Time course analysis showed the appearance of cleaved caspase-1 in cells by day 1 and sustained expression until day 7 after radiation. Also, cells showing inflammasome activation coexpressed the cell surface apoptosis marker annexin V. The role of caspase-1 as a trigger for hematopoietic cell losses after radiation was studied in caspase-1(-/-) mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase-1(-/-) mice than in control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase-1 activation in cells. Finally, we demonstrate that radiation-induced caspase-1 activation occurs by a Nod-like receptor family protein 3-independent mechanism because radiation-exposed Nlrp3(-/-) mice showed caspase-1 activation profiles that were indistinguishable from those of wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation. PMID- 25539821 TI - Analysis of foot and ankle disorders and prediction of gait in multiple sclerosis rehabilitation. AB - BACKGROUND: Multiple sclerosis (MS) is a disease of the central nervous system probably based on the autoimmune mechanism against myelin and the action of lymphocyte T. In the last 50 years, more than 150 descriptive studies regarding MS have focused on the etiopathogeny, treatment, diagnosis and prevention of the progressive evolution of MS. Most recently, studies in the field of rehabilitation and diagnosis have tried to present the postural aspects of control/foot and ankle control and gait pattern in MS. The aim of this study is focused on biomechanical foot analyses of MS patients. METHODS: Our clinical research and functional assessment was based on a scale like the EDSS/Kurtzke score: biomechanical foot assessment used the RSscan force plate to assess the foot loading, impulse and foot-ankle angle (subtalar angle), and pressure distribution methods for statistical analyses. The study included MS patients at the Neurologic Rehabilitation Unit, Craiova, we studied 48 patients (46.04 +/- 10.99 years) diagnosed with MS. RESULTS: This study shows that the major lesion is to the pyramidal system and the average value for functionality index (EDSS score) is 3.03 +/- 0.13, where 3 means easy paraparesis or hemiparesis. In considering postural strategies, we observed an instability left to right to be more evident in the swing phase and it influences the under the foot impulse for the next step and postural control. From the analysis of the data and pressure centre position, we can see that the high pressure is on metatarsian II to III and more or less at the heel. This means the development of an ankle strategy necessary to restore balance, stability and motor control cannot be assessed other than by clinical evaluation. Even if many physicians and physical therapists do use the functional scale in their daily assessment, it does not help us achieve a complex assessment of gait and lower limb behaviour during gait, nor does it provide information about the impact of gait on daily activities and on quality of life. CONCLUSIONS: Biomechanical assessment can help the clinician predict the functional evolution of MS patients without visible clinical gait disorders and allows the development of a strategy for rehabilitation to prevent an incorrect ankle/ankle and foot position, resulting in a lack of motor control. PMID- 25539822 TI - Bioinspired formation of 3D hierarchical CoFe2O4 porous microspheres for magnetic controlled drug release. AB - Bioinspired by the morphology of dandelion pollen grains, we successfully prepared a template-free solution-based method for the large-scale preparation of three-dimensional (3D) hierarchical CoFe2O4 porous microspheres. Besides, on the basis of the effect of the reaction time on the morphology evolution of the precursor, we proposed an in situ dissolution-recrystallization growth mechanism with morphology and phase change to understand the formation of dandelion pollenlike microspheres. Doxorubicin hydrochloride, an anticancer drug, is efficiently loaded into the CoFe2O4 microspheres. The magnetic nanoparticles as field-controlled drug carriers offer a unique power of magnetic guidance and field-triggered drug-release behavior. Therefore, 3D hierarchical CoFe2O4 porous microspheres demonstrate the great potential for drug encapsulation and controlled drug-release applications. PMID- 25539820 TI - TLR2 modulates antibodies required for intestinal ischemia/reperfusion-induced damage and inflammation. AB - In multiple clinical conditions, including trauma and hemorrhage, reperfusion magnifies ischemic tissue damage. Ischemia induces expression of multiple neoantigens, including lipid alterations that are recognized by the serum protein, beta2-glycoprotein I (beta2-GPI). During reperfusion, binding of beta2 GPI by naturally occurring Abs results in an excessive inflammatory response that may lead to death. As beta2-GPI is critical for intestinal ischemia/reperfusion (IR)-induced tissue damage and TLR2 is one of the proposed receptors for beta2 GPI, we hypothesized that IR-induced intestinal damage and inflammation require TLR2. Using TLR2(-/-) mice, we demonstrate that TLR2 is required for IR-induced mucosal damage, as well as complement activation and proinflammatory cytokine production. In response to IR, TLR2(-/-) mice have increased serum beta2-GPI compared with wild-type mice, but beta2-GPI is not deposited on ischemic intestinal tissue. In addition, TLR2(-/-) mice also did not express other novel Ags, suggesting a sequential response. Unlike other TLRs, TLR2(-/-) mice lacked the appropriate Ab repertoire to induce intestinal IR tissue damage or inflammation. Together, these data suggest that, in addition to the inflammatory response, IR-induced injury requires TLR2 for naturally occurring Ab production. PMID- 25539825 TI - Granulomatosis with polyangiitis granulomata show increased uptake of FDG. PMID- 25539823 TI - SETIL: Italian multicentric epidemiological case-control study on risk factors for childhood leukaemia, non hodgkin lymphoma and neuroblastoma: study population and prevalence of risk factors in Italy. AB - BACKGROUND: Aetiology of childhood leukaemia and childhood neoplasm is poorly understood. Information on the prevalence of risk factors in the childhood population is limited. SETIL is a population based case-control study on childhood leukaemia, conducted with two companion studies on non-Hodgkin Lymphoma (NHL) and neuroblastoma. The study relies on questionnaire interviews and 50 Hz magnetic field (ELF-MF) indoor measurements. This paper discusses the SETIL study design and includes descriptive information. METHODS: The study was carried out in 14 Italian regions (78.3% of Italian population aged 0-10). It included leukaemia, NHL and neuroblastoma cases incident in 0-10 year olds in 1998-2001, registered by the Italian Association of Paediatric Haematology and Oncology (AIEOP) (accrual over 95% of estimated incidence). Two controls for each leukaemia case were randomly sampled from the Local Health Authorities rolls, matched by gender, birthdate and residence. The same controls were used in NHL and neuroblastoma studies. Parents were interviewed at home on: physical agents (ELF-MF and ionizing radiation), chemicals (smoking, solvents, traffic, insecticides), occupation, medical and personal history of children and parents, infectious diseases, immunizations and associated factors. Occupational exposure was collected using job specific modules. ELF-MF was measured in the main rooms (spot measurement) and close to child's bed (48 hours measurement). RESULTS: The study included: 683 leukaemia cases (87% ALL, 13% AnLL), 97 NHL, 155 neuroblastomas, and 1044 controls. CONCLUSIONS: SETIL represents a data source on exposure of Italian children to a broad array of potential carcinogenic factors. PMID- 25539826 TI - Ofatumumab: a novel treatment for severe systemic lupus erythematosus. PMID- 25539827 TI - Increased expression of chemerin in endothelial cells due to Fli1 deficiency may contribute to the development of digital ulcers in systemic sclerosis. AB - OBJECTIVES: Chemerin is a member of adipocytokines with a chemoattractant effect on plasmacytoid dendritic cells and macrophages and pro-angiogenic properties. We investigated the potential role of chemerin in the development of SSc. METHODS: Chemerin expression was evaluated by immunostaining and/or real-time quantitative RT-PCR in human and murine skin. The mechanisms regulating chemerin expression in dermal fibroblasts and endothelial cells were examined using the gene silencing technique and chromatin immunoprecipitation. Serum chemerin levels were determined by ELISA in 64 SSc patients and 19 healthy subjects. RESULTS: In SSc lesional skin, chemerin was up-regulated in small blood vessels, while it was down-regulated in fibroblasts surrounded with thickened collagen bundles. The decreased expression of chemerin was significantly reversed by TGF-beta1 antisense oligonucleotide in cultured SSc dermal fibroblasts and chemerin expression was markedly decreased in dermal fibroblasts of bleomycin-treated mice. Gene silencing of transcription factor Fli1, which binds to the chemerin promoter, induced chemerin expression in human dermal microvascular endothelial cells and Fli1(+/-) mice exhibited elevated chemerin expression in dermal blood vessels. Serum chemerin levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. In SSc patients with normal renal function, patients with digital ulcers had higher serum chemerin levels than those without. CONCLUSION: Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-beta, while it is up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. Increased chemerin expression in dermal blood vessels may be associated with the development of digital ulcers in SSc. PMID- 25539829 TI - Reproducibility enhancement and differential expression of non predefined functional gene sets in human genome. AB - BACKGROUND: Transcriptogram profiling is a method to present and analyze transcription data in a genome-wide scale that reduces noise and facilitates biological interpretation. An ordered gene list is produced, such that the probability that the genes are functionally associated exponentially decays with their distance on the list. This list presents a biological logic, evinced by the selective enrichment of successive intervals with Gene Ontology terms or KEGG pathways. Transcriptograms are expression profiles obtained by taking the average of gene expression over neighboring genes on this list. Transcriptograms enhance reproducibility and precision for expression measurements of functionally correlated gene sets. RESULTS: Here we present an ordering list for Homo sapiens and apply the transcriptogram profiling method to different datasets. We show that this method enhances experiment reproducibility and enhances signal. We applied the method to a diabetes study by Hwang and collaborators, which focused on expression differences between cybrids produced by the hybridization of mitochondria of diabetes mellitus donors with osteosarcoma cell lines, depleted of mitochondria. We found that the transcriptogram method revealed significant differential expression in gene sets linked to blood coagulation and wound healing pathways, and also to gene sets that do not represent any metabolic pathway or Gene Ontology term. These gene sets are connected to ECM-receptor interaction and secreted proteins. CONCLUSION: The transcriptogram profiling method provided an automatic way to define sets of genes with correlated expression, reduce noise in genome-wide transcription profiles, and enhance measure reproducibility and sensitivity. These advantages enabled biologic interpretation and pointed to differentially expressed gene sets in diabetes mellitus which were not previously defined. PMID- 25539830 TI - TDP-43 pathology in the basal forebrain and hypothalamus of patients with amyotrophic lateral sclerosis. AB - INTRODUCTION: Amyotrophic lateral sclerosis is a neurodegenerative disease characterized clinically by motor symptoms including limb weakness, dysarthria, dysphagia, and respiratory compromise, and pathologically by inclusions of transactive response DNA-binding protein 43 kDa (TDP-43). Patients with amyotrophic lateral sclerosis also may demonstrate non-motor symptoms and signs of autonomic and energy dysfunction as hypermetabolism and weight loss that suggest the possibility of pathology in the forebrain, including hypothalamus. However, this region has received little investigation in amyotrophic lateral sclerosis. In this study, the frequency, topography, and clinical associations of TDP-43 inclusion pathology in the basal forebrain and hypothalamus were examined in 33 patients with amyotrophic lateral sclerosis: 25 men and 8 women; mean age at death of 62.7 years, median disease duration of 3.1 years (range of 1.3 to 9.8 years). RESULTS: TDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n=10) and hypothalamus (n=7). This pathology was associated with non-motor system TDP-43 pathology (Chi2=17.5, p=0.00003) and bulbar symptoms at onset (Chi2=4.04, p=0.044), but not age or disease duration. Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W=11, p=0.023). CONCLUSIONS: This is the first systematic demonstration of pathologic involvement of the basal forebrain and hypothalamus in amyotrophic lateral sclerosis. Furthermore, the findings suggest that involvement of the basal forebrain and hypothalamus has significant phenotypic associations in amyotrophic lateral sclerosis, including site of symptom onset, as well as deficits in energy metabolism with loss of body mass index. PMID- 25539828 TI - Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. AB - RA is a complex multifactorial chronic disease that transitions through several stages. Multiple studies now support that there is a prolonged phase in early RA development during which there is serum elevation of RA-related autoantibodies including RF and ACPAs in the absence of clinically evident synovitis. This suggests that RA pathogenesis might originate in an extra-articular location, which we hypothesize is a mucosal site. In discussing this hypothesis, we will present herein the current understanding of mucosal immunology, including a discussion about the generation of autoimmune responses at these surfaces. We will also examine how other factors such as genes, microbes and other environmental toxins (including tobacco smoke) could influence the triggering of autoimmunity at mucosal sites and eventually systemic organ disease. We will also propose a research agenda to improve our understanding of the role of mucosal inflammation in the development of RA. PMID- 25539831 TI - Downregulation of cystathionine beta-synthase and cystathionine gamma-lyase expression stimulates inflammation in kidney ischemia-reperfusion injury. AB - Inflammation plays a critical role in kidney ischemia-reperfusion injury but mechanisms of increased proinflammatory cytokine expression are not completely understood. Kidney has a high expression of cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) that can synthesize hydrogen sulfide. CBE and CSE are also responsible for the synthesis of cysteine, an essential precursor for glutathione, an antioxidant. Reduced hydrogen sulfide and glutathione production is associated with multiple organ injury. Although pro- and anti-inflammatory effects of hydrogen sulfide have been reported, its role in ischemia-reperfusion induced inflammation in the kidney has not been well addressed. The aim of this study was to investigate the effect of CBS and CSE-mediated hydrogen sulfide and glutathione production on kidney inflammatory response and the mechanism involved. The left kidney of Sprague-Dawley rat was subjected to 45-min ischemia followed by reperfusion for 24 h. Ischemia-reperfusion caused a significant decrease in CBS and CSE mRNA and protein levels with a concomitant reduction of glutathione and hydrogen sulfide production in the kidney while the expression of proinflammatory cytokine expression (MCP-1, IL-6) was elevated. Hypoxia reoxygenation of proximal tubular cells led to a decrease in CBS and CSE expression and an increase in proinflammatory cytokine expression. Supplementation of glutathione or hydrogen sulfide donor (NaHS) effectively attenuated cytokine expression in tubular cells. These results suggested that ischemia-reperfusion impaired CBS and CSE-mediated glutathione and hydrogen sulfide production in the kidney, which augmented the expression of proinflammatory cytokines. Regulation of CBS and CSE expression may be therapeutically relevant in alleviating ischemia-reperfusion-induced inflammation and improving kidney function. PMID- 25539832 TI - Visuomotor deficits during locomotion in previously concussed athletes 30 or more days following return to play. AB - Current protocols for returning athletes to play (RTP) center around resolution of physical symptoms of concussion. However, recent research has identified that balance and cognitive deficits persist beyond physical symptom recovery. Protocols that involve testing dynamic balance and visuomotor integration have been recommended as potential tools for better understanding of length of impairment following concussion. A dynamic, visuomotor paradigm was undertaken in the current study to assess decision making in athletes who had sustained a concussion >30 days before study participation and had been cleared to RTP (N = 10). Two obstacles created a gap that varied between 0.6 and 1.8* participants' individual shoulder width in open space. Participants made decisions to navigate through or deviate around the gap created by the two obstacles. The results revealed that previously concussed athletes were highly variable in their decision making and demonstrated variable Medial-Lateral (ML) center of mass (COM) control when approaching the obstacles, when compared with nonconcussed, age-matched controls. As such, they showed poor visuomotor control and decision making, as well as poor dynamic stability compared to controls. Visuomotor deficits were persistent in the sample of previously concussed individuals, well beyond deficits identified by current RTP standards. This study suggests that dynamic, visuomotor integration tasks may be of benefit to increase rigor in RTP protocols and increase safety of athletes returning to sport. PMID- 25539833 TI - Endurance exercise induces REDD1 expression and transiently decreases mTORC1 signaling in rat skeletal muscle. AB - Working muscle conserves adenosine triphosphate (ATP) for muscle contraction by attenuating protein synthesis through several different pathways. Regulated in development and DNA damage response 1 (REDD1) is one candidate protein that can itself attenuate muscle protein synthesis during muscle contraction. In this study, we investigated whether endurance exercise induces REDD1 expression in association with decreased mammalian target of rapamycin (mTOR) complex I (mTORC1) signaling and global protein synthesis in rat skeletal muscle. After overnight fasting, rats ran on a treadmill at a speed of 28 m/min for 60 min, and were killed before and immediately, 1, 3, 6, 12, and 24 h after exercise. REDD1 mRNA and corresponding protein levels increased rapidly immediately after exercise, and gradually decreased back to the basal level over a period of 6 h in the gastrocnemius muscle. Phosphorylation of mTOR Ser2448 and S6K1 Thr389 increased with the exercise, but diminished in 1-3 h into the recovery period after cessation of exercise. The rate of protein synthesis, as determined by the surface sensing of translation (SUnSET) method, was not altered by exercise in fasted muscle. These results suggest that REDD1 attenuates exercise-induced mTORC1 signaling. This may be one mechanism responsible for blunting muscle protein synthesis during exercise and in the early postexercise recovery period. PMID- 25539834 TI - Bioinformatic identification of connective tissue growth factor as an osteogenic protein within skeletal muscle. AB - Aging is associated with increasing incidence of osteoporosis; a skeletal disorder characterized by compromised bone strength that may predispose patients to an increased risk of fracture. It is imperative to identify novel ways in which to attenuate such declines in the functional properties of bone. The purpose of this study was to identify, through in silico, in vitro, and in vivo approaches, a protein secreted from skeletal muscle that is putatively involved in bone formation. We performed a functional annotation bioinformatic analysis of human skeletal muscle-derived secretomes (n = 319) using DAVID software. Cross referencing was conducted using OMIM, Unigene, UniProt, GEO, and CGAP databases. Signal peptides and transmembrane residues were analyzed using SignalP and TMHMM software. To further investigate functionality of the identified protein, L6 and C2C12 myotubes were grown for in vitro analysis. C2C12 myotubes were subjected to 16 h of glucose deprivation (GD) prior to analysis. In vivo experiments included analysis of 6-week calorie restricted (CR) rat muscle samples. Bioinformatic analysis yielded 15 genes of interest. GEO dataset analysis identified BMP5, COL1A2, CTGF, MGP, MMP2, and SPARC as potential targets for further processing. Following TMHMM and SignalP processing, CTGF was chosen as a candidate gene. CTGF expression level was increased during L6 myoblast differentiation (P < 0.01). C2C12 myotubes showed no change in response to GD. Rat soleus muscle samples exhibited an increase in CTGF expression (n = 16) in response to CR (35%) (P < 0.05). CTGF was identified as a skeletal muscle expressed protein through bioinformatic analysis of skeletal muscle-derived secretomes and in vitro/in vivo analysis. Future study is needed to determine the role of muscle-derived CTGF in bone formation and remodeling processes. PMID- 25539835 TI - Loading-associated expression of TRIM72 and caveolin-3 in antigravitational soleus muscle in mice. AB - Effects of mechanical loading on the expression level of tripartite motif containing 72 (TRIM72) and caveolin-3 (Cav-3) in mouse soleus muscle were investigated. Mice were subjected to (1) continuous hindlimb suspension (HS) for 2 weeks followed by 1-week ambulation recovery or (2) functional overloading (FO) on the soleus by cutting the distal tendons of the plantaris and gastrocnemius muscles. Soleus muscle atrophy was induced by 2-week hindlimb suspension (HS). Reloading-associated regrowth of atrophied soleus muscle was observed by 1-week reloading following HS. HS also depressed the expression level of insulin receptor substrate-1 (IRS-1) mRNA, TRIM72, Cav-3, and phosphorylated Akt (p Akt)/total Akt (t-Akt), but increased the phosphorylated level of p38 mitogen activated protein kinase (p-p38MAPK) in soleus muscle. Thereafter, the expression level of MyoD mRNA, TRIM72 (mRNA, and protein), and Cav-3 was significantly increased and recovered to the basal level during 1-week reloading after HS. Although IRS-1 expression was also upregulated by reloading, the expression level was significantly lower than that before HS. Significant increase in p-Akt and phosphorylated p70 S6 kinase (p-p70S6K) was observed by 1-day reloading. On the other hand, 1-week functional overloading (FO) induced soleus muscle hypertrophy. In FO-associated hypertrophied soleus muscle, the expression level of IRS-1 mRNA, MyoD mRNA, TRIM72 mRNA, p-Akt, and p-p70S6K was increased, but the expression of Cav-3 and p-p38MAPK was decreased. FO had no effect on the protein expression level of TRIM72. These observations suggest that the loading-associated upregulation of TRIM72 protein in skeletal muscle may depress the regrowth of atrophied muscle via a partial suppression of IRS-1. In addition, downregulation of Cav-3 in skeletal muscle may depress overloading-induced muscle hypertrophy. PMID- 25539836 TI - Performance of the European Working Group on Sarcopenia in Older People algorithm in screening older adults for muscle mass assessment. AB - BACKGROUND: There is a lack of consensus on the diagnosis of sarcopenia. A screening and diagnostic algorithm was proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). OBJECTIVE: To assess the performance of the EWGSOP algorithm in determining the proportion of subjects suspected of having sarcopenia and selected to undergo subsequent muscle mass (MM) measurement. DESIGN: A cross-sectional study. SETTING: The cohorts, Frailty in Brazilian Older People Study-Rio de Janeiro (FIBRA-RJ), Brazil; Coyoacan Cohort (CC), Mexico City, Mexico; and Toledo Study for Healthy Aging (TSHA), Toledo, Spain. SUBJECTS: Three thousand two hundred and sixty community-dwelling individuals, 65 years and older. METHODS: Initially, the EWGSOP algorithm was applied using its originally proposed cut-off values for gait speed and handgrip strength; in the second step, values tailored for the specific cohorts were used. RESULTS: Using the originally suggested EWGSOP cut-off points, 83.4% of the total cohort (94.4% in TSHA, 75.5% in FIBRA-RJ, 67.8% in CC) would have been considered as suspected of sarcopenia. Adapted cut-off values lowered the proportion of abnormal results to 34.2% (quintile-based approach) and 23.71% (z-score approach). CONCLUSIONS: The algorithm proposed by the EWGSOP is of limited clinical utility in screening older adults for sarcopenia due to the high proportion of subjects selected to further undergo MM assessment. Tailoring cut-off values to specific characteristics of the population being studied reduces the number of people selected for MM assessment, probably improving the performance of the algorithm. Further research including the objective measure of MM is needed to determine the accuracy of these specific cut-off points. PMID- 25539837 TI - Understanding DNA-binding specificity by bacteria hybrid selection. AB - Understanding how sequence-specific protein-DNA interactions direct cellular function is of great interest to the research community. High-throughput methods have been developed to determine DNA-binding specificities; one such technique, the bacterial one-hybrid (B1H) system, confers advantages including ease of use, sensitivity and throughput. In this review, we describe the evolution of the B1H system as a tool capable of screening large DNA libraries to investigate protein DNA interactions of interest. We discuss how DNA-binding specificities produced by the B1H system have been used to predict regulatory targets. Additionally, we examine how this approach has been applied to characterize two common DNA-binding domain families-homeodomains and Cys2His2 zinc fingers-both in organism-wide studies and with synthetic approaches. In the case of the former, the B1H system has produced large catalogs of protein specificity and nuanced information about previously recovered DNA targets, thereby improving our understanding of these proteins' functions in vivo and increasing our capacity to predict similar interactions in other species. In the latter, synthetic screens of the same DNA binding domains have further refined our models of specificity, through analyzing comprehensive libraries to uncover all proteins able to bind a complete set of targets, and, for instance, exploring how context-in the form of domain position within the parent protein-may affect specificity. Finally, we recognize the limitations of the B1H system and discuss its potential for use in the production of designer proteins and in studies of protein-protein interactions. PMID- 25539839 TI - Integrating yoga therapy in the management of urinary incontinence: a case report. AB - A 63-year-old overweight female prediagnosed of stress urinary incontinence presented with exacerbated events of urine leakage. She was advised a residential lifestyle and behavioral program, primarily consisting of a monitored yoga therapy module, apart from her ongoing anticholinergic medicine, for 21 days. Assessments were based on a frequency volume chart, a bladder diary for the entire duration of treatment, and the International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence Short Form questionnaire on the days of admission and discharge. A total of 1.9 kg of weight loss was observed during her stay. Usage of pad, as reported in her diary, reduced from 3 to 1 per day. Her International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence Short Form score reduced from 16 to 9, indicating better continence. She expressed subjective well-being and confidence in her social interactions. This is probably the first case report demonstrating feasibility of integration of yoga therapy in the management of urinary incontinence. PMID- 25539838 TI - Hierarchy of non-glucose sugars in Escherichia coli. AB - BACKGROUND: Understanding how cells make decisions, and why they make the decisions they make, is of fundamental interest in systems biology. To address this, we study the decisions made by E. coli on which genes to express when presented with two different sugars. It is well-known that glucose, E. coli's preferred carbon source, represses the uptake of other sugars by means of global and gene-specific mechanisms. However, less is known about the utilization of glucose-free sugar mixtures which are found in the natural environment of E. coli and in biotechnology. RESULTS: Here, we combine experiment and theory to map the choices of E. coli among 6 different non-glucose carbon sources. We used robotic assays and fluorescence reporter strains to make precise measurements of promoter activity and growth rate in all pairs of these sugars. We find that the sugars can be ranked in a hierarchy: in a mixture of a higher and a lower sugar, the lower sugar system shows reduced promoter activity. The hierarchy corresponds to the growth rate supported by each sugar- the faster the growth rate, the higher the sugar on the hierarchy. The hierarchy is 'soft' in the sense that the lower sugar promoters are not completely repressed. Measurement of the activity of the master regulator CRP-cAMP shows that the hierarchy can be quantitatively explained based on differential activation of the promoters by CRP-cAMP. Comparing sugar system activation as a function of time in sugar pair mixtures at sub-saturating concentrations, we find cases of sequential activation, and also cases of simultaneous expression of both systems. Such simultaneous expression is not predicted by simple models of growth rate optimization, which predict only sequential activation. We extend these models by suggesting multi-objective optimization for both growing rapidly now and preparing the cell for future growth on the poorer sugar. CONCLUSION: We find a defined hierarchy of sugar utilization, which can be quantitatively explained by differential activation by the master regulator cAMP-CRP. The present approach can be used to understand cell decisions when presented with mixtures of conditions. PMID- 25539840 TI - A goodness-of-fit test for the random-effects distribution in mixed models. AB - In this paper, we develop a simple diagnostic test for the random-effects distribution in mixed models. The test is based on the gradient function, a graphical tool proposed by Verbeke and Molenberghs to check the impact of assumptions about the random-effects distribution in mixed models on inferences. Inference is conducted through the bootstrap. The proposed test is easy to implement and applicable in a general class of mixed models. The operating characteristics of the test are evaluated in a simulation study, and the method is further illustrated using two real data analyses. PMID- 25539841 TI - E-Health, another mechanism to recruit and retain healthcare professionals in remote areas: lessons learned from EQUI-ResHuS project in Mali. AB - BACKGROUND: The aim of this study was to evaluate the perceived influence of telehealth on recruitment and retention of healthcare professionals in remote areas in Mali. METHODS: After 15 months of diagnosis imaging training and telehealth activities at four project sites in remote Mali, between May 2011 and August 2012, a 75-item questionnaire was administered to healthcare professionals to assess the various factors related to Information and Communication Technologies (ICT), especially telehealth, and their influence on health personnel recruitment and retention. Questions assessing perceived impact of telehealth on recruitment and retention of healthcare professionals were rated on a five-point Likert scale. Dependent variables were perceived influence of ICT on recruitment and retention and independent variables were access to ICT, ICT training, ICT use, perceived benefits and drawbacks of telehealth, and perceived barriers to recruitment and retention. A multiple linear regression was performed to identify variables explaining the respondents' perceptions regarding telehealth influence on recruitment and retention. RESULTS: Data analysis showed that professionals in remote areas have very positive perceptions of telehealth in general. Many benefits of telehealth for recruitment and retention were highlighted, with perceived benefits of ICT (p = 0.0478), perceived effects of telehealth on recruitment (p = 0.0018), telehealth training (0.0338) and information on telehealth (0.0073) being the strongest motivators for recruitment, while the perceived effects of telehealth on retention (p = 0.0018) was the only factor significantly associated with retention. CONCLUSIONS: Based on our study results, telehealth could represent a mechanism for recruiting and retaining health professionals in remote areas and could reduce the isolation of these professionals through networking opportunities. PMID- 25539842 TI - A cross-sectional survey of the mental health needs of refugees and asylum seekers attending a refugee health clinic: a study protocol for using research to inform local service delivery. AB - BACKGROUND: Refugees and asylum seekers have high rates of risk factors for mental disorders. In recent years, Australia has experienced a rapid increase in asylum seeker arrivals, creating new challenges for services in areas with high settlement numbers. This paper describes the design, including analytic framework, of a project set in a refugee health service in the state of Victoria, Australia, as part of their response to meeting the mental health needs of their burgeoning local population of refugees and asylum seekers. In order to assist service planning, the primary aim of this study is to determine: 1) an overall estimate of the prevalence of psychiatric disorders; 2) the specific prevalence of post-traumatic stress disorder 3) the perceived need and unmet need for mental health treatment. The secondary aim of the study is to establish matched risk ratios based on an Australian-born matched comparison group from the 2007 National Survey of Mental Health and Well-Being. METHODS/DESIGN: A cross sectional survey is used to estimate the prevalence of psychiatric disorders in refugees and asylum seekers attending a local refugee health service. Measures include the Kessler Psychological Distress Scale-10, the Post-Traumatic Stress Disorder-8, the General-practice User's Perceived-need Inventory together with service utilisation questions from the National Survey of Mental Health and Well Being. Data collected from refugees and asylum seekers (n = 130) is matched to existing data from Australian-born residents drawn from the 2007 National Survey of Mental Health and Well-Being (n = 520) to produce estimates of the risk ratio. DISCUSSION: The paper describes a prototype for what is possible within regular services seeking to plan for and deliver high quality mental health care to refugees and asylum seekers. A novel project output will be the development and dissemination of an epidemiological methodology to reliably compare mental health status in a relatively small target sample with a matched comparator group. PMID- 25539844 TI - Detour matrix-based adjacent path eccentric distance sum indices for QSAR/QSPR. Part I: development and evaluation. AB - In the present study, three detour matrix-based topological indices (TIs) termed as adjacent path eccentric distance sum indices 1-3 (denoted by (A)xi(1)(PDS), (A)xi(2)(PDS) and (A)xi(3)(PDS)) as well as their topochemical versions (denoted by (A)xi(1c)(PDS), (A)xi(2c)(PDS) and (A)xi(3c)(PDS)) have been conceptualised. Values of the proposed TIs were computed for all possible cyclic and acyclic structures containing three, four, five vertices using an in-house computer programme. Proposed TIs were evaluated for discriminating power, degeneracy, intercorrelation and sensitivity towards branching as well relative position of substituent(s) in cyclic structures. Mathematical properties of one of the proposed TIs were also studied. Exceptionally high discriminating power, high sensitivity towards branching as well as relative position(s) of substituent(s) in cyclic structures and negligible degeneracy offer proposed indices a vast potential for use in characterisation of structures, similarity/dissimilarity studies, lead identification and optimisation, combinatorial library design and quantitative structure-activity/property/toxicity/pharmacokinetic relationship studies so as to facilitate drug design. PMID- 25539843 TI - Quantification of epigenetic biomarkers: an evaluation of established and emerging methods for DNA methylation analysis. AB - BACKGROUND: DNA methylation is an important epigenetic mechanism in several human diseases, most notably cancer. The quantitative analysis of DNA methylation patterns has the potential to serve as diagnostic and prognostic biomarkers, however, there is currently a lack of consensus regarding the optimal methodologies to quantify methylation status. To address this issue we compared five analytical methods: (i) MethyLight qPCR, (ii) MethyLight digital PCR (dPCR), methylation-sensitive and -dependent restriction enzyme (MSRE/MDRE) digestion followed by (iii) qPCR or (iv) dPCR, and (v) bisulfite amplicon next generation sequencing (NGS). The techniques were evaluated for linearity, accuracy and precision. RESULTS: MethyLight qPCR displayed the best linearity across the range of tested samples. Observed methylation measured by MethyLight- and MSRE/MDRE qPCR and -dPCR were not significantly different to expected values whilst bisulfite amplicon NGS analysis over-estimated methylation content. Bisulfite amplicon NGS showed good precision, whilst the lower precision of qPCR and dPCR analysis precluded discrimination of differences of < 25% in methylation status. A novel dPCR MethyLight assay is also described as a potential method for absolute quantification that simultaneously measures both sense and antisense DNA strands following bisulfite treatment. CONCLUSIONS: Our findings comprise a comprehensive benchmark for the quantitative accuracy of key methods for methylation analysis and demonstrate their applicability to the quantification of circulating tumour DNA biomarkers by using sample concentrations that are representative of typical clinical isolates. PMID- 25539845 TI - Detour matrix-based adjacent path eccentric distance sum indices for (Q)SAR/QSPR. Part II: application in development of models for COX-2 inhibitory activity of indomethacin derivatives. AB - In present study, adjacent path eccentric distance sum indices proposed in Part-I of the manuscript were successfully utilised for the development of models for cycloxygenase-2 (COX-2) inhibitory activity. Values of diverse molecular descriptors (MDs) for each of 38 indomethacin analogues involved in the dataset were computed. A total of 55 diverse MDs were ultimately shortlisted for further analysis. The suitable models were developed using decision tree (DT), random forest (RF) and moving average analysis (MAA). The DT identified the proposed topological index (TI)-(A)xi(3)(PDS) as one of the important indices. The accuracy of prediction of DT, RF and MAA-based models varied from 81.58% to 97.37%. The statistical significance of proposed models was assessed through inter-correlation analysis, sensitivity, specificity, non-error rate and Mathews correlation coefficient. Proposed models offer vast potential for providing lead structures for the development of potent anti-inflammatory agents devoid of COX-1 side effects. PMID- 25539846 TI - Adaptive tree-based search for stochastic simulation algorithm. AB - Stochastic modelling and simulation is a well-known approach for predicting the behaviour of biochemical systems. Its main applications lie in those systems wherein the inherently random fluctuations of some species are significant, as often is the case whenever just a few macromolecules have a large effect on the rest of the system. The Gillespie's stochastic simulation algorithm (SSA) is a standard method to properly realise the stochastic nature of reactions. In this paper we propose an improvement to SSA based on the Huffman tree, a binary tree which is used to define an optimal data compression algorithm. We exploit results from that area to devise an efficient search for next reactions, moving from linear time complexity to logarithmic complexity. We combine this idea with others from literature, and compare the performance of our algorithm with previous ones. Our experiments show that our algorithm is faster, especially on large models. PMID- 25539847 TI - Efficient fast heuristic algorithms for minimum error correction haplotyping from SNP fragments. AB - Availability of complete human genome is a crucial factor for genetic studies to explore possible association between the genome and complex diseases. Haplotype, as a set of single nucleotide polymorphisms (SNPs) on a single chromosome, is believed to contain promising data for disease association studies, detecting natural positive selection and recombination hotspots. Various computational methods for haplotype reconstruction from aligned fragment of SNPs have already been proposed. This study presents a novel approach to obtain paternal and maternal haplotypes form the SNP fragments on minimum error correction (MEC) model. Reconstructing haplotypes in MEC model is an NP-hard problem. Therefore, our proposed methods employ two fast and accurate clustering techniques as the core of their procedure to efficiently solve this ill-defined problem. The assessment of our approaches, compared to conventional methods, on two real benchmark datasets, i.e., ACE and DALY, proves the efficiency and accuracy. PMID- 25539848 TI - Exploring systems affected by the heat shock response in Plasmodium falciparum via protein association networks. AB - The heat shock response is a general mechanism by which organisms deal with physical insults such as sudden changes in temperature, osmotic and oxidative stresses, and exposure to toxic substances. Plasmodium falciparum is exposed to drastic temperature changes as a part of its life cycle and maintains an extensive repertoire of heat shock response-related proteins. As these proteins serve to maintain the parasite in the face of anti-malarial drugs as well, better understanding of the heat shock-related systems in the malaria parasite will lead to therapeutic approaches that frustrate these systems, leading to more effective use of anti-malarials. Here we use protein association networks to broaden our understanding of the systems impacted by and/or implicated in the heat shock response. PMID- 25539849 TI - The oncogenic and prognostic potential of eight microRNAs identified by a synergetic regulatory network approach in lung cancer. AB - Transcription factors (TFs) and microRNAs (miRNAs), the two main gene regulators in the biological system, control the gene expression at the transcriptional and post-transcriptional level, respectively. However, little is known regarding whether the miRNATF co-regulatory mechanisms, predicted by several studies, truly reflect the molecular interactions in cellular systems. To tackle this important issue, we developed an integrative framework by utilising four independent miRNA and matched mRNA expression profiling datasets to identify reproducible regulations, and demonstrated this approach in non-small cell lung cancer (NSCLC). Our analyses pinpointed several reproducible miRNA-TF co-regulatory networks in NSCLC from which we systematically prioritised eight hub miRNAs that may have strong oncogenic characteristics. Here, we discussed the major findings of our study and explored the oncogenic and prognostic potential of eight prioritised miRNAs through literature-mining based analysis and patient survival analysis. The findings provide additional insights into the miRNA-TF co regulation in lung cancer. PMID- 25539850 TI - Reversed shoulder arthroplasty with inversed bearing materials: 2-year clinical and radiographic results in 101 patients. AB - INTRODUCTION: This study documents 2-year clinical and radiographic results following reversed total shoulder arthroplasty using a novel prosthesis with inverted bearing materials (polyethylene glenoid; metal humeral component). This design was intended to avoid massive PE abrasion on the humeral side. Therefore, we predicted a lack of subsequent osteolysis-induced exacerbation of scapular notching, and because of other design features and modified operating technique a reduced notching rate. MATERIALS AND METHODS: An ongoing, prospective, international, multicenter study of patients implanted with a novel prosthesis at six European centers. The current analysis presents 2-year follow-up data (patients operated between December 2007 and July 2009). Clinical evaluation tools comprised the Constant-Murley score (CS), the American Shoulder and Elbow Surgeon score, range of motion, and a visual analog scale to assess pain and satisfaction. Radiographs were evaluated for notching and radiolucent lines. Any complications were recorded. RESULTS: In total, 113 prostheses (113 patients) with a mean follow-up of 27.6 (+/-3.6) months were analyzed. CS increased from 22.5 (+/-13.7) to 65.3 (+/-14.9) points (p = 0.06). Inferior scapular notching (only grade 1 and 2) was identified in 20.5 % of patients, with no signs of PE induced osteolysis. 4.4 % of patients experienced an implant-related complication. CONCLUSIONS: Inversion of the materials led to another type of notching with no signs of PE-induced osteolysis and no increase in the risk of short-term complications. Clinical results were comparable with other prostheses. Mid- to long-term results are required before any firm conclusions on clinical outcome and survival can be drawn. PMID- 25539851 TI - Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis. AB - It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3-5 wk (early study) or during 5-8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD. PMID- 25539852 TI - Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction. AB - Increased vascular endothelial permeability and inflammation are major pathological mechanisms of pulmonary edema and its life-threatening complication, the acute respiratory distress syndrome (ARDS). We have previously described potent protective effects of hepatocyte growth factor (HGF) against thrombin induced hyperpermeability and identified the Rac pathway as a key mechanism of HGF-mediated endothelial barrier protection. However, anti-inflammatory effects of HGF are less understood. This study examined effects of HGF on the pulmonary endothelial cell (EC) inflammatory activation and barrier dysfunction caused by the gram-negative bacterial pathogen lipopolysaccharide (LPS). We tested involvement of the novel Rac-specific guanine nucleotide exchange factor Asef in the HGF anti-inflammatory effects. HGF protected the pulmonary EC monolayer against LPS-induced hyperpermeability, disruption of monolayer integrity, activation of NF-kB signaling, expression of adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and production of IL 8. These effects were critically dependent on Asef. Small-interfering RNA-induced downregulation of Asef attenuated HGF protective effects against LPS-induced EC barrier failure. Protective effects of HGF against LPS-induced lung inflammation and vascular leak were also diminished in Asef knockout mice. Taken together, these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti inflammatory effects. Modulation of Asef activity may have important implications in therapeutic strategies aimed at the treatment of sepsis and acute lung injury/ARDS-induced gram-negative bacterial pathogens. PMID- 25539855 TI - The influence of anthropometry and body composition on children's bone health: the childhood health, activity and motor performance school (the CHAMPS) study, Denmark. AB - Overweight, physical inactivity and sedentary behaviour have become increasing problems during the past decade. Increased sedentary behaviour may change the body composition (BC) by increasing the fat mass relative to the lean mass (LM). These changes may influence bone health to describe how anthropometry and BC predict the development of the bone accruement. The longitudinal study is a part of The CHAMPS study-DK. Children were DXA scanned at baseline and at 2-year follow-up. BC (LM, BF %) and BMC, BMD and BA were measured. The relationship between bone traits, anthropometry and BC was analysed by multilevel regression analyses. Of the invited children, 742/800 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow-up. Mean (range) of age at baseline was 9.5 years (7.7-12.1). Height, BMI, LM and BF % predicted bone mineral accrual and bone size positively and independently. Height and BMI are both positive predictors of bone accruement. LM is a more precise predictor of bone traits than BF % in both genders. The effects of height and BMI and LM on bone accruement are nearly identical in the two genders, while changes in BF % have different but positive effects on bone accretion in both boys and girls. PMID- 25539853 TI - Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice. AB - Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ~50% less elastin and ~100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice. PMID- 25539854 TI - Thioredoxin-deficient mice, a novel phenotype sensitive to ambient air and hypersensitive to hyperoxia-induced lung injury. AB - Pulmonary oxygen toxicity is a major clinical problem for patients undergoing supplemental oxygen therapy. Thioredoxin (Trx) is an endogenous antioxidant protein that regenerates oxidatively inactivated proteins. We examined how Trx contributes to oxygen tolerance by creating transgenic mice with decreased levels of functional thioredoxin (dnTrx-Tg) using a dominant-negative approach. These mice showed decreased Trx activity in the lung although the expression of mutant protein is three times higher than the wild-type mice. Additionally, we found that these mice showed increased oxidation of endogenous Trx in room air. When exposed to hyperoxia (>90% O2) for 4 days, they failed to recover and showed significant mortality. Even in normal oxygen levels, these mice displayed a significant decrease in aconitase and NADH dehydrogenase activities, decreased mitochondrial energy metabolism, increased p53 and Gadd45alpha expression, and increased synthesis of proinflammatory cytokines. These effects were further increased by hyperoxia. We also generated mice overexpressing Trx (Trx-Tg) and found they maintained lung redox balance during exposure to high oxygen and thus were resistant to hyperoxia-induced lung injury. These mice had increased levels of reduced Trx in the lung in normoxia as well as hyperoxia. Furthermore, the levels of aconitase and NADH dehydrogenase activities were maintained in these mice concomitant with maintenance of mitochondrial energy metabolism. The genotoxic stress markers such as p53 or Gadd45alpha remained in significantly lower levels in hyperoxia compared with dnTrx-Tg or wild-type mice. These studies establish that mice deficient in functional Trx exhibit a phenotype of sensitivity to ambient air and hypersensitivity to hyperoxia. PMID- 25539856 TI - The association between vitamin D status and parameters for bone density and quality is modified by body mass index. AB - The association of vitamin D status with bone mineral density (BMD) and Quantitative Ultrasound measurements (QUS) has been inconsistent in previous studies, probably caused by moderating effects. This study explored (1) the association of vitamin D status with QUS and BMD, and (2) whether these associations were modified by body mass index (BMI), age, gender, or physical activity. Two-independent cohorts of the Longitudinal Aging Study Amsterdam (LASA I, 1995/1996, aged >=65; LASA-II, 2008/2009, aged 61-71) and baseline measurement of the B-vitamins for the prevention of osteoporotic fractures (B-PROOF) study (2008-2011, aged 65+) were used. QUS measurements [broadband ultrasound attenuation (BUA) and speed of sound (SOS)] were performed at the calcaneus in all three cohorts (N = 1,235, N = 365, N = 1319); BMD was measured by Dual X-ray absorptiometry (DXA) in B-PROOF (N = 1,162 and 1,192 for specific sites) and LASA I (N = 492 and 503). The associations of vitamin D status with BUA and BMD were modified by BMI. Only in persons with low-to-normal BMI (<25 kg/m(2)) and serum 25(OH)D <25 nmol/L was associated with lower BUA as compared to the reference group (>=50 nmol/L) in LASA-I and B-PROOF. Furthermore, in LASA-I, these individuals had lower BMD at the hip and lumbar spine. In LASA-II, no associations with BUA were observed. Vitamin D status was not associated with SOS, and these associations were not modified by the effect modifiers tested. The association between vitamin D status and BUA and BMD was modified by BMI in the older-aged cohorts: there was only an association in individuals with BMI <25 kg/m(2). PMID- 25539857 TI - Increased endoplasmic reticulum stress in mouse osteocytes with aging alters Cox 2 response to mechanical stimuli. AB - Aging reduces bone mass as well as the anabolic response of bone to mechanical stimuli, resulting in osteopenia. Endoplasmic reticulum (ER) stress impairs the response of myogenic cells to anabolic stimuli, and is involved in sarcopenia, but whether ER stress also contributes to osteopenia is unknown. Therefore, we tested whether ER stress exists in bones of aged mice, and whether this impairs the osteocyte response to mechanical stimulation. Primary osteocytes were obtained from long bones of adult (8 months) and old (24-26 months) mice, treated with or without the pharmacological ER stress inducer tunicamycin, and either or not subjected to mechanical loading by pulsating fluid flow (PFF). The osteocyte response to PFF was assessed by measuring cyclooxygenase-2 (Cox-2) mRNA levels and nitric oxide (NO) production. mRNA levels of ER stress markers were higher in old versus adult osteocytes (+40% for activating transcription factor-4, +120% for C/EBP homologous protein, and +120% for spliced X-box binding protein-1, p < 0.05). The Cox-2 response to PFF was fourfold decreased in cells from old bones (p < 0.001), while tunicamycin decreased PFF-induced Cox-2 expression by threefold in cells from adult bones (p < 0.01). PFF increased NO production by 50% at 60 min in osteocytes from old versus adult bones (p < 0.01). In conclusion, our data indicate that the expression of several ER stress markers was higher in osteocytes from bones of old compared to adult mice. Since ER stress altered the response of osteocytes to mechanical loading, it could be a novel factor contributing to osteopenia. PMID- 25539858 TI - Differences in bone mineral density, markers of bone turnover and extracellular matrix and daily life muscular activity among patients with recent motor incomplete versus motor-complete spinal cord injury. AB - Spinal cord injury (SCI) leads to severe bone loss, but the associated mechanisms are poorly described in incomplete SCI individuals. The purpose of the study is to compare alterations in bone mineral density (BMD) and serum biomarkers of bone turnover in recent motor-incomplete to -complete SCI men, as well as to describe their physical activity and spasticity. We studied 31 men with acute SCI. Whole body DXA scans, serum biomarkers and self-reported activity and spasticity were examined 1 and/or 3 and 12 months after the injury. We observed a decrease in proximal femur BMD (p < 0.02) in both the groups. Serum phosphate and carboxy terminal-collagen crosslinks were significantly lower in motor-incomplete versus complete SCI men, whereas albumin-corrected Ca(2+) (p = 0.02) were lower only 3 months after injury. When data from all 31 SCI participants were pooled, we observed increased serum matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of MMP-2 (TIMP-2) (p < 0.02) whereas TIMP-1 decreased (p = 0.03). BMD correlated positively with self-reported activity (r = 0.59, p = 0.04) and negatively with spasticity (r = 0.74, p = 0.02) 12 months after injury. As a summary, men with motor-incomplete SCI developed significant proximal femur bone loss 12 months after injury and exhibited increased bone resorption throughout the first year after the injury. Compared with complete SCI men, incomplete SCI men show attenuated bone resorption. Our pooled data show increased turnover of extracellular matrix after injury and that increased exercise before and after injury correlated with reduced bone loss. PMID- 25539859 TI - Psychometric properties and factor structure of the 13-item satisfaction with daily occupations scale when used with people with mental health problems. AB - BACKGROUND: In mental health care practice and research it is increasingly recognized that clients' subjective perceptions of everyday occupations, such as satisfaction, are important in recovery from mental illness. Instruments thus need to be developed to assess satisfaction with everyday occupations. The aim of the present study was to assess psychometric properties of the 13-item Satisfaction with Daily Occupation (SDO-13) when used with people with mental health problems, including its internal consistency, factor structure, construct validity and whether the scale produced ceiling or floor effects. An additional question concerned if the factor structure varied whether the participants were, or were not, presently engaged in the activity they rated. METHODS: The interview based SDO-13 includes items pertaining to work/studies, leisure, home maintenance, and self-care occupations. Whether the person currently performs an occupation or not, he/she is asked to indicate his/her satisfaction with that occupation. The SDO-13 was completed with 184 persons with mental illness. Residual variables were created to remove the variation linked with currently performing the targeted occupation or not and to assess the factor structure of the SDO-13. The indicators of general satisfaction with daily occupations, self esteem and global functioning were used to assess construct validity. The statistical methods included tests of homogeneity, confirmatory factor analysis and Pearson correlations. RESULTS: The internal consistency was satisfactory at 0.79. A three-factor solution indicated that the construct behind the SDO-13 was composed of three facets; Taking care of oneself and the home, Work and studies, and Leisure and relaxation. The same factor structure was valid for both original scores and the residuals. An expected pattern of correlations with the indicators was mainly found, suggesting basic construct validity. No ceiling or floor effects were found. CONCLUSIONS: Taken together, the findings suggest the SDO-13 is a reliable and robust instrument that may be used to get an overview of the satisfaction people living with mental illness derive from their daily occupations. PMID- 25539860 TI - Thymectomy for non-thymomatous myasthenia gravis: a propensity score matched study. AB - BACKGROUND: The efficacy of thymectomy in patients with non-thymomatous Myasthenia Gravis (MG) is still unclear. Main limitations have been variable outcome definitions, lack of a control group and adjustment for confounding. OBJECTIVE: To study the efficacy of thymectomy in achieving remission or minimal manifestation (R/MM) status in patients with non-thymomatous MG. METHODS: Patients with generalized MG and minimum follow-up of 6 months were included. Demographic data and treatments were recorded, as well as the MGFA post intervention status at the last visit. Propensity scores were used to create a matched cohort of treated and untreated patients. Standard and Bayesian Cox models were used to study treatment effects. RESULTS: Of 395 patients included, 183(46%) had a thymectomy. Thymectomy patients were younger (p < 0.001), with more females (p < 0.001) and more patients in MGFA classes 4-5 at diagnosis (p = 0.01). A matched cohort of thymectomized patients and controls (n = 98) was created. The hazard ratio (HR) for the matched cohort was 1.9 (CI:1.6-2.3), favoring thymectomy. The predicted R/MM rate was 21% in treated and 6% in controls at 5 years (Absolute difference:15%). A Bayesian Cox model for the matched cohort had an estimated probability of thymectomy efficacy (HR > 1) of 96% using a non-informative prior, and 79% using a skeptical prior. DISCUSSION: When controlling for potential confounders, thymectomized patients had a higher probability of achieving R/MM status through time compared to controls. This study provides class III evidence of the efficacy of thymectomy in non thymomatous myasthenia gravis. PMID- 25539861 TI - Specific genotypes of human papillomavirus in 125 high-grade squamous lesions and invasive cervical cancer cases from Congolese women. AB - BACKGROUND: Knowledge on HPV prevalence and genotype distribution in HSIL and ICC is highly essential for the introduction of an effective vaccination program and appropriate epidemiological monitoring of viral ecology before and after vaccination in Congo. This study aimed to determine the specific-HPV genotypes in HSIL and ICC among women in southwestern Congo. METHODS: 125 archival paraffin embedded biopsy collected between 2008 and 2012 and histologically diagnosed were investigated. DNA extraction was performed using the phenol/chloroform method. HPV search was performed by nested-PCR using MY09/MY11 and GP5+/GP6+ consensus primers followed by direct sequencing. RESULTS: The mean age of participants was 44.3 +/- 8.2 years. Overall, HPV prevalence was 89.6% (112/125) with all high risk genotypes. HPV-DNA was detected in 81.5% (53/65) of HSIL and 98.3% (59/60) of ICC. HPV 16 the most common genotype was detected in 47.1% (25/53) of HSIL and 52.5% (31/59) of ICC. Other types identified were: HPV 33 (22.6%), HPV 18 (15%), HPV 31 (11.3%) and HPV 69 (3.7%) in HSIL, and HPV 33 (28.8%), HPV 18 (11.8%), HPV 31 (5%) and HPV 35 (1.7%) in ICC. Knowing that the ADC accounted for 6.7% (4/60) of ICC cases, HPV 18 was identified in 25% (1/4) of these cases against 75% (3/4) for HPV 16. CONCLUSION: Our study showed that HPV 16, 33, 18 and 31 were the four most common genotypes in women with HSIL and ICC. These findings indicate that current vaccines against HPV could help to reduce the burden of cervical cancer in Congo. PMID- 25539862 TI - Cell-density-dependent manifestation of partial characteristics for neuronal precursors in a newly established human gliosarcoma cell line. AB - Gliosarcoma cell line K308 was established from a primary tumor specimen removed from a 51-year-old male Han Chinese patient. Besides the typical characteristics of gliosarcoma cells, K308 cells express abundant glutaminase and can release large amount of glutamate. K308 exhibited cell-density-dependent expression of neuronal precursor markers, particularly nestin. At low density, the majority of K308 cells were nestin negative (approximately 70%) and nestin levels remained homogenous within each single-cell-derived colony when K308 proliferated. After reaching confluence, however, the majority of K308 cells turned nestin positive. These confluent K308 cells were also Sox2 positive and could form tumor spheres even in serum-containing media. PMID- 25539863 TI - Comparison of TGFbR2 down-regulation in expanded HSCs on MBA/DBM scaffolds coated by UCB stromal cells. AB - Bone marrow transplants (BMTs) are mainly limited by a low number of CD34(+) cells. The transforming growth factor-beta (TGF-beta) pathway downregulation is a key factor that increases cell self-renewal. In nature, hematopoietic stem cells (HSCs) are in a microenvironment, surrounded by cells in a three-dimensional (3D) configuration. The aim of this study is to investigate the association between a 3D culture and the delivery ratio of downregulation. Demineralized bone matrix (DBM) and mineralized bone allograft (MBA) scaffolds were coated using unrestricted somatic stem cells (USSCs) as the feeder layer. Umbilical cord blood (UCB)-CD34(+) cells were then ex vivo expanded in them and transfected by small interfering RNA (siRNA) against TGFbR2, a type 2 receptor in the TGF-beta pathway. Finally, quantitative real-time PCR, flow cytometry, and clonogenic assay were performed. In a global comparison, we observed that the highest expansion ratio, lowest expression level, and the highest CD34 marker belonged to the simple 2D culture transfected group. This suggests that TGFbR2 downregulation in a 2D culture can be done more effectively. The siRNA delivery system and the transfection ratio in an ex vivo environment, which mimicks in vivo conditions, have low efficiency. Genetic modification of the cells needs free 3D spaces to enable better transfection. PMID- 25539865 TI - Recovery of fibroblast-like cells from refrigerated goat skin up to 41 d of animal death. AB - Successful cloning of animals using somatic cell nuclear transfer requires undamaged nuclear DNA from desired donor cell types. In vitro culture of cells is one way of ensuring nuclear integrity. The goal of this study was to evaluate the limits of postmortem cell survival/culture in refrigerated goat ear skin tissues which could be used for long-term storage and cloning of animals in future. To achieve this, 60 explants from 6 different goats were cultured after 0, 3, 6, 9, 13, 16, 20, 23, 27, 30, 33, 37, and 41 d postmortem and observed under inverted microscope for outgrowth of fibroblast-like cells, after 10-12 d of culture. Explants from all time points including 19% from 41-dpm tissues exhibited outgrowth. However, the percentage of outgrowth positive explants, as well as culture confluence, reduced with increasing postmortem time interval. Cell cultures established from primary outgrowth of 41-dpm tissues when compared for their growth profile with similarly obtained 0-dpm cultures revealed similar growth curve and cell morphology. Cytogenetic analysis of 41-dpm tissue-derived cell populations revealed a normal female karyotype with 60 XX homologous chromosomes indicating genetic stability of the cell population. In conclusion, these results show that refrigerated skin tissue remains alive for more than a month and that the cells derived from such tissues are normal and can be cryopreserved for long-term storage and future cloning of animals with desired genetics. PMID- 25539864 TI - An agarose gel-based neurosphere culture system leads to enrichment of neuronal lineage cells in vitro. AB - Stem cell-based therapy holds great potential especially for neurological disorders. However, clinical applications await further understanding of many aspects of stem cell differentiation and development of technology enabling manipulation of stem cells into desired cell types in the central nervous system. Here, we developed a new method that leads to enrichment of neuronal lineage cells in neural stem cell cultures. The protocol involves cultivation of primary cells derived from the forebrains of rat E18 embryos above a layer of nonadhesive hard agarose gel in the form of neurospheres. In contrast to the neurospheres that were cultured above an anti-adhesive hydrogel layer, the primary cells that were cultured above a layer of agarose gel preferentially differentiated into beta-III tubulin-positive neurons when allowed to undergo differentiation in vitro.In an effort to investigate the mechanism behind this observation, we found that the gene expression of a vertebrate neuronal determination gene (neurogenin1) was enhanced in the neurospheres that proliferated above a layer of agarose gel as compared with the control, and the gene expression level of neurogenin1 was quite well correlated with the rigidity of agarose gel. These results indicate that agarose gel can contribute, at least in part, to enrich neuronal progenitors and immature postmitotic neurons during neurosphere formation and may provide additional information to establish efficient protocols for the neural stem cell-based study. PMID- 25539866 TI - Phoenix flagships: Conservation values and guanaco reintroduction in an anthropogenic landscape. AB - Multiple forms of valuation contribute to public acceptance of conservation projects. Here, we consider how esthetic, intrinsic, and utilitarian values contribute to public attitudes toward a proposed reintroduction of guanaco (Lama guanicoe) in a silvopastoral system of central Chile. The nexus among landscape perceptions and valuations, support for reintroductions, and management of anthropogenic habitats is of increasing interest due to the proliferation of conservation approaches combining some or all of these elements, including rewilding and reconciliation ecology, for example. We assessed attitudes and values through an online questionnaire for residents of Santiago, Chile, using multiple methods including photo-montages and Likert scale assessments of value based statements. We also combined the questionnaire approach with key informant interviews. We find strong support for the reintroduction of guanacos into the Chilean silvopastoral system ('espinal') in terms of esthetic and intrinsic values but less in terms of utilitarian values. Respondents preferred a scenario of espinal with guanacos and expressed interest in visiting it, as well as support for the reintroduction project on the basis that guanacos are native to central Chile. We suggest that reintroduced guanacos could serve as a 'phoenix flagship species' for espinal conservation, that is, a flagship species that has gone regionally extinct and is known but not associated with the region in the cultural memory. We consider how the lack of local cultural identity can both help and weaken phoenix flagships, which we expect to become more common. PMID- 25539868 TI - Clergy Wellness: An Assessment of Perceived Barriers to Achieving Healthier Lifestyles. AB - This study sought to obtain a better understanding of how clergy view their health and to investigate their self-reported health status. Additionally, this study sought to explore personal and professional barriers among clergy to living a healthier life. An electronic 32-item survey was sent to all practicing clergy in Kansas East and West conferences of United Methodist church by the Kansas Area Office of the United Methodist Church. Survey items included participants' demographic information and health conditions (e.g., diabetes, heart disease, high blood pressure, high cholesterol). The self-reported general health, mental health, and physical health data were also collected to compare to the general population in Kansas. Clergy were also asked to identify perceived barriers to health. A total of 150 clergy participated in the survey. The majority (93.7 %) self-reported their health as good, very good, or excellent. Participating clergy self-reported a higher prevalence of chronic diseases (diabetes, heart disease, high blood pressure, and high cholesterol) than the Kansas general population, but those differences were not statistically significant. More than three-fourths (77.4 %) of the participating clergy reported weights and heights that classified them as either overweight or obese. Lack of family time was the most frequently reported personal barrier to achieving a healthier lifestyle. An unpredictable work schedule was reported as the most frequent professional barrier to achieving a healthier lifestyle. This study suggests that Kansas clergy generally view their overall health status favorably despite being overweight or obese. Clergy also self-reported higher prevalence of chronic diseases than the general Kansas population, though the prevalence was not statistically different. This study provides additional insight into clergy health and offers suggestions to address the barriers preventing clergy from working toward better health. PMID- 25539867 TI - Immuno-cytogenetic manifestation of epigenetic chromatin modification marks in plants. AB - Histone proteins and the nucleosomes along with DNA are the essential components of eukaryotic chromatin. Post-translational histone-DNA interactions and modifications eventually offer significant alteration in the chromatin environment and potentially influence diverse fundamental biological processes, some of which are known to be epigenetically inherited and constitute the "epigenetic code". Such chromatin modifications evidently uncover remarkable diversity and biological specificity associated with distinct patterns of covalent histone marks. The past few years have witnessed major breakthroughs in plant biology research by utilizing chromatin modification-specific antibodies through molecular cytogenetic tools to ascertain hallmark signatures of chromatin domains on the chromosomes. Here, we survey current information on chromosomal distribution patterns of chromatin modifications with special emphasis on histone methylation, acetylation, phosphorylation, and centromere-specific histone 3 (CENH3) marks in plants using immuno-FISH as a basic tool. Major available information has been classified under typical and comparative cytogenetic detection of chromatin modifications in plants. Further, spatial distribution of chromatin environment that exists between different cell types such as angiosperm/gymnosperm, monocot/dicot, diploid/polyploids, vegetative/generative cells, as well as different stages, i.e., mitosis versus meiosis has also been discussed in detail. Several challenges and future perspectives of molecular cytogenetics in the grooming field of plant chromatin dynamics have also been addressed. PMID- 25539869 TI - Staff and service users' views on a 'Consent for Contact' research register within psychosis services: a qualitative study. AB - BACKGROUND: Recruitment to mental health research can be challenging. 'Consent for Contact' (C4C) is a novel framework which may expedite recruitment and contribute to equitable access to research. This paper discusses stakeholder perspectives on using a C4C model in services for people with psychosis. METHOD: This is a cross sectional study investigating the views of service users and staff using qualitative methods. Eight focus groups were recruited: five with service users (n = 26) and three with clinicians (n = 17). Purposive sampling was applied in order to reflect the local population in terms of ethnicity, experience of psychiatric services and attitudes towards research. RESULTS: Staff and service users alike associated the principle of 'consent for contact' with greater service user autonomy and favourable conditions for research recruitment. Fears around coercion and inappropriate uses of clinical records were common and most marked in service users identifying as having a negative view to research participation. Staff working in inpatient services reported that consenting for future contact might contribute to paranoid ideation. All groups agreed that implementation should highlight safeguards and the opt-in nature of the register. CONCLUSIONS: Staff and service users responded positively to C4C. Clinicians explaining C4C to service users should allay anxieties around coercion, degree of commitment, and use of records. For some service users, researcher access to records is likely to be the most challenging aspect of the consultation. PMID- 25539870 TI - Managing major depressive disorder through the use of adjunct therapies. AB - Although many treatments for Major Depressive Disorder (MDD) exist, only half of all patients respond to initial trial of pharmacotherapy and only a third will achieve remission with that trial. First-line therapies for the management of MDD include psychotherapy or pharmacotherapy, alone or in combination. Given the disappointing rates of response and remission to initial therapy, clinicians are looking for methods to improve the management of MDD, such as through the use of adjunct therapies. The first article in this series, by Katzman and Chokka, discusses gaps in the treatment of MDD and proposes measures to change and strengthen future practice guidelines. Epstein et al. summarize the findings of clinical studies, systematic analyses, and reviews of trials supporting the use of adjunct therapy for the treatment of MDD. Velehorschi et al. review emerging research identifying common pathophysiological processes between MDD and three of its comorbidities. Lastly, Cameron and Habert highlight the challenges that primary care physicians face in the management of MDD. Ultimately, the goal of treatment is to not only relieve symptoms of MDD, but achieve sustained remission. This supplement was written to address the issues of less than ideal outcomes and approaches to enhancing response and remission rates. PMID- 25539871 TI - Pharmacological approaches to manage persistent symptoms of major depressive disorder: rationale and therapeutic strategies. AB - Major depressive disorder (MDD) is a highly prevalent chronic psychiatric illness associated with significant morbidity, mortality, loss of productivity, and diminished quality of life. Typically, only a minority of patients responds to treatment and meet criteria for remission as residual symptoms may persist, the result of an inadequate course of treatment and/or the presence of persistent side effects. The foremost goal of treatment should be to restore patients to full functioning and eliminate or relieve all MDD symptoms, while being virtually free of troublesome side effects. The current available pharmacological options to manage persistent depressive symptoms include augmentation or adjunctive combination strategies, both of which target selected psychobiological systems and specific mood and somatic symptoms experienced by the patient. As well, non pharmacological interventions including psychotherapies may be used in either first-line or adjunctive approaches. However, the evidence to date with respect to available adjunct therapies is limited by few studies and those published have utilized only a small number of subjects and lack enough data to allow for a consensus of expert opinion. This underlines the need for further longer term, large population-based studies and those that include comorbid populations, all of which are seen in real world community psychiatry. PMID- 25539872 TI - Food for thought: understanding the value, variety and usage of management algorithms for major depressive disorder. AB - By 2020, depression is projected to be among the most important contributors to the global burden of disease. A plethora of data confirms that despite the availability of effective therapies, major depressive disorder continues to exact an enormous toll; this, in part, is due to difficulties reaching complete remission, as well as the specific associated costs of both the disorder's morbidity and mortality. The negative effects of depression include those on patients' occupational functioning, including absenteeism, presenteeism, and reduced opportunities for educational and work success. The use of management algorithms has been shown to improve treatment outcomes in major depressive disorder and may be less costly than "usual care" practices. Nevertheless, many patients with depression remain untreated. As well, even those who are treated often continue to experience suboptimal quality of life. As such, the treatment algorithms in this article may improve outcomes for patients suffering with depression. This paper introduces some of the principal reasons underlying these treatment gaps and examines measures or recommendations that might be changed or strengthened in future practice guidelines to bridge them. PMID- 25539873 TI - Understanding the role of adjunctive nonpharmacological therapies in management of the multiple pathways to depression. AB - Major depressive disorder (MDD) is a common disorder with a lifetime prevalence of 16.2% and the fourth highest cause of disability globally. It is hypothesized to be a syndromatic manifestation of multiple pathological processes leading to similar clinical manifestation. MDD is associated with at least three categories of peripheral hormone-type factors including neurotrophic factors, proinflammatory cytokines, and processes that impair regulation of the hypothalamic-pituitary-adrenocortical axis. Neuroimaging studies have identified functional abnormalities including subcortical systems associated with reward and emotion processing, medial prefrontal and anterior cingulate cortical regions and the lateral prefrontal cortical systems involved in cognitive control and voluntary emotion regulation. Studies investigating the effects of psychotherapy and pharmacotherapy on functional brain measures show normalization of brain function with return to euthymia. Nevertheless, approximately 50% of patients with MDD will not respond sufficiently and 60 to 70% will not achieve full remission with first-line pharmacotherapy, therefore clinicians strive to improve patient responses through the use of adjunct therapies. This review discusses recent research in the various biological processes associated with MDD as well as recent data in support of the use of adjunctive non-pharmacological therapies including psychotherapy, bibliotherapy, Internet therapy, "natural" or herbal approaches, exercise therapy, and somatic therapies. PMID- 25539874 TI - Optimizing the management of depression: primary care experience. AB - This article is intended to identify some of the most important challenges faced by family physicians when treating MDD and to provide practical solutions. Key issues, reviewed from a primary care view point will include: treating to remission (and not just response), identification of high-risk groups, diagnosis, acute treatment approaches (including pharmacotherapy and the management of related side effects), the use of psychotherapy and somatic therapies, assessment of the adequacy of treatment including the assessment of remission, response measurement, optimal follow-up care throughout the phase of treatment, the key components of patient education and strategies for partial/limited response to the first-line antidepressant (switching, augmentation and combination strategies), how to provide support for improved treatment adherence, and approaches to prevent the recurrence of depressive episodes. PMID- 25539875 TI - Clinical and pathological features of Nerium oleander extract toxicosis in wistar rats. AB - BACKGROUND: Nerium oleander has been widely studied for medicinal purposes for variety of maladies. N. oleander has also been reported having noxious effects because of its number of components that may show signs of toxicity by inhibiting plasma lemma Na+, K+-ATPase. The present study was performed to scrutinize the toxic effect of N. oleander leaves extract and its clinical and pathological features in wistar rats. RESULTS: Hematological analysis showed significant variations in RBCs count (P = 0.01), Hb (P = 0.001), Hct (P = 0.0003), MCV (P = 0.013), lymphocyte count (P = 0.015), neutrophil count (P = 0.003), monocyte count (P = 0.012) and eosinophil count (P = 0.006). Histopathological studies have shown that in T1 group noticeable infiltration of inflammatory cells was found with low level of vascular damage. In T2 group, increased proportion of binucleated and inflammatory cells, hepatic necrosis, widening of sinusoidal spaces and mild level of vascular damage was observed. CONCLUSION: Taken together these findings we can conclude that N. oleander leaves extract significantly affects on experimental animals due to its toxicity. Efforts must be exerted to purify different chemical components from extract with no inflammation as this plant is utilized in folk medicine with narrow therapeutic indices. PMID- 25539876 TI - Palliative laparoscopic resection of renal cell carcinoma metastatic to the stomach: report of a case. AB - The most common sites of metastases in renal cell carcinoma (RCC) are lung and bone. However, unusual sites, including the stomach, are characteristic of RCC.This article presents a case of a metastatic RCC (lung and liver) with a symptomatic gastric metastasis treated by a laparoscopic wedge resection (LWR).A 66-year-old woman, diagnosed with RCC underwent a right nephrectomy. During her follow-up, an upper gastrointestinal (GI) endoscopy showed an ulcerated lesion at the stomach. A biopsy of the specimen revealed metastatic RCC. The patient underwent a palliative LWR and was discharged home 8 days after surgery.Therefore, LWR is a relatively simple technique with the advantages of minimal invasive access in the treatment of palliative cases. PMID- 25539877 TI - Structured assessment for prospective identification of safety signals in electronic medical records: evaluation in the health improvement network. AB - BACKGROUND: Pharmacovigilance signal detection largely relies on individual case reports, but longitudinal health data are being explored as complementary information sources. Research to date has focused on the ability of epidemiological methods to distinguish established adverse drug reactions (ADRs) from unrelated adverse events. OBJECTIVE: The aim of this study was to evaluate a process for structured clinical and epidemiological assessment of temporally associated drugs and medical events in electronic medical records. METHODS: Pairs of drugs and medical events were selected for review on the basis of their temporal association according to a calibrated self-controlled cohort analysis in The Health Improvement Network. Six assessors trained in pharmacovigilance and/or epidemiology evaluated seven drugs each, with up to 20 medical events per drug. A pre-specified questionnaire considered aspects related to the nature of the temporal pattern, demographic features of the cohort, concomitant medicines, earlier signs and symptoms, and possible confounding by underlying disease. This informed a classification of drug-event pairs as known ADRs, meriting further evaluation, or dismissed. RESULTS: The number of temporally associated medical events per drug ranged from 11 to 307 (median 50) for the 42 selected drugs. Out of the 509 relevant drug-event combinations subjected to the assessment, 127 (25 %) were classified as known ADRs. Ninety-one (24 %) of the remaining pairs were classified as potential signals meriting further evaluation and 291 (76 %) were dismissed. Suggestive temporal patterns and lack of clear alternative explanations were the most common reasons that drug-event pairs were classified as meriting further evaluation. Earlier signs and symptoms and confounding by the underlying disease were the most common reasons that drug-event pairs were dismissed. CONCLUSIONS: Exploratory analysis of electronic medical records can detect important potential safety signals. However, effective signal detection requires that statistical signal detection be combined with clinical and epidemiological review to achieve an acceptable false positive rate. PMID- 25539878 TI - The US Food and Drug Administration-European Medicines Agency collaboration in pharmacovigilance: common objectives and common challenges. AB - On 19 February 2014, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) announced the formation of a cluster on pharmacovigilance topics. The cluster is designed to complement, and not replace, other international activities in this field. It builds upon years of interactions between the two agencies. The creation of the cluster formalizes this longstanding and productive relationship and facilitates more systematic exchange of information and expertise. PMID- 25539879 TI - Long-term effects of baroreflex activation therapy on glucose metabolism. AB - AIMS: Sympathetic overactivity is one critical factor associated with the development of arterial hypertension, impaired insulin secretion and resistance. Some antihypertensives exert beneficial effects on glucose metabolism, whereas others lead to an impairment of metabolic state with consecutive weight gain. In resistant hypertension, baroreflex activation therapy (BAT) reduces arterial blood pressure (BP) by inhibition of the sympathetic nervous system. The objective of this study was to evaluate whether BAT influences metabolic state in patients with resistant hypertension. METHODS: Thirty patients with resistant hypertension (10 with known diabetes mellitus) were prospectively included into this study. Blood pressure, BMI, weight, fasting glucose, insulin, C-peptide, hemoglobin A1c, HOMA-IR, HOMA-beta, ISQuickI, and glucose levels during oral glucose tolerance test were measured at baseline and 6 months after BAT activation. RESULTS: Fasting glucose was significantly reduced after 6 months of BAT, whereas mean 2-h glucose levels during oral glucose tolerance test, fasting insulin levels, C-peptide levels, hemoglobin A1c, HOMA-IR, HOMA-beta, ISQuickI, weight, and BMI remained unchanged. CONCLUSION: Despite improvement in fasting glucose, BAT exerts neither sustained additional beneficial effects nor an impairment of metabolic state. Thus, chronic BAT might be an effective interventional method to reduce BP without metabolic disadvantages. PMID- 25539880 TI - Breastfeeding is protective to diabetes risk in young adults: a longitudinal study. AB - AIM: It is unclear whether any breastfeeding or a certain duration of breastfeeding is protective against the development of diabetes in adult offspring. METHODS: We followed a sub-sample of 3,595 offspring born in the Mater Hospital in Brisbane, Australia between 1981 and 1983 and for whom we had doctor diagnosed self-reported diabetes at age 21 years and maternal reported duration of breastfeeding at 6-month post-natal follow-up. Multiple logistic regression was used to examine the independent associations of duration of breastfeeding (never breastfeed, breastfed <4 months and breastfed >=4 months) with offspring diabetes by age 21 years. RESULTS: Of 3,595 young adults, 45 (1.25 %) developed diabetes by age 21 years. The odds ratio of experiencing diabetes was 0.58 (95 % CI 0.29, 1.16) for offspring who were breastfed <4 months, and it was 0.29 (95 % CI 0.13, 0.63), for offspring who were breastfed at least 4 months compared to the never breastfed offspring. Adjusting for potential confounding and mediating factors including maternal age, education, pre-pregnancy body mass index (BMI), smoking, offspring sports, TV and their BMI at 21 years did not substantially alter this association. CONCLUSIONS: Findings of this study suggest that infants who are breastfed for longer than 4 months have a substantial protective effect against the development of diabetes in young adulthood, which is independent of current BMI. Promoting breastfeeding for a minimum of 4 months may be a useful strategy for the prevention of diabetes among young adults. PMID- 25539882 TI - Sex-specific effect of BMI on insulin sensitivity and TNF-alpha expression. PMID- 25539881 TI - Association of apolipoprotein B, LDL-C and vascular stiffness in adolescents with type 1 diabetes. AB - AIMS: LDL cholesterol (LDL-C) is the current lipid standard for cardiovascular disease (CVD)-risk assessment in type 1 diabetes. Apolipoprotein B (apoB) may be helpful to further stratify CVD risk. We explored the association between apoB and pulse wave velocity (PWV) to determine if apoB would improve CVD-risk stratification, especially in type 1 diabetes adolescents with borderline LDL-C (100-129 mg/dL). We hypothesized that type 1 diabetes adolescents with borderline LDL-C and elevated apoB (>=90 mg/dL) would have increased PWV compared to those with borderline LDL-C and normal apoB (<90 mg/dL), and that apoB would explain more of the variability of PWV than alternative lipid indices. METHODS: Fasting lipids, including apoB, were collected in 267 adolescents, age 12-19 years, with diabetes duration >5 years and HbA1c 8.9 +/- 1.6 %. Triglyceride to HDL-C ratio (TG/HDL-C) and nonHDL-cholesterol (nonHDL-C) were calculated. PWV was measured in the carotid-femoral segment. RESULTS: ApoB, nonHDL-C and TG/HDL-C correlated with PWV (p < 0.0001). ApoB, nonHDL-C and TG/HDL-C remained significantly associated with PWV in fully adjusted models. In adolescents with borderline LDL-C (n = 61), PWV was significantly higher in those with elevated apoB than in those with normal apoB (5.6 +/- 0.6 vs. 5.2 +/- 0.6 m/s, p < 0.01) and also remained significant after adjustment for CVD-risk factors (p = 0.0002). Moreover, in those with borderline LDL-C, apoB explained more of the variability of PWV than nonHDL-C and TG/HDL-C. CONCLUSION: Elevated apoB is associated with increased arterial stiffness in type 1 diabetes adolescents. Measurement of apoB in addition to LDL-C may be helpful in stratifying CVD risk in type 1 diabetes adolescents, especially in those with borderline LDL-C. PMID- 25539883 TI - Regularity of follow-up, glycemic burden, and risk of microvascular complications in patients with type 2 diabetes: a 9-year follow-up study. AB - AIMS: To assess the relationship between regularity of follow-up and risk of complications in patients with type 2 diabetes (T2DM) followed up for 9 years at a tertiary diabetes center in India. METHODS: We compared glycemic burden [cumulative time spent above a HbA1c of 53 mmol/mol (7 %)] and incidence of diabetes complications (retinopathy, neuropathy, nephropathy, peripheral arterial disease, coronary heart disease) between 1,783 T2DM patients with "regular follow up" (minimum of three visits and two HbA1c tests every year from 2003 to 2012), and 1,798 patients with "irregular follow-up" (two visits or less and one HbA1c or less per year during the same time period), retrospectively identified from medical records. Cox proportional hazards models were used to estimate risk associated with diabetes complications. RESULTS: Compared to those with regular follow-up, the irregular follow-up group had significantly higher mean fasting and postprandial plasma glucose, HbA1c, glycemic burden, total and LDL cholesterol, and triglycerides at every time point during the 9 years of follow up. Those with irregular follow-up had double the total and mean monthly glycemic burden and 1.98 times higher risk of retinopathy (95 % CI 1.62, 2.42) and 2.11 times higher risk of nephropathy (95 % CI 1.73, 2.58) compared to those with regular follow-up, even after adjusting for time-varying confounding variables. Complications tended to develop significantly earlier and were more severe in those with irregular follow-up. CONCLUSION: Among patients with type 2 diabetes, regular follow-up was associated with significantly lower glycemic burden and lower incidence of retinopathy and nephropathy over a 9-year period. PMID- 25539884 TI - The Manchester Acute Coronary Syndromes (MACS) decision rule: validation with a new automated assay for heart-type fatty acid binding protein. AB - OBJECTIVE: The Manchester Acute Coronary Syndromes (MACS) decision rule may enable acute coronary syndromes to be immediately 'ruled in' or 'ruled out' in the emergency department. The rule incorporates heart-type fatty acid binding protein (h-FABP) and high sensitivity troponin T levels. The rule was previously validated using a semiautomated h-FABP assay that was not practical for clinical implementation. We aimed to validate the rule with an automated h-FABP assay that could be used clinically. METHODS: In this prospective diagnostic cohort study we included patients presenting to the emergency department with suspected cardiac chest pain. Serum drawn on arrival was tested for h-FABP using an automated immunoturbidimetric assay (Randox) and high sensitivity troponin T (Roche). The primary outcome, a diagnosis of acute myocardial infarction (AMI), was adjudicated based on 12 h troponin testing. A secondary outcome, major adverse cardiac events (MACE; death, AMI, revascularisation or new coronary stenosis), was determined at 30 days. RESULTS: Of the 456 patients included, 78 (17.1%) had AMI and 97 (21.3%) developed MACE. Using the automated h-FABP assay, the MACS rule had the same C-statistic for MACE as the original rule (0.91; 95% CI 0.88 to 0.92). 18.9% of patients were identified as 'very low risk' and thus eligible for immediate discharge with no missed AMIs and a 2.3% incidence of MACE (n=2, both coronary stenoses). 11.1% of patients were classed as 'high-risk' and had a 92.0% incidence of MACE. CONCLUSIONS: Our findings validate the performance of a refined MACS rule incorporating an automated h-FABP assay, facilitating use in clinical settings. The effectiveness of this refined rule should be verified in an interventional trial prior to implementation. TRIAL REGISTRATION NUMBER: UK CRN 8376. PMID- 25539885 TI - Use of columnar cacti in the Tehuacan Valley, Mexico: perspectives for sustainable management of non-timber forest products. AB - BACKGROUND: TEK, ecological and economic aspects of columnar cacti were studied in the Tehuacan Valley, Mexico to design sustainable regimes of fruit harvest. We analysed the amounts of edible fruit, seeds and flowers produced per hectare of cardonal, jiotillal and tetechera forests, their economic value and actual extraction rates, hypothesizing that the economic benefits of these NTFP would potentially be comparable to maize agriculture, which involves forest removal. METHODS: Our study comprised the whole territory of the community of Quiotepec, Oaxaca. Sustainable gathering rates were analysed through population dynamics models and simulations of harvesting regimes (10%, 25%, and 50% of fruit gathered) per hectare of forest type. We used estimations on economic benefit and ecological impact of these scenarios to evaluate their relative sustainability, compared with maize agroforestry systems harbouring 2-47% of vegetation cover. RESULTS: For the whole territory, the total annual fruit production is 509.3 ton of Pachycereus weberi, 267.4 ton of Neobuxbaumia tetetzo, 99.5 ton of Escontria chiotilla, and 8.1 ton of Myrtillocactus geometrizans. The total economic value of fruits per hectare was $315.00 U.S. dollars for cardonal, $244.60 for jiotillal, and $113.80 for tetechera, whereas rainfed agriculture of maize was on average $945.52. Demographic models for E. chiotilla and N. tetetzo indicate that 70% and 95% of fruit harvesting, respectively maintain lambda > 1, but these harvest rates cannot be recommendable since the models do not consider the high inter-annual environmental variations and the non-estimated amount of fruit consumed by natural frugivorous. Extracting 25% of fruit is ecologically more sustainable, but with low economic benefits. Agroforestry systems maintaining the higher vegetation cover provide economic benefits from agriculture and forest resources. CONCLUSIONS: Combining forest extraction and agroforestry systems are ideal scenarios to sustainable fruit harvest programmes. In addition, fair commerce of transformed products would substantially favour goals of sustainable management. PMID- 25539887 TI - The journal and priority. PMID- 25539886 TI - Fibrates protect against vascular endothelial dysfunction induced by paclitaxel and carboplatin chemotherapy for cancer patients: a pilot study. AB - BACKGROUND: Although we previously demonstrated that paclitaxel and carboplatin chemotherapy (TCchem) is associated with vascular toxicities, the underlying mechanisms remain unclear. Cisplatin is known to inhibit PPARalpha following microvascular damage to the kidneys. The primary aim of this study was to evaluate whether TCchem induces vascular endothelial dysfunction via systemic PPARalpha deficiency. In addition, human umbilical vein endothelial cells (HUVECs) were used to elucidate the mechanisms responsible for TCchem-induced vascular toxicities. METHODS: This study enrolled 45 gynecological cancer patients with normal lipid profiles who underwent surgical treatment followed by TCchem. The elevated triglyceride (TG) group included patients (n = 19) who exhibited hypertriglyceridemia during TCchem, and the stable TG group (n = 15) included patients with a normal TG level. Eleven patients exhibiting hypertriglyceridemia during TCchem were administered bezafibrate (fibrate group). Endothelial dysfunction was evaluated based on flow-mediated dilation (FMD) values and serum pentraxin-3 levels measured before TCchem and immediately after the final TCchem. HUVECs were used to elucidate the biological mechanisms underlying the endothelial dysfunction induced by TCchem. RESULTS: The administration of TCchem induced hypertriglyceridemia in 66 percent of the participants, and bezafibrate reduced the serum TG levels. Meanwhile, the decrease in flow-mediated dilatation (%FMD) induced by TCchem improved following treatment with bezafibrate. The serum pentraxin-3 level increased rapidly after TCchem and decreased following bezafibrate treatment. An in vitro examination demonstrated TCchem attenuated nitric oxide production and PPARalpha activity in HUVECs, which was partially improved by treatment with bezafibrate. CONCLUSION: Bezafibrate prevents endothelial dysfunction induced by TCchem via TG-dependent and TG-independent mechanisms. PMID- 25539888 TI - Focus groups to explore healthcare professionals' experiences of care coordination: towards a theoretical framework for the study of care coordination. AB - BACKGROUND: Strategies to improve care coordination between primary and hospital care do not always have the desired results. This is partly due to incomplete understanding of the key concepts of care coordination. An in-depth analysis of existing theoretical frameworks for the study of care coordination identified 14 interrelated key concepts. In another study, these 14 key concepts were further explored in patients' experiences. Additionally, "patient characteristics" was identified as a new key concept in patients' experiences and the previously identified key concept "quality of relationship" between healthcare professionals was extended to "quality of relationship" with the patient. Together, these 15 interrelated key concepts resulted in a new theoretical framework. The present study aimed at improving our understanding of the 15 previously identified key concepts and to explore potentially previous unidentified key concepts and the links between these by exploring how healthcare professionals experience care coordination. METHODS: A qualitative design was used. Six focus groups were conducted including primary healthcare professionals involved in the care of patients who had breast cancer surgery at three hospitals in Belgium. Data were analyzed using constant comparative analysis. RESULTS: All 15 previously identified key concepts of care coordination were further explored in healthcare professionals' experiences. Links between these 15 concepts were identified, including 9 newly identified links. The concept "external factors" was linked with all 6 concepts relating to (inter)organizational mechanisms; "task characteristics", "structure", "knowledge and information technology", "administrative operational processes", "cultural factors" and "need for coordination". Five of these concepts related to 3 concepts of relational coordination; "roles", "quality of relationship" and "exchange of information". The concept of "task characteristics" was only linked with "roles" and "exchange of information". The concept "patient characteristics" related with the concepts "need for coordination" and "patient outcome". Outcome was influenced by "roles", "quality of relationship" and "exchange of information". CONCLUSIONS: External factors and the (inter)organizational mechanism should enhance "roles" and "quality of relationship" between healthcare professionals and with the patient as well as "exchange of information", and setting and sharing of common "goals" to improve care coordination and quality of care. PMID- 25539890 TI - Palpation simulator with stable haptic feedback. AB - BACKGROUND: The main difficulty in constructing palpation simulators is to compute and to generate stable and realistic haptic feedback without vibration. When a user haptically interacts with highly non-homogeneous soft tissues through a palpation simulator, a sudden change of stiffness in target tissues causes unstable interaction with the object. MATERIAL AND METHODS: We propose a model consisting of a virtual adjustable damper and an energy measuring element. The energy measuring element gauges energy which is stored in a palpation simulator and the virtual adjustable damper dissipates the energy to achieve stable haptic interaction. RESULTS: To investigate the haptic behavior of the proposed method, impulse and continuous inputs are provided to target tissues. If a haptic interface point meets with the hardest portion in the target tissues modeled with a conventional method, we observe unstable motion and feedback force. However, when the target tissues are modeled with the proposed method, a palpation simulator provides stable interaction without vibration. CONCLUSION: The proposed method overcomes a problem in conventional haptic palpation simulators where unstable force or vibration can be generated if there is a big discrepancy in material property between an element and its neighboring elements in target tissues. PMID- 25539889 TI - Dynamic Assessment of the Endothelialization of Tissue-Engineered Blood Vessels Using an Optical Coherence Tomography Catheter-Based Fluorescence Imaging System. AB - BACKGROUND: Lumen endothelialization of bioengineered vascular scaffolds is essential to maintain small-diameter graft patency and prevent thrombosis postimplantation. Unfortunately, nondestructive imaging methods to visualize this dynamic process are lacking, thus slowing development and clinical translation of these potential tissue-engineering approaches. To meet this need, a fluorescence imaging system utilizing a commercial optical coherence tomography (OCT) catheter was designed to visualize graft endothelialization. METHODS: C7 DragonFlyTM intravascular OCT catheter was used as a channel for delivery and collection of excitation and emission spectra. Poly-dl-lactide (PDLLA) electrospun scaffolds were seeded with endothelial cells (ECs). Seeded cells were exposed to Calcein AM before imaging, causing the living cells to emit green fluorescence in response to blue laser. By positioning the catheter tip precisely over a specimen using high-fidelity electromechanical components, small regions of the specimen were excited selectively. The resulting fluorescence intensities were mapped on a two dimensional digital grid to generate spatial distribution of fluorophores at single-cell-level resolution. Fluorescence imaging of endothelialization on glass and PDLLA scaffolds was performed using the OCT catheter-based imaging system as well as with a commercial fluorescence microscope. Cell coverage area was calculated for both image sets for quantitative comparison of imaging techniques. Tubular PDLLA scaffolds were maintained in a bioreactor on seeding with ECs, and endothelialization was monitored over 5 days using the OCT catheter-based imaging system. RESULTS: No significant difference was observed in images obtained using our imaging system to those acquired with the fluorescence microscope. Cell area coverage calculated using the images yielded similar values. Nondestructive imaging of endothelialization on tubular scaffolds showed cell proliferation with cell coverage area increasing from 15 +/- 4% to 89 +/- 6% over 5 days. CONCLUSION: In this study, we showed the capability of an OCT catheter-based imaging system to obtain single-cell resolution and to quantify endothelialization in tubular electrospun scaffolds. We also compared the resulting images with traditional microscopy, showing high fidelity in image capability. This imaging system, used in conjunction with OCT, could potentially be a powerful tool for in vitro optimization of scaffold cellularization, ensuring long-term graft patency postimplantation. PMID- 25539891 TI - Are there morally relevant differences between hymen restoration and bloodless treatment for Jehovah's Witnesses? AB - BACKGROUND: Hymen reconstruction is a controversial measure performed to help young females under threat of honour-related violence. Official guidelines often reject offering hymen reconstructions. On the other hand, extraordinary measures in order to enable operations of Jehovah's Witnesses who want a bloodless operation in order to avoid religiously related sanctions are often considered praiseworthy. The aim is thus to examine whether or not there are relevant differences between these two measures. DISCUSSION: We identified twelve potential differences. One difference could be considered relevant (patient safety), but in favour of hymenoplastic operations. SUMMARY: Since we did not identify enough relevant differences to justify offering bloodless operations to Jehovah's Witnesses but not offering hymen reconstruction due to honour-related norms, we conclude that these two groups of patients should be treated equally. This means that neither of the patient groups should be offered these extraordinary operations or that both groups of patients should be offered such operations. Similarly, there are no reasons for judging those who perform the operations differently. PMID- 25539892 TI - Management of constipation in Parkinson's disease. AB - INTRODUCTION: Constipation is a frequent non-motor feature of Parkinson's disease (PD). It is the most common gastrointestinal symptom of the disease and it can precede motor symptoms by as much as 20 years. Constipation can produce discomfort and affect activities of daily living, productivity and quality of life, thus warranting early diagnosis and treatment. AREAS COVERED: In this review, the safety and efficacy of traditional and novel strategies for constipation management will be discussed. A treatment algorithm for constipation in PD will be presented. EXPERT OPINION: Polyethylene glycol and lubiprostone are first-line compounds recommended by evidence-based medicine guidelines for the treatment of constipation due to slow colonic transit in PD. Management of constipation secondary to defecatory dysfunction due to pelvic floor dyssynergia can be done by levodopa or apomorphine injections, botulinum toxin type A injection into the puborectalis muscle, and nonpharmacological interventions, like biofeedback therapy or functional magnetic stimulation, which showed some benefit in PD patients with constipation, but in general more extensive studies are warranted. PMID- 25539893 TI - Hyperopia: a meta-analysis of prevalence and a review of associated factors among school-aged children. AB - BACKGROUND: Studies show great variability in the prevalence of hyperopia among children. This study aimed to synthesize the existing knowledge about hyperopia prevalence and its associated factors in school children and to explore the reasons for this variability. METHODS: This systematic review followed PRISMA guidelines. Searching several international databases, the review included population- or school-based studies assessing hyperopia through cycloplegic autorefraction or cycloplegic retinoscopy. Meta-analysis of hyperopia prevalence was performed following MOOSE guidelines and using the random effects model. RESULTS: The review included 40 cross-sectional studies. The prevalence of hyperopia ranged from 8.4% at age six, 2-3% from 9 to 14 years and approximately 1% at 15 years. With regard to associated factors, age has an inverse association with hyperopia. The frequency of hyperopia is higher among White children and those who live in rural areas. There is no consensus about the association between hyperopia and gender, family income and parental schooling. CONCLUSION: Future studies should use standardized methods to classify hyperopia and sufficient sample size when evaluating age-specific prevalence. Furthermore, it is necessary to deepen the understanding about the interactions among hyperopic refractive error and accommodative and binocular functions as a way of identifying groups of hyperopic children at risk of developing visual, academic and even cognitive function sequelae. PMID- 25539894 TI - Normal adult survival but reduced Bemisia tabaci oviposition rate on tomato lines carrying an introgression from S. habrochaites. AB - BACKGROUND: Host plant resistance has been proposed as one of the most promising approaches in whitefly management. Already in 1995 two quantitative trait loci (Tv-1 and Tv-2) originating from S. habrochaites CGN1.1561 were identified that reduced the oviposition rate of the greenhouse whitefly (Trialeurodes vaporariorum). After this first study, several others identified QTLs affecting whitefly biology as well. Generally, the QTLs affecting oviposition were highly correlated with a reduction in whitefly survival and the presence of high densities of glandular trichomes type IV. The aim of our study was to further characterize Tv-1 and Tv-2, and to determine their role in resistance against Bemisia tabaci. RESULTS: We selected F2 plants homozygous for the Tv-1 and Tv-2 QTL regions and did three successive backcrosses without phenotypic selection. Twenty-three F2BC3 plants were phenotyped for whitefly resistance and differences were found in oviposition rate of B. tabaci. The F2BC3 plants with the lowest oviposition rate had an introgression on Chromosome 5 in common. Further F2BC4, F2BC4S1 and F2BC4S2 families were developed, genotyped and phenotyped for adult survival, oviposition rate and trichome type and density. It was possible to confirm that an introgression on top of Chr. 5 (OR-5), between the markers rs 2009 and rs-7551, was responsible for reducing whitefly oviposition rate. CONCLUSION: We found a region of 3.06 Mbp at the top of Chr. 5 (OR-5) associated with a reduction in the oviposition rate of B. tabaci. This reduction was independent of the presence of the QTLs Tv-1 and Tv-2 as well as of the presence of trichomes type IV. The OR-5 locus will provide new opportunities for resistance breeding against whiteflies, which is especially relevant in greenhouse cultivation. PMID- 25539895 TI - Natriuresis and blood pressure reduction in hypertensive patients with diabetes mellitus: the NESTOR study. AB - The antihypertensive effect of indapamide has never been clearly understood, particularly in hypertensive patients with diabetes mellitus. A total of 565 patients were randomly selected to receive either indapamide 1.5 mg or enalapril 10 mg daily for 12 months. Brachial blood pressure (BP) and plasma and urinary electrolytes were measured at baseline and at the end of follow-up. Sodium and potassium levels and excretion rates were measured in overnight urine collections. After 12 months' treatment, similar significant reductions were observed in systolic and diastolic BP and pulse pressure levels in both treatment arms (P < .001). However, age, body mass index, diabetes duration, and plasma sodium reductions were shown to be major, independent factors influencing BP reduction with indapamide, but not with enalapril. Regression coefficients were positive for age and plasma sodium reductions (P <= .009) but negative for body mass index and diabetes duration (P <= .008). Similar findings were observed for pulse pressure. These results were more notable in elderly patients, did not differ regardless of whether BP reduction was measured in absolute or percent values, and were associated with increased sodium and potassium excretion rates.Indapamide is more effective than enalapril at reducing BP in elderly diabetic hypertensives with marked sodium retention. PMID- 25539896 TI - A possible mechanism for the progression of chronic renal disease and congestive heart failure. AB - Chronic neurologic diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as various forms of chronic renal disease and systolic congestive heart failure, are among the most common progressive degenerative disorders encountered in medicine. Each disease follows a nearly relentless course, albeit at varying rates, driven by progressive cell dysfunction and drop-out. The neurologic diseases are characterized by the progressive spread of disease-causing proteins (prion-like proteins) from cell to cell. Recent evidence indicates that cell autonomous renin angiotensin systems operate in heart and kidney, and it is known that functional intracrine proteins can also spread between cells. This then suggests that certain progressive degenerative cardiovascular disorders such as forms of chronic renal insufficiency and systolic congestive heart failure result from dysfunctional renin angiotensin system intracrine action spreading in kidney or myocardium. PMID- 25539897 TI - RESPeRATE: the role of paced breathing in hypertension treatment. AB - Despite a good adherence to lifestyle modifications and antihypertensive drugs, hypertension remains resistant in more than one-third of patients, thus creating the need for additional strategies, including non-pharmacologic approaches. Slow and deep breathing ("paced breathing") associated in the past with meditation has a direct antihypertensive effect by increasing baroreflex sensitivity. With the method of guiding the pace of breathing, a US Food and Drug Administration certified device, RESPeRATE, may offer an easy, efficient, inexpensive, and noninvasive option for treating hypertension. Multiple studies showed a significant reduction of blood pressure when RESPeRATE was evaluated in a home and office setting. In conclusion, this review outlines the pathophysiologic background of paced respiration, describes RESPeRATE clinical trials, and presents briefly other guided breathing alternatives. PMID- 25539899 TI - Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease. AB - Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in developed countries of the world, while the main cause of mortality and morbidity in COPD patients are acute exacerbations and cardiovascular diseases. With regard to the frequency of exacerbations the phenotype "frequent exacerbators" has been defined, which, besides a more severe clinical course and a significantly higher total mortality, is also characterised by an elevated risk of cardiovascular mortality, as some indicators show us. It is notable that during the exacerbation of COPD, next to other changes, a significant aggravation of endothelial function occurs while the ED and COPD relationship seems very complex and is still in greater part unknown. Making the pathophysiological link between the frequency of exacerbations of COPD and ED could change our understanding of the character of this type of pulmonary disease. We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with ancillary systemic effects. Our opinion is that differences in COPD phenotype do not only determine the clinical picture but could also be of key importance in defining the progressivity of the disease. ED, which in these patients persists between frequent exacerbations, could be the main cause of the progression of pulmonary disease, and not only of the high cardiovascular risk of these patients. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms, could contemporaneously induce new exacerbations of COPD, the progression of pulmonary changes and the development of systemic atherosclerosis as a main extrapulmonary manifestation in these patients. Such a model defines endothelium as a common soil of progressive pulmonary and cardiovascular changes in FE COPD. It can fully explain all the elements of the clinical course and co-morbidity in FE COPD, for which we still do not have adequate explanation. PMID- 25539898 TI - Molecular mechanisms involved in HIV-1 Tat-mediated induction of IL-6 and IL-8 in astrocytes. AB - BACKGROUND: HIV-associated neurocognitive disorders (HAND) exist in approximately 50% of infected individuals even after the introduction of highly active antiretroviral therapy. HIV-1 Tat has been implicated in HIV-associated neurotoxicity mediated through production of pro-inflammatory cytokines like IL-6 and IL-8 by astrocytes among others as well as oxidative stress. However, the underlying mechanism(s) in the up-regulation of IL-6 and IL-8 are not clearly understood. The present study was designed to determine the mechanism(s) responsible for IL-6 and IL-8 up-regulation by HIV-1 Tat. METHODS: SVG astrocytes were transiently transfected with a plasmid encoding HIV-1 Tat. The HIV-1 Tat mediated mRNA and protein expression levels of both IL-6 and IL-8 in SVG astrocytes were quantified using real time RT-PCR and multiplex cytokine assay respectively. We also employed immunocytochemistry for staining of IL-6 and IL-8. The underlying signaling mechanism(s) were identified using pharmacological inhibitors and siRNA for different intermediate steps involved in PI3K/Akt, p38 MAPK and JNK MAPK pathways. Appropriate controls were used in the experiments and the effect of pharmacological antagonists and siRNA were observed on both mRNA expression and protein levels. RESULTS: Both IL-6/IL-8 mRNA and protein showed peak expressions at 6 hours and 96 hours post-transfection, respectively. Elevated levels of IL-6/IL-8 were also confirmed by immunocytochemistry. Our studies indicated that both NF-kB and AP-1 transcription factors were involved in IL-6 and IL-8 expression mediated by HIV-1 Tat; however, AP-1 was differentially activated for either cytokine. In the case of IL-6, p38delta activated AP-1 whereas JNK but not p38 MAPK was involved in AP-1 activation for IL-8 production. On the other hand both PI3K/Akt and p38 MAPK (beta subunit) were found to be involved in activation of NF-kappaB that led to IL-6 and IL-8 production. CONCLUSION: Our results demonstrate HIV-1 Tat-mediated induction of both IL-6 and IL-8 in a time-dependent manner in SVG astrocytes. Furthermore, we also showed the involvement of NF-kappaB and AP-1 transcription factors regulated by PI3/Akt, p38 MAPK and JNK MAPK upstream signaling molecules. These results present new therapeutic targets that could be used in management of HAND. PMID- 25539900 TI - Atherosclerosis regulation via media lipid-driven VSMC cholesterol efflux switch. AB - It is known, that initial events in atherosclerosis arise in the intima with a parallel influx of inflammatory cells. I propose the opposite - that the disease onset begins from the media vascular smooth muscle cell (VSMC) involvement and through its utilization of modified low-density lipoproteins (LDL), and free or esterified cholesterol. Other oxidized lipoprotein molecules remain in the media which are non-removed by high-density lipoproteins (HDL), owing to their structural damages after local vasa vasorum and adventitia lymphatic disorders. Mechanism by which VSMC ingulf and degrade them includes lipid-driven activation of VSMC reverse cholesterol transport pathways from the media to macrophages, and from the last - to plasma HDL (non-damaged) and apoA-1 or - directly to them. When some of the pathways are impaired, its demands a reprogramming of the existing cholesterol removal route to another, or selective gene involvements and transcriptional regulation of inflammatory signaling. Intima cell call-effects may be linked after their down-regulation with the expression of cytokines, chemokines by migrating VSMC to stem cells for dose-dependent proliferation, VSMC and macrophage maturation in non- and inflammatory phases of early or late atherosclerosis. PMID- 25539901 TI - Antibiotics in frozen bone grafts can cause allergic reactions in recipient patients. AB - Antibiotic prophylaxis is a routine procedure during total hip arthroplasty (THA), and the vast majority of cadavers within the multitissue procurement receive one or more antibiotics. Upon harvesting, bone grafts are stored in the bone banks on the temperature as low as -80 degrees C for up to 5 years. It is shown in the literature that the antibiotics remain active and viable in the bone grafts even after being exposed to extremely low temperatures in the prolonged periods. Possibility of remnant antibiotic concentrations in the bone grafts and the fact that these antibiotic remnants maintain active even after being exposed to extremely low temperatures create the environment in which the possibility for the allergic reaction in sensitive patient receiving bone graft exists. We hypothesize that harvested bone grafts containing active antibiotic substance have the potential for local and systemic allergic reaction in sensitive recipient patients thus increasing morbidity and the costs of the treatment. Allergic reactions can mimic surgical site infections as well with the consequent substantial pitfalls in the treatment. Following that, in the setting of an assumed but not confirmed surgical site infection, the immunological evaluation on antibiotics for recipients of bone grafts could be added to the standard diagnostic algorithms. In addition, bone banks should be obliged to provide information of all potential drugs that can be found in every specific bone graft to the end users. PMID- 25539903 TI - No dawn yet of a new age in spinal cord rehabilitation. PMID- 25539902 TI - Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET. AB - Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological alpha synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 +/- 9 years) and 12 age-matched control subjects (three female; age 62 +/- 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological alpha-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed. PMID- 25539904 TI - Limb function and quality of life after various reconstruction methods according to tumor location following resection of osteosarcoma in distal femur. AB - BACKGROUND: We tried to compare the functional and psychosocial outcomes after various reconstruction methods according to tumor location following resection of osteosarcoma in distal femur. METHODS: We retrospectively reviewed 51 patients who underwent limb-salvage surgery of osteosarcoma in distal femur in our institution, 30 males and 21 females with an average age of 21 years (range 13-51 years). We classified osteosarcoma in distal femur into 3 types, and organized affected limb reconstruction methods after wide resection. MSTS and QOL scores were used to analyze the functional and psychological outcomes. RESULTS: After a mean follow-up of 43 months (12-225 months), there is no difference on functional results and QOL scores among three reconstruction groups (p > 0.05) and among three types groups (p > 0.05). No difference could be noticed on tumor-free survival and total survival among three reconstruction groups (p > 0.05) and three type groups (p > 0.05). In <=2-year, better functional scores could be found in prosthesis group, rather than the other two inactivated-bone groups (p < 0.05). CONCLUSIONS: Biological reconstruction with alcohol-inactivated autograft replantation could avoid prosthesis related complications and achieved comparable results with prosthesis following resection of osteosarcoma in distal femur. Different reconstruction options could be chosen according to tumor location, such as the distance to Insall line. PMID- 25539905 TI - Outcome of highly active antiretroviral therapy in HIV-infected Indian children. AB - BACKGROUND: With the advent of highly active antiretroviral therapy (HAART), HIV infection has become a chronic condition in children with improved survival and quality of life. Reports on long term effectiveness of non-nucleoside reverse transcriptase inhibitor based HAART in HIV-infected children in developing countries are limited. METHODS: A chart review was conducted and children who received at least six months of HAART between 2004-2011 at All India Institute of Medical Sciences (AIIMS), Delhi were included. The clinical, immunological and virological responses to HAART were documented. Factors predicting non-adherence and non-response to treatment were described. RESULTS: One seventy five children (boys: 74.9%) were included in the study, with a median follow up of 43 (IQR: 17, 68) months. The median age at diagnosis was 119 (IQR: 75, 156) months. The median CD4 count at start of HAART was 340 cells/MUL (IQR: 185,704), which increased to 924 cells/MUL (IQR: 591,1278) at 48 months after HAART and plateaued at 749 (IQR: 542,1056) cells/ MUL after 90 months of therapy. The weight for age (WAZ) and height for age (HAZ) z score both showed improvement with time after HAART initiation [baseline: WAZ -2.8 (IQR: -4,-1.6), HAZ -2.1 (IQR: -3.4,-0.69); at 42 months of therapy: WAZ -1.2 (IQR: -2.1, 0.01), HAZ -0.75(IQR: -1.6,-0.37)]. Adverse events were reported in 21 (12%) children. Non-adherence to therapy, treatment failure and death were noted in 35 (20%), 9 (5.1%) and 6 (3.4%) children respectively. CONCLUSIONS: Our experience shows that HAART in HIV infected children is effective, safe and is associated with good immunological and virological response as well as improvement in growth parameters. PMID- 25539906 TI - A reduction of viral mRNA, proteins and induction of altered morphogenesis reveals the anti-HTLV-1 activity of the labdane-diterpene myriadenolide in vitro. AB - BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) has been associated with leukemia/lymphoma (ATL) and myelopathy/tropical spastic paraparesis (HAM/TSP), in addition to other inflammatory diseases as well as infection complications. Therapeutic approaches for HTLV-1-related pathologies are limited. The labdane diterpene myriadenolide (AMY) is a natural product that exhibit biological activities, such as anti-inflammatory and antiviral activity as reported for HIV and herpesvirus. RESULTS: We demonstrated that this natural product was able to inhibit the expression of gag-pol mRNA and substantially reduced the expression of the structural proteins p19 and gp46. Comparison of treated and untreated cells shows that AMY alters both the morphology and the release of viral particles. The Atomic Force Microscopy assay showed that the AMY treatment reduced the number of particles on the cell surface by 47%. CONCLUSION: We demonstrated that the labdane diterpene myriadenolide reduced the expression of the structural proteins and the budding of viral particles, besides induces altered morphogenesis of HTLV-1, conferring on AMY a new antiviral activity that may be useful for the development of new compounds with specific anti-HTLV-1 activity. PMID- 25539907 TI - Systematic analysis of the clinical and biochemical characteristics of maternally inherited hypertension in Chinese Han families associated with mitochondrial. AB - BACKGROUND: Mitochondrial DNA mutations may be associated with cardiovascular disease, including the common cardiac vascular disease, hypertension. METHODS: In this study we performed segregation analysis and systematically evaluated the entire mitochondrial genome in nine maternally inherited hypertension probands from Chinese Han families. We also performed clinical, genetic and molecular characterization of 74 maternally inherited members from these families and 216 healthy controls. RESULTS: In the maternally inherited members, 12 had coronary heart disease (CHD), six had cerebrovascular disease, five had diabetes, nine had hyperlipidemia and three had renal disease. Laboratory tests showed that the sodium and potassium levels in blood of the maternally inherited members were higher than those of the control group (P < 0.01), while no differences were observed in fasting blood glucose (FBG), total cholesterol (TC), triglyceride, low density lipoprotein cholesterol (LDL-c) and creatinine levels (P > 0.05). The high density lipoprotein cholesterol (HDL-c) level of the maternally inherited members was lower than that of the control group (P = 0.04). The whole mitochondrial DNA sequence analysis revealed a total of 172 base changes, including 17 in ribosomal RNA (rRNA) genes, four in transfer RNA (tRNA) genes, and 22 amino acid substitutions. The remainder were synonymous changes or were located in non-coding regions. We identified seven amino acid changes in the nine maternally inherited hypertension families, including four mutations in ATPase6 and three in Cytb. More interestingly, tRNA(Ser(UCN)) 7492 T > C was absent in controls and was present in <1% of 2704 mtDNAs, indicating potential functional significance. CONCLUSIONS: This study showed that mutations in mtDNA may contribute to the pathogenesis of hypertension in these Chinese Han families. In the near future, identification of additional mtDNA mutations may indicate further candidate genes for hypertension. PMID- 25539909 TI - Design, synthesis, docking study and cytotoxic activity evaluation of some novel letrozole analogs. AB - BACKGROUND: Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7). METHODS: Our synthetic route for designed compounds started from 4-bromotolunitrile which was reacted with 1H-1,2,4-triazole to afford 4-(4-cyanobenzyl)-1,2,4-triazole. The reaction of later compound with aromatic aldehydes led to formation of the designed compounds. Eleven novel derivatives 1a-k were tested for their cytotoxic activities on three human breast cancer cell lines. RESULTS: Among the synthesized compound, 4-[2-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1 yl)ethenyl]benzonitrile (1c) showed the highest activity against MCF-7 and MDA-MB 231 cell lines and 4-[2-(4-methoxyphenyl)-1-(1H-1,2,4-triazol-1 yl)ethenyl]benzonitrile (1 h) exhibited highest activity against T47D cell line. According to cytotoxic activities results, compound 4-[2-(4-dimethylamino)-1-(1H 1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 k) showed comparative activity against T47D and MDA-MB-231 cell lines with compound (1 h) and our reference drug Etoposide. CONCLUSION: In the process of anti-cancer drug discovery, to find new potential anti-breast cancer agents, we designed and synthesized a novel series of letrozole analogs. Cytotoxicity evaluation revealed that compounds (1c) and (1 k) were the most potent compounds with comparative activity with Etoposide. The results revealed that pi-pi interactions are responsible for the enzyme inhibitions of compounds (1 c) and (1 k). PMID- 25539910 TI - Thromboelastometry and organ failure in trauma patients: a prospective cohort study. AB - INTRODUCTION: Data on the incidence of a hypercoagulable state in trauma, as measured by thromboelastometry (ROTEM), is limited and the prognostic value of hypercoagulability after trauma on outcome is unclear. We aimed to determine the incidence of hypercoagulability after trauma, and to assess whether early hypercoagulability has prognostic value on the occurrence of multiple organ failure (MOF) and mortality. METHODS: This was a prospective observational cohort study in trauma patients who met the highest trauma level team activation. Hypercoagulability was defined as a G value of >= 11.7 dynes/cm(2) and hypocoagulability as a G value of <5.0 dynes/cm(2). ROTEM was performed on admission and 24 hours later. RESULTS: A total of 1,010 patients were enrolled and 948 patients were analyzed. Median age was 38 (interquartile range (IQR) 26 to 53), 77% were male and median injury severity score was 13 (IQR 8 to 25). On admission, 7% of the patients were hypercoagulable and 8% were hypocoagulable. Altogether, 10% of patients showed hypercoagulability within the first 24 hours of trauma. Hypocoagulability, but not hypercoagulability, was associated with higher sequential organ failure assessment scores, indicating more severe MOF. Mortality in patients with hypercoagulability was 0%, compared to 7% in normocoagulable and 24% in hypocoagulable patients (P <0.001). EXTEM CT, alpha and G were predictors for occurrence of MOF and mortality. CONCLUSIONS: The incidence of a hypercoagulable state after trauma is 10% up to 24 hours after admission, which is broadly comparable to the rate of hypocoagulability. Further work in larger studies should define the clinical consequences of identifying hypercoagulability and a possible role for very early, targeted use of anticoagulants. PMID- 25539911 TI - Functional mechanisms of drought tolerance in subtropical maize (Zea mays L.) identified using genome-wide association mapping. AB - BACKGROUND: Earlier studies were focused on the genetics of temperate and tropical maize under drought. We identified genetic loci and their association with functional mechanisms in 240 accessions of subtropical maize using a high density marker set under water stress. RESULTS: Out of 61 significant SNPs (11 were false-discovery-rate-corrected associations), identified across agronomic traits, models, and locations by subjecting the accessions to water stress at flowering stage, 48% were associated with drought-tolerant genes. Maize gene models revealed that SNPs mapped for agronomic traits were in fact associated with number of functional traits as follows: stomatal closure, 28; flowering, 15; root development, 5; detoxification, 4; and reduced water potential, 2. Interactions of these SNPS through the functional traits could lead to drought tolerance. The SNPs associated with ABA-dependent signalling pathways played a major role in the plant's response to stress by regulating a series of functions including flowering, root development, auxin metabolism, guard cell functions, and scavenging reactive oxygen species (ROS). ABA signalling genes regulate flowering through epigenetic changes in stress-responsive genes. ROS generated by ABA signalling are reduced by the interplay between ethylene, ABA, and detoxification signalling transductions. Integration of ABA-signalling genes with auxin-inducible genes regulates root development which in turn, maintains the water balance by regulating electrochemical gradient in plant. CONCLUSIONS: Several genes are directly or indirectly involved in the functioning of agronomic traits related to water stress. Genes involved in these crucial biological functions interacted significantly in order to maintain the primary as well as exclusive functions related to coping with water stress. SNPs associated with drought-tolerant genes involved in strategic biological functions will be useful to understand the mechanisms of drought tolerance in subtropical maize. PMID- 25539913 TI - The prion protein is critical for DNA repair and cell survival after genotoxic stress. AB - The prion protein (PrP) is highly conserved and ubiquitously expressed, suggesting that it plays an important physiological function. However, despite decades of investigation, this role remains elusive. Here, by using animal and cellular models, we unveil a key role of PrP in the DNA damage response. Exposure of neurons to a genotoxic stress activates PRNP transcription leading to an increased amount of PrP in the nucleus where it interacts with APE1, the major mammalian endonuclease essential for base excision repair, and stimulates its activity. Preventing the induction of PRNP results in accumulation of abasic sites in DNA and impairs cell survival after genotoxic treatment. Brains from Prnp(-/-) mice display a reduced APE1 activity and a defect in the repair of induced DNA damage in vivo. Thus, PrP is required to maintain genomic stability in response to genotoxic stresses. PMID- 25539914 TI - A new recombineering system for Photorhabdus and Xenorhabdus. AB - Precise and fluent genetic manipulation is still limited to only a few prokaryotes. Ideally the highly advanced technologies available in Escherichia coli could be broadly applied. Our efforts to apply lambda Red technology, widely termed 'recombineering', in Photorhabdus and Xenorhabdus yielded only limited success. Consequently we explored the properties of an endogenous Photorhabdus luminescens lambda Red-like operon, Plu2934/Plu2935/Plu2936. Bioinformatic and functional tests indicate that Plu2936 is a 5'-3' exonuclease equivalent to Redalpha and Plu2935 is a single strand annealing protein equivalent to Redbeta. Plu2934 dramatically enhanced recombineering efficiency. Results from bioinformatic analysis and recombineering assays suggest that Plu2934 may be functionally equivalent to Redgamma, which inhibits the major endogenous E. coli nuclease, RecBCD. The recombineering utility of Plu2934/Plu2935/Plu2936 was demonstrated by engineering Photorhabdus and Xenorhabdus genomes, including the activation of the 49-kb non-ribosomal peptide synthase (NRPS) gene cluster plu2670 by insertion of a tetracycline inducible promoter. After tetracycline induction, novel secondary metabolites were identified. Our work unlocks the potential for bioprospecting and functional genomics in the Photorhabdus, Xenorhabdus and related genomes. PMID- 25539915 TI - High-resolution HDX-MS reveals distinct mechanisms of RNA recognition and activation by RIG-I and MDA5. AB - RIG-I and MDA5 are the major intracellular immune receptors that recognize viral RNA species and undergo a series of conformational transitions leading to the activation of the interferon-mediated antiviral response. However, to date, full length RLRs have resisted crystallographic efforts and a molecular description of their activation pathways remains hypothetical. Here we employ hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) to probe the apo states of RIG-I and MDA5 and to dissect the molecular details with respect to distinct RNA species recognition, ATP binding and hydrolysis and CARDs activation. We show that human RIG-I maintains an auto-inhibited resting state owing to the intra molecular HEL2i-CARD2 interactions while apo MDA5 lacks the analogous intra molecular interactions and therefore adopts an extended conformation. Our work demonstrates that RIG-I binds and responds differently to short triphosphorylated RNA and long duplex RNA and that sequential addition of RNA and ATP triggers specific allosteric effects leading to RIG-I CARDs activation. We also present a high-resolution protein surface mapping technique that refines the cooperative oligomerization model of neighboring MDA5 molecules on long duplex RNA. Taken together, our data provide a high-resolution view of RLR activation in solution and offer new evidence for the molecular mechanism of RLR activation. PMID- 25539912 TI - WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. AB - TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%+/-8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%+/-2% vs. 57.4%+/-1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%+/-1.5% in lithium treated cells vs. 56.6+/-3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%+/-8% for lithium treated cells vs. 27%+/-3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high risk medulloblastomas. PMID- 25539916 TI - DNA ligase III acts as a DNA strand break sensor in the cellular orchestration of DNA strand break repair. AB - In the current model of DNA SSBR, PARP1 is regarded as the sensor of single strand breaks (SSBs). However, biochemical studies have implicated LIG3 as another possible SSB sensor. Using a laser micro-irradiation protocol that predominantly generates SSBs, we were able to demonstrate that PARP1 is dispensable for the accumulation of different single-strand break repair (SSBR) proteins at sites of DNA damage in live cells. Furthermore, we show in live cells for the first time that LIG3 plays a role in mediating the accumulation of the SSBR proteins XRCC1 and PNKP at sites of DNA damage. Importantly, the accumulation of LIG3 at sites of DNA damage did not require the BRCT domain mediated interaction with XRCC1. We were able to show that the N-terminal ZnF domain of LIG3 plays a key role in the enzyme's SSB sensing function. Finally, we provide cellular evidence that LIG3 and not PARP1 acts as the sensor for DNA damage caused by the topoisomerase I inhibitor, irinotecan. Our results support the existence of a second damage-sensing mechanism in SSBR involving the detection of nicks in the genome by LIG3. PMID- 25539917 TI - Mycobacterial RNA isolation optimized for non-coding RNA: high fidelity isolation of 5S rRNA from Mycobacterium bovis BCG reveals novel post-transcriptional processing and a complete spectrum of modified ribonucleosides. AB - A major challenge in the study of mycobacterial RNA biology is the lack of a comprehensive RNA isolation method that overcomes the unusual cell wall to faithfully yield the full spectrum of non-coding RNA (ncRNA) species. Here, we describe a simple and robust procedure optimized for the isolation of total ncRNA, including 5S, 16S and 23S ribosomal RNA (rRNA) and tRNA, from mycobacteria, using Mycobacterium bovis BCG to illustrate the method. Based on a combination of mechanical disruption and liquid and solid-phase technologies, the method produces all major species of ncRNA in high yield and with high integrity, enabling direct chemical and sequence analysis of the ncRNA species. The reproducibility of the method with BCG was evident in bioanalyzer electrophoretic analysis of isolated RNA, which revealed quantitatively significant differences in the ncRNA profiles of exponentially growing and non-replicating hypoxic bacilli. The method also overcame an historical inconsistency in 5S rRNA isolation, with direct sequencing revealing a novel post-transcriptional processing of 5S rRNA to its functional form and with chemical analysis revealing seven post-transcriptional ribonucleoside modifications in the 5S rRNA. This optimized RNA isolation procedure thus provides a means to more rigorously explore the biology of ncRNA species in mycobacteria. PMID- 25539919 TI - Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase. AB - Human RAD51 protein catalyzes DNA pairing and strand exchange reactions that are central to homologous recombination and homology-directed DNA repair. Successful recombination/repair requires the formation of a presynaptic filament of RAD51 on ssDNA. Mutations in BRCA2 and other proteins that control RAD51 activity are associated with human cancer. Here we describe a set of mutations associated with human breast tumors that occur in a common structural motif of RAD51. Tumor associated D149N, R150Q and G151D mutations map to a Schellman loop motif located on the surface of the RecA homology domain of RAD51. All three variants are proficient in DNA strand exchange, but G151D is slightly more sensitive to salt than wild-type (WT). Both G151D and R150Q exhibit markedly lower catalytic efficiency for adenosine triphosphate hydrolysis compared to WT. All three mutations alter the physical properties of RAD51 nucleoprotein filaments, with G151D showing the most dramatic changes. G151D forms mixed nucleoprotein filaments with WT RAD51 that have intermediate properties compared to unmixed filaments. These findings raise the possibility that mutations in RAD51 itself may contribute to genome instability in tumor cells, either directly through changes in recombinase properties, or indirectly through changes in interactions with regulatory proteins. PMID- 25539920 TI - Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors. AB - Anti-microRNA (miRNA) oligonucleotides (AMOs) with 2'-O-Methyl (2'OMe) residues are commonly used to study miRNA function and can achieve high potency, with low cytotoxicity. Not withstanding this, we demonstrate the sequence-dependent capacity of 2'OMe AMOs to inhibit Toll-like receptor (TLR) 7 and 8 sensing of immunostimulatory RNA, independent of their miRNA-targeting function. Through a screen of 29 AMOs targeting common miRNAs, we found a subset of sequences highly inhibitory to TLR7 sensing in mouse macrophages. Interspecies conservation of this inhibitory activity was confirmed on TLR7/8 activity in human peripheral blood mononuclear cells. Significantly, we identified a core motif governing the inhibitory activity of these AMOs, which is present in more than 50 AMOs targeted to human miRNAs in miRBaseV20. DNA/locked nucleic acids (LNA) AMOs synthesized with a phosphorothioate backbone also inhibited TLR7 sensing in a sequence dependent manner, demonstrating that the off-target effects of AMOs are not restricted to 2'OMe modification. Taken together, our work establishes the potential for off-target effects of AMOs on TLR7/8 function, which should be taken into account in their therapeutic development and in vivo application. PMID- 25539918 TI - Immediate chromatin immunoprecipitation and on-bead quantitative PCR analysis: a versatile and rapid ChIP procedure. AB - Genome-wide chromatin immunoprecipitation (ChIP) studies have brought significant insight into the genomic localization of chromatin-associated proteins and histone modifications. The large amount of data generated by these analyses, however, require approaches that enable rapid validation and analysis of biological relevance. Furthermore, there are still protein and modification targets that are difficult to detect using standard ChIP methods. To address these issues, we developed an immediate chromatin immunoprecipitation procedure which we call ZipChip. ZipChip significantly reduces the time and increases sensitivity allowing for rapid screening of multiple loci. Here we describe how ZipChIP enables detection of histone modifications (H3K4 mono- and trimethylation) and two yeast histone demethylases, Jhd2 and Rph1, which were previously difficult to detect using standard methods. Furthermore, we demonstrate the versatility of ZipChIP by analyzing the enrichment of the histone deacetylase Sir2 at heterochromatin in yeast and enrichment of the chromatin remodeler, PICKLE, at euchromatin in Arabidopsis thaliana. PMID- 25539922 TI - Mechanism of RecQ helicase mechanoenzymatic coupling reveals that the DNA interactions of the ADP-bound enzyme control translocation run terminations. AB - The processing of various DNA structures by RecQ helicases is crucial for genome maintenance in both bacteria and eukaryotes. RecQ helicases perform active destabilization of DNA duplexes, based on tight coupling of their ATPase activity to moderately processive translocation along DNA strands. Here, we determined the ATPase kinetic mechanism of E. coli RecQ helicase to reveal how mechanoenzymatic coupling is achieved. We found that the interaction of RecQ with DNA results in a drastic acceleration of the rate-limiting ATP cleavage step, which occurs productively due to subsequent rapid phosphate release. ADP release is not rate limiting and ADP-bound RecQ molecules make up a small fraction during single stranded DNA translocation. However, the relatively rapid release of the ADP bound enzyme from DNA causes the majority of translocation run terminations (i.e. detachment from the DNA track). Thus, the DNA interactions of ADP-bound RecQ helicase, probably dependent on DNA structure, will mainly determine translocation processivity and may control the outcome of DNA processing. Comparison with human Bloom's syndrome (BLM) helicase reveals that similar macroscopic parameters are achieved by markedly different underlying mechanisms of RecQ homologs, suggesting diversity in enzymatic tuning. PMID- 25539923 TI - Arrangements of human telomere DNA quadruplex in physiologically relevant K+ solutions. PMID- 25539921 TI - Enhancers compete with a long non-coding RNA for regulation of the Kcnq1 domain. AB - The imprinted Kcnq1 domain contains a differentially methylated region (KvDMR) in intron 11 of Kcnq1. The Kcnq1ot1 non-coding RNA emerges from the unmethylated paternal KvDMR in antisense direction, resulting in cis-repression of neighboring genes. The KvDMR encompasses the Kcnq1ot1 promoter, CTCF sites and other DNA elements, whose individual contribution to regulation of the endogenous domain is unknown. We find that paternal inheritance of a deletion of the minimal Kcnq1ot1 promoter derepresses the upstream Cdkn1c gene. Surprisingly, Kcnq1ot1 transcripts continue to emerge from alternative sites, evidence that silencing depends, not on the ncRNA, but on the promoter sequence. Detailed analyses of Kcnq1ot during cardiogenesis show substantial chromatin reorganization coinciding with discontinuous RNA production in both wild-type and mutant mice, with loss of imprinting. We show that CTCF binds to both methylated and unmethylated alleles of the KvDMR. Furthermore, we report a multitude of enhancers within the Kcnq1ot1 region, and present conformational dynamics of a novel heart enhancer engaged in Kcnq1 expression. Our results have important implications on tissue-specific imprinting patterns and how transcriptional mechanisms compete to maximize the expression of vital genes, in addition to shifting our perception on the role of the long ncRNA in regulating this imprinted domain. PMID- 25539924 TI - Incorporation of histone H3.1 suppresses the lineage potential of skeletal muscle. AB - Lineage potential is triggered by lineage-specific transcription factors in association with changes in the chromatin structure. Histone H3.3 variant is thought to play an important role in the regulation of lineage-specific genes. To elucidate the function of H3.3 in myogenic differentiation, we forced the expression of GFP-H3.1 to alter the balance between H3.1 and H3.3 in mouse C2C12 cells that could be differentiated into myotubes. GFP-H3.1 replaced H3.3 in the regulatory regions of skeletal muscle (SKM) genes and induced a decrease of H3K4 trimethylation (H3K4me3) and increase of H3K27 trimethylation (H3K27me3). Similar results were obtained by H3.3 knockdown. In contrast, MyoD-dependent H3.3 incorporation into SKM genes in fibroblasts induced an increase of H3K4me3 and H3K27me3. In mouse embryos, a bivalent modification of H3K4me3 and H3K27me3 was formed on H3.3-incorporated SKM genes before embryonic skeletal muscle differentiation. These results suggest that lineage potential is established through a selective incorporation of specific H3 variants that governs the balance of histone modifications. PMID- 25539925 TI - SwiftLib: rapid degenerate-codon-library optimization through dynamic programming. AB - Degenerate codon (DC) libraries efficiently address the experimental library-size limitations of directed evolution by focusing diversity toward the positions and toward the amino acids (AAs) that are most likely to generate hits; however, manually constructing DC libraries is challenging, error prone and time consuming. This paper provides a dynamic programming solution to the task of finding the best DCs while keeping the size of the library beneath some given limit, improving on the existing integer-linear programming formulation. It then extends the algorithm to consider multiple DCs at each position, a heretofore unsolved problem, while adhering to a constraint on the number of primers needed to synthesize the library. In the two library-design problems examined here, the use of multiple DCs produces libraries that very nearly cover the set of desired AAs while still staying within the experimental size limits. Surprisingly, the algorithm is able to find near-perfect libraries where the ratio of amino-acid sequences to nucleic-acid sequences approaches 1; it effectively side-steps the degeneracy of the genetic code. Our algorithm is freely available through our web server and solves most design problems in about a second. PMID- 25539926 TI - Regulation of the transcriptional program by DNA methylation during human alphabeta T-cell development. AB - Thymocyte differentiation is a complex process involving well-defined sequential developmental stages that ultimately result in the generation of mature T-cells. In this study, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages. Gain and loss of methylation occurred during thymocyte differentiation, but DNA demethylation was much more frequent than de novo methylation and more strongly correlated with gene expression. These changes took place in CpG-poor regions and were closely associated with T-cell differentiation and TCR function. Up to 88 genes that encode transcriptional regulators, some of whose functions in T-cell development are as yet unknown, were differentially methylated during differentiation. Interestingly, no reversion of accumulated DNA methylation changes was observed as differentiation progressed, except in a very small subset of key genes (RAG1, RAG2, CD8A, PTCRA, etc.), indicating that methylation changes are mostly unique and irreversible events. Our study explores the contribution of DNA methylation to T-cell lymphopoiesis and provides a fine-scale map of differentially methylated regions associated with gene expression changes. These can lay the molecular foundations for a better interpretation of the regulatory networks driving human thymopoiesis. PMID- 25539927 TI - Conditional mutual inclusive information enables accurate quantification of associations in gene regulatory networks. AB - Mutual information (MI), a quantity describing the nonlinear dependence between two random variables, has been widely used to construct gene regulatory networks (GRNs). Despite its good performance, MI cannot separate the direct regulations from indirect ones among genes. Although the conditional mutual information (CMI) is able to identify the direct regulations, it generally underestimates the regulation strength, i.e. it may result in false negatives when inferring gene regulations. In this work, to overcome the problems, we propose a novel concept, namely conditional mutual inclusive information (CMI2), to describe the regulations between genes. Furthermore, with CMI2, we develop a new approach, namely CMI2NI (CMI2-based network inference), for reverse-engineering GRNs. In CMI2NI, CMI2 is used to quantify the mutual information between two genes given a third one through calculating the Kullback-Leibler divergence between the postulated distributions of including and excluding the edge between the two genes. The benchmark results on the GRNs from DREAM challenge as well as the SOS DNA repair network in Escherichia coli demonstrate the superior performance of CMI2NI. Specifically, even for gene expression data with small sample size, CMI2NI can not only infer the correct topology of the regulation networks but also accurately quantify the regulation strength between genes. As a case study, CMI2NI was also used to reconstruct cancer-specific GRNs using gene expression data from The Cancer Genome Atlas (TCGA). CMI2NI is freely accessible at http://www.comp-sysbio.org/cmi2ni. PMID- 25539928 TI - Modelling chemotherapy effects on granulopoiesis. AB - BACKGROUND: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and -dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. RESULTS: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. CONCLUSION: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment. PMID- 25539929 TI - Effects of B-type natriuretic peptide on cardiovascular biomarkers in healthy volunteers. AB - Cardiovascular biomarkers provide independent prognostic information in the assessment of mortality and cardiovascular complications. However, little is known about possible interactions between these biomarkers. In the present study, we evaluated the influence of B-type natriuretic peptide (BNP) on midregional proadrenomedullin (MR-proADM), C-terminal-proendothelin-1 (CT-proET-1), growth differentiation factor-15 (GDF-15), midregional-proatrial natriuretic peptide (MR proANP), copeptin, and procalcitonin in healthy volunteers. Ten healthy male subjects (mean age 24 yr) participating in a randomized, placebo-controlled, single-blinded crossover study received placebo or 3.0 pmol.kg(-1).min(-1) human BNP 32 during a continuous infusion lasting for 4 h. Effects of BNP on other cardiovascular biomarkers were assessed. BNP did not change concentrations of MR proADM, copeptin, CT-proET1, GDF-15, or procalcitonin. In contrast, MR-proANP was significantly decreased during BNP infusion. BNP as an established cardiovascular biomarker did not affect plasma concentrations of other cardiovascular biomarkers in a model of healthy volunteers. PMID- 25539930 TI - Respiratory cortical processing to inspiratory resistances during wakefulness in children with the obstructive sleep apnea syndrome. AB - Children with the obstructive sleep apnea syndrome (OSAS) have impaired respiratory afferent cortical processing during sleep that persists after treatment of OSAS. However, it is unknown whether this impairment is present during wakefulness and, if so, whether it improves after OSAS treatment. We hypothesized that children with OSAS, during wakefulness, have abnormal cortical processing of respiratory stimuli manifested by blunted respiratory-related evoked potentials (RREP) and that this resolves after OSAS treatment. We measured RREP during wakefulness in 26 controls and 21 children with OSAS before and after treatment. Thirteen participants with OSAS repeated testing 3-6 mo after adenotonsillectomy. RREP were elicited by interruption of inspiration by total occlusion and 30 and 20 cmH2O/l per s resistances. Nf at Fz latency elicited by occlusion was longer in children with OSAS at baseline compared with controls (78.8 +/- 24.8 vs. 63.9 +/- 19.7 ms, P = 0.05). All other peak amplitudes and latencies were similar between the two groups. After OSAS treatment, Nf at Fz latency elicited by 30 cmH2O/l per s decreased significantly (before, 88 +/- 26 vs. after, 71 +/- 25 ms, P = 0.02), as did that elicited by 20 cmH2O/l per s (85 +/- 27 vs. 72 +/- 24 ms, P = 0.004). The amplitude of N1 at Cz elicited by occlusion increased from -3.4 +/- 5.6 to -7.4 +/- 3 MUV (P = 0.049) after treatment. We concluded that children with OSAS have partial delay of respiratory afferent cortical processing during wakefulness that improves after treatment. PMID- 25539932 TI - Significant mechanical interactions at physiological lengths and relative positions of rat plantar flexors. AB - In situ studies involving supraphysiological muscle lengths and relative positions have shown that connective tissue linkages connecting adjacent muscles can transmit substantial forces, but the physiological significance is still subject to debate. The present study investigates effects of such epimuscular myofascial force transmission in the rat calf muscles. Unlike previous approaches, we quantified the mechanical interaction between the soleus (SO) and the lateral gastrocnemius and plantaris complex (LG+PL) applying a set of muscle lengths and relative positions corresponding to the range of knee and ankle angles occurring during normal movements. In nine deeply anesthetized Wistar rats, the superficial posterior crural compartment was exposed, and distal and proximal tendons of LG+PL and the distal SO tendon were severed and connected to force transducers. The target muscles were excited simultaneously. We found that SO active and passive tendon force was substantially affected by proximally lengthening of LG+PL mimicking knee extension (10% and 0.8% of maximal active SO force, respectively; P < 0.05). Moreover, SO relative position significantly changed the LG+PL length-force relationship, resulting in nonunique values for passive slack-length and optimum-length estimates. We conclude that also, for physiological muscle conditions, isometric force of rat triceps surae muscles is determined by its muscle-tendon unit length as well as by the length and relative position of its synergists. This has implications for understanding the neuromechanics of skeletal muscle in normal and pathological conditions, as well as for studies relying on the assumption that muscles act as independent force actuators. PMID- 25539931 TI - Role of the ovarian cycle on neural cardiovascular control in sleep-deprived women. AB - The midluteal (ML) phase of the ovarian cycle is often sympathoexcitatory compared with the early follicular (EF) phase. We recently reported that 24-h total sleep deprivation (TSD) augmented cardiovascular reactivity in both men and women, but that sex differences existed in resting muscle sympathetic nerve activity (MSNA) responses to TSD. In the present study, we hypothesized increased resting MSNA and augmented cardiovascular reactivity to acute laboratory stressors during the ML phase in sleep-deprived women. Heart rate (HR), mean arterial pressure (MAP), forearm vascular conductance (FVC), and MSNA were measured in 14 eumenorrheic women (age, 20 +/- 1 yr) during 10 min supine rest, 5 min mental stress (MS) trial, and 2 min cold pressor test (CPT) trial. Subjects were tested twice after TSD: once during EF phase and once during ML phase (randomized, crossover design). Estradiol (29 +/- 2 vs. 63 +/- 8 pg/ml, P = 0.001) and progesterone (1.6 +/- 0.2 vs. 4.4 +/- 0.7 ng/ml, P = 0.002) were elevated during the ML phase. Resting supine MAP (75 +/- 2 vs. 72 +/- 1 mmHg, P = 0.042) was lower during the ML phase. In contrast, resting supine HR, MSNA, and FVC were not significantly different between EF and ML phases. MAP, HR and FVC reactivity to MS were not statistically different between the EF and ML phases. Similarly, MAP and HR reactivity to CPT were not different between the ovarian phases. Contrary to our original hypothesis, the ML phase was not associated with sympathoexcitation or exaggerated cardiovascular reactivity in sleep-deprived premenopausal women. However, our data reveal elevated resting blood pressure during the EF phase in sleep-deprived women. PMID- 25539933 TI - Menthol suppresses laryngeal C-fiber hypersensitivity to cigarette smoke in a rat model of gastroesophageal reflux disease: the role of TRPM8. AB - Patients with gastroesophageal reflux disease (GERD) display enhanced laryngeal reflex reactivity to stimuli that may be due to sensitization of the laryngeal C fibers by acid and pepsin. Menthol, a ligand of transient receptor potential melastatin-8 (TRPM8), relieves throat irritation. However, the possibility that GERD induces laryngeal C-fiber hypersensitivity to cigarette smoke (CS) and that menthol suppresses this event has not been investigated. We delivered CS into functionally isolated larynxes of 160 anesthetized rats. Laryngeal pH 5-pepsin treatment, but not pH 5-denatured pepsin, augmented the apneic response to CS, which was blocked by denervation or perineural capsaicin treatment (a procedure that blocks the conduction of C fibers) of the superior laryngeal nerves. This augmented apnea was partially attenuated by capsazepine [an transient receptor potential vanilloid 1 (TRPV1) antagonist], SB-366791 (a TRPV1 antagonist), and HC030031 [a transient receptor potential ankyrin 1 (TRPA1) antagonist] and was completely prevented by a combination of TRPV1 and TRPA1 antagonists. Local application of menthol significantly suppressed the augmented apnea and this effect was reversed by pretreatment with AMTB (a TRPM8 antagonist). Our electrophysiological studies consistently revealed that laryngeal pH 5-pepsin treatment increased the sensitivity of laryngeal C-fibers to CS. Likewise, menthol suppressed this laryngeal C-fiber hypersensitivity and its effect could be reversed by pretreatment with AMTB. Our results suggest that laryngeal pH 5 pepsin treatment increases sensitivity to CS of both TRPV1 and TRPA1, which are presumably located at the terminals of laryngeal C-fibers. This sensory sensitization leads to enhanced laryngeal reflex reactivity and augmentation of the laryngeal C-fiber responses to CS, which can be suppressed by menthol acting via TRPM8. PMID- 25539934 TI - TWEAK-Fn14 pathway activation after exercise in human skeletal muscle: insights from two exercise modes and a time course investigation. AB - The cell surface receptor Fn14/TWEAKR was recently reported by our laboratory to be a prominent marker in the resistance exercise (RE) induced Transcriptome. The purpose of the present study was to extend our Transcriptome findings and investigate the gene and protein expression time course of markers in the TWEAK Fn14 pathway following RE or run exercise (RUN). Vastus lateralis muscle biopsies were obtained from 6 RE subjects [25 +/- 4 yr, 1-repetition maximum (RM): 99 +/- 27 kg] pre- and 0, 1, 2, 4, 8, 12, and 24 h post RE (3 * 10 at 70% 1-RM). Lateral gastrocnemius biopsies were obtained from 6 RUN subjects [25 +/- 4 yr, maximum oxygen uptake (VO2max): 63 +/- 8 ml.kg(-1).min(-1)] pre- and 0, 1, 2, 4, 8, 12, and 24 h after a 30-min RUN (75% VO2max). After RE, Fn14 gene and protein expression were induced (P < 0.05) and peaked at 8 and 12 h, respectively. Downstream markers analyzed showed evidence of TWEAK-Fn14 signaling through the alternative NF-kappaB pathway after RE. After RUN, Fn14 gene expression was induced (P < 0.05) to a much lesser extent and peaked at 24 h. Fn14 protein expression was only measurable on a sporadic basis, and there was weak evidence of alternative NF-kappaB pathway signaling after RUN. TWEAK gene and protein expression were not influenced by either exercise mode. These are the first human data to show a transient activation of the TWEAK-Fn14 axis in the recovery from exercise, and our data suggest the level of activation is exercise mode dependent. Furthermore, our collective data support a myogenic role for TWEAK Fn14 through the alternative NF-kappaB pathway in human skeletal muscle. PMID- 25539936 TI - Structure of the cortical cytoskeleton in fibers of postural muscles and cardiomyocytes of mice after 30-day 2-g centrifugation. AB - Altered external mechanical loading during spaceflights causes negative effects on muscular and cardiovascular systems. The aim of the study was estimation of the cortical cytoskeleton statement of the skeletal muscle cells and cardiomyocytes. The state of the cortical cytoskeleton in C57BL6J mice soleus, tibialis anterior muscle fibers, and left ventricle cardiomyocytes was investigated after 30-day 2-g centrifugation ("2-g" group) and within 12 h after its completion ("2-g + 12-h" group). We used atomic force microscopy for estimating cell's transverse stiffness, Western blotting for measuring protein content, and RT-PCR for estimating their expression level. The transverse stiffness significantly decreased in cardiomyocytes (by 16%) and increased in skeletal muscles fibers (by 35% for soleus and by 29% for tibialis anterior muscle fibers) in animals of the 2-g group (compared with the control group). For cardiomyocytes, we found that, in the 2-g + 12-h group, alpha-actinin-1 content decreased in the membranous fraction (by 27%) and increased in cytoplasmic fraction (by 28%) of proteins (compared with the levels in the 2-g group). But for skeletal muscle fibers, similar changes were noted for alpha-actinin-4, but not for alpha-actinin-1. In conclusion, we showed that the different isoforms of alpha-actinins dissociate from cortical cytoskeleton under increased/decreased of mechanical load. PMID- 25539935 TI - Characterizing rapid-onset vasodilation to single muscle contractions in the human leg. AB - Rapid-onset vasodilation (ROV) following single muscle contractions has been examined in the forearm of humans, but has not yet been characterized in the leg. Given known vascular differences between the arm and leg, we sought to characterize ROV following single muscle contractions in the leg. Sixteen healthy men performed random ordered single contractions at 5, 10, 20, 40, and 60% of their maximum voluntary contraction (MVC) using isometric knee extension made with the leg above and below heart level, and these were compared with single isometric contractions of the forearm (handgrip). Single thigh cuff compressions (300 mmHg) were utilized to estimate the mechanical contribution to leg ROV. Continuous blood flow was determined by duplex-Doppler ultrasound and blood pressure via finger photoplethysmography (Finometer). Single isometric knee extensor contractions produced intensity-dependent increases in peak leg vascular conductance that were significantly greater than the forearm in both the above- and below-heart level positions (e.g., above heart level: leg 20% MVC, +138 +/- 28% vs. arm 20% MVC, +89 +/- 17%; P < 0.05). Thigh cuff compressions also produced a significant hyperemic response, but these were brief and smaller in magnitude compared with single isometric contractions in the leg. Collectively, these data demonstrate the presence of a rapid and robust vasodilation to single muscle contractions in the leg that is largely independent of mechanical factors, thus establishing the leg as a viable model to study ROV in humans. PMID- 25539937 TI - The factors affecting adherence to a long-term interval walking training program in middle-aged and older people. AB - No long-term exercise training regimen with high adherence and effectiveness in middle-aged and older people is broadly available in the field. We assessed the adherence to, and effects of, our long-term training program comprising an interval walking training (IWT) and an information technology network system and the factors affecting adherence. Middle-aged and older men and women [n = 696, aged 65 +/- 7(SD) yr] underwent IWT. The subjects were instructed to repeat five or more sets of fast and slow walking for 3 min each at >=70 and 40% peak aerobic capacity for walking (VO2peak), respectively, per day >=4 days/wk for 22 mo. Adherence was assessed as training days accomplished relative to the target of 4 days/wk over 22 mo. The effects on the VO2peak and lifestyle-related disease score were evaluated every 6 mo. The independent factors affecting adherence were assessed by multiple-regression analysis after adjustment for baseline physical characteristics and other possible covariates, including vasopressin V1a receptor polymorphisms. The adherence over 22 mo averaged 70% and was highly correlated with a 13% reduction in the lifestyle-related disease score (R(2) = 0.94, P = 0.006) and with a 12% increase in VO2peak (R(2) = 0.94, P = 0.006). The major determinant of higher adherence was lower baseline body mass index (BMI) (P < 0.0001) and male sex (P < 0.0001). For men, in addition to BMI, nonsmokers (P = 0.031) and V1a receptor polymorphisms (P = 0.033) were independent determinants of higher adherence. Thus the long-term IWT program is an effective regimen. Moreover, baseline BMI and sex for all subjects, and smoking and V1a receptor polymorphisms for men, were associated with adherence. PMID- 25539938 TI - Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise. AB - Physical exercise has proven cardiovascular benefits, yet there is no clear understanding of the related molecular mechanisms leading to this. Here we determined the beneficial epigenetic effects of exercise after sprint interval training, a form of exercise known to improve cardiometabolic health. We quantified genome-wide leukocyte DNA methylation of 12 healthy young (18-24 yr) men before and after 4 wk (thrice weekly) of sprint interval training using the 450K BeadChip (Illumina) and validated gene expression changes in an extra seven subjects. Exercise increased subjects' cardiorespiratory fitness and maximal running performance, and decreased low-density lipoprotein cholesterol concentration in conjunction with genome-wide DNA methylation changes. Notably, many CpG island and gene promoter regions were demethylated after exercise, indicating increased genome-wide transcriptional changes. Among genes with DNA methylation changes, epidermal growth factor (EGF), a ligand of the epidermal growth factor receptor known to be involved in cardiovascular disease, was demethylated and showed decreased mRNA expression. Additionally, we found that in microRNAs miR-21 and miR-210, gene DNA methylation was altered by exercise causing a cascade effect on the expression of the mature microRNA involved in cardiovascular function. Our findings demonstrate that exercise alters DNA methylation in circulating blood cells in microRNA and protein-coding genes associated with cardiovascular physiology. PMID- 25539940 TI - Instantaneous quantification of skeletal muscle activation, power production, and fatigue during cycle ergometry. AB - A rapid switch from hyperbolic to isokinetic cycling allows the velocity-specific decline in maximal power to be measured, i.e., fatigue. We reasoned that, should the baseline relationship between isokinetic power (Piso) and electromyography (EMG) be reproducible, then contributions to fatigue may be isolated from 1) the decline in muscle activation (muscle activation fatigue); and 2) the decline in Piso at a given activation (muscle fatigue). We hypothesized that the EMG-Piso relationship is linear, velocity dependent, and reliable for instantaneous fatigue assessment at intolerance during and following whole body exercise. Healthy participants (n = 13) completed short (5 s) variable-effort isokinetic bouts at 50, 70, and 100 rpm to characterize baseline EMG-Piso. Repeated ramp incremental exercise tests were terminated with maximal isokinetic cycling (5 s) at 70 rpm. Individual baseline EMG-Piso relationships were linear (r(2) = 0.95 +/ 0.04) and velocity dependent (analysis of covariance). Piso at intolerance (two legs, 335 +/- 88 W) was ~45% less than baseline [630 +/- 156 W, confidence interval of the difference (CIDifference) 211, 380 W, P < 0.05]. Following intolerance, Piso recovered rapidly (F = 44.1; P < 0.05; eta(2) = 0.79): power was reduced (P < 0.05) vs. baseline only at 0-min (CIDifference 80, 201 W) and 1 min recovery (CIDifference 13, 80 W). Activation fatigue and muscle fatigue (one leg) were 97 +/- 55 and 60 +/- 50 W, respectively. Mean bias +/- limits of agreement for reproducibility were as follows: baseline Piso 1 +/- 30 W; Piso at 0-min recovery 3 +/- 35 W; and EMG at Piso 3 +/- 14%. EMG power is linear, velocity dependent, and reproducible. Deviation from this relationship at the limit of tolerance can quantify the "activation" and "muscle" related components of fatigue during cycling. PMID- 25539941 TI - Physiology in Medicine: A physiologic approach to prevention and treatment of acute high-altitude illnesses. AB - With the growing interest in adventure travel and the increasing ease and affordability of air, rail, and road-based transportation, increasing numbers of individuals are traveling to high altitude. The decline in barometric pressure and ambient oxygen tensions in this environment trigger a series of physiologic responses across organ systems and over a varying time frame that help the individual acclimatize to the low oxygen conditions but occasionally lead to maladaptive responses and one or several forms of acute altitude illness. The goal of this Physiology in Medicine article is to provide information that providers can use when counseling patients who present to primary care or travel medicine clinics seeking advice about how to prevent these problems. After discussing the primary physiologic responses to acute hypoxia from the organ to the molecular level in normal individuals, the review describes the main forms of acute altitude illness--acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema--and the basic approaches to their prevention and treatment of these problems, with an emphasis throughout on the physiologic basis for the development of these illnesses and their management. PMID- 25539939 TI - Postdinner resistance exercise improves postprandial risk factors more effectively than predinner resistance exercise in patients with type 2 diabetes. AB - Abnormally elevated postprandial glucose and triacylglycerol (TAG) concentrations are risk factors for cardiovascular disease in type 2 diabetes. The most effective time to exercise to lower postprandial glucose and TAG concentrations is unknown. Thus the aim of this study was to determine what time is more effective, either pre- or postdinner resistance exercise (RE), at improving postprandial risk factors in patients with type 2 diabetes. Thirteen obese patients with type 2 diabetes completed three trials in a random order in which they consumed a dinner meal with 1) no RE (NoRE), 2) predinner RE (RE -> M), and 3) postdinner RE beginning 45 min after dinner (M -> RE). Clinical outcome measures included postprandial glucose and TAG concentrations. In addition, postprandial acetaminophen (gastric emptying), endocrine responses, free fatty acids, and beta-cell function (mathematical modeling) were measured to determine whether these factors were related to changes in glucose and TAG. The TAG incremental area under the curve (iAUC) was ~92% lower (P <= 0.02) during M -> RE compared with NoRE and RE -> M, an effect due in part to lower very-low-density lipoprotein-1 TAG concentrations. The glucose iAUC was reduced (P = 0.02) by ~18 and 30% during the RE -> M and M -> RE trials, respectively, compared with NoRE, with no difference between RE trials. RE -> M and M -> RE reduced the insulin iAUC by 35 and 48%, respectively, compared with NoRE (P < 0.01). The glucagon like peptide-1 iAUC was ~50% lower (P <= 0.02) during M -> RE compared with NoRE and RE -> M. Given that predinner RE only improves postprandial glucose concentrations, whereas postdinner RE improves both postprandial glucose and TAG concentrations, postdinner RE may lower the risk of cardiovascular disease more effectively. PMID- 25539942 TI - beta-Alanine supplementation enhances human skeletal muscle relaxation speed but not force production capacity. AB - beta-Alanine (BA) supplementation improves human exercise performance. One possible explanation for this is an enhancement of muscle contractile properties, occurring via elevated intramuscular carnosine resulting in improved calcium sensitivity and handling. This study investigated the effect of BA supplementation on in vivo contractile properties and voluntary neuromuscular performance. Twenty-three men completed two experimental sessions, pre- and post 28 days supplementation with 6.4 g/day of BA (n = 12) or placebo (PLA; n = 11). During each session, force was recorded during a series of knee extensor contractions: resting and potentiated twitches and octet (8 pulses, 300 Hz) contractions elicited via femoral nerve stimulation; tetanic contractions (1 s, 1 100 Hz) via superficial muscle stimulation; and maximum and explosive voluntary contractions. BA supplementation had no effect on the force-frequency relationship, or the force responses (force at 25 and 50 ms from onset, peak force) of resting or potentiated twitches, and octet contractions (P > 0.05). Resting and potentiated twitch electromechanical delay and time-to-peak tension were unaffected by BA supplementation (P > 0.05), although half-relaxation time declined by 7-12% (P < 0.05). Maximum and explosive voluntary forces were unchanged after BA supplementation. BA supplementation had no effect on evoked force responses, implying that altered calcium sensitivity and/or release are not the mechanisms by which BA supplementation influences exercise performance. The reduced half-relaxation time with BA supplementation might, however, be explained by enhanced reuptake of calcium, which has implications for the efficiency of muscle contraction following BA supplementation. PMID- 25539943 TI - Evaluation of scientific impact: insights and incites. PMID- 25539944 TI - Infective endocarditis of a transcatheter pulmonary valve in comparison with surgical implants. AB - BACKGROUND: Melody valved stents (Medtronic Inc, Minneapolis, Minnesota, USA) have become a very competitive therapeutic option for pulmonary valve replacement in patients with congenital heart disease. After adequate prestenting of the right ventricular outflow tract (RVOT) Melody valved stents have a good medium term functional result but are exposed to infective endocarditis (IE). PATIENTS AND METHODS: Retrospective study of tertiary centre Congenital Heart Disease database; to compare incidence of IE in three different types of valved conduits in RVOT: Melody valved stent, cryopreserved homograft (European Homograft Bank) and Contegra graft (Medtronic Inc). RESULTS: Between 1989 and 2013, 738 conduits were implanted in 677 patients. 107 Melody valved stents were implanted in 107 patients; IE occurred in 8 (7.5%) patients during a follow-up of 2.0 years (IQR 2.4 years, range 0.3-7.8 years). 577 Homografts were implanted in 517 patients; IE occurred in 14 patients (2.4%) during a median follow-up of 6.5 years (IQR 9.2 years; range 0.1-23.7 years). Finally, 54 Contegra grafts were implanted in 53 patients; 11 patients (20.4%) had IE during a follow-up of 8.8 years (IQR 7.7 years; range 0.2-3.5 years). Survival free of IE by Kaplan-Meier for homografts was 98.7% at 5 years and 97.3% at 10 years; for Contegra 87.8% at 5 years and 77.3% at 10 years and for Melody 84.9% at 5 years (log-rank test; p<0.001). CONCLUSIONS: The Contegra conduit and Melody valved stents have a significantly higher incidence of IE than homografts. IE is a significant threat for long-term conduit function. PMID- 25539945 TI - Prevalence and prognostic implications of anaemia and iron deficiency in Tanzanian patients with heart failure. AB - OBJECTIVE: To determine the prevalence, correlates and prognostic implications of anaemia and iron deficiency (ID) in patients with heart failure (HF) in Tanzania. METHOD: This was a cross-sectional and prospective observational study conducted at Muhimbili National Hospital in Dar es Salaam, Tanzania. Patients were >= 18 years of age, with HF defined according to the Framingham criteria. The primary outcome was anaemia and the secondary outcome was a composite of hospitalisation for HF or all-cause mortality. RESULTS: A total of 401 HF patients (median age 56 years, IQR 41-67 years; women 51%) were included. The prevalence of anaemia was 57%. The overall prevalence of ID was 49% distributed as 69% versus 21% in subjects with and without anaemia (p < 0.001). Normocytic anaemia was seen in 18% of the patients while none had macrocytic anaemia. The risk of having anaemia was positively associated with residency outside Dar es Salaam (OR 1.72 (95% CI 1.02 to 2.89); p = 0.038), atrial fibrillation (4.12 (1.60 to 10.61); p=0.003), LVEF < 45% (2.70 (1.57 to 4.67); p < 0.001) and negatively (ORs per unit decrease) with creatinine clearance (0.98 (0.97 to 0.99); p = 0.012) and total cholesterol (0.78 (0.63 to 0.98); p = 0.029). One-year survival free from a composite endpoint was 70%. The presence of ID anaemia increased the likelihood for an event (HR 2.67; 95% CI 1.39 to 5.07; p = 0.003), while anaemia without ID did not influence the risk. CONCLUSIONS: ID anaemia was common in Tanzanian patients with HF and was independently associated with the risk for hospitalisation or death. PMID- 25539947 TI - ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. AB - BACKGROUND: There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families. METHODS: Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients. RESULTS: We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres. CONCLUSIONS: Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy. PMID- 25539948 TI - Laughter is not always funny: breath-holding spells in familial dysautonomia. AB - Familial dysautonomia (FD) is a genetic disease characterized by primary autonomic dysfunction including parasympathetic hypersensitivity. Breath-holding spells (BHS) are believed to be caused by autonomic dysregulation mediated via the vagus nerve and increased in patients with a family history of BHS. Details and understanding of its pathophysiology are lacking. In this retrospective study of patients with FD, the incidence of BHS was higher at 53.3%, compared with previous studies in normal children. Laughter as a precipitating factor for BHS has not been previously reported in FD and occurred in 10% of patients in this study. Lower lung volumes, chronic lung disease, chronic CO2 retention, and inadequate autonomic compensation occur in those with FD leading to a higher incidence and severity of BHS when crying or laughing. Thus, FD may be a good model for understanding manifestations of the autonomic nervous system dysfunction and contribute to our knowledge of BHS mechanisms. PMID- 25539946 TI - Is a planned caesarean section in women with cardiac disease beneficial? AB - OBJECTIVES: In the general population, planned caesarean section is thought to be safer in high-risk situations as it avoids the greater risk of an emergency caesarean section. Only limited data exist on the optimal mode of delivery in women with structural heart disease. We investigated the relationship between mode of delivery and pregnancy outcome in women with pre-existing heart disease. METHODS: The Registry on Pregnancy and Cardiac Disease is an on-going, global, prospective observational registry of women with structural heart disease. We report on 1262 deliveries, between January 2007 and June 2011. RESULTS: The caesarean section was planned in 393 women (31%): 172 (44%) for cardiac and 221 (56%) for obstetric reasons of whom 53 delivered by emergency caesarean section. Vaginal delivery was planned in 869 (69%) women, of whom 726 (84%) actually delivered vaginally and 143 (16%) had an emergency caesarean section. Perinatal mortality(1.1 vs 2.7, p=0.14) and low apgar score (11.9 vs 10.1, p=0.45) were not significantly different in women who had a caesarean section or vaginal delivery; gestational age(37 vs 38 weeks p=0.003) and birth weight (3073 vs 2870 g p<0.001) were lower in women delivered by caesarean section compared with women delivered by vaginal delivery. In those delivered by elective or emergency caesarean section, there was no difference in maternal mortality (1.8% vs 1.5%, p=1.0), postpartum heart failure (8.8% vs 8.2% p=0.79) or haemorrhage (6.2% vs 5.1% p=0.61). CONCLUSIONS: These data suggest that planned caesarean section does not confer any advantage over planned vaginal delivery, in terms of maternal outcome, but is associated with an adverse fetal outcome. PMID- 25539949 TI - Digital photography in skin cancer screening by mobile units in remote areas of Brazil. AB - BACKGROUND: Non-melanoma skin cancer (NMSC) is one of the most common neoplasms in the world. Despite the low mortality rates, NMSC can still cause severe sequelae when diagnosed at advanced stages. Malignant melanoma, the third most common type of skin cancer, has more aggressive behavior and a worse prognosis. Teledermatology provides a new tool for monitoring skin cancer, especially in countries with a large area and unequal population distribution. This study sought to evaluate the performance of digital photography in skin cancer diagnosis in remote areas of Brazil. METHODS: A physician in a Mobile Prevention Unit (MPU) took four hundred sixteen digital images of suspicious lesions between April 2010 and July 2011. All of the photographs were electronically sent to two oncologists at Barretos Cancer Hospital who blindly evaluated the images and provided a diagnosis (benign or malignant). The absolute agreement rates between the diagnoses made by direct visual inspection (by the MPU physician) and through the use of digital imaging (by the two oncologists) were calculated. The oncologists' accuracy in predicting skin cancer using digital imaging was assessed by means of overall accuracy (correct classification rate), sensitivity, specificity and predictive value (positive and negative). A skin biopsy was considered the gold standard. RESULTS: Oncologist #1 classified 59 lesions as benign with the digital images, while oncologist #2 classified 27 lesions as benign using the same images. The absolute agreement rates with direct visual inspection were 85.8% for oncologist #1 (95% CI: 77.1-95.2) and 93.5% for oncologist #2 (95% CI: 84.5-100.0). The overall accuracy of the two oncologists did not differ significantly. CONCLUSIONS: Given the high sensitivity and PPV, Teledermatology seems to be a suitable tool for skin cancer screening by MPU in remote areas of Brazil. PMID- 25539950 TI - Scoping review of toolkits as a knowledge translation strategy in health. AB - BACKGROUND: Significant resources are invested in the production of research knowledge with the ultimate objective of integrating research evidence into practice. Toolkits are becoming increasingly popular as a knowledge translation (KT) strategy for disseminating health information, to build awareness, inform, and change public and healthcare provider behavior. Toolkits communicate messages aimed at improving health and changing practice to diverse audiences, including healthcare practitioners, patients, community and health organizations, and policy makers. This scoping review explores the use of toolkits in health and healthcare. METHODS: Using Arksey and O'Malley's scoping review framework, health based toolkits were identified through a search of electronic databases and grey literature for relevant articles and toolkits published between 2004 and 2011. Two reviewers independently extracted data on toolkit topic, format, target audience, content, evidence underlying toolkit content, and evaluation of the toolkit as a KT strategy. RESULTS: Among the 253 sources identified, 139 met initial inclusion criteria and 83 toolkits were included in the final sample. Fewer than half of the sources fully described the toolkit content and about 70% made some mention of the evidence underlying the content. Of 83 toolkits, only 31 (37%) had been evaluated at any level (27 toolkits were evaluated overall relative to their purpose or KT goal, and 4 toolkits evaluated the effectiveness of certain elements contained within them). CONCLUSIONS: Toolkits used to disseminate health knowledge or support practice change often do not specify the evidence base from which they draw, and their effectiveness as a knowledge translation strategy is rarely assessed. To truly inform health and healthcare, toolkits should include comprehensive descriptions of their content, be explicit regarding content that is evidence-based, and include an evaluation of the their effectiveness as a KT strategy, addressing both clinical and implementation outcomes. PMID- 25539951 TI - Suicide in South Asia: a scoping review. AB - BACKGROUND: Globally, suicide is an important cause of mortality. In low- and middle income settings, it is difficult to find unequivocal data to establish suicide rates. The objective of this review is to synthesize the reporting of suicide incidence in six south Asian countries. METHODS: We conducted a scoping review combining peer-reviewed studies (PubMed, PsycINFO, EMBASE) with in-country searches for grey literature in Afghanistan, Pakistan, Sri Lanka, India, Nepal and Bangladesh. The review included mapping reported suicide rates, quality appraisals of the studies, use of definitions of suicide and means of committing suicide. RESULTS: In total, 114 studies and reports were included in the review, including 50 peer-reviewed publications. Reported suicide rates varied widely from 0.43/100,000 to 331.0/100,000. The average suicide rate across studies was found to be high compared to the world average, however many studies were of poor quality or not representative. The majority of studies failed to explicitly define suicide (84% of the published articles and 92% of the grey literature documents). Poisoning and hanging were consistently the most common methods of committing suicide on the sub-continent. CONCLUSIONS: The reported suicide rates in South Asia are high compared to the global average, but there is a paucity of reliable data on suicide rates in South Asia. Reports are likely to diminish rather than exaggerate the magnitude of suicide rates. There is an urgent need to establish new, or evaluate existing, national suicide surveillance systems in the South Asian countries. PMID- 25539952 TI - Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome. AB - BACKGROUND: Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy. METHODS: PATIENTS: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Deu Hospital. Two patients refused to participate in the treatment protocol. METHODS: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot. TREATMENT PROTOCOL: The follow-up periods ranged from one to eight years. Cases 1-4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day. RESULTS: No adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients. Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy. CONCLUSIONS: Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS. TRIAL REGISTRATION: Eudrac T2007-00-6748-23. PMID- 25539954 TI - New oral anticoagulants for the treatment of acute venous thromboembolism: are they safer than vitamin K antagonists? A meta-analysis of the interventional trials. AB - New oral anticoagulants (NOACs) may represent an alternative to standard therapy with vitamin K antagonists (VKA). However, up to the present, it is unknown whether these drugs are safer than VKA. The aim of this study was to perform a meta-analysis of the interventional trials with NOACs vs VKA in patients with acute venous thromboembolism (VTE) to obtain the balance between clinical efficacy and complications. A meta-analysis of double blind randomized controlled trials (RCTs) was performed. We included RCTs that compared, in acute VTE, the beneficial and harmful effects of NOACs (ximelagatran, apixaban, dabigatran, edoxaban and rivaroxaban) vs VKA (warfarin). Seven studies including 29,482 patients were selected. Compared with warfarin, recurrent VTE and death from any cause were not significantly reduced by NOACs. Myocardial infarction was significantly increased with NOACs compared with warfarin (RR 2.55; 95% CI 1.1 5.6; p = 0.02). NOACs significantly reduced the major bleedings (RR 0.63; 95% CI 0.47-0.83; p = 0.001). This meta-analysis suggests that treatment with NOACs in patients with acute VTE is not inferior to conventional therapy with warfarin for recurrent VTE and death from any cause, but there might be an increased incidence of myocardial infarction. PMID- 25539955 TI - Mortality at 30 and 90 days in elderly patients with pulmonary embolism: a retrospective cohort study. AB - Pulmonary Embolism (PE) incidence increases with age. Data on mortality and prognosis in elderly patients with suspected PE are lacking. (1) To assess 30- and 90-day mortality in subjects with PE from an elderly population seen in the emergency department (ED); (2) to test the prognostic accuracy of a simplified Pulmonary Embolism Severity Index (sPESI) coupled to a highly sensitive cardiac Troponin T (hs-cTnT) level. A retrospective cohort study was performed, including patients evaluated in the ED of Vimercate Hospital for clinically suspected PE from 2010 to 2012. Study population: n = 470, 63.4% women, mean age +/- SD 73.06 +/- 16.0 years, 40% aged >=80 and 77.7% >=65 years old, confirmed PE: 22.6% (106 cases). Within 30 and 90 days, mortality among patients with confirmed PE was 14.2% (8.8-22.0) and 20.8% (16.5-41.7). In subjects aged >=80 years, 30-day mortality was 18.9% among patients with confirmed PE, and 12.6% among those with PE excluded (p = 0.317). Ninety-day mortality rates were 29.7 and 19.9%, respectively (p = 0.193). In patients with confirmed PE, Negative Predictive Value of sPESI was 94.1% (80.3-99.3) for 30 days and 88.2% (72.3-96.7) for 90-day mortality. Adding the hs-cTnT level to sPESI did not improve its performance. (1) In an elderly population referring to the ED with clinically suspected PE, mortality was high both in subjects with and without confirmed PE; (2) the ability of sPESI and hs-cTnT to predict PE mortality seems to be lower than reported in studies based on data from younger populations. Better risk stratification tools will be necessary to improve clinical management in this setting. PMID- 25539956 TI - Collegiality without borders. PMID- 25539957 TI - The WHO 2014 global tuberculosis report--further to go. PMID- 25539953 TI - The translation initiation complex eIF3 in trypanosomatids and other pathogenic excavates--identification of conserved and divergent features based on orthologue analysis. AB - BACKGROUND: The initiation of translation in eukaryotes is supported by the action of several eukaryotic Initiation Factors (eIFs). The largest of these is eIF3, comprising of up to thirteen polypeptides (eIF3a through eIF3m), involved in multiple stages of the initiation process. eIF3 has been better characterized from model organisms, but is poorly known from more diverged groups, including unicellular lineages represented by known human pathogens. These include the trypanosomatids (Trypanosoma and Leishmania) and other protists belonging to the taxonomic supergroup Excavata (Trichomonas and Giardia sp.). RESULTS: An in depth bioinformatic search was carried out to recover the full content of eIF3 subunits from the available genomes of L. major, T. brucei, T. vaginalis and G. duodenalis. The protein sequences recovered were then submitted to homology analysis and alignments comparing them with orthologues from representative eukaryotes. Eleven putative eIF3 subunits were found from both trypanosomatids whilst only five and four subunits were identified from T. vaginalis and G. duodenalis, respectively. Only three subunits were found in all eukaryotes investigated, eIF3b, eIF3c and eIF3i. The single subunit found to have a related Archaean homologue was eIF3i, the most conserved of the eIF3 subunits. The sequence alignments revealed several strongly conserved residues/region within various eIF3 subunits of possible functional relevance. Subsequent biochemical characterization of the Leishmania eIF3 complex validated the bioinformatic search and yielded a twelfth eIF3 subunit in trypanosomatids, eIF3f (the single unidentified subunit in trypanosomatids was then eIF3m). The biochemical data indicates a lack of association of the eIF3j subunit to the complex whilst highlighting the strong interaction between eIF3 and eIF1. CONCLUSIONS: The presence of most eIF3 subunits in trypanosomatids is consistent with an early evolution of a fully functional complex. Simplified versions in other excavates might indicate a primordial complex or secondary loss of selected subunits, as seen for some fungal lineages. The conservation in eIF3i sequence might indicate critical functions within eIF3 which have been overlooked. The identification of eIF3 subunits from distantly related eukaryotes provides then a basis for the study of conserved/divergent aspects of eIF3 function, leading to a better understanding of eukaryotic translation initiation. PMID- 25539958 TI - Afghanistan in transition: call for investment in nutrition. PMID- 25539959 TI - Polio in Pakistan's North Waziristan. PMID- 25539960 TI - Moving beyond sanitation's diarrhoea fixation. PMID- 25539961 TI - Effectiveness of a rural sanitation programme: finding the gaps. PMID- 25539962 TI - Capacity building in longitudinal HIV research. PMID- 25539963 TI - SHARE: a milestone in joint programming for HIV and intimate partner violence. PMID- 25539964 TI - Role of big data in the early detection of Ebola and other emerging infectious diseases. PMID- 25539965 TI - Controlling Ebola through mHealth strategies. PMID- 25539967 TI - Intimate partner violence and HIV in ten sub-Saharan African countries: what do the Demographic and Health Surveys tell us? AB - BACKGROUND: Many studies have identified a significant positive relation between intimate partner violence and HIV in women, but adjusted analyses have produced inconsistent results. We systematically assessed the association, and under what condition it holds, using nationally representative data from ten sub-Saharan African countries, focusing on physical, sexual, and emotional violence, and on the role of male controlling behaviour. METHODS: We assessed cross-sectional data from 12 Demographic and Health Surveys from ten countries in sub-Saharan Africa. The data are nationally representative for women aged 15-49 years. We estimated odds ratios using logistic regression with and without controls for demographic and socioeconomic factors and survey-region fixed effects. Exposure was measured using physical, sexual, emotional violence, and male controlling behaviour, and combinations of these. The samples used were ever-married women, married women, and women in their first union. Depending on specification, the sample size varied between 11 231 and 45 550 women. FINDINGS: There were consistent and strong associations between HIV infection in women and physical violence, emotional violence, and male controlling behaviour (adjusted odds ratios ranged from 1.2 to 1.7; p values ranged from <0.0001 to 0.0058). The evidence for an association between sexual violence and HIV was weaker and only significant in the sample with women in their first union. The associations were dependent on the presence of controlling behaviour and a high regional HIV prevalence rate; when women were exposed to only physical, sexual, or emotional violence, and no controlling behaviour, or when HIV prevalence rates are lower than 5%, the adjusted odds ratios were, in general, close to 1 and insignificant. INTERPRETATION: The findings indicate that male controlling behaviour in its own right, or as an indicator of ongoing or severe violence, puts women at risk of HIV infection. HIV prevention interventions should focus on high-prevalence areas and men with controlling behaviour, in addition to violence. FUNDING: Swedish National Science Foundation and Gothenburg Centre of Globalization and Development, University of Gothenburg, Gothenburg, Sweden. PMID- 25539968 TI - Intimate partner violence and HIV: clearing up confusion. PMID- 25539966 TI - Effectiveness of an integrated intimate partner violence and HIV prevention intervention in Rakai, Uganda: analysis of an intervention in an existing cluster randomised cohort. AB - BACKGROUND: Intimate partner violence (IPV) is associated with HIV infection. We aimed to assess whether provision of a combination of IPV prevention and HIV services would reduce IPV and HIV incidence in individuals enrolled in the Rakai Community Cohort Study (RCCS), Rakai, Uganda. METHODS: We used pre-existing clusters of communities randomised as part of a previous family planning trial in this cohort. Four intervention group clusters from the previous trial were provided standard of care HIV services plus a community-level mobilisation intervention to change attitudes, social norms, and behaviours related to IPV, and a screening and brief intervention to promote safe HIV disclosure and risk reduction in women seeking HIV counselling and testing services (the Safe Homes and Respect for Everyone [SHARE] Project). Seven control group clusters (including two intervention groups from the original trial) received only standard of care HIV services. Investigators for the RCCS did a baseline survey between February, 2005, and June, 2006, and two follow-up surveys between August, 2006, and April, 2008, and June, 2008, and December, 2009. Our primary endpoints were self-reported experience and perpetration of past year IPV (emotional, physical, and sexual) and laboratory-based diagnosis of HIV incidence in the study population. We used Poisson multivariable regression to estimate adjusted prevalence risk ratios (aPRR) of IPV, and adjusted incidence rate ratios (aIRR) of HIV acquisition. This study was registered with ClinicalTrials.gov, number NCT02050763. FINDINGS: Between Feb 15, 2005, and June 30, 2006, we enrolled 11 448 individuals aged 15-49 years. 5337 individuals (in four intervention clusters) were allocated into the SHARE plus HIV services group and 6111 individuals (in seven control clusters) were allocated into the HIV services only group. Compared with control groups, individuals in the SHARE intervention groups had fewer self-reports of past-year physical IPV (346 [16%] of 2127 responders in control groups vs 217 [12%] of 1812 responders in intervention groups; aPRR 0.79, 95% CI 0.67-0.92) and sexual IPV (261 [13%] of 2038 vs 167 [10%] of 1737; 0.80, 0.67-0.97). Incidence of emotional IPV did not differ (409 [20%] of 2039 vs 311 [18%] of 1737; 0.91, 0.79-1.04). SHARE had no effect on male-reported IPV perpetration. At follow-up 2 (after about 35 months) the intervention was associated with a reduction in HIV incidence (1.15 cases per 100 person-years in control vs 0.87 cases per 100 person-years in intervention group; aIRR 0.67, 95% CI 0.46-0.97, p=0.0362). INTERPRETATION: SHARE could reduce some forms of IPV towards women and overall HIV incidence, possibly through a reduction in forced sex and increased disclosure of HIV results. Findings from this study should inform future work toward HIV prevention, treatment, and care, and SHARE's ecological approach could be adopted, at least partly, as a standard of care for other HIV programmes in sub-Saharan Africa. FUNDING: Bill & Melinda Gates Foundation, US National Institutes of Health, WHO, President's Emergency Plan for AIDS Relief, Fogarty International Center. PMID- 25539969 TI - Prevalence of chronic obstructive pulmonary disease and associated risk factors in Uganda (FRESH AIR Uganda): a prospective cross-sectional observational study. AB - BACKGROUND: In sub-Saharan Africa, little is known about the damage to respiratory health caused by biomass smoke and tobacco smoke. We assessed the prevalence of chronic obstructive pulmonary disease (COPD) and related risk factors in a rural region of Uganda. METHODS: We did this prospective observational cross-sectional study in rural Masindi, Uganda. We randomly selected people above the age of 30 years from 30 villages. Trained local health care workers asked validated questionnaires and administered spirometry to participants. We defined COPD as FEV1:FVC less than the lower limit of normal. We calculated prevalence of COPD and tested its association with risk factors. FINDINGS: Between April 13, and Aug 14, 2012, we invited 620 people to participate, of whom 588 provided acceptable spirometry and were analysed. Mean age was 45 years (SD 13.7); 297 (51%) were women. 546 (93%) were exposed to biomass smoke. The prevalence of COPD was 16.2% (15.4% in men, 16.8% in women). Prevalence was highest in people aged 30-39 years (17 [38%] of 45 men, 20 [40%] of 50 women). 20 (44%) of 45 men with COPD were current smokers (mean age 40 years, SD 7.5), 11 (24%) were former smokers (mean age 49 years, SD 11.0); four [8%] of 50 women were current smokers (mean age 52 years, SD 18.1), nine (18%) were former smokers (mean age 64 years, SD 16.2). Mean Clinical COPD Questionnaire score was 0.81 (SD 0.78), mean Medical Research Council dyspnoea score was 1.33 (SD 0.65); 28 (30%) of 95 patients had had one or more exacerbations past 12 months. COPD was associated with wheeze (odds ratio 2.17, 95% CI 1.09-4.34; p=0.028) and being a former smoker (1.96, 1.07-3.59; p=0.029). INTERPRETATION: In this rural district of Uganda, COPD starts early in life. Major risk factors were biomass smoke for both sexes and tobacco smoke for men. In addition to high smoking prevalence in men, biomass smoke could be a major health threat to men and women in rural areas of Uganda. FUNDING: International Primary Care Respiratory Group. PMID- 25539970 TI - Funding AIDS programmes in the era of shared responsibility: an analysis of domestic spending in 12 low-income and middle-income countries. AB - BACKGROUND: As the incomes of many AIDS-burdened countries grow and donors' budgets for helping to fight the disease tighten, national governments and external funding partners increasingly face the following question: what is the capacity of countries that are highly affected by AIDS to finance their responses from domestic sources, and how might this affect the level of donor support? In this study, we attempt to answer this question. METHODS: We propose metrics to estimate domestic AIDS financing, using methods related to national prioritisation of health spending, disease burden, and economic growth. We apply these metrics to 12 countries in sub-Saharan Africa with a high prevalence of HIV/AIDS, generating scenarios of possible future domestic expenditure. We compare the results with total AIDS financing requirements to calculate the size of the resulting funding gaps and implications for donors. FINDINGS: Nearly all 12 countries studied fall short of the proposed expenditure benchmarks. If they met these benchmarks fully, domestic spending on AIDS would increase by 2.5 times, from US$2.1 billion to $5.1 billion annually, covering 64% of estimated future funding requirements and leaving a gap of around a third of the total $7.9 billion needed. Although upper-middle-income countries, such as Botswana, Namibia, and South Africa, would become financially self-reliant, lower-income countries, such as Mozambique and Ethiopia, would remain heavily dependent on donor funds. INTERPRETATION: The proposed metrics could be useful to stimulate further analysis and discussion around domestic spending on AIDS and corresponding donor contributions, and to structure financial agreements between recipient country governments and donors. Coupled with improved resource tracking, such metrics could enhance transparency and accountability for efficient use of money and maximise the effect of available funding to prevent HIV infections and save lives. FUNDING: US Centers for Disease Control and Prevention. PMID- 25539971 TI - The silent epidemic of COPD in Africa. PMID- 25539972 TI - The complexity of resource allocation for health. PMID- 25539973 TI - Nutritional status according to the stages of Alzheimer's disease. AB - OBJECTIVE: To assess the nutritional status of Alzheimer's disease (AD) patients with no other associated dementia, according to disease stage. DESIGN: Cross sectional observational study. SETTING: Neurobehavioral Diseases Outpatient Clinic, Clinical Hospital, Ribeirao Preto Medical School (University of Sao Paulo). PARTICIPANTS: The sample consisted of 36 individuals of both genders with AD diagnosis, and no other associated type of dementia, in various stages of the disease, according to the Clinical Dementia Rating (CDR 0.5-3). MEASUREMENTS: Nutritional status was evaluated using the Mini Nutritional Assessment (MNA) and anthropometric measurements such as weight, body mass index (BMI) and arm, waist, abdomen and hip circumferences. In addition, body composition was assessed by bioelectrical impedance analysis (BIA). RESULTS: The mean age of the group was 74.2 +/- 10.1 years, 72.2 % of them were women. The MNA showed that most of these individuals were at risk for malnutrition (55.5 %) and many of them (43.7 %) were underweight according to BMI. Data from BIA analysis revealed that 41.7 % of these individuals had a quantity of body fat classified as malnutrition and 11.1 % had a phase angle (PA) below recommended values for age group. There was a negative and significant correlation of lean mass and PA with age, and of global MNA evaluation with CDR, as well as a positive correlation of MNA total score with fat mass and BMI. Worse classifications of nutritional status obtained by MNA scores were also observed in the more severe stages of the disease, according to the CDR. CONCLUSION: Patients with AD are mostly elderly with changes in body composition that are typical of aging, with signs of peripheral malnutrition and preservation of abdominal fat. However, greater impairment of general nutritional status was observed in the more advanced stages of AD, creating a situation of greater vulnerability for these patients. PMID- 25539974 TI - The identification of fall history using maximal and rapid isometric torque characteristics of the hip extensors in healthy, recreationally active elderly females: a preliminary investigation. AB - BACKGROUND AND AIMS: Maximal and rapid torque characteristics of the hip extensor muscles play an important role in fall prevention and other balance-related performances; however, few studies have investigated the ability of these variables at identifying fall-history status in healthy, recreationally active elderly adults. This study aimed to examine the effectiveness of maximal and rapid isometric torque characteristics of the hip extensor muscles to differentiate between healthy, recreationally active elderly females with (fallers) and without (non-fallers) a history a falls. METHODS: Six elderly female fallers (mean +/- SD: age = 73 +/- 7 year; mass = 68 +/- 16 kg; height = 160 +/- 5 cm) and nine elderly female non-fallers (age = 71 +/- 7 year; mass = 66 +/- 16 kg; height = 157 +/- 6 cm) performed two isometric maximal voluntary contractions (MVCs) of the hip extensor muscles. Peak torque (PT) and absolute and relative rate of torque development (RTD) at the early (0-50 ms) and late (100-200 ms) phases of muscle contraction were examined during each MVC. RESULTS: Absolute and relative RTD at 0-50 ms were greater (P = 0.039 and 0.011, respectively) in the non-fallers compared to the fallers. However, no group related differences (P = 0.160-0.573) were observed for PT nor absolute and relative RTD at 100-200 ms. CONCLUSIONS: Early rapid strength production of the hip extensor muscles may be a sensitive and effective measure for discriminating between elderly females of different fall histories. These findings may provide important insight regarding implications for the assessment of fall risk and in the development of proper training programs aimed at minimizing the occurrence of falls and other balance-related injuries in the elderly. PMID- 25539975 TI - Replication of a gene-environment interaction Via Multimodel inference: additive genetic variance in adolescents' general cognitive ability increases with family of-origin socioeconomic status. AB - The present study of general cognitive ability attempts to replicate and extend previous investigations of a biometric moderator, family-of-origin socioeconomic status (SES), in a sample of 2,494 pairs of adolescent twins, non-twin biological siblings, and adoptive siblings assessed with individually administered IQ tests. We hypothesized that SES would covary positively with additive-genetic variance and negatively with shared-environmental variance. Important potential confounds unaddressed in some past studies, such as twin-specific effects, assortative mating, and differential heritability by trait level, were found to be negligible. In our main analysis, we compared models by their sample-size corrected AIC, and base our statistical inference on model-averaged point estimates and standard errors. Additive-genetic variance increased with SES-an effect that was statistically significant and robust to model specification. We found no evidence that SES moderated shared-environmental influence. We attempt to explain the inconsistent replication record of these effects, and provide suggestions for future research. PMID- 25539976 TI - The TRANSNephro-study examining a new transition model for post-kidney transplant adolescents and an analysis of the present health care: study protocol for a randomized controlled trial. AB - BACKGROUND: The transition from pediatric to nephrology care is not yet a standardized procedure. The result is an increased risk of deteriorating transplant function, with the potential for premature transplant failure. METHODS/DESIGN: In phase I of this study, we shall evaluate the current patient transition situation in all existing German pediatric and nephrology departments (n = 17), including an evaluation of the views of physicians, nurses, and psychosocial support staff regarding transition. Phase II will be a prospective, randomized study in which we compare current unstructured transition (control group) to structured transition (intervention group). The structured transition approach integrates the core elements of the Berliner TransitionsProgramm in combination with two facilitating smartphone apps. The primary endpoint of this study will be therapy adherence, as reflected by group variation coefficients of immunosuppressive agent levels. As a secondary outcome, we will compare patients' self-reported quality of life, satisfaction of patients and their parents with each transition model, and how patient-centered healthcare components are utilized. These secondary parameters will be assessed with established instruments or with instruments developed (and pilot tested) in phase I of the project. DISCUSSION: The long-term goal of this work is to provide a model of structured transition from pediatric to adult care for adolescent nephrology patients, in order to improve transplant survival and patient wellbeing. TRIAL REGISTRATION: Identifier: Clinicaltrials.gov: ISRCTN22988897, registered on 24 April 2014). PMID- 25539977 TI - Demyelinating disease and anti-N-methyl-D-aspartate receptor immunoglobulin G antibodies: a case report. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor immunoglobulin G antibodies directed against the GluN1 subunit are considered highly specific for anti-N methyl-D-aspartate receptor encephalitis, a severe clinical syndrome characterized by seizures, psychiatric symptoms, orofacial dyskinesia and autonomic dysfunction. CASE PRESENTATION: Here we report a 33 year old Caucasian male patient with clinically definite multiple sclerosis who was found to be positive for anti-N-methyl-D-aspartate receptor antibodies. Rituximab therapy was initiated. On the 18 months follow-up visit the patient was found to be clinically stable, without typical signs of anti-N-methyl-D-aspartate receptor encephalitis. CONCLUSION: Our findings add to the growing evidence for a possible association between anti-N-methyl-D-aspartate receptor encephalitis and demyelinating diseases. PMID- 25539978 TI - Spatial clustering of physical activity and obesity in relation to built environment factors among older women in three U.S. states. AB - BACKGROUND: Identifying spatial clusters of chronic diseases has been conducted over the past several decades. More recently these approaches have been applied to physical activity and obesity. However, few studies have investigated built environment characteristics in relation to these spatial clusters. This study's aims were to detect spatial clusters of physical activity and obesity, examine whether the geographic distribution of covariates affects clusters, and compare built environment characteristics inside and outside clusters. METHODS: In 2004, Nurses' Health Study participants from California, Massachusetts, and Pennsylvania completed survey items on physical activity (N = 22,599) and weight status (N = 19,448). The spatial scan statistic was utilized to detect spatial clustering of higher and lower likelihood of obesity and meeting physical activity recommendations via walking. Clustering analyses and tests that adjusted for socio-demographic and health-related variables were conducted. Neighborhood built environment characteristics for participants inside and outside spatial clusters were compared. RESULTS: Seven clusters of physical activity were identified in California and Massachusetts. Two clusters of obesity were identified in Pennsylvania. Overall, adjusting for socio-demographic and health related covariates had little effect on the size or location of clusters in the three states with a few exceptions. For instance, adjusting for husband's education fully accounted for physical activity clusters in California. In California and Massachusetts, population density, intersection density, and diversity and density of facilities in two higher physical activity clusters were significantly greater than in neighborhoods outside of clusters. In contrast, in two other higher physical activity clusters in California and Massachusetts, population density, diversity of facilities, and density of facilities were significantly lower than in areas outside of clusters. In Pennsylvania, population density, intersection density, diversity of facilities, and certain types of facility density inside obesity clusters were significantly lower compared to areas outside the clusters. CONCLUSIONS: Spatial clustering techniques can identify high and low risk areas for physical activity and obesity. Although covariates significantly differed inside and outside the clusters, patterns of differences were mostly inconsistent. The findings from these spatial analyses could eventually facilitate the design and implementation of more resource-efficient, geographically targeted interventions for both physical activity and obesity. PMID- 25539980 TI - Single-incision laparoscopic appendectomy versus conventional 3-port laparoscopic appendectomy for appendicitis: an updated meta-analysis of randomized controlled trials. AB - PURPOSE: To compare the efficacy and safety of single-incision laparoscopic appendectomy (SILA) and conventional 3-port laparoscopic appendectomy (3-port LA) for appendectomy. METHODS: We searched the PubMed, Embase, Springer link, and the Cochrane library databases up to April, 2014, for relevant randomized controlled trials (RCTs). Data were pooled by weighted mean differences (WMDs) or odds ratios (ORs) with their 95% confidence intervals (CIs). RESULTS: We found 11 RCTs, with a collective total of 731 patients treated with SILA and 725 patients treated with 3-point LA. Results indicated no significant differences between SILA and 3-port LA in primary outcomes, including wound infection, intra abdominal abscess, postoperative ileus, and total postoperative complications, and some secondary outcomes, including postoperative pain scores and length of hospital stay. However, SILA was associated with significantly longer operative times (WMD = 6.78, 95% CI = 3.78-9.79, P < 0.00001) and higher doses of analgesia (WMD = 0.96, 95% CI = 0.45-1.47, P = 0.0002) than the 3-port LA. CONCLUSION: Although there was no significant difference in the safety of SILA vs. that of 3 port LA, our findings do not support the application of SILA because of its significantly longer operative times and the higher doses of analgesia required compared with those for 3-point LA. PMID- 25539981 TI - Relationship between the distal migration and length of the distal landing zone after endovascular aneurysm repair (EVAR). AB - BACKGROUND AND PURPOSE: Endovascular aneurysm repair (EVAR) is the main treatment for patients with abdominal aortic aneurysms. This study examines the relationship between the migration of the distal landing zone and the length of the landing zone. MATERIALS AND METHODS: The subjects of this study were 36 patients who underwent contrast-enhanced computed tomography 1 year after EVAR. We constructed curved multi-planar reconstruction imaging and measured the length of migration, the angle of the common iliac artery, and the diameter of the distal landing zone. RESULTS: The mean length of migration was 1.2 +/- 1.7 mm. Fifty-four legs had a distal landing zone of over 15 mm and 18 legs had a distal landing zone of less than 15 mm. Four (7.4 %) of the 54 legs with a landing zone of over 15 mm and 3 (16.7 %) of the 18 legs with a landing zone of less than 15 mm had migration of over 3 mm. This difference was significant (P = 0.05). CONCLUSION: The rate of migration on the distal landing zone 1 year after EVAR was reasonable when the length of the landing zone was about 15 mm. It is possible that significant migration can occur in patients with distal landing zones less than 10 mm in length. PMID- 25539979 TI - Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. AB - BACKGROUND: Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ischemia increase succinate blood levels, we investigated the role of this metabolite during a heart ischemic event, using human and rodent models. RESULTS: We found that succinate causes cardiac hypertrophy in a GPR91 dependent manner. GPR91 activation triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), the expression of calcium/calmodulin dependent protein kinase IIdelta (CaMKIIdelta) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm, which are hypertrophic-signaling events. Furthermore, we found that serum levels of succinate are increased in patients with cardiac hypertrophy associated with acute and chronic ischemic diseases. CONCLUSIONS: These results show for the first time that succinate plays an important role in cardiomyocyte hypertrophy through GPR91 activation, and extend our understanding of how ischemia can induce hypertrophic cardiomyopathy. PMID- 25539982 TI - Cucumber ECERIFERUM1 (CsCER1), which influences the cuticle properties and drought tolerance of cucumber, plays a key role in VLC alkanes biosynthesis. AB - Most land plants have a wax layer which covers their aerial parts to protect them from environmental stresses, such as drought, UV radiation, and pathogenic invasion. The wax biosynthesis has been well studied previously in Arabidopsis, but it still remains elusive in cucumber. Here, we isolated a CER1 homolog CsCER1 in cucumber, and we found that the expression of CsCER1 in the cucumber line 3401 which shows waxy fruit phenotype is much higher than that in the cucumber line 3413 which displays glossy fruit phenotype. Spatial and temporal expression analyses revealed that CsCER1 is specifically expressed in the epidermis where waxes are synthesized, and sub-cellular location showed that CsCER1 protein is localized to the endoplasmic reticulum. The expression of CsCER1 can be induced by low temperature, drought, salt stress and abscisic acid. In addition, abnormal expressions of CsCER1 in transgenic cucumber plants have dramatic effects on very long-chain (VLC) alkanes biosynthesis, cuticle permeability, and drought resistance. Our data suggested that CsCER1 plays an important role in VLC alkanes biosynthesis in cucumber. PMID- 25539984 TI - First evidence of in vivo pro-angiogenic activity of cerebrospinal fluid samples from multiple sclerosis patients. AB - Increased vascular density and endothelial cell proliferation have been demonstrated in multiple sclerosis (MS) white matter, as well as an elevated vascular endothelial growth factor expression was detected in reactive astrocytes of both active and inactive chronic demyelinated lesions and in sera of MS patients during clinical relapses. In this study, we have investigated the angiogenic activity of cerebrospinal fluid (CSF) samples from MS patients with different stages of disease by means of the chick embryo chorioallantoic membrane (CAM), a well-known assay to study angiogenesis in vivo. Results have shown that CSF samples from MS patients induced a significant (p < 0.05) angiogenic response in CAM in comparison with CSF from neurological controls. The vessel density was higher (p < 0.0001) in secondary (23.60 +/- 1.14) and primary (23.50 +/- 1.87) progressive patients in comparison with relapsing MS (17.25 +/- 1.75) and clinically isolated syndrome suggestive of MS (13.00 +/- 1.79), and a significant correlation (r = 0.611, p = 0.005) was found between the angiogenic response and disability level. The results of this preliminary report demonstrate for the first time an angiogenic activity in vivo of CSF samples from MS patients and confirm the importance of angiogenesis as a key event in MS pathogenesis and progression. PMID- 25539983 TI - "When they see us, it's like they have seen the benefits!": experiences of study benefits negotiations in community-based studies on the Kenyan Coast. AB - BACKGROUND: Benefit sharing in health research has been the focus of international debates for many years, particularly in developing countries. Whilst increasing attention is being given to frameworks that can guide researchers to determine levels of benefits to participants, there is little empirical research from developing countries on the practical application of these frameworks, including in situations of extreme poverty and vulnerability. In addition, the voices of those who often negotiate and face issues related to benefits in practice - frontline researchers and fieldworkers (FWs) - are rarely included in these debates. Against this background, this paper reports on experiences of negotiating research participation and benefits as described by fieldworkers, research participants and researchers in two community based studies. METHODS: The findings reported here are from a broader social science study that explored the nature of interactions between fieldworkers and participants in two community based studies on the Kenyan Coast. Between January and July 2010, data were collected using participant observation, and through group discussions and in-depth interviews with 42 fieldworkers, 4 researchers, and 40 study participants. RESULTS: Participants highly appreciated the benefits provided by studies, particularly health care benefits. Fieldworkers were seen by participants and other community members as the gatekeepers and conduits of benefits, even though those were not their formal roles. Fieldworkers found it challenging to ignore participant and community requests for more benefits, especially in situations of extreme poverty. However, responding to requests by providing different sorts and levels of benefits over time, as inadvertently happened in one study, raised expectations of further benefits and led to continuous negotiations between fieldworkers and participants. CONCLUSIONS: Fieldworkers play an important intermediary role in research; a role imbued with multiple challenges and ethical dilemmas for which they require appropriate support. Further more specific empirical research is needed to inform the development of guidance for researchers on benefit sharing, and on responding to emergency humanitarian needs for this and other similar settings. PMID- 25539985 TI - The Accuracy of Computer Image-Guided Template for Mandibular Angle Ostectomy. AB - BACKGROUND: Mandibular angle ostectomy (MAO) is commonly used to correct prominent mandibular angles through an intraoral approach. However, limited vision in the operative site may lead to difficulties or complications during surgery. Therefore, it is necessary to develop an effective method for helping surgeons to perform MAO more precisely and safely. METHODS: In this study, we report a novel method of a computer image-guided surgical template for navigation of MAO, and evaluate its accuracy and clinical outcomes. Nine patients with a prominent mandibular angle were enrolled in this study. A pair of stereolithographic templates was fabricated by computer-aided image design and 3D printing. In all cases, bilateral MAO was performed under the guide of these templates. Post-operative effects were evaluated by 3D curve functions and maximal shell-to-shell deviations. RESULTS: All patients were satisfied with their cosmetic outcomes. The mean and SD of ICC between R-Sim and R-Post were 0.958 +/- 0.011; between L-Sim and L-Post, 0.965 +/- 0.014; and between R-Post and L-Post, 0.964 +/- 0.013. The maximal shell-to-shell deviations between the simulated mandibular contour and post-operative mandibular contour on the right and left sides were 2.02 +/- 0.32 and 1.97 +/- 0.41 mm, respectively. CONCLUSION: The results of this study suggest that this new technique could assist surgeons in making better pre-surgical plans and ensure more accurate and safer manipulation for completion of this procedure. PMID- 25539986 TI - Mesotherapy with an Intradermal Hyaluronic Acid Formulation for Skin Rejuvenation: An Intrapatient, Placebo-Controlled, Long-Term Trial Using High Frequency Ultrasound. AB - Mesotherapy with hyaluronic acid (HA) is a treatment approach currently used for skin rejuvenation. High-frequency ultrasound (20-100 MHz) is a non-invasive technique that has been used to evaluate age-related dermal changes. The presence and the degree of a typical subepidermal low-echogenic band (SLEB) are photoaging related: the lower the SLEB echogenicity, the higher the photoaging. The aim of this trial was to evaluate, through ultrasound imaging, the long-term effects of microinjections of HA on SLEB echogenicity. Twenty-two women with clinical and ultrasound signs of moderate photoaging were enrolled in the study. Treatment consisted of multiple microinjections of HA salts of biotechnological origin on the dorsum of one hand, once weekly for 4 weeks and, successively, once monthly for 4 months (group A) or 9 months (group B). The dorsum of the other hand of each subject was injected with saline solution and used as a control. In all subjects, high-frequency ultrasound (22 MHz) was performed to evaluate SLEB echogenicity changes during treatment. Eighteen out of 22 patients completed the study. At the end of 4 weeks, an ultrasound increase of dermal echogenicity was observed in 13 subjects (seven of group A and six of group B), which we considered as "responders". In these patients, the Student's t-test showed a significant increase from baseline of SLEB pixel numbers of +24 % (P < 0.01) versus +6 % with placebo. In the same subjects, after an additional 4 months of monthly injections, the mean increase was +18 % (P < 0.05) versus +4 % with placebo. In patients from group B that completed 10 months of treatment, the increase from baseline of SLEB pixel numbers was +18 % (P < 0.05) versus 0 % with placebo. Our study suggests that mesotherapy with HA may effectively improve skin aging and photoaging, as supported by quantifiable ultrasound data showing significant changes in SLEB density over time. PMID- 25539987 TI - Dermo-Fascial Suspension for Better Contouring and Long Lasting Results in Reduction Mammoplasty. AB - BACKGROUND: Recent techniques use the superficial fascia system for anchoring the glandular tissue to the chest wall for minimal tension skin repair in contrast to classic dermal suspension. OBJECTIVE: To evaluate the use of dermo-fascial flap in suspension of the breast tissue to the chest wall in reduction mammoplasty to achieve better breast shape, projection, and contour. PATIENTS AND METHODS: Forty patients who underwent superiomedial reduction mammoplasty were divided into two equal groups. Group I patients underwent classic superior-medial dermo-glandular pedicle (Findlay's technique) reduction mammoplasty, while in group II, a laterally based dermo-fascial flap was used for suspension of the breast tissue to the chest wall. Preoperative and postoperative measurements of the suprasternal notch-nipple and nipple-inframammary fold distances were recorded and statistically analyzed. RESULTS: Mild asymmetry occurred in nine cases (5-GI, 4-GII), surgical scar revision was done in seven patients (4-GI, 3-GII), and superficial infection occurred in four patients (2-GI, 2-GII). Group II showed better clinical satisfaction and highly significant statistical differences in postoperative measurements compared to GI (P < 0.0001). CONCLUSION: The use of a dermo-fascial flap to support the glandular pedicle in reduction mammoplasty improves the shape; projection and contour of the breast. It also helps to have long lasting results and reduce recurrent breast ptosis especially in patients with poor skin quality. PMID- 25539988 TI - Orthodontic miniscrews: an experimental campaign on primary stability and bone properties. AB - OBJECTIVE: To evaluate the primary stability of different shaped miniscrews through the acquisition of data regarding maximum insertion torque, pullout force, and a radiodiagnosic evaluation of bone characteristics. MATERIALS AND METHODS: Sixty fresh porcine bone samples were scanned by computed tomography (CT) and cone-beam computed tomography (CBCT). By means of a dedicated software, CT and CBCT images were analysed to measure the insertion-site cortical thickness, cortical density, and marrow bone density. Sixty miniscrews of 12 different types were implanted with no predrilling pilot hole in the bone samples. Every device was tightened by means of a digital torque screwdriver and torque data were collected. Subsequently, pullout tests were performed. Spearman and Pearson correlations were employed to compare any relationship between continuous variables. RESULTS: Different types of miniscrews did not show statistically significant differences in their torque value (P = 0.595), instead a significant difference was revealed by considering their load measures (P = 0.039). Cortical bone thickness resulted strongly correlated both with value of load (P < 0.001), and modestly with torque measures (P = 0.004). A strong positive correlation was found between CT and CBCT both for cortical density (P < 0.001) and marrow bone density (P < 0.001). CONCLUSION: Bone characteristics play the major role in miniscrews primary stability. PMID- 25539990 TI - Retinal artery occlusion as the manifestation of left atrial myxoma: a case report. AB - BACKGROUND: Retinal artery occlusion caused by myxoma is relatively rare. There are several points that should be taken into consideration to avoid overlooking this disorder. CASE PRESENTATION: This case report describes a 43-year-old woman with sudden vision loss in her left eye for 20 days after single sudden syncope. Fundus examination of the left eye showed obscure boundary of optic disc with, reflective dispersion of the retina and poor light reflex of central fovea. A retinal artery occlusion was found in her left eye. Echocardiography revealed a tumor in the left atrium. Visual capacity improved a little during the follow-up. CONCLUSION: In any patients with retinal artery occlusion, detailed medical history and echocardiography should be carried out to exclude heart diseases. PMID- 25539991 TI - Current knowledge in Polypodium leucotomos effect on skin protection. AB - This article provides an overview of pharmacology, toxicity, pharmacokinetics and clinical data of Polypodium leucotomos L. (PL). PL aerial part has proven to exert antioxidant, photoprotective and immunomodulatory activities; its mechanism of action is complex and includes several activities: (1) PL diminishes the production of reactive oxygen and nitrogen species (ROS, RNS); (2) PL inhibits the photoisomerization of trans-urocanic acid (t-UCA); (3) PL inhibits apoptosis induced by ultraviolet radiation; (4) PL prevents damage to genetic material and (5) PL enhances DNA repair. PL is not mutagenic and does not induce acute or chronic toxicity. Its biological effects have been proved in cell cultures, animal models, murine models and in human beings. Photoprotective activity has been assessed in healthy volunteers as well as in patients suffering from several cutaneous diseases such as vitiligo, psoriasis, idiopathic photodermatosis or melasma. PL results to be an efficient treatment especially for sensitive cutaneous phototypes and adds extra protection when ultraviolet radiation (UVR) exposure cannot be avoided, such as wide or narrow band UVB phototherapy or treatment with psoralens plus UVA exposure radiation. PMID- 25539989 TI - Patient education in chronic heart failure in primary care (ETIC) and its impact on patient quality of life: design of a cluster randomised trial. AB - BACKGROUND: Chronic heart failure, is increasing due to the aging population and improvements in heart disease detection and management. The prevalence is estimated at ~10% of the French general practice patient population over 59 years old. The primary objective of this study is to improve the quality of life for heart failure patients though a complex intervention involving patient and general practitioner (GP) education in primary care. METHODS: A randomised, cluster controlled trial, stratified over 4 areas of the Auvergne region in France comparing intervention and control groups. The inclusion criteria are: patients older than 50 years with New York Heart Association (NYHA) stage I, II, or III heart failure, with reduced ejection fraction or with preserved ejection fraction. Heart failure should be confirmed by the patient's cardiologist according to the European Society of Cardiology guidelines criteria. The exclusion criteria include: severe cognitive disorders, living in an institution, participating in another clinical trial, having NYHA stage IV heart failure, or a lack of French language skills. The complex intervention consists of training at the GP practice with an interactive 2-day workshop to provide a patient's education programme. GPs are trained to perform case management, lifestyle counselling and motivational interviewing, to educate patients on the main topics including clinical alarm signs, physical activity, diet and cardiovascular risk factors. The patients' education sessions are scheduled at 1, 4, 7, 10, 13 and 19 months following the start of the trial. The primary outcome to be assessed is the impact on the quality of life as determined using two questionnaires: the Minnesota Living with Heart Failure Questionnaire and SF-36. To detect a difference in the mean quality of life at 19 months, we anticipate studying a minimum of 400 patients from 80 GPs. DISCUSSION: This trial will provide insight into the effectiveness of a complex intervention to educate patients with heart failure including a 2-day GP workshop and patients' education programme in the setting of a GP consultation to improve the quality of life in patients with chronic heart failure. This complex intervention tool could be used during initial and further medical training. TRIAL REGISTRATION: ETIC is a cluster randomised, controlled trial registered on ClinicalTrials.gov [ NCT01065142 , 2010, Feb 8] and the French drug agency [Agence Nationale de Securite du Medicament et des produits de sante; registration number: 2009-A01142-55, on March 5th, 2010]. PMID- 25539994 TI - IgG4-related systemic disease mimicking renal pelvic cancer: a rare case. AB - BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity. Characteristic features of IgG4-RD are elevated serum IgG4 levels, infiltration of IgG4-positive cells, mass-forming lesions with fibrosis and good response to corticosteroids. The variable imaging features of IgG4-RD and the overlap with other differential diagnoses often pose a diagnostic challenge, as they frequently mimic malignant tumors or other inflammatory diseases in the abdomen. CASE PRESENTATION: A 54-year-old woman visited our hospital with left flank discomfort and palpebral edema. Computed tomography, magnetic resonance imaging, retrograde pyelography and positron emission tomography/computed tomography indicated renal pelvic cancer. However, after a left-sided nephroureteral cystectomy was performed, the mass was pathologically confirmed as an IgG4 related lesion. Her elevated serum IgG4 level and a past history of sicca complex supported the diagnosis of IgG4-RD. CONCLUSIONS: It is critical to recognize the importance of laboratory examinations such as serum IgG4 level if a patient has a past history of rheumatic disease. PMID- 25539993 TI - Comparative analysis of diversity and utilization of edible plants in arid and semi-arid areas in Benin. AB - BACKGROUND: Agrobiodiversity is said to contribute to the sustainability of agricultural systems and food security. However, how this is achieved especially in smallholder farming systems in arid and semi-arid areas is rarely documented. In this study, we explored two contrasting regions in Benin to investigate how agroecological and socioeconomic contexts shape the diversity and utilization of edible plants in these regions. METHODS: Data were collected through focus group discussions in 12 villages with four in Bassila (semi-arid Sudano-Guinean region) and eight in Boukoumbe (arid Sudanian region). Semi-structured interviews were carried out with 180 farmers (90 in each region). Species richness and Shannon Wiener diversity index were estimated based on presence-absence data obtained from the focus group discussions using species accumulation curves. RESULTS: Our results indicated that 115 species belonging to 48 families and 92 genera were used to address food security. Overall, wild species represent 61% of edible plants collected (60% in the semi-arid area and 54% in the arid area). About 25% of wild edible plants were under domestication. Edible species richness and diversity in the semi-arid area were significantly higher than in the arid area. However, farmers in the arid area have developed advanced resource-conserving practices compared to their counterparts in the semi-arid area where slash-and burn cultivation is still ongoing, resulting in natural resources degradation and loss of biodiversity. There is no significant difference between the two areas for cultivated species richness. The interplay of socio-cultural attributes and agroecological conditions explains the diversity of food plants selected by communities. CONCLUSIONS: We conclude that if food security has to be addressed, the production and consumption policies must be re-oriented toward the recognition of the place of wild edible plants. For this to happen we suggest a number of policy and strategic decisions as well as research and development actions such as a thorough documentation of wild edible plants and their contribution to household diet, promotion of the ''bringing into cultivation" practices, strengthening of livestock-crop integration. PMID- 25539995 TI - Clinical application of ultrasound for preparation of (99m)Tc-sestamibi complex. AB - OBJECTIVE: The main aim of this investigation is the clinical application of ultrasound irradiation technique as an alternative method to reconstitute sestamibi kits in comparison of water boiling bath method. METHODS: The 740-3700 MBq (20-100 mCi) (99m)Tc-MIBI (sestamibi) complex samples were prepared due to ultrasound irradiation technique or boiled water bath method as a standard method. Twenty patients (8 men and 12 women; age range 30-72, median 52.45 years) have been referred to Golestan hospital for myocardial perfusion imaging (MPI). The subjects have been divided randomly into group A (3 men, 7 women, age range 36-67, median 51.7 years) and group B (5 men, 5 women, age range 30-72, median 50.3 years), respectively. The (99m)Tc-MIBI radiopharmaceuticals have been prepared by Ultrasound irradiation technique administrated to group A and (99m)Tc MIBI complex samples due to the boiled water bath technique administrated to the other group. For all patients, the 2-day stress/rest MPI protocol was performed. RESULTS: The radio-HPLC and TLC studies have indicated that the (99m)Tc-MIBI complex samples with good yields could be prepared successfully due to new developed technique. The scintigraphy imaging studies have demonstrated that the (99m)Tc-sestamibi prepared due to the above-mentioned modalities shows very identical biodistribution in the heart, thyroid, lung, liver, gallbladder, kidneys, stomach, large intestine and bladder of the subjects. Any unexpected accumulation of radiotracer samples have not been observed in our approach. CONCLUSIONS: The ultrasound irradiation technique is convenient and sufficient method to prepare (99m)Tc-sestamibi. It can be recommended as an alternative method to reconstitute sestamibi kits particularly in emergency situations to reduce potentially medical risk by avoiding any delay in acute therapy for myocardial infarction. PMID- 25539992 TI - Synergy of leptin/STAT3 with HER2 receptor induces tamoxifen resistance in breast cancer cells through regulation of apoptosis-related genes. AB - PURPOSE: Tamoxifen is a major treatment modality for estrogen receptor positive breast cancer, but the occurrence of resistance remains a problem. Recently, obesity-related leptin has been found to interfere with tamoxifen in breast cancer MCF-7 cells. In the present study we investigated the effect of leptin on three tamoxifen-treated breast cancer cell types (i.e., MDA-MB-231, MCF-7 and MCF 7/HER2). METHODS: The effect of tamoxifen/leptin treatment was evaluated using a MTT cell viability assay. mRNA expression was assessed by real time PCR and protein expression by Western blotting. WWOX, Survivin and BCL2 gene promoter activities were evaluated by chromatin immunoprecipitation. RESULTS: Cell viability assays revealed that estrogen receptor negative MDA-MB-231 cells were resistant, that estrogen receptor positive MCF-7 cells were sensitive and that MCF-7/HER2 cells were relatively resistant to tamoxifen, while leptin co administration 'rescued' MCF-7 and, especially, MCF-7/HER2 cells from the anti proliferative effect of tamoxifen. The cell lines also exhibited a different phosphorylation status of STAT3, a transcription factor that is activated by the obesity related leptin receptor b (Ob-Rb). Most importantly, chromatin immunoprecipitation assays revealed differential STAT3 binding to the anti apoptotic BCL2 and pro-apoptotic WWOX gene promoters in MCF-7 and MCF-7/HER2 cells, leading to concomitant modifications of its mRNA/protein expression levels, thus providing a selective advantage to HER2 over-expressing MCF-7/HER2 cells after treatment with tamoxifen and tamoxifen plus leptin. CONCLUSIONS: Our study provides novel evidence indicating that synergy between the leptin/Ob Rb/STAT3 signalling pathway and the HER2 receptor protects tamoxifen-treated HER2 over-expressing cells from the inhibitory effect of tamoxifen through differential regulation of apoptosis-related genes. PMID- 25539996 TI - Robotic natural orifice transluminal endoscopic surgery (R-NOTES): literature review and prototype system. AB - In minimally invasive surgery methods such as laparoscopic surgery, surgical instruments are introduced through small incisions to minimize patient trauma and recovery times. To reduce the number of incisions, new techniques such as natural orifice transluminal endoscopic surgery (NOTES) have been proposed. Compared to laparoscopic surgery, the NOTES approach, which requires new technology and improved instruments, presents some unique challenges. Robotic NOTES (R-NOTES) could be an enabling technology for these procedures. In this paper, we first review relevant work in R-NOTES. We then present our work and the system architecture for an R-NOTES prototype system incorporating wireless command and control. The system was tested twice in swine animal studies. PMID- 25539998 TI - Nitrogen recycling from fuel-extracted algal biomass: residuals as the sole nitrogen source for culturing Scenedesmus acutus. AB - In this study, the reuse of nitrogen from fuel-extracted algal residues was investigated. The alga Scenedesmus acutus was found to be able to assimilate nitrogen contained in amino acids, yeast extracts, and proteinaceous alga residuals. Moreover, these alternative nitrogen resources could replace nitrate in culturing media. The ability of S. acutus to utilize the nitrogen remaining in processed algal biomass was unique among the promising biofuel strains tested. This alga was leveraged in a recycling approach where nitrogen is recovered from algal biomass residuals that remain after lipids are extracted and carbohydrates are fermented to ethanol. The protein-rich residuals not only provided an effective nitrogen resource, but also contributed to a carbon "heterotrophic boost" in subsequent culturing, improving overall biomass and lipid yields relative to the control medium with only nitrate. Prior treatment of the algal residues with Diaion HP20 resin was required to remove compounds inhibitory to algal growth. PMID- 25539997 TI - Does FTO have a paradoxical effect in fetal life? AB - BACKGROUND: Low weight at birth is associated with obesity in later life. One hypothesis to explain such an association is that genetic variants that increase the risk of obesity also reduce fetal weight. Recently, obesity in adults was found to be associated with common variants of the fat mass and obesity associated (FTO) gene. We examined the association between FTO polymorphisms and birth weight in a singleton, full-term birth cohort of 494 newborn-mother pairs without any complications. RESULTS: The risk alleles for obesity ("A" allele for the rs9939609 FTO variant and "G" allele for the rs9930506 FTO variant) were associated with low weight at birth. The mean differences per risk allele were 79 g (95% CI: -129 to -30; p = 0.002) for rs9939609 and -84 g (95% CI: -131 to 36; P < 0.001) for rs9930506. The level of association remained statistically significant after adjustment for the maternal risk allele and for variables usually associated with birth weight (-50 g, 95% CI: -99 to 0; p = 0.05 for rs9939609 and -48 g, 95% CI: -100 to 0; p = 0.05 for rs9930506). In the follow up, the allelic difference in weight was attenuated over time. CONCLUSIONS: The FTO variants that confer a predisposition to obesity later in life appear to be associated with low weight at birth. This finding favors the hypothesis of a common genetic denominator that predisposes to a low weight at birth and obesity in adults. PMID- 25539999 TI - Evolution of alpha- and beta-globin genes and their regulatory systems in light of the hypothesis of domain organization of the genome. AB - The alpha- and beta-globin gene domains are a traditional model for study of the domain organization of the eucaryotic genome because these genes encode hemoglobin, a physiologically important protein. The alpha-globin and beta-globin gene domains are organized in completely different ways, while the expression of globin genes is tightly coordinated, which makes it extremely interesting to study the origin of these genes and the evolution of their regulatory systems. In this review, the organization of the alpha- and beta-globin gene domains and their genomic environment in different taxonomic groups are comparatively analyzed. A new hypothesis of possible evolutionary pathways for segregated alpha and beta-globin gene domains of warm-blooded animals is proposed. PMID- 25540000 TI - Mutations in mitochondrial DNA and approaches for their correction. AB - Apart from the nucleus, the mitochondrion is the only organelle of an animal cell that contains its own genome. Mitochondrial DNA is much less in size than the nuclear one and codes for only several dozens of biological macromolecules. Nevertheless, mutations in mitochondrial genes often result in the occurrence of serious hereditary neuromuscular diseases. New mitochondrial DNA mutations and their relations to clinical symptoms are continuously reported in the scientific literature. In this review, we summarize existing data about such mutations, and also about contemporary gene therapy approaches that have been developed for their suppression. PMID- 25540001 TI - Mammalian hibernation and regulation of lipid metabolism: a focus on non-coding RNAs. AB - Numerous species will confront severe environmental conditions by undergoing significant metabolic rate reduction. Mammalian hibernation is one such natural model of hypometabolism. Hibernators experience considerable physiological, metabolic, and molecular changes to survive the harsh challenges associated with winter. Whether as fuel source or as key signaling molecules, lipids are of primary importance for a successful bout of hibernation and their careful regulation throughout this process is essential. In recent years, a plethora of non-coding RNAs has emerged as potential regulators of targets implicated in lipid metabolism in diverse models. In this review, we introduce the general characteristics associated with mammalian hibernation, present the importance of lipid metabolism prior to and during hibernation, as well as discuss the potential relevance of non-coding RNAs such as miRNAs and lncRNAs during this process. PMID- 25540002 TI - SOX2 overexpression affects neural differentiation of human pluripotent NT2/D1 cells. AB - SOX2 is one of the key transcription factors involved in maintenance of neural progenitor identity. However, its function during the process of neural differentiation, including phases of lineage-specification and terminal differentiation, is still poorly understood. Considering growing evidence indicating that SOX2 expression level must be tightly controlled for proper neural development, the aim of this research was to analyze the effects of constitutive SOX2 overexpression on outcome of retinoic acid-induced neural differentiation of pluripotent NT2/D1 cells. We demonstrated that in spite of constitutive SOX2 overexpression, NT2/D1 cells were able to reach final phases of neural differentiation yielding both neuronal and glial cells. However, SOX2 overexpression reduced the number of mature MAP2-positive neurons while no difference in the number of GFAP-positive astrocytes was detected. In-depth analysis at single-cell level showed that SOX2 downregulation was in correlation with both neuronal and glial phenotype acquisitions. Interestingly, while in mature neurons SOX2 was completely downregulated, astrocytes with low level of SOX2 expression were detected. Nevertheless, cells with high level of SOX2 expression were incapable of entering in either of two differentiation pathways, neurogenesis or gliogenesis. Accordingly, our results indicate that fine balance between undifferentiated state and neural differentiation depends on SOX2 expression level. Unlike neurons, astrocytes could maintain low level of SOX2 expression after they acquired glial fate. Further studies are needed to determine whether differences in the level of SOX2 expression in GFAP-positive astrocytes are in correlation with their self-renewal capacity, differentiation status, and/or their phenotypic characteristics. PMID- 25540003 TI - Properties of hybrid complexes composed of photosynthetic reaction centers from the purple bacterium Rhodobacter sphaeroides and quantum dots in lecithin liposomes. AB - Quantum dots (QDs) can absorb ultraviolet and long-wavelength light energy much more efficiently than natural light-harvesting proteins and transfer the excitation energy to photosynthetic reaction centers (RCs). Inclusion into liposomes of RC membrane pigment-protein complexes combined with QDs as antennae opens new opportunities for using such hybrid systems as a basis for artificial energy-transforming devices that potentially can operate with greater efficiency and stability than devices based only on biological components. RCs from Rhodobacter sphaeroides and QDs with fluorescence maximum at 530 nm (CdSe/ZnS with hydrophilic covering) were embedded in lecithin liposomes by extrusion of a solution of multilayer lipid vesicles through a polycarbonate membrane or by dialysis of lipids and proteins dispersed with excess detergent. The dimensions of the resulting hybrid systems were evaluated using dynamic light scattering and by transmission cryoelectron microscopy. The efficiency of RC and QD interaction within the liposomes was estimated using fluorescence excitation spectra of the photoactive bacteriochlorophyll of the RCs and by measuring the fluorescence decay kinetics of the QDs. The functional activity of the RCs in hybrid complexes was fully maintained, and their stability was even increased. PMID- 25540004 TI - Unexpectedly strong effect of caffeine on the vitality of western honeybees (Apis mellifera). AB - We examined the influence of caffeine on honeybee lifespan, Nosema resistance, key enzyme activities, metabolic compound concentrations, and total DNA methylation levels. Caffeine slowed age-related metabolic tendencies. Bees that consumed caffeine lived longer and were not infested with Nosema spp. Caffeine treated workers had higher protein concentrations. The levels increased with aging but they then decreased in older bees. Caffeine increased the activities of antioxidant enzymes (SOD, GPx, CAT, GST), AST, ALT, ALP, neutral proteases, and protease inhibitors, and the concentrations of uric acid, triglycerides, cholesterol, glucose, and Ca2+. Acidic and alkaline protease activities were lower in the bees treated with caffeine. Creatinine and Mg2+ concentrations were higher in the caffeine-treated workers but only up to 14 days of age. Caffeine significantly decreased DNA methylation levels in older bees. The compound could be considered as a natural diet supplement increasing apian resistance to stress factors. Our studies will enhance possibilities of using Apis mellifera as a model organism in gerontological studies. PMID- 25540005 TI - Heat shock induces production of reactive oxygen species and increases inner mitochondrial membrane potential in winter wheat cells. AB - Heat shock leads to oxidative stress. Excessive ROS (reactive oxygen species) accumulation could be responsible for expression of genes of heat-shock proteins or for cell death. It is known that in isolated mammalian mitochondria high protonic potential on the inner membrane actuates the production of ROS. Changes in viability, ROS content, and mitochondrial membrane potential value have been studied in winter wheat (Triticum aestivum L.) cultured cells under heat treatment. Elevation of temperature to 37-50 degrees C was found to induce elevated ROS generation and increased mitochondrial membrane potential, but it did not affect viability immediately after treatment. More severe heat exposure (55-60 degrees C) was not accompanied by mitochondrial potential elevation and increased ROS production, but it led to instant cell death. A positive correlation between mitochondrial potential and ROS production was observed. Depolarization of the mitochondrial membrane by the protonophore CCCP inhibited ROS generation under the heating conditions. These data suggest that temperature elevation leads to mitochondrial membrane hyperpolarization in winter wheat cultured cells, which in turn causes the increased ROS production. PMID- 25540006 TI - PPX1 gene overexpression has no influence on polyphosphates in Saccharomyces cerevisiae. AB - The role of exopolyphosphatase PPX1 in polyphosphate metabolism in yeasts has been studied in strains of Saccharomyces cerevisiae with inactivated PPX1 and PPN1 genes transformed by the expression vector carrying the yeast PPX1 gene. Exopolyphosphatase activity in transformant strains increased 90- and 40-fold compared to the DeltaPPX1 and DeltaPPN1 strains, respectively. The purified recombinant exopolyphosphatase PPX1 was similar to the PPX1 of wild strains in its substrate specificity and requirement for divalent metal cations. It was more active with tripolyphosphate and low molecular mass polyphosphates than with high molecular mass polyphosphates and required Mg2+ for its activity. The high level of recombinant PPX1 expression caused no decrease in polyphosphate content in the cells of the transformant. This fact suggests the restricted role of PPX1 in polyphosphate metabolism in yeasts. PMID- 25540007 TI - Effect of naphthalene on photosystem 2 photochemical activity of pea plants. AB - The effect of a typical polyaromatic hydrocarbon, naphthalene (Naph), on photosystem 2 (PS-2) photochemical activity in thylakoid membrane preparations and 20-day-old pea leaves was studied. Samples were incubated in water in the presence of Naph (0.078, 0.21, and 0.78 mM) for 0.5-24 h under white light illumination (15 MUmol photons.m(-2).s(-1)). The PS-2 activity was determined by studying fast and delayed chlorophyll (Chl) a fluorescence. Incubation of samples in water solutions at Naph concentrations of 0.21 and 0.78 mM led to a decrease in the maximum PS-2 quantum efficiency (Fv/Fm), noticeable changes in the polyphasic induction kinetics of fluorescence (OJIP), and a decrease in the amplitudes of the fast and slow components of delayed fluorescence of Chl a. The rate of release of electrolytes from leaves that were preliminarily incubated with Naph (0.21 mM) was also increased. Significant decrease in the fluorescence parameters in thylakoid membrane preparations was observed at Naph concentration of 0.03 mM and 12-min exposure of the samples. Chlorophyll (a and b) and carotenoid content (mg per gram wet mass) was insignificantly changed. The quantum yields of electron transfer from QA to QB (phiET2o) and also to the PS-1 acceptors (phiRE1o) were reduced. These results are explained by the increase in the number of QB-non-reducing centers of PS-2, which increased with increasing Naph concentration and exposure time of leaves in Naph solution. The suppression of PS-2 activity was partly abolished in the presence of the electron donor sodium ascorbate. Based on these results, it is suggested that Naph distorts cell membrane intactness and acts mainly on the PS-2 acceptor and to a lesser degree on the PS-2 donor side. PMID- 25540008 TI - Overexpression of the Jatropha curcas JcERF1 gene coding an AP2/ERF-type transcription factor increases tolerance to salt in transgenic tobacco. AB - The JcERF1 gene, which is related to the ERF family (ethylene responsive factor coding genes), was isolated and characterized from the oil tree Jatropha curcas. The JcERF1 protein contains conserved an AP2/EREBP DNA-binding domain of 58 amino acid residues. The JcERF1 gene could be induced by abscisic acid, high salinity, hormones, and osmotic stress, suggesting that JcERF1 is regulated by certain components of the stress-signaling pathway. The full-length and C-terminus of JcERF1 driven by the GAL4 promoter functioned effectively as a transactivator in yeast, while its N-terminus was completely inactive. Transient expression analysis using a JcERF1-mGFP fusion gene in onion epidermal cells revealed that the JcERF1 protein is targeted to the nucleus. Transgenic tobacco plants carrying CaMV35S::JcERF1 fragments were shown to be much more salt tolerant compared to wild-type plants. Our results indicate that JcERF1 is a new member of the ERF transcription factors family that may play an important role in tolerance to environmental stress. PMID- 25540009 TI - Antibacterial potential of a basic phospholipase A2 (VRV-PL-V) of Daboia russellii pulchella (Russell's Viper) venom. AB - Microbial/bacterial resistance against antibiotics is considered as a potentially serious threat to public health. Further, as these antibiotics elicit side effects, there is interest in developing new molecules with novel modes of action from diverse organisms. Along these lines, in this study the antibacterial potential of the basic protein VRV-PL-V (Vipera russellii venom phospholipase A2 fraction V) of Daboia russellii pulchella venom was evaluated. VRV-PL-V demonstrated a potent antibacterial activity against all the human pathogenic strains tested. It inhibited more effectively Gram-positive bacteria like Staphylococcus aureus and Bacillus subtilis when compared to Gram-negative bacteria like Escherichia coli, Vibrio cholerae, Klebsiella pneumoniae, and Salmonella paratyphi. It inhibited bacterial growth with MIC values ranging from 13 to 24 ug/ml. The antibacterial potential of VRV-PL-V was comparable to the standards used like gentamycin, chloramphenicol, and streptomycin. There was a strong correlation between PLA2 activities and hemolytic and antibacterial activity. It was found that even in the presence of p-bromophenacyl bromide (an inhibitor of PLA2 enzymatic activity), there was marked antibacterial activity, suggesting dissociation or partial overlapping of the bactericidal/antimicrobial domains. Therefore, this study shows that although there is a strong correlation between enzymatic and antimicrobial activities of VRV-PL-V, it may also possess other properties that mimic bactericidal/membrane permeability-increasing protein. PMID- 25540010 TI - Iron metabolism after application of modified magnetite nanoparticles in rats. AB - The influence of modified nanosized magnetite (NSM) particles (magnetic microspheres coated with chitosan and magnetoliposomes) after a single intravenous infusion of their suspensions on iron metabolism in rats has been studied. Modern physical and chemical methods (X-ray fluorescence, dynamic light scattering, transmission electron microscopy) were used for standardization of the modified NSM particles (their size, structure, zeta-potential, and concentration were determined). Atomic emission spectroscopy was used to reveal the dynamics of iron content in rat liver, spleen, lungs, and kidneys during 120 days. Colorimetric and immunoturbidimetric methods were used to determine the concentrations of plasma iron and the proteins involved in its metabolism - ceruloplasmin, transferrin, and ferritin. Their dynamics throughout the experiments were studied. PMID- 25540011 TI - pH-Induced conformational isomerization of leghemoglobin from Arachis hypogea. AB - The pH dependence of proteins is related to the thermodynamic stability and electrostatic interactions in the native state of a protein. Here we report the pH-induced conformational transition of the heme protein leghemoglobin (Lb) isolated from root nodules of the leguminous plant Arachis hypogea. Unlike the other heme proteins myoglobin, hemoglobin, and cytochrome c, the structural characteristics and interactions of Lb is almost unknown, though its functional importance is already established since it binds oxygen to maintain the environment for N2 fixation. We investigated pH-induced unfolding of this protein and identified a number of conformational isomers using multiple fluorescence observables as a function of pH titration. We have characterized the acid- and base-induced conformational transitions among the structural states over the pH range 2-11. Depending on the solution conditions, Lb can exist in one of three phases: pH 2, 3, 4; pH 5, 6, 7; pH 8, 9, 10. The secondary structure as revealed by CD spectroscopy indicated the maximum percentage of alpha-helix to be present at pH 7, where the structure of Lb is also most rigid according to fluorescence anisotropy experiments. The fluorescence lifetime of tryptophan was observed to be maximum at pH 10 and minimum at pH 6, suggesting unfolding transitions of Lb. Thus, alteration of the microenvironment of the globin moiety during pH transition ultimately leads to the conformational change of this monomeric protein Lb. PMID- 25540012 TI - Increasing DNA substrate specificity of the EcoDam DNA-(adenine N(6)) methyltransferase by site-directed mutagenesis. AB - DNA methylation catalyzed by DNA methyltransferases (MTases) is widespread in prokaryotes. In an attempt to find EcoDam variants with enhanced preference for hemimethylated DNA, the L122, P134, and V133 residues were replaced with other amino acids using site directed mutagenesis, and the catalytic activity of all variants on unmethylated and hemimethylated substrates was studied. Our results showed that, in addition to L122A, the L122S and L122A/V133L EcoDam variants were able to sense the methylation status of the 5'-GATC-3' double-stranded target recognition site and methylated only hemimethylated DNA. PMID- 25540013 TI - Expression of hp1 family genes and their plausible role in formation of flamenco phenotype in D. melanogaster. AB - Results of expression analysis of transcription of the flamenco locus that controls transposition of the mobile genetic element gypsy, RNA interference system genes ago3, zuc, aub, and HP1 heterochromatin protein family genes hp1a, hp1b, hp1c, hp1d (rhino), and hp1e in D. melanogaster SS strain mutant on the flamenco gene are presented. We show that the number of transcripts in the SS strain that are formed in the flamenco locus is unchanged in some freely chosen points, and this is different from the wild-type strain where a decreased number of transcripts is observed, which clearly is a result of processing of the flamenco locus primary transcript, a predecessor of piRNA. At the same time, expression of genes of the RNA interference system is not affected, but there is a reduced level of hp1d gene expression in ovary tissue. We suggest that the hp1d gene product is directly or indirectly involved in the flamenco locus primary transcript processing. PMID- 25540014 TI - The International Monetary Fund and the Ebola outbreak. PMID- 25540015 TI - TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain. AB - BACKGROUND: Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood-brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-alpha is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress responsive kinases. OBJECTIVE: To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain. METHODS: Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-alpha expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining. RESULTS: The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-alpha and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-alpha inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI. CONCLUSION: TNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS sensitized HI in the immature brain. PMID- 25540016 TI - Systematic reviews of observational studies of risk of thrombosis and bleeding in urological surgery (ROTBUS): introduction and methodology. AB - BACKGROUND: Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery. METHODS/DESIGN: We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors. DISCUSSION: This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk (including modeling of timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010342. PMID- 25540017 TI - Magnetic resonance image tissue classification using an automatic method. AB - BACKGROUND: Brain segmentation in magnetic resonance images (MRI) is an important stage in clinical studies for different issues such as diagnosis, analysis, 3-D visualizations for treatment and surgical planning. MR Image segmentation remains a challenging problem in spite of different existing artifacts such as noise, bias field, partial volume effects and complexity of the images. Some of the automatic brain segmentation techniques are complex and some of them are not sufficiently accurate for certain applications. The goal of this paper is proposing an algorithm that is more accurate and less complex). METHODS: In this paper we present a simple and more accurate automated technique for brain segmentation into White Matter, Gray Matter and Cerebrospinal fluid (CSF) in three-dimensional MR images. The algorithm's three steps are histogram based segmentation, feature extraction and final classification using SVM. The integrated algorithm has more accurate results than what can be obtained with its individual components. To produce much more efficient segmentation method our framework captures different types of features in each step that are of special importance for MRI, i.e., distributions of tissue intensities, textural features, and relationship with neighboring voxels or spatial features. RESULTS: Our method has been validated on real images and simulated data, with desirable performance in the presence of noise and intensity inhomogeneities. CONCLUSIONS: The experimental results demonstrate that our proposed method is a simple and accurate technique to define brain tissues with high reproducibility in comparison with other techniques. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_207. PMID- 25540018 TI - Is robotic arm stereotactic body radiation therapy "virtual high dose ratebrachytherapy" for prostate cancer? An analysis of comparative effectiveness using published data [corrected]. AB - High-dose rate brachytherapy (HDR-BT) monotherapy and robotic arm (i.e., CyberKnife) stereotactic body radiation therapy (SBRT) are emerging technologies that have become popular treatment options for prostate cancer. Proponents of both HDR-BT monotherapy and robotic arm SBRT claim that these modalities are as efficacious as intensity-modulated radiation therapy in treating prostate cancer. Moreover, proponents of robotic arm SBRT believe it is more effective than HDR-BT monotherapy because SBRT is non-invasive, touting it as 'virtual HDR-BT.' We perform a comparative effective analysis of the two technologies. The tumor control rates and toxicities of HDR-BT monotherapy and robotic arm SBRT are promising. However, at present, it would be inappropriate to state that HDR-BT monotherapy and robotic arm SBRT are as efficacious or effective as other treatment modalities for prostate cancer, which have stronger foundations of evidence. Studies reporting on these technologies have relatively short follow-up time, few patients and are largely retrospective. PMID- 25540019 TI - Endophytic microbial community in two transgenic maize genotypes and in their near-isogenic non-transgenic maize genotype. AB - BACKGROUND: Despite all the benefits assigned to the genetically modified plants, there are still no sufficient data available in literature concerning the possible effects on the microbial communities associated with these plants. Therefore, this study was aimed at examining the effects of the genetic modifications of two transgenic maize genotypes (MON810--expressing the insecticidal Bt-toxin and TC1507--expressing the insecticidal Bt-toxin and the herbicide resistance PAT [phosphinothricin-N-acetyltransferase]) on their endophytic microbial communities, in comparison to the microbial community found in the near-isogenic non-transgenic maize (control). RESULTS: The structure of the endophytic communities (Bacteria, Archaea and fungi) and their composition (Bacteria) were evaluated by denaturing gradient gel electrophoresis (DGGE) and the construction of clone libraries, respectively. DGGE analysis and the clone libraries of the bacterial community showed that genotype TC1507 slightly differed from the other two genotypes. Genotype TC1507 showed a higher diversity within its endophytic bacterial community when compared to the other genotypes. Although some bacterial genera were found in all genotypes, such as the genera Burkholderia, Achromobacer and Stenotrophomonas, some were unique to genotype TC1507. Moreover, OTUs associated with Enterobacter predominated only in TC1507 clone libraries. CONCLUSION: The endophytic bacterial community of the maize genotype TC1507 differed from the communities of the maize genotype MON810 and of their near-isogenic parental genotypes (non-Bt or control). The differences observed among the maize genotypes studied may be associated with insertion of the gene coding for the protein PAT present only in the transgenic genotype TC1507. PMID- 25540020 TI - The accuracy of estimating chronological age from Demirjian and Nolla methods in a Portuguese and Spanish sample. AB - BACKGROUND: Age determination has great importance in many clinical decisions, being commonly used in odontopediatrics, orthodontics, pediatrics, and forensic medicine. The Nolla and Demirjian et al. methods have been used for these purposes. However, estimating chronological age by means of the dental mineralization stage is not a straightforward analysis, and it is fundamental to test the validity of these methods and their applicability to populations. In this article we intend to compare the accuracy of estimating chronological age from dental age measured with the Nolla and Demirjian methods in a Portuguese and Spanish sample, considering the variables of sex and age-group. METHODS: The sample was composed of 821 orthopantomographs of healthy Portuguese (n = 270) and Spanish (n = 551) subjects from 4 to 34 years old. For the Nolla and Demirjian methods, seven mandibular left teeth were examined, staged according to the dental maturity scale of each method. We obtained a good index of inter-rater agreement, a good internal consistency for the teeth assessment, and a good temporal consistency. RESULTS: Dental age was calculated for each method. The Demirjian et al. method tends to overestimate the real age of participants and the Nolla method tends to underestimate it. The accuracy of both methods varied between the sexes and age groups. Both methods were found to be more precise with males. As the age-group increases, the predictive capacities of both methods diminish. The Nolla method was more accurate than the Demirjian method in early and late childhood for both sexes. Neither method could predict chronological age in adults. CONCLUSIONS: We can estimate chronological age for early and late childhood, through the Nolla and Demirjian methods, with the former showing greater predictive capacities than the latter. The Demirjian method tends to overestimate age and the Nolla method tends to underestimate it, leading to the importance of forming regression equations adapted to the population studied. Nolla and Demirjian formulas adapted to our sample were created as a function of sex and age-group. PMID- 25540021 TI - A 3-biomarker-panel predicts renal outcome in patients with proteinuric renal diseases. AB - BACKGROUND: Clinical and histological parameters are valid prognostic markers in renal disease, although they may show considerable interindividual variability and sometimes limited prognostic value. Novel molecular markers and pathways have the potential to increase the predictive prognostic value of the so called "traditional markers". METHODS: Transcriptomics profiles from laser-capture microdissected proximal tubular epithelial cells from routine kidney biopsies were correlated with a chronic renal damage index score (CREDI), an inflammation score (INSCO), and clinical parameters. We used data from 20 renal biopsies with various proteinuric renal diseases with a median follow-up of 49 months (discovery cohort). For validation we performed microarrays from whole kidney biopsies from a second cohort consisting of 16 patients with a median follow-up time of 28 months (validation cohort). RESULTS: 562 genes correlated with the CREDI score and 285 genes correlated with the INSCO panel, respectively. 39 CREDI and 90 INSCO genes also correlated with serum creatinine at follow-up. After hierarchical clustering we identified 5 genes from the CREDI panel, and 10 genes from the INSCO panel, respectively, which showed kidney specific gene expression. After exclusion of genes, which correlated to each other by > 50% we identified VEGF-C from the CREDI panel and BMP7, THBS1, and TRIB1 from the INSCO panel. Traditional markers for chronic kidney disease progression and inflammation score predicted 44% of the serum creatinine variation at follow-up. VEGF-C did not further enhance the predictive value, but BMP7, THBS1 and TRIB1 together predicted 94% of the serum creatinine at follow up (p < 0.0001). The model was validated in a second cohort of patients yielding also a significant prediction of follow up creatinine (48%, p = 0.0115). CONCLUSION: We identified and validated a panel of three genes in kidney biopsies which predicted serum creatinine at follow-up and therefore might serve as biomarkers for kidney disease progression. PMID- 25540022 TI - Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. AB - BACKGROUND: Several systematic reviews and meta-analyses demonstrated the association between depression and the risk of coronary heart disease (CHD), but the previous reviews had some limitations. Moreover, a number of additional studies have been published since the publication of these reviews. We conducted an updated meta-analysis of prospective studies to assess the association between depression and the risk of CHD. METHODS: Relevant prospective studies investigating the association between depression and CHD were retrieved from the PubMed, Embase, Web of Science search (up to April 2014) and from reviewing reference lists of obtained articles. Either a random-effects model or fixed effects model was used to compute the pooled risk estimates when appropriate. RESULTS: Thirty prospective cohort studies with 40 independent reports met the inclusion criteria. These groups included 893,850 participants (59,062 CHD cases) during a follow-up duration ranging from 2 to 37 years. The pooled relative risks (RRs) were 1.30 (95% CI, 1.22-1.40) for CHD and 1.30 (95% CI, 1.18-1.44) for myocardial infarction (MI). In the subgroup analysis by follow-up duration, the RR of CHD was 1.36 (95% CI, 1.24-1.49) for less than 15 years follow-up, and 1.09 (95% CI, 0.96-1.23) for equal to or more than 15 years follow-up. Potential publication bias may exist, but correction for this bias using trim-and-fill method did not alter the combined risk estimate substantially. CONCLUSIONS: The results of our meta-analysis suggest that depression is independently associated with a significantly increased risk of CHD and MI, which may have implications for CHD etiological research and psychological medicine. PMID- 25540023 TI - Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients. AB - INTRODUCTION: Proton pump inhibitors (PPI) have been linked to Clostridium difficile infection (CDI) but there are few data specific to ICU patients. We evaluated duration of PPI exposure as a potential risk factor for hospital acquired CDI in the ICU. METHODS: This retrospective, case-control study was conducted using the Multiparameter Intelligent Monitoring in Intensive Care II database, a large publically available database of more than 35,000 ICU patients. Adult patients with CDI were identified using the ICD-9 code for Clostridium difficile listed as a secondary diagnosis. To be included, patients had to be present in an ICU for >= 48 hours prior to Clostridium difficile acquisition. These patients were then matched to patients without CDI using the ICD-9 primary diagnosis, age (+/-5 years) and SOFA score (+/-1). Successfully matched patients were reviewed for PPI exposure and other potential confounding variables for CDI. PPI exposure was characterized as short (<2 days) or long (>= 2 days). Multivariate modeling was performed to identify independent risk factors for CDI. RESULTS: There were 408 patients evaluated and 81% received a PPI. The percentage of patients who had a long exposure to PPIs was 83% in the CDI group compared to 73% with controls (P = 0.012). Upon inclusion of the following variables into a multivariate analysis (long PPI exposure, histamine-2-receptor antagonist administration, antibiotic administration, immunosuppression and study duration), long PPI exposure (odds ratio (OR) (95% confidence interval (CI) = 2.03 (1.23 to 3.36), P = 0.006) and antibiotic use (OR (95% CI) = 2.52 (1.23 to 5.18), P = 0.012) were identified as independent predictors of CDI. CONCLUSIONS: Proton pump inhibitors are independent risk factors for the development of CDI in ICU patients. This risk is particularly exposed after two or more days of therapy. PMID- 25540024 TI - Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Abeta-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Abeta agents. AB - Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Abeta in a very complete model of Alzheimer's disease amyloidosis, the McGill R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Abeta antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the gamma-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Abeta selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis. PMID- 25540026 TI - Can only histological evaluation determine the allocation of ECD kidneys? AB - INTRODUCTION: There is a recent debate on the "transplantability" of ECD (Expanded Criteria Donors) kidneys and the selection criteria used to allocate them to single or double transplantation. Remuzzi et al. have defined a protocol incorporating pre-transplant donor biopsy to guide the use of older donor organs. They allocated organs as single or double transplants on the basis of histological findings. We aim to show the pros and cons of the only histological evaluation in the allocation of ECD kidneys, to compare the different experiences in United States and Europe and thus to discuss whether this tool should be used alone or included in a comprehensive clinical and histopathological evaluation. DISCUSSION: In the United States many Authors stated that the biopsy actually increases the percentage of kidney discarded and they raised questions about the importance of the biopsy in evaluating ECD kidneys for transplantation. On the other hand, the experiences of the majority of european transplant centers showed that allocating kidneys as single or dual transplant based on biopsy findings may achieve good graft and patient outcomes. Moreover, the experience of some centers as ours showed that kidneys allocated as DKT (Dual Kidney Transplant) on the basis of Remuzzi's score could have been suitable for single transplantation suggesting the need of an adjustment of the Remuzzi Score System. Many Authors, who are in favor of histological evaluation, actually believe that a comprehensive clinical and histopathological assessment before transplantation remains necessary. We lack precise national- or international-based selection criteria to guide clinicians. An adjustment of the Remuzzi Score System could be taken into consideration such as narrowing the indication for DKT from those ECD kidneys with higher scores and including the histological evaluation in a multifactor score. PMID- 25540027 TI - The Moderating Effect of Social Support on the Relationship Between Impulsivity and Suicide in Rural China. AB - This study was to investigate the relationship among social support, impulsivity, and suicide, so as to test the hypothesis that social support moderates the effect of impulsivity on suicide for the rural young suicides in China. Subjects were 392 consecutively recruited suicides aged 15-34 years and 416 community controls of the same age range sampled in China. The case-control data were obtained using psychological autopsy. The results showed that high social support had the protective effect among individuals with low impulsivity. It can be concluded that impulsivity is a potential area for further study of suicidal behavior. The suicide prevention efforts in rural China may address impulsivity. PMID- 25540028 TI - Community mental health service utilization after the L'Aquila earthquake. AB - This study investigated the use of the facilities for the mental health by the population affected by the L'Aquila (Italy) 2009 earthquake. The data about the activities of the Mental Health Centre of L'Aquila during the years from 2008 to 2010 were obtained by the service Information System. In the months following the event the percentage of referrals was reduced. Failure to use specialized facilities after disasters should not be seen as reassuring. It is conceivable that a relevant rate of frank or sub-threshold psychopathology is present that the traditional mental health facilities may not be able to intercept. PMID- 25540025 TI - Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression. AB - BACKGROUND: Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression. METHODS: A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Biotrove OpenArray(r) NT Cycler. Clinical tumor stage, diagnostic PSA serum levels, and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator. RESULTS: SNPs rs11615 (ERCC1) and rs17503908 (ATM) appeared as risk factors for prostate cancer aggressiveness. Patients wild homozygous for these SNPs (AA and TT, respectively) were at higher risk for developing cT2b - cT4 (OR = 2.21 (confidence interval (CI) 95% 1.47 - 3.31), p < 0.001) and Gleason scores >= 7 (OR = 2.22 (CI 95% 1.38 - 3.57), p < 0.001), respectively. Moreover, those patients wild homozygous for both SNPs had the greatest risk of presenting D'Amico high-risk tumors (OR = 2.57 (CI 95% 1.28 5.16)). CONCLUSIONS: Genetic variants at DNA repair genes are associated with prostate cancer progression, and would be taken into account when assessing the malignancy of prostate cancer. PMID- 25540029 TI - The EQ-5D-5L index score is more discriminative than the EQ-5D-3L index score in diabetes patients. AB - PURPOSE: To compare the discriminative power of the index scores of EQ-5D-5L (5L) and EQ-5D-3L (3L) in diabetes patients in China. METHODS: A consecutive sample of type 2 diabetes mellitus (T2DM) patients in the clinics self-completed the two versions of EQ-5D. The 3L index score was obtained from the Chinese 3L value set; the 5L index score was predicted from the 3L index score using an interim scoring. Relative efficiency (RE) of the 5L and 3L index scores was calculated to compare their ability in differentiating between T2DM patients with and without one of ten clinical conditions. The efficiency of the 5L and 3L health state classification systems was assessed using the Shannon index (H') and in terms of ceiling effects. RESULTS: A total of 289 T2DM patients participated in this study. The 5L score was systematically lower than the 3L score for T2DM patients with and without a condition (range -0.36 to -0.06). The 5L score exhibited higher discriminative power in nine of ten conditions, with the mean RE value being 1.92. 5L had higher H' values than 3L in all the five EQ-5D dimensions: mobility (1.14 vs. 0.70), self-care (0.44 vs. 0.33), usual activities (0.72 vs. 0.47), pain/discomfort (1.58 vs. 1.10), and anxiety/depression (1.03 vs. 0.67). The overall ceiling effects decreased from 56.7 % (3L) to 36.7 % (5L). CONCLUSION: The 5L index score is more discriminative than the 3L index score in T2DM patients and therefore is preferable for use in this population. PMID- 25540030 TI - Two-photon excitation fluorescence microscopy and its application in functional connectomics. AB - Two-photon excitation fluorescence microscopy has become widely used in various life science fields in this decade. In the field of neuroscience in particular, in vivo two-photon microscopy has provided vital information on neural activity and brain function. In the current era of connectomics, visualization of the morphology and activity of numerous neurons in ever larger regions of the living brain are required within short periods. Based on this viewpoint, we discuss the fundamentals, advantages and potential of two-photon excitation fluorescence microscopy for the investigation of neural circuit functions. PMID- 25540031 TI - Modifications of cysteine residues in the transmembrane and cytoplasmic domains of a recombinant hemagglutinin protein prevent cross-linked multimer formation and potency loss. AB - BACKGROUND: Recombinant hemagglutinin (rHA) is the active component in Flublok(r); a trivalent influenza vaccine produced using the baculovirus expression vector system (BEVS). HA is a membrane bound homotrimer in the influenza virus envelope, and the purified rHA protein assembles into higher order rosette structures in the final formulation of the vaccine. During purification and storage of the rHA, disulfide mediated cross-linking of the trimers within the rosette occurs and results in reduced potency. Potency is measured by the Single Radial Immuno-diffusion (SRID) assay to determine the amount of HA that has the correct antigenic form. RESULTS: The five cysteine residues in the transmembrane (TM) and cytoplasmic (CT) domains of the rHA protein from the H3 A/Perth/16/2009 human influenza strain have been substituted to alanine and/or serine residues to produce three different site directed variants (SDVs). These SDVs have been evaluated to determine the impact of the TM and CT cysteines on potency, cross-linking, and the biochemical and biophysical properties of the rHA. Modification of these cysteine residues prevents disulfide bond cross-linking in the TM and CT, and the resulting rHA maintains potency for at least 12 months at 25 degrees C. The strategy of substituting TM and CT cysteines to prevent potency loss has been successfully applied to another H3 rHA protein (from the A/Texas/50/2012 influenza strain) further demonstrating the utility of the approach. CONCLUSION: rHA potency can be maintained by preventing non-specific disulfide bonding and cross-linked multimer formation. Substitution of carboxy terminal cysteines is an alternative to using reducing agents, and permits room temperature storage of the vaccine. PMID- 25540032 TI - Invariance and plasticity in the Drosophila melanogaster metabolomic network in response to temperature. AB - BACKGROUND: Metabolomic responses to extreme thermal stress have recently been investigated in Drosophila melanogaster. However, a network level understanding of metabolomic responses to longer and less drastic temperature changes, which more closely reflect variation in natural ambient temperatures experienced during development and adulthood, is currently lacking. Here we use high-resolution, non targeted metabolomics to dissect metabolomic changes in D. melanogaster elicited by moderately cool (18 degrees C) or warm (27 degrees C) developmental and adult temperature exposures. RESULTS: We find that temperature at which larvae are reared has a dramatic effect on metabolomic network structure measured in adults. Using network analysis, we are able to identify modules that are highly differentially expressed in response to changing developmental temperature, as well as modules whose correlation structure is strongly preserved across temperature. CONCLUSIONS: Our results suggest that the effect of temperature on the metabolome provides an easily studied and powerful model for understanding the forces that influence invariance and plasticity in biological networks. PMID- 25540033 TI - Need to know: the need for cognitive closure impacts the clinical practice of obstetrician/gynecologists. AB - BACKGROUND: Need for cognitive closure (NFCC) has been shown to be a consistent and measurable trait. It has effects on decision making and has been associated with more rapid decision making, higher reliance on heuristics or biases for decision making, reduced tolerance for ambiguity, and reduced interest in searching for alternatives. In medical practice, these tendencies may lead to lower quality of decision making. METHODS: This study measured NFCC in 312 obstetrician/gynecologists using a survey-style approach. Physicians were administered a short NFCC scale and asked questions about their clinical practice. RESULTS: Obstetrician/gynecologists with high NFCC were found to be less likely to address a number of clinical questions during well-woman exams, and were more likely to consult a greater number of sources when prescribing new medications. CONCLUSIONS: NFCC of physicians may have an important impact on practice. It is possible that increased training during residency or medical school could counteract the detrimental effects of NFCC, and steps can be taken through increased use of electronic reminder systems could orient physicians to the appropriate questions to ask patients. PMID- 25540034 TI - Associations Between Thrombin Generation and the Risk of Cardiovascular Disease in Elderly Patients: Results From the PROSPER Study. AB - BACKGROUND: Hypercoagulability may be an important contributor to the pathophysiology of atherosclerosis and atherothrombosis. As thrombin fulfills a central role in coagulation and links to several cellular mechanisms involved in arterial disease, we hypothesized that thrombin generation is associated with cardiovascular events in elderly patients. METHODS: We studied the relationship between plasma thrombin generation and incident coronary heart disease (CHD) and stroke in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). From this multicenter prospective cohort, 4,932 samples of subjects (70-82 years) with pre-existing vascular disease or risk factors were available for thrombin generation measurements. RESULTS: Within the 3.2 years of follow-up incident stroke and CHD was observed in 227 and 545 subjects, respectively. Baseline thrombin generation was significantly decreased in subjects with incident stroke compared with subjects without: normalized peak height 71.1+/-40.8% versus 82.3+/ 44.9%, p = .0002, and normalized endogenous thrombin potential 79.1+/-23.3% versus 87.0+/-24.8%, p < .0001 (mean and SDs). Thrombin generation was independently and inversely associated with stroke risk: hazard ratio 0.71 (95%CI: 0.60-0.85), 0.68 (95%CI: 0.58-0.79), for normalized peak height and normalized endogenous thrombin potential, respectively (all p < .001). In subjects with incident CHD, thrombin generation was comparable to subjects without a coronary event. Only an increased normalized peak height was significantly associated with incident CHD (hazard ratio 1.17 [95% CI: 1.06 1.28], p = .002). CONCLUSIONS: We demonstrate that a delayed and decreased thrombin generation is a strong and independent predictor for stroke in elderly people at increased risk of vascular disease. However, no convincing consistent association could be demonstrated between thrombin generation and incident CHD. PMID- 25540035 TI - A comparison of cognitive-behavioral couple therapy and lidocaine in the treatment of provoked vestibulodynia: study protocol for a randomized clinical trial. AB - BACKGROUND: Provoked vestibulodynia (PVD), a frequent form of chronic genital pain, is associated with decreased sexual function for afflicted women, as well as impoverished sexual satisfaction for women and their partners. Pain and sexuality outcomes for couples with PVD are influenced by interpersonal factors, such as pain catastrophizing, partner responses to pain, ambivalence over emotional expression, attachment style and perceived relationship and sexual intimacy. Despite recommendations in the literature to include the partner in cognitive-behavioral therapy targeted at improving pain and sexuality outcomes, no randomized clinical trial has tested the efficacy of this type of intervention and compared it to a first-line medical intervention. METHODS: This bi-center, randomized clinical trial is designed to examine the efficacy of cognitive behavioral couple therapy compared to topical lidocaine. It is conducted across two Canadian university-hospital centers. Eligible women diagnosed with PVD and their partners are randomized to one of the two interventions. Evaluations are conducted using structured interviews and validated self-report measures at three time points: Pre-treatment (T1: prior to randomization), post-treatment (T2), and 6-month follow-up (T3). The primary outcome is the change in reported pain during intercourse between T1 and T2. Secondary outcomes focus on whether there are significant differences between the two treatments at T2 and T3 on (a) the multidimensional aspects of women's pain and (b) women and partners' sexuality (sexual function and satisfaction), psychological adjustment (anxiety, depression, catastrophizing, self-efficacy, and quality of life), relationship factors (partner responses and dyadic adjustment) and self-reported improvement and treatment satisfaction. In order to detect an effect size as small as 0.32 for secondary outcomes, a sample of 170 couples is being recruited (27% dropout expected). A clinically significant decrease in pain is defined as a 30% reduction. DISCUSSION: The randomized clinical trial design is the most appropriate to examine the efficacy of cognitive-behavioral couple therapy, a recently developed and pilot-tested psychosocial intervention for couples coping with PVD, in comparison to a frequent first-line treatment option, topical lidocaine. Findings from this study will provide important information about empirically supported treatment options for PVD, and inform future treatment development and research for this patient population. TRIAL REGISTRATION: Clinicaltrials.gov NCT01935063; registration date: 27 August 27 2013. PMID- 25540036 TI - Substance use in people at clinical high-risk for psychosis. AB - BACKGROUND: Some high-risk (HR) mental states for psychosis may lack diagnostic specificity and predictive value. Furthermore, psychotic-like experiences found in young populations may act not only as markers for psychosis but also for other non-psychotic psychiatric disorders. A neglected consideration in these populations is the effect of substance misuse and its role in the development of such mental states or its influence in the evolution toward full psychotic presentations. Therefore, the main aim of this study was to thoroughly describe past and current substance use profiles of HR individuals by comparing a consecutive cohort of young people at high risk referred to a population-based early intervention clinical service with a random sample of healthy volunteers (HV) recruited from the same geographical area. METHODS: We compared alcohol and substance use profiles of sixty help-seeking HR individuals and 60 healthy volunteers (HV). In addition to identification of abuse/dependence and influence on psychotic-like experiences, differences between HR individuals and HV were assessed for gender, ethnicity, occupational status, age of lifetime first substance use, prevalence and frequency of substance use. RESULTS: There were no cases of substance use disorder or dependence in either groups. HR individuals were significantly younger than HV when they first started to use substances (p = 0.014). The prevalence of overall HR substance use was similar to that of HV. Although HR individuals reported less cannabinoid use than HV currently (15% vs. 27%), and more in the past (40% vs. 30%), the differences were not statistically significant (p = 0.177 & 0.339 respectively). Current frequency of use was significantly higher for HR individuals than HV for alcohol (p = 0.001) and cannabinoids (p = 0.03). In this sample, only 5% of HR individuals converted to psychosis over a two-year follow-up. CONCLUSIONS: Certain profiles of substance use could potentially play a significant part in the evolution of HR presentations. Therefore, substance use may well represent a clinical domain that requires further emphasis and more detailed consideration in future studies. PMID- 25540038 TI - Antiviral therapy for chronic hepatitis B in China. AB - The vaccination program against hepatitis B virus (HBV) has greatly reduced the incidence of HBV infection. However, almost one-fourth of the HBV infected patients worldwide are still located in China. The healthcare burden from chronic HBV infection is a big challenge for the Chinese government and clinicians. Antiviral therapy plays a central role in controlling chronic HBV infection and preventing the disease progression. However, due to the specific economic and medical system issues, the first-line antiviral agents recommended by the AASLD and EASL have not been widely used for Chinese patients. In this review, we will discuss some key issues in the area of antiviral treatment for chronic hepatitis B in China. PMID- 25540037 TI - Natural history of chronic hepatitis B virus infection. AB - Hepatitis B virus infection represents a major global health problem. Currently, there are more than 240 million chronically infected people worldwide. The development of chronic hepatitis B virus-mediated liver disease may lead to liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Recently, the discovery of the viral entry receptor sodium taurocholate cotransporting polypeptide has facilitated new approaches for a better understanding of viral physiopathology. Hopefully, these novel insights may give rise to the development of more effective antiviral therapy concepts during the next years. In this review, we will discuss the natural history of hepatitis B virus infection including the viral biology, the clinical course of infection and the role of the immune response. PMID- 25540040 TI - An empirical study to determine factors that motivate and limit the implementation of ICT in healthcare environments. AB - BACKGROUND: The maturity and usage of wireless technology has influenced health services, and this has raised expectations from users that healthcare services will become more affordable due to technology growth. There is increasing evidence to justify this expectation, as telehealth is becoming more and more prevalent in many countries. Thus, health services are now offered beyond the boundaries of traditional hospitals, giving rise to many external factors dictating their quality. This has led us to investigate the factors that motivate and limit the implementation of ICT applications in the healthcare domain. METHODS: We used a mixed method approach with the qualitative aspects leading the quantitative aspects. The main reason for this approach was to understand and explore the domain through the qualitative aspects as we could be part of the discussion. Then we conducted a quantitative survey to extract more responses in order to justify the claims explored in the qualitative process. RESULTS: We found that there are a number of internal and external factors influencing ICT adoption in the healthcare environment so that services can be provided via ICT tools. These factors were grouped under factors contributing to improved outcomes, efficiency and the management of technology. We conceptualised that these three groups of factors drive ICT implementation to assure health services. CONCLUSIONS: The main lesson learned from this research was that Information Systems discipline needs to urgently consider health informatics as a serious growth area. We also found that as IS researchers, we need to 'mix' with the health environment in order to understand the environment and then develop suitable methods to answer posited research questions. PMID- 25540039 TI - Distinct gene signatures in aortic tissue from ApoE-/- mice exposed to pathogens or Western diet. AB - BACKGROUND: Atherosclerosis is a progressive disease characterized by inflammation and accumulation of lipids in vascular tissue. Porphyromonas gingivalis (Pg) and Chlamydia pneumoniae (Cp) are associated with inflammatory atherosclerosis in humans. Similar to endogenous mediators arising from excessive dietary lipids, these Gram-negative pathogens are pro-atherogenic in animal models, although the specific inflammatory/atherogenic pathways induced by these stimuli are not well defined. In this study, we identified gene expression profiles that characterize P. gingivalis, C. pneumoniae, and Western diet (WD) at acute and chronic time points in aortas of Apolipoprotein E (ApoE-/-) mice. RESULTS: At the chronic time point, we observed that P. gingivalis was associated with a high number of unique differentially expressed genes compared to C. pneumoniae or WD. For the top 500 differentially expressed genes unique to each group, we observed a high percentage (76%) that exhibited decreased expression in P. gingivalis-treated mice in contrast to a high percentage (96%) that exhibited increased expression in WD mice. C. pneumoniae treatment resulted in approximately equal numbers of genes that exhibited increased and decreased expression. Gene Set Enrichment Analysis (GSEA) revealed distinct stimuli associated phenotypes, including decreased expression of mitochondrion, glucose metabolism, and PPAR pathways in response to P. gingivalis but increased expression of mitochondrion, lipid metabolism, carbohydrate and amino acid metabolism, and PPAR pathways in response to C. pneumoniae; WD was associated with increased expression of immune and inflammatory pathways. DAVID analysis of gene clusters identified by two-way ANOVA at acute and chronic time points revealed a set of core genes that exhibited altered expression during the natural progression of atherosclerosis in ApoE-/- mice; these changes were enhanced in P. gingivalis-treated mice but attenuated in C. pneumoniae-treated mice. Notable differences in the expression of genes associated with unstable plaques were also observed among the three pro-atherogenic stimuli. CONCLUSIONS: Despite the common outcome of P. gingivalis, C. pneumoniae, and WD on the induction of vascular inflammation and atherosclerosis, distinct gene signatures and pathways unique to each pro-atherogenic stimulus were identified. Our results suggest that pathogen exposure results in dysregulated cellular responses that may impact plaque progression and regression pathways. PMID- 25540041 TI - A cluster randomised controlled trial of a telephone-based intervention targeting the home food environment of preschoolers (The Healthy Habits Trial): the effect on parent fruit and vegetable consumption. AB - BACKGROUND: The home food environment is an important setting for the development of dietary patterns in childhood. Interventions that support parents to modify the home food environment for their children, however, may also improve parent diet. The purpose of this study was to assess the impact of a telephone-based intervention targeting the home food environment of preschool children on the fruit and vegetable consumption of parents. METHODS: In 2010, 394 parents of 3-5 year-old children from 30 preschools in the Hunter region of Australia were recruited to this cluster randomised controlled trial and were randomly assigned to an intervention or control group. Intervention group parents received four weekly 30-minute telephone calls and written resources. The scripted calls focused on; fruit and vegetable availability and accessibility, parental role modelling, and supportive home food routines. Two items from the Australian National Nutrition Survey were used to assess the average number of serves of fruit and vegetables consumed each day by parents at baseline, and 2-, 6-, 12-, and 18-months later, using generalised estimating equations (adjusted for baseline values and clustering by preschool) and an intention-to-treat-approach. RESULTS: At each follow-up, vegetable consumption among intervention parents significantly exceeded that of controls. At 2-months the difference was 0.71 serves (95% CI: 0.58-0.85, p < 0.0001), and at 18-months the difference was 0.36 serves (95% CI: 0.10-0.61, p = 0.0067). Fruit consumption among intervention parents was found to significantly exceed consumption of control parents at the 2 ,12- and 18-month follow-up, with the difference at 2-months being 0.26 serves (95% CI: 0.12-0.40, p = 0.0003), and 0.26 serves maintained at 18-months, (95% CI: 0.10-0.43, p = 0.0015). CONCLUSIONS: A four-contact telephone-based intervention that focuses on changing characteristics of preschoolers' home food environment can increase parents' fruit and vegetable consumption. (ANZCTR12609000820202). PMID- 25540042 TI - Prematurity and low birth weight lead to altered bone geometry, strength, and quality in children. AB - PURPOSE: Prematurity and low birth weight are associated with a decrease in bone mass. Aim of the study was to investigate bone geometry, strength, and quality in children born at term small for gestational age (term SGA), premature appropriate for gestational age (prem AGA), and premature SGA (prem SGA). METHODS: 91 patients (46 f, 45 m), mean age 11.28 years, height SDS 0.03 +/- 0.21, and BMI SDS -0.31 +/- 0.19. 20 were term SGA, 22 prem SGA, and 49 prem AGA. Bone geometry was assessed on the 2nd metacarpal bone, by evaluating the outer and inner diameter, the cortical area, medullary area, metacarpal index, cross-sectional area, and bone strength. Bone quality was evaluated by ultrasound and expressed as amplitude-dependent speed of sound and bone transmission time (BTT). RESULTS: Term SGA, prem SGA, and prem AGA had values of bone geometry, strength, and quality significantly lower than our reference range (p < 0.05). Findings in the three groups were similar, apart from BTT, which was significantly reduced in prem SGA (p < 0.05). Fat percentage was the main determinant of BTT. CONCLUSIONS: Children born either prematurely or SGA seem to have smaller and weaker bones. Those born both premature and SGA were the most affected. PMID- 25540043 TI - Isolation of a series of fatty acid components of Ongokea gore seed (Isano) oil and their detailed structural analysis. AB - The total oil production capacity of isano oil is estimated at about 10,000 tons annually. Previous studies of this oil revealed that it is rich in fatty acids including a conjugated diyne moiety. This makes isano oil an excellent candidate for sustainable applications development. However, only a few of its fatty acids have been isolated and identified so far. In this study, we have reinvestigated this oil by characterizing its physicochemical properties and isolating several of its fatty acids as ethyl esters for their detailed structural analysis and identification. Six ethyl esters of fatty acids constituting isanic oil were isolated by flash column chromatography and semipreparative HPLC. The detailed structural analysis of these fatty acid esters by infrared, high resolution, mass spectroscopy, and nuclear magnetic resonance (1-D and 2-D) allowed determining unequivocally their chemical structure. The main fatty acid component of the oil (35.7 %) was identified as isanic acid. Four minor acids were found to possess also two conjugated triple bonds, while the sixth fatty acid does not contain carbon-carbon triple bonds nor double bonds but possessed a cis epoxide function. Results obtained in this study are currently being used to explore potential applications of isano oil. PMID- 25540044 TI - Dental caries and associated factors among primary school children in Bahir Dar city: a cross-sectional study. AB - BACKGROUND: Dental caries is the most common chronic infectious disease of childhood caused by the interaction of bacteria, mainly Streptococcus mutans and sugary foods on tooth enamel. This study aimed at determining the prevalence and associated factors of dental caries among primary school children at Bahir Dar city. METHODS: A school based cross-sectional study was conducted at Bahir Dar city from October 2013 to January 2014. Systematic random sampling technique was used to select the children. Structured questionnaire was used to interview children and/or parents to collect socio demographic variables. Clinical dental information obtained by experienced dentist using dental caries criteria set by World Health Organization. Binary and multiple logistic regression analysis were computed to investigate factors associated with dental caries. RESULTS: Of the 147 children, 82 (55.4%) were girls. Majority of the children (67.6%) cleaned their teeth using traditional method (small stick of wood made of a special type of plant). The proportion of children having dental caries was 32 (21.8%). Primary tooth decay accounted for 24 (75%) of dental caries. The proportion of missed teeth was 7 (4.8%). The overall proportion of toothache and dental plaque among school children were 40 (27.2%) and 99 (67.3%), respectively. Grade level of 1-4 (AOR = 3.9, CI = 1.49 -10.4), poor habit of tooth cleaning (AOR = 2.6, CI = 1.08 - 6.2), dental plaque (AOR = 5.3, CI = 1.6 - 17.7) and toothache (AOR = 6.3, CI = 2.4 - 15.4) were significantly associated with dental caries. CONCLUSION: Dental caries is a common public health problem in school children associated with poor oral hygiene, dietary and dental visit habits. Therefore, prevention measures such as health education on oral hygiene, dietary habits and importance of dental visit are obligatory for children. PMID- 25540045 TI - Biotechnological potential of yeast isolates from cachaca: the Brazilian spirit. AB - This study identified phenotypic traits appropriate for biotechnological applications of 118 yeasts isolated from cachaca distilleries. Different properties were verified: capacity to use alternative carbon sources; ability to tolerate high concentrations of sucrose, ethanol, methanol, aluminum and zinc as well as different pH values and foam production. Pichia guilliermondii and Pichia anomala strains were identified as the most promising ones for application in the second-generation biofuel industry, showing ability to grow on high glycerol concentrations. Other isolates, identified as Saccharomyces cerevisiae, produced bioethanol comparable to the industrial strains, and were therefore ideal for use in the first-generation ethanol industry. Some of these strains also showed high resistance to aluminum, as observed in sugarcane juice, and to inter-cycle washings with diluted sulphuric acid, as performed in the industrial bioethanol production process. In summary, yeast isolates from cachaca distilleries displayed robustness and phenotypic plasticity, which makes them interesting for biotechnological applications. PMID- 25540046 TI - Deletion of genes involved in glutamate metabolism to improve poly-gamma-glutamic acid production in B. amyloliquefaciens LL3. AB - Here, we attempted to elevate poly-gamma-glutamic acid (gamma-PGA) production by modifying genes involved in glutamate metabolism in Bacillus amyloliquefaciens LL3. Products of rocR, rocG and gudB facilitate the conversion from glutamate to 2-oxoglutarate in Bacillus subtillis. The gene odhA is responsible for the synthesis of a component of the 2-oxoglutarate dehydrogenase complex that catalyzes the oxidative decarboxylation of 2-oxoglutarate to succinyl coenzyme A. In-frame deletions of these four genes were performed. In shake flask experiments the gudB/rocG double mutant presented enhanced production of gamma-PGA, a 38 % increase compared with wild type. When fermented in a 5-L fermenter with pH control, the gamma-PGA yield of the rocR mutant was increased to 5.83 g/L from 4.55 g/L for shake flask experiments. The gudB/rocG double mutant produced 5.68 g/L gamma-PGA compared with that of 4.03 g/L for the wild type, a 40 % increase. Those results indicated the possibility of improving gamma-PGA production by modifying glutamate metabolism, and identified potential genetic targets to improve gamma-PGA production. PMID- 25540047 TI - Polyethyleneimine-grafted collagen fiber as a carrier for cell immobilization. AB - Collagen fiber (CF), an abundant natural biopolymer, features many favorable properties that make it a potential carrier for cell immobilization. In the present investigation, CF was grafted with polyethyleneimine (PEI) using glutaraldehyde (GA) as the cross-linking agent, resulting in the formation of a novel CF based carrier (CF-PEI). The properties of CF-PEI as a carrier were evaluated by the immobilization of Microbacterium arborescens (CICC 20196), which has glucose isomerase (EC 5.3.1.5) activity. It was found that M. arborescens cells immobilized on CF-PEI exhibited higher glucose isomerization than those using activated carbon or anion exchange resin as the carriers. The Michaelis constant (K m) of the isomerization reaction for the CF-PEI-immobilized M. arborescens cells was 0.528 mol/L, which was slightly higher than that of free cells (0.473 mol/L). In addition, the apparent activation energies (E a) of free and immobilized cells on CF-PEI were almost the same at 60 kJ/mol. In an isomerization reaction of glucose to fructose in a fixed-bed reactor, CF-PEI immobilized M. arborescens cells showed appreciable activity and operational stability. The corresponding isomerization ratio was as high as 41 % for 20 days, and the half-life was about 40 days. PMID- 25540048 TI - Expression of V(H)-linker-V(L) orientation-dependent single-chain Fv antibody fragment derived from hybridoma 2E6 against aflatoxin B1 in Escherichia coli. AB - Aflatoxin B1 (AFB1) is a toxic secondary metabolic product, which threatens human and animal health. Antibody is a key factor for immunoassay against toxic stuff like AFB1, and single-chain Fv antibody fragment (scFv) has become a popular format of genetically engineered antibody. In this study, four hybridoma cell lines against AFB1 were obtained, and then scFvs 2E6 derived from hybridoma cell line 2E6 were constructed in different V(H)/V(L) orientations. Subsequently, scFvs 2E6 were expressed in E. coli BL21(DE3) mainly in the form of inclusion body. SDS-PAGE, Western blot and ELISA were employed to characterize scFvs 2E6. The results revealed that the yield of inclusion body of scFvs 2E6 in either V(H)/V(L) orientation was similar; however, only the scFv in V(H)-linker-V(L) orientation showed anti-AFB1 bioactivity after refolding. The present study underscores the importance of choosing optimal V(H)/V(L) orientation for scFv construction, and scFv may be favorable for immunoassays in food industry. PMID- 25540049 TI - Glucocorticoid use is associated with increase in HDL and no change in other lipids in rheumatoid arthritis patients. AB - The aim of this article was to examine the association of glucocorticoid use and dose and changes in the lipid profile in rheumatoid arthritis (RA) patients. RA patients between January 1, 2001, and November 30, 2011, who received oral or intravenous glucocorticoids and who had lipid levels within 1 year before and 1 year after ongoing (at least 3 months) glucocorticoids use along with RA patients who did not take glucocorticoids (controls) were included. Glucocorticoid exposure was calculated as a weighted daily dose in prednisone equivalents and analyzed using as cutoff dose prednisone equivalent of 7.5 mg/day. Outcomes were changes in high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), triglycerides, and TC/HDL ratio and were calculated in linear regression models adjusting for relevant confounders. In total, 202 subjects on glucocorticoids and 436 controls were included. The glucocorticoid group of >=7.5 mg/day had the greatest increase in HDL of 6.0 mg/dL (p = 0.003 compared to controls) with lower increases of 3.1 and 2.4 mg/dL in the glucocorticoid group of <7.5 mg/day and controls, respectively. There were no significant differences in other parameters of the lipid profile between the two glucocorticoid groups and controls. In this RA cohort, glucocorticoid dose equivalent of prednisone >=7.5 mg/day was associated with increased HDL and no change in LDL or TC/HDL ratio compared to no glucocorticoid use These results suggest that this glucocorticoid dose is not associated with an atherogenic lipid profile in RA, a finding that is important in this patient population at high risk for cardiovascular disease. PMID- 25540051 TI - Diffuse filiform polyposis of the small intestine without inflammatory bowel disease. AB - Filiform polyposis is a rare disease, which typically occurs in patients with inflammatory bowel disease. We report a case of filiform polyposis occurring in a 56-year-old man with no history or evidence of inflammatory bowel disease. The patient's main symptoms were melena and anemia. We performed an emergency exploratory laparotomy, in which we observed worm-like polyps spread almost along the entire small intestine, and a partial resection of the small intestine to treat bleeding in the bowel was carried out. Two days later, the patient was noted to have melena again, and we performed an abdominal angiographic embolization, successfully stopping the bleeding. Histologic evaluation of the excised specimen revealed chronic inflammatory cells within the lamina propria without hyperplastic or adenomatous epithelial changes. Although the surgery was very successful, careful management of the patient was required, owing to the great risk of re-bleeding. PMID- 25540050 TI - Characterization of ex vivo cultured neuronal- and glial- like cells from human idiopathic epiretinal membranes. AB - BACKGROUND: Characterization of the neuro-glial profile of cells growing out of human idiopathic epiretinal membranes (iERMs) and testing their proliferative and pluripotent properties ex vivo is needed to better understand the pathogenesis of their formation. METHODS: iERMs obtained during uneventful vitrectomies were cultivated ex vivo under adherent conditions and assessed by standard morphological and immunocytochemical methods. The intracellular calcium dynamics of the outgrowing cells was assessed by fluorescent dye Fura-2 in response to acetylcholine (ACh)- or mechano- stimulation. RESULTS: The cells from the iERMs formed sphere-like structures when cultured ex vivo. The diameter of the spheres increased by 5% at day 6 and kept an increasing tendency over a month time. The outgrowing cells from the iERM spheres had mainly glial- and some neuronal- like morphology. ACh- or mechano- stimulation of these cells induced intracellular calcium propagation in both cell types; in the neuronal-like cells resembling action potential from the soma to the dendrites. Immunocytochemistry confirmed presence of glial- and neuronal cell phenotype (GFAP and Nestin-1 positivity, respectively) in the iERMs, as well as presence of pluripotency marker (Sox2). CONCLUSION: iERMs contain cells of neuronal- and glial- like origin which have proliferative and pluripotent potential, show functionality reflected through calcium dynamics upon ACh and mechano- stimulation, and a corresponding molecular phenotype. PMID- 25540052 TI - FRET-based analysis of protein-nucleic acid interactions by genetically incorporating a fluorescent amino acid. AB - Protein-nucleic acid interaction is an important process in many biological phenomena. In this study, a fluorescence resonance energy transfer (FRET)-based protein-DNA binding assay has been developed, in which a fluorescent amino acid is genetically incorporated into a DNA-binding protein. A coumarin-containing amino acid was incorporated into a DNA-binding protein, and the mutant protein specifically produced a FRET signal upon binding to its cognate DNA labeled with a fluorophore. The protein-DNA binding affinity was then measured under equilibrium conditions. This method is advantageous for studying protein-nucleic acid interactions, because it is performed under equilibrium conditions, technically easy, and applicable to any nucleic acid-binding protein. PMID- 25540053 TI - Second-order conditioning of LiCl-induced gaping with flavor and contextual cues. AB - Conditioned gaping occurs through a classically conditioned association between a flavor or a context (CS) and an unconditioned stimulus (US) that produces nausea, such as lithium chloride (LiCl; US). Rats display conditioned gaping to a flavor or context previously associated with nausea; thus, our aim was to investigate whether rats acquire second-order conditioning to a flavor experienced in a nausea-paired context. In Experiment 1, rats were assigned to one of three groups, based upon the contingency of the first order pairing (CS1 context and LiCl) and the contingency of the second-order pairing (CS2 saccharin CS1 context) including: Group Paired/Paired (P/P), Group Paired/Unpaired (P/U) and Group Unpaired/Paired (U/P). In the initial context conditioning, rats were injected with LiCl (Paired) or Saline (Unpaired) prior to a 30 min confinement in a distinctive context (CS1). Drug-free second-order conditioning training among Groups P/P and U/P then consisted of a 5 min intraoral infusion of 0.1 % saccharin (CS2) in the context (CS1), while Group P/U received saccharin in the home cage 24 hr prior to the CS1 exposure. Twenty four hr later, the rats were tested for second-order conditioning during a 2 min taste reactivity (TR) test. Saccharin (CS2) elicited gaping in Group P/P, but not Groups P/U or U/P. Experiment 2 revealed that second-order conditioning was produced in rats given 4 or 8 first-order conditioning trials, but not 2 trials. These results demonstrate that an excitatory contextual CS+ has the potential to confer second-order conditioning to a novel flavor in the absence of any direct pairing with LiCl. PMID- 25540054 TI - Angular photogrammetric analysis of the soft tissue profile in 12-year-old southern Chinese. AB - INTRODUCTION: To quantify average angular measurements that define the soft tissue profiles of 12-year-old southern Chinese and to determine gender differences. MATERIALS AND METHODS: A random population sample of 514 12-year-old children was recruited (about 10% of a Hong Kong Chinese birth cohort). Photographs were taken in natural head posture and 12 soft tissue landmarks were located on the photos to measure 12 angular measurements using ImageJ (V1.45s) for Windows. Approximately 10% of photographs were reanalyzed and method error was calculated. Angular norm values for the 12 parameters were determined and gender differences were assessed using 2 sample T-test with 95% confidence interval. RESULTS: The response rate was 54.1% (278/514). Norm values for the 12 angular measurements were generated. The greatest variability was found for the nasolabial (Cm-Sn-Ls) and labiomental (Li-Sm-Pg) angles. Gender differences were found in 4 angular parameters: vertical nasal angle (N-Prn/TV) (p < 0.05), cervicomental angle (G-Pg/C-Me) (p < 0.001), facial convexity angle (G-Sn-Pg) (p < 0.01) and total facial convexity angle (G-Prn-Pg)(p < 0.01). CONCLUSION: Norm values for 12 angular measurements among 12-year-old southern Chinese children were provided and some variability noted. Gender differences were apparent in several angular measurements. This study has implications in developing norm values for southern Chinese and for comparison with other ethnic groups. PMID- 25540055 TI - Female sex worker's participation in the community mobilization process: two distinct forms of participations and associated contextual factors. AB - BACKGROUND: Community mobilization is a participatory intervention strategy used among Female Sex Workers (FSW's) to address HIV risks through behavior change and self empowerment. This study quantitatively measure and differentiate theoretically defined forms of FSW participation's and identify their contextual associated factors. METHOD: Data was derived from cross-sectional Integrated Bio Behavioral Assessment conducted among FSW's in Andhra Pradesh (AP) (n = 3370), Maharashtra (MH) (n = 3133) and Tamil Nadu (TN) (n = 2140) of India during 2009 2010. Information's about socio-demography, community mobilization and participation experiences were collected. Conceptual model for two contexts of mobilization entailing distinct FSW participations were defined as participation in "collective" and "public" spaces respectively. Bivariate and multiple regression analysis were used. RESULT: The level of participation in "collective" and "public" spaces was lowest in MH (43.9% & 11.7% respectively), higher in TN (82.2% & 22.5% respectively) and AP (64.7% & 33.1%). Bivariate and multivariate regression analysis highlighted the distinct nature of "participations" through their varied associations with FSW mobilization and background status.In MH, street FSWs showed significantly lower collective participation (36.5%) than brothel FSWs (46.8%) and street FSWs showed higher public participation (16.2%) than brothel FSWs (9.7%). In AP both collective and public participation were significantly high among street FSWs (62.7% and 34.7% respectively) than brothel FSW's (55.2% and 25.4% respectively).Regression analysis showed FSWs with "community identity", were more likely to participate in public spaces in TN and AP (AOR 2.4, 1.5-3.8 & AOR 4.9, CI 2.3-10.7) respectively. FSWs with "collective identity" were more likely to participate in collective spaces in TN, MH and AP (AOR 27.2 CI 13.7-53.9; AOR 7.3, CI 3.8-14.3; AOR 5.7 CI 3-10.9 respectively). FSWs exhibiting "collective agency" were more likely to participate in public spaces in TN, MH and AP (AOR 2.3 CI 1-3.4; AOR 4.5- CI 2.6-7.8; AOR 2.2 CI 1.5 3.1) respectively. CONCLUSION: Findings reveal FSWs participation as a dynamic process inherently evolving along with the community mobilization process in match with its contexts. Participation in "Collective" and Public spaces" is indicators, symbolizing FSWs passage from the disease prevention objectives towards empowerment, which would help better understand and evaluate community mobilization interventions. PMID- 25540056 TI - Three-dimensional power Doppler indices at 18-22 weeks' gestation for prediction of fetal growth restriction or pregnancy-induced hypertension. AB - BACKGROUND: We assessed placental perfusion based on placental vascular sonobiopsy (PVS) at 18-22 weeks of gestation in a low-risk population to predict fetal growth restriction (FGR) or pregnancy-induced hypertension [PIH; gestational hypertension (GH) and preeclampsia (PE)]. METHODS: PVS using three dimensional (3D) power Doppler ultrasound with the VOCAL imaging analysis program was performed in 226 pregnancies [FGR, 25; appropriate-for-gestational age (AGA) 191; and large-for-gestational age (LGA), 10] [PIH, 13 (GH, 7 and PE, 6) and non PIH, 213] at 18-22 weeks of gestation. 3D power Doppler indices such as the vascularization index (VI), flow index (FI), and vascularization flow index (VFI) using PVS were calculated in each placenta. RESULTS: There were no significant differences in VI, FI, or VFI values among FGR, AGA, and LGA pregnancies. No significant differences in VI, FI, or VFI values between PHI and non-PIH pregnancies were noted. There were also no significant differences in VI, FI, or VFI values between GH and PE pregnancies. CONCLUSIONS: 3D power Doppler placental vascular indices at 18-22 weeks could not be used to predict high-risk pregnancies that develop FGR or PIH in a low-risk population. PMID- 25540057 TI - Successful ablation at the left coronary sinus cusp of an accessory pathway at the aortic-mitral continuity. PMID- 25540058 TI - Minor Changes in Core Temperature Prior to Cardiac Arrest Influence Outcomes: An Experimental Study. AB - AIM: To investigate whether slight variations in core temperature prior to cardiac arrest (CA) influence short-term outcomes and mitochondrial functions. METHODS AND MATERIALS: Three groups of New Zealand White rabbits (n = 12/group) were submitted to 15 minutes of CA at 38 degrees C (T-38 group), 39 degrees C (T 39), or 40 degrees C (T 40) and 120 minutes of reperfusion. A Sham-operated group (n = 6) underwent only surgery. Restoration of spontaneous circulation (ROSC), survival, hemodynamics, and pupillary reactivity were recorded. Animals surviving to the end of the observation period were euthanized to assess fresh brain and heart mitochondrial functions (permeability transition and oxidative phosphorylation). Markers of brain and heart damages were also measured. RESULTS: The duration of asphyxia required to induce CA was significantly lower in the T 40 group when compared to the T-38 group (P < .05). The rate of ROSC was >80% in all groups (P = nonsignificant [ns]). Survival significantly differed among the T 38, T-39, and T-40 groups: 10 (83%) of 12, 7 (58%) of 12, and 4 (33%) of 12, respectively (log-rank test, P = .027). At the end of the protocol, none of the animals in the T-40 group had pupillary reflexes compared to 8 (67%) of 12 in the T-38 group (P < .05). Troponin and protein S100B were significantly higher in the T-40 versus T-38 group (P < .05). Cardiac arrest significantly impaired both inner mitochondrial membrane integrity and oxidative phosphorylation in all groups. Brain mitochondria disorders were significantly more severe in the T-40 group compared to the T-38 group (P < .05). CONCLUSION: Small changes in body temperature prior to asphyxial CA significantly influence brain mitochondrial functions and short-term outcomes in rabbits. PMID- 25540059 TI - Atorvastatin Reduces the Incidence of Postoperative Atrial Fibrillation in Statin Naive Patients Undergoing Isolated Heart Valve Surgery: A Double-Blind, Placebo Controlled Randomized Trial. AB - BACKGROUND: Atorvastatin has been demonstrated to reduce the incidence of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery, but its effect on isolated heart valve surgery is unknown. METHODS: In a randomized, double-blinded, placebo-controlled trial, 58 patients who underwent isolated heart valve surgery supported by on-pump cardiopulmonary bypass were randomly assigned to receive either placebo (n = 29) or 40 mg of atorvastatin once daily starting 3 days preoperatively and continuing within 5 days postoperatively (n = 29). A continuous monitoring tool and an electrocardiographic Holter monitoring were used for detecting the POAF (Clinical Trial Registration: www.clinicaltrials.gov; Unique Identifier: NTC02084069). RESULTS: The patients' median age was 49 years, and 67% were female. In all, 6 (21%) and 13 (45%) cases of POAF were observed in the atorvastatin and placebo groups, respectively (P = .050). The duration of AF before re-establishment of sinus rhythm was significantly lower in the atorvastatin group than in the placebo group (median of 70 vs 132 minutes, P = .026). The lengths of intensive care unit and hospital stay were comparable between the groups. The increase in postoperative white blood cell count was significantly lower in the atorvastatin group than in the placebo group (median of 1.5 vs 2.3 * 10(3)/uL, respectively, P = .019). After adjustment, the atorvastatin treatment was associated with a decrease in the risk of developing POAF (odds ratio 0.122, 95% confidence interval 0.027-0.548, P = .006). CONCLUSION: Perioperative treatment with 40 mg of atorvastatin is useful to decrease the incidence of POAF in the statin-naive patients undergoing isolated heart valve surgery. PMID- 25540060 TI - Analysis of psilocin, bufotenine and LSD in hair. AB - A method for the simultaneous extraction of the hallucinogens psilocin, bufotenine, lysergic acid diethylamide (LSD) as well as iso-LSD, nor-LSD and O-H LSD from hair with hydrochloride acid and methanol is presented. Clean-up of the hair extracts is performed with solid phase extraction using a mixed-mode cation exchanger. Extracts are measured with liquid chromatography coupled with electrospray tandem mass spectrometry. The method was successfully validated according to the guidelines of the 'Society of Toxicological and Forensic Chemistry' (GTFCh). To obtain reference material hair was soaked in a solution of the analytes in dimethyl sulfoxide/methanol to allow incorporation into the hair. These fortified hair samples were used for method development and can be employed as quality controls. PMID- 25540061 TI - Acute 3,4-methylenedioxy-N-ethylcathinone (ethylone) intoxication and related fatality: a case report with postmortem concentrations. AB - A 30-year-old man reportedly ingested pills and used illicit drugs with another person. They both fell asleep that night and the following afternoon the other person found him dead. There were used hypodermic needles and a metal spoon with dark tarry substance at the death scene, and two recent puncture sites were found on his body. It was uncertain if he had a history of illicit drug use. Postmortem blood initially screened borderline positive for methamphetamine by ELISA. An alkaline drug screen-detected ethylone which was subsequently confirmed and quantified by a specific GC-MS SIM analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (0.39 mg/L), central blood (0.38 mg/L), liver (1.4 mg/kg), vitreous (0.58 mg/L), urine (20 mg/L) and gastric contents (12 mg). Other compounds detected in peripheral blood were morphine (0.05 mg/L), alprazolam (<0.05 mg/L), delta-9-THC (<1 ng/mL), delta-9-carboxy-THC (3.6 ng/mL) and naproxen (<5 mg/L). A urine screen (GC-MS) also confirmed 6 monoacetylmorphine, codeine and sildenafil. The cause of death was certified due to mixed ethylone, heroin and alprazolam intoxication. The manner of death was certified as accident. PMID- 25540062 TI - Effects of racing games on risky driving behaviour, and the significance of personality and physiological data. AB - BACKGROUND: Racing games have emerged as top-selling products in the video and computer game industry. The effect of playing racing games on the inclination of gamers to take risks has been investigated. METHOD: Two experiments were conducted. In experiment 1, the impact of personality traits on the effects of playing racing games on risk-taking inclination was examined. The Vienna Test System, which includes the Eysenck Personality Profile Test and the Vienna Risk Taking Test, was used to measure risk-taking inclination and risk-taking while driving. Experiment 2 was designed and conducted to analyse the effects of different intensity levels of car racing games on risk-taking inclination, and to study the relationship between physiological data and risk-taking inclination. Physiological data on skin conductance, heart rate and blood pressure were measured with the NeuroDyne System. RESULTS: Participants playing a racing game were more inclined to take risks in critical road traffic situations than those playing a neutral game. The adventurousness dimension of the Eysenck Personality Profile Test correlated significantly positively with risk-taking inclination. More importantly, the effect of the intensity level of a racing game on risk taking inclination was significant. The higher the intensity level of the racing game, the higher the risk-taking inclination while driving. The effect of intensity level of the racing game on skin conductance was significantly positive. Skin conductance correlated significantly positively with risk-taking inclination. CONCLUSIONS: The effect of playing racing games on risk-taking inclination is linked to personality and physiological data. Some recommendations are proposed as a result of this study for racing game management. PMID- 25540063 TI - Epidemiology of non-fatal US emergency room visits for road crashes involving pedestrians in wheelchairs. AB - This study aims to quantify and describe the risk of non-fatal pedestrian injury among persons who use wheelchairs in the US. Cases of pedestrian injury between 2002 and 2010 among persons using wheelchairs were identified in the National Electronic Injury Surveillance System to generate national injury estimates. Between 2002 and 2010, an estimated 9348 (95% CI 4912 to 13,784) people were treated in emergency departments for non-fatal pedestrian injuries sustained while using wheelchairs. Using wheelchair-use denominators calculated from the Survey of Income and Program Participation, this equates to an incidence rate of 31.3 (95% CI 16.4 to 46.1) per 100,000 person-years. Injury risk was 3.5 times higher for men than women (p<0.001). Contusions, abrasions, and lacerations (42.7%) and fractures (16.4%) were most common. The head and neck (24.7%) and lower extremities (28.4%) were most often injured. A fifth (21.4%) of injuries required hospitalisation, and 89.2% occurred in traffic on public roadways. PMID- 25540064 TI - A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome positive chronic myeloid leukemia. AB - This phase 1/2 study evaluated the safety and pharmacokinetics (part 1) and efficacy and safety (part 2) of bosutinib in Japanese Philadelphia chromosome positive (Ph+) chronic-phase (CP) or advanced-phase chronic myeloid leukemia (CML) patients resistant/intolerant to previous imatinib (2L) or imatinib+dasatinib/nilotinib (3L). Based on dose-limiting toxicities and previous studies, the part 2 bosutinib starting dose was 500 mg/day (n = 63). For CP CML 2L (n = 28), the cumulative major cytogenetic response (MCyR) rate by week 24 was 36 % (primary endpoint); the cumulative major molecular response (MMR) rate through the study was 43 %. Transformation to accelerated/blast phase (AP/BP) was observed in one patient. Progression-free survival (PFS) and overall survival (OS) rates at 96 weeks were 94 and 96 %, respectively. Of seven advanced-phase 2L patients, one had confirmed complete hematologic response at week 84, and one had AP/BP transformation. PFS and OS rates at week 96 were 21 and 43 %. For 3L (n = 11), cumulative MCyR rate by week 24 was 18 %; cumulative MMR rate was 18 %; no transformations occurred. Common non-hematologic adverse events (AEs) were diarrhea (95 %), rash (57 %), and nasopharyngitis (51 %). Sixteen patients discontinued due to adverse events; no deaths occurred within 30 days of the last dose. Bosutinib 500 mg/day demonstrated efficacy and manageable toxicity in Japanese Ph+ CML patients resistant/intolerant to imatinib. PMID- 25540065 TI - A meta-analysis comparing clinical characteristics and outcomes in CALR-mutated and JAK2V617F essential thrombocythaemia. AB - A systematic review and meta-analysis were carried out to compare the clinical features and outcomes in calreticulin (CALR)-mutated and JAK2V617F patients of essential thrombocythemia (ET). Compared with JAK2V617F ET patients, CALR-mutated ET was associated with a clear increase in male predominance [OR 1.71 (95 % CI 1.28-2.28), P < 0.001, I(2)) = 51.6] and a significant decrease in thrombosis events [OR 0.40 (95 % CI 0.32-0.50), P < 0.001, I(2) = 0]. No difference was observed in hemorrhagic events [OR 0.86 (95 % CI 0.52-1.42), P = 0.558, I(2) = 0] or splenomegaly [OR 0.8 (95 % CI 0.55-1.14), P = 0.217 I (2) = 42.9]. CALR mutated ET did not show better overall survival (OS) [HR 1.03 (95 % CI 0.74-1.44) P = 0.854, I(2) = 47.6] but showed better thrombosis-free survival (TFS) [HR 0.62 (0.44-0.87), P = 0.005, I(2) = 0] than JAK2V617F ET. In conclusion, CALR-mutated ET and JAK2V617F ET may represent two different subgroups of essential thrombocythaemia with respect to clinical features and outcomes. PMID- 25540066 TI - Improved prediction of clinical outcome in chronic myeloid leukemia. AB - We sought to develop and compare prognostic models, based on clinical and/or morphometric diagnostic data, to enable better prediction of complete cytogenetic response (CCgR). This prospective longitudinal study included a consecutive series of patients with chronic myeloid leukemia (CML) who were started on imatinib therapy. Logistic regression analysis using backward selection was performed with CCgR at 6, 12, and 18 months as the outcome variables. We evaluated both calibration and discrimination of the model. Internal validation of the model was performed with bootstrapping techniques. A total of 40 patients on imatinib therapy were included in the final analysis. Of these, 25 (62.5 %), 29 (72.5 %), and 32 (80 %), respectively, achieved CCgR at 6, 12, and 18 months after initiation of imatinib. Models included EUTOS score on diagnosis and one of the following morphometric parameters: microvascular density, length of the minor axis, area or circularity of the blood vessel. Models including morphometric parameters and EUTOS score were superior for prediction of CCgR at 6, 12, and 18 months. In particular, the superior models showed better specificity than EUTOS score alone. Using morphometric parameters in conjunction with EUTOS score improves prediction of CCgR. If validated, these models could aid in individual patient risk stratification. PMID- 25540067 TI - Advanced airway management is necessary in prehospital trauma patients. AB - BACKGROUND: Treatment of airway compromise in trauma patients is a priority. Basic airway management is provided by all emergency personnel, but the requirement for on-scene advanced airway management is controversial. We attempted to establish the demand for on-scene advanced airway interventions. Trauma patients managed with standard UK paramedic airway interventions were assessed to determine whether airway compromise had been effectively treated or whether more advanced airway management was required. METHODS: A prospective observational study was conducted to identify trauma patients requiring prehospital advanced airway management attended by a doctor-paramedic team. The team assessed and documented airway compromise on arrival, interventions performed before and after their arrival, and their impact on airway compromise. RESULTS: Four hundred and seventy-two patients required advanced airway intervention and received 925 airway interventions by ground-based paramedics. Two hundred and sixty-nine patients (57%) still had airway compromise on arrival of the enhanced care team; no oxygen had been administered to 52 patients (11%). There were 45 attempted intubations by ground paramedics with a 64% success rate and 11% unrecognized oesophageal intubation rate. Doctor-paramedic teams delivering prehospital anaesthesia achieved definitive airway management for all patients. CONCLUSIONS: A significant proportion of severely injured trauma patients required advanced airway interventions to effectively treat airway compromise. Standard ambulance service interventions were only effective for a proportion of patients, but might not have always been applied appropriately. Complications of advanced airway management occurred in both provider groups, but failed intubation and unrecognized oesophageal intubation were a particular problem in the paramedic intubation group. PMID- 25540069 TI - Postoperative pain after laparoscopic cholecystectomy is not reduced by intraoperative analgesia guided by analgesia nociception index (ANI(r)) monitoring: a randomized clinical trial. AB - BACKGROUND: Laparoscopic cholecystectomy frequently results in significant immediate postoperative pain. A new pain monitor, analgesic nociception index (ANI(r)), based on heart rate variability, has recently been approved for intraoperative nociception monitoring. We designed a single-blind, parallel group, randomized control trial to test the hypothesis that protocol-driven intraoperative analgesia guided by ANI during laparoscopic cholecystectomy would improve titration of intraoperative analgesics leading to decreased postoperative pain. METHODS: One hundred and twenty consecutive adult participants presenting for elective laparoscopic cholecystectomy were recruited. Participants were randomly allocated by sealed envelope to receive intraoperative morphine either guided by ANI via a protocol (intervention group) or guided by the anaesthetist with ANI concealed (control group). All participants received paracetamol, parecoxib, fentanyl at induction, and local anaesthetic to port sites. The primary endpoint was the presence of moderate/severe pain (visual analogue scale >=50 mm) at any of the four time points in the first postoperative hour. Secondary endpoints included postoperative rescue morphine. RESULTS: Sixty participants were randomized to each group, and all but one drop-out from the intervention group were analysed. The usage of ANI guidance did not result in a decrease in the rate of moderate/severe pain (50.8% vs 45.0%: difference of 5.8%, 95% confidence interval, -23.7% to 12.1%, P=0.58), or the use of postoperative rescue analgesia. CONCLUSIONS: This randomized control trial of intraoperative ANI-guided morphine administration in elective laparoscopic cholecystectomy failed to show any advantage over the current standard of care, and demonstrated a high level of postoperative pain, despite the use of multimodal analgesia. CLINICAL TRIAL REGISTRATION: ANZCTR Reference ACTRN12612000953831 (URL: http://www.anzctr.org.au/trial_view.aspx?ID=362949). PMID- 25540068 TI - Emergence from general anaesthesia and evolution of delirium signs in the post anaesthesia care unit. AB - BACKGROUND: Emergence from anaesthesia is often accompanied by signs of delirium, including fluctuating mental status and inattention. The evolution of these signs of delirium requires investigation since delirium in the post-anaesthesia care unit (PACU) may be associated with worse outcomes. METHODS: Adult patients emerging from anaesthesia were assessed for agitated emergence in the operating room using the Richmond Agitation-Sedation Scale (RASS). The Confusion Assessment Method for the Intensive Care Unit was then used to evaluate delirium signs at PACU admission and during PACU stay at 30 min, 1 h, and discharge. Signs consistent with delirium were classified as hyperactive vs hypoactive based upon a positive CAM-ICU assessment and the concomitant RASS score. Multivariable logistic regression was utilized to assess potential risk factors for delirium during PACU stay including age, American Society of Anesthesiologists classification, and opioid and benzodiazepine exposure. RESULTS: Among 400 patients enrolled, 19% had agitated emergence. Delirium signs were present at PACU admission, 30 min, 1 h, and PACU discharge in 124 (31%), 59 (15%), 32 (8%), and 15 (4%) patients, respectively. In patients with delirium signs, hypoactive signs were present in 56% at PACU admission and in 92% during PACU stay. Perioperative opioids were associated with delirium signs during PACU stay (P=0.02). CONCLUSIONS: A significant proportion of patients develop delirium signs in the immediate postoperative period, primarily manifesting with a hypoactive subtype. These signs often persist to PACU discharge, suggesting the need for structured delirium monitoring in the PACU to identify patients potentially at risk for worse outcomes in the postoperative period. PMID- 25540070 TI - Local knowledge and exploitation of the avian fauna by a rural community in the semi-arid zone of northeastern Brazil. AB - BACKGROUND: The present study examined the exploitation of bird species by the residents of a rural community in the Brazilian semi-arid zone, and their preferences for species with different characteristics. METHODS: The 24 informants were identified using the "snowball" approach, and were interviewed using semi-structured questionnaires and check-sheets for the collection of data on their relationship with the bird species that occur in the region. The characteristics that most attract the attention of the interviewees were the song and the coloration of the plumage of a bird, as well as its body size, which determines its potential as a game species, given that hunting is an important activity in the region. RESULTS: A total of 98 species representing 32 families (50.7% of the species known to occur in the region) were reported during interviews, being used for meat, pets, and medicinal purposes. Three species were used as zootherapeutics - White-naped Jay was eaten whole as a cure for speech problems, the feathers of Yellow-legged Tinamou were used for snakebite, Smooth billed Ani was eaten for "chronic cough" and Small-billed Tinamou and Tataupa Tinamou used for locomotion problems. The preference of the informants for characteristics such as birdsong and colorful plumage was a significant determinant of their preference for the species exploited. Birds with cynegetic potential and high use values were also among the most preferred species. Despite the highly significant preferences for certain species, some birds, such as those of the families Trochilidae, Thamnophilidae, and Tyrannidae are hunted randomly, independently of their attributes. CONCLUSION: The evidence collected on the criteria applied by local specialists for the exploitation of the bird fauna permitted the identification of the species that suffer hunting pressure, providing guidelines for the development of conservation and management strategies that will guarantee the long-term survival of the populations of these bird species in the region. PMID- 25540071 TI - Robot-assisted ultrasound imaging: overview and development of a parallel telerobotic system. AB - Ultrasound imaging is frequently used in medicine. The quality of ultrasound images is often dependent on the skill of the sonographer. Several researchers have proposed robotic systems to aid in ultrasound image acquisition. In this paper we first provide a short overview of robot-assisted ultrasound imaging (US). We categorize robot-assisted US imaging systems into three approaches: autonomous US imaging, teleoperated US imaging, and human-robot cooperation. For each approach several systems are introduced and briefly discussed. We then describe a compact six degree of freedom parallel mechanism telerobotic system for ultrasound imaging developed by our research team. The long-term goal of this work is to enable remote ultrasound scanning through teleoperation. This parallel mechanism allows for both translation and rotation of an ultrasound probe mounted on the top plate along with force control. Our experimental results confirmed good mechanical system performance with a positioning error of < 1 mm. Phantom experiments by a radiologist showed promising results with good image quality. PMID- 25540072 TI - Modest association between the discharge modified Rankin Scale score and symptomatic intracerebral hemorrhage after intravenous thrombolysis. AB - BACKGROUND: Thirty- and 90-day modified Rankin Scale (mRS) scores are used to monitor adverse outcome or symptomatic intracerebral hemorrhage (sICH) in ischemic stroke patients after intravenous (IV) thrombolytic therapy. Discharge mRS scores are more readily available and could serve as a proxy for 30- or 90 day mRS data. Our goal was to evaluate agreement between the discharge mRS score and sICH. Additionally, we tested for correlations between the discharge mRS score and 8 clinical scores developed to predict sICH or adverse outcomes based on 90-day mRS data. METHODS: Clinical data were analyzed from 210 patients receiving IV thrombolysis from January 2009 till December 2013 at the Yale New Haven Hospital. Agreement between sICH and the discharge mRS score was assessed using linear kappa. Eight clinical scores were calculated for each patient and compared with the discharge mRS score by univariate logistic regression. Goodness of fit was tested by receiver operating characteristic (ROC) analysis and by Hosmer-Lemeshow statistics. RESULTS: We found only modest agreement between sICH and unfavorable discharge mRS scores (mRS >= 5), with kappa .22, P = .0001. All 8 clinical scores tested showed good agreement with discharge mRS score of 5 or more (ROC area >.7). CONCLUSIONS: The discharge mRS score shows only modest agreement with sICH and therefore cannot be recommended as a proxy for 30- or 90 day mRS data. However, the discharge mRS score correlates strongly with clinical scores predicting long-term adverse outcome; therefore, assessment of discharge mRS scores may be of some clinical benefit. PMID- 25540073 TI - Integrative analysis of high-throughput RNAi screen data identifies the FER and CRKL tyrosine kinases as new regulators of the mitogenic ERK-dependent pathways in transformed cells. AB - BACKGROUND: Cell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells. RESULTS: The functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth. CONCLUSION: Based on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations. PMID- 25540074 TI - Devices for stem cell isolation and delivery: current need for drug discovery and cell therapy. AB - Isolation and purification of stem cells and their delivery into diseased or aged tissues or organs need special devices for proper transplantation of stem cells in order to achieve high cell retention at transplant site for repair or regeneration of tissues and organs. The clinical and preclinical importance of special devices such as Celution System, Isolex cell separation device, magnetic surface-enhanced Raman spectroscopic dots, microfluidic devices, immunomagnetic cell separation for stem cell separation and isolation are the main focus in this paper. Further, devices like trans-coronary delivery, trans-endocardial delivery, intracoronary delivery devices for stem cell application to the heart are described. Devices for stem cell application to the brain, the spinal cord and other tissues are also explained. We highlighted scaffolds with incorporated stem cells and other encapsulation devices used to transplant stem cells. Current needs of devices for stem cells isolation, purification and delivery for drug discovery and cell therapy are discussed. PMID- 25540075 TI - Chlamydia pneumoniae infection of monocytes in vitro stimulates innate and adaptive immune responses relevant to those in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which infection with Chlamydia pneumoniae (Cpn) has been associated. Cpn is an obligate intracellular respiratory pathogen that may enter the central nervous system (CNS) following infection and trafficking of monocytes through the blood brain barrier. Following this entry, these cells may secrete pro-inflammatory cytokines and chemokines that have been identified in the AD brain, which have been thought to contribute to AD neurodegeneration. The objectives of this work were: (i) to determine if Cpn infection influences monocyte gene transcript expression at 48 hours post-infection and (ii) to analyze whether pro inflammatory cytokines are produced and secreted from these cells over 24 to 120 hours post-infection. METHODS: Gene transcription was analyzed by RT-PCR using an innate and adaptive immunity microarray with 84 genes organized into 5 functional categories: inflammatory response, host defense against bacteria, antibacterial humoral response, septic shock, and cytokines, chemokines and their receptors. Statistical analysis of the results was performed using the Student's t-test. P values <= 0.05 were considered to be significant. ELISA was performed on supernatants from uninfected and Cpn-infected THP1 monocytes followed by statistical analysis with ANOVA. RESULTS: When Cpn-infected THP1 human monocytes were compared to control uninfected monocytes at 48 hours post-infection, 17 genes were found to have a significant 4-fold or greater expression, and no gene expression was found to be down-regulated. Furthermore, cytokine secretion (IL 1beta, IL-6, IL-8) appears to be maintained for an extended period of infection. CONCLUSIONS: Utilizing RT-PCR and ELISA techniques, our data demonstrate that Cpn infection of THP1 human monocytes promotes an innate immune response and suggests a potential role in the initiation of inflammation in sporadic/late-onset Alzheimer's disease. PMID- 25540078 TI - Transcatheter aortic valve implantation mortality risk score: are we ready to gaze into our next "crystal ball"? PMID- 25540076 TI - Patient factors associated with SSRI dose for depression treatment in general practice: a primary care cross sectional study. AB - BACKGROUND: Antidepressant prescribing continues to rise. Increased long-term prescribing and higher doses are contributing to current growth; however, patient factors associated with the use of higher doses remain unknown. This study's aim was to investigate patient factors associated with selective serotonin re-uptake inhibitor (SSRI) prescribed daily dose for depression treatment in general practice. METHODS: A stratified sample of low to high prescribing practices were selected. Routine individual patient-level data were extracted one practice at a time: September 2009 to January 2011. Patients included were >=18 years, and prescribed an SSRI for depression. Logistic regression analysis was undertaken to assess individual predictor variables on SSRI daily dose by standard therapeutic dose versus higher dose, as SSRIs demonstrate flat dose response curves for depression treatment. Predictor variables included: age, gender, deprivation, co morbidity, smoking status, being prescribed the same SSRI for >=2 years, and patients' general practice. For a subgroup of patients a second sub-group analysis included long-term benzodiazepine and/or z-hypnotic (B&Z) as a predictor variable. RESULTS: Inter-practice SSRI prescribing varied significantly; practice point prevalence ranged from 2.5% (94/3697) to 11.9% (359/3007) of the practice population >=18 years old; median 7.3% (250/3421) (chi2 = 2277.2, df = 10, p < 0.001). Overall point prevalence was 6.3% (3518/52575), with 5.8% (3066/52575) prescribed SSRIs for depression of whom 84.7% (2596/3066) had data for regression analysis. Higher SSRI doses were significantly associated with, in descending order of magnitude, individual practice attended, being prescribed the same SSRI for >=2 years (Odds Ratio (OR) 1.80, 95% CI 1.49 to 2.17, p < 0.001) and living in a more deprived area (OR 1.55, 95% CI 1.11 to 2.16, p = 0.009). Higher SSRI doses in the B&Z subgroup were significantly associated with individual practice attended, being prescribed a long-term B&Z (OR 2.05 95% CI 1.47 to 2.86, p < 0.001) and being prescribed the same SSRI for >=2 years (OR 1.94, 95% CI 1.53 to 2.47, p < 0.001). CONCLUSION: Higher SSRI doses for depression were associated with practice attended and being prescribed the same antidepressant for >=2 years. As long-term antidepressant use increases, the use of higher doses may further contribute to prescribing growth. PMID- 25540077 TI - Assessment of genetic variation within a global collection of lentil (Lens culinaris Medik.) cultivars and landraces using SNP markers. AB - BACKGROUND: Lentil is a self-pollinated annual diploid (2n = 2* = 14) crop with a restricted history of genetic improvement through breeding, particularly when compared to cereal crops. This limited breeding has probably contributed to the narrow genetic base of local cultivars, and a corresponding potential to continue yield increases and stability. Therefore, knowledge of genetic variation and relationships between populations is important for understanding of available genetic variability and its potential for use in breeding programs. Single nucleotide polymorphism (SNP) markers provide a method for rapid automated genotyping and subsequent data analysis over large numbers of samples, allowing assessment of genetic relationships between genotypes. RESULTS: In order to investigate levels of genetic diversity within lentil germplasm, 505 cultivars and landraces were genotyped with 384 genome-wide distributed SNP markers, of which 266 (69.2%) obtained successful amplification and detected polymorphisms. Gene diversity and PIC values varied between 0.108-0.5 and 0.102-0.375, with averages of 0.419 and 0.328, respectively. On the basis of clarity and interest to lentil breeders, the genetic structure of the germplasm collection was analysed separately for cultivars and landraces. A neighbour-joining (NJ) dendrogram was constructed for commercial cultivars, in which lentil cultivars were sorted into three major groups (G-I, G-II and G-III). These results were further supported by principal coordinate analysis (PCoA) and STRUCTURE, from which three clear clusters were defined based on differences in geographical location. In the case of landraces, a weak correlation between geographical origin and genetic relationships was observed. The landraces from the Mediterranean region, predominantly Greece and Turkey, revealed very high levels of genetic diversity. CONCLUSIONS: Lentil cultivars revealed clear clustering based on geographical origin, but much more limited correlation between geographic origin and genetic diversity was observed for landraces. These results suggest that selection of divergent parental genotypes for breeding should be made actively on the basis of systematic assessment of genetic distance between genotypes, rather than passively based on geographical distance. PMID- 25540079 TI - Transcatheter valve-in-valve implantation for failing prosthetic valves. PMID- 25540080 TI - Transcatheter mitral valve-in-ring with the Melody prosthesis: a new therapeutic opportunity. PMID- 25540081 TI - Successful first-in-man Melody transcatheter valve implant in a dehisced mitral annuloplasty ring transapical valve-in-ring implant. AB - AIMS: A "valve-in-ring" (ViR) procedure involves the transcatheter implant of a valved stent in a prosthetic mitral ring. The presence of a partial dehiscence of the prosthetic ring is a major contraindication for a ViR due to inefficacious sealing. We describe an alternative method of ViR implant to achieve proper valve sealing in the case of ring dehiscence. METHODS AND RESULTS: A 76-year-old male patient suffered from severe central mitral regurgitation due to annuloplasty ring dehiscence and leaflet tethering. ECG-gated multidetector computed tomography was used for preoperative planning. Standard transapical access was gained through a minimally invasive left thoracotomy in the 5th intercostal space. A customised Melody valve with two PTFE sutures fixed to the apex was used. The intervention was performed without complications, the patient recovered well, and transthoracic echo revealed no mitral regurgitation through the implanted valve with a transvalvular gradient of 4 mmHg. CONCLUSIONS: The implantation of a long covered stent such as the Melody valve allows successful sealing following a ViR even in case of partially detached annuloplasty rings. This procedure is a proof of concept that proper sealing can be achieved at the leaflet level without the use of radial force at the annular level. PMID- 25540082 TI - Successful first-in-man percutaneous transapical-transseptal Melody mitral valve in-ring implantation after complicated closure of a para-annular ring leak. AB - AIMS: Transcatheter techniques can theoretically be applied to the treatment of para-annular ring (PAR) leaks. Little is known about their potential application and resultant complications in such cases. We describe the first-in-man percutaneous transapical-transseptal Melody valve-in-ring (ViR) implantation after a complication from percutaneous PAR leak closure. METHODS AND RESULTS: A 49-year-old woman, at high operative risk, presented with congestive heart failure secondary to severe para-ring/extravalvular regurgitation two months after bypass surgery and mitral ring annuloplasty. Successful percutaneous closure of the leak was performed using an AMPLATZER Vascular Plug IV. One month later, she developed haemolysis with severe PAR regurgitation, through and around the device. After device retrieval and placement of an AMPLATZER Muscular VSD occluder, the patient developed severe intravalvular regurgitation. Completely percutaneous, transseptal delivery of a Melody ViR was performed over a transapical-transseptal, arteriovenous rail. Echocardiography revealed trivial residual regurgitation through the implanted valve with mild transvalvular gradients. CONCLUSIONS: Percutaneous closure of mitral PAR leaks after ring annuloplasty in the high-risk patient is feasible (proof-of-concept), particularly when the leak is para-ring/extravalvular. Potential complications include severe intravalvular mitral regurgitation caused by disruption of the mitral apparatus and/or ring deformation during device deployment, which can be successfully treated via percutaneous transapical-transseptal ViR implantation. PMID- 25540083 TI - Failing transcatheter aortic valve treated by transcatheter aortic valve in transcatheter aortic valve (TAV-in-TAV) implantation: valve safety versus valve durability. PMID- 25540084 TI - Self-expandable valve implantation within a failed balloon-expandable valve. PMID- 25540086 TI - The evaluation of hepatic fibrosis scores in children with nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in children and can progress to liver cirrhosis during childhood. Patients with more advanced fibrosis on biopsy tend to have more liver complications. Noninvasive hepatic fibrosis scores have been developed for adult patients with NAFLD; however, these scores have not been validated in children. The aim of our study was to evaluate some of these scores in assessing the presence of fibrosis in children with biopsy-proven NAFLD. METHODS: Our study consisted of 92 biopsy-proven NAFLD children from five major US centers. Fibrosis was determined by an experienced pathologist (F0-4). Clinically significant fibrosis was defined as fibrosis stage >= 2, and advanced fibrosis was defined as F3-4. The following fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 index. ROC was performed to assess the performance of different scores for prediction of presence of any, significant, or advanced fibrosis. A p value < 0.05 was considered statistically significant. RESULTS: Mean age was 13.3 +/- 3 years, and 33 % were females. Eleven (12 %) subjects had no fibrosis, 35 (38 %) had fibrosis score of 1, 26 (28 %) had fibrosis score of 2, and 20 (22 %) had a score of 3. APRI had a fair diagnostic accuracy for the presence of any fibrosis (AUC of 0.80) and poor diagnostic accuracy for significant or advanced fibrosis. AST/ALT, NFS, and FIB-4 index all either had poor diagnostic accuracy or failed to diagnose the presence of any, significant, or advanced fibrosis. CONCLUSION: Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing significant fibrosis in children with NAFLD. Our results highlight the urgent need to develop a reliable pediatric fibrosis score. PMID- 25540085 TI - Screening for colorectal cancer in African Americans: determinants and rationale for an earlier age to commence screening. AB - Colorectal cancer (CRC) screening is a cost-effective approach to reduce morbidity, mortality, and prevalence of CRC in populations. Current recommendations for asymptomatic populations begin screening at age 50 years, after which ~95% of cancers occur. Determinants that modify timing and frequency for screening include: personal/family history of adenomas or CRC, age of onset of lesions, and presence or potential to harbor high-risk conditions like inflammatory bowel disease (IBD), familial adenomatous polyposis (FAP), or Lynch syndrome. Although race, like family history, is heritable, it has not engendered inclusion in systematic screening recommendations despite multiple studies demonstrating disparity in the incidence and mortality from CRC, and the potential for targeted screening to reduce disparity. African Americans, when compared to Caucasians, have lower CRC screening utilization, younger presentation for CRC, higher CRC prevalence at all ages, and higher proportion of CRCs before age 50 years (~11 vs. 5%); are less likely to transmit personal/family history of adenomas or CRC that may change screening age; show excess of high-risk proximal adenomas, matched with 7-15% excess right-sided CRCs that lack microsatellite instability; show higher frequencies of high-risk adenomas for every age decile; and demonstrate genetic biomarkers associated with metastasis. These epidemiological and biological parameters put African Americans at higher risk from CRC irrespective of socioeconomic issues, like IBD, FAP, and Lynch patients. Including race as a factor in national CRC screening guidelines and commencing screening at an age earlier than 50 years seems rational based on the natural history and aggressive behavior in this population. PMID- 25540087 TI - Complete resection of colorectal adenomas: what are the important factors in fellow training? AB - BACKGROUND: The complete removal of adenomatous polyps is important for reducing interval cancer after colonoscopy. AIMS: To identify factors affecting the completeness of colonoscopic polypectomies and to evaluate the experience level of fellows who achieve competence compared with that of experts. METHODS: Medical records of 1,860 patients who underwent at least one polypectomy for an adenomatous polyp at Seoul National University Hospital between March 2011 and February 2013 were retrospectively reviewed. A total of 3,469 adenomatous polyps were included. The lateral and deep margins of the resected polyps were evaluated to check the resection completeness. RESULTS: Of the 3,469 adenomatous polyps, 1,389 (40.0 %) were removed by two experts and 2,080 (60.0 %) were removed by seven fellows. In the expert-treated group, larger size [odds ratio (OR) 2.81 for >=20 mm, 95 % confidence interval (CI) 1.64-4.84, P < 0.001] and right-sided location (OR 1.31, 95 % CI 1.05-1.63, P = 0.019) were associated with incomplete resection. In the fellow-treated group, not only polyp characteristics [right sided location (OR 1.41, 95 % CI 1.18-1.69, P < 0.001)], but also the cumulative number of procedures was also related to resection completeness. After 300 polypectomies, the complete resection rate of the fellows was comparable to that of the experts. CONCLUSIONS: In the fellow-treated group, the level of procedure experience was closely associated with the polypectomy outcomes. Meticulous attention is critical to ensure the completeness of polypectomies performed by trainee endoscopists during the training program. PMID- 25540088 TI - Indirect competitive assays on DVD for direct multiplex detection of drugs of abuse in oral fluids. AB - On-site oral fluid testing for drugs of abuse has become prominent in order to take immediate administrative action in an enforcement process. Herein, we report a DVD technology-based indirect competitive immunoassay platform for the quantitative detection of drugs of abuse. A microfluidic approach was adapted to prepare multiplex immunoassays on a standard DVD-R, an unmodified multimode DVD/Blu-Ray drive to read signal, and a free disc-quality analysis software program to process the data. The DVD assay platform was successfully demonstrated for the simultaneous, quantitative detection of drug candidates (morphine and cocaine) in oral fluids with high selectivity. The detection limit achieved was as low as 1.0 ppb for morphine and 5.0 ppb for cocaine, comparable with that of standard mass spectrometry and ELISA methods. PMID- 25540090 TI - Crisis in the provision of intensive care services: the case for high-dependency care. AB - Several reports have recently highlighted the problem of providing sufficient intensive care beds to meet the needs of critically ill patients (Bennett, 1995; Department of Health (DoH), 1995a). In response to these reports, the British Association of Critical Care Nurses (BACCN) issued a position statement which expressed the belief that: PMID- 25540091 TI - Managed care 1: an opportunity for nursing. AB - Managed care is a clinical system that is currently gaining popularity in the UK. The emphasis is on quality patient care and containment of costs by reducing fragmentation of care delivery. This article describes some of the tools of a managed care system and will focus on a description of a care map and the background to the development of the concept. PMID- 25540089 TI - (Cost)-effectiveness of a multi-component intervention for adults with epilepsy: study protocol of a Dutch randomized controlled trial (ZMILE study). AB - BACKGROUND: In patients with epilepsy, poor adherence to anti-epileptic drugs has been shown to be the most important cause of poorly controlled epilepsy. Furthermore, it has been noted that the quality of life among patients with epilepsy can be improved by counseling and treatments aimed at increasing their self-efficacy and concordance, thus stimulating self-management skills. However, there is a need for evidence on the effectiveness of such programs, especially within epilepsy care. Therefore, we have developed a multi-component intervention (MCI) which combines a self-management/education program with e-Health interventions. Accordingly, the overall objective of this study is to assess the (cost)-effectiveness and feasibility of the MCI, aiming to improve self-efficacy and concordance in patients with epilepsy. METHODS: A RCT in two parallel groups will be conducted to compare the MCI with a control condition in epilepsy patients. One hundred eligible epilepsy patients will be recruited and allocated to either the intervention or control group. The intervention group will receive the MCI consisting of a self-management/education program of six meetings, including e-Health interventions, and will be followed for 12 months. The control group will receive care as usual and will be followed for 6 months, after which patients will be offered the possibility of participating in the MCI. The study will consist of three parts: 1) a clinical effectiveness study, 2) a cost effectiveness study, and 3) process evaluation. The primary outcome will be self efficacy. Secondary outcomes include adherence, side effects, change in seizure severity & frequency, improved quality of life, proactive coping, and societal costs. Outcome assessments will be done using questionnaires at baseline and after 3, 6, 9, and 12 months (last two applicable only for intervention group). DISCUSSION: In times of budget constraints, MCI could be a valuable addition to the current healthcare provision for epilepsy, as it is expected that higher concordance and self-efficacy will result in reduced use of healthcare resources and an increased QOL. Accordingly, this study is aimed helping patients to be their own provider of health care, shifting epilepsy management from professionals to self-care by patients equipped with appropriate skills and tools. TRIAL REGISTRATION NUMBER: NTR4484 . PMID- 25540092 TI - Etiological classification of depression based on the enzymes of tryptophan metabolism. AB - BACKGROUND: Viewed in terms of input and output, the mechanisms of depression are still akin to a black box. However, there must be main pivots for diverse types of depression. From recent therapeutic observations, both the serotonin (5-HT) and kynurenine pathways of tryptophan metabolism may be of particular importance to improved understanding of depression. Here, I propose an etiological classification of depression, based on key peripheral and central enzymes of tryptophan metabolism. DISCUSSION: Endogenous depression is caused by a larger genetic component than reactive depression. Besides enterochromaffin and mast cells, tryptophan hydroxylase 1 (TPH1), primarily expressed in the gastrointestinal tract, is also found in 5-hydroxytryptophan-producing cells (5 HTP cells) in normal intestinal enterocytes, which are thought to essentially shunt 5-HT production in 5-HT-producing cells. Genetic studies have reported an association between TPH1 and depression, or the responsiveness of depression to antidepressive medication. Therefore, it is possible that hypofunctional 5-HTP cells (reflecting TPH1 dysfunction) in the periphery lead to deficient brain 5-HT levels. Additionally,it has been reported that higher TPH2 expression in depressed suicides may reflect a homeostatic response to deficient 5-HT levels. Subsequently, endogenous depression may be caused by TPH1 dysfunction combined with compensatory TPH2 activation. Reactive depression results from life stresses and involves the hypothalamic-pituitary-adrenal axis, with resulting cortisol production inducing tryptophan 2,3-dioxygenase (TDO) activation. In secondary depression, caused by inflammation, infection, or oxidative stress, indoleamine 2,3-dioxygenase (IDO) is activated. In both reactive and secondary depression, the balance between 3-hydroxykynurenine (3-HK) and kynurenic acid may shift towards 3-HK production via kynurenine-3-monooxygenase (KMO) activation. By shifting the equilibrium position of key enzymes of tryptophan metabolism, the classical classification of depression can be reorganized, as below. Peripheral classification of depression by key enzymes: TPH1 dysfunction, TDO activation, IDO activation. Central classification: TPH2 activation, KMO activation. SUMMARY: Etiological classification of depression expressed by peripheral (TPH1, TDO, IDO) and central (TPH2, KMO)enzymes of tryptophan metabolism may enable depression to be viewed as a clear box, with the inner components available for inspection and treatment. PMID- 25540094 TI - Multilevel modeling and value of information in clinical trial decision support. AB - BACKGROUND: Clinical trials are the main method for evaluating safety and efficacy of medical interventions and have produced many advances in improving human health. The Women's Health Initiative overturned a half-century of harmful practice in hormone therapy, the National Lung Screening Trial identified the first successful lung cancer screening tool and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial overturned decades-long assumptions. While some trials identify unforeseen safety issues or harms, many fail to demonstrate efficacy. Large trials require substantial resources; to ensure reliable outcomes, we must seek ways to improve the predictive information used as the basis of trials. RESULTS: Here we demonstrate a modeling framework for linking knowledge of underlying biological mechanism to evaluate the expectation of trial outcomes. Key features include the ability to propagate uncertainty in biological mechanism to uncertainty in trial outcome and mechanisms for identifying knowledge gaps most responsible for unexpected outcomes. The framework was used to model the effect of selenium supplementation for prostate cancer prevention and parallels the Selenium and Vitamin E Cancer Prevention Trial that showed no efficacy despite suggestive data from secondary endpoints in the Nutritional Prevention of Cancer trial and found increased incidence of high-grade prostate cancer in certain subgroups. CONCLUSION: Using machine learning methods, we identified the parameters of the model that are most predictive of trial outcome and found that the top four are directly related to the rates of reactions producing methylselenol and transporting extracellular selenium into the cell as selenide. This modeling process demonstrates how the approach can be used in advance of a large clinical trial to identify the best targets for conducting further research to reduce the uncertainty in the trial outcome. PMID- 25540095 TI - Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: challenges and solutions 2014. AB - Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are a defining feature of ANCA associated vasculitides (AAV). They play a pivotal role in disease pathophysiology and have strongly improved early diagnosis and treatment of these infrequent, but potentially fatal diseases. Neutrophils and their products are major players in initiating the autoimmune response and tissue destruction in vasculitic as well as granulomatous inflammation. This review highlights recent findings on old and novel players (ANCA, neutrophils, neutrophil extracellular traps, fibroblasts, immune cells and complement) and puts them into context with the current understanding of disease mechanisms in AAV. PMID- 25540093 TI - The role of the Nrf2/Keap1 pathway in obesity and metabolic syndrome. AB - Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key regulator of antioxidant signaling that may prevent the development of metabolic syndrome and related cardiovascular diseases. However, emerging evidence shows that lack of Nrf2 could ameliorate insulin resistance, adipogenesis and adipocyte differentiation. Consistent with this, overexpression of Nrf2 gene could also cause insulin resistance under certain conditions. Furthermore, an increasing number of studies indicate that redox balance can be a critical element that contributes to the contradictory effects of Nrf2 on insulin sensitivity and resistance. Reactive oxygen species can promote normal insulin-mediated signal transduction under physiological conditions but also induce insulin resistance under certain pathological conditions. Therefore, the contradictory effects of Nrf2 on insulin signaling pathways may be related to its regulation of redox homeostasis. This review attempts to summarize the latest developments in our understanding of the mechanisms of Nrf2-mediated signaling and its role in the modulation of metabolic homeostasis. PMID- 25540096 TI - Paradoxical response to furosemide in uromodulin-associated kidney disease. AB - Mutations in the UMOD gene coding for uromodulin cause autosomal dominant tubulointerstitial kidney disease. Uromodulin is known to regulate transport processes in the thick ascending limb, but it remains unknown whether UMOD mutations are associated with functional tubular alterations in the early phase of the disease. The responses to furosemide and to a water deprivation test were compared in a 32-year-old female patient carrying the pathogenic UMOD mutation p.C217G and her unaffected 31-year-old sister. A single dose of furosemide induced an intense headache with exaggerated decrease in blood pressure (Deltasyst: 30 versus 20 mmHg; Deltadiast: 18 versus 5 mmHg) and body weight (Delta2.6 kg versus Delta0.9 kg over 3 h) in the proband versus unaffected sib. The diuretic response and the fall in urine osmolality were also more important and detected earlier in the affected sib. Water deprivation led to increased plasma osmolality and urine concentration in both siblings; however, the response to desmopressin was attenuated in the affected sib. These data reveal that mutations of uromodulin cause specific transport alterations, including exaggerated response to furosemide and a failure to maximally concentrate urine, in the early phase of the disease. PMID- 25540097 TI - Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden. AB - OBJECTIVES: The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden. METHODS: In the health care districts surrounding the Skane University Hospital in Lund [mean population >=18 years (1997-2008), 188 400] and the University Hospital in Linkoping [mean population >=18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period. RESULTS: Eighty-two patients (Lund 44 + Linkoping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linkoping 14). The annual incidence rate per million inhabitants aged >=18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020. CONCLUSIONS: In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage. PMID- 25540099 TI - Effect of bariatric surgery combined with medical therapy versus intensive medical therapy or calorie restriction and weight loss on glycemic control in Zucker diabetic fatty rats. AB - Bariatric surgery rapidly improves Type 2 diabetes mellitus (T2DM). Our objective was to profile and compare the extent and duration of improved glycemic control following Roux-en-Y gastric (RYGB) bypass surgery and vertical sleeve gastrectomy (SG) and compare against calorie restriction/weight loss and medical combination therapy-based approaches using the Zucker diabetic fatty rat (ZDF) rodent model of advanced T2DM. Male ZDF rats underwent RYGB (n = 15) or SG surgery (n = 10) at 18 wk of age and received postsurgical insulin treatment, as required to maintain mid-light-phase glycemia within a predefined range (10-15 mmol/l). In parallel, other groups of animals underwent sham surgery with ad libitum feeding (n = 6), with body weight (n = 8), or glycemic matching (n = 8) to the RYGB group, using food restriction or a combination of insulin, metformin, and liraglutide, respectively. Both bariatric procedures decreased the daily insulin dose required to maintain mid-light-phase blood glucose levels below 15 mmol/l, compared with those required by body weight or glycemia-matched rats (P < 0.001). No difference was noted between RYGB and SG with regard to initial efficacy. SG was, however, associated with higher food intake, weight regain, and higher insulin requirements vs. RYGB at study end (P < 0.05). Severe hypoglycemia occurred in several rats after RYGB. RYGB and SG significantly improved glycemic control in a rodent model of advanced T2DM. While short-term outcomes are similar, long-term efficacy appears marginally better after RYGB, although this is tempered by the increased risk of hypoglycemia. PMID- 25540098 TI - Impaired myogenic response and autoregulation of cerebral blood flow is rescued in CYP4A1 transgenic Dahl salt-sensitive rat. AB - We have reported that a reduction in renal production of 20-HETE contributes to development of hypertension in Dahl salt-sensitive (SS) rats. The present study examined whether 20-HETE production is also reduced in the cerebral vasculature of SS rats and whether this impairs the myogenic response and autoregulation of cerebral blood flow (CBF). The production of 20-HETE, the myogenic response of middle cerebral arteries (MCA), and autoregulation of CBF were compared in SS, SS 5(BN) rats and a newly generated CYP4A1 transgenic rat. 20-HETE production was 6 fold higher in cerebral arteries of CYP4A1 and SS-5(BN) than in SS rats. The diameter of the MCA decreased to 70 +/- 3% to 65 +/- 6% in CYP4A1 and SS-5(BN) rats when pressure was increased from 40 to 140 mmHg. In contrast, the myogenic response of MCA isolated from SS rats did not constrict. Administration of a 20 HETE synthesis inhibitor, HET0016, abolished the myogenic response of MCA in CYP4A1 and SS-5(BN) rats but had no effect in SS rats. Autoregulation of CBF was impaired in SS rats compared with CYP4A1 and SS-5(BN) rats. Blood-brain barrier leakage was 5-fold higher in the brain of SS rats than in SS-5(BN) and SS.CYP4A1 rats. These findings indicate that a genetic deficiency in the formation of 20 HETE contributes to an impaired myogenic response in MCA and autoregulation of CBF in SS rats and this may contribute to vascular remodeling and cerebral injury following the onset of hypertension. PMID- 25540100 TI - Guanylin activates Cl(-) secretion into the lumen of seawater eel intestine via apical Cl(-) channel under simulated in vivo conditions. AB - Guanylin (GN) action on seawater eel intestine was examined under simulated in vivo conditions, where isotonic luminal fluid has low NaCl and high MgSO4 (MgSO4 Ringer). In Ussing chamber, MgSO4 Ringer induced serosa-negative potential difference (PD) even after bumetanide treatment, which is due to the higher paracellular Na(+) permeability over Cl(-), as confirmed by the replacement by MgCl2 (no Cl(-) gradient) or Na2SO4 Ringer (no Na(+) gradient). Luminal GN reversed serosa-negative PD, probably by enhancing Cl(-) secretion into the lumen, as the GN effect was blocked by apical Cl(-) channel blockers [diphenylamine-2-carboxylic acid (DPC), 5-nitro-2-(3-phenylpropylamino) benzoic acid, glibenclamide but not cystic fibrosis transmembrane regulator (CFTR)inh 172] or replacement of luminal fluid by MgCl2 Ringer. The blockers' effect was undetectable when normal Ringer was on both sides. In the sac preparation, NaCl secretion occurred into the lumen (Na(+) > Cl(-)), and GN further enhanced Cl(-) secretion (Cl(-) > Na(+)), resulting in water secretion. These GN effects were also blocked by DPC. Quantitative analyses showed that isotonic NaCl is absorbed when luminal fluid is normal Ringer, but, when luminal fluid is MgSO4 Ringer, hypertonic NaCl, almost equivalent to seawater, is secreted into the lumen after GN. These results indicate that GN stimulates the secretion of hypertonic NaCl into the lumen of seawater eel intestine, like rectal gland of marine elasmobranchs, to get rid of excess NaCl although marine teleost intestine is thought to have only absorptive-type cells with a unique Na-K-Cl cotransport system. The secreted NaCl may activate the cotransport system and further help absorb water in the final segment of seawater eel intestine. PMID- 25540101 TI - Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity. AB - Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca(2+) concentration ([Ca(2+)]i) in single vagal afferent neurons. The Oxt-induced [Ca(2+)]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca(2+)]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity. PMID- 25540102 TI - The effect of chronic treadmill exercise and acetaminophen on collagen and cross linking in rat skeletal muscle and heart. AB - The purpose of this study was to determine whether exercise and/or acetaminophen (APAP) alter collagen and cross-linking in the rat gastrocnemius muscle, soleus muscle, and heart. Male Wistar rats (n = 50; 8 wk old) were divided into placebo (PLA) or APAP groups and sedentary (SED) or exercised (RUN) groups. APAP (200 mg/kg) was administered daily by oral gavage. Exercised groups ran on a treadmill 5 days/wk for 8 wk with progression to 60 min/day, 20 m/min, and 8 degrees incline. Tissues were assayed for collagen (hydroxyproline) and hydroxylyslpyridinoline (HP) and lysylpyridinoline (LP) cross-links by HPLC. Collagen content (MUg/mg dry weight) was greater in both the gastrocnemius (SED PLA: 114 +/- 16 vs. RUN-PLA: 244 +/- 32; P < 0.001) and soleus (SED-PLA: 51 +/- 7 vs. RUN-PLA: 99 +/- 27; P = 0.005) of exercised animals. In contrast, collagen content was not significantly greater in exercised animals treated with APAP (SED APAP: 113 +/- 16 vs. RUN-APAP: 145 +/- 21) and soleus (SED-APAP: 55 +/- 8 vs. RUN APAP: 57 +/- 10). HP cross-linking (mmol/mol collagen) in the gastrocnemius (SED PLA: 126 +/- 28, RUN-PLA: 50 +/- 7, SED-APAP: 41 +/- 7, and RUN-APAP: 30 +/- 4) and soleus muscles (SED-PLA: 547 +/- 107, RUN-PLA: 318 +/- 92, SED-APAP: 247 +/- 64, and RUN-APAP: 120 +/- 17) was lower in exercised rats compared with sedentary rats (P < 0.05). Cross-linking was further reduced in animals treated with APAP (P < 0.05). Neither heart collagen nor cross-linking was influenced by exercise or APAP (P > 0.05). Our findings suggest that exercise and APAP have tissue specific effects on muscle collagen. Given the widespread use of APAP as an analgesic and antipyretic, further work in humans is warranted. PMID- 25540104 TI - Billing and insurance-related administrative costs in United States' health care: synthesis of micro-costing evidence. AB - BACKGROUND: The United States' multiple-payer health care system requires substantial effort and costs for administration, with billing and insurance related (BIR) activities comprising a large but incompletely characterized proportion. A number of studies have quantified BIR costs for specific health care sectors, using micro-costing techniques. However, variation in the types of payers, providers, and BIR activities across studies complicates estimation of system-wide costs. Using a consistent and comprehensive definition of BIR (including both public and private payers, all providers, and all types of BIR activities), we synthesized and updated available micro-costing evidence in order to estimate total and added BIR costs for the U.S. health care system in 2012. METHODS: We reviewed BIR micro-costing studies across healthcare sectors. For physician practices, hospitals, and insurers, we estimated the % BIR using existing research and publicly reported data, re-calculated to a standard and comprehensive definition of BIR where necessary. We found no data on % BIR in other health services or supplies settings, so extrapolated from known sectors. We calculated total BIR costs in each sector as the product of 2012 U.S. national health expenditures and the percentage of revenue used for BIR. We estimated "added" BIR costs by comparing total BIR costs in each sector to those observed in existing, simplified financing systems (Canada's single payer system for providers, and U.S. Medicare for insurers). Due to uncertainty in inputs, we performed sensitivity analyses. RESULTS: BIR costs in the U.S. health care system totaled approximately $471 ($330 - $597) billion in 2012. This includes $70 ($54 $76) billion in physician practices, $74 ($58 - $94) billion in hospitals, an estimated $94 ($47 - $141) billion in settings providing other health services and supplies, $198 ($154 - $233) billion in private insurers, and $35 ($17 - $52) billion in public insurers. Compared to simplified financing, $375 ($254 - $507) billion, or 80%, represents the added BIR costs of the current multi-payer system. CONCLUSIONS: A simplified financing system in the U.S. could result in cost savings exceeding $350 billion annually, nearly 15% of health care spending. PMID- 25540103 TI - Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. AB - Despite compelling evidence that oxytocin (OT) is effective in reducing body weight (BW) in diet-induced obese (DIO) rodents, studies of the effects of OT in humans and rhesus monkeys have primarily focused on noningestive behaviors. The goal of this study was to translate findings in DIO rodents to a preclinical translational model of DIO. We tested the hypothesis that increased OT signaling would reduce BW in DIO rhesus monkeys by inhibiting food intake and increasing energy expenditure (EE). Male DIO rhesus monkeys from the California National Primate Research Center were adapted to a 12-h fast and maintained on chow and a daily 15% fructose-sweetened beverage. Monkeys received 2* daily subcutaneous vehicle injections over 1 wk. We subsequently identified doses of OT (0.2 and 0.4 mg/kg) that reduced food intake and BW in the absence of nausea or diarrhea. Chronic administration of OT for 4 wk (0.2 mg/kg for 2 wk; 0.4 mg/kg for 2 wk) reduced BW relative to vehicle by 3.3 +/- 0.4% (~0.6 kg; P < 0.05). Moreover, the low dose of OT suppressed 12-h chow intake by 26 +/- 7% (P < 0.05). The higher dose of OT reduced 12-h chow intake by 27 +/- 5% (P < 0.05) and 8-h fructose sweetened beverage intake by 18 +/- 8% (P < 0.05). OT increased EE during the dark cycle by 14 +/- 3% (P < 0.05) and was associated with elevations of free fatty acids and glycerol and reductions in triglycerides suggesting increased lipolysis. Together, these data suggest that OT reduces BW in DIO rhesus monkeys through decreased food intake as well as increased EE and lipolysis. PMID- 25540105 TI - Seasonal changes of diagnostic potential in the detection of Anoplocephala perfoliata equine infections in the climate of Central Europe. AB - For this study, 724 gastrointestinal tracts of slaughter horses were investigated to determine the prevalence, intensity of Anoplocephala perfoliata and tapeworm development stages over the second, third and fourth quarter of 2012 and the first quarter of 2013. For each positive horse, faecal samples were collected from the rectum or small colon for coproscopic examinations. The samples were analysed using dedicated modified sedimentation-flotation methods. In total, 52 horses were infected with A. perfoliata in the course of the study, with an overall prevalence of 7.2 %. The prevalence changed over the study period; however, not markedly. The overall mean of A. perfoliata abundance was 12.3 (3.23) and did not differ significantly between the quarters. Mean invasion intensity did not differ significantly between the quarters. The quantity of mature tapeworms did not differ significantly over the study period; however, there was a significant difference in the number of immature tapeworms. The highest number of mature tapeworms was found in the first quarter of 2013. The number of detected tapeworm eggs rose significantly over the study period. The total number of tapeworms did not have a significant influence on the presence/absence of detected eggs. However, there was a noticeable difference between the number of mature tapeworms and presence/absence of eggs in faeces. This clearly indicates that the efficacy of the modified sedimentation-flotation method is influenced by seasonality, and therefore the most effective and reliable time for detection of A. perfoliata in equines is the first quarter of the year. PMID- 25540107 TI - Editorial comment. PMID- 25540108 TI - Editorial comment. PMID- 25540109 TI - Editorial comment. PMID- 25540106 TI - The prediction of treatment outcomes by early maladaptive schemas and schema modes in obsessive-compulsive disorder. AB - BACKGROUND: Higher levels of early maladaptive schemas (EMS) and schema modes according to schematherapy by Jeffrey Young are present in obsessive-compulsive disorder (OCD) compared to healthy controls. This study examines the relationship of EMS and schema modes to OC symptom severity and the predictive value of EMS and schema modes on treatment outcome in inpatients receiving Cognitive Behavioral Therapy (CBT) with Exposure and Response Prevention (ERP). The main assumption was a negative association between the EMS of the domain 'disconnection' and dysfunctional coping and parent schema modes and the treatment outcome. METHODS: EMS, schema modes, depression and traumatic childhood experiences were measured in 70 patients with OCD. To analyze the predictors, two regression analyses were conducted considering multiple variables, such as depression, as covariates. RESULTS: Regression analyses demonstrated that higher scores on the EMS named failure and emotional inhibition and depressive symptom severity at pretreatment were significantly related to poor outcome and explained a high percentage of the variance in OC symptoms at posttreatment. No influence on the treatment outcome was observed for schema modes, other EMS or other covariates. CONCLUSIONS: The results support the approach to extend the CBT with ERP treatment with therapeutic elements focusing on maladaptive schemas, particularly in non-responders. PMID- 25540112 TI - Editorial comment. PMID- 25540115 TI - New editorial board 2015-2017. PMID- 25540113 TI - Characterization of the substitution pattern of cellulose derivatives using carbohydrate-binding modules. AB - BACKGROUND: Derivatized celluloses, such as methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC), are of pharmaceutical importance and extensively employed in tablet matrices. Each batch of derivatized cellulose is thoroughly characterized before utilized in tablet formulations as batch-to-batch differences can affect drug release. The substitution pattern of the derivatized cellulose polymers, i.e. the mode on which the substituent groups are dispersed along the cellulose backbone, can vary from batch-to-batch and is a factor that can influence drug release. RESULTS: In the present study an analytical approach for the characterization of the substitution pattern of derivatized celluloses is presented, which is based on the use of carbohydrate-binding modules (CBMs) and affinity electrophoresis. CBM4-2 from Rhodothermus marinus xylanase 10A is capable of distinguishing between batches of derivatized cellulose with different substitution patterns. This is demonstrated by a higher migration retardation of the CBM in acrylamide gels containing batches of MC and HPMC with a more heterogeneous distribution pattern. CONCLUSIONS: We conclude that CBMs have the potential to characterize the substitution pattern of cellulose derivatives and anticipate that with use of CBMs with a very selective recognition capacity it will be possible to more extensively characterize and standardize important carbohydrates used for instance in tablet formulation. PMID- 25540114 TI - The Dynamic Family Home: a qualitative exploration of physical environmental influences on children's sedentary behaviour and physical activity within the home space. AB - BACKGROUND: Recent changes in home physical environments, such as decreasing outdoor space and increasing electronic media, may negatively affect health by facilitating sedentariness and reducing physical activity. As children spend much of their time at home they are particularly vulnerable. This study qualitatively explored family perceptions of physical environmental influences on sedentary behaviour and physical activity within the home space. METHODS: Home based interviews were conducted with 28 families with children aged 9-13 years (total n = 74 individuals), living in Perth, Australia. Families were stratified by socioeconomic status and selected to provide variation in housing. Qualitative methods included a family interview, observation and home tour where families guided the researcher through their home, enabling discussion while in the physical home space. Audio recordings were transcribed verbatim and thematically analysed. RESULTS: Emergent themes related to children's sedentariness and physical activity included overall size, space and design of the home; allocation of home space; equipment within the home space; perceived safety of the home space; and the changing nature of the home space. Families reported that children's activity options were limited when houses and yards were small. In larger homes, multiple indoor living rooms usually housed additional sedentary entertainment options, although parents reported that open plan home layouts could facilitate monitoring of children's electronic media use. Most families reported changing the allocation and contents of their home space in response to changing priorities and circumstances. CONCLUSIONS: The physical home environment can enhance or limit opportunities for children's sedentary behaviour and physical activity. However, the home space is a dynamic ecological setting that is amenable to change and is largely shaped by the family living within it, thus differentiating it from other settings. While size and space were considered important, how families prioritise the use of their home space and overcome the challenges posed by the physical environment may be of equal or greater importance in establishing supportive home environments. Further research is required to tease out how physical, social and individual factors interact within the family home space to influence children's sedentary behaviour and physical activity at home. PMID- 25540116 TI - Bioreactor expansion of human mesenchymal stem cells according to GMP requirements. AB - In cell therapy, the use of autologous and allogenic human mesenchymal stem cells is rising. Accordingly, the supply of cells for clinical applications in highest quality is required. As hMSCs are considered as an advanced therapy medicinal products (ATMP), they underlie the requirements of GMP and PAT according to the authorities (FDA and EMA). The production process of these cells must therefore be documented according to GMP, which is usually performed via a GMP protocol based on standard operating procedures. This chapter provides an example of such a GMP protocol for hMSC, here a genetically modified allogenic cell line, based on a production process in a microcarrier-based stirred tank reactor including process monitoring according to PAT and final product quality assurance. PMID- 25540117 TI - Induced Pluripotent Stem Cells from Nonhuman Primates. AB - Induced pluripotent stem cells from nonhuman primates (NHPs) have unique roles in cell biology and regenerative medicine. Because of the relatedness of NHPs to humans, NHP iPS cells can serve as a source of differentiated derivatives that can be used to address important questions in the comparative biology of primates. Additionally, when used as a source of cells for regenerative medicine, NHP iPS cells serve an invaluable role in translational experiments in cell therapy. Reprogramming of NHP somatic cells requires the same conditions as previously established for human cells. However, throughout the process, a variety of modifications to the human cell protocols must be made to accommodate significant species differences. PMID- 25540119 TI - Adjuvant treatment of chronic osteomyelitis of the tibia following exogenous trauma using OSTEOSET((r))-T: a review of 21 patients in a regional trauma centre. AB - Surgical debridement and prolonged systemic antibiotic therapy are an established management strategy for infection after tibial fractures. Local antibiotic delivery via cement beads has shown improved outcome but requires further surgery for extraction of beads. OSTEOSET((r))-T is a resorbable bone void filler composed of calcium sulphate and 4 % tobramycin that is packed easily into bone defects. This is a review of the outcomes of 21 patients treated with OSTEOSET((r))-T for osteomyelitis of the tibia. This is a retrospective case note and clinical review. In all cases, the strategy was debridement, with removal of any implants, with excision back to bleeding bone. OSTEOSET((r))-T pellets were packed into any contained defects or the intra-medullary canal with further bony stabilisation (n = 9) and soft tissue reconstruction (n = 7) undertaken as required. Intravenous vancomycin and meropenem were administered after sampling with substitution to targeted antibiotic therapy for between 6 weeks and 6 months. The average follow-up was 15 months. Union rate after tibial reconstruction was 100 %. Wound complications were encountered in 52 %: a wound discharge in the early post-operative period was noted in seven patients (33 %) independent of site of pellet placement. In the 14 cases without a wound leak, five developed wound complications (p = 0.06, Fisher's exact test) either from delayed wound-healing or pin-site infections. One patient developed a transient acute kidney injury and one refractory osteomyelitis. OSTEOSET((r))-T is an effective adjunct in the treatment of chronic tibial osteomyelitis following trauma based on the low incidence of relapse of infection within the period of follow-up in this study, but significant wound complications and one transient nephrotoxic event were also recorded. PMID- 25540120 TI - Surgical treatment of intra-articular calcaneal fractures: description of a technique using an adjustable uniplanar external fixator. AB - Several surgical techniques are available for the treatment of intra-articular calcaneal fractures. The use of a uniplanar external fixator is an option for the treatment of fractures classified as Sanders types 2 and 3. Satisfactory reduction and stabilisation of the fracture are achieved by means of mini incisions and fixator adjustment. The advantages of this technique include less soft-tissue damage, avoidance of internal implants and early weight-bearing with the potential to improve postoperative recovery. PMID- 25540118 TI - GA(3) enhances root responsiveness to exogenous IAA by modulating auxin transport and signalling in Arabidopsis. AB - KEY MESSAGE: We used auxin-signalling mutants, auxin transport mutants, and auxin related marker lines to show that exogenously applied GA enhances auxin-induced root inhibition by affecting auxin signalling and transport. Variation in root elongation is valuable when studying the interactions of phytohormones. Auxins influence the biosynthesis and signalling of gibberellins (GAs), but the influence of GAs on auxins in root elongation is poorly understood. This study was conducted to investigate the effect of GA3 on Arabidopsis root elongation in the presence of auxin. Root elongation was inhibited in roots treated with both IAA and GA3, compared to IAA alone, and the effect was dose dependent. Further experiments showed that GA3 could modulate auxin signalling based on root elongation in auxin-signalling mutants and the expression of auxin-responsive reporters. The GA3-enhanced inhibition of root elongation observed in the wild type was not found in the auxin-signalling mutants tir1-1 and axr1-3. GA3 increased DR5::GUS expression in the root meristem and elongation zones, and IAA2::GUS in the columella. The DR5rev::GFP signal was enhanced in columella cells of the root caps and in the elongation zone in GA3-treated seedling roots. A reduction was observed in the stele of PAC-treated roots. We also examined the effect of GA3 on auxin transport. The enhanced responsiveness caused by GA3 was not observed in the auxin influx mutant aux1-7 or the efflux mutant eir1-1. Additional molecular data demonstrated that GA3 could promote auxin transport via AUX1 and PIN proteins. However, GA3-induced PIN gene expression did not fully explain GA-enhanced PIN protein accumulation. These results suggest that GA3 is involved in auxin-mediated primary root elongation by modulating auxin signalling and transport, and thus enhances root responsiveness to exogenous IAA. PMID- 25540121 TI - Pseudo-arthrosis of the spine of the scapula: a case report with a delayed diagnosis. AB - Scapular spine fractures are rare injuries. The aim of this study was to evaluate a late-diagnosed scapular spine pseudo-arthrotic patient. Because of the surrounding soft tissue mass and overlapping of the scapula with the thoracal bones on a roentgenogram, diagnosis may be missed or delayed for years. We present a case of scapular spine pseudo-arthrosis in a 50-year-old man, who sustained a traffic accident 2 years ago. He was treated as a soft tissue injury of the left shoulder and later as a rotator cuff tear. His scapular spine fracture was diagnosed as pseudo-arthrosis of the scapular spine with a diagnostic delay of 2 years. Isolated scapular spine fractures are rare, usually associated with other injuries and frequently treated non-operatively. Sagging of the acromion as a result of a scapular spine fracture may mimic supraspinatus outlet impingement. If a painful pseudo-arthrosis limits the function of a shoulder, fractured ends should be fixed until union occurs. Although scapular spine fractures are rarely seen, they must take place in the differential diagnosis of impingement syndromes of the shoulder. PMID- 25540123 TI - Multifinality of peer victimization: maladjustment patterns and transitions from early to mid-adolescence. AB - Peer victimization is a common and pervasive experience in childhood and adolescence and is associated with various maladjustment symptoms, including internalizing, externalizing, and somatic problems. This variety suggests that peer victimization is multifinal where exposure to the same risk leads to different outcomes. However, very little is known about the relative likelihood of each form of maladjustment. We used a latent profile approach to capture multiple possible outcomes and examined prediction by peer victimization. We also examined the role of peer victimization with regard to stability and change in maladjustment. Maladjustment symptoms and peer victimization were assessed from the participants of the large cohort study TRacking Adolescents' Individual Lives Survey in early and mid-adolescence. Latent profile and latent transition analyses were conducted to examine associations between victimization and maladjustment profile and to test the role of victimization in maladjustment profile transitions. Four maladjustment profiles were identified for early adolescence (Low, Internalizing, Externalizing, Comorbid) and three profiles (Low, Internalizing, Externalizing) were identified for mid-adolescence. Internalizing problems were more likely in victimized adolescents than low symptom levels or externalizing problems. Victimized adolescents were at greater risk to develop internalizing problems between early and mid-adolescence than non victimized adolescents. Peer victimization is multifinal mostly when outcomes are examined separately. If multiple outcomes are tested simultaneously, internalizing problems seem to be the most likely outcome. PMID- 25540124 TI - Nlrx1 regulates neuronal cell death. AB - BACKGROUND: Regulation of cell death during neurodegeneration is one of the key factors that play a role in the speed at which a disease progresses. Out of several cellular pathways responsible for this progression, necrosis and apoptosis are situated on the opposite spectrum of cell death regulation. Necrosis produces an environment that promotes inflammation and cytotoxicity and apoptosis is a highly organized process that maintains tissue homeostasis. A recently discovered protein, Nlrx1, regulates inflammatory and cell death responses during infection. FINDINGS: Using transfections of N2A cell line, we demonstrate that Nlrx1 redirects cells away from necrosis and towards an apoptotic pathway following rotenone treatments. In addition, Nlrx1 promotes DRP1 phosphorylation and increases mitochondrial fission. CONCLUSION: Our results suggest a novel molecular pathway for regulating mitochondrial dynamics and neuronal death. Nlrx1 may play an important role in neurodegenerative diseases, where necrosis is a prominent factor. PMID- 25540125 TI - Algorithm-supported visual error correction (AVEC) of heart rate measurements in dogs, Canis lupus familiaris. AB - Dog heart rate (HR) is characterized by a respiratory sinus arrhythmia, and therefore makes an automatic algorithm for error correction of HR measurements hard to apply. Here, we present a new method of error correction for HR data collected with the Polar system, including (1) visual inspection of the data, (2) a standardized way to decide with the aid of an algorithm whether or not a value is an outlier (i.e., "error"), and (3) the subsequent removal of this error from the data set. We applied our new error correction method to the HR data of 24 dogs and compared the uncorrected and corrected data, as well as the algorithm supported visual error correction (AVEC) with the Polar error correction. The results showed that fewer values were identified as errors after AVEC than after the Polar error correction (p < .001). After AVEC, the HR standard deviation and variability (HRV; i.e., RMSSD, pNN50, and SDNN) were significantly greater than after correction by the Polar tool (all p < .001). Furthermore, the HR data strings with deleted values seemed to be closer to the original data than were those with inserted means. We concluded that our method of error correction is more suitable for dog HR and HR variability than is the customized Polar error correction, especially because AVEC decreases the likelihood of Type I errors, preserves the natural variability in HR, and does not lead to a time shift in the data. PMID- 25540126 TI - A comparison of scanpath comparison methods. AB - Interest has flourished in studying both the spatial and temporal aspects of eye movement behavior. This has sparked the development of a large number of new methods to compare scanpaths. In the present work, we present a detailed overview of common scanpath comparison measures. Each of these measures was developed to solve a specific problem, but quantifies different aspects of scanpath behavior and requires different data-processing techniques. To understand these differences, we applied each scanpath comparison method to data from an encoding and recognition experiment and compared their ability to reveal scanpath similarities within and between individuals looking at natural scenes. Results are discussed in terms of the unique aspects of scanpath behavior that the different methods quantify. We conclude by making recommendations for choosing an appropriate scanpath comparison measure. PMID- 25540127 TI - Partial genetic suppression of a loss-of-function mutant of the neuronal ceroid lipofuscinosis-associated protease TPP1 in Dictyostelium discoideum. AB - Neuronal ceroid lipofuscinosis (NCL) is the most common childhood-onset neurodegenerative disease. NCL is inevitably fatal, and there is currently no treatment available. Children with NCL show a progressive decline in movement, vision and mental abilities, and an accumulation of autofluorescent deposits in neurons and other cell types. Late-infantile NCL is caused by mutations in the lysosomal protease tripeptidyl peptidase 1 (TPP1). TPP1 cleaves tripeptides from the N-terminus of proteins in vitro, but little is known about the physiological function of TPP1. TPP1 shows wide conservation in vertebrates but it is not found in Drosophila, Caenorhabditis elegans or Saccharomyces cerevisiae. Here, we characterize ddTpp1, a TPP1 ortholog present in the social amoeba Dictyostelium discoideum. Lysates from cells lacking ddTpp1 show a reduced but not abolished ability to cleave a TPP1 substrate, suggesting that other Dictyostelium enzymes can perform this cleavage. ddTpp1 and human TPP1 localize to the lysosome in Dictyostelium, indicating conserved function and trafficking. Cells that lack ddTpp1 show precocious multicellular development and a reduced ability to form spores during development. When cultured in autophagy-stimulating conditions, cells lacking ddTpp1 rapidly decrease in size and are less viable than wild-type cells, suggesting that one function of ddTpp1 could be to limit autophagy. Cells that lack ddTpp1 exhibit strongly impaired development in the presence of the lysosome-perturbing drug chloroquine, and this phenotype can be suppressed through a secondary mutation in the gene that we name suppressor of tpp1(-) A (stpA), which encodes a protein with some similarity to mammalian oxysterol binding proteins (OSBPs). Taken together, these results suggest that targeting specific proteins could be a viable way to suppress the effects of loss of TPP1 function. PMID- 25540128 TI - In vitro treatment of HepG2 cells with saturated fatty acids reproduces mitochondrial dysfunction found in nonalcoholic steatohepatitis. AB - Activity of the oxidative phosphorylation system (OXPHOS) is decreased in humans and mice with nonalcoholic steatohepatitis. Nitro-oxidative stress seems to be involved in its pathogenesis. The aim of this study was to determine whether fatty acids are implicated in the pathogenesis of this mitochondrial defect. In HepG2 cells, we analyzed the effect of saturated (palmitic and stearic acids) and monounsaturated (oleic acid) fatty acids on: OXPHOS activity; levels of protein expression of OXPHOS complexes and their subunits; gene expression and half-life of OXPHOS complexes; nitro-oxidative stress; and NADPH oxidase gene expression and activity. We also studied the effects of inhibiting or silencing NADPH oxidase on the palmitic-acid-induced nitro-oxidative stress and subsequent OXPHOS inhibition. Exposure of cultured HepG2 cells to saturated fatty acids resulted in a significant decrease in the OXPHOS activity. This effect was prevented in the presence of a mimic of manganese superoxide dismutase. Palmitic acid reduced the amount of both fully-assembled OXPHOS complexes and of complex subunits. This reduction was due mainly to an accelerated degradation of these subunits, which was associated with a 3-tyrosine nitration of mitochondrial proteins. Pretreatment of cells with uric acid, an antiperoxynitrite agent, prevented protein degradation induced by palmitic acid. A reduced gene expression also contributed to decrease mitochondrial DNA (mtDNA)-encoded subunits. Saturated fatty acids induced oxidative stress and caused mtDNA oxidative damage. This effect was prevented by inhibiting NADPH oxidase. These acids activated NADPH oxidase gene expression and increased NADPH oxidase activity. Silencing this oxidase abrogated totally the inhibitory effect of palmitic acid on OXPHOS complex activity. We conclude that saturated fatty acids caused nitro-oxidative stress, reduced OXPHOS complex half-life and activity, and decreased gene expression of mtDNA-encoded subunits. These effects were mediated by activation of NADPH oxidase. That is, these acids reproduced mitochondrial dysfunction found in humans and animals with nonalcoholic steatohepatitis. PMID- 25540129 TI - Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology. AB - Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH agonist-based treatments for DS. PMID- 25540131 TI - Cloning of some heat shock proteins genes for further transcriptional study of Planktothrix agardhii exposed to abiotic stress. AB - Planktothrix agardhii is one of the freshwater cyanobacteria that can produce the hepatotoxin microcystins (MC)-a real threat to human and animal health. Knowledge of the biological role of MC in producing organisms is highly desired to understand the driving force of MC production. Recently, emerging evidences have suggested that MC may have protective role in cells facing environmental stress. If this is true, one should expect differences in the cellular protective mechanisms between MC-containing and MC-deficient mutant strains. To test this hypothesis, it would be essential to investigate the consequences of the loss of MC in Planktothrix in the transcriptional responses of its heat shock proteins (Hsps) to abiotic stresses-an important component of cellular stress response. However, a crucial first step is prerequisite for the isolation of hsp genes here, as the genome of Planktothrix has not been fully published. Therefore, we have successfully isolated four hsp genes including clpC (hsp100), htpG (hsp90), groEL (hsp60), and groES (hsp10) from Planktothrix agardhii PCC 7805 using ramped annealing PCR (RAN-PCR) with consensus-degenerate hybrid oligonucleotide primers (CODEHOP) and annealing control primer (ACP) system. In addition, some putative regulatory sequences found in the upstream region of groESL operon of Planktothrix agardhii were also discussed. PMID- 25540130 TI - The effect of maternal diabetes on the Wnt-PCP pathway during embryogenesis as reflected in the developing mouse eye. AB - Embryopathies that develop as a consequence of maternal diabetes have been studied intensely in both experimental and clinical scenarios. Accordingly, hyperglycaemia has been shown to downregulate the expression of elements in the non-canonical Wnt-PCP pathway, such as the Dishevelled-associated activator of morphogenesis 1 (Daam1) and Vangl2. Daam1 is a formin that is essential for actin polymerization and for cytoskeletal reorganization, and it is expressed strongly in certain organs during mouse development, including the eye, neural tube and heart. Daam1(gt/gt) and Daam1(gt/+) embryos develop ocular defects (anophthalmia or microphthalmia) that are similar to those detected as a result of hyperglycaemia. Indeed, studying the effects of maternal diabetes on the Wnt-PCP pathway demonstrated that there was strong association with the Daam1 genotype, whereby the embryopathy observed in Daam1(gt/+) mutant embryos of diabetic dams was more severe. There was evidence that embryonic exposure to glucose in vitro diminishes the expression of genes in the Wnt-PCP pathway, leading to altered cytoskeletal organization, cell shape and cell polarity in the optic vesicle. Hence, the Wnt-PCP pathway appears to influence cell morphology and cell polarity, events that drive the cellular movements required for optic vesicle formation and that, in turn, are required to maintain the fate determination. Here, we demonstrate that the Wnt-PCP pathway is involved in the early stages of mouse eye development and that it is altered by diabetes, provoking the ocular phenotype observed in the affected embryos. PMID- 25540132 TI - Site properties have a stronger influence than fire severity on ectomycorrhizal fungi and associated N-cycling bacteria in regenerating post-beetle-killed lodgepole pine forests. AB - Following a pine beetle epidemic in British Columbia, Canada, we investigated the effect of fire severity on rhizosphere soil chemistry and ectomycorrhizal fungi (ECM) and associated denitrifying and nitrogen (N)-fixing bacteria in the root systems of regenerating lodgepole pine seedlings at two site types (wet and dry) and three fire severities (low, moderate, and high). The site type was found to have a much larger impact on all measurements than fire severity. Wet and dry sites differed significantly for almost all soil properties measured, with higher values identified from wet types, except for pH and percent sand that were greater on dry sites. Fire severity caused few changes in soil chemical status. Generally, bacterial communities differed little, whereas ECM morphotype analysis revealed ectomycorrhizal diversity was lower on dry sites, with a corresponding division in community structure between wet and dry sites. Molecular profiling of the fungal ITS region confirmed these results, with a clear difference in community structure seen between wet and dry sites. The ability of ECM fungi to colonize seedlings growing in both wet and dry soils may positively contribute to subsequent regeneration. We conclude that despite consecutive landscape disturbances (mountain pine beetle infestation followed by wildfire), the "signature" of moisture on chemistry and ECM community structure remained pronounced. PMID- 25540133 TI - Neurofeedback training of alpha-band coherence enhances motor performance. AB - OBJECTIVE: Neurofeedback training of motor cortex activations with brain-computer interface systems can enhance recovery in stroke patients. Here we propose a new approach which trains resting-state functional connectivity associated with motor performance instead of activations related to movements. METHODS: Ten healthy subjects and one stroke patient trained alpha-band coherence between their hand motor area and the rest of the brain using neurofeedback with source functional connectivity analysis and visual feedback. RESULTS: Seven out of ten healthy subjects were able to increase alpha-band coherence between the hand motor cortex and the rest of the brain in a single session. The patient with chronic stroke learned to enhance alpha-band coherence of his affected primary motor cortex in 7 neurofeedback sessions applied over one month. Coherence increased specifically in the targeted motor cortex and in alpha frequencies. This increase was associated with clinically meaningful and lasting improvement of motor function after stroke. CONCLUSIONS: These results provide proof of concept that neurofeedback training of alpha-band coherence is feasible and behaviorally useful. SIGNIFICANCE: The study presents evidence for a role of alpha-band coherence in motor learning and may lead to new strategies for rehabilitation. PMID- 25540134 TI - Changes in prevalence of chronic obstructive pulmonary disease and asthma in the US population and associated risk factors. AB - Chronic lower airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma, are currently the third leading cause of death in the United States. We aimed to evaluate changes in prevalence of and risk factors for COPD and asthma among the US adult population. We evaluated changes in prevalence of self-reported doctor-diagnosed COPD (i.e. chronic bronchitis and emphysema) and asthma and self-reported respiratory symptoms comparing data from the 1988-1994 and 2007-2010 National Health and Nutrition Examination Surveys. To investigate changes in the severity of each outcome over the two periods, we calculated changes in the proportions of spirometry-based airflow obstruction for each outcome. Prevalence of doctor-diagnosed chronic bronchitis and emphysema decreased significantly mainly among males, while asthma increased only among females. The self-reported disease and the respiratory symptoms were associated with increased prevalence of airflow obstruction for both periods. However, the prevalence of airflow obstruction decreased significantly in the second period among those with shortness of breath and doctor-diagnosed respiratory conditions (chronic bronchitis, emphysema, and asthma). COPD outcomes and asthma were associated with lower education, smoking, underweight and obesity, and occupational dusts and fumes exposure. Chronic lower airway diseases continue to be major public health problems. However, decreased prevalence of doctor diagnosed chronic bronchitis and emphysema (in males) and decreased prevalence of airflow obstruction in those with respiratory symptoms and doctor-diagnosed respiratory diseases may indicate a declining trend and decrease in disease severity between the two periods. Continued focus on prevention of these diseases through public health interventions is prudent. PMID- 25540135 TI - Barriers to access and re-attendance for treatment of podoconiosis: a qualitative study in northern Ethiopia. AB - BACKGROUND: Podoconiosis is a chronic non-infectious lymphoedema affecting individuals exposed to red clay soil in endemic areas. Evidence from International Orthodox Christian Charities (IOCC) treatment centers' registers suggests that a significant proportion of registered patients with podoconiosis fail to re-attend for treatment, putting them at risk of worsening disability associated with the lymphoedema and attacks of acute adenolymphangitis. The aim of this study was to explore barriers to access and re-attendance of patients with podoconiosis in northern Ethiopia. METHODS: A cross-sectional qualitative study was conducted at three IOCC treatment sites from February to April 2013. Twenty-eight patients and three project leaders took part in in-depth interviews. Three focus group discussions were undertaken with 22 patients, patient association leaders and project staff members. RESULTS: Barriers to access and to continued attendance at treatment centers were recognized by all participant groups. The following reasons were reported: lay beliefs about the disease's causation and presentation, occupational, geographic and financial barriers, stigma and conflicting expectations of treatment services. CONCLUSIONS: This study illustrates the multiple, step-wise barriers to accessing treatment faced by podoconiosis patients. These factors are dynamic, frequently interact and result from competing social and economic priorities. PMID- 25540136 TI - Influence of microelement concentration on the intensity of alcohol withdrawal syndrome. AB - AIMS: To establish a nutritional and constitutional profile concerning the micronutrient plasma concentration of patients who suffer from AWS. METHOD: Observational case control study to determine whether patients who exhibited symptoms of AWS (N = 60) had micronutrient plasmatic concentration deficiencies when compared with healthy controls (N = 34). RESULTS: There were statistically significant differences between the concentrations of nutrients that are correlated with glutamate hyperactivity (zinc, magnesium and folate/vitamin B12/homocysteine). CONCLUSION: Evidence from literature and our experiment suggests that brain activity, especially the glutamatergic system, might be directly involved in micronutrient concentrations. Therefore, their supplementation to the AWS patient might improve symptom evolution. PMID- 25540137 TI - Magnesium in man: implications for health and disease. AB - Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia. PMID- 25540141 TI - NOD-like receptors: versatile cytosolic sentinels. AB - Nucleotide binding oligomerization domain (NOD)-like receptors are cytoplasmic pattern-recognition receptors that together with RIG-I-like receptor (retinoic acid-inducible gene 1), Toll-like receptor (TLR), and C-type lectin families make up the innate pathogen pattern recognition system. There are 22 members of NLRs in humans, 34 in mice, and even a larger number in some invertebrates like sea urchins, which contain more than 200 receptors. Although initially described to respond to intracellular pathogens, NLRs have been shown to play important roles in distinct biological processes ranging from regulation of antigen presentation, sensing metabolic changes in the cell, modulation of inflammation, embryo development, cell death, and differentiation of the adaptive immune response. The diversity among NLR receptors is derived from ligand specificity conferred by the leucine-rich repeats and an NH2-terminal effector domain that triggers the activation of different biological pathways. Here, we describe NLR genes associated with different biological processes and the molecular mechanisms underlying their function. Furthermore, we discuss mutations in NLR genes that have been associated with human diseases. PMID- 25540140 TI - Leukocyte homing, fate, and function are controlled by retinoic acid. AB - Although vitamin A was recognized as an "anti-infective vitamin" over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell- and humoral-mediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases. PMID- 25540139 TI - The organic anion transporter (OAT) family: a systems biology perspective. AB - The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Nuclear receptors and other transcription factors, such as Hnf4alpha and Hnf1alpha, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling. PMID- 25540144 TI - Ex uno plures: molecular designs for embryonic pluripotency. AB - Pluripotent cells in embryos are situated near the apex of the hierarchy of developmental potential. They are capable of generating all cell types of the mammalian body proper. Therefore, they are the exemplar of stem cells. In vivo, pluripotent cells exist transiently and become expended within a few days of their establishment. Yet, when explanted into artificial culture conditions, they can be indefinitely propagated in vitro as pluripotent stem cell lines. A host of transcription factors and regulatory genes are now known to underpin the pluripotent state. Nonetheless, how pluripotent cells are equipped with their vast multilineage differentiation potential remains elusive. Consensus holds that pluripotency transcription factors prevent differentiation by inhibiting the expression of differentiation genes. However, this does not explain the developmental potential of pluripotent cells. We have presented another emergent perspective, namely, that pluripotency factors function as lineage specifiers that enable pluripotent cells to differentiate into specific lineages, therefore endowing pluripotent cells with their multilineage potential. Here we provide a comprehensive overview of the developmental biology, transcription factors, and extrinsic signaling associated with pluripotent cells, and their accompanying subtypes, in vitro heterogeneity and chromatin states. Although much has been learned since the appreciation of mammalian pluripotency in the 1950s and the derivation of embryonic stem cell lines in 1981, we will specifically emphasize what currently remains unclear. However, the view that pluripotency factors capacitate differentiation, recently corroborated by experimental evidence, might perhaps address the long-standing question of how pluripotent cells are endowed with their multilineage differentiation potential. PMID- 25540145 TI - Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. AB - Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na(+)-K(+)-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na(+)-K(+) ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases. PMID- 25540146 TI - Use of donor breast milk in neonatal units in the UK. PMID- 25540147 TI - A physiological approach to the timing of umbilical cord clamping at birth. AB - Umbilical cord clamping at birth has a major impact on an infant's cardiovascular system that varies in significance depending upon whether the infant has commenced breathing. As umbilical venous return is a major source of preload for the left ventricle during fetal life, recent experimental evidence has shown that clamping the umbilical cord severely limits cardiac venous return in the absence of pulmonary ventilation. As a result, cardiac output greatly reduces and remains low until breathing commences. Once the infant begins breathing, aeration of the lung triggers a large increase in pulmonary blood flow, which replaces umbilical venous return as the source of preload for the left ventricle. As a result, cardiac output markedly increases, as indicated by an increase in heart rate immediately after birth. Thus, infants born apnoeic and hypoxic and have their cords immediately clamped, are likely to have a restricted cardiac output combined with hypoxia. As increased cardiac output is a major physiological defence mechanism that counteracts the effects of hypoxaemia, limiting the increase in cardiac output exposes the infant to ischaemia along with hypoxia. However, if the infant commences breathing, aerates its lungs and increases pulmonary blood flow before the umbilical cord is clamped, then pulmonary venous return can immediately take over the supply of left ventricular preload upon cord clamping. As a result, there is no intervening period of reduced preload and cardiac output and the large swings in arterial pressures and flows are reduced leading to a more stable circulatory transition. PMID- 25540148 TI - Encephalocele presenting as an oropharyngeal mass. PMID- 25540149 TI - High-dose infliximab therapy in Crohn's disease: clinical experience, safety, and efficacy. AB - BACKGROUND: Inadequate response to infliximab [IFX] therapy in Crohn's disease [CD] may necessitate dose intensification. We evaluated safety and efficacy of high-dose IFX [HD IFX] [greater than 10mg/kg every 8 weeks] in CD and characterized predictors of response to HD IFX intensification. METHODS: Electronic medical records were queried for CD patients between 2010 and 2012 who received HD IFX and were reviewed for history, medications, laboratory data, efficacy, and safety. RESULTS: In all, 86 patients received HD IFX for CD at doses between 10 and 22.5mg/kg every 4 to 7 weeks. In early HD IFX therapy [week 1-16], 25.8% and 59.1% experienced full and partial response, respectively. In later HD IFX therapy [week 38-100], 27.9% and 34.4% experienced full and partial response, respectively. Median serum IFX levels increased from 1.7 to 7.3 u/mL [p = 0.017], and median C-reactive protein [CRP] values decreased from 20.5 at baseline to 4.7 mg/L after 16 weeks [p < 0.001]. Baseline CRP values were significantly elevated in the group that responded at 1-16 weeks compared with nonresponders [22.0 vs 3.5mg/L, p < 0.01]. HD IFX therapy was discontinued in 26% and 7.3% of patients for inadequate response and adverse events, respectively. Eleven cases of infection required hospitalization for a serious infection rate of 7.41 events per 100 patient-years. CONCLUSIONS: HD IFX therapy may benefit CD patients who have failed standard doses of IFX. HD IFX therapy may be associated with more serious adverse events compared with standard dosing. Baseline CRP value may predict clinical response to HD IFX. PMID- 25540150 TI - Health & Demographic Surveillance System Profile: The Birbhum population project (Birbhum HDSS). AB - The Birbhum HDSS was established in 2008 and covers 351 villages in four administrative blocks in rural areas of Birbhum district of West Bengal, India. The project currently follows 54 585 individuals living in 12557 households. The population being followed up is economically underprivileged and socially marginalized. The HDSS, a prospective longitudinal cohort study, has been designed to study changes in population demographic, health and healthcare utilization. In addition to collecting data on vital statistics and antenatal and postnatal tracking, verbal autopsies are being performed. Moreover, periodic surveys capturing socio-demographic and economic conditions have been conducted twice. Data on nutritional status (children as well as adults), non-communicable diseases, smoking etc. have also been collected in special surveys. Currently, intervention studies on anaemia, undernutrition and common preschool childhood morbidities through behavioural changes are under way. For access to the data, a researcher needs to send a request to the Data Manager [suri.shds@gmail.com]. Data are shared in common formats like comma-separated files (csv) or Microsoft Excel (xlsx) or Microsoft Access Database (mdb).The HDSS will soon upgrade its data management system to a more integrated platform, coordinated and guided by INDEPTH data sharing policy. PMID- 25540138 TI - Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. AB - Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease. PMID- 25540143 TI - Electronic connection between the quinone and cytochrome C redox pools and its role in regulation of mitochondrial electron transport and redox signaling. AB - Mitochondrial respiration, an important bioenergetic process, relies on operation of four membranous enzymatic complexes linked functionally by mobile, freely diffusible elements: quinone molecules in the membrane and water-soluble cytochromes c in the intermembrane space. One of the mitochondrial complexes, complex III (cytochrome bc1 or ubiquinol:cytochrome c oxidoreductase), provides an electronic connection between these two diffusible redox pools linking in a fully reversible manner two-electron quinone oxidation/reduction with one electron cytochrome c reduction/oxidation. Several features of this homodimeric enzyme implicate that in addition to its well-defined function of contributing to generation of proton-motive force, cytochrome bc1 may be a physiologically important point of regulation of electron flow acting as a sensor of the redox state of mitochondria that actively responds to changes in bioenergetic conditions. These features include the following: the opposing redox reactions at quinone catalytic sites located on the opposite sides of the membrane, the inter monomer electronic connection that functionally links four quinone binding sites of a dimer into an H-shaped electron transfer system, as well as the potential to generate superoxide and release it to the intermembrane space where it can be engaged in redox signaling pathways. Here we highlight recent advances in understanding how cytochrome bc1 may accomplish this regulatory physiological function, what is known and remains unknown about catalytic and side reactions within the quinone binding sites and electron transfers through the cofactor chains connecting those sites with the substrate redox pools. We also discuss the developed molecular mechanisms in the context of physiology of mitochondria. PMID- 25540151 TI - Statistical ecology comes of age. AB - The desire to predict the consequences of global environmental change has been the driver towards more realistic models embracing the variability and uncertainties inherent in ecology. Statistical ecology has gelled over the past decade as a discipline that moves away from describing patterns towards modelling the ecological processes that generate these patterns. Following the fourth International Statistical Ecology Conference (1-4 July 2014) in Montpellier, France, we analyse current trends in statistical ecology. Important advances in the analysis of individual movement, and in the modelling of population dynamics and species distributions, are made possible by the increasing use of hierarchical and hidden process models. Exciting research perspectives include the development of methods to interpret citizen science data and of efficient, flexible computational algorithms for model fitting. Statistical ecology has come of age: it now provides a general and mathematically rigorous framework linking ecological theory and empirical data. PMID- 25540152 TI - Population properties affect inbreeding avoidance in moose. AB - Mechanisms reducing inbreeding are thought to have evolved owing to fitness costs of breeding with close relatives. In small and isolated populations, or populations with skewed age- or sex distributions, mate choice becomes limited, and inbreeding avoidance mechanisms ineffective. We used a unique individual based dataset on moose from a small island in Norway to assess whether inbreeding avoidance was related to population structure and size, expecting inbreeding avoidance to be greater in years with larger populations and even adult sex ratios. The probability that a potential mating event was realized was negatively related to the inbreeding coefficient of the potential offspring, with a stronger relationship in years with a higher proportion or number of males in the population. Thus, adult sex ratio and population size affect the degree of inbreeding avoidance. Consequently, conservation managers should aim for sex ratios that facilitate inbreeding avoidance, especially in small and isolated populations. PMID- 25540153 TI - Evidence for frequent incest in a cooperatively breeding mammal. AB - As breeding between relatives often results in inbreeding depression, inbreeding avoidance is widespread in the animal kingdom. However, inbreeding avoidance may entail fitness costs. For example, dispersal away from relatives may reduce survival. How these conflicting selection pressures are resolved is challenging to investigate, but theoretical models predict that inbreeding should occur frequently in some systems. Despite this, few studies have found evidence of regular incest in mammals, even in social species where relatives are spatio temporally clustered and opportunities for inbreeding frequently arise. We used genetic parentage assignments together with relatedness data to quantify inbreeding rates in a wild population of banded mongooses, a cooperatively breeding carnivore. We show that females regularly conceive to close relatives, including fathers and brothers. We suggest that the costs of inbreeding avoidance may sometimes outweigh the benefits, even in cooperatively breeding species where strong within-group incest avoidance is considered to be the norm. PMID- 25540142 TI - Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels. AB - K(+) channels fulfill roles spanning from the control of excitability to the regulation of transepithelial transport. Here we review two groups of K(+) channels, pH-regulated K2P channels and the transport group of Kir channels. After considering advances in the molecular aspects of their gating based on structural and functional studies, we examine their participation in certain chosen physiological and pathophysiological scenarios. Crystal structures of K2P and Kir channels reveal rather unique features with important consequences for the gating mechanisms. Important tasks of these channels are discussed in kidney physiology and disease, K(+) homeostasis in the brain by Kir channel-equipped glia, and central functions in the hearing mechanism in the inner ear and in acid secretion by parietal cells in the stomach. K2P channels fulfill a crucial part in central chemoreception probably by virtue of their pH sensitivity and are central to adrenal secretion of aldosterone. Finally, some unorthodox behaviors of the selectivity filters of K2P channels might explain their normal and pathological functions. Although a great deal has been learned about structure, molecular details of gating, and physiological functions of K2P and Kir K(+) transport channels, this has been only scratching at the surface. More molecular and animal studies are clearly needed to deepen our knowledge. PMID- 25540154 TI - Baculovirus infection triggers a positive phototactic response in caterpillars to induce 'tree-top' disease. AB - Many parasites manipulate host behaviour to enhance parasite transmission and survival. A fascinating example is baculoviruses, which often induce death in caterpillar hosts at elevated positions ('tree-top' disease). To date, little is known about the underlying processes leading to this adaptive host manipulation. Here, we show that the baculovirus Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) triggers a positive phototactic response in S. exigua larvae prior to death and causes the caterpillars to die at elevated positions. This light-dependent climbing behaviour is specific for infected larvae, as movement of uninfected caterpillars during larval development was light-independent. We hypothesize that upon infection, SeMNPV captures a host pathway involved in phototaxis and/or light perception to induce this remarkable behavioural change. PMID- 25540156 TI - Children reject inequity out of spite. AB - When confronted with inequality, human children and adults sacrifice personal gain to reduce the pay-offs of other individuals, exhibiting apparently spiteful motivations. By contrast, sacrifice of personal gain by non-human animals is often interpreted as frustration. Spite may thus be a uniquely human motivator. However, to date, no empirical study has demonstrated that psychological spite actually drives human behaviour, leaving the motivation for inequity aversion unclear. Here, we ask whether 4- to 9-year-old children and adults reject disadvantageous inequity (less for self, more for peer) out of spite or frustration. We show that children, but not adults, are more likely to reject disadvantageous allocations when doing so deprives their peer of a better reward (spite) than when their peer has already received the better reward (frustration). Spiteful motivations are thus present early in childhood and may be a species-specific component of humans' developing cooperative and competitive behaviour. PMID- 25540155 TI - Chemical and biological insecticides select distinct gene expression patterns in Aedes aegypti mosquito. AB - Worldwide evolution of mosquito resistance to chemical insecticides represents a major challenge for public health, and the future of vector control largely relies on the development of biological insecticides that can be used in combination with chemicals (integrated management), with the expectation that populations already resistant to chemicals will not become readily resistant to biological insecticides. However, little is known about the metabolic pathways affected by selection with chemical or biological insecticides. Here we show that Aedes aegypti, a laboratory mosquito strain selected with a biological insecticide (Bacillus thuringiensis israelensis, Bti) evolved increased transcription of many genes coding for endopeptidases while most genes coding for detoxification enzymes were under-expressed. By contrast, in strains selected with chemicals, genes encoding detoxification enzymes were mostly over-expressed. In all the resistant strains, genes involved in immune response were under transcribed, suggesting that basal immunity might be a general adjustment variable to compensate metabolic costs caused by insecticide selection. Bioassays generally showed no evidence for an increased susceptibility of selected strains towards the other insecticide type, and all chemical-resistant strains were as susceptible to Bti as the unselected parent strain, which is a good premise for sustainable integrated management of mosquito populations resistant to chemicals. PMID- 25540157 TI - Marked colour divergence in the gliding membranes of a tropical lizard mirrors population differences in the colour of falling leaves. AB - Populations of the Bornean gliding lizard, Draco cornutus, differ markedly in the colour of their gliding membranes. They also differ in local vegetation type (mangrove forest versus lowland rainforest) and consequently, the colour of falling leaves (red and brown/black in mangrove versus green, brown and black in rainforest). We show that the gliding membranes of these lizards closely match the colours of freshly fallen leaves in the local habitat as they appear to the visual system of birds (their probable predators). Furthermore, gliding membranes more closely resembled colours of local fallen leaves than standing foliage or fallen leaves in the other population's habitat. This suggests that the two populations have diverged in gliding membrane coloration to match the colours of their local falling leaves, and that mimicking falling leaves is an adaptation that functions to reduce predation by birds. PMID- 25540159 TI - Ants show a leftward turning bias when exploring unknown nest sites. AB - Behavioural lateralization in invertebrates is an important field of study because it may provide insights into the early origins of lateralization seen in a diversity of organisms. Here, we present evidence for a leftward turning bias in Temnothorax albipennis ants exploring nest cavities and in branching mazes, where the bias is initially obscured by thigmotaxis (wall-following) behaviour. Forward travel with a consistent turning bias in either direction is an effective nest exploration method, and a simple decision-making heuristic to employ when faced with multiple directional choices. Replication of the same bias at the colony level would also reduce individual predation risk through aggregation effects, and may lead to a faster attainment of a quorum threshold for nest migration. We suggest the turning bias may be the result of an evolutionary interplay between vision, exploration and migration factors, promoted by the ants' eusociality. PMID- 25540158 TI - Molecular evolution of Dmrt1 accompanies change of sex-determining mechanisms in reptilia. AB - In reptiles, sex-determining mechanisms have evolved repeatedly and reversibly between genotypic and temperature-dependent sex determination. The gene Dmrt1 directs male determination in chicken (and presumably other birds), and regulates sex differentiation in animals as distantly related as fruit flies, nematodes and humans. Here, we show a consistent molecular difference in Dmrt1 between reptiles with genotypic and temperature-dependent sex determination. Among 34 non-avian reptiles, a convergently evolved pair of amino acids encoded by sequence within exon 2 near the DM-binding domain of Dmrt1 distinguishes species with either type of sex determination. We suggest that this amino acid shift accompanied the evolution of genotypic sex determination from an ancestral condition of temperature-dependent sex determination at least three times among reptiles, as evident in turtles, birds and squamates. This novel hypothesis describes the evolution of sex-determining mechanisms as turnover events accompanied by one or two small mutations. PMID- 25540160 TI - Microhabitats in the tropics buffer temperature in a globally coherent manner. AB - Vegetated habitats contain a variety of fine-scale features that can ameliorate temperate extremes. These buffered microhabitats may be used by species to evade extreme weather and novel climates in the future. Yet, the magnitude and extent of this buffering on a global scale remains unknown. Across all tropical continents and using 36 published studies, we assessed temperature buffering from within microhabitats across various habitat strata and structures (e.g. soil, logs, epiphytes and tree holes) and compared them to non-buffered macro-scale ambient temperatures (the thermal control). Microhabitats buffered temperature by 3.9 degrees C and reduced maximum temperatures by 3.5 degrees C. Buffering was most pronounced in tropical lowlands where temperatures were most variable. With the expected increase in extreme weather events, microhabitats should provide species with a local layer of protection that is not captured by traditional climate assessments, which are typically derived from macro-scale temperatures (e.g. satellites). Our data illustrate the need for a next generation of predictive models that account for species' ability to move within microhabitats to exploit favourable buffered microclimates. PMID- 25540161 TI - Epidemic dropsy 2013: case series. AB - Epidemic dropsy (ED) is caused due to intoxication with Argemone mexicana. Here we report a case series of three families, all of whom were residents of Uttar Pradesh, India, who presented in August 2013 with all the classical features of ED. We aim to highlight the importance of this malady even though the sale of unbottled mustard oil is illegal in India. PMID- 25540162 TI - Salmonella Typhimurium pneumonia in a patient with multiple myeloma. AB - Pneumonia due to non-typhoidal Salmonella is a rarely reported entity. A fatal case of Salmonella pneumonia is reported here where Salmonella Typhimurium was isolated from the endotracheal aspirate and blood culture. PMID- 25540163 TI - Bilateral eyelid ecchymosis and subconjunctival haemorrhage manifesting as presenting feature in a case of dengue haemorrhagic fever. AB - We report a case of bilateral eyelid ecchymosis and subconjunctival haemorrhage, a rare presenting feature of dengue haemorrhagic fever. A 17-year-old boy presented to the emergency department with complaints of redness in both eyes and vomiting. He had bilateral eyelid ecchymosis with subconjunctival haemorrhage. Complete blood count revealed a significantly reduced platelet count of 11000/uL suggestive of dengue haemorrhagic fever (DHF). Ocular manifestations were followed by other systemic haemorrhagic manifestations of dengue later on which violates the usual sequence of events of dengue fever. Bilateral eyelid ecchymosis is a rare clinical manifestation and a rare presenting feature of dengue fever and one has to keep high index of suspicion for presence of dengue whenever a case of fever presents with lid ecchymosis/haemorrhage. PMID- 25540164 TI - Pre-treatment practices among patients attending an Animal Bite Management clinic at a primary health centre in Haryana, North India. AB - A cross-sectional study was carried out at the Animal Bite Management (ABM) clinic in a primary health centre in the Faridabad district of Haryana. Information about socio-demographic characteristics, animal bite exposure and pre treatment practices was obtained. Clinical examination determined the severity of the bite. All 619 patients who reported to the ABM clinic during January 2011 to December 2012 were included. Out of the total, 38% had applied chilli-oil paste, and 4% antiseptics to the wound as pre-treatment; only 30.6% had washed the wound with water. There was a direct association between traditional pre-treatment practices and delay in seeking treatment for animal bites which was statistically significant (P = 0.01). Health education of the general population with culturally appropriate Information, Education and Communication material is therefore a necessary strategy to reduce delay in seeking appropriate treatment. PMID- 25540165 TI - Penetrating keratoplasty restoring vision in an unusual case of corneal opacity following exposure to Euphorbia latex. AB - The milky sap of the Euphorbia plant is highly toxic and causes inflammation to the skin and eyes. Damage to the eye ranges from superficial epithelial defects, keratoconjunctivitis, mild to moderate corneal edema, anterior uveitis, Descemet membrane folds, raised intraocular pressure and rarely corneal opacity in severe untreated cases. Here we report a case of visual restoration by optical penetrating keratoplasty in a patient with severe corneal opacity following exposure to Euphorbia latex. PMID- 25540166 TI - Unusual presentation of Enterobius vermicularis in conjunctival sac. AB - We report an unusual case of extraintestinal infection with adult Enterobius vermicularis worms in the conjunctival sac of a two-and-a-half year old boy from Alipurduar, West Bengal, India. Only two other similar cases have been reported in the English literature, one from Assam, India in 1976, and the other from Illinois and California in 2011. PMID- 25540167 TI - A comment on 'a unique case of facial burn superinfected with Dermatobia hominis larvae'. AB - A recently reported case of a massive infection of a facial wound by Dermatobia hominis is almost certainly a misidentification of the insect. PMID- 25540168 TI - Autonomy and confidentiality: patients' perspectives. AB - BACKGROUND: Little is known about patients' opinions about their rights in autonomy and confidentiality concerning their illness and this study was conducted to assess it. METHODS: This multi-centred, cross-sectional study was conducted in outpatient clinics in Khartoum, Sudan. It was delivered to 295 respondents. Data were managed using Microsoft Excel 2010 and SPSS. RESULTS: Eighty-five percent of the patients wanted to know about their conditions, of whom 17% wanted to choose their treatment and 29% believed they had the right to refuse treatment. Most of the respondents would not wish to hide information from their doctors. There was a wide variation at the rate of patients hiding information from their relatives, depending on their diagnosis (HIV 90%, malignancy 16.7% and tuberculosis 0%.) CONCLUSION: Respondents want to choose their treating doctor, know about their diseases, be consulted before a procedure. They would like to leave technical issues to their treating doctors without jeopardising their own rights. PMID- 25540169 TI - Study of acute febrile illness: a 10-year descriptive study and a proposed algorithm from a tertiary care referral hospital in rural Kerala in Southern India. AB - Acute febrile illness (AFI), the initial diagnosis of whose cause is often presumptive, can sometimes be a challenge for the treating physician. To address this issue we carried out a hospital- based descriptive study. More than half (51.5%) of the patients were presumed to have viral fever. Most of the patients (60%) were in the productive phase of life (age range, 18-45 years). The outcome was worst among those aged over 65 years. A definite seasonal trend was observed with a peak in incidence with the arrival of the monsoon in Kerala. Public awareness regarding fevers in the pre-monsoon season should be heightened. Special care should be given to the elderly as they are often the most vulnerable. The use of the proposed locally based algorithm may avoid unnecessary investigations and treatment. PMID- 25540170 TI - Fall risk and incidence reduction in high risk individuals with multiple sclerosis: a pilot randomized control trial. AB - OBJECTIVE: To determine the feasibility of three fall prevention programs delivered over 12 weeks among individuals with multiple sclerosis: (A) a home based exercise program targeting physiological risk factors; (B) an educational program targeting behavioral risk factors; and (C) a combined exercise-and education program targeting both factors. DESIGN: Randomized controlled trial. SETTING: Home-based training with assessments at research laboratory. PARTICIPANTS: A total of 103 individuals inquired about the investigation. After screening, 37 individuals with multiple sclerosis who had fallen in the last year and ranged in age from 45-75 years volunteered for the investigation. A total of 34 participants completed postassessment following the 12-week intervention. INTERVENTION: Participants were randomly assigned into one of four conditions: (1) wait-list control (n = 9); (2) home-based exercise (n = 11); (3) education (n = 9); or (4) a combined exercise and education (n = 8) group. MEASURES: Before and after the 12-week interventions, participants underwent a fall risk assessment as determined by the physiological profile assessment and provided information on their fall prevention behaviors as indexed by the Falls Prevention Strategy Survey. Participants completed falls diaries during the three-months postintervention. RESULTS: A total of 34 participants completed postintervention testing. Procedures and processes were found to be feasible. Overall, fall risk scores were lower in the exercise groups (1.15 SD 1.31) compared with the non exercise groups (2.04 SD 1.04) following the intervention (p < 0.01). There was no group difference in fall prevention behaviors (p > 0.05). CONCLUSIONS: Further examination of home-based exercise/education programs for reducing falls in individuals with multiple sclerosis is warranted. A total of 108 participants would be needed in a larger randomized controlled trial.ClinicalTrials.org #NCT01956227. PMID- 25540171 TI - Development of a rehabilitation goal menu for inpatients with neurological disorders: application in a Saudi Arabian context. AB - OBJECTIVE: To develop a rehabilitation goal menu based on understanding the specific goals that are important to neurological inpatients and that fall within commonly identified rehabilitation domains. DESIGN: Qualitative methods (semi structured interview, focus groups) to develop a goal menu followed by cross sectional study to measure participants' goal rankings. SETTING: Rehabilitation hospital in Saudi Arabia. SUBJECTS: A total of 130 participants with neurological injury. MAIN MEASURES: Participant rankings of rehabilitation goals and self reported level of difficulty in areas such as mobility, self-care, accessibility, productivity, and leisure. RESULTS: A 10-item goal menu was developed based on initial focus groups, semi-structured interviews, and literature review. The overall highest ranked rehabilitation goal was Functional Mobility/Locomotion, followed by Self-Care and Religious/Life Philosophy. Self-reported level of difficulty with mobility was strongly associated with the ranking of Functional Mobility/Locomotion as a rehabilitation goal. However, there was little correspondence between reported difficulty and priority ranking of self-care. Subsequent factor analysis of detailed goal items suggest that the goal menu could be reduced to seven items. CONCLUSIONS: This study provided an understanding of which rehabilitation goals are important to Saudi clients with neurological disorders that could be used to facilitate their contribution to the goal-setting process. PMID- 25540172 TI - Acute erythematous eruptions: what is the diagnosis? PMID- 25540174 TI - Inhibitory motor neurons of the esophageal myenteric plexus are mechanosensitive. AB - Mechanosensitivity of enteric neurons has been reported in the small intestine and colon, but not in the esophagus. Our earlier in vivo studies show that mechanical stretch of the esophagus in the axial direction induces neurally mediated relaxation of the lower esophageal sphincter, possibly through mechanosensitive motor neurons. However, this novel notion that the motor neurons are mechanosensitive has not been examined in isolated esophageal myenteric motor neurons. The goal of our present study was to examine the mechanosensitivity of esophageal motor neurons in primary culture and elucidate the underlying molecular mechanisms. Immmunocytochemical analysis revealed that >95% cells were positive for the neuronal marker protein gene product 9.5 and that 66% of these cells costained with protein gene product 9.5 and neuronal nitric oxide (NO) synthase. Hypotonic solution induced an increase in the cytoplasm volume in all cells that was independent of extracellular Ca(2+). Hypotonic solution and mechanical stretch induced cytoplasmic free Ca(2+) signaling in ~65% of neurons in the presence, but not absence, of extracellular Ca(2+). Neurons grown on the elastic membrane responded to mechanical stretch by an increase in neuronal size and Ca(2+) signaling simultaneously. Hypotonic stretch-induced cytoplasmic free Ca(2+) signaling was not affected by extracellular Mg(2+), 5-nitro-2-(3 phenylpropylamino)benzoic acid, and nifedipine but was attenuated by 2 aminoethoxydiphenyl borate, Gd(3+), and Grammostola mechanotoxin 4, blockers of the stretch-activated ion channels. In ~57% of the neurons, hypotonic stretch also induced Ca(2+)-dependent cytoplasmic NO production, which was abolished by Grammostola mechanotoxin 4. These results prove that the esophageal inhibitory motor neurons possess a mechanosensitive property and also provide novel insights into the stretch-activated ion channel-Ca(2+)-NO signaling pathway in these neurons. PMID- 25540175 TI - The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. AB - The endoplasmic reticulum (ER) is a multifunctional organelle critical for the proper folding and assembly of secreted and transmembrane proteins. Perturbations of ER functions cause ER stress, which activates a coordinated system of transcriptional and translational controls called the unfolded protein response (UPR), to cope with accumulation of misfolded proteins and proteotoxicity. It results in ER homeostasis restoration or in cell death. Senescence is a complex cell phenotype induced by several stresses such as telomere attrition, DNA damage, oxidative stress, and activation of some oncogenes. It is mainly characterized by a cell enlargement, a permanent cell-cycle arrest, and the production of a secretome enriched in proinflammatory cytokines and components of the extracellular matrix. Senescent cells accumulate with age in tissues and are suspected to play a role in age-associated diseases. Since senescence is a stress response, the question arises of whether an ER stress could occur concomitantly with senescence and participate in the onset or maintenance of the senescent features. Here, we described the interconnections between the UPR signaling and the different aspects of the cellular senescence programs and discuss the implication of UPR modulations in this context. PMID- 25540176 TI - Considerations when quantitating protein abundance by immunoblot. AB - The development of the immunoblot to detect and characterize a protein with an antisera, even in a crude mixture, was a breakthrough with wide-ranging and unpredictable applications across physiology and medicine. Initially, this technique was viewed as a tool for qualitative, not quantitative, analyses of proteins because of the high number of variables between sample preparation and detection with antibodies. Nonetheless, as the immunoblot method was streamlined and improved, investigators pushed it to quantitate protein abundance in unpurified samples as a function of treatment, genotype, or pathology. This short review, geared at investigators, reviewers, and critical readers, presents a set of issues that are of critical importance for quantitative analysis of protein abundance: 1) Consider whether tissue samples are of equivalent integrity and assess how handling between collection and assay influences the apparent relative abundance. 2) Establish the specificity of the antiserum for the protein of interest by providing clear images, molecular weight markers, positive and negative controls, and vendor details. 3) Provide convincing evidence for linearity of the detection system by assessing signal density as a function of sample loaded. 4) Recognize that loading control proteins are rarely in the same linear range of detection as the protein of interest; consider protein staining of the gel or blot. In summary, with careful attention to sample integrity, antibody specificity, linearity of the detection system, and acceptable loading controls, investigators can implement quantitative immunoblots to convincingly assess protein abundance in their samples. PMID- 25540177 TI - Neurological outcomes and cure rates of embolization of brain arteriovenous malformations with n-butyl cyanoacrylate or Onyx: a meta-analysis. AB - BACKGROUND: In the past decade, preoperative endovascular embolization of cerebral arteriovenous malformations (AVMs) became an essential tool in the treatment of these entities. With the current expansion of technology and wide incorporation of new devices, the indications for the use of endovascular embolization have expanded to include embolization for cure. This has been facilitated by the wide use of the new liquid embolic agents (ethylene-vinyl alcohol co-polymer (EVOH)) in addition to n-butyl cyanoacrylate (NBCA). The aim of this study was to review the current published literature for these two agents and report on permanent neurological injuries and cure rate. METHODS: Published literature citing embolization results for AVMs using liquid embolic agents was reviewed. Papers reporting on permanent complication rates and complete angiographic cure were reviewed. A meta-analysis was performed based on these two variables for the two embolic agents. RESULTS: 103 studies met the selection criteria. Poor neurological outcomes for NBCA and EVOH were 5.2% and 6.8%, respectively (OR 1.4; p=0.56). AVM complete obliteration rate was seen in 13.7% in the NBCA group and in 24% in the EVOH group (OR 1.9). This OR decreased to 1.35 in the subgroup analysis for patients treated after the year 2000. CONCLUSIONS: NBCA continues to have a trend towards lower permanent complication rates, but EVOH had higher angiographic cure rates. The recent literature has demonstrated an increase in the cure rate of AVMs with endovascular embolization techniques yet with a possible increase in permanent neurological deficits and mortality. PMID- 25540178 TI - Infarct growth despite full reperfusion in endovascular therapy for acute ischemic stroke. AB - AIM: To explore the predictors of infarct core expansion despite full reperfusion after intra-arterial therapy (IAT). METHODS: We retrospectively reviewed 604 consecutive patients who underwent IAT for anterior circulation large vessel occlusion acute ischemic stroke in two tertiary centers (2008-2013/2010-2013). Sixty patients selected by MRI or CT perfusion presenting within <24 h of onset with modified Thrombolysis In Cerebral Infarction (mTICI) grade 3 or 2c reperfusion were included. Significant infarct growth (SIG) was defined as infarct expansion >11.6 mL. RESULTS: Mean age was 67.0+/-13.7 years, 56% were men. Mean National Institute of Health Stroke Scale (NIHSS) score was 16.2+/-6.1, time from onset to puncture was 6.8+/-3.1 h, and procedure length was 1.3+/-0.6 h. MRI was used for baseline core analysis in 43% of patients. Mean baseline infarct volume was 17.1+/-19.1 mL, absolute infarct growth was 30.6+/-74.5 mL, and final infarct volume was 47.7+/-77.7 mL. Overall, 35% of patients had SIG. Three of 21 patients (14%) treated with stent-retrievers had SIG compared with 14 of 39 (36%) with first-generation devices. Eight of 21 patients (38%) with intravenous tissue plasminogen activator (IV t-PA) had infarct growth compared with 25/39 (64%) without. 23% of patients with SIG had a modified Rankin Scale score <=2 at 3 months compared with 48% of those without SIG. Multivariate logistic regression indicated that race affected infarct growth. Use of IV t-PA (p=0.03) and stent-retrievers (p=0.03) were independently and inversely correlated with SIG. CONCLUSIONS: Despite full reperfusion, infarct growth is relatively frequent and may explain poor clinical outcomes in this setting. Ethnicity was found to influence SIG. Use of IV t-PA and stent-retrievers were associated with less infarct core expansion. PMID- 25540179 TI - Alfred J Luessenhop and the dawn of a new superspecialty: endovascular neurosurgery. AB - Endovascular neurosurgery, or interventional neuroradiology, has developed rapidly over the last 50 years and has posed a challenge to the established mode of open surgery. Alfred J Luessenhop, an American neurosurgeon, is credited with the first embolization of a cranial arteriovenous malformation and the first intracranial arterial catheterization to occlude an aneurysm. This review describes the life and work of the surgeon who can be regarded as the father of endovascular neurosurgery. PMID- 25540180 TI - Risk of distal embolization with stent retriever thrombectomy and ADAPT. AB - BACKGROUND: There is a discrepancy in clinical outcomes and the achieved recanalization rates with stent retrievers in the endovascular treatment of ischemic stroke. It is our hypothesis that procedural release of embolic particulate may be one contributor to poor outcomes and is a modifiable risk. The goal of this study is to assess various treatment strategies that reduce the risk of distal emboli. METHODS: Mechanical thrombectomy was simulated in a vascular phantom with collateral circulation. Hard fragment-prone clots (HFC) and soft elastic clots (SECs) were used to generate middle cerebral artery (MCA) occlusions that were retrieved by the Solitaire FR devices through (1) an 8 Fr balloon guide catheter (BGC), (2) a 5 Fr distal access catheter at the proximal aspect of the clot in the MCA (Solumbra), or (3) a 6 Fr guide catheter with the tip at the cervical internal carotid artery (guide catheter, GC). Results from mechanical thrombectomy were compared with those from direct aspiration using the Penumbra 5MAX catheter. The primary endpoint was the size distribution of emboli to the distribution of the middle and anterior cerebral arteries. RESULTS: Solumbra was the most efficient method for reducing HFC fragments (p<0.05) while BGC was the best method for preventing SEC fragmentation (p<0.05). The risk of forming HFC distal emboli (>1000 um) was significantly increased using GC. A non statistically significant benefit of direct aspiration was observed in several subgroups of emboli with size 50-1000 um. However, compared with the stent retriever mechanical thrombectomy techniques, direct aspiration significantly increased the risk of SEC fragmentation (<50 um) by at least twofold. CONCLUSIONS: The risk of distal embolization is affected by the catheterization technique and clot mechanics. PMID- 25540181 TI - The chemical component dictionary: complete descriptions of constituent molecules in experimentally determined 3D macromolecules in the Protein Data Bank. AB - The Chemical Component Dictionary (CCD) is a chemical reference data resource that describes all residue and small molecule components found in Protein Data Bank (PDB) entries. The CCD contains detailed chemical descriptions for standard and modified amino acids/nucleotides, small molecule ligands and solvent molecules. Each chemical definition includes descriptions of chemical properties such as stereochemical assignments, chemical descriptors, systematic chemical names and idealized coordinates. The content, preparation, validation and distribution of this CCD chemical reference dataset are described. AVAILABILITY AND IMPLEMENTATION: The CCD is updated regularly in conjunction with the scheduled weekly release of new PDB structure data. The CCD and amino acid variant reference datasets are hosted in the public PDB ftp repository at ftp://ftp.wwpdb.org/pub/pdb/data/monomers/components.cif.gz, ftp://ftp.wwpdb.org/pub/pdb/data/monomers/aa-variants-v1.cif.gz, and its mirror sites, and can be accessed from http://wwpdb.org. CONTACT: jwest@rcsb.rutgers.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25540182 TI - The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens. AB - SUMMARY: Neglected tropical diseases (NTDs) caused by helminths constitute some of the most common infections of the world's poorest people. The etiological agents are complex and recalcitrant to standard techniques of molecular biology. Drug screening against helminths has often been phenotypic and typically involves manual description of drug effect and efficacy. A key challenge is to develop automated, quantitative approaches to drug screening against helminth diseases. The quantal dose-response calculator (QDREC) constitutes a significant step in this direction. It can be used to automatically determine quantitative dose response characteristics and half-maximal effective concentration (EC50) values using image-based readouts from phenotypic screens, thereby allowing rigorous comparisons of the efficacies of drug compounds. QDREC has been developed and validated in the context of drug screening for schistosomiasis, one of the most important NTDs. However, it is equally applicable to general phenotypic screening involving helminths and other complex parasites. AVAILABILITY AND IMPLEMENTATION: QDREC is publically available at: http://haddock4.sfsu.edu/qdrec2/. Source code and datasets are at: http://tintin.sfsu.edu/projects/phenotypicAssays.html. CONTACT: rahul@sfsu.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25540183 TI - RRDistMaps: a UCSF Chimera tool for viewing and comparing protein distance maps. AB - MOTIVATION: Contact maps are a convenient method for the structural biologists to identify structural features through two-dimensional simplification. Binary (yes/no) contact maps with a single cutoff distance can be generalized to show continuous distance ranges. We have developed a UCSF Chimera tool, RRDistMaps, to compute such generalized maps in order to analyze pairwise variations in intramolecular contacts. An interactive utility, RRDistMaps, visualizes conformational changes, both local (e.g. binding-site residues) and global (e.g. hinge motion), between unbound and bound proteins through distance patterns. Users can target residue pairs in RRDistMaps for further navigation in Chimera. The interface contains the unique features of identifying long-range residue motion and aligning sequences to simultaneously compare distance maps. AVAILABILITY AND IMPLEMENTATION: RRDistMaps was developed as part of UCSF Chimera release 1.10, which is freely available at http://rbvi.ucsf.edu/chimera/download.html, and operates on Linux, Windows, and Mac OS. CONTACT: conrad@cgl.ucsf.edu. PMID- 25540185 TI - UProC: tools for ultra-fast protein domain classification. AB - MOTIVATION: With rapidly increasing volumes of biological sequence data the functional analysis of new sequences in terms of similarities to known protein families challenges classical bioinformatics. RESULTS: The ultrafast protein classification (UProC) toolbox implements a novel algorithm ('Mosaic Matching') for large-scale sequence analysis. UProC is by three orders of magnitude faster than profile-based methods and in a metagenome simulation study achieved up to 80% higher sensitivity on unassembled 100 bp reads. AVAILABILITY AND IMPLEMENTATION: UProC is available as an open-source software at https://github.com/gobics/uproc. Precompiled databases (Pfam) are linked on the UProC homepage: http://uproc.gobics.de/. CONTACT: peter@gobics.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25540184 TI - J-Circos: an interactive Circos plotter. AB - SUMMARY: Circos plots are graphical outputs that display three dimensional chromosomal interactions and fusion transcripts. However, the Circos plot tool is not an interactive visualization tool, but rather a figure generator. For example, it does not enable data to be added dynamically nor does it provide information for specific data points interactively. Recently, an R-based Circos tool (RCircos) has been developed to integrate Circos to R, but similarly, Rcircos can only be used to generate plots. Thus, we have developed a Circos plot tool (J-Circos) that is an interactive visualization tool that can plot Circos figures, as well as being able to dynamically add data to the figure, and providing information for specific data points using mouse hover display and zoom in/out functions. J-Circos uses the Java computer language to enable, it to be used on most operating systems (Windows, MacOS, Linux). Users can input data into J-Circos using flat data formats, as well as from the Graphical user interface (GUI). J-Circos will enable biologists to better study more complex chromosomal interactions and fusion transcripts that are otherwise difficult to visualize from next-generation sequencing data. AVAILABILITY AND IMPLEMENTATION: J-circos and its manual are freely available at http://www.australianprostatecentre.org/research/software/jcircos CONTACT: j.an@qut.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25540186 TI - Knowledge-based modeling of peptides at protein interfaces: PiPreD. AB - MOTIVATION: Protein-protein interactions (PPIs) underpin virtually all cellular processes both in health and disease. Modulating the interaction between proteins by means of small (chemical) agents is therefore a promising route for future novel therapeutic interventions. In this context, peptides are gaining momentum as emerging agents for the modulation of PPIs. RESULTS: We reported a novel computational, structure and knowledge-based approach to model orthosteric peptides to target PPIs: PiPreD. PiPreD relies on a precompiled and bespoken library of structural motifs, iMotifs, extracted from protein complexes and a fast structural modeling algorithm driven by the location of native chemical groups on the interface of the protein target named anchor residues. PiPreD comprehensive and systematically samples the entire interface deriving peptide conformations best suited for the given region on the protein interface. PiPreD complements the existing technologies and provides new solutions for the disruption of selected interactions. AVAILABILITY AND IMPLEMENTATION: Database and accessory scripts and programs are available upon request to the authors or at http://www.bioinsilico.org/PIPRED. CONTACT: narcis.fernandez@gmail.com. PMID- 25540187 TI - Wilder's principle: pre-treatment value determines post-treatment response. PMID- 25540189 TI - Ultrasonography of fractures in sports medicine. AB - High-resolution ultrasound is emerging as an important imaging modality in fracture assessment due to its availability, ease of use and multiplanar capabilities. Its usefulness includes injury assessment for the presence of a fracture when obtaining radiographs is not immediately available, detecting occult fractures not revealed on radiographs, and diagnosing bone stress injury before radiographic changes. Sonographic evaluation of bone, however, has limitations and should always be coupled with radiographs and possibly advanced imaging modalities such as CT and MR when clinically indicated. PMID- 25540188 TI - Mucosal microbiome in patients with recurrent aphthous stomatitis. AB - Recurrent aphthous stomatitis (RAS) is the most common disease affecting oral mucosae. Etiology is unknown, but several factors have been implicated, all of which influence the composition of microbiota residing on oral mucosae, which in turn modulates immunity and thereby affects disease progression. Although no individual pathogens have been conclusively shown to be causative agents of RAS, imbalanced composition of the oral microbiota may play a key role. In this study, we sought to determine composition profiles of bacterial microbiota in the oral mucosa associated with RAS. Using high-throughput 16S rRNA gene sequencing, we characterized the most abundant bacterial populations residing on healthy and ulcerated mucosae in patients with RAS (recruited using highly stringent criteria) and no associated medical conditions; we also compared these to the bacterial microbiota of healthy controls (HCs). Phylum-level diversity comparisons revealed decreased Firmicutes and increased Proteobacteria in ulcerated sites, as compared with healthy sites in RAS patients, and no differences between RAS patients with healthy sites and HCs. Genus-level analysis demonstrated higher abundance of total Bacteroidales in RAS patients with healthy sites over HCs. Porphyromonadaceae comprising species associated with periodontal disease and Veillonellaceae predominated in ulcerated sites over HCs, while no quantitative differences of these families were observed between healthy sites in RAS patients and HCs. Streptococcaceae comprising species associated with oral health predominated in HCs over ulcerated sites but not in HCs over healthy sites in RAS patients. This study demonstrates that mucosal microbiome changes in patients with idiopathic RAS--namely, increased Bacteroidales species in mucosae of RAS patients not affected by active ulceration. While these changes suggest a microbial role in initiation of RAS, this study does not provide data on causality. Within this limitation, the study contributes to the understanding of the potential role of mucosal microbiome changes in oral mucosal disease. PMID- 25540190 TI - Violence Against Latinas: The Effects of Undocumented Status on Rates of Victimization and Help-Seeking. AB - This study investigated whether legal status was related to interpersonal victimization and help-seeking by comparing Latina immigrants with permanent legal status with Latina immigrants who are undocumented on rates of reported interpersonal victimization, types of perpetrators, and rates of help-seeking. Data come from the Sexual Assault Among Latinas (SALAS) study, which interviewed 1,377 immigrant Latinas about their lifetime histories of sexual assault, physical assault, stalking, and threats along with help-seeking efforts. Results did not reveal significant differences between legal status and reported victimization rates or types of perpetrators. However, undocumented Latinas (n = 91) were less likely to seek formal help than those with permanent status. Results of this study indicate that undocumented status does not independently put women at risk of victimization, but that responses to violence are related to legal status. PMID- 25540191 TI - Engaging men as coproducers in health care. PMID- 25540192 TI - Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI 1 in mouse models of thrombosis and stroke. AB - Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissue-type plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding. PMID- 25540193 TI - Inflammatory signaling regulates hematopoietic stem and progenitor cell emergence in vertebrates. AB - Inflammatory signaling has been shown to be essential for stress hematopoiesis in adult bone marrow, either through increasing proliferation or by directing differentiation of hematopoietic stem and progenitor cells (HSPCs) toward myeloid or lymphoid lineages. However, its role in embryonic normal hematopoiesis has been unknown. Here, we demonstrate that in both zebrafish and mouse embryos, inflammatory signaling is necessary and sufficient for HSPC emergence, in the absence of infection or pathological inflammation. Mechanistically, inflammatory signaling regulates hemogenic endothelium-derived HSPC development through a conserved Toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain enhancer of activated B core (NF-kappaB) signaling, which then promotes Notch activity, a well-known signal required for HSPC specification in vertebrates. Our findings establish a previously unrecognized link between inflammatory signaling and HSPC emergence, and provide new insights into regenerative medicine and novel therapies to treat innate immune-related diseases. PMID- 25540194 TI - The importance of pharmacist providing patient education in oncology. AB - The world's increasing diversity requires health care professionals to adjust delivery methods of teaching to accommodate different cultural values and beliefs. The ability to communicate effectively across languages and various cultural practices directly affects patient education outcomes. Pharmacist should be aware of varying modalities and considerations when counseling a patient diagnosed with cancer and undergoing chemotherapy. In more recent years, the medical profession has seen an increase in patient outcomes due to using the multidisciplinary team approach and has benefited by implementing Medication Therapy Management (MTM) programs at various institutions. For the clinical pharmacist, this would mean documentation for these services should be precise and accurate based on the specific patients needs. There are several factors involved in the care and therapy of the patient with cancer. Clinical oncology pharmacist should be aware of the ever-changing role in oncology and be able to implement new practices at their facility for better patient outcomes. PMID- 25540195 TI - Abl2/Abl-related gene stabilizes actin filaments, stimulates actin branching by actin-related protein 2/3 complex, and promotes actin filament severing by cofilin. AB - Both Arp2/3 complex and the Abl2/Arg nonreceptor tyrosine kinase are essential to form and maintain diverse actin-based structures in cells, including cell edge protrusions in fibroblasts and cancer cells and dendritic spines in neurons. The ability of Arg to promote cell edge protrusions in fibroblasts does not absolutely require kinase activity, raising the question of how Arg might modulate actin assembly and turnover in the absence of kinase function. Arg has two distinct actin-binding domains and interacts physically and functionally with cortactin, an activator of the Arp2/3 complex. However, it was not known whether and how Arg influences actin filament stability, actin branch formation, or cofilin-mediated actin severing or how cortactin influences these reactions of Arg with actin. Arg or cortactin bound to actin filaments stabilizes them from depolymerization. Low concentrations of Arg and cortactin cooperate to stabilize filaments by slowing depolymerization. Arg stimulates formation of actin filament branches by Arp2/3 complex and cortactin. An Arg mutant lacking the C-terminal calponin homology actin-binding domain stimulates actin branch formation by the Arp2/3 complex, indicative of autoinhibition. ArgDeltaCH can stimulate the Arp2/3 complex even in the absence of cortactin. Arg greatly potentiates cofilin severing of actin filaments, and cortactin attenuates this enhanced severing. The ability of Arg to stabilize filaments, promote branching, and increase severing requires the internal (I/L)WEQ actin-binding domain. These activities likely underlie important roles that Arg plays in the formation, dynamics, and stability of actin-based cellular structures. PMID- 25540196 TI - A new role for annexin A11 in the early secretory pathway via stabilizing Sec31A protein at the endoplasmic reticulum exit sites (ERES). AB - Exit of cargo molecules from the endoplasmic reticulum (ER) for transport to the Golgi is the initial step in intracellular vesicular trafficking. The coat protein complex II (COPII) machinery is recruited to specialized regions of the ER, called ER exit sites (ERES), where it plays a central role in the early secretory pathway. It has been known for more than two decades that calcium is an essential factor in vesicle trafficking from the ER to Golgi apparatus. However, the role of calcium in the early secretory pathway is complicated and poorly understood. We and others previously identified Sec31A, an outer cage component of COPII, as an interacting protein for the penta-EF-hand calcium-binding protein ALG-2. In this study, we show that another calcium-binding protein, annexin A11 (AnxA11), physically associates with Sec31A by the adaptor function of ALG-2. Depletion of AnxA11 or ALG-2 decreases the population of Sec31A that is stably associated with the ERES and causes scattering of juxtanuclear ERES to the cell periphery. The synchronous ER-to-Golgi transport of transmembrane cargoes is accelerated in AnxA11- or ALG-2-knockdown cells. These findings suggest that AnxA11 maintains architectural and functional features of the ERES by coordinating with ALG-2 to stabilize Sec31A at the ERES. PMID- 25540197 TI - Leukotriene-C4 synthase, a critical enzyme in the activation of store-independent Orai1/Orai3 channels, is required for neointimal hyperplasia. AB - Leukotriene-C4 synthase (LTC4S) generates LTC4 from arachidonic acid metabolism. LTC4 is a proinflammatory factor that acts on plasma membrane cysteinyl leukotriene receptors. Recently, however, we showed that LTC4 was also a cytosolic second messenger that activated store-independent LTC4-regulated Ca(2+) (LRC) channels encoded by Orai1/Orai3 heteromultimers in vascular smooth muscle cells (VSMCs). We showed that Orai3 and LRC currents were up-regulated in medial and neointimal VSMCs after vascular injury and that Orai3 knockdown inhibited LRC currents and neointimal hyperplasia. However, the role of LTC4S in neointima formation remains unknown. Here we show that LTC4S knockdown inhibited LRC currents in VSMCs. We performed in vivo experiments where rat left carotid arteries were injured using balloon angioplasty to cause neointimal hyperplasia. Neointima formation was associated with up-regulation of LTC4S protein expression in VSMCs. Inhibition of LTC4S expression in injured carotids by lentiviral particles encoding shRNA inhibited neointima formation and inward and outward vessel remodeling. LRC current activation did not cause nuclear factor for activated T cells (NFAT) nuclear translocation in VSMCs. Surprisingly, knockdown of either LTC4S or Orai3 yielded more robust and sustained Akt1 and Akt2 phosphorylation on Ser-473/Ser-474 upon serum stimulation. LTC4S and Orai3 knockdown inhibited VSMC migration in vitro with no effect on proliferation. Akt activity was suppressed in neointimal and medial VSMCs from injured vessels at 2 weeks postinjury but was restored when the up-regulation of either LTC4S or Orai3 was prevented by shRNA. We conclude that LTC4S and Orai3 altered Akt signaling to promote VSMC migration and neointima formation. PMID- 25540199 TI - Polysaccharide A from the capsule of Bacteroides fragilis induces clonal CD4+ T cell expansion. AB - For 3 decades, the view of MHCII-dependent antigen presentation has been completely dominated by peptide antigens despite our 2004 discovery in which MHCII was shown to present processed fragments of zwitterionic capsular polysaccharides to T cells. Published findings further demonstrate that polysaccharide A (PSA) from the capsule of Bacteroides fragilis is a potent activator of CD4(+) T cells and that these T cells have important biological functions, especially in the maintenance of immunological homeostasis. However, little is known about the nature of T cell recognition of the polysaccharide MHCII complex or the phenotype of the resulting activated cells. Here, we use next-generation sequencing of the alphabetaT cell receptor of CD4(+) T cells from mice stimulated with PSA in comparison with protein antigen simulation and non immunized controls and found that PSA immunization induced clonal expansion of a small subset of suppressive CD4(+)CD45RB(low) effector/memory T cells. Moreover, the sequences of the complementarity-determining region 3 (CDR3) loop from top clones indicate a lack of specific variable beta and joining region use and average CDR3 loop length. There was also a preference for a zwitterionic motif within the CDR3 loop sequences, aligning well with the known requirement for a similar motif within PSA to enable T cell activation. These data support a model in which PSA, and possibly other T cell-dependent polysaccharide antigens, elicits a clonal and therefore specific CD4(+) T cell response often characterized by pairing dual-charged CDR3 loop sequences with dual-charged PSA. PMID- 25540198 TI - Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1alpha protein expression through the ubiquitin-proteasome degradation pathway. AB - Our previous in vitro studies have identified hepatocyte nuclear factor 1alpha (HNF1alpha) as an obligated trans-activator for PCSK9 gene expression and demonstrated its functional involvement in the suppression of PCSK9 expression by berberine (BBR), a natural cholesterol-lowering compound. In this study, we investigated the mechanism underlying the inhibitory effect of BBR on HNF1alpha mediated PCSK9 transcription. Administration of BBR to hyperlipidemic mice and hamsters lowered circulating PCSK9 concentrations and hepatic PCSK9 mRNA levels without affecting the gene expression of HNF1alpha. However, hepatic HNF1alpha protein levels were markedly reduced in BBR-treated animals as compared with the control. Using HepG2 cells as a model system, we obtained evidence that BBR treatment let to accelerated degradation of HNF1alpha protein. By applying inhibitors to selectively block the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway, we show that HNF1alpha protein content in HepG2 cells was not affected by bafilomycin A1 treatment, but it was dose-dependently increased by UPS inhibitors bortezomib and MG132. Bortezomib treatment elevated HNF1alpha and PCSK9 cellular levels with concomitant reductions of LDL receptor protein. Moreover, HNF1alpha protein displayed a multiubiquitination ladder pattern in cells treated with BBR or overexpressing ubiquitin. By expressing GFP HNF1alpha fusion protein in cells, we observed that blocking UPS resulted in accumulation of GFP-HNF1alpha in cytoplasm. Importantly, we show that the BBR reducing effects on HNF1alpha protein and PCSK9 gene transcription can be eradicated by proteasome inhibitors. Altogether, our studies using BBR as a probe uncovered a new aspect of PCSK9 regulation by ubiquitin-induced proteasomal degradation of HNF1alpha. PMID- 25540200 TI - Tau monoclonal antibody generation based on humanized yeast models: impact on Tau oligomerization and diagnostics. AB - A link between Tau phosphorylation and aggregation has been shown in different models for Alzheimer disease, including yeast. We used human Tau purified from yeast models to generate new monoclonal antibodies, of which three were further characterized. The first antibody, ADx201, binds the Tau proline-rich region independently of the phosphorylation status, whereas the second, ADx215, detects an epitope formed by the Tau N terminus when Tau is not phosphorylated at Tyr(18). For the third antibody, ADx210, the binding site could not be determined because its epitope is probably conformational. All three antibodies stained tangle-like structures in different brain sections of THY-Tau22 transgenic mice and Alzheimer patients, and ADx201 and ADx210 also detected neuritic plaques in the cortex of the patient brains. In hippocampal homogenates from THY-Tau22 mice and cortex homogenates obtained from Alzheimer patients, ADx215 consistently stained specific low order Tau oligomers in diseased brain, which in size correspond to Tau dimers. ADx201 and ADx210 additionally reacted to higher order Tau oligomers and presumed prefibrillar structures in the patient samples. Our data further suggest that formation of the low order Tau oligomers marks an early disease stage that is initiated by Tau phosphorylation at N-terminal sites. Formation of higher order oligomers appears to require additional phosphorylation in the C terminus of Tau. When used to assess Tau levels in human cerebrospinal fluid, the antibodies permitted us to discriminate patients with Alzheimer disease or other dementia like vascular dementia, indicative that these antibodies hold promising diagnostic potential. PMID- 25540201 TI - Inhibition of 5-lipoxygenase selectively triggers disruption of c-Myc signaling in prostate cancer cells. AB - Myc is up-regulated in almost all cancer types and is the subject of intense investigation because of its pleiotropic effects controlling a broad spectrum of cell functions. However, despite its recognition as a stand-alone molecular target, development of suitable strategies to block its function is hindered because of its nonenzymatic nature. We reported earlier that arachidonate 5 lipoxygenase (5-Lox) plays an important role in the survival and growth of prostate cancer cells, although details of the underlying mechanisms have yet to be characterized. By whole genome gene expression array, we observed that inhibition of 5-Lox severely down-regulates the expression of c-Myc oncogene in prostate cancer cells. Moreover, inhibition of 5-Lox dramatically decreases the protein level, nuclear accumulation, DNA binding, and transcriptional activities of c-Myc. Both the 5-Lox inhibition-induced down-regulation of c-Myc and induction of apoptosis are mitigated when the cells are treated with 5 oxoeicosatetraenoic acid, a metabolite of 5-Lox, confirming a role of 5-Lox in these processes. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and maintains their transformed phenotype. Interestingly, MK591, a specific 5-Lox inhibitor, strongly affects the viability of Myc-overactivated prostate cancer cells and completely blocks their invasive and soft agar colony forming abilities, but it spares nontransformed cells where expression of 5-Lox is undetectable. These findings indicate that the oncogenic function of c-Myc in prostate cancer cells is regulated by 5-Lox activity, revealing a novel mechanism of 5-Lox action and suggesting that the oncogenic function of c-Myc can be suppressed by suitable inhibitors of 5-Lox. PMID- 25540202 TI - gamma-Aminobutyric A receptor (GABA(A)R) regulates aquaporin 4 expression in the subependymal zone: relevance to neural precursors and water exchange. AB - Activation of gamma-aminobutyric A receptors (GABA(A)Rs) in the subependymal zone (SEZ) induces hyperpolarization and osmotic swelling in precursors, thereby promoting surface expression of the epidermal growth factor receptor (EGFR) and cell cycle entry. However, the mechanisms underlying the GABAergic modulation of cell swelling are unclear. Here, we show that GABA(A)Rs colocalize with the water channel aquaporin (AQP) 4 in prominin-1 immunopositive (P(+)) precursors in the postnatal SEZ, which include neural stem cells. GABA(A)R signaling promotes AQP4 expression by decreasing serine phosphorylation associated with the water channel. The modulation of AQP4 expression by GABA(A)R signaling is key to its effect on cell swelling and EGFR expression. In addition, GABA(A)R function also affects the ability of neural precursors to swell in response to an osmotic challenge in vitro and in vivo. Thus, the regulation of AQP4 by GABA(A)Rs is involved in controlling activation of neural stem cells and water exchange dynamics in the SEZ. PMID- 25540203 TI - Structure and function analysis of nucleocapsid protein of tomato spotted wilt virus interacting with RNA using homology modeling. AB - The nucleocapsid (N) protein of tomato spotted wilt virus (TSWV) plays key roles in assembling genomic RNA into ribonucleoprotein (RNP), which serves as a template for both viral gene transcription and genome replication. However, little is known about the molecular mechanism of how TSWV N interacts with genomic RNA. In this study, we demonstrated that TSWV N protein forms a range of higher ordered oligomers. Analysis of the RNA binding behavior of N protein revealed that no specific oligomer binds to RNA preferentially, instead each type of N oligomer is able to bind RNA. To better characterize the structure and function of N protein interacting with RNA, we constructed homology models of TSWV N and N-RNA complexes. Based on these homology models, we demonstrated that the positively charged and polar amino acids in its predicted surface cleft of TSWV N are critical for RNA binding. Moreover, by N-RNA homology modeling, we found that the RNA component is deeply embedded in the predicted protein cleft; consistently, TSWV N-RNA complexes are relatively resistant to digestion by RNase. Collectively, using homology modeling, we determined the RNA binding sites on N and found a new protective feature for N protein. Our findings also provide novel insights into the molecular details of the interaction of TSWV N with RNA components. PMID- 25540205 TI - Journals' peer review system sometimes overlooks important research. PMID- 25540204 TI - Autophagy induction by histone deacetylase inhibitors inhibits HIV type 1. AB - Histone deacetylase inhibitors (HDACi) are being evaluated in a "shock-and-kill" therapeutic approach to reverse human immunodeficiency virus type-1 (HIV) latency from CD4(+) T cells. Using this approach, HDACi have induced HIV RNA synthesis in latently infected cells from some patients. The hope is that the increase in viral production will lead to killing of the infected cell either by the virus itself or by the patient's immune system, a "sterilizing cure." Although administered within the context of combination antiretroviral therapy, the infection of bystander cells remains a concern. In this study, we investigated the effect of HDACi (belinostat, givinostat, panobinostat, romidepsin, and vorinostat) on the productive infection of macrophages. We demonstrate that the HDACi tested do not alter the initial susceptibility of macrophages to HIV infection. However, we demonstrate that HDACi decrease HIV release from macrophages in a dose-dependent manner (belinostat < givinostat < vorinostat < panobinostat < romidepsin) via degradation of intracellular HIV through the canonical autophagy pathway. This mechanism involves unc-51-like autophagy activating kinase 1 (ULK1) and the inhibition of the mammalian target of rapamycin and requires the formation of autophagosomes and their maturation into autolysosomes in the absence of increased cell death. These data provide further evidence in support of a role for autophagy in the control of HIV infection and suggest that careful consideration of off-target effects will be essential if HDACi are to be a component of a multipronged approach to eliminate latently infected cells. PMID- 25540206 TI - An unusual cause for a relatively common radiographic abnormality. AB - A 59-year-old Indian woman presented to the respiratory clinic with chest pains, long-standing swallowing difficulties and a chest radiograph, which was reported as showing a shadow in the right paratracheal region. A CT scan was obtained and was reported as demonstrating a right-sided paratracheal lymph node and varicosities adjacent to the inferior vena cava. Histology from an endobronchial ultrasound-guided biopsy revealed a heavily blood-stained sample but showed no evidence of granulomas or malignancy. Subsequently, the images were reviewed, with the conclusion that they were actually of an engorged azygos vein compressing the oesophagus. MRI confirmed the absence of mediastinal lymphadenopathy and the presence of a prominent hemiazygos vein compressing the oesophagus. This case highlights the importance of including anatomical abnormalities in the differential diagnosis and reassessing patients when the history and investigations do not correlate. PMID- 25540207 TI - Acute confusion secondary to steroid eye drops. AB - We present a case of a 90-year-old woman who presented to the acute medical unit with a new onset presentation of confusion. Her abbreviated mental test on admission was 5/10. Biochemical screen including full blood count, urea and electrolytes, C reactive protein and liver function test and imaging such as chest X-ray and CT of the head were normal. The patient had recently been started on steroid eye drops for shingles. Suspension of this medication was followed by a resolution of confusion with the abbreviated mental test on discharge improving to 9/10. To the best of our knowledge, this is the first presentation of a link between steroid eye drops and acute confusion. PMID- 25540208 TI - An unusual cause of jaundice in a patient with breast cancer. AB - A 48-year old woman with metastatic breast cancer and extensive bone marrow infiltration was admitted with extreme lethargy, jaundice and deranged liver function tests. She had been started on anastrozole in May 2013 for bony metastases, detected on a bone scan. A CT scan performed at that time had shown no evidence of metastatic or nodal disease elsewhere. Over the subsequent 2 months, the patient had become progressively jaundiced. Outpatient abdominal ultrasound and CT liver had shown a fatty liver with no focal lesions. She was admitted in August 2013 with bilirubin 567, alkaline phosphatase 385, alanine aminotransferase 98, albumin 25 and international normalised ratio 1.9. The patient ultimately had a liver biopsy, which demonstrated features of drug induced steatohepatitis, and anastrozole was found to have been the probable cause. This case explores the differentials of jaundice in a patient with cancer and describes a rare cause of drug-induced liver injury. PMID- 25540209 TI - A diagnosis of haemolytic-uraemic syndrome blurred by alcohol abuse. AB - A 60-year-old man with a history of alcohol abuse was admitted to the intensive care unit (ICU) for status epilepticus. At first, laboratory and imagery findings were almost normal, and the symptoms were attributed to severe alcohol withdrawal due to a history of gastroenteritis reported by his family. But, during the following days, haemolytic anaemia, thrombocytopenia, acute renal failure, and ischaemic and haemorrhagic lesions seen on a cerebral CT scan led to the diagnosis of haemolytic-uraemic syndrome (HUS). Despite these severe complications, the patient made a good recovery following ICU and plasma exchange with fresh frozen plasma (FFP), but cognitive deficit still existed after 1 month. It is important to know that neurological manifestations can precede typical biological and radiological signs in HUS, and to not be misled in the diagnosis process, especially when a more common differential diagnosis is possible. PMID- 25540210 TI - Recurrent clot anuria following laparoscopic pyeloplasty in a solitary functioning kidney: managing with double guide wire technique. AB - Clot anuria in a solitary functioning kidney is an emergency situation. Haematuria with clot anuria in an early postoperative period represents a challenge, as treatment options are limited. Manipulation of the anastomotic site may lead to anastomotic disruption and urinoma while use of thrombolytic therapy poses the danger of increasing haematuria. We report a case of anuria due to clot retention in the upper tract following laparoscopic dismembered pyeloplasty in a solitary functioning kidney, managed successfully with double guide wire technique. PMID- 25540211 TI - Expanding the indications: distal femoral osteotomy used successfully to treat recurrent knee effusion. AB - Distal femoral osteotomy (DFO) is successful in treating painful valgus arthritis of the knee. We present a case where painless recurrent knee effusion was attributed to constitutional valgus. The absence of pain made the indication for surgery atypical so DFO was carefully considered and planned. A small correction was performed, bringing alignment closer to neutral with complete resolution of the recurrent effusion. We suggest that the indications for knee osteotomy can be expanded to include recurrent joint effusion in carefully selected patients. PMID- 25540213 TI - Meckel's diverticulum with intussusception in a 5-year-old patient with Down's syndrome. AB - Meckel's diverticulum is understood to be the commonest congenital malformation within the gastrointestinal tract with a prevalence of 2%, as found on autopsy studies. Although many cases are asymptomatic, complications can occur including haemorrhage, diverticulitis, chronic ulceration and intestinal obstruction. Intussusception is also a complication, but extremely rare. We present a rare case of Meckel's diverticulum causing intussusception, which was surgically resolved, in a 5-year-old girl. Our aim through this case report is to generate greater awareness of this complication and to provide some potential guidance towards its treatment. PMID- 25540212 TI - A woman's experience of tapering from buprenorphine during pregnancy. AB - Although opioid maintenance treatment (OMT) is the treatment of choice for pregnant opioid-dependent patients, some professionals argue that tapering the medication dose will reduce the severity of neonatal abstinence syndrome (NAS). This case description is based on the patient's detailed blog, and medical records from her general practitioner and the hospital. The patient is an employed, 32-year-old drug-abstinent woman in OMT. Her taper from 24 mg of buprenorphine started at 14 weeks' gestation and is slow, with withdrawal symptoms increasing gradually. In pregnancy week 31, she is off buprenorphine but she has severe withdrawal symptoms. She chose to go back on 4 mg of buprenorphine. The patient's son was born in pregnancy week 38+3, weighs 2950 g and does not require pharmacological treatment for NAS. The fetus most probably did experience fetal stress during the patient's tapering. It was the right decision by the patient to go back on buprenorphine. PMID- 25540214 TI - Sunitinib and improved diabetes control. AB - There is increasing use of tyrosine kinase inhibitors as targeted therapy for several malignancies. Sunitinib is the first-line treatment for renal cancer and we report a case of a man receiving this medication who also had diabetes. When started on sunitinib he experienced improvement in his diabetes control with reduction in his insulin requirements, which later worsened when sunitinib was reduced or stopped. Several retrospective studies have been performed demonstrating this effect with sunitinib, but to date no prospective studies have been reported. Most tyrosine kinase inhibitors reduce blood glucose levels in diabetics, but some agents, such as nilotinib, may increase them. There is no consensus on the mechanism of action of sunitinib in reducing glucose levels. Several theories have been postulated, such as increased insulin secretion, increased insulin sensitivity, reduced loss of islet cells, the gastrointestinal side effects of sunitinib, or an interaction with other antihyperglycaemic agents. PMID- 25540215 TI - Idiopathic aneurysmal giant right atrial enlargement with thrombus formation. AB - A 12-year-old boy presented to our outpatient department with progressive dyspnoea and palpitations of 6-month duration. Cardiovascular system examination revealed a short ejection systolic murmur at the left lateral heart border. Chest X-ray showed gross cardiomegaly. Two-dimensional ECHO revealed massive aneurysmal right atrial (RA) enlargement, low-pressure tricuspid regurgitation and dysplastic tricuspid valve with compression of the left atrium (LA) and left ventricle (LV). Cardiac CT showed grossly enlarged RA compressing the LA, LV, right pulmonary artery and right upper lobe pulmonary vein. Initially, the patient refused surgery. On follow-up, a thrombus was seen in the giant RA and the patient agreed to and underwent successful surgery. Absence of pericardium was specifically excluded on cardiac MRI and on surgery. Resected atrial tissue showed wall thinning and focal fibrosis establishing idiopathic dilation of the RA. The patient is on regular follow-up. PMID- 25540217 TI - The effect of sensory feedback on crayfish posture and locomotion: I. Experimental analysis of closing the loop. AB - The effect of proprioceptive feedback on the control of posture and locomotion was studied in the crayfish Procambarus clarkii (Girard). Sensory and motor nerves of an isolated crayfish thoracic nerve cord were connected to a computational neuromechanical model of the crayfish thorax and leg. Recorded levator (Lev) and depressor (Dep) nerve activity drove the model Lev and Dep muscles to move the leg up and down. These movements released and stretched a model stretch receptor, the coxobasal chordotonal organ (CBCO). Model CBCO length changes drove identical changes in the real CBCO; CBCO afferent responses completed the feedback loop. In a quiescent preparation, imposed model leg lifts evoked resistance reflexes in the Dep motor neurons that drove the leg back down. A muscarinic agonist, oxotremorine, induced an active state in which spontaneous Lev/Dep burst pairs occurred and an imposed leg lift excited a Lev assistance reflex followed by a Lev/Dep burst pair. When the feedback loop was intact, Lev/Dep burst pairs moved the leg up and down rhythmically at nearly three times the frequency of burst pairs when the feedback loop was open. The increased rate of rhythmic bursting appeared to result from the positive feedback produced by the assistance reflex. PMID- 25540216 TI - Human perceptual overestimation of whole body roll tilt in hypergravity. AB - Hypergravity provides a unique environment to study human perception of orientation. We utilized a long-radius centrifuge to study perception of both static and dynamic whole body roll tilt in hypergravity, across a range of angles, frequencies, and net gravito-inertial levels (referred to as G levels). While studies of static tilt perception in hypergravity have been published, this is the first to measure dynamic tilt perception (i.e., with time-varying canal stimulation) in hypergravity using a continuous matching task. In complete darkness, subjects reported their orientation perception using a haptic task, whereby they attempted to align a hand-held bar with their perceived horizontal. Static roll tilt was overestimated in hypergravity, with more overestimation at larger angles and higher G levels, across the conditions tested (overestimated by ~35% per additional G level, P < 0.001). As our primary contribution, we show that dynamic roll tilt was also consistently overestimated in hypergravity (P < 0.001) at all angles and frequencies tested, again with more overestimation at higher G levels. The overestimation was similar to that for static tilts at low angular velocities but decreased at higher angular velocities (P = 0.006), consistent with semicircular canal sensory integration. To match our findings, we propose a modification to a previous Observer-type canal-otolith interaction model. Specifically, our data were better modeled by including the hypothesis that the central nervous system treats otolith stimulation in the utricular plane differently than stimulation out of the utricular plane. This modified model was able to simulate quantitatively both the static and the dynamic roll tilt overestimation in hypergravity measured experimentally. PMID- 25540219 TI - A function for binaural integration in auditory grouping and segregation in the inferior colliculus. AB - Responses of neurons to binaural, harmonic complex stimuli in urethane anesthetized guinea pig inferior colliculus (IC) are reported. To assess the binaural integration of harmonicity cues for sound segregation and grouping, responses were measured to harmonic complexes with different fundamental frequencies presented to each ear. Simultaneously gated harmonic stimuli with fundamental frequencies of 125 Hz and 145 Hz were presented to the left and right ears, respectively, and recordings made from 96 neurons with characteristic frequencies >2 kHz in the central nucleus of the IC. Of these units, 70 responded continuously throughout the stimulus and were excited by the stimulus at the contralateral ear. The stimulus at the ipsilateral ear excited (EE: 14%; 10/70), inhibited (EI: 33%; 23/70), or had no significant effect (EO: 53%; 37/70), defined by the effect on firing rate. The neurons phase locked to the temporal envelope at each ear to varying degrees depending on signal level. Many of the cells (predominantly EO) were dominated by the response to the contralateral stimulus. Another group (predominantly EI) synchronized to the contralateral stimulus and were suppressed by the ipsilateral stimulus in a phasic manner. A third group synchronized to the stimuli at both ears (predominantly EE). Finally, a group only responded when the waveform peaks from each ear coincided. We conclude that these groups of neurons represent different "streams" of information but exhibit modifications of the response rather than encoding a feature of the stimulus, like pitch. PMID- 25540218 TI - Impaired firing properties of dentate granule neurons in an Alzheimer's disease animal model are rescued by PPARgamma agonism. AB - Early cognitive impairment in Alzheimer's disease (AD) correlates with medial temporal lobe dysfunction, including two areas essential for memory formation: the entorhinal cortex and dentate gyrus (DG). In the Tg2576 animal model for AD amyloidosis, activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma) with rosiglitazone (RSG) ameliorates hippocampus-dependent cognitive impairment and restores aberrant synaptic activity at the entorhinal cortex to DG granule neuron inputs. It is unknown, however, whether intrinsic firing properties of DG granule neurons in these animals are affected by amyloid-beta pathology and if they are sensitive to RSG treatment. Here, we report that granule neurons from 9-mo-old wild-type and Tg2576 animals can be segregated into two cell types with distinct firing properties and input resistance that correlate with less mature type I and more mature type II neurons. The DG type I cell population was greater than type II in wild-type littermates. In the Tg2576 animals, the type I and type II cell populations were nearly equal but could be restored to wild-type levels through cognitive enhancement with RSG. Furthermore, Tg2576 cell firing frequency and spike after depolarization were decreased in type I and increased in type II cells, both of which could also be restored to wild-type levels upon RSG treatment. That these parameters were restored by PPARgamma activation emphasizes the therapeutic value of RSG against early AD cognitive impairment. PMID- 25540220 TI - Decomposition of surface EMG signals from cyclic dynamic contractions. AB - Over the past 3 decades, various algorithms used to decompose the electromyographic (EMG) signal into its constituent motor unit action potentials (MUAPs) have been reported. All are limited to decomposing EMG signals from isometric contraction. In this report, we describe a successful approach to decomposing the surface EMG (sEMG) signal collected from cyclic (repeated concentric and eccentric) dynamic contractions during flexion/extension of the elbow and during gait. The increased signal complexity introduced by the changing shapes of the MUAPs due to relative movement of the electrodes and the lengthening/shortening of muscle fibers was managed by an incremental approach to enhancing our established algorithm for decomposing sEMG signals obtained from isometric contractions. We used machine-learning algorithms and time-varying MUAP shape discrimination to decompose the sEMG signal from an increasingly challenging sequence of pseudostatic and dynamic contractions. The accuracy of the decomposition results was assessed by two verification methods that have been independently evaluated. The firing instances of the motor units had an accuracy of ~90% with a MUAP train yield as high as 25. Preliminary observations from the performance of motor units during cyclic contractions indicate that during repetitive dynamic contractions, the control of motor units is governed by the same rules as those evidenced during isometric contractions. Modifications in the control properties of motoneuron firings reported by previous studies were not confirmed. Instead, our data demonstrate that the common drive and hierarchical recruitment of motor units are preserved during concentric and eccentric contractions. PMID- 25540221 TI - Testosterone modulates preattentive sensory processing and involuntary attention switches to emotional voices. AB - Testosterone is capable of altering facial threat processing. Voices, similar to faces, convey social information. We hypothesized that administering a single dose of testosterone would change voice perception in humans. In a placebo controlled, randomly assigned, double-blind crossover design, we administered a single dose of testosterone or placebo to 18 healthy female volunteers and used a passive auditory oddball paradigm. The mismatch negativity (MMN) and P3a in responses to fearfully, happily, and neutrally spoken syllables dada and acoustically matched nonvocal sounds were analyzed, indicating preattentive sensory processing and involuntary attention switches. Results showed that testosterone administration had a trend to shorten the peak latencies of happy MMN and significantly enhanced the amplitudes of happy and fearful P3a, whereas the happy- and fearful-derived nonvocal MMN and P3a remained unaffected. These findings demonstrated acute effect of testosterone on the neural dynamics of voice perception. Administering a single dose of testosterone modulates preattentive sensory processing and involuntary attention switches in response to emotional voices. PMID- 25540222 TI - Temporal and spatial limits of pattern motion sensitivity in macaque MT neurons. AB - Many neurons in visual cortical area MT signal the direction of motion of complex visual patterns, such as plaids composed of two superimposed drifting gratings. To compute the direction of pattern motion, MT neurons combine component motion signals over time and space. To determine the spatial and temporal limits of signal integration, we measured the responses of single MT neurons to a novel set of "pseudoplaid" stimuli in which the component gratings were alternated in time or space. As the temporal or spatial separation of the component gratings increased, neuronal selectivity for the direction of pattern motion decreased. Using descriptive models of signal integration, we inferred the temporal and spatial structure of the mechanisms that compute pattern direction selectivity. The median time constant for integration was roughly 10 ms, a timescale characteristic of integration by single cortical pyramidal neurons. The median spatial integration field was roughly one-third of the MT receptive field diameter, suggesting that the spatial limits are set by stages of processing in earlier areas of visual cortex where receptive fields are smaller than in MT. Interestingly, pattern direction-selective neurons had shorter temporal integration times than component direction-selective neurons but similar spatial integration windows. We conclude that pattern motion can only be signaled by MT neurons when the component motion signals co-occur within relatively narrow spatial and temporal limits. We interpret these results in the framework of recent hierarchical models of MT. PMID- 25540223 TI - Parallel processing streams for motor output and sensory prediction during action preparation. AB - Sensory consequences of one's own actions are perceived as less intense than identical, externally generated stimuli. This is generally taken as evidence for sensory prediction of action consequences. Accordingly, recent theoretical models explain this attenuation by an anticipatory modulation of sensory processing prior to stimulus onset (Roussel et al. 2013) or even action execution (Brown et al. 2013). Experimentally, prestimulus changes that occur in anticipation of self generated sensations are difficult to disentangle from more general effects of stimulus expectation, attention and task load (performing an action). Here, we show that an established manipulation of subjective agency over a stimulus leads to a predictive modulation in sensory cortex that is independent of these factors. We recorded magnetoencephalography while subjects performed a simple action with either hand and judged the loudness of a tone caused by the action. Effector selection was manipulated by subliminal motor priming. Compatible priming is known to enhance a subjective experience of agency over a consequent stimulus (Chambon and Haggard 2012). In line with this effect on subjective agency, we found stronger sensory attenuation when the action that caused the tone was compatibly primed. This perceptual effect was reflected in a transient phase-locked signal in auditory cortex before stimulus onset and motor execution. Interestingly, this sensory signal emerged at a time when the hemispheric lateralization of motor signals in M1 indicated ongoing effector selection. Our findings confirm theoretical predictions of a sensory modulation prior to self generated sensations and support the idea that a sensory prediction is generated in parallel to motor output (Walsh and Haggard 2010), before an efference copy becomes available. PMID- 25540224 TI - Functional territories in primate substantia nigra pars reticulata separately signaling stable and flexible values. AB - Gaze is strongly attracted to visual objects that have been associated with rewards. Key to this function is a basal ganglia circuit originating from the caudate nucleus (CD), mediated by the substantia nigra pars reticulata (SNr), and aiming at the superior colliculus (SC). Notably, subregions of CD encode values of visual objects differently: stably by CD tail [CD(T)] vs. flexibly by CD head [CD(H)]. Are the stable and flexible value signals processed separately throughout the CD-SNr-SC circuit? To answer this question, we identified SNr neurons by their inputs from CD and outputs to SC and examined their sensitivity to object values. The direct input from CD was identified by SNr neuron's inhibitory response to electrical stimulation of CD. We found that SNr neurons were separated into two groups: 1) neurons inhibited by CD(T) stimulation, located in the caudal-dorsal-lateral SNr (cdlSNr), and 2) neurons inhibited by CD(H) stimulation, located in the rostral-ventral-medial SNr (rvmSNr). Most of CD(T)-recipient SNr neurons encoded stable values, whereas CD(H)-recipient SNr neurons tended to encode flexible values. The output to SC was identified by SNr neuron's antidromic response to SC stimulation. Among the antidromically activated neurons, many encoded only stable values, while some encoded only flexible values. These results suggest that CD(T)-cdlSNr-SC circuit and CD(H) rvmSNr-SC circuit transmit stable and flexible value signals, largely separately, to SC. The speed of signal transmission was faster through CD(T)-cdlSNr-SC circuit than through CD(H)-rvmSNr-SC circuit, which may reflect automatic and controlled gaze orienting guided by these circuits. PMID- 25540226 TI - Asymmetry and modulation of spike timing in electrically coupled neurons. AB - Electrical coupling mediates interactions between neurons of the thalamic reticular nucleus (TRN), which play a critical role in regulating thalamocortical and corticothalamic communication by inhibiting thalamic relay cells. Accumulating evidence has shown that asymmetry of electrical synapses is a fundamental and dynamic property, but the effect of asymmetry on coupled networks is unexplored. Recording from patched pairs in rat brain slices, we investigate asymmetry in the subthreshold regime and show that electrical synapses can exert powerful effects on the spike times of coupled neighbors. Electrical synaptic signaling modulates spike timing by 10-20 ms, in an effect that also exhibits asymmetry. Furthermore, we show through modeling that coupling asymmetry expands the set of outputs for pairs of coupled neurons through enhanced regions of synchrony and reversals of spike order. These results highlight the power and specificity of signaling exerted by electrical synapses, which contribute to information flow across the brain. PMID- 25540227 TI - Flexibility of the axial central pattern generator network for locomotion in the salamander. AB - In tetrapods, limb and axial movements are coordinated during locomotion. It is well established that inter- and intralimb coordination show considerable variations during ongoing locomotion. Much less is known about the flexibility of the axial musculoskeletal system during locomotion and the neural mechanisms involved. Here we examined this issue in the salamander Pleurodeles waltlii, which is capable of locomotion in both aquatic and terrestrial environments. Kinematics of the trunk and electromyograms from the mid-trunk epaxial myotomes were recorded during four locomotor behaviors in freely moving animals. A similar approach was used during rhythmic struggling movements since this would give some insight into the flexibility of the axial motor system. Our results show that each of the forms of locomotion and the struggling behavior is characterized by a distinct combination of mid-trunk motor patterns and cycle durations. Using in vitro electrophysiological recordings in isolated spinal cords, we observed that the spinal networks activated with bath-applied N-methyl-d-aspartate could generate these axial motor patterns. In these isolated spinal cord preparations, the limb motor nerve activities were coordinated with each mid-trunk motor pattern. Furthermore, isolated mid-trunk spinal cords and hemicords could generate the mid-trunk motor patterns. This indicates that each side of the cord comprises a network able to generate coordinated axial motor activity. The roles of descending and sensory inputs in the behavior-related changes in axial motor coordination are discussed. PMID- 25540225 TI - Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex. AB - In rodent cortex GABAA receptor (GABAAR)-mediated synapses are a significant source of input onto GABA neurons, and the properties of these inputs vary among GABA neuron subtypes that differ in molecular markers and firing patterns. Some features of cortical interneurons are different between rodents and primates, but it is not known whether inhibition of GABA neurons is prominent in the primate cortex and, if so, whether these inputs show heterogeneity across GABA neuron subtypes. We thus studied GABAAR-mediated miniature synaptic events in GABAergic interneurons in layer 3 of monkey dorsolateral prefrontal cortex (DLPFC). Interneurons were identified on the basis of their firing pattern as fast spiking (FS), regular spiking (RS), burst spiking (BS), or irregular spiking (IS). Miniature synaptic events were common in all of the recorded interneurons, and the frequency of these events was highest in FS neurons. The amplitude and kinetics of miniature inhibitory postsynaptic potentials (mIPSPs) also differed between DLPFC interneuron subtypes in a manner correlated with their input resistance and membrane time constant. FS neurons had the fastest mIPSP decay times and the strongest effects of the GABAAR modulator zolpidem, suggesting that the distinctive properties of inhibitory synaptic inputs onto FS cells are in part conferred by GABAARs containing alpha1 subunits. Moreover, mIPSCs differed between FS and RS interneurons in a manner consistent with the mIPSP findings. These results show that in the monkey DLPFC GABAAR-mediated synaptic inputs are prominent in layer 3 interneurons and may differentially regulate the activity of different interneuron subtypes. PMID- 25540228 TI - Estimating the time course of population excitatory postsynaptic potentials in motoneurons of spastic stroke survivors. AB - Hyperexcitable motoneurons are likely to contribute to muscle hypertonia after a stroke injury; however, the origins of this hyperexcitability are not clear. One possibility is that the effective duration of the Ia excitatory postsynaptic potential (EPSP) is prolonged, increasing the potential for temporal summation of EPSPs, making action potential initiation easier. Accordingly, the purpose of this study was to quantify the time course of EPSPs in motoneurons of stroke survivors. The experimental protocol, which was based on parameters derived from simulation, involved sequential subthreshold electrical stimuli delivered to the median nerve of hemispheric stroke survivors. The resulting H-reflex responses were recorded in the flexor carpi radialis muscle. H-reflex response probability was then used to quantify the time course of the underlying EPSPs in the motoneuron pool. A population EPSP was estimated based on the probability of evoking an H reflex from the second electrical stimulus in the absence of a reflex response to the first stimulus. The accuracy of this time-course estimate was quantified using a computer simulation that explored a range of feasible EPSP parameters. Our experimental results showed that in all five hemispheric stroke survivors the rate of decay of the population EPSP was consistently slower in spastic compared with the contralateral motoneuron pools. We propose that one potential mechanism for hyperexcitability of motoneurons in spastic stroke survivors may be linked to this prolongation of the Ia EPSP time course. Our subthreshold double-stimulation approach also provides a noninvasive tool for quantifying the time course of EPSPs in both healthy and pathological conditions. PMID- 25540229 TI - Validation of a rapid, semiautomatic image analysis tool for measurement of gastric accommodation and emptying by magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) has advantages for the assessment of gastrointestinal structures and functions; however, processing MRI data is time consuming and this has limited uptake to a few specialist centers. This study introduces a semiautomatic image processing system for rapid analysis of gastrointestinal MRI. For assessment of simpler regions of interest (ROI) such as the stomach, the system generates virtual images along arbitrary planes that intersect the ROI edges in the original images. This generates seed points that are joined automatically to form contours on each adjacent two-dimensional image and reconstructed in three dimensions (3D). An alternative thresholding approach is available for rapid assessment of complex structures like the small intestine. For assessment of dynamic gastrointestinal function, such as gastric accommodation and emptying, the initial 3D reconstruction is used as reference to process adjacent image stacks automatically. This generates four-dimensional (4D) reconstructions of dynamic volume change over time. Compared with manual processing, this semiautomatic system reduced the user input required to analyze a MRI gastric emptying study (estimated 100 vs. 10,000 mouse clicks). This analysis was not subject to variation in volume measurements seen between three human observers. In conclusion, the image processing platform presented processed large volumes of MRI data, such as that produced by gastric accommodation and emptying studies, with minimal user input. 3D and 4D reconstructions of the stomach and, potentially, other gastrointestinal organs are produced faster and more accurately than manual methods. This system will facilitate the application of MRI in gastrointestinal research and clinical practice. PMID- 25540230 TI - Characterization of slow waves generated by myenteric interstitial cells of Cajal of the rabbit small intestine. AB - Slow waves (slow wavesICC) were recorded from myenteric interstitial cells of Cajal (ICC-MY) in situ in the rabbit small intestine, and their properties were compared with those of mouse small intestine. Rabbit slow wavesICC consisted of an upstroke depolarization followed by a distinct plateau component. Ni(2+) and nominally Ca(2+)-free solutions reduced the rate-of-rise and amplitude of the upstroke depolarization. Replacement of Ca(2+) with Sr(2+) enhanced the upstroke component but decreased the plateau component of rabbit slow wavesICC. In contrast, replacing Ca(2+) with Sr(2+) decreased both components of mouse slow wavesICC. The plateau component of rabbit slow wavesICC was inhibited in low extracellular-Cl(-)-concentration (low-[Cl(-)]o) solutions and by 4,4' diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of Cl(-) channels, cyclopiazonic acid (CPA), an inhibitor of internal Ca(2+) pumps, or bumetanide, an inhibitor of Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). Bumetanide also inhibited the plateau component of mouse slow wavesICC. NKCC1-like immunoreactivity was observed mainly in ICC-MY in the rabbit small intestine. Membrane depolarization with a high-K(+) solution reduced the upstroke component of rabbit slow wavesICC. In cells depolarized with elevated external K(+), DIDS, CPA, and bumetanide blocked slow wavesICC. These results suggest that the upstroke component of rabbit slow wavesICC is partially mediated by voltage dependent Ca(2+) influx, whereas the plateau component is dependent on Ca(2+) activated Cl(-) efflux. NKCC1 is likely to be responsible for Cl(-) accumulation in ICC-MY. The results also suggest that the mechanism of the upstroke component differs in rabbit and mouse slow wavesICC in the small intestine. PMID- 25540231 TI - Colon distention induces persistent visceral hypersensitivity by mechanotranscription of pain mediators in colonic smooth muscle cells. AB - Abdominal pain and distention are major complaints in irritable bowel syndrome. Abdominal distention is mainly attributed to intraluminal retention of gas or solid contents, which may cause mechanical stress to the gut wall. Visceral hypersensitivity (VHS) may account for abdominal pain. We sought to determine whether tonic colon distention causes persistent VHS and if so whether mechanical stress-induced expression (mechanotranscription) of pain mediators in colonic smooth muscle cells (SMCs) plays a role in VHS. Human colonic SMCs were isolated and stretched in vitro to investigate whether mechanical stress upregulates expression of the pain mediator cyclooxygenase-2 (COX-2). Rat colon was distended with a 5-cm-long balloon, and gene expression of COX-2, visceromotor response (VMR), and sensory neuron excitability were determined. Static stretch of colonic SMCs induced marked expression of COX-2 mRNA and protein in a force- and time dependent manner. Subnoxious tonic distention of the distal colon at ~30-40 mmHg for 20 or 40 min induced COX-2 expression and PGE2 production in colonic smooth muscle, but not in the mucosa layer. Lumen distention also increased VMR in a force- and time-dependent manner. The increase of VMR persisted for at least 3 days. Patch-clamp experiments showed that the excitability of colon projecting sensory neurons in the dorsal root ganglia was markedly augmented, 24 h after lumen distention. Administration of COX-2 inhibitor NS-398 partially but significantly attenuated distention-induced VHS. In conclusion, tonic lumen distention upregulates expression of COX-2 in colonic SMC, and COX-2 contributes to persistent VHS. PMID- 25540235 TI - Induction of rhythmic transient depolarizations associated with waxing and waning of slow wave activity in intestinal smooth muscle. AB - Cannon described in 1902 the segmentation motor activity of the small intestine (Canon WB. J Med Res 7: 72-75, 1902). This motor pattern can arise when low frequency transient depolarizations are evoked in the interstitial cells of Cajal associated with the deep muscular plexus (ICC-DMP) network, which then affect the omnipresent slow wave activity: changing its regular amplitude into a waxing and waning pattern. The objective of the present study was to investigate physiological stimuli that could induce the low-frequency component. Intracellular recordings were obtained from circular muscle with or without attached mucosa. Decanoic acid (1 mM) and butyric acid (10 mM) both evoked low frequency transient depolarizations but through different mechanisms. Decanoic acid-induced waxing and waning was initiated by purely myogenic means when perfused onto exposed circular muscle. Butyric acid required the intact mucosa and uninhibited neural activity to elicit the low-frequency response. Evidence is provided that the transient rhythmic depolarizations occur in the absence of interstitial cells of Cajal associated with the myenteric plexus (ICC-MP). Onset of the slow transient depolarizations was stimulated by addition of N(omega) nitro-l-arginine (l-NNA; 100 MUM); thus the low-frequency component seems to be under chronic inhibition by nitric oxide. Excitatory tachykinergic stimulation induced the low-frequency component since substance P (0.5 MUM) evoked it in the presence of neural blockade. In summary, interplay between two networks of myogenic pacemakers, neural activity, and nutrient factors such as fatty acids plays a role in the generation of the rhythmic low-frequency component that is essential for the development of the checkered segmentation motor pattern. PMID- 25540234 TI - Humans are more sensitive to the taste of linoleic and alpha-linolenic than oleic acid. AB - Health concerns have led to recommendations to replace saturated fats with unsaturated fats. However, addition of unsaturated fatty acids may lead to changes in the way foods are perceived in the oral cavity. This study tested the taste sensitivity to and emulsion characteristics of oleic, linoleic, and alpha linolenic acids. The hypothesis tested was that oral sensitivity to nonesterified fatty acids would increase with degree of unsaturation but that in vitro viscosities and particle sizes of these emulsions would not differ. Oral taste thresholds were obtained using the three-alternative, forced-choice, ascending method. Each participant was tested on each fat 7 times, for a total of 21 study visits, to account for learning effects. Viscosities were obtained for the blank solutions and all three emulsions. Results indicate lower oral thresholds to linoleic and alpha-linolenic than oleic acid. At higher shear rates, 5% oleic and linoleic acid were more viscous than other samples. More-dilute emulsions showed no significant differences in viscosity. Particle sizes of the emulsions increased very slightly with increasing unsaturation. Together, the emulsion characteristics and oral sensitivity data support a taste mechanism for nonesterified fatty acid detection. PMID- 25540233 TI - Upregulation of bile acid receptor TGR5 and nNOS in gastric myenteric plexus is responsible for delayed gastric emptying after chronic high-fat feeding in rats. AB - Chronic high-fat feeding is associated with functional dyspepsia and delayed gastric emptying. We hypothesize that high-fat feeding upregulates gastric neuronal nitric oxide synthase (nNOS) expression, resulting in delayed gastric emptying. We propose this is mediated by increased bile acid action on bile acid receptor 1 (TGR5) located on nNOS gastric neurons. To test this hypothesis, rats were fed regular chow or a high-fat diet for 2 wk. Rats fed the high-fat diet were subjected to concurrent feeding with oral cholestyramine or terminal ileum resection. TGR5 and nNOS expression in gastric tissue was measured by immunohistochemistry, PCR, and Western blot. Gastric motility was assessed by organ bath and solid-phase gastric emptying studies. The 2-wk high-fat diet caused a significant increase in neurons coexpressing nNOS and TGR5 in the gastric myenteric plexus and an increase in nNOS and TGR5 gene expression, 67 and 111%, respectively. Enhanced nonadrenergic, noncholinergic (NANC) relaxation, deoxycholic acid (DCA)-induced inhibition in fundic tissue, and a 26% delay in gastric emptying accompanied these changes. A 24-h incubation of whole-mount gastric fundus with DCA resulted in increased nNOS and TGR5 protein expression, 41 and 37%, respectively. Oral cholestyramine and terminal ileum resection restored the enhanced gastric relaxation, as well as the elevated nNOS and TGR5 expression evoked by high-fat feeding. Cholestyramine also prevented the delay in gastric emptying. We conclude that increased levels of circulatory bile acids induced by high-fat feeding upregulate nNOS and TGR5 expression in the gastric myenteric plexus, resulting in enhanced NANC relaxation and delayed gastric emptying. PMID- 25540236 TI - Wrinkles enhance the diffuse reflection from the dragonfly Rhyothemis resplendens. AB - The dorsal surfaces of the hindwings of the dragonfly Rhyothemis resplendens (Odonata: Libellulidae) reflect a deep blue from the multilayer structure in its wing membrane. The layers within this structure are not flat, but distinctly 'wrinkled', with a thickness of several hundred nanometres and interwrinkle crest distances of 5 um and greater. A comparison between the backscattered light from R. resplendens and a similar, but un-'wrinkled' multilayer in the damselfly Matronoides cyaneipennis (Odonata: Calopterygidae) shows that the angle over which incident light is backscattered is increased by the wrinkling in the R. resplendens structure. Whereas the reflection from the flat multilayer of M. cyaneipennis is effectively specular, the reflection from the wrinkled R. resplendens multilayer spans 1.47 steradians (equivalent to +/-40 degrees for all azimuthal angles). This property enhances the visibility of the static wing over a broader angle range than is normally associated with a smooth multilayer, thereby markedly increasing its conspicuousness. PMID- 25540232 TI - The gastrointestinal microbiota and colorectal cancer. AB - The human gut is home to a complex and diverse microbiota that contributes to the overall homeostasis of the host. Increasingly, the intestinal microbiota is recognized as an important player in human illness such as colorectal cancer (CRC), inflammatory bowel diseases, and obesity. CRC in itself is one of the major causes of cancer mortality in the Western world. The mechanisms by which bacteria contribute to CRC are complex and not fully understood, but increasing evidence suggests a link between the intestinal microbiota and CRC as well as diet and inflammation, which are believed to play a role in carcinogenesis. It is thought that the gut microbiota interact with dietary factors to promote chronic inflammation and CRC through direct influence on host cell physiology, cellular homeostasis, energy regulation, and/or metabolism of xenobiotics. This review provides an overview on the role of commensal gut microbiota in the development of human CRC and explores its association with diet and inflammation. PMID- 25540237 TI - Network morphospace. AB - The structure of complex networks has attracted much attention in recent years. It has been noted that many real-world examples of networked systems share a set of common architectural features. This raises important questions about their origin, for example whether such network attributes reflect common design principles or constraints imposed by selectional forces that have shaped the evolution of network topology. Is it possible to place the many patterns and forms of complex networks into a common space that reveals their relations, and what are the main rules and driving forces that determine which positions in such a space are occupied by systems that have actually evolved? We suggest that these questions can be addressed by combining concepts from two currently relatively unconnected fields. One is theoretical morphology, which has conceptualized the relations between morphological traits defined by mathematical models of biological form. The second is network science, which provides numerous quantitative tools to measure and classify different patterns of local and global network architecture across disparate types of systems. Here, we explore a new theoretical concept that lies at the intersection between both fields, the 'network morphospace'. Defined by axes that represent specific network traits, each point within such a space represents a location occupied by networks that share a set of common 'morphological' characteristics related to aspects of their connectivity. Mapping a network morphospace reveals the extent to which the space is filled by existing networks, thus allowing a distinction between actual and impossible designs and highlighting the generative potential of rules and constraints that pervade the evolution of complex systems. PMID- 25540238 TI - Magnetoreception in birds: the effect of radio-frequency fields. AB - The avian magnetic compass, probably based on radical pair processes, works only in a narrow functional window around the local field strength, with cryptochrome 1a as most likely receptor molecule. Radio-frequency fields in the MHz range have been shown to disrupt the birds' orientation, yet the nature of this interference is still unclear. In an immuno-histological study, we tested whether the radio frequency fields interfere with the photoreduction of cryptochrome, but this does not seem to be the case. In behavioural studies, birds were not able to adjust to radio-frequency fields like they are able to adjust to static fields outside the normal functional range: neither a 2-h pre-exposure in a 7.0 MHz field, 480 nT, nor a 7-h pre-exposure in a 1.315 MHz field, 15 nT, allowed the birds to regain their orientation ability. This inability to adjust to radio-frequency fields suggests that these fields interfere directly with the primary processes of magnetoreception and therefore disable the avian compass as long as they are present. They do not have lasting adverse after-effects, however, as birds immediately after exposure to a radio-frequency field were able to orient in the local geomagnetic field. PMID- 25540240 TI - Avoiding or restricting defectors in public goods games? AB - When creating a public good, strategies or mechanisms are required to handle defectors. We first show mathematically and numerically that prior agreements with posterior compensations provide a strategic solution that leads to substantial levels of cooperation in the context of public goods games, results that are corroborated by available experimental data. Notwithstanding this success, one cannot, as with other approaches, fully exclude the presence of defectors, raising the question of how they can be dealt with to avoid the demise of the common good. We show that both avoiding creation of the common good, whenever full agreement is not reached, and limiting the benefit that disagreeing defectors can acquire, using costly restriction mechanisms, are relevant choices. Nonetheless, restriction mechanisms are found the more favourable, especially in larger group interactions. Given decreasing restriction costs, introducing restraining measures to cope with public goods free-riding issues is the ultimate advantageous solution for all participants, rather than avoiding its creation. PMID- 25540239 TI - A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET. AB - Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient's disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [(18)F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model-data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning. PMID- 25540241 TI - Joint modelling of serological and hospitalization data reveals that high levels of pre-existing immunity and school holidays shaped the influenza A pandemic of 2009 in the Netherlands. AB - Obtaining a quantitative understanding of the transmission dynamics of influenza A is important for predicting healthcare demand and assessing the likely impact of intervention measures. The pandemic of 2009 provides an ideal platform for developing integrative analyses as it has been studied intensively, and a wealth of data sources is available. Here, we analyse two complementary datasets in a disease transmission framework: cross-sectional serological surveys providing data on infection attack rates, and hospitalization data that convey information on the timing and duration of the pandemic. We estimate key epidemic determinants such as infection and hospitalization rates, and the impact of a school holiday. In contrast to previous approaches, our novel modelling of serological data with mixture distributions provides a probabilistic classification of individual samples (susceptible, immune and infected), propagating classification uncertainties to the transmission model and enabling serological classifications to be informed by hospitalization data. The analyses show that high levels of immunity among persons 20 years and older provide a consistent explanation of the skewed attack rates observed during the pandemic and yield precise estimates of the probability of hospitalization per infection (1-4 years: 0.00096 (95%CrI: 0.00078-0.0012); 5-19 years: 0.00036 (0.00031-0.0044); 20-64 years: 0.0015 (0.00091-0.0020); 65+ years: 0.0084 (0.0028-0.016)). The analyses suggest that in The Netherlands, the school holiday period reduced the number of infectious contacts between 5- and 9-year-old children substantially (estimated reduction: 54%; 95%CrI: 29-82%), thereby delaying the unfolding of the pandemic in The Netherlands by approximately a week. PMID- 25540242 TI - Conformity enhances network reciprocity in evolutionary social dilemmas. AB - The pursuit of highest payoffs in evolutionary social dilemmas is risky and sometimes inferior to conformity. Choosing the most common strategy within the interaction range is safer because it ensures that the payoff of an individual will not be much lower than average. Herding instincts and crowd behaviour in humans and social animals also compel to conformity in their own right. Motivated by these facts, we here study the impact of conformity on the evolution of cooperation in social dilemmas. We show that an appropriate fraction of conformists within the population introduces an effective surface tension around cooperative clusters and ensures smooth interfaces between different strategy domains. Payoff-driven players brake the symmetry in favour of cooperation and enable an expansion of clusters past the boundaries imposed by traditional network reciprocity. This mechanism works even under the most testing conditions, and it is robust against variations of the interaction network as long as degree normalized payoffs are applied. Conformity may thus be beneficial for the resolution of social dilemmas. PMID- 25540243 TI - The role of the surface on microglia function: implications for central nervous system tissue engineering. AB - In tissue engineering, it is well accepted that a scaffold surface has a decisive impact on cell behaviour. Here we focused on microglia-the resident immune cells of the central nervous system (CNS)-and on their response to poly(trimethylene carbonate-co-epsilon-caprolactone) (P(TMC-CL)) fibrous and flat surfaces obtained by electrospinning and solvent cast, respectively. This study aims to provide cues for the design of instructive surfaces that can contribute to the challenging process of CNS regeneration. Cell morphology was evidently affected by the substrate, mirroring the surface main features. Cells cultured on flat substrates presented a round shape, while cells with elongated processes were observed on the electrospun fibres. A higher concentration of the pro inflammatory cytokine tumour necrosis factor-alpha was detected in culture media from microglia on fibres. Still, astrogliosis is not exacerbated when astrocytes are cultured in the presence of microglia-conditioned media obtained from cultures in contact with either substrate. Furthermore, a significant percentage of microglia was found to participate in the process of myelin phagocytosis, with the formation of multinucleated giant cells being observed only on films. Altogether, the results presented suggest that microglia in contact with the tested substrates may contribute to the regeneration process, putting forward P(TMC-CL) substrates as supporting matrices for nerve regeneration. PMID- 25540244 TI - Ocean acidification alters the material properties of Mytilus edulis shells. AB - Ocean acidification (OA) and the resultant changing carbonate saturation states is threatening the formation of calcium carbonate shells and exoskeletons of marine organisms. The production of biominerals in such organisms relies on the availability of carbonate and the ability of the organism to biomineralize in changing environments. To understand how biomineralizers will respond to OA the common blue mussel, Mytilus edulis, was cultured at projected levels of pCO2 (380, 550, 750, 1000 uatm) and increased temperatures (ambient, ambient plus 2 degrees C). Nanoindentation (a single mussel shell) and microhardness testing were used to assess the material properties of the shells. Young's modulus (E), hardness (H) and toughness (KIC) were measured in mussel shells grown in multiple stressor conditions. OA caused mussels to produce shell calcite that is stiffer (higher modulus of elasticity) and harder than shells grown in control conditions. The outer shell (calcite) is more brittle in OA conditions while the inner shell (aragonite) is softer and less stiff in shells grown under OA conditions. Combining increasing ocean pCO2 and temperatures as projected for future global ocean appears to reduce the impact of increasing pCO2 on the material properties of the mussel shell. OA may cause changes in shell material properties that could prove problematic under predation scenarios for the mussels; however, this may be partially mitigated by increasing temperature. PMID- 25540246 TI - Diagnostic accuracy of electrically elicited multiplet discharges in patients with motor neuron disease. AB - OBJECTIVE: To determine and compare the diagnostic accuracy of electrically elicited multiplet discharges (MDs) and fasciculation potentials (FPs) in motor neuron disease (MND). METHODS: Patients were eligible when they had MND in their differential diagnosis and were referred for electromyogram (EMG). Stimulated high-density surface EMG of the thenar muscles was performed on the same day as standard EMG examination. High-density recordings were analysed for presence of MDs and needle EMG of any muscle investigated in the cervical region for presence of FPs. RESULTS: Of the 61 patients enrolled in this diagnostic study, 24 patients were clinically diagnosed with amyotrophic lateral sclerosis (ALS) and 11 patients with progressive muscular atrophy (PMA). Another diagnosis was made in 26 patients. Sixteen patients in whom MDs were detected were diagnosed with either ALS (n = 11) or PMA (n = 5; sensitivity = 47.1%, PPV = 94.1%). MDs were detected in only one patient initially diagnosed with PMA, but in whom later on, multifocal motor neuropathy could not be excluded (specificity = 96.2%). Electrically elicited MDs had a higher specificity than FPs (96.2% vs 53.9%, p < 0.001, n = 26) and lower sensitivity (47.1% vs 85.3%, p = 0.002, n = 34). When considering presence of MDs in MND as neurogenic EMG abnormality, lower motor neuron involvement of >= 1 EMG region increased from 50% to 73.5% (p = 0.008, n = 34). CONCLUSIONS: Electrically evoked MDs are highly specific for ALS and PMA and are an early sign of lower motor neuron dysfunction. PMID- 25540247 TI - Seasonal variation in Guillain-Barre syndrome: a systematic review, meta-analysis and Oxfordshire cohort study. AB - INTRODUCTION: Evidence for seasonal variation in incidence and subtype of Guillain-Barre syndrome (GBS) is contradictory, but has implications for provision of neurological services and understanding pathogenesis. METHODS: We searched PubMed and EMBASE between inception and January 2014, including all studies reporting seasonal incidence of GBS. We included a retrospective cohort study of patients with GBS at the John Radcliffe Hospital, Oxford 2001-2012 and determined the seasonal variation in GBS incidence and length of stay. The incidence rate ratio (IRR) for winter versus summer was pooled across studies by fixed and random effects meta-analysis weighted by inverse variance, stratified by geographical region, infectious prodrome and GBS subtype. RESULTS: Across 9836 patients from 42 studies there was a 14% increased risk of GBS in winter versus summer (IRR=1.14, 1.02-1.27, p=0.020), with significant heterogeneity between studies (I(2)=77%, p<0.0001), including significant seasonal variation in Oxford (n=140; p=0.037) for winter versus summer (IRR=1.92, 1.18-3.11, p=0.004) but a non-significantly reduced length of stay for winter versus other seasons (15 vs 21 days, p=0.08). Across all studies, there was greater seasonal variation with respiratory prodrome (IRR=3.06, 1.84-5.11, p<0.0001) than diarrhoeal prodrome (IRR=1.10, 0.60-2.00, p=0.76) and a greater incidence in winter in Western countries (IRR=1.28), the Far East (IRR=1.20) and Middle East (IRR=1.12), with a lower incidence in the Indian subcontinent (IRR=0.86) and Latin America (IRR=0.75). DISCUSSION: Incidence of GBS was greater in winter than summer, but this was not evident in all geographical regions. This is likely to be related to regional variation in prodromal illnesses. PMID- 25540248 TI - Abused women with children who are first-time users of a shelter or applicants for a protection order: entry data of a 7-year prospective analysis. AB - Worldwide, two models of care are offered most often to abused women-safe shelter and justice services. No evidence exists on the differential effectiveness of the services. To provide evidence, 300 abused women, 150 first-time users of a shelter and 150 first-time applicants for a protection order, signed informed consent to participate in a 7-year study. Safety, abuse, and functioning of the women and their children were measured. Compared with women seeking justice services, women in shelters reported more abuse and depression and less support. The baseline characteristics of these 300 women are presented with implications for practice and policy. PMID- 25540249 TI - When women tell: intimate partner violence and the factors related to police notification. AB - We analyze how victim perceptions of mandatory arrest policies, perpetrator substance use, and presence of children are related to decisions to invoke law enforcement assistance. Logistic regression was used on survey responses from women receiving care in domestic violence shelters. Results suggest that as victim support for mandatory arrest increases, the odds of law enforcement notification of the abuse also increase. Accordingly, mandatory arrest may simply be reducing the probability of reporting intimate partner violence (IPV) among those who do not support the policy, instead of reducing IPV. Results also suggest that perpetrator substance use plays a significant role in law enforcement notification. PMID- 25540250 TI - Outcomes associated with common and immigrant-group-specific responses to intimate terrorism. AB - The research for this article used available qualitative data from separate studies of South Asian-, Vietnamese-, and Hispanic-origin women victimized by intimate terrorism. Regardless of country of origin, period, or U.S. community, women used similar ways to cope. Consistent with perpetrators' misogynistic attitudes and aim of enforcing patriarchal expectations, many women responded to abuse from positions of powerlessness and fear. Instrumental help from family and friends and, depending on the group, advocacy agencies or counseling services assisted women in leaving men or stopping the abuse. Women used multiple coping strategies, often adding new approaches when those used initially failed. PMID- 25540245 TI - The diffusion of docetaxel in patients with metastatic prostate cancer. AB - BACKGROUND: Diffusion of new cancer treatments can be both inefficient and incomplete. The uptake of new treatments over time (diffusion) has not been well studied. We analyzed the diffusion of docetaxel in metastatic prostate cancer. METHODS: We identified metastatic prostate cancer patients diagnosed from 1995 to 2007 using the Surveillance, Epidemiology, and End Results Program (SEER) Medicare database. Medicare claims through 2008 were analyzed. We assessed cumulative incidence of docetaxel by socioeconomic, demographic, and comorbidity variables, and compared diffusion patterns to landmark events including release of phase III results and FDA approval dates. We compared docetaxel diffusion patterns in prostate cancer to those in metastatic breast, lung, ovarian, and gastric cancers. To model docetaxel use over time, we used the classic "mixed influence" deterministic diffusion model. All statistical tests were two-sided. RESULTS: We identified 6561 metastatic prostate cancer patients; 1350 subsequently received chemotherapy. Among patients who received chemotherapy, docetaxel use was 95% by 2008. Docetaxel uptake was statistically significantly slower (P < .01) for patients older than 65 years, blacks, patients in lower income areas, and those who experienced poverty. Eighty percent of docetaxel diffusion occurred prior to the May, 2004 release of phase III results showing superiority of docetaxel over standard-of-care. The maximum increase in the rate of use of docetaxel occurred nearly simultaneously for prostate cancer as for all other cancers combined (in 2000). CONCLUSION: Efforts to increase the diffusion of treatments with proven survival benefits among disadvantaged populations could lead to cancer population survival gains. Docetaxel diffusion mostly preceded phase III evidence for its efficacy in castration-resistant prostate cancer, and appeared to be a cancer-wide-rather than a disease-specific-phenomenon. Diffusion prior to definitive evidence indicates the prevalence of off-label chemotherapy use. PMID- 25540251 TI - Does neighborhood environment differentiate intimate partner femicides from other femicides? AB - We examined the association between neighborhood-level factors and intimate partner femicide (IPF) using Wisconsin Violent Death Reporting System (WVDRS) data and Wisconsin Coalition Against Domestic Violence (WCADV) reports, in concert with neighborhood-level information. After controlling for individual characteristics, neighborhood-level disadvantage was associated with a decreased likelihood of IPF status, as compared with other femicides, whereas neighborhood level residential instability was associated with an increased likelihood of IPF status. Neighborhood plays a role in differentiating IPFs from other femicides in our study area. Our findings demonstrate the importance of multilevel strategies for understanding and reducing the burden of intimate partner violence. PMID- 25540252 TI - World assumptions, religiosity, and PTSD in survivors of intimate partner violence. AB - Intimate partner violence (IPV) is among the most frequent types of violence annually affecting women. One frequent outcome of violence exposure is posttraumatic stress disorder (PTSD). The theory of shattered world assumptions represents one possible explanation for adverse mental health outcomes following trauma, contending that trauma disintegrates individuals' core assumptions that the world is safe and meaningful, and that the self is worthy. Research that explores world assumptions in relationship to survivors of IPV has remained absent. A more consistent finding in research on IPV suggests that religiosity is strongly associated with survivors' reactions to, and recovery from, IPV. The present study found that world assumptions was a significant mediator of the relationship between IPV exposure and PTSD symptoms. Religiosity was also significantly, positively related to PTSD symptoms, but was not significantly related to amount of IPV exposure. Though African American women reported more IPV exposure and greater religiosity than European American women in the sample, there were no interethnic differences in PTSD symptom endorsement. Implications of these findings are discussed. PMID- 25540253 TI - The relation between alcohol use and psychological, physical, and sexual dating violence perpetration among male college students. AB - The prevalence of alcohol use and dating violence are shockingly high among male college students, making this a particularly high-risk group for alcohol-related aggression. Expanding upon previous research, the current study examined the relations between three indicators of alcohol use and three types of dating violence among 204 male college students. We also examined whether hazardous drinkers reported more violence perpetration than non-hazardous drinkers. Results demonstrated that alcohol use was related to all types of aggression, and hazardous drinkers are at greater risk of violence perpetration than non hazardous drinkers. Implications for dating violence prevention programs and future research are discussed. PMID- 25540254 TI - What counts? A mixed-methods study to inform evaluation of shelters for abused women. AB - Shelters for abused women have expanded from "safe havens" to providing a range of residential and outreach services, and face increasing pressure to demonstrate "value for money" by providing evaluation metrics that may or may not reflect what they actually do. We conducted interviews and surveys with 68 shelter directors in Ontario, Canada, and found that differences in service philosophy and how abuse is defined influence decisions about who receives services and the shelter's role in the broader community; these in turn affect how the work of shelters is positioned. Implications for shelter service evaluation are discussed. PMID- 25540255 TI - Changing attitudes about being a bystander to violence: translating an in-person sexual violence prevention program to a new campus. AB - Bystander approaches to reducing sexual violence train community members in prosocial roles to interrupt situations with risk of sexual violence and be supportive community allies after an assault. This study employs a true experimental design to evaluate the effectiveness of Bringing in the BystanderTM through 1-year post-implementation with first-year students from two universities (one rural, primarily residential; one urban, heavily commuter). We found significant change in bystander attitudes for male and female student program participants compared with the control group on both campuses, although the pattern of change depended on the combination of gender and campus. PMID- 25540256 TI - Exploring the potential for changing gender norms among cricket coaches and athletes in India. AB - This study explored gender norms with cricket coaches and athletes in India to adapt a coach-delivered gender violence prevention program from the United States for the urban Indian context. Interviews and focus groups conducted among coaches and adolescent cricketers highlight the extent to which coaches and athletes articulate prevailing inequitable notions about gender and recognition of the power coaches wield. Adapting a violence prevention program that emphasizes gender norms change may be feasible with Indian cricket coaches but is likely to require attention to defining gender equity and challenging cultural assumptions with coaches prior to implementing the program with athletes. PMID- 25540257 TI - Intimate partner homicide: new insights for understanding lethality and risks. AB - Research on covictims, family members, and close friends who have lost loved ones to intimate partner homicide (IPH) is a neglected area of study. We conducted phenomenological interviews with covictims to gain insights into risk and lethality, examined affidavits from criminal case files, and reviewed news releases. The data uncovered acute risk factors prior to the homicide, identified changes in the perpetrators' behavior and the perpetrators' perceived loss of control over the victim, and described barriers that victims faced when attempting to gain safety. Findings suggest that recognizing acute risk factors is an important area for future IPH research. PMID- 25540258 TI - The role of economic factors on women's risk for intimate partner violence: a cross-national comparison of Canada and the United States. AB - National data from Canada and the United States are used to examine the connection between women's economic contributions to the family and their risk for physical and emotional abuse. Analyses show that American women are at a twofold greater risk; however, the relationship between economic variables and the risk of both physical violence and coercive control are more complex. Income serves to reduce the risk of both violence and coercive control for both Canadian and American women, whereas education serves as a clear protective factor for American women, but does not provide the same benefit for Canadian women. PMID- 25540263 TI - Key characteristics of specular stereo. AB - Because specular reflection is view-dependent, shiny surfaces behave radically differently from matte, textured surfaces when viewed with two eyes. As a result, specular reflections pose substantial problems for binocular stereopsis. Here we use a combination of computer graphics and geometrical analysis to characterize the key respects in which specular stereo differs from standard stereo, to identify how and why the human visual system fails to reconstruct depths correctly from specular reflections. We describe rendering of stereoscopic images of specular surfaces in which the disparity information can be varied parametrically and independently of monocular appearance. Using the generated surfaces and images, we explain how stereo correspondence can be established with known and unknown surface geometry. We show that even with known geometry, stereo matching for specular surfaces is nontrivial because points in one eye may have zero, one, or multiple matches in the other eye. Matching features typically yield skew (nonintersecting) rays, leading to substantial ortho-epipolar components to the disparities, which makes deriving depth values from matches nontrivial. We suggest that the human visual system may base its depth estimates solely on the epipolar components of disparities while treating the ortho epipolar components as a measure of the underlying reliability of the disparity signals. Reconstructing virtual surfaces according to these principles reveals that they are piece-wise smooth with very large discontinuities close to inflection points on the physical surface. Together, these distinctive characteristics lead to cues that the visual system could use to diagnose specular reflections from binocular information. PMID- 25540264 TI - Supra-additive contribution of shape and surface information to individual face discrimination as revealed by fast periodic visual stimulation. AB - Face perception depends on two main sources of information--shape and surface cues. Behavioral studies suggest that both of them contribute roughly equally to discrimination of individual faces, with only a small advantage provided by their combination. However, it is difficult to quantify the respective contribution of each source of information to the visual representation of individual faces with explicit behavioral measures. To address this issue, facial morphs were created that varied in shape only, surface only, or both. Electrocephalogram (EEG) were recorded from 10 participants during visual stimulation at a fast periodic rate, in which the same face was presented four times consecutively and the fifth face (the oddball) varied along one of the morphed dimensions. Individual face discrimination was indexed by the periodic EEG response at the oddball rate (e.g., 5.88 Hz/5 = 1.18 Hz). While shape information was discriminated mainly at right occipitotemporal electrode sites, surface information was coded more bilaterally and provided a larger response overall. Most importantly, shape and surface changes alone were associated with much weaker responses than when both sources of information were combined in the stimulus, revealing a supra-additive effect. These observations suggest that the two kinds of information combine nonlinearly to provide a full individual face representation, face identity being more than the sum of the contribution of shape and surface cues. PMID- 25540265 TI - Bone-specific alkaline phosphatase by immunoassay or electrophoresis: their use in clinical practice. AB - BACKGROUND: Measurement of bone-specific alkaline phosphatase (BALP) may be useful in diagnosing and monitoring metabolic bone disease. This study aimed to evaluate the BALP immunoassay and compare it with electrophoresis (densitometry) for the quantitation of BALP. METHODS: Metra BALP immunoassay kits were used for the method comparison. BALP was also quantitated by electrophoresis (densitometry) in seven patients with active Paget's disease. RESULTS: Immunoassay results did not correlate well with densitometrically quantitated BALP, as there was a statistically significant (p<0.01), negative bias (22%) for results obtained by immunoassay compared with those derived by densitometry. Possible interference in the immunoassay with other isoforms of alkaline phosphatase (ALP) such as liver, placental and intestinal was also observed. The Metra BALP immunoassay is quoted as having an upper dynamic limit of 140 U/L and recommends that samples only require dilution above this level; we observed inconsistent results upon dilution of samples below this level. CONCLUSIONS: Immunoassay and electrophoresis did not correlate well for BALP quantitation. Possible interference with other isoforms of ALP was observed with the BALP immunoassay. The accuracy of the BALP immunoassay is questionable at higher concentrations. PMID- 25540266 TI - Improved detection of hereditary haemochromatosis. AB - AIMS: There is high prevalence of hereditary haemochromatosis (HH) in North European populations, yet the diagnosis is often delayed or missed in primary care. Primary care physicians frequently request serum ferritin (SF) estimation but appear uncertain as how to investigate patients with raised SF values. Our aim was to develop a laboratory algorithm with high predictive value for the diagnosis of HH in patients from primary care with raised SF values. METHODS: Transferrin saturation (Tsat) was measured on SF samples sent from primary care; 1657 male and 2077 female patients age >= 30 years with SF >= 200 MUg/L. HFE genotyping was performed on all 878 male and 867 female patients with Tsat >30%. RESULTS: This study identified 402 (206 men; 196 women) C282Y carriers and 132 (58 men; 74 women) C282Y homozygotes. Optimal limits for combined SF and Tsat values for HH recognition were established. The detection rate for homozygous C282Y HH for male patients with both SF >= 300 MUg/L and Tsat >50% was 18.8% (52/272) and 16.3% (68/415) for female patients with both SF >= 200 MUg/L and Tsat >40%. CONCLUSIONS: The large number of SF requests received from primary care should be used as a resource to improve the diagnosis of HH in areas of high prevalence. PMID- 25540267 TI - Matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry (MS) for the identification of mycobacteria from MBBacT ALERT 3D liquid cultures and Lowenstein-Jensen (LJ) solid cultures. AB - AIMS: Conventional methods for the identification of mycobacteria can be demanding and prolonged. Molecular methodologies, although rapid, are expensive and often exclusive to reference laboratories. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) presents a possible alternative method for the identification and differentiation of mycobacteria. This study describes the design and validation of a mycobacteria inactivation protocol and subsequent evaluation of MALDI-TOF MS for the identification of mycobacteria in a clinical microbiology laboratory setting. METHODS: A total of 65 non-tuberculous mycobacteria (NTM) isolates and 86 Mycobacterium tuberculosis complex (MTC) isolates were tested on the Bruker MALDI Biotyper Microflex, V.3.1. NTM solid-culture (Lowenstein-Jensen, LJ slopes) isolates (n=21) and liquid-culture (MBBacT ALERT 3D bottles) isolates (n=44) were tested. MTC solid-culture isolates (n=30) and liquid-culture isolates (n=56) were also tested. Isolates were subjected to the validated inactivation protocol and analysed on the MALDI-TOF MS instrument. RESULTS: The inactivation protocol designed was successfully validated and applied to all test isolates. MALDI-TOF MS correctly identified 82.8% of all isolates analysed; 96.7% and 96.4% of MTC isolates and 76.2% and 52.3% of NTM isolates were successfully identified from solid and liquid culture, respectively. MALDI-TOF MS failed to identify 35.4% (n=23) of NTM isolates and 3.5% (n=3) of MTC isolates. CONCLUSIONS: MALDI-TOF MS has potential for identifying mycobacteria in the clinical laboratory setting, by reducing identification turnaround time and laboratory costs in isolate referral. Isolates that failed to be identified are explained by limitations of the method. PMID- 25540268 TI - An inactivated Ross River virus vaccine is well tolerated and immunogenic in an adult population in a randomized phase 3 trial. AB - Ross River virus (RRV) is endemic in Australia and several South Pacific Islands. More than 90,000 cases of RRV disease, which is characterized by debilitating polyarthritis, were reported in Australia in the last 20 years. There is no vaccine available to prevent RRV disease. A phase 3 study was undertaken at 17 sites in Australia to investigate the safety and immunogenicity of an inactivated whole-virus Vero cell culture-derived RRV vaccine in 1,755 healthy younger adults aged 16 to 59 years and 209 healthy older adults aged >=60 years. Participants received a 2.5-MUg dose of Al(OH)(3)-adjuvanted RRV vaccine, with a second and third dose after 3 weeks and 6 months, respectively. Vaccine-induced RRV-specific neutralizing and total IgG antibody titers were measured after each immunization. Vaccine safety was monitored over the entire study period. The vaccine was safe and well-tolerated after each vaccination. No cases of arthritis resembling RRV disease were reported. The most frequently reported systemic reactions were headache, fatigue, and malaise; the most frequently reported injection site reactions were tenderness and pain. After the third immunization, 91.5% of the younger age group and 76.0% of the older age group achieved neutralizing antibody titers of >=1:10; 89.1% of the younger age group and 70.9% of the older age group achieved enzyme-linked immunosorbent assay (ELISA) titers of >=11 PanBio units. A whole-virus Vero cell culture-derived RRV vaccine is well tolerated in an adult population and induces antibody titers associated with protection from RRV disease in the majority of individuals. (This study is registered at www.clinicaltrials.gov under registration no. NCT01242670.). PMID- 25540270 TI - Survey of immunological features of the alpha-like proteins of Streptococcus agalactiae. AB - Nearly all Streptococcus agalactiae (group B streptococcus [GBS]) strains express a protein which belongs to the so-called alpha-like proteins (Alps), of which Calpha, Alp1, Alp2, Alp3, Rib, and Alp4 are known to occur in GBS. The Alps are chimeras which form mosaic structures on the GBS surface. Both N- and C-terminal stretches of the Alps possess immunogenic sites of dissimilar immunological specificity. In this review, we have compiled data dealing with the specificity of the N- and C-terminal immunogenic sites of the Alps. The majority of N terminal sites show protein specificity while the C-terminal sites show broader cross-reactivity. Molecular serotyping has revealed that antibody-based serotyping has often resulted in erroneous Alp identification, due to persistence of cross-reacting antibodies in antisera for serotyping. Retrospectively, this could be expected on the basis of sequence analysis results. Some of the historical R proteins are in fact Alps. The data included in the review may provide a basis for decisions regarding techniques for the preparation of specific antisera for serotyping of GBS, for use in other approaches in GBS research, and for decision making in the context of GBS vaccine developments. PMID- 25540271 TI - Prospective cohort study on the effectiveness of influenza and pneumococcal vaccines in preventing pneumonia development and hospitalization. AB - Pneumonia and acute exacerbation of chronic illness are leading causes of influenza-related hospitalization. Therefore, influenza and pneumococcal vaccinations are strongly recommended for adults with comorbidities. Using a hospital-based influenza surveillance system, we performed a multicenter, prospective cohort study of patients visiting emergency rooms with influenza-like illness (ILI) during the influenza epidemic period in 2013 to 2014. Patients aged >= 19 years were enrolled, and clinical data were collected. Multivariate analyses were performed to estimate the effectiveness of influenza and pneumococcal vaccination in preventing pneumonia development and hospitalization. During study periods, 2,262 patients with ILI were registered. Among 2,217 patients with available vaccination records, 31.9% (707 patients) and 9.7% (216 patients) had received influenza and pneumococcal vaccines, respectively. Among patients who had been administered a pneumococcal vaccine, 94.4% had received the 23-valent polysaccharide vaccine (PPV23). The adjusted rates of effectiveness of the influenza vaccine for preventing pneumonia development and hospitalization were 64.0% (95% confidence interval [CI] = 29% to 81%) and 35.0% (95% CI = 12% to 52%), respectively. Pneumococcal vaccination did not reduce pneumonia development or hospitalization. In conclusion, influenza rather than PPV23 vaccination may reduce pneumonia development and hospitalization in patients with preceding ILI. PMID- 25540269 TI - Experimental human infection with Norwalk virus elicits a surrogate neutralizing antibody response with cross-genogroup activity. AB - The human noroviruses (NoVs) are genetically diverse, rapidly evolving RNA viruses and are the major cause of epidemic gastroenteritis of humans. Serum antibodies that block the interaction of NoVs and NoV viruslike particles (VLPs) with host attachment factors are considered surrogate neutralizing antibodies in the absence of cell culture and small-animal replication models for the human NoVs. A serological assay for NoV-blocking antibodies was used to assess the breadth of the heterotypic antibody response in the context of an experimental challenge study with a human NoV. Heterotypic histo-blood group antigen (HBGA) blocking activity against GI.4, GI.7, and GII.4 NoVs increased significantly in the serum of individuals (n = 18) infected with Norwalk virus (GI.1). Although the fold increases and peak titers of heterotypic antibody were more modest than titers of antibody reactive with the challenge antigen, Norwalk virus infection elicited a serological rise even against the novel Sydney variant of GII.4 NoVs. These observations indicate that the development of a broadly cross-protective NoV vaccine containing a limited number of genotypes may be possible. PMID- 25540272 TI - Tuberculosis vaccine types and timings. AB - Traditionally, the design of new vaccines directed against Mycobacterium tuberculosis, the most successful bacterial pathogen on the planet, has focused on prophylactic candidates that would be given to individuals while they are still young. It is becoming more apparent, however, that there are several types of vaccine candidates now under development that could be used under various conditions. Thus, in addition to prophylactic vaccines, such as recombinant Mycobacterium bovis BCG or BCG-boosting vaccines, other applications include vaccines that could prevent infection, vaccines that could be given in emergency situations as postexposure vaccines, vaccines that could be used to facilitate chemotherapy, and vaccines that could be used to reduce or prevent relapse and reactivation disease. These approaches are discussed here, including the type of immunity we are trying to specifically target, as well as the limitations of these approaches. PMID- 25540274 TI - Immunogenicity, safety, and antibody persistence at 3, 5, and 10 years postvaccination in adolescents randomized to booster immunization with a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliomyelitis vaccine administered with a hepatitis B virus vaccine concurrently or 1 month apart. AB - An understanding of the antibody persistence elicited by a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliovirus vaccine (Tdap-IPV) after adolescent vaccination is important to optimize booster dosing intervals. Our objectives were to compare the safety and immunogenicity of Tdap IPV coadministered with hepatitis B vaccine (HepB) and sequential administration and evaluate humoral immunity at 3, 5, and 10 years after Tdap-IPV vaccination in adolescents. This phase II randomized, controlled, and open-label study enrolled 280 11- to 14-year-old adolescents with up to 10 years postvaccination follow-up. Group 1 (n = 145) received Tdap-IPV, followed by a HepB dose 1 month later, and group 2 (n = 135) received both vaccines simultaneously. No consistent increases in solicited reactions or unsolicited adverse events occurred with coadministration. All vaccinees attained seroprotective antibody levels at >=0.01 IU/ml for diphtheria and tetanus, at a >=1:8 dilution for poliovirus (serotypes 1, 2, and 3), and >=10 mIU/ml for hepatitis B at 1 month postvaccination. Clinically relevant immunologic interactions did not occur with coadministration. For pertussis, all participants achieved seropositivity levels (at or above the lower limit of quantitation), and 72.7% to 95.8% had 4-fold increases in pertussis antibodies at 1 month postvaccination. At 10 years postvaccination, the remaining participants (62.8% of the original cohort) maintained seroprotective levels of >=0.01 IU/ml for diphtheria and tetanus, a >=1:8 dilution for all 3 poliovirus serotypes, and 74.1% to 98.2% maintained pertussis seropositivity levels depending on the antigen tested. There were no differences between the groups. These results support the coadministration of Tdap-IPV and HepB to adolescents and suggest that vaccination with Tdap-IPV can offer protection for 10 years after an adolescent booster vaccination. PMID- 25540273 TI - Post hoc analysis of the PATRICIA randomized trial of the efficacy of human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against incident and persistent infection with nonvaccine oncogenic HPV types using an alternative multiplex type-specific PCR assay for HPV DNA. AB - The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12 month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.). PMID- 25540275 TI - Chikungunya virus RNA and antibody testing at a National Reference Laboratory since the emergence of Chikungunya virus in the Americas. AB - Since first reported in the Americas in December 2013, chikungunya virus (CHIKV) infections have been documented in travelers returning from the Caribbean, with many cases identified by CHIKV antibody and/or RNA testing at our laboratory. We used our large data set to characterize the relationship between antibody titers and RNA detection and to estimate IgM persistence. CHIKV RNA was measured by nucleic acid amplification and CHIKV IgG/IgM by indirect immunofluorescence. Of the 1,306 samples submitted for RNA testing in January through September 2014, 393 (30%) were positive; for 166 RNA-positive samples, CHIKV antibody testing was also ordered, and 84% were antibody negative. Of the 6,971 sera submitted for antibody testing in January through September 2014, 1,811 (26%) were IgM positive; 1,461 IgM positives (81%) were also IgG positive. The relationship between the CHIKV antibody titers and RNA detection was evaluated using 376 IgM positive samples (138 with RNA testing ordered and 238 deidentified and tested for RNA). RNA detection showed no significant association with the IgM titer but was inversely related to the IgG titer; 63% of the IgG negative sera were RNA positive, compared to 36% of sera with low IgG titers (1:10 to 1:80) and 16% with IgG titers of >=1:160. Using second-sample results from 62 seroconverters, we estimated that CHIKV IgM persists for 110 days (95% confidence interval, 78 to 150 days) after the initial antibody-negative sample. These findings indicate that (i) RNA detection is more sensitive than antibody detection early in CHIKV infection, (ii) in the absence of RNA results, the IgG titer of the IgM-positive samples may be a useful surrogate for viremia, and (iii) CHIKV IgM persists for approximately 4 months after symptom onset. PMID- 25540276 TI - Immunization with Brucella VirB proteins reduces organ colonization in mice through a Th1-type immune response and elicits a similar immune response in dogs. AB - VirB proteins from Brucella spp. constitute the type IV secretion system, a key virulence factor mediating the intracellular survival of these bacteria. Here, we assessed whether a Th1-type immune response against VirB proteins may protect mice from Brucella infection and whether this response can be induced in the dog, a natural host for Brucella. Splenocytes from mice immunized with VirB7 or VirB9 responded to their respective antigens with significant and specific production of gamma interferon (IFN-gamma), whereas interleukin-4 (IL-4) was not detected. Thirty days after an intraperitoneal challenge with live Brucella abortus, the spleen load of bacteria was almost 1 log lower in mice immunized with VirB proteins than in unvaccinated animals. As colonization reduction seemed to correlate with a Th1-type immune response against VirB proteins, we decided to assess whether such a response could be elicited in the dog. Peripheral blood mononuclear cells (PBMCs) from dogs immunized with VirB proteins (three subcutaneous doses in QuilA adjuvant) produced significantly higher levels of IFN gamma than cells from control animals upon in vitro stimulation with VirB proteins. A skin test to assess specific delayed-type hypersensitivity was positive in 4 out of 5 dogs immunized with either VirB7 or VirB9. As both proteins are predicted to locate in the outer membrane of Brucella organisms, the ability of anti-VirB antibodies to mediate complement-dependent bacteriolysis of B. canis was assessed in vitro. Sera from dogs immunized with either VirB7 or VirB9, but not from those receiving phosphate-buffered saline (PBS), produced significant bacteriolysis. These results suggest that VirB-specific responses that reduce organ colonization by Brucella in mice can be also elicited in dogs. PMID- 25540277 TI - The trophic responses of two different rodent-vector-plague systems to climate change. AB - Plague, the causative agent of three devastating pandemics in history, is currently a re-emerging disease, probably due to climate change and other anthropogenic changes. Without understanding the response of plague systems to anthropogenic or climate changes in their trophic web, it is unfeasible to effectively predict years with high risks of plague outbreak, hampering our ability for effective prevention and control of the disease. Here, by using surveillance data, we apply structural equation modelling to reveal the drivers of plague prevalence in two very different rodent systems: those of the solitary Daurian ground squirrel and the social Mongolian gerbil. We show that plague prevalence in the Daurian ground squirrel is not detectably related to its trophic web, and that therefore surveillance efforts should focus on detecting plague directly in this ecosystem. On the other hand, plague in the Mongolian gerbil is strongly embedded in a complex, yet understandable trophic web of climate, vegetation, and rodent and flea densities, making the ecosystem suitable for more sophisticated low-cost surveillance practices, such as remote sensing. As for the trophic webs of the two rodent species, we find that increased vegetation is positively associated with higher temperatures and precipitation for both ecosystems. We furthermore find a positive association between vegetation and ground squirrel density, yet a negative association between vegetation and gerbil density. Our study thus shows how past surveillance records can be used to design and improve existing plague prevention and control measures, by tailoring them to individual plague foci. Such measures are indeed highly needed under present conditions with prevailing climate change. PMID- 25540278 TI - Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving. AB - Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28 degrees C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca(2+) transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation-contraction coupling across an acute 20 degrees C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range. PMID- 25540279 TI - Feather corticosterone reveals effect of moulting conditions in the autumn on subsequent reproductive output and survival in an Arctic migratory bird. AB - For birds, unpredictable environments during the energetically stressful times of moulting and breeding are expected to have negative fitness effects. Detecting those effects however, might be difficult if individuals modulate their physiology and/or behaviours in ways to minimize short-term fitness costs. Corticosterone in feathers (CORTf) is thought to provide information on total baseline and stress-induced CORT levels at moulting and is an integrated measure of hypothalamic-pituitary-adrenal activity during the time feathers are grown. We predicted that CORTf levels in northern common eider females would relate to subsequent body condition, reproductive success and survival, in a population of eiders nesting in the eastern Canadian Arctic during a capricious period marked by annual avian cholera outbreaks. We collected CORTf data from feathers grown during previous moult in autumn and data on phenology of subsequent reproduction and survival for 242 eider females over 5 years. Using path analyses, we detected a direct relationship between CORTf and arrival date and body condition the following year. CORTf also had negative indirect relationships with both eider reproductive success and survival of eiders during an avian cholera outbreak. This indirect effect was dramatic with a reduction of approximately 30% in subsequent survival of eiders during an avian cholera outbreak when mean CORTf increased by 1 standard deviation. This study highlights the importance of events or processes occurring during moult on subsequent expression of life-history traits and relation to individual fitness, and shows that information from non destructive sampling of individuals can track carry-over effects across seasons. PMID- 25540281 TI - Experimental defaunation of terrestrial mammalian herbivores alters tropical rainforest understorey diversity. AB - It has been suggested that tropical defaunation may unleash community-wide cascading effects, leading to reductions in plant diversity. However, experimental evidence establishing cause-effect relationships thereof is poor. Through a 5 year exclosure experiment, we tested the hypothesis that mammalian defaunation affects tree seedling/sapling community dynamics leading to reductions in understorey plant diversity. We established plot triplets (n = 25) representing three defaunation contexts: terrestrial-mammal exclosure (TE), medium/large mammal exclosure (PE) and open access controls (C). Seedlings/saplings 30-100 cm tall were marked and identified within each of these plots and re-censused three times to record survival and recruitment. In the periods 2010-2011 and 2011-2013, survival was greater in PE than in C plots and recruitment was higher in TE plots than in C plots. Overall, seedling density increased by 61% in TE plots and 23% in PE plots, whereas it decreased by 5% in C plots. Common species highly consumed by mammals (e.g. Brosimum alicastrum and Ampelocera hottlei) increased in their abundance in TE plots. Rarefaction curves showed that species diversity decreased in TE plots from 2008 to 2013, whereas it remained similar for C plots. Given the prevalence of tropical defaunation, we posit this is an anthropogenic effect threatening the maintenance of tropical forest diversity. PMID- 25540280 TI - Genomic evidence for rod monochromacy in sloths and armadillos suggests early subterranean history for Xenarthra. AB - Rod monochromacy is a rare condition in vertebrates characterized by the absence of cone photoreceptor cells. The resulting phenotype is colourblindness and low acuity vision in dim-light and blindness in bright-light conditions. Early reports of xenarthrans (armadillos, sloths and anteaters) suggest that they are rod monochromats, but this has not been tested with genomic data. We searched the genomes of Dasypus novemcinctus (nine-banded armadillo), Choloepus hoffmanni (Hoffmann's two-toed sloth) and Mylodon darwinii (extinct ground sloth) for retinal photoreceptor genes and examined them for inactivating mutations. We performed PCR and Sanger sequencing on cone phototransduction genes of 10 additional xenarthrans to test for shared inactivating mutations and estimated the timing of inactivation for photoreceptor pseudogenes. We concluded that a stem xenarthran became an long-wavelength sensitive-cone monochromat following a missense mutation at a critical residue in SWS1, and a stem cingulate (armadillos, glyptodonts and pampatheres) and stem pilosan (sloths and anteaters) independently acquired rod monochromacy early in their evolutionary history following the inactivation of LWS and PDE6C, respectively. We hypothesize that rod monochromacy in armadillos and pilosans evolved as an adaptation to a subterranean habitat in the early history of Xenarthra. The presence of rod monochromacy has major implications for understanding xenarthran behavioural ecology and evolution. PMID- 25540282 TI - Paradoxical effects of coupling infectious livestock populations and imposing transport restrictions. AB - Spatial heterogeneity of a host population of mobile agents has been shown to be a crucial determinant of many aspects of disease dynamics, ranging from the proliferation of diseases to their persistence and to vaccination strategies. In addition, the importance of regional and structural differences grows in our modern world. Little is known, though, about the consequences when traits of a disease vary regionally. In this paper, we study the effect of a spatially varying per capita infection rate on the behaviour of livestock diseases. We show that the prevalence of an infectious livestock disease in a community of animals can paradoxically decrease owing to transport connections to other communities in which the risk of infection is higher. We study the consequences for the design of livestock transportation restriction measures and establish exact criteria to discriminate those connections that increase the level of infection in the community from those that decrease it. PMID- 25540283 TI - Mutualism between co-introduced species facilitates invasion and alters plant community structure. AB - Generalized mutualisms are often predicted to be resilient to changes in partner identity. Variation in mutualism-related traits between native and invasive species however, can exacerbate the spread of invasive species ('invasional meltdown') if invasive partners strongly interact. Here we show how invasion by a seed-dispersing ant (Myrmica rubra) promotes recruitment of a co-introduced invasive over native ant-dispersed (myrmecochorous) plants. We created experimental communities of invasive (M. rubra) or native ants (Aphaenogaster rudis) and invasive and native plants and measured seed dispersal and plant recruitment. In our mesocosms, and in laboratory and field trials, M. rubra acted as a superior seed disperser relative to the native ant. By contrast, previous studies have found that invasive ants are often poor seed dispersers compared with native ants. Despite belonging to the same behavioural guild, seed dispersing ants were not functionally redundant. Instead, native and invasive ants had strongly divergent effects on plant communities: the invasive plant dominated in the presence of the invasive ant and the native plants dominated in the presence of the native ant. Community changes were not due to preferences for coevolved partners: variation in functional traits of linked partners drove differences. Here, we show that strongly interacting introduced mutualists can be major drivers of ecological change. PMID- 25540291 TI - Cyclodextrin Micellar LC for Direct Selective Analysis of Combined Dosage Drugs in Urine. AB - Two cyclodextrin micellar liquid chromatographic methods were developed and applied to the simultaneous determination of bisoprolol/hydrochlorothiazide and atenolol/chlorthalidone combinations in urine matrices without sample pretreatment. These combined beta-blockers and diuretics chemotherapies are commonly used in the treatment of hypertension and cardiovascular diseases. Hybrid isocratic mobile phases containing hydroxypropyl-beta-cyclodextrin, sodium dodecyl sulfate, phosphate buffer and methanol on a Luna C18 column with 0.5 mL min(-1) flow rate and 25.0 degrees C column temperature were used. The methods were sensitive enough for the determination of analytes at the therapeutic urine levels with limits of detections down to 1.0 ug mL(-1); relative standard deviations and recoveries were ranged between 1.5-4.4% and 98.00-109.52%, respectively. Urinary excretion studies showed that the detection of drugs is possible up to 24 h after their ingestion. The selective proposed separations with less consumption of organic solvents over the hitherto ones could be attributed to the four point competitive interactions among analysts, pseudostationary phases and a real stationary phase. PMID- 25540284 TI - Monophosphoryl lipid A inhibits the cytokine response of endothelial cells challenged with LPS. AB - Monophosphoryl lipid A (MPLA) is a TLR4 agonist that is used as an immunomodulator in human vaccines; additionally, it has been shown to be protective in models of sepsis. As endothelial cells regulate inflammation, we hypothesized that MPLA would decrease activation of human umbilical vein endothelial cells (HUVECs) to LPS. We studied HUVECs challenged with LPS (100 ng/ml), MPLA (0.001-100 ug/ml) or a combination. Secretion of IL-6, RANTES (CCL5) and IP-10 (CXCL10) were assessed by ELISA. Activation of MAPK phosphorylation and cytokine transcription were assessed by Western blot analysis and PCR, respectively. MPLA alone was a weak stimulator of myeloid differentiation primary response protein 88-dependent IL-6 and did not induce TIR-domain-containing adapter-inducing IFN-beta (TRIF)-dependent chemokine responses. MPLA significantly reduced LPS-mediated IL-6 production. This inhibitory effect was also conferred for the TRIF-dependent chemokines RANTES and IP-10. Inhibition of LPS-mediated activation by MPLA was associated with reduced p38 phosphorylation and mRNAs encoding inflammatory cytokines. MPLA inhibition of LPS signaling appeared to be at the level of the TLR4 receptor, acting as a receptor antagonist with weak agonistic properties. This study provides evidence of a novel mechanism for the inhibitory effect of MPLA on LPS-induced endothelial activation. PMID- 25540292 TI - Seasonal Variation of Alkaloid Contents and Anti-Inflammatory Activity of Rhizoma coptidis Based on Fingerprints Combined with Chemometrics Methods. AB - The fingerprints of Rhizoma coptidis (Huanglian) collected in different growing periods were established by high-performance liquid chromatography (HPLC), and the seasonal variations of six alkaloids, namely berberine, palmatine, jateorrhizine, coptisine, epiberberine and columbamine were assessed. In order to highlight the differences of their HPLC fingerprints, three chemometrics methods including Spearman's rank correlation, hierarchical clustering analysis (HCA) and principal component analysis were applied. The anti-inflammatory activity of R. coptidis collected in different developing stages was measured by NO inhibition assay. The relationship between HPLC fingerprints and anti-inflammatory activity named spectrum-effect relationship was investigated by partial least squares regression. The anti-inflammatory activity was positively correlated with the alkaloid contents. Berberine, palmatine, coptisine, jateorrhizine and epiberberine were the main anti-inflammatory components on the basis of the quantitative determination of the six alkaloids and spectrum-effect investigation. The collecting time of R. coptidis impacted the plant's alkaloid contents and its anti-inflammatory activity. PMID- 25540293 TI - Length change patterns in the lateral extra-articular structures of the knee and related reconstructions. AB - BACKGROUND: Lateral extra-articular soft tissue reconstructions in the knee may be used as a combined procedure in revision anterior cruciate ligament surgery as well as in primary treatment for patients who demonstrate excessive anterolateral rotatory instability. Only a few studies examining length change patterns and isometry in lateral extra-articular reconstructions have been published. PURPOSE: To determine a recommended femoral insertion area and graft path for lateral extra-articular reconstructions by measuring length change patterns through a range of knee flexion angles of several combinations of tibial and femoral insertion points on the lateral side of the knee. STUDY DESIGN: Controlled laboratory study. METHODS: Eight fresh-frozen cadaveric knees were freed of skin and subcutaneous fat. The knee was then mounted in a kinematics rig that loaded the quadriceps muscles and simulated open-chain knee flexion. The length changes of several combinations of tibiofemoral points were measured at knee flexion angles between 0 degrees and 90 degrees by use of linear variable displacement transducers. The changes in length relative to the 0 degrees measurement were recorded. RESULTS: The anterior fiber region of the iliotibial tract displayed a significantly different (P < .001) length change pattern compared with the posterior fiber region. The reconstructions that had a femoral insertion site located proximal to the lateral epicondyle and with the grafts passed deep to the lateral collateral ligament displayed similar length change patterns to each other, with small length increases during knee extension. These reconstructions also showed a significantly lower total strain range compared with the reconstruction located anterior to the epicondyle (P < .001). CONCLUSION: These findings show that the selection of graft attachment points and graft course affects length change pattern during knee flexion. A graft attached proximal to the lateral femoral epicondyle and running deep to the lateral collateral ligament will provide desirable graft behavior, such that it will not suffer excessive tightening or slackening during knee motion. CLINICAL RELEVANCE: These results provide a surgical rationale for lateral extra-articular soft tissue reconstruction in terms of femoral graft fixation site and graft route. PMID- 25540294 TI - Sports activity after treatment of residual hip dysplasia with triple pelvic osteotomy using the Tonnis and Kalchschmidt technique. AB - BACKGROUND: Pelvic osteotomies are performed to prevent the progression of osteoarthritis and its associated pain due to adult hip dysplasia, particularly for young patients with no or low-grade osteoarthritis. No data are available concerning levels of sporting activity before and after triple pelvic osteotomy (TPO). Therefore, the aim of this study was to provide comprehensive data on levels of sporting activity and the subjective outcome of patients after this complex operation. HYPOTHESIS: Patients can return to a higher level of sports activity after TPO compared with their preoperative level. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 2003 and 2011, a total of 116 triple pelvic osteotomies were performed at a single institution; the Tonnis and Kalchschmidt technique was used on 91 patients. After exclusion criteria for this study were applied, 77 patients remained (59 females and 18 males); the mean +/- SD age at operation was 26 +/- 3.9 years. To study outcomes, patients were asked to complete both the Harris hip score (HHS) and the Hip disability and Osteoarthritis Outcome Score (HOOS) preoperatively and at postoperative follow up. Their level of activity was determined according to the University of California, Los Angeles (UCLA) activity score. Patients rated their hip movement and overall satisfaction preoperatively and at postoperative follow-up using a visual analog scale for sporting activity, physical fitness level, and level of pain experienced while performing their sport. RESULTS: The mean +/- SD follow-up time was 6.2 +/- 1.4 years. The mean HHS changed significantly from 63.3 +/- 15.6 preoperatively to 90.1 +/- 10.8 at follow-up (P < .001), and the mean HOOS changed significantly from 52.9 +/- 20.1 to 82 +/- 17.1 at follow-up (P < .001). The mean UCLA activity score changed significantly from 4.8 +/- 2.1 to 7.7 +/- 1.4 at follow-up (P < .001). CONCLUSION: Patients achieved a higher level of sports activity postoperatively. The postoperative level of participation in sports was superior, with a shift from low- to high-impact activities. PMID- 25540295 TI - Modified suture-bridge technique to prevent a marginal dog-ear deformity improves structural integrity after rotator cuff repair. AB - BACKGROUND: The arthroscopic suture-bridge technique has proved to provide biomechanically firm fixation of the torn rotator cuff to the tuberosity by increasing the footprint contact area and pressure. However, a marginal dog-ear deformity is encountered not infrequently when this technique is used, impeding full restoration of the torn cuff. PURPOSE: To evaluate the structural and functional outcomes of the use of a modified suture-bridge technique to prevent a marginal dog-ear deformity compared with a conventional suture-bridge method in rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence 2. METHODS: A consecutive series of 71 patients aged 50 to 65 years who underwent arthroscopic rotator cuff repair for full-thickness medium-sized to massive tears was evaluated. Patients were divided into 2 groups according to repair technique: a conventional suture-bridge technique (34 patients; group A) versus a modified suture-bridge technique to prevent a marginal dog-ear deformity (37 patients; group B). Radiographic evaluations included postoperative cuff integrity using MRI. Functional evaluations included pre- and postoperative range of motion (ROM), pain visual analog scale (VAS), the University of California, Los Angeles (UCLA) shoulder rating scale, the Constant score, and the American Shoulder and Elbow Surgeons (ASES) score. All patients were followed up clinically at a minimum of 1 year. RESULT: When the 2 surgical techniques were compared, postoperative structural integrity by Sugaya classification showed the distribution of types I:II:III:IV:V to be 4:20:2:4:4 in group A and 20:12:4:0:1 in group B. More subjects in group B had a favorable Sugaya type compared with group A (P < .001). The postoperative healed:retear rate was 26:8 in group A and 36:1 in group B, with a significantly lower retear rate in group B (P = .011). However, there were no significant differences in ROM and all functional outcome scores between the 2 groups postoperatively. When surgical techniques were compared across healed (n = 62) and retear (n = 9) groups, significantly fewer modified suture-bridge technique repairs were found in the retear group (P = .03). There were significant differences between healed and retear groups in functional outcome scores, with worse results in the retear group. CONCLUSION: A modified suture-bridge technique to prevent a marginal dog-ear deformity provided better structural outcomes than a conventional suture-bridge technique for medium sized to massive rotator cuff tears. This technique may ultimately provide better functional outcomes by decreasing the retear rate. PMID- 25540296 TI - Anterior cruciate ligament function in providing rotational stability assessed by medial and lateral tibiofemoral compartment translations and subluxations. AB - BACKGROUND: Rotational knee stability provided by the anterior cruciate ligament (ACL) in the pivot-shift phenomena involves analysis of more complex robotic testing profiles and resulting tibiofemoral compartment kinematics and subluxations. HYPOTHESES: Using anterior-posterior tibial forces along with internal and valgus tibial moments will produce a major anterior subluxation of both tibiofemoral compartments not obtained with internal and valgus moments alone. Increasing the internal torque in pivot-shift testing will constrain the anterior subluxations of the medial and central tibial compartments. STUDY DESIGN: Controlled laboratory study. METHODS: A 6 degrees of freedom robotic knee testing system applied anterior translation and rotational loading profiles in 10 cadaveric knees before and after ACL sectioning. Changes in knee motion limits were measured, and medial and lateral tibiofemoral compartment translations were determined by digitization of tibial plateau anatomic landmarks. Loading profiles simulated Lachman and tibial rotation tests as well as typical pivot-shift loading profiles from prior in vitro and in vivo studies. RESULTS: After ACL sectioning, anterior tibial translation increased by 10.3 +/- 3.7 mm at 25 degrees of flexion (P < .001). Internal tibial rotation increased by 1.6 degrees +/- 1.1 degrees (5 N.m; P > .05). In pivot-shift tests (anterior translation, 100 N; internal rotation, 1 N.m; valgus, 7 N.m), the tibial rotation center shifted outside the medial tibial margin, with abnormal anterior translation of both compartments (medial, 12.9 +/- 3.9 mm; lateral, 7.5 +/- 3.7 mm; P < .001), with internal rotation decreasing by 4.1 degrees +/- 3.5 degrees (P < .05). A greater internal rotation torque (5 vs 1 N.m) in the pivot-shift test constrained and limited anterior tibial translation and prevented anterior subluxation of the medial compartment (P < .001). CONCLUSION: Sectioning of the ACL produces major increases in tibiofemoral compartment translations and only small increases in internal tibial rotation. The simulation of the pivot shift requires a combined loading profile of anterior translation, internal rotation, and valgus, which produces the greatest anterior subluxation of the medial and lateral tibiofemoral compartments. This testing profile is recommended to be included along with other loading profiles for future ACL studies. The application of a high internal rotation torque in cadaveric pivot-shift tests constrains anterior tibial subluxation of the medial and center compartments and appears less ideal for analysis of ACL function and graft reconstructions. CLINICAL RELEVANCE: Surgeons should be cautious in interpreting conclusions on ACL function and graft reconstructions without knowing the resulting tibiofemoral subluxations or loading conditions that may limit maximum anterior tibial femoral subluxations. PMID- 25540297 TI - Adolescents demonstrate greater gait balance control deficits after concussion than young adults. AB - BACKGROUND: Age has been described as a factor that affects recovery after concussion. The recommended management protocol is to treat adolescents in a more cautious manner than adults. However, few studies have prospectively and longitudinally assessed the way these age groups perform on motor tasks after concussion. PURPOSE: To examine dual-task gait balance control deficits after concussion in a group of adolescents and young adults in reference to matched control subjects within 72 hours of injury and throughout 2 months after injury. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Adolescents and young adults who sustained a concussion and individually matched controls completed a whole-body motion gait analysis while simultaneously performing a cognitive task. Subjects with concussion reported to the laboratory within 72 hours after injury and at the following time points: 1 week, 2 weeks, 1 month, and 2 months after injury. Control subjects completed the same protocol at similar time points. Gait balance control measurements included whole-body center-of-mass (COM) medial lateral displacement/velocity and anterior velocity. RESULTS: A total of 38 subjects with concussion, 19 young adults (mean +/- SD age, 20.3 +/- 2.4 years) and 19 adolescents (mean +/- SD age, 15.1 +/- 1.1 years), and 38 individually matched control subjects were tested. Within 72 hours of injury, adolescents displayed significantly greater COM medial-lateral displacement (P = .001) and peak velocity (P = .001) relative to their control group, and the young adult concussion group displayed significantly less peak COM anterior velocity than their control group (P = .01). Across the 2 months of testing, adolescents with concussion displayed significantly greater total COM medial-lateral displacement than did adolescent controls (P = .001), while young adults with concussion did not significantly differ from their matched controls (P = .07). CONCLUSION: An examination of gait balance control during dual-task walking revealed that after concussion, in reference to matched controls, adolescents demonstrated greater gait balance control deficits than did young adults initially and throughout the 2-month postinjury period, supporting the recommendation of conservative management for adolescents after concussion. PMID- 25540298 TI - MRI volume and signal intensity of ACL graft predict clinical, functional, and patient-oriented outcome measures after ACL reconstruction. AB - BACKGROUND: Clinical, functional, and patient-oriented outcomes are commonly used to evaluate the efficacy of treatments after anterior cruciate ligament (ACL) injury; however, these evaluation techniques do not directly measure the biomechanical changes that occur with healing. PURPOSE: To determine if the magnetic resonance (MR) image-derived parameters of graft volume and signal intensity (SI), which have been used to predict the biomechanical (ie, structural) properties of the graft in animal models, correlate with commonly used clinical (anteroposterior [AP] knee laxity), functional (1-legged hop), and patient-oriented outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS]) in patients 3 and 5 years after ACL reconstruction. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Based on a subset of participants enrolled in an ongoing ACL reconstruction clinical trial, AP knee laxity, 1-legged hop test, and KOOS were assessed at 3- and 5-year follow-up. Three-dimensional, T1-weighted MR images were collected at each visit. Both the volume and median SI of the healing graft were determined and used as predictors in a multiple regression linear model to predict the traditional outcome measures. RESULTS: Graft volume combined with median SI in a multiple linear regression model predicted 1-legged hop test at both the 3- and 5-year follow-up visits (R(2) = 0.40, P = .008 and R(2) = 0.62, P = .003, respectively). Similar results were found at the 5-year follow-up for the KOOS quality of life (R(2) = 0.49, P = .012), sport/function (R(2) = 0.37, P = .048), pain (R(2) = 0.46, P = .017), and symptoms (R(2) = 0.45, P = .021) subscores, although these variables were not significant at 3 years. The multiple linear regression model for AP knee laxity at 5-year follow-up approached significance (R(2) = 0.36, P = .088). CONCLUSION: The MR parameters (volume and median SI) used to predict ex vivo biomechanical properties of the graft in an animal model have the ability to predict clinical or in vivo outcome measures in patients at 3- and 5-year follow up. CLINICAL RELEVANCE: Results from this study may enhance clinical evaluation of graft health by relating the MR parameters of volume and median SI to traditional outcome measures and could potentially aid researchers in determining the appropriate timing for athletes to return to sport. PMID- 25540300 TI - Social phobia among long-term internally displaced persons: An epidemiological study of adults in two internally displaced person settlements in Sudan. AB - BACKGROUND: Despite the high worldwide prevalence and association with other mental disorders and disability, only few studies are available on social phobia in low-income countries. AIMS: This study aims to assess the prevalence, socio demographic correlates and comorbidity of social phobia and its association with disability among long-term internally displaced persons (IDPs) in one urban and one rural area in Central Sudan. METHODS: This cross-sectional study was implemented in two IDP areas in Central Sudan. Data were collected during face-to face interviews using structured questionnaires to assess socio-demographic factors and the Mini International Neuropsychiatric Interview (MINI) to determine psychiatric diagnoses. A total of 1,876 adults were enrolled from both study areas. RESULTS: The overall lifetime prevalence of social phobia was 14.2%, with higher rates among IDPs in the rural area and among those who were less educated. Social phobia was associated with other mental disorders in both study areas. Disability and prolonged displacement increased the risk of having social phobia in the rural area. CONCLUSION: Further work needs to be done to improve our understanding and to establish proper interventions in dealing with social phobia, other common mental disorders and disability among long-term IDPs in these impoverished areas. PMID- 25540301 TI - ECMO: the new four letter word. PMID- 25540299 TI - Cost-sharing, physician utilization, and adverse selection among Medicare beneficiaries with chronic health conditions. AB - Pooled data from the 2007, 2009, and 2011/2012 California Health Interview Surveys were used to compare the number of self-reported annual physician visits among 36,808 Medicare beneficiaries >=65 in insurance groups with differential cost-sharing. Adjusted for adverse selection and a set of health covariates, Medicare fee-for-service (FFS) only beneficiaries had similar physician utilization compared with HMO enrollees but fewer visits compared with those with supplemental (1.04, p = .001) and Medicaid (1.55, p = .003) coverage. FFS only beneficiaries in very good or excellent health had fewer visits compared with those of similar health status with supplemental (1.30, p = .001) or Medicaid coverage (2.15, p = .002). For subpopulations with several chronic conditions, FFS only beneficiaries also had fewer visits compared with beneficiaries with supplemental or Medicaid coverage. Observed differences in utilization may reflect efficient and necessary physician utilization among those with chronic health needs. PMID- 25540302 TI - Commentary on: real-time data acquisition and alerts may reduce reaction time and improve perfusionist performance during cardiopulmonary bypass. PMID- 25540303 TI - Acute idiopathic transverse myelitis in children: early predictors of relapse and disability. AB - OBJECTIVE: To identify early prognostic factors of relapse and disability in children presenting with an acute idiopathic transverse myelitis (TM). METHODS: Ninety-five children with acute idiopathic TM from 2 national European cohorts (France and United Kingdom) of CNS demyelinating diseases in children were identified and studied for early factors that predict relapse and disability using logistic regression models. RESULTS: Sixteen (17%) relapsed, with a diagnosis of multiple sclerosis in 13 (14%) and neuromyelitis optica in 3 (3%). Logistic regression revealed 2 main criteria as risk factors for relapse: female sex (odds ratio [OR] 3.21, 95% confidence interval [CI] 0.88-11.78) and presence of associated brain lesions (OR 14.0, 95% CI 2.8-69.3). Twenty-eight (30%) children had a poor outcome defined by a Kurtzke Expanded Disability Status Scale score >=4 or an American Spinal Injury Association impairment (ASIA) scale 800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85. CONCLUSIONS: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine. PMID- 25540309 TI - Comorbidity increases the risk of hospitalizations in multiple sclerosis. AB - OBJECTIVE: We aimed to evaluate the association between comorbidity and rates of hospitalization in the multiple sclerosis (MS) population as compared to a matched cohort from the general population. METHODS: Using population-based administrative data from the Canadian province of Manitoba, we identified 4,875 persons with MS and a matched general population cohort of 24,533 persons. We identified all acute care hospitalizations in the period 2007-2011. Using general linear models, we evaluated the association between comorbidity status and hospitalization rates (all-cause, non-MS-related, MS-related) in the 2 populations, adjusting for age, sex, and socioeconomic status. RESULTS: Comorbidity was common in both cohorts. Over the 5-year study period, the MS population had a 1.5-fold higher hospitalization rate (adjusted rate ratio [aRR] 1.56; 95% confidence interval [CI] 1.44-1.68) than the matched population. Any comorbidity was associated with a 2-fold increased risk of non-MS-related hospitalization rates (aRR 2.21; 95% CI 1.73-2.82) in the MS population, but a nearly 4-fold increase in hospitalization rates in the matched population (aRR 3.85; 95% CI 3.40-4.35). Comorbidity was not associated with rates of hospitalization for MS-related reasons, regardless of how comorbidity status was defined. CONCLUSIONS: In the MS population, comorbidity is associated with an increased risk of all-cause hospitalizations, suggesting that the prevention and management of comorbidity may reduce hospitalizations. PMID- 25540312 TI - Cervical cord lesion load is associated with disability independently from atrophy in MS. AB - OBJECTIVE: To investigate whether spinal cord (SC) lesion load, when quantified on axial images with high in-plane resolution, is associated with disability in multiple sclerosis (MS). METHODS: Twenty-eight healthy controls and 92 people with MS had cervical SC 3T MRI with axial phase sensitive inversion recovery, T2, and magnetization transfer (MT) sequences. We outlined all visible focal lesions from C2 to C4 to obtain lesion load and also measured upper cervical cord area. We measured MT ratio in normal-appearing cord tissue and in lesions. Disability was recorded using the Expanded Disability Status Scale (EDSS) and MS Functional Composite. We used linear regression models to determine associations with disability. RESULTS: SC lesion load was significantly higher in both secondary progressive MS (SPMS) (p = 0.008) and primary progressive MS (PPMS) (p = 0.02) compared to relapsing-remitting MS (RRMS); in each comparison, adjustment was made for age, sex, and brain volume. These differences were not evident when EDSS was added as a covariate. SC area was significantly lower in both SPMS (p < 0.001) and PPMS (p = 0.009) compared to RRMS. In a multiple regression model, cord lesion load (p < 0.001), cord area (p = 0.003), age (p < 0.001), and sex (p = 0.001) were independently associated with EDSS (R(2) = 0.58). Cord lesion load (p = 0.003), cord area (p = 0.034), and brain parenchymal fraction (p = 0.007) were independently associated with the 9-hole peg test (R(2) = 0.42). CONCLUSIONS: When quantified on axial MRI with high in-plane resolution, upper cervical cord lesion load is significantly and independently correlated with physical disability and is higher in progressive forms of MS than RRMS. PMID- 25540311 TI - Small nerve fiber involvement in CMT1A. AB - OBJECTIVE: To assess the involvement of small nerve fibers in Charcot-Marie-Tooth type 1A (CMT1A). METHODS: We used indirect immunofluorescence and confocal microscopy on punch biopsies from glabrous (fingertip) and hairy (thigh and leg) skin of 20 unrelated patients with CMT1A to quantify somatic and autonomic nerve fibers. In particular, we quantified epidermal nerve fibers (ENF), Meissner corpuscles (MC), intrapapillary myelinated endings (IME), and sudomotor nerves. We correlated morphologic data with findings from quantitative sensory testing, sudomotor output, sympathetic skin response, and cardiovascular reflexes. A control population of healthy age- and sex-matched controls was included with a matching ratio of 1:2. RESULTS: We found a length-dependent loss of ENFs that worsened with aging. We also observed a loss of MCs, IMEs, and sudomotor nerves. The loss of ENF at distal leg correlated with the increase in heat-pain thresholds (p < 0.05) and with tactile thresholds (p < 0.05). Sudomotor nerve fiber loss correlated with ENF density (p < 0.05) and sweating output (p < 0.001). CONCLUSIONS: We demonstrated through morphologic, physical, and psychophysical testing that small somatic and autonomic fibers are abnormal and cause symptoms in patients with CMT1A. Awareness of such symptoms by the clinician could lead to better treatment. PMID- 25540313 TI - Understanding risk of relapse and risk of disability after childhood transverse myelitis. PMID- 25540315 TI - Comment: Childhood maltreatment and headache disorders. PMID- 25540314 TI - Increasing stroke incidence and prevalence of risk factors in a low-income Chinese population. AB - OBJECTIVE: We investigated secular trends in incidence of first-ever stroke and the prevalence of stroke risk factors within the same population in rural China. METHODS: In 1985, 15,438 residents from a township of Tianjin, China, were recruited to the Tianjin Brain Study, a population-based stroke surveillance study. Stroke events and all deaths were registered annually. Because imaging technology was first available in 1992, we analyzed the incidence of first-ever stroke over 3 study periods-1992-1998, 1999-2005, and 2006-2012-from 1992 to 2012. Risk factor surveys were conducted in 1991 and 2011. RESULTS: The age standardized incidence of first-ever stroke per 100,000 person-years increased rapidly from 124.5 in 1992-1998 to 190.0 in 1999-2005 and to 318.2 in 2006-2012; incidence increased annually by 6.5% overall and by 12% among men aged 45-64 years (p < 0.05). From 1992 to 2012, the age at first-ever stroke in men was earlier by 3.3 years overall, but a similar trend was not observed in women. Concurrently, the prevalence of high fasting glucose and alcohol consumption increased significantly in both men and women, especially in men aged <45 years; the prevalence of obesity and high fasting glucose increased by 8.8-fold and 11 fold, respectively, from 1992 to 2012. CONCLUSIONS: The incidence of stroke in rural China increased rapidly, particularly among middle-aged adults, along with a concurrent increase in risk factor prevalence. These findings suggest that without controlling these risk factors, stroke incidence will continue to increase over future decades in China. PMID- 25540316 TI - Comorbidity increases the risk of hospitalizations in MS: prevention opportunities. PMID- 25540318 TI - Fine-tuning risk assessment with antiepileptic drug use in pregnancy. PMID- 25540317 TI - Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers. AB - OBJECTIVE: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD. METHODS: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen. RESULTS: The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers. CONCLUSIONS: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes. PMID- 25540319 TI - Lessons to be learned from the largest study of cognition in American women with HIV disease. PMID- 25540320 TI - The spectrum of acute encephalitis: causes, management, and predictors of outcome. AB - OBJECTIVE: To describe and analyze etiologies, clinical presentations, therapeutic management, and outcomes of patients with acute encephalitis and identify outcome predictors. METHODS: We conducted a retrospective review of patients diagnosed with acute encephalitis at Mayo Clinic Rochester between January 2000 and December 2012. On the basis of the final diagnosis, the patients were categorized into 3 groups: viral encephalitis, autoimmune encephalitis, and encephalitis of unknown/other etiology. Multivariate logistic regression analysis was used to analyze factors associated with good (modified Rankin Scale scores of 0-2) or poor (scores of 3-6) outcome at hospital discharge. RESULTS: We identified 198 patients (100 [50.5%] men and 98 [49.5%] women) with a median age of 58 years (range 41.8-69). Etiologies included viral infection (n = 95, 48%), autoimmune (n = 44, 22%), and unknown/others (n = 59, 30%). Good outcome at discharge was achieved by 48 patients (50.5%) with viral encephalitis, 17 (40.5%) with autoimmune encephalitis, and 32 (54.2%) with unknown/other etiologies. Mortality rates were 8%, 12%, and 5% in each of the 3 categories, respectively. On multivariate regression analysis, the factors that were associated with poor outcome were age 65 years or older (p = 0.0307), immunocompromised state (p = 0.0153), coma (p = 0.0062), mechanical ventilation (p = 0.0124), and acute thrombocytopenia (p = 0.0329). CSF polymorphonuclear cell count was also strongly associated with poor outcome in viral encephalitis (p = 0.0027). CONCLUSIONS: Advanced age, immunocompromised state, coma, mechanical ventilation, and acute thrombocytopenia portend a worse prognosis in acute encephalitis. In contrast, the etiology of encephalitis, development of seizures or focal neurologic deficit, and MRI findings were not associated with clinical outcomes. PMID- 25540321 TI - Electrospun polyvinyl alcohol/carbon dioxide modified polyethyleneimine composite nanofiber scaffolds. AB - A novel biocompatible polyvinyl alcohol/carbon dioxide modified polyethyleneimine (PVA/PEI-CO2) composite nanofiber was fabricated by a green and facile protocol, which reduces the cytotoxicity of PEI through the surface modification of the PEI with CO2. The (13)C NMR spectrum, elemental analysis, and TGA show that CO2 has been incorporated in the PEI surface resulting in a relatively stable structure. The resulting PVA/PEI-CO2 composite nanofibers have been characterized by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), contact angle, and scanning electron microscopy (SEM). The results show that the average diameters of the nanofibers range from 265 +/- 53 nm to 423 +/- 80 nm. The cytotoxicity of PVA/PEI-CO2 composite nanofibers was assessed by cytotoxicity evaluation using the growth and cell proliferation of normal mice Schwann cells. SEM and the MTT assay demonstrated the promotion of cell growth and proliferation on the PVA/PEI-CO2 composite scaffold. It suggests that PEI-CO2 can have tremendous potential applications in biological material research. PMID- 25540322 TI - Comment on "An antidepressant decreases CSF Abeta production in healthy individuals and in transgenic AD mice". PMID- 25540323 TI - Reply to comment on "An antidepressant decreases CSF Abeta production in healthy individuals and in transgenic AD mice". PMID- 25540324 TI - Recurrent epimutation of SDHC in gastrointestinal stromal tumors. AB - Succinate dehydrogenase (SDH) is a conserved effector of cellular metabolism and energy production, and loss of SDH function is a driver mechanism in several cancers. SDH-deficient gastrointestinal stromal tumors (dSDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT/PDGFRA mutations. dSDH GISTs often harbor deleterious mutations in SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx), but some are SDHx wild type (WT). To further elucidate mechanisms of SDH deactivation in SDHx-WT GIST, we performed targeted exome sequencing on 59 dSDH GISTs to identify 43 SDHx-mutant and 16 SDHx-WT cases. Genome-wide DNA methylation and expression profiling exposed SDHC promoter specific CpG island hypermethylation and gene silencing in SDHx-WT dSDH GISTs [15 of 16 cases (94%)]. Six of 15 SDHC-epimutant GISTs occurred in the setting of the multitumor syndrome Carney triad. We observed neither SDHB promoter hypermethylation nor large deletions on chromosome 1q in any SDHx-WT cases. Deep genome sequencing of a 130-kbp (kilo-base pair) window around SDHC revealed no recognizable sequence anomalies in SDHC-epimutant tumors. More than 2000 benign and tumor reference tissues, including stem cells and malignancies with a hypermethylator epigenotype, exhibit solely a non-epimutant SDHC promoter. Mosaic constitutional SDHC promoter hypermethylation in blood and saliva from patients with SDHC-epimutant GIST implicates a postzygotic mechanism in the establishment and maintenance of SDHC epimutation. The discovery of SDHC epimutation provides a unifying explanation for the pathogenesis of dSDH GIST, whereby loss of SDH function stems from either SDHx mutation or SDHC epimutation. PMID- 25540327 TI - Flipping the switch: power, social dominance, and expectancies of mental energy change. AB - Research suggests that high levels of interpersonal power can promote enhanced executive functioning capabilities. The present work explored whether this effect is contingent upon expectancies concerning power's downstream cognitive consequences. Study 1 showed that social dominance orientation (SDO) predicted idiosyncratic expectancies of mental energy change toward interpersonal power. Study 2 showed that SDO moderated the executive functioning changes associated with interpersonal power and that this moderation effect was contingent upon changes in perceived mental depletion. Study 3 showed that directly manipulating expectancies of mental energy change concerning interpersonal power moderated the executive functioning consequences of power and that this moderation effect was contingent upon SDO and changes in perceived mental depletion. Together, the present findings underscore the importance of expectancies and individual differences in understanding the effects of interpersonal power. PMID- 25540326 TI - mTOR inhibition improves immune function in the elderly. AB - Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly. PMID- 25540325 TI - Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease. AB - Age-related neurodegenerative disorders including Alzheimer's disease and Huntington's disease (HD) consistently show elevated DNA damage, but the relevant molecular pathways in disease pathogenesis remain unclear. One attractive gene is that encoding the ataxia-telangiectasia mutated (ATM) protein, a kinase involved in the DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free. Persistently elevated ATM signaling has been demonstrated in Alzheimer's disease and in mouse models of other neurodegenerative diseases. We show that ATM signaling was consistently elevated in cells derived from HD mice and in brain tissue from HD mice and patients. ATM knockdown protected from toxicities induced by mutant Huntingtin (mHTT) fragments in mammalian cells and in transgenic Drosophila models. By crossing the murine Atm heterozygous null allele onto BACHD mice expressing full length human mHTT, we show that genetic reduction of Atm gene dosage by one copy ameliorated multiple behavioral deficits and partially improved neuropathology. Small-molecule ATM inhibitors reduced mHTT-induced death of rat striatal neurons and induced pluripotent stem cells derived from HD patients. Our study provides converging genetic and pharmacological evidence that reduction of ATM signaling could ameliorate mHTT toxicity in cellular and animal models of HD, suggesting that ATM may be a useful therapeutic target for HD. PMID- 25540328 TI - Liberals think more analytically (more "WEIRD") than conservatives. AB - Henrich, Heine, and Norenzayan summarized cultural differences in psychology and argued that people from one particular culture are outliers: people from societies that are Western, educated, industrialized, rich, and democratic (WEIRD). This study shows that liberals think WEIRDer than conservatives. In five studies with more than 5,000 participants, we found that liberals think more analytically (an element of WEIRD thought) than moderates and conservatives. Study 3 replicates this finding in the very different political culture of China, although it held only for people in more modernized urban centers. These results suggest that liberals and conservatives in the same country think as if they were from different cultures. Studies 4 to 5 show that briefly training people to think analytically causes them to form more liberal opinions, whereas training them to think holistically causes shifts to more conservative opinions. PMID- 25540329 TI - Two activities of long-chain acyl-coenzyme A synthetase are involved in lipid trafficking between the endoplasmic reticulum and the plastid in Arabidopsis. AB - In plants, fatty acids are synthesized within the plastid and need to be distributed to the different sites of lipid biosynthesis within the cell. Free fatty acids released from the plastid need to be converted to their corresponding coenzyme A thioesters to become metabolically available. This activation is mediated by long-chain acyl-coenzyme A synthetases (LACSs), which are encoded by a family of nine genes in Arabidopsis (Arabidopsis thaliana). So far, it has remained unclear which of the individual LACS activities are involved in making plastid-derived fatty acids available to cytoplasmic glycerolipid biosynthesis. Because of its unique localization at the outer envelope of plastids, LACS9 was regarded as a candidate for linking plastidial fatty export and cytoplasmic use. However, data presented in this study show that LACS9 is involved in fatty acid import into the plastid. The analyses of mutant lines revealed strongly overlapping functions of LACS4 and LACS9 in lipid trafficking from the endoplasmic reticulum to the plastid. In vivo labeling experiments with lacs4 lacs9 double mutants suggest strongly reduced synthesis of endoplasmic reticulum derived lipid precursors, which are required for the biosynthesis of glycolipids in the plastids. In conjunction with this defect, double-mutant plants accumulate significant amounts of linoleic acid in leaf tissue. PMID- 25540330 TI - FLAVODIIRON2 and FLAVODIIRON4 proteins mediate an oxygen-dependent alternative electron flow in Synechocystis sp. PCC 6803 under CO2-limited conditions. AB - This study aims to elucidate the molecular mechanism of an alternative electron flow (AEF) functioning under suppressed (CO2-limited) photosynthesis in the cyanobacterium Synechocystis sp. PCC 6803. Photosynthetic linear electron flow, evaluated as the quantum yield of photosystem II [Y(II)], reaches a maximum shortly after the onset of actinic illumination. Thereafter, Y(II) transiently decreases concomitantly with a decrease in the photosynthetic oxygen evolution rate and then recovers to a rate that is close to the initial maximum. These results show that CO2 limitation suppresses photosynthesis and induces AEF. In contrast to the wild type, Synechocystis sp. PCC 6803 mutants deficient in the genes encoding FLAVODIIRON2 (FLV2) and FLV4 proteins show no recovery of Y(II) after prolonged illumination. However, Synechocystis sp. PCC 6803 mutants deficient in genes encoding proteins functioning in photorespiration show AEF activity similar to the wild type. In contrast to Synechocystis sp. PCC 6803, the cyanobacterium Synechococcus elongatus PCC 7942 has no FLV proteins with high homology to FLV2 and FLV4 in Synechocystis sp. PCC 6803. This lack of FLV2/4 may explain why AEF is not induced under CO2-limited photosynthesis in S. elongatus PCC 7942. As the glutathione S-transferase fusion protein overexpressed in Escherichia coli exhibits NADH-dependent oxygen reduction to water, we suggest that FLV2 and FLV4 mediate oxygen-dependent AEF in Synechocystis sp. PCC 6803 when electron acceptors such as CO2 are not available. PMID- 25540332 TI - Clinical Outcomes of SMART Versus Luminexx Nitinol Stent Implantation for Aortoiliac Artery Disease: A Propensity Score-Matched Multicenter Study. AB - BACKGROUND: Endovascular therapy for aortoiliac (AI) lesions using stents is widely accepted. However, the long-term outcome of 2 different types of nitinol stents for AI lesions is unknown. The aim of this study was to examine the long term outcome of the SMART and Luminexx nitinol stents for the treatment of de novo AI lesions. METHODS: This study was a multicenter retrospective analysis of a prospectively maintained database. The study enrolled consecutive patients undergoing primary stenting for de novo AI artery stenosis between January 2005 and December 2009. A total of 1503 lesions in 1229 patients treated with SMART or Luminexx primary stenting were enrolled. The primary end point was primary patency, secondary end points were the primary assisted patency, secondary patency, and major adverse limb events (MALEs), which included major amputation and major reintervention. To minimize the differences between the groups, a propensity score matching analysis was performed, and 284 lesions per group were analyzed to identify outcomes. RESULTS: After the propensity score matching analysis, the lesion length was 60 +/- 37 and 57 +/- 31 mm (P = .275), and the reference vessel diameter was 8.2 +/- 1.5 and 8.3 +/- 1.5 mm (P = .482) in the SMART and Luminexx groups, respectively. The primary patency at 3 years was not significantly different between the groups (83.5% vs 82.2%, P = .842, respectively). The assisted primary patency and secondary patency rates were also not significantly different (91.7% vs 93.2%, P = .340, 99.2% vs 98.8%, P = .922). In addition, the MALE rate was not significantly different between the groups (98.3% vs 97.3%, P = .821). CONCLUSION: The current data suggest that the use of nitinol stents for the AI artery provided good long-term patency and freedom from MALE for 3 years of follow-up, regardless of whether SMART or Luminexx stents were used. PMID- 25540333 TI - Evolutionary theory in letters to the editor. AB - This research note presents the results of a content analysis of 234 letters to the editors that discuss evolutionary theory and were published in American newspapers. We find that letters to the editor both support and hinder the cause of teaching evolutionary theory in American secondary schools. On the one hand, anti-evolutionary theory messages are marginalized in the letters section. This marginalization signals a low level of legitimacy for creationism. It might also contribute to the sense of tension that sustains creationist identities. On the other hand, relatively few letters explicitly note the fact that scientists or the scientific community accept evolution. Interestingly, the obscuration of the scientific community's support for evolutionary theory occurs both in letters supporting and opposing evolutionary theory. PMID- 25540334 TI - Complete Genome Sequence of Porcine Circovirus Type 2 Strain HB-MC1. AB - Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD). Here, we report the complete genome sequence of PCV2 strain HB-MC1, which belongs to PCV2d. PMID- 25540331 TI - DEVELOPMENTALLY REGULATED PLASMA MEMBRANE PROTEIN of Nicotiana benthamiana contributes to potyvirus movement and transports to plasmodesmata via the early secretory pathway and the actomyosin system. AB - The intercellular movement of plant viruses requires both viral and host proteins. Previous studies have demonstrated that the frame-shift protein P3N PIPO (for the protein encoded by the open reading frame [ORF] containing 5' terminus of P3 and a +2 frame-shift ORF called Pretty Interesting Potyviridae ORF and embedded in the P3) and CYLINDRICAL INCLUSION (CI) proteins were required for potyvirus cell-to-cell movement. Here, we provide genetic evidence showing that a Tobacco vein banding mosaic virus (TVBMV; genus Potyvirus) mutant carrying a truncated PIPO domain of 58 amino acid residues could move between cells and induce systemic infection in Nicotiana benthamiana plants; mutants carrying a PIPO domain of seven, 20, or 43 amino acid residues failed to move between cells and cause systemic infection in this host plant. Interestingly, the movement defective mutants produced progeny that eliminated the previously introduced stop codons and thus restored their systemic movement ability. We also present evidence showing that a developmentally regulated plasma membrane protein of N. benthamiana (referred to as NbDREPP) interacted with both P3N-PIPO and CI of the movement-competent TVBMV. The knockdown of NbDREPP gene expression in N. benthamiana impeded the cell-to-cell movement of TVBMV. NbDREPP was shown to colocalize with TVBMV P3N-PIPO and CI at plasmodesmata (PD) and traffic to PD via the early secretory pathway and the actomyosin motility system. We also show that myosin XI-2 is specially required for transporting NbDREPP to PD. In conclusion, NbDREPP is a key host protein within the early secretory pathway and the actomyosin motility system that interacts with two movement proteins and influences virus movement. PMID- 25540335 TI - Draft Genome Sequence of the Novel Black-Pigmented Planococcus sp. Strain CAU13. AB - Presented here is the whole-genome sequence of a previously uncharacterized species of the genus Planococcus. A 16S sequence analysis shows that this bacterium exhibits 98% sequence identity to the closest relative of Planococcus kocurii. Whereas most species of Planococcus produce yellow to orange pigments, the species described here produces black pigmentation. PMID- 25540336 TI - Whole-Genome Sequencing Identifies an Atypical Listeria monocytogenes Strain Isolated from Pet Foods. AB - Four Listeria isolates, including an atypical strain, were isolated from various pet foods and sequenced. We report here the draft genome sequences of these isolates and a comparative genomic analysis with a closely related human clinical isolate. An analysis of the atypical strain identified a frameshift mutation in the prfA gene. PMID- 25540337 TI - A Newly Sequenced Alcaligenes faecalis Strain: Implications for Novel Temporal Symbiotic Relationships. AB - We report here the draft genome sequence of Alcaligenes faecalis strain MOR02, a bacterium that is able to colonize nematodes in a temporary fashion and kill insects for their own benefit. The availability of the genome should enable us to explain these phenotypes. PMID- 25540338 TI - Draft Genome Sequence of Pseudomonas mediterranea Strain CFBP 5447T, a Producer of Filmable Medium-Chain-Length Polyhydroxyalkanoates. AB - Pseudomonas mediterranea strain CFBP 5447(T) is a phytopathogenic bacterium isolated from tomato plants affected by pith necrosis disease. Moreover, its ability to produce medium-chain-length polyhydroxyalkanoates (mcl-PHAs) in culture from different carbon sources and valuable microbial products, such as cyclic lipopeptides, has been well documented. Here, we report the first draft genome sequence of this species. PMID- 25540339 TI - Genome Sequence of a Pandrug-Resistant Pseudomonas aeruginosa Strain, YN-1. AB - A highly rampant multidrug-resistant strain of Pseudomonas aeruginosa appeared in a hospital in Yunnan Province, China. Here, we report the genome sequence of the pandrug-resistant (PDR) P. aeruginosa strain recovered from a patient in 2013. PMID- 25540340 TI - Complete genome sequence of a common midwife toad virus-like ranavirus associated with mass mortalities in wild amphibians in the Netherlands. AB - A ranavirus associated with mass mortalities in wild water frogs (Pelophylax spp.) and other amphibians in the Netherlands since 2010 was isolated, and its complete genome sequence was determined. The virus has a genome of 107,772 bp and shows 96.5% sequence identity with the common midwife toad virus from Spain. PMID- 25540341 TI - Whole-Genome Sequence of Borrelia garinii Strain 935T Isolated from Ixodes persulcatus in South Korea. AB - We report here the genome sequence of Borrelia garinii strain 935T isolated from Ixodes persulcatus in South Korea. The 1,176,739 bp (G+C content, 27.73%) genome consists of 1,194 coding regions, 4 rRNA genes, and 33 aminoacyl-tRNA synthetase genes. This is the first whole-genome report of a Korean Borrelia species isolate. PMID- 25540342 TI - Complete Genome Sequences of Bordetella pertussis Isolates B1917 and B1920, Representing Two Predominant Global Lineages. AB - Bordetella pertussis is the causative agent of pertussis, a disease which has resurged despite vaccination. We report the complete, annotated genomes of isolates B1917 and B1920, representing two lineages predominating globally in the last 50 years. The B1917 lineage has been associated with the resurgence of pertussis in the 1990s. PMID- 25540343 TI - Complete Genome Sequencing of Borrelia valaisiana and Borrelia afzelii Isolated from Ixodes persulcatus Ticks in Western Siberia. AB - Lyme disease, caused by bacteria of the Borrelia burgdorferi sensu lato complex, is the most frequent tick-borne infection in Eurasia. Here, we report the complete genome sequence of the Borrelia valaisiana Tom 4006 and Borrelia afzelii Tom 3107 strains isolated from Ixodes persulcatus ticks in western Siberia. PMID- 25540344 TI - Draft Genome Sequence of Lactobacillus casei Lbs2. AB - We report here a 3.2-Mb draft assembled genome of Lactobacillus casei Lbs2. The bacterium shows probiotic and immunomodulatory activities. The genome assembly and annotation will help to identify molecules and pathways responsible for interaction between the host immune system and the microbe. PMID- 25540345 TI - Complete Genome Sequence of a Klebsiella pneumoniae Isolate with Chromosomally Encoded Carbapenem Resistance and Colibactin Synthesis Loci. AB - Klebsiella pneumoniae is an important nosocomial pathogen, and multidrug resistant strains have become a worldwide concern. Here, we report the complete genome of a K. pneumoniae isolate with chromosomally integrated blaKPC genes and a colibactin synthesis locus. PMID- 25540346 TI - Complete Genome Sequence for Treponema sp. OMZ 838 (ATCC 700772, DSM 16789), Isolated from a Necrotizing Ulcerative Gingivitis Lesion. AB - The oral treponeme bacterium Treponema sp. OMZ 838 was originally isolated from a human necrotizing ulcerative gingivitis (NUG) lesion. Its taxonomic status remains uncertain. The complete genome sequence length was determined to be 2,708,067 bp, with a G+C content of 44.58%, and 2,236 predicted coding DNA sequences (CDS). PMID- 25540347 TI - Genome Sequences of Three Highly Copper-Resistant Salmonella enterica subsp. I Serovar Typhimurium Strains Isolated from Pigs in Denmark. AB - Salmonella typhimurium is the causative agent of typhoid fever, which causes nearly 21.7 million illnesses and 217,000 deaths around the world each year. Here, we describe the draft genome sequences of the Salmonella typhimurium strains S7, S15, and S23, isolated from copper-fed pigs in Denmark and containing additional putative determinants conferring resistances to copper and other metals and metalloids. PMID- 25540348 TI - Draft Genome Sequence of Elizabethkingia meningoseptica, Isolated from a Postoperative Endophthalmitis Patient. AB - We present the draft genome assembly of an Elizabethkingia meningoseptica strain isolated from a 67-year-old postoperative endophthalmitis patient who suffered loss of vision in the right eye. The draft genome assembly has 167 contigs with a total size of 4,019,665 bp encoding multiple drug-resistant genes. PMID- 25540349 TI - Complete Genome Sequence of Klebsiella pneumoniae Sequence Type 17, a Multidrug Resistant Strain Isolated during Tigecycline Treatment. AB - Klbesiella pneumoniae is one of the most important human pathogens and frequently causes many diseases. To facilitate the comparative genome analysis in tigecycline resistance mechanism, we report the complete chromosomal sequence of a multidrug-resistance K. pneumoniae strain before tigecycline treatment for reference genome. PMID- 25540350 TI - Complete Genome Sequence of Streptococcus agalactiae CNCTC 10/84, a Hypervirulent Sequence Type 26 Strain. AB - Streptococcus agalactiae (group B Streptococcus [GBS]) is a human pathogen with a propensity to cause neonatal infections. We report the complete genome sequence of GBS strain CNCTC 10/84, a hypervirulent clinical isolate frequently used to study GBS pathogenesis. Comparative analysis of this sequence may shed light on novel pathogenic mechanisms. PMID- 25540351 TI - Genome Sequences of Two Copper-Resistant Escherichia coli Strains Isolated from Copper-Fed Pigs. AB - The draft genome sequences of two copper-resistant Escherichia coli strains were determined. These had been isolated from copper-fed pigs and contained additional putative operons conferring copper and other metal and metalloid resistances. PMID- 25540352 TI - Draft Genome Sequence of Rice Isolate Pseudomonas chlororaphis EA105. AB - Pseudomonas chlororaphis EA105, a strain isolated from rice rhizosphere, has shown antagonistic activities against a rice fungal pathogen, and could be important in defense against rice blast. We report the draft genome sequence of EA105, which is an estimated size of 6.6 Mb. PMID- 25540354 TI - Influenza pH1N1 Virus Accumulated H275Y Mutation in Neuraminidase during Propagation in MDCK Cells. AB - Here, we sequenced the genome of the influenza A/Finland/741 M/2014(H1N1) virus and found that the virus accumulated oseltamivir resistance mutation H275Y in its neuraminidase during propagation in cell culture. This indicates that propagation in cell culture modifies virus genomes. The instability of influenza genomes should be taken into consideration during drug-sensitivity studies. PMID- 25540353 TI - Draft Genome Sequence of Violacein-Producing Marine Bacterium Pseudoalteromonas sp. 520P1. AB - Here, we report a draft 5.25-Mb genome sequence of Pseudoalteromonas sp. 520P1, a marine violacein-producing bacterium isolated from the Pacific coast of Japan. Genome annotation by BLAST searches revealed the presence of one acylhomoserine lactone (AHL) synthase (luxI) and five AHL receptor protein (luxR) gene homologs. PMID- 25540355 TI - Whole-Genome Sequence of "Candidatus Liberibacter solanacearum" Strain R1 from California. AB - The draft whole-genome sequence of "Candidatus Liberibacter solanacearum" strain R1, isolated from and maintained in tomato plants in California, is reported. The R1 strain has the genome size of 1,204,257 bp, G+C content of 35.3%, 1,101 predicted open reading frames, and 57 RNA genes. PMID- 25540356 TI - Draft Genome Sequence of Clostridium butyricum Strain NOR 33234, Isolated from an Elderly Patient with Diarrhea. AB - Clostridium butyricum is one of the species frequently present in patients' stool samples. However, the identification of this species is sometimes difficult. Here, we present the draft genome of Clostridium butyricum NOR 33234, which was isolated from a patient with suspected Clostridium difficile infection-associated diarrhea and resembles Clostridium clostridioforme in biochemical tests. PMID- 25540357 TI - Whole-Genome Analysis of Aeromonas hydrophila Strain 187, Exhibiting Quorum Sensing Activity. AB - Aeromonas hydrophila is a quorum-sensing (QS) bacterium that causes diarrhea in humans upon infection. Here, we report the genome of pathogenic Aeromonas hydrophila strain 187, which possesses a QS gene responsible for signaling molecule N-acyl homoserine lactone (AHL) synthesis and has been found to be located at contig 36. PMID- 25540358 TI - Genome Sequence of Afipia felis Strain 76713, Isolated in Hospital Water Using an Amoeba Co-Culture Procedure. AB - Afipia felis is a Gram-negative alphaproteobacterium originally described as the agent of cat-scratch disease (CSD). We sequenced the genome from a strain of A. felis, which was recovered from a hospital water sample using an amoebal co culture procedure. It is composed of 3,989,646 bp, with a G+C content of 61.27% and encodes 4,068 protein-coding genes and 53 RNA genes. PMID- 25540359 TI - Reduction of HIV-1 infectivity through endoplasmic reticulum-associated degradation-mediated Env depletion. AB - During the HIV-1 replicative cycle, the gp160 envelope is processed in the secretory pathway to mature into the gp41 and gp120 subunits. Misfolded proteins located within the endoplasmic reticulum (ER) are proteasomally degraded through the ER-associated degradation (ERAD) pathway, a quality control system operating in this compartment. Here, we exploited the ERAD pathway to induce the degradation of gp160 during viral production, thus leading to the release of gp120-depleted viral particles. PMID- 25540360 TI - Circovirus transport proceeds via direct interaction of the cytoplasmic dynein IC1 subunit with the viral capsid protein. AB - Microtubule transport of circovirus from the periphery of the cell to the nucleus is essential for viral replication in early infection. How the microtubule is recruited to the viral cargo remains unclear. In this study, we observed that circovirus trafficking is dependent on microtubule polymerization and that incoming circovirus particles colocalize with cytoplasmic dynein and endosomes. However, circovirus binding to dynein was independent of the presence of microtubular alpha-tubulin and translocation of cytoplasmic dynein into the nucleus. The circovirus capsid (Cap) subunit enhanced microtubular acetylation and directly interacted with intermediate chain 1 (IC1) of dynein. N-terminal residues 42 to 100 of the Cap viral protein were required for efficient binding to the dynein IC1 subunit and for retrograde transport. Knockdown of IC1 decreased virus transport and replication. These results demonstrate that Cap is a direct ligand of the cytoplasmic dynein IC1 subunit and an inducer of microtubule alpha-tubulin acetylation. Furthermore, Cap recruits the host dynein/microtubule machinery to facilitate transport toward the nucleus by an endosomal mechanism distinct from that used for physiological dynein cargo. IMPORTANCE: Incoming viral particles hijack the intracellular trafficking machinery of the host in order to migrate from the cell surface to the replication sites. Better knowledge of the interaction between viruses and virus proteins and the intracellular trafficking machinery may provide new targets for antiviral therapies. Currently, little is known about the molecular mechanisms of circovirus transport. Here, we report that circovirus particles enter early endosomes and utilize the microtubule-associated molecular motor dynein to travel along microtubules. The circovirus capsid subunit enhances microtubular acetylation, and N-terminal residues 42 to 100 directly interact with the dynein IC1 subunit during retrograde transport. These findings highlight a mechanism whereby circoviruses recruit dynein for transport to the nucleus via the dynein/microtubule machinery. PMID- 25540361 TI - The proteasomal Rpn11 metalloprotease suppresses tombusvirus RNA recombination and promotes viral replication via facilitating assembly of the viral replicase complex. AB - RNA viruses co-opt a large number of cellular proteins that affect virus replication and, in some cases, viral genetic recombination. RNA recombination helps viruses in an evolutionary arms race with the host's antiviral responses and adaptation of viruses to new hosts. Tombusviruses and a yeast model host are used to identify cellular factors affecting RNA virus replication and RNA recombination. In this study, we have examined the role of the conserved Rpn11p metalloprotease subunit of the proteasome, which couples deubiquitination and degradation of proteasome substrates, in tombusvirus replication and recombination in Saccharomyces cerevisiae and plants. Depletion or mutations of Rpn11p lead to the rapid formation of viral RNA recombinants in combination with reduced levels of viral RNA replication in yeast or in vitro based on cell extracts. Rpn11p interacts with the viral replication proteins and is recruited to the viral replicase complex (VRC). Analysis of the multifunctional Rpn11p has revealed that the primary role of Rpn11p is to act as a "matchmaker" that brings the viral p92(pol) replication protein and the DDX3-like Ded1p/RH20 DEAD box helicases into VRCs. Overexpression of Ded1p can complement the defect observed in rpn11 mutant yeast by reducing TBSV recombination. This suggests that Rpn11p can suppress tombusvirus recombination via facilitating the recruitment of the cellular Ded1p helicase, which is a strong suppressor of viral recombination, into VRCs. Overall, this work demonstrates that the co-opted Rpn11p, which is involved in the assembly of the functional proteasome, also functions in the proper assembly of the tombusvirus VRCs. IMPORTANCE: RNA viruses evolve rapidly due to genetic changes based on mutations and RNA recombination. Viral genetic recombination helps viruses in an evolutionary arms race with the host's antiviral responses and facilitates adaptation of viruses to new hosts. Cellular factors affect viral RNA recombination, although the role of the host in virus evolution is still understudied. In this study, we used a plant RNA virus, tombusvirus, to examine the role of a cellular proteasomal protein, called Rpn11, in tombusvirus recombination in a yeast model host, in plants, and in vitro. We found that the cellular Rpn11 is subverted for tombusvirus replication and Rpn11 has a proteasome-independent function in facilitating viral replication. When the Rpn11 level is knocked down or a mutated Rpn11 is expressed, then tombusvirus RNA goes through rapid viral recombination and evolution. Taken together, the results show that the co-opted cellular Rpn11 is a critical host factor for tombusviruses by regulating viral replication and genetic recombination. PMID- 25540363 TI - Regulation of herpesvirus reactivation by host microRNAs. AB - The interplay between latent and lytic modes of infection is central to successful infection of all herpesviruses, yet knowledge of the determinants that govern reactivation of these viruses from latent to lytic infection is limited. Recently, several studies have identified roles for specific cellular microRNAs in inhibiting reactivation of various herpesviruses, thereby promoting latent infections. These studies are discussed in the context of current knowledge on mechanisms of regulation of reactivation of specific herpesviruses. PMID- 25540362 TI - RNase L targets distinct sites in influenza A virus RNAs. AB - Influenza A virus (IAV) infections are influenced by type 1 interferon-mediated antiviral defenses and by viral countermeasures to these defenses. When IAV NS1 protein is disabled, RNase L restricts virus replication; however, the RNAs targeted for cleavage by RNase L under these conditions have not been defined. In this study, we used deep-sequencing methods to identify RNase L cleavage sites within host and viral RNAs from IAV PR8DeltaNS1-infected A549 cells. Short hairpin RNA knockdown of RNase L allowed us to distinguish between RNase L dependent and RNase L-independent cleavage sites. RNase L-dependent cleavage sites were evident at discrete locations in IAV RNA segments (both positive and negative strands). Cleavage in PB2, PB1, and PA genomic RNAs suggests that viral RNPs are susceptible to cleavage by RNase L. Prominent amounts of cleavage mapped to specific regions within IAV RNAs, including some areas of increased synonymous site conservation. Among cellular RNAs, RNase L-dependent cleavage was most frequent at precise locations in rRNAs. Our data show that RNase L targets specific sites in both host and viral RNAs to restrict influenza virus replication when NS1 protein is disabled. IMPORTANCE: RNase L is a critical component of interferon-regulated and double-stranded-RNA-activated antiviral host responses. We sought to determine how RNase L exerts its antiviral activity during influenza virus infection. We enhanced the antiviral activity of RNase L by disabling a viral protein, NS1, that inhibits the activation of RNase L. Then, using deep-sequencing methods, we identified the host and viral RNAs targeted by RNase L. We found that RNase L cleaved viral RNAs and rRNAs at very precise locations. The direct cleavage of IAV RNAs by RNase L highlights an intimate battle between viral RNAs and an antiviral endonuclease. PMID- 25540364 TI - Hepatitis B virus regulates apoptosis and tumorigenesis through the microRNA-15a Smad7-transforming growth factor beta pathway. AB - Hepatitis B virus (HBV) infection causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). Previously, we found that HBV mRNAs can absorb microRNA-15a (miR 15a) to affect apoptosis through the Bcl-2 pathway. We asked whether HBV could inhibit apoptosis and promote tumorigenesis through different pathways. In this study, we found that the transforming growth factor beta (TGF-beta) pathway inhibitory factor Smad7 is a novel target of miR-15a. We demonstrated that HBV can upregulate the level of Smad7 by downregulating miR-15a. Furthermore, we examined the level of Smad7 in liver samples from HBV-infected HCC patients and found that HBV mRNAs are positively correlated with the level of Smad7. By taking the approach of using immunoblotting and luciferase reporter assays, we revealed that HBV can abrogate TGF-beta signaling via upregulating Smad7. By using annexin V staining and caspase 3/7 activity assays, we found that HBV can inhibit TGF beta-induced apoptosis of HepG2 cells. We also showed that HBV can promote tumor growth in BALB/c nude mice through upregulating the expression of Smad7. In conclusion, we demonstrated that HBV can upregulate Smad7 expression and inhibit TGF-beta signaling, which makes the cells resistant to TGF-beta-induced apoptosis and promotes tumorigenesis. IMPORTANCE: Hepatitis B virus (HBV) infection causes chronic hepatitis, which can eventually lead to hepatocellular carcinoma (HCC). TGF-beta signaling is closely linked to liver fibrosis, cirrhosis, and subsequent HCC progression and plays a unique role in the pathogenesis of HCC. At the early stage of tumor formation, TGF-beta functions as a tumor suppressor that inhibits cell proliferation and induces apoptosis. Previously, we found that HBV mRNAs can sponge off miR-15a to affect apoptosis through the Bcl-2 pathway. In this study, we identified that the TGF-beta-inhibitory factor Smad7 is a novel target of miR 15a. We reveal that HBV can abrogate TGF-beta signaling via upregulating Smad7, inhibit TGF-beta-induced apoptosis, as well as promote tumor development. Our study provides evidence to support the idea that viral RNAs can exert their functions as competing endogenous RNAs (ceRNAs) toward microRNA and participate in important cellular processes. PMID- 25540365 TI - Suppression of transforming growth factor beta receptor 2 and Smad5 is associated with high levels of microRNA miR-155 in the oral mucosa during chronic simian immunodeficiency virus infection. AB - Chronic human immunodeficiency virus and simian immunodeficiency virus (HIV and SIV) infections are characterized by mucosal inflammation in the presence of anti inflammatory cytokines such as transforming growth factor beta (TGFbeta). The mechanisms for refractiveness to TGFbeta are not clear. Here we show that the expression of microRNA miR-155 was significantly upregulated in the oropharyngeal mucosa during chronic SIV infection and was coincident with downregulation of TGFbeta receptor 2 (TGFbeta-R2) and SMAD5, key TGFbeta signaling genes that harbor putative target sites for miR-155. Ectopic expression of miR-155 in vitro was found to significantly downregulate TGFbeta-R2 and Smad5 expression, suggesting a role for miR-155 in the suppression of TGFbeta-R2 and SMAD5 genes in vivo. The downregulation of TGFbeta signaling genes by miR-155 likely contributes to the nonresponsiveness to TGFbeta during SIV infection and may inadvertently aid in increased immune activation during HIV and SIV infections. PMID- 25540366 TI - Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis. AB - Previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (VSV) type I interferon receptor (IFNAR) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. To address whether locally active IFN-beta was induced proximally, we studied spatiotemporal conditions of VSV-mediated IFN-beta induction. To this end, we performed infection studies with IFN-beta reporter mice. One day after intravenous (i.v.) VSV infection, luciferase induction was detected in lymph nodes. Upon i.n. infection, luciferase induction was discovered at similar sites with delayed kinetics, whereas on days 3 and 4 postinfection enhanced luciferase expression additionally was detected in the foreheads of reporter mice. A detailed analysis of cell type-specific IFN-beta reporter mice revealed that within the olfactory bulb IFN-beta was expressed by neuroectodermal cells, primarily by astrocytes and to a lesser extent by neurons. Importantly, locally induced type I IFN triggered distal parts of the brain as indicated by the analysis of ISRE-eGFP mice which after i.n. VSV infection showed enhanced green fluorescent protein (eGFP) expression throughout the brain. Compared to wild-type mice, IFN-beta(-/-) mice showed increased mortality to i.n. VSV infection, whereas upon i.v. infection no such differences were detected highlighting the biological significance of intracerebrally expressed IFN-beta. In conclusion, upon i.n. VSV instillation, IFN-beta responses mounted by astrocytes within the olfactory bulb critically contribute to the antiviral defense by stimulating distal IFN-beta-negative brain areas and thus arresting virus spread. IMPORTANCE: The central nervous system has long been considered an immune privileged site. More recently, it became evident that specialized immune mechanisms are active within the brain to control pathogens. Previously, we showed that virus, which entered the brain via the olfactory route, was arrested within the olfactory bulb by a type I IFN-dependent mechanism. Since peripheral type I IFN would not readily cross the blood-brain barrier and within the brain thus far no abundant type I IFN responses have been detected, here we addressed from where locally active IFN originated from. We found that upon intranasal VSV instillation, primarily astrocytes, and to a lesser extent neurons, were stimulated within the olfactory bulb to mount IFN-beta responses that also activated and protected distal brain areas. Our results are surprising because in other infection models astrocytes have not yet been identified as major type I IFN producers. PMID- 25540367 TI - The Epstein-Barr virus BamHI C promoter is not essential for B cell immortalization in vitro, but it greatly enhances B cell growth transformation. AB - Epstein-Barr virus (EBV) infection of B cells leads to the sequential activation of two viral promoters, Wp and Cp, resulting in the expression of six EBV nuclear antigens (EBNAs) and the viral Bcl2 homologue BHRF1. The viral transactivator EBNA2 is required for this switch from Wp to Cp usage during the initial stages of infection. EBNA2-dependent Cp transcription is mediated by the EBNA2 response element (E2RE), a region that contains at least two binding sites for cellular factors; one of these sites, CBF1, interacts with RBP-JK, which then recruits EBNA2 to the transcription initiation complex. Here we demonstrate that the B cell-specific transcription factor BSAP/Pax5 binds to a second site, CBF2, in the E2RE. Deletion of the E2RE in the context of a recombinant virus greatly diminished levels of Cp-initiated transcripts during the initial stages of infection but did not affect the levels of Wp-initiated transcripts or EBNA mRNAs. Consistent with this finding, viruses deleted for the E2RE were not markedly impaired in their ability to induce B cell transformation in vitro. In contrast, a larger deletion of the entire Cp region did reduce EBNA mRNA levels early after infection and subsequently almost completely ablated lymphoblastoid cell line (LCL) outgrowth. Notably, however, rare LCLs could be established following infection with Cp-deleted viruses, and these were indistinguishable from wild-type-derived LCLs in terms of steady-state EBV gene transcription. These data indicate that, unlike Wp, Cp is dispensable for the virus' growth transforming activity. IMPORTANCE: Epstein-Barr virus (EBV), a B lymphotropic herpesvirus etiologically linked to several B cell malignancies, efficiently induces B cell proliferation leading to the outgrowth of lymphoblastoid cell lines (LCLs). The initial stages of this growth-transforming infection are characterized by the sequential activation of two viral promoters, Wp and Cp, both of which appear to be preferentially active in target B cells. In this work, we have investigated the importance of Cp activity in initiating B cell proliferation and maintaining LCL growth. Using recombinant viruses, we demonstrate that while Cp is not essential for LCL outgrowth in vitro, it enhances transformation efficiency by >100-fold. We also show that Cp, like Wp, interacts with the B cell-specific activator protein BSAP/Pax5. We suggest that EBV has evolved this two-promoter system to ensure efficient colonization of the host B cell system in vivo. PMID- 25540368 TI - A multivalent clade C HIV-1 Env trimer cocktail elicits a higher magnitude of neutralizing antibodies than any individual component. AB - The sequence diversity of human immunodeficiency virus type 1 (HIV-1) presents a formidable challenge to the generation of an HIV-1 vaccine. One strategy to address such sequence diversity and to improve the magnitude of neutralizing antibodies (NAbs) is to utilize multivalent mixtures of HIV-1 envelope (Env) immunogens. Here we report the generation and characterization of three novel, acute clade C HIV-1 Env gp140 trimers (459C, 405C, and 939C), each with unique antigenic properties. Among the single trimers tested, 459C elicited the most potent NAb responses in vaccinated guinea pigs. We evaluated the immunogenicity of various mixtures of clade C Env trimers and found that a quadrivalent cocktail of clade C trimers elicited a greater magnitude of NAbs against a panel of tier 1A and 1B viruses than any single clade C trimer alone, demonstrating that the mixture had an advantage over all individual components of the cocktail. These data suggest that vaccination with a mixture of clade C Env trimers represents a promising strategy to augment vaccine-elicited NAb responses. IMPORTANCE: It is currently not known how to generate potent NAbs to the diverse circulating HIV-1 Envs by vaccination. One strategy to address this diversity is to utilize mixtures of different soluble HIV-1 envelope proteins. In this study, we generated and characterized three distinct, novel, acute clade C soluble trimers. We vaccinated guinea pigs with single trimers as well as mixtures of trimers, and we found that a mixture of four trimers elicited a greater magnitude of NAbs than any single trimer within the mixture. The results of this study suggest that further development of Env trimer cocktails is warranted. PMID- 25540369 TI - Intracellular expression of camelid single-domain antibodies specific for influenza virus nucleoprotein uncovers distinct features of its nuclear localization. AB - Perturbation of protein-protein interactions relies mostly on genetic approaches or on chemical inhibition. Small RNA viruses, such as influenza A virus, do not easily lend themselves to the former approach, while chemical inhibition requires that the target protein be druggable. A lack of tools thus constrains the functional analysis of influenza virus-encoded proteins. We generated a panel of camelid-derived single-domain antibody fragments (VHHs) against influenza virus nucleoprotein (NP), a viral protein essential for nuclear trafficking and packaging of the influenza virus genome. We show that these VHHs can target NP in living cells and perturb NP's function during infection. Cytosolic expression of NP-specific VHHs (alphaNP-VHHs) disrupts virus replication at an early stage of the life cycle. Based on their specificity, these VHHs fall into two distinct groups. Both prevent nuclear import of the viral ribonucleoprotein (vRNP) complex without disrupting nuclear import of NP alone. Different stages of the virus life cycle thus rely on distinct nuclear localization motifs of NP. Their molecular characterization may afford new means of intervention in the virus life cycle. IMPORTANCE: Many proteins encoded by RNA viruses are refractory to manipulation due to their essential role in replication. Thus, studying their function and determining how to disrupt said function through pharmaceutical intervention are difficult. We present a novel method based on single-domain-antibody technology that permits specific targeting and disruption of an essential influenza virus protein in the absence of genetic manipulation of influenza virus itself. Characterization of such interactions may help identify new targets for pharmaceutical intervention. This approach can be extended to study proteins encoded by other viral pathogens. PMID- 25540370 TI - Lymph node but not intradermal injection site macrophages are critical for germinal center formation and antibody responses to rabies vaccination. AB - Replication-deficient rabies virus (RABV)-based vaccines induce rapid and potent antibody responses via T cell-independent and T cell-dependent mechanisms. To further investigate early events in vaccine-induced antibody responses against RABV infections, we studied the role of macrophages as mediators of RABV-based vaccine immunogenicity. In this report, we show that a recombinant matrix gene deleted RABV-based vaccine (rRABV-DeltaM) infects and activates primary murine macrophages in vitro. Immunization of mice with live RABV-based vaccines results in accumulation of macrophages at the site of immunization, which suggests that macrophages in tissues support the development of effective anti-RABV B cell responses. However, we show that draining lymph node macrophages, but not macrophages at the site of immunization, are essential for the generation of germinal center B cells, follicular T helper cells, and RABV-specific antibodies. Our findings have implications for the design of new RABV-based vaccines for which early immunological events are important for the protection against RABV in postexposure settings. IMPORTANCE: More than two-thirds of the world's population live in regions where rabies is endemic. Postexposure prophylaxis is the primary means of treating humans. Identifying immunological principles that guide the development of rapid and potent antibody responses against rabies infections will greatly increase our ability to produce more-effective rabies vaccines. Here we report that macrophages in the draining lymph node, but not in the tissue at the site of immunization are important for vaccine-induced antibody responses to rabies. Information gleaned from this study may help guide the development of a single-dose vaccine against rabies infections. PMID- 25540371 TI - Recombinant subgroup B human respiratory syncytial virus expressing enhanced green fluorescent protein efficiently replicates in primary human cells and is virulent in cotton rats. AB - Human respiratory syncytial virus (HRSV) is the most important viral cause of severe respiratory tract disease in infants. Two subgroups (A and B) have been identified, which cocirculate during, or alternate between, yearly epidemics and cause indistinguishable disease. Existing in vitro and in vivo models of HRSV focus almost exclusively on subgroup A viruses. Here, a recombinant (r) subgroup B virus (rHRSV(B05)) was generated based on a consensus genome sequence obtained directly from an unpassaged clinical specimen from a hospitalized infant. An additional transcription unit containing the gene encoding enhanced green fluorescent protein (EGFP) was introduced between the phosphoprotein and matrix genes (position 5) of the genome to generate rHRSV(B05)EGFP(5). The recombinant viruses replicated efficiently in both HEp-2 cells and in well-differentiated normal human bronchial cells grown at air-liquid interface. Intranasal infection of cotton rats (Sigmodon hispidus) resulted in high numbers of EGFP(+) cells in epithelia of the nasal septum and conchae. When administered in a relatively large inoculum volume, the virus also replicated efficiently in bronchiolar epithelial cells and spread extensively in both the upper and lower respiratory tracts. Virus replication was not observed in ciliated epithelial cells of the trachea. This is the first virulent rHRSV strain with the genetic composition of a currently circulating wild-type virus. In vivo tracking of infected cells by means of EGFP fluorescence in the absence of cytopathic changes increases the sensitivity of virus detection in HRSV pathogenesis studies. IMPORTANCE: Virology as a discipline has depended on monitoring cytopathic effects following virus culture in vitro. However, wild-type viruses isolated from patients often do not cause significant changes to infected cells, necessitating blind passage. This can lead to genetic and phenotypic changes and the generation of high-titer, laboratory-adapted viruses with diminished virulence in animal models of disease. To address this, we determined the genome sequence of an unpassaged human respiratory syncytial virus from a sample obtained directly from an infected infant, assembled a molecular clone, and recovered a wild-type recombinant virus. Addition of a gene encoding enhanced green fluorescent protein allowed this wild type virus to be tracked in primary human cells and living animals in the absence of significant cytopathic effects. Imaging of fluorescent cells proved to be a highly valuable tool for monitoring the spread of virus and may help improve assays for evaluating novel intervention strategies. PMID- 25540373 TI - Postentry restriction of Mason-Pfizer monkey virus in mouse cells. AB - Mason-Pfizer monkey virus (M-PMV) is a prototypical betaretrovirus responsible for simian AIDS (SAIDS) in rhesus macaques. It has been shown previously that mouse cells are resistant to infection by HIV-1 and other primate lentiviruses. However, the susceptibility of mouse cells to primate retroviruses such as M-PMV remains unexplored. In the present study, using single-round green fluorescent protein (GFP) reporter viruses, we showed that various mouse cell lines are unable to support the early stages of M-PMV replication. The block to infection occurs postentry and is independent of the viral envelope. Using quantitative real-time PCR, we showed that the block to infection occurs after reverse transcription but before formation of circular DNA or proviral DNA. Finally, we showed that the M-PMV block in mouse cells is not attributable to the previously characterized mouse restriction factor Fv1. Overall, these findings suggest that mouse cells exhibit a previously uncharacterized block to M-PMV infection. IMPORTANCE: Here we document a novel postentry restriction to M-PMV infection in mouse cells. The block occurs after reverse transcription but before the formation of circular or proviral DNA and is independent of the previous characterized mouse restriction factor Fv1. PMID- 25540372 TI - Pathogenicity and transmissibility of novel reassortant H3N2 influenza viruses with 2009 pandemic H1N1 genes in pigs. AB - At least 10 different genotypes of novel reassortant H3N2 influenza viruses with 2009 pandemic H1N1 [A(H1N1)pdm09] gene(s) have been identified in U.S. pigs, including the H3N2 variant with a single A(H1N1)pdm09 M gene, which has infected more than 300 people. To date, only three genotypes of these viruses have been evaluated in animal models, and the pathogenicity and transmissibility of the other seven genotype viruses remain unknown. Here, we show that three H3N2 reassortant viruses that contain 3 (NP, M, and NS) or 5 (PA, PB2, NP, M, and NS) genes from A(H1N1)pdm09 were pathogenic in pigs, similar to the endemic H3N2 swine virus. However, the reassortant H3N2 virus with 3 A(H1N1)pdm09 genes and a recent human influenza virus N2 gene was transmitted most efficiently among pigs, whereas the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes was transmitted less efficiently than the endemic H3N2 virus. Interestingly, the polymerase complex of reassortant H3N2 virus with 5 A(H1N1)pdm09 genes showed significantly higher polymerase activity than those of endemic and reassortant H3N2 viruses with 3 A(H1N1)pdm09 genes. Further studies showed that an avian-like glycine at position 228 at the hemagglutinin (HA) receptor binding site is responsible for inefficient transmission of the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes. Taken together, our results provide insights into the pathogenicity and transmissibility of novel reassortant H3N2 viruses in pigs and suggest that a mammalian-like serine at position 228 in the HA is critical for the transmissibility of these reassortant H3N2 viruses. IMPORTANCE: Swine influenza is a highly contagious zoonotic disease that threatens animal and public health. Introduction of 2009 pandemic H1N1 virus [A(H1N1)pdm09] into swine herds has resulted in novel reassortant influenza viruses in swine, including H3N2 and H1N2 variants that have caused human infections in the United States. We showed that reassortant H3N2 influenza viruses with 3 or 5 genes from A(H1N1)pdm09 isolated from diseased pigs are pathogenic and transmissible in pigs, but the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes displayed less efficient transmissibility than the endemic and reassortant H3N2 viruses with 3 A(H1N1)pdm09 genes. Further studies revealed that an avian-like glycine at the HA 228 receptor binding site of the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes is responsible for less efficient transmissibility in pigs. Our results provide insights into viral pathogenesis and the transmission of novel reassortant H3N2 viruses that are circulating in U.S. swine herds and warrant future surveillance. PMID- 25540374 TI - Viromes, not gene markers, for studying double-stranded DNA virus communities. AB - Microbes have recently been recognized as dominant forces in nature, with studies benefiting from gene markers that can be quickly, informatively, and universally surveyed. Viruses, where explored, have proven to be powerful modulators of locally and globally important microbes through mortality, horizontal gene transfer, and metabolic reprogramming. However, community-wide virus studies have been challenged by the lack of a universal marker. Here, I propose that viral metagenomics has advanced to largely take over study of double-stranded DNA viruses. PMID- 25540375 TI - Influenza virus reservoirs and intermediate hosts: dogs, horses, and new possibilities for influenza virus exposure of humans. AB - Influenza A virus (IAV) infections in hosts outside the main aquatic bird reservoirs occur periodically. Although most such cross-species transmission events result in limited onward transmission in the new host, sustained influenza outbreaks have occurred in poultry and in a number of mammalian species, including humans, pigs, horses, seals, and mink. Recently, two distinct strains of IAV have emerged in domestic dogs, with each circulating widely for several years. Here, we briefly outline what is known about the role of intermediate hosts in influenza emergence, summarize our knowledge of the new canine influenza viruses (CIVs) and how they provide key new information on the process of host adaptation, and assess the risk these viruses pose to human populations. PMID- 25540376 TI - Virus evolution toward limited dependence on nonessential functions of the host: the case of bacteriophage SPP1. AB - All viruses are obligate intracellular parasites and depend on certain host cell functions for multiplication. However, the extent of such dependence and the exact nature of the functions provided by the host cell remain poorly understood. Here, we investigated if nonessential Bacillus subtilis genes are necessary for multiplication of bacteriophage SPP1. Screening of a collection of 2,514 single gene knockouts of nonessential B. subtilis genes yielded only a few genes necessary for efficient SPP1 propagation. Among these were genes belonging to the yuk operon, which codes for the Esat-6-like secretion system, including the SPP1 receptor protein YueB. In addition, we found that SPP1 multiplication was negatively affected by the absence of two other genes, putB and efp. The gene efp encodes elongation factor P, which enhances ribosome activity by alleviating translational stalling during the synthesis of polyproline-containing proteins. PutB is an enzyme involved in the proline degradation pathway that is required for infection in the post-exponential growth phase of B. subtilis, when the bacterium undergoes a complex genetic reprogramming. The putB knockout shortens significantly the window of opportunity for SPP1 infection during the host cell life cycle. This window is a critical parameter for competitive phage multiplication in the soil environment, where B. subtilis rarely meets conditions for exponential growth. Our results in combination with those reported for other virus-host systems suggest that bacterial viruses have evolved toward limited dependence on nonessential host functions. IMPORTANCE: A successful viral infection largely depends on the ability of the virus to hijack cellular machineries and to redirect the flow of building blocks and energy resources toward viral progeny production. However, the specific virus-host interactions underlying this fundamental transformation are poorly understood. Here, we report on the first systematic analysis of virus-host cross talk during bacteriophage infection in Gram-positive bacteria. We show that lytic bacteriophage SPP1 is remarkably independent of nonessential genes of its host, Bacillus subtilis, with only a few cellular genes being necessary for efficient phage propagation. We hypothesize that such limited dependence of the virus on its host results from a constant "evolutionary arms race" and might be much more widespread than currently thought. PMID- 25540377 TI - Structural and functional analysis of surface proteins from an A(H3N8) influenza virus isolated from New England harbor seals. AB - In late 2011, an A(H3N8) influenza virus infection resulted in the deaths of 162 New England harbor seals. Virus sequence analysis and virus receptor binding studies highlighted potential markers responsible for mammalian adaptation and a mixed receptor binding preference (S. J. Anthony, J. A. St Leger, K. Pugliares, H. S. Ip, J. M. Chan, Z. W. Carpenter, I. Navarrete-Macias, M. Sanchez-Leon, J. T. Saliki, J. Pedersen, W. Karesh, P. Daszak, R. Rabadan, T. Rowles, W. I. Lipkin, MBio 3:e00166-00112, 2012, http://dx.doi.org/10.1128/mBio.00166-12). Here, we present a detailed structural and biochemical analysis of the surface antigens of the virus. Results obtained with recombinant proteins for both the hemagglutinin and neuraminidase indicate a true avian receptor binding preference. Although the detection of this virus in new species highlights an increased potential for cross-species transmission, our results indicate that the A(H3N8) virus currently poses a low risk to humans. IMPORTANCE: Cross-species transmission of zoonotic influenza viruses increases public health concerns. Here, we report a molecular and structural study of the major surface proteins from an A(H3N8) influenza virus isolated from New England harbor seals. The results improve our understanding of these viruses as they evolve and provide important information to aid ongoing risk assessment analyses as these zoonotic influenza viruses continue to circulate and adapt to new hosts. PMID- 25540378 TI - A viable recombinant rhabdovirus lacking its glycoprotein gene and expressing influenza virus hemagglutinin and neuraminidase is a potent influenza vaccine. AB - The emergence of novel influenza viruses that cause devastating human disease is an ongoing threat and serves as an impetus for the continued development of novel approaches to influenza vaccines. Influenza vaccine development has traditionally focused on producing humoral and/or cell-mediated immunity, often against the viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Here, we describe a new vaccine candidate that utilizes a replication-defective vesicular stomatitis virus (VSV) vector backbone that lacks the native G surface glycoprotein gene (VSVDeltaG). The expression of the H5 HA of an H5N1 highly pathogenic avian influenza virus (HPAIV), A/Vietnam/1203/04 (VN1203), and the NA of the mouse-adapted H1N1 influenza virus A/Puerto Rico/8/34 (PR8) in the VSVDeltaG vector restored the ability of the recombinant virus to replicate in cell culture, without the requirement for the addition of trypsin. We show here that this recombinant virus vaccine candidate was nonpathogenic in mice when given by either the intramuscular or intranasal route of immunization and that the in vivo replication of VSVDeltaG-H5N1 is profoundly attenuated. This recombinant virus also provided protection against lethal H5N1 infection after a single dose. This novel approach to vaccination against HPAIVs may be widely applicable to other emerging strains of influenza virus. IMPORTANCE: Preparation for a potentially catastrophic influenza pandemic requires novel influenza vaccines that are safe, can be produced and administered quickly, and are effective, both soon after administration and for a long duration. We have created a new influenza vaccine that utilizes an attenuated vesicular stomatitis virus (VSV) vector, to deliver and express influenza virus proteins against which vaccinated animals develop potent antibody responses. The influenza virus hemagglutinin and neuraminidase proteins, expressed on the surface of VSV particles, allowed this vaccine to grow in cell culture and induced a potent antibody response in mice that was effective against infection with a lethal influenza virus. The mice showed no adverse reactions to the vaccine, and they were protected against an otherwise lethal influenza infection after only 14 days postvaccination and after as many as 140 days postvaccination. The ability to rapidly produce this safe and effective vaccine in cell culture is additionally advantageous. PMID- 25540379 TI - Alpha-defensin HD5 inhibits furin cleavage of human papillomavirus 16 L2 to block infection. AB - Human papillomavirus (HPV) is a significant oncogenic virus, but the innate immune response to HPV is poorly understood. Human alpha-defensin 5 (HD5) is an innate immune effector peptide secreted by epithelial cells in the genitourinary tract. HD5 is broadly antimicrobial, exhibiting potent antiviral activity against HPV at physiologic concentrations; however, the specific mechanism of HD5 mediated inhibition against HPV is unknown. During infection, the HPV capsid undergoes several critical cell-mediated viral protein processing steps, including unfolding and cleavage of the minor capsid protein L2 by host cyclophilin B and furin. Using HPV16 pseudovirus, we show that HD5 interacts directly with the virus and inhibits the furin-mediated cleavage of L2 at the cell surface during infection at a step downstream of the cyclophilin B-mediated unfolding of L2. Importantly, HD5 does not affect the enzymatic activity of furin directly. Thus, our data support a model in which HD5 prevents furin from accessing L2 by occluding the furin cleavage site via direct binding to the viral capsid. IMPORTANCE: Our study elucidates a new antiviral action for alpha defensins against nonenveloped viruses in which HD5 directly interferes with a critical host-mediated viral processing step, furin cleavage of L2, at the cell surface. Blocking this key event has deleterious effects on the intracellular steps of virus infection. Thus, in addition to informing the antiviral mechanisms of alpha-defensins, our studies highlight the critical role of furin cleavage in HPV entry. Innate immune control, mediated in part by alpha-defensins expressed in the genital mucosa, may influence susceptibility to HPV infections that lead to cervical cancer. Moreover, understanding the mechanism of these natural antivirals may inform the design of therapeutics to limit HPV infection. PMID- 25540380 TI - Human coagulation factor X-adenovirus type 5 complexes poorly stimulate an innate immune response in human mononuclear phagocytes. AB - One of the first lines of host defense against many viruses in vertebrates is the innate immune system, which detects pathogen-associated molecular patterns (PAMPs) using pathogen recognition receptors (PRR). The dynamic interactions between pathogens and hosts create, in some cases, species-specific relationships. Recently, it was shown that murine factor X (mFX)-armored human adenovirus (HAd) stimulated a mFX-Toll-like receptor 4 (TLR4)-associated response in mouse macrophages in vitro and in vivo. Given the importance of studies using animals to better understand host-pathogen interactions, we asked if human FX (hFX)-armored HAd type 5 (HAd5) was capable of activating innate immune sensors in primary human mononuclear phagocytes. To this end, we assayed human mononuclear phagocytes for their ability to be stimulated by hFX-armored HAd5 via a TLR/NF-kappaB pathway, in particular, a TLR4 pathway. In our hands, we found no significant interaction, activation, or maturation of human mononuclear phagocytes caused by the presence of hFX-armored HAd5. IMPORTANCE: Animals, and mice in particular, are often used as informative and powerful surrogates for how pathogens interact with natural host systems. When possible, extended and targeted studies in the natural host can then be performed. Our data will help us understand the differences in preclinical testing in mice and clinical use in humans in order to improve treatment for HAd diseases and Ad vector effectiveness. PMID- 25540381 TI - Natural killer cells can inhibit the transmission of human cytomegalovirus in cell culture by using mechanisms from innate and adaptive immune responses. AB - Human cytomegalovirus (HCMV) transmission within the host is important for the pathogenesis of HCMV diseases. Natural killer (NK) cells are well known to provide a first line of host defense against virus infections. However, the role of NK cells in the control of HCMV transmission is still unknown. Here, we provide the first experimental evidence that NK cells can efficiently control HCMV transmission in different cell types. NK cells engage different mechanisms to control the HCMV transmission both via soluble factors and by cell contact. NK cell-produced interferon gamma (IFN-gamma) suppresses HCMV production and induces resistance of bystander cells to HCMV infection. The UL16 viral gene contributes to an immune evasion from the NK cell-mediated control of HCMV transmission. Furthermore, the efficacy of the antibody-dependent NK cell-mediated control of HCMV transmission is dependent on a CD16-158V/F polymorphism. Our findings indicate that NK cells may have a clinical relevance in HCMV infection and highlight the need to consider potential therapeutic strategies based on the manipulation of NK cells. IMPORTANCE: Human cytomegalovirus (HCMV) infects 40% to 100% of the human population worldwide. After primary infection, mainly in childhood, the virus establishes a lifelong persistence with possible reactivations. Most infections remain asymptomatic; however, HCMV represents a major health problem since it is the most frequent cause of infection-induced birth defects and is responsible for high morbidity and mortality in immunocompromised patients. The immune system normally controls the infection by antibodies and immune effector cells. One type of effector cells are the natural killer (NK) cells, which provide a rapid response to virus-infected cells. NK cells participate in viral clearance by inducing the death of infected cells. NK cells also secrete antiviral cytokines as a consequence of the interaction with an infected cell. In this study, we investigated the mechanisms by which NK cells control HCMV transmission, from the perspectives of immune surveillance and immune evasion. PMID- 25540382 TI - The unusual fold of herpes simplex virus 1 UL21, a multifunctional tegument protein. AB - UL21 is a conserved protein in the tegument of alphaherpesviruses and has multiple important albeit poorly understood functions in viral replication and pathogenesis. To provide a roadmap for exploration of the multiple roles of UL21, we determined the crystal structure of its conserved N-terminal domain from herpes simplex virus 1 to 2.0-A resolution, which revealed a novel sail-like protein fold. Evolutionarily conserved surface patches highlight residues of potential importance for future targeting by mutagenesis. PMID- 25540383 TI - Papillomavirus E7 oncoproteins share functions with polyomavirus small T antigens. AB - Many of the small DNA tumor viruses encode transforming proteins that function by targeting critical cellular pathways involved in cell proliferation and survival. In this study, we have examined whether some of the functions of the polyomavirus small T antigens (ST) are shared by the E6 and E7 oncoproteins of two oncogenic papillomaviruses. Using three different assays, we have found that E7 can provide some simian virus 40 (SV40) or murine polyomavirus (PyV) ST functions. Both human papillomavirus 16 (HPV16) and bovine papillomavirus (BPV1) E7 proteins are capable of partially substituting for SV40 ST in a transformation assay that also includes SV40 large T antigen, the catalytic subunit of cellular telomerase, and oncogenic Ras. Like SV40 ST, HPV16 E7 has the ability to override a quiescence block induced by mitogen deprivation. Like PyV ST, it also has the ability to inhibit myoblast differentiation. At least two of these activities are dependent upon the interaction of HPV16 E7 with retinoblastoma protein family members. For small T antigens, interaction with PP2A is needed for each of these functions. Even though there is no strong evidence that E6 or E7 share the ability of small T to interact with PP2A, E7 provides these functions related to cellular transformation. IMPORTANCE: DNA tumor viruses have provided major insights into how cancers develop. Some viruses, like the human papillomaviruses, can cause cancer directly. Both the papillomaviruses and the polyomaviruses have served as tools for understanding pathways that are often perturbed in cancer. Here, we have compared the functions of transforming proteins from several DNA tumor viruses, including two papillomaviruses and two polyomaviruses. We tested the papillomavirus E6 and E7 oncoproteins in three functional assays and found that E7 can provide some or all of the functions of the SV40 small T antigen, another well-characterized oncoprotein, in two of these assays. In a third assay, papillomavirus E7 has the same effect as the murine polyomavirus small T protein. In summary, we report several new functions for the papillomavirus E7 proteins, which will contribute new insights into the roles of viruses in cancer and the cellular pathways they perturb in carcinogenesis. PMID- 25540384 TI - Chicken and duck myotubes are highly susceptible and permissive to influenza virus infection. AB - Skeletal muscle, at 30 to 40% of body mass, is the most abundant soft tissue in the body. Besides its primary function in movement and posture, skeletal muscle is a significant innate immune organ with the capacity to produce cytokines and chemokines and respond to proinflammatory cytokines. Little is known about the role of skeletal muscle during systemic influenza A virus infection in any host and particularly avian species. Here we used primary chicken and duck multinucleated myotubes to examine their susceptibility and innate immune response to influenza virus infections. Both chicken and duck myotubes expressed avian and human sialic acid receptors and were readily susceptible to low pathogenicity (H2N3 A/mallard duck/England/7277/06) and high-pathogenicity (H5N1 A/turkey/England/50-92/91 and H5N1 A/turkey/Turkey/1/05) avian and human H1N1 (A/USSR/77) influenza viruses. Both avian host species produced comparable levels of progeny H5N1 A/turkey/Turkey/1/05 virus. Notably, the rapid accumulation of viral nucleoprotein and matrix (M) gene RNA in chicken and duck myotubes was accompanied by extensive cytopathic damage with marked myotube apoptosis (widespread microscopic blebs, caspase 3/7 activation, and annexin V binding at the plasma membrane). Infected chicken myotubes produced significantly higher levels of proinflammatory cytokines than did the corresponding duck cells. Additionally, in chicken myotubes infected with H5N1 viruses, the induction of interferon beta (IFN-beta) and IFN-inducible genes, including the melanoma differentiation-associated protein 5 (MDA-5) gene, was relatively weak compared to infection with the corresponding H2N3 virus. Our findings highlight that avian skeletal muscle fibers are capable of productive influenza virus replication and are a potential tissue source of infection. IMPORTANCE: Infection with high pathogenicity H5N1 viruses in ducks is often asymptomatic, and skeletal muscle from such birds could be a source of infection of humans and animals. Little is known about the ability of influenza A viruses to replicate in avian skeletal muscle fibers. We show here that cultured chicken and duck myotubes were highly susceptible to infection with both low- and high-pathogenicity avian influenza viruses. Infected myotubes of both avian species displayed rapid virus accumulation, apoptosis, and extensive cellular damage. Our results indicate that avian skeletal muscle fibers of chicken and duck could be significant contributors to progeny production of highly pathogenic H5N1 viruses. PMID- 25540385 TI - Functional comparison of herpes simplex virus 1 (HSV-1) and HSV-2 ICP27 homologs reveals a role for ICP27 in virion release. AB - Numerous studies have focused on the regulatory functions of ICP27, an immediate early (IE) protein of herpes simplex virus 1 (HSV-1). However, its homolog in HSV 2, termed ICP27t2, has been little studied. Here, we used two different approaches to functionally compare ICP27t2 and ICP27. In transfection-based assays, ICP27t2 closely resembled ICP27 in its capacity to enhance HSV-1 late gene expression, suppress the splicing of a viral intron, and complement the growth of an HSV-1 ICP27 null mutant. To study ICP27t2 in the context of viral infection, we engineered K2F1, an HSV-1 mutant that encodes ICP27t2 in place of ICP27. In Vero cells, K2F1 replicated with wild-type (WT) kinetics and yields, expressed delayed-early and late proteins normally, and was fully capable of activating several cellular signal transduction pathways that are ICP27 dependent. Thus, we conclude that ICP27t2 and ICP27 are functionally very similar and that ICP27t2 can mediate all ICP27 activities that are required for HSV-1 replication in cell culture. Surprisingly, however, we found that K2F1 forms plaques that are morphologically different from those of WT HSV-1. Investigation of this trait demonstrated that it results from the decreased release of progeny virions into the culture medium. This appears to be due to a reduction in the detachment of K2F1 progeny from the extracellular surface of the infected cell. We identified two HSV-1 ICP27 amino-terminal deletion mutants with a similar release defect. Together, these results demonstrate that ICP27 plays a heretofore unappreciated role in modulating the efficiency of progeny virion release. IMPORTANCE: ICP27 is an essential, multifunctional regulatory protein that has a number of critical roles in the HSV-1 life cycle. Although ICP27 homologs are encoded by all known members of the Herpesviridae, previous work with several of these homologs has shown that they cannot substitute for ICP27 in the context of HSV-1-infected cells. Here, we identify ICP27t2 as the first homolog that can efficiently replace ICP27 in HSV-1 infection. Unexpectedly, our results also reveal that the sequence of the ICP27 gene can affect the release of HSV-1 progeny virions from the infected cell. Thus, our comparative study has revealed a novel function for ICP27 in the regulation of virus release. PMID- 25540387 TI - Regulation of multiple stages of hepadnavirus replication by the carboxyl terminal domain of viral core protein in trans. AB - Mutational analyses have indicated that the carboxyl-terminal domain (CTD) of hepadnavirus core protein and its state of phosphorylation are critical for multiple steps in viral replication. Also, CTD interacts with host proteins in a phosphorylation state-dependent manner. To ascertain the role of CTD in viral replication without perturbing its sequence and the role of CTD-host interactions, CTD of the human hepatitis B virus (HBV) or duck hepatitis B virus (DHBV) core protein, either the wild type (WT) or with alanine or glutamic acid/aspartic acid substitutions at the phosphorylation sites, was expressed in cells replicating DHBV with the WT core protein. A dramatic decrease in phosphorylation of the DHBV core protein (DHBc) was observed when the WT and most HBV core protein CTD (HCTD) variants were coexpressed in trans, which was accompanied by a profound reduction of viral core DNA and, in particular, the double-stranded DNA. One HCTD variant that failed to change DHBc phosphorylation also had no effect on DHBV core DNA. All WT and variant HCTDs and DHBc CTDs (DCTDs) decreased the DHBV covalently closed circular (CCC) DNA. Identification of CTD-host interactions indicated that CDK2 binding by CTD may mediate its inhibitory effect on DHBc phosphorylation and reverse transcription via competition with DHBc for the host kinase, whereas importin alpha binding by CTD may contribute to inhibition of CCC DNA production by competitively blocking the nuclear import of viral nucleocapsids. These results suggest the possibility of blocking multiple steps of viral replication, especially CCC DNA formation, via inhibition of CTD functions. IMPORTANCE: Mutational analyses have suggested that the carboxyl-terminal domain (CTD) of hepadnavirus core protein is critical for viral replication. However, results from mutational analyses are open to alternative interpretations. Also, how CTD affects virus replication remains unclear. In this study, we took an alternative approach to mutagenesis by overexpressing CTD alone in cells replicating the virus with the wild-type core protein to determine the roles of CTD in viral replication. Our results revealed that CTD can inhibit multiple stages of viral replication, and its effects may be mediated at least in part through specific host interactions. They suggest that CTD, or its mimics, may have therapeutic potential. Furthermore, our experimental approach should be broadly applicable as a complement to mutagenesis for studying protein functions and interactions while at the same time providing a means to identify the relevant interacting factors. PMID- 25540388 TI - Antibody profiling of bipolar disorder using Escherichia coli proteome microarrays. AB - To profile plasma antibodies of patients with bipolar disorder (BD), an E. coli proteome microarray comprising ca. 4200 proteins was used to analyze antibody differences between BD patients and mentally healthy controls (HCs). The plasmas of HCs and patients aged 18-45 years with bipolar I disorder (DSM-IV) in acute mania (BD-A) along with remission (BD-R) were collected. The initial samples consisting of 19 BD-A, 20 BD-R, and 20 HCs were probed with the microarrays. After selecting protein hits that recognized the antibody differences between BD and HC, the proteins were purified to construct BD focus arrays for training diagnosis committees and validation. Additional six BD-A, six BD-R, six HCs, and nine schizophrenic disorder (SZ, as another psychiatric control) samples were individually probed with the BD focus arrays. The trained diagnosis committee in BD-A versus HC combined top six proteins, including rpoA, thrA, flhB, yfcI, ycdU, and ydjL. However, the optimized committees in BD-R versus HC and BD-A versus BD R were of low accuracy (< 0.6). In the single blind test using another four BD-A, four HC, and four SZ samples, the committee of BD-A versus HC was able to classify BD-A versus HC and SZ with 75% sensitivity and 80% specificity that both HC and SZ were regarded as negative controls. The consensus motif of the six proteins, which form the committee of BD-A versus HC, is [KE]DIL[AG]L[LV]I[NL][IC][SVKH]G[LV][VN][LV] by Gapped Local Alignment of Motifs. We demonstrated that the E. coli proteome microarray is capable of screening BD plasma antibody differences and the selected proteins committee was successfully used for BD diagnosis with 79% accuracy. PMID- 25540386 TI - The genome of the nucleopolyhedrosis-causing virus from Tipula oleracea sheds new light on the Nudiviridae family. AB - A large double-stranded DNA (dsDNA) virus that produces occlusion bodies, typical of baculoviruses, has been described to infect crane fly larvae of the genus Tipula (Diptera, Tipulidae). Because of a lack of genomic data, this virus has remained unclassified. Electron microscopy of an archival virus isolated from Tipula oleracea, T. oleracea nudivirus (ToNV), showed irregularly shaped occlusion bodies measuring from 2 to 5 MUm in length and 2 MUm in middiameter, filled with rod-shape virions containing single nucleocapsids within a bilayer envelope. Whole-genome amplification and Roche 454 sequencing revealed a complete circular genome sequence of 145.7 kb, containing five direct repeat regions. We predicted 131 open reading frames, including a homolog of the polyhedrin gene encoding the major occlusion body protein of T. paludosa nucleopolyhedrovirus (NPV). BLAST searches demonstrated that ToNV had 21 of the 37 baculovirus core genes but shared 52 genes with nudiviruses (NVs). Phylogenomic analyses indicated that ToNV clearly belongs to the Nudiviridae family but should probably be assigned to a new genus. Among nudiviruses, ToNV was most closely related to the Penaeus monodon NV and Heliothis zea NV clade but distantly related to Drosophila innubia NV, the other nudivirus infecting a Diptera. Lastly, ToNV was found to be most closely related to the nuvidirus ancestor of bracoviruses. This was also reflected in terms of gene content, as ToNV was the only known exogenous virus harboring homologs of the Cc50C22.6 and 27b (Cc50C22.7) genes found in the nudiviral genomic cluster involved in bracovirus particle production. IMPORTANCE: The Nudiviridae is a family of arthropod dsDNA viruses from which striking cases of endogenization have been reported (i.e., symbiotic bracoviruses deriving from a nudivirus and the endogenous nudivirus of the brown planthopper). Although related to baculoviruses, relatively little is known about the genomic diversity of exogenous nudiviruses. Here, we characterized, morphologically and genetically, an archival sample of the Tipula oleracea nudivirus (ToNV), which has the particularity of forming occlusion bodies. Comparative genomic and phylogenomic analyses showed ToNV to be to date the closest known relative of the exogenous ancestor of bracoviruses and that ToNV should be assigned to a new genus. Moreover, we revised the homology relationships of nudiviral genes and identified a new set of 32 core genes for the Nudiviridae, of which 21 were also baculovirus core genes. These findings provide important insights into the evolutionary history of large arthropod dsDNA viruses. PMID- 25540390 TI - Assessment of coinfection of sexually transmitted pathogen microbes by use of the anyplex II STI-7 molecular kit. AB - Anyplex STI-7 is a new molecular kit that detects seven sexually transmitted pathogens. Among 202 subjects screened for genital infection, 143 (70.4%) were diagnosed with at least one pathogen, in concordance with reference methods. In addition, the Anyplex STI-7 demonstrated coinfections, such as that with Ureaplasma parvum and Chlamydia trachomatis, in young women. PMID- 25540389 TI - The neddylation-cullin 2-RBX1 E3 ligase axis targets tumor suppressor RhoB for degradation in liver cancer. AB - The neddylation-cullin-RING E3 ligase (CRL) pathway has recently been identified as a potential oncogenic event and attractive anticancer target; however, its underlying mechanisms have not been well elucidated. In this study, RhoB, a well known tumor suppressor, was identified and validated with an iTRAQ-based quantitative proteomic approach as a new target of this pathway in liver cancer cells. Specifically, cullin 2-RBX1 E3 ligase, which requires NEDD8 conjugation for its activation, interacted with RhoB and promoted its ubiquitination and degradation. In human liver cancer tissues, the neddylation-CRL pathway was overactivated and reversely correlated with RhoB levels. Moreover, RhoB accumulation upon inhibition of the neddylation-CRL pathway for anticancer therapy contributed to the induction of tumor suppressors p21 and p27, apoptosis, and growth suppression. Our findings highlight the degradation of RhoB via the neddylation-CRL pathway as an important molecular event that drives liver carcinogenesis and RhoB itself as a pivotal effector for anticancer therapy targeting this oncogenic pathway. PMID- 25540391 TI - (1,3)-beta-d-glucan in cerebrospinal fluid for diagnosis of fungal meningitis associated with contaminated methylprednisolone injections. AB - Prompt diagnosis and treatment of fungal meningitis are critical, but culture is insensitive. (1,3)-beta-d-Glucan (BDG) testing is FDA approved for serological diagnosis of invasive fungal disease; however, BDG testing is not approved for cerebrospinal fluid (CSF), and the appropriate cutoff value is unknown. We aimed to validate the diagnostic accuracy of CSF BDG measurements for fungal meningitis among patients exposed to contaminated methylprednisolone acetate (MPA). A retrospective observational study was conducted at St. Joseph Mercy Hospital and Vanderbilt University from November 2013 to February 2014. Patients were included if they had received a contaminated MPA injection. Cases were classified as probable or proven meningitis according to Centers for Disease Control and Prevention guidelines. CSF BDG testing was performed according to the package insert instructions for serum samples, and results were validated using Clinical and Laboratory Standards Institute procedures (MiraVista Diagnostics). Of 233 patients, 45 had meningitis (28 proven cases), 53 had spinal/paraspinal infections (19 proven cases), and 135 did not develop disease. Using the manufacturer's cutoff value (>=80 pg/ml), the sensitivity and specificity were 96% and 95%, respectively, for proven meningitis and 84% and 95% for probable or proven meningitis. Receiver operating characteristic analysis identified the optimal cutoff value for proven meningitis to be 66 pg/ml (sensitivity, 100%; specificity, 94%) and that for probable or proven meningitis to be 66 pg/ml (sensitivity, 91%; specificity, 92%). Our results suggest that CSF BDG measurements are highly sensitive and specific for the diagnosis of fungal meningitis associated with contaminated MPA injections. Further study on the utility of CSF BDG testing for other types of fungal meningitis is needed. PMID- 25540392 TI - Molecular profiling of Escherichia coli O157:H7 and non-O157 strains isolated from humans and cattle in Alberta, Canada. AB - Virulence markers in Shiga toxin-producing Escherichia coli (STEC) and their association with diseases remain largely unknown. This study determines the importance of 44 genetic markers for STEC (O157 and non-O157) from human clinical cases and their correlation to disease outcome. STEC isolated from a cattle surveillance program were also included. The virulence genes tested were present in almost all O157:H7 isolates but highly variable in non-O157 STEC isolates. Patient age was a significant determinant of clinical outcome. PMID- 25540393 TI - Septic arthritis and osteomyelitis due to Bordetella petrii. AB - A case of Bordetella petrii septic arthritis and osteomyelitis in an elbow resulted from a dirt bike accident in Hawaii. Two months of intravenous antibiotics and repeated surgeries were required to cure this infection. Our case, and literature review, suggests that extended-spectrum penicillins, tetracycline, and trimethoprim-sulfamethoxazole are good treatment options. PMID- 25540394 TI - A valuable antigen detection method for diagnosis of acute hepatitis E. AB - Hepatitis E virus (HEV) is a serious public health problem. The commonly used tests that are specific for current HEV infection diagnosis include the detection of anti-HEV IgM and HEV RNA. Here, we report an improved enzyme-linked immunosorbent assay (ELISA) method for HEV antigen detection with a linear range equivalent to 6.3 * 10(3) to 9.2 * 10(5) RNA copies per ml. The monoclonal antibody (MAb) 12F12, a high-ability MAb that binds HEV virus, was selected as the capture antibody from a panel of 95 MAbs. The positive period of HEV antigenemia in infected monkeys using this test was, on average, 3 weeks longer than previously reported and covered the majority of the acute phase. The positive detection rates of IgM, RNA, and new antigen from the first serum samples collected from 16 confirmed acute hepatitis E patients were 81% (13/16), 81% (13/16), and 100% (16/16), respectively. In three patients, the initial serum specimens that tested negative for IgM, despite the presence of symptoms of acute hepatitis and elevated alanine aminotransferase (ALT) levels, were positive for HEV antigen and HEV RNA. In contrast, the serum samples of the three RNA-negative patients were antigen positive (and IgM positive), possibly due to the degradation of HEV nucleic acids. Our results suggest that this new antigen detection method has acceptable concordance with RNA detection and could serve as an important tool for diagnosing acute hepatitis E. PMID- 25540395 TI - Pyogranulomatous pneumonia in goats caused by an undescribed Porphyromonas species, "Porphyromonas katsikii". AB - A yet-undescribed bacterial species, tentatively named "Porphyromonas katsikii," was isolated from individuals of a small goat herd with pyogranulomatous pneumonia during an outbreak of acute respiratory disease. The isolated bacteria grew in the form of black-pigmented colonies after 14 days of incubation under anaerobic conditions at 37 degrees C on a tryptic soy blood agar medium. The bacteria were identified as a yet-undescribed Porphyromonas species by determination of the nucleotide sequence of the rrs 16S rRNA gene, and this species was tentatively named Porphyromonas katsikii. PCR amplification with specific primers for this yet-undescribed species revealed the presence of P. katsikii in the lung tissue of all affected animals, while no PCR signals were evidenced from the lungs of healthy goats or from goats with pasteurellosis caused by Mannheimia haemolytica. These data indicate P. katsikii as the causative agent of acute respiratory distress. P. katsikii is phylogenetically related to Porphyromonas somerae and Porphyromonas levii, which cause pathologies in humans and animals, respectively. P. katsikii was not detected by PCR from samples of the gingival pockets or of the faces of healthy goats. PMID- 25540396 TI - First report of Sphingomonas koreensis as a human pathogen in a patient with meningitis. AB - Sphingomonas koreensis is an aerobic Gram-negative rod originally described in 2001 following isolation from natural mineral water in Korea. Here, we report a case study with Sphingomonas koreensis as the causative agent of meningitis. To our knowledge, this is the first documented case of Sphingomonas koreensis as a human pathogen. PMID- 25540397 TI - Comparison of the next-generation Xpert MRSA/SA BC assay and the GeneOhm StaphSR assay to routine culture for identification of Staphylococcus aureus and methicillin-resistant S. aureus in positive-blood-culture broths. AB - A bloodstream infection with Staphylococcus aureus, including methicillin resistant S. aureus (MRSA), is a serious condition that carries a high mortality rate and is also associated with significant hospital costs. The rapid and accurate identification and differentiation of methicillin-susceptible S. aureus (MSSA) and MRSA directly from positive blood cultures has demonstrated benefits in both patient outcome and cost-of-care metrics. We compare the next-generation Xpert MRSA/SA BC (Xpert) assay to the GeneOhm StaphSR (GeneOhm) assay for the identification and detection of S. aureus and methicillin resistance in prospectively collected blood culture broths containing Gram-positive cocci. All results were compared to routine bacterial culture as the gold standard. Across 8 collection and test sites, the Xpert assay demonstrated a sensitivity of 99.6% (range, 96.4% to 100%) and a specificity of 99.5% (range, 98.0% to 100%) for identifying S. aureus, as well as a sensitivity of 98.1% (range, 87.5% to 100%) and a specificity of 99.6% (range, 98.3% to 100%) for identifying MRSA. In comparison, the GeneOhm assay demonstrated a sensitivity of 99.2% (range, 95.2% to 100%) and a specificity of 96.5% (range, 89.2% to 100%) for identifying S. aureus, as well as a sensitivity of 94.3% (range, 87.5% to 100%) and a specificity of 97.8% (range, 96.1% to 100%) for identifying MRSA. Five of six cultures falsely reported as negative for MRSA by the GeneOhm assay were correctly identified as positive by the Xpert assay, while one culture falsely reported as negative for MRSA by the Xpert assay was correctly reported as positive by the GeneOhm assay. PMID- 25540398 TI - Bartonella, a common cause of endocarditis: a report on 106 cases and review. AB - Bartonella spp. are fastidious bacteria that cause blood culture-negative endocarditis and have been increasingly reported. In this study, we included all patients retrospectively and prospectively diagnosed with Bartonella endocarditis in our French reference center between 2005 and 2013. Our diagnosis was based on the modified Duke criteria and microbiological findings, including serological and PCR results. To review the published literature, we searched all human Bartonella endocarditis cases published in the PubMed database between January 2005 and October 2013. We report here a large series of 106 cases, which include 59 cases that had not previously been reported or mentioned. Indirect immunofluorescence assays, Western blotting, and real-time PCR from total blood, serum, and valve tissue exhibited sensitivities of 58%, 100%, 33%, 36%, and 91%, respectively. The number of cases reported in the literature between 2005 and 2013 increased to reach a cumulative number of 196 cases. The number of cases reported in the literature by other centers is increasing more rapidly than that reported by our French reference center (P < 10(-2)). Currently, there is a lack of criteria for the diagnosis of Bartonella endocarditis. We suggest that a positive PCR result from a cardiac valve or blood specimen, an IgG titer of >=800 using an immunofluorescence assay, or a positive Western blot assay be considered major Duke criteria for Bartonella endocarditis. There is no real increase in the incidence of these infections but rather a better understanding and interest in the disease resulting from the improvement of diagnostic tools. PMID- 25540399 TI - Stability of Chlamydia trachomatis on storage of dry swabs for accurate detection by nucleic acid amplification tests. PMID- 25540400 TI - Global multilocus sequence typing analysis of Mycoplasma bovis isolates reveals two main population clusters. AB - Mycoplasma bovis is a major bovine pathogen associated with bovine respiratory disease complex and is responsible for substantial economic losses worldwide. M. bovis is also associated with other clinical presentations in cattle, including mastitis, otitis, arthritis, and reproductive disorders. To gain a better understanding of the genetic diversity of this pathogen, a multilocus sequence typing (MLST) scheme was developed and applied to the characterization of 137 M. bovis isolates from diverse geographical origins, obtained from healthy or clinically infected cattle. After in silico analysis, a final set of 7 housekeeping genes was selected (dnaA, metS, recA, tufA, atpA, rpoD, and tkt). MLST analysis demonstrated the presence of 35 different sequence types (STs) distributed in two main clonal complexes (CCs), defined at the double-locus variant level, namely, CC1, which included most of the British and German isolates, and CC2, which was a more heterogeneous and geographically distant group of isolates, including European, Asian, and Australian samples. Index of association analysis confirmed the clonal nature of the investigated M. bovis population, based on MLST data. This scheme has demonstrated high discriminatory power, with the analysis showing the presence of genetically distant and divergent clusters of isolates predominantly associated with geographical origins. PMID- 25540401 TI - High Staphylococcus aureus colonization prevalence among patients with skin and soft tissue infections and controls in an urban emergency department. AB - Staphylococcus aureus is a commensal species that can also be a formidable pathogen. In the United States, an epidemic of community-acquired methicillin resistant Staphylococcus aureus (MRSA) infections has been occurring for the last 15 years. In the context of a study in which we identified patients with skin and soft tissue infections (SSTIs) and randomized them to receive one of two antimicrobial treatment regimens, we assessed S. aureus colonization in the nares, throat, and perianal skin on the day of enrollment and 40 days after therapy. We compared the prevalence of colonization between the SSTI patients and an uninfected control population. A total of 144 subjects and 130 controls, predominantly African American, participated in this study, and 116 returned for a 40-day follow-up visit. Of the SSTI patients, 76% were colonized with S. aureus at enrollment, as were 65% of the controls. Patients were more likely than the controls to be colonized with USA300 MRSA (62/144 [43.1%] versus 11/130 [8.5%], respectively; P < 0.001). The nares were not the most common site of colonization. The colonization prevalence diminished somewhat after antibiotic treatment but remained high. The isolates that colonized the controls were more likely than those in the patients to be methicillin-susceptible S. aureus (MSSA) (74/84 [88.1%] versus 56/106 [52.8%], respectively; P < 0.001). In conclusion, the prevalence of S. aureus colonization among SSTI patients was high and often involved USA300 MRSA. The prevalence diminished somewhat with antimicrobial therapy but remained high at the 40-day follow-up visit. Control subjects were also colonized at a high prevalence but most often with a genetic background not associated with a clinical infection in this study. S. aureus is a commensal species and a pathogen. Plans for decolonization or eradication should take this distinction into account. PMID- 25540402 TI - gyrB analysis as a tool for identifying Nocardia species and exploring their phylogeny. AB - gyrB is used to improve the identification of the Nocardia species N. brasiliensis, N. higoensis, N. ignorata, N. otitidiscaviarum, N. paucivorans, N. pneumoniae, N. puris, N. takedensis, N. veterana, and N. vinacea, but it does not improve the identification of another 12 Nocardia studied species. gyrB provides typing and phylogenetic markers for N. carnea, N. transvalensis, N. brasiliensis, and N. otitidiscaviarum. PMID- 25540403 TI - Performance of Vitek 2 for antimicrobial susceptibility testing of Enterobacteriaceae with Vitek 2 (2009 FDA) and 2014 CLSI breakpoints. AB - Vitek 2 (bioMerieux Inc., Durham, NC) is a widely used commercial antimicrobial susceptibility test system. We compared the MIC results obtained using the Vitek 2 AST-GN69 and AST-XN06 cards to those obtained by CLSI broth microdilution (BMD) for 255 isolates of Enterobacteriaceae, including 25 isolates of carbapenem resistant Enterobacteriaceae. In total, 25 antimicrobial agents were examined. For 10 agents, the MIC data were evaluated using two sets of breakpoints: (i) the Vitek 2 breakpoints, which utilized the 2009 FDA breakpoints at the time of the study and are equivalent to the 2009 CLSI M100-S19 breakpoints, and (ii) the 2014 CLSI M100-S24 breakpoints. There was an overall 98.7% essential agreement (EA). The categorical agreement was 95.5% (CA) using the Vitek 2 breakpoints and 95.7% using the CLSI breakpoints. There was 1 very major error (VME) (0.05%) observed using the Vitek 2 breakpoints (cefazolin) and 8 VMEs (0.5%) using the CLSI breakpoints (2 each for aztreonam, cefepime, and ceftriaxone, and 1 for cefazolin and ceftazidime). Fifteen major errors (MEs) (0.4%) were noted using the Vitek 2 breakpoints and 8 (0.5%) using the CLSI breakpoints. Overall, the Vitek 2 performance was comparable to that of BMD for testing a limited number of Enterobacteriaceae commonly isolated by clinical laboratories. Ongoing studies are warranted to assess performance in isolates with emerging resistance. PMID- 25540404 TI - Infection with Mycobacterium microti in animals in France. AB - We describe here 35 animal cases of tuberculosis due to Mycobacterium microti in France (2002-2014). Recently, molecular tools that overcome the difficulty of confirming infection by this potentially zoonotic agent have revealed an increasing number of cases, suggesting that its prevalence may have been underestimated. PMID- 25540405 TI - Correlation between sputum and bronchoalveolar lavage fluid cultures. AB - A correlation study of the cultured bacteria from paired sputum and bronchoalveolar lavage fluid samples was performed. The rates of concordant culture-positive paired specimens that were isolated within 1 or 7 days were 93.7% and 96.5%, respectively, suggesting that the culture of readily collectable sputum specimens may result in useful microbiologic diagnosis. PMID- 25540408 TI - IJE series old and new. PMID- 25540406 TI - Endogenous human milk peptide release is greater after preterm birth than term birth. AB - BACKGROUND: Hundreds of naturally occurring milk peptides are present in term human milk. Preterm milk is produced before complete maturation of the mammary gland, which could change milk synthesis and secretion processes within the mammary gland, leading to differences in protein expression and enzymatic activity, thereby resulting in an altered peptide profile. OBJECTIVE: This study examined differences in peptides present between milk from women delivering at term and women delivering prematurely. METHODS: Nano-LC tandem mass spectrometry was employed to identify naturally occurring peptides and compare their abundances between term and preterm human milk samples at multiple time points over lactation. Term milk samples were collected from 8 mothers and preterm milk was collected from 14 mothers. The 28 preterm and 32 term human milk samples were divided into 4 groups based on day of collection (<14, 14-28, 29-41, and 42-58 d). RESULTS: Preterm milk peptide counts, ion abundance, and concentration were significantly higher in preterm milk than term milk. Bioinformatic analysis of the cleavage sites for peptides identified suggested that plasmin was more active in preterm milk than term milk and that cytosol aminopeptidase and carboxypeptidase B2 likely contribute to extensive milk protein breakdown. Many identified milk peptides in both term and preterm milk overlapped with known functional peptides, including antihypertensive, antimicrobial, and immunomodulatory peptides. CONCLUSION: The high protein degradation by endogenous proteases in preterm milk might attenuate problems because of the preterm infant's immature digestive system. This trial was registered at clinicaltrials.gov as NCT01817127. PMID- 25540407 TI - Vitamin A kinetics in neonatal rats vs. adult rats: comparisons from model-based compartmental analysis. AB - A critical role for vitamin A (VA) in development is well established, but still relatively little is known about whole-body VA metabolism in early postnatal life. Recently, methods of mathematical modeling have begun to shed light on retinol kinetics in the postnatal growth period and on the effect of retinoid supplementation on retinol kinetics. Comparison of kinetic parameters from tracer studies in neonatal rats with those previously determined in models of VA metabolism in the adult suggests both similarities and differences in the relative transfer rates of plasma retinol to extrahepatic tissues, resulting in similarities and differences in kinetic parameters and inferences about physiologic processes. Similarities between neonatal and adult models include the capacity for efficient digestion and absorption of VA; characteristics of a high response system; extensive retinol recycling among liver, plasma, and extrahepatic tissues; and comparable VA disposal rates. Differences between neonatal and adult models include that, in neonates, retinol turnover is faster and retinol recycling is much more extensive; there is a greater role for extrahepatic tissues in the uptake of chylomicron VA; and the intestine plays an important role in chylomicron VA uptake, especially in neonatal rats treated with a supplement containing VA. In summary, retinol kinetic modeling in the neonatal rat has provided a first view of whole-body VA metabolism in this age group and suggests that VA kinetics in neonatal rats differs in many ways from that in adults, perhaps reflecting an adaption to the lower VA concentration found in neonates compared with adults. PMID- 25540410 TI - Pesticides and human health. PMID- 25540411 TI - Lifetime shift work exposure: association with anthropometry, body composition, blood pressure, glucose and heart rate variability. AB - OBJECTIVE: To evaluate the association between lifetime exposure to shift work and blood pressure, fasting glucose (FG), anthropometric variables, body composition and heart rate variability (HRV). METHODS: Male shift workers (N=438) were evaluated using principal component (PC) analysis. The variables used were: weight, body mass index (BMI), waist circumference (WC), neck circumference (NC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body fat mass (BFKg), body fat percentage (BF%), visceral fat area (VFA), FG, systolic (SBP) and diastolic blood pressure (DBP), and HRV variables. ECG was performed, extracting heart rate (HR), root mean square of the successive differences (RMSSD), high frequency (HF), low frequency (LF) and the LF/HF ratio. Using linear regression models, the lifetime shift work exposure was associated with each PC. RESULTS: Five PCs were obtained, which accounted for 79.6% of the total variation of the data. PC1 (weight, BMI, WC, NC, HC, WHR, WHtR, BFKg, BF% and VFA) was designated as body obesity; PC2 (HF, RMSSD and LF) as good cardiac regulation; PC3 (SBP and DBP) as blood pressure; PC4 (LF/HF ratio and HR) as bad cardiac regulation and PC5 (WHR and FG) as insulin resistance. After age adjustment, the regression analysis showed that lifetime shift work was negatively associated with PC2 and positively associated with PC3. CONCLUSIONS: The association of lifetime shift work exposure with PC2 and PC3 suggests that shift work promotes unfavourable changes in autonomic cardiac control related to a decrease in parasympathetic modulation and an increase in blood pressure. PMID- 25540412 TI - Differential roles of delay-period neural activity in the monkey dorsolateral prefrontal cortex in visual-haptic crossmodal working memory. AB - Previous studies have shown that neurons of monkey dorsolateral prefrontal cortex (DLPFC) integrate information across modalities and maintain it throughout the delay period of working-memory (WM) tasks. However, the mechanisms of this temporal integration in the DLPFC are still poorly understood. In the present study, to further elucidate the role of the DLPFC in crossmodal WM, we trained monkeys to perform visuo-haptic (VH) crossmodal and haptic-haptic (HH) unimodal WM tasks. The neuronal activity recorded in the DLPFC in the delay period of both tasks indicates that the early-delay differential activity probably is related to the encoding of sample information with different strengths depending on task modality, that the late-delay differential activity reflects the associated (modality-independent) action component of haptic choice in both tasks (that is, the anticipation of the behavioral choice and/or active recall and maintenance of sample information for subsequent action), and that the sustained whole-delay differential activity likely bridges and integrates the sensory and action components. In addition, the VH late-delay differential activity was significantly diminished when the haptic choice was not required. Taken together, the results show that, in addition to the whole-delay differential activity, DLPFC neurons also show early- and late-delay differential activities. These previously unidentified findings indicate that DLPFC is capable of (i) holding the coded sample information (e.g., visual or tactile information) in the early delay activity, (ii) retrieving the abstract information (orientations) of the sample (whether the sample has been haptic or visual) and holding it in the late delay activity, and (iii) preparing for behavioral choice acting on that abstract information. PMID- 25540413 TI - What are the roles of V-ATPases in membrane fusion? PMID- 25540415 TI - Energetic basis for the molecular-scale organization of bone. AB - The remarkable properties of bone derive from a highly organized arrangement of coaligned nanometer-scale apatite platelets within a fibrillar collagen matrix. The origin of this arrangement is poorly understood and the crystal structures of hydroxyapatite (HAP) and the nonmineralized collagen fibrils alone do not provide an explanation. Moreover, little is known about collagen-apatite interaction energies, which should strongly influence both the molecular-scale organization and the resulting mechanical properties of the composite. We investigated collagen-mineral interactions by combining dynamic force spectroscopy (DFS) measurements of binding energies with molecular dynamics (MD) simulations of binding and atomic force microscopy (AFM) observations of collagen adsorption on single crystals of calcium phosphate for four mineral phases of potential importance in bone formation. In all cases, we observe a strong preferential orientation of collagen binding, but comparison between the observed orientations and transmission electron microscopy (TEM) analyses of native tissues shows that only calcium-deficient apatite (CDAP) provides an interface with collagen that is consistent with both. MD simulations predict preferred collagen orientations that agree with observations, and results from both MD and DFS reveal large values for the binding energy due to multiple binding sites. These findings reconcile apparent contradictions inherent in a hydroxyapatite or carbonated apatite (CAP) model of bone mineral and provide an energetic rationale for the molecular-scale organization of bone. PMID- 25540416 TI - Epstein-Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes. AB - Epstein-Barr Virus (EBV) conversion of B-lymphocytes to Lymphoblastoid Cell Lines (LCLs) requires four EBV nuclear antigen (EBNA) oncoproteins: EBNA2, EBNALP, EBNA3A, and EBNA3C. EBNA2 and EBNALP associate with EBV and cell enhancers, up regulate the EBNA promoter, MYC, and EBV Latent infection Membrane Proteins (LMPs), which up-regulate BCL2 to protect EBV-infected B-cells from MYC proliferation-induced cell death. LCL proliferation induces p16(INK4A) and p14(ARF)-mediated cell senescence. EBNA3A and EBNA3C jointly suppress p16(INK4A) and p14(ARF), enabling continuous cell proliferation. Analyses of the EBNA3A human genome-wide ChIP-seq landscape revealed 37% of 10,000 EBNA3A sites to be at strong enhancers; 28% to be at weak enhancers; 4.4% to be at active promoters; and 6.9% to be at weak and poised promoters. EBNA3A colocalized with BATF-IRF4, ETS-IRF4, RUNX3, and other B-cell Transcription Factors (TFs). EBNA3A sites clustered into seven unique groups, with differing B-cell TFs and epigenetic marks. EBNA3A coincidence with BATF-IRF4 or RUNX3 was associated with stronger EBNA3A ChIP-Seq signals. EBNA3A was at MYC, CDKN2A/B, CCND2, CXCL9/10, and BCL2, together with RUNX3, BATF, IRF4, and SPI1. ChIP-re-ChIP revealed complexes of EBNA3A on DNA with BATF. These data strongly support a model in which EBNA3A is tethered to DNA through a BATF-containing protein complexes to enable continuous cell proliferation. PMID- 25540418 TI - ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. AB - Transplantation of endothelial cells (ECs) is a promising therapeutic approach for ischemic disorders. In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver. Although many attempts have been made to generate ECs from pluripotent stem cells and nonvascular cells, the minimum number of transcription factors that specialize in directly inducing vascular ECs remains undefined. Here, by screening 18 transcription factors that are important for both endothelial and hematopoietic development, we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Willebrand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2. PMID- 25540417 TI - Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. AB - Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of kappaB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: to limit inflammasome priming and metaflammation. PMID- 25540419 TI - Reply to Konsolaki and Skaliora: Habituation, hyperlocomotion, and "genuine hyperlocomotion". PMID- 25540420 TI - Motor vs. cognitive elements of apparent "hyperlocomotion": a conceptual and experimental clarification. PMID- 25540421 TI - Reply to Warren et al. and Shay et al.: Commonalities across species do exist and are potentially important. PMID- 25540423 TI - Genomic responses to inflammation in mouse models mimic humans: we concur, apples to oranges comparisons won't do. PMID- 25540422 TI - Mice are not men. PMID- 25540424 TI - Adverse events in patients with return emergency department visits. AB - OBJECTIVES: This study describes the proportion of emergency department (ED) returns within 7 days due to adverse events, defined as adverse outcomes related to healthcare received. DESIGN: Prospective cohort study. SETTING: We used an electronically triggered adverse event surveillance system at a tertiary care ED from May to June 2010 to examine ED returns within 7 days of index visit. PARTICIPANTS: One of three trained nurses determined whether the visit was related to index emergency care. For such records, one of three trained emergency physicians conducted adverse event determinations. MAIN OUTCOME MEASURE: We determined adverse event type and severity and analysed the data with descriptive statistics, chi(2) tests and logistic regression. RESULTS: Of 13,495 index ED visits, 923 (6.8%) were followed by ED returns within 7 days. The median age of all patients was 47 years and 52.8% were women. After nursing review, 211 cases required physician review. Of these, 53 visits were adverse events (positive predictive value (PPV)=5.7%, 95% CI 4.4% to 7.4%) and 30 (56.6%) were preventable. Common adverse event types involved management, diagnostic or medication issues. We observed one potentially preventable death and 58.5% of adverse events resulting in transient disability. The PPV of a modified trigger with a cut-off of return within 72 h, resulting in admission was 11.9% (95% CI 6.8% to 18.9%). CONCLUSIONS: Our electronic trigger efficiently identified adverse events among 12% of patients with ED returns within 72 h, requiring hospital admission. Given the high degree of preventability of the identified adverse events, this trigger also holds promise as a performance measurement tool. PMID- 25540425 TI - Arrestins regulate cell spreading and motility via focal adhesion dynamics. AB - Focal adhesions (FAs) play a key role in cell attachment, and their timely disassembly is required for cell motility. Both microtubule-dependent targeting and recruitment of clathrin are critical for FA disassembly. Here we identify nonvisual arrestins as molecular links between microtubules and clathrin. Cells lacking both nonvisual arrestins showed excessive spreading on fibronectin and poly-d-lysine, increased adhesion, and reduced motility. The absence of arrestins greatly increases the size and lifespan of FAs, indicating that arrestins are necessary for rapid FA turnover. In nocodazole washout assays, FAs in arrestin deficient cells were unresponsive to disassociation or regrowth of microtubules, suggesting that arrestins are necessary for microtubule targeting-dependent FA disassembly. Clathrin exhibited decreased dynamics near FA in arrestin-deficient cells. In contrast to wild-type arrestins, mutants deficient in clathrin binding did not rescue the phenotype. Collectively the data indicate that arrestins are key regulators of FA disassembly linking microtubules and clathrin. PMID- 25540427 TI - Stepping stone: a cytohesin adaptor for membrane cytoskeleton restraint in the syncytial Drosophila embryo. AB - Cytohesin Arf-GEFs are conserved plasma membrane regulators. The sole Drosophila cytohesin, Steppke, restrains Rho1-dependent membrane cytoskeleton activity at the base of plasma membrane furrows of the syncytial embryo. By mass spectrometry, we identified a single major Steppke-interacting protein from syncytial embryos, which we named Stepping stone (Sstn). By sequence, Sstn seems to be a divergent homologue of the mammalian cytohesin adaptor FRMD4A. Our experiments supported this relationship. Specifically, heterophilic coiled-coil interactions linked Sstn and Steppke in vivo and in vitro, whereas a separate C terminal region was required for Sstn localization to furrows. Sstn mutant and RNAi embryos displayed abnormal, Rho1-dependent membrane cytoskeleton expansion from the base of pseudocleavage and cellularization furrows, closely mimicking Steppke loss-of-function embryos. Elevating Sstn furrow levels had no effect on the steppke phenotype, but elevating Steppke furrow levels reversed the sstn phenotype, suggesting that Steppke acts downstream of Sstn and that additional mechanisms can recruit Steppke to furrows. Finally, the coiled-coil domain of Steppke was required for Sstn binding and in addition homodimerization, and its removal disrupted Steppke furrow localization and activity in vivo. Overall we propose that Sstn acts as a cytohesin adaptor that promotes Steppke activity for localized membrane cytoskeleton restraint in the syncytial Drosophila embryo. PMID- 25540426 TI - FAP206 is a microtubule-docking adapter for ciliary radial spoke 2 and dynein c. AB - Radial spokes are conserved macromolecular complexes that are essential for ciliary motility. A triplet of three radial spokes, RS1, RS2, and RS3, repeats every 96 nm along the doublet microtubules. Each spoke has a distinct base that docks to the doublet and is linked to different inner dynein arms. Little is known about the assembly and functions of individual radial spokes. A knockout of the conserved ciliary protein FAP206 in the ciliate Tetrahymena resulted in slow cell motility. Cryo-electron tomography showed that in the absence of FAP206, the 96-nm repeats lacked RS2 and dynein c. Occasionally, RS2 assembled but lacked both the front prong of its microtubule base and dynein c, whose tail is attached to the front prong. Overexpressed GFP-FAP206 decorated nonciliary microtubules in vivo. Thus FAP206 is likely part of the front prong and docks RS2 and dynein c to the microtubule. PMID- 25540428 TI - ADAM10 controls collagen signaling and cell migration on collagen by shedding the ectodomain of discoidin domain receptor 1 (DDR1). AB - Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and transmits signals from various collagens in epithelial cells. However, how DDR1 dependent signaling is regulated has not been understood. Here we report that collagen binding induces ADAM10-dependent ectodomain shedding of DDR1. DDR1 shedding is not a result of an activation of its signaling pathway, since DDR1 mutants defective in signaling were shed in an efficient manner. DDR1 and ADAM10 were found to be in a complex on the cell surface, but shedding did not occur unless collagen bound to DDR1. Using a shedding-resistant DDR1 mutant, we found that ADAM10-dependent DDR1 shedding regulates the half-life of collagen-induced phosphorylation of the receptor. Our data also revealed that ADAM10 plays an important role in regulating DDR1-mediated cell adhesion to achieve efficient cell migration on collagen matrices. PMID- 25540429 TI - Emergence and subsequent functional specialization of kindlins during evolution of cell adhesiveness. AB - Kindlins are integrin-interacting proteins essential for integrin-mediated cell adhesiveness. In this study, we focused on the evolutionary origin and functional specialization of kindlins as a part of the evolutionary adaptation of cell adhesive machinery. Database searches revealed that many members of the integrin machinery (including talin and integrins) existed before kindlin emergence in evolution. Among the analyzed species, all metazoan lineages-but none of the premetazoans-had at least one kindlin-encoding gene, whereas talin was present in several premetazoan lineages. Kindlin appears to originate from a duplication of the sequence encoding the N-terminal fragment of talin (the talin head domain) with a subsequent insertion of the PH domain of separate origin. Sequence analysis identified a member of the actin filament-associated protein 1 (AFAP1) superfamily as the most likely origin of the kindlin PH domain. The functional divergence between kindlin paralogues was assessed using the sequence swap (chimera) approach. Comparison of kindlin 2 (K2)/kindlin 3 (K3) chimeras revealed that the F2 subdomain, in particular its C-terminal part, is crucial for the differential functional properties of K2 and K3. The presence of this segment enables K2 but not K3 to localize to focal adhesions. Sequence analysis of the C terminal part of the F2 subdomain of K3 suggests that insertion of a variable glycine-rich sequence in vertebrates contributed to the loss of constitutive K3 targeting to focal adhesions. Thus emergence and subsequent functional specialization of kindlins allowed multicellular organisms to develop additional tissue-specific adaptations of cell adhesiveness. PMID- 25540431 TI - Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells. AB - Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel-derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent. PMID- 25540430 TI - Nup2 requires a highly divergent partner, NupA, to fulfill functions at nuclear pore complexes and the mitotic chromatin region. AB - Chromatin and nuclear pore complexes (NPCs) undergo dramatic changes during mitosis, which in vertebrates and Aspergillus nidulans involves movement of Nup2 from NPCs to the chromatin region to fulfill unknown functions. This transition is shown to require the Cdk1 mitotic kinase and be promoted prematurely by ectopic expression of the NIMA kinase. Nup2 localizes with a copurifying partner termed NupA, a highly divergent yet essential NPC protein. NupA and Nup2 locate throughout the chromatin region during prophase but during anaphase move to surround segregating DNA. NupA function is shown to involve targeting Nup2 to its interphase and mitotic locations. Deletion of either Nup2 or NupA causes identical mitotic defects that initiate a spindle assembly checkpoint (SAC) dependent mitotic delay and also cause defects in karyokinesis. These mitotic problems are not caused by overall defects in mitotic NPC disassembly-reassembly or general nuclear import. However, without Nup2 or NupA, although the SAC protein Mad1 locates to its mitotic locations, it fails to locate to NPCs normally in G1 after mitosis. Collectively the study provides new insight into the roles of Nup2 and NupA during mitosis and in a surveillance mechanism that regulates nucleokinesis when mitotic defects occur after SAC fulfillment. PMID- 25540433 TI - Fast protein-depletion system utilizing tetracycline repressible promoter and N end rule in yeast. AB - A protein depletion by promoter shutoff or protein destabilization is an important tool in investigation of functions of essential genes. Various approaches using different repressible promoters, inducible degrons, or their combinations were developed. While successful, the current techniques have a drawback in that they require fusion of a large degradation tag to the target protein and/or a change in growth conditions to repress the promoter. We describe efficient protein depletion using the combination of a metabolically inert tetracycline repressible promoter with tetracycline aptamer and constitutive target protein destabilization by means of ubiquitin fusion. The target protein does not require a tag, and its elimination is several fold faster compared with standard promoter shutoff systems. A depletion time of <40 min was sufficient to achieve a robust phenotype. PMID- 25540432 TI - Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology. AB - Seipin is necessary for both adipogenesis and lipid droplet (LD) organization in nonadipose tissues; however, its molecular function is incompletely understood. Phenotypes in the seipin-null mutant of Saccharomyces cerevisiae include aberrant droplet morphology (endoplasmic reticulum-droplet clusters and size heterogeneity) and sensitivity of droplet size to changes in phospholipid synthesis. It has not been clear, however, whether seipin acts in initiation of droplet synthesis or at a later step. Here we utilize a system of de novo droplet formation to show that the absence of seipin results in a delay in droplet appearance with concomitant accumulation of neutral lipid in membranes. We also demonstrate that seipin is required for vectorial budding of droplets toward the cytoplasm. Furthermore, we find that the normal rate of droplet initiation depends on 14 amino acids at the amino terminus of seipin, deletion of which results in fewer, larger droplets that are consistent with a delay in initiation but are otherwise normal in morphology. Importantly, other functions of seipin, namely vectorial budding and resistance to inositol, are retained in this mutant. We conclude that seipin has dissectible roles in both promoting early LD initiation and in regulating LD morphology, supporting its importance in LD biogenesis. PMID- 25540434 TI - Insights into the cellular mechanism of the yeast ubiquitin ligase APC/C-Cdh1 from the analysis of in vivo degrons. AB - The anaphase-promoting complex/cyclosome (APC/C) controls a variety of cellular processes through its ability to target numerous protein substrates for timely degradation. Substrate selection by this ubiquitin ligase depends on related activator proteins, Cdc20 and Cdh1, which bind and activate the APC/C at distinct cell cycle stages. Biochemical and structural studies revealed that Cdc20 and Cdh1 carry conserved receptor domains to recognize specific sequence motifs in substrates, such as D and KEN boxes. The mechanisms for ordered degradation of APC/C substrates, however, remain incompletely understood. Here we describe minimal degradation sequences (degrons) sufficient for rapid APC/C-Cdh1-specific in vivo degradation. The polo kinase Cdc5-derived degron contained an essential KEN motif, whereas a single RxxL-type D box was the relevant signal in the Cdc20 derived degradation domain, indicating that either motif may support specific recognition by Cdh1. In both degrons, the APC/C recognition motif was flanked by a nuclear localization sequence. Forced localization of the degron constructs revealed that proteolysis mediated by APC/C-Cdh1 is restricted to the nucleus and maximally active in the nucleoplasm. Levels of Iqg1, a cytoplasmic Cdh1 substrate, decreased detectably later than the nucleus-localized Cdh1 substrate Ase1, indicating that confinement to the nucleus may allow for temporal control of APC/C-Cdh1-mediated proteolysis. PMID- 25540435 TI - AtDsPTP1 acts as a negative regulator in osmotic stress signalling during Arabidopsis seed germination and seedling establishment. AB - Dual-specificity protein phosphatases (DsPTPs) target both tyrosine and serine/threonine residues and play roles in plant growth and development. We have characterized an Arabidopsis mutant, dsptp1, which shows a higher seed germination rate and better root elongation under osmotic stress than the wild type. By contrast, its overexpression line, DsPTP1-OE, shows inhibited seed germination and root elongation; and its complemented line, DsPTP1-Com, resembles the wild type and rescues DsPTP1-OE under osmotic stress. Expression of AtDsPTP1 is enhanced by osmotic stress in seed coats, bases of rosette leaves, and roots. Compared with the wild type, the dsptp1 mutant shows increased proline accumulation, reduced malondialdehyde (MDA) content and ion leakage, and enhanced antioxidant enzyme activity in response to osmotic stress. AtDsPTP1 regulates the transcript levels of various dehydration-responsive genes under osmotic stress. Abscisic acid (ABA) accumulation in dsptp1 under osmotic stress is reduced with reduced expression of the ABA-biosynthesis gene NCED3 and increased expression of the ABA-catabolism gene CYP707A4. AtDsPTP1 also regulates the expression of key components in the ABA-signalling pathway. In conclusion, AtDsPTP1 regulates ABA accumulation, and acts as a negative regulator in osmotic stress signalling during Arabidospsis seed germination and seedling establishment. PMID- 25540437 TI - Photosynthetic complex stoichiometry dynamics in higher plants: biogenesis, function, and turnover of ATP synthase and the cytochrome b6f complex. AB - During plant development and in response to fluctuating environmental conditions, large changes in leaf assimilation capacity and in the metabolic consumption of ATP and NADPH produced by the photosynthetic apparatus can occur. To minimize cytotoxic side reactions, such as the production of reactive oxygen species, photosynthetic electron transport needs to be adjusted to the metabolic demand. The cytochrome b6f complex and chloroplast ATP synthase form the predominant sites of photosynthetic flux control. Accordingly, both respond strongly to changing environmental conditions and metabolic states. Usually, their contents are strictly co-regulated. Thereby, the capacity for proton influx into the lumen, which is controlled by electron flux through the cytochrome b6f complex, is balanced with proton efflux through ATP synthase, which drives ATP synthesis. We discuss the environmental, systemic, and metabolic signals triggering the stoichiometry adjustments of ATP synthase and the cytochrome b6f complex. The contribution of transcriptional and post-transcriptional regulation of subunit synthesis, and the importance of auxiliary proteins required for complex assembly in achieving the stoichiometry adjustments is described. Finally, current knowledge on the stability and turnover of both complexes is summarized. PMID- 25540436 TI - Length and activity of the root apical meristem revealed in vivo by infrared imaging. AB - Understanding how cell division and cell elongation influence organ growth and development is a long-standing issue in plant biology. In plant roots, most of the cell divisions occur in a short and specialized region, the root apical meristem (RAM). Although RAM activity has been suggested to be of high importance to understand how roots grow and how the cell cycle is regulated, few experimental and numeric data are currently available. The characterization of the RAM is difficult and essentially based upon cell length measurements through destructive and time-consuming microscopy approaches. Here, a new non-invasive method is described that couples infrared light imaging and kinematic analyses and that allows in vivo measurements of the RAM length. This study provides a detailed description of the RAM activity, especially in terms of cell flux and cell division rate. We focused on roots of hydroponic grown poplars and confirmed our method on maize roots. How the RAM affects root growth rate is studied by taking advantage of the high inter-individual variability of poplar root growth. An osmotic stress was applied and did not significantly affect the RAM length, highlighting its homeostasis in short to middle-term responses. The methodology described here simplifies a lot experimental procedures, allows an increase in the number of individuals that can be taken into account in experiments, and means new experiments can be formulated that allow temporal monitoring of the RAM length. PMID- 25540438 TI - Adventitious rooting declines with the vegetative to reproductive switch and involves a changed auxin homeostasis. AB - Adventitious rooting, whereby roots form from non-root tissues, is critical to the forestry and horticultural industries that depend on propagating plants from cuttings. A major problem is that age of the tissue affects the ability of the cutting to form adventitious roots. Here, a model system has been developed using Pisum sativum to differentiate between different interpretations of ageing. It is shown that the decline in adventitious rooting is linked to the ontogenetic switch from vegetative to floral and is mainly attributed to the cutting base. Using rms mutants it is demonstrated that the decline is not a result of increased strigolactones inhibiting adventitious root formation. Monitoring endogenous levels of a range of other hormones including a range of cytokinins in the rooting zone revealed that a peak in jasmonic acid is delayed in cuttings from floral plants. Additionally, there is an early peak in indole-3-acetic acid levels 6h post excision in cuttings from vegetative plants, which is absent in cuttings from floral plants. These results were confirmed using DR5:GUS expression. Exogenous supplementation of young cuttings with either jasmonic acid or indole-3-acetic acid promoted adventitious rooting, but neither of these hormones was able to promote adventitious rooting in mature cuttings. DR5:GUS expression was observed to increase in juvenile cuttings with increasing auxin treatment but not in the mature cuttings. Therefore, it seems the vegetative to floral ontogenetic switch involves an alteration in the tissue's auxin homeostasis that significantly reduces the indole-3-acetic acid pool and ultimately results in a decline in adventitious root formation. PMID- 25540439 TI - Lipotubuloids in ovary epidermis of Ornithogalum umbellatum act as metabolons: suggestion of the name 'lipotubuloid metabolon'. AB - A metabolon is a temporary, structural-functional complex formed between sequential metabolic enzymes and cellular elements. Cytoplasmic domains called lipotubuloids are present in Ornithogalum umbellatum ovary epidermis. They consist of numerous lipid bodies entwined with microtubules, polysomes, rough endoplasmic reticulum (RER), and actin filaments connected to microtubules through myosin and kinesin. A few mitochondria, Golgi structures, and microbodies are also observed and also, at later development stages, autolytic vacuoles. Each lipotubuloid is surrounded by a tonoplast as it invaginates into a vacuole. These structures appear in young cells, which grow intensively reaching 30-fold enlargement but do not divide. They also become larger due to an increasing number of lipid bodies formed in the RER by the accumulation of lipids between leaflets of the phospholipid bilayer. When a cell ceases to grow, the lipotubuloids disintegrate into individual structures. Light and electron microscope studies using filming techniques, autoradiography with [(3)H]palmitic acid, immunogold labelling with antibodies against DGAT2, phospholipase D1 and lipase, and double immunogold labelling with antibodies against myosin and kinesin, as well as experiments with propyzamide, a microtubule activity inhibitor, have shown that lipotubuloids are functionally and structurally integrated metabolons [here termed lipotubuloid metabolons (LMs)] occurring temporarily in growing cells. They synthesize lipids in lipid bodies in cooperation with microtubules. Some of these lipids are metabolized and used by the cell as nutrients, and others are transformed into cuticle whose formation is mediated by cutinsomes. The latter were discovered in planta using specific anti cutinsome antibodies visualized by gold labelling. Moreover, LMs are able to rotate autonomously due to the interaction of microtubules, actin filaments, and motor proteins, which influence microtubules by changing their diameter. PMID- 25540441 TI - Aphid salivary proteases are capable of degrading sieve-tube proteins. AB - Sieve tubes serve as transport conduits for photo-assimilates and other resources in angiosperms and are profitable targets for piercing-sucking insects such as aphids. Sieve-tube sap also contains significant amounts of proteins with diverse functions, for example in signalling, metabolism, and defence. The identification of salivary proteases in Acyrthosiphon pisum led to the hypothesis that aphids might be able to digest these proteins and by doing so suppress plant defence and access additional nitrogen sources. Here, the scarce knowledge of proteases in aphid saliva is briefly reviewed. In order to provide a better platform for discussion, we conducted a few tests on in vitro protease activity and degradation of sieve-tube sap proteins of Cucurbita maxima by watery saliva. Inhibition of protein degradation by EDTA indicates the presence of different types of proteases (e.g. metalloproteses) in saliva of A. pisum. Proteases in the watery saliva from Macrosiphum euphorbiae and A. pisum were able to degrade the most abundant phloem protein, which is phloem protein 1. Our results provide support for the breakdown of sieve-element proteins by aphid saliva in order to suppress/neutralize the defence responses of the plant and to make proteins of sieve-tube sap accessible as a nitrogen source, as is discussed in detail. Finally, we discuss whether glycosylation of sieve-element proteins and the presence of protease inhibitors may confer partial protection against the proteolytic activity of aphid saliva. PMID- 25540440 TI - Apoplastic and intracellular plant sugars regulate developmental transitions in witches' broom disease of cacao. AB - Witches' broom disease (WBD) of cacao differs from other typical hemibiotrophic plant diseases by its unusually long biotrophic phase. Plant carbon sources have been proposed to regulate WBD developmental transitions; however, nothing is known about their availability at the plant-fungus interface, the apoplastic fluid of cacao. Data are provided supporting a role for the dynamics of soluble carbon in the apoplastic fluid in prompting the end of the biotrophic phase of infection. Carbon depletion and the consequent fungal sensing of starvation were identified as key signalling factors at the apoplast. MpNEP2, a fungal effector of host necrosis, was found to be up-regulated in an autophagic-like response to carbon starvation in vitro. In addition, the in vivo artificial manipulation of carbon availability in the apoplastic fluid considerably modulated both its expression and plant necrosis rate. Strikingly, infected cacao tissues accumulated intracellular hexoses, and showed stunted photosynthesis and the up regulation of senescence markers immediately prior to the transition to the necrotrophic phase. These opposite findings of carbon depletion and accumulation in different host cell compartments are discussed within the frame of WBD development. A model is suggested to explain phase transition as a synergic outcome of fungal-related factors released upon sensing of extracellular carbon starvation, and an early senescence of infected tissues probably triggered by intracellular sugar accumulation. PMID- 25540442 TI - Systematic analysis of phloem-feeding insect-induced transcriptional reprogramming in Arabidopsis highlights common features and reveals distinct responses to specialist and generalist insects. AB - Phloem-feeding insects (PFIs), of which aphids are the largest group, are major agricultural pests causing extensive damage to crop plants. In contrast to chewing insects, the nature of the plant response to PFIs remains poorly characterized. Scrutiny of the literature concerning transcriptional responses of model and crop plant species to PFIs reveals surprisingly little consensus with respect to the transcripts showing altered abundance following infestation. Nevertheless, core features of the transcriptional response to PFIs can be defined in Arabidopsis thaliana. This comparison of the PFI-associated transcriptional response observed in A. thaliana infested by the generalists Myzus persicae and Bemisia tabaci with the specialist Brevicoryne brassicae highlights the importance of calcium-dependent and receptor kinase-associated signalling. We discuss these findings within the context of the complex cross talk between the different hormones regulating basal immune response mechanisms in plants. We identify PFI-responsive genes, highlighting the importance of cell wall-associated kinases in plant-PFI interactions, as well as the significant role of kinases containing the domain of unknown function 26. A common feature of plant-PFI interaction is enhanced abundance of transcripts encoding WRKY transcription factors. However, significant divergence was observed with respect to secondary metabolism dependent upon the insect attacker. Transcripts encoding enzymes and proteins associated with glucosinolate metabolism were decreased following attack by the generalist M. persicae but not by the specialist B. brassicae. This analysis provides a comprehensive overview of the molecular patterns associated with the plant response to PFIs and suggests that plants recognize and respond to perturbations in the cell wall occurring during PFI infestation. PMID- 25540449 TI - Illuminating dark cases: veterinary forensic pathology emerges. PMID- 25540450 TI - Human long noncoding RNAs are substantially less folded than messenger RNAs. AB - Long noncoding RNAs (lncRNAs) do not code for proteins but function as RNAs. Because the functions of an RNA rely on either its sequence or secondary structure, lncRNAs should be folded at least as strongly as messenger RNAs (mRNAs), which serve as messengers for translation and are generally thought to lack secondary structure-dependent RNA-level functions. Contrary to this prediction, analysis of genome-wide experimental data of human RNA folding reveals that lncRNAs are substantially less folded than mRNAs even after the control of expression level and GC% (percentage of guanines and cytosines), although both lncRNAs and mRNAs are more strongly folded than expected by chance. In contrast to mRNAs, lncRNAs show neither the positive correlation between folding strength and expression level nor the negative correlation between folding strength and evolutionary rate. These and other results support that although RNA folding undoubtedly plays a role in RNA biology it is also important in translation and/or protein biology. PMID- 25540452 TI - Deeply diverged alleles in the Arabidopsis AREB1 transcription factor drive genome-wide differences in transcriptional response to the environment. AB - Gene regulatory variation is an important driver of the evolution of physiological and developmental responses to the environment. The abscisic acid (ABA) signaling pathway has long been studied as a key component of the cellular response to abiotic stresses in plants. We identify two haplotypes in an Arabidopsis thaliana transcription factor, AREB1, which plays a central role in ABA-mediated response to osmotic stress. These two haplotypes show the sequence signature of long-term maintenance of genetic diversity, suggesting a role for a diversifying selection process such as balancing selection. We find that the two haplotypes, distinguished by a large number of single nucleotide polymorphisms and the presence or absence of four small insertion/deletions in AREB1 intron 1 and exon 2, are at roughly equal frequencies in Arabidopsis, and show high linkage disequilibrium and deep sequence divergence. We use a transgenic approach, along with mRNA Sequencing-based assay of genome-wide expression levels, and find considerable functional divergence between alleles representing the two haplotype groups. Specifically, we find that, under benign soil-water conditions, transgenic lines containing different AREB1 alleles differ in the expression of a large number of genes associated with pathogen response. There are relatively modest gene expression differences between the two transgenic lines under restricted soil water content. Our finding of pathogen-related activity expands the known roles of AREB1 in A. thaliana and reveals the molecular basis of gene-by-environment interaction in a putatively adaptive plant regulatory protein. PMID- 25540453 TI - Why There Are No Essential Genes on Plasmids. AB - Mobile genetic elements such as plasmids are important for the evolution of prokaryotes. It has been suggested that there are differences between functions coded for by mobile genes and those in the "core" genome and that these differences can be seen between plasmids and chromosomes. In particular, it has been suggested that essential genes, such as those involved in the formation of structural proteins or in basic metabolic functions, are rarely located on plasmids. We model competition between genotypically varying bacteria within a single population to investigate whether selection favors a chromosomal location for essential genes. We find that in general, chromosomal locations for essential genes are indeed favored. This is because the inheritance of chromosomes is more stable than that for plasmids. We define the "degradation" rate as the rate at which chance genetic processes, for example, mutation, deletion, or translocation, render essential genes nonfunctioning. The only way in which plasmids can be a location for functioning essential genes is if chromosomal genes degrade faster than plasmid genes. If the two degradation rates are equal, or if plasmid genes degrade faster than chromosomal genes, functioning essential genes will be found only on chromosomes. PMID- 25540451 TI - RELAX: detecting relaxed selection in a phylogenetic framework. AB - Relaxation of selective strength, manifested as a reduction in the efficiency or intensity of natural selection, can drive evolutionary innovation and presage lineage extinction or loss of function. Mechanisms through which selection can be relaxed range from the removal of an existing selective constraint to a reduction in effective population size. Standard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection, because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection. Here, we present a general hypothesis testing framework (RELAX) for detecting relaxed selection in a codon-based phylogenetic framework. Given two subsets of branches in a phylogeny, RELAX can determine whether selective strength was relaxed or intensified in one of these subsets relative to the other. We establish the validity of our test via simulations and show that it can distinguish between increased positive selection and a relaxation of selective strength. We also demonstrate the power of RELAX in a variety of biological scenarios where relaxation of selection has been hypothesized or demonstrated previously. We find that obligate and facultative gamma-proteobacteria endosymbionts of insects are under relaxed selection compared with their free-living relatives and obligate endosymbionts are under relaxed selection compared with facultative endosymbionts. Selective strength is also relaxed in asexual Daphnia pulex lineages, compared with sexual lineages. Endogenous, nonfunctional, bornavirus-like elements are found to be under relaxed selection compared with exogenous Borna viruses. Finally, selection on the short wavelength sensitive, SWS1, opsin genes in echolocating and nonecholocating bats is relaxed only in lineages in which this gene underwent pseudogenization; however, selection on the functional medium/long-wavelength sensitive opsin, M/LWS1, is found to be relaxed in all echolocating bats compared with nonecholocating bats. PMID- 25540454 TI - Cophylogeny reconstruction via an approximate Bayesian computation. AB - Despite an increasingly vast literature on cophylogenetic reconstructions for studying host-parasite associations, understanding the common evolutionary history of such systems remains a problem that is far from being solved. Most algorithms for host-parasite reconciliation use an event-based model, where the events include in general (a subset of) cospeciation, duplication, loss, and host switch. All known parsimonious event-based methods then assign a cost to each type of event in order to find a reconstruction of minimum cost. The main problem with this approach is that the cost of the events strongly influences the reconciliation obtained. Some earlier approaches attempt to avoid this problem by finding a Pareto set of solutions and hence by considering event costs under some minimization constraints. To deal with this problem, we developed an algorithm, called Coala, for estimating the frequency of the events based on an approximate Bayesian computation approach. The benefits of this method are 2-fold: (i) it provides more confidence in the set of costs to be used in a reconciliation, and (ii) it allows estimation of the frequency of the events in cases where the data set consists of trees with a large number of taxa. We evaluate our method on simulated and on biological data sets. We show that in both cases, for the same pair of host and parasite trees, different sets of frequencies for the events lead to equally probable solutions. Moreover, often these solutions differ greatly in terms of the number of inferred events. It appears crucial to take this into account before attempting any further biological interpretation of such reconciliations. More generally, we also show that the set of frequencies can vary widely depending on the input host and parasite trees. Indiscriminately applying a standard vector of costs may thus not be a good strategy. PMID- 25540455 TI - Taxon-rich phylogenomic analyses resolve the eukaryotic tree of life and reveal the power of subsampling by sites. AB - Most eukaryotic lineages are microbial, and many have only recently been sampled for phylogenetic studies or remain in the "dark area" of the tree of life where there are no molecular data. To assess relationships among eukaryotic lineages, we perform a taxon-rich phylogenomic analysis including 232 eukaryotes selected to maximize taxonomic diversity and up to 1554 genes chosen as vertically inherited based on their broad distribution among eukaryotes. We also include sequences from 486 bacteria and 84 archaea to assess the impact of endosymbiotic gene transfer (EGT) from plastids and to detect contamination. Overall, our analyses are consistent with other less taxon-rich estimates of the eukaryotic tree of life, and we recover strong support for five major clades: Amoebozoa, Excavata (without the genus Malawimonas), Opisthokonta, Archaeplastida, and SAR (Stramenopila, Alveolata, and Rhizaria). Our analyses also highlight the existence of "orphan" lineages, lineages that lack robust placement in the eukaryotic tree of life, and indicate the possibility of as yet undiscovered diversity. In analyses including bacteria and archaea, we find that approximately 10% of the 1554 genes, which we choose because they are found in four or five of the five major eukaryotic clades and hence may be more likely to be inherited vertically, appear to have been acquired from cyanobacteria through EGT in photosynthetic lineages. Removing these EGT genes places the green algae as sister to the glaucophytes instead of the red algae, suggesting that unknowingly including genes of plastid origin, and combining them with genes of nuclear origin, may mislead phylogenetic estimates. Finally, the large size of our data set allows comparative analyses of subsets of data; alignments built from randomly sampled sites provide greater support, particularly for deep relationships, than do equivalent-sized data sets built from randomly sampled genes. PMID- 25540456 TI - Assessing approaches for inferring species trees from multi-copy genes. AB - With the availability of genomic sequence data, there is increasing interest in using genes with a possible history of duplication and loss for species tree inference. Here we assess the performance of both nonprobabilistic and probabilistic species tree inference approaches using gene duplication and loss and coalescence simulations. We evaluated the performance of gene tree parsimony (GTP) based on duplication (Only-dup), duplication and loss (Dup-loss), and deep coalescence (Deep-c) costs, the NJst distance method, the MulRF supertree method, and PHYLDOG, which jointly estimates gene trees and species tree using a hierarchical probabilistic model. We examined the effects of gene tree and species sampling, gene tree error, and duplication and loss rates on the accuracy of phylogenetic estimates. In the 10-taxon duplication and loss simulation experiments, MulRF is more accurate than the other methods when the duplication and loss rates are low, and Dup-loss is generally the most accurate when the duplication and loss rates are high. PHYLDOG performs well in 10-taxon duplication and loss simulations, but its run time is prohibitively long on larger data sets. In the larger duplication and loss simulation experiments, MulRF outperforms all other methods in experiments with at most 100 taxa; however, in the larger simulation, Dup-loss generally performs best. In all duplication and loss simulation experiments with more than 10 taxa, all methods perform better with more gene trees and fewer missing sequences, and they are all affected by gene tree error. Our results also highlight high levels of error in estimates of duplications and losses from GTP methods and demonstrate the usefulness of methods based on generic tree distances for large analyses. PMID- 25540458 TI - A tribute to G. Gilbert Ashwell. PMID- 25540459 TI - Egalitarianism, Housework, and Sexual Frequency in Marriage. AB - Changes in the nature of marriage have spurred a debate about the consequences of shifts to more egalitarian relationships, and media interest in the debate has crystallized around claims that men who participate in housework get more sex. However, little systematic or representative research supports the claim that women, in essence, exchange sex for men's participation in housework. Although research and theory support the expectation that egalitarian marriages are higher quality, other studies underscore the ongoing importance of traditional gender behavior and gender display in marriage. Using data from Wave II of the National Survey of Families and Households, this study investigates the links between men's participation in core (traditionally female) and non-core (traditionally male) household tasks and sexual frequency. Results show that both husbands and wives in couples with more traditional housework arrangements report higher sexual frequency, suggesting the importance of gender display rather than marital exchange for sex between heterosexual married partners. PMID- 25540460 TI - Evidence for the complex relationship between free amino acid and sugar concentrations and acrylamide-forming potential in potato. AB - Free amino acids and reducing sugars participate in the Maillard reaction during high-temperature cooking and processing. This results not only in the formation of colour, aroma and flavour compounds, but also undesirable contaminants, including acrylamide, which forms when the amino acid that participates in the reaction is asparagine. In this study, tubers of 13 varieties of potato (Solanum tuberosum), which had been produced in a field trial in 2010 and sampled immediately after harvest or after storage for 6 months, were analysed to show the relationship between the concentrations of free asparagine, other free amino acids, sugars and acrylamide-forming potential. The varieties comprised five that are normally used for crisping, seven that are used for French fry production and one that is used for boiling. Acrylamide formation was measured in heated flour, and correlated with glucose and fructose concentration. In French fry varieties, which contain higher concentrations of sugars, acrylamide formation also correlated with free asparagine concentration, demonstrating the complex relationship between precursor concentration and acrylamide-forming potential in potato. Storage of the potatoes for 6 months at 9 degrees C had a significant, variety-dependent impact on sugar and amino acid concentrations and acrylamide forming potential. PMID- 25540461 TI - Food security: the challenge of increasing wheat yield and the importance of not compromising food safety. AB - Current wheat yield and consumption is considered in the context of the historical development of wheat, from early domestication through to modern plant breeding, the Green Revolution and wheat's place as one of the world's most productive and important crops in the 21st Century. The need for further improvement in the yield potential of wheat in order to meet current and impending challenges is discussed, including rising consumption and the demand for grain for fuel as well as food. Research on the complex genetics underlying wheat yield is described, including the identification of quantitative trait loci and individual genes, and the prospects of biotechnology playing a role in wheat improvement in the future are discussed. The challenge of preparing wheat to meet the problems of drought, high temperature and increasing carbon dioxide concentration that are anticipated to come about as a result of climate change is also reviewed. Wheat yield must be increased while not compromising food safety, and the emerging problem of processing contaminants is reviewed, focussing in particular on acrylamide, a contaminant that forms from free asparagine and reducing sugars during high temperature cooking and processing. Wheat breeders are strongly encouraged to consider the contaminant issue when breeding for yield. PMID- 25540463 TI - CrasyDSE: A framework for solving Dyson-Schwinger equations. AB - : Dyson-Schwinger equations are important tools for non-perturbative analyses of quantum field theories. For example, they are very useful for investigations in quantum chromodynamics and related theories. However, sometimes progress is impeded by the complexity of the equations. Thus automating parts of the calculations will certainly be helpful in future investigations. In this article we present a framework for such an automation based on a C++ code that can deal with a large number of Green functions. Since also the creation of the expressions for the integrals of the Dyson-Schwinger equations needs to be automated, we defer this task to a Mathematica notebook. We illustrate the complete workflow with an example from Yang-Mills theory coupled to a fundamental scalar field that has been investigated recently. As a second example we calculate the propagators of pure Yang-Mills theory. Our code can serve as a basis for many further investigations where the equations are too complicated to tackle by hand. It also can easily be combined with DoFun, a program for the derivation of Dyson-Schwinger equations. PROGRAM SUMMARY: Program title: CrasyDSE Catalogue identifier: AEMY _v1_0 Program summary URL: http://cpc.cs.qub.ac.uk/summaries/AEMY_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 49030 No. of bytes in distributed program, including test data, etc.: 303958 Distribution format: tar.gz Programming language: Mathematica 8 and higher, C++. Computer: All on which Mathematica and C++ are available. Operating system: All on which Mathematica and C++ are available (Windows, Unix, Mac OS). Classification: 11.1, 11.4, 11.5, 11.6. Nature of problem: Solve (large) systems of Dyson-Schwinger equations numerically. Solution method: Create C++ functions in Mathematica to be used for the numeric code in C++. This code uses structures to handle large numbers of Green functions. Unusual features: Provides a tool to convert Mathematica expressions into C++ expressions including conversion of function names. Running time: Depending on the complexity of the investigated system solving the equations numerically can take seconds on a desktop PC to hours on a cluster. PMID- 25540462 TI - A gold cyano complex in nitromethane: MD simulation and X-ray diffraction. AB - The solvation structure around the dicyanoaurate(I) anion (Au(CN)2-) in a dilute nitromethane (CH3NO2) solution is presented from X-ray diffraction measurements and molecular dynamics simulation (NVT ensemble, 460 nitromethane molecules at room temperature). The simulations are based on a new solute-solvent force-field fitted to a training set of quantum-chemically derived interaction energies. Radial distribution functions from experiment and simulation are in good agreement. The solvation structure has been further elucidated from MD data. Several shells can be identified. We obtain a solvation number of 13-17 nitromethane molecules with a strong preference to be oriented with their methyl groups towards the solute. PMID- 25540464 TI - Fabrication and thermo-mechanical behavior of ultra-fine porous copper. AB - Porous materials with ligament sizes in the submicrometer to nanometer regime have a high potential for future applications such as catalysts, actuators, or radiation tolerant materials, which require properties like high strength-to weight ratio, high surface-to-volume ratio, or large interface density as for radiation tolerance. The objective of this work was to manufacture ultra-fine porous copper, to determine the thermo-mechanical properties, and to elucidate the deformation behavior at room as well as elevated temperatures via nanoindentation. The experimental approach for manufacturing the foam structures used high pressure torsion, subsequent heat treatments, and selective dissolution. Nanoindentation at different temperatures was successfully conducted on the ultra-fine porous copper, showing a room temperature hardness of 220 MPa. During high temperature experiments, oxidation of the copper occurred due to the high surface area. A model, taking into account the mechanical properties of the copper oxides formed during the test, to describe the measured mechanical properties in dependence on the proceeding oxidation was developed. The strain rate sensitivity of the copper foam at room temperature was ~0.03 and strongly correlated with the strain rate sensitivity of ultra-fine grained bulk copper. Although oxidation occurred near the surface, the rate-controlling process was still the deformation of the underlying copper. An increase in the strain rate sensitivity was observed, comparably to that of ultra-fine-grained copper, which can be linked to thermally activated processes at grain boundaries. Important insights into the effects of oxidation on the deformation behavior were obtained by assessing the activation volume. Oxidation of the ultra-fine porous copper foam, thereby hindering dislocations to exit to the surface, resulted in a pronounced reduction of the apparent activation volume from ~800 to ~50 b3, as also typical for ultra-fine grained materials. PMID- 25540465 TI - UNCERTAINTY IN EARLY OCCUPATIONAL ASPIRATIONS: ROLE EXPLORATION OR AIMLESSNESS? AB - Many youth in the United States lack clear occupational aspirations. This uncertainty in achievement ambitions may benefit socioeconomic attainment if it signifies "role exploration," characterized by career development, continued education, and enduring partnerships. By contrast, uncertainty may diminish attainment if it instead leads to "aimlessness," involving prolonged education without the acquisition of a degree, residential dependence, and frequent job changes. We use nationally representative data from the National Education Longitudinal Study (NELS) to examine how uncertainty in occupational aspirations in adolescence (age 16) affects wage attainments in young adulthood (age 26). Results suggest that youth with uncertain career ambitions earn significantly lower hourly wages in young adulthood than youth with professional and non professional aspirations, supporting the view that uncertainty heightens the risk of labor-market problems. PMID- 25540466 TI - Unequal Trajectories: Racial and Class Differences in Residential Exposure to Industrial Hazard. AB - The unequal exposure to industrial hazards via differential residential attainment and/or differential sitings of toxic facilities is a long-standing environmental justice issue. This study examines individual trajectories of residential exposure to the risk of industrial hazard over nearly two decades. Using a latent class growth analysis on longitudinal geocoded data merged with the neighborhood-level pollution measures, we discover large racial differences in trajectories of pollution exposure. A majority of individuals are exposed to above-average pollution levels at some point during the study period, but blacks are more likely than whites to experience persistent exposure to high pollution. These differences are only partially explained by racial differences in suburban neighborhood attainment, socioeconomic status, and the frequency of inter neighborhood moves. Immobile blacks also saw their exposure increase. PMID- 25540467 TI - Correcting Duporcq's theorem. AB - In 1898, Ernest Duporcq stated a famous theorem about rigid-body motions with spherical trajectories, without giving a rigorous proof. Today, this theorem is again of interest, as it is strongly connected with the topic of self-motions of planar Stewart-Gough platforms. We discuss Duporcq's theorem from this point of view and demonstrate that it is not correct. Moreover, we also present a revised version of this theorem. PMID- 25540468 TI - A hybrid neural networks-fuzzy logic-genetic algorithm for grade estimation. AB - The grade estimation is a quite important and money/time-consuming stage in a mine project, which is considered as a challenge for the geologists and mining engineers due to the structural complexities in mineral ore deposits. To overcome this problem, several artificial intelligence techniques such as Artificial Neural Networks (ANN) and Fuzzy Logic (FL) have recently been employed with various architectures and properties. However, due to the constraints of both methods, they yield the desired results only under the specific circumstances. As an example, one major problem in FL is the difficulty of constructing the membership functions (MFs).Other problems such as architecture and local minima could also be located in ANN designing. Therefore, a new methodology is presented in this paper for grade estimation. This method which is based on ANN and FL is called "Coactive Neuro-Fuzzy Inference System" (CANFIS) which combines two approaches, ANN and FL. The combination of these two artificial intelligence approaches is achieved via the verbal and numerical power of intelligent systems. To improve the performance of this system, a Genetic Algorithm (GA) - as a well known technique to solve the complex optimization problems - is also employed to optimize the network parameters including learning rate, momentum of the network and the number of MFs for each input. A comparison of these techniques (ANN, Adaptive Neuro-Fuzzy Inference System or ANFIS) with this new method (CANFIS-GA) is also carried out through a case study in Sungun copper deposit, located in East-Azerbaijan, Iran. The results show that CANFIS-GA could be a faster and more accurate alternative to the existing time-consuming methodologies for ore grade estimation and that is, therefore, suggested to be applied for grade estimation in similar problems. PMID- 25540469 TI - Ab initio study of the formation and degradation reactions of chlorinated phenols. AB - The formation, stability, and reactivity of chlorinated phenoxyl radicials was studied using ab initio methods. All 19 congeners from mono- to penta-chlorinated species were considered. The radical species are formed in combustion reactions via unimolecular scission of the phenoxyl-hydrogen bond or hydrogen atom abstraction by hydrogen atom or hydroxyl radical. The resulting radicals are stable with respect to unimolecular decomposition and reaction with molecular oxygen is relatively slow. Activation energies are similar to those of the phenoxyl radical for both the decomposition pathway and the reaction with molecular oxygen at the more reactive para-position. Calculations were performed with the model chemistries B3LYP/6-31G(d,p), BHandHLYP/6-31G(d,p), BHandHLYP/aug cc-pVDZ and QCISD(T)/6-31G(d,p)//BHandHLYP/6-31G(d,p) (for selected reactions.) The results suggest the radicals are sufficiently stable and unreactive to be moderately persistent in the atmosphere, especially when associated with some types of particulate matter. An additivity analysis is made to decompose the relative energetics of the congeners into contributions from hydrogen bonding, resonance stabilization, and repulsive interactions. The results of this analysis correlate well with the results of the calculations. PMID- 25540470 TI - Bayesian piecewise mixture model for racial disparity in prostate cancer progression. AB - Racial differences in prostate cancer incidence and mortality have been reported. Several authors hypothesize that African Americans have a more rapid growth rate of prostate cancer compared to Caucasians, that manifests in higher recurrence and lower survival rates in the former group. In this paper we propose a Bayesian piecewise mixture model to characterize PSA progression over time in African Americans and Caucasians, using follow-up serial PSA measurements after surgery. Each individual's PSA trajectory is hypothesized to have a latent phase immediately following surgery followed by a rapid increase in PSA indicating regrowth of the tumor. The true time of transition from the latent phase to the rapid growth phase is unknown, and can vary across individuals, suggesting a random change point across individuals. Furthermore, some patients may not experience the latent phase due to the cancer having already spread outside the prostate before undergoing surgery. We propose a two-component mixture model to accommodate patients both with and without a latent phase. Within the framework of this mixture model, patients who do not have a latent phase are allowed to have different rates of PSA rise; patients who have a latent phase are allowed to have different PSA trajectories, represented by subject-specific change points and rates of PSA rise before and after the change point. The proposed Bayesian methodology is implemented using Markov Chain Monte Carlo techniques. Model selection is performed using deviance information criteria based on the observed and complete likelihoods. Finally, we illustrate the methods using a prostate cancer dataset. PMID- 25540471 TI - Advances in CMOS Solid-state Photomultipliers for Scintillation Detector Applications. AB - Solid-state photomultipliers (SSPMs) are a compact, lightweight, potentially low cost alternative to a photomultiplier tube for a variety of scintillation detector applications, including digital-dosimeter and medical-imaging applications. Manufacturing SSPMs with a commercial CMOS process provides the ability for rapid prototyping, and facilitates production to reduce the cost. RMD designs CMOS SSPM devices that are fabricated by commercial foundries. This work describes the characterization and performance of these devices for scintillation detector applications. This work also describes the terms contributing to device noise in terms of the excess noise of the SSPM, the binomial statistics governing the number of pixels triggered by a scintillation event, and the background, or thermal, count rate. The fluctuations associated with these terms limit the resolution of the signal pulse amplitude. We explore the use of pixel-level signal conditioning, and characterize the performance of a prototype SSPM device that preserves the digital nature of the signal. In addition, we explore designs of position-sensitive SSPM detectors for medical imaging applications, and characterize their performance. PMID- 25540472 TI - Effect of motion inputs on the wear prediction of artificial hip joints. AB - Hip joint simulators have been largely used to assess the wear performance of joint implants. Due to the complexity of joint movement, the motion mechanism adopted in simulators varies. The motion condition is particularly important for ultra-high molecular weight polyethylene (UHMWPE) since polyethylene wear can be substantially increased by the bearing cross-shear motion. Computational wear modelling has been improved recently for the conventional UHMWPE used in total hip joint replacements. A new polyethylene wear law is an explicit function of the contact area of the bearing and the sliding distance, and the effect of multidirectional motion on wear has been quantified by a factor, cross-shear ratio. In this study, the full simulated walking cycle condition based on a walking measurement and two simplified motions, including the ISO standard motion and a simplified ProSim hip simulator motion, were considered as the inputs for wear modelling based on the improved wear model. Both the full simulation and simplified motions generated the comparable multidirectional motion required to reproduce the physiological wear of the bearing in vivo. The predicted volumetric wear of the ProSim simulator motion and the ISO motion conditions for the walking cycle were 13% and 4% lower, respectively, than that of the measured walking condition. The maximum linear wear depths were almost the same, and the areas of the wear depth distribution were 13% and 7% lower for the ProSim simulator and the ISO condition, respectively, compared with that of the measured walking cycle motion condition. PMID- 25540473 TI - Farm systems assessment of bioenergy feedstock production: Integrating bio economic models and life cycle analysis approaches. AB - Climate change and energy security concerns have driven the development of policies that encourage bioenergy production. Meeting EU targets for the consumption of transport fuels from bioenergy by 2020 will require a large increase in the production of bioenergy feedstock. Initially an increase in 'first generation' biofuels was observed, however 'food competition' concerns have generated interest in second generation biofuels (SGBs). These SGBs can be produced from co-products (e.g. cereal straw) or energy crops (e.g. miscanthus), with the former largely negating food competition concerns. In order to assess the sustainability of feedstock supply for SGBs, the financial, environmental and energy costs and benefits of the farm system must be quantified. Previous research has captured financial costs and benefits through linear programming (LP) approaches, whilst environmental and energy metrics have been largely been undertaken within life cycle analysis (LCA) frameworks. Assessing aspects of the financial, environmental and energy sustainability of supplying co-product second generation biofuel (CPSGB) feedstocks at the farm level requires a framework that permits the trade-offs between these objectives to be quantified and understood. The development of a modelling framework for Managing Energy and Emissions Trade Offs in Agriculture (MEETA Model) that combines bio-economic process modelling and LCA is presented together with input data parameters obtained from literature and industry sources. The MEETA model quantifies arable farm inputs and outputs in terms of financial, energy and emissions results. The model explicitly captures fertiliser: crop-yield relationships, plus the incorporation of straw or removal for sale, with associated nutrient impacts of incorporation/removal on the following crop in the rotation. Key results of crop-mix, machinery use, greenhouse gas (GHG) emissions per kg of crop product and energy use per hectare are in line with previous research and industry survey findings. Results show that the gross margin - energy trade-off is L36 GJ-1, representing the gross margin forgone by maximising net farm energy cf. maximising farm gross margin. The gross margin-GHG emission trade-off is L0.15 kg-1 CO2 eq, representing the gross margin forgone per kg of CO2 eq reduced when GHG emissions are minimised cf. maximising farm gross margin. The energy-GHG emission trade-off is 0.03 GJ kg 1 CO2 eq quantifying the reduction in net energy from the farm system per kg of CO2 eq reduced when minimising GHG emissions cf. maximising net farm energy. When both farm gross margin and net farm energy are maximised all the cereal straw is baled for sale. Sensitivity analysis of the model in relation to different prices of cereal straw shows that it becomes financially optimal to incorporate wheat straw at price of L11 t-1 for this co-product. Local market conditions for straw and farmer attitudes towards incorporation or sale of straw will impact on the straw price at which farmers will supply this potential bioenergy feedstock and represent important areas for future research. PMID- 25540475 TI - Enthalpies of formation of Cd-Pr intermetallic compounds and thermodynamic assessment of the Cd-Pr system. AB - In the present study standard enthalpies of formation were measured by reaction and solution calorimetry at stoichiometric compositions of Cd2Pr, Cd3Pr, Cd58Pr13 and Cd6Pr. The corresponding values were determined to be -46.0, -38.8, -35.2 and -24.7 kJ/mol(at), respectively. These data together with thermodynamic data and phase diagram information from literature served as input data for a CALPHAD-type optimization of the Cd-Pr phase diagram. The complete composition range could be described precisely with the present models, both with respect to phase equilibria as well as to thermodynamic input data. The thermodynamic parameters of all intermetallic compounds were modelled following Neumann-Kopp rule. Temperature dependent contributions to the individual Gibbs energies were used for all compounds. Extended solid solubilities are well described for the low- and high-temperature modifications of Pr and also for the intermetallic compound CdPr. A quite good agreement with all viable data available from literature was found and is presented. PMID- 25540474 TI - Thermodynamic study of the cerium-cadmium system. AB - Cadmium vapor pressures were determined over Ce-Cd samples by an isopiestic method. The measurements were carried out in the temperature range from 690 to 1080 K and over a composition range of 48-85 at% Cd. From the vapor pressures thermodynamic activities of Cd were derived for all samples at their respective sample temperatures, and partial molar enthalpies of Cd were obtained from the temperature dependence of the activities. With these partial molar enthalpies the Cd activities were converted to a common temperature of 823 K. By means of a Gibbs-Duhem integration Ce activities were calculated, using a corresponding literature value for the two-phase field (CeCd11+L) as integration constant. Finally integral Gibbs energies were calculated for the composition range 48-100 at% Cd with a minimum value of -37 kJ g-atom-1 at 823 K in the phase CeCd. Phase boundaries of the intermetallic compounds CeCd, CeCd2, Ce13Cd58, and CeCd11 were estimated from the vapor pressure measurements and from SEM analyses. PMID- 25540476 TI - Solving the dynamic ambulance relocation and dispatching problem using approximate dynamic programming. AB - Emergency service providers are supposed to locate ambulances such that in case of emergency patients can be reached in a time-efficient manner. Two fundamental decisions and choices need to be made real-time. First of all immediately after a request emerges an appropriate vehicle needs to be dispatched and send to the requests' site. After having served a request the vehicle needs to be relocated to its next waiting location. We are going to propose a model and solve the underlying optimization problem using approximate dynamic programming (ADP), an emerging and powerful tool for solving stochastic and dynamic problems typically arising in the field of operations research. Empirical tests based on real data from the city of Vienna indicate that by deviating from the classical dispatching rules the average response time can be decreased from 4.60 to 4.01 minutes, which corresponds to an improvement of 12.89%. Furthermore we are going to show that it is essential to consider time-dependent information such as travel times and changes with respect to the request volume explicitly. Ignoring the current time and its consequences thereafter during the stage of modeling and optimization leads to suboptimal decisions. PMID- 25540477 TI - Leaf area and light use efficiency patterns of Norway spruce under different thinning regimes and age classes. AB - Silviculture focuses on establishing forest stand conditions that improve the stand increment. Knowledge about the efficiency of an individual tree is essential to be able to establish stand structures that increase tree resource use efficiency and stand level production. Efficiency is often expressed as stem growth per unit leaf area (leaf area efficiency), or per unit of light absorbed (light use efficiency). We tested the hypotheses that: (1) volume increment relates more closely with crown light absorption than leaf area, since one unit of leaf area can receive different amounts of light due to competition with neighboring trees and self-shading, (2) dominant trees use light more efficiently than suppressed trees and (3) thinning increases the efficiency of light use by residual trees, partially accounting for commonly observed increases in post thinning growth. We investigated eight even-aged Norway spruce (Picea abies (L.) Karst.) stands at Barnkopf, Austria, spanning three age classes (mature, immature and pole-stage) and two thinning regimes (thinned and unthinned). Individual leaf area was calculated with allometric equations and absorbed photosynthetically active radiation was estimated for each tree using the three-dimensional crown model Maestra. Absorbed photosynthetically active radiation was only a slightly better predictor of volume increment than leaf area. Light use efficiency increased with increasing tree size in all stands, supporting the second hypothesis. At a given tree size, trees from the unthinned plots were more efficient, however, due to generally larger tree sizes in the thinned stands, an average tree from the thinned treatment was superior (not congruent in all plots, thus only partly supporting the third hypothesis). PMID- 25540478 TI - Effects of different types of contraction in abdominal bracing on the asymmetry of left and right abdominal muscles. AB - [Purpose] The purpose of this study was to investigate the effective strength levels of abdominal muscle contraction using the bracing contraction method. [Subjects] The experiment was conducted with 31 healthy male (M=15) and female (F=16) adults attending D University in Busan; all participants had less than obesity level BMI (BMI<30). [Methods] Bracing contraction was performed by the subjects in the hook-lying position at maximum and minimum pressure levels, five times each, using a Pressure Biofeedback Unit (PBU), and the mean measurement value was calculated. The maximum pressure level was set at 100% and the half maximum pressure level was set at 50%. Each subject's left and right abdominal muscle thicknesses were then measured by ultrasound imaging in each state: at rest, 100% contraction, and 50% contraction. [Results] No significant differences were found between the left and right sides of the transversus abdominis (TrA) at rest, 50%, or 100% contraction. The external oblique abdominis (EO) and internal oblique abdominis (IO) showed no significant difference at rest or at the 50% contraction. However, a significant difference was noted at 100% contraction for the EO and IO. [Conclusion] Application of abdominal contraction using bracing can achieve symmetry in the left and right abdominal muscles at less than the maximum contractile strength. The occurrence of asymmetry in the left and right abdominal muscles at the maximum contractile strength suggests that the most suitable contractile strength in this exercise is less than the maximum contractile strength. PMID- 25540479 TI - Effectiveness of a home exercise program in combination with ultrasound therapy for temporomandibular joint disorders. AB - [Purpose] This study compared the effectiveness of home exercise alone versus home exercise combined with ultrasound for patients with temporomandibular joint disorders. [Subjects and Methods] This study enrolled 23 female and 15 male patients who were divided randomly into two groups. The home exercise group performed a home exercise program consisting of an exercise program and patient education, and the home exercise combined with ultrasound group received ultrasound therapy in addition to the home exercise program. Pain intensity was evaluated using a visual analogue scale. Pain free maximum mouth opening was evaluated at baseline and 2 weeks after the treatment. [Results] There was no difference between the two groups in baseline values. After the treatment, the visual analogue scale decreased and pain free maximum mouth opening scores improved significantly in each group. Additionally, both values were higher in the home exercise combined with ultrasound group than in the home exercise group. [Conclusion] The combination of home exercise combined with ultrasound appears to be more effective at providing pain relief and increasing mouth opening than does home exercise alone for patients with temporomandibular joint disorders. PMID- 25540480 TI - Comparison of the Efficacy of Different Long-term Interventions on Chronic Low Back Pain Using the Cross-sectional Area of the Multifidus Muscle and the Thickness of the Transversus Abdominis Muscle as Evaluation Indicators. AB - [Purpose] The purpose of this study was to examine the different effects of long term intervention between proprioceptive neuromuscular facilitation (PNF) and neuromuscular joint facilitation (NJF) patterns for the pelvis on chronic low back pain as assessed by the cross-sectional area of the multifidus muscle and the thickness of the transversus abdominis muscle. [Subjects] The subjects were 12 young people (five males, seven females) who had experienced chronic low back pain on one side for more than 6 months. [Methods] The subjects were treated by resting, PNF or NJF therapy, and each treatment was administered for one month. Ultrasonography was used to measure the changes in the transversus abdominis muscle thickness and the multifidus muscle cross-sectional area. [Results] The thickness of the transversus abdominis muscle and the cross-sectional area of the multifidus muscle in the NJF group, after resting, increased significantly and were higher than those in the PNF group. [Conclusion] The results show that significantly better improvement can be obtained for chronic low back pain by applying long-term intervention of NJF patterns. PMID- 25540481 TI - Reliability of Isometric Knee Extension Muscle Strength Measurements of Healthy Elderly Subjects Made with a Hand-held Dynamometer and a Belt. AB - [Purpose] The purpose of this study was to examine the reliability of three isometric knee extension strength measurements (IKE) made with a hand-held dynamometer (HHD) and a belt of healthy elderly living in the community as subjects. [Subjects] The subject cohort consisted of 186 healthy elderly people, aged 65 to 79 years, living in local communities. [Methods] IKE of the leg subjects used to kick a ball was measured. IKE of each subject was measured three times using an HHD-belt at intervals of 30 seconds. The reliability of the larger of the first two measurements (LV2) as well as the third measurement (3V) was investigated. [Results] The intraclass correlation coefficients [ICC (1, 1)] for LV2 and 3V were 0.955. Bland-Altman analysis showed a fixed bias, and the limits of agreement ranged from -5.6 to 4.6. [Conclusion] The ICC results show that the test-retest reproducibility of IKE measurements of healthy elderly subjects using an HHD-belt is high. However, Bland-Altman analysis showed a fixed bias, suggesting the need for three measurements. PMID- 25540482 TI - Verification of the Correlation between Cognitive Function and Lower Limb Muscle Strength for the Community-dwelling Elderly. AB - [Purpose] The purpose of this study was to evaluate the lower limb muscle strength of the community-dwelling elderly, with or without cognitive decline, using isometric knee extension strength (IKES) and the 30-second chair stand test (CS-30). [Subjects] A total of 306 community-dwelling elderly participated in this study. Assessment items were the CS-30, IKES, Mini-Mental State Examination (MMSE), and Trail-Making Test Part A (TMT-A). [Methods] Participants were divided into three groups according to their MMSE score: cognitive impairment (MMSE <= 24), cognitive decline (MMSE 25 to 27), and normal (MMSE >= 28). We compared IKES and CS-30 among the three groups. [Results] IKES was not significantly different among the three groups. However, the CS-30 was significantly different among the three groups. Upon further analysis the CS-30 score of each group, when adjusted for age and TMT-A, did not indicate a significant difference. [Conclusion] These results suggest that the lower limb muscle strength of the elderly does not differ with cognitive decline. Moreover, we suggest that when using the CS-30 score as an indicator of lower limb muscle strength attentional function should be taken into account. PMID- 25540483 TI - Analysis of biochemical markers related to Fatty liver patients. AB - [Purpose] This study was designed to study the correlation between biochemical tests and fatty liver. [Subjects and Methods] The study subjects were 242 people who received an abdominal ultrasound examination at a general hospital in Seoul, Korea, from March 2012 to March 2013. After the abdominal ultrasound examination, the subjects were categorized according to the presence or absence of fatty liver (n = 118 and 124, respectively). [Results] Comparison of biochemical markers revealed that glucose, total protein, aspartate transminase, alanine transaminase and triglyceride were higher in fatty liver patients. Risk analysis of general characteristics determined that hypertensive and diabetic patients had a 2.475- and 2.026-times greater risk of onset of fatty liver, respectively. The comparison of fatty liver with individual characteristics and biochemical markers revealed a 1.804-times greater chance of fatty liver when total protein was high, 0.964-times greater chance when high density lipoprotein was elevated and 1.204 times greater chance when triglyceride was elevated. When hypertension became severe, the chance of experiencing onset of fatty liver was 2.848 times higher. [Conclusion] Fatty liver is a representative disease of obese people in general and more active attention is necessary for its prevention and treatment. A direct cause of fatty liver was not found. Large-scale prospective studies will be required. PMID- 25540484 TI - The Effect of Somatosensory and Cognitive-motor Tasks on the Paretic Leg of Chronic Stroke Patients in the Standing Posture. AB - [Purpose] The purpose of this study was to investigate how different standing surfaces alter somatosensory input and how postural control is affected by these changes during the performance of a dual task with a cognitive-motor aspect. [Subjects] The subjects were 20 chronic stroke patients: 18 males, 2 females. [Methods] COP total distance, sway velocity, and the weight load on the paretic leg were measured while subjects performed the following three tasks (somatosensory task, cognitive-motor task, and dual task). [Results] Both COP total distance and sway velocity significantly decreased during the performance of all tasks. COP total distance and sway velocity significantly decreased during the somatosensory task and the dual task. The weight load significantly increased during performance of the somatosensory task and the dual task. [Conclusion] Compensatory mechanisms in the non-paretic leg were limited by placing it on an air cushion, and we observed an increase in somatosensory input from the paretic leg due to an enhanced weight load. PMID- 25540485 TI - Rehabilitation Exercises to Induce Balanced Scapular Muscle Activity in an Anti gravity Posture. AB - [Purpose] The purpose of this study was to compare the intramuscular balance ratios of the upper trapezius muscle (UT) and the lower trapezius muscle (LT), and the intermuscular balance ratios of the UT and the serratus anterior muscle (SA) among prone extension (ProExt), prone horizontal abduction with external rotation (ProHAbd), forward flexion in the side-lying position (SideFlex), side lying external rotation (SideEr), shoulder flexion with glenohumeral horizontal abduction load (FlexBand), and shoulder flexion with glenohumeral horizontal adduction load (FlexBall) in the standing posture. [Methods] The electromyographic (EMG) activities of the UT, LT and SA were measured during the tasks. The percentage of maximum voluntary isometric contraction (%MVIC) was calculated for each muscle, and the UT/LT ratios and the UT/SA ratios were compared among the tasks. [Results] The UT/LT ratio with the FlexBand was not significantly different from those of the four exercises in the side-lying and prone postures. The UT/SA ratio with the FlexBall demonstrated appropriate balanced activity. [Conclusion] In an anti-gravity posture, we recommend the FlexBand and the FlexBall for inducing balanced UT/LT and UT/SA ratios, respectively. PMID- 25540486 TI - Evaluation of open and closed kinetic chain exercises in rehabilitation following anterior cruciate ligament reconstruction. AB - [Purpose] To compare outcomes of anterior cruciate ligament (ACL) reconstruction after open kinetic chain (OKC) exercises and closed kinetic chain (CKC) exercises. [Subjects and Methods] The subjects comprised 11 female and 47 male patients who are randomly divided into two groups: which performed a CKC exercise program Group I and Group II which performed an OKC exercise program. Pain intensity was evaluated using visual analogue scale (VAS). Knee flexion was evaluated using a universal goniometer, and thigh circumference measurements were taken with a tape measure at baseline and at 3 months and 6 months after the treatment. Lysholm scores were used to assess knee function. [Results] There were no significant differences between the two groups at baseline. Within each group, VAS values and knee flexion were improved after the surgery. These improvements were significantly higher in the CKC group than in the OKC group. There were increases in thigh circumference difference at the 3 and 6 month assessments post surgery. A greater improvement in the Lysholm score was observed in the CKC group at 6 months. [Conclusion] The CKC exercise program was more effective than OKC in improving the knee functions of patients with ACL reconstruction. PMID- 25540487 TI - Effect of forward and backward locomotion training on anaerobic performance and anthropometrical composition. AB - [Purpose] Forward walking (FW) and backward walking (BW) on a treadmill is a common tool for lower extremity rehabilitation in the clinical setting. The purpose of this study was to evaluate the effects on anaerobic performance and anthropometrical adaptations during FW and BW on a treadmill. [Subjects and Methods] A convenience sample of thirty healthy male subjects with a mean age of 20.93 +/- 2.54 years participated in this study. Subjects were divided into 2 groups, a Forward Walking Group (FWG) (n=15) and a Backward Walking Group (BWG) (n=15), which performed FW and BW on a treadmill at 10 degrees inclination, respectively. The training consisted of three sessions per week for 6 weeks. Study outcomes such as anaerobic performance and anthropometrical body composition were measured at pre- and post-intervention. [Results] Both FW and BW improved anaerobic performance significantly, and the BW group showed better performance than FW. However, changes in anthropometrical body composition were found to be not significant after six weeks of intervention in both the FW and BW groups. [Conclusions] BW training in rehabilitation can be considered more effective than FW at improving anaerobic performance. We also conclude that six weeks of FW and BW training is insufficient for eliciting changes in the body composition. PMID- 25540488 TI - Relationships of stroke patients' gait parameters with fear of falling. AB - [Purpose] The purpose of this study was to assess the correlation of gait parameters with fear of falling in stroke survivors. [Subjects] In total, 12 patients with stroke participated. [Methods] The subjects performed on a Biodex Gait Trainer 2 for 5 min to evaluate characteristic gait parameters. The kinematic gait parameters measured were gait speed, step cycle, step length, and time on each foot (step symmetry). All the subjects also completed a fall anxiety survey. [Results] Correlations between gait parameters and fear of falling scores were calculated. There was a moderate degree of correlation between fear of falling scores and the step cycle item of gait parameters. [Conclusions] According to our results, the step cycle gait parameter may be related to increased fall anxiety. PMID- 25540489 TI - Indoor Gateball's Influence on Life Satisfaction and the Prevention of Falls by the Elderly. AB - [Purpose] The purpose of this study was to investigate the effects of indoor gateball exercise on life satisfaction and the prevention of falls by the elderly. [Subjects] Sixteen elderly subjects aged 65 or more, residents in nursing care facilities, were randomly divided into two groups. [Methods] One group performed indoor gateball exercise for 30 minutes a day, five times per week. The Tetrax fall index and life satisfaction were measured before and after four weeks of gateball exercise. [Results] The indoor gate ball exercise group showed significant improvements in the fall index and life satisfaction. [Conclusion] The indoor gateball exercise used in this study should be considered as a therapeutic method for the elderly, for improving their life satisfaction and because of its effectiveness in preventing falls. PMID- 25540490 TI - The Relationship between Household Income and Physical Activity in Korea. AB - [Purpose] Based on the relationship between obesity and physical activity, several recent studies have reported that level of exercise is associated with household income. Hence, the purpose of this study is to explore the relationship between household income and physical activity in Korea. [Subjects and Methods] In 2012, 9,000 Koreans (4,479 men and 4,521 women) aged 10-89 years participated in the Korean Survey of Citizens' Sports Participation project. This survey provided us with information on the amount of physical activity undertaken each week and the household incomes of a nationally representative sample of respondents. The relationship between household income and physical activity was then evaluated by conducting multiple logistic regression analysis after controlling for participant age. [Results] The present findings show a strong relationship between household income and physical activity for Korean men and women. [Conclusion] Further well-designed studies should be performed in order to determine the individual effects of household income on physical activity. PMID- 25540491 TI - Preventive effects of antioxidants and exercise on muscle atrophy induced by ischemic reperfusion. AB - [Purpose] This study aimed to determine whether muscle atrophy induced by ischemic reperfusion injury in rats can be prevented by the administration of antioxidants and exercise. [Subjects] Rats were randomly divided into five groups: non-treated, ischemic, exercise, ascorbic acid and exercise, and tocopherol and exercise. [Methods] The relative weight ratio of the soleus muscle and the length of the soleus muscle fiber cross-section minor axis were used for the evaluation of muscle atrophy. Pain was assessed as the weight-bearing ratio of the ischemic side. A multiple comparison test and the paired t-test were used for the statistical analyses. [Results] Compared with the non-treated group, the relative weight ratios of the soleus muscle and the lengths of the soleus muscle fiber cross-section minor axis significantly decreased in the other groups. Excluding the non-treated group, the relative weight ratios of the soleus muscle were heaviest in the tocopherol and exercise group. Excluding the non-treated group, the lengths of the soleus muscle fiber cross-section minor axis were longest in the tocopherol and exercise group, followed by the ischemic, exercise, and ascorbic acid and exercise groups. The amount of antioxidant substances did not decrease on the weight-bearing ratio of the ischemic side. [Conclusion] In this study, using an experimental rat model, we confirmed that antioxidants and exercise effect muscle atrophy induced by ischemic reperfusion. The results show that muscle regeneration was facilitated by phagocytosis in the tocopherol and exercise group. PMID- 25540492 TI - Influence of Hip Joint Position on Muscle Activity during Prone Hip Extension with Knee Flexion. AB - [Purpose] This study investigated the selective activation of the gluteus maximus during a prone hip extension with knee flexion exercise, with the hip joint in different positions. [Subjects] The subjects were 21 healthy, male volunteers. [Methods] Activities of the right gluteus maximus, right hamstrings, bilateral lumbar erector spinae, and bilateral lumbar multifidus were measured using surface electromyography during a prone hip extension with knee flexion exercise. Measurements were made with the hip joint in each of 3 positions: (1) a neutral hip joint position, (2) an abduction hip joint position, and (3) an abduction with external rotation hip joint position. [Results] Gluteus maximus activity was significantly higher when the hip was in the abduction with external rotation hip joint position than when it was in the neutral hip joint and abduction hip joint positions. Gluteus maximus activity was also significantly higher in the abduction hip joint position than in the neutral hip joint position. Hamstring activity was significantly lower when the hip was in the abduction with external rotation hip joint position than when it was in the neutral hip joint and abduction hip joint positions. [Conclusion] Abduction and external rotation of the hip during prone hip extension with knee flexion exercise selectively activates the gluteus maximus. PMID- 25540493 TI - Effects of Cervical Flexion on the Flexion-relaxation Ratio during Smartphone Use. AB - [Purpose] The purpose of this study was to measure the cervical flexion relaxation ratio (FRR) and intensity of neck pain and identify the differences according to postures adopted while using smartphones. [Subjects] Fifteen healthy adults with no neck pain, spinal trauma, or history cervical surgery participated in this study. [Methods] The activity of the cervical erector spinae muscle was recorded while performing a standardized cervical flexion-extension movement in three phases (flexion, sustained full flexion, extension). And neck pain intensity was recorded using a visual analog scale (VAS) with values between 0 and 10. Postures held while using a smartphone are distinguished between desk postures and lap postures. The FRR was calculated by dividing the maximal muscle activation during the extension phase by average activation during the complete flexion phase. [Results] No significant differences were found in the FRR between desk posture, lap posture, and baseline, though the intensity of the neck pain increased in the lap posture. [Conclusion] The FRR could be a significant criterion of neuromuscular impairment in chronic neck pain or lumbar pain patients, but it is impossible to distinguish neck pain that is caused by performing task for a short time. Prolonged lap posture might cause neck pain, so the use of smartphones for a long time in this posture should be avoided. PMID- 25540494 TI - Effects of indoor horseback riding and virtual reality exercises on the dynamic balance ability of normal healthy adults. AB - [Purpose] The objective of this study was to determine the effect of indoor horseback riding and virtual reality exercises on the dynamic balance ability of normal adults. [Subjects] This study enrolled 24 normal adults and divided them into two groups: an indoor horseback riding exercise group (IHREG, n = 12) and a virtual reality exercise group (VREG, n = 12). [Methods] IHREG exercised on indoor horseback riding equipment and VREG exercised using the Nintendo Wii Fit three times a week for six weeks. The Biodex Balance System was used to analyze dynamic balance as measured by the overall stability index (OSI), anteroposterior stability index (APSI), and mediolateral stability index (MLSI). [Results] In the within-group comparison, IHREG and VERG both showed significant decreases in the dynamic balance indexes of OSI, APSI, and MLSI after the intervention, but no significant difference was found between the groups. [Conclusion] Both indoor horseback riding and virtual reality exercises were effective at improving the subjects' dynamic balance ability as measured by OSI, APSI, and MLSI, and can be used as additional exercises for patients with conditions affecting postural control. PMID- 25540496 TI - Effects of self stretching on pain and musculoskeletal symptom of bus drivers. AB - [Purpose] The aim of this study was to evaluate the musculoskeletal symptoms, pain and risk of postures as well as the effects of stretching exercise on the work-related symptoms and pain of bus drivers. [Subjects and Methods] Eighty-one drivers were randomly recruited from a bus corporation for this study. Information about pain levels, painful regions, and general characteristics of subjects was obtained using the symptom research form (KOSHA Code H-30-2003). The level of pain was assessed on a scale of numeric rating scale (NRS) which is divided by 10. Ergonomic posture assessment was conducted using the rapid upper limb assessment (RULA). Self-stretching exercise was performed for 4 weeks by the bus drivers who suffered from neck and shoulder pain. [Results] Musculoskeletal symptoms were present in the order of shoulder, neck, lower back and lower extremities. Compared with other jobs, the final score, and the action level of bus drivers were very high, showing 57.6% of action levels 3 and 4. A statistically significant decrease of pain was shown after the self-stretching intervention. There was also a significant decrease of musculoskeletal symptoms in the neck and shoulders after the self-stretching exercise. [Conclusion] Performing stretching for musculoskeletal symptoms had a positive influence on the symptoms and reduced pain. PMID- 25540495 TI - Relationships between Gross Motor Abilities and Problematic Behaviors of Handicapped Children in Different Age Groups. AB - [Purpose] In this study, we examined problematic behaviors of independent-walking and non-independent-walking handicapped children in the infant, school child and adolescent development phases, using the Japanese version of the Aberrant Behavior Checklist (ABC-J) to determine if such behaviors relate to their gross motor abilities. [Subjects and Methods] The subjects were 86 handicapped children who were receiving physical therapy. The subjects were classified into three groups by age. Using the Gross Motor Function Classification System (GMFCS), each group was further divided into an independent-walking group and non-independent walking group. Thirteen physical therapists and 8 occupational therapists, who were treating the subject children, rated the subjects using the ABC-J. [Results] Significant differences were observed between the independent-walking and the non independent-walking groups in the stereotypy and lethargy scores of infants. [Conclusion] For schoolchildren and adolescents, no significant differences were observed between the independent-walking and the non-independent-walking groups in their problematic behavior scores. PMID- 25540497 TI - Muscle activity of the gluteus medius at different gait speeds. AB - [Purpose] The present study aimed to determine the changes in the muscle activities of the gluteus medius, latissimus dorsi, and gluteus maximus at different gait speeds, to collect basic data for the study of the gluteus medius. [Subjects and Methods] The subjects were 18 young and healthy male adults whose mean age, height, and weight were 26.4 years, 173.37 cm, and 72.5 kg, respectively. Electromyograpy was used to measure the maximum voluntary isometric contraction of each muscle three times and the values averaged. Then, the subjects walked on a treadmill at gait speeds of 1.5 m/s, 2.5 m/s, and 3.5 m/s and the muscle activity of each muscle was measured. [Results] The gluteus medius showed no significant difference in muscle activity among the different gait speeds. [Conclusion] For selectively strengthening the gluteus medius, to establish the external stability of the pelvis during walking, weight loading or sloped treadmills are effective interventions. However, different gait speeds exert no significant effect on the selective strengthening of the gluteus medius. PMID- 25540498 TI - Slow Expiration Reduces External Oblique Muscle Activity during Maximum Trunk Flexion. AB - [Purpose] The purpose of this study was to demonstrate the effects of expiration on abdominal muscle activity during maximum trunk flexion. [Subjects] Twenty-one healthy university students (10 men, 11 women) participated in this study. [Methods] Electromyography (EMG) was used to quantify the activity of the right rectus abdominis, external oblique, and internal oblique muscles. The paired t test was used to examine the significance of differences in the abdominal muscles between maximum trunk flexion with breath holding and slow expiration. [Results] There was a significantly lower EMG activity in the external oblique muscle during maximum trunk flexion with slow expiration. [Conclusion] The results of this study indicate that slow expiration reduces external oblique muscle activity during maximum trunk flexion performed by healthy young subjects. PMID- 25540499 TI - Effects of Progressive Body Weight Support Treadmill Forward and Backward Walking Training on Stroke Patients' Affected Side Lower Extremity's Walking Ability. AB - [Purpose] The purpose of the present study was to examine the effects of progressive body weight supported treadmill forward and backward walking training (PBWSTFBWT), progressive body weight supported treadmill forward walking training (PBWSTFWT), progressive body weight supported treadmill backward walking training (PBWSTBWT), on stroke patients' affected side lower extremity's walking ability. [Subjects and Methods] A total of 36 chronic stroke patients were divided into three groups with 12 subjects in each group. Each of the groups performed one of the progressive body weight supported treadmill training methods for 30 minute, six times per week for three weeks, and then received general physical therapy without any other intervention until the follow-up tests. For the assessment of the affected side lower extremity's walking ability, step length of the affected side, stance phase of the affected side, swing phase of the affected side, single support of the affected side, and step time of the affected side were measured using optogait and the symmetry index. [Results] In the within group comparisons, all the three groups showed significant differences between before and after the intervention and in the comparison of the three groups, the PBWSTFBWT group showed more significant differences in all of the assessed items than the other two groups. [Conclusion] In the present study progressive body weight supported treadmill training was performed in an environment in which the subjects were actually walked, and PBWSTFBWT was more effective at efficiently training stroke patients' affected side lower extremity's walking ability. PMID- 25540500 TI - Factors Related to Stages of Exercise Behavior Change among University Students Based on the Transtheoretical Model. AB - [Purpose] The purpose of this study was to identify the distribution of stages of change in the exercise behavior of university students the transtheoretical model. [Subjects and Methods] Study subjects at four universities in G city were surveyed. A total of 1,000 questionnaires were distributed, and 959 responses were analyzed. The collected data was analyzed using descriptive statistics and multiple logistic regression analysis. [Results] Factors that contributed to the transition from the pre-contemplation stage to the contemplation stage included change-experimental processes (C-EP) and change-behavioral processes (C-BP). Factors that contributed to the transition from the contemplation stage to the preparation stage were C-BP and decisional decisional balance-cons (DB-C). Self efficacy was the factor that contributed to the transition from the preparation stage to the action stage. However, there was no factor that contributed to the transition from the action stage to the maintenance stage. [Conclusion] When exercise behavior change is low, strategies such as giving one-to-one training, having the subjects read relevant books, and providing information are needed. When exercise behavior change is high, it is necessary to heighten self-efficacy by having subjects select and freely conduct appropriate kinds of exercises. PMID- 25540501 TI - Changes in Glucose, TNF-alpha and IL-6 Blood Levels in Middle-aged Women Associated with Aerobic Exercise and Meditation Training. AB - [Purpose] The purpose of this study was to investigate the effects of exercise therapy on glucose, TNF-alpha and IL-6 blood levels in middle-aged women. [Subjects] A total of 46 participants were assigned to four groups: Type D personality+Exercise (n=12), Type D+no-Exercise (n=12), not-Type D+Exercise (n=12), and not-Type D+no-Exercise (n=10). [Methods] Blood glucose was measured by the hexokinase method. An enzyme-linked immunosorbent assay (ELISA) was used to measure the circulating plasma levels of TNF-alpha and IL-6 (Quantikine HS, R&D Systems, Minneapolis, USA). An aerobic exercise program and meditation were conducted in parallel by the Exercise groups for 10 months. Stretching was performed for 10 min as a warm-up, and then walking and running on a treadmill at 60 to 70% of HRmax were performed for 40 min three times a week. Blood samples were processed according to standard laboratory procedures. [Results] Fasting glucose showed a significant interaction effect among groups, group*time, and post-test. TNF-alpha showed a significant difference among groups, and was lower in the not-Type D personality+Exercise group than in the other three groups. IL-6 showed a significant difference among the groups. [Conclusion] In conclusion, personality may affect the established effect of exercise on cytokine activity. Type D personality was independently associated with significant immune activation, and increase in TNF-alpha activity was observed among Type D participants. PMID- 25540502 TI - Correlations between Muscle Activities and Strap Length and Types of School Bag during Walking. AB - [Purpose] The purpose of this study was to examine correlations between muscle activities and strap length and type of the school bag during walking. [Subjects and Methods] The subjects of this study were 20 healthy students. An 8-channel electromyograph (8-EMG) (Pocket EMG, BTS, Italy) was used to measure the muscle activities of the right upper trapezius, left upper trapezius, right erector spinae and left erector spinae during walking with the bag. The collected data were analyzed using Kendall's coefficient of concordance. [Results] The muscle activities of the right upper trapezius, left upper trapezius, right erector spinae and left erector spinae were significantly higher when walking with a shoulder bag than when walking with a backpack. No significant correlations were found between muscle activities and strap lengths of the bag. [Conclusion] While carrying a bag, the activities of the trunk muscles were influenced more by the type of the bag than by the strap length. These results indicate that a backpack is a better method of carrying a load than a shoulder bag. PMID- 25540503 TI - Factors Related to Gait Function in Post-stroke Patients. AB - [Purpose] Gait function after a stroke is an important factor for determining a patient's ability to independently perform activities of daily living (ADL). The objective of this study was to elucidate the factors associated with gait function in post-stroke patients. [Subjects] Thirty-nine stroke patients (16 females and 23 males; average age 67.82 +/- 10.96 years; post-onset duration: 200.18 +/- 27.14 days) participated in this study. [Methods] Their gait function, motor function (Manual Muscle Test [MMT] and Brunnstrom stage), level of cognition (Mini-Mental State Examination score [MMSE], and the Loewenstein Occupational Therapy Cognitive Assessment for the Geriatric Population [LOTCA G]), and ADL (Korean modified Barthel index [K-MBI]) were assessed. [Results] The degree of gait function showed significant positive correlations with the following variables: MMT of the elbow, knee, ankle and wrist; Brunnstrom stage; MMSE; LOTCA-G subscores except motor praxis; K-MBI. Stepwise linear regression analysis revealed the Brunnstrom stage was the only explanatory variable closely associated with gait level. [Conclusion] Gait function of post-stroke patients was related to motor function, cognition, and ADL. In particular, there is a significant association between gait level and the Brunnstrom stages, reflecting the importance of monitoring the motor recovery of gait function in post-stroke patients. PMID- 25540504 TI - Analgesic effects of transcutaneous electrical nerve stimulation and interferential current on experimental ischemic pain models: frequencies of 50 hz and 100 hz. AB - [Purpose] This study compared the analgesic effects of transcutaneous electrical nerve stimulation (TENS) and interferential currents (IFC) on induced ischemic pain in healthy volunteers. [Subjects] The subjects were 36 volunteers (18 male, 18 female) without known pathology that could cause pain. Their mean age was 24.5+/-2.2 years. [Methods] A single-blind and parallel-group method was used. Subjects were randomly allocated to receive each 50 Hz TENS, 50 Hz IFC, 100 Hz TENS, and 100 Hz IFC. This study experimentally induced ischemic pain in otherwise pain-free subjects using a modified version of the submaximal effort tourniquet technique. Subjects completed twelve cycles of the ischemic-induced pain test. The primary outcome measure was the change in self-reported of pain intensity during one of four possible treatments. [Results] There were significant effects for Time, which were attributed to a significant reduction in pain intensity for all groups. There were no significant effects for groups or group-time interaction. The 50 Hz IFC treatment was more comfortable than the other treatments in the present study, and it is likely to be better accepted and tolerated by patients. [Conclusion] We conclude that there were no differences in the analgesic effects of the four treatments under the present experimental conditions. The 50 Hz IFC treatment is more comfortable than the other treatments. PMID- 25540505 TI - Effects of Robot-assisted Gait Training Combined with Functional Electrical Stimulation on Recovery of Locomotor Mobility in Chronic Stroke Patients: A Randomized Controlled Trial. AB - [Purpose] The purpose of the present study was to investigate the effects of robot-assisted gait training combined with functional electrical stimulation on locomotor recovery in patients with chronic stroke. [Subjects] The 20 subjects were randomly assigned into either an experimental group (n = 10) that received a combination of robot-assisted gait training and functional electrical stimulation on the ankle dorsiflexor of the affected side or a control group (n = 10) that received robot-assisted gait training only. [Methods] Both groups received the respective therapies for 30 min/day, 3 days/week for 5 weeks. The outcome was measured using the Modified Motor Assessment Scale (MMAS), Timed Up-and-Go Test (TUG), Berg Balance Scale (BBS), and gait parameters through gait analysis (Vicon 370 motion analysis system, Oxford Metrics Ltd., Oxford, UK). All the variables were measured before and after training. [Results] Step length and maximal knee extension were significantly greater than those before training in the experimental group only. Maximal Knee flexion showed a significant difference between the experimental and control groups. The MMAS, BBS, and TUG scores improved significantly after training compared with before training in both groups. [Conclusion] We suggest that the combination of robot-assisted gait training and functional electrical stimulation encourages patients to actively participate in training because it facilitates locomotor recovery without the risk of adverse effects. PMID- 25540506 TI - An Examination of Limb Position for Measuring Toe-grip Strength. AB - [Purpose] The purpose of the present study was to investigate the limb position at which the maximum toe-grip strength could be exerted as well as measurement reproducibility. [Subjects] Twenty healthy young women were selected. [Methods] We measured toe-grip strength under three conditions: 90 degrees hip and knee flexion while sitting, 90 degrees hip flexion and knee extension while sitting, and a standing position. [Results] We found that toe-grip strength was significantly lower in the 90 degrees hip flexion and knee extension sitting position than in the 90 degrees hip and knee flexion sitting position and standing position. Moreover, the 90 degrees hip and knee flexion sitting position produced the best intraclass correlation coefficient (r = 0.813). [Conclusion] The results suggest that 90 degrees hip and knee flexion while sitting is the most suitable limb position for measuring toe-grip strength, as this position allows maximum strength to be exerted and allows measurements to be repeated. PMID- 25540507 TI - Age-related Changes in Maximum Pelvic Anteversion and Retroversion Angles Measured in the Sitting Position. AB - [Purpose] The purpose of this study was to investigate the relationship between age and the maximum pelvic anteversion and retroversion angles, as well as the associated pelvic range of motion, measured in a sitting position with free knee movement. [Subjects] A total of 132 healthy volunteers (74 women, 58 men; age range, 20-79 years) were divided into six groups based on age (20-29, 30-39, 40 49, 50-59, 60-69, and 70-79 years). [Methods] The maximum pelvic anteversion and retroversion angles were measured manually five times by a goniometer in a sitting position that allowed free movement of the knee joints. [Results] There was a significant effect of age group on the maximum pelvic anteversion and retroversion angles and pelvic range of motion (the difference between these angles). There was a significant correlation between age and the maximum pelvic anteversion angle, maximum pelvic retroversion angle, and pelvic range of motion. [Conclusion] The maximum pelvic anteversion and retroversion angles and pelvic range of motion were significantly correlated with age. The maximum pelvic anteversion angle and pelvic range of motion were most affected by age. PMID- 25540508 TI - Comparison of Hip Stabilization Muscle Use during Neutral Sit to Stand and Sit to Stand Involving Isometric Hip Abduction in Elderly Females. AB - [Purpose] The purpose of this study was to compare the activation of the gluteus medius (Gmed), rectus femoris (RF), and biceps femoris (BF) muscles during neutral (N) sit to stand (STS) and STS involving hip abduction (ABD) in elderly females. [Subjects] We recruited 16 healthy elderly females with no pain in the knee joint or any other orthopedic problems of the lower limbs. [Methods] The activities of the dominant lower extremity muscles were measured using a wireless electromyography (EMG) system. Subjects then undertook a total of six STS trials: three for neutral STS and three for STS involving hip abduction. [Results] In the pre-TO phase, activation of the RF muscle was significantly increased during hip ABD. In the post-TO phase during hip ABD, Gmed muscle activation was significantly increased, and RF muscle activation was significantly decreased. [Conclusion] This study suggests that STS involving hip ABD is more effective in decreasing Gmed activation and reducing RF effort in elderly females. PMID- 25540509 TI - Comparison of Physical Fitness Status between Middle-aged and Elderly Male Laborers According to Lifestyle Behaviors. AB - [Purpose] We sought to examine the relationship between lifestyle behavior and physical fitness in middle-aged and elderly laborers. [Subjects] In total, 2,469 male laborers between 45 and 64 years of age residing in eight cities in South Korea were studied between January and December 2007. [Methods] Age, height, and weight were evaluated as general characteristics. Lifestyle behavior items included exercise, dietary habits, smoking, drinking, and sleeping hours. Physical fitness was assessed by measuring muscle strength, muscle endurance, flexibility, reflexes, and agility. [Results] In terms of physical fitness status, all items except handgrip strength showed significant changes according to exercise frequency. Dietary habits were associated with significant differences in the Sargent jump and whole-body reaction time between groups. Smoking and drinking were associated with significant differences in sit-ups between subgroups. Sleeping hours demonstrated significant differences in the Sargent jump and whole-body reaction time between groups. [Conclusion] Although there were differences according to physical fitness status, exercise frequency, dietary habits, smoking, drinking, and sleeping hours showed significant associations with physical fitness. Thus, healthy lifestyle behaviors, such as regular exercise, regular dietary habits, not smoking, moderate drinking, and adequate sleep, are important for physical fitness management and work capacity improvement in middle-aged and elderly laborers. PMID- 25540510 TI - Assessment of the validity and internal consistency of a performance evaluation tool based on the Japanese version of the modified barthel index for elderly people living at home. AB - [Purpose] This study aimed to examine the validity and internal consistency of the Japanese version of a performance evaluation tool for activities of daily living (ADL) based on the modified Barthel Index (PET-MBI) among elderly people at home. [Subjects] The subjects were elderly people living at home in Japan. [Methods] A cross-sectional study was performed at five home care facilities for elderly people in Japan. ADL performance was evaluated for 128 participants using the PET-MBI, which included 10 self-care items. We used confirmatory factor analysis to estimate the factorial validity. We assessed data model fitness with the chi(2) statistic, the Goodness of Fit Index (GFI), Adjusted Goodness of Fit Index (AGFI), and Root Mean Square Error of Approximation (RMSEA). Cronbach's alpha coefficient was used to determine the internal consistency. [Results] The mean age of the participants was 79.1+/-8.9 years. Among the 126 participants included in the analysis, 67 were women (53.2%). The single-factor model demonstrated a fair fit to the data, with the chi(2) statistic = 74.9 (df =35), GFI = 0.88, AGFI = 0.81, and RMSEA = 0.096, and the path coefficients of each item ranged from 0.44 to 0.95. The alpha coefficient of the 10-item scale was 0.93. [Conclusion] The PET-MBI for elderly people at home was well validated. PMID- 25540511 TI - Phosphorylation of Heat Shock Protein 27 is Increased by Cast Immobilization and by Serum-free Starvation in Skeletal Muscles. AB - [Purpose] Cast immobilization- and cell starvation-induced loss of muscle mass are closely associated with a dramatic reduction in the structural muscle proteins. Heat shock proteins are molecular chaperones that are constitutively expressed in several eukaryotic cells and have been shown to protect against various stressors. However, the changes in the phosphorylation of atrophy-related heat shock protein 27 (HSP27) are still poorly understood in skeletal muscles. In this study, we examine whether or not phosphorylation of HSP27 is changed in the skeletal muscles after cast immobilization and serum-free starvation with low glucose in a time-dependent manner. [Methods] We undertook a HSP27 expression and high-resolution differential proteomic analysis in skeletal muscles. Furthermore, we used western blotting to examine protein expression and phosphorylation of HSP27 in atrophied gastrocnemius muscle strips and L6 myoblasts. [Results] Cast immobilization and starvation significantly upregulated the phosphorylation of HSP27 in a time-dependent manner, respectively. [Conclusion] Our results suggest that cast immobilization- and serum-free starvation-induced atrophy may be in part related to changes in the phosphorylation of HSP27 in rat skeletal muscles. PMID- 25540512 TI - Self-reported Exhaustion is Associated with Small Life Space in Older Adults with Mild Cognitive Impairment. AB - [Purpose] Older adults experience exhaustion-induced health problems, such as poor physical function and low physical activity levels. The associations between self-reported exhaustion and physical function and activity are not clear in older adults with mild cognitive impairment (MCI). The aim of this study was to investigate the relationships between self-reported exhaustion and physical function and activity in older adults with mild cognitive impairment. [Subjects] A total of 356 older adults with mild cognitive impairment (mean age = 71.6 +/- 0.3 years, 50.8% women) were included in this study. [Methods] Self-reported exhaustion was identified by one item from the Study of Osteoporotic Fractures index. Gait speed, gait endurance, and life space were also assessed. [Results] Sixty-two participants reported having exhaustion, giving a 17.4% prevalence of self-reported exhaustion among these individuals. Logistic regression analysis showed that the Life-Space Assessment score was the only parameter significantly independently associated with exhaustion status (adjusted odds ratio 0.97, 95% confidence interval 0.95-0.99). [Conclusion] These results suggest that self reported exhaustion is associated with life space. Future research is needed to identify ways for older people with MCI to improve their exhaustion status. PMID- 25540513 TI - The influence of lumbar joint mobilization on joint position sense in normal adults. AB - [Purpose] The purpose of this study was to determine the effects of lumbar joint mobilization on the joint position sense (JPS) of normal adults. [Subjects] A total of 30 normal adults were divided into an experimental group (n = 15) and a control group (n = 15). [Methods] The experimental group received lumbar joint mobilization and massage, and the control group received massage only. Both the experimental and control groups were evaluated for joint position error (JPE) by using a digital dual inclinometer before and after the experiment. [Results] In the before and after comparison for the experimental group, statistically significant differences were found in flexion, extension, left lateral flexion, and right lateral flexion. There was no statistically significant difference in the before and after comparison for the control group. [Conclusion] Because lumbar joint mobilization can reduce JPE and improve JPS, its use in the treatment of patients with lumbar problems is recommended. PMID- 25540514 TI - Relationship between Postural Sway and Dynamic Balance in Stroke Patients. AB - [Purpose] The purpose of the current study was to investigate the relationship between postural sway and dynamic balance in post stroke patients. [Subjects] Thirty-one stroke patients (20 men and 11 women; age 64.25 years; stroke duration 12.70 months; MMSE-K score 26.35) participated in this study. [Methods] This study applied a cross-sectional design. A Good Balance system was used for measurement of the postural sway velocity (anteroposterior and mediolateral) and velocity moment of subjects under the eyes open and eyes closed conditions in a standing posture. The postural sway of subjects was measured under two surface conditions (stable and unstable surfaces). [Results] On the unstable surface (foam), no significant correlation was observed between postural sway and dynamic balance except for the berg balance scale (BBS) score and anteroposterior postural sway velocity under the eyes open condition, anteroposterior postural sway velocity under the eyes closed condition, and postural sway velocity moment. In addition, in the stable condition, no significant correlation was observed between postural sway and dynamic balance. [Conclusion] Our results indicate that a decrease in postural sway does not necessarily reflect improvement of dynamic balance ability. We believe that this finding may be useful in balance rehabilitation for prevention of falls after a stroke. PMID- 25540516 TI - Effect of the Intrinsic Foot Muscle Exercise Combined with Interphalangeal Flexion Exercise on Metatarsalgia with Morton's Toe. AB - [Purpose] This study examined the effects of the intrinsic foot muscle exercise combined with interphalangeal flexion exercise on metatarsalgia with Morton's toe. [Subject] A 38-year-old male with Morton's toe, who complained of pain in his left metatarsophalangeal joints was the subject. [Methods] The pressure pain threshold, peak contact pressure of the metatarsophalangeal region during gait, and the navicular drop were measured before and after the intrinsic foot muscles exercises combined with interphalangeal flexion exercise. [Results] After exercising for 2 weeks, the pressure pain threshold increased from 1 to 1.5 kg, while the peak contact pressure decreased from 0.63 to 0.50 kg/cm(2), and the navicular drop improved from 5 to 8 mm. [Conclusion] The results show that the combined exercises alleviated the pain while walking by reducing the excessive pressure on the metatarsophalangeal region, and the improvement of gait with Morton's toe. PMID- 25540515 TI - Effect of lumbar stabilization exercises on the balance ability of patients with stroke: a systematic review. AB - [Purpose] This study performed a systematic literature review of the ability of lumbar stabilization exercises (LSE) to improve the balance ability of stroke patients. [Subjects and Methods] A systematic review was conducted of four databases. The papers retrieved were evaluated based on the following inclusion criteria: 1) design, a controlled clinical trial; 2) intervention, LSE; 3) outcome, change in balance ability; and 4) year of publication, 2000 to 2013. [Results] The findings of 6 papers were compared to determine the effects of lumbar stabilization exercises on stroke patients' balance abilities. The papers had methodological quality scores of 5-8 on the PEDro scale. [Conclusion] Lumbar stabilization exercises have a positive influence on stroke patients' balance abilities. PMID- 25540517 TI - Effects of cervical deep muscle strengthening in a neck pain: a patient with klippel-feil syndrome. AB - [Purpose] This study aimed to identify the effects of cervical deep muscle strengthening (CDS) on neck pain in a patient with Klippel-Feil syndrome (KFS). [Subjects and Methods] The subjects was a 39 year-old woman with neck pain and KFS that included incomplete block vertebrae in the C2-3 segments and block vertebrae in the C6-7 segments. The subject performed an exercise program including cervical strengthening exercise (level 1) and CDS exercise (level 2) for 6 weeks. Neck pain intensity was measured using the visual analogue scale (VAS) and the pressure pain threshold (PPT). All measurements were obtained before and after the CDS exercise program. [Results] The VAS and PPT measurements decreased; range of motion in the cervical joint increased. [Conclusion] CDS exercises were effective interventions for reducing neck pain in a patient with Klippel-Feil syndrome. PMID- 25540518 TI - Effects of yogic exercises on life stress and blood glucose levels in nursing students. AB - [Purpose] This study was performed to investigate the effects of yogic exercises on life stress and blood glucose levels in nursing students. [Subjects and Methods] The study was a randomized controlled trial. Twenty-seven undergraduate nursing students were randomly selected, with 12 assigned to an exercise group and 15 assigned to a control group. The yogic exercises intervention was undertaken for 60 minutes one day a week for 12 weeks. It consisted of physical exercise (surya namaskara) combined with relaxation and meditation (shavasana and yoga nidra). Life stress was measured by the Life Stress Scale for College Students, and postprandial blood glucose levels were measured with a digital glucometer. [Results] The exercise group measurements were significantly decreased in both life stress and postprandial blood glucose levels compared with the control group. [Conclusion] These findings indicate that yogic exercises would reduce life stress and lower postprandial blood glucose levels in nursing students. PMID- 25540519 TI - The effects of a complex exercise program with the visual block on the walking and balance abilities of elderly people. AB - [Purpose] The purpose of this study was to investigate the effect of a complex exercise program for elderly people who had experienced a fall on their balance, gait, vestibular senses, and proprioceptive senses when their visual sense was blocked. [Subjects and Methods] The subjects were 30 healthy elderly people aged 65 or older. They were equally and randomly divided into a visual block (VB) group (those whose eyes were covered) and a visual permission (VP) group. The subjects performed the complex exercise program for 30 minutes, twice a day, five day a week for 4 weeks a total of 20 times. Outcome measures were the10 meter walking test (10MWT), stair up/down test (SUDT), Berg balance scale (BBS), vestibular stepping test (VST), proprioception test (PT). [Results] After the intervention, the VB group showed improvements in 10MWT, VST, and PT. The VP group showed improvements in 10MWT and PT. The significant improvement in VST observed in the VB group was significantly greater than that in the VP group. [Conclusion] The complex exercise program for elderly people helped enhance their balance ability and gait, and improved their vestibular sense. PMID- 25540520 TI - From the Editor's desk. PMID- 25540521 TI - Hemodynamic effects of dexmedetomidine during intra-operative electrocorticography for epilepsy surgery. PMID- 25540522 TI - Isolated nuclear III nerve paresis secondary to neurocysticercosis showing spontaneous clinical improvement. PMID- 25540523 TI - Commentary. PMID- 25540524 TI - Commentary. PMID- 25540525 TI - Kleptomania: Beyond serotonin. PMID- 25540526 TI - Reposing the herniated spinal nerves following accidental iatrogenic dural tear in spine surgery-The "no touch hip flexion technique". PMID- 25540527 TI - Comment on dreaded complications of mistaken identity: Hygroma versus effusion following decompressive craniotomy. PMID- 25540529 TI - Commentary. PMID- 25540528 TI - Opsoclonus - Myoclonus syndrome induced by phenytoin intoxication. PMID- 25540530 TI - Melkersson-Rosenthal syndrome. PMID- 25540531 TI - Neurogenic bladder following myelopathies: Has it any correlation with neurological and functional recovery? AB - OBJECTIVES: To observe neurogenic bladder pattern in patients with myelopathy by performing urodynamic study (UDS) and to observe whether it has any correlation with functional and neurological recovery. PATIENTS AND METHODS: This prospective study was conducted with 90 patients with myelopathy, both traumatic and non traumatic (males = 65) in a university tertiary research hospital in India between January 2011 and December 2013. Mean age was 33.5 +/- 13.2 years (range 15-65 years), mean duration of injury was 82.63 +/- 88.3 days (range 14-365 days) and mean length of stay (LOS) in the rehabilitation unit 42.5 +/- 23.3 days (range 14-130 days). The urodynamic study was performed in all the patients to assess the neurogenic bladder pattern. Management was based on the UDS findings. Functional recovery was assessed using Barthel index (BI) scores and spinal cord independence measures (SCIM) scores. Neurological recovery was assessed using ASIA impairment scale (AIS). We tried to correlate neurogenic bladder patterns with recovery. RESULTS: Fifty patients (55.6%) had overactive detrusor with 25 each had detrusor sphincter dyssynergia (DSD) and synergic sphincter. Thirty eight patients had hypoactive/acontractile detrusor and two had normal studies. No significant correlation observed between neurogenic bladder pattern and change in BI scores (P = 0.696), SCIM scores (P = 0.135) or change in ASIA status (P = 0.841) in the study. CONCLUSIONS: More than half of the patients with myelopathies had overactive detrusor with or without dyssynergic sphincter according to the urodynamic study. Neurogenic bladder patterns had no significant correlation with functional and neurological recovery in these patients. PMID- 25540532 TI - Hemodynamic effects of dexmedetomidine during intra-operative electrocorticography for epilepsy surgery. AB - BACKGROUND: Dexmedetomidine, a predominant alpha-2-adrenergic agonist has been used in anesthetic practice to provide good sedation. The drug is being recently used in neuroanesthesia during awake surgery for brain tumors and in functional neurosurgery. MATERIALS AND METHODS: This prospective study analyzed the hemodynamic effects of dexmedetomidine infusion during electrocorticography in patients undergoing surgery for mesial temporal sclerosis. Dexmedetomidine infusion was administered during intra-operative electrocorticography recording, 15 minutes after the end tidal MAC of N2O and isoflurane were decreased to zero. Anesthesia was maintained with O2 : air mixture = 50:50, vecuronium and fentanyl. Heart rate (HR), mean arterial pressure (MAP) and end tidal carbon dioxide (ETCO2) were recorded across at induction, 2 min prior to dexmedetomidine (PreDEX), 5 min during dexmedetomidine infusion (DEX; 1 MUg/kg), 5 min after stopping dexmedetomidine and 10 minutes after stopping dexmedetomidine. RESULTS: Forty patients with mesial temporal sclerosis (M: F = 27:13, mean age = 28.15 +/- 10.9 years; duration of epilepsy = 12.0 +/- 7.9 years) underwent anterior temporal lobe resection with amygdalohippocampectomy for drug-resistant epilepsy. Infusion of dexmedetomidine caused a transient fall in HR in 87.5% of patients and an increase in MAP in 62.5% of patients, which showed a tendency to revert back towards PreDEX values within 10 min after stopping the infusion. Sixty-five percent of the patients showed <=25% reduction and 10% of them showed >25% reduction in HR. 47.5% of the patients showed <=25% increase and 15% of them showed >25% increase in MAP. These changes were over a narrow range and within physiological limits. CONCLUSION: The infusion of dexmedetomidine for a short period causes reduction of HR and increase in MAP in patients, however the variations are within acceptable range. PMID- 25540533 TI - Correlation between plasma total nitric oxide levels and cerebral vasospasm and clinical outcome in patients with aneurysmal subarachnoid hemorrhage in Indian population. AB - CONTEXT: Cerebral vasospasm remains a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Reduced bioavailability of nitric oxide has been associated with the development of cerebral vasospasm after aSAH. Such data is not available in Indian population. AIMS: The objective of the study was to measure the plasma total nitric oxide (nitrite and nitrate-NO x ) level in aSAH patients and healthy controls treated at a tertiary hospital in India and to investigate a possible association between plasma total nitric oxide level and cerebral vasospasm and clinical outcome following treatment in patients with aSAH. SETTINGS AND DESIGN: A case-control study of aSAH patients was conducted. Plasma total NO x levels were estimated in aSAH patients with and without vasospasm and compared the results with NO x levels in healthy individuals. MATERIALS AND METHODS: aSAH in patients was diagnosed on the basis of clinical and neuro-imaging findings. Plasma total NO x levels in different subject groups were determined by Griess assay. RESULTS: Plasma total NO x level was found to be significantly decreased in patients with aSAH when compared to controls. Plasma total NO x level in the poor-grade SAH group was lower than that in the good-grade SAH group. Plasma total NO x level further reduced in patients with angiographic (P < 0.05) and clinical vasospasm. CONCLUSIONS: Reduced plasma NO x level is seen in aSAH patients as compared to normal individuals. In aSAH patients reduced levels are associated with increased incidence of cerebral vasospasm and poor outcome. Plasma total NO x level could be used as a candidate biomarker for predicting vasospasm and outcome for this pathology. PMID- 25540534 TI - Leprosy elimination: A myth busted. AB - BACKGROUND: Leprosy is mainly a chronic infectious disease caused by Mycobacterium leprae. The disease mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract and eyes. Though the target of leprosy elimination was achieved at national level in 2006 even then a large proportion of leprosy cases reported globally still constitute from India. AIM AND OBJECTIVE: To study the clinico-epidemiological profile of new cases of leprosy in a rural tertiary hospital. MATERIALS AND METHODS: Thirty-five newly diagnosed cases of leprosy presented in out-patient/admitted in the department of Dermatology, Venereology and Leprosy (between September 2012 and August 2013) were included in the study. Detailed history regarding leprosy, deformity, sensory loss, skin smear for AFB and histopathological examination were done in every patient. RESULTS: The incidence was more in age group of 20 to 39 years (48.57%) and 40 to 59 years (37.14%). 68.57% were males. 48.57% cases were found to have facial deformity and ear lobe thickening was found to be pre-dominant form of facial deformity. Ulnar (88.87%) and common peroneal nerve (34.28%) were the most commonly involved nerves. The split skin smear examination was found to be positive in 27 out of 35 cases. On histopathological examination 10 patients (28.57%) were of lepromatous pole (LL), 4 (11.43%) were of indeterminate, 6 (17.14%) were of tuberculoid type (TT), 4 BT (11.4%) and 1 BL type (2.8%). CONCLUSIONS: This study helps in concluding that leprosy is still not eliminated. Active surveillance is still needed to detect the sub-clinical cases and undiagnosed cases. PMID- 25540535 TI - Leprosy: Education as first priority. PMID- 25540536 TI - Pre-hospital care among victims of road traffic accident in a rural area of Tamil Nadu: A cross-sectional descriptive study. AB - BACKGROUND: The World Health Organization has estimated that globally almost 1.24 million people die annually on the world's roads. The aim of the study was to assess the attributes of pre-hospital care in road traffic accidents (RTAs) victim brought to the health care establishment and to evaluate the pre-hospital trauma care provided in the rural areas of Kancheepuram district of Tamil Nadu. MATERIALS AND METHODS: A cross-sectional descriptive study of 3 months duration (June 2014 to August 2014) was conducted in the Shri Sathya Sai Medical College and Research Institute, Kancheepuram. The method of sampling was universal sampling and all RTA victims satisfying the inclusion criteria were included in the study. During the entire study duration, total 200 RTA victims were included. A pre-tested semi-structured questionnaire was used to elicit the desired information after the victims of RTAs are stabilized. Ethical clearance was obtained from the Institutional Ethics Committee prior to the start of the study. Written informed consent was obtained from the study participants (patient/guardian of children) before obtaining any information from them. Data entry and statistical analysis were done using SPSS version 18. Frequency distributions and percentages were computed for all the variables. RESULTS: Majority of the RTA victims 158 (79%) were from the age-group of 15-45 years. Most of the accidents were reported in night time [77 (38.5%)], on week-ends [113 (56.5%)], and involved two-wheelers [153 (76.5%)]. Almost 66 (33%) of the victims were not aware of the existence of emergency ambulance services. Also, only 15 (7.5%) victims were brought to the hospital in the emergency ambulance, of which only 3 victims were accompanied by a doctor. CONCLUSION: To conclude, the study indicates that a significant proportion of people were unaware about the emergency trauma ambulance services and the existing pre-hospital care services lack in multiple dimensions in a rural area of South India. PMID- 25540537 TI - Study of psychiatric comorbidity in patients with headache using a short structured clinical interview in a rural neurology clinic in Western India. AB - BACKGROUND: Psychiatric disorders are common in patients attending neurology clinics with headache. Evaluation of psychiatric comorbidity in patients with headache is often missed in the busy neurology clinics. AIMS: To assess the prevalence of Axis-I DSM-IV psychiatric disorders in patients with primary headache disorders in a rural-based tertiary neurology clinic in Western India. SETTINGS AND DESIGN: : A cross-sectional observation survey was conducting assessing all patients with migraine, tension-type headache and chronic daily headache attending the Neurology Clinic of Shree Krishna Hospital, a rural medical teaching hospital in Karamsad, in Gujarat in Western India. MATERIALS AND METHODS: A total of 101 consecutive consenting adults with headache were interviewed using Mini International Neuropsychiatric Interview (M.I.N.I.), a structured diagnostic clinical interview to assess prevalence of Axis-I DSM-IV psychiatric disorders. STATISTICAL ANALYSIS: Descriptive statistics were calculated using SPSS software version 16 and a binomial regression model was used to study the relationship of psychiatric co-morbidity with patient-related factors. RESULTS: 49 out of 101 (48.5%) patients with headache suffered from depressive disorders (dysthymia or depression or suicidality), 18 out of 101 patients with headache (17.90%) suffered from anxiety related disorders (generalized anxiety disorder or agoraphobia or social phobia or panic disorder). CONCLUSIONS: Axis-I psychiatric disorders are a significant comorbidity among patients with headache disorders. M.I.N.I. can be used as a short, less time consuming instrument to assess all patients with headache disorders. PMID- 25540538 TI - A study of Guillain-Barre syndrome with reference to cranial neuropathy and its prognostic implication. AB - BACKGROUND: Focused studies on cranial neuropathy in Guillain-Barre syndrome (GBS) and its prognostic implication are not done previously. AIM: To study the clinical profile of GBS patients with special reference to cranial neuropathy and its prognostic implication. MATERIALS AND METHODS: The study included 61 patients with GB syndrome, fulfilling Asbury Cornblath's criteria for GB syndrome. A pre designed semi-structured questionnaire was used to obtain data regarding demographic profile and clinical profile. All patients underwent detailed neurological examination, investigations including nerve conduction studies and CSF examination and treated according to the severity of the illness. Patients were followed up for 6 months. During analysis two groups were made depending on cranial nerve involvement, and compared with respect to various parameters. RESULTS: Out of 61 patients 38 (62.3%) patients had cranial nerve palsies, in that 25 had multiple cranial nerve palsies, and 13 had single isolated nerve palsy. A majority of 30 (49.2%) had bulbar palsy, 28 (46%) had facial nerve palsy, and all had bilateral involvement except 3 patients who had unilateral palsy. Hypoglossal nerve involvement was seen in six (10%) patients and four (6.5%) patients had ophthalmoplegia. Only one had bilateral vestibulocochlear nerve palsy. On comparing various clinico-electrophysiological parameters among patients of GB syndrome with and without cranial nerve involvement, the presence of respiratory paralysis, IVIg and ventilatory support requirement had significant association with cranial nerve involvement in GBS. CONCLUSION: Our study found a correlation between cranial nerve palsies and severity of the illness. Cranial nerve innervated muscles recover earlier as compared to distal limb muscles. No association was found between outcome at 6 months and cranial nerve involvement. PMID- 25540539 TI - Demography, types, outcome and relationship of surgically treated intracranial suppuration complicating chronic suppurative otitis media and bacterial rhinosinusitis. AB - INTRODUCTION: Surgically treated intracranial suppurations (ICS) are uncommon, life-threatening neurosurgical emergencies. They can result from complication of chronic suppurative otitis media (CSOM) and bacterial rhinosinusitis (BRS). The objective of this study was to know the frequency of BRS and CSOM and relate it to its rare complication of surgically treated ICS while also describing the demography, type and outcome of ICS that resulted from BRS and CSOM. MATERIALS AND METHODS: All patients that presented to the Otorhinolaryngological department and Neurosurgical unit of the same institution with clinical and radiological features of CSOM, BRS, and ICS were prospectively studied over a 5-year period. Patients were followed up for a minimum of 3 months. RESULTS: Two thousand, two hundred and seventy-nine patients presented during the 5-year study period. Of all these patients, 1511 had CSOM (66.3%) and 768 (33.7%) presented with features of BRS. Eleven (0.73%) had ICS complicating their CSOM while 8 (1.04%) cases of surgically treated ICS followed BRS. Bacterial rhinosinusitis was not more likely to lead to ICS (P = 0.4348). The Odds ratio (OR) of a child <= 18 years of age with CSOM developing ICS was 5.24 (95% Confidence interval 1.13-24.34; P = 0.0345), while it was 7.60 (95% Confidence interval 1.52-37.97; P = 0.0134) for children with BRS. CONCLUSIONS: The most common type of ICS complicating CSOM and BRS was brain abscess and subdural empyema, respectively. Children are more prone to develop surgical ICS following CSOM and BRS. The proportion of males that had ICS was higher in both CSOM and BRS patients. Optimal outcome is achieved in patients that presented with GCS of 13 and above. PMID- 25540540 TI - Incorporating patients' perceptions of their health into clinical decision-making processes. PMID- 25540541 TI - Baclofen in the short-term maintenance treatment of benzodiazepine dependence. AB - Benzodiazepine (BZD) dependence is a significant public health problem. Apart from the long-term tapering doses of BZD, no others drugs are available for the maintenance treatment of BZD dependence. Baclofen has been used in alcohol and other drug dependence as long-term anti-craving agent. Since alcohol and BZD act through the GABA receptor, we attempted to study the effect of Baclofen as maintenance treatment in a series of five cases with BZD dependence. PMID- 25540542 TI - Trichophagia along with trichobezoar in the absence of trichotillomania. AB - Trichobezoars are rarely described in the absence of trichotillomania. In this report we present a case of trichobezoar associated with trichophagia in the absence of trichotillomania. A 16-year-old girl presented to surgery outpatient with complaints of pain in abdomen and vomiting for the last 6 months. Physical examination revealed a 14 * 16 cm firm, tender, mass with smooth surface, irregular margins, which was mobile with respiration. Ultrasound abdomen revealed a bizarre lesion in the right upper and middle abdomen suggestive of gastric bezoars. Upper gastrointestinal endoscopy did not reveal any abnormality in the esophagus and showed a large mobile mass in the stomach. In view of trichobezoar, psychiatry consultation was sought. Exploration of history revealed that the patient was eating hairs and clay since early childhood. As per patient she would eat hairs thrown by others. She would like the taste of hair and had strong persistent desire to eat hair and would go out searching for the same. At times she would also eat clay. However, she denied of pulling her own hairs. Physical examination of scalp and other body parts did not show any evidence of alopecia or pulling of hair/short hair. She was managed surgically and was counseled about the consequences of eating hairs and clays and was encouraged not to eat hair. To conclude our case suggests that patients can have trichobezoar and trichophagia even in the absence of trichotillomania. PMID- 25540543 TI - Commentary. PMID- 25540544 TI - Cotard's syndrome: Two case reports and a brief review of literature. AB - Cotard's syndrome is a rare neuropsychiatric condition in which the patient denies existence of one's own body to the extent of delusions of immortality. One of the consequences of Cotard's syndrome is self-starvation because of negation of existence of self. Although Cotard's syndrome has been reported to be associated with various organic conditions and other forms of psychopathology, it is less often reported to be seen in patients with catatonia. In this report we present two cases of Cotard's syndrome, both of whom had associated self starvation and nutritional deficiencies and one of whom had associated catatonia. PMID- 25540545 TI - Penetrating brain injury with machete, stuck to calvarium: Hurdles in imaging and solutions. AB - Penetrating brain injury is a less common form of traumatic brain injury in civilian set up, with a higher mortality and morbidity. A detailed preoperative imaging is warranted to ascertain the extent of injury and involvement of neurovascular structures. We present a rare case of penetrating brain injury with a long machete, who underwent emergency craniotomy, removal of the weapon, debridement and evacuation of the brain contusion and dural repair. Due to the sheer size of the weapon stuck to the calvarium, only X-rays could be performed preoperatively. The difficulties posed by the case, requiring modifications in standard imaging, possible solutions to address the problem and individualized management techniques are discussed in this report. PMID- 25540546 TI - Isolated intramedullary spinal cord cysticercosis. AB - Neurocysticercosis is a major cause of epilepsy in developing countries. Cysticercal involvement of the spinal cord is rare even in endemic areas and accounts for 0.7 to 5.85% of all cases. We present a 19-year-old man who presented with weakness of both lower limbs and urinary complaints in the form of straining of micturition with increased frequency, in whom preoperative MRI revealed a well-defined cystic lesion in dorso-lumber cord extending from D11 to L1 level, which on pathological examination was found to be intramedullary cysticercosis. PMID- 25540547 TI - Commentary. PMID- 25540548 TI - The sociodemographic, clinical and pharmacotherapy characteristics influencing quality of life in patients with epilepsy: A cross-sectional study. AB - CONTEXT: Quality of life (QOL) assessment in patients with epilepsy (PWE) is increasingly recognized as an important component in the management of epilepsy. AIMS: The objective of the present study was to assess influence of sociodemographic, clinical and pharmacotherapy characteristics collectively on QOL in adult PWE. SETTINGS AND DESIGN: This was a cross-sectional, observational study in patients with confirmed diagnosis of epilepsy. MATERIALS AND METHODS: QOL was assessed using modified QOLIE-10 questionnaire for epilepsy. Univariate and multiple regression analysis were done to determine factors associated with poor QOL, respectively. RESULTS: There were 451 PWE, with a mean age 27.3 +/- 8.15 years, 251 (56%) males and 191 (42%) had monthly income < 5000 Indian national rupees (INR)/month. The QOLIE score was 64.1 +/- 15.97 (Mean +/- SD). The univariate analysis showed factors such as lower monthly income, focal epilepsy, seizure frequency, antiepileptic drug (AED) polytherapy, conventional AEDs and frequent adverse drug reactions (ADRs) had significant negative influence on various domains of QOLIE-10 questionnaire. Multiple regression analysis showed seizure frequency as a significant predictor of most QOL domains and overall score, while ADRs as a significant predictor of all the domains. Seizure type was a predictive factor for domains like emotional well-being and overall score. CONCLUSION: Present findings showed patients on monotherapy had better QOL while those having lower monthly income, having focal epilepsy and who received conventional AEDs had negative influence on QOL scores. Further, higher seizure frequency and occurrence of ADRs were significant predictors of all the domains of QOL in PWE. PMID- 25540549 TI - Extensive heterotopic ossification in patient with tubercular meningitis. AB - Tubercular meningitis is a severe form of central nervous system tuberculosis with high morbidity and mortality. Apart from neurological deficits, musculoskeletal involvement is also seen in very few cases in the form of heterotopic ossification around immobile joints. A 35-year-old male case of tubercular meningitis with left hemiparesis presented with multiple joint restriction of range of motion. On clinical examination, palpable firm masses around multiple joints with painful restriction of movements were seen. X-ray films of multiple joints revealed heterotopic ossification over left shoulder, hip and knee joint with bony ankylosis of left hip and soft tissue contractures. Very few reports have been published in the literature for association of heterotopic ossification with tubercular meningitis with such extensive joint involvement which compels us to report this clinical association of tubercular meningitis. This report is intended to create caution among physicians and other caregivers for this debilitating complication of tubercular meningitis and in face of high prevalence of tuberculosis and tubercular meningitis, employ methods to prevent and treat. PMID- 25540550 TI - Cerebellar ataxia in a young patient: A rare path to lupus. AB - Cerebellar ataxia is a rare manifestation of neuropsychiatric systemic lupus erythematosus (SLE). Development of vasculitic infarcts in the cerebellum is the most plausible reason of this manifestation. We report the case of a patient who presented with characteristic skin rashes of lupus along with cerebellar signs. Imaging of brain in this patient revealed prominent cerebellar atrophy. She was treated with mycophenolate mofetil and oral corticosteroid, and there was no further progression of her neurological signs after the initiation of therapy. In the clinical context of varied presentations of neurolupus, this is one of the rare sightings and our treatment protocol holds promise as first-line therapy in future. PMID- 25540551 TI - Commentary. PMID- 25540552 TI - Syringomyelia secondary to cervical spondylosis: Case report and review of literature. AB - Syringomyelia secondary to cervical spondylosis is a rare entity to encounter in clinical practice. We discuss the case of a 53-year-old lady who presented with a syringomyelic syndrome and was found to have cervical spondylosis on imaging. Cine-MRI revealed an obstruction of cerebrospinal fluid (CSF) flow in the cervical spinal subarachnoid space. Decompression of the same led to clinical and radiological improvement. There is a potential causal association between cervical spondylosis and syringomyelia. MRI CSF flow studies may help in deciding the course of treatment in such cases. A subset of patients with cervical spondylosis and concurrent spinal cord signal intensity changes may show reversal of the same following intervention. PMID- 25540553 TI - Commentary. PMID- 25540554 TI - Anterior cervical discectomy in a patient with huge thyroid tissue (goiter). AB - Enlarged thyroid gland (goiter) may hinder to reach anterior part of the vertebrae or may impose more retraction than usual. The patient had left arm pain, and his left biceps muscle strength was 3/5 and triceps muscle strength was 4/5. Physical examination of his neck showed no abnormality. We performed anterior cervical discectomy, but we did not reach to the anterior part of the vertebrae due to enlarged thyroid gland even making moderately forceful medial retraction. It is therefore, we performed thyroidectomy previously, and later we performed anterior cervical discectomy at the level of cervical 5-6 and cervical 6-7. It will be wise to excise the goiter and later continue to cervical discectomy rather than using forceful retraction in cases with no preoperative detection as in our case to prevent damage of the recurrent laryngeal nerve and hoarseness due to pressure effect of the medial retraction during the anterior cervical approach. PMID- 25540555 TI - Mania following organophosphate poisoning. AB - Organophosphate poisoning is the most common poisoning in developing countries. Although the acute muscarinic and nicotinic side-effects of organophosphate poisoning are well known and easily recognized, but neuropsychiatric changes are rarely reported. We are reporting a case of a 33-year-old female who developed manic episode following acute organophosphate poisoning. PMID- 25540556 TI - Commentary. PMID- 25540557 TI - Disseminated neurocysticercosis presenting as isolated acute monocular painless vision loss. AB - Neurocysticercosis, the most common parasitic infection of the nervous system, is known to affect the brain, eyes, muscular tissues and subcutaneous tissues. However, it is very rare for patients with ocular cysts to have concomitant cerebral cysts. Also, the dominant clinical manifestation of patients with cerebral cysts is either seizures or headache. We report a patient who presented with acute monocular painless vision loss due to intraocular submacular cysticercosis, who on investigation had multiple cerebral parenchymal cysticercal cysts, but never had any seizures. Although such a vision loss after initiation of antiparasitic treatment has been mentioned previously, acute monocular vision loss as the presenting feature of ocular cysticercosis is rare. We present a brief review of literature along with this case report. PMID- 25540558 TI - Commentary. PMID- 25540559 TI - Commentary. PMID- 25540560 TI - A case of communicating rami between the median and musculocutaneous nerves passing through the substance of an accessory head of biceps brachii. PMID- 25540561 TI - An innovative low-cost head-rest for anesthesia in prone position. PMID- 25540562 TI - The butterfly pattern in a patient with chromosome 7 deletion. PMID- 25540563 TI - Third ventricular cavernoma: Report of two cases. PMID- 25540564 TI - Postmenopausal endometriosis: An enigma revisited. PMID- 25540565 TI - Fertility preservation in young patients' with cancer. AB - Preservation of fertility is an important issue in the management of young cancer patients. Though embryo cryostorage is a well-established procedure, it can only be availed by couples. Recent studies have indicated increasing success rates with mature and immature oocyte cryopreservation. Cryostorage induces injuries on the human oocytes which can be minimized by slow freezing and vitrification. Selection of candiidates is crucial so that the most suitable technique can be offered without any delay in initiation of cancer therapy. Factors affecting suitability are age of patient, assessment of ovarian reserve, hormonal status and type and stage of neoplastic disease. Encouraging results have been obtained with oocyte in vitro maturation (IVM) followed by vitrification for cryostorage. Data on the use of vitrified eggs in routine in vitro fertilization (IVF) show that pregnancy rates can be comparable to those achieved with fresh oocytes. PMID- 25540567 TI - The effect of exercise on quality of life in postmenopausal women referred to the Bone densitometry centers of Iran University of Medical Sciences. AB - BACKGROUND: One of the most critical stages of women's lives is menopause and one of the aims of health for all in the 21st century is the improvement of the quality of life. AIM AND OBJECTIVE: The aim of this study was to determine the effect of exercise on quality of life in postmenopausal women. MATERIALS AND METHODS: This study was designed by a randomized-controlled trial. Eighty volunteer postmenopausal women who experienced the menopause period naturally and have been taking hormone replacement treatment (HRT) were divided into two groups randomly (exercise group n = 40, control group n = 40). The Nottingham Health Profile (NHP) was used to assess quality of life in both groups before and after 8 weeks. The exercise group participated in an exercise program, which was composed of sub-maximal aerobic exercises for an 8-week period 5 times a week. Quality of life in two groups was compared at the end of 8 weeks. RESULTS: The results showed that there was a statistically significant difference in the exercise group for the NHP indicating an improvement in the quality of life (P < 0.05). CONCLUSION: We concluded that quality of life on postmenopausal women could be improved with a regular and controlled exercise program of 8 weeks. Thus, implementing appropriate educational programs to promote the quality of life in postmenopausal women is recommended. PMID- 25540566 TI - Dermatosis associated with menopause. AB - Menopause is defined as permanent irreversible cessation of menses brought by decline in ovarian follicular activity. Hormonal alteration results in various physical, psychological, and sexual changes in menopausal women. Associated dermatological problems can be classified as physiological changes, age-related changes, changes due to estrogen deficiency and due to hormone replacement therapy. Dermatosis seen due to estrogen deficiency includes Atrophic Vulvovaginitis, Vulvar Lichen Sclerosus, Dyaesthetic Vulvodynia, Hirsutism, Alopecia, Menopausal Flushing, Keratoderma Climactericum, Vulvovaginal Candidiasis. Dermatologists and gynecologists need to be familiar with the problems of menopausal women, as with increase in life expectancy, women passing through this phase is rising. PMID- 25540568 TI - Effect of yoga therapy on physical and psychological quality of life of perimenopausal women in selected coastal areas of Karnataka, India. AB - BACKGROUND: Perimenopausal period is characterized by a continuous decline in ovarian function due to which women are vulnerable to various physical and psychological symptoms affecting their quality of life. Currently these symptoms are managed by hormone replacement therapy. However, hormonal therapy can cause complications including malignancy which has resulted in search for various alternative therapies to improve the quality of life (QOL). Yoga is one such alternative therapy shown to enhance the QOL at all stages of human life associated with the chronic illness. There are very few scientific studies regarding the effect of yoga on perimenopause and in this study we investigated the effects of yoga therapy on physical and psychological symptoms using the standardized questionnaire. OBJECTIVE: To study the effect of yoga therapy on physical, psychological, vasomotor and sexual symptoms of perimenopause. MATERIALS AND METHODS: It is a prospective non-randomized control study of 216 perimenopausal women with 12 weeks of intervention. The subjects were divided in two groups with either yoga therapy [n = 111] or exercise [n = 105] as the interventional tool. The symptoms control and QOL before and after intervention in both the groups were assessed by using the menopausal QOL questionnaire. RESULTS: The perimenopausal symptoms in all the four domains were improved by yoga therapy, thus significantly improving the overall QOL compared to the control group. CONCLUSION: This study clearly demonstrates the effectiveness of yoga therapy in managing the distressing perimenopausal symptoms. It is easy, safe, non-expensive alternative therapy helping the well-being of perimenopausal women and must be encouraged in the regular management of perimenopausal symptoms. PMID- 25540569 TI - Pattern of palpable breast lesions on fine needle aspiration: A retrospective analysis of 902 cases. AB - BACKGROUND: Breast lumps constitute a significant proportion of surgical cases in women of both developed and developing countries. The aim of this study is to look the frequency distribution of various breast lesions on fine needle aspiration (FNA). MATERIALS AND METHODS: The 902 patients who presented with palpable breast lump, irrespective of age and sex were included in the study. Frequency distribution of various breast lesions with respect to age and sex was studied. Cytology grading in breast carcinoma was correlated in 69 cases with histology grading. RESULTS: The majority (N = 871) of patients were females with maximum (N = 566) patients between second and third decade. The 773 patients had benign breast lesions and maximum (N = 341) patients were in the second decade. Fibroadenoma was the commonest benign lesion followed by fibrocystic change and mastitis. Out of 119 malignant breast lesions, 31.93% [N = 38] were between 41-50 years of age, 28.57% [N = 34] in 51-60 years and 22.68% [N = 27] in between 31-40 years of age. Out of 119 malignant breast lumps and majority were infiltrating ductal carcinoma (N = 108). Cytology grading correlated maximum with histology grade in Grade I followed by Grade II and Grade III. CONCLUSION: With experienced hands, FNA is safe, cost effective and a reliable technique for preoperative evaluation of palpable breast lumps. FNA features are more informative when combined with physical and radiology findings (Triple test). Fibroadenoma, fibrocystic change and mastitis form the major bulk of benign breast lesions. Epithelioid cells when seen in inflammatory breast FNA smears, tuberculosis must be ruled out. In India, breast carcinoma arises in younger patients as compared to western countries. Grading of breast carcinomas must be done on FNA smears for selecting neoadjuvent therapy. Clinical breast examination and mammography screening in females should be encouraged in developing countries from the third decade onwards for early detection of breast carcinoma. PMID- 25540570 TI - Sarcoma-like mural nodule in a borderline mucinous tumor of the ovary: A rare entity. AB - Sarcoma-like mural nodule (SLMN) is a very uncommon and misleading benign entity which may be associated with benign, borderline or malignant mucinous neoplasm of the ovary. It should be distinguished from other malignant mural nodules with sarcoma, carcinosarcoma or anaplastic carcinoma for proper management. We report a rare case of SLMN in a borderline mucinous tumor of the ovary in a 30-year-old lady. In spite of having confusing histopathological features the final diagnosis was made depending on the younger age of the patient, well circumscription of the nodule, absence of vascular invasion and immunohistochemical profile. PMID- 25540571 TI - Squamous cell carcinoma arising in mature cystic teratoma of ovary. AB - Squamous cell carcinoma of the ovary is a rare condition and usually arises in mature cystic teratoma (MCT) or dermoid cyst of the ovary. The reported incidence of malignant transformation in MCT is approximately 2%. A case of squamous cell carcinoma arising in a dermoid cyst of the ovary presenting at an early stage is presented here. A 53-year-old postmenopausal lady, presented with the complaint of pain in right lower abdomen since one month and a large complex abdomino pelvic mass on examination and investigations. Final histopathology was reported as squamous cell carcinoma of left ovary arising from dermoid cyst and a benign dermoid cyst in the right ovary. The patient was assigned to squamous cell carcinoma of the ovary arising in a mature cystic teratoma, surgical stage Ic2. In view of the poor prognosis, adjuvant chemotherapy was started. PMID- 25540572 TI - Sclerosing peritonitis with unilateral ovarian luteinized thecoma in a post menopausal woman: A case report. AB - A unique case of unilateral ovarian luteinized thecoma with sclerosing peritonitis is reported because the association between these two conditions is extremely rare. Etiology is not clearly known. A 50-year-old post-menopausal woman presented with pain abdomen and huge swelling. Pelvic contrast-enhanced computed tomography (CECT) revealed a heterogenous enhancing mass arising possibly from ovary and adherent to uterus, bowl loops, and omentum. A spindle cell neoplasm without definite features of malignancy was reported in computed tomography (CT)-guided fine-needle aspiration cytology (FNAC). Ascitic fluid was negative for malignancy. Her serum carcinoembryonic antigen (CEA) (1.1ng/ml) and CA125 (27.6MU/ml) level was within normal limits. Total abdominal hysterectomy with bilateral supracolic omentectomy, resection of part of colon, and supracolic omentectomy was done. Histopathological diagnosis was luteinized thecoma with sclerosing peritonitis. Tumor cells were immunoreactive to smooth muscle antigen (SMA) and CD 99 and non- reactive to ER, PR, Calretinine, and Cytokeratin. Patient developed post-operative sepsis and enterocutaneous fistula, which was managed conservatively and was kept in follow-up. According to current concept, in spite of its large size, wide-spread involvement, mitotic activity, and complications due to peritoneal involvement, behavior of this rare clinical entity is benign. PMID- 25540573 TI - Uterine leiomyosarcoma: A case report. AB - Uterine leiomyosarcoma is a rare uterine malignancy that arises from the smooth muscles of uterine wall. It accounts for only 1-2% of uterine malignancies. We report a case of a 60-year-old female who presented with postmenopausal bleeding and was diagnosed later to be a case of leiomyosarcoma of uterus. The diagnosis of leiomyosarcoma is made by histopathological examination, and surgery is the only treatment. The prognosis for female with uterine sarcoma primarily depends on the extent of disease at the time of diagnosis and the mitotic index. PMID- 25540574 TI - Geriatric care in India: A long way to go. PMID- 25540575 TI - Induction of bulb organogenesis in in vitro cultures of tarda tulip (Tulipa tarda Stapf.) from seed-derived explants. AB - A protocol for obtaining bulbs via in vitro organogenesis was developed for tarda tulip (Tulipa tarda Stapf). Scale explants were obtained from bulbs formed at the base of seedlings or from adventitious bulbs that developed from callus tissue forming on stolons or on germinating seeds. Some explants were subjected to chilling at 5 degrees C for 12 wk. The culture media contained 3 or 6% sucrose and was supplemented with either no growth regulators, either 0.5 MUM 6-benzyl aminopurine (BAP) or 18.9 or 94.6 MUM abscisic acid (ABA). Cultures were maintained in the dark at 20 degrees C. Callus tissue developed mainly on media without growth regulators or with BAP. Callus was formed from up to 96% of explants derived from non-chilled adventitious bulbs that were treated with 3% sucrose and 0.5 MUM BAP. Less callus was formed from chilled explants compared with non-chilled explants. Newly formed adventitious bulbs appeared on the explants via direct and indirect organogenesis. The media with BAP promoted the formation of adventitious bulbs at a rate of 56-92% from non-chilled explants, whereas a maximum rate of 36% was observed from chilled explants. ABA inhibited the induction of adventitious bulbs and callus. The adventitious bulbs obtained in these experiments contained a meristem, which was evidence that they had developed properly. PMID- 25540576 TI - Scleral gene expression during recovery from myopia compared with expression during myopia development in tree shrew. AB - PURPOSE: During postnatal refractive development, the sclera receives retinally generated signals that regulate its biochemical properties. Hyperopic refractive error causes the retina to produce "GO" signals that, through the direct emmetropization pathway, cause scleral remodeling that increases the axial elongation rate of the eye, reducing the hyperopia. Myopia causes the retina to generate "STOP" signals that produce scleral remodeling, slowing the axial elongation rate and reducing the myopia. Our aim was to compare the pattern of gene expression produced in the sclera by the STOP signals with the GO gene expression signature we described previously. METHODS: The GO gene expression signature was produced by monocular -5 diopter (D) lens wear for 2 days (ML-2) or 4 days (ML-4); an additional "STAY" condition was examined after eyes had fully compensated for a -5 D lens after 11 days of lens wear (ML-11). After 11 days of 5 D lens wear had produced full refractive compensation, gene expression in the STOP condition was examined during recovery (without the lens) for 2 days (REC-2) or 4 days (REC-4). The untreated contralateral eyes served as a control in all groups. Two age-matched normal groups provided a comparison with the treated groups. Quantitative real-time PCR was used to measure mRNA levels for 55 candidate genes. RESULTS: The STAY group compensated fully for the lens (treated eye versus control eye, -5.1+/-0.2 D). Wearing the lens, the hyperopic signal for elongation had dissipated (-0.3+/-0.3 D). In the STOP groups, the refraction in the recovering eyes became less myopic relative to the control eyes (REC-2, +1.3+/-0.3 D; REC-4, +2.6+/-0.4 D). In the STAY group, three genes showed significant downregulation. However, many genes that were significantly altered in GO showed smaller, nonsignificant, expression differences in the same direction in STAY, suggesting the gene expression signature in STAY is a greatly weakened form of the GO signature. In the STOP groups, a different gene expression pattern was observed, characterized by mostly upregulation with larger fold differences after 4 days than after 2 days of recovery. Eleven of the 55 genes examined showed significant bidirectional GO/STOP regulation in the ML-2 and REC-2 groups, and 13 genes showed bidirectional regulation in the ML-4 and REC-4 groups. Eight of these genes (NPR3, CAPNS1, NGEF, TGFB1, CTGF, NOV, TIMP1, and HS6ST1) were bidirectionally regulated at both time points in the GO and STOP conditions. An additional 15 genes showed significant regulation in either GO or STOP conditions but not in both. CONCLUSIONS: Many genes are involved in scleral remodeling and the control of axial length. The STOP (recovery) gene expression signature in the sclera involves some of the same genes, bidirectionally regulated, as the GO signature. However, other genes, regulated in GO, are not differentially regulated in STOP, and others show differential regulation only in STOP. PMID- 25540577 TI - PTBP-dependent PSD-95 and CamKIIalpha alternative splicing in the lens. AB - PURPOSE: Parallels described between neurons and lens fiber cells include detailed similarities in sub-cellular structures that increasingly show shared expression of genes involved in the construction and function of these structures in neurons. Intriguingly, associated modes of molecular regulation of these genes that had been thought to distinguish neurons have been identified in the lens as well. Both elongated cell types form membrane protrusions with similar size, shape, and spacing that exclude microtubules, contain F-actin, and are coated with the clathrin/AP-2 adaptor. Lenses express glutamate and gamma-aminobutyric acid (GABA) receptors with signaling and channel proteins shown to act together at neuronal membranes. Postsynaptic density protein 95 (PSD-95) and Ca(2+)/calmodulin-dependent protein kinase (CaMKIIalpha) expression and functions illustrate the integration of aspects of neuronal molecular and cell biology and were investigated here in the lens. METHODS: Immunofluorescence, immunoblot, and RT-PCR methods were used to assess protein expression and alternative transcript splicing. RESULTS: We showed the essential dendritic spine scaffold protein PSD 95 is expressed in lenses and demonstrated lens PSD-95 transcripts undergo polypyrimidine tract binding protein (PTBP)-dependent alternative splicing of its pivotal exon 18 required to avoid nonsense-mediated decay, and showed PTBP dependent alternative splicing of CaMKIIalpha transcripts in the lens. The PSD-95 protein was observed at fiber cell membranes overlapping with N-methyl-D aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate and GABA receptor proteins, tyrosine phosphatase STEP, CaMKIIalpha, the Ca(V)1.3 calcium channel, and clathrin, which were previously identified at lens fiber cell membranes. During neurogenesis, miR-124 is expressed that suppresses PTBP1 and promotes these splicing events. miR-124 is also expressed in mammalian lenses and upregulated during lens regeneration in amphibians, consistent with previous demonstrations of PTBP1,2 and PTBP-dependent PTBP2 exon 10 splicing in rodent lenses. CONCLUSIONS: Findings of this dendritic spine scaffold protein and conservation of its key mode of molecular regulation in the lens provides further evidence that key aspects of the neuron morphogenetic program are shared with the lens. PMID- 25540578 TI - Optic disc topography in Malay patients with normal-tension glaucoma and primary open-angle glaucoma. AB - BACKGROUND: There are limited data concerning the optic disc topography in normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG) patients living in Southeast Asian countries. This study aims to compare optic disc parameters in patients with NTG and POAG in Malaysia and to discuss the results in comparison with studies of NTG and POAG in other Asian countries. METHODS: This prospective cross-sectional study was performed in two hospitals with glaucoma service in Malaysia from 2010 to 2012. Seventy-seven patients of Malay ethnicity were enrolled in this study, including 32 NTG patients and 45 POAG patients. Using the Heidelberg Retinal Tomograph III, we measured optic disc area, cup area, rim area, cup volume, rim volume, cup-to-disc area ratio, mean cup depth, maximum cup depth, cup shape measure, height variation contour, mean retinal nerve fiber layer thickness, and retinal nerve fiber layer cross-sectional area. RESULTS: The eyes for NTG patients had significantly larger optic disc areas (2.65 [standard deviation, 0.41] vs 2.40 [standard deviation, 0.36] mm(2), respectively; P=0.006) and cup areas (1.54 [standard deviation, 0.43] vs 1.32 [standard deviation, 0.40] mm(2), respectively; P=0.027) compared with the eyes of POAG patients. Comparison of the other parameters between the two groups revealed no significant difference (P>0.050). The moderate and severe NTG patients showed significantly deeper cups and larger disc and cup areas when compared with the moderate and severe POAG patients (P<0.050). CONCLUSION: The NTG patients in this study have notably larger optic disc and cup areas than the POAG patients. Our observations are consistent with those reported in studies of NTG and POAG patients in Korea. The deeper cups and larger disc and cup areas may serve as indicators of severity when comparing NTG with POAG. However, these findings require verification with IOP and visual field results. PMID- 25540579 TI - The impact of timolol maleate on the ocular tolerability of fixed-combination glaucoma therapies. AB - Glaucomatous optic atrophy is the second most common cause of blindness worldwide, and lowering intraocular pressure (IOP) is the only proven method to slow or stop the progression of the disease. Approximately 40% of patients with elevated IOP will require more than one medication to obtain a modest 20% reduction in IOP, and as a result, some patients may require two medications, provided in either two separate bottles or in one bottle with the use of fixed combination therapies. Each therapy has its own unique safety and efficacy profile. Topical beta-blockers have a particularly favorable ocular-tolerability profile, and several studies of fixed-combination medications containing the beta blocker timolol maleate have shown a lower prevalence of some ocular adverse events for the fixed-combination therapy compared to the non-beta-blocker individual component. In this review, we examined clinical data pertaining to the ocular surface tolerability of fixed-combination medications containing timolol maleate in comparison to the individual components. In particular, preference was given to prospective, randomized, multicenter trials of 3 months in duration or longer that compared a fixed-combination therapy to monotherapy with the individual components. A review of the literature revealed that some fixed combination therapies can provide a reduced risk of common side effects compared to their individual components, with conjunctival hyperemia and ocular allergy being less frequent in some timolol-containing fixed-combination therapies. This effect appears to be most significant for latanoprost 0.005%, bimatoprost 0.03%, and brimonidine 0.2%. PMID- 25540580 TI - Resistance exercise with different volumes: blood pressure response and forearm blood flow in the hypertensive elderly. AB - BACKGROUND: The purpose of this study was to evaluate the effect of two sessions of resistance exercise with different volumes on post-exercise hypotension, forearm blood flow, and forearm vascular resistance in hypertensive elderly subjects. METHODS: The study was conducted with ten hypertensive elderly (65+/-3 years, 28.7+/-3 kg/m(2)) subjected to three experimental sessions, ie, a control session, exercise with a set (S1), and exercise with three sets (S3). For each session, the subjects were evaluated before and after intervention. In the pre intervention period, blood pressure, forearm blood flow, and forearm vascular resistance were measured after 10 minutes of rest in the supine position. Thereafter, the subjects were taken to the gym to perform their exercise sessions or remained at rest during the same time period. Both S1 and S3 comprised a set of ten repetitions of ten exercises, with an interval of 90 seconds between exercises. Subsequently, the measurements were again performed at 10, 30, 50, 70, and 90 minutes of recovery (post-intervention) in the supine position. RESULTS: Post-exercise hypotension was greater in S3 than in S1 (systolic blood pressure, 26.5+/-4.2 mmHg versus -17.9+/-4.7 mmHg; diastolic blood pressure, -13.8+/-4.9 mmHg versus -7.7+/-5 mmHg, P<0.05). Similarly, forearm blood flow and forearm vascular resistance changed significantly in both sessions with an increase and decrease, respectively, that was more evident in S3 than in S1 (P<0.05). CONCLUSION: Resistance exercises with higher volume were more effective in causing post-exercise hypotension, being accompanied by an increase in forearm blood flow and a reduction of forearm vascular resistance. PMID- 25540581 TI - Validity of a screening tool for detecting subtle cognitive impairment in the middle-aged and elderly. AB - The present study tested 121 middle-aged and elderly community-dwelling individuals on the computer-based Subtle Cognitive Impairment Test (SCIT) and compared their performance with that on several neuropsychological tests. The SCIT had excellent internal consistency, as demonstrated by a high split-half reliability measure (0.88-0.93). Performance on the SCIT was unaffected by the confounding factors of sex, education level, and mood state. Many participants demonstrated impaired performance on one or more of the neuropsychological tests (Controlled Oral Word Association Task, Rey Auditory and Verbal Learning Task, Grooved Pegboard [GP], Complex Figures). Performance on SCIT subtests correlated significantly with performance on many of the neuropsychological subtests, and the best and worst performing quartiles on the SCIT subtest discriminated between good and poor performers on other subtests, collectively indicating concurrent validity of the SCIT. Principal components analysis indicated that SCIT performance does not cluster with performance on most of the other cognitive tests, and instead is associated with decision-making efficacy, and processing speed and efficiency. Thus, the SCIT is responsive to the processes that underpin multiple cognitive domains, rather than being specific for a single domain. Since the SCIT is quick and easy to administer, and is well tolerated by the elderly, it may have utility as a screening tool for detecting cognitive impairment in middle-aged and elderly populations. PMID- 25540582 TI - Effects of PEGylation on the physicochemical properties and in vivo distribution of organic nanotubes. AB - Application of organic nanotubes (ONTs) into drug nanocarriers ultimately requires validation in live animals. For improving the dispersibility in biological media and in vivo distribution, the outer surface of an ONT was functionalized with polyethylene glycol (PEG) via the coassembly of an ONT forming lipid with 5-20 mol% of a PEG-tethered lipid analogue (PEG-lipid). Firstly, the effect of PEGylation on the psysicochemical properties of ONTs, such as morphology and dispersibility, was investigated. PEGylation of ONTs slightly reduced the average length and effectively prevented the aggregation in phosphate buffered saline (PBS). The PEGylated ONTs even showed high thermal stability in aqueous dispersion at least up to 95 degrees C. Secondly, differential scanning calorimetry and powder X-ray diffraction indicated that ~10 mol% of PEG-lipid was completely incorporated into the ONTs, while 20 mol% of PEG-lipid encountered a partial phase separation during coassembly. In the heating differential scanning calorimetry runs, the resultant PEGylated ONTs with 5 mol% PEG-lipid showed no sign of phase separation up to 180 degrees C under lyophilized condition, while those with 10 mol% and 20 mol% PEG-lipid showed some phase separation of the PEG lipid above 120 degrees C. Finally, PEGylation significantly affected the tissue distribution and prolonged the persistence time in the blood in mice. Non PEGylated ONTs was quickly cleared from the circulation after intravenous infusion and preferentially accumulated in the lung, while PEGylated ONTs was mainly trapped in the liver and could circulate in the blood up to 24 hours. This study provided valuable information of physicochemical properties and the in vivo distribution behavior of PEGylated ONTs for their potential application into drug nanocarriers. PMID- 25540583 TI - Chemical modulation of M13 bacteriophage and its functional opportunities for nanomedicine. AB - M13 bacteriophage (phage) has emerged as an attractive bionanomaterial owing to its genetically tunable surface chemistry and its potential to self-assemble into hierarchical structures. Furthermore, because of its unique nanoscopic structure, phage has been proposed as a model system in soft condensed physics and as a biomimetic building block for structured functional materials. Genetic engineering of phage provides great opportunities to develop novel nanomaterials with functional surface peptide motifs; however, this biological approach is generally limited to peptides containing the 20 natural amino acids. To extend the scope of phage applications, strategies involving chemical modification have been employed to incorporate a wider range of functional groups, including synthetic chemical compounds. In this review, we introduce the design of chemoselective phage functionalization and discuss how such a strategy is combined with genetic engineering for a variety of medical applications, as reported in recent literature. PMID- 25540584 TI - Reprogramming fibroblasts to pluripotency using arginine-terminated polyamidoamine nanoparticles based non-viral gene delivery system. AB - Induced pluripotent stem cells (iPSCs) have attracted keen interest in regenerative medicine. The generation of iPSCs from somatic cells can be achieved by the delivery of defined transcription factor (Oct4, Sox2, Klf4, and c Myc[OSKM]). However, most instances of iPSC-generation have been achieved by potentially harmful genome-integrating viral vectors. Here we report the generation of iPSCs from mouse embryonic fibroblasts (MEFs) using arginine terminated generation 4 polyamidoamine (G4Arg) nanoparticles as a nonviral transfection vector for the delivery of a single plasmid construct carrying OSKM (pOSKM). Our results showed that G4Arg nanoparticles delivered pOSKM into MEFs at a significantly higher transfection efficiency than did conventional transfection reagents. After serial transfections of pOSKM-encapsulated G4Arg nanoparticles, we successfully generated iPSCs from MEFs. Our study demonstrates that G4Arg nanoparticles may be a promising candidate for generating of virus-free iPSCs that have great potential for clinical application. PMID- 25540585 TI - Self-assembled micelles of amphiphilic poly(L-phenylalanine)-b-poly(L-serine) polypeptides for tumor-targeted delivery. AB - The aim of this work was to design, synthesize, and characterize self-assembled micelles based on polypeptides as a potential antitumor drug carrier. Amphiphilic poly(L-phenylalanine)-b-poly(L-serine) (PFS) polypeptides were obtained through the polymerization of N-carboxyanhydride. As a novel hydrophilic segment, poly(L serine) was utilized to enhance tumor targeting due to a large demand of tumors for serine. PFS could self-assemble into micelles with an average diameter of 110 240 nm and a slightly negative charge. PFS polypeptides adopted random coil in pH 7.4 phosphate-buffered saline and could partly transform to alpha-helix induced by trifluoroethanol. PFS micelles with a low critical micelle concentration of 4.0 MUg mL(-1) were stable in pH 5-9 buffers and serum albumin solution. PFS micelles had a loading capacity of 3.8% for coumarin-6 and exhibited a sustained drug release. Coumarin-6 loaded rhodamine B isothiocyanate-labeled PFS micelles were incubated with Huh-7 tumor cells to study the correlation between drugs and carriers during endocytosis. The uptake of drugs was consistent with the micelles, illustrating that the intracellular transport of drugs highly depended on the micelles. PFS micelles diffused in whole cytoplasm while coumarin-6 assumed localized distribution, suggesting that the micelles could release the loaded drugs in particular areas. The internalization mechanism of PFS micelles was involved with clathrin-mediated endocytosis and macropinocytosis. Excess serine inhibited the uptake of PFS micelles, which demonstrated that serine receptors played a positive role in the internalization of PFS. The more interesting thing was that the uptake inhibition impacted on normal cells but not on tumor cells at the physiological concentration of serine. The difference in the uptake of PFS micelles was fourfold as high between the tumor cells and the normal cells, which indicated that PFS micelles had good tumor targeting in vitro. In conclusion, PFS micelles reported in this work were a promising drug delivery system for tumor targeting therapy. PMID- 25540586 TI - Reduced serum brain-derived neurotrophic factor in patients with first onset vitiligo. AB - PURPOSE: Vitiligo is an acquired pigmentary skin disease that can cause serious cosmetic problems. There have been numerous and well established studies that have demonstrated the comorbidity of various psychiatric disorders in patients with vitiligo. However, to our knowledge, there have been no studies investigating whether a psychiatric biomarker, such as brain-derived neurotrophic factor (BDNF), is associated with vitiligo. PATIENTS AND METHODS: This study was conducted in Namik Kemal University Medical Faculty, Departments of Dermatology and Psychiatry between January 2013 and September 2014. After meeting inclusion and exclusion criteria, serum BDNF levels were assayed in 57 patients with first onset vitiligo and no known current or past psychiatric disorder and compared with BDNF levels in 58 age and sex matched healthy subjects. RESULTS: The age and female/male ratios were similar between groups. The mean values of serum BDNF were 1.57+/-0.97 ng/dL and 2.37+/-1.73 ng/dL in the vitiligo group and in the healthy control group, respectively. The mean BDNF level was significantly higher in the healthy control group compared with the vitiligo group (t=2.76, P=0.007). CONCLUSION: This is the first study to compare serum BDNF levels between patients with vitiligo and healthy subjects. The reduced level of serum BDNF in patients with vitiligo may be directly related to the etiology of vitiligo or associated with the high percentage of psychiatric disorders in that patient population. Further studies are needed to support our preliminary results. PMID- 25540587 TI - Trabectedin for advanced soft tissue sarcomas: optimizing use. AB - Patients with locally advanced or metastatic soft tissue sarcoma have a poor outlook with median survival in the order of 1 year. There is therefore an urgent need for novel agents to impact this disease. Trabectedin is one such novel agent that has demonstrated activity for patients with advanced soft tissue sarcoma and it was licensed in Europe in 2007 for patients in the second-line setting or first-line in those patients deemed unsuitable to receive cytotoxics. In order to best serve patients with novel agents, it is imperative to understand the mechanism or mechanisms of action and the best ways of assessing response in order to optimize antitumor activity. Frequently, the mechanism of action and the optimal means of assessing response will be different from those of traditional cytotoxics. Trial design should reflect these factors to ensure that active drugs are not wrongly marked as futile. This review discusses a number of factors that may influence the optimization of trabectedin use. These factors include the administration schedule, the optimal timing of trabectedin administration in the disease process, the histopathological and molecular subtypes that may be most sensitive to trabectedin, the challenge of assessing response, particularly using radiology, and, finally, the safety considerations with this agent. PMID- 25540588 TI - Effects of exercise timing on sleep architecture and nocturnal blood pressure in prehypertensives. AB - BACKGROUND: During nocturnal sleep, blood pressure (BP) "dips" compared to diurnal BP, reducing stress on the cardiovascular system. Both the hypotensive response elicited by acute aerobic exercise and sleep quality can impact this dipping response. PURPOSE: The purpose of this study was to investigate the effects of aerobic exercise timing on circadian BP changes and sleep architecture. MATERIALS AND METHODS: Twenty prehypertensive subjects completed the study. During four test sessions, participants first completed a graded exercise test to exhaustion and then performed 30 minutes of treadmill exercise at 7 am (7A), 1 pm (1P), and 7 pm (7P) in a random, counterbalanced order at 65% of the heart rate obtained at peak oxygen uptake. An ambulatory cuff was used to monitor BP responses during 24 hours following exercise, and an ambulatory sleep monitoring headband was worn during sleep following each session. RESULTS: Aerobic exercise at 7A invoked a greater dip in nocturnal systolic BP than exercise at 1P or 7P, although the greatest dip in nocturnal diastolic BP occurred following 7P. Compared to 1P, 7A also invoked greater time spent in deep sleep. CONCLUSION: These data indicate that early morning may be the most beneficial time to engage in aerobic exercise to enhance nocturnal BP changes and quality of sleep. PMID- 25540589 TI - Use of radiofrequency in cosmetic dermatology: focus on nonablative treatment of acne scars. AB - Acne is a common affliction among many teens and some adults that usually resolves over time. However, the severe sequela of acne scarring can lead to long term psychological and psychiatric problems. There exists a multitude of modalities to treat acne scars such as more invasive surgical techniques, subcision, chemical peels, ablative lasers, fractional lasers, etc. A more recent technique for the treatment of acne scars is nonablative radiofrequency (RF) that works by passing a current through the dermis at a preset depth to produce small thermal wounds in the dermis which, in turn, stimulates dermal remodeling to produce new collagen and soften scar defects. This review article demonstrates that out of all RF modalities, microneedle bipolar RF and fractional bipolar RF treatments offers the best results for acne scarring. An improvement of 25%-75% can be expected after three to four treatment sessions using one to two passes per session. Treatment results are optimal approximately 3 months after final treatment. Common side effects can include transient pain, erythema, and scabbing. Further studies are needed to determine what RF treatment modalities work best for specific scar subtypes, so that further optimization of RF treatments for acne scars can be determined. PMID- 25540590 TI - Differential NF-kappaB and MAPK activation underlies fluoride- and TPA-mediated CXCL8 (IL-8) induction in lung epithelial cells. AB - Different toxic agents have a varying potential to induce the production of the proinflammatory chemokine, CXCL8 (interleukin [IL]-8), in lung cells. A critical question is which mechanisms determine the magnitude and persistence of the CXCL8 responses to different stimuli. To approach this, we compared the potential of the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), and sodium fluoride (NaF) to induce CXCL8 responses in A549 cells, with emphasis on the importance of nuclear factor kappa B (NF-kappaB)- and mitogen-activated protein kinase (MAPK) signaling. Notably, TPA induced a greater release of CXCL8 than did NaF. Furthermore, TPA induced a strong, rapid, but transient upregulation of CXCL8 messenger (m)RNA, whereas NaF induced a weaker, more delayed, but persistent upregulation. With respect to signaling, TPA led to an early, strong, and relatively transient extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and a less marked and even more transient phosphorylation of c jun-N-terminal kinases (JNK1/2) and p38. In contrast, NaF elicited a lower, but relatively sustained increase in phosphorylation of ERK1/2, and a marked phosphorylation of p38 and JNK1/2, with the JNK1/2 response as most transient. Only ERK1/2 inhibition affected the TPA response, whereas inhibition of all the three MAPK cascades reduced NaF-induced CXCL8 release. TPA also induced an early, marked phosphorylation/translocation of p65 (NF-kappaB), whereas NaF induced slower, less pronounced effects on p65. The CXCL8 responses by TPA and NaF were reduced by p65-siRNA. In conclusion, all MAPK cascades were involved in NaF induced CXCL8 release, whereas only ERK1/2 activation was involved in response to TPA. Furthermore, NF-kappaB activation appeared to be indispensable for CXCL8 induction. The early response, magnitude, and persistency of MAPK and NF-kappaB signaling seemed to be critical determinants for the potential to induce CXCL8. These findings underscore that a strong, rapid, and relatively transient activation of ERK1/2 in combination with NF-kB may be sufficient for a strong induction of CXCL8, which may exceed the effects of a more moderate ERK1/2 activation in combination with activation of p38, JNK1/2, and NF-kappaB. PMID- 25540592 TI - Patient profiling in diabetes and role of canagliflozin. AB - BACKGROUND: Physicians attempt to achieve glycemic goals in patients with type 2 diabetes mellitus (T2DM) through various means, including glucose-lowering medications. There is interindividual variability in response to medications, which can be partially explained by the presence of genetic polymorphisms that affect drug metabolism. Pharmacogenomics studies the hereditary basis of interpatient variations in drug response and aims to identify subgroups of patients whose drug management could be tailored accordingly. The aim of this review is to explore patient profiling in the management of T2DM with a focus on the sodium glucose transporter inhibitor canagliflozin. METHODS: The PubMed database was searched using the terms "pharmacogenomics" and "diabetes" through May 31, 2014. Published articles and abstracts presented at national/international meetings were considered. RESULTS AND CONCLUSION: Genome wide association studies have opened the door for patient profiling and research into genetic variants in multifactorial T2DM. Clinically, it may be possible to tailor the type of medication used based on the presence or absence of the various genetic variants. However, the polymorphisms studied may only explain some of the variability in response to T2DM drugs and needs further validation to ensure its authenticity. There are still unidentified factors which appear to play a role in the interindividual variability seen in clinical practice. The potential exists for pharmacogenomics to promote efficacious, safe, and cost effective individualized diabetes management. Pharmacogenomics is still in its early stages, and the idea of defining patients genetically to predict individual responses to drugs and obtain safe and effective T2DM management is promising, in spite of existing barriers. Currently, clinical profiling of patients with T2DM and using an individualized approach with most drugs, including canagliflozin, based on comorbid conditions still remains the most accepted approach for the management of T2DM. PMID- 25540591 TI - Drug-induced impairment of renal function. AB - Pharmaceutical agents provide diagnostic and therapeutic utility that are central to patient care. However, all agents also carry adverse drug effect profiles. While most of these are clinically insignificant, some drugs may cause unacceptable toxicity that impacts negatively on patient morbidity and mortality. Recognizing adverse effects is important for administering appropriate drug doses, instituting preventive strategies, and withdrawing the offending agent due to toxicity. In the present article, we will review those drugs that are associated with impaired renal function. By focusing on pharmaceutical agents that are currently in clinical practice, we will provide an overview of nephrotoxic drugs that a treating physician is most likely to encounter. In doing so, we will summarize risk factors for nephrotoxicity, describe clinical manifestations, and address preventive and treatment strategies. PMID- 25540593 TI - Mycophenolic acid AUC in Thai kidney transplant recipients receiving low dose mycophenolate and its association with UGT2B7 polymorphisms. AB - BACKGROUND: Despite use of a lower mycophenolate dose in Thai kidney transplant patients, acceptable graft and patient outcomes can be achieved. We therefore examined the pharmacokinetics of mycophenolic acid (MPA) by area under the curve (AUC) and investigated genetic contribution in mycophenolate metabolism in this population. METHODS: Kidney transplant recipients with stable graft function who were receiving mycophenolate mofetil 1,000 mg/d in combination with either cyclosporine or tacrolimus, and prednisolone were studied. The MPA concentration was measured by fluorescence polarization immunoassay (FPIA), at predose and 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. Genetic polymorphisms in UGT1A8, UGT1A9, and UGT2B7 were examined by denaturing high-performance liquid chromatography (DHPLC)-based single-base extension (SBE) analysis. RESULTS: A total 138 patients were included in study. The mean AUC was 39.49 mg-h/L (28.39 89.58 mg-h/L), which was in the therapeutic range. The correlation between the predose MPA concentration and AUC was poor. The mean AUC in the tacrolimus group was higher than that in the cyclosporine group. Polymorphisms in UGT2B7 showed significant association with AUC. CONCLUSION: Most of our patients with reduced mycophenolate dose had the AUC within the therapeutic range. Genetic polymorphisms in UGT2B7 may play a role in MPA metabolism in Thai kidney transplant patients. PMID- 25540594 TI - Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. AB - Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance. PMID- 25540595 TI - Infiltration of liposome bupivacaine into the transversus abdominis plane for postsurgical analgesia in robotic laparoscopic prostatectomy: a pilot study. AB - BACKGROUND: Transversus abdominis plane (TAP) infiltration has been increasingly used for postsurgical analgesia in abdominal/pelvic procedures; however, duration/extent of analgesia with standard local anesthetics is limited. This pilot study assessed the preliminary efficacy and safety of two volumes of liposome bupivacaine administered via TAP infiltration in patients undergoing robotic laparoscopic prostatectomy. METHODS: In this single-center, open-label, prospective study, patients older than 18 years received TAP infiltration with liposome bupivacaine immediately after surgery. The first 12 patients received a total volume of 20 mL liposome bupivacaine (266 mg); the next 12 received 40 mL liposome bupivacaine (266 mg). The liposome bupivacaine was diluted with 0.9% normal saline. The primary efficacy measure was duration of analgesia, measured by time to first opioid administration. Secondary outcome measures included patient-assessed pain scores, opioid use, and opioid-related adverse events (AEs). RESULTS: Twenty-four patients received liposome bupivacaine (20 mL, n=12; 40 mL, n=12) and were included in the primary analysis. Three refused participation in a 10-day follow-up visit and did not complete the study. Median time to first opioid administration after surgery was 23 and 26 minutes for the 20 and 40 mL groups, respectively. Mean total amount of postsurgical opioids ranged from 25.4 to 27.3 mg; after hospital discharge to day 10, both groups required a mean of 0.7 oxycodone/acetaminophen tablets/day. Mean pain scores of 4.4 and 5.3 were reported at 1 hour and 3.1 and 3.9 at 2 hours postsurgery, with 20 and 40 mL doses, respectively. Neither group had mean scores higher than 3.0 at any further assessments. No opioid-related or treatment-related serious AEs were reported. CONCLUSION: Median time to first opioid administration did not differ between the two groups. No differences in secondary outcomes were observed on the basis of volume administered. These initial findings suggest further study of liposome bupivacaine administered via TAP infiltration as part of a multimodal analgesic regimen in laparoscopic robotic prostatectomy may be warranted. PMID- 25540596 TI - Immunohistochemical analysis of aldehyde dehydrogenase isoforms and their association with estrogen-receptor status and disease progression in breast cancer. AB - In many types of tumors, especially breast tumors, aldehyde dehydrogenase (ALDH) activity has been used to identify cancer stem-like cells within the tumor. The presence and quantity of these cells are believed to predict the response of tumors to chemotherapy. Therefore, identification and eradication of these cells would be necessary to cure the patient. However, there are 19 different ALDH isoforms that could contribute to the enzyme activity. ALDH1A1 and ALDH1A3 are among the isoforms mostly responsible for the increased ALDH activity observed in these stem-like cells, although the main isoforms vary in different tissues and tumor types. In the study reported here, we attempted to determine if ALDH1A1 or ALDH1A3, specifically, correlate with tumor stage, grade, and hormone-receptor status in breast-cancer patients. While there was no significant correlation between ALDH1A1 and any of the parameters tested, we were able to identify a positive correlation between ALDH1A3 and tumor stage in triple-negative cancers. In addition, ALDH1A3 was negatively correlated with estrogen-receptor status. Our data suggest that ALDH1A3 could be utilized as a marker to identify stem-like cells within triple-negative tumors. PMID- 25540597 TI - STD patients' preferences for HIV prevention strategies. AB - The objective of this pilot study was to explore the knowledge of and preferences regarding effective biomedical interventions among high risk individuals attending a sexually transmitted diseases clinic, and to examine the effect of a brief information intervention on preference. Participants completed a baseline assessment, attended a presentation on human immunodeficiency virus (HIV) prevention methods, and completed a postintervention assessment. Outcome measures included: demographics and sexual risk factors, self-perceived HIV risk, and knowledge and attitudes regarding new biomedical methods of HIV prevention. After the baseline evaluation, participants were provided with information on new biomedical prevention strategies. Participants were given the option to review the information by reading a pamphlet or by viewing a brief video containing the same information. Participants (n=97) were female (n=51) and male (n=46). At baseline, only a small minority of participants were aware of the newer biomedical strategies to prevent HIV infection. Postintervention, 40% endorsed having heard about the use of HIV medications to prevent HIV infection; 72% had heard that male circumcision can decrease the risk of acquiring HIV infection in men; and 73% endorsed knowledge of the potential role of microbicides in decreasing the risk of acquiring HIV. Following the intervention, the most preferred prevention method was male condoms, followed by preexposure prophylaxis, and microbicides. The least preferred methods were male circumcision and female condoms. This study provides preliminary information on knowledge and attitudes regarding newer biomedical interventions to protect against HIV infection. PMID- 25540598 TI - Evaluation of a Safe Motherhood project in Ntcheu district, Malawi. AB - PURPOSE: This study evaluated knowledge and practices of childbearing women on key childcare practices within the Safe Motherhood project, administered by the Ntcheu District Health Office in the Republic of Malawi. The study excluded men and elderly women. METHODS: The design was cross-sectional, and utilized quantitative and qualitative data collection and analysis procedures. Data were also collected through review of participant health records. RESULTS: Although the findings showed that all participants (100%, n=400) had general knowledge on maternal and child health care, they did not have comprehensive information, and few mothers were practicing the recommended key child health care practices. Only 42.4% (n=170) knew the appropriate number of visits a woman should make to the antenatal clinic, and very few knew the appropriate time at which to access antenatal care. Only 55% (n=220) of participants breastfed their babies exclusively. Some participants introduced supplementary feeds as early as a month after birth, and not all women delivered at the health facility. Failure to actively involve men and elderly women in maternal and child health issues had a negative impact on women's ability to fully implement key maternal and childcare practices. CONCLUSION AND RECOMMENDATIONS: There is a need to actively involve men and elderly women in maternal and child health issues since, in the ideal Malawian context, a child is raised not just by the mother, but also by all who live in the village. Additionally, elderly women are the guardians of members of the childbearing group, and are a traditional reservoir of experience into which young women can tap. There is also a need to engage Community Nurse-Midwives in facilitating women's groups that provide comprehensive antenatal information to mothers, who may then put knowledge into practice. PMID- 25540599 TI - Messages on pregnancy and family planning that providers give women living with HIV in the context of a Positive Health, Dignity, and Prevention intervention in Mozambique. AB - BACKGROUND: Family planning is an important HIV prevention tool for women living with HIV (WLHIV). In Mozambique, the prevalence of HIV among women of reproductive age is 13.1% and the average fertility rate is high. However, family planning and reproductive health for WLHIV are under-addressed in Mozambique. This study explores provider descriptions of reproductive health messages in order to identify possible barriers and facilitators to successfully addressing family planning and pregnancy concerns of WLHIV. METHODS: In 2006, a Positive Health, Dignity, and Prevention program was introduced in Mozambique focused on training health care providers to work with patients to reduce their transmission risks. Providers received training on multiple components, including family planning and prevention of mother-to-child transmission (PMTCT). In-depth interviews were conducted with 31 providers who participated in the training in five rural clinics in three provinces. Data were analyzed using qualitative content analysis. RESULTS: Analysis showed that providers' clinical messages on family planning, pregnancy, and PMTCT for WLHIV could be arranged along a continuum. Provider statements ranged from saying that WLHIV should not become pregnant and condoms are the only valid form of family planning for WLHIV, to suggesting that WLHIV can have safe pregnancies. CONCLUSION: These data indicate that many providers continue to believe that WLHIV should not have children and this represents a challenge for integrating family planning into the care of WLHIV. Also, not offering WLHIV a full selection of family planning methods severely limits their ability to protect themselves from unintended pregnancies and to fully exercise their reproductive rights. Responding to the reproductive health needs of WLHIV is a critical component in HIV prevention and could increase the success of PMTCT programs. PMID- 25540600 TI - The Photodynamic Bone Stabilization System: a minimally invasive, percutaneous intramedullary polymeric osteosynthesis for simple and complex long bone fractures. AB - The treatment of osteoporotic long bone fractures is difficult due to diminished bone density and compromised biomechanical integrity. The majority of osteoporotic long bone fractures occur in the metaphyseal region, which poses additional problems for surgical repair due to increased intramedullary volume. Treatment with internal fixation using intramedullary nails or plating is associated with poor clinical outcomes in this patient population. Subsequent fractures and complications such as screw pull-out necessitate additional interventions, prolonging recovery and increasing health care costs. The Photodynamic Bone Stabilization System (PBSS) is a minimally invasive surgical technique that allows clinicians to repair bone fractures using a light-curable polymer contained within an inflatable balloon catheter, offering a new treatment option for osteoporotic long bone fractures. The unique polymer compound and catheter application provides a customizable solution for long bone fractures that produces internal stability while maintaining bone length, rotational alignment, and postsurgical mobility. The PBSS has been utilized in a case series of 41 fractures in 33 patients suffering osteoporotic long bone fractures. The initial results indicate that the use of the light-cured polymeric rod for this patient population provides excellent fixation and stability in compromised bone, with a superior complication profile. This paper describes the clinical uses, procedural details, indications for use, and the initial clinical findings of the PBSS. PMID- 25540601 TI - Learning psychology as a challenging process towards development as well as "studies as usual": a thematic analysis of medical students' reflective writing. AB - Reflective writing in medical training has been shown to be most effective when combined with some form of personal meeting or dialog. During a course in medical psychology for medical students, reflective texts were followed up by an individual personal talk with a teacher from the course. Thematic analysis of the texts revealed four separate sub-themes: 1) the course has enabled me and the class to develop, which is good albeit arduous; 2) understanding myself is a resource in understanding people as well as knowing psychology; 3) the course provided me with new, purely intellectual skills as well as eye-openers; and 4) the receiving teacher is an integral part of my reflective writing. The main theme, capturing the students' writing process, concluded that students perceive the course as "Learning psychology as a challenging process towards development" as well as "studies as usual". Ethical, psychological, and pedagogical aspects are discussed in the paper. PMID- 25540602 TI - Improvements in CanMEDS competencies for medical students in an interdisciplinary and voluntary setting. AB - BACKGROUND: To practice medicine, doctors must master leadership, communication, team management, and collaboration, in addition to medical knowledge. The CanMEDS framework describes seven roles of a doctor, but the six nonmedical expert roles are de-emphasized in the academic medical curriculum. Innovative opportunities are needed for medical students to develop as participants in a world of interdisciplinary health care. METHODS: We founded a volunteer-based, interdisciplinary, student-run project called SUNDdag (HEALTHday) with 60 students from 12 different educational backgrounds. To evaluate the learning outcomes of the project, we conducted a cross-sectional study using an anonymous, self-administered questionnaire. RESULTS: Students joined the project due to it being health-promoting, volunteer-based, and interdisciplinary. The medical students reported a significant increase of skills in all seven roles except for "medical expert". They reported an increased understanding of the non-health related students' skills. CONCLUSION: In their future careers, medical students must collaborate with health care professionals in a team-based approach to patient care and with non-health-related professionals in administrative tasks. Interdisciplinary volunteer-based initiatives like SUNDdag are potential platforms for medical students to improve their CanMEDS competencies. We encourage students to initiate similar projects and we encourage faculties to support volunteer-based, interdisciplinary initiatives due to their favorable cost-benefit ratio. PMID- 25540603 TI - Evolutionary and neuropsychological perspectives on addictive behaviors and addictive substances: relevance to the "food addiction" construct. AB - It has been argued that food cannot be "addictive", unlike conventional drugs of abuse, because it is an essential part of life. In this paper, evidence is reviewed, largely from an evolutionary psychobiological perspective, that plant based psychoactive drugs (such as those derived from the opium poppy and the coca leaf) and gambling-related behaviors were once adaptive for human health and survival in a similar manner as energy-based foods were for nourishment. "Evolutionary mismatch" viewpoints contend that certain behaviors were enhanced during the hunter-gatherer lifestyle - from which our genetic endowment had its origins - because they bestowed both survival and reproductive advantages to the species. However, in the context of advanced technology and other rapid environmental changes, these same behaviors have tended to become maladaptive and greatly overexpressed. Similar to the manufactured purification of psychotropic plant-based substances, the reward impact of processed and hyperpalatable foods, with their high levels of sugar, fat, and salt, is much increased from foods produced in nature. It is concluded therefore that what was once beneficial and necessary for our survival has been altered and ultraprocessed into edible products that may be disadvantageous and potentially addictive. PMID- 25540604 TI - Modelling the adsorption of short alkanes in protonated chabazite: The impact of dispersion forces and temperature. AB - The adsorption of alkanes in a protonated zeolite has been investigated at different levels of theory. At the lowest level we use density-functional theory (DFT) based on semi-local (gradient-corrected) functionals which account only for the interaction of the molecule with the acid site. To describe the van der Waals (vdW) interactions between the saturated molecule and the inner wall of the zeolite we use (i) semi-empirical pair interactions, (ii) calculations using a non-local correlation functional designed to include vdW interactions, and (iii) an approach based on calculations of the dynamical response function within the random-phase approximation (RPA). The effect of finite temperature on the adsorption properties has been studied by performing molecular dynamics (MD) simulations based on forces derived from DFT plus semi-empirical vdW corrections. The simulations demonstrate that even at room temperature the binding of the molecule to the acid site is frequently broken such that only the vdW interaction between the alkane and the zeolite remains. The finite temperature adsorption energy is calculated as the ensemble average over a sufficiently long molecular dynamics run, it is significantly reduced compared to the T = 0 K limit. At a higher level of theory where MD simulations would be prohibitively expensive we propose a simple scheme based on the averaging over the adsorption energies in the acid and in the purely siliceous zeolite to account for temperature effects. With these corrections we find an excellent agreement between the RPA predictions and experiment. PMID- 25540605 TI - Independent confirmation of juvenile idiopathic arthritis genetic risk loci previously identified by immunochip array analysis. AB - BACKGROUND: Our understanding of the genetic factors underlying juvenile idiopathic arthritis (JIA) is growing, but remains incomplete. Recently, a number of novel genetic loci were reported to be associated with JIA at (or near) genome wide significance in a large case-control discovery sample using the Immunochip genotyping array. However, independent replication of findings has yet to be performed. We therefore attempted to replicate these newly identified loci in the Australian CLARITY JIA case-control sample. FINDINGS: Genotyping was successfully performed on a total of 404 JIA cases (mean age 6.4 years, 68% female) and 676 healthy child controls (mean age 7.1 years, 42% female) across 19 SNPs previously associated with JIA. We replicated a significant association (p < 0.05, odds ratio (OR) in a direction consistent with the previous report) for seven loci, six replicated for the first time--C5orf56-IRF1 (rs4705862), ERAP2-LNPEP (rs27290), PRR5L (rs4755450), RUNX1 (rs9979383), RUNX3 (rs4648881), and UBE2L3 (rs2266959). CONCLUSIONS: We have carried out the first independent replication of association for six genes implicated in JIA susceptibility. Our data significantly strengthens the evidence that these loci harbor true disease associated variants. Thus, this study makes an important contribution to the growing body of international data that is revealing the genetic risk landscape of JIA. PMID- 25540606 TI - Characterizing phenotype with tracer based metabolomics. AB - In the post-genomic era, a pressing challenge to biological scientists is to understand the organization of gene functions, the interaction between gene and nutrient environment, and the genesis of phenotypes. Metabolomics, the quantitation of low molecular weight compounds, has been used to provide a phenotypic description of a cell or tissue by a set of metabolites. Gene function is hypothesized from its correlation with the corresponding set of macromolecules by transcriptomics or proteomics. Another approach to genotype-phenotype correlation is by the reconstruction of genome-scale metabolic maps. The utilization of specific pathways as predicted by reaction network analysis provides the phenotypic characterization of a cell, which can be plotted on a phenotypic phase plane. Tracer based metabolomics is the experimental approach to reaction network analysis using stable isotope tracers. The redistribution of the isotope tracer among metabolic intermediates is used to identify a finite number of pathways, the utilization of which is characteristic of the phenotypic behavior of cells. In this paper, we review tracer based metabolomic methods for the construction of phenotypic phase plane plots, and discuss the functional implications of phenotypic phase plane analysis. Examples of phenotypic changes in response to differentiation, inhibition of signaling pathways and perturbation in nutrient environment are provided. PMID- 25540607 TI - Consistency of arsenic speciation in global tobacco products with implications for health and regulation. AB - BACKGROUND: Tobacco smoke is a major risk to the health of its users and arsenic is among the components of smoke present at concentrations of toxicological concern. There are significant variations in human toxicity between inorganic and organic arsenic species and the aim of this study was to determine whether there are predictable relationships among major arsenic species in tobacco that could be useful for risk assessment. METHODS: 14 samples of tobacco were studied spanning a wide range of concentrations in samples from different geographical regions, including certified reference materials and cigarette products. Inorganic and major organic arsenic species were extracted from powdered tobacco samples by nitric acid using microwave digestion. Concentrations of arsenic species in these extracts were determined using HPLC-ICPMS. RESULTS: The concentrations of total inorganic arsenic species range from 144 to 3914 MUg kg( 1), while organic species dimethylarsinic acid (DMA) ranges from 21 to 176 MUg As kg(-1), and monomethylarsonic acid (MA) ranges from 30 to 116 MUg kg(-1). The percentage of species eluted compared to the total arsenic extracted ranges from 11.1 to 36.8% suggesting that some As species (possibly macro-molecules, strongly complexed or in organic forms) do not elute from the column. This low percentage of column-speciated arsenic is indicative that more complex forms of arsenic exist in the tobacco. All the analysed species correlate positively with total arsenic concentration over the whole compositional range and regression analysis indicates a consistent ratio of about 4:1 in favour of inorganic arsenic compared with MA + DMA. CONCLUSIONS: The dominance of inorganic arsenic species among those components analysed is a marked feature of the diverse range of tobaccos selected for study. Such consistency is important in the context of a WHO expert panel recommendation to regulate tobacco crops and products using total arsenic concentration. If implemented more research would be required to develop models that accurately predict the smoker's exposure to reduced inorganic arsenic species on the basis of leaf or product concentration and product design features. PMID- 25540608 TI - Using auditory pre-information to solve the cocktail-party problem: electrophysiological evidence for age-specific differences. AB - Speech understanding in complex and dynamic listening environments requires (a) auditory scene analysis, namely auditory object formation and segregation, and (b) allocation of the attentional focus to the talker of interest. There is evidence that pre-information is actively used to facilitate these two aspects of the so-called "cocktail-party" problem. Here, a simulated multi-talker scenario was combined with electroencephalography to study scene analysis and allocation of attention in young and middle-aged adults. Sequences of short words (combinations of brief company names and stock-price values) from four talkers at different locations were simultaneously presented, and the detection of target names and the discrimination between critical target values were assessed. Immediately prior to speech sequences, auditory pre-information was provided via cues that either prepared auditory scene analysis or attentional focusing, or non specific pre-information was given. While performance was generally better in younger than older participants, both age groups benefited from auditory pre information. The analysis of the cue-related event-related potentials revealed age-specific differences in the use of pre-cues: Younger adults showed a pronounced N2 component, suggesting early inhibition of concurrent speech stimuli; older adults exhibited a stronger late P3 component, suggesting increased resource allocation to process the pre-information. In sum, the results argue for an age-specific utilization of auditory pre-information to improve listening in complex dynamic auditory environments. PMID- 25540610 TI - Role of neuropsin in parvalbumin immunoreactivity changes in hippocampal basket terminals of mice reared in various environments. AB - In vitro approaches have suggested that neuropsin (or kallikrein 8/KLK8), which controls gamma-aminobutyric acid (GABA) neurotransmission through neuregulin-1 (NRG-1) and its receptor (ErbB4), is involved in neural plasticity (Tamura et al., 2012, 2013). In the present study, we examined whether parvalbumin (PV) positive neuronal networks, the majority of which are ErbB4-positive GABAergic interneurons, are controlled by neuropsin in tranquil and stimulated voluntarily behaving mice. Parvalbumin-immunoreactive fibers surrounding hippocampal pyramidal and granular neurons in mice reared in their home cage were decreased in neuropsin-deficient mice, suggesting that neuropsin controls PV immunoreactivity. One- or two-week exposures of wild mice to novel environments, in which they could behave freely and run voluntarily in a wheel resulted in a marked upregulation of both neuropsin mRNA and protein in the hippocampus. To elucidate the functional relevance of the increase in neuropsin during exposure to a rich environment, the intensities of PV-immunoreactive fibers were compared between neuropsin-deficient and wild-type (WT) mice under environmental stimuli. When mice were transferred into novel cages (large cages with toys), the intensity of PV-immunoreactive fibers increased in WT mice and neuropsin deficient mice. Therefore, behavioral stimuli control a neuropsin-independent form of PV immunoreactivity. However, the neuropsin-dependent part of the change in PV-immunoreactive fibers may occur in the stimulated hippocampus because increased levels of neuropsin continued during these enriched conditions. PMID- 25540609 TI - Neuronal involvement in muscular atrophy. AB - The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression. PMID- 25540611 TI - Altering endoplasmic reticulum stress in a model of blast-induced traumatic brain injury controls cellular fate and ameliorates neuropsychiatric symptoms. AB - Neuronal injury following blast-induced traumatic brain injury (bTBI) increases the risk for neuropsychiatric disorders, yet the pathophysiology remains poorly understood. Blood-brain-barrier (BBB) disruption, endoplasmic reticulum (ER) stress, and apoptosis have all been implicated in bTBI. Microvessel compromise is a primary effect of bTBI and is postulated to cause subcellular secondary effects such as ER stress. What remains unclear is how these secondary effects progress to personality disorders in humans exposed to head trauma. To investigate this we exposed male rats to a clinically relevant bTBI model we have recently developed. The study examined initial BBB disruption using Evan's blue (EB), ER stress mechanisms, apoptosis and impulsive-like behavior measured with elevated plus maze (EPM). Large BBB openings were observed immediately following bTBI, and persisted for at least 6 h. Data showed increased mRNA abundance of stress response genes at 3 h, with subsequent increases in the ER stress markers C/EBP homologous protein (CHOP) and growth arrest and DNA damage-inducible protein 34 (GADD34) at 24 h. Caspase-12 and Caspase-3 were both cleaved at 24 h following bTBI. The ER stress inhibitor, salubrinal (SAL), was administered (1 mg/kg i.p.) to investigate its effects on neuronal injury and impulsive-like behavior associated with bTBI. SAL reduced CHOP protein expression, and diminished Caspase 3 cleavage, suggesting apoptosis attenuation. Interestingly, SAL also ameliorated impulsive-like behavior indicative of head trauma. These results suggest SAL plays a role in apoptosis regulation and the pathology of chronic disease. These observations provide evidence that bTBI involves ER stress and that the unfolded protein response (UPR) is a promising molecular target for the attenuation of neuronal injury. PMID- 25540612 TI - Anesthetic action on extra-synaptic receptors: effects in neural population models of EEG activity. AB - The role of extra-synaptic receptors in the regulation of excitation and inhibition in the brain has attracted increasing attention. Because activity in the extra-synaptic receptors plays a role in regulating the level of excitation and inhibition in the brain, they may be important in determining the level of consciousness. This paper reviews briefly the literature on extra-synaptic GABA and NMDA receptors and their affinity to anesthetic drugs. We propose a neural population model that illustrates how the effect of the anesthetic drug propofol on GABAergic extra-synaptic receptors results in changes in neural population activity and the electroencephalogram (EEG). Our results show that increased tonic inhibition in inhibitory cortical neurons cause a dramatic increase in the power of both delta- and alpha- bands. Conversely, the effects of increased tonic inhibition in cortical excitatory neurons and thalamic relay neurons have the opposite effect and decrease the power in these bands. The increased delta activity is in accord with observed data for deepening propofol anesthesia; but is absolutely dependent on the inclusion of extrasynaptic (tonic) GABA action in the model. PMID- 25540614 TI - Event-related potentials and biomarkers of psychiatric diseases: the necessity to adopt and develop multi-site guidelines. PMID- 25540616 TI - Automated detection of sleep spindles in the scalp EEG and estimation of their intracranial current sources: comments on techniques and on related experimental and clinical studies. PMID- 25540615 TI - When holding your horses meets the deer in the headlights: time-frequency characteristics of global and selective stopping under conditions of proactive and reactive control. AB - The ability to inhibit unwanted thoughts or actions is crucial for successful functioning in daily life; however, this ability is often impaired in a number of psychiatric disorders. Despite the relevance of inhibition in everyday situations, current models of inhibition are rather simplistic and provide little generalizability especially in the face of clinical disorders. Thus, given the importance of inhibition for proper cognitive functioning, the need for a paradigm, which incorporates factors that will subsequently improve the current model for understanding inhibition, is of high demand. A popular paradigm used to assess motor inhibition, the stop-signal paradigm, can be modified to further advance the current conceptual model of inhibitory control and thus provide a basis for better understanding different facets of inhibition. Namely, in this study, we have developed a novel version of the stop-signal task to assess how preparation (that is, whether reactive or proactive) and selectivity of the stopping behavior effect well-known time-frequency characteristics associated with successful inhibition and concomitant behavioral measures. With this innovative paradigm, we demonstrate that the selective nature of the stopping task modulates theta and motoric beta activity and we further provide the first account of delta activity as an electrophysiological feature sensitive to both manipulations of selectivity and preparatory control. PMID- 25540613 TI - Hypothalamic glucose sensing: making ends meet. AB - The neuroendocrine system governs essential survival and homeostatic functions. For example, growth is needed for development, thermoregulation maintains optimal core temperature in a changing environment, and reproduction ensures species survival. Stress and immune responses enable an organism to overcome external and internal threats while the circadian system regulates arousal and sleep such that vegetative and active functions do not overlap. All of these functions require a significant portion of the body's energy. As the integrator of the neuroendocrine system, the hypothalamus carefully assesses the energy status of the body in order to appropriately partition resources to provide for each system without compromising the others. While doing so the hypothalamus must ensure that adequate glucose levels are preserved for brain function since glucose is the primary fuel of the brain. To this end, the hypothalamus contains specialized glucose sensing neurons which are scattered throughout the nuclei controlling distinct neuroendocrine functions. We hypothesize that these neurons play a key role in enabling the hypothalamus to partition energy to meet these peripheral survival needs without endangering the brain's glucose supply. This review will first describe the varied mechanisms underlying glucose sensing in neurons within discrete hypothalamic nuclei. We will then evaluate the way in which peripheral energy status regulates glucose sensitivity. For example, during energy deficit such as fasting specific hypothalamic glucose sensing neurons become sensitized to decreased glucose. This increases the gain of the information relay when glucose availability is a greater concern for the brain. Finally, changes in glucose sensitivity under pathological conditions (e.g., recurrent insulin hypoglycemia, diabetes) will be addressed. The overall goal of this review is to place glucose sensing neurons within the context of hypothalamic control of neuroendocrine function. PMID- 25540617 TI - Enhanced timing abilities in percussionists generalize to rhythms without a musical beat. AB - The ability to entrain movements to music is arguably universal, but it is unclear how specialized training may influence this. Previous research suggests that percussionists have superior temporal precision in perception and production tasks. Such superiority may be limited to temporal sequences that resemble real music or, alternatively, may generalize to musically implausible sequences. To test this, percussionists and nonpercussionists completed two tasks that used rhythmic sequences varying in musical plausibility. In the beat tapping task, participants tapped with the beat of a rhythmic sequence over 3 stages: finding the beat (as an initial sequence played), continuation of the beat (as a second sequence was introduced and played simultaneously), and switching to a second beat (the initial sequence finished, leaving only the second). The meters of the two sequences were either congruent or incongruent, as were their tempi (minimum inter-onset intervals). In the rhythm reproduction task, participants reproduced rhythms of four types, ranging from high to low musical plausibility: Metric simple rhythms induced a strong sense of the beat, metric complex rhythms induced a weaker sense of the beat, nonmetric rhythms had no beat, and jittered nonmetric rhythms also had no beat as well as low temporal predictability. For both tasks, percussionists performed more accurately than nonpercussionists. In addition, both groups were better with musically plausible than implausible conditions. Overall, the percussionists' superior abilities to entrain to, and reproduce, rhythms generalized to musically implausible sequences. PMID- 25540618 TI - Comparison of EEG propagation speeds under emotional stimuli on smartphone between the different anxiety states. AB - The current study evaluated the effect of different anxiety states on information processing as measured by an electroencephalography (EEG) using emotional stimuli on a smartphone. Twenty-three healthy subjects were assessed for their anxiety states using The State Trait Anxiety Inventory (STAI) and divided into two groups: low anxiety (I, II) or high anxiety (III and IV, V). An EEG was performed while the participant was presented with emotionally laden audiovisual stimuli (resting, pleasant, and unpleasant sessions) and emotionally laden sentence stimuli (pleasant sentence, unpleasant sentence sessions) and EEG data was analyzed using propagation speed analysis. The propagation speed of the low anxiety group at the medial coronal for resting stimuli for all time segments was higher than those of high anxiety group. The low anxiety group propagation speeds at the medial sagittal for unpleasant stimuli in the 0-30 and 60-150 s time frames were higher than those of high anxiety group. The propagation speeds at 150 s for all stimuli in the low anxiety group were significantly higher than the correspondent propagation speeds of the high anxiety group. These events suggest that neural information processes concerning emotional stimuli differ based on current anxiety state. PMID- 25540619 TI - Heterogeneity of heterogeneities in neuronal networks. PMID- 25540620 TI - Development and evaluation of a self-administered on-line test of memory and attention for middle-aged and older adults. AB - There is a need for rapid and reliable Internet-based screening tools for cognitive assessment in middle-aged and older adults. We report the psychometric properties of an on-line tool designed to screen for cognitive deficits that require further investigation. The tool is composed of measures of memory and executive attention processes known to be sensitive to brain changes associated with aging and with cognitive disorders that become more prevalent with age. Measures included a Spatial Working Memory task, Stroop Interference task, Face Name Association task, and Number-Letter Alternation task. Normative data were collected from 361 healthy adults age 50-79 who scored in the normal range on a standardized measure of general cognitive ability. Participants took the 20 minute on-line test on their home computers, and a subset of 288 participants repeated the test 1 week later. Analyses of the individual tasks indicated adequate internal consistency, construct validity, test-retest reliability, and alternate version reliability. As expected, scores were correlated with age. The four tasks loaded on the same principle component. Demographically-corrected z scores from the individual tasks were combined to create an overall score, which showed good reliability and classification consistency. These results indicate the tool may be useful for identifying middle-aged and older adults with lower than expected scores who may benefit from clinical evaluation of their cognition by a health care professional. PMID- 25540621 TI - Rikkunshito, a ghrelin potentiator, ameliorates anorexia-cachexia syndrome. AB - Anorexia-cachexia syndrome develops during the advanced stages of various chronic diseases in which patients exhibit a decreased food intake, weight loss, and muscle tissue wasting. For these patients, this syndrome is a critical problem leading to an increased rate of morbidity and mortality. The present pharmacological therapies for treating anorexia-cachexia have limited effectiveness. The Japanese herbal medicine rikkunshito is often prescribed for the treatment of anorexia and upper gastrointestinal (GI) disorders. Thus, rikkunshito is expected to be beneficial for the treatment of patients with anorexia-cachexia syndrome. In this review, we summarize the effects of rikkunshito and its mechanisms of action on anorexia-cachexia. Persistent loss of appetite leads to a progressive depletion of body energy stores, which is frequently associated with cachexia. Consequently, regulating appetite and energy homeostasis is critically important for treating cachexia. Ghrelin is mainly secreted from the stomach, and it plays an important role in initiating feeding, controlling GI motility, and regulating energy expenditure. Recent clinical and basic science studies have demonstrated that the critical mechanism of rikkunshito underlies endogenous ghrelin activity. Interestingly, several components of rikkunshito target multiple gastric and central sites, and regulate the secretion, receptor sensitization, and degradation of ghrelin. Rikkunshito is effective for the treatment of anorexia, body weight loss, muscle wasting, and anxiety-related behavior. Furthermore, treatment with rikkunshito was observed to prolong survival in an animal model of cachexia. The use of a potentiator of ghrelin signaling, such as rikkunshito, may represent a novel approach for the treatment of anorexia-cachexia syndrome. PMID- 25540622 TI - Alterations in function and expression of ABC transporters at blood-brain barrier under diabetes and the clinical significances. AB - Diabetes is a systematic metabolic disease, which often develops a number of well recognized vascular complications including brain complications which may partly result from the dysfunction of blood-brain barrier (BBB). BBB is generally considered as a mechanism for protecting the brain from unwanted actions resulting from substances in the blood and maintaining brain homeostasis via monitoring the entry or efflux of compounds. ATP-binding cassette (ABC) family of transporters including P-glycoprotein (P-GP) and breast cancer-related protein (BCRP), widely expressed in the luminal membrane of the microvessel endothelium and in the apical membrane of the choroids plexus epithelium, play important roles in the function of BBB. However, these transporters are easily altered by some diseases. The present article was focused on the alteration in expression and function of both P-GP and BCRP at BBB by diabetes and the clinical significances. PMID- 25540623 TI - Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans. AB - In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80%) of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30-50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al., 2013), and evaluated against clinical data from the literature (Mogensen, 1971; Wolf et al., 2009; Polidori et al., 2013). The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30-50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to SGLT1/2 modulation. PMID- 25540624 TI - Distribution of the amelogenin protein in developing, injured and carious human teeth. AB - Amelogenin is the major enamel matrix protein with key roles in amelogenesis. Although for many decades amelogenin was considered to be exclusively expressed by ameloblasts, more recent studies have shown that amelogenin is also expressed in other dental and no-dental cells. However, amelogenin expression in human tissues remains unclear. Here, we show that amelogenin protein is not only expressed during human embryonic development but also in pathological conditions such as carious lesions and injuries after dental cavity preparation. In developing embryonic teeth, amelogenin stage-specific expression is found in all dental epithelia cell populations but with different intensities. In the different layers of enamel matrix, waves of positive vs. negative immunostaining for amelogenin are detected suggesting that the secretion of amelogenin protein is orchestrated by a biological clock. Amelogenin is also expressed transiently in differentiating odontoblasts during predentin formation, but was absent in mature functional odontoblasts. In intact adult teeth, amelogenin was not present in dental pulp, odontoblasts, and dentin. However, in injured and carious adult human teeth amelogenin is strongly re-expressed in newly differentiated odontoblasts and is distributed in the dentinal tubuli under the lesion site. In an in vitro culture system, amelogenin is expressed preferentially in human dental pulp cells that start differentiating into odontoblast-like cells and form mineralization nodules. These data suggest that amelogenin plays important roles not only during cytodifferentiation, but also during tooth repair processes in humans. PMID- 25540625 TI - Transcriptome analysis of host-associated differentiation in Bemisia tabaci (Hemiptera: Aleyrodidae). AB - Host-associated differentiation is one of the driving forces behind the diversification of phytophagous insects. In this study, host induced transcriptomic differences were investigated in the sweetpotato whitefly Bemisia tabaci, an invasive agricultural pest worldwide. Comparative transcriptomic analyses using coding sequence (CDS), 5' and 3' untranslated regions (UTR) showed that sequence divergences between the original host plant, cabbage, and the derived hosts, including cotton, cucumber and tomato, were 0.11-0.14%, 0.19 0.26%, and 0.15-0.21%, respectively. In comparison to the derived hosts, 418 female and 303 male transcripts, respectively, were up-regulated in the original cabbage strain. Among them, 17 transcripts were consistently up-regulated in both female and male whiteflies originated from the cabbage host. Specifically, two ESTs annotated as Cathepsin B or Cathepsin B-like genes were significantly up regulated in the original cabbage strain, representing a transcriptomic response to the dietary challenges imposed by the host shifting. Results from our transcriptome analysis, in conjunction with previous reports documenting the minor changes in their reproductive capacity, insecticide susceptibility, symbiotic composition and feeding behavior, suggest that the impact of host associated differentiation in whiteflies is limited. Furthermore, it is unlikely the major factor contributing to their rapid range expansion/invasiveness. PMID- 25540626 TI - Risk factors for pancreatic cancer: underlying mechanisms and potential targets. PMID- 25540627 TI - Antenatal Depression is Not Associated with Low-Birth Weight: A Study from Urban Pakistan. AB - BACKGROUND: Low-birth weight (LBW) (<2500 g) is considered to be a leading cause of cognitive impairment and physical disabilities in children. Incidence of LBW in South Asia has been reported to be as high as 33%. We investigated the association between antenatal depression and LBW in an urban community, in Karachi, Pakistan. METHODS: A total of 1357 pregnant women in their third trimester were recruited into the study. They were screened for antenatal depression with Edinburgh postnatal depression scale. Self-reporting questionnaire was also used to measure psychological distress. Birth weights of 763 newborns were obtained from the hospital records. RESULTS: We did not find a significant association between antenatal depression and LBW (odds ratio 0.881, 95%CI 0.732-1.060) in mothers attending a charity run hospital in an urban setting in Pakistan. CONCLUSION: Antenatal depression is not associated with LBW in this urban population in Pakistan. However, the prevalence of depression is high during pregnancy. There is a need to develop culturally adapted psychosocial interventions to address the high rates of depression for this population group. PMID- 25540629 TI - Jointly structuring triadic spaces of meaning and action: book sharing from 3 months on. AB - This study explores the emergence of triadic interactions through the example of book sharing. As part of a naturalistic study, 10 infants were visited in their homes from 3-12 months. We report that (1) book sharing as a form of infant caregiver-object interaction occurred from as early as 3 months. Using qualitative video analysis at a micro-level adapting methodologies from conversation and interaction analysis, we demonstrate that caregivers and infants practiced book sharing in a highly co-ordinated way, with caregivers carving out interaction units and shaping actions into action arcs and infants actively participating and co-ordinating their attention between mother and object from the beginning. We also (2) sketch a developmental trajectory of book sharing over the first year and show that the quality and dynamics of book sharing interactions underwent considerable change as the ecological situation was transformed in parallel with the infants' development of attention and motor skills. Social book sharing interactions reached an early peak at 6 months with the infants becoming more active in the coordination of attention between caregiver and book. From 7 to 9 months, the infants shifted their interest largely to solitary object exploration, in parallel with newly emerging postural and object manipulation skills, disrupting the social coordination and the cultural frame of book sharing. In the period from 9 to 12 months, social book interactions resurfaced, as infants began to effectively integrate manual object actions within the socially shared activity. In conclusion, to fully understand the development and qualities of triadic cultural activities such as book sharing, we need to look especially at the hitherto overlooked early period from 4 to 6 months, and investigate how shared spaces of meaning and action are structured together in and through interaction, creating the substrate for continuing cooperation and cultural learning. PMID- 25540628 TI - Interplay between singing and cortical processing of music: a longitudinal study in children with cochlear implants. AB - Informal music activities such as singing may lead to augmented auditory perception and attention. In order to study the accuracy and development of music related sound change detection in children with cochlear implants (CIs) and normal hearing (NH) aged 4-13 years, we recorded their auditory event-related potentials twice (at T1 and T2, 14-17 months apart). We compared their MMN (preattentive discrimination) and P3a (attention toward salient sounds) to changes in piano tone pitch, timbre, duration, and gaps. Of particular interest was to determine whether singing can facilitate auditory perception and attention of CI children. It was found that, compared to the NH group, the CI group had smaller and later timbre P3a and later pitch P3a, implying degraded discrimination and attention shift. Duration MMN became larger from T1 to T2 only in the NH group. The development of response patterns for duration and gap changes were not similar in the CI and NH groups. Importantly, CI singers had enhanced or rapidly developing P3a or P3a-like responses over all change types. In contrast, CI non-singers had rapidly enlarging pitch MMN without enlargement of P3a, and their timbre P3a became smaller and later over time. These novel results show interplay between MMN, P3a, brain development, cochlear implantation, and singing. They imply an augmented development of neural networks for attention and more accurate neural discrimination associated with singing. In future studies, differential development of P3a between CI and NH children should be taken into account in comparisons of these groups. Moreover, further studies are needed to assess whether singing enhances auditory perception and attention of children with CIs. PMID- 25540630 TI - Rethinking the senses and their interactions: the case for sensory pluralism. AB - I argue for sensory pluralism. This is the view that there are many forms of sensory interaction and unity, and no single category that classifies them all. In other words, sensory interactions do not form a single natural kind. This view suggests that how we classify sensory systems (and the experiences they generate) partly depends on our explanatory purposes. I begin with a detailed discussion of the issue as it arises for our understanding of thermal perception, followed by a general account and defense of sensory pluralism. PMID- 25540632 TI - Extending the reach of mousetracking in numerical cognition: a comment on Fischer and Hartmann (2014). PMID- 25540631 TI - Reduced visual surround suppression in schizophrenia shown by measuring contrast detection thresholds. AB - Visual perception in schizophrenia is attracting a broad interest given the deep knowledge that we have about the visual system in healthy populations. One example is the class of effects known collectively as visual surround suppression. For example, the visibility of a grating located in the visual periphery is impaired by the presence of a surrounding grating of the same spatial frequency and orientation. Previous studies have suggested abnormal visual surround suppression in patients with schizophrenia. Given that schizophrenia patients have cortical alterations including hypofunction of NMDA receptors and reduced concentration of GABA neurotransmitter, which affect lateral inhibitory connections, then they should be relatively better than controls at detecting visual stimuli that are usually suppressed. We tested this hypothesis by measuring contrast detection thresholds using a new stimulus configuration. We tested two groups: 21 schizophrenia patients and 24 healthy subjects. Thresholds were obtained using Bayesian staircases in a four alternative forced-choice detection task where the target was a grating within a 3? Butterworth window that appeared in one of four possible positions at 5? eccentricity. We compared three conditions, (a) target with no-surround, (b) target embedded within a surrounding grating of 20? diameter and 25% contrast with same spatial frequency and orthogonal orientation, and (c) target embedded within a surrounding grating with parallel (same) orientation. Previous results with healthy populations have shown that contrast thresholds are lower for orthogonal and no-surround (NS) conditions than for parallel surround (PS). The log-ratios between parallel and NS thresholds are used as an index quantifying visual surround suppression. Patients performed poorly compared to controls in the NS and orthogonal-surround conditions. However, they performed as well as controls when the surround was parallel, resulting in significantly lower suppression indices in patients. To examine whether the difference in suppression was driven by the lower NS thresholds for controls, we examined a matched subgroup of controls and patients, selected to have similar thresholds in the NS condition. Patients performed significantly better in the PS condition than controls. This analysis therefore indicates that a PS raised contrast thresholds less in patients than in controls. Our results support the hypothesis that inhibitory connections in early visual cortex are impaired in schizophrenia patients. PMID- 25540633 TI - Social signal processing for studying parent-infant interaction. AB - Studying early interactions is a core issue of infant development and psychopathology. Automatic social signal processing theoretically offers the possibility to extract and analyze communication by taking an integrative perspective, considering the multimodal nature and dynamics of behaviors (including synchrony). This paper proposes an explorative method to acquire and extract relevant social signals from a naturalistic early parent-infant interaction. An experimental setup is proposed based on both clinical and technical requirements. We extracted various cues from body postures and speech productions of partners using the IMI2S (Interaction, Multimodal Integration, and Social Signal) Framework. Preliminary clinical and computational results are reported for two dyads (one pathological in a situation of severe emotional neglect and one normal control) as an illustration of our cross-disciplinary protocol. The results from both clinical and computational analyzes highlight similar differences: the pathological dyad shows dyssynchronic interaction led by the infant whereas the control dyad shows synchronic interaction and a smooth interactive dialog. The results suggest that the current method might be promising for future studies. PMID- 25540634 TI - Remembering faces with emotional expressions. AB - It is known that happy faces create more robust identity recognition memory than faces with some other expressions. However, this advantage was not verified against all basic expressions. Moreover, no research has assessed whether similar differences also exist among other expressions. To tackle these questions, we compared the effects of six basic emotional expressions on recognition memory using a standard old/new recognition task. The experiment also examined whether exposure to different emotional expressions at training creates variable effects on transfer of the trained faces to a new/neutral expression. Our results suggest that happy faces produced better identity recognition relative to disgusted faces, regardless of whether they were tested in the same image or a new image displaying a neutral expression. None of the other emotional expressions created measurable advantage for recognition memory. Overall, our data lend further support for the happy face advantage for long-term recognition memory. However, our detailed analyses also show that the advantage of happy expression on identity recognition may not be equally discernible from all other emotional expressions. PMID- 25540635 TI - Facing danger: how do people behave in times of need? The case of adult attachment styles. AB - Bowlby's (1982) attachment theory has generated an enormous body of research and conceptual elaborations. Although attachment theory and research propose that attachment security provides a person with many adaptive advantages, during all phases of the life cycle, numerous studies indicate that almost half of the human species can be classified as insecurely attached or insecure with respect to attachment. It seems odd that evolution left humans in this vulnerable position, unless there are some advantages to individuals or groups, under at least some conditions, of anxious and avoidant attachment styles. I argue that a social group containing members with different attachment patterns may be more conducive to survival than a homogeneous group of securely attached individuals because each attachment disposition has specific adaptive advantages that promote the survival of the individual and people around him or her when facing threats and perils. In making this argument, I extend the scope of attachment theory and research by considering a broader range of adaptive functions of insecure attachment strategies, and present data to support my argument. PMID- 25540636 TI - High prevalence of self-reported photophobia in adult ADHD. AB - Many adult outpatients with attention-deficit/hyperactivity disorder (ADHD) report an oversensitivity to light. We explored the link between ADHD and photophobia in an online survey (N = 494). Self-reported photophobia was prevalent in 69% of respondents with, and in 28% of respondents without, ADHD (symptoms). The ADHD (symptoms) group wore sunglasses longer during daytime in all seasons. Photophobia may be related to the functioning of the eyes, which mediate dopamine and melatonin production systems in the eye. In the brain, dopamine and melatonin are involved in both ADHD and circadian rhythm disturbances. Possibly, the regulation of the dopamine and melatonin systems in the eyes and in the brain are related. Despite the study's limitations, the results are encouraging for further study on the pathophysiology of ADHD, eye functioning, and circadian rhythm disturbances. PMID- 25540637 TI - Mechanical regulation of bone regeneration: theories, models, and experiments. AB - How mechanical forces influence the regeneration of bone remains an open question. Their effect has been demonstrated experimentally, which has allowed mathematical theories of mechanically driven tissue differentiation to be developed. Many simulations driven by these theories have been presented, however, validation of these models has remained difficult due to the number of independent parameters considered. An overview of these theories and models is presented along with a review of experimental studies and the factors they consider. Finally limitations of current experimental data and how this influences modeling are discussed and potential solutions are proposed. PMID- 25540638 TI - Molecular pathways involved in pregnancy-induced prevention against breast cancer. AB - Pregnancy produces a protective effect against breast cancer in women who had their first full term pregnancy (FTP) in their middle twenties. The later in life the first delivery occurs, the higher the risk of breast cancer development. Also, transiently during the postpartum period, the risk of developing breast cancer increases. This transient increased risk is taken over by a long-lasting protective period. The genomic profile of parous women has shown pregnancy induces a long-lasting "genomic signature" that explains the preventive effect on breast cancer. This signature reveals that chromatin remodeling is the driver of the differentiation process conferred by FTP. The chromatin remodeling process may be the ultimate step mediating the protection of the breast against developing breast cancer in post-menopausal years. PMID- 25540640 TI - Long-term impact of farm management and crops on soil microorganisms assessed by combined DGGE and PLFA analyses. AB - In the present study, long-term organic and conventional managements were compared at the experimental field of Monsampolo del Tronto (Marche region, Italy) with the aim of investigating soil chemical fertility and microbial community structure. A polyphasic approach, combining soil fertility indicators with microbiological analyses (plate counts, PCR-denaturing gradient gel electrophoresis [DGGE] and phospholipid fatty acid analysis [PLFA]) was applied. Organic matter, N as well as some important macro and micronutrients (K, P, Mg, Mn, Cu, and Zn) for crop growth, were more available under organic management. Bacterial counts were higher in organic management. A significant influence of management system and management x crop interaction was observed for total mesophilic bacteria, nitrogen fixing bacteria and actinobacteria. Interestingly, cultivable fungi were not detected in all analyzed samples. PLFA biomass was higher in the organic and Gram positive bacteria dominated the microbial community in both systems. Even if fungal biomass was higher in organic management, fungal PCR-DGGE fingerprinting revealed that the two systems were very similar in terms of fungal species suggesting that 10 years were not enough to establish a new dynamic equilibrium among ecosystem components. A better knowledge of soil biota and in particular of fungal community structure will be useful for the development of sustainable management strategies. PMID- 25540639 TI - The effect of altering the mechanical loading environment on the expression of bone regenerating molecules in cases of distraction osteogenesis. AB - Distraction osteogenesis (DO) is a surgical technique where gradual and controlled separation of two bony fragments following an osteotomy leads to the induction of new bone formation in the distracted gap. DO is used for limb lengthening, correction of bony deformities, and the replacement of bone loss secondary to infection, trauma, and tumors. Although DO gives satisfactory results in most cases, one major drawback of this technique is the prolonged period of time the external fixator has to be kept on until the newly formed bone consolidates thus leading to numerous complications. Numerous attempts at accelerating bone formation during DO have been reported. One specific approach is manipulation of the mechanical environment during DO by applying changes in the standard protocol of distraction. Attempts at changing this mechanical environment led to mixed results. Increasing the rate or applying acute distraction, led to poor bone formation in the distracted zone. On the other hand, the addition of compressive forces (such as weight bearing, alternating distraction with compression or by over-lengthening, and then shortening) has been reported to increase bone formation. It still remains unclear why these alterations may lead to changes in bone formation. While the cellular and molecular changes occurring during the standard DO protocol, specifically increased expression of transforming growth factor-beta1, platelet-derived growth factor, insulin-like growth factor, basic fibroblast growth factor, vascular endothelial growth factor, and bone morphogenic proteins have been extensively investigated, the literature is sparse on the changes occurring when this protocol is altered. It is the purpose of this article to review the pertinent literature on the changes in the expression of various proteins and molecules as a result of changes in the mechanical loading technique in DO and try to define potential future research directions. PMID- 25540642 TI - Powerful fermentative hydrogen evolution of photosynthate in the cyanobacterium Lyngbya aestuarii BL J mediated by a bidirectional hydrogenase. AB - Cyanobacteria are considered good models for biohydrogen production because they are relatively simple organisms with a demonstrable ability to generate H2 under certain physiological conditions. However, most produce only little H2, revert readily to H2 consumption, and suffer from hydrogenase sensitivity to O2. Strains of the cyanobacteria Lyngbya aestuarii and Microcoleus chthonoplastes obtained from marine intertidal cyanobacterial mats were recently found to display much better H2 production potential. Because of their ecological origin in environments that become quickly anoxic in the dark, we hypothesized that this differential ability may have evolved to serve a role in the fermentation of the photosynthate. Here we show that, when forced to ferment internal substrate, these cyanobacteria display desirable characteristics of physiological H2 production. Among them, the strain L. aestuarii BL J had the fastest specific rates and attained the highest H2 concentrations during fermentation of photosynthate, which proceeded via a mixed acid fermentation pathway to yield acetate, ethanol, lactate, H2, CO2, and pyruvate. Contrary to expectations, the H2 yield per mole of glucose was only average compared to that of other cyanobacteria. Thermodynamic analyses point to the use of electron donors more electronegative than NAD(P)H in Lyngbya hydrogenases as the basis for its strong H2 production ability. In any event, the high specific rates and H2 concentrations coupled with the lack of reversibility of the enzyme, at the expense of internal, photosynthetically generated reductants, makes L. aestuarii BL J and/or its enzymes, a potentially feasible platform for large-scale H2 production. PMID- 25540641 TI - Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. AB - The incidence of the autoimmune disease, type 1 diabetes (T1D), has increased dramatically over the last half century in many developed countries and is particularly high in Finland and other Nordic countries. Along with genetic predisposition, environmental factors are thought to play a critical role in this increase. As with other autoimmune diseases, the gut microbiome is thought to play a potential role in controlling progression to T1D in children with high genetic risk, but we know little about how the gut microbiome develops in children with high genetic risk for T1D. In this study, the early development of the gut microbiomes of 76 children at high genetic risk for T1D was determined using high-throughput 16S rRNA gene sequencing. Stool samples from children born in the same hospital in Turku, Finland were collected at monthly intervals beginning at 4-6 months after birth until 2.2 years of age. Of those 76 children, 29 seroconverted to T1D-related autoimmunity (cases) including 22 who later developed T1D, the remaining 47 subjects remained healthy (controls). While several significant compositional differences in low abundant species prior to seroconversion were found, one highly abundant group composed of two closely related species, Bacteroides dorei and Bacteroides vulgatus, was significantly higher in cases compared to controls prior to seroconversion. Metagenomic sequencing of samples high in the abundance of the B. dorei/vulgatus group before seroconversion, as well as longer 16S rRNA sequencing identified this group as Bacteroides dorei. The abundance of B. dorei peaked at 7.6 months in cases, over 8 months prior to the appearance of the first islet autoantibody, suggesting that early changes in the microbiome may be useful for predicting T1D autoimmunity in genetically susceptible infants. The cause of increased B. dorei abundance in cases is not known but its timing appears to coincide with the introduction of solid food. PMID- 25540643 TI - Far from being well understood: multiple protein phosphorylation events control cell differentiation in Bacillus subtilis at different levels. PMID- 25540644 TI - Salmonella as a model for non-cognate Th1 cell stimulation. AB - Salmonella has been a model pathogen for examining CD4 T cell activation and effector functions for many years due to the strength of the Th1 cell response observed during Salmonella infections, the relative ease of use of Salmonella, the availability of Salmonella-specific T cell reagents, and the well characterized nature of the model system, the pathogen, and the immune response elicited. Herein, we discuss the use of Salmonella as a model pathogen to explore the complex interaction of T cells with their inflammatory environment. In particular, we address the issue of bystander activation of naive T cells and non cognate stimulation of activated and memory T cells. Further, we compare and contrast our current knowledge of these non-cognate responses in CD8 versus CD4 T cells. Finally, we make a case for Salmonella as a particularly appropriate model pathogen in the study of non-cognate CD4 T cell responses based on the strength of the Th1 response during infection, the requirement for CD4 T cells in bacterial clearance, and the well-characterized inflammatory response to conserved molecular patterns induced by Salmonella infection. PMID- 25540646 TI - Constructing a framework for risk analyses of climate change effects on the water budget of differently sloped vineyards with a numeric simulation using the Monte Carlo method coupled to a water balance model. AB - Grapes for wine production are a highly climate sensitive crop and vineyard water budget is a decisive factor in quality formation. In order to conduct risk assessments for climate change effects in viticulture models are needed which can be applied to complete growing regions. We first modified an existing simplified geometric vineyard model of radiation interception and resulting water use to incorporate numerical Monte Carlo simulations and the physical aspects of radiation interactions between canopy and vineyard slope and azimuth. We then used four regional climate models to assess for possible effects on the water budget of selected vineyard sites up 2100. The model was developed to describe the partitioning of short-wave radiation between grapevine canopy and soil surface, respectively, green cover, necessary to calculate vineyard evapotranspiration. Soil water storage was allocated to two sub reservoirs. The model was adopted for steep slope vineyards based on coordinate transformation and validated against measurements of grapevine sap flow and soil water content determined down to 1.6 m depth at three different sites over 2 years. The results showed good agreement of modeled and observed soil water dynamics of vineyards with large variations in site specific soil water holding capacity (SWC) and viticultural management. Simulated sap flow was in overall good agreement with measured sap flow but site-specific responses of sap flow to potential evapotranspiration were observed. The analyses of climate change impacts on vineyard water budget demonstrated the importance of site-specific assessment due to natural variations in SWC. The improved model was capable of describing seasonal and site-specific dynamics in soil water content and could be used in an amended version to estimate changes in the water budget of entire grape growing areas due to evolving climatic changes. PMID- 25540645 TI - Histological Analysis of gammadelta T Lymphocytes Infiltrating Human Triple Negative Breast Carcinomas. AB - Breast cancer is the leading cause of cancer death in women and the second most common cancer worldwide after lung cancer. The remarkable heterogeneity of breast cancers influences numerous diagnostic, therapeutic, and prognostic factors. Triple-negative breast carcinomas (TNBCs) lack expression of HER2 and the estrogen and progesterone receptors and often contain lymphocytic infiltrates. Most of TNBCs are invasive ductal carcinomas (IDCs) with poor prognosis, whereas prognostically more favorable subtypes such as medullary breast carcinomas (MBCs) are somewhat less frequent. Infiltrating T-cells have been associated with an improved clinical outcome in TNBCs. The prognostic role of gammadelta T-cells within CD3(+) tumor-infiltrating T lymphocytes remains unclear. We analyzed 26 TNBCs, 14 IDCs, and 12 MBCs, using immunohistochemistry for the quantity and patterns of gammadelta T-cell infiltrates within the tumor microenvironment. In both types of TNBCs, we found higher numbers of gammadelta T-cells in comparison with normal breast tissues and fibroadenomas. The numbers of infiltrating gammadelta T-cells were higher in MBCs than in IDCs. gammadelta T-cells in MBCs were frequently located in direct contact with tumor cells, within the tumor and at its invasive border. In contrast, most gammadelta T-cells in IDCs were found in clusters within the tumor stroma. These findings could be associated with the fact that the patient's prognosis in MBCs is better than that in IDCs. Further studies to characterize these gammadelta T-cells at the molecular and functional level are in progress. PMID- 25540647 TI - Polyphenol oxidase as a biochemical seed defense mechanism. AB - Seed dormancy and resistance to decay are fundamental survival strategies, which allow a population of seeds to germinate over long periods of time. Seeds have physical, chemical, and biological defense mechanisms that protect their food reserves from decay-inducing organisms and herbivores. Here, we hypothesize that seeds also possess enzyme-based biochemical defenses, based on induction of the plant defense enzyme, polyphenol oxidase (PPO), when wild oat (Avena fatua L.) caryopses and seeds were challenged with seed-decaying Fusarium fungi. These studies suggest that dormant seeds are capable of mounting a defense response to pathogens. The pathogen-induced PPO activity from wild oat was attributed to a soluble isoform of the enzyme that appeared to result, at least in part, from proteolytic activation of a latent PPO isoform. PPO activity was also induced in wild oat hulls (lemma and palea), non-living tissues that cover and protect the caryopsis. These results are consistent with the hypothesis that seeds possess inducible enzyme-based biochemical defenses arrayed on the exterior of seeds and these defenses represent a fundamental mechanism of seed survival and longevity in the soil. Enzyme-based biochemical defenses may have broader implications since they may apply to other defense enzymes as well as to a diversity of plant species and ecosystems. PMID- 25540648 TI - Rac1 signaling in the establishment of the fucoid algal body plan. AB - Fucoid zygotes use environmental vectors, including sunlight, to initiate a growth axis a few hours after fertilization. The first division is then transversely oriented by the growth axis, producing daughter cells of distinct fates. The tip growing rhizoid cell gives rise to the holdfast, anchoring the alga to the intertidal substratum, while the opposite thallus cell mainly generates the photosynthetic and reproductive stipe and fronds. Elaboration of this simple growth axis thus establishes the basic body plan of the adult; and elucidating the mechanisms responsible for formation of the growth axis is paramount to understanding fucoid morphogenesis. Recent studies have culminated in a model whereby sunlight, and perhaps other environmental cues, activate the signaling protein Rac1 at the rhizoid pole. Here it sets in motion nucleation of a patch of actin filaments that in turn, targets ions, proteins, and cellular processes to the future growth site. At germination, Rac1 initiates morphogenesis by inducing transformation of the patch of actin filaments to a structure that delivers vesicles to the growing tip, and a few hours later orients the spindle and cytokinetic plate. PMID- 25540649 TI - Reversible ubiquitylation in plant biology. PMID- 25540651 TI - Genetic considerations for mollusk production in aquaculture: current state of knowledge. AB - In 2012, world mollusk production in aquaculture reached a volume of 15,171,000 tons, representing 23% of total aquaculture production and positioning mollusks as the second most important category of aquaculture products (fishes are the first). Clams and oysters are the mollusk species with the highest production levels, followed in descending order by mussels, scallops, and abalones. In view of the increasing importance attached to genetic information on aquaculture, which can help with good maintenance and thus the sustainability of production, the present work offers a review of the state of knowledge on genetic and genomic information about mollusks produced in aquaculture. The analysis was applied to mollusks which are of importance for aquaculture, with emphasis on the 5 species with the highest production levels. According to FAO, these are: Japanese clam Ruditapes philippinarum; Pacific oyster Crassostrea gigas; Chilean mussel Mytilus chilensis; Blood clam Anadara granosa and Chinese clam Sinonovacula constricta. To date, the genomes of 5 species of mollusks have been sequenced, only one of which, Crassostrea gigas, coincides with the species with the greatest production in aquaculture. Another important species whose genome has been sequenced is Mytilus galloprovincialis, which is the second most important mussel in aquaculture production, after M. chilensis. Few genetic improvement programs have been reported in comparison with the number reported in fish species. The most commonly investigated species are oysters, with at least 5 genetic improvement programs reported, followed by abalones with 2 programs and mussels with one. The results of this work will establish the current situation with respect to the genetics of mollusks which are of importance for aquaculture production, in order to assist future decisions to ensure the sustainability of these resources. PMID- 25540653 TI - Does the rattle of Crotalus durissus terrificus reveal its dietary history? AB - BACKGROUND: Environmental devastation threatens the survival of many species, including venomous snakes such as the South American rattlesnake Crotalus durissus terrificus. This observation is based on the decrease of snakes collected and donated to Brazilian research institutes. Nevertheless, some individuals have managed to survive and procreate. The question is how these snakes are adapting in these new environmental conditions. METHODS: To answer it, the carbon-13 level of rattlesnakes and their feed (either laboratory or wild mice) was evaluated by isotope-ratio mass spectrometry. Thus, rattle segments from 16 adults and 15 offspring of captive snakes, and of three wild newborn C. d. terrificus were evaluated as well as 17 Mus musculus mice captured in traps, four live feeder mice and the ration offered to mice at animal houses. RESULTS: The isotopic exchange time of the captive adult snakes (n = 16) varied between 33 and 37 months and of captive-born animals (n = 15), until reaching a plateau of equilibrium, varied from 18 to 24 months. Regarding the captured Mus musculus (n = 17), 88.23% (n = 15) were from a C4 environment. Of the six rattle rings from offspring of captured C. d. terrificus, five were from a C4 environment, whereas of the 170 rattle rings studied, 60% originated from a C3 environment and 40% from a C4. The same carbon-13 values were found in captive snakes. CONCLUSIONS: Based on the present results, it can be inferred that most C. d. terrificus snakes (60%) fed animals from a C3 environment; birds consist of an alimentary alternative for snakes, as well as rodents, small reptiles and amphibians; different venom compositions among snakes from the same region may be related to the food type; the primary rattle of offspring reflects the maternal diet during gestation; and, finally, the different rattle rings indicate the alimentary history of these animals. PMID- 25540652 TI - An integrative assessment to determine the genotoxic hazard of estuarine sediments: combining cell and whole-organism responses. AB - The application of the Comet assay in environmental monitoring remains challenging in face of the complexity of environmental stressors, e.g., when dealing with estuarine sediments, that hampers the drawing of cause-effect relationships. Although the in vitro Comet assay may circumvent confounding factors, its application in environmental risk assessment (ERA) still needs validation. As such, the present work aims at integrating genotoxicity and oxidative DNA damage induced by sediment-bound toxicants in HepG2 cells with oxidative stress-related effects observed in three species collected from an impacted estuary. Distinct patterns were observed in cells exposed to crude mixtures of sediment contaminants from the urban/industrial area comparatively to the ones from the rural/riverine area of the estuary, with respect to oxidative DNA damage and oxidative DNA damage. The extracts obtained with the most polar solvent and the crude extracts caused the most significant oxidative DNA damage in HepG2 cells, as measured by the formamidopyrimidine-DNA glycosylase (FPG) modified Comet assay. This observation suggests that metals and unknown toxicants more hydrophilic than polycyclic aromatic hydrocarbons may be important causative agents, especially in samples from the rural part of the estuary, where oxidative DNA damage was the most significant. Clams, sole, and cuttlefish responded differentially to environmental agents triggering oxidative stress, albeit yielding results accordant with the oxidative DNA damage observed in HepG2 cells. Overall, the integration of in vivo biomarker responses and Comet assay data in HepG2 cells yielded a comparable pattern, indicating that the in vitro FPG modified Comet assay may be an effective and complementary line-of-evidence in ERA even in particularly challenging, natural, scenarios such as estuarine environments. PMID- 25540650 TI - Noncoding RNAs regulate NF-kappaB signaling to modulate blood vessel inflammation. AB - Cardiovascular diseases such as atherosclerosis are one of the leading causes of morbidity and mortality worldwide. The clinical manifestations of atherosclerosis, which include heart attack and stroke, occur several decades after initiation of the disease and become more severe with age. Inflammation of blood vessels plays a prominent role in atherogenesis. Activation of the endothelium by inflammatory mediators leads to the recruitment of circulating inflammatory cells, which drives atherosclerotic plaque formation and progression. Inflammatory signaling within the endothelium is driven predominantly by the pro-inflammatory transcription factor, NF-kappaB. Interestingly, activation of NF-kappaB is enhanced during the normal aging process and this may contribute to the development of cardiovascular disease. Importantly, studies utilizing mouse models of vascular inflammation and atherosclerosis are uncovering a network of noncoding RNAs, particularly microRNAs, which impinge on the NF-kappaB signaling pathway. Here we summarize the literature regarding the control of vascular inflammation by microRNAs, and provide insight into how these microRNA-based pathways might be harnessed for therapeutic treatment of disease. We also discuss emerging areas of endothelial cell biology, including the involvement of long noncoding RNAs and circulating microRNAs in the control of vascular inflammation. PMID- 25540654 TI - Saliva as a surrogate to explore the association between lipid profiles and chronic periodontitis: A case-control study. AB - BACKGROUND: There is abundance of literature delving into whether periodontal infection contributes to changes in serum lipid profiles. Whole saliva is an important physiologic fluid that contains a highly complex mixture of substances. Research on salivary lipid profiles and chronic periodontitis remains unexplored and limited. This study was designed with an aim to investigate the association between the chronic periodontitis and salivary lipid levels and to make use of saliva as a non-invasive diagnostic aid. MATERIALS AND METHODS: This case-control study included 60 subjects of which, 40 were diagnosed as having chronic periodontitis based on the probing depth and clinical attachment levels and 20 healthy subjects as control group. Whole saliva was collected and lipid concentrations (total cholesterol (TC), triglycerides (TG), low density lipoprotein [LDL] and high density lipoprotein [HDL]) were assessed by enzymatic methods and the values were read in ultraviolet-Spectrophotometer. Data was analyzed using student's t test for equality of means. P < 0.05 was considered to be statistically significant. RESULTS: The mean difference in the concentrations of TC and TG in saliva of chronic periodontitis patients were statistically significant (P = 0.02) when compared to the healthy. HDL and LDL concentrations were not statistically significant, but there was a difference in their means. LDL was higher in chronic periodontitis and HDL mean levels were high among the healthy. CONCLUSION: Increased salivary lipids in chronic periodontitis patients suggest an association between hyperlipidemia and periodontitis. The relatively easy and non-invasive nature of saliva can be used as a diagnostic tool to assess the lipid status. Further research is needed to determine its specificity as a surrogate to serum lipid profiles. PMID- 25540655 TI - Noise levels of dental equipment used in dental college of Damascus University. AB - BACKGROUND: In dental practical classes, the acoustic environment is characterized by high noise levels in relation to other teaching areas. The aims of this study were to measure noise levels produced during the different dental learning clinics, by equipments used in dental learning areas under different working conditions and by used and brand new handpieces under different working conditions. MATERIALS AND METHODS: The noise levels were measured by using a noise level meter with a microphone, which was placed at a distance of 15 cm from a main noise source in pre-clinical and clinical areas. In laboratories, the microphone was placed at a distance of 15 cm and another reading was taken 2 m away. Noise levels of dental learning clinics were measured by placing noise level meter at clinic center. The data were collected, tabulated and statistically analyzed using t-tests. Significance level was set at 5%. RESULTS: In dental clinics, the highest noise was produced by micro motor handpiece while cutting on acrylic (92.2 dB) and lowest noise (51.7 dB) was created by ultrasonic scaler without suction pump. The highest noise in laboratories was caused by sandblaster (96 dB at a distance of 15 cm) and lowest noise by stone trimmer when only turned on (61.8 dB at a distance of 2 m). There was significant differences in noise levels of the equipment's used in dental laboratories and dental learning clinics (P = 0.007). The highest noise level recorded in clinics was at pedodontic clinic (67.37 dB). CONCLUSIONS: Noise levels detected in this study were considered to be close to the limit of risk of hearing loss 85 dB. PMID- 25540656 TI - Dental caries and treatment needs of Yemeni children with down syndrome. AB - BACKGROUND: Oral health in Down syndrome (DS) children has some peculiar aspects that must be considered in the follow-up of these patients. The objective of the present study was to assess the prevalence of dental caries and treatment needs among children with DS in Yemen and also to investigate the association between these outcomes with various socio-demographic and clinical variables. MATERIALS AND METHODS: This cross-sectional study involved 96 children with DS aged between 6 and 15 years. Data were gathered through the use of a questionnaire and clinical observation. The dentition status and the treatment needs were recorded according to World Health Organization recommendations. ANOVA, Chi-square test, t test and multiple regression analyses were applied using the statistical package for the social sciences (SPSS, Chicago, IL, USA) version 20.0 software, with P < 0.05 considered as significant. RESULTS: The results showed that 93.8% of the subjects had dental caries; overall, decayed missing filled surfaces (dmfs), decayed missing filled teeth (dmft), DMFS, DMFT were 10.35, 4.44, 4.32 and 2.45, respectively. Stepwise linear regression analysis has revealed that age was the most important predictor for DMFT and DMFS, while early age and less frequent teeth brushing were the most predictors for dmft and dmfs. Restorative care and extractions were the most needed specific treatments. CONCLUSION: The findings of this study demonstrate that children with DS in Yemen have a high prevalence of dental caries and extensive unmet needs of dental treatment. They would benefit from frequent oral health assessment. PMID- 25540657 TI - Microshear bond strength of composite resins to enamel and porcelain substrates utilizing unfilled versus filled resins. AB - BACKGROUND: Failures such as marginal discoloration and composite chipping are still the problems of tooth-colored restorations on the substrate of enamel and porcelain, which some of these problems are consequently as a result of failures in the bonding layer. Using filled resin has been recently introduced to increase the bond strength of this layer. The aim of this study was to compare the microshear bond strength (MU-SBS) of composite resins to enamel incubated in periods of 24 h and 9 months and porcelain with unfilled resin and flowable composites (filled resin). MATERIALS AND METHODS: In this in vitro study, two groups of 75 enamel samples with different storage times (24 h and 9 months) and a group of 75 porcelain samples were used. They were divided into 5 experimental groups of 15 samples in each. Composite cylinders in tygon tubes were bonded on the surface of acid-etched enamel and pretreated porcelain. Wave, Wave MV, Wave HV, Grandioflow and Margin Bond were used as bonding agents. The MU-SBS was measured at the speed of 1.0 mm/min. The bond strengths were analyzed with one way analysis of variance (ANOVA) test followed by Tukey test. P < 0.05 was selected as the level of statistical significance in this study. RESULTS: The results showed that for enamel (24 h), the MU-SBS of the Wave MV and Wave HV groups were significantly lower than the Margin Bond group. Tukey test indicated the absence of a significant difference between the MU-SBS of the Wave group and the Margin Bond group. However, the MU-SBS of the Grandioflow group was significantly higher than the one for the Margin Bond as a bonding agent. In enamel (9 months), there was a significant difference between the Grandioflow and Margin Bond groups. Regarding bonding to the porcelain the one-way ANOVA test did not show a significant difference among the groups. CONCLUSION: This study revealed that flowable composites (filled resins) can be used instead of unfilled resins in bonding composite resins to enamel and porcelain substrates. PMID- 25540658 TI - Cytotoxicity of chlorhexidine-hydrogen peroxide combination in different concentrations on cultured human periodontal ligament fibroblasts. AB - BACKGROUND: A strong antimicrobial synergism between chlorhexidine (CHX) and hydrogen peroxide (H2O2) has been reported, but there is not enough data on the cytotoxicity of this combination. The primary aim of this study was to evaluate the cytotoxicity of CHX-H2O2 combination in different concentrations and secondary aim is to assess the influence of H2O2 on cytotoxicity of CHX on cultured human periodontal ligament (PDL) fibroblasts. MATERIALS AND METHODS: The PDL cells were cultured from healthy human third molar teeth and were exposed to six prepared solutions (0.2% and 2% CHX separately and in combination with 1% and 3% H2O2). The MTT assay was applied to assess their effects on the viability of the PDL cells. Two-way analysis of variance approach and subgroup analysis was performed to evaluate the differences in mean cell viability values. A level of P < 0.05 was considered as statistically significant. RESULTS: All tested solutions were toxic to PDL cells. There was a significant interaction effect between CHX and H2O2. The 2% CHX combined with 3% H2O2 was the most and 0.2% CHX was the least cytotoxic solutions. The 2% CHX was significantly more toxic than 0.2% CHX and H2O2 combinations. The cytotoxicity of 0.2% CHX and H2O2 combinations did not significantly rise by increasing the concentration of H2O2 from 1% to 3%. CONCLUSION: H2O2 affected the cytotoxicity of CHX in a variable concentration dependent manner. Based on the results of this study, it can be concluded that 2% CHX alone and in combination with either 1 or 3% H2O2 are significantly more toxic than 0.2% CHX alone and in combination with 1 and 3% H2O2. Therefore, to benefit from the synergistic antimicrobial effect between CHX and H2O2, with a minimal cytotoxicity, it is recommended to use 0.2% concentration of CHX combined with 3% H2O2. PMID- 25540659 TI - The role of tobacco as an etiological agent for oral cancer: Cytomorphometrical analysis of the buccal mucosa in tobacco users. AB - BACKGROUND: Histopathological diagnosis of lesions arising from the intake of tobacco is based on subjective evaluation of morphological alterations within the lesional tissue. Oral exfoliative cytology is a non-invasive diagnostic technique for early detection of oral premalignant and malignant lesions. Morphometric techniques have been advocated as objective and reproducible methods of detecting changes before they are visible by routine microscopy and can facilitate differentiation of normal and abnormal epithelium. This study was conducted to assess the morphometric parameters (cell diameter, nuclear diameter and nuclear cytoplasmic ratio [N:C ratio]) in tobacco smokers and chewers and to evaluate the variations, if any. MATERIALS AND METHODS: The study was conducted on cytological smears obtained from oral lesions of patients with habit of tobacco smoking (Group B) and tobacco chewing (Group C). Group A comprised of subjects free from oral lesions and not using tobacco in any form. Patients with both the habits were excluded. The smears were stained using Papanicoloaou staining method. For morphometric analysis, Microimage 3.0 image analysis software was employed. The statistical test employed was an analysis of variance and P < 0.05 was considered as significant. RESULTS: The results of this study showed that the cellular diameter was progressively reduced and nuclear diameter progressively increased from Group A to Group B to Group C. The N:C ratio also showed a progressive increase from Group A to Group C. CONCLUSION: The results confirmed that tobacco chewing and smoking influenced the cytomorphology of normal appearing buccal mucosa and the degree of these changes were found to be greater in chewers as compared to smokers. PMID- 25540660 TI - Validity and reliability of a three-dimensional dental cast simulator for arch dimension measurements. AB - BACKGROUND: The accuracy and reproducibility of measurements in a locally made three dimensional (3D) simulator was assessed and compared with manual caliper measurements. MATERIALS AND METHODS: A total of 20 casts were scanned by our laser scanner. Software capabilities included dimensional measurements, transformation and rotation of the cast as a whole, separation and rotation of each tooth and clip far. Two orthodontists measured the intercanine width, intermolar width and canine, molar and arch depth on the casts and in 3D simulator. For calculating the reliability coefficient and comparing random and systematic errors between the two methods, intra-class correlation coefficient of reliability (ICC), Dahlberg and paired t-test were used, respectively. The ICC and Dahlberg's formula were also applied to assess intra-examiner and inter examiner reliability of measurements on the casts and in the simulator (P < 0.05). RESULTS: Canine and molar depth measurements had low reliability on the casts. Reliability between methods for the remaining three variables was 0.87, 0.98 and 0.98 in the maxilla and 0.92, 0.77 and 0.94 in the mandible, respectively. The method error was between 0.31 and 0.48 mm. The mean intra observer difference were 0.086 and 0.23 mm in the 3D method and caliper. The inter-observer differences were 0.21 and 0.42 mm, respectively. CONCLUSION: The maximum average absolute difference between the two methods was <0.5 mm, indicating that the new system is indeed clinically acceptable. The examiner reliability was higher in 3D measurements. PMID- 25540661 TI - Comparison of speech performance in labial and lingual orthodontic patients: A prospective study. AB - BACKGROUND: The intensity and duration of speech difficulty inherently associated with lingual therapy is a significant issue of concern in orthodontics. This study was designed to evaluate and to compare the duration of changes in speech between labial and lingual orthodontics. MATERIALS AND METHODS: A prospective longitudinal clinical study was designed to assess speech of 24 patients undergoing labial or lingual orthodontic treatment. An objective spectrographic evaluation of/s/sound was done using software PRAAT version 5.0.47, a semiobjective auditive evaluation of articulation was done by four speech pathologists and a subjective assessment of speech was done by four laypersons. The tests were performed before (T1), within 24 h (T2), after 1 week (T3) and after 1 month (T4) of the start of therapy. The Mann-Whitney U-test for independent samples was used to assess the significance difference between the labial and lingual appliances. A speech alteration with P < 0.05 was considered to be significant. RESULTS: The objective method showed a significant difference to be present between the two groups for the/s/sound in the middle position (P < 0.001) at T3. The semiobjective assessment showed worst speech performance in the lingual group to be present at T3 for vowels and blends (P < 0.01) and at T3 and T4 for alveolar and palatal consonants (P < 0.01). The subjective assessment also showed a significant difference between the two groups at T3 (P < 0.01) and T4 (P < 0.05). CONCLUSION: Both appliance systems caused a comparable speech difficulty immediately after bonding (T2). Although the speech recovered within a week in the labial group (T3), the lingual group continued to experience discomfort even after a month (T4). PMID- 25540662 TI - Transcutaneous electrical nerve stimulation therapy: An adjuvant pain controlling modality in TMD patients - A clinical study. AB - BACKGROUND: The use of transcutaneous electrical nerve stimulation (TENS) in dentistry was first described in 1967, by Shane and Kessler, but it has yet to gain widespread acceptance in dentistry. A study was undertaken to evaluate the effectiveness of TENS therapy as an adjuvant modality and to compare it with the conventional medication in controlling pain in temporomandibular disorder (TMD) patients. MATERIALS AND METHODS: The study was carried out in the Department of Oral Medicine and Radiology, Yenepoya Dental College and Hospital, Mangalore. A total of 40 patients with the clinical symptom of pain associated with TMDs were randomly divided into two groups. Group A (control) patients were treated with medication (analgesics and muscle relaxants) alone, while group B patients were treated with TENS therapy in combination with medication. The intensity of the pain was assessed using the Visual Analog Scale (VAS). The results were analyzed with the student's 't' test. A P-value < 0.05 was considered as significant. RESULTS: A significant improvement was observed in both the TENS and the control group in terms of pain control. On comparative analysis, adjuvant TENS therapy was found to be more effective than medication alone, in controlling pain. (P value = 0.019). CONCLUSION: The observed data suggest that TENS therapy can be used as an adjuvant modality in the management of pain associated with TMDs. This study justifies the use of TENS therapy in the management of TMD. PMID- 25540663 TI - Bacterial colonization on coated and uncoated orthodontic wires: A prospective clinical trial. AB - BACKGROUND: The advantages of coated orthodontic wires such as esthetic and their effects on reduced friction, corrosion and allergic reaction and the significant consequences of plaque accumulation on oral health encouraged us to assess bacterial colonization on these wires. MATERIALS AND METHODS: A total of 18 (9 upper and 9 lower) epoxy resin coated 16 * 22 nickel-titanium wires (Spectra, GAC, USA) and 18 (9 upper and 9 lower) non-coated 16 * 22 nickel-titanium wires (Sentalloy, GAC, USA) with isolated packages were selected and sterilized before application. The samples were divided randomly between upper and lower arches in 18 patients and hence that every patient received one coated and one uncoated wire at the same time. Samples were removed and cut in equal lengths after 3 weeks and placed in phosphate buffered saline buffer. After separation of bacteria in trypsin and ethylenediaminetetraacetic acid solution, the diluted solution was cultured in blood agar and bacterial colony forming units were counted. Finally, the data was analyzed using the paired t-test and the significance was set at 0.05. RESULTS: Mean of bacterial colonization on uncoated wires was more than that of coated wires (P < 0.001). CONCLUSION: Bacterial plaque accumulation on epoxy resin coated nickel-titanium orthodontic wires is significantly lower than uncoated nickel-titanium wires. PMID- 25540664 TI - Evaluation of relationship between oral health-related quality of life and occlusion traits among female adolescents. AB - BACKGROUND: The aim of this study was to determine the impact of malocclusions on oral health-related quality of life (OHRQOL) among female adolescents. MATERIALS AND METHODS: This is an observational cross-sectional descriptive study. A total of 129 female students with age ranges between 14 and 17 years old were randomly selected from Mashhad (Iran) high schools and were asked to fill out an OHRQOL questionnaire included in four parts: Oral symptoms, functional limitations, emotional well-being and social well-being. Each participant was clinically examined to assess her malocclusion according to the index of complexity, outcome and need (ICON) and finally the data were entered to SPSS 11.5 and the relation between these two variables was assessed with Pearson correlation test. P < 0.05 was considered as statistically significant. RESULTS: There was statistically significant correlation between ICON scores and quality of life (P = 0.0176). Being separately assessed, among four parts of the questionnaire, only emotional well-being was significantly correlated with the ICON score (P < 0.05). CONCLUSION: Malocclusions play a vital role in OHRQOL. However, in female adolescents among four parts of OHRQOL, emotional well-being had significant relationship with malocclusions. PMID- 25540665 TI - Shear bond strength of resin composite bonded with two adhesives: Influence of Er: YAG laser irradiation distance. AB - BACKGROUND: Dental surfaces prepared with different Er:YAG laser distance may have different characteristics compared with those prepared with conventional instruments. The aim of this study was to investigate the effect of Er:YAG laser irradiation distance from enamel and dentin surfaces on the shear bond strength of composite with self-etch and etch and rinse bonding systems compared with conventional preparation method. MATERIALS AND METHODS: Two hundred caries-free human third molars were randomly divided into twenty groups (n = 10). Ten groups were designated for enamel surface (E1-E10) and ten for dentin surface (D1-D10). Er: YAG laser (2940 nm) was used on the E1-E8 (240 mJ, 25 Hz) and D1-D8 (140 mJ, 30 Hz) groups at four different distances of 0.5 (standard), 2, 4 and 11 mm. Control groups (E9, E10, D9 and D10) were ground with medium grit diamond bur. The enamel and dentin specimens were divided into two subgroups that were bonded with either Single Bond or Clearfil SE Bond. Resin composite (Z100) was dispensed on prepared dentin and enamel. The shear bond strengths were tested using a universal testing machine. Data were analyzed by SPSS12 statistical software using three way analysis of variance, Tukey and independent t-test. P < 0.05 was considered as significant. RESULTS: There was a significant difference between enamel and dentin substrates (P < 0.001) and between lased and un-lased groups; the un-lased group had significantly higher bond strength (P < 0.001). Shear bond strength increased significantly with an increase in the laser irradiation distance (P < 0.05) on enamel surfaces (in both bonding agent subgroups) and on dentin surfaces (in the Single Bond subgroup). CONCLUSION: Laser irradiation decreases shear bond strength. Irradiation distance affects shear bond strength and increasing the distance would decrease the negative effects of laser irradiation. PMID- 25540666 TI - Corono-radicular biological restoration of maxillary central incisors by direct method. AB - This case report refers to the esthetic and functional restorations of extensively damaged maxillary central incisors with dental caries in a 32-year old woman, with the use of posts and crowns made from natural extracted teeth. Proper restoration of such teeth with the use of natural teeth fragments are known as "biological restoration." Biological restorations can be done by using the fragments of the patients own tooth and if that is not available, tooth fragment can be obtained from an extracted tooth. These biological posts and crowns present a low cost option and an alternative technique for the morphofunctional recovery of extensively damaged teeth. There are limitations with the use of natural extracted teeth (homogenous bonding) for restoration such as the difficulty of finding teeth with a similar color and shape as that of the destroyed element, or patient may refuse to accept a tooth fragment from another patient, which prevents execution of the restoration. PMID- 25540667 TI - The role of cone beam computed tomography in the endodontic management of a mandibular first molar with three distal canals. AB - The presence of three root canals in the distal root of the mandibular first permanent molars is rare; based on in vitro studies its incidence is reported to be between 0.2% and 3%. With the advent of cone beam computed tomography (CBCT) as an adjunctive diagnostic aid, the determination of root canal anatomy in teeth with extra canals and complex canal configurations has become more precise. CBCT provides three dimensional visualization of the pulp canal space, allowing the clinician in determining the spatial relationships of the root canals with each other at various cross sectional levels along the length of the root. The present report discusses the endodontic management of a mandibular first permanent molar with three canals in the distal root, employing CBCT as an adjunctive diagnostic aid to conventional radiography. PMID- 25540668 TI - Autogenous wisdom tooth transplantation: A case series with 6-9 months follow-up. AB - Tooth transplantation can be considered a valid and predictable treatment option for rehabilitating young patients with permanent teeth loss. This study presents several cases of successful autogenous tooth transplantation with a 6-9 months follow-up. Tooth auto-transplantation can be considered a reasonable option for replacing missing teeth when a donor tooth is available. The auto-transplantation of a right mandibular third molar with compromised function and esthetics to replace the residual roots resulting from coronal destruction due to extensive carious lesion of the second molar in the same quadrant as shown in the presented cases can result a viable treatment alternative especially in a young patient that cannot undergo dental implant therapy. Transplantation of mature third molar seems to be a promising method for replacing a lost permanent molar tooth and restoring esthetics and function. This clinical procedure showed excellent functional and esthetical long-term results in the analyzed cases. PMID- 25540669 TI - Imaging and Timing Performance of 1cm * 1cm Position-sensitive Solid-state Photomultiplier. AB - We have designed and built a large-area 1cm * 1cm position-sensitive solid-state photomultiplier (PS-SSPM) for use in detector design for medical imaging applications. Our new large-area PS-SSPM concept implements resistive network between the micro-pixels, which are photodiodes operated in Geiger mode, called Geiger Photodiodes (GPDs), to provide continuous position sensitivity. Here we present imaging and timing performance of the large-area PS-SSPM for different temperatures and operating biases to find the optimum operating parameters for the device in imaging applications. A detector module was built by coupling a polished 8*8 LYSO array, with 1*1*20 mm3 elements, to a 1*1 cm2 PS-SSPM. Flood images recorded at room temperature show good crystal separation as all 64 elements were separated from each other. Cooling the device at 10 degrees C showed significant improvement. The device optimum bias voltage was ~4.5V over breakdown voltage. The coincidence timing resolution was improved significantly by increasing the operating bias, as well as by lowering the temperature to 0 degrees C. Results show excellent imaging performance and good timing response with a large-area PS-SSPM device. PMID- 25540670 TI - "Walking alongside:" collaborative practices in mental health and substance use care. AB - BACKGROUND: Although the importance of collaboration is well established as a principle in research and in theory, what it actually means for practitioners to collaborate in practice, to be partners in a collaborative relationship, has thus far been given less attention. The aim of this study was to identify key characteristics of the ways in which mental health practitioners collaborate with service users and their families in practice. METHODS: This was a qualitative action research study, with a cooperative inquiry approach that used multi-staged focus group discussions with ten mental health care and social work practitioners in community mental health and substance use care. Thematic analysis was applied to identify common characteristics. RESULTS: We identified three major themes related to practitioners' experiences of collaborative practices: (1) walking alongside through negotiated dialogues, (2) maintaining human relationships, and (3) maneuvering relationships and services. CONCLUSIONS: It appears that even with the rich knowledgebase that has developed on the merits of collaborative relationships, it continues to be challenging for practitioners to reorient their practice accordingly. The findings of this study indicate that the practitioners focus on two types of processes as characterizing collaborative practice: one focusing on conversations among practitioners and service users and their families and the other focusing on management and control among health care providers, service sectors, and service users (i.e., inter/intra-system collaboration). PMID- 25540671 TI - Familial 1q22 microduplication associated with psychiatric disorders, intellectual disability and late-onset autoimmune inflammatory response. AB - BACKGROUND: Despite the extensive use of chromosomal microarray technologies in patients with neurodevelopmental disorders has permitted the identification of an increasing number of causative submicroscopic rearrangements throughout the genome, constitutional duplications involving chromosome 1q22 have seldom been described in those patients. RESULTS: We report on a pedigree with seven affected members showing varying degrees of behavioural and emotional disturbances including general anxiety disorder, mood disorders, and intellectual disability. Two adult female patients also showed late onset autoimmune inflammatory responses characterized by alopecia, skin ulcers secondary to inflammatory vasculitis, interstitial lung disease, and Raynaud's phenomenon. Array-CGH analysis identified in the affected individuals a 290 Kb microduplication in the chromosome 1q22. The rearrangement involves eleven known genes and is not present in the databases of polymorphic copy number variants. CONCLUSIONS: The rearrangement segregates with the neurological clinical features observed in our patients, suggesting that dosage imbalance of one or more genes in this genomic region may lead to the observed phenotype. The association between the microduplication and the inflammatory disease is much less evident. Additional reported patients carrying similar microduplications are needed to clarify this aspect. PMID- 25540672 TI - Serum prolidase activity is associated with non-diabetic metabolic syndrome. AB - OBJECTIVE: The aim of this study was to determine the role of serum prolidase activity and the possible association with oxidative stress parameters in non diabetic metabolic syndrome. METHODS: 30 obese patients without metabolic syndrome (MetS), 34 non-diabetic obese patients with MetS, and 23 volunteer control subjects were enrolled in the study. Fasting plasma glucose (FPG), plasma glucose following 75 g glucose administration, high-density lipoprotein- cholesterol (HDL-C), high-density lipoprotein- cholesterol (LDL-C), total cholesterol, triglyceride (TG), total antioxidant status (TAS), total oxidative status (TOS), oxidative stress index (OSI), and prolidase activities of all subjects were analyzed. RESULTS: Prolidase levels was significantly higher in MetS group compared to both obese and control groups (p < 0.001 and p < 0.05 respectively). Prolidase was also higher in the obese group than in the control group (p < 0.05). Prolidase was negatively correlated with TAS and HDL-C (r = 0,362, p < 0.001; r = -0.320, p < 0.01, respectively) and positively correlated with BMI, weight, waist-c, SBP, DBP, TG, TC, LDL-C. CONCLUSION: Prolidase activity may have a role in the pathogenesis of metabolic syndrome. PMID- 25540673 TI - The inverse niche model for food webs with parasites. AB - Although parasites represent an important component of ecosystems, few field and theoretical studies have addressed the structure of parasites in food webs. We evaluate the structure of parasitic links in an extensive salt marsh food web, with a new model distinguishing parasitic links from non-parasitic links among free-living species. The proposed model is an extension of the niche model for food web structure, motivated by the potential role of size (and related metabolic rates) in structuring food webs. The proposed extension captures several properties observed in the data, including patterns of clustering and nestedness, better than does a random model. By relaxing specific assumptions, we demonstrate that two essential elements of the proposed model are the similarity of a parasite's hosts and the increasing degree of parasite specialization, along a one-dimensional niche axis. Thus, inverting one of the basic rules of the original model, the one determining consumers' generality appears critical. Our results support the role of size as one of the organizing principles underlying niche space and food web topology. They also strengthen the evidence for the non random structure of parasitic links in food webs and open the door to addressing questions concerning the consequences and origins of this structure. PMID- 25540674 TI - Dynamics of nutrient uptake strategies: lessons from the tortoise and the hare. AB - Many autotrophs vary their allocation to nutrient uptake in response to environmental cues, yet the dynamics of this plasticity are largely unknown. Plasticity dynamics affect the extent of single versus multiple nutrient limitation and thus have implications for plant ecology and biogeochemical cycling. Here we use a model of two essential nutrients cycling through autotrophs and the environment to determine conditions under which different plastic or fixed nutrient uptake strategies are adaptive. Our model includes environment-independent costs of being plastic, environment-dependent costs proportional to the rate of plastic change, and costs of being mismatched to the environment, the last of which is experienced by both fixed and plastic types. In equilibrium environments, environment-independent costs of being plastic select for tortoise strategies-fixed or less plastic types-provided that they are sufficiently close to co-limitation. At intermediate levels of environmental fluctuation forced by periodic nutrient inputs, more hare-like plastic strategies prevail because they remain near co-limitation. However, the fastest is not necessarily the best. The most adaptive strategy is an intermediate level of plasticity that keeps pace with environmental fluctuations, but is not faster. At high levels of environmental fluctuation, the environment-dependent cost of changing rapidly to keep pace with the environment becomes prohibitive and tortoise strategies again dominate. The existence and location of these thresholds depend on plasticity costs and rate, which are largely unknown empirically. These results suggest that the expectations for single nutrient limitation versus co-limitation and therefore biogeochemical cycling and autotroph community dynamics depend on environmental heterogeneity and plasticity costs.Electronic supplementary material The online version of this article (doi:10.1007/s12080-010-0110-0) contains supplementary material, which is available to authorized users. PMID- 25540675 TI - Simple models for complex systems: exploiting the relationship between local and global densities. AB - Simple temporal models that ignore the spatial nature of interactions and track only changes in mean quantities, such as global densities, are typically used under the unrealistic assumption that individuals are well mixed. These so-called mean-field models are often considered overly simplified, given the ample evidence for distributed interactions and spatial heterogeneity over broad ranges of scales. Here, we present one reason why such simple population models may work even when mass-action assumptions do not hold: spatial structure is present but it relates to global densities in a special way. With an individual-based predator-prey model that is spatial and stochastic, and whose mean-field counterpart is the classic Lotka-Volterra model, we show that the global densities and densities of pairs (or spatial covariances) establish a bi-power law at the stationary state and also in their transient approach to this state. This relationship implies that the dynamics of global densities can be written simply as a function of those densities alone without invoking pairs (or higher order moments). The exponents of the bi-power law for the predation rate exhibit a remarkable robustness to changes in model parameters. Evidence is presented for a connection of our findings to the existence of a critical phase transition in the dynamics of the spatial system. We discuss the application of similar modified mean-field equations to other ecological systems for which similar transitions have been described, both in models and empirical data.Electronic supplementary material The online version of this article (doi:10.1007/s12080-011 0116-2) contains supplementary material, which is available to authorized users. PMID- 25540676 TI - Why dispersal should be maximized at intermediate scales of heterogeneity. AB - Dispersal is a fundamental biological process that results in the redistribution of organisms due to the interplay between the mode of dispersal, the range of scales over which movement occurs, and the scale of spatial heterogeneity, in which patchiness may occur across a broad range of scales. Despite the diversity of dispersal mechanisms and dispersal length scales in nature, we posit that a fundamental scaling relationship should exist between dispersal and spatial heterogeneity. We present both a conceptual model and mathematical formalization of this expected relationship between the scale of dispersal and the scale of patchiness, which predicts that the magnitude of dispersal (number of individuals) among patches should be maximized when the scale of spatial heterogeneity (defined in terms of patch size and isolation) is neither too fine nor too coarse relative to the gap-crossing abilities of a species. We call this the "dispersal scaling hypothesis" (DSH). We demonstrate congruence in the functional form of this relationship under fundamentally different dispersal assumptions, using well-documented isotropic dispersal kernels and empirically derived dispersal parameters from diverse species, in order to explore the generality of this finding. The DSH generates testable hypotheses as to when and under what landscape scenarios dispersal is most likely to be successful. This provides insights into what management scenarios might be necessary to either restore landscape connectivity, as in certain conservation applications, or disrupt connectivity, as when attempting to manage landscapes to impede the spread of an invasive species, pest, or pathogen. PMID- 25540677 TI - CHARACTERIZING WHITE MATTER CONNECTIVITY IN MAJOR DEPRESSIVE DISORDER: AUTOMATED FIBER QUANTIFICATION AND MAXIMUM DENSITY PATHS. AB - Diffusion-weighted imaging allows for in vivo assessment of white matter structure, which can be used to assess aberrations associated with disease. Several new methods permit the automated assessment of important white matter characteristics. In the current study we used Automated Fiber Quantification (AFQ) to assess differences between depressed and nondepressed individuals in 18 major white matter tracts. We then used the Maximum Density Path (MDP) method to further characterize group differences identified with AFQ. The results of the AFQ analyses indicated that fractional anisotropy (FA; an index of white matter integrity) along bilateral corticospinal tracts (CST) was higher in depressed than in nondepressed individuals. MDP analyses revealed that white matter anomalies were restricted to four subregions that included the corona radiata and the internal and external capsules. These results provide further evidence that MDD is associated with abnormalities in cortical-to-subcortical connectivity. PMID- 25540678 TI - Comparative analysis of NRF2-responsive gene expression in AcPC-1 pancreatic cancer cell line. AB - NRF2 is a nuclear transcription factor activated in response to oxidative stress and related with metabolizing of xenotoxic materials and ABC transporter mediated drug resistance. We studied the expression of mRNAs under the siRNA-mediated knockdown of NRF2 and tBHQ-treated condition in AsPC-1 metastatic pancreatic cancer cell line to understand the AsPC-1 specific role(s) of NRF2 and further to investigate the relationship between drug resistance and metastatic plasticity and mobility of AsPc1. Here we show that the genes of aldo-keto reductases, cytochrome P450 family, aldehyde dehydrogenase, thioredoxin reductase, ABC transporter and epoxide hydrolase responsible for drug metabolism or oxidative stress concisely responded to NRF2 stabilization and knockdown of NRF2. In addition the expression of PIR, a candidate of oncogene and KISS1, a suppressor of metastasis were affected by NRF2 stabilization and knockdown. Our result provide comprehensive understanding of NRF2 target genes of drug response, oxidative stress response and metastasis in AsPc-1 metastatic pancreatic cancer cell line. PMID- 25540679 TI - Association study between autistic-like traits and polymorphisms in the autism candidate regions RELN, CNTNAP2, SHANK3, and CDH9/10. AB - BACKGROUND: Autistic-like traits (ALTs) are continuously distributed in the general population, with the autism spectrum disorder (ASD) at the upper extreme end. A genetic overlap has been shown between ALTs and ASD, indicating that common variation in ASD candidate genes may also influence ALTs. In our study, we have investigated the SNP rs4307059 that has been associated with both ALTs and ASD. In addition, we genotyped polymorphisms in a selection of genes involved in synaptic functioning, that is, SHANK3, RELN, and CNTNAP2, which repeatedly have been associated with ASD. The possible associations of these polymorphisms with ALTs, as well as genetic factors for neurodevelopmental problems (NDPs), were investigated in a large cohort from the general population: The Child and Adolescent Twin Study in Sweden. For analyses of ALTs and NDPs, 12,319 subjects (including 2,268 monozygotic (MZ) and 3,805 dizygotic (DZ) twin pairs) and 8,671 subjects (including 2,243 MZ and 2,044 DZ twin pairs), respectively, were included in the analyses. FINDINGS: We could not replicate the previous association between rs4307059 and social communication impairment. Moreover, common variations in CNTNAP2 (rs7794745 and rs2710102), RELN (rs362691), and SHANK3 (rs9616915) were not significantly associated with ALTs in our study. CONCLUSIONS: Our results do not suggest that the investigated genes, which previously has been found associated with ASD diagnosis, have any major influence on ALTs in children from the general population. PMID- 25540680 TI - A use case study on late stent thrombosis for ontology-based temporal reasoning and analysis. AB - In this paper, we show how we have applied the Clinical Narrative Temporal Relation Ontology (CNTRO) and its associated temporal reasoning system (the CNTRO Timeline Library) to trend temporal information within medical device adverse event report narratives. 238 narratives documenting occurrences of late stent thrombosis adverse events from the Food and Drug Administration's (FDA) Manufacturing and User Facility Device Experience (MAUDE) database were annotated and evaluated using the CNTRO Timeline Library to identify, order, and calculate the duration of temporal events. The CNTRO Timeline Library had a 95% accuracy in correctly ordering events within the 238 narratives. 41 narratives included an event in which the duration was documented, and the CNTRO Timeline Library had an 80% accuracy in correctly determining these durations. 77 narratives included documentation of a duration between events, and the CNTRO Timeline Library had a 76% accuracy in determining these durations. This paper also includes an example of how this temporal output from the CNTRO ontology can be used to verify recommendations for length of drug administration, and proposes that these same tools could be applied to other medical device adverse event narratives in order to identify currently unknown temporal trends. PMID- 25540682 TI - Resting state amygdala-prefrontal connectivity predicts symptom change after cognitive behavioral therapy in generalized social anxiety disorder. AB - BACKGROUND: Aberrant amygdala-prefrontal interactions at rest and during emotion processing are implicated in the pathophysiology of generalized social anxiety disorder (gSAD), a common disorder characterized by fears of potential scrutiny. Cognitive behavioral therapy (CBT) is first-line psychotherapy for gSAD and other anxiety disorders. While CBT is generally effective, there is a great deal of heterogeneity in treatment response. To date, predictors of success in CBT for gSAD include reduced amygdala reactivity and increased activity in prefrontal regulatory regions (e.g., anterior cingulate cortex, "ACC") during emotion processing. However, studies have not examined whether tonic (i.e., at rest) coupling of amygdala and these prefrontal regions also predict response to CBT. RESULTS: Twenty-one patients with gSAD participated in resting-state functional magnetic resonance imaging (fMRI) before 12 weeks of CBT. Overall, symptom severity was significantly reduced after completing CBT; however, the patients varied considerably in degree of symptom change. Whole-brain voxel-wise findings showed symptom improvement after CBT was predicted by greater right amygdala pregenual ACC ("pgACC") connectivity and greater left amygdala-pgACC coupling encompassing medial prefrontal cortex. In support of their predictive value, area under receiver operating characteristic curve was significant for the left and right amygdala-pgACC in relation to treatment responders. CONCLUSIONS: Improvement after CBT was predicted by enhanced resting-state bilateral amygdala prefrontal coupling in gSAD. Preliminary results suggest baseline individual differences in a fundamental circuitry that may underlie emotion regulation contributed to variation in symptom change after CBT. Findings offer a new approach towards using a biological measure to foretell who will most likely benefit from CBT. In particular, the departure from neural predictors based on illness-relevant stimuli (e.g., socio-emotional stimuli in gSAD) permits the development of biomarkers that reflect commonalities in the neurobiology of anxiety and mood disorders. PMID- 25540681 TI - Brain white matter integrity and association with age at onset in pediatric obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and debilitating neuropsychiatric illness thought to involve abnormal connectivity of widespread brain networks, including frontal-striatal-thalamic circuits. At least half of OCD cases arise in childhood and their underlying neuropathology may differ at least in part from that of adult-onset OCD. Yet, only a few studies have examined brain white matter (WM) integrity in childhood-onset OCD using diffusion tensor imaging (DTI), and none have examined potential associations with age at onset. RESULTS: In this study, 17 youth with OCD and 19 healthy control subjects, ages 10 to 19 years, underwent DTI on a 3T Siemens scanner. DSM-IV diagnoses were established with standardized interviews, and OCD symptom severity was evaluated using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Voxel-wise analyses were conducted on data processed with tract-based spatial statistics (TBSS) to derive measures of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). OCD patients had significantly lower FA in seven WM clusters, with over 80% of significant voxels in bilateral frontal cortex and corpus callosum (CC). There were no regions of significantly higher FA in patients compared with controls. Patients also had significantly higher RD in right frontal cortex and right body of the CC. Earlier age at onset of OCD correlated significantly with lower FA in the right thalamus and with higher RD in the right CC. FA and RD were not significantly associated with symptom severity. CONCLUSIONS: These findings point to compromised WM integrity and reduced myelination in some brain regions of children with OCD, particularly the CC and fiber tracts that connect the frontal lobes to widespread cortical and subcortical targets. They also suggest that age at onset may be a moderator of some of the WM changes in pediatric OCD. PMID- 25540683 TI - Alate susceptibility in ants. AB - Pathogens are predicted to pose a particular threat to eusocial insects because infections can spread rapidly in colonies with high densities of closely related individuals. In ants, there are two major castes: workers and reproductives. Sterile workers receive no direct benefit from investing in immunity, but can gain indirect fitness benefits if their immunity aids the survival of their fertile siblings. Virgin reproductives (alates), on the other hand, may be able to increase their investment in reproduction, rather than in immunity, because of the protection they receive from workers. Thus, we expect colonies to have highly immune workers, but relatively more susceptible alates. We examined the survival of workers, gynes, and males of nine ant species collected in Peru and Canada when exposed to the entomopathogenic fungus Beauveria bassiana. For the seven species in which treatment with B. bassiana increased ant mortality relative to controls, we found workers were significantly less susceptible compared with both alate sexes. Female and male alates did not differ significantly in their immunocompetence. Our results suggest that, as with other nonreproductive tasks in ant colonies like foraging and nest maintenance, workers have primary responsibility for colony immunity, allowing alates to specialize on reproduction. We highlight the importance of colony-level selection on individual immunity in ants and other eusocial organisms. PMID- 25540684 TI - Differences in the thermal physiology of adult Yarrow's spiny lizards (Sceloporus jarrovii) in relation to sex and body size. AB - Sexual size dimorphism (SSD) is often assumed to reflect the phenotypic consequences of differential selection operating on each sex. Species that exhibit SSD may also show intersexual differences in other traits, including field-active body temperatures, preferred temperatures, and locomotor performance. For these traits, differences may be correlated with differences in body size or reflect sex-specific trait optima. Male and female Yarrow's spiny lizards, Sceloporus jarrovii, in a population in southeastern Arizona exhibit a difference in body temperature that is unrelated to variation in body size. The observed sexual variation in body temperature may reflect divergence in thermal physiology between the sexes. To test this hypothesis, we measured the preferred body temperatures of male and female lizards when recently fed and fasted. We also estimated the thermal sensitivity of stamina at seven body temperatures. Variation in these traits provided an opportunity to determine whether body size or sex-specific variation unrelated to size shaped their thermal physiology. Female lizards, but not males, preferred a lower body temperature when fasted, and this pattern was unrelated to body size. Larger individuals exhibited greater stamina, but we detected no significant effect of sex on the shape or height of the thermal performance curves. The thermal preference of males and females in a thermal gradient exceeded the optimal temperature for performance in both sexes. Our findings suggest that differences in thermal physiology are both sex- and size-based and that peak performance at low body temperatures may be adaptive given the reproductive cycles of this viviparous species. We consider the implications of our findings for the persistence of S. jarrovii and other montane ectotherms in the face of climate warming. PMID- 25540685 TI - The phenotypic variance gradient - a novel concept. AB - Evolutionary ecologists commonly use reaction norms, which show the range of phenotypes produced by a set of genotypes exposed to different environments, to quantify the degree of phenotypic variance and the magnitude of plasticity of morphometric and life-history traits. Significant differences among the values of the slopes of the reaction norms are interpreted as significant differences in phenotypic plasticity, whereas significant differences among phenotypic variances (variance or coefficient of variation) are interpreted as differences in the degree of developmental instability or canalization. We highlight some potential problems with this approach to quantifying phenotypic variance and suggest a novel and more informative way to plot reaction norms: namely "a plot of log (variance) on the y-axis versus log (mean) on the x-axis, with a reference line added". This approach gives an immediate impression of how the degree of phenotypic variance varies across an environmental gradient, taking into account the consequences of the scaling effect of the variance with the mean. The evolutionary implications of the variation in the degree of phenotypic variance, which we call a "phenotypic variance gradient", are discussed together with its potential interactions with variation in the degree of phenotypic plasticity and canalization. PMID- 25540686 TI - Do highly ornamented and less parasitized males have high quality sperm? - an experimental test for parasite-induced reproductive trade-offs in European minnow (Phoxinus phoxinus). AB - Parasites take their resources from hosts and thus directly reduce available resources for hosts' own body functions, such as growth and reproduction. Furthermore, parasite infections cause significant indirect costs to their hosts in terms of increased investments on immune defense. In this study, we investigated the impact of parasite infection on the sperm quality and expression of secondary sexual ornamentation (saturation of the red abdominal colouration and number of breeding tubercles) in the Eurasian minnow (Phoxinus phoxinus). We exposed minnows to a high and low dose of common nonspecific fish ectoparasite, the glochidia larvae of duck mussel (Anodonta anatina) and tested whether parasite infection leads to trade-off in sperm quality and/or ornamental expression. We found that glochidia infection reduces the curvature of the sperm swimming trajectory, number of breeding tubercles, and possibly male competitive ability, but does not affect expression of male color ornamentation. Furthermore, glochidia infection was found to reduce sperm motility, but only when all the noninfected individuals were excluded from the model. Supporting one of the predictions by phenotype-linked fertility hypothesis both in high-infection and low-infection group male breeding colouration was positively associated with sperm quality. Our results suggest that although glochidia infection may have negative impact on male reproductive success, parasite-induced costs may not create strong trade-off between breeding colouration and sperm quality or that such trade-off become detectable only in resource-limited conditions. PMID- 25540687 TI - An integrated modeling approach to estimating Gunnison sage-grouse population dynamics: combining index and demographic data. AB - Evaluation of population dynamics for rare and declining species is often limited to data that are sparse and/or of poor quality. Frequently, the best data available for rare bird species are based on large-scale, population count data. These data are commonly based on sampling methods that lack consistent sampling effort, do not account for detectability, and are complicated by observer bias. For some species, short-term studies of demographic rates have been conducted as well, but the data from such studies are typically analyzed separately. To utilize the strengths and minimize the weaknesses of these two data types, we developed a novel Bayesian integrated model that links population count data and population demographic data through population growth rate (lambda) for Gunnison sage-grouse (Centrocercus minimus). The long-term population index data available for Gunnison sage-grouse are annual (years 1953-2012) male lek counts. An intensive demographic study was also conducted from years 2005 to 2010. We were able to reduce the variability in expected population growth rates across time, while correcting for potential small sample size bias in the demographic data. We found the population of Gunnison sage-grouse to be variable and slightly declining over the past 16 years. PMID- 25540688 TI - A phylogenetic analysis of the British flora sheds light on the evolutionary and ecological factors driving plant invasions. AB - Darwin's naturalization hypothesis predicts that invasive species should perform better in their novel range in the absence of close relatives in the native flora due to reduced competition. Evidence from recent taxonomic and phylogenetic-based studies, however, is equivocal. We test Darwin's naturalization hypothesis at two different spatial scales using a fossil-dated molecular phylogenetic tree of the British native and alien flora (ca. 1600 species) and extensive, fine-scale survey data from the 1998 Countryside Survey. At both landscape and local scales, invasive species were neither significantly more nor less related to the native flora than their non-invasive alien counterparts. Species invasiveness was instead correlated with higher nitrogen and moisture preference, but not other life history traits such as life-form and height. We argue that invasive species spread in Britain is hence more likely determined by changes in land use and other anthropogenic factors, rather than evolutionary history. Synthesis. The transition from non-invasive to invasive is not related to phylogenetic distinctiveness to the native community, but instead to their environmental preferences. Therefore, combating biological invasions in the Britain and other industrialized countries need entirely different strategies than in more natural environments. PMID- 25540689 TI - Phylogeography and palaeodistribution modelling of Nassauvia subgenus Strongyloma (Asteraceae): exploring phylogeographical scenarios in the Patagonian steppe. AB - The Patagonian steppe is an immense, cold, arid region, yet phylogeographically understudied. Nassauvia subgen. Strongyloma is a characteristic element of the steppe, exhibiting a continuum of morphological variation. This taxon provides a relevant phylogeographical model not only to understand how past environmental changes shaped the genetic structure of its populations, but also to explore phylogeographical scenarios at the large geographical scale of the Patagonian steppe. Here, we (1) assess demographic processes and historical events that shaped current geographic patterns of haplotypic diversity; (2) analyze hypotheses of isolation in refugia, fragmentation of populations, and/or colonization of available areas during Pleistocene glaciations; and (3) model extant and palaeoclimatic distributions to support inferred phylogeographical patterns. Chloroplast intergenic spacers, rpl32-trnL and trnQ-5'rps16, were sequenced for 372 individuals from 63 populations. Nested clade analysis, analyses of molecular variance, and neutrality tests were performed to assess genetic structure and range expansion. The present potential distribution was modelled and projected onto a last glacial maximum (LGM) model. Of 41 haplotypes observed, ten were shared among populations associated with different morphological variants. Populations with highest haplotype diversity and private haplotypes were found in central-western and south-eastern Patagonia, consistent with long-term persistence in refugia during Pleistocene. Palaeomodelling suggested a shift toward the palaeoseashore during LGM; new available areas over the exposed Atlantic submarine platform were colonized during glaciations with postglacial retraction of populations. A scenario of fragmentation and posterior range expansion may explain the observed patterns in the center of the steppe, which is supported by palaeomodelling. Northern Patagonian populations were isolated from southern populations by the Chubut and the Deseado river basins during glaciations. Pleistocene glaciations indirectly impacted the distribution, demography, and diversification of subgen. Strongyloma through decreased winter temperatures and water availability in different areas of its range. PMID- 25540690 TI - Vegetation in clear-cuts depends on previous land use: a century-old grassland legacy. AB - Plant species richness in central and northern European seminatural grasslands is often more closely linked to past than present habitat configuration, which is indicative of an extinction debt. In this study, we investigate whether signs of historical grassland management can be found in clear-cuts after at least 80 years as coniferous production forest by comparing floras between clear-cuts with a history as meadow and as forest in the 1870s in Sweden. Study sites were selected using old land-use maps and data on present-day clear-cuts. Species traits reflecting high capacities for dispersal and persistence were used to explain any possible links between the plants and the historical land use. Clear cuts that were formerly meadow had, on average, 36% higher species richness and 35% higher richness of grassland indicator species, as well as a larger overall seed mass and lower anemochory, compared to clear-cuts with history as forest. We suggest that the plants in former meadows never disappeared after afforestation but survived as remnant populations. Many contemporary forests in Sweden were managed as grasslands in the 1800s. As conservation of remaining grassland fragments will not be enough to reduce the existing extinction debts of the flora, these young forests offer opportunities for grassland restoration at large scales. Our study supports the concept of remnant populations and highlights the importance of considering historical land use for understanding the distribution of grassland plant species in fragmented landscapes, as well as for policy-making and conservation. PMID- 25540691 TI - Validation of outlier loci through replication in independent data sets: a test on Arabis alpina. AB - Outlier detection and environmental association analysis are common methods to search for loci or genomic regions exhibiting signals of adaptation to environmental factors. However, a validation of outlier loci and corresponding allele distribution models through functional molecular biology or transplant/common garden experiments is rarely carried out. Here, we employ another method for validation, namely testing outlier loci in specifically designed, independent data sets. Previously, an outlier locus associated with three different habitat types had been detected in Arabis alpina. For the independent validation data set, we sampled 30 populations occurring in these three habitat types across five biogeographic regions of the Swiss Alps. The allele distribution model found in the original study could not be validated in the independent test data set: The outlier locus was no longer indicative of habitat-mediated selection. We propose several potential causes of this failure of validation, of which unaccounted genetic structure and technical issues in the original data set used to detect the outlier locus were most probable. Thus, our study shows that validating outlier loci and allele distribution models in independent data sets is a helpful tool in ecological genomics which, in the case of positive validation, adds confidence to outlier loci and their association with environmental factors or, in the case of failure of validation, helps to explain inconsistencies. PMID- 25540692 TI - Tick-borne encephalitis virus subtypes emerged through rapid vector switches rather than gradual evolution. AB - Tick-borne encephalitis is the most important human arthropod-borne virus disease in Europe and Russia, with an annual incidence of about 13 thousand people. Tick borne encephalitis virus (TBEV) is distributed in the natural foci of forest and taiga zones of Eurasia, from the Pacific to the Atlantic coast. Currently, there are three mutually exclusive hypotheses about the origin and distribution of TBEV subtypes, although they are based on the same assumption of gradual evolution. Recently, we have described the structure of TBEV populations in terms of a clusteron approach, a clusteron being a structural unit of viral population [Kovalev and Mukhacheva (2013) Infect. Genet. Evol., 14, 22-28]. This approach allowed us to investigate questions of TBEV evolution in a new way and to propose a hypothesis of quantum evolution due to a vector switch. We also consider a possible mechanism for this switch occurring in interspecific hybrids of ticks. It is necessarily accompanied by a rapid accumulation of mutations in the virus genome, which is contrary to the generally accepted view of gradual evolution in assessing the ages of TBEV populations. The proposed hypothesis could explain and predict not only the formation of new subtypes, but also the emergence of new vector-borne viruses. PMID- 25540693 TI - Population structure and phylogeography reveal pathways of colonization by a migratory marine reptile (Chelonia mydas) in the central and eastern Pacific. AB - Climate, behavior, ecology, and oceanography shape patterns of biodiversity in marine faunas in the absence of obvious geographic barriers. Marine turtles are an example of highly migratory creatures with deep evolutionary lineages and complex life histories that span both terrestrial and marine environments. Previous studies have focused on the deep isolation of evolutionary lineages (>3 mya) through vicariance; however, little attention has been given to the pathways of colonization of the eastern Pacific and the processes that have shaped diversity within the most recent evolutionary time. We sequenced 770 bp of the mtDNA control region to examine the stock structure and phylogeography of 545 green turtles from eight different rookeries in the central and eastern Pacific. We found significant differentiation between the geographically separated nesting populations and identified five distinct stocks (F ST = 0.08-0.44, P < 0.005). Central and eastern Pacific Chelonia mydas form a monophyletic group containing 3 subclades, with Hawaii more closely related to the eastern Pacific than western Pacific populations. The split between sampled central/eastern and western Pacific haplotypes was estimated at around 0.34 mya, suggesting that the Pacific region west of Hawaii has been a more formidable barrier to gene flow in C. mydas than the East Pacific Barrier. Our results suggest that the eastern Pacific was colonized from the western Pacific via the Central North Pacific and that the Revillagigedos Islands provided a stepping-stone for radiation of green turtles from the Hawaiian Archipelago to the eastern Pacific. Our results fit with a broader paradigm that has been described for marine biodiversity, where oceanic islands, such as Hawaii and Revillagigedo, rather than being peripheral evolutionary "graveyards", serve as sources and recipients of diversity and provide a mechanism for further radiation. PMID- 25540694 TI - Evolutionary history of a widespread tree species Acer mono in East Asia. AB - East Asia has the most diverse temperate flora in the world primarily due to the lack of Pleistocene glaciation and the geographic heterogeneity. Although increasing phylogeography studies in this region provided more proofs in this issue, discrepancies and uncertainty still exist, especially in northern temperate deciduous broad-leaved and coniferous mixed forest region (II). And a widespread plant species could reduce the complexity to infer the relationship between diversity and physiographical pattern. Hence, we studied the evolution history of a widespread temperate tree, Acer mono, populations in region II and the influence of physiographic patterns on intraspecific genetic diversity. Analyses of chloroplast sequences and nuclear microsatellites indicated high levels of genetic diversity. The diversity distribution was spatially heterogeneous and a latitudinal cline existed in both markers. The spatial distribution pattern between genetic diversity within A. mono and the diversity at species level was generally consistent. Western subtropical evergreen broad leaved forest subregion (IVb) had a unique ancient chloroplast clade (CP3) and a nuclear gene pool (GP5) with dominance indicating the critical role of this area in species diversification. Genetic data and ecological niche model results both suggested that populations in region II disappeared during the last glacial maximum (LGM) and recovered from south of Changbai Mt. and the Korean Peninsula. Two distribution centers were likely during the LGM, one in the north edge of warm temperate deciduous broad-leaved forest region (III) and another in the south edge of region III. This was reflected by the genetic pattern with two spatially independent genetic groups. This study highlights the key role of region III in sustaining genetic diversity in the northern range and connecting diversity between southern and northern range. We elucidated the diversity relationship between vegetation regions which could facilitate the understanding of biodiversity origin and maintenance in East Asia. PMID- 25540695 TI - Genetic signs of multiple colonization events in Baltic ciscoes with radiation into sympatric spring- and autumn-spawners confined to early postglacial arrival. AB - Presence of sympatric populations may reflect local diversification or secondary contact of already distinct forms. The Baltic cisco (Coregonus albula) normally spawns in late autumn, but in a few lakes in Northern Europe sympatric autumn and spring- or winter-spawners have been described. So far, the evolutionary relationships and taxonomic status of these main life history forms have remained largely unclear. With microsatellites and mtDNA sequences, we analyzed extant and extinct spring- and autumn-spawners from a total of 23 Swedish localities, including sympatric populations. Published sequences from Baltic ciscoes in Germany and Finland, and Coregonus sardinella from North America were also included together with novel mtDNA sequences from Siberian C. sardinella. A clear genetic structure within Sweden was found that included two population assemblages markedly differentiated at microsatellites and apparently fixed for mtDNA haplotypes from two distinct clades. All sympatric Swedish populations belonged to the same assemblage, suggesting parallel evolution of spring-spawning rather than secondary contact. The pattern observed further suggests that postglacial immigration to Northern Europe occurred from at least two different refugia. Previous results showing that mtDNA in Baltic cisco is paraphyletic with respect to North American C. sardinella were confirmed. However, the inclusion of Siberian C. sardinella revealed a more complicated pattern, as these novel haplotypes were found within one of the two main C. albula clades and were clearly distinct from those in North American C. sardinella. The evolutionary history of Northern Hemisphere ciscoes thus seems to be more complex than previously recognized. PMID- 25540696 TI - Size doesn't matter, sex does: a test for boldness in sister species of Brachyrhaphis fishes. AB - The effect of divergent natural selection on the evolution of behavioral traits has long been a focus of behavioral ecologists. Predation, due to its ubiquity in nature and strength as a selective agent, has been considered an important environmental driver of behavior. Predation is often confounded with other environmental factors that could also play a role in behavioral evolution. For example, environments that contain predators are often more ecologically complex and "risky" (i.e., exposed and dangerous). Previous work shows that individuals from risky environments are often more bold, active, and explorative than those from low-risk environments. To date, most comparative studies of environmentally driven behavioral divergence are limited to comparisons among populations within species that occur in divergent selective environments but neglect comparisons between species following speciation. This limits our understanding of how behavior evolves post-speciation. The Central American live-bearing fish genus Brachyrhaphis provides an ideal system for examining the relationship between selective environments and behavior, within and between species. Here, we test for differences in boldness between sister species B. roseni and B. terrabensis that occur in streams with and without piscivorous predators, respectively. We found that species do differ in boldness, with species that occur with predators being bolder than those that do not. Within each species, we found that sexes differed in boldness, with males being bolder than females. We also tested for a relationship between size (a surrogate for metabolic rate) and boldness, but found no size effects. Therefore, sex, not size, affects boldness. These results are consistent with the hypothesis that complex and risky environments favor individuals with more bold behavioral traits, but they are not consistent with the hypothesis that size (and therefore metabolic rate) drives divergence in boldness. Finally, our results provide evidence that behavioral trait divergence continues even after speciation is complete. PMID- 25540697 TI - Phylogeographic study of Chinese seabuckthorn (Hippophae rhamnoides subsp. sinensis Rousi) reveals two distinct haplotype groups and multiple microrefugia on the Qinghai-Tibet Plateau. AB - Historical climate change can shape the genetic pattern of a species. Studies on this phenomenon provide great advantage in predicting the response of species to current and future global climate change. Chinese seabuckthorn (Hippophae rhamnoides subsp. sinensis) is one of the most important cultivated plants in Northwest China. However, the subspecies history and the potential genetic resources within the subspecies range remain unclear. In this study, we utilized two intergenic chloroplast regions to characterize the spatial genetic distribution of the species. We found 19 haplotypes in total, 12 of which were unique to the Chinese seabuckthorn. The populations observed on the Qinghai-Tibet Plateau (QTP) consisted of most of the haplotypes, while in the northeast of the range of the subspecies, an area not on the QTP, only four haplotypes were detected. Our study also revealed two distinct haplotype groups of the subspecies with a sharp transition region located in the south of the Zoige Basin. 89.96% of the genetic variation located between the regions. Mismatch analysis indicated old expansions of these two haplotype groups, approximately around the early stage of Pleistocene. Additional morphological proofs from existing studies and habitat differentiation supported a long independent colonization history among the two regions. Potential adaptation probably occurred but needs more genome and morphology data in future. Chinese seabuckthorn have an older population expansion compared with subspecies in Europe. The lack of large land ice sheets and the heterogeneous landscape of the QTP could have provided extensive microrefugia for Chinese seabuckthorn during the glaciation period. Multiple localities sustaining high-frequency private haplotypes support this hypothesis. Our study gives clear insight into the distribution of genetic resources and the evolutionary history of Chinese seabuckthorn. PMID- 25540698 TI - Rewilding the tropics, and other conservation translocations strategies in the tropical Asia-Pacific region. AB - Alarm over the prospects for survival of species in a rapidly changing world has encouraged discussion of translocation conservation strategies that move beyond the focus of 'at-risk' species. These approaches consider larger spatial and temporal scales than customary, with the aim of recreating functioning ecosystems through a combination of large-scale ecological restoration and species introductions. The term 'rewilding' has come to apply to this large-scale ecosystem restoration program. While reintroductions of species within their historical ranges have become standard conservation tools, introductions within known paleontological ranges-but outside historical ranges-are more controversial, as is the use of taxon substitutions for extinct species. Here, we consider possible conservation translocations for nine large-bodied taxa in tropical Asia-Pacific. We consider the entire spectrum of conservation translocation strategies as defined by the IUCN in addition to rewilding. The taxa considered are spread across diverse taxonomic and ecological spectra and all are listed as 'endangered' or 'critically endangered' by the IUCN in our region of study. They all have a written and fossil record that is sufficient to assess past changes in range, as well as ecological and environmental preferences, and the reasons for their decline, and they have all suffered massive range restrictions since the late Pleistocene. General principles, problems, and benefits of translocation strategies are reviewed as case studies. These allowed us to develop a conservation translocation matrix, with taxa scored for risk, benefit, and feasibility. Comparisons between taxa across this matrix indicated that orangutans, tapirs, Tasmanian devils, and perhaps tortoises are the most viable taxa for translocations. However, overall the case studies revealed a need for more data and research for all taxa, and their ecological and environmental needs. Rewilding the Asian-Pacific tropics remains a controversial conservation strategy, and would be difficult in what is largely a highly fragmented area geographically. PMID- 25540701 TI - Erratum. PMID- 25540702 TI - Athletic ability assessment: a movement assessment protocol for athletes. AB - BACKGROUND/PURPOSE: Movement ability is an often-overlooked component of sports science and sports medicine research and needs to be considered alongside the appraisal of physical fitness and performance characteristics. To achieve this, a standardised assessment tool is required. The purpose of this paper is to introduce a new method for assessing movement ability and present results for intra- and inter-rater reliability. METHODS: National level female football players (n=17) were assessed using a novel movement assessment tool, the Athletic Ability Assessment (AAA). Athletes were assessed according to the scoring criteria by the primary researcher in real-time and via video on two separate occasions to estimate intra-tester reliability. Inter-tester reliability was estimated using the difference between five other testers' video-based scores. RESULTS: The intra-tester minimal detectable change (MDC) for the composite AAA score was 2.9 points (90% confidence limits; 2.3 - 4.2 points) (2.5%; 2.0 - 3.6%) with an intraclass correlation coefficient (ICC) of 0.97 (0.92 - 0.99). Inter tester MDC for the composite AAA score was 2.8 points (2.5 - 3.3 points) (2.4%; 2.1 - 2.8%) with an ICC 0.96 (0.94 - 0.98) Individual exercise scores for the intra- and inter-tester show a similar range MDC of between 0.4 - 1.1 points and kappa statistic level of agreement between 0.32 -0.77. CONCLUSIONS: Results of the reliability analysis suggest high levels of agreement between scorers for total scores and provide reference values for minimal detectable changes using the AAA. The aim of the AAA is to become a reliable movement assessment protocol that addresses specific sporting populations. The reliability of AAA scoring established in this study is the first step in supporting the utilization of the AAA in future research. LEVEL OF EVIDENCE: 2b. PMID- 25540703 TI - Real-time test-retest and interrater reliability of select physical performance measures in physically active college-aged students. AB - BACKGROUND: A new 16-item physical performance measure screening battery (16-PPM) was developed in order to expand on established movement based qualitatively scored functional screening batteries to encompass a broader spectrum of quantitatively scored functional constructs such as strength, endurance, and power. PURPOSE/HYPOTHESIS: The purpose of this study was quantify the real-time tests-retest and expert versus novice interrater reliability of the 16-PPM screen on a group of physically active college-aged individuals. The authors' hypothesized that the test-retest and interrater reliability of quantitatively scored performance measures would be highly correlated (ICC >= 0.75) and that qualitatively-scored movement screening tests would be moderately correlated (K w = 0.41-0.60). STUDY DESIGN: Cohort reliability study. METHODS: Nineteen (8 males, 11 females) healthy physically active college-aged students completed the 16-PPM on two days, one week apart. RESULTS: The majority of the quantitatively scored components of the 16-PPMs demonstrated good expert-novice interrater reliability (ICC > 0.75), while qualitatively scored tests had moderate (K w = 0.41-0.60) to substantial (K w = 0.61-0.80) agreement. Test-retest reliability was consistent between raters, with most quantitatively scored PPMs exhibiting superior reliability to the qualitatively scored PPMs. CONCLUSIONS: The 16-PPM test items showed good test-retest and interrater reliability. However, results indicate that expert raters may be more reliable than novice raters for qualitatively scored tests. The validity of this 16-PPM needs to be determined in future studies. CLINICAL RELEVANCE: Physical performance screening batteries may be used to help identify individuals at risk for future athletic injury; however, current PPMs that rely on qualitatively scored movement screens have exhibited inconsistent and questionable injury prediction validity. The addition of reliable quantitatively scored PPMs may complement qualitatively scored PPMs to improve the battery's predictive ability. LEVEL OF EVIDENCE: Level III. PMID- 25540704 TI - Lower limb muscle activity during forefoot and rearfoot strike running techniques. AB - PURPOSE/BACKGROUND: Distance running offers a method to improve fitness but also has a risk of lower limb overuse injuries. Foot strike technique has been suggested as a method to alter loading of the lower limb and possibly minimize injury risk. However, there is a dearth of information regarding neuromuscular response to variations in running techniques. The purpose of this investigation was to compare the EMG activity that occurs during FFS running and RFS running, focusing on the biceps femoris, semitendenosis, rectus femoris, vastus medialis oblique, tibialis anterior (TA), medial head of gastrocnemeus (MGas), lateral head of gastrocnemius (LGas), and soleus. METHODS: healthy adults (6 male, 8 female; age, 24.2 +/- 0.8 years, height 170.1 +/- 7.8 cm; mass 69.8 +/-10.9 kg; Body Mass Index 24.1 +/- 3.0 kg.m2) participated in the study. All participants performed a RFS and FFS running trial at 8.85 kph. A 3D motion capture system was used to collect kinematic data and electromyography was used to define muscle activity. Two-tailed paired t-tests were used to examine differences in outcomes between RFS and FFS conditions. RESULTS: The ankle was significantly more plantarflexed during FFS running (p = .0001) but there were no significant differences in knee and hip angles (p = .618 & .200, respectively). There was significantly less activity in tibialis anterior (TA) (p < .0001) and greater activity in the MGas (p= .020) during FFS running. The LGas and soleus did not change activity (p = .437 & .490, respectively). CONCLUSIONS: FFS running demonstrated lower muscular activity in the TA and increased activation in the MGas. CLINICAL RELEVANCE: FFS and RFS running have the potential to off-load injury prone tissues by changing between techniques. However, future studies will be necessary to establish more direct mechanistic connections between running technique and injury. PMID- 25540705 TI - Quantifying frontal plane knee motion during single limb squats: reliability and validity of 2-dimensional measures. AB - BACKGROUND: Clinical assessment of lower limb kinematics during dynamic tasks may identify individuals who demonstrate abnormal movement patterns that may lead to etiology of exacerbation of knee conditions such as patellofemoral joint (PFJt) pain. PURPOSE: The purpose of this study was to determine the reliability, validity and associated measurement error of a clinically appropriate two dimensional (2-D) procedure of quantifying frontal plane knee alignment during single limb squats. METHODS: Nine female and nine male recreationally active subjects with no history of PFJt pain had frontal plane limb alignment assessed using three-dimensional (3-D) motion analysis and digital video cameras (2-D analysis) while performing single limb squats. The association between 2-D and 3 D measures was quantified using Pearson's product correlation coefficients. Intraclass correlation coefficients (ICCs) were determined for within- and between-session reliability of 2-D data and standard error of measurement (SEM) was used to establish measurement error. RESULTS: Frontal plane limb alignment assessed with 2-D analysis demonstrated good correlation compared with 3-D methods (r = 0.64 to 0.78, p < 0.001). Within-session (0.86) and between-session ICCs (0.74) demonstrated good reliability for 2-D measures and SEM scores ranged from 2 degrees to 4 degrees . CONCLUSION: 2-D measures have good consistency and may provide a valid measure of lower limb alignment when compared to existing 3-D methods. CLINICAL RELEVANCE: Assessment of lower limb kinematics using 2-D methods may be an accurate and clinically useful alternative to 3-D motion analysis when identifying individuals who demonstrate abnormal movement patterns associated with PFJt pain. LEVEL OF EVIDENCE: 2b. PMID- 25540706 TI - Gluteal muscle activity during weightbearing and non-weightbearing exercise. AB - BACKGROUND: Researchers suggest that decreased strength of the gluteus medius (GMed) and the gluteus maximus (GMax) muscles contributes to the etiology of various orthopedic pathologies of the knee. Currently, equivocal evidence exists regarding Electromyography (EMG) activity of gluteal musculature during weightbearing (WB) and non-weightbearing (NWB) exercise. The purpose of this study was to compare GMed and GMax muscle activation during WB functional exercise and NWB 10 repetition maximum (RM) exercises. METHODS: Surface EMG electrodes recorded the muscle activity of the GMax and GMed as subjects performed three sets of 10 repetitions of the following exercises: (1) forward step-up, (2) lateral step-up, (3) 10 repetition maximum (10 RM) side-lying hip abduction and (4) 10 RM prone hip extension. The 10 RM resistances were determined one week prior to data collection. RESULTS: The GMed was recruited significantly more during side-lying 10 RM than the remaining exercises (side lying, 99.9+/-17% vs. lateral step-up, 61+/-20%; Forward step-up, 62.7+/-18.2%; prone, 38+/-22.2%)(p<0.001). The GMax was recruited to the greatest extent during prone 10 RM hip extension (prone, 100.7+/-14.5% vs. forward step-up, 28.7+/ 18.7%; lateral step-up, 31+/-19.9%; side-lying, 38+/-23.3%)(p<0.001). DISCUSSION: These results suggest that performing a 10 RM NWB exercise results in greater muscle activation than two functional WB exercise without load in young, healthy individuals. In addition, forward and lateral step-ups failed to effectively recruit the GMax at a high enough level to achieve a strengthening stimulus. The GMed was recruited to a higher extent than the GMax during the stepping tasks which might be further augmented if the activity is performed with an additional external load. LEVEL OF EVIDENCE: III. PMID- 25540699 TI - Challenges in analysis and interpretation of microsatellite data for population genetic studies. AB - Advancing technologies have facilitated the ever-widening application of genetic markers such as microsatellites into new systems and research questions in biology. In light of the data and experience accumulated from several years of using microsatellites, we present here a literature review that synthesizes the limitations of microsatellites in population genetic studies. With a focus on population structure, we review the widely used fixation (F ST) statistics and Bayesian clustering algorithms and find that the former can be confusing and problematic for microsatellites and that the latter may be confounded by complex population models and lack power in certain cases. Clustering, multivariate analyses, and diversity-based statistics are increasingly being applied to infer population structure, but in some instances these methods lack formalization with microsatellites. Migration-specific methods perform well only under narrow constraints. We also examine the use of microsatellites for inferring effective population size, changes in population size, and deeper demographic history, and find that these methods are untested and/or highly context-dependent. Overall, each method possesses important weaknesses for use with microsatellites, and there are significant constraints on inferences commonly made using microsatellite markers in the areas of population structure, admixture, and effective population size. To ameliorate and better understand these constraints, researchers are encouraged to analyze simulated datasets both prior to and following data collection and analysis, the latter of which is formalized within the approximate Bayesian computation framework. We also examine trends in the literature and show that microsatellites continue to be widely used, especially in non-human subject areas. This review assists with study design and molecular marker selection, facilitates sound interpretation of microsatellite data while fostering respect for their practical limitations, and identifies lessons that could be applied toward emerging markers and high-throughput technologies in population genetics. PMID- 25540707 TI - Influence of patterned electrical neuromuscular stimulation on quadriceps activation in individuals with knee joint injury. AB - BACKGROUND: Neuromuscular Electrical Stimulation is a common intervention to address muscle weakness, however presents with many limitations such as fatigue, muscle damage, and patient discomfort that may influence its effectiveness. One novel form of electrical stimulation purported to improve neuromuscular re education is Patterned Electrical Neuromuscular Stimulation (PENS), which is proposed to mimic muscle-firing patterns of healthy individuals. PENS provides patterned stimulating to the agonist muscle, antagonist muscle and then agonist muscle again in an effort to replicate firing patterns. PURPOSE: The purpose of this study was to determine the effect of a single PENS treatment on knee extension torque and quadriceps activation in individuals with quadriceps inhibition. METHODS: 18 subjects (10 males and 8 females: 24.2+/-3.4 years, 175.3+/-11.8cm, 81.8+/-12.4kg) with a history of knee injury/pain participated in this double-blinded randomized controlled laboratory trial. Participants demonstrated quadriceps inhibition with a central activation ratio of <=90%. Maximal voluntary isometric contraction of the quadriceps and central activation ratio were measured before and after treatment. The treatment intervention was a 15-minute patterned electrical stimulation applied to the quadriceps and hamstring muscles with a strong motor contraction or a sham group, who received an identical set up as the PENS group, but received a 1mA subsensory stimulation. A 2*2 (group * time) ANCOVA was used to determine differences in maximal voluntary isometric contraction and central activation ratio between groups. The maximal voluntary isometric contraction was selected as a covariate due to baseline differences. RESULTS: There were no differences in change scores between pre- and post-intervention for maximal voluntary isometric contraction: (PENS: 0.09+/-0.32Nm/kg and Sham 0.15+/-0.18Nm/kg, p=0.713), or central activation ratio:(PENS: -1.22+/-6.06 and Sham: 1.48+/-3.7, p=0.270). CONCLUSIONS: A single Patterned Electrical Neuromuscular Stimulation treatment did not alter quadriceps central activation ratio or maximal voluntary isometric contraction. Unlike other types of muscle stimulation, PENS did not result in a reduction of quadriceps torque. LEVEL OF EVIDENCE: Level III. PMID- 25540708 TI - Effects of lower extremity and trunk muscles recruitment on serratus anterior muscle activation in healthy male adults. AB - BACKGROUND: Poor activation of the serratus anterior (SA) muscle may result in abnormal shoulder rhythm, and secondarily contribute to impingement and rotator cuff tears. Sequential activation of the trunk, pelvis, and lower extremity (LE) muscles is required to facilitate the transfer of appropriate forces from these body segments to the upper extremity. Myofascial connections that exist in the body, and LE and trunk muscles (TM) activity may influence scapular and upper limb activity. The purpose of this study was to investigate the effect of simultaneous recruitment of the LE muscles and TM on the SA muscle activation when performing a forward punch plus (FPP) and six variations of the FPP exercise. STUDY DESIGN: Experimental, within-subject repeated measures. METHODS: Surface electromyographic (EMG) activity of the SA, latissimus dorsi, and external oblique muscles on the dominant side, bilateral gluteus maximus muscles, and contra-lateral femoral adductor muscles were analyzed in forward punch plus (FPP) movement and six variations in twenty one healthy male adults. The percentage of maximum voluntary isometric contraction (%MVIC) for each muscle was compared across various exercises using a 1-way repeated -measures analysis of variance with Sidak pair wise comparison as post-hoc test (p < 0.05). RESULTS: Pairwise comparisons found that the EMG activity of the serratus anterior (SA) during the FPP with contralateral closed chain leg extension (CCLE), FPP with ipsilateral closed chain leg extension (ICLE), FPP with closed chain serape effect (CS), and FPP with open chain serape effect (OS) showed significantly higher EMG activity than the FPP. CONCLUSIONS: Simultaneous recruitment of the lower extremity and trunk muscles increases the activation of the SA muscle during the FPP exercise. CLINICAL RELEVANCE: Rehabilitation clinicians should have understanding of the kinetic chain relationships between the LE, the trunk, and the upper extremity while prescribing exercises. The results of this study may improve clinicians' ability to integrate the kinetic chain model in a shoulder rehabilitation program. LEVEL OF EVIDENCE: 2b. PMID- 25540709 TI - Reliability of and the relationship between ultrasound measurement and three clinical assessments of humeral torsion. AB - PURPOSE/BACKGROUND: Differences in humeral torsion have been observed between overhead athletes and non-athletes. Although humeral torsion may be an adaptive process for athletic performance, it may be associated with injury. Methods for measuring humeral torsion have consisted of radiography, computer tomography, and ultrasound imaging. However, diagnostic imaging may be costly and not available to all clinicians. The implementation of clinical assessments may be an alternative way to measure humeral torsion. Before clinical measures can be recommended, these assessments need to be evaluated for validity and reliability of each test. The purpose of this study was to assess the intratester and intertester reliability of three clinical tests, intratester reliability of ultrasound measures, and the validity of each clinical test to ultrasound measures. METHODS: Thirty participants (male: 12, female: 18; age: 20+/-2 years; height: 174.24+/-9.35 cm; mass: 70.53+/-11.06 kg; body mass index: 23.13+/-2.47 kg/m(2); years in sport: 9+/-4 years) with experience in overhead sports were assessed for humeral torsion, bilaterally. Humeral torsion was assessed using musculoskeletal ultrasound by a single assessor, and using three separate clinical assessments by two independent assessors. Clinical assessments included the angle of rotation during both the bicipital tuberosity palpation with the shoulder abducted at 90 degrees (Palp90) or 45 degrees (Palp45), and the angle of external rotation during horizontal adduction (HADD). RESULTS: Intratester reliability for the ultrasound measure was good (ICC=0.907), along with intratester reliability for both assessors across each clinical assessment (ICC's > 0.769). Poor to moderate reliability was observed between assessors for each clinical assessment (ICC=0.256 Palp90, ICC=0.419 Palp45, ICC=0.243 HADD. Only the Palp90 measure had a fair but significant (r=0.326, p=0.011) relationship with ultrasound measures. CONCLUSION: Individual assessors can achieve reliable ultrasound, bicipital tuberosity palpation and HADD values across multiple trials; however, these measures are not consistent between assessors. Additionally, only one clinical test had a fair but significant relationship with ultrasound measures. Improved testing procedures may be needed to increase between assessor reliability and strength of relationships to ultrasound measures. Current application of clinical assessments to measure humeral torsion is limited. LEVEL OF EVIDENCE: 3b; Grade of Recommendation C. PMID- 25540711 TI - Competency revalidation study of specialty practice in sports physical therapy. AB - BACKGROUND AND PURPOSE: Every ten years the American Board of Physical Therapy Specialties conducts a practice analysis to revalidate and revise the description of specialty practice for sports physical therapy (SPT). The primary purpose of this paper is to describe the process and results of the most recent analysis, which defines the competencies that distinguish the subspecialty practice of (SPT). Additionally, the study allowed for the comparison of responses of board certified specialists in SPT to respondents who were not specialists while reflecting on demographic changes and evolving trends since the previous analysis of this physical therapy specialty practice was conducted 10 years ago. METHODS: A survey instrument based on guidelines from the American Board of Physical Therapy Specialties was developed by the Sports Specialty Council (SSC) and a panel of subject matter experts (SME) in SPT to re-evaluate contemporary practice. The instrument was pilot tested and following revisions, was sent to 1780 physical therapists, 930 of whom were board certified specialists in SPT and 850 of whom were randomly selected members of the Sports Physical Therapy Section (SPTS) who were not board certified specialists in SPT. 414 subjects returned completed surveys for a 23% response rate. 235 of the respondents were known to be board certified sports specialists, 120 did not indicate their specialty status, and 35 were non-specialists in SPT. All were members of the SPTS of the American Physical Therapy Association. The survey responses were analyzed using descriptive statistics. Univariate comparisons were performed using parametric and nonparametric statistical tests in order to evaluate differences between specialist and non-specialist item responses. RESULTS: The survey results were reviewed by the SSC and a panel of SME. Using a defined decision making process, the results were used to determine the competencies that define the specialty practice of SPT. Survey results were also used to develop the SPT specialty board examination blueprint and define the didactic curriculum required of accredited SPT residency programs. A number of significant comparisons between the specialists and non-specialists were identified. CONCLUSION: The competency revalidation process culminated in the publication of the 4th edition of the Sports Physical Therapy Description of Specialty Practice in November of 2013. This document serves to guide the process related to the attainment and maintenance of the board certified clinical specialization in SPT. In anticipation of the continued evolution of this specialty practice, this process will be repeated every 10 years to reassess the characteristics of these providers and the factors they consider critically important and unique to the practice of SPT. PMID- 25540710 TI - Associations between the female athlete triad and injury among high school runners. AB - PURPOSE/BACKGROUND: During the 2013-14 school year, over 763,000 female athletes participated in interscholastic running sports in the United States. Recent studies have indicated associations between the female athlete triad (Triad) and stress fracture or other musculoskeletal injuries in elite or collegiate female running populations. Little is known about these relationships in an adolescent interscholastic running population. The purpose of this study was to determine the associations between Triad and risk of lower extremity musculoskeletal injury among adolescent runners. METHODS: Eighty-nine female athletes competing in interscholastic cross-country and track in southern California were followed, prospectively. The runners were monitored throughout their respective sport season for lower extremity musculoskeletal injuries. Data collected included daily injury reports, Eating Disorder Examination Questionnaire (EDE-Q) that assessed disordered eating attitudes/behaviors, a questionnaire on menstrual history and demographic characteristics, a dual-energy x-ray absorptiometry scan that measured whole-body bone mineral density (BMD) and body composition (lean tissue and fat mass), and anthropometric measurements. RESULTS: Thirty-eight runners (42.7%) incurred at least one lower extremity musculoskeletal injury. In the BMD Z-score <= -1 standard deviation (SD) adjusted model, low BMD relative to age (BMD Z-score of <= -1SD) was significantly associated (Odds Ratio [OR]=4.6, 95% confidence interval [CI]: 1.5-13.3) with an increased occurrence of musculoskeletal injury during the interscholastic sport season. In the BMD Z score <= -2 SDs adjusted model, a history of oligo/amenorrhea was significantly associated (OR=4.1, 95% CI: 1.2-13.5) with increased musculoskeletal injury occurrence. CONCLUSION: Oligo/amenorrhea and low BMD were associated with musculoskeletal injuries among the female interscholastic cross-country and track runners. CLINICAL RELEVANCE: Regular, close monitoring of adolescent female runners during seasonal and off-season training may be warranted, so that potential problems can be recognized and addressed promptly in order to minimize the risk of running injury. LEVEL OF EVIDENCE: 2. PMID- 25540712 TI - A novel approach to treatment for chronic avulsion fracture of the ischial tuberosity in three adolescent athletes: a case series. AB - BACKGROUND AND INCIDENCE: Ischial tuberosity fracture and its associated complications are an under recognized diagnosis in the adolescent athlete. Apophyseal injuries of the pelvis in the skeletally immature athlete can occur in multiple locations but are most common at the ischial tuberosity, affecting males more commonly than females. DESCRIPTION OF INJURY AND CURRENT MANAGEMENT: The most common cause of ischial tuberosity avulsion fracture is a quick eccentric load to the proximal hamstrings, occurring with kicking as in soccer, football, or dance. Signs and symptoms are similar to a proximal hamstring injury but avulsion injuries often go undiagnosed, as radiographs are not frequently obtained. In acute cases, rest and relative immobilization are the recommended course of care. In chronic cases, including those with delayed diagnosis, or those that remain symptomatic after initial care due to non-union or associated sciatic nerve adhesions, surgery is often performed in order to restore normal anatomy, alleviate symptoms, and help return the athlete to full activity. PURPOSE: The authors' share a novel treatment approach consisting of ultrasound guided percutaneous needle fenestration for the treatment of three adolescent athletes with symptomatic delayed diagnoses of ischial tuberosity fractures. Needle fenestration was followed by a physical therapy progression which was developed based on tissue healing rates, symptom presentation, and the available literature related to proximal hamstring injuries. OUTCOMES: Two athletes reported elimination of pain, full functional recovery and return to sport without limitations as measured by use of the Numeric Pain Rating Scale, the Global Rating of Change Scale, and the Lower Extremity Functional Scale. One athlete reported elimination of pain and full functional recovery and chose to return to a new sport. Symptoms of possible concurrent hamstring syndrome are discussed as well the management of this condition. DISCUSSION/CONCLUSIONS: This case series introduced a novel approach for treatment of symptomatic delayed union ischial tuberosity fractures in three adolescents prior to consideration of surgical intervention. Percutanous needle fenestration and the described subsequent rehabilitation provided positive treatment outcomes in the presented cases, including full return to athletic and recreational endeavors. LEVEL OF EVIDENCE: Level 5. PMID- 25540713 TI - Lumbar manipulation and exercise in the management of anterior knee pain and diminished quadriceps activation following acl reconstruction: a case report. AB - BACKGROUND AND PURPOSE: Quadriceps weakness is a common finding following knee injuries or surgery, and can be associated with significant functional limitations. This weakness or muscle inhibition may be due to central inhibitory mechanisms, rather than local peripheral dysfunction. Lumbopelvic manipulation has been shown to effect efferent muscle output by altering nociceptive processing. The purpose of this report is to describe the physical therapy management of anterior knee pain and chronic quadriceps weakness utilizing side lying rotational lumbar thrust manipulation and therapeutic exercise for an individual eight months status-post ACL reconstruction. CASE DESCRIPTION: A 20 year-old male presented to physical therapy eight months following anterior cruciate ligament (ACL) reconstruction of the left knee with primary complaints of residual anterior knee pain and quadriceps weakness. The subject was treated with a multimodal approach using side-lying rotational lumbar thrust manipulation in addition to therapeutic exercise. OUTCOMES: The subject was seen in physical therapy for eight sessions over eight weeks. Lower Extremity Functional Scale (LEFS) scores improved from 58/80 to 72/80, quadriceps force, measured by hand held dynamometry (HHD), was improved from 70.6 lbs to 93.5 lbs and the subject was able to return to pain free participation in recreational sports. DISCUSSION: Therapeutic exercises can facilitate improved quadriceps strength, however, in cases where quadriceps weakness persists and there is concurrent pain, other interventions should be considered. In this case, lower quarter stabilization exercise and lumbar thrust manipulation was associated with improved functional outcomes in a subject with anterior knee pain and quadriceps weakness. Side-lying rotational lumbar thrust manipulation may be a beneficial adjunctive intervention to exercise in subjects with quadriceps weakness. LEVEL OF EVIDENCE: 5, Single case report. PMID- 25540714 TI - Motor control training for an amateur baseball pitcher with isolated paralysis of trapezius: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: A case of an athlete with accessory nerve injury has not been previously reported although there have been a number of case reports and case series of non-athletes with accessory nerve injury. This case study reports motor control intervention for an amateur baseball pitcher with isolated paralysis of the right trapezius who lost pitching control after changing his pitching technique. The subject was able to restore ball control during overhead throwing after physiotherapy. CASE DESCRIPTION: The subject of this case report was a 20-year-old amateur male baseball pitcher, who presented with long-standing isolated paralysis of the right trapezius and a six month history of loss of ball control with shoulder pain during pitching. He was seen for a second opinion following unsuccessful conservative management and underwent physiotherapy to restore his ball control during pitching. Restriction of cervical rotation range of motion and decreased position sense during shoulder abduction and external rotation were revealed in the physical examination. Proprioceptive exercise was commenced with and without visual feedback to acquire a reproducible abduction angle in the cocking phase of a baseball pitch. His pitching form was modified to ensure his arm was being raised effectively in the cocking phase. Pitching drills that were utilized were targeted motor control of the upper quarter, and were progressed in steps. Cervical joint mobilization was undertaken to allow adequate range of motion for visualization of the target while pitching. OUTCOMES: His position sense and cervical range of motion were restored. His pitching control was restored with conservative therapy on by the eighth week of intervention. DISCUSSION: The subject was able to return to competitive level of amateur baseball with accurate ball control. This case report demonstrates that achievement of control of a skilled upper quarter activity, such as baseball pitching, is possible with conservative management even in the presence of paralysis of trapezius, a major contributor to the movement. LEVEL OF EVIDENCE: 4 (single case report). PMID- 25540715 TI - Midshaft humeral fracture following a proximal humeral fracture: a case report. AB - BACKGROUND AND PURPOSE: Proximal humeral fractures are relatively uncommon injuries. While previous research has led to effective clinical and diagnostic evaluation and treatment of proximal fractures, less is currently known regarding the typical evaluation and treatment of midshaft humeral fractures. The purpose of this case is to describe the clinical reasoning and utilization of diagnostic imaging in the physical therapy management of a midshaft humeral fracture, sustained during the course of rehabilitation of a proximal humerus fracture. CASE DESCRIPTION: A 63-year-old female recreational tennis player presented to physical therapy, progressing well following a proximal humeral fracture, sustained 18 weeks prior. During the course of care, the patient had a significant regression in range of motion and function, with increased pain, following a seemingly trivial injury. Based on a cluster of subjective and objective flags, the therapist was concerned about a new fracture. The therapist communicated findings with a physician and recommended plain film radiographs before continuing therapy. OUTCOMES: Radiographs showed an oblique displaced fracture extending through the midshaft of the humerus. The patient ultimately underwent surgical plating. At one-year post injury e-mail follow up, she had functional mobility of her left arm, and was playing tennis recreationally three times a week. DISCUSSION: In this case, a patient who was progressing well following a proximal humeral fracture sustained a separate displaced fracture of the midshaft of the humerus, not associated with therapy. Her reported mechanism was not consistent with a typical injury. This highlights the need for clinicians, specifically physical therapists, to cluster subjective information, objective data, and the patient's medical history when interpreting patient appropriateness for therapy, and to optimize outcomes. LEVEL OF EVIDENCE: 5 (single case report). PMID- 25540716 TI - Rehabilitation following an acute traumatic first rib fracture in a collegiate football player: a case report and literature review. AB - BACKGROUND AND PURPOSE: Isolated fractures involving the first rib are rare and often difficult to diagnose. There is a paucity of literature regarding isolated fractures and even fewer reported cases involving those due to contact. The purpose of this case report is to describe the mechanism of injury, differential diagnosis, rehabilitation, and return to sport decision making for an isolated first rib fracture secondary to acute trauma in a collegiate football player. CASE DESCRIPTION: An 18 year-old right-hand dominant male collegiate football player was involved in a facemask-to-facemask collision during a football game while playing defensive back. His chief complaint during the sideline evaluation was left-sided neck and shoulder pain with concomitant clicking reported with active movement of his left shoulder. OUTCOMES: A musculoskeletal ultrasound performed in the training room suggested a possible scapular spine fracture. However, a subsequent magnetic resonance image revealed an acute isolated anterolateral fracture of the first rib. The subject was treated conservatively with extensive rehabilitation and was able to return to full participation for summer training camp as well as the fall football season at the same level of play as prior to injury. DISCUSSION: An isolated first rib fracture is extremely rare due to the unique anatomical location of the first rib posterior to the clavicle, as well as the surrounding shoulder girdle and associated layer of musculature. Identifying this injury can be challenging due to vaguely reported symptoms and the paucity of reported incidences. In the setting of an isolated injury, conservative management including structured rehabilitation can lead to successful outcomes and return to play. This is the first published rehabilitation guideline for an acute isolated first-rib fracture secondary to trauma. LEVEL OF EVIDENCE: 4 - Single case report. PMID- 25540717 TI - On the Use of Local Assessments for Monitoring Centrally Reviewed Endpoints with Missing Data in Clinical Trials. AB - Due to ethical and logistical concerns it is common for data monitoring committees to periodically monitor accruing clinical trial data to assess the safety, and possibly efficacy, of a new experimental treatment. When formalized, monitoring is typically implemented using group sequential methods. In some cases regulatory agencies have required that primary trial analyses should be based solely on the judgment of an independent review committee (IRC). The IRC assessments can produce difficulties for trial monitoring given the time lag typically associated with receiving assessments from the IRC. This results in a missing data problem wherein a surrogate measure of response may provide useful information for interim decisions and future monitoring strategies. In this paper, we present statistical tools that are helpful for monitoring a group sequential clinical trial with missing IRC data. We illustrate the proposed methodology in the case of binary endpoints under various missingness mechanisms including missing completely at random assessments and when missingness depends on the IRC's measurement. PMID- 25540719 TI - Oregon's Medicaid Transformation: An Innovative Approach To Holding A Health System Accountable For Spending Growth. AB - In 2012, Oregon initiated a significant transformation of its Medicaid program, catalyzed in part through an innovative arrangement with the Centers for Medicare and Medicaid Services (CMS), which provided an upfront investment of $1.9 billion to the state. In exchange, Oregon agreed to reduce the rate of Medicaid spending by 2 percentage points without degrading quality. A failure to meet these targets triggers penalties on the order of hundreds of millions of dollars from CMS. We describe the novel arrangement with CMS and how the CCO structure compares to Accountable Care Organizations (ACOs) and managed care organizations (MCOs). PMID- 25540718 TI - Prophylactic lithium treatment and cognitive performance in patients with a long history of bipolar illness: no simple answers in complex disease-treatment interplay. AB - Cognitive impairment in patients with bipolar disorder (BD) is not restricted to symptomatic phases. It is also present in euthymia. There is evidence of differences in the brain's structure between bipolar patients and healthy individuals, as well as changes over time in patients. Lithium constitutes the gold standard in long-term prophylactic treatment. Appropriate therapy that prevents new episodes improves the disease's course and reduces the frequency of harmful outcomes. Interestingly, preclinical data suggest that lithium has a (additional) neuroprotective effect. There is limited data on its related effects in humans and even less on its long-term application. In this multi-center cross sectional study from the International Group for the Study of Lithium-treated Patients (IGSLi), we compared three groups: bipolar patients without long-term lithium treatment (non-Li group; <3 months cumulative lithium exposure, >=24 months ago), bipolar patients with long-term lithium treatment (Li group, ongoing treatment >=24 months), and healthy subjects (controls). Strict inclusion and exclusion criteria were defined; the inclusion criteria for patients were diagnosis of BD types I or II, duration of illness >=10 years, >=5 episodes in patient's history and a euthymic mood state. Neurocognitive functioning was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the California Verbal Learning Test (CVLT), and a visual backward masking (VBM) task. A total of 142 subjects were included, 31 in the non-Li and 58 in the Li group, as well as 53 healthy controls. Treated patients with long-standing BD and controls did not differ significantly in overall cognitive functioning and verbal learning, recall, and recognition; regardless of whether lithium had been part of the treatment. Patients, however, demonstrated poorer early visual information processing than healthy controls, with the lithium-treated patients performing worse than those without. Our data suggest that bipolar patients with a long illness history and effective prophylactic treatment do not reveal significantly impaired general cognitive functioning or verbal learning and memory. However, they are worse at processing early visual information. Accompanying volumetric and spectroscopic data suggest cell loss in patients not treated with lithium that may be counterbalanced by long-term lithium treatment. PMID- 25540720 TI - Antibiotic susceptibility and molecular epidemiology of Acinetobacter calcoaceticus-baumannii complex strains isolated from a referral hospital in northern Vietnam. AB - Acinetobacter calcoaceticus-baumannii complex is a common cause of hospital acquired infections (HAIs) globally, remarkable for its high rate of antibiotic resistance, including to carbapenems. There are few data on the resistance of A. baumannii in Vietnam, which are essential for developing evidence-based treatment guidelines for HAIs. Antibiotic susceptibility testing was conducted by VITEK(r)2, and pulsed-field gel electrophoresis (PFGE) was performed on 66 clinical A. baumannii complex isolates recovered during 2009 at the National Hospital of Tropical Diseases (NHTD), a referral hospital in Hanoi, Vietnam. Basic demographic and clinical data were collected and analysed using descriptive statistics. Most isolates came from lower respiratory tract specimens (59; 89.4%) from intensive care unit (ICU) patients [64/65 (98.5%) with available data] who had been admitted to NHTD for >=2 days [42/46 (91.3%) with available data]. More than 90% of the isolates were resistant to the tested beta-lactamase/beta lactamase inhibitors, cephalosporins, carbapenems, fluoroquinolones and trimethoprim/sulfamethoxazole. Moreover, 25.4% (16/63) were resistant to all tested beta-lactams, quinolones and aminoglycosides. All isolates remained sensitive to colistin and 58.7% were susceptible to tigecycline. Of the 66 isolates, 49 could be classified into eight PFGE types (A-H). Every PFGE type, except D, had cluster(s) of three or more isolates with a temporal relationship. In conclusion, these data suggest a significant rise in A. baumannii antibiotic resistance in Vietnam. Clustering within PFGE types supports cross-transmission of A. baumannii within the ICU at NHTD. Increased research and resources in optimising treatment, infection control and antibiotic stewardship are needed. PMID- 25540721 TI - Neuropsychiatric genetics in developing countries: Current challenges. AB - Neuropsychiatric disorders (NPDs) constitute a heavy burden on public health systems around the world and studies have demonstrated that the negative impact of NPDs is larger in Low and Middle Income Countries (LMICs). In recent decades, several studies have come to the understanding that genetic factors play a major role in the risk for a large number of NPDs. However, few neuropsychiatric genetics studies have been published from LMICs. In this Editorial, we discuss important issues impinging on advances in neuropsychiatric genetics research in LMICs. It is essential that scientists educate policymakers and officials of funding agencies on the importance of providing adequate funding for research in these areas. Development of local well-supported research programs focused on NPD genetics should be an important asset to develop; it would facilitate the establishment of sustainable research efforts that could lead to appropriate diagnosis and specific, affordable and feasible interventions in LMICs. It is important to point out that research into the biological basis of human NPDs is not only an academic effort reserved for a few elite institutions in economically developed countries, but it is vitally important for the mental health of people around the world. PMID- 25540722 TI - Pharmacological management of behavioral symptoms associated with dementia. AB - Dementia is a clinical syndrome with features of neurocognitive decline. Subtypes of dementia include Alzheimer's, frontotemporal, Parkinson's, Lewy body disease, and vascular type. Dementia is associated with a variety of neuropsychiatric symptoms that may include agitation, psychosis, depression, and apathy. These symptoms can lead to dangerousness to self or others and are the main source for caregiver burnout. Treatment of these symptoms consists of nonpharmacological and pharmacological interventions. However, there are no Food and Drug Administration approved medications for the treatment of behavioral and psychological symptoms of dementia. Pharmacological interventions are used off-label. This article reviews the current evidence supporting or negating the use of psychotropic medications along with safety concerns, monitoring, regulations, and recommendations. PMID- 25540723 TI - Memantine: New prospective in bipolar disorder treatment. AB - We review preclinical and clinical evidences strongly suggesting that memantine, an old drug currently approved for Alzheimer's dementia, is an effective treatment for acute mania and for the prevention of manic/hypomanic and depressive recurrences of manic-depressive illness. Lithium remains the first line for the treatment and prophylaxis of bipolar disorders, but currently available treatment alternatives for lithium resistant patients are of limited and/or questionable efficacy. Thus, research and development of more effective mood stabilizer drugs is a leading challenge for modern psychopharmacology. We have demonstrated that 21 d administration of imipramine causes a behavioural syndrome similar to a cycle of bipolar disorder, i.e., a mania followed by a depression, in rats. Indeed, such treatment causes a behavioural supersensitivity to dopamine D2 receptor agonists associated with an increase sexual activity and aggressivity (mania). The dopamine receptor sensitization is followed, after imipramine discontinuation, by an opposite phenomenon (dopamine receptor desensitization) and an increased immobility time (depression) in the forced swimming test of depression. Memantine blocks the development of the supersensitivity and the ensuing desensitization associated with the depressive like behavior. On the basis of these observations we have suggested the use of memantine in the treatment of mania and in the prophylaxis of bipolar disorders. To test this hypothesis we performed several naturalistic studies that showed an acute antimanic effect and a long-lasting and progressive mood-stabilizing action (at least 3 years), without clinically relevant side effects. To confirm the observations of our naturalistic trials we are now performing a randomized controlled clinical trial. Finally we described the studies reporting the efficacy of memantine in manic-like symptoms occurring in psychiatric disorders other than bipolar. LIMITATIONS: A randomized controlled clinical trial is needed to confirm our naturalistic observations. CONCLUSION: We believe that this review presents enough pharmacological and clinical information to consider the administration of memantine in the treatment of bipolar disorders that no respond to standard mood stabilizers. PMID- 25540724 TI - Development of alexithymic personality features. AB - The purpose of this paper is to review the current literature regarding the development of alexithymic personality features. Modern brain imaging technologies provide interesting data on the associations of alexithymia with different aberrations in brain function related to emotion regulation; however, the development of these deviations is poorly understood. A notable amount of research covers the relation of alexithymia to different environmental factors. Many of these associations, for example, with low socio-economic status and general psychopathology in childhood, are well established. However, the retrospective and cross-sectional designs commonly used in these studies, as well as the use of self-report measures, hinder the ability to firmly establish causality. Certain individual developmental factors, such as lagging speech development and congenital cardiac malformations in childhood, have been associated with the development of alexithymia. Regarding the stability of alexithymia, a systematic review of the literature was conducted for this paper. In addition to being characterized as a personality feature in the general population, alexithymia also clearly has a state-like dimension that results in increases and decreases in alexithymic features in conjunction with mental disorder symptoms. An essential question is whether the alexithymic features in adulthood are, in fact, infantile features of a restricted ability to identify and describe emotions that simply persist in individuals through adolescence to adulthood. To firmly establish the roots of alexithymia development, longitudinal studies, particularly in younger populations, are needed. Furthermore, multifaceted study settings are encouraged. PMID- 25540725 TI - Peptides from adipose tissue in mental disorders. AB - Adipose tissue is a dynamic endocrine organ that is essential to regulation of metabolism in humans. A new approach to mental disorders led to research on involvement of adipokines in the etiology of mental disorders and mood states and their impact on the health status of psychiatric patients, as well as the effects of treatment for mental health disorders on plasma levels of adipokines. There is evidence that disturbances in adipokine secretion are important in the pathogenesis, clinical presentation and outcome of mental disorders. Admittedly leptin and adiponectin are involved in pathophysiology of depression. A lot of disturbances in secretion and plasma levels of adipokines are observed in eating disorders with a significant impact on the symptoms and course of a disease. It is still a question whether observed dysregulation of adipokines secretion are primary or secondary. Moreover findings in this area are somewhat inconsistent, owing to differences in patient age, sex, socioeconomic status, smoking habits, level of physical activity, eating pathology, general health or medication. This was the rationale for our detailed investigation into the role of the endocrine functions of adipose tissue in mental disorders. It seems that we are continually at the beginning of understanding of the relation between adipose tissue and mental disorders. PMID- 25540726 TI - Eating disorders and psychosis: Seven hypotheses. AB - Psychotic disorders and eating disorders sometimes occur in the same person, and sometimes, but not always, at the same time. This can cause diagnostic confusion and uncertainty about treatment. This paper examines seven ways in which symptoms of both conditions can co-exist. The literature on this topic consists to a large extent of case reports, so that firm conclusions cannot be drawn from their examination. There is no consistent sequence in the co-occurrence of the two conditions-eating disorders sometimes precede, and sometimes follow the onset of psychosis. The advent of the psychosis, and sometimes the treatment of the psychosis can cure the eating disorder, but it can sometimes aggravate it. Psychosis is not necessarily a mark of severity in the course of an eating disorder, and food refusal can occur independent of severity in psychotic illness, but it can be a cause of death. There is some genetic association and some overlap of physiologic, cognitive and brain structure deficits in the two types of disorder. The connection between the two, however, remains speculative. The area of comorbidity and overlapping symptoms in psychiatry requires more research. Clinical recommendations include attention to the different individual ways in which these two disparate conditions often overlap. PMID- 25540728 TI - Racial disparities in psychotic disorder diagnosis: A review of empirical literature. AB - Psychotic disorder diagnoses are common in the United States and internationally. However, racial disparities in rates of psychotic disorder diagnoses have been reported across time and mental health professions. This literature review provides an updated and comprehensive summary of empirical research on race and diagnosis of psychotic disorders spanning a 24-year period. Findings reveal a clear and pervasive pattern wherein African American/Black consumers show a rate of on average three to four higher than Euro-American/White consumers. Latino American/Hispanic consumers were also disproportionately diagnosed with psychotic disorders on average approximately three times higher compared to Euro American/White consumers. In addition, a trend among international studies suggests that immigrant racial minority consumers receiving mental health services may be assigned a psychotic disorder diagnosis more frequently than native consumers sharing a majority racial background. Potential explanations for this phenomenon are discussed, including possible clinical bias and sociological causes such as differential access to healthcare and willingness to participate in mental health services. Directions for future research should include the exploration of disproportionate diagnoses according to race through qualitative interviewing as well as empirical investigation. PMID- 25540730 TI - Polydipsia, hyponatremia and rhabdomyolysis in schizophrenia: A case report. AB - The prevalence of polydipsia among patients with schizophrenia is 6%-20%. Around 10%-20% of patients with polydipsia may develop hyponatremia and even complicated with rhabdomyolysis. Here we presented a 40-year-old man with schizophrenia, who had received paliperidone 15 mg/d for more than one year, and polydipsia was noted. In Jan, 2014, he developed hyponatremia (Na 113 mEq/L) with consciousness disturbance. After 3% NaCl (500 cc/d) intravenous supplement for three days, the hyponatremia was corrected, but rhabdomyolysis developed with a substantial elevation in the level of creatine kinase (CK) to 30505 U/L. After hydration, the CK level gradually decreased to 212 U/L. Both the hyponatremia itself and quick supplementation of NaCl can cause rhabdomyolysis. If rhabdomyolysis is not recognized, insufficient hydration or water restriction for polydipsia may further exacerbate the rhabdomyolysis with a lethal risk. In this case, we highlight the possible complication of rhabdomyolysis with polydipsia-induced hyponatremia. In addition to monitoring the serum sodium level, the monitoring of CK is also important; and switching of antipsychotic may improve the polydipsia. PMID- 25540727 TI - Antecedents and sex/gender differences in youth suicidal behavior. AB - Suicide is the second leading cause of death in youth globally; however, there is uncertainty about how best to intervene. Suicide rates are typically higher in males than females, while the converse is true for suicide attempts. We review this "gender paradox" in youth, and in particular, the age-dependency of these sex/gender differences and the developmental mechanisms that may explain them. Epidemiologic, genetic, neurodevelopmental and psychopathological research have identified suicidal behaviour risks arising from genetic vulnerabilities and sex/gender differences in early adverse environments, neurodevelopment, mental disorder and their complex interconnections. Further, evolving sex-/gender defined social expectations and norms have been thought to influence suicide risk. In particular, how youth perceive and cope with threats and losses (including conforming to others' or one's own expectations of sex/gender identity) and adapt to pain (through substance use and help-seeking behaviours). Taken together, considering brain plasticity over the lifespan, these proposed antecedents to youth suicide highlight the importance of interventions that alter early environment(s) (e.g., childhood maltreatment) and/or one's ability to adapt to them. Further, such interventions may have more enduring protective effects, for the individual and for future generations, if implemented in youth. PMID- 25540729 TI - Factors associated with hopelessness in epileptic patients. AB - AIM: To investigate factors related to hopelessness in a sample of epileptic patients, including measures of depression and quality of life (QOL). METHODS: Sixty-nine participants were administered the following psychometric instruments: Beck Depression Inventory-II, Beck Hopelessness Scale (BHS), and QOL in Epilepsy (QOLIE)-89. Patients were dichotomized into two categories: those affected by epilepsy with generalized tonic-clonic seizures vs those having epilepsy with partial seizures. RESULTS: The groups differed on the QOLIE Role Limitation/Emotional dimension. Patients with generalized seizures reported more limitations in common social/role activities related to emotional problems than patients with other types of epilepsy (89.57 +/- 25.49 vs 72.86 +/- 36.38; t 63 = -2.16; P < 0.05). All of the respondents reported moderate to severe depression, and 21.7% of patients with generalized seizures and 28.6% of patients with other diagnoses had BHS total scores >= 9 indicating a higher suicidal risk. The study did not control for years of the illness. CONCLUSION: Patients with generalized seizures reported more limitations in common social/role activities related to emotional problems compared to patients with other types of seizures. Patients at increased suicide risk as evaluated by the BHS were older than those who had a lower suicidal risk. Future studies are required to further investigate the impact of hopelessness on the outcome of epileptic patients. PMID- 25540731 TI - Pancreas transplantation in type II diabetes mellitus. AB - Although the diagnosis of type 2 diabetes mellitus was once considered a contraindication to simultaneous pancreas-kidney transplantation, a growing body of evidence has revealed that similar graft and patient survival can be achieved when compared to type 1 diabetes mellitus recipients. A cautious strategy regarding candidate selection may limit appropriate candidates from additional benefits in terms of quality of life and potential amelioration of secondary side effects of the disease process. Although our current understanding of the disease has changed, uniform listing characteristics to better define and study this population have limited available data and must be established. PMID- 25540732 TI - Challenges in pediatric renal transplantation. AB - Transplantation in children is the best option to treat renal failure. Over the last 25 years the improvements in therapy have dramatically reduced the risk of early acute rejection and graft loss, however the long term results in terms of graft survival and morbidity still require search for new immunosuppressive regimens. Tolerance of the graft and minimization of side effects are the challenges for improving the outcome of children with a grafted kidney. Notwithstanding the difficulties in settling in children large multicenter trials to derive statistically useful data, many important contributions in the last years brought important modifications in the immunosuppressive therapy, including minimization protocols of steroids and calcineurin inhibitors and new induction drugs. New methods for diagnosis of anti HLA antibodies and some new protocols to improve both chance and outcome of transplantation in immunized subjects represent area of ongoing research of extreme interest for children. PMID- 25540733 TI - Female gender in the setting of liver transplantation. AB - The evolution of liver diseases to end-stage liver disease or to acute hepatic failure, the evaluation process for liver transplantation, the organ allocation decision-making, as well as the post-transplant outcomes are different between female and male genders. Women's access to liver transplantation is hampered by the use of model for end-stage liver disease (MELD) score, in which creatinine values exert a systematic bias against women due to their lower values even in the presence of variable degrees of renal dysfunction. Furthermore, even when correcting MELD score for gender-appropriate creatinine determination, a quantifiable uneven access to transplant prevails, demonstrating that other factors are also involved. While some of the differences can be explained from the epidemiological point of view, hormonal status plays an important role. Moreover, the pre-menopausal and post-menopausal stages imply profound differences in a woman's physiology, including not only the passage from the fertile age to the non-fertile stage, but also the loss of estrogens and their potentially protective role in delaying liver fibrosis progression, amongst others. With menopause, the tendency to gain weight may contribute to the development of or worsening of pre-existing metabolic syndrome. As an increasing number of patients are transplanted for non-alcoholic steatohepatitis, and as the average age at transplant increases, clinicians must be prepared for the management of this particular condition, especially in post-menopausal women, who are at particular risk of developing metabolic complications after menopause. PMID- 25540735 TI - Psychopathological aspects of kidney transplantation: Efficacy of a multidisciplinary team. AB - Renal transplantation is a well established treatment for end-stage renal disease, allowing most patients to return to a satisfactory quality of life. Studies have identified many problems that may affect adaptation to the transplanted condition and post-operative compliance. The psychological implications of transplantation have important consequences even on strictly physical aspects. Organ transplantation is very challenging for the patient and acts as an intense stressor stimulus to which the patient reacts with neurotransmitter and endocrine-metabolic changes. Transplantation can result in a psychosomatic crisis that requires the patient to mobilize all bio-psycho-social resources during the process of adaptation to the new foreign organ which may result in an alteration in self-representation and identity, with possible psychopathologic repercussions. These reactions are feasible in mental disorders, e.g., post-traumatic stress disorder, adjustment disorder, and psychosomatic disorders. In organ transplantation, the fruitful collaboration between professionals with diverse scientific expertise, calls for both a guarantee for mental health and greater effectiveness in challenging treatments for a viable association between patients, family members and doctors. Integrated and multidisciplinary care should include uniform criteria and procedures for standard assessments, for patient autonomy, adherence to therapy, new coping strategies and the adoption of more appropriate lifestyles. PMID- 25540737 TI - Role of liver transplantation in the management of hepatoblastoma in the pediatric population. AB - Hepatoblastoma (HB) is the most common primary liver tumor in children and accounts for two-thirds of all malignant liver neoplasms in the pediatric population. For patients with advanced HB (unresectable or unresponsive to chemotherapy), combined treatment with chemotherapy and liver transplantation is an excellent option. The etiology of HB is mostly obscure because of its extreme rarity although some inherited syndromes and very low birth weight have been associated with it. The prognosis for children with HB has significantly improved in the past three decades thanks to advancements in chemotherapy, surgical resection and postoperative care. In 2002 a surgical staging system called pretreatment extent of disease (PRETEXT) was designed to allow a universal, multidisciplinary approach to patients with HB. Between one-third to two-thirds of patients initially present with unresectable tumors or distant metastases, but up to 85% of these tumors become operable after neoadjuvant chemotherapy. Patients with PRETEXT categories 1, 2, and some 3 are referred for neoadjuvant chemotherapy followed by surgical resection with the goal of complete tumor removal. Classic treatments regimens include a combination of cisplatin, fluorouracil, and vincristine or cisplatin and doxorubicin. Liver transplantation is the only treatment option for unresectable HB. In 2010 the pediatric end-stage liver disease, a pediatric-specific scoring system that determines a patient's ranking on the liver transplant list, began to award additional "exception" points for patients with HB. We analyzed the Standard Transplant Analysis and Research dataset to assess the impact of changes in exception point criteria for HB on outcomes after liver transplantation at Texas Children's Hospital in Houston, Texas. We found that patients who were listed for transplantation with current HB exception criteria experienced a shorter waitlist time but survival was similar between the two eras. PMID- 25540734 TI - What's new in clinical solid organ transplantation by 2013. AB - Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials. PMID- 25540738 TI - 1400W reduces ischemia reperfusion injury in an ex-vivo porcine model of the donation after circulatory death kidney donor. AB - AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase (iNOS) inhibitor in a model of donation after circulatory death (DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective iNOS inhibitor 1400W (10 mg/kg) was administered before reperfusion (n = 6) vs control group (n = 7). Creatinine (1000 MUmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples. RESULTS: Kidneys treated with 1400W had a higher level of creatinine clearance (CrCl) [area under the curve (AUC) CrCl: 2.37 +/- 0.97 mL/min per 100 g vs 0.96 +/- 0.32 mL/min per 100 g, P = 0.004] and urine output [Total: 320 +/- 96 mL vs 156 +/- 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium (AUC, Fr ex Na+: Control, 186.3% +/- 81.7%.h vs 1400W, 153.4% +/- 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400W group after 1 h of reperfusion (1h Pr/Cr: 1400W 9068 +/- 6910 mg/L/mmol/L vs Control 21586 +/- 5464 mg/L/mmol/L, P = 0.026). Levels of 8 isoprostane were significantly lower in the 1400W group [8-iso/creatinine ratio: Control 239 +/- 136 pg/L/mmol/L vs 1400W 139 +/- 47 pg/L/mmol/L, P = 0.041]. CONCLUSION: This study demonstrated that 1400W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress. PMID- 25540739 TI - Effect of titanium dioxide nanoparticles on zebrafish embryos and developing retina. AB - AIM: To investigate the impact of titanium dioxide nanoparticles (TiO2 NPs) on embryonic development and retinal neurogenesis. METHODS: The agglomeration and sedimentation of TiO2 NPs solutions at different dilutions were observed, and the ultraviolet-visible spectra of their supernatants were measured. Zebrafish embryos were experimentally exposed to TiO2 NPs until 72h postfertilization (hpf). The retinal neurogenesis and distribution of the microglia were analyzed by immunohistochemistry and whole mount in situ hybridization. RESULTS: The 1 mg/L was determined to be an appropriate exposure dose. Embryos exposed to TiO2 NPs had a normal phenotype. The neurogenesis was initiated on time, and ganglion cells, cones and rods were well differentiated at 72 hpf. The expression of fms mRNA and the 4C4 antibody, which were specific to microglia in the central nervous system (CNS), closely resembled their endogenous profile. CONCLUSION: These data demonstrate that short-term exposure to TiO2 NPs at a low dose does not lead to delayed embryonic development or retinal neurotoxicity. PMID- 25540736 TI - Diagnosis and management of coronary allograft vasculopathy in children and adolescents. AB - Coronary allograft vasculopathy remains one of the leading causes of death beyond the first year post transplant. As a result of denervation following transplantation, patients lack ischaemic symptoms and presentation is often late when the graft is already compromised. Current diagnostic tools are rather invasive, or in case of angiography, significantly lack sensitivity. Therefore a non-invasive tool that could allow early diagnosis would be invaluable.This paper review the disease form its different diagnosis techniques,including new and less invasive diagnostic tools to its pharmacological management and possible treatments. PMID- 25540740 TI - Gene transfer to human trabecular meshwork cells in vitro and ex vivo using HIV based lentivirus. AB - AIM: To investigate whether the enhanced green fluorescent protein (EGFP) reporter gene could be transferred into human trabecular meshwork (HTM) cells by a HIV-based lentivirus both in vitro and ex vivo. METHODS: The HIV-based lentivirus that contains an EF1-alpha promoter driving EGFP expression cassette was constructed following the standard molecular cloning methods. The cultured HTM cells were transduced at a range of multiplicity of infection (MOI) with HIV based lentivirus. EGFP positive cell populations were detected by flow cytometry. Human anterior eye segments were cultured with perfusion culture system and transfected by HIV-based lentivirus with a 1*10(8) transducing unit (TU) virus in perfusion liquid. The intraocular pressure was recorded every 8h for 21d. The expression of EGFP in the anterior segment of the human eye was detected by fluorescence microscopy. Furthermore, the distribution of EGFP expression was confirmed by anti-EGFP immunohistochemical staining. RESULTS: The HIV-based lentivirus which contains an EF1-alpha promoter driving EGFP expression cassette was constructed successfully. After HTM cells were transduced with HIV-based lentivirus containing EGFP in vitro, the ratio of EGFP positive cells to the total cell number reached 92.3%, with the MOI of 15. After the lentivirus containing EGFP were used to transduce human anterior eye segments, the EGFP could be directly detected by fluorescence microscopy in vivo. Immunohistochemistry staining revealed that 88.19% EGFP-positive trabecular meshwork (TM) cells were observed in the human anterior segment. Nevertheless, the intraocular pressure in the lentivirus-transduced group kept constant when compared with control group (P>0.05). CONCLUSION: EGFP gene could be efficiently transferred into HTM cells both in vitro and ex vivo by using HIV-based lentivirus. PMID- 25540741 TI - Reliability of Tonolab measurements in rats. AB - AIM: To assess the repeatability and reproducibility of Tonolab tonometer in rats with high intraocular pressure (IOP) and evaluate its ability to detect IOP changes in rats with general anaesthesia. METHODS: Left eyes of adult Fischer rats (F344) were photocoagulated by 532 nm diode laser to induce high IOP. Hypertensive eyes of 30 conscious rats were randomly chosen to measure IOP on a single occasion. Two observers independently and alternately undertook IOP measurements consecutively for three times using the same Tonolab tonometer blind to the other observer's IOP measurements. The within subject standard deviation (Sw), coefficient of variation (CVw) (100*Sw/overall mean), and intraclass correlation coefficient (ICC) were calculated to evaluate intra-observer repeatability. Inter-observer difference was analysed by using 95% limits of agreement described by Bland-Altman and paired sample t-test. Also, another 13 normal F344 rats were intraperitoneally administrated with ketamine/xylazine or chloral hydrate, and IOPs of both eyes were measured by a single operator once every 5min until animals came to conscious. IOPs at various time points were compared by using one-way ANOVAs. RESULTS: Mean IOP was 35.58 mm Hg (range 17.33 to 65.33 mm Hg). For intraobserver repeatability, the Sw, CVw and ICC of high IOP for two observers were 5.20 mm Hg/3.41 mm Hg, 9.98%/8.08% and 0.820/0.928 respectively. The inter-observer difference was 14.76%+/-19.76% of the mean IOP of two observers, with a 95% limits of agreement -23.97% to 53.50%, and the difference between mean IOP of these two observers was statistically significant (P=0.001). IOPs dropped slightly during the first 15min post-aneathesia, with a IOP change between 0.17 and 1.17 mm Hg. IOPs changed from basline of 11.75+/-2.05 mm Hg (n=12) to 8.75+/-1.06 mm Hg 20min post-anesthesia (P=0.001), and this hypotensive condition persisted until 80min post-anesthesia. CONCLUSION: In this sample of hypertensive rats, Tonolab measurements demonstrated high levels of intraobserver repeatability, however, its interobserver reproducibility was poor. Longitudinal changes of IOP caused by genral anaesthesia can be sensitively detected by Tonolab. So we suggested that measurements of IOP using Tonolab are best measured by a single observer, and it could be included in experimental glaucoma. PMID- 25540742 TI - Tonicity response element binding protein associated with neuronal cell death in the experimental diabetic retinopathy. AB - AIM: To study the contribution of tonicity response element binding protein (TonEBP) in retinal ganglion cell (RGC) death of diabetic retinopathy (DR). METHODS: Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin (STZ). Control mice received vehicle (phosphate-buffered saline). All mice were killed 2mo after injections, and the extent of cell death and the protein expression levels of TonEBP and aldose reductase (AR) were examined. RESULTS: The TonEBP and AR protein levels and the death of RGC were significantly increased in the retinas of diabetic mice compared with controls 2mo after the induction of diabetes. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) positive signals co-localized with TonEBP immunoreactive RGC. These changes were increased in the diabetic retinas compared with controls. CONCLUSION: The present data show that AR and TonEBP are upregulated in the DR and TonEBP may contribute to apoptosis of RGC in the DR. PMID- 25540743 TI - Pigment epithelium-derived factor protects the morphological structure of retinal Muller cells in diabetic rats. AB - AIM: To investigate if pigment epithelium-derived factor (PEDF) has any protective effect on the retinal Muller cells of Sprague-Dawley rats suffering from diabetes mellitus. METHODS: Sixty Sprague-Dawley rats were randomly divided into a negative control group, a group receiving 0.1 ug/uL PEDF, another group receiving 0.2 ug/uL PEDF, and a group receiving balanced salt solution (BSS). Rats in both the PEDF and BSS groups were treated intravitreally based on previously established diabetic models. After 4wk of treatment, morphological alterations of Muller cells and protein expression of glutamine synthase (GS) and glial fibrillary acidic protein (GFAP) were analyzed. RESULTS: PEDF at either 0.1 ug/uL or 0.2 ug/uL significantly improved the structures of both nuclei and organelles of Muller cells compared to the BSS-treated group. Expression of GS was significantly higher in the 0.2 ug/uL PEDF group than that in the BSS group (P=0.012), but expression of GFAP was significantly lower in the 0.2 ug/uL PEDF group than that in the BSS group (P=0.000); however, there were no significant differences in expression of these proteins between the 0.1 ug/uL PEDF group and the BSS group (P=0.608, P=0.152). CONCLUSION: PEDF protects the morphological ultrastructure of Muller cells, improves the expression of glutamate synthase and prevents cell gliosis. PMID- 25540744 TI - Effects of different concentrations of tetramethylpyrazine, an active constituent of Chinese herb, on human corneal epithelial cell damaged by hydrogen peroxide. AB - AIM: To discuss the effects of different concentrations of tetramethylpyrazine (TMP), an active constituent of Chinese herb, on damaged Shandong human corneal epithelial cell (SDHCEC) induced by hydrogen peroxide. METHODS: We detected the combined effects of TMP with concentrations ranging from 4 mg/mL to 0.03 mg/mL and 800 uM hydrogen peroxide on SDHCEC. The methyl thiazolyl tetrazolium (MTT) assay was processed at 3, 6 and 12h separately while the detection of cell apoptosis at 6h only by flow cytometry. RESULTS: The viability of SDHCEC with 0.5 mg/mL, 0.25 mg/mL, 0.125 mg/mL and 0.06 mg/mL TMP joint with 800 uM hydrogen peroxide at 3h and 6h was significantly higher than that with 800 uM hydrogen peroxide only, P<0.05. However, except 0.25 mg/mL, TMP with other concentrations joint with 800 uM hydrogen peroxide at 12h could not significantly inhibit decreased SDHCEC viability induced by 800 uM hydrogen peroxide. At 12h, TMP of 0.5 mg/mL, 0.25 mg/mL, 0.125 mg/mL and 0.06 mg/mL could significantly inhibit SDHCEC early apoptosis induced by 800 uM hydrogen peroxide, most remarkable at 0.25 mg/mL TMP, P<0.05. CONCLUSION: Our results suggested that hydrogen peroxide can induce apoptosis related damage to SDHCEC. TMP can protect SDHCEC from the damage, and the protective effects may be associated with its anti-apoptosis mechanism. PMID- 25540745 TI - Suppression of laser-induced choroidal neovascularization by intravitreal injection of tristetraprolin. AB - AIM: To examine the effect of intravitreal adenoviral vector-mediated tristetraprolin (Ad-TTP) on VEGF mRNA expression in a rat model of laser-induced choroidal neovascularization. METHODS: Ad-TTP was prepared using a commercial kit. Retinal laser-induced photocoagulation (10 spots per eye) was performed on rats in this experimental choroidal neovascularization (CNV) model. Rats were divided into four groups: control (single intravitreal injection of balanced salt solution, n=10), laser-induced CNV (photocoagulation only, n=20), laser-induced CNV plus Ad-TTP injection (photocoagulation plus a single intravitreal Ad-TTP injection, n=20) and Ad-TTP injection only (n=10). Changes in choroidal morphology were evaluated in ten rats in the laser only and the laser plus Ad-TTP groups. Two weeks after laser injury, the size of CNV was calculated by perfusion with high-molecular-weight fluorescein isothiocyanate (FITC)-dextran. VEGF mRNA expression in retina-choroid tissue from ten rats in each group was measured by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Two weeks after treatment, the area of laser-induced CNV was reduced by approximately 60% in the rats given the Ad-TTP injection compared with that in the laser-only group. There was a tendency toward decreased VEGF mRNA expression in the Ad-TTP injection groups. CONCLUSION: A single intravitreal injection of Ad-TTP significantly suppressed CNV size in this experimental laser-induced CNV model. Ad-TTP injection also decreased VEGF mRNA expression compared with that in the laser-induced CNV group. The present study is meaningful as the first study to investigate the effect of tristetraprolin delivered via intravitreal injection. PMID- 25540746 TI - A histological study of rabbit corneas after transepithelial corneal crosslinking using partial epithelial photoablation or ethanol treatment. AB - AIM: To evaluate the histological changes after transepithelial corneal crosslinking (CXL) using partial thickness excimer laser ablation or epithelial ethanol application in an experimental rabbit study. METHODS: Right eyes of twenty-four rabbits were studied. Four eyes received total epithelial debridement (group I). Four eyes received partial thickness epithelial ablation with excimer laser (group II). Twelve eyes were treated with different durations (30s and 60s) and concentrations (18% to 48%) of ethanol (group III). Riboflavin was applied for 30min intervals along with topical proparacaine drops with benzalkonium chloride, and 370 nm irradiation was performed for 30min, while riboflavin was instilled every 3min. Four eyes (group IV) received 48% ethanol for 30s without riboflavin and irradiation. Eyes were collected after 24h and examined histologically. RESULTS: All eyes in group I showed keratocyte loss in the superficial 300 u of corneal storma. In group II, 1-4 layers of epithelium were preserved and no keratocyte loss occurred. In group III, CXL after treatment with ethanol up to 24% concentration and up to 60s revealed no keratocyte loss. CXL after treatment with 48% and higher ethanol concentrations yielded keratocyte loss in the superficial 200 u to 300 u of cornea. CONCLUSION: Incomplete excimer laser ablation of the epithelium or treatment with ethanol up to 24% concentration and up to 60s duration yielded no stromal keratocyte loss. To get the same histological appearance seen in epithelial debridement group, partial thickness excimer laser epithelial ablation or ethanol application is not adequate for transepithelial CXL. PMID- 25540747 TI - Corneal injury and its protection using hydro-gel patch during general anesthesia. AB - AIM: To evaluate corneal injury during general anesthesia and analyze the protective effect of medical hydro-gel eye patch in clinics. METHODS: Seventy-six patients with 152 eyes undergoing general anesthesia were included. None had positive corneal fluorescein staining before surgery. Both eyes of each patient were analyzed, with one randomly allocated to receive medical hydro-gel eye patch, and the other to receive common adhesive tape as a control. Corneal injuries were evaluated by scoring fluorescein staining under a hand-held slit lamp immediately after surgery in postanesthesia care unit and 24h thereafter. Patients' discomforts were also evaluated. RESULTS: Twelve eyes (15.8%) in the hydro-gel patch group and 30 eyes (39.5%) in the adhesive tape group showed corneal injury immediately after surgery. The eyes protected with hydro-gel patch showed statistically less corneal fluorescein staining than the control group. Four eyes in hydro-gel patch group and 6 eyes in adhesive tape group suffered discomfort immediately after surgery without intergroup difference and all discomforts disappeared after 24h (P=0.257). No side effect was observed in hydro gel patch group, while 5 eyes had brow avulsion and 2 got skin itching in adhesive tape group. CONCLUSION: Corneal injury complication was more frequent than we thought following general anesthesia. The medical hydro-gel eye patch can protect the occurrence of corneal injury following general anesthesia. PMID- 25540748 TI - Elevation of serum apelin-13 associated with proliferative diabetic retinopathy in type 2 diabetic patients. AB - AIM: To compare apelin-13, a ligand of G-protein-coupled receptor which has been shown to be involved in retinal angiogenesis, and vascular endothelial growth factor (VEGF) serum levels in type 2 diabetes mellitus (T2DM) with or without retinopathy, and to investigate the relationship between the serum concentration of apelin-13 and diabetes retinopathy. METHODS: Sixty-nine patients with T2DM were enrolled. Of the 69 patients, 16 had proliferative diabetic retinopathy (PDR group), 23 had non-PDR (NPDR group) and 30 had no retinopathy (T2DM group). Subjects' information, including demographics, medical history, and use of medications were recorded. Their serum samples were collected for measuring the levels of C-reactive protein (CRP), serum lipid and glycosylated hemoglobin. Apelin-13 and VEGF serum levels were measured by enzyme-linked immunosorbent assay. Kruskal-Wallis test and one-way ANOVA were used to compare the differences among these groups. Chi-square test was used to assess categorical variables. Correlations between variables were investigated by Spearman rho correlation test and stepwise regression analysis. All statistical analyses were performed through SPSS 17.0 software. RESULTS: Sex, age, body mass index (BMI), blood pressure, CRP, hemoglobin A1c (HbA1c) have no significantly difference in the three groups. Serum level of apelin-13 was significantly elevated in PDR group as compared with T2DM group (P=0.041). Differences of VEGF serum concentration in the three groups were statistically significant (P=0.007, P=0.007 and P<0.001, respectively). Spearman rho correlation test showed that serum apelin-13 was positively correlated with BMI, serum triglycerides, VEGF, but not with age, duration of diabetes, blood pressure, CRP, HbA1c and total-cholesterol. Stepwise regression analysis showed that BMI also significantly associated with serum apelin-13 (P=0.002), while VEGF and serum triglycerides were irrelevant. CONCLUSION: This study elucidated a positive association of apelin-13 serum level with PDR, but not with VEGF. Apelin-13 may influence the promotion of PDR but unrelated with VEGF. PMID- 25540749 TI - Visual acuity and endothelial cell density with respect to the graft thickness in Descemet's stripping automated endothelial keratoplasty: one year results. AB - AIM: To evaluate the visual acuity and endothelial cell density according to the thickness in Descemet's stripping automated endothelial keratoplasty (DSAEK) one year after surgery. METHODS: DSAEK patients' data were reviewed. Thirty-seven eyes of 37 patients who underwent DSAEK for pseudophakic bullous keratopathy (PBK) were included in this study. Graft thickness was measured with optical coherence tomography (OCT) 12mo after DSAEK. Eyes were divided into 3 groups based on the graft thickness: thick (>200 um), medium-thick (150-200 um) and thin (<150 um). Best corrected visual acuity (BCVA), endothelial cells density (ECD) and complications were assessed and comparisons were done between groups. RESULTS: There was no significant difference in age, sex, preoperative BCVA, or follow-up period between DSAEK groups. At postoperative 12mo, mean BCVA was 0.28+/-0.10 in thick graft group, 0.52+/-0.08 in medium-thick graft group, and 0.72+/-0.06 in thin graft group. Thin grafts showed better postoperative BCVA as compared with the medium-thick and thick grafts (P=0.001). Thick graft group had 1637.44+/-88.19-mm(2), medium thick graft had 1764.50+/-34.28-mm(2) and thin graft group had 1845.30+/-65.62-mm(2) ECD at 12mo after the surgery. Thin graft group had better ECD at 12mo after surgery (P=0.001). CONCLUSION: Thin grafts after DSAEK ensure better visual rehabilitation. Eyes with thin grafts had significantly lesser loss of ECD compared to eyes with medium-thick and thick grafts one year after surgery. PMID- 25540750 TI - Curative effect assessment of bandage contact lens in neurogenic keratitis. AB - AIM: To observe the curative effect of bandage contact lens in neurogenic keratitis. METHODS: Twenty cases of neurogenic keratitis were studied at the Department of Ophthalmology, the first Affiliated Hospital of China Medical University, between October 2012 and June 2013. These included 13 males and 7 females, aged from 35 to 88y. Patients were voluntarily divided into an experimental group (lens wearing group, n=10) and control group (drug therapy, n=10). In experimental group patients wore silicone hydrogel bandage soft contact lens. Both groups used the following eyedrops: 0.5% levofloxacin TID; 0.5% Sodium carboxymethyl cellulose QID; fibroblast growth factor BID; ganciclovir BID [cases complicated with herpes simplex virus (HSV)]; compound tropicamide BID (cases concurrent hypopyon). The healing time of corneal ulcer and complication rates were observed in the two groups. RESULTS: The healing time of corneal ulcer in the experimental group was 10.80+/-4.44d versus 46.70+/-13.88d in the control group (P<0.05). No complications occurred in the experimental group, except for the lens falling off twice in one case, the patient recovered eight days after rewearing the lens. While in the control group, all cases vascularized, 2 cases were complicated with descemetocele that recovered with amniotic membrane transplantation and 1 case was complicated with corneal perforation that recovered by autologous conjunctival flap covering. CONCLUSION: Bandage contact lens is a safe and effective method of treating neurogenic keratitis and significantly shortened the healing time of corneal ulcer. PMID- 25540751 TI - Influence factors for successful corneal donation among Chinese adults: data from Nanjing between 2001 and 2012. AB - AIM: To investigate the factors that may influence the successful corneal donation among adults in China. METHODS: This retrospective study was conducted in 2012. The eligible participants were all the adults registered in Nanjing Red Cross Eye Bank to donate their corneas after death during the period of 2001 and 2012. Multivariate logistic regression models were applied to investigate the influence factors for successful donation, the outcome events. RESULTS: Totally, 210 of 328 (64.0%) registered potential donors successfully donated their corneas after death. The mean (SD) age at registration was 64.7 (12.5) for all participants, with 65.5 (10.1) and 63.2 (15.8) for successful and unsuccessful donors, respectively. With multivariate logistic regression analysis, five factors, the willingness of donation, age, education level, residence area, and cause of death were identified to be associated with successful corneal donation. CONCLUSION: The willingness of donation and some socio-demographic factors might substantially affect their successful donation after death for people who registered to donate corneas. PMID- 25540752 TI - Quantification of corneal neovascularization after ex vivo limbal epithelial stem cell therapy. AB - AIM: To assess cultured limbal epithelial stem cell transplantation in patients with limbal stem cell deficiency by analyzing and quantifying corneal neovascularization. METHODS: This retrospective, interventional case series included eight eyes with total limbal stem cell deficiency. Ex vivo limbal epithelial stem cells were cultured on human amniotic membrane using an animal free culture method. The clinical parameters of limbal stem cell deficiency, impression cytology, and quantification of corneal neovascularization were evaluated before and after cultured limbal stem cell transplantation. The area of corneal neovascularization, vessel caliber (VC), and invasive area (IA) were analyzed before and after stem cell transplantation by image analysis software. Best-corrected visual acuity (BCVA), epithelial transparency, and impression cytology were also measured. RESULTS: One year after surgery, successful cases showed a reduction (improvement) of all three parameters of corneal neovascularization [neovascular area (NA), VC, IA], while failed cases did not. NA decreased a mean of 32.31% (P=0.035), invasion area 29.37% (P=0.018) and VC 14.29% (P=0.072). BCVA improved in all eyes (mean follow-up, 76+/-21mo). Epithelial transparency improved significantly from 2.00+/-0.93 to 0.88+/-1.25 (P=0.014). Impression cytology showed that three cases failed after limbal epithelial stem cell therapy before 1y of follow-up. CONCLUSION: This method of analyzing and monitoring surface vessels is useful for evaluating the epithelial status during follow-up, as successful cases showed a bigger reduction in corneal neovascularization parameters than failed cases. Using this method, successful cases could be differentiated from failed cases. PMID- 25540753 TI - Amniotic membrane welded to contact lens by 1470-nm diode laser: a novel method for sutureless amniotic membrane transplantation. AB - AIM: To avoid the side effects of the suture usage by welding amniotic membrane (AM) to contact lens (CL) with laser. METHODS: AM was taken from pregnant women and cleaned from blood clots with sterile phosphate-buffered physiological saline solution which included antibiotics. Stromal side of the AM was spread inside of the CL and it was welded to CL by 1470 nm diode laser. 600 um diameter fiber tip of the laser was contacted with the epithelial side of the AM from 4 separate points. After welding excess amniotic membrane around the CL was cut with a scalpel. RESULTS: Stromal side of the AM was spread inside of the CL and then with laser fiber, different power levels and exposure times were applied on the epithelium of AM and 340 mW for seven seconds was found optimal. CL and AM attached with the spot welding effect in 4 points by touching fiber tip. CL-AM welded complex did not separated from each other while holding AM that extend beyond the CL with the help of two forceps. CONCLUSION: As a conclusion, it was aimed in this study to achieve the success of the conventional amniotic membrane transplantation (AMT)with the easiness of applying a CL and to avoid risks and side effects of corneal or conjunctival suturing. The results showed that the application of the CL-AM complex will be as easy as the application of a CL and lasts shortly. PMID- 25540754 TI - Comparison of surgically induced astigmatism in various incisions in manual small incision cataract surgery. AB - AIM: To determine the surgically induced astigmatism (SIA) in Straight, Frown and Inverted V shape (Chevron) incisions in manual small incision cataract surgery (SICS). METHODS: A prospective cross sectional study was done on a total of 75 patients aged 40y and above with senile cataract. The patients were randomly divided into three groups (25 each). Each group received a particular type of incision (Straight, Frown or Inverted V shape incisions). Manual SICS with intraocular lens (IOL) implantation was performed. The patients were compared 4wk post operatively for uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA) and SIA. All calculations were performed using the SIA calculator version 2.1, a free software program. The study was analyzed using SPSS version 15.0 statistical analysis software. RESULTS: The study found that 89.5% of patients in Straight incision group, 94.2% in Frown incision group and 95.7% in Inverted V group attained BCVA post-operatively in the range of 6/6 to 6/18. Mean SIA was minimum (-0.88+/-0.61D*90 degrees) with Inverted V incision which was statistically significant. CONCLUSION: Inverted V (Chevron) incision gives minimal SIA. PMID- 25540755 TI - Spontaneous resolution of macular edema after silicone oil removal. AB - AIM: To investigate the macular changes in eyes filled with silicone oil (SO) and course of these changes after SO removal. METHODS: A retrospective optical coherence tomography scan review was conducted for twenty-four patients who underwent uncomplicated pars plana vitrectomy with SO tamponade for complex retinal detachments were detected with optical coherence tomography before, and one week, one month and three months after SO removal. RESULTS: Mean duration of SO tamponade was 3.6+/-1.0mo (range: 3-7mo). Cystoid macular edema (CME) was detected in 3 eyes before SO removal. Submacular fluid was represented in 1 eye before silicone SO removal. Resolution of CME and submacular fluid was achieved 1mo after SO removal in all eyes. Mean best corrected visual acuity (BCVA) was 1.15+/-0.65 (range, hand movement to 0.2) before SO removal in the eyes without macular changes. After SO removal, the mean BCVA values at 1wk and 1 and 3mo, and 0.82+/-0.23, 0.76+/-0.21, and 0.70+/-0.19, all of which were significantly better than baseline (P=0.030, 0.017, 0.006 respectively). In the eyes with macular CME and subretinal fluid the mean BCVA was significantly improved at 3mo after SO removal compared with baseline (P=0.037). CONCLUSION: Decreased visual acuity in eyes filled with SO could be caused by macular complications due to SO. CME and subretinal fluid may resolve without any additional macular surgery after SO removal. PMID- 25540756 TI - Uveitis associated with multiple sclerosis: complications and visual prognosis. AB - AIM: To determine the frequency, subtype, complications, treatment and visual prognosis of uveitis in patients with multiple sclerosis (MS). METHODS: A total of 1702 MS patients' medical records were reviewed for a history of uveitis both with a neurologist and an ophthalmologist. RESULTS: Nine patients (0.52%) with uveitis were detected. Eight of them were female, one was male. The mean age was 42.0+/-14.1y (range 22-66). Seven patients were relapsing remitting MS, two were secondary progressive MS. The mean duration of MS was 10.8+/-10.3y, and the mean duration of uveitis 10.3+/-9.9y. The onset of uveitis preceded that of MS (four patients) by a mean of 5.0+/-4.3y (range 1-11). MS diagnosed prior to the onset of uveitis (five patients) by an interval of 0.75-16y (mean 4.95+/-6.24y). There were 16 affected eyes of nine patients. The most common types of uveitis were panuveitis and intermediate uveitis. Uveitis was bilateral in most patients. The most common complications were cataract and glaucoma, and patients with such complications were surgically treated. The range of visual acuity of affected eyes was 20/800 to 20/22, with only six of 16 affected eyes better than 20/40. After treatment, the visual acuity of the affected eyes was better than 20/40 in 11 of 16 eyes. CONCLUSION: Uveitis should be considered when assessing an MS patient with visual loss, as surgical interventions other than medical treatments may be needed to improve visual function. Complications could be seen more often when posterior segment is involved. PMID- 25540757 TI - Relationship between pinguecula formation and exposure to tandoor ovens in a hospital-based study. AB - AIM: To investigate the relationship between pinguecula and the use of tandoor ovens. METHODS: A total of 539 women, ranging in age from 20 to 86y who attended an outpatient clinic were enrolled. All the patients were asked whether they used tandoor ovens. Women exposed to tandoor ovens (n=286) were accepted as participants in the study group and they were compared with participants in the control group (n=253). The age, presence of pinguecula, duration of exposure to tandoor ovens as years and occupations were recorded for all the subjects. RESULTS: Mean duration for exposure to tandoor was 20.26y (range 1-62y) in the study group. The rate of pinguecula in the study group was 82.2% (235/286), and the rate in the control group was 37.5% (95/253); this difference was statistically significant (P<0.05). Pinguecula was seen in 61.2% (330/539) of all the participants. CONCLUSION: Pinguecula is strongly associated with exposure to tandoor ovens. PMID- 25540758 TI - Bilateral same-session intravitreal injections of anti-vascular endothelial growth factors. AB - AIM: To document the indications, safety and possible complications of bilateral same-session intravitreal anti-vascular endothelial growth factor (VEGF) injections performed in the ophthalmic operating room. METHODS: A retrospective case series study. Consecutive records of seventy four patients receiving simultaneous bilateral intravitreal injections of either ranibizumab or bevacizumab, between September 2010 and September 2013, were reviewed and the outcomes were assessed. Data collected included number of injections, indications for injections, pre-injection and post-injection visual acuity (VA), pre injection and post-injection intraocular pressure and ocular and systemic complications/complaints after each injection. RESULTS: A total of 342 injections were administered to 74 patients, with a mean of 4.62 injections per patient. Seventy-three patients received bevacizumab (Avastin; Genentech Inc., South San Francisco, California, USA) alone, and only one patient received both bevacizumab and ranibizumab (Lucentis; Genentech Inc.) distributed between the injections. Pre- and post-injection VA follow-up measurements were available for 65 patients. Mean follow up period was 22mo. The indications for initiating therapy were choroidal neovascular membrane from age-related macular degeneration (3 patients) and diabetic macular edema (71 patients). The mean Snellen VA before each injection was 6/22. The next post-injection follow-up mean Snellen VA was 6/20. One patient had a painful, culture-positive endophthalmitis in one eye 3d after bilateral bevacizumab. Another patient had a painless subconjunctival hemorrhage in one eye. No other ocular or systemic adverse side effects/complaints have been registered in this study group. CONCLUSION: Bilateral same-session intravitreal injections using a separate povidone-iodine preparation, speculum, needle, and syringe for each eye are well-tolerated. None of the subjects in this study requested to switch to alternating unilateral injections. Proper patient counseling as to the risk of complications with this procedure is necessary. PMID- 25540759 TI - Spectral domain optical coherence tomography cross-sectional image of optic nerve head during intraocular pressure elevation. AB - AIM: To analyze changes of the optic nerve head (ONH) and peripapillary region during intraocular pressure (IOP) elevation in patients using spectral domain optical coherence tomography (SD-OCT). METHODS: Both an optic disc 200*200 cube scan and a high-definition 5-line raster scan were obtained from open angle glaucoma patients presented with monocular elevation of IOP (>=30 mm Hg) using SD OCT. Additional baseline characteristics included age, gender, diagnosis, best corrected visual acuity, refractive error, findings of slit lamp biomicroscopy, findings of dilated stereoscopic examination of the ONH and fundus, IOP, pachymetry findings, and the results of visual field. RESULTS: The 24 patients were selected and divided into two groups: group 1 patients had no history of IOP elevation or glaucoma (n=14), and group 2 patients did have history of IOP elevation or glaucoma (n=10). In each patient, the study eye with elevated IOP was classified into group H (high), and the fellow eye was classified into group L (low). The mean deviation (MD) differed significantly between groups H and L when all eyes were considered (P=0.047) and in group 2 (P=0.042), not in group 1 (P=0.893). Retinal nerve fiber layer (RNFL) average thickness (P=0.050), rim area (P=0.015), vertical cup/disc ratio (P=0.011), cup volume (P=0.028), inferior quadrant RNFL thickness (P=0.017), and clock-hour (1, 5, and 6) RNFL thicknesses (P=0.050, 0.012, and 0.018, respectively), cup depth (P=0.008), central prelaminar layer thickness (P=0.023), mid-inferior prelaminar layer thickness (P=0.023), and nasal retinal slope (P=0.034) were significantly different between the eyes with groups H and L. CONCLUSION: RNFL average thickness, rim area, vertical cup/disc ratio, cup volume, inferior quadrant RNFL thickness, and clock hour (1, 5, and 6) RNFL thicknesses significantly changed during acute IOP elevation. PMID- 25540760 TI - Evaluation of choroidal thickness using spectral-domain optical coherence tomography in patients with severe obstructive sleep apnea syndrome: a comparative study. AB - AIM: To assess choroidal thickness in patients with severe obstructive sleep apnea syndrome (OSAS) and compare them with healthy controls, using spectral domain optical coherence tomography (OCT). METHODS: In this observational, cross sectional study, choroidal thicknesses of 23 newly severe OSAS patients and 23 body mass index- age- and sex-matched healthy subjects were measured using a high speed, high-resolution frequency domain-OCT device (lambda=840 nm, 26000 A scans/s, 5 um axial resolution). All patients underwent a complete ophthalmic examination before the measurements. OCT measurements were taken at the same time of day (9:00 a.m.), in order to minimize the effects of diurnal variation. RESULTS: There was a statistically significant difference in median choroidal thickness between the OSAS patients (201 um; range 145-237 um) and the controls (324 um; range 296-383 um; P<0.001). There were significant differences at all measurement points (P<0.001 for all). The apnea-hypopnea index (AHI) values were more than 30 in all OSAS patients and the mean AHI was 48.57+/-6.54. The interexaminer intraclass correlation coefficient (ICC) for the mean choroidal thickness was 0.938 (95%CI, 0.908-0.985) and ICC was greater than 0.90 for all measurement points. CONCLUSION: The decreased choroidal thickness of patients with severe OSAS might be related to the the autonomic disregulation associated with this disease. Further studies are needed to evaluate the etiopathologic relationship between choroidal thickness and OSAS. PMID- 25540761 TI - Surgical results of the slipped medial rectus muscle after hang back recession surgery. AB - AIM: To analyze the surgical results of a slipped medial rectus muscle (MRM) after hang back recession surgery for esotropia. METHODS: Twenty-one patients who underwent re-exploration for diagnosed slipped muscle after hang back recession surgery were included in this retrospective study. Dynamic magnetic resonance imaging was performed to identify the location of the slipped muscle. Ocular motility was evaluated with assessment with prism and cover test in gaze at cardinal positions. The operations were performed by the same consultant. Intraoperative forced duction test was performed under general anesthesia. The empty sheath of the slipped MRM was resected and the muscle was advanced to the original insertion site in all patients. RESULTS: The average age of 21 patients who had consecutive exotropia with a slipped MRM at the time of presentation was 17.4+/-5.4y (5-50y). The average duration between the first operation and the diagnosis of the slipped muscle was 25mo (12 to 36mo). The mean follow up after the corrective surgery was 28mo. The mean preoperative adduction limitation in the field of action of the slipped muscle was -2.26 (ranging from -1 to -4). All patients had full adduction postoperatively. CONCLUSION: The diagnosis of the slipped muscle should be confirmed during the strabismus surgery. The slipped muscle may be caused due to insufficient suture and excessive rubbing of the eye. When divergent strabismus is observed after the recession of the MRM, a slipped muscle should be considered in the differential diagnosis. PMID- 25540762 TI - A comparison between monocanalicular and pushed monocanalicular silicone intubation in the treatment of congenital nasolacrimal duct obstruction. AB - AIM: To compare the success rate of monocanalicular versus pushed monocanalicular silicone intubation (PMCI) of the nasolacrimal duct for congenital nasolacrimal duct obstruction (CNLDO). METHODS: In a prospective randomized clinical trial 53 eyes of 49 patients with CNLDO underwent either monocanalicular silicone intubation (MCI) (n=28 eyes) or PMCI (n=25 eyes). All procedures were performed by 1 oculoplastic surgeon. Treatment success was defined as the complete resolution of epiphora at 3mo after tube removal. RESULTS: The surgical outcome was assessed in 20 eyes with MCI and 20 eyes with PMCI. The mean age of treatment was 26.25+/-10.08mo (range, 13-49mo) for MCI and 26.85+/-12.25mo (range, 16-68mo) for PMCI. Treatment success was achieved in 18 of 20 eyes (90.0%) in the MCI group compared with 10 of 20 eyes (50%) in the PMCI group (P=0.01). In the PMCI group, the tube loss (30%) was greater than the MCI group (5%), however the differences between the 2 groups proved to be not significant (P=0.91). CONCLUSION: Our results indicate that MCI has higher success rate in CNLDO treatment compared with PMCI in this small series of patients. PMID- 25540763 TI - Long-term postoperative outcomes of bilateral lateral rectus recession vs unilateral recession-resection for intermittent exotropia. AB - AIM: To discuss the long-term postoperative results of bilateral lateral rectus recession (BLR) and unilateral lateral rectus recession-medial rectus resection (RR) in therapy of intermittent exotropia. METHODS: We retrospectively analyzed 213 cases of intermittent exotropia who underwent surgery between 2008 and 2010. The patients were grouped into BLR group and RR group. Motor outcomes were divided into three groups on the basis of the angle of deviation after surgery: overcorrection (esotropia/phoria >5(Delta)), orthophoria (esotropia/phoria <=5(Delta) to exotropia/phoria <=10(Delta)), and undercorrection/recurrence (exotropia/phoria >10(Delta)). Titmus test was used to evaluate stereoacuity, the stereoacuity <800s of arc meaned the patients had stereopsis. Surgical outcome including motor criteria and sensory status were compared at postoperative 6, 12, 24mo and at 36mo examination between groups. RESULTS: At 12, 24mo after surgery, the motor outcomes had no difference (P>0.05) between groups. However, the motor outcomes at 6, 36mo were signally different in each group, indicating the success rate in RR group at 6mo was higher than that in BLR group (83.02% vs 82.24%, P<0.05) but the result was contrary at the 3y examination (60.75% vs 43.40%, P<0.05). No statistical significance were found in the sensory outcomes between the groups at mean of 3.7y follow-up. CONCLUSION: The motor outcomes in RR group were better than in BLR group at 6mo after surgery, while the 3y outcomes were better in BLR group. This may be due to the recurrence rate of the BLR was lower than the RR group's. PMID- 25540764 TI - Comparison of intravitreal bevacizumab with macular photocoagulation for treatment of diabetic macular edema: a systemic review and Meta-analysis. AB - AIM: To further evaluate the efficacy and safety of intravitreal bevacizumab (IVB) versus macular photocoagulation (MPC) in treatment of diabetic macular edema (DME) by Meta-analysis. METHODS: Pertinent publications were identified through systemic searches of PubMed, Medline, EMBASE, and the Cochrane Controlled Trials Register up to 30 November, 2013. Changes in central macular thickness (CMT) in um and best-corrected visual acuity (BCVA) in logMAR equivalents were extracted at 1, 3, 6, 12 and 24mo after initial treatment, and a Meta-analysis was carried out to compare results between groups receiving IVB and MPC. RESULTS: Five randomized controlled trial (RCTs) and one high-quality comparative study were identified and included. Our Meta-analysis revealed that both IVB and MPC resulted in the improvements of CMT and BCVA in eyes with DME at 1mo after initial treatment, with IVB being significantly superior to MPC (P=0.01 and 0.02, respectively). The improvements of both measure outcomes at 3, 6, 12 and 24mo after treatment did not vary significantly between the IVB groups and MPC groups (CMT at 3mo, P=0.85; at 6mo, P=0.29; at 12mo, P=0.56; at 24mo, P=0.71; BCVA at 3mo, P=0.31; at 6mo, P= 0.30; at 12mo, P=0.23; at 24mo, P=0.52). However, the number of observed adverse events was low in all studies. CONCLUSION: Current evidence shows IVB treatment trends to be more effective in improvements of macular edema and vision in eyes with DME at an earlier follow up (1mo) compared with MPC. At other time, both interventions have comparable efficacy without statistical significances. PMID- 25540766 TI - Incidental frontoparietal parasagittal meningioma in a patient with acute bilateral optic neuritis. PMID- 25540765 TI - Surgical treatment for residual or recurrent strabismus. AB - Although the surgical treatment is a relatively effective and predictable method for correcting residual or recurrent strabismus, such as posterior fixation sutures, medial rectus marginal myotomy, unilateral or bilateral rectus re recession and resection, unilateral lateral rectus recession and adjustable suture, no standard protocol is established for the surgical style. Different surgical approaches have been recommended for correcting residual or recurrent strabismus. The choice of the surgical procedure depends on the former operation pattern and the surgical dosages applied on the patients, residual or recurrent angle of deviation and the operator's preference and experience. This review attempts to outline recent publications and current opinion in the management of residual or recurrent esotropia and exotropia. PMID- 25540767 TI - Common eye drops and their implications for pH measurements in the management of chemical eye injuries. PMID- 25540768 TI - Primary malignant melanoma of lacrimal sac. PMID- 25540769 TI - Comment on anisometropia magnitude and visual deficits in previously untreated anisometropic amblyopia. PMID- 25540770 TI - Experiences and expectations for glioma immunotherapeutic approaches. PMID- 25540774 TI - Challenges in epidemiological and statistical evaluations of effect modifiers and confounders. PMID- 25540771 TI - Ascorbate as a co-factor for fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. AB - Ascorbate is a specific co-factor for a large family of enzymes known as the Fe- and 2-oxoglutarate-dependent dioxygenases. These enzymes are found throughout biology and catalyze the addition of a hydroxyl group to various substrates. The proline hydroxylase that is involved in collagen maturation is well known, but in recent times many new enzymes and functions have been uncovered, including those involved in epigenetic control and hypoxia-inducible factor (HIF) regulation. These discoveries have provided crucial mechanistic insights into how ascorbate may affect tumor biology. In particular, there is growing evidence that HIF-1 dependent tumor progression may be inhibited by increasing tumor ascorbate levels. However, rigorous clinical intervention studies are lacking. This review will explore the physiological role of ascorbate as an enzyme co-factor and how this mechanism relates to cancer biology and treatment. The use of ascorbate in cancer should be informed by clinical studies based on such mechanistic hypotheses. PMID- 25540772 TI - Exploring the chicken embryo as a possible model for studying Listeria monocytogenes pathogenicity. AB - Listeria monocytogenes is a bacterial pathogen capable of causing severe infections in humans, often with fatal outcomes. Many different animal models exist to study L. monocytogenes pathogenicity, and we have investigated the chicken embryo as an infection model: What are the benefits and possible drawbacks? We have compared a defined wild-type strain with its isogenic strains lacking well-characterized virulence factors. Our results show that wild-type L. monocytogenes, already at a relatively low infection dose (~5 * 10(2) cfu), caused death of the chicken embryo within 36 h, in contrast to strains lacking the main transcriptional activator of virulence, PrfA, or the cytolysin LLO. Surprisingly, strains lacking the major adhesins InlA and InlB caused similar mortality as the wild-type strain. In conclusion, our results suggest that the chicken embryo is a practical model to study L. monocytogenes infections, especially when analyzing alternative virulence pathways independent of the InlA and InlB adhesins. However, the route of infection might be different from a human infection. The chicken embryo model and other Listeria infection models are discussed. PMID- 25540775 TI - A new role for public health in bioterrorism deterrence. PMID- 25540773 TI - Protein-based biofilm matrices in Staphylococci. AB - Staphylococcus aureus and Staphylococcus epidermidis are the most important etiological agents of biofilm associated-infections on indwelling medical devices. Biofilm infections may also develop independently of indwelling devices, e.g., in native valve endocarditis, bone tissue, and open wounds. After attachment to tissue or indwelling medical devices that have been conditioned with host plasma proteins, staphylococcal biofilms grow, and produce a specific environment which provides the conditions for cell-cell interaction and formation of multicellular communities. Bacteria living in biofilms express a variety of macromolecules, including exopolysaccharides, proteins, extracellular eDNA, and other polymers. The S. aureus surface protein C and G (SasC and SasG), clumping factor B (ClfB), serine aspartate repeat protein (SdrC), the biofilm-associated protein (Bap), and the fibronectin/fibrinogen-binding proteins (FnBPA and FnBPB) are individually implicated in biofilm matrix formation. In S. epidermidis, a protein named accumulation-associated protein (Aap) contributes to both the primary attachment phase and the establishment of intercellular connections by forming fibrils on the cell surface. In S. epidermidis, proteinaceous biofilm formation can also be mediated by the extracellular matrix binding protein (Embp) and S. epidermidis surface protein C (SesC). Additionally, multifunctional proteins such as extracellular adherence protein (Eap) and extracellular matrix protein binding protein (Emp) of S. aureus and the iron-regulated surface determinant protein C (IsdC) of S. lugdunensis can promote biofilm formation in iron-depleted conditions. This multitude of proteins intervene at different stages of biofilm formation with certain proteins contributing to biofilm accumulation and others mediating primary attachment to surfaces. This review examines the contribution of proteins to biofilm formation in Staphylococci. The potential to develop vaccines to prevent protein-dependent biofilm formation during staphylococcal infection is discussed. PMID- 25540776 TI - Microalgal Metabolic Network Model Refinement through High-Throughput Functional Metabolic Profiling. AB - Metabolic modeling provides the means to define metabolic processes at a systems level; however, genome-scale metabolic models often remain incomplete in their description of metabolic networks and may include reactions that are experimentally unverified. This shortcoming is exacerbated in reconstructed models of newly isolated algal species, as there may be little to no biochemical evidence available for the metabolism of such isolates. The phenotype microarray (PM) technology (Biolog, Hayward, CA, USA) provides an efficient, high-throughput method to functionally define cellular metabolic activities in response to a large array of entry metabolites. The platform can experimentally verify many of the unverified reactions in a network model as well as identify missing or new reactions in the reconstructed metabolic model. The PM technology has been used for metabolic phenotyping of non-photosynthetic bacteria and fungi, but it has not been reported for the phenotyping of microalgae. Here, we introduce the use of PM assays in a systematic way to the study of microalgae, applying it specifically to the green microalgal model species Chlamydomonas reinhardtii. The results obtained in this study validate a number of existing annotated metabolic reactions and identify a number of novel and unexpected metabolites. The obtained information was used to expand and refine the existing COBRA-based C. reinhardtii metabolic network model iRC1080. Over 254 reactions were added to the network, and the effects of these additions on flux distribution within the network are described. The novel reactions include the support of metabolism by a number of d amino acids, l-dipeptides, and l-tripeptides as nitrogen sources, as well as support of cellular respiration by cysteamine-S-phosphate as a phosphorus source. The protocol developed here can be used as a foundation to functionally profile other microalgae such as known microalgae mutants and novel isolates. PMID- 25540777 TI - Comprehensive reconstruction and visualization of non-coding regulatory networks in human. AB - Research attention has been powered to understand the functional roles of non coding RNAs (ncRNAs). Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established on-line repositories. The interactions involve RNA, DNA, proteins, and diseases. ncRNA-DB is available at http://ncrnadb.scienze.univr.it/ncrnadb/. It is equipped with three interfaces: web based, command-line, and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape. PMID- 25540779 TI - Comparative study on National Burn Registry in America, England, Australia and Iran. AB - CONTEXT: Iran experiences a high rate of burns accompanied by painful consequences, death and a lot of disabilities. In order to reduce the burden of this injury, some strategies such as designing and implementation of registration systems are essential. AIMS: The aim of this study was to compare National Burn Registry in America, England, Australia and Iran. MATERIALS AND METHODS: This study was comparative-descriptive in which data collected from the National Burn Registry of America, England, Australia and Iran studied in 2013. The study population included National Burn Registry of these countries and data was collected using raw data forms. STATISTICAL ANALYSIS USED: Data on each country was categorized according to objectives and comparisons took place using comparative tables. Finally, descriptive-theoretical analysis of the findings was performed. RESULTS: National Security Agency and National Burn Repository in America, National Institute of Health and the Ministry of Health in England and the Department of Health and Senior in Australia are responsible for national burning registry. A seven-axial model was proposed for Iran's National Registry. America's registry system is broader than other countries due to its cooperation with Canada, Sweden and Asia. CONCLUSION: The aim of the Burn Registry System is to gather, store, edit, categorize, analyze and distribute all burns, injured data from all health care centers in a specific population and provide valuable information about the occurrence, time and regional distribution of burn injury. PMID- 25540778 TI - A novel laccase with potent antiproliferative and HIV-1 reverse transcriptase inhibitory activities from mycelia of mushroom Coprinus comatus. AB - A novel laccase was isolated and purified from fermentation mycelia of mushroom Coprinus comatus with an isolation procedure including three ion-exchange chromatography steps on DEAE-cellulose, CM-cellulose, and Q-Sepharose and one gel filtration step by fast protein liquid chromatography on Superdex 75. The purified enzyme was a monomeric protein with a molecular weight of 64 kDa. It possessed a unique N-terminal amino acid sequence of AIGPVADLKV, which has considerably high sequence similarity with that of other fungal laccases, but is different from that of C. comatus laccases reported. The enzyme manifested an optimal pH value of 2.0 and an optimal temperature of 60 degrees C using 2,2' azinobis(3-ethylbenzothiazolone-6-sulfonic acid) diammonium salt (ABTS) as the substrate. The laccase displayed, at pH 2.0 and 37 degrees C, K(m) values of 1.59 mM towards ABTS. It potently suppressed proliferation of tumor cell lines HepG2 and MCF7, and inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) with an IC50 value of 3.46 MUM, 4.95 MUM, and 5.85 MUM, respectively, signifying that it is an antipathogenic protein. PMID- 25540780 TI - A comparative study on iMed((c)) and European database for multiple sclerosis to propose a common language of multiple sclerosis data elements. AB - CONTEXT: Establishing and developing minimum data set (MDS), controlled vocabularies, taxonomies and classification systems are requirements of health information system in every society. AIMS: The aim of this study was to propose an integrated multiple sclerosis (MS) data set by comparing European database for multiple sclerosis (EDMUS Coordinating Center Lyon, France) and iMed((c)) software's (iMed, Merck Serono SA - Geneva). EDMUS is being developed at the EDMUS coordinating centers in Lyon, France and iMed((c)) is owned and distributed by Merck Serono in Geneva, Switzerland. SETTINGS AND DESIGNS: Retrieval of data of MDS performed through scholars responsible in related agencies and clinics. MATERIALS AND METHODS: This research was an applied. The study was comparative exploratory. In this study, data elements in iMed((c)) and EDMUS software's were compared. Data collecting tool was data raw form. STATISTICAL ANALYSIS USED: Results analyzing was carried out in a descriptive-comparative method. MS data elements were proposed in three general categories: administrative; clinical; and socio-economic. In this study, a MS data set was suggested by studying data elements of EDMUS and iMed((c)) softwares. RESULTS: The MS data set includes administrative, clinical and socio-economic data elements that collect information of MS patients during the treatment course. iMed((c)), EDMUS and other available databases are suitable patterns for determining and recognizing MS key data elements. CONCLUSION: Developing MS data set in this study and studying other available MS information systems result in establishing standardized MS data set. By establishing this data set, it will be possible to present MS MDS internationally. MS MDS is the main base of establishing MS information systems at different levels. PMID- 25540781 TI - A Review on influencing criteria for selecting supplier of information technology services in the hospital. AB - Organizations try to outsource their activities as much as possible in order to prevent the problems and use organizational capabilities in Information Technology (IT) field. The purpose of this paper was first, to express the effective criteria for selecting suppliers of IT services, second, to explain the advantages and disadvantages of outsourcing IT in hospitals. This study was narrative review, which search was conducted with the help of libraries, books, conference proceedings, and databases of Science Direct, PubMed, Proquest, Springer, and SID (Scientific Information Database). In our searches, we employed the following keywords and their combinations: Outsourcing, information technology, hospital, decision making, and criteria. The preliminary search resulted in 120 articles, which were published between 2000 and 2013 during July 2013. After a careful analysis of the content of each paper, a total of 46 papers were selected based on their relevancy. The criteria and sub-criteria influencing outsourcing decisions in Iranian hospitals were identified in six major categories including administrative issues, issues related to the service/product, technology factors, environmental factors, risks, and economic factors associated with 15 sub-criteria containing business integration, dependence on suppliers, human resources, focus on core competencies, facilities and physical capital, innovation, quality, speed of service delivery, flexibility, market capabilities, geographical location, security, management control, cost, and financial capability. Identify the advantages and disadvantages of outsourcing and effective criteria in IT services supplier selection causes the managers be able to take the most appropriate decision to select supplier of IT services. This is a general review on influencing criteria for electing of supplier of information technology services in hospitals. PMID- 25540782 TI - Comparison of Iranian National Medical Library with digital libraries of selected countries. AB - INTRODUCTION: The important role of information and communication technologies and their influence on methods of storing, retrieving information in digital libraries, has not only changed the meanings behind classic library activates but has also created great changes in their services. However, it seems that not all digital libraries provide their users with similar services and only some of them are successful in fulfilling their role in digital environment. The Iranian National Medical library is among those that appear to come short compared to other digital libraries around the world. By knowing the different services provided by digital libraries worldwide, one can evaluate the services provided by Iranian National Medical library. The goal of this study is a comparison between Iranian National Medical library and digital libraries of selected countries. MATERIALS AND METHODS: This is an applied study and uses descriptive - survey method. The statistical population is the digital libraries around the world which were actively providing library services between October and December 2011 and were selected by using the key word "Digital Library" in Google search engine. The data-gathering tool was direct access to the websites of these digital libraries. The statistical study is descriptive and Excel software was used for data analysis and plotting of the charts. RESULTS: The findings showed that among the 33 digital libraries investigated worldwide, most of them provided Browse (87.87%), Search (84.84%), and Electronic information retrieval (57.57%) services. The "Help" in public services (48/48%) and "Interlibrary Loan" in traditional services (27/27%) had the highest frequency. The Iranian National Medical library provides more digital services compared to other libraries but has less classic and public services and has less than half of possible public services. Other than Iranian National Medical library, among the 33 libraries investigated, the leaders in providing different services are Library of University of California in classic services, Count Way Library of Medicine in digital services, and Library of Finland in public services. RESULTS AND DISCUSSION: The results of this study show that among the digital libraries investigated, most provided similar public, digital, and classic services and The Iranian National Medical library has been somewhat successful in providing these services compared to other digital libraries. One can also conclude that the difference in services is at least in part due to difference in environments, information needs, and users. CONCLUSION: Iranian National Medical Library has been somewhat successful in providing library services in digital environment and needs to identify the services which are valuable to its users by identifying the users' needs and special characteristics of its environment. PMID- 25540784 TI - Improvement of hospital processes through business process management in Qaem Teaching Hospital: A work in progress. AB - In a world of continuously changing business environments, organizations have no option; however, to deal with such a big level of transformation in order to adjust the consequential demands. Therefore, many companies need to continually improve and review their processes to maintain their competitive advantages in an uncertain environment. Meeting these challenges requires implementing the most efficient possible business processes, geared to the needs of the industry and market segments that the organization serves globally. In the last 10 years, total quality management, business process reengineering, and business process management (BPM) have been some of the management tools applied by organizations to increase business competiveness. This paper is an original article that presents implementation of "BPM" approach in the healthcare domain that allows an organization to improve and review its critical business processes. This project was performed in "Qaem Teaching Hospital" in Mashhad city, Iran and consists of four distinct steps; (1) identify business processes, (2) document the process, (3) analyze and measure the process, and (4) improve the process. Implementing BPM in Qaem Teaching Hospital changed the nature of management by allowing the organization to avoid the complexity of disparate, soloed systems. BPM instead enabled the organization to focus on business processes at a higher level. PMID- 25540783 TI - The effects of an interventional program based on self-care model on health related quality of life outcomes in hemodialysis patients. AB - BACKGROUND: Hemodialysis patients have lower quality of life and one of the ways to improve their quality of life is providing self-care education to them using some models including self-care model. This study aimed to determine and evaluate the effects of using self-care model on health and quality of life outcomes in hemodialysis patients. MATERIALS AND METHODS: This was a quasi-experimental study conducted in 2012 on the patients who were referred to a military hospital in Tehran, Iran to be treated with hemodialysis. All 32 patients referred to this hospital in 2012 were selected and studied. Required data were collected using the Short Form-36 (SF-36) standard questionnaire and a researcher-made questionnaire. The educational intervention was implemented using self-care model. Collected data were analyzed using SPSS for Windows version 18.0 and some statistical tests including paired samples t-test, Wilcoxon and McNemar tests. RESULTS: The results showed that the mean and standard deviation (SD) of patients' parameters including weight and blood pressure improved significantly after the educational intervention compared to before the intervention (P < 0.001). Also, all dimensions of the quality of life of hemodialysis patients, including physical function, role physical, bodily pain, general health, vitality, social function, mental health, and role emotional improved compared to those before the intervention (P < 0.001). CONCLUSION: Implementing the self-care model increased the quality of life of hemodialysis patients. Therefore, the use of this model in hemodialysis patients is recommended. PMID- 25540785 TI - Self-medication among students in Isfahan University of Medical Sciences based on Health Belief Model. AB - BACKGROUND: The prevalence of self-medication is high all over the world, especially in Iran. But there is a paucity of studies to explore self-medication activities among the university students. Therefore, the present study was undertaken to determine the self-medication among student in Isfahan University of Medical Sciences, based on Health Belief Model (HBM). MATERIALS AND METHODS: This cross-sectional study was conducted in 197 medical students of Isfahan University of Medical Sciences who were randomly chosen by a stratified random sampling method in 2009. The data were collected using a validated and reliable questionnaire based on HBM. Statistical analysis was performed using SPSS software (ver. 16). Descriptive and analytical statistics (independent t-test and test) were used. A two-tailed P value lower than 0.05 was considered statistically significant. RESULTS: The mean and standard deviation of participants' age was 22.00 +/- 2.77 years. 67.3% of the sample consisted of females. The mean scores of knowledge, perceived susceptibility, perceived severity, perceived benefits, and perceived barrier were 80.36 +/- 18.29, 40.92 +/- 13.89, 61.48 +/- 19.03, 59.11 +/- 18.46, and 30.36 +/- 12.40, respectively. According to the results, 84.98% of students had experienced self-medication at least for one disease during the past 6 months. CONCLUSIONS: The prevalence of self-medication in medical students is high and we can consider it as a health problem. So, we need educational interventions for the students, using HBM constructs. PMID- 25540786 TI - Informational needs and related problems of family caregivers of heart failure patients: A qualitative study. AB - BACKGROUND: Heart failure is incurable disease and patients often have an ongoing decline once diagnosed. The symptoms of heart failure may impair the ability of patient to perform activities of daily living. As heart failure progresses, patients normally increase their reliance on family caregivers. AIMS: This paper explored the informational needs and related problems of family caregivers of heart failure patients as a part of the findings of a study exploring experiences of family caregivers in the caregiving situation. SETTING AND DESIGN: Using a qualitative design, 19 family caregivers from three educational hospitals in Isfahan, Iran, were recruited. MATERIALS AND METHODS: Participants were selected by purposive sampling. Data were collected through semi-structured interviews. Interviews were transcribed verbatim and analyzed concurrently. RESULTS: Four major themes were emerged from the analysis of the transcripts: "Lack of care related knowledge", "Inaccessibility to responsible source of information", "Lack of guidance from healthcare team" and "caring with ambiguity due to unpredictable nature of the disease". Caregivers believed that they did not have the basic knowledge related to disease and medication administration. They received little guidance and support from the health care team on the caregiving roles. They experienced high level of ambiguity and stress in caregiving tasks due to lack of care-related knowledge and unpredictable nature of disease. CONCLUSION: The care, which was performed by the caregivers of HF patients, is beyond of their knowledge, capabilities, and resources. Nurses and other healthcare providers can use the findings of this study to develop effective educational and supportive programs to facilitate these needs. PMID- 25540787 TI - Validation of the partner version of the multidimensional vaginal penetration disorder questionnaire: A tool for clinical assessment of lifelong vaginismus in a sample of Iranian population. AB - BACKGROUND: The role of spousal response in woman's experience of pain during the vaginal penetration attempts believed to be an important factor; however, studies are rather limited in this area. The aim of this study was to develop and investigate the psychometric indexes of the partner version of a multidimensional vaginal penetration disorder questionnaire (PV-MVPDQ); hence, the clinical assessment of spousal psychosexual reactions to vaginismus by specialists will be easier. MATERIALS AND METHODS: A mixed-methods sequential exploratory design was used, through that, the findings from a thematic qualitative research with 20 unconsummated couples, which followed by an extensive literature review used for development of PV-MVPDQ. A consecutive sample of 214 men who their wives' suffered from lifelong vaginismus (LLV) based on Diagnostic and Statistical Manual of Mental Disorders 4(th) version (DSM)-IVTR criteria during a cross sectional design, completed the questionnaire and additional questions regarding their demographic and sexual history. Validation measures and reliability were conducted by exploratory factor analysis (EFA) and Cronbach's alpha coefficient through SPSS version 16 manufactured by SPSS Inc. (IBM corporation, Armonk, USA). RESULTS: After conducting EFA PV-MVPDQ emerged as having 40 items and 7 dimensions: Helplessness, sexual information, vicious cycle of penetration, hypervigilance and solicitous, catastrophic cognitions, sexual and marital adjustment and optimism. Subscales of PV-MVPDQ showed a significant reliability (0.71-0.85) and results of test-retest were satisfactory. CONCLUSION: The present study shows PV-MVPDQ is a multi-dimensional valid and reliable self-report questionnaire for assessment of cognitions, sexual and marital relations related to vaginal penetrations in spouses of women with LLV. It may assist specialists to base on which clinical judgment and appropriate planning for clinical management. PMID- 25540788 TI - Application of joinpoint regression in determining breast cancer incidence rate change points by age and tumor characteristics in women aged 30-69 (years) and in Isfahan city from 2001 to 2010. AB - BACKGROUND AND OBJECTIVES: Breast cancer is a major threat to women's health. Evaluation of the changes in trend of the incidence rate provides valuable information for the assessment and planning of development indicators of each country. The aim of the present study was to apply the JoinPoint regression model for determining changes in the trend of the breast cancer incidence rate in Isfahan. MATERIALS AND METHODS: In this cross-sectional study, 3640 women with breast cancer referring to oncology and radiotherapy departments of Seyed-al Shohada and Milad cancer treatment centers of Isfahan during 2001-2010 were studied and sampling was not done. Joinpoint regression model was used to investigate the pattern of breast cancer incidence rate. Response and independent variables were the natural logarithm of the age-standardized incidence rates and year of diagnosis of breast cancer, respectively, in which various levels of cancer tumor characteristics (P < 0.05) were analyzed. RESULTS: The incidence rates increased annually in the age groups of 40-44 years (6.2%), 45-49 years (5.3%), and 55-59 years (5.3%). The trend of incidence rates in women with tumor size <=2 cm (18.2%), well (moderately) differentiated tumor grade [8% (10.2%)], positive estrogen (progesterone) hormone receptor status [10.5% (6.9%)], and the proportion of positive lymph node to surgery node <=25% (nonsignificant) was upward. CONCLUSION: The trend of incidence rates with tumor size <=2 cm, well differentiated tumor grade, moderately differentiated tumor grade, and positive estrogen and progesterone hormone receptors was upward. The pattern of breast cancer can help in cancer prevention and prognosis, and in selecting the best type of surgery. PMID- 25540789 TI - Survey of social health insurance structure in selected countries; providing framework for basic health insurance in Iran. AB - INTRODUCTION AND OBJECTIVES: Health system reforms are the most strategic issue that has been seriously considered in healthcare systems in order to reduce costs and increase efficiency and effectiveness. The costs of health system finance in our country, lack of universal coverage in health insurance, and related issues necessitate reforms in our health system financing. The aim of this research was to prepare a structure of framework for social health insurance in Iran and conducting a comparative study in selected countries with social health insurance. MATERIALS AND METHODS: This comparative descriptive study was conducted in three phases. The first phase of the study examined the structure of health social insurance in four countries - Germany, South Korea, Egypt, and Australia. The second phase was to develop an initial model, which was designed to determine the shared and distinguishing points of the investigated structures, for health insurance in Iran. The third phase was to validate the final research model. The developed model by the Delphi method was given to 20 professionals in financing of the health system, health economics and management of healthcare services. Their comments were collected in two stages and its validity was confirmed. FINDINGS: The study of the structure of health insurance in the selected countries shows that health social insurance in different countries have different structures. Based on the findings of the present study, the current situation of the health system, and the conducted surveys, the following framework is suitable for the health social insurance system in Iran. The Health Social Insurance Organization has a unique service by having five funds of governmental employees, companies and NGOs, self-insured, villagers, and others, which serves as a nongovernmental organization under the supervision of public law and by decision- and policy-making of the Health Insurance Supreme Council. Membership in this organization is based on the nationality or residence, which the insured by paying the insurance premiums within 6-10% of their income and employment status, are entitled to use the services. Providing services to the insured are performed by indirect forms. Payments to the service providers for the fee of inpatient and outpatient services are conservative and the related diagnostic groups system. CONCLUSIONS: Paying attention to the importance of modification of the fragmented health insurance system and financing the country's healthcare can reduce much of the failure of the health system, including the access of the public to health services. The countries according to the degree of development, governmental, and private insurance companies and existing rules must use the appropriate structure, comprehensive approach to the structure, and financing of the health social insurance on the investigated basis and careful attention to the intersections and differentiation. Studied structures, using them in the proposed approach and taking advantages of the perspectives of different beneficiaries about discussed topics can be important and efficient in order to achieve the goals of the health social insurance. PMID- 25540790 TI - Quality assessment of Isfahan Medical Faculty web site electronic services and prioritizing solutions using analytic hierarchy process approach. AB - CONTEXT: Implementing information technology in the best possible way can bring many advantages such as applying electronic services and facilitating tasks. Therefore, assessment of service providing systems is a way to improve the quality and elevate these systems including e-commerce, e-government, e-banking, and e-learning. AIMS: This study was aimed to evaluate the electronic services in the website of Isfahan University of Medical Sciences in order to propose solutions to improve them. Furthermore, we aim to rank the solutions based on the factors that enhance the quality of electronic services by using analytic hierarchy process (AHP) method. MATERIALS AND METHODS: Non-parametric test was used to assess the quality of electronic services. The assessment of propositions was based on Aqual model and they were prioritized using AHP approach. The AHP approach was used because it directly applies experts' deductions in the model, and lead to more objective results in the analysis and prioritizing the risks. After evaluating the quality of the electronic services, a multi-criteria decision making frame-work was used to prioritize the proposed solutions. STATISTICAL ANALYSIS USED: Non-parametric tests and AHP approach using Expert Choice software. RESULTS: The results showed that students were satisfied in most of the indicators. Only a few indicators received low satisfaction from students including, design attractiveness, the amount of explanation and details of information, honesty and responsiveness of authorities, and the role of e services in the user's relationship with university. After interviewing with Information and Communications Technology (ICT) experts at the university, measurement criteria, and solutions to improve the quality were collected. The best solutions were selected by EC software. According to the results, the solution "controlling and improving the process in handling users complaints" is of the utmost importance and authorities have to have it on the website and place great importance on updating this process. CONCLUSIONS: Although, 4 out of the 22 indicators used in the test hypothesis were not confirmed, the results show that these assumptions are accepted at 95% confidence level. To improve the quality of electronic services, special attention should be paid to "services interaction." As the results showed having "controlling and improving the process in handling users complaints" on the website is the first and most important one and the process of "changing brand/factory name/address in the text of the factory license/renewal or modification of manufacturing license/changing the formula" is the least important one. PMID- 25540791 TI - Meta-analysis of the role of delivery mode in postpartum depression (Iran 1997 2011). AB - BACKGROUND: Postpartum period is the riskiest time for mood disorders and psychosis. Postpartum depression is the most important mood disorder after delivery, which can be accompanied by mother-child and family relationship disorders. Meta-analysis with the integration of research results demonstrates to investigate the association between the mode of delivery and postpartum depression. MATERIALS AND METHODS: This meta-analysis uses the Rosenthal and Robin approach. For this purpose, 18 studies which were acceptable in terms of methodology were selected and meta-analysis was conducted on them. Research instrument was a checklist of meta-analysis. After summarizing the results of the studies, effect sizes were calculated manually and combined based on meta analysis method. RESULTS: The findings showed that the amount of effect size (in term of Cohen d) of delivery mode on postpartum depression was 0/30 (P < 0.001). CONCLUSION: Delivery mode on maternal mental health is assessed medium. Meta analysis also indicates moderator variables role, and researcher must focus in these variables. PMID- 25540792 TI - The relationship between functional health literacy and health promoting behaviors among older adults. AB - BACKGROUND: Health literacy is a measure of individual's ability to read, comprehend, and act on medical instructions. Older adults are one of the most important at risk groups affected by the impact of inadequate health literacy. Health promoting behaviors in older adults have potential impact on their health and quality of life and reduce the costs incurred to health care. Given the paucity of information health literacy and health promoting behavior, the purpose of this study was to examine health literacy level in older adults and the relationship between health literacy and health promoting behaviors. MATERIALS AND METHOD: A cross-sectional survey of 354 older adults was conducted in Isfahan. The method of sampling was clustering. Health literacy was measured using the Test of Functional Health Literacy in Adults (TOFHLA). Data were collected via home interviewing. Health promoting behaviors were measured based on self-reported smoking status, exercise, and consumption of fruit and vegetables. The collected data were analyzed using descriptive statistics and one way ANOVA and chi2 tests under SPSS 18 software. RESULTS: The sample group averaged 67 +/- 6.97 years in age. Approximately 79.6% of adults were found to have inadequate health literacy. They tended to be older, have fewer years of schooling, lower household income, and being female Individuals with inadequate health literacy were more likely to report limitations in activity and lower consumption of fruit and vegetables (P < 0.001). No significant association was found between health literacy and smoking status. CONCLUSION: Considering high prevalence of inadequate health literacy among older adults, and its inverse relationship with some health promoting behaviors. Simple educational materials and effective interventions for low health literacy people can improve health promotion in society and mitigate the adverse health effects of low health literacy. PMID- 25540793 TI - Barriers related to fecal occult blood test for colorectal cancer screening in moderate risk individuals. AB - INTRODUCTION AND OBJECTIVE: Colorectal cancer is one of the most important and most common cancer and second leading cause of cancer deaths worldwide. Through secondary prevention of this cancer, effective proactive measures would be taken to treat and to prevent the incidence of the disease. The fecal occult blood test (FOBT) has priority over other methods and is recommended for adults above 50 years. This study was carried out to assess perceived barriers related to participating in colorectal cancer screening programs among average risk population, based on health belief model. MATERIALS AND METHODS: A cross sectional survey of 196 individuals of more than 50 years was conducted in Isfahan. The target group consisted of people going to laboratories for doing FOBT test (n = 98), and those who refrained from going to laboratories (n = 98). The questionnaire was used based on barrier assessment question associated with performing fecal occult blood test. The data collected were analyzed using descriptive and inferential statistics methods. RESULTS: The mean score of perceived barriers in the first group was 40.9 and in other group was 56.54, with significant difference statistically (P < 0.001). Lack of information, fear of cancer diagnosis, lack of recommendation by doctors, and not setting the priority of time for doing the test were some of barriers reported by the nongoing group. DISCUSSION AND CONCLUSION: According to this study, it seems that there is an urgent need to more information to be provided for the public about colorectal cancer and its prevention through screening, as important step to increase the rate of early detection and curb the mortality rate, costs, and improve community health outcomes. PMID- 25540794 TI - Evaluation of the quality of the college library websites in Iranian medical Universities based on the Stover model. AB - INTRODUCTION: Today, the websites of college and university libraries play an important role in providing the necessary services for clients. These websites not only allow the users to access different collections of library resources, but also provide them with the necessary guidance in order to use the information. The goal of this study is the quality evaluation of the college library websites in Iranian Medical Universities based on the Stover model. MATERIAL AND METHODS: This study uses an analytical survey method and is an applied study. The data gathering tool is the standard checklist provided by Stover, which was modified by the researchers for this study. The statistical population is the college library websites of the Iranian Medical Universities (146 websites) and census method was used for investigation. The data gathering method was a direct access to each website and filling of the checklist was based on the researchers' observations. Descriptive and analytical statistics (Analysis of Variance (ANOVA)) were used for data analysis with the help of the SPSS software. FINDINGS: The findings showed that in the dimension of the quality of contents, the highest average belonged to type one universities (46.2%) and the lowest average belonged to type three universities (24.8%). In the search and research capabilities, the highest average belonged to type one universities (48.2%) and the lowest average belonged to type three universities. In the dimension of facilities provided for the users, type one universities again had the highest average (37.2%), while type three universities had the lowest average (15%). In general the library websites of type one universities had the highest quality (44.2%), while type three universities had the lowest quality (21.1%). Also the library websites of the College of Rehabilitation and the College of Paramedics, of the Shiraz University of Medical Science, had the highest quality scores. DISCUSSION: The results showed that there was a meaningful difference between the quality of the college library websites and the university types, resulting in college libraries of type one universities having the highest average score and the college libraries of type three universities having the lowest score. PMID- 25540795 TI - Performance of the libraries in Isfahan University of Medical Sciences based on the EFQM model. AB - INTRODUCTION: Performance measurement is inevitable for university libraries. Hence, planning and establishing a constant and up-to-date measurement system is required for the libraries, especially the university libraries. The primary studies and analyses reveal that the EFQM Excellence Model has been efficient, and the administrative reform program has focused on the implementation of this model. Therefore, on the basis of these facts as well as the need for a measurement system, the researchers measured the performance of libraries in schools and hospitals supported by Isfahan University of Medical Sciences, using the EFQM Organizational Excellence Model. MATERIALS AND METHODS: This descriptive research study was carried out by a cross-sectional survey method in 2011. This research study included librarians and library directors of Isfahan University of Medical Sciences (70 people). The validity of the instrument was measured by the specialists in the field of Management and Library Science. To measure the reliability of the questionnaire, the Cronbach's alpha coefficient value was measured (0.93). The t-test, ANOVA, and Spearman's rank correlation coefficient were used for measurements. The data were analyzed by SPSS. RESULTS: Data analysis revealed that the mean score of the performance measurement for the libraries under study and between nine dimensions the highest score was 65.3% for leadership dimension and the lowest scores were 55.1% for people and 55.1% for society results. CONCLUSION: In general, using the ninth EFQM model the average level of all dimensions, which is in good agreement with normal values, was assessed. However, compared to other results, the criterion people and society results were poor. It is Recommended by forming the expert committee on criterion people and society results by individuals concerned with the various conferences and training courses to improve the aspects. PMID- 25540797 TI - A Delphi study to curriculum modifying through the application of the course objective and competencies. AB - BACKGROUND: In order to incorporate new knowledge, skills and emerging concepts from dynamic fields of public health into ongoing courses reform of curriculums sounds necessary. Accordingly, this study was performed to modify health education curriculum of public health undergraduate level. MATERIALS AND METHODS: Using Delphi technique, 18 health education lecturers from Tehran, Tabriz, Yazd, Shiraz, Gonabad, Ghazvin, Avhvaz and Kurdistan Universities Medical of Sciences based on their expertize in health education with PhD degree as scientific members, also 5 heads of departments according to working at health deputy for at least more than 5 years were asked during three rounds through panel experts to suggest and rate topics they deemed most important to graduate public health experts and curricula related to the areas of knowledge and skills in health education course. RESULTS: The experts suggested that health enhancing behaviors and reduce health risks, advocate health, behavior change theories and developing a framework are key objects in the curriculum. Much more new topical outlines were related to previous course. Skills rated as important included need assessment and health communication. The most evaluators suggested that adding a practicum unit to two theory units will be helpful. CONCLUSION: The results from our survey suggested that changes in the course definition including new course objectives, topical outlines, and required skills were deemed important by the lecturers and were appropriately integrated into the health education course curriculum. The new curriculum should be evaluated constantly to seek and provide experiences that will best prepare students to meet challenges as a health educator. PMID- 25540796 TI - The effect of self-care education program on reducing HbA1c levels in patients with type 2 diabetes. AB - BACKGROUND: Diabetes as the most common diseases caused by metabolic disorders is an important global challenge. This is a disease that requires lifelong self-care because self-care and improved quality of life is cost effective. This study is aimed to determine the impact of self-care education program on reducing HbA1c, type 2 diabetic patients and was conducted in Zahedan. MATERIALS AND METHODS: This is an experimental study done on 138 diabetic female patients in Zahedan city, in 2011 (1390). This sampling method of patients was based on inclusion and exclusion criteria of the Diabetes Center, at Hazrat Ali Asghar Hospital (AS) in Zahedan. Samples were divided randomly in to two groups: 69 cases and 69 controls. Data collected included validity and reliability confirmed questionnaire. Checklist was based on patients 'performance of reporting and (HbA1c) testing. Before the educational intervention, the checklist of questions for recording the (HbA1c) test for both the groups were completed, and study samples received 5 sessions of education (with the group discussion and film show) for a month. However, the control group received only routine training. Three months after the educational intervention, both groups completed the questionnaire and the check list and data using SPSS software and the appropriate tests were analyzed. RESULTS: Findings showed that the mean domain scores of area of knowledge, attitude and practice educational groups, were recorded as (46.6 +/ 8.57, 46.5 +/- 0.86 and 29.06 +/- 10.02), respectively. And after education scores of knowledge, attitude and practice were recorded as (52.80 +/- 2.20, 12.98 +/- 1.02 and 39.69 +/- 4.74), respectively, and in study group significant difference (P < 0/001) was seen. CONCLUSION: Self-care training in striation leads to improve knowledge, attitude and self-care performance of the study samples and also improves the average (HbA1c). Because it seems to increase the active participation of learners in their care that they have experienced with this training method and their motivation enhanced them to learn better self care. So this type of care education should be given to the attention of nurses and healthcare's staff. PMID- 25540798 TI - Effect of needs-assessment-based psychoeducation for families of patients with schizophrenia on quality of life of patients and their families: A controlled study. AB - INTRODUCTION: Family psychoeducation is one of the most routine interventions in a schizophrenic patients' management. We evaluated the effects of a needs assessment-based educational program in comparison with the current program on global function and quality of life (QOL) of the patients and their families. MATERIALS AND METHODS: In this controlled study, 60 schizophrenia patients and their families were allocated for a needs-assessment-based psychoeducation (treatment) and current education (control) programs. The family members of both the groups participated in 10 sessions of education, within about six months. The patients' global function and QOL were assessed with the global assessment of function (GAF) and the Schizophrenia Quality of Life Scales (SQLS), respectively. The families' QOL was assessed with the World Health Organization's (WHO) Quality of Life-BREF (WHOQOL-BREF). Assessments were done at the beginning and then every six months, for a total of 18 months. RESULTS: Forty-two cases completed the study. Global function was improved with the treatment (P = 0.002), but not in the control group (P = 0.601). The patients' quality of life in the treatment group showed significant improvement on the psychosocial (P < 0.01) and symptoms/side effects subscale scores (P < 0.01), but not on the energy subscale score (P > 0.1). There was no significant change in the family's quality of life in both groups. CONCLUSIONS: The family psychoeducational needs assessment may lead to more improvement in schizophrenic patients' global function and quality of life, but has no significant effect on their families' quality of life. It is recommended that the psychiatric care centers develop their psychoeducation profiles based on the needs-assessment program. PMID- 25540799 TI - Folding Proteins at 500 ns/hour with Work Queue. AB - Molecular modeling is a field that traditionally has large computational costs. Until recently, most simulation techniques relied on long trajectories, which inherently have poor scalability. A new class of methods is proposed that requires only a large number of short calculations, and for which minimal communication between computer nodes is required. We considered one of the more accurate variants called Accelerated Weighted Ensemble Dynamics (AWE) and for which distributed computing can be made efficient. We implemented AWE using the Work Queue framework for task management and applied it to an all atom protein model (Fip35 WW domain). We can run with excellent scalability by simultaneously utilizing heterogeneous resources from multiple computing platforms such as clouds (Amazon EC2, Microsoft Azure), dedicated clusters, grids, on multiple architectures (CPU/GPU, 32/64bit), and in a dynamic environment in which processes are regularly added or removed from the pool. This has allowed us to achieve an aggregate sampling rate of over 500 ns/hour. As a comparison, a single process typically achieves 0.1 ns/hour. PMID- 25540800 TI - Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection. AB - OBJECT: Ischemic brain injury is the leading cause for death and long-term disability in patients who suffer cardiac arrest and embolic stroke. Excitotoxicity and subsequent Ca(2+)-overload lead to ischemic neuron death. We explore a novel mechanism concerning the role of the excitatory extracellular calcium-sensing receptor (CaSR) in the induction of ischemic brain injury. METHOD: Mice were exposed to forebrain ischemia and the actions of CaSR were determined after its genes were ablated specifically in hippocampal neurons or its activities were inhibited pharmacologically. Since the CaSR forms a heteromeric complex with the inhibitory type B gamma-aminobutyric acid receptor 1 (GABABR1), we compared neuronal responses to ischemia in mice deficient in CaSR, GABABR1, or both, and in mice injected locally or systemically with a specific CaSR antagonist (or calcilytic) in the presence or absence of a GABABR1 agonist (baclofen). RESULTS: Both global and focal brain ischemia led to CaSR overexpression and GABABR1 downregulation in injured neurons. Genetic ablation of Casr genes or blocking CaSR activities by calcilytics rendered robust neuroprotection and preserved learning and memory functions in ischemic mice, partly by restoring GABABR1 expression. Concurrent ablation of Gabbr1 gene blocked the neuroprotection caused by the Casr gene knockout. Coinjection of calcilytics with baclofen synergistically enhanced neuroprotection. This combined therapy remained robust when given 6 h after ischemia. INTERPRETATION: Our study demonstrates a novel receptor interaction, which contributes to ischemic neuron death through CaSR upregulation and GABABR1 downregulation, and feasibility of neuroprotection by concurrently targeting these two receptors. PMID- 25540802 TI - Power spectra for screening parkinsonian patients for mild cognitive impairment. AB - OBJECTIVE: Mild cognitive impairment in Parkinson's disease (PD-MCI) is diagnosed based on the results of a standardized set of cognitive tests. We investigate whether quantitative EEG (qEEG) measures could identify differences between cognitively normal PD (PD-CogNL) and PD-MCI patients. METHODS: High-resolution EEG was recorded in 53 patients with Parkinson's disease (PD). Relative power in five frequency bands was calculated globally and for ten regions. Peak and median frequencies were determined. qEEG results were compared between groups. Effect sizes of all variables were calculated. The best separating variable was used to demonstrate subject-wise classification. RESULTS: Lower mean values were observed in global alpha1 power and alpha1 power in five brain regions (left hemisphere: frontal, central, temporal, occipital; right hemisphere: temporal, P < 0.05), differentiating between PD-CogNL and PD-MCI groups. Effect sizes were high, ranging from 0.79 to 0.87. Median frequency was 8.56 +/- 0.74 Hz and was not different between the groups. The variable with the best subject-wise classification was the power in the alpha1 band in the right temporal region. The area under the corresponding receiver operating characteristic (ROC) curve was 0.72. The optimal classification threshold yielded a sensitivity of 65.9% and a specificity of 66.7%. The positive and negative predictive values were 87.1% and 36.4%, respectively. INTERPRETATION: Reduction in alpha1 band power in nondemented PD patients, particularly in the right temporal region, is highly indicative of MCI in PD patients. The results might be used to assist in time efficient diagnosis of PD-MCI and avoid the drawbacks of test-retest effect in repeated neuropsychological testing. PMID- 25540801 TI - Endomicroscopy and electromyography of neuromuscular junctions in situ. AB - OBJECTIVE: Electromyography (EMG) is used routinely to diagnose neuromuscular dysfunction in a wide range of peripheral neuropathies, myopathies, and neuromuscular degenerative diseases including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Definitive neurological diagnosis may also be indicated by the analysis of pathological neuromuscular innervation in motor point biopsies. Our objective in this study was to preempt motor-point biopsy by combining live imaging with electrophysiological analysis of slow degeneration of neuromuscular junctions (NMJs) in vivo. METHODS: We combined conventional needle electromyography with fiber-optic confocal endomicroscopy (CEM), using an integrated hand-held, 1.5-mm-diameter probe. We utilized as a test bed, various axotomized muscles in the hind limbs of anaesthetized, double-homozygous thy1.2YFP16: Wld (S) mice, which coexpress the Wallerian-degeneration Slow (Wld(S)) protein and yellow fluorescent protein (YFP) in motor neurons. We also tested exogenous vital stains, including Alexa488-alpha-bungarotoxin; the styryl pyridinium dye 4-Di-2-Asp; and a GFP conjugate of botulinum toxin Type A heavy chain (GFP-HcBoNT/A). RESULTS: We show that an integrated EMG/CEM probe is effective in longitudinal evaluation of functional and morphological changes that take place over a 7-day period during axotomy-induced, slow neuromuscular synaptic degeneration. EMG amplitude declined in parallel with overt degeneration of motor nerve terminals. EMG/CEM was safe and effective when nerve terminals and motor endplates were selectively stained with vital dyes. INTERPRETATION: Our findings constitute proof-of-concept, based on live imaging in an animal model, that combining EMG/CEM may be useful as a minimally invasive precursor or alternative to motor-point biopsy in neurological diagnosis and for monitoring local administration of potential therapeutics. PMID- 25540803 TI - Degree of corticospinal tract damage correlates with motor function after stroke. AB - OBJECTIVES: Direct injury to the corticospinal tract (CST) is a major factor defining motor impairment after stroke. Diffusion tensor imaging (DTI) tractography allows definition of the CST. We sought to determine whether DTI based assessment of the degree of CST damage correlates with motor impairment at each phase of ischemic stroke. METHODS: We evaluated patients at the acute (3-7 days), subacute (30 days), and chronic (90 days) phases of ischemic stroke with DTI and clinical motor scores (upper extremity Fugl-Myer test [UE-FM], motor items of the National Institutes of Health Stroke Scale [mNIHSS]). The CST was identified and virtual fiber numbers (FN) were calculated for the affected and contralateral CST. We used Spearman correlation to study the relationship of FN ratio (FNr) (affected/unaffected CST) with motor scores at each time point, and the regression model to study the association of the acute parameters with chronic motor scores. RESULTS: We studied 23 patients. Mean age was 66.7 (+/-12) years. FNr correlated with UE-FM score in the acute (r = 0.50, P = 0.032), subacute (r = 0.57, P = 0.007), and chronic (r = 0.67, P = 0.0008) phase, and with mNIHSS in the acute (r = -0.48, P = 0.043), subacute (r = -0.58, P = 0.006), and chronic (r = -0.75, P = 0.0001) phase. The combination of acute NIHSS and FNr significantly predicted chronic UE-FM score (r = 0.74, P = 0.0001). INTERPRETATION: DTI-defined degree of CST injury correlates with motor impairment at each phase of ischemic stroke. The combination of baseline FNr and NIHSS predicts motor outcome. DTI-derived CST assessment could become a surrogate marker of motor impairment in the design of neurorestorative clinical trials. PMID- 25540804 TI - Analysis of graft survival in a trial of stem cell transplant in ALS. AB - OBJECTIVE: The first US Food and Drug Administration-approved clinical trial to treat amyotrophic lateral sclerosis (ALS) with neural stem cell-based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord-derived neural stem cells (HSSCs) transplanted into the spinal cord in patients with ALS. METHODS: Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real-time PCR methods (qPCR). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells. RESULTS: Genomic DNA from donor HSSCs was identified in all cases, comprising 0.67-5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a "nest" of cells identified on H&E staining were XY-positive by FISH, confirming donor origin. A subset of XY positive cells labeled for the neuronal marker NeuN and stem cell marker SOX2. INTERPRETATION: This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSCs survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients. PMID- 25540806 TI - Pediatric anti-NMDA receptor encephalitis is seasonal. AB - In the majority of pediatric anti-N-methyl-d-aspartate receptor encephalitis (NMDARe) cases, the underlying cause of antibody production and subsequent disease remains unknown. We aimed to characterize this poorly understood population, investigating epidemiological factors potentially related to disease etiology, particularly season of onset. In this retrospective case review study, we analyzed data from the 29 pediatric subjects with anti-NMDAR antibodies and found that symptoms were first reported in the warm months of April-September in 78% of non-tumor-related NMDARe (NT-NMDARe) cases. These findings support further investigation into a possible seasonal trigger of NT-NMDARe. PMID- 25540805 TI - Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions. AB - OBJECTIVE: Mutations in nuclear-encoded mitochondrial DNA (mtDNA) polymerase (POLG) are known to cause autosomal dominant chronic progressive external ophthalmoplegia (adCPEO) with accumulation of multiple mtDNA deletions in muscles. However, no animal model with a heterozygous Polg mutation representing mtDNA impairment and symptoms of CPEO has been established. To understand the pathogenic mechanism of CPEO, it is important to determine the age dependency and tissue specificity of mtDNA impairment resulting from a heterozygous mutation in the Polg gene in an animal model. METHODS: We assessed behavioral phenotypes, tissue-specific accumulation of mtDNA deletions, and its age dependency in heterozygous Polg (D257A) knock-in mice carrying a proofreading-deficient mutation in the Polg. RESULTS: Heterozygous Polg (D257A) knock-in mice exhibited motor dysfunction in a rotarod test. Polg (+/D257A) mice had significant accumulation of multiple mtDNA deletions, but did not show significant accumulation of point mutations or mtDNA depletion in the brain. While mtDNA deletions increased in an age-dependent manner regardless of the tissue even in Polg (+/+) mice, the age-dependent accumulation of mtDNA deletions was enhanced in muscles and in the brain of Polg (+/D257A) mice. INTERPRETATION: Heterozygous Polg (D257A) knock-in mice showed tissue-specific, age-dependent accumulation of multiple mtDNA deletions in muscles and the brain which was likely to result in neuromuscular symptoms. Polg (+/D257A) mice may be used as an animal model of adCPEO associated with impaired mtDNA maintenance. PMID- 25540807 TI - Unusual Stuve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy. AB - A woman was isozygous for a novel mutation in the leukemia inhibitory factor receptor gene (LIFR) (c.2170C>G; p.Pro724Ala) which disrupts LIFR downstream signaling and results in Stuve-Wiedemann syndrome (STWS). She inherited two identical chromosomes 5 from her mother, heterozygous for the LIFR mutation. The presentation was typical for STWS, except there was no long bone dysplasia. Prominent cold-induced sweating and heat intolerance lead to an initial diagnosis of cold-induced sweating syndrome, excluded by exome sequencing. Skin biopsies provide the first human evidence of failed postnatal cholinergic differentiation of sympathetic neurons innervating sweat glands in cold-induced sweating, and of a neuropathy. PMID- 25540808 TI - An allometric scaling relationship in the brain of preterm infants. AB - Allometry has been used to demonstrate a power-law scaling relationship in the brain of premature born infants. Forty-nine preterm infants underwent neonatal MRI scans and neurodevelopmental testing at age 2. Measures of cortical surface area and total cerebral volume demonstrated a power-law scaling relationship (alpha = 1.27). No associations were identified between these measures and investigated clinical variables. Term equivalent cortical surface area and total cerebral volume measures and scaling exponents were not related to outcome. These findings confirm a previously reported allometric scaling relationship in the preterm brain, and suggest that scaling is not a sensitive indicator of aberrant cortical maturation. PMID- 25540811 TI - Beaming Visible Light with a Plasmonic Aperture Antenna. AB - We investigate experimentally the parameter space defining, in the visible range, the far-field diffraction properties of a single circular subwavelength aperture surrounded by periodic circular grooves milled on a metallic film. Diffraction patterns emerging from such an antenna are recorded under parallel- and perpendicular-polarized illumination at a given illumination wavelength. By monitoring the directivity and the gain of the antenna with respect to a single aperture, we point out the role played by the near-field surface plasmon excitations. The results can be analyzed through a Huygens-Fresnel model, accounting for the coherent interaction between the field radiated by the hole and the plasmonic field, propagating along the antenna surface and diffracted away in free space. PMID- 25540809 TI - Adjuvant therapies for HIV-associated neurocognitive disorders. AB - OBJECTIVE: HIV-associated neurocognitive disorder (HAND) is a frequent and heterogeneous complication of HIV, affecting nearly 50% of infected individuals in the combined antiretroviral therapy (cART) era. This is a particularly devastating statistic because the diagnosis of HAND confers an increased risk of HIV-associated morbidity and mortality in affected patients. While cART is helpful in the treatment of the more severe forms of HAND, there is a therapeutic gap in the milder forms of HAND, where cART is less effective. Multiple adjuvant therapies with various mechanisms of action have been studied (N-methyl D aspartate [NMDA]-receptor antagonists, MAO-B inhibitors, tetracycline-class antibiotics, and others), but none have shown a clear positive effect in HAND. While this lack of efficacy may be because the appropriate therapeutic targets have not yet been determined, we aimed to discuss that study results may also influenced by clinical trial design. METHODS: This report is a systematic review of clinical trials of adjuvant therapies for HAND performed from January 1996 through June 2014. RESULTS: Possible drawbacks in study design, including lack of standardized case definitions, poorly defined target populations, inappropriate dose selection and measurable outcomes, and brief study durations may have masked true underlying mechanistic effects of previously investigated adjuvant therapies for HAND in specific patient populations. CONCLUSIONS: A proposal for streamlining and maximizing the likelihood of success in future clinical studies using a 'learning and confirming' investigational paradigm, incorporating stronger adaptive Phase I/II study designs, computerized modeling, and population/goal of treatment-specific Phase III clinical trials is presented. PMID- 25540812 TI - Third Harmonic Mechanism in Complex Plasmonic Fano Structures. AB - We perform third harmonic spectroscopy of dolmen-type nanostructures, which exhibit plasmonic Fano resonances in the near-infrared. Strong third harmonic emission is predominantly radiated close to the low energy peak of the Fano resonance. Furthermore, we find that the third harmonic polarization of the subradiant mode interferes destructively and diminishes the nonlinear signal in the far-field. By comparing the experimental third harmonic spectra with finite element simulations and an anharmonic oscillator model, we find strong indications that the source of the third harmonic is the optical nonlinearity of the bare gold enhanced by the resonant plasmonic polarization. PMID- 25540813 TI - A parallel decoding algorithm for short polar codes based on error checking and correcting. AB - We propose a parallel decoding algorithm based on error checking and correcting to improve the performance of the short polar codes. In order to enhance the error-correcting capacity of the decoding algorithm, we first derive the error checking equations generated on the basis of the frozen nodes, and then we introduce the method to check the errors in the input nodes of the decoder by the solutions of these equations. In order to further correct those checked errors, we adopt the method of modifying the probability messages of the error nodes with constant values according to the maximization principle. Due to the existence of multiple solutions of the error-checking equations, we formulate a CRC-aided optimization problem of finding the optimal solution with three different target functions, so as to improve the accuracy of error checking. Besides, in order to increase the throughput of decoding, we use a parallel method based on the decoding tree to calculate probability messages of all the nodes in the decoder. Numerical results show that the proposed decoding algorithm achieves better performance than that of some existing decoding algorithms with the same code length. PMID- 25540814 TI - Optimal control strategy design based on dynamic programming for a dual-motor coupling-propulsion system. AB - A dual-motor coupling-propulsion electric bus (DMCPEB) is modeled, and its optimal control strategy is studied in this paper. The necessary dynamic features of energy loss for subsystems is modeled. Dynamic programming (DP) technique is applied to find the optimal control strategy including upshift threshold, downshift threshold, and power split ratio between the main motor and auxiliary motor. Improved control rules are extracted from the DP-based control solution, forming near-optimal control strategies. Simulation results demonstrate that a significant improvement in reducing energy loss due to the dual-motor coupling propulsion system (DMCPS) running is realized without increasing the frequency of the mode switch. PMID- 25540815 TI - Gossypol promotes degeneration of ovarian follicles in rats. AB - The present study aimed to determine if gossypol interferes with ovarian follicles in rats. Twenty-four female Wistar rats were assigned to two equal groups: one control group and the other dosed with gossypol (25 mg/kg/day, subcutaneously) for 15 days. Ovarian follicles were histologically classified according to the stage of development and as normal or atretic. Gossypol treatment reduced the length of estrous with an increase in the duration of the diestrus phase. This compound was responsible for reduced serum levels of T4 and progesterone. Treatment with gossypol was responsible for a significant reduction in the number of normal ovarian follicles and a significant increase in the number of atretic follicles, both in all stages of development. Thus, treatment of rats with gossypol was responsible for reduction in the number of viable follicles and changes in hormone levels that resulted in interference of the estrous cycle. PMID- 25540816 TI - Exploring traditional and cyberbullying among Irish adolescents. AB - OBJECTIVES: This study aimed to explore the associations of traditional and cyberbullying victimisation with self-reported health and life satisfaction, and to examine whether involvement in risk behaviours contributes to these health outcomes. METHODS: We asked questions on involvement in traditional and cyberbullying, risk behaviours, self-reported health and life satisfaction to school children. In total, 318 students aged from 15 to 18 years old in 8 post primary schools in Ireland completed the survey. RESULTS: Children who were victims of bullying were more likely to report poor health, low life satisfaction and engaging in risky behaviours. Although not statistically significant, we found that cyber victimisation was positively associated with increased reporting of poor health and low life satisfaction. CONCLUSION: Traditional bullying is the most common type of bullying among school children in Ireland, and overall, seems to have a stronger association with poor health. However, a sizable proportion of children are victims of cyberbullying or of both cyberbullying and traditional bullying. It is, therefore, important to acknowledge, identify and address all types of bullying to improve the health outcomes of children. PMID- 25540817 TI - Reconstructive Endovascular Treatment of Spontaneous Symptomatic Large or Giant Vertebrobasilar Dissecting Aneurysms: Clinical and Angiographic Outcomes. AB - PURPOSE: To investigate the clinical and angiographic outcomes of spontaneous symptomatic large or giant vertebrobasilar dissecting aneurysms (VBDAs) following reconstructive endovascular treatment (EVT) with stent(s). METHODS: We retrospectively identified 21 patients with spontaneous symptomatic large or giant VBDAs who had been treated with reconstructive EVT between September 2009 and September 2013 in our department. There were 20 men and 1 woman, with a mean age of 46.5 years (range: 17-67 years). Clinical and angiographic data were reviewed and evaluated. RESULTS: Reconstructive EVT with sole stenting (SS, 10 cases) or stent-assisted coiling (SAC, 11 cases) technique was technically feasible in all cases. Angiographic follow-up results confirmed delayed thrombosis of the aneurysm sac in only two of the eight cases after SS, and recurrence of the aneurysm sac in six of the nine cases after SAC. Postoperative complications or poor neurologic outcomes occurred in seven cases (33.3 %). Three patients died after SS, including postoperative subarachnoid hemorrhage in one case and pulmonary embolism in one case. The other patient died soon after SAC, without radiologic result to confirm the causes of death. Other adverse events after treatment include ischemic complication in two cases, intramural hemorrhage in one case, aggravation of initial mass effect in one case. As to the other 14 cases, the post-procedural processes were uneventful and no complication was observed. The condition of them was improved in seven cases (33.3 %), and unchanged in seven cases (33.3 %) during follow-up. CONCLUSIONS: Reconstructive EVT with traditional intracranial stent(s) for the treatment of large and giant VBDAs carries a high failure rate and substantial risk of complications. The outcome of treating these difficult lesions with traditional intracranial stenting seems questionable and unpredictable. PMID- 25540818 TI - Genetic characterization of the wheat association mapping initiative (WAMI) panel for dissection of complex traits in spring wheat. AB - KEY MESSAGE: The wheat association mapping initiative is appropriate for gene discovery without the confounding effects of phenology and plant height. The wheat association mapping initiative (WAMI) population is a set of 287 diverse advanced wheat lines with a narrow range of variation for days to heading (DH) and plant height (PH). This study aimed to characterize the WAMI and showed that this diverse panel has a favorable genetic background in which stress adaptive traits and their alleles contributing to final yield can be identified with reduced confounding major gene effects through genome-wide association studies (GWAS). Using single nucleotide polymorphism (SNP) markers, we observed lower gene diversity on the D genome, compared with the other genomes. Population structure was primarily related to the distribution of the 1B.1R rye translocation. The narrow range of variation for DH and PH in the WAMI population still entailed segregation for a few markers associated with the former traits, while Rht genes were associated with grain yield (GY). Genotype by environment (G * E) interaction for GY was primarily explained by Rht-B1, Vrn-A1 and markers on chromosomes 2D and 3A when running GWAS with genotype scores from the G * E biplot. The use of PC scores from the G * E biplot seems a promising tool to determine genes and markers associated with complex interactions across environments. The WAMI panel lends itself to GWAS for complex trait dissection by avoiding the confounding effects of DH and PH which were reduced to a minimum (using Rht-B1 and Vrn-A1 scores as covariables), with significant associations with GY on chromosomes 2D, 3A and 3B. PMID- 25540819 TI - High risk HPV E6 oncoproteins impair the subcellular distribution of the four and a half LIM-only protein 2 (FHL2). AB - HPVs are the causative agents of approximately 5% of all human cancers, with cervical cancer being the most predominant. To understand the mechanism of action of the viral E6 oncoprotein, we analysed the effects of E6 upon potential cellular target proteins. One candidate is FHL-2, involved in the regulation of signal transduction pathways from the multimeric complexes assembled at focal adhesions. We show that both HPV E6 and E6(*) can interact with FHL-2 in vitro, but unlike most E6 targets, FHL-2 does not appear to be an E6 degradation target. Analysis of the patterns of FHL-2 distribution within HPV-positive tumour-derived cells shows a significant alteration in the pattern of FHL-2 localisation when compared to non-HPV containing cells. This perturbation of FHL-2 distribution is proteasome-dependent and inhibition of E6 expression restores the normal distribution of FHL-2. These results confirm FHL-2 as a new interacting partner of the HPV-E6 oncoproteins. PMID- 25540820 TI - Development of an isoform-specific tandem mass spectrometry assay for absolute quantitation of maize lipid transfer proteins. AB - Precise and accurate quantitation of maize grain allergens is important for seed and food industries. The major allergen in maize grain is Zea m 14, a lipid transfer protein (LTP). The B73 maize genome encodes for at least six LTPs sharing 15%-87% sequence identity to Zea m 14. Phylogenetic analysis of the maize LTP family revealed one gene that corresponds to Zea m 14 (denoted as LTPa) and two other genes sharing 43% (LTPc) and 74% (LTPb) identity with Zea m 14 that are putative homologues. Using stable isotope peptide mimics as internal standards for LTPs, we present a multiple reaction monitoring mass spectrometry approach for multiplexed, absolute quantitation of all three LTP proteins and alternative transcript models therein. To validate quantitative accuracy, a redundant peptide, simultaneously representing the two most abundant LTPs, was included. Analysis of 21 maize varieties revealed LTPa was most prominently expressed in maize grain, ranging from 9 to 32 MUg LTP/mg protein. Proteins belonging to the LTPb and LTPc gene models were also expressed but at approximately 10- and 100 fold lower levels than LTPa, respectively. The quantitative results provided by the redundant peptide show around 95% agreement with the sum of the two unique peptides, thus providing support for the LTP gene models and validating the accuracy of this method. Though not all Zea m 14-related LTPs are abundant in grain, their high sequence homology and detectable expression in maize grain signify that LTPb and LTPc are putative allergens and should be accounted for in any quantitation strategy for maize LTP allergens. PMID- 25540821 TI - Metastable nanobubbles at the solid-liquid interface due to contact angle hysteresis. AB - Nanobubbles exist at solid-liquid interfaces between pure water and hydrophobic surfaces with very high stability, lasting in certain cases up to several days. Not only semispherical but also other shapes, such as micropancakes, are known to exist at such interfaces. However, doubt has been raised as to whether or not the nanobubbles are gas-phase entities. In this study, surface nanobubbles at a pure water-highly ordered pyrolytic graphite (HOPG) interface were investigated by peak force quantitative nanomechanics (PF-QNM). Multiple isolated nanobubbles generated by the solvent-exchange method were present on the terraced areas, avoiding the steps of the HOPG surface. Adjacent nanobubbles coalesced and formed metastable nanobubbles. Coalescence was enhanced by the PF-QNM measurement. We determined that nanobubbles can exist for a long time because of nanoscale contact angle hysteresis at the water-HOPG interface. Moreover, the hydrophilic steps of HOPG were avoided during coalescence, providing evidence that the nanobubbles are truly gas phase. PMID- 25540823 TI - Bridging adhesion of mussel-inspired peptides: role of charge, chain length, and surface type. AB - The 3,4-dihydroxyphenylalanine (Dopa)-containing proteins of marine mussels provide attractive design paradigms for engineering synthetic polymers that can serve as high performance wet adhesives and coatings. Although the role of Dopa in promoting adhesion between mussels and various substrates has been carefully studied, the context by which Dopa mediates a bridging or nonbridging macromolecular adhesion to surfaces is not understood. The distinction is an important one both for a mechanistic appreciation of bioadhesion and for an intelligent translation of bioadhesive concepts to engineered systems. On the basis of mussel foot protein-5 (Mfp-5; length 75 res), we designed three short, simplified peptides (15-17 res) and one relatively long peptide (30 res) into which Dopa was enzymatically incorporated. Peptide adhesion was tested using a surface forces apparatus. Our results show that the short peptides are capable of weak bridging adhesion between two mica surfaces, but this adhesion contrasts with that of full length Mfp-5, in that (1) while still dependent on Dopa, electrostatic contributions are much more prominent, and (2) whereas Dopa surface density remains similar in both, peptide adhesion is an order of magnitude weaker (adhesion energy E(ad) ~ -0.5 mJ/m(2)) than full length Mfp-5 adhesion. Between two mica surfaces, the magnitude of bridging adhesion was approximately doubled (E(ad) ~ -1 mJ/m(2)) upon doubling the peptide length. Notably, the short peptides mediate much stronger adhesion (E(ad) ~ -3.0 mJ/m(2)) between mica and gold surfaces, indicating that a long chain length is less important when different interactions are involved on each of the two surfaces. PMID- 25540825 TI - Aqueous based synthesis of antimicrobial-decorated graphene. AB - Ramizol(r) (1,3,5-tris[(1E)-2'-(4'-benzoic acid)vinyl]benzene) is a potent amphiphilic anti-microbial agent. It is essentially a planar molecule and can interact with the surface of graphene via extended pi-pi interactions. Herein we demonstrate the utility of Ramizol(r) in potentially acting as a molecular 'wedge' to exfoliate graphene and stabilise it in water. The non-covalent attachment of Ramizol(r) on the graphene surface enables release of Ramizol(r) by altering the pH of the solution. Furthermore, the stabilised composite material demonstrates antibacterial activity against Staphylococcus aureus which leads to potential in biomedical applications with graphene acting as a drug carrier as well as enhancing the structural strength of the composite material. PMID- 25540826 TI - Preparation and characterization of poly(AA co PVP)/PGS composite and its application for methylene blue adsorption. AB - Poly (AA co PVP)/PGS (PAPP) composite adsorbent was prepared by radical polymerization from Acrylic acid (AA), Polyvinylpyrrolidone (PVP) and Palygorskite (PGS), using N,N-methylenebisacrylamide (MBA) as cross-linker and potassium persulfate (KPS) as initiator. The PAPP was characterized with Fourier transform infrared (FT-IR), thermogravimetric analysis (TG), scanning electron microscope (SEM) and transmission electron microscopy (TEM). PAPP was used as adsorbent for the removal of methylene blue from aqueous solutions. The influences of pH, adsorption temperature and adsorption time on the adsorption properties of the composite to the dye were also investigated. Meanwhile, the adsorption rate data and adsorption equilibrium date were analyzed based on the pseudo-first-order and pseudo-second-order kinetic model, Langmuir and Freundlich isotherm models, respectively. The results indicating that the kinetic behavior better fit with the pseudo-second-order kinetic model. The maximum equilibrium adsorption capacity (q(m)) is 1815 mg/g at 289 K. The isotherm behavior can be explained by the Langmuir isotherm models. The activation energy was also evaluated for the removal of methylene blue onto PAPP. These results demonstrate that this composite material could be used as a good adsorbent for the removal of cationic dyes from wastewater. PMID- 25540822 TI - Experimental strategies for functional annotation and metabolism discovery: targeted screening of solute binding proteins and unbiased panning of metabolomes. AB - The rate at which genome sequencing data is accruing demands enhanced methods for functional annotation and metabolism discovery. Solute binding proteins (SBPs) facilitate the transport of the first reactant in a metabolic pathway, thereby constraining the regions of chemical space and the chemistries that must be considered for pathway reconstruction. We describe high-throughput protein production and differential scanning fluorimetry platforms, which enabled the screening of 158 SBPs against a 189 component library specifically tailored for this class of proteins. Like all screening efforts, this approach is limited by the practical constraints imposed by construction of the library, i.e., we can study only those metabolites that are known to exist and which can be made in sufficient quantities for experimentation. To move beyond these inherent limitations, we illustrate the promise of crystallographic- and mass spectrometric-based approaches for the unbiased use of entire metabolomes as screening libraries. Together, our approaches identified 40 new SBP ligands, generated experiment-based annotations for 2084 SBPs in 71 isofunctional clusters, and defined numerous metabolic pathways, including novel catabolic pathways for the utilization of ethanolamine as sole nitrogen source and the use of d-Ala-d-Ala as sole carbon source. These efforts begin to define an integrated strategy for realizing the full value of amassing genome sequence data. PMID- 25540824 TI - Urchin-like LaVO4/Au composite microspheres for surface-enhanced Raman scattering detection. AB - The availability of sensitive, reproducible and stable substrate is critically important for surface enhanced Raman scattering (SERS)-based application, but it still remains a challenge up to now. In this work, urchin-like LaVO4 microspheres prepared by a hydrothermal method were used as a template to fabricate SERS substrate by deposition of Au nanoparticle onto the surfaces of LaVO4 microspheres. The coverage of Au nanoparticles on the surfaces of LaVO4 microspheres can be easily controlled by varying the amount of Au precursor. SERS measurement showed that the coverage of Au nanoparticles on the surfaces of LaVO4 microspheres had a great effect on SERS activity. The SERS signals collected from 80 microspheres indicated that as-prepared SERS substrate exhibited a good reproducibility. Detection of melamine molecules with a low concentration (1.0*10(-9)M) was used as an example to show the possible application of such substrate. In addition, the effect of iron ion (Fe(3+)) on detection melamine from the mixture of melamine and benzoic acid was also investigated. It was found that the interference of benzoic acid in detecting melamine from the mixture can be removed by adding Fe(3+). PMID- 25540827 TI - Optimization of tetracycline hydrochloride adsorption on amino modified SBA-15 using response surface methodology. AB - Several researchers are focused on preparation of mesoporous silica as drug carriers with high loading efficiency to control or sustain the drug release. Carriers with highly loaded drug are utilized to minimize the time of drug intake. In this study, amino modified SBA-15 was synthesized through grafting with amino propyl triethoxy silane and then loaded with tetracycline hydrochloride. The drug loading was optimized by using the response surface method considering various factors including drug to silica ratio, operation time, and temperature. The drug to silica ratio indicated as the most influential factor on the drug loading yield. Further, a quadratic polynomial equation was developed to predict the loading percentage. The experimental results indicated reasonable agreement with the predicted values. The modified and drug loaded mesoporous particles were characterized by FT-IR, SEM, TEM, X-ray diffraction (XRD), elemental analysis and N2 adsorption-desorption. The release profiles of tetracycline-loaded particles were studied in different pH. Also, Higuchi equation was used to analyze the release profile of the drug and to evaluate the kinetic of drug release. The drug release rate followed the conventional Higuchi model that could be controlled by amino-functionalized SBA-15. Further, the drug delivery system based on amino modified SBA-15 exhibits novel features with an appropriate usage as an anti-bacterial drug delivery system with effective management of drug adsorption and release. PMID- 25540828 TI - Preparation and characterization of gamma-AlOOH @CS magnetic nanoparticle as a novel adsorbent for removing fluoride from drinking water. AB - For this study, a novel adsorbent of gamma-AlOOH @CS (pseudoboehmite and chitosan shell) magnetic nanoparticles (ACMN) with magnetic separation capabilities was developed to remove fluoride from drinking water. The adsorbent was first characterized, and then its performance in removing fluoride was evaluated. Kinetic data demonstrated rapid fluoride adsorption with more than 80% fluoride adsorption within the initial 20 min and equilibrium reached in 60 min. Based on the results of kinetic and isotherm models, the fluoride adsorption process on the ACMN's surface was a monolayer adsorption on a homogeneous surface. Thermodynamic parameters presented that the adsorption process is spontaneous and endothermic in nature. The mechanism for the adsorption involved electrostatic interaction and hydrogen bonding. Moreover, the calculated adsorption capacity of the ACMN for fluoride using the Langmuir model was 67.5 mg/g (20 degrees C, pH=7.0+/-0.1), higher than other fluoride removal adsorbents. This nanoadsorbent performed well over a pH range of 4-10. The study found that PO4(3-) was the co existing anion most able to hinder the nanoparticle's fluoride adsorption, followed by NO3(-) then Cl(-). Experimental results suggest that ACMN is a promising adsorbent for treating fluoride-contaminated water. PMID- 25540829 TI - Dynamic architecture of the purinosome involved in human de novo purine biosynthesis. AB - Enzymes in human de novo purine biosynthesis have been demonstrated to form a reversible, transient multienzyme complex, the purinosome, upon purine starvation. However, characterization of purinosomes has been limited to HeLa cells and has heavily relied on qualitative examination of their subcellular localization and reversibility under wide-field fluorescence microscopy. Quantitative approaches, which are particularly compatible with human disease relevant cell lines, are necessary to explicitly understand the purinosome in live cells. In this work, human breast carcinoma Hs578T cells have been utilized to demonstrate the preferential utilization of the purinosome under purine depleted conditions. In addition, we have employed a confocal microscopy-based biophysical technique, fluorescence recovery after photobleaching, to characterize kinetic properties of the purinosome in live Hs578T cells. Quantitative characterization of the diffusion coefficients of all de novo purine biosynthetic enzymes reveals the significant reduction of their mobile kinetics upon purinosome formation, the dynamic partitioning of each enzyme into the purinosome, and the existence of three intermediate species in purinosome assembly under purine starvation. We also demonstrate that the diffusion coefficient of the purine salvage enzyme, hypoxanthine phosphoribosyltransferase 1, is not sensitive to purine starvation, indicating exclusion of the salvage pathway from the purinosome. Furthermore, our biophysical characterization of nonmetabolic enzymes clarifies that purinosomes are spatiotemporally different cellular bodies from stress granules and cytoplasmic protein aggregates in both Hs578T and HeLa cells. Collectively, quantitative analyses of the purinosome in Hs578T cells led us to provide novel insights for the dynamic architecture of the purinosome assembly. PMID- 25540830 TI - Automatic characterization of thoracic aortic aneurysms from CT images. AB - Accurate determination of the diameter is an important step for diagnosis and follow-up of aortic abnormalities such as aneurysms, caused by dilation of the vessel lumen. In this work we focus on the development of an automatic method for measuring the calibre of the thoracic aorta. The method is based on the application of principal component analysis on normal planes extracted from the aorta to establish the main axis of each section of the vessel. Two experiments were performed in order to test the accuracy and the rotational invariance of the developed method. Accuracy was determined by using a database of 15 clinical cases, where our method and a commercial software, which was considered as the gold standard, were compared. For the rotational invariance check, phantom images in different orientations were obtained and the diameter was measured with the proposed method. For clinical cases, a good agreement was observed between our method and the gold standard. The Bland Altman plots indicated that all of the values were within the acceptable limits of agreement with a bias of 0.2mm between both methods. For phantom cases, an ANOVA test revealed that the results achieved for the data sets acquired for the different orientations were not statistically different (F=1.88, p=0.153), which demonstrates the robustness of the method for rotations. The proposed method is applicable for measuring the diameter in all tested cases, and the results achieved underscored the capability of our approach for automatic characterization of thoracic aortic aneurysms. PMID- 25540831 TI - Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor. AB - BACKGROUND: Serotonin syndrome is a potentially life-threatening adverse drug reaction that most commonly results from adverse interactions between drugs. Because serotonin syndrome can be fatal and is often difficult to diagnose, it is vital for health professionals to know about this reaction. We report a typical case of transient serotonin syndrome secondary to tramadol-Citalopram combination. This case report highlights the value of awareness of the early and subtle signs of serotonin syndrome. CASE REPORT: A 44-year-old female with past medical history of chronic pancreatitis, back pain, and major depression was brought to the emergency room (ER) with altered mental status, jerky movements in extremities, generalized weakness, and vomiting. CONCLUSIONS: Most physicians are aware of serotonin syndrome secondary to antidepressants but do not think about other classes of medications such as analgesics. Clinicians should also be aware of the possibility of serotonin syndrome when encountering a patient taking serotonergic drugs who presents with characteristic symptoms of serotonin syndrome. PMID- 25540832 TI - Predictive processing of novel compounds: evidence from Japanese. AB - Our study argues that pre-head anticipatory processing operates at a level below the level of the sentence. A visual-world eye-tracking study demonstrated that, in processing of Japanese novel compounds, the compound structure can be constructed prior to the head if the prosodic information on the preceding modifier constituent signals that the Compound Accent Rule (CAR) is being applied. This prosodic cue rules out the single head analysis of the modifier noun, which would otherwise be a natural and economical choice. Once the structural representation for the head is computed in advance, the parser becomes faster in identifying the compound meaning. This poses a challenge to models maintaining that structural integration and word recognition are separate processes. At the same time, our results, together with previous findings, suggest the possibility that there is some degree of staging during the processing of different sources of information during the comprehension of compound nouns. PMID- 25540833 TI - The dual function of social gaze. AB - Ears cannot speak, lips cannot hear, but eyes can both signal and perceive. For human beings, this dual function makes the eyes a remarkable tool for social interaction. For psychologists trying to understand eye movements, however, their dual function causes a fundamental ambiguity. In order to contrast signaling and perceiving functions of social gaze, we manipulated participants' beliefs about social context as they looked at the same stimuli. Participants watched videos of faces of higher and lower ranked people, while they themselves were filmed. They believed either that the recordings of them would later be seen by the people in the videos or that no-one would see them. This manipulation significantly changed how participants responded to the social rank of the target faces. Specifically, when they believed that the targets would later be looking at them, and so could use gaze to signal information, participants looked proportionally less at the eyes of the higher ranked targets. We conclude that previous claims about eye movements and face perception that are based on a single social context can only be generalized with caution. A complete understanding of face perception needs to address both functions of social gaze. PMID- 25540834 TI - Decay of host-associated Bacteroidales cells and DNA in continuous-flow freshwater and seawater microcosms of identical experimental design and temperature as measured by PMA-qPCR and qPCR. AB - It is difficult to compare decay kinetics for genetic markers in an environmental context when they have been determined at different ambient temperatures. Therefore, we investigated the persistence of the host-associated genetic markers BacHum, BacCow and BacCan as well as the general Bacteroidales marker BacUni in both intact Bacteroidales cells and as total intracellular and extracellular marker DNA in controlled batch experiments at two temperatures using PMA-qPCR. Fecal Bacteroidales cells and DNA persisted longer at the lower temperature. Using the modified Arrhenius function to calculate decay constants for the same temperature, we then compared the decay of host-associated Bacteroidales cells and their DNA at 14 degrees C in field-based flow-through microcosms containing human, cow, and dog feces suspended in freshwater or seawater and previously operated with an identical experimental design. The time for a 2-log reduction (T99) was used to characterize host-associated Bacteroidales decay. Host associated genetic markers as determined by qPCR had similar T99 values in freshwater and seawater at 14 degrees C when compared under both sunlight and dark conditions. In contrast, intact Bacteroidales cells measured by PMA-qPCR had shorter T99 values in seawater than in freshwater. The decay constants of Bacteroidales cells were a function of physical (temperature) and chemical (salinity) parameters, suggesting that environmental parameters are key input variables for Bacteroidales survival in a predictive water quality model. Molecular markers targeting total Bacteroidales DNA were less susceptible to the variance of temperature, salinity and sunlight, implying that measurement of markers in both intact cells and DNA could enhance the predictive power of identifying fecal pollution across all aquatic environments. Monitoring Bacteroidales by qPCR alone rather than by PMA-qPCR does not always identify the contribution of recent fecal contamination because a signal may be detected that does not reflect a recent fecal event. PMID- 25540835 TI - Combined BAC and MIEX pre-treatment of secondary wastewater effluent to reduce fouling of nanofiltration membranes. AB - Biological activated carbon (BAC) and magnetic ion exchange resin (MIEX) were used to pre-treat secondary wastewater effluent (SWWE) and assessed for their capacity to reduce fouling of a nanofiltration membrane. BAC pre-treated water facilitated a lower but a steady flux while MIEX treated water resulted in a higher but a rapidly declining flux. Their combined use increased average flux from 58 to 89%. MIEX combined with BAC, in that order, was superior in reducing membrane fouling. Measurement of average Stokes radius (m) and apparent molecular weight distribution of dissolved organic matter (DOM), by nuclear magnetic resonance (NMR) and liquid chromatography organic carbon detection (LC-OCD), respectively, revealed that the microbial activity of BAC changed the nature of organic matter, probably by increasing the size of DOM molecules. BAC generally decreased the lower apparent molecular weight (LMW) fraction of dissolved organic carbon (DOC). Hence, the removal of LMW DOC and an increase of average Stokes radius (m) of DOM appeared to be important in facilitating a longer steady flux. Specifically, the combined MIEX/BAC pre-treatments appeared to target and reduce the foulants in SWWE that are largely responsible for the reduction of flux in nanofiltration membranes. PMID- 25540836 TI - Effect of ozone on biopolymers in biofiltration and ultrafiltration processes. AB - The focus of this full-scale study was to determine the effect of ozone on biopolymer concentrations in biofiltration and ultrafiltration (UF) processes treating surface water from Lake Ontario. Ozonation was out of service for maintenance for 9 months, hence, it was possible to investigate ozone's action on biologically active carbon contactors (BACCs) and UF, in terms of biopolymer removal. Given the importance of biopolymers for fouling, this fraction was quantified using a chromatographic technique. Ozone pre-treatment was observed to positively impact the active biomass in biofilters. However, since an increase of the active biomass did not result in higher biopolymer removal, active biomass concentration cannot be a surrogate for biofiltration performance. It was evident that increasing empty bed contact time (EBCT) from 4 to 19 min only had a positive effect on biopolymer removal through BACCs when ozone was out of service. However, as a mass balance experiment showed, ozone-free operation resulted in higher deposition of biopolymers on a UF membrane and slight deterioration in its performance. PMID- 25540837 TI - Effects of ionic strength and ion pairing on (plant-wide) modelling of anaerobic digestion. AB - Plant-wide models of wastewater treatment (such as the Benchmark Simulation Model No. 2 or BSM2) are gaining popularity for use in holistic virtual studies of treatment plant control and operations. The objective of this study is to show the influence of ionic strength (as activity corrections) and ion pairing on modelling of anaerobic digestion processes in such plant-wide models of wastewater treatment. Using the BSM2 as a case study with a number of model variants and cationic load scenarios, this paper presents the effects of an improved physico-chemical description on model predictions and overall plant performance indicators, namely effluent quality index (EQI) and operational cost index (OCI). The acid-base equilibria implemented in the Anaerobic Digestion Model No. 1 (ADM1) are modified to account for non-ideal aqueous-phase chemistry. The model corrects for ionic strength via the Davies approach to consider chemical activities instead of molar concentrations. A speciation sub-routine based on a multi-dimensional Newton-Raphson (NR) iteration method is developed to address algebraic interdependencies. The model also includes ion pairs that play an important role in wastewater treatment. The paper describes: 1) how the anaerobic digester performance is affected by physico-chemical corrections; 2) the effect on pH and the anaerobic digestion products (CO2, CH4 and H2); and, 3) how these variations are propagated from the sludge treatment to the water line. Results at high ionic strength demonstrate that corrections to account for non ideal conditions lead to significant differences in predicted process performance (up to 18% for effluent quality and 7% for operational cost) but that for pH prediction, activity corrections are more important than ion pairing effects. Both are likely to be required when precipitation is to be modelled. PMID- 25540838 TI - The effect of inorganic carbon on microbial interactions in a biofilm nitritation anammox process. AB - The overarching goal of this study was to determine the role of inorganic carbon (IC) in influencing the microbial ecology, performance and nitrogen turnover by individual microbial communities of a biofilm based combined nitritation-anammox process. IC limitation was transiently imposed by reducing the IC input from 350% to 40% of the stoichiometric requirement for 40 days. The principal impact observed during IC limitation was the overgrowth of nitrite oxidizing bacteria (NOB) at the expense of anaerobic ammonia oxidizing bacteria (AMX). On the other hand, the concentrations of ammonia oxidizing bacteria (AOB) were relatively stable during the imposition of and recovery from IC limitation. The resulting dominance of NOB, in terms of their concentration and contribution to nitrite consumption over AMX, resulted, in turn, in a decrease in overall nitrogen removal from 78 +/- 2.0% before IC limitation to 46 +/- 2.9% during IC limitation. Upon recovery back to non-limiting IC input, it took an inordinately long time (about 57*HRT) for the N-removal to recover back to pre-limitation conditions. Even after recovery, NOB were still persistent in the biofilm and could not be washed out to pre-limitation concentrations. The emission of nitrous oxide (N2O) and nitric oxide (NO), likely from AOB, transiently increased in concert with transient increases in ammonia and hydroxylamine concentrations during the period of IC limitation. Therefore, an unintended consequence of IC limitation in nitritation-anammox systems can be an increase in their greenhouse gas footprint, in addition to compromised process performance. Most emphasis to date on nitritation and anammox studies has been on the nitrogen cycle. The results of this study demonstrate that the differing strategies used by AOB, NOB and AMX to compete for their preferred assimilative carbon source can also significantly influence the microbial ecology, performance and carbon footprint of such processes. PMID- 25540839 TI - Monitoring Bacteroides spp. markers, nutrients, metals and Escherichia coli in soil and leachate after land application of three types of municipal biosolids. AB - A lysimeter-based field study was done to monitor the transfer of culturable Escherichia coli, general (ALLBAC), human (Hf183) and swine (PIG-BAC-1) specific 16S rRNA Bacteroides spp. markers, nutrients and metals through soils and leachate over time following land application of a CP1/Class A as well as two CP2/Class B municipal biosolids (MBs). Hf183 markers were detected up to six days following application in soils receiving dewatered and liquid MBs, but not in leachate, suggesting their use in source tracking is better suited for recent pollution events. The CP2/Class B biosolids and swine manure contributed the highest microbial load with E. coli loads (between 2.5 and 3.7 log CFU (100 mL)( 1)) being greater than North American concentration recommendations for safe recreational water. ALLBAC persisted in soils and leachate receiving all treatments and was detected prior to amendment application demonstrating its unsuitability for identifying the presence of fecal pollution. A significant increase in NO3-N (for Lystek and dewatered MBs) and total-P (for dewatered and liquid MBs) in leachate was observed in plots receiving the CP1/Class A and CP2/Class B type MBs which exceeded North American guidelines, suggesting impact to surface water. Metal (As, Cd, Cr, Co, Cu, Pb, Mo, Ni, Se, Zn and Hg) transfer was negligible in soil and leachate samples receiving all treatments. This study is one of the first to examine the fate of E. coli and Bacteroides spp. markers in situ following the land application of MBs where surface runoff does not apply. PMID- 25540840 TI - Adsorption properties of surface chemically pure sodium perfluoro-n-alkanoates at the air/water interface: counterion effects within homologous series of 1:1 ionic surfactants. AB - The unusual behavior of saturation adsorption calculated from experimental equilibrium surface tension (sigma(e)) versus logarithm of concentration (c) isotherms within the homologous series of aqueous sodium perfluoro-n-alkanoate solutions represents a particular problem in the adsorption of homologous ionic 1:1 amphiphiles at fluid interfaces. Special precautions were taken to guarantee surface-chemical purity for all solutions, avoiding falsifying effects by surface active trace impurities. Surprisingly, all homologues' adsorption isotherms reveal ideal surface behavior. The minimal surface area demand per molecule adsorbed for shorter-chain homologues slightly decreases with increasing chain lengths but then goes up steeply after having passed a minimum. A similar feature has been observed with the chemically quite different homologous series of the hydrocarbon surfactants of sodium-n-alkylsulfates. Comparing the corresponding 3D saturation concentrations in the boundary layer and in the bulk, it becomes evident that at high bulk concentrations when boundary layer and bulk concentrations are of the same order of magnitude the adsorption behavior may be treated as that of a pseudononionic surfactant. However, under conditions of the homologues' strongest surface activity, adsorption seems to become increasingly governed by electrostatic repulsion, resulting in increasingly greater cross sectional areas. Deviation from pseudononionic behavior sets in when the Debye length becomes distinctly greater than the adsorbent's diameter at saturation. Formerly available theories on ionic amphiphiles' adsorption deal either with electrical conditions of surfactant ions and counterions in the adsorption boundary layer or alternatively with pseudononionic behavior neglecting the former theories completely. Warszynski et al.'s novel theoretical model of the "surface quasi-two-dimensional electrolyte" seems to be capable of describing the adsorption of ionic amphiphiles at fluid interfaces in general. We conclude that the conditions of the two alternative approaches may be met within homologous series of ionic amphiphiles as limiting cases only. PMID- 25540841 TI - Light-triggered reversible self-assembly of gold nanoparticle oligomers for tunable SERS. AB - A photoresponsive amphiphilic gold nanoparticle (AuNP) is achieved through the decoration of AuNP with hydrophilic poly(ethylene glycol) (PEG) and hydrophobic photoresponsive polymethacrylate containing spiropyran units (PSPMA). Owing to the photoresponsive property of spiropyran units, the amphiphilic AuNPs can easily achieve the controllable assembly/disassembly behaviors under the trigger by light. Under visible light, spiropyran units provide weak intermolecular interactions between neighbored AuNPs, leading to isolated AuNPs in the solution. While under UV light irradiation, spiropyran units in the polymer brushes transform into merocyanine isomer with conjugated structure and zwitterionic state, promoting the integration of adjacent AuNPs through pi-pi stacking and electrostatic attractions, further leading to the formation of Au oligomers. The smart reversible AuNP oligomers exhibited switchable plasmonic coupling for tuning surface-enhanced Raman scattering (SERS) activity, which is promising for the application of SERS based sensors and optical imaging. PMID- 25540842 TI - Survival of Salmonella Typhimurium in poultry-based meat preparations during grilling, frying and baking. AB - The burden of food-borne diseases still represents a threat to public health; in 2012, the domestic setting accounted for 57.6% of strong-evidence EU food-borne Salmonella outbreaks. Next to cross-contamination, inadequate cooking procedure is considered as one of the most important factors contributing to food-borne illness. The few studies which have assessed the effect of domestic cooking on the presence and numbers of pathogens in different types of meat have shown that consumer-style cooking methods can allow bacteria to survive and that the probability of eating home-cooked poultry meat that still contains surviving bacteria after heating is higher than previously assumed. Thus, the main purpose of this study was to reproduce and assess the effect of several types of cooking treatments (according to label instructions and not following label instructions) on the presence and numbers of Salmonella Typhimurium DT 104 artificially inoculated in five types of poultry-based meat preparations (burgers, sausages, ready-to-cook-kebabs, quail roulades and extruded roulades) that are likely to be contaminated by Salmonella. Three contamination levels (10 cfu/g; 100 cfu/g and 1000 cfu/g) and three cooking techniques (grilling, frying and baking) were applied. Cooking treatments performed according to label instructions eliminated Salmonella Typhimurium (absence per 25g) for contamination levels of 10 and 100 cfu/g but not for contamination levels of 1000 cfu/g. After improper cooking, 26 out of 78 samples were Salmonella-positive, and 23 out of these 26 samples were artificially contaminated with bacterial loads between 100 and 1000 cfu/g. Nine out of 26 samples provided quantifiable results with a minimum level of 1.4MPN/g in kebabs (initial inoculum level: 100 cfu/g) after grilling and a maximum level of 170MPN/g recorded in sausages (initial inoculum level: 1000 cfu/g) after grilling. Kebabs were the most common Salmonella-positive meat product after cooking, followed by sausages, burgers and extruded roulades; in relation to the type of cooking treatment applied, Salmonella Typhimurium was detected mostly after frying. Thus, following label instructions mostly, but not always, produced safe cooked poultry-based meat preparations, while the application of inadequate cooking treatments was not able to assure complete elimination of Salmonella from the products even with a low contamination level (10cfu/g). Consequently, there is a need to develop guidelines for producers and consumers and promote a multidisciplinary educational campaign in order to provide information on safe cooking and time-temperature combinations able to maintain the organoleptic qualities of meat. PMID- 25540843 TI - Remarkable stimulation of emission quenching on a clay surface. AB - Tetra-cationic pyrene derivative (Py(4+)) and tris(bipyridine)ruthenium(II) (Ru(2+)) were hybridized onto the surface of a synthesized clay. We observed the remarkable stimulation of excited Py(4+) emission quenching on the clay surface, with a very large apparent quenching rate constant (kq = 7.4 +/- 0.7 * 10(15) L mol(-1) s(-1)). PMID- 25540844 TI - The long-term efficacy of cryoballoon vs irrigated radiofrequency ablation for the treatment of atrial fibrillation: A meta-analysis. AB - OBJECTIVES: The main purpose of this meta-analysis was to compare the long-term efficacy of cryoballoon ablation (CBA) with irrigated radiofrequency catheter ablation (RFCA) for the treatment of atrial fibrillation (AF). METHODS: The Medline, Cochrane Library and Embase Database were searched for clinical studies published up to October 2014. Studies that fulfilled our predefined inclusion criteria were included. The primary clinical outcome was the proportion of patients free from AF (follow-up>=3months), and the secondary clinical outcomes included acute pulmonary vein (PV) isolated rate, fluoroscopy time, procedure time and complications. RESULTS: After a literature search in the major databases, three randomized controlled trials (RCTs) and eight retrospective trials with a total of 1216 patients were identified. Pool-analysis demonstrated that, as compared RFCA, CBA was associated with a similar proportion of patients free from AF at a mean 16.5months follow-up (66.9% vs 65.1%; relative risk [RR]: 1.01; 95% CI: 0.94 to 1.07, P=0.87). Acute PV isolation rate (RR: 0.92; 95% CI: 0.82 to 1.03) and fluoroscopy time (weighted mean difference WMD: -8.60; 95% CI: 18.29 to 3.69) were not statistically significant difference. The procedure time was shorter in CBA group ([WMD]: -31.94; 95% CI: -60.43 to -3.45). Transient phrenic nerve palsy was uniquely observed in the CBA group (5.4%, P<0.00001) and resolved in all during the follow-up period, total complication was similar in both groups (RR: 1.30; 95% CI: 0.91 to 1.85). CONCLUSIONS: CBA was as effective as RFCA for the treatment of atrial fibrillation during long-term follow-up with comparable procedural features. PMID- 25540845 TI - Systematic review of cardiac electrical disease in Kearns-Sayre syndrome and mitochondrial cytopathy. AB - Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterised by onset before the age of 20years, progressive external ophthalmoplegia, and pigmentary retinopathy, accompanied by either cardiac conduction defects, elevated cerebrospinal fluid protein or cerebellar ataxia. 50% of patients with KSS develop cardiac complications. The most common cardiac manifestation is conduction disease which may progress to complete atrioventricular block or bradycardia-related polymorphic ventricular tachycardia (PMVT). The management of cardiac electrical disease associated with KSS and mitochondrial cytopathy is systematically reviewed including the case of a 23year-old female patient with KSS who developed a constellation of cardiac arrhythmias including rapidly progressive conduction system disease and monomorphic ventricular tachycardia with myocardial scarring. The emerging role of cardiac magnetic resonance imaging (CMR) in detecting subclinical cardiac involvement is also highlighted. This review illustrates the need for cardiologists to be informed about this rare but emerging condition. PMID- 25540846 TI - Red blood cells as bioindicators of cardiovascular risk in Kawasaki disease: A case report. PMID- 25540847 TI - Current status of persistent organic pesticides residues in air, water, and soil, and their possible effect on neighboring countries: a comprehensive review of India. AB - Though the use of pesticides has offered significant economic benefits by enhancing the production and yield of food and fibers and the prevention of vector-borne diseases, evidence suggests that their use has adversely affected the health of human populations and the environment. Pesticides have been widely distributed and their traces can be detected in all areas of the environment (air, water and soil). Despite the ban of DDT and HCH in India, they are still in use, both in domestic and agricultural settings. In this comprehensive review, we discuss the production and consumption of persistent organic pesticides, their maximum residual limit (MRL) and the presence of persistent organic pesticides in multicomponent environmental samples (air, water and soil) from India. In order to highlight the global distribution of persistent organic pesticides and their impact on neighboring countries and regions, the role of persistent organic pesticides in Indian region is reviewed. Based on a review of research papers and modeling simulations, it can be concluded that India is one of the major contributors of global persistent organic pesticide distribution. This review also considers the health impacts of persistent organic pesticides, the regulatory measures for persistent organic pesticides, and the status of India's commitment towards the elimination of persistent organic pesticides. PMID- 25540848 TI - Occurrence of cyclic and linear siloxanes in indoor air from Albany, New York, USA, and its implications for inhalation exposure. AB - Cyclic and linear siloxanes are used in a wide variety of household and consumer products. Nevertheless, very few studies have reported the occurrence of these compounds in indoor air or inhalation exposure to these compounds. In this study, five cyclic (D3-D7) and nine linear siloxanes (L3-L11) were determined in 60 indoor air samples collected in Albany, New York, USA. The mean concentrations of individual siloxanes in particulate and vapor phases ranged from <12 MUg g(-1) (for octamethyltrisiloxane [L3], decamethyltetrasiloxane [L4]) to 2420 MUg g(-1) (for decamethylcyclopentasiloxane [D5]) and from 1.05 ng m(-3) to 543 ng m(-3), respectively. The mean concentrations of individual siloxanes in combined particulate and vapor phases of bulk indoor air ranged from 1.41 ng m(-3) (for L4) to 721 ng m(-3) (for D5). Cyclic siloxanes hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4), D5, dodecamethylcyclohexasiloxane (D6), and octadecamethylcycloheptasiloxane (D7) were found in all indoor air samples. The mean concentrations of total siloxanes (i.e., sum of cyclic and linear siloxanes) ranged from 249 ng m(-3) in laboratories to 6210 ng m(-3) in salons, with an overall mean concentration of 1470 ng m(-3) in bulk indoor air samples. The calculated mean daily inhalation exposure doses of total siloxanes (sum of 14 siloxanes) for infants, toddlers, children, teenagers, and adults were 3.18, 1.59, 0.76, 0.34, and 0.27 MUg/kg-bw/day, respectively. PMID- 25540849 TI - Two specific tongue regions receive bilateral hypoglossal innervation: a study in neonatal rat pups. AB - OBJECTIVE: The purpose of this study was to investigate the functional role of bilateral hypoglossal (XII) nerve innervation of the tongue. MATERIALS AND METHODS: The possibility of bilateral innervation of XII nerve in the tongue was examined using postmortem fibre tracing in normal neonatal rats. In addition, immunohistochemical testing for synaptophysin or vesicular acetylcholine transporter (VAChT) was carried out in unilaterally XII nerve-resected neonatal rats. RESULTS: Postmortem fibre tracing revealed constant distribution of the nerve fibres extending across the midline and existence of bilateral innervated area in the rostroventral and caudodorsal regions of the tongue. Synaptophysin positive and VAChT-positive nerve terminals were also distributed continuously from the XII nerve-intact to the nerve-resected side across the midline of the tongue. The contralaterally projecting VAChT-positive nerve terminals were more numerous in suckling P2 rats (6.6 +/- 0.5/section) than those in non-suckling P2 rats (4.9 +/- 0.3/section) 24 h after nerve resection. Furthermore, the contralaterally projecting VAChT-positive nerve terminals were more numerous in P7 rats with nerve resection on P1 (6.3 +/- 0.2/section) than those in P7 rats with nerve resection on P6 (3.1 +/- 0.8/section). CONCLUSION: We concluded that neonatal rats have two specific tongue regions receiving bilateral XII innervation, which allowed suckling in unilaterally XII nerve-resected neonatal rats. PMID- 25540850 TI - Gene therapy in dentistry: tool of genetic engineering. Revisited. AB - Advances in biotechnology have brought gene therapy to the forefront of medical research. The concept of transferring genes to tissues for clinical applications has been discussed nearly half a century, but the ability to manipulate genetic material via recombinant DNA technology has brought this goal to reality. The feasibility of gene transfer was first demonstrated using tumour viruses. This led to development of viral and nonviral methods for the genetic modification of somatic cells. Applications of gene therapy to dental and oral problems illustrate the potential impact of this technology on dentistry. Preclinical trial results regarding the same have been very promising. In this review we will discuss methods, vectors involved, clinical implication in dentistry and scientific issues associated with gene therapy. PMID- 25540851 TI - Contamination and health risks of soil heavy metals around a lead/zinc smelter in southwestern China. AB - Anthropogenic emissions of toxic metals from smelters are a global problem. The objective of this study was to investigate the distribution of toxic metals in soils around a 60 year-old Pb/Zn smelter in a town in Yunnan Province of China. Topsoil and soil core samples were collected and analyzed to determine the concentrations of various forms of toxic metals. The results indicated that approximately 60 years of Pb/Zn smelting has led to significant contamination of the local soil by Zn, Pb, Cd, As, Sb, and Hg, which exhibited maximum concentrations of 8078, 2485, 75.4, 71.7, 25.3, and 2.58mgkg(-1), dry wet, respectively. Other metals, including Co, Cr, Cu, Mn, Ni, Sc, and V, were found to originate from geogenic sources. The concentrations of smelter driven metals in topsoil decreased with increasing distance from the smelter. The main contamination by Pb, Zn, and Cd was found in the upper 40cm of soil around the Pb/Zn smelter, but traces of Pb, Zn, and Cd contamination were found below 100cm. Geogenic Ni in the topsoil was mostly bound in the residual fraction (RES), whereas anthropogenic Cd, Pb, and Zn were mostly associated with non-RES fractions. Therefore, the smelting emissions increased not only the concentrations of Cd, Pb, and Zn in the topsoil but also their mobility and bioavailability. The hazard quotient and hazard index showed that the topsoil may pose a health risk to children, primarily due to the high Pb and As contents of the soil. PMID- 25540852 TI - On the track for an efficient detection of Escherichia coli in water: A review on PCR-based methods. AB - Ensuring water safety is an ongoing challenge to public health providers. Assessing the presence of fecal contamination indicators in water is essential to protect public health from diseases caused by waterborne pathogens. For this purpose, the bacteria Escherichia coli has been used as the most reliable indicator of fecal contamination in water. The methods currently in use for monitoring the microbiological safety of water are based on culturing the microorganisms. However, these methods are not the desirable solution to prevent outbreaks as they provide the results with a considerable delay, lacking on specificity and sensitivity. Moreover, viable but non-culturable microorganisms, which may be present as a result of environmental stress or water treatment processes, are not detected by culture-based methods and, thus, may result in false-negative assessments of E. coli in water samples. These limitations may place public health at significant risk, leading to substantial monetary losses in health care and, additionally, in costs related with a reduced productivity in the area affected by the outbreak, and in costs supported by the water quality control departments involved. Molecular methods, particularly polymerase chain reaction-based methods, have been studied as an alternative technology to overcome the current limitations, as they offer the possibility to reduce the assay time, to improve the detection sensitivity and specificity, and to identify multiple targets and pathogens, including new or emerging strains. The variety of techniques and applications available for PCR-based methods has increased considerably and the costs involved have been substantially reduced, which together have contributed to the potential standardization of these techniques. However, they still require further refinement in order to be standardized and applied to the variety of environmental waters and their specific characteristics. The PCR-based methods under development for monitoring the presence of E. coli in water are here discussed. Special emphasis is given to methodologies that avoid pre-enrichment during the water sample preparation process so that the assay time is reduced and the required legislated sensitivity is achieved. The advantages and limitations of these methods are also reviewed, contributing to a more comprehensive overview toward a more conscious research in identifying E. coli in water. PMID- 25540853 TI - The toxicity of binary mixture of Cu (II) ion and phenols on Tetrahymena thermophila. AB - The toxicity of binary mixture of Cu(2+) and phenols (phenol; o-nitrophenol; m nitrophenol; p-nitrophenol) was evaluated using Tetrahymena thermophila as the model organism, by microcalorimetry, optical density, field emission scanning electron microscope (FESEM) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). The growth curves and metabolic properties of Tetrahymena exposed to Cu(2+) and phenols were monitored by microcalorimetry. Binary mixture toxicity changed with the concentration of Cu(2+)/phenols and the order of toxicity was Cu(2+)/phenol=30 years, from the Tehran Lipid and Glucose Study (TLGS) were enrolled. Abdominal obesity was defined using national waist circumference cut-off points of >=89 cm for men and >=91 cm for women. Metabolic health was defined as <=1 components of metabolic syndrome (excluding waist circumference), using the Joint Interim Statement (JIS) definition. RESULTS: At baseline, 3745 individuals (52.7%) were abdominal obese and 23.5% (n = 881) of these were categorized as "metabolically healthy abdominal obese" (MHAO). A total of 638 CVD events occurred during a median follow-up of 10 years (1999-2011). "Metabolically healthy non-abdominal obese" was considered as the reference group. After adjustment for various variables, MHAO individuals were at increased risk for CVD events compared with the reference group (HR: 1.64, CI: 1.09-2.47). Both the metabolically unhealthy phenotypes (with and without abdominal obesity) were also at increased risk. We also observed the same pattern using insulin resistance data for categorizing abdominal obesity phenotypes. CONCLUSION: Abdominal obesity and presence of metabolic derangements are both important risk factors for future CVD. MHAO may not be a benign condition regarding future CVD events, which highlights the importance of prevention and treatment of abdominal obesity, even in the absence of metabolic derangements. PMID- 25540857 TI - Induced neural beta oscillations predict categorical speech perception abilities. AB - Neural oscillations have been linked to various perceptual and cognitive brain operations. Here, we examined the role of these induced brain responses in categorical speech perception (CP), a phenomenon in which similar features are mapped to discrete, common identities despite their equidistant/continuous physical spacing. We recorded neuroelectric activity while participants rapidly classified sounds along a vowel continuum (/u/ to /a/). Time-frequency analyses applied to the EEG revealed distinct temporal dynamics in induced (non-phase locked) oscillations; increased beta (15-30Hz) coded prototypical vowel sounds carrying well-defined phonetic categories whereas increased gamma (50-70Hz) accompanied ambiguous tokens near the categorical boundary. Notably, changes in beta activity were strongly correlated with the slope of listeners' psychometric identification functions, a measure of the "steepness" of their categorical percept. Our findings demonstrate that in addition to previously observed evoked (phase-locked) correlates of CP, induced brain activity in the beta-band codes the ambiguity and strength of categorical speech percepts. PMID- 25540858 TI - Sex hormones in early infancy seem to predict aspects of later language development. AB - Sex differences in the development of cognitive behavior such as language have long been of great research interest. Lately, researchers have started to associate language function and brain differences with diverse sex hormones (e.g., testosterone/estradiol). However, results concerning the impact of early postnatal sex hormone concentration on the child's later language development are rare. Here, we analyze the impact of testosterone and estradiol in girls and boys as well as their neurophysiological phonemic discrimination at age 5months on language development at age 4years. Interestingly, we found strong positive estradiol and negative testosterone impact on later language performance at age 4years, which was true for both girls and boys. These results demonstrate that postnatal sex hormone surge might be viewed as one factor determining later language development, independent of gender. PMID- 25540859 TI - Assessment of region, farming system, irrigation source and sampling time as food safety risk factors for tomatoes. AB - In the mid-Atlantic region of the United States, small- and medium-sized farmers use varied farm management methods and water sources to produce tomatoes. It is unclear whether these practices affect the food safety risk for tomatoes. This study was conducted to determine the prevalence, and assess risk factors for Salmonella enterica, Shiga toxin-producing Escherichia coli (STEC) and bacterial indicators in pre-harvest tomatoes and their production areas. A total of 24 organic and conventional, small- to medium-sized farms were sampled for six weeks in Maryland (MD), Delaware (DE) and New Jersey (NJ) between July and September 2012, and analyzed for indicator bacteria, Salmonella and STEC. A total of 422 samples--tomato fruit, irrigation water, compost, field soil and pond sediment samples--were collected, 259 of which were tomato samples. A low level of Salmonella-specific invA and Shiga toxin genes (stx1 or stx2) were detected, but no Salmonella or STEC isolates were recovered. Of the 422 samples analyzed, 9.5% were positive for generic E. coli, found in 5.4% (n=259) of tomato fruits, 22.5% (n=102) of irrigation water, 8.9% (n=45) of soil, 3/9 of pond sediment and 0/7 of compost samples. For tomato fruit, farming system (organic versus conventional) was not a significant factor for levels of indicator bacteria. However, the total number of organic tomato samples positive for generic E. coli (1.6%; 2/129) was significantly lower than for conventional tomatoes (6.9% (9/130); (chi(2) (1)=4.60, p=0.032)). Region was a significant factor for levels of Total Coliforms (TC) (p=0.046), although differences were marginal, with western MD having the highest TC counts (2.6 log CFU/g) and NJ having the lowest (2.0 log CFU/g). Tomatoes touching the ground or plastic mulch harbored significantly higher levels of TC compared to vine tomatoes, signaling a potential risk factor. Source of irrigation water was a significant factor for all indicator bacteria (p<0.0001), and groundwater had lower bacterial levels than surface water. End of line surface water samples were not significantly different from source water samples, but end of line groundwater samples had significantly higher bacterial counts than source (p<0.0001), suggesting that Good Agricultural Practices that focus on irrigation line maintenance might be beneficial. In general, local effects other than cropping practices, including topography, land use and adjacent industries, might be important factors contributing to microbiological inputs on small- and medium-sized farms in the mid-Atlantic region. PMID- 25540860 TI - Risk assessment of Salmonella in Danish meatballs produced in the catering sector. AB - A modular process risk model approach was used to assess health risks associated with Salmonella spp. after consumption of the Danish meatball product (frikadeller) produced with fresh pork in a catering unit. Meatball production and consumption were described as a series of processes (modules), starting from 1.3kg meat pieces through conversion to 70g meatballs, followed by a dose response model to assess the risk of illness from consumption of these meatballs. Changes in bacterial prevalence, concentration, and unit size were modelled within each module. The risk assessment was built using observational data and models that were specific for Salmonella spp. in meatballs produced in the catering sector. Danish meatballs are often pan-fried followed by baking in an oven before consumption, in order to reach the core temperature of 75 degrees C recommended by the Danish Food Safety Authority. However, in practice this terminal heat treatment in the oven may be accidentally omitted. Eleven production scenarios were evaluated with the model, to test the impact of heat treatments and cooling rates at different room temperatures. The risk estimates revealed that a process comprising heat treatment of meatballs to core temperatures higher than 70 degrees C, and subsequent holding at room temperatures lower than 20 degrees C, for no longer than 3.5h, were very effective in Salmonella control. The current Danish Food Safety Authority recommendation of cooking to an internal temperature of 75 degrees C is conservative, at least with respect to Salmonella risk. Survival and growth of Salmonella during cooling of meatballs not heat treated in oven had a significant impact on the risk estimates, and therefore, cooling should be considered a critical step during meatball processing. PMID- 25540861 TI - Perceived physical appearance and life satisfaction: a moderated mediation model of self-esteem and life experience of deaf and hearing adolescents. AB - In this study, we investigated the relationship between perceived physical appearance and life satisfaction, and the role of self-esteem as mediator and life experience as moderator of the relationship in deaf and hearing adolescents. 118 Chinese deaf adolescents (55.1% male; mean age = 15.12 years, standard deviation [SD] = 2.13) from 5 special education schools and 132 Chinese hearing adolescents (53.8% male; mean age = 13.11 years, SD = .85) completed anonymous questionnaires regarding perceived physical appearance, self-esteem, and life satisfaction. Perceived physical appearance, self-esteem, and life satisfaction were significantly and positively associated with each other. Moreover, self esteem partially mediated the relationship between perceived physical appearance and life satisfaction; however, this indirect link was weaker for deaf adolescents than it was for hearing adolescents. Implications of the findings and future research directions are discussed, as are potential interventions that can be applied to increase subjective well-being in deaf adolescents. PMID- 25540862 TI - Predictors in Internet-delivered cognitive behavior therapy and behavioral stress management for severe health anxiety. AB - Severe health anxiety can be effectively treated with exposure-based Internet delivered cognitive behavior therapy (ICBT), but information about which factors that predict outcome is scarce. Using data from a recently conducted RCT comparing ICBT (n = 79) with Internet-delivered behavioral stress management (IBSM) (n = 79) the presented study investigated predictors of treatment outcome. Analyses were conducted using a two-step linear regression approach and the dependent variable was operationalized both as end state health anxiety at post treatment and as baseline-to post-treatment improvement. A hypothesis driven approach was used where predictors expected to influence outcome were based on a previous predictor study by our research group. As hypothesized, the results showed that baseline health anxiety and treatment adherence predicted both end state health anxiety and improvement. In addition, anxiety sensitivity, treatment credibility, and working alliance were significant predictors of health anxiety improvement. Demographic variables, i.e. age, gender, marital status, computer skills, educational level, and having children, had no significant predictive value. We conclude that it is possible to predict a substantial proportion of the outcome variance in ICBT and IBSM for severe health anxiety. The findings of the present study can be of high clinical value as they provide information about factors of importance for outcome in the treatment of severe health anxiety. PMID- 25540863 TI - Direction of attention bias to threat relates to differences in fear acquisition and extinction in anxious children. AB - Anxious children show attention biases towards and away from threat stimuli. Moreover, threat avoidance compared to vigilance predicts a poorer outcome from exposure-based treatments, such as cognitive-behavioural therapy (CBT), yet the mechanisms underlying this differential response are unclear. Pavlovian fear conditioning is a widely accepted theory to explain the acquisition and extinction of fear, including exposure-based treatments, such as CBT. In typical fear conditioning experiments, anxious children have shown larger physiological responses to an aversive unconditional stimulus (i.e., US on CS+ trials) and to non-reinforced stimuli (CS-) during fear acquisition and to both CSs during fear extinction compared to non-anxious peers. This study examined whether threat avoidance compared to threat vigilance was related to differences in fear acquisition and extinction in anxious children. Thirty-four clinically-anxious children completed a visual probe task including angry-neutral face pairs to determine the direction of threat attention bias as well as a discriminant conditioning and extinction task in which a geometric shape CS+ was paired with an aversive tone US, while the CS- geometric shape was always presented alone during acquisition trials. Both CSs were presented alone during extinction trials. Fear acquisition and extinction were indexed by skin conductance responses (SCR) and subjective measures. Children were classified as threat vigilant (N = 18) and threat avoidant (n = 16) based on the direction of threat attention bias on the visual probe task. During acquisition, threat avoidant relative to threat vigilant anxious children displayed larger orienting SCRs to both CSs during the first block of trials and larger third interval SCRs to the US on CS+ trials as well as on CS- trials. During extinction, threat avoidant anxious children showed delayed extinction of SCRs to both the CS+ and CS- and reported higher subjective anxiety ratings after extinction compared to threat vigilant anxious children. Threat avoidant anxious children may be more reactive physiologically to novel cues and to stimuli that become associated with threat and this may interfere with extinction learning. These findings could help explain previous evidence that threat avoidant anxious children do not respond as well as threat vigilant anxious children to exposure-based CBT. PMID- 25540864 TI - Query and test for synthetic cannabinoids in drug treatment and research. PMID- 25540865 TI - Endorsement of the CONSORT guidelines, trial registration, and the quality of reporting randomised controlled trials in leading nursing journals: A cross sectional analysis. AB - OBJECTIVE: To establish the reporting quality of trials published in leading nursing journals and investigate associations between CONSORT Statement or trial registration endorsment and reporting of design elements. METHODS: The top 15 nursing journals were searched using Medline for randomised controlled trials published in 2012. Journals were categorised as CONSORT and trial registration promoting based on requirements of submitting authors or the journal's webpage as at January 2014. Data on sequence generation, allocation concealment, follow up, blinding, baseline equivalence and sample size calculation were extracted by one author and independently verified by the second author against source data. RESULTS: Seven journals were CONSORT promoting and three of these journals were also trial registration promoting. 114 citations were identified and 83 were randomised controlled trials. Eighteen trials (21.7%) were registered and those published in trial registration promoting journals were more likely to be registered (RR 2.64 95%CI 1.14-6.09). We assessed 68.7% of trials to be low risk of bias for sequence generation, 20.5% for allocation concealment, 38.6% for blinding, 55.4% for completeness of follow up and 79.5% for baseline equivalence. Trials published in CONSORT promoting journals were more likely to be at low risk of bias for blinding (RR 2.33, 95%CI 1.01-5.34) and completeness of follow up (RR 1.77, 95%CI 1.02-3.10), but journal endorsement of the CONSORT Statement or trial registration otherwise had no significant effect. Trials published in CONSORT and trial registration promoting journals were more likely to have high quality sample size calculations (RR 2.91, 95%CI 1.18-7.19 and RR 1.69, 95%CI 1.08-2.64, respectively). CONCLUSION: Simple endorsement of the CONSORT Statement and trials registration is insufficient action to encourage improvement of the quality of trial reporting across the most important of trial design elements. PMID- 25540866 TI - Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden. AB - Irritable bowel syndrome (IBS) is a functional disorder defined by symptoms in the absence of overt pathology. Colonic spirochetosis (CS), defined by histologic observation of spirochetal strains of Brachyspira in colonic biopsies, is uncommon and considered of doubtful significance. We aimed to determine the prevalence of CS in the general population, identify subtle colon pathologies, and evaluate a link with symptoms of IBS. Colonoscopy was performed in 745 subjects (aged 19-70 years, mean age 51 years, 43% male) with biopsies (ileum and 4 colonic sites) from a random population sample, Stockholm, Sweden, who completed a validated questionnaire of gastrointestinal symptoms; IBS was identified by Rome III criteria. CS was identified by histology and immunohistochemistry. In a general population, 17 individuals (2.28%; 95% confidence interval, 1.2%-3.5%) were diagnosed as having CS by histology; 6 (35%) had IBS. CS was always present in the sigmoid colon, but only 14 rectal biopsies. Eosinophils were increased in colon biopsies in CS cases versus controls, in the transverse (P = .02), sigmoid colon (P = .001), and rectum (P = .0005) with subepithelial eosinophil clusters (P = .053). Lymphoid follicles (at any site) were present in 13 CS (P = .0003). There was a 3-fold increased risk of IBS in CS (odds ratio, 3.59; 95% confidence interval, 1.27-10.11; P = .015). Polyps and diverticular disease were similar in CS cases and controls. The prevalence of CS in a general population is 2% and associated with nonconstipating IBS. Colonic eosinophilia with lymphoid follicles may signify the presence of CS. PMID- 25540867 TI - Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. AB - The prognostic and predictive implications of programmed death-ligand 1 (PD-L1) is unknown in sarcoma. We sought to examine the immune milieu in sarcoma specimens. We evaluated PD-L1 expression by immunohistochemistry in sarcoma specimens and quantified tumor-infiltrating lymphocytes (TIL). We correlated expression with clinical parameters and outcomes. Fifty sarcoma patients treated at Memorial Sloan Kettering Cancer Center were selected. Using the DAKO PD-L1 immunohistochemistry assay and archival formalin-fixed paraffin-embedded tissue specimens; PD-L1 expression was examined. Macrophage and lymphocyte PD-L1 status was determined qualitatively. TIL was quantified. Associations between PD-L1 expression in tumor, macrophages and lymphocytes, TIL and clinical-pathological characteristics were performed. The median age was 46 years (range, 22-76), and 66% of patients were men. Tumor, lymphocyte and macrophage PD-L1 expression was noted in 12%, 30% and 58%, respectively, with the highest prevalence in gastrointestinal stromal tumors (29%). Lymphocyte and macrophage infiltration was present in 98% and 90%, respectively. There was no association between clinical features, overall survival and PD-L1 expression in tumor or immune infiltrates. Lymphocyte and macrophage infiltration is common in sarcoma, but PD-L1 tumor expression is uncommon in sarcoma with the highest frequency observed in gastrointestinal stromal tumors. There was no association between PD-L1 expression, TIL and clinicopathological features and overall survival; however, this is limited by the heterogenous patient sample and minimal death events in the studied cohort. PMID- 25540869 TI - Protective effects of thymol against nephrotoxicity induced by cisplatin with using 99mTc-DMSA in mice. AB - BACKGROUND: In this study, we investigated the protective effect of thymol as a natural compound against cisplatin-induced nephrotoxicity by quantitative renal 99mTc-DMSA uptake and compared its effect with histopathology in mice. MATERIALS AND METHODS: Mice were divided into six groups as control, cisplatin (7.5 mg/kg, intraperitoneally), thymol+cisplatin (thymol; 50 and 150 mg/kg+cisplatin; 7.5 mg/kg) and thymol (50 and 150 mg/kg). Thymol was orally administrated for two days before cisplatin injection and continued for 4 days. (99m)Tc-DMSA was injected through the tail of mice after the drug administration. The percentage of the injected dose per gram of kidney tissue (%ID/g) was calculated. In other experiment, kidneys of treated mice were assessed for histopathology. RESULTS: 99mTc-DMSA uptake per gram tissue of the kidneys as %ID/g was 85.27+/-21.81, 45.55+/-5.50, 65.02+/-32.21 and 88.46+/-20.46 in the control, cisplatin, thymol (50 mg/kg)+cisplatin and thymol (150 mg/kg)+cisplatin. Thymol administration with cisplatin resulted in a significant increase in the level of %ID/g. Histopathological examinations showed a protective effect of thymol against cisplatin nephrotoxicity in mice. CONCLUSION: The results showed that thymol significantly attenuates the cisplatin-induced nephrotoxicity in mice, and 99mTc DMSA uptake in kidney is a suitable method for assessment of nephrotoxicity in mice. PMID- 25540870 TI - Analysis of potential risk factors for cancer incidence in patients with aristolochic acid nephropathy from Wenzhou, China. AB - BACKGROUND: The purpose of this study was to investigate the cancer incidence in patients with end-stage aristolochic acid nephropathy (AAN). METHODS: A total of 102 patients with end-stage AAN treated in our hospital between 2004 and 2013 were included in this study. The correlation of cancer incidence with age, gender, dosage of aristolochic acid (AA), the type of renal replacement therapies, and the polymorphisms of quinone oxidoreductase 1 (NQO1) C609T and cytochrome P450 1A1 (CYP1A1) A4889G was examined. RESULTS: The cancer incidence rate in our patients was 41.2% (42 in 102) including 39 cases of urinary cancer. The mortality rate in the patients with cancer was significantly higher than that in the patients without cancer (31%, 13/42 vs. 11.7%, 7/60, p<0.05). Thirteen patients developed cancer before entering end-stage renal disease (ESRD). Cancer incidence was significantly associated with the dosage of AA consumption (p=0.091). Hemodialysis, peritoneal dialysis and renal transplant did not affect the cancer incidence in our patients differently, but appeared to be associated with cancer at particular locations of urinary system. The patients undergoing hemodialysis seemed to more likely have bladder cancer (72.72%), while the patients receiving peritoneal dialysis appeared to develop cancer predominantly in the upper urinary tract (66.67%). CONCLUSIONS: The cancer initiation in our patients seems significantly correlate with the dosage of AA consumption. Different renal replacement therapies appear to be associated with cancer at particular locations of urinary system in our patients. PMID- 25540871 TI - Malaria-associated hypoglycaemia in children. AB - In the developing world, hypoglycemia is a frequent complication among admitted children, particularly in malaria-endemic areas, and a defining feature of severe malaria and associated with high case fatality rates (CFR). This complication could be much more common than currently considered, particularly because it frequently occurs without a direct immediate clinical translation. Its etiology has not yet been fully understood and is likely to be multifactorial. Routine screening and treatment of hypoglycemia, as recommended by international guidelines, may be challenging to perform in developing countries on account of the limited resources available. In this review, we discuss the published literature in relation with the incidence, risk factors, and consequences of hypoglycemia among malaria patients, aiming to improve our current understanding of this common and life-threatening complication of malaria. PMID- 25540874 TI - Safe definitive orthopaedic surgery (SDS): repeated assessment for tapered application of Early Definitive Care and Damage Control?: an inclusive view of recent advances in polytrauma management. PMID- 25540873 TI - Secondary acrodermatitis enteropathica-like lesions in a child with newly diagnosed coeliac disease. AB - Zinc deficiency in patients with coeliac disease (CD) may result either from cumulative loss of insoluble zinc complexes or impaired zinc absorption because of damaged intestinal epithelial cell membrane. Zinc deficiency in CD is mild to moderate, though severe deficiency can occur in refractory or chronic CD cases with poor response to gluten-free diet (GFD). A boy aged 19 months presented with persistent diarrhoea, was diagnosed with CD, and developed severe zinc deficiency with acrodermatitis enteropathica-like disease while on GFD and zinc supplementation. PMID- 25540872 TI - Escherichia coli strains of phylogenetic group B2 and D and bacteriocin production are associated with advanced colorectal neoplasia. AB - BACKGROUND: Colorectal cancer (CRC) is the 3rd most common cancer worldwide and the Czech Republic has the 6th highest incidence of CRC worldwide. Large intestinal microbiota play in its etiopathogenesis important role. Bacteriocins are proteins, produced by bacteria from the Enterobacteriaceae family. The aim of our prospective study was to assess the colonization of large intestinal mucosa by Escherichia coli strains and to investigate their bacteriocin production. METHODS: A total of 30 consecutive patients with colorectal adenoma, CRA (17 men, 13 women, aged 39-79, mean age 63 +/- 9), 30 patients with CRC (23 men, 7 women, aged 38-86, mean age 67 +/- 11) and 20 healthy controls (9 men, 11 women, age 23 84, mean age 55 +/- 15) were enrolled into prospective study. Mucosal biopsies were taken in the caecum, transverse colon and rectum during pancolonoscopy. Microbiological culture, isolation and identification of bacteria followed. Bacteriocin production was assessed by growth inhibition of indicator strains E. coli K12-Row, E. coli C6 (phi), and Shigella sonnei 17. Identification of bacteriocin-encoding determinants and E. coli phylogroups was performed using PCR methods. RESULTS: A total of 622 strains were isolated and further investigated. A significantly higher frequency of simultaneous production of colicins and microcins was revealed in the group of patients with CRC, when compared to patients with CRA, p = 0.031. A significantly higher frequency of E. coli phylogroup D was found in patients with CRC, when compared to controls, p = 0.044. A significantly higher prevalence of bacteriocinogeny was confirmed in patients with advanced adenoma when compared to patients with non-advanced adenoma, p = 0.010. Increasing bacteriocinogeny was associated with an increasing stage of CRC (assessed according to TNM classification). Either E. coli phylogroup B2 or E. coli phylogroup D were isolated in biopsies of patients with right-sided CRC. A statistically higher incidence of E. coli phylogroup B2 was found in patients with right-sided CRC when compared to patients with left-sided CRC, p = 0.028. CONCLUSIONS: Large intestinal mucosa of patients with more advanced colorectal neoplasia is colonized with more virulent strains of E. coli and higher production of bacteriocins is observed in these patients when compared to those with less advanced colorectal neoplasia. PMID- 25540875 TI - Primary hyperparathyroidism and multiple myeloma complicated by Fanconi syndrome: a fortuitous association? PMID- 25540876 TI - [The future, in France, of enhanced recovery after surgery seen from the economical perspective]. AB - INTRODUCTION: The programmes of fast-track or enhanced recovery after surgery offer obvious advantages in terms of better postoperative outcomes and shorter hospital stay in many surgical specialties. However, the implementation of such programmes as strategic innovations has economic challenges that have not been well evaluated in a large scale, while they can influence the future of this innovation. METHODS: Simulation study was performed in 5 surgical units of digestive surgery, orthopaedics, and urologic surgery in the aim to help them to implement programmes of enhanced recovery. Several types of surgery were considered: colorectal, pancreatic, hepatic, hip, knee, shoulder, and bladder. All costs related to the implementation, hospitalisation (pre-, per-, and postoperative courses), and support of the project on the long-term, were calculated. RESULTS: The fixed and variable costs varied according to the surgical specialities. The calculation method allowed us to find that the gained standard value for one hospital-day was 180 ?. The residual credit was as high as 202 000 ? per year at the effective end of implementation in all surgical units, i.e. within 2-3 years. CONCLUSION: Beyond all medical advantages (namely better recovery for the patients, less postoperative morbidity, and reinforcement of the teamwork), the implementation of enhanced recovery programmes for high volume surgery will be cost-effective for our care units also in terms of health care performance. PMID- 25540878 TI - [Comparison of two national quality of life surveys for patients with end stage renal disease between 2005-2007 and 2011: indicators slightly decreased]. AB - BACKGROUND: The Epidemiology Network and Nephrology Information provides since 2001 the epidemiological monitoring of end stage renal disease (ESRD) in France. Two cross-sectional studies to estimate the level of quality of life in ESRD patients were performed in 2005 and 2007 and repeated in 2011. The main objective is to analyze the evolution of the quality of life of ESRD between these two surveys. METHODS: The studies were conducted on a representative sample of subjects aged 18 and over, prevalent dialysis or holders of a functioning kidney transplant last year, followed in center dialysis and/or transplantation in one of the eight French regions selected. The quality of life was measured by a generic questionnaire, and two specifics questionnaires. RESULTS: The evolution of the quality of life deteriorated slightly between 2005-2007 and 2011. There is however few dimensions affected. The variation in scores is not meaningful in general, with maximum decreases less than 4 points according to the statistical methods used. This diminution is not clinically significant. DISCUSSION: The quality of life in dialysis patients or transplant did not evolve between 2005 2007 and 2011. Currently, it is difficult to assess the benefits of the national plan for improving the quality of life of people with chronic diseases because the last data are too close to the end of the plan. PMID- 25540879 TI - Don't Lose Sight of Quality. PMID- 25540877 TI - Isolation, characterization, and functional analysis of ferret lymphatic endothelial cells. AB - The lymphatic endothelium (LE) serves as a conduit for transport of immune cells and soluble antigens from peripheral tissues to draining lymph nodes (LNs), contributing to development of host immune responses and possibly dissemination of microbes. Lymphatic endothelial cells (LECs) are major constituents of the lymphatic endothelium. These specialized cells could play important roles in initiation of host innate immune responses through sensing of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including toll-like receptors (TLRs). LECs secrete pro-inflammatory cytokines and chemokines to create local inflammatory conditions for recruitment of naive antigen presenting cells (APCs) such as dendritic cells (DCs) to sites of infection and/or vaccine administration. In this study, we examined the innate immune potential of primary LEC populations derived from multiple tissues of an animal model for human infectious diseases - the ferret. We generated a total of six primary LEC populations from lung, tracheal, and mesenteric LN tissues from three different ferrets. Standard RT-PCR characterization of these primary LECs showed that they varied in their expression of LEC markers. The ferret LECs were examined for their ability to respond to poly I:C (TLR3 and RIG-I ligand) and other known TLR ligands as measured by production of proinflammatory cytokine (IFNalpha, IL6, IL10, Mx1, and TNFalpha) and chemokine (CCL5, CCL20, and CXCL10) mRNAs using real time RT-PCR. Poly I:C exposure induced robust proinflammatory responses by all of the primary ferret LECs. Chemotaxis was performed to determine the functional activity of CCL20 produced by the primary lung LECs and showed that the LEC-derived CCL20 was abundant and functional. Taken together, our results continue to reveal the innate immune potential of primary LECs during pathogen-host interactions and expand our understanding of the roles LECs might play in health and disease in animal models. PMID- 25540880 TI - Prevalence of BK polyomavirus infection and association with renal dysfunction in pediatric heart transplant recipients. AB - BACKGROUND: BK polyomavirus (BKV) infection and nephropathy complicate renal allografts; however, their effect in the native kidneys of pediatric heart transplant (HTx) recipients is unknown. We assessed the prevalence of BKV infection and its association with kidney dysfunction in survivors of pediatric HTx. METHODS: A single-center retrospective study compared pediatric (aged <18 years ) HTx recipients, with and without BKV (controls), who received an allograft from May 1989 to July 2013. Screening of urine for BKV was performed in patients with chronic kidney disease (CKD) stage >=2 since 2006, and since April 2012 in all HTx recipients at least at an annual evaluation. Serum for BKV DNA was assayed if BK viruria was present. Data collected included recipient and donor demographics, the immunosuppressive regimen, and history of Epstein-Bar virus (EBV) and cytomegalovirus infection. Statistics included Fisher's exact test, chi-square test, Student's t-test, and multivariate logistic regression. RESULTS: Of 98 eligible recipients, 83 (85%) were screened: 28 (34%) had BK viruria, and 7 had BK viremia. One viremic patient had biopsy-proven BKV nephropathy that progressed to end-stage renal disease. Risk factors for BK viruria were (1) longer duration since HTx (6.02 vs 2.95 years; p = 0.01), (2) worsening estimated glomerular filtration rate (71.3 vs 86.3 ml/min/1.73 m(2), p = 0.03), (3) history of EBV infection (p = 0.0002), and (4) use of sirolimus (p = 0.0003). After multivariate logistic-regression, only history of EBV infection remained associated with BKV infection (p = 0.015). CONCLUSIONS: BKV may lead to BK viremia and BK nephropathy in pediatric HTx patients. Routine screening for BK viruria should be considered. PMID- 25540881 TI - Systolic blood pressure on discharge after left ventricular assist device insertion is associated with subsequent stroke. AB - BACKGROUND: Stroke is a significant complication in patients supported with continuous-flow left ventricular assist devices (CF-LVAD) and hypertension is a significant risk factor for stroke, but the association between blood pressure and stroke in LVAD patients is not well characterized. METHODS: We identified 275 consecutive patients who survived implant hospitalization between January 2005 and April 2013. Patients were grouped according to systolic blood pressure (SBP) as above a median and below a median of 100 mm Hg by their averaged systolic blood pressure during the 48 hours before discharge from implantation hospitalization. The groups were compared for the primary outcome of time to stroke. RESULTS: The above-median SBP group had mean SBP of 110 mm Hg and the below-median SBP group had mean SBP of 95 mm Hg. There were no significant between-group differences in body mass index, smoking, vascular disease, hypertension, atrial fibrillation, or prior stroke. During a mean follow-up of 16 months, stroke occurred in 16% of the above-median SBP group vs in 7% of the below-median SBP group (hazard ratio, 2.38; 95% confidence interval, 1.11-5.11), with a similar proportion of hemorrhagic and ischemic strokes in each group. In Cox proportional hazard models adjusting for age, diabetes, or prior stroke, the hazard ratio remained statistically significant. SBP as a continuous variable predictor of stroke had an area under the curve of 0.64 in a receiver operating characteristic curve analysis. CONCLUSIONS: In this large, CF-LVAD cohort, elevated SBP was independently associated with a greater risk of subsequent stroke. These results identify management of hypertension as a potential modifiable risk factor for reducing the incidence of stroke in patients supported by CF-LVAD. PMID- 25540882 TI - Too hot to handle? Hot water bottle injuries in Sydney, Australia. AB - OBJECTIVE: Hot water bottles are frequently used in the community as a source of warmth, and to alleviate a number of medical symptoms. In Australia it is believed that over 500,000 water bottles are sold annually (Whittam et al., 2010). This simple treatment is known to result in significant burns and has led to mandatory labeling requirements on hot water bottles in Australia. Despite this, few published studies have documented the incidence and nature of burns sustained through their use. This study aimed to assess the incidence, causation and outcome of hot water bottle burns presenting to a major burn trauma unit in Sydney (Australia). METHODS: The New South Wales Agency for Clinical Innovation Statewide Burn Injury database and admission data to the Concord Hospital Burns Injury Unit (major treatment unit) provided information on hot water bottle burns occurring between 2005 and 2013. Demographic details, cause of burn, burn depth, total burn surface area (%TBSA), and outcome of burn were ascertained. In order to assess the burn potential of hot water bottles, a separate study examined the thermic properties of hot water bottles in 'real life' scenarios. FINDINGS: There were 155 hot water bottle burn presentations resulting in 41 admissions and 24 grafts. The majority of patients were female, and most burns resulted from appliance rupture when used for local pain relief. Patients had an average TBSA of 2.4%. Burns patients were slightly more likely to reside in areas with greater socio-economic disadvantage. In real life scenarios, hot water bottles were shown to retain heat over 50 degrees C for at least 3 hours (h). CONCLUSIONS: Hot water bottles are a source of common and preventable burns in the community, with women being more at risk than men. Hot water bottles may retain harmful levels of heat over an extended period of time. Additional labeling requirements pertaining to the longevity of hot water bottles and their use among people especially at risk of burns (i.e. children, the elderly, patients who have undergone recent surgery and/or those with conditions associated with sensory impairment) may further reduce the incidence and severity of hot water bottle burns in the community. PMID- 25540883 TI - Is Laser Doppler imaging (LDI) a measure of burn depth? PMID- 25540884 TI - Outpatient presentations to burn centers: data from the Burns Registry of Australia and New Zealand outpatient pilot project. AB - BACKGROUND: Most studies about burn injury focus on admitted cases. AIM: To compare outpatient and inpatient presentations at burn centers in Australia to inform the establishment of a repository for outpatient burn injury. METHODS: Data for sequential outpatient presentations were collected at seven burn centers in Australia between December 2010 and May 2011 and compared with inpatient admissions from these centers recorded by the Burns Registry of Australia and New Zealand for the corresponding period. RESULTS: There were 788 outpatient and 360 inpatient presentations. Pediatric outpatients included more children <3 years of age (64% vs 33%), scald (52% vs 35%) and contact burns (39% vs 24%). Adult outpatients included fewer males (58% vs 73%) and intentional injuries (3.3% vs 10%), and more scald (46% vs 30%) and contact burns (24% vs 13%). All pediatric, and 98% of adult, outpatient presentations involved a %TBSA<10. The pattern of outpatient presentations was consistent between centers. CONCLUSIONS: Outpatient presentations outnumbered inpatient admissions by 2.2:1. The pattern of outpatient burns presenting to burn centers differed to inpatient admission data, particularly with respect to etiology and burn severity, highlighting the importance of the need for outpatient data to enhance burn injury surveillance and inform prevention. PMID- 25540885 TI - Rapid measurement of tacrolimus in whole blood by paper spray-tandem mass spectrometry (PS-MS/MS). AB - BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides sensitivity and specificity for monitoring tacrolimus drug level in blood, but it requires an LC system and sample preparation, which is not amenable to random access testing typical of immunoassays. Paper spray (PS) ionization generates gas phase analyte ions directly from dried blood spots without sample preparation and LC. We evaluated a PS-MS/MS method for tacrolimus drug monitoring in a clinical diagnostic laboratory. METHODS: Whole blood sample was mixed with stable isotope labeled internal standard ([(13)C, (2)H2]-FK506) and spotted onto a cartridge containing triangular shaped card paper. After drying, samples were analyzed by PS MS/MS in the selected reaction monitoring (SRM) mode, with a run time of 3 min/sample. RESULTS: Analytical measurement range was 1.5-30 ng/ml. Assay inter day imprecision was 13%, 8%, and 5% at tacrolimus concentrations of 4.5, 10.5, and 24.5 ng/ml, respectively. Accuracy was determined by pure tacrolimus solution and was confirmed by result correlation to an immunoassay (slope=1.0, intercept= 0.02; r(2)=0.99), and to a conventional LC-MS/MS method (slope=0.90, intercept=0.4; r(2)=0.94). CONCLUSIONS: PS-MS/MS provides accurate results for tacrolimus with rapid turnaround time amenable to random access testing protocols. PMID- 25540886 TI - Amniotic lamellar body count: predicting and distinguishing neonatal respiratory complications in twin pregnancies. AB - BACKGROUND: Twin pregnancies have a higher rate of preterm births, making precise prediction of neonatal respiratory disorders essential. We herein examined the amniotic lamellar body count (LBC) and found it to be an accurate predictor of respiratory disorders in twin pregnancies. METHODS: Five hundred fourteen amniotic fluid samples, comprising 132 dichorionic twin (DCT) and 125 monochorionic twin (MCT) gestations, were obtained at cesarean section performed at 29 to 38 gestational weeks. Samples were analyzed immediately without centrifugation. RESULTS: There were 26 neonates (5.1%) with respiratory distress syndrome (RDS) and 43 (8.4%) with transient tachypnea of the newborn (TTN). The LBC in neonates with TTN (5.12*10(4)/MUl) was between the counts in RDS (1.26*10(4)/MUl) and controls (10.6*10(4)/MUl), which differed significantly. Twin concordance rates were significantly higher for TTN in MCT gestations than DCT gestations (p=0.003) and delta LBC value was significantly smaller in MCT (3.15+/-0.4*10(4)/MUl) than DCT (5.17+/-0.5*10(4)/MUl) gestations (p=0.003). CONCLUSIONS: The amniotic LBC is useful for predicting respiratory disorders, including RDS and TTN, in twin pregnancies. The data in this study may indicate a genetic predisposition to TTN among MCTs. PMID- 25540887 TI - Elevated levels of 14-3-3 proteins, serotonin, gamma enolase and pyruvate kinase identified in clinical samples from patients diagnosed with colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC), a heterogeneous disease that is common in both men and women, continues to be one of the predominant cancers worldwide. Lifestyle, diet, environmental factors and gene defects all contribute towards CRC development risk. Therefore, the identification of novel biomarkers to aid in the management of CRC is crucial. The aim of the present study was to identify candidate biomarkers for CRC, and to develop a better understanding of their role in tumourogenesis. METHODS: In this study, both plasma and tissue samples from patients diagnosed with CRC, together with non-malignant and normal controls were examined using mass spectrometry based proteomics and metabolomics approaches. RESULTS: It was established that the level of several biomolecules, including serotonin, gamma enolase, pyruvate kinase and members of the 14-3-3 family of proteins, showed statistically significant changes when comparing malignant versus non-malignant patient samples, with a distinct pattern emerging mirroring cancer cell energy production. CONCLUSION: The diagnosis and management of CRC could be enhanced by the discovery and validation of new candidate biomarkers, as found in this study, aimed at facilitating early detection and/or patient stratification together with providing information on the complex behaviour of cancer cells. PMID- 25540888 TI - UK gears up to decode 100,000 genomes from NHS patients. PMID- 25540889 TI - Multiple myeloma. AB - Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future. PMID- 25540890 TI - Ebola and Marburg vaccines for Africa: one step closer. PMID- 25540892 TI - [Evidence-based medicine and clinical practice in octogenarians: the management of hypercholesterolemia]. PMID- 25540891 TI - Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial. AB - BACKGROUND: Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein. METHODS: RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18-50 years were randomly assigned (5:1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov, number NCT00997607. FINDINGS: 108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37-75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28-66) in the group that received both vaccines. 15 of 30 (50%, 31-69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31-69) in the group that received both vaccines. Nine of 29 (31%, 15-51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10-42) in the group that received both vaccines. 19 of 30 (63%, 44-80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 13 of 30 (43%, 25-63) participants in the EBO vaccine group had a T cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17-53) in the group that received both vaccines. 15 of 29 (52%, 33-71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25-63) in the group that received both vaccines. INTERPRETATION: This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa. FUNDING: US Department of Defense Infectious Disease Clinical Research Program and US National Institutes of Health Intramural Research Program. PMID- 25540893 TI - [University studies plan in geriatric medicine developed using a modified Delphi technique]. AB - INTRODUCTION: The increase in the number of frail elderly people has led to the necessity that all doctors of the future acquire sufficient knowledge on human ageing and the skills in the management of the patient of advanced age, as well as the diseases associated with ageing. Few countries offer geriatric medicine within undergraduate training. The purpose of the present project was to obtain a consensus between European geriatricians on the minimum requirements that medical students must achieve at the end of their university degree course. MATERIAL AND METHODS: A modified Delphi process was used. Firstly, experts in education and geriatrics proposed a set of learning objectives based on a review of the literature. Three Delphi rounds were then performed, in which a panel of 49 experts representing 29 countries affiliated to the European Union of Medical Specialists took part. This enabled them to reach a consensus on a definitive study plan. RESULTS: The number of disagreements after the Delphi rounds 1 and 2 were 81 and 53, respectively. Full agreement was reached after the third round. The definitive study plan consisted of detailed objectives grouped under 10 general training objectives. CONCLUSIONS: A consensus has been reached between European geriatricians that sets specific training objectives for medical students. Great efforts will be required for the introduction of these requirements, given the variability there is in the quality of teaching in geriatrics. This study plan is a first step in helping to improve geriatrics teaching in faculties of medicine, and will also serve as a basis to make advances in the training in post-graduate geriatrics throughout Europe. PMID- 25540895 TI - Parental Communication and Experiences and Knowledge of Adolescent Siblings of Children with 22q11.2 Deletion Syndrome. AB - 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion in humans. There have been few studies assessing the impact of this condition on the family and no previous studies conducted on unaffected siblings of children with 22q11DS. The goal of this study was to determine the frequency, method, and content of information being communicated by parents to unaffected siblings about the condition and to assess unaffected siblings' knowledge of 22q11DS and perceptions of the impact of the condition on their affected sibling and themselves. Families were recruited from several 22q11DS educational and support organizations and asked to complete a single anonymous online survey. Families were eligible to participate if they had one child with 22q11DS and at least one unaffected child between the ages of 12 and 17. Survey questions were developed based on previous literature and authors' expertise with individuals with 22q11DS. Responses to quantitative and qualitative questions were analyzed to calculate frequencies and proportions and to extract themes, respectively. A total of 25 families (defined as a unit of at least one parent, one affected child, and at least one unaffected child) participated in the study. Parents shared genetic information less often as compared to behavioral and medical information. Siblings of children with 22q11DS had both positive and negative experiences in having a brother or sister with this condition. Genetic counselors can use the results of this study to develop anticipatory guidance for parents of children with 22q11DS in talking with their unaffected children about the condition. PMID- 25540897 TI - Comparison on three classification techniques for sex estimation from the bone length of Asian children below 19 years old: an analysis using different group of ages. AB - Sex estimation is used in forensic anthropology to assist the identification of individual remains. However, the estimation techniques tend to be unique and applicable only to a certain population. This paper analyzed sex estimation on living individual child below 19 years old using the length of 19 bones of left hand applied for three classification techniques, which were Discriminant Function Analysis (DFA), Support Vector Machine (SVM) and Artificial Neural Network (ANN) multilayer perceptron. These techniques were carried out on X-ray images of the left hand taken from an Asian population data set. All the 19 bones of the left hand were measured using Free Image software, and all the techniques were performed using MATLAB. The group of age "16-19" years old and "7-9" years old were the groups that could be used for sex estimation with as their average of accuracy percentage was above 80%. ANN model was the best classification technique with the highest average of accuracy percentage in the two groups of age compared to other classification techniques. The results show that each classification technique has the best accuracy percentage on each different group of age. PMID- 25540896 TI - Genetic Information-Seeking Behaviors and Knowledge among Family Members and Patients with Inherited Bone Marrow Failure Syndromes. AB - Inherited bone marrow failure syndromes (IBMFS) including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are rare genetic disorders characterized by hematologic complications and increased risk of cancer. Patients and their families likely experience obstacles in obtaining sufficient health information given their disorders' rarity. To investigate this possibility, we examined information-seeking behaviors and levels of general and disorder-specific genetic knowledge among 315 members of 174 families with an IBMFS, and how information-seeking behaviors and socio demographic factors may be associated with their genetic knowledge. Cross sectional survey data indicated that participants were most likely to have ever used the Internet or healthcare providers for genetic information. On average, participants correctly answered 57 % of items assessing general genetic knowledge and 49-59 % of disorder-specific knowledge items. Greater knowledge was associated with greater education and ever experiencing genetic counseling, attending a scientific meeting, and seeking information from the Internet and scientific literature. Among families with Fanconi anemia (whose family support organization has the longest history of providing information), greater disorder specific genetic knowledge was also associated with seeking information from support groups and other affected families. Results suggest that families with IBMFS have uncertainty regarding genetic aspects of their disorder, and highlight potential channels for delivering educational resources. PMID- 25540898 TI - Isolated unilateral pulmonary vein atesia in adults. PMID- 25540899 TI - Pertussis in Adults: A Growing Diagnosis in the Pulmonology Clinic. PMID- 25540894 TI - Microenvironmental regulation of therapeutic response in cancer. AB - The tumor microenvironment (TME) not only plays a pivotal role during cancer progression and metastasis but also has profound effects on therapeutic efficacy. In the case of microenvironment-mediated resistance this can involve an intrinsic response, including the co-option of pre-existing structural elements and signaling networks, or an acquired response of the tumor stroma following the therapeutic insult. Alternatively, in other contexts, the TME has a multifaceted ability to enhance therapeutic efficacy. This review examines recent advances in our understanding of the contribution of the TME during cancer therapy and discusses key concepts that may be amenable to therapeutic intervention. PMID- 25540901 TI - Unilateral congenital atresia in adults. A case report and review of the literature. PMID- 25540900 TI - "Correct use of inhaled corticosteroids in chronic obstructive pulmonary disease": a consensus document. AB - INTRODUCTION: Indications for inhaled corticosteroids (IC) in combination with long-acting bronchodilators (LABD) are well defined in clinical practice guidelines. However, there are some doubts about their efficacy and safety. The aim of this document is to establish an expert consensus to clarify these issues. METHOD: A coordinator group was formed, which systematically reviewed the scientific evidence with the aim of identifying areas of uncertainty about the efficacy of ICs, the adverse effects associated with their use and criteria for withdrawal. Their proposals were submitted to a panel of experts and the Delphi technique was used to test the level of consensus. RESULTS: Twenty-five experts participated in the panel, and consensus was reached on the use of IC in the mixed chronic obstructive pulmonary disease (COPD)-asthma phenotype and in frequent exacerbators, and on not using IC in association with LABD for improving lung function in COPD. There was no general consensus on restricting the use of IC to prevent adverse effects. The panel did agree that IC withdrawal is feasible but should be undertaken gradually, and patients who have discontinued must be evaluated in the short term. CONCLUSIONS: Consensus was reached regarding the indication of IC in mixed COPD-asthma and frequent exacerbator phenotypes. The potential for adverse effects must be taken into consideration, but there is no consensus on whether limiting use is justified. The withdrawal of ICs was uniformly agreed to be feasible. PMID- 25540902 TI - The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. AB - Schizophrenia is a severe psychiatric illness that is characterized by reduced cortical connectivity, for which the underlying biological and genetic causes are not well understood. Although the currently approved antipsychotic drug treatments, which primarily modulate dopaminergic function, are effective at reducing positive symptoms (i.e. delusions and hallucinations), they do little to improve the disabling cognitive and negative (i.e. anhedonia) symptoms of patients with schizophrenia. This review details the recent genetic and neurobiological findings that link N-methyl-D-aspartate receptor (NMDAR) hypofunction to the etiology of schizophrenia. It also highlights potential treatment strategies that augment NMDA receptor function to treat the synaptic deficits and cognitive impairments. PMID- 25540903 TI - Cationic micelle delivery of Trp2 peptide for efficient lymphatic draining and enhanced cytotoxic T-lymphocyte responses. AB - Neutral particles 20-45 nm in diameter showed potential as tumor antigen vectors because they targeted the draining lymph nodes after subcutaneous injection. However, they were weakly immune-stimulatory and could also spread throughout the body, raising the risk of systemic toxicity. Here we explored whether incorporating positively charged amphiphilic polymers into micelles improves their site specificity and immunogenicity. Cationic polyethylenimine (2k)-stearic acid (PSA) micelles were loaded with the melanoma antigen peptide Trp2; they showed an average size of 28.7+/-8.2 nm and an encapsulation efficiency of 99.21+/-5.38%. Empty PSA micelles acted as a robust adjuvant in vitro, promoting maturation, proliferation and migration of bone marrow-derived dendritic cells in a dose-dependent manner. After subcutaneous injection into mice, Trp2-loaded PSA micelles accumulated preferentially in the medulla and paracortex of the draining lymph nodes and were present at negligible levels in the systemic circulation. Mice immunized with Trp2-loaded PSA micelles showed significantly higher Trp2 specific cytotoxic T lymphocyte activity than mice immunized with free Trp2 or a mixture of Trp2 and empty PSA micelles. In a B16-F10 murine melanoma model, Trp2 loaded PSA micelles inhibited tumor growth significantly more than did free Trp2 and PSA micelles caused less systemic toxicity. These findings suggest that cationic PSA micelles loaded with Trp2 may be a potential approach for melanoma immunotherapy. PMID- 25540904 TI - Mechanistic profiling of the siRNA delivery dynamics of lipid-polymer hybrid nanoparticles. AB - Understanding the delivery dynamics of nucleic acid nanocarriers is fundamental to improve their design for therapeutic applications. We investigated the carrier structure-function relationship of lipid-polymer hybrid nanoparticles (LPNs) consisting of poly(DL-lactic-co-glycolic acid) (PLGA) nanocarriers modified with the cationic lipid dioleoyltrimethyl-ammoniumpropane (DOTAP). A library of siRNA loaded LPNs was prepared by systematically varying the nitrogen-to-phosphate (N/P) ratio. Atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM) combined with small angle X-ray scattering (SAXS) and confocal laser scanning microscopy (CLSM) studies suggested that the siRNA-loaded LPNs are characterized by a core-shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core-shell structure influences the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA-DOTAP lipoplexes from the LPNs. Based on these results, we suggest a model for the nanostructural characteristics of the LPNs, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix. PMID- 25540905 TI - The synergistic effect of ultrasound and chemical penetration enhancers on chorioamnion mass transport. AB - In our previous study we proposed the use of chemical penetration enhancers for noninvasive detection of fetus abnormalities that can also be utilized for direct fetal drug delivery. In an attempt to further increase the mass transport rate across the amniotic membrane, thus shortening the procedure and improving the applicability of the proposed procedure, the effect and mechanism of combining ultrasound exposure with chemical penetration enhancers' application were assessed. The combined effect was evaluated in vitro on post-delivery human amniotic membrane and ex vivo on rat's whole amniotic sac. Ultrasound effect has been assessed by dye experiments using a customized image analysis program. Additional insights of ultrasound effect's mechanism on biological membranes are presented. Previously we have determined that chemical penetration enhancers affect the fetal membranes via two mechanisms termed as 'extractors' and 'fluidizers'. In this study, we found that combining ultrasound with a 'fluidizer' CPE (e.g. bupivacaine) results in a synergistic enhancement (90-fold) of fetal membrane's mass transport, while combining ultrasound with 'extractors' (e.g. ethanol and NMP) results in an antagonistic effect. The combined procedure is faster and gain greater accuracy than the applications of sole chemical penetration enhancers. PMID- 25540906 TI - Identification and further development of potent TBK1 inhibitors. AB - The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules. PMID- 25540908 TI - Assessing quality of care in paediatric inflammatory bowel disease: focusing on self-reported outcomes. PMID- 25540907 TI - Defining the target in cancer of the oesophagus: direct radiotherapy planning with fluorodeoxyglucose positron emission tomography-computed tomography. AB - AIMS: Target definition in radiotherapy treatment planning (RTP) of oesophageal cancer is challenging and guided by a combination of diagnostic modalities. This planning study aimed to evaluate the contribution of single positron emission tomography-computed tomography (PET-CT) in the treatment position to RTP. MATERIALS AND METHODS: Nineteen patients referred for radiotherapy from April to December 2008 were retrospectively identified. Two sets of target volumes were delineated using the planning CT and the (18)F-fluoro-deoxy-D-glucose ((18)F-FDG) PET-CT data sets, respectively. Target volumes were compared in length, volume and geographic conformality. Radiotherapy plans were generated and compared for both data sets. RESULTS: PET-CT planning target volume (PET-CT(PTV)) was larger than the CT target (CT(PTV)) in 12 cases and smaller in seven. The median PTV conformality index was 0.82 (range 0.44-0.98). Radiotherapy plans conforming to normal tissue dose constraints were achieved for both sets of PTV in 16 patients (three patients could not be treated to the prescription dose with either technique due to very large target volumes and significant risk of normal tissue toxicity). Previously undetected locoregional nodal involvement seen on PET-CT in three cases was localised and included in the PTV. In nine cases, the CTPTV plan delivered less than 95% dose to 95% of the PET-CT(PTV), raising concern about potential for geographical miss. CONCLUSION: A single scan with diagnostic PET-CT in the treatment position for RTP allows greater confidence in anatomical localisation and interpretation of biological information. The use of PET-CT may result in larger PTV volumes in selected cases, but did not exclude patients from radical treatment within accepted normal tissue tolerance. PMID- 25540909 TI - Cross section measurements of deuteron induced nuclear reactions on natural tungsten up to 34 MeV. AB - (186g)Re is a beta-/gamma emitter of great interest for nuclear medicine. It has shown successful results on bone metastases palliation and has similar chemical properties as (99m)Tc, the most commonly used imaging agent. (186g)Re is routinely produced using rhenium target in nuclear reactor. Higher specific activity could be obtained using accelerators. In this paper, production cross section values are presented for the (nat)W(d,x)(186g)Re reaction up to 34MeV, using the stacked-foils method and gamma spectrometry. From this data set, the thick target production yield of (186g)Re is determined and compared with the validated values of the IAEA and also with the proton route. The production cross sections of the (nat)W(d,x)(183,182g,184m,184g,181)Re and (nat)W(d,x)(187)W reactions have also been determined. A good agreement is found with the literature. Our data are compared with the version 1.6 (December 2013) of the TALYS code which shows discrepancies both on the shape and on the amplitude for these deuteron induced reactions. PMID- 25540910 TI - In-out-in pinning for phalangeal fractures. AB - Although a commonly used technique, percutaneous pinning of phalangeal fractures is tricky because of the difficulties associated with getting the correction pin orientation when entering the medullary canal of one fragment from the outer cortex of the other fragment. This has led us to develop the "in-out-in" pinning technique. The principle consists of entering the medullary canal of one of the fragments directly from the fracture site. The pin is inserted and drilled outward through the outer cortex. The second pin is inserted in the same manner. The fragments are then aligned and the pins pushed forward in the medullary canal of the other fragment. PMID- 25540911 TI - Factors associated with health-promoting behavior of people with or at high risk of metabolic syndrome: Based on the health belief model. AB - PURPOSE: The purpose of this study is to identify the associations between self efficacy and the various factors in the Health Belief Model (HBM), and the health promoting behaviors of people with, or at high risk of, Metabolic Syndrome (MS). METHODS: 132 adults with two or more MS components were included in this cross sectional study. Health-promoting behavior, self-efficacy and the four-constructs of HBM (perceived threat, cues, benefits, and barriers) were measured using validated tools. The contributions of each HBM factor towards the respective behavior were identified using a three-step hierarchical regression approach. RESULTS: After controlling for age, gender, education level, income and knowledge of MS, HBM factors accounted for 11% of the total variance in health-promoting behaviors. Beliefs about barriers were found to be a significant predictor of exercise (beta=-.28, p<.01) and diet management (beta=-.24, p=<.01), suggesting that a higher level of perceived barrier was associated with a lower frequency of health-promoting behaviors. In the final model, self-efficacy explained an additional 31% of the variance in exercise behavior and 13% in diet management behavior. CONCLUSIONS: Self-efficacy and perceived barriers made independent contributions to health-promoting behavior among people with, or at high risk of, MS. Community health program targeting this particular group should tailor strategies that can enhance individuals' self-efficacy and address barriers perceived. PMID- 25540912 TI - In situ chondrogenic differentiation of bone marrow stromal cells in bioactive self-assembled peptide gels. AB - Articular cartilage is a specific tissue that lacks nerves and blood vessels and has limited self-repair abilities. Accordingly, it is necessary to develop new technology for the regeneration of cartilage to overcome therapeutic limitations. Recently, there have been several studies investigating the use of peptide hydrogel scaffolds, which are biocompatible and have low immunogenicity, for cartilage tissue engineering. In this study, we used self-assembled peptide hydrogels with repeating peptide sequences and bioactive motifs at the end of repeating sequences, which are collagen mimetic peptides (CMPs). CMPs that have a unique collagen-like triple helical conformation have been shown to associate with collagen molecules and fibers via a strand invasion process. In order to confirm the biological activities of the modified bioactive peptide hydrogels, the role of functional motifs in in situ chondrogenic differentiation of rabbit bone marrow stromal cells (rBMSCs) was examined. To compensate for the weaker mechanical properties of peptide hydrogels, we used poly (L-lactide-co caprolactone) (PLCL) scaffolds, which were loaded with the self-assembled peptides into which the bioactive motifs had been incorporated. Then, we performed in vitro and in vivo analyses with the rBMSC/PLCL-peptide hydrogel complexes. The results indicated that the secretion of a cartilage-specific extracellular matrix and gene expression concerned with chondrogenic differentiation were increased by CMP motifs. In conclusion, it was confirmed that CMP-modified self-assembled peptide hydrogels could effectively enhance chondrogenic differentiation in situ, and, consequently, they could be a good biomaterial for cartilage tissue engineering. PMID- 25540913 TI - The essence of female-male physiological dimorphism: differential Ca2+ homeostasis enabled by the interplay between farnesol-like endogenous sesquiterpenoids and sex-steroids? The Calcigender paradigm. AB - Ca(2+) is the most omnipresent pollutant on earth, in higher concentrations a real threat to all living cells. When [Ca(2+)]i rises above 100 nM (=resting level), excess Ca(2+) needs to be confined in the SER and mitochondria, or extruded by the different Ca(2+)-ATPases. The evolutionary origin of eggs and sperm cells has a crucial, yet often overlooked link with Ca(2+)-homeostasis. Because there is no goal whatsoever in evolution, gametes did neither originate "with the purpose" of generating a progeny nor of increasing fitness by introducing meiosis. The explanation may simply be that females "invented the trick" to extrude eggs from their body as an escape strategy for getting rid of toxic excess Ca(2+) resulting from a sex-hormone driven increased influx into particular cells and tissues. The production of Ca(2+)-rich milk, seminal fluid in males and all secreted proteins by eukaryotic cells may be similarly explained. This view necessitates an upgrade of the role of the RER-Golgi system in extruding Ca(2+). In the context of insect metamorphosis, it has recently been (re)discovered that (some isoforms of) Ca(2+)-ATPases act as membrane receptors for some types of lipophilic ligands, in particular for endogenous farnesol-like sesquiterpenoids (FLS) and, perhaps, for some steroid hormones as well. A novel paradigm, tentatively named "Calcigender" emerges. Its essence is: gender specific physiotypes ensue from differential Ca(2+)-homeostasis enabled by genetic differences, farnesol/FLS and sex hormones. Apparently the body of reproducing females gets temporarily more poisoned by Ca(2+) than the male one, a selective benefit rather than a disadvantage. PMID- 25540914 TI - Preparation and characterization of human ADCK3, a putative atypical kinase. AB - AarF domain containing kinase 3 (ADCK3) is a mitochondrial protein known to have a role in the electron transport chain. Despite being required for the biosynthesis of coenzyme Q10, a lipid-soluble electron transporter found to be essential for aerobic cellular respiration, the precise biological function of ADCK3 remains unknown. Patients with mutations in ADCK3 experience an onset of neurological disorders from childhood, including cerebellar ataxia and exercise intolerance. After extensive screening for soluble recombinant protein expression, an N-terminal fusion of maltose-binding protein was found to facilitate the overexpression of the human ADCK3 kinase domain in Escherichia coli as a soluble and biologically active entity. For the first time our work reveals Mg(2+)-dependent ATPase activity of ADCK3, providing strong support for the theoretical prediction of this protein being a functional atypical kinase. PMID- 25540915 TI - Are red mullet efficient as bio-indicators of mercury contamination? A case study from the French Mediterranean. AB - Mercury (Hg) is one of the main chemicals currently altering Mediterranean ecosystems. Red mullet (Mullus barbatus and M. surmuletus) have been widely used as quantitative bio-indicators of chemical contamination. In this study, we reassess the ability of these species to be used as efficient bio-indicators of Hg contamination by monitoring during 18 months Hg concentrations in muscle tissue of mullet sampled from 5 French Mediterranean coastal areas. Mean concentrations ranged between 0.23 and 0.78 MUg g(-1) dry mass for both species. Values were consistent with expected contamination patterns of all sites except Corsica. Results confirmed that red mullets are efficient bio-indicators of Hg contamination. Nevertheless, the observed variability in Hg concentrations calls for caution regarding the period and the sample size. Attention should be paid to environmental and biologic specificities of each studied site, as they can alter the bioaccumulation of Hg, and lead to inferences about environmental Hg concentrations. PMID- 25540916 TI - Climatic impact on community of filamentous macroalgae in the Neva estuary (eastern Baltic Sea). AB - In presented study the impact of climatic factors and North Atlantic Oscillation (NAO) on macroalgal community was analysed. Also the factors influencing algal community were defined with help of Principal Component and Classification analysis. It was found that climatic impact may depend on habitat features and that on different sites biomass of macroalgae correlated with different weather factors. Wind and surf may affect biomass of macroalgae adversely on some sites and at the same time on other sites they may accumulate biomass, transferring it is from adjacent areas. High direct correlation with temperature was found on sites which were protected from surf and had no stagnant events. Seasonal biomass inversely significantly correlated with average seasonal wind speed and annual NAO-index. PMID- 25540917 TI - A comparison of methods for in vivo assessment of cortical porosity in the human appendicular skeleton. AB - The recent advent of high-resolution peripheral quantitative computed tomography (HR-pQCT) provides new opportunities to measure in vivo human bone microarchitecture. Increasingly, cortical porosity (CtPo) is of particular interest due to its relationship with bone quality and turnover. The two approaches that have emerged to measure CtPo from HR-pQCT are threshold-based and density-based methods, and the purpose of this work was to compare the performance of each against a gold-standard synchrotron radiation micro-computed tomography (SRMUCT) measurement. Human cadaveric cortical bone specimens (N=23) were measured by SRMUCT and HR-pQCT, and high correlations were found for both methods. The density-based approach had an r2=0.939 (95% confidence interval (CI) of +6.17% to +20.99%) and consistently overestimated porosity as measured by SRMUCT, while the threshold-based approach had an r2=0.977 and consistently underestimated porosity (95% CI of -2.60% to -10.76%). The density-based approach is prone to beam hardening artifacts and susceptible to natural variations of tissue mineral density (TMD), but is less affected by motion artifacts that may occur in in vivo scans. The threshold-based method has the advantage that it provides structural information that complements the cortical porosity measure, such as number of pores and connectivity, and can accurately detect the larger pores which are the most relevant to bone biomechanical strength. With the first generation HR-pQCT systems the accuracy of detecting pores larger than 140 MUm diameter is excellent (r2=0.983; 95% CI of -4.88% to +2.45%). The accuracy of the threshold-based method will improve as new HR-pQCT systems emerge and provide a robust quantitative approach to measure cortical porosity. PMID- 25540918 TI - Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. AB - In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways. PMID- 25540919 TI - Resveratrol prevents high glucose-induced epithelial-mesenchymal transition in renal tubular epithelial cells by inhibiting NADPH oxidase/ROS/ERK pathway. AB - Resveratrol (RSV) is reported to have renoprotective activity against diabetic nephropathy, while the mechanisms underlying its function have not been fully elucidated. In this study, we investigate the effect and related mechanism of RSV against high glucose-induced epithelial to mesenchymal transition (EMT) in human tubular epithelial cells (HK-2). A typical EMT is induced by high glucose in HK-2 cells, accompanied by increased levels of reactive oxygen species (ROS). RSV exhibits a strong ability to inhibit high glucose-induced EMT by decreasing intracellular ROS levels via down-regulation of NADPH oxidase subunits NOX1 and NOX4. The activation of extracellular signal-regulated kinase (ERK1/2) is found to be involved in high glucose-induced EMT in HK-2 cells. RSV, like NADPH oxidase inhibitor diphenyleneiodonium, can block ERK1/2 activation induced by high glucose. Our results demonstrate that RSV is a potent agent against high glucose induced EMT in renal tubular cells via inhibition of NADPH oxidase/ROS/ERK1/2 pathway. PMID- 25540920 TI - The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis. AB - The steroidogenic acute regulatory (StAR) protein regulates the rate-limiting step in steroidogenesis, i.e. the delivery of cholesterol from the outer (OMM) to the inner (IMM) mitochondrial membrane. StAR is a 37-kDa protein with an N terminal mitochondrial targeting sequence that is cleaved off during mitochondrial import to yield 30-kDa intramitochondrial StAR. StAR acts exclusively on the OMM and its activity is proportional to how long it remains on the OMM. However, the precise fashion and the molecular mechanism in which StAR remains on the OMM have not been elucidated yet. In this work we will discuss the role of mitochondrial fusion and StAR phosphorylation by the extracellular signal regulated kinases 1/2 (ERK1/2) as part of the mechanism that regulates StAR retention on the OMM and activity. PMID- 25540921 TI - Effect of thymosin beta 4 in the presence of up-regulation of the insulin-like growth factor-1 signaling pathway on high-glucose-exposed vascular endothelial cells. AB - Thymosin beta 4 (Tbeta4), which regulates vascular cell growth, can ameliorate some of the problems associated with diabetes. However, the precise signaling mechanisms by which Tbeta4 protects against hyperglycemia-induced damage to endothelial cells have not been investigated in detail. Thus, the aim of this study was to elucidate the role of Tbeta4 in diabetes and the possible involvement of insulin-like growth factor-1 (IGF-1), which affects cellular survival, metabolism, and glucose homeostasis in high-glucose (HG)-injured human umbilical vein endothelial cells (HUVECs). Immunoblotting assays revealed that under HG blockade conditions, Tbeta4 did not alter the insulin-signaling pathway, but induced overexpression of IGF-1 protein, leading to activation of factors in alternative signaling pathway. Small interfering RNA of Tbeta4 and IGF-1 were studied to clarify relationship between Tbeta4 and IGF-1. These findings suggest that IGF-1 induction by Tbeta4 ameliorates the damage in HG-injured HUVECs which manifest as diabetic vascular disorder. PMID- 25540922 TI - Innate immunity alterations in idiopathic interstitial pneumonias and rheumatoid arthritis-associated interstitial lung diseases. AB - BACKGROUND: This is a prospective cohort study elucidating innate immunity in idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) and RA associated non specific interstitial pneumonia (RA-NSIP). METHODS: 23 IPF subjects, 9 COP subjects, 5 RA-UIP subjects, 8 RA-NSIP subjects were enrolled. 10 subjects were excluded. 19 healthy subjects served as controls. Blood and bronchoalveolar lavage (BAL) were obtained. Natural killer (NK) and NKT cells, NK cells apoptosis and the expression of triggering receptor expressed on myeloid cells type 1 (TREM-1) were assessed. Tumor necrosis factor-alpha (TNF-alpha) production was measured in cell cultures after stimulation with lipopolysaccharide endotoxin (LPS) and Pam3CysSK3, and in BAL. Surface expression of Toll-like receptors (TLR) 2 and 4 on peripheral blood monocytes (PBMC's) and circulating NK cells was also assessed. RESULTS: RA-NSIP had low blood NKs, marginally insignificant (p=0.07). These NKs poorly produced TNF-alpha after LPS stimulation. TLR's expression on NK cells was similar throughout disease groups and controls. PBMC's mainly from IPF patients exhibited low TNF-alpha production after LPS stimulation but not after Pam3CysSK3 stimulation, while TLR4 expression on PBMC's was found normal in all study groups. TLR2 expression on PBMC's was increased in IPF, but mainly in COP, RA-UIP and RA-NSIP (p=0.015). TREM-1 expression was significant on COP monocytes and on COP neutrophils versus controls. RA-NSIP monocytes also exhibited TREM-1 expression (p=0.07). Decreased TNF-alpha concentration in BAL was finally observed in IPF and RA-UIP. CONCLUSIONS: Innate immunity in the lungs and the peripheral circulation in IPF and RA-UIP are similar and more fibrotic than in RA-NSIP which is characterized by NK cell depletion and dysfunction. TREM-1 and TLR's likely affect patterns of inflammation in various interstitial lung diseases. PMID- 25540923 TI - Antioxidant and anti-inflammatory activities contribute to the prophylactic effect of semi-purified fractions obtained from the crude methanol extract of Muntingia calabura leaves against gastric ulceration in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In traditional medicine, the leaves, flowers, barks and roots of Muntingia calabura L. (Muntingiaceae) have been employed as a treatment for various ailments including dyspepsia and to relieve pain caused by gastritis and peptic ulcer disease. The methanolic extract of Muntingia calabura leaves (MEMC) has been proven in the previous study to possess significant antiulcer activity. In this study, we attempted to determine the prophylactic effect of the fractions obtained from MEMC against ethanol-induced gastric lesion in rats and the involvement of antioxidants and anti-inflammatory mediators. MATERIALS AND METHODS: The MEMC was fractionated with petroleum ether (PEF), ethyl acetate (EAF) and distilled water (AQF). These fractions were investigated for possible antiulcer property using ethanol-induced gastric ulcer rat model. The rats were administered orally once daily with 8% Tween 80 (control), 100mg/kg ranitidine, or the fractions, in the doses of 100, 250, and 500 mg/kg, for 7 days, followed by ulcer induction using absolute ethanol. The rats were euthanized; macroscopic and histological observations of the stomach were done. The ulcer area (UA) was determined and the percentage protection afforded by the fractions was calculated. The fractions were subjected to antioxidant studies including the superoxide and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, oxygen radical absorbance capacity (ORAC) and total phenolic content (TPC) assay. Involvement of nitric oxide (NO) and inflammatory mediators such as lipoxygenase (LOX) and xanthine oxidase (XO) were evaluated. Phytochemical screening and HPLC analysis of the fractions were also conducted. RESULTS: Pre treatment of PEF and EAF significantly (p<0.001) attenuated the gastric lesions as compared to the control group in a dose-dependent manner. On the other hand, 100 and 250 mg/kg of AQF significantly (p<0.001) prevented the ulcer formation but at the highest dose (500 mg/kg), AQF failed to significantly reduce the ulcer formation, showing a dose-independent antiulcerative effect of AQF. The histological evaluation supported the observed gastroprotective activity of PEF, EAF and AQF. All the fractions showed high superoxide and DPPH scavenging activity, meanwhile the EAF showed highest TPC followed by PEF and AQF. These fractions also significantly (p<0.05) inhibited the NO while maintaining the viability of the cells. EAF exhibited high inhibition towards both the LOX and XO enzymes, meanwhile PEF and AQF exerted high LOX inhibition but low XO inhibition. Phytochemical screening and HPLC profiling suggested the presence of flavonoid- and tannin based compounds in PEF and EAF. CONCLUSION: It can be concluded that the prophylactic effect of the fractions on gastric ulceration in rats is associated with its high antioxidant activity and its ability to effectively inhibit the inflammation mediators. Presence of several flavonoids and gallic acid explains the effectiveness of the fractions in affording protection against gastric damages. PMID- 25540925 TI - Reduction in voluntary ethanol intake following repeated oral administration of Jodina rhombifolia lyophilized aqueous extract in male Wistar rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Jodina rhombifolia (Hook. & Arn.) Reissek (SANTALACEAE) is utilized in Argentine folk medicine for the treatment of alcoholism. AIM OF THE STUDY: To evaluate the antialcoholic activity of Jodina rhombifolia lyophilized aqueous extract (JRLE) in male Wistar rats. MATERIALS AND METHODS: Rats were housed individually in standard plastic cages with wood chip bedding. Throughout the duration of experiment, ethanol was offered in the standard home-cage; two-bottle free-choice regimen between an ethanolic solution (20% in tap water, v/v) and tap water with unlimited access for 24h per day for 10 consecutive days. Rats were administrated intragastrically twice daily (1 ml/200 g) for 10 consecutive days, with the control vehicle (distilled water) or one of the doses of JRLE (125, 250 and 500 mg/Kg weight). Body weight, ethanol, water and food intake were measured every day at the same hour during the 10 days of experimentation. RESULTS: The reducing effect of JRLE on daily ethanol intake was evidenced from the first day of treatment and persisted throughout the entire treatment period. The treatment did not significantly affect daily water intake neither the body weight gain. Daily food intake was higher in rat groups treated with JRLE. CONCLUSION: The results obtained in the present preliminary study show that repeated administration of JRLE, markedly reduces ethanol voluntary intake in male Wistar rats. The reduction of consumption was of remarkable magnitude and stable during the treatment 10-days. PMID- 25540924 TI - Acute and subchronic toxicity as well as evaluation of safety pharmacology of Galla chinensis solution. AB - Galla chinensis has been popularly used in traditional Chinese medicine which is beneficial for the treatment of various diseases, such as inflammation, dysentery, toxicosis and sore. However, it has not previously been evaluated for safety through systematic toxicological studies. In the present study, acute and subchronic oral toxicity studies and safety pharmacology evaluation of Galla chinensis solution (GCS) were conducted in specific pathogen-free (SPF) Sprague Dawley (SD) rats. Acute administration of GCS was done as single dose from 3333 mg to 6912 mg per kg/bodyweight (bw) and subchronic toxicity study for 30 days was done by daily oral administration of GCS at doses of 500, 1500 and 2500 mg/kg body weight in SPF SD rats. The acute toxicity study showed the LD50 of GCS was greater than 5000 mg/kg. The results of sunchronic toxicity study showed that the no-observed effect level of GCS was lesser than 1500 mg/kg bw day, which suggested three times higher than that of recommended dose for clinical applications (500 mg/kg bw day). The dose at 2500 mg/kg bw day of GCS may slow down the growth of rats and lead to degeneration and necrosis of tissue cells to some extent. In the safety pharmacology study, GCS did not produce any side effects to rats in central nervous system, cardiovascular system and respiratory system. Therefore, from the results of the study presented herein, it could be concluded that the use of appropriate levels (one to three times of recommended dose for clinical applications) of GCS as a topical preparations is considered safe. PMID- 25540926 TI - Xysmalobium undulatum (Uzara) research- how everything began. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xysmalobium undulatum (Uzara) is a traditionally used medicinal plant from South Africa. It found its way into European research in the early 20th century and is widely used as a remedy against diarrhoea. The purpose of this study was to explore the circumstances of knowledge transfer and early research into phytochemistry and therapeutic potential of Xysmalobium undulatum. RESULTS: The drug was brought to Europe through a former soldier, Wilhelm Heinrich Adolph Hopf (1887-1929). Some details about his life are provided here the first time, as well as some aspects of early research on the drug, which has mainly been done at the University of Marburg, Germany. PMID- 25540927 TI - Imaging of thoracic aortic injury. AB - Isthmic aortic rupture or disruption should be systematically sought when there is high kinetic energy trauma to the thorax. This condition is extremely serious and life threatening. It needs to be diagnosed rapidly but diagnostic pitfalls must be avoided. CT angiography is the standard examination. The main CT signs of rupture or disruption of the thoracic aorta are periaortic hematoma, intimal flap, pseudo-aneurysm and contrast agent extravasation. There are three types of lesion: intimal, subadventitial or pseudo-aneurysmal, and complete rupture with lesion of the three tunicae, and it is important to grade them for better therapeutic management. The main diagnostic pitfalls of the CT scan are the presence of a ductus diverticulum and post-isthmic fusiform dilatation. Associated lesions must not be overlooked. The most common are ruptures of the aortic root and the thoracic aorta in the diaphragmatic hiatus. PMID- 25540928 TI - Contribution of imaging in the initial management of ballistic trauma. AB - INTRODUCTION: The purpose of this study is to specify the role of imaging in the initial management of ballistic traumas. METHODS: This is a retrospective study that colligated 83 victims of a gunshot wound during demonstrations, treated in our trauma centre between 12 January and 3 February 2011. All of the patients were haemodynamically stable and examined by conventional radiography and/or ultrasound and/or 16-slice CT-scan (CT). RESULTS: The mean age of the victims was 26years with a sex ratio of 0.02. All wounds were unique. Injury to the limbs was most common in 75.5% of the cases (n=64) followed by that of the torso in 19.5% of the cases (n=16). Wounds in the spine (n=2), brain (n=2) and facial skeleton (n=1) were observed. Conventional x-rays objectified 32 cases of open fractures 95% of which were in the legs. Twenty-one of the victims of gunshot wounds had a CT-scan that objectified the path of the bullet and an assessment of the wound was made in all cases. The confrontation of the data from the CT-scan and that noted during surgery and during the monitoring demonstrated that the CT-scan is very efficient in the diagnosis of pleural effusion, vascular wounds, thoracic parenchymatous wounds and wounds of the solid organs and brain lesions and the facial skeleton. However, the sensitivity is low for the diagnosis of hollow organs. CONCLUSION: The CT-scan is very useful in the initial care of stable patients with gunshot wounds as regards the haemodynamics and helps objectify the path of the bullet and obtain a precise assessment of the damage. Conventional x rays are unavoidable for wounds to the legs and spine. PMID- 25540929 TI - Balloon occlusion versus wedged hepatic venography using iodinated contrast for targeting the portal vein during TIPS. AB - PURPOSE: To assess the efficacy, safety and gain in procedure time of the technique of balloon occlusion hepatic venography with iodinated contrast used to target the portal vein during TIPS. The technique is assessed versus wedged hepatic venography. MATERIALS AND METHODS: Fifty-eight TIPS were prospectively included. The portal vein was located in 30 cases by the wedged hepatic venography (group 1) and in 28 cases by balloon occlusion hepatic venography (group 2). To compare both techniques a "portogram quality" score was defined using a 5 points scale. The time required to achieve portal puncture was also recorded. The complications of both procedures were assessed and classified in groups as intrahepatic hematoma or intraperitoneal hemorrhage. RESULTS: The right portal vein was visualized in a significantly higher number of patients using balloon than with wedged retrograde venography 71.3% (20/28) versus 13.3% (4/30) respectively (P=0.002). The quality score for the portogram was significantly higher for balloon hepatic venography 2.21 than for wedged hepatic venography 1.07 (P=0.002). The mean time required to puncture the portal vein was significantly shorter when the right branch of the portal vein was visualized 21 min versus 33.5 min (P=0.046). We recorded one intrahepatic hematoma (3.3%) and 4 intraperitoneal hemorrhage (13.3%) secondary to wedged hepatic venography. There were no complications with balloon occlusion hepatic venography (P=0.053). CONCLUSION: The use of balloon occlusion hepatic venography improves the quality of the retrograde portal venography to target the portal vein and decreases procedure time. The balloon technique is also burdened with fewer complications than the standard wedged hepatic venography. PMID- 25540930 TI - Sleep depth and continuity before and after chronic exercise in older men: electrophysiological evidence. AB - During later life sleep depth (slow-wave sleep, SWS) and maintenance exhibit deleterious changes, with possible negative effects on daytime function. This study assessed the effect of chronic, supervised exercise on sleep using laboratory-based polysomnography (PSG) and repeated measures in older adults. Thirteen men aged 64+/-3served as their own controls and had their sleep measured for a total of 6 nights: 3 before and 3 after the 16-week training intervention. Each sequence involved 1 familiarization trial followed by 2 experimental nights (exercise night; nonexercise night) measured using 13-channel PSG (combined electroencephalography, electromyography, and electro-oculography). The exercise challenges consisted of inclined treadmill brisk walking (60min, 68-69% VO2peak). The intervention successfully improved some parameters of aerobic fitness, i.e. ventilatory thresholds 1 and 2 (P<0.05). Acute exercise triggered increases in circulating free fatty acids and lactate levels both at baseline and after the intervention (P<0.05). Noteworthy, acute exercise following training resulted in a 71% increase in SWS during subsequent sleep in comparison with the nonexercise condition before training, respectively 2.4% and 1.4% (P<0.05). Following training, acute exercise reduced total wake time by 30% and REM onset latency by 14% (P<0.05). Acute exercise improved sleep continuity by decreasing total wake time. These results show that aerobic training could increase sleep depth and continuity, during active days, in elderly men. In habitual exercisers, these effects of aerobic exercise on sleep, although modest, might counteract those resulting from aging. PMID- 25540932 TI - Novel insights into the evolution and structural characterization of dyskerin using comprehensive bioinformatics analysis. AB - Dyskerin is a conserved nucleolar protein. Several related genetic diseases are caused by defects in dyskerin. We hypothesized that having a comprehensive bioinformatic analysis of dyskerin will help to develop new drugs for this diseases. We predicted protein domains and compared sequences and structures to detect the universe of dyskerin-like proteins. We identified conserved features of shared domains in the three superkingdoms. We analyzed the phylogenetic diversity, confirming that there is a strong structural conservation. Also, we studied the relationship of dyskerin-like proteins with other proteins through an integrative protein-protein interaction approach. Most of them are conserved among homologous eukaryotic and archaeal proteins. Our results highlighted the preservation of proteins interacting with dyskerin. We identified conserved dyskerin interactor proteins between the different eukaryotes organisms. Furthermore, we studied the existence of dyskerin-like proteins in different species. Also, we compared and analyzed the secondary structure with the hydrophobic profile, confirming that all have hydrophilic properties highly conserved among proteins. The greatest difference was observed in the NTE and CTE regions. Another aspect studied was the comparison and analysis of tertiary structures. In our knowledge, this is the first time that these analyses were performed in such a comprehensive manner. PMID- 25540931 TI - Parabrachial lesions in rats disrupt sodium appetite induced by furosemide but not by calcium deprivation. AB - An appetite for CaCl2 and NaCl occurs in young rats after they are fed a diet lacking Ca or Na, respectively. Bilateral lesions of the parabrachial nuclei (PBN) disrupt normal taste aversion learning and essentially eliminate the expression of sodium appetite. Here we tested whether similar lesions of the PBN would disrupt the calcium-deprivation-induced appetite for CaCl2 or NaCl. Controls and rats with PBN lesions failed to exhibit a calcium-deprivation induced appetite for CaCl2. Nevertheless, both groups did exhibit a significant calcium-deprivation-induced appetite for 0.5M NaCl. Thus, while damage to the second central gustatory relay in the PBN disrupts the appetite for 0.5M NaCl induced by furosemide, deoxycorticosterone acetate, and polyethylene glycol, the sodium appetite induced by dietary CaCl2 depletion remains intact. PMID- 25540933 TI - Comparative phosphoproteome analysis of Magnaporthe oryzae-responsive proteins in susceptible and resistant rice cultivars. AB - To explore the molecular mechanisms involved in the rice-Magnaporthe oryzae interaction, we conducted a time-course phosphoproteomic analysis of leaf samples from resistant and susceptible rice cultivars infected with M. oryzae, with emphasis on the initial biotrophic phase of the interaction. Phosphoproteomic profiling analysis led to the identification of 56 M. oryzae-regulated phosphoprotein spots. MALDI-TOF/TOF analysis unveiled 53 phosphoproteins belonging to 12 functional categories. Phosphorylation within 7 identified phosphoproteins was verified by mapping the phosphorylation sites by nanoLC MS/MS. Although the phosphoproteins involved in photosynthesis, antioxidation, and protein folding showed similar changes in both compatible and incompatible interactions, differential regulation between the two interactions was documented for the phosphorylation status of defense-related proteins, signaling-related proteins, microtubule-associated proteins, energy-related enzymes, and amino acid synthesis-related proteins. Rice resistance is likely related to several rapidly and strongly triggered signal transduction cascades (e.g., Rac GTPases- and H2O2 mediated rice defense signaling) resulting in a multiple-level activation of defense responses. The six differentially expressed mRNA encoding proteins were measured by quantitative real-time PCR (qRT-PCR). This study provides useful clues for the further exploration of the sophisticated regulatory mechanisms of M. oryzae-rice interactions. BIOLOGICAL SIGNIFICANCE: Although large-scale identification of phosphorylated proteins has been carried out in rice, there is little report on the rice phosphoproteome in response to pathogens in general and in response to M. oryzae in particular. In this study, a time-course comparative phosphoproteomics was performed to analyze the changes of phosphoprotein profiles in rice leaves during early compatible and incompatible interactions with M. oryzae by using a combination of PEG prefractionation, Al(OH)3-MOAC, 2-DE, Pro-Q DPS and mass spectrometry. Fifty-six M. oryzae-regulated phosphoproteins were identified successfully and phosphorylation within 7 identified phosphoproteins was verified by mapping the phosphorylation sites by nanoLC-MS/MS. Our study provides novel insights into the functions of proteins involved in rice resistance and the molecular mechanism of rice resistance against M. oryzae. Furthermore, we propose the working model for the signaling pathways of rice defense in response to M. oryzae. PMID- 25540934 TI - Protein sHSP26 improves chloroplast performance under heat stress by interacting with specific chloroplast proteins in maize (Zea mays). AB - We recently demonstrated that chloroplast small HSP26 (sHSP26) is abundant in maize leaves under heat stress and potentially involved in maize heat tolerance. However, it largely remains unclear how sHSP26 functions in maize under heat stress. Here, 2-DE-based proteomics, RNA interference (RNAi), co immunoprecipitation (Co-IP) and yeast two-hybrid (Y2H) were used to reveal chloroplast proteins interacting with sHSP26 and how sHSP26 functions under heat stress. After the silencing of sHSP26, a total of 45 protein spots from isolated protoplasts were greatly changed in abundance, of which 33 spots are chloroplastic. Co-IP revealed that nine proteins possibly associated with sHSP26. Y2H demonstrated that six chloroplast proteins interact with sHSP26 under heat stress. In particular, four proteins, including ATP synthase subunit beta, chlorophyll a-b binding protein, oxygen-evolving enhancer protein 1 and photosystem I reaction center subunit IV, strongly interacted with sHSP26 and their abundance greatly declined after RNAi of sHSP26 under heat stress. In addition, H2O2 accumulation in the chloroplasts significantly increased the expression of sHSP26, and the suppression of sHSP26 expression significantly reduced the O2 evolution rate of photosystem II under heat stress. Overall, these findings demonstrate the relevance of sHSP26 in protecting maize chloroplasts under heat stress. BIOLOGICAL SIGNIFICANCE: Maize is one of the most important crops worldwide. Frequent heat stress reduces significantly the yield and quality of maize. Our results demonstrated that sHSP26 improved maize chloroplast performance under heat stress by interacting with specific proteins. These findings are useful for understanding the mechanism of heat stress response and heat-tolerant molecular breeding in maize. PMID- 25540935 TI - Transcriptome and proteome analysis of Eucalyptus infected with Calonectria pseudoreteaudii. AB - Cylindrocladium leaf blight is one of the most severe diseases in Eucalyptus plantations and nurseries. There are Eucalyptus cultivars with resistance to the disease. However, little is known about the defense mechanism of resistant cultivars. Here, we investigated the transcriptome and proteome of Eucalyptus leaves (E. urophylla*E. tereticornis M1), infected or not with Calonectria pseudoreteaudii. A total of 8585 differentially expressed genes (|log2 ratio| >=1, FDR <=0.001) at 12 and 24hours post-inoculation were detected using RNA-seq. Transcriptional changes for five genes were further confirmed by qRT-PCR. A total of 3680 proteins at the two time points were identified using iTRAQ technique.The combined transcriptome and proteome analysis revealed that the shikimate/phenylpropanoid pathway, terpenoid biosynthesis, signalling pathway (jasmonic acid and sugar) were activated. The data also showed that some proteins (WRKY33 and PR proteins) which have been reported to involve in plant defense response were up-regulated. However, photosynthesis, nucleic acid metabolism and protein metabolism were impaired by the infection of C. pseudoreteaudii. This work will facilitate the identification of defense related genes and provide insights into Eucalyptus defense responses to Cylindrocladium leaf blight. BIOLOGICAL SIGNIFICANCE: In this study, a total of 130 proteins and genes involved in the shikimate/phenylpropanoid pathway, terpenoid biosynthesis, signalling pathway, cell transport, carbohydrate and energy metabolism, nucleic acid metabolism and protein metabolism in Eucalyptus leaves after infected with C. pseudoreteaudii were identified. This is the first report of a comprehensive transcriptomic and proteomic analysis of Eucalyptus in response to Calonectria sp. PMID- 25540936 TI - Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation? AB - The mismatched minor histocompatibility antigens present on Y chromosome (H-Y) in male recipients receiving stem cells from female donors may contribute to the graft-versus-leukemia effect and results in a reduced relapse rate, especially in patients with high-risk disease. We retrospectively compared the outcomes of male patients with acute myeloid leukemia who received an allogeneic hematopoietic stem cell transplant (HSCT) from female donors (F-M) (174 patients) versus other gender combinations (667 patients). Median age was 50 years (range, 18 to 74 years). For the whole group, the 1-year cumulative incidence of relapse was significantly lower in F-M group (34.1% versus 41.3%, P = .044), whereas nonrelapse mortality (NRM) was higher (23.2% versus 15.7%, P = .004). For patients younger than 50 years beyond first complete remission, the F-M group was associated with lower relapse rate (42.5% versus 55.2%, P = .045) whereas NRM was not significantly different (35.8% versus 25.5%, P = .141). Although survival was not significantly improved, transplantation from a female donor for male recipient was associated with a lower relapse rate. When relapse is the most common concern for treatment failure, especially for younger patients, a female donor for a male recipient might be beneficial to decrease relapse rate after transplantation. Future studies are needed to explore how the H-Y mismatch may improve survival after transplantation. PMID- 25540937 TI - Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. AB - To expand the current knowledge about azacitidine (Aza) and donor lymphocyte infusions (DLI) as salvage therapy for relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify predictors for response and survival, we retrospectively analyzed data of 154 patients with acute myeloid leukemia (AML, n = 124), myelodysplastic (MDS, n = 28), or myeloproliferative syndrome (n = 2). All patients received a median number of 4 courses of Aza (range, 4 to 14) and DLI were administered to 105 patients (68%; median number of DLI, 2; range, 1 to 7). Complete and partial remission rates were 27% and 6%, respectively, resulting in an overall response rate of 33%. Multivariate analysis identified molecular-only relapse (hazard ratio [HR], 9.4; 95% confidence interval [CI], 2.0 to 43.5; P = .004) and diagnosis of MDS (HR, 4.1; 95% CI, 1.4 to 12.2; P = .011) as predictors for complete remission. Overall survival (OS) at 2 years was 29% +/- 4%. Molecular-only relapse (HR, .14; 95% CI, .03 to .59; P = .007), diagnosis of MDS (HR, .33; 95% CI, .16 to .67; P = .002), and bone marrow blasts <13% (HR, .54; 95% CI, .32 to .91; P = .021) were associated with better OS. Accordingly, 2-year OS rate was higher in MDS patients (66% +/- 10%, P = .001) and correlated with disease burden in patients with AML. In summary, Aza and DLI is an effective and well-tolerated treatment option for patients with relapse after allo-HSCT, in particular those with MDS or AML and low disease burden. The latter finding emphasizes the importance of stringent disease monitoring and early intervention. PMID- 25540938 TI - Pregnancy is characterized by widespread deep-tissue hypersensitivity independent of lumbopelvic pain intensity, a facilitated response to manual orthopedic tests, and poorer self-reported health. AB - Lumbopelvic pain is common in pregnancy but the sensitization factors underlying the condition are largely unknown. This study characterized the somatosensory profile of pregnant and nonpregnant women and the relationship between pain, hypersensitivity, and commonly used manual clinical tests. Thirty-nine pregnant and 22 nonpregnant women were included. Although lumbopelvic pain was not an inclusion criterion, the pregnant women were divided into low- and high-pain groups following data collection. The sensitivity to light brush, pin-prick, and pressure pain was assessed bilaterally at 3 sites in the lumbopelvic region, at the shoulder, and in the lower leg. Responses to the active straight leg raise test and pain provocation tests of the sacroiliac joint were recorded. Participants completed questionnaires addressing emotional and physical well being and rated disability using the Pelvic Girdle Questionnaire. Compared with controls, the high-pain group rated the active straight leg raise test as more difficult (P < .05), and both pain groups had more positive pain provocation tests (P < .05). The pregnant groups demonstrated significantly lower pressure pain thresholds at most assessment sites compared with controls (P < .05), but self-reported disability and pain were not correlated with pressure pain thresholds within pregnant participants. The high-pain group reported worse emotional health and poorer sleep quality than controls (P < .05). PERSPECTIVE: This article presents the somatosensory profile of a healthy pregnant cohort. The results indicate that pain sensitivity increases during pregnancy possibly owing to the physical changes the body undergoes during pregnancy but also owing to changes in emotional health. This should be accounted for in clinical management of pregnant women with lumbopelvic pain. PMID- 25540940 TI - Caesium inhibits the colonization of Medicago truncatula by arbuscular mycorrhizal fungi. AB - Contamination of soils with radioisotopes of caesium (Cs) is of concern because of their emissions of harmful beta and gamma radiation. Radiocaesium enters the food chain through vegetation and the intake of Cs can affect the health of organisms. Arbuscular mycorrhizal (AM) fungi form mutualistic symbioses with plants through colonization of the roots and previous studies on the influence of AM on Cs concentrations in plants have given inconsistent results. These studies did not investigate the influence of Cs on AM fungi and it is therefore not known if Cs has a direct effect on AM colonization. Here, we investigated whether Cs influences AM colonization and if this effect impacts on the influence of Rhizophagus intraradices on Cs accumulation by Medicago truncatula. M. truncatula was grown with or without R. intraradices in pots containing different concentrations of Cs. Here, we present the first evidence that colonization of plants by AM fungi can be negatively affected by increasing Cs concentrations in the soil. Mycorrhizal colonization had little effect on root or shoot Cs concentrations. In conclusion, the colonization by AM fungi is impaired by high Cs concentrations and this direct effect of soil Cs on AM colonization might explain the inconsistent results reported in literature that have shown increased, decreased or unaffected Cs concentrations in AM plants. PMID- 25540939 TI - Presurgical psychosocial predictors of acute postsurgical pain and quality of life in children undergoing major surgery. AB - Limited research has examined presurgical risk factors for poor outcomes in children after major surgery. This longitudinal study examined presurgical psychosocial and behavioral factors as predictors of acute postsurgical pain intensity and health-related quality of life (HRQOL) in children 2 weeks after major surgery. Sixty children aged 10 to 18 years, 66.7% female, and their parent/guardian participated in the study. Children underwent baseline assessment of pain (daily electronic diary), HRQOL, sleep (actigraphy), and psychosocial factors (anxiety, pain catastrophizing). Caregivers reported on parental pain catastrophizing. Longitudinal follow-up assessment of pain and HRQOL was conducted at home 2 weeks after surgery. Regression analyses adjusting for baseline pain revealed that presurgery sleep duration (beta = -.26, P < .05) and parental pain catastrophizing (beta = .28, P < .05) were significantly associated with mean pain intensity reported by children 2 weeks after surgery, with shorter presurgery sleep duration and greater parental catastrophizing about child pain predicting greater pain intensity. Adjusting for baseline HRQOL, presurgery child state anxiety (beta = -.29, P < .05) was significantly associated with HRQOL at 2 weeks, with greater anxiety predicting poorer HRQOL after surgery. In conclusion, child anxiety, parental pain catastrophizing, and sleep patterns are potentially modifiable factors that predict poor outcomes in children after major surgery. PERSPECTIVE: This study addresses an important gap in literature, examining presurgical risk factors for poorer acute postsurgical outcomes in children undergoing major surgery. Knowledge of these factors will enable presurgical identification of children at risk for poorer outcomes and guide further research developing prevention and intervention strategies for these children. PMID- 25540941 TI - Proteasome activation: An innovative promising approach for delaying aging and retarding age-related diseases. AB - Aging is a natural process accompanied by a progressive accumulation of damage in all constituent macromolecules (nucleic acids, lipids and proteins). Accumulation of damage in proteins leads to failure of proteostasis (or vice versa) due to increased levels of unfolded, misfolded or aggregated proteins and, in turn, to aging and/or age-related diseases. The major cellular proteolytic machineries, namely the proteasome and the lysosome, have been shown to dysfunction during aging and age-related diseases. Regarding the proteasome, it is well established that it can be activated either through genetic manipulation or through treatment with natural or chemical compounds that eventually result to extension of lifespan or deceleration of the progression of age-related diseases. This review article focuses on proteasome activation studies in several species and cellular models and their effects on aging and longevity. Moreover, it summarizes findings regarding proteasome activation in the major age-related diseases as well as in progeroid syndromes. PMID- 25540942 TI - Degradation characteristics of metoprolol during UV/chlorination reaction and a factorial design optimization. AB - Metoprolol (MTP), a hypertension depressor, has been increasingly detected even after conventional water treatment processes. In this study, the removal of MTP was compared using chlorination (Cl2), UV-C photolysis, and UV/chlorination (Cl2/UV) reactions. The results showed that the UV/chlorination reaction was most effective for MTP removal. MTP removal during UV/chlorination reaction was optimized under various conditions of UV intensity (1.1-4.4 mW/cm(2)), chlorine dose (1-5 mg/L as Cl2), pH (2-9), and dissolved organic matter (DOM, 1-4 mgC/L) using a two-level factorial design with 16 experimental combinations of the four factors. Among the factors examined, DOM scavenging by OH radicals was the most dominant in terms of MTP removal during UV/chlorination reaction. The established model fit well with the experimental results using to various water samples including surface waters, filtered and tap water samples. The optimized conditions (UV intensity=4.4 mW/cm(2), [Cl2]=5 mg/L, pH 7, and [DOM]=0.8-1.1 mgC/L) of the model removed more than 78.9% of MTP for filtered water samples during UV/chlorination reaction. Using LC-MS/MS, five byproducts of MTP (molecular weight: 171, 211, 309, 313, and 341, respectively) were identified during UV/chlorination reaction. Based on this information, the MTP transformation mechanism during UV/chlorination was suggested. Our results imply that applying UV/chlorination process after filtration stage in the water treatment plant (WTP) would be the most appropriate for effective removal of MTP. PMID- 25540943 TI - A new multiple-stage electrocoagulation process on anaerobic digestion effluent to simultaneously reclaim water and clean up biogas. AB - A new multiple-stage treatment process was developed via integrating electrocoagulation with biogas pumping to simultaneously reclaim anaerobic digestion effluent and clean up biogas. The 1st stage of electrocoagulation treatment under the preferred reaction condition led to removal efficiencies of 30%, 81%, 37% and >99.9% for total solids, chemical oxygen demand, total nitrogen and total phosphorus, respectively. Raw biogas was then used as a reactant and pumped into the effluent to simultaneously neutralize pH of the effluent and remove H2S in the biogas. The 2nd stage of electrocoagulation treatment on the neutralized effluent showed that under the selected reaction condition, additional 60% and 10% of turbidity and chemical oxygen demand were further removed. The study concluded a dual-purpose approach for the first time to synergistically combine biogas purification and water reclamation for anaerobic digestion system, which well addresses the downstream challenges of anaerobic digestion technology. PMID- 25540944 TI - Effect of bolus volume and consistency on swallowing events duration in healthy subjects. AB - BACKGROUND/AIMS: Swallowing is a complex function with the control of the swallowing center being located in the brain stem. Our aim in this investigation was to evaluate, in healthy volunteers, the oral and pharyngeal transit of 2 bolus volumes and 2 consistencies, and the influence of these boluses on the proportion of pharyngeal clearance duration/hyoid movement duration. METHODS: Videofluoroscopic evaluation of swallows was performed in 30 healthy volunteers, aged 29-77 years (mean 58 years). The subjects swallowed in duplicate of 5 mL and 10 mL of thick liquid barium and honey thick barium. We measured the duration of oral transit, pharyngeal transit, pharyngeal clearance, upper esophageal sphincter opening, hyoid movement, oropharyngeal transit, and the relation pharyngeal clearance duration/hyoid movement duration. RESULTS: A 10 mL bolus volume caused a longer UES opening duration than a 5 mL bolus volume, for both consistencies. The pharyngeal transit was longer for honey thick bolus consistency than for thick liquid, with both the volumes of 5 mL and 10 mL. For pharyngeal clearance, the difference was significant only with the 10 mL bolus volume. There was no difference associated with bolus volume or consistency in the relation between pharyngeal clearance duration and hyoid movement duration. CONCLUSIONS: Increase in the swallowed bolus volume causes a longer UES opening duration and an increase in bolus consistency from thick liquid to honey thick causes a longer pharyngeal transit duration. The proportion between pharyngeal clearance and hyoid movement does not change with bolus volume or bolus consistency. PMID- 25540945 TI - Multi-facets of Corticotropin-releasing Factor in Modulating Inflammation and Angiogenesis. AB - The family of corticotropin-releasing factor (CRF) composed of 4 ligands including CRF, urocortin (Ucn) 1, Ucn2, and Ucn3 is expressed both in the central nervous system and the periphery including the gastrointestinal tract. Two different forms of G protein coupled receptors, CRF1 and CRF2, differentially recognize CRF family members, mediating various biological functions. A large body of evidence suggests that the CRF family plays an important role in regulating inflammation and angiogenesis. Of particular interest is a contrasting role of the CRF family during inflammatory processes. The CRF family can exert both proand anti-inflammatory functions depending on the type of receptors, the tissues, and the disease phases. In addition, there has been a growing interest in a possible role of the CRF family in angiogenesis. Regulation of angiogenesis by the CRF family has been shown to modulate endogenous blood vessel formation, inflammatory neovascularization and cardiovascular function. This review outlines the effect of the CRF family and its receptors on 2 major biological events: inflammation and angiogenesis, and provides a possibility of their application for the treatment of inflammatory vascular diseases. PMID- 25540946 TI - Leu72Met408 Polymorphism of the Ghrelin Gene Is Associated With Early Phase of Gastric Emptying in the Patients With Functional Dyspepsia in Japan. AB - BACKGROUND/AIMS: There are no available data about the relationship between ghrelin gene genotypes and early phase of gastric emptying in functional dyspepsia (FD) as defined by Rome III classification. METHODS: We enrolled 74 patients presenting with typical symptoms of FD and 64 healthy volunteers. Gastric motility was evaluated using the 13C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and self-rating questionnaires for depression (SRQ-D) scores to determine status of depression. The Arg51Gln (346G->A), preproghrelin (3056T->C), Leu72Met (408C->A), Gln90Leu (3412T->A) and G-protein ?3 (825C->T) polymorphisms were analyzed in the DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. RESULTS: There was a significant relationship between the Gln90Leu3412 genotype and SRQ-D score in FD patients (P = 0.009). Area under the curve at 15 minutes (AUC15) value was significantly associated with the Leu72Met408 genotype (P = 0.015) but not with entire gastric emptying. CONCLUSIONS: The Leu72Met (408C->A) single nucleotide polymorphism was significantly associated with early phase of gastric emptying in FD patients. Further studies will be necessary to clarify the association between ghrelin gene single nucleotide polymorphisms and early phase of gastric emptying in FD patients. PMID- 25540947 TI - Brain-based Correlations Between Psychological Factors and Functional Dyspepsia. AB - BACKGROUND/AIMS: Increasing evidence shows involvement of psychological disorders in functional dyspepsia (FD), but how psychological factors exert their influences upon FD remains largely unclear. The purpose of the present study was to explore the brain-based correlations of psychological factors and FD. METHODS: Based on Fluorine-18-deoxyglucose positron emission tomography-computed tomography, the altered cerebral glycometabolism was investigated in 40 FD patients compared with 20 healthy controls during resting state using statistical parametric mapping software. RESULTS: FD patients exhibited increased glucose metabolism in multiple regions relative to controls (P< 0.001, family-wise error corrected). After controlling for the dyspeptic symptoms, increased aberrations persisted within the insula, anterior cingulate cortex (ACC), middle cingulate cortex (MCC) and middle frontal cortex (midFC), which was related to anxiety and depression score. Interestingly, FD patients without anxiety/depression symptoms also showed increased glycometabolism within the insula, ACC, MCC and midFC. Moreover, FD patients with anxiety/depression symptoms exhibited more significant hypermetabolism within the above 4 sites compared with patients without anxiety/depression symptoms. CONCLUSIONS: Our results suggested that the altered cerebral glycometabolism may be in a vicious cycle of psychological vulnerabilities and increased gastrointestinal symptoms. PMID- 25540948 TI - A brief photo-biography of crack users from Rio de Janeiro's metropolitan area: their settings and tools. AB - This brief report presents and comments pictures taken during fieldwork carried out in drug scenes, located in the metropolitan area of Rio de Janeiro, Brazil, as part of the National Crack Cocaine Survey, 2011-2013. The pictures depict contrasting settings where the ethnographic and epidemiologic components took place, as well as tools and devices used for smoking crack cocaine. As can be easily visualized, settings and tools tend to be quite variable, frequently beyond/in opposition to stereotypes. PMID- 25540949 TI - Seeing is believing, looks are deceiving: what does one see in images of drugs and drug use(rs)? AB - Images of drugs and drug use(rs) convey meaning, feelings, and beliefs, and what is being seen is often believed. Images can also deceive in content, meaning, and belief. Drug use(r) researchers, who use images as data, must be cautious in interpreting what is being conveyed and why. As technological advances continue to shape the creation, modification, storage, and analysis of images, researchers must be ever more vigilant about what they are seeing and believing. PMID- 25540950 TI - AIDS, people who use drugs, and altruism: reflection on a personal image. PMID- 25540952 TI - Integration of HIV infant testing into immunization programmes: a systematic review. AB - Background: Integration of HIV infant testing into immunization sessions is one of the strategies designed to increase coverage of early infant diagnosis. Objective: To determine the evidence on the outcomes of such integration. Methods: A systematic review of peer-reviewed and grey literature was undertaken from electronic sources such as MEDLINE, Google Scholar, websites of international agencies, past conferences and ministries of health reports published between year 2002 and 2013. Randomized controlled trials, observational and qualitative studies were searched and those meeting selection criteria were selected and relevant information extracted using structured tool. Statistical pooling was not possible owing to the heterogeneity of the study designs and outcome measures. Results: Of the nine articles which met the selection criteria, none used a randomized controlled design. Of these, five articles measured mother's acceptability of their infants being tested for HIV during its first pentavalent or DPT vaccination visit, and 89.5-100% accepted. Four articles reported the proportion of mothers who returned for HIV test results, ranging from 56.8% to 86.0%. Increased uptake of HIV testing following integration was confirmed by two articles. Only one study in Tanzania determined the uptake of vaccinations following integration, with urban facilities showing stable or slight increase of monthly vaccine uptake while decreases were observed across the rural sites. In two articles, stigma was perceived by service-providers and mothers as the potential risk following integration, particularly in rural settings. Discussion: Despite the limited number of articles, the findings in this systematic review suggest that HIV testing during immunization clinic visits is acceptable and feasible as a possible model for service delivery. However, the impact on vaccination uptake needs further study. PMID- 25540951 TI - Charting a path toward combination therapy for Alzheimer's disease. AB - It is acknowledged that progress in combined therapeutic approaches for Alzheimer's disease (AD) will require an unprecedented level of collaboration. At a meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition and the Critical Path Institute, investigators from industry, academia and regulatory agencies agreed on the need for combinatorial approaches to treating AD. The need for advancing multiple targets includes recognition for novel adaptive trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination. A combination trial now being planned may test drugs targeting different pathogenic pathways or multiple targets along a common pathway. Collaborations and consortia-based strategies are pivotal for success and a regulatory framework is recommended for success. PMID- 25540953 TI - The diagnostic value of routine antenatal ultrasound in screening for congenital uropathies. AB - BACKGROUND: Antenatal hydronephrosis (ANH) is characteristic for congenital obstructive abnormalities of the urinary tract (COAUT). COAUT is the most common cause of urinary tract infections (UTI's) in newborns. The prognosis of mild to moderate ANH is unclear. The aim of this study was to determine the diagnostic value of antenatal ultrasound screening for ANH in order to inform patients correctly. METHODS: A retrospective cohort study over the period 2009-2011, evaluating all structural ultrasounds and proven cases of ANH. Also, evaluation of all patients diagnosed with UTIs caused by COAUT in the same period. RESULTS: About 7003 children underwent antenatal screening. Of them, 0.7% (n = 47) were diagnosed with ANH. In the same period, 257 children without ANH had a proven UTI. Of them, 4.3% (n = 11) were diagnosed with COAUT, which was not found during antenatal screening. The predictive value of the antenatal ultrasound was higher in the third trimester than the second trimester (sensitivity 0.97 versus 0.62, respectively). CONCLUSION: Antenatal ultrasound screening is a reliable method in diagnosing ANH. Third trimester scanning is more specific for diagnosing ANH than second trimester scanning. Our findings allow collaborating gynecologists and pediatricians to inform patients more accurately in the future after the antenatal detection of COAUT. PMID- 25540954 TI - Assessment of indications for percutaneous endoscopic gastrostomy--development of a predictive model. AB - OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is used for long-term enteral nutrition in neurological patients with dysphagia (NEUR), in head and neck cancer patients prior to chemoradiation therapy (head and neck malignancy group [HNM]), or in cases of oropharyngeal or esophageal tumor obstruction or stricture (OBSTR). Considerable morbidity and overall mortality is reported. Aim was to analyze the complication rates and mortality with PEG and to identify subgroups with poor outcomes. MATERIAL AND METHODS: Patients underwent PEG (n = 401) in a single tertiary care center. Indications, characteristics, and causes of death were recorded. RESULTS: Number of patients in groups: HNM 135 (34%), OBSTR 74 (18%), and NEUR 192 (48%); follow-up time median (interquartile range): 17 (39) months; the time PEG used for feeding: 4 (7) months. A total of 91 patients (23%) had 110 complications, 31 patients (8%) had early (<=30 days) complications, and 49 patients (12%) major complications. Two deaths (0.5%, 2 peritonitis) were related to PEG. The 30-day mortality was 11% (n = 47). According to multivariate analysis, an increased 30-day mortality was associated with >=75 years of age, American Society of Anesthesiologists (ASA) class IV, a Charlson comorbidity index (CCI) >=4, body mass index (BMI) <18.5, and ongoing antibiotic therapy. With this model, 95% specificity was obtained in the 30-day survival figures. CONCLUSION: The presented predictive model derived from our analysis may recognize patients with poor outcome when referred for PEG. The parameters in the present model (age, ASA class, CCI score, BMI, and data of ongoing antibiotic treatment) are easily measurable, and it is possible to integrate them into everyday work. PMID- 25540955 TI - Culex gelidus: an emerging mosquito vector with potential to transmit multiple virus infections. AB - Culex gelidus Theobald has emerged as a major vector of Japanese encephalitis virus (JEV) in India, Southeast Asian countries and Australia. The species has expanded its geographic distribution from the Indian subcontinent to Japan, China, other Southeast Asian countries, Island nations in Australasian region and Australia. In recent years, a sudden increase in its population especially in the urban and sub-urban areas has been observed in several countries, thus, becoming a dominant mosquito species. The virus has been repeatedly isolated from from different geographical locations making it one of the most important vectors of JEV. Apart from JEV, other viruses of public health importance, viz. Getah, Ross River (RRV), Sindbis and Tembusu have been isolated from the mosquito. Experimental studies have shown that the mosquito Cx. qelidus is highly competent to transmit West Nile, Kunjin and Murray valley encephalitis viruses with infection and transmission rates of >80 and >50%, respectively for each virus. The species is also found competent to transmit RRV, but at a lower rate. Experimental studies have shown that the species is susceptible to chikungunya, Chandipura and Chittoor (Batai) viruses. Development of resistance to DDT and malathion has also been detected in the species recently. The invasive nature, ability to breed both in fresh and dirty waters, development of resistance to insecticides, high anthropophily and its potential to transmit important human viruses pose an increased threat of viral encephalitis in India and Oriental region especially in the light of explosive increase in its population. PMID- 25540956 TI - Problem of ticks and tick-borne diseases in India with special emphasis on progress in tick control research: a review. AB - Ticks, as vectors of several zoonotic diseases, are ranked second only to mosquitoes as vectors. The diseases spread by ticks are a major constraint to animal productivity while causing morbidity and mortality in both animals and humans. A number of tick species have been recognised since long as vectors of lethal pathogens, viz. Crimean-Congo haemorrhagic fever virus (CCHFV), Kyasanur forest disease virus (KFDV), Babesia spp, Theileria, Rickettsia conorii, Anaplasma marginale, etc. and the damages caused by them are well-recognised. There is a need to reassess the renewed threat posed by the tick vectors and to prioritize the tick control research programme. This review is focused on the major tick-borne human and animal diseases in India and the progress in vector control research with emphasis on acaricide resistance, tick vaccine and the development of potential phytoacaricides as an integral part of integrated tick control programme. PMID- 25540957 TI - Spatial epidemiology of American cutaneous leishmaniasis in a municipality of west Sao Paulo State, Brazil. AB - BACKGROUND & OBJECTIVES: In the last decade, in the state of Sao Paulo, 5898 cases of cutaneous leishmaniasis (CL) were reported. This study was undertaken to analyze the epidemiology of CL in the municipality of Teodoro Sampaio, in Sao Paulo State, Brazil, based on a geographic approach, as very little is known of the relationship between CL and the spatial transformation process. METHODS: This is a population-based quantitative, descriptive and cross-sectional case study. Surveys of the official notifications in the healthcare center and official sources from 1998 to 2011 were analysed. The data were described based on statistics and the Kernel method to detect hotspots of transmission. RESULTS: The age group between 21 and 40 yr was most affected, with 24 cases (57.9%). Of the 41 cases reported between 1998 and 2011, 33 cases were having low education status and 31 cases (75.6%) were males. The spatial and temporal distribution was aggregated in three-year periods which permitted the identification of two microfoci, in periods I (1998-2000) and III (2005-2007). INTERPRETATION & CONCLUSION: The disease has presented, in recent years, a pattern of sporadic transmission or microfoci, and continues to maintain enzootic cycles of Leishmania in a sylvatic environment, ensuring the perpetuation of the pathogen in nature, and the risk of emergence of new cases of CL in domestic animals and humans. PMID- 25540958 TI - Identification of risk factors for malaria control by focused interventions in Ranchi district, Jharkhand, India. AB - BACKGROUND & OBJECTIVES: Ranchi, the capital of Jharkhand state is endemic for malaria, particularly the Bundu Primary Health Centre (PHC) is the worst affected. Therefore, a study was initiated during 2009 using remote sensing (RS) and geographical information system (GIS) to identify risk factors responsible for high endemicity in this PHC. METHODS: Bundu and Angara in Ranchi district were identified as high and low malaria endemic PHCs based on epidemiological data of three years (2007-09). The habitation, streams, other water body, landform, PHC and village boundary thematic maps were prepared using IRS-P6/LISS III-IV imageries and macro level breeding sites were identified. Digital elevation model (DEM) of the PHCs was generated using Cartosat Stereo Pair images and from DEM, slope map was derived to calculate flat area. From slope, aspect map was derived to indicate direction of water flow. Length of perennial streams, area under rocky terrain and buffer zones of 250, 500 and 750 m were constructed around streams. High resolution remote sensing imageries were used to identify micro level breeding sites. Based on macro-micro breeding sites, six villages from each PHC were selected randomly having combination of different parameters representing all ecotypes. Entomological data were collected during 2010-11 in pre- and post-monsoon seasons following standard techniques and analyzed statistically. Differential analysis was attempted to comprehend socioeconomic and other determinants associated with malaria transmission. RESULTS: The study identified eight risk factors responsible for higher malaria endemicity in Bundu in comparison to Angara PHC based on ecological, entomological, socioeconomic and other local parameters. CONCLUSION: Focused interventions in integrated vector management (IVM) mode are required to be carried out in the district for better management and control of disease. PMID- 25540959 TI - Detection of point mutation in Plasmodium falciparum ATPase6 gene associated with artemisinin resistance from Assam and Arunachal Pradesh. AB - BACKGROUND & OBJECTIVES: Resistance against partner drugs of artemisinin has been reported from different parts of India. The study aims to find out the single nucleotide polymorphisms in Plasmodium falciparum ATPase6 gene associated with artemisinin resistance. METHODS: Blood samples were collected from 141 patients with P. falciparum monoinfection in malaria endemic zones of Assam and Arunachal Pradesh. A 645 bp portion of PfATPase6 gene was amplified and sequenced to determine the frequency of mutations associated with resistance to artemisinin. RESULTS: Mutations at codon S769N, which have been proposed to confer artemisinin resistance, were not detected in our study samples. Instead of that a novel non synonymous mutation (C-T) at 1847 bp position resulting in serine to phenylalanine alteration at codon S616F was detected from the P. falciparum field isolates in Changlang district of Arunachal Pradesh, whereas no mutation was detected in any of the analyzed samples in Assam indicating that wild type PfATPase6 genotype was found circulating in this region. Overall, based on the mutational pattern, two haplotypes of PfATPase6 gene were observed during the study, the wild type and mutant S616F allele. The overall haplotype diversity (Hd) was found to be: 0.069 and nucleotide diversity (per site Pi): 0.00012. Highest haplotype diversity was recorded in Changlang district of Arunachal Pradesh having Hd value of 0.33333 along with single polymorphic site and nucleotide diversity (Pi): 0.00060. A pair-wise fixation index (FST) value of 0.16667 indicates great genetic differentiation within the parasite population of Changlang district with the population of Karbi Anglong, Chirang, Tinsukia, Sivasagar, Jorhat, NC Hills, Lakhimpur, Golaghat and Dibrugarh districts of Assam and Lohit district of Arunachal Pradesh. INTERPRETATION & CONCLUSION: A better understanding of the distribution of antimalarial drug resistance with malaria parasite may provide insight into some of the epidemiological determinants of the increasing case burden. PMID- 25540960 TI - Artemisia vulgaris L. ethanolic leaf extract reverses thrombocytopenia/thrombocytosis and averts end-stage disease of experimental severe Plasmodium berghei murine malaria. AB - BACKGROUND & OBJECTIVES: Artemisinin isolated from Artemisia annua is the most potent antimalarial against chloroquine resistant Plasmodium falciparum malaria. We previously reported that the ethanolic leaf extract of Artemisia vulgaris, an invasive weed and the only Artemisia species in Sri Lanka, possess both potent and safe antimalarial activity (in terms of antiparasitic properties) in a P. berghei murine malaria model. We report here a prototype study that investigated antidisease activities of A. vulgaris ethanolic leaf extract (AVELE) in a P. berghei ANKA murine malaria model that elicit pathogenesis similar to falciparum malaria. Profound thrombocytosis and thrombocytopenia in mice were detected in early-stage (Day 3), and at a later stage of infection (Day 6), respectively. Plasmodium berghei infected mice, 7 or 8 days post-infection reached end-stage disease with rapid drop in body temperature and usually die within 24 h, as a consequence of cerebral malaria. METHODS: Three doses of the AVELE (500, 750 and 1000 mg/kg) were used to assess antidisease activity of A. vulgaris in terms of survival, effects on thrombocyte related pathology and end-stage disease, antipyretic activity, and antinociception, using standard methodology. RESULTS: The 1000 mg/kg dose of AVELE significantly increased survival, reversed the profound thrombocytopenia/ thrombocytosis (p <=0.01), altered the end-stage disease (p <=0.05), and manifested significant antipyretic and antinociceptive (p <=0.05) activities. INTERPRETATION & CONCLUSION: We conclude that a crude ethanolic leaf extract of A. vulgaris, showed potent antimalarial properties, in terms of antidisease activities; antipyretic activity, peripheral and central antinociception, increased survival, averted end-stage disease and reversed thrombocytopenia/thrombocytosis. PMID- 25540961 TI - Evaluation of antileishmanial activity and cytotoxicity of the extracts of Berberis vulgaris and Nigella sativa against Leishmania tropica. AB - BACKGROUND & OBJECTIVES: Leishmaniasis is a major public health problem, and the alarming spread of parasite resistance underlines the importance of discovering new therapeutic products. The present study aims to investigate the in vitro antileishmanial activity and cytotoxicity of the ethanolic extract of Berberis vulgaris fruits and chloroform extract of Nigella sativa seeds against Leishmania tropica. METHODS: In this study, antileishmanial activity of B. vulgaris and N. sativa extracts on promastigote and amastigote stages of L. tropica in comparison to meglumine antimoniate (MA) was evaluated, using MTT assay and macrophage model, respectively. MTT test was also used to assess the cytotoxicity of extracts on murine macrophages. The significance of differences was determined by analysis of variances (ANOVA) and student's t-test using SPSS software. RESULTS: The results showed that ethanolic extract of B. vulgaris (IC50 4.83 MUg/ml) and chloroform extract of N. sativa (IC50 7.83 MUg/ml) significantly reduced the viability of promastigotes of L. tropica in comparison to MA (IC50 11.26 MUg/ml). Furthermore, extracts of B. vulgaris (IC50 24.03 MUg/ml) and N. sativa (IC50 30.21 MUg/ml) significantly decreased the growth rate of amastigotes in each macrophage as compared with positive control (p <0.05). Our findings also revealed that extracts of B. vulgaris and N. sativa had no significant cytotoxicity against murine macrophages. CONCLUSION: The B. vulgaris and N. sativa extracts exhibited an effective leishmanicidal activity against L. tropica on in vitro model. Further, works are required to evaluate the exact effect of these extracts on Leishmania species using a clinical setting. PMID- 25540962 TI - Larvicidal activity of the leaf extracts of Spondias mombin Linn. (Anacardiaceae) from various solvents against malarial, dengue and filarial vector mosquitoes (Diptera: Culicidae). AB - BACKGROUND & OBJECTIVES: Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus are vector mosquitoes of dengue, malaria, and filariasis, respectively. Since no vaccine is available to treat these diseases, the control of the main mosquito vectors is essential. As conventional insecticides have limited success, plants may be alternative larvicidal agents, since they contain a rich source of bioactive chemicals. The aim of this study was to evaluate the larvicidal activity of methanol crude extract, hexane, dichloromethane, acetone, ethyl acetate and methanol fractions of Spondias mombin leaf against IV instar larvae of dengue, malaria, and lymphatic filariasis vector mosquitoes. METHODS: A total of 25, IV instar larvae of each target mosquito species were exposed to various concentrations (125-1000 ppm) and were assayed in the laboratory by using the protocol of WHO 2005; the LC50 values were determined by Probit analysis. RESULTS: Hexane, dichloromethane and acetone fractions were the most effective against Ae. aegypti with LC50 values of 22.54, 42.13, 45.18 ppm, respectively. Hexane fraction registered the highest activity with LC50 of 92.20 ppm against An. gambiae. It was still hexane fraction that showed better toxicity with LC50 of 326.53 ppm against Cx. quinquefasciatus. CONCLUSION: The Spondias mombin leaf extracts proved to be a strong candidate for a natural, safe and stable mosquito larvicide to be used in population control of Ae. aegypti, An. gambiae and Cx. quinquefasciatus and so may replace the conventional Diclorvos to control malaria, dengue and filariasis in Nigeria. PMID- 25540963 TI - Field evaluation of phostoxin and zinc phosphide for the control of zoonotic cutaneous leishmaniasis in a hyperendemic area, central Iran. AB - BACKGROUND & OBJECTIVES: ZCL is a growing threat in many rural areas of Iran which involves 17 out of 31 provinces. This study was conducted from April to November 2011 for evaluation of the efficacy of phostoxin and zinc phosphide against rodents. METHODS: Rodent control operations were carried out using phostoxin and zinc phosphide. To evaluate the effect of rodent control operation on the main vector density, an entomological survey was carried out. The effects of the operation on the disease incidence were also evaluated. RESULTS: After intervention, the reduction rate of rodent burrows was 32.68% in the village treated with phostoxin and 58.14% in the village treated with zinc phosphide. The number of rodent holes in the control area showed 6.66-fold increase at the end of the study. The incidence of the disease decreased to 19.23 and 11.40 in areas treated with phostoxin and zinc phosphide, respectively. A total of 4243 adult sandflies were collected and identified. The most common and dominant species was Phlebotomus papatasi. In the village treated with phostoxin, the density of P. papatasi in outdoors was lower than indoors. Nevertheless, the density of P. papatasi in the village treated with zinc phosphide was higher in outdoors. INTERPRETATION & CONCLUSION: It is concluded that phostoxin is less effective and has low safety in comparison with zinc phosphide, so that this rodenticide can be used only in special situations such as lack or ineffective rodenticides and only in the colonies far from human and animal dwelling places in small scales. PMID- 25540964 TI - Dengue vectors prevalence and the related risk factors involved in the transmission of dengue in Thiruvananthapuram district, Kerala, South India. AB - BACKGROUND & OBJECTIVES: A longitudinal, entomological and virological study was conducted from 2007 to 2010 in four dengue fever affected areas of Thiruvananthapuram district, Kerala to understand the risk factors involved in the dengue transmission. METHODS: Aedes surveys were carried out seasonally in the selected localities both indoors and peridomestic sites. Water holding containers were sampled for the presence of immature. Outdoor and indoor resting/landing mosquitoes were collected. Blood meal identification was performed by gel diffusion test and viral assay using the ELISA test. RESULTS: The species found were Aedes (Stegomyia) aegypti (Linn.), Ae. (Stegomyia) albopictus (Skuse) and Ae. (Stegomyia) vittatus (Bigot). Aedes aegypti and Ae. albopictus immature stages were also found during the study period. Aedes aegypti was the only prevalent species in the water-starved Vizhinjam, a rural coastal area with breteau index (BI) ranging from 40 to 271. Aedes albopictus was recorded in rest of the three surveyed localities-two urban and one rural ghat areas of Thiruvananthapuram district. INTERPRETATION & CONCLUSION: The vector control measures should be focused mainly on source reduction of water storage containers present in both outdoor (Ae. albopictus and Ae. vittatus) and indoor (Ae. aegypti). To achieve effective vector management, a public health response beyond routine larviciding or focal spraying is essential throughout the year. PMID- 25540965 TI - Use of different coloured ovitraps in the surveillance of Aedes mosquitoes in an arid-urban area of western Rajasthan, India. AB - BACKGROUND & OBJECTIVES: In the absence of any commercially available dengue vaccine or antiviral therapy, controlling the primary mosquito vector, Aedes aegypti, is currently the only means to prevent dengue outbreaks. Ovitraps are being employed as a sensitive method for detecting the presence of Ae. aegypti. Size, colour, material, paddle and use of oviposition attractant have been reported as important factors influencing the efficacy of ovitraps. METHODS: For the study of coloured ovitraps baited with grass infusion, 24 households were randomly selected in a locality and five ovitraps/premises were installed. Weekly ovitrap surveys were conducted during the study for four times. Ovitrap data were analyzed on the basis of its location, day-wise percent positivity, presence of eggs laid and inference of different ovitrap parameters were drawn. RESULTS: Grass infusion, used in the ovitraps has highest attractiveness on Day 6 in comparison to other days. Percent positivity of different coloured ovitraps revealed that red coloured ovitraps have highest positivity (92.7%), followed by black and orange (91.7% each), green (76.3%) and transparent (45.8%). The individual colour-wise ovitrap positivity revealed that the highest ovitrap positivity on Day 1 was recorded for black colour (21.8%), which on D2 and D3, in case of red colour (37.5 and 26%). However, on D4, D5 and D6 highest number of positive ovitraps was recorded in orange coloured (12.5, 21.9 and 31.3%, respectively) and on D7 highest number of positive ovitraps were recorded in transparent (21.9%), followed by green coloured ovitrap (20.8%). The overall location-wise ovitraps positivity revealed that highest positivity was recorded among the ovitraps installed inside bathrooms (92.0%), followed by bedrooms (85.0%), lobby (66.7%) and stores (48.3%). INTERPRETATION & CONCLUSION: The study revealed that for immediate detection of the presence of gravid females in a particular locality during epidemics, the black coloured ovitraps may be useful, however, in normal situations for surveillance of the vector species, the orange coloured ovitraps might be more suitable. Bathrooms were found to be the highest positive location for pitching ovitraps. PMID- 25540966 TI - Eco-virological survey of Aedes mosquito larvae in selected dengue outbreak areas in Malaysia. AB - BACKGROUND & OBJECTIVESI: Transovarial transmission of dengue virus in the Aedes vectors is now a well-documented phenomenon reported from many parts of the endemic areas in the world, which played an important role in initiating and maintaining the outbreak in human populations. This study investigated the factors affecting breeding habitats and the relationship with transovarial dengue virus in larvae of Aedes aegypti and Ae. albopictus. METHODS: Larval surveillance was conducted in dengue outbreak areas in Malaysia from 2008 until 2009. Sampling was carried out based on habitat type, water condition (substrate type), canopy coverage, temperature and pH at breeding habitats. RT-PCR was performed to detect presence of transovarial dengue virus in larvae collected in the study areas. RESULTS: A total of 789 breeding habitats were identified during this study and the majority of these breeding sites were plastic containers (57.46%). Aedes albopictus dominated most of the water condition surveyed, while Ae. aegypti indicated preference toward habitats with clear water. Aedes aegypti was selective in selecting ovipositional sites compared to Ae. albopictus where shaded areas were shown to be the most preferred. From a total of 363 mosquito larvae pools, 23 (6.3%) pools were positive for dengue virus where 18 of them were from Ae. albopictus and five were from Ae. aegypti mosquito larvae pools. INTERPRETATION & CONCLUSION: This study indicated the presence of transovarial transmission of dengue virus in immature Ae. aegypti and Ae. albopictus in the field. This study also showed that combination of water conditions, canopy coverage, temperature and pH of breeding habitats were the factors affecting the larval population. The study suggested that larval survey programme could serve as a tool not only to monitor the local dengue vector distribution but also to provide objective information for taking appropriate action by the community against dengue vectors. PMID- 25540967 TI - Replication potential and different modes of transmission of West Nile virus in an Indian strain of Culex gelidus Theobald (Diptera: Culicidae) mosquitoes. AB - BACKGROUND & OBJECTIVES: Culex gelidus mosquito, an important vector of Japanese encephalitis virus, has shown to transmit West Nile virus (WNV), Kunjin and Murray Valley encephalitis viruses experimentally. An attempt was, therefore, made to study the replication kinetics and vector competence of an Indian strain of Cx. gelidus to WNV. METHODS: Mosquitoes were infected by both intrathoracic inoculation and oral feeding and studied the growth kinetics by determining the virus titre on different days post-infection (PI). Vector competence was studied by determining the presence of WNV in saliva on subsequent days PI. Horizontal transmission was determined by demonstrating infection in infant mice by bite of mosquitoes that were fed on viraemic mice previously. Vertical transmission was studied by screening progeny derived from infected mosquitoes. Trans-stadial transmission was determined by screening adult mosquitoes emerged from parenterally inoculated IV instar larvae. RESULTS: The mosquito replicated WNV to 7log10 TCID50/ml on Day 8 PI and maintained the titre for 14 days. Virus dissemination to legs and salivary glands could be detected, but not to ovaries up to Day 10 PI. The mosquitoes picked up infection from viraemic blood and transmitted successfully to infant mice on subsequent feeding. Trans-stadial transmission also could be demonstrated. However, vertical transmission could not be demonstrated. INTERPRETATION & CONCLUSION: The replication potential, maintenance of WNV for prolonged periods and ability to transmit WNV experimentally makes the mosquito a serious threat to public health especially in the wake of active WNV activity in certain parts of India. PMID- 25540968 TI - Study of clinical profile of acute respiratory distress syndrome and acute lung injury in Plasmodium vivax malaria. PMID- 25540969 TI - Treatment outcome of inpatient malaria cases: a study in a tertiary care hospital of Odisha, India. PMID- 25540970 TI - Usefulness of Sd30 in the diagnosis of arthritis of filarial origin. PMID- 25540971 TI - Asymptomatic malaria in apparently healthy schoolchildren. PMID- 25540972 TI - A Dyadic Action Control Trial in Overweight and Obese Couples (DYACTIC). AB - BACKGROUND: Enhancing physical activity in overweight and obese individuals is an important means to promote health in this target population. The Health Action Process Approach (HAPA), which was the theoretical framework of this study, focuses on individual self-regulation variables for successful health behavior change. One key self-regulation variable of this model is action control with its three subfacets awareness of intentions, self-monitoring and regulatory effort. The social context of individuals, however, is usually neglected in common health behavior change theories. In order to integrate social influences into the HAPA, this randomized controlled trial investigated the effectiveness of a dyadic conceptualization of action control for promoting physical activity. METHODS/DESIGN: This protocol describes the design of a single-blind randomized controlled trial, which comprises four experimental groups: a dyadic action control group, an individual action control group and two control groups. Participants of this study are overweight or obese, heterosexual adult couples who intend to increase their physical activity. Blocking as means of a gender balanced randomization is used to allocate couples to conditions and partners to either being the target person of the intervention or to the partner condition. The ecological momentary intervention takes place in the first 14 days after baseline assessment and is followed by another 14 days diary phase without intervention. Follow-ups are one month and six months later. Subsequent to the six-months follow-up another 14 days diary phase takes place.The main outcome measures are self-reported and accelerometer-assessed physical activity. Secondary outcome measures are Body Mass Index (BMI), aerobic fitness and habitual physical activity. DISCUSSION: This is the first study examining a dyadic action control intervention in comparison to an individual action control condition and two control groups applying a single-blind randomized control trial. Challenges with running couples studies as well as advantages and disadvantages of certain design-related decisions are discussed. This RCT was funded by the Swiss National Science Foundation (PP00P1_133632/1) and was registered on 27/04/2012 at http://www.isrctn.com/ISRCTN15705531. PMID- 25540973 TI - Characterization of lean patients with nonalcoholic fatty liver disease: potential role of high hemoglobin levels. AB - OBJECTIVE: Overweight and obesity are major risk factors for the development of nonalcoholic fatty liver disease (NAFLD). However, a minority of NAFLD patients have a body mass index (BMI) <25 kg/m(2) (lean NAFLD). We sought to investigate whether significant differences exist between lean NAFLD and more common forms of NAFLD associated with overweight/obesity. PATIENTS AND METHODS: A total of 483 consecutive patients with biopsy-proven NAFLD were enrolled. Lean NAFLD was defined as having a BMI <25 kg/m(2). We identified 37 patients with lean NAFLD (7.6%). RESULTS: Compared with NAFLD patients with overweight/obesity, lean NAFLD patients were younger, had lower blood pressure values, higher levels of hemoglobin, a lower prevalence of the metabolic syndrome, and less severe hepatic fibrosis. In NAFLD patients with overweight/obesity, diabetes was the only independent predictor of nonalcoholic steatohepatitis (NASH). In lean NAFLD, the only variable independently associated with NASH was hemoglobin. Alanine aminotransferase and diabetes were independent predictors of fibrosis >=2 in NAFLD patients with overweight/obesity, whereas hemoglobin was the only independent predictor of fibrosis >=2 in lean NAFLD. CONCLUSION: In summary, lean NAFLD patients are younger and show less severe hepatic fibrosis. However, such subjects have higher hemoglobin levels, which seem to predict the histological severity. PMID- 25540974 TI - Implications of enterotoxigenic Escherichia coli genomics for vaccine development. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity and mortality caused by diarrhea in children less than 5 years of age in low- and middle-income countries. Despite a wealth of research elucidating the mechanisms of disease, the immunological responses and vaccine development, ETEC is still relatively uncharacterized when it comes to regulation of virulence and detailed immune mechanisms. The recent emergence of next-generation sequencing now offers the possibility to screen genomes of ETEC strains isolated globally to identify novel vaccine targets in addition to those already established. In this review, we discuss how recent findings on ETEC genomics using novel sequencing techniques will aid in finding novel protective antigens that can be used in vaccine approaches. PMID- 25540975 TI - Extremes of weight gain and weight loss with detailed assessments of energy balance: Illustrative case studies and clinical recommendations. AB - Extreme weight changes, or changes in weight greater than 10 kg within a 2-year period, can be caused by numerous factors that are much different than typical weight fluctuations. This paper uses two interesting cases of extreme weight change (a female who experienced extreme weight gain and a male who experienced extreme weight loss) from participants in the Energy Balance Study to illustrate the physiological and psychosocial variables associated with the weight change over a 15-month period, including rigorous assessments of energy intake, physical activity (PA) and energy expenditure, and body composition. In addition, we provide a brief review of the literature regarding the relationship between energy balance (EB) and weight change, as well as insight into proper weight management strategies. The case studies presented here are then placed in the context of the literature regarding EB and weight change. This report further supports previous research on the importance of regular doses of PA for weight maintenance, and that even higher volumes of PA are necessary for weight loss. Practitioners should emphasize the importance of PA to their patients and take steps to monitor their patients' involvement in PA. PMID- 25540976 TI - Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders. AB - Abnormal dopamine neurotransmission has been linked to a wide array of motor, cognitive, and psychiatric disorders. Dopamine binds and regulates intracellular signals through D1-like (D1 and D5) and D2-like (D2, D3, and D4) G-protein coupled receptors. Activation of D1- like receptors stimulates cAMP/PKA signaling via Gs mediated activation of adenylyl cyclase. In contrast, activation of D2 like receptors inhibits cAMP/PKA signaling by Gi inhibition of adenylyl cyclase. In the brain, dopamine signaling is tightly regulated by cyclic nucleotide phosphodiesterases (PDEs). PDEs are a family of enzymes that selectively degrade cAMP and cGMP. There are 11 different families of PDEs that vary in their substrate specificity, kinetic properties, mode of regulation, intracellular localization, and tissue expression patterns. A number of PDE families are highly expressed in the striatum including PDE1, PDE2, PDE4, and PDE10. There is a growing amount of evidence to suggest that these enzymes play a critical role in modulating dopamine signaling and selective inhibitors of these enzymes are currently being explored as novel therapeutics to treat schizophrenia, Huntington's disease, cognitive disorders and Parkinson's disease. The aim of this review is to summarize the distinct roles of different PDEs in regulating dopamine signaling in the striatum. In addition, we will briefly review the therapeutic potential of selective PDE inhibitors to treat neurological and psychiatric disorders associated with abnormal striatal function. PMID- 25540978 TI - Assessment of the learning environment in prosthodontic department based on Dental College Learning Environment Survey by the graduates of a dental institute in India. AB - The purpose of this study was to determine dental graduates' perceptions of learning environment in a prosthodontic department in a dental institute in India. The 60-item closed-ended, cross-sectional questionnaire with five options was completed by the dental graduates and the dentists. The data obtained was analyzed using statistical software. The mean, SD, frequency and percentages were calculated wherever appropriate. The questionnaire was answered by 242 dentists and dental graduates. Of the seven Dental College Learning Environment Survey scales, the highest mean scores were for student to student interaction (2.76 +/- 0.53) followed by meaningful learning experience (2.67 +/- 0.39). The lowest scores were for flexibility (2.26 +/- 0.51) followed by supportiveness (2.40 +/- 0.59). The lowest mean scores obtained for the 'flexibility scale' conveys that the opportunity for the faculty and students to modify the learning environment are less than for the other categories, and there is thus a need to modify the learning environment. Faculty should also increase their support to the students by contributing to an effective and meaningful interaction by creating a congenial environment. PMID- 25540977 TI - Estradiol, dopamine and motivation. AB - The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol's adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors. PMID- 25540979 TI - Linker-free deposition and adhesion of Photosystem I onto nanostructured TiO2 for biohybrid photoelectrochemical cells. AB - Photosystem I (PSI) from oxygenic photosynthetic organisms is an attractive sensitizer for nano-biohybrid solar cells as it has a combined light-harvesting and reaction center in one protein complex and operates at a quantum yield close to one in biological systems. Using a linker-free deposition technique enabled by an electrospray system, PSI was coupled to 1-D nanostructured titanium dioxide thin films to fabricate an electrode for a photoelectrochemical cell. After deposition, the surfactant in the PSI aggregate was dissolved in the surfactant free electrolyte, ensuring that partly hydrophobic PSI was not resuspended and stayed in contact with titanium dioxide. A maximum current density of 4.15 mA cm( 2) was measured after 10 min of electrospray deposition, and this is the highest current density reported so far for PSI-based photoelectrochemical cells. The high current is attributed to 1D nanostructure of titanium dioxide and orientation of the PSI onto the surface, which allows easy transfer of electrons. PMID- 25540980 TI - The role of higher protein diets in weight control and obesity-related comorbidities. AB - The importance of the relative dietary content of protein, carbohydrate and the type of carbohydrate (that is, glycemic index (GI)) for weight control under ad libitum conditions has been controversial owing to the lack of large scale studies with high diet adherence. The Diet, Obesity and Genes (DioGenes) European multicentre trial examined the importance of a slight increase in dietary protein content, reduction in carbohydrate and the importance of choosing low (LGI) vs high GI (HGI) carbohydrates for weight control in 932 obese families. Only the adults underwent a diet of 800 kcal per day for 8 weeks, and after losing ~11kg they were randomized to one of five energy ad libitum diets for 6 months. The diets differed in protein content and GI. The high-protein (HP) diet groups consumed 5.4% points more energy from protein than the normal protein (NP) groups, and the LGI diet groups achieved 5.1% lower GI than the HGI groups. The effect of HP and LGI was additive on weight loss and maintenance, and the combination was successful in preventing weight regain and reducing drop-out rate among the adults after the 11kg weight loss. This diet also reduced body fatness and prevalence of overweight and obesity among their children and had consistent beneficial effects on blood pressure, blood lipids and inflammation in both parents and children. After 1 year, mainly the HP effects were maintained. Putative genes have been identified that suggest this diet to be particularly effective in 67% of the population. In conclusion, the DioGenes diet has shown to be effective for prevention of weight regain and for weight reduction in overweight children under ad libitum conditions. The less-restrictive dietary approach fits into a normal food culture, and has been translated into popular diet and cook books in several languages. PMID- 25540981 TI - Lack of Day/Night variation in fibroblast growth factor 21 levels in young healthy men. AB - BACKGROUND: Fibroblast growth factor (FGF) 21 is an endocrine factor with an emerging role as a metabolic regulator. We previously reported the presence of a significant day/night variation of FGF-21 in energy-replete, healthy female subjects. However the day/night patterns of secretion in male subjects remain to be fully elucidated. To elucidate day/night pattern of FGF-21 levels in male subjects in the energy-replete state, its relationship to FFA and to investigate whether a sexual dimorphism exists in FGF-21 physiology. METHODS: Eight healthy lean male subjects were studied for up to 5 days while on an isocaloric diet. Blood samples were obtained for measurement of FGF-21 and free fatty acids (FFA) hourly from 0800 AM on day 4 till 0800AM on day 5. RESULTS: FGF-21 did not exhibit any statistically significant day/night variation pattern of circulating FGF-21 levels during the isocaloric fed state in male subjects. FGF-21 levels in male subjects are closely cross-correlated with FFA levels, similar to female subjects. CONCLUSIONS: A sexual dimorphism exists in FGF-21 physiology; that as opposed to female subjects, no significant day/night variation exists in FGF-21 rhythm in male subjects in the energy-replete state. Circulating pattern of FGF 21, similar to the female subjects, was highly cross-correlated to the FFA levels in the male subjects, signifying that the sexual dimorphism in FGF-21 physiology may be related to the differing lipid metabolism in both the genders. PMID- 25540983 TI - Sex hormones and brain dopamine functions. AB - Sex hormones exert differential effects on a variety of sensitive tissues like the reproductive tract, gonads, liver, bone and adipose tissue, among others. In the brain, sex hormones act as neuroactive steroids regulating the function of neuroendocrine diencephalic structures like the hypothalamus. In addition, steroids can exert physiological effects upon cortical, limbic and midbrain structures, influencing different behaviors such as memory, learning, mood and reward. In the last three decades, the role of sex hormones on monoamine neurotransmitters in extra-hypothalamic areas related to motivated behaviors, learning and locomotion has been the focus of much research. The purpose of this thematic issue is to present the state of art concerning the effects of sex hormones on the neurochemical regulation of dopaminergic midbrain areas involved in neurobiological and pathological processes, such as addiction to drugs of abuse. We also discuss evidence of how neonatal exposure to sex hormones or endocrine disrupting chemicals can produce long-term changes on the neurochemical regulation of dopaminergic neurons in the limbic and midbrain areas. PMID- 25540982 TI - Fasting for weight loss: an effective strategy or latest dieting trend? AB - With the increasing obesity epidemic comes the search for effective dietary approaches for calorie restriction and weight loss. Here I examine whether fasting is the latest 'fad diet' as portrayed in popular media and discuss whether it is a safe and effective approach or whether it is an idiosyncratic diet trend that promotes short-term weight loss, with no concern for long-term weight maintenance. Fasting has long been used under historical and experimental conditions and has recently been popularised by 'intermittent fasting' or 'modified fasting' regimes, in which a very low-calorie allowance is allowed, on alternate days (ADF) or 2 days a week (5:2 diet), where 'normal' eating is resumed on non-diet days. It is a simple concept, which makes it easy to follow with no difficult calorie counting every other day. This approach does seem to promote weight loss, but is linked to hunger, which can be a limiting factor for maintaining food restriction. The potential health benefits of fasting can be related to both the acute food restriction and chronic influence of weight loss; the long-term effect of chronic food restriction in humans is not yet clear, but may be a potentially interesting future dietary strategy for longevity, particularly given the overweight epidemic. One approach does not fit all in the quest to achieve body weight control, but this could be a dietary strategy for consideration. With the obesity epidemic comes the search for dietary strategies to (i) prevent weight gain, (ii) promote weight loss and (iii) prevent weight regain. With over half of the population of the United Kingdom and other developed countries being collectively overweight or obese, there is considerable pressure to achieve these goals, from both a public health and a clinical perspective. Certainly not one dietary approach will solve these complex problems. Although there is some long-term success with gastric surgical options for morbid obesity, there is still a requirement for dietary approaches for weight management for the overweight and obese population, particularly as invasive interventions carry post-operative risk of death due to complications. Effective dietary interventions are required that promote long-term adherence and sustained beneficial effects on metabolic and disease markers. In general, such interventions need to be palatable and satiating, meet minimal nutritional requirements, promote loss of fat and preserve lean body mass, ensure long-term safety, be simple to administer and monitor and have widespread public health utility. Intermittent fasting or alternate day fasting may be an option for achieving weight loss and maintenance. PMID- 25540984 TI - Lipid-based mRNA vaccine delivery systems. AB - Synthetic mRNAs can become biopharmaceutics allowing vaccination against cancer, bacterial and virus infections. Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Although immune responses are generated by naked mRNAs, their formulations with chemical carriers are expected to provide more specificity and internalization in dendritic cells (DCs) for better immune responses and dose reduction. This review reports lipid-based formulations (LBFs) that have proved preclinical efficacy. The selective delivery of mRNA LBFs to favor intracellular accumulation in DCs and reduction of the effective doses is discussed, notably to decorate LBFs with carbohydrates or glycomimetics allowing endocytosis in DCs. We also report how smart intracellular delivery is achieved using pH-sensitive lipids or polymers for an efficient mRNA escape from endosomes and limitations regarding cytosolic mRNA location for translation. PMID- 25540986 TI - The excess long-term mortality in peptic ulcer bleeding is explained by nonspecific comorbidity. AB - OBJECTIVE: Previous studies have concluded that peptic ulcer bleeding (PUB) is associated with increased long-term mortality. The underlying mechanism of this excess mortality is poorly understood. The aim of the present study was to examine if PUB patients have an increased long-term mortality compared to a matched control group when adjusting for comorbidity and socioeconomic status. Additionally, we identified predictive factors for mortality and examined causes of death. MATERIAL AND METHODS: We performed an observational study, comparing consecutive patients admitted with PUB with a matched control cohort from the source population. Predictors of mortality were identified using proportional hazards models. Causes of death were retrieved from death certificates. Long-term mortality was analyzed with adjustment for Charlson comorbidity index (CCI) and average income in residence municipality using proportional hazards models. RESULTS: We included 455 PUB cases and 2224 control subjects. Median follow up was 9.7 years, and median survival for the PUB and control cohorts was 7 and 12 years, respectively (p < 0.001). PUB patients had a higher level of comorbidity (mean CCI: 0.92 vs. 0.49; p < 0.0001). After adjustments, PUB patients had an excess mortality lasting at least 10 years after presentation. Age, comorbidity, male sex, anemia, and smoking were predictors for long-term mortality. The distribution of causes of death was similar in the two cohorts. CONCLUSION: PUB patients have an increased long-term mortality that is explained by nonspecific comorbidity. PMID- 25540985 TI - Rapid cytometric antibiotic susceptibility testing utilizing adaptive multidimensional statistical metrics. AB - Flow cytometry holds promise to accelerate antibiotic susceptibility determinations; however, without robust multidimensional statistical analysis, general discrimination criteria have remained elusive. In this study, a new statistical method, probability binning signature quadratic form (PB-sQF), was developed and applied to analyze flow cytometric data of bacterial responses to antibiotic exposure. Both sensitive lab strains (Escherichia coli and Pseudomonas aeruginosa) and a multidrug resistant, clinically isolated strain (E. coli) were incubated with the bacteria-targeted dye, maltohexaose-conjugated IR786, and each of many bactericidal or bacteriostatic antibiotics to identify changes induced around corresponding minimum inhibition concentrations (MIC). The antibiotic induced damages were monitored by flow cytometry after 1-h incubation through forward scatter, side scatter, and fluorescence channels. The 3-dimensional differences between the flow cytometric data of the no-antibiotic treated bacteria and the antibiotic-treated bacteria were characterized by PB-sQF into a 1-dimensional linear distance. A 99% confidence level was established by statistical bootstrapping for each antibiotic-bacteria pair. For the susceptible E. coli strain, statistically significant increments from this 99% confidence level were observed from 1/16x MIC to 1x MIC for all the antibiotics. The same increments were recorded for P. aeruginosa, which has been reported to cause difficulty in flow-based viability tests. For the multidrug resistant E. coli, significant distances from control samples were observed only when an effective antibiotic treatment was utilized. Our results suggest that a rapid and robust antimicrobial susceptibility test (AST) can be constructed by statistically characterizing the differences between sample and control flow cytometric populations, even in a label-free scheme with scattered light alone. These distances vs paired controls coupled with rigorous statistical confidence limits offer a new path toward investigating initial biological responses, screening for drugs, and shortening time to result in antimicrobial sensitivity testing. PMID- 25540988 TI - A review of adherence to the guidelines for coronary CT angiography quantitative stenosis grading thresholds in published research. AB - BACKGROUND: The degree of coronary stenosis of potential hemodynamic significance is central to the interpretation of coronary computed tomography angiography (CCTA), but has been variably defined in the literature. Societal guidelines have attempted to address this issue via recommended thresholds. OBJECTIVES: We surveyed the various thresholds for defining significant coronary stenosis reported in research published since the introduction of the Society for Cardiovascular Computed Tomography guidelines regarding the interpretation and reporting of CCTA. METHODS: We systematically reviewed the results of bibliographic searches of all original research articles on CCTA, focusing on studies reporting > 25 subjects, to assess the definitions of severity of coronary lesions as found on CCTA. To enable comparisons, we stratified the methods of reporting lesion severity into >= 50%, 50% to 69%, and "others" (including infrequent reporting methods). RESULTS: Fifty-nine11 published studies were identified and met inclusion criteria. Eighteen studies reported the severity of coronary stenosis using a definition of 50% to 69% as moderate stenosis; 35 studies defined >= 50% coronary stenosis as "stenosis," "significant stenosis," or "obstructive lesion" without distinguishing a threshold for moderate versus severe stenosis. Six studies utilized other thresholds, such as 20% to 75%, 40% to 69%, 40% to 70%, 40% to 79%, and 50% to 75% to define moderate coronary stenosis. CONCLUSIONS: Fifty-three of 59 studies were graded in accordance with the recommended threshold of >= 50% defining potentially significant stenosis, with 18 studies reporting precisely in accordance with the guidelines-recommended thresholds of >= 50% narrowing as defining moderate stenosis and >= 70% narrowing as defining severe stenosis. Six studies were reported using alternative thresholds for significant stenosis. However, a majority of research studies published since 2009 do not follow the societal guidelines for stenosis grading, since these studies do not clearly describe the degree of coronary stenosis. PMID- 25540987 TI - A core outcome set for clinical trials on non-specific low back pain: study protocol for the development of a core domain set. AB - BACKGROUND: Low back pain (LBP) is one of the most disabling and costly disorders affecting modern society, and approximately 90% of patients are labelled as having non-specific LBP (NSLBP). Several interventions for patients with NSLBP have been assessed in clinical trials, but heterogeneous reporting of outcomes in these trials has hindered comparison of results and performance of meta-analyses. Moreover, there is a risk of selective outcome reporting bias. To address these issues, the development of a core outcome set (COS) that should be measured in all clinical trials for a specific health condition has been recommended. A standardized set of outcomes for LBP was proposed in 1998, however, with evolution in COS development methodology, new instruments, interventions, and understanding of measurement properties, it is appropriate to update that proposal. This protocol describes the methods used in the initial step in developing a COS for NSLBP, namely, establishing a core domain set that should be measured in all clinical trials. METHODS/DESIGN: An International Steering Committee including researchers, clinicians, and patient representatives from four continents was formed to guide the development of this COS. The approach of initiatives like Core Outcome Measures in Effectiveness Trials (COMET) and Outcome Measures in Rheumatology (OMERACT) was followed. Participants were invited to participate in a Delphi study aimed at generating a consensus-based core domain set for NSLBP. A list of potential core domains was drafted and presented to the Delphi participants who were asked to judge which domains were core. Participant suggestions about overlap, aggregation, or addition of potential core domains were addressed during the study. The patients' responses were isolated to assess whether there was substantial disagreement with the rest of the Delphi panel. A priori thresholds for consensus were established before each Delphi round. All participants' responses were analysed from a quantitative and qualitative perspective to ascertain that no substantial discrepancies between the two approaches emerged. DISCUSSION: We present the initial step in developing a COS for NSLBP. The next step will be to determine which measurement instruments adequately cover the domains. PMID- 25540989 TI - A sensitivity analysis on the variability in accelerometer data processing for monitoring physical activity. AB - BACKGROUND: Accelerometers are gaining popularity for measuring physical activity, but there are many different ways to process accelerometer data. A sensitivity analysis was conducted to study the effect of varying accelerometer data processing protocols on estimating the association between PA level and socio-demographic characteristics using the National Health and Nutrition Examination Survey (NHANES) accelerometer data. METHODS: The NHANES waves 2003 2004 and 2005-2006 accelerometer data (n=14,072) were used to investigate the effect of changing the accelerometer non-wearing time and valid day definitions on the demographic composition of the filtered datasets and the association between physical activity (PA) and socio-demographic characteristics (sex, age, race, educational level, marital status). RESULTS: Under different filtering rules (minimum number of valid day and definition of non-wear time), the demographic characteristics of the final sample varied. The proportion of participants aged 20-29 decreased from 18.9% to 15.8% when the minimum number of valid days required increased from 1 to 4 (p for trend<0.001), whereas that for aged >=70 years increased from 18.9% to 20.6% (p for trend<0.001). Furthermore, with different filters, the effect of these demographic variables and PA varied, with some variables being significant under certain filtering rules but becoming insignificant under some other rules. CONCLUSIONS: The sensitivity analysis showed that the significance of the association between socio-demographic variables and PA could be varied with the definition of non-wearing time and minimum number of valid days. PMID- 25540990 TI - Role of frozen section analysis in nodular thyroid pathology. AB - INTRODUCTION: Frozen section (FS) analysis used to be the principal examination guiding surgical strategy. The development and recent standardization of fine needle aspiration cytology (FNAC) challenges it as a systematic attitude. The present study assessed the current contribution of FS, comparing it with FNAC as a diagnostic tool guiding surgery. MATERIAL AND METHODS: A retrospective diagnostic study analyzed 1515 thyroid samples over a 6-year period. Two hundred and fifty-two of the patients had undergone both FNAC (analyzed in our unit) and FS, revealing 69 cancers. RESULTS: The sensitivity and specificity of FS and FNAC were 75.36% and 100% versus 31.88% and 100%, respectively. In case of malignancy on FNAC (22 patients), FS did not influence indications for surgery. In case of non-malignant FNAC findings, FS diagnosed cancer in 13% of cases (30/230). In the subgroup of follicular lesions (Bethesda 3 and 4), FS modified surgical strategy in only 6.2% of cases (6/97), but diagnosed 13 of the 16 cancers (81.25%) in case of Bethesda 5 on FNAC (21 cases) and in 9 of the 13 cancers (69%) associated with non-diagnostic FNAC results (Bethesda 1: 70 cases). CONCLUSION: Although its contribution is small, FS optimizes surgery in certain cases. Systematic implementation may be economically justified, especially in follicular lesions diagnosed on FNAC, improving interpretation of a difficult and operator-dependent test, as is essential in certain FNAC results. PMID- 25540991 TI - French Otorhinolaryngology Society guidelines for day-case nasal surgery. AB - OBJECTIVES: The French Otorhinolaryngology Society (SFORL) set up a work group to draw up a consensus document on day-case surgery in four rhinologic procedures: endoscopic middle meatal antrostomy (French National Health Insurance (CCAM) code GBPE001), septoplasty (GAMA007), and reduction of nasal bone fracture using a direct approach (LAEA007) and using a closed technique (LAEP002). MATERIALS AND METHODS: Methodology followed the French Health Authority (HAS) "Methodological Bases for Drawing Up Professional Guidelines by Formalized Consensus" published in January 2006; the method chosen was the short version of the RAND/UCLA Appropriateness Method (without editorial group), as the work group topic was highly specialized, with few experts available. RESULTS: Ahead of any day-case sinonasal surgery, it is recommended that patient eligibility criteria be respected and hemorrhagic risk assessed; preference should be given to short procedures involving little variation in surgery time and minimizing blood-loss, and associated procedures (e.g., septoplasty+turbinectomy) should be avoided. The patient and family should be informed of specific hemorrhagic, orbital and/or neuromeningeal risks, onset of which may preclude discharge home. Uni- or bilateral postoperative nasal packing is not a contraindication to day-case management. CONCLUSION: All four procedures may be performed on a day-case basis. Eligibility criteria should be systematically respected, but hemorrhagic risk, which is very specific to the sinonasal organ, is to be assessed on a case-by case basis, as it is a major issue in this kind of management for a non negligible number of patients. PMID- 25540992 TI - Relation between unimanual capacities and bimanual performance in hemiplegic cerebral-palsied children: impact of synkinesis. AB - OBJECTIVE: Analyze the link between unimanual capacities and bimanual performance in cerebral-palsied (CP) hemiplegic children, aged between 5 and 18 years old, studying specifically the impact of synkinesis. MATERIAL AND METHODS: 71 CP hemiplegic children (35 boys and 36 girls - with average age of 8 years and 6 months; MACS levels from I to III; GMFCS from I to IV) took part in a transversal study, assessed - Melbourne Test (MUUL) for unimanual capacities, and Assisting Hand Assessment (AHA) for bimanual performance - with a specific scale to analyze synkinesis during Box and Block test for affected and healthy hands, collecting synkinesis type, duration and intensity. RESULTS: There is a strong correlation between unimanual capacities (MUUL) and bimanual performance (AHA) (r = 0.871). Neither age nor gender contribute to bimanual performance (AHA). Multiple linear regression shows that MUUL contributes to bimanual performance variance (AHA) by 70%. Synkinesis is partly correlated to capacities (MUUL) and accounts for 10% of the variance of the gap between capacities and bimanual performance. CONCLUSION: A high relationship between unimanual capacities and bimanual performance is confirmed by this study; some authors demonstrated impact of sensory troubles, we demonstrate that synkinesis influences the use of unimanual capacities in bimanual performance. PMID- 25540993 TI - Osseointegration of multiphase anodic spark deposition treated porous titanium implants in an ovine model. AB - Modification of titanium oxide by multiphase anodic spark deposition (ASD) has the potential to increase bioactivity and hasten osseointegration and biological fixation in uncemented arthroplasty. This study assessed the in vivo performance of control (Ti), plasma-sprayed HA-coated (TiHA) and ASD (Biospark) treated (TiAn) porous titanium implants with a solid core using a standard uncemented implant fixation sheep model. Cortical interfacial shear-strength and bone ingrowth in cortical and cancellous sites were quantified following 12 weeks in situ. Ultimate shear-strength for the Ti, TiHA and TiAn coatings was 33+/-9.5, 35.4+/-8.4 and 33.8+/-7.8 MPa, respectively, which was limited by coating delamination. ASD treatment was associated with significantly higher mean bone ingrowth at both sites. These results support the osteoconductive potential of the BioSpark treatment of porous titanium. PMID- 25540994 TI - Total joint arthroplasty in transplant recipients: in-hospital adverse outcomes. AB - This study aims to determine in-hospital complications and mortality in transplant recipients following total joint arthroplasty. The Nationwide Inpatient Sample database was queried for patients with history of transplant and joint arthroplasty (primary or revision) from 1993 to 2011. Kidney transplant increased risk of surgical site infection (SSI) and wound infections (OR=2.03), systemic infection (OR=2.85), deep venous thrombosis (OR=2.07), acute renal failure (ARF) (OR=3.48), respiratory (OR=1.34), and cardiac (OR=1.21) complications. Liver transplant was associated with SSI/wound infections (OR=2.32), respiratory complications (OR=1.68), cardiac complications (OR=1.34), and ARF (OR=4.48). Other transplants grouped together were associated with wound complications (OR=2.13), respiratory complications (OR=2.06), and ARF (OR=4.42). Our study suggests these patients may be at increased risk of in-hospital complications, particularly ARF in renal and liver transplant patients. PMID- 25540995 TI - Usefulness of ultrasonography for detection of pseudotumors after metal-on-metal total hip arthroplasty. AB - We retrospectively analyzed 83 metal-on-metal total hip arthroplasties in 74 patients. Ultrasonography and magnetic resonance imaging (MRI) of each hip were performed to detect abnormal patterns and pseudotumors. We examined the reliability of ultrasonography for detecting pseudotumors in comparison with MRI. We also compared the acetabular component inclination between patients with and without pseudotumors. The mean positive and negative predictive values for pseudotumor detection by ultrasonography were 65% and 91%, respectively. The mean positive and negative likelihood ratios were 5.78 and 0.32, respectively. There was no clear association between pseudotumor presence and acetabular component inclination. We concluded that ultrasonography is a suitable technique to screen for the presence of pseudotumors. We also need to distinguish between bearing related and taper junction corrosion-related complications. PMID- 25540996 TI - Adverse clinical outcomes in a primary modular neck/stem system. PMID- 25540997 TI - Contemporary perspectives on cognition in addictive behaviors. PMID- 25540998 TI - Enhancing classification accuracy utilizing globules and dots features in digital dermoscopy. AB - The interest in image dermoscopy has been significantly increased recently and skin lesion images are nowadays routinely acquired for a number of skin disorders. An important finding in the assessment of a skin lesion severity is the existence of dark dots and globules, which are hard to locate and count using existing image software tools. In this work we present a novel methodology for detecting/segmenting and count dark dots and globules from dermoscopy images. Segmentation is performed using a multi-resolution approach based on inverse non linear diffusion. Subsequently, a number of features are extracted from the segmented dots/globules and their diagnostic value in automatic classification of dermoscopy images of skin lesions into melanoma and non-malignant nevus is evaluated. The proposed algorithm is applied to a number of images with skin lesions with known histo-pathology. Results show that the proposed algorithm is very effective in automatically segmenting dark dots and globules. Furthermore, it was found that the features extracted from the segmented dots/globules can enhance the performance of classification algorithms that discriminate between malignant and benign skin lesions, when they are combined with other region-based descriptors. PMID- 25540999 TI - Re: Bibliometrics study on authorship trends in periodontal literature from 1995 to 2010. Geminiani A, Ercoli C, Feng C, Caton JG. (J Periodontol 2014; 85:e136 e143). PMID- 25541000 TI - Authors' response. PMID- 25541001 TI - Choanal atresia: histochemical, immunohistochemical and ultrastructure study of the nasal mucosa. AB - OBJECTIVES: To study the nasal mucosal changes in cases with choanal atresia at the light and electron microscope and to compare the results with the normal side in unilateral cases. STUDY DESIGN: Cross sectional study. SETTING: Tertiary University hospital, departments of Otolaryngology and pathology. METHODS: Sixteen patients diagnosed to have choanal atresia (seven bilateral and nine unilateral); ranging in age from 3 days to 9 years; were included in this study. During surgical repair, a biopsy of the inferior turbinate mucosa was taken. Biopsy from patent side in unilateral choanal atresia was also taken (as a control). Then biopsies were subjected to histopathological, histochemical, immunohistochemical and ultrastructure studies. RESULTS: The nasal mucosa in choanal atresia side (weather unilateral or bilateral) showed distorted cilia, marked increase of mucous submucosal glands associated with marked reduction of goblet cell density and lymphocytic cellular infiltration. The patent side (control) showed normal respiratory epithelium with obviously noted intra epithelial goblet cells. Submucosal glands were less in number and activity than in the atretic side. CONCLUSIONS: Choanal atresia showed a condition of the nasal mucous membrane with characteristic excessive nasal tenacious secretion; mostly actively secreted besides some effect of lack of drainage due to interrupted cilia. Further studies are required to evaluate the impact of atresia repair on detected features. PMID- 25541003 TI - Adaptive difference in daily timing of hatch in two locust species, Schistocerca gregaria and Locusta migratoria: the effects of thermocycles and phase polyphenism. AB - This study examined the effects of temperature and phase polyphenism on egg hatching time in the desert locust, Schistocerca gregaria, and the migratory locust, Locusta migratoria. The two species exhibited differences and similarities in hatching behavior when exposed to different temperature conditions. In 12-h thermocycles of various temperatures, the S. gregaria eggs hatched during the cryoperiod (low temperature period), whereas L. migratoria eggs hatched during the thermoperiod (high temperature period). The eggs of both species hatched during the species-specific period of the thermoperiod in response to a temperature difference as small as 1 degrees C. Furthermore, the locusts adjusted hatching time to a new thermal environment that occurred shortly before the expected hatching time. In both species, the hatching of the eggs was synchronized to a specific time of the day, and two hatching peaks separated by approximately 1 day were observed at a constant temperature after the eggs were transferred from thermocycles 3 days before hatching. Eggs laid by gregarious females hatched earlier than those laid by solitarious females in S. gregaria but this difference was not observed in L. migratoria. PMID- 25541002 TI - Combining cross-metathesis and activity-based protein profiling: new beta-lactone motifs for targeting serine hydrolases. AB - beta-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of alpha-methylene-beta lactones offers rapid access to structurally diverse, previously unexplored beta lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead beta-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the alpha methylene-beta-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes. PMID- 25541004 TI - Core RNAi machinery and gene knockdown in the emerald ash borer (Agrilus planipennis). AB - The RNA interference (RNAi) technology has been widely used in insect functional genomics research and provides an alternative approach for insect pest management. To understand whether the emerald ash borer (Agrilus planipennis), an invasive and destructive coleopteran insect pest of ash tree (Fraxinus spp.), possesses a strong RNAi machinery that is capable of degrading target mRNA as a response to exogenous double-stranded RNA (dsRNA) induction, we identified three RNAi pathway core component genes, Dicer-2, Argonaute-2 and R2D2, from the A. planipennis genome sequence. Characterization of these core components revealed that they contain conserved domains essential for the proteins to function in the RNAi pathway. Phylogenetic analyses showed that they are closely related to homologs derived from other coleopteran species. We also delivered the dsRNA fragment of AplaScrB-2, a beta-fructofuranosidase-encoding gene horizontally acquired by A. planipennis as we reported previously, into A. planipennis adults through microinjection. Quantitative real-time PCR analysis on the dsRNA-treated beetles demonstrated a significantly decreased gene expression level of AplaScrB 2 appearing on day 2 and lasting until at least day 6. This study is the first record of RNAi applied in A. planipennis. PMID- 25541005 TI - Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene modulates age effects on working memory. AB - Decline in working memory (WM) functions during aging has been associated with hippocampal dysfunction mediated by age-related changes to the corticotropin releasing hormone (CRH) system. Recent reports suggest that GG-homozygous individuals of single nucleotide polymorphisms (rs110402 and rs242924) in the CRH receptor 1 (CRHR1) gene show increased stress vulnerability and decreased BOLD responses in WM relevant regions. However, until now, no study investigated the interaction effects of variation in the CRHR1 gene and age on individual differences in WM. Here, young, middle-aged and old subjects (N = 466) were genotyped for rs110402 and rs242924 within the CRHR1 gene and an n-back task was used to investigate the hypothesis that vulnerable genotypes (GG-homozygotes) would show impaired WM functions that might be magnified by increased CRH production with advancing age. Our results show an impact of genotype already in middle-age with significantly better performance in AT-carriers. Working memory performance in AT-carriers did not differ between young and middle-aged subjects, but was significantly impaired in old age. In GG-homozygotes, severe working memory dysfunction occurred already in middle age. Our data indicate that GG homozygotes of CRHR1 rs110402 and rs242924 represent a genetically driven subtype of early WM impairments due to alterations in hippocampal CRHR1 activation. Early interventions that have proven effective in delaying cognitive decline appear to be particularly important for these subjects at risk for premature memory decline, who are in the prime of their personal and professional lives. PMID- 25541007 TI - [Shigellosis, the importance of hygiene in prevention]. PMID- 25541006 TI - Validity of procalcitonin for the diagnosis of bacterial infection in elderly patients. AB - INTRODUCTION: PCT has been consolidated as a key tool in the diagnosis of bacterial infections in general population. Few studies have been conducted to determine the applicability of this test in elderly patients. METHODS: Study of validity of PCT on elderly patients. Two groups were formed; the first group was formed by patients aged 75 years or older, under bacterial infection criteria and PCT on the initial Lab test. The second group was formed by patients aged 75 years or older with any noninfectious disease; these patients were asked PCT in the initial Lab test. Sensitivity, specificity, positive and negative likelihood ratio were calculated. RESULTS: 161 patients were included, 95 with probable bacterial infection and 66 without infection. Patients with probable bacterial infection criteria, 72% of them had PCT >0.5 ng/mL. Patients without infection, 8% of the patients had PCT >0.5 ng/mL. Sensitivity and specificity of PCT to bacterial infection with the cutoff value of 0.5 ng/mL was 72% and 92%, respectively. CONCLUSION: PCT can be used in elderly patients to diagnose bacterial infections because it has proved good sensitivity and high specificity. PMID- 25541008 TI - [Expression of gamma interferon during HPV and Chlamydia trachomatis infection in cervical samples]. AB - INTRODUCTION: The aim of this study was to mesure the expression of gamma interferon in HPV and Chlamydia trachomatis infection in squamous intraepithelial lesions. METHOD: Samples from 100 patients diagnosed by colposcopy with or without squamous intraepithelial lesions were used in the present study. Each patient was found to be infected by HPV and C.trachomatis. Relative gamma interferon mRNA expression was assessed using a real-time reverse transcriptase PCR assay (RT-PCR). RESULTS: The relative units of expression of gamma interferon mRNA were 13, 1.8 and 0.3, for HPV and C.trachomatis co-infection, or HPV or C.trachomatis infection, respectively. CONCLUSION: HPV and C.trachomatis could overstimulate the expression of gamma interferon. PMID- 25541010 TI - [Abdominal lesions in a patient with rheumatoid arthritis]. PMID- 25541009 TI - [Group B streptococcal early-onset neonatal sepsis in the area of Barcelona (2004 2010). Analysis of missed opportunities for prevention]. AB - OBJECTIVES: To study the evolution of the incidence of early-onset neonatal sepsis (EOS) by Streptococcus agalactiae in the area of Barcelona and to analyze failure of compliance with the prevention protocol. METHODS: A retrospective review was carried out on EOS cases in 8 Health-Care Centers in the Barcelona area between 2004 and 2010. RESULTS: Forty-nine newborns from 48 mothers were diagnosed with EOS. The incidence was 0.290/00 living newborns (0.18-0.470/00), with no significant differences in the fluctuations along the 7 years. The mortality rate was 8.16%. In 68.5% cases the maternal colonization studies were negative, and in 21% these studies were not performed. No risk factors were detected in 58.3% of pregnant women, and 22.9% of births were premature. In 58% of cases intra-partum antibiotic prophylaxis was not administered because it was not indicated, and in 42% due to failure to follow the protocol (3 strains were resistant to erythromycin). Resistance to clindamycin was 33.3%. The Streptococcus agalactiae serotypes more frequently isolated were iii, v, and ia. CONCLUSIONS: No significant changes were detected in the incidence of Streptococcus agalactiae EOS in the 7 years of the study. The increased sensitivity of screening methods with the use of molecular techniques, the performance of susceptibility testing of strains isolated from pregnant women, and the improvement of communication between Health-Care Centers, can contribute to a better implementation of the protocol, as well as to reduce the incidence of EOS. PMID- 25541011 TI - [Acute ataxia associated with a human herpesvirus 6 infection]. PMID- 25541012 TI - [Infectious diseases in the adult population admitted to a general hospital]. AB - INTRODUCTION: To determine the infectious diseases (ID) that led to hospital admission of the foreign population>14 years. MATERIAL AND METHODS: A retrospective study of foreign patients admitted to hospital (2000-2012). RESULTS: A total of 3,087 foreigners were admitted with infectious diseases. Of these, 73.6% were from low income countries, and 26.4% from high income countries. Most of them (86.9%) were admitted with common ID, 11.8% with transmissible ID, and 1.6% with tropical ID. Tropical ID and transmissible ID were higher in patients from low income countries (14.7%) than from high income countries (9.7%, p<0.001). The main tropical ID was malaria (74%). The main transmissible ID were tuberculosis (40.3%), hepatitis (27.8%), and HIV/AIDS (27.5%). CONCLUSION: Common ID were the main reason for admission in foreign population. PMID- 25541013 TI - Molecular identification of python species: development and validation of a novel assay for forensic investigations. AB - Python snake species are often encountered in illegal activities and the question of species identity can be pertinent to such criminal investigations. Morphological identification of species of pythons can be confounded by many issues and molecular examination by DNA analysis can provide an alternative and objective means of identification. Our paper reports on the development and validation of a PCR primer pair that amplifies a segment of the mitochondrial cytochrome b gene that has been suggested previously as a good candidate locus for differentiating python species. We used this DNA region to perform species identification of pythons, even when the template DNA was of poor quality, as might be the case with forensic evidentiary items. Validation tests are presented to demonstrate the characteristics of the assay. Tests involved the cross-species amplification of this marker in non-target species, minimum amount of DNA template required, effects of degradation on product amplification and a blind trial to simulate a casework scenario that provided 100% correct identity. Our results demonstrate that this assay performs reliably and robustly on pythons and can be applied directly to forensic investigations where the presence of a species of python is in question. PMID- 25541014 TI - Immediately loaded non-submerged versus delayed loaded submerged dental implants: a meta-analysis. AB - The purpose of the present meta-analysis was to test the null hypothesis of no difference in the implant failure rate, postoperative infection, and marginal bone loss for patients being rehabilitated with immediately loaded non-submerged dental implants or delayed loaded submerged implants, against the alternative hypothesis of a difference. An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomized or not. The search strategy resulted in 28 publications. The inverse variance method was used for a random- or fixed-effects model, depending on the heterogeneity. The estimates of an intervention were expressed as the risk ratio (RR) and mean difference (MD) in millimetres. Twenty three studies were judged to be at high risk of bias, one at moderate risk of bias, and four studies were considered at low risk of bias. The difference between procedures (submerged vs. non-submerged implants) significantly affected the implant failure rate (P = 0.02), with a RR of 1.78 (95% confidence interval (CI) 1.12-2.83). There was no apparent significant effect of non-submerged dental implants on the occurrence of postoperative infection (P = 0.29; RR 2.13, CI 0.52 8.65) or on marginal bone loss (P = 0.77; MD -0.03, 95% CI -0.23 to 0.17). PMID- 25541015 TI - Evaluation of the use of plasma rich in growth factors with immediate implant placement in periodontally compromised extraction sites: a controlled prospective study. AB - This study was conducted to evaluate the use of plasma rich in growth factors (PRGFs) with immediate implant placement in periodontally compromised extraction sites. Fifteen patients with chronic periodontitis were included. Each received two implants placed immediately after extraction in the anterior region of the mandible. One of the two implants was treated with PRGFs (group I), while the other was not and served as a control (group II). Implant survival, plaque index (PI), bleeding index (BI), probing pocket depth (PPD), and marginal bone loss (MBL) were evaluated for both groups. Complete soft tissue healing occurred in all patients and all implants were successfully osseointegrated over 12 months. At 12 months, results showed mean PPD values of 3.8 +/- 0.3mm at the control site (group II) and 3.4 +/- 0.4mm at the test site (group I); the mean MBL values were 1.1 +/- 0.1mm at the control site and 0.6 +/- 0.1mm at the test site. There were no statistically significant differences between the test and control groups regarding PI or BI, while there were statistical differences between the test and control groups regarding PPD and MBL throughout the follow-up period. PMID- 25541016 TI - Occurrence of glycine in the core oligosaccharides of Hafnia alvei lipopolysaccharides--identification of disubstituted glycoform. AB - Endotoxins (lipopolysaccharides, LPS) are the main surface antigens and virulence factors of Gram-negative bacteria involved for example in the development of nosocomial infections and sepsis. They consist of three main regions: O-specific polysaccharide, core oligosaccharide, and lipid A. Bacteria modify LPS structure to escape the immune defence, but also to adapt to environmental conditions. LPS's structures are highly diversified in the O-specific polysaccharide region to evade bactericidal factors of immune system, but retain some common epitopes that are potential candidates for therapeutic strategies against bacterial infections. Common occurrence of glycine within the structure of LPS is a known phenomenon and was previously reported for variety of species. Since glycine residue substitutes mainly core oligosaccharide of LPS, especially inner core region, it was also considered as a part of common epitope for broad-reactive antimicrobial antibodies. Herein, we used multiple-stage electrospray ionisation mass spectrometry to identify glycine substitution in core oligosaccharide type characteristic for Hafnia alvei LPS, and isolated from five strains of different O-serotypes: 32, PCM 1190, PCM 1192, PCM 1200, and PCM 1209. The location of glycine in core oligosaccharide was determined in detail for LPS 1190 using ESI MS(n). Three glycoforms were identified, including two mono-glycinylated and one diglycinylated core oligosaccharides. PMID- 25541017 TI - Fluorous-based carbohydrate quartz crystal microbalance. AB - Fluorous chemistry has brought many applications from catalysis to separation science, from supramolecular materials to analytical chemistry. However, fluorous based quartz crystal microbalance (QCM) has not been reported so far. In the current paper, fluorous interaction has been firstly utilized in QCM, and carbohydrate-protein interaction and carbohydrate-carbohydrate interaction have been detected afterward. PMID- 25541018 TI - A summary for molecular regulations of miRNAs in breast cancer. AB - BACKGROUND: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. MicroRNAs (miRNAs) are naturally-occurring, non-coding small RNA molecules that can modulate protein coding-genes, which makes it contributing to nearly all the physiological and pathological processes. Progression of breast cancer and resistance to endocrine therapies have been attributed to the possibility of hormone-responsive miRNAs involved in the regulation of certain signaling pathways. METHODOLOGY: This review introduces better understanding of miRNAs to provide promising advances for treatment. miRNAs have multiple targets, and they were found to regulate different signaling pathways; consequently it is important to characterize their mechanisms of action and their cellular targets in order to introduce miRNAs as novel and promising therapies. RESULTS: This review summarizes the molecular mechanisms of miRNAs in TGF-beta signaling, apoptosis, metastasis, cell cycle, ER signaling, and drug resistance. CONCLUSION: Finally, miRNAs will be introduced as promising molecules to be used in the fight against breast cancer and its developed drug resistance. PMID- 25541019 TI - Prognostic significance of active and modified forms of endothelin 1 in patients with heart failure with reduced ejection fraction. AB - OBJECTIVES: Concentrations of endothelin I (ET1) are elevated in CHF patients and, like other biomarkers that reflect hemodynamic status and cardiac pathophysiology, are prognostic. The Singulex assay (Sgx-ET1) measures the active form of ET1, with a short in vivo half-life and the Brahms assay measures C terminal endothelin-1 (CT-ET1), a modified (degraded) product with longer half life. We aimed to determine the prognostic importance of active and modified forms of endothelin 1 (Singulex and Brahms assays) in comparison with other commonly measured biomarkers of inflammation, hemodynamic status and cardiac physiology in CHF. DESIGN AND METHODS: Plasma biomarkers (Sgx-ET1, CT-ET1, NTproBNP, IL-6, TNFalpha, cTnI, VEGF, hs-CRP, Galectin-3, ST2) were measured in 134 NYHA class II and III CHF patients with systolic dysfunction. Prognostic importance of biomarkers for hospitalization or death were calculated by both logistic regression and Kaplan-Meier survival analyses. RESULTS: CT-ET1 (OR=5.2, 95% CI=1.7-15.7) and Sgx-ET1 (OR=2.9, CI=1.1-7.7) were independent predictors of hospitalization and death and additively predicted events after adjusting for age, sex, and other significant biomarkers. Other biomarkers did not improve the model. Similarly, in Cox regression analysis, only CT-ET1 (HR 3.4, 95% CI=1.4 8.4), VEGF (2.7, 95% CI=1.3-5.4), and Sgx-ET1 (HR 2.6, 95% CI=1.2-5.6) were independently prognostic. CONCLUSIONS: Elevated concentrations of endothelin 1 predict mortality and hospitalizations in HF patients. Endothelin 1 was more prognostic than commonly obtained hemodynamic, inflammatory, and fibrotic biomarkers. Two different assays of endothelin 1 independently and synergistically were prognostic, suggesting either complementary information or extreme prognostic importance. PMID- 25541020 TI - Interstitial lung disease in anti-synthetase syndrome: initial and follow-up CT findings. AB - PURPOSE: To describe the initial and follow-up CT features of interstitial lung disease associated with anti-synthetase syndrome (AS-ILD). MATERIALS AND METHODS: Two independent thoracic radiologists retrospectively analysed thin-section CT images obtained at diagnosis of AS-ILD in 33 patients (17 positive for anti-Jo1, 13 for anti-PL12, and three for anti-PL7 antibodies). They evaluated the pattern, distribution and extent of the CT abnormalities. They also evaluated the change in findings during follow-up (median 27 months; range 13-167 months) in 26 patients. RESULTS: At diagnosis, ground-glass opacities (100%), reticulations (87%) and traction bronchiectasis (76%) were the most common CT findings. Consolidations were present in 45% of patients. A non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP) or mixed NSIP-OP CT pattern were observed in 15 out of 33 (45%), seven out of 33 (21%) and eight out of 33 (24%) patients, respectively, whereas the CT pattern was indeterminate in three patients. During follow-up, consolidations decreased or disappeared in 11 out of 12 patients (92%), among which seven within the first 6 months, but honeycombing progressed or appeared in ten out of 26 patients (38%) and overall disease extent increased in nine out of 26 patients (35%). CONCLUSION: CT features at diagnosis of AS-ILD mainly suggest NSIP and OP, isolated or in combination. Consolidations decrease or disappear in most cases but the disease may progress to fibrosis in more than one third of patients. PMID- 25541021 TI - Photoperiodic regulation of nuclear melatonin receptor RORalpha in lymphoid organs of a tropical rodent Funambulus pennanti: role in seasonal oxidative stress. AB - The orphan nuclear receptor RORalpha of RZR/ROR family has been suggested to mediate the genomic actions of melatonin on the expression of antioxidant enzymes. However, no direct evidences exist. In the present study we explored the role of photoperiod (natural and artificial) in regulation of RORalpha and its association with the photoperiod induced antioxidant defense system in the lymphoid organs (spleen and thymus) of seasonally breeding, tropical squirrels, Funambulus pennanti. The photoperiod mediated regulation of antioxidant status was checked along with the RORalpha expression and circulatory melatonin level in the squirrels. The enhancement of the antioxidant capacity of serum and lymphoid organ was concomitant with the short photoperiod (10L:14D) induced high levels of plasma melatonin. Further, peripheral melatonin level enhanced the AANAT activity as well as the melatonin synthesis in the lymphoid tissues. RORalpha expression presented an inverse correlation with the plasma level of melatonin as well as the short day induced antioxidant enzyme activity in the lymphoid organs. The results suggest that for reduction of seasonal oxidative stress melatonin might not be utilizing the nuclear receptor RORalpha pathway; rather the rise in circulatory melatonin collectively with tissue specific melatonin might be protecting the splenic and thymic lymphocytes from the seasonal oxidative stress. PMID- 25541022 TI - Polygraphic respiratory events during sleep in children treated with home continuous positive airway pressure: description and clinical consequences. AB - OBJECTIVE: Data are scarce on respiratory events during sleep for children treated at home with continuous positive airway pressure (CPAP). The present study aimed to characterize the respiratory events with CPAP during sleep and to analyze their clinical consequences. PATIENTS/METHODS: Consecutive polygraphies (PG) performed on stable children treated with CPAP were analyzed and scored using SomnoNIV Group definitions. For every respiratory event, the presence of a 3% oxygen desaturation and/or an autonomic arousal was systematically searched. Nocturnal gas exchange was assessed using summary data of oximetry and transcutaneous carbon dioxide pressure recordings. RESULTS: Twenty-nine consecutive polygraphies, performed on 26 children (mean age 7.8 +/- 6.2 years, mean CPAP use 10.6 +/- 14.4 months), were analyzed. The index of total respiratory events was low (median value 1.4/h, range 0-34). The mean number of different types of respiratory events per PG was 2 +/- 1 (range 0-4), with always a predominant event. Partial or total upper airway obstruction without a decrease in ventilatory drive was the most frequent event and was the most frequently associated with an oxygen desaturation (in 30% of the events) and an autonomic arousal (in 55% of the events). Weak correlations were observed between nocturnal oximetry and PG results. CONCLUSIONS: The index of respiratory events during CPAP treatment for stable children is low. As these events may be associated with an oxygen desaturation or an autonomic arousal, and as nocturnal gas exchange cannot predict PG results, a systematic sleep study seems justified for the routine follow-up of children treated with CPAP. PMID- 25541023 TI - Sleep brain networks and sleep depth during somatosensory stimulation. PMID- 25541024 TI - Is time to search the Wells Score 4.0? AB - BACKGROUND: Wells score for deep vein thrombosis presents problems for implementation in the hospital emergencies, mainly due to the complexity of its enforcement. OBJECTIVE: To assess whether the inclusion of D-dimer as a predictor might lead to a simplification of this clinical decision rule. PATIENTS AND METHODS: A database of deep vein thrombosis patients was studied by logistic regression model in which the 10 predictors in the Wells score and the dimer D were included. The diagnosis was made with compression ultrasonography with Doppler signal. D-dimer was determined by a quantitative method of latex, a technique immunofiltration or a turbidimetric technique. RESULTS: 577 patients (54.1% women) were studied, with a mean age of 66.7 (14.2) years. 25.1% were diagnosed with deep vein thrombosis. Only four variables were independent, building a weighted model with greater predictive ability (area under the curve) than the original model (0.844 vs. 0.751, p<0.001). Both models showed an acceptable safety, with a similar rate of failure (0.8% vs. 1%). The simplified model allowed to select a higher percentage of patients who could have benefited from the non performance of the imaging test (20.6% vs. 15.8%, p=0.039). CONCLUSIONS: The introduction of D-dimer in a regression model simplifies the Wells score and maintain the same efficacy and safety, which could improve its implementation in the hospital emergencies. PMID- 25541025 TI - Molecular cloning, expression and characterization of programmed cell death 10 from sheep (Ovis aries). AB - Programmed cell death 10 (PDCD10) is a highly conserved adaptor protein. Its mutations result in cerebral cavernous malformations (CCMs). In this study, PDCD10 cDNA from the buffy coat of Small Tail Han sheep (Ovis aries) was cloned from a suppression subtractive hybridization cDNA library, named OaPDCD10. The full-length cDNA of OaPDCD10 was 1343bp with a 639bp open reading frame (ORF) encoding 212 amino acid residues. Tissue distribution of OaPDCD10 mRNA determined that it was ubiquitously expressed in all tested tissue samples, and the highest expression was observed in the heart. The differential expression of OaPDCD10 between infected sheep (challenged with Brucella melitensis) and vaccinated sheep (vaccinated with Brucella suis S2) was also investigated. The results revealed that, compared to the control group, the expression of OaPDCD10 from infected and vaccinated sheep was both significantly up-regulated (p<0.05). Moreover, the expression levels of OaPDCD10 from the vaccinated sheep were significantly higher than the infected sheep (p<0.05) after 30days post-inoculation. The recombinant OaPDCD10 (rOaPDCD10) protein was expressed in Escherichia coli BL21 (DE3), and then purified by affinity chromatography. The rOaPDCD10 protein was demonstrated to induce apoptosis and promote cell proliferation. Our studies are intended to discover potential diagnostic biomarkers of brucellosis to discern infected sheep from vaccinated sheep, and OaPDCD10 could be considered as a potential diagnostic biomarker of brucellosis. PMID- 25541026 TI - Identification, expression and immunological responses to bacterial challenge following vaccination of BLT1 gene from turbot, Scophthalmus maximus. AB - Leukotriene B4 (LTB4) is well known as a chemoattractant for leucocytes, recent studies also showed its involvement in adaptive immunity. The purpose of this work is to report the cloning, characterization and gene expression of leukotriene B4 receptor (BLT1) in turbot (Scophthalmus maximus), as well as the immunological response to challenge following vaccination with a live attenuated vaccine Vibrio anguillarum MVAV6203. The full cDNA sequence of turbot BLT1 was cloned. The open reading frame consists of 1119bp nucleotides, which translate into 372 amino acid protein. A high conservation of amino acid sequence was found in the seven transmembrane (TM) domains and intracellular loops. The intracellular loop 3 consisting of a unique cluster of basic amino acid residues might be associated with signal transduction. High amino acid similarity and a phylogenetic tree confirmed it as a leukotriene B4 receptor member. The BLT1 gene is expressed in a wide range of tissues with the highest expression in kidney followed by spleen. The expression of turbot BLT1 was significantly up-regulated in spleen, gut and gill after vaccination and in kidney and skin after challenge. These results suggest a potential role of turbot BLT1 in protection against infection. PMID- 25541028 TI - One day at a time: improving the patient experience during and after intensive chemotherapy for younger and older AML patients. AB - Few studies have focused on survivorship issues in AML patients that have successfully completed treatment, and no study examined age-related differences in survivorship. Therefore, our purpose was to explore the survivorship issues encountered by AML survivors, and explore if these survivorship issues are different for younger and older survivors. Lastly, we explored advice for future patients provided by younger and older AML survivors on how to survive the period of intensive chemotherapy (IC). We conducted a prospective qualitative study with 26 participants (14 younger (age 18-59), 12 older (age 60 or older)) who underwent IC. Data were analyzed using Grounded Theory. Both younger and older survivors reported persistent health issues and functional limitations; however, older participants were more satisfied with their post-treatment function and quality of life. Face-to-face communication, phase-specific information, step-by step education, and home nursing care were important factors to cope with treatment. Provision of written educational material was highlighted by younger participants. Frequent travel to hospital and long waiting times were identified as undesirable. In conclusion, although we observed that many survivorship issues during and shortly after a diagnosis are similar among younger and older survivors, some issues differ by age, pointing out the need for customized approaches. PMID- 25541027 TI - Analysis of outcomes in patients with supra-diaphragmatic vs infra-diaphragmatic diffuse large B cell lymphoma treated with R-CHOP therapy. AB - The prognostic implications of infra-diaphragmatic (InD) versus supra diaphragmatic (SpD) primary lesions in limited-stage diffuse large B-cell lymphoma (DLBCL) remains unknown. This retrospective study aimed to assess the prognostic impact of spD and InD lesions as well as presence of gastrointestinal (GI) involvements in adults with limited-stage DLBCL. We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. The median age was 63 years (range, 18-80 years). The primary sites were SpD in 109 patients, and InD in 69. No statistical differences in progression free survival (PFS) or overall survival (OS) were observed between patients with SpD lesions and those with InD lesions. However, when patients with SpD lesions, InD lesions with (n=35), and without (n=34) GI involvement were compared, the presence of GI lesions was associated with favorable PFS. The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS, whereas the presence of GI lesions was correlated with favorable PFS (P=0.024, HR 0.09). PMID- 25541029 TI - Statin use has negative clinical impact on non-germinal center in patients with diffuse large B cell lymphoma in rituximab era. AB - Rituximab improved prognosis in diffuse large B cell lymphoma (DLBCL). However, activity of rituximab may be reduced by conformational change in CD20 by statin induced cholesterol depletion. Conformation change in CD20 could impair the binding of rituximab and significantly decrease the killing effect of lymphoma cells. R-CHOP therapy could counteract the prognostic gap between GC type and non GC type. We investigated whether statin use could have different clinical impacts on immunohistochemical DLBCL subtypes in the rituximab era. We analyzed data from 409 patients with de novo DLBCL who received R-CHOP therapy. During median follow up time of 38.6 months, 3-year progression-free survival (PFS) and overall survival (OS) in the GC type were similar to those in the non-GC type (PFS, p=0.125; OS, p=0.201). Moreover, survivals were comparable between patients with statin therapy and those without the statin therapy (PFS, p=0.282; OS, p=0.273). We also analyzed whether statin therapy would have clinical significance by immunophenotypes in patients treated with R-CHOP therapy. The non-GC type with statin therapy had inferior PFS and OS compared to other groups (PFS, p=0.008; OS, p=0.006). In multivariate analysis, statin therapy had significant negative impacts on survivals of the non-GC type independent of other clinical factors (PFS, hazard ratio/HR: 1.553, 95% CI: 1.058-2.279, p=0.024; OS, HR=1.532, 95% CI: 1.041-2.255, p=0.023). Therefore, statin therapy negatively affected the clinical outcome of the non-GC phenotype, but it was beneficial to R-CHOP therapy in DLBCL. PMID- 25541030 TI - The use of aspirin for primary and secondary prevention in venous thromboembolism and other cardiovascular disorders. AB - Cardiovascular disease (CVD) includes a number of conditions such as myocardial infarction, coronary heart disease, stroke, and venous thromboembolism. CVD is a leading health problem worldwide and a major cause of mortality, morbidity, and disability; it is also associated with high healthcare costs. The incidence of CVD is predicted to increase in the forthcoming years, and thus it is crucial that physicians are aware of the benefits and limitations of the available therapies to ensure patients receive optimized treatment. Current clinical practice guidelines provide recommendations on the use of anticoagulants and antiplatelets for both the prevention and treatment of CVD. Aspirin is the most studied antiplatelet agent in this context. The benefits of aspirin are well documented and supported by data from robust clinical trials for CVD conditions, such as acute coronary syndrome and stroke prevention in patients with atrial fibrillation. However, the clinical benefits of aspirin are less clear for other conditions, namely for primary prevention of venous thromboembolism after major orthopaedic surgery, particularly in comparison with newer drugs such as the direct oral anticoagulants. This article provides an outline of the current guidelines and a critical assessment of the efficacy and safety data supporting the recommendations for the use of aspirin in the treatment and prevention of venous thromboembolism and other cardiovascular disorders. PMID- 25541031 TI - Monocyte CD40 expression in young healthy female smokers and/or oral contraceptives users without additional risk factors for atherosclerosis. AB - OBJECTIVE: Atherosclerosis, as an inflammatory disease, is characterized by pathologically altered levels of cytokines. We investigated whether smoking and/or oral contraceptives (OCs) affect the CD40/CD40L plasma levels and expression in young females without other risk factors for atherosclerosis. PATIENTS AND METHODS: A case-control single-center design was used. Expression levels of CD40/CD40L were analyzed in healthy non-pregnant, pre-menopausal, non smoking women who did not take OCs (n=49), women who currently smoke and take OCs (n=40), and women who are only smokers (n=40) or currently take OCs (n=42). RESULTS: In OC users, there was a significant increase in CD40 mRNA expression in circulating monocytes as compared with smokers and control group. However, there were no significant differences in CD40 mRNA expression in monocytes between smokers and non-smokers. Interestingly, CD40 mRNA expression in women taking OCs and currently smoking was significantly decreased compared to only OC users (p<0.001). With regard to plasma CD40 levels there were significant differences between OC-users and control group. However, contrary to our expectations, there were no significant differences in expression levels of CD40L between four groups. In vitro experiments demonstrated enhanced CD40 mRNA and surface expression in human monocyte-derived macrophages stimulated with estrogens. Furthermore, nicotine pretreatment led to a suppression of estrogens stimulated CD40 induction. CONCLUSIONS: In young healthy females without additional risk factors for atherosclerosis, OCs, but not smoking, are associated with dramatic changes in CD40 gene and plasma levels. These findings may be providing an important link between OCs and enhancement of pro-inflammatory and atherothrombotic conditions in healthy women. PMID- 25541032 TI - Thrombin generation test in children and adolescents with chronic liver disease. AB - INTRODUCTION: The aim of this study was to evaluate if real-time thrombin generation assay provides additional information to assess the hemostatic balance in children with liver disease as compared to routine coagulation tests. PATIENTS AND METHODS: Sixty-three children with chronic liver disease were enrolled at our tertiary referral center for pediatric hepatology, eight whose routine coagulation tests gave abnormal results (Group A) and 55 whose test results were normal (Group B). Abnormal routine coagulation test was defined as at least one of the following: international normalized ratio>=1.4, activated partial thromboplastin time>44 sec., fibrinogen<1.5 g/L. Platelet-poor plasma was analyzed with the fluorogenic Calibrated Automated Thrombogram to test for thrombin generation, including endogenous thrombin potential. Further, routine coagulation tests and plasma levels of pro- and anticoagulant factors were measured. Twenty age-matched children without liver disease served as controls. RESULTS: The endogenous thrombin potential in the 55 patients with normal routine coagulation tests was not significantly different from that in controls. Group A had significantly lower levels not only of procoagulant factors (II, V, VII, X) but simultaneously also of the anticoagulant factors antithrombin, protein S free, and protein C. These patients had a reduced endogenous thrombin potential compared to Group B, in agreement with their routine coagulation test results. CONCLUSION: Thrombin generation analysis seems to give information on the hemostatic balance consistent with routine coagulation test results in children with liver disease. Further development and clinical evaluation of the method are warranted. PMID- 25541033 TI - Predictors of intraoperative hypotension and bradycardia. AB - BACKGROUND: Perioperative hypotension and bradycardia in the surgical patient are associated with adverse outcomes, including stroke. We developed and evaluated a new preoperative risk model in predicting intraoperative hypotension or bradycardia in patients undergoing elective noncardiac surgery. METHODS: Prospective data were collected in 193 patients undergoing elective, noncardiac surgery. Intraoperative hypotension was defined as systolic blood pressure <90 mm Hg for >5 minutes or a 35% decrease in the mean arterial blood pressure. Intraoperative bradycardia was defined as a heart rate of <60 beats/min for >5 minutes. A logistic regression model was developed for predicting intraoperative hypotension or bradycardia with bootstrap validation. Model performance was assessed using area under the receiver operating curves and Hosmer-Lemeshow tests. RESULTS: A total of 127 patients developed hypotension or bradycardia. The average age of participants was 67.6 +/- 11.3 years, and 59.1% underwent major surgery. A final 5-item score was developed, including preoperative Heart rate (<60 beats/min), preoperative hypotension (<110/60 mm Hg), Elderly age (>65 years), preoperative renin-Angiotensin blockade (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers), Revised cardiac risk index (>=3 points), and Type of surgery (major surgery), entitled the "HEART" score. The HEART score was moderately predictive of intraoperative bradycardia or hypotension (odds ratio, 2.51; 95% confidence interval, 1.79-3.53; C-statistic, 0.75). Maximum points on the HEART score were associated with an increased likelihood ratio for intraoperative bradycardia or hypotension (likelihood ratio, +3.64). CONCLUSIONS: The 5-point HEART score was predictive of intraoperative hypotension or bradycardia. These findings suggest a role for using the HEART score to better risk-stratify patients preoperatively and may help guide decisions on perioperative management of blood pressure and heart rate lowering medications and anesthetic agents. PMID- 25541034 TI - Hypertension and new treatment approaches targeting the sympathetic nervous system. AB - The prevalence of primary and resistant hypertension in the United States is increasing. Even with an ever-expanding array of pharmacotherapy available, a large percentage of patients do not meet guideline blood pressure (BP) goals. Not achieving BP goals clearly increases cardiovascular morbidity and mortality, and results in the progression of kidney disease. The inability to adequately control BP is multifactorial, however a major contributing factor, besides inadequate diuretic therapy, is the failure of pharmacotherapy to inhibit the sympathetic nervous system (SNS) effectively. Tolerability of anti-hypertensives targeting the SNS is moderate at best. Consequently, device-driven approaches are being developed and tested. Recent investigation includes renal denervation and baroreflex activation therapy, which show promising, but at times conflicting, results. PMID- 25541035 TI - Perspective taking abilities in amnestic mild cognitive impairment and Alzheimer's disease. AB - Perspective taking is the ability to imagine what a scene looks like from a different viewpoint, which has been reported to be impaired in Alzheimer's disease (AD). This study compared overhead and first-person view perspective taking abilities in patients with mild cognitive impairment (MCI) and AD. A newly developed Arena Perspective Taking Task (APTT), using an environment of a circular arena, was used to compare 23 AD patients and 38 amnestic MCI patients with 18 healthy controls. The results were contrasted with a published perspective taking test (Standardized Road-Map Test of Direction Sense, RMTDS). The AD group was impaired in both overhead and first-person view APTT versions, but the impairment in the overhead view version applied specifically to women. Patients with aMCI were impaired in the first-person view but not in the overhead view version. Substantial sexual differences were found in the overhead but not in the first-person view APTT version. The RMTDS resembled both APTT versions: patients with aMCI were impaired in this test and also women in both patient groups were less accurate than men. Using the receiver operating characteristic analysis, the highest predictive power for MCI and AD patients diagnosis versus controls was observed for their success rate in the first-person view version. The results suggest distinction between overhead and first-person view perspective taking in the impairment of aMCI patients and the sex differences. The first-person view perspective taking is a potentially important candidate psychological marker for AD. PMID- 25541037 TI - Effects of repetitive transcranial magnetic stimulation on synaptic plasticity and apoptosis in vascular dementia rats. AB - This study aims to determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) protects pyramidal cells from apoptosis and promotes hippocampal synaptic plasticity in a vascular dementia (VaD) rat model. Following establishment of a VaD rat model using two-vessel occlusion (2VO), learning and memory were evaluated via the Morris Water Maze (MWM), hippocampal CA1 neuron ultrastructure was examined via electron microscopy, and hippocampal synaptic plasticity was assessed by long-term potentiation (LTP). Western blot was used to detect the expression of N-methyl-d-aspartic acid receptor 1 (NMDAR1), Bcl-2, and Bax. Compared with VaD group, rats treated with low-frequency rTMS had reduced escape latencies, increased swimming time in the target quadrant (P<0.05), and significantly less synaptic structure damage. LTP at hippocampal CA3-CA1 synapses was enhanced (P<0.05). Low-frequency rTMS significantly up-regulated NMDAR1 and Bcl-2 expression and down-regulated Bax expression. Low-frequency rTMS improves learning and memory, protects the synapse, and increases synaptic plasticity in VaD model rats. Increased Bcl-2 expression and reduced Bax expression may be a novel protective mechanism of low-frequency rTMS treatment for VaD. PMID- 25541036 TI - Sign-tracking predicts increased choice of cocaine over food in rats. AB - The purpose of this study was to determine whether the tendency to sign-track to a food cue was predictive of rats' choice of cocaine over food. First, rats were trained on a procedure where insertion of a retractable lever was paired with food. A sub-group of rats - sign-trackers - primarily approached and contacted the lever, while another sub-group - goal-trackers - approached the site of food delivery. Rats were then trained on a choice task where they could choose between an infusion of cocaine (1.0 mg/kg) and a food pellet (45 mg). Sign-trackers chose cocaine over food significantly more often than did goal-trackers. These results support the incentive-salience theory of addiction and add to a growing number of studies which suggest that sign-trackers may model an addiction-prone phenotype. PMID- 25541038 TI - Context-dependent neuroelectric responses during motor control. AB - Research on brain responses during motor control is usually performed under typical laboratory settings. However, everyday life and the laboratory differ in many aspects, such as purposeful and motivated behavior; and there's no awareness of "being measured" in everyday life. In the laboratory, movements are usually explicitly instructed, overtly measured and follow no intrinsic motivated purpose. Therefore, here we present a new method to measure and reliably analyze neuroelectric brain responses by EEG, as well as kinematics during the performance of grasping movements in two different behavioral contexts. One context (L) simulates a typical laboratory task and another context (E) uses selected features of everyday behavior. However, in both tasks the mechanical constraints and stimuli for the movement are exactly the same. Amplitudes of event-related N200 and P300 measured at the brain's midline were differentially affected by the two contexts. P300 was increased in L compared to E. N200 was distinct at anterior electrode sites (Fz, Cz) in context E, while it was elevated at posterior electrode sites (Pz, Oz) in context L. For the first time, kinematic and electrophysiological recordings are combined to analyze identical movements, performed in varied behavioral contexts. The results indicate that brain responses measured under typical laboratory context may not be necessarily transferred to everyday life; thus, the present approach offers a wide range of new questions to analyze context-dependent brain responses. PMID- 25541039 TI - Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson's disease. AB - Parkinson's disease (PD) is characterized by progressive loss of nigrostriatal dopaminergic neurons that results in motor deficits including resting tremor, rigidity, bradykinesia, and postural instability. Despite decades of intensive study, the underlying molecular mechanisms are not fully understood. Multiple lines of evidence indicate that mitochondrial dysfunction and oxidative stress contribute to neuronal death, which is the key feature of neurodegeneration. Mitochondria are pivotal organelles that host essential functions in neuronal viability including energy production, oxidative phosphorylation, calcium buffering, redox homeostasis and apoptosis. SIRT5, which localizes in the mitochondrial matrix, is nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase. The physiological and pathophysiological functions of SIRT5 in vivo remain elusive although it is known to be an important energy sensor. Here, we investigated the role of SIRT5 in the pathogenesis of PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We present evidence that SIRT5 deficiency, by itself, does not affect motor and non-motor functions; however, lack of SIRT5 exacerbates MPTP-induced motor deficits. Consistently, MPTP-exposed SIRT5 knockout mice exhibited more severe nigrostriatal dopaminergic degeneration than that observed in wild-type controls. Furthermore, deletion of SIRT5 leads to a larger decrease, relative to control, in the expression level of manganese superoxide dismutase (SOD2), a mitochondria-specific antioxidant enzyme, after MPTP induction. These findings indicate that SIRT5 ameliorates MPTP induced nigrostriatal dopaminergic degeneration via preserving mitochondrial antioxidant capacity. PMID- 25541040 TI - TMS evidence for a selective role of the precuneus in source memory retrieval. AB - The posteromedial cortex including the precuneus (PC) is thought to be involved in episodic memory retrieval. Here we used continuous theta burst stimulation (cTBS) to disentangle the role of the precuneus in the recognition memory process in a sample of healthy subjects. During the encoding phase, subjects were presented with a series of colored pictures. Afterwards, during the retrieval phase, all previously presented items and a sample of new pictures were presented in black, and subjects were asked to indicate whether each item was new or old, and in the latter case to indicate the associated color. cTBS was delivered over PC, posterior parietal cortex (PPC) and vertex before the retrieval phase. The data were analyzed in terms of hits, false alarms, source errors and omissions. cTBS over the precuneus, but not over the PPC or the vertex, induced a selective decrease in source memory errors, indicating an improvement in context retrieval. All the other accuracy measurements were unchanged. These findings suggest a direct implication of the precuneus in successful context-dependent retrieval. PMID- 25541041 TI - Element composition and mineralogical characterisation of air pollution control residue from UK energy-from-waste facilities. AB - Air pollution control (APC) residues from energy-from-waste (EfW) are alkaline (corrosive) and contain high concentrations of metals, such as zinc and lead, and soluble salts, such as chlorides and sulphates. The EPA 3050B-extractable concentrations of 66 elements, including critical elements of strategic importance for advanced electronics and energy technologies, were determined in eight APC residues from six UK EfW facilities. The concentrations of Ag (6-15 mg/kg) and In (1-13 mg/kg), as well as potential pollutants, especially Zn (0.26 0.73 wt.%), Pb (0.05-0.2 wt.%), As, Cd, Cu, Mo, Sb, Sn and Se were found to be enriched in all APC residues compared to average crustal abundances. Results from a combination of scanning electron microscopy with energy dispersive X-ray spectroscopy and also powder X-ray diffraction, thermal analysis and Fourier transform infrared spectroscopy give an exceptionally full understanding of the mineralogy of these residues, which is discussed in the context of other results in the literature. The present work has shown that the bulk of the crystalline phases present in the investigated APC residues include Ca-based phases, such as CaCl(x)OH(2-x), CaCO3, Ca(OH)2, CaSO4, and CaO, as well as soluble salts, such as NaCl and KCl. Poorly-crystalline aragonite was identified by FTIR. Sulphur appears to have complex redox speciation, presenting as both anhydrite and hannebachite in some UK EfW APC residues. Hazardous elements (Zn and Pb) were widely associated with soluble Ca- and Cl-bearing phases (e.g. CaCl(x)OH(2-x) and sylvite), as well as unburnt organic matter and aluminosilicates. Specific metal bearing minerals were also detected in some samples: e.g., Pb present as cerussite; Zn in gahnite, zincowoodwardite and copper nickel zinc oxide; Cu in tenorite, copper nickel zinc oxide and fedotovite. Aluminium foil pieces were present and abundantly covered by fine phases, particularly in any cracks, probably in the form of Friedel's salt. PMID- 25541042 TI - Neuronostatin: peripheral site of action in mouse stomach. AB - Neuronostatin is a 13-amino acid peptide encoded by somatostatin gene. It is distributed in different organs including gastrointestinal tract and has been involved in the control of food intake and gastrointestinal motility, likely through an action in the brain. So far, there are no reports about the occurrence of peripheral action sites in the gut. Therefore, the purpose of the present study was to examine, in the mouse, the effects of peripheral administration of neuronostatin on food intake within 24h and on gastrointestinal motility and to analyse neuronostatin actions on the gastric and intestinal mechanical activity in isolated preparations in vitro. When compared with PBS-treated mice, intraperitoneal neuronostatin reduced food intake in doses ranging from 1 to 15ng/g b.w. only in the first hour postinjection with a maximum effect obtained at the dose of 15ng/g b.w. (-46.9%). The peptide (15ng/g b.w.) significantly reduced gastric emptying rate (-31.1%) and gastrointestinal intestinal transit. Non-amidated neuronostatin failed to affect food intake, gastric emptying and intestinal transit, suggesting the specificity of action. In vitro, neuronostatin induced concentration-dependent gastric relaxation, which was abolished by tetrodotoxin. Neuronostatin failed to affect the spontaneous mechanical activity or the evoked cholinergic contractions in duodenum. These results suggest that exogenous neuronostatin is able to reduce mouse gastric motility by acting peripherally in the stomach, through intramural nervous plexuses. This indirectly action could cause reduction of food intake in the short term. PMID- 25541043 TI - Hemokinin-1 is an important mediator of endotoxin-induced acute airway inflammation in the mouse. AB - OBJECTIVE: Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. METHODS: Acute pneumonitis was induced in Tac4 gene-deleted (Tac4(-/-)) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. RESULTS: All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin 1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4(-/-) mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4(-/-) mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. CONCLUSIONS: We provide the first evidence that hemokinin-1 plays a crucial pro inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions. PMID- 25541044 TI - Effect of carnosine supplementation on apoptosis and irisin, total oxidant and antioxidants levels in the serum, liver and lung tissues in rats exposed to formaldehyde inhalation. AB - The main objective of the study has been to show whether carnosine has positive effects on liver and lung tissues of rats exposed to a range of formaldehyde concentrations, and to explore how irisin expression and antioxidant capacity are altered in these tissues by carnosine supplementation. Sprague-Dawley type male rats were divided into 8 groups with 6 animals in each: (I) Control; no chemical supplementation); (II) sham (100mg/kg/day carnosine); (III) low dose formaldehyde (LDFA) for 5 days/week; (IV) LDFA for 5 days/week and carnosine); (V) moderate dose formaldehyde (MDFA) for 5 days/week); (VI) MDFA for 5 days/week and carnosine; (VII) high dose formaldehyde (HDFA) for 5 days/week; (VIII) and HDFA for 5 days/week and carnosine. Sham and control groups were exposed to normal air. Irisin levels of the serum, liver and lung tissue supernatants were analyzed by ELISA, while the REL method was used to determine total oxidant/antioxidant capacity. Irisin production by the tissues was detected immunohistochemically. Increasing doses of FA decreased serum/tissue irisin and total antioxidant levels relative to the controls, as also to increases in TUNEL expressions, total oxidant level, oxidant and apoptosis index. Irisin expression was detected in hepatocyte and sinusoidal cells of the liver and parenchymal cells of the lung. In conclusion, while FA exposure reduces irisin and total oxidant in the serum, liver and lung tissues in a dose-dependent manner and increases the total antioxidant capacity, carnosine supplementation reduces the oxidative stress and restores the histopathological and biochemical signs. PMID- 25541045 TI - Highly oxygenated sesquiterpenes in Artemisia alba Turra. AB - Ten new sesquiterpene alcohols of which seven germacranes, a eudesmane, a guaiane and an oplopane were isolated from the aerial parts of Artemisia alba Turra. Their structures and relative stereochemistry were elucidated by spectral methods ((1)H and (13)C NMR, COSY, HSQC, HMBC, NOESY, and MS). In addition, the known 7 hydroxycadin-4-en-3-one, centaureidin and axillarin were found for the first time in the studied species. PMID- 25541049 TI - Preserving pathogens with pandemic potential. PMID- 25541050 TI - Neglected tropical diseases take hold in the USA. PMID- 25541055 TI - Anti-septic activity of alpha-cubebenoate isolated from Schisandra chinensis. AB - Sepsis is a life-threatening, infectious, systemic inflammatory disease. In this study, we investigated the therapeutic effect of alpha-cubebenoate, a novel compound isolated from Schisandra chinensis against polymicrobial sepsis in a cecal ligation and puncture (CLP) experimental model. Administration of alpha cubebenoate strongly enhanced survival in the CLP model. alpha-cubebenoate administration also markedly blocked CLP-induced lung inflammation and increased bactericidal activity by enhancing phagocytic activity and hydrogen peroxide generation in mouse bone marrow-derived macrophages and neutrophils. Expression of two important inflammatory cytokines, IL-1beta and IL-6, was strongly increased in the CLP model, and this was dramatically blocked by alpha cubebenoate. Lymphocyte apoptosis and caspase-3 activation, which are associated with immune paralysis during sepsis, were markedly attenuated by alpha cubebenoate. Taken together, our findings indicate that alpha-cubebenoate, a natural compound isolated from Schisandra chinensis, is a powerful potential anti septic agent. PMID- 25541056 TI - Butein, a tetrahydroxychalcone, suppresses pro-inflammatory responses in HaCaT keratinocytes. AB - Up-regulation of cell adhesion molecules and pro-inflammatory cytokines contributes to enhanced monocyte adhesiveness and infiltration into the skin, during the pathogenesis of various inflammatory skin diseases, including atopic dermatitis. In this study, we examined the anti-inflammatory effects of butein, a tetrahydroxychalcone, and its action mechanisms using TNF-alpha-stimulated keratinocytes. Butein significantly inhibited TNF-alpha-induced ICAM-I expression and monocyte adhesion in human keratinocyte cell line HaCaT. Butein also decreased TNF-alpha-induced pro-inflammatory mediators, such as IL-6, IP-10 and MCP-1, in HaCaT cells. Butein decreased TNF-alpha-induced ROS generation in a dose-dependent manner in HaCaT cells. In addition, treatment of HaCaT cells with butein suppressed TNF-alpha-induced MAPK activation. Furthermore, butein suppressed TNF-alpha-induced NF-kappaB activation. Overall, our results indicate that butein has immunomodulatory activities by inhibiting expression of pro inflammatory mediators in keratinocytes. Therefore, butein may be used as a therapeutic agent for the treatment of inflammatory skin diseases. PMID- 25541057 TI - Quantification of neurosteroids during pregnancy using selective ion monitoring mass spectrometry. AB - Analytical techniques used to quantify neurosteroids in biological samples are often compromised by non-specificity and limited dynamic range which can result in erroneous results. A relatively rapid and inexpensive gas chromatography-mass spectrometry (GC-MS) was developed to simultaneously measure nine neurosteroids, including allopregnanolone, estradiol, and progesterone, as well as 25-hydroxy vitamin D3 in plasma samples collected from adult women subjects during and after pregnancy. Sample preparation involved solid-phase extraction and derivatization, followed by automated injection on a GC equipped with a mass selective detector (MSD) operated in single ion monitoring (SIM) mode to yield a run time of less than 11min. Method detection limits for all neurosteroids ranged from 30 to 200pg/mL (parts per trillion), with coefficients of variation that ranged from 3% to 5% based on intra-assay comparisons run in triplicate. Although concentrations of estradiol measured by chemiluminescent immunoassay (CIA) were consistent with values determined by GC-MS values, CIA yielded considerable higher values of progesterone, suggesting antibody cross reactions resulting from low specificity. Mean neurosteroid levels and representative time-course data demonstrate the ability of the method to quantify changes in multiple neurosteroids during pregnancy, including rapid declines in neurosteroid levels associated with delivery. This simplified GC-MS method holds particular promise for research and clinical laboratories that require simultaneous quantification of multiple neurosteroids, but lack the resources and expertise to support advanced liquid chromatography-tandem mass spectrometry facilities. PMID- 25541058 TI - Microwave assisted synthesis and biomedical potency of salicyloyloxy and 2 methoxybenzoyloxy androstane and stigmastane derivatives. AB - A convenient microwave assisted solvent free synthesis as well as conventional synthesis of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives 7-19 from appropriate steroidal precursors 1-6 and methyl salicylate is reported. The microwave assisted synthesis in most cases was more successful regarding reaction time and product yields. It was more environmentally friendly too, compared to the conventional method. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests, as well as their inhibition potency exerted on hydroxysteroid dehydrogenase enzymes (Delta(5)-3betaHSD, 17betaHSD2 and 17betaHSD3). All of the tested compounds were effective in OH radical neutralization, particularly compounds 9, 11 and 14, which exhibited about 100-fold stronger activity than commercial antioxidants BHT and BHA. In DPPH radical scavenging new compounds were effective, but less than reference compounds. 2-Methoxybenzoyl ester 10 exhibited strong cytotoxicity against MDA-MB-231 cells. Most compounds inhibited growth of PC-3 cells, where salicyloyloxy stigmastane derivative 15 showed the best inhibition potency. Compounds 9, 10 and 11 were the best inhibitors of 17betaHSD2 enzyme. X-ray structure analysis and molecular mechanics calculations (MMC) were performed for the best cytotoxic agents, compounds 10 and 15. A comparison of crystal and MMC structures of compounds 10 and 15 revealed that their molecules conformations are stable even after releasing of the influence of crystalline field and that the influence of crystal packing on molecular conformation is not predominant. PMID- 25541059 TI - Formation of Delta(1) and Delta(6) testosterone metabolites by human hepatocytes. AB - The existence of urinary testosterone (T) metabolites conjugated with cysteine has been recently reported. The formation of a ring double bond by a phase I metabolic transformation and the subsequent nucleophilic conjugation with glutathione was proposed as a putative metabolic pathway for the occurrence of these metabolites in urine. The main goal of the present study was to confirm the first step of the postulated pathway. For that purpose, human hepatocyte cells systems were incubated with a pure T standard. The cell culture supernatants were analyzed by liquid chromatography coupled to mass spectrometry using a selected reaction monitoring method. Major T metabolites such as androsterone and 4 androstene-3,17-dione, together with the recently reported Delta(1) and Delta(6) metabolites were simultaneously quantified. The formation of 1,4-androstadien 3,17-dione, 4,6-androstadien-3,17-dione, 17beta-hydroxy-4,6-androstadien-3-one and 17beta-hydroxy-1,4-androstadien-3-one (boldenone) after incubation of T in hepatocyte cell cultures was demonstrated by comparing the retention times and the ion ratios of the metabolites with those obtained by analysis of commercial standards. Thus, the formation of double bonds Delta(1) and Delta(6) by hepatic phase I metabolism of T was confirmed. Analogously to T, this pathway might also be present in other steroids, opening the possibility of targeting additional biomarkers. PMID- 25541060 TI - Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells. AB - In previous studies, we confirmed that mitofusin-2 (Mfn2) induced apoptosis in hepatocellular carcinoma (HCC) cells. However, the exact molecular mechanism remained unclear. Mfn2 expressed lower in tumour tissues, compared with adjacent non-cancer tissues. Furthermore, Mfn2 immunostaining was very weak in HCC tissue (P < 0.05) and was significantly associated with tumour size and TNM stage (P = 0.038 and 0.040, respectively), and patients with HCC with lower Mfn2 expression had a poorer prognosis. Overexpression of Mfn2 induced HepG2 cells apoptosis, reduced the mitochondrial membrane potential (DeltaPsim) and endoplasmic reticulum (ER) calcium ion (Ca(2+)) concentrations, and elevated intracellular reactive oxygen species (ROS) and mitochondrial Ca(2+) concentrations. However, when HepG2 cells overexpressing Mfn2 were treated with both heparin and RU360, there was no induction of apoptosis, decline in DeltaPsim or ER Ca(2+), or increase in intracellular ROS or mitochondrial Ca(2+). We also found downregulation in the expression of mitochondrial calcium uptake1 and 2 (MICU1 and MICU2) in cells transfected with Adv-Mfn2. Thus, we confirmed that Mfn2 induced apoptosis in HCC cells by triggering influx of Ca(2+) into the mitochondria from the ER. PMID- 25541062 TI - AZD6244 inhibits cisplatin-induced ERK1/2 activation and potentiates cisplatin associated cytotoxicity in K-ras G12D preclinical models. AB - Although cisplatin has been widely used as a component of standard treatments for advanced non-small cell lung cancers (NSCLC) with KRAS-activating mutations, clinical outcomes remain suboptimal. Among the resistance mechanisms to cisplatin, activation of the MAPK cascade, which plays an important role in cancer cell stress and death, offers a promising therapeutic target. Using KRAS mutant NSCLC cells and a mouse model, we evaluated the efficacy of adding the MEK1/2 inhibitor AZD6244 as an addition for cisplatin-based chemotherapy. Cisplatin increased phosphorylation of MEK1/2 and ERK1/2 and reduced Bcl-2 like 11 (BIM) expression in NSCLC cells and the mouse model. BIM silencing in NSCLC cells using shRNA led to a blunted cytotoxic response to cisplatin, while prevention of BIM loss with the MEK1/2 inhibitor synergized cisplatin-mediated cell death. The combination of cisplatin and AZD6244 yielded a superior response to cisplatin alone in K-ras mice. In conclusion, an MEK1/2 inhibitor potentiated the anti-tumor effects of cisplatin in KRAS-dependent lung cancer cells and an animal model through inhibition of BIM degradation. These findings warrant further studies of clinical applications of MEK1/2 inhibitors in cisplatin-based chemotherapy for lung cancer. PMID- 25541063 TI - Cytotoxic and genotoxic effects of high concentrations of the immunosuppressive drugs cyclosporine and tacrolimus in MRC-5 cells. AB - Immunosuppressive drugs are used to suppress immune system activity in transplant patients and reduce the risk of organ rejection. The present study evaluated the potential cytotoxic, genotoxic and mutagenic of the immunosuppressive drugs cyclosporine (CsA) and tacrolimus (FK-506) on normal human fibroblasts (MRC-5 cells). Based on plasma concentrations of the immunosuppressive drugs, which were obtained from the records of kidney transplant patients at the Kidney Institute of Londrina, Brazil, 11 concentrations of each immunosuppressive were chosen to evaluate cell viability using the MTT assay. From these results, CsA and FK-506 concentrations of 135, 300, 675, and 1520 ng/ml and 8, 16, 24, and 32 ng/ml, respectively, were evaluated using (i) the comet assay, (ii) the nuclear division index (NDI), (iii) the micronucleus test (CBMN) and (iv) cell proliferation curves generated by quantifying cell numbers and protein levels. In this study, 1520 to 3420 ng/ml CsA decreased cell viability after 48 h of exposure. Genotoxic effects were observed only with a concentration of 1520 ng/ml after 3h of exposure and with concentrations of 675 and 1520 ng/ml after 24h of exposure. Mutagenic effects were observed only for the concentration of 1520 ng/ml. FK-506 decreased cell viability after 72 h of exposure for concentrations up to 20 ng/ml; genotoxic effects were observed with concentrations up to 8 ng/ml for both treatment times (3 and 24h) and mutagenic effects were observed with concentrations of 24 and 32 ng/ml after 24h of treatment. The cell proliferation curves demonstrated the absence of cytostatic effects of these drugs, and these data were confirmed by the NDI analysis. Our results suggest that concentrations lower than 300 ng/ml of CsA and 16 ng/ml of FK-506 are safe for use, as they did not induce genotoxic and mutagenic damage or affect MRC-5 cell viability and proliferation. PMID- 25541061 TI - Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. AB - The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic. PMID- 25541064 TI - Reference values of olfactory function for Mexico City inhabitants. AB - BACKGROUND AND AIMS: Olfactory testing is useful in the differential diagnosis of age-related pathologies. To provide baseline reference values for clinical use in Mexico City we investigated the relation between olfactory capabilities and the principal population parameters of age, sex, and smoking habits in a large sample of healthy inhabitants. METHODS: We applied the internationally recognized and commercially available Sniffin' Sticks test battery to 916 men and women from across the adult life span. The Sniffin' Sticks test evaluates three key aspects of olfactory function: 1) ability to detect an odor, 2) to discriminate between odors, and 3) to identify odors. RESULTS: We found a significant decline in olfactory function from the 5th decade of age, and that detection threshold was the most sensitive measure of this. We did not find a significant difference between men and women or between smokers and non-smokers. In confirmation of our previous studies of the negative effect of air pollution on olfactory function, Mexico City inhabitants had poorer overall performance than corresponding subjects previously tested in the neighboring but less polluted Mexican state of Tlaxcala. CONCLUSIONS: Although we basically confirm findings on general demographic patterns of olfactory performance from other countries, we also demonstrate the need to take into account local cultural, environmental and demographic factors in the clinical evaluation of olfactory performance of Mexico City inhabitants. The Sniffin' Sticks test battery, with some adjustment of stimuli to correspond to Mexican culture, provides an easily administered means of assessing olfactory health. PMID- 25541065 TI - Monitoring changes in the nutritional content of ready-to-eat grain-based dessert products manufactured and purchased between 2005 and 2012. AB - BACKGROUND: Monitoring changes in the nutritional content of food/beverage products and shifts in consumer purchasing behaviors is needed to measure the effectiveness of efforts by both food manufacturers and policy makers to improve dietary quality in the United States. OBJECTIVE: To examine changes in the nutritional content (eg, energy, saturated fat, and sugar density) of ready-to eat (RTE) grain-based dessert (GBD) products manufactured and purchased between 2005 and 2012. DESIGN: Nutrition Facts panel information from commercial databases was linked to RTE GBD products purchased by households (N=134,128) in the Nielsen Homescan longitudinal dataset 2005-2012. STATISTICAL ANALYSIS: Linear regression models were used to examine changes in the energy, saturated fat, and sugar density of RTE GBD products manufactured in each year between 2005 and 2012. Random effects models controlling for demographics, household composition/size, and geographic location were used to examine changes in household purchases of RTE GBD products (in grams) and the average energy, saturated fat, and sugar density of RTE GBD products purchased. RESULTS: The saturated fat density (grams/100 g) of RTE GBD products increased significantly from 6.5+/-0.2 in 2005 to 7.3+/-0.2 and 7.9+/-0.2 for pre-existing and newly introduced products in 2012, respectively. Between 2005 and 2012, the energy density (kilocalories/100 g) of RTE GBD products purchased decreased significantly from 433+/-0.2 to 422+/-0.2, the saturated fat density (grams/100 g) of products purchased increased significantly from 6.3+/-0.01 to 6.6+/-0.01, the sugar density (grams/100 g) of products purchased decreased significantly from 32.4+/-0.03 to 31.3+/-0.02, and household purchases of RTE GBD products (in grams) decreased by 24.1%+/-0.4%. CONCLUSIONS: These results highlight an opportunity for both food manufacturers and public health officials to develop new strategies to shift consumer purchases toward products with lower energy, saturated fat, and sugar densities in addition to decreasing overall purchases of RTE GBDs. PMID- 25541066 TI - Effect of the ultrasound-assisted preliminary maceration on the efficiency of the essential oil distillation from selected herbal raw materials. AB - The objective of the study was the estimation of the ultrasound-assisted preliminary maceration effect on the efficiency of essential oil distillation and on its qualitative and quantitative composition. The experiment included analyses on three herbal materials, i.e. peppermint leaves (Mentha piperita L.), marjoram herb (Origanum majorana L.), and chamomile flowers (Chamomilla recutita (L.) Rauschert). The study showed that the application of preliminary water maceration of raw material, augmented with ultrasounds, had a statistically significant increasing effect on the amount of oil distilled, in the case of mint leaf from 1.32% to 1.46% v/w, and in the case of marjoram herb from 1.13% to 1.27% v/w. In the case of chamomile flowers no significant effect of ultrasound on the amount of oil obtained was observed. Generally, comparing the composition of essential oils obtained in the experiments with the requirements of the relevant standards no unfavourable effect of the distillation augmenting techniques applied was noted. Therefore, it should be expected that the studied distillates of volatile fractions will have the desired biological activity. PMID- 25541067 TI - ULTRASONOGRAPHY: on the way to becoming an internationally renowned journal. PMID- 25541068 TI - Henoch-Schonlein purpura: ultrasonography of scrotal and penile involvement. AB - Testicular or scrotal involvement has been reported in children with Henoch Schonlein purpura (HSP), but there are very few reports on penile involvement. We report the initial and follow-up ultrasonographic findings of scrotal and penile involvement of HSP in a 5-year-old boy. On ultrasonography, scrotal soft tissue thickening and epididymal swelling with increased vascularity were noted, and on the penis, a focal mass-like lesion appeared on the dorsal surface of the distal penis, having a hypoechoic mass-like appearance without visible vascular flow on a Doppler study. After 2 days of treatment, follow-up ultrasonography showed normal scrotum and penis with a resolved soft tissue mass-like lesion. Therefore, we think that HSP ultrasonographic findings involving the scrotum and penis might help to diagnose scrotal and penile involvement in a case of HSP and to avoid unnecessary medication and/or surgical procedures. PMID- 25541069 TI - Necrotic lymphoma in a patient with post-transplantation lymphoproliferative disorder: ultrasonography and CT findings with pathologic correlation. AB - Seventeen months after kidney transplantation for the treatment of nephrotic syndrome, a retroperitoneal mass was incidentally detected in a 30-year-old man during routine follow-up. Ultrasonography revealed a mass measuring 5.5 cm*4.3 cm located between the liver and the atrophic right kidney, which showed markedly heterogeneous internal echogenicity. Contrast-enhanced computed tomography displayed a mild degree of enhancement only at the periphery of the mass, while the center lacked perceivable intensification. The patient underwent surgical resection. The final pathological diagnosis was non-Hodgkin lymphoma (diffuse large B-cell lymphoma), and extensive necrosis was observed on microscopic examination. We found that the prominent heterogeneous echogenicity of the mass (an unusual finding of lymphoma) demonstrated on ultrasonography is a result of extensive necrosis, which may sometimes occur in patients with post transplantation lymphoproliferative disorder. PMID- 25541070 TI - Evaluation of a new standardized enzymatic isolation protocol for human umbilical cord-derived stem cells. AB - The umbilical cord (UC) represents an important source of mesenchymal stem cells (MSC). These human UC-derived MSC (UC-MSC) have already been isolated using a protocol based on the migratory and plastic adhesive properties of MSC (UC-MSC Mig). The UC-MSC-Mig isolation method, however, is difficult to standardize. Therefore, we developed an enzymatic isolation protocol (UC-MSC-Enz) to overcome the above mentioned disadvantages. First, we investigated the UC-MSC-Enz for their MSC properties. We found that UC-MSC-Enz express the MSC markers CD73, CD90 and CD105 and are able to differentiate into osteoblasts, adipocytes and chondroblasts fulfilling the MSC criteria of the International Society for Cellular Therapy. Previously we found that UC-MSC-Mig are unique among MSCs due to their significant expression of several hepatic (progenitor) markers. Therefore, we also investigated the expression of hepatic transcription factors and other hepatic markers in UC-MSC-Enz at both the mRNA and protein level. We found that the expression of hepatic transcription factors (GATA4, GATA6, SOX9 and SOX17) and hepatic markers (AFP, DPP4, CX43, DKK1, DSG2, KRT18 and KRT19) in UC-MSC-Enz was not significantly different from those of UC-MSC-Mig. Consequently, this optimized enzyme-based method represents a fast, robust and standardized way to isolate UC-MSC for a broad range of applications. PMID- 25541071 TI - Functional city zoning. Environmental assessment of eco-geological substance migration flows. AB - One of the unsolved problems today is that of the division of the natural (geochemical background) and anthropogenic components of substance migration flows, such as complex integrated systems in the supergene zone. Not only qualitative, but also quantitative assessment of each component allows greater understanding of the correlation between the processes within the geological body and their impact on the environment. This study is based on academic knowledge in the field of geological sciences and study group research-developments aimed at the detailed examination of the migration of pollutants in anthropogenically modified city soils and the creation of a methodological framework in the field of the geochemical zoning of substance migration flows in the hypergenesis zone. We demonstrate that certain parameters of "zero-level" pollutant concentration for functional area land use can be developed for each city - the state of the environment before the beginning of a new stage of technogenesis. PMID- 25541072 TI - Polychlorinated biphenyl exposure and corticosterone levels in seven polar seabird species. AB - The role of polychlorinated biphenyls (PCBs) on exposure-related endocrine effects has been poorly investigated in wild birds. This is the case for stress hormones including corticosterone (CORT). Some studies have suggested that environmental exposure to PCBs and altered CORT secretion might be associated. Here we investigated the relationships between blood PCB concentrations and circulating CORT levels in seven free-ranging polar seabird species occupying different trophic positions, and hence covering a wide range of PCB exposure. Blood ?7PCB concentrations (range: 61-115,632 ng/g lw) were positively associated to baseline or stress-induced CORT levels in three species and negatively associated to stress-induced CORT levels in one species. Global analysis suggests that in males, baseline CORT levels generally increase with increasing blood ?7PCB concentrations, whereas stress-induced CORT levels decrease when reaching high blood ?7PCB concentrations. This study suggests that the nature of the PCB CORT relationships may depend on the level of PCB exposure. PMID- 25541073 TI - On the chemical biology of the nitrite/sulfide interaction. AB - Sulfide (H2S/HS(-)) has been demonstrated to exert an astounding breadth of biological effects, some of which resemble those of nitric oxide (NO). While the chemistry, biochemistry and potential pathophysiology of the cross-talk between sulfide and NO have received considerable attention lately, a comparable assessment of the potential biological implications of an interaction between nitrite and sulfide is lacking. This is surprising inasmuch as nitrite is not only a known bioactive oxidation product of NO, but also efficiently converted to S-nitrosothiols in vivo; the latter have been shown to rapidly react with sulfide in vitro, leading to formation of S/N-hybrid species including thionitrite (SNO( )) and nitrosopersulfide (SSNO(-)). Moreover, nitrite is used as a potent remedy against sulfide poisoning in the clinic. The chemistry of interaction between nitrite and sulfide or related bioactive metabolites including polysulfides and elemental sulfur has been extensively studied in the past, yet much of this information appears to have been forgotten. In this review, we focus on the potential chemical biology of the interaction between nitrite and sulfide or sulfane sulfur molecules, calling attention to the fundamental chemical properties and reactivities of either species and discuss their possible contribution to the biology, pharmacology and toxicology of both nitrite and sulfide. PMID- 25541074 TI - Factors affecting quality of temperature models for the pre-appearance interval of forensically useful insects. AB - In the case of many forensically important insects an interval preceding appearance of an insect stage on a corpse (called the pre-appearance interval or PAI) is strongly temperature-dependent. Accordingly, it was proposed to estimate PAI from temperature by using temperature models for PAI of particular insect species and temperature data specific for a given case. The quality of temperature models for PAI depends on the protocols for PAI field studies. In this article we analyze effects of sampling frequency and techniques, temperature data, as well as the size of a sample on the quality of PAI models. Models were created by using data from a largely replicated PAI field study, and their performance in estimation was tested with external body of PAI data. It was found that low frequency of insect sampling distinctly deteriorated temperature models for PAI. The effect of sampling techniques was clearly smaller. Temperature data from local weather station gave models of poor quality, however their retrospective correction clearly improved the models. Most importantly, current results demonstrate that sample size in PAI field studies may be substantially reduced, with no model deterioration. Samples consisting of 11-14 carcasses gave models of high quality, as long as the whole range of relevant temperatures was studied. Moreover, it was found that carcasses exposed in forests and carcasses exposed in early spring are particularly important, as they ensure that PAI data is collected at low temperatures. A preliminary best practice model for PAI field studies is given. PMID- 25541075 TI - Evaluation and comparison of postmortem hydrocodone concentrations in peripheral blood, central blood and liver specimens: a minimal potential for redistribution. AB - Postmortem changes can alter the concentration of drugs in the vascular compartment as compared with concentrations originally present at the time of death. Numerous drugs have been reported to increase due to postmortem redistribution (PMR). The potential for PMR of hydrocodone, a therapeutic opioid analgesic used to manage pain, is of particular interest due to its wide use. Hydrocodone concentrations in 39 peripheral blood, central blood, and liver specimens were compared. Dihydrocodeine (DHC), a commonly encountered hydrocodone metabolite, was present in 61% of the cases with an average concentration that was 29% of the hydrocodone value. Central blood to peripheral blood hydrocodone ratios were well correlated (R(2)=0.965) with an average (+/-S.D.) of 1.3 (+/ 0.35) and a median of 1.2. The liver to peripheral blood (L/P) hydrocodone ratio was also well correlated (R(2)=0.915) with an average (+/-S.D.) of 3.4 (+/-1.7) L/kg and a median of 3.0 L/kg. This low L/P ratio suggests that hydrocodone is unlikely to undergo substantial PMR changes. PMID- 25541076 TI - The effects of dietary soybean isoflavones on growth, innate immune responses, hepatic antioxidant abilities and disease resistance of juvenile golden pompano Trachinotus ovatus. AB - The present study was conducted to investigate the effects of dietary soybean isoflavones (SI) supplementation on growth performance, innate immune responses, hepatic antioxidant abilities, heat shock protein 70 (HSP70) gene expression and resistance to the pathogen Vibrio harveyi in Trachinotus ovatus. A basal diet was supplemented with SI at 0, 10, 20, 40, 60, 80 mg kg(-1) feed for 8 weeks. Significantly maximum weight gain (WG) and specific growth rate (SGR) were observed in treatment with 40 mg kg(-1) SI supplement (P < 0.05). Feed conversion ratio (FCR), feeding rate (FR) and survival rate were not significantly different among treatments. Fish fed a diet with 40 mg kg(-1) SI showed significant increase in plasma total protein content, complement 3 content, lysozyme activity as well as respiratory burst activity, but decrease in alanine aminotransferase and aspartate aminotransferase activities (P < 0.05). Increased plasma alkaline phosphatase activity, hepatic total antioxidative capacity, catalase activity and superoxide dismutase activity were also noticed in fish fed SI at 40 or 60 mg kg( 1) (P < 0.05). On the contrary, the lowest hepatic malondialdehyde (MDA) content was observed in fish fed SI at 40 mg kg(-1) (P < 0.05). Compared with the control, the relative level of HSP70 mRNA in fish fed SI at 40-80 mg kg(-1) were significantly increased, respectively (P < 0.05). After challenge with V. harveyi, significant higher post-challenge survival was observed in fish fed diets with 40-80 mg kg(-1) SI supplement than that in control group (P < 0.05). These results indicated that dietary intake containing SI could enhance the immune ability of fish and improve its resistance to infection by V. harveyi. Especially supplementation with 40 mg kg(-1) SI to the fish for 8 weeks showed remarkable improvement in the growth, non-specific immune responses, hepatic antioxidant abilities and HSP70 gene expression. PMID- 25541077 TI - Generation and evaluation of virulence attenuated mutants of Edwardsiella tarda as vaccine candidates to combat edwardsiellosis in flounder (Paralichthys olivaceus). AB - Edwardsiella tarda is an intracellular pathogen that causes edwardsiellosis in fish. The development of a live attenuated vaccine may be an effective approach for preventing this disease in fish. In this study, we introduced deletions of esrB, esaC, evpH, rpoS, and purA into the E. tarda LSE40DeltaaroA strain, thereby generating five double-gene mutants (DeltaaroADeltaesrB, DeltaaroADeltaesaC, DeltaaroADeltarpoS, DeltaaroADeltaevpH, and DeltaaroADeltapurA) and two triple gene mutants (DeltaaroADeltaesrBDeltaevpH and DeltaaroADeltaesaCDeltaevpH). When blue gourami (Trichogaster trichopterus) was used as a fish model for the primary screening and evaluation of the vaccine candidates, all mutants were attenuated significantly by more than 2 to 3 logs in terms of the 50% lethal dose (LD(50)). Five double-gene mutants yielded relative percentage survival (RPS) rates of 26.1 82.6% after challenge with wild-type E. tarda. The DeltaaroADeltaesrB mutant that conferred the highest RPS (82.6%) in blue gourami was also evaluated in flounder (Paralichthys olivaceus). After vaccination via intramuscular (i.m.) injection or immersion, this mutant could persist in the flounder for 14-35 days and it induced higher serum antibody titers than the control fish (P < 0.01). Flounder vaccinated via i.m. injection at doses of 10(3)-10(7) CFU/fish had RPS rates of 14.3-66.7% after i.m. challenge with 10(4) CFU/fish using wild-type E. tarda. Flounder vaccinated via immersion at a dose of 10(7) CFU/ml exhibited 100% RPS against immersion challenge with 10(7) CFU/ml using wild-type E. tarda. These results indicate that the DeltaaroADeltaesrB mutant could be used as an effective live vaccine to combat edwardsiellosis in flounder. PMID- 25541078 TI - A novel phagocytic receptor (CgNimC) from Pacific oyster Crassostrea gigas with lipopolysaccharide and gram-negative bacteria binding activity. AB - Phagocytosis is an evolutionarily conserved process to ingest the invading microbes and apoptotic or necrotic corpses, playing vital roles in defensing invaders and maintenance of normal physiological conditions. In the present study, a new Nimrod family phagocytic receptor with three EGF-like domains was identified in Pacific oyster Crassostrea gigas (designated CgNimC). CgNimC shared homology with other identified multiple EGF-like domain containing proteins. The mRNA transcripts of CgNimC were mainly distributed in mantle and hemocytes. Its relative expression level in hemocytes was significantly (P < 0.01) up-regulated after the injection of bacteria Vibrio anguillarum. Different to the NimC in Drosophila and Anopheles gambiae, the recombinant protein of CgNimC (rCgNimC) could bind directly to two gram-negative bacteria V. anguillarum and Vibrio splendidus, but not to gram-positive bacteria Staphylococci aureus, Micrococcus luteus or fungi Yarrowia lipolytica and Pichia pastoris. The affinity of rCgNimC toward M. luteus and Y. lipolytica was enhanced when the microorganisms were pre incubated with the cell free hemolymph. rCgNimC exhibited higher affinity to lipopolysaccharide (LPS) and relatively lower affinity to peptidoglycan (PGN), while no affinity to glucan (GLU). After the CgNimC receptor was blocked by anti rCgNimC antibody in vitro, the phagocytic rate of hemocytes toward two gram negative bacteria V. anguillarum and V. splendidus was reduced significantly (P < 0.05), but no significant change of phagocytic rate was observed toward M. luteus and Y. lipolytica. All these results implied that CgNimC, with significant binding capability to LPS and gram-negative bacteria, was a novel phagocytic receptor involved in immune response of Pacific oyster. Further, it was speculated that receptors of Nimrod family might function as a phagocytic receptor to recognize PAMPs on the invaders and its recognition could be promoted by opsonization of molecules in hemolymph. PMID- 25541079 TI - Crayfish hematopoietic tissue cells but not hemocytes are permissive for white spot syndrome virus replication. AB - Hemocytes are the major immune cells of crustaceans which are believed to be essential for the pathogenesis of white spot syndrome virus (WSSV) infection. Crayfish hemocytes and hematopoietic tissue (HPT) cells have been found to be susceptible to WSSV infection, but the procedure of WSSV infection to both cell types has not yet been carefully investigated. In this study, we analyzed the infection and proliferation of WSSV in crayfish hemocytes as well as HPT cells in detail through transmission electronic microscopy (TEM). The results showed that WSSV could enter both hemocytes and HPT cells through endocytosis, but the production of progeny virus was only achieved in HPT cells. Further investigation demonstrated that although WSSV could transcribe its genes in both cell types, viral genome replication and structural protein expression were unsuccessful in hemocytes, which may be responsible for the failure of progeny production. Therefore, we propose that both hemocytes and HPT cells are susceptible to WSSV infection but only HPT cells are permissive to WSSV replication. These findings will extend our knowledge of the interaction between WSSV and the host immune system. PMID- 25541080 TI - Identification and characterization of the cDNAs encoding the two subunits of Chinese mitten crab (Eriocheir sinensis) calcineurin: their implications in stress and immune response. AB - Calcineurin (CN), the only Ca(2+)/calmodulin-activated serine/threonine protein phosphatase, is a key effector participating in Ca(2+)-dependent signal transduction pathways in a number of cellular processes under normal, stress and pathological conditions. However, the expression and the relevance of CN in stress and immune response have not been characterized in crustaceans. Here, we identified the cDNAs that encode the two subunits of CN (termed EsCN-A and EsCN B, respectively) in Chinese mitten crab Eriocheir sinensis and analysed their expression patterns in response to stress and immune challenges. The catalytic subunit EsCN-A is comprised of 511 amino acids with a theoretical molecular mass of 57.5 kDa and shows 80% sequence identity with human beings CN-A alpha isoform, while the regulatory subunit EsCN-B protein is composed of 170 amino acids with an estimated molecular mass of 19.3 kDa and shares 88% sequence identity with human beings CN-B type 1. Tissue distribution analysis reveals that both EsCN-A and EsCN-B mRNA transcripts are expressed in all tested tissues with the greatest expression in hepatopancreas and the lowest expression in haemocytes. In addition, both EsCN-A and EsCN-B genes could be significantly up-regulated but with different expression patterns by ambient salinity (150/00 and 300/00 salinities) and pH (pH 6 and 8.5) stresses in gill, hepatopancreas, haemocytes, intestine and muscle. Furthermore, EsCN-A and EsCN-B were up-regulated by LPS and Poly(I:C) immune stimulations in E. sinensis haemocytes in vitro. Moreover, EsCN A and EsCN-B mRNA were significantly up-regulated in haemocytes, gill, hepatopancreas, intestine and muscle in response to Edwardsiella tarda challenge in vivo. Finally, we revealed the importance of EsCN in LPS-induced nitric oxide production in E. sinensis haemocytes. Together our observations suggest that EsCN, the important downstream effector of CaM-mediated signalling pathway(s), may possess vital roles in stress and immune response in the Chinese mitten crab. PMID- 25541081 TI - Cognitive informatics in biomedicine and healthcare. AB - Cognitive Informatics (CI) is a burgeoning interdisciplinary domain comprising of the cognitive and information sciences that focuses on human information processing, mechanisms and processes within the context of computing and computer applications. Based on a review of articles published in the Journal of Biomedical Informatics (JBI) between January 2001 and March 2014, we identified 57 articles that focused on topics related to cognitive informatics. We found that while the acceptance of CI into the mainstream informatics research literature is relatively recent, its impact has been significant - from characterizing the limits of clinician problem-solving and reasoning behavior, to describing coordination and communication patterns of distributed clinical teams, to developing sustainable and cognitively-plausible interventions for supporting clinician activities. Additionally, we found that most research contributions fell under the topics of decision-making, usability and distributed team activities with a focus on studying behavioral and cognitive aspects of clinical personnel, as they performed their activities or interacted with health information systems. We summarize our findings within the context of the current areas of CI research, future research directions and current and future challenges for CI researchers. PMID- 25541082 TI - IFN-alpha induces IL-10 production and tilt the balance between Th1 and Th17 in Behcet disease. AB - BACKGROUND AND AIMS: Interferon alpha (IFN-alpha) is an effective treatment for patients with active Behcet disease (BD). Besides its antiviral property, IFN alpha is a cytokine with pleiotropic effects that can generate an anti inflammatory environment or inhibit specific inflammatory T cells such as Th1 and Th17 cells. However, it is not known, in BD patients, whether IFN-alpha inhibits pro inflammatory T cells, or induces anti-inflammatory properties in T cells. METHODS: Total memory CD45RO(+) T cells purified from peripheral blood mononuclear cells (PBMCs) obtained from patients with active BD (N=5), systemic lupus erythematosus (SLE, N=5) or healthy control (HC, N=6) were cultured in vitro with or without IFN-alpha. Levels of IFN-gamma, IL-17, IL-10, IL-6, and TNF alpha in the supernatants were analyzed by ELISA, Cytometric Beads Array (CBA) or intracellular cytokine staining. We analyzed the production of IL-10 on the memory subsets Th1 (mTh1), Th2 (mTh2) and Th17 (mTh17). RESULTS: IFN-alpha significantly increased IFN-gamma level in memory CD4(+) T cells in BD patients and HC, but not SLE patients. IL17 was not inhibited by IFN-alpha in BD or in SLE patients. However, IFN-alpha modulated the pro- and anti-inflammatory cytokines secreted by T cells as it increased the IL-10/IL-6 ratio in BD and HC, but not SLE patients. We further demonstrated that IFN-alpha increased IL-10 secretion in each memory subset mTh1, mTh2 and mTh17. CONCLUSIONS: In BD, IFN-alpha promotes a regulatory Th1 response through IL-10 secretion. This effect may explain the efficacy of IFN-alpha in inflammatory disease. PMID- 25541083 TI - Computational Fluid Dynamics to Evaluate the Management of a Giant Internal Carotid Artery Aneurysm. AB - BACKGROUND: Giant intracranial aneurysms are rare lesions that present uniquely complex therapeutic challenges. Computational fluid dynamics (CFD) has been used to simulate the hemodynamic environments of developing and ruptured cerebral aneurysms. In this study, we use CFD to examine retrospectively hemodynamic changes during the complicated clinical course of a giant carotid aneurysm. OBJECTIVE: To take an innovative, CFD-based approach to retrospective analysis of the surgical management and clinical course of a giant carotid aneurysm. METHODS: Pre- and posttreatment image data were first segmented to produce computational aneurysm models. Flow within the models was then simulated using CFD. Simulated flow and wall shear stress (WSS) profiles were analyzed and used to examine hemodynamic changes during the clinical course of the patient, after 2 independent treatments. RESULTS: Greater WSS magnitudes and a more localized flow impingement region were observed at the distal portion of the aneurysm after both clinical interventions. These relative, acute changes in hemodynamic features at the distal aneurysm wall were greatest after the second intervention and may have preceded rupture of the aneurysm in that region. CONCLUSIONS: The application of CFD to the management of a giant intracranial aneurysm showed unexpected posttreatment changes in flow and WSS profiles. The simulation results offer a viable explanation for the observed clinical course. This study demonstrates potential for the use of CFD preoperatively for decision-making in the surgical and endovascular management of intracranial aneurysms. PMID- 25541084 TI - External Ventricular Drains versus Intraparenchymal Intracranial Pressure Monitors in Traumatic Brain Injury: A Prospective Observational Study. AB - BACKGROUND: Intracranial pressure (ICP) monitoring is the standard of care for patients with traumatic brain injury (TBI) and is used frequently. However, the efficacy of treatment based on the type of ICP monitor used for improving patient outcome has not been assessed prospectively. This study explores whether the type of ICP monitoring device used affects the neurologic outcomes of patients with TBI. METHODS: A prospective, observational study was conducted in 122 patients with TBI >=13 years old with indications for monitoring who were being treated in neurosurgical intensive care units between January 2009 and December 2012. All enrolled patients required monitoring randomly using an external ventricular drain (EVD) or intraparenchymal fiberoptic monitor (IPM). Patients were placed into 2 groups depending on the type of monitoring device. Clinically relevant outcomes, refractory intracranial hypertension, survival rates, and device related complications were compared between the 2 groups. RESULTS: There was a significant between-group difference in the Glasgow Outcome Scale score 6 months after injury, which was the primary outcome. Refractory intracranial hypertension was diagnosed in 44 of 122 patients, and patients monitored using IPM had a higher percentage of refractory intracranial hypertension (51.7% vs. 21.0%, P < 0.001). The 1-month survival rate was 90.3% in the EVD group and 76.7% in the IPM group (log-rank test, P = 0.04), and patients managed with EVDs had a significantly higher 6-month postinjury survival rate compared with patients treated with IPMs (88.7% vs. 68.3%, log-rank test, P = 0.006). There was no statistically significant difference between the groups in device-related complications (P = 0.448). CONCLUSIONS: Device selection for ICP monitoring provides prognostic discrimination, and use of EVDs may have a bigger advantage in controlling refractory intracranial hypertension. Based on our findings, we recommend routine placement of an EVD in patients with TBI, unless only parenchymal-type monitoring is available. PMID- 25541085 TI - Treatment and outcomes among 102 posterior inferior cerebellar artery aneurysms: a comparison of endovascular and microsurgical clip ligation. AB - BACKGROUND: The vicinity of brainstem and cranial nerves as well as the limited operative working space make clip ligation of posterior inferior cerebellar artery (PICA) aneurysms challenging. The small caliber of the PICA and the broad neck often associated with these aneurysms also create challenges in preserving this artery during treatment. Few data exist to compare the 2 treatment approaches for aneurysms in this location. OBJECT: To assess treatment outcomes for PICA aneurysms based on mode of management and anatomical location. METHODS: A prospectively maintained database was queried for PICA aneurysms treated from 2000 through 2012. Patients were categorized on the basis of their aneurysm's anatomical location, presentation status, treatment modality, and subsequent complications. Descriptive, univariate, and multivariate statistical analyses were performed. RESULTS: A total of 113 PICA aneurysms were identified; 11 did not undergo treatment. Of the remaining 102 aneurysms, 77% were ruptured and 64% were treated microsurgically. In the ruptured group, patients with more proximally located aneurysms such as vertebral and proximal PICA aneurysms were more likely to experience hydrocephalus and cranial nerve deficits after treatment. Endovascular therapy was less likely to cause postoperative deficit or lead to a need for percutaneous endoscopic gastrostomy. Most importantly, discharge, 6-month, and 1-year outcomes were predicted based on presenting Hunt and Hess score and patient's age, not aneurysm location or management mode. CONCLUSIONS: PICA aneurysms are challenging and require a multimodality treatment paradigm. Although microsurgery is associated with more short-term postoperative complications, presenting grade and patient's age remain the primary predictors of long-term outcome. PMID- 25541086 TI - Proximity to busy highways and local resident perceptions of air quality. AB - This study investigated variations in perceptions of air quality as a function of residential proximity to busy highways, across two suburbs of South Auckland, New Zealand. While plenty is known about the spatial gradients of highway emissions, very little is known about variation of lay understanding at the fine spatial scale and whether there are gradients in severity of concerns. One-hundred and four near-highway residents agreed to participate in a semi-structured interview on their knowledge and attitudes towards highway traffic emissions. Proximity to the highway edge varied within 5-380 m at the predominantly downwind side of the highway and 13-483 m at the upwind side. Likert-type ordered response questions were analysed using multivariate regression. Inverse linear relationships were identified for distance from highway and measures of concern for health impacts, as well as for noise (p<0.05). Positive linear relationships were identified for distance from highway and ratings of both outdoor and indoor air quality (p<0.05). Measures of level of income had no conclusive statistically significant effect on perceptions. Additional discussion was made surrounding participant's open-ended responses, within the context of limited international research. Findings indicate that there may be quantifiable psychological benefits of separating residents just a short distance (40 m+) from highways and that living within such close proximity can be detrimental to wellbeing by restricting local outdoor activity. This work lends additional rationale for a residential separation buffer of ~100 m alongside major highways in the interests of protecting human health. PMID- 25541088 TI - Preparation of janus particles with different stabilizers and formation of one dimensional particle arrays. AB - Janus particles with two hemispheres having different stabilizers, a polystyrene (PS) phase stabilized by poly(acrylic acid) (PAA) (PS(PAA)) and a poly(methyl methacrylate) (PMMA) phase stabilized by poly(vinylpyrrolidone) (PVP) (PMMA(PVP)), were synthesized by the solvent-absorbing/releasing method of PS(PAA)/PMMA(PVP) composite particles with a core-shell structure. The PS(PAA)/PMMA(PVP) composite particles were prepared by seeded dispersion polymerization of MMA using PVP as stabilizer in the presence of PS seed particles stabilized by PAA. We also demonstrated the facile formation of the colloidal chains via hydrogen bonding interaction between different stabilizers. PMID- 25541087 TI - Depressive-like behaviors in a rat model of chronic cerebral hypoperfusion. AB - The vascular depression hypothesis suggests that there is an association between cerebrovascular pathophysiology and depression in the elderly. We investigated depressive-like behaviors and perturbations in the hypothalamus-pituitary-adrenal (HPA) axis in a rat model of chronic cerebral hypoperfusion. We modeled chronic cerebral hypoperfusion by permanent occlusion of the bilateral common carotid arteries (BCCAo) in Wistar rats. Sucrose preference, forced swim, and social interaction tests were performed to measure depressive-like behaviors. The plasma levels of adrenocorticotropic hormone and corticosterone, and the hippocampal expression of the glucocorticoid receptor (GR) were assessed. Sucrose preference (P = 0.045) and social withdrawal (P = 0.038) were significantly enhanced in BCCAo rats. Increased plasma levels of corticosterone (P = 0.034) and impaired cytosolic-to-nuclear translocation of the GR protein were observed in the hippocampus (P = 0.038) of BCCAo rats. Our experimental results support the clinical hypothesis that vascular depression can be induced by chronic cerebral hypoperfusion. Increased HPA axis activity and perturbation of the GR signaling pathway in the hippocampus may be associated with depressive-like behaviors in rats with chronic cerebral hypoperfusion. PMID- 25541089 TI - The problems of antibiotic resistance in cystic fibrosis and solutions. AB - Chronic respiratory infection is the main cause of morbidity and mortality in cystic fibrosis (CF) patients. One of the hallmarks of these infections, led by the opportunistic pathogen Pseudomonas aeruginosa, is their long-term (lifelong) persistence despite intensive antimicrobial therapy. Antimicrobial resistance in CF is indeed a multifactorial problem, which includes physiological changes, represented by the transition from the planktonic to the biofilm mode of growth and the acquisition of multiple (antibiotic resistance) adaptive mutations catalyzed by frequent mutator phenotypes. Emerging multidrug-resistant CF pathogens, transmissible epidemic strains and transferable genetic elements (such as those encoding class B carbapenemases) also significantly contribute to this concerning scenario. Strategies directed to combat biofilm growth, prevent the emergence of mutational resistance, promote the development of novel antimicrobial agents against multidrug-resistant strains and implement strict infection control measures are thus needed. PMID- 25541090 TI - Derivative multiple reaction monitoring and single herb calibration approach for multiple components quantification of traditional Chinese medicine analogous formulae. AB - In comparison with monotherapy in western medicine, traditional Chinese medicine (TCM) advocates combinational therapy for treating diseases and TCM formula is a representative for this approach. Despite of extensive clinical applications of TCM formulae, knowledge about their pharmacological activities, mechanisms of action and cellular targets remains limited. A main contributing factor to these unanswered questions is unavailability of chemical compositions and their contents in the formulae. Several challenges hinder global qualitative and quantitative analysis of the formulae, including large quantities of constituents, potential physicochemical changes during decoction and lack of authentic standards. Herein we introduced an integrated strategy based on liquid chromatography coupled with mass spectrometry (LC-MS) systems to address such challenges. First, liquid chromatography-ion trap and quadrupole time-of-flight mass spectrometry (LC-IT/MS and LC-QTOF/MS) were utilized to characterize chemical profiling of the formulae. Meanwhile, MS(2) of IT/MS produced major parameters for derivative multiple reaction monitoring (DeMRM) on liquid chromatography-triple quadrupole mass spectrometry (LC-TQ/MS), which offered rapid and direct transition design in the quantitative assay. Instead of authentic standards, serial dilutions of single herbs were employed in this study to construct calibration curves necessary for calculating relative concentrations of components. Xiao-Banxia decoction and its four analogous formulae were then taken to exemplify the feasibility of currently proposed methodology. Among the 160 qualitatively identified components, a total of 138 components were semi quantified for these decoctions. Based on these results, we demonstrated that co decoction of different herbs could result in concentration variations of components and this effect was more prominent when certain herbs were combined. Our results indicated that the present strategy would significantly contribute to chemical studies on TCM and its utilities could be extended to other research fields, such as metabolomics and comparative chemistry. PMID- 25541091 TI - Herbs and spices: characterization and quantitation of biologically-active markers for routine quality control by multiple headspace solid-phase microextraction combined with separative or non-separative analysis. AB - Herbs and spices are used worldwide as food flavoring, thus determination of their identity, origin, and quality is mandatory for safe human consumption. An analysis strategy based on separative (HS-SPME-GC-MS) and non-separative (HS-SPME MS) approaches is proposed for the volatile fraction of herbs and spices, for quality control and to quantify the aromatic markers with a single analysis directly on the plant material as such. Eight-to-ten lots of each of the following herbs/spices were considered: cloves (Syzygium aromaticum (L.) Merr. & Perry), American peppertree (Schinus molle L.), black pepper and white pepper (Piper nigrum L.), rosemary (Rosmarinus officinalis L.), sage (Salvia officinalis L.) and thyme (Thymus vulgaris L.). Homogeneity, origin, and chemotypes of the investigated lots of each herb/spice were defined by fingerprinting, through statistical elaboration with principal component analysis (PCA). Characterizing aromatic markers were directly quantified on the solid matrix through multiple headspace extraction-HS-SPME (MHS-SPME). Reliable results were obtained with both separative and non-separative methods (where the latter were applicable); the two were in full agreement, RSD% ranging from 1.8 to 7.7% for eugenol in cloves, 2.2 18.4% for carvacrol+thymol in thyme, and 3.1-16.8% for thujones in sage. PMID- 25541093 TI - Congenital malformations in newborns--a challenge unmet for decades. PMID- 25541092 TI - Fabricating electrospun cellulose nanofibre adsorbents for ion-exchange chromatography. AB - Protein separation is an integral step in biopharmaceutical manufacture with diffusion-limited packed bed chromatography remaining the default choice for industry. Rapid bind-elute separation using convective mass transfer media offers advantages in productivity by operating at high flowrates. Electrospun nanofibre adsorbents are a non-woven fibre matrix of high surface area and porosity previously investigated as a bioseparation medium. The effects of compression and bed layers, and subsequent heat treatment after electrospinning cellulose acetate nanofibres were investigated using diethylaminoethyl (DEAE) or carboxylate (COO) functionalisations. Transbed pressures were measured and compared by compression load, COO adsorbents were 30%, 70% and 90% higher than DEAE for compressions 1, 5 and 10MPa, respectively, which was attributed to the swelling effect of hydrophilic COO groups. Dynamic binding capacities (DBCs) at 10% breakthrough were measured between 2000 and 12,000CV/h (2s and 0.3s residence times) under normal binding conditions, and DBCs increased with reactant concentration from 4 to 12mgBSA/mL for DEAE and from 10 to 21mglysozyme/mL for COO adsorbents. Comparing capacities of compression loads applied after electrospinning showed that the lowest load tested, 1MPa, yielded the highest DBCs for DEAE and COO adsorbents at 20mgBSA/mL and 27mglysozyme/mL, respectively. At 1MPa, DBCs were the highest for the lowest flowrate tested but stabilised for flowrates above 2000CV/h. For compression loads of 5MPa and 10MPa, adsorbents recorded lower DBCs than 1MPa as a result of nanofibre packing and reduced surface area. Increasing the number of bed layers from 4 to 12 showed decreasing DBCs for both adsorbents. Tensile strengths were recorded to indicate the mechanical robustness of the adsorbent and be related to packing the nanofibre adsorbents in large scale configurations such as pleated cartridges. Compared with an uncompressed adsorbent, compressions of 1, 5 and 10MPa showed increases of 30%, 110% and 110%, respectively, for both functionalisations. The data presented show that capacity and mechanical strength can be balanced through compression after electrospinning and is particular to different functionalisations. This trade-off is critical to the development of nanofibre adsorbents into different packing configurations for application and scale up in bioseparation. PMID- 25541094 TI - Spreading codes enables the blind estimation of the hemodynamic response with short-events sequences. AB - Finite impulse response (FIR) filters are considered the least constrained option for the blind estimation of the hemodynamic response function (HRF). However, they have a tendency to yield unstable solutions in the case of short-events sequences. There are solutions based on regularization, e.g. smooth FIR (sFIR), but at the cost of a regularization penalty and prior knowledge, thus breaking the blind principle. In this study, we show that spreading codes (scFIR) outperforms FIR and sFIR in short-events sequences, thus enabling the blind and dynamic estimation of the HRF without numerical instabilities and the regularization penalty. The scFIR approach was applied in short-events sequences of simulated and experimental functional magnetic resonance imaging (fMRI) data. In general terms, scFIR performed the best with both simulated and experimental data. While FIR was unable to compute the blind estimation of two simulated target HRFs for the shortest sequences (15 and 31 events) and sFIR yielded shapes barely correlated with the targets, scFIR achieved a normalized correlation coefficient above 0.9. Furthermore, scFIR was able to estimate in a responsive way dynamic changes of the amplitude of a simulated target HRF more accurately than FIR and sFIR. With experimental fMRI data, the ability of scFIR to estimate the real HRF obtained from a training data set was superior in terms of correlation and mean-square error. The use of short-events sequences for the blind estimation of the HRF could benefit patients in terms of scanning time or intensity of magnetic field in clinical tests. Furthermore, short-events sequences could be used, for instance, on the online detection of rapid shifts of visual attention that, according to literature, entails rapid changes in the amplitude of the HRF. PMID- 25541095 TI - Real-time EEG-based detection of fatigue driving danger for accident prediction. AB - This paper proposes a real-time electroencephalogram (EEG)-based detection method of the potential danger during fatigue driving. To determine driver fatigue in real time, wavelet entropy with a sliding window and pulse coupled neural network (PCNN) were used to process the EEG signals in the visual area (the main information input route). To detect the fatigue danger, the neural mechanism of driver fatigue was analyzed. The functional brain networks were employed to track the fatigue impact on processing capacity of brain. The results show the overall functional connectivity of the subjects is weakened after long time driving tasks. The regularity is summarized as the fatigue convergence phenomenon. Based on the fatigue convergence phenomenon, we combined both the input and global synchronizations of brain together to calculate the residual amount of the information processing capacity of brain to obtain the dangerous points in real time. Finally, the danger detection system of the driver fatigue based on the neural mechanism was validated using accident EEG. The time distributions of the output danger points of the system have a good agreement with those of the real accident points. PMID- 25541096 TI - Granular cell tumor of the breast: a case report. AB - INTRODUCTION: A granular cell tumor involving the breast parenchyma was first described by Abrikossoff in 1931. Localization of this lesion to the breast is very rare, accounting for between 5% and 15% of all granular cell tumor cases. We present this case because of the rarity of this tumor. It is frequently confused with breast carcinoma on clinical and radiological examination, and its diagnosis can therefore be challenging for clinicians, radiologists and pathologists. CASE PRESENTATION: We report the case of a 32-year-old Moroccan woman who presented with a palpable mass in her right breast. Mammography and ultrasound examination revealed a heterogeneous, irregular and poorly limited mass, located at the union of the outer quadrants of her right breast. The mass was in contact with her latissimus dorsi and suspicious for malignancy. A histological examination combined with immunohistochemical study revealed it to be a granular cell tumor. CONCLUSION: Although a granular cell tumor of the breast is a rare breast neoplasm, it should be considered in the differential diagnosis of benign and malignant lesions. Pathologists should bear in mind a granular cell tumor when examining material containing cells with abundant granular cytoplasm to avoid misdiagnosing breast carcinoma, which could lead to unnecessary surgery. PMID- 25541097 TI - Successful treatment of open jaw and jaw deviation dystonia with botulinum toxin using a simple intraoral approach. AB - Oromandibular dystonia (OMD) is a focal dystonia that involves the mouth, jaw, and/or tongue. It can be classified as idiopathic, tardive dystonia or secondary to other neurological disorders and subdivided into jaw opening, jaw closing, jaw deviation and lip pursing. The muscles involved in jaw opening dystonia are usually the digastrics and lateral pterygoids. It is known that the lateral pterygoids may be approached both internally and externally. The external approach is the most common; however neurologists experienced in treating patients with botulinum toxin can safely and with no extra cost perform the intraoral procedure. We report our experience in the treatment of jaw opening and jaw deviation dystonia using the intraoral injection approach. Eight patients were selected from the University of Florida with a clinical diagnosis of open jaw/jaw deviation dystonia. All of them were injected with onabotulinum toxin A using the internal approach and the clinical global impression scale was applied. The mean age of the patients was 67 (standard deviation [SD] 10.2) years, with a disease duration of 10.2 (SD 7.7) years and the mean distance they traveled to our institution was 448 km (278 miles). After treatment, six patients scored as very much improved in the clinical global impression scale and two patients scored as much improved. Only one patient reported an adverse event of nasal speech following one of the injections that improved after 4 weeks. Botulinum toxin injections for open jaw/jaw deviation dystonia can be safely performed with the intraoral approach without the need of special devices other than electromyography. PMID- 25541098 TI - Reversible morbidity markers in subclinical hypothyroidism. AB - IMPORTANCE: Subclinical hypothyroidism (SCH) is a common clinical entity with a putative role in a wide range of disorders. The impact of SCH on mortality and markers of morbidity has been demonstrated, but studies have shown inconsistent results. Evidence regarding the effect of levothyroxine treatment on reversing morbidity markers is emerging, but the value of treatment is still unclear. OBJECTIVE: The objectives of this review were to assess recent, high-quality studies evaluating the role of SCH in cardiovascular health, cognition, mood, pregnancy, anemia, and renal disease; to examine the effects of levothyroxine on reducing mortality or reversing markers of morbidity in these conditions; and to consider how new research insights may help guide clinical practice. EVIDENCE REVIEW: A PubMed search was conducted (using 'subclinical hypothyroidism' [Title/Abstract] AND morbidity [MeSH Subheading] as search criteria) and was restricted to human studies published in the English language between 1990 and 2013. Subsequent searches of retrieved articles yielded further studies, which were included based on quality. Emphasis was given to large observational studies, well-conducted meta-analyses, and randomized controlled trials. FINDINGS: The difficulty of diagnosing SCH, particularly in the elderly, may underlie many of the conflicting results seen in the literature. Increased understanding of the at-risk patient population will result in better selection of study subjects and, likely, unequivocal results. Regardless of the current confusion, emerging evidence suggests that certain markers of morbidity are reversed by levothyroxine therapy across the disorders examined here. CONCLUSION AND RELEVANCE: Future large, well-controlled studies will not only clarify the role of SCH but also help identify patients for whom levothyroxine treatment will provide the most benefit. PMID- 25541099 TI - A 3-year follow-up of ceria-stabilized zirconia/alumina nanocomposite (Ce-TZP/A) frameworks for fixed dental prostheses. AB - PURPOSE: Zirconia/alumina nanocomposite stabilized with cerium oxide (Ce-TZP/A) shows significantly higher mechanical strength than yttrium-oxide-partially stabilized zirconia (Y-TZP) and allows post-sintered machining that does not require any subsequent treatment. The aim of this prospective study was to assess the clinical performance of veneered Ce-TZP/A frameworks for fixed dental prostheses. METHODS: Fifteen patients with 22 Ce-TZP/A fixed prostheses were included in this study. The fixed dental prostheses were cemented with resin cement (baseline) and were evaluated at baseline and at 1, 6, 12, 24 and 36 months after cementation. Clinical events, including fracture and loss of retention, secondary caries, and marginal integrity, were recorded. The biologic outcome was judged by comparing the pre-treatment and post-treatment bleeding on probing (BOP), and probing pocket depth (PPD) of the abutment teeth. Radiographic examination was also performed at 12, 24 and 36 months. RESULTS: The mean observation period was 35.9+/-5.5 months. During this period, one abutment tooth was extracted due to root fracture and the survival rate was 95.2%. No significant change in BOP, PPD, and radiographic image was found during the 36 month follow-up period. CONCLUSION: Within the limitations of this study, Ce TZP/A was found to provide sufficient stability as a framework material in all regions. Special attention, however, must be paid to designing framework that provides sufficient support for the veneer. Furthermore, studies with longer observation periods and more patients are needed. PMID- 25541101 TI - Is BRIEF a useful instrument in day to day care of patients with phenylketonuria? AB - OBJECTIVES: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. STUDY DESIGN: Adult PKU patients (n = 55; mean age 28.3 +/- 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). RESULTS: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. CONCLUSIONS: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients. PMID- 25541100 TI - Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II. AB - The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. METHODS: As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. RESULTS: While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. CONCLUSIONS: Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient. PMID- 25541102 TI - Shotgun proteomics reveals possible mechanisms for cognitive impairment in Mucopolysaccharidosis I mice. AB - Mucopolysaccharidosis type I (MPS I) is due to deficient alpha-L-iduronidase (IDUA) which leads to storage of undegraded glycosaminoglycans (GAG). The severe form of the disease is characterized by mental retardation of unknown etiology. Trying to unveil the mechanisms that lead to cognitive impairment in MPS I, we studied alterations in the proteome from MPS I mouse hippocampus. Eight-month old mice presented increased LAMP-1 expression, GAG storage in neurons and glial cells, and impaired aversive and non-aversive memory. Shotgun proteomics was performed and 297 proteins were identified. Of those, 32 were differentially expressed. We found elevation in proteins such as cathepsins B and D; however their increase did not lead to cell death in MPS I brains. Glial fibrillary acid protein (GFAP) was markedly elevated, and immunohistochemistry confirmed a neuroinflammatory process that could be responsible for neuronal dysfunction. We didn't observe any differences in ubiquitin expression, as well as in other proteins related to protein folding, suggesting that the ubiquitin system is working properly. Finally, we observed alterations in several proteins involved in synaptic plasticity, including overexpression of post synaptic density-95 (PSD95) and reduction of microtubule-associated proteins 1A and 1B. These results together suggest that the cognitive impairment in MPS I mice is not due to massive cell death, but rather to neuronal dysfunction caused by multiple processes, including neuroinflammation and alterations in synaptic plasticity. PMID- 25541103 TI - Satisfaction with care and decision making among parents/caregivers in the pediatric intensive care unit: a comparison between English-speaking whites and Latinos. AB - PURPOSE: Because of previously documented health care disparities, we hypothesized that English-speaking Latino parents/caregivers would be less satisfied with care and decision making than English-speaking non-Latino white (NLW) parents/caregivers. MATERIALS AND METHODS: An intensive care unit (ICU) family satisfaction survey, Family Satisfaction in the Intensive Care Unit Survey (pediatric, 24 question version), was completed by English-speaking parents/caregivers of children in a cardiothoracic ICU at a university-affiliated children's hospital in 2011. English-speaking NLW and Latino parents/caregivers of patients, younger than 18 years, admitted to the ICU were approached to participate on hospital day 3 or 4 if they were at the bedside for greater than or equal to 2 days. Analysis of variance, chi(2), and Student t tests were used. Cronbach alphas were calculated. RESULTS: Fifty parents/caregivers completed the survey in each group. Latino parents/caregivers were younger, more often mothers born outside the United States, more likely to have government insurance or no insurance, and had less education and income. There were no differences between the groups' mean overall satisfaction scores (92.6 +/- 8.3 and 93.0 +/- 7.1, respectively; P = .80). The Family Satisfaction in the Intensive Care Unit Survey (pediatric, 24 question version) showed high internal consistency reliability (alpha = .95 and .91 for NLW and Latino groups, respectively). CONCLUSIONS: No disparities in ICU satisfaction with care and decision making between English speaking NLW and Latino parents/caregivers were found. PMID- 25541105 TI - Epilogue. PMID- 25541104 TI - sTREM-1 predicts intensive care unit and 28-day mortality in cancer patients with severe sepsis and septic shock. AB - INTRODUCTION: The innate immune response molecules and their use as a predictor of mortality in cancer patients with severe sepsis and septic shock are poorly investigated. OBJECTIVE: To analyze the value of interleukin (IL)-1beta, IL-6, IL 8, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), and high-mobility group box 1 (HMGB-1) as predictors of mortality in cancer patients with severe sepsis and septic shock compared with septic patients without malignancies. DESIGN: Prospective, observational cohort study. SETTING: Tertiary level adult intensive care unit (ICU). SUBJECTS: Seventy-five patients with severe sepsis or septic shock, 40 with cancer and 35 without. INTERVENTIONS AND MEASUREMENTS: Laboratory data were collected at ICU admission, 24 and 48 hours after. Plasma concentrations of HMGB-1 and sTREM-1 were measured by enzyme-linked immunosorbent assay, whereas cytokines were measured by cytometric bead array. RESULTS: Intensive care unit mortality in cancer and noncancer patients was 40% and 28.6% (P = .29), and 28-day mortality was 45% and 34.3% (P = .34). Proinflammatory cytokines IL-1beta, IL-6, IL-8, IL-12, and TNF-alpha showed significantly higher values in the cancer group. Interleukin-10 at 48 hours (P = .01), sTREM-1 in all measurements (P < .01) and HMGB-1 at 24 hours (P < .01) showed significantly lower values in the cancer group. In addition, for the cancer group, sTREM-1 at 24 hours (P = .02) and 48 hours (P = .01) showed higher levels in nonsurvivors patients. The area under the receiver operating characteristic curve for predicting ICU mortality for sTREM-1 was 0.73 (95% confidence interval, 0.57 0.89; P = .01). Multivariate logistic analysis showed that the days spent in mechanical ventilation and levels of sTREM-1 and IL-1beta at 48 hours were independent predictors of ICU mortality; corticosteroids requirement and levels of sTREM-1 and TNF-alpha at 24 hours were independent predictors of 28-day mortality. CONCLUSIONS: Patients with cancer have different immune profile in sepsis when compared with patients without cancer, as demonstrated for levels of cytokines, sTREM-1 and HMGB-1. sTREM-1 and days spent in mechanical ventilation proved to be good predictors of ICU and 28-day mortality in cancer patients. PMID- 25541106 TI - Clearing the air: steps for lung cancer screening success. AB - The results from the National Lung Screening Trial and the subsequent United States Preventative Services Task Force grade B recommendation in favor of using a screening low-dose chest computed tomography (S-LDCT) for early detection of lung cancer have generated a lot of excitement in the lung cancer community. Although that excitement has been tempered by the Medicare Evidence Development and Coverage Advisory Committee's recent decision not to recommend that Medicare cover S-LDCT, screening computed tomography remains a popular topic in medical imaging literature. As many practices are now considering implementing these S LDCT programs, we review the challenges for establishing such a screening program and discuss some tips for successfully implementing a lung cancer screening program. PMID- 25541107 TI - Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes. AB - The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel loaded long-circulating liposomes that maintain size, charge and integrity during storage. PMID- 25541110 TI - Pyloric stenosis after a Roux-en-Y gastric bypass: a case report. PMID- 25541109 TI - Replication and evaluation of a proposed two-factor Binge Eating Scale (BES) structure in a sample of bariatric surgery candidates. AB - BACKGROUND: The Binge Eating Scale (BES) is a widely-used self-report measure of binge eating severity. Hood et al. reported a 2-factor structure for the BES in a sample of bariatric surgery candidates, with factors labeled feelings/cognitions and behavioral manifestations. The present study aims to replicate and extend the factor structure obtained by Hood et al. by testing the utility of a bifactor model that removes binge eating severity variance, which the total BES score purports to assess, in another sample of bariatric surgery candidates. METHODS: Bariatric surgery candidates (n = 517; 71.2% women; mean body mass index = 49.50 kg/m(2); SD = 10.17) were sampled. Twenty-four percent met DSM-IV-TR diagnostic criteria for binge eating disorder. RESULTS: Consistent with previous research, a 2-factor structure for the BES was supported; however, the 2 factors were substantially correlated (r = .89). A bifactor model significantly improved model fit, supporting the presence of a higher-order severity factor accounting for a significant amount of variance. This factor was primarily marked by binge eating severity as demonstrated by associations with number of objective binge eating episodes and DSM-IV-TR diagnosis. In the bifactor model, the feelings/cognitions factor was modestly associated with self-reported mood psychopathology. However, contrary to expectations, the behavioral manifestation factor was not associated with empirically derived behavioral problems. CONCLUSIONS: The current findings partially converge with those of Hood et al. However, the use of the BES as a 2 factor measure is not recommended at this point because of lack of incremental validity demonstrated by the behavioral manifestation factor. Continued use of the BES as a unidimensional measure of binge eating severity, in conjunction with a comprehensive clinical interview, can provide useful guidance for presurgical treatment recommendations. PMID- 25541108 TI - Generic GPCR residue numbers - aligning topology maps while minding the gaps. AB - Generic residue numbers facilitate comparisons of, for example, mutational effects, ligand interactions, and structural motifs. The numbering scheme by Ballesteros and Weinstein for residues within the class A GPCRs (G protein coupled receptors) has more than 1100 citations, and the recent crystal structures for classes B, C, and F now call for a community consensus in residue numbering within and across these classes. Furthermore, the structural era has uncovered helix bulges and constrictions that offset the generic residue numbers. The use of generic residue numbers depends on convenient access by pharmacologists, chemists, and structural biologists. We review the generic residue numbering schemes for each GPCR class, as well as a complementary structure-based scheme, and provide illustrative examples and GPCR database (GPCRDB) web tools to number any receptor sequence or structure. PMID- 25541111 TI - The value of routine gastroscopy before laparoscopic Roux-en-Y gastric bypass surgery in Chinese patients. AB - BACKGROUND: Obesity is closely related to upper gastrointestinal diseases. China has a high incidence of gastropathy. Postoperative examination of the distal stomach becomes extremely difficult after laparoscopic Roux-en-Y gastric bypass surgery (LRYGB). Whether preoperative routine gastroscopy should be performed at all remains controversial. The objective of this study was to explore the value of routine gastroscopy before performing LRYGB in Chinese patients. METHODS: The preoperative gastroscopy reports of 180 patients who had undergone LRYGB for morbid obesity and/or metabolic syndrome in the Department of Gastrointestinal Surgery of our hospital from January 2009 to August 2013 were retrospectively analyzed. RESULTS: Gastroscopy showed chronic superficial gastritis (n = 159, 88.3%), reflux esophagitis (n = 19, 10.6%), erosion (n = 69, 38.3%), hiatal hernia (n = 5, 2.8%), gastric ulcer (n = 3, 1.7%), duodenal ulcer (n = 32, 17.8%), and gastric polyps (n = 10, 5.6%). CONCLUSION: It is useful to perform gastroscopy before LRYGB. The findings of this investigation can help physicians to develop tailored therapies and procedures and thus improve the prognosis considerably. Gastroscopy should be routinely performed in Chinese patients who are planning to undergo bariatric surgery. PMID- 25541112 TI - Editorial: cognitive dysfunction in major depressive disorder - pathophysiology, clinical implications and treatment opportunities). PMID- 25541113 TI - Commentary-1 (research highlights: USP30 regulates the mitophagy-mediated neuroprotection in Parkinson's disease). PMID- 25541114 TI - Commentary-2: repairing the dopamine system in the brain with adult neurogenesis. PMID- 25541115 TI - [Nerve sheath tumours]. AB - Peripheral nerve sheath tumors are common neoplasms in daily practice. Diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer; but on occasion, they are diagnostically challenging (especially with locally aggressive and malignant tumors). This article aims to provide an update of the data (clinical, histological, immunohistochemistry and genomic) of benign, intermediate and malignant peripheral nerve sheath tumors, thanks to the latest WHO "Classification of Tumors of Soft Tissue and Bone", published in 2013, which includes a new chapter on "Nerve Sheath Tumors". Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches. PMID- 25541116 TI - [Intra-abdominal soft tissue tumors. What needs to be known to reach the diagnosis with the help of immunohistochemistry, FISH and molecular biology]. AB - Connective tissue tumors located inside the abdomen are a rare heterogeneous group of tumors, except for gastro-intestinal stromal tumors. They may be benign, malignant, or intermediate in terms of biologic potential. Pathologists have to remember the list of all the lesions possibly involved, with their immunohistochemical characteristics, and to know which molecular analyses are needed, with which expected results, and by which team they can be performed. The main tumor types are discussed with diagnostic tools and treatment consequences. PMID- 25541117 TI - [Histopathological diagnostic concordance in bone and soft tissue sarcomas between two comprehensive cancer centers from eastern and western Europe: a collaborative experience]. AB - INTRODUCTION: This study aims to assess the degree of concordance of histological diagnosis of bone and soft tissue sarcomas between a Comprehensive Cancer Center (CCC) of Eastern Europe - not specialized in this area of pathology - and an important CCC of Western Europe, which is one of the coordinators of a clinical reference network in sarcoma pathology. The goal is to have an overview of the sarcomatous pathology in a region of Eastern Europe and to discover diagnostic discrepancies between the two centers, while determining their cause. MATERIALS AND METHODS: The initial diagnosis was compared with the revised diagnosis on 110 specimens from 88 patients with bone or soft tissue sarcomas from East-European CCC, in a one-year period of time. RESULTS: Complete diagnostic agreement was observed in 55 cases (62.5%), a partial agreement in 23 cases (26.1%) and a major disagreement in 10 cases (11.4%). Major discrepancies of the histological type was observed in only 3 cases (3.4%): one case of discordance benign/malignant and 2 cases of discordance mesenchymal/non mesenchymal. Minor histological discrepancies - not affecting the management of the patient - were observed in 18 cases (20.4%). A major discordance in grading - potentially changing the management of the patient - was noted in 7 cases (7.9%), and a minor discrepancy in 5 cases (5.7%). DISCUSSIONS: Some histological types were clearly overdiagnosed, like "adult fibrosarcomas" and "malignant peripheral nerve sheet tumors" (MPNST), mostly converted after the audit into "undifferentiated spindle cell sarcomas" or other types of sarcomas. Some "unclassified" sarcomas and "undifferentiated pleomorphic sarcomas" could be re-classified with the aid of an extensive panel of antibodies. Overall, immunohistochemistry was responsible, but not in exclusivity, for half of the minor discrepancies, and for 2 out of 3 cases of major histological discrepancies. Otherwise, the main cause of discrepancies was the difficulties in the interpretation of the morphology. Molecular biology was decisive in one case. Most grading discrepancies resulted from the appreciation of the mitotic index. CONCLUSIONS: The profile of the sarcomatous pathology in the northwest region of Romania does not appear to differ significantly from other parts of Europe or the world, but a prospective epidemiological study would be necessary to confirm this assessment. The expansion of immunohistochemical antibody panel, the over-specialization of pathologists and, in the future, the establishment of a national network of referral centers in sarcoma pathology, are required for a high level of histological diagnosis in Eastern Europe. A periodic external audit, continuing this trans-European collaboration between the two centers, would be beneficial for monitoring progress. PMID- 25541118 TI - [Phenotypic and genetic features in neurofibromatosis type 1 in children]. AB - INTRODUCTION: Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease, nevertheless the number of publications providing clinical and genetic data from a significant number of children is limited. MATERIAL AND METHODS: The available clinical, epidemiological, radiological and genetic data from 239 children with NF1, who attended at a specialist NF1 clinic between January 2011 and December 2013 were recorded. RESULTS: All the 239 patients had a clinical and/or genetic diagnosis of NF1. The mean age at diagnosis was 2.65+/-2.85 years. In our series 99.6% met the diagnostic criteria of cafe au lait spots, 93.7% those of axillary and inguinal freckling, 7.1% showed typical bone lesion, 38.1% neurofibromas, 23% plexiform neurofibromas, 31.4% optic pathway glioma, Lisch nodules were present in 43.1%, and 28% patients had a first degree relative affected with NF1. The NF1 genetic study was performed in 86 patients, and a description of the gene mutations found in 72 of them is presented. Furthermore, other clinical data previously associated with NF1, either because of their frequency or their severity, are detailed. CONCLUSIONS: The difficulty for clinical diagnosis of NF1 early ages is still evident. Although, the need for further studies in asymptomatic patients is discussed, cranial MRI in children with NF1 may be helpful in the clinical diagnosis, given the high frequency of optic glioma observed in this cohort. PMID- 25541119 TI - Changes in illness perceptions mediated the effect of cognitive behavioural therapy in severe functional somatic syndromes. AB - OBJECTIVE: Although there is substantial evidence that cognitive behavioural therapy alleviates symptoms in functional somatic syndromes, the mechanisms of change are less investigated. This study examined whether changes in illness perceptions mediated the effect of cognitive behavioural therapy. METHODS: We analysed additional data from a randomised controlled trial comparing completers of cognitive behavioural group therapy (46 patients) to an enhanced usual care group (66 patients). Proposed mediators (illness perceptions) and primary (physical health) and secondary (somatic symptoms and illness worry) outcomes were assessed by means of questionnaires at referral, baseline, end of treatment, and 10 and 16 months after randomisation. Multiple mediation analysis determined whether (1) changes in specific illness perceptions during treatment mediated the effect of cognitive behavioural therapy (primary analysis), and (2) whether changes in illness perceptions during the whole trial period were associated with improved outcome (secondary analysis). RESULTS: Improvements in illness perceptions during treatment partially mediated the effect of cognitive behavioural therapy on physical health one year after treatment (sum of indirect effects 1.556, BCa 95% CI (0.006; 3.620)). Improving perceived control was particularly important. Changes in illness perceptions from baseline to 16 months after randomisation were associated with clinically meaningful improvements in physical health, somatic symptoms and illness worry during the same period. CONCLUSION: Our results suggest that changing patients' illness perceptions is an important process in cognitive behavioural therapy for functional somatic syndromes. Challenging patients' own understanding of their illness may hence be a key element of successful treatment. PMID- 25541120 TI - Anxiety in epilepsy: a neglected disorder. AB - OBJECTIVE: Anxiety disorders and symptoms are highly prevalent and problematic comorbidities in people with epilepsy (PWE), yet they remain poorly understood and often go undetected. This research aimed to further our understanding about anxiety in PWE. METHODS: Study 1 assessed the effectiveness of the commonly utilised yet unvalidated measure (Hospital Anxiety Depression Scale-Anxiety subscale; HADS-A) to identify DSM-IV anxiety disorders in 147 adult epilepsy outpatients. RESULTS: This study found that although the HADS-A had reasonable specificity (75%), its poor sensitivity (61%) and inadequate area under the curve (.68) deemed it unreliable as a screener for anxiety disorders in this population. METHODS: Study 2 aimed to further our understanding of the relationship between anxiety disorders, as defined by clinical interview, and psychosocial correlates in PWE. One hundred and twenty-two participants from Study 1 completed a battery of psychosocial measures. RESULTS: Multivariate analysis revealed that the presence of an anxiety disorder was associated with unemployment, which was found to be the only independent predictor. That is, despite the fact that psychosocial factors together contributed to the variance in anxiety disorders none were revealed to be significant independent predictors. CONCLUSION: These findings add to the literature indicating that the HADS may indicate distress, but does not adequately identify people with anxiety disorders and highlights the urgent need for the development of a reliable anxiety screening measure for PWE. Further, the results suggest that anxiety disorders in PWE are likely to be multiply determined with respect to psychosocial factors and require further investigation. PMID- 25541121 TI - Molecular tracing of white muscardine in the silkworm, Bombyx mori (Linn.) II. Silkworm white muscardine is not caused by artificial release or natural epizootic of Beauveria bassiana in China. AB - The fungal pathogen Beauveria bassiana causes serious economic losses in sericulture. Its origin is usually attributed to the release of B. bassiana insecticides against pine caterpillars (Dendrolimus punctuatus). In the present study, 488 B. bassiana isolates obtained from silkworm (Bombyx mori) collected from 13 Chinese provinces, and 327 B. bassiana isolates obtained from D. punctatus collected from 9 provinces, were analyzed for population genetic structure using the ISSR technique based on genetic distance. A UPGMA dendrogram clustered them into three independent clades: two B. mori clades and one D. punctatus clade. A 3-D principal component analysis further divided them into two completely independent host groups, revealing high host-specificity. This suggested that white muscardine occurring in B. mori populations throughout southern China was not caused by any B. bassiana strain either naturally prevailing in D. punctatus populations or by any strain artificially released as a fungal insecticide against D. punctatus. We further investigated the genetic differentiation coefficient Gst and gene flow between B. mori-pathogenic and D. punctatus-pathogenic B. bassiana isolates from across China and from five provinces inhabited by both B. mori and D. punctatus. The Gst value across China was computed as 0.410, while the values of the five provinces ranged from 0.508 to 0.689; all above 0.25, which is the threshold for significant genetic differentiation. This suggests that B. bassiana strains isolated from the two different hosts maintained their respective heredity without a convergent homogenization trend, and reduces the possibility that the host range of the caterpillar isolates could expand and enhance their virulence in B. mori. These findings indicate that the use of B. bassiana does not threaten the safety of sericulture. PMID- 25541122 TI - Coronary artery bypass graft surgery versus drug-eluting stents for patients with isolated proximal left anterior descending disease. AB - BACKGROUND: Few recent studies have compared the outcomes of coronary artery bypass graft (CABG) surgery with percutaneous coronary interventions (PCIs) in patients with isolated (single vessel) proximal left anterior descending (PLAD) coronary artery disease in the era of drug-eluting stents (DES). OBJECTIVES: The goal of this study was to compare outcomes in patients with PLAD who underwent CABG and PCI with DES. METHODS: New York's Percutaneous Coronary Interventions Reporting System was used to identify and track all patients who underwent CABG surgery and received DES for isolated PLAD disease between January 1, 2008 and December 31, 2010, and who were followed-up through December 31, 2011. A total of 5,340 of 6,064 (88%) patients received DES. Patients were matched to vital statistics data to obtain mortality after discharge and matched to New York's administrative data to obtain readmissions for myocardial infarction (MI) and stroke. To minimize selection bias, patients were propensity matched into 715 CABG and/or DES pairs, and 3 outcome measures were compared across the pairs. RESULTS: Kaplan-Meier estimates for CABG and DES did not significantly differ for mortality or mortality, MI, and/or stroke, but repeat revascularization rates were lower for CABG (7.09% vs. 12.98%; p = 0.0007). After further adjustment with Cox proportional hazards models, there were still no significant differences in 3 year mortality rates (CABG and/or DES adjusted hazard ratio (AHR): 1.14; 95% confidence interval [CI]: 0.70 to 1.85) or mortality, MI, and/or stroke rates (AHR: 1.15; 95% CI: 0.76 to 1.73), and the repeat revascularization rate remained significantly lower for CABG patients (AHR: 0.54; 95% CI: 0.36 to 0.81). CONCLUSIONS: Despite the higher rating in current guidelines of CABG (Class IIa vs. Class IIb) for patients with isolated PLAD disease, there were no differences in mortality or mortality, MI, and/or stroke, although CABG patients had significantly lower repeat revascularization rates. PMID- 25541123 TI - Revascularization strategy for proximal LAD disease: left internal mammary to LAD artery still rules the roost. PMID- 25541124 TI - The incremental risk of noncardiac surgery on adverse cardiac events following coronary stenting. AB - BACKGROUND: Recent coronary stent placement and noncardiac surgery contribute to the risk of adverse cardiac events, but the relative contributions of these two factors have not been quantified. OBJECTIVES: This research was designed to determine the incremental risk of noncardiac surgery on myocardial infarction (MI) and coronary revascularization following coronary stenting. METHODS: A U.S. retrospective cohort study of patients receiving coronary stents at Veterans Affairs medical centers between 2000 and 2010 was used to match patients undergoing noncardiac surgery within 24 months of stent placement to two patients with stents not undergoing surgery. Patients were matched on stent type and cardiac risk factors present at the time of stent placement. A composite endpoint of MI and/or cardiac revascularization for the 30-day interval post-surgery was calculated. Adjusted risk differences (RD) were compared across time periods following stent implantation, using generalized estimating equations. RESULTS: We matched 20,590 surgical patients to 41,180 nonsurgical patients. During the 30 day interval following noncardiac surgery, the surgical cohort had higher rates of the composite cardiac endpoint (3.1% vs. 1.9%; RD: 1.3%; 95% confidence interval: 1.0% to 1.5%). The incremental risk of noncardiac surgery adjusted for surgical characteristics ranged from 3.5% immediately following stent implantation to 1% at 6 months, after which it remained stable out to 24 months. Factors associated with a significant reduction in risk following surgery more than 6 months post-stent included elective inpatient procedures (DeltaRD: 1.8%; p = 0.01), high-risk surgery (DeltaRD: 3.7%; p = 0.01), and drug-eluting stent (DES) (DeltaRD: 1.3%; p = 0.01). CONCLUSIONS: The incremental risk of noncardiac surgery on adverse cardiac events among post-stent patients is highest in the initial 6 months following stent implantation and stabilizes at 1.0% after 6 months. Elective, high-risk, inpatient surgery, and patients with DES may benefit most from delay from a 6-month delay after stent placement. PMID- 25541125 TI - What to do when a patient with coronary stents needs surgery? PMID- 25541127 TI - The obesity paradox in heart failure: weighing the evidence. PMID- 25541126 TI - Pre-morbid body mass index and mortality after incident heart failure: the ARIC Study. AB - BACKGROUND: Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding. OBJECTIVES: This study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF. METHODS: In the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured >=6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI >=30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF. RESULTS: Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 +/- 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes. CONCLUSIONS: Our results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients. PMID- 25541128 TI - Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery. AB - BACKGROUND: Increases in serum creatinine (DeltaSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication. OBJECTIVES: This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI. METHODS: Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (>=100% DeltaSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline <=48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to DeltaSCr increases of >=50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values [Corrected]. RESULTS: Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than DeltaSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL-/pCysC+ composite was superior to DeltaSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than DeltaSCr strata. CONCLUSIONS: Composites of functional and tubular damage biomarkers are superior to DeltaSCr for predicting discrete characteristics of AKI. PMID- 25541129 TI - Improving detection of cardiac surgery-associated acute kidney injury. PMID- 25541131 TI - Paving the way for novel treatment strategies in genetic cardiomyopathies. PMID- 25541130 TI - Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. AB - BACKGROUND: Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere. OBJECTIVES: The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM. METHODS: Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (Mypn(WT/Q526X)) and homozygote mice harboring the human MYPN-Q529X mutation. RESULTS: Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated Mypn(Q526X) protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers. CONCLUSIONS: Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence of mutant Mypn(Q526X) protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in Mypn(WT/Q526X) hearts. PMID- 25541132 TI - Vaccine for atherosclerosis. AB - Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall, with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens. Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis. Hence, it is conceivable that an immunomodulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis. This review discusses: 1) the complex role of important components of the innate and adaptive immune systems in atherogenesis; 2) the nature of many antigens that have been tested successfully in vaccine formulations to reduce atherosclerosis in pre-clinical experimental models; and 3) the potential opportunities and challenges for clinical application of vaccination for atherosclerosis in the future. PMID- 25541133 TI - Defining "severe" secondary mitral regurgitation: emphasizing an integrated approach. AB - Secondary mitral regurgitation (MR) is associated with poor outcomes, but its correction does not reverse the underlying left ventricular (LV) pathology or improve the prognosis. The recently published American Heart Association/American College of Cardiology guidelines on valvular heart disease generated considerable controversy by revising the definition of severe secondary MR from an effective regurgitant orifice area (EROA) of 0.4 to 0.2 cm(2), and from a regurgitant volume (RVol) of 60 to 30 ml. This paper reviews hydrodynamic determinants of MR severity, showing that EROA and RVol values associated with severe MR depend on LV volume. This explains disparities in the evidence associating a lower EROA threshold with suboptimal survival. Redefining MR severity purely on EROA or RVol may cause significant clinical problems. As the guidelines emphasize, defining severe MR requires careful integration of all echocardiographic and clinical data, as measurement of EROA is imprecise and poorly reproducible. PMID- 25541134 TI - Learning lessons: the Libby Zion case revisited. PMID- 25541135 TI - Different potencies of angiotensin receptor blockers at suppressing adrenal beta Arrestin1-dependent post-myocardial infarction hyperaldosteronism. PMID- 25541136 TI - Is 3-dimensional echocardiographic area strain diagnostically superior to longitudinal and circumferential strain? PMID- 25541137 TI - Reply: Is 3-dimensional echocardiographic area strain diagnostically superior to longitudinal and circumferential strain? PMID- 25541138 TI - Comparing time use in individuals at different stages of psychosis and a non clinical comparison group. AB - Social functioning difficulties are a common and disabling feature of psychosis and have also been identified in the prodromal phase. However, debate exists about how such difficulties should be defined and measured. Time spent in structured activity has previously been linked to increased psychological wellbeing in non-clinical samples and may provide a useful way of assessing social functioning in clinical settings. The current study compared hours in structured activity, assessed with the Time Use Survey, in three clinical groups at different stages of psychosis: individuals with at-risk mental states (N=199), individuals with first-episode psychosis (N=878), and individuals with delayed social recovery following the remission of psychotic symptoms (N=77). Time use in the three clinical groups was also compared with norms from an age-matched non clinical group (N=5686) recruited for the Office for National Statistics UK 2000 Time Use Survey. Cutoff scores for defining social disability and recovery were examined. All three clinical groups spent significantly fewer hours per week in structured activity than individuals in the non-clinical group. Reduced activity levels were observed before the onset of psychosis in individuals with at-risk mental states. Additional reductions in activity were observed in the first episode psychosis and delayed recovery groups compared to the at-risk mental state group. Assessing time spent in structured activity provides a useful way to assess social disability and recovery across the spectrum of psychosis. PMID- 25541139 TI - Cognitive correlates of gray matter abnormalities in adolescent siblings of patients with childhood-onset schizophrenia. AB - Patients with childhood onset schizophrenia (COS) display widespread gray matter (GM) structural brain abnormalities. Healthy siblings of COS patients share some of these structural abnormalities, suggesting that GM abnormalities are endophenotypes for schizophrenia. Another possible endophenotype for schizophrenia that has been relatively unexplored is corticostriatal dysfunction. The corticostriatal system plays an important role in skill learning. Our previous studies have demonstrated corticostriatal dysfunction in COS siblings with a profound skill learning deficit and abnormal pattern of brain activation during skill learning. This study investigated whether structural abnormalities measured using volumetric brain morphometry (VBM) were present in siblings of COS patients and whether these were related to deficits in cognitive skill learning. Results revealed smaller GM volume in COS siblings relative to controls in a number of regions, including occipital, parietal, and subcortical regions including the striatum, and greater GM volume relative to controls in several subcortical regions. Volume in the right superior frontal gyrus and cerebellum were related to performance differences between groups on the weather prediction task, a measure of cognitive skill learning. Our results support the idea that corticostriatal and cerebellar impairment in unaffected siblings of COS patients are behaviorally relevant and may reflect genetic risk for schizophrenia. PMID- 25541141 TI - Freezing under pressure: a new method for cryopreservation. AB - The ability to preserve cells, tissues, and organs with minimal damage for an extended period of time is essential for advancements in medicine and research. Current methods for cryopreservation are based on using high concentrations (up to 60% v/v) of cryoprotective agents (CPAs) which are toxic to living cells. The effect of pressure and a low concentration of dimethyl sulfoxide (Me2SO) or glycerol, on hemolysis of human red blood cells (RBCs) after freezing and thawing were investigated. Pressure was applied during cooling and freezing the RBCs and a minimum in hemolysis was reached at approximately 120 MPa. Either 5% v/v Me2SO or 8% v/v glycerol concentration in combination with 120 MPa pressure was sufficient to obtain 8% or less hemolysis of RBCs after cooling at a 35 degrees C/min or a 160 degrees C/min rate. The preliminary results suggest that the method may help to solve the CPAs toxicity problem. PMID- 25541140 TI - TLR7, IFNgamma, and T-bet: their roles in the development of ABCs in female biased autoimmunity. AB - The majority of autoimmune diseases have a strong gender bias, affecting mostly females. Gender-specific factors like sex-hormones, the presence or absence of a second X chromosome, and gender-specific gut microbiota may contribute to this bias. In this review we will discuss the role of the X chromosome encoded toll like receptor 7 (TLR7) and interferon gamma (IFNgamma) in the development of autoimmunity. We will also review recent data indicating how these factors may affect an immune response in a gender-dependent manner. PMID- 25541142 TI - Percutaneous cryoablation for inoperable malignant lung tumors: midterm results. AB - OBJECTIVE: To retrospectively analyze the efficacy and short- to mid-term survival rate of cryoablation for malignant lung tumors. METHODS: Percutaneous CT guided cryoablation for 45 malignant lung tumors in 26 patients during 41 sessions from 2009 to 2013 were performed. Follow up CT-scan were used to determine local tumor progression. Survival rate, local tumor control rate and associated risk factors were analyzed. RESULTS: The immediate during and short term complications with CTCAE grade 2 or upper include pneumothorax (15%), pleural effusion (20%), pulmonary hemorrhage (24%), pneumonitis (15%), hemothorax (15%), hemoptysis (10%), pain (20%), bronchopleural fistula (n=1), and empyema (n=2). Life-threatening bleeding or hemodynamic instability was not observed. There was no procedural-related mortality. Overall survival rate of 1, 2, 3 years are 96%, 88%, 88%. For curative intent, local tumor control (LTC) rate of 1, 2, 3 years are 75%, 72%, 72%. CONCLUSION: Cryoablation for malignant lung tumors is effective and feasible in local control of tumor growth, with good short- to mid term survival rate, as an alternative option for inoperable patients. PMID- 25541143 TI - In vitro cadmium effects on ECM gene expression in human bronchial epithelial cells. AB - Occupational and environmental exposure to the heavy metal cadmium (Cd) and its inhalation from cigarette smoke are associated with emphysema. Many growth factors and extracellular matrix (ECM) cell signaling molecules are directly involved in the epithelial bronchial cell pathway. This study investigated the direct effects of Cd on the production of several ECM components in human bronchial epithelial cells (BEAS-2B) that were exposed in vitro for 48 h to sub toxic and toxic concentrations of Cd. Gene expression of collagens, metalloproteases (MMPs), integrins, tenascin and vitronectin were quantified by RT-PCR. To study apoptosis cascade, annexin assay and cellular cytotoxicity by MTT assay were performed. We also investigated whether an imbalance in the TGFbeta/TGFbeta receptor (TGFbetaR) expression mediated Cd effects. The results showed the sub-toxic Cd dose significantly increased tenascin, vitronectin, beta1 and beta5 integrin gene expression. The toxic Cd dose decreased type IV and V collagen, alpha1, alpha2 and beta3 integrins. Both Cd doses down-regulated type I collagen and up-regulated metalloproteases. Each Cd dose caused a different imbalance in the complex pattern of TGFbeta and its receptors. No alteration in classic apoptotic marker protein expression was observed in presence of the sub toxic dose of Cd, suggesting this metal alters ECM production without apoptotic activation. In conclusion, all these data show even sub-toxic Cd dose exposure alters the specific gene expression of several ECM components that are crucially implicated in the mechanical properties of lung parenchyma supporting the hypothesis that the mechanism underlying Cd-induced lung disease may involve downstream changes in TGFbeta/TGFbetaR signaling. PMID- 25541144 TI - Primary angiosarcoma of the pancreas mimicking severe acute pancreatitis--case report. AB - Primary angiosarcoma of the pancreas is an extremely rare neoplasm that often mimicks severe acute pancreatitis. A 58-year-old man was admitted with clinical and laboratory signs of severe acute pancreatitis. Contrast enhanced CT scan demonstrated haemorrhagic necrotizing inflammation of the pancreas involving the pancreatic tail, splenic hilum and small bowels with multiple peripancreatic and free abdominal fluid collection. Percutaneous drainage was performed. After 13 days, laparotomy was indicated because of persistent intra-abdominal bleeding, fever and a palpable, rapidly growing mass in the left upper quadrant of the abdomen. During the operation a necrotic, haemorrhagic mass was found in the pancreatic tail; a frozen section showed malignancy, although the tumour was unresectable. Despite all conservative and surgical therapeutic attempts, the patient died within four weeks after diagnosis. Final histology justified primary angiosarcoma of the pancreas. If a patient with signs of severe acute pancreatitis has fever without elevated PCT, the presence of a malignant tumour of the pancreas should be considered. PMID- 25541145 TI - Osteogenic poly(epsilon-caprolactone)/poloxamine homogeneous blends prepared by supercritical foaming. AB - Homogeneous poly(epsilon-caprolactone) (PCL) and poloxamines (PLXs) porous blends were prepared using a supercritical carbon dioxide-assisted foaming/mixing (SFM) approach aiming to obtain cytocompatible implantable materials presenting tunable morphologies, bioerosion rates, bioactive molecules release and osteogenic features. Pure PCL, pure PLXs (T908 and T1107 varieties) and three distinct PCL:PLX 75:25, 50:50, 25:75% w/w blends, with and without the osteogenic and angiogenic bioactive molecule simvastatin were processed at constant pressure of 20 MPa and temperature of 40 degrees C or 43 degrees C, for T1107 and T908, respectively. Obtained porous blends were characterized applying a wide range of techniques and in vitro methods. Calorimetric analysis showed that hydrophilic T908 and T1107 PLXs are miscible with PCL for all tested compositions. Prepared PCL:PLX porous blends rapidly lost mass when immersed into phosphate buffer pH 7.4 due to PLXs dissolution and then went through slow and almost constant erosion rates for the subsequent weeks due to PCL slow hydrolytic degradation, which explains the rapid initial release of simvastatin and its subsequent sustained release for longer periods of time. PCL and PCL:PLX 75:25% w/w porous blends, containing or not simvastatin, showed a high cytocompatibility with SAOS 2 cells. In addition, prepared biomaterials promoted mesenchymal stem cells proliferation and their differentiation into osteoblasts. Overall, obtained results showed novel possibilities of addressing local treatment of small bone defects/fractures using highly porous PCL:PLX homogeneous blends. PMID- 25541146 TI - Development of a protective dermal drug delivery system for therapeutic DNAzymes. AB - RNA-cleaving DNAzymes are a potential novel class of nucleic acid-based active pharmaceutical ingredients (API). However, developing an appropriate drug delivery system (DDS) that achieves high bioavailability is challenging. Especially in a dermal application, DNAzymes have to overcome physiological barriers composed of penetration barriers and degrading enzymes. The focus of the present study was the development of a protective and penetration-enhanced dermal DDS that was tailor made for DNAzymes. DNAzyme Dz13 was used as a potential API for topical therapy against actinic keratosis. In the progress of development and selection, different preservatives, submicron emulsions (SMEs) and the physiological pH range were validated with respect to the API's integrity. A physicochemical stable SME of a pharmaceutical grade along with a high API integrity was achieved. Additionally, two developed protective systems, consisting of a liposomal formulation or chitosan-polyplexes, reduced the degradation of Dz13 in vitro. A combination of SME and polyplexes was finally validated at the skin and cellular level by in vitro model systems. Properties of penetration, degradation and distribution were determined. The result was enhanced skin penetration efficiency and increased cellular uptake with a high protective efficiency for DNAzymes due to the developed protective DDS. PMID- 25541147 TI - Determination of protein phase diagrams by microbatch experiments: exploring the influence of precipitants and pH. AB - Knowledge of protein phase behavior is essential for downstream process design in the biopharmaceutical industry. Proteins can either be soluble, crystalline or precipitated. Additionally liquid-liquid phase separation, gelation and skin formation can occur. A method to generate phase diagrams in high throughput on an automated liquid handling station in microbatch scale was developed. For lysozyme from chicken egg white, human lysozyme, glucose oxidase and glucose isomerase phase diagrams were generated at four different pH values - pH 3, 5, 7 and 9. Sodium chloride, ammonium sulfate, polyethylene glycol 300 and polyethylene glycol 1000 were used as precipitants. Crystallizing conditions could be found for lysozyme from chicken egg white using sodium chloride, for human lysozyme using sodium chloride or ammonium sulfate and glucose isomerase using ammonium sulfate. PEG caused destabilization of human lysozyme and glucose oxidase solutions or a balance of stabilizing and destabilizing effects for glucose isomerase near the isoelectric point. This work presents a systematic generation and extensive study of phase diagrams of proteins. Thus, it adds to the general understanding of protein behavior in liquid formulation and presents a convenient methodology applicable to any protein solution. PMID- 25541148 TI - Childhood trauma is associated with maladaptive personality traits. AB - The association between childhood trauma and personality traits has been poorly characterized and reported. Our aim was to evaluate whether distinct types of childhood abuse and neglect are associated with various personality dimensions using data from a large web-based survey. A total of 12,225 volunteers responded anonymously to the Internet versions of the Temperament and Character Inventory Revised (TCI-R) and the Childhood Trauma Questionnaire (CTQ) via our research website, but only 8,114 subjects (75.7% women, mean age 34.8+/-11.3yrs) who met the criteria for validity were included in the analysis. Childhood trauma was positively associated with harm avoidance and was negatively associated with self directedness and, to a lesser extent, with cooperativeness. The associations were robust with emotional abuse and neglect but were non-significant or mild with physical trauma. Emotional neglect was associated with reduced reward dependence and persistence. All types of abuse, but not neglect, were associated with increased novelty seeking scores. Reporting of childhood trauma, especially of an emotional nature, was associated with maladaptive personality traits. Further investigation of the effects of different types of childhood trauma on psychological and neurobiological parameters is warranted. PMID- 25541149 TI - UV light selectively inhibits spinal cord inflammation and demyelination in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). The incidence of MS is inversely related to sun light exposure or ultraviolet radiation (UVR). UVR was found to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of MS, independent of vitamin D production. The mechanism of this suppression remains to be elucidated. To this end, several elements of an immune response in the spinal cord, spleen and skin during development of EAE were studied. As expected, UVR (10kJ/m(2)) inhibits inflammation and demyelination of the spinal cord. Most significant, UVR dramatically reduced spinal cord chemokine CCL5 mRNA and protein levels. UVR also suppressed IL-10 in skin and spleen but not the spinal cord. As expected from the UVR action on skin, macrophage population and IFN-gamma levels are increased in that organ. UVR had no effect on lymphocyte proliferation and IFN-gamma in spleen. From these measurements, we suggest that UVR suppression of EAE prevents the migration of inflammatory cells into the CNS by a focal inhibition of chemokine CCL-5 in the CNS and a systemic elevation of immunosuppressive IL-10. PMID- 25541150 TI - Biological properties of ligand-dependent activation of the MET receptor kinase in acute myeloid leukemia. PMID- 25541153 TI - Replication factor C3 is a CREB target gene that regulates cell cycle progression through the modulation of chromatin loading of PCNA. AB - CREB (cyclic AMP response element-binding protein) is a transcription factor overexpressed in normal and neoplastic myelopoiesis and regulates cell cycle progression, although its oncogenic mechanism has not been well characterized. Replication factor C3 (RFC3) is required for chromatin loading of proliferating cell nuclear antigen (PCNA) which is a sliding clamp platform for recruiting numerous proteins in the DNA metabolism. CREB1 expression, which was activated by E2F, was coupled with RFC3 expression during the G1/S progression in the KG-1 acute myeloid leukemia (AML) cell line. There was also a direct correlation between the expression of RFC3 and CREB1 in human AML cell lines as well as in the AML cells from the patients. CREB interacted directly with the CRE site in RFC3 promoter region. CREB-knockdown inhibited primarily G1/S cell cycle transition by decreasing the expression of RFC3 as well as PCNA loading onto the chromatin. Exogenous expression of RFC3 was sufficient to rescue the impaired G1/S progression and PCNA chromatin loading caused by CREB knockdown. These studies suggest that RFC3 may have a role in neoplastic myelopoiesis by promoting the G1/S progression and its expression is regulated by CREB. PMID- 25541151 TI - You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia. AB - A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia. PMID- 25541154 TI - Oxytocin improves the expression of cardiac specific markers in porcine bone marrow stem cells differentiation. AB - Bone marrow stem cells (BMSCs) treated with 5-azacytidine possess myogenic differentiation potential. Oxytocin (OT) induces cardiomyogenesis in murine embryonic and cardiac stem cells. We attempted to isolate, characterize, and induce OT-mediated cardiomyogenic differentiation of porcine pBMSCs. Cells were treated as: control, OT, and 5-azacytidine groups. During early passages, transcripts of Oct4, GATA4, OT receptor, and phospholamban were expressed. RT-PCR showed upregulation of GATA4 in OT and 5-azacytidine-induced groups. Immunocytochemistry revealed higher expressions of cardiac troponin T and myosin heavy chain in OT than in 5-azacytidine-induced groups (p < 0.01). Western blot analysis showed upregulation of cardiac troponin I in OT-induced pBMSCs (p < 0.01). We infer pBMSCs should be induced during early passages, when expressing transcription factors related to pluripotency and cardiomyogenesis, as well as OT receptor. The more abundant expression of cardiac specific proteins in OT-treated pBMSCs suggests OT could be a more potent cardiomyogenic inducer of pBMSC. PMID- 25541152 TI - MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. AB - MicroRNAs (miRNAs) represent important regulators of gene expression besides transcriptional control. miRNA regulation can be involved in the cell developmental fate decisions, but can also have more subtle roles in buffering stochastic fluctuations in gene expression. They participate in pathways fundamental to B-cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins. miRNAs influence B-cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. In this review, we discuss miRNAs with essential functions in malignant B-cell development (such as miR-150, miR-155, miR-21, miR-34a, miR-17-92 and miR-15-16). We also put these miRNAs in the context of normal B-cell differentiation, as this is intimately connected to neoplastic B-cell development. We review miRNAs' role in the most common B-cell malignancies, including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). We focus on miR-contribution to the regulation of important signalling pathways (such as NF-kappaB, PI3K/AKT and TGF-beta), BCR signalling and its modulators (such as PTEN, SHIP-1, ZAP-70, GAB1 and BTK), anti- and pro apoptotic proteins (such as BCL2, MCL1, TCL1, BIM, p53 and SIRT1) and transcription factors (such as MYC, MYB, PU.1, FOXP1 and BCL6). We also discuss the association of miRNAs' expression levels with the patients' survival and response to therapy, summarizing their potential use as predictive and prognostic markers. Importantly, the targeting of miRNAs (like use of anti-miR-155 or miR 34a mimic) could provide a novel therapeutic approach as evidenced by tumour regression in xenograft mouse models and initial promising data from clinical trials. PMID- 25541155 TI - Persistence of docetaxel-induced neuropathy and impact on quality of life among breast cancer survivors. AB - BACKGROUND: This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer. METHODS: One thousand and thirty-one patients with early-stage breast cancer, who received at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality of Life Questionnaire (QLQ)-C30) after 1-3years. FINDINGS: Upon completion of docetaxel treatment, 241 patients (23%) reported PN, grades 2-4. PN persisted for 1-3years among 81 (34%) while PN regressed to grades 0-1 among 160 (66%). Among 790 patients (77%) without PN, 76 (10%) developed PN 1-3years later while 714 (90%) stayed free from PN. Significant risk factors for persistent PN were age ?55 (p=0.001), maximum grade of PN during docetaxel treatment (p<0.0001), persistent muscle and joint pain (p<0.0001), stomatitis (p=0.047) and fatigue (p=0.001). Persistent PN had a significant negative correlation with health-related quality of life (HRQOL), functional scales and symptom scales. INTERPRETATIONS: Overall, 15% of breast cancer survivors treated with docetaxel report PN 1-3years after treatment with a significant negative impact on HRQOL. PMID- 25541156 TI - Assessing skin sensitization hazard in mice and men using non-animal test methods. AB - Sensitization, the prerequisite event in the development of allergic contact dermatitis, is a key parameter in both hazard and risk assessments. The pathways involved have recently been formally described in the OECD adverse outcome pathway (AOP) for skin sensitization. One single non-animal test method will not be sufficient to fully address this AOP and in many cases the use of a battery of tests will be necessary. A number of methods are now fully developed and validated. In order to facilitate acceptance of these methods by both the regulatory and scientific communities, results of the single test methods (DPRA, KeratinoSens, LuSens, h-CLAT, (m)MUSST) as well for a the simple '2 out of 3' ITS for 213 substances have been compiled and qualitatively compared to both animal and human data. The dataset was also used to define different mechanistic domains by probable protein-binding mechanisms. In general, the non-animal test methods exhibited good predictivities when compared to local lymph node assay (LLNA) data and even better predictivities when compared to human data. The '2 out of 3' prediction model achieved accuracies of 90% or 79% when compared to human or LLNA data, respectively and thereby even slightly exceeded that of the LLNA. PMID- 25541157 TI - Viral hepatitis: setting sights on the right target. PMID- 25541161 TI - TB-HAART trial. PMID- 25541162 TI - TB-HAART trial. PMID- 25541163 TI - TB-HAART trial--authors' reply. PMID- 25541164 TI - Effect of empirical treatment on outcomes of clinical trials of diagnostic assays for tuberculosis. PMID- 25541165 TI - Effect of empirical treatment on outcomes of clinical trials of diagnostic assays for tuberculosis. PMID- 25541166 TI - Automated text message reminders to promote good health. PMID- 25541167 TI - Pre-exposure prophylaxis for migration-associated HIV in China. PMID- 25541168 TI - Automated text message reminders to promote good health. PMID- 25541169 TI - Interpretation of probabilistic forecasts of epidemics. PMID- 25541170 TI - Tuberculosis post-2015: looking to the future with optimism. PMID- 25541171 TI - New HIV diagnoses in MSM in high-income countries. PMID- 25541175 TI - Bromine, bear-claw scratch fasciotomies, and the Eagle effect: management of group A streptococcal necrotising fasciitis and its association with trauma. AB - Necrotising fasciitis is a rare, but potentially fatal, soft-tissue infection. Historical depictions of the disease have been described since classical times and were mainly recorded in wartime reports of battle injuries. Although several different species of bacteria can cause necrotising fasciitis, perhaps the most widely known is group A streptococcus (GAS). Infection control, early surgical debridement, and antibiotic therapy are now the central tenets of the clinical management of necrotising fasciitis; these treatment approaches all originate from those used in wars in the past 150 years. We review reports from the 19th century, early 20th century, and mid-20th century onwards to show how the management of necrotising fasciitis has progressed in parallel with prevailing scientific thought and medical practice. Historically, necrotising fasciitis has often, but not exclusively, been associated with penetrating trauma. However, along with a worldwide increase in invasive GAS disease, recent reports have cited cases of necrotising fasciitis following non-combat-related injuries or in the absence of antecedent events. We also investigate the specific association between GAS necrotising fasciitis and trauma. In the 21st century, molecular biology has improved our understanding of GAS pathogenesis, but has not yet affected attributable mortality. PMID- 25541176 TI - Lymphocytosis in a baby with pertussis. PMID- 25541177 TI - Maturation of mismatch negativity and P3a response across adolescence. AB - Adolescents experience significant changes in various physiological and psychological domains due to changes in their brain's structure and function. A lot is known about structural changes in the brain across adolescence. However, less research has investigated changes in brain function during this period. In this study, we tracked the maturation of the auditory mismatch negativity (MMN) and P3a brain responses - both posited as neural indices of auditory discrimination - in 90 adolescents aged 10-18 years. We found that P3a mean amplitude and latency decreased significantly across adolescence, but there was no reliable change in the MMN. These results suggest that neural processes associated with passive auditory processing continue to develop well into adolescence. PMID- 25541178 TI - Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats. AB - The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-alpha, IL1 beta and IFN-gamma), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase 12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus. PMID- 25541179 TI - Polyphosphate kinase of Lysinibacillus sphaericus and its effects on accumulation of polyphosphate and bacterial growth. AB - Lysinibacillus sphaericus produces parasporal crystal proteins (Bin toxins) that are specifically toxic to Culex and Anopheles mosquito larvae. It has long persistence in mosquito breeding sites due to the recycle of spores in mosquito cadaver and certain environments. This bacterium is unable to metabolize sugar (except N-acetylglucosamine) but can use proteinaceous materials. Previous studies have shown that inorganic polyphosphate (polyP) is essential for cell growth and responses to nutritional stringencies and environmental stresses and branched-chain amino acids (BCAAs) are useful intracellular signals for bacterial adaption to nutritional environments. However, relatively little is known about the role of polyP and the regulation link between polyP and BCAAs in nutritional limitation adaptation in a bacterium incapable of polysaccharide utilization. Here, a primary enzyme involved in polyP biosynthesis, polyphosphate kinase (PPK), was identified from L. sphaericus, and the polyP accumulation in different nutritional media was investigated. Furthermore, a ppk null mutant and the ppk complemented strain were constructed and the effect of deletion on cell growth, polyP accumulation and expression of BCAAs biosynthetic genes (ilvBHC) was surveyed. The result showed that deletion of ppk resulted in a deficiency in polyP accumulation rather than cell growth in Luria-Bertani (LB) medium. Further studies demonstrated that the cell growth was evidently retarded and the ilvBHC expression was significantly reduced when ppk mutant was transferred from LB to limited-amino acid (LA) medium and that these phenotypes were significantly restored in the ppk-complemented strain. These results suggested that PPK plays a role in polyP accumulation and expression of genes involved in BCAAs biosynthesis, providing a hint for further understanding of the role of PPK in nutritional limitation in L. sphaericus. PMID- 25541180 TI - Morphologic studies of cell endogenous repopulation in decellularized aortic and pulmonary homografts implanted in sheep. AB - PURPOSES: The rationale of this study was to assess morphologically the effects of implantation of decellularized aortic and pulmonary homografts into growing sheep, with the objective to establish type and extent of cell repopulation and propensity to dystrophic calcification over a prolonged period of time. METHODS: Pulmonary and aortic homografts were obtained from healthy euthanized juvenile sheep (35-45kg). Complete decellularization was accomplished in 0.5% sodium deoxycholate and 0.5% sodium dodecylsulfate for 24h. Twelve homografts from 11 animals were studied as follows: Gross, X-ray, histology, immunohistochemistry, morphometry, transmission electron microscopy and calcium content spectroscopy investigations were carried out. RESULTS: Decellularization appeared complete in unimplanted homografts. The extracellular matrix was intact. Explanted homografts showed soft, pliable cusps without gross calcium deposits and tears; calcium content showed slight difference between aortic and pulmonary cusps (5.505+/-2.04 vs. 2.77+/-1.06mg/g dry weight, P=.04). Microscopic calcifications were observed in two aortic homografts on smooth muscle cells of repopulated homograft wall and on valvular interstitial cells, respectively. Inflammatory infiltrates were never seen. Cell repopulation occurred in homograft wall with actin smooth muscle and vimentin positive cells in media lamellar units (cell density per millimeter squared, 885.4+/-424.38 in native vs. 172.64+/-160.33 in implanted homograft, P<.01) as well as in cusps (cell density per millimeter squared, 495.96+/-63.92 in native vs. 184.66+/-140.74 in implanted homograft, P<.01). The percentage area of recellularization was 71.27+/-3.03 in the homograft wall and 22.16+/-3.06 in the cusps. Thickness of pulmonary explanted homograft wall and cusps was 900.68+/ 321.52MUm vs. 994.36+/-135.92MUm and 204.75+/-66.64MUm vs. 231.04+/-105.94, respectively (P=NS), whereas in aortic homograft wall and cusps it was 1358.604+/ 423.79MUm vs. 2065.32+/-431.46MUm, P=.016, and 248.01+/-93.95MUm vs. 390.30+/ 104.81MUm, P=.03, respectively. The endothelial lining was restored. CONCLUSION: Endogenous cell repopulation in decellularized homografts occurs and persists following implantation, at both wall and cusp level, without evidence of immune reaction. Even in the long term, the cusps exhibit no structural deterioration and negligible calcification. PMID- 25541181 TI - Fatal delayed cardiac tamponade due to rupture of micropseudoaneurysm of left anterior descending coronary artery following stab to the chest. AB - Traumatic coronary pseudoaneurysm has been described to be mainly associated to iatrogenic lesion of the coronary arteries. However, chest-stab-wound-related coronary pseudoaneurysm caused by isolated partial incision of a coronary artery giving rise to fatal delayed cardiac tamponade is very rare. We describe an autopsy case in which this potentially fatal complication developed 8 days later after a thoracic stab wound. Unfortunately, the imaging examination failed to detect this defect during hospitalization. Postmortem examination revealed that the posterior wall of the left anterior descending coronary artery was intact but that the anterior wall was incised, forming a micropseudoaneurysm which had ruptured. This case highlights that isolated coronary artery injuries must be considered in any patient with a penetrating wound to the thorax, and coronary pseudoaneurysms should not be missed in these patients. PMID- 25541182 TI - Parkinson's disease severity and use of dopaminergic medications. AB - BACKGROUND: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected. OBJECTIVE: The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD. METHODS: A non parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life. RESULTS: The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine. CONCLUSION: This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy. PMID- 25541183 TI - Effects of salinity on the accumulation of hemocyte aggregates and bacteria in the gills of Callinectes sapidus, the Atlantic blue crab, injected with Vibrio campbellii. AB - In addition to respiration and ion regulation, crustacean gills accumulate and eliminate injected particles, along with hemocyte aggregates that form in response to those particles. Here we report that the dose of Vibrio campbellii previously shown to induce a decrease in respiration and hemolymph flow across the gill in the Atlantic blue crab, Callinectes sapidus, also triggered the formation of aggregates containing four or more hemocytes in the gills, compared with saline-injected controls. More bacteria were trapped and rendered non culturable per unit weight by anterior respiratory gills than posterior gills specialized for ion regulation. Further, more bacteria accumulated in the anterior gills of animals held at 30 ppt than those at 10 ppt. Thus, the role of the gills in immune defense comes at an energetic cost to this and likely to other crustaceans; this cost is influenced by acclimation salinity and the position and specialized function of individual gills. PMID- 25541184 TI - Cloning and expression of the epithelial sodium channel and its role in osmoregulation of aquatic and estivating African lungfish Protopterus annectens. AB - The epithelial sodium channel (ENaC) is a sodium (Na(+))-selective aldosterone stimulated ion channel involved in Na(+) transport homeostasis of tetrapods. We examined full-length cDNA sequences and tissue distributions of ENaCalpha, ENaCbeta, and ENaCgamma subunits in the African lungfish Protopterus annectens. Protopterus ENaC (pENaC) comprises 3 subunits: pENaCalpha, pENaCbeta, and pENaCgamma. pENaCalpha, pENaCbeta, and pENaCgamma subunits are closely related to alpha, beta, and gamma subunits of the Australian lungfish Neoceratodus forsteri ENaC (nENaC), respectively. Three ENaC subunit mRNAs were highly expressed in the gills and moderately expressed in the kidney and rectum of P. annectens. During estivation for 2-4weeks and 2-3months, plasma Na(+) concentration was relatively stable, but plasma urea concentration significantly increased in comparison with the control fish kept in a freshwater environment. Plasma aldosterone concentration and mRNA expression of the ENaCalpha subunit gradually and significantly decreased in the gills and kidney after 2months of estivation. Thus, aldosterone-dependent Na(+) absorption via ENaC probably exists in the epithelial cells of osmoregulatory organs of lungfish kept in fresh water, whereas plasma Na(+) concentration may be maintained by a mechanism independent of aldosterone-ENaC axis during estivation in lungfish. PMID- 25541186 TI - "I used to be as fit as a linnet" - beliefs, attitudes, and environmental supportiveness for physical activity in former mining areas in the North-East of England. AB - Studies of geographical variations in physical activity behaviours have suggested that activity levels are particularly low in areas that have undergone employment loss associated with the decline of industry. This is of concern given that affected populations are already at risk of poor health. Applying focus group methodology amongst 19 participants in four groups, this study aims to unpack how broader societal and environmental changes associated with industrial decline affect beliefs and attitudes towards physical activity in ex-mining communities in the North-East of England. Identified core themes comprise the direct impact of deindustrialisation on social and physical environments. Based on our findings, we provide evidence for mechanisms that operate via loss of occupational physical activity as well as the progressive development of environments that are not fit to support population activity levels. Particularly important was the loss of recreational facilities, public green spaces and sports facilities that were owned and organised by the miners themselves with support from the mining companies. Attitudes and beliefs directly related to the areas' industrial past were also seen to be key. We suggest that the development of interventions considering the socio-cultural history and socio-economic reality of communities could be a promising route to encourage more active lifestyles in deprived areas with particularly low levels of physical activity. PMID- 25541185 TI - Heart rate variability predicts levels of inflammatory markers: Evidence for the vagal anti-inflammatory pathway. AB - Evidence from numerous animal models shows that vagal activity regulates inflammatory responses by decreasing cytokine release. Heart rate variability (HRV) is a reliable index of cardiac vagal regulation and should be inversely related to levels of inflammatory markers. Inflammation is also regulated by sympathetic inputs, but only one previous paper controlled for this. In a larger and more representative sample, we sought to replicate those results and examine potential sex differences in the relationship between HRV and inflammatory markers. Using data from the MIDUS II study, we analyzed the relationship between 6 inflammatory markers and both HF-HRV and LF-HRV. After controlling for sympathetic effects measured by urinary norepinephrine as well as a host of other factors, LF-HRV was found to be inversely associated with fibrinogen, CRP and IL 6, while HF-HRV was inversely associated with fibrinogen and CRP. We did not observe consistent sex differences. These results support the existence of the vagal anti-inflammatory pathway and suggest that it has similar effects in men and women. PMID- 25541187 TI - Automated model selection in covariance estimation and spatial whitening of MEG and EEG signals. AB - Magnetoencephalography and electroencephalography (M/EEG) measure non-invasively the weak electromagnetic fields induced by post-synaptic neural currents. The estimation of the spatial covariance of the signals recorded on M/EEG sensors is a building block of modern data analysis pipelines. Such covariance estimates are used in brain-computer interfaces (BCI) systems, in nearly all source localization methods for spatial whitening as well as for data covariance estimation in beamformers. The rationale for such models is that the signals can be modeled by a zero mean Gaussian distribution. While maximizing the Gaussian likelihood seems natural, it leads to a covariance estimate known as empirical covariance (EC). It turns out that the EC is a poor estimate of the true covariance when the number of samples is small. To address this issue the estimation needs to be regularized. The most common approach downweights off diagonal coefficients, while more advanced regularization methods are based on shrinkage techniques or generative models with low rank assumptions: probabilistic PCA (PPCA) and factor analysis (FA). Using cross-validation all of these models can be tuned and compared based on Gaussian likelihood computed on unseen data. We investigated these models on simulations, one electroencephalography (EEG) dataset as well as magnetoencephalography (MEG) datasets from the most common MEG systems. First, our results demonstrate that different models can be the best, depending on the number of samples, heterogeneity of sensor types and noise properties. Second, we show that the models tuned by cross-validation are superior to models with hand-selected regularization. Hence, we propose an automated solution to the often overlooked problem of covariance estimation of M/EEG signals. The relevance of the procedure is demonstrated here for spatial whitening and source localization of MEG signals. PMID- 25541189 TI - Significance of neurovascular contact in classical trigeminal neuralgia. AB - Neurovascular contact is considered a frequent cause of classical trigeminal neuralgia and microvascular decompression with transposition of a blood vessel is preferred over other surgical options in medically refractory patients with classical trigeminal neuralgia. However, the prevalence of neurovascular contact has not been investigated in a representative cohort of patients with classical trigeminal neuralgia based in a neurological setting and using high-quality neuroimaging and blinded evaluation. We aimed to investigate whether presence and degree of neurovascular contact are correlated to pain side in classical trigeminal neuralgia. Consecutive classical trigeminal neuralgia patients with unilateral symptoms were referred to 3.0 T magnetic resonance imaging and included in a cross-sectional study. Magnetic resonance imaging scans were evaluated blindly and graded according to presence and degree of neurovascular contact. Severe neurovascular contact was defined as displacement or atrophy of the trigeminal nerve. A total of 135 patients with classical trigeminal neuralgia were included. Average age of disease onset was 53.0 years (95% confidence interval mean 40.5-55.5) and current age was 60.1 years (95% % confidence interval mean 57.5-62.7). Eighty-two (61%, 95% confidence interval 52-69%) patients were female. Neurovascular contact was prevalent both on the symptomatic and asymptomatic side [89% versus 78%, P = 0.014, odds ratio = 2.4 (1.2-4.8), P = 0.017], while severe neurovascular contact was highly prevalent on the symptomatic compared to the asymptomatic side [53% versus 13%, P < 0.001, odds ratio = 11.6 (4.7-28.9), P < 0.001]. Severe neurovascular contact was caused by arteries in 98%. We conclude that neurovascular contact causing displacement or atrophy of the trigeminal nerve is highly associated with the symptomatic side in classical trigeminal neuralgia as opposed to neurovascular contact in general. Our findings demonstrate that severe neurovascular contact is involved in the aetiology of classical trigeminal neuralgia and that it is caused by arteries located in the root entry zone. PMID- 25541188 TI - LINKS: learning-based multi-source IntegratioN frameworK for Segmentation of infant brain images. AB - Segmentation of infant brain MR images is challenging due to insufficient image quality, severe partial volume effect, and ongoing maturation and myelination processes. In the first year of life, the image contrast between white and gray matters of the infant brain undergoes dramatic changes. In particular, the image contrast is inverted around 6-8months of age, and the white and gray matter tissues are isointense in both T1- and T2-weighted MR images and thus exhibit the extremely low tissue contrast, which poses significant challenges for automated segmentation. Most previous studies used multi-atlas label fusion strategy, which has the limitation of equally treating the different available image modalities and is often computationally expensive. To cope with these limitations, in this paper, we propose a novel learning-based multi-source integration framework for segmentation of infant brain images. Specifically, we employ the random forest technique to effectively integrate features from multi-source images together for tissue segmentation. Here, the multi-source images include initially only the multi-modality (T1, T2 and FA) images and later also the iteratively estimated and refined tissue probability maps of gray matter, white matter, and cerebrospinal fluid. Experimental results on 119 infants show that the proposed method achieves better performance than other state-of-the-art automated segmentation methods. Further validation was performed on the MICCAI grand challenge and the proposed method was ranked top among all competing methods. Moreover, to alleviate the possible anatomical errors, our method can also be combined with an anatomically-constrained multi-atlas labeling approach for further improving the segmentation accuracy. PMID- 25541190 TI - The perception of touch and the ventral somatosensory pathway. AB - In humans, touching the skin is known to activate, among others, the contralateral primary somatosensory cortex on the postcentral gyrus together with the bilateral parietal operculum (i.e. the anatomical site of the secondary somatosensory cortex). But which brain regions beyond the postcentral gyrus specifically contribute to the perception of touch remains speculative. In this study we collected structural magnetic resonance imaging scans and neurological examination reports of patients with brain injuries or stroke in the left or right hemisphere, but not in the postcentral gyrus as the entry site of cortical somatosensory processing. Using voxel-based lesion-symptom mapping, we compared patients with impaired touch perception (i.e. hypoaesthesia) to patients without such touch impairments. Patients with hypoaesthesia as compared to control patients differed in one single brain cluster comprising the contralateral parietal operculum together with the anterior and posterior insular cortex, the putamen, as well as subcortical white matter connections reaching ventrally towards prefrontal structures. This finding confirms previous speculations on the 'ventral pathway of somatosensory perception' and causally links these brain structures to the perception of touch. PMID- 25541192 TI - Increased upper airway collapsibility in a mouse model of Marfan syndrome. AB - Marfan syndrome (MFS) is a genetic disorder caused by mutations in the FBN1 gene that codifies for fibrilin-1. MFS affects elastic fiber formation and the resulting connective tissue shows abnormal tissue laxity and organization. Although an increased prevalence of obstructive sleep apnea among patients with MFS has been described, the potential effects of this genetic disease on the collapsible properties of the upper airway are unknown. The aim of this study was to assess the collapsible properties of the upper airway in a mouse model of MFS Fbn1((C1039G/+)) that is representative of most of the clinical manifestations observed in human patients. The upper airway in wild-type and Marfan mice was cannulated and its critical pressure (Pcrit) was measured in vivo by increasing the negative pressure through a controlled pressure source. Pcrit values from MFS mice were higher (less negative) compared to wild-type mice (-3.1+/-0.9cmH2O vs. 7.8+/-2.0cm H2O) suggesting that MFS increases the upper airway collapsibility, which could in turn explain the higher prevalence of OSA in MFS patients. PMID- 25541191 TI - Independent information from cerebrospinal fluid amyloid-beta and florbetapir imaging in Alzheimer's disease. AB - Reduced cerebrospinal fluid amyloid-beta42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-beta biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-beta were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE epsilon4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-beta were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE epsilon4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-beta was more strongly related to APOE epsilon4 whereas positron emission tomography amyloid-beta was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid beta positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-beta provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-beta but normal positron emission tomography amyloid-beta, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-beta may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-beta may be more strongly related to disease progression. PMID- 25541193 TI - Surveillance for hepatocellular carcinoma: can we focus on the mission? PMID- 25541194 TI - Subsequent Bacterial Infections in Patients With Cirrhosis and the Role of Proton Pump Inhibitors. PMID- 25541195 TI - Considering the kinetics of mRNA synthesis in the analysis of the genome and epigenome reveals determinants of co-transcriptional splicing. AB - When messenger RNA splicing occurs co-transcriptionally, the potential for kinetic control based on transcription dynamics is widely recognized. Indeed, perturbation studies have reported that when transcription kinetics are perturbed genetically or pharmacologically splice patterns may change. However, whether kinetic control is contributing to the control of splicing within the normal range of physiological conditions remains unknown. We examined if the kinetic determinants for co-transcriptional splicing (CTS) might be reflected in the structure and expression patterns of the genome and epigenome. To identify and then quantitatively relate multiple, simultaneous CTS determinants, we constructed a scalable mathematical model of the kinetic interplay of RNA synthesis and CTS and parameterized it with diverse next generation sequencing (NGS) data. We thus found a variety of CTS determinants encoded in vertebrate genomes and epigenomes, and that these combine variously for different groups of genes such as housekeeping versus regulated genes. Together, our findings indicate that the kinetic basis of splicing is functionally and physiologically relevant, and may meaningfully inform the analysis of genomic and epigenomic data to provide insights that are missed when relying on statistical approaches alone. PMID- 25541196 TI - Cmr4 is the slicer in the RNA-targeting Cmr CRISPR complex. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) loci and CRISPR associated (Cas) proteins form an adaptive immune system that protects prokaryotes against plasmids and viruses. The Cmr complex, a type III-B effector complex, uses the CRISPR RNA (crRNA) as a guide to target RNA. Here, we show that the Cmr complex of Pyrococcus furiosus cleaves RNA at multiple sites that are 6 nt apart and are positioned relative to the 5'-end of the crRNA. We identified Cmr4 as the slicer and determined its crystal structure at 2.8 A resolution. In the crystal, Cmr4 forms a helical filament that most likely reflects its structural organization in the Cmr complex. The putative active site is located at the inner surface of the filament where the guide and substrate RNA are thought to bind. The filament structure of Cmr4 accounts for multiple periodic cleavage sites on the substrate. Our study provides new insights into the structure and mechanism of the RNA-targeting Cmr complex. PMID- 25541197 TI - Creating a monomeric endonuclease TALE-I-SceI with high specificity and low genotoxicity in human cells. AB - To correct a DNA mutation in the human genome for gene therapy, homology-directed repair (HDR) needs to be specific and have the lowest off-target effects to protect the human genome from deleterious mutations. Zinc finger nucleases, transcription activator-like effector nuclease (TALEN) and CRISPR-CAS9 systems have been engineered and used extensively to recognize and modify specific DNA sequences. Although TALEN and CRISPR/CAS9 could induce high levels of HDR in human cells, their genotoxicity was significantly higher. Here, we report the creation of a monomeric endonuclease that can recognize at least 33 bp by fusing the DNA-recognizing domain of TALEN (TALE) to a re-engineered homing endonuclease I-SceI. After sequentially re-engineering I-SceI to recognize 18 bp of the human beta-globin sequence, the re-engineered I-SceI induced HDR in human cells. When the re-engineered I-SceI was fused to TALE (TALE-ISVB2), the chimeric endonuclease induced the same HDR rate at the human beta-globin gene locus as that induced by TALEN, but significantly reduced genotoxicity. We further demonstrated that TALE-ISVB2 specifically targeted at the beta-globin sequence in human hematopoietic stem cells. Therefore, this monomeric endonuclease has the potential to be used in therapeutic gene targeting in human cells. PMID- 25541199 TI - Corrections to 'Microfluidic circuit analysis I: Ion current relationships for thin slits and pipes', J. Colloid Interface Sci. 365 (2012) 1-15 and 'Microfluidic circuit analysis II: Implications of ion conservation for microchannels connected in series', J. Colloid Interface Sci. 365 (2012) 16-27. PMID- 25541198 TI - Molecular crowding overcomes the destabilizing effects of mutations in a bacterial ribozyme. AB - The native structure of the Azoarcus group I ribozyme is stabilized by the cooperative formation of tertiary interactions between double helical domains. Thus, even single mutations that break this network of tertiary interactions reduce ribozyme activity in physiological Mg(2+) concentrations. Here, we report that molecular crowding comparable to that in the cell compensates for destabilizing mutations in the Azoarcus ribozyme. Small angle X-ray scattering, native polyacrylamide gel electrophoresis and activity assays were used to compare folding free energies in dilute and crowded solutions containing 18% PEG1000. Crowder molecules allowed the wild-type and mutant ribozymes to fold at similarly low Mg(2+) concentrations and stabilized the active structure of the mutant ribozymes under physiological conditions. This compensation helps explains why ribozyme mutations are often less deleterious in the cell than in the test tube. Nevertheless, crowding did not rescue the high fraction of folded but less active structures formed by double and triple mutants. We conclude that crowding broadens the fitness landscape by stabilizing compact RNA structures without improving the specificity of self-assembly. PMID- 25541200 TI - Contaminant degradation by irradiated semiconducting silver chloride particles: kinetics and modelling. AB - The kinetics and mechanism of light-mediated formic acid (HCOO(-)) degradation in the presence of semiconducting silver chloride particles are investigated in this study. Our experimental results show that visible-light irradiation of AgCl(s) results in generation of holes and electrons with the photo-generated holes and its initial oxidation product carbonate radical, oxidizing HCOO(-) to form CO2. The HCOO(-) degradation rate increases with increase in silver concentration due to increase in rate of photo-generation of holes while the increase in chloride concentration decreases the degradation rate of HCOO(-) as a result of the scavenging of holes by Cl(-), thereby resulting in decreased holes and carbonate radical concentration. The results obtained indicate that a variety of other solution conditions including dioxygen concentration, bicarbonate concentration and pH influence the availability of holes and hence the HCOO(-) degradation rate in a manner consistent with our understanding of key processes. Based on our experimental results, we have developed a kinetic model capable of predicting AgCl(s)-mediated HCOO(-) photo-degradation over a wide range of conditions. PMID- 25541201 TI - Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors. AB - Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds 7h (IC50=2.40 MUM) and 12c (IC50=2.00 MUM) exhibited best inhibitory activity and selectivity against hMAO-A, surpassing that of the positive control Clorgyline (IC50=2.76 MUM). Based on selective activity of hMAO-A, SAR analysis showed that the order of N1 substituent contribution was bromo (3)>piperidinyl (4)>morpholinyl (5)>imidazolyl (6), and compounds with electron-withdrawing substituents (-F, Cl) at C3 or C5 phenyl ring of 2-pyrazoline nucleus dedicated stronger MAO-A inhibitory activity. Molecular docking showed that compounds 7h and 12c were nicely bound to hMAO-A via two hydrogen bonds (SER209, GLU216), one Pi-Pi interaction and three hydrogen bonds (SER209, GLU216, TYR69), one Sigma-Pi interaction, respectively. In addition, the substituent at C3 position of 2 pyrazoline with the N1 acetyl has little effect on MAO-A inhibitory activity. These data support further studies to assess rational design of more efficiently selective hMAO inhibitors in the future. PMID- 25541202 TI - High metabolic in vivo stability and bioavailability of a palmitoylated ghrelin receptor ligand assessed by mass spectrometry. AB - The constitutive activity of the ghrelin receptor is of high physiological and pathophysiological relevance. In-depth structure-activity relationship studies revealed a palmitoylated ghrelin receptor ligand that displays an in vitro binding affinity in the low nanomolar range. Activity studies revealed inverse agonistic as well as antagonistic properties and in vitro metabolic analysis indicated a high stability in blood serum and liver homogenate. For metabolic testing in vivo, a combined approach of stable isotopic labeling and mass spectrometry-based analysis was established. Therefore, a heavy isotopic version of the peptide containing a (13)C-labeled palmitic acid was synthesized and a 1:1 ratio of a (12)C/(13)C-peptide mixture was injected into rats. Biological samples were analyzed by multiple reaction monitoring allowing simultaneous peptide detection and quantification. Measurements revealed a suitable bioavailability over 24h in rat serum and subsequent high-resolution mass spectrometry investigations showed only negligible degradation and slow body clearance. Hence, this method combination allowed the identification and evaluation of a highly potent and metabolically stable ghrelin receptor ligand in vivo. PMID- 25541203 TI - Selective binding to monoamine oxidase A: in vitro and in vivo evaluation of (18)F-labeled beta-carboline derivatives. AB - In this study we synthesized four different (18)F-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [(18)F]fluoro-d2-methyl tosylate and 2 [(18)F]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic (18)F-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [(18)F]fluoro-d2-methyl-harmol and 2 [(18)F]fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic (18)F-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purification and formulation for each tracer was optimized and evaluated in vitro and in vivo. Stability tests in human serum showed that all tracers were stable over the observation period of 60 min. MUPET studies using of the synthesized tracers revealed that the tracers carrying PEG spacers showed no sufficient brain uptake. Consequently, the (18)F-fuoro alkylated tracers [(18)F]fluoro-d2-methyl harmol and 2-[(18)F]fluoroethyl-harmol were further evaluated showing SUVs in the brain of 1.0+/-0.2 g/mL and 3.4+/-0.5 g/mL after 45 min, respectively. In blockade studies the selectivity and specificity of both tracers were demonstrated. However, for [(18)F]fluoro-d2-methyl-harmol a rapid washout from the brain was also observed. In vitro binding assays revealed that 2 [(18)F]fluoroethyl-harmol (IC50=0.54+/-0.06 nM) has a higher affinity than the (18)F-fluoro-d2-methylated ligand (IC50=12.2+/-0.6 nM), making 2 [(18)F]fluoroethyl-harmol superior to the other evaluated compounds and a promising tracer for PET imaging of the MAO A. PMID- 25541204 TI - Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors. AB - Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue 27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15 MUM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents. PMID- 25541205 TI - MicroRNA-21: a central regulator of fibrotic diseases via various targets. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that diversely regulate physiological and pathophysiological processes by specifically binding to different regions of targeting messenger RNAs (mRNAs). Fibrosis is characterized by the abnormal proliferation of fibroblasts and the deposition of the extracellular matrix (ECM). Both clinical and experimental animal studies have revealed that aberrant expression of miRNAs is closely associated with the development of fibrotic diseases. microRNA-21 (miR-21) is a ubiquitously expressed miRNA that is traditionally considered to be an oncogenic miRNA (oncomiR). Recent studies have demonstrated that elevated expression of miR-21 may play a vital role in the development of fibrosis by promoting the proliferation of interstitial fibroblasts and increasing the abnormal deposition of the ECM. In this review, we comprehensively summarize the role of miR-21 in tissue fibrosis. Furthermore, we highlight miR-21 as a potential diagnostic and prognostic marker and therapeutic target for fibrosis diseases. PMID- 25541206 TI - Higher serum carcinoembryonic antigen levels associate with more frequent development of incident fractures in Korean women: a longitudinal study using the national health insurance claim data. AB - BACKGROUND: Pro-inflammatory cytokines play important roles in bone metabolism and several studies have shown that carcinoembryonic antigen (CEA) may promote inflammation. We investigated the association of serum CEA levels with the risk of osteoporosis and incident fracture. METHODS: We performed a small cross sectional study with 302 Korean women and a large, longitudinal study with 7192 Korean women in an average 3-year follow-up period. For the cross-sectional study, bone mineral density (BMD) and bone turnover markers (BTMs) were measured. For the longitudinal study, incident fractures in the follow-up period were identified by using the selected International Classification of Diseases, 10th revision (ICD-10) codes and the nationwide claims database of the Health Insurance Review and Assessment Service of Korea. RESULTS: In the cross-sectional study, serum CEA levels correlated negatively with BMD at the lumbar spine (gamma=-0.023; P=0.029) and positively with BTMs (gamma=0.122 to 0.138, P=0.002 to P<0.001) after adjustment for confounding variables. In the longitudinal study, 254 (3.5%) women developed incident fractures in the follow-up period (2.8+/-1.3 years). After adjustment for potential confounders, the hazard ratio (HR) per 1 ng/mL increment of the baseline CEA level for the development of incident fracture was 1.22 [95% confidence interval (CI): 1.05-1.42]. The HR was markedly higher in subjects in the highest CEA quartile category compared with those in the lowest CEA quartile category (HR=1.54, 95% CI: 1.04-2.28). CONCLUSION: Therefore, serum CEA may be a biomarker of the risk of incident fracture in postmenopausal Korean women. PMID- 25541208 TI - Investigation the mechanism of the apoptosis induced by lactacystin in gastric cancer cells. AB - The study aims to investigate the relationship between nuclear factor (nuclear factor kappa B (NF-kappaB)) viability and lactacystin-mediated cell apoptosis in gastric cancer cells. Two gastric cancer cell lines (MKN28 and SGC7901) were treated with lactacystin-a proteasome inhibitor for 24 h. The cell viability, toxicity, and death were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method. DNA binding viability of NF-kappaB and caspase-3 viability were analyzed by ELISA; the expression of p65 NF-kappaB nuclear protein was detected by immunocytochemistry and Western blot. Lactacystin reduced DNA binding viability of NF-kappaB (t = 3.0,P = 0.013) and the NF-kappaB viability (compared to the 5, 10 MUmol/L MKN28 cell (p53 mutant) line, P < 0.001) and the expression of p65 NF-kappaB nuclear protein decreased parallelled to concentrations of lactacystin in MKN28 cell line, while without obvious effects on NF-kappaB viability in SGC7901 cell line (P = 0.381), while the viability of caspase-3 increased also along with the raising of lactacystin concentrations (compared to control, 5 MUmol/L: SGC7901 cell line P = 0.029, MKN28 cell line P < 0.001; 10 MUmol/L: SGC7901 cell line, P < 0.001, MKN28 cell line, P < 0.001). It was concluded that lactacystin had diversified killing effects on gastric cancer cells. The mechanism may be related to induce the apoptosis by downregulation of nuclear factor kappa B viability. There may be additional cell survival/death pathway in SGC7901 gastric cancer cells. PMID- 25541207 TI - HIF-1alpha regulates bone formation after osteogenic mechanical loading. AB - HIF-1 is a transcription factor typically associated with angiogenic gene transcription under hypoxic conditions. In this study, mice with HIF-1alpha deleted in the osteoblast lineage (DeltaHIF-1alpha) were subjected to damaging or non-damaging mechanical loading known to produce woven or lamellar bone, respectively, at the ulnar diaphysis. By microCT, DeltaHIF-1alpha mice produced significantly less woven bone than wild type (WT) mice 7days after damaging loading. This decrease in woven bone volume and extent was accompanied by a significant decrease in vascularity measured by immunohistochemistry against vWF. Additionally, osteocytes, rather than osteoblasts, appear to be the main bone cell expressing HIF-1alpha following damaging loading. In contrast, 10days after non-damaging mechanical loading, dynamic histomorphometry measurements demonstrated no impairment in loading-induced lamellar bone formation in DeltaHIF 1alpha mice. In fact, both non-loaded and loaded ulnae from DeltaHIF-1alpha mice had increased bone formation compared with WT ulnae. When comparing the relative increase in periosteal bone formation in loaded vs. non-loaded ulnae, it was not different between DeltaHIF-1alpha mice and controls. There were no significant differences observed between WT and DeltaHIF-1alpha mice in endosteal bone formation parameters. The increases in periosteal lamellar bone formation in DeltaHIF-1alpha mice are attributed to non-angiogenic effects of the knockout. In conclusion, these results demonstrate that HIF-1alpha is a pro-osteogenic factor for woven bone formation after damaging loading, but an anti-osteogenic factor for lamellar bone formation under basal conditions and after non-damaging loading. PMID- 25541209 TI - The implications of nonlocality. PMID- 25541210 TI - Post-transplant lymphoproliferative disorder after kidney transplantation: time to adopt monitoring of Epstein-Barr virus? AB - Although post-transplant lymphoproliferative disorder is a classical complication encountered after kidney transplantation, its diagnosis can still be challenging and its outcome life-threatening. Most cases are related to Epstein-Barr virus (EBV) infection and occur mainly in the first year post-transplant, favoured by the seronegative EBV status of the recipient transplanted with a kidney from a seropositive donor, and strong immunosuppression. We report the case of a young kidney-pancreas transplant recipient who developed post-transplant lymphoproliferative disorder (PTLD) early after transplantation, with a rapid fatal issue. We review the pathogenesis, clinical presentation, and management of PTLD with a focus on prevention. PMID- 25541211 TI - Patient characteristics that influence enrollment and attendance in aerobic exercise early after stroke. AB - OBJECTIVE: To identify patient characteristics that influence physiotherapist's decisions on enrollment and attendance in a structured aerobic exercise program early after stroke. DESIGN: Retrospective chart review. SETTING: Rehabilitation hospital. PARTICIPANTS: Consecutive sample of people (N=345) admitted to inpatient stroke rehabilitation over a 2-year period. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient demographic characteristics, preexisting medical conditions, and poststroke outcome variables (neurological deficit, physical impairment, balance control, and functional mobility and independence) were compared between individuals enrolled and not enrolled in a structured aerobic exercise program. The rate of attendance was calculated for the enrolled group. RESULTS: One hundred twenty-nine patients (38%) were enrolled in the structured aerobic exercise program. Patients who were older (P=.0093) and had cardiac disease (P=.012), cardioembolic sources (P=.0094), and arthritis (P=.031) were less likely to be enrolled in the structured aerobic exercise program. Poststroke outcome variables were not associated with enrollment. Among those enrolled, the rate of attendance was positively correlated with the FIM cognitive rating (r=.27; P=.0031). CONCLUSIONS: Enrollment in structured aerobic exercise programs during inpatient stroke rehabilitation can be limited by safety concerns related to patients' cardiovascular and musculoskeletal status. Barriers associated with the perception of cardiovascular risk factors should be confronted because they do not preclude participation in cardiac rehabilitation. In addition, poststroke deficits do not limit participation in adapted aerobic exercise early after stroke. It is likely that the characteristics of the structured aerobic exercise program were integral to accommodate the breadth of poststroke deficits encountered in this study. Future research investigating physiotherapist and practice environment factors that influence the decision to prescribe and implement aerobic exercise is warranted. PMID- 25541212 TI - Interface of physics and biology: engineering virus-based nanoparticles for biophotonics. AB - Virus-based nanoparticles (VNPs) have been used for a wide range of applications, spanning basic materials science and translational medicine. Their propensity to self-assemble into precise structures that offer a three-dimensional scaffold for functionalization has led to their use as optical contrast agents and related biophotonics applications. A number of fluorescently labeled platforms have been developed and their utility in optical imaging demonstrated, yet their optical properties have not been investigated in detail. In this study, two VNPs of varying architectures were compared side-by-side to determine the impact of dye density, dye localization, conjugation chemistry, and microenvironment on the optical properties of the probes. Dyes were attached to icosahedral cowpea mosaic virus (CPMV) and rod-shaped tobacco mosaic virus (TMV) through a range of chemistries to target particular side chains displayed at specific locations around the virus. The fluorescence intensity and lifetime of the particles were determined, first using photochemical experiments on the benchtop, and second in imaging experiments using tissue culture experiments. The virus-based optical probes were found to be extraordinarily robust under ultrashort, pulsed laser light conditions with a significant amount of excitation energy, maintaining structural and chemical stability. The most effective fluorescence output was achieved through dye placement at optimized densities coupled to the exterior surface avoiding conjugated ring systems. Lifetime measurements indicate that fluorescence output depends not only on spacing the fluorophores, but also on dimer stacking and configurational changes leading to radiationless relaxation and these processes are related to the conjugation chemistry and nanoparticle shape. For biological applications, the particles were also examined in tissue culture, from which it was found that the optical properties differed from those found on the benchtop due to effects from cellular processes and uptake kinetics. Data indicate that fluorescent cargos are released in the endolysosomal compartment of the cell targeted by the virus-based optical probes. These studies provide insight into the optical properties and fates of fluorescent proteinaceous imaging probes. The cellular release of cargo has implications not only for virus-based optical probes, but also for drug delivery and release systems. PMID- 25541213 TI - Acquisition of Streptococcus pneumoniae in South African children vaccinated with 7-valent pneumococcal conjugate vaccine at 6, 14 and 40 weeks of age. AB - BACKGROUND: Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the South African immunization program using 6, 14 and 40 weeks dosing schedule (2+1), with no catch-up in older children since April 2009. We investigated pneumococcal colonization acquisition in children who received this schedule and also compared it to historical cohorts of PCV-naive children (n=123 in 2007) and children who received a 3+1 PCV7 schedule (n=124 in 2005/06). METHODS: Two hundred and fifty children aged 6-12 weeks were enrolled from December 2009 to April 2010. Participants had nasopharyngeal swabs collected on eight occasions between enrolment and 2-years of age. Standard methods were undertaken for bacterial culture and Streptococcus pneumoniae were serotyped using the Quellung method. Pneumococcal and Staphylococcus aureus colonization in the present study was compared to colonization in two historical longitudinal cohorts. RESULTS: S. pneumoniae was identified in 1081 (61.4%) of 1761 swabs collected in the current cohort. Pneumococcal colonization peaked at 41-weeks of age (76.8%) and decreased to 62.8% by 2-years of age (p=0.002); PCV7-serotype colonization decreased during the same period from 28.6% to 15.6% (p=0.001). Children from the current cohort compared to PCV-naive children were less likely to be colonized by PCV7-serotypes from 40-weeks to 2-years of age and acquired PCV7-serotypes less frequently. No differences in overall pneumococcal, PCV7 serotype and non-PCV7-serotype colonization or new serotype acquisitions were detected comparing the current cohort to the historical cohort who received the 3+1 PCV7 schedule. Staphylococcus aureus colonization was similar in all three cohorts. CONCLUSION: A 2+1 PCV7 schedule implemented in South Africa was temporally associated with reduced risk of vaccine-serotype colonization compared to historically unvaccinated children. Also, vaccine-serotype acquisition rate using the 2+1 schedule was similar to that in the 3+1 dosing cohort, suggesting that similar indirect protection against pneumococcal disease could be derived from either schedule in South Africa. PMID- 25541215 TI - Validation of the Fear of Pelvic Examination Scale (F-PEXS)--measuring students' fear of performing a pelvic examination. AB - INTRODUCTION: Medical students of both genders often show signs of fear before they perform their first pelvic examination. This situation puts a novice in a special setting of intimacy never experienced before and where different emotions may emerge. A specially designed questionnaire, the Fear of Pelvic Examination Scale (F-PEXS) has been developed to assess fear in this context. The aim of this paper is to describe the validation of the F-PEXS. METHODS: Undergraduate medical students (N = 100) answered the F-PEXS one week before, prior to and after a learning session with professional patients to assess levels of anxiety towards performing the pelvic exam. The validity of the scale was examined using item analysis, reliability assessments and analysis of the construct validity in comparing the F-PEXS with the Spielberger State and Trait Anxiety Inventory and Beck's Anxiety Inventory. RESULTS: The F-PEXS has very good reliability (Cronbach's alpha 0.96) and good construct validity. The mean score on the F-PEXS did not differ between gender either before or after the learning session. CONCLUSIONS: The F-PEXS can be used to assess students' fear of performing the pelvic examination, to evaluate new strategies for learning the pelvic exam and to evaluate the outcome of such interventions. PMID- 25541214 TI - Controlling measles using supplemental immunization activities: a mathematical model to inform optimal policy. AB - BACKGROUND: The Measles & Rubella Initiative, a broad consortium of global health agencies, has provided support to measles-burdened countries, focusing on sustaining high coverage of routine immunization of children and supplementing it with a second dose opportunity for measles vaccine through supplemental immunization activities (SIAs). We estimate optimal scheduling of SIAs in countries with the highest measles burden. METHODS: We develop an age-stratified dynamic compartmental model of measles transmission. We explore the frequency of SIAs in order to achieve measles control in selected countries and two Indian states with high measles burden. Specifically, we compute the maximum allowable time period between two consecutive SIAs to achieve measles control. RESULTS: Our analysis indicates that a single SIA will not control measles transmission in any of the countries with high measles burden. However, regular SIAs at high coverage levels are a viable strategy to prevent measles outbreaks. The periodicity of SIAs differs between countries and even within a single country, and is determined by population demographics and existing routine immunization coverage. CONCLUSIONS: Our analysis can guide country policymakers deciding on the optimal scheduling of SIA campaigns and the best combination of routine and SIA vaccination to control measles. PMID- 25541216 TI - Testing direct and moderating effects of coping styles on the relationship between perceived stress and antenatal anxiety symptoms. AB - OBJECTIVE: The objective of this study was to test the direct and moderating effects of different coping styles in mitigating perceived stress associated with antenatal anxiety symptoms among 755 pregnant women in Chengdu. METHODS: A cross sectional study using a questionnaire survey was carried out. The Perceived Stress Scale, the Trait Coping Style Questionnaire and the Zung Self-rating Anxiety Scale were used to measure stress, coping and anxiety symptoms, respectively. Hierarchical regression analysis was used to test the direct and moderating effects of coping styles in the relationship between perceived stress and antenatal anxiety symptoms. RESULTS: Direct effects of negative coping (NC) styles were found. Women with higher NC scores were more likely to have anxiety symptoms. Positive coping (PC) styles had moderating effects on perceived stress, whereas NC styles did not. CONCLUSION: The findings of this study highlight the direct and moderating effects of coping styles. This knowledge is important to healthcare professionals in planning health service provision. Health services should dedicate resources to teaching pregnant women how to enhance PC styles, alter NC styles and cultivate optimistic thinking to alleviate anxiety symptoms. PMID- 25541217 TI - Mind-body group treatment for women coping with infertility: a pilot study. AB - OBJECTIVES: To evaluate the feasibility of a 10-week mind-body intervention (MBI) for women coping with fertility challenges, examine the impact of an MBI on psychological distress and cortisol levels, and assess adherence to MBI skills 12 months after completion of the intervention. DESIGN: Prospective open pilot study of 51 women with infertility enrolled in a group MBI. Psychological variables and salivary cortisol levels were obtained pre- and post-intervention; a 12-month follow-up survey assessed MBI skill adherence. Participants completed practice logs throughout the intervention. RESULTS: Participants attended an average of eight sessions (SD = 2.0), and practiced mind-body techniques which elicited the relaxation response (RR) an average of 5.9 (SD = 0.8) days/week and 20.1 (SD = 9.9) min/day; 80% completed the post-treatment assessment. The intervention resulted in a significant increase in perceived social support and a decrease in depressive symptoms and perceived stress; however, there were no significant changes in cortisol levels. Sixty-eight percent of the participants completed the 12-month follow-up, with 51% reporting continuation of RR-eliciting practice. CONCLUSION: This group of women with infertility provided with an MBI showed decreased symptoms of depression and stress and increased perceived social support. The protocol was feasible and participants reported a high degree of adherence and maintenance to the skills taught during the intervention. The findings indicate the value of appropriate evaluation against a control group. PMID- 25541218 TI - Psychological factors and trimester-specific gestational weight gain: a systematic review. AB - Excess gestational weight gain (GWG), which has reached epidemic proportions, is associated with numerous adverse pregnancy outcomes. Early pregnancy provides a unique opportunity for counseling pregnant women since many women are motivated to engage in healthy behaviors. A systematic review was conducted to summarize the relation between psychological factors and trimester-specific GWG, i.e. GWG measured at the end of each trimester. Eight databases were searched for affect, cognition and personality factors. The guidelines on meta-analysis of Observational Studies in Epidemiology were followed. The methodological quality of each study was assessed using a modified Newcastle-Ottawa Scale. Of 3620 non duplicate titles and abstracts, 74 articles underwent full-text review. Two cohort studies met the inclusion criteria. Distress was negatively associated with first trimester GWG among both adolescents and non-adolescents. Body image dissatisfaction was associated with second trimester GWG only among non adolescents. No association emerged between perceived stress, state and trait anxiety and body image dissatisfaction among adolescents and trimester-specific GWG. The relation between trimester-specific GWG and a number of weight-related and dietary-related cognitions, affective states and personality traits remain unexplored. Given the limited number of studies, further high-quality evidence is required to examine the association between psychological factors and trimester specific GWG, especially for cognitive and personality factors. PMID- 25541219 TI - Novel coiled-coil proteins regulate exocyst association with cortical microtubules in xylem cells via the conserved oligomeric golgi-complex 2 protein. AB - Xylem vessel cells develop secondary cell walls in distinct patterns. Cortical microtubules are rearranged into distinct patterns and regulate secondary cell wall deposition; however, it is unclear how exocytotic membrane trafficking is linked to cortical microtubules. Here, we show that the novel coiled-coil proteins vesicle tethering 1 (VETH1) and VETH2 recruit EXO70A1, an exocyst subunit essential for correct patterning of secondary cell wall deposition, to cortical microtubules via the conserved oligomeric Golgi complex (COG) 2 protein. VETH1 and VETH2 encode an uncharacterized domain of an unknown function designated DUF869, and were preferentially up-regulated in xylem cells. VETH1 green fluorescent protein (GFP) and VETH2-GFP co-localized at novel vesicle-like small compartments, which exhibited microtubule plus-end-directed and end tracking dynamics. VETH1 and VETH2 interacted with COG2, and this interaction promoted the association between cortical microtubules and EXO70A1 These results suggest that the VETH-COG2 complex ensures the correct secondary cell wall deposition pattern by recruiting exocyst components to cortical microtubules. PMID- 25541220 TI - Current challenges in the recognition, prevention and treatment of perioperative pulmonary atelectasis. AB - Innovations in surgery have significantly increased the number of procedures performed every year. While more individuals benefit from better surgical techniques and technology, a larger group of patients previously deemed ineligible for surgery now undergo high-complexity surgical procedures. Despite continuous improvements in the operating room and post-operative care, post operative pulmonary complications (PPCs) continue to pose a serious threat to successful outcomes. PPCs are common, serious and costly. Growing awareness of the impact of PPCs has led to intensified efforts to understand the underlying causes. Current evidence demonstrates that a high proportion of PPCs are directly traceable to the pre-operative risk for and perioperative development of atelectasis. The substantial costs and losses associated with PPCs demand strategies to reduce their prevalence and impact. Effective interventions will almost certainly produce cost savings that significantly offset current economic and human resource expenditures. The purpose of this review is to describe the most common challenges encountered in the recognition, prevention and management of perioperative atelectasis. Expanding awareness and understanding of the role of atelectasis as a cause of PPCs can reduce their prevalence, impact important clinical outcomes and reduce the financial burden associated with treating these complications. PMID- 25541221 TI - In memoriam Donald E. Gardner, PhD, ATS (1931-2014). PMID- 25541222 TI - The effects of strain and ploidy on the physiological responses of rainbow trout (Oncorhynchus mykiss) to pH 9.5 exposure. AB - We characterized the physiological effects of exposure to pH9.5 on one domesticated and four wild strains of diploid and triploid juvenile rainbow trout (Oncorhynchus mykiss) over two consecutive years. In the first year, 35-70% of the individuals from the wild strains showed a loss of equilibrium (LOE) at 12 h exposure to pH9.5, with all fish from wild strains experiencing a LOE by 48 h. In contrast, <20% of the domesticated strain showed LOE over the 48 h exposure to pH9.5. In our second experiment, similar strain effects were observed, but far fewer fish showed LOE (<=50% in all strains) over 72 h at pH9.5. In both experiments, there was no effect of ploidy on time to LOE. In the fish that did not show LOE, high pH exposure resulted in significant increases in plasma, brain and muscle ammonia, with no effect of strain or ploidy on the extent of ammonia accumulation. Glutamine accumulated in the brain during high pH exposure, with a stoichiometric decrease in glutamate, but no differences were noted among strains or ploidies. Lactate also accumulated in the plasma to a similar extent in all trout strains and ploidies. Plasma chloride decreased at 24h exposure in all trout strains and ploidies, but recovered by 72 h. No change was observed in plasma sodium. Overall, our data suggest that the domesticated strain of trout is more tolerant of pH9.5 than the wild strains, but these differences in tolerance cannot be explained by our sub-lethal assessment of ammonia balance or ion regulation. PMID- 25541223 TI - A 16-week secondary abdominal ectopic pregnancy with a simultaneous intratubal placenta and abdominal fetus. AB - An unusual case of a simultaneous tubal and abdominal ectopic pregnancy with the placenta in the intact tube and fetus in the abdominal cavity demonstrating the pathogenesis of secondary abdominal pregnancy subsequently managed by laparoscopic salpingectomy and removal of the abdominal fetus. PMID- 25541224 TI - Should unobstructed gasping be facilitated and confirmed before administering adrenaline, otherwise, give titrated vasopressin? AB - A recent commentary, "Resuscitation That's (Un)Shockable: Time to Get the Adrenaline Flowing", published in the New England Journal of Medicine Journal Watch called attention to a relatively recent study showing that a large and increasing percentage of patients with in-hospital cardiac arrests exhibit initial nonshockable rhythms (asystole or pulseless electrical activity [PEA]; 82% in 2009 vs 69% in 2000) and a most recent study that concluded that neurologically intact survival to hospital discharge after in-hospital cardiac arrest was significantly more likely after earlier epinephrine administration. It was found that delayed administration of epinephrine was associated significantly with lower chance for survival to hospital discharge, in stepwise fashion (12%, 10%, 8%, and 7% survival, respectively, for patients receiving their first epinephrine dose<=3, 4-6, 7-9, and >9 minutes after arrest). Although early use of epinephrine to manage patients with nonshockable rhythms lacks strong evidence to support efficacy, focus on time to epinephrine administration-in addition to high-quality chest compressions-might be the best early intervention. However, evidence may strongly support the recommendation that adrenaline needs to be used very early because without effective-depth cardiopulmonary resuscitation (CPR) with complete recoil, epinephrine may only be effective when gasping is present, which is a time-limited phenomenon. However, because very few rescuers can perform effective-depth chest compressions with complete recoil, gasping is critically necessary for adequate ventilation and generation of adequate coronary and cerebral perfusion. However, under acidemic conditions and high catecholamine levels and/or absence of gasping, vasopressin should be administered instead. PMID- 25541225 TI - Diagnostic value of plasma signal peptide-Cub-Egf domain-containing protein-1 (SCUBE-1) in an experimental model of acute ischemic stroke. AB - OBJECTIVES: This study was intended to examine possible diagnostic value of plasma Signal Peptide-Cub-Egf domain-containing protein-1 (SCUBE1) levels in an experimental model of acute ischemic stroke. METHODS: Twenty-four female Sprague Dawley rats were divided into four groups. Blood and brain tissue specimens were collected immediately following artery ligation (control; Group 1), 1h after ligation (Group 2), 2 h after ligation (Group 3) and 6h after ligation (Group 4). SCUBE1 levels were investigated in the serum specimens. The brain samples were examined histopathologically. Correlation analysis was performed between the values. RESULTS: Median SCUBE1 values were 1.75 ng/ml in the control group, 3.80 ng/ml, 3.71 ng/ml and 4.19 ng/ml in the groups 2, 3 and 4, respectively (n=6 for each, P=0.004, for each group compared to control values). Histopathological analysis revealed median atrophic neuron percentages of 16% (in group 1), 42%, 55% and 76% in group 2, 3 and 4 respectively (n=6 for each, P=0.004, for each group compared to control group). A higly significant correlation was determined between SCUBE-1 levels and percentage of atrophic neurons (r=0.744 P=0.000). CONCLUSIONS: In this experimental model of acute ischemic stroke plasma SCUBE1 levels rose from the 1st hour of induced stroke and remained high up to 6th hour tested. Results of this experimental study has a potential to become the basis for a clinical study to confirm whether SCUBE1 can be used as a biomarker in the early diagnosis of acute ischemic stroke patients. PMID- 25541226 TI - The impact of age on outcomes of elderly ED patients ventilated due to community acquired pneumonia. AB - OBJECTIVES: There is no consensus on whether mechanical ventilation should be initiated for advanced age with community-acquired pneumonia (CAP). This study investigated the effects of age on the outcomes of mechanical ventilation in the emergency department (ED) for advanced age with CAP. METHODS: We retrospectively investigated the medical records of advanced age (age, >=65 years) with CAP who required mechanical ventilation in the ED of our hospital between January 2006 and December 2012. The patients were divided into 65 to 74, 75 to 84, and 85 years or older age groups. The following outcomes were measured: number of patients weaned from mechanical ventilation, in-hospital mortality, ventilator free days, and intensive care unit days. Multiple logistic regression analysis was used to identify risk factors associated with mortality and weaning from mechanical ventilation. RESULTS: Seventy-one patients (mean age, 79.5 years) were included. The overall in-hospital mortality rate was 43.7%. No significant differences were observed among the 3 groups with regard to weaning from mechanical ventilation (P=.59), in-hospital mortality (P=.90), ventilator-free days (P=.83), or intensive care unit days (P=.12). Age was not significantly associated with weaning from mechanical ventilation or in-hospital mortality among advanced age. Diabetes mellitus was an independent factor for weaning from mechanical ventilation (P=.048) and was relatively associated with mortality (P=.051). CONCLUSIONS: Age, in itself, may not be a factor limiting the initiation of mechanical ventilation in the ED in advanced age with CAP. Further studies should determine appropriate indications for mechanical ventilation in the ED for these patients. PMID- 25541227 TI - Long-term Effects of Plant Stanols on the Lipid Profile of Patients With Hypercholesterolemia. A Randomized Clinical Trial. AB - INTRODUCTION AND OBJECTIVES: Plant stanol consumption may improve long-term cholesterol control. The aim of the present study was to evaluate the effectiveness of 2g/day of plant stanols in reducing low-density lipoprotein cholesterol levels in patients with hypercholesterolemia. METHODS: This randomized, double-blind, and placebo-controlled study included 182 adults diagnosed with hypercholesterolemia. A yogurt drink containing 2g of plant stanols was administered to 91 participants in the intervention group; 91 participants in the control group received unsupplemented yogurt. The primary end point was the change in the lipid profile at 12 months. RESULTS: Low-density lipoprotein cholesterol levels at 12 months were significantly more reduced in the stanol intervention group than in the control group: 13.7 (95% confidence interval, 3.2-24.1) mg/dL (P=.011). A reduction of more than 10% in low-density lipoprotein cholesterol was achieved by a significantly higher proportion of participants in the intervention group (relative risk=1.7; 95% confidence interval, 1.1-2.7). In this group, the mean (standard deviation) level of low density lipoprotein cholesterol decreased by 11.0% (23.9%). CONCLUSIONS: Our results confirm that administration of plant stanols at a dosage of 2 g/day for 12 months significantly reduces (by slightly more than 10%) the concentrations of low-density lipoprotein cholesterol in individuals with hypercholesterolemia. Trial registration (www.ClinicalTrials.gov): Current Controlled Trials NCT01406106. PMID- 25541228 TI - High prevalence of multi-drug resistant Streptococcus pneumoniae among healthy children in Thailand. AB - Antibiotic resistance in Streptococcus pneumoniae is an emerging health problem worldwide. The incidence of antimicrobial-resistant S. pneumoniae is increasing, and nasal colonization of S. pneumoniae in children increases the risk of pneumococcal infection. In this study, the prevalence of S. pneumoniae nasal colonization was studied in Thai children from three different districts. S. pneumoniae nasal colonization was found in 38 of 237 subjects (16.0%). The carriage rate indicated higher rates in two rural districts (18.2% and 29.8%) than in the urban district (2.8%). The antibiotic susceptibility pattern was determined using the disk diffusion method. Prevalence of multi-drug resistance S. pneumoniae (MDR-SP) was 31.6%. Resistance to commonly prescribed antibiotics was found for ampicillin (5.3%), azithromycin (26.3%), cefepime (2.6%), chloramphenicol (18.4%), clindamycin (18.4%), erythromycin (21.1%), oxacillin (44.7%), trimethoprim/sulfamethoxazole (78.9%) and tetracycline (15.8%). All isolates were sensitive to ceftriaxone. The pulsed-field gel electrophoresis pattern was used to compare genetic diversity of the S. pneumoniae isolates. PFGE demonstrated the variation in genotypes of S. pneumoniae from different areas. High prevalence of multi-drug resistance S. pneumoniae nasal colonization in healthy Thai children was indicated. Effective strategies for appropriate use of antibiotics are therefore needed in the community. PMID- 25541229 TI - Strengthening cardiovascular disease prevention in remote indigenous communities in Australia's Northern Territory. AB - BACKGROUND: In 2012 the Northern Territory Department of Health commenced the Chronic Conditions Management Model - strengthening cardiovascular disease prevention in remote Indigenous communities. Interventions included providing regular functional reporting and decision support to frontline primary health care teams. METHODS: Longitudinal (three monthly) clinical audits of cardiac prevention services were undertaken between 2012 and 2014. Our primary outcome was population coverage of cardiovascular risk assessment for Indigenous clients aged 20 years and older. Secondary outcomes for those identified at high risk were (i) assessment of modifiable cardiac risk factors, (ii) prescription of risk lowering medications, and (iii) the proportion of high risk clients achieving clinical targets for risk reduction. RESULTS: As of August 2014, 7266 clients have had their cardiovascular risk assessed, improving population coverage from 23% in mid June 2012 to 58.5%. For 2586 high risk clients, 1728 (67%) and 1416 (55%) were prescribed blood pressure and lipid lowering therapy and for those clinically re-assessed, 1366 (57%) and 989 (40%) were achieving clinical targets for risk reduction for blood pressure and lipids respectively. CONCLUSIONS: Functional reporting and decision support was associated with improvement in cardiovascular risk assessment coverage and a sustained proportion of high risk clients achieving clinical targets for cardiovascular risk reduction. Further intervention-based research is required to close the gap between identification of risk and risk reduction. PMID- 25541230 TI - [Systemic sclerosis and occupational exposures: About a case in a driller powderman]. AB - INTRODUCTION: Erasmus' syndrome is the association between systemic sclerosis and silica exposure. CASE REPORT: We report a case of this syndrome in a driller powderman exposed to silica and nitro compounds contained in explosives. CONCLUSION: Physiopathology and etiologies of systemic sclerosis are still not well known. However, nitric oxide, a product of nitro compounds metabolism, is involved in the physiopathology of the disease: it seems thus licit to wonder about the consequences of an uncontrolled occupational exposure to nitric oxide on the vascular function, already damaged by systemic sclerosis. To a wider extent, our report highlights the importance of a comprehensive and detailed collection of occupational exposures for patients diagnosed with systemic sclerosis. PMID- 25541231 TI - [The pre-pregnancy counseling]. AB - Pre-pregnancy counseling is one of the keys of success of pregnancy in women with autoimmune or systemic diseases, especially lupus or antiphospholipid syndrome. This type of consultation should be offered to all women with systemic diseases, giving the possibility to allow a pregnancy or to explain why this project should be delayed, to anticipate some problems, to give comprehensive informations to the couple, to organize the multidisciplinary monitoring, to adapt treatments, and finally, to verify the validity of some vaccinations. The generalization of pre-pregnancy counseling should allow to minimize risks for both mother and fetus, then, to improve the prognosis of these high risk pregnancies. PMID- 25541233 TI - The morphological diversity of dermatoglyphic patterns on fingers: a simple and objective method for measurement. AB - The paper contains a proposal for a simple way of measuring the morphological diversity of patterns on fingers. The mono/polymorphism index (Imp) is the sum of 45 mutual absolute differences between the numerical values of the patterns depending on their degree of morphological complexity. Wendt's 7-degree scale was used to quantify the patterns. The value Imp=0 denotes monomorphism, i.e., the presence of the same type of pattern on all the fingers of both hands, while high values denote a mosaic of patterns of diverse morphology (polymorphism). Elements of the individual values of the Imp index comprise mutual homolateral differences (10 differences for the fingers of the left hand and 10 differences for the right), on the basis of which an assessment was made between the sides of the body, and additionally 25 heterolateral differences. Generally, greater degree of morphological diversity in patterns is found in males, and on the fingers of the right hand in both sexes. The arithmetic mean of the Imp index differs significantly between males (55.17) and females (52.08). Its values are not directly related to the degree of morphological complexity of patterns included in the Wendt's index. There were found, however, intra-familial connections for this trait. In light of the values of the indices of correlation and association, it may be concluded that there are relatively weak but statistically significant parents-offspring relations, as well as between siblings. An objective way to determine the values of the Imp index would make it possible to use it both for the morphological characterization of dermatoglyphs in different populations and also in clinical, auxological and genetic research. PMID- 25541234 TI - Cranial placodes: models for exploring the multi-facets of cell adhesion in epithelial rearrangement, collective migration and neuronal movements. AB - Key to morphogenesis is the orchestration of cell movements in the embryo, which requires fine-tuned adhesive interactions between cells and their close environment. The neural crest paradigm has provided important insights into how adhesion dynamics control epithelium-to-mesenchyme transition and mesenchymal cell migration. Much less is known about cranial placodes, patches of ectodermal cells that generate essential parts of vertebrate sensory organs and ganglia. In this review, we summarise the known functions of adhesion molecules in cranial placode morphogenesis, and discuss potential novel implications of adhesive interactions in this crucial developmental process. The great repertoire of placodal cell behaviours offers new avenues for exploring the multiple roles of adhesion complexes in epithelial remodelling, collective migration and neuronal movements. PMID- 25541235 TI - All things not being equal: readmission associated with procedure type. AB - BACKGROUND: There is an accelerated effort to reduce hospital readmissions despite minimal data detailing risk factors associated with this outcome. MATERIALS AND METHODS: We analyzed National Surgical Quality Improvement Project data from January 1, 2011-December 31, 2011, evaluating all patients undergoing one of 34 targeted operative procedures across all surgical specialties. Multivariate regression models of risk for readmission were developed including targeted procedure codes, demographic variables, preoperative variables, intraoperative variables, and postoperative adverse events. Our main outcome measure was hospital readmission. RESULTS: A total of 217, 389 patients met study inclusion criteria. Minimal associations existed between patient factors and risk of readmission. Adverse events including unplanned operating room return (odds ratio [OR] 8.5; confidence interval [CI] 8.0-9.0), pulmonary embolism (OR 8.2; CI 7.1-9.6), deep incisional infection (OR 7.5; CI 6.7-8.5), and organ space infection (OR 5.8; CI 5.3-6.3) were associated with increased risk of readmission. Our data suggest the type of procedure performed is significantly associated with risk of readmission. Furthermore, multivariate analysis revealed procedures, involving the pancreas, rectum, bladder, and lower extremity vascular bypass, were associated with the highest risk of readmission. CONCLUSIONS: Postoperative complications demonstrated stronger association with readmission than patient factors. Focused analysis of higher risk procedures may provide insight into strategies for risk reduction. PMID- 25541236 TI - Pancreatic perfusion data and post-pancreaticoduodenectomy outcomes. AB - BACKGROUND: Precise risk assessment for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) may be facilitated using imaging modalities. Computed tomography perfusion (CTP) of the pancreas may represent histologic findings. This study aimed to evaluate the utility of CTP data for the risk of POPF after PD, in relation to histologic findings. METHODS: Twenty patients who underwent preoperative pancreatic CTP measurement using 320-detector row CT before PD were investigated. Clinicopathologic findings, including CTP data, were analyzed to assess the occurrence of POPF. In addition, the correlation between CTP data and histologic findings was evaluated. RESULTS: POPF occurred in 11 cases (grade A, 6; grade B, 5; and grade C, 0). In CTP data, both high arterial flow (AF) and short mean transit time (MTT) were related to POPF occurrence (P = 0.001, P = 0.001). AF was negatively correlated with fibrosis in the pancreatic parenchyma (r = -0.680), whereas MTT was positively correlated with fibrosis (r = 0.725). AF >80 mL/min/100 mL and MTT <16 s showed high sensitivity, specificity, positive predictive value, and negative predictive value (80.0%, 100.0%, 100.0%, and 83.3%, respectively) for the occurrence of POPF. CONCLUSIONS: CTP data for the pancreas were found to be correlated with the occurrence of POPF after PD. Alterations in the blood flow to the remnant pancreas may reflect histological changes, including fibrosis in the pancreatic stump, and influence the outcome after PD. CTP may thus facilitate objective and quantitative risk assessment of POPF after PD. PMID- 25541237 TI - Complications after sternal reconstruction: a 16-y experience. AB - BACKGROUND: Unlike risk factors associated with sternotomy complications, those associated with sternal reconstruction have not been well elucidated. We sought to examine complication rates after sternal wound reconstruction and to identify perioperative risk factors associated with these complications. METHODS: We evaluated the records of 230 consecutive patients who underwent sternal reconstruction with muscle flaps after cardiac surgery. Patient demographics, clinical comorbidities, and operative procedure types were evaluated against two outcome variables-major complications and reconstructive failure. RESULTS: The mean age of our cohort was 62 y. Major complications (readmission, reoperation, or death) occurred in 76 patients (33%), including mortality rate of 3.5%. Obesity, chronic obstructive pulmonary disease, and type of reconstructive procedure correlated with an increased risk of major complications. Reconstructive failure occurred in 39 patients (17%) and was associated with female gender, obesity, previous coronary artery bypass graft procedure, and prior left internal mammary artery usage. Regression analyses demonstrated that obesity is independently associated with an increased risk of major complications and that women are at an increased risk of reconstructive failure. Reconstructions involving the rectus abdominis were correlated with an increased risk of major complications, but this difference was not significant in multiple regression analysis. CONCLUSIONS: Usual risk factors for sternal wound development after cardiac surgery include diabetes, age, obesity, tobacco use, history of stroke, bilateral left internal mammary artery harvest, and significant blood transfusion. In distinction, this study found that the risks independently associated with major complications and reconstructive failures after reconstruction of sternal wounds are limited to obesity and female gender. PMID- 25541238 TI - Animal model of reversible, right ventricular failure. AB - BACKGROUND: Heart failure is a leading cause of death but very little is known about right ventricular (RV) failure (RVF) and right ventricular recovery (RVR). A robust animal model of reversible, RVF does not exist, which currently limits research opportunities and clinical progress. We sought to develop an animal model of reversible, pressure-overload RVF to study RVF and RVR. MATERIALS AND METHODS: Fifteen New Zealand rabbits underwent implantation of a fully implantable, adjustable, pulmonary artery band. Animals were assigned to the control, RVF, and RVR groups (n = 5 for each). For the RVF and RVR groups, the pulmonary artery bands were serially tightened to create RVF and released for RVR. Echocardiographic, cardiac magnetic resonance imaging, and histologic analysis were performed. RESULTS: RV chamber size and wall thickness increased during RVF and regressed during RVR. RV volumes were 1023 MUL +/- 123 for control, 2381 MUL +/- 637 for RVF, and 635 MUL +/- 549 for RVR, and RV wall thicknesses were 0.98 mm +/- 0.12 for controls (P = 0.05), 1.72 mm +/- 0.60 for RVF, and 1.16 mm +/- 0.03 for RVR animals (P = 0.04), respectively. Similarly, heart weight, liver weight, cardiomyocyte size, and the degree of cardiac and hepatic fibrosis increased with RVF and decreased during RVR. CONCLUSIONS: We report an animal model of chronic, reversible, pressure-overload RVF to study RVF and RVR. This model will be used for preclinical studies that improve our understanding of the mechanisms of RVF and that develop and test RV protective and RVR strategies to be studied later in humans. PMID- 25541239 TI - Suprapubic single-incision laparoscopic segmental small bowel resection with intracorporeal manual anastomosis. PMID- 25541241 TI - Phagocytic activity of monocytes, their subpopulations and granulocytes during post-transplant adverse events after hematopoietic stem cell transplantation. AB - Phagocytosis of granulocytes and monocytes presents a major mechanism that contributes to the clearance of pathogens and cell debris. We analyzed the phagocytic activity of the peripheral blood cell monocytes, three monocyte subpopulations and granulocytes before and up to one year after hematopoietic stem cell transplantation, as well as during transplant-related adverse events. 25 pediatric patients and young adults (median age of 11.0 years) with hemato oncological malignancies and non malignancies were enrolled in the prospective study. Ingestion of fluorescence-labeled Escherichia coli bacteria was used to assess the phagocytic activity of monocytes and their subpopulations and granulocytes by means of flow cytometry in the patient group as well as in a control group (n=36). During sepsis, a significant increase of phagocytic activity of monocytes (P=0.0003) and a significant decrease of the phagocytic activity of granulocytes (P=0.0003) and the CD14+ CD16++ monocyte subpopulation (P=0.0020) occurred. At the onset of a veno-occlusive disease, a significant increase of phagocytic activity in the CD14++ CD16+ monocyte subpopulation (P=0.001) and a significant decrease in the phagocytic activity of the CD14++ CD16- monocyte subpopulation (P=0.0048) were observed. In conclusion, the phagocytic activity of monocytes, their subpopulations and granulocytes might be a useful and easy determinable parameter that enables identification of post transplant complications after hematopoietic stem cell transplantation. The alterations of phagocytic activity contribute to the altered immune response that accompanies adverse events after hematopoietic stem cell transplantation. PMID- 25541240 TI - Bacterial-induced cell reprogramming to stem cell-like cells: new premise in host pathogen interactions. AB - Bacterial pathogens employ a myriad of strategies to alter host tissue cell functions for bacterial advantage during infection. Recent advances revealed a fusion of infection biology with stem cell biology by demonstrating developmental reprogramming of lineage committed host glial cells to progenitor/stem cell-like cells by an intracellular bacterial pathogen Mycobacterium leprae. Acquisition of migratory and immunomodulatory properties of such reprogrammed cells provides an added advantage for promoting bacterial spread. This presents a previously unseen sophistication of cell manipulation by hijacking the genomic plasticity of host cells by a human bacterial pathogen. The rationale for such extreme fate conversion of host cells may be directly linked to the exceedingly passive obligate life style of M. leprae with a degraded genome and host cell dependence for both bacterial survival and dissemination, particularly the use of host derived stem cell-like cells as a vehicle for spreading infection without being detected by immune cells. Thus, this unexpected link between cell reprogramming and infection opens up a new premise in host-pathogen interactions. Furthermore, such bacterial ingenuity could also be harnessed for developing natural ways of reprogramming host cells for repairing damaged tissues from infection, injury and diseases. PMID- 25541242 TI - Chagas disease reactivation in HIV-coinfected patients: histopathological aspects. AB - INTRODUCTION: Chagas disease reactivation has been described in severely immunocompromised patients by various etiologies, including in HIV-coinfected patients. OBJECTIVE: This study aimed to perform histopathological and immunohistochemical evaluation of the brain, myocardium, esophagus and large bowel of autopsied patients with CHD and/or acquired immunodeficiency syndrome in comparison with control patients. MATERIAL AND METHODS: Autopsy reports were reviewed from 1998 to 2012 and eight adult subjects were selected and divided into four groups: RE, CH, AI and CO. Sections of brain, myocardium, esophagus and large bowel were collected from each subject and processed for histological and immunohistochemical analysis. The histological sections stained with HE, Giemsa and picrosirius were used to quantify the density of inflammatory cells, the density of mast cells, and the percentage of collagen, respectively. Immunohistochemical analysis of IL17 and CD31 was performed. RESULTS: The density of mast cells in the myocardium was significantly higher in the CH group than in the other groups. The density of mast cells in the esophagus and in the large bowel was significantly higher when compared to the other groups. The percentage of collagen in the esophagus, myocardium and large bowel was significantly lower in the RE group than in the CO group. The CH group had a higher percentage of collagen in the myocardium and in the large bowel in relation to the other groups. The density of cells immunostained with anti-IL17 was significantly higher in the large bowel and in the myocardium in the CH group than in the CO group. There was higher density of vessels immunostained with anti-CD31 in the myocardium and esophagus of the AI group than in the other groups. There were no significant correlations between the density of mast cells and percentage of collagen in the RE, CO, CH and AI groups. CONCLUSION: Brain lesions observed in patients with CDR, as well as the higher density of cells immunostained with anti IL17 at these sites, suggest that this cytokine was increasing local inflammation with subsequent tissue damage due to inflammation. Furthermore, the higher density of mast cells in the esophagus and large bowel of these subjects suggests that these cells might play a major role in esophageal and intestinal inflammation. PMID- 25541243 TI - Family members affected by a relative's substance misuse looking for social support: who are they? AB - BACKGROUND: This study proposes to describe family members in the city of Sao Paulo who are seeking support in mutual self-help groups to deal with a substance misusing relative. METHOD: Five hundred participants (one participant per family) completed a structured questionnaire collecting socio-demographic information, length of time taken to seek help, and where they sought help. Participants were recruited from the mutual self-help group 'Amor Exigente' in the city of Sao Paulo, Brazil. RESULTS: Parents of substance misusers counted as the largest group of family members. It took an average time of 3.7 years for the family members to discover their relatives' substance misuse. 42% had then sought help immediately; it took an average of 2.6 years for the remaining 58% of the sample to seek some form of support. A belief that the substance misuse of their relatives was just a transient problem or that they could cope with the situation by themselves were among the most indicated reasons for delay in seeking help. DISCUSSION: Findings stress the importance of implementing services that take into account the difficulties families have in finding help to deal with the substance misusing relative. PMID- 25541244 TI - Monitoring new psychoactive substances (NPS) in The Netherlands: data from the drug market and the Poisons Information Centre. AB - BACKGROUND: In recent years, the number of new psychoactive substances (NPS) appearing on the illicit drug market strongly increased. However, little is known about their toxic effects and risks. Therefore, we determined the most frequently occurring NPS in The Netherlands and combined this with data regarding drug related intoxications. METHODS: Data from the Drugs Information and Monitoring System (DIMS) and the Dutch Poisons Information Centre (DPIC) were combined and jointly analyzed. RESULTS: The number of drug samples submitted to DIMS for analysis containing NPS increased from 22 in 2007 to 431 samples in 2013. The most frequently submitted NPS in 2013 included 4-bromo-2,5 dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA), methoxetamine (MXE) and 6-(2-aminopropyl)benzofuran (6-APB). From 2012 onwards, the number of NPS bought as drug of choice exceeded those appearing as adulterants in established drugs. The DPIC was consulted about 35 NPS exposures in 2013, most frequently involving 4-FA, mephedrone, MXE, 2C-B and 6-APB. Following NPS exposure, neurological and psychological symptoms were most frequently reported, like agitation and hallucinations. In addition, cardiovascular symptoms like hypertension and tachycardia often occurred. CONCLUSIONS: NPS are currently being purchased as drug of choice in The Netherlands and their availability and use is increasing. Although pharmacological and toxicological data are scarce, NPS can induce pronounced clinical effects. Therefore, the monitoring of trends in NPS prevalence needs to be continued, combined with reported clinical effects, and preferably supported by analytical confirmation of exposures in such patients. PMID- 25541245 TI - Molecular evidence for cryptic candidate species in Iberian Pelodytes (Anura, Pelodytidae). AB - Species delineation is a central topic in evolutionary biology, with current efforts focused on developing efficient analytical tools to extract the most information from molecular data and provide objective and repeatable results. In this paper we use a multilocus dataset (mtDNA and two nuclear markers) in a geographically comprehensive population sample across Iberia and Western Europe to delineate candidate species in a morphologically cryptic species group, Parsley frogs (genus Pelodytes). Pelodytes is the sole extant representative of an ancient, historically widely distributed anuran clade that currently includes three species: P. caucasicus in the Caucasus; P. punctatus in Western Europe, from Portugal to North-Western Italy; and P. ibericus in Southern Iberia. Phylogenetic analyses recovered four major well-supported haplotype clades in Western Europe, corresponding to well demarcated geographical subdivisions and exhibiting contrasting demographic histories. Splitting times date back to the Plio-Pleistocene and are very close in time. Species-tree analyses recovered one of these species lineages, corresponding to P. ibericus (lineage B), as the sister taxon to the other three major species lineages, distributed respectively in: western Iberian Peninsula, along the Atlantic coast and part of central Portugal (lineage A); Central and Eastern Spain (lineage C); and North-eastern Spain, France and North-western Italy (lineage D). The latter is in turn subdivided into two sub-clades, one in SE France and NW Italy and the other one from NE Spain to NW France, suggesting the existence of a Mediterranean-Atlantic corridor along the Garonne river. An information theory-based validation approach implemented in SpedeSTEM supports an arrangement of four candidate species, suggesting the need for a taxonomic revision of Western European Pelodytes. PMID- 25541247 TI - White clay drainage in chronic tophaceous gout. PMID- 25541246 TI - A new mechanism links preamyloid oligomer formation in the myocyte stress response associated with atrial fibrillation. PMID- 25541248 TI - A three-year clinical evaluation of a one-step self-etch and a two-step etch-and rinse adhesive in non-carious cervical lesions. AB - OBJECTIVES: The aim of the study was to assess a one-step self-etch adhesive (Futurabond M, 1-SE) and a two-step etch-and-rinse adhesive (Solobond M, 2-ER) used in combination with the nano-hybrid composite (Amaris) in a prospective clinical study on non-carious cervical lesions. METHODS: 110 restorations were placed in 40 patients and graded over 36 months according to aesthetical, functional and biological criteria (Clinical Oral Investigations 2007;11:5). The four-step etch-and-rinse adhesive Syntac classic (4-ER) combined with the nano hybrid composite Tetric EvoCeram was used as a control. Cumulative failure rates (CFR), retention rates and Kaplan-Meier survival curves were calculated for each observation period. RESULTS: After 3 years, the CFR of 33.3% in the 2-ER group was significantly higher compared to those of the 1-SE group (9.1%, p = 0.019) and of the 4-ER group (8.3%, p = 0.035). Additionally, retention rates in the 1 SE and the 4-ER groups were higher compared to 2-ER (p = 0.012 each) after 36 months. Annual failure rates ranged between 2.8% for 4-ER, 3.0% for 1-SE and 11.1% for 2-ER. During the study, restorations in all groups showed progressive marginal deterioration within the limits of clinical acceptance. After 3 years, restorations in the 2-ER and the 4-ER group showed more small defects at dentin than at enamel margins. CONCLUSIONS: The 1-SE group was clinically as successful as the 4-ER, with both performing better than the 2-ER group. Futurabond M/Amaris can be recommended for the restoration of sclerotic non-carious cervical lesions. CLINICAL SIGNIFICANCE: Number protocol 192/2008. PMID- 25541249 TI - Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. AB - Mounting evidence suggests that brain inflammation mediated by glial cells may contribute to epileptogenesis. Minocycline is a second-generation tetracycline and has potent antiinflammatory effects independent of its antimicrobial action. The present study aimed to investigate whether minocycline could exert antiepileptogenic effects in a rat lithium-pilocarpine model of temporal lobe epilepsy. The temporal patterns of microglial and astrocytic activation were examined in the hippocampal CA1 and the adjacent cortex following pilocarpine induced status epilepticus (SE). These findings displayed that SE caused acute and persistent activation of microglia and astrocytes. Based on these findings, Minocycline was administered once daily at 45 mg/kg for 14 days following SE. Six weeks after termination of minocycline treatment, spontaneous recurrent seizures (SRS) were recorded by continuous video monitoring. Minocycline inhibited the SE induced microglial activation and the increased production of interleukin-1beta and tumor necrosis factor-alpha in the hippocampal CA1 and the adjacent cortex, without affecting astrocytic activation. In addition, Minocycline prevented the SE-induced neuronal loss in the brain regions examined. Moreover, minocycline significantly reduced the frequency, duration, and severity of SRS during the two weeks monitoring period. These results demonstrated that minocycline could mitigate SE-induced brain inflammation and might exert disease-modifying effects in an animal model of temporal lobe epilepsy. These findings offer new insights into deciphering the molecular mechanisms of epileptogenesis and exploring a novel therapeutic strategy for prevention of epilepsy. PMID- 25541250 TI - rTMS on left prefrontal cortex contributes to memories for positive emotional cues: a comparison between pictures and words. AB - The present research explored the cortical correlates of emotional memories in response to words and pictures. Subjects' performance (Accuracy Index, AI; response times, RTs; RTs/AI) was considered when a repetitive Transcranial Magnetic Stimulation (rTMS) was applied on the left dorsolateral prefrontal cortex (LDLPFC). Specifically, the role of LDLPFC was tested by performing a memory task, in which old (previously encoded targets) and new (previously not encoded distractors) emotional pictures/words had to be recognized. Valence (positive vs. negative) and arousing power (high vs. low) of stimuli were also modulated. Moreover, subjective evaluation of emotional stimuli in terms of valence/arousal was explored. We found significant performance improving (higher AI, reduced RTs, improved general performance) in response to rTMS. This "better recognition effect" was only related to specific emotional features, that is positive high arousal pictures or words. Moreover no significant differences were found between stimulus categories. A direct relationship was also observed between subjective evaluation of emotional cues and memory performance when rTMS was applied to LDLPFC. Supported by valence and approach model of emotions, we supposed that a left lateralized prefrontal system may induce a better recognition of positive high arousal words, and that evaluation of emotional cue is related to prefrontal activation, affecting the recognition memories of emotions. PMID- 25541251 TI - Decreased anti-regenerative effects after spinal cord injury in spry4-/- mice. AB - Previously, we have demonstrated a role for fibroblast growth factor (Fgf) in spinal cord regeneration in both zebrafish and mouse. We have shown that exogenous Fgf2 treatment attenuates astrocytic gliosis and induces glia cells to become progenitors that undergo neurogenesis as well as differentiating into bipolar astrocytes that support axonal regeneration (Goldshmit et al., 2012, 2014). One of the downstream signaling target genes of Fgf is spry4, which acts as a feedback inhibitor for Fgf signaling. In this study we examined the effects of increased endogenous Fgf signaling, in spry4-/- mice, on the early events that occur after spinal cord injury (SCI). We demonstrate that in spry4-/- mice inflammatory responses, such as tumor necrosis factor alpha (TNFalpha) secretion and macrophage/neutrophil invasion into the lesion site are reduced. In addition, astrocytic gliosis is attenuated and neuronal survival is increased. These results further support a pro-regenerative role of Fgf after SCI, and suggest that increased endogenous Fgf signaling after SCI may contribute to functional recovery and therefore presents this pathway as a target for new therapy development. PMID- 25541252 TI - Genetic and epigenetic alterations in Toll like receptor 2 and wound healing impairment in type 2 diabetes patients. AB - AIM: Persistent hyperglycemic microenvironment in type 2 diabetes mellitus (T2DM) leads to the development of secondary complications like wound healing impairment. Proper co-ordination of innate immune system plays an integral role in wound healing. Toll like receptors (TLRs) are prominent contributors for the induction of the innate immune and inflammation response. TLR2 is an important extracellular member in mammalian TLR family and has been shown to be a potent player in the wound healing mechanism. METHODS: Expressional status of TLR2 was seen in wounds of T2DM cases with respect to the severity of wounds in 110 human lower extremity wounds. The methylation status of TLR2 promoter was also examined. RESULTS: Although TLR2 transcripts were downregulated in T2DM wounds compared to control, their levels tend to increase with the severity of T2DM wounds. The methylation status of TLR2 gene promoter was not significantly different among different grades of wounds in T2DM subjects. The CpG sites investigated were totally or partially methylated in majority of DFU cases. CONCLUSION: TLR2 down regulation in wounds of T2DM patients compared to non diabetic patients may lead to development of non healing chronic ulcers in them. PMID- 25541253 TI - Structures and binding studies of the complexes of phospholipase A2 with five inhibitors. AB - Phospholipase A2 (PLA2) catalyzes the hydrolysis of phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is used as a substrate in the next step of the multistep pathway leading to the production of eicosanoids. The eicosanoids, in extremely low concentrations, are required in a number of physiological processes. However, the increase in their concentrations above the essential physiological requirements leads to various inflammatory conditions. In order to prevent the unwanted rise in the concentrations of eicosanoids, the actions of PLA2 and other enzymes of the pathway need to be blocked. We report here the structures of five complexes of group IIA PLA2 from Daboia russelli pulchella with tightly binding inhibitors, (i) p-coumaric acid, (ii) resveratrol, (iii) spermidine, (iv) corticosterone and (v) gramine derivative. The binding studies using fluorescence spectroscopy and surface plasmon resonance techniques for the interactions of PLA2 with the above five compounds showed high binding affinities with values of dissociation constants (KD) ranging from 3.7*10(-8) M to 2.1*10(-9) M. The structure determinations of the complexes of PLA2 with the above five compounds showed that all the compounds bound to PLA2 in the substrate binding cleft. The protein residues that contributed to the interactions with these compounds included Leu2, Leu3, Phe5, Gly6, Ile9, Ala18, Ile19, Trp22, Ser23, Cys29, Gly30, Cys45, His48, Asp49 and Phe106. The positions of side chains of several residues including Leu2, Leu3, Ile19, Trp31, Lys69, Ser70 and Arg72 got significantly shifted while the positions of active site residues, His48, Asp49, Tyr52 and Asp99 were unperturbed. PMID- 25541254 TI - Human beta-defensin-3 increases the expression of interleukin-37 through CCR6 in human keratinocytes. AB - BACKGROUND: Interleukin (IL)-37, a new member of the IL-1 family, is characterized as a fundamental inhibitor of innate immunity: it dampens the production of proinflammatory cytokines, protects against inflammatory and autoimmune diseases, and plays a potent immunosuppressive role in the pathogenesis of psoriasis. IL-37 is highly expressed in psoriatic skin, in which human beta-defensins (hBDs) have been detected. Although hBDs enhance the production of cytokines, including IL-1 cytokines, whether they stimulate the production of IL-37 remains unclear. OBJECTIVES: To assess the ability of hBDs to stimulate IL-37 expression/production by human keratinocytes and to determine the mechanism involved. METHODS: Real-time PCR and Western blotting were used to evaluate IL-37 expression. Caspase activities were assessed using colorimetric assay kits. A CCR6 antibody, siRNA, and caspase, Smad3, MAPK and NF-kappaB inhibitors were used to investigate the signaling mechanism of hBDs. RESULTS: Among the four hBDs used, only hBD-3 up-regulated the mRNA and protein expression of IL-37. The combination of TNF-alpha, EGF and poly (I:C) with hBD-3 synergistically enhanced the mRNA but not the protein expression of IL-37. Furthermore, hBD-3 increased the release of IL-37 into the culture supernatants. Evaluation of the signaling mechanism of hBD-3 suggested that caspases 1 and 4, Smad3, CCR6, MAPKs and NF-kappaB were required for hBD-3-mediated IL-37 expression. CONCLUSIONS: The finding that hBD-3 stimulates IL-37 expression, a novel target for the pathogenesis and therapy of cutaneous inflammatory diseases, provides evidence that hBDs contribute to the suppression of inflammatory and innate immune responses through the regulation of IL-37 expression. PMID- 25541255 TI - Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ). AB - The medication-related osteonecrosis of the jaw (MRONJ) is believed to be a therapy-resistant entity. Although the application of the recommended conservative and surgical treatment regimens have returned variable success rates, the increased awareness and experience with MRONJ suggests that surgical therapy can halt the progression of the disease, thereby allowing a histology based diagnosis of the osteonecrosis. Surgical treatment protocols can achieve success rates of over 90% and novel techniques such as the visualization of bone fluorescence can assist in the intra-operative delineation of the osteonecrosis and standardize the procedure. PMID- 25541256 TI - In vitro susceptibility of filamentous fungi from mycotic keratitis to azole drugs. AB - OBJECTIVE: The in vitro antifungal activities of azole drugs viz., itraconazole, voriconazole, ketoconazole, econazole and clotrimazole were investigated in order to evaluate their efficacy against filamentous fungi isolated from mycotic keratitis. METHODS: The specimen collection was carried out from fungal keratitis patients attending Aravind eye hospital and Post-graduate institute of ophthalmology, Coimbatore, India and was subsequently processed for the isolation of fungi. The dilutions of antifungal drugs were prepared in RPMI 1640 medium. Minimum inhibitory concentrations (MICs) were determined and MIC50 and MIC90 were calculated for each drug tested. RESULTS: A total of 60 fungal isolates were identified as Fusarium spp. (n=30), non-sporulating moulds (n=9), Aspergillus flavus (n=6), Bipolaris spp. (n=6), Exserohilum spp. (n=4), Curvularia spp. (n=3), Alternaria spp. (n=1) and Exophiala spp. (n=1). The MICs of ketoconazole, clotrimazole, voriconazole, econazole and itraconazole for all the fungal isolates ranged between 16 MUg/mL and 0.03 MUg/mL, 4 MUg/mL and 0.015 MUg/mL, 8 MUg/mL and 0.015 MUg/mL, 8 MUg/mL and 0.015 MUg/mL and 32 MUg/mL and 0.06 MUg/mL respectively. From the MIC50 and MIC90 values, it could be deciphered that in the present study, clotrimazole was more active against the test isolates at lower concentrations (0.12-5 MUg/mL) when compared to other drugs tested. CONCLUSION: The results suggest that amongst the tested azole drugs, clotrimazole followed by voriconazole and econazole had lower MICs against moulds isolated from mycotic keratitis. PMID- 25541257 TI - The translational revolution and use of biologics in patients with inflammatory skin diseases. AB - Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases characterized by immune-mediated inflammation and abnormal keratinocyte differentiation. Although T-cell infiltration characterizes both diseases, T-cell polarization differs. Psoriasis is currently the best model for translational medicine because many targeted therapeutics have been developed and testing of targeted therapeutics has cemented psoriasis as IL-23/TH17 polarized. In patients with AD, although therapeutic development is approximately a decade behind that in patients with psoriasis, there is now active development and testing of targeted therapeutics against various immune axes (TH2, TH22, and IL-23/TH17). These clinical trials and subsequent molecular analyses using human samples will be able to clarify the relative roles of polar cytokines in patients with AD. PMID- 25541258 TI - Fe(II)EDTA-NO reduction by a newly isolated thermophilic Anoxybacillus sp. HA from a rotating drum biofilter for NOx removal. AB - The reduction of Fe(II)EDTA-NO is one of the core processes in BioDeNOx, an integrated physicochemical and biological technique for NOx removal from industrial flue gases. A newly isolated thermophilic Anoxybacillus sp. HA, identified by 16S rRNA sequence analysis, could simultaneously reduce Fe(II)EDTA NO and Fe(III)EDTA. A maximum NO removal efficiency of 98.7% was achieved when 3mM Fe(II)EDTA-NO was used in the nutrient solution at 55 degrees C. Results of this study strongly indicated that the biological oxidation of Fe(II)EDTA played an important role in the formation of Fe(III)EDTA in the anaerobic system. Fe(II)EDTA-NO was more competitive than Fe(III)EDTA as an electron acceptor, and the presence of Fe(III)EDTA slightly affected the reduction rate of Fe(II)EDTA NO. At 55 degrees C, the maximum microbial specific growth rate MUmax reached the peak value of 0.022h(-1). The maximum NO removal efficiency was also measured (95.4%) under this temperature. Anoxybacillus sp. HA, which grew well at 50 degrees C-60 degrees C, is a potential microbial resource for Fe(II)EDTA-NO reduction at thermophilic temperatures. PMID- 25541260 TI - Uterine artery embolization for symptomatic uterine fibroids. AB - BACKGROUND: Uterine fibroids cause heavy prolonged bleeding, pain, pressure symptoms and subfertility. The traditional method of treatment has been surgery as medical therapies have not proven effective. Uterine artery embolization has been reported to be an effective and safe alternative to treat fibroids in women not desiring future fertility. There is a significant body of evidence that is based on case controlled studies and case reports. This is an update of the review previously published in 2012. OBJECTIVES: To review the benefits and risks of uterine artery embolization (UAE) versus other medical or surgical interventions for symptomatic uterine fibroids. SEARCH METHODS: We searched sources including the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and trial registries. The search was last conducted in April 2014. We contacted authors of eligible randomised controlled trials to request unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) of UAE versus any medical or surgical therapy for symptomatic uterine fibroids. The primary outcomes of the review were patient satisfaction and live birth rate (among women seeking live birth). DATA COLLECTION AND ANALYSIS: Two of the authors (AS and JKG) independently selected studies, assessed quality and extracted data. Evidence quality was assessed using GRADE methods. MAIN RESULTS: Seven RCTs with 793 women were included in this review. Three trials compared UAE with abdominal hysterectomy, two trials compared UAE with myomectomy, and two trials compared UAE with either type of surgery (53 hysterectomies and 62 myomectomies).With regard to patient satisfaction rates, our findings were consistent with satisfaction rates being up to 41% lower or up to 48% higher with UAE compared to surgery within 24 months of having the procedure (odds ratio (OR) 0.94; 95% confidence interval (CI) 0.59 to 1.48, 6 trials, 640 women, I(2) = 5%, moderate quality evidence). Findings were also inconclusive at five years of follow-up (OR 0.90; 95% CI 0.45 to 1.80, 2 trials, 295 women, I(2) = 0%, moderate quality evidence). There was some indication that UAE may be associated with less favourable fertility outcomes than myomectomy, but it was very low quality evidence from a subgroup of a single study and should be regarded with extreme caution (live birth: OR 0.26; 95% CI 0.08 to 0.84; pregnancy: OR 0.29; 95% CI 0.10 to 0.85, 1 study, 66 women).Similarly, for several safety outcomes our findings showed evidence of a substantially higher risk of adverse events in either arm or of no difference between the groups. This applied to intra procedural complications (OR 0.91; 95% CI 0.42 to 1.97, 4 trials, 452 women, I(2) = 40%, low quality evidence), major complications within one year (OR 0.65; 95% CI 0.33 to 1.26, 5 trials, 611 women, I(2) = 4%, moderate quality evidence) and major complications within five years (OR 0.56; CI 0.27 to 1.18, 2 trials, 268 women). However, the rate of minor complications within one year was higher in the UAE group (OR 1.99; CI 1.41 to 2.81, 6 trials, 735 women, I(2) = 0%, moderate quality evidence) and two trials found a higher minor complication rate in the UAE group at up to five years (OR 2.93; CI 1.73 to 4.93, 2 trials, 268 women).UAE was associated with a higher rate of further surgical interventions (re interventions within 2 years: OR 3.72; 95% CI 2.28 to 6.04, 6 trials, 732 women, I(2) = 45%, moderate quality evidence; within 5 years: OR 5.79; 95% CI 2.65 to 12.65, 2 trials, 289 women, I(2) = 65%). If we assumed that 7% of women will require further surgery within two years of hysterectomy or myomectomy, between 15% and 32% will require further surgery within two years of UAE.The evidence suggested that women in the UAE group were less likely to require a blood transfusion than women receiving surgery (OR 0.07; 95% CI 0.01 to 0.52, 2 trials, 277 women, I(2) = 0%). UAE was also associated with a shorter procedural time (two studies), shorter length of hospital stay (seven studies) and faster resumption of usual activities (six studies) in all studies that measured these outcomes; however, most of these data could not be pooled due to heterogeneity between the studies.The quality of the evidence varied, and was very low for live birth, moderate for satisfaction ratings, and moderate for most safety outcomes. The main limitations in the evidence were serious imprecision due to wide confidence intervals, failure to clearly report methods, and lack of blinding for subjective outcomes. AUTHORS' CONCLUSIONS: When we compared patient satisfaction rates at up to two years following UAE versus surgery (myomectomy or hysterectomy) our findings are that there is no evidence of a difference between the interventions. Findings at five year follow-up were similarly inconclusive. There was very low quality evidence to suggest that myomectomy may be associated with better fertility outcomes than UAE, but this information was only available from a selected subgroup in one small trial.We found no clear evidence of a difference between UAE and surgery in the risk of major complications, but UAE was associated with a higher rate of minor complications and an increased likelihood of requiring surgical intervention within two to five years of the initial procedure. If we assume that 7% of women will require further surgery within two years of hysterectomy or myomectomy, between 15% and 32% will require further surgery within two years of UAE. This increase in the surgical re intervention rate may balance out any initial cost advantage of UAE. Thus although UAE is a safe, minimally invasive alternative to surgery, patient selection and counselling are paramount due to the much higher risk of requiring further surgical intervention. PMID- 25541259 TI - Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH high population associated with an accelerated scavenging system in reactive oxygen species. AB - OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma. PMID- 25541261 TI - Diabetes and alcohol: Double jeopardy with regard to oxidative toxicity and sexual dysfunction in adult male Wistar rats. AB - The aim of this study was to test whether diabetic rats exposed to alcohol demonstrate a higher degree of reproductive toxicity and suffer with elevated oxidative toxicity when compared with alcohol exposed control rats. Diabetes was induced by injecting single dose of streptozotocin and alcohol was administered through orogastric tube once daily for a period of 55 days. Daily sperm production, epididymal sperm count, motile, viable and HOS-tail coiled sperms, serum testosterone levels and testicular 3beta- and 17beta-hydroxysteroid dehydrogenase activity levels were significantly decreased in diabetic rats. Significant reduction in testicular and epididymal superoxide dismutase and catalase activity levels, and elevation in lipid peroxidation products were observed in diabetic rats. Similar reproductive and oxidative toxicity was observed in alcohol treated control rats. Further, alcohol exposed diabetic rats showed additional deterioration in reproductive endpoints and noteworthy elevation in oxidative toxicity suggesting that treatment with alcohol further deteriorates sexual dysfunction in STZ-induced diabetic rats. PMID- 25541262 TI - Prostate cancer trends in Latvia during 1990-2012: incidence, prevalence, mortality, and survival rates. AB - BACKGROUND AND OBJECTIVE: Prostate cancer (PCa) is one of the most common form of cancer in males worldwide. One of the highest PCa-related mortality rates in the world is observed in Latvia. MATERIALS AND METHODS: Our study included male patients diagnosed with PCa between 1990 and 2012. We analyzed incidence, prevalence and mortality trends using joinpoint analysis. Kaplan-Meier analysis was performed for 5-, 10-, 15- and 20-year overall survival and cancer-specific survival rates. RESULTS: A total of 14,083PCa patients with a mean age of initial PCa diagnosis being 70.1 (SD 8.6) was registered. The standardized incidence rates (per 100,000) increased from 18.9 in 1990 to 74.7 in 2012, while the standardized prevalence rates (per 100,000) increased from 69.9 in 1990 to 437.6 in 2012. Standardized PCa mortality rates (per 100,000) also rose from 13.2 in 1990 to 27.2 in 2006 followed by statistically insignificant decrease continuing up to 2012. The mean 5-year cancer-specific survival rates increased from 43.6% in 1990 to 70.7% in 2007, and the mean 10-year cancer-specific survival rates from 32.9% in 1990 to 40.5% in 2001. CONCLUSIONS: This study revealed that the incidence, prevalence and mortality rates increased between 1990 and 2012, and although the 5- and 10-year overall and cancer-specific survival rates improved over the reviewed period they still needed to get better. PMID- 25541263 TI - How useful is antireflux surgery in lung transplant patients with gastroesophageal reflux? AB - BACKGROUND AND OBJECTIVE: Respiratory function deteriorates over time after lung transplant. Reflux disease with pulmonary complications is a possible cause of this decline. This case series we aim to assess whether respiratory function improves after Nissen fundoplication in lung transplant patients and if surgery reduces gastroesophageal reflux disease (GERD) symptoms and use of proton pump inhibitors (PPIs). MATERIALS AND METHODS: A retrospective case series of lung transplant patients with reflux disease and Nissen fundoplication. Clinical symptoms, pH-metry data, use of PPIs were recorded before the procedure and up to 18 months postoperatively. The FEV1 values before and after Nissen fundoplication were recorded at 3 monthly intervals. Patients' satisfaction scores were recorded before operation and postoperatively. RESULTS: A total of 64 lung transplant patients were selected. After Nissen fundoplication, the pH studies were done on 26 patients. The mean overall acid exposure fraction was 1.03% (P<0.05). FEV1 declined for 6 months postoperatively and then gradually improved. The comparison of FEV1 at 3 months preoperatively to 3 months postoperatively showed no significant difference (P=0.067) as well as at 6 months. A significant improvement in clinical GERD symptoms was achieved after antireflux surgery; however, the patients remained receiving PPIs. CONCLUSIONS: NF has been established as a safe operation for lung transplant patients. Late Nissen fundoplication did not improve lung function significantly amongst lung transplanted patients; however, patients with symptomatic GERD may have benefited from Nissen fundoplication in terms of symptom relief. A multicenter randomized control trial is needed to assess the effect of early unselected reflux control on respiratory function and graft survival. PMID- 25541264 TI - The family needs of parents of preschool children with cerebral palsy: the impact of child's gross motor and communications functions. AB - BACKGROUND AND OBJECTIVE: An understanding of the needs of families of preschool children with cerebral palsy (CP) is of essential importance if efficient and cost-effective services are to be provided to them. The aims of this study were to identify the most frequently expressed needs of families with preschool children with CP; differences in the amount and types of family needs based on the child's gross motor function and communication function level; and the impact of the child's gross motor function and communication function level on the type and amount of family needs. MATERIALS AND METHODS: A total of 227 parents of preschool children with CP completed a modified version of the Family Needs Survey and a demographic questionnaire. Children's gross motor function level and communication function level was classified using the Gross Motor Function Classification System (GMFCS) and the Communication Function Classification System (CFCS), respectively. RESULTS: The total number of family needs differed based on GMFCS and CFCS levels. Children's GMFCS and CFCS level were not significant predictors of overall family needs (adjusted R(2)=0.163). In this model the GMFCS level of children did not account for the total number of family needs, while the CFCS level did. CONCLUSIONS: Child's limitations in terms of communication and gross motor functions must be taken into consideration when planning services for families with preschool children with CP. PMID- 25541265 TI - Atherogenic index as a predictor of atherosclerosis in subjects with familial Mediterranean fever. AB - BACKGROUND AND OBJECTIVE: Numerous inflammatory and innate immune pathways are involved in atherogenesis. We aimed to investigate the atherogenic index and other lipid parameters in individuals with familial Mediterranean fever (FMF), as a predictor of atherosclerosis. MATERIALS AND METHODS: A total of 60 patients with FMF and 60 healthy age- and sex-matched controls were included in this study. The patients with acute infection, chronic metabolic and rheumatic diseases, use of drugs other than colchicine and smoking history were excluded. CRP, ESR, total cholesterol, triglycerides, LDL-C, and HDL-C levels of patients and the control group were measured. Atherogenic index (TG/HDL-C) was calculated. RESULTS: We found that the atherogenic index values of the patients were significantly higher than those of the control group. HDL-C levels were lower and ESR and TG levels were higher in patients. Total cholesterol, LDL-C and CRP levels did not differ significantly between the two groups. There was no significant difference in the values of total cholesterol, LDL-C, triglycerides (TG), HDL-C, and atherogenic indexes between the groups of patients with and without M694V mutation. CONCLUSIONS: Elaboration of clinical models of inflammation-induced atherogenesis may further advance our knowledge of multiple inflammatory pathways implicated in atherogenesis and provide a useful tool for cardiovascular prevention. We believe that the atherogenic index also be used as a preliminary indication of accelerated atherosclerosis in FMF. However, large scale prospective studies on this issue are needed. PMID- 25541266 TI - Impedance plethysmography as an alternative method for the diagnosis of peripheral arterial disease. AB - BACKGROUND AND OBJECTIVE: In the diagnosis of peripheral artery disease (PAD), the ankle-brachial index (ABI) is considered as the standard, and other noninvasive methods have received too little attention. Therefore, the aim of the study was to determine the diagnostic accuracy of impedance plethysmography in diagnosing PAD and to compare this method with other methods. MATERIALS AND METHODS: A total of 66 patients with a mean age of 76.1+/-9.6 years who had been treated for various cardiovascular diseases at Kaunas Clinical Hospital during 2011-2012 were enrolled into the study. All the patients were screened for PAD. Impedance plethysmography was performed with a new-generation NiccomoTM device. The receiver operating characteristic analysis was employed to determine the diagnostic accuracy of 4 parameters of impedance plethysmography: crest time (CT), crest width (CW), pulse amplitude (Pampl), and alternating blood flow (ABF). RESULTS: There were a significant correlation between the ABI and the CT (r=-0.699, P<0.001), between the ABI and the ABF (r=0.552; P<0.001), and between the ABI and the Pampl only among men (r=0.652; P<0001). No correlation was found between the ABI and the CW. Among all the parameters, the CT had the highest sensitivity and specificity (73.2% and 96.0%, respectively). Other parameters had the following sensitivities and specificities: ABF, 61.0% and 96.0%; and Pampl, 90.0% and 20.0%, respectively. CONCLUSIONS: Impedance plethysmography, especially its parameter CT, is an alternative noninvasive method in diagnosing PAD and could be used for the screening of patients with PAD. PMID- 25541267 TI - Evaluation of left ventricular longitudinal function and synchrony after dual chamber pacemaker implantation. AB - BACKGROUND AND OBJECTIVE: To evaluate left ventricular (LV) longitudinal function and dyssynchrony mechanisms after dual chamber pacemaker implantation. MATERIALS AND METHODS: The speckle tracking imaging technique was used for quantification of global longitudinal function of the left ventricle and for dyssynchrony evaluation before pacemaker implantation and after 3-month follow-up. The study group consisted of 98 patients with conventional indications for dual chamber pacemaker implantation. RESULTS: Speckle tracking echocardiographic methods and image postprocessing revealed impairment of global longitudinal strain and significant LV dyssynchrony derived from 12 basal and mid-septum segments usually untraceable with conventional echocardiographic methods. Despite good physical performance and ejection fraction, global longitudinal strain significantly decreased in all patients from -15.08+/-0.46 to -13.56+/-0.5 (P<0.05) as well as mitral annulus movement decreased from 11.57+/-2.41 to 8.46+/-1.74cm/s (P<0.001) and from 12.55+/-2.75 to 10.78+/-2.82mm (P<0.001). It was expected that patients with dual chamber pacemaker will develop inter- and intraventricular dyssynchrony, but our study showed that pacing lead position did not prevent from LV dysynchronisation and only changed the mechanism. CONCLUSIONS: Global longitudinal strain and LV dyssynchrony assessment enables us to detect early signs of LV dysfunction. Mechanisms of dyssynchrony development will be useful for pacemaker programing choices in order to prevent further dyssynchronisation. PMID- 25541268 TI - Detection and evaluation of ventricular repolarization alternans: an approach to combined ECG, thoracic impedance, and beat-to-beat heart rate variability analysis. AB - BACKGROUND AND OBJECTIVE: Beat-to-beat alteration in ventricles repolarization reflected by alternans of amplitude and/or shape of ECG S-T,T segment (TWA) is known as phenomena related with risk of severe arrhythmias leading to sudden cardiac death. Technical difficulties have caused limited its usage in clinical diagnostics. Possibilities to register and analyze multimodal signals reflecting heart activity inspired search for new technical solutions. First objective of this study was to test whether thoracic impedance signal and beat-to-beat heart rate reflect repolarization alternans detected as TWA. The second objective was revelation of multimodal signal features more comprehensively representing the phenomena and increasing its prognostic usefulness. MATERIALS AND METHODS: ECG, and thoracic impedance signal recordings made during 24h follow-up of the patients hospitalized in acute phase of myocardial infarction were used for investigation. Signal morphology variations reflecting estimates were obtained by the principal component analysis-based method. Clinical outcomes of patients (survival and/or rehospitalization in 6 and 12 months) were compared to repolarization alternans and heart rate variability estimates. RESULTS: Repolarization alternans detected as TWA was also reflected in estimates of thoracic impedance signal shape and variation in beat-to-beat heart rate. All these parameters showed correlation with clinical outcomes of patients. The strongest significant correlation showed magnitude of alternans in estimates of thoracic impedance signal shape. CONCLUSIONS: The features of ECG, thoracic impedance signal and beat-to-beat variability of heart rate, give comprehensive estimates of repolarization alternans, which correlate, with clinical outcomes of the patients and we recommend using them to improve diagnostic reliability. PMID- 25541269 TI - Mechanical function of left atrium and pulmonary vein sleeves before and after their antrum isolation. AB - BACKGROUND AND OBJECTIVE: Pulmonary vein (PV) sleeves are established as the main substrate taking part in the mechanisms of atrial fibrillation (AF) initiation. However, we have extremely few data concerning their physiological role in the heart contractility. The aim of the study was to estimate the mechanical function of the left atrium (LA) and PV sleeves before and early after their isolation. MATERIALS AND METHODS: A total of 17 patients with a mean age of 57.4+/-8.3 years who underwent PVs isolation due to AF were enrolled in the study. A day before the procedure a computed tomography (CT) of the LA and PVs and dopplerography of transmitral flow were performed. During the procedure the mechanical function of the LA and PV sleeves were estimated by transesophageal echocardiography and manometry in the left heart chambers. RESULTS: During the invasive study the patterns of the heart chambers and PV sleeves pressure were identified. These patterns confirmed the active role of the PV sleeves in LA filling and active LA relaxation during left ventricular systole. After PV isolation an alteration of transmitral blood flow and increase of LA pressure were registered. However, diastolic dysfunction was ruled out by LV manometry, thereby testifying LA mechanical function disturbance. The change in PV hemodynamics also occurred as a result of the decrease in PV sleeves contractility, revealed by manometry and paired CT scans. CONCLUSIONS: The PVs take an active part in left atrial filling by contraction of their sleeves. Antrum isolation of the PVs leads to the deterioration of their contractility and LA reservoir function. PMID- 25541270 TI - Health profile of the urban community members in Lithuania: do socio-demographic factors matter? AB - BACKGROUND AND OBJECTIVE: Objective of the study was to explore self-perceived health status, health determinants and its associations with socio-demographic factors among urban community members in Lithuania. MATERIALS AND METHODS: Data were obtained from a European survey on urban health, conducted as part of the EURO-URHIS 2 project. The postal questionnaire survey of 3200 adults from Kaunas and Siauliai (Lithuania) was conducted in 2010. A total of 1407 valid questionnaires were analyzed. Statistical analysis was carried out by using SPSS 17.0 inside Complex Sample module that takes design effects into account. RESULTS: Younger respondents (aged 19-64 years) perceived most of the health status indicators better than the older ones (65+ years), while they were less likely to report healthy lifestyle and less often perceived their neighborhood as being socially cohesive than the older ones. Men less frequently experienced psychological problems, indicated regular contacts with friends and/or family and had a greater tendency to be overweighed and obese, daily smokers and drinkers compared to women. Those having secondary or lower educational level perceived most of the health status indicators worse than those with university educational level. Respondents living with a partner less often experienced psychological problems than those living alone. Respondents who indicated having enough money for daily expenses more often perceived their health and health determinants better. CONCLUSIONS: The results of this study demonstrate associations between socio-demographic factors and self-perceived health status, lifestyle and factors of living environment among urban community members in Lithuania. PMID- 25541271 TI - Close relationship of segmental spinal artery to posterior left atrium in patients with osteophyte formation enlarged left atrium and atrial fibrillation. PMID- 25541272 TI - Producing morphologically complex words: an ERP study with children and adults. AB - A widely studied morphological phenomenon in psycholinguistic research is the plurals-inside-compounds effect in English, which is the avoidance of regular plural modifiers within compounds (e.g., *rats hunter). The current study employs event-related brain potentials (ERPs) to investigate the production of plurals inside-compounds in children and adults. We specifically examined the ERP correlates of producing morphologically complex words in 8-year-olds, 12-year olds and adults, by recording ERPs during the silent production of compounds with plural or singular modifiers. Results for both children and adults revealed a negativity in response to compounds produced from regular plural forms when compared to compounds formed from irregular plurals, indicating a highly specific brain response to a subtle linguistic contrast. Although children performed behaviourally with an adult-like pattern in the task, we found a broader distribution and a considerably later latency in children's brain potentials than in adults', indicating that even in late childhood the brain networks involved in language processing are subject to subtle developmental changes. PMID- 25541273 TI - Light and electron microscopic studies on the pigmented epithelium and photoreceptors of the retina of common buzzard (Buteo buteo). AB - The current study is essentially carried out to reveal the histological and ultra structural details of the retinal pigmented epithelium (RPE) and photoreceptors cell layers of a common buzzard (Buteo buteo). The recorded results revealed that the neural retina of common buzzard consisted of seven distinct cell layers. The inner nuclear layer was markedly revealed as the thickest one among these layers. A highly melanized RPE was recorded in between the choroid and neural retina. Histologically, the RPE was represented by a single layer of cuboidal epithelial cells with centrally located nucleus. Ultrastructurally, the RPE cells showed numerous melanosomes, mitochondria, phagosomes, myeloid bodies, smooth endoplasmic reticulum (SER), but very rare rough endoplasmic reticulum (RER). The photoreceptor cell layer was represented by three categories of photoreceptor cells: few single rods, numerous single and double cones. Each double cone consisted of a short accessory cone and a long principle cone. The photoreceptor outer segment consisted of bi-membranous discs that are enclosed by outer membrane. Moreover, the inner segment of rods consisted of an ellipsoid and an inner hyperboloid. The hyperboloid was rich with RER, polysomes, Golgi apparatus and autophagic vacuoles. Furthermore, the inner segment of single cone and accessory cone consisted of an ellipsoid, paraboloid and myoid regions, while, the inner segment of principle cone lacked the paraboloid regions. At the proximal end of each inner segment for all types of cones, there was a large heterogeneous oil droplet. The paraboloid region was markedly rich with glycogen granules. The myoid region exhibited the same organelles but with little glycogen granules when compared with hyperboloid. PMID- 25541274 TI - DNA damage: beta zero versus beta plus thalassemia. AB - BACKGROUND: beta thalassemia results in an increase in the alpha to non-alpha chain ratio. Iron released from unpaired alpha chains in RBCs and that ensuing from regular transfusions is the major cause of cellular damage. The use of iron chelators to counter the iron overload is accompanied by side-effects. The extent of iron toxicity could vary from one patient to another and could help in determining the optimal chelator dose for each patient. AIM: To observe the pro oxidant/antioxidant disturbance and the extent of DNA damage in beta thalassemia patients with different beta globin gene anomalies. METHODS: The formation of Reactive Oxygen Species (ROS ) was observed by incubation of cell suspensions with 2',7', dichlorofluorescin-diacetate (DCFH DA) and DNA damage was demonstrated by single cell gel electrophoresis. Heinz bodies were observed by staining blood smears. SUBJECTS: The study group comprised 50 regularly transfused beta thalassemia patients and 40 non thalassemic controls. RESULTS: While Heinz bodies and nucleated RBCs were seen in all the patients, oxidation of DCFH and DNA damage were seen to be associated with the beta globin gene defect. DNA damage was found to be greater in beta(0) homozygotes as compared to the beta(+) homozygotes, and was maximum in patients presenting with the 619 base pair deletion. CONCLUSION: In the present study, iron toxicity, as indicated by DNA damage, has been seen to vary in the patients. Thus, monitoring of the dose of iron chelators, according to the type of mutation in the beta globin gene, may help improve the compliance of beta thalassemics to chelation therapy and prevent side-effects in patients with beta plus mutations. PMID- 25541275 TI - Assessment of fat-free mass from bioelectrical impedance analysis in obese women with Prader-Willi syndrome. AB - BACKGROUND: Fat-free mass (FFM) is lower in obese subjects with Prader-Willi syndrome (PWS) than in obese subjects without PWS. FFM prediction equations developed in non-PWS subjects may, thus, not work in PWS subjects. AIM: To test whether the estimation of FFM from bioelectrical impedance analysis (BIA) in PWS subjects requires population-specific equations. METHODS: Using dual-energy X-ray absorptiometry, this study measured FFM in 27 PWS and 56 non-PWS obese women and evaluated its association with the impedance index at 50 kHz (ZI50), i.e. the ratio between squared height and whole-body impedance at 50 kHz. RESULTS: At the same level of ZI50, PWS women had a lower FFM than non-PWS women. However, when PWS-specific equations were used, FFM was accurately estimated at the population level. An equation employing a dummy variable coding for PWS status was able to explain 85% of the variance of FFM with a root mean squared error of 3.3 kg in the pooled sample (n = 83). CONCLUSION: Population-specific equations are needed to estimate FFM from BIA in obese PWS women. PMID- 25541276 TI - The association between blood cadmium level and airflow obstruction in Korean men. AB - BACKGROUND: Most humans are exposed to environmental contaminants via inhalation. Various toxic inhalants cause lung damage with pathologic changes to the airway system. Lung function decline is an important cause of morbidity and mortality worldwide. AIM: To consider the potential burden of cadmium on pulmonary disease, this study examined the relationship between blood cadmium levels and airflow obstruction in a Korean general population. SUBJECTS AND METHODS: Data from the Korean National Health and Nutrition Examination Surveys from 2008-2011 were used. Male participants were selected who were older than 40 years, who had completed a reliable pulmonary function test and for who measurements of blood cadmium levels were available (n = 1974). The pulmonary function tests were undertaken and airflow obstruction was defined when forced vital capacity/forced expiratory volume in 1 second ratio < 0.7. RESULTS: In an age-adjusted logistic regression model, blood cadmium levels correlated with the risk of obstructive airflow pattern in total participants as well as in smokers or never smokers. Further adjustment for BMI, current occupation and educational level did not attenuate these associations among total participants, smokers and never smokers (OR = 2.53, 95% CI = 1.83-3.50 in total; OR = 2.17, 95% CI = 1.55-3.02 in smokers; OR = 3.71, 95% CI = 1.48-9.33 in never smokers). CONCLUSIONS: In conclusion, blood cadmium level was associated with airflow obstruction independently of smoking history and that association was still significant in never smokers. Careful attention is needed for the general population who are potentially exposed to cadmium. PMID- 25541277 TI - A modified Lewis ECG lead system for ambulatory monitoring of atrial arrhythmias. AB - BACKGROUND: When using a reduced ECG lead system with three leads or less, the analysis of atrial activity during arrhythmias can become problematic due to low signal amplitude and noise. Long ago, Sir Thomas Lewis proposed a lead system for atrial activity enhancement in which two electrodes are placed directly on the chest, however, these leads are sensitive to arm movement artifacts. In this study, a modified Lewis lead system is proposed that is better suited for ambulatory applications since the electrodes are placed in areas with less muscle. MATERIALS AND METHODS: The proposed modification is compared to the original Lewis leads as well as to the ES lead of the EASI system. Forty-one healthy volunteers and 10 patients with atrial fibrillation participated. RESULTS: The modified Lewis lead has nearly 3 times as large atrial amplitude as the original Lewis leads, and is associated with the largest amplitude of atrial activity when compared to the amplitude of electromyographic activity in healthy volunteers. CONCLUSION: The results suggest that the proposed modification of the Lewis lead system has potential to improve ambulatory monitoring of atrial arrhythmias. PMID- 25541278 TI - The effect of obstructive sleep apnea on QRS complex morphology. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been reported to be associated with an increased risk of ventricular arrhythmias and conduction disturbances. The aim of this study was to analyze the QRS complex morphology potentially indicative of intraventricular conduction impairment in patients with mild to severe OSA. MATERIAL AND METHODS: One hundred ninety-three consecutive patients, who underwent complete overnight polysomnography, were divided into four groups based on the OSA severity: (1) no OSA, (2) mild OSA, (3) moderate OSA and (4) severe OSA (apnea-hypopnea index <5, 5-15, 15-30, >30/h, respectively). Resting 12-lead ECG was recorded, the QRS parameters included QRS amplitude in individual leads, QRS spatial vector magnitude (QRSmax), electrical axis (EA), ECG criteria for left ventricular hypertrophy (ECG-LVH) and right ventricular hypertrophy (ECG RVH), and occurrence of fragmented QRS (fQRS). RESULTS: Severity of OSA was significantly associated with a gradual significant shift of the electrical axis to the left (45.5+/-22.5 degrees ; 34.8+/-17.1 degrees ; 32.9+/-18.2 degrees ; 29.8+/-10.0 degrees ; respectively), while the QRSmax values were low in all patient groups, with a significant difference between no OSA and severe OSA groups. The multivariate analysis showed that QRSmax was independently associated with age and the interaction between gender and OSA severity (p=0.001, and p=0.004, respectively; adjusted R(2)=0.178). The electrical axis was found to be independently associated with age and OSA severity (p=0.037, and p=0.026, respectively; R(2)=0.109). Changes of electrical axis and of QRSmax were reflected in corresponding changes in the amplitude of 12-lead ECG and in low occurrence of ECG-LVH and ECG-RVH criteria. The OSA groups had higher occurrence of fQRS. CONCLUSION: OSA patients displayed a combination of changes in QRS complex morphology, the leftward shift of EA, low QRS voltage and fQRS, suggestive of depolarization sequence deterioration that might be indicative of considerable electrical remodeling. PMID- 25541279 TI - Ameliorative potential of omega 3 fatty acids and HMG-CoA reductase inhibitors on experimentally-induced non-alcoholic steatohepatitis. AB - Non-alcoholic steatohepatitis (NASH) has a relation to obesity. It may lead to hepatocellular carcinoma. To date, the therapeutic options are limited due to complex pathogenesis. This study aimed to investigate the effect of atorvastatin and omega 3 fatty acids on experimentally-induced NASH. Sixty male albino rats were divided into 6 equal groups; control group, high fat emulsion/sucrose (HFE/S) diet, HFE/S+carboxymethyl cellulose, HFE/S +Atorvastatin, HFE/S+Fish oil and HFE/S+Atorvastatin+Fish oil. Serum alanine aminotransferase, total cholesterol (TC), triglycerides (TG), high density lipoproteins, insulin, glucose, C-reactive protein and quantitative insulin sensitivity check index were measured. Also, hepatic TC, TG, malondialdehyde, tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-beta1) were determined. Liver sections were examined histopathologically. Atorvastatin improved lipid profile, inflammation and oxidative stress but did not improve insulin resistance, hepatic TGF-beta1 or body weight while fish oil improved lipid profile, decreased inflammation and oxidative stress, improved insulin resistance, hepatic TGF-beta1 and body weight compared to HFE/S group. Atorvastatin/fish oil combination produced significant improvement in the lipid profile, inflammation, oxidative stress, insulin resistance, hepatic TGF-beta1 and body weight compared to the use of each of these drugs alone. This might be attributed to the effect of fish oil on the lipid profile, inflammatory cytokines, insulin resistance and TGF-beta1 which potentiates the effect of atorvastatin on NASH. PMID- 25541280 TI - Building a patchwork - The yeast plasma membrane as model to study lateral domain formation. AB - The plasma membrane (PM) has to fulfill a wide range of biological functions including selective uptake of substances, signal transduction and modulation of cell polarity and cell shape. To allow efficient regulation of these processes many resident proteins and lipids of the PM are laterally segregated into different functional domains. A particularly striking example of lateral segregation has been described for the budding yeast PM, where integral membrane proteins as well as lipids exhibit very slow translational mobility and form a patchwork of many overlapping micron-sized domains. Here we discuss the molecular and physical mechanisms contributing to the formation of a multi-domain membrane and review our current understanding of yeast PM organization. Many of the fundamental principles underlying membrane self-assembly and organization identified in yeast are expected to equally hold true in other organisms, even for the more transient and elusive organization of the PM in mammalian cells. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. PMID- 25541282 TI - Monitoring of autophagy is complicated--salinomycin as an example. AB - Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10 MUM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30 MUM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response. PMID- 25541283 TI - Genetic approaches of the Fe-S cluster biogenesis process in bacteria: Historical account, methodological aspects and future challenges. AB - Since their discovery in the 50's, Fe-S cluster proteins have attracted much attention from chemists, biophysicists and biochemists. However, in the 80's they were joined by geneticists who helped to realize that in vivo maturation of Fe-S cluster bound proteins required assistance of a large number of factors defining complex multi-step pathways. The question of how clusters are formed and distributed in vivo has since been the focus of much effort. Here we review how genetics in discovering genes and investigating processes as they unfold in vivo has provoked seminal advances toward our understanding of Fe-S cluster biogenesis. The power and limitations of genetic approaches are discussed. As a final comment, we argue how the marriage of classic strategies and new high throughput technologies should allow genetics of Fe-S cluster biology to be even more insightful in the future. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25541281 TI - Selective dendritic susceptibility to bioenergetic, excitotoxic and redox perturbations in cortical neurons. AB - Neurodegenerative and neurological disorders are often characterised by pathological changes to dendrites, in advance of neuronal death. Oxidative stress, energy deficits and excitotoxicity are implicated in many such disorders, suggesting a potential vulnerability of dendrites to these situations. Here we have studied dendritic vs. somatic responses of primary cortical neurons to these types of challenges in real-time. Using a genetically encoded indicator of intracellular redox potential (Grx1-roGFP2) we found that, compared to the soma, dendritic regions exhibited more dramatic fluctuations in redox potential in response to sub-lethal ROS exposure, and existed in a basally more oxidised state. We also studied the responses of dendritic and somatic regions to excitotoxic NMDA receptor activity. Both dendritic and somatic regions experienced similar increases in cytoplasmic Ca2+. Interestingly, while mitochondrial Ca2+ uptake and initial mitochondrial depolarisation were similar in both regions, secondary delayed mitochondrial depolarisation was far weaker in dendrites, potentially as a result of less NADH depletion. Despite this, ATP levels were found to fall faster in dendritic regions. Finally we studied the responses of dendritic and somatic regions to energetically demanding action potential burst activity. Burst activity triggered PDH dephosphorylation, increases in oxygen consumption and cellular NADH:NAD ratio. Compared to somatic regions, dendritic regions exhibited a smaller degree of mitochondrial Ca2+ uptake, lower fold-induction of NADH and larger reduction in ATP levels. Collectively, these data reveal that dendritic regions of primary neurons are vulnerable to greater energetic and redox fluctuations than the cell body, which may contribute to disease-associated dendritic damage. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25541284 TI - The role of N-glycan in folding, trafficking and pathogenicity of myelin oligodendrocyte glycoprotein (MOG). AB - Myelin oligodendrocyte glycoprotein (MOG) is a type I integral membrane protein that is expressed in the central nervous system. MOG has a single N-glycosylation site within its extracellular domain. MOG has been linked with pathogenesis of multiple sclerosis; anti-MOG antibodies have been detected in the sera of multiple sclerosis patients. N-glycosylation is an important post-translational modification of protein that might impact their folding, localization and function. However, the role of sugar in the biology of MOG is not well understood. In this study, we created a mutant MOG lacking N-linked glycan and tested its properties. We concluded that the lack of sugar did not impact on MOG abundance in the absence of endoplasmic reticulum molecular chaperone calnexin. We also show that the absence of N-glycan did not interfere with MOG's subcellular localization and it did not result in activation of endoplasmic reticulum stress. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25541285 TI - The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome. AB - Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca(2+) handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF 1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1 associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed. PMID- 25541286 TI - Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NFkappaB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells. AB - Oxidized low-density lipoprotein (oxLDL) is a key contributor to atherogenesis through multiple mechanisms, including the reactive oxygen species (ROS)-mediated nuclear factor-kappaB (NFkappaB) signaling pathway. Although shikonin, one of the main active components isolated from the Chinese herb Lithospermum erythrorhizon, has been shown to possess cardioprotective, antioxidative, and anti-inflammatory effects, the mechanisms underlying these actions are not well understood. In this study, we used EA.hy926 endothelial-like cells to examine the anti-atherogenic activity of shikonin. Shikonin (0-1 MUM) concentration-dependently induced heme oxygenase-1, glutamate cysteine ligase modifier subunit, catalase, superoxide dismutase 1, glutathione peroxidase 1, and glutathione reductase protein and mRNA expression and glutathione content via activation of the phosphatidylinositol 3 kinase (PI3K)/Akt/Nrf2 signaling pathway. In the presence of oxLDL (40 MUg/ml), shikonin pretreatment reversed oxLDL-induced ROS production, antioxidant response element reporter activity, NFkappaB nuclear translocation, and intercellular adhesion molecule (ICAM)-1 and E-selectin expression and suppressed the increase of monocyte adhesion to endothelial cells. Nrf2 knockdown by using RNA interference attenuated the ability of shikonin to inhibit oxLDL-induced NFkappaB DNA binding activity, adhesion molecule expression, and monocyte adhesion. Taken together, these results suggest that shikonin protects against oxLDL-induced endothelial damage by suppressing ROS/NFkappaB-mediated ICAM-1 and E-selectin expression via up-regulation of PI3K/Akt/Nrf2-dependent antioxidant enzyme expression. PMID- 25541287 TI - The dynamic pain connectome. AB - Traditionally, studies of how pain and attention modulate one another involved explicit cognitive-state manipulations. However, emerging evidence suggests that spontaneous brain-wide network communication is intrinsically dynamic on multiple timescales, and attentional states are in constant fluctuation. Here, in light of studies on neural mechanisms of spontaneous attentional fluctuations and pain variability, we introduce the concept of a dynamic 'pain connectome' in the brain. We describe how recent progress in our understanding of individual differences in intrinsic attention to pain and neural network dynamics in chronic pain can facilitate development of personalized pain therapies. Furthermore, we emphasize that the dynamics of pain-attention interactions must be accounted for in the contemporary search for a 'neural signature' of the pain connectome. PMID- 25541288 TI - Do sensorimotor beta-oscillations maintain muscle synergy representations in primary motor cortex? AB - Coherent beta-oscillations are a dominant feature of the sensorimotor system yet their function remains enigmatic. We propose that, in addition to cell intrinsic and/or local network interactions, they are supported by activity propagating recurrently around closed neural 'loops' between primary motor cortex (M1), muscles, and back to M1 via somatosensory pathways. Individual loops reciprocally connect individual muscle synergies ('motor primitives') with their representations in M1, and the conduction time around each loop resonates with the periodic spiking of its constituent neurons/muscles. During beta oscillations, this resonance strengthens within-loop connectivity (via long-term potentiation, LTP), whereas non-resonance between different loops weakens connectivity (via long-term depression, LTD) between M1 representations of different muscle synergies. In this way, beta-oscillations help maintain accurate and discrete representations of muscle synergies in M1. PMID- 25541290 TI - Beyond risky alcohol use: screening non-medical use of prescription drugs at National Alcohol Screening Day. AB - INTRODCUTION: Recent epidemiological data has indicated an increasing trend in the non-medical use of prescription drugs (NMUPD) among college students. NMUPD has shown a strong relationship with heavy alcohol use and associated negative consequences. Despite the trends and association with other risky behavior, there remain large gaps in the literature regarding this hazardous behavior. To date, no study has examined the prevalence of NMUPD among student attending National Alcohol Screening Day (NASD), and few studies have explored motives contributing to NMUPD, as well as the relationship between motives, NMUPD, and alcohol use. METHODS: The current study examined the prevalence and motives for NMUPD among undergraduate students (N=128) attending NASD. RESULTS: Overall, 42% of the sample reported NMUPD at least once in their lifetime, 29.7% at least once in the past year, and 18.0% reported simultaneously engaging in alcohol consumption and NMUPD. Pain relievers were the most frequently used drug class for lifetime use, and stimulants were the most frequently reported for past year use. Most students reported NMUPD for functional reasons. Students that engaged in binge drinking were three times more likely to report NMUPD. CONCLUSIONS: The findings from the current study suggest that events like NASD may provide a platform for screening and discussing NMUPD, and its associated risk with heavy alcohol use. PMID- 25541291 TI - Cyber addictions: toward a psychosocial perspective. AB - The concept of cyberaddiction is far from being unanimously accepted by scientists (Ko, Yen, Yen, Chen, & Chen 2012; Pezoa-Jares, Espinoza-Luna & Vasquez Medina 2012; Nadeau et al., 2011; Perraton, Fusaro & Bonenfant 2011). The same is true of addiction to videogames (Hellman, Schoenmakers, Nordstrom, & Van Holst 2013; Coulombe 2010); or to Facebook (Andreassen et al., 2012; Levard & Soulas, 2010). While certain researchers wished to see this condition included in the DSM 5 (Block, 2008), others question the operational and practical bases for the diagnostic criteria. Some see cyberaddiction as a problem linked more to time management, to brain deficits, to an impulse-control disorder or to psychosocial conditions while others consider it to be a pre-existing comorbidity. Considering that most addiction problems are generally understood more as individual and pathological problems rather than the result of psychosocial conditions (poverty, unemployment, weak social ties, social exclusion, hyper individualism, etc), the aim of this article is to propose a psychosocial perspective for this emerging trend in cyberaddictions. To what extent social conditions and cyberaddiction behaviors constitute a potential pathology? Can we include a psychosocial approach to gain a more general picture of this contemporary issue? In response to these questions, a contextualization and an attempt to define cyberaddiction will be followed by an analysis of some major issues in the development of this type of addiction. A demonstration of the cycle of addiction on how people develop addictions, including cyberaddictions, will be done within a psychosocial perspective in order to seize the multifactorial aspects of this addiction. PMID- 25541292 TI - Evidence from the field: Findings on issues related to planning, implementing and evaluating gender-based programs. AB - An Initiative of the United States Department of Health and Human Services' Office on Women's Health (OWH), Coalition for a Healthier Community (CHC), supports ten grantees across the U.S. in the implementation of gender-based health interventions targeting women and girls. A national evaluation is assessing whether gender-focused public health systems approaches are sustainable and cost effective in addressing health disparities in women and girls. To inform the evaluation, a systematic examination was conducted of literature in both the public and private sector designed to track, assess, understand, and improve women's health, public health systems approaches, and the cost-effectiveness and sustainability of gender-based programs. A two-person team assured the quality of the results following the review of abstracts and full-text articles. Of 123 articles meeting eligibility criteria (See inclusion criteria described in Section 2.2 below), only 18 met inclusion criteria specific to a focus on a systems approach, cost-effectiveness and/or sustainability. Studies assessing systems approaches suggested their effectiveness in changing perceptions and increasing knowledge within a community; increasing involvement of local decision makers and other community leaders in women's health issues; and increasing community capacity to address women and girls' health. Further evaluation of the cost-effectiveness and sustainability of gender-based approaches is needed. PMID- 25541293 TI - Engaging Native Hawaiians and Pilipinos in creating supportive and safe violence free communities for women through a piloted "talkstory" intervention: Implications for program development. AB - In Hawaii, 20% of women have been victims of intimate partner violence (IPV). Although disaggregated data specific to Native Hawaiians or Pilipinos (The official Filipino language recognizes both Filipino (Filipina) and Pilipino (Pilipina) as terms for the citizens of the country. Participants in this study chose to use the terms Pilipino (Pilipina). Retrieved from: www.pilipino express.com/history-a-culture/in-other-words) are limited, greater than 70% of women murdered in Hawaii as a result of IPV are Pilipino or native Hawaiian. A consortium was formed to assist Native Hawaiian and Pilipino women addressing abuse and strengthening support from the community. A quasi-experimental community-based participatory research study was designed to assess a community "talkstory" intervention for IPV. "Talkstory" refers to informal gatherings considered to be a laid-back conversation involving a "reciprocal exchange of thoughts, ideas, feelings about self, and other issues" (Affonso et al., 1996. Journal of Obstetric, Gynecologic, & Neonatal Nursing, 25, 738). This article describes the development of an intervention to address IPV in Hawaii and presents the findings obtained from the pilot studies. Results from the pilot study were used to modify the proposed "talkstory" intervention, revise the data collection tools, and provide the program developers with insights into how the community viewed IPV. The most significant change was an increased perception of their awareness, knowledge, and confidence to address IPV following the intervention. PMID- 25541289 TI - The role of prostaglandins in allergic lung inflammation and asthma. AB - Prostaglandins (PGs) are products of the COX pathway of arachidonic acid metabolism. There are five primary PGs, PGD2, PGE2, PGF2, PGI2 and thromboxane A2, all of which signal through distinct seven transmembrane, G-protein coupled receptors. Some PGs may counteract the actions of others, or even the same PG may have opposing physiologic or immunologic effects, depending on the specific receptor through which it signals. In this review, we examine the effects of COX activity and the various PGs on allergic airway inflammation and physiology that is associated with asthma. We also highlight the potential therapeutic benefit of targeting PGs in allergic lung inflammation and asthma based on basic science, animal model and human studies. PMID- 25541294 TI - Surveillance of antifungal susceptibilities in clinical isolates of Candida species at 36 hospitals in China from 2009 to 2013. AB - BACKGROUND: The purpose of this study was to determine the species distribution and to monitor the antifungal susceptibility profiles of clinical Candida isolates collected in China from 2009 to 2013. METHODS: The antifungal susceptibilities of 952 Candida isolates were tested. RESULTS: Candida albicans was the most common species, accounting for 65.7% of the total isolates. The most frequently isolated non-albicans Candida species in this study was Candida glabrata (193, 20.3%). Nearly 7.6%, 3.2%, 1.8%, and 1.1% of the 952 isolates exhibited decreased susceptibility to fluconazole, voriconazole, itraconazole, and flucytosine, respectively. Moreover, seven C. albicans and one Candida krusei had an amphotericin B minimum inhibitory concentration (MIC) of 2 MUg/ml. CONCLUSIONS: The distribution of species and the prevalence of antifungal resistance in Candida isolates varied among different areas in China. Continuous monitoring of resistance patterns is necessary to control the spread of resistance in clinical isolates of Candida species. PMID- 25541295 TI - Severe human Babesia divergens infection in Norway. AB - Human babesiosis is a rare but potentially life-threatening parasitic disease transmitted by ixodid ticks, and has not previously been reported in Norway. We report a case of severe babesiosis that occurred in Norway in 2007. The patient had previously undergone a splenectomy. He was frequently exposed to tick bites in an area endemic for bovine babesiosis in the west of Norway. The patient presented with severe haemolysis and multiorgan failure. Giemsa-stained blood smears revealed 30% parasitaemia with Babesia spp. He was treated with quinine in combination with clindamycin, apheresis, and supportive treatment with ventilatory support and haemofiltration, and made a complete recovery. This is the first case reported in Norway; however Babesia divergens seroprevalence in cattle in Norway is high, as is the risk of Ixodes ricinus tick bite in the general population. Babesiosis should be considered in the differential diagnosis of unexplained febrile haemolytic disease. PMID- 25541296 TI - Evolution of pneumococcal infections in adult patients during a four-year period after vaccination of a pediatric population with 13-valent pneumococcal conjugate vaccine. AB - OBJECTIVES: To describe the distribution of vaccine and non-vaccine pneumococcal serotypes from adult patients for different clinical scenarios, after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV-13) for children. METHODS: This was a prospective study of pneumococcal infections in adult patients (January 2010 to April 2014) in Hospital Son Llatzer, Mallorca (Spain). Two different periods of time were compared, the first before (first period) and the second after (second period) the introduction of PCV-13. Information related to clinical characteristics, outcomes of infection, pneumococcal serotypes, and antibiotic susceptibility was collected. RESULTS: We studied 407 episodes (371 patients), 201 in the first period and 206 in the second period. The majority of patients were male; the median patient age was 68 (range 15-99) years. Infections due to PCV-13 serotypes decreased from 59.7% to 47.6% (p=0.014), mainly serotypes 3, 7, 18C, 19F, and 23F. In the second period, PCV-13 serotypes were the cause of pneumonia in 58.2% of cases and in 40.8% of invasive infections, but these serotypes were not related with any outcome variable. No differences in hospital or intensive care unit admission, severity, or mortality were observed between the two periods. Susceptibility to penicillin (98.2% vs. 95.1%, p=0.03) and amoxicillin (96.5% vs. 91%, p=0.007) was slightly higher in the first period. CONCLUSIONS: Although a reduction in infections due to vaccine serotypes was observed, close to half of infections in adult patients were caused by PCV-13 serotypes. Even after pediatric vaccination with PCV-13, vaccine serotypes were still responsible for most pneumonia and invasive disease, underscoring the importance of implementing current guidelines and extending vaccination to other risk groups. PMID- 25541298 TI - Arabinoxylan rice bran (MGN-3/Biobran) enhances natural killer cell-mediated cytotoxicity against neuroblastoma in vitro and in vivo. AB - BACKGROUND AIMS: Natural killer cell (NK) cytotoxic activity plays a major role in natural immunologic defences against malignancies. NK cells are emerging as a tool for adoptive cancer immunotherapies. Arabinoxylan rice bran (MGN-3/Biobran) has been described as a biological response modifier that can enhance the cytotoxic activity of NK cells. This study evaluated the effect of MGN-3/Biobran on NK cell activation, expansion and cytotoxicity against neuroblastoma cells. METHODS: NK cells were enriched with magnetic beads and stimulated with MGN 3/Biobran. NK cell activation was evaluated via analysis of their phenotype, and their expansion capability was tracked. The in vitro cytotoxic ability of the activated NK cells was tested against K562, Jurkat, A673, NB1691, A-204, RD and RH-30 cell lines and the in vivo cytotoxic ability against the NB1691 cell line. RESULTS: MGN-3/Biobran stimulation of NK cells induced a higher expression of the activation-associated receptors CD25 and CD69 than in unstimulated cells (P < 0.05). The expression of NKG2D, DNAM, NCRs and TLRs remained unchanged. Overnight MGN-3/Biobran stimulation increased NK cell cytotoxic activity against all cell lines tested in vitro and decelerated neuroblastoma growth in vivo. The mechanism is not mediated by lipopolysaccharide contamination in MGN-3/Biobran. Furthermore, the addition of MGN-3/Biobran promoted NK cell expansion and decreased T cells in vitro. CONCLUSIONS: Our data show that MGN-3/Biobran upregulates NK cell activation markers, stimulates NK cell cytotoxic activity against neuroblastoma in vitro and in vivo and selectively augments the expansion of NK cells. These results may be useful for future NK cell therapeutic strategies of the treatment of neuroblastoma. PMID- 25541297 TI - Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease. AB - OBJECTIVE: The matricellular protein NOV/CCN3, is implicated in osteoarthritis (OA) and targeted mutation of NOV in mice (Nov(del3)) leads to joint abnormalities. This investigation tested whether NOV is required for joint homeostasis and if its disruption causes joint degeneration. METHOD: NOV expression in the adult mouse joint was characterized by immunohistochemistry. A detailed comparison of the joints of Nov(del3)-/- and Nov(del3)+/+ (wild-type) males and females at 2, 6 and 12 months of age was determined by X-ray, histology and immunohistochemistry. RESULTS: NOV protein was found in specific cells in articular cartilage, meniscus, synovium and ligament attachment sites in adult knees. Nov(del3)-/- males exhibited severe OA-like pathology at 12 months (OARSI score 5.0 +/- 0.5, P < 0.001), affecting all tissues of the joint: erosion of the articular cartilage, meniscal enlargement, osteophytic outgrowths, ligament degeneration and expansion of fibrocartilage. Subchondral sclerosis and changes in extracellular matrix composition consistent with OA, were also seen. The density of articular cartilage cells in Nov(del3)+/+ knee joints is maintained at a constant level from 2 to 12 months of age whereas this is not the case in Nov(del3)-/- mice. Compared with age and sex-matched Nov(del3)+/+ mice, a significant increase in articular cartilage density was seen in Nov(del3)-/- males at 2 months, whereas a significant decrease was seen at 6 and 12 months in both Nov(del3)-/- males and females. CONCLUSION: NOV is required for the maintenance of articular cartilage and for joint homeostasis, with disruption of NOV in ageing Nov(del3)-/- male mice causing OA-like disease. PMID- 25541299 TI - Preventive effects of CTLA4Ig-overexpressing adipose tissue--derived mesenchymal stromal cells in rheumatoid arthritis. AB - BACKGROUND AIMS: Rheumatoid arthritis is a systemic autoimmune disorder. In this study, we first compared the therapeutic effects of syngeneic and xenogeneic adipose tissue-derived stem cells on a collagen-induced arthritis mouse model. Second, we investigated the synergistic preventive effects of CTLA4Ig and adipose tissue-derived mesenchymal stromal cells (ASCs) as a therapeutic substance. METHODS: Arthritis was induced in all groups except for the normal, saline (N) group, using chicken type II collagen (CII). Animals were divided into C (control, saline), H (hASCs), M (mASCs) and N groups (experiment I) and C, H, CT (CTLA4Ig-overexpressing human ASC [CTLA4Ig-hASCs]) and N groups (experiment II), according to transplanted material. Approximately 2 * 10(6) ASCs or 150 MUL of saline was intravenously administered on days 24, 27, 30 and 34, and all animals were killed on days 42 to 44 after CII immunization. RESULTS: Anti-mouse CII autoantibodies were significantly lower in the H, M and CT groups than in the C group. Cartilage damage severity score and C-telopeptide of type II collagen were significantly lower in the CT group than in the C group. The serum levels of IL-6 were significantly lower in the H, M and CT groups than in the C group. The serum levels of keratinocyte chemoattractant were significantly lower in the CT group than the C group. CONCLUSIONS: There were similar effects of ASCs on the decrease of anti-mouse CII autoantibody levels between syngeneic and xenogeneic transplantations, and CTLA4Ig-hASCs showed synergistic preventive effects compared with non-transduced hASCs. PMID- 25541300 TI - Editorial to special issue on "white matter pathology". PMID- 25541301 TI - Conservation genetics of high-arctic Gull species at risk: I. Diversity in the mtDNA control region of circumpolar populations of the Endangered Ivory Gull (Pagophila eburnea). AB - The high-arctic Ivory Gull (Pagophila eburnea) has recently undergone a sharp decline in numbers, and in Canada it is listed as "Endangered" under the Species At-Risk Act. To test for circumpolar genetic distinctiveness, we examined 264 bp of the mtDNA Control Region Domain I from 127 museum specimens collected during the breeding season from northern Canada, Greenland, and Norway, and during the non-breeding season from adjacent overwintering grounds in Canada, Greenland, and a disjunct area in Alaska adjacent to the Bering Sea. Partition of genetic variance according to various phylogeographic and breeding ground models indicates no strong population structure, except that Alaska birds are consistently differentiated from other locations, and there are significant temporal shifts in haplotype frequencies. The evidence suggests that Ivory Gulls in Canada, Greenland, and Norway are a single genetic entity, in contrast to Alaska birds, which may represent a distinctive Siberian population. PMID- 25541302 TI - Conservation genetics of high-arctic Gull species at risk: II. Diversity in the mtDNA control region of Threatened Ross's Gull (Rhodostethia rosea). AB - Ross's Gull (Rhodostethia rosea) is the rarest of Canadian high-arctic gulls, and is listed as Threatened under Canada's Species-At-Risk Act. The large majority of birds breed in Siberia: the origins and affinities of four extremely small breeding colonies observed since 1978 in the Canadian high arctic are unknown. We compared a 515-bp region of the mtDNA Control Region amplified from material in museum collections taken from non-breeding birds in Canada (n = 8) and Alaska (n = 6), the latter passage migrants from the Siberian populations. The Alaskan birds all have distinct haplotypes that differ by as many as six SNPs: Canadian birds taken in the vicinity of the breeding colonies show only two of these. We hypothesize the origins of the Canadian breeding colonies as recent founder events by small numbers of passage migrants from Siberia via Alaska. Ross's Gull maintains a very tenuous breeding presence in the Canadian high Arctic. PMID- 25541303 TI - The complete mitochondrial genome of the tobacco budworm, Helicoverpa assulta. AB - The complete mitochondrial genome of the tobacco budworm Helicoverpa assulta was sequenced. It is 15,351 bp in length, and contains 22 transfer RNA genes, 13 protein-coding genes (PCGs), 2 rRNA genes and a non-coding AT-rich region. The H. assulta mitogenome displays a very high level of identity (99.76%) with Helicoverpa armigera. The genome base composition is 40.50% A, 40.40% T, 11.32% C and 7.70% G. Similar to other Lepidoptera insects, all PCGs are initiated by a typical ATN codon, except CO1, which starts with CGA. Nine PCGs have the standard, complete stop codon (TAA), and the other four PCGs end with the incomplete stop codon TA-. PMID- 25541304 TI - Sequence and analysis of mtDNA control region in Cnaphalacrocis medinalis Guenee and Marasmia patnalis Bradley (Lepidoptera: Pyralidae). AB - Rice leaffolders Cnaphalocrocis medinalis and Marasmia patnalis (Lepidoptera: Pyralidae) are important rice pests and morphologically related with same damage methods. The control region of mitochondrial DNA (mtDNA) in two rice leaffolders C. medinalis and M. patnalis were sequenced and analyzed. The control regions of the two rice leaffolders are located between 12S ribosomal RNA and tRNAMet, and exhibit conserved structural elements. We identified the poly T stretches, (TA)n block, and stem-loop structure. There are no long tandem repeats found in mtDNA control region in the two rice leaffolders studied. Nevertheless, we did not find the GA-rich block in mtDNA control regions of the two rice leaffolders. The molecular-based phylogenies support the traditional morphologically based view of relationships of Pyralidae within the Ditrysia. The addition of the C. medinalis and M. patnalis mtDNA control regions to the literature promotes the understanding of the molecular evolution of Pyralidae in Ditrysia. PMID- 25541305 TI - The complete mitogenome of the porcelain crab Petrolisthes haswelli Miers, 1884 (Crustacea: Decapoda: Anomura). AB - The mitochondrial genome sequence of the porcellanid crab, Petrolisthes haswelli is provided, making it the second for the family Porcellanidae and the third for the superfamily Galatheoidea. Petrolisthes haswelli has a mitogenome of 15,348 bp consisting of 13 protein-coding genes, two ribosomal subunit genes, 22 transfer RNAs and a non-coding AT-rich region. The base composition of the P. haswelli mitogenome is 35.66% for T, 18.65% for C, 34.35% for A and 11.34% for G, with an AT bias of 70.01%. The mitogenome gene order is identical to the mitogenome of Neopetrolisthes maculatus, the only other species of the family with a sequenced mitogenome. PMID- 25541306 TI - The complete mitochondrial genome of the phytopathogenic fungus Phomopsis longicolla. AB - The complete mitochondrial genome of the ascomycete fungus Phomopsis longicolla was sequenced using Illumina HiSeq platform. It consists of 53,439 bp with high (65.6%) A + T content and includes 14 conserved protein subunits of the mitochondrial oxidative phosphorylation system, two ribosomal RNAs and 25 tRNA genes. To our knowledge, this is the first complete mitochondrial genome of the Diaporthales member. PMID- 25541307 TI - The complete mitogenome of purple mottled shore crab Cyclograpsus granulosus H. Milne-Edwards, 1853 (Crustacea: Decapoda: Grapsoidea). AB - The mitochondrial genome sequence of the purple mottled shore crab, Cyclograpsus granulosus, is documented (GenBank accession number: LN624373), which makes it the third for genera of the superfamily Grapsoidea. Cyclograpsus granulosus has a mitogenome of 16,300 bp consisting of 13 protein-coding genes, two ribosomal subunit genes, 22 transfer RNAs and a non-coding AT-rich region. The base composition of the C. granulosus mitogenome is 36.15% for T, 19.54% for C, 33.14% for A and 11.17% for G, with an AT bias of 69.29%. The mitogenome gene order is atypical for the brachyuran crabs, but is identical to species of the genus Eriocheir from the same family. PMID- 25541308 TI - The complete mitochondrial genome of skipjack tuna (Katsuwonus pelamis) determined by HiSeq sequencing. AB - The mitochondrial genome of skipjack tuna, Katsuwonus pelamis, was obtained by using HiSeq next-generation sequencing technique. The circular mitogenome is 16,515 bp in length, with the gene number and arrangement being similar to those observed in other teleost fish. Overall base composition is A 28.49%, T 24.58%, C 30.27% and G 16.66%, respectively. Among 13 protein-coding genes, seven of which share the complete stop codon TAA while others terminate with TA or T, all these genes use ATG as start codon except for COI. PMID- 25541309 TI - Whole mitochondrial genome sequence for an osteoarthritis model of Guinea pig (Caviidae; Cavia). AB - Animal models played an important role in osteoarthritis studies. Here, the complete mitochondrial genome sequence of the Guinea pig was reported for the first time. The total length of the mitogenome was 16,797 bp. It contained the typical structure, including two ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes and one non-coding control region (D-loop region). The overall composition of the mitogenome was estimated to be 34.9% for A, 26.1% for T, 26.0% for C and 13.0% for G showing an A-T (61.0%)-rich feature. This mitochondrial genome sequence will provide new genetic resource into osteoarthritis disease. PMID- 25541310 TI - Whole mitochondrial genome sequencing and analysis for chronic obstructive pulmonary disease rat strain. AB - Mitochondrial genome plays a central role in aging, cancer, apoptosis and metabolism. We sequenced a complete mitochondrial genome sequence of a rat chronic obstructive pulmonary disease rat strain for the first time. The total length of the mitochondrial genome was 16,310 bp and coding 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes. This genome describing information will supply the potential use of mtDNA mutations as markers in cancer. PMID- 25541311 TI - The complete mitochondrial genome of the Epinephelus corallicola (Perciformes: Serranidae). AB - We presented the complete mitochondrial genome of the Epinephelus corallicola in this study. The mitochondrial genome is 16,647 bp long and consists of 13 protein coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The gene order and composition of Epinephelus corallicola mitochondrial genome was similar to that of most other vertebrates. The nucleotide compositions of the light strand are 26.60% of A, 15.89% of C, 28.66% of T and 28.85% of G. With the exception of the NADH dehydrogenase subunit 6 (ND6) and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. PMID- 25541312 TI - Mitochondrial genome of the Trans-Andean shovelnose catfish Sorubim cuspicaudus (Siluriformes, Pimelodidae). AB - The Trans-Andean shovelnose catfish Sorubim cuspicaudus is the largest species within the genus Sorubim. In this work, the pyrosequencing technology was used to obtain the complete mitochondrial genome sequence of S. cuspicaudus. The 16,544 bp molecule contains 13 protein-coding genes, 22 tRNAs, 2 ribosomal RNAs and exhibit perfect synteny with other South-American catfishes. PMID- 25541313 TI - Complete mitochondrial genomes of the yellow-bellied slider turtle Trachemys scripta scripta and anoxia tolerant red-eared slider Trachemys scripta elegans. AB - The complete mitochondrial genomes of the yellow-bellied slider (Trachemys scripta scripta) and anoxia tolerant red-eared slider (Trachemys scripta elegans) turtles were sequenced to analyze gene arrangement. The complete mt genomes of T. s. scripta and elegans were circular molecules of 16,791 bp and 16,810 bp in length, respectively, and included an A + 1 frameshift insertion in ND3 and ND4L genes. The AT content of the overall base composition of scripta and elegans was 61.2%. Nucleotide sequence divergence of the mt-genome (p distance) between scripta and elegans was 0.4%. A detailed comparison between the mitochondrial genomes of the two subspecies is shown. PMID- 25541314 TI - The complete mitogenome of Asian Gray Shrews, Crocidura attenuata (Soricidae). AB - The Asian Gray Shrews, Crocidura attenuate, belongs to the family Soricidae. This widespread Asian species ranges from India and perhaps Pakistan in the west of its range, through much of eastern China and mainland Southeast Asia. In this study, the complete mitochondrial genome sequence of Crocidura attenuata was determined. The mitogenome is 17,534 base pairs in length and contains 13 protein coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one control region, with a base composition of 32.8% A, 31.8% T, 22.4% C and 13.0% G. The present study contributes to illuminating taxonomic status of Crocidura attenuata, and may facilitate further investigation of the molecular evolution of Soricidae. PMID- 25541315 TI - Molecular identification of antelope horn by melting curve analysis. AB - Antelope horn is a valuable Chinese traditional medicine and widely used in clinic. However, with the deterioration of antelope's living environment and a lot of killing, the saiga population begins falling and in some places plummet. Since the increasing demand of this expensive and good bioactive medicine, the horn of artiodactyla animals is often used as the antelope horn. The adulterated or impostor not only cause damage to clinical medicine but also affect the antelope resources protection and sustainable development. Here, in order to establish a melting curve analysis (MCA) method to distinguish the antelope horn from other animal horns and identify the decoction pieces and Chinese patent medicine in a fast and easy way, animal horns and its decoction pieces, Chinese patent medicines were collected from the market and the DNA of all the collected samples were extracted. The melting curve of two universal fragments (COI and Cyt b) was scanned and Cyt b was selected as feasibility fragment for identifying authentic antelope horn from eight adulterant animal horns. After optimizing the condition for MCA, inspecting the precision and the replication of the method, a reference melting curve modern was established and we performed MCA on the antelope horns, fakes, and adulterants on a 1:1 mix, decoction pieces, and Chinese patent medicine. Thus, this study provides fast and easy methods so that MCA can detect the truth, fakes, and adulterations of antelope horns. PMID- 25541316 TI - Complete mitochondrial genome of Sebastes owstoni (Scorpaenidae, Scorpaeniformes) from the East Sea, Korea. AB - Sebastes owstoni is a popular fishery species in the north-western Pacific Ocean. To obtain basic information on its mitochondrial DNA (mtDNA), the complete mitogenome of S. owstoni was subjected to the next-generation sequencing. The assembled mtDNA was 16,465 bp in length, comprising 13 protein-coding genes (PCGs), 2 rRNAs, 22 tRNAs and a control region. The complete mitogenome comprised of 27.7% A, 26.6% T, 17.3% G and 28.4% C, indicating a slight AT bias (54.3%). The start codon of all PCGs was ATG, with the exception of COX1 (GTG). The stop codons in the PCGs were mainly TAA, with the exception of ND1 and ND3 (TAG), ND4 (AGA) and Cytb (incomplete termination codon, T). All tRNAs had a typical cloverleaf shape, with the exception of tRNASer (AGY), which lacked the DHU arm. The sequenced mitogenome of S. owstoni can be used in genetics-based management initiatives or for constructing the mitochondrial lineages within Scorpaenidae. PMID- 25541317 TI - Whole mitochondrial genome sequencing and analysis for rat squamous cell carcinoma tissue cell. AB - Mitochondrial genome plays a central role in aging, cancer, apoptosis and metabolism. Squamous cell carcinoma is one of the major types of non-small cell lung cancer. We sequenced a complete mitochondrial genome sequence of a rat squamous cell carcinomas cell tissue for the first time. The total length of the mitochondrial genome was 16,319 bp, with 13 protein-coding genes, two ribosomal RNA genes and 22 transfer RNA genes. This genome describing information will supply the potential use of mtDNA mutations as markers in cancer. PMID- 25541318 TI - The complete mitochondrial genome of Cosmoscarata bispecularis (Hemiptera, Cicadomorpha, Cercopoidea, Cercopidae). AB - To characterize froghopper mitochondrial genome (mitogenome) features, in this study, the mitochondrial genome of Cosmoscarata bispecularis (Hemiptera, Cicadomorpha, Cercopoidea, Cercopidae) was sequenced and annotated. The complete genome is 15,426 bp in length. It contains 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes and a control region (A + T-rich region). All the PCGs initiate with the standard start codons ATN and all the tRNAs can be folded into typical cloverleaf secondary structures except tRNASer(GCT), which only formed a simple loop. The control region is consisted of 861 bp bases located between the srRNA gene and the tRNAlle-tRNAGln-tRNAMet(IQM) gene cluster. The measure of complete mitogenome sequence of C. bispecularis will provide fundamental data for the phylogenetic and biogeographic studies of the Cercopoidea and Hemiptera. PMID- 25541319 TI - Reliability of the measures of weight-bearing distribution obtained during quiet stance by digital scales in subjects with and without hemiparesis. AB - Described as an alternative way of assessing weight-bearing asymmetries, the measures obtained from digital scales have been used as an index to classify weight-bearing distribution. This study aimed to describe the intra-test and the test/retest reliability of measures in subjects with and without hemiparesis during quiet stance. The percentage of body weight borne by one limb was calculated for a sample of subjects with hemiparesis and for a control group that was matched by gender and age. A two-way analysis of variance was used to verify the intra-test reliability. This analysis was calculated using the differences between the averages of the measures obtained during single, double or triple trials. The intra-class correlation coefficient (ICC) was utilized and data plotted using the Bland-Altman method. The intra-test analysis showed significant differences, only observed in the hemiparesis group, between the measures obtained by single and triple trials. Excellent and moderate ICC values (0.69 0.84) between test and retest were observed in the hemiparesis group, while for control groups ICC values (0.41-0.74) were classified as moderate, progressing from almost poor for measures obtained by a single trial to almost excellent for those obtained by triple trials. In conclusion, good reliability ranging from moderate to excellent classifications was found for participants with and without hemiparesis. Moreover, an improvement of the repeatability was observed with fewer trials for participants with hemiparesis, and with more trials for participants without hemiparesis. PMID- 25541320 TI - Phosphorus removal and N2O production in anaerobic/anoxic denitrifying phosphorus removal process: long-term impact of influent phosphorus concentration. AB - This study was conducted to investigate the long-term impact of influent phosphorus concentration on denitrifying phosphorus removal and N2O production during denitrifying phosphorous removal process. The results showed that, denitrifying phosphate accumulating organisms (DPAOs) could become dominant populations quickly in anaerobic/anoxic SBR by providing optimum cultivating conditions, and the reactor performed well for denitrifying phosphorus removal. The influent phosphorus concentration significantly affected anaerobic poly-beta hydroxyalkanoates (PHA) synthesis, denitrifying phosphorus removal, and N2O production during the denitrifying phosphorus removal process. As the influent phosphorus concentration was more than 20 mg L(-1), the activity of DPAOs began to be inhibited due to the transformation of the available carbon source type. Meanwhile, N2O production was inhibited with the mitigation of anoxic NO2(-)-N accumulation. Adoption of a modified feeding could enhance denitrifying phosphorus removal and inhibit N2O production during denitrifying phosphorous removal processes. PMID- 25541321 TI - Effect of the accuracy of pH control on hydrogen fermentation. AB - pH, known as the most important parameter in H2 fermentation, cannot be precisely controlled in a scaled-up fermenter as in a lab fermenter. In the preset work, to assess the effect of pH control accuracy on H2 fermentation, the pH was controlled at 6.0+/-0.1, 6.0+/-0.3, 6.0+/-0.5, 6.0+/-0.7, and 6.0+/-0.9 during batch fermentation of food waste. Up to deviation of +/-0.3, a high H2 yield of 1.67-1.73 mol H2/mol hexose(added) was attained with producing butyrate as a major metabolite (>70% of total organic acids produced). A huge drop of H2 production, however, was observed at deviation >+/-0.5 with lowered substrate utilization and increased production of lactate. Next generation sequencing results showed that Clostridium was found to be the dominant genus (76.4% of total number of sequences) at deviation of +/-0.1, whereas the dominant genus was changed to lactic acid bacteria such as Streptococcus and Lactobacillus with increase of deviation value. PMID- 25541323 TI - Biventricular reverse remodeling after successful alcohol septal ablation for obstructive hypertrophic cardiomyopathy. AB - The aim of the present study was to investigate the long-term effects of alcohol septal ablation (ASA) on left ventricular (LV) and right ventricular (RV) remodeling in patients with obstructive hypertrophic cardiomyopathy (HC) using cardiovascular magnetic resonance (CMR). CMR was performed at baseline and 16 months after ASA in 38 patients with obstructive HC (mean age 48 +/- 9 years) despite optimal medical treatment. ASA resulted in significant reductions of LV outflow tract gradient (mean 89 +/- 22 vs 24 +/- 12 mm Hg, p <0.001) and improvements in New York Heart Association functional class (p <0.001) during the follow-up period. LV remote mass and septal mass decreased from 98.34 +/- 37.02 to 84.23 +/- 34.71 g and from 77.56 +/- 16.40 to 68.43 +/- 14.02 g, respectively (p <0.001 for both) at 16-month follow-up. There were significant reductions of RV mass (mean 53.69 +/- 7.12 vs 47.49 +/- 6.17 g, p <0.001) and improvements in RV end-diastolic volume (mean 110.58 +/- 22.47 vs 124.22 +/- 24.17 ml, p <0.001) and the RV ejection fraction (p <0.001) during 16-month follow-up. Linear regression analysis showed that LV outflow tract gradient reduction was correlated significantly with LV remote mass reduction (r = 0.475, p = 0.003) and RV mass reduction (r = 0.535, p = 0.001) at 16-month follow-up. In conclusion, successful ASA can lead to positive biventricular reverse remodeling, showing significant reductions of RV and LV mass as well as increased RV and LV end diastolic volumes during follow-up. PMID- 25541322 TI - A novel and robust conditioning lesion induced by ethidium bromide. AB - Molecular and cellular mechanisms underlying the peripheral conditioning lesion remain unsolved. We show here that injection of a chemical demyelinating agent, ethidium bromide, into the sciatic nerve induces a similar set of regeneration associated genes and promotes a 2.7-fold greater extent of sensory axon regeneration in the spinal cord than sciatic nerve crush. We found that more severe peripheral demyelination correlates with more severe functional and electrophysiological deficits, but more robust central regeneration. Ethidium bromide injection does not activate macrophages at the demyelinated sciatic nerve site, as observed after nerve crush, but briefly activates macrophages in the dorsal root ganglion. This study provides a new method for investigating the underlying mechanisms of the conditioning response and suggests that loss of the peripheral myelin may be a major signal to change the intrinsic growth state of adult sensory neurons and promote regeneration. PMID- 25541324 TI - Trends and predictors of smoking cessation after percutaneous coronary intervention (from Olmsted County, Minnesota, 1999 to 2010). AB - Smoke-free ordinance implementation and advances in smoking cessation (SC) treatment have occurred in the past decade; however, little is known about their impact on SC in patients with coronary artery disease. We conducted a retrospective cohort study of 2,306 consecutive patients from Olmsted County, Minnesota, who underwent their first percutaneous coronary intervention (PCI) from 1999 to 2009, and assessed the trends and predictors of SC after PCI. Smoking status was ascertained by structured telephone survey 6 and 12 months after PCI (ending in 2010). The prevalence of smoking in patients who underwent PCI increased nonsignificantly from 20% in 1999 to 2001 to 24% in 2007 to 2009 (p = 0.14), whereas SC at 6 months after PCI decreased nonsignificantly from 50% (1999 to 2001) to 49% (2007 to 2009), p = 0.82. The 12-month quit rate did not change significantly (48% in 1999 to 2001 vs 56% in 2007 to 2009, p = 0.38), even during the time periods after the enactment of smoke-free policies. The strongest predictor of SC at 6 months after PCI was participation in cardiac rehabilitation (odds ratio [OR] 3.17, 95% confidence interval [CI] 2.05 to 4.91, p <0.001), older age (OR 1.42 per decade, 95% CI 1.16 to 1.73, p <0.001), and concurrent myocardial infarction at the time of PCI (OR 1.77, 95% CI 1.18 to 2.65, p = 0.006). One-year mortality was lower in the group of smokers compared with never smokers (3% vs 7%, p <0.001). In conclusion, SC rates have not improved after PCI over the past decade in our cohort, despite the presence of smoke-free ordinances and improved treatment strategies. Improvements in delivery of systematic services aimed at promoting SC (such as cardiac rehabilitation) should be part of future efforts to improve SC rates after PCI. PMID- 25541325 TI - Efficacy and Safety of an Attenuated-Dose Sunitinib Regimen in Metastatic Renal Cell Carcinoma: Results From a Prospective Registry in Singapore. AB - BACKGROUND: The use of sunitinib at conventional doses (50 mg/d, 6-week cycles: 4 weeks of treatment, then 2 weeks of no treatment) in Asian patients with metastatic renal cell carcinoma (mRCC) is associated with high real-world toxicities. PATIENTS AND METHODS: Patients with mRCC treated with sunitinib between 2005 and 2012 at 4 centers representing a near-national cohort (n = 160) in Singapore were evaluated. One hundred twenty-seven consecutive patients in 1 center were treated with a novel attenuated-dose sunitinib regimen (37.5 mg/d, 6 week cycle: 4 weeks of treatment, then 2 weeks of no treatment) with outcomes captured in a prospective registry. Efficacy and safety outcomes of these patients were compared against those who received sunitinib at conventional dosing (n = 33) at all 4 centers. Statistical modeling was adjusted for baseline prognostic criteria and therapy line where possible. RESULTS: Overall survival from treatment initiation (OSinitiation), overall survival from the first documented metastasis (OStotal), and progression-free survival (PFS) were similar for patients who received first-line sunitinib for conventional relative to attenuated dose regimens (OSinitiation: 18.3 vs. 16.5 months, respectively; P = .54; OStotal: 27.4 vs. 21.8 months, respectively; P = .45; PFS: 6.7 vs. 7.9 months, respectively; P = .64), similar to real-world outcomes in Western studies. A marked lower rate of severe toxicities, dose delays, and reductions were observed with the attenuated dose regimen, with 75/127 (59%), rather than 28/33 (85%) for the conventional dose arm who experienced Grade >= 3 toxicities (P = .0088); 31/127 (24%) rather than 19/33 (58%) who experienced dose delays (P = .0004); and 44/127 (35%) rather than 23/33 (70%) who experienced dose reduction (P = .0005) during their course of treatment. CONCLUSION: An attenuated dose regimen of sunitinib yielded comparable real-world efficacy outcomes, with considerable reduction in toxicities as documented in a prospective registry. PMID- 25541326 TI - Autonomic dysfunction in acute ischemic stroke: an underexplored therapeutic area? AB - Impaired autonomic function, characterized by a predominance of sympathetic activity, is common in patients with acute ischemic stroke. This review describes methods to measure autonomic dysfunction in stroke patients. It summarizes a potential relationship between ischemic stroke-associated autonomic dysfunction and factors that have been associated with worse outcome, including cardiac complications, blood pressure variability changes, hyperglycemia, immune depression, sleep disordered breathing, thrombotic effects, and malignant edema. Involvement of the insular cortex has been suspected to play an important role in causing sympathovagal imbalance, but its exact role and that of other brain regions remain unclear. Although sympathetic overactivity in patients with ischemic stroke appears to be a negative prognostic factor, it remains to be seen whether therapeutic strategies that reduce sympathetic activity or increase parasympathetic activity might improve outcome. PMID- 25541327 TI - Bacteriology of urinary tract infections in emergency patients aged 0-36 months. AB - BACKGROUND: Because urinary tract infection (UTI) is the most frequent source of serious bacterial infections in young children, we studied the bacteriology of such infections in our institution. OBJECTIVES: Pediatric urine cultures were reviewed for age- and sex-specific differences in testing, prevalence, causative organisms, and antibiotic sensitivities. METHODS: A retrospective 5-year observational study of all urine cultures from Emergency Department patients aged 0-36 months found 4403 cultures. Primary outcomes were numbers of cultures obtained, infections found, the organisms isolated, and their antibiotic sensitivities. RESULTS: Boys were cultured much less frequently (overall 4.7% vs. 19.4% of girls, p < 0.001). Three hundred ninety-six cultures yielded infection episodes. Although far fewer boys were cultured, their overall positive culture rate (10.9%) was significantly higher than for girls (8.4%; p = 0.01), with more Gram-positive organisms (52.3%; vs. 18.6% Gram-positives in girls; p < 0.001). The rate of positive cultures in boys and girls remained 8.4% and 10.3%, respectively, even in 2-year-olds. Trimethoprim-sulfamethoxazole and amoxicillin/clavulanic acid were effective against all isolates. CONCLUSIONS: Age and sex-based assumptions guiding evaluation for and treatment of UTIs in young children should be reevaluated. We may not be culturing enough young boys, risking missed UTIs with potential for renal injury in this vulnerable group. Based on their significant rate of Gram-positive infections, those boys we treat empirically might benefit more from trimethoprim/sulfamethoxazole or amoxicillin/clavulanic acid than from third-generation cephalosporins. The persistence of positive cultures in 2-year-olds suggests we should be culturing beyond 24 months in both sexes. Urine Gram stains should be more frequently considered. PMID- 25541328 TI - Molecular insight into heart development and congenital heart disease: An update review from the Arab countries. AB - Congenital heart defect (CHD) has a major influence on affected individuals as well as on the supportive and associated environment such as the immediate family. Unfortunately, CHD is common worldwide with an incidence of approximately 1% and consequently is a major health concern. The Arab population has a high rate of consanguinity, fertility, birth, and annual population growth, in addition to a high incidence of diabetes mellitus and obesity. All these factors may lead to a higher incidence and prevalence of CHD within the Arab population than in the rest of the world, making CHD of even greater concern. Sadly, most Arab countries lack appropriate public health measures directed toward the control and prevention of congenital malformations and so the importance of CHD within the population remains unknown but is thought to be high. In approximately 85% of CHD patients, the multifactorial theory is considered as the pathologic basis. The genetic risk factors for CHD can be attributed to large chromosomal aberrations, copy number variations (CNV) of particular regions in the chromosome, and gene mutations in specific nuclear transcription pathways and in the genes that are involved in cardiac structure and development. The application of modern molecular biology techniques such as high-throughput nucleotide sequencing and chromosomal array and methylation array all have the potential to reveal more genetic defects linked to CHD. Exploring the genetic defects in CHD pathology will improve our knowledge and understanding about the diverse pathways involved and also about the progression of this disease. Ultimately, this will link to more efficient genetic diagnosis and development of novel preventive therapeutic strategies, as well as gene-targeted clinical management. This review summarizes our current understanding of the molecular basis of normal heart development and the pathophysiology of a wide range of CHD. The risk factors that might account for the high prevalence of CHD within the Arab population and the measures required to be undertaken for conducting research into CHD in Arab countries will also be discussed. PMID- 25541329 TI - Quantitative T-wave alternans analysis for guiding medical therapy: an underexploited opportunity. AB - Reducing the toll of sudden cardiac death (SCD) remains a major challenge in cardiology, as it is the leading cause of adult mortality in the industrially developed world, claiming 310,000 lives annually in the United States alone. The main contemporary noninvasive index of cardiovascular risk, left ventricular ejection fraction (LVEF), has not proved adequately reliable, as the majority of individuals who die suddenly have relatively preserved cardiac mechanical function. Monitoring of T-wave alternans (TWA), a beat-to-beat fluctuation in ST segment or T-wave morphology, is an attractive approach to risk stratification on both scientific and clinical grounds, as this ECG phenomenon has been shown using the FDA-cleared Spectral and Modified Moving Average methods to assess risk for cardiovascular mortality including SCD in studies enrolling >12,000 individuals with depressed or preserved LVEF. The evidence supporting TWA as a therapeutic target is reviewed. PMID- 25541330 TI - Matricellular protein periostin contributes to hepatic inflammation and fibrosis. AB - Periostin actively contributes to tissue injury, fibrosis, atherosclerosis, and inflammatory diseases; however, its role in hepatic fibrosis is unclear. Herein, we revealed that periostin expression was significantly up-regulated in carbon tetrachloride- and bile duct ligation-induced mice with acute and chronic liver fibrosis. Deficiency in periostin abrogated the development of liver fibrosis in mice. Carbon tetrachloride treatment significantly increased alpha-smooth muscle actin, fibronectin, and collagen I levels in wild-type mice, which were unaffected in periostin-knockout mice. Periostin-deficient mice showed a significantly reduced area of collagen deposition and decreased levels of serum alanine aminotransferase and aspartate aminotransferase compared with wild-type mice after 2 weeks of carbon tetrachloride administration. Chemokine ligand 2, IL 6, IL-1beta, tumor necrosis factor-alpha, and tissue inhibitor of metalloproteinases 1 mRNA levels were significantly lower in periostin-deficient mice than in wild-type mice after carbon tetrachloride treatment. Periostin colocalized with hepatic stellate cell-derived collagen I and alpha-smooth muscle actin in mouse acute and chronic fibrotic liver tissues. Transforming growth factor (TGF)-beta1 markedly induced periostin expression in primary mouse hepatic stellate cells. Periostin-deficient mice showed significantly lower levels of TGF beta1 and TGF-beta2 compared with wild-type mice after carbon tetrachloride treatment. High levels of periostin in patients with acute or chronic hepatitis correlated with TGF-beta1 and TGF-beta2 expression in serum from patients with hepatitis. Data indicate that periostin is a novel mediator of hepatic fibrosis development. PMID- 25541331 TI - Dysregulation of the epigenome in human breast cancer: contributions of gene specific DNA hypermethylation to breast cancer pathobiology and targeting the breast cancer methylome for improved therapy. AB - Triple-negative breast cancers (including basal-like and claudin-low molecular subtypes) represent 20% to 25% of all breast cancers, but disproportionately contribute to breast cancer-associated death. We have identified a novel fundamental biological property of triple-negative breast cancers: most triple negative breast cancers express aberrant DNA hypermethylation due to overexpression of DNA methyltransferase 3b (and hyperactivity of the DNA methyltransferase enzymes). DNA methyltransferase 3b overexpression occurs secondary to loss of miRNA-mediated post-transcriptional regulation. The resulting hyperactivity of DNA methyltransferase 3b produces concurrent DNA methylation-dependent silencing of numerous critical gene targets (including tumor suppressors and pro-apoptotic genes) and resistance to cytotoxic chemotherapy. This observation presents new opportunities for development of innovative treatment strategies on the basis of the epigenome as a novel therapeutic target in triple-negative breast cancers. Epigenetic therapy represents a new principle in cancer treatment in which restoration of critical molecular pathways occurs secondary to reexpression of silenced genes that encode negative mediators of cancer cell growth. PMID- 25541332 TI - Data compression in wireless sensors network using MDCT and embedded harmonic coding. AB - One of the major applications of wireless sensors networks (WSNs) is vibration measurement for the purpose of structural health monitoring and machinery fault diagnosis. WSNs have many advantages over the wired networks such as low cost and reduced setup time. However, the useful bandwidth is limited, as compared to wired networks, resulting in relatively low sampling. One solution to this problem is data compression which, in addition to enhancing sampling rate, saves valuable power of the wireless nodes. In this work, a data compression scheme, based on Modified Discrete Cosine Transform (MDCT) followed by Embedded Harmonic Components Coding (EHCC) is proposed to compress vibration signals. The EHCC is applied to exploit harmonic redundancy present is most vibration signals resulting in improved compression ratio. This scheme is made suitable for the tiny hardware of wireless nodes and it is proved to be fast and effective. The efficiency of the proposed scheme is investigated by conducting several experimental tests. PMID- 25541334 TI - Evaluating the usefulness of patient education materials on surgical site infection: a systematic assessment. AB - Patient education is important for the prevention of surgical site infections (SSIs). The usefulness of available patient education materials is unclear. Using a validated evaluation tool, the Patient Education Materials Assessment Tool, we systematically assessed patient education materials for SSI. We found that available materials performed poorly, and further research is needed in this area. PMID- 25541335 TI - Vaccination coverage among students from a German health care college. AB - Health care students are at risk of acquiring and transmitting vaccine preventable diseases. The purpose of this study was to assess their vaccination status and the influence of determining factors on their vaccination status. Unsatisfactory vaccination rates (43.8%-94.1%) and significant effects regarding age, sex, and socioeconomic status were found; therefore, there is an increased need for education and motivation for vaccinations in student training. PMID- 25541333 TI - Maintenance of improvement in spinal mobility, physical function and quality of life in patients with ankylosing spondylitis after 5 years in a clinical trial of adalimumab. AB - OBJECTIVE: Chronic pain and progressive loss of physical function with AS may adversely affect health-related quality of life (HRQoL). The objective of this study was to assess the 5-year data regarding spinal mobility, physical function and HRQoL in patients with AS who participated in the Adalimumab Trial Evaluating Long-term Efficacy and Safety for AS (ATLAS) study. METHODS: Patients received blinded adalimumab 40 mg or placebo every other week for 24 weeks, then open label adalimumab for up to 5 years. Spinal mobility was evaluated using linear BASMI (BASMIlin). BASDAI, total back pain, CRP, BASFI, Short Form-36 and AS quality of life (ASQoL) were also assessed. Correlations between BASMIlin and clinical, functional and ASQoL outcomes after 12 weeks and after 5years of adalimumab exposure were evaluated using Spearman's rank correlation. Associations were further analysed using multivariate regression. RESULTS: Three hundred and eleven patients received >=1 dose of adalimumab; 125 of the 208 patients originally randomized to adalimumab received treatment for 5 years. Improvements in BASMIlin were sustained through 5 years, with a mean change of 0.6 from baseline in the population who completed 5 years of treatment with adalimumab. Improvements in disease activity, physical function and ASQoL were also sustained through 5 years. BASMIlin was significantly correlated with all evaluated clinical outcomes (P < 0.001). The highest correlation was with BASFI at 12 weeks (r = 0.52) and at 5 years (r = 0.65). Multivariate regression analysis confirmed this association (P < 0.001). CONCLUSION: Treatment with adalimumab for up to 5 years demonstrated sustained benefits in spinal mobility, disease activity, physical function and HRQoL in patients with active AS. Spinal mobility was significantly associated with short- and long-term physical function in these patients. TRIAL REGISTRATION: Clinicaltrials.gov; https://clinicaltrials.gov/NCT00085644. PMID- 25541336 TI - Varicella seroprevalence among health care workers. PMID- 25541337 TI - Molecular epidemiology of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae in different facilities in Southern Brazil. AB - BACKGROUND: Klebsiella pneumoniae carbapenemase-producing K pneumoniae (KPC-KP) outbreaks have been reported in many countries, including Brazil. The incidence of KPC-KP infection has increased in the first semester of 2011 in Curitiba, the capital of Parana, in Southern Brazil.The aim of this study was to characterize the infections and clonal diversity of KPC-KP isolates from several institutions in Curitiba. METHODS: KPC-KP from several clinical samples and rectal swabs taken between April 2010 and July 2012 were included. One isolate per patient was evaluated. All isolates were submitted to polymerase chain reaction (PCR) for blaKPC. The genetic relatedness was evaluated using strain clustering by an automated repetitive extragenic palindromic (rep) PCR-based typing system. RESULTS: There were 641 samples that were positive for K pneumoniae carbapenemase 2 carbapenemase. There were 129 samples randomly selected for clonality evaluation. PCR and strain clustering by the automated rep PCR-based typing system identified 7 clones (A-C and E-H). Clone E was identified in only 1 hospital, and all other clones were found in >2 hospitals. Clones C and G were the most disseminated among hospitals. The infection and colonization occurred in 14 out of the 32 main hospitals in town. Similar clones were found in 2 hospitals that are administered by the same group. Another clone (H) was found in 2 hospitals receiving patients from the same municipal emergency unit. CONCLUSION: The KPC-KP outbreak in Curitiba is polyclonal, and the source is unknown. Some hospitals share the same clones. PMID- 25541338 TI - Bleeding reduction after topical application of tranexamic acid together with Betadine solution in total knee arthroplasty. A randomised controlled study. AB - INTRODUCTION: Topical application of tranexamic acid to the knee joint before closure in total knee arthroplasty reduces postoperative bleeding without increase in complication. However, it is unknown the effectiveness of topic TXA performed with other topical medications, like povidone-iodine solution. MATERIALS AND METHODS: One hundred and twenty-five patients were randomized to receive 100mL of povidone-iodine solution (control: group A) or 1.5 (group B) and 3.0 g (group C) of topical TXA in povidone-iodine solution applied into the knee before closure in total knee arthroplasty. RESULTS: The patients in the TXA groups had higher mean postoperative hemoglobin levels (P=0.01 and P=0.03 in groups B and C, respectively) and a reduced postoperative blood loss in the TXA groups (P=0.07 and P=0.09 in groups B and C, respectively). No significant complications were observed. DISCUSSION: In this study, topical application of tranexamic acid after total knee arthroplasty together with povidone-iodine solution results in higher postoperative hemoglobin levels and lower blood loss compared with those in the control group without other complications. LEVEL OF EVIDENCE: I - I: high-powered prospective randomized trial. PMID- 25541339 TI - Rate of dislodgment of ureteral stents when using an extraction string after endoscopic urological surgery. AB - PURPOSE: Ureteral stents are manufactured with an extraction string tethered to the distal end, which facilitates removal after urological surgery. However, the string may allow for stent dislodgment. We report the stent dislodgment rate in a multi-institutional series. MATERIALS AND METHODS: We retrospectively reviewed the records of ureteroscopy cases at 3 academic endourology practices. Demographic and operative data were obtained as well as string use and stent dislodgment data. Categorical variables were assessed with the Fisher exact test and the Student t-test was used to assess continuous variables. RESULTS: Of the 512 cases a string was used in 98 (19.1%) comprising 41 females (41.8%) and 57 males (58.2%). The stent was dislodged in 10 women and 3 men. No dislodgment occurred when a string was not used. When stratified by gender, 5.3% of men and 24.4% of women with a string experienced stent dislodgment (p = 0.013). Women were more than fourfold more likely to experience stent dislodgment than men (RR 4.6, 95% CI 1.36-15.8, p = 0.01). CONCLUSIONS: Almost 15% of patients in whom a stent is placed with a string sustain stent dislodgment and most of these patients will be women. We recommend considering the risks of dislodgment in each patient who undergoes ureteroscopy with stent placement and considering string removal if the surgeon believes that dislodgment could result in adverse events such as severe colic or obstruction. PMID- 25541341 TI - Glucoamylases from Penicillium verruculosum and Myceliophthora thermophila: analysis of differences in activity against polymeric substrates based on 3D model structures of the intact enzymes. AB - Two glucoamylases, a recombinant enzyme from Penicillium verruculosum (PvGla) heterologously expressed in Penicillium canescens RN3-11-7 (niaD-) strain and a native glucoamylase from Myceliophthora thermophila (MtGla), were purified and their properties were studied. MtGla displayed 2-5-fold higher specific activities against soluble starch, amylose and amylopectin than PvGla. MtGla also provided higher glucose yields in extended hydrolysis of the polymeric substrates. Analysis of 3D model structures of the intact PvGla and MtGla, which were built using the 2vn7.pdb crystal structure of the intact Trichoderma reesei glucoamylase (TrGla) as a template, showed that the reason for lower hydrolytic performance of PvGla in comparison to MtGla may be less strong interactions between the enzyme domains as well as a longer (by 17 residues) linker in the first enzyme. PMID- 25541340 TI - The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy. AB - PURPOSE: Androgen deprivation therapy may promote the development of the metabolic syndrome in patients with prostate cancer. We assessed the prevalence of the full metabolic syndrome and its components during the first year of androgen deprivation therapy. MATERIALS AND METHODS: This observational, multicenter, prospective study included 539 patients with prostate cancer scheduled to receive 3-month depot luteinizing hormone-releasing hormone analogs for more than 12 months. Waist circumference, body mass index, lipid profile, blood pressure and fasting glucose were evaluated at baseline and after 6 and 12 months. The metabolic syndrome was assessed according to NCEP ATP III criteria (2001) and 4 other definitions (WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005). RESULTS: At 6 and 12 months after the initiation of androgen deprivation therapy, significant increases were observed in waist circumference, body mass index, fasting glucose, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterol. No significant changes in blood pressure 130/85 or greater were detected. A nonsignificant increase of 3.9% in the prevalence of the full metabolic syndrome (ATP III) was observed (22.9% at baseline vs 25.5% and 26.8% at 6 and 12 months, respectively). The prevalence of the metabolic syndrome at baseline varied according to the definition used, ranging from 9.4% (WHO) to 50% (IDF). At 12 months significant increases in prevalence were observed with the WHO (4.1%) and AHA/NHLBI (8.1%) definitions. CONCLUSIONS: Androgen deprivation therapy produces significant early effects on waist circumference, body mass index, fasting glucose, triglycerides and cholesterol. The prevalence of and increase in the metabolic syndrome depend on the defining criteria. Counseling patients on the prevention, early detection and treatment of specific metabolic alterations is recommended. PMID- 25541342 TI - Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats. AB - The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day*7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity. Three days after the insult, a marked reduction of [(18)F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of GABAA receptor expression in hippocampus. PMID- 25541343 TI - Reliability testing of two classification systems for osteoarthritis and post traumatic arthritis of the elbow. AB - HYPOTHESIS AND BACKGROUND: The severity of elbow arthritis is one of many factors that surgeons must evaluate when considering treatment options for a given patient. Elbow surgeons have historically used the Broberg and Morrey (BM) and Hastings and Rettig (HR) classification systems to radiographically stage the severity of post-traumatic arthritis (PTA) and primary osteoarthritis (OA). We proposed to compare the intraobserver and interobserver reliability between systems for patients with either PTA or OA. METHODS: The radiographs of 45 patients were evaluated at least 2 weeks apart by 6 evaluators of different levels of training. Intraobserver and interobserver reliability were calculated by Spearman correlation coefficients with 95% confidence intervals. Agreement was considered almost perfect for coefficients >0.80 and substantial for coefficients of 0.61 to 0.80. RESULTS: In patients with both PTA and OA, intraobserver reliability and interobserver reliability were substantial, with no difference between classification systems. There were no significant differences in intraobserver or interobserver reliability between attending physicians and trainees for either classification system (all P > .10). The presence of fracture implants did not affect reliability in the BM system but did substantially worsen reliability in the HR system (intraobserver P = .04 and interobserver P = .001). CONCLUSIONS: The BM and HR classifications both showed substantial intraobserver and interobserver reliability for PTA and OA. Training level differences did not affect reliability for either system. Both trainees and fellowship-trained surgeons may easily and reliably apply each classification system to the evaluation of primary elbow OA and PTA, although the HR system was less reliable in the presence of fracture implants. PMID- 25541344 TI - Development of a catheter functionalized by a polydopamine peptide coating with antimicrobial and antibiofilm properties. AB - Catheter-associated urinary tract infections (CAUTIs) are the most common hospital-acquired infections worldwide, aggravating the problem of antimicrobial resistance and patient morbidity. There is a need for a potent and robust antimicrobial coating for catheters to prevent these infections. An ideal coating agent should possess high antimicrobial efficacy and be easily and economically conjugated to the catheter surface. In this study, we report a simple yet effective immobilization strategy to tether a potent synthetic antimicrobial peptide, CWR11, onto catheter-relevant surfaces. Polydopamine (PD) was deposited as a thin adherent film onto a polydimethylsiloxane (PDMS) surface to facilitate attachment of CWR11 onto the PD-functionalized polymer. Surface characterization of the CWR11-tethered surfaces confirmed the successful immobilization of peptides onto the PD-coated PDMS. The CWR11-immobilized PDMS slides displayed excellent antimicrobial (significant inhibition of 5*10(4) colony-forming units of CAUTI-relevant microbes) and antibiofilm (~92% enhanced antibacterial adherence) properties. To assess its clinical relevance, the PD-based immobilization platform was translated onto commercial silicone-coated Foley catheters. The CWR11-impregnated catheter displayed potent bactericidal properties against both Gram-positive and Gram-negative bacteria, and retained its antimicrobial functionality for at least 21days, showing negligible cytotoxicity against human erythrocyte and uroepithelial cells. The outcome of this study demonstrates the proof-of-concept potential of a polydopamine-CWR11 functionalized catheter to combat CAUTIs. PMID- 25541345 TI - Cooperative control of blood compatibility and re-endothelialization by immobilized heparin and substrate topography. AB - A wide variety of environmental cues provided by the extracellular matrix, including biophysical and biochemical cues, are responsible for vascular cell behavior and function. In particular, substrate topography and surface chemistry have been shown to regulate blood and vascular compatibility individually. The combined impact of chemical and topographic cues on blood and vascular compatibility, and the interplay between these two types of cues, are subjects that are currently being explored. In the present study, a facile polydopamine mediated approach is introduced for immobilization of heparin on topographically patterned substrates, and the combined effects of these cues on blood compatibility and re-endothelialization are systematically investigated. The results show that immobilized heparin and substrate topography cooperatively modulate anti-coagulation activity, endothelial cell (EC) attachment, proliferation, focal adhesion formation and endothelial marker expression. Meanwhile, the substrate topography is the primary determinant of cell alignment and elongation, driving in vivo-like endothelial organization. Importantly, combining immobilized heparin with substrate topography empowers substantially greater competitive ability of ECs over smooth muscle cells than each cue individually. Moreover, a model is proposed to elucidate the cooperative interplay between immobilized heparin and substrate topography in regulating cell behavior. PMID- 25541346 TI - Reasons for cannabis use in first-episode psychosis: does strength of endorsement change over 12 months? AB - BACKGROUND: Why patients with psychosis use cannabis remains debated. The self medication hypothesis has received some support but other evidence points towards an alleviation of dysphoria model. This study investigated the reasons for cannabis use in first-episode psychosis (FEP) and whether strength in their endorsement changed over time. METHODS: FEP inpatients and outpatients at the South London and Maudsley, Oxleas and Sussex NHS Trusts UK, who used cannabis, rated their motives at baseline (n=69), 3 months (n=29) and 12 months (n=36). A random intercept model was used to test the change in strength of endorsement over the 12 months. Paired-sample t-tests assessed the differences in mean scores between the five subscales on the Reasons for Use Scale (enhancement, social motive, coping with unpleasant affect, conformity and acceptance and relief of positive symptoms and side effects), at each time-point. RESULTS: Time had a significant effect on scores when controlling for reason; average scores on each subscale were higher at baseline than at 3 months and 12 months. At each time point, patients endorsed 'enhancement' followed by 'coping with unpleasant affect' and 'social motive' more highly for their cannabis use than any other reason. 'Conformity and acceptance' followed closely. 'Relief of positive symptoms and side effects' was the least endorsed motive. CONCLUSIONS: Patients endorsed their reasons for use at 3 months and 12 months less strongly than at baseline. Little support for the self-medication or alleviation of dysphoria models was found. Rather, patients rated 'enhancement' most highly for their cannabis use. PMID- 25541347 TI - What are depressive symptoms in acutely ill patients with schizophrenia spectrum disorder? AB - BACKGROUND: Aim was to examine depressive symptoms in acutely ill schizophrenia patients on a single symptom basis and to evaluate their relationship with positive, negative and general psychopathological symptoms. METHODS: Two hundred and seventy-eight patients suffering from a schizophrenia spectrum disorder were analysed within a naturalistic study by the German Research Network on Schizophrenia. Using the Calgary Depression Scale for Schizophrenia (CDSS) depressive symptoms were examined and the Positive and Negative Syndrome Scale (PANSS) was applied to assess positive, negative and general symptoms. Correlation and factor analyses were calculated to detect the underlying structure and relationship of the patient's symptoms. RESULTS: The most prevalent depressive symptoms identified were depressed mood (80%), observed depression (62%) and hopelessness (54%). Thirty-nine percent of the patients suffered from depressive symptoms when applying the recommended cut-off of a CDSS total score of >6 points at admission. Negligible correlations were found between depressive and positive symptoms as well as most PANSS negative and global symptoms despite items on depression, guilt and social withdrawal. The factor analysis revealed that the factor loading with the PANSS negative items accounted for most of the data variance followed by a factor with positive symptoms and three depression associated factors. LIMITATIONS: The naturalistic study design does not allow a sufficient control of study results for the effect of different pharmacological treatments possibly influencing the appearance of depressive symptoms. CONCLUSION: Results suggest that depressive symptoms measured with the CDSS are a discrete symptom domain with only partial overlap with positive or negative symptoms. PMID- 25541348 TI - Updates on the sporulation process in Clostridium species. AB - Sporulation is an important strategy for certain bacterial species within the phylum Firmicutes to survive longer periods of time in adverse conditions. All spore-forming bacteria have two phases in their life; the vegetative form, where they can maintain all metabolic activities and replicate to increase numbers, and the spore form, where no metabolic activities exist. Although many essential components of sporulation are conserved among the spore-forming bacteria, there are differences in the regulation and the pathways among different genera, even at the species level. While we have gained much information from the most studied spore-forming bacterial genus, Bacillus, we still lack an in-depth understanding of spore formation in the genus Clostridium. Clostridium and Bacillus share the master regulator of sporulation, Spo0A, and its downstream pathways, but there are differences in the activation of the Spo0A pathway. While Bacillus species use a multi-component phosphorylation pathway for phosphorylation of Spo0A, termed phosphorelay, such a phosphorelay system is absent in Clostridium. On the other hand, a number of genes regulated by the different sporulation-specific transcription factors are conserved between different Clostridium and Bacillus species. In this review, we discuss the recent findings on Clostridium sporulation and compare the sporulation mechanism in Clostridium and Bacillus. PMID- 25541349 TI - Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors. AB - A trial-level meta-analysis was conducted to determine the relative risk (RR) of pancreatitis associated with multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Eligible studies included randomized phase 2 and 3 trials comparing arms with and without an FDA-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib). Statistical analyses calculated the RR and 95% confidence intervals (CI). A total of 10,578 patients from 16 phase III trials and 6 phase II trials were selected. The RR for all grade and high-grade pancreatitis for the TKI vs. no TKI- arms was 1.95 (p=0.042, 95% CI: 1.02 to 3.70) and 1.89 (p=0.069, 95% CI: 0.95 to 373), respectively. No differential impact of malignancy type or specific TKI agent was seen on RR of all grade of high grade pancreatitis. Better patient selection and monitoring may mitigate the risk of severe pancreatitis. PMID- 25541350 TI - A systematic review and meta-analysis of clinical trials of bladder-sparing trimodality treatment for muscle-invasive bladder cancer (MIBC). AB - PURPOSE: Despite the numerous prospective and retrospective studies published during the last 2 decades aiming at testing the safety and the efficacy of trimodality therapy (TMT) as a conservative treatment, an optimal therapeutic strategy has not yet been identified. We made a systematic overview of the 5-year outcomes from 31 trials of combined chemotherapy and radiation (CRT) after transurethral resection of muscle-infiltrating bladder tumours (TURBT), the so called trimodality therapy. We took into consideration the results of each trial i.e. the rate of complete response (CR), local muscle-invasive local failure (LF), salvage cystectomy (SC), 5-year overall survival (OS) and 5-year bladder intact survival (BIS) from 3315 patients. RESULTS: About half of the patients were treated with a preliminary induction followed by a consolidation CRT course in CR, or SC in non-CR patients (split treatment). The remaining half of the patients underwent an upfront full-dose CRT course (continuous treatment) with SC reserved to non-CR patients. Excellent results were obtained by trimodality therapy (TMT), with 78% CR, 28% muscle infiltrating LF and 21% SC in patients with MIBC. The 5-year OS and BIS rates were 56% and 42%, respectively. At univariate analysis, CR, and SC rates appeared to be significantly better in the continuous than in the split treatment group. Multivariate analysis confirmed the former regimen as a significant prognostic variables only for CR, while CP-based regimen was a significant prognostic factor for SC. The subgroup analysis revealed a significant improvement in 5-year OS rate of continuous over split treatment in later stage tumours. No relevant benefit was observed with the addition of other drugs to cisplatin (CP) or neo-adjuvant chemotherapy (NATC) to CRT, although, in patients receiving NACT, significantly better CR and OS rates were seen in the continuous than split treatment. CONCLUSIONS: The results of this overview seem to indicate that TMT is able to produce excellent 5-year OS rates, no matter how it is done (continuous or split). No significant difference in 5-year OS rates could be observed between the two treatment regimens, although the continuous may offer some advantage compared to split treatment in terms of higher CR and, likely lower SC rates. The highest benefit might be achieved in later stage tumours, using a total radiation equivalent dose when delivered in 2Gy/fraction (EQD2) of more than 60Gy in combination with CP based regimes and preceded by 2-3 NACT cycles. Appropriate randomized trials should be addressed to confirm the results of the present review. PMID- 25541351 TI - Hippocampal DHCR24 down regulation in a rat model of streptozotocin-induced cognitive decline. AB - The DHCR24 (24-dehydrocholesterol reductase) gene codes a multifunctional protein which consists of enzymatic, antioxidant, and anti-apoptotic activities. It exists in almost all neurons and protects the neural cells against amyloid beta toxicity. Several studies have shown the down regulation of DHCR24 in Alzheimer's disease. We examined the time profile of DHCR24-mRNA alteration in an animal model of streptozotocin (STZ)-induced cognitive impairment. The DHCR24 mRNA levels of hippocampus and cognitive impairment were evaluated at 7, 14, and 21 days after intracerebroventricular (ICV)-STZ/Saline administration. DHCR24 expression was down regulated at 14 and 21 days after ICV-STZ administration. The decrease in expression of DHCR24 preceded the onset of the cognitive impairment. These results suggest the potential relation between DHCR24 expression and cognitive impairment. PMID- 25541352 TI - [Risk of rectal perforation during intention to treat laser photovaporization of prostate with transrectal ultrasound guidance: a report of 4 cases]. AB - CONTEXT: Transrectal ultrasound guidance (TUG) during prostate endoscopic surgery can optimize the procedure by reducing the risk of capsular perforation and ascertain the treatment completeness. TUG is proposed during photoselective vaporisation of prostate (PVP). OBJECTIVE: To report four cases of rectal perforations during PVP with TUG and assess their occurrence. MATERIALS AND METHODS: This is a retrospective study including prostate endoscopic surgeries with TUG, performed in two centers between November 2011 and May 2013. Rectal perforations were identified. Surgical data, treatment modalities and postoperative outcomes of rectal perforations were analysed. RESULTS: Four rectal perforations were identified among 450 surgical procedures. Median age and prostate volume were 80 years old [62-91] and 40mL [13-150], respectively. Two perforations occurred during PVP with Greenlight((r)) XPS 180W. Two perforations occurred during transurethral resection of prostate or cervicoprostatic incision. Patients were treated by systematic urinary drainage associated with colostomy or direct suture. Two patients died from this complication and two patients have satisfying functional outcomes at one year. CONCLUSION: TUG during prostate endoscopic surgery could lead to rectal perforation by protusion of the prostate and therefore should be used cautiously. LEVEL OF EVIDENCE: 5. PMID- 25541353 TI - Hysteroscopic resection in the management of early-stage endometrial cancer: report of 2 cases and review of the literature. PMID- 25541354 TI - Size estimates remain stable in the face of differences in performance outcome variability in an aiming task. AB - In perceptual-motor tasks such as dart throwing, those who hit the target more successfully report the target to be bigger than those who hit less successfully. While initial evidence seemed to support the recent contention that the variability in performance (rather than the amount of successful hits) may scale reported target size, here we provide counterevidence for this hypothesis. We systematically manipulated performance outcomes in a shuffling task by means of magnetic fields. Participants were asked to slide a disk on a wooden board towards a circular target. Using a within-subjects design, in two conditions throw outcomes were manipulated to produce either high or low variability in performance outcome, while the mean success of performance (i.e., the mean error) remained constant across conditions. Despite the successful manipulations of high and low variability in the performance outcomes, results revealed that size estimates of the target remained stable. PMID- 25541355 TI - Independent measurement of femoral cortical thickness and cortical bone density using clinical CT. AB - The local structure of the proximal femoral cortex is of interest since both fracture risk, and the effects of various interventions aimed at reducing that risk, are associated with cortical properties focused in particular regions rather than dispersed over the whole bone. Much of the femoral cortex is less than 3mm thick, appearing so blurred in clinical CT that its actual density is not apparent in the data, and neither thresholding nor full-width half-maximum techniques are capable of determining its width. Our previous work on cortical bone mapping showed how to produce more accurate estimates of cortical thickness by assuming a fixed value of the cortical density for each hip. However, although cortical density varies much less over the proximal femur than thickness, what little variation there is leads to errors in thickness measurement. In this paper, we develop the cortical bone mapping technique by exploiting local estimates of imaging blur to correct the global density estimate, thus providing a local density estimate as well as more accurate estimates of thickness. We also consider measurement of cortical mass surface density and the density of trabecular bone immediately adjacent to the cortex. Performance is assessed with ex vivo clinical QCT scans of proximal femurs, with true values derived from high resolution HRpQCT scans of the same bones. We demonstrate superior estimation of thickness than is possible with alternative techniques (accuracy 0.12 +/- 0.39 mm for cortices in the range 1-3mm), and that local cortical density estimation is feasible for densities >800 mg/cm(3). PMID- 25541356 TI - Groove binding interaction between daphnetin and calf thymus DNA. AB - The binding characteristics of daphnetin with calf thymus DNA (ctDNA) were investigated by multispectroscopic and chemometric approaches coupled with DNA viscosity measurements, melting studies and molecular docking technique. The expanded UV-vis spectral data matrix was processed by multivariate curve resolution-alternating least-squares method to obtain the concentration profiles of the components (daphnetin, ctDNA and daphnetin-ctDNA complex) to quantitatively monitor the daphnetin-ctDNA interaction. The groove mode of daphnetin binding to ctDNA was concluded by little change in melting temperature, viscosity of ctDNA and iodide quenching effect as well as increase in single stranded DNA quenching effect. Moreover, the quantitative data for the competitive binding between daphnetin and Hoechst 33258 for ctDNA obtained by resolving the three-way synchronous fluorescence spectra data using parallel factor analysis modeling further supported the groove binding. The molecular docking visualized the results of the Fourier transform infrared analysis that the adenine and thymine bases in the minor groove of ctDNA were the main binding sites for daphnetin, and the circular dichroism spectra showed that the groove binding of daphnetin to ctDNA led to the conformational change in ctDNA from B form to A-form. This study revealed the interaction mechanism of daphnetin with ctDNA. PMID- 25541357 TI - Thioredoxin h isoforms from rice are differentially reduced by NADPH/thioredoxin or GSH/glutaredoxin systems. AB - Rice (Oryza sativa L.) has multiple potential genes encoding thioredoxin (Trx) h and NADP-thioredoxin reductase (NTR). These NTR and Trx h isoforms, known as cytoplasmic NTR/Trx system along with multiple members of glutaredoxin (Grx) family constitute a complex redox control system in rice. In the present study, we investigated the kinetic parameters of two rice NTRs, OsNTRA and OsNTRB, toward three endogenous Trx h isoforms, OsTrx1, OsTrx20, and OsTrx23. The results showed that in contrast with OsTrx1 and OsTrx23, the isoform OsTrx20 was not reduced by OsNTR isoforms. The kcat/Km values of OsNTRB and OsNTRA toward OsTrx1 was six- and 13-fold higher than those values toward OsTrx23, respectively, suggesting that OsNTR isoforms do not reduce different OsTrx h isoforms, equivalently. Furthermore, the possible reduction of OsTrx isoforms by the glutathione (GSH)/Grx system was investigated through the heterologous expression of a gene encoding OsGrx9, a bicysteinic CPYC Grx found in rice. Whereas OsTrx23 was not reduced by GSH, OsTrx20 and with less efficiently OsTrx1 were reduced by GSH or GSH/Grx. Therefore, it seems that OsTrx1 can be reduced either by OsNTR or GSH/Grx. These data for the first time provides an evidence for cross-talking between NTR/Trx and GSH/Grx systems in rice. PMID- 25541358 TI - Insights into anti-parasitism induced by a C-type lectin from Bothrops pauloensis venom on Toxoplasma gondii. AB - Here we evaluate the effects of BpLec, a C-type lectin isolated from Bothrops pauloensis snake venom, on Toxoplasma gondii parasitism. BpLec (0.195-12.5 MUg/mL) did not interfere with HeLa (host cell) viability by MTT assay, whereas higher doses decreased viability and changed HeLa morphology. In addition, the host cell treatment before infection did not influence adhesion and proliferation indexes. BpLec did not alter T. gondii tachyzoite viability, as carried out by trypan blue exclusion, but decreased both adhesion and parasite replication, when tachyzoites were treated before infection. Galactose (0.4 M) inhibited the BpLec effect on adhesion assays, suggesting that BpLec probably recognize some glycoconjugate from T. gondii membrane. Additionally, we performed cytokine measurements from supernatants collected from HeLa cells infected with T. gondii tachyzoites previously treated with RPMI or BpLec. MIF and IL-6 productions by HeLa cells were increased by BpLec treatment. Also, TGF-beta1 secretion was diminished post-infection, although this effect was not dependent on BpLec treatment. Taken together, our results show that BpLec is capable of reducing T. gondii parasitism after tachyzoite treatment and may represent an interesting tool in the search for parasite antigens involved in these processes. PMID- 25541359 TI - Fucoidan from Turbinaria conoides: a multifaceted 'deliverable' to combat pancreatic cancer progression. AB - The presence of occult metastases at the time of diagnosis together with the lack of effective chemotherapies pose a dire need for designing new and targeted therapeutics for pancreatic cancer. Fucoidans from brown algae can be regarded as potential candidates in view of their antioxidant, anti-cancer and anti angiogenic potential. Herein, we investigated the antioxidant and anti-cancer effects of fucoidans, sulfated polysaccharides from Turbinaria conoides (TCFE) in pancreatic cancer cell lines. TCFE exerted significant antioxidant activities against various free radicals. Significant inhibition of cell proliferation and, induction of apoptotic cell death were observed in pancreatic cancer cells in response to TCFE. Also, TCFE exhibited significant anti-angiogenic potential. Evidently, gelatin zymography revealed that TCFE inhibited matrix metalloproteases -2 and -9 activities in pancreatic cancer cells. These results clearly indicate that TCFE could serve as a potential 'deliverable' to alleviate pancreatic cancer progression by inhibiting tumor cell proliferation and angiogenesis. PMID- 25541360 TI - Diversity of acoustic streaming in a rectangular acoustofluidic field. AB - Diversity of acoustic streaming field in a 2D rectangular chamber with a traveling wave and using water as the acoustic medium is numerically investigated by the finite element method. It is found that the working frequency, the vibration excitation source length, and the distance and phase difference between two separated symmetric vibration excitation sources can cause the diversity in the acoustic streaming pattern. It is also found that a small object in the acoustic field results in an additional eddy, and affects the eddy size in the acoustic streaming field. In addition, the computation results show that with an increase of the acoustic medium's temperature, the speed of the main acoustic streaming decreases first and then increases, and the angular velocity of the corner eddies increases monotonously, which can be clearly explained by the change of the acoustic dissipation factor and shearing viscosity of the acoustic medium with temperature. Commercialized FEM software COMSOL Multiphysics is used to implement the computation tasks, which makes our method very easy to use. And the computation method is partially verified by an established analytical solution. PMID- 25541361 TI - Sleep patterns and sleepiness among young students: A longitudinal study before and after admission as trainees and apprentices. AB - In developing countries, youngsters start to work during the high school years. Several studies have shown the difficulties associated with double shift, i.e. to work and study concomitantly, and its negative health consequences. Work and study time, as social synchronizers, have significant effects on the sleep-wake cycle (SWC). The purpose of this study was to evaluate sleep patterns and sleepiness in young students before and after entering the workforce as apprentices or trainees. Participants were 40 adolescents (26 males), 15-18 years old (mean = 15.8 years old) engaged in a first-job program at a non-governmental organization (NGO) while attending evening high school in the outskirts of the city of Sao Paulo, Brazil. The participants wore actigraphs (Ambulatory Monitoring, Inc.) and registered subjective sleepiness on KSS (Karolinska Sleepiness Scale) along 7 consecutive days, before and after admission to the job. Descriptive analyses were performed, and the variables were tested by means of the t-test and repeated measures ANOVA taking factors day of the week and time of the day into consideration. The participants' sleep duration on weekdays exhibited significant difference before and after starting work (F = 4.55; p = 0.04); the mean sleep duration was 492 min (SD = 44 min) before admission to the job to decrease to 405 min (SD = 58 min) after starting work. The mid-sleep time exhibited significant difference on weekdays before and after starting work (04:57 h; SD = 45 min versus 03:30 h; SD = 54 min; F = 4.91; p = 0.03). Finally, also sleepiness on weekdays (F = 6.41; p = 0.04) and at the waking time (F = 10.75; p < 0.01) exhibited significant difference before and after admission to the job. This article emphasizes the fact that social synchronizers like working during the day and studying in the evening changed the participants' SWC and were associated with sleep restriction. Brazilian governmental incentives notwithstanding, simultaneous performance of several activities by young workers should be considered as an occupational health hazard. Employment policies targeting young workers should take the dual shift - study and work - and its effects on the sleep-wake cycle into account. PMID- 25541362 TI - MALDI-TOF mass spectrometry for rapid identification of clinical fungal isolates based on ribosomal protein biomarkers. AB - This study aimed to evaluate the identification of clinical fungal isolates (yeast and molds) by protein profiling using Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS). A total of 125 clinical fungal culture isolates (yeast and filamentous fungi) were collected. The test set included 88 yeast isolates (Candida albicans, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida parapsilosis, Candida rugosa, Candida tropicalis and Cryptococcus neoformans) and 37 isolates of molds (Alternaria spp., Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Cunninghamella spp., Histoplasma capsulatum, Microsporum gypseum, Microsporum nanum, Rhizomucor spp. and Trichophyton spp.). The correlation between MALDI TOF MS and conventional identification for all these 125 fungal isolates included in the study was 87.2% at the species level and 90.4% at the genus level. MALDI TOF MS results revealed that the correlation in yeast (n=88) identification was 100% both at the genus and species levels whereas, the correlation in mold (n=37) identification was more heterogeneous i.e. 10.81% isolates had correct identification up to the genus level, 56.7% isolates had correct identification both at the genus and species levels, whereas 32.42% isolates were deemed Not Reliable Identification (NRI). But, with the modification in sample preparation protocol for molds, there was a significant improvement in identification. 86.4% isolates had correct identification till the genus and species levels whereas, only 2.7% isolates had Not Reliable Identification. In conclusion, this study demonstrates that MALDI-TOF MS could be a possible alternative to conventional techniques both for the identification and differentiation of clinical fungal isolates. However, the main limitation of this technique is that MS identification could be more precise only if the reference spectrum of the fungal species is available in the database. PMID- 25541363 TI - Fast and reliable bacterial identification direct from positive blood culture using a new TFA sample preparation protocol and the Vitek(r) MS system. AB - A simple and reliable protocol using 0.1% trifluoroacetic acid (TFA) was developed to identify bacteria directly from blood cultures on the Vitek(r) MS system. Results presented a correlation of 99% for Gram-negative bacteria at species level, and 86.3% and 82.3% of Gram-positive bacteria at the genus and species levels, respectively. PMID- 25541364 TI - Inhibition of thioredoxin-1 with siRNA exacerbates apoptosis by activating the ASK1-JNK/p38 pathway in brain of a stroke model rats. AB - Apoptosis is critical for the development of cerebral ischemia/reperfusion injury. Thioredoxin-1(Trx-1) protein has been reported to have anti-apoptotic effects in a variety of cell types, and it has been implicated in brain injury after middle cerebral artery occlusion (MCAO). Thus, we studied the effects of Trx1 silencing after MCAO in rats and examined whether inhibition of endogenous Trx1 could increase tissue levels of apoptosis. Male Sprague-Dawley rats (N=170) were subjected to 1h of middle cerebral arterial occlusion followed by 24h of reperfusion. Trx1 siRNAs were injected into rat brains 24h prior to MCAO. Then, 24h after MCAO, brains were collected from euthanized rats for investigation. Treatment with Trx1 siRNA significantly increased mortality, behavioral deficits, and cerebral infarction volume and exacerbated neuronal cell apoptotic death after MCAO injury. Western blot revealed increased expression of apoptotic proteins such as P-ASK1, P-JNK, P-p38, cleaved caspase-3 and increased the level of cytochrome c in the cytosolic fraction in the Trx1 siRNA-treated group. Co immunoprecipitation assay suggested an interaction between Trx1 and ASK1 in normal rat brains and Trx1 siRNA dissociated ASK1-Trx1 binding complex. Our data suggest that Trx1 siRNA increases apoptotic stress-induced ASK1 activation and this represents further evidence that Trx1 is an endogenous anti-apoptotic molecule that diminishes focal cerebral ischemia/reperfusion injury. Its mechanism of action is likely related to attenuation of the ASK1-JNK/p38 signaling pathway. PMID- 25541366 TI - Melanin-concentrating hormone (MCH) modulates the activity of dorsal raphe neurons. AB - Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto hypothalamic area. These neurons send dense projections to the dorsal raphe nucleus (DRN). Serotonergic neurons of the DRN are involved in the control of sleep and play a critical role in major depression. Previously, we demonstrated that microinjections of MCH into the DRN resulted in an increase in REM sleep and produce a depressive-like effect. In the present study we examined the mechanisms that mediate these effects by employing neuroanatomical and electrophysiological techniques. First, we determined that rhodamine-labeled MCH (R-MCH), when microinjected into the lateral ventricle, is internalized in serotonergic and non serotonergic DRN neurons in rats and cats. These data strongly suggest that these neurons express MCHergic receptors. Second, in rats, we demonstrated that the microinjection of MCH into the lateral ventricle results in a significant decrease in the firing rate in 59% of the neurons recorded in the DRN; the juxtacellular administration of MCH reduced the discharge in 80% of these neurons. Some of the neurons affected by MCH were likely serotonergic on the basis of their electrophysiological and pharmacological properties. We conclude that MCH reduces the activity of serotonergic neurons of the DRN. These and previous data suggest that the MCHergic modulation of serotonergic activity within the DRN is involved in the regulation of REM sleep as well as in the pathophysiology of depressive disorders. PMID- 25541367 TI - Is the newly designed distal tip of the LMA Supreme an advantage or a disadvantage? PMID- 25541365 TI - Age differences in brain activity related to unsuccessful declarative memory retrieval. AB - Although memory recall is known to be reduced with normal aging, little is known about the patterns of brain activity that accompany these recall failures. By assessing faulty memory, we can identify the brain regions engaged during retrieval attempts in the absence of successful memory and determine the impact of aging on this functional activity. We used functional magnetic resonance imaging to examine age differences in brain activity associated with memory failure in three memory retrieval tasks: autobiographical (AM), episodic (EM) and semantic (SM). Compared to successful memory retrieval, both age groups showed more activity when they failed to recall a memory in regions consistent with the salience network (SLN), a brain network also associated with non-memory errors. Both groups also showed strong functional coupling among SLN regions during incorrect trials and in intrinsic patterns of functional connectivity. In comparison to young adults, older adults demonstrated (1) less activity within the SLN during unsuccessful AM trials; (2) weaker intrinsic functional connectivity between SLN nodes and dorsolateral prefrontal cortex; and (3) less differentiation of SLN functional connectivity during incorrect trials across memory conditions. These results suggest that the SLN is engaged during recall failures, as it is for non-memory errors, which may be because errors in general have particular salience for adapting behavior. In older adults, the dedifferentiation of functional connectivity within the SLN across memory conditions and the reduction of functional coupling between it and prefrontal cortex may indicate poorer inter-network communication and less flexible use of cognitive control processes, either while retrieval is attempted or when monitoring takes place after retrieval has failed. This article is part of a Special Issue entitled SI: Memory & Aging. PMID- 25541368 TI - The perioperative handoff protocol: evaluating impacts on handoff defects and provider satisfaction in adult perianesthesia care units. AB - STUDY OBJECTIVE: To evaluate a new perioperative handoff protocol in the adult perianesthesia care units (PACUs). DESIGN: Prospective, unblinded cross-sectional study. SETTING: Perianesthesia care unit in a tertiary care facility serving 55,000 patients annually. PATIENTS: One hundred three surgery patients. INTERVENTIONS: During a 4-week preintervention phase, 53 perioperative handoffs were observed, and data were collected daily by a trained observer. Educational sessions were conducted to train perioperative practitioners on the new protocol. Two weeks after implementation, 50 consecutive handoffs were observed, and practitioners were surveyed with the same methodology as in the preintervention phase. MEASUREMENTS: Type of information shared, type and duration of procedure, total duration of handoff, number and type of providers at the bedside, number of report interruptions, environmental distractions, and any other disruptive events. Observers also tracked technical/equipment problems to include malfunctioning or compromised operation of medical equipment, such as the cardiac monitor, transducer, oxygen tank, and pulse oximeter. MAIN RESULTS: A total of 103 handoffs were observed (53 preintervention and 50 postintervention). The mean number of defects per handoff decreased from 9.92 to 3.68 (P < .01). The mean number of missed information items from the surgery report decreased from 7.57 to 1.2 items per handoff and from 2.02 to 0.94 (P < .01) for the anesthesia report. Technical defects reported by unit nurses decreased from 0.34 to 0.10 (P = .04). Verbal reports delivered by surgeons increased from 21.2% to 83.3%. Although the mean duration of handoffs increased by 2 minutes (P = .01), the average time from patient arrival at PACU to handoff start was reduced by 1.5 minutes (P = .01). Satisfaction with the handoff improved significantly among PACU nurses. CONCLUSIONS: The perioperative handoff protocol implementation was associated with improved information sharing and reduced handoff defects. PMID- 25541369 TI - Rare cause of oesophagus perforation. AB - INTRODUCTION: Oesophagus perforations, which are generally caused by iatrogenic injuries, are a serious clinical event. There are still high rates of mortality and morbidity and there is no gold standard of surgical treatment. PRESENTATION OF CASE: The case is here presented of a 54-year old female with complaints of dysphagia after having swallowed a bone in food, who was determined with oesophagus perforation on CT examination. DISCUSSION: Oesophagus perforation generally occurs secondary to interventional procedures and rarely develops associated with foreign bodies. Treatment depends on the perforation site and dimension. CONCLUSION: While conservative primary surgical repair may be chosen for cervical lesions, more aggressive approaches such as resection and delayed reconstruction are recommended for thoracic lesions. Early determination and appropriate treatment are life-saving. PMID- 25541370 TI - Intraoperative near-infrared fluorescence imaging of a paraganglioma using methylene blue: A case report. AB - INTRODUCTION: Intraoperative identification of tumors can be challenging. Near infrared (NIR) fluorescence imaging is an innovative technique that can assist in intraoperative identification of tumors, which may otherwise be undetectable. PRESENTATION OF CASE: A 19-year-old patient with symptoms, normetanephrine levels and radiological findings suspicious for a paraganglioma, a rare tumor arising from extra-adrenal chromaffin cells within the sympathetic nervous system, is presented. Intraoperative NIR fluorescence imaging using intravenous administration of methylene blue (MB) assisted in intraoperative detection of the tumor, and even identified a smaller second lesion, which was not identified during surgery by visual inspection. DISCUSSION: Although the exact mechanism of MB accumulation in neuroendocrine tumors is unclear, it is described in both preclinical and clinical studies. CONCLUSION: In this report, we describe the first case of intraoperative NIR fluorescence imaging of a paraganglioma using MB, which identified an otherwise undetectable lesion. PMID- 25541371 TI - Lung granuloma mimicking pulmonary arteriovenous malformation: Report of a case. AB - INTRODUCTION: While hypervascular lesions in the lung are known to mimic pulmonary arteriovenous malformation (PAVM), here we report a rare case of lung granuloma mimicking PAVM, on which video-assisted thoracic surgery (VATS) was performed. PRESENTATION OF CASE: A 76-year-old woman without any symptom was admitted to our hospital because of abnormal shadow in the left lung field on chest X-ray. A 20mm*14mm nodule with well-defined margins and smooth contours in the left upper segment was detected in her chest computed tomography (CT). Contrast-enhanced three-dimensional CT (3D-CT) revealed an enhanced solitary lung nodule, which was connected with linear structures suggestive of feeding artery and drainage vein. Thus, we made a preoperative diagnosis of PAVM by performing partial pulmonary resection by VATS. Intraoperatively, elastic hard nodule was palpable in the left upper segment and bruit was not convincing. Histopathological findings revealed multiple foci of coagulative necrosis surrounded by epithelioid cell granuloma containing Langhans-type multinucleated giant cells, involving the medium-sized blood vessels in the pulmonary parenchyma. Abnormal vascular structures, such as PAVM were not convincing. Based on these findings, a diagnosis of left lung granuloma was made. DISCUSSION: Preoperatively, it was difficult to distinguish the left lung granuloma from PAVM, because hypervascular lesion, such as inflammatory changes can present as strongly enhanced nodules after injection of contrast material. CONCLUSION: Surgical approach seems appropriate, not only for the purpose of diagnosis, but also for the safety in treatment of a PAVM. PMID- 25541372 TI - 'Would you eat cultured meat?': Consumers' reactions and attitude formation in Belgium, Portugal and the United Kingdom. AB - Cultured meat has evolved from an idea and concept into a reality with the August 2013 cultured hamburger tasting in London. Still, how consumers conceive cultured meat is largely an open question. This study addresses consumers' reactions and attitude formation towards cultured meat through analyzing focus group discussions and online deliberations with 179 meat consumers from Belgium, Portugal and the United Kingdom. Initial reactions when learning about cultured meat were underpinned by feelings of disgust and considerations of unnaturalness. Consumers saw few direct personal benefits but they were more open to perceiving global societal benefits relating to the environment and global food security. Both personal and societal risks were framed in terms of uncertainties about safety and health, and possible adverse societal consequences dealing with loss of farming and eating traditions and rural livelihoods. Further reflection pertained to skepticism about 'the inevitable' scientific progress, concern about risk governance and control, and need for regulation and proper labeling. PMID- 25541373 TI - Urocortin--from Parkinson's disease to the skeleton. AB - Urocortin (Ucn 1), a 40 amino acid long peptide related to corticotropin releasing factor (CRF) was discovered 19 years ago, based on its sequence homology to the parent molecule. Its existence was inferred in the CNS because of anatomical and pharmacological discrepancies between CRF and its two receptor subtypes. Although originally found in the brain, where it has opposing actions to CRF and therefore confers stress-coping mechanisms, Ucn 1 has subsequently been found throughout the periphery including heart, lung, skin, and immune cells. It is now well established that this small peptide is involved in a multitude of physiological and pathophysiological processes, due to its receptor subtype distribution and promiscuity in second messenger signalling pathways. As a result of extensive studies in this field, there are now well over one thousand peer reviewed publications involving Ucn 1. In this review, we intend to highlight some of the less well known actions of Ucn 1 and in particular its role in neuronal cell protection and maintenance of the skeletal system, both by conventional methods of reviewing the literature and using bioinformatics, to highlight further associations between Ucn 1 and disease conditions. Understanding how Ucn 1 works in these tissues, will help to unravel its role in normal and pathophysiological processes. This would ultimately allow the generation of putative medical interventions for the alleviation of important diseases such as Parkinson's disease, arthritis, and osteoporosis. PMID- 25541374 TI - Residues required for phosphorylation of translation initiation factor eIF2alpha under diverse stress conditions are divergent between yeast and human. AB - PERK, PKR, HRI and GCN2 are the four mammalian kinases that phosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2alpha) on Ser51. This phosphorylation event is conserved among many species and attenuates protein synthesis in response to diverse stress conditions. In contrast, Saccharmyces cerevisiae expresses only the GCN2 kinase. It was demonstrated previously in S. cerevisiae that single point mutations in eIF2alpha's N-terminus severely impaired phosphorylation at Ser51. To assess whether similar recognition patterns are present in mammalian eIF2alpha, we expressed human eIF2alpha's with these mutations in mouse embryonic fibroblasts and assessed their phosphorylation under diverse stress conditions. Some of the mutations prevented the stress induced phosphorylation of eIF2alpha by all mammalian kinases, thus defining amino acid residues in eIF2alpha (Gly 30, Leu 50, and Asp 83) that are required for substrate recognition. We also identified residues that were less critical or not required for recognition by the mammalian kinases (Ala 31, Met 44, Lys 79, and Tyr 81), even though they were essential for recognition of the yeast eIF2alpha by GCN2. We propose that mammalian eIF2alpha kinases evolved to maximize their interactions with the evolutionarily conserved Ser51 residue of eIF2alpha in response to diverse stress conditions, thus adding to the complex signaling pathways that mammalian cells have over simpler organisms. PMID- 25541375 TI - TRAIL-based tumor sensitizing galactoxyloglucan, a novel entity for targeting apoptotic machinery. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive target for cancer therapy due to its ability to selectively induce apoptosis in cancer cells, without causing significant toxicity in normal tissues. We previously reported that galactoxyloglucan (PST001) possesses significant antitumor and immunomodulatory properties. However, the exact mechanism in mediating this anticancer effect is unknown. This study, for the first time, indicated that PST001 sensitizes non-small cell lung cancer (A549) and nasopharyngeal (KB) cells to TRAIL-mediated apoptosis. In vitro studies suggested that PST001 induced apoptosis primarily via death receptors and predominantly activated caspases belonging to the extrinsic apoptotic cascade. Microarray profiling of PST001 treated A549 and KB cells showed the suppression of survivin (BIRC5) and anti-apoptotic Bcl-2, as well as increased cytochrome C. TaqMan low density array analysis of A549 cells also confirmed that the induction of apoptosis by the polysaccharide occurred through the TRAIL-DR4/DR5 pathways. This was finally confirmed by in silico analysis, which revealed that PST001 binds to TRAIL-DR4/DR5 complexes more strongly than TNF and Fas ligand-receptor complexes. In summary, our results suggest the potential of PST001 to be developed as an anticancer agent that not only preserves innate biological activity of TRAIL, but also sensitizes cancer cells to TRAIL-mediated apoptosis. PMID- 25541377 TI - Molecular mechanisms of maternal vascular dysfunction in preeclampsia. AB - In preeclampsia, as a heterogeneous syndrome, multiple pathways have been proposed for both the causal as well as the perpetuating factors leading to maternal vascular dysfunction. Postulated mechanisms include imbalance in the bioavailability and activity of endothelium-derived contracting and relaxing factors and oxidative stress. Studies have shown that placenta-derived factors [antiangiogenic factors, microparticles (MPs), cell-free nucleic acids] are released into the maternal circulation and act on the vascular wall to modify the secretory capacity of endothelial cells and alter the responsiveness of vascular smooth muscle cells to constricting and relaxing stimuli. These molecules signal their deleterious effects on the maternal vascular wall via pathways that provide the molecular basis for novel and effective therapeutic interventions. PMID- 25541376 TI - Heart failure and respiratory hospitalizations are reduced in patients with heart failure and chronic obstructive pulmonary disease with the use of an implantable pulmonary artery pressure monitoring device. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). Elevated pulmonary arterial (PA) pressure can be seen in both conditions and has been shown to predict morbidity and mortality. METHODS AND RESULTS: A total of 550 subjects with New York Heart Association functional class III HF were randomly assigned to the treatment (n = 270) and control (n = 280) groups in the CHAMPION Trial. Physicians had access to the PA pressure measurements in the treatment group only, in which HF therapy was used to lower the elevated pressures. HF and respiratory hospitalizations were compared in both groups. A total of 187 subjects met criteria for classification into the COPD subgroup. In the entire cohort, the treatment group had a 37% reduction in HF hospitalization rates (P < .0001) and a 49% reduction in respiratory hospitalization rates (P = .0061). In the COPD subgroup, the treatment group had a 41% reduction in HF hospitalization rates (P = .0009) and a 62% reduction in respiratory hospitalization rates (P = .0023). The rate of respiratory hospitalizations in subjects without COPD was not statistically different (P = .76). CONCLUSIONS: HF management incorporating hemodynamic information from an implantable PA pressure monitor significantly reduces HF and respiratory hospitalizations in HF subjects with comorbid COPD compared with standard care. PMID- 25541378 TI - Detection and genetic characterization of porcine group A rotaviruses in asymptomatic pigs in smallholder farms in East Africa: predominance of P[8] genotype resembling human strains. AB - Viral enteritis is a serious problem accounting for deaths in neonatal animals and humans worldwide. The absence of surveillance programs and diagnostic laboratory facilities have resulted in a lack of data on rotavirus associated diarrheas in pigs in East Africa. Here we describe the incidence of group A rotavirus (RVA) infections in asymptomatic young pigs in East Africa. Of the 446 samples examined, 26.2% (117/446) were positive for RVA. More nursing piglets (78.7%) shed RVA than weaned (32.9%) and grower (5.8%) pigs. RVA incidence was higher in pigs that were either housed_free-range (77.8%) or tethered_free-range (29.0%) than those that were free-range or housed or housed-tethered pigs. The farms with larger herd size (>10 pigs) had higher RVA prevalence (56.5%) than farms with smaller herd size (24.1-29.7%). This study revealed that age, management system and pig density significantly (p<0.01) influenced the incidence of RVA infections, with housed_free-range management system and larger herd size showing higher risks for RVA infection. Partial (811-1604nt region) sequence of the VP4 gene of selected positive samples revealed that different genotypes (P[6], P[8] and P[13]) are circulating in the study area with P[8] being predominant. The P[6] strain shared nucleotide (nt) and amino acid (aa) sequence identity of 84.4-91.3% and 95.1-96.9%, respectively, with known porcine and human P[6] strains. The P[8] strains shared high nt and aa sequence identity with known human P[8] strains ranging from 95.6-100% to 92-100%, respectively. The P[13] strains shared nt and aa sequence identity of 83.6-91.7% and 89.3-96.4%, respectively, only with known porcine P[13] strains. No P[8] strains yielded RNA of sufficient quality/quantity for full genome sequencing. However analysis of the full genome constellation of the P[6], two P[13] and one untypeable strains revealed that the P[6] strain (Ke-003-5) genome constellation was G26-P[6]-I5-R1 C1-M1-A8-N1-T1-E1-H1, P[13] strains (Ug-049 and Ug-453) had G5-P[13]-I5-R1-C1-M1 A8-N1-T7-E1-H1 while the untypeable strain (Ug-218) had G5-P[?]-I5-R1-C1-M1-A8-N1 T1-E1-H? In conclusion, P[6] and P[8] genotypes detected were genetically closely related to human strains suggesting the possibility of interspecies transmission. Further studies are required to determine the role of RVA in swine enteric disease burden and to determine the genetic/antigenic heterogeneity of the circulating strains for development of accurate diagnostic tools and to implement appropriate prophylaxis programs. PMID- 25541379 TI - The use of quantitative PCR to detect Felis catus papillomavirus type 2 DNA from a high proportion of queens and their kittens. AB - Squamous cell carcinomas are common feline skin cancers that have been associated with infection with Felis catus papillomavirus type 2 (FcaPV-2). Currently, little is known about the epidemiology of FcaPV-2 infection. The aim of this study was to develop a real-time PCR assay to quantify FcaPV-2 DNA in plucked hairs and skin swabs from 11 healthy breeding queens and their kittens. Samples were taken prior to kittening and then 2, 7 and 28 days after kittening to determine the age at which the kittens were first exposed to the virus. FcaPV-2 DNA was amplified from all of the queens and from 91% of the kittens at 2 days of age. There was a wide range in the quantity of FcaPV-2 DNA detected, from 1 to 92,520 copies per swab, and from 0.01 to 234 copies per copy of reference gene DNA in the hair plucks. The quantity of FcaPV-2 DNA detected in samples collected from the kittens was strongly correlated to that of their respective queens and the mean viral DNA load was similar for cats within a household but varied significantly between households. This is the first time that quantitative PCR has been used to detect FcaPV-2 DNA and the results suggest that the virus is ubiquitous but there is a wide variation of viral DNA loads. Kittens appear to be exposed to FcaPV-2 early in life, presumably from direct contact with their queen. These results are important when determining if FcaPV-2 infection of cats is preventable. PMID- 25541380 TI - Saline-filled laparoscopic surgery: A basic study on partial hepatectomy in a rabbit model. AB - BACKGROUND: There is still a poor understanding of the effects of pneumoperitoneum with insufflation of carbon dioxide gas (CO2) on malignant cells, and pneumoperitoneum has a negative impact on cardiopulmonary responses. A novel saline-filled laparoscopic surgery (SAFLS) is proposed, and the technical feasibility of performing saline-filled laparoscopic partial hepatectomy (LPH) was evaluated in a rabbit model. MATERIAL AND METHODS: Twelve LPH were performed in rabbits, with six procedures performed using an ultrasonic device with CO2 pneumoperitoneum (CO2 group) and six procedures performed using a bipolar resectoscope (RS) in a saline-filled environment (saline group). Resection time, CO2 and saline consumption, vital signs, blood gas analysis, complications, interleukin-1 beta (IL-1beta) and C-reactive protein (CRP) levels were measured. The effectiveness of the resections was evaluated by the pathological findings. RESULTS: LPH was successfully performed with clear observation by irrigation and good control of bleeding by coagulation with RS. There were no significant differences in all perioperative values, IL-1betaand CRP levels between the two groups. All pathological specimens of the saline group showed that the resected lesions were coagulated and regenerated as well as in the CO2 group. CONCLUSIONS: SAFLS is feasible and provides a good surgical view with irrigation and identification of bleeding sites. PMID- 25541381 TI - Biodegradation of propyzamide by Comamonas testosteroni W1 and cloning of the propyzamide hydrolase gene camH. AB - Propyzamide is a widely used benzamide herbicide for controlling weeds in lettuce, soybeans, cotton and other crops. An efficient propyzamide-degrading strain W1 was firstly isolated from activated sludge and identified as Comamonas testosteroni. A metabolite of propyzamide by strain W1 was firstly identified. The novel gene camH encoding a hydrolase that catalyzed the amide bond cleavage of propyzamide was cloned from strain W1. The gene contained an open reading frame of 1452 bp, the deduced amino acid sequence showed low identity with other amidases. The recombinant enzyme CamH was expressed in Escherichia coli BL21 and purified. CamH displayed the highest activity at 30 degrees C and pH 8.0 with propyzamide as the substrate. These results provide important knowledge on the fate of propyzamide in the biodegradation, and elucidate the biodegradation mechanism of propyzamide by the strain W1. PMID- 25541382 TI - Flexible modeling of disease activity measures improved prognosis of disability progression in relapsing-remitting multiple sclerosis. AB - OBJECTIVES: To illustrate the advantages of updating time-varying measures of disease activity and flexible modeling in prognostic clinical studies using the example of the association between the frequency of past relapses and occurrence of ambulation-related disability in multiple sclerosis (MS). STUDY DESIGN AND SETTING: Longitudinal population-based study of 288 patients from Burgundy, France, diagnosed with relapsing-remitting MS in 1990-2003. The end point was a nonreversible moderate MS disability (European Database for Multiple Sclerosis score >= 3.0 derived from Extended Disability Status Scale). Alternative time varying measures of attacks frequency included (1) conventional number of early MS attacks in the first 2 years after diagnosis; and two new measures, continuously updated during the follow-up; (2) cumulative number of past attacks; and (3) number of recent attacks, during the past 2 years. Multivariate analyses used Cox proportional hazards model and its flexible generalization, which accounted for time-dependent changes in the hazard ratios (HRs) for different attack frequency measures. RESULTS: HRs for all measures decreased significantly with increasing follow-up time. The proposed updated number of recent attacks improved model's fit to data, relative to alternative measures of attack frequency, and was associated with a statistically significantly increased hazard of developing ambulation-related MS disability in the next 2 years during the entire follow-up period. CONCLUSION: Updated measures of recent disease activity, such as frequency of recent attacks and modeling of their time-dependent effects, may substantially improve prognosis of clinical outcomes, such as development of MS disability. PMID- 25541383 TI - Investigation of infectivity of neonates and adults from different rat strains to Toxoplasma gondii Prugniaud shows both variation which correlates with iNOS and Arginase-1 activity and increased susceptibility of neonates to infection. AB - Mouse models differ considerably from humans with regard to clinical symptoms of toxoplasmosis caused by Toxoplasma gondii and, by comparison, the rat model is more representative of this disease in humans. In the present study, we found that different strains of adult and newborn rats (Lewis, Wistar, Sprague Dawley, Brown Norway and Fischer 344) exhibited remarkable variation in the number of brain cysts following inoculation with the T.gondii Prugniaud strain. In adult rats, large numbers of cysts (1231 +/- 165.6) were observed in Fischer 344, but none in the other four. This situation was different in newborn rats aged from 5 to 20 days old. All Fischer 344 and Brown Norway newborns were cyst-positive while cyst-positive infection in Sprague Dawley neonates ranged from 54.5% to 60% depending on their age at infection. In Wistar and Lewis rat neonates, however, cyst-positivity rates of 0-42.9% and 0-25% were found respectively. To investigate whether rat strain differences in infectivity could be related to inherent strain and genetic differences in the host immune response, we correlated our data with previously reported strain differences in iNOS/Arginase ratio in adult rats and found them to be linked. These results show that interactions between host genetic background and age of rat influence T.gondii infection. PMID- 25541384 TI - Experimental study of the relationship between Plasmodium gametocyte density and infection success in mosquitoes; implications for the evaluation of malaria transmission-reducing interventions. AB - The evaluation of transmission reducing interventions (TRI) to control malaria widely uses membrane feeding assays. In such assays, the intensity of Plasmodium infection in the vector might affect the measured efficacy of the candidates to block transmission. Gametocyte density in the host blood is a determinant of the infection success in the mosquito, however, uncertain estimates of parasite densities and intrinsic characteristics of the infected blood can induce variability. To reduce this variation, a feasible method is to dilute infectious blood samples. We describe the effect of diluting samples of Plasmodium containing blood samples to allow accurate relative measures of gametocyte densities and their impact on mosquito infectivity and TRI efficacy. Natural Plasmodium falciparum samples were diluted to generate a wide range of parasite densities, and fed to Anopheles coluzzii mosquitoes. This was compared with parallel dilutions conducted on Plasmodium berghei infections. We examined how blood dilution influences the observed blocking activity of anti-Pbs28 monoclonal antibody using the P. berghei/Anopheles stephensi system. In the natural species combination P. falciparum/An. coluzzii, blood dilution using heat-inactivated, infected blood as diluents, revealed positive near linear relationships, between gametocyte densities and oocyst loads in the range tested. A similar relationship was observed in the P. berghei/An. stephensi system when using a similar dilution method. In contrast, diluting infected mice blood with fresh uninfected blood dramatically increases the infectiousness. This suggests that highly infected mice blood contains inhibitory factors or reduced blood moieties, which impede infection and may in turn, lead to misinterpretation when comparing individual TRI evaluation assays. In the lab system, the transmission blocking activity of an antibody specific for Pbs28 was confirmed to be density-dependent. This highlights the need to carefully interpret evaluations of TRI candidates, regarding gametocyte densities in the P. berghei/An. stephensi system. PMID- 25541386 TI - Recognition of a monoclonal antibody against a small molecular weight antigen by monitoring the antigen-antibody reaction using fluorescence labeled structured peptides. AB - Interaction between proteins (as analytes) and de novo designed structured peptides as capture molecules cause structural changes, which are reflected in fluorescent-intensity changes of labeled peptides in a dose dependent manner. In contrast to conventional detection methods our detection system does not involve the detection of specific molecules themselves in a 1:1 manner, but uses the principle of the differences in fluorescent intensity changes of capture peptides upon addition of analytes. Instead of the use of secondary antibodies we have attempted monitoring these structural changes by an array of de novo designed synthetic and structured peptides. In the present study we have focused on a recognition system, 5-fluorouracil, as a low molecular antigen and a monoclonal antibody against 5-FU. The fluorescent intensity changes of fluorescent labeled peptides have been measured after incubation with a monoclonal antibody and again after further incubation with the antigen, 5-FU. Unique intensity changes were found for several peptides in the fluorescent peptide library that allowed the visualization as a color-coded protein fingerprint. The peptide screen used in the present study offers a useful detection system as capture molecules for peptide-based microarrays. PMID- 25541385 TI - Purification and kinetic analysis of cytosolic and mitochondrial thioredoxin glutathione reductase extracted from Taenia solium cysticerci. AB - Thioredoxin glutathione reductases (TGRs) (EC 1.8.1.9) were purified to homogeneity from the cytosolic (cTsTGR) and mitochondrial (mTsTGR) fractions of Taenia solium, the agent responsible for neurocysticercosis, one of the major central nervous system parasitic diseases in humans. TsTGRs had a relative molecular weight of 132,000, while the corresponding value per subunit obtained under denaturing conditions, was of 62,000. Specific activities for thioredoxin reductase and glutathione reductase substrates for both TGRs explored were in the range or lower than values obtained for other platyhelminths and mammalian TGRs. cTsTGR and mTsTGR also showed hydroperoxide reductase activity using hydroperoxide as substrate. Km(DTNB) and Kcat(DTNB) values for cTsTGR and mTsTGR (88 uM and 1.9 s(-1); 45 uM and 12.6 s(-1), respectively) and Km(GSSG) and Kcat(GSSG) values for cTsTGR and mTsTGR (6.3 uM and 0.96 s(-1); 4 uM and 1.62 s( 1), respectively) were similar to or lower than those reported for mammalian TGRs. Mass spectrometry analysis showed that 12 peptides from cTsTGR and seven from mTsTGR were a match for gi|29825896 thioredoxin glutathione reductase [Echinococcus granulosus], confirming that both enzymes are TGRs. Both T. solium TGRs were inhibited by the gold compound auranofin, a selective inhibitor of thiol-dependent flavoreductases (I50 = 3.25, 2.29 nM for DTNB and GSSG substrates, respectively for cTsTGR; I50 = 5.6, 25.4 nM for mTsTGR toward the same substrates in the described order). Glutathione reductase activity of cTsTGR and mTsTGR exhibited hysteretic behavior with moderate to high concentrations of GSSG; this result was not observed either with thioredoxin, DTNB or NADPH. However, the observed hysteretic kinetics was suppressed with increasing amounts of both parasitic TGRs. These data suggest the existence of an effective substitute which may account for the lack of the detoxification enzymes glutathione reductase and thioredoxin reductase in T. solium, as has been described for very few other platyhelminths. PMID- 25541387 TI - A comparative study of trans- and cis-isomers of a bone-seeking agent, DO2A2P. AB - The macrocyclic bone-seeking agent, DO2A2P, bears a cyclen core and two pairs of peripheral phosphonate and carboxylate groups. The geometric disposition of the peripheral functionalities gives arise to a pair of geometric isomers: cis-DO2A2P and trans-DO2A2P. In order to compare the biological behavior of the isomer pair, cis-DO2A2P was synthesized. Both isomers were successfully radiolabeled with (177)Lu, which might potentiate their applications in both radiotherapy and imaging of bone diseases. Through a set of biological assays including the hydroxyapatite binding, in vitro stability, and in vivo distribution, we demonstrated that the geometric pair of DO2A2P had virtually identical biological properties. PMID- 25541388 TI - Pharmacophore based virtual screening, synthesis and SAR of novel inhibitors of Mycobacterium sulfotransferase. AB - A planned 3D-pharmacophore mapping was carried out on the basis of chemical features associated with known Stf0 inhibitors. Four models (model 1-4) were obtained after GASP (Genetic Algorithm Similarity Program) refinement of seven models (D-1 to D-7) generated by using DISCOtech. The selected GASP model-1 has two hydrogen bond acceptor, two hydrogen bond donor and four hydrophobic points. This model was used for virtual screening (VS) of large public databases along with in house generated knowledge base database. VS followed by docking of selected compounds on Stf0 active site was carried and pose analysis done. Seven hits were identified after all the computational studies, of which 2 hits were synthesized along with their analogs and evaluated for antitubercular activity. IH-45 was found promising after in vitro assay. PMID- 25541389 TI - The ACDC pilot trial: targeting the anterior cingulate by double cone coil rTMS for the treatment of depression. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral-prefrontal cortex (DLPFC) with conventional figure-of-8 (=butterfly) coils has been used as an antidepressant therapeutic tool for almost twenty years. Very recently, an innovative rTMS coil, the so-called double cone coil (DC), was introduced allowing the modulation of the anterior cingulate cortex (AC). We investigated safety and therapeutic effectiveness of this stimulation in a naturalistic clinical setting. METHOD: Forty-five patients suffering a moderate to severe depressive episode were randomized to receive 15 sessions of either conventional rTMS of the left DLPFC ("butterfly-rTMS"; 10 Hz; 2000 stimuli/day, RMT 110%), mediofrontal double cone coil stimulation of the anterior cingulate cortex ("ACDC-rTMS" with equal parameters), or sham-stimulation. The primary outcome was the change in the 21-items Hamilton Rating Scale for Depression (HAMD) from baseline to the end of treatment. Secondary outcome measures were changes over the course of the trial regarding the HAMD, the Beck Depression Inventory (BDI), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF) scales. RESULTS: There was a significant group * time interaction effect regarding the primary outcome (F = 3.269; df = 2,37; P = 0.049). Post-hoc t-testing revealed a significant effect for the comparison ACDC vs. butterfly at week 3/end of treatment (T = 2.646; df = 26; P = 0.014). No severe adverse events occurred during the study. ACDC-stimulation was well tolerated by the majority of patients similar like butterfly-rTMS and sham stimulation. CONCLUSION: This pilot study demonstrated the feasibility of ACDC rTMS-stimulation as an add-on-treatment for depression. Its clinical effects warrant further investigation in the future. PMID- 25541390 TI - The role of symmetry in the theory of inelastic high-energy electron scattering and its application to atomic-resolution core-loss imaging. AB - The inelastic scattering of a high-energy electron in a solid constitutes a bipartite quantum system with an intrinsically large number of excitations, posing a considerable challenge for theorists. It is demonstrated how and why the utilization of symmetries, or approximate symmetries, can lead to significant improvements in both the description of the scattering physics and the efficiency of numerical computations. These ideas are explored thoroughly for the case of core-loss excitations, where it is shown that the coupled angular momentum basis leads to dramatic improvements over the bases employed in previous work. The resulting gains in efficiency are demonstrated explicitly for K-, L- and M-shell excitations, including such excitations in the context of atomic-resolution imaging in the scanning transmission electron microscope. The utilization of other symmetries is also discussed. PMID- 25541391 TI - DNA polymerase beta-dependent cell survival independent of XRCC1 expression. AB - Base excision repair (BER) is a primary mechanism for repair of base lesions in DNA such as those formed by exposure to the DNA methylating agent methyl methanesulfonate (MMS). Both DNA polymerase beta (pol beta)- and XRCC1-deficient mouse fibroblasts are hypersensitive to MMS. This is linked to a repair deficiency as measured by accumulation of strand breaks and poly(ADP-ribose) (PAR). The interaction between pol beta and XRCC1 is important for recruitment of pol beta to sites of DNA damage. Endogenous DNA damage can substitute for MMS induced damage such that BER deficiency as a result of either pol beta- or XRCC1 deletion is associated with sensitivity to PARP inhibitors. Pol beta shRNA was used to knock down pol beta in Xrcc1(+/+) and Xrcc1(-/-) mouse fibroblasts. We determined whether pol beta-mediated cellular resistance to MMS and PARP inhibitors resulted entirely from coordination with XRCC1 within the same BER sub pathway. We find evidence for pol beta-dependent cell survival independent of XRCC1 expression for both types of agents. The results suggest a role for pol beta-dependent, XRCC1-independent repair. PAR immunofluorescence data are consistent with the hypothesis of a decrease in repair in both pol beta knock down cell variants. PMID- 25541393 TI - The physiological response of soft tissue to periodic repositioning as a strategy for pressure ulcer prevention. AB - BACKGROUND: Individuals who have reduced mobility are at risk of developing pressure ulcers if they are subjected to sustained static postures. To reduce this risk, clinical guidelines advocate healthcare professionals reposition patients regularly. Automated tilting mechanisms have recently been introduced to provide periodic repositioning. This study compared the performance of such a prototype mattress to conventional manual repositioning. METHODS: Ten healthy participants (7 male and 3 female, aged 23-66 years) were recruited to compare the effects of an automated tilting mattress to standard manual repositioning, using the 30 degrees tilt. Measures during the tilting protocols (supine, right and left tilt) included comfort and safety scores, interface pressures, inclinometer angles and transcutaneous gas tensions (sacrum and shoulder). Data from these outcomes were compared between each protocol. FINDINGS: Results indicated no significant differences for either interface pressures or transcutaneous gas responses between the two protocols (P>0.05 in both cases). Indeed a small proportion of participants (~30%) exhibited changes in transcutaneous oxygen and carbon dioxide values in the shoulder during a right tilt for both protocols. The tilt angles at the sternum and the pelvis were significantly less in the automated tilt compared to the manual tilt (mean difference=9.4-11.5 degrees , P<0.001). Participants reported similar comfort scores for both protocols, although perceived safety was reduced on the prototype mattress. INTERPRETATION: Although further studies are required to assess its performance in maintaining tissue viability, an automated tilting mattress offers the ability to periodically reposition vulnerable individuals, with potential economic savings to health services. PMID- 25541392 TI - Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking. AB - BACKGROUND: Difficulties in ambulation are one of the main problems reported by patients with multiple sclerosis. A previous study by our research group showed increased recruitment of muscle groups during walking, but the influence of skeletal muscle properties, such as muscle fiber activity, has not been fully elucidated. The purpose of this investigation was to use the novel method of calculating glucose uptake heterogeneity in the leg muscles of patients with multiple sclerosis and compare these results to healthy controls. METHODS: Eight patients with multiple sclerosis (4 men) and 8 healthy controls (4 men) performed 15 min of treadmill walking at a comfortable self-selected speed following muscle strength tests. Participants were injected with ~ 8 mCi of [(18)F] fluorodeoxyglucose during walking after which positron emission tomography/computed tomography imaging was performed. FINDINGS: No differences in muscle strength were detected between multiple sclerosis and control groups (P>0.27). Within the multiple sclerosis, group differences in muscle volume existed between the stronger and weaker legs in the vastus lateralis, semitendinosus, and semimembranosus (P<0.03). Glucose uptake heterogeneity between the groups was not different for any muscle group or individual muscle of the legs (P>0.16, P>=0.05). INTERPRETATIONS: Patients with multiple sclerosis and healthy controls showed similar muscle fiber activity during walking. Interpretations of these results, with respect to our previous study, suggest that walking difficulties in patients with multiple sclerosis may be more associated with altered central nervous system motor patterns rather than alterations in skeletal muscle properties. PMID- 25541394 TI - Synthesis, crystal structure, and properties of a 1-D terbium-substituted monolacunary Keggin-type polyoxotungstate. AB - A new 1-D linear chainlike terbium-substituted polyoxometalate [Tb(H2O)2(alpha PW11O39)](4-) (1) has been synthesized in aqueous solution and characterized by elemental analysis, inductively coupled plasma atomic emission spectrometry (ICP AES), X-ray powder diffraction (XRPD), IR spectrum, thermal analysis, electrospray ionization mass spectrometry (ESI-MS), and X-ray single-crystal diffraction. X-ray structural analysis reveals that 1 displays a 1-D linear chain containing [Tb(H2O)2(alpha-PW11O39)](4-) moieties. The Tb(III) cation incorporated into the monolacunary Keggin-type [alpha-PW11O39](7-) unit resides in a distorted monocapped triangular prismatic geometry and acts as a linker to join two adjacent [alpha-PW11O39](7-) units to form a 1-D chain structure. Solid state photoluminescent property of 1 has been investigated at room temperature and the photoluminescent emission mainly results from the synergistic effect of the Tb(III) cation and the Na7[alpha-PW11O39] precursor. The ESI-MS spectrum of 1 confirms that the polyanion [Tb(H2O)(HPW11O39)](3-) is stable in aqueous solution. PMID- 25541395 TI - DNA binding, photo-induced DNA cleavage and cytotoxicity studies of lomefloxacin and its transition metal complexes. AB - This work was focused on a study of the DNA binding and cleavage properties of lomefloxacin (LMF) and its ternary transition metal complexes with glycine. The nature of the binding interactions between compounds and calf thymus DNA (CT-DNA) was studied by electronic absorption spectra, fluorescence spectra and thermal denaturation experiments. The obtained results revealed that LMF and its complexes could interact with CT-DNA via partial/moderate intercalative mode. Furthermore, the DNA cleavage activities of the compounds were investigated by gel electrophoresis. Mechanistic studies of DNA cleavage suggest that singlet oxygen ((1)O2) is likely to be the cleaving agent via an oxidative pathway, except for Cu(II) complex which proceeds via both oxidative and hydrolytic pathways. Antimicrobial and antitumor activities of the compounds were also studied against some kinds of bacteria, fungi and human cell lines. PMID- 25541396 TI - Potential natural sensitizers extracted from the skin of Canarium odontophyllum fruits for dye-sensitized solar cells. AB - Possibility of use of dye extract from skin samples of a seasonal, indigenous fruit from Borneo, namely Canarium odontophyllum, in dye sensitized solar cells (DSSCs) are explored. Three main groups of flavonoid pigments are detected and these pigments exhibit different UV-vis absorption properties, and hence showing different light harvesting capabilities. When applied in DSSCs. The detected pigment constituents of the extract consist of aurone (maritimein), anthocyanidin (pelargonidin) and anthocyanidin (cyanidin derivatives). When tested in DSSC, the highest conversion efficiency of 1.43% is exhibited by cyanidin derivatives, and this is followed by conversion efficiencies of 0.51% and 0.79% for aurone and pelargonidin, respectively. It is shown that individual pigments, like cyanidin derivatives and pelargonidin, exhibit higher power conversion efficiency when compared to that of C.odontophyllum skin pigment mixture (with a conversion efficiency of only 0.68%). The results indicate a possibility of masking effects of the pigments when used as a mixture. The acidification of C.odontophyllum skin pigments with concentrated hydrochloric acid improves the conversion efficiency of the mixture from 0.68% to 0.99%. The discussion in this paper will draw data and observations from the variation in absorption and adsorption properties, the HOMO-LUMO levels, the energy band gaps and the functional group compositions of the detected flavonoids. PMID- 25541397 TI - Fluorescence sensors for Zn(2+) based on conjugated indole Schiff base. AB - Two novel fluorescence probes based on conjugated Schiff base for the detection of Zn(2+) were developed. Corresponding molecular geometries, orbital energies, electron contributions and absorption properties of the fluorescence probes were calculated at B3LYP/6-31G(*) by density functional theory. The fluorescence properties of the probes were investigated by UV-vis and fluorescence spectrometer. Results indicate that the probes exhibit excellent sensitivity and selectivity for Zn(2+) compared with metal ions examined. For example, the enhancement efficiency of the compound 2 for Zn(2+) is up to 846%. The detection limit of the sensor toward Zn(2+) could low to 1.0*10(-7)M. Moreover, mechanisms for the high selectivity and sensitivity of the probes to Zn(2+) were studied. PMID- 25541398 TI - Identification of the man-made barium copper silicate pigments among some ancient Chinese artifacts through spectroscopic analysis. AB - This article describes the complementary application of non-invasive micro-Raman spectroscopy and energy dispersive X-ray fluorescence spectrometry to the characterization of some ancient Chinese silicate artifacts. A total of 28 samples dated from fourth century BC to third century AD were analyzed. The results of chemical analysis showed that the vitreous PbO-BaO-SiO2 material was used to sinter these silicate artifacts. The barium copper silicate pigments including BaCuSi4O10, BaCuSi2O6 and BaCu2Si2O7 were widely identified from colorful areas of the samples by Raman spectroscopy. In addition, other crystalline phases such as Fe2O3, BaSi2O5, BaSO4, PbCO3 and quartz were also identified. The present study provides very valuable information to trace the technical evolution of man-made barium copper silicate pigments and their close relationship with the making of ancient PbO-BaO-SiO2 glaze and glass. PMID- 25541399 TI - Effect of deposition parameters on the structural properties of ZnO nanopowders prepared by microwave-assisted hydrothermal synthesis. AB - ZnO nanopowders were synthesized via microwave-assisted hydrothermal method at different deposition (microwave irradiation) times and pH values. The effects of pH and deposition (microwave irradiation) time on the crystalline structure and orientation of the ZnO nanopowders have been investigated by X-ray diffraction (XRD) study. XRD observations showed that the crystalline quality of ZnO nanopowders increased with increasing pH value. The crystallite size and texture coefficient values of ZnO nanopowders were calculated. The structural quality of ZnO nanopowder was improved by deposition parameters. Field emission scanning electron microscope (FESEM) was used to analyze the surface morphology of the ZnO nanopowders. Microwave irradiation time and pH value showed a significant effect on the surface morphology. PMID- 25541400 TI - Effect of meso-substituents on the electronic transitions of BODIPY dyes: DFT and RI-CC2 study. AB - In this work, the influence of substituents on the electronic transitions of model 8-R-BODIPY dyes (R=NMe2, NH2, OH, CH3, H, F, SH, Cl, Br, CF3, CN, and NO2) was investigated theoretically using time-dependent density functional theory (TD DFT) and ab initio coupled-cluster doubles (CC2) quantum chemical calculations. Quantum chemical modeling shows a direct relationship between the electron donating and electron withdrawing character of substituents expressed by Hammett substituent constants (sigmap) and changes in energy of the HOMO-LUMO gap modulating spectral shifts of the S0->S1 transition. Good linear correlations of the calculated LUMO energies and sigmap as well as the shape of the HOMO and LUMO allow to obtain a reasonable explanation for the observed effects of substituents. PMID- 25541401 TI - 3,6-diHydroxyflavone/bovine serum albumin interaction in cyclodextrin medium: absorption and emission monitoring. AB - Photophysical properties of a bioactive flavonol which can be used as a model for polyhydroxylated natural flavonols, 3,6-diHydroxyflavone (3,6-diHF) in cyclodextrins (CDs)/bovine serum albumin (BSA) systems have been studied by absorption and fluorescence spectroscopy. The influence of CDs nature and of the different molar ratios BSA/CDs on the fluorescent characteristics of 3,6-diHF, and on the excited - state intramolecular proton transfer (ESIPT) process were studied. Quantitative information on the interaction between 3,6-diHF and BSA in CDs medium, were estimated. The influence of temperature (25-60 degrees C range) on the intrinsic fluorescence of BSA in 3,6-diHF/BSA/CDs systems, was investigated. The results are discussed with relevance to 3,6-diHF as a potential sensitive fluorescence probe in the systems of biological interest. PMID- 25541402 TI - A DFT investigation of structure, spectroscopic properties and tautomerism of the anticonvulsant drug Lyrica. AB - The Lyrica (Pregabalin) is a novel anticonvulsant and neuropathic pain drug, which could exist as four possible conformers. Herein, employing density functional theory (DFT), and handling the solvent effects with the PCM model, the structural parameters, energetic behavior, natural bond orbital analysis (NBO), as well as tautomerism mechanization of the Lyrica are investigated. The L1 (-OH form) is the most stable conformer of the Lyrica, which can be tautomerized to the L5 (-NH form) tautomer. The tautomerism reaction includes an intramolecular proton transfer, which affects considerably the structural parameters and atomic charges of the L1. The DFT-computed NMR chemical shifts and IR vibrational frequencies are good in agreement with the experimental values, confirming suitability of the optimized geometry for the Lyrica. PMID- 25541403 TI - The triazine-based azo-azomethine dyes; synthesis, characterization, spectroscopy, solvatochromism and biological properties of 2,2'-(((6-methoxy 1,3,5-triazine-2,4-diyl)bis(sulfanediyl)bis(2,1 phenylene))bis(azanylylidene)bis(methanylylidene))bis(4-(phenyldiazenyl)phenol). AB - The macrocyclic azo-azomethine dyes 2,2'-(((6-methoxy-1,3,5-triazine-2,4 diyl)bis(sulfanediyl)bis(2,1 phenylene))bis(azanylylidene)bis(methanylylidene))bis(4-(phenyldiazenyl)phenol) and its derivatives were synthesized and characterized by elemental analysis, mass, FT-IR, UV-vis and NMR spectroscopy. The solvatochromism as well as effects of substitutions on the electronic absorption of these compounds have been studied in the DMSO, DMF, THF, CH3CN, CH3OH and CH3COOH as solvents. Also they positive solvatochromism behaviors are explained on the basis of intramolecular hydrogen bonding, enol-keto tautomeric and dipole moment changes. Compounds having electron donating substituent on the phenyl ring showed good antioxidant activity. However, none of them has a considerable antibacterial activity. PMID- 25541404 TI - Synthesis, structural characterization and theoretical approach of 3-(2,6 dichlorobenzyl)-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine. AB - 3-(2,6-Dichlorobenzyl)-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine (DNOI) was synthesized and characterized by X-ray diffraction, FT-IR, FT-Raman and UV-Vis spectra. The X-ray diffraction study showed that DNOI has a one dimensional configuration, due to the intermolecular C9H?O1 and N4H?O2 hydrogen bonds. The benzene ring and the oxadiazine rings are tilted with respect to each other by 63.07 degrees (C3N1C5C6). Vibrational spectra and electronic spectra measurements were made for the compound. Optimized geometrical structure and harmonic vibrational frequencies were computed with DFT (B3LYP, B3P86, and M062X) methods using 6-311++G(d,p) basis set. Assignments of the observed spectra were proposed. The equilibrium geometries computed by all of the methods were compared with X-ray diffraction results. The absorption spectra of the title compound were computed both in gas phase and in CH3OH solution using TD-B3LYP/6-311++G(d,p) and PCM-B3LYP/6-311++G(d,p) approaches, respectively. The calculated results provide a good description of positions of the bands maxima in the observed electronic spectrum. Temperature dependence of thermodynamic parameters in the range of 100 1000K were determined, entropy, heat capacity and enthalpy changes were increasing with temperature increasing, while for Gibbs free energy is decreasing with temperature increasing. The bond orbital occupancies, contribution from parent natural bond orbital (NBO), the natural atomic hybrids was calculated and discussed. PMID- 25541405 TI - Spectral and conformational studies on 3-pyridinealdazine by DFT approach. AB - 3-Pyridinealdazine was synthesized and characterized by FT-IR, (1)H, (13)C NMR and mass spectroscopy. The conformations of azine was determined theoretically besides selected geometrical parameters, HOMO-LUMO energies, polarizability, hyperpolarizability, natural bond orbital (NBO), atomic charges, Mulliken charges and atom in molecule (AIM) analysis were also calculated. The optimized geometry of the symmetrical azine, HOMO-LUMO and molecular electrostatic potential (MEP) surface were also evaluated using B3LYP/6-31G(d,p) basis set. (13)C NMR data were also computed using Gaussian-03 package and compared with the observed values according to density functional theory (DFT) method and analyzed. PMID- 25541406 TI - Application of unfolded principal component analysis-radial basis function neural network for determination of celecoxib in human serum by three-dimensional excitation-emission matrix fluorescence spectroscopy. AB - This study describes a simple and rapid approach of monitoring celecoxib (CLX). Unfolded principal component analysis-radial basis function neural network (UPCA RBFNN) and excitation-emission spectra were combined to develop new model in the determination of CLX in human serum samples. Fluorescence landscapes with excitation wavelengths from 250 to 310nm and emission wavelengths in the range 280-450nm were obtained. The figures of merit for the developed model were evaluated. High performance liquid chromatography (HPLC) technique was also used as a standard method. Accuracy of the method was investigated by analysis of the serum samples spiked with various concentration of CLX and a recovery of 103.63% was obtained. The results indicated that the proposed method is an interesting alternative to the traditional techniques normally used for determining CLX such as HPLC. PMID- 25541407 TI - Effect of chronic p,p'-dichlorodiphenyldichloroethylene (DDE) exposure on high fat diet-induced alterations in glucose and lipid metabolism in male C57BL/6H mice. AB - Diabetes mellitus is a highly prevalent metabolic disease affecting 29.1 million people or 9.3% of the population of the United States. The most prevalent form of diabetes is type 2 diabetes (T2D) which comprises 90-95% of all reported cases of diabetes. While the exact cause of T2D remains an enigma, known risk factors include age, weight, sedentary lifestyle, poor dietary habits, and genetic predisposition. However, these risk factors can not sufficiently explain the increasing prevalence of T2D. Recently, environmental exposures have been explored as potential risk factors. Indeed, epidemiological and limited empirical studies have revealed elevated serum concentrations of certain persistent organic pollutants (POPs), including the bioaccumulative metabolite of p,p' dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), are positively correlated with increased T2D prevalence. The goal of the present study is to determine if chronic exposure to DDE promotes T2D in a widely used in vivo model, the high saturated fat-fed mouse. Male C57BL/6H mice were exposed to DDE (2.0mg/kg) or vehicle (corn oil; 1ml/kg) via gavage for 5 consecutive days, then every 7 days for the duration of the study. One week following the 5 day consecutive DDE dosing, animals were placed on either a low fat (10%kcal from lard) or high fat (45%kcal from lard) diet (HFD) for 13 weeks. Chronic exposure to DDE promoted fasting hyperglycemia after 4 and 8 weeks on the HFD diet and normalized fasting blood glucose levels at week 13. This DDE mediated decrease in fasting hyperglycemia was preceded by improved glucose tolerance at week 12. In addition to normalizing fasting hyperglycemia at the end of high fat feeding, DDE exposure decreased HFD-induced fasting hyperinsulinemia, homeostasis model assessment of insulin resistance (HOMA-IR) values, and hepatic steatosis. Therefore, based on the current data, chronic DDE exposure appears to have a biphasic effect on HFD-induced hyperglycemia in the male C57BL/6H mouse characterized by elevated fasting blood glucose at weeks 4 and 8 of HFD intake followed by normoglycemia upon sacrifice. In addition, chronic DDE exposure reduced HFD-induced hepatic steatosis upon sacrifice. These results indicate chronic exposure to DDE can directly affect systemic glucose and hepatic lipid metabolism and that these effects can be diet dependent. PMID- 25541408 TI - Midterm survival after thoracic endovascular aortic repair in more than 10,000 Medicare patients. AB - OBJECTIVE: Aneurysms and dissections of the descending thoracic aorta represent a complex substrate with a variety of therapeutic options. The introduction of thoracic endovascular aortic repair (TEVAR) has revolutionized the treatment of thoracic aortic disease. However, longitudinal analyses of post-TEVAR outcomes appropriately stratified by aortic disease remain limited. METHODS: A total of 11,996 patients undergoing TEVAR from 2005-2010 were identified from the Medicare/Centers for Medicare and Medicaid Services database. Patients were stratified by underlying aortic disease and the presence of Current Procedural Terminology (CPT) codes. Survival was assessed using Kaplan-Meier analysis. Cox proportional hazards analysis determined predictors of survival from TEVAR. RESULTS: After TEVAR, patients had a median survival of 57.6 months (95% confidence interval, 54.9-61.3 months). Although patients without CPT codes had significantly fewer recorded comorbidities, TEVAR survival was comparable between patients with and without CPT codes (56.3 vs 59.5 months, P = .54). The early and late incidence of death varied significantly by aortic disease. Patients with aortic rupture, acute aortic dissection, and aortic trauma had the highest early incidence of death, whereas late survival was highest in patients with acute aortic dissection, aortic trauma, and isolated thoracic aortic aneurysm. Although hospital TEVAR volume was not associated with survival, an independent hospital effect (determined by using a mixed-effect Cox model) associated certain hospitals with a hazard for death 50% of what it was at other hospitals. CONCLUSIONS: TEVAR has been applied to a multitude of aortic diseases in the Medicare population; early and late post-TEVAR survival varies by aortic disease. The late incidence of death remains high in TEVAR recipients, although certain aortic diagnoses such as acute aortic dissection, aortic trauma, and isolated thoracic aortic aneurysm were associated with improved late survival. An independent hospital effect, but not hospital volume, is correlated with post TEVAR survival. Future analyses of TEVAR outcomes using the Medicare database should adjust for underlying aortic diagnoses and the presence of CPT codes. PMID- 25541410 TI - Outcomes of coronary artery bypass grafting in patients with inflammatory rheumatic diseases: an 11-year nationwide cohort study. AB - OBJECTIVE: Patients with inflammatory rheumatic diseases have an increased risk of developing coronary atherosclerosis. However, outcomes of surgical revascularization in these patients have been rarely studied. We aimed to determine whether, or which, inflammatory rheumatic diseases may pose effects on mortality and adverse cardiac outcomes after coronary artery bypass grafting. METHODS: By using the National Health Insurance Research Database of Taiwan, we identified 40,639 adult patients who underwent first-time coronary artery bypass grafting between 2000 and 2010. Among these patients, 101 had rheumatoid arthritis, 56 had systemic lupus erythematosus, and 73 had ankylosing spondylitis. The odds ratios (ORs) of operative mortality and hazard ratios (HRs) of overall mortality and adverse cardiac outcomes after coronary artery bypass grafting (ie, myocardial infarction and repeat revascularization) in relation to rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis were estimated. RESULTS: With adjustment for potential confounders including patient characteristics, hospital levels, and combined surgery, systemic lupus erythematosus was an independent predictor for operative mortality (adjusted OR, 2.63; 95% confidence interval [CI], 1.04-6.65; P = .04) and ankylosing spondylitis was marginally associated with operative mortality (adjusted OR, 2.41; 95% CI, 0.99-5.88; P = .054). Systemic lupus erythematosus was a significantly independent predictor for overall mortality during the follow-up period (adjusted HR, 2.23; 95% CI, 1.51-3.31; P < .0001) and might increase the risk of repeat revascularization (adjusted HR, 1.89; 95% CI, 0.97-3.68; P = .06). Neither rheumatoid arthritis nor ankylosing spondylitis was significantly associated with overall mortality and adverse cardiac outcomes. CONCLUSIONS: Our study may help surgeons and physicians recognize the potential risks inherent to systemic lupus erythematosus and ankylosing spondylitis when conducting coronary artery bypass grafting and providing follow-up care. PMID- 25541411 TI - Trends in cancer prognosis in a population-based cohort survey: can recent advances in cancer therapy affect the prognosis? AB - BACKGROUND: The aim of the study was to investigate trends in cancer prognosis by examining the relationship between period of diagnosis and probability of death from cancer in a population-based cohort. METHODS: Within a cohort of Japanese men and women aged 40-69 years and free of prior diagnosis of cancer and cardiovascular disease at baseline, data from 4403 patients diagnosed with cancer between 1990 and 2006 and followed up until 2012 were analyzed using survival regression models to assess the presence of an effect of the period of diagnosis (before 1998 versus after 1998) on the risk of dying from cancer. RESULTS: We noted a significant decrease in risk of dying from cancer among individuals diagnosed after 1998 with lung cancer (hazard ratio [HR]=0.676 [0.571-0.800]) or colorectal cancer (HR=0.801 [0.661-0.970]). A decrease in the estimated five-year probability of death from cancer was also noted between the first (before 1998) and the second (after 1998) period of diagnosis for lung and colorectal cancers (e.g., 85.4% vs. 73.3% for lung cancer and 44.6% vs. 37.7% for colorectal cancer, respectively, for stage III in men aged 60 at diagnosis). CONCLUSIONS: This study presented the first scientific evidence of improvement in prognosis for lung and colorectal cancer patients in a population-based cohort in Japan. Our results suggest that recent advances in cancer treatment could have influenced cancer survival differently among lung, colorectal and gastric cancers. PMID- 25541412 TI - The emotions of graduating medical students about prior patient care experiences. AB - OBJECTIVES: To determine the emotional responses to patient care activities described by fourth year medical students. METHODS: Qualitative content analysis for emerging themes in letters written by graduating medical students to patients during a Capstone Course. The patient need not be alive and the letter would never be sent. RESULTS: Six themes emerged from student letters: (1) Sorrow for the depths of patient suffering; (2) Gratitude towards patients and their families; (3) Personal responsibility for care provided to patients; (4) Regret for poor care provided by the student or student's team; (5) Shattered expectations about medicine and training; and (6) Anger towards patients. Students expressed sensitivity to vulnerable patients, including those who were alone, unable to communicate, or for whom care was biased. Students' expressed powerlessness (inability to cure, managing a work-life balance, and challenges with hierarchy) in some essays. CONCLUSION: At graduation, medical students describe strong emotions about previous patient care experiences, including difficulty witnessing suffering, disappointment with medicine, and gratitude to patients and their families PRACTICE IMPLICATIONS: Providing regular opportunities for writing throughout medical education would allow students to recognize their emotions, reflect upon them and promote wellness that would benefit students and their patients. PMID- 25541413 TI - Allosteric activation of the 5-HT3AB receptor by mCPBG. AB - The 5-HT3AB receptor contains three A and two B subunits in an A-A-B-A-B order. However, serotonin function at the 5-HT3AB receptor has been shown to depend solely on the A-A interface present in the homomeric receptor. Using mutations at sites on both the primary (E122) and complementary (Y146) faces of the B subunit, we demonstrate that meta-chlorophenyl biguanide (mCPBG), a 5-HT3 selective agonist, is capable of binding to and activating the 5-HT3AB receptor at all five subunit interfaces of the heteromer. Further, mCPBG is capable of allosterically modulating the activity of serotonin from these sites. While these five binding sites are similar enough that they conform to a monophasic dose - response relationship, we uncover subtle differences in the heteromeric binding sites. We also find that the A-A interface appears to contribute disproportionately to the efficacy of 5-HT3AB receptor activation. PMID- 25541414 TI - Evidence for the existence of pyrimidinergic transmission in rat brain. AB - The uridine nucleotides uridine-5'-triphosphate (UTP) and uridine-5'-diphosphate (UDP) have previously been identified in media from cultured cells. However, no study to date has demonstrated their presence in brain extracellular fluid (ECF) obtained in vivo. Using a novel method, we now show that UTP and UDP, as well as uridine, are detectable in dialysates of striatal ECF obtained from freely-moving rats. Intraperitoneal (i.p.) administration of uridine or exposure of striatum to depolarizing concentrations of potassium chloride increases extracellular uridine, UTP and UDP, while tetrodotoxin (TTX) decreases their ECF levels. Uridine administration also enhances cholinergic neurotransmission which is accompanied by enhanced brain levels of diacylglycerol (DAG) and inositol trisphosphate (IP3) and blocked by suramin, but not by PPADS (pyridoxalphosphate 6-azophenyl-2',4'-disulfonic acid) or MRS2578 suggesting a possible mediation of P2Y2 receptors activated by UTP. These observations suggest that uridine, UTP and UDP may function as pyrimidinergic neurotransmitters, and that enhancement of such neurotransmission underlies pharmacologic effects of exogenous uridine on the brain. PMID- 25541415 TI - The effect of mental health on long-term health-related quality of life following a road traffic crash: results from the UQ SuPPORT study. AB - BACKGROUND: Most research on the consequences of road traffic crashes (RTCs) has focused on serious injury cohorts, yet RTC survivors with minor injury are also affected. This study investigates the relationship between mental health and health-related quality of life (QoL) following an RTC for those with predominately minor injuries. METHODS: A longitudinal cohort design with an opt in consenting procedure was used. A letter of invitation was sent to 3146 claimants within the Compulsory Third Party (CTP) motor vehicle insurance scheme in Queensland, Australia, with a total of 382 (12%) responding to the invitation and consenting to participate in the study. Retention was high (65%) at 24 months. Survey and telephone interview data were collected at approximately 6, 12 and 24 months post-RTC. Health-related QoL (SF-36 v2) data from at least one wave was known for 343 participants. The sample was predominantly female (62%), with an average age of 48.6 years. RESULTS: Participants consistently reported physical and mental health-related QoL below Australian norms. A multilevel regression analysis found overall physical health-related QoL improved with higher expectations of returning to work, but was lower with age, increasing pain, expectations of persistent pain, heightened perceived threat to life, and the presence of Posttraumatic Stress Disorder (PTSD) or Major Depressive Episode (MDE). Overall, mental health-related QoL did not improve with time, was higher with increased social support and expectations of returning to work, but was lower with increasing pain and the presence of PTSD, MDE or Generalised Anxiety Disorder (GAD). Contrary to expectations, lower injury severity was related to poorer mental health-related QoL. CONCLUSIONS: Individuals with predominately minor RTC-related injuries have poor physical and mental health-related QoL, particularly when pain levels are high and comorbid psychiatric disorders are present. Of particular concern is that the low levels of reported health-related QoL do not appear to improve by 2 years post-RTC. The potential risk factors found in this study may be useful indicators for early identification and enhanced rehabilitation of those at risk of poor recovery. PMID- 25541416 TI - The association between hypertension and traumatic intracranial haemorrhage. AB - BACKGROUND: Control of blood pressure is considered essential in the management of trauma patients. In patients with head injuries, both hypotension and hypertension are associated with poor outcomes. The present study was undertaken to ascertain whether hypertension at emergency triage is associated with traumatic intracranial haemorrhage. METHODS: From September 2012 to August 2013, data were collected prospectively for patients who presented with head injury and who received a brain CT examination at a university hospital. Factors associated with intracranial haemorrhage were identified, and logistic regression analysis was used to examine the association between hypertension at emergency department triage and traumatic brain haemorrhage. RESULTS: Of a total of 1457 patients enrolled in this study, 252 (17.3%) experienced traumatic intracranial haemorrhage. After controlling for factors associated with traumatic intracranial haemorrhage, an increased risk of intracranial haemorrhage following an initial brain CT scan was identified for patients presenting initially with a systolic blood pressure >= 180 mm Hg (odds ratio, 1.80; 95% confidence interval, 1.20 2.71, compared with those with 90-139 mm Hg). CONCLUSION: The presence of hypertension at emergency triage is associated with traumatic intracranial haemorrhage. PMID- 25541417 TI - The effect of osteoporotic treatment on the functional outcome, re-fracture rate, quality of life and mortality in patients with hip fractures: a prospective functional and clinical outcome study on 520 patients. AB - Numerous high quality studies have shown the positive effects of various osteoporotic medical treatment regimens on bone mass and on the reduction of risk for new spinal, hip and non-spinal fractures in osteoporotic patients. However, the effect of osteoporotic treatment on the functional and clinical outcome of patients who have sustained hip fractures and been treated surgically has not yet been addressed. Five hundred and twenty patients out of 611 who were admitted (2009-2011), operated on due to a hip fracture and completed their follow-up evaluations were included in this study. Data related to functional outcome scores, re-fracture rate, quality of life and mortality rate were prospectively recorded, analysed and correlated to osteoporotic medical treatment. There were 151 (25%) men and 369 (71%) women with a mean age of 80.7 years (range, 60 to 90 years). At a mean follow-up of 27.5 months (range, 24 to 36 months) a mortality rate of 23.6% at 2 years was recorded. Mean values of functional and quality of life scores were found to have progressively improved within two years after surgery. Seventy-eight (15%) patients were taking osteoporotic treatment before their hip fracture and 89 (17.1%) started afterwards. Osteoporotic treatment proved to be an important predictor of functional recovery (all p values<0.05), re-fracture rate (p=0.028) and quality of life (EQ-5D, all dimensions, p values<0.05). Osteoporotic treatment did not affect post-fracture mortality rates. Osteoporotic treatment taken before or initiated after fracture is a strong predictor of functional and clinical outcome in patients with hip fractures treated surgically. PMID- 25541418 TI - Assessing trauma care provider judgement in the prediction of need for life saving interventions. AB - INTRODUCTION: Human judgement on the need for life-saving interventions (LSI) in trauma is poorly studied, especially during initial casualty management. We prospectively examined early clinical judgement and compared clinical experts' predictions of LSI to their later occurrence. PATIENTS AND METHODS: Within 10-15 min of direct trauma admission, we surveyed the predictions of pre-hospital care providers (PHP, 92% paramedics), trauma centre nurses (RN), and attending or fellow trauma physicians (MD) on the need for LSI. The actual outcomes including fluid bolus, intubation, transfusion (<1h and 1-6h), and emergent surgical interventions were observed. Cohen's kappa statistic (K) and percentage agreement were used to measure agreement among provider responses. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were calculated to compare clinical judgement to actual patient interventions. RESULTS: Among 325 eligible trauma patient admissions, 209 clinical judgement of LSIs were obtained from all three providers. Cohen's kappa statistic for agreement between pairs of provider groups demonstrated no "disagreement" (K<0) between groups, "fair" agreement for fluid bolus (K=0.12-0.19) and blood transfusion 0-6h (K=0.22-0.39), and "moderate" (K=0.45-0.49) agreement between PHP and RN regarding intubation and surgical interventions, but no "excellent" (K >= 0.81) agreement between any pair of provider groups for any intervention. The percentage agreement across the different clinician groups ranged from 50% to 83%. NPV was 90-99% across providers for all interventions except fluid bolus. CONCLUSIONS: Expert clinical judgement provides a benchmark for the prediction of major LSI use in unstable trauma patients. No excellent agreement exists across providers on LSI predictions. It is possible that quality improvement measures and computer modelling-based decision-support could reduce errors of LSI commission and omission found in resuscitation at major trauma centres and enhance decision-making in austere trauma settings by less well-trained providers than those surveyed. PMID- 25541419 TI - Predicting patients that require care at a trauma center: analysis of injuries and other factors. AB - INTRODUCTION: The detection of occult or unpredictable injuries in motor vehicle crashes (MVCs) is crucial in correctly triaging patients and thus reducing fatalities. The purpose of the study was to develop a metric that indicates the likelihood that an injury sustained in a MVC would require management at a Level I/II trauma centre (TC) versus a non-trauma centre (non-TC). METHODS: Transfer Scores (TSs) were computed for 240 injuries that comprise the top 95% most frequently occurring injuries in the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) with an Abbreviated Injury Scale (AIS) severity of 2 or greater. A TS for each injury was computed using the proportions of patients involved in a MVC from the National Inpatient Sample (NIS) that were transferred to a TC or managed at a non-TC. Similarly, a TSMAIS that excludes patients with higher severity co-injuries was calculated using the proportion of patients with a maximum AIS (MAIS) equal to the AIS severity of a given injury. RESULTS: The results indicated for injuries of a given AIS severity, body region, and injury type, there were large variations in the TSMAIS. Overall results demonstrated higher TSMAIS values when injuries were internal, haemorrhagic, intracranial or of moderate severity (AIS 3-5). Specifically, injuries to the head possessed a TSMAIS that ranged from 0.000 to 0.889, with head injuries of AIS 3-5 severities being the most likely to be transferred. DISCUSSION AND CONCLUSIONS: The analysis indicated that the TSMAIS is not solely correlated with AIS severity and therefore it captures other important aspects of injury such as predictability and trauma system capabilities. The TS and TSMAIS can be useful in advanced automatic crash notification (AACN) research for the detection of highly unpredictable injuries in MVCs that require direct transport to a TC. PMID- 25541420 TI - Postinterventional passive expansion of partially dilated transjugular intrahepatic portosystemic shunt stents. AB - PURPOSE: To investigate passive transjugular intrahepatic portosystemic shunt (TIPS) stent expansion in patients with intentional "underdilation" (eg, 10-mm stent, 8-mm balloon) during TIPS creation. MATERIALS AND METHODS: Custom in-house software was developed for objective quantification of cross-sectional stent area from computed tomography (CT) data. The technique was validated by in vitro experiments. The study included 39 patients (22 men; mean age, 59.2 y) who underwent TIPS creation (VIATORR stent graft [W. L. Gore & Associates, Flagstaff, Arizona]; n = 29; WALLSTENT endoprosthesis [Boston Scientific, Marlborough, Massachusetts], n = 10) with stent underdilation. Follow-up CT data of the patients were used to quantify in vivo stent area changes. Data were analyzed by variance analysis and entered into a general linear model to test for interrelations between stent area changes and clinical (eg, cirrhosis grade) and procedural parameters. RESULTS: In vitro validation of the in-house software showed good agreement and reproducibility without overestimation of stent area. Mean clinical follow-up time in patients was 787 days (range, 7-2,450 d). At the time of intervention, VIATORR stent grafts and WALLSTENT endoprostheses were dilated to an average of 64.4% +/- 2.3% and 65.63% +/- 8.52% of nominal area, respectively. At the last imaging follow-up evaluation, this value had increased in all stents to a mean of 87.8% +/- 7.9% (VIATORR) and 82.34% +/- 19.6% (WALLSTENT) in the TIPS tract (P < .05). Multivariate analysis revealed the time after intervention to be the only predictor of stent area in the TIPS tract. There was no significant association between stent expansion and clinical or procedure-related parameters. CONCLUSIONS: The area of self-expanding stents implanted in the liver for TIPS creation with dilation to less than nominal diameter significantly increases over time. This increase has to be considered as an additional factor influencing the long-term portosystemic gradient. PMID- 25541421 TI - Evidence linking FMR1 mRNA and attentional demands of stepping and postural control in women with the premutation. AB - Recent studies in young adult females with the fragile X mental retardation 1 (FMR1) gene premutation (PM) have shown subtle but significant impairments in executive control and postural stability. Less is known about the influence of age and FMR1 gene expression on executive control and postural stability in females with the PM. Here, we examined the attentional demands of reactive stepping using a well-validated measure of choice stepping reaction time under dual-task interference. We explored the interrelationships between step initiation times during a concurrent verbal fluency task and specific impairments in executive control previously reported in females with the PM. Our results showed increased dual-task interference on step initiation times and variability in female PM compared with control subjects. In addition, we observed greater choice stepping reaction time dual-task costs above the breakpoint of 81 CGG repeats relative to below this CGG range. Dual-task interference on both reaction time and movement time were significantly predicted by low working memory capacity in female PM carriers. Importantly, we revealed that FMR1 messenger RNA level is the most significant predictor accounting for dual-task stepping variability in both reaction time and movement time in PM females. These findings for the first time provide evidence linking elevated FMR1 messenger RNA levels that have been previously associated with FMR1 RNA toxicity and deficits in cerebellar motor and cognitive networks in a subgroup of at-risk PM women. PMID- 25541423 TI - Computed-tomography modeled polyether ether ketone (PEEK) implants in revision cranioplasty. AB - PURPOSE: Traditional cranioplasty methods focus on pre-operative or intraoperative hand molding. Recently, CT-guided polyether ether ketone (PEEK) plate reconstruction enables precise, time-saving reconstruction. This case series aims to show a single institution experience with use of PEEK cranioplasty as an effective, safe, precise, reusable, and time-saving cranioplasty technique in large, complex cranial defects. METHODS: We performed a 6-year retrospective review of cranioplasty procedures performed at our affiliated hospitals using PEEK implants. A total of nineteen patients underwent twenty-two cranioplasty procedures. Pre-operative, intra-operative, and post-operative data was collected. RESULTS: Nineteen patients underwent twenty-two procedures. Time interval from injury to loss of primary cranioplasty averaged 57.7 months (0-336 mo); 4.0 months (n=10, range 0-19) in cases of trauma. Time interval from primary cranioplasty loss to PEEK cranioplasty was 11.8 months for infection (n=11, range 6-25 mo), 12.2 months for trauma (n=5, range 2-27 mo), and 0.3 months for cosmetic or functional reconstructions (n=3, range 0-1). Similar surgical techniques were used in all patients. Drains were placed in 11/22 procedures. Varying techniques were used in skin closure, including adjacent tissue transfer (4/22) and free tissue transfer (1/22). The PEEK plate required modification in four procedures. Three patients had reoperation following PEEK plate reconstruction. CONCLUSION: Cranioplasty utilizing CT-guided PEEK plate allows easy inset, anatomic accuracy, mirror image aesthetics, simplification of complex 3D defects, and potential time savings. Additionally, it's easily manipulated in the operating room, and can be easily re-utilized in cases of intraoperative course changes or infection. PMID- 25541424 TI - Electroejaculation and semen buffer evaluation in the microbat Carollia perspicillata. AB - Scientific interests and conservation needs currently stress the necessity to better understanding bat reproductive biology. In this study, we present the first, safe, inexpensive, and reliable method to obtain sperm from a microbat species (Carollia perspicillata) by electroejaculation. This method revealed to be highly efficient (100% success rate). We obtained ejaculates composed of two characteristically different fractions. We compared three buffers and recommend using an Earle's balanced salt solution as a semen extender. Earle's balanced salt solution provided significant repeatable measure of swimming ability (intraclass correlation coefficient: 0.74, P < 0.01) and proportion of motile sperms (intraclass correlation coefficient: 0.08, P = 0.01) and allowed sperm to maintain optimal swimming capacity over time. None of the buffers could dissolve all the coagulated sperm. Although the trypsin buffer freed a larger fraction of spermatozoa in the ejaculate, it impaired swimming ability without improving motility, viability, and stamina. We thus argue that the sperm population analyzed with Earle's balanced salt solution is a representative of the ejaculate. Finally, we found that the mean sperm velocity of C perspicillata (78.8 MUm/s) is lower than that predicted by regressing sperm velocity on relative testes mass, a proxy of sperm competition. The question as to whether C perspicillata is an outsider for sperm velocity, or whether bats evolved yet another unique mechanism to cope with sperm competition deserves more investigations. PMID- 25541425 TI - NMR crystallography of ezetimibe co-crystals. AB - An efficient, simplified protocol for solvent-drop assisted co-crystal preparation of ezetimibe (a drug for the treatment of primary hypercholesterolemia) with both imidazole and l-proline has been derived. The structures of the white powders were successfully solved via "NMR crystallography" combining solid-state NMR, powder X-ray diffraction and DFT chemical shift computations. Detailed insights into the likely crystallization mechanism were obtained from competition experiments, where efficient co crystallization was feasible using ezetimibe monohydrate as precursor indicating that the crystal water acts as "molecular catalyst". It was also found that co crystallization of imidazole is favored over l-proline, thus suggesting a clear preference of neutral hydrogen bonds compared to charge-assisted motifs. PMID- 25541422 TI - Intraneuronal Abeta accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK 3. AB - Amyloid beta-protein (Abeta) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Abeta42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K(+) currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Abeta42-induced effects. Extracellular perfusion and subsequent internalization of Abeta42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 alpha-subunit, a molecular determinant of A-type K(+) currents, at Ser-616. In acute hippocampal slices derived from an adult triple-transgenic Alzheimer's mouse model, characterized by endogenous intracellular accumulation of Abeta42, CA1 pyramidal neurons exhibit hyperexcitability accompanied by increased phosphorylation of Kv4.2 at Ser-616. Collectively, these data suggest that intraneuronal Abeta42 accumulation leads to an intracellular cascade culminating into caspases activation and GSK-3-dependent phosphorylation of Kv4.2 channels. These findings provide new insights into the toxic mechanisms triggered by intracellular Abeta42 and offer potentially new therapeutic targets for Alzheimer's disease treatment. PMID- 25541426 TI - If there is a "time to target temperature paradox" in post-cardiac arrest care, would we know? PMID- 25541427 TI - Video laryngoscopy improves the first-attempt success in endotracheal intubation during cardiopulmonary resuscitation among novice physicians. AB - AIM: To compare the first-attempt success in endotracheal intubation (ETI) during cardiopulmonary resuscitation (CPR) using direct laryngoscopy (DL) and video laryngoscopy (VL) (GlideScope((r))) among novice emergency physicians (EPs). METHODS: This study is a historically controlled clinical design. From May 2011 to April 2013 out-of-hospital cardiac arrest patients were intubated during CPR by novice EPs. CPR data was automatically recorded by pre-installed video and subsequently analysed. The primary outcome was the success rate of the first attempt at ETI. In addition, time to successful ETI from first-attempt (T complete), duration of chest compression interruptions, and incidence of oesophageal intubation were compared. RESULTS: Of 305 patients undergoing ETI, 83 were intubated by novice EPs. The success rate of first-attempt ETI in the VL group (n=49) was higher than that in the DL group (n=34, 91.8% vs. 55.9%; p<0.001). The median T-complete was significantly shorter with VL than with DL (37 [29-55] vs. 62 [56-110] s; p<0.001). Oesophageal intubation was observed only in the DL group (n=6, 17.6%). The median duration of chest compression interruptions was greater with DL (7 [3-6] s) than with VL (0 [0-0] s). Improvements in ETI during CPR were observed in the VL group after the first 3 months, but not the DL group during regular use for 1 year. CONCLUSIONS: For novice EPs, the VL could significantly improve the first-attempt success in ETI during CPR while the DL couldn't improve it. PMID- 25541428 TI - Efficacy of diffusion-weighted magnetic resonance imaging performed before therapeutic hypothermia in predicting clinical outcome in comatose cardiopulmonary arrest survivors. AB - AIM OF THE STUDY: To develop a clinically relevant and qualitative brain magnetic resonance imaging (MRI) scoring system for acute stage comatose cardiac arrest patients. METHODS: Consecutive comatose post-cardiopulmonary arrest patients were prospectively enrolled. Routine brain MRI sequences were scored by two independent and blinded experts. Predefined brain regions were qualitatively scored on diffusion-weighted imaging (DWI) sequences according to the severity of the abnormality on a scale from 0 to 4. The mean score provided by the raters determined poor outcome defined under the Cerebral Performance Categories 3, 4, or 5. DWI scans were repeated after therapeutic hypothermia (TH). The same qualitative scoring system was applied and results were compared to the initial scores. RESULTS: Out of 24 recruited patients, 19 with brain MRI scans were included. Of the 19 included patients, seven showed a good outcome at hospital discharge and 12 patients showed poor neurologic outcome. Median time from the arrest to the initial DWI was 166min (IQR 114-240min). At 100% specificity, the overall, cortex, and cortex plus deep grey nuclei scores predicted poor patient outcome with a sensitivity of 91.7-100% (95% CI). Follow-up DWI scans after TH showed worse results than initial scans. CONCLUSION: A qualitative MRI scoring system effectively assessed the severity of hypoxic-ischaemic brain injury following cardiopulmonary arrest. The scoring system may provide useful prognostic information in comatose cardiopulmonary arrest patients. PMID- 25541430 TI - The significance of pre-arrest factors in out-of-hospital cardiac arrests witnessed by emergency medical services: a report from the Victorian Ambulance Cardiac Arrest Registry. AB - BACKGROUND: The significance of pre-arrest factors in out-of-hospital cardiac arrests (OHCA) witnessed by emergency medical services (EMS) is not well established. The purpose of this study was to assess the association between prodromal symptoms and pre-arrest clinical observations on the arresting rhythm and survival in EMS witnessed OHCA. METHODS: Between 1st January 2003 and 31st December 2011, 1056 adult EMS witnessed arrests of a presumed cardiac aetiology were identified from the Victorian Ambulance Cardiac Arrest Registry. Pre-arrest prodromal features and clinical characteristics were extracted from the patient care record. Backward elimination logistic regression was used to identify pre arrest factors associated with an initial shockable rhythm and survival to hospital discharge. RESULTS: The median age was 73.0 years, 690 (65.3%) were male, and the rhythm of arrest was shockable in 465 (44.0%) cases. The most commonly reported prodromal symptoms prior to arrest were chest pain (48.8%), dyspnoea (41.8%) and altered consciousness (37.8%). An unrecordable systolic blood pressure was observed in 34.4%, a respiratory rate <13 or >24min(-1) was present in 43.1%, and 45.5% had a Glasgow coma score <15. In the multivariable analysis, the following pre-arrest factors were significantly associated with survival: age, public location, aged care facility, chest pain, arm or shoulder pain, dyspnoea, dizziness, vomiting, ventricular tachycardia, pulse rate, systolic blood pressure, respiratory rate, Glasgow coma score, aspirin and inotrope administration. CONCLUSION: Pre-arrest factors are strongly associated with the arresting rhythm and survival following EMS witnessed OHCA. Potential opportunities to improve outcomes exist by way of early recognition and management of patients at risk of OHCA. PMID- 25541429 TI - Higher achieved mean arterial pressure during therapeutic hypothermia is not associated with neurologically intact survival following cardiac arrest. AB - INTRODUCTION: To determine if higher achieved mean arterial blood pressure (MAP) during treatment with therapeutic hypothermia (TH) is associated with neurologically intact survival following cardiac arrest. METHODS: Retrospective analysis of a prospectively collected cohort of 188 consecutive patients treated with TH in the cardiovascular intensive care unit of an academic tertiary care hospital. RESULTS: Neurologically intact survival was observed in 73/188 (38.8%) patients at hospital discharge and in 48/162 (29.6%) patients at a median follow up interval of 3 months. Patients in shock at the time of admission had lower baseline MAP at the initiation of TH (81 versus 87mmHg; p=0.002), but had similar achieved MAP during TH (80.3 versus 83.7mmHg; p=0.11). Shock on admission was associated with poor survival (18% versus 52%; p<0.001). Vasopressor use among all patients was common (84.6%) and was not associated with increased mortality. A multivariable analysis including age, initial rhythm, time to return of spontaneous circulation, baseline MAP and achieved MAP did not demonstrate a relationship between MAP achieved during TH and poor neurological outcome at hospital discharge (OR 1.28, 95% CI 0.40-4.06; p=0.87) or at outpatient follow up (OR 1.09, 95% CI 0.32-3.75; p=0.976). CONCLUSION: We did not observe a relationship between higher achieved MAP during TH and neurologically intact survival. However, shock at the time of admission was clearly associated with poor outcomes in our study population. These data do not support the use of vasopressors to artificially increase MAP in the absence of shock. There is a need for prospective, randomized trials to further define the optimum blood pressure target during treatment with TH. PMID- 25541431 TI - Video laryngoscopy versus direct laryngoscopy for tracheal intubation during in hospital cardiopulmonary resuscitation. AB - AIM: Tracheal intubation during cardiopulmonary resuscitation (CPR) is a high risk procedure. Here, we investigated the efficacy of video laryngoscopy for tracheal intubation during CPR. METHODS: Data regarding tracheal intubation during CPR from in-hospital cardiac arrests occurring between January 2011 and December 2013 (n=229) were prospectively collected and retrospectively analyzed. RESULTS: The initial laryngoscopy method was video laryngoscopy in 121 patients (52.8%) and direct laryngoscopy in 108 patients (47.2%). The rate of successful intubation at the first attempt was higher with video laryngoscopy (71.9%; 87/121) than with direct laryngoscopy (52.8%; 57/108; p=0.003). The rate of success at the first attempt was higher for experienced (73.0%; 84/115) than inexperienced operators, including residents (52.6%; 60/114; p=0.001). Mortality at day 28 after CPR was not significantly different between patients with successful tracheal intubation at the first attempt and without (68.1% [98/144] vs. 67.1% [57/85]; p=0.876). In multivariate logistic regression analysis, a predicted difficult airway (odds ratio [95% confidence interval]=0.22 [0.10 0.49]; p<0.001), intubation by an experienced operator (2.63 [1.42-4.87]; p=0.002), and use of video laryngoscopy rather than direct laryngoscopy (2.42 [1.30-4.45]; p=0.005) were independently associated with a successful tracheal intubation at the first attempt. CONCLUSION: Use of video laryngoscopy during CPR from in-hospital cardiac arrest is independently associated with successful tracheal intubation at the first attempt. PMID- 25541432 TI - The role of type I interferons and other cytokines in dermatomyositis. AB - Much work has been done to unveil the mechanisms behind the pathogenesis of dermatomyositis (DM) - mainly those involving certain pathogenic cytokines, termed "pathokines" as the principal cytokines involved. Recently, it has become clear that a group of cytokines known as type I interferons (IFN-Is) play a significant role in the development of DM. We review the literature published between 1946 and 2014 using an Ovid Medline database search to provide an update on the role of IFN-Is and other cytokines in the pathogenesis of DM. We provide information about the genes and proteins induced by IFN-Is and potential mechanisms by which these downstream products relate to clinical disease activity. We also explore findings of other autoimmune phenomena that may contribute to disease onset and activity including T-helper 17 (Th17) cells and associated interleukins, as well as autoantibodies. Finally, we provide a brief update on current treatment options for DM as well as some new immunomodulatory treatment modalities in development. PMID- 25541433 TI - Relationship of common vascular endothelial growth factor polymorphisms and haplotypes with the risk of cervical cancer in Tunisians. AB - OBJECTIVE: We investigated the association between common vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) and the risk of cervical cancer (CC) in Tunisian patients and control women. METHODS: Study subjects comprised 86 CC cases and 124 control women. Genotyping of VEGF rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068, rs833070, rs3025039 SNPs was done by real-time PCR. RESULTS: Higher minor allele frequencies (MAF) of rs699947 (-2578C/A) [P=0.04; OR (95% CI)=1.52 (1.02-2.29)], and rs1570360 ( 1154G/A) [P=0.04; OR (95% CI)=1.58 (1.01-2.47)] were seen in CC cases compared to control women. Marked differences in the distribution of rs699947 (P=9*10(-4)) and rs1570360 (P=0.03) genotypes were seen between CC cases and control groups; the distribution of the remaining SNPs was comparable between CC cases and control women. The association of rs699947 and rs1570360 with heightened CC risk with was seen in the heterozygous, and more so in the homozygous states. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068 and rs833070 but weak or no LD between rs3025039 and the other SNPs. Seven-locus (rs699947/rs833061/rs1570360/rs2010963/rs25648/rs833068/ rs833070) haploview analysis identified only CTGCCAG haplotype to be positively associated with CC [P=0.022; OR(95% CI)=1.74 (1.08-2.79)]. CONCLUSION: Specific VEGF variants (rs699947, rs1570360) and haplotype (CTGCCAG) may contribute to the development of CC among Tunisian women. PMID- 25541435 TI - Prognostic impact of hepatic resection for hepatocellular carcinoma: the role of the surgeon in achieving R0 resection--a retrospective cohort study. AB - INTRODUCTION: Improvement in long-term survival of patients with hepatocellular carcinoma (HCC) has followed the developments in surgical techniques and multidisciplinary therapies. The role of the surgeon has rarely been studied and to fill this research gap we offer this study which has reviewed the outcome of surgery in attempted curative resection for this condition. METHODS: The clinical data of patients who underwent partial hepatectomy for HCC from January 2003 to December 2010 at the First People's Hospital of Foshan were collected and retrospectively analyzed. RESULTS: Of 104 HCC patients, the 1-, 3-, and 5-year disease free survival (DFS) rates were 64.8%, 45.5%, and 38.5%, respectively, and the 1-, 3-, and 5-year overall survival (OS) rates were 86.3%, 63.6%, and 57.2%, respectively. Negative resection margin and tumor TNM stage were independent prognostic factors of DFS and OS (P<0.0001). CONCLUSIONS: Negative resection margin and tumor TNM stage were the two most significant prognostic factors of survival in HCC patients after partial hepatectomy. As TNM stage is a factor not subjected to control, surgeons can improve the long-term survival of patients with HCC by ensuring an appropriate negative resection margin. PMID- 25541434 TI - Cytokines pre-determined by genetic factors are involved in pathogenesis of Rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is associated with the presence of autoreactive CD4 T cells that produce pro-inflammatory cytokines. The role of genetic factors in the predilection to develop RA is strongly supported by the increased presence of certain HLA class II molecules in patients. The HLA class II genes are highly polymorphic and are critical for generating an immune response to clear infections. Production of Th1 and Th17 response by the CD4 T cells helps to clear infections. HLA-DQ8 is a promiscuous binder and presents many peptides generating immune response and producing a Th17 response. DRB1*0401 is associated with the production of both IL-17 and IFN-gamma. Thus both DR4 and DQ8 can clear infections by producing TH1/Th17 cytokines, but their presence increases the risk of developing RA. Using transgenic mice expressing human HLA genes, we have shown that HLA polymorphism determines the cytokine profile. DRB1*04 molecules modulate the DQ8-restricted response and determine the outcome of arthritis in mice carrying DR4/DQ8 haplotype. Thus, interaction between DQ and DR molecules determines the cytokine milieu and propensity of the HLA haplotype to predispose to autoimmunity. PMID- 25541436 TI - 17beta-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function: a preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutation. AB - OBJECTIVE: We investigated the effect of ovariectomy (OVX) and 17beta-estradiol (E2) replacement on both mitochondrial and myocardial function in cTnT-Q92 transgenic mice generated by cardiac-restricted expression of a human hypertrophic cardiomyopathy (HCM) mutation. METHODS: The cTnT-Q92 mice were ovariectomized at twenty weeks of age and were treated with either placebo (OVX group) or E2 (OVX+E2 group) for twelve weeks before being sacrificed. Wild-type and cTnT-Q92 female mice receiving sham operation were used as controls. Indices of diastolic function such as mitral early (E) and late (A) inflow as well as isovolumic relaxation time (IVRT) were measured by echocardiography. A Clark-type electrode was used to detect respiratory control, and ATP levels were determined at the mitochondrial level using HPLC. Key components related to mitochondrial energy metabolism, such as peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma coactivator 1alpha (PGC-1alpha) and nuclear respiratory factor-1 (NRF-1), were also analyzed using Western blot and RT-PCR. The levels of oxidative stress markers were determined by measuring malondialdehyde (MDA) using the thiobarbituric acid assay. RESULTS: The cTnT-Q92 mice had impaired diastolic function compared with wild-type mice (E/A ratio, 1.39 +/- 0.04 vs. 1.21 +/- 0.01, p<0.001; IVRT, 19.17 +/- 0.85 vs. 22.15 +/- 1.43 ms, p=0.028). In response to ovariectomy, cardiac function further decreased compared with that observed in cTnT-Q92 mice that received the sham operation (E/A ratio, 1.15 +/- 0.04 vs. 1.21 +/- 0.01, p<0.001; IVRT, 28.31 +/- 0.39 vs. 22.15 +/- 1.43 ms, p=0.002). Myocardial energy metabolism, as determined by ATP levels (3.49 +/- 0.31 vs. 5.07 +/- 0.47 MUmol/g, p<0.001), and the mitochondrial respiratory ratio (2.04 +/- 0.10 vs. 2.63 +/- 0.11, p=0.01) also decreased significantly. By contrast, myocardial concentrations of MDA increased significantly in the OVX group, and PGC-1alpha, PPARalpha and NRF-1decreased significantly. E2 supplementation significantly elevated myocardial ATP levels (4.55 +/- 0.21 vs. 3.49 +/- 0.31 MUmol/g, p=0.003) and mitochondrial respiratory function (3.93 +/- 0.05 vs. 2.63 +/- 0.11, p=0.001); however, it reduced the MDA level (0.21 +/- 0.02 vs. 0.36 +/- 0.03 nmol/g, p<0.001), which subsequently improved diastolic function (E/A ratio, 1.35 +/- 0.06 vs. 1.15 +/- 0.04, p<0.001; IVRT, 18.22 +/- 1.16 vs. 28.31 +/- 0.39 ms, p=0.007). CONCLUSIONS: Our study has shown that 17beta-estradiol improved myocardial diastolic function, prevented myocardial energy dysregulation, and reduced myocardial oxidative stress in cTnT-Q92 mice. PMID- 25541437 TI - Detection and functional portrayal of a novel class of dihydrotestosterone derived selective progesterone receptor modulators (SPRM). AB - In early pregnancy, abortion can be induced by blocking the actions of progesterone receptors (PR). However, the PR antagonist, mifepristone (RU38486), is rather unselective in clinical use because it also cross-reacts with other nuclear receptors. Since the ligand-binding domain of human progesterone receptor (hPR) and androgen receptor (hAR) share 54% identity, we hypothesized that derivatives of dihydrotestosterone (DHT), the cognate ligand for hAR, might also regulate the hPR. Compounds designed and synthesized in our laboratory were investigated for their affinities for hPRB, hAR, glucocorticoid receptor (hGRalpha) and mineralocorticoid receptor (hMR), using whole cell receptor competitive binding assays. Agonistic and antagonistic activities were characterized by reporter assays. Nuclear translocation was monitored using cherry-hPRB and GFP-hAR chimeric receptors. Cytostatic properties and apoptosis were tested on breast cancer cells (MCF7, T-47D). One compound presented a favorable profile with an apparent neutral hPRB antagonistic function, a selective cherry-hPRB nuclear translocation and a cytostatic effect. 3D models of human PR and AR with this ligand were constructed to investigate the molecular basis of selectivity. Our data suggest that these novel DHT-derivatives provide suitable templates for the development of new selective steroidal hPR antagonists. PMID- 25541439 TI - Increased TSH in obesity: Evidence for a BMI-independent association with leptin. AB - AIM: This study aimed to determine whether the association between thyroid stimulating hormone (TSH) and body mass index (BMI) is related to leptin concentration in obese individuals. METHODS: Plasma TSH and leptin assays were performed in 800 consecutive patients, hospitalized for a nutritional checkup, with a BMI >= 30 kg/m(2). Various anthropometric, hormonal and metabolic parameters, including age, weight, BMI, insulin, leptin and TSH, were measured or calculated. Univariate and multivariate regression analyses were performed to identify any significant relationships between these parameters. Also, characteristics of the patients in the lowest and highest quartiles of TSH distribution were compared. RESULTS: TSH was positively correlated with both BMI and leptin. When multiple regression analysis was performed, TSH and leptin maintained a significant association independent of BMI. Patients in the fourth quartile of TSH distribution displayed higher BMI and higher leptin levels in comparison to the first quartile. CONCLUSION: Our study has confirmed an increase in TSH in conjunction with BMI in obese subjects. This increase was correlated with leptin independently of BMI. It is hypothesized that the increase in TSH observed in obese subjects was the consequence of both fat mass accumulation and a positive energy-balance. PMID- 25541440 TI - Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review. AB - Transdermal drug delivery (TDD) is limited by the outer layer of the skin, i.e., the stratum corneum. Research on TDD has become very active in the recent years and various technologies have been developed to overcome the resistance of the stratum corneum to molecular diffusion. In particular, researchers have started to consider the possibility of combining the TDD technologies in order to have further increase in drug permeability. Both microneedles (MNs) and ultrasound are promising technologies. They achieve enhancement in drug permeation via different mechanisms and therefore give a good potential for combining with each other. This review will focus on discussing the potential of this combinational technique along with other important issues, e.g., the mechanisms of ultrasound and MNs as it is and these mechanisms which are coupled via the two systems (i.e. MNs and ultrasound). We discuss the possible ways to achieve this combination as well as how this combination would increase the permeability. Some of the undeveloped (weaker) research areas of MNs and sonophoresis are also discussed in order to understand the true potential of combining the two technologies when they are developed further in the future. We propose several hypothetical combinations based on the possible mechanisms involved in MNs and ultrasound. Furthermore, we carry out a cluster analysis by which we determine the significance of this combinational method in comparison with some other selected combinational methods for TDD (e.g., MNs and iontophoresis). Using a time series analysis tool (ARIMA model), the current trend and the future development of combined MNs and ultrasound are also analysed. Overall, the review in this paper indicates that combining MNs and ultrasound is a promising TDD method for the future. PMID- 25541438 TI - HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44(+)/CD24(-/low) tumor-initiating subpopulation in basal-like breast cancer. AB - Tumor-initiating cells (also known as cancer stem cells) are the subpopulation of cells shown to be responsible for tumor initiation, maintenance and recurrence. In breast cancer, CD44(+)/CD24(-/low) cells were identified as tumor-initiating cells. We previously reported that a Gemini vitamin D analog, 1,25-dihydroxy-20R 21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro cholecalciferol (BXL0124), reduced CD44(+)/CD24(-/low) cells in MCF10DCIS basal like breast cancer cells. Since Notch has been identified as one of the key signaling pathways involved in breast cancer stem cells, the effect of BXL0124 on the Notch signaling pathway was investigated in breast cancer. The CD44(+)/CD24( /low) subpopulation of MCF10DCIS cells showed elevated Notch1 signaling and increased cell proliferation compared to the CD44(+)/CD24(high) subpopulation. Treatment with the Gemini vitamin D analog BXL0124 decreased the level of activated Notch1 receptor. In addition, mRNA and protein levels of the Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly reduced by treatment with BXL0124, which was followed by repression of c-Myc, a key downstream target of Notch signaling. Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by treatment with BXL0124. The inhibitory effect of BXL0124 on Notch signaling was reversed by knockdown of HES1. Overexpression of HES1 inhibited Notch1 signaling and reduced the CD44(+)/CD24(-/low) subpopulation, confirming a role of HES1 in Notch1 signaling. In conclusion, the Gemini vitamin D analog, BXL0124, represses the tumor-initiating subpopulation by HES1-mediated inhibition of Notch1 signaling. The present study demonstrates BXL0124 as a potent inhibitor of Notch signaling to target tumor-initiating cells in basal-like breast cancer. This article is part of a Special Issue entitled "17th Vitamin D Workshop". PMID- 25541442 TI - Editor's annual report: strengthening the core, expanding the range. PMID- 25541441 TI - In vivo study of the mucus-permeating properties of PEG-coated nanoparticles following oral administration. AB - The aim of this work was to investigate the mucus-permeating properties of poly(ethyleneglycol)-coated nanoparticles prepared from the copolymer of methyl vinyl ether and maleic anhydride (Gantrez(r) AN) after oral administration in rats. Nanoparticles were "decorated" with PEGs of different molecular masses (PEG2000, PEG6000 and PEG10000) at a PEG-to-polymer ratio of 0.125. All the PEG coated nanoparticles displayed a mean size of ~150 nm, slightly negative zeta values and a "brush" conformation as determined from the calculation of the PEG density. For in vivo studies, nanoparticles were labelled with either (99m)Tc or fluorescent tags. Naked nanoparticles displayed a higher ability to interact with the mucosa of the stomach than with the small intestine. However, these interactions were restricted to the mucus layer covering the epithelial surface, as visualised by fluorescence microscopy. On the contrary, PEG-coated nanoparticles moved rapidly to the intestine, as determined by imaging, and, then, were capable to develop important interactions with the mucosa, reaching the surface of the epithelium. These mucus permeating properties were more intense for nanoparticles coated with PEG2000 or PEG6000 than with PEG10000. However, the capability of nanocarriers to develop adhesive interactions within the mucosa decreased when prepared at excessive PEG densities. PMID- 25541443 TI - JVIR: the beginning (1987-1995). PMID- 25541444 TI - Thrombolysis and iliofemoral vein stent placement in cancer patients with lower extremity swelling attributed to lymphedema. AB - PURPOSE: To assess the effects of iliofemoral vein stent placement on symptomatic lower extremity swelling (LES), presumed to be lymphedema, in patients with cancer. MATERIALS AND METHODS: During the period 2005-2013, 62 patients (38 female; age, 60.4 y +/- 15.4) with histology-proven metastatic disease and LES resistant to standard therapies were evaluated and found to have venous outflow obstruction. Stents were placed in the iliofemoral veins or inferior vena cava, or both, and evaluated by color Doppler ultrasound or contrast-enhanced computed tomography during the follow-up period. Patient symptoms were assessed using the Venous Disability Score (VDS) and the Galway Limb Swelling score, a patient directed, 5-question symptom scoring system. RESULTS: Stents were successfully placed in all patients. During the follow-up period, in-stent thrombosis occurred in 13 patients, and additional stents were placed in 3 patients to treat luminal narrowing. The mean VDS improved significantly (P < .05): from 3.0 +/- 0 on the day of the procedure to 2.95 +/- 0.22 on day 3, 2.0 +/- 0.33 on day 7, and 1.87 +/- 0.34 on day 30. The mean Galway Limb Swelling score also improved significantly (P < 0.001): from 3.6 +/- 0.74 on the day of the procedure to 1.96 +/- 0.91 on day 3, 1.06 +/- 0.78 on day 7, and 0.6 +/- 0.66 on day 30. During the follow-up period, 60 patients died as a result of their underlying malignancy (mean, 230 d; range, 5-1,080 d). CONCLUSIONS: Iliofemoral or iliocaval venous stent placement may have a valuable role in patients with metastatic disease and symptomatic LES associated with venous obstruction. PMID- 25541445 TI - Percutaneous discal cyst rupture in a professional football player using sublaminar epidural injection for thecal sac displacement. AB - A case of percutaneous discal cyst rupture in a 25-year-old professional American football player is reported. The patient presented with a 3-day history of severe left-sided back pain. Magnetic resonance imaging examination demonstrated a discal cyst effacing the left L4-L5 lateral recess, with interposed thecal sac. A sublaminar epidural injection was performed displacing the thecal sac, exposing the discal cyst, and allowing for percutaneous perforation. The patient had complete resolution of symptoms after discal cyst rupture and was able to compete in a professional football game 3 days later. Computed tomography-guided percutaneous rupture is a therapeutic modality that may be considered for treatment of a symptomatic discal cyst. PMID- 25541446 TI - Prostatic artery embolization for treatment of benign prostatic hyperplasia in patients with prostates > 90 g: a prospective single-center study. AB - PURPOSE: To describe the safety and efficacy of prostatic artery embolization (PAE) with spherical microparticles to treat lower urinary tract symptoms associated with benign prostatic hyperplasia in patients with prostate volume > 90 g. MATERIALS AND METHODS: This prospective, single-center, single-arm study was conducted in 35 patients with prostate volumes ranging from 90-252 g. Mean patient age was 64.8 years (range, 53-77 y). Magnetic resonance imaging, uroflowmetry, and the International Prostate Symptom Score (IPSS) were used to assess clinical and functional outcomes. RESULTS: Mean prostate size decreased significantly from 135.1 g before PAE to 91.9 g at 3 months of follow-up (P < .0001). Mean IPSS and quality-of-life index improved from 18.3 to 2.7 and 4.8 to 0.9 (P < .0001 for both), respectively. A significant negative correlation was observed between prostate-specific antigen at 24 hours after PAE and IPSS 3 months after PAE (P = .0057). CONCLUSIONS: PAE is a safe and effective treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia in patients with prostate volume > 90 g. Excessively elevated prostate-specific antigen within 24 hours of PAE is associated with lower symptom burden in short term follow-up. PMID- 25541447 TI - Match day: online search trends reflect growing interest in IR training. AB - Google Trends was used to characterize the relationship between the interventional radiology (IR) applicant pool and related Internet queries for "IR fellowship" from July 2006 to July 2013. Results were compared with National Residency Match Panel data by regression analysis and one-way analysis of variance. Search traffic for IR fellowship demonstrated a statistically significant linear annual increase (R(2) = 0.87; P = .0013). Total IR applicants increased by 184% (R(2) = 0.98; P = .0216). Search traffic was predictive of applicants for each match year (R(2) = 0.92; P = .0004) and programs filled (R(2) = 0.93; P = .0003). Internet queries mirror trainee professional interests, with significant increases in search traffic related to IR fellowship and strong correlation with growth in applicants. PMID- 25541448 TI - The hangman technique: a modified loop snare technique for the retrieval of inferior vena cava filters with embedded hooks. AB - The loop snare technique is a method for inferior vena cava (IVC) filter retrieval that creates a wire loop between the filter legs; this technique may fail in cases with an embedded hook. This report describes the hangman technique, a modified loop snare technique for filter retrieval that creates a wire loop between the filter neck and IVC wall for release of embedded filter hooks. The hangman technique was attempted in 11 cases complicated by tilt (mean tilt, 13.3 degrees +/- 3.9) and an embedded hook (mean dwell time, 194.5 d) with a retrieval success rate of 81.8% (9 of 11 cases) and no associated complications. PMID- 25541449 TI - Bard Denali inferior vena cava filter fracture and embolization resulting in cardiac tamponade: a device failure analysis. AB - A 46-year-old woman underwent inferior vena cava filter placement before bariatric surgery and returned within 6 months for routine removal. She complained of a 1-week history of severe chest pain, and during retrieval, two fractured filter components were identified including one arm in the right ventricle. The filter body and one fragment were successfully retrieved, but the fragment in the right ventricle was refractory to percutaneous retrieval. During open-heart surgery, the fragment was found traversing through the ventricular wall resulting in cardiac tamponade. Electron microscopic fragment analysis revealed high-cycle metal fatigue indicating the filter design failed to withstand this patient's natural inferior vena cava biomechanical motions. PMID- 25541450 TI - Endovascular removal of an embedded superior vena cava filter after 6 years. PMID- 25541451 TI - "Vanishing stenosis": angiographic finding related to device-vessel interaction. PMID- 25541452 TI - Endovascular recanalization of a hepatic vein in Budd-Chiari syndrome: a collateral loop-guided approach. PMID- 25541453 TI - Use of PhaSeal transfer system during chemoembolization to prevent unintentional leakage of chemotherapeutic agents during preparation and delivery. PMID- 25541454 TI - New inside-out access treatment option for femoral artery pseudoaneurysms: a report of two cases. PMID- 25541455 TI - Catheter-directed pharmacologic thrombolysis for acute pulmonary embolism immediately following lung transplantation. PMID- 25541456 TI - Endovascular management of inferior vena cava invasion by hepatic hydatid cyst. PMID- 25541457 TI - Characterization of tweety gene (ttyh1-3) expression in Xenopus laevis during embryonic development. AB - The tweety family of genes encodes large-conductance chloride channels and has been implicated in a wide array of cellular processes including cell division, cell adhesion, regulation of calcium activity, and tumorigenesis, particularly in neuronal cells. However, their expression patterns during early development remain largely unknown. Here, we describe the spatial and temporal patterning of ttyh1, ttyh2, and ttyh3 in Xenopus laevis during early embryonic development. Ttyh1 and ttyh3 are initially expressed at the late neurula stage are and primarily localized to the developing nervous system; however ttyh1 and ttyh3 both show transient expression in the somites. By swimming tadpole stages, all three genes are expressed in the brain, spinal cord, eye, and cranial ganglia. While ttyh1 is restricted to proliferative, ventricular zones, ttyh3 is primarily localized to postmitotic regions of the developing nervous system. Ttyh2, however, is strongly expressed in cranial ganglia V, VII, IX and X. The differing temporal and spatial expression patterns of ttyh1, ttyh2, and ttyh3 suggest that they may play distinct roles throughout embryonic development. PMID- 25541458 TI - Determinants of treatment waiting times for head and neck cancer in the Netherlands and their relation to survival. AB - INTRODUCTION: Waiting to start treatment has been shown to be associated with tumor progression and upstaging in head and neck squamous cell carcinomas (HNSCCs). This diminishes the chance of cure and might lead to unnecessary mortality. We investigated the association between waiting times and survival in the Netherlands and assessed which factors were associated to longer waiting times. METHODS: Patient (age, sex, socioeconomic status (SES), tumor (site, stage) and treatment (type, of institute of diagnosis/treatment) characteristics for patients with HNSCC who underwent treatment were extracted from the Netherlands Cancer Registry (NCR) for 2005-2011. Waiting time was defined as the number of days between histopathological diagnosis and start of treatment. Univariable and multivariable Cox regression was used to evaluate survival. RESULTS: In total, 13,140 patients were included, who had a median waiting time of 37days. Patients who were more likely to wait longer were men, patients with a low SES, oropharynx tumors, stage IV tumors, patients to be treated with radiotherapy or chemoradiation, and patients referred for treatment to a Head and Neck Oncology Center (HNOC) from another hospital. The 5-year overall survival was 58% for all patients. Our multivariable Cox regression model showed that longer waiting time, was significantly related to a higher hazard of dying (p<0.0001). CONCLUSION: This is the first large population-based study showing that longer waiting time for surgery, radiotherapy or chemoradiation is a significant negative prognostic factor for HNSCC patients. PMID- 25541459 TI - The contribution of TMS-EEG coregistration in the exploration of the human cortical connectome. AB - Recent developments in neuroscience have emphasised the importance of integrated distributed networks of brain areas for successful cognitive functioning. Our current understanding is that the brain has a modular organisation in which segregated networks supporting specialised processing are linked through a few long-range connections, ensuring processing integration. Although such architecture is structurally stable, it appears to be flexible in its functioning, enabling long-range connections to regulate the information flow and facilitate communication among the relevant modules, depending on the contingent cognitive demands. Here we show how insights brought by the coregistration of transcranial magnetic stimulation and electroencephalography (TMS-EEG) integrate and support recent models of functional brain architecture. Moreover, we will highlight the types of data that can be obtained through TMS-EEG, such as the timing of signal propagation, the excitatory/inhibitory nature of connections and causality. Last, we will discuss recent emerging applications of TMS-EEG in the study of brain disorders. PMID- 25541460 TI - Biological determinants of depression following bereavement. AB - There is considerable variability among people in their response to bereavement. While most people adapt well to bereavement, some develop exaggerated and/or pathological responses and may meet criteria for a major depressive episode. Many studies have investigated the effect of psychosocial factors on bereavement outcome but biological factors have not received much attention, hence the focus of this paper. The biological factors studied to date in relation to bereavement outcomes include genetic polymorphisms, neuroendocrine factors, and immunologic/inflammatory markers. In addition, animal studies have shown the alterations of brain neurotransmitters as well as changes in the plasma levels of the neurotrophic growth factors under the influence of peer loss. Recent studies have also investigated the biological basis of stress resilience, and have found a few genetic polymorphisms and potential biomarkers as protective factors in the face of adversity. Longitudinal studies that include data collection prior to, and also after, bereavement and which chart both biological and psychological measures are needed to develop profiles for the prediction of response to bereavement and personalised interventions. PMID- 25541461 TI - Photosynthetic production of glycerol by a recombinant cyanobacterium. AB - Cyanobacteria are prokaryotic organisms capable of oxygenic photosynthesis. Glycerol is an important commodity chemical. Introduction of phosphoglycerol phosphatase 2 from Saccharomyces cerevisiae into the model cyanobacterium Synechocystis sp. PCC6803 resulted in a mutant strain that produced a considerable amount of glycerol from light, water and COPhotosynthetic production . Mild salt stress (200 mM NaCl) on the cells led to an increase of the extracellular glycerol concentration of more than 20%. Under these conditions the mutant accumulated glycerol to an extracellular concentration of 14.3 mM after 17 days of culturing. PMID- 25541462 TI - Development of cultivation strategies for friulimicin production in Actinoplanes friuliensis. AB - Actinoplanes friuliensis is a rare actinomycete which produces the highly potent lipopeptide antibiotic friulimicin. This lipopeptide antibiotic is active against a broad range of multi-resistant gram-positive bacteria such as methicillin resistant Enterococcus sp. and Staphylococcus aureus (MRE, MRSA) strains. Antibiotic biosynthesis and regulation in actinomycetes is very complex. In order to study the biosynthesis of these species and to develop efficient production processes, standardized cultivation conditions are a prerequisite. For this reason a chemically defined production medium for A. friuliensis was developed. With this chemically defined medium it was possible to analyze the influence of medium components on growth and antibiotic biosynthesis. These findings were used to develop process strategies for friulimicin production. The focus of the project presented here was to develop cultivation strategies which included fed batch and continuous cultivation processes. In fed-batch processes, volumetric productivities for friulimicin of 1-2 mg/l h were achieved. In a perfusion process, a very simple cell retention system, which works via sedimentation of the mycelial cell pellets, was used. With this system, stable continuous cultivations with cell retention were dependent on the dilution rate. With a dilution rate of 0.05 h(-1), cell retention worked well and volumetric productivity of friulimicin was enhanced to 3-5 mg/l h. With a higher dilution rate of 0.1 h(-1), friulimicin production ceased because cell retention was not possible any longer with this simple cell retention system. In order to support process development, cultivation data were used to characterize metabolic fluxes in the developed friulimicin production processes. PMID- 25541463 TI - Engineering of Ralstonia eutropha for the production of poly(3-hydroxybutyrate-co 3-hydroxyvalerate) from glucose. AB - Production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) with Ralstonia eutropha relies on the addition of propionate during fermentation, and propionate consumption is one of the major factors affecting the cost of PHBV production. In this study, 7 strains were obtained by genetic manipulating the methylcitric acid cycle and the methylmalonyl-CoA pathway in R. eutropha. Disruption of prpC1 and prpC2 genes did not affect cell growth and PHBV accumulation. All 7 strains were able to accumulation high amounts of PHBVs with 3HV fractions of 0.41-29.1 mol% during cultivation in flasks. Fermentation in 7.5-L fermenter showed that genetically engineered Rem-8 was able to yield biomass of 132.8 CDWg/L, of which 68.6% were PHBV with 3HV fraction of 26.0 mol% in the biopolymer, indicating promising potentials of commercialization in the future. PMID- 25541464 TI - Yeast as a model system to screen purine derivatives against human CDK1 and CDK2 kinases. AB - Cyclin-dependent kinases (Cdk) play crucial roles in cell cycle progression. Aberrant activation of Cdk1 has been observed in a number of primary tumors and Cdk2 is deregulated in various malignancies. The therapeutic value of targeting Cdk1 and Cdk2 has been explored in a number of experimental systems. In the present study, taking advantage of the fact that deletion of the yeast CDC28 gene is functionally complemented by human CDK1 or CDK2, we set up an in vivo screen system to evaluate the inhibitory potency of purine derivatives against these two human Cdks. We constructed three isogenic strains highly sensitive to small molecules and harboring genes CDK1, CDK2 or CDC28, under the control of the CDC28 promoter. In a proof of principle assay, we determined the inhibitory effect of 82 purine derivatives on the growth rate of these strains. Thirty-three of them were revealed to be able to inhibit the Cdk1- or Cdk2-harboring strains but not the Cdc28-harboring strain, suggesting a specific inhibitory effect on human Cdks. Our data demonstrate that the yeast-based assay is an efficient system to identify potential specific inhibitors that should be preferentially selected for further investigation in cultured human cell lines. PMID- 25541465 TI - Effect of styrene maleic acid WIN55,212-2 micelles on neuropathic pain in a rat model. AB - Cannabinoid receptor agonists are moderately effective at reducing neuropathic pain but are limited by psychoactivity. We developed a styrene maleic acid (SMA) based on the cannabinoid WIN 55,212-2 (WIN) and tested in a rat model of neuropathic pain and in the rotarod test. We hypothesized that miceller preparation can ensure prolonged plasma half-life being above the renal threshold of excretion. Furthermore, SMA-WIN could potentially reduce the central nervous system effects of encapsulated WIN by limiting its transport across the blood brain barrier. Using the chronic constriction injury model of sciatic neuropathy, the SMA-WIN micelles were efficacious in the treatment of neuropathic pain for a prolonged period compared to control (base WIN). Attenuation of chronic constriction injury-induced mechanical allodynia occurred for up to 8 h at a dose of 11.5 mg/kg of SMA-WIN micelles. To evaluate central effects on motor function, the rotarod assessment was utilized. Results showed initial impairment caused by SMA-WIN micelles to be identical to WIN control for up to 1.5 h. Despite this, the SMA-WIN micelle formulation was able to produce prolonged analgesia over a time when there was decreased impairment in the rotarod test compared with base WIN. PMID- 25541466 TI - A low-molecular-weight heparin-coated doxorubicin-liposome for the prevention of melanoma metastasis. AB - Tumor metastasis is the biggest challenge in cancer therapy. During the metastasis process, metastatic cells could acquire stealth ability toward immune system through the formation of a protection cloak by hijacking platelets (PTs). Heparins, a heterogeneous mixture of glycosaminoglycans, can inhibit metastatic cascades by blocking P-selectin-mediated intercellular adhesion between tumor cells and PTs. In this study, low-molecular-weight heparin-coated doxorubicin loaded liposome (LMWH-DOX-Lip) was developed for metastasis preventative therapy. The formation of LMWH-DOX-Lip was based on electrostatic interactions between the negatively charged heparins and cationic lipids. LMWH-DOX-Lip prepared at the optimum prescription possessed high entrapment efficiency, ideal particle size and zeta potential. Morphology of LMWH-DOX-Lip was characterized by atomic force microscopy and transmission electron microscopy. The results of confocal microscopic observations and flow cytometry analysis indicated that LMWH-DOX-Lip mediated an efficient cellular uptake in B16F10 melanoma cell line. Besides, LMWH DOX-Lip displayed an increased cytotoxic over their unmodified counterparts. Furthermore, the inhibition effect of LMWH-DOX-Lip on adhesion between tumor cells and PTs/P-selectin was observed. In vivo study performed on a pulmonary melanoma mouse model revealed a substantially tumor metastasis prevention by LMWH DOX-Lip. All these results suggested that LMWH-DOX-Lip could significantly inhibit metastasis through preventing the tumor cell-platelet interactions and in the meantime suppressed tumor growth. PMID- 25541467 TI - Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase--Carbonyl reductase 1. AB - Curcumin is a major component of the plant Curcuma longa L. It is traditionally used as a spice and coloring in foods and is an important ingredient in curry. Curcuminoids have anti-oxidant and anti-inflammatory properties and gained increasing attention as potential neuroprotective and cancer preventive compounds. In the present study, we report that curcumin is a potent tight binding inhibitor of human carbonyl reductase 1 (CBR1, Ki=223 nM). Curcumin acts as a non-competitive inhibitor with respect to the substrate 2,3-hexandione as revealed by plotting IC50-values against various substrate concentrations and most likely as a competitive inhibitor with respect to NADPH. Molecular modeling supports the finding that curcumin occupies the cofactor binding site of CBR1. Interestingly, CBR1 is one of the most effective human reductases in converting the anthracycline anti-tumor drug daunorubicin to daunorubicinol. The secondary alcohol metabolite daunorubicinol has significantly reduced anti-tumor activity and shows increased cardiotoxicity, thereby limiting the clinical use of daunorubicin. Thus, inhibition of CBR1 may increase the efficacy of daunorubicin in cancer tissue and simultaneously decrease its cardiotoxicity. Western-blots demonstrated basal expression of CBR1 in several cell lines. Significantly less daunorubicin reduction was detected after incubating A549 cell lysates with increasing concentrations of curcumin (up to 60% less with 50 MUM curcumin), suggesting a beneficial effect in the co-treatment of anthracycline anti-tumor drugs together with curcumin. PMID- 25541469 TI - Adipose tissue content and distribution in children and adolescents with bronchial asthma. AB - BACKGROUND: The excess of adipose tissue and the pattern of adipose tissue distribution in the body seem to play an important role in the complicated dependencies between obesity and risk of developing asthma. The aim of the present study was to determine nutritional status in children and adolescents with bronchial asthma with special emphasis on adipose tissue distribution evaluated on the basis of skin-fold thicknesses, and to determine the relationships between patterns of adipose tissue distribution and the course of the disease. METHODS: Anthropometric data on height, weight, circumferences and skin-fold thicknesses were extracted from the medical histories of 261 children diagnosed with asthma bronchitis. Values for children with asthma were compared to Polish national growth reference charts. Distribution of subcutaneous adipose tissue was evaluated using principal components analysis (PCA). Multivariate linear regression analyses tested the effect of three factors on subcutaneous adipose tissue distribution: type of asthma, the severity of the disease and the duration of the disease. RESULTS: Mean body height in the children examined in this study was lower than in their healthy peers. Mean BMI and skin-fold thicknesses were significantly higher and lean body mass was lower in the study group. Excess body fat was noted, especially in girls. Adipose tissue was preferentially deposited in the trunk in girls with severe asthma, as well as in those who had been suffering from asthma for a longer time. The type of asthma, atopic or non-atopic, had no observable effect on subcutaneous adipose tissue distribution in children examined. CONCLUSIONS: The data suggest that long treated subjects and those with severe bronchial asthma accumulate more adipose tissue on the trunk. It is important to regularly monitor nutritional status in children with asthma, especially in those receiving high doses of systemic or inhaled glucocorticosteroids, and long-term treatment as well. PMID- 25541468 TI - Aldose reductase expression as a risk factor for cataract. AB - Aldose reductase (AR) is thought to play a role in the pathogenesis of diabetic eye diseases, including cataract and retinopathy. However, not all diabetics develop ocular complications. Paradoxically, some diabetics with poor metabolic control appear to be protected against retinopathy, while others with a history of excellent metabolic control develop severe complications. These observations indicate that one or more risk factors may influence the likelihood that an individual with diabetes will develop cataracts and/or retinopathy. We hypothesize that an elevated level of AR gene expression could confer higher risk for development of diabetic eye disease. To investigate this hypothesis, we examined the onset and severity of diabetes-induced cataract in transgenic mice, designated AR-TG, that were either heterozygous or homozygous for the human AR (AKR1B1) transgene construct. AR-TG mice homozygous for the transgene demonstrated a conditional cataract phenotype, whereby they developed lens vacuoles and cataract-associated structural changes only after induction of experimental diabetes; no such changes were observed in AR-TG heterozygotes or nontransgenic mice with or without experimental diabetes induction. We observed that nondiabetic AR-TG mice did not show lens structural changes even though they had lenticular sorbitol levels almost as high as the diabetic AR-TG lenses that showed early signs of cataract. Over-expression of AR led to increases in the ratio of activated to total levels of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal (JNK1/2), which are known to be involved in cell growth and apoptosis, respectively. After diabetes induction, AR-TG but not WT controls had decreased levels of phosphorylated as well as total ERK1/2 and JNK1/2 compared to their nondiabetic counterparts. These results indicate that high AR expression in the context of hyperglycemia and insulin deficiency may constitute a risk factor that could predispose the lens to disturbances in signaling through the ERK and JNK pathways and thereby alter the balance of cell growth and apoptosis that is critical to lens transparency and homeostasis. PMID- 25541470 TI - Prevalence and related factors of chronic kidney disease (CKD) among long-lived individuals (LLI) over 95 years of age. AB - BACKGROUND: CKD, a functional decline or break down of kidney, has been increasingly recognized as a public health problem and a predictor of poor outcomes (i.e., cardiovascular disease, dementia) and mortality among general populations. However, little is known regarding the prevalence and related factors of CKD among Chinese LLI over 95 years of age. METHODS: We used data of LLI from the Rugao longevity cohort, a population-based association study conducted in Rugao, a longevity town of China. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Demographic exposures and biochemical markers were correlated with CKD. RESULTS: The prevalence of CKD among LLI in Rugao is 23.8%. Traditional risk factors for CKD among general population, such as hypertension, diabetes, and dyslipidemia, did not have associations with CKD. However, overweight, central adiposity, and hyperuricemia were associated with increased risk of CKD, with crude odds ratios of 2.41 (95% CI=1.23-4.69), 2.61 (95% CI=1.42-4.77), and 5.69 (95% CI=2.75-11.76), respectively. In addition, higher magnesium and filtration marker beta2 microglobulin (beta2M) were associated with CKD, with crude odds ratios of 2.47 (95% CI=1.38-4.43) and 16.38 (95% CI=6.76-39.64), respectively. CONCLUSIONS: We observe a high prevalence and unique related factors of CKD among the LLI in Rugao, which suggest that early screening and risk intervention of CKD are imperative to maintain a high quality of life and postpone the occurrence of poor outcomes. PMID- 25541471 TI - Preparative separation of echinocandin B from Aspergillus nidulans broth using macroporous resin adsorption chromatography. AB - Echinocandin B (ECB), an echinocandin type of lipopeptide antibiotic produced by Aspergillus nidulans, is a precursor for the synthesis of novel anti-fungal drug anidulafungin. In this work, a separation strategy involving one-step macroporous resin adsorption chromatography was established for ECB purification from Aspergillus nidulans CCTCC M 2010275 fermentation broth. Among nine macroporous resin adsorbents tested, the non-polar resin HP-20 had the best adsorption and desorption performance. The static equilibrium adsorption data fitted well with the Langmuir equation, and the adsorption kinetic followed the pseudo-second order model. The separation parameters of ECB from broth were optimised by dynamic adsorption/desorption experiments with the column packed with HP-20 resin. Under optimal conditions, the purity increased by 3.8-fold from 23.2% in broth to 88.5% in eluent with 87.1% recovery yield by a one-step treatment. Our study provided a one-step and effective method for large-scale production of ECB, and offered references for separating other echinocandins from broth. PMID- 25541473 TI - Beyond biomarkers in drug discovery and development. PMID- 25541472 TI - Micro-scale strategy to detect spermine and spermidine by MALDI-TOF MS in foods and identification of apoptosis-related proteins by nano-flow UPLC-MS/MS after treatment with spermine and spermidine. AB - Spermine and spermidine are multiple-nitrogen compounds found in many foods. Both compounds are essential for cell growth and human health. This study established a simple and fast method of detecting spermine and spermidine in food samples by matrix-assisted laser desorption/ionization combined with time-of-flight mass spectrometry (MALDI-TOF MS). After a simple sample preparation procedure, spermine and spermidine were directly detected by MALDI-TOF MS with no additional purification procedure. The calibration curves for spermine and spermidine ranged from 0.1 to 10 MUg/mL. In intra- and inter-batch assays of three different concentrations of spermine and spermidine, all relative standard deviations and relative errors were below 18.9%. These experimental results confirmed the practicability and effectiveness of the proposed MALDI-TOF MS method for fast determination of spermine and spermidine in food samples. Furthermore, since spermine and spermidine have important roles in apoptosis, up-regulation and down regulation of spermine and spermidine during apoptosis were analyzed. After treating NRK-52E cells with spermine and spermidine, the cells were lysed, and cell proteins were collected, and digested. Apoptosis-related proteins were then identified by tandem MS. PMID- 25541474 TI - Target identification and validation in brain reward dysfunction. AB - Addictive disorders (substance-use disorder and gambling disorder) are collected together in the fifth edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) partially because of a common brain origin, which seems to involve dysfunction of the reward system. Beyond these disorders, other neuropsychiatric diseases also share abnormal reward sensitivity, maladaptive impulsivity or compulsive behaviours, and have been reunited under the 'reward deficiency syndrome' (RDS) umbrella. Research in this field could then provide novel drugs with positive actions in all these diseases, but many animal models used for this purpose lack enough translational value to enable the identification of novel targets and should be then avoided. As we discuss here, only selected protocols could provide reliable targets that would be common to the whole family of diseases, thus qualifying for further validation in patients. PMID- 25541475 TI - Managing multiple myeloma in the over 70s: a review. AB - Multiple myeloma (MM) remains an incurable malignancy. Approximately 37% of patients with plasma cell myeloma are over the age of 75 and the median age of diagnosis is 70. The management approach to over 70s differs from younger patients, as treatment goals may vary and underlying co-morbidities and expected treatment related toxicities have to be taken into account. Individualisation of management is important, aiming to achieve the best response whilst minimising adverse events. A proportion of patients will be unable to tolerate any treatment with palliation being appropriate. Age alone should not be a barrier to treatment however, with some fit patients over the age of 70 potentially benefitting from intensive treatment options including high dose chemotherapy with autologous stem cell rescue. Comprehensive geriatric assessment is indicated in the over 70s; this should be employable in a clinic outpatient setting to make it feasible. Outcomes of this assessment potentially help physicians' choice of therapy. For decades the combination of Melphalan and prednisolone was the standard of care for older MM patients. Over the last ten years, newer drugs and combinations have improved therapeutic options for patients but are yet to demonstrate vast improvement in overall survival in this cohort. PMID- 25541476 TI - Antibiotic susceptibility of Propionibacterium acnes isolated from orthopaedic implant-associated infections. AB - INTRODUCTION: Prosthetic joint infections (PJIs) caused by Propionibacterium acnes account for a larger proportion of the total number of PJIs than previously assumed and thus knowledge of the antimicrobial susceptibility patterns of P. acnes is of great value in everyday clinical practice. MATERIALS AND METHODS: Using Etest, the present study investigated the susceptibility of 55 clinical isolates of P. acnes, obtained from orthopaedic implant-associated infections of the knee joint (n = 5), hip joint (n = 17), and shoulder joint (n = 33), to eight antimicrobial agents: benzylpenicillin, clindamycin, metronidazole, fusidic acid, doxycycline, moxifloxacin, linezolid and rifampicin. Synergy testing was also conducted, in which rifampicin was combined with each of the remaining seven antibiotics. RESULTS: All isolates (n = 55) were susceptible to most of the antibiotics tested, with the exception of 100% resistance to metronidazole, five (9.1%) isolates displaying decreased susceptibility to clindamycin, and one (1.8%) to moxifloxacin. None of the antimicrobial agents investigated were synergistic with each other when combined and nine isolates were antagonistic for various antimicrobial combinations. The majority of the antimicrobial combinations had an indifferent effect on the isolates of P. acnes. However, the combination of rifampicin and benzylpenicillin showed an additive effect on nearly half of the isolates. CONCLUSION: Almost all P. acnes, isolated from orthopaedic implant-associated infections, predominantly PJIs, were susceptible to the antibiotics tested, with the exception of complete resistance to metronidazole. Synergy test could not demonstrate any synergistic effect but additive effects were found when combining various antibiotics. Antagonistic effects were rare. PMID- 25541477 TI - The natural history of molluscum contagiosum in children. PMID- 25541478 TI - Time to resolution and effect on quality of life of molluscum contagiosum in children in the UK: a prospective community cohort study. AB - BACKGROUND: Molluscum contagiosum is one of the 50 most prevalent diseases worldwide, but scarce epidemiological data exist for childhood molluscum contagiosum. We aimed to describe the time to resolution, transmission to household child contacts, and effect on quality of life of molluscum contagiosum in children in the UK. METHODS: Between Jan 1, and Oct 31, 2013, we recruited 306 children with molluscum contagiosum aged between 4 and 15 years in the UK either by referral by general practitioner or self-referral (with diagnosis made by parents by use of the validated Molluscum Contagiosum Diagnostic Tool for Parents [MCDTP]). All participants were asked to complete a questionnaire at recruitment about participant characteristics, transmission, and quality of life. We measured quality of life with the Children's Dermatology Life Quality Index (CDLQI). Participants were prospectively followed up every month to check on their recovery from molluscum contagiosum and transmission to other children in the same household, until the child's lesions were no longer visible. FINDINGS: The mean time to resolution was 13.3 months (SD 8.2). 80 (30%) of 269 cases had not resolved by 18 months; 36 (13%) had not resolved by 24 months. We recorded transmission to other children in the household in 102 (41%) of 250 cases. Molluscum contagiosum had a small effect on quality of life for most participants, although 33 (11%) of 301 participants had a very severe effect on quality of life (CDLQI score >13). A greater number of lesions was associated with a greater effect on quality of life (H=55.8, p<0.0001). INTERPRETATION: One in ten children with molluscum contagiosum is likely to have a substantial effect on their quality of life and therefore treatment should be considered for some children, especially those with many lesions or who have been identified as having a severe effect on quality of life. Patients with molluscum contagiosum and their parents need to be given accurate information about the expected natural history of the disorder. Our data provide the most reliable estimates of the expected time to resolution so far and can be used to help set realistic expectations. FUNDING: Wales School of Primary Care Research (WSPCR) and Cardiff University. PMID- 25541479 TI - International Journal of Drug Policy moves to twelve issues. PMID- 25541480 TI - The evidence of Tobacco rattle virus impact on host plant organelles ultrastructure. AB - Tobraviruses, like other (+) stranded RNA viruses of plants, replicate their genome in cytoplasm and use such usual membranous structures like endoplasmic reticulum. Based on the ultrastructural examination of Tobacco rattle virus (TRV) infected potato and tobacco leaf tissues, in this work we provide evidence of the participation of not only the membranous and vesicular ER structures but also other cell organelles during the viral infection cycle. Non-capsidated TRV PSG particles (potato isolate from the Netherlands) (long and short forms) were observed inside the nucleus while the presence of TRV capsid protein (CP) was detected in the nucleus caryolymph and within the nucleolus area. Both capsidated and non-capsidated viral particles were localized inside the strongly disorganized chloroplasts and mitochondria. The electron-dense TRV particles were connected with vesicular structures of mitochondria as well as with chloroplasts in both potato and tobacco tissues. At 15-30 days after infection, vesicles filled with TRV short particles were visible in mitochondria revealing the expanded cristae structures. Immunodetection analysis revealed the TRV PSG CP epitope inside chloroplast with disorganized thylakoids structure as well as in mitochondria of different tobacco and potato tissues. The ultrastructural analysis demonstrated high dynamics of the main cell organelles during the TRV PSG-Solanaceous plants interactions. Moreover, our results suggest a relationship between organelle changes and different stages of virus infection cycle and/or particle formation. PMID- 25541481 TI - Diagnostic imaging of hepatic lymphoma. AB - Hepatic lymphoma is a rare disease with poor prognosis because of delayed diagnosis. The disease comprises primary, metastatic, and intravascular hepatic lymphomas. The pathological characteristics of lymphomas differ contributing to difficulty in early diagnosis. Early diagnosis and appropriate treatment result in improved prognosis; therefore, diagnostic radiology and its development with various contrast agents are critical for improving disease outcomes. Herein, we review hepatic lymphomas and summarize the results of imaging studies in correlation with pathological characteristics. The information provided will help physicians in early diagnosis and thereby improving prognosis. PMID- 25541482 TI - Occurrence and molecular characterization of Cryptosporidium spp. and Enterocytozoon bieneusi in dairy cattle, beef cattle and water buffaloes in China. AB - Cryptosporidium spp. and Enterocytozoon bieneusi are important protists in a wide range of vertebrate hosts, causing diarrheal diseases. Cattle are considered potential reservoirs of Cryptosporidium infection in humans, although their role in the transmission of E. bieneusi is not clear. In the present work, 793 fecal specimens from dairy cattle, native beef cattle, and water buffaloes on 11 farms in China were examined for the presence of Cryptosporidium spp. and E. bieneusi using nested PCR targeting the small subunit (SSU) rRNA gene of Cryptosporidium spp. and the internal transcribed spacer (ITS) of E. bieneusi. For Cryptosporidium, 144/446 (32.3%) dairy cattle, 44/166 (26.5%) beef cattle, and 43/181 (23.8%) water buffaloes were PCR-positive. Sequence analysis was successful for 213 of the 231 Cryptosporidium-positive isolates; among them 94 had Cryptosporidium andersoni, 61 had Cryptosporidium bovis, 54 had Cryptosporidium ryanae, 2 had a Cryptosporidium suis-like genotype, and 2 had mixed infections of C. bovis and C. ryanae. In dairy and beef cattle, C. andersoni and C. bovis were the most common species, whereas C. ryanae was the dominant species in water buffaloes. The latter species produced SSU rRNA sequences different between cattle and water buffaloes. For E. bieneusi, the infection rate of E. bieneusi in dairy cattle, beef cattle and water buffaloes was 4.9%, 5.4% and 2.2%, respectively. All 35 E. bieneusi-positive specimens were successfully sequenced, revealing the presence of four genotypes: three Group 2 genotypes previously reported in cattle as well as humans (I, J and BEB4) and one Group 1 genotype recently reported in yaks (CHN11). Genotypes I and J were the most common genotypes in dairy and beef cattle, while genotype CHN11 was the only genotype seen in water buffaloes. Thus, the distribution of Cryptosporidium spp. and E. bieneusi in water buffaloes might be different from in dairy and beef cattle in China. These findings indicate that some of the Cryptosporidium species and all four E. bieneusi genotypes identified in bovine animals in the study areas may have zoonotic potential. PMID- 25541483 TI - Anthelmintic resistance in nematodes of beef cattle in south-west Western Australia. AB - Anthelminthic resistance in nematodes of beef cattle is an emerging issue globally with implications for effective parasite control. The prevalence of resistance in beef cattle in the Mediterranean-style climatic zone of south-west Western Australia was assessed on 19 farms, using faecal egg count reduction tests. Pre-treatment faecal worm egg counts were compared with counts at 14 days after treatments with ivermectin (injectable), fenbendazole (oral), or levamisole (oral). A separately grazed group treated with topical ivermectin (pour-on) and sampled at 28 days was included as a comparison against injectable ivermectin. The results demonstrate that resistance is common, with failure of at least one anthelmintic (<95% reduction for each species, by arithmetic means) for either of the major species Cooperia oncophora or Ostertagia ostertagi on 17 of the 19 properties. Resistance to ivermectin (injectable) was demonstrated in C. oncophora in 59% of tests, but ivermectin was fully effective against O. ostertagi by this route. Conversely, O. ostertagi resistant to fenbendazole and levamisole were present on 50% and 67% of farms respectively, with both fully effective against C. oncophora. The finding of Haemonchus placei on several properties was unexpected but the egg counts were low and there is no suggestion of pathogenic effects. An indication of reduced efficacy of the pour-on ivermectin formulation compared to the injectable was apparent against both C. oncophora and O. ostertagi, and this may have implications for resistance development, given the widespread use of topical treatments reported in this region. This survey confirms that anthelminthic resistance in nematodes of beef cattle is common in Western Australia and the pattern of occurrence is in general agreement with surveys elsewhere in Australia and in other countries. PMID- 25541484 TI - Trichostrongylus colubriformis induces IgE-independent CD13, CD164 and CD203c mediated activation of basophils in an in vitro intestinal epithelial cell co culture model. AB - Gastrointestinal nematodes pose a major risk to the farming of small ruminants worldwide. Infections are typically controlled by anthelmintics, however as resistance to anthelmintics increases, it is necessary that the mechanism of host responses are understood in order to develop alternative control options. It is hypothesised that basophils are involved in the initiation of an anti-parasite immune response, independent of IgE. In this study, the in vitro activation states of CD203c(+) basophil-like KU812 cells were determined in the presence of Trichostrongylus colubriformis parasitised HT29 epithelial cells with or without mucin. Cell surface expression of CD164, CD107a and CD13 antigens on gated CD203(+) cells were determined and qRT-PCR was used to examine gene expression changes of IL33 (a Th2 cytokine) and the high affinity IgE receptor (FcERIalpha) within the co-culture. When KU812 basophils encountered T. colubriformis and/or mucin in a parasitised epithelium, the basophils increased cell surface expression of CD13 and CD164 antigens, independent of IgE. T. colubriformis also increased the number of CD203c(+) KU812 cells that expressed CD13 and CD164 antigens. These data support the in vivo observations of T. colubriformis primary infections in guinea pigs and sheep. PMID- 25541485 TI - Disruption of Snf3/Rgt2 glucose sensors decreases lifespan and caloric restriction effectiveness through Mth1/Std1 by adjusting mitochondrial efficiency in yeast. AB - Down-regulation of intracellular nutrient signal pathways was proposed to be a primary mechanism of caloric restriction (CR)-mediated lifespan extension. However, the link between lifespan and glucose sensors in the plasma membrane was poorly understood in yeast. Herein, a mutant that lacked glucose sensors (snf3Deltargt2Delta) had impaired glucose fermentation, showed decreased chronological lifespan (CLS), and reduced CLS extension by CR. The mutant also had reduced mitochondrial efficiency, as inferred by increased mitochondrial superoxide and decreased ATP levels. Mth1 and Std1, which are downstream effectors of the Snf3/Rgt2 pathway, were required for viability through mitochondrial function but not fermentative metabolism. PMID- 25541486 TI - Botulinum neurotoxin homologs in non-Clostridium species. AB - Clostridial neurotoxins (CNTs) are the deadliest toxins known and the causative agents of botulism and tetanus. Despite their structural and functional complexity, no CNT homologs are currently known outside Clostridium. Here, we report the first homologs of Clostridium CNTs within the genome of the rice fermentation organism Weissella oryzae SG25. One gene in W. oryzae S25 encodes a protein with a four-domain architecture and HExxH protease motif common to botulinum neurotoxins (BoNTs). An adjacent gene with partial similarity to CNTs is also present, and both genes seem to have been laterally transferred into the W. oryzae genome from an unknown source. Identification of mobile, CNT-related genes outside of Clostridium has implications for our understanding of the evolution of this important toxin family. PMID- 25541487 TI - Uncapped 5' ends of mRNAs targeted by cytoplasmic capping map to the vicinity of downstream CAGE tags. AB - In mammalian transcriptomes approximately 25% of 5' ends determined by Capped Analysis of Gene Expression (CAGE) map to locations within spliced exons. The current study sought to determine if the cytoplasmic capping complex participates in generating these downstream CAGE tags. 5'-RACE was used to amplify the uncapped ends of target transcripts that accumulate when cytoplasmic capping is blocked. Sequencing of these RACE products mapped the positions of uncapped ends either exactly to or just downstream of archived CAGE tags. These findings support a role for cytoplasmic capping in generating the downstream capped ends identified by CAGE. PMID- 25541488 TI - Inhibition of miR-34b and miR-34c enhances alpha-synuclein expression in Parkinson's disease. AB - Mounting evidence suggests that microRNA (miR) dysregulation contributes to neurodegenerative disorders including Parkinson's disease (PD). MiR-34b and miR 34c have been previously shown to be down-regulated in the brains of patients with PD. Here, we demonstrate that miR-34b and miR-34c repress the expression of alpha-synuclein (alpha-syn), a key protein in PD pathogenesis. Inhibition of miR 34b and miR-34c expression in human dopaminergic SH-SY5Y cells increased alpha syn levels and stimulated aggregate formation. Additionally, a single nucleotide polymorphism (SNP) in the 3'-UTR of alpha-syn was found to lower the miR-34b mediated repression of the protein. Our results suggest that down-regulation of miR-34b and miR-34c in the brain, as well as an SNP in the 3'-UTR of alpha-syn can increase alpha-syn expression, possibly contributing to PD pathogenesis. PMID- 25541489 TI - MicroRNAs in the immune organs of chickens and ducks indicate divergence of immunity against H5N1 avian influenza. AB - Chickens are susceptible to the highly pathogenic H5N1 strain of avian influenza virus (HPAIV), whereas ducks are not. Here, we used high-throughput sequencing to analyse the microRNA expression in the spleen, thymus and bursa of Fabricius of H5N1-HPAIV-infected and non-infected chickens and ducks. We annotated the genomic positions of duck microRNAs and we compared the microRNA repertoires of chickens and ducks. Our results showed that the microRNA expression patterns in the homologous immune organs of specific-pathogen-free (SPF) chickens and ducks diverge substantially. Moreover, there was larger divergence between the microRNA expression patterns in immune organs of HPAIV-infected chickens than HPAIV infected ducks. Together, our results might help to elucidate the roles of microRNAs in the divergent immunity of chickens and ducks against H5N1 HPAIV. PMID- 25541490 TI - Effects of detyrosinated tubulin on Na+,K+-ATPase activity and erythrocyte function in hypertensive subjects. AB - Formation of tubulin/Na(+),K(+)-ATPase (NKA) complex in erythrocytes of hypertensive subjects results in a 50% reduction in NKA activity. We demonstrate here that detyrosinated tubulin, which is increased in hypertensive erythrocytes membranes, enhances the inhibitory effect of acetylated tubulin on NKA activity. Moreover, we report a reduced content and activity of the enzyme tubulin tyrosine ligase in erythrocytes of hypertensive subjects. Such alterations are related to changes in erythrocyte deformability. Our findings indicate that the detyrosination/tyrosination cycle of tubulin is important in regulation of NKA activity, and that abnormalities in this cycle are involved in hypertension development. PMID- 25541491 TI - Revisiting the mechanism of activation of cyclic AMP receptor protein (CRP) by cAMP in Escherichia coli: lessons from a subunit-crosslinked form of CRP. AB - Cyclic AMP receptor protein (CRP), the global transcription regulator in prokaryotes, is active only as a cAMP-CRP complex. Binding of cAMP changes the conformation of CRP, transforming it from a transcriptionally 'inactive' to an 'active' molecule. These conformers are also characterized by distinct biochemical properties including the ability to form an S-S crosslink between the C178 residues of its two monomeric subunits. We studied a CRP variant (CRP(cl)), in which the subunits are crosslinked. We demonstrate that CRP(cl) can activate transcription even in the absence of cAMP. Implications of these results for the crystallographically-determined structure of cAMP-CRP are discussed. PMID- 25541492 TI - Mesolimbic dopamine dynamically tracks, and is causally linked to, discrete aspects of value-based decision making. AB - BACKGROUND: To make appropriate choices, organisms must weigh the costs and benefits of potential valuable outcomes, a process known to involve the nucleus accumbens (NAc) and its dopaminergic input. However, it is currently unknown if dopamine dynamically tracks alterations in expected reward value online as behavioral preferences change and if so, if it is causally linked to specific components of value such as reward magnitude and/or delay to reinforcement. METHODS: Electrochemical methods were used to measure subsecond NAc dopamine release during a delay discounting task where magnitude was fixed but delay varied across blocks (n = 7 rats). Next, to assess whether this dopamine signaling was causally related to specific components of choice behavior, we employed selective optogenetic stimulation of dopamine terminals in the NAc using a modified delay discounting task in which both delay and magnitude varied independently (n = 23 rats). RESULTS: Cues predictive of available choices evoked dopamine release that scaled with the rat's preferred choices and dynamically shifted as delay to reinforcement for the large reward increased. In the second experiment, dopamine signaling was causally related to features of decision making, as optogenetically enhanced dopamine release within the NAc during predictive cue presentation was sufficient to alter subsequent value-related choices. Importantly, this dopamine-mediated shift in choice was limited to delay based, but not magnitude-based, decisions. CONCLUSIONS: These findings indicate that NAc dopamine dynamically tracks delay discounting and establishes a causal role for this signaling in a subset of value-based associative strategies. PMID- 25541493 TI - Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients. AB - BACKGROUND: Major psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls. METHODS: We identified articles by searching MEDLINE, PsycINFO, and Thomson Reuters Web of Knowledge databases and the reference lists of identified studies. RESULTS: Study inclusion criteria were met by 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. Levels of interleukin (IL)-1beta and IL-6 were significantly increased in blood and postmortem brain samples of patients with suicidality compared with both patients without suicidality and healthy control subjects (p < .05 for each). In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p < .01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p < .05). CONCLUSIONS: We found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1beta and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients. Rigorously designed longitudinal studies are needed to evaluate these associations further. PMID- 25541494 TI - Bilateral filter regularized accelerated Demons for improved discontinuity preserving registration. AB - The classical accelerated Demons algorithm uses Gaussian smoothing to penalize oscillatory motion in the displacement fields during registration. This well known method uses the L2 norm for regularization. Whereas the L2 norm is known for producing well behaving smooth deformation fields it cannot properly deal with discontinuities often seen in the deformation field as the regularizer cannot differentiate between discontinuities and smooth part of motion field. In this paper we propose replacement the Gaussian filter of the accelerated Demons with a bilateral filter. In contrast the bilateral filter not only uses information from displacement field but also from the image intensities. In this way we can smooth the motion field depending on image content as opposed to the classical Gaussian filtering. By proper adjustment of two tunable parameters one can obtain more realistic deformations in a case of discontinuity. The proposed approach was tested on 2D and 3D datasets and showed significant improvements in the Target Registration Error (TRE) for the well known POPI dataset. Despite the increased computational complexity, the improved registration result is justified in particular abdominal data sets where discontinuities often appear due to sliding organ motion. PMID- 25541495 TI - The mystery of chronic lymphocytic leukemia (CLL): Why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology? AB - Chronic lymphocytic leukemia/small lymphocytic lymphoma is common in persons of predominately European descent but rare in Asians. Why is unknown but is likely genetically-determined. Environmental factors may also operate but are likely to be less important. When CLL occurs in Asians it has different features than CLL in persons of predominately European descent. The reason(s) for this is also not understood. We reviewed data on CLL in Asians (mostly Han Chinese but also other ethnic groups) and compared these data with those from persons of predominately European descent with CLL. CLL incidence was about 5-10-fold less in Asians. Asians with CLL are younger, have atypical morphologic and immunologic features, an increased proportion of IGHV mutations and rearrangements and briefer freedom from-progression than persons of predominately European descent with CLL. These observations provide clues to the etiology and biology of CLL. But the mystery continues; more research is needed. PMID- 25541498 TI - Increased expression of Fas receptor and Fas ligand in the culture of the peripheral blood mononuclear cells stimulated with Borrelia burgdorferi sensu lato. AB - Apoptosis of the lymphocytes plays an essential role in the regulation of inflammatory/immune responses and its abnormalities may contribute to a chronic infection, persistent inflammation and autoimmunity. Its role in the pathogenesis of the late Lyme borreliosis manifestations has not been studied so far. We have measured Th lymphocyte apoptosis rate, membrane expression of pro-apoptotic Fas receptor, and supernatant concentrations of selected soluble pro- and anti apoptotic mediators in cultures of peripheral blood mononuclear cells from 16 patients with disseminated Lyme borreliosis (6 with osteoarticular symptoms, 7 with neuroborreliosis and 3 with acrodermatitis chronica atrophicans) and 8 healthy controls. The cultures stimulated for 48h with live Borrelia burgdorferi sensu stricto, B. garinii or B. afzelii spirochetes. Fraction of the apoptotic Th (CD3+CD4+) lymphocytes and expression of Fas in this cell population was measured cytometrically and concentrations of soluble Fas, soluble Fas ligand, IL-10, IL 12 and TGF-beta in culture supernatant with ELISA assays. The expression of IL 10, soluble and membrane Fas and soluble Fas ligand was increased under stimulation and higher in the presence of B. burgdorferi sensu stricto than the other species. Apoptosis rate was not affected. There was no difference between Lyme borreliosis patients and controls. IL-10 concentration correlated negatively with the membrane Fas expression and apoptosis under stimulation with B. afzelii and B. garinii. Expression of Fas/FasL system is up-regulated under stimulation with B. burgdorferi, but without corresponding increase in lymphocyte apoptosis. Variable responses observed with different B. burgdorferi species may reflect differences in the pathogenesis of the infection in vivo. PMID- 25541500 TI - Dissociating the neural mechanisms of distance and spatial reference frames. AB - This study investigated if the neural mechanisms involved in processing distance (near and far) and frame of reference (egocentric and allocentric) can be dissociated. 36 participants completed a conjunction visual search task using either an egocentric (deciding if the target was to their left or right) or an allocentric (deciding if the target was to the left or right of a reference object) frame. Both tasks were performed in near (57 cm) and far (171 cm) space conditions. Participants were separated into three groups, and each received transcranial magnetic stimulation (TMS) to a different site; right posterior parietal cortex (rPPC), right ventral occipital cortex (rVO), or right frontal eye field (rFEF) in addition to sham TMS. The results show that rFEF is critical in the processing of each search at each distance whereas, contrary to previous detection results, TMS over rVO did not affect performance for any condition. TMS over rPPC revealed that specialised egocentric processing in the parietal cortex does not generalise to far space, providing evidence of a separation of the reference frame/distance conflation in the literature. PMID- 25541499 TI - Spatial proximity amplifies valence in emotional memory and defensive approach avoidance. AB - In urban areas, people often have to stand or move in close proximity to others. The egocentric distance to stimuli is a powerful determinant of defensive behavior in animals. Yet, little is known about how spatial proximity to others alters defensive responses in humans. We hypothesized that the valence of social cues scales with egocentric distance, such that proximal social stimuli have more positive or negative valence than distal stimuli. This would predict enhanced defensive responses to proximal threat and reduced defensive responses to proximal reward. We tested this hypothesis across four experiments using 3-D virtual reality simulations. Results from Experiment 1 confirmed that proximal social stimuli facilitate defensive responses, as indexed by fear-potentiated startle, relative to distal stimuli. Experiment 2 revealed that interpersonal defensive boundaries flexibly increase with aversive learning. Experiment 3 examined whether spatial proximity enhances memory for aversive experiences. Fear memories for social threats encroaching on the body were more persistent than those acquired at greater interpersonal distances, as indexed by startle. Lastly, Experiment 4 examined how egocentric distance influenced startle responses to social threats during defensive approach and avoidance. Whereas fear-potentiated startle increased with proximity when participants actively avoided receiving shocks, startle decreased with proximity when participants tolerated shocks to receive monetary rewards, implicating opposing gradients of distance on threat versus reward. Thus, proximity in egocentric space amplifies the valence of social stimuli that, in turn, facilitates emotional memory and approach-avoidance responses. These findings have implications for understanding the consequences of increased urbanization on affective interpersonal behavior. PMID- 25541502 TI - Unhealthy how? Implicit and explicit affective evaluations of different types of unhealthy foods. AB - The present study examines the utility of distinguishing nutritional characteristics in implicit and explicit affective evaluations of foods, both nomothetically and idiographically. To this end, we employ indirect and direct versions of the affect misattribution procedure (AMP; Payne, Cheng, Govorun, & Stewart, 2005) to assess affective evaluations of foods that vary along dimensions of added fat and added sugar. Normatively, both added fat and added sugar are associated with more positive affective evaluations. Idiographically, both hunger and external eating are associated with more positive fat-based affective evaluations. Patterns of results were similar across implicit and explicit affective evaluations, inconsistent with a dual-process conceptualization of affective evaluation. Overall, the current work supports the utility of continuing to employ more stringently characterized image stimuli with known nutritional properties, as well as structurally similar measures of implicit and explicit affective evaluations in future work. PMID- 25541501 TI - Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement. AB - Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2-24 h post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Muller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16-24 hpf) produced retinal defects like those seen with ethanol exposure between 2 and 24 hpf. Significantly, during an ethanol-sensitive time window (16 24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects. PMID- 25541503 TI - Ethnic differences in the effects of media on body image: the effects of priming with ethnically different or similar models. AB - Media exposure has been positively correlated with body dissatisfaction. While body image concerns are common, being African American has been found to be a protective factor in the development of body dissatisfaction. METHOD: Participants either viewed ten advertisements showing 1) ethnically-similar thin models; 2) ethnically-different thin models; 3) ethnically-similar plus-sized models; and 4) ethnically-diverse plus-sized models. Following exposure, body image was measured. RESULTS: African American women had less body dissatisfaction than Caucasian women. Ethnically-similar thin-model conditions did not elicit greater body dissatisfaction scores than ethnically-different thin or plus-sized models nor did the ethnicity of the model impact ratings of body dissatisfaction for women of either race. There were no differences among the African American women exposed to plus-sized versus thin models. Among Caucasian women exposure to plus-sized models resulted in greater body dissatisfaction than exposure to thin models. DISCUSSION: Results support existing literature that African American women experience less body dissatisfaction than Caucasian women even following exposure to an ethnically-similar thin model. Additionally, women exposed to plus sized model conditions experienced greater body dissatisfaction than those shown thin models. PMID- 25541504 TI - Clinical and histopathologic predictors of reoperation due to recurrence of leiomyoma after laparotomic myomectomy. AB - OBJECTIVE: To assess clinical and histopathologic risk factors for reoperation after laparotomic myomectomy due to leiomyoma recurrence. METHODS: A case-control study was conducted of patients who underwent their first myomectomy for leiomyoma without receiving gonadotropin-releasing hormone analogues at Ankara University School of Medicine, Ankara, Turkey, between January 2000 and December 2004. Medical records and histopathologic samples were reviewed, and participants completed a telephone interview. Patients in the case group had undergone reoperation within 5 years; those in the control group had not required further surgery. RESULTS: There were 51 patients in the case group and 61 controls. The number of women who had given birth after the index surgery was lower among cases than controls (4 [7.8%] vs 13 [21.3%]; P=0.048), as was the median size of the largest leiomyoma removed (4 cm [range 3-10] vs 5 cm [range 3-25]; P=0.009). Reoperation was more likely among patients aged at least 40 years at index surgery (OR 1.10; 95% CI 1.18-7.78; P=0.021) and those with myxoid change (OR 2.04; 95% CI 1.07-55.41; P=0.043). The number of leiomyomas removed was negatively associated with reoperation (OR 0.30; 95% CI 0.58-0.93; P=0.012). CONCLUSION: Young age, removal of many or large leiomyomas, and pregnancy after myomectomy decreased reoperation risk, whereas myxoid change increased risk. PMID- 25541505 TI - Obstetric and gynecologic admissions to the intensive care unit at Khartoum Hospital, Sudan. PMID- 25541506 TI - Apical thrombus after pericardiectomy for constrictive pericarditis. PMID- 25541507 TI - Bedside ultrasonographic measurement of the inferior vena cava fails to predict fluid responsiveness in the first 6 hours after cardiac surgery: a prospective case series observational study. AB - OBJECTIVE: To assess validity of respiratory variation of inferior vena cava (IVC) diameter to predict fluid responsiveness and guide fluid therapy in mechanically ventilated patients during the first 6 hours after elective cardiac surgery. DESIGN: Prospective observational case series study. SETTING: Single center hospital. PATIENTS: 50 consecutive patients undergoing elective cardiac surgery. INTERVENTIONS: Transthoracic bedside echocardiography. MEASUREMENTS AND MAIN RESULTS: Parameters derived from ultrasonographic assessment of the IVC diameter (collapsibility index [CI], distensibility index [DI], and IVC/aorta index). In the whole study group, change in fluid balance correlated with change in IVC maximum diameter (p = 0.034, r = 0.176). IVC-CI and IVC-DI correlated with IVC/aorta index. A weak correlation between central venous pressure (CVP) and IVC derived parameters (IVC-CI and IVC-DI) was noticed. Despite statistical significance (p<0.05), all observed correlations expressed low statistical power (r<0.21). There were no statistically significant differences between fluid responders and nonresponders in relation to clinical parameters, CVP, ultrasound IVC measurement, and IVC-derived indices. CONCLUSION: Dynamic IVC-derived parameters (IVC-CI, IVC-DI, and IVC/aorta index) and CVP are not reliable predictors of fluid responsiveness in the first 6 hours after cardiac surgery. Complexity of physiologic factors modulating cardiac performance in this group may be responsible for the difficulty in finding a plausible monitoring tool for fluid guidance. Bedside ultrasonographic measurement of IVC is unable to predict fluid responsiveness in the first 6 hours after cardiac surgery. PMID- 25541508 TI - Bond strength of restorative materials to hydroxyapatite inserts and dimensional changes of insert-containing restorations during polymerization. AB - OBJECTIVE: To determine the shear bond strength (SBS) between synthetic controlled porous hydroxyapatite (HAP) inserts and restorative materials and dimensional changes of insert-containing restorations during curing. METHODS: Cylinder-shaped HAP inserts (4mm in diameter, 1.6mm thick) were cemented in dentin discs (5mm*1.6mm), cut mid-coronally from human third molars, using one of the following materials: universal microhybrid composite Filtek Z250, flowable composite Filtek Ultimate or glass-ionomer Vitrebond (all 3M ESPE). SBS of the same materials to HAP inserts was tested in a universal testing machine. Three dimensional digital image correlation system Aramis (GOM) was used to measure strains and displacements. Data were statistically analyzed using one-way ANOVA with Tukey's post-test (alpha=0.05). RESULTS: SBS of restorative materials to HAP inserts ranged between 12.2+/-2.1MPa (Filtek Z250) and 0.7+/-0.4MPa (Filtek Z250 without an adhesive). The 'total-etch' approach of adhesive application significantly increased SBS of both Filtek Z250 (12.2+/-2.1MPa) and Filtek Ultimate flowable (9.5+/-2.5MPa) compared to the 'self-etch' approach (8.2+/ 1.6MPa and 4.4+/-0.9MPa, respectively) (p<0.05). HAP inserts reduced polymerization shrinkage to below 0.5% as well as displacements in the central region of the restorations. Peripheral shrinkage of restorative materials was similar with and without HAP inserts as were displacements of Filtek Z250 and Vitrebond. SIGNIFICANCE: Replacing major part of dentin clinically, especially in large cavities, HAP inserts may shorten clinical working time, improve dimensional stability of the restoration by reducing central shrinkage and displacements and provide adhesive bonding to universal composites following a 'total-etch' approach. PMID- 25541509 TI - Genetic polymorphisms in alcohol dehydrogenase, aldehyde dehydrogenase and alcoholic chronic pancreatitis susceptibility: a meta-analysis. AB - PURPOSE: This study was aimed to determine the relationship of alcohol metabolizing enzymes ADH2, ADH3, and ALDH2 polymorphisms with the susceptibility to alcoholic chronic pancreatitis (ACP). METHODS: Meta-analyses that evaluated the association of ADH2, ADH3, and ALDH2 variations with ACP were performed. RESULTS: Eight case-control studies were selected for analysis. The overall data revealed a significant association of ADH2 polymorphism (OR=1.56, 95% CI=1.42 1.72, P=0.000 for dominant model; OR=1.63, 95% CI=1.55-1.71, P=0.000 for homozygote comparison model; OR=1.11, 95% CI=1.01-1.22, P=0.030 for allelic contrast model), ADH3 polymorphism (OR=0.95, 95% CI=0.86-1.06, P=0.389 for dominant; OR=0.64, 95% CI=0.44-0.93, P=0.020 for homozygote comparison; and OR=0.87, 95% CI=0.77-0.99, P=0.039 for allelic contrast model) and ALDH2 polymorphism (OR=0.57, 95% CI=0.40-0.81, P=0.002 for dominant; OR=0.50, 95% CI=0.23-1.08, P=0.079 for homozygote comparison; and OR=0.58, 95% CI=0.41-0.84, P=0.003 for allelic contrast model) with ACP risk. The subgroup analyses suggested that the variant ADH2*2/*2+*1/*2, ADH2*2/*2 genotype and ADH2*2 allele significantly increased ACP risk among Asian individuals; the variant ADH3*2/*2 genotype and ADH3*2 allele significantly decreased ACP risk among non-Asian individuals; and the variant ALDH2*2/*2+*1/*2 genotype and ALDH2*2 allele significantly decreased ACP risk among Asians. CONCLUSIONS: ADH2, ADH3 and ALDH2 polymorphisms may be susceptibility facts of ACP, and it may be ethnic and race dependent. PMID- 25541510 TI - [Course and neurological/behavioral development of preterm children]. AB - Preterm birth remains a public health priority given that one child out of ten is born before 37 weeks of gestation. Survival without major neonatal morbidity has increased in high-income countries, in particular in France and in cases of extreme preterm birth before 27 weeks of gestation. Rate of severe handicaps, such as cerebral palsy, is probably decreasing, but specific cognitive disabilities in a variety of domains remain frequent, interfering with normal learning abilities at school and explaining the high rate of special education needs. Prevalence of sequelae increases when gestational age at birth decreases. However, because there are more moderate to late preterm children compared to very preterm children, the absolute number of children with specific cognitive or neurological disabilities is equivalent in these two groups. Better characterization of the development in a recent cohort of very preterm children is necessary to improve the early detection of variations in normal neurodevelopment and to propose trials with remediation actions targeting working memory and language for example. These protocols could decrease the rates of learning disabilities at school. PMID- 25541511 TI - Differing levels of acute hypoxia do not influence maximal anaerobic power capacity. AB - OBJECTIVE: The purpose of this study was to determine the effects of different inspired oxygen fractions (Fio2) on average and peak power capacity during consecutive jumps to assess the effectiveness of a hypoxic explosive-strength program. METHODS: Eight physically active subjects (aged 33.62 +/- 4.07 years; height, 1.77 +/- 0.05 m; weight, 74.38 +/- 6.86 kg) completed a Bosco jump test, consisting of a series of 15-second "all-out" jumps with 3 minutes of recovery, performed in a normoxia condition (N [Fio2 = 21%]) and in two hypoxic conditions: moderate hypoxia (MH [Fio2 16.5% o2]) and high hypoxia (HH [13.5% o2]). A force platform provided the average and the maximal power output (W) generated during consecutive jumps. Measurements were also taken of lactate, creatine kinase, arterial oxygen saturation, and perceived exertion using the Borg fatigue scale. RESULTS: The average power outputs throughout the entire sets were similar between N (3187 +/- 46) and MH (3184 +/- 15; P > .05), but slightly greater with HH (3285 +/- 43) compared with N (P < .05). Values for lactate during N (7.5 +/- 3.0), MH (7.7 +/- 4.0), and HH (7.9 +/- 3.0; P > .05), and for creatine kinase (values before, 69.8 +/- 15; and 24 hours after in N [79.4 +/- 15.60], MH [85.2 +/- 26.7], and HH [84.3 +/- 47.2]; P > .05) were similar for all conditions. Only during exercise in hypoxia were moderate and severe hypoxemia induced as the sets increased and Fio2 was lower (P < .05). At the same time, the perceived exertion reported by subjects was substantially higher at HH (8.9 +/- 1.1) than at N (7.1 +/- 1.9; P < .05). CONCLUSIONS: Jumping power output was not negatively affected by mild or high hypoxia in comparison with normoxia during an anaerobic workout despite having higher hypoxemia and a greater perception of exertion. PMID- 25541512 TI - Emotional communication in the context of joint attention for food stimuli: effects on attentional and affective processing. AB - Guided by distinct theoretical frameworks (the embodiment theories, shared-signal hypothesis, and appraisal theories), we examined the effects of gaze direction and emotional expressions (joy, disgust, and neutral) of virtual characters on attention orienting and affective reactivity of participants while they were engaged in joint attention for food stimuli contrasted by preference (disliked, moderately liked, and liked). The participants were exposed to videos of avatars looking at food and displaying facial expressions with their gaze directed either toward the food only or toward the food and participants consecutively. We recorded eye-tracking responses, heart rate, facial electromyography (zygomatic, corrugator, and levator labii regions), and food wanting/liking. The avatars' joy faces increased the participants' zygomatic reactions and food liking, with mutual eye contact boosting attentional responses. Eye contact also fostered disgust reactions to disliked food, regardless of the avatars' expressions. The findings show that joint attention for food accompanied by face-to-face emotional communication elicits differential attentional and affective responses. The findings appear consistent with the appraisal theories of emotion. PMID- 25541513 TI - Context-sensitivity of the feedback-related negativity for zero-value feedback outcomes. AB - The present study investigated whether the same visual stimulus indicating zero value feedback (?0) elicits feedback-related negativity (FRN) variation, depending on whether the outcomes correspond with expectations or not. Thirty-one volunteers performed a monetary incentive delay (MID) task while EEG was recorded. FRN amplitudes were comparable and more negative when zero-value outcome deviated from expectations than with expected gain or loss, supporting theories emphasising the impact of unexpectedness and salience on FRN amplitudes. Surprisingly, expected zero-value outcomes elicited the most negative FRNs. However, source localisation showed that such outcomes evoked less activation in cingulate areas than unexpected zero-value outcomes. Our study illustrates the context dependency of identical zero-value feedback stimuli. Moreover, the results indicate that the incentive cues in the MID task evoke different reward prediction error signals. These prediction signals differ in FRN amplitude and neuronal sources, and have to be considered in the design and interpretation of future studies. PMID- 25541514 TI - The effect of experimental sleep fragmentation on error monitoring. AB - Experimental sleep fragmentation (SF) is characterized by frequent brief arousals without reduced total sleep time and causes daytime sleepiness and impaired neurocognitive processes. This study explored the impact of SF on error monitoring. Thirteen adults underwent auditory stimuli-induced high-level (H) and low-level (L) SF nights. Flanker task performance and electroencephalogram data were collected in the morning following SF nights. Compared to LSF, HSF induced more arousals and stage N1 sleep, decreased slow wave sleep and rapid-eye movement sleep (REMS), decreased subjective sleep quality, increased daytime sleepiness, and decreased amplitudes of P300 and error-related positivity (Pe). SF effects on N1 sleep were negatively correlated with SF effects on the Pe amplitude. Furthermore, as REMS was reduced by SF, post-error accuracy compensations were greatly reduced. In conclusion, attentional processes and error monitoring were impaired following one night of frequent sleep disruptions, even when total sleep time was not reduced. PMID- 25541515 TI - Transcranial direct current stimulation, implicit alcohol associations and craving. AB - Previous research has shown that stimulation of the left dorsolateral prefrontal cortex (DLPFC) enhances working memory (e.g. in the n-back task), and reduces craving for cigarettes and alcohol. Stimulation of the right inferior frontal gyrus (IFG) improves response inhibition. The underlying mechanisms are not clearly understood, nor is it known whether IFG stimulation also reduces craving. Here, we compared effects of DLPFC, IFG, and sham stimulation on craving in heavy drinkers in a small sample (n=41). We also tested effects of tDCS on overcoming response biases due to associations between alcohol and valence and alcohol and approach, using implicit association tests (IATs). Mild craving was reduced after DLPFC stimulation. Categorization of valence attribute words in the IAT was faster after DLPFC stimulation. We conclude that DLPFC stimulation can reduce craving in heavy drinkers, but found no evidence for tDCS induced changes in alcohol biases, although low power necessitates caution. PMID- 25541516 TI - Enhanced production of antifungal lipopeptides by Bacillus amyloliquefaciens for biocontrol of postharvest disease. AB - Food security to sustain increasing populations is a global concern. A major factor threatening food security is crop spoilage during postharvest storage. Reduction of postharvest spoilage has mainly been addressed by the application of synthetic chemicals. Bacillus lipopeptides, specifically lipopeptide homologues exhibiting antifungal efficacy, offer an alternative environmentally benign protocol for reduction of postharvest phytopathogens. This work is directed towards Bacillus lipopeptide production for biocontrol of postharvest phytopathogens in general and fungal phytopathogens in particular. Bacillus amyloliquefaciens DSM 23117 was identified as an organism with superior potential for lipopeptide production, via screening of 4 Bacillus candidates, in terms of antifungal lipopeptide concentration, yield, productivity and preferred homologue ratio. Efficacy of B. amyloliquefaciens lipopeptides against Botrytis cinerea substantiated appropriateness of this Bacillus species. Subsequent process modification of B. amyloliquefaciens cultures demonstrated that the concentration and ratio of the lipopeptides were significantly influenced by process conditions and further, distinguished nitrate and oxygen availability as key parameters defining optimal lipopeptide production. Discrete B. amyloliquefaciens cultures supplied with 4, 8, 10 and 12 g/L NH4NO3 demonstrated optimal lipopeptide concentration, yield and productivity, with respect to both total and antifungal lipopeptides, in the culture containing 8 g/L NH4NO3. Enhancement of total and antifungal lipopeptide kinetics similar to those quantified on increasing the nitrate from 4 to 8 g/L NH4NO3 were exhibited in B. amyloliquefaciens cultures when the oxygen in the sparge gas was increased from 21 to 30 mol%. The enhancement of lipopeptide production under conditions of increased nitrate and increased oxygen supply is explained in terms of increased availability of nitrogen for synthesis. This work has highlighted key parameters for maximisation of Bacillus lipopeptide production and manipulation of antifungal/surfactin ratios for optimum efficacy and informs on future development of process strategies towards production optimisation of antifungal lipopeptides as a green alternative to synthetic chemicals. PMID- 25541517 TI - A review of pharmaceutical extrusion: critical process parameters and scaling-up. AB - Hot melt extrusion has been a widely used process in the pharmaceutical area for three decades. In this field, it is important to optimize the formulation in order to meet specific requirements. However, the process parameters of the extruder should be as much investigated as the formulation since they have a major impact on the final product characteristics. Moreover, a design space should be defined in order to obtain the expected product within the defined limits. This gives some freedom to operate as long as the processing parameters stay within the limits of the design space. Those limits can be investigated by varying randomly the process parameters but it is recommended to use design of experiments. An examination of the literature is reported in this review to summarize the impact of the variation of the process parameters on the final product properties. Indeed, the homogeneity of the mixing, the state of the drug (crystalline or amorphous), the dissolution rate, the residence time, can be influenced by variations in the process parameters. In particular, the impact of the following process parameters: temperature, screw design, screw speed and feeding, on the final product, has been reviewed. PMID- 25541518 TI - Recombination in viruses: mechanisms, methods of study, and evolutionary consequences. AB - Recombination is a pervasive process generating diversity in most viruses. It joins variants that arise independently within the same molecule, creating new opportunities for viruses to overcome selective pressures and to adapt to new environments and hosts. Consequently, the analysis of viral recombination attracts the interest of clinicians, epidemiologists, molecular biologists and evolutionary biologists. In this review we present an overview of three major areas related to viral recombination: (i) the molecular mechanisms that underlie recombination in model viruses, including DNA-viruses (Herpesvirus) and RNA viruses (Human Influenza Virus and Human Immunodeficiency Virus), (ii) the analytical procedures to detect recombination in viral sequences and to determine the recombination breakpoints, along with the conceptual and methodological tools currently used and a brief overview of the impact of new sequencing technologies on the detection of recombination, and (iii) the major areas in the evolutionary analysis of viral populations on which recombination has an impact. These include the evaluation of selective pressures acting on viral populations, the application of evolutionary reconstructions in the characterization of centralized genes for vaccine design, and the evaluation of linkage disequilibrium and population structure. PMID- 25541519 TI - New Wolbachia supergroups detected in quill mites (Acari: Syringophilidae). AB - Wolbachia is the most abundant intracellular bacterial genus infecting a wide range of arthropods and filarial nematodes. Wolbachia have evolved parasitic, mutualistic and commensal relationships with their hosts but in arthropods generally act as reproductive parasites, inducing a wide range of phenotypic effects such as cytoplasmic incompatibility, parthenogenesis, feminization and male-killing. Up to now, the genus has been divided into 14 supergroups successively named A-O. Here, we describe two new Wolbachia supergroups from syringophilid mites (Acari: Cheyletoidea). These obligatory ectoparasites of birds inhabit the quills of feathers in many avian groups. The species of this family reproduce in a haplodiploid mode sensu arrhenotoky and are usually strongly female-biased. Based on the sequences of four protein-coding genes (ftsZ, gltA and groEL and coxA) and the 16S rRNA we identified strains of three Wolbachia supergroups (F and two distinct, yet undescribed ones) in five quill mite species. Our results suggest that in some cases the distribution of the bacteria can be better correlated with the mite's bird host rather than with mite taxonomy as such. The discovery of two new Wolbachia supergroups not only broadens the knowledge of the diversity of this bacterium but also raises questions about potential effects induced in quill mites and transmission mechanisms of the endosymbionts in this peculiar bacteria-quill mite-bird system. PMID- 25541521 TI - Multiple spontaneous hypertensive intracerebral hemorrhages. AB - Hypertensive intracerebral hemorrhage is usually a 1-time event, and recurrences are rare. Most recurrences develop as part of long-term failure of blood pressure control. The simultaneous development of 2 or more spontaneous hypertensive, nontraumatic intraparenchymal cerebral hemorrhages is rare and constitutes less than 5.6% of all hypertensive cerebral hemorrhages, and only isolated cases have been recorded in the literature. We report an unusual case where there were spontaneous, simultaneous and sequential, thalamic, cerebellar, and cerebral hemorrhages in a patient with known hypertension. PMID- 25541520 TI - Maternal human leukocyte antigen-G (HLA-G) genetic variants associate with in utero mother-to-child transmission of HIV-1 in Black South Africans. AB - A 14-bp insertion/deletion (indel) within the 3' untranslated region (3'UTR) that affects HLA-G expression has been associated with HIV-1 mother-to-child transmission (MTCT). However, other 3'UTR single nucleotide polymorphisms (SNPs) that influence HLA-G mRNA stability have been described but not analysed in the context of MTCT, and little is known about the role of HLA-G alleles. We examined HLA-G alleles and 3'UTR SNPs, including the 14-bp indel, in 216 mother-infant pairs from Johannesburg, South Africa. Mother-infant pairs were classified as HIV 1 non-transmitting (NT, n=144) or HIV-1 transmitting (TR, n=72) with either intrapartum (IP, n=29) or in utero (IU, n=19) infected infants. We found HLA-G allele, G(*)01:01:02 (in strong linkage disequilibrium with the 14-bp insertion) and +3187G SNP were significantly over-represented in IU-TR mothers compared to NT mothers (P=0.036, OR=2.26; P=0.011, OR=2.96, respectively). These findings suggest that maternal HLA-G alleles and/or SNPs that might alter expression of HLA-G potentially influence IU HIV-1 MTCT. PMID- 25541522 TI - Diagnostic accuracy of ultrasonographic and nerve conduction studies in ulnar neuropathy at the elbow. AB - OBJECTIVE: To report diagnostic accuracy of ultrasonography (US) and compare it to standard 10-cm nerve conduction studies (NCSs), and short-segment NCSs (SSNCSs) across the elbow in the diagnosis of ulnar neuropathy at the elbow (UNE). METHODS: In a broad spectrum of consecutive patients with suspected UNE a prospective and blinded study was performed. This included a clinical examination, electrodiagnostic (EDx) and US studies. In clinically definite UNE patients we compared the sensitivity of SSNCSs, of 10-cm NCSs across the elbow, and of US. The specificity was calculated in asymptomatic controls. RESULTS: We studied 113 affected arms in 109 patients; definite UNE was diagnosed in 81, and alternative conditions in 12 arms. The sensitivity of SSNCSs was 89%, of 10-cm NCSs 83%, and of US 71%. We found the highest sensitivity of US in patients with axonal UNE (93%), followed by conduction slowing (82%) and conduction block (55%). Specificity of SSNCSs was 80%, of 10-cm NCSs 82%, and of US 82%. CONCLUSION: The present study found the highest diagnostic accuracy of SSNCSs (85%), followed by 10-cm NCSs (83%), and of US (77%). SIGNIFICANCE: US is particularly useful in patients with axonal UNE, while SSNCSs in UNE with conduction block. PMID- 25541523 TI - Abdominal acupuncture reduces laser-evoked potentials in healthy subjects. AB - OBJECTIVE: Acupuncture is known to reduce clinical pain, although the exact mechanism is unknown. The aim of the current study was to investigate the effect of acupuncture on laser-evoked potential amplitudes and laser pain perception. METHODS: In order to evaluate whether abdominal acupuncture is able to modify pain perception, 10 healthy subjects underwent a protocol in which laser-evoked potentials (LEPs) and laser pain perception were collected before the test (baseline), during abdominal acupuncture, and 15 min after needle removal. The same subjects also underwent a similar protocol in which, however, sham acupuncture without any needle penetration was used. RESULTS: During real acupuncture, both N1 and N2/P2 amplitudes were reduced, as compared to baseline (p<0.01). The reduction lasted up to 15 min after needle removal. Furthermore, laser pain perception was reduced during real acupuncture, although the difference was marginally significant (p=0.06). CONCLUSIONS: Our results show that abdominal acupuncture reduces LEP amplitude in healthy subjects. SIGNIFICANCE: Our results provide a theoretical background for the use of abdominal acupuncture as a therapeutic approach in the treatment of pain conditions. Future studies will have to be conducted in clinical painful syndromes, in order to confirm the analgesic effect of acupuncture in patients suffering from pain. PMID- 25541524 TI - Transcranial motor evoked potentials during anesthesia with desflurane versus propofol--A prospective randomized trial. AB - OBJECTIVE: This study aimed to evaluate differences in transcranial electrical motor evoked potential (tcMEP) amplitudes between desflurane/remifentanil and propofol/remifentanil anesthesia treatment plans in patients without preexisting motor deficits (PMDs) undergoing carotid endarterectomy (CEA). METHODS: This prospective trial included 21 patients who were randomly assigned to an effect group (Group(DESFLURANE); n=14) or a control group (Group(STANDARD-PROPOFOL); n=7). tcMEP amplitudes were measured 35 min post-induction (T1) either with desflurane or propofol. Treatment was then changed to propofol in Group(DESFLURANE). After an additional 35 min, the tcMEP amplitudes were reevaluated (T2). Differences in amplitudes (DW) between T1 and T2 were calculated for each patient, and the means of these differences were compared between groups. RESULTS: tcMEPs were recorded in all 21 patients. At T1, the mean amplitude was 840.1 (SD 50.3) MUV and 358.9 (SD 74) MUV for Group(STANDARD PROPOFOL) and Group(DESFLURANE), respectively. The absolute mean difference (T1 T2) between groups was -496.75 MUV (p=0.0006). CONCLUSION: Desflurane reduces the tcMEP amplitude significantly more than propofol in patients without PMDs undergoing CEA. SIGNIFICANCE: TcMEPs were recorded in all patients regardless of the anesthesia regimen. In patients with initially small amplitudes, desflurane may limit tcMEP recording because it produces a remarkable amplitude reduction, even in patients without PMDs. PMID- 25541525 TI - Cloning and molecular modeling of a thermostable carboxylesterase from the chicken uropygial glands. AB - Starting from total uropygial glands mRNAs, chicken uropygial carboxylesterase (cuCES) cDNA was synthesized by RT-PCR and cloned into the PGEM-T vector. Amino acid sequence of the cuCES is compared to that of human liver carboxylesterase 1 (hCES1). Given the high amino acid sequence homology between the two enzymes, a 3 D structure model of the chicken carboxylesterase was built using the structure of hCES1 as template. By following this model and utilizing molecular dynamics (MD) simulations, the resistance of the chicken carboxylesterase at high temperatures could be explained. The docking of substrate analogs into the cuCES active site was used to explain the fact that the chicken carboxylesterase cannot hydrolyze efficiently large substrate molecules. PMID- 25541526 TI - Molecular recognition of CYP26A1 binding pockets and structure-activity relationship studies for design of potent and selective retinoic acid metabolism blocking agents. AB - All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A, plays a major role in the regulation of cellular differentiation and proliferation, and it is also an important pharmacological agent particularly used in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. However, ATRA is very easy to be metabolized into 4-hydroxyl-RA in vivo by CYP26A1, an inducible cytochrome P450 enzyme, eventually into more polar metabolites. Therefore, it is vital to develop specific retinoic acid metabolism blocking agents (RAMBAs) to inhibit the metabolic enzyme CYP26A1 in the treatment of relevant diseases aforementioned. In this study, CYP26A1 and its interactions with retinoic acid-competitive metabolism blocking agents were investigated by a combined ligand- and structure-based approach. First, since the crystal structure of CYP26A1 protein has not been determined, we constructed the 3D structure of CYP26A1 using homology modeling. In order to achieve a deeper insight into the mode of action of RAMBAs in the active site, the molecular superimposition model and the common feature pharmacophore model were constructed, and molecular docking was performed. The molecular superimposition model is composed of three features: the main chain groups, side chain groups, and azole groups. The common feature pharmacophore model consists of five chemical features: four hydrophobic groups and one hydrogen acceptor (HHHHA). The results of molecular docking show that the characteristic groups of RAMBAs were mapped into three different active pockets, respectively. A structure-activity relationship (SAR) was obtained by a combination of the molecular superimposition and docking results with the pharmacophore model. This study gives more insight into the interaction model inside the CYP26A1 active site and provides guidance for the design of more potent and possibly more selective RAMBAs. PMID- 25541527 TI - Exploration of the structural requirements of HIV-protease inhibitors using pharmacophore, virtual screening and molecular docking approaches for lead identification. AB - Pharmacoinformatics approaches are widely used in the field of drug discovery as it saves time, investment and animal sacrifice. In the present study, pharmacore based virtual screening was adopted to identify potential HIV-protease ligands as anti-HIV agents. Pharmacophore is the 3D orientation and spatial arrangement of functional groups that are critical for binding at the active site cavity. Virtual screening retrieves potential hit molecules from databases based on imposed criteria. A set of 30 compounds were selected with inhibition constant as training set from 129 compounds of dataset set and subsequently the pharmacophore model was developed. The selected best model consists of hydrogen bond acceptor and donor, hydrophobic and aromatic ring, features critical for HIV-protease inhibitors. The model exhibits high correlation (R=0.933), less rmsd (1.014), high cross validated correlation coefficient (Q(2)=0.872) among the ten models examined and validated by Fischer's randomization test at 95% confidence level. The acceptable parameters of test set prediction, such as R(pred)(2)=0.768 and r(m(test))(2)=0.711 suggested that external predictivity of the model was significant. The pharmacophore model was used to perform a virtual screening employing the NCI database. Initial hits were sorted using a number of parameters and finally seven compounds were proposed as potential HIV-protease molecules. One potential HIV-protease ligand is reportedly confirmed as an active agent for anti-HIV screening, validating the current approach. It can be postulated that the pharmacophore model facilitates the selection of novel scaffold of HIV protease inhibitors and can also allow the design of new chemical entities. PMID- 25541528 TI - An infectious disease/fever screening radar system which stratifies higher-risk patients within ten seconds using a neural network and the fuzzy grouping method. AB - OBJECTIVES: To classify higher-risk influenza patients within 10 s, we developed an infectious disease and fever screening radar system. METHODS: The system screens infected patients based on vital signs, i.e., respiration rate measured by a radar, heart rate by a finger-tip photo-reflector, and facial temperature by a thermography. The system segregates subjects into higher-risk influenza (HR-I) group, lower-risk influenza (LR-I) group, and non-influenza (Non-I) group using a neural network and fuzzy clustering method (FCM). We conducted influenza screening for 35 seasonal influenza patients and 48 normal control subjects at the Japan Self-Defense Force Central Hospital. Pulse oximetry oxygen saturation (SpO2) was measured as a reference. RESULTS: The system classified 17 subjects into HR-I group, 26 into LR-I group, and 40 into Non-I group. Ten out of the 17 HR-I subjects indicated SpO2 <96%, whereas only two out of the 26 LR-I subjects showed SpO2 <96%. The chi-squared test revealed a significant difference in the ratio of subjects showed SpO2 <96% between HR-I and LR-I group (p < 0.001). There were zero and nine normal control subjects in HR-I and LR-I groups, respectively, and there was one influenza patient in Non-I group. CONCLUSIONS: The combination of neural network and FCM achieved efficient detection of higher-risk influenza patients who indicated SpO2 96% within 10 s. PMID- 25541529 TI - Attitude toward, acceptance of and knowledge about female sterilization as a method of contraception. AB - OBJECTIVE: Surgical sterilization via tubal ligation or the disconnection of the tubes is a method of permanent contraception. The aim of this study was to evaluate the attitude, acceptance and knowledge of women about female sterilization as a method of contraception in terms of the social and cultural backgrounds of those women. STUDY DESIGN: Prospective study based on an anonymous questionnaire that analyzed background knowledge, attitude, influence factors and motivation regarding sterilization, as well as the reasons for declining. The questionnaire also attempted to evaluate the effects on the self-esteem of the women, as well as the impact of religious dogma and the related beliefs. RESULTS: One thousand, eight hundred questionnaires were distributed, and 1247 women completed the questionnaire-a response rate of 69.3%. There were mainly positive attitudes toward sterilization as a contraceptive method. Cultural background, including religion and faith; the mother's experiences and point of view; knowledge; family planning and the actual life situation have an influence on the attitudes toward and acceptance of sterilization as a contraceptive method and on the final choice of a contraceptive method. CONCLUSION: Cultural background and present life situation have a great impact on the attitude toward and acceptance of sterilization as a method of contraception, thus influencing the final choice of a contraceptive method. Detailed counselling about this topic is essential and should be improved. PMID- 25541530 TI - Determinants of health-related quality of life in the postpartum period after obstetric complications. AB - OBJECTIVE: To determine the influence of socio-demographic, clinical parameters and obstetric complications on postpartum health-related quality of life (HRQoL). STUDY DESIGN: We used data of three randomized controlled trials to investigate HRQoL determinants in women after an obstetric complication. The DIGITAT and HYPITAT trials compared induction of labor and expectant management in women with intra-uterine growth restriction (IUGR) and hypertensive disorders. The WOMB trial randomized anemic women after postpartum hemorrhage to red blood cell transfusion or expectant management. The HRQoL-measure Short-Form36 was completed at six weeks postpartum. Multivariable analyses were used to identify which parameters affected the Short-Form36 physical component score (PCS) and mental component score (MCS). RESULTS: HRQoL analyses included 1391 women (60%) of the 2310 trial participants. HYPITAT and DIGITAT participants had significantly lower MCS than WOMB participants. In multivariable analysis, PCS after elective and emergency cesarean section was 5-6 points lower than after vaginal delivery. Gestational hypertension, neonatal admission and delivery in an academic hospital had a small negative effect on PCS. No effect was found for randomization status, maternal age, BMI, country of birth, education, parity, induction of labor, analgesics, birth weight, perineal laceration, delivery of placenta, postpartum hemorrhage, congenital anomaly, urinary tract infection, thromboembolic event or endometritis. MCS was influenced only mildly by these parameters. CONCLUSIONS: IUGR and hypertensive disorders lead to lower HRQoL scores postpartum than PPH. In a heterogeneous obstetric population, only mode of delivery by cesarean section has a profound, negative impact, on physical HRQoL (PCS). No profound impacts on MCS were detected. PMID- 25541531 TI - PTPN22 and uterine leiomyomas. AB - OBJECTIVE: It has been suggested that the development of uterine leiomyomas is positively influenced by an immune system in a chronically inflammatory state and that a lower level of regulating T cell (Treg cells) would play a central role. Since it has been suggested that the W620 variant of protein tyrosine phosphatase non-receptor type 22 (PTPN22) decreases the number of Treg cells, we investigated a possible relationship between PTPN22 polymorphism and uterine leiomyomas. STUDY DESIGN: We studied 203 white women from Rome who were hospitalized for symptomatic leiomyomas requiring surgical intervention. These women were considered in a previous paper regarding the relationship between ACP1 and dimension of leiomyomas. As controls we studied 355 healthy women from the same population with comparable age and without clinical evidence of leiomyomas. All women gave written informed consent to participate to the study. Chi square test of independence and T-test for difference between means were performed by SPSS package. RESULTS: Considering the whole sample, a borderline association between PTPN22 and leiomyomas was observed: the *C/*T genotype is more frequent in cases than in controls. This association is marked and statistically significant in younger women only. The main diameter of tumor is significantly greater in *C/*T than in *C/*C women. This effect is present in younger women only. The *C/*T genotype also shows a higher tendency to intramural localization, but no effect of age is observed upon this association. CONCLUSIONS: The data suggest a positive effect of *C/*T genotype on susceptibility to leiomyomas in younger women. In these women a *C/*T genotype favors the growth of leiomyomas. PMID- 25541532 TI - A single amino acid at N-terminal region of the 2b protein of cucumber mosaic virus strain m1 has a pivotal role in virus attenuation. AB - Host responses to infection by a mild strain of cucumber mosaic virus, termed CMV m1, were re-examined in several plant species in comparison with those by a severe strain CMV-Y. Mild systemic symptoms were developed on the six plant species inoculated with CMV-m1. Virus titer in the Nicotiana benthamiana plants infected with CMV-m1 was significantly lower than those infected with CMV-Y, although infection by CMV-m1 interfered with further infection by CMV-Y in the plants. Subsequently, the attenuated virulence of CMV-m1 was analyzed by reassortment and recombination analyses between CMV-m1 and CMV-Y RNAs. The results suggested that the 2b protein of CMV-m1 (m1-2b) is involved in the formation of mild symptoms in N. benthamiana. Furthermore, site-directed mutagenesis demonstrated that Thr18 of m1-2b is responsible for formation of mild symptoms. Local RNA silencing suppressor activity of m1-2b was a little lower than that of severe strain CMV-Y. We discuss the relationship between attenuation of CMV-m1 and the features of m1-2b. PMID- 25541533 TI - Estimating industrial and domestic environmental releases of perfluorooctanoic acid and its salts in China from 2004 to 2012. AB - China has been documented as one of the few remaining producers of perfluorooctanoic acid and its salts (PFOA/PFO) and the world's major contamination hotspot. However, limited information has been available for evaluating their environmental releases in China and the contribution to global PFOA/PFO burden. Here we present the first source-specific inventory for environmental releases of PFOA/PFO in China from 2004 to 2012, using a bottom-up approach for industrial sources and an inverse approach for domestic sources. Our results show that China became the current world's largest PFOA/PFO emitter, with cumulative environmental releases reaching 250tonnes (t) over the period of nine years. The eastern region was identified as the hotspot of environmental releases. Most of the national environmental releases were due to the activities of the fluorochemical industry (94.0%) rather than domestic use of PFOA/PFO related consumer products (6.0%). Fluoropolymer manufacturing and processing, a dominating industrial source, contributed 83.7% of the national environmental releases. In contrast to the general decline trends in annual industrial environmental releases of PFOA/PFO in most industrialized countries, the trend increased in China because of the expansion of production as a result of the global geographical transition in fluorochemical industry. Based on these results, we recommend that the future reduction options are required in industrial sector in China. PMID- 25541534 TI - Regression based state space adaptive model of two-phase anaerobic reactor. AB - In this paper, a linear state space model for the two-phase anaerobic reactor system was developed based on historical data. Subsequently, the model was used to predict its future behavior. The state space model developed involved correlation analysis and model development. The model would be updated at every time point when a new data set became available, giving it an "adaptive" feature. The model was then applied to monitor two-phase anaerobic co-digestion of a feed comprising 2 industrial secondary sludges and 2 industrial wastewaters. The case study showed the proposed model was able to provide good predictions of various process parameters. In addition, it also predicted impending process failure and this would have allowed the operator to take necessary measures to prevent or reduce impact of such failure during plant operation. PMID- 25541535 TI - Maternal high-zinc diet attenuates intestinal inflammation by reducing DNA methylation and elevating H3K9 acetylation in the A20 promoter of offspring chicks. AB - A20 is an anti-inflammatory protein that suppresses ubiquitin-dependent nuclear factor kappaB (NF-kappaB) signaling, which can be regulated by the microelement zinc (Zn). In mammals, Zn deficiency contributes to a decrease in A20 abundance, which impairs the gut mucosa barrier. However, it is unclear whether the epigenetic reprogramming of the A20 promoter is involved in enhanced Zn-induced intestinal immunity, especially in avian species. Herein, we show that maternal organic Zn exposure resulted in significantly improved intestinal morphological characteristics, increased mucin 2 (MUC2) abundance and secretory IgA (sIgA) production in progeny jejunums. Maternal and offspring Zn supplementation partially alleviated Zn-deficiency-induced inflammatory response, accompanied by repression of NF-kappaB signaling. Additionally, we observed DNA hypomethylation and histone H3 at lysine 9 (H3K9) hyperacetylation at the A20 promoter region and subsequent activated A20 expression in Zn-supplemented hens compared with control. Notably, maternal dietary organic Zn exposure exhibited greater attenuation of gut impairment, along with increased MUC2 expression and sIgA level, and decreased the abundance of TNF-alpha and A20 relative to the inorganic Zn group. Furthermore, enhanced acetylated H3K9 and A20 transcription at day 14 was found in the offspring adequate dietary Zn group. Thus, A20 may be a novel inflammatory-suppressed factor of chick gut that is persistently promoted by dietary Zn supplementation via epigenetic modifications at A20 promoter. PMID- 25541536 TI - Season of birth and subclinical psychosis: systematic review and meta-analysis of new and existing data. AB - Season of birth (SOB) has been shown to modify the risk of several health outcomes, including a number of neuropsychiatric disorders. Empirical evidence indicates that subclinical forms of psychosis in the general population share some risk factors with categorical diagnoses of psychosis. Hence, by systematically reviewing and meta-analyzing new and existing data, the current work aimed to determine whether there is evidence of an association between winter SOB and subclinical psychosis in the general population. Our meta-analytic results do not indicate an association between winter SOB and schizotypy in adult populations, although they indicate winter SOB may be a risk factor for psychotic experiences or symptoms in children around 12-15 years (OR=1.12, 95%CI:1.03 1.21). In the whole new dataset for adults (n=481, mean age=22.8 years) no association was detected in either an unadjusted model or adjusting for gender and age. Overall, our results indicate that the association between winter SOB and increased subclinical psychosis may hold in children, but does not in the broad general adult population. Nevertheless, the epidemiological and clinicopathological significance of winter SOB as a risk factor for subclinical psychosis would probably be slight due to the small effect sizes indicated by the reports available to date. PMID- 25541537 TI - The experience of aggressive outbursts in Intermittent Explosive Disorder. AB - Conceptualizations of Intermittent Explosive Disorder (IED) have suffered from a scarcity of research investigating the subjective experience and phenomenology of the aggressive outbursts among those with IED relative to those who partake in more normative forms of aggression. Furthermore, though some studies have shown that individuals with IED are more impaired and have a poorer quality of life, few studies looked at negative outcomes specific to an individual with IED's aggressive behavior. The purpose of this study was to examine the subjective experience and social, occupational, and legal consequences of aggressive outbursts in IED. We assessed individuals with IED (n=410), psychiatric controls (n=133), and healthy controls (HC) (n=154) in the experiential correlates present before, during, and after an aggressive outburst as well as the consequences of aggressive outbursts. Results indicated that before and during aggressive outbursts, individuals with IED experienced more intense anger, physiological reactivity, and feelings of dyscontrol as well as more remorse after an aggressive outburst. Furthermore, individuals with IED report more negative consequences of their aggressive outbursts. These results provide an account of how the subjective experience and consequences of aggressive outbursts in IED differ from those with more normative forms of aggression. PMID- 25541539 TI - The design and statistical analysis of animal experiments: introduction to this issue. AB - Animal research has made major contributions to the health and welfare of humans and domestic animals. Immunization, first developed against rabies and anthrax by Pasteur using dogs, sheep, and rabbits, is now used to control many infectious diseases. The first drug, Salvarsan, was developed by Ehrlich using rabbits infected with the organism causing syphilis. This was the forerunner of the many drugs developed by the pharmaceutical industry today. The discovery of vitamins using rats has almost eliminated diseases such as scurvy and rickets; and hormones, such as insulin discovered following work in dogs, have helped to control many metabolic diseases. These and many other advances have enabled physicians to treat a wide range of human diseases. But many diseases continue to cause suffering. PMID- 25541538 TI - An examination of the broader effects of warzone experiences on returning Iraq/Afghanistan veterans' psychiatric health. AB - The objective of the present research was to test the hypotheses that: (1) Iraq/Afghanistan war veterans experience a wide range of psychiatric symptomatology (e.g., obsessive-compulsive symptoms, hypochondriasis, somatization); and (2) general psychiatric symptomatology among Iraq/Afghanistan war veterans is associated with their warzone experiences. To achieve this objective, Iraq/Afghanistan war veterans (N=155) completed a screening questionnaire that assessed a wide range of psychiatric symptoms along with a measure of warzone experiences. As expected, returning veterans reported significant elevations across a wide range of clinical scales. Approximately three-fourths screened positive on at least one clinical subscale, and a one third screened positive on five or more. In addition, nearly all of these conditions were associated with veterans' warzone experiences (average r=0.36); however, this association was much stronger among veterans with posttraumatic stress disorder (PTSD) (average r=0.33) than among veterans without PTSD (average r=0.15). We also observed that approximately 18% of the variance in total psychiatric symptomatology was attributable to warzone experiences above and beyond the effects of childhood trauma and demographic factors. Taken together, these findings suggest that returning veterans experience a broad array of psychiatric symptoms that are strongly associated with their warzone experiences. PMID- 25541540 TI - Refinement of experimental design and conduct in laboratory animal research. AB - The scientific literature of laboratory animal research is replete with papers reporting poor reproducibility of results as well as failure to translate results to clinical trials in humans. This may stem in part from poor experimental design and conduct of animal experiments. Despite widespread recognition of these problems and implementation of guidelines to attenuate them, a review of the literature suggests that experimental design and conduct of laboratory animal research are still in need of refinement. This paper will review and discuss possible sources of biases, highlight advantages and limitations of strategies proposed to alleviate them, and provide a conceptual framework for improving the reproducibility of laboratory animal research. PMID- 25541541 TI - Animal husbandry and experimental design. AB - If the scientist needs to contact the animal facility after any study to inquire about husbandry details, this represents a lost opportunity, which can ultimately interfere with the study results and their interpretation. There is a clear tendency for authors to describe methodological procedures down to the smallest detail, but at the same time to provide minimal information on animals and their husbandry. Controlling all major variables as far as possible is the key issue when establishing an experimental design. The other common mechanism affecting study results is a change in the variation. Factors causing bias or variation changes are also detectable within husbandry. Our lives and the lives of animals are governed by cycles: the seasons, the reproductive cycle, the weekend-working days, the cage change/room sanitation cycle, and the diurnal rhythm. Some of these may be attributable to routine husbandry, and the rest are cycles, which may be affected by husbandry procedures. Other issues to be considered are consequences of in-house transport, restrictions caused by caging, randomization of cage location, the physical environment inside the cage, the acoustic environment audible to animals, olfactory environment, materials in the cage, cage complexity, feeding regimens, kinship, and humans. Laboratory animal husbandry issues are an integral but underappreciated part of investigators' experimental design, which if ignored can cause major interference with the results. All researchers should familiarize themselves with the current routine animal care of the facility serving them, including their capabilities for the monitoring of biological and physicochemical environment. PMID- 25541542 TI - Evidence should trump intuition by preferring inbred strains to outbred stocks in preclinical research. AB - Inbred strains of mice such as C57BL and BALB/c are more widely used in published work than outbred stocks of mice such as ICR and CD-1. In contrast, outbred stocks of rats such as Wistar and Sprague-Dawley are more widely used than inbred strains such as F344 and LEW. The properties of inbred and outbred mice and rats are briefly reviewed, and it is concluded that, with some exceptions, there is a strong case for using inbred strains in most controlled experiments. This is because they are usually more uniform, so that fewer animals are usually needed to detect a specified response and they are more repeatable, because they are genetically defined (i.e., the strain can be identified using genetic markers) and less liable to genetic change. Yet many scientists continue to use outbred animals. In Daniel Kahneman's book "Thinking Fast and Slow" he explains that we can answer questions in 2 ways: "fast" by intuition or "slow" by analytical reasoning. The former method is instantaneous, requires no thought but is not evidence based. Analytical reasoning is evidence based but requires hard work, which we all avoid. He has found that "... when faced with a difficult question, we often answer an easier one instead, usually without noticing the substitution." The target question of whether to choose outbred or inbred strains in controlled experiments is a difficult one requiring knowledge of the characteristics of these strains and the principles of experimental design. A substitute question, "are humans and outbred stocks both genetically heterogeneous," is easily answered in the affirmative. It is likely that many scientists are intuitively answering the substitute question and are assuming that they have answered the target question. If so they may be using the wrong animals in their research. Nor is the fact that humans and outbred stocks are alike in being genetically heterogeneous a reason for using them. The whole concept of a "model" is that it is similar to the target in some respects but different in others. Rats and mice differ from humans in that we can control their genotype. This is a positive attribute that enormously increases their value in research. Funding organizations should support research in comparing the 2 types in real experiments. PMID- 25541543 TI - Critical appraisal of studies using laboratory animal models. AB - In this manuscript we discuss an approach to critically appraising papers based on the results of laboratory animal experiments. The roles of external and internal validity in critically appraising the results of a paper are introduced. The risk of bias domains used by the Cochrane Handbook of Systematic Reviews of Interventions form the basis for assessing internal validity. The bias domains discussed include the selection bias, performance bias, outcome assessment bias, attrition bias, and reporting bias. Further, an approach to considering the role of chance in research findings is discussed. PMID- 25541544 TI - Meta-analyses of animal studies: an introduction of a valuable instrument to further improve healthcare. AB - In research aimed at improving human health care, animal studies still play a crucial role, despite political and scientific efforts to reduce preclinical experimentation in laboratory animals. In animal studies, the results and their interpretation are not always straightforward, as no single study is executed perfectly in all steps. There are several possible sources of bias, and many animal studies are replicates of studies conducted previously. Use of meta analysis to combine the results of studies may lead to more reliable conclusions and a reduction of unnecessary duplication of animal studies. In addition, due to the more exploratory nature of animal studies as compared to clinical trials, meta-analyses of animal studies have greater potential in exploring possible sources of heterogeneity. There is an abundance of literature on how to perform meta-analyses on clinical data. Animal studies, however, differ from clinical studies in some aspects, such as the diversity of animal species studied, experimental design, and study characteristics. In this paper, we will discuss the main principles and practices for meta-analyses of experimental animal studies. PMID- 25541545 TI - The usefulness of systematic reviews of animal experiments for the design of preclinical and clinical studies. AB - The question of how animal studies should be designed, conducted, and analyzed remains underexposed in societal debates on animal experimentation. This is not only a scientific but also a moral question. After all, if animal experiments are not appropriately designed, conducted, and analyzed, the results produced are unlikely to be reliable and the animals have in effect been wasted. In this article, we focus on one particular method to address this moral question, namely systematic reviews of previously performed animal experiments. We discuss how the design, conduct, and analysis of future (animal and human) experiments may be optimized through such systematic reviews. In particular, we illustrate how these reviews can help improve the methodological quality of animal experiments, make the choice of an animal model and the translation of animal data to the clinic more evidence-based, and implement the 3Rs. Moreover, we discuss which measures are being taken and which need to be taken in the future to ensure that systematic reviews will actually contribute to optimizing experimental design and thereby to meeting a necessary condition for making the use of animals in these experiments justified. PMID- 25541547 TI - Teaching experimental design. AB - Awareness of poor design and published concerns over study quality stimulated the development of courses on experimental design intended to improve matters. This article describes some of the thinking behind these courses and how the topics can be presented in a variety of formats. The premises are that education in experimental design should be undertaken with an awareness of educational principles, of how adults learn, and of the particular topics in the subject that need emphasis. For those using laboratory animals, it should include ethical considerations, particularly severity issues, and accommodate learners not confident with mathematics. Basic principles, explanation of fully randomized, randomized block, and factorial designs, and discussion of how to size an experiment form the minimum set of topics. A problem-solving approach can help develop the skills of deciding what are correct experimental units and suitable controls in different experimental scenarios, identifying when an experiment has not been properly randomized or blinded, and selecting the most efficient design for particular experimental situations. Content, pace, and presentation should suit the audience and time available, and variety both within a presentation and in ways of interacting with those being taught is likely to be effective. Details are given of a three-day course based on these ideas, which has been rated informative, educational, and enjoyable, and can form a postgraduate module. It has oral presentations reinforced by group exercises and discussions based on realistic problems, and computer exercises which include some analysis. Other case studies consider a half-day format and a module for animal technicians. PMID- 25541548 TI - Randomized block experimental designs can increase the power and reproducibility of laboratory animal experiments. AB - Randomized block experimental designs have been widely used in agricultural and industrial research for many decades. Usually they are more powerful, have higher external validity, are less subject to bias, and produce more reproducible results than the completely randomized designs typically used in research involving laboratory animals. Reproducibility can be further increased by using time as a blocking factor. These benefits can be achieved at no extra cost. A small experiment investigating the effect of an antioxidant on the activity of a liver enzyme in four inbred mouse strains, which had two replications (blocks) separated by a period of two months, illustrates this approach. The widespread failure to use these designs more widely in research involving laboratory animals has probably led to a substantial waste of animals, money, and scientific resources and slowed down the development of new treatments for human and animal diseases. PMID- 25541546 TI - The significance of meaning: why do over 90% of behavioral neuroscience results fail to translate to humans, and what can we do to fix it? AB - The vast majority of drugs entering human trials fail. This problem (called "attrition") is widely recognized as a public health crisis, and has been discussed openly for the last two decades. Multiple recent reviews argue that animals may be just too different physiologically, anatomically, and psychologically from humans to be able to predict human outcomes, essentially questioning the justification of basic biomedical research in animals. This review argues instead that the philosophy and practice of experimental design and analysis is so different in basic animal work and human clinical trials that an animal experiment (as currently conducted) cannot reasonably predict the outcome of a human trial. Thus, attrition does reflect a lack of predictive validity of animal experiments, but it would be a tragic mistake to conclude that animal models cannot show predictive validity. A variety of contributing factors to poor validity are reviewed. The need to adopt methods and models that are highly specific (i.e., which can identify true negative results) in order to complement the current preponderance of highly sensitive methods (which are prone to false positive results) is emphasized. Concepts in biomarker-based medicine are offered as a potential solution, and changes in the use of animal models required to embrace a translational biomarker-based approach are outlined. In essence, this review advocates a fundamental shift, where we treat every aspect of an animal experiment that we can as if it was a clinical trial in a human population. However, it is unrealistic to expect researchers to adopt a new methodology that cannot be empirically justified until a successful human trial. "Validation with known failures" is proposed as a solution. Thus new methods or models can be compared against existing ones using a drug that has translated (a known positive) and one that has failed (a known negative). Current methods should incorrectly identify both as effective, but a more specific method should identify the negative compound correctly. By using a library of known failures we can thereby empirically test the impact of suggested solutions such as enrichment, controlled heterogenization, biomarker-based models, or reverse translated measures. PMID- 25541549 TI - The place of experimental design and statistics in the 3Rs. AB - The 3Rs--replacement, reduction, and refinement--can be applied to any animal experiment by researchers and other bodies seeking to conduct those studies in as humane a manner as possible. Key to the success of this endeavor is an appreciation of the principles of good experimental design and analysis; these need to be considered in concert before any data is collected. Indeed, many of the principles central to helping achieve the objectives of the 3Rs-such as conducting valid, reliable, and efficient experiments; clearly and transparently reporting findings; and ensuring that an appreciation and understanding of animal welfare plays a central role in laboratory practice-are to the betterment of research per se. PMID- 25541550 TI - Making the most of clustered data in laboratory animal research using multi-level models. AB - In the following review article, I address the fitting of multi-level models for the analysis of hierarchical data in laboratory animal medicine. Using an example of paternal dietary effects on the weight of offspring in a mouse model, this review outlines the reasons and benefits of using a multi-level modeling approach. To start, the concept of clustered/autocorrelated data is introduced, and the implications of ignoring the effects of clustered data on measures of association/model coefficients and their statistical significance are discussed. The limitations of other methods compared with multi-level modeling for analyzing clustered data are addressed in terms of statistical power, control of potential confounding effects associated with group membership, proper estimation of associations and their statistical significance, and adjusting for multiple levels of clustering. In addition, the benefits of being able to estimate variance partition coefficients and intra-class correlation coefficients from multi-level models is described, and the concepts of more complex correlation structures and various methods for fitting multi-level models are introduced. The current state of learning materials including textbooks, websites, and software for the nonstatistician is outlined to describe the accessibility of multi-level modeling approaches for laboratory animal researchers. PMID- 25541551 TI - Vein grafts to augment flexor tendon repairs: a biomechanical study on strength and gap resistance. AB - The ultimate tensile repair strength and gap formation of the pig extensor tendons repaired with a standard 4-strand Savage with epitendinous suture repair, was compared with a new technique of adding a vein sleeve. Force and displacement data were recorded, and video images during linear cyclic loading up to failure. At 35 N, video-graphic observation detected significantly smaller gap lengths in the standard and vein repair specimens compared with standard repair specimens (p = 0.047). The incidence of 3 mm gaps between the repaired tendon ends in the standard repair group was 20 %, but no 3 mm gaps were seen in the standard and vein specimens. The addition of a vein sleeve increased the ultimate tensile strength of the standard repair from 50.4 N (4.5) to 55.4 N (4.5); this was statistically significant (p = 0.03). This study demonstrated that the addition of a vein graft prevented gap formation and increased ultimate tensile strength of tendon repair. PMID- 25541552 TI - Efficacy of expressed breast milk in reducing pain during ROP screening--a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of expressed breast milk (EBM) on neonatal pain during screening for retinopathy of prematurity (ROP). METHODS: Neonates who were on oral feeds undergoing ROP screening were included. Babies were randomized into intervention group (EBM + Standard practice) and control group. The standard practice is proparacaine, nesting and swaddling. Pain was assessed by PIPP scale, during and at 1 and 5 min after the procedure by the principal investigator who was blinded. RESULTS: The groups were similar in baseline characteristics. The group receiving EBM had significantly lower PIPP scores during the procedure 12.7 +/- 1.69 compared to the control group 15.5 +/- 1.78 (p < 0.05). The beneficial effect persisted at 1 min and 5 min after the procedure 6.20 +/- 1.9 vs. 12.4 +/- 2.54 (p <= 0.05) at 1 min; 3.2 +/- 1.5 and 6.85 +/- 2.4 (p < 0.05) at 5 min. CONCLUSION: Oral EBM significantly reduces pain during and after ROP screening. PMID- 25541554 TI - Serum bilirubin and the risk of hypertension. AB - BACKGROUND: Experimental studies suggest oxidative stress could lead to the development of hypertension. Serum bilirubin is a major contributor to the antioxidant capacity in blood plasma and has been identified as an independent cardiovascular risk factor in cohort studies. However, data on the relationship between bilirubin and blood pressure are scarce and inconclusive. METHODS: We analysed data from the National Health and Nutrition Examination Surveys (NHANES) 1999-2012 (N=31069). Fifty multiple imputed data sets were generated and analysed to avoid selection/confounding bias due to excluding individuals/variables with missing values. A minimal sufficient adjustment set of variables (MSAS) needed to estimate the unconfounded effect of bilirubin on blood pressure and hypertension (systolic/diastolic blood pressure >= 140/90 mmHg or using antihypertensive medication) was identified using the back-door criterion and included in all regression models. RESULTS: After adjustment for the MSAS variables, systolic blood pressure decreased progressively up to -2.5 mmHg (p<0.001) and the prevalence of hypertension was up to 25% lower (P<0.001) in those with bilirubin >= 1.0 mg/dl-the highest two deciles-compared with those with 0.1-0.4 mg/dl-the lowest decile. Sensitivity analyses showed these results were unlikely to be explained by residual confounding or selection bias. CONCLUSIONS: High serum bilirubin may decrease the risk of hypertension by inactivating and inhibiting the synthesis of reactive oxygen species in vascular cells. Strategies to boost the bioavailability of circulating and tissue bilirubin or to mimic bilirubin's antioxidant properties could have a significant impact on prevention and control of hypertension as well as coronary heart disease. PMID- 25541553 TI - Adiposity is associated with DNA methylation profile in adipose tissue. AB - BACKGROUND: Adiposity is a risk factor for type 2 diabetes and cardiovascular disease, suggesting an important role for adipose tissue in the development of these conditions. The epigenetic underpinnings of adiposity are not well understood, and studies of DNA methylation in relation to adiposity have rarely focused on target adipose tissue. Objectives were to evaluate whether genome-wide DNA methylation profiles in subcutaneous adipose tissue and peripheral blood leukocytes are associated with measures of adiposity, including central fat mass, body fat distribution and body mass index. METHODS: Participants were 106 men and women (mean age 47 years) from the New England Family Study. DNA methylation was evaluated using the Infinium HumanMethylation450K BeadChip. Adiposity phenotypes included dual-energy X-ray absorptiometry-assessed android fat mass, android:gynoid fat ratio and trunk:limb fat ratio, as well as body mass index. RESULTS: Adipose tissue genome-wide DNA methylation profiles were associated with all four adiposity phenotypes, after adjusting for race, sex and current smoking (omnibus p-values <0.001). After further adjustment for adipose cell-mixture effects, associations with android fat mass, android:gynoid fat ratio, and trunk:limb fat ratio remained. In gene-specific analyses, adiposity phenotypes were associated with adipose tissue DNA methylation in several genes that are biologically relevant to the development of adiposity, such as AOC3, LIPE, SOD3, AQP7 and CETP. Blood DNA methylation profiles were not associated with adiposity, before or after adjustment for blood leukocyte cell mixture effects. CONCLUSION: Findings show that DNA methylation patterns in adipose tissue are associated with adiposity. PMID- 25541556 TI - Does farm fungicide use induce azole resistance in Aspergillus fumigatus? AB - Azole resistance of Aspergillus fumigatus isolates has been reported worldwide and it would appear to be mainly due to a point mutation in the 14alpha-sterol demethylase (CYP51A) gene, which is the target enzyme for azoles. The mutation has been confirmed in isolates from patients who received long-term itraconazole (ITZ) therapy and from agricultural fields where high levels of azole fungicides were employed. However, the relationship between farm environments and azole resistant A. fumigatus has not been fully studied. In this investigation, 50 isolates of A. fumigatus were obtained from a farm where tetraconazole has been sprayed twice a year for more than 15 years. The mean minimum inhibitory concentration (MIC) of isolates was 0.74 (0.19-1.5) mg/L against ITZ, which was below the medical resistance level of ITZ. The sequence of CYP51A from isolates indicated no gene mutations in isolates from the farm. Antifungal susceptibility of isolates to tetraconazole showed that spraying with tetraconazole did not induce resistance to tetraconazole or ITZ in A. fumigatus. PMID- 25541555 TI - Generation of stable mutants and targeted gene deletion strains in Cryptococcus neoformans through electroporation. AB - Cryptococcus neoformans is the etiologic agent of cryptococcal meningitis that causes more than half a million deaths worldwide each year. This capsulated basidiomycetous yeast also serves as a model for micropathogenic studies. The ability to make stable mutants, either via ectopic integration or homologous recombination, has been accomplished using biolistic transformation. This technical advance has greatly facilitated the research on the basic biology and pathogenic mechanisms of this pathogen in the past two decades. However, biolistic transformation is costly, and its reproducibility varies widely. Here we found that stable ectopic integration or targeted gene deletion via homologous replacement could be accomplished through electroporative transformation. The stability of the transformants obtained through electroporation and the frequency of homologous replacement is highly dependent on the selective marker. A frequency of homologous recombination among the stable transformants obtained by electroporation is comparable to those obtained by biolistic transformation (~10%) when dominant drug selection markers are used, which is much higher than what has been previously reported for electroporation when auxotrophic markers were used (0.001% to 0.1%). Furthermore, disruption of the KU80 gene or generation of gene deletion constructs using the split marker strategy, two approaches known to increase homologous replacement among transformants obtained through biolistic transformation, also increase the frequency of homologous replacement among transformants obtained through electroporation. Therefore, electroporation provides a low cost alternative for mutagenesis in Cryptococcus. PMID- 25541557 TI - Positive (1-3) B-d-glucan and cross reactivity of fungal assays in coccidioidomycosis. AB - Fungal antigen testing in immunosuppressed patients has emerged as a powerful diagnostic tool. Some assays are relatively nonspecific, and misinterpretation can have severe clinical consequences. Additionally, when new assays become commercially available it is important to evaluate the potential for cross reactivity. We recently observed several immunosuppressed patients with positive (1->3)-beta-D-glucan (BG) who were eventually diagnosed with coccidioidomycosis in the endemic area of Tucson, Arizona. Although the BG assay is known to detect glucans of many fungal pathogens, reports of cross-reactivity with Coccidioides remain sparsely reported. To test the cross-reactivity of fungal antigens in detection assays, serum samples from patients with coccidioidomycosis testing positive for Coccidioides antigen were evaluated for BG. Of 12 samples positive for Coccidioides antigen (>=0.07 ng/ml), 11 (92%) were positive by BG (>80 pg/ml), and of 11 positive for Aspergillus galactomannan, 10 (91%) were positive by BG (>80 pg/ml). We conclude that the BG assay is nonspecific, detecting glucans from many fungal pathogens, including Coccidioides. In the endemic area, a positive BG warrants further specific testing. PMID- 25541558 TI - In vitro inhibitory activity of terpenic derivatives against clinical and environmental strains of the Sporothrix schenkii complex. AB - Sporotrichosis is a subacute or chronic subcutaneous infection, caused by the fungus Sporothrix schenkii complex, occurring in human and animal tissues. Potassium iodide and itraconazole have been used as effective therapy for first choice treatment, while amphotericin B may be indicated for disseminated infection. However, the adverse effects of potassium iodide and amphotericin B or the long duration of therapy with itraconazole often weigh against their use, leading to the search for alternatives for the treatment of severe infections. Terpinen-4-ol and farnesol are components of essential oils present in many plant species and have been described to have antifungal activity against microorganisms. In this study, 40 strains of Sporothrix spp. were tested for the susceptibility to terpinen-4-ol and farnesol. Changes in cytoplasmic membrane permeability were also investigated. Terpenes inhibited all Sporothrix strains with MIC values ranging from 87.9 to 1,429.8 MUg/ml for terpinen-4-ol and from 0.003 to 0.222 MUg/ml for farnesol. The MFC values ranged from 177.8 to 5,722.6 MUg/ml and from 0.027 to 0.88 MUg/ml, respectively, for terpinen-4-ol and farnesol. Farnesol was the most active compound for the Sporothrix strains. Significant loss of 260 and 280 nm-absorbing material did not occur after treatment with concentrations equivalent to the MIC and sub-MIC of the tested terpenes, when compared to corresponding untreated samples. The failure of terpenes to lyse Sporothrix cells suggests that their primary mechanism of action is not by causing irreversible cell membrane damage. Thus, new studies are needed to better understand the mechanisms involved in the antifungal activity. PMID- 25541559 TI - Transposable elements and two other molecular markers as typing tools for the genus Paracoccidioides. AB - Studies comparing Paracoccidioides brasiliensis and Paracoccidioides lutzii have shown that these fungi have significant genomic differences that may have implications in the clinical manifestation, diagnosis, and treatment of paracoccidioidomycosis caused by them. Thus, molecular typing methods are required that can distinguish between various species of Paracoccidioides. The aim of this study was to explore the potential use as molecular markers of the transposable elements Trem A-H recently identified and characterized in the genus Paracoccidioides as a means of differentiating the species. We take advantage of the abundance and distribution of these transposons in the Paracoccidioides genomes to develop a simple and highly reproducible polymerase chain reaction (PCR)-based technique. Furthermore we compare the performance of this test with two other molecular markers already in use to identify these fungi. PMID- 25541560 TI - Lack of 1-3-B-D-glucan detection in adults with bacteraemia. AB - Bacteraemia was reported to be associated with false-positive 1->3-beta-D-glucan (BG) assay results. We thus prospectively assessed the reactivity of the BG (Fungitell) in samples of 21 adults with bacteraemia: . BG was negative in all and is s therefore an unlikely cause of false positive BG in adults. PMID- 25541561 TI - Detection of fungal DNA in peritoneal fluids by a PCR DNA low-density microarray system and quantitation of serum (1-3)-beta-D-glucan in the diagnosis of peritoneal candidiasis. AB - Microbiological documentation of peritoneal candidiasis (PC) is hampered by the low numbers of yeasts observable by direct microscopic examination and recoverable by culture methods. The performance of a polymerase chain reaction (PCR) DNA Low-Density Microarray System (CLART STIs B) was compared to that of BACTEC FX automated culture method for the detection of Candida spp. in 161 peritoneal fluids (PF) from patients with peritonitis. The clinical utility of (1 3)-beta-d-glucan (BDG) antigenemia in the diagnosis of PC was evaluated in 42 of these patients. The overall agreement between the PCR assay and the culture method was good (kappa = 0.790), and their sensitivities were 93.5% and 74.19%, respectively. Serum BDG levels in patients with Candida spp. in PFs (median, 200.3 pg/mL; Range, 22.0-523.4 pg/mL) was significantly higher (P = 0.002) than those found in patients without the yeast (median, 25.3 pg/mL; Range, 0-523.4 pg/mL). Our study demonstrates the potential clinical utility of molecular methods and the measurement of serum BDG levels for the diagnosis of PC. PMID- 25541562 TI - Interactive model building for Q-learning. AB - Evidence-based rules for optimal treatment allocation are key components in the quest for efficient, effective health care delivery. Q-learning, an approximate dynamic programming algorithm, is a popular method for estimating optimal sequential decision rules from data. Q-learning requires the modeling of nonsmooth, nonmonotone transformations of the data, complicating the search for adequately expressive, yet parsimonious, statistical models. The default Q learning working model is multiple linear regression, which is not only provably misspecified under most data-generating models, but also results in nonregular regression estimators, complicating inference. We propose an alternative strategy for estimating optimal sequential decision rules for which the requisite statistical modeling does not depend on nonsmooth, nonmonotone transformed data, does not result in nonregular regression estimators, is consistent under a broader array of data-generation models than Q-learning, results in estimated sequential decision rules that have better sampling properties, and is amenable to established statistical approaches for exploratory data analysis, model building, and validation. We derive the new method, IQ-learning, via an interchange in the order of certain steps in Q-learning. In simulated experiments IQ-learning improves on Q-learning in terms of integrated mean squared error and power. The method is illustrated using data from a study of major depressive disorder. PMID- 25541563 TI - Intended and Unintended Effects of State-Mandated High School Science and Mathematics Course Graduation Requirements on Educational Attainment. AB - Mathematics and science course graduation requirement (CGR) increases in the 1980s and 1990s might have had both intended and unintended consequences. Using logistic regression with Census and American Community Survey (ACS) data (n = 2,892,444), we modeled CGR exposure on (a) high school dropout, (b) beginning college, and (c) obtaining any college degree. Possible between-groups differences were also assessed. We found that higher CGRs were associated with higher odds to drop out of high school, but results for the college-level outcomes varied by group. Some were less likely to enroll, whereas others who began college were more likely to obtain a degree. Increased high school dropout was consistent across the population, but some potential benefit was also observed, primarily for those reporting Hispanic ethnicity. PMID- 25541564 TI - Mind, Machine, and Creativity: An Artist's Perspective. AB - Harold Cohen is a renowned painter who has developed a computer program, AARON, to create art. While AARON has been hailed as one of the most creative AI programs, Cohen consistently rejects the claims of machine creativity. Questioning the possibility for AI to model human creativity, Cohen suggests in so many words that the human mind takes a different route to creativity, a route that privileges the relational, rather than the computational, dimension of cognition. This unique perspective on the tangled web of mind, machine, and creativity is explored by an application of three relational models of the mind to an analysis of Cohen's talks and writings, which are available on his website: www.aaronshome.com. PMID- 25541565 TI - Does Calculation or Word-Problem Instruction Provide A Stronger Route to Pre Algebraic Knowledge? AB - The focus of this study was connections among 3 aspects of mathematical cognition at 2nd grade: calculations, word problems, and pre-algebraic knowledge. We extended the literature, which is dominated by correlational work, by examining whether intervention conducted on calculations or word problems contributes to improved performance in the other domain and whether intervention in either or both domains contributes to pre-algebraic knowledge. Participants were 1102 children in 127 2nd-grade classrooms in 25 schools. Teachers were randomly assigned to 3 conditions: calculation intervention, word-problem intervention, and business-as-usual control. Intervention, which lasted 17 weeks, was designed to provide research-based linkages between arithmetic calculations or arithmetic word problems (depending on condition) to pre-algebraic knowledge. Multilevel modeling suggested calculation intervention improved calculation but not word problem outcomes; word-problem intervention enhanced word-problem but not calculation outcomes; and word-problem intervention provided a stronger route than calculation intervention to pre-algebraic knowledge. PMID- 25541566 TI - An immersogeometric variational framework for fluid-structure interaction: application to bioprosthetic heart valves. AB - In this paper, we develop a geometrically flexible technique for computational fluid-structure interaction (FSI). The motivating application is the simulation of tri-leaflet bioprosthetic heart valve function over the complete cardiac cycle. Due to the complex motion of the heart valve leaflets, the fluid domain undergoes large deformations, including changes of topology. The proposed method directly analyzes a spline-based surface representation of the structure by immersing it into a non-boundary-fitted discretization of the surrounding fluid domain. This places our method within an emerging class of computational techniques that aim to capture geometry on non-boundary-fitted analysis meshes. We introduce the term "immersogeometric analysis" to identify this paradigm. The framework starts with an augmented Lagrangian formulation for FSI that enforces kinematic constraints with a combination of Lagrange multipliers and penalty forces. For immersed volumetric objects, we formally eliminate the multiplier field by substituting a fluid-structure interface traction, arriving at Nitsche's method for enforcing Dirichlet boundary conditions on object surfaces. For immersed thin shell structures modeled geometrically as surfaces, the tractions from opposite sides cancel due to the continuity of the background fluid solution space, leaving a penalty method. Application to a bioprosthetic heart valve, where there is a large pressure jump across the leaflets, reveals shortcomings of the penalty approach. To counteract steep pressure gradients through the structure without the conditioning problems that accompany strong penalty forces, we resurrect the Lagrange multiplier field. Further, since the fluid discretization is not tailored to the structure geometry, there is a significant error in the approximation of pressure discontinuities across the shell. This error becomes especially troublesome in residual-based stabilized methods for incompressible flow, leading to problematic compressibility at practical levels of refinement. We modify existing stabilized methods to improve performance. To evaluate the accuracy of the proposed methods, we test them on benchmark problems and compare the results with those of established boundary-fitted techniques. Finally, we simulate the coupling of the bioprosthetic heart valve and the surrounding blood flow under physiological conditions, demonstrating the effectiveness of the proposed techniques in practical computations. PMID- 25541567 TI - COVARIANCE ASSISTED SCREENING AND ESTIMATION. AB - Consider a linear model Y = X beta + z, where X = Xn,p and z ~ N(0, In ). The vector beta is unknown and it is of interest to separate its nonzero coordinates from the zero ones (i.e., variable selection). Motivated by examples in long memory time series (Fan and Yao, 2003) and the change-point problem (Bhattacharya, 1994), we are primarily interested in the case where the Gram matrix G = X'X is non-sparse but sparsifiable by a finite order linear filter. We focus on the regime where signals are both rare and weak so that successful variable selection is very challenging but is still possible. We approach this problem by a new procedure called the Covariance Assisted Screening and Estimation (CASE). CASE first uses a linear filtering to reduce the original setting to a new regression model where the corresponding Gram (covariance) matrix is sparse. The new covariance matrix induces a sparse graph, which guides us to conduct multivariate screening without visiting all the submodels. By interacting with the signal sparsity, the graph enables us to decompose the original problem into many separated small-size subproblems (if only we know where they are!). Linear filtering also induces a so-called problem of information leakage, which can be overcome by the newly introduced patching technique. Together, these give rise to CASE, which is a two-stage Screen and Clean (Fan and Song, 2010; Wasserman and Roeder, 2009) procedure, where we first identify candidates of these submodels by patching and screening, and then re examine each candidate to remove false positives. For any procedure beta for variable selection, we measure the performance by the minimax Hamming distance between the sign vectors of beta and beta. We show that in a broad class of situations where the Gram matrix is non-sparse but sparsifiable, CASE achieves the optimal rate of convergence. The results are successfully applied to long memory time series and the change-point model. PMID- 25541568 TI - Mechanistic Hierarchical Gaussian Processes. AB - The statistics literature on functional data analysis focuses primarily on flexible black-box approaches, which are designed to allow individual curves to have essentially any shape while characterizing variability. Such methods typically cannot incorporate mechanistic information, which is commonly expressed in terms of differential equations. Motivated by studies of muscle activation, we propose a nonparametric Bayesian approach that takes into account mechanistic understanding of muscle physiology. A novel class of hierarchical Gaussian processes is defined that favors curves consistent with differential equations defined on motor, damper, spring systems. A Gibbs sampler is proposed to sample from the posterior distribution and applied to a study of rats exposed to non injurious muscle activation protocols. Although motivated by muscle force data, a parallel approach can be used to include mechanistic information in broad functional data analysis applications. PMID- 25541569 TI - Predictors of Rural Health Clinics Managers' Willingness to Join Accountable Care Organizations. AB - PURPOSE: The implementation of the Patient Protection and Affordable Care Act has facilitated the development of an innovative and integrated delivery care system, Accountable Care Organizations (ACOs). It is timely, to identify how health care managers in rural health clinics are responding to the ACO model. This research examines RHC managers' perceived benefits and barriers for implementing ACOs from an organizational ecology perspective. METHODOLOGY/APPROACH: A survey was conducted in Spring of 2012 covering the present RHC network working infrastructures - 1) Organizational social network; 2) organizational care delivery structure; 3) ACO knowledge, perceived benefits, and perceived barriers; 4) quality and disease management programs; and 5) health information technology (HIT) infrastructure. One thousand one hundred sixty clinics were surveyed in the United States. They cover eight southeastern states (Alabama, Florida, Georgia, Kentucky, Mississippi, North Carolina, South Carolina, and Tennessee) and California. A total of ninety-one responses were received. FINDINGS: RHC managers' personal perceptions on ACO's benefits and knowledge level explained the most variance in their willingness to join ACOs. Individual perceptions appear to be more influential than organizational and context factors in the predictive analysis. RESEARCH LIMITATIONS/IMPLICATIONS: The study is primarily focused in the Southeastern region of the U.S. The generalizability is limited to this region. The predictors of rural health clinics' participation in ACOs are germane to guide the development of organizational strategies for enhancing the general knowledge about the innovativeness of delivering coordinated care and containing health care costs inspired by the Affordable Care Act. ORIGINALITY/VALUE OF PAPER: Rural health clinics are lagged behind the growth curve of ACO adoption. The diffusion of new knowledge about pros and cons of ACO is essential to reinforce the health care reform in the United States. PMID- 25541570 TI - Predictors of Gains During Inpatient Rehabilitation in Patients with Stroke- A Review. AB - Stroke remains a major cause of disability. The cost of stroke rehabilitation is substantial. Understanding the factors that predict response to inpatient stroke rehabilitation may be useful, for example, to best individualize the content of therapy, or to maximize the efficiency with which resources are directed. This review reviewed the literature and found that numerous variables were associated with outcome after inpatient stroke rehabilitation. The strongest evidence exists for factors such as age, stroke subtype, nutritional status, psychosocial factors such as living with family prior to stroke or presence of a caregiver. Functional status on admission, urinary incontinence, post-stroke infection, and aphasia each can also impact prognosis. Strengths and weaknesses of cited studies are considered in an attempt to inform design of future studies examining the factors that predict response to inpatient rehabilitation after stroke. PMID- 25541571 TI - Spin-label W-band EPR with seven-loop-six-gap resonator: Application to lens membranes derived from eyes of a single donor. AB - Spin-label W-band (94 GHz) EPR with a five-loop-four-gap resonator (LGR) was successfully applied to study membrane properties (L. Mainali, J.S. Hyde, W.K. Subczynski, Using spin-label W-band EPR to study membrane fluidity in samples of small volume, J. Magn. Reson. 226 (2013) 35-44). In that study, samples were equilibrated with the selected gas mixture outside the resonator in a sample volume ~100 times larger than the sensitive volume of the LGR and transferred to the resonator in a quartz capillary. A seven-loop-six-gap W-band resonator has been developed. This resonator permits measurements on aqueous samples of 150 nL volume positioned in a polytetrafluoroethylene (PTFE) gas permeable sample tube. Samples can be promptly deoxygenated or equilibrated with an air/nitrogen mixture inside the resonator, which is significant in saturation-recovery measurements and in spin-label oximetry. This approach was tested for lens lipid membranes derived from lipids extracted from two porcine lenses (single donor). Profiles of membrane fluidity and the oxygen transport parameter were obtained from saturation-recovery EPR using phospholipid analog spin-labels. Cholesterol analog spin-labels allowed discrimination of the cholesterol bilayer domain and acquisition of oxygen transport parameter profiles across this domain. Results were compared with those obtained previously for membranes derived from a pool of 100 lenses. Results demonstrate that EPR at W-band can be successfully used to study aqueous biological samples of small volume under controlled oxygen concentration. PMID- 25541572 TI - The Teenage Brain: The Stress Response and the Adolescent Brain. AB - Adolescence is a time of many psychosocial and physiological changes. One such change is how an individual responds to stressors. Specifically, adolescence is marked by significant shifts in hypothalamic-pituitary-adrenal (HPA) axis reactivity, resulting in heightened stress-induced hormonal responses. It is presently unclear what mediates these changes in stress reactivity and what impacts they may have on an adolescent individual. However, stress-sensitive limbic and cortical brain areas that continue to mature during adolescence may be particularly vulnerable to these shifts in responsiveness. Consequently, perturbations of the maturing adolescent brain may contribute to the increase in stress-related psychological dysfunctions, such as anxiety, depression, and drug abuse, often observed during this stage of development. The purpose of this review is to describe the changes that occur in HPA function during adolescence, as well as briefly discuss the possible ramifications of these changes on the developing brain and psychological health. PMID- 25541573 TI - Constructing linkage map based on a four-way cross population. AB - Currently, developing genetic linkage map mostly use the derived-populations from crossing of two homogenous parents, which only covers limited genetic diversity and is inappropriate for some species, such as tobacco with lower diversity in genome. It is very general that there are no sufficient polymorphic markers to construct linkage map and ineffective to conduct marker-assisted selection (MAS) and quantitative trait locus (QTL) mapping based on lower density linkage map. This study proposed a method for developing genetic linkage map based on a four way cross population. Computer simulation was conducted to investigate the feasibility and effectiveness of the method and a supporting program was designed. The main procedures and features of the proposed method were summarized as follows: 1) estimating genetic distance of any paired markers based on maximum likelihood method; 2) splitting all markers into different groups (linkage group) by cluster analysis based on genetic distance of markers; 3) for each linkage group, two end markers were first determined, then the marker order could be determined by inserting other markers in appropriate position by distance analysis of any three neighboring markers. Monte Carlo simulation showed that the proposed method is feasible, effective, and applicable in other derived populations from crossing of two homogenous parents. PMID- 25541574 TI - Exploring Preschool Children's Science Content Knowledge. AB - RESEARCH FINDINGS: The purpose of this study was to describe children's science content knowledge and examine the early predictors of science content knowledge in a sample of 194 typically developing preschool children. Children's science content knowledge was assessed in the fall (Time 1) and spring (Time 2) of the preschool year. Results showed that children exhibited significant gains in science content knowledge over the course of the preschool year. Hierarchical linear modeling results indicated that the level of maternal education (i.e., holding at least a bachelor's degree) significantly predicted children's Time 1 science content knowledge. Children's cognitive, math, and language skills at Time 1 were all significant concurrent predictors of Time 1 science content knowledge. However, only Time 1 math skills significantly predicted residualized gains in science content knowledge (i.e., Time 2 scores with Time 1 scores as covariates). PRACTICE OR POLICY: Factors related to individual differences in young children's science content knowledge may be important for early childhood educators to consider in their efforts to provide more support to children who may need help with science learning. PMID- 25541575 TI - Attachment Fertility Theory: Complex Systems of Mechanisms Simplify Sex, Mating, and Sexual Risks. PMID- 25541576 TI - Lessons Learned in Enhancing Behavioral Parent Training for High-Risk Families of Youth with ADHD. PMID- 25541577 TI - Left main coronary artery thrombosis revealing angio-Behcet syndrome. AB - Although acute myocardial infarction commonly results from coronary atherothrombosis, there are several other etiologies that should be taken initially into account, especially in young adults without significant atherosclerotic risk factors. Thrombophilia and coronary arteritis are, in this context, examples of etiologies that should be looked after. Through this article, we present a case of Behcet's disease with arterial involvement diagnosed after myocardial infarction resulting from thrombosis of the left main coronary artery in a 38-year-old young man without any particular past medical history. PMID- 25541578 TI - A Bivariate Mixed-Effects Location-Scale Model with application to Ecological Momentary Assessment (EMA) data. AB - A bivariate mixed-effects location-scale model is proposed for estimation of means, variances, and covariances of two continuous outcomes measured concurrently in time and repeatedly over subjects. Modeling the two outcomes jointly allows examination of BS and WS association between the outcomes and whether the associations are related to covariates. The variance-covariance matrices of the BS and WS effects are modeled in terms of covariates, explaining BS and WS heterogeneity. The proposed model relaxes assumptions on the homogeneity of the within-subject (WS) and between-subject (BS) variances. Furthermore, the WS variance models are extended by including random scale effects. Data from a natural history study on adolescent smoking are used for illustration. 461 students, from 9th and 10th grades, reported on their mood at random prompts during seven consecutive days. This resulted in 14,105 prompts with an average of 30 responses per student. The two outcomes considered were a subject's positive affect and a measure of how tired and bored they were feeling. Results showed that the WS association of the outcomes was negative and significantly associated with several covariates. The BS and WS variances were heterogeneous for both outcomes, and the variance of the random scale effects were significantly different from zero. PMID- 25541579 TI - When people shed religious identity in Ireland and Austria: Evidence from censuses. AB - BACKGROUND: Disaffiliation from religion is an important factor behind the rapid rise in persons claiming no religious affiliation in many advanced industrial countries. Scholars typically think of disaffiliation as a life course process that is confined to young adults, with little change occurring among older adults, yet few studies have examined this assumption outside the United States and Great Britain. OBJECTIVE: We evaluate whether the young-adult model of disaffiliation from religion applies in Ireland and Austria, two historically Catholic-majority countries with different levels of non-affiliation growth. METHODS: We use census data on religious affiliation in Ireland (1971-2011) and Austria (1971-2001) to track aggregate changes in the percentage reporting no religious affiliation over the life course for successive birth cohorts. RESULTS: We find support for the young-adult model in Ireland. However, recent cohorts in Austria exhibit a distinct pattern of disaffiliation that continues into middle adulthood. Our analysis suggests that mid-life disaffiliation in Austria is connected to a religious tax, which we argue spurs nominally affiliated adults to disaffiliate themselves, as their income rises and the costs of religious affiliation increase. CONCLUSION: Our findings offer insight into some of the social factors behind recent religious change across Europe and highlight the need for more cross-national research on the age and cohort dimensions of this change. PMID- 25541580 TI - The Effect of Reading Duration on the Reliability and Validity of Middle School Students' ORF Performance. AB - We evaluated the technical adequacy of oral reading fluency (ORF) probes in which 1,472 middle school students with and without reading difficulties read fluency probes for 60 s versus reading the full passage. Results suggested that the reliability of 60-s probes (rs >= .75) was not substantively different than full passage probes (rs >= .77) among struggling readers and typically developing readers in Grades 6 to 8. The correlation of 60-s and the full passage probes with norm-referenced measures of ORF ranged from .32 to .83, and the correlation with norm-referenced measures of reading comprehension ranged from .32 to .54, indicating that both measures were moderately valid and adequate for use among middle school students. Last, full passage probes with sensitivity rates ranging from .40 to .45 were only slightly more sensitive for identifying at-risk readers than 60-s probes, with sensitivity rates ranging from .36 to .40, suggesting that the full passage probes identified a slightly higher percentage of at-risk students with reading difficulties. PMID- 25541581 TI - Nickel foil microcantilevers for magnetic manipulation and localized heating. AB - Cellular manipulation has been investigated by a number of techniques. In this manuscript nickel foil microcantilevers were used for magnetophoresis and manipulation of microparticles and magnetically labeled HeLa cells. The cantilevers were also used for localized heating in liquid, reaching biologically relevant temperatures. This work aims to develop cantilevers for sample enrichment, manipulation, and thermal applications, offering an inexpensive and versatile solution compatible with standard tools in research and clinical diagnostic testing, such as microwell plates. PMID- 25541582 TI - Capillary Network-Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization. PMID- 25541584 TI - Moving Forward With fMRI Data. AB - The use of fMRI to inform cognitive theory depends upon the assumption that there is an isomorphic relationship between functional states and brain states. Even if this assumption is accepted, employing fMRI to make cognitive inferences is not straightforward. We discuss these inferential difficulties and describe an example in which fMRI data has had a significant impact on a cognitive theory despite them. The embodied cognition framework states that accessing a conceptual feature engages the same processes that are active when the feature is directly experienced. fMRI studies have consistently found that accessing a feature activates cortical regions slightly anterior to the regions activated when the feature is experienced. We suggest that this neural dissociation between accessing and perceiving a feature is inconsistent with the strong form of embodied cognition theory and that this inconsistency would likely not have been identified without fMRI. We describe how the observation of this forward shift has led to new ways of thinking about perceptual and conceptual representations and the relation between them. Finally, we argue that despite the strong assumptions that are needed to make functional inferences from fMRI, this does not detract from its value as a source of convergent evidence. PMID- 25541583 TI - Modeling in vitro cellular responses to silver nanoparticles. AB - Engineered nanoparticles (NPs) have been widely demonstrated to induce toxic effects to various cell types. In vitro cell exposure systems have high potential for reliable, high throughput screening of nanoparticle toxicity, allowing focusing on particular pathways while excluding unwanted effects due to other cells or tissue dosimetry. The work presented here involves a detailed biologically based computational model of cellular interactions with NPs; it utilizes measurements performed in human cell culture systems in vitro, to develop a mechanistic mathematical model that can support analysis and prediction of in vivo effects of NPs. The model considers basic cellular mechanisms including proliferation, apoptosis, and production of cytokines in response to NPs. This new model is implemented for macrophages and parameterized using in vitro measurements of changes in cellular viability and mRNA levels of cytokines: TNF, IL-1b, IL-6, IL-8, and IL-10. The model includes in vitro cellular dosimetry due to nanoparticle transport and transformation. Furthermore, the model developed here optimizes the essential cellular parameters based on in vitro measurements, and provides a "stepping stone" for the development of more advanced in vivo models that will incorporate additional cellular and NP interactions. PMID- 25541585 TI - Enabling Ontology Based Semantic Queries in Biomedical Database Systems. AB - There is a lack of tools to ease the integration and ontology based semantic queries in biomedical databases, which are often annotated with ontology concepts. We aim to provide a middle layer between ontology repositories and semantically annotated databases to support semantic queries directly in the databases with expressive standard database query languages. We have developed a semantic query engine that provides semantic reasoning and query processing, and translates the queries into ontology repository operations on NCBO BioPortal. Semantic operators are implemented in the database as user defined functions extended to the database engine, thus semantic queries can be directly specified in standard database query languages such as SQL and XQuery. The system provides caching management to boosts query performance. The system is highly adaptable to support different ontologies through easy customizations. We have implemented the system DBOntoLink as an open source software, which supports major ontologies hosted at BioPortal. DBOntoLink supports a set of common ontology based semantic operations and have them fully integrated with a database management system IBM DB2. The system has been deployed and evaluated with an existing biomedical database for managing and querying image annotations and markups (AIM). Our performance study demonstrates the high expressiveness of semantic queries and the high efficiency of the queries. PMID- 25541586 TI - A FRET-Based Biosensor for Imaging SYK Activities in Living Cells. AB - Spleen tyrosine kinase (SYK) is crucial to cellular functions mediated by immunoreceptors and integrins. We have developed and characterized a new genetically-encoded Forster resonance energy transfer (FRET)-based biosensor for studying the dynamics of SYK activities in living cells at a subcellular level. It contains an N-terminal ECFP, SH2 domain, a peptide derived from a SYK substrate VAV2, and a C-terminal YPet. Upon the specific phosphorylation by SYK in vitro, the biosensor substrate peptide bound to the intramolecular SH2 domain to reduce the FRET efficiency. Transfection of the biosensor did not affect activation of the endogenous SYK in host cells. Phosphorylation of the biosensor followed the same kinetics as the endogenous VAV2. Using FRET imaging and ratiometric analysis with this SYK biosensor, we visualized and quantified the realtime activation of SYK in K562 cells upon IgG Fc engagement of Fcc receptor IIA and in mouse embryonic fibroblasts upon stimulation by the platelet derived growth factor. These results demonstrate our biosensor as a powerful tool for studying cellular signaling that involves SYK. PMID- 25541588 TI - Imputation of Truncated p-Values For Meta-Analysis Methods and Its Genomic Application. AB - Microarray analysis to monitor expression activities in thousands of genes simultaneously has become routine in biomedical research during the past decade. a tremendous amount of expression profiles are generated and stored in the public domain and information integration by meta-analysis to detect differentially expressed (DE) genes has become popular to obtain increased statistical power and validated findings. Methods that aggregate transformed p-value evidence have been widely used in genomic settings, among which Fisher's and Stouffer's methods are the most popular ones. In practice, raw data and p-values of DE evidence are often not available in genomic studies that are to be combined. Instead, only the detected DE gene lists under a certain p-value threshold (e.g., DE genes with p value < 0.001) are reported in journal publications. The truncated p-value information makes the aforementioned meta-analysis methods inapplicable and researchers are forced to apply a less efficient vote counting method or naively drop the studies with incomplete information. The purpose of this paper is to develop effective meta-analysis methods for such situations with partially censored p-values. We developed and compared three imputation methods-mean imputation, single random imputation and multiple imputation-for a general class of evidence aggregation methods of which Fisher's and Stouffer's methods are special examples. The null distribution of each method was analytically derived and subsequent inference and genomic analysis frameworks were established. Simulations were performed to investigate the type Ierror, power and the control of false discovery rate (FDR) for (correlated) gene expression data. The proposed methods were applied to several genomic applications in colorectal cancer, pain and liquid association analysis of major depressive disorder (MDD). The results showed that imputation methods outperformed existing naive approaches. Mean imputation and multiple imputation methods performed the best and are recommended for future applications. PMID- 25541587 TI - Characterization of regional deformation and material properties of the intact explanted vein by microCT and computational analysis. AB - PURPOSE: Detailed mechanical information of the vein is important to better understand remodeling of the vessel in disease states, but has been difficult to obtain due to its thinness, unique geometry, and limitations of mechanical testing. This study presents a novel method for characterizing deformation of the intact explanted vein under physiological loads and determining its material properties by combining high-resolution imaging and computational analysis. METHODS: High-resolution CT (microCT) was used to image an iodine-stained, excised porcine internal jugular vein sample under extension to 100% and 120% of in situ length, and inflation and 2, 10, 20 mmHg of pressure, inside a microCT compatible hydrostatic loading chamber. Regional strains were measured with the finite element (FE) image registration method known as Hyperelastic Warping. Material properties were approximated with inverse FE characterization by optimizing stiffness-related coefficients so to match simulated strains to the experimental measurements. RESULTS: The observed morphology and regional strain of the vein were found to be relatively heterogeneous. The regional variability in the measured strain was primarily driven by geometry. Although iodine treatment may result in tissue stiffening, which requires additional investigation, it is effective in allowing detailed detection of vein geometry. CONCLUSIONS: The feasibility and utility of using microCT and computational analysis to characterize mechanical responses and material properties of the vein were demonstrated. The presented method is a promising alternative or addition to mechanical testing for characterizing veins or other similarly delicate vessels in their native anatomical configuration under a wide range of realistic or simulated environmental and loading conditions. PMID- 25541589 TI - A NASA discovery has current applications in orthopaedics. AB - Low-level laser therapy (LLLT) has been actively used for nearly 40 yr, during which time it has been known to reduce pain, inflammation, and edema. It also has the ability to promote healing of wounds, including deep tissues and nerves, and prevent tissue damage through cell death. Much of the landmark research was done by the National Aeronautics and Space Administration (NASA), and these studies provided a springboard for many additional basic science studies. Few current clinical studies in orthopaedics have been performed, yet only in the past few years have basic science studies outlined the mechanisms of the effect of LLLT on the cell and subsequently the organism. This article reviews the basic science of LLLT, gives a historical perspective, and explains how it works, exposes the controversies and complications, and shows the new immediately applicable information in orthopaedics. PMID- 25541590 TI - Divergent Regioselectivity in Photoredox-Catalyzed Hydrofunctionalization Reactions of Unsaturated Amides and Thioamides. AB - A direct method to construct 2-oxazolines and 2-thiazolines from corresponding allylic amides and thioamides is reported. The redox-neutral intramolecular hydrofunctionalization is enabled by a dual catalyst system comprised of the 9 mesityl-N-methyl acridinium tetrafluoroborate and phenyl disulphide and exhibits complete selectivity for the anti-Markovnikov regioisomeric products. The cyclization of allylic thioamides is postulated to operate via a modified mechanism in which oxidation of the thioamide, rather than the alkene, is responsible for the observed reactivity. PMID- 25541592 TI - 3-D Scaffold Platform for Optimized Non-viral Transfection of Multipotent Stem Cells. AB - Optimization of non-viral gene delivery from biomaterials is of critical importance, as several material parameters are known to influence non-viral transfection efficiency. A series of previous studies have achieved screening of gene delivery vectors on two dimensional (2D) substrates, which have direct relevance to cell culture applications. There is an additional need to create screening systems that are 3-dimensional (3D), and can thus be applied to emerging tissue engineering applications. Here, we report an enhanced throughput, 3D scaffold platform to screen for the influence of mineral coating properties on stem cell transfection. Mineral coatings with a range of physicochemical properties were formed on the scaffolds within a 96-well plate format, while maintaining an interconnected macroporous scaffold structure. A series of general gene delivery parameters, including plasmid amount, N/P ratio, and cell density, were efficiently screened in scaffolds using a luciferase-encoding plasmid as a reporter. In addition, human mesenchymal stem cell (hMSC) transfection with a plasmid encoding bone morphogenetic protein-2 (BMP-2) was successfully optimized by screening a library of mineral coatings, resulting in over 5-fold increases in BMP-2 production when compared to standard techniques. Notably, the majority of BMP-2 was incorporated into the mineral coating following secretion from the cells. The 3D mineral coated scaffold platform described here may accelerate gene delivery optimization and improve the predictability of the screening systems, which could facilitate translation of gene delivery to clinical applications. PMID- 25541593 TI - What Makes Green Cities Unique? Examining the Economic and Political Characteristics of the Grey-to-Green Continuum. AB - In the United States, urbanization processes have resulted in a large variety-or "continuum"-of urban landscapes. One entry point for understanding the variety of landscape characteristics associated with different forms of urbanization is through a characterization of vegetative (green) land covers. Green land covers i.e., lawns, parks, forests-have been shown to have a variety of both positive and negative impacts on human and environmental outcomes-ranging from increasing property values, to mitigating urban heat islands, to increasing water use for outdoor watering purposes. While considerable research has examined the variation of vegetation distribution within cities and related social and economic drivers, we know very little about whether or how the economic characteristics and policy priorities of green cities differ from those of "grey" cities-those with little green land cover. To address this gap, this paper seeks to answer the question how do the economic characteristics and policy priorities of green and grey cities differ in the United States? To answer this question, MODIS data from 2001 to 2006 are used to characterize 373 US cities in terms of their vegetative greenness. Information from the International City/County Management Association's (ICMA) 2010 Local Government Sustainability Survey and 2009 Economic Development Survey are used to identify key governance strategies and policies that may differentiate green from grey cities. Two approaches for data analysis-ANOVA and decision tree analysis-are used to identify the most important characteristics for separating each category of city. The results indicate that grey cities tend to place a high priority on economic initiatives, while green cities place an emphasis on social justice, land conservation, and quality of life initiatives. PMID- 25541591 TI - Interaction of Materials and Biology in Total Joint Replacement - Successes, Challenges and Future Directions. AB - Total joint replacement (TJR) has revolutionized the treatment of end-stage arthritic disorders. This success is due, in large part, to a clear understanding of the important interaction between the artificial implant and the biology of the host. All surgical procedures in which implants are placed in the body evoke an initial inflammatory reaction, which generally subsides over several weeks. Thereafter, a series of homeostatic events occur leading to progressive integration of the implant within bone and the surrounding musculoskeletal tissues. The eventual outcome of the operation is dependent on the characteristics of the implant, the precision of the surgical technique and operative environment, and the biological milieu of the host. If these factors and events are not optimal, adverse events can occur such as the development of chronic inflammation, progressive bone loss due to increased production of degradation products from the implant (periprosthetic osteolysis), implant loosening or infection. These complications can lead to chronic pain and poor function of the joint reconstruction, and may necessitate revision surgery or removal of the prosthesis entirely. Recent advances in engineering, materials science, and the immunological aspects associated with orthopaedic implants have fostered intense research with the hope that joint replacements will last a lifetime, and facilitate pain-free, normal function. PMID- 25541595 TI - Tradition of healthy food access in low-income neighborhoods: Price and variety of curbside produce vending compared to conventional retailers. AB - This paper describes the longstanding, naturally emergent model of curbside vending of whole fruit and vegetable produce across several low-income, low health Philadelphia neighborhoods. We conducted open-ended interviews with managers of 11 curbside produce vendors and compared prices and varieties of fruits and vegetables with the 11 closest conventional outlets. We find that produce trucks offer significantly lower prices on common fruit and vegetable items and they carry a variety of items comparable to that carried by limited assortment grocery stores. We conclude with recommendations regarding zoning, licensing, and Supplemental Nutrition Assistance Program (SNAP) authorization that could stabilize and expand this model of healthy food access. PMID- 25541594 TI - TGF-beta signaling and the development of osteoarthritis. AB - Osteoarthritis (OA) is a common joint degenerative disease affecting the whole joint structure, including articular cartilage, subchondral bone and synovial tissue. Although extensive work has been done in recent years to explore the molecular mechanism underlying this disease, the pathogenesis of OA is still poorly understood and currently, there is no effective disease-modifying treatment for OA. Recently, both in vitro and in vivo studies suggest that confirmed (TGF-beta)/SMAD pathway plays a critical role during OA development. This short review will focus on the function and signaling mechanisms of TGF beta/SMAD pathway in articular chondrocytes, mesenchymal progenitor cells of subchondral bone and synovial lining cells during OA development. PMID- 25541597 TI - Urban Dwelling American Indian Adolescent Girls' Beliefs Regarding Health Care Access and Trust. AB - Indigenous people, specifically American Indians (AI), have historically had a greater mistrust of the medical system compared to their White counterparts. The purpose of this paper is to explore the perceptions of AI adolescent girls living in an urban, Midwest area about health care providers, health care systems, and access to health care as related to sexual health care. Using grounded theory methodology, twenty 15-19 year old AI girls participated in talking circles and individual interviews. Two distinct themes emerged related to sexual health care: 1) AI adolescent girls trust their health care providers and the health care system; and 2) Access to health care is critical to practicing safe sex and obtaining information about healthy sexual practices. These findings are unique and may help health care providers and social workers providing care and support to the urban adolescent AI girl. PMID- 25541596 TI - Genomic Instability and Cancer. AB - Genomic instability is a characteristic of most cancer cells. It is an increased tendency of genome alteration during cell division. Cancer frequently results from damage to multiple genes controlling cell division and tumor suppressors. It is known that genomic integrity is closely monitored by several surveillance mechanisms, DNA damage checkpoint, DNA repair machinery and mitotic checkpoint. A defect in the regulation of any of these mechanisms often results in genomic instability, which predisposes the cell to malignant transformation. Posttranslational modifications of the histone tails are closely associated with regulation of the cell cycle as well as chromatin structure. Nevertheless, DNA methylation status is also related to genomic integrity. We attempt to summarize recent developments in this field and discuss the debate of driving force of tumor initiation and progression. PMID- 25541599 TI - Changes in Positive Self-Views Mediate the Effect of Cognitive-Behavioral Therapy for Social Anxiety Disorder. AB - Social Anxiety Disorder (SAD) is thought to be characterized by maladaptive self views. This study investigated whether (1) patients with SAD (n=75) differ at baseline from healthy controls (HC; n=43) in negative and positive self-views, (2) Cognitive-Behavioral Therapy (CBT) for SAD vs. waitlist control (WL) produces statistically and clinically significant changes in negative and positive self views, (3) changes in self-views mediate the effect of CBT on social anxiety symptoms, and (4) changes in self-views during CBT related to social anxiety symptoms at 1-year post-CBT. As expected, patients endorsed more negative and fewer positive self-views than HC at baseline. Compared to WL, CBT yielded statistically and clinically significant changes, specifically, fewer negative and more positive self-views. Mediational analysis indicated that increased positive (but not reduced negative) self-views mediated the effect of CBT on social anxiety reduction. Correlational analyses determined that increased positive self-views were associated with social anxiety symptom reduction at 1 year-post-CBT. PMID- 25541598 TI - The partitioning and copy number control systems of the selfish yeast plasmid: an optimized molecular design for stable persistence in host cells. AB - The multi-copy 2 micron plasmid of Saccharomyces cerevisiae, a resident of the nucleus, is remarkable for its high chromosome-like stability. The plasmid does not appear to contribute to the fitness of the host, nor does it impose a significant metabolic burden on the host at its steady state copy number. The plasmid may be viewed as a highly optimized selfish DNA element whose genome design is devoted entirely towards efficient replication, equal segregation and copy number maintenance. A partitioning system comprised of two plasmid coded proteins, Rep1 and Rep2, and a partitioning locus STB is responsible for equal or nearly equal segregation of plasmid molecules to mother and daughter cells. Current evidence supports a model in which the Rep-STB system promotes the physical association of the plasmid with chromosomes and thus plasmid segregation by a hitchhiking mechanism. The Flp site-specific recombination system housed by the plasmid plays a critical role in maintaining steady state plasmid copy number. A decrease in plasmid population due to rare missegregation events is rectified by plasmid amplification via a recombination induced rolling circle replication mechanism. Appropriate plasmid amplification, without runaway increase in copy number, is ensured by positive and negative regulation of FLP gene expression by plasmid coded proteins and by the control of Flp level/activity through host mediated post-translational modification(s) of Flp. The Flp system has been successfully utilized to understand mechanisms of site specific recombination, to bring about directed genetic alterations for addressing fundamental problems in biology, and as a tool in biotechnological applications. PMID- 25541600 TI - The effects of handwriting experience on functional brain development in pre literate children. AB - In an age of increasing technology, the possibility that typing on a keyboard will replace handwriting raises questions about the future usefulness of handwriting skills. Here we present evidence that brain activation during letter perception is influenced in different, important ways by previous handwriting of letters versus previous typing or tracing of those same letters. Preliterate, five-year old children printed, typed, or traced letters and shapes, then were shown images of these stimuli while undergoing functional MRI scanning. A previously documented "reading circuit" was recruited during letter perception only after handwriting-not after typing or tracing experience. These findings demonstrate that handwriting is important for the early recruitment in letter processing of brain regions known to underlie successful reading. Handwriting therefore may facilitate reading acquisition in young children. PMID- 25541602 TI - Methodical and pre-analytical characteristics of a multiplex cancer biomarker immunoassay. AB - AIM: To test the methodical and pre-analytical performance of a new multiplex cancer biomarker panel using magnetic beads. METHODS: The MILLIPLEX((r)) MAP Human Circulating Cancer Biomarker Magnetic Bead Panel 1 comprises the tumor markers carcinoembryonic antigen, alpha-fetoprotein, total prostate-specific antigen, cancer antigen 15-3, cancer antigen 19-9, cancer antigen 125, cytokeratine 19-fragment, beta-human chorionic gonadotropin, human epididymis protein 4, osteopontin, prolactin, the cell death and angiogenesis markers soluble Fas, soluble Fas-ligand, tumor necrosis factor related apoptosis-inducing ligand, vascular endothelial growth factor and the immunological markers interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha, transforming growth factor alpha, fibroblast growth factor-2, macrophage migration inhibitory factor, leptin, hepatocyte growth factor, and stem cell factor. We determined intra- and inter-assay imprecision as well as dilution linearity using quality controls and serum pools. Furthermore, the stability of the 24 biomarkers examined in this panel was ascertained by testing the influence of different storage temperatures and time span before centrifugation. RESULTS: For all markers measured in the synthetic internal quality controls, the intra-assay imprecision ranged between 2.26% and 9.41%, while for 20 of 24 measured markers in the physiological serum pools, it ranged between 1.68% and 12.87%. The inter-assay imprecision ranged between 1.48%-17.12% for 23 biomarkers in synthetic, and between 4.59%-23.88% for 18 biomarkers in physiological quality controls. Here, single markers with very low concentration levels had increased imprecision rates. Dilution linearity was acceptable (70%-130% recovery) for 20 biomarkers. Regarding pre-analytical influencing factors, most markers were stable if blood centrifugation was delayed or if serum was stored for up to 24 h at 4 degrees C and 25 degrees C after centrifugation. Comparable results were obtained in serum and plasma for most markers. However, great changes were observed for single markers. CONCLUSION: MILLIPLEX((r)) MAP Human Circulating Cancer Biomarker Magnetic Bead Panel 1 assay is a stable and precise method for detection of most biomarkers included in the kit. However, single markers have to be interpreted with care. PMID- 25541603 TI - A gut feeling to cure diabetes: potential mechanisms of diabetes remission after bariatric surgery. AB - A cure for type 2 diabetes was once a mere dream but has now become a tangible and achievable goal with the unforeseen success of bariatric surgery in the treatment of both obesity and type 2 diabetes. Popular bariatric procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy exhibit high rates of diabetes remission or marked improvement in glycemic control. However, the mechanism of diabetes remission following these procedures is still elusive and appears to be very complex and encompasses multiple anatomical and physiological changes. In this article, calorie restriction, improved beta-cell function, improved insulin sensitivity, and alterations in gut physiology, bile acid metabolism, and gut microbiota are reviewed as potential mechanisms of diabetes remission after Roux en-Y gastric bypass and sleeve gastrectomy. PMID- 25541604 TI - Current concepts in diabetic retinopathy. AB - For the past several decades, tremendous efforts have been made to decrease the complications of diabetes, including diabetic retinopathy. New diagnostic modalities like ultrawide field fundus fluorescein angiography and spectral domain optical coherence tomography has allowed more accurate diagnosis of early diabetic retinopathy and diabetic macular edema. Antivascular endothelial growth factors are now extensively used to treat diabetic retinopathy and macular edema with promising results. There remains uncertainty over the long term effects and the socioeconomic costs of these agents. PMID- 25541606 TI - Is GDF15 a Novel Biomarker to Predict the Development of Prediabetes or Diabetes? PMID- 25541605 TI - Therapeutic Approaches for Preserving or Restoring Pancreatic beta-Cell Function and Mass. AB - The goal for the treatment of patients with diabetes has today shifted from merely reducing glucose concentrations to preventing the natural decline in beta cell function and delay the progression of disease. Pancreatic beta-cell dysfunction and decreased beta-cell mass are crucial in the development of diabetes. The beta-cell defects are the main pathogenesis in patients with type 1 diabetes and are associated with type 2 diabetes as the disease progresses. Recent studies suggest that human pancreatic beta-cells have a capacity for increased proliferation according to increased demands for insulin. In humans, beta-cell mass has been shown to increase in patients showing insulin-resistance states such as obesity or in pregnancy. This capacity might be useful for identifying new therapeutic strategies to reestablish a functional beta-cell mass. In this context, therapeutic approaches designed to increase beta-cell mass might prove a significant way to manage diabetes and prevent its progression. This review describes the various beta-cell defects that appear in patients with diabetes and outline the mechanisms of beta-cell failure. We also review common methods for assessing beta-cell function and mass and methodological limitations in vivo. Finally, we discuss the current therapeutic approaches to improve beta cell function and increase beta-cell mass. PMID- 25541601 TI - Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases. AB - Thalassaemia major (TM) and Friedreich's ataxia (FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients. Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide. PMID- 25541608 TI - Effectiveness of 3-day continuous glucose monitoring for improving glucose control in type 2 diabetic patients in clinical practice. AB - BACKGROUND: The aim of this study was to investigate whether adjusting diabetic treatment regimens according to the information obtained from a continuous glucose monitoring system (CGMS) might lead to improved glycemic control in patients with type 2 diabetes. METHODS: We reviewed the medical charts of 172 patients who used the CGMS for 1 year starting in December 2008 and the records of 1,500 patients who visited their regular outpatient clinics during December 2008. Of these patients, a total of 65 CGMS patients and 301 regular outpatients (control group) were enrolled in the study after propensity score matching. There were no differences in baseline glycated hemoglobin (HbA1c), age, and duration of diabetes between the CGMS and the control groups after propensity score matching. The changes in the HbA1c levels from baseline to 6 months were calculated. RESULTS: The CGMS group showed a significant improvement in the HbA1c level compared to the control group at 3 months (7.9%+/-1.6% vs. 7.4%+/-1.2%, P=0.001) and at 6 months (7.4%+/-1.2% vs. 7.9%+/-1.6%, P=0.010). There were significant differences in the treatment modality changes between the CGMS group and the control group. CONCLUSION: Using a 3-day CGMS was advantageous for improving glucose control in patients with type 2 diabetes and may help these patients to optimize glycemic control in clinical practice. PMID- 25541607 TI - Arterial Stiffness by Aerobic Exercise Is Related with Aerobic Capacity, Physical Activity Energy Expenditure and Total Fat but not with Insulin Sensitivity in Obese Female Patients with Type 2 Diabetes. AB - BACKGROUND: Arterial stiffness is an important factor in atherosclerosis. Thus we examined whether aerobic exercise could reduce arterial stiffness in obese women with type 2 diabetes without diabetic complication. METHODS: A total of 35 women with type 2 diabetes (body mass index, 26.6+/-2.8 kg/m(2); age, 56.4+/-1.9 years; duration of diabetes, 4.7+/-4.8 years) were assigned to aerobic exercise group (AEG) or control group (CG). AEG completed a 12-week exercise program (3.6 to 5.2 metabolic equivalents, 3 day/week, 60 min/day), with their exercise activities monitored by accelerometers. We measured abdominal total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) by computed tomography, insulin sensitivity by insulin tolerance test (KITT), and augmentation index (AIx) by SphygmoCor at baseline and at the end of the 12-week program. RESULTS: The AIx was improved in the AEG compared with the CG (P<0.001). The percent change of AIx had significant correlation with the improvement of physical activity energy expenditure (PAEE), aerobic capacity, TFA, and SFA (r=-0.416, P=0.013; r=0.560, P<0.001; r=0.489, P=0.003; r=0.531, P=0.001, respectively), but not with insulin sensitivity, energy intake, or VFA. CONCLUSION: Improvement in aortic stiffness by aerobic exercise is related with the improvement of aerobic capacity, PAEE, and total fat but not with insulin sensitivity or energy intake in obese women with type 2 diabetes. PMID- 25541609 TI - The glycated albumin to glycated hemoglobin ratio might not be associated with carotid atherosclerosis in patients with type 1 diabetes. AB - BACKGROUND: The ratio of glycated albumin to glycated hemoglobin (GA/A1c) is known to be elevated in subjects with type 2 diabetes mellitus (T2DM) who had decreased insulin secretion. Additionally, the carotid intima media thickness (IMT) is greater in T2DM patients with higher GA/A1c ratios. We investigated whether increased GA/A1c ratio and IMT are also associated in type 1 diabetes mellitus (T1DM), which is characterized by lack of insulin secretory capacity. METHODS: In this cross-sectional study, we recruited 81 T1DM patients (33 men, 48 women; mean age 44.1+/-13.0 years) who underwent carotid IMT, GA, and HbA1c measurements. RESULTS: The mean GA/A1c ratio was 2.90. Based on these results, we classified the subjects into two groups: group I (GA/A1c ratio <2.90, n=36) and group II (GA/A1c ratio >=2.90, n=45). Compared with group I, the body mass indexes (BMIs), waist circumferences, and IMTs were lower in group II. GA/A1c ratio was negatively correlated with BMI, urine albumin to creatinine ratio (P<0.001 for both), and both the mean and maximal IMT (P=0.001, both). However, after adjusting the confounding factors, we observed that IMT was no longer associated with GA/A1c ratio. CONCLUSION: In contrast to T2DM, IMT was not significantly related to GA/A1c ratio in the subjects with T1DM. This suggests that the correlations between GA/A1c ratio and the parameters known to be associated with atherosclerosis in T2DM could be manifested differently in T1DM. Further studies are needed to investigate these relationships in T1DM. PMID- 25541610 TI - A cross-sectional study of the phenotypes of obesity and insulin resistance in adults with down syndrome. AB - BACKGROUND: Despite the confluence of multiple cardiovascular risk factors, subclinical atherosclerotic damage and cardiovascular events remain extremely rare in adults with Down syndrome (DS). We aim to determine the prevalence of obesity and metabolic disorders in an adult cohort with DS and to compare our findings with adults without DS. METHODS: Cross-sectional study of 51 consecutively selected adults with DS living in the community and 51 healthy controls in an outpatient clinic of a tertiary care hospital in Madrid, Spain. Epidemiological data (age and gender), anthropometric data (body mass index and waist-to-height ratio), coexisting clinical conditions, and laboratory data (fasting glucose, insulin, glycated hemoglobin, creatinine, thyroid hormones, vitamins, and lipid profile) were measured and compared between the groups. RESULTS: Adults with DS were significantly younger and more often men with a higher prevalence of overweight and obesity than controls. Their waist-to-height ratio was higher, and they more frequently had abdominal obesity. The results of an analysis adjusted for age and gender revealed no differences in fasting insulin levels, homeostatic model assessment indexes, or lipid profile between adults with DS and controls. CONCLUSION: Adults with DS presented a high prevalence of overweight and obesity. However, we found no differences in lipid profile, prevalence of insulin resistance, or metabolic syndrome between adults with DS and controls. PMID- 25541611 TI - GDF15 Is a Novel Biomarker for Impaired Fasting Glucose. AB - BACKGROUND: Growth differentiation factor-15 (GDF15) is a protein that belongs to the transforming growth factor beta superfamily. An elevated serum level of GDF15 was found to be associated with type 2 diabetes mellitus (T2DM). T2DM is an inflammatory disease that progresses from normal glucose tolerance (NGT) to impaired fasting glucose (IFG). Hence, we aimed to validate the relationship between GDF15 and IFG. METHODS: The participants were divided into the following three groups: NGT (n=137), IFG (n=29), and T2DM (n=75). The controls and T2DM outpatients visited the hospital for routine health check-ups. We used fasting blood glucose to detect IFG in nondiabetic patients. We checked the body mass index (BMI), C-reactive protein level, metabolic parameters, and fasting serum GDF15 level. RESULTS: Age, BMI, triglyceride, insulin, glucose, homeostatic model assessment-insulin resistance (HOMA-IR), and GDF15 levels were elevated in the IFG and T2DM groups compared to the NGT group. In the correlation analysis between metabolic parameters and GDF15, age and HOMA-IR had a significant positive correlation with GDF15 levels. GDF15 significantly discriminated between IFG and NGT, independent of age, BMI, and HOMA-IR. The serum levels of GDF15 were more elevated in men than in women. As a biomarker for IFG based on the receiver operating characteristic curve analysis, the cutoff value of GDF15 was 510 pg/mL in males and 400 pg/mL in females. CONCLUSION: GDF15 had a positive correlation with IR independent of age and BMI, and the serum level of GDF15 was increased in the IFG and T2DM groups. GDF15 may be a novel biomarker for detecting IFG in nondiabetic patients. PMID- 25541612 TI - Glycated Hemoglobin Value for Fasting Plasma Glucose of 126 mg/dL in Korean: The 2011 Korea National Health and Nutrition Examination Survey. AB - We aimed to estimate the cutoff value of glycated hemoglobin (HbA1c, A1c) for fasting plasma glucose (FPG) of 126 mg/dL in the Korean adult population, using the 2011 Korea National Health and Nutrition Examination Survey. A total of 5,421 participants without a history of diabetes and over 19 years of age were included in the analysis. A point-wise area under the receiver operating characteristic curve was used to estimate the optimal A1c cutoff value. A1c threshold of 6.1% produced the highest sum of sensitivity (85.2%) and specificity (90.5%) for FPG of 126 mg/dL (area under the curve, 0.941, P<0.001). A1c of 6.5% produced a sensitivity of 67.7% and specificity of 98.0% for FPG of 126 mg/dL. Considering A1c as one of three criteria for the diagnosis of diabetes and the specificity of an A1c cutoff of 6.5%, the current diagnostic criteria of A1c>=6.5% might be acceptable in the Korean adult population. PMID- 25541613 TI - Letter: genome-wide association study identifies two novel Loci with sex-specific effects for type 2 diabetes mellitus and glycemic traits in a korean population (diabetes metab j 2014;38:375-87). PMID- 25541614 TI - Response: genome-wide association study identifies two novel Loci with sex specific effects for type 2 diabetes mellitus and glycemic traits in a korean population (diabetes metab j 2014;38:375-87). PMID- 25541615 TI - SELF-GENERATED ACTIONS DURING LEARNING OBJECTS AND SOUNDS CREATE SENSORI-MOTOR SYSTEMS IN THE DEVELOPING BRAIN. AB - Previous research shows that sensory and motor systems interact during verb perception, and that these interactions are formed through self-generated actions that refer to verb labels during development. Here we expand on these findings by investigating whether self-generated actions lead to sensori-motor interaction during sound perception and visual perception. The current research exposes young children to novel sounds that are produced by object movement through either a) actively exploring the objects and producing the sounds or b) by seeing and hearing an experimenter interact with the objects. Results demonstrate that the motor system was recruited during auditory perception only after learning involved self-generated interactions with objects. Interestingly, visual association regions were also active during both sound perception and visual perception after active exploratory learning, but not after passive observation. Therefore, in the developing brain, associations are built upon real-world interactions of body and environment, leading to sensori-motor representations of both objects and sounds. PMID- 25541616 TI - B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. AB - Gene therapy strategies for congenital myopathies may require repeat administration of adeno-associated viral (AAV) vectors in response to several limitations inherent to the clinical design: 1) administration of doses below therapeutic efficacy in patients enrolled in early phase clinical trials; 2) progressive reduction of the therapeutic gene expression over time as a result of increasing muscle mass in patients treated at a young age; and 3) a possibly faster depletion of pathogenic myofibers in this patient population. Immune responses triggered by the first vector administration, and to subsequent ones, represent a major obstacle for successful gene transfer in young patient population. Anti-capsid and anti-transgene product related humoral and cell mediated responses have been previously observed in all preclinical models and human subjects who received gene therapy or ERT treatment for congenital myopathies. Immune responses may result in reduced efficacy of the gene transfer over time and/or may preclude for the possibility of re-administration of the same vector. This study presents a case of Pompe patient dosed with an AAV1-GAA vector after receiving Rituximab and Sirolimus to modulate the immune responses. A key finding of this single subject case report is the observation that B-cell ablation with rituximab prior to AAV vector exposure results in non responsiveness to both capsid and transgene, therefore allowing the possibility of repeat administration in the future. This observation is significant for future gene therapy studies and establishes a clinically relevant approach to blocking immune responses to AAV vectors. PMID- 25541617 TI - SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE. AB - Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3 or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects. PMID- 25541618 TI - Nanoparticle-Film Plasmon Ruler Interrogated with Transmission Visible Spectroscopy. AB - The widespread use of plasmonic nanorulers (PNRs) in sensing platforms has been plagued by technical challenges associated with the development of methods to fabricate precisely controlled nanostructures with high yield and characterize them with high throughput. We have previously shown that creating PNRs in a nanoparticle-film (NP-film) format enables the fabrication of an extremely large population of uniform PNRs with 100% yield using a self-assembly approach, which facilitates high-throughput PNR characterization using ensemble spectroscopic measurements and eliminates the need for expensive microscopy systems required by many other PNR platforms. We expand upon this prior work herein, showing that the NP-film PNR can be made compatible with aqueous sensing studies by adapting it for use in a transmission localized surface plasmon resonance spectroscopy format, where the coupled NP-film resonance responsible for the PNR signal is directly probed using an extinction measurement from a standard spectrophotometer. We designed slide holders that fit inside standard spectrophotometer cuvettes and position NP-film samples so that the coupled NP film resonance can be detected in a collinear optical configuration. Once the NP film PNR samples are cuvette-compatible, it is straightforward to calibrate the PNR in aqueous solution and use it to characterize dynamic, angstrom-scale distance changes resulting from pH-induced swelling of polyelectrolyte (PE) spacer layers as thin as 1 PE layer and also of a self-assembled monolayer of an amine-terminated alkanethiol. This development is an important step toward making PNR sensors more user-friendly and encouraging their widespread use in various sensing schemes. PMID- 25541619 TI - Individual Template-Stripped Conductive Gold Pyramids for Tip-Enhanced Dielectrophoresis. AB - Gradient fields of optical, magnetic, or electrical origin are widely used for the manipulation of micro- and nanoscale objects. Among various device geometries to generate gradient forces, sharp metallic tips are one of the most effective. Surface roughness and asperities present on traditionally produced tips reduce trapping efficiencies and limit plasmonic applications. Template-stripped, noble metal surfaces and structures have sub-nm roughness and can overcome these limits. We have developed a process using a mix of conductive and dielectric epoxies to mount template-stripped gold pyramids on tungsten wires that can be integrated with a movable stage. When coupled with a transparent indium tin oxide (ITO) electrode, the conductive pyramidal tip functions as a movable three dimensional dielectrophoretic trap which can be used to manipulate submicrometer scale particles. We experimentally demonstrate the electrically conductive functionality of the pyramidal tip by dielectrophoretic manipulation of fluorescent beads and concentration of single-walled carbon nanotubes, detected with fluorescent microscopy and Raman spectroscopy. PMID- 25541620 TI - Nonlinear Midinfrared Photothermal Spectroscopy Using Zharov Splitting and Quantum Cascade Lasers. AB - We report on the mid-infrared nonlinear photothermal spectrum of the neat liquid crystal 4-octyl-4'-cyanobiphenyl (8CB) using a tunable Quantum Cascade Laser (QCL). The nonequilibrium steady state characterized by the nonlinear photothermal infrared response undergoes a supercritical bifurcation. The bifurcation, observed in heterodyne two-color pump-probe detection, leads to ultrasharp nonlinear infrared spectra similar to those reported in the visible region. A systematic study of the peak splitting as a function of absorbed infrared power shows the bifurcation has a critical exponent of 0.5. The observation of an apparently universal critical exponent in a nonequilibrium state is explained using an analytical model analogous of mean field theory. Apart from the intrinsic interest for nonequilibrium studies, nonlinear photothermal methods lead to a dramatic narrowing of spectral lines, giving rise to a potential new contrast mechanism for the rapidly emerging new field of mid infrared microspectroscopy using QCLs. PMID- 25541621 TI - Diffusion Reflection and Fluorescence Lifetime Imaging Microscopy Study of Fluorophore-Conjugated Gold Nanoparticles or Nanorods in Solid Phantoms. AB - In this paper we report the optical properties of fluorescein-conjugated gold nanoparticles (GNPs) in solid phantoms using diffusion reflection (DR) and fluorescence lifetime imaging microscopy (FLIM). The GNPs attached with fluorescein in solution were studied by fluorescence correlation spectroscopy. The intensity decays were recorded to reveal the fluorescence lifetime of fluorescein while in the near-field vicinity of the GNPs. The DR method was used to explore the solid phantoms containing GNPs, indicating the light propagation from the surface of solid phantoms. The resulting DR slopes of the reflected intensity showed the higher the GNP concentration, the bigger the slope. Fluorescence intensity, lifetime, and anisotropy images of solid phantoms were investigated by FLIM. The exploration of optical properties and molecular imaging combined with DR and FLIM methods is a new approach that has not been established until now. The combined DR-FLIM technique is expected to provide discrimination based on unique spectroscopic fingerprints of GNPs that could be utilized for cell imaging. This paper includes a combined study with a variety of methods, which may lead to multimodal imaging for surfaces (by FLIM) and deep penetration (up to cm by the DR) together. PMID- 25541622 TI - Unique metastases of ALK mutated lung cancer activated to the adnexa of the uterus. AB - Anaplastic lymphoma kinase (ALK) fusion positive non-small cell lung cancer (NSCLC) is a relatively novel molecular subtype in lung cancer. ALK targeted therapies such as crizotinib increase survival benefit in this patient population. However, further understanding of the disease subtype including patterns of metastasis and pathways of treatment resistance are needed. We describe a 50 year-old-woman diagnosed with stage IV NSCLC, T2N3M1b, ALK fusion positive disease. Although her initial sites of metastasis included the liver and bone, her story is notable for crizotinib resistant growth of a metastatic lesion to her adnexa. This report brings to attention unique mechanisms of metastasis in ALK positive patients. PMID- 25541624 TI - Estimation of the parameters of Burr type III distribution based on dual generalized order statistics. AB - The estimation of the parameters of Burr type III distribution based on dual generalized order statistics is considered by using the maximum likelihood (ML) approach as well as the Bayesian approach. The exact expression of the expected Fisher information matrix of the parameters in the distribution is obtained. Also, an approximation based on Lindley is used to obtain the Bayes estimator. To compare the maximum likelihood estimator and the Bayes estimator of the parameters, Monte Carlo simulation study is performed. PMID- 25541623 TI - The magnitude and impact of bullying among school pupils in Muscat, Oman: a cross sectional study. AB - Research about bullying among school pupils in the Arab/Muslim population is scarce. This study evaluates the characteristics of bullying and its impact among school pupils in Oman via cross-sectional survey among eighth grade school pupils (n = 1,229) during the academic year 2006-2007. The participants were selected using stratified random selection among 6 administrative divisions of one the governorates in the country. Data were collected using self-completed structured questionnaires. This study found similar percentages of males and females (76%) have experienced one form of bullying, and the majority of the incidents (80%) occurred in the vicinity of the school. In almost half of the cases, the bullying was initiated by a student of the same age or older than the victim. The most common type of bullying encountered in this study was verbal (47.7%), followed by misuse (45.9%), physical (43.9%), and, finally, social isolation/exclusion (22.5%). Although the failure of an academic year was uncommon among victims of bullying, the number of pupils who missed 4-6 and >= 7 school days was higher among bullied pupils. If this study will withstand further research, educational initiatives are needed to mitigate the rate of bullying in Oman. PMID- 25541626 TI - Static and dynamic experimental analysis of the galloping stability of porous H section beams. AB - The phenomenon of self-induced vibrations of prismatic beams in a cross-flow has been studied for decades, but it is still of great interest due to their important effects in many different industrial applications. This paper presents the experimental study developed on a prismatic beam with H-section. The aim of this analysis is to add some additional insight into the behaviour of the flow around this type of bodies, in order to reduce galloping and even to avoid it. The influence of some relevant geometrical parameters that define the H-section on the translational galloping behaviour of these beams has been analysed. Wind loads coefficients have been measured through static wind tunnel tests and the Den Hartog criterion applied to elucidate the influence of geometrical parameters on the galloping properties of the bodies under consideration. These results have been completed with surface pressure distribution measurements and, besides, dynamic tests have been also performed to verify the static criterion. Finally, the morphology of the flow past the tested bodies has been visualised by using smoke visualization techniques. Since the rectangular section beam is a limiting case of the H-section configuration, the results here obtained are compared with the ones published in the literature concerning rectangular configurations; the agreement is satisfactory. PMID- 25541625 TI - Effect of Antrodia camphorata on inflammatory arterial thrombosis-mediated platelet activation: the pivotal role of protein kinase C. AB - Antrodia camphorata is a rare Taiwanese medicinal mushroom. Antrodia camphorata extract has been reported to exhibit antioxidant, anti-inflammation, antimetastasis, and anticancer activities and plays a role in liver fibrosis, vasorelaxation, and immunomodulation. Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Platelet activation plays a crucial role in intravascular thrombosis, which is involved in a wide variety of cardiovascular diseases. However, the effect of Antrodia camphorata on platelet activation remains unclear. We examined the effects of Antrodia camphorata on platelet activation. In the present study, Antrodia camphorata treatment (56-224 MUg/mL) inhibited platelet aggregation induced by collagen, but not U46619, an analogue of thromboxane A2, thrombin, and arachidonic acid. Antrodia camphorata inhibited collagen-induced calcium (Ca(2+)) mobilization and phosphorylation of protein kinase C (PKC) and Akt. In addition, Antrodia camphorata significantly reduced the aggregation and phosphorylation of PKC in phorbol-12, 13-dibutyrate (PDBu) activated platelets. In conclusion, Antrodia camphorata may inhibit platelet activation by inhibiting of Ca(2+) and PKC cascade and the Akt pathway. Our study suggests that Antrodia camphorata may be a potential therapeutic agent for preventing or treating thromboembolic disorders. PMID- 25541627 TI - Use of a Poroelastic Model to Predict Intramuscular Pressure. AB - Measurement of individual muscle tension in a clinical setting has yet to be achieved. Previous investigators have suggested that the tension in skeletal muscle, comprised of approximately 70% fluid, could be determined using interstitial muscle fluid pressure (IMP). A computational model is needed to aid in understanding IMP distribution in muscles of varying geometry and contractile states without exhaustive testing. The first aim of this study was to determine a set of transversely isotropic material properties (i.e., permeability, relaxed modulus, and drained Poisson's ratio) for excised skeletal muscle using inverse finite element analysis with a poroelastic constitutive formulation on tension data from either longitudinal or transverse uniaxial load-relaxation tests of skeletal muscle tissue. The second aim was to compare pore pressure estimated from a model to experimental pressure measurements to assess its ability to accurately predict IMP. Results of this study indicated that skeletal muscle was transversely isotropic under load-relaxation as demonstrated by significant differences in the drained Poisson's ratio. It was also noted that the drained Poisson's ratios under both longitudinal and transverse loading were negative in these tests of excised muscle tissue. Pore pressure calculated with this model provided a good prediction of the development of IMP. These results point to the benefit of using a poroelastic model of skeletal muscle to predict IMP. PMID- 25541628 TI - GA-Based Selection of Vaginal Microbiome Features Associated with Bacterial Vaginosis. AB - In this paper, we successfully apply GEFeS (Genetic & Evolutionary Feature Selection) to identify the key features in the human vaginal microbiome and in patient meta-data that are associated with bacterial vaginosis (BV). The vaginal microbiome is the community of bacteria found in a patient, and meta-data include behavioral practices and demographic information. Bacterial vaginosis is a disease that afflicts nearly one third of all women, but the current diagnostics are crude at best. We describe two types of classifies for BV diagnosis, and show that each is associated with one of two treatments. Our results show that the classifiers associated with the 'Treat Any Symptom' version have better performances that the classifier associated with the 'Treat Based on N-Score Value'. Our long term objective is to develop a more accurate and objective diagnosis and treatment of BV. PMID- 25541629 TI - Development of Analytical Approach for an Automated Analysis of Continuous Long Term Single Lead ECG for Diagnosis of Paroxysmal Atrioventricular Block. AB - Reliable detection of significant ECG features such as the P-wave, QRS-complex and T-wave are of major clinical importance. In this paper we introduce a new algorithm based on synchrosqueezing wavelet transform for detection of P-waves in long-term ECG recordings. Synchrosqueezing is a powerful time-frequency analysis tool that provides precise frequency representation of a multicomponent signal through mode decomposition. First, we analyzed four wavelet filters with different filter parameters, to identify the best specification for quantification of QRS and P-wave. Second, the algorithm was tested on ECG recording comprising of events with paroxysmal atrioventricular block and validated through visual scanning. Using morlet wavelet with a peak frequency of 5Hz and separation of 0.1Hz, our proposed algorithm was able to detect 95.5% of P waves. From this study, it appears that synchrosqueezing wavelet transform may provide a powerful robust technique for automated ECG analysis. PMID- 25541630 TI - Knowledge-constrained K-medoids Clustering of Regulatory Rare Alleles for Burden Tests. AB - Rarely occurring genetic variants are hypothesized to influence human diseases, but statistically associating these rare variants to disease is challenging due to a lack of statistical power in most feasibly sized datasets. Several statistical tests have been developed to either collapse multiple rare variants from a genomic region into a single variable (presence/absence) or to tally the number of rare alleles within a region, relating the burden of rare alleles to disease risk. Both these approaches, however, rely on user-specification of a genomic region to generate these collapsed or burden variables, usually an entire gene. Recent studies indicate that most risk variants for common diseases are found within regulatory regions, not genes. To capture the effect of rare alleles within non-genic regulatory regions for burden tests, we contrast a simple sliding window approach with a knowledge-guided k-medoids clustering method to group rare variants into statistically powerful, biologically meaningful windows. We apply these methods to detect genomic regions that alter expression of nearby genes. PMID- 25541631 TI - Giant aortic arch aneurysm complicating Kawasaki disease: an original case report. AB - Kawasaki disease (KD) is a common acute vasculitis in pediatric population that usually involves small and middle-sized arteries, commonly coronary arteries. Although the incidence and natural course of coronary aneurysms after KD are well documented, related reports on peripheral arterial and aortic aneurysms are scarce. We report an original case of a giant aortic aneurysm involving the horizontal part of aortic arch in a 28 months- old patient diagnosed with Kawasaki Disease. This complication was managed by steroids therapy in the beginning than surgery was indicated because of mechanical complication and risk of rupture. PMID- 25541632 TI - Cardiac anomalies in Cantrell's pentalogy: From ventricular diverticulum to complete thoracic ectopia cordis. AB - Cantrell's pentalogy is a very rare syndrome associating varying degrees of midline wall defects and congenital cardiac anomalies. It is characterized by a combination of five anomalies that are: a midline supra umbilical abdominal wall defect, a sternal defect, an anterior diaphragmatic defect, a diaphragmatic pericardial defect and a congenital intra cardiac defect. Ectopia cordis, defined as a developmental defect in which the heart is abnormally located partially or totally outside the thorax, is in some cases a part of this syndrome. We report two cases of Cantrell's pentalogy in which cardiac ectopia was complete in one case and limited to left ventricular diverticulum in the other case. Both cases had a common intracardiac defect which is a double outlet right ventricle. The first case underwent surgical repair of the intracardiac lesions with resection of the diverticulum associated to repair of the midline defects with good outcome. The second case that presented with complete extra thoracic ectopia cordis died because of sepsis. We review through this article the main characteristics of Cantrell's pentalogy, we highlight the diversity of anatomic lesions and study the prognosis of this syndrome. PMID- 25541633 TI - The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes. AB - AIMS/HYPOTHESIS: The influence of glucagon on glycaemic control in type 1 diabetes is debated. We investigated the relationship between postprandial glucagon levels and HbA1c during a period up to 60 months after diagnosis of childhood type 1 diabetes. METHODS: The Danish remission phase cohort comprised 129 children (66 boys) with type 1 diabetes whose mean (SD) age at onset was 10.0 (3.9) years. Liquid mixed-meal tests were performed prospectively at 1, 3, 6 and 12 months and a subset of 40 patients completed follow-up at 60 months. Postprandial (90 min) plasma levels of glucagon, glucose (PG), C-peptide, total glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and HbA1c were analysed. Multivariate regression (repeated measurements with all five visits included) was applied and results expressed as relative change (95% CI). RESULTS: Postprandial glucagon levels increased 160% from 1 to 60 months after diagnosis (p < 0.0001). A doubling in postprandial PG corresponded to a 21% increase in postprandial glucagon levels (p = 0.0079), whereas a doubling in total GLP-1 levels corresponded to a 33% increase in glucagon levels (p < 0.0001). Postprandial glucagon associated negatively with postprandial C-peptide (p = 0.017). A doubling in postprandial glucagon corresponded to a 3% relative increase in HbA1c levels (p = 0.0045). CONCLUSIONS/INTERPRETATION: Postprandial glucagon levels were associated with deterioration of glycaemic control and declining beta cell function in the first 5 years after diagnosis of type 1 diabetes. The positive association of glucagon with total GLP-1 and PG suggests that physiological regulation of alpha cell secretion in type 1 diabetes is seriously disturbed. PMID- 25541634 TI - Stabilized, superparamagnetic functionalized graphene/Fe3O4@Au nanocomposites for a magnetically-controlled solid-state electrochemiluminescence biosensing application. AB - Herein, a multifunctional nanoarchitecture has been developed by integrating the branched poly(ethylenimine) functionalized graphene/iron oxide hybrids (BGNs/Fe3O4) and luminol capped gold nanoparticles (luminol-AuNPs). The luminescent luminol-AuNPs as an electrochemiluminescence marker can be assembled on the nanocarrier of BGNs/Fe3O4 hybrids efficiently via the Au-N chemical bonds and electrostatic adsorption. Meanwhile, the multifunctional nanoarchitecture has been proved with excellent electron transfer, good stability, high emission intensity, etc. Furthermore, we successfully developed an ultrasensitive magnetically-controlled solid-state electrochemiluminescence (ECL) platform for label-free determination of HeLa cells using this multifunctional nanocomposite. Excellent performance of the magnetically-controlled ECL biosensing platform has been achieved including a high sensitivity for HeLa cells with a linear range from 20 to 1 * 10(4) cells/mL, good stability, and reproducibility. PMID- 25541636 TI - Cyclic stretch induced gene expression of extracellular matrix and adhesion molecules in human periodontal ligament cells. AB - OBJECTIVE: Periodontal ligament (PDL) cells play an important role in maintaining periodontal homeostasis upon force loading caused by mastication or orthodontic force. Previous studies revealed stretch-induced realignment of human PDL cells, but the mechanism for this phenomenon still remains unclear. As extracellular matrix (ECM) and adhesion molecules play critical roles in cell migration and alignment, this study aimed to identify mechanoresponsive genes related to ECM and adhesion in human PDL cells. DESIGN: Human PDL cells were exposed to 10% stretch strain for 6 or 24 h, and the expression of 84 genes related to ECM and adhesion were analyzed with real-time PCR array. The protein expression of integrin alpha5 was examined by Western blot and flow cytometric analysis. RESULTS: Among the genes screened, 6 were up-regulated and 3 were down-regulated after 6 h stretch. There were 12 up-regulated and 2 down-regulated genes after 24 h stretch. These differentially expressed genes included genes encoding cell-cell adhesion molecules (CD44, ICAM1), cell-matrix adhesion molecules (ITGA5, ITGA6, ITGAL, ITGB2, SPP1), basement membrane constituents (SPARC, TNC), collagens and ECM constituents (COL5A1, COL11A1, FN1), ECM proteases (ADAMTS1, ADAMTS8, MMP8) and inhibitors (TIMP1), as well as other adhesion-related molecules (CTGF, CTNND2, TGFBI, CLEC3B). Both the cytosolic and membrane integrin alpha5 protein levels were up-regulated in response to stretch. CONCLUSION: This study identified several force-sensitive genes related to ECM and adhesion in stretched human PDL cells and should facilitate future studies on the stretch-induced cell realignment and mechanic force related periodontal remodelling by providing potential target genes. PMID- 25541637 TI - Determination of fatty acids and stable carbon isotopic ratio in subcutaneous fat to identify the feeding regime of Iberian pigs. AB - Discrimination among the types of feeding regimes for Iberian pigs is currently a highly demanded challenge by the Iberian pig sector. In the present research, discrimination among feeding regimes has been achieved by the combination of two analytical methods (based on FAMEs analysis by GC-FID and determination of delta(13)C by IRMS) previously used independently without success. In the present study, 80 samples of adipose tissue from Iberian pigs subjected to four different feedings were analyzed. The study of the variables more influenced by the feeding regime has allowed us to configure panels of markers with predictive power for the studied feedings by multivariate ROC analysis. The results provided values of specificity and sensitivity higher than 85% in most cases. The statistical combination of results from different analytical methods could be the key to develop models for the correct discrimination of Iberian pigs according to the feeding regime. PMID- 25541639 TI - PCL/alginate composite scaffolds for hard tissue engineering: fabrication, characterization, and cellular activities. AB - Alginates have been used widely in biomedical applications because of good biocompatibility, low cost, and rapid gelation in the presence of calcium ions. However, poor mechanical properties and fabrication-ability for three-dimensional shapes have been obstacles in hard-tissue engineering applications. To overcome these shortcomings of alginates, we suggest a new composite system, consisting of a synthetic polymer, poly(epsilon-caprolactone), and various weight fractions (10 40 wt %) of alginate. The fabricated composite scaffolds displayed a multilayered 3D structure, consisting of microsized composite struts, and they provided a 100% offset for each layer. To show the feasibility of the scaffold for hard tissue regeneration, the composite scaffolds fabricated were assessed not only for physical properties, including surface roughness, tensile strength, and water absorption and wetting, but also in vitro osteoblastic cellular responses (cell seeding efficiency, cell viability, fluorescence analyses, alkaline phosphatase (ALP) activity, and mineralization) by culturing with preosteoblasts (MC3T3-E1). Due to the alginate components in the composites, the scaffolds showed significantly enhanced wetting behavior, water-absorption (~12-fold), and meaningful biological activities (~2.1-fold for cell-seeding efficiency, ~2.5 fold for cell-viability at 7 days, ~3.4-fold for calcium deposition), compared with a pure PCL scaffold. PMID- 25541641 TI - ZnSe.0.5N2H4 hybrid nanostructures: a promising alternative photocatalyst for solar conversion. AB - As the molecular precursor of ZnSe, ZnSe.0.5N2H4 inorganic-organic hybrids have received relatively less attention due to the feasibility of their further processing and decomposition into pure-phase ZnSe. Here we demonstrated that ZnSe.0.5N2H4 hybrid nanostructures, which were prepared using a facile hydrazine assisted hydrothermal method, may practically harvest solar energy for photoconversion applications. By modulating the volume ratio of hydrazine hydrate to deionized water employed in the synthesis, the morphology of the grown ZnSe.0.5N2H4 can be varied, which included nanowires, nanobelts and nanoflakes. With the relatively long exciton lifetime and highly anisotropic structure, ZnSe.0.5N2H4 nanowires performed much better in the photodegradation of rhodamine B than the other two counterpart products. As compared to pure ZnSe nanoparticles and single-phase ZnSe nanowires obtained from further processing ZnSe.0.5N2H4, the ZnSe.0.5N2H4 hybrid nanowires exhibited superior photocatalytic performance under visible light illumination. The hybrid nanowires were further decorated with Au particles to endow them with structural and compositional diversities. Time-resolved photoluminescence spectra suggested that almost 40% of the photoexcited electrons in ZnSe.0.5N2H4 nanowires can be transported to the decorated Au, which enabled a fuller extent of participation of charge carriers in the photocatalytic process and thus conduced to a significant enhancement in the photocatalytic activity. The demonstrations from this work illustrate that ZnSe.0.5N2H4 hybrid nanostructures can serve as a versatile photocatalyst platform for advanced photocatalytic applications. PMID- 25541640 TI - Neurologically-related sequelae associated with mild traumatic brain injury. AB - OBJECTIVE: Mild traumatic brain injury (mTBI) accounts for more than 75% of traumatic brain injuries every year. This study examines the temporal association between non-blast mTBI and the onset of neurologic sequelae to illuminate risks of post-concussive syndrome, epilepsy and chronic pain. METHODS: A large historical prospective study was conducted utilizing electronically-recorded demographic, medical and military-specific data for over half a million active duty US Air Force Airmen. This study utilized diagnostic codes to identify mTBI exposures, two control groups and three post-mTBI time periods. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards modelling. RESULTS: HRs were higher when mTBI exposed Airmen were compared with the full cohort and lower when compared with the other injured group. When compared to the other injured group, mTBI was positively associated with epilepsy/recurrent seizure outcomes, post-concussive syndrome and pain disorders. HRs tended to be highest within the first 30 days and decreased over time. CONCLUSIONS: Findings support that mTBI may have a prolonged neurological impact. Findings are also likely generalizable to young adult populations with exposure to non-blast related mTBI, including civilians, as those included in this study were young adults with a high prevalence of recreational/sports and motor vehicle injuries. PMID- 25541638 TI - RXR agonist modulates TR: corepressor dissociation upon 9-cis retinoic acid treatment. AB - Transcriptional regulation controlled by thyroid hormone receptor (TR) drives events such as development, differentiation, and metabolism. TRs may act either as homodimers or as heterodimers with retinoid X receptor (RXR). Thyroid hormone T3 preferentially binds TR-RXR heterodimers, which activate transcription through coactivator recruitment. However, it is unclear whether TR-RXR heterodimers may also be responsive to the canonical RXR agonist 9-cis retinoic acid (9C) in the context of physiological gene regulation. New structural studies suggest that 9C promotes the displacement of bound coactivators from the heterodimer, modifying TR-RXR activity. To shed light on the molecular mechanisms that control TR-RXR function, we used biophysical approaches to characterize coregulator recruitment to TR-TR or to TR-RXR in the presence of T3 and/or 9C as well as cell-based assays to establish the functional significance of biophysical findings. Using cell-based and fluorescence assays with mutant and wild-type TR, we show that 9C does indeed have a function in the TR-RXR heterodimer context, in which it induces the release of corepressors. Furthermore, we show that 9C does not promote detectable conformational changes in the structure of the TR-RXR heterodimer and does not affect coactivator recruitment. Finally, our data support the view that DNA binding domain and Hinge regions are important to set up NR-coactivator binding interfaces. In summary, we showed that the RXR agonist 9C can regulate TR function through its modulation of corepressor dissociation. PMID- 25541642 TI - Long minority carrier diffusion lengths in bridged silicon nanowires. AB - Nanowires have large surface areas that create new challenges for their optoelectronic applications. Lithographic processes involved in device fabrication and substrate interfaces can lead to surface defects and substantially reduce charge carrier lifetimes and diffusion lengths. Here, we show that using a bridging method to suspend pristine nanowires allows for circumventing detrimental fabrication steps and interfacial effects associated with planar device architectures. We report electron diffusion lengths up to 2.7 MUm in bridged silicon nanowire devices, much longer than previously reported values for silicon nanowires with a diameter of 100 nm. Strikingly, electron diffusion lengths are reduced to only 45 nm in planar devices incorporating nanowires grown under the same conditions. The highly scalable silicon nanobridge devices with the demonstrated long diffusion lengths may find exciting applications in photovoltaics, sensing, and photodetectors. PMID- 25541643 TI - Rh(III)-catalyzed redox-neutral C-H activation of pyrazolones: an economical approach for the synthesis of N-substituted indoles. AB - A new strategy is reported for the economical synthesis of indoles bearing an N (3-aminobut-2-enoyl) substituent through Rh(III)-catalyzed redox-neutral C-H activation of pyrazolones and alkynes. This approach utilizes cheap substrates and mild reaction conditions to access a unique class of indoles via a N-N bond oxidative cleavage without loss of the N-terminus, therefore meeting all the atom/step/redox economy principles. PMID- 25541644 TI - Incorporating land-use requirements and environmental constraints in low-carbon electricity planning for California. AB - The land-use implications of deep decarbonization of the electricity sector (e.g., 80% below 1990 emissions) have not been well-characterized quantitatively or spatially. We assessed the operational-phase land-use requirements of different low-carbon scenarios for California in 2050 and found that most scenarios have comparable direct land footprints. While the per MWh footprint of renewable energy (RE) generation is initially higher, that of fossil and nuclear generation increases over time with continued fuel use. We built a spatially explicit model to understand the interactions between resource quality and environmental constraints in a high RE scenario (>70% of total generation). We found that there is sufficient land within California to meet the solar and geothermal targets, but areas with the highest quality wind and solar resources also tend to be those with high conservation value. Development of some land with lower conservation value results in lower average capacity factors, but also provides opportunity for colocation of different generation technologies, which could significantly improve land-use efficiency and reduce permitting, leasing, and transmission infrastructure costs. Basing siting decisions on environmentally constrained long-term RE build-out requirements produces significantly different results, including better conservation outcomes, than implied by the current piecemeal approach to planning. PMID- 25541645 TI - Copper-mediated trifluoromethylation using phenyl trifluoromethyl sulfoxide. AB - A new method for the generation of trifluoromethylcopper ("CuCF3") species from readily available phenyl trifluoromethyl sulfoxide has been developed. The "CuCF3" reagent can be applied in efficient trifluoromethylations of aryl iodides and activated aryl bromides in the absence of additional ligands. Furthermore, the "CuCF3" species can also undergo oxidative cross-coupling with terminal alkynes and arylboronic acids. PMID- 25541646 TI - Treatment of hypertension in chronic kidney disease patients under specialized care: one-center cross-sectional analyses. AB - AIM: The study analyzed hypertension management and control rates among non dialysis, non-transplanted hypertensive chronic kidney disease (CKD) patients under specialized care in Gdansk nephrology center in 1996-2011. PATIENTS AND METHODS: It was a retrospective, cross-sectional study analyzing data from medical records of 190, 490, 1799 and 1696 subjects with CKD, who received outpatient care in 1996, 2001, 2006 and 2011, and were included in four independent surveys, respectively. RESULTS: The average number of antihypertensive drugs per patient increased significantly (p < 0.01) as follows 1.74 +/- 0.9 (1996), 2.08 +/- 1.01 (2011), 2.5 +/- 1.19 (2006) and 2.65 +/- 1.18 (2011). The percentage of patients receiving diuretics, beta-blockers and drugs inhibiting renin-angiotensin-aldosterone increased significantly in subsequent years, while a frequency of therapy with calcium channel blockers decreased (p < 0.001). 16%, 30%, 42% and 54% of subjects had causal BP values < 140/90 mmHg (p < 0.001). When specific thresholds for CKD patients according to JNC recommendations were used, the control rate was worse but also showed significant improvement in the second, third and final surveys, i.e. 9%, 12%, 14% and 24% (p < 0.001). The subgroup analysis revealed that a better control rate was observed in following groups: < 65 years old; I-II stage of CKD; primary glomerulonephritis; without cardiovascular complications or diabetes. CONCLUSION: The study may show an improvement in the effectiveness of antihypertensive treatment in CKD patients under specialized care in Gdansk Nephrology Centre in 1996-2011. PMID- 25541635 TI - Stem cells, progenitor cells, and lineage decisions in the ovary. AB - Exploring stem cells in the mammalian ovary has unleashed a Pandora's box of new insights and questions. Recent evidence supports the existence of stem cells of a number of the different cell types within the ovary. The evidence for a stem cell model producing mural granulosa cells and cumulus cells is strong, despite a limited number of reports. The recent identification of a precursor granulosa cell, the gonadal ridge epithelial-like cell, is exciting and novel. The identification of female germline (oogonial) stem cells is still very new and is currently limited to just a few species. Their origins and physiological roles, if any, are unknown, and their potential to produce oocytes and contribute to follicle formation in vivo lacks robust evidence. The precursor of thecal cells remains elusive, and more compelling data are needed. Similarly, claims of very small embryonic-like cells are also preliminary. Surface epithelial cells originating from gonadal ridge epithelial-like cells and from the mesonephric epithelium at the hilum of the ovary have also been proposed. Another important issue is the role of the stroma in guiding the formation of the ovary, ovigerous cords, follicles, and surface epithelium. Immune cells may also play key roles in developmental patterning, given their critical roles in corpora lutea formation and regression. Thus, while the cellular biology of the ovary is extremely important for its major endocrine and fertility roles, there is much still to be discovered. This review draws together the current evidence and perspectives on this topic. PMID- 25541647 TI - PEAR1 is not a human hypertension-susceptibility gene. AB - OBJECTIVE: Platelet endothelial aggregation receptor 1 (PEAR1) is a membrane protein involved in platelet contact-induced activation and sustained platelet aggregation. Experimental studies identified PEAR1, as a candidate gene that may be linked to the blood-pressure driven kidney injury in salt-sensitive Dahl rats. AIM: In a family-based European population study (mean age 39.7 years; 52.2% women), we searched for association of changes in blood pressure or incidence of hypertension with genetic variation in PEAR1. METHODS: Among 1973 randomly recruited people, genotyped for PEAR1, we measured blood pressure at baseline and follow-up. RESULTS: Median follow-up was 10.0 years. While accounting for family clusters and blood pressure at baseline and with adjustments applied for sex, age, body mass index, smoking and drinking, total cholesterol, and antihypertensive drug treatment, all associations of systolic and diastolic blood pressure changes with nine single nucleotide polymorphisms (SNPs) in PEAR1 were all non-significant (p >= 0.059). With similar adjustments, the incidence of hypertension (397 cases among 1532 participants were normotensive at baseline [25.9%]) was not related to the SNPs in PEAR1 (hazard ratios <= 1.09; p >= 0.09). CONCLUSION: Our study suggests that PEAR1 is not a hypertension susceptibility gene in humans. PMID- 25541648 TI - Torque spectroscopy for the study of rotary motion in biological systems. PMID- 25541649 TI - Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy. AB - Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C. PMID- 25541651 TI - The Relationship between P-Selectin Polymorphisms and Thrombosis in Antiphospholipid Syndrome: A Pilot Case-Control Study. AB - OBJECTIVE: The selectins are cell adhesion molecules that mediate the interactions among leukocytes, activated platelets, and endothelial cells. We aimed to investigate whether P-selectin polymorphisms are associated with thrombosis in patients with antiphospholipid syndrome (APS). MATERIALS AND METHODS: The diagnosis and classification of APS were based on the report of an international workshop. Genomic DNA was extracted from citrated blood samples of all subjects. Three single nucleotide polymorphisms associated with the P selectin coding region (S290N, c.1087G>A; N562D, c.1902G>A; T715P, c.2363A>C) were assessed. RESULTS: There were 26 APS (65%) patients with thrombosis. The number of patients without thrombosis was 14 (35%). The frequency of the N562D-DN genotype was significantly higher in patients with APS than in healthy controls (p=0.003). The frequency of this genotype was significantly higher in patients with APS with thrombosis compared with patients with no thrombosis (p=0.03). The N562D-NN genotype was found at a higher frequency in patients with APS than in healthy controls (p=0.004). CONCLUSION: Our results suggest that the N562D polymorphism of the DN genotype of P-selectin is associated with an increased risk of thrombosis in patients with APS. PMID- 25541650 TI - Diagnosis of Invasive Fungal Diseases in Hematological Malignancies: A Critical Review of Evidence and Turkish Expert Opinion (TEO-2). AB - One of the most problematic issues in hematological malignancies is the diagnosis of invasive fungal diseases. Especially, the difficulty of mycological diagnosis and the necessity of immediate intervention in molds have led to the adoption of "surrogate markers" that do not verify but rather strongly suggest fungal infection. The markers commonly used are galactomannan (GM), beta-glucan, and imaging methods. Although there are numerous studies on these diagnostic approaches, none of these markers serve as a support for the clinician, as is the case in human immunodeficiency virus (HIV) or cytomegalovirus (CMV) infections. This paper has been prepared to explain the diagnostic tests. As molecular tests have not been standardized and are not used routinely in the clinics, they will not be mentioned here. PMID- 25541652 TI - Serum Bcl-2 Levels in Patients with beta-Thalassemia Minor: A Pilot Study. AB - OBJECTIVE: Anti-apoptotic proteins such as Bcl-2 and Bcl-xL may play a role in the survival of erythroid progenitor cells. Information about these proteins in patients with beta-thalassemia minor is limited. We aimed to determine the levels of serum Bcl-2 in patients with beta-thalassemia minor. MATERIALS AND METHODS: Ninety-seven patients (60 females and 37 males with mean age of 29+/-21 years) with beta-thalassemia minor were enrolled in this study. The diagnosis of beta thalassemia minor was based on whole blood counts, family history, and HbA2 levels estimated by high-performance liquid chromatography. The control group comprised 23 healthy adults (17 females and 6 males with mean age of 58+/-9 years) without anemia. The levels of serum Bcl-2 were measured by enzyme-linked immunosorbent assay. Mann-Whitney U tests were used in statistical evaluation and p<0.05 was accepted as statistically significant. RESULTS: Although there was no statistically significant difference between patients with beta-thalassemia minor and the control group for the level of serum Bcl-2 (p>0.05), these levels were higher in beta-thalassemia minor patients than controls. CONCLUSION: There are damaged beta chains in beta-thalassemia minor. Therefore, it is expected that premature death of red blood cells may occur due to apoptosis. The mean age of the control group was higher than that of the beta-thalassemia minor group; this may be why Bcl-2 levels were higher in the beta-thalassemia minor group. It is known that older age constitutes a risk for increased apoptosis. Other proteins (Bad, Bax, etc.) and pathways [CD95 (Fas) ligand] associated with apoptosis should be evaluated in future studies including more patients. PMID- 25541653 TI - Duffy and kidd genotyping facilitates pretransfusion testing in patients undergoing long-term transfusion therapy. AB - OBJECTIVE: Conventional serologic typing of red blood cell systems other than ABO and RhD can be inaccurate and difficult to interpret in patients who have recently undergone blood transfusion. While molecular-based assays are not used routinely, the usefulness of genotyping was investigated in order to determine patients who may benefit from this procedure. MATERIALS AND METHODS: Blood samples were taken from 101 patients with haemato-oncological, chronic renal, or gastroenterological diseases and from 50 donor controls; the samples were tested for Fya and Fyb by applying serologic and genetic methods. All patients had received 3 or more units of RBCs during the last 3 months. An average of 6.1 RBC units were transfused per patient. The average length of time from transfusion until blood sampling was 24.4 days. The haemagglutination test was applied for serological analysis, and the restriction length polymorphism assay was used for genotyping. RESULTS: In total, 33 (32.7%) patients showed positive reactions with anti-Fya or anti-Fyb while being negative genetically. False-positive Fya results were found in 23 samples, and false-positive Fyb in 10 specimens. During the last 3 months, significantly more RBC units were transfused to patients with discrepant results than to those with accurate phenotyping/genotyping results: median of 5 (mean +/- SE: 6.85+/-0.69) versus median of 4 (mean: 5.71+/-0.51), respectively (p=0.025). The median length of time after the last transfusion was 25 days (mean: 28.72+/-2.23 days) in the group with accurate phenotyping/genotyping results versus a median of 14 days (mean: 15.52+/-1.95 days) in the group with discrepant results (p=0.001). Phenotypes and genotypes coincided in all donor samples. CONCLUSION: Genotyping assays for the Duffy system should be considered if the patient underwent blood transfusion less than 3 or 4 weeks before the sample collection. If the time frame from RBC transfusion exceeds 6 weeks, Duffy phenotyping can provide accurate results. PMID- 25541654 TI - Bone-Specific Alkaline Phosphatase Levels among Patients with Multiple Myeloma Receiving Various Therapy Options. AB - OBJECTIVE: This study aimed to investigate the impact of the different therapy regimens used in multiple myeloma (MM) on bone-specific alkaline phosphatase (BALP) levels. MATERIALS AND METHODS: One hundred and thirteen patients with MM were included in the study. Patients were grouped according to the regimens they received, as follows: group 1, melphalan and prednisolone (MP); group 2, vincristine, adriablastin, and dexamethasone (VAD); group 3, thalidomide plus dexamethasone; and group 4, bortezomib plus dexamethasone. BALP levels were measured before treatment and at the third and sixth months of treatment. A fifth group consisted of patients in the post-treatment remission period at study entry (no-treatment group). RESULTS: The BALP levels at the third and sixth months of the treatment were significantly higher than the pre-treatment levels in the bortezomib and the no-treatment groups, whereas no significant difference was observed in the MP, VAD, and thalidomide groups. CONCLUSION: Considering that BALP is a surrogate marker of bone formation, our study suggests that bortezomib more efficiently leads to the improvement of bone disease in myeloma than other treatment options. PMID- 25541655 TI - The relationship of T helper-2 pathway components interleukin-4, interleukin-10, immunoglobulin e, and eosinophils with prognostic markers in non-hodgkin lymphoma: a case-control study. AB - OBJECTIVE: Increased risk for non-Hodgkin lymphoma (NHL) is associated with infections and environmental agents. We hypothesized that these factors chronically trigger the T helper-2 (Th2) pathway and result in lymphoma. We investigated the role of the Th2 pathway by exploring the relationships between components of the Th2 pathway, interleukin (IL)-10, IL-4, immunoglobulin E (IgE), and eosinophils, and prognostic markers of NHL. MATERIALS AND METHODS: Thirty-one NHL patients and 27 healthy controls were enrolled. IL-10, IL-4, IgE, and eosinophils were measured. IL-4 and IL-10 were analyzed with the enzyme amplified sensitivity immunoassay method. RESULTS: High IL-10 levels were correlated with several poor prognostic features, short early survival, and lymphopenia. There was a positive correlation between albumin and IL-4 levels and a negative correlation between IL-10 and albumin. There was no relationship related with eosinophils and IgE. We found remnant increased IL-4, which could be a clue for the triggering of the Th2 pathway in the background. CONCLUSION: There is a need for differently designed studies to detect the place of the Th2 pathway in NHL. PMID- 25541656 TI - The Association of HLA Class 1 and Class 2 Antigens with Multiple Myeloma in Iranian Patients. AB - OBJECTIVE: Multiple myeloma (MM) is a B-cell malignancy characterized by the clonal proliferation of malignant plasma cells. According to results of some studies, it has been suggested that the HLA class 1 and 2 genes have susceptibility effects on MM. Studies of different populations have reported different HLA class 1 and 2 alleles that affect MM. In this study, we assessed the association of HLA class 1 and class 2 antigens with MM in Iranian patients. MATERIALS AND METHODS: We performed a case-control genotyping study with 105 Iranian MM patients that were selected from the bone marrow transplantation department of Taleghani Hospital and 150 controls using single specific primer polymerase chain reaction with the HLA-Ready Gene ABDR Kit. RESULTS: Our results demonstrated that 21% of patients versus 12% of controls and 11% of patients versus 3% of controls carried HLA-A*03 and HLA-B*18, respectively. The MM patients had a significant increase in the frequency of HLA-A*03 and HLA-B*18 alleles in comparison to control subjects (p=0.039, OR=2.057 and p=0.013, OR=3.567, respectively). CONCLUSION: Our findings suggested that the HLA-A*03 and HLA-B*18 alleles have significant susceptibility effects on MM in the Iranian population. However, compared to other populations, the above-mentioned alleles had different statuses. Since there are not many studies evaluating and calculating this association among ethnic groups, further studies among other populations are needed to explain the exact association of the HLA genes with MM. PMID- 25541657 TI - New insights on iron study in myelodysplasia. AB - OBJECTIVE: Hepcidin plays a pivotal role in iron homeostasis. It is predominantly produced by hepatocytes and inhibits iron release from macrophages and iron uptake by intestinal epithelial cells. Competitive ELISA is the current method of choice for the quantification of serum hepcidin because of its lower detection limit, low costs, and high throughput. This study aims to discuss the role of hepcidin in the pathogenesis of iron overload in recently diagnosed myelodysplasia (MDS) cases. MATERIALS AND METHODS: The study included 21 recently diagnosed MDS patients and 13 healthy controls. Ferritin, hepcidin, and soluble transferrin receptor (sTFR) were measured in all subjects. RESULTS: There were 7 cases of hypocellular MDS, 8 cases of refractory cytopenia with multilineage dysplasia, and 6 cases of refractory anemia with excess blasts. No difference was observed among the 3 MDS subtypes in terms of hepcidin, sTFR, and ferritin levels (p>0.05). Mean hepcidin levels in the MDS and control groups were 55.8+/-21.5 ng/mL and 19.9+/-2.6 ng/mL, respectively. Mean sTFR was 45.7+/-8.8 nmol/L in MDS patients and 31.1+/-5.6 nmol/L in the controls. Mean ferritin levels were significantly higher in MDS patients than in controls (539.14+/-83.5 ng/mL vs. 104.6+/-42.9 ng/mL, p<0.005). There was a statistically significant correlation between hepcidin and sTFR (r=0.45, p=0.039). No difference in hepcidin levels between males and females was observed, although it was lower in males in comparison to females (47.9+/-27.6 vs. 66.7+/-35.7, p>0.05). CONCLUSION: Hepcidin may not be the main cause of iron overload in MDS. Further studies are required to test failure of production or peripheral unresponsiveness to hepcidin in MDS cases. PMID- 25541658 TI - Intravascular large B-cell lymphoma diagnosed on prostate biopsy: a case report. AB - Intravascular large B-cell lymphoma (IVLBCL) is a very rare type of non-Hodgkin lymphoma, usually affecting elderly patients and characterized by selective infiltration of neoplastic cells within blood vessels' lumina. IVLBCL diagnosed with prostatic involvement is extremely rare. We report a patient of 65 years old, having mostly neurological complaints but diagnosed with IVLBCL upon histopathological examination of transurethral prostate resection material, which revealed large neoplastic cell infiltration totally limited within the lumens of small vessels. By immunohistochemistry, neoplastic cell infiltration was positive with MUM1, bcl-6, and bcl-2 and negative with ALK1, CD10, and CD30, with a high Ki-67 proliferation index. CD34 and CD31 staining showed expression in endothelial cells, highlighting the intravascular nature of neoplastic infiltrate. The patient unfortunately refused to receive treatment and died of the disease 8 months after the diagnosis. IVLBCL, though very rare, should be considered in differential diagnosis of all organ biopsies with intravascular infiltration. Further improvements in the understanding of the pathogenesis and biology of this rare type of lymphoma are mandatory. PMID- 25541659 TI - Primary splenic angiosarcoma revealed by bone marrow metastasis. AB - Primary splenic angiosarcomas are the most common malignant non-hematopoietic tumors of the spleen. Metastatic diseases were found in 69% of patients in a reported series but the incidence of bone marrow involvement is unclear. We report a rare case of a 25-years-old Moroccan woman with unsuspected primary splenic angiosarcoma revealed by bone marrow metastasis. She presented with serious anemia and splenomegaly. Bone marrow biopsy revealed proliferating spindle cells. Computed tomography scanning showed an enlarged spleen with heterogeneous lesions. Splenectomy was performed and retrospective histological study of the spleen confirmed the diagnosis. She died 1 year after splenectomy. PMID- 25541660 TI - Aplastic anemia associated with oral terbinafine: a case report and review of the literature. AB - Onychomycosis (OM) is a common fungal infection of the toenails and/or fingernails that is highly prevalent in the general population and also responsible for significant morbidity. OM is caused by dermatophytes, nondermatophytic molds, or yeast. Today systemic antifungal agents are considered as the gold standard for all types of OM. Here we report a case of aplastic anemia associated with oral terbinafine use and a review of the literature on hematological toxicities associated with terbinafine. PMID- 25541661 TI - Significant differences in thymic index of thalassemia major patients. PMID- 25541662 TI - c.761C>T Mutation Linked Hyper IgM Syndrome Presenting with Hypertransaminasemia and Arthritis. PMID- 25541663 TI - Blastic plasmacytoid dendritic cell neoplasm: single-center experience with two cases in one year. PMID- 25541664 TI - Mogamulizumab treatment in a hemodialysis patient with adult T-cell leukemia/lymphoma. PMID- 25541665 TI - Chediak-higashi syndrome: a case report of a girl without silvery hair and oculocutaneous albinism presenting with hemophagocytic lymphohistiocytosis. PMID- 25541666 TI - Gaucher Cells or Pseudo-Gaucher Cells: That's the Question. PMID- 25541667 TI - Quilty effect after extracorporeal photopheresis in a patient with severe refractory cardiac allograft rejection. PMID- 25541668 TI - A pediatric patient with intravenous cyclosporine anaphylaxis who tolerated the oral form. PMID- 25541669 TI - Acquired hemophilia. PMID- 25541670 TI - Generalized Necrobiotic Xanthogranuloma in a Patient with Multiple Myelomaus Patient with Isolated Neutropenia and Diminished Expression of CD55 and CD59 Similar to Paroxysmal Nocturnal Hemoglobinuria. PMID- 25541671 TI - Aggressive multiple myeloma with unusual morphology. PMID- 25541672 TI - Quantitative proteomics of bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis. AB - The proteomic analysis of bronchoalveolar lavage fluid (BALF) can give insight into pulmonary disease pathology and response to therapy. Here, we describe the first gel-free quantitative analysis of BALF in idiopathic pulmonary fibrosis (IPF), a chronic and fatal scarring lung disease. We utilized two-dimensional reversed-phase liquid chromatography and ion-mobility-assisted data-independent acquisition (HDMSE) for quantitation of >1000 proteins in immunodepleted BALF from the right middle and lower lobes of normal controls and patients with IPF. Among the analytes that were increased in IPF were well-described mediators of pulmonary fibrosis (osteopontin, MMP7, CXCL7, CCL18), eosinophil- and neutrophil derived proteins, and proteins associated with fibroblast foci. For additional discovery and targeted validation, BALF was also screened by multiple reaction monitoring (MRM), using the JPT Cytokine SpikeMix library of >400 stable isotope labeled peptides. A refined MRM assay confirmed the robust expression of osteopontin, and demonstrated, for the first time, upregulation of the pro fibrotic cytokine, CCL24, in BALF in IPF. These results show the utility of BALF proteomics for the molecular profiling of fibrotic lung diseases and the targeted quantitation of soluble markers of IPF. More generally, this study addresses critical quality control measures that should be widely applicable to BALF profiling in pulmonary disease. PMID- 25541673 TI - Self-reproduction of nanoparticles through synergistic self-assembly. AB - We describe a self-reproduction mechanism of nanometer-sized particles (i.e., nanodiscs) through chemical ligation of the precursors and self-assembly of the building blocks. The ligation reaction was accelerated on lipid bilayer surfaces, and the products spontaneously assembled into nanodiscs with lipid molecules. With the increase in the number of nanodiscs, a rapid proliferation of the nanodiscs occurred through the spatial rearrangements of the molecules between the pre-existing nanodiscs and the unreacted materials, rather than template- or complex-enhanced ligation of the precursors. The subsequent process of surface enhanced ligation of integrated precursors matured the nanoparticles into identical copies of the pre-existing assembly. Our study showed that the synergistic self-assembly mechanism probably underlie the self-replication principles for heterogeneous multimolecular systems. PMID- 25541674 TI - Haptoglobin genotypes polymorphism as a risk factor for subclinical atherosclerosis in beta-thalassemia major children; a single center Egyptian study. AB - Background/Objectives Haptoglobin (Hp) is an antioxidant protein. Its genotypic polymorphism had been proposed to influence vascular complications among diabetics, but no data are available about this association among thalassemia patients so far. We have investigated the assumption of an association between Hp genotypes and subclinical atherosclerosis among beta-thalassemia major (TM) children. Methods One hundred beta-TM children and 70 matched healthy controls were included. Serum ferritin level and fasting lipid profile were assayed. Haptoglobin genotyping was determined by amplification gel electrophoresis. Carotid intima media thickness (cIMT) was measured using high resolution ultrasound. Results The relative distribution of the three Hp genotypes among thalassemia group and the control group were 18 and 14.3% for Hp1-1; 38 and 37.1% for Hp2-1; and 44 and 48.6% for Hp2-2 respectively. There was no significant difference between patients and controls regarding Hp genotypes distribution. Hp2 2 genotype TM children had significantly higher cIMT compared to other genotypes (P < 0.0001). Elevated cIMT was significantly represented in Hp2-2 genotype patients (P < 0.0001) who had higher serum ferritin compared to their counterparts (P < 0.05). Hp2-2 patients were five times more likely to suffer from subclinical atherosclerosis than Hp1-1 and six times than Hp2-1 genotype patients (P = 0.008 and 0.001, respectively); a difference that persisted significant after adjustment for some risk factors compared to Hp2-1 patients (OR 3.96; P = 0.02). Conclusions Hp2-2 genotype is a significant predictor for premature atherosclerosis in TM children and confers them an increased risk for iron overload. PMID- 25541675 TI - Palladium(II)-catalyzed intramolecular tandem aminoalkylation via divergent C(sp3)-H functionalization. AB - We have developed a Pd(II)-catalyzed oxidative tandem aminoalkylation via divergent C(sp(3))-H functionalization, affording three- and five-membered-ring fused indolines in good yields under two optimized conditions, respectively. The mechanism studies have indicated that the benzylic C-H cleavage involved in the former transformation is the rate-determining step, while the cleavage of amide alpha-C-H in the latter is not. This is the first example of a Pd-catalyzed tandem reaction involving C(sp(3))-H activation without the employment of prefunctionalized reagents (e.g., halogenated and boron reagents) and directing groups, representing a green and economic protocol for the construction of N containing heterocycles. PMID- 25541677 TI - Mesophases and ionic conductivities of simple organic salts of M(m-iodobenzoate) (M = Li(+), Na(+), K(+), Rb(+), and Cs(+)). AB - Simple organic salts such as (Li(+))(m-IBA) (1), (Na(+))(m-IBA) (2), (K(+))(m IBA) (3), (Rb(+))(m-IBA) (4), and (Cs(+))(m-IBA) (5) (m-IBA = m-iodobenzoate) were shown to form a mesophase before crystal melting or decomposition. The crystals were obtained in the hydrated form, e.g., 1.(H2O), 2.(H2O), 3.0.5(H2O), 4.(H2O), and 5.(H2O); they were then converted into dehydrated forms by increasing the temperature to ~450 K. Optically anisotropic-layered mesophases were observed in unhydrated crystals 2, 3, 4, and 5, whereas an optically isotropic mesophase (e.g., rotator phase) was found for crystal 1. The single crystal X-ray structural analysis of the hydrated crystals revealed an inorganic organic alternate layer structure, which is consistent with the average molecular orientation in the layered mesophase. The m-IBA anions formed a pi-stacking columnar structure in the hydrated crystals, while one- or two-dimensional M(+)~O networks were observed in the inorganic layers. Our results showed that the M(+)~O interactions and their connectivity are strongly influenced by the size of the cations. The reconstruction of the M(+)~O networks by removing H2O molecules was crucial for the formation of the mesophases. A strong response of both the real and imaginary parts of the dielectric constant was observed around the solid mesophase phase-transition temperatures of crystals 1-5, with the ionic conductions playing a critical role. PMID- 25541676 TI - Hearing loss among HIV-seropositive and HIV-seronegative men and women. AB - IMPORTANCE: Age-related hearing loss affects quality of life. Data on hearing loss among aging human immunodeficiency virus-seropositive (HIV+) adults are limited. OBJECTIVE: To evaluate pure-tone hearing thresholds among HIV+ and HIV seronegative (HIV-) adults and to determine whether HIV disease variables and antiretroviral therapy are associated with pure-tone threshold levels. DESIGN, SETTING, AND PARTICIPANTS: A total of 262 men (117 HIV+) from the Baltimore, Maryland/Washington, DC, site of the Multicenter AIDS Cohort Study and 134 women (105 HIV+) from the Washington, DC, site of the Women's Interagency HIV Study participated. Pure-tone air conduction thresholds were collected in a sound treated room for each ear at frequencies from 250 through 8000 Hz. Linear mixed regression models tested the effect of HIV on hearing after adjustment for age, sex, race, and noise exposure history. MAIN OUTCOMES AND MEASURES: Low-frequency pure-tone average (LPTA) at 250, 500, 1000, and 2000 Hz and high-frequency PTA (HPTA) at 3000, 4000, 6000, and 8000 Hz. Differential HIV effects for LPTA and HPTA and better/worse ear were also examined. CD4+ and CD8+ T-cell counts, log10 plasma HIV RNA concentrations, receipt of AIDS diagnosis, and cumulative duration of antiretroviral therapy were included in the models for HIV+ participants only. RESULTS: HPTA and LPTA were significantly higher (18%: estimated ratio, 1.18 [95% CI, 1.02-1.36]; P = .02; and 12%: estimated ratio, 1.12 [95% CI, 1.00-1.26]; P = .05, respectively) for HIV+ participants compared with HIV- participants for the better ear. The direction of the effect was consistent across both the better and worse ears. There were no significant associations between HIV disease variables or treatment variables and LPTA or HPTA. CONCLUSIONS AND RELEVANCE: The HIV+ adults had significantly poorer lower-frequency and higher-frequency hearing than HIV- adults. High-frequency hearing loss is consistent with an accelerated aging (presbycusis); low-frequency hearing loss in middle age is unexpected. Because some vowels and consonants have predominantly low-frequency acoustic energy, poor low-frequency hearing may impair communication in HIV+ individuals. PMID- 25541678 TI - Biobased polyurethanes prepared from different vegetable oils. AB - In this study, a series of biobased polyols were prepared from olive, canola, grape seed, linseed, and castor oil using a novel, solvent/catalyst-free synthetic method. The biobased triglyceride oils were first oxidized into epoxidized vegetable oils with formic acid and hydrogen peroxide, followed by ring-opening reaction with castor oil fatty acid. The molecular structures of the polyols and the resulting polyurethane were characterized. The effects of cross linking density and the structures of polyols on the thermal, mechanical, and shape memory properties of the polyurethanes were also investigated. PMID- 25541679 TI - Anticoagulant complications in facial plastic and reconstructive surgery. AB - IMPORTANCE: The decision whether to discontinue antiplatelet and/or anticoagulant medications before a facial plastic surgical procedure is a complicated and multifactorial process that involves weighing the risk of perioperative thromboembolic complications with bleeding-related complications. OBJECTIVE: To determine the complication rates in patients who undergo a range of facial plastic surgical procedures while receiving antiplatelet and/or anticoagulation therapy. DESIGN, SETTING, AND PARTICIPANTS: A total of 9204 surgical procedures from January 1, 2007, through December 31, 2012, at an academic medical center and its affiliated surgical sites were analyzed, with patients who continued receiving antiplatelet and/or anticoagulation (aspirin, clopidogrel bisulphate, and warfarin sodium) therapy during the perioperative period identified and compared with a matched case-control group of patients who did not receive antiplatelet and/or anticoagulation therapy during this period. INTERVENTIONS: Facial plastic surgery procedures and perioperative management. MAIN OUTCOME AND MEASURES: Complication rates of wound healing (dehiscence or necrosis), infection, bleeding (hematoma or ecchymosis), and return to the operating room. RESULTS: Patients who received aspirin therapy at the time of surgery were not more likely to have a complication compared with control patients (odds ratio [95% CI], 0.73 [0.45-1.17]). Patients who received warfarin had increased perioperative bleeding (odds ratio [95% CI], 3.80 [1.15-12.60]) and postoperative infections (odds ratio [95% CI], 7.29 [1.17-45.40]) compared with control patients. Serious complications (flap necrosis, dehiscence, or return to the operating room) were not increased with warfarin use. CONCLUSIONS AND RELEVANCE: This study demonstrates that patients who undergo facial plastic surgery may continue taking antiplatelet and/or anticoagulation therapy during the perioperative period safely with minimal serious complications. LEVEL OF EVIDENCE: 3. PMID- 25541680 TI - Improving operative flow during pediatric airway evaluation: a quality improvement initiative. AB - IMPORTANCE: Microlaryngoscopy and bronchoscopy procedures (MLBs) are short duration, high-acuity procedures that carry risk. Poor case flow and communication exacerbate such potential risk. Efficient operative flow is critical for patient safety and resource expenditure. OBJECTIVES: To identify areas for improvement and evaluate the effectiveness of a multidisciplinary quality-improvement (QI) initiative. DESIGN, SETTING, AND PARTICIPANTS: A QI project using the "Plan-Do-Study-Act" (PDSA) cycle was implemented to assess MLBs performed on pediatric patients in a tertiary academic children's hospital. Forty MLBs were audited using a QI evaluation tool containing 144 fields. Each MLB was evaluated for flow, communication, and timing. Opportunities for improvement were identified. Subsequently, QI interventions were implemented in an iterative cycle, and 66 MLBs were audited after the intervention. INTERVENTIONS: Specific QI interventions addressed issues of personnel frequently exiting the operating room (OR) and poor preoperative preparation, identified during QI audit as areas for improvement. Interventions included (1) conducting "huddles" between surgeon and OR staff to discuss needed equipment; (2) implementing improvements to surgeon case ordering and preference cards review; (3) posting an OR door sign to limit traffic during airway procedures; and (4) discouraging personnel breaks during airway procedures. MAIN OUTCOMES AND MEASURES: Operating room exiting behavior of OR personnel, preoperative preparation, and case timing were assessed and compared before and after the QI intervention. RESULTS: Personnel exiting the OR during the MLB was identified as a preintervention issue, with the surgical technologist, circulator, or surgeon exiting the room in 55% of cases (n = 22). The surgical technologist and circulator left the room to retrieve equipment in 40% of cases (n = 16), which indicated the need for increased preoperative preparation to improve case timing and operative flow. The QI interventions implemented to address these concerns included education regarding break timing, improvements in communication, and improvements in ordering and preparation of equipment. After the QI intervention, the surgical technologist exiting rate decreased from 20% (n = 8) to 8% (n = 5), and the circulator exiting rate decreased from 38% (n = 15) to 27% (n = 17). In addition, the rate of surgeon exiting decreased significantly (from 25% [n = 10 of 40] to 9% [n = 6 of 66]) (P = .03). The surgical technologist and circulating nurse remaining in the room were significantly associated with decreased operating time (1.84-minute decrease for surgical technologist [P = .04] and 1.95-minute decrease for circulating nurse [P = .001]). CONCLUSIONS AND RELEVANCE: Gains were made in personnel exiting behavior and case timing after implementation of the QI interventions, potentially leading to decreased risk. This process is easily reproduced and is widely accepted by stakeholders. PMID- 25541681 TI - Asymptomatic retinal gumma. PMID- 25541682 TI - High levels of heterogeneity in the HIV cascade of care across different population subgroups in British Columbia, Canada. AB - BACKGROUND: The HIV cascade of care (cascade) is a comprehensive tool which identifies attrition along the HIV care continuum. We executed analyses to explicate heterogeneity in the cascade across key strata, as well as identify predictors of attrition across stages of the cascade. METHODS: Using linked individual-level data for the population of HIV-positive individuals in BC, we considered the 2011 calendar year, including individuals diagnosed at least 6 months prior, and excluding individuals that died or were lost to follow-up before January 1st, 2011. We defined five stages in the cascade framework: HIV 'diagnosed', 'linked' to care, 'retained' in care, 'on HAART' and virologically 'suppressed'. We stratified the cascade by sex, age, risk category, and regional health authority. Finally, multiple logistic regression models were built to predict attrition across each stage of the cascade, adjusting for stratification variables. RESULTS: We identified 7621 HIV diagnosed individuals during the study period; 80% were male and 5% were <30, 17% 30-39, 37% 40-49 and 40% were >= 50 years. Of these, 32% were MSM, 28% IDU, 8% MSM/IDU, 12% heterosexual, and 20% other. Overall, 85% of individuals 'on HAART' were 'suppressed'; however, this proportion ranged from 60%-93% in our various stratifications. Most individuals, in all subgroups, were lost between the stages: 'linked' to 'retained' and 'on HAART' to 'suppressed'. Subgroups with the highest attrition between these stages included females and individuals <30 years (regardless of transmission risk group). IDUs experienced the greatest attrition of all subgroups. Logistic regression results found extensive statistically significant heterogeneity in attrition across the cascade between subgroups and regional health authorities. CONCLUSIONS: We found that extensive heterogeneity in attrition existed across subgroups and regional health authorities along the HIV cascade of care in B.C., Canada. Our results provide critical information to optimize engagement in care and health service delivery. PMID- 25541683 TI - A procedure for a mechanical evaluation of an undefined osteo-protective material. AB - Falls represent a major care and cost problem to health and social services world widely, since 50% of falls result in an injury. In this work, is proposed a methodology to evaluate protective pads materials and geometry performance, in order to reduce impact results in a fall event. Since the material properties and the pad geometry are the key factors to make the protection possible when a fall event occurs, our approach relies on the use of mechanical tests to evaluate the properties of the material and in the study of the pad response during a fall. For this, were used compression, tensile and instrumented falling weight tests, that allow a fully characterization of the materials that can be employed in the protective pads. Likewise, to gather precise information on falls events, in order to study the pad response during a fall, a set of laboratory fall trials were created using a camera-less inertial motion capture (mocap) system. This allow the acquisition of dynamic information of falls, namely acceleration and velocity that can be used to create a finite element analysis (FEA) model, where different segments from the human body can be evaluated when the protective pad is associated to it. Through the proposed methodology, different materials and pad geometries can be studied towards maximizing the performance of protection pads for falls. The mocap system allows the acquisition of fall data, and also the creation of a human body geometrical model, representative of the fall. From the mechanical trials, was showed that the spacer fabric embedded with silicone has the higher ability to reduce the peak force in case of impact when compared with all the other specimens. The compression and the tensile tests allow the mechanical definition of the material, and with this the material definition on the FEA model. PMID- 25541684 TI - Comparison of long-term survival of patients with solitary large hepatocellular carcinoma of BCLC stage A after liver resection or transarterial chemoembolization: a propensity score analysis. AB - BACKGROUND: The aim of this study was to compare the long-term outcome of patients with a solitary large (> 5 cm) hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage A who received liver resection (LR) or transarterial chemoembolization (TACE). METHODS: Our study examined 128 patients treated by LR and 90 treated by TACE. To reduce bias in patient selection, we conducted propensity score analysis in the present study and 54 pairs of patients after propensity score matching were generated, their long-term survival was compared using the Kaplan-Meier method. Independent predictors of survival were identified by multivariate analysis. RESULTS: Long-term survival was significantly better for the LR group by log-rank test (P < 0.001). In multivariate analysis, tumor size, serum ALT level and TACE independently predicted survival. Despite similar baseline characteristics after propensity score matching, LR group still had significantly better survival (1 year, 68.5 vs. 55.0%; 3 years, 47.6 vs. 21.2%; 5 years, 41.3 vs. 18.5%; P = 0.007) than TACE group. The LR and TACE groups had comparable 30- and 90-day post-treatment mortality. Multivariate analysis showed that serum ALT level, serum AFP level and TACE independently predicted survival by multivariate analysis after propensity score matching. CONCLUSION: Our propensity-score-matched study suggested that LR provided significantly better long-term survival than TACE for a solitary large HCC of the BCLC stage A, regardless of tumor size. PMID- 25541686 TI - IDO1 and IDO2 non-synonymous gene variants: correlation with crohn's disease risk and clinical phenotype. AB - BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1) is one of the most over expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog) are important either as CD risk alleles or as modifiers of CD phenotype. METHODS: Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734) and non-IBD controls (n = 354) were genotyped for established IDO1 and IDO2 non synonymous single nucleotide polymorphisms (SNPs) and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T). RESULTS: IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS) and not linked to Crohn's disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohn's disease (p = 0.025). No IDO2 SNPs associated with a particular Crohn's disease clinical phenotype. CONCLUSIONS: This work highlights the functional importance of IDO enzymes in human Crohn's disease and establishes relative rates of IDO genetic variants in a US population. PMID- 25541687 TI - Network meta-analysis using R: a review of currently available automated packages. AB - Network meta-analysis (NMA)--a statistical technique that allows comparison of multiple treatments in the same meta-analysis simultaneously--has become increasingly popular in the medical literature in recent years. The statistical methodology underpinning this technique and software tools for implementing the methods are evolving. Both commercial and freely available statistical software packages have been developed to facilitate the statistical computations using NMA with varying degrees of functionality and ease of use. This paper aims to introduce the reader to three R packages, namely, gemtc, pcnetmeta, and netmeta, which are freely available software tools implemented in R. Each automates the process of performing NMA so that users can perform the analysis with minimal computational effort. We present, compare and contrast the availability and functionality of different important features of NMA in these three packages so that clinical investigators and researchers can determine which R packages to implement depending on their analysis needs. Four summary tables detailing (i) data input and network plotting, (ii) modeling options, (iii) assumption checking and diagnostic testing, and (iv) inference and reporting tools, are provided, along with an analysis of a previously published dataset to illustrate the outputs available from each package. We demonstrate that each of the three packages provides a useful set of tools, and combined provide users with nearly all functionality that might be desired when conducting a NMA. PMID- 25541688 TI - GLIMMPSE Lite: calculating power and sample size on smartphone devices. AB - Researchers seeking to develop complex statistical applications for mobile devices face a common set of difficult implementation issues. In this work, we discuss general solutions to the design challenges. We demonstrate the utility of the solutions for a free mobile application designed to provide power and sample size calculations for univariate, one-way analysis of variance (ANOVA), GLIMMPSE Lite. Our design decisions provide a guide for other scientists seeking to produce statistical software for mobile platforms. PMID- 25541689 TI - Switching of pyruvate kinase isoform L to M2 promotes metabolic reprogramming in hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is an aggressive tumor, with a high mortality rate due to late symptom presentation and frequent tumor recurrences and metastasis. It is also a rapidly growing tumor supported by different metabolic mechanisms; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are unclear. In this study, we found that pyruvate kinase M2 (PKM2) was frequently over-expressed in human HCCs and its over-expression was associated with aggressive clinicopathological features and poor prognosis of HCC patients. Furthermore, knockdown of PKM2 suppressed aerobic glycolysis and cell proliferation in HCC cell lines in vitro. Importantly, knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced lung metastasis in vivo. Of significance, PKM2 over expression in human HCCs was associated with a down-regulation of a liver specific microRNA, miR-122. We further showed that miR-122 interacted with the 3UTR of the PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed a novel biological mechanism involved in HCC metabolic reprogramming. PMID- 25541691 TI - High reproducibility of histological characterization by whole virtual slide quantification; an example using carotid plaque specimens. AB - OBJECTIVE: Tissue biobanks are an important source for discovery and validation studies aiming for new proteins that are causally related with disease development. There is an increasing demand for accurate and reproducible histological characterization, especially for subsequent analysis and interpretation of data in association studies. We assessed reproducibility of one semiquantative and two quantitative methods for histological tissue characterization. We introduce a new automated method for whole digital slide quantification. Carotid atherosclerotic plaques were used to test reproducibility. METHODS: 50 atherosclerotic plaques that were obtained during carotid endarterectomy were analysed. For the semiquantitative analysis, 6 different plaque characteristics were scored in categories by two independent observers, and Cohen's kappa was used to test intra- and interobserver reproducibility. The computer-aided method (assessed by two independent observers) and automated method were tested on CD68 (for macrophages) and alpha smooth muscle actin (for smooth muscle cells) stainings. Agreement for these two methods (done on a continuous scale) was assessed by intraclass correlation coefficients (ICCs). RESULTS: For the semiquantitative analysis, kappa values ranged from 0.55 to 0.69 for interobserver variability, and were slightly higher for intraobserver reproducibility in both observers. The computer-aided method yielded intra- and interobserver ICCs between 0.6 and 0.9. The new automated method performed most optimal regarding reproducibility, with ICCs ranging from 0.92 to 0.97. CONCLUSIONS: The analysis of performance of three methods for histological slide characterization on carotid atherosclerotic plaques showed high precision and agreement in repeated measurements for the automated method for whole digital slide quantification. We suggest that this method can fulfill the need for reproducible histological quantification. PMID- 25541690 TI - Insulin- and warts-dependent regulation of tracheal plasticity modulates systemic larval growth during hypoxia in Drosophila melanogaster. AB - Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability. PMID- 25541692 TI - Mechanical stress downregulates MHC class I expression on human cancer cell membrane. AB - In our body, cells are continuously exposed to physical forces that can regulate different cell functions such as cell proliferation, differentiation and death. In this work, we employed two different strategies to mechanically stress cancer cells. The cancer and healthy cell populations were treated either with mechanical stress delivered by a micropump (fabricated by deep X-ray nanolithography) or by ultrasound wave stimuli. A specific down-regulation of Major Histocompatibility Complex (MHC) class I molecules expression on cancer cell membrane compared to different kinds of healthy cells (fibroblasts, macrophages, dendritic and lymphocyte cells) was observed, stimulating the cells with forces in the range of nano-newton, and pressures between 1 and 10 bar (1 bar = 100.000 Pascal), depending on the devices used. Moreover, Raman spectroscopy analysis, after mechanical treatment, in the range between 700-1800 cm(-1), indicated a relative concentration variation of MHC class I. PCA analysis was also performed to distinguish control and stressed cells within different cell lines. These mechanical induced phenotypic changes increase the tumor immunogenicity, as revealed by the related increased susceptibility to Natural Killer (NK) cells cytotoxic recognition. PMID- 25541693 TI - Outcomes of bronchial artery embolization for life-threatening hemoptysis secondary to tuberculosis. AB - OBJECTIVE: To appraise the immediate and long-term outcomes of bronchial arterial embolization for life-threatening hemoptysis secondary to tuberculosis. METHODS: 112 patients with life-threatening hemoptysis due to tuberculosis underwent bronchial artery embolization from January 2004 to February 2014. Life threatening hemoptysis was defined as expectoration of at least 400 ml of blood in 24 hour. The median follow-up is 20 months, ranging from 2 to 52 months. RESULTS: The hemoptysis control rate was 86.6% at 14 days, 84.8% at 30 days, 78.6% at 240 days, 75.9% at 360 days, respectively. None of these characteristics, including gender, age and tuberculosis status, was significantly associated with immediate control of bleeding. Patients with active tuberculosis had a significantly longer recurrence-free duration than did patients with inactive tuberculosis (P = 0.040), which was further confirmed by Cox regression hazards model (P = 0.046). There was no spinal cord complication or mortality related to bronchial artery embolization. The most common complication was transient chest pain. CONCLUSION: Bronchial arterial embolization is an effective and safe technique in the management of life-threatening hemoptysis secondary to tuberculosis. Active tuberculosis may be associated with a lower rate of recurrence of hemoptysis. PMID- 25541694 TI - Evidence for the involvement of loosely bound plastosemiquinones in superoxide anion radical production in photosystem II. AB - Recent evidence has indicated the presence of novel plastoquinone-binding sites, QC and QD, in photosystem II (PSII). Here, we investigated the potential involvement of loosely bound plastosemiquinones in superoxide anion radical (O2-) formation in spinach PSII membranes using electron paramagnetic resonance (EPR) spin-trapping spectroscopy. Illumination of PSII membranes in the presence of the spin trap EMPO (5-(ethoxycarbonyl)-5-methyl-1-pyrroline N-oxide) resulted in the formation of O2-, which was monitored by the appearance of EMPO-OOH adduct EPR signal. Addition of exogenous short-chain plastoquinone to PSII membranes markedly enhanced the EMPO-OOH adduct EPR signal. Both in the unsupplemented and plastoquinone-supplemented PSII membranes, the EMPO-OOH adduct EPR signal was suppressed by 50% when the urea-type herbicide DCMU (3-(3,4-dichlorophenyl)-1,1 dimethylurea) was bound at the QB site. However, the EMPO-OOH adduct EPR signal was enhanced by binding of the phenolic-type herbicide dinoseb (2,4-dinitro-6-sec butylphenol) at the QD site. Both in the unsupplemented and plastoquinone supplemented PSII membranes, DCMU and dinoseb inhibited photoreduction of the high-potential form of cytochrome b559 (cyt b559). Based on these results, we propose that O2- is formed via the reduction of molecular oxygen by plastosemiquinones formed through one-electron reduction of plastoquinone at the QB site and one-electron oxidation of plastoquinol by cyt b559 at the QC site. On the contrary, the involvement of a plastosemiquinone formed via the one-electron oxidation of plastoquinol by cyt b559 at the QD site seems to be ambiguous. In spite of the fact that the existence of QC and QD sites is not generally accepted yet, the present study provided more spectroscopic data on the potential functional role of these new plastoquinone-binding sites. PMID- 25541695 TI - Performance of real-time elastography for the staging of hepatic fibrosis: a meta analysis. AB - BACKGROUND: With the rapid development of real-time elastography (RTE), a variety of measuring methods have been developed for the assessment of hepatic fibrosis. We evaluated the overall performance of four methods based on RTE by performing meta-analysis of published literature. METHODS: Online journal databases and a manual search from April 2000 to April 2014 were used. Studies from different databases that meet inclusion criteria were enrolled. The statistical analysis was performed using a random-effects model and fixed-effects model for the overall effectiveness of RTE. The area under the receiver operating characteristic curve (AUROC) was calculated for various means. Fagan plot analysis was used to estimate the clinical utility of RTE, and the heterogeneity of the studies was explored with meta-regression analysis. RESULTS: Thirteen studies from published articles were enrolled and analyzed. The combined AUROC of the liver fibrosis index (LFI) for the evaluation of significant fibrosis (F>=2), advanced fibrosis (F>=3), and cirrhosis (F = 4) were 0.79, 0.94, and 0.85, respectively. The AUROC of the elasticity index (EI) ranged from 0.75 to 0.92 for F>=2 and 0.66 to 0.85 for F = 4. The overall AUROC of the elastic ratio of the liver for the intrahepatic venous vessels were 0.94, 0.93, and 0.96, respectively. The AUROC of the elastic ratio of the liver for the intercostal muscle in diagnosing advanced fibrosis and cirrhosis were 0.96 and 0.92, respectively. There was significant heterogeneity in the diagnostic odds ratio (DOR) for F>=2 of LFI mainly due to etiology (p<0.01). CONCLUSION: The elastic ratio of the liver for the intrahepatic vein has excellent precision in differentiating each stage of hepatic fibrosis and is recommend to be applied to the clinic. PMID- 25541696 TI - Vascular endothelial growth factor genotypes and haplotypes contribute to the susceptibility of obstructive sleep apnea syndrome. AB - BACKGROUND: To investigate whether VEGF polymorphisms (-460 T/C, +405 G/C, and +936 C/T)/haplotypes influence the susceptibility of obstructive sleep apnea (OSA). METHOD: A prospective case-control study was conducted to evaluate the genetic effects of VEGF polymorphisms on the development of OSA. 150 patients and 225 healthy controls were recruited for this study and their genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression analysis. RESULT: Our study showed that the -460 C allele (C vs. T: OR = 1.95, 95% CI = 1.38-2.76) and +936 T allele (T vs. C: OR = 1.48, 95% CI = 1.02-2.15) were associated with an increased OSA risk, whereas +405 C allele was associated with a decreased susceptibility to OSA (C vs. G: OR = 0.61, 95% CI = 0.45-0.83). Compared with the most common haplotype CCT, CGC (OR = 2.22, 95% CI = 1.19-4.13) and TGC (OR = 3.83, 95% CI = 1.56-9.40) were associated with a significantly increased risk of OSA. CONCLUSION: These observations implied that VEGF gene polymorphisms might be associated with the susceptibility to OSA. These results need to be validated by other independent studies, especially in diverse ethnic populations. PMID- 25541697 TI - Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. AB - Mesenchymal stem/stromal cells (MSCs) are promising cell sources for regenerative therapies due to their multipotency and ready availability, but their application can be complicated by patient-specific factors like age or illness. MSCs have been investigated for the treatment of many musculoskeletal disorders, including osteoarthritis and osteoporosis. Due to the prevalence of these diseases in older populations, researchers have studied how aging affects MSC properties and have found that proliferation and differentiation potential are impaired. However, these effects have never been compared among MSCs isolated from multiple tissue sources in the same, healthy donor. Revealing differences in how MSCs are affected by age could help identify an optimal cell source for musculoskeletal therapies targeting older patients. MSCs were isolated from young and old rabbit bone marrow, muscle, and adipose tissue. Cell yield and viability were quantified after isolation procedures, and expansion properties were assessed using assays for proliferation, senescence, and colony formation. Multipotency was also examined using lineage-specific stains and spectrophotometry of metabolites. Results were compared between age groups and among MSC sources. Results showed that MSCs are differentially influenced by aging, with bone marrow-derived stem cells having impaired proliferation, senescence, and chondrogenic response, whereas muscle-derived stem cells and adipose-derived stem cells exhibited no negative effects. While age reduced overall cell yield and adipogenic potential of all MSC populations, osteogenesis and clonogenicity remained unchanged. These findings indicate the importance of age as a factor when designing cell-based therapies for older patients. PMID- 25541699 TI - The dynamic process of interspecific interactions of competitive nitrogen capture between intercropped wheat (Triticum aestivum L.) and Faba Bean (Vicia faba L.). AB - Wheat (Triticum aestivum L.)/faba bean (Vicia faba L.) intercropping shows significant overyielding and high nitrogen (N)-use efficiency, but the dynamics of plant interactions have rarely been estimated. The objective of the present study was to investigate the temporal dynamics of competitive N acquisition between intercropped wheat and faba bean with the logistic model. Wheat and faba bean were grown together or alone with limited N supply in pots. Data of shoot and root biomass and N content measured from 14 samplings were fitted to logistic models to determine instantaneous rates of growth and N uptake. The superiority of instantaneous biomass production and N uptake shifted from faba bean to wheat with their growth. Moreover, the shift of superiority on N uptake occurred 7-12 days earlier than that of biomass production. Interspecific competition stimulated intercropped wheat to have a much earlier and stronger superiority on instantaneous N uptake compared with isolated wheat. The modeling methodology characterized the temporal dynamics of biomass production and N uptake of intercropped wheat and faba bean in different planting systems, which helps to understand the underlying process of plant interaction for intercropping plants. PMID- 25541698 TI - Bladder cancer biomarker discovery using global metabolomic profiling of urine. AB - Bladder cancer (BCa) is a common malignancy worldwide and has a high probability of recurrence after initial diagnosis and treatment. As a result, recurrent surveillance, primarily involving repeated cystoscopies, is a critical component of post diagnosis patient management. Since cystoscopy is invasive, expensive and a possible deterrent to patient compliance with regular follow-up screening, new non-invasive technologies to aid in the detection of recurrent and/or primary bladder cancer are strongly needed. In this study, mass spectrometry based metabolomics was employed to identify biochemical signatures in human urine that differentiate bladder cancer from non-cancer controls. Over 1000 distinct compounds were measured including 587 named compounds of known chemical identity. Initial biomarker identification was conducted using a 332 subject sample set of retrospective urine samples (cohort 1), which included 66 BCa positive samples. A set of 25 candidate biomarkers was selected based on statistical significance, fold difference and metabolic pathway coverage. The 25 candidate biomarkers were tested against an independent urine sample set (cohort 2) using random forest analysis, with palmitoyl sphingomyelin, lactate, adenosine and succinate providing the strongest predictive power for differentiating cohort 2 cancer from non-cancer urines. Cohort 2 metabolite profiling revealed additional metabolites, including arachidonate, that were higher in cohort 2 cancer vs. non-cancer controls, but were below quantitation limits in the cohort 1 profiling. Metabolites related to lipid metabolism may be especially interesting biomarkers. The results suggest that urine metabolites may provide a much needed non-invasive adjunct diagnostic to cystoscopy for detection of bladder cancer and recurrent disease management. PMID- 25541700 TI - The mouse MC13 mutant is a novel ENU mutation in collagen type II, alpha 1. AB - Phenotype-driven mutagenesis experiments are a powerful approach to identifying novel alleles in a variety of contexts. The traditional disadvantage of this approach has been the subsequent task of identifying the affected locus in the mutants of interest. Recent advances in bioinformatics and sequencing have reduced the burden of cloning these ENU mutants. Here we report our experience with an ENU mutagenesis experiment and the rapid identification of a mutation in a previously known gene. A combination of mapping the mutation with a high density SNP panel and a candidate gene approach has identified a mutation in collagen type II, alpha I (Col2a1). Col2a1 has previously been studied in the mouse and our mutant phenotype closely resembles mutations made in the Col2a1 locus. PMID- 25541701 TI - Fourier transform infrared with attenuated total reflectance applied to the discrimination of freshwater planktonic coccoid green microalgae. AB - Despite the recent advances on fine taxonomic discrimination in microorganisms, namely using molecular biology tools, some groups remain particularly problematic. Fine taxonomy of green algae, a widely distributed group in freshwater ecosystems, remains a challenge, especially for coccoid forms. In this paper, we propose the use of the Fourier Transform Infrared (FTIR) spectroscopy as part of a polyphasic approach to identify and classify coccoid green microalgae (mainly order Sphaeropleales), using triplicated axenic cultures. The attenuated total reflectance (ATR) technique was tested to reproducibility of IR spectra of the biological material, a primary requirement to achieve good discrimination of microalgal strains. Spectral window selection was also tested, in conjunction with the first derivative treatment of spectra, to determine which regions of the spectrum provided better separation and clustering of strains. The non-metric multidimensional scaling (NMDS), analysis of similarities (ANOSIM) and hierarchical clusters (HCA), demonstrated a correct discrimination and classification of closely related strains of chlorophycean coccoid microalgae, with respect to currently accepted classifications. FTIR-ATR was highly reproducible, and provided an excellent discrimination at the strain level. The best separation was achieved by analyzing the spectral windows of 1500-1200 cm( 1) and 900-675 cm(-1), which differs from those used in previously studies for the discrimination of broad algal groups, and excluding spectral regions related to storage compounds, which were found to give poor discrimination. Furthermore, hierarchical cluster analyses have positioned the strains tested into clades correctly, reproducing their taxonomic orders and families. This study demonstrates that FTIR-ATR has great potential to complement classical approaches for fine taxonomy of coccoid green microalgae, though a careful spectrum region selection is needed. PMID- 25541702 TI - Genetic diversity and population structure in a legacy collection of spring barley landraces adapted to a wide range of climates. AB - Global environmental change and increasing human population emphasize the urgent need for higher yielding and better adapted crop plants. One strategy to achieve this aim is to exploit the wealth of so called landraces of crop species, representing diverse traditional domesticated populations of locally adapted genotypes. In this study, we investigated a comprehensive set of 1485 spring barley landraces (Lrc1485) adapted to a wide range of climates, which were selected from one of the largest genebanks worldwide. The landraces originated from 5 degrees to 62.5 degrees N and 16 degrees to 71 degrees E. The whole collection was genotyped using 42 SSR markers to assess the genetic diversity and population structure. With an average allelic richness of 5.74 and 372 alleles, Lrc1485 harbours considerably more genetic diversity than the most polymorphic current GWAS panel for barley. Ten major clusters defined most of the population structure based on geographical origin, row type of the ear and caryopsis type - and were assigned to specific climate zones. The legacy core reference set Lrc648 established in this study will provide a long-lasting resource and a very valuable tool for the scientific community. Lrc648 is best suited for multi environmental field testing to identify candidate genes underlying quantitative traits but also for allele mining approaches. PMID- 25541703 TI - Increased access to care and appropriateness of treatment at private sector drug shops with integrated management of malaria, pneumonia and diarrhoea: a quasi experimental study in Uganda. AB - INTRODUCTION: Drug shops are a major source of care for children in low income countries but they provide sub-standard care. We assessed the feasibility and effect on quality of care of introducing diagnostics and pre-packaged paediatric dosage drugs for malaria, pneumonia and diarrhoea at drug shops in Uganda. METHODS: We adopted and implemented the integrated community case management (iCCM) intervention within registered drug shops. Attendants were trained to perform malaria rapid diagnostic tests (RDTs) in each fever case and count respiratory rate in each case of cough with fast/difficult breathing, before dispensing recommended treatment. Using a quasi-experimental design in one intervention and one non-intervention district, we conducted before and after exit interviews for drug seller practices and household surveys for treatment seeking practices in May-June 2011 and May-June 2012. Survey adjusted generalized linear models and difference-in-difference analysis was used. RESULTS: 3759 (1604 before/2155 after) household interviews and 943 (163 before/780 after) exit interviews were conducted with caretakers of children under-5. At baseline, no child at a drug shop received any diagnostic testing before treatment in both districts. After the intervention, while no child in the non-intervention district received a diagnostic test, 87.7% (95% CI 79.0-96.4) of children with fever at the intervention district drug shops had a parasitological diagnosis of malaria, prior to treatment. The prevalence ratios of the effect of the intervention on treatment of cough and fast breathing with amoxicillin and diarrhoea with ORS/zinc at the drug shop were 2.8 (2.0-3.9), and 12.8 (4.2-38.6) respectively. From the household survey, the prevalence ratio of the intervention effect on use of RDTs was 3.2 (1.9-5.4); Artemisinin Combination Therapy for malaria was 0.74 (0.65-0.84), and ORS/zinc for diarrhoea was 2.3 (1.2-4.7). CONCLUSION: iCCM can be utilized to improve access and appropriateness of care for children at drug shops. PMID- 25541705 TI - Life table parameters of three Mirid Bug (Adelphocoris) species (Hemiptera: Miridae) under contrasted relative humidity regimes. AB - The genus Adelphocoris (Hemiptera: Miridae) is a group of important insect pests of Bt cotton in China. The three dominant species are A. lineolatus, A. suturalis, and A. fasciaticollis, and these species have different population dynamics. The causal factors for the differences in population dynamics have not been determined; one hypothesis is that humidity may be important for the growth of Adelphocoris populations. In the laboratory, the demographic parameters of the three Adelphocoris species were compared when the mirid bugs were subjected to various levels of relative humidity (40, 50, 60, 70 and 80% RH). Middle to high levels of RH (60, 70 and 80%) were associated with higher egg and nymph survival rates and increased adult longevity and female fecundity. Lower humidity levels (40 and 50% RH) had negative effects on the survival of nymphs, adult longevity and fecundity. The intrinsic rate of increase (rm), the net reproductive rate (R0) and the finite rate of increase (lambda) for each Adelphocoris species increased with increasing RH. Significant positive relationships were found between RH and the life table parameters, rm, R0 and lambda for the three Adelphocoris species. These results will help to better understand the phenology of the three Adelphocoris species, and the information can be used in population growth models to optimize pest forecasting and management strategies for these key pests. PMID- 25541704 TI - Endothelial protein C receptor gene variants not associated with severe malaria in ghanaian children. AB - BACKGROUND: Two recent reports have identified the Endothelial Protein C Receptor (EPCR) as a key molecule implicated in severe malaria pathology. First, it was shown that EPCR in the human microvasculature mediates sequestration of Plasmodium falciparum-infected erythrocytes. Second, microvascular thrombosis, one of the major processes causing cerebral malaria, was linked to a reduction in EPCR expression in cerebral endothelial layers. It was speculated that genetic variation affecting EPCR functionality could influence susceptibility to severe malaria phenotypes, rendering PROCR, the gene encoding EPCR, a promising candidate for an association study. METHODS: Here, we performed an association study including high-resolution variant discovery of rare and frequent genetic variants in the PROCR gene. The study group, which previously has proven to be a valuable tool for studying the genetics of malaria, comprised 1,905 severe malaria cases aged 1-156 months and 1,866 apparently healthy children aged 2-161 months from the Ashanti Region in Ghana, West Africa, where malaria is highly endemic. Association of genetic variation with severe malaria phenotypes was examined on the basis of single variants, reconstructed haplotypes, and rare variant analyses. RESULTS: A total of 41 genetic variants were detected in regulatory and coding regions of PROCR, 17 of which were previously unknown genetic variants. In association tests, none of the single variants, haplotypes or rare variants showed evidence for an association with severe malaria, cerebral malaria, or severe malaria anemia. CONCLUSION: Here we present the first analysis of genetic variation in the PROCR gene in the context of severe malaria in African subjects and show that genetic variation in the PROCR gene in our study population does not influence susceptibility to major severe malaria phenotypes. PMID- 25541706 TI - A comparison between ultraviolet disinfection and copper alginate beads within a vortex bioreactor for the deactivation of bacteria in simulated waste streams with high levels of colour, humic acid and suspended solids. AB - We show in this study that the combination of a swirl flow reactor and an antimicrobial agent (in this case copper alginate beads) is a promising technique for the remediation of contaminated water in waste streams recalcitrant to UV-C treatment. This is demonstrated by comparing the viability of both common and UV C resistant organisms in operating conditions where UV-C proves ineffective - notably high levels of solids and compounds which deflect UV-C. The swirl flow reactor is easy to construct from commonly available plumbing parts and may prove a versatile and powerful tool in waste water treatment in developing countries. PMID- 25541707 TI - Antiretroviral treatment program retention among HIV-infected children in the Democratic Republic of Congo. AB - BACKGROUND: Retaining patients with HIV infection in care is still a major challenge in sub- Saharan Africa, particularly in the Democratic Republic of Congo (DRC) where the antiretroviral treatment (ART) coverage is low. Monitoring retention is an important tool for evaluating the quality of care. METHODS AND FINDINGS: A review of medical records of HIV-infected children was performed in three health facilities in the DRC: the Amo-Congo Health center, the Monkole Clinic in Kinshasa, and the HEAL Africa Clinic in Goma. Medical records of 720 children were included. Kaplan Meier curves were constructed with the probability of retention at 6 months, 1 year, 2 years and 3 years. Retention rates were: 88.2% (95% CI: 85.1%-90.8%) at 6 months; 85% (95% CI: 81.5%-87.6%) at one year; 79.4% (95%CI: 75.5%-82.8%) at two years and 74.7% (95% CI: 70.5%-78.5%) at 3 years. The retention varied across study sites: 88.2%, 66.6% and 92.5% at 6 months; 84%, 59% and 90% at 12 months and 75.7%, 56.3% and 85.8% at 24 months respectively for Amo-Congo/Kasavubu, Monkole facility and HEAL Africa. After multivariable Cox regression four variables remained independently associated with attrition: study site, CD4 cell count <350 cells/uL, children younger than 2 years and children whose caregivers were member of an independent church. CONCLUSIONS: Attrition remains a challenge for pediatric HIV positive patients in ART programs in DRC. In addition, the low coverage of pediatric treatment exacerbates the situation of pediatric HIV/AIDS. PMID- 25541708 TI - Statin use and cognitive function: population-based observational study with long term follow-up. AB - We aimed to evaluate the association between statin use and cognitive function. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0; best score, 175 points) and the Visual Association Test (VAT; low performance, 0-10; high performance, 11-12 points) in an observational study that included 4,095 community-dwelling participants aged 35-82 years. Data on statin use were obtained from a computerized pharmacy database. Analysis were done for the total cohort and subsamples matched on cardiovascular risk (N = 1232) or propensity score for statin use (N = 3609). We found that a total of 904 participants (10%) used a statin. Statin users were older than non-users: mean age (SD) 61 (10) vs. 52 (11) years (p<0.001). The median duration of statin use was 3.8 (interquartile range, 1.6-4.5) years. Unadjusted, statin users had worse cognitive performance than non-users. The mean RFFT score (SD) in statin users and non-users was 58 (23) and 72 (26) points, respectively (p<0.001). VAT performance was high in 261 (29%) statin users and 1351 (43%) non-users (p<0.001). However, multiple regression analysis did not show a significant association of RFFT score with statin use (B, -0.82; 95%CI, -2.77 to 1.14; p = 0.41) nor with statin solubility, statin dose or duration of statin use. Statin users with high doses or long-term use had similar cognitive performance as non users. This was found in persons with low as well as high cardiovascular risk, and in younger as well as older subjects. Also, the mean RFFT score per quintile of propensity score for statin use was comparable for statin users and non-users. Similar results were found for the VAT score as outcome measure. In conclusion, statin use was not associated with cognitive function. This was independent of statin dose or duration of statin use. PMID- 25541709 TI - Progressive decrease in the potential usefulness of meningococcal serogroup B vaccine (4CMenB, Bexsero(r)) in Gipuzkoa, Northern Spain. AB - The effectiveness of a vaccine is determined not only by the immunogenicity of its components, but especially by how widely it covers the disease-causing strains circulating in a given region. Because vaccine coverage varies over time, this study aimed to detect possible changes that could affect vaccine protection during a specific period in a southern European region. The 4CMenB vaccine is licensed for use in Europe, Canada, and Australia and is mainly directed against Neisseria meningitidis serogroup B. This vaccine contains four main immunogenic components: three recombinant proteins, FHbp, Nhba and NadA, and an outer membrane vesicle [PorA P1.4]. The allelic distribution of FHbp, Nhba, NadA, and PorA antigens in 82 invasive isolates (B and non-B serogroups) isolated from January 2008 to December 2013 were analyzed. 4CMenB was likely protective against 61.8% and 50% of serogroup B and non-B meningococci, respectively, in the entire period, but between 2012 and 2013, the predicted protection fell below 45% (42.1% for serogroup B isolates).The observed decreasing trend in the predicted protection during the 6 years of the study (Chi2 for trend = 4.68, p = 0.03) coincided with a progressive decrease of several clonal complexes (e.g., cc11, cc32 and cc41/44), which had one or more antigens against which the vaccine would offer protection. PMID- 25541710 TI - Four dimensional digital tomosynthesis using on-board imager for the verification of respiratory motion. AB - PURPOSE: To evaluate respiratory motion of a patient by generating four dimensional digital tomosynthesis (4D DTS), extracting respiratory signal from patients' on-board projection data, and ensuring the feasibility of 4D DTS as a localization tool for the targets which have respiratory movement. METHODS AND MATERIALS: Four patients with lung and liver cancer were included to verify the feasibility of 4D-DTS with an on-board imager. CBCT acquisition (650-670 projections) was used to reconstruct 4D DTS images and the breath signal of the patients was generated by extracting the motion of diaphragm during data acquisition. Based on the extracted signal, the projection data was divided into four phases: peak-exhale phase, mid-inhale phase, peak-inhale phase, and mid exhale phase. The binned projection data was then used to generate 4D DTS, where the total scan angle was assigned as +/-22.5 degrees from rotation center, centered on 0 degrees and 180 degrees for coronal "half-fan" 4D DTS, and 90 degrees and 270 degrees for sagittal "half-fan" 4D DTS. The result was then compared with 4D CBCT which we have also generated with the same phase distribution. RESULTS: The motion of the diaphragm was evident from the 4D DTS results for peak-exhale, mid-inhale, peak-inhale and mid-exhale phase assignment which was absent in 3D DTS. Compared to the result of 4D CBCT, the view aliasing effect due to arbitrary angle reconstruction was less severe. In addition, the severity of metal artifacts, the image distortion due to presence of metal, was less than that of the 4D CBCT results. CONCLUSION: We have implemented on-board 4D DTS on patients data to visualize the movement of anatomy due to respiratory motion. The results indicate that 4D-DTS could be a promising alternative to 4D CBCT for acquiring the respiratory motion of internal organs just prior to radiotherapy treatment. PMID- 25541711 TI - Molecular analysis of Acinetobacter baumannii strains isolated in Lebanon using four different typing methods. AB - This study analyzed 42 Acinetobacter baumannii strains collected between 2009 2012 from different hospitals in Beyrouth and North Lebanon to better understand the epidemiology and carbapenem resistance mechanisms in our collection and to compare the robustness of pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), repetitive sequence-based PCR (rep-PCR) and blaOXA-51 sequence-based typing (SBT). Among 31 carbapenem resistant strains, we have detected three carbapenem resistance genes: 28 carried the blaOXA-23 gene, 1 the blaOXA-24 gene and 2 strains the blaOXA-58 gene. This is the first detection of blaOXA-23 and blaOXA-24 in Lebanon. PFGE identified 11 types and was the most discriminating technique followed by rep-PCR (9 types), blaOXA-51 SBT (8 types) and MLST (7 types). The PFGE type A'/ST2 was the dominant genotype in our collection present in Beyrouth and North Lebanon. The clustering agreement between all techniques was measured by adjust Wallace coefficient. An overall agreement has been demonstrated. High values of adjust Wallace coefficient were found with followed combinations: PFGE to predict MLST types = 100%, PFGE to predict blaOXA-51 SBT = 100%, blaOXA-51 SBT to predict MLST = 100%, MLST to predict blaOXA-51 SBT = 84.7%, rep-PCR to predict MLST = 81.5%, PFGE to predict rep-PCR = 69% and rep-PCR to predict blaOXA-51 SBT = 67.2%. PFGE and MLST are gold standard methods for outbreaks investigation and population structure studies respectively. Otherwise, these two techniques are technically, time and cost demanding. We recommend the use of blaOXA-51 SBT as first typing method to screen isolates and assign them to their corresponding clonal lineages. Repetitive sequence-based PCR is a rapid tool to access outbreaks but careful interpretation of results must be always performed. PMID- 25541712 TI - Psoriasis and the risk of pneumonia: a population-based study. AB - BACKGROUND: Psoriasis is a prevalent autoimmune disorder. Various studies have reported on the relationship between psoriasis and chronic diseases but very few have explored the association between psoriasis and subsequent acute infection. This retrospective cohort study aimed to compare the risk of pneumonia between subjects with and those without psoriasis. METHODS: The medical records of 14,022 patients with psoriasis and 14,022 without psoriasis were obtained from the Taiwan Longitudinal Health Insurance Database 2000. Each patient was followed-up for a three-year period. Cox proportional hazard regressions were performed to compare difference of subsequent pneumonia incidence between subjects with and those without psoriasis. RESULTS: There were 206 (1.47%) subjects with psoriasis and 138 (0.98%) without psoriasis hospitalized for pneumonia. By Cox proportional hazard regressions analysis, the HR (hazard ratio) of pneumonia requiring hospitalization for patients with psoriasis was 1.50 (95% confidence interval [CI]: 1.21-1.86) compared to patients without psoriasis. The adjusted HR was 1.40 (95% CI: 1.12-1.73). The adjusted HR of pneumonia hospitalization for subjects with mild and severe psoriasis was 1.36 (95% CI: 1.09-1.70) and 1.68 (95% CI: 1.12-2.52), respectively, compared to those without psoriasis. CONCLUSIONS: Patients with psoriasis have significantly higher incidence of pneumonia compared to those without psoriasis. PMID- 25541713 TI - Glycyrrhizin suppresses the expressions of HMGB1 and relieves the severity of traumatic pancreatitis in rats. AB - BACKGROUND: High mobility group box 1 (HMGB1) plays important roles in a large variety of diseases; glycyrrhizin (GL) is recognized as an HMGB1 inhibitor. However, few studies have focused on whether glycyrrhizin can potentially improve the outcome of traumatic pancreatitis (TP) by inhibiting HMGB1. METHODS: A total of 60 male Wistar rats were randomly divided into three groups (n = 20 in each): Control group, TP group and TP-GL group. Pancreatic trauma was established with a custom-made biological impact machine-III, and GL was administered at 15 minutes after the accomplishment of operation. To determine survival rates during the first 7 days after injury, another 60 rats (n = 20 in each) were grouped and treated as mentioned above. At 24 hours of induction of TP, the histopathological changes in pancreas were evaluated and serum amylase levels were tested. Serum tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and HMGB1 were measured using enzyme linked immunosorbent assay. HMGB1 expressions in pancreas were measured using immunohistochemical staining, Western blot and Real-Time PCR analysis. RESULTS: Serum levels of HMGB1, TNF-alpha and IL-6 were increased dramatically in TP group at 24 hours after induction of TP. However, these indicators were reduced significantly by GL administration in TP-GL group comparing with TP group (P < 0.05). Meanwhile, survival analysis showed that the seven-day survival rate in TP-GL group was significantly higher than that in TP group (85% versus 65%, P < 0.05). GL treatment significantly decreased the pancreatic protein and mRNA expressions of HMGB1 and ameliorated the pancreatic injury in rats with TP. CONCLUSIONS: Glycyrrhizin might play an important role in improving survival rates and ameliorating pancreatic injury of TP by suppression of the expressions of HMGB1 and other proinflammatory cytokine. PMID- 25541714 TI - I-FABP as biomarker for the early diagnosis of acute mesenteric ischemia and resultant lung injury. AB - Acute mesenteric ischemia (AMI) is a life-threatening condition that can result in multiple organ injury and death. A timely diagnosis and treatment would have a significant impact on the morbidity and mortality in high-risk patient population. The purpose of this study was to investigate if intestinal fatty acid binding protein (I-FABP) and alpha-defensins can be used as biomarkers for early AMI and resultant lung injury. C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery. A time course of intestinal ischemia from 0.5 to 3 h was performed and followed by reperfusion for 2 h. Additional mice were treated with N-acetyl-cysteine (NAC) at 300 mg/kg given intraperitoneally prior to reperfusion. AMI resulted in severe intestinal injury characterized by neutrophil infiltrate, myeloperoxidase (MPO) levels, cytokine/chemokine levels, and tissue histopathology. Pathologic signs of ischemia were evident at 1 h, and by 3 h of ischemia, the full thickness of the intestine mucosa had areas of coagulative necrosis. It was noted that the levels of alpha-defensins in intestinal tissue peaked at 1 h and I-FABP in plasma peaked at 3 h after AMI. Intestinal ischemia also resulted in lung injury in a time dependent manner. Pretreatment with NAC decreased the levels of intestinal alpha defensins and plasma I-FABP, as well as lung MPO and cytokines. In summary, the concentrations of intestinal alpha-defensins and plasma I-FABP predicted intestinal ischemia prior to pathological evidence of ischemia and I-FABP directly correlated with resultant lung injury. The antioxidant NAC reduced intestinal and lung injury induced by AMI, suggesting a role for oxidants in the mechanism for distant organ injury. I-FABP and alpha-defensins are promising biomarkers, and may guide the treatment with antioxidant in early intestinal and distal organ injury. PMID- 25541715 TI - CREB targets define the gene expression signature of malignancies having reduced levels of the tumor suppressor tristetraprolin. AB - The RNA-binding protein Tristetraprolin (TTP, ZFP36) functions as a tumor suppressor that impairs the development and disables the maintenance of MYC driven lymphoma. In addition, other human cancers expressed reduced levels of TTP, suggesting that it may function as a tumor suppressor in several malignancies. To identify genes that may be associated with TTP tumor suppressor functions in human cancer, we analyzed The Cancer Genome Atlas (TCGA) breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, and colon adenocarcinoma datasets. These analyses defined a signature of 50 genes differentially regulated between high and low TTP-expressing tumors. Notably, patients with low TTP-expressing breast cancer and lung adenocarcinoma had decreased survival rates and more aggressive tumors with increased necrosis. In addition, analysis across non-TCGA tumor gene expression databases identified a broad spectrum of human cancers having similarities with the TTP-low tumor gene signature, including pancreatic, bladder, and prostate cancer. TTP has documented roles in regulating mRNAs encoding inflammatory proteins, and pathway analysis identified several inflammatory pathways that are altered in tumors with low TTP expression. Surprisingly, the TTP-low tumor gene signature includes a core component of 20 under-expressed CREB target genes, suggesting that the regulation of CREB activity may be related to the tumor suppressor function of TTP. Thus, reduced levels of TTP are a potential biomarker for human cancers with poor outcome, and targeting the CREB pathway may be a therapeutic route for treating aggressive TTP-low tumors. PMID- 25541717 TI - The accuracy of spot sign in predicting hematoma expansion after intracerebral hemorrhage: a systematic review and meta-analysis. AB - PURPOSE: The role of spot sign on computed tomography angiography (CTA) for predicting hematoma expansion (HE) after primary intracerebral hemorrhage (ICH) has been the focus of many studies. Our study sought to evaluate the predictive accuracy of spot signs for HE in a meta-analytic approach. MATERIALS AND METHODS: The database of Pubmed, Embase, and the Cochrane Library were searched for eligible studies. Researches were included if they reported data on HE in primary ICH patients, assessed by spot sign on first-pass CTA. Studies with additional data of second-pass CTA, post-contrast CT (PCCT) and CT perfusion (CTP) were also included. RESULTS: 18 studies were pooled into the meta-analysis, including 14 studies of first-pass CTA, and 7 studies of combined CT modalities. In evaluating the accuracy of spot sign for predicting HE, studies of first-pass CTA showed that the sensitivity was 53% (95% CI, 49%-57%) with a specificity of 88% (95% CI, 86%-89%). The pooled positive likelihood ratio (PLR) was 4.70 (95% CI, 3.28-6.74) and the negative likelihood ratio (NLR) was 0.44 (95% CI, 0.34-0.58). For studies of combined CT modalities, the sensitivity was 73% (95% CI, 67%-79%) with a specificity of 88% (95% CI, 86%-90%). The aggregated PLR was 6.76 (95% CI, 3.70 12.34) and the overall NLR was 0.17 (95% CI 0.06-0.48). CONCLUSIONS: Spot signs appeared to be a reliable imaging biomarker for HE. The additional detection of delayed spot sign was helpful in improving the predictive accuracy of early spot signs. Awareness of our results may impact the primary ICH care by providing supportive evidence for the use of combined CT modalities in detecting spot signs. PMID- 25541716 TI - The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120. AB - GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids. PMID- 25541718 TI - First reported chikungunya fever outbreak in the republic of Congo, 2011. AB - BACKGROUND: Chikungunya is an Aedes -borne disease characterised by febrile arthralgia and responsible for massive outbreaks. We present a prospective clinical cohort study and a retrospective serological study relating to a CHIK outbreak, in the Republic of Congo in 2011. METHODOLOGY AND FINDINGS: We analysed 317 suspected cases, of which 308 (97.2%) lived in the city of Brazzaville (66.6% in the South area). Amongst them, 37 (11.7%) were CHIKV+ve patients (i.e., biologically confirmed by a real-time RT-PCR assay), of whom 36 (97.3%) had fever, 22 (66.7%) myalgia and 32 (86.5%) arthralgia. All tested negative for dengue. The distribution of incident cases within Brazzaville districts was compared with CHIKV seroprevalence before the outbreak (34.4% in 517 blood donors), providing evidence for previous circulation of CHIKV. We applied a CHIK clinical score to 126 patients recruited within the two first day of illness (including 28 CHIKV+ves (22.2%)) with sensitivity (78.6%) and specificity (72.4%) values comparing with those of the referent study in Reunion Island. The negative predictive value was high (92%), but the positive predictive value (45%) indicate poor potential contribution to medical practice to identify CHIKV+ve patients in low prevalence outbreaks. However, the score allowed a slightly more accurate follow-up of the evolution of the outbreak than the criterion "fever+arthralgia". The complete sequencing of a Congolase isolate (Brazza_MRS1) demonstrated belonging to the East/Central/South African lineage and was further used for producing a robust genome-scale CHIKV phylogenetic analysis. CONCLUSIONS/SIGNIFICANCE: We describe the first Chikungunya outbreak declared in the Republic of Congo. The seroprevalence study conducted amongst blood donors before outbreak provided evidence for previous CHIKV circulation. We suggest that a more systematic survey of the entomological situation and of arbovirus circulation is necessary in Central Africa for better understanding the environmental, microbiological and sociological determinants of emergence. PMID- 25541720 TI - The evolution of heterogeneities altered by mutational robustness, gene expression noise and bottlenecks in gene regulatory networks. AB - Intra-population heterogeneity is commonly observed in natural and cellular populations and has profound influence on their evolution. For example, intra tumor heterogeneity is prevalent in most tumor types and can result in the failure of tumor therapy. However, the evolutionary process of heterogeneity remains poorly characterized at both genotypic and phenotypic level. Here we study the evolution of intra-population heterogeneities of gene regulatory networks (GRN), in particular mutational robustness and gene expression noise as contributors to the development of heterogeneities. By in silico simulations, it was found that the impact of these factors on GRN can, under certain conditions, promote phenotypic heterogeneity. We also studied the effect of population bottlenecks on the evolution of GRN. When the GRN population passes through such bottlenecks, neither mutational robustness nor population fitness was observed to be substantially altered. Interestingly, however, we did detect a significant increase in the number of potential "generator" genes which can substantially induce population fitness, when stimulated by mutational hits. PMID- 25541719 TI - Mining CK2 in cancer. AB - Cancer is a leading cause of death worldwide. Cancer cells proliferate uncontrollably and, many cases, spread to other parts of the body. A protein historically involved in cancer is protein kinase CK2. CK2 is a serine-threonine kinase that has been involved in cell growth, cell proliferation and cell apoptosis. CK2 functions as an oncogene when overexpressed in mouse tissues, and can synergize with known oncogenes, such as ras, to induce cell transformation in cells in culture. CK2, typically the CK2alpha protein, is found elevated in a number of human tumors. However, we have little information on CK2alpha' and CK2beta proteins, and scarce information on CK2 gene transcript expression. Here, we explore the expression of CK2 transcripts in primary tumor tissues using the database Oncomine in the six cancers with the highest mortality in the U.S.A. In addition, we studied the correlation between CK2 expression and overall survival using the Kaplan-Meier Plotter database in breast, ovarian, and lung cancers. We found widespread upregulation in the expression of CK2 genes in primary tumor tissues. However, we found underexpression of CK2alpha' transcripts in some tumors, increased CK2beta transcripts in some invasive tumors, and deregulation of CK2 transcripts in some tumor precursors. There was also correlation between CK2 expression levels and patient survival. These data provides additional evidence for CK2 as a biomarker for cancer studies and as a target for cancer therapy. PMID- 25541721 TI - Field trial evaluation of the performances of point-of-care tests for screening G6PD deficiency in Cambodia. AB - BACKGROUND: User-friendly, accurate, point-of-care rapid tests to detect glucose 6-phosphate dehydrogenase deficiency (G6PDd) are urgently needed at peripheral level to safely recommend primaquine for malaria elimination. METHODS: The CareStart G6PD RDT (AccessBio, New Jersey, USA), a novel rapid diagnostic test and the most commonly used test, the fluorescent spot test (FST) were assessed against the quantitatively measured G6PD enzyme activity for detecting G6PDd. Subjects were healthy males and non-pregnant females aged 18 years or older residing in six villages in Pailin Province, western Cambodia. FINDINGS: Of the 938 subjects recruited, 74 (7.9%) were severe and moderately severe G6PD deficient (enzyme activity <30%), mostly in male population; population median G6PD activity was 12.0 UI/g Hb. The performances of the CareStart G6PD RDT and the FST, according to different cut-off values used to define G6PDd were very similar. For the detection of severe and moderately severe G6PDd (enzyme activity < 30%, < 3.6 UI/g Hb) in males and females, sensitivity and negative (normal status) predictive value were 100% for both point-of-care tools. When the G6PDd cut-off value increased (from < 40% to < 60%), the sensitivity for both PoCs decreased: 93.3% to 71.7% (CareStart G6PD RDT, p = 10(-6)) and 95.5% to 73.2% (FST, p = 10(-6)) while the specificity for both PoCs remained similar: 97.4% to 98.3% (CareStart G6PD RDT, p = 0.23) and 98.7% to 99.6% (FST, p = 0.06). The cut off values for classifying individuals as normal were 4.0 UI/g Hb and 4.3 UI/g Hb for the CareStart G6PD RDT and the FST, respectively. CONCLUSIONS: The CareStart G6PD RDT reliably detected moderate and severe G6PD deficient individuals (enzyme activity <30%), suggesting that this novel point-of-care is a promising tool for tailoring appropriate primaquine treatment for malaria elimination by excluding individuals with severe G6PDd for primaquine treatment. PMID- 25541722 TI - Gender matters: the relationship between social anxiety and alcohol-related consequences. AB - BACKGROUND AND OBJECTIVES: Identification of risk factors for alcohol-related consequences is an important public health concern. Both gender and social anxiety have been associated with alcohol-related consequences broadly, but it is unknown whether these variables are differentially related to specific types of alcohol-related consequences for American college students. METHODS: In the present study, 573 undergraduate students (M(age) = 19.86 years, SD = 1.40; range 18 to 25; 68.9% female) completed an on-line assessment of social anxiety, alcohol use, and four types of alcohol-related consequences (personal, social, physical, and role). Poisson regressions were run to examine social anxiety, gender, and the interaction between social anxiety and gender as predictors of each type of alcohol-related consequences. RESULTS: After controlling for alcohol use, social anxiety was positively associated with all four types of consequences, and females endorsed higher rates of physical, personal, and role consequences. The interaction between social anxiety and gender was statistically significant only for physical consequences, with social anxiety having a stronger effect for males. DISCUSSION AND CONCLUSIONS: These findings, which diverge somewhat from those of a prior study with Australian college students, are discussed in the context of a biopsychosocial model of social anxiety and substance use problems. SCIENTIFIC SIGNIFICANCE: This study highlights the importance of further investigating cultural differences in the relationships among social anxiety, gender, and alcohol-related consequences. PMID- 25541724 TI - Light dulls and darkens bird eggs. AB - Although egg color is generally consistent within individual birds and robust to environmental variation, recent evidence suggests a degree of susceptibility to environmental perturbation or modulation of egg color. Most of this variation manifests via the physiology of the laying female, but some direct impacts of the environment on laid eggs have also been discovered. Here we test whether light changes bird egg color and we quantify its effect, by subjecting variable blue green eggs of Ruppell's weaver (Ploceus galbula) to a broad-spectrum light source under laboratory conditions, and measuring egg reflectance every few hours. Eggshells gradually decreased in reflectance across the entire measured wavelength spectrum of 250-800 nm. Reflectance peaks were disproportionately affected, such that the height decreased of both the blue-green peak and the smaller UV peak typical of blue-green eggs. The reflectance of lighter eggs was affected slightly more than that of darker eggs. These changes are similar to previous results for changes over long periods of time in darkness, suggesting that light might hasten the same process of pigment degradation that proceeds even without light. Comparison between the experimental light source and both sunlight and typical artificial lighting situations raises the possibility that significant color change might occur during incubation in some birds, but indicates that eggshell illumination in museums for short periods of study is unlikely to affect their color to a detectable extent. Additional research should be performed on eggs of other species and in other light environments, with an eye to an eventual generalized model of the effect of light on eggshell color. PMID- 25541723 TI - Molecular, physiological and biochemical responses of Theobroma cacao L. genotypes to soil water deficit. AB - Six months-old seminal plants of 36 cacao genotypes grown under greenhouse conditions were subjected to two soil water regimes (control and drought) to assess, the effects of water deficit on growth, chemical composition and oxidative stress. In the control, soil moisture was maintained near field capacity with leaf water potentials (PsiWL) ranging from -0.1 to -0.5 MPa. In the drought treatment, the soil moisture was reduced gradually by withholding additional water until PsiWL reached values of between -2.0 to -2.5 MPa. The tolerant genotypes PS-1319, MO-20 and MA-15 recorded significant increases in guaiacol peroxidase activity reflecting a more efficient antioxidant metabolism. In relation to drought tolerance, the most important variables in the distinguishing contrasting groups were: total leaf area per plant; leaf, stem and total dry biomass; relative growth rate; plant shoot biomass and leaf content of N, Ca, and Mg. From the results of these analyses, six genotypes were selected with contrasting characteristics for tolerance to soil water deficit [CC-40, C. SUL-4 and SIC-2 (non-tolerant) and MA-15, MO-20, and PA-13 (tolerant)] for further assessment of the expression of genes NCED5, PP2C, psbA and psbO to water deficit. Increased expression of NCED5, PP2C, psbA and psbO genes were found for non-tolerant genotypes, while in the majority of tolerant genotypes there was repression of these genes, with the exception of PA-13 that showed an increased expression of psbA. Mutivariate analysis showed that growth variables, leaf and total dry biomass, relative growth rate as well as Mg content of the leaves were the most important factor in the classification of the genotypes as tolerant, moderately tolerant and sensitive to water deficit. Therefore these variables are reliable plant traits in the selection of plants tolerant to drought. PMID- 25541725 TI - Effects of N-acetylcysteine on human ovarian tissue preservation undergoing cryopreservation procedure. AB - The aim of the study was to evaluate the effects of the antioxidant N acetylcysteine (NAC), added in freezing/thawing solutions, on reactive oxygen species (RRS) levels and on ovarian tissue preservation after cryopreservation. Ovarian samples from 10 subjects suffering from cancer diseases were cryopreserved using the slow freezing/rapid thawing standard protocol without or with NAC supplementation. RRS levels produced during cryopreservation were monitored by electron paramagnetic resonance (EPR) spectroscopy. The preservation of fresh ovarian tissue (t0), thawed tissue (t1 and t1 NAC) and thawed tissue maintained at 4 degrees C for 2 hrs (t2 and t2 NAC) was analysed by light microscopy, transmission electron microscopy, Ki67 immunohistochemical and TUNEL analysis. It was possible to design a maximum peak for RRS production at t1, which slightly decreased at t2. NAC reduced the extent of RRS levels in cryopreserved ovarian tissues if compared with non-supplemented ones, although not restoring RRS production to baseline values. Comparative analysis between the two cryopreservation protocols showed that a better preservation of morphological characteristics, proliferation index and DNA integrity of ovarian tissue was obtained using NAC and no differences between t1NAC and t2NAC were observed. The employment of NAC during cryopreservation procedure could be an useful strategy for preserving the function of endogenous cellular systems. Nevertheless, further studies on the viability of thawed ovarian tissue are needed to support the feasibility of this approach in clinical settings. PMID- 25541726 TI - Vaccinating sons against HPV: results from a U.S. national survey of parents. AB - PURPOSE: The quadrivalent HPV vaccination was approved for use in males ages 9 to 26 in 2009 and recommended for routine administration in 2011. The purpose of this study was to uncover predictable commonalities amongst parents who chose to vaccinate their 11-17 year old sons against HPV. METHODS: We compiled data from a U.S. national sample of 779 parents with sons 11-17 years old using a web-based survey to gather information about behavioral and sociodemographic factors which predicted receipt of 1 or more HPV vaccine doses based on parental report. Predictors were first modeled individually for univariable associations. Significant predictors (p<0.10) were combined in a multivariable model. RESULTS: In the adjusted model, independent predictors included receipt of flu vaccination, health insurance coverage and sexual health topic discussions with sons. Sons who had received a flu shot in the last two years more frequently received at least one dose of the vaccine (OR 1.82; 95% CI 1.45-2.26). Sons covered by private health insurance had decreased odds of HPV vaccination (OR 0.56 95% CI 0.37-0.83). Lastly, parents who had discussed sexual health topics with their sons were more likely to vaccinate (OR 1.61; 95% CI 1.37-1.89). CONCLUSIONS: Male vaccination rates in the U.S. have increased, but males continue to be under-immunized. Utilization of health care is an important factor in HPV vaccine uptake; therefore, health care providers should use every contact as an opportunity to vaccinate. Communication about sexual health topics may provide a forum for parents and health care providers to have conversations about HPV vaccination as those more comfortable discussing these topics may also be more comfortable discussing HPV vaccination. PMID- 25541727 TI - ReNE: a cytoscape plugin for regulatory network enhancement. AB - One of the biggest challenges in the study of biological regulatory mechanisms is the integration, americanmodeling, and analysis of the complex interactions which take place in biological networks. Despite post transcriptional regulatory elements (i.e., miRNAs) are widely investigated in current research, their usage and visualization in biological networks is very limited. Regulatory networks are commonly limited to gene entities. To integrate networks with post transcriptional regulatory data, researchers are therefore forced to manually resort to specific third party databases. In this context, we introduce ReNE, a Cytoscape 3.x plugin designed to automatically enrich a standard gene-based regulatory network with more detailed transcriptional, post transcriptional, and translational data, resulting in an enhanced network that more precisely models the actual biological regulatory mechanisms. ReNE can automatically import a network layout from the Reactome or KEGG repositories, or work with custom pathways described using a standard OWL/XML data format that the Cytoscape import procedure accepts. Moreover, ReNE allows researchers to merge multiple pathways coming from different sources. The merged network structure is normalized to guarantee a consistent and uniform description of the network nodes and edges and to enrich all integrated data with additional annotations retrieved from genome wide databases like NCBI, thus producing a pathway fully manageable through the Cytoscape environment. The normalized network is then analyzed to include missing transcription factors, miRNAs, and proteins. The resulting enhanced network is still a fully functional Cytoscape network where each regulatory element (transcription factor, miRNA, gene, protein) and regulatory mechanism (up regulation/down-regulation) is clearly visually identifiable, thus enabling a better visual understanding of its role and the effect in the network behavior. The enhanced network produced by ReNE is exportable in multiple formats for further analysis via third party applications. ReNE can be freely installed from the Cytoscape App Store (http://apps.cytoscape.org/apps/rene) and the full source code is freely available for download through a SVN repository accessible at http://www.sysbio.polito.it/tools_svn/BioInformatics/Rene/releases/. ReNE enhances a network by only integrating data from public repositories, without any inference or prediction. The reliability of the introduced interactions only depends on the reliability of the source data, which is out of control of ReNe developers. PMID- 25541728 TI - Phosphoinositide-3 kinase inhibition modulates responses to rhinovirus by mechanisms that are predominantly independent of autophagy. AB - Human rhinoviruses (HRV) are a major cause of exacerbations of airways disease. Aspects of cell signalling responses to HRV infection remain unclear, particularly with regard to signalling via PI3K, and the PI3K-dependent pathway, autophagy. We investigated the roles of PI3K and autophagy in the responses of epithelial cells to major and minor group HRV infection. The PI3K inhibitor 3-MA, commonly used to inhibit autophagy, markedly reduced HRV-induced cytokine induction. Further investigation of potential targets of 3-MA and comparison of results using this inhibitor to a panel of general and class I-selective PI3K inhibitors showed that several PI3Ks cooperatively regulate responses to HRV. Targeting by siRNA of the autophagy proteins Beclin-1, Atg7, LC3, alone or in combination, or targeting of the autophagy-specific class III PI3K had at most only modest effects on HRV-induced cell signalling as judged by induction of proinflammatory cytokine production. Our data indicate that PI3K and mTOR are involved in induction of proinflammatory cytokines after HRV infection, and that autophagy has little role in the cytokine response to HRV or control of HRV replication. PMID- 25541730 TI - A standardised abundance index from commercial spotting data of southern bluefin tuna (Thunnus maccoyii): random effects to the rescue. AB - Commercial aerial spotting of surface schools of juvenile southern bluefin tuna (SBT), Thunnus maccoyii, is conducted as part of fishing operations in the Great Australian Bight in summer. This provides the opportunity to efficiently collect large amounts of data on sightings of SBT. The data can potentially be used to construct a time-series index of relative abundance by standardising the data for issues such as weather, spotter ability and ocean conditions. Unlike a statistically designed survey, the commercial spotting is governed by business considerations and fishing operations. The SBT dataset is therefore highly unbalanced with regard to spotters operating in each season. This complicates the standardisation of the data, particularly with regard to interactions between covariates. We show how a generalized additive model with random effects can simplify both the fitting of the model and the construction of an index, while also avoiding the need to leave out strata or interaction terms that are important. The approach is applicable to standardisation of more traditional catch and effort data. PMID- 25541729 TI - Pea fiber and wheat bran fiber show distinct metabolic profiles in rats as investigated by a 1H NMR-based metabolomic approach. AB - This study aimed to examine the effect of pea fiber (PF) and wheat bran fiber (WF) supplementation in rat metabolism. Rats were assigned randomly to one of three dietary groups and were given a basal diet containing 15% PF, 15% WF, or no supplemental fiber. Urine and plasma samples were analyzed by NMR-based metabolomics. PF significantly increased the plasma levels of 3-hydroxybutyrate, and myo-inositol as well as the urine levels of alanine, hydroxyphenylacetate, phenylacetyglycine, and alpha-ketoglutarate. However, PF significantly decreased the plasma levels of isoleucine, leucine, lactate, and pyruvate as well as the urine levels of allantoin, bile acids, and trigonelline. WF significantly increased the plasma levels of acetone, isobutyrate, lactate, myo-inositol, and lipids as well as the urine levels of alanine, lactate, dimethylglycine, N methylniconamide, and alpha-ketoglutarate. However, WF significantly decreased the plasma levels of amino acids, and glucose as well as the urine levels of acetate, allantoin, citrate, creatine, hippurate, hydroxyphenylacetate, and trigonelline. Results suggest that PF and WF exposure can promote antioxidant activity and can exhibit common systemic metabolic changes, including lipid metabolism, energy metabolism, glycogenolysis and glycolysis metabolism, protein biosynthesis, and gut microbiota metabolism. PF can also decrease bile acid metabolism. These findings indicate that different fiber diet may cause differences in the biofluid profile in rats. PMID- 25541731 TI - Does the Earth's magnetic field serve as a reference for alignment of the honeybee Waggle dance? AB - The honeybee (Apis mellifera) waggle dance, which is performed inside the hive by forager bees, informs hive mates about a potent food source, and recruits them to its location. It consists of a repeated figure-8 pattern: two oppositely directed turns interspersed by a short straight segment, the "waggle run". The waggle run consists of a single stride emphasized by lateral waggling motions of the abdomen. Directional information pointing to a food source relative to the sun's azimuth is encoded in the angle between the waggle run line and a reference line, which is generally thought to be established by gravity. Yet, there is tantalizing evidence that the local (ambient) geomagnetic field (LGMF) could play a role. We tested the effect of the LGMF on the recruitment success of forager bees by placing observation hives inside large Helmholtz coils, and then either reducing the LGMF to 2% or shifting its apparent declination. Neither of these treatments reduced the number of nest mates that waggle dancing forager bees recruited to a feeding station located 200 m north of the hive. These results indicate that the LGMF does not act as the reference for the alignment of waggle dancing bees. PMID- 25541732 TI - A hierarchical bayesian model to quantify uncertainty of stream water temperature forecasts. AB - Providing generic and cost effective modelling approaches to reconstruct and forecast freshwater temperature using predictors as air temperature and water discharge is a prerequisite to understanding ecological processes underlying the impact of water temperature and of global warming on continental aquatic ecosystems. Using air temperature as a simple linear predictor of water temperature can lead to significant bias in forecasts as it does not disentangle seasonality and long term trends in the signal. Here, we develop an alternative approach based on hierarchical Bayesian statistical time series modelling of water temperature, air temperature and water discharge using seasonal sinusoidal periodic signals and time varying means and amplitudes. Fitting and forecasting performances of this approach are compared with that of simple linear regression between water and air temperatures using i) an emotive simulated example, ii) application to three French coastal streams with contrasting bio-geographical conditions and sizes. The time series modelling approach better fit data and does not exhibit forecasting bias in long term trends contrary to the linear regression. This new model also allows for more accurate forecasts of water temperature than linear regression together with a fair assessment of the uncertainty around forecasting. Warming of water temperature forecast by our hierarchical Bayesian model was slower and more uncertain than that expected with the classical regression approach. These new forecasts are in a form that is readily usable in further ecological analyses and will allow weighting of outcomes from different scenarios to manage climate change impacts on freshwater wildlife. PMID- 25541733 TI - Production of novel antibiotics zeamines through optimizing Dickeya zeae fermentation conditions. AB - Dickeya zeae strain EC1 was recently shown to produce a new type of phytotoxins designated as zeamine and zeamine II, which are potent wide-spectrum antibiotics against Gram-positive and Gram-negative bacterial pathogens, suggesting their promising potential as clinical medicines. In this study, the optimized medium composition and culture conditions for biosynthesis of novel antibiotics zeamines have been established by using response surface methodology, largely increasing the yield of zeamines from original about 7.35 ug . mL(-1) in minimal medium to about 150 ug . mL(-1) in LS5 medium. The study identified the major factors contributing to zeamines production, which include nitrate, sucrose, asparaginate, mineral elements Mg2+ and K+, and optimized amount of phosphate. In addition, the results showed that overexpression of zmsK in D. zeae strain EC1 could further increase zeamines yield to about 180 ug . mL(-1) in LS5 medium. The findings from this study could facilitate further characterization and utilization of these two novel antibiotics, and also provide useful clues for understanding the regulatory mechanisms that govern D. zeae virulence. PMID- 25541734 TI - Dissemination bias in systematic reviews of animal research: a systematic review. AB - BACKGROUND: Systematic reviews of preclinical studies, in vivo animal experiments in particular, can influence clinical research and thus even clinical care. Dissemination bias, selective dissemination of positive or significant results, is one of the major threats to validity in systematic reviews also in the realm of animal studies. We conducted a systematic review to determine the number of published systematic reviews of animal studies until present, to investigate their methodological features especially with respect to assessment of dissemination bias, and to investigate the citation of preclinical systematic reviews on clinical research. METHODS: Eligible studies for this systematic review constitute systematic reviews that summarize in vivo animal experiments whose results could be interpreted as applicable to clinical care. We systematically searched Ovid Medline, Embase, ToxNet, and ScienceDirect from 1st January 2009 to 9th January 2013 for eligible systematic reviews without language restrictions. Furthermore we included articles from two previous systematic reviews by Peters et al. and Korevaar et al. RESULTS: The literature search and screening process resulted in 512 included full text articles. We found an increasing number of published preclinical systematic reviews over time. The methodological quality of preclinical systematic reviews was low. The majority of preclinical systematic reviews did not assess methodological quality of the included studies (71%), nor did they assess heterogeneity (81%) or dissemination bias (87%). Statistics quantifying the importance of clinical research citing systematic reviews of animal studies showed that clinical studies referred to the preclinical research mainly to justify their study or a future study (76%). DISCUSSION: Preclinical systematic reviews may have an influence on clinical research but their methodological quality frequently remains low. Therefore, systematic reviews of animal research should be critically appraised before translating them to a clinical context. PMID- 25541735 TI - Acute graft-versus-host disease of the kidney in allogeneic rat bone marrow transplantation. AB - Allogeneic hematopoietic cell or bone marrow transplantation (BMT) causes graft versus-host-disease (GVHD). However, the involvement of the kidney in acute GVHD is not well-understood. Acute GVHD was induced in Lewis rats (RT1l) by transplantation of Dark Agouti (DA) rat (RT1(a)) bone marrow cells (6.0 * 10(7) cells) without immunosuppression after lethal irradiation (10 Gy). We examined the impact of acute GVHD on the kidney in allogeneic BMT rats and compared them with those in Lewis-to-Lewis syngeneic BMT control and non-BMT control rats. In syngeneic BMT and non-BMT control rats, acute GVHD did not develop by day 28. In allogeneic BMT rats, severe acute GVHD developed at 21-28 days after BMT in the skin, intestine, and liver with decreased body weight (>20%), skin rush, diarrhea, and liver dysfunction. In the kidney, infiltration of donor-type leukocytes was by day 28. Mild inflammation characterized by infiltration of CD3(+) T-cells, including CD8(+) T-cells and CD4(+) T-cells, and CD68(+) macrophages to the interstitium around the small arteries was noted. During moderate to severe inflammation, these infiltrating cells expanded into the peritubular interstitium with peritubular capillaritis, tubulitis, acute glomerulitis, and endarteritis. Renal dysfunction also developed, and the serum blood urea nitrogen (33.9 +/- 4.7 mg/dL) and urinary N-acetyl-beta-D glucosaminidase (NAG: 31.5 +/- 15.5 U/L) levels increased. No immunoglobulin and complement deposition was detected in the kidney. In conclusion, the kidney was a primary target organ of acute GVHD after BMT. Acute GVHD of the kidney was characterized by increased levels of urinary NAG and cell-mediated injury to the renal microvasculature and renal tubules. PMID- 25541736 TI - The transcriptomic and proteomic landscapes of bone marrow and secondary lymphoid tissues. AB - BACKGROUND: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas strategy that combines high throughput transcriptomics with affinity-based proteomics. RESULTS: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. CONCLUSIONS: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images. PMID- 25541739 TI - Outcome of Multiple Implants and Dissociation of Fluocinolone Acetonide Intravitreal Implant (Retisert) in a Series of 187 Consecutive Implants. AB - PURPOSE: To evaluate outcomes of long-term follow-up of Retisert multiple implantation and dissociation in eyes with chronic noninfectious uveitis. METHODS: Review of 187 consecutive Retisert implants. Outcomes of multiple implantation and spontaneous medication pellet-strut dissociation were evaluated. RESULTS: A total of 187 consecutive Retisert implants were reviewed. Eight implants were removed. The prevalence of spontaneous dissociation was 2.6% (5/187). The rate of dissociation increased to 11.11% (2/18) in cases of multiple implants. The mean period between Retisert implantation and spontaneous dissociation was 65.05 months. The mean period between implants in the same eye was 55.25 months. In cases of multiple implantations the old implant was not removed and 17.64% (3/17) of eyes required glaucoma filtering surgery. CONCLUSION: The rate of spontaneous dissociation of Retisert medication pellet strut in eyes with single implant for noninfectious uveitis is low, which tends to increase in eyes with multiple implants. PMID- 25541740 TI - The Autism Diagnostic Observation Schedule and narrative assessment: Evidence for specific narrative impairments in autism spectrum disorders. AB - PURPOSE: The Autism Diagnostic Observation Schedule (ADOS) contains a narrative generation task in which clients tell a story from a wordless picture book; however, the resulting narrative is not usually examined for its linguistic properties. This study aimed to examine narrative generation in autism spectrum disorder (ASD) by comparing narratives elicited from children with ASD during the ADOS to those produced by language-matched typically-developing (TD) peers. METHOD: Participants were children with ASD (n = 11) and TD controls (n = 17). Both groups were aged 9-15 years and were matched for expressive and receptive language skills and non-verbal intelligence. Narratives were analysed for local structure elements (length, fluency, errors, semantics and syntax), cohesion and global elements (story grammar and internal state language). RESULT: Results indicated that the narratives of the children with ASD were syntactically less complex, contained more ambiguous pronouns and included fewer story grammar elements than their control counterparts; with further analysis showing differences between younger and older children. CONCLUSION: The present findings provide evidence that children with ASD exhibit subtle story generation impairments and provide preliminary support for the inclusion of narratives elicited as part of the ADOS in the assessment of specific language skills in this population. PMID- 25541737 TI - Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation. AB - Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism. PMID- 25541741 TI - Mealtime management in Australian residential aged care: Comparison of documented, reported and observed care. AB - PURPOSE: Mealtime management in Residential aged care facilities (RACFs) should be holistic and comply with the principles of person-centred care (PCC) to ensure residents' medical, nutritional and psychosocial mealtime needs are met. However, this is not always achieved and multiple issues with mealtime management in RACFs exist. The aim of the current study was to compare documented, reported and observed mealtime management to explore factors influencing optimal mealtime care. METHOD: Data were triangulated from: (a) review of 14 resident files; (b) observation of 41 mealtimes; (c) questionnaires with 14 residents; and (d) questionnaires with 29 staff. RESULT: Results revealed multiple discrepancies between data sources leading to the delivery of sub-optimal mealtime care. Poor documentation impacted staff knowledge of required mealtime practices resulting in occasions of inconsistent and inappropriate care. Observational and interview data highlighted discrepancies between residents' mealtime preferences and actual practice. In many instances observed care was not holistic nor consistent with PCC. CONCLUSION: Given the significant medical, nutritional and psychosocial risks associated with poor mealtime management, systematic changes in policy, staff training and multidisciplinary care are needed. PMID- 25541742 TI - Levothyroxine improves abnormal cardiac bioenergetics in subclinical hypothyroidism: a cardiac magnetic resonance spectroscopic study. AB - CONTEXT: It is well established that subclinical hypothyroidism (SCH) is associated with mild cardiac dysfunction, but it is unknown whether there is an underlying impairment of cardiac bioenergetic function. OBJECTIVE: The objective of the study was to quantify the cardiac phosphocreatine to adenosine triphosphate ratio (PCr to ATP) in SCH, compared with healthy controls, and to measure the effect of 6 months of levothyroxine treatment. DESIGN AND SETTING: This was a 6-month, prospective, case-controlled interventional study. PARTICIPANTS AND MAIN OUTCOME MEASURES: The PCr to ATP ratio was measured using phosphorus-31 magnetic resonance spectroscopy in subjects with SCH at baseline and after levothyroxine therapy (1.6 MUg/kg . d) and compared with age- and gender-matched euthyroid controls. All subjects were free of overt heart disease. RESULTS: Twenty-one subjects with SCH (normal free T4 and serum TSH between 4.1 and 10 mIU/L) and 17 controls were matched for age (mean age 40.5 vs 43.3 y) and sex (females 81% vs 82%) but differed in mean TSH (6.5 vs 2.1 mIU/L, P < .001). At baseline the mean (+/- SD) PCr to ATP ratio in SCH was lower than in controls (1.80 +/- 0.26 vs 2.07 +/- 0.20, P = .001). In the 16 subjects studied after levothyroxine treatment, the PCr to ATP ratio improved (from 1.74 +/- 0.24 to 1.91 +/- 0.26, P = .004) and approached controls (borderline loss of significance, P = .051). On multivariate analysis, SCH was independently associated with a reduced PCr to ATP ratio, even after adjusting for confounding variables (body mass index and fasting glucose) (P = .001). CONCLUSION: Our results demonstrate early cardiac bioenergetic impairment in SCH, which is reversible with levothyroxine therapy. This mechanistic insight provides justification for longitudinal trials to determine whether improvement in bioenergetic function improves cardiovascular outcome. PMID- 25541743 TI - Active dendritic cell immunotherapy for glioblastoma: Current status and challenges. AB - Dendritic cell (DC) immunotherapy is developing as a promising treatment modality for patients with glioblastoma multiforme (GBM). The aim of this article is to review the data from clinical trials and prospective studies evaluating the safety and efficacy of DC vaccines for newly diagnosed (ND)- and recurrent (Rec) GBM and for other high-grade gliomas (HGGs). By searching all major databases we identified and reviewed twenty-two (n=22) such studies, twenty (n=20) of which were phase I and II trials, one was a pilot study towards a phase I/II trial and one was a prospective study. GBM patients were exclusively recruited in 12/22 studies, while 10/22 studies enrolled patients with any diagnosis of a HGG. In 7/22 studies GBM was newly diagnosed. In the vast majority of studies the vaccine was injected subcutaneously or intradermally and consisted of mature DCs pulsed with tumour lysate or peptides. Median overall survival ranged between 16.0 and 38.4 months for ND-GBM and between 9.6 and 35.9 months for Rec-GBM. Vaccine related side effects were in general mild (grade I and II), with serious adverse events (grade III, IV and V) reported only rarely. DC immunotherapy therefore appears to have the potential to increase the overall survival in patients with HGG, with an acceptable side effect profile. The findings will require confirmation by the ongoing and future phase III trials. PMID- 25541744 TI - Quinolinyl-thienyl chalcones as monoamine oxidase inhibitors and their in silico modeling studies. AB - Mitochondrial enzymes monoamine oxidases were thought to be an emerging and useful therapeutic target for neurodegenerative disorders. Monoamine oxidases have two isoforms, A and B. MAO-A is related with metabolism of amine neurotransmitters in the brain whereas MAO-B is concerned with aging related neurodegenerative disorders. Therefore the identification, characterization and discovery of potent MAO-A and B inhibitors is very crucial in research. A series of quinolyl-thienyl chalcones were tested against MAO-A and B. Among the screened compounds, most of them revealed potent MAO-A and B inhibition. Compound 5i presented most potent MAO-A inhibition having IC50 values 0.047 uM, while 4l showed excellent inhibitory potency against MAO-B among all the tested compound having IC50 values 0.063 uM. Molecular modelling studies were performed against human MAO-A and MAO-B for the explanation of binding site interactions. PMID- 25541745 TI - Investigation of the N-BP Binding at FPPS by Combined Computational Approaches. AB - Nitrogen-containing bisphosphonates (N-BPs) are important drugs widely used in a variety of bone resorption diseases. These compounds target the farnesyl pyrophosphate synthase (FPPS), a key enzyme of the mevalonate pathway involved in several pathologies. The inhibition of FPPS is a promising pharmacological approach and the development of structure-based methods for the prediction of the enzyme-inhibitor binding energy, can provide a guide for the rational design of new N-BPs. In this study multiple docking and post-docking strategies were applied to develop an effective computational workflow able to correctly predict the binding geometry and energy of a diverse set of known N-BPs. Preliminarily, we identified a model structure of the target allowing to predict the binding pose for all studied ligands and improving the estimation of the target-ligand interaction energies. A significant correlation between calculated and experimental binding affinities was found by dividing the whole group of N-BPs inhibitors into two subsets according to the structure's size, suggesting that the contributions to the binding energy are differently weighted in the two groups and that the FPPS inhibition mechanism may be based on ligand dimensions. The obtained quantitative models can be further exploited for either screening or optimization studies of newly designed N-BPs. PMID- 25541746 TI - Synthesis and In-Vitro Cytotoxicity of (E)-N,2,3-Triarylacrylamide Derivatives as Analogs of Combretastatin A-4. AB - A new series of (E)-N,2,3-triarylacrylamide derivatives were designed and synthesized as potent anticancer agents. Cytotoxicity of the 26 target compounds was evaluated in vitro against six cancer cell lines (HCT116, A549, MDA-MB-468, HepG2, SKNMC and SK-OV-3) by Sulforhodamine B colorimetric assay. The most promising compound, 4h, was as potent as the reference drug cisplatin (DDP). Preliminary structure-activity relationship (SAR) data provided guidance for further design and discovery of (E)- N,2,3-triarylacrylamide scaffold anticancer agents. PMID- 25541748 TI - Sulfur nanodots electrodeposited on ni foam as high-performance cathode for Li-S batteries. AB - In this Letter, we report the preparation of sulfur nanodots (2 nm average) electrodeposited on flexible nickel foam and their application as high performance cathode of Li-S batteries. An electrodepostion method was applied to prepare the cathode at room temperature and the sulfur mass was controllable from 0.21 to 4.79 mg/cm(2) in a large area of over 100 cm(2). The optimized cathode with 0.45 mg/cm(2) S on Ni foam displayed high initial discharge capacity (1458 mAh/g at 0.1 C), high rate capability (521 mAh/g at 10 C), and long cycling stability (895 mAh/g after 300 cycles at 0.5 C and 528 mAh/g after 1400 cycles at 5 C). Moreover, in situ Raman and transmission electron microscopy analysis demonstrated the fundamentals of reversible electrochemical reaction between S and Li2S nanodots. This fast, facile, and one-step cathode preparation method with excellent electrochemical performance will lead to technological advances of S cathode in Li-S batteries. PMID- 25541747 TI - Calorimetric investigation of copper binding in the N-terminal region of the prion protein at low copper loading: evidence for an entropically favorable first binding event. AB - Although the Cu(2+)-binding sites of the prion protein have been well studied when the protein is fully saturated by Cu(2+), the Cu(2+)-loading mechanism is just beginning to come into view. Because the Cu(2+)-binding modes at low and intermediate Cu(2+) occupancy necessarily represent the highest-affinity binding modes, these are very likely populated under physiological conditions, and it is thus essential to characterize them in order to understand better the biological function of copper-prion interactions. Besides binding-affinity data, almost no other thermodynamic parameters (e.g., DeltaH and DeltaS) have been measured, thus leaving undetermined the enthalpic and entropic factors that govern the free energy of Cu(2+) binding to the prion protein. In this study, isothermal titration calorimetry (ITC) was used to quantify the thermodynamic parameters (K, DeltaG, DeltaH, and TDeltaS) of Cu(2+) binding to a peptide, PrP(23-28, 57-98), that encompasses the majority of the residues implicated in Cu(2+) binding by full-length PrP. Use of the buffer N-(2-acetomido)-aminoethanesulfonic acid (ACES), which is also a well-characterized Cu(2+) chelator, allowed for the isolation of the two highest affinity binding events. Circular dichroism spectroscopy was used to characterize the different binding modes as a function of added Cu(2+). The Kd values determined by ITC, 7 and 380 nM, are well in line with those reported by others. The first binding event benefits significantly from a positive entropy, whereas the second binding event is enthalpically driven. The thermodynamic values associated with Cu(2+) binding by the Abeta peptide, which is implicated in Alzheimer's disease, bear striking parallels to those found here for the prion protein. PMID- 25541749 TI - DOCKTITE-a highly versatile step-by-step workflow for covalent docking and virtual screening in the molecular operating environment. AB - The formation of a covalent bond with the target is essential for a number of successful drugs, yet tools for covalent docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, a highly versatile workflow for covalent docking in the Molecular Operating Environment (MOE) combining automated warhead screening, nucleophilic side chain attachment, pharmacophore-based docking, and a novel consensus scoring approach. The comprehensive validation study includes pose predictions of 35 protein/ligand complexes which resulted in a mean RMSD of 1.74 A and a prediction rate of 71.4% with an RMSD below 2 A, a virtual screening with an area under the curve (AUC) for the receiver operating characteristics (ROC) of 0.81, and a significant correlation between predicted and experimental binding affinities (rho = 0.806, R(2) = 0.649, p < 0.005). PMID- 25541751 TI - Broad spectrum antibacterial and antifungal polymeric paint materials: synthesis, structure-activity relationship, and membrane-active mode of action. AB - Microbial attachment and subsequent colonization onto surfaces lead to the spread of deadly community-acquired and hospital-acquired (nosocomial) infections. Noncovalent immobilization of water insoluble and organo-soluble cationic polymers onto a surface is a facile approach to prevent microbial contamination. In the present study, we described the synthesis of water insoluble and organo soluble polymeric materials and demonstrated their structure-activity relationship against various human pathogenic bacteria including drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE), and beta lactam-resistant Klebsiella pneumoniae as well as pathogenic fungi such as Candida spp. and Cryptococcus spp. The polymer coated surfaces completely inactivated both bacteria and fungi upon contact (5 log reduction with respect to control). Linear polymers were more active and found to have a higher killing rate than the branched polymers. The polymer coated surfaces also exhibited significant activity in various complex mammalian fluids such as serum, plasma, and blood and showed negligible hemolysis at an amount much higher than minimum inhibitory amounts (MIAs). These polymers were found to have excellent compatibility with other medically relevant polymers (polylactic acid, PLA) and commercial paint. The cationic hydrophobic polymer coatings disrupted the lipid membrane of both bacteria and fungi and thus showed a membrane-active mode of action. Further, bacteria did not develop resistance against these membrane-active polymers in sharp contrast to conventional antibiotics and lipopeptides, thus the polymers hold great promise to be used as coating materials for developing permanent antimicrobial paint. PMID- 25541752 TI - Characterizing the performance of XOR games and the Shannon capacity of graphs. AB - In this Letter we give a set of necessary and sufficient conditions such that quantum players of a two-party XOR game cannot perform any better than classical players. With any such game, we associate a graph and examine its zero-error communication capacity. This allows us to specify a broad new class of graphs for which the Shannon capacity can be calculated. The conditions also enable the parametrization of new families of games that have no quantum advantage for arbitrary input probability distributions, up to certain symmetries. In the future, these might be used in information-theoretic studies on reproducing the set of quantum nonlocal correlations. PMID- 25541753 TI - Geometric scaling of Efimov states in a 6Li-133Cs mixture. AB - In few-body physics, Efimov states are an infinite series of three-body bound states that obey universal discrete scaling symmetry when pairwise interactions are resonantly enhanced. Despite abundant reports of Efimov states in recent cold atom experiments, direct observation of the discrete scaling symmetry remains an elusive goal. Here we report the observation of three consecutive Efimov resonances in a heteronuclear Li-Cs mixture near a broad interspecies Feshbach resonance. The positions of the resonances closely follow a geometric series 1, lambda, lambda2. The observed scaling constant lambda(exp)=4.9(4) is in good agreement with the predicted value of 4.88. PMID- 25541750 TI - Mass spectrometry-based detection and assignment of protein posttranslational modifications. AB - Recent advances in mass spectrometry (MS)-based proteomics allow the identification and quantitation of thousands of posttranslational modification (PTM) sites in a single experiment. This follows from the development of more effective class enrichment strategies, new high performance instrumentation and bioinformatic algorithms with rigorous scoring strategies. More widespread use of these combined capabilities have led to a vast expansion in our knowledge of the complexity of biological processes mediated by PTMs. The classes most actively pursued include phosphorylation, ubiquitination, O-GlcNAcylation, methylation, and acetylation. Very recently succinylation, SUMOylation, and citrullination have emerged. Among the some 260 000 PTM sites that have been identified in the human proteome thus far, only a few have been assigned to key regulatory and/or other biological roles. Here, we provide an update of MS-based PTM analyses, with a focus on current enrichment strategies coupled with revolutionary advances in high performance MS. Furthermore, we discuss examples of the discovery of recently described biological roles of PTMs and address the challenges of defining site-specific functions. PMID- 25541754 TI - Representation of Berry phase by the trajectories of Majorana stars. AB - The Majorana's stellar representation, which represents the evolution of a quantum state with the trajectories of the Majorana stars on a Bloch sphere, provides an intuitive way to study a physical system with a high dimensional projective Hilbert space. In this Letter, we study the Berry phase by these stars and their loops on the Bloch sphere. It is shown that the Berry phase of a general spin state can be expressed by an elegant formula with the solid angles of Majorana star loops. Furthermore, these results can be used to a general state with arbitrary dimensions. To demonstrate our theory, we study a two mode interacting boson system. Finally, the relation between stars' correlations and quantum entanglement is discussed. PMID- 25541755 TI - Is the angular momentum of an electron conserved in a uniform magnetic field? AB - We show that an electron moving in a uniform magnetic field possesses a time varying "diamagnetic" angular momentum. Surprisingly this means that the kinetic angular momentum of the electron may vary with time, despite the rotational symmetry of the system. This apparent violation of angular momentum conservation is resolved by including the angular momentum of the surrounding fields. PMID- 25541756 TI - Apparatus for measuring the thermal Casimir force at large distances. AB - We describe a Casimir apparatus based on a differential force measurement between a Au-coated sphere and a planar slab divided in two regions, one of which is made of high-resistivity (dielectric) Si, and the other of Au. The crucial feature of the setup is a semitransparent plane parallel conducting overlayer, covering both regions. The setup offers two important advantages over existing Casimir setups. On one hand, it leads to a large amplification of the difference between the Drude and the plasma prescriptions that are currently used to compute the thermal Casimir force. On the other hand, thanks to the screening power of the overlayer, it is in principle immune from electrostatic forces caused by potential patches on the plates surfaces, that plague present large distance Casimir experiments. If a semitransparent conductive overlayer with identical patch structure over the Au-Si regions of the plate can be manufactured, similar to the opaque overlayers used in recent searches of non-Newtonian gravitational forces based on the isoelectronic technique, the way will be paved for a clear observation of the thermal Casimir force up to separations of several microns, and an unambiguous discrimination between the Drude and the plasma prescriptions. PMID- 25541757 TI - Coherent quantum dynamics in steady-state manifolds of strongly dissipative systems. AB - Recently, it has been realized that dissipative processes can be harnessed and exploited to the end of coherent quantum control and information processing. In this spirit, we consider strongly dissipative quantum systems admitting a nontrivial manifold of steady states. We show how one can enact adiabatic coherent unitary manipulations, e.g., quantum logical gates, inside this steady state manifold by adding a weak, time-rescaled, Hamiltonian term into the system's Liouvillian. The effective long-time dynamics is governed by a projected Hamiltonian which results from the interplay between the weak unitary control and the fast relaxation process. The leakage outside the steady-state manifold entailed by the Hamiltonian term is suppressed by an environment-induced symmetrization of the dynamics. We present applications to quantum-computation in decoherence-free subspaces and noiseless subsystems and numerical analysis of nonadiabatic errors. PMID- 25541758 TI - Coexistence, interfacial energy, and the fate of microemulsions of 2D dipolar bosons. AB - The superfluid-crystal quantum phase transition of a system of purely repulsive dipolar bosons in two dimensions is studied by quantum Monte Carlo simulations at zero temperature. We determine freezing and melting densities and estimate the energy per unit length of a macroscopic interface separating the two phases. The results rule out the microemulsion scenario for any physical realization of this system, given the exceedingly large predicted size of the bubbles. PMID- 25541759 TI - Experimental entanglement redistribution under decoherence channels. AB - When an initially entangled pair of qubits undergoes local decoherence processes, there are a number of ways in which the original entanglement can spread throughout the multipartite system consisting of the two qubits and their environments. Here, we report theoretical and experimental results regarding the dynamics of the distribution of entanglement in this system. The experiment employs an all optical setup in which the qubits are encoded in the polarization degrees of freedom of two photons, and each local decoherence channel is implemented with an interferometer that couples the polarization to the path of each photon, which acts as an environment. We monitor the dynamics and distribution of entanglement and observe the transition from bipartite to multipartite entanglement and back, and show how these transitions are intimately related to the sudden death and sudden birth of entanglement. The multipartite entanglement is further analyzed in terms of three- and four-partite entanglement contributions, and genuine four-qubit entanglement is observed at some points of the evolution. PMID- 25541760 TI - Critical capacitance and charge-vortex duality near the superfluid-to-insulator transition. AB - Using a generalized reciprocity relation between charge and vortex conductivities at complex frequencies in two space dimensions, we identify the capacitance in the insulating phase as a measure of vortex condensate stiffness. We compute the ratio of boson superfluid stiffness to vortex condensate stiffness at mirror points to be 0.21(1) for the relativistic O(2) model. The product of dynamical conductivities at mirror points is used as a quantitative measure of deviations from self-duality between charge and vortex theories. We propose the finite wave vector compressibility as an experimental measure of the vortex condensate stiffness for neutral lattice bosons. PMID- 25541761 TI - Isometric fluctuation relations for equilibrium states with broken symmetry. AB - We derive a set of isometric fluctuation relations, which constrain the order parameter fluctuations in finite-size systems at equilibrium and in the presence of a broken symmetry. These relations are exact and should apply generally to many condensed-matter physics systems. Here, we establish these relations for magnetic systems and nematic liquid crystals in a symmetry-breaking external field, and we illustrate them on the Curie-Weiss and the XY models. Our relations also have implications for spontaneous symmetry breaking, which are discussed. PMID- 25541762 TI - New confining force solution of the QCD axion domain-wall problem. AB - The serious cosmological problems created by the axion-string-axion-domain-wall system in standard axion models are alleviated by positing the existence of a new confining force. The instantons of this force can generate an axion potential that erases the axion strings long before QCD effects become important, thus preventing QCD-generated axion walls from ever appearing. Axion walls generated by the new confining force would decay so early as not to contribute significantly to the energy in axion dark matter. PMID- 25541763 TI - Standard rulers, candles, and clocks from the low-redshift universe. AB - We measure the length of the baryon acoustic oscillation (BAO) feature, and the expansion rate of the recent Universe, from low-redshift data only, almost model independently. We make only the following minimal assumptions: homogeneity and isotropy, a metric theory of gravity, a smooth expansion history, and the existence of standard candles (supernovae) and a standard BAO ruler. The rest is determined by the data, which are compilations of recent BAO and type IA supernova results. Making only these assumptions, we find for the first time that the standard ruler has a length of 103.9+/-2.3h-1 Mpc. The value is a measurement, in contrast to the model-dependent theoretical prediction determined with model parameters set by Planck data (99.3+/-2.1h-1 Mpc). The latter assumes the cold dark matter model with a cosmological constant, and that the ruler is the sound horizon at radiation drag. Adding passive galaxies as standard clocks or a local Hubble constant measurement allows the absolute BAO scale to be determined (142.8+/-3.7 Mpc), and in the former case the additional information makes the BAO length determination more precise (101.9+/-1.9h-1 Mpc). The inverse curvature radius of the Universe is weakly constrained and consistent with zero, independently of the gravity model, provided it is metric. We find the effective number of relativistic species to be N(eff)=3.53+/-0.32, independent of late-time dark energy or gravity physics. PMID- 25541764 TI - Consistent use of the standard model effective potential. AB - The stability of the standard model is determined by the true minimum of the effective Higgs potential. We show that the potential at its minimum when computed by the traditional method is strongly dependent on the gauge parameter. It moreover depends on the scale where the potential is calculated. We provide a consistent method for determining absolute stability independent of both gauge and calculation scale, order by order in perturbation theory. This leads to a revised stability bounds m(h)(pole)>(129.4+/-2.3) GeV and m(t)(pole)<(171.2+/ 0.3) GeV. We also show how to evaluate the effect of new physics on the stability bound without resorting to unphysical field values. PMID- 25541765 TI - SU(2)*U(1) gauge invariance and the shape of new physics in rare B decays. AB - New physics effects in B decays are routinely modeled through operators invariant under the strong and electromagnetic gauge symmetries. Assuming the scale for new physics is well above the electroweak scale, we further require invariance under the full standard model gauge symmetry group. Retaining up to dimension-six operators, we unveil new constraints between different new physics operators that are assumed to be independent in the standard phenomenological analyses. We illustrate this approach by analyzing the constraints on new physics from rare B(q) (semi-)leptonic decays. PMID- 25541769 TI - Nuclear matter from effective quark-quark interaction. AB - We study neutron matter and symmetric nuclear matter with the quark-meson model for the two-nucleon interaction. The Bethe-Bruckner-Goldstone many-body theory is used to describe the correlations up to the three hole-line approximation with no extra parameters. At variance with other nonrelativistic realistic interactions, the three hole-line contribution turns out to be non-negligible and to have a substantial saturation effect. The saturation point of nuclear matter, the compressibility, the symmetry energy, and its slope are within the phenomenological constraints. Since the interaction also reproduces fairly well the properties of the three-nucleon system, these results indicate that the explicit introduction of the quark degrees of freedom within the considered constituent quark model is expected to reduce the role of three-body forces. PMID- 25541770 TI - Breakdown of the dipole approximation in strong-field ionization. AB - We report the breakdown of the electric dipole approximation in the long wavelength limit in strong-field ionization with linearly polarized few-cycle mid infrared laser pulses at intensities on the order of 1013 W/cm2. Photoelectron momentum distributions were recorded by velocity map imaging and projected onto the beam propagation axis. We observe an increasing shift of the peak of this projection opposite to the beam propagation direction with increasing laser intensities. From a comparison with semiclassical simulations, we identify the combined action of the magnetic field of the laser pulse and the Coulomb potential as the origin of our observations. PMID- 25541771 TI - Many-body localization in dipolar systems. AB - Systems of strongly interacting dipoles offer an attractive platform to study many-body localized phases, owing to their long coherence times and strong interactions. We explore conditions under which such localized phases persist in the presence of power-law interactions and supplement our analytic treatment with numerical evidence of localized states in one dimension. We propose and analyze several experimental systems that can be used to observe and probe such states, including ultracold polar molecules and solid-state magnetic spin impurities. PMID- 25541772 TI - Fabry-Perot interferometer with quantum mirrors: nonlinear light transport and rectification. AB - Optical transport represents a natural route towards fast communications, and it is currently used in large scale data transfer. The progressive miniaturization of devices for information processing calls for the microscopic tailoring of light transport and confinement at length scales appropriate for upcoming technologies. With this goal in mind, we present a theoretical analysis of a one dimensional Fabry-Perot interferometer built with two highly saturable nonlinear mirrors: a pair of two-level systems. Our approach captures nonlinear and nonreciprocal effects of light transport that were not reported previously. Remarkably, we show that such an elementary device can operate as a microscopic integrated optical rectifier. PMID- 25541773 TI - Subwavelength multilayer dielectrics: ultrasensitive transmission and breakdown of effective-medium theory. AB - We show that a purely dielectric structure made of alternating layers of deep subwavelength thicknesses exhibits novel transmission effects which completely contradict conventional effective medium theories exactly in the regime in which those theories are commonly used. We study waves incident at the vicinity of the effective medium's critical angle for total internal reflection and show that the transmission through the multilayer structure depends strongly on nanoscale variations even at layer thicknesses smaller than lambda/50. In such deep subwavelength structures, we demonstrate dramatic changes in the transmission for variations in properties such as periodicity, order of the layers, and their parity. In addition to its conceptual importance, such sensitivity has important potential applications in sensing and switching. PMID- 25541774 TI - Improving the self-guiding of an ultraintense laser by tailoring its longitudinal profile. AB - Self-guiding of an ultraintense laser requires the refractive index to build up rapidly to a sufficient value before the main body of the pulse passes by. We show that placing a low-intensity precursor in front of the main pulse mitigates the diffraction of its leading edge and facilitates reaching a self-guided state that remains stable for more than 10 Rayleigh lengths. Furthermore, this precursor slows the phase slippage between the trapped electrons and the wakefield and leads to an accelerating structure that is more stable, contains more energy, and is sustained longer. Examples from three-dimensional particle-in cell simulations show that the conversion efficiency from the laser to the self trapped electrons increases by an order of magnitude when using the precursor. PMID- 25541776 TI - Field-reversed bubble in deep plasma channels for high-quality electron acceleration. AB - We study hollow plasma channels with smooth boundaries for laser-driven electron acceleration in the bubble regime. Contrary to the uniform plasma case, the laser forms no optical shock and no etching at the front. This increases the effective bubble phase velocity and energy gain. The longitudinal field has a plateau that allows for monoenergetic acceleration. We observe as low as 10-3 rms relative witness beam energy uncertainty in each cross section and 0.3% total energy spread. By varying the plasma density profile inside a deep channel, the bubble fields can be adjusted to balance the laser depletion and dephasing lengths. Bubble scaling laws for the deep channel are derived. Ultrashort pancakelike laser pulses lead to the highest energies of accelerated electrons per Joule of laser pulse energy. PMID- 25541775 TI - Multi-GeV electron beams from capillary-discharge-guided subpetawatt laser pulses in the self-trapping regime. AB - Multi-GeV electron beams with energy up to 4.2 GeV, 6% rms energy spread, 6 pC charge, and 0.3 mrad rms divergence have been produced from a 9-cm-long capillary discharge waveguide with a plasma density of ~7*1017 cm-3, powered by laser pulses with peak power up to 0.3 PW. Preformed plasma waveguides allow the use of lower laser power compared to unguided plasma structures to achieve the same electron beam energy. A detailed comparison between experiment and simulation indicates the sensitivity in this regime of the guiding and acceleration in the plasma structure to input intensity, density, and near-field laser mode profile. PMID- 25541777 TI - Static dielectric permittivity of ice from first principles. AB - The static permittivity of ice is computed from first principles as a function of the electric field, together with the generalized Kirkwood factor. The molecular dipole in ice is unambiguously obtained by an original method combining a slab approach and Berry phase calculations, and the fluctuations of the polarization are sampled by Monte Carlo runs using first-principles model Hamiltonians for different proton configurations. Common approximations in the exchange correlation functionals overestimate the dielectric permittivity and enhance ferroelectric configurations and the Kirkwood factor, whereas dielectric saturation effects compare well with experiment. PMID- 25541766 TI - Measurement of the inclusive electron neutrino charged current cross section on carbon with the T2K near detector. AB - The T2K off-axis near detector ND280 is used to make the first differential cross section measurements of electron neutrino charged current interactions at energies ~1 GeV as a function of electron momentum, electron scattering angle, and four-momentum transfer of the interaction. The total flux-averaged nu(e) charged current cross section on carbon is measured to be ?sigma?(phi)=1.11+/ 0.10(stat)+/-0.18(syst)*10-38 cm2/nucleon. The differential and total cross section measurements agree with the predictions of two leading neutrino interaction generators, NEUT and GENIE. The NEUT prediction is 1.23*10-38 cm2/nucleon and the GENIE prediction is 1.08*10-38 cm2/nucleon. The total nu(e) charged current cross-section result is also in agreement with data from the Gargamelle experiment. PMID- 25541778 TI - Making the cut: lattice kirigami rules. AB - In this Letter we explore and develop a simple set of rules that apply to cutting, pasting, and folding honeycomb lattices. We consider origami-like structures that are extrinsically flat away from zero-dimensional sources of Gaussian curvature and one-dimensional sources of mean curvature, and our cutting and pasting rules maintain the intrinsic bond lengths on both the lattice and its dual lattice. We find that a small set of rules is allowed providing a framework for exploring and building kirigami-folding, cutting, and pasting the edges of paper. PMID- 25541779 TI - Critical dynamical heterogeneities close to continuous second-order glass transitions. AB - We analyze, using inhomogeneous mode-coupling theory, the critical scaling behavior of the dynamical susceptibility at a distance epsilon from continuous second-order glass transitions. We find that the dynamical correlation length xi behaves generically as epsilon(-1/3) and that the upper critical dimension is equal to six. More surprisingly, we find that xi grows with time as ln2t exactly at criticality. All of these results suggest a deep analogy between the glassy behavior of attractive colloids or randomly pinned supercooled liquids and that of the random field Ising model. PMID- 25541780 TI - Structural relaxation is a scale-free process. AB - We show that in deeply supercooled liquids, structural relaxation proceeds via the accumulation of Eshelby events, i.e. local rearrangements that create long ranged and anisotropic stresses in the surrounding medium. Such events must be characterized using tensorial observables and we construct an analytical framework to probe their correlations using local stress data. By analyzing numerical simulations, we then demonstrate that events are power-law correlated in space, with a time-dependent amplitude which peaks at the alpha relaxation time tau(alpha). This effect, which becomes stronger near the glass transition, results from the increasingly important role of local stress fluctuations in facilitating relaxation events. Our finding precludes the existence of any length scale beyond which the relaxation process decorrelates. PMID- 25541781 TI - How "hot precursors" modify island nucleation: a rate-equation model. AB - We propose a novel island nucleation and growth model explicitly including transient (ballistic) mobility of the monomers deposited at rate F, assumed to be in a hot precursor state before thermalizing. In limiting regimes, corresponding to fast (diffusive) and slow (ballistic) thermalization, the island density N obeys scaling N?F(alpha). In between is found a rich, complex behavior, with various distinctive scaling regimes, characterized by effective exponents alpha(eff) and activation energies that we compute exactly. Application to N(F,T) of recent organic-molecule deposition experiments yields an excellent fit. PMID- 25541782 TI - Local adiabatic mixing of Kramers pairs of Majorana bound states. AB - We consider Kramers pairs of Majorana bound states under adiabatic time evolution. This is important for the prospects of using such bound states as parity qubits. We show that local adiabatic perturbations can cause a rotation in the space spanned by the Kramers pair. Hence, the quantum information is unprotected against local perturbations, in contrast to the case of single localized Majorana bound states in systems with broken time reversal symmetry. We give an analytical and a numerical example for such a rotation, and specify sufficient conditions under which a rotation is avoided. We give a general scheme for determining when these conditions are satisfied and exemplify it with a general model of a quasi-1D time reversal symmetric topological superconductor. PMID- 25541783 TI - Quantum transport evidence for the three-dimensional Dirac semimetal phase in Cd3As2. AB - We report the quantum transport properties of Cd3As2 single crystals in a magnetic field. A large linear quantum magnetoresistance is observed near room temperature. With decreasing temperature, the Shubnikov-de Haas oscillations appear in both the longitudinal resistance R(xx) and the transverse Hall resistance R(xy). From the strong oscillatory component DeltaR(xx), a linear dependence of the Landau index n on 1/B is obtained, and it gives an n-axis intercept between 1/2 and 5/8. This clearly reveals a nontrivial pi Berry's phase, which is a distinguished feature of Dirac fermions. Our quantum transport results provide bulk evidence for the existence of a three-dimensional Dirac semimetal phase in Cd3As2. PMID- 25541784 TI - Magnitude of the magnetic exchange interaction in the heavy-fermion antiferromagnet CeRhIn5. AB - We have used high-resolution neutron spectroscopy experiments to determine the complete spin wave spectrum of the heavy-fermion antiferromagnet CeRhIn5. The spin wave dispersion can be quantitatively reproduced with a simple frustrated J1 J2 model that also naturally explains the magnetic spin-spiral ground state of CeRhIn5 and yields a dominant in-plane nearest-neighbor magnetic exchange constant J0=0.74(3) meV. Our results pave the way to a quantitative understanding of the rich low-temperature phase diagram of the prominent CeTIn5 (T=Co, Rh, Ir) class of heavy-fermion materials. PMID- 25541785 TI - Shining light on transition-metal oxides: unveiling the hidden Fermi liquid. AB - We use low energy optical spectroscopy and first principles local density approximation plus dynamical mean field theory calculations to test the hypothesis that the anomalous transport properties of strongly correlated metals originate in the strong temperature dependence of their underlying resilient quasiparticles. We express the resistivity in terms of an effective plasma frequency omega(p)* and an effective scattering rate 1/tau(tr)*. We show that in the archetypal correlated material V2O3, omega(p)* increases with increasing temperature, while the plasma frequency from the partial sum rule exhibits the opposite trend. 1/tau(tr)* has a more pronounced temperature dependence than the scattering rate obtained from the extended Drude analysis. The theoretical calculations of these quantities are in quantitative agreement with experiment. We conjecture that these are robust properties of all strongly correlated metals, and test the conjecture by carrying out a similar analysis on thin film NdNiO3 on a LaAlO3 substrate. PMID- 25541786 TI - Phase diagram of the triangular extended Hubbard model. AB - We study the extended Hubbard model on the triangular lattice as a function of filling and interaction strength. The complex interplay of kinetic frustration and strong interactions on the triangular lattice leads to exotic phases where long-range charge order, antiferromagnetic order, and metallic conductivity can coexist. Variational Monte Carlo simulations show that three kinds of ordered metallic states are stable as a function of nearest neighbor interaction and filling. The coexistence of conductivity and order is explained by a separation into two functional classes of particles: part of them contributes to the stable order, while the other part forms a partially filled band on the remaining substructure. The relation to charge ordering in charge transfer salts is discussed. PMID- 25541787 TI - Spin-lattice relaxation times of single donors and donor clusters in silicon. AB - An atomistic method of calculating the spin-lattice relaxation times (T1) is presented for donors in silicon nanostructures comprising of millions of atoms. The method takes into account the full band structure of silicon including the spin-orbit interaction. The electron-phonon Hamiltonian, and hence, the deformation potential, is directly evaluated from the strain-dependent tight binding Hamiltonian. The technique is applied to single donors and donor clusters in silicon, and explains the variation of T1 with the number of donors and electrons, as well as donor locations. Without any adjustable parameters, the relaxation rates in a magnetic field for both systems are found to vary as B5, in excellent quantitative agreement with experimental measurements. The results also show that by engineering electronic wave functions in nanostructures, T1 times can be varied by orders of magnitude. PMID- 25541767 TI - Measurements of direct CP-violating asymmetries in charmless decays of bottom baryons. AB - We report final measurements of direct CP-violating asymmetries in charmless decays of neutral bottom hadrons to pairs of charged hadrons with the upgraded Collider Detector at the Fermilab Tevatron. Using the complete ?s=1.96 TeV proton-antiproton collisions data set, corresponding to 9.3 fb-1 of integrated luminosity, we measure A(Lambda(b)0->ppi-)=+0.06+/-0.07(stat)+/-0.03(syst) and A(Lambda(b)0->pK-)=-0.10+/-0.08(stat)+/-0.04(syst), compatible with no asymmetry. In addition we measure the CP-violating asymmetries in B(s)0->K-pi+ and B0->K+pi- decays to be A(B(s)0->K-pi+)=+0.22+/-0.07(stat)+/-0.02(syst) and A(B0->K+pi-)= 0.083+/-0.013(stat)+/-0.004(syst), respectively, which are significantly different from zero and consistent with current world averages. PMID- 25541788 TI - Plasmons in strongly correlated systems: spectral weight transfer and renormalized dispersion. AB - We study the charge-density dynamics within the two-dimensional extended Hubbard model in the presence of long-range Coulomb interaction across the metal insulator transition point. To take into account strong correlations we start from self-consistent extended dynamical mean-field theory and include nonlocal dynamical vertex corrections through a ladder approximation to the polarization operator. This is necessary to fulfill charge conservation and to describe plasmons in the correlated state. The calculated plasmon spectra are qualitatively different from those in the random-phase approximation: they exhibit a spectral density transfer and a renormalized dispersion with enhanced deviation from the canonical ?q behavior. Both features are reminiscent of interaction induced changes found in single-electron spectra of strongly correlated systems. PMID- 25541789 TI - Electronic transport in graphene with aggregated hydrogen adatoms. AB - Hydrogen adatoms and other species covalently bound to graphene act as resonant scattering centers affecting the electronic transport properties and inducing Anderson localization. We show that attractive interactions between adatoms on graphene and their diffusion mobility strongly modify the spatial distribution, thus fully eliminating isolated adatoms and increasing the population of larger size adatom aggregates. Such spatial correlation is found to strongly influence the electronic transport properties of disordered graphene. Our scaling analysis shows that such aggregation of adatoms increases conductance by up to several orders of magnitude and results in significant extension of the Anderson localization length in the strong localization regime. We introduce a simple definition of the effective adatom concentration x*, which describes the transport properties of both random and correlated distributions of hydrogen adatoms on graphene across a broad range of concentrations. PMID- 25541790 TI - High conductance 2D transport around the Hall mobility peak in electrolyte-gated rubrene crystals. AB - We report the observation of the Hall effect at hole densities up to 6*1013 cm-2 (0.3 holes/molecule) on the surface of electrolyte-gated rubrene crystals. The perplexing peak in the conductance as a function of gate voltage is confirmed to result from a maximum in mobility, which reaches 4 cm2 V-1 s-1 at 2.5*1013 cm-2. Measurements to liquid helium temperatures reveal that this peak is markedly asymmetric, with bandlike and hopping-type transport occurring on the low density side, while unconventional, likely electrostatic-disorder-affected transport dominates the high density side. Most significantly, near the mobility peak the temperature coefficient of the resistance remains positive to as low as 120 K, the low temperature resistance becomes weakly temperature dependent, and the conductance reaches within a factor of 2 of e2/h, revealing conduction unprecedentedly close to a two-dimensional metallic state. PMID- 25541791 TI - Multiple quantum phases in graphene with enhanced spin-orbit coupling: from the quantum spin Hall regime to the spin Hall effect and a robust metallic state. AB - We report an intriguing transition from the quantum spin Hall phase to the spin Hall effect upon segregation of thallium adatoms adsorbed onto a graphene surface. Landauer-Buttiker and Kubo-Greenwood simulations are used to access both edge and bulk transport physics in disordered thallium-functionalized graphene systems of realistic sizes. Our findings not only quantify the detrimental effects of adatom clustering in the formation of the topological state, but also provide evidence for the emergence of spin accumulation at opposite sample edges driven by spin-dependent scattering induced by thallium islands, which eventually results in a minimum bulk conductivity ~4e2/h, insensitive to localization effects. PMID- 25541792 TI - Coherent control of a single 29Si nuclear spin qubit. AB - Magnetic fluctuations caused by the nuclear spins of a host crystal are often the leading source of decoherence for many types of solid-state spin qubit. In group IV semiconductor materials, the spin-bearing nuclei are sufficiently rare that it is possible to identify and control individual host nuclear spins. This Letter presents the first experimental detection and manipulation of a single 29Si nuclear spin. The quantum nondemolition single-shot readout of the spin is demonstrated, and a Hahn echo measurement reveals a coherence time of T2=6.3(7) ms-in excellent agreement with bulk experiments. Atomistic modeling combined with extracted experimental parameters provides possible lattice sites for the 29Si atom under investigation. These results demonstrate that single 29Si nuclear spins could serve as a valuable resource in a silicon spin-based quantum computer. PMID- 25541793 TI - Limits to metallic conduction in atomic-scale quasi-one-dimensional silicon wires. AB - The recent observation of ultralow resistivity in highly doped, atomic-scale silicon wires has sparked interest in what limits conduction in these quasi-1D systems. Here we present electron transport measurements of gated Si:P wires of widths 4.6 and 1.5 nm. At 4.6 nm we find an electron mobility, MU(el)?60 cm2/V s, in excellent agreement with that of macroscopic Hall bars. Metallic conduction persists to millikelvin temperatures where we observe Gaussian conductance fluctuations of order deltaG~e2/h. In thinner wires (1.5 nm), metallic conduction breaks down at G?e2/h, where localization of carriers leads to Coulomb blockade. Metallic behavior is explained by the large carrier densities in Si:P delta-doped systems, allowing the occupation of all six valleys of the silicon conduction band, enhancing the number of 1D channels and hence the localization length. PMID- 25541794 TI - Fractional quantum Hall effect and Wigner crystal of interacting composite fermions. AB - In two-dimensional electron systems confined to GaAs quantum wells, as a function of either tilting the sample in a magnetic field or increasing density, we observe multiple spin-polarization transitions of the fractional quantum Hall states at filling factors nu=4/5 and 5/7. The number of observed transitions provides evidence that these are fractional quantum Hall states of interacting two-flux composite fermions. Moreover, the fact that the reentrant integer quantum Hall effect near nu=4/5 always develops following the transition to full spin polarization of the nu=4/5 fractional quantum Hall state links the reentrant phase to a pinned ferromagnetic Wigner crystal of composite fermions. PMID- 25541795 TI - Non-Poissonian quantum jumps of a fluxonium qubit due to quasiparticle excitations. AB - As the energy relaxation time of superconducting qubits steadily improves, nonequilibrium quasiparticle excitations above the superconducting gap emerge as an increasingly relevant limit for qubit coherence. We measure fluctuations in the number of quasiparticle excitations by continuously monitoring the spontaneous quantum jumps between the states of a fluxonium qubit, in conditions where relaxation is dominated by quasiparticle loss. Resolution on the scale of a single quasiparticle is obtained by performing quantum nondemolition projective measurements within a time interval much shorter than T1, using a quantum-limited amplifier (Josephson parametric converter). The quantum jump statistics switches between the expected Poisson distribution and a non-Poissonian one, indicating large relative fluctuations in the quasiparticle population, on time scales varying from seconds to hours. This dynamics can be modified controllably by injecting quasiparticles or by seeding quasiparticle-trapping vortices by cooling down in a magnetic field. PMID- 25541796 TI - Multilevel interference resonances in strongly driven three-level systems. AB - We study multiphoton resonances in a strongly driven three-level quantum system, where one level is periodically swept through a pair of levels with constant energy separation E. Near the multiphoton resonance condition nhomega=E, where n is an integer, we find qualitatively different behavior for n even or odd. We explain this phenomenon in terms of families of interfering trajectories of the multilevel system. Remarkably, the behavior is insensitive to fluctuations of the energy of the driven level, and survives deep into the strong dephasing regime. The setup can be relevant for a variety of solid state and atomic or molecular systems. In particular, it provides a clear mechanism to explain recent puzzling experimental observations in strongly driven double quantum dots. PMID- 25541797 TI - Asymmetric frequency conversion in nonlinear systems driven by a biharmonic pump. AB - A novel mechanism of asymmetric frequency conversion is investigated in nonlinear dispersive devices driven parametrically with a biharmonic pump. When the relative phase between the first and second harmonics combined in a two-tone pump is appropriately tuned, nonreciprocal frequency conversion, either upward or downward, can occur. Full directionality and efficiency of the conversion process is possible, provided that the distribution of pump power over the harmonics is set correctly. While this asymmetric conversion effect is generic, we describe its practical realization in a model system consisting of a current-biased, resistively shunted Josephson junction. Here, the multiharmonic Josephson oscillations, generated internally from the static current bias, provide the pump drive. PMID- 25541798 TI - Imaging Josephson vortices on the surface superconductor Si(111)-(?7*?3)-In using a scanning tunneling microscope. AB - We have studied the superconducting Si(111)-(?7*?3)-In surface using a 3He-based low-temperature scanning tunneling microscope. Zero-bias conductance images taken over a large surface area reveal that vortices are trapped at atomic steps after magnetic fields are applied. The crossover behavior from Pearl to Josephson vortices is clearly identified from their elongated shapes along the steps and significant recovery of superconductivity within the cores. Our numerical calculations combined with experiments clarify that these characteristic features are determined by the relative strength of the interterrace Josephson coupling at the atomic step. PMID- 25541800 TI - Finite-temperature spin dynamics in a perturbed quantum critical Ising chain with an E8 symmetry. AB - A spectrum exhibiting E8 symmetry is expected to arise when a small longitudinal field is introduced in the transverse-field Ising chain at its quantum critical point. Evidence for this spectrum has recently come from neutron scattering measurements in cobalt niobate, a quasi-one-dimensional Ising ferromagnet. Unlike its zero-temperature counterpart, the finite-temperature dynamics of the model has not yet been determined. We study the dynamical spin structure factor of the model at low frequencies and nonzero temperatures, using the form factor method. Its frequency dependence is singular, but differs from the diffusion form. The temperature dependence of the nuclear magnetic resonance (NMR) relaxation rate has an activated form, whose prefactor we also determine. We propose NMR experiments as a means to further test the applicability of the E8 description for CoNb2O6. PMID- 25541799 TI - Flux-dependent crossover between quantum and classical behavior in a dc SQUID. AB - In a coupled system of one classical and one quantum mechanical degree of freedom, the quantum degree of freedom can facilitate the escape of the whole system. Such unusual escape characteristics have been theoretically predicted as the "Munchhausen effect." We implement such a system by shunting one of the two junctions of a dc SQUID with an additional capacitance. In our experiments, we detect a crossover between quantum and classical escape processes related to the direction of escape. We find that, under varying external magnetic flux, macroscopic quantum tunneling periodically alternates with thermally activated escape, a hallmark of the "Munchhausen effect." PMID- 25541802 TI - Chiral anomaly and diffusive magnetotransport in Weyl metals. AB - We present a microscopic theory of diffusive magnetotransport in Weyl metals and clarify its relation to the chiral anomaly. We derive coupled diffusion equations for the total and axial charge densities and show that the chiral anomaly manifests as a magnetic-field-induced coupling between them. We demonstrate that a universal experimentally observable consequence of this coupling in magnetotransport in Weyl metals is a quadratic negative magnetoresistance, which will dominate all other contributions to magnetoresistance under certain conditions. PMID- 25541801 TI - Magnetization and microstructure dynamics in Fe/MnAs/GaAs(001): Fe magnetization reversal by a femtosecond laser pulse. AB - Thin film magnetization reversal without applying external fields is an attractive perspective for applications in sensors and devices. One way to accomplish it is by fine-tuning the microstructure of a magnetic substrate via temperature control, as in the case of a thin Fe layer deposited on a MnAs/GaAs(001) template. This work reports a time-resolved resonant scattering study exploring the magnetic and structural properties of the Fe/MnAs system, using a 100 fs optical laser pulse to trigger local temperature variations and a 100 fs x-ray free-electron laser pulse to probe the induced magnetic and structural dynamics. The experiment provides direct evidence that a single optical laser pulse can reverse the Fe magnetization locally. It reveals that the time scale of the magnetization reversal is slower than that of the MnAs structural transformations triggered by the optical pulse, which take place after a few picoseconds already. PMID- 25541803 TI - Breaking the symmetry of forward-backward light emission with localized and collective magnetoelectric resonances in arrays of pyramid-shaped aluminum nanoparticles. AB - We propose aluminum nanopyramids (ANPs) as magnetoelectric optical antennas to tailor the forward versus backward luminescence spectrum. We present light extinction and emission experiments for an ANP array wherein magnetoelectric localized resonances couple to in-plane diffracted orders. This coupling leads to spectrally sharp collective resonances. Luminescent molecules drive both localized and collective resonances, and we experimentally demonstrate an unconventional forward versus backward luminescence spectrum. Through analytical calculations, we show that the magnetic, magnetoelectric, and quadrupolar moments of ANPs-which lie at the origin of the observed effects-are enhanced by their tapering and height. Full-wave simulations show that localized and delocalized magnetic surface waves, with an excitation strength depending on the plane wave direction, direct the forward versus backward emitted intensity. PMID- 25541805 TI - Pattern selection in growing tubular tissues. AB - Tubular organs display a wide variety of surface morphologies including circumferential and longitudinal folds, square and hexagonal undulations, and finger-type protrusions. Surface morphology is closely correlated to tissue function and serves as a clinical indicator for physiological and pathological conditions, but the regulators of surface morphology remain poorly understood. Here, we explore the role of geometry and elasticity on the formation of surface patterns. We establish morphological phase diagrams for patterns selection and show that increasing the thickness or stiffness ratio between the outer and inner tubular layers induces a gradual transition from circumferential to longitudinal folding. Our results suggest that physical forces act as regulators during organogenesis and give rise to the characteristic circular folds in the esophagus, the longitudinal folds in the valves of Kerckring, the surface networks in villi, and the crypts in the large intestine. PMID- 25541804 TI - Short-range correlations in the magnetic ground state of Na4Ir3O8. AB - The magnetic ground state of the J(eff)=1/2 hyperkagome lattice in Na4Ir3O8 is explored via combined bulk magnetization, muon spin relaxation, and neutron scattering measurements. A short-range, frozen state comprised of quasistatic moments develops below a characteristic temperature of T(F)=6 K, revealing an inhomogeneous distribution of spins occupying the entirety of the sample volume. Quasistatic, short-range spin correlations persist until at least 20 mK and differ substantially from the nominally dynamic response of a quantum spin liquid. Our data demonstrate that an inhomogeneous magnetic ground state arises in Na4Ir3O8 driven either by disorder inherent to the creation of the hyperkagome lattice itself or stabilized via quantum fluctuations. PMID- 25541806 TI - Experimental support for tilt-dependent theory of biomembrane mechanics. AB - Recent simulations have indicated that the traditional model for topographical fluctuations in biomembranes should be enriched to include molecular tilt. Here we report the first experimental data supporting this enrichment. Utilizing a previously posited tilt-dependent model, a height-height correlation function was derived. The x-ray scattering from a liquid crystalline stack of oriented fluid phase lipid bilayers was calculated and compared with experiment. By fitting the measured scattering intensity, both the bending modulus K(c)=8.3+/-0.6*10-20 J and the tilt modulus K(theta)=95+/-7 mN/m were determined for DOPC lipid bilayers at 30 degrees C. PMID- 25541807 TI - Relaxation in yield stress systems through elastically interacting activated events. AB - We study consequences of long-range elasticity in thermally assisted dynamics of yield stress materials. Within a two-dimensional mesoscopic model we calculate the mean-square displacement and the dynamical structure factor for tracer particle trajectories. The ballistic regime at short time scales is associated with a compressed exponential decay in the dynamical structure factor, followed by a subdiffusive crossover prior to the onset of diffusion. We relate this crossover to spatiotemporal correlations and thus go beyond established mean field predictions. PMID- 25541808 TI - Self-propulsion of pure water droplets by spontaneous Marangoni-stress-driven motion. AB - We report spontaneous motion in a fully biocompatible system consisting of pure water droplets in an oil-surfactant medium of squalane and monoolein. Water from the droplet is solubilized by the reverse micellar solution, creating a concentration gradient of swollen reverse micelles around each droplet. The strong advection and weak diffusion conditions allow for the first experimental realization of spontaneous motion in a system of isotropic particles at sufficiently large Peclet number according to a straightforward generalization of a recently proposed mechanism [S. Michelin, E. Lauga, and D. Bartolo, Phys. Fluids 25, 061701 (2013); S. Michelin and E. Lauga, J. Fluid Mech. 747, 572 (2014)]. Experiments with a highly concentrated solution of salt instead of water, and tetradecane instead of squalane, confirm the above mechanism. The present swimming droplets are able to carry external bodies such as large colloids, salt crystals, and even cells. PMID- 25541810 TI - International trade network: fractal properties and globalization puzzle. AB - Globalization is one of the central concepts of our age. The common perception of the process is that, due to declining communication and transport costs, distance becomes less and less important. However, the distance coefficient in the gravity model of trade, which grows in time, indicates that the role of distance increases rather than decreases. This, in essence, captures the notion of the globalization puzzle. Here, we show that the fractality of the international trade system (ITS) provides a simple solution for the puzzle. We argue that the distance coefficient corresponds to the fractal dimension of ITS. We provide two independent methods, the box counting method and spatial choice model, which confirm this statement. Our results allow us to conclude that the previous approaches to solving the puzzle misinterpreted the meaning of the distance coefficient in the gravity model of trade. PMID- 25541809 TI - Biphasic, lyotropic, active nematics. AB - We perform dynamical simulations of a two-dimensional active nematic fluid in coexistence with an isotropic fluid. Drops of active nematic become elongated, and an effective anchoring develops at the nematic-isotropic interface. The activity also causes an undulatory instability of the interface. This results in defects of positive topological charge being ejected into the nematic, leaving the interface with a diffuse negative charge. Quenching the active lyotropic fluid results in a steady state in which phase-separating domains are elongated and then torn apart by active stirring. PMID- 25541811 TI - Copper- and cobalt-catalyzed direct coupling of sp(3) alpha-carbon of alcohols with alkenes and hydroperoxides. AB - A zerovalent copper- and cobalt-catalyzed direct coupling of the sp(3) alpha carbon of alcohols with alkenes and hydroperoxides was developed in which the hydroperoxides acted as radical initiator and then coupling partner. 1,3-Enynes and vinylarenes underwent alkylation-peroxidation to give beta-peroxy alcohols and beta-hydroxyketones correspondingly with excellent functional group tolerance. The resulting beta-peroxy alcohols could be further transformed into beta-hydroxyynones and propargylic 1,3-diols. PMID- 25541812 TI - Stable selective gratings in LC polymer by photoinduced helix pitch modulation. AB - A cholesteric mixture based on the nematic liquid crystalline side-chain polymer doped with a chiral-photochromic compound was prepared and used as an active medium for creation of stable polarization selective gratings by phototunable modulation of the helix pitch. Such modulation was fabricated in the polymer mixture by a nonpolarized UV-irradiation with spatially modulated intensity that causes E-Z isomerization of a chiral-photochromic dopant, decreasing its helical twisting power. It was shown that the gratings recorded by UV-exposure through a mask are strongly selective to the handedness of circular polarized light. The studied polymer film forms a right-handed helical structure and, correspondingly, the diffraction of only the right-circularly polarized light was found in the transmittance mode. The maximum diffraction efficiencies were found for the wavelength values between the maxima of selective light reflection. The films obtained open very interesting possibilities for further development of materials with stable gratings operating in the entire visible spectral range. Both the position and the width of the spectral range of an efficient diffraction can be easily controlled by the UV exposure and concentration of the dopant. The materials obtained and methods developed can be used for creation of specific diffraction elements for optics and photonics. PMID- 25541813 TI - Glass-liquid phase separation in highly supersaturated aqueous solutions of telaprevir. AB - Amorphous solid dispersions are of great current interest because they can improve the delivery of poorly water-soluble compounds. It has been recently noted that the highly supersaturated solutions generated by dissolution of some ASDs can undergo a phase transition to a colloidal, disordered, drug-rich phase when the concentration exceeds the "amorphous solubility" of the drug. The purpose of this study was to investigate the phase behavior of supersaturated solutions of telaprevir, which is formulated as an amorphous solid dispersion in the commercial product. Different analytical techniques including proton nuclear magnetic resonance spectroscopy (NMR), ultraviolet spectroscopy (UV), fluorescence spectroscopy and flux measurements were used to evaluate the properties of aqueous supersaturated solutions of telaprevir. It was found that highly supersaturated solutions of telaprevir underwent glass-liquid phase separation (GLPS) when the concentration exceeded 90 MUg/mL, forming a water saturated colloidal, amorphous drug-rich phase with a glass transition temperature of 52 degrees C. From flux measurements, it was observed that the "free" drug concentration reached a maximum at the concentration where GLPS occurred, and did not increase further as the concentration was increased. This phase behavior, which results in a precipitate and a metastable equilibrium between a supersaturated solution and a drug-rich phase, is obviously important in the context of evaluating amorphous solid dispersion formulations and their crystallization routes. PMID- 25541814 TI - Development of a Bronsted acid-promoted arene-ynamide cyclization toward the total syntheses of marinoquinolines A and C and aplidiopsamine A. AB - A Bronsted acid-promoted arene-ynamide cyclization has been developed to construct the 3H-pyrrolo[2,3-c]quinolines. This reaction consists of the generation of a highly reactive keteniminium intermediate from arene-ynamide activated by a Bronsted acid and electrophilic aromatic substitution reaction to give arene-fused quinolines in high yields. This methodology enabled facile access to marinoquinolines A and C and aplidiopsamine A. PMID- 25541815 TI - Lewis acid catalyzed cascade reaction of 3-(2-benzenesulfonamide)propargylic alcohols to spiro[indene-benzosultam]s. AB - A highly efficient and convenient construction of the spiro[indene-benzosultam] skeleton from propargylic alcohols has been developed. The reaction proceeded in a Lewis acid catalyzed cascade process, including the trapping of allene carbocation with sulfonamide, electrophilic cyclization, and intramolecular Friedel-Crafts alkylation. In the presence of NIS or NBS, iodo/bromo-substituted spiro[indene-benzosultam]s could be prepared in excellent yields. PMID- 25541816 TI - Evidence for deep acceptor centers in plant photosystem I crystals. AB - Dry micrometer-thick crystalline photosystem I (PSI) has been shown to generate unprecedented large photovoltage under illumination. We use variable-temperature Kelvin probe force microscopy to show that deep acceptor centers are responsible for this anomalous photovoltage. We assumed that these centers are located close to the positively charged F(B)(2+) clusters, forming a coupled center that effectively captures the photoexcited electron into a deep state. We extract the main inherent parameters of the deep centers, which are extremely important in the potential use of photosynthetic proteins in various optoelectronic devices. PMID- 25541817 TI - Evaluation of efficacy of regional and local anesthesia techniques in arteriovenous fistula criation for dialysis. AB - Both, regional and local anesthesia are used for dialysis arterio-venous fistula (AVF) formation in end-stage renal disease patients. There are no prospective, randomized clinical trials comparing effectiveness of these types of anesthesia in these patients. It was a prospective, randomized study. 103 patients with ESRD underwent dialysis AVF operations on upper limb. The patients have been randomly divided in two groups. Group I: 49 patients in whom the operations have been done under the local anesthesia; and Group II: 54 patients in whom the operation has been performed under the vertical infraclavicular block. Radio-Cefalic, Brachio Cefalic and Brachio-Basilic(I stage transposition) fistulas have been created in all patients.Influence of the type of anesthesia on intra- and postoperative pain has been evaluated and compared between the groups. The mean follow-up was 359.5 days in Group I and 340.5 days in Group II (p-NS).The mean patients age was 59.7+/-13.1 years and 60.1+/-14 years in local and regional anesthesia groups, respectively (p=NS). For the whole group, significantly less number of patients with regional anesthesia required additional perioperative analgesics as compared with the local anesthesia group (p=0.0363). Time to postoperative pain initiation was significantly higher in Group II (2.3 hours) as compared with the Group I (1.7 hours, p=0.0477). The need for postoperative pain killers was significantly less in regional as compared with the local anesthesia (p=0.0318). Duration of operation was significantly less in regional (67.5 min.) as compared with local anesthesia (134.7 min. p=0.0007) group. This difference has been detected in Brachio-Cefalic and Brachio-Basilic fistulas (p=0.0257 and 0.001, respectively) but not in Radio-Cefalic one. No anesthesia related complications have been detected. Insufficiency of regional anesthesia has been identified in 3 cases (5.5%).In 5 patients from regional anesthesia group (9.4%) as a result of vasodilation have made more simplified operation. Regional anesthesia provides significantly betterperiperativeanalgesiaas compared with the local anesthesia in AVF operations. It can change the tactic of surgery, significantly decreases the operation time and should be a method of choice for some forms AVF operations. PMID- 25541768 TI - Precision measurement of the mass and lifetime of the Xib- baryon. AB - We report on measurements of the mass and lifetime of the Xi(b)- baryon using about 1800 Xi(b)- decays reconstructed in a proton-proton collision data set corresponding to an integrated luminosity of 3.0 fb-1 collected by the LHCb experiment. The decays are reconstructed in the Xi(b)-->Xi(c)0pi-, Xi(c)0->pK-K pi+ channel and the mass and lifetime are measured using the Lambda(b)0 >Lambda(c)+pi- mode as a reference. We measure M(Xi(b)-)-M(Lambda(b)0)=178.36+/ 0.46+/-0.16 MeV/c2, (tau(Xi(b)-)/tau(Lambda(b)0)=1.089+/-0.026+/-0.011, where the uncertainties are statistical and systematic, respectively. These results lead to a factor of 2 better precision on the Xi(b)- mass and lifetime compared to previous best measurements, and are consistent with theoretical expectations. PMID- 25541818 TI - Correlation of sex steroid and gonadotropin levels with body mass index in underweight and overweight female patients. AB - Both extreme underweight or overweight negatively affects reproductive health, but evidence is inconsistent in terms of mechanisms by which low or high BMI causes reproductive problems. The aim of our study was to investigate associations of sex steroids and gonadotropins with BMI in underweight and overweight patients since childhood. In this study 48 underweight and 55 overweight/obese females underwent full clinical-hormonal analyses. Polycystic ovarian syndrome and metabolic syndrome was the most frequent in overweight and obese patients, whilst non-classical congenital adrenal hyperplasia and ovarian dysfunction prevailed in underweight patients (P=.000). FSH (P=.013) and SHBG (P=.000) levels were higher in patients with low BMI, whilst FT (p=.019) and TT (p=.003) levels were higher in high BMI patients. No difference was found in terms of AMH (P>.05). BMI negatively correlated with FSH (P=.009) and SHBG (P=.001) and positively correlated with FT (P=.001) and TT (P=.002). So sex steroid and gonadotropin levels are determined by particular reproductive disorders, which are associated to childhood BMI and progression of BMI changes. PMID- 25541819 TI - [Peculiarities of clinical and metabolic adaptation of newborns extracted by repeated cesarean section]. AB - The aim of the article was to study the cellular adaptation of newborn extracted by repeated cesarean section (RCS). The study of functional activity of monocytes was conducted. The activity of succinate dehydrogenase (SDG) and glutamate dehydrogenase (GDG), acid phosphatase (AP) and myeloperoxidase (MPO) of 120 newborns, extracted by RCS was determined by means of cytochemical methods. Analyses were performed in the dynamics of the neonatal period on 1-3, 5-7, 28-30 days of life of the infants. It was found that neonatal exposure to PCB on the cell membrane and intracellular structures is accompanied by high activity of the lysosomal acid phosphatase marker and low activity of mitochondrial enzymes SDG and GDG. Reduced activity of MPO from the 1st day of life and the lack of normalization of this index on the 28-30 days of life shows the exhaustion of mechanisms that determine the margin of safety of adaptive responses. PMID- 25541820 TI - [Dynamics of dental status of pregnant women in conjunction with their vegetative and psycho-emotional performance]. AB - The aim of this study was to investigate the dynamics of the dental status in relation to the vegetative and psycho-emotional changes in women in the 1st, 2nd, and 3rd trimester of pregnancy. Dental and clinical neurological examination was conducted to study psycho-emotional and vegetative status of 51 pregnant women aged 19-36 years, who were registered in the antenatal clinic of Poltava. The analysis of the relationship between dental indicators, vegetative and psycho emotional status of women in the 1st, 2nd, and 3rd trimester of pregnancy are presented. Analysis of the results showed that in women in the 3rd trimester the index values of DMF and PMA grow. Despite the evidence that oral health worsens in the 3rd trimester good oral health is maintained. The vegetative function of the body and a high level of adaptive-compensatory capacity of the organism are maintained. The revealed changes of dental health, features of autonomic regulation and psycho-emotional status of pregnant women should be considered when planning dental preventive measures. PMID- 25541821 TI - [The clinical effectiveness of long-term azithromycin in patients with chronic generalized periodontitis]. AB - The purpose of the study was to compare the clinical response to two regimes of azithromycin use in the complex of non-surgical periodontal therapy. After initial periodontal therapy of chronic generalized periodontitis (CGP), 60 patients were randomly assigned to three groups. In group I patients underwent standard medical care; In group II - patients underwent standard medical care and azithromycin: 500 mg once per day, during 3 days; In group III: 500 mg once per day, during 7 days, followed by 500 mg once per week during 12 weeks. Clinical periodontal indices were recorded before treatment and after 1, 3, 6, and 12 months. In group I after 3 months of treatment the clinical effect was lost in 65% of patients. In group III after 12 months clinical effect persisted in 80% of cases. CGP exacerbations frequency was significantly lower in group III compared with group I (chi2=8,03; r=0,0046). The long-term azithromycin at the CGP results in significantly clinical benefit of 80% patients for at least one year and satisfactorily tolerated. PMID- 25541822 TI - [Analysis of risk factors of development of re-ischemic stroke]. AB - The aim of the research was to study risk factors of development of re-ischemic stroke. Clinical and laboratory investigation of 46 patients with ischemic stroke was conducted. In group I the asymptomatic form of an ischemic insult was revealed in 22 (47,8%) of patients, of which 13 (59%) of patients one transferred insult, and at the others of 9 (41%) - more than one insult is revealed. In group with the diagnosed repeated asymptomatic insult, an arterial hypertensia came to light at 24 (100%) of patients, reliably above (p<0,01) the ischemic heart disease 13 (59,0%) and chronic heart condition 18 (81,8%) diagnosed. On MRT at 36,4% of patients with the diagnosed repeated asymptomatic insult the centers are located in the same pool of blood supply of the same hemisphere, as at the first insult, that reliably (r<0,01) correlated with a degree of expressiveness of neurologic deficiency. The obtained given assessments of risk factors of progress of an insult assist early revealing of asymptomatic insults. PMID- 25541823 TI - [Effect of concomitant chronic kidney disease on the xanthine metabolism in patients with chronic heart failure]. AB - It is believed that patients with decreased glomerular filtration rate have stronger association between serum uric acid levels and increased risk of cardiovascular disease. However, it is unclear whether the presence of concomitant chronic kidney disease modifies the xanthine metabolism. The aim of this study was to examine xanthine metabolism violations in chronic heart failure (CHF) patients with concomitant chronic kidney disease (CKD), and evaluate its impact on uric acid levels and xanthine oxidase activity. The study population consisted of 112 patients, aged 72,5+/-0,98 years. The main group of patients consisted of 72 within CKD patients and the comparison group - of 40 non-CKD participants. We noted high and almost equal detection of xanthine metabolism violations in CHF patients with CKD as well as in non-CKD patients. This data indicate greater severity of the xanthine metabolism violations in patients with concomitant CKD. PMID- 25541824 TI - [Correction of psycho-emotional state by the biofeedback method in patients with metabolic syndrome]. AB - Metabolic syndrome is one of the important clinical problems of medicine. The aim of this study was to demonstrate the efficacy of heart rate variability biofeedback method in correction of mental and emotional state in patients with metabolic syndrome. For this task was set to study the dynamics of indicators of mental and emotional stress by biofeedback based hardware-software complex "Amblyocor" in patients with metabolic syndrome. Course of heart rate variability biofeedback passed 10 patients with the metabolic syndrome. During biofeedback sessions conducted tests that assess psycho-emotional state by 5 characters. Data processing was performed using software package "Statistica 8.0" and showed a statistically significant decrease in indicators of mental and emotional stress, that demonstrates the effectiveness of biofeedback in the correction of mental and emotional stress in patients with metabolic syndrome. PMID- 25541825 TI - [Dependence of clinical and laboratory indicators of the level of systemic inflammation in patients with psoriasis of moderate severity with concomitant metabolic syndrome]. AB - The purpose of this study is to establish the relationship between clinical and laboratory indicators of the level of systemic inflammation in patients with psoriasis with concomitant metabolic syndrome. Clinical and laboratory studies conducted in 40 patients with uncomplicated common plaque psoriasis, the stationary stage, the average degree of severity with concomitant metabolic syndrome. There is a clear relationship between the level of hs-CRP and indices PASI, BSA, BMI, SAT, insulin, HOMA, IL-6, TNF-alpha and ceruloplasmin. This indicates the relationship between the severity of psoriasis, metabolic disorders and systemic inflammation. Systemic inflammatory process is accompanied by insulin resistance, disorders of lipid and nitrogen metabolism and regulation of vascular tone. Increase in the intensity of systemic inflammation is accompanied by increased skin lesions, increased systolic blood pressure and disorders of lipid and carbohydrate metabolism. Processes of systemic inflammation andinsulin resistance in patients with psoriasis and metabolic syndrome may be potential targets of complex therapy. PMID- 25541826 TI - [Prognostic and predictive value of koilocytosis, expression of e6 hpv types 16/18, p16ink4a, p53 in locally advanced squamous cell carcinomas of oral cavity and oropharynx, associated with human papillomavirus]. AB - To determine the predictive and prognostic value of koilocytosis, expression of E6 HPV types 16/18, p16INK4a, p53 in patients with locally advanced HPV associated squamous cell carcinoma of oral cavity and oropharynx. In biopsy specimens of squamous cell carcinomas of oral cavity and oropharynx from 60 patients performed koylocytes count, immunohistochemical detection of HPV 16/18 types E6 protein, proteins p16INK4a and p53. Koilocytosis was detected in 50 patients (83.3%); in all 60 patients (100%) were simultaneous expression of p16INK4a and E6 HPV types 16/18; p53 expression was found in 37 patients (61.7%). After combined treatment (induction chemotherapy followed by radiotherapy) stable disease (SD) was detected in 11 patients (18.3%), partial response (PR) - in 25 patients (41.7%), complete response (CR) - in 24 patients (40.0%). There were no cases of disease progression. Treatment effect correlated with expression of p16INK4a (rho = 0.3, p = 0.024) and expression of p53 (rho = - 0.3, p = 0.019). Patients with a low expression of p16INK4a (2 points) and high expression of p53 (4 "+") had a high level of SD and had no CR. For all patients, the median of overall survival (OS) was 17 months, 1-year cumulative survival rate was 66.7%, 2 year cumulative survival rate - 35.0%. Median of overall survival was correlated with koilocytosis (rho=0.5, p<0,001) and expression of E6 HPV types 16/18 (rho=0.9, p<0.001), p16INK4a (rho=0.9, p=0.037), p53 (rho=-0.9; p<0.001). Patients with low expression of p53 (0 and 1 "+") had cumulative 1-year survival rates 87% and 90%, respectively (p<0.001), 2-year survival rates - 52% and 80%, respectively (p=0.015). In the Cox proportional hazards model the significant prognostic factors were prevalence of primary tumor (OR 2.2, 95% CI 1.3 - 3.5, p=0.003) and p53 expression (OR 1.3, 95% CI 1.1=1.7, p=0.016). High expression of p16INK4a associated with a high effect of combined treatment, high expression of a p53 - with low effect of treatment. Koilocytosis and expression of E6 HPV 16/18 types have no predictive value. Median of overall survival correlated with koilocytosis, expression of E6 HPV types 16/18 and p16INK4a. P53 expression is an independent predictor of negative prognosis for overall survival. Increase in the level of p53 expression is associated with a reduction in overall survival and cumulative 1- and 2-year survival rate. For patients with low expression of p16INK4a or high p53 expression, surgery is advisable to consider as first stage of treatment. PMID- 25541827 TI - Clinical and diagnostic features and treatment of giardiasis. AB - Giardia is the most common causes of protozoan diarrhea that lead to significant morbidity and mortality worldwide. Giardiasis can be cause of disturbance of host immune response. The treatment of Giardiasis is unsuccessful in some cases. The purpose of this study was to determine the clinical features and the content of secretory immunoglobulin A (sIgA) among adults and to evaluate efficiency of new plant preparation "Sausalin". The clinical studies were conducted in Karaganda Regional Infection Hospital (Kazakhstan). 250 patients with giardiasis were randomly assigned to receive sausalin at a dose 720 mg/day or ornidazole at 1500 mg/day. Clinical symptoms of giardisis and efficiency of treatment were evaluated. Protozoal clearance rate and clinical symptoms were assessed. Stool samples were collected from 40 patients and examined the content of sIgA. Our study found the prevalence of abdominal pain, dyspeptic syndrome and the symptoms of intoxication in patients with giardiasis. The increase the level of sIgA was detected, especially in females (88 mg/l). Sausalin was more effectiveness than ornidazole. After the treatment, the clearance rate of giardia (85.71% vs. 42.19%; P<0.05) and the clinical efficacy were significantly higher in the sausalin-treated group than in the ornidazole-treated group. The features of clinic manifestations of giardiasis were identified in population of Kazakhstan. Our data suggest the higher level of sIgA was significantly associated with features of clinic manifestations that the participant had. Treatment with sausalin was more effective than treatment with ornidazole. Further research is needed to explain the existence relationship between Giardia infection and host immune response. PMID- 25541828 TI - [Clinical characteristics of mumps infection in children and adult patients]. AB - The aim of the article was to study clinical manifestations of mumps infection (infectious parotitis) - a viral illness that affects glands that produce saliva, pancreas, and nervous system in children and adult patients. 219 patients (42 children and 177 adults) with mumps infection were studied. The investigation showed that parotid salivary gland disorder was the most common in adults; sublinguitis - inflammation of the sublingual gland was the most common in children. Serous meningitis occurred exclusively in preschool and early school age. Pancreatitis was less common in children than in adults. Infectious parotitis involving the parotid salivary gland was taking its normal course with positive outcome. Pancreatitis and serous meningitis occurred at the 3-5 day of illness with infectious parotitis. Pancreatitis was with positive outcome, with the exceptions of adult patients with pain syndrome (repair process delayed to 1 1.5 months). Mean duration of hospitalization for children with infectious parotitis was 7 days, for adults - 10-14 days. Mean duration of hospitalization for patients with serous meningitis was 14 days. Study showed that in 20,1% of 16 27 years old males developed orchitis. PMID- 25541829 TI - [RDBH-method and big DyeTM terminator technology in accurate diagnosis of beta thalassemia and the allelic polymorphism of beta-globin cluster]. AB - IThe purpose of this study was to evaluate of the efficiency of RDBH-method and Big DyeTM Terminator technology in an accurate diagnosis of beta-thalassemia and the allelic polymorphism of beta-globin cluster. It was done a complete hematology analysis (HB, MCH, MCV, MCHC, RBC, Hct, HbA2, HbF, Serum iron, Serum ferritin at four children (males, 6-10 years old) and their parents. Molecular analysis included Reverse Dot-Blot Hybridization StripAssay (RDBH) and DNA sequencing on ABI PRISM Big DyeTM Terminator. Hematologic and molecular parameters were contradictory. The homozygosity for beta0-thalassemia (beta0IVS2.1[G>A] and beta0codon 8[-AA]) at three boys with the mild clinical manifestation and heterozygosity of their parents for mutations, and the absence of beta-globin mutations at parents and a boy who holds monthly transfusion was established by RDBH-analysis. DNA sequencing by technology Big DyeTM Terminator showed polymorphism at positions -551 and -521 of Cap5'-region (-650-250) - (AT)7(T)7 and (AT)8(T)5. Application of the integrated clinical-molecular approach is an ideal method for an accurate diagnosis, identification of asymptomatic carriers and a reduce of the risk of complications from beta thalassemia, moreover screening of gammaG-gene and the level of fetal hemoglobin in early childhood will help manage of beta-thalassemia clinic and prevent heavy consequences of the disease. PMID- 25541830 TI - Congenital chylothorax in newborn with trisomy 21. AB - Neonatal chylothorax results from the accumulation of chyle in the pleural space and may be either congenital or an acquired condition. Congenital chylothorax is most likely due to abnormal development or obstruction of the lymphatic system. It is often associated with hydrops fetalis. It can be idiopathic or may be associated with various chromosomal anomalies including Trisomy 21, Turner syndrome, Noonan syndrome, and other genetic abnormalities. Congenital pulmonary lymphangiectasia and generalized lymphangiomatosis have also been reported to be associated with congenital chylothorax. Several case reports indicate that congenital chylothorax can recur in subsequent offspring, suggesting a possible underlying genetic etiology. It is important to identify infants with chylothorax, as there are specific issues that need to be addressed in the management of these patients. We present a case of newborn with trysomy 21 (trisomy 21 was diagnosed antenatally by amniocentesis with support of Association "Perinatology"), who developed moderate Respiratory Distress Syndrome, chest X-ray and US reveal pleural effusion on right side rapid intervention was made before deterioration, requiring intensive life-saving measures. In the neonate, chylous effusion is not a common cause of pleural effusions. It is characterized as an exudate because of the high protein and lipid content once the infant is fed. The fluid will be clear/yellow to slightly cloudy in the unfed state and will quickly become milky following feeding, as chylomicrons appear in the fluid. Lymphocytes predominate in the differential cell count of chyle. The volume of fluid output can be high, and management can be challenging. We review the common manifestations of congenital chylotoraxes and emphasize the importance of early diagnosis and intervention in preventing devastating outcomes from this condition. PMID- 25541831 TI - [Cytogenetic features of teenage girls with secondary amenorrhea]. AB - Some features of the chromosome apparatus status were studied in 25 adolescent girls, aged 14-18, with secondary amenorrhea and in 29 girls of the same age with a regular menstrual cycle. Materials for cytogenetic analysis were preparations of chromosomes at the stage of metaphase obtained from the culture of the peripheral blood lymphocytes. The technique of the culture preparation was carried out according to the standard method. 2225 metaphase plates were analyzed in girls with secondary amenorrhea, and 2603 plates were tested in their healthy age-mates. An increased total level of chromosomal aberrations and a rise in the frequency of disorders in the chromatid, chromosome and genome types of peripheral blood lymphocytes have been registered in the examined persons as compared with their healthy age-mates. We have shown, that polyploid cell registered in 15 times oftener in adolescent girls with SA as compared with healthy girls. It can be assumed that some marked changes in the frequency of chromosomal aberrations in patients with secondary amenorrhea and in their healthy age-mates may arise both as a result of exposure to the multiple environmental factors and disorders of rather complicated processes of DNA damages reparation. PMID- 25541832 TI - [Genomic instability in atherosclerosis]. AB - A comparative study of the level of genomic instability, parameters of quantitative and structural mutations of chromosomes (aberration, aneuploidy, polyploidy) in lymphocyte cultures from patients with atherosclerosis of age 80 years and older (control group - 30-35 years old) was conducted. The possibility of correction of disturbed genomic indicators by peptide bioregulators - Livagen (Lys-Glu-Asp-Ala) and cobalt ions with separate application or in combination was also studied. Control was lymphocyte culture of two healthy respective age groups. It was also shown that patients with atherosclerosis exhibit high level of genomic instability in all studied parameters, regardless of age, which may suggest that there is marked increase in chromatin condensation in atherosclerosis. It was also shown that Livagen (characterized by modifying influence on chromatin) separately and in combination with cobalt ions, promotes normalization of altered genomic indicators of atherosclerosis in both age groups. The results show that Livagen separately and in combination with cobalt ions has impact on chromatin of patients with atherosclerosis. The identified protective action of Livagen proves its efficacy in prevention of atherosclerosis. PMID- 25541833 TI - Embryonal antitumor modulator of mkrtchyan prevents streptozotocin-induced damage of mouse and human pancreatic Beta cells in primary culture. AB - Restoration of beta cell functional activity is a cracial in diabetes type I treatment. Earlier, we have shown that embryonal antitumor modulator, created by prof. L. Mkrtchyan (EATM), expresses protective activity in rat diabetes model. In the present study, we sought to evaluate whether EATM directly acts on beta cell and protects them from streptozotocin (STZ) induced damage in primary mouse and human pancreatic beta cell cultures. Beta cells were isolated by treatment of whole pancreas (mouse) or piece of pancreatic tissue (human) with collagenase and trypsine. Human pancreatic beta cells were isolated from the piece of tissue obtained from caucasian 30-year old male undergoing surgery for benign pancreatic cysts. Beta cell damage was induced by STZ. Experiments carried out on mice beta cells showed higher effectiveness of EATM in concentration 0.01 mg/ml which almost completely abolished damage of cells induced by STZ in concentration 0.1 mg/ml and retained their functional activity. Experiments with human beta showed similar results and demonstrated EATM-induced stimulation of insulin production by intact beta cells. PMID- 25541834 TI - [Issue of correlation between radiological and pathomorphological examinations (review)]. AB - Modern research technologies in clinical practice, ultrasound, CT, MRI altered the widespread adoption of the essential conditions and pathological processes in early verification, which is the basis of timely and optimal treatment. Therefore, it is very important to reveal morphological characteristic of pathological changes in each organ, primarily in tumors, which determine the specificity of ultrasound and computer-tomography images. The review presents the information about the latest development relating to the results of radiological and histopathomorphological examinations. It is shown that in most cases the radiological research requires combined morphological control, which largely determines the targeted and effective treatment. PMID- 25541835 TI - [Alterations of immunebalance in the rats blood during experimental preeclampsia]. AB - The aim of the study was to establish a violation of hormonal (progesterone and estradiol) and immune balance (interleukins IL-2, IL-10, TNF-alpha) in the rats blood at different stages of experimental PE induced by hypoxia placenta. For the purpose of modeling of PE in pregnant rats, at 10-thday of gestation the lumen of the abdominal aorta below the renal artery was narrowed by the silk thread a third of its diameter (0.2 mm). Blood for the study was taken at the18thand25th day of pregnancy. In the blood content of interleukins(IL-2, IL-10, TNF-alpha) and the concentration of progesterone and estradiol by immunoenzymaticassay were measured. A results of research established that with increasing of the gestational age in the rats with experimental PE estradiol and progesterone content in the blood increased much slower than in the control animals. At the same time in the blood of pregnant rats with placental hypoxia in the second trimester TNF-alpha level was by 80% higher and the level of IL-10 was 30% lower than in the control animals. With the increase of gestational age (in the third trimester) in animals of the experimental group blood content of IL-2 and TNF alpha increased sharply (by 50% and 30%), whereas the level of IL-10 did not change compared with baseline values. In the control group of animals, alterations in the cytokines content were much slower. It was concluded that violation of the synthesis of progesterone in hypoxic placenta and its insufficient content in the blood during pregnancy is one of the causes of disorders of the immune balance in the body of pregnant rats. Observation of the dynamics of progesterone in the blood during pregnancy may be informative for the early diagnosis of PE and its timely treatment. PMID- 25541836 TI - [Modifications of chemical composition of blood serum in chronic nitrate intoxication (experimental research)]. AB - Nitrates (salts of nitric acid) are very common substances in nature and are present in almost all living organisms. Relevance of research about features of various pathological processes in chronic nitric intoxication significantly associated with the fact that the intake of nitro compounds has significantly increased in recent years, especially in rural areas where local water sources are used. Investigations were carried out on 20 white Wistar rats. Two series of the experiment ware held: Group I - intact animals (10 animals); Group II - animals after administration of sodium nitrate at a dose of 200 mg/kg in the form of an aqueous solution intragastrically for 60 days (10 animals). Chronic nitrate intoxication leads to a significant increase of the level of serum chondroitin rats with permanent indicators glycoproteins indicates that the products disorganization of proteoglycans from the bone to the blood serum. Increasing of overall level glycosaminoglycans and the third fraction (heparan sulfate), and reducing of the 2-nd fraction (chondroitin-4-sulfate) glycosaminoglycans in serum may be indicative of a chronic lesion of sodium nitrite intoxication general connective tissue (including bone tissues and liver parenchymal). PMID- 25541837 TI - [Anti-platelet therapy in patients with acute coronary syndromes]. AB - The basis for different manifestations of acute coronary syndromes (ACS) is a common anatomical substrate represented as dysfunction of endothelium, chronic inflammation and impairment of the surface of atherosclerotic plaque, slowdown of blood flow and forming of intravascular thrombus (atherothrombosis). Close interrelation between the processes of atherogenesis and thromb formation makes reasonable application of long-term anti-thrombotic therapy aimed at secondary prevention of cardio-vascular complications. The leading role in prevention of atherosclerosis is given to anti-platelet drugs that inhibit the function of platelets. Analysis of the results of numerous clinical trials demonstrated that probably there is no need in developing anti-platelets of new generation in order to achieve success in treatment of ACS. It would be reasonable to achieve deeper understanding of the pathologic process and be more insistent in selecting the therapy. PMID- 25541838 TI - Clinical variability of ocular involvement in mycosis fungoides. AB - IMPORTANCE: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma and may rarely infiltrate the ocular structures. Ophthalmic findings in MF can be highly variable. The most commonly involved ocular tissue is the eyelid skin, but intraocular involvement can be seen in patients with extensive systemic disease. To our knowledge, an isolated eyelid mass as an initial manifestation of MF has not been previously reported. OBSERVATIONS: We report a series of 4 cases of ocular involvement in patients with MF demonstrating a highly variable ophthalmic presentation of this disease. The development of an isolated eyelid mass was an initial manifestation of MF in 1 of the patients. Isolated anterior uveitis, vitritis, and choroidal mass are described in 3 patients with aggressive systemic disease. CONCLUSIONS AND RELEVANCE: Infiltration of the ocular structures by MF is rare, but the involvement of different ocular tissues and a highly variable clinical presentation can be seen. Eyelid lesion may be an initial manifestation of MF. These cases suggest that intraocular involvement occurs in patients with aggressive systemic disease and usually portends a poor prognosis for survival. PMID- 25541839 TI - Staged laryngotracheoplasty in adult laryngotracheal stenosis: predictors of long term decannulation. AB - IMPORTANCE: This study reviews a single center's experience of performing staged laryngotracheoplasty (LTP) for the treatment of laryngotracheal stenosis with the ultimate goal of attaining long-term airway patency without restenosis. OBJECTIVE: To identify staged LTP as an efficacious surgical treatment option for laryngotracheal stenosis. DESIGN, SETTING, AND PARTICIPANTS: From January 2000 to January 2012, patients at a tertiary care academic institution presenting with diagnoses of laryngeal or laryngotracheal stenosis were retrospectively identified. Medical records from adult patients were inspected, and patient demographics, clinical data, and clinical outcomes were recorded. All patients undergoing staged LTP were initially included. Patients with history of head and neck malignant neoplasm were excluded. INTERVENTIONS: Staged LTP. MAIN OUTCOMES AND MEASURES: The primary outcome was long-term decannulation, defined as decannulation for duration of at least 6 months. RESULTS: Sixty-one patients were included in this study. The mean (SD) patient age was 47.1 (16.7) at the time of first-stage LTP and had a mean (range) follow-up of 5.32 (0.5-17.3) years from the first-stage reconstruction. Etiology of stenosis included prolonged intubation in 27 patients (44%), autoimmune disease in 9 (15%), idiopathic causes in 11 (18%), blunt laryngeal trauma in 10 (16%), and other causes in 4 (7%). Forty-nine patients (80%) were successfully decannulated, while to date 12 (20%) remain tracheostomy or tympanostomy tube dependent. Univariate analyses showed no significant association between decannulation and age (P = .35), sex (P = .52), history of intubation (P = .22), surgeon (P = .20), etiology of stenosis (P = .91), or length of stenosis (P = .31). Multivariate logistic regression analysis showed a significant inverse relationship between grade of stenosis and probability of decannulation (P = .01). CONCLUSIONS AND RELEVANCE: Staged LTP is an option for the reconstruction laryngotracheal stenosis. Our experience shows excellent decannulation rates in the selected patients with stenosis, many of whom have failed treatment with other surgical modalities. PMID- 25541840 TI - Association between missense mutations in the BBS2 gene and nonsyndromic retinitis pigmentosa. AB - IMPORTANCE: A large number of genes can cause inherited retinal degenerations when mutated. It is important to identify the cause of disease for a better disease prognosis and a possible gene-specific therapeutic intervention. OBJECTIVE: To identify the cause of disease in families with nonsyndromic retinitis pigmentosa. DESIGN, SETTING, AND PARTICIPANTS: Patients and family members were recruited for the study and underwent clinical evaluation and genetic analyses. MAIN OUTCOMES AND MEASURES: Identification of sequence variants in genes using next-generation sequencing. RESULTS: We performed exome sequencing for 4 families, which was followed by Sanger sequencing of the identified mutations in 120 ethnicity-matched patients. In total, we identified 4 BBS2 missense mutations that cause nonsyndromic retinitis pigmentosa. Three siblings of Moroccan Jewish ancestry were compound heterozygotes for p.A33D and p.P134R, and 6 patients belonging to 4 families of Ashkenazi Jewish ancestry were homozygous for either p.D104A or p.R632P, or compound heterozygous for these 2 mutations. The mutations cosegregated with retinitis pigmentosa in the studied families, and the affected amino acid residues are evolutionarily conserved. CONCLUSIONS AND RELEVANCE: Our study shows that BBS2 mutations can cause nonsyndromic retinitis pigmentosa and highlights yet another candidate for this genetically heterogeneous condition. PMID- 25541841 TI - Surgical treatment of Achilles tendon ruptures: the comparison of open and percutaneous methods in a rabbit model. AB - BACKGROUND: This study was intended to investigate the healing properties of open and percutaneous techniques in a rabbit model and compare histological, electron microscopical, and biomechanical findings of the healed tendon between the groups. METHODS: Twenty-six rabbits were randomly assigned to two groups of thirteen rabbits each. Percutaneous tenotomy of the Achilles tendon (AT) was applied through a stab incision on the right side 1.5 cm above the calcaneal insertion in all animals. Using the same Bunnell suture, the first group was repaired with the open and the second group was repaired with the percutaneous method. ATs were harvested at the end of eight weeks for biomechanical and histological evaluation. RESULTS: When the sections were evaluated for fibrillar density under electron microscopy, it was noted that fibrils were more abundant in the percutaneous repair group. The tendon scores in the percutaneous group were less than the open group indicating closer histological morphology to normal. The difference was not significant (p=0.065). The mean force to rupture the tendon was 143.7+/- 9.5 N in percutaneous group and 139.2+/-8.2 N in the open group. The difference was not significant (p=0.33). CONCLUSION: Percutaneous techniques provide as good clinical results as the open techniques do. The healing tendon shows better findings in histological and electron microscopical level with percutaneous technique. PMID- 25541842 TI - The effects of sildenafil in liver and kidney injury in a rat model of severe scald burn: a biochemical and histopathological study. AB - BACKGROUND: Severe burn induces systemic inflammation and reactive oxygen species leading to lipid peroxidation which may play role in remote organs injury. Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate specific phosphodiesterase-5. Sildenafil reduces oxidative stress and inflammation in distant organs. The aim of the present study was to evaluate the effects of different dosages of sildenafil in remote organs injury. METHODS: A total of thirty-two rats were randomly divided into four equal groups. The groups were designated as follows: Sham, Control, 10, and T20 mg/kg sildenafil treatment groups. Levels of malondialdehyde (MDA), vascular endothelial growth factor (VEGF), VEGF receptor (Flt-1), activities of glutathione peroxidase (Gpx), levels of total antioxidative capacity (TAC), and total oxidant status (TOS) were measured in both tissues and serum, and a semi-quantitative scoring system was used for the evaluation of histopathological findings. RESULTS: Sildenafil increased levels of Gpx, and Flt-1, and decreased MDA and VEGF levels in tissues. Sildenafil also increased serum levels of TAC and Flt-1 and decreased TOS, OSI, and VEGF. CONCLUSION: Sildenafil decreased inflammation scores in remote organs in histopathological evaluation. It has protective effects in severe burn-related remote organ injuries by decreasing oxidative stress and inflammation. PMID- 25541843 TI - Thymoquinone attenuates trauma induced spinal cord damage in an animal model. AB - BACKGROUND: Spinal cord injury (SCI) is one of the most devastating conditions leading to neurological impairment and disabilities. The aim of the study was to investigate the potential neuroprotective effect of thymoquinone (TQ) histopathologically in an experimental model of traumatic spinal cord injury (SCI). METHODS: Twenty-four male Wistar albino rats were randomly divided into 4 groups: control group; SCI group; SCI-induced and 10 mg/kg/day TQ administered group; SCI-induced and 30 mg/kg/day TQ administered group. TQ was given as intraperitoneal for three days prior to injury and four days following injury. Spinal cord segment between T8 and T10 were taken for histopathologic examination. Hemorrhage, spongiosis and liquefactive necrosis were analyzed semiquantatively for histopathological changes. RESULTS: Administration of TQ at a dose of 10 mg/kg did not cause any significant change on the histological features of neuronal degeneration as compared to the SCI group (p=0.269); however, 30 mg/kg TQ significantly decreased the histological features of spinal cord damage below that of the SCI group (p=0.011). CONCLUSION: Data from this study suggest that TQ supplementation attenuates trauma induced spinal cord damage. Thus, TQ needs to be taken into consideration, for it may have a neuroprotective effect in trauma induced spinal cord damage. PMID- 25541844 TI - Fournier's gangrene: review of 120 patients and predictors of mortality. AB - BACKGROUND: Fournier's gangrene (FG) is a devastating and potentially fatal disease requiring prompt and aggressive debridement. In this study, it was aimed to assess the predictors of mortality in a large cohort. METHODS: Prospectively maintained data of patients with FG were analyzed. Demographic data, duration of symptoms, Uludag Fournier's Gangrene Severity Index (UFGSI) scores, co morbidities [particularly diabetes mellitus (DM)], etiologies, number of debridement, stoma requirements, length of intensive care unit and hospital stay, and morbidity and mortality rates were reviewed. Multivariate analysis was performed in order to determine factors affecting mortality. RESULTS: 120 patients (81 males) were included in the study. Median age was 58 (22-85) years. UFGSI score was median 9 (1-30). DM was present in 69 (57.5%) patients. Etiology of FG was perianal in fifty-nine, urogenital in 52, and skin in 9 patients. Median debridement count was 3 (1-12). Thirty-one patients required stoma. Forty eight patients were admitted to intensive care unit and 25 patients required mechanical ventilation. Overall mortality rate was 20.8%. Multivariate analysis revealed UFGSI as the only predictor of mortality (p=0.001). Mortality rate was 13.64 times higher for patients with a UFGSI score of 9 or higher. CONCLUSION: Fournier's gangrene is a mortal disease requiring emergency surgery. UFGSI is an efficient predictor of mortality for patients with FG. PMID- 25541845 TI - A series of civilian fatalities during the war in Syria. AB - BACKGROUND: A considerable number of deaths due to firearm injuries have occurred during wars all over the world. In this study, it is aimed to evaluate demographic characteristics and injury properties of cases died during civil war in Syria. METHODS: The postmortem examination and autopsy reports of 321 forensic deaths occurred between January and December 2012 were analyzed, retrospectively. Of the 321 forensic deaths,186 cases were injured and died in the civil war in Syria and, therefore, included in the scope of the study. Four cases died by natural causes or traffic accidents were excluded. RESULTS: Cases were most commonly (n=73, 39.2%) aged between 21 and 30 years, and 21.5% (n=40) of cases aged under 20 years. Of females, 68.8% (n=11) were children and young adults under 20 years of age. An overwhelming majority of deaths (n=125, 67.2%) were caused by explosive and shrapnel injuries, followed by (n=49, 26.3%) gunshot injuries related deaths. CONCLUSION: This study indicated that a significant proportion of those who died after being injured in the Syrian war were children, women and elderly people. The nature and localization of the observed injuries indicated open attacks by military forces regardless of targets being civilians and human rights violations. PMID- 25541846 TI - The prognostic value of pro-calcitonin, CRP and thyroid hormones in secondary peritonitis: a single-center prospective study. AB - BACKGROUND: Infections and sepsis remain the leading cause of morbidity and mortality in secondary peritonitis. Clinicians are still challenged with the task of finding an early and reliable diagnosis of septic complications. The role of inflammatory markers (Procalcitonin (PCT), C-reactive Protein (CRP) and thyroid hormones in determining the severity of secondary peritonitis was evaluated in this study. METHODS: On the preoperative and first, third, fifth, seventh, and fourteenth postoperative days, PCT, CRP, and thyroid hormone concentrations were measured in serum taken from eighty-four consecutive patients who were operated on for secondary peritonitis between January 2008 and January 2010. All data was entered and analyzed using the Statistical Package for Social Sciences, version 15.0 and clinical parameters were compared using the student's t-test. RESULTS: For the groups diagnosed with perforated viscus, PCT concentrations were significantly low in contrast to high thyroid hormone levels in patients who developed postoperative complications or died when compared to patients whose postoperative course was uneventful or discharged. The PCT concentration significantly correlated with the CRP concentration and WBC count. CONCLUSION: In the absence of postoperative complications, PCT is a better predictor of outcome than CRP in secondary peritonitis. Our study showed that a low thyroid hormone level can serve as an important prognostic parameter of disease severity in secondary peritonitis. PMID- 25541847 TI - Features of the traffic accidents happened in the province of Aydin between 2005 and 2011. AB - BACKGROUND: In this study, it was aimed to analyze the traffic accidents with postmortem examinations and autopsies. METHODS: From the one thousand eight hundred and fifteen forensic autopsies, reports of 334 traffic accidents were searched. Features such as the scene of the accident, type of the accident, type of the vehicles involved in the accident, the year, season, day and hour of the accident, the positions of the victims in the traffic, concomitant orthopedic injuries, whether autopsy was performed, and cause of death were investigated. RESULTS: Among the one thousand eight hundred and fifteen forensic death cases, observed cause of death was determined to be traffic accidents in 334 (18.4%) cases. Male cases accounted 84.1%, and male to female ratio was 5.3 to 1. From the reports, 32.6% of the accidents happened in summer and most commonly during holidays (33%). The rate of the accidents happened in the city center was 35.3% and 32.9% of these cases died due to pedestrian collision. Moreover, it was determined that the most injured person was the driver. Automobiles took the lead in the causes of the traffic accidents. CONCLUSION: It is realized that traffic accident-related deaths have a substantial place among forensic deaths and continue to be an important public health problem. It is conspicuous that improving public education on traffic safety, increasing traffic management and control measures are of great significance. PMID- 25541848 TI - Evaluation of liver injury in a tertiary hospital: a retrospective study. AB - BACKGROUND: Liver is the most frequently injured intraabdominal organ following abdominal trauma. Liver injury in polytraumatized patients can vary from minor contusions to major lacerations and is associated with morbidity and mortality. The objective of this study was to evaluate the outcome of liver injury in polytraumatized patients. METHODS: Only surgically treated 82 patients with liver injury over an eight year period (2005-2013) were included in this study and analyzed retrospectively. Data collected included demographics, laboratory findings, intraoperative findings, operative management, and outcome. The patients were divided into two groups and the mortality and survival data were compared. RESULTS: The overall mortality rate was 18.3% (15 of 82 patients). 34 (41.5%) patients had blunt, forty-eight (48.5%) had penetrating trauma. There were multiple traumas in forty-seven (57%) patients. Forty-seven (57%) patients had total of seventy one coexisting intraabdominal injuries. Forty-six (56.1%) patients had stable and thirty-six (43.9%) had unstable hemodynamics on admission. In mortality group AST, ALT, LDH, APTT, PT, INR, and creatinine levels were high, fibrinogen levels and platelet counts were low on admission. CONCLUSION: Hemodynamic instability, coexisting musculoskeletal and chest injury, high APTT, PT, INR, AST, ALT, LDH levels, and low fibrinogen levels and platelet counts on admission should be considered as predictive factors for mortality. PMID- 25541849 TI - Comparison of early surgery (unroofing-curettage) and elective surgery (Karydakis flap technique) in pilonidal sinus abscess cases. AB - BACKGROUND: The aim of this study is to compare the effectiveness and success of early (acute) period local surgical intervention (unroofing-curettage) followed by dressing and secondary healing with the surgery performed in elective conditions (pilonidal sinus excision and Karydakis flap) following conventional abscess treatment (drainage-antibiotic therapy) in pilonidal sinus abscess cases. METHODS: The data of the patients treated for pilonidal sinus abscesses in our clinic between January 2012 and March 2013 were analyzed, retrospectively. Those who had early surgery were determined as Group S, and those who had elective surgery following drainage-antibiotic therapy were determined as Group K. Patients in both groups were compared in terms of age, gender, complications, recurrence rate and healing time. Patients were followed for an average of 14 months. RESULTS: Of the 53 patients included in the study, 28 were in Group S and 25 in Group K. The mean age and gender distribution of both groups were similar and a significant difference was not found between the groups in terms of complication development and recurrence. However, there was a statistically significant difference between the groups in terms of treatment duration (p=0.02). CONCLUSION: In treating acute pilonidal abscesses, the Karydakis method, following drainage-antibiotic therapy, is a preferable method due to its shorter treatment duration and higher patient comfort. PMID- 25541850 TI - A practice report of bladder injuries due to gunshot wounds in Syrian refugees. AB - BACKGROUND: This study was intended to report our recent experience of bladder injuries due to gunshots in the Syrian conflict and review the literature regarding diagnosis and treatment. METHODS: Twenty-two cases with abdominal and inguinal firearm wounds and bladder ruptures sustained in the Syrian conflict were reported. Age, mechanism/location of damage, associated injuries, Revised Trauma Score (RTS), Injury Severity Score (ISS), Trauma Injury Severity Score (TRISS), and complications were analyzed. The severity of the bladder injuries was classified according to the American Association for the Surgery of Trauma Organ Injury Scaling (AAST-OIS grade ?II database).The type of the bladder rupture was defined according to the classification System for Bladder Injury Based on Findings at CT Cystography. RESULTS: The mean age was 26 years (range, 18-36). The mean ISS was 22 (10-57), mean TRISS was 0.64 (0.004-0.95), and mean RTS was 6.97 (3.30-7.84). In the mortality group, the mean ISS, TRISS, and RTS were 48 (36-57), 0.016 (0.004-0.090), and 4.10 (3.30-4.92), respectively; whereas, the mean ISS, TRISS, and RTS were found as 21 (10-26), 0.64 (0.49-0.95), and 7.24 (5.65-7.84), respectively in the survival group (P=0.06). CT-cystography showed seventeen type 2, three type 4, and two type 5 bladder injuries. According to AAST-OIS, there were nine grade IV, six grade III, five grade II, and two grade V injuries. CONCLUSION: In war settings, when injuries are often severe and multiple surgical exploration and closure are mandatory, mortality risk is associated with high ISS and low TRISS and RTS values. PMID- 25541851 TI - Multi-detector angio-CT and the use of D-dimer for the diagnosis of acute mesenteric ischemia in geriatric patients. AB - BACKGROUND: There is no specific laboratory method for the diagnosis of acute mesenteric ischemia (AMI). In this study, we aimed to determine the efficacy of the D-dimer test in selected cases prior to multi-detector angio-CT, which is expensive and has side effects. METHODS: Patients, over 65, with abdominal pain were included in this study. The D-dimer test was applied to 230 (34%) of 676 abdominal pain patients admitted to our emergency service. The D-dimer levels of the patients diagnosed with AMI by angio-CT were compared. RESULTS: In AMI patients sensitivity of the D-dimer test was 84.6% and the specificity was 47.9%. Elevated D-dimer levels and AF were observed in 90.9% of the patients diagnosed with AMI by CT. CONCLUSION: D-dimer levels were elevated in the AMI patients. Patients suspected of having AMI with unclear clinical results and patients with D-dimer levels above 1000 ng/ml and AF should undergo further evaluation. PMID- 25541852 TI - A shocking craniofacial penetrating injury by a steel bar. AB - Owing to the diversity in cause and damage, there is no standard surgical treatment method for a complicated penetrating craniofacial injury. The treatment of a complicated penetrating head injury caused by a steel bar is presented here. A 66-year-old woman fell onto a steel bar at a construction site and it penetrated the mandible, entered the sinus and orbital cavities, and reached the base of the frontal bone. A multi-disciplinary team including a neurosurgeon, otolaryngologist, and plastic surgeon was involved in removing the steel bar. The patient survived without sequelae except for blindness in the right eye. Despite the lack of standardized surgical treatment for a complicated penetrating craniofacial injury, aggressive treatment by a multidisciplinary team can result in good outcomes. PMID- 25541853 TI - Partial penectomy after debridement of a Fournier's gangrene progressing with an isolated penile necrosis. AB - Fournier's gangrene (FG) is a rare and often fulminant necrotizing fasciitis of the perineum and genital region frequently due to polymicrobial infection. This truly emergent condition is typically seen in elderly, diabetic and immune compromised patients. Here, we report an unusual case of FG with isolated glans penis necrosis in a diabetic 77-year-old male patient presented to the emergency department complaining 5 days of pain and darkening of the glans penis. Examination of the patient's glans penis was consistent with FG and included significant erythema and infectious discharge. He was given intravenous antibiotics and emergency debridement was done. On following days, the necrotic area spread to distal parts of both cavernosal areas. Partial penectomy was performed. Isolated penile involvement in FG is very rare. Performing partial penectomy in appropriate cases can save penile length, stop the progression of disease, and increase the quality of life. PMID- 25541854 TI - The journey of gastric phytobezoar followed by tomography. AB - Phytobezoars are a rare cause of intestinal obstruction. They are usually present in patients with predisposing factors such as previous gastric surgery, diabetes, and edentulousness. In this case report, an uncommon cause of intestinal obstruction due to the migration of gastric phytobezoar in a patient with no known predisposing factor is reported. PMID- 25541855 TI - Successful treatment of a hepatic abscess formed secondary to fish bone penetration by laparoscopic removal of the foreign body: report of a case. AB - Although foreign body ingestion is a common problem in children, it is also seen among adults. Perforation of the gut by a foreign body, followed by migration of the foreign body to the liver is quite rare. Most fish bone ingestions have uneventful outcome. However, occasionally, it can cause serious complications if the gastrointestinal tract is perforated. Herein, a case of liver abscess caused by a fish bone is reported. To the best of our knowledge, it is the first case in our country. PMID- 25541856 TI - Postmenopausal cell and tissue sex-hormone metabolism: mechanisms of intracrinology. PMID- 25541857 TI - Setting goals in chronic care: Shared decision making as self-management support by the family physician. AB - INTRODUCTION: Self-management is considered a potential answer to the increasing demand for family medicine by people suffering from a chronic condition or multi morbidity. A key element of self-management is goal setting. Goal setting is often defined as a moment of agreement between a professional and a patient. In the self-management literature, however, goal setting is regarded as a circular process. Still, it is unclear how professionals working in family medicine can put it into practice. This background paper aims to contribute to the understanding of goal setting within self-management and to identify elements that need further development for practical use. Debate: Four questions for debate emerge in this article: (1) What are self-management goals? (2) What is necessary to accomplish the process of goal setting within self-management? (3) How can professionals decide on the degree of support needed for goal setting within self-management? (4) How can patients set their goals and how can they be supported? IMPLICATIONS: Self-management goals can be set for different (life) domains. Using a holistic framework will help in creating an overview of patients' goals that do not merely focus on medical issues. It is a challenge for professionals to coach their patients to think about and set their goals themselves. More insight in patients' willingness and ability to set self management goals is desirable. Moreover, as goal setting is a circular process, professionals need to be supported to go through this process with their patients. PMID- 25541858 TI - Personality-related core beliefs in patients diagnosed with fibromyalgia plus depression: A comparison with depressed and healthy control groups. AB - BACKGROUND: Personality has an important role in understanding both fibromyalgia syndrome (FMS) and major depressive disorder (MDD). AIMS: This study considers the question that specific personality features may characterize depressed FMS patients. MATERIALS AND METHODS: To this end, 125 individuals were included in the study: 40 of them diagnosed with FMS+ MDD, 40 with MDD only and 45 healthy controls. Individual Beck Depression Inventory (BDI) and Personality Belief Questionnaire-Short Form (PBQ-SF) scores were compared between the three groups. RESULTS: The mean scores for each personality domain of the PBQ-SF were the highest in the MDD group and the lowest mean scores appeared in the control group. Dependent personality and obsessive-compulsive personality scores were higher in the MDD group (t = 2.510, P = 0.014 and t = 2.240, P = 0.028, respectively) in comparison with the FM+ MDD group. However, this difference disappeared when PBQ-SF scores were controlled for depression severity. CONCLUSIONS: Although some common personality features are evident in FMS patients, it seems that the differences identified are primarily related to depression symptom severity. PMID- 25541859 TI - Validation of the Impulsive/Premeditated Aggression Scale in Mexican psychiatric patients. AB - INTRODUCTION: Aggression has been linked to several psychiatric disorders. None of the available instruments validated in Mexico is able to classify aggression as impulsive or premeditated. The Impulsive/Premeditated Aggression Scale (IPAS) is a self-report instrument designed to characterize aggressiveness as predominately impulsive or premeditated. OBJECTIVE: The aim of the study was to determine the validity and reliability of the IPAS in a sample of Mexican psychiatric patients. METHOD: A total of 163 patients diagnosed with affective, anxiety or psychotic disorder were included. A principal-component factor analysis was performed to obtain construct validity of the IPAS impulsive and premeditated aggression subscales; convergent validity as well as internal consistency of subscales were also determined. RESULTS: The rotated matrix accounted for 33.4% of the variance. Significant values were obtained for convergent validity and reliability of the IPAS subscales. CONCLUSION: The IPAS is an adequate instrument, which might be used to differentiate the type of aggressive behavior in Mexican psychiatric patients. PMID- 25541861 TI - Dr. Frederick H. Kasten 1927 -2014. PMID- 25541860 TI - Comparative Analysis of Anterior Chamber Flare Grading between Clinicians with Different Levels of Experience and Semi-automated Laser Flare Photometry. AB - PURPOSE: To assess correlation for anterior chamber flare grading between clinicians with different levels of experience and with semi-automated flare reading in a cohort of patients with heterogeneous uveitic entities. METHODS: Fifty-nine observations from 36 patients were recorded and analyzed for statistical association. In each patient, flare was assessed objectively using the Kowa FM-700 laser flare photometer, and subjective masked grading by two clinicians was performed. RESULTS: The study demonstrated disparity in flare readings between clinical graders with one step disagreement in clinical grading in 26 (44.06%) eyes (p < 0.001) and concordance between the flare readings by experienced grader and flare photometry. After review of semi-automated flare readings, management was changed in 11% of the patients. CONCLUSION: Laser flare photometry can be a valuable tool to remove the observer bias in grading flare for selected cohort of uveitis patients. It can be further applied to titrate therapy in intraocular inflammation. PMID- 25541862 TI - Neuroanatomical mechanism on the effect of distraction in working memory maintenance in patients with schizophrenia. AB - This study utilized functional magnetic resonance imaging (fMRI) to discriminate brain activation patterns associated with the effect of distraction during working memory (WM) maintenance for human faces in healthy controls and patients with schizophrenia. Event-related fMRI data were obtained while the subjects performed WM maintenance in a delayed-response WM task with task-irrelevant distracters. Compared with healthy controls, patients showed significantly decreased activities in the superior frontal gyrus, dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex, anterior cingulate cortex, inferior parietal gyrus, and fusiform gyrus during the delayed-response WM task with human face distracters. The blood-oxygen-level-dependent signal changes in the DLPFC were negatively correlated with both of the scores of the Positive Subscale and General Psychopathology Subscale under the Positive and Negative Syndrome Scale during the WM maintenance for the human faces in the patients. This study will be helpful in understanding the neural mechanisms in the general impairment of the inhibition control in schizophrenia. PMID- 25541863 TI - Pituitary volume in medication-naive adults with obsessive compulsive disorder. AB - Pituitary volume is considered to reflect hypothalamic-pituitary-adrenal axis dysregulation, and this has been studied in various psychiatric disorders. This study demonstrates that pituitary volume as assessed through the region of interest manual tracing method in 50 medication-naive adult patients with obsessive-compulsive disorder was not significantly different compared with 40 healthy control subjects (687.80 +/- 126.60 versus 694.73 +/- 131.59, F=0.55, p=0.46). The authors also compared the patients with obsessive-compulsive disorder without any comorbid axis I conditions (N=35) with healthy control subjects and found no difference in the pituitary volumes (681.62 +/- 130.85 versus 694.72 +/- 131.59, F=0.90, p=0.35). This emphasizes the need to examine hypothalamo-pituitary axis structures after taking into consideration various potential confounders such as medications and depression. PMID- 25541864 TI - Heart rate variability in intensive care unit patients with delirium. AB - Sympathovagal balance, assessed with heart rate variability (HRV), may be altered in intensive care unit (ICU) delirium. HRV was measured in the frequency domain [low frequencies (LF)=0.04-0.15 Hz and high frequencies (HF)=0.15-0.40 Hz] with HF in normalized units (HFnu) to evaluate parasympathetic tone and LF:HF ratio for sympathovagal balance. The authors assessed 726 ICU patients and excluded patients with conditions affecting HRV. No difference could be found between patients with (N=13) and without (N=12) delirium by comparing the mean (+/ standard deviation) of the HFnu (75+/-7 versus 68+/-23) and the LF:HF ratio ( 0.7+/-1.0 versus -0.1+/-1.1). This study suggests that autonomic function is not altered in ICU delirium. PMID- 25541865 TI - Negative attention bias and processing deficits during the cognitive reappraisal of unpleasant emotions in HIV+ women. AB - Deficits in emotional processing may be attributed to HIV disease or comorbid psychiatric disorders. Electrocortical markers of emotional attention, i.e., amplitude of the P2 and late positive potential (LPP), were compared between 26 HIV+ women and 25 healthy controls during an emotional regulation paradigm. HIV+ women showed early attention bias to negative stimuli indexed by greater P2 amplitude. In contrast, compared with the passive viewing of unpleasant images, HIV+ women demonstrated attenuation of the early and late LPP during positive reappraisal. This interaction remained significant after adjusting for individual differences in apathy, anxiety, and depression. Post hoc analyses implicated time since HIV diagnosis with LPP attenuation during positive reappraisal. Advancing HIV disease may disrupt neural generators associated with the cognitive reappraisal of emotions independent of psychiatric function. PMID- 25541866 TI - Reduced telomere length in neurodegenerative disorders may suggest shared biology. AB - Early cell death is a feature of neurodegenerative disorders. Telomere shortening is related to premature cellular senescence and could be a marker for cellular pathology in neurological diseases. Relative telomere length in dementia (N=70), Huntington's disease (N=35), ataxia telangiectasia (N=9), and age-group matched control samples (N=105) was measured as relative telomere copy/single copy gene ratios. Individuals with Huntington's disease had the lowest relative telomere copy/single copy gene ratio (0.21), followed by ataxia telangiectasia (0.31) and dementia (0.48). The younger control group had the highest relative telomere copy/single copy gene ratio (1.07). The reduced telomere length could be indicative of shared biological pathways across these disorders contributing to cellular senescence. PMID- 25541867 TI - Mental health diagnoses and health care utilization in persons with dementia, Parkinson's disease, and stroke. AB - In late life, neurological disturbances, depression, and anxiety frequently complicate the clinical presentation but are often undertreated. An administrative database of 3,034 male veterans, age 55 years and older, with a diagnosis of dementia, Parkinson's disease, or stroke was examined for the prevalence of mood and anxiety disorders and mental health service use. Those with more than one of these neurological diagnoses were most likely to have a comorbid depressive or anxiety disorder. The majority of patients with anxiety and depression were prescribed antidepressants. Mental health specialty visits were less frequent than medication treatment overall but most common for those with dementia only. These data suggest that specialty mental health care remains a significant unmet need for individuals with neurological disorders complicated by depression and anxiety. PMID- 25541868 TI - Antimicrobial resistance: the nurse's essential role. PMID- 25541869 TI - Florence Nightingale Foundation honours scholars. PMID- 25541870 TI - Management of occupational blood exposures: looking at progress. AB - Occupational blood exposure (OBE) is a well-recognised hazard in the healthcare setting. A 4-year review of OBE in a large Irish teaching hospital over 2008-2011 found encouraging results, but identified deficits in documentation, communication and follow-up. The process was repeated 1 year later to determine if improvements were achieved and recommendations implemented. In 2012, 110 OBEs were reported, of which 81% were reported within 72 hours of the injury. The administration of first aid was adequately documented in 85% of cases and confirmation of the provision of appropriate information and/or counselling in 72% of the cases. Attendance for follow-up was broadly in line with the previous review. The findings and recommendations contributed to improvements in practice. However, to ensure these are ongoing, the reinforcement of an educational strategy in a systematic way is fundamental. PMID- 25541871 TI - The ins and outs of fluid balance in the acutely ill patient. AB - Many reports and studies have highlighted concerns with fluid management in acute care settings. The level of knowledge displayed by nurses and the influence this has on fluid management is often analysed. Nurses measure patients' fluid intake and output in the belief that medical staff will use the data to prescribe appropriate fluid management. However, in reality, medical staff often disregard such data as inaccurate, with terms such as 'OTT' (out to toilet) clearly affecting the accuracy of data. Consequently, practitioners require a comprehensive understanding of fluid physiology and the potential risks to the patient when there is inappropriate documentation of fluid status. The use of the fluid balance chart is examined as a means to assess fluid status, and other supplementary assessment strategies are also considered. The aim is to ensure comprehensive assessment and evaluation of an individual's fluid status, thereby guiding appropriate fluid management in the acute care setting. PMID- 25541872 TI - Proactivity in VTE prevention: a concept analysis. AB - Venous thromboembolism (VTE) prevention is an international patient safety issue. The author has observed gaps in prescription and provision of VTE prophylaxis, and that the attitude to VTE is often reactive rather than proactive. This concept analysis aims to explore proactivity and apply it to VTE prevention to address this. Ten databases were searched (1992-2012) using the keywords proactive, proactivity, nurse, nursing, VTE/venous thromboembolism, prevent/prevention/preventing, behaviour, DVT/PE (deep vein thrombosis, pulmonary embolism). The Walker and Avant (2010) method of concept analysis identified the defining attributes as personal initiative, taking charge and feedback-seeking behaviour. Antecedents and consequences have been identified, and empirical referents are demonstrated. Defining proactivity in VTE prevention has the potential to increase prescription and, crucially, provision of prophylaxis, thereby improving patient care, reducing avoidable harm and improving the patient experience. PMID- 25541873 TI - Antibiotic resistance and irrational prescribing in paediatric clinics in Greece. AB - INTRODUCTION: Greece is among the countries with the highest rates of antimicrobial resistance (AMR) and simultaneous antibiotic consumption. AIM: The aim of this study was to assess the perceptions and knowledge of AMR and irrational antibiotic prescribing of nurses working in paediatric hospitals in Greece. METHOD: A self-administered questionnaire was distributed to nurses in paediatric hospitals and paediatric clinics in Greece. Descriptive and multivariate statistical analyses were performed. Levels of significance were two tailed and statistical significance was p=0.05. RESULTS: A total of 87% of participants reported irrational prescribing to be an important cause of AMR. Diagnostic uncertainty was stated by 55.5% as the main cause of irrational antibiotic prescribing and 94% suggested the use of protocols and guidelines as the main measure to control overprescribing. Parental demand for antibiotics in hospitals has increased according to 51.8% of respondents. Strong correlation was observed between social-demographic characteristics and antibiotic resistance, as well as irrational prescribing. CONCLUSIONS: Assessing nurses' knowledge and perceptions of antimicrobial resistance and irrational prescribing is vital as nurses actively participate in the antibiotics administration process and antimicrobial management in Greece. Their involvement could contribute to educate patients and parents on the public-health implications of overprescribing and antimicrobial resistance. PMID- 25541874 TI - Development and implementation of a Safeguarding Tracker Tool. AB - This article reports on the development and implementation of a Safeguarding Tracker Tool at one hospital that cares for vulnerable patients who are suffering from early onset dementia, Huntingdon's disease and alcohol-related brain injury. The tool was developed in association with the local multi-agency safeguarding hub (MASH). The hospital has in place systems and processes for training staff in their safeguarding role and have developed a Safeguarding Tracker Tool to record individual safeguarding concerns, communicate with and involve all relevant people and agencies, investigate the concern and establish an action plan. PMID- 25541875 TI - Newly qualified nurses' experiences of a preceptorship. AB - RESEARCH QUESTION: What was the experience of preceptorship like for newly qualified registered nurses in a healthcare trust? METHOD: A qualitative approach was used with data collected using semi-structured one-to-one interviews with eight participants who had recently completed their preceptorship period. The data was analysed using Newell and Burnard's (2011) Pragmatic Approach to Qualitative Data Analysis, which involved a six-stage analysis process. FINDINGS: Two main categories emerged from the data. These were Support Requirements and Expectations of Preceptorship. Support was further broken down into two themes: time and build confidence. Expectations of preceptorship was further broken down into two themes; understanding the process and understanding the preceptor's role. CONCLUSION: The participants felt that preceptorship offered support and helped them in developing their confidence in the transition to registrant. It would appear that consistency of provision of preceptorship is a key issue that would warrant further study. PMID- 25541876 TI - Management of abdominal pain in children. AB - Abdominal pain (AP) is a very common complaint caused by a variety of conditions. Mild or moderate AP affects practically all children of all ages. The pain usually settles spontaneously without medical intervention. AP severe enough to require medical intervention has both surgical and non-surgical causes. It is responsible for considerable morbidity, missed school days, and significant use of health resources. Children usually present either with an acute or recurrent AP. In comparison, chronic AP with persistent symptoms, lasting days or weeks, is rare in children. Surgical conditions may be the underlying causes in acute AP, but non-surgical conditions are diagnosed more commonly in children with recurrent AP. Management can be difficult, time-consuming and often clinically challenging to diagnose and treat. In most instances, the cause of AP can be diagnosed through the history and physical examination. The main objective in managing an affected child is to differentiate between benign, self-limited conditions such as constipation or gastroenteritis, and more life-threatening surgical conditions such as intussusception or appendicitis. Irritable bowel syndrome (IBS) and Crohn's disease should be considered in any child presenting with recurrent AP. PMID- 25541877 TI - Best interests of adults who lack capacity part 2: key considerations. AB - Last month's article discussed the key concepts underpinning the notion of best interests. In this article the author discusses the requirements for determining the best interests of an adult who lacks capacity under the provisions of the Mental Capacity Act 2005 and its code of practice (Department for Constitutional Affairs 2007). PMID- 25541878 TI - Mentorship part 1: the role in the learning environment. AB - Mentors play a vital role in the education of preregistration nursing students. Because the learning environments in which the students are placed are crucial for the development of the future workforce, it could be argued that mentors are the 'gatekeepers' of the nursing profession. However, the mentor's role is not an easy one and, with the added pressures of modern health care, there appear to be greater demands placed on nurses, which in turn affect the mentor's role. This article will be the first in a series of five looking at aspects of the mentor and the mentor's role in practice. This first article will focus on the mentor and the role of the mentor in practice, together with the identification of 'toxic mentors', who can hinder learning in the clinical environment. It is in working together with the mentor that students will learn the true nature of nursing from a 'hands-on' perspective, applying in practice the knowledge learned in class. PMID- 25541879 TI - Transforming care following Winterbourne: learning disabilities. PMID- 25541880 TI - Can the NHS survive the winter? PMID- 25541881 TI - Measuring the impact of nurses and nursing: the core values. PMID- 25541882 TI - A view from Valencia. AB - Emma Blakey wanted to experience life as a nursing student in Spain, to see a different way of nursing and to explore the impact of austerity measures. She reflects on her time in Valencia and how this experience has influenced her nursing practice. PMID- 25541883 TI - NHS hospital complaints: are we still going round in circles? AB - In the second part of his two-part column John Tingle discusses the report published by the Patients Association on the state of the NHS Complaints system. PMID- 25541884 TI - Written communication: from staff nurse to nurse consultant. PMID- 25541885 TI - Open all hours? PMID- 25541886 TI - Structural, spectroscopic, and theoretical comparison of traditional vs recently discovered Ln(2+) ions in the [K(2.2.2-cryptand)][(C5H4SiMe3)3Ln] complexes: the variable nature of Dy(2+) and Nd(2+). AB - The Ln(3+) and Ln(2+) complexes, Cp'3Ln, 1, (Cp' = C5H4SiMe3) and [K(2.2.2 cryptand)][Cp'3Ln], 2, respectively, have been synthesized for the six lanthanides traditionally known in +2 oxidation states, i.e., Ln = Eu, Yb, Sm, Tm, Dy, and Nd, to allow direct structural and spectroscopic comparison with the recently discovered Ln(2+) ions of Ln = Pr, Gd, Tb, Ho, Y, Er, and Lu in 2. 2-La and 2-Ce were also prepared to allow the first comparison of all the lanthanides in the same coordination environment in both +2 and +3 oxidation states. 2-La and 2-Ce show the same unusual structural feature of the recently discovered +2 complexes, that the Ln-(Cp' ring centroid) distances are only about 0.03 A longer than in the +3 analogs, 1. The Eu, Yb, Sm, Tm, Dy, and Nd complexes were expected to show much larger differences, but this was observed for only four of these traditional six lanthanides. 2-Dy and 2-Nd are like the new nine ions in this tris(cyclopentadienyl) coordination geometry. A DFT-based model explains the results and shows that a 4f (n)5d(1) electron configuration is appropriate not only for the nine recently discovered Ln(2+) ions in 2 but also for Dy(2+) and Nd(2+), which traditionally have 4f (n+1) electron configurations like Eu(2+), Yb(2+), Sm(2+), and Tm(2+). These results indicate that the ground state of a lanthanide ion in a molecule can be changed by the ligand set, a previously unknown option with these metals due to the limited radial extension of the 4f orbitals. PMID- 25541887 TI - N-aminopyridinium salts as precursors for N-centered radicals--direct amidation of arenes and heteroarenes. AB - Readily prepared N-aminopyridinium salts are valuable precursors for the generation of N-centered radicals. Reduction of these salts by single electron transfer allows for clean generation of amidyl radicals. It is shown that direct radical C-H amination of heteroarenes and arenes can be achieved with N aminopyridinium salts under mild conditions by using photoredox catalysis. PMID- 25541888 TI - Development of a novel fingerprint for chemical reactions and its application to large-scale reaction classification and similarity. AB - Fingerprint methods applied to molecules have proven to be useful for similarity determination and as inputs to machine-learning models. Here, we present the development of a new fingerprint for chemical reactions and validate its usefulness in building machine-learning models and in similarity assessment. Our final fingerprint is constructed as the difference of the atom-pair fingerprints of products and reactants and includes agents via calculated physicochemical properties. We validated the fingerprints on a large data set of reactions text mined from granted United States patents from the last 40 years that have been classified using a substructure-based expert system. We applied machine learning to build a 50-class predictive model for reaction-type classification that correctly predicts 97% of the reactions in an external test set. Impressive accuracies were also observed when applying the classifier to reactions from an in-house electronic laboratory notebook. The performance of the novel fingerprint for assessing reaction similarity was evaluated by a cluster analysis that recovered 48 out of 50 of the reaction classes with a median F-score of 0.63 for the clusters. The data sets used for training and primary validation as well as all python scripts required to reproduce the analysis are provided in the Supporting Information. PMID- 25541890 TI - Novel growth hormone-releasing hormone receptor gene mutations in Turkish children with isolated growth hormone deficiency. AB - OBJECTIVE: Isolated growth hormone deficiency (IGHD) is defined as a medical condition associated with growth failure due to insufficient production of GH or lack of GH action. Mutations in the gene encoding for GH-releasing hormone receptor (GHRHR) have been detected in patients with IGHD type IB. However, genetic defects on GHRHR causing IGHD in the Turkish population have not yet been reported. To identify mutations on GHRHR gene in a population of Turkish children with IGHD. METHODS: Ninety-six Turkish children with IGHD were included in this study. Exon1-13 and exon/intron boundaries of GHRHR were amplified by suitable primers. The polymerase chain reaction products for GHRHR gene were sequenced with primers. RESULTS: We analyzed the GHRHR gene for mutations in ninety-six patients with IGHD based on sequence results. We identified novel p.K264E, p.S317T, p.S330L, p.G369V, p.T257A and C base insertion on position 380 (c.380inserC) mutations. In 5 of the patients, the mutation was homozygote and in 1-heterozygote (p.S317T). CONCLUSION: Six new missense mutations and one first case of insertion mutations for the GHRHR gene are reported. PMID- 25541889 TI - Adipokines in breast milk: an update. AB - Epidemiological surveys indicate that nutrition in infancy is implicated in the long-term tendency to obesity and that a longer duration of breastfeeding is associated with a protective effect against metabolic disorders later in life. However, the precise cause of this association is not well understood. Recent studies on the compounds present in human breast milk have identified various adipokines, including leptin, adiponectin, resistin, obestatin, nesfatin, ghrelin and apelins. Some of these compounds are involved in the regulation of food intake and energy balance. The presence of these adipokines in breast milk suggests that they may be responsible for the regulation of growth in early infancy and that they could influence the energy balance and development of metabolic disorders in childhood and adulthood. PMID- 25541891 TI - Mitochondrial ATPase subunit 6 and cytochrome B gene variations in obese Turkish children. AB - OBJECTIVE: Due to the importance of energy metabolism in mitochondria, mitochondrial genome variations are evaluated in energy-related diseases such as obesity. To date, several nuclear genes were found to be related to obesity. Our aim in this study was to investigate the presence of polymorphisms in mitochondrial ATPase subunit 6 (mt-ATP6) and cytochrome b (mt-CytB) genes that may be associated with childhood obesity. METHODS: The mt-ATP6 and mt-CytB genes were amplified and entirely sequenced in a series of 100 obese and in an equal number of healthy Turkish children aged between 6-14 years. RESULTS: A total of 118 synonymous and nonsynonymous variations were detected in the obese and control groups. Only two previously reported synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene were found to be significantly higher in the obese group compared to the control group (p<0.05). In the mt-ATP6 gene, one novel nonsynonymous substitution (mt.8726C>T) and one novel synonymous substitution (mt.9108A>T) were found. In the mt-CytB gene, one nonsynonymous substitution (mt.14880T>C) and two synonymous substitutions (mt.14891C>T and mt.15091C>T) were novel substitutions. CONCLUSION: Two synonymous substitutions (mt.8614T>C and mt.8994G>A) in the mt-ATP6 gene may be associated with childhood obesity. Our study provides the first data about mitochondrial genome variations in a Turkish obese population and also the first in obese children. More cases should be screened in obese groups in order to understand the effects of mitochondrial polymorphisms in the development of obesity. PMID- 25541892 TI - Arm anthropometry indices in Turkish children and adolescents: changes over a three-year period. AB - OBJECTIVE: Time-related changes and comparisons for mid-upper arm circumference (MUAC), triceps skinfold thickness (TSF), arm fat area (AFA) are lacking for Turkish children and adolescents. To determine the arm anthropometry indices (MUAC, TSF, AFA) in children and adolescents and to also assess the changes in these indices over a 3-year time period. METHODS: The data of the Anthropometry of Turkish Children Aged 0-6 Years (ATCA-06) study and the Second Study of Determination of the Anthropometric Measurements of Turkish Children and Adolescents (DAMTCA-II) were used to calculate the arm anthropometry percentiles in a total group of 6982 children and adolescents aged 28 days to 17 years. The 3rd-97th percentiles were computed by the LMS method. RESULTS: In girls, 50th percentile MUAC values linearly increased with age. In boys, 50th percentile TSF values linearly increased until 10 years of age and decreased after age 11 years, while in girls, TSF values increased linearly with age. 50th percentile values for AFA showed a linear increase in both genders with age. Significant differences were found between the 5th, 50th and 95th percentile values for MUAC and AFA obtained in the two studies (DAMTCA-II and DAMTCA-I) in both boys and girls. CONCLUSIONS: The prominent finding was the significant and alarming increase in arm anthropometry indices in both genders within as short period of time as three years. PMID- 25541893 TI - Relationship between body composition parameters and metabolic syndrome in young Thai adults. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between body composition parameters, i.e. waist circumference, android fat mass (AFM), gynoid fat mass (GFM), android to gynoid fat mass ratio (AG ratio) and metabolic syndrome (MS) risk components in young Thai adults. METHODS: This was a cross sectional study conducted among 391 adolescents (174 male, 217 female). The body mass index (BMI), waist circumference, blood pressure, triglyceride, high-density lipoprotein (HDL) cholesterol and glucose levels were determined. AFM, GFM and AG ratio were assessed by dual-energy X-ray absorptiometry (DXA). Linear regression analysis was done to assess the relationship of waist circumference, AFM, GFM and AG ratio with MS risk components' score, separately. RESULTS: Among 391 young adults aged 18.5-21.8 years, MS was found in 5.9%. Participants with MS (n=23) had a significantly higher weight, height and BMI than those without MS. There was no statistically significant difference in bone mineral density between the two groups. At univariable linear regression analysis, waist circumferences, AFM, GFM and AG ratio showed significant relationship with MS risk components' score. However, after adjusting for gender, birth weight and BMI, AG ratio demonstrated greater relationship with MS risk components' score (beta 1.89, 95%CI 1.096 2.978) than waist circumference (beta 0.046, 95%CI 0.033-0.058) and AFM (beta 0.979, 95%CI 0.667-1.290). No significant association was observed between GFM and MS risk components' score (beta 0.077, 95%CI -0.089-0.243). CONCLUSION: The results from this study indicated that AG ratio is a stronger predictor of MS than waist circumference and AFM in young Thai adults. The role of AG ratio for the diagnosis of MS needs to be further investigated. PMID- 25541894 TI - Growth patterns of children of same geographic background reared in different environments. AB - OBJECTIVE: Growth charts are essential tools used to assess children's health status. The aim of the present study was to determine the effect of environmental factors on the growth of children of a common geographic background. We constructed growth charts for children living in the East of Turkey and compared them with those for Turkish children living in other regions or countries. METHODS: Growth data were obtained from 6 917 school children living in Eastern Turkey. The median values on smoothed percentile curves for the study subjects were compared with those for Turkish children living in the West of Turkey, in Western Europe and in Germany. RESULTS: Children living in Turkey were lighter than their European peers at early ages. Weight curves of children living in the West of Turkey reached those of their European peers, after 11 years of age in boys and after 12 years of age in girls. At all ages, girls and boys in our region had the lowest weight values. Between 7 and 11 years of age, the median height in boys and girls were similar in the West of Turkey and in Europe. At older ages, median height was higher in Turkey. Girls and boys living in Eastern Turkey were the shortest children until 16 years of age; after that age, their height was similar to their peers. CONCLUSIONS: Weight may interact with environmental factors, but genetic potential appears to be the most important factor determining height at 17 years of age. Growth patterns of children should be evaluated using specific reference values for specific regions. PMID- 25541895 TI - The effect of L-thyroxine treatment on hypothyroid symptom scores and lipid profile in children with subclinical hypothyroidism. AB - OBJECTIVE: To evaluate i) the frequency of typical hypothyroidism symptoms in children with subclinical hypothyroidism (SH), ii) to evaluate the association of SH with lipoproteins and iii) to investigate possible improving effects of L thyroxine (LT4) treatment on these findings. METHODS: Twenty-seven children with SH who had elevated thyroid-stimulating hormone (TSH: >4.94 uIU/L) but normal free T4 levels and healthy euthyroid children of similar age and sex were enrolled in the study. Anthropometric and laboratory (lipid profile and thyroid function tests) measurements were performed at diagnosis and six months after euthyroidism was achieved. All children were also subjected to a questionnaire on hypothyroid symptoms at diagnosis. The SH patients were subjected to the questionnaire also following treatment. Pre-treatment data were compared with those of controls and post-treatment measurements. RESULTS: Anthropometric and laboratory parameters of the groups were not statistically different except for higher TSH levels in the SH group. Serum lipoprotein levels and dyslipidemia frequency were similar between the groups. Compared to the controls, hypothyroidism symptom score was significantly higher in the SH group. Six months after euthyroidism was achieved, a significant reduction in the hypothyroid symptom score was obtained in the SH group. Except for significantly higher serum TSH values, no significant differences regarding demographic characteristics, symptom scores and lipid parameters were present between patients with Hashimoto's thyroiditis and the remaining SH patients. CONCLUSION: The results of this study showed that in children with SH i) the hypothyroidism symptom score was significantly higher than in euthyroid children, ii) LT4 treatment improved the hypothyroidism symptom score and iii) SH does not seem to be associated with dyslipidemia. PMID- 25541896 TI - The effects of passive smoking on the six-minute walk test in obese pediatric cases. AB - OBJECTIVE: The aim of this study was to evaluate whether exposure to second-hand smoke affected the six-minute walk test (6 MWT) of obese non-asthmatic pediatric cases. METHODS: Obese pediatric patients (body mass index >95th p) with no existing co-morbidities were included in the study. Smoke exposure was assessed with a self-reported questionnaire completed by the parents. The subjects were divided into two groups: Group 1 consisting of obese children exposed to passive smoking and Group 2 of obese children not exposed to passive smoking. In addition to 6 MWT, spirometric flow and volume, including forced expiratory volume in 1 s and peak expiratory flow rate, were also measured in all subjects. The results of the 6 MWT were assessed to determine any association with passive smoking. RESULTS: The study included 75 obese pediatric cases (40 male, 35 female) with a mean age of 9.06 +/- 0.97 years. The 6 MWT results in Group 1 was 501.88 +/- 62.12 meters and in Group 2 559.63 +/- 72.93 meters. The difference was statistically significant (p=0.001). CONCLUSIONS: Passive smoking may negatively affect the respiratory and cardiovascular capacity in obese children, who are already at risk of lower cardiopulmonary function. The evaluation of 6 MWT in these pediatric patients may be useful for monitoring and families should be warned about potential problems due to smoking. PMID- 25541897 TI - Prepubertal unilateral gynecomastia: report of 2 cases. AB - Prepubertal unilateral gynecomastia is an extremely rare condition. At present, its etiology and management strategy are not well known. Two unrelated prepubertal boys of ages 8 and 9 who presented with complaints of unilateral enlargement of breast tissue are reported. Physical examination, biochemical, hormonal and oncologic work-up findings were normal. Both patients were treated with peripheral liposuction successfully. Histopathological and immunohistochemical examinations showed benign fibroglandular gynecomastia and intensive (3+) estrogen receptor expression in 100% of periductal epithelial cells. Although an extremely rare and generally benign condition, patients with prepubertal unilateral gynecomastia should have a full endocrine and oncologic work-up. PMID- 25541898 TI - ROHHAD Syndrome: Reasons for Diagnostic Difficulties in Obesity. AB - A very rare syndrome of rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) has been recently described as causing morbidity due to hypothalamic dysfunction and respiratory arrest. Its prognosis is poor and often cardiac arrest occurs due to alveolar hypoventilation. This disorder can mimic genetic obesity syndromes and several endocrine disorders. We present a 13-year-old female patient who was reported to be healthy until the age of 3 years. She was admitted to our emergency department, presenting with respiratory distress. Features matching ROHHAD syndrome such as rapid-onset obesity, alveolar hypoventilation, central hypothyroidism, hyperprolactinemia, Raynaud phenomenon and hypothalamic hypernatremia were detected in the patient. In addition to these features, the patient was found to have hypergonadotropic hypogonadism and megaloblastic anemia. Because of its high mortality and morbidity, the possibility of ROHHAD syndrome needs to be considered in all pediatric cases of early- and rapid-onset obesity associated with hypothalamic-pituitary endocrine dysfunction. PMID- 25541899 TI - Importance of insulin immunoassays in the diagnosis of factitious hypoglycemia. AB - We report two cases emphasizing the importance of insulin assays for evaluation of hypoglycemia in diabetic patients. Case 1 was a 96/12-year-old female patient with type 1 diabetes mellitus and case 2 was a 1010/12-year-old male patient with DIDMOAD. Both patients were on a basal-bolus insulin regimen. Both were admitted because of persistent hypoglycemia. Analyses of serum samples obtained at the time of hypoglycemia initially showed low insulin and C-peptide levels. Recurrent episodes of unexplained hypoglycemia necessitated measurement of insulin levels by using different insulin assays, which revealed hyperinsulinemic hypoglycemia with low C-peptide levels, findings which confirmed a diagnosis of factitious hypoglycemia. Surreptitious administration of insulin should not be excluded in diabetic patients with hypoglycemia without taking into account the rate of cross reactivity of insulin analogues with the insulin assay used. PMID- 25541900 TI - Atypical Presentation of Hashimoto's Disease in an Adolescent: Thyroid-Associated Ophthalmopathy. AB - Hashitoxicosis is generally differentiated from Graves' hyperthyroidism by its shorter course and absence of ophthalmopathy. In this case report, we describe an adolescent girl who presented with significant clinical findings of hyperthyroidism, a diffuse goiter with homogenously increased uptake in scintigraphy, and with ocular findings of ophthalmopathy. The thyroid stimulating hormone receptor antibody test was positive, and the family history revealed thyroid-associated ophthalmopathy. Clinical findings supported the diagnosis of Hashimoto's disease (HD) in the follow-up period. Radioactive iodine uptake investigation was found to be a reliable method for differential diagnosis. Attention was drawn to the rarity of pediatric cases of HD who present with ophthalmopathy. PMID- 25541901 TI - Is Hyperpigmentation on the First Day of Life Always Associated with IMAGe Syndrome? AB - IMAGe syndrome is an exceedingly rare condition first described in 1999. Components of the syndrome are intrauterine growth retardation (IUGR), metaphyseal dysplasia, congenital adrenal hypoplasia and genital anomalies. Cases generally present with life-threatening adrenal insufficiency in the neonatal period. Herein, we describe a patient with pronounced IUGR diagnosed with severe hyperpigmentation and adrenal insufficiency in the neonatal term in order to attract the attention to this rare entity. PMID- 25541902 TI - Tale of two isomers: complexities of human odor perception for cis- and trans-4 methylcyclohexane methanol from the chemical spill in West Virginia. AB - Application of gas chromatography with mass spectrometric and human olfactory "sniffer" detectors reveals the nature of odorous chemicals from an industrial chemical spill. Crude 4-methylcyclohexane methanol (4-MCHM) spilled in a river and then contaminated drinking water and air for over 300000 consumers living in West Virginia. Olfactory gas chromatography allows investigators to independently measure the odor of chemical components in a mixture. Crude 4-MCHM is comprised of several major cyclohexane components, four of which have distinct isomer pairs. The cis- and trans-4-MCHM isomers are the only components to have distinct odors at the concentrations used in this study. The trans-4-MCHM is the dominant odorant with descriptors of "licorice" and "sweet". Trans-4-MCHM has an air odor threshold concentration of 0.060 ppb-v (95% CI: 0.040-0.091). The odor threshold concentrations are not influenced by gender or age but are lower by a factor of 5 for individuals with prior exposure compared to naive subjects. Individual trans 4-MCHM odor threshold concentrations vary by more than a factor of 100. The cis-4 MCHM isomer has approximately a 2000-fold higher odor threshold concentration, different descriptors, and an even wider individual response range. PMID- 25541903 TI - A new oxyfluorinated titanium phosphate anode for a high-energy lithium-ion battery. AB - Na3[Ti2P2O10F] was synthesized by a hydrothermal method. It has an open framework structure consisting of TiFO5 octahedra and PO4 tetrahedra. The feasibility of Na3[Ti2P2O10F] as an anode material for lithium-ion batteries was first studied. Na3[Ti2P2O10F] exhibits a reversible capacity of more than 200 mAh g(-1) at a discharge/charge current rate of 20 mA g(-1) (~0.1 C) and 105 mA g(-1) at a discharge/charge current rate of 400 mA g(-1) (~2 C) with a lower intercalation voltage. The result of in situ X-ray diffraction test shows the structural evolution during the first discharge/charge cycle. The structure of Na3[Ti2P2O10F] was kept during discharge/charge with a slight change of the lattice parameters, which indicates a lithium solid solution behavior. PMID- 25541904 TI - Pulmonary effects of synthetic marijuana: chest radiography and CT findings. AB - OBJECTIVE: The purpose of this article is to present the first chest radiographic and CT descriptions of organizing pneumonia in response to smoking synthetic marijuana. CONCLUSION: Chest radiographs showed a diffuse miliary-micronodular pattern. Chest CT images showed diffuse centrilobular nodules and tree-in-bud pattern and a histopathologic pattern of organizing pneumonia with or without patchy acute alveolar damage. This distinct imaging pattern should alert radiologists to include synthetic marijuana abuse in the differential diagnosis. PMID- 25541906 TI - Nanopatterning of mobile lipid monolayers on electron-beam-sculpted Teflon AF surfaces. AB - Direct electron-beam lithography is used to fabricate nanostructured Teflon AF surfaces, which are utilized to pattern surface-supported monolayer phospholipid films with 50 nm lateral feature size. In comparison with unexposed Teflon AF coatings, e-beam-irradiated areas show reduced surface tension and surface potential. For phospholipid monolayer spreading experiments, these areas can be designed to function as barriers that enclose unexposed areas of nanometer dimensions and confine the lipid film within. We show that the effectiveness of the barrier is defined by pattern geometry and radiation dose. This surface preparation technique represents an efficient, yet simple, nanopatterning strategy supporting studies of lipid monolayer behavior in ultraconfined spaces. The generated structures are useful for imaging studies of biomimetic membranes and other specialized surface applications requiring spatially controlled formation of self-assembled, molecularly thin films on optically transparent patterned polymer surfaces with very low autofluorescence. PMID- 25541905 TI - Peptide amyloid surface display. AB - Homomeric self-assembly of peptides into amyloid fibers is a feature of many diseases. A central role has been suggested for the lateral fiber surface affecting gains of toxic function. To investigate this, a protein scaffold that presents a discrete, parallel beta-sheet surface for amyloid subdomains up to eight residues in length has been designed. Scaffolds that present the fiber surface of islet amyloid polypeptide (IAPP) were prepared. The designs show sequence-specific surface effects apparent in that they gain the capacity to attenuate rates of IAPP self-assembly in solution and affect IAPP-induced toxicity in insulin-secreting cells. PMID- 25541907 TI - Identification and quantification of adducts between oxidized rosmarinic acid and thiol compounds by UHPLC-LTQ-Orbitrap and MALDI-TOF/TOF tandem mass spectrometry. AB - LTQ Orbitrap MS/MS was used to identify the adducts between quinones derived from rosmarinic acid (RosA) and thiol compounds, including cysteine (Cys), glutathione (GSH), and peptides digested from myosin. Two adducts of quinone-RosA/Cys and quinone-RosA/2Cys, one quinone-RosA/GSH adduct, and three quinone-RosA/peptide adducts were identified by extracted ion and MS(2) fragment ion chromatograms. By using MALDI-TOF/TOF MS, the adduction reaction between RosA and myosin in myofibrillar protein isolates was determined, demonstrating that the accurate reaction site was at Cys949 of myosin. The effect of reaction conditions, including stirring time, temperature, and oxidative stress, on the formation of adducts was further investigated. The formation of quinone-RosA/Cys and quinone RosA/GSH increased with stirring time. Both adducts increased with temperature, whereas the reactivity of the addition reaction of GSH was higher than that of Cys. With increasing oxidation stress, the formation of quinone-RosA/GSH adduct increased and that of quinone-RosA/Cys adduct decreased. PMID- 25541908 TI - Directed metalation of 1-ester-substituted indolizines: base/electrophile controlled regioselective functionalization. AB - A variety of C-2 and C-5 difunctionalized indolizines have been prepared through the reaction of 1-ester-substituted indolizines with organometallic bases followed by a reaction with different electrophiles. Metalation takes place under mild conditions allowing the isolation of a number of difunctionalized indolizines in good yields. The regioselectivity of the reaction appears to be governed by the nature of the base and electrophile. PMID- 25541909 TI - Alkyl chain length dependence of the field-effect mobility in novel anthracene derivatives. AB - We report six asymmetric alkylated anthracene-based molecules with different alkyl side chain lengths for use in organic field-effect transistors (OFETs). Alkyl side chains can potentially improve the solubility and processability of anthracene derivatives. The crystallinity and charge mobility of the anthracene derivatives may be improved by optimizing the side chain length. The highest field-effect mobility of the devices prepared here was 0.55 cm(2)/(V s), for 2-(p pentylphenylethynyl)anthracene (PPEA). The moderate side chain length appeared to be optimal for promoting self-organization among asymmetric anthracene derivatives in OFETs, and was certainly better than the short or long alkyl side chain lengths, as confirmed by X-ray diffraction measurements. PMID- 25541910 TI - Regulation of Heat Shock Proteins by miRNAs in human breast cancer. AB - Metabolic rates of cancer cells are faster compared to normal cells. This faster rate yields aberrant protein folding and causes loss of protein function. Therefore, cancer cells need more Heat Shock Proteins (HSPs) for proper substrate protein folding on oncogenic pathways. Pseudogenes regulate tumor suppressors and oncogenes, and pseudogenes are deregulated in cancer progression. Further, alterations in miRNA expression have been identified in different cancer types. MiRNAs also have both oncogenic and tumour-suppressive roles in breast cancer post-transcriptional gene regulation. Breast cancer is a genetic disease and we performed miRNA analysis in human breast cancer cell lines to identify miRNAs in association with HSPs and pseudogenes by employing CellMiner; a web-based suite. CellMiner integrates several databases and help analysing microarray metadata. The experimental data provide a platform for researchers to compare macromolecules' relationships in NCI-60 cell lines. Breast cancer associated miRNAs gathered from literature and analyzed by employing this suite, significantly correlated HSP genes and pseudogenes in the breast cancer are determined as; HSPA13, HSP90AB1, TRAP1, HSPB1, DNAJB4, HSPD1 and HSP90AA4P, HSPB1P1, DNAJC8P1, HSPD1P9 respectively. HSPs involved in breast cancer are regulated by several miRNAs and miRNA regulators from CellMiner data found as hsa miR-17, hsa-miR-22, hsa-miR-93, hsa-miR-106a, hsa-miR-125b, hsa-miR-130a, and hsamiR- 141. Cross check of the determined miRNAs and target HSPs was performed by target site prediction software. Comparison of the experimental data from CellMiner and software predicted data indicate differences. CellMiner data provide a vast miRNA types compared to prediction softwares-web tools data and reported miRNAs in the literature. Therefore, reported key miRNAs in this work that are not studied earlier may help cancer researchers to uncover novel posttranslational regulation mechanisms. Cancer cells use HSP network as an escape mechanism from apoptosis, therefore inhibition of associated HSPs by modulating miRNAs may provide a novel therapy for the tumorigenesis. PMID- 25541911 TI - Silencing of miRNA-126 in kidney ischemia reperfusion is associated with elevated SDF-1 levels and mobilization of Sca-1+/Lin- progenitor cells. AB - Integrity of the capillary network in the kidney is essential in the recovery from ischemia/ reperfusion injury (IRI), a phenomenon central to kidney transplantation and acute kidney injury. MicroRNA- 126 (miR-126) is known to be important in maintaining vascular homeostasis by facilitating vascular regeneration and modulating the mobilization of vascular progenitor cells. Stromal cell-derived factor 1 (SDF-1), important in the mobilization of vascular progenitor cells, is a direct target of miR-126 and modulation of miR-126 was previously shown to affect the number of circulating Sca-1(+)/Lin(-) vascular progenitor cells in a mouse model for hind limb ischemia. Here, we assessed the in vivo contribution of miR-126 to progenitor cell mobilization and kidney function following IRI in mice. A three day follow up of blood urea levels following kidney IRI demonstrated that systemic antagomir silencing of miR-126 did not impact the loss or subsequent restoration of kidney function. However, whole kidney lysates displayed elevated gene expression levels of Sdf-1, Vegf-A and eNOS after IRI as a result of systemic silencing of miR-126. Furthermore, FACS-analysis on whole blood three days after surgery revealed a marked up regulation of the number of circulating Sca-1(+)/Lin(-) progenitor cells in the antagomir-126 treated mice, in an ischemia dependent manner. Our data indicate that silencing of miR-126 can enhance renal expression of Sdf-1 after IRI, leading to the mobilization of vascular progenitor cells into the circulation. PMID- 25541912 TI - MicroRNAs in the intracellular space, regulation of organelle specific pathways in health and disease. AB - MicroRNAs (miRNA) are small (~22 nucleotide] non-coding RNA molecules originally characterised as nonsense or junk DNA. Emerging research suggests that these molecules have diverse regulatory roles in an array of molecular, cellular and physiological processes. MiRNAs are versatile and highly stable molecules, therefore, they are able to exist as intracellular or extracellular miRNAs. The purpose of this paper is to review the function and role of miRNAs in the intracellular space with specific focus on the interactions between miRNAs and organelles such as the mitochondria and the rough endoplasmic reticulum. Understanding the role of miRNAs in the intracellular space may be vital in understanding the mechanism of certain diseases. PMID- 25541913 TI - Role of microRNA in the diagnosis and therapy of hepatocellular carcinoma: a new frontier. AB - The incidence of hepatocellular carcinoma continues to increase worldwide, representing one of the premier causes of cancer-related deaths. It is closely related to liver fibrosis and cirrhosis (and their underlying etiologies), thus making its treatment a challenge, as one has to simultaneously manage both the liver disease, as well as the malignancy. Although there are a variety of different therapies proposed, the two main ones that can actually lead to a therapeutic result, are surgical resection and orthotopic liver transplantation. However, the challenge remains in terms of early diagnosis of the disease, identifying the steps that lead to its progression and choosing the best treatment for each patient. Regarding this latter comment, it has been determined that not all cancers are the same, in the sense that their molecular make-up and alterations are what dictate their specific behavior and aggressiveness; which would be helpful to know if the goal is to choose a patient- and tumor-oriented individualized approach, that will yield better results. Critical in this effort has been and continues to be the role of microRNA, which appears to play a central role in the progression, diagnosis and management of hepatocellular carcinoma. This paper will attempt to clarify the role of microRNA in these areas and provide a window to the future. PMID- 25541914 TI - Worm in the eye. PMID- 25541915 TI - Tonsillar Helicobacter pylori colonization in chronic tonsillitis: systematic review and meta-analysis. AB - IMPORTANCE: Helicobacter pylori colonization contributes significantly to multiple disease states, but its role in the development of tonsillar infection is unclear. Understanding the causes of chronic tonsillitis is important in clinical decision making of this commonly treated disease. OBJECTIVE: To assess the correlation between H pylori colonization of tonsillar tissue in chronic tonsillitis and in noninfectious hyperplastic tonsils. DATA SOURCES: We searched PubMed, MEDLINE, the Cochrane Trial Registry (through June 2014) and relevant article bibliographies. STUDY SELECTION: Systematic review and meta-analysis of studies assessing the correlation between H pylori colonization in tonsillar tissues of patients undergoing tonsillectomy for either chronic tonsillitis or noninfectious causes. Included studies hypothesized that H pylori played a role in the development of chronic tonsillitis. All included studies investigated the presence of H pylori in tonsillar tissue removed for various indications. Included studies must have used an accepted method of testing for H pylori. DATA EXTRACTION AND ANALYSIS: Studies were systematically reviewed by 2 independent reviewers for inclusion. Reported results of H pylori testing between tissues removed for infectious or noninfectious causes were systematically reviewed. The odds ratio of Hpylori colonization in tissue removed for chronic tonsillitis compared with tissue removed for noninfectious causes was calculated using a random-effects model. RESULTS: Six studies met inclusion criteria and had suitable data for pooling (n = 436). Of these, 2 studies measured H pylori colonization of tonsillar tissue in pediatric populations. One study analyzed tissue in both adult and pediatric populations. Noninfectious indications for tonsillectomy included sleep apnea or sleep-related breathing disorder, obstruction, carcinoma, and tonsillar hypertrophy. Overall, tonsillar H pylori colonization was found not to be significantly present more often in tissue samples removed secondary to recurrent infection rather than to noninfectious indications. The odds ratio of H pylori colonization in the tonsils of patients with chronic tonsillitis was 1.993 (95% CI, 0.909-4.371) (P = .09). CONCLUSIONS AND RELEVANCE: Helicobacter pylori colonization was not found to be more prevalent on tonsillar tissue with chronic or recurrent infections. The reviewed studies provide no evidence that H pylori infection plays a role in the pathogenesis or development of chronic tonsillitis. PMID- 25541916 TI - Perimetry in young and neurologically impaired children: the Behavioral Visual Field (BEFIE) Screening Test revisited. AB - IMPORTANCE: Visual field examination in young or neurologically impaired children is a challenge. As a result, the Behavioral Visual Field (BEFIE) Screening Test was developed in 1995. OBJECTIVES: To evaluate the applicability of the BEFIE test in a large population of young or neurologically impaired children, its reliability and consistency of findings across time, and its potential diagnostic value compared with standard conventional perimetry. DESIGN, SETTING, AND PARTICIPANTS: The BEFIE tests were performed at an academic tertiary center and measured the peripheral visual field extension in degrees by observing an individual's response to a stimulus on a graded arc that moved from the periphery to the center of the visual field along different meridians. Patient files from all children who underwent this test were retrospectively analyzed. In total, 1788 BEFIE tests were performed in 835 children (median age, 3.4 years). MAIN OUTCOMES AND MEASURES: Reliability and results of all tests were longitudinally evaluated. The diagnostic value of the BEFIE test was assessed by comparing monocular BEFIE test results with those of standard conventional perimetry in children who underwent both. RESULTS: Of 1788 tests, 74% (95% CI, 72%-76%) were considered reliable from the age of 4 months and older, with increasing success with higher ages; 56% reliable in children younger than 1 year; 71% reliable in children between 1 and 2 years; and more than 75% reliable in children 2 years and older (Spearman r = 0.506; P = .11). Peripheral visual field defects were found in 28% (95% CI, 25%-31%) of all first reliable tests. In 75% of children who underwent serial testing, results were consistent and there were good explanations in the case of discrepancies. Comparison of monocular BEFIE tests with standard conventional perimetry results in 147 eyes yielded a positive predictive value of 98% (95% CI, 94%-100%), negative predictive value of 66% (95% CI, 56%-75%), specificity of 98% (95% CI, 95%-100%), sensitivity of 60% (95% CI, 50%-71%), and superior sensitivity of 80% (95% CI, 70%-91%) when only absolute peripheral visual field defects at standard conventional perimetry were accounted for. CONCLUSIONS AND RELEVANCE: These data suggest that the BEFIE test is a valuable tool to detect peripheral visual field defects when standard conventional perimetry cannot be performed in young or neurologically impaired children. PMID- 25541917 TI - Comparison of internal organ injuries by blunt abdominal trauma in rats with empty or full stomach. AB - BACKGROUND: The aim of the study was to investigate if there was a difference in injury in intra-abdominal viscera due to blunt abdominal trauma sustained by rats with empty or full stomach and to examine which viscera is affected most, based on the direction of the trauma. METHODS: Since there is no data in the literature on the force of trauma, a pilot study was carried out before commencing the experimental study. An apparatus was built to determine the trauma force that would not cause sudden death, and rats were allowed free fall from a height of 40 and 45 cm so that they would land on their abdomen. The most appropriate force of trauma (F=69.978 N) and absorbed energy (E=1/2mv2=0.979 Joules) were obtained in rats weighing 250 g that fell from a height of 40 cm. RESULTS: Thirty six rats were included in the study and separated into six groups. Any statistically significant differences between groups with regard to the stomach being empty or full during trauma and its direction were examined (anterior, right/left sided). CONCLUSION: It was observed that there were differences in injuries sustained by the internal organs depending on the fullness or emptiness of the stomach and the direction of the trauma. PMID- 25541918 TI - The fate of suboptimal anastomosis after colon resection: An experimental study. AB - BACKGROUND: The fate of suboptimal anastomosis is unknown and early detection of anastomotic leakage after colon resection is crucial for the proper management of patients. METHODS: Twenty-six rats were assigned to "Control", "Leakage" and "Suboptimal anastomosis" groups where they underwent either sham laparotomy, cecal ligation, and puncture or anastomosis with four sutures following colon resection, respectively. At the fifth hour and on the third and ninth days; peripheral blood and peritoneal washing samples through relaparotomy were obtained. The abdomen was inspected macroscopically for anastomotic healing. Polymerase chain reaction (PCR) with 16s rRNA and E.coli-specific primers were run on all samples along with aerobic and anaerobic cultures. RESULTS: The sensitivity and specificity of PCR on different bodily fluids with 16s rRNA and E.coli-specific primers were 100% and 78%, respectively. All samples of peritoneal washing fluids on the third and ninth days showed presence of bacteria in both PCR and culture. The inspection of the abdomen revealed signs of anastomotic leakage in eight rats (80%), whereas mortality related with anastomosis was detected in two (20%). CONCLUSION: Anastomotic leakage with suboptimal anastomosis after colon resection is high and the early detection is possible by running PCR on peritoneal samples as early as 72 hours. PMID- 25541919 TI - Effects of citicoline on level of consciousness, serum level of fetuin-A and matrix Gla-protein (MGP) in trauma patients with diffuse axonal injury (DAI) and GCS<=8. AB - BACKGROUND: Citicoline, a neuroprotective drug, has been suggested to improve level of consciousness, mitigating secondary to brain damage and ectopic vascular calcification, following post-traumatic neurogenesis and angiogenesis, inducing calcification modulators, like fetuin-A and matrix Gla-protein (MGP). This study aimed to investigate effects of citicoline on levels of consciousness, serum levels of fetuin-A and MGP in patients with severe traumatic brain injury. METHODS: This double blind randomized controlled trial (RCT) was conducted on patients with diagnosis of diffuse axonal injury (DAI) and GCS<=8. The cases were treated with citicoline (500 mg every 6 hours) intravenously for fifteen days. Daily GCS assessment and intermittent blood sampling were done for both cases and controls. RESULTS: Fifty-eight patients were included in the study and during the study period, mean GCS levels improved in both groups; however, the difference was inconsiderable (p>0.05). Serum levels of fetuin-A, a negative phase reactant, increased in the group treated with citicoline (p=0.012), while these changes were insignificant for the controls (p=0.455). Serum levels of MGP, a calcification inhibitor, increased in the cases (p=0.046). The alterations were inconsequential in the control group (p=0.405). CONCLUSION: The findings of this study suggest neutral effects of citicoline on level of consciousness and GCS. Through increasing levels of fetuin-A and MGP, citicoline may have protective effects against inflammatory damage and vascular calcification secondary to head trauma. PMID- 25541920 TI - Bowel and mesenteric injury in blunt trauma: diagnostic efficiency and importance of experience in using multidetector computed tomography. AB - BACKGROUND: The purpose of this study was to investigate the diagnostic efficiency of multidetector computed tomography (MDCT) in the detection of blunt bowel and mesenteric injuries (BBMI), and the role of different experience levels in using MDCT. METHODS: This study included a test group of twenty-seven patients with surgically important BBMI in whom the diagnoses were confirmed after surgical intervention (23 men and 4 women; mean age, 40.7+/-16.2; range, 18-76), and a control group of twenty-one matched patients without BBMI who underwent laparotomy for trauma during the same time period (16 men and 5 women; mean age, 38.9+/-14.5; range, 20-68) and sixteen-detector computed tomography prior to surgery. Intraoperative findings were compared with MDCT findings. RESULTS: High accuracy, specificity, and positive predictive values in MDCT findings with respect to intraperitoneal free air, mesenteric air, thickened (>4-5 mm) and defected bowel wall, increased contrast enhancement on bowel wall, and mesenteric hematoma were found among others (p<0.01). Sensitivities and specificities of the diagnosis of BBMI by the resident and staff radiologist was 74% and 71%, and 85% and 100%, respectively. CONCLUSION: MDCT displays BBMI with high sensitivity and specificity, and can predict the need for surgery. Experience in radiology is an important factor for appropriate interpretation of the MDCT findings. PMID- 25541921 TI - The clinical value of leucocyte count and neutrophil percentage in diagnosing uncomplicated (simple) appendicitis and predicting complicated appendicitis. AB - BACKGROUND: The aim of this study was to establish the diagnostic value of leucocyte count and neutrophil percentage in both diagnosing simple appendicitis and predicting complicated appendicitis. METHODS: The patients who underwent appendectomy with a clinical diagnosis of acute appendicitis (AA) between January 2011 and December 2012 were studied retrospectively. The data of total WBC count, neutrophil ratio, and physical findings were analyzed. Sensitivities and specificities of leucocyte count and neutrophil ratio were calculated. RESULTS: One hundred and fifty-nine patients, diagnosed with acute appendicitis, were operated. Simple appendicitis was detected in 82.4% of the patients and complicated appendicitis in 17.6%. Leucocyte count had low sensitivity and specificity for diagnosing acute appendicitis (67.5% and 36.3%, respectively). Neutrophil ratio had a sensitivity rate of 60.1% and specificity rate of 90.9%. Complicated appendicitis was more common in male patients. Leucocyte count was statistically higher in patients with complicated appendicitis. CONCLUSION: Two inflammatory markers, leucocyte count and neutrophil ratio, were evaluated for diagnosing acute appendicitis. Neutrophil ratio had higher sensitivity and specificity for acute appendicitis. On the other hand, increased leucocyte count and male gender was found to be a risk factor for complicated appendicitis. PMID- 25541922 TI - Penile fasciocutaneous flap urethroplasty in long segment urethral stricture. AB - BACKGROUND: The aim of this study was to evaluate the success of penile fasciocutaneous flap urethroplasty in the treatment of long segment urethral stricture. METHODS: In this study, seventeen patients with long segment urethral stricture were included. In regard to the length of the narrow segment, vertical or circular penile skin fasciocutaneous flap was anastomosed on 18 F urethral catheter. In the first week and 6th month after removal of the urethral catheter, patients were controlled by uroflowmetry and postvoiding residual urine volume measurement by ultrasound. RESULTS: The mean age of the patients was 52 (range: 17 to 67 years). The mean follow up-time was 60 months (range: 12-96 months). Mean length of stricture was 105 mm (range: 40-150 mm). Vertical and circular penile fasciocutaneous flaps were used in four and 13 patients, respectively. Maximum urine flow rate and postvoiding residual urine assessment in the first week after removal of the urethral catheter were 19.1 ml/s (range: 9 to 31 ml/s) and 12.9 cm3 (range: 0 to 40 cm3), respectively. Same parameters in the postoperative 6th month were 17.4 ml/s (range; 8 to 25 ml/s) and 15.2 cm3 (range; 0 to 40 cm3), respectively. CONCLUSION: Our long term results revealed that penile fasciocutaneous flap urethroplasty method seemed to be a reasonable treatment option in the treatment of long segment urethral stricture. PMID- 25541923 TI - The role of headache management in minor head injury before performing brain CT scan--can intravenous morphine sulfate predict intracranial injury? AB - BACKGROUND: The aim of this study was to examine the association between the responses of headache to IV morphine and the findings of brain CT scan in minor head injury (MHI), and to propose a new risk indicator to identify patients requiring CT scanning. METHODS: A total of 1857 MHI patients >=15 years of age, presenting with headache and a GCS score of 14 or 15 were included in the study. Intravenous morphine sulfate was administered, and thereafter, patients were assessed for the relief or persistence of headache. Subsequently, a brain CT scan was obtained from all patients. RESULTS: Patients were divided into two age groups: 15-60 and >60 years. There was a significant association between the response of headache to morphine and the result of brain CT in both age groups (p<0.001). In patients aged between 15 and 60, none whose headache had responded to morphine showed any abnormal findings in CT scan (sensitivity=100%). In the >60 group, sensitivity was 58.3% for abnormal CT and 71.4% for neurosurgical intervention. CONCLUSION: This study suggests that a headache not relieved by morphine is a risk indicator for intracranial injury. This protocol can be used in rural areas with limited access to CT scan as an adjunct to the existing criteria for selecting patients with MHI for CT scanning. PMID- 25541924 TI - Treatment and results in pediatric traumatic hip dislocation: case series and review of the literature. AB - BACKGROUND: Six acute traumatic hip dislocations in pediatric patients were retrospectively analyzed. Types of dislocations, associated lesions, treatment methods, complications, and clinical and radiological outcomes were reviewed. METHODS: Six child patients treated due to traumatic hip dislocation between 2007 and 2011 in our clinic were included in the study. While five of the patients were male, one was female; the average age was 8 years and 8 months. The mean follow-up was 25.2+/-10 months. There were posterior dislocations in five cases and transepiphyseal fractured dislocation in one case. Four cases were treated by closed reduction while two cases were treated with open reduction method. RESULTS: In the last control of the patients, asymmetric widening in the hip joint was found due to osteochondral fracture in one patient and coxa magna occurred in one patient. Avascular necrosis developed in one case with transepiphyseal fractured dislocation. Harris hip score evaluation was found excellent in five cases and bad in the case with fractured dislocation. CONCLUSION: Traumatic hip dislocation is a rare condition. It should be treated with preferably closed method as soon as possible. Repetitive reduction trials should be avoided. Open reduction should be performed to recognize accompanying lesions after advanced radiologic examinations such as computerized tomography and magnetic resonance imaging. PMID- 25541925 TI - [Using pedicled rectus abdominis musculocutaneous flaps in thigh and lumber defects]. AB - BACKGROUND: A series of previously described but rarely used variations of the pedicled, extended or vertical rectus abdominis musculocutaneous flap (Extended RAM, VRAM) were reviewed. METHODS: Skin paddle dimensions, ranged 8 to 28 cm in width and 10 to 35 cm in length, were used in five consecutive patients. Four flaps were placed deep to the inguinal ligament to repair the thigh as proximal to the knee region; the remaining one flap was passed transabdominally to cover the defect of the lumbar region. RESULTS: No flaps necrosis were seen and in one case wound healing problems required minimal operative intervention. Successful transfer of the VRAM and extended RAM with low rate of complication for the thigh and lumbar region defects were demonstrated to be safe and reasonable options of flap reconstruction. DISCUSSION: The flaps had the advantages of being robust and well-vascularized, easy and fast to harvest, and not requiring microsurgery experience. PMID- 25541926 TI - [Atypical trajectory of gunshot injury]. AB - Gunshot injuries are common medical-legal issues. Atypical tract lines resulting from this type of injuries cause difficulties in diagnosis and treatment. In this paper, a gunshot injury on the right anterior thigh extending to the right hemithorax was presented. A 67-year-old Syrian refugee patient was brought to the emergency service due to gunshot injury. Bullet entrance hole was determined on the right anterior thigh region; however, exit side could not be seen. Bullet was determined on the right thorax at tomography and the patient was taken to operation due to diaphragm rupture and lung parenchymal injury. Other body parts must be examined radiologically for the bullet which cannot be determined at gunshot injury side. PMID- 25541927 TI - Traumatic abdominal hernia complicated by necrotizing fasciitis. AB - Necrotizing fasciitis is a critical illness involving skin and soft tissues, which may develop after blunt abdominal trauma causing abdominal wall hernia and representing a great challenge for physicians. A 52-year-old man was brought to the emergency department after a road accident, presenting blunt abdominal trauma with a large non-reducible mass in the lower-right abdomen. A first, CT showed abdominal hernia without signs of complication. Three hours after ICU admission, he developed hemodynamic instability. Therefore, a new CT scan was requested, showing signs of hernia complication. He was moved to the operating room where a complete transversal section of an ileal loop was identified. Five hours after surgery, he presented a new episode of hemodynamic instability with signs of skin and soft tissue infection. Due to the high clinical suspicion of necrotizing fasciitis development, wide debridement was performed. Following traumatic abdominal wall hernia (TAWH), patients can present unsuspected injuries in abdominal organs. Helical CT can be falsely negative in the early moments, leading to misdiagnosis. Necrotizing fasciitis is a potentially fatal infection and, consequently, resuscitation measures, wide-spectrum antibiotics, and early surgical debridement are required. This type of fasciitis can develop after blunt abdominal trauma following wall hernia without skin disruption. PMID- 25541928 TI - Complete cervical tracheal transection caused by blunt neck trauma: case report. AB - This study aimed to report the survival of a rare case of complete tracheal transection followed by blunt neck trauma. A 66-year-old man was presented in the emergency room after a motorcycle accident in which a rope was wrapped around his neck. Although alert, he was in respiratory distress. A computed tomographic scan showed transection of the cervical trachea. Emergency neck exploration revealed that the tracheal laceration had been cut from the tracheal anterior third ring to the posterior first ring and the anterior esophageal wall had ruptured. Laryngectomy, tracheostomy, and esophagopharyngeal anastomosis were performed. Prompt airway management and immediate neck exploration is important for survival in these cases. PMID- 25541929 TI - Right ventricle collapse secondary to hepatothorax caused by diaphragm rupture due to blunt trauma. AB - Traumatic diaphragm ruptures occur frequently after motor vehicle accidents through penetrating traumas. In 90% of the patients, traumatic diaphragm rupture commonly coexists with other organ injuries. Posteroanterior chest x-ray, computed tomography, magnetic resonance imaging, upper gastrointestinal system contrast-enhanced examinations, and thoraxoscopy/laparoscopy are several modalities which can be used for diagnosing traumatic diaphragm rupture in clinical practice. A case of right ventricle collapse secondary to hepatothorax caused by diaphragm rupture was presented in this study. Patient was diagnosed by posteroanterior chest x-ray and computed tomography. Emergency surgery was planned due to hemodynamic instability. When mechanical pressure on the right ventricle disappeared, hemodynamic improvement was observed simultaneously. PMID- 25541930 TI - The Role of 18F-FDG PET/CT in the Evaluation of Gastric Cancer Recurrence. AB - OBJECTIVE: F-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been widely used for staging, re-staging and for monitoring therapy-induced changes and response to therapy in patients with various types of cancer, but its utilization for gastric cancer has been limited. This study aimed to assess the diagnostic performance of 18F-FDG PET/CT for detecting recurrence in gastric cancer patients with radiologic or clinical suspicion of recurrence and its clinical impact on making decision. METHODS: We performed a retrospective review of 130 consecutive patients who underwent PET/CT scans for post-treatment surveillance of gastric cancer between January 2008 and March 2012. The mean time between the initial diagnosis of gastric cancer and PET/CT studies was 44 weeks with a median of 18 weeks. The number and site of positive FDG uptake were analyzed and correlated with the final diagnosis by calculating the diagnostic values. We evaluated the diagnostic accuracy of PET/CT for detecting the recurrence in terms of whether or not histology had been SRC/musinous adenocarcinoma. The changes in the clinical management of patients were also evaluated according to the results of PET/CT. RESULTS: Of all 130 patients, 91 patients were confirmed to have true recurrence. The sensitivity, specificity, positive predictive value, negative predictive value and the accuracy of PET/CT for diagnosing true recurrence on a per-person basis were 91.2%, 61.5%, 84.6%, 75.0% and 82.3% respectively. Final diagnoses were confirmed histopathologically in 59 (45.4%) of 130 patients and by clinical and radiological follow-up in the remaining 71 (54.6%) patients. In the subgroup with SRC/mucinous adenocarcinoma differentiation of the primary tumor, there was no statistically significant difference in terms of diagnostic accuracy of PET/CT on a per-person basis. In addition, PET/CT results changed the patients' management in 20 (15%) cases. CONCLUSIONS: 18F-FDG PET/CT can provide useful information in discriminating true recurrence in patients with suspected gastric cancer recurrence and may have significant impact on clinical decisions/patient management in a considerable percentage of patients. PMID- 25541931 TI - The effect of high dose radioiodine therapy on formation of radiation retinopathy during thyroid cancer treatment. AB - OBJECTIVE: Non-thyroidal complication of high-dose radioiodine therapy for thyroid carcinoma might cause salivary and lacrimal gland dysfunction, which may be transient or permanent in a dose-dependent manner. However, radiation retinopathy complicating 131I therapy, has not been previously well characterized. The aim of this study was to evaluate the extent of retinal damage among patients who had received high doses of radioiodine treatment. METHODS: Forty eyes of 20 patients (3 male, 17 female) who received 250-1000 mCi during 131I therapy and on ophthalmological follow up for a year after the last treatment were included in the study. Mean age of the study group was 50 years (range 25-70 years). In ophthalmologic examination, visual acuity was measured in order to determine visual loss. Intraocular pressure was measured in all the patients. Then lens examination was carried out with slit lamp biomicroscopy in order to investigate cataract or partial lens opacities. Fundus observation was carried out through the dilated pupil with slit lamp biomicroscopy using 90 D noncontact lens. RESULT: The best corrected visual aquity with Snellen chart was found as 1.0 in 36 eyes (90%) and between 0.6 and 0.9 (10%) in 4 eyes (10%). At the biomicroscopic fundus examination, retinal hemorrhage consistent with radiation retinopathy, microaneurysm, microinfarction, edema or exudation, vitreus hemorrhage, partial or total optical disc pallor indicating papillopathy in the optic disc were not observed in any of the eyes. CONCLUSION: This result indicates that there is not any significant correlation between repeated high dose radioiodine therapy and radiation retinopathy in differentiated thyroid carcinomas. Even though there is not a significant restriction in use of higher doses of radioiodine therapy in differentiated thyroid carcinoma, more extensive studies are needed in order to obtain more accurate data on possible occurrence of retinopathy. PMID- 25541932 TI - Predictors and Diagnostic Significance of the Adenosine Related Side Effects on Myocardial Perfusion SPECT/CT Imaging. AB - OBJECTIVE: The aim of this study was to investigate the relationship between patient characteristics and adenosine-related side-effects during stress myocard perfusion imaging (MPI). The effect of presence of adenosine-related side-effects on the diagnostic value of MPI with integrated SPECT/CT system for coronary artery disease (CAD), was also assessed in this study. METHODS: Total of 281 patients (109 M, 172 F; mean age:62.6+/-10) who underwent standard adenosine stress protocol for MPI, were included in this study. All symptoms during adenosine infusion were scored according to the severity and duration. For the estimation of diagnostic value of adenosine MPI with integrated SPECT/CT system, coronary angiography (CAG) or clinical follow-up were used as gold standard. RESULTS: Total of 173 patients (61.6%) experienced adenosine-related side-effects (group 1); flushing, dyspnea, and chest pain were the most common. Other 108 patients completed pharmacologic stress (PS) test without any side-effects (group 2). Test tolerability were similar in the patients with cardiovascular or airway disease to others, however dyspnea were observed significantly more common in patients with mild airway disease. Body mass index (BMI) >=30 kg/m2 and age <=45 years were independent predictors of side-effects. The diagnostic value of MPI was similar in both groups. Sensitivity of adenosine MPI SPECT/CT was calculated to be 86%, specificity was 94% and diagnostic accuracy was 92% for diagnosis of CAD. CONCLUSION: Adenosine MPI is a feasible and well tolerated method in patients who are not suitable for exercise stress test as well as patients with cardiopulmonary disease. However age <=45 years and BMI >=30 kg/m2 are the positive predictors of adenosine-related side-effects, the diagnostic value of adenosine MPI SPECT/CT is not affected by the presence of adenosine related side effects. PMID- 25541933 TI - Comparison of thyroid blood flow and uptake indices using technetium-99m pertechnetate in patients with graves' disease and euthyroid subjects. AB - OBJECTIVE: The aim of the present study was to evaluate parameters of early blood flow (EBF) including duration of EBF, perfusion index (PI), uptake indexes 1 and 2 (UI1 and UI2) derived from dynamic thyroid scintigraphy in patients with Graves' disease (GD), and euthyroid (EI). Maximum instant uptake and maximum uptake of the thyroid gland were also assessed. METHODS: A total of 50 patients with GD and EI were included in this study. Each patient underwent two dynamic scans of 1-minute (20 images at 3 seconds) and 20-minute (20 images at 1 minute) with 99mTcO4. The time-activity curve of a 1-minute scan was employed to derive EBF parameters; likewise, the time-activity curve of a 20-minute scan was used to determine maximum instant uptake, and the gradient of the curve from the 10th to 20th minute was used to assess maximum uptake. RESULTS: Values of EBF duration, PI, UI1, UI2, and maximum instant uptake were significantly lower in patients with GD than in those with EI (p<0.05). The calculated gradient of the second half of the curves for all of the patients ranged from 0 to 0.88 and was significantly higher in patients with GD than in those with EI. CONCLUSION: Lower values of PI, UI1, UI2 and durations of EBF, along with faster maximum instant uptake in patients with GD in comparison to EI are indicators of a heightened desire for hyper-functioning thyroid glands of patients with GD to absorb 99mTcO4. Additionally, because of the uprising gradient at the end of the 20 minute time-activity curve, a maximum thyroid uptake of 99mTcO4 was achieved at more than 20 minutes after the radiopharmaceutical injection. PMID- 25541934 TI - Radionuclide imaging of dual ectopic thyroid in a preadolescent girl. AB - Ectopic thyroid is a congenital defect in which the thyroid gland is located away from the usual pretracheal location. Dual ectopic thyroid, which consists of two foci of thyroid tissue, is very rare. In this case dual ectopic thyroid with subclinical hypothyroidism in a 10-year-old-girl was reported. The absence of the thyroid gland in the pretracheal location was revealed by ultrasonography (USG). Two foci of ectopic thyroid tissue located at the base of the tongue and infrahyoid region were determined by Technetium-99m pertechnetate thyroid scintigraphy. It can be concluded that if the thyroid gland is not visible by USG, ectopic thyroid tissue should be evaluated with scintigraphy. PMID- 25541935 TI - FDG PET-CT Finding in Bilateral Renal and Bone Involvement of Diffuse Large B Cell Lymphoma. AB - Thirty-six year old male patient with pathological fracture of the left tibia underwent intramedullary and soft tissue curettage. The histopathological examination revealed diffuse large B cell lymphoma. The patient underwent F18-FDG PET-CT scanning for initial staging. FDG PET-CT scan revealed hypermetabolic lesions at the left tibia and in bilateral kidneys. After the systemic chemotherapy and local radiotherapy to the tibia, repeated FDG PET/CT scan showed improvement of the previous hypermetabolic lesions, suggesting good response to therapy. Bone and renal involvement is an uncommon variant of diffuse large B cell lymphoma and FDG PET-CT is an useful whole body imaging modality in these cases. PMID- 25541936 TI - General randomized response techniques using Polya's Urn process as a randomization device. AB - In this paper, interesting improvements in [1] and [2] randomized response techniques have been proposed. The proposed randomized response technique applies Polya's urn process (see [3]) to obtain data from respondents. One of the suggested technique requires reporting the number of draws to observe a fixed number of cards of certain type. On the contrary, the number of cards of a certain type is to be reported in case of second proposed randomized response model. Based on the information collected through the suggested techniques, two different unbiased estimators of proportion of a sensitive attribute have been suggested. A detailed comparative simulation study has also been done. The results are also supported by means of a small scale survey. PMID- 25541937 TI - Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the relative efficacy of ranibizumab (RBZ) monotherapy or combined with laser (RBZ + Laser) versus laser monotherapy for the treatment of diabetic macular edema (DME). METHODS: A comprehensive literature search using PUBMED, ClinicalTrials.gov, and the Cochrane Library to identify randomized controlled trials (RCTs) comparing RBZ or RBZ + Laser to laser monotherapy in patients with DME. Efficacy estimates were determined by comparing weighted mean differences (WMD) in the change of best corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline, and the risk ratios (RR) for the proportions of patients with at least 15 letters change from baseline. Safety analysis estimated the RR of cardiac disorders at 6 to 12 months in RBZ therapy vs. laser monotherapy. Statistical analysis was performed using the RevMan 5.1 software. RESULTS: Seven RCTs were selected for this meta-analysis, including 1749 patients (394 patients in the RBZ group, 642 patients in the RBZ + Laser group, and 713 patients in the laser group). RBZ and RBZ + Laser were superior to laser monotherapy in the mean change of BCVA and CMT from baseline (WMD = 5.65, 95% confidence interval (CI), 4.44-6.87, P<0.00001; WMD = 5.02, 95% CI, 3.83 6.20, P<0.00001, and WMD = -57.91, 95% CI, -77.62 to -38.20, P<0.00001; WMD = 56.63, 95% CI, -104.81 to -8.44, P = 0.02, respectively). The pooled RR comparing the proportions of patients with at least 15 letters improvement or deterioration were also in favor of RBZ and RBZ + Laser (RR = 2.94, 95% CI, 1.82-4.77, P<0.00001; RR = 2.04, 95% CI, 1.50-2.78, P<0.00001, and RR = 0.21, 95% CI, 0.06 0.71, P = 0.01; RR = 0.52, 95% CI, 0.29-0.95, P = 0.03, respectively). There were no significant differences between RBZ and RBZ + Laser for any of the parameters. There were no difference in the safety profile between RBZ and laser. CONCLUSION: RBZ and RBZ + Laser had better visual and anatomic outcomes than laser monotherapy in the treatment of DME. RBZ + Laser seemed to be equivalent to RBZ. PMID- 25541938 TI - Detection of optogenetic stimulation in somatosensory cortex by non-human primates--towards artificial tactile sensation. AB - Neuroprosthesis research aims to enable communication between the brain and external assistive devices while restoring lost functionality such as occurs from stroke, spinal cord injury or neurodegenerative diseases. In future closed-loop sensorimotor prostheses, one approach is to use neuromodulation as direct stimulus to the brain to compensate for a lost sensory function and help the brain to integrate relevant information for commanding external devices via, e.g. movement intention. Current neuromodulation techniques rely mainly of electrical stimulation. Here we focus specifically on the question of eliciting a biomimetically relevant sense of touch by direct stimulus of the somatosensory cortex by introducing optogenetic techniques as an alternative to electrical stimulation. We demonstrate that light activated opsins can be introduced to target neurons in the somatosensory cortex of non-human primates and be optically activated to create a reliably detected sensation which the animal learns to interpret as a tactile sensation localized within the hand. The accomplishment highlighted here shows how optical stimulation of a relatively small group of mostly excitatory somatosensory neurons in the nonhuman primate brain is sufficient for eliciting a useful sensation from data acquired by simultaneous electrophysiology and from behavioral metrics. In this first report to date on optically neuromodulated behavior in the somatosensory cortex of nonhuman primates we do not yet dissect the details of the sensation the animals exerience or contrast it to those evoked by electrical stimulation, issues of considerable future interest. PMID- 25541939 TI - Instrumented static and dynamic balance assessment after stroke using Wii Balance Boards: reliability and association with clinical tests. AB - BACKGROUND AND OBJECTIVES: The Wii Balance Board (WBB) is a globally accessible device that shows promise as a clinically useful balance assessment tool. Although the WBB has been found to be comparable to a laboratory-grade force platform for obtaining centre of pressure data, it has not been comprehensively studied in clinical populations. The aim of this study was to investigate the measurement properties of tests utilising the WBB in people after stroke. METHODS: Thirty individuals who were more than three months post-stroke and able to stand unsupported were recruited from a single outpatient rehabilitation facility. Participants performed standardised assessments incorporating the WBB and customised software (static stance with eyes open and closed, static weight bearing asymmetry, dynamic mediolateral weight shifting and dynamic sit-to-stand) in addition to commonly employed clinical tests (10 Metre Walk Test, Timed Up and Go, Step Test and Functional Reach) on two testing occasions one week apart. Test retest reliability and construct validity of the WBB tests were investigated. RESULTS: All WBB-based outcomes were found to be highly reliable between testing occasions (ICC = 0.82 to 0.98). Correlations were poor to moderate between WBB variables and clinical tests, with the strongest associations observed between task-related activities, such as WBB mediolateral weight shifting and the Step Test. CONCLUSIONS: The WBB, used with customised software, is a reliable and potentially useful tool for the assessment of balance and weight-bearing asymmetry following stroke. Future research is recommended to further investigate validity and responsiveness. PMID- 25541941 TI - A novel medical image protection scheme using a 3-dimensional chaotic system. AB - Recently, great concerns have been raised regarding the issue of medical image protection due to the increasing demand for telemedicine services, especially the teleradiology service. To meet this challenge, a novel chaos-based approach is suggested in this paper. To address the security and efficiency problems encountered by many existing permutation-diffusion type image ciphers, the new scheme utilizes a single 3D chaotic system, Chen's chaotic system, for both permutation and diffusion. In the permutation stage, we introduce a novel shuffling mechanism, which shuffles each pixel in the plain image by swapping it with another pixel chosen by two of the three state variables of Chen's chaotic system. The remaining variable is used for quantification of pseudorandom keystream for diffusion. Moreover, the selection of state variables is controlled by plain pixel, which enhances the security against known/chosen-plaintext attack. Thorough experimental tests are carried out and the results indicate that the proposed scheme provides an effective and efficient way for real-time secure medical image transmission over public networks. PMID- 25541940 TI - Inhibition of TMEM16A expression suppresses growth and invasion in human colorectal cancer cells. AB - Metastasis leads to poor prognosis in colorectal cancer patients, and there is a growing need for new therapeutic targets. TMEM16A (ANO1, DOG1 or TAOS2) has recently been identified as a calcium-activated chloride channel (CaCC) and is reported to be overexpressed in several malignancies; however, its expression and function in colorectal cancer (CRC) remains unclear. In this study, we found expression of TMEM16A mRNA and protein in high-metastatic-potential SW620, HCT116 and LS174T cells, but not in primary HCT8 and SW480 cells, using RT-PCR, western blotting and immunofluorescence labeling. Patch-clamp recordings detected CaCC currents regulated by intracellular Ca(2+) and voltage in SW620 cells. Knockdown of TMEM16A by short hairpin RNAs (shRNA) resulted in the suppression of growth, migration and invasion of SW620 cells as detected by MTT, wound-healing and transwell assays. Mechanistically, TMEM16A depletion was accompanied by the dysregulation of phospho-MEK, phospho-ERK1/2 and cyclin D1 expression. Flow cytometry analysis showed that SW620 cells were inhibited from the G1 to S phase of the cell cycle in the TMEM16A shRNA group compared with the control group. In conclusion, our results indicate that TMEM16A CaCC is involved in growth, migration and invasion of metastatic CRC cells and provide evidence for TMEM16A as a potential drug target for treating metastatic colorectal carcinoma. PMID- 25541942 TI - Botulinum toxin to improve results in cleft lip repair: a double-blinded, randomized, vehicle-controlled clinical trial. AB - BACKGROUND: Most patients with facial scarring would value even a slight improvement in scar quality. Botulinum toxin A is widely used to alleviate facial dynamic rhytides but is also believed to improve scar quality by reducing wound tension during healing. The main objective was to assess the effect of Botulinum toxin on scars resultant from standardized upper lip wounds. METHODS: In this double-blinded, randomized, vehicle-controlled, prospective clinical trial, 60 consecutive consenting adults undergoing cleft lip scar revision (CLSR) surgery between July 2010 and March 2012 were randomized to receive botulinum toxin A (n = 30) or vehicle (normal saline; n = 30) injections into the subjacent orbicularis oris muscle immediately after wound closure. Scars were independently assessed at 6-months follow-up in blinded fashion using: Vancouver Scar Scale (VSS), Visual Analogue Scale (VAS) and photographic plus ultrasound measurements of scar widths. RESULTS: 58 patients completed the trial. All scar assessment modalities revealed statistically significantly better scars in the experimental than the vehicle-control group. CONCLUSION: Quality of surgical upper lip scars, which are oriented perpendicular to the direction of pull of the underlying orbicularis oris muscle, is significantly improved by its temporary paralysis during wound healing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01429402. PMID- 25541943 TI - Heat shock protein 90 has roles in intracellular calcium homeostasis, protein tyrosine phosphorylation regulation, and progesterone-responsive sperm function in human sperm. AB - Heat shock protein 90 plays critical roles in client protein maturation, signal transduction, protein folding and degradation, and morphological evolution; however, its function in human sperm is not fully understood. Therefore, our objective in this study was to elucidate the mechanism by which heat shock protein 90 exerts its effects on human sperm function. By performing indirect immunofluorescence staining, we found that heat shock protein 90 was localized primarily in the neck, midpiece, and tail regions of human sperm, and that its expression increased with increasing incubation time under capacitation conditions. Geldanamycin, a specific inhibitor of heat shock protein 90, was shown to inhibit this increase in heat shock protein 90 expression in western blotting analyses. Using a multifunctional microplate reader to examine Fluo-3 AM loaded sperm, we observed for the first time that inhibition of heat shock protein 90 by using geldanamycin significantly decreased intracellular calcium concentrations during capacitation. Moreover, western blot analysis showed that geldanamycin enhanced tyrosine phosphorylation of several proteins, including heat shock protein 90, in a dose-dependent manner. The effects of geldanamycin on human sperm function in the absence or presence of progesterone was evaluated by performing chlortetracycline staining and by using a computer-assisted sperm analyzer. We found that geldanamycin alone did not affect sperm capacitation, hyperactivation, and motility, but did so in the presence of progesterone. Taken together, these data suggest that heat shock protein 90, which increases in expression in human sperm during capacitation, has roles in intracellular calcium homeostasis, protein tyrosine phosphorylation regulation, and progesterone stimulated sperm function. In this study, we provide new insights into the roles of heat shock protein 90 in sperm function. PMID- 25541944 TI - Allele Workbench: transcriptome pipeline and interactive graphics for allele specific expression. AB - Sequencing the transcriptome can answer various questions such as determining the transcripts expressed in a given species for a specific tissue or condition, evaluating differential expression, discovering variants, and evaluating allele specific expression. Differential expression evaluates the expression differences between different strains, tissues, and conditions. Allele-specific expression evaluates expression differences between parental alleles. Both differential expression and allele-specific expression have been studied for heterosis (hybrid vigor), where the hybrid has improved performance over the parents for one or more traits. The Allele Workbench software was developed for a heterosis study that evaluated allele-specific expression for a mouse F1 hybrid using libraries from multiple tissues with biological replicates. This software has been made into a distributable package, which includes a pipeline, a Java interface to build the database, and a Java interface for query and display of the results. The required input is a reference genome, annotation file, and one or more RNA Seq libraries with optional replicates. It evaluates allelic imbalance at the SNP and transcript level and flags transcripts with significant opposite directional allele-specific expression. The Java interface allows the user to view data from libraries, replicates, genes, transcripts, exons, and variants, including queries on allele imbalance for selected libraries. To determine the impact of allele specific SNPs on protein folding, variants are annotated with their effect (e.g., missense), and the parental protein sequences may be exported for protein folding analysis. The Allele Workbench processing results in transcript files and read counts that can be used as input to the previously published Transcriptome Computational Workbench, which has a new algorithm for determining a trimmed set of gene ontology terms. The software with demo files is available from https://code.google.com/p/allele-workbench. Additionally, all software is ready for immediate use from an Atmosphere Virtual Machine Image available from the iPlant Collaborative (www.iplantcollaborative.org). PMID- 25541945 TI - Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naive T-cells but no enduring cell-autonomous defects in T-cell function. AB - Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4(+)/CD8(+) T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells. PMID- 25541946 TI - Two desmin gene mutations associated with myofibrillar myopathies in Polish families. AB - Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, alpha-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization. PMID- 25541947 TI - Occupational screening for tuberculosis and the use of a borderline zone for interpretation of the IGRA in German healthcare workers. AB - INTRODUCTION: Healthcare workers (HCWs) in low incidence countries with contact to patients with tuberculosis (TB) are considered a high-risk group for latent TB infection (LTBI) and therefore are routinely screened for LTBI. The German Occupational TB Network data is analyzed in order to estimate the prevalence and incidence of LTBI and to evaluate putative risk factors for a positive IGRA and the performance of IGRA in serial testing. METHODS: 3,823 HCWs were screened with the Quantiferon Gold in Tube (QFT) at least once; a second QFT was performed on 817 HCWs either in the course of contact tracing or serial examination. Risk factors for a positive QFT were assessed by a questionnaire. RESULTS: We observed a prevalence of LTBI of 8.3%. Putative risk factors for a positive QFT result were age >55 years (OR 6.89), foreign country of birth(OR 2.39), personal history of TB (OR 6.25) and workplace, e.g. infection ward (OR 1.76) or geriatric care (OR 1.99). Of those repeatedly tested, 88.2% (721/817) tested consistently QFT negative and 47 were consistently QFT-positive (5.8%). A conversion was observed in 2.8%(n = 21 of 742 with a negative first QFT) and a reversion occurred in 37.3% (n = 28 of 75 with a positive first QFT). Defining a conversion as an increase of the specific interferon concentration from <0.2 to >0.7 IU/ml, the conversion rate decreased to 1.2% (n = 8). Analogous to this, the reversion rate decreased to 18.8% (n = 9) [corrected]. DISCUSSION: In countries with a low incidence of TB and high hygiene standards, the LTBI infection risk for HCWs seems low. Introducing a borderline zone from 0.2 to <= 0.7 IU/ml may help to avoid unnecessary X-rays and preventive chemotherapy. No case of active TB was detected. Therefore, it might be reasonable to further restrict TB screening to HCWs who had unprotected contact with infectious patients or materials. PMID- 25541948 TI - Adding years to your life (or at least looking like it): a simple normalization underlies adaptation to facial age. AB - Adaptation has been widely used to probe how experience shapes the visual encoding of faces, but the pattern of perceptual changes produced by adaptation and the neural mechanisms these imply remain poorly characterized. We explored how adaptation alters the perceived age of faces, a fundamental facial attribute which can uniquely and reliably be scaled by observers. This allowed us to measure how adaptation to one age level affected the full continuum of perceived ages. Participants guessed the ages of faces ranging from 18-89, before or after adapting to a different set of faces composed of younger, older, or middle-aged adults. Adapting to young or old faces induced opposite linear shifts in perceived age that were independent of the model's age. Specifically, after adapting to younger or older faces, faces of all ages appeared 2 to 3 years older or younger, respectively. In contrast, middle-aged adaptors induced no aftereffects. This pattern suggests that adaptation leads to a simple and uniform renormalization of age perception, and is consistent with a norm-based neural code for the mechanisms mediating the perception of facial age. PMID- 25541949 TI - Upregulation of Unc-51-like kinase 1 by nitric oxide stabilizes SIRT1, independent of autophagy. AB - SIRT1 is central to the lifespan and vascular health, but undergoes degradation that contributes to several medical conditions, including diabetes. How SIRT1 turnover is regulated remains unclear. However, emerging evidence suggests that endothelial nitric oxide synthase (eNOS) positively regulates SIRT1 protein expression. We recently identified NO as an endogenous inhibitor of 26S proteasome functionality with a cellular reporter system. Here we extended this finding to a novel pathway that regulates SIRT1 protein breakdown. In cycloheximide (CHX)-treated endothelial cells, NONOate, an NO donor, and A23187, an eNOS activator, significantly stabilized SIRT1 protein. Similarly, NO enhanced SIRT1 protein, but not mRNA expression, in CHX-free cells. NO also stabilized an autophagy-related protein unc-51 like kinase (ULK1), but did not restore SIRT1 protein levels in ULK1-siRNA-treated cells or in mouse embryonic fibroblasts (MEF) from Ulk1-/- mice. This suggests that ULK1 mediated the NO regulation of SIRT1. Furthermore, adenoviral overexpression of ULK1 increased SIRT1 protein expression, while ULK1 siRNA treatment decreased it. Rapamycin-induced autophagy did not mimic these effects, suggesting that the effects of ULK1 were autophagy independent. Treatment with MG132, a proteasome inhibitor, or siRNA of beta TrCP1, an E3 ligase, prevented SIRT1 reduction induced by ULK1-siRNA. Mechanistically, ULK1 negatively regulated 26S proteasome functionality, which was at least partly mediated by O-linked-GlcNAc transferase (OGT), probably by increased O-GlcNAc modification of proteasomal subunit Rpt2. The NO-ULK1-SIRT1 axis was likely operative in the whole animal: both ULK1 and SIRT1 protein levels were significantly reduced in tissue homogenates in eNOS-knockout mice (lung) and in db/db mice where eNOS is downregulated (lung and heart). Taken together, the results show that NO stabilizes SIRT1 by regulating 26S proteasome functionality through ULK1 and OGT, but not autophagy, in endothelial cells. PMID- 25541950 TI - Gd-EOB-DTPA-enhanced MR guidance in thermal ablation of liver malignancies. AB - OBJECTIVE: To evaluate the potency of Gd-EOB-DTPA to support hepatic catheter placement in laser ablation procedures by quantifying time-dependent delineation effects for instrumentation and target tumor within liver parenchyma. Monitoring potential influence on online MR thermometry during the ablation procedure is a secondary aim. MATERIALS AND METHODS: 30 cases of MR-guided laser ablation were performed after i.v. bolus injection of gadoxetic acid (0.025 mmol/Kg Gd-EOB DTPA; Bayer Healthcare, Berlin, Germany). T1-weighted GRE sequences were used for applicator guidance (FLASH 3D) in the catheter placement phase and for therapy monitoring (FLASH 2D) in the therapy phase. SNR and consecutive CNR values were measured for elements of interest plotted over time both for catheter placement and therapy phase and compared with a non-contrast control group of 19 earlier cases. Statistical analysis was realized using the paired Wilcoxon test. RESULTS: Sustainable signal elevation of liver parenchyma in the contrast-enhanced group was sufficient to silhouette both target tumor and applicator against the liver. Differences in time dependent CNR alteration were highly significant between contrast-enhanced and non-contrast interventions for parenchyma and target on the one hand (p = 0.020) and parenchyma and instrument on the other hand (p = 0.002). Effects lasted for the whole procedure (monitoring up to 60 min) and were specific for the contrast-enhanced group. Contrasting maxima were seen after median 30 (applicator) and 38 (tumor) minutes, in the potential core time of a multineedle procedure. Contrast influence on T1 thermometry for real-time monitoring of thermal impact was not significant (p = 0.068-0.715). CONCLUSION: Results strongly support anticipated promotive effects of Gd-EOB-DTPA for MR guided percutaneous liver interventions by proving and quantifying the delineating effects for therapy-relevant elements in the procedure. Time benefit, cost effectiveness and oncologic outcome of the described beneficiary effects will have to be part of further investigations. PMID- 25541951 TI - Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency. AB - Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn) we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient derivative substrate combination fed into the Kreb's cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca2+ load in comparison to controls, and 400 nM extramitochondrial Ca2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle. PMID- 25541952 TI - Adaptive combination of P-values for family-based association testing with sequence data. AB - Family-based study design will play a key role in identifying rare causal variants, because rare causal variants can be enriched in families with multiple affected subjects. Furthermore, different from population-based studies, family studies are robust to bias induced by population substructure. It is well known that rare causal variants are difficult to detect from single-locus tests. Therefore, burden tests and non-burden tests have been developed, by combining signals of multiple variants in a chromosomal region or a functional unit. This inevitably incorporates some neutral variants into the test statistics, which can dilute the power of statistical methods. To guard against the noise caused by neutral variants, we here propose an 'adaptive combination of P-values method' (abbreviated as 'ADA'). This method combines per-site P-values of variants that are more likely to be causal. Variants with large P-values (which are more likely to be neutral variants) are discarded from the combined statistic. In addition to performing extensive simulation studies, we applied these tests to the Genetic Analysis Workshop 17 data sets, where real sequence data were generated according to the 1000 Genomes Project. Compared with some existing methods, ADA is more robust to the inclusion of neutral variants. This is a merit especially when dichotomous traits are analyzed. However, there are some limitations for ADA. First, it is more computationally intensive. Second, pedigree structures and founders' sequence data are required for the permutation procedure. Third, unrelated controls cannot be included. We here show that, for family-based studies, the application of ADA is limited to dichotomous trait analyses with full pedigree information. PMID- 25541954 TI - Elastography using multi-stream GPU: an application to online tracked ultrasound elastography, in-vivo and the da Vinci Surgical System. AB - A system for real-time ultrasound (US) elastography will advance interventions for the diagnosis and treatment of cancer by advancing methods such as thermal monitoring of tissue ablation. A multi-stream graphics processing unit (GPU) based accelerated normalized cross-correlation (NCC) elastography, with a maximum frame rate of 78 frames per second, is presented in this paper. A study of NCC window size is undertaken to determine the effect on frame rate and the quality of output elastography images. This paper also presents a novel system for Online Tracked Ultrasound Elastography (O-TRuE), which extends prior work on an offline method. By tracking the US probe with an electromagnetic (EM) tracker, the system selects in-plane radio frequency (RF) data frames for generating high quality elastograms. A novel method for evaluating the quality of an elastography output stream is presented, suggesting that O-TRuE generates more stable elastograms than generated by untracked, free-hand palpation. Since EM tracking cannot be used in all systems, an integration of real-time elastography and the da Vinci Surgical System is presented and evaluated for elastography stream quality based on our metric. The da Vinci surgical robot is outfitted with a laparoscopic US probe, and palpation motions are autonomously generated by customized software. It is found that a stable output stream can be achieved, which is affected by both the frequency and amplitude of palpation. The GPU framework is validated using data from in-vivo pig liver ablation; the generated elastography images identify the ablated region, outlined more clearly than in the corresponding B mode US images. PMID- 25541953 TI - Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection. AB - The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/uL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPalpha, sAPPbeta) and amyloid beta (Abeta) fragments 1-42, 1-40 and 1 38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPalpha and beta were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Abeta peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management. PMID- 25541957 TI - Detection of the elite structure in a virtual multiplex social system by means of a generalised K-core. AB - Elites are subgroups of individuals within a society that have the ability and means to influence, lead, govern, and shape societies. Members of elites are often well connected individuals, which enables them to impose their influence to many and to quickly gather, process, and spread information. Here we argue that elites are not only composed of highly connected individuals, but also of intermediaries connecting hubs to form a cohesive and structured elite-subgroup at the core of a social network. For this purpose we present a generalization of the K-core algorithm that allows to identify a social core that is composed of well-connected hubs together with their 'connectors'. We show the validity of the idea in the framework of a virtual world defined by a massive multiplayer online game, on which we have complete information of various social networks. Exploiting this multiplex structure, we find that the hubs of the generalised K core identify those individuals that are high social performers in terms of a series of indicators that are available in the game. In addition, using a combined strategy which involves the generalised Kcore and the recently introduced M-core, the elites of the different 'nations' present in the game are perfectly identified as modules of the generalised K-core. Interesting sudden shifts in the composition of the elite cores are observed at deep levels. We show that elite detection with the traditional K-core is not possible in a reliable way. The proposed method might be useful in a series of more general applications, such as community detection. PMID- 25541956 TI - Using information from the electronic health record to improve measurement of unemployment in service members and veterans with mTBI and post-deployment stress. AB - OBJECTIVE: The purpose of this pilot study is 1) to develop an annotation schema and a training set of annotated notes to support the future development of a natural language processing (NLP) system to automatically extract employment information, and 2) to determine if information about employment status, goals and work-related challenges reported by service members and Veterans with mild traumatic brain injury (mTBI) and post-deployment stress can be identified in the Electronic Health Record (EHR). DESIGN: Retrospective cohort study using data from selected progress notes stored in the EHR. SETTING: Post-deployment Rehabilitation and Evaluation Program (PREP), an in-patient rehabilitation program for Veterans with TBI at the James A. Haley Veterans' Hospital in Tampa, Florida. PARTICIPANTS: Service members and Veterans with TBI who participated in the PREP program (N = 60). MAIN OUTCOME MEASURES: Documentation of employment status, goals, and work-related challenges reported by service members and recorded in the EHR. RESULTS: Two hundred notes were examined and unique vocational information was found indicating a variety of self-reported employment challenges. Current employment status and future vocational goals along with information about cognitive, physical, and behavioral symptoms that may affect return-to-work were extracted from the EHR. The annotation schema developed for this study provides an excellent tool upon which NLP studies can be developed. CONCLUSIONS: Information related to employment status and vocational history is stored in text notes in the EHR system. Information stored in text does not lend itself to easy extraction or summarization for research and rehabilitation planning purposes. Development of NLP systems to automatically extract text-based employment information provides data that may improve the understanding and measurement of employment in this important cohort. PMID- 25541958 TI - Association of single nucleotide polymorphisms in VDR and DBP genes with HBV related hepatocellular carcinoma risk in a Chinese population. AB - BACKGROUND: Polymorphisms of genes encoding components of the vitamin D pathway including vitamin D receptor (VDR) and vitamin D binding protein (DBP) have been widely investigated because of the complex role played by vitamin D in cancer tumorogenesis. In this study, we investigated the association between VDR and DBP gene polymorphisms and HBV-related HCC risk in a Chinese population. METHODS: Study subjects were divided into three groups: 184 HBV patients with HCC, 296 HBV patients without HCC, and 180 healthy controls. The VDR rs2228570, and rs3782905 and the DBP rs7041 polymorphisms were genotyped using PCR-RFLP and the VDR rs11568820 polymorphism was genotyped by PCR-SSP, respectively. DNA sequencing was performed to validate the genotype results. RESULTS: We found that there were significant differences in the genotype and allele frequencies of the VDR rs2228570 and DBP rs7041 polymorphisms between HBV patients with HCC and healthy controls. The rs2228570 T allele was associated with a significant increased HBV related HCC risk as compared with the C allele. The rs2228570 TT and TT/TC genotypes were correlated with a significant increased HBV-related HCC risk when compared with the wild-type CC homozygote. Similarly, the rs7041 G allele was associated with a significant increased HBV-related HCC risk as compared with the T allele. The rs7041 GG and GG/TG genotypes were correlated with a significant increased HBV-related HCC risk when compared with the wild-type TT homozygote. However, we did not observe any significant effect of VDR rs11568820, and rs3782905 polymorphisms on HBV-related HCC risk in this population. In haplotype analysis, we also did not find any significant differences in haplotype frequencies of the VDR gene between HBV patients with HCC and the healthy controls. CONCLUSIONS: We conclude that the VDR rs2228570 and DBP rs7041 polymorphisms may contribute to increased susceptibility to HBV-related HCC in the Chinese population. Due to the marginal significance, further large and well designed studies in diverse ethnic populations are needed to confirm our results. PMID- 25541959 TI - Significant improvement in dynamic visual acuity after cataract surgery: a promising potential parameter for functional vision. AB - PURPOSE: Dynamic visual acuity (DVA) is a relatively independent parameter for evaluating the ability to distinguish details of a moving target. The present study has been designed to discuss the extent to which age-related cataract impacts DVA in elderly individuals and to determine whether it could be restored after bilateral phacoemulsification combined with intraocular lens implantation surgery. METHODS: Twenty-six elderly cataract patients scheduled for binocular cataract surgery and 30 elderly volunteers without cataract were enrolled in the study. DVA at 15, 30, 60 and 90 degree per second (dps) was assessed, and velocity-dependent visual acuity decreases between consecutive speed levels were calculated. RESULTS: Compared with the control group, the patient group exhibited significantly worse DVA performance at all speed levels (p<0.001), and the decreases in velocity-dependent visual acuity were more serious in the patient group at the intervals of 0-15 dps (p<0.001), 15-30 dps (p = 0.007) and 30-60 dps (p = 0.008). Postoperatively, DVA performance at every speed level in the patient group clearly improved (p<0.001) and recovered to levels compatible to the control group. The decrease in visual acuity with increasing speed was less pronounced than during the preoperative phase (p0-15 dps = 0.001, p15-30 dps<0.001 and p30-60 dps = 0.001) and became similar to that of the control group. The postoperative visual benefit regarding DVA was more pronounced than the improvement in static visual acuity (p15 dps = 0.001 and p<0.001 at 30 dps, 60 dps and 90 dps). CONCLUSIONS: The impact of age-related cataract on DVA was more severe than its effects on static visual acuity. After cataract surgery, not only static vision of the patients was restored markedly, but also the dynamic vision. DVA could be an important adjunct to the current evaluation system of functional vision, thereby meriting additional attention in clinical assessment. PMID- 25541960 TI - Comparative evaluation of combined navigated laser photocoagulation and intravitreal ranibizumab in the treatment of diabetic macular edema. AB - OBJECTIVE: To evaluate if a standardized combination therapy regimen, utilizing 3 monthly ranibizumab injections followed by navigated laser photocoagulation, reduces the number of total ranibizumab injections required for treatment of diabetic macular edema (DME). RESEARCH DESIGN AND METHODS: A 12-month, prospective comparison of 66 patients with center-involving DME: 34 patients with combination therapy were compared to 32 patients treated with ranibizumab monotherapy. All patients initially received 3 monthly ranibizumab injections (loading phase) and additional injections pro re nata (PRN). Combination therapy patients additionally received navigated laser photocoagulation after the loading phase. Main outcome measures were mean number of injections after the loading phase and change in BCVA from baseline to month 12. RESULTS: Navigated laser combination therapy and ranibizumab monotherapy similarly improved mean BCVA letter score (+8.41 vs. +6.31 letters, p = 0.258). In the combination group significantly less injections were required after the 3 injection loading phase (0.88 +/- 1.23 vs. 3.88 +/- 2.32, p< = 0.001). By month 12, 84% of patients in the monotherapy group had required additional ranibizumab injections as compared to 35% in the combination group (p< = 0.001). CONCLUSIONS: Navigated laser combination therapy demonstrated significant visual gains in most patients. Retreatment rate and number of injections were significantly lower compared to ranibizumab monotherapy and compared to the results of conventional laser combination therapy previously reported in pivotal anti-VEGF studies. PMID- 25541961 TI - A note on an exon-based strategy to identify differentially expressed genes in RNA-seq experiments. AB - RNA-sequencing (RNA-seq) has rapidly become the method of choice in many genome wide transcriptomic studies. To meet the high expectations posed by this technology, powerful computational techniques are needed to translate the measurements into biological and biomedical understanding. A number of statistical procedures have already been developed to identify differentially expressed genes between distinct sample groups. With these methods statistical testing is typically performed after the data has been summarized at the gene level. As an alternative strategy, developed with the aim to improve the results, we demonstrate a method in which statistical testing at the exon level is performed prior to the summary of the results at the gene level. Using publicly available RNA-seq datasets as case studies, we illustrate how this exon-based strategy can improve the performance of the widely used differential expression software packages as compared to the conventional gene-based strategy. In particular, we show how it enables robust detection of moderate but systematic changes that are missed when relying on single gene-level summary counts only. PMID- 25541962 TI - Investigating microenvironmental regulation of human chordoma cell behaviour. AB - The tumour microenvironment is complex and composed of many different constituents, including matricellular proteins such as connective tissue growth factor (CCN2), and is characterized by gradients in oxygen levels. In various cancers, hypoxia and CCN2 promote stem and progenitor cell properties, and regulate the proliferation, migration and phenotype of cancer cells. Our study was aimed at investigating the effects of hypoxia and CCN2 on chordoma cells, using the human U-CH1 cell line. We demonstrate that under basal conditions, U CH1 cells express multiple CCN family members including CCN1, CCN2, CCN3 and CCN5. Culture of U-CH1 cells in either hypoxia or in the presence of recombinant CCN2 peptide promoted progenitor cell-like characteristics specific to the notochordal tissue of origin. Specifically, hypoxia induced the most robust increase in progenitor-like characteristics in U-CH1 cells, including increased expression of the notochord-associated markers T, CD24, FOXA1, ACAN and CA12, increased cell growth and tumour-sphere formation, and a decrease in the percentage of vacuolated cells present in the heterogeneous population. Interestingly, the effects of recombinant CCN2 peptide on U-CH1 cells were more pronounced under normoxia than hypoxia, promoting increased expression of CCN1, CCN2, CCN3 and CCN5, the notochord-associated markers SOX5, SOX6, T, CD24, and FOXA1 as well as increased tumour-sphere formation. Overall, this study highlights the importance of multiple factors within the tumour microenvironment and how hypoxia and CCN2 may regulate human chordoma cell behaviour. PMID- 25541963 TI - Carriers of loss-of-function mutations in EXT display impaired pancreatic beta cell reserve due to smaller pancreas volume. AB - Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol.l-1.min-1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol.l-1.min-1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0+/-15.8 vs. controls 96.5+/-26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors. PMID- 25541964 TI - Sperm morphology in two house mouse subspecies: do wild-derived strains and wild mice tell the same story? AB - Being subject to intense post-copulatory selection, sperm size is a principal determining component of male fitness. Although previous studies have presented comparative sperm size data at higher taxonomic levels, information on the evolution of sperm size within species is generally lacking. Here, we studied two house mouse subspecies, Mus musculus musculus and Mus musculus domesticus, which undergo incipient speciation. We measured four sperm dimensions from cauda epididymis smears of 28 wild-caught mice of both subspecies. As inbred mouse strains are frequently used as proxies for exploring evolutionary processes, we further studied four wild-derived inbred strains from each subspecies. The subspecies differed significantly in terms of sperm head length and midpiece length, and these differences were consistent for wild mice and wild-derived strains pooled over genomes. When the inbred strains were analyzed individually, however, their strain-specific values were in some cases significantly shifted from subspecies-specific values derived from wild mice. We conclude that: (1) the size of sperm components differ in the two house mouse subspecies studied, and that (2) wild-derived strains reflect this natural polymorphism, serving as a potential tool to identify the genetic variation driving these evolutionary processes. Nevertheless, we suggest that more strains should be used in future experiments to account for natural variation and to avoid confounding results due to reduced variability and/or founder effect in the individual strains. PMID- 25541965 TI - GSK3beta is increased in adipose tissue and skeletal muscle from women with gestational diabetes where it regulates the inflammatory response. AB - Infection and inflammation, through their ability to increase pro-inflammatory cytokines and chemokines and adhesion molecules, are thought to play a central role in the pathophysiology of insulin resistance and type 2 diabetes. Recent studies have shown that glycogen synthase kinase 3 (GSK3) plays a central role in regulating this inflammation. There are, however, no studies on the role of GSK3 in pregnancies complicated by gestational diabetes mellitus (GDM). Thus, the aims of this study were (i) to determine whether GSK3 is increased in adipose tissue and skeletal muscle from women with GDM; and (ii) to investigate the effect of GSK3 inhibition on inflammation in the presence of inflammation induced by bacterial endotoxin lipopolysaccharide (LPS) or the pro-inflammatory cytokine IL 1beta. Human omental adipose tissue and skeletal muscle were obtained from normal glucose tolerant (NGT) women and BMI-matched women with diet-control GDM at the time of Caesarean section. Western blotting was performed to determine GSK3 protein expression. Tissue explants were performed to determine the effect of the GSK3 inhibitor CHIR99021 on markers of inflammation. When compared to women with NGT, omental adipose tissue and skeletal muscle obtained from women with diet controlled GDM had significantly higher GSK3beta activity as evidenced by a decrease in the expression of GSK3beta phosphorylated at serine 9. The GSK3 inhibitor CHIR99021 significantly reduced the gene expression and secretion of the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6; the pro-inflammatory chemokines IL-8 and MCP-1; and the adhesion molecules ICAM-1 and VCAM-1 in tissues stimulated with LPS or IL-1beta. In conclusion, GSK3 activity is increased in GDM adipose tissue and skeletal muscle and regulates infection- and inflammation-induced pro-inflammatory mediators. PMID- 25541966 TI - Predicting the phenotypic values of physiological traits using SNP genotype and gene expression data in mice. AB - Predicting phenotypes using genome-wide genetic variation and gene expression data is useful in several fields, such as human biology and medicine, as well as in crop and livestock breeding. However, for phenotype prediction using gene expression data for mammals, studies remain scarce, as the available data on gene expression profiling are currently limited. By integrating a few sources of relevant data that are available in mice, this study investigated the accuracy of phenotype prediction for several physiological traits. Gene expression data from two tissues as well as single nucleotide polymorphisms (SNPs) were used. For the studied traits, the variance of the effects of the expression levels was more likely to differ among the genes than were the effects of SNPs. For the glucose concentration, the total cholesterol amount, and the total tidal volume, the accuracy by cross validation tended to be higher when the gene expression data rather than the SNP genotype data were used, and a statistically significant increase in the accuracy was obtained when the gene expression data from the liver were used alone or jointly with the SNP genotype data. For these traits, there were no additional gains in accuracy from using the gene expression data of both the liver and lung compared to that of individual use. The accuracy of prediction using genes that were selected differently was examined; the use of genes with a higher tissue specificity tended to result in an accuracy that was similar to or greater than that associated with the use of all of the available genes for traits such as the glucose concentration and total cholesterol amount. Although relatively few animals were evaluated, the current results suggest that gene expression levels could be used as explanatory variables. However, further studies are essential to confirm our findings using additional animal samples. PMID- 25541967 TI - CCR5 gene disruption via lentiviral vectors expressing Cas9 and single guided RNA renders cells resistant to HIV-1 infection. AB - CCR5, a coreceptor for HIV-1 entry, is a major target for drug and genetic intervention against HIV-1. Genetic intervention strategies have knocked down CCR5 expression levels by shRNA or disrupted the CCR5 gene using zinc finger nucleases (ZFN) or Transcription activator-like effector nuclease (TALEN). In the present study, we silenced CCR5 via CRISPR associated protein 9 (Cas9) and single guided RNAs (sgRNAs). We constructed lentiviral vectors expressing Cas9 and CCR5 sgRNAs. We show that a single round transduction of lentiviral vectors expressing Cas9 and CCR5 sgRNAs into HIV-1 susceptible human CD4+ cells yields high frequencies of CCR5 gene disruption. CCR5 gene-disrupted cells are not only resistant to R5-tropic HIV-1, including transmitted/founder (T/F) HIV-1 isolates, but also have selective advantage over CCR5 gene-undisrupted cells during R5 tropic HIV-1 infection. Importantly, using T7 endonuclease I assay we did not detect genome mutations at potential off-target sites that are highly homologous to these CCR5 sgRNAs in stably transduced cells even at 84 days post transduction. Thus we conclude that silencing of CCR5 via Cas9 and CCR5-specific sgRNAs could be a viable alternative strategy for engineering resistance against HIV-1. PMID- 25541968 TI - Effects of blood transportation on human peripheral mononuclear cell yield, phenotype and function: implications for immune cell biobanking. AB - Human biospecimen collection, processing and preservation are rapidly emerging subjects providing essential support to clinical as well as basic researchers. Unlike collection of other biospecimens (e.g. DNA and serum), biobanking of viable immune cells, such as peripheral blood mononuclear cells (PBMC) and/or isolated immune cell subsets is still in its infancy. While certain aspects of processing and freezing conditions have been studied in the past years, little is known about the effect of blood transportation on immune cell survival, phenotype and specific functions. However, especially for multicentric and cooperative projects it is vital to precisely know those effects. In this study we investigated the effect of blood shipping and pre-processing delay on immune cell phenotype and function both on cellular and subcellular levels. Peripheral blood was collected from healthy volunteers (n = 9): at a distal location (shipped overnight) and in the central laboratory (processed immediately). PBMC were processed in the central laboratory and analyzed post-cryopreservation. We analyzed yield, major immune subset distribution, proliferative capacity of T cells, cytokine pattern and T-cell receptor signal transduction. Results show that overnight transportation of blood samples does not globally compromise T- cell subsets as they largely retain their phenotype and proliferative capacity. However, NK and B cell frequencies, the production of certain PBMC-derived cytokines and IL-6 mediated cytokine signaling pathway are altered due to transportation. Various control experiments have been carried out to compare issues related to shipping versus pre-processing delay on site. Our results suggest the implementation of appropriate controls when using multicenter logistics for blood transportation aiming at subsequent isolation of viable immune cells, e.g. in multicenter clinical trials or studies analyzing immune cells/subsets. One important conclusion might be that despite changes due to overnight shipment, highly standardized central processing (and analysis) could be superior to multicentric de-central processing with more difficult standardization. PMID- 25541969 TI - Scholarly context not found: one in five articles suffers from reference rot. AB - The emergence of the web has fundamentally affected most aspects of information communication, including scholarly communication. The immediacy that characterizes publishing information to the web, as well as accessing it, allows for a dramatic increase in the speed of dissemination of scholarly knowledge. But, the transition from a paper-based to a web-based scholarly communication system also poses challenges. In this paper, we focus on reference rot, the combination of link rot and content drift to which references to web resources included in Science, Technology, and Medicine (STM) articles are subject. We investigate the extent to which reference rot impacts the ability to revisit the web context that surrounds STM articles some time after their publication. We do so on the basis of a vast collection of articles from three corpora that span publication years 1997 to 2012. For over one million references to web resources extracted from over 3.5 million articles, we determine whether the HTTP URI is still responsive on the live web and whether web archives contain an archived snapshot representative of the state the referenced resource had at the time it was referenced. We observe that the fraction of articles containing references to web resources is growing steadily over time. We find one out of five STM articles suffering from reference rot, meaning it is impossible to revisit the web context that surrounds them some time after their publication. When only considering STM articles that contain references to web resources, this fraction increases to seven out of ten. We suggest that, in order to safeguard the long-term integrity of the web-based scholarly record, robust solutions to combat the reference rot problem are required. In conclusion, we provide a brief insight into the directions that are explored with this regard in the context of the Hiberlink project. PMID- 25541970 TI - The influence of the CHIEF pathway on colorectal cancer-specific mortality. AB - Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors) pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product) to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555) and rectal cancer (n = 754) cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035). Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR) were associated with colon cancer mortality (PARTP < 0.05); JAK2 (PARTP = 0.0086), PIK3CA (PARTP = 0.0098), and SMAD3 (PARTP = 0.0059) had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05). SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002). Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1) were significantly associated with rectal cancer (PARTP < 0.05). The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74) and was 10.99 (95% CI 5.30, 22.78) for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies. PMID- 25541971 TI - A genetic linkage map of sole (Solea solea): a tool for evolutionary and comparative analyses of exploited (flat)fishes. AB - Linkage maps based on markers derived from genes are essential evolutionary tools for commercial marine fish to help identify genomic regions associated with complex traits and subject to selective forces at play during exploitation or selective breeding. Additionally, they allow the use of genomic information from other related species for which more detailed information is available. Sole (solea solea L.) is a commercially important flatfish species in the North Sea, subject to overexploitation and showing evidence of fisheries-induced evolutionary changes in growth- and maturation-related traits. Sole would definitely benefit from a linkage map to better understand how evolution has shaped its genome structure. This study presents a linkage map of sole based on 423 single nucleotide polymorphisms derived from expressed sequence tags and 8 neutral microsatellite markers. The total map length is 1233.8 cM and consists of 38 linkage groups with a size varying between 0 to 92.1 cM. Being derived from expressed sequence tags allowed us to align the map with the genome of four model fish species, namely medaka (Oryzias latipes), Nile tilapia (Oreochromis niloticus), three-spined stickleback (Gasterosteus aculeatus) and green spotted pufferfish (Tetraodon nigroviridis). This comparison revealed multiple conserved syntenic regions with all four species, and suggested that the linkage groups represent 21 putative sole chromosomes. The map was also compared to the linkage map of turbot (Scophthalmus maximus), another commercially important flatfish species and closely related to sole. For all putative sole chromosomes (except one) a turbot homolog was detected, confirming the even higher degree of synteny between these two flatfish species. PMID- 25541972 TI - Deciphering host genotype-specific impacts on the metabolic fingerprint of Listeria monocytogenes by FTIR spectroscopy. AB - Bacterial pathogens are known for their wide range of strategies to specifically adapt to host environments and infection sites. An in-depth understanding of these adaptation mechanisms is crucial for the development of effective therapeutics and new prevention measures. In this study, we assessed the suitability of Fourier Transform Infrared (FTIR) spectroscopy for monitoring metabolic adaptations of the bacterial pathogen Listeria monocytogenes to specific host genotypes and for exploring the potential of FTIR spectroscopy to gain novel insights into the host-pathogen interaction. Three different mouse genotypes, showing different susceptibility to L. monocytogenes infections, were challenged with L. monocytogenes and re-isolated bacteria were subjected to FTIR spectroscopy. The bacteria from mice with different survival characteristics showed distinct IR spectral patterns, reflecting specific changes in the backbone conformation and the hydrogen-bonding pattern of the protein secondary structure in the bacterial cell. Coupling FTIR spectroscopy with chemometrics allowed us to link bacterial metabolic fingerprints with host infection susceptibility and to decipher longtime memory effects of the host on the bacteria. After prolonged cultivation of host-passaged bacteria under standard laboratory conditions, the host's imprint on bacterial metabolism vanished, which suggests a revertible metabolic adaptation of bacteria to host environment and loss of host environment triggered memory effects over time. In summary, our work demonstrates the potential and power of FTIR spectroscopy to be used as a fast, simple and highly discriminatory tool to investigate the mechanism of bacterial host adaptation on a macromolar and metabolic level. PMID- 25541973 TI - The Dishevelled, EGL-10 and pleckstrin (DEP) domain-containing protein DEPDC7 binds to CARMA2 and CARMA3 proteins, and regulates NF-kappaB activation. AB - The molecular complexes containing BCL10, MALT1 and CARMA proteins (CBM complex) have been recently identified as a key component in the signal transduction pathways that regulate activation of Nuclear Factor kappaB (NF-kappaB) transcription factor. Herein we identified the DEP domain-containing protein DEPDC7 as cellular binding partners of CARMA2 and CARMA3 proteins. DEPDC7 displays a cytosolic distribution and its expression induces NF-kappaB activation. Conversely, shRNA-mediated abrogation of DEPDC7 results in impaired NF-kappaB activation following G protein-coupled receptors stimulation, or stimuli that require CARMA2 and CARMA3, but not CARMA1. Thus, this study identifies DEPDC7 as a CARMA interacting molecule, and provides evidence that DEPDC7 may be required to specifically convey on the CBM complex signals coming from activated G protein-coupled receptors. PMID- 25541974 TI - Cyberdiversity: improving the informatic value of diverse tropical arthropod inventories. AB - In an era of biodiversity crisis, arthropods have great potential to inform conservation assessment and test hypotheses about community assembly. This is because their relatively narrow geographic distributions and high diversity offer high-resolution data on landscape-scale patterns of biodiversity. However, a major impediment to the more widespread application of arthropod data to a range of scientific and policy questions is the poor state of modern arthropod taxonomy, especially in the tropics. Inventories of spiders and other megadiverse arthropods from tropical forests are dominated by undescribed species. Such studies typically organize their data using morphospecies codes, which make it difficult for data from independent inventories to be compared and combined. To combat this shortcoming, we offer cyberdiversity, an online community-based approach for reconciling results of independent inventory studies where current taxonomic knowledge is incomplete. Participating scientists can upload images and DNA barcode sequences to dedicated databases and submit occurrence data and links to a web site (www.digitalSpiders.org). Taxonomic determinations can be shared with a crowdsourcing comments feature, and researchers can discover specimens of interest available for loan and request aliquots of genomic DNA extract. To demonstrate the value of the cyberdiversity framework, we reconcile data from three rapid structured inventories of spiders conducted in Vietnam with an independent inventory (Doi Inthanon, Thailand) using online image libraries. Species richness and inventory completeness were assessed using non-parametric estimators. Community similarity was evaluated using a novel index based on the Jaccard replacing observed with estimated values to correct for unobserved species. We use a distance-decay framework to demonstrate a rudimentary model of landscape-scale changes in community composition that will become increasingly informative as additional inventories participate. With broader adoption of the cyberdiversity approach, networks of information-sharing taxonomists can more efficiently and effectively address taxonomic impediments while elucidating landscape scale patterns of biodiversity. PMID- 25541975 TI - Bacterial community composition in three freshwater reservoirs of different alkalinity and trophic status. AB - In order to investigate the factors controlling the bacterial community composition (BCC) in reservoirs, we sampled three freshwater reservoirs with contrasted physical and chemical characteristics and trophic status. The BCC was analysed by 16S rRNA gene amplicon 454 pyrosequencing. In parallel, a complete dataset of environmental parameters and phytoplankton community composition was also collected. BCC in the analysed reservoirs resembled that of epilimnetic waters of natural freshwater lakes with presence of Actinobacteria, Alpha- and Betaproteobacteria, Cytophaga-Flavobacteria-Bacteroidetes (CFB) and Verrucomicrobia groups. Our results evidenced that the retrieved BCC in the analysed reservoirs was strongly influenced by pH, alkalinity and organic carbon content, whereas comparatively little change was observed among layers in stratified conditions. PMID- 25541977 TI - Multi-reader multi-case studies using the area under the receiver operator characteristic curve as a measure of diagnostic accuracy: systematic review with a focus on quality of data reporting. AB - INTRODUCTION: We examined the design, analysis and reporting in multi-reader multi-case (MRMC) research studies using the area under the receiver-operating curve (ROC AUC) as a measure of diagnostic performance. METHODS: We performed a systematic literature review from 2005 to 2013 inclusive to identify a minimum 50 studies. Articles of diagnostic test accuracy in humans were identified via their citation of key methodological articles dealing with MRMC ROC AUC. Two researchers in consensus then extracted information from primary articles relating to study characteristics and design, methods for reporting study outcomes, model fitting, model assumptions, presentation of results, and interpretation of findings. Results were summarized and presented with a descriptive analysis. RESULTS: Sixty-four full papers were retrieved from 475 identified citations and ultimately 49 articles describing 51 studies were reviewed and extracted. Radiological imaging was the index test in all. Most studies focused on lesion detection vs. characterization and used less than 10 readers. Only 6 (12%) studies trained readers in advance to use the confidence scale used to build the ROC curve. Overall, description of confidence scores, the ROC curve and its analysis was often incomplete. For example, 21 (41%) studies presented no ROC curve and only 3 (6%) described the distribution of confidence scores. Of 30 studies presenting curves, only 4 (13%) presented the data points underlying the curve, thereby allowing assessment of extrapolation. The mean change in AUC was 0.05 (-0.05 to 0.28). Non-significant change in AUC was attributed to underpowering rather than the diagnostic test failing to improve diagnostic accuracy. CONCLUSIONS: Data reporting in MRMC studies using ROC AUC as an outcome measure is frequently incomplete, hampering understanding of methods and the reliability of results and study conclusions. Authors using this analysis should be encouraged to provide a full description of their methods and results. PMID- 25541978 TI - Comparing multiple criteria for species identification in two recently diverged seabirds. AB - Correct species identification is a crucial issue in systematics with key implications for prioritising conservation effort. However, it can be particularly challenging in recently diverged species due to their strong similarity and relatedness. In such cases, species identification requires multiple and integrative approaches. In this study we used multiple criteria, namely plumage colouration, biometric measurements, geometric morphometrics, stable isotopes analysis (SIA) and genetics (mtDNA), to identify the species of 107 bycatch birds from two closely related seabird species, the Balearic (Puffinus mauretanicus) and Yelkouan (P. yelkouan) shearwaters. Biometric measurements, stable isotopes and genetic data produced two stable clusters of bycatch birds matching the two study species, as indicated by reference birds of known origin. Geometric morphometrics was excluded as a species identification criterion since the two clusters were not stable. The combination of plumage colouration, linear biometrics, stable isotope and genetic criteria was crucial to infer the species of 103 of the bycatch specimens. In the present study, particularly SIA emerged as a powerful criterion for species identification, but temporal stability of the isotopic values is critical for this purpose. Indeed, we found some variability in stable isotope values over the years within each species, but species differences explained most of the variance in the isotopic data. Yet this result pinpoints the importance of examining sources of variability in the isotopic data in a case-by-case basis prior to the cross application of the SIA approach to other species. Our findings illustrate how the integration of several methodological approaches can help to correctly identify individuals from recently diverged species, as each criterion measures different biological phenomena and species divergence is not expressed simultaneously in all biological traits. PMID- 25541980 TI - Cyanea capillata bell kinematics analysis through corrected in situ imaging and modeling using strategic discretization techniques. AB - Obtaining accurate kinematic data of animals is essential for many biological studies and bio-inspired engineering. Many animals, however, are either too large or too delicate to transport to controlled environments where accurate kinematic data can be easily obtained. Often, in situ recordings are the only means available but are often subject to multi-axis motion and relative magnification changes with time leading to large discrepancies in the animal kinematics. Techniques to compensate for these artifacts were applied to a large jellyfish, Cyanea capillata, freely swimming in ocean waters. The bell kinematics were captured by digitizing exumbrella profiles for two full swimming cycles. Magnification was accounted for by tracking a reference point on the ocean floor and by observing the C. capillata exumbrella arclength in order to have a constant scale through the swimming cycles. A linear fit of the top bell section was used to find the body angle with respect to the camera coordinate system. Bell margin trajectories over two swimming cycles confirmed the accuracy of the correction techniques. The corrected profiles were filtered and interpolated to provide a set of time-dependent points along the bell. Discrete models of the exumbrella were used to analyze the bell kinematics. Exumbrella discretization was conducted using three different methods. Fourier series were fitted to the discretized models and subsequently used to analyze the bell kinematics of the C. capillata. The analysis showed that the bell did not deform uniformly over time with different segments lagging behind each other. Looping of the bell trajectory between contraction and relaxation was also present through most of the exumbrella. The bell margin had the largest looping with an outer path during contraction and inner path during relaxation. The subumbrella volume was approximated based on the exumbrella kinematics and was found to increase during contraction. PMID- 25541979 TI - Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring. AB - AIMS: Despite the wide use of metformin in metabolically challenged pregnancies, the long-term effects on the metabolism of the offspring are not known. We studied the long-term effects of prenatal metformin exposure during metabolically challenged pregnancy in mice. MATERIALS AND METHODS: Female mice were on a high fat diet (HFD) prior to and during the gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD) and subjected to HFD at adulthood (10-11 weeks). Body weight and several metabolic parameters (e.g. body composition and glucose tolerance) were measured during the study. Microarray and subsequent pathway analyses on the liver and subcutaneous adipose tissue of the male offspring were performed at postnatal day 4 in a separate experiment. RESULTS: Prenatal metformin exposure changed the offspring's response to HFD. Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. Microarray and annotation analyses revealed metformin-induced changes in several metabolic pathways from which electron transport chain (ETC) was prominently affected both in the neonatal liver and adipose tissue. CONCLUSION: This study shows the beneficial effects of prenatal metformin exposure on the offspring's glucose tolerance and fat mass accumulation during HFD. The transcriptome data obtained at neonatal age indicates major effects on the genes involved in mitochondrial ATP production and adipocyte differentiation suggesting the mechanistic routes to improved metabolic phenotype at adulthood. PMID- 25541983 TI - Effects of sex and reproductive state on interactions between free-roaming domestic dogs. AB - Free-roaming dogs (Canis familiaris) are common worldwide, often maintaining diseases of domestic pets and wildlife. Management of these dogs is difficult and often involves capture, treatment, neutering and release. Information on the effects of sex and reproductive state on intraspecific contacts and disease transmission is currently lacking, but is vital to improving strategic management of their populations. We assessed the effects of sex and reproductive state on short-term activity patterns and contact rates of free-roaming dogs living in an Australian Indigenous community. Population, social group sizes and rates of contact were estimated from structured observations along walked transects. Simultaneously, GPS telemetry collars were used to track dogs' movements and to quantify the frequency of contacts between individual animals. We estimated that the community's dog population was 326 +/- 52, with only 9.8 +/- 2.5% confined to a house yard. Short-term activity ranges of dogs varied from 9.2 to 133.7 ha, with males ranging over significantly larger areas than females. Contacts between two or more dogs occurred frequently, with entire females and neutered males accumulating significantly more contacts than spayed females or entire males. This indicates that sex and reproductive status are potentially important to epidemiology, but the effect of these differential contact rates on disease transmission requires further investigation. The observed combination of unrestrained dogs and high contact rates suggest that contagious disease would likely spread rapidly through the population. Pro-active management of dog populations and targeted education programs could help reduce the risks associated with disease spread. PMID- 25541981 TI - Microbial community structure and diversity in an integrated system of anaerobic aerobic reactors and a constructed wetland for the treatment of tannery wastewater in Modjo, Ethiopia. AB - A culture-independent approach was used to elucidate the microbial diversity and structure in the anaerobic-aerobic reactors integrated with a constructed wetland for the treatment of tannery wastewater in Modjo town, Ethiopia. The system has been running with removal efficiencies ranging from 94%-96% for COD, 91%-100% for SO4(2-) and S(2-), 92%-94% for BOD, 56%-82% for total Nitrogen and 2%-90% for NH3 N. 16S rRNA gene clone libraries were constructed and microbial community assemblies were determined by analysis of a total of 801 unique clone sequences from all the sites. Operational Taxonomic Unit (OTU)--based analysis of the sequences revealed highly diverse communities in each of the reactors and the constructed wetland. A total of 32 phylotypes were identified with the dominant members affiliated to Clostridia (33%), Betaproteobacteria (10%), Bacteroidia (10%), Deltaproteobacteria (9%) and Gammaproteobacteria (6%). Sequences affiliated to the class Clostridia were the most abundant across all sites. The 801 sequences were assigned to 255 OTUs, of which 3 OTUs were shared among the clone libraries from all sites. The shared OTUs comprised 80 sequences belonging to Clostridiales Family XIII Incertae Sedis, Bacteroidetes and unclassified bacterial group. Significantly different communities were harbored by the anaerobic, aerobic and rhizosphere sites of the constructed wetland. Numerous representative genera of the dominant bacterial classes obtained from the different sample sites of the integrated system have been implicated in the removal of various carbon- containing pollutants of natural and synthetic origins. To our knowledge, this is the first report of microbial community structure in tannery wastewater treatment plant from Ethiopia. PMID- 25541982 TI - Formation of fenestrae in murine liver sinusoids depends on plasmalemma vesicle associated protein and is required for lipoprotein passage. AB - Liver sinusoidal endothelial cells (LSEC) are characterized by the presence of fenestrations that are not bridged by a diaphragm. The molecular mechanisms that control the formation of the fenestrations are largely unclear. Here we report that mice, which are deficient in plasmalemma vesicle-associated protein (PLVAP), develop a distinct phenotype that is caused by the lack of sinusoidal fenestrations. Fenestrations with a diaphragm were not observed in mouse LSEC at three weeks of age, but were present during embryonic life starting from embryonic day 12.5. PLVAP was expressed in LSEC of wild-type mice, but not in that of Plvap-deficient littermates. Plvap(-/-) LSEC showed a pronounced and highly significant reduction in the number of fenestrations, a finding, which was seen both by transmission and scanning electron microscopy. The lack of fenestrations was associated with an impaired passage of macromolecules such as FITC-dextran and quantum dot nanoparticles from the sinusoidal lumen into Disse's space. Plvap-deficient mice suffered from a pronounced hyperlipoproteinemia as evidenced by milky plasma and the presence of lipid granules that occluded kidney and liver capillaries. By NMR spectroscopy of plasma, the nature of hyperlipoproteinemia was identified as massive accumulation of chylomicron remnants. Plasma levels of low density lipoproteins (LDL) were also significantly increased as were those of cholesterol and triglycerides. In contrast, plasma levels of high density lipoproteins (HDL), albumin and total protein were reduced. At around three weeks of life, Plvap-deficient livers developed extensive multivesicular steatosis, steatohepatitis, and fibrosis. PLVAP is critically required for the formation of fenestrations in LSEC. Lack of fenestrations caused by PLVAP deficiency substantially impairs the passage of chylomicron remnants between liver sinusoids and hepatocytes, and finally leads to liver damage. PMID- 25541984 TI - Selective lentiviral gene delivery to CD133-expressing human glioblastoma stem cells. AB - Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133 expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. Here, we present CD133-LV, a lentiviral vector presenting a single chain antibody against CD133 on its envelope, as a vehicle for the selective transduction of CD133-expressing GSCs. We show that CD133-LV selectively transduces CD133+ human GSCs in dose-dependent manner and that transduced cells maintain their stem-like properties. The transduction efficiency of CD133-LV is reduced by an antibody that recognizes the same epitope on CD133 as the viral envelope and by shRNA-mediated knockdown of CD133. Conversely, the rate of transduction by CD133-LV is augmented by overexpression of CD133 in primary human GBM cultures. CD133-LV selectively transduces CD133-expressing cells in intracranial human GBM xenografts in NOD.SCID mice, but spares normal mouse brain tissue, neurons derived from human embryonic stem cells and primary human astrocytes. Our findings indicate that CD133-LV represents a novel tool for the selective genetic manipulation of CD133-expressing GSCs, and can be used to answer important questions about how these cells contribute to tumor biology and therapy resistance. PMID- 25541985 TI - Controlled release of dutasteride from biodegradable microspheres: in vitro and in vivo studies. AB - The aim of the present work was to study the in vitro/in vivo characteristics of dutasteride loaded biodegradable microspheres designed for sustained release of dutasteride over four weeks. An O/W emulsion-solvent evaporation method was used to incorporate dutasteride, which is of interest in the treatment of benign prostatic hyperplasia (BPH), into poly(lactide-co-glycolide) (PLGA). A response surface method (RSM) with central composite design (CCD) was employed to optimize the formulation variables. A prolonged in vitro drug release profile was observed, with a complete release of the entrapped drug within 28 days. The pharmacokinetics study showed sustained plasma drug concentration-time profile of dutasteride loaded microspheres after subcutaneous injection into rats. The in vitro drug release in rats correlated well with the in vivo pharmacokinetics profile. The pharmacodynamics evaluated by determination of the BPH inhibition in the rat models also showed a prolonged pharmacological response. These results suggest the potential use of dutasteride loaded biodegradable microspheres for the management of BPH over long periods. PMID- 25541986 TI - Males and females contribute unequally to offspring genetic diversity in the polygynandrous mating system of wild boar. AB - The maintenance of genetic diversity across generations depends on both the number of reproducing males and females. Variance in reproductive success, multiple paternity and litter size can all affect the relative contributions of male and female parents to genetic variation of progeny. The mating system of the wild boar (Sus scrofa) has been described as polygynous, although evidence of multiple paternity in litters has been found. Using 14 microsatellite markers, we evaluated the contribution of males and females to genetic variation in the next generation in independent wild boar populations from the Iberian Peninsula and Hungary. Genetic contributions of males and females were obtained by distinguishing the paternal and maternal genetic component inherited by the progeny. We found that the paternally inherited genetic component of progeny was more diverse than the maternally inherited component. Simulations showed that this finding might be due to a sampling bias. However, after controlling for the bias by fitting both the genetic diversity in the adult population and the number of reproductive individuals in the models, paternally inherited genotypes remained more diverse than those inherited maternally. Our results suggest new insights into how promiscuous mating systems can help maintain genetic variation. PMID- 25541987 TI - Hydrophobin fusion of an influenza virus hemagglutinin allows high transient expression in Nicotiana benthamiana, easy purification and immune response with neutralizing activity. AB - The expression of recombinant hemagglutinin in plants is a promising alternative to the current egg-based production system for the influenza vaccines. Protein stabilizing fusion partners have been developed to overcome the low production yields and the high downstream process costs associated with the plant expression system. In this context, we tested the fusion of hydrophobin I to the hemagglutinin ectodomain of the influenza A (H1N1)pdm09 virus controlled by the hybrid En2PMA4 transcriptional promoter to rapidly produce high levels of recombinant antigen by transient expression in agro-infiltrated Nicotiana benthamiana leaves. The fusion increased the expression level by a factor of ~ 2.5 compared to the unfused protein allowing a high accumulation level of 8.6% of the total soluble proteins. Hemagglutinin was located in ER-derived protein bodies and was successfully purified by combining an aqueous-two phase partition system and a salting out step. Hydrophobin interactions allowed the formation of high molecular weight hemagglutinin structures, while unfused proteins were produced as monomers. Purified protein was shown to be biologically active and to induce neutralizing antibodies after mice immunization. Hydrophobin fusion to influenza hemagglutinin might therefore be a promising approach for rapid, easy, and low cost production of seasonal or pandemic influenza vaccines in plants. PMID- 25541988 TI - Changes in nematode communities in different physiographic sites of the condor seamount (north-East atlantic ocean) and adjacent sediments. AB - Several seamounts are known as 'oases' of high abundances and biomass and hotspots of biodiversity in contrast to the surrounding deep-sea environments. Recent studies have indicated that each single seamount can exhibit a high intricate habitat turnover. Information on alpha and beta diversity of single seamount is needed in order to fully understand seamounts contribution to regional and global biodiversity. However, while most of the seamount research has been focused on summits, studies considering the whole seamount structure are still rather poor. In the present study we analysed abundance, biomass and diversity of nematodes collected in distinct physiographic sites and surrounding sediments of the Condor Seamount (Azores, North-East Atlantic Ocean). Our study revealed higher nematode biomass in the seamount bases and values 10 times higher in the Condor sediments than in the far-field site. Although biodiversity indices did not showed significant differences comparing seamount sites and far-field sites, significant differences were observed in term of nematode composition. The Condor summit harboured a completely different nematode community when compared to the other seamount sites, with a high number of exclusive species and important differences in term of nematode trophic diversity. The oceanographic conditions observed around the Condor Seamount and the associated sediment mixing, together with the high quality of food resources available in seamount base could explain the observed patterns. Our results support the hypothesis that seamounts maintain high biodiversity through heightened beta diversity and showed that not only summits but also seamount bases can support rich benthic community in terms of standing stocks and diversity. Furthermore functional diversity of nematodes strongly depends on environmental conditions link to the local setting and seamount structure. This finding should be considered in future studies on seamounts, especially in view of the potential impacts due to current and future anthropogenic threats. PMID- 25541990 TI - Core self-evaluation and burnout among Nurses: the mediating role of coping styles. AB - OBJECTIVES: This study aimed to determine the potential association between core self-evaluation and the burnout syndrome among Chinese nurses, and the mediating role of coping styles in this relationship. METHODS: A cross-sectional survey was conducted in Shenyang, China, from May to July, 2013. A questionnaire which consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the Core Self Evaluation Scale (CSE), and the Simplified Coping Style Questionnaire (CSQ), was completed by a total of 1,559 nurses. Hierarchical linear regression analyses and the Sobel test were performed to determine the mediating role of coping styles on the relationship between CSE and burnout. RESULTS: Nurses who had higher self evaluation characteristics, reported less emotional exhaustion and cynicism, and higher professional efficacy. Coping style had a partial mediating effect on the relationship between CSE and the burnout syndrome among nurses. CONCLUSIONS: Core self-evaluation had effects on burnout and coping style was a mediating factor in this relationship among Chinese nurses. Therefore, the improvement of coping strategies may be helpful in the prevention of burnout among nurses, thus enhancing professional performance. PMID- 25541989 TI - LDL-migration index (LDL-MI), an indicator of small dense low-density lipoprotein (sdLDL), is higher in non-alcoholic steatohepatitis than in non-alcoholic fatty liver: a multicenter cross-sectional study. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with increased risks of atherosclerotic diseases, including cardiovascular disease. However, the difference in risk between patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) has not yet been determined. Accumulating evidence has shown that high amounts of small dense low-density lipoprotein (sdLDL) are closely associated with atherosclerotic diseases. This study investigated differences in risk factors for atherosclerotic diseases, especially LDL-migration index (LDL-MI), an indicator of sdLDL, between patients with NAFL and NASH. METHODS: LDL-MI was analyzed in a primary cohort of 156 patients with NAFLD, including 53 with NAFL and 103 with NASH, and a validation cohort of 69 patients with NAFLD, including 25 with NAFL and 44 with NASH. RESULTS: In the primary cohort, NASH was associated with elevated LDL-MI (p = 0.039). Multiple regression analysis showed that NASH and the non-use of lipid lowering medications were independently correlated with higher LDL-MI in all patients with NAFLD. Among patients not on lipid lowering medications, those with NASH had significantly higher LDL-MI than those with NAFL (p = 0.001). These findings were confirmed in a validation cohort, in that LDL-MI was significantly higher in patients with NASH than with NAFL (p = 0.043). CONCLUSION: This study is the first to show that LDL-MI, an indicator of sdLDL, was higher in patients with NASH than with NAFL, suggesting that the risk of atherosclerotic diseases may be higher in NASH than NAFL. Patients with NASH should be followed closely, especially for the progression of liver pathology and atherosclerotic diseases. TRIAL REGISTRATION: UMIN000009614. PMID- 25541991 TI - Testing DNA barcode performance in 1000 species of European lepidoptera: large geographic distances have small genetic impacts. AB - This study examines the performance of DNA barcodes (mt cytochrome c oxidase 1 gene) in the identification of 1004 species of Lepidoptera shared by two localities (Finland, Austria) that are 1600 km apart. Maximum intraspecific distances for the pooled data were less than 2% for 880 species (87.6%), while deeper divergence was detected in 124 species. Despite such variation, the overall DNA barcode library possessed diagnostic COI sequences for 98.8% of the taxa. Because a reference library based on Finnish specimens was highly effective in identifying specimens from Austria, we conclude that barcode libraries based on regional sampling can often be effective for a much larger area. Moreover, dispersal ability (poor, good) and distribution patterns (disjunct, fragmented, continuous, migratory) had little impact on levels of intraspecific geographic divergence. Furthermore, the present study revealed that, despite the intensity of past taxonomic work on European Lepidoptera, nearly 20% of the species shared by Austria and Finland require further work to clarify their status. Particularly discordant BIN (Barcode Index Number) cases should be checked to ascertain possible explanatory factors such as incorrect taxonomy, hybridization, introgression, and Wolbachia infections. PMID- 25541992 TI - Prodromal Huntington disease as a model for functional compensation of early neurodegeneration. AB - Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD) with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI) and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT) tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation. PMID- 25541993 TI - Characterization of the MeCP2R168X knockin mouse model for Rett syndrome. AB - Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2(R168X) mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2(R168X) mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging. PMID- 25541994 TI - SIRT6 minor allele genotype is associated with >5-year decrease in lifespan in an aged cohort. AB - Aging is a natural process involving complex interplay between environment, metabolism, and genes. Sirtuin genes and their downstream targets have been associated with lifespan in numerous organisms from nematodes to humans. Several target proteins of the sirtuin genes are key sensors and/or effectors of oxidative stress pathways including FOXO3, SOD3, and AKT1. To examine the relationship between single nucleotide polymorphisms (SNP) at candidate genes in these pathways and human lifespan, we performed a molecular epidemiologic study of an elderly cohort (>=65 years old.). Using age at death as a continuous outcome variable and assuming a co-dominant genetic model within the framework of multi-variable linear regression analysis, the genotype-specific adjusted mean age at death was estimated for individual SNP genotypes while controlling for age related risk factors including smoking, body mass index, alcohol consumption and co-morbidity. Significant associations were detected between human lifespan and SNPs in genes SIRT3, SIRT5, SIRT6, FOXO3 and SOD3. Individuals with either the CC or CT genotype at rs107251 within SIRT6 displayed >5-year mean survival advantages compared to the TT genotype (5.5 and 5.9 years, respectively; q-value = 0.012). Other SNPs revealed genotype-specific mean survival advantages ranging from 0.5 to 1.6 years. Gender also modified the effect of SNPs in SIRT3, SIRT5 and AKT1 on lifespan. Our novel findings highlight the impact of sirtuins and sirtuin-related genotypes on lifespan, the importance of evaluating gender and the advantage of using age as a continuous variable in analyses to report mean age at death. PMID- 25541995 TI - A recombinant horseshoe crab plasma lectin recognizes specific pathogen associated molecular patterns of bacteria through rhamnose. AB - Horseshoe crab is an ancient marine arthropod that, in the absence of a vertebrate-like immune system, relies solely on innate immune responses by defense molecules found in hemolymph plasma and granular hemocytes for host defense. A plasma lectin isolated from the hemolymph of Taiwanese Tachypleus tridentatus recognizes bacteria and lipopolysaccharides (LPSs), yet its structure and mechanism of action remain unclear, largely because of limited availability of horseshoe crabs and the lack of a heterogeneous expression system. In this study, we have successfully expressed and purified a soluble and functional recombinant horseshoe crab plasma lectin (rHPL) in an Escherichia coli system. Interestingly, rHPL bound not only to bacteria and LPSs like the native HPL but also to selective medically important pathogens isolated from clinical specimens, such as Gram-negative Pseudomonas aeruginosa and Klebsiella pneumoniae and Gram positive Streptococcus pneumoniae serotypes. The binding was demonstrated to occur through a specific molecular interaction with rhamnose in pathogen associated molecular patterns (PAMPs) on the bacterial surface. Additionally, rHPL inhibited the growth of P. aeruginosa PAO1 in a concentration-dependent manner. The results suggest that a specific protein-glycan interaction between rHPL and rhamnosyl residue may further facilitate development of novel diagnostic and therapeutic strategies for microbial pathogens. PMID- 25541996 TI - Effect of single nucleotide polymorphism Rs189037 in ATM gene on risk of lung cancer in Chinese: a case-control study. AB - BACKGROUND: Accumulated evidence has indicated that ataxia-telangiectasia mutated (ATM) gene polymorphisms are closely related to lung cancer. We aimed to explore the prognostic value of rs189037 (G>A), one of ATM single nucleotide polymorphisms (SNPs), and detect whether it involves in the risk of lung cancer in Chinese Han people. METHODS: In this hospital-based matched case-control study, 852 lung cancer patients and 852 healthy controls have been put into comparison to analyze the association between rs189037 and lung cancer risk in Chinese. The single nucleotide polymorphisms were determined by TaqMan real-time PCR and we used SPSS software to perform the statistical analyses. RESULTS: Individuals carrying variant AA genotype of rs189037 had higher lung cancer risk (adjusted OR: 1.56) than those carrying GG genotype. After analyzing data respectively from different groups divided by genders and smoking status, we observed that the risk effect of AA genotype on the lung cancer was significant in females, non-smokers and female non-smokers, as well as the risk effect of GA genotype in male smokers. Compared with non-smokers carrying GG genotype, smokers carrying at least one A allele had higher risk of developing lung cancer than those with GG genotype (adjusted OR: 3.52 vs. adjusted OR: 2.53). CONCLUSIONS: This study suggested that rs189037 (G>A) polymorphism is associated with lung cancer risk in Chinese Han population. AA genotype and A allele may be dangerous lung cancer signals in Chinese and make contribution to diagnostic and treatment value. PMID- 25541997 TI - A novel model of IgE-mediated passive pulmonary anaphylaxis in rats. AB - Mast cells are central effector cells in allergic asthma and are augmented in the airways of asthma patients. Attenuating mast cell degranulation and with it the early asthmatic response is an important intervention point to inhibit bronchoconstriction, plasma exudation and tissue oedema formation. To validate the efficacy of novel pharmacological interventions, appropriate and practicable in vivo models reflecting mast cell-dependent mechanisms in the lung, are missing. Thus, we developed a novel model of passive pulmonary anaphylaxis in rats. Rats were passively sensitized by concurrent intratracheal and intradermal (ear) application of an anti-DNP IgE antibody. Intravenous application of the antigen, DNP-BSA in combination with Evans blue dye, led to mast cell degranulation in both tissues. Quantification of mast cell degranulation in the lung was determined by (1) mediator release into bronchoalveolar lavage, (2) extravasation of Evans blue dye into tracheal and bronchial lung tissue and (3) invasive measurement of antigen-induced bronchoconstriction. Quantification of mast cell degranulation in the ear was determined by extravasation of Evans blue dye into ear tissue. We pharmacologically validated our model using the SYK inhibitor Fostamatinib, the H1-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG) and the beta2-adrenergic receptor agonist Formoterol. Fostamatinib was equally efficacious in lung and ear. Desloratadine effectively inhibited bronchoconstriction and ear vascular leakage, but was less effective against pulmonary vascular leakage, perhaps reflecting the differing roles for histamine receptor sub-types. DSCG attenuated both vascular leakage in the lung and bronchoconstriction, but with a very short duration of action. As an inhaled approach, Formoterol was more effective in the lung than in the ear. This model of passive pulmonary anaphylaxis provides a tissue relevant readout of early mast cell activity and pharmacological benchmarking broadly reflects responses observed in patients with asthma. PMID- 25541998 TI - Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi infected non-human primates. AB - Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important. PMID- 25541999 TI - Detection of SRSF2-P95 mutation by high-resolution melting curve analysis and its effect on prognosis in myelodysplastic syndrome. AB - Hotspot mutations of serine/arginine-rich splicing factor 2 (SRSF2) gene have been identified in a proportion of hematologic malignancies including myelodysplastic syndrome (MDS). The aim of the present study was to develop a new approach to screen SRSF2 mutation and analyze the clinical relevance of SRSF2 mutations in Chinese MDS. A protocol based on high-resolution melting analysis (HRMA) was established to screen SRSF2-P95 mutation in 108 MDS patients and was compared with Sanger sequencing. The clinical relevance of SRSF2 mutations was further evaluated. HRMA identified five (4.6%) cases with SRSF2 mutation, completely validated by Sanger sequencing without false positive or negative results. The sensitivities of HRMA and Sanger sequencing were 10% and 25% for the detection of SRSF2-P95H mutation, respectively, against the background of wild type DNA. Patients with SRSF2 mutation had shorter overall survival time than those with wild-type SRSF2 in both the whole cohort of cases and those with normal karyotype (P = 0.069 and 0.023, respectively). Multivariate analysis confirmed SRSF2 mutation as an independent risk factor in both patient populations. We established a fast, high-throughput, and inexpensive HRMA-based method to screen SRSF2 mutation, which could be used in clinical diagnostic laboratories. SRSF2 mutations were significantly associated with mortality rate in the MDS affected Chinese. PMID- 25542000 TI - Perfusion index derived from a pulse oximeter can detect changes in peripheral microcirculation during uretero-renal-scopy stone manipulation (URS-SM). AB - BACKGROUND: The objective of this study was to test the effect of removal of a ureteral obstruction (renal calculus) from anesthetized patients on the perfusion index (PI), as measured by a pulse oximeter, and on the estimated glomerular filtration rate (eGFR). PATIENTS AND METHODS: This prospective study enrolled 113 patients with unilateral ureteral obstructions (kidney stones) who were scheduled for ureteroscopy (URS) laser lithotripsy. One urologist graded patient hydronephrosis before surgery. A pulse oximeter was affixed to each patient's index finger ipsilateral to the intravenous catheter, and a non-invasive blood pressure cuff was placed on the contralateral side. Ipsilateral double J stents and Foley catheters were inserted and left indwelling for 24 h. PI and mean arterial pressure (MAP) were determined at baseline, 5 min after anesthesia, and 10 min after surgery; eGFR was determined at admission, 1 day after surgery, and 14 days after surgery. RESULTS: Patients with different grades of hydronephrosis had similar age, eGFR, PI, mean arterial pressure (MAP), and heart rate (HR). PI increased significantly in each hydronephrosis group after ureteral stone disintegration. None of the groups had significant post-URS changes in eGFR, although eGFR increased in the grade I hydronephrosis group after 14 days. The percent change of PI correlates significantly with the percent change of MAP, but not with that of eGFR. CONCLUSION: Our results demonstrate that release of a ureteral obstruction leads to a concurrent increase of PI during anesthesia. Measurement of PI may be a valuable tool to monitor the successful release of ureteral obstructions and changes of microcirculation during surgery. There were also increases in eGFR after 14 days, but not immediately after surgery. PMID- 25542001 TI - Clinical presentation, convalescence, and relapse of rocky mountain spotted fever in dogs experimentally infected via tick bite. AB - Rocky Mountain spotted fever (RMSF) is a tick-borne disease caused by R. rickettsii in North and South America. Domestic dogs are susceptible to infection and canine RMSF can be fatal without appropriate treatment. Although clinical signs of R. rickettsii infection in dogs have been described, published reports usually include descriptions of either advanced clinical cases or experimental infections caused by needle-inoculation of cultured pathogen rather than by tick bite. The natural progression of a tick-borne R. rickettsii infection has not been studied in sufficient detail. Here, we provide a detailed description of clinical, hematological, molecular, and serological dynamics of RMSF in domestic dogs from the day of experimental exposure to infected ticks through recovery. Presented data indicate that neither the height/duration of fever nor detection of rickettsial DNA in dogs' blood by PCR are good indicators for clinical prognosis. Only the apex and subsequent subsidence of neutrophilia seem to mark the beginning of recovery and allow predicting a favorable outcome in Rickettsia infected dogs, even despite the continuing persistence of mucosal petechiae and skin rash. On the other hand the appropriate (doxycycline) antibiotic therapy of sufficient duration is crucial in prevention of RMSF relapses in dogs. PMID- 25542003 TI - Influenza surveillance and incidence in a rural area in China during the 2009/2010 influenza pandemic. AB - BACKGROUND: Most influenza surveillance is based on data from urban sentinel hospitals; little is known about influenza activity in rural communities. We conducted influenza surveillance in a rural region of China with the aim of detecting influenza activity in the 2009/2010 influenza season. METHODS: The study was conducted from October 2009 to March 2010. Real-time polymerase chain reaction was used to confirm influenza cases. Over-the-counter (OTC) drug sales were daily collected in drugstores and hospitals/clinics. Space-time scan statistics were used to identify clusters of ILI in community. The incidence rate of ILI/influenza was estimated on the basis of the number of ILI/influenza cases detected by the hospitals/clinics. RESULTS: A total of 434 ILI cases (3.88% of all consultations) were reported; 64.71% of these cases were influenza A (H1N1) pdm09. The estimated incidence rate of ILI and influenza were 5.19/100 and 0.40/100, respectively. The numbers of ILI cases and OTC drug purchases in the previous 7 days were strongly correlated (Spearman rank correlation coefficient [r] = 0.620, P = 0.001). Four ILI outbreaks were detected by space-time permutation analysis. CONCLUSIONS: This rural community surveillance detected influenza A (H1N1) pdm09 activity and outbreaks in the 2009/2010 influenza season and enabled estimation of the incidence rate of influenza. It also provides a scientific data for public health measures. PMID- 25542002 TI - ARAP3 functions in hematopoietic stem cells. AB - ARAP3 is a GTPase-activating protein (GAP) that inactivates Arf6 and RhoA small GTPases. ARAP3 deficiency in mice causes a sprouting angiogenic defect resulting in embryonic lethality by E11. Mice with an ARAP3 R302,303A mutation (Arap3KI/KI) that prevents activation by phosphoinositide-3-kinase (PI3K) have a similar angiogenic phenotype, although some animals survive to adulthood. Here, we report that hematopoietic stem cells (HSCs) from rare adult Arap3KI/KI bone marrow are compromised in their ability to reconstitute recipient mice and to self-renew. To elucidate the potential cell-autonomous and non-cell-autonomous roles of ARAP3 in hematopoiesis, we conditionally deleted Arap3 in hematopoietic cells and in several cell types within the HSC niche. Excision of Arap3 in hematopoietic cells using Vav1-Cre does not alter the ability of ARAP3-deficient progenitor cells to proliferate and differentiate in vitro or ARAP3-deficient HSCs to provide multi lineage reconstitution and to undergo self-renewal in vivo. Thus, our data suggest that ARAP3 does not play a cell-autonomous role in HSPCs. Deletion of Arap3 in osteoblasts and mesenchymal stromal cells using Prx1-Cre resulted in no discernable phenotypes in hematopoietic development or HSC homeostasis in adult mice. In contrast, deletion of Arap3 using vascular endothelial cadherin (VEC or Cdh5)-driven Cre resulted in embryonic lethality, however HSCs from surviving adult mice were largely normal. Reverse transplantations into VEC-driven Arap3 conditional knockout mice revealed no discernable difference in HSC frequencies or function in comparison to control mice. Taken together, our investigation suggests that despite a critical role for ARAP3 in embryonic vascular development, its loss in endothelial cells minimally impacts HSCs in adult bone marrow. PMID- 25542004 TI - A snapshot of the hepatic transcriptome: ad libitum alcohol intake suppresses expression of cholesterol synthesis genes in alcohol-preferring (P) rats. AB - Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d) is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P) rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (~ 7.43 g ethanol/kg/day) in inbred alcohol-preferring (iP10a) rats. Chronic consumption led to down regulation of nine genes in the cholesterol biosynthesis pathway, including HMG CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake. PMID- 25542005 TI - Analysis of potato virus Y coat protein epitopes recognized by three commercial monoclonal antibodies. AB - BACKGROUND: Potato virus Y (PVY, genus Potyvirus) causes substantial economic losses in solanaceous plants. Routine screening for PVY is an essential part of seed potato certification, and serological assays are often used. The commercial, commonly used monoclonal antibodies, MAb1128, MAb1129, and MAb1130, recognize the viral coat protein (CP) of PVY and distinguish PVYN strains from PVYO and PVYC strains, or detect all PVY strains, respectively. However, the minimal epitopes recognized by these antibodies have not been identified. METHODOLOGY/PRINCIPAL FINDINGS: SPOT peptide array was used to map the epitopes in CP recognized by MAb1128, MAb1129, and MAb1130. Then alanine replacement as well as N- and C terminal deletion analysis of the identified peptide epitopes was done to determine critical amino acids for antibody recognition and the respective minimal epitopes. The epitopes of all antibodies were located within the 30 N terminal-most residues. The minimal epitope of MAb1128 was 25NLNKEK30. Replacement of 25N or 27N with alanine weakened the recognition by MAb1128, and replacement of 26L, 29E, or 30K nearly precluded recognition. The minimal epitope for MAb1129 was 16RPEQGSIQSNP26 and the most critical residues for recognition were 22I and 23Q. The epitope of MAb1130 was defined by residues 5IDAGGS10. Mutation of residue 6D abrogated and mutation of 9G strongly reduced recognition of the peptide by MAb1130. Amino acid sequence alignment demonstrated that these epitopes are relatively conserved among PVY strains. Finally, recombinant CPs were produced to demonstrate that mutations in the variable positions of the epitope regions can affect detection with the MAbs. CONCLUSIONS/SIGNIFICANCE: The epitope data acquired can be compared with data on PVY CP-encoding sequences produced by laboratories worldwide and utilized to monitor how widely the new variants of PVY can be detected with current seed potato certification schemes or during the inspection of imported seed potatoes as conducted with these MAbs. PMID- 25542007 TI - MicroRNA-302a functions as a putative tumor suppressor in colon cancer by targeting Akt. AB - Micro RNAs (miRNAs) are important regulators involved in various physical and pathological processes, including cancer. The miRNA-302 family has been documented as playing a critical role in carcinogenesis. In this study, we investigated the role of miRNA-302a in colon cancer. MiRNA-302a expression was detected in 44 colon cancer tissues and 10 normal colon tissues, and their clinicopathological significance was analyzed. Cell proliferation and cell cycle analysis were performed on colon cancer cells that stably expressed miRNA-302a. The target gene of miRNA-302a and the downstream pathway were further investigated. Compared with normal colon tissues, miRNA-302a expression was downregulated in colon cancer tissues. Overexpression of miRNA-302a induced G1/S cell cycle arrest in colon cancer cells, and suppressed colon cancer cell proliferation both in vitro and in vivo. Furthermore, miRNA-302a inhibited AKT expression by directly binding to its 3' untranslated region, resulting in subsequent alterations of the AKT-GSK3beta-cyclin D1 pathway. These results reveal miRNA-302a as a tumor suppressor in colon cancer, suggesting that miRNA 302a may be used as a potential target for therapeutic intervention in colon cancer. PMID- 25542006 TI - Expression of Ror2 mediates invasive phenotypes in renal cell carcinoma. AB - Ror2 is a Wnt ligand receptor that is overexpressed in a variety of tumors including clear cell renal cell carcinoma (ccRCC). Here we demonstrate that expression of wild type Ror2 results in increased tumorigenic properties in in vitro cell culture and in vivo xenograft models. In addition, Ror2 expression produced positive changes in both cell migration and invasion, which were dependent on matrix metalloprotease 2 (MMP2) activity. Mutations in key regions of the kinase domain of Ror2 resulted in the abrogation of increased tumor growth, cell migration, and cell invasion observed with expression of wild-type Ror2. Finally, we examined Ror2 expression as a prognostic biomarker for ccRCC utilizing the TCGA ccRCC dataset. High expression of Ror2 showed a significant correlation with higher clinical stage, nuclear grade, and tumor stage. Furthermore, high expression of Ror2 in ccRCC patients correlated with significant lower overall survival, cancer specific survival, and recurrence free survival. Together, these findings suggest that Ror2 plays a central role in influencing the ccRCC phenotype, and can be considered as a negative prognostic biomarker and potential therapeutic target in this cancer. PMID- 25542008 TI - Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical. AB - Histamine H3 receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [125I]WYE-230949, as a potential radionuclide imaging agent for the histamine H3 receptor in brain. [125I]WYE-230949 had a high in vitro affinity for the rat histamine H3 receptor (Kd of 6.9 nM). The regional distribution of [125I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H3 receptor. Rat brain uptake of intravenously injected [125I]WYE-230949 was low (0.11 %ID/g) and the ratio of specific: non-specific binding was less than 1.4, as determined by ex vivo autoradiography. In plasma, metabolism of [125I]WYE-230949 into a less lipophilic species occurred, such that less than 38% of the parent compound remained 30 minutes after injection. Brain uptake and metabolism of [125I]WYE-230949 were increased and specific binding was reduced in anaesthetised compared to conscious rats. [125I]WYE230949 is not a potential radiotracer for imaging rat histamine H3 receptors in vivo due to low brain uptake, in vivo metabolism of the parent compound and low specific binding. PMID- 25542010 TI - Optical coherence tomography and autofluorescence imaging of human tonsil. AB - For the first time, we present co-registered autofluorescence imaging and optical coherence tomography (AF/OCT) of excised human palatine tonsils to evaluate the capabilities of OCT to visualize tonsil tissue components. Despite limited penetration depth, OCT can provide detailed structural information about tonsil tissue with much higher resolution than that of computed tomography, magnetic resonance imaging, and Ultrasound. Different tonsil tissue components such as epithelium, dense connective tissue, lymphoid nodules, and crypts can be visualized by OCT. The co-registered AF imaging can provide matching biochemical information. AF/OCT scans may provide a non-invasive tool for detecting tonsillar cancers and for studying the natural history of their development. PMID- 25542011 TI - The neuron regrowth is associated with the proliferation of neural precursor cells after leukemia inhibitory factor administration following spinal cord injury in mice. AB - OBJECTIVES: To explore whether LIF could promote the proliferation of neural precursor cells (NPCs) and to analyze the correlation between increased NPCs and FluoroGold (FG) labeled neurons in mice after spinal cord injury (SCI). METHODS: Motor behavior was assessed using Rotarod and Platform Hang tests; neurons in the corticospinal and rubrospinal systems were labeled with FG, NPCs were immustained with nestin-FITC conjugate. The numbers of FG-labeled neurons and NPCs were estimated, and the correlation between FG-labeled neurons and NPCs was assessed. RESULTS: Mice in the SCI group showed negligible recovery of locomotor behavior; in contrast, mice in the LIF group showed a statically significant improvement. Both FG-labeled neurons and NPCs were significantly increased in the LIF group compared to the SCI group, and this increase in FG-labeled neurons and NPCs showed a clear association above the lesion level. CONCLUSIONS: LIF could promote locomotive behaviors in mice post-SCI by encouraging the proliferation of NPCs; LIF may in fact be a potential cytokine for the induction of NPCs post-SCI. PMID- 25542014 TI - Identification and predicting short-term prognosis of early cardiorenal syndrome type 1: KDIGO is superior to RIFLE or AKIN. AB - OBJECTIVE: Acute kidney injury (AKI) in patients hospitalized for acute heart failure (AHF) is usually type 1 of the cardiorenal syndrome (CRS) and has been associated with increased morbidity and mortality. Early recognition of AKI is critical. This study was to determine if the new KDIGO criteria (Kidney Disease: Improving Global Outcomes) for identification and short-term prognosis of early CRS type 1 was superior to the previous RIFLE and AKIN criteria. METHODS: The association between AKI diagnosed by KDIGO but not by RIFLE or AKIN and in hospital mortality was retrospectively evaluated in 1005 Chinese adult patients with AHF between July 2008 and May 2012. AKI was defined as RIFLE, AKIN and KDIGO criteria, respectively. Cox regression was used for multivariate analysis of in hospital mortality. RESULTS: Within 7 days on admission, the incidence of CRS type 1 was 38.9% by KDIGO criteria, 34.7% by AKIN, and 32.1% by RIFLE. A total of 110 (10.9%) cases were additional diagnosed by KDIGO criteria but not by RIFLE or AKIN. 89.1% of them were in Stage 1 (AKIN) or Stage Risk (RIFLE). They accounted for 18.4% (25 cases) of the overall death. After adjustment, this proportion remained an independent risk factor for in-hospital mortality [odds ratios (OR)3.24, 95% confidence interval(95%CI) 1.97-5.35]. Kaplan-Meier curve showed AKI patients by RIFLE, AKIN, KDIGO and [K(+)R(-)+K(+)A(-)] had lower hospital survival than non-AKI patients (Log Rank P<0.001). CONCLUSION: KDIGO criteria identified significantly more CRS type 1 episodes than RIFLE or AKIN. AKI missed diagnosed by RIFLE or AKIN criteria was an independent risk factor for in hospital mortality, indicating the new KDIGO criteria was superior to RIFLE and AKIN in predicting short-term outcomes in early CRS type 1. PMID- 25542013 TI - European surveillance network for influenza in pigs: surveillance programs, diagnostic tools and Swine influenza virus subtypes identified in 14 European countries from 2010 to 2013. AB - Swine influenza causes concern for global veterinary and public health officials. In continuing two previous networks that initiated the surveillance of swine influenza viruses (SIVs) circulating in European pigs between 2001 and 2008, a third European Surveillance Network for Influenza in Pigs (ESNIP3, 2010-2013) aimed to expand widely the knowledge of the epidemiology of European SIVs. ESNIP3 stimulated programs of harmonized SIV surveillance in European countries and supported the coordination of appropriate diagnostic tools and subtyping methods. Thus, an extensive virological monitoring, mainly conducted through passive surveillance programs, resulted in the examination of more than 9 000 herds in 17 countries. Influenza A viruses were detected in 31% of herds examined from which 1887 viruses were preliminary characterized. The dominating subtypes were the three European enzootic SIVs: avian-like swine H1N1 (53.6%), human-like reassortant swine H1N2 (13%) and human-like reassortant swine H3N2 (9.1%), as well as pandemic A/H1N1 2009 (H1N1pdm) virus (10.3%). Viruses from these four lineages co-circulated in several countries but with very different relative levels of incidence. For instance, the H3N2 subtype was not detected at all in some geographic areas whereas it was still prevalent in other parts of Europe. Interestingly, H3N2-free areas were those that exhibited highest frequencies of circulating H1N2 viruses. H1N1pdm viruses were isolated at an increasing incidence in some countries from 2010 to 2013, indicating that this subtype has become established in the European pig population. Finally, 13.9% of the viruses represented reassortants between these four lineages, especially between previous enzootic SIVs and H1N1pdm. These novel viruses were detected at the same time in several countries, with increasing prevalence. Some of them might become established in pig herds, causing implications for zoonotic infections. PMID- 25542012 TI - Prospective associations of coronary heart disease loci in African Americans using the MetaboChip: the PAGE study. AB - BACKGROUND: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans. METHODS AND RESULTS: Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1 * 10(-8)), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium. CONCLUSIONS: Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans. PMID- 25542015 TI - Predictive value of assessing diastolic strain rate on survival in cardiac amyloidosis patients with preserved ejection fraction. AB - OBJECTIVES: Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSRdias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%). BACKGROUND: Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LSsys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSRdias also related to outcome in these patients. METHODS: Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65+/-9 years). Global and segmental LSsys and LSRdias were obtained in six LV segments from apical 4-chamber views. RESULTS: Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5-35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6 +/- 2 vs. 8 +/- 3 mm), global LSRdias and basal-septal LSRdias were significantly lower in non-survivors than in survivors (all p < 0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LSsys, global LSRdias, basal-septal LSRdias and E/LSRdias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.17-3.26, P = 0.010), global LSRdias (HR = 7.30, 95% CI 2.08-25.65, P = 0.002), and E/LSRdias (HR = 2.98, 95% CI 1.54-5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSRdias was optimal at a cutoff value of 0.85 S-1 (sensitivity 68%, specificity 67%). Global LSRdias < 0.85 S-1 predicted a 4-fold increased mortality in CA patients with preserved LVEF. CONCLUSIONS: STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF. PMID- 25542018 TI - Constructive autoassociative neural network for facial recognition. AB - Autoassociative artificial neural networks have been used in many different computer vision applications. However, it is difficult to define the most suitable neural network architecture because this definition is based on previous knowledge and depends on the problem domain. To address this problem, we propose a constructive autoassociative neural network called CANet (Constructive Autoassociative Neural Network). CANet integrates the concepts of receptive fields and autoassociative memory in a dynamic architecture that changes the configuration of the receptive fields by adding new neurons in the hidden layer, while a pruning algorithm removes neurons from the output layer. Neurons in the CANet output layer present lateral inhibitory connections that improve the recognition rate. Experiments in face recognition and facial expression recognition show that the CANet outperforms other methods presented in the literature. PMID- 25542016 TI - The roles of co-chaperone CCRP/DNAJC7 in Cyp2b10 gene activation and steatosis development in mouse livers. AB - Cytoplasmic constitutive active/androstane receptor (CAR) retention protein (CCRP and also known as DNAJC7) is a co-chaperone previously characterized to retain nuclear receptor CAR in the cytoplasm of HepG2 cells. Here we have produced CCRP knockout (KO) mice and demonstrated that CCRP regulates CAR at multiple steps in activation of the cytochrome (Cyp) 2b10 gene in liver: nuclear accumulation, RNA polymerase II recruitment and epigenetic modifications. Phenobarbital treatment greatly increased nuclear CAR accumulation in the livers of KO males as compared to those of wild type (WT) males. Despite this accumulation, phenobarbital induced activation of the Cyp2b10 gene was significantly attenuated. In ChIP assays, a CAR/retinoid X receptor-alpha (RXRalpha) heterodimer binding to the Cyp2b10 promoter was already increased before phenobarbital treatment and further pronounced after treatment. However, RNA polymerase II was barely recruited to the promoter even after phenobarbital treatment. Histone H3K27 on the Cyp2b10 promoter was de-methylated only after phenobarbital treatment in WT but was fully de-methylated before treatment in KO males. Thus, CCRP confers phenobarbital induced de-methylation capability to the promoter as well as the phenobarbital responsiveness of recruiting RNA polymerase II, but is not responsible for the binding between CAR and its cognate sequence, phenobarbital responsive element module. In addition, KO males developed steatotic livers and increased serum levels of total cholesterol and high density lipoprotein in response to fasting. CCRP appears to be involved in various hepatic regulations far beyond CAR mediated drug metabolism. PMID- 25542017 TI - Identification of genes associated with reproduction in the Mud Crab (Scylla olivacea) and their differential expression following serotonin stimulation. AB - The central nervous system (CNS) is often intimately involved in reproduction control and is therefore a target organ for transcriptomic investigations to identify reproduction-associated genes. In this study, 454 transcriptome sequencing was performed on pooled brain and ventral nerve cord of the female mud crab (Scylla olivacea) following serotonin injection (5 ug/g BW). A total of 197,468 sequence reads was obtained with an average length of 828 bp. Approximately 38.7% of 2,183 isotigs matched with significant similarity (E value < 1e-4) to sequences within the Genbank non-redundant (nr) database, with most significant matches being to crustacean and insect sequences. Approximately 32 putative neuropeptide genes were identified from nonmatching blast sequences. In addition, we identified full-length transcripts for crustacean reproductive related genes, namely farnesoic acid o-methyltransferase (FAMeT), estrogen sulfotransferase (ESULT) and prostaglandin F synthase (PGFS). Following serotonin injection, which would normally initiate reproductive processes, we found up regulation of FAMeT, ESULT and PGFS expression in the female CNS and ovary. Our data here provides an invaluable new resource for understanding the molecular role of the CNS on reproduction in S. olivacea. PMID- 25542020 TI - Higher dimensional Gaussian-type solitons of nonlinear Schrodinger equation with cubic and power-law nonlinearities in PT-symmetric potentials. AB - Two families of Gaussian-type soliton solutions of the (n+1)-dimensional Schrodinger equation with cubic and power-law nonlinearities in PT-symmetric potentials are analytically derived. As an example, we discuss some dynamical behaviors of two dimensional soliton solutions. Their phase switches, powers and transverse power-flow densities are discussed. Results imply that the powers flow and exchange from the gain toward the loss regions in the PT cell. Moreover, the linear stability analysis and the direct numerical simulation are carried out, which indicates that spatial Gaussian-type soliton solutions are stable below some thresholds for the imaginary part of PT-symmetric potentials in the defocusing cubic and focusing power-law nonlinear medium, while they are always unstable for all parameters in other media. PMID- 25542019 TI - JARID2 is involved in transforming growth factor-beta-induced epithelial mesenchymal transition of lung and colon cancer cell lines. AB - Histone methylation plays a crucial role in various biological and pathological processes including cancer development. In this study, we discovered that JARID2, an interacting component of Polycomb repressive complex-2 (PRC2) that catalyzes methylation of lysine 27 of histone H3 (H3K27), was involved in Transforming Growth Factor-beta (TGF-beta)-induced epithelial-mesenchymal transition (EMT) of A549 lung cancer cell line and HT29 colon cancer cell line. The expression of JARID2 was increased during TGF-beta-induced EMT of these cell lines and knockdown of JARID2 inhibited TGF-beta-induced morphological conversion of the cells associated with EMT. JARID2 knockdown itself had no effect in the expression of EMT-related genes but antagonized TGF-beta-dependent expression changes of EMT-related genes such as CDH1, ZEB family and microRNA-200 family. Chromatin immunoprecipitation assays showed that JARID2 was implicated in TGF beta-induced transcriptional repression of CDH1 and microRNA-200 family genes through the regulation of histone H3 methylation and EZH2 occupancies on their regulatory regions. Our study demonstrated a novel role of JARID2 protein, which may control PRC2 recruitment and histone methylation during TGF-beta-induced EMT of lung and colon cancer cell lines. PMID- 25542021 TI - The relationship between the expression of ethylene-related genes and papaya fruit ripening disorder caused by chilling injury. AB - Papaya (Carica papaya L.) is sensitive to low temperature and easy to be subjected to chilling injury, which causes fruit ripening disorder. This study aimed to investigate the relationship between the expression of genes related to ethylene and fruit ripening disorder caused by chilling injury. Papaya fruits were firstly stored at 7 degrees C and 12 degrees C for 25 and 30 days, respectively, then treated with exogenous ethylene and followed by ripening at 25 degrees C for 5 days. Chilling injury symptoms such as pulp water soaking were observed in fruit stored at 7 degrees C on 20 days, whereas the coloration and softening were completely blocked after 25 days, Large differences in the changes in the expression levels of twenty two genes involved in ethylene were seen during 7 degrees C-storage with chilling injury. Those genes with altered expression could be divided into three groups: the group of genes that were up regulated, including ACS1/2/3, EIN2, EIN3s/EIL1, CTR1/2/3, and ERF1/3/4; the group of genes that were down-regulated, including ACO3, ETR1, CTR4, EBF2, and ERF2; and the group of genes that were un-regulated, including ACO1/2, ERS, and EBF1. The results also showed that pulp firmness had a significantly positive correlation with the expression of ACS2, ACO1, CTR1/4, EIN3a/b, and EBF1/2 in fruit without chilling injury. This positive correlation was changed to negative one in fruit after storage at 7 degrees C for 25 days with chilling injury. The coloring index displayed significantly negative correlations with the expression levels of ACS2, ACO1/2, CTR4, EIN3a/b, ERF3 in fruit without chilling injury, but these correlations were changed into the positive ones in fruit after storage at 7 degrees C for 25 days with chilling injury. All together, these results indicate that these genes may play important roles in the abnormal softening and coloration with chilling injury in papaya. PMID- 25542022 TI - Piloting laboratory quality system management in six health facilities in Nigeria. AB - BACKGROUND: Achieving accreditation in laboratories is a challenge in Nigeria like in most African countries. Nigeria adopted the World Health Organization Regional Office for Africa Stepwise Laboratory (Quality) Improvement Process Towards Accreditation (WHO/AFRO- SLIPTA) in 2010. We report on FHI360 effort and progress in piloting WHO-AFRO recognition and accreditation preparedness in six health facility laboratories in five different states of Nigeria. METHOD: Laboratory assessments were conducted at baseline, follow up and exit using the WHO/AFRO- SLIPTA checklist. From the total percentage score obtained, the quality status of laboratories were classified using a zero to five star rating, based on the WHO/AFRO quality improvement stepwise approach. Major interventions include advocacy, capacity building, mentorship and quality improvement projects. RESULTS: At baseline audit, two of the laboratories attained 1- star while the remaining four were at 0- star. At follow up audit one lab was at 1- star, two at 3-star and three at 4-star. At exit audit, four labs were at 4- star, one at 3 star and one at 2-star rating. One laboratory dropped a 'star' at exit audit, while others consistently improved. The two weakest elements at baseline; internal audit (4%) and occurrence/incidence management (15%) improved significantly, with an exit score of 76% and 81% respectively. The elements facility and safety was the major strength across board throughout the audit exercise. CONCLUSION: This effort resulted in measurable and positive impact on the laboratories. We recommend further improvement towards a formal international accreditation status and scale up of WHO/AFRO- SLIPTA implementation in Nigeria. PMID- 25542023 TI - Impact of groundwater table and plateau zokors (Myospalax baileyi) on ecosystem respiration in the Zoige Peatlands of China. AB - Peatlands contain large amount of carbon stock that is vulnerable to release into the atmosphere. Mostly because of human impact, the peatlands at Zoige Wetlands face severe degradation, and the groundwater table is now lower than before, which has increased the population of the plateau zokor, a burrowing rodent. However, the impact of these changes on ecosystem carbon flows has not been studied. To investigate how the plateau zokor and the groundwater level alter the ecosystem respiration of the Zoige peatlands, we sampled the CO2 flux of hummocks shaped by the zokors and compared it with the CO2 flux of undisturbed sites with different groundwater table levels. The soil organic carbon (SOC), soil water content (SWC) and soil temperature at 5 cm (T5) were measured. SOC showed no significant difference among the four sampling sites and did not correlate with the CO2 flux, while SWC was found to partly determine the CO2 flux. A linear equation could adequately describe the relationship between the natural logarithm of the ecosystem respiration and the soil temperature. It is demonstrated that descending groundwater table might accelerate ecosystem respiration and the CO2 flux from hummocks was higher than the CO2 flux from the control site in the non growing season. With rising temperature, the CO2 flux from the control site accelerated faster than that from the hummocks. Our results show that ecosystem respiration was significantly lower from hummocks than at the control site in the growing season. The results on the impact of zokors on greenhouse gas emissions presented in this paper provide a useful reference to help properly manage not only this, but other litter-burrowing mammals at peatland sites. PMID- 25542025 TI - Multifractal properties of a closed contour: a peek beyond the shape analysis. AB - In recent decades multifractal analysis has been successfully applied to characterize the complex temporal and spatial organization of such diverse natural phenomena as heartbeat dynamics, the dendritic shape of neurons, retinal vessels, rock fractures, and intricately shaped volcanic ash particles. The characterization of multifractal properties of closed contours has remained elusive because applying traditional methods to their quasi-one-dimensional nature yields ambiguous answers. Here we show that multifractal analysis can reveal meaningful and sometimes unexpected information about natural structures with a perimeter well-defined by a closed contour. To this end, we demonstrate how to apply multifractal detrended fluctuation analysis, originally developed for the analysis of time series, to an arbitrary shape of a given study object. In particular, we show the application of the method to fish otoliths, calcareous concretions located in fish's inner ear. Frequently referred to as the fish's "black box", they contain a wealth of information about the fish's life history and thus have recently attracted increasing attention. As an illustrative example, we show that a multifractal approach can uncover unexpected relationships between otolith contours and size and age of fish at maturity. PMID- 25542024 TI - Establishment of human patient-derived endometrial cancer xenografts in NOD scid gamma mice for the study of invasion and metastasis. AB - OBJECTIVE: Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis. METHODS: Endometrial tumor tissue fragments (1.5 mm * 1.5 mm) from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6-8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers. RESULTS: Four cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor alpha, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor. CONCLUSION: Endometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer. PMID- 25542026 TI - A new bibliometric index based on the shape of the citation distribution. AB - In order to improve the h-index in terms of its accuracy and sensitivity to the form of the citation distribution, we propose the new bibliometric index [symbol in text]. The basic idea is to define, for any author with a given number of citations, an "ideal" citation distribution which represents a benchmark in terms of number of papers and number of citations per publication, and to obtain an index which increases its value when the real citation distribution approaches its ideal form. The method is very general because the ideal distribution can be defined differently according to the main objective of the index. In this paper we propose to define it by a "squared-form" distribution: this is consistent with many popular bibliometric indices, which reach their maximum value when the distribution is basically a "square". This approach generally rewards the more regular and reliable researchers, and it seems to be especially suitable for dealing with common situations such as applications for academic positions. To show the advantages of the [symbol in text]-index some mathematical properties are proved and an application to real data is proposed. PMID- 25542027 TI - Genome-wide identification of hsp40 genes in channel catfish and their regulated expression after bacterial infection. AB - Heat shock proteins (HSPs) consist of a large group of chaperones whose expression is induced by high temperature, hypoxia, infection and a number of other stresses. Among all the HSPs, Hsp40 is the largest HSP family, which bind to Hsp70 ATPase domain in assisting protein folding. In this study, we identified 57 hsp40s in channel catfish (Ictalurus punctatus) through in silico analysis using RNA-Seq and genome databases. These genes can be classified into three different types, Type I, II and III, based on their structural similarities. Phylogenetic and syntenic analyses provided strong evidence in supporting the orthologies of these HSPs. Meta-analyses of RNA-Seq datasets were conducted to analyze expression profile of Hsp40s following bacterial infection. Twenty seven hsp40s were found to be significantly up- or down-regulated in the liver after infection with E. ictaluri; 19 hsp40s were found to be significantly regulated in the intestine after infection with E. ictaluri; and 19 hsp40s were found to be significantly regulated in the gill following infection with F. columnare. Altogether, a total of 42 Hsp40 genes were regulated under disease situations involving three tissues and two bacterial infections. The significant regulated expression of Hsp40 genes after bacterial infection suggested their involvement in disease defenses in catfish. PMID- 25542028 TI - Nitric oxide synthase (NOS) inhibition during porcine in vitro maturation modifies oocyte protein S-nitrosylation and in vitro fertilization. AB - Nitric oxide (NO) is a molecule involved in many reproductive processes. Its importance during oocyte in vitro maturation (IVM) has been demonstrated in various species although sometimes with contradictory results. The objective of this study was to determine the effect of NO during IVM of cumulus oocyte complexes and its subsequent impact on gamete interaction in porcine species. For this purpose, IVM media were supplemented with three NOS inhibitors: NG-nitro-L arginine methyl ester (L-NAME), NG-monomethyl-L-arginine (L-NMMA) and aminoguanidine (AG). A NO donor, S-nitrosoglutathione (GSNO), was also used. The effects on the cumulus cell expansion, meiotic resumption, zona pellucida digestion time (ZPdt) and, finally, on in vitro fertilization (IVF) parameters were evaluated. The oocyte S-nitrosoproteins were also studied by in situ nitrosylation. The results showed that after 42 h of IVM, AG, L-NAME and L-NMMA had an inhibitory effect on cumulus cell expansion. Meiotic resumption was suppressed only when AG was added, with 78.7% of the oocytes arrested at the germinal vesicle state (P<0.05). Supplementation of the IVM medium with NOS inhibitors or NO donor did not enhance the efficiency of IVF, but revealed the importance of NO in maturation and subsequent fertilization. Furthermore, protein S-nitrosylation is reported for the first time as a pathway through which NO exerts its effect on porcine IVM; therefore, it would be important to determine which proteins are nitrosylated in the oocyte and their functions, in order to throw light on the mechanism of action of NO in oocyte maturation and subsequent fertilization. PMID- 25542029 TI - The endemic insular and peninsular species Chaetodipus spinatus (Mammalia, Heteromyidae) breaks patterns for Baja California. AB - The Baja California peninsula is the second longest, most geographically isolated peninsula on Earth. Its physiography and the presence of many surrounding islands has facilitated studies of the underlying patterns and drivers of genetic structuring for a wide spectrum of organisms. Chaetodipus spinatus is endemic to the region and occurs on 12 associated islands, including 10 in the Gulf of California and two in the Pacific Ocean. This distribution makes it a model species for evaluating natural historical barriers. We test hypotheses associated with the relationship between the range of the species, patterns in other species, and its relationship to Pleistocene-Holocene climatic changes. We analyzed sequence data from mtDNA genes encoding cytochrome b (Cytb) and cytochrome c oxidase subunits I (COI) and III (COIII) in 26 populations including all 12 islands. The matrilineal genealogy, statistical parsimony network and Bayesian skyline plot indicated an origin of C. spinatus in the southern part of the peninsula. Our analyses detected several differences from the common pattern of peninsular animals: no mid-peninsula break exists, Isla Carmen hosts the most divergent population, the population on an ancient southern Midriff island does not differ from peninsular populations, and a mtDNA peninsular discordance occurs near Loreto. PMID- 25542031 TI - A model to explain plant growth promotion traits: a multivariate analysis of 2,211 bacterial isolates. AB - Plant growth-promoting bacteria can greatly assist sustainable farming by improving plant health and biomass while reducing fertilizer use. The plant microorganism-environment interaction is an open and complex system, and despite the active research in the area, patterns in root ecology are elusive. Here, we simultaneously analyzed the plant growth-promoting bacteria datasets from seven independent studies that shared a methodology for bioprospection and phenotype screening. The soil richness of the isolate's origin was classified by a Principal Component Analysis. A Categorical Principal Component Analysis was used to classify the soil richness according to isolate's indolic compound production, siderophores production and phosphate solubilization abilities, and bacterial genera composition. Multiple patterns and relationships were found and verified with nonparametric hypothesis testing. Including niche colonization in the analysis, we proposed a model to explain the expression of bacterial plant growth promoting traits according to the soil nutritional status. Our model shows that plants favor interaction with growth hormone producers under rich nutrient conditions but favor nutrient solubilizers under poor conditions. We also performed several comparisons among the different genera, highlighting interesting ecological interactions and limitations. Our model could be used to direct plant growth-promoting bacteria bioprospection and metagenomic sampling. PMID- 25542032 TI - HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer. AB - HSP90 inhibitors are currently undergoing clinical evaluation in combination with antimitotic drugs in non-small cell lung cancer (NSCLC), but little is known about the cellular effects of this novel drug combination. Therefore, we investigated the molecular mechanism of action of IPI-504 (retaspimycin HCl), a potent and selective inhibitor of HSP90, in combination with the microtubule targeting agent (MTA) docetaxel, in preclinical models of NSCLC. We identified a subset of NSCLC cell lines in which these drugs act in synergy to enhance cell death. Xenograft models of NSCLC demonstrated tumor growth inhibition, and in some cases, regression in response to combination treatment. Treatment with IPI 504 enhanced the antimitotic effects of docetaxel leading to the hypothesis that the mitotic checkpoint is required for the response to drug combination. Supporting this hypothesis, overriding the checkpoint with an Aurora kinase inhibitor diminished the cell death synergy of IPI-504 and docetaxel. To investigate the molecular basis of synergy, an unbiased stable isotope labeling by amino acids in cell culture (SILAC) proteomic approach was employed. Several mitotic regulators, including components of the ubiquitin ligase, anaphase promoting complex (APC/C), were specifically down-regulated in response to combination treatment. Loss of APC/C by RNAi sensitized cells to docetaxel and enhanced its antimitotic effects. Treatment with a PLK1 inhibitor (BI2536) also sensitized cells to IPI-504, indicating that combination effects may be broadly applicable to other classes of mitotic inhibitors. Our data provide a preclinical rationale for testing the combination of IPI-504 and docetaxel in NSCLC. PMID- 25542033 TI - Genome-wide comparisons of phylogenetic similarities between partial genomic regions and the full-length genome in Hepatitis E virus genotyping. AB - Besides the complete genome, different partial genomic sequences of Hepatitis E virus (HEV) have been used in genotyping studies, making it difficult to compare the results based on them. No commonly agreed partial region for HEV genotyping has been determined. In this study, we used a statistical method to evaluate the phylogenetic performance of each partial genomic sequence from a genome wide, by comparisons of evolutionary distances between genomic regions and the full-length genomes of 101 HEV isolates to identify short genomic regions that can reproduce HEV genotype assignments based on full-length genomes. Several genomic regions, especially one genomic region at the 3'-terminal of the papain-like cysteine protease domain, were detected to have relatively high phylogenetic correlations with the full-length genome. Phylogenetic analyses confirmed the identical performances between these regions and the full-length genome in genotyping, in which the HEV isolates involved could be divided into reasonable genotypes. This analysis may be of value in developing a partial sequence-based consensus classification of HEV species. PMID- 25542034 TI - Stochastic process underlying emergent recognition of visual objects hidden in degraded images. AB - When a degraded two-tone image such as a "Mooney" image is seen for the first time, it is unrecognizable in the initial seconds. The recognition of such an image is facilitated by giving prior information on the object, which is known as top-down facilitation and has been intensively studied. Even in the absence of any prior information, however, we experience sudden perception of the emergence of a salient object after continued observation of the image, whose processes remain poorly understood. This emergent recognition is characterized by a comparatively long reaction time ranging from seconds to tens of seconds. In this study, to explore this time-consuming process of emergent recognition, we investigated the properties of the reaction times for recognition of degraded images of various objects. The results show that the time-consuming component of the reaction times follows a specific exponential function related to levels of image degradation and subject's capability. Because generally an exponential time is required for multiple stochastic events to co-occur, we constructed a descriptive mathematical model inspired by the neurophysiological idea of combination coding of visual objects. Our model assumed that the coincidence of stochastic events complement the information loss of a degraded image leading to the recognition of its hidden object, which could successfully explain the experimental results. Furthermore, to see whether the present results are specific to the task of emergent recognition, we also conducted a comparison experiment with the task of perceptual decision making of degraded images, which is well known to be modeled by the stochastic diffusion process. The results indicate that the exponential dependence on the level of image degradation is specific to emergent recognition. The present study suggests that emergent recognition is caused by the underlying stochastic process which is based on the coincidence of multiple stochastic events. PMID- 25542035 TI - High rates of HIV seroconversion in pregnant women and low reported levels of HIV testing among male partners in Southern Mozambique: results from a mixed methods study. AB - INTRODUCTION: Prevention of acute HIV infections in pregnancy is required to achieve elimination of pediatric HIV. Identification and support for HIV negative pregnant women and their partners, particularly serodiscordant couples, are critical. A mixed method study done in Southern Mozambique estimated HIV incidence during pregnancy, associated risk factors and factors influencing partner's HIV testing. METHODS: Between April 2008 and November 2011, a prospective cohort of 1230 HIV negative pregnant women was followed during pregnancy. A structured questionnaire, HIV testing, and collection of dried blood spots were done at 2-3 scheduled visits. HIV incidence rates were calculated by repeat HIV testing and risk factors assessed by Poisson regression. A qualitative study including 37 individual interviews with men, women, and nurses and 11 focus group discussions (n = 94) with men, women and grandmothers explored motivators and barriers to uptake of male HIV testing. RESULTS: HIV incidence rate was estimated at 4.28/100 women-years (95%CI: 2.33-7.16). Significant risk factors for HIV acquisition were early sexual debut (RR 3.79, 95%CI: 1.04-13.78, p = 0.04) and living in Maputo Province (RR 4.35, 95%CI: 0.97-19.45, p = 0.05). Nineteen percent of women reported that their partner had tested for HIV (93% knew the result with 8/213 indicating an HIV positive partner), 56% said their partner had not tested and 19% did not know their partner test status. Of the 14 seroconversions, only one reported being in a serodiscordant relationship. Fear of discrimination or stigma was reported as a key barrier to male HIV testing, while knowing the importance of getting tested and receiving care was the main motivator. CONCLUSIONS: HIV incidence during pregnancy is high in Southern Mozambique, but knowledge of partners' HIV status remains low. Knowledge of both partners' HIV status is critical for maximal effectiveness of prevention and treatment services to reach elimination of pediatric HIV/AIDS. PMID- 25542037 TI - A new exponential ratio-type estimator with linear combination of two auxiliary variables. AB - In sample surveys, it is usual to make use of auxiliary information to increase the precision of estimators. We propose a new exponential ratio-type estimator of a finite population mean using linear combination of two auxiliary variables and obtain mean square error (MSE) equation for proposed estimator. We find theoretical conditions that make proposed estimator more efficient than traditional multivariate ratio estimator using information of two auxiliary variables, the estimator of Bahl and Tuteja and the estimator proposed by Abu Dayeh et al. In addition, we support these theoretical results with the aid of two numerical examples. PMID- 25542036 TI - Exhaled breath analysis using electronic nose in cystic fibrosis and primary ciliary dyskinesia patients with chronic pulmonary infections. AB - The current diagnostic work-up and monitoring of pulmonary infections may be perceived as invasive, is time consuming and expensive. In this explorative study, we investigated whether or not a non-invasive exhaled breath analysis using an electronic nose would discriminate between cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) with or without various well characterized chronic pulmonary infections. We recruited 64 patients with CF and 21 with PCD based on known chronic infection status. 21 healthy volunteers served as controls. An electronic nose was employed to analyze exhaled breath samples. Principal component reduction and discriminant analysis were used to construct internally cross-validated receiver operator characteristic (ROC) curves. Breath profiles of CF and PCD patients differed significantly from healthy controls p = 0.001 and p = 0.005, respectively. Profiles of CF patients having a chronic P. aeruginosa infection differed significantly from to non-chronically infected CF patients p = 0.044. We confirmed the previously established discriminative power of exhaled breath analysis in separation between healthy subjects and patients with CF or PCD. Furthermore, this method significantly discriminates CF patients suffering from a chronic pulmonary P. aeruginosa (PA) infection from CF patients without a chronic pulmonary infection. Further studies are needed for verification and to investigate the role of electronic nose technology in the very early diagnostic workup of pulmonary infections before the establishment of a chronic infection. PMID- 25542038 TI - An integrative analysis of PIK3CA mutation, PTEN, and INPP4B expression in terms of trastuzumab efficacy in HER2-positive breast cancer. AB - The phosphoinositide-3-kinase (PI3K) pathway is commonly deregulated in breast cancer through several mechanisms, including PIK3CA mutation and loss of phosphatase and tensin homolog (PTEN) and inositol polyphosphate 4-phosphatase-II (INPP4B). We aimed to evaluate the predictive relevance of these biomarkers to trastuzumab efficacy in HER2-positive disease. We evaluated the effect of trastuzumab in 43 breast cancer patients with HER2-overexpression who received neoadjuvant treatment. PIK3CA mutation was examined by direct sequencing and digital PCR assay, and PIK3CA copy number was assessed by digital PCR assay of pretreatment tissues. PTEN, pAkt, and INPP4B were assessed by immunohistochemistry. Direct sequencing detected mutant DNA in 21% of all patients, but the incidence increased to 49% using digital PCR. The pathological complete response (pCR) rate in patients with PIK3CA mutations was 29% compared with 67% for those without PIK3CA mutations (P = 0.093), when the mutation was defined as positive if the mutant proportion was more than 10% of total genetic content by digital PCR. Low PTEN expression was associated with less pCR compared to high expression (33% versus 72%, P = 0.034). There were no significant associations of PIK3CA copy number, pAKt, or INPP4B with trastuzumab efficacy. In multivariate analysis, activation of the PI3K pathway due to either PIK3CA mutation or low PTEN were related to poorer response to trastuzumab (OR of predictive pCR was 0.11, 95%CI; 0.03-0.48). In conclusion, activating the PI3K pathway is associated with low pCR to trastuzumab-based treatment in HER2 positive breast cancer. Combined analysis of PIK3CA mutation and PTEN expression may serve as critical indicators to identify patients unlikely to respond to trastuzumab. PMID- 25542040 TI - Paul Drude's prediction of nonreciprocal mutual inductance for Tesla transformers. AB - Inductors, transmission lines, and Tesla transformers have been modeled with lumped-element equivalent circuits for over a century. In a well-known paper from 1904, Paul Drude predicts that the mutual inductance for an unloaded Tesla transformer should be nonreciprocal. This historical curiosity is mostly forgotten today, perhaps because it appears incorrect. However, Drude's prediction is shown to be correct for the conditions treated, demonstrating the importance of constraints in deriving equivalent circuits for distributed systems. The predicted nonreciprocity is not fundamental, but instead is an artifact of the misrepresentation of energy by an equivalent circuit. The application to modern equivalent circuits is discussed. PMID- 25542039 TI - Effectiveness of a worksite social & physical environment intervention on need for recovery, physical activity and relaxation; results of a randomized controlled trial. AB - OBJECTIVE: To investigate the effectiveness of a worksite social and physical environment intervention on need for recovery (i.e., early symptoms of work related mental and physical fatigue), physical activity and relaxation. Also, the effectiveness of the separate interventions was investigated. METHODS: In this 2 * 2 factorial design study, 412 office employees from a financial service provider participated. Participants were allocated to the combined social and physical intervention, to the social intervention only, to the physical intervention only or to the control group. The primary outcome measure was need for recovery. Secondary outcomes were work-related stress (i.e., exhaustion, detachment and relaxation), small breaks, physical activity (i.e., stair climbing, active commuting, sport activities, light/moderate/vigorous physical activity) and sedentary behavior. Outcomes were measured by questionnaires at baseline, 6 and 12 months follow-up. Multilevel analyses were performed to investigate the effects of the three interventions. RESULTS: In all intervention groups, a non-significant reduction was found in need for recovery. In the combined intervention (n = 92), exhaustion and vigorous physical activities decreased significantly, and small breaks at work and active commuting increased significantly compared to the control group. The social intervention (n = 118) showed a significant reduction in exhaustion, sedentary behavior at work and a significant increase in small breaks at work and leisure activities. In the physical intervention (n = 96), stair climbing at work and active commuting significantly increased, and sedentary behavior at work decreased significantly compared to the control group. CONCLUSION: None of the interventions was effective in improving the need for recovery. It is recommended to implement the social and physical intervention among a population with higher baseline values of need for recovery. Furthermore, the intervention itself could be improved by increasing the intensity of the intervention (for example weekly GMI-sessions), providing physical activity opportunities and exercise schemes, and by more drastic environment interventions (restructuring entire department floor). TRIAL REGISTRATION: Nederlands Trial Register NTR2553. PMID- 25542042 TI - A multicomponent approach to identify predictors of hospital outcomes in older in patients: a multicentre, observational study. AB - BACKGROUND: The identification of older patients at risk of poor hospital outcomes (e.g. longer hospital stay, in-hospital mortality, and institutionalisation) is important to provide an effective healthcare service. OBJECTIVE: To identify factors related to older patients' clinical, nutritional, functional and socio-demographic profiles at admission to an acute care ward that can predict poor hospital outcomes. DESIGN AND SETTING: The CRiteria to assess appropriate Medication use among Elderly complex patients project was a multicentre, observational study performed in geriatric and internal medicine acute care wards of seven Italian hospitals. SUBJECTS: One thousand one hundred twenty-three consecutively admitted patients aged 65 years or older. METHODS: Hospital outcomes were length of stay, in-hospital mortality, and institutionalisation. RESULTS: Mean age of participants was 81 years, 56% were women. Median length of stay was 10 (7-14) days, 41 patients died during hospital stay and 37 were newly institutionalised. Number of drugs before admission, metastasized cancer, renal failure or dialysis, infection, falls at home during the last year, pain, and walking speed were independent predictors of LoS. Total dependency in activities of daily living and inability to perform grip strength test were independent predictors of in-hospital mortality. Malnutrition and total dependency in activities of daily living were independent predictors of institutionalisation. CONCLUSIONS: Our results confirm that not only diseases, but also multifaceted aspects of ageing such as physical function and malnutrition are strong predictors of hospital outcomes and suggest that these variables should be systematically recorded. PMID- 25542041 TI - Incomplete radiofrequency ablation enhances invasiveness and metastasis of residual cancer of hepatocellular carcinoma cell HCCLM3 via activating beta catenin signaling. AB - BACKGROUND: Radiofrequency ablation (RFA) is one of the curative therapies for hepatocellular carcinoma (HCC), however, accelerated progression of residual HCC after incomplete RFA has been reported more frequently. The underlying molecular mechanism of this phenomenon remains to be elucidated. In this study, we used an incomplete RFA orthotopic HCC nude mouse model to study the invasive and metastatic potential of residual cancer as well as the correlated mechanism. METHODS: The incomplete RFA orthotopic nude mouse models were established using high metastatic potential HCC cell line HCCLM3 and low metastatic potential HCC cell line HepG2, respectively. The changes in cellular morphology, motility, metastasis and epithelial-mesenchymal transition (EMT), and HCC cell molecular markers after in vitro and in vivo incomplete RFA intervention were observed. RESULTS: Pulmonary and intraperitoneal metastasis were observed in an in vivo study. The underlying pro-invasive mechanism of incomplete RFA appeared to be associated with promoting EMT, including down-regulation of E-cadherin and up regulation of N-cadherin and vimentin. These results were in accordance with the in vitro response of HCC cells to heat intervention. Further studies demonstrated that beta-catenin was a pivotal factor during this course and blocking beta catenin reduced metastasis and EMT phenotype changes in heat-treated HCCLM3 cells in vitro. CONCLUSION: Incomplete RFA enhanced the invasive and metastatic potential of residual cancer, accompanying with EMT-like phenotype changes by activating beta-catenin signaling in HCCLM3 cells. PMID- 25542043 TI - Central nervous system PET-CT imaging reveals regional impairments in pediatric patients with Wolfram syndrome. AB - Wolfram syndrome (WFS) is inherited as an autosomal recessive disease with main clinical features of diabetes mellitus, optic atrophy, diabetes insipidus and deafness. However, various neurological defects may also be detected. The aim of this study was to evaluate aspects of brain structure and function using PET-CT (positron emission tomography and computed tomography) and MRI (magnetic resonance imaging) in pediatric patients with WFS. Regional changes in brain glucose metabolism were measured using standardized uptake values (SUVs) based on images of (18F) fluorodeoxyglucose (FDG) uptake in 7 WFS patients aged 10.1-16.0 years (mean 12.9+/-2.4) and in 20 healthy children aged 3-17.9 years (mean 12.8+/ 4.1). In all patients the diagnosis of WFS was confirmed by DNA sequencing of the WFS1 gene. Hierarchical clustering showed remarkable similarities of glucose uptake patterns among WFS patients and their differences from the control group. SUV data were subsequently standardized for age groups <13 years old and>13 years old to account for developmental differences. Reduced SUVs in WFS patients as compared to the control group for the bilateral brain regions such as occipital lobe (-1.24+/-1.20 vs. -0.13+/-1.05; p = 0.028) and cerebellum (-1.11+/-0.69 vs. 0.204+/-1.00; p = 0.036) were observed and the same tendency for cingulate ( 1.13+/-1.05 vs. -0.15+/-1.12; p = 0.056), temporal lobe (-1.10+/-0.98 vs. -0.15+/ 1.10; p = 0.057), parietal lobe (-1.06+/-1.20 vs. -0.08+/-1.08; p = 0.058), central region (-1.01+/-1.04 vs. -0.09+/-1.06; p = 0.060), basal ganglia (-1.05+/ 0.74 vs. -0.20+/-1.07; p = 0.066) and mesial temporal lobe (-1.06+/-0.82 vs. 0.26+/-1.08; p = 0.087) was also noticed. After adjusting for multiple hypothesis testing, the differences in glucose uptake were non-significant. For the first time, regional differences in brain glucose metabolism among patients with WFS were shown using PET-CT imaging. PMID- 25542044 TI - Copro prevalence and estimated risk of Entamoeba histolytica in Diarrheic patients at Beni-Suef, Egypt. AB - Amoebiasis diagnosis is usually based on microscopy that cannot differentiate pathogenic E. histolytica from morphologically identical non-pathogenic species. 194 fecal samples were collected from diarrheic &/or dysenteric patients and examined for Entamoeba complex microscopically, E. histolytica/E. dispar coproantigen using ICT and E. histolytica coproantigen using Tech lab E. histolytica II ELISA test. Entamoeba complex trophozoites/cysts, E. histolytica/E. dispar coproantigen and E. histolytica coproantigen were detected in 22.2, 14.4 and 3.6 % of samples, respectively. Microscopy and ICT method had limited sensitivity with poor PPV (9.3 and 7.1 %, respectively) and both slightly agree with ELISA test. The prevalence of E. histolytica was low (3.6 %) in studied individuals and was 14 times lower than non-pathogenic amoebae. E. histolytica detection studied individuals was positively associated with mucoid and bloody stool, which makes them disease predictors. E. histolytica fecal ELISA assay for E. histolytica detection surpassed microscopy and E. histolytica/E. dispar ICT assay. This has highlighted the need for practical non-microscopic detection methods that can differentiate between amoeba infections to avoid unnecessary and possibly harmful therapies and to determine the true prevalence and epidemiology of E. histolytica. PMID- 25542045 TI - Carbapenemase-producing Enterobacteriaceae: the end of the antibiotic era? AB - Infections produced by carbapenemase-producing Enterobacteriaceae (CPE) are increasing worldwide. Therapeutic options are scarce because many of these bacteria are resistant to other antimicrobial groups. Furthermore, the dissemination of some carbapenemases and CPE is occurring rapidly. Health care authorities should be aware of the relevance of this problem, and coordinated surveillance and control strategies at all levels of the health system should be undertaken. The Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) and The Spanish Network for Research on Infectious Diseases (REIPI, Institute of Health Carlos III, Ministry of Health, Spain) has selected a panel of Spanish experts on infections caused by CPE from the areas of clinical microbiology, infectious diseases and public health to review and discuss the most controversial issues regarding this increasing threat. PMID- 25542046 TI - Carbapenemases in Enterobacteriaceae: types and molecular epidemiology. AB - The most important mechanism of carbapenem resistance in Enterobacteriaceae is the production of carbapenemases, although resistance can also result from the synergistic activity between AmpC-type or (to a lesser extent) extended-spectrum beta-lactamases combined with decreased outer membrane permeability. Three major molecular classes of carbapenemases are recognized: A, B and D. Classes A and D are serine-beta-lactamases, whereas class B are metallo-beta-lactamases (their hydrolytic activity depends on the presence of zinc). In addition to carbapenems, carbapenemases also hydrolyze other beta-lactams, but the concrete substrate profile depends on the enzyme type. In general terms, class A enzymes are to some extent inhibited by clavulanic acid, and class B enzymes do not affect monobactams and are inhibited by zinc chelators. Given Enterobacteriaceae producing carbapenemases usually also contain gene coding for other mechanisms of resistance to beta-lactams, it is not unusual for the organisms to present complex beta-lactam resistance phenotypes. Additionally, these organisms frequently contain other genes that confer resistance to quinolones, aminoglycosides, tetracyclines, sulphonamides and other families of antimicrobial agents, which cause multiresistance or even panresistance. Currently, the most important type of class A carbapenemases are KPC enzymes, whereas VIM, IMP and (particularly) NDM in class B and OXA-48 (and related) in class D are the more relevant enzymes. Whereas some enzymes are encoded by chromosomal genes, most carbapenemases are plasmid-mediated (with genes frequently located in integrons), which favors the dissemination of the enzymes. Detailed information of the genetic platforms and the context of the genes coding for the most relevant enzymes will be presented in this review. PMID- 25542047 TI - Epidemiology of infections caused by carbapenemase-producing Enterobacteriaceae: reservoirs and transmission mechanisms. AB - The dissemination of carbapenemase-producing Enterobacteriaceae has occurred very quickly and has crossed borders rapidly between countries and continents. In some areas, it has exceeded the holding capacity of health systems, reaching epidemic proportions. This form of dissemination has not been the same for all enzymes, with KPC, NDM and OXA-48 genes having a greater ability to spread. These enzymes have primarily been spread clonally in the case of KPC-producing Klebsiella pneumoniae from the initial epicenter located in New York, with a very small number of strains causing outbreaks. For NDM and OXA- 48, these resistance determinants have been vehiculized by clones with a high transmission capacity; however, simultaneous horizontal transmission is also playing an important role. The most important identified reservoirs are colonized or infected individuals from endemic areas or centers with outbreaks, but the contaminated goods from these endemic areas also play a part. An international effort is needed to control the spread of these multiresistant pathogens. PMID- 25542048 TI - Evolution of carbapenemase-producing Enterobacteriaceae at the global and national level: what should be expected in the future? AB - In recent years, Enterobacteriaceae isolates have increased their potential to become highly drug resistant by acquiring resistance to carbapenems, primarily due to the production of acquired carbapenemases. The carbapenemases detected in Enterobacteriaceae are largely of the KPC, VIM, NDM, IMP and OXA-48 types. Although the epidemiological origin and geographic distribution of carbapenemases are clearly different, they all first appeared in the late 20th Century. Only a decade later, these enzymes have already become established and have expanded globally. An important epidemiological change has occurred in Spain in recent years, characterized by a rapid increase in the number of cases of carbapenemase producing Enterobacteriaceae (CPE), causing both nosocomial outbreaks and single infections. The impact of CPE in Spain is primarily due to OXA-48-producing and VIM-1-producing Klebsiella pneumoniae isolates, although other species such as Escherichia coli and Enterobacter cloacae are also increasing. The emergence of CPE as a cause of community-onset infections is a matter of great concern. Taking into account recent experience, and considering the fact that increasing numbers of patients are becoming infected by CPE and reservoirs of carbapenemases are growing globally, the trend of the CPE epidemic points toward a rise in its incidence. To prevent a massive CPE pandemic, a well-coordinated response from all health professionals and national and supranational authorities is clearly needed. PMID- 25542049 TI - Detection of carbapenemase-producing Enterobacteriaceae in various scenarios and health settings. AB - Detection of carbapenemase-producing Enterobacteriaceae (CPE) is an important task at microbiology laboratories in hospitals. As the prevalence of CPE is increasing worldwide, the implementation of phenotypically based screening as well as confirmatory procedures to detect CPE are important for microbiologists. In addition to detection of carbapenem hydrolysis, the inhibition of activity against a carbapenem in the presence of several inhibitor compounds specific to class A, B, or class C beta-lactamases is a useful method to confirm the presence of carbapenemases in bacterial isolates. There is also a proteomic approach that compares the MALDI-TOF spectrum generated by the intact carbapenem (non hydrolyzed) with that obtained after hydrolysis of the beta-lactam ring by beta lactamase to reveal the presence of carbapenemases in bacterial isolates. Proteomic methods will probably be more frequently implemented in laboratories in the near future. Finally, molecular methods to directly or indirectly detect the presence of a carbapenemase genes are increasingly being used in microbiology laboratories. One of the main advantages of these methods is their speed, and also that they can be used directly with the clinical sample without the need for an isolated bacterial colony. Multiplex PCR, real-time PCR, DNA microarrays and pyrosequencing are some examples of molecular-based tests. Their main disadvantage is their cost, although prices are going down as the range of services increases. Surveillance of carriers is also an important task for infection control purposes. In this case, commercially available chromogenic medium supplemented with low carbapenem concentrations has shown an excellent ability to detect CPE. Moreover, molecular methods to detect specific carbapenemase genes directly from rectal swabs, stools, or other colonization sources have had excellent results. PMID- 25542050 TI - Breakpoints for carbapenemase-producing Enterobacteriaceae: is the problem solved? AB - The imipenem and meropenem breakpoints for Enterobacteriaceae established by the Clinical and Laboratory Standards Institute (CLSI) are somewhat lower than those established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), but are identical for ertapenem and doripenem. The differences are primarily due to the various pharmacokinetic/pharmacodynamic (PK/PD) approaches used to define these breakpoints. Both approaches use the Monte Carlo simulation with a probability of target attainment (PTA) for reaching the PD target of free drug concentration above the minimum inhibitory concentration (MIC) at least 40% of the time (~40%fT >MIC). EUCAST uses PTA mean values with confidence intervals (CIs) of 95% and 99%, whereas the CI used by CLSI is 90%. In addition, CLSI uses an "inflated variance" that takes into account the variability of PK parameters in various types of patients, particularly those who are critically ill. By employing this approach, the susceptible CLSI breakpoint captures a higher number of carbapenemase-producing Enterobacteriaceae (CPE) than EUCAST. EUCAST, however, has recently defined cut-off values for screening CPE. Both committees recommend reporting carbapenem susceptibility results "as tested," demonstrating carbapenemase production only for epidemiological purposes and infection control. New clinical data could potentially modify this recommendation because carbapenemase production also influences specific treatment guidance concerning carbapenems in combination with other antimicrobials in infections due to CPE. This advice should not be followed when imipenem or meropenem MICs are >8mg/L, which is coincident with the EUCAST resistant breakpoints for these carbapenems. PMID- 25542051 TI - Infections caused by carbapenemase-producing Enterobacteriaceae: risk factors, clinical features and prognosis. AB - Infections caused by carbapenem-producing Enterobacteriaceae (CPE) can present as several infectious syndromes, but they primarily present as respiratory, urinary and blood stream infections (primary or catheter-related) that are usually found as nosocomial or healthcare-associated infections. The risk of CPE infection is influenced by individual factors, such as the length of the hospital stay and their exposure to invasive procedures and/or to antimicrobials. Of note, exposure to several antimicrobials, not only carbapenems, has been linked to CPE colonization; the duration of antibiotic exposure is one of the primary drivers of CPE acquisition. Individual risk factors must be considered jointly with the local epidemiology of these microorganisms in healthcare institutions. Overall, these infections have a high associated mortality. Mortality is influenced by host factors (e.g., age, comorbidity and immune deficiency), infection-related variables (e.g., type and severity of the infection) and treatment-related factors such as the delay in the initiation of appropriate antimicrobial therapy and the use or monotherapy or combined antimicrobial therapy. Gaining knowledge concerning the epidemiology, clinical features and prognostic features of CPE infection could be useful for improving infection prevention and for the management of patients with infections caused by these microorganisms. PMID- 25542052 TI - Treatment of infections caused by carbapenemase-producing Enterobacteriaceae. AB - Treatment of infections caused by carbapenemase-producing Enterobacteriaceae (CPE) is currently one of the most important challenges of infectious diseases. The available information is based on in vitro studies, some animal model data and a few case studies and retrospective cohorts; appropriate data are lacking or are very scarce for some old antibiotics that are still occasionally used. Because of the heterogeneity in clinical situations, in specific carbapenemases and in the susceptibility of isolates, individualized treatment decisions must usually be made. Here we review the different antibiotics that might be useful for treating infections caused by CPE. PMID- 25542053 TI - Future alternatives for the treatment of infections caused by carbapenemase producing Enterobacteriaceae: what is in the pipeline? AB - The emergence and spread of carbapenemase-producing Enterobacteriaceae is an important and very concerning problem. There is an urgent need of new antibimicrobials for treating these infections. Currently there are some options in the pipeline. Several new beta-lactamase and carbapenemase inhibitors as avibactam and MK-7655, combined with old or new betalactams are a very interesting option. Some combinations as ceftazidime-avibactam are in the late stages of clinical development and could reach the market in the next years. New aminoglycosides as plazomicin, tetracycline derivates as eravacycline, and several other new molecules as monosulfactams are currently in different stages of development. PMID- 25542054 TI - Control strategies for carbapenemase-producing Enterobacteriaceae at different levels of the healthcare system. AB - There has been a rapid increase in recent years in the incidence of infection and colonization by carbapenemase-producing Enterobacteriaceae (CPE). A number of clusters and outbreaks have been reported, some of which have been contained, providing evidence that these clusters and outbreaks can be managed effectively when the appropriate control measures are implemented. This review outlines strategies recommended to control CPE dissemination both at the healthcare facility level (acute and long-term care) and from the public health point of view. A dedicated prepared plan should be required to prevent the spread of CPE at the hospital level. At the front line, activities should include management of patients at admission and new cases, active surveillance culturing and definition of high-risk groups. High compliance with standard precautions for all patients and full or modified contact precautions for defined categories of patients should be implemented. Long-term care facilities are areas where dissemination can also take place but more importantly they can become a reservoir as patients are admitted and released to other Health care facilities. From the public health point of view, surveillance must be tailored to identify regional spread and interfacility transmission to prevent further dissemination. Finally, a comprehensive set of activities at various levels is necessary to prevent further spread of these bacteria in the community. PMID- 25542055 TI - [Drugs news]. PMID- 25542056 TI - [Epidemiology of neonatal surgical emergencies in Ouagadougou]. AB - OBJECTIVE: The purpose of this study was to determine the rate of neonatal surgery emergencies and to highlight the main causes and difficulties related to better handling of these emergencies. PATIENTS AND METHODS: We conducted a 1-year descriptive prospective study from September 2009 to September 2010 based on 102 cases collected. At admission, we studied the patients' age, the pathologies encountered, the related malformations, the terms for better management, and prognosis. FINDINGS: In 1 year, we registered 102 cases of neonatal surgical emergencies affecting the digestive tract (63.7%), the anterior side of the abdomen (24.5%), trauma (6.7%), and tumors (2%). Males comprised 60.8% of the cases. The sex-ratio was 1.55. The frequency of such cases was 3.94%. The average age of patients was 5 days with the 0- to 5-day-old age group presenting most frequently. The average hospitalization lasted 2.75 days and the admission method was the reference in 75.5%. Congenital pathology accounted for 95.5% of cases with anorectal malformations (ARM) (35; 95%) and omphaloceles (28.1%). Hirschsprung disease was the main cause of bowel obstruction other than ARM (50%). The average time to surgery was about 2.54 days. The overall mortality of neonatal surgical emergencies was 30.3% and postoperative mortality 32.35%. The late consultation, poverty, a shortage of qualified staff, prematurity, low birth weight, congenital disease, and related malformations were the leading factors of a poor prognosis. Acquisition of effective technical means, staff training, measures to combat poverty, and better prenatal care would improve the management of neonatal surgical emergencies. CONCLUSION: Neonatal surgical emergencies include conditions that require immediate and adequate support. The continuous training of healthcare workers at all levels in the detection of neonatal emergencies and equipping healthcare facilities are an absolute necessity to provide better management and reduce the mortality rate. PMID- 25542057 TI - PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. AB - BACKGROUND: We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation. METHODS: In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease. FINDINGS: 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached). INTERPRETATION: Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation. PMID- 25542059 TI - beta-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study. AB - Most adult patients receiving extracorporeal membrane oxygenation (ECMO) require antibiotic therapy, however the pharmacokinetics of beta-lactams have not been well studied in these conditions. In this study, data from all patients receiving ECMO support and meropenem (MEM) or piperacillin/tazobactam (TZP) were reviewed. Drug concentrations were measured 2h after the start of a 30-min infusion and just before the subsequent dose. Therapeutic drug monitoring (TDM) results in ECMO patients were matched with those in non-ECMO patients for (i) drug regimen, (ii) renal function, (iii) total body weight, (iv) severity of organ dysfunction and (v) age. Drug concentrations were considered adequate if they remained 4-8* the clinical MIC breakpoint for Pseudomonas aeruginosa for 50% (TZP) or 40% (MEM) of the dosing interval. A total of 41 TDM results (27 MEM; 14 TZP) were obtained in 26 ECMO patients, with 41 matched controls. There were no significant differences in serum concentrations or pharmacokinetic parameters between ECMO and non-ECMO patients, including Vd [0.38 (0.27-0.68) vs. 0.46 (0.33-0.79)L/kg; P=0.37], half-life [2.6 (1.8-4.4) vs. 2.9 (1.7-3.7)h; P=0.96] and clearance [132 (66-200) vs. 141 (93-197)mL/min; P=0.52]. The proportion of insufficient (13/41 vs. 12/41), adequate (15/41 vs. 19/41) and excessive (13/41 vs. 10/41) drug concentrations was similar in ECMO and non-ECMO patients. Achievement of target concentrations of these beta-lactams was poor in ECMO and non-ECMO patients. The influence of ECMO on MEM and TZP pharmacokinetics does not appear to be significant. PMID- 25542060 TI - Identification of a Pseudomonas aeruginosa co-producing NDM-1, VIM-5 and VIM-6 metallo-beta-lactamases in Denmark using whole-genome sequencing. PMID- 25542061 TI - The utility of remote supervision with feedback as a method to deliver high volume critical care ultrasound training. AB - OBJECTIVE: Despite international agreement that critical care ultrasound (CCUS) is an essential skill for intensive care providers, CCUS training and dissemination is complicated by a shortage of educators. Newer technology now permits remote, offline supervision as a method of overseeing trainees undergoing CCUS instruction. DESIGN: This was a retrospective, descriptive report of a CCUS curriculum and its output of clinical ultrasound examinations at an academic critical care training program over a 1-year period. The curriculum consisted of typical didactic and hands-on training as well as wireless archiving of examinations with remote, offline oversight and feedback provided by the director using ultrasound management software. SETTING: A tertiary-care, academic critical care training program. MEASUREMENTS AND MAIN RESULTS: Twenty-nine trainees acquired and archived a total of 2531 CCUS studies (average 76 studies per trainee) for 1 year. Of these, 1807 (71%) examinations had a typewritten report generated by the operator, and 1788 of these examinations were overread and subjected to feedback from the curriculum director. The predominant application of CCUS was for cardiac (62%), thoracic (32%), and abdominal (5%) assessment. CONCLUSIONS: This study suggests that the use of wireless archiving and offline oversight in a CCUS curriculum is a feasible and highly-efficient strategy permitting a small number of faculty to supervise a large number of trainees. This approach provides an efficient method to address unmet demand for CCUS education. PMID- 25542058 TI - Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative. AB - BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. PMID- 25542063 TI - Expression of alpha1-acid glycoprotein and lipopolysaccharide binding protein in visceral and subcutaneous adipose tissue of dairy cattle. AB - Adipose tissue is an endocrine compartment that plays an important role in immune defence by producing and releasing a wide range of proteins, including acute phase proteins (APPs). The liver is the main organ of APP synthesis, although extrahepatic production has also been reported. In the present study, expression of two APPs in dairy cattle, lipopolysaccharide binding protein (LBP) and alpha1 acid glycoprotein (AGP), was determined in four visceral (pericardial, mesenteric, omental and retroperitoneal) and three subcutaneous (withers, tail head and sternum) adipose tissue depots. mRNA expression was evaluated using qualitative and quantitative PCR, protein profiles were assessed by Western blot analysis and cellular localisation was determined by immunohistochemistry. The presence of LBP and AGP was demonstrated at mRNA and protein levels in all seven adipose tissue depots. Expression of AGP and LBP suggests that they may have roles as local and systemic inflammatory adipokines. PMID- 25542062 TI - Fracture pattern characteristics and associated injuries of high-energy, large fragment, partial articular radial head fractures: a preliminary imaging analysis. AB - BACKGROUND: High-energy radial head injuries often present with a large partial articular displaced fragment with any number of surrounding injuries. The objective of the study was to determine the characteristics of large fragment, partial articular radial head fractures and determine any significant correlation with specific injury patterns. MATERIALS AND METHODS: Patients sustaining a radial head fracture from 2002-2010 were screened for participation. Twenty-five patients with documented partial articular radial head fractures were identified and completed the study. Our main outcome measurement was computed tomography (CT)-based analysis of the radial head fracture. The location of the radial head fracture fragment was evaluated from the axial CT scan in relation to the radial tuberosity used as a reference point. The fragment was characterized by location as anteromedial (AM), anterolateral (AL), posteromedial (PM) or posterolateral (PL) with the tuberosity referenced as straight posterior. All measurements were performed by a blinded, third party hand and upper extremity fellowship trained orthopedic surgeon. Fracture pattern, location, and size were then correlated with possible associated injuries obtained from prospective clinical data. RESULTS: The radial head fracture fragments were most commonly within the AL quadrant (16/25; 64 %). Seven fracture fragments were in the AM quadrant and two in the PM quadrant. The fragment size averaged 42.5 % of the articular surface and spanned an average angle of 134.4( degrees ). Significant differences were noted between AM (49.5 %) and AL (40.3 %) fracture fragment size with the AM fragments being larger. Seventeen cases had associated coronoid fractures. Of the total 25 cases, 13 had fracture dislocations while 12 remained reduced following the injury. The rate of dislocation was highest in radial head fractures that involved the AM quadrant (6/7; 85.7 %) compared to the AL quadrant (7/16; 43.7 %). No dislocations were observed with PM fragments. Ten of the 13 (78 %) fracture dislocations had associated lateral collateral ligament (LCL)/medial collateral ligament tear. The most common associated injuries were coronoid fractures (68 %), dislocations (52 %), and LCL tears (44 %). CONCLUSION: The most common location for partial articular radial head fractures is the AL quadrant. The rate of elbow dislocation was highest in fractures involving the AM quadrant. Cases with large fragment, partial articular radial head fractures should undergo a CT scan; if associated with >30 % or >120( degrees ) fracture arc, then the patient should be assessed closely for obvious or occult instability. These are key associations that hopefully greatly aid in the consultation and preoperative planning settings. LEVEL OF EVIDENCE: Diagnostic III. PMID- 25542064 TI - Clinical and antiviral effect of a single oral dose of famciclovir administered to cats at intake to a shelter. AB - Although famciclovir is efficacious in feline herpesvirus type 1 (FHV-1)-infected cats, effects of a single dose early in disease course have not been reported. In this two part, randomized, masked, placebo controlled study, cats received a single dose of 125 mg famciclovir (n = 43) or placebo (n = 43; pilot study), or 500 mg famciclovir (n = 41) or placebo (n = 40; clinical trial) on entering a shelter. FHV-1 PCR testing was performed, bodyweight and food intake were recorded, and signs of respiratory disease were scored prior to and 7 days following treatment. FHV-1 DNA was detected in 40% of cats in both parts at study entry. In the pilot study, ocular and nasal discharge scores increased from days 1 to 7 in famciclovir and placebo treated cats. Sneezing scores increased and bodyweight decreased in famciclovir-treated cats. The proportion of cats in which FHV-1 DNA was detected increased over time in all cats in the pilot study. In the clinical trial, food intake and median clinical disease scores for nasal discharge and sneezing increased from days 1 to 7 in both groups and demeanor scores worsened in famciclovir-treated cats. The proportion of cats shedding FHV 1 DNA was greater on day 7 than on day 1 in cats receiving 500 mg famciclovir. A single dose of famciclovir (125 or 500 mg) administered at shelter intake was not efficacious in a feline population in which 40% were already shedding FHV-1. PMID- 25542066 TI - Unlocking the presequence import pathway. AB - Translocation of presequence-containing precursor proteins into the inner mitochondrial membrane and matrix is an essential process that is facilitated by the translocase of the outer membrane (TOM) together with the presequence translocase of the inner membrane (TIM23). After initial recognition by receptors of the TOM complex followed by transport across the outer membrane, the precursor emerges into the intermembrane space (IMS). Recognition of the presequence by Tim50 triggers rearrangements of the presequence translocase, priming it for inner membrane translocation. Subsequently, the precursor can be released into the membrane or translocated into the mitochondrial matrix aided by the import motor. This heat-shock protein 70 (Hsp70)-based motor drives precursor unfolding and translocation and is subject to dynamic remodelling. Here, we review recent advances in understanding of the mechanisms underlying protein transport along the presequence pathway. PMID- 25542065 TI - Transarterial chemoembolization in soft-tissue sarcoma metastases to the liver - the use of imaging biomarkers as predictors of patient survival. AB - BACKGROUND: The clinical management of patients with metastatic soft-tissue sarcoma of the liver is complicated by the paucity of reliable clinical data. This study evaluated the safety profile, survival outcome as well as the role of imaging biomarkers of tumor response in metastatic soft-tissue sarcoma (mSTS) of the liver treated with conventional transarterial chemoembolization (cTACE). MATERIALS/METHODS: This retrospective analysis included 30 patients with mSTS of the liver treated with cTACE. The safety profile, overall survival (OS) and progression-free survival (PFS) after the procedure were evaluated. Tumor response in each patient was assessed using RECIST, modified (m) RECIST and EASL guidelines. In addition, a 3D quantification of the enhancing tumor volume (quantitative [q] EASL) was performed. For each method, patients were classified as responders (R) and non-responders (NR), and evaluated using Kaplan-Meier and multivariate Cox proportional hazard ratio (HR) analysis. RESULTS: No Grade III or IV toxicities were reported in a total of 77 procedures (mean, 2.6/patient). Median OS was 21.2 months (95% CI, 13.4-28.9) and PFS was 6.3 months (95% CI, 4.4 8.2). The enhancement-based techniques identified 11 (44%), 12 (48%) and 12 (48%) patients as R according to EASL, mRECIST and qEASL, respectively. No stratification was achieved with RECIST. Multivariate analysis identified tumor response according to mRECIST and qEASL as reliable predictors of improved patient survival (P=0.019; HR 0.3 [0.1-0.8] and P=0.006; HR 0.2 [0.1-0.6], respectively). CONCLUSION: This study confirmed the role of cTACE as a safe salvage therapy option in patients with mSTS of the liver. The demonstrated advantages of enhancement-based tumor response assessment techniques over size based criteria validate mRECIST and qEASL as preferable methods after intraarterial therapy. PMID- 25542067 TI - Covariation of gene frequencies in a stepping-stone lattice of populations. AB - For a one- or two-dimensional lattice of finite length consisting of populations, each of which has the same population size, the classical stepping-stone model has been used to approximate the patterns of variation at neutral loci in geographic regions. In the pioneering papers by Maruyama (1970a, 1970b, 1971) the changes of gene frequency at a locus subject to neutral mutation between two alleles, migration, and random genetic drift were modeled by a vector autoregression model. Maruyama was able to use the spectrum of the migration matrix, but to do this he had to introduce approximations in which there was either extra mutation in the terminal populations, or extra migration from the subterminal population into the terminal population. In this paper a similar vector autoregression model is used, but it proves possible to obtain the eigenvalues and eigenvectors of the migration matrix without those approximations. Approximate formulas for the variances and covariances of gene frequencies in different populations are obtained, and checked by numerical iteration of the exact covariances of the vector autoregression model. PMID- 25542068 TI - Efficiency of tranexamic acid in perioperative blood loss in hip arthroplasty: a systematic literature review and meta-analysis. AB - INTRODUCTION AND OBJECTIVE: Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding in mortality risk situations such as trauma. Our objective was to conduct a systematic literature review to evaluate the effectiveness and safety of TXA in reducing bleeding in hip arthroplasty. MATERIAL AND METHODS: A systematic literature review and meta-analysis of primary studies similar to controlled trials was performed. Literature was searched in MEDLINE, Embase, Cochrane, LILACS, SciELO and Google Scholar. The review was proposed and undertaken by 2 reviewers and the inclusion criteria were: a) patients undergoing arthroplasty for primary unilateral hip replacement; b) comparison of a treatment group with TXA to a control group that received a placebo or no treatment at all, and c) outcome measures, total blood loss, number of patients receiving allogeneic transfusion and/or incidence of thromboembolic complications. The search was restricted to studies published from 1966 to June 2013. RESULTS: A total of 16 studies with 246 patients were retrieved for this review. The total blood loss outcome evidenced a weighted mean difference in favor of TXA vs. controls undergoing hip arthroplasty (-0.45 [P<0.001, 95% CI 0.65 to -0.24]). Weighted relative risk was estimated for the allogeneic transfusion requirement outcome, showing a trend in favor the TXA arm, with fewer patients requiring allogeneic transfusion in hip surgery (0.8 [P<0.02, 95% CI 0.57 to 1.11]); however, this trend was not statistically significant. LIMITATIONS: There is a noticeable difference in methods for quantifying total blood loss across the studies reviewed. The need for transfusion outcomes are probably not significant taking into account the number of events in the TXA group. CONCLUSIONS: TXA can be routinely used to reduce intra- and post-operative blood loss in primary hip arthroplasty. PMID- 25542069 TI - Assessing the agonist profiles of the prostacyclin analogues treprostinil and naxaprostene, particularly their DP1 activity. AB - In this study, the inhibitory profiles of the prostacyclin analogues treprostinil and naxaprostene on several isolated smooth muscle preparations have been investigated. Treprostinil was an agonist for prostanoid DP1, EP2 and IP receptors, but not EP4 receptors; its DP1 potency was only 3-4 times less than PGD2 itself. Naxaprostene was much more selective for IP receptors and tended towards partial agonism. Treprostinil is a 13,14-dihydro analogue and the role of conformation around C12-15 in controlling agonist specificity is debated; the synthesis of new analogues is proposed and possible clinical usage discussed. In terms of selective prostanoid antagonists employed, BW-A868C/MK-0524 (DP1), ACA 23 (EP2) and GW-627368 (EP4) were found fit for purpose. However, the IP antagonist RO-1138452 was compromised by alpha1 and alpha2-adrenoceptor-mediated contractile activity on rat tail artery and anti-muscarinic activity on mouse trachea. There is a need for IP receptor antagonists with better selectivity and higher affinity. PMID- 25542070 TI - The effects of situated learning and health knowledge involvement on health communications. AB - BACKGROUND: Many patients use websites, blogs, or online social communities to gain health knowledge, information about disease symptoms, and disease diagnosis opinions. The purpose of this study is to use the online platform of blogs to explore whether the framing effect of information content, situated learning of information content, and health knowledge involvement would affect health communication between doctors and patients and further explore whether this would increase patient willingness to seek treatment. METHODS: This study uses a survey to collect data from patient subjects who have used online doctor blogs or patients who have discussed medical information with doctors on blogs. The number of valid questionnaire samples is 278, and partial least square is used to conduct structural equation model analysis. RESULTS: Research results show that situated learning and health knowledge involvement have a positive effect on health communication. The negative framing effect and health knowledge involvement would also affect the patient's intention to seek medical help. In addition, situated learning and health knowledge involvement would affect the intention to seek medical help through communication factors. CONCLUSIONS: Blogs are important communication channels between medical personnel and patients that allow users to consult and ask questions without time limitations and enable them to obtain comprehensive health information. PMID- 25542071 TI - Thiamine and magnesium deficiencies: keys to disease. AB - Thiamine deficiency (TD) is accepted as the cause of beriberi because of its action in the metabolism of simple carbohydrates, mainly as the rate limiting cofactor for the dehydrogenases of pyruvate and alpha-ketoglutarate, both being critical to the action of the citric acid cycle. Transketolase, dependent on thiamine and magnesium, occurs twice in the oxidative pentose pathway, important in production of reducing equivalents. Thiamine is also a cofactor in the dehydrogenase complex in the degradation of the branched chain amino acids, leucine, isoleucine and valine. In spite of these well accepted facts, the overall clinical effects of TD are still poorly understood. Because of the discovery of 2-hydroxyacyl-CoA lyase (HACL1) as the first peroxisomal enzyme in mammals found to be dependent on thiamine pyrophosphate (TPP) and the ability of thiamine to bind with prion protein, these factors should improve our clinical approach to TD. HACL1 has two important roles in alpha oxidation, the degradation of phytanic acid and shortening of 2-hydroxy long-chain fatty acids so that they can be degraded further by beta oxidation. The downstream effects of a lack of efficiency in this enzyme would be expected to be critical in normal brain metabolism. Although TD has been shown experimentally to produce reversible damage to mitochondria and there are many other causes of mitochondrial dysfunction, finding TD as the potential biochemical lesion would help in differential diagnosis. Stresses imposed by infection, head injury or inoculation can initiate intermittent cerebellar ataxia in thiamine deficiency/dependency. Medication or vaccine reactions appear to be more easily initiated in the more intelligent individuals when asymptomatic marginal malnutrition exists. Erythrocyte transketolase testing has shown that thiamine deficiency is widespread. It is hypothesized that the massive consumption of empty calories, particularly those derived from carbohydrate and fat, results in a high calorie/thiamine ratio as a major cause of disease. Because mild to moderate TD results in pseudo hypoxia in the limbic system and brainstem, emotional and stress reflexes of the autonomic nervous system are stimulated and exaggerated, producing symptoms often diagnosed as psychosomatic disease. If the biochemical lesion is recognized at this stage, the symptoms are easily reversible. If not, and the malnutrition continues, neurodegeneration follows and results in a variety of chronic brain diseases. Results from acceptance of the hypothesis could be tested by performing erythrocyte transketolase tests to pick out those with TD and supplementing the affected individuals with the appropriate dietary supplements. PMID- 25542072 TI - Genetic therapies to lower cholesterol. AB - This review surveys the state-of-the-art in genetic therapies for familial hypercholesterolaemia (FH), caused most commonly by mutations in the LDL receptor (LDLR) gene. FH manifests as highly elevated low density lipoprotein (LDL) cholesterol levels and consequently accelerated atherosclerosis. Modern pharmacological therapies for FH are insufficiently efficacious to prevent premature cardiovascular disease, can cause significant adverse effects and can be expensive. Genetic therapies for FH have been mooted since the mid 1990s but gene replacement strategies using viral vectors have so far been unsuccessful. Other strategies involve knocking down the expression of Apolipoprotein B100 (APOB100) and the protease PCSK9 which designates LDLR for degradation. The antisense oligonucleotide mipomersen, which knocks down APOB100, is currently marketed (with restrictions) in the USA, but is not approved in Europe due to its adverse effects. To address this problem, we have devised a novel therapeutic concept, APO-skip, which is based on modulation of APOB splicing, and which has the potential to deliver a cost-effective, efficacious and safe therapy for FH. PMID- 25542073 TI - Towards a social and context-aware multi-sensor fall detection and risk assessment platform. AB - For elderly people fall incidents are life-changing events that lead to degradation or even loss of autonomy. Current fall detection systems are not integrated and often associated with undetected falls and/or false alarms. In this paper, a social- and context-aware multi-sensor platform is presented, which integrates information gathered by a plethora of fall detection systems and sensors at the home of the elderly, by using a cloud-based solution, making use of an ontology. Within the ontology, both static and dynamic information is captured to model the situation of a specific patient and his/her (in)formal caregivers. This integrated contextual information allows to automatically and continuously assess the fall risk of the elderly, to more accurately detect falls and identify false alarms and to automatically notify the appropriate caregiver, e.g., based on location or their current task. The main advantage of the proposed platform is that multiple fall detection systems and sensors can be integrated, as they can be easily plugged in, this can be done based on the specific needs of the patient. The combination of several systems and sensors leads to a more reliable system, with better accuracy. The proof of concept was tested with the use of the visualizer, which enables a better way to analyze the data flow within the back-end and with the use of the portable testbed, which is equipped with several different sensors. PMID- 25542074 TI - Single- and multiple-dose pharmacokinetics of a hydrocodone bitartrate extended release tablet formulated with abuse-deterrence technology in healthy, naltrexone blocked volunteers. AB - PURPOSE: A hydrocodone extended-release (ER) formulation was developed to provide sustained pain relief with twice-daily dosing. Developed using the CIMA abuse deterrence technology platform (CIMA Labs Inc, Brooklyn Park, Minnesota), this formulation also provides resistance against rapid release of hydrocodone when tablets are comminuted and resistance against dose dumping when tablets are taken with alcohol. Two open-label studies evaluated hydrocodone ER pharmacokinetics (PK) after single- and multiple-dose administration in healthy, naltrexone blocked subjects. METHODS: In the single-dose period of both studies, healthy subjects aged 18 to 45 years of age received hydrocodone ER (study 1, 45 mg; study 2, 90 mg). In the multiple-dose period of study 1, subjects received one 45 mg hydrocodone ER tablet twice daily from the morning of day 1 through the morning of day 6. In the multiple-dose period of study 2, subjects received hydrocodone ER twice daily, titrated to 90 mg over 10 days (days 1 and 2, 45 mg; days 3 and 4, 60 mg; days 5-10, 90 mg). All subjects received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post dose in the single-dose period and after the final dose in the multiple-dose period. PK measures included maximum observed plasma drug concentration (C(max)), area under the plasma drug concentration by time curve from time 0 to the time of the last measurable drug concentration (AUC(0-t)), time to C(max) (T(max)), observed accumulation ratio (R(obs)), and steady-state plasma concentration (C(ss)). Safety and tolerability were assessed. FINDINGS: The PK analyses included 36 subjects from study 1 and 33 from study 2. Plasma hydrocodone PK parameters after single- and multiple-dose administration of hydrocodone ER 45 mg (study 1) were dose-normalized to 90 mg and pooled with data from study 2. As expected, C(max) was higher (125.4 vs 57.2 ng/mL), AUC(0-t) was higher (2561 vs 1095 ng.h/mL), and T(max) occurred earlier (5.0 vs 8.0 hours) with multiple-dose administration. Mean R(obs) after multiple-dose administration of hydrocodone ER was also slightly higher than predicted from single-dose data (2.8 vs 2.4). C(ss) were achieved within 5 days of twice-daily administration of both doses. Mean fluctuation with hydrocodone ER 45 or 90 mg was 36.4% and 33.9%, respectively, and mean swing was 46.9% and 43.5%, respectively. The incidence of adverse events was similar in the single-dose (33%) and multiple-dose (29%) periods in study 1 and slightly higher in the multiple-dose (76%) than in the single-dose (53%) period in study 2. IMPLICATIONS: The PK profile of hydrocodone ER was qualitatively similar after single- and multiple-dose administration. The steady state profile demonstrated sustained exposure with limited swing and fluctuation. Single and multiple doses of hydrocodone ER (45 and 90 mg) were generally well tolerated in healthy subjects receiving naltrexone; however, exposure to naltrexone may have confounded the interpretation of safety findings. PMID- 25542075 TI - Intratympanic steroid therapy as a salvage treatment for sudden sensorineural hearing loss after failure of conventional therapy: a meta-analysis of randomized, controlled trials. AB - PURPOSE: Systemic steroid therapy (SST) for sudden sensorineural hearing loss (SSNHL) is considered the only effective treatment, but the results are not satisfactory in clinical practice. Intratympanic steroid (ITS) treatment has been adopted as a salvage treatment for patients in whom previous SST failed. However, the uncertain results of ITS treatment as a salvage treatment present patients with the dilemma of accepting or refusing ITS treatment. The goal of this study was to review relevant studies and analyze the pooled data to determine whether ITS treatment is effective for SSNHL after the failure of SST. METHODS: A literature search of the PubMed, Embase, and Cochrane databases to May 2014 was performed without restrictions regarding the language of publication. The studies were screened after reading the abstract and full text. Only prospective, randomized, controlled trials that evaluated the effect of ITS therapy on SSNHL adult patients after SST failed were included in the meta-analysis. Improvements in pure tone averages and the number of patients with no improvement were extracted and entered into RevMan software to meta-analyze the overall effect of ITS on SSNHL after SST failed. FINDINGS: A total of 543 studies were identified, and 41 of these studies were found to be eligible and related to ITS therapy after SST failed. Ultimately, 5 randomized, controlled trials containing data from 102 patients in the ITS group and 101 control subject were included. The pooled results revealed that ITS therapy was able to improve the hearing levels of SSNHL patients who had responded poorly to SST. IMPLICATIONS: ITS therapy might be an effective approach to the treatment of SSNHL after SST fails. PMID- 25542077 TI - Interview with Magnus Ingelman-Sundberg. PMID- 25542078 TI - Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination. AB - We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7-15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum. PMID- 25542076 TI - Amphetamines, new psychoactive drugs and the monoamine transporter cycle. AB - In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects. PMID- 25542079 TI - Altered neuronal activity in the primary motor cortex and globus pallidus after dopamine depletion in rats. AB - The involvement of dopamine (DA) neuron loss in the etiology of Parkinson's disease has been well documented. The neural mechanisms underlying the effects of DA loss and the resultant motor dysfunction remain unknown. To gain insights into how loss of DA disrupts the electrical processes in the cortico-subcortical network, the present study explores the effects of DA neuron depletion on electrical activity in the primary motor cortex (M1), on the external and the internal segment of the globus pallidus (GPe and GPi respectively), and on their temporal relationships. Comparison of local field potentials (LFPs) in these brain regions from unilateral hemispheric DA neuron depleted rats and neurologically intact rats revealed that the spectrum power of LFPs in 12-70Hz (for M1, and GPe) and in 25-40Hz (for GPi) was significantly greater in the DA depleted rats than that in the control group. These changes were associated with a shortening of latency in LFP activities between M1 and GPe, from several hundred milliseconds in the intact animals to close to zero in the DA depleted animals. LFP oscillations in M1 were significantly more synchronized with those in GPe in the DA depleted rats compared with those in the control rats. By contrast, the synchronization of oscillation in LFP activities between M1 and GPi did not differ between the DA depleted and intact rats. Not surprisingly, rats that had DA neuron depletion spent more time along the ladder compared with the control rats. These data suggest that enhanced oscillatory activity and increased synchronization of LFPs may contribute to movement impairment in the rat model of Parkinson's disease. PMID- 25542080 TI - Estimating community health needs against a Triple Aim background: What can we learn from current predictive risk models? AB - INTRODUCTION: To support providers and commissioners in accurately assessing their local populations' health needs, this study produces an overview of Dutch predictive risk models for health care, focusing specifically on the type, combination and relevance of included determinants for achieving the Triple Aim (improved health, better care experience, and lower costs). METHODS: We conducted a mixed-methods study combining document analyses, interviews and a Delphi study. Predictive risk models were identified based on a web search and expert input. Participating in the study were Dutch experts in predictive risk modelling (interviews; n=11) and experts in healthcare delivery, insurance and/or funding methodology (Delphi panel; n=15). RESULTS: Ten predictive risk models were analysed, comprising 17 unique determinants. Twelve were considered relevant by experts for estimating community health needs. Although some compositional similarities were identified between models, the combination and operationalisation of determinants varied considerably. CONCLUSIONS: Existing predictive risk models provide a good starting point, but optimally balancing resources and targeting interventions on the community level will likely require a more holistic approach to health needs assessment. Development of additional determinants, such as measures of people's lifestyle and social network, may require policies pushing the integration of routine data from different (healthcare) sources. PMID- 25542081 TI - Monitoring C-reactive protein levels during medical management of acute appendicitis to predict the need for surgery. AB - PURPOSE: To clarify the role of medical treatment in the management of acute appendicitis and the value of C-reactive protein (CRP) for predicting its failure. MATERIALS AND METHODS: Patients with clinically diagnosed acute appendicitis, confirmed by imaging studies, were enrolled in this study. We measured leukocyte counts and CRP levels and recorded success and recurrence rates and the efficiency of medical treatment during follow-up. The efficiency of CRP values to predict failure of medical treatment was evaluated using receiver operating characteristics (ROC) curve analysis. RESULTS: The subjects comprised 193 patients (mean age 30.9 years) who received medical treatment for acute appendicitis. The mean follow-up period was 12.3 (6-24) months and the early success rate of medical treatment was 86.5 % (160/185). Fifteen (9.3 %) patients suffered recurrence during follow-up. The leukocyte and CRP levels in these two groups of patients were not significantly different at the beginning of the treatment, but the increase in the CRP value differed significantly between the two groups during the follow-up period (p < 0.001). ROC curve analysis suggested that the optimum CRP cut-off point for unsuccessful medical treatment was 80.8 mg/L, with 81.82 % sensitivity and 84.34 % specificity (p < 0.001). CONCLUSION: The success rate for treating acute appendicitis medically is high, with antibiotic treatment being effective as the firstline therapy for many unselected patients. An increase in CRP levels to 80.8 mg/L and above seems to be a meaningful parameter for determining a lack of response to medical treatment. PMID- 25542082 TI - Prevention of postoperative small bowel obstruction in gastric cancer. AB - Postoperative adhesion is a frequent problem in patients undergoing surgery. In particular, gastrectomy is associated with a high risk of bowel obstruction. However, there are few reports of small bowel obstruction (SBO) after gastrectomy in the English-language literature. We reviewed the literature to assess the effectiveness of various techniques for preventing adhesion in patients treated with gastrectomy. We assumed that strategies used to prevent postoperative adhesion associated with colorectal surgery, cholecystectomy, appendectomy and gynecologic procedures are similar to those used in gastrectomy. We therefore reviewed reports on the prevention of postoperative SBO in any abdominal surgical procedure, focusing especially on gastrectomy. General intraoperative preventive techniques, such as the use of starch-free gloves, saline irrigation at a temperature below 37 degrees C and laparoscopic techniques whenever possible, may reduce the incidence of SBO in patients with gastric cancer who undergo gastrectomy. If preserving the omentum is unrelated to the survival rate of patients with gastric cancer, this technique should be recommended for preventing postoperative SBO. The use of hyaluronic acid/carboxymethylcellulose bioabsorbable membranes should also be considered in patients undergoing gastrectomy. However, demonstrating the advantages of bioabsorbable membranes would require larger randomized studies with a longer follow-up period. PMID- 25542084 TI - Thin-film voltammetry and its analytical applications: a review. AB - Electrochemical reactions at the interfaces of immiscible electrolyte solutions (ITIES) are of fundamental importance in the fields of chemical, biological and pharmaceutical sciences. Four-electrode cell setup, scanning electrochemical microscopy (SECM) and thin-film voltammetry are the three most frequently used methods for studying the electrochemical processes at these interfaces. The principle, experimental design, advantages and challenges of the three methods are described and compared. The thin-film voltammetry is highlighted for its simplicity in experimental operation and kinetic data analysis. Its versatile analytical applications are discussed in detail, including the study of redox properties of hydrophobic compounds, evaluation of interfacial electron transfer kinetics, synthesis of nanoparticles/nanostructures, and illustration of cross membrane ion transport phenomena. PMID- 25542083 TI - Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas. AB - Glioblastoma is a devastating primary brain tumor resistant to conventional therapies. In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. The data showed that synergy between curcumin and temozolomide was not achieved due to redundant mechanisms that lead to activating protective autophagy both in vitro and in vivo. Autophagy preceded apoptosis, and blocking this response with autophagy inhibitors (3-methyl-adenine, ATG7 siRNA and chloroquine) rendered cells susceptible to temozolomide and curcumin alone or combinations by increasing apoptosis. While curcumin inhibited STAT3, NFkappaB and PI3K/Akt to affect survival, temozolomide-induced autophagy relied on the DNA damage response and repair components ATM and MSH6, as well as p38 and JNK1/2. However, the most interesting observation was that both temozolomide and curcumin required ERK1/2 to induce autophagy. Blocking this ERK1/2-mediated temozolomide and curcumin induced autophagy with resveratrol, a blood-brain barrier permeable drug, improved temozolomide/curcumin efficacy in brain-implanted tumors. Overall, the data presented demonstrate that autophagy impairs the efficacy of temozolomide/curcumin, and inhibiting this phenomenon could provide novel opportunities to improve brain tumor treatment. PMID- 25542085 TI - New approach to the determination phosphorothioate oligonucleotides by ultra high performance liquid chromatography coupled with inductively coupled plasma mass spectrometry. AB - This text presents a novel method for the separation and detection of phosphorothioate oligonucleotides with the use of ion pair ultra high performance liquid chromatography coupled with inductively coupled plasma mass spectrometry The research showed that hexafluoroisopropanol/triethylamine based mobile phases may be successfully used when liquid chromatography is coupled with such elemental detection. However, the concentration of both HFIP and TEA influences the final result. The lower concentration of HFIP, the lower the background in ICP-MS and the greater the sensitivity. The method applied for the analysis of serum samples was based on high resolution inductively coupled plasma mass spectrometry. Utilization of this method allows determination of fifty times lower quantity of phosphorothioate oligonucleotides than in the case of quadrupole mass analyzer. Monitoring of (31)P may be used to quantify these compounds at the level of 80 MUg L(-1), while simultaneous determination of sulfur is very useful for qualitative analysis. Moreover, the results presented in this paper demonstrate the practical applicability of coupling LC with ICP-MS in determining phosphorothioate oligonucleotides and their metabolites in serum within 7 min with a very good sensitivity. The method was linear in the concentration range between 0.2 and 3 mg L(-1). The limit of detection was in the range of 0.07 and 0.13 mg L(-1). Accuracy varied with concentration, but was in the range of 3%. PMID- 25542086 TI - Definition and detection of data-based uniqueness in evaluating bilinear (two way) chemical measurements. AB - Multivariate curve resolution methods, frequently used in analyzing bilinear data sets, result in ambiguous decomposition in general. Implementing the adequate constraints may lead to reduce the so-called rotational ambiguity drastically, and in the most favorable cases to the unique solution. However, in some special cases, non-negativity constraint as minimal information of the system is a sufficient condition to resolve profiles uniquely. Although, several studies on exploring the uniqueness of the bilinear non-negatively constrained multivariate curve resolution methods have been made in the literature, it has still remained a mysterious question. In 1995, Manne published his profile-based theorems giving the necessary and sufficient conditions of the unique resolution. In this study, a new term, i.e., data-based uniqueness is defined and investigated in details, and a general procedure is suggested for detection of uniquely recovered profile(s) on the basis of data set structure in the abstract space. Close inspection of Borgen plots of these data sets leads to realize the comprehensive information of local rank, and these argumentations furnish a basis for data based uniqueness theorem. The reported phenomenon and its exploration is a new stage (it can be said fundament) in understanding and describing the bilinear (matrix-type) chemical data in general. Our proposed detection tool is restricted to three-component systems because of the visual limitations of the Borgen plot, but the theorem is universal for systems with more than three components. A recently published experimental four-component system is used for illustrating this theorem in the case of systems with more than three components. PMID- 25542087 TI - Antimony film screen-printed carbon electrode for stripping analysis of Cd(II), Pb(II), and Cu(II) in natural samples. AB - An in-situ antimony film screen-printed carbon electrode (in-situ SbSPCE) was successfully used for the determination of Cu(II) simultaneously with Cd(II) and Pb(II) ions, by means of differential pulse anodic stripping voltammetry (DPASV), in a certified reference groundwater sample with a very high reproducibility and good trueness. This electrode is proposed as a valuable alternative to in-situ bismuth film electrodes, since no competition between the electrodeposited copper and antimony for surface sites was noticed. In-situ SbSPCE was microscopically characterized and experimental parameters such as deposition potential, accumulation time and pH were optimized. The best voltammetric response for the simultaneous determination of Cd(II), Pb(II) and Cu(II) ions was achieved when deposition potential was -1.2 V, accumulation time 120 s and pH 4.5. The detection and quantification limits at levels of MUg L(-1) suggest that the in situ SbSPCE could be fully suitable for the determination of Cd(II), Pb(II) and Cu(II) ions in natural samples. PMID- 25542088 TI - Fast extraction of amphenicols residues from raw milk using novel fabric phase sorptive extraction followed by high-performance liquid chromatography-diode array detection. AB - A simple, sensitive, reliable, and fast analytical method was developed for the simultaneous determination of amphenicols residues in raw milk by combining fabric phase sorptive extraction (FPSE) and high-performance liquid chromatography-diode array detection. FPSE, a new generation green sample preparation technique, efficiently incorporates the advanced and tunable material properties of sol-gel derived microextraction sorbents with the rich surface chemistry of a cellulose fabric substrate, resulting in a flexible, highly sensitive, and fast microextraction device capable of extracting target analytes directly from complicated sample matrices. Due to the strong chemical bonding between the sol-gel sorbent and substrate, the microextraction device demonstrates a very high chemical and solvent stability. Therefore, any organic solvent/solvent mixture can be used as the eluent/back-extraction solvent. Herein, a highly polar polymer coated FPSE media was created using short-chain poly(ethylene glycol) (PEG) and the applicability of this novel microextraction device to extract highly polar amphenicol antibiotics from raw milk was investigated. Due to the intense affinity of amphenicols towards the strongly polar sol-gel PEG-coated FPSE device, absolute recovery of the selected antibiotics residues were found to be 44% for thiamphenicol, 66.4% for florfenicol, and 81.4% for chloramphenicol. The developed method was validated in terms of sensitivity, linearity, accuracy, precision, and selectivity according to European Decision 657/2002/EC. Decision limit (CCalpha) values were 52.49 MUg kg(-1) for thiamphenicol, 55.23 MUg kg(-1) for florfenicol, and 53.8 MUg kg(-1) for chloramphenicol, while the corresponding results for detection capability (CCbeta) were 56.8 MUg kg(-1), 58.99 MUg kg(-1), and 55.9 MUg kg(-1), respectively. PMID- 25542089 TI - A method for rapid screening of interactions of pharmacologically active compounds with albumin. AB - We determine the association constants for ligand-protein complex formation using the flow injection method. We carry out the measurements at high flow rates (F=1 mL min(-1)) of a carrier phase. Therefore, determination of the association constant takes only a few minutes. Injection of 1 nM of the ligand (10 MUL of 1 MUM concentration of the ligand solution) is sufficient for a single measurement. This method is tested and verified for a number of complexes of selected drugs (cefaclor, etodolac, sulindac) with albumin (BSA). We obtain K=4.45*10(3) M(-1) for cefaclor, K=1.00*10(5) M(-1) for etodolac and K=1.03*10(5) M(-1) for sulindac in agreement with the literature data. We also determine the association constants of 20 newly synthesized 3beta- and 3alpha-aminotropane derivatives with potential antipsychotic activity--ligands of 5-HT1A, 5-HT2A and D2 receptors with the albumin. Results of the studies reported here indicate that potential antipsychotic drugs bind weakly to the transporter protein (BSA) with K~10(2) 10(3) M(-1). Our method allows measuring K in a wide range of values (10(2)-10(9) M(-1)). This range depends only on the solubility of the ligand and sensitivity of the detector. PMID- 25542090 TI - Application of pyrolysis-mass spectrometry and pyrolysis-gas chromatography-mass spectrometry with electron-ionization or resonance-enhanced-multi-photon ionization for characterization of crude oils. AB - A novel analytical system for gas-chromatographic investigation of complex samples has been developed, that combines the advantages of several analytical principles to enhance the analytical information. Decomposition of high molecular weight structures is achieved by pyrolysis and a high separation capacity due to the chromatographic step provides both an universal as well as a selective and sensitive substance detection. The latter is achieved by simultaneously applying electron ionization quadrupole mass spectrometry (EI-QMS) for structural elucidation and [1+1]-resonance-enhanced-multi-photon ionization (REMPI) combined with time-of-flight mass spectrometry (ToFMS). The system has been evaluated and tested with polycyclic aromatic hydrocarbon (PAH) standards. It was applied to crude oil samples for the first time. In such highly complex samples several thousands of compounds are present and the identification especially of low concentrated chemical species such as PAH or their polycyclic aromatic sulfur containing heterocyclic (PASH) derivatives is often difficult. Detection of unalkylated and alkylated PAH together with PASH is considerably enhanced by REMPI-ToFMS, at times revealing aromatic structures which are not observable by EI-QMS due to their low abundance. On the other hand, the databased structure proposals of the EI-QMS analysis are needed to confirm structural information and isomers distinction. The technique allows a complex structure analysis as well as selective assessment of aromatic substances in one measurement. Information about the content of sulfur containing compounds plays a significant role for the increase of efficiency in the processing of petroleum. PMID- 25542091 TI - Pushing the surface-enhanced Raman scattering analyses sensitivity by magnetic concentration: a simple non core-shell approach. AB - A simple and accessible method for molecular analyses down to the picomolar range was realized using self-assembled hybrid superparamagnetic nanostructured materials, instead of complicated SERS substrates such as core-shell, surface nanostructured, or matrix embedded gold nanoparticles. Good signal-to-noise ratio has been achieved in a reproducible way even at concentrations down to 5*10(-11) M using methylene blue (MB) and phenanthroline (phen) as model species, exploiting the plasmonic properties of conventional citrate protected gold nanoparticles and alkylamine functionalized magnetite nanoparticles. The hot spots were generated by salt induced aggregation of gold nanoparticles (AuNP) in the presence of those analytes. Then, the aggregates of AuNP/analyte were decorated with small magnetite nanoparticles by electrostatic self-assembly forming MagSERS hybrid nanostructured materials. SERS peaks were enhanced up to 100 times after magnetic concentration in a circular spot using a magnet in comparison with the respective dispersion of the nanostructured material. PMID- 25542092 TI - Evaluation of aromatic amines with different purities and different solvent vehicles in the Ames test. AB - Of all the in vitro mutagenicity assays, the Ames test displays the best correlation with rodent carcinogenicity and therefore carries significant weight with the food and drug regulatory bodies. Aromatic amines (AA) are ubiquitous structural groups in food and drug molecules despite the well-documented mutagenic and carcinogenic propensity for many representatives. Furthermore, recent regulatory guidelines (that is ICH M7) requires the hazard assessment of actual and potential impurities by two complementary (Q)SAR prediction methodologies if no carcinogenicity or bacterial mutagenicity data is available. One methodology should be expert-rule-based and the second should be statistics based. Having encountered numerous reports of contradictory Ames results for members of this chemotype, we undertook systematic Ames tests on a diverse set of 14 AAs of differing purities in different solvents, and as free bases and their salts. The aim of this work was to investigate the reliability of the Ames test for this chemotype leading to the creation of a reference set of AAs for use by medicinal chemists and in silico modelling. Contrary to previous experience, which led to the investigations reported in this publication, the anticipated transformation from an Ames-positive to an Ames-negative after purification only occurred for one compound. Furthermore, this result proved inconclusive after testing as the HCl salt in DMSO and in water. The anticipated change in class from mutagen to non-mutagen, did not occur and this can be read as evidence for the reliability of the Ames test for AAs. PMID- 25542093 TI - The role of IL-10 in microbiome-associated immune modulation and disease tolerance. AB - Current research on the microbiome of humans and other species is revealing a fundamental role for the interaction between the microbiota and the immune system in determining the health status of the host. In these studies, the cytokine interleukin-10 (IL-10) is emerging as an important player. We present here an overview of the developments in the field emphasizing how the microbiota composition and its interplay with immune cells affect the health of the host through changes in IL-10 production. In addition, we explore the function that IL 10-producing immune cells may have on the qualitative and quantitative changes in the microbiota and thus influence the balance between microbial commensalism and pathogenicity. In the last section of this review, we present a summary of the strategies that target IL-10 for therapeutic purposes using probiotics, purified proteins or biologicals. PMID- 25542094 TI - New pathogenic and therapeutic paradigms in atopic dermatitis. AB - Atopic Dermatitis (AD) is a common inflammatory skin disease with increasing prevalence in industrialized countries. Up to one-third of adults with AD have moderate-to-severe disease, leading to a large, unmet need for effective treatments. While current therapeutics focus mainly on symptom control, major advances have been made in translational research, with the goal of developing drugs to eradicate disease. A translational revolution is now occurring in AD, similar to the one that has occurred in psoriasis over the past decade. Research has focused on elucidating immune pathways responsible for AD, including Th2, Th22, and Th17 pathways, with testing of immune antagonists specific to these axes. An IL-4R antagonist, dupilumab, is the first drug that shows great promise in phase II trials. By studying clinical and molecular responses following treatment with specific immune antagonists, our understanding of and ability to treat AD will expand. PMID- 25542096 TI - Changes in the frequency of swallowing during electrical stimulation of superior laryngeal nerve in rats. AB - The aim of the present study was to investigate the adaptation of the swallowing reflex in terms of reduced swallowing reflex initiation following continuous superior laryngeal nerve stimulation. Forty-four male Sprague Dawley rats were anesthetized with urethane. To identify swallowing, electromyographic activity of the left mylohyoid and thyrohyoid muscles was recorded. To evoke the swallowing response, the superior laryngeal nerve (SLN), recurrent laryngeal nerve, or cortical swallowing area was electrically stimulated. Repetitive swallowing evoked by continuous SLN stimulation was gradually reduced, and this reduction was dependent on the resting time duration between stimulations. Prior SLN stimulation also suppressed subsequent swallowing initiation. The reduction in evoked swallows induced by recurrent laryngeal nerve or cortical swallowing area stimulation was less than that following superior laryngeal nerve stimulation. Decerebration had no effect on the reduction in evoked swallows. Prior subthreshold stimulation reduced subsequent initiation of swallowing, suggesting that there was no relationship between swallowing movement evoked by prior stimulation and the subsequent reduction in swallowing initiation. Overall, these data suggest that reduced sensory afferent nerve firing and/or trans-synaptic responses, as well as part of the brainstem central pattern generator, are involved in adaptation of the swallowing reflex following continuous stimulation of swallow-inducing peripheral nerves and cortical areas. PMID- 25542097 TI - Selective autophagy: lysophagy. AB - Autophagy is a bulk degradation system that is induced under stress conditions such as nutrient deprivation. Selective autophagy, including xenophagy and mitophagy, is believed to play important roles in the development of several diseases. Consequently, selective autophagy represents a potential therapeutic target. Recent work showed that the lysosome, a membrane-bound acidic organelle, is selectively sequestered by autophagy when its membrane is injured; this phenomenon is called "lysophagy". Lysosomes can be injured by diverse causes, including amyloid proteins and mineral crystals such as silica and monosodium urate, which would trigger neurodegeneration and other diseases. In this section, we provide an overview of methods for monitoring lysophagy in mammalian cultured cells. These methods can be used to evaluate the involvement of molecules of interest in selective autophagy, and in screens aimed at identifying novel proteins engaged in selective autophagy. PMID- 25542095 TI - Serum IL-9, IL-17, and TGF-beta levels in subjects with diabetic kidney disease (CURES-134). AB - The role of inflammation in both diabetes and diabetic kidney disease (DKD) is becoming more widely accepted. However, the role of recently characterized T cell cytokines interleukin (IL)-9 and IL-17 in diabetes and especially DKD is less well studied. Transforming growth factor beta (TGF-beta) controls the secretion of both of these cytokines. In this study, we estimated the levels of IL-9, IL 17, and TGF-beta in the serum of subjects with normal glucose tolerance (NGT = 88) and subjects with type 2 diabetes without (diabetes mellitus (DM) = 65) and with DKD (DKD = 97) using enzyme-linked immunosorbent assay (ELISA), and we correlated these levels with the clinical risk factors of diabetes and DKD. IL-17 levels showed a serial decline and TGF-beta levels showed a serial increase from NGT to DM to DKD (p < 0.001). However, the IL-9 levels were significantly reduced in the DM group compared to the NGT and DKD group (p < 0.001). While TGF-beta and IL-17 showed a positive and negative correlation, respectively, with fasting and postprandial glucose levels and glycated hemoglobin (HbA1c), IL-9 showed positive correlation with urea and microalbuminuria. Apart from pro-inflammatory cytokines, T helper (Th) cytokines might play an important role in insulin resistance and DKD. PMID- 25542098 TI - PTEN secretion in exosomes. AB - PTEN was discovered as a membrane-associated tumor suppressor protein nearly two decades ago, but the concept that it can be secreted and taken up by recipient cells is revolutionary. Since then, various laboratories have reported that PTEN is indeed secreted and available for uptake by other cells in at least two different guises. First, PTEN may be packaged and exported within extracellular vesicles (EV) called exosomes. Second, PTEN may also be secreted as a naked protein in a longer isoform called PTEN-long. While the conditions favouring the secretion of PTEN-long remain unknown, PTEN secretion in exosomes is enhanced by the Ndfip1/Nedd4 ubiquitination system. In this report, we describe conditions for packaging PTEN in exosomes and their potential use for mediating non cell autonomous functions in recipient cells. We suggest that this mode of PTEN transfer may potentially provide beneficial PTEN for tumor suppression, however it may also propagate deleterious versions of mutated PTEN causing tumorigenesis. PMID- 25542099 TI - A comparative study on properties of micro and nanopapers produced from cellulose and cellulose nanofibres. AB - Cellulose nanocrystals (CNCs) and cellulose nanofibres (CNFs) were successfully extracted from cellulose obtained from maize stalk residues. A variety of techniques, such as Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD) and thermogravimetric analysis (TGA) were used for characterization and the experimental results showed that lignin and hemicellulose were removed to a greater extent by following the chemical methods. Atomic force microscopy (AFM) results confirmed that the diameters of CNCs and CNFs were ranging from 3 to 7 nm and 4 to 10nm, respectively, with their lengths in micro scale. CNCs suspension showed a flow of birefringence, however, the same was not observed in the case of suspension containing CNFs. XRD analysis confirmed that CNCs had high crystallinity index in comparison to cellulose and CNFs. Nanopapers were prepared from CNCs and CNFs by solvent evaporation method. Micropapers were also prepared from cellulose pulp by the same technique. Nanopapers made from CNFs showed less transparency as compared to nanopapers produced from CNCs whereas high transparency as compared to micropaper. Nanopapers produced from CNFs provided superior mechanical properties as compared to both micropaper and nanopapers produced from CNCs. Also, nanopapers produced from CNFs were thermally more stable as compared to nanopapers produced from CNCs but thermally less stable as compared to micropapers. PMID- 25542100 TI - A rapid extraction method for glycogen from formalin-fixed liver. AB - Liver glycogen, a highly branched polymer, acts as our blood-glucose buffer. While past structural studies have extracted glycogen from fresh or frozen tissue using a cold-water, sucrose-gradient centrifugation technique, a method for the extraction of glycogen from formalin-fixed liver would allow the analysis of glycogen from human tissues that are routinely collected in pathology laboratories. In this study, both sucrose-gradient and formalin-fixed extraction techniques were carried out on piglet livers, with the yields, purities and size distributions (using size exclusion chromatography) compared. The formalin extraction technique, when combined with a protease treatment, resulted in higher yields (but lower purities) of glycogen with size distributions similar to the sucrose-gradient centrifugation technique. This formalin extraction procedure was also significantly faster, allowing glycogen extraction throughput to increase by an order of magnitude. Both extraction techniques were compatible with mass spectrometry proteomics, with analysis showing the two techniques were highly complementary. PMID- 25542101 TI - Preparation and adsorption property of xylan/poly(acrylic acid) magnetic nanocomposite hydrogel adsorbent. AB - Adsorbents based on natural polysaccharides have attracted increasing interest because of their low-cost and biodegradability, particularly, polysaccharide based nanocomposite adsorbents. In this study the xylan/poly(acrylic acid) magnetic nanocomposite hydrogel adsorbent was prepared from wheat straw xylan and Fe3O4 nanoparticles, and its adsorption property was studied on methylene blue removal. The prepared hydrogel adsorbent had a semi-interpenetrating network structure and exhibited a macro-porous structure with interconnected porous channels. Super-paramagnetic characteristic behavior was observed from magnetic analysis using a vibrating sample magnetometer. The optimum condition for methylene blue adsorption on the adsorbent was found at pH 8 with an adsorbent dosage of 3g/L and an initial concentration of 400mg/L, and the removal percentage reached above 90%. The adsorption isotherm of methylene blue on the prepared hydrogel adsorbent was fitted to the Langmuir model, and the pseudo second-order kinetic model could describe the adsorption process. All obtained results indicated that the prepared hydrogel adsorbent is promising for water treatment applications. PMID- 25542102 TI - Physical and mechanical properties in biodegradable films of whey protein concentrate-pullulan by application of beeswax. AB - Different ratios of whey protein concentrate (WPC):pullulan (PUL) (70:30, 50:50, 30:70%w/w) and various rates of beeswax (BW) (0, 10, 20, and 30%w/wglycerol) were applied to prepare biodegradable WPC-PUL films containing glycerol as a plasticizer, for the first time. Thickness, moisture content, water solubility, water vapour permeability, colour, and mechanical properties of prepared films were measured. Higher ratios of WPC:PUL led to more desirable physical and mechanical properties; in other words, lower rates of thickness, moisture content, water solubility and water vapour permeability, and higher elongations were achieved. Application of BW (especially in higher contents) could successfully improve colour indices, diminish water solubility (nearly 12%) and water vapour permeability (approximately 3*10(-11)gm(-1)s(-1)Pa(-1)), and increase tensile strength (by about 7MPa) of WPC-PUL blend films. Our edible films enjoyed great whiteness and ignorable yellowness indices, making it a suitable alternative for application in food products. Overall, WPC70-PUL30 containing 30% BW resulted in the best performance of physical and mechanical aspects as an optimum film. PMID- 25542103 TI - Efficacy of Zhuling polyporus polysaccharide with BCG to inhibit bladder carcinoma. AB - There is growing interest in reducing Bacille Calmette-Guerin (BCG) side effects while keeping intact its therapeutic efficacy. In the present study, we evaluated the efficacy of Sclerotia of Polyporus umbellatus FRIES (Zhuling) and its main ingredient Polyporus Polysaccharide (PPS) to attenuate side effects of BCG therapy in vivo. The results show that bladder cancer development in model rats exhibited significantly reduced cancer invasiveness with Zhuling PPS combined with BCG. Flow cytometric (FCM) analysis showed expression of costimulatory molecules CD86, CD40, and TLR4/CD14 significantly increased with Zhuling PPS in combination with BCG. Similarly, immunohistochemical analysis revealed stronger CD86 and CD40 staining. Our findings show Zhuling PPS strongly reduced side effects and displayed synergistic effects during BCG instillation in rat bladder cancer models. The findings also suggest that the attenuation effect may result from direct activation of dendritic cell (DC) TLR4. PMID- 25542104 TI - Characterization of hydroxypropyl-beta-cyclodextrins with different substitution patterns via FTIR, GC-MS, and TG-DTA. AB - The structure and thermal properties of hydroxylpropyl-beta-cyclodextrins (HPCDs) with different degrees of substitution (DS) and different substitution sites were evaluated via GC-MS, FTIR, and TG-DTA combined thermoanalytical techniques. The results of GC-MS provided the DS and substitution pattern of the HPCD samples. The IR spectra of HPCDs showed all characteristic peaks corresponding to cyclodextrin. Furthermore, the characteristic peaks for methyl in the hydroxypropyl group at 2960 and 1,375 cm(-1) were observed. The thermal decomposition temperature of HPCDs was about 300 degrees C to 400 degrees C and enhanced linearly as the molecular DS increased. The rate of DS rise of HPCDs prepared at a strong alkaline condition was higher than that prepared in a weak alkaline solution. PMID- 25542105 TI - Preparation of the oligosaccharides derived from Flammulina velutipes and their antioxidant activities. AB - The oligosaccharides were prepared from Flammulina velutipes by hydrolysis of F. velutipes polysaccharides with hydrogen peroxide (H2O2). The yields of F. velutipes derived oligosaccharides (FVOs) were monitored during the hydrolysis process. FVOs yields were affected by three factors, i.e. reaction temperature, H2O2 concentration, and time, which were optimized by using an orthogonal design experiments as follows: reaction temperature 70 degrees C, H2O2 concentration 3%, and reaction time 6h. Under these optimum conditions, the maximal yield of the oligosaccharides reached 17.10%, which was higher than that of hot water extraction method. The oligosaccharides were partially characterized by Fourier transform infrared spectrum, monosaccharide composition, and antioxidant activity. The results indicate that the oligosaccharides derived from F. velutipes showed strong hydroxyl radical activity and reducing capacity at the concentration of 100 MUg/mL. PMID- 25542106 TI - Hydrothermal conversion of xylose, glucose, and cellulose under the catalysis of transition metal sulfates. AB - Hydrothermal conversion (HTC) is an important thermochemical process to upgrade low-cost biomass into valuable chemicals or fuels. As compared with non-catalytic HTC, catalytic HTC shows high energy efficiency on biomass upgradation. In this work, the catalytic performances of various transition metal sulfates (Mn(2+), Fe(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), and Zn(2+)) in the HTCs of xylose, glucose, and cellulose under different conditions were explored. Among these catalysts, Zn(2+) and Ni(2+) showed obvious effects on the conversions of xylose, glucose, and cellulose into lactic acid, while Cu(2+) and Fe(3+), which could significantly accelerate the hydrolysis of cellulose into glucose at 200 degrees C, displayed high efficiency on converting glucose and cellulose into levulinic acid and formic acid at high temperature. Additionally, significant positive correlative relationships among xylose, glucose, and cellulose degradations were observed. This study is helpful for screening appropriate catalysts for biomass upgradation through catalytic HTC of monosaccharide. PMID- 25542107 TI - Cell-wall polysaccharide composition and glycanase activity of Silene vulgaris callus transformed with rolB and rolC genes. AB - The aim of this research is to investigate the effects of the Agrobacterium rhizogenes rol genes on the composition of cell-wall polysaccharides and glycanase activity in the campion callus. The expression of the rolC gene reduces the yield of campion pectin, while the expression of the rolB or rolC gene inhibits the volumetric production of both pectin and intracellular arabinogalactan. The rol genes are involved in regulating the activity of glycanases and esterases, thereby contributing to the modification of polysaccharide structures, their molecular weight (Mw) and the degree of pectin methyl esterification (DE). The increase in pectin arabinose residue appears to be connected to a decrease in intracellular and extracellular alpha-l arabinofuranosidase activity in transgenic campion calluses. In transgenic calluses expressing the rolB and rolC genes, the increase in pectin galactose residue is likely due to a decrease in beta-galactosidase activity. The decrease in the Mw of pectin and its d-galacturonic acid content appears to be connected to an increase in extracellular polygalacturonase activity. Finally, the increase in pectinesterase activity causes a decrease in the DE of pectin. Thus, the expression of rolB and rolC genes in campion callus has a considerable effect on pectin's sugar composition, DE and Mw, while it appears to have an insignificant influence on intracellular and extracellular arabinogalactans. PMID- 25542108 TI - Investigation of Salecan/poly(vinyl alcohol) hydrogels prepared by freeze/thaw method. AB - Salecan is a novel water-soluble extracellular-glucan produced by a new kind of salt-tolerant strain Agrobacterium sp. ZX09 and can be applied in food and medicine industries. In this work, Salecan (Sal) was incorporated into poly(vinyl alcohol) (PVA) to prepare novel Sal/PVA hybrid hydrogels by repeated freeze-thaw processing. Physicochemical and biological characteristics of the hydrogels were investigated to evaluate their potential as cell adhesion materials. By increasing the Salecan content in the hybrid hydrogels, their swelling capacity increased notably, while the compressive modulus decreased. Observed by SEM, Sal/PVA hydrogels had a homogeneous porous structure. The degradation rate of the hydrogels can be controlled by tailoring the composition ratio of Sal/PVA. Furthermore, cells could adhere well on the surface of Sal/PVA hydrogels. In conclusion, these results make Sal/PVA hydrogels attractive materials for biomedical applications. PMID- 25542109 TI - Peroxidase-mediated conjugation of corn fiber gum and bovine serum albumin to improve emulsifying properties. AB - The emulsifying properties of corn fiber gum (CFG), a naturally occurring polysaccharide-protein complex, was improved by kinetically controlled formation of hetero-covalent linkages with bovine serum albumin (BSA), using horseradish peroxidase (HRP). The formation of hetero-crosslinked CFG-BSA conjugates was confirmed using ultraviolet-visible and Fourier-transform infrared analyses. The optimum CFG-BSA conjugates were prepared at a CFG:BSA weight ratio of 10:1, and peroxidase:BSA weight ratio of 1:4000. Selected CFG-BSA conjugates were used to prepare oil-in-water emulsions; the emulsifying properties were better than those of emulsions stabilized with only CFG or BSA. Measurements of mean droplet sizes and zeta potentials showed that CFG-BSA-conjugate-stabilized emulsions were less susceptible to environmental stresses, such as pH changes, high K ionic strengths, and freeze-thaw treatments than CFG- or BSA-stabilized emulsions. These conjugates have potential applications as novel emulsifiers in food industry. PMID- 25542110 TI - Synthesis of starch-g-lactic acid copolymer with high grafting degree catalyzed by ammonia water. AB - The study of starch-g-lactic acid copolymer has gained much attention for its completely degradable property, but its intricate synthetic procedure and low graft degree inhibited its further application. In this work, the synthesis of starch-g-lactic acid copolymer was attempted via the catalysis of ammonia water by one-step process, and the structure of starch-g-lactic acid copolymer was characterized by means of IR, (13)C NMR and HMBC. The synthetic conditions were optimized as follows, the starch was activated for 2h at 80 degrees C at first, starch and lactic acid with weight ratios of 1:4 reacted for 4h at 90 degrees C in vacuum. The starch-g-lactic acid copolymer can be finally obtained with graft degree of starch 58.9%. PMID- 25542111 TI - Eco-friendly finishing agent for cotton fabrics to improve flame retardant and antibacterial properties. AB - This research work deals with flame retardant and antibacterial finishing agent for cellulosic fabrics using TiO2 nanoparticles and chitosan phosphate. TiO2 nanoparticles were prepared by sol-gel method using titanium tetraisopropoxide. The size of TiO2 nanoparticles was characterized using transmission electron microscope (TEM). The application of nano TiO2 onto cellulosic fabrics (cotton 100%) was achieved in presence of polycarboxylic acid [1,2,3,4-butane tetracarboxylic acid (BTCA)] with sodium hypophosphite (SHP) as catalyst and chitosan phosphate through conventional pad-dry-cure method. The effect of the finishing on the physical properties, flammability and antibacterial properties of cross-linked fabrics are investigated. Thermal gravimetric analysis (TGA) was employed to investigate the thermal decomposition behaviour of the treated samples. Limited oxygen indexes (LOI) of the treated cotton fabrics were investigated. The treated cotton fabric also reveals excellent antibacterial properties. PMID- 25542112 TI - NMR characterization of cellulose acetate: chemical shift assignments, substituent effects, and chemical shift additivity. AB - A series of cellulose acetates (CA) with degrees of substitution (DS) ranging from 2.92-0.92 dissolved in dimethylsulfoxide (DMSO)-d6 and cellulose dissolved in tetrabutylammonium fluoride (TBAF)/DMSO-d6 were investigated by two dimensional NMR spectroscopy. The NMR spectroscopic analysis allowed the determination of the (1)H and (13)C NMR chemical shifts of the eight anhydroglucose units (AGUs) that contain CA: 2,3,6-tri-, 2,3-di-, 2,6-di-, 3,6-di , 2-mono-, 3-mono-, 6-mono-, and unacetylated AGUs. A comparative analysis of the chemical shift data revealed the substituent effect of acetyl groups at the 2-, 3 , and 6-positions on the (1)H and (13)C nuclei in the same AGU. In addition, chemical shift additivity could be applied to the (1)H and (13)C chemical shifts of CA because the chemical shifts of the diacetylated and triacetylated AGUs could be almost completely explained by the acetyl substituent effects at the 2-, 3-, and 6-positions. PMID- 25542113 TI - Structure characterization and antitumor activity of a polysaccharide from the alkaline extract of king oyster mushroom. AB - A water-soluble polysaccharide, designated as KOMAP, was isolated and purified from the alkaline extract of king oyster mushroom, which was composed of glucose (Glc), mannose (Man) and arabinose (Ara) in a molar ratio of 6.2:2.1:2.0. It had an average molecular weight of 2.1*10(4)Da. GC-MS analysis revealed that KOMAP was a linear structure of the polymer with a backbone composed of beta-1,4-linked glucopyranosyl and beta-1,3,6-linked mannopyranosyl units, which was terminated with alpha-1-linked arabinofuranosyl unit at C-6 position of beta-1,3,6-linked mannopyranosyl residue along the main chain in the ratio of 3.1:1. The results in the animal experiment showed that 50, 100 and 200mg/mL of KOMAP not only inhibited the tumor growth, but also increased relative thymus and spleen indices, LPS- or ConA-induced lymphocytes proliferation, and serum cytokine IL-2, TNF-alpha, and IFN-gamma levels, as well as the activities of NK cells and CTLs in spleen of Renca tumor-bearing mice. In summary, our data indicate that the KOMAP exerts effective immunoregulatory and anti-tumor activities in vivo. PMID- 25542114 TI - Water-induced local ordering of chitosan polymer chains in thin layer films. AB - Carbon-13 NMR (CP-MAS and FSLG (1)H-(13)C HETCOR) have been applied to chitosan salt films synthesized in acetic acid and exposed to different relative humidity environments (32% or 75%) at 20 degrees C for 1 month. It gives insight in the relationship between structure and functional properties according to the hydration level of this biomaterial as a film. The acetate ions trapped in the chitosan act as structuring agents between chitosan chains for the low hydration state. But, increasing the moisture content induces spontaneous removal of acetic acid and a subsequent modification in the film structure, with an increase in local ordering. HETCOR experiments also showed a multiplicity of signals for most of the observed carbon atoms and in particular those implied in the glycosidic linkage, which reveals different water-induced conformational states. Changing the water content allows to modify the polymer structure and therefore to modulate the properties such as controlled release of active compounds trapped in chitosan-based coatings, e.g., for medicated dressing or active packaging. PMID- 25542115 TI - Fabrication of hydrophobic, electrically conductive and flame-resistant carbon aerogels by pyrolysis of regenerated cellulose aerogels. AB - In this paper, we reported miscellaneous carbon aerogels prepared by pyrolysis of regenerated cellulose aerogels that were fabricated by dissolution in a mild NaOH/PEG solution, freeze-thaw treatment, regeneration, and freeze drying. The as prepared carbon aerogels were subsequently characterized by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), nitrogen adsorption measurements, X-ray diffraction (XRD), Raman spectroscopy, and water contact angle (WCA) tests. The results showed that the carbon aerogels with pore diameters of 1-60 nm maintained interconnected three-dimensional (3D) network after the pyrolysis, and showed type-IV adsorption isotherm. The pyrolysis process leaded to the decomposition of oxygen-containing functional groups, the destruction of cellulose crystalline structure, and the formation of highly disordered amorphous graphite. Moreover, the carbon aerogels also had strong hydrophobicity, electrical conductivity and flame retardance, which held great potential in the fields of waterproof, electronic devices and fireproofing. PMID- 25542116 TI - Structure and properties of moisture-resistant konjac glucomannan films coated with shellac/stearic acid coating. AB - A series of moisture-resistant konjac glucomannan films were prepared by coating shellac/stearic acid emulsion on deacetylated konjac glucomannan films (dKGM). The effect of stearic acid content on structure and properties of the coated films were investigated by field emission scanning electron microscopy (FE SEM), Fourier transform infrared spectroscopy (FT-IR), ultraviolet spectroscopy (UV), water vapor permeability (WVP), water uptake, water contact angle, and tensile testing. The results revealed that shellac in the coating adhered intimately to the surface of dKGM film, and provided a substrate for the dispersion of stearic acid which played an important role in enhancement of the moisture barrier properties and mechanical properties of the coated films. The WVP of the coated films decreased from 2.63*10(-11) to 0.37*10(-11)g/(msPa) and the water contact angle increased from 68 degrees to 101.2 degrees when stearic acid content increased from 0wt% to 40wt%, showing the potential applications in food preservation. PMID- 25542117 TI - Preparation of bulk sodium carboxymethyl cellulose aerogels with tunable morphology. AB - Homogeneous and bulk carboxymethyl cellulose hydrogel and aerogel were prepared by a novel process, using Fe(3+) and d-(+)-gluconic acid-lactone as cross-linker and releasing agent, respectively. The results showed that the mass fraction of Fe(3+) has a great effect on CMC aerogels' structure, crystallization and morphology. By adjusting the mass fraction of Fe(3+), granular, three-dimensional network and rod-like morphology were obtained, responding to varying density and porosity. The aerogel had low density (low to 0.0568 g/cm(3)) and high porosity (up to 90.45%). Meantime. Combination patterns between carboxylate ion and iron ion were checked by FTIR. Furthermore, with the addition of Fe(3+), lattice mismatch of CMC emerged and led to decreasing crystalline degree and thermal stability. This work would play an important role in the handy and extensive application of CMC aerogels. PMID- 25542118 TI - PCL/chitosan/Zn-doped nHA electrospun nanocomposite scaffold promotes adipose derived stem cells adhesion and proliferation. AB - Chitosan (Ch), and poly(E-caprolactone) (PCL), widely used as biomaterials with desirable properties for tissue engineering applications, were both blended with zinc-doped hydroxyapatite nanoparticles(nZnHA) and electrospun into nanofibrous scaffolds using formic acid/acetic acid. The rationale behind this study was to demonstrate that presence of small quantities of Zn(2+) ions doped in HA nanoparticles can improve biocompatibility of PCL/Ch blends. SEM observation revealed that average fiber diameter was increased from about 136 nm for a PCL/Ch blend, to around 210 nm for PCL/Ch/nZnHA nanocomposite. PCL/Ch/nZnHA scaffolds offered higher elastic modulus (about 3-fold) and tensile strength (nearly 1.5 fold) than the corresponding PCL/Ch scaffolds. In-vitro biocompatibility studies using human adipose derived stem cells (hAD-MSCs), demonstrated that the presence of only 5 wt% nZnHA in PCL/Ch/nZnHA nanocomposites enhanced hAD-MSCs' attachment compared to PCL/Ch and PCL/Ch/nHA. Finally, hAD-MSCs proliferation occurred at significantly higher rates of 1.5, 1.3 and 1.2 times on PCL/Ch/nZnHA scaffold compared to PCL, PCL/Ch and PCL/Ch/nHA, respectively. PMID- 25542119 TI - Properties of alginate fiber spun-dyed with fluorescent pigment dispersion. AB - Spun-dyed alginate fiber was prepared by the spun-dyeing method with the mixture of fluorescent pigment dispersion and sodium alginate fiber spinning solution, and its properties were characterized by SEM, TGA, DSC, and XRD. The results indicate that fluorescent pigment dispersion prepared with esterified poly (styrene-alt maleic acid) had excellent compatibility with sodium alginate fiber spinning solution, and small amount of fluorescent pigment could reduce the viscosity of spun-dyed spinning solutions. SEM photo of spun-dyed alginate fiber indicated that fewer pigment particles deposited on its surface. TGA, DSC, and XRD results suggested that thermal properties and crystal phase of spun-dyed alginate fibers had slight changes compared to the original alginate fibers. The fluorescence intensity of spun-dyed alginate fiber reached its maximum when the content of fluorescent pigment was 4%. The spun-dyed alginate fiber showed excellent rubbing and washing fastness. PMID- 25542120 TI - Crystalline characteristics of cellulose fiber and film regenerated from ionic liquid solution. AB - Regenerated cellulose fiber, fiber extrudate, and film were produced from cellulose solution prepared with raw pulp and ionic liquid solvent 1-butyl-3 methylimidazolium chloride ([BMIM]Cl). Spinning setting was based on a dry-jet and wet-spun approach including extrusion, coagulation, drawing, drying, and winding. Crystallization of the experimental fiber, fiber extrudate, and film was evaluated using a technique of wide angle X-ray diffraction (WAXD). Crystallinity index, crystallite size, and crystal orientation factor were calculated and compared among these samples. Influence of die shape, die dimension, and drawing speed on the regenerated cellulose crystallinity was discussed. The study indicated that the pulp cellulose was a Cellulose I type structure. The cellulose regeneration from the [BMIM]Cl solution completed a transformation from this intermediate phase to a final Cellulose II phase. The die shape and dimension and drawing speed were all important factors affecting the crystallinity of regenerated cellulose fiber and film. PMID- 25542121 TI - Complexation of estragole as pure compound and as main component of basil and tarragon essential oils with cyclodextrins. AB - Inclusion complexes of estragole (ES) as pure compound and as main component of basil and tarragon essential oils (EOs) with alpha-cyclodextrin (alpha-CD), beta cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), randomly methylated-beta-cyclodextrin (RAMEB), a low methylated-beta-cyclodextrin (CRYSMEB) and gamma-cyclodextrin (gamma-CD) were characterized. Formation constants (Kf) of the complexes were determined in aqueous solution by nonlinear regression analysis using static headspace gas chromatography (SH-GC) and UV visible spectroscopy. Solid inclusion complexes were prepared by the freeze drying method for different CD:ES molar ratios and were characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). Inclusion complexes formation allowed the controlled release of ES. Moreover, increased DPPH radical scavenging activity and photostability of ES and ES containing EOs (ESEOs) were observed in the presence of CDs. These findings suggest that encapsulation with CDs could be an efficient tool to improve the use of ES and ESEOs in aromatherapy, cosmetic and food fields. PMID- 25542122 TI - The reuse of wastepaper for the extraction of cellulose nanocrystals. AB - The study reports on the preparation of cellulose nanocrystals (CNCs) from wastepaper, as an environmental friendly approach of source material, which can be a high availability and low-cost precursor for cellulose nanomaterial processing. Alkali and bleaching treatments were employed for the extraction of cellulose particles followed by controlled-conditions of acid hydrolysis for the isolation of CNCs. Attenuated total reflectance Fourier Transform Infrared (ATR FTIR) spectroscopy was used to analyze the cellulose particles extracted while Transmission electron microscopy images confirmed the presence of CNCs. The diameters of CNCs are in the range of 3-10nm with a length of 100-300nm while a crystallinity index of 75.9% was determined from X-ray diffraction analysis. The synthesis of this high aspect ratio of CNCs paves the way toward alternative reuse of wastepaper in the production of CNCs. PMID- 25542123 TI - Amorphized cellulose as filler in biocomposites based on poly(E-caprolactone). AB - Amorphous cellulose particles, obtained through a solvent-free mechano-chemical process, have been tested for the first time as a potential filler for biodegradable composites based on poly(E-caprolactone) (PCL). Commercial cellulose fibers have been also tested for comparison. An effective interfacial strategy based on a compatibilizing agent, a modified PCL, has been used to improve the polymer/filler interfacial adhesion. Composites have been tested through physico-mechanical characterizations and soil burial degradation tests, in order to evaluate the influence of cellulose structure and morphology and polymer/filler interfacial adhesion on the final properties of the realized materials. The use of the amorphous cellulose particles combined with the presence of a suitable interfacial agent has allowed to modulate relevant technological properties of the realized composites, such as tensile and thermal properties, water absorption, water vapor transmission rate and biodegradation kinetic. PMID- 25542124 TI - Flame retardant cotton fibers produced using novel synthesized halogen-free phosphoramide nanoparticles. AB - Flame retardant cotton fibers were successfully produced using five new nanosized phosphoramide compounds synthesized by ultrasonic method. The (1)H NMR spectra of compounds 1-3 illustrate (3)J(H,H)cis and (3)J(H,H)trans corresponding to the splittings of cis and trans protons present in the CHCH2 bond. Comparing the char lengths of cotton fibers treated with phosphoramides 1-5 indicates that the samples with greater degree of grafting (DG) provide smaller char lengths so that the least and the greatest char lengths are observed for the treated fibers with phosphoramides 1 and 5, respectively. The very close DG and char lengths of compounds 1 and 2 can be described based on their chemical structures containing 4-nitroaniline and 4-chloro-3-trifluoromethyl aniline groups that both can release electrons through their resonance effects to their corresponding PN bonds and enhance the PN system synergistic effect. The TGA/DSC analyses on the treated fibers revealed that the maximum weight losses at 800 degrees C are occurred within the range 43.52% (for fiber treated with 1) to 56.37 (for fiber treated with 5) which are all smaller than that of the raw fiber (56.83%). The in vitro antibacterial activity experiments on phosphoramides 1-5 displayed the greatest and the least antibacterial activities for compounds 2 and 4, respectively. Furthermore, when these phosphoramides are applied on the cotton fibers, they also demonstrate the above order for the antibacterial activities. PMID- 25542125 TI - In situ mapping of the effect of additional mutations on starch granule structure in amylose-extender (ae) maize kernels. AB - Optical (KI/I2-staining, polarised) and FTIR microscopy has been used to monitor starch granule structure within wild-type (wt), GEMS-0067 and waxy-amylose extender (wx-ae) maize mutant kernels. In the GEMS-0067 mutant containing the high amylose modifier (HAM) gene(s) plus the recessive ae gene, structural heterogeneity characteristic of the ae mutation was reduced markedly. However, enhanced variation in granule shape and size was observed distributed spatially within the kernel, which appears to be related to new heterogeneity in internal starch granule structure. In wx-ae starch mutants the ae gene led to heterogeneity of starch granule structure equivalent to that in single ae mutants, plus new structural heterogeneity coincident with novel induced variation in granule size and shape. PMID- 25542126 TI - Theranostic magnetoliposomes coated by carboxymethyl dextran with controlled release by low-frequency alternating magnetic field. AB - The aim of this work was to construct carboxymethyl dextran (CMD)-coated magnetoliposomes (MLs), another stealth MLs alternative to PEGylated MLs, for theranostic application. Particularly, the on-demand release of CMD-MLs under low frequency alternating magnetic field (LF-AMF) was studied. We found that as prepared MLs exhibited good stability and high drug loading ability for doxorubicin (DOX). Cytotoxicity assay against human neuroblastoma SH-SY5Y cells showed that the DOX-loaded CMD-MLs were less toxic than free DOX due to the sustained release of DOX. However, the release of DOX-loaded CMD-MLs was enhanced by low-frequency alternating magnetic field without hyperthermia generation. The MLs also acted as an efficient T2-weighted contrast agent during in vitro MRI measurements. The above results provide useful information on in vivo diagnostic/therapeutic efficacy of DOX-loaded CMD-MLs for some cancers, such as brain cancers. PMID- 25542127 TI - Synthesis, anti-oxidant activity, and biodegradability of a novel recombinant polysaccharide derived from chitosan and lactose. AB - A novel recombinant polysaccharide (RP) based on polysaccharide-disaccharide was synthesized from oligo-chitosan (oligo-CS) and reducing lactose using Maillard reaction with the yield of 85.1%. Chemical structure and thermal stability of RP was characterized by Fourier transform infrared spectrum (FT-IR), solid-state nuclear magnetic resonance spectroscopy (CP/MAS (13)C-NMR), and thermo gravimetric analysis (TGA). The anti-oxidant activity of RP was preliminarily investigated by its scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. Biodegradability of RP was also examined by the observation of growth status of Aspergillus niger colony. It was demonstrated that RP achieved excellent radical-scavenging efficiency (>80%) at high concentrations of DPPH and its scavenging ability was superior to that of CS, suggesting that anti-oxidant property of CS was remarkably promoted by chemical modification with reducing lactose via Maillard reaction. And biodegradation test revealed that RP had better biodegradability than CS. PMID- 25542128 TI - Molecular, mesoscopic and microscopic structure evolution during amylase digestion of extruded maize and high amylose maize starches. AB - Extrusion processing of cereal starch granules with high (>50%) amylose content is a promising approach to create nutritionally desirable resistant starch, i.e. starch that escapes digestion in the small intestine. Whilst high amylose content seems to be required, the structural features responsible for the slow digestion of extrudates are not fully understood. We report the effects of partial enzyme digestion of extruded maize starches on amylopectin branch length profiles, double and single helix contents, crystallinity and lamellar periodicity. Comparing results for three extruded maize starches (27, 57, and 84% apparent amylose) that differ in amylase-sensitivity allows conclusions to be drawn concerning the rate-determining features operating under the digestion conditions used. Enzyme resistance is shown to originate from a combination of molecular and mesoscopic factors, including both recrystallization and an increase in very short branches during the digestion process. This is in contrast to the behaviour of the same starches in the granular form (Shrestha et al., 2012) where molecular and mesoscopic factors are secondary to microscopic structures in determining enzyme susceptibility. Based on the structure of residual material after long time digestion (>8h), a model for resistant starch from processed high amylose maize starches is proposed based on a fringed micelle structure with lateral aggregation and enzyme susceptibility both limited by attached clusters of branch points. PMID- 25542130 TI - A novel metal coordination enabled in carboxylated alginic acid for effective fluoride removal. AB - This article enlightens the synthesis of carboxylated alginic acid (CAA) and metal ions coordinated CAA (M-CAA) for defluoridation studies in batch mode. The oxidation of alginic acid (AA) with KMnO4 gives CAA and the metal coordination was enabled in CAA by using high valence metal ions viz., La(3+) (La-CAA) and Zr(4+) (Zr-CAA). The synthesized materials Zr-CAA, La-CAA and CAA possess the defluoridation capacities (DCs) of 4064, 3137 and 880 mgF(-)/kg respectively. An enhanced DC was observed for metal-coordinated CAA (M-CAA) than CAA. The defluoridation experiments were carried with numerous influencing parameters like contact time, pH and competitor anions for optimization. The characterization of materials was carried out using FTIR, EDAX and SEM analysis. The sorption data was fitted with various isotherms and kinetic models. The values of thermodynamic parameters indicate the nature of fluoride removal is spontaneous and endothermic. At field conditions, M-CAA reduce the fluoride concentration below the tolerance limit. PMID- 25542129 TI - Ink jet printing of bio-treated linen, polyester fabrics and their blend. AB - Cellulosic fabrics were surface modified using Brewer's yeast filtrate and cellulase enzymes (Valumax A828, Valumax A356) to enhance its affinity to ink jet printing. The effect of enzymes on the surface structure and morphology of the cellulosic fabrics used has been illustrated using scanning electron microscope. Related test as tensile strength have been measured. The bio-treated cellulosic fabrics were digitally printed and the colour strength (K/S) and % increase in K/S were measured. Effect of different conditions (enzyme concentration, temperature and time) was investigated to obtain the optimum condition of each enzyme for each fabric that or which was indicated by higher colour strength. Results show a noticeable increase in the K/S especially for cellulosic linen and its blend compared to the standard samples. The optimum conditions to obtain the higher K/S by using Brewer's yeast filtrate and the other two cellulase enzymes in the pre-treatment of ink jet samples were obtained. PMID- 25542131 TI - Elaboration, morphology and properties of starch/polyester nano-biocomposites based on sepiolite clay. AB - The incorporation of nano-sized sepiolite clays into thermoplastic starch/poly(butylene adipate-co-terephthalate) (TPS/PBAT) blends has been investigated with the goal of improving the matrix properties. TPS/PBAT nano biocomposites were elaborated with two different proportions of the polymeric phases. The influence of the sepiolite nanoclays on the mechanical, thermal and structural properties of the corresponding blends was evaluated. SEM images confirmed the good dispersion of the sepiolite clay, with a low occurrence of small aggregates in the polymeric matrix. Wide-angle X-ray diffraction showed no significant alteration of the crystalline structures of PBAT and starch induced by the sepiolite clay. The addition of sepiolite slightly affected the thermal degradation of the nano-biocomposites; however, the mechanical tests revealed an increase in some mechanical properties, demonstrating that sepiolite is a promising nanofiller for TPS-based materials. PMID- 25542132 TI - Digestibility prediction of cooked plantain flour as a function of water content and temperature. AB - The effect of temperature (T=55-120 degrees C) and water content (X1=1.4-2.0 kg kg(-1) dry basis) on the gelatinization and digestibility of plantain flour (Dominico Harton genotype) were investigated. The degree of plantain starch gelatinization (alpha) was measured by DSC and modelled as a function of T and X1, using the Weibull model. Rapidly digestible starch (RDS) and resistant starch (RS) fractions were evaluated for different alpha values. An appropriate dimensionless variable was introduced to the analyzed and modelled RDS and RS as a function of alpha. Starch gelatinization begins at a temperature above 59.6 +/- 0.5 degrees C and alpha is strongly dependent on T in non-limiting water conditions. The combined effects of T and X1 on the RDS and RS can be explained by alpha. We demonstrate that various heat treatments and water contents lead to the same alpha, with the same RDS and RS values. PMID- 25542133 TI - Thermodynamic modelling of asphaltene precipitation and related phenomena. AB - Asphaltenes are considered to be the heaviest and most polar fractions of crude oils and are frequently implicated in problems encountered during production and refining as a result of phase separation. In recent years, considerable effort has been given to understanding the phase behaviour of these structurally heterogeneous materials from both experimental and computational perspectives. Various experimental studies have confirmed the long-advanced colloidal behaviour of asphaltenes in organic media, and this has inspired a number of modelling strategies. The present review is specifically concerned with advances in modelling asphaltene phase behaviour with emphasis on the use of the statistical associating fluid theory (SAFT), which it attempts to place into the wider context of thermodynamic treatments. PMID- 25542134 TI - Evaluation of cytotoxic and apoptotic effects of individual and mixed 7 ketophytosterol oxides on human intestinal carcinoma cells. AB - Phytosterol oxidation products (POPs) are constituents of the human diet. Definitive information on the toxic or biological effects of POPs is limited and in some cases contradictory. This study evaluates the cytotoxicity of four individual 7-ketophytosterol oxides, including 7-ketositosterol (7K-SI), 7 ketocampesterol (7K-CA), 7-ketobrassicasterol (7K-BR), 7-ketostigmasterol (7K ST), and a mixture of 7-ketophytosterols (7K-MIX) toward a human intestinal carcinoma (HIC) cell line. Results showed that all tested compounds reduced cell proliferation in a dose-dependent manner; especially 7K-SI and 7K-CA exhibited higher activities. Both compounds increased early apoptotic cells and caused cell cycle arrest in the G1 phase with cell accumulation in the S phase. No evidence of cell death was observed induced by 7K-ST and 7K-MIX. Furthermore, 7K-SI, 7K CA, and 7K-BR induced apoptosis by enhancing caspase-3 activity and the modulatory effects of Bcl-2, while 7K-ST and 7K-MIX did not involve caspase-3 activation and Bcl-2 down-regulation. PMID- 25542135 TI - Real time analysis of volatile organic compounds (VOCs) in centenarians. AB - Centenarians are a model to study human longevity and the physiological process of aging. A plethora of studies on this model show the complexity of the system. Laboratory studies fail to find a biomarker of senescence. The real time exhaled breath volatile organic compounds (VOCs) has been suggested as a new biomarker to detect and monitor physiological processes in the respiratory system. VOCs exhaled by centenarians have not been studied in the general population and across-age-groups. In the present study we investigated, in real time, the breath properties and VOC exhaled content in healthy centenarians as compared with non centenarian seniors and young healthy subjects. We found distinctly different breath pattern and distribution profiles of VOCs in the centenarians. Thus, the VOCs measurement allowed to discriminate the differences between the age-groups. We propose a VOCs fingerprint as a biomarker underlying the physiological mechanisms of aging and longevity. Longevity should be considered physiologically as a new phase of life, characteristic of the well adapted subject. PMID- 25542136 TI - An acridine orange spore germination fluorescence microscopy versus spectral paradox. AB - The metachromatic fluorophore acridine orange (AO) has demonstrated green fluorescent staining of dormant Bacillus spores and orange to red staining of transcriptionally active vegetative cells when used in the mid-micoMolar range. Despite the microscopic observation of numerous bright orange to red fluorescent vegetative cells following germination induction, no clear spectral emission peaks > 590 nm have ever been reported for spectrofluorometric analysis involving AO in conjunction with spore germination. This microscopy versus spectrofluorometry paradox is documented in the present report and hypotheses are put forth to explain the very weak spectral changes in the red region which do not appear to correlate with the abundant orange-red fluorescence of nascent vegetative cells seen through the fluorescence microscope. PMID- 25542137 TI - Ochratoxin A promotes porcine circovirus type 2 replication in vitro and in vivo. AB - Ochratoxin A (OTA), a worldwide mycotoxin found in food and feeds, is a potent nephrotoxin in animals and humans. Porcine circovirus-associated disease (PCVAD), including porcine dermatitis and nephropathy syndrome, is a worldwide swine disease. To date, little is known concerning the relationship between OTA and porcine circovirus type 2 (PCV2), the primary causative agent of PCVAD. The effects of OTA on PCV2 replication and their mechanisms were investigated in vitro and in vivo. The results in vitro showed that low doses of OTA significantly increased PCV2 DNA copies and the number of infected cells. Maximum effects were observed at 0.05 MUg/ml OTA. The results in vivo showed that PCV2 replication was significantly increased in serum and tissues of pigs fed 75 MUg/kg OTA compared with the control group and pigs fed 150 MUg/kg OTA. In addition, low doses of OTA significantly depleted reduced glutathione and mRNA expression of NF-E2-related factor 2 and gamma-glutamylcysteine synthetase; increased reactive oxygen species, oxidants, and malondialdehyde; and induced p38 and ERK1/2 phosphorylation in PK15 cells. Adding N-acetyl-L-cysteine reversed the changes induced by OTA. Knockdown of p38 and ERK1/2 by their respective specific siRNAs or inhibition of p38 and ERK1/2 phosphorylation by their respective inhibitors (SB203580 and U0126) eliminated the increase in PCV2 replication induced by OTA. These data indicate that low doses of OTA promoted PCV2 replication in vitro and in vivo via the oxidative stress-mediated p38/ERK1/2 MAPK signaling pathway. This suggests that low doses of OTA are potentially harmful to animals, as they enhance virus replication, and partly explains why the morbidity and severity of PCVAD vary significantly in different pig farms. PMID- 25542138 TI - Markers of macromolecular oxidative damage in maternal serum and risk of neural tube defects in offspring. AB - Neural tube defects (NTDs) are among the most common and severe congenital malformations. To examine the association between markers of macromolecular oxidative damage and risk of NTDs, we measured levels of 8-hydroxy-2' deoxyguanosine (8-OHdG), protein carbonyl (PC), and 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) in maternal serum samples of 117 women with NTD-affected pregnancies and 121 women with healthy term newborns. We found higher levels of 8 OHdG and PC in the NTD group than in the control group; however, we did not observe a statistically significant difference in 8-iso-PGF2alpha levels between the NTD and the control groups. NTD risk increased with increasing quartiles of 8 OHdG [odds ratio (OR)=1.17; 95% confidence interval (CI) 0.39-3.51; OR=2.19; 95% CI, 0.68-7.01; OR=3.70; 95% CI, 1.30-10.51, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.009], and with increasing quartiles of PC (OR=2.26; 95% CI, 0.66-7.69; OR=3.86; 95% CI, 1.17 12.80; OR=5.98; 95% CI, 1.82-19.66, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.002]. Serum levels of 8-OHdG were higher in women who did not take folic acid supplements during the periconceptional period. These results suggest that oxidative stress is present in women carrying pregnancies affected by NTDs. PMID- 25542139 TI - Maternal diet during pregnancy and unilateral retinoblastoma. AB - PURPOSE: Previous studies have suggested a role for parental diet in childhood cancer prevention, but there are few studies of retinoblastoma. The aim of this study was to examine the relation between maternal diet and unilateral retinoblastoma. METHODS: A case-control study of 163 unilateral RB cases and 136 controls ascertained information on maternal diet during pregnancy using a standardized food frequency questionnaire. Logistic regression was used to assess the relation between retinoblastoma and food groups and dietary patterns. RESULTS: We observed a negative association between retinoblastoma and intake of fruit [odds ratio (OR) 0.38, 95 % confidence interval (CI) 0.14-1.02]. Positive associations were seen with intake of cured meats (OR 5.07, 95 % CI 1.63-15.70) and fried foods (OR 4.89, 95 % CI 1.72-13.89). A food pattern of high fruits and vegetables and low fried food and sweets was negatively associated with disease (OR 0.75, 95 % CI 0.61-0.92). CONCLUSION: Our study provides preliminary evidence that mothers who consume diets higher in fruit and lower in fried foods and cured meats during pregnancy may reduce the risk of unilateral retinoblastoma in their offspring. PMID- 25542140 TI - Total, direct, and indirect effects of paan on oral cancer. AB - PURPOSE: Paan (betel leaf and betel nut quid) used with or without tobacco has been positively associated with oral cancer. Oral submucous fibrosis (OSMF), a precancerous condition caused by paan, lies on the causal pathway between paan use and oral cancer. The purpose of this analysis was to estimate the effect of paan consumption on oral cancer risk when it is mediated by OSMF. METHODS: We used mediation methods proposed by VanderWeele, which are based on causal inference principles, to characterize the total, direct, and indirect effects of paan, consumed with and without tobacco, on oral cancer mediated by OSMF. We reanalyzed case-control data collected from three hospitals in Karachi, Pakistan, between July 1996 and March 1998. RESULTS: For paan without tobacco, the total effect on oral cancer was OR 7.39, 95 % CI 1.01, 38.11, the natural indirect effect (due to OSMF among paan users) was OR 2.48, 95 % CI 0.99, 10.44, and the natural direct effect (due to paan with OSMF absent) was OR 3.32, 95 % CI 0.68, 10.07. For paan with tobacco, the total direct effect was OR 15.68, 95 % CI 3.00, 54.90, the natural indirect effect was OR 2.18, 95 % CI 0.82, 5.52, and the natural direct effect was OR 7.27, 95 % CI 2.15, 20.43. CONCLUSIONS: Paan, whether or not it contained tobacco, raised oral cancer risk irrespective of OSMF. Oral cancer risk was higher among those who used paan with tobacco. PMID- 25542141 TI - Evaluation of the toxicity data for peracetic acid in deriving occupational exposure limits: a minireview. AB - Peracetic acid (PAA) is a peroxide-based chemistry that is highly reactive and can produce strong local effects upon direct contact with the eyes, skin and respiratory tract. Given its increasing prominence in industry, attention has focused on health hazards and associated risks for PAA in the workplace. Occupational exposure limits (OEL) are one means to mitigate risks associated with chemical hazards in the workplace. A mini-review of the toxicity data for PAA was conducted in order to determine if the data were sufficient to derive health-based OELs. The available data for PAA frequently come from unpublished studies that lack sufficient study details, suffer from gaps in available information and often follow unconventional testing methodology. Despite these limitations, animal and human data suggest sensory irritation as the most sensitive endpoint associated with inhalation of PAA. Rodent RD50 data (the concentration estimated to cause a 50% depression in respiratory rate) were selected as the critical studies in deriving OELs. Based on these data, a range of 0.36-0.51mg/m(3) (0.1-0.2ppm) was calculated for a time-weighted average (TWA), and 1.2-1.7mg/m(3) (0.4-0.5ppm) as a range for a short-term exposure limit (STEL). These ranges compare favorably to other published OELs for PAA. Considering the applicable health hazards for this chemistry, a joint TWA/STEL OEL approach for PAA is deemed the most appropriate in assessing workplace exposures to PAA, and the selection of specific values within these proposed ranges represents a risk management decision. PMID- 25542142 TI - Metabolism of modified mycotoxins studied through in vitro and in vivo models: an overview. AB - Mycotoxins are toxic, secondary metabolites produced by fungi. They occur in a wide variety of food and feed commodities, and are of major public health concern because they are the most hazardous of all food and feed contaminants in terms of chronic toxicity. In the past decades, it has become clear that in mycotoxin contaminated commodities, many structurally related compounds generated by plant metabolism, fungi or food processing coexist with their free mycotoxins, defined as modified mycotoxins. These modified xenobiotics might endanger animal and human health as they are possibly hydrolysed into their free toxins in the digestive tract of mammals, and may consequently contribute to an unexpected high toxicity. As modified toxins represent an emerging issue, it is not a surprise that for most toxicological tests data are scarce to non-existent. Therefore, there is a need to elucidate the disposition and kinetics of both free and modified mycotoxins in mammals to correctly interpret occurrence data and biomonitoring results. This review emphasizes the current knowledge on the metabolism of modified mycotoxins using in vitro and in vivo models. PMID- 25542143 TI - Characterization of human lymphoblastoid cell lines as a novel in vitro test system to predict the immunotoxicity of xenobiotics. AB - Evaluating immunomodulatory effects of xenobiotics is an important component of the toxicity studies. Herein we report on the establishment of a novel invitro test system for the immunotoxicity screening of xenobiotics based on human lymphoblastoid cell lines (LCLs). Four immunotoxic compounds; tributyltin chloride, cyclosporine A, benzo(a)pyrene and verapamil hydrochloride, as well as three immune-inert compounds; urethane, furosemide and mannitol were selected for characterization. The treatment of LCLs with immunosuppressive compounds resulted in reduced viability. The IC50 values determined in human LCLs were in agreement with the data obtained for human peripheral mononuclear cells. Since cytokine production reflects lymphocytes responses to external stimuli, we evaluated the functional responses of LCLs by monitoring their pro-inflammatory and immunoregulatory cytokine production. Our findings prove that LCLs allowed for reliable differentiation between immunomodulatory and immune-inert compounds. Hence, pre-treatment with immunomodulatory compounds led to a decrease in the production of pro-inflammatory TNFalpha, IL-6 and immunoregulatory IL-2, IL-4, IL 10 and IFNgamma cytokines, when compared to untreated ionomycin/PMA stimulated cells. Moreover, testing a panel of ten LCLs derived from unrelated healthy individuals reflects inter-individual variability in response to immunomodulatory xenobiotics. In conclusion, LCLs provide a novel alternative method for the testing of the immunotoxic effects of xenobiotics. PMID- 25542145 TI - T-2 toxin regulates steroid hormone secretion of rat ovarian granulosa cells through cAMP-PKA pathway. AB - T-2 toxin is a secondary metabolite produced by Fusarium genus and is a common contaminant in food and feedstuffs of cereal origin. In porcine granulosa cells(GC), T-2 toxin has been shown to inhibit the steroidogenesis; however, the mechanism has not been well understood. Gonadotropin-stimulated steroidogenesis is regulated by the cAMP-PKA pathway. In this study, we investigated potential mechanisms for T-2 toxin-induced reproductive toxicity focusing on the critical steps of the cAMP-PKA pathway affected by T-2 toxin. We first analyzed the effects of T-2 toxin on progesterone and estrogen production in rat granulosa cells. For this purpose the granulosa cells were cultured for 48 h in 10% fetal bovine serum-containing medium followed by 24h in serum-free medium containing FSH (10 ng/ml) and androstenedione (3 ng/ml), both are required for normal steroidogenesis. Treatment of these cells with T-2 toxin dose-dependently inhibited the growth of cells and the steroid hormone production. Cellular cyclic AMP levels were dose-dependently inhibited by T-2 toxin (0, 1, 10 and 100 nM, 24 h). Furthermore, we found that although the induction of progesterone by 8-Br cAMP (a FSH mimetic) and 22R-HC (substrate for progesterone) could both be inhibited by T-2 toxin treatment, the T-2-imposed inhibitory effects could be reversed by increasing doses of 22R-HC, while increasing 8-Br-cAMP had no effects, suggesting that T2 toxin targeted at distinct mechanisms. cAMP stimulated steroidogenic acute regulatory protein (StAR) is a rate limiting protein in progesterone synthesis. Exposure to T2 toxin caused significant suppression of StAR expression as determined by Western blotting and semi quantitative RT-PCR suggesting StAR is a sensitive target for T-2 toxin. Taken together, our results strongly suggest that T2 toxin inhibits steroidogenesis by suppressing cAMP-PKA pathway and StAR is a target for T-2-toxin. The antisteroidogenesis effects were observable at low T-2 dose (1 ng/ml) suggesting T-2 toxin has an endocrine disruptive effect. PMID- 25542146 TI - Role of dermal exposure in systemic intake of methylenediphenyl diisocyanate (MDI) among construction and boat building workers. AB - The causal relationship between inhalation exposure to methylenediphenyl diisocyanate (MDI) and the risk of occupational asthma is well known, but the role of dermal exposure and dermal uptake of MDI in this process is still unclear. The aims of this study were to measure dermal exposure to and the dermal uptake of MDI among workers (n=24) who regularly handle MDI-urethanes. Dermal exposure was measured by the tape-strip technique from four sites on the dominant hand and arm. The workers with the highest exposure (n=5) were biomonitored immediately after their work shift, in the evening and the next morning, using urinary 4,4'methylenedianiline (MDA) as a marker. Dermal uptake was evaluated by comparing workers' MDA excretions both when they were equipped with respiratory protective devices (RPDs) and when they did not use them. The measured amounts of MDI on their hands varied from below 0.1 to 17 MUg/10 cm(2) during the test. MDI concentrations were in the range of 0.08 to 27 MUg m(-3) in the breathing zone outside the RPDs. MDA concentrations varied from 0.1 to 0.2 MUmol mol(-1) creatinine during the test period. The decreasing effect of RPDs on inhalation exposure was absent in the next morning urine samples; this excretion pattern might be an indication of dermal uptake of MDI. PMID- 25542144 TI - Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR. AB - Activation of human pregnane X receptor (hPXR)-regulated expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1) plays an important role in mediating adverse drug interactions. Given the common use of natural products as part of adjunct human health behavior, there is a growing concern about natural products for their potential to induce undesired drug interactions through the activation of hPXR-regulated CYP3A4 and MDR1. Here, we studied whether 3,3'-diindolylmethane (DIM), a natural health supplement, could induce hPXR-mediated regulation of CYP3A4 and MDR1 in human hepatocytes and intestinal cells. DIM, at its physiologically relevant concentrations, not only induced hPXR transactivation of CYP3A4 promoter activity but also induced gene expression of CYP3A4 and MDR1. DIM decreased intracellular accumulation of MDR1 substrate rhodamine 123, suggesting that DIM induces the functional expression of MDR1. Pharmacologic inhibition or genetic knockdown of hPXR resulted in attenuation of DIM induced CYP3A4 and MDR1 gene expression, suggesting that DIM induces CYP3A4 and MDR1 in an hPXR-dependent manner. Together, these results support our conclusion that DIM induces hPXR-regulated CYP3A4 and MDR1 gene expression. The inductive effects of DIM on CYP3A4 and MDR1 expression caution the use of DIM in conjunction with other medications metabolized and transported via CYP3A4 and MDR1, respectively. PMID- 25542147 TI - Biomonitoring of airborne platinum group elements in urban traffic police officers. AB - In the present study, an attempt was made to study the levels of platinum (Pt), palladium (Pd), and rhodium (Rh) in respirable suspended particulate matter samples and respective blood samples of occupationally exposed traffic personnel in selected sites of Hyderabad city. The maximum concentration of platinum group elements in air dust samples of Hyderabad city were as follows: Pt = 1,416 ug/m(3), Pd = 1,024 ug/m(3), and Rh = 1,352 ug/m(3). The blood samples of occupationally exposed personnel of Hyderabad city showed Pt as high as 6.65, Pd as high as 2.15, and Rh as high as 4.95 ug/l. The results showed an important aspect of bioaccumulation tendency of these metals with increase in age and years of occupational exposure. PMID- 25542148 TI - Salinity-dependent nickel accumulation and oxidative stress responses in the euryhaline killifish (Fundulus heteroclitus). AB - The mechanisms of nickel (Ni) toxicity in marine fish remain unclear, although evidence from freshwater (FW) fish suggests that Ni can act as a pro-oxidant. This study investigated the oxidative stress effects of Ni on the euryhaline killifish (Fundulus heteroclitus) as a function of salinity. Killifish were exposed to sublethal levels (5, 10, and 20 mg L(-1)) of waterborne Ni for 96 h in FW (0 ppt) and 100 % saltwater (SW) (35 ppt). In general, SW was protective against both Ni accumulation and indicators of oxidative stress [protein carbonyl formation and catalase (CAT) activity]. This effect was most pronounced at the highest Ni exposure level. For example, FW intestine showed increased Ni accumulation relative to SW intestine at 20 mg Ni L(-1), and this was accompanied by significantly greater protein carbonylation and CAT activity in this tissue. There were exceptions, however, in that although liver of FW killifish at the highest exposure concentration showed greater Ni accumulation relative to SW liver, levels of CAT activity were greatly decreased. This may relate to tissue- and salinity-specific differences in oxidative stress responses. The results of the present study suggest (1) that there was Ni-induced oxidative stress in killifish, (2) that the effects of salinity depend on differences in the physiology of the fish in FW versus SW, and (3) that increased levels of cations (sodium, calcium, potassium, and magnesium) and anions (SO4 and Cl) in SW are likely protective against Ni accumulation in tissues exposed to the aquatic environment. PMID- 25542149 TI - Erratum to: Altered functional connectivity networks in acallosal and socially impaired BTBR mice. PMID- 25542150 TI - Different conformational dynamics of beta-arrestin1 and beta-arrestin2 analyzed by hydrogen/deuterium exchange mass spectrometry. AB - Arrestins have important roles in G protein-coupled receptor (GPCR) signaling including desensitization of GPCRs and G protein-independent signaling. There have been four arrestins identified: arrestin1, arrestin2 (e.g. beta-arrestin1), arrestin3 (e.g. beta-arrestin2), and arrestin4. beta-Arrestin1 and beta-arrestin2 are ubiquitously expressed and regulate a broad range of GPCRs, while arrestin1 and arrestin4 are expressed in the visual system. Although the functions of beta arrestin1 and beta-arrestin2 widely overlap, beta-arrestin2 has broader receptor selectivity, and a few studies have suggested that beta-arrestin1 and beta arrestin2 have distinct cellular functions. Here, we compared the conformational dynamics of beta-arrestin1 and beta-arrestin2 by hydrogen/deuterium exchange mass spectrometry (HDX-MS). We also used the R169E mutant as a pre-activation model system. HDX-MS data revealed that beta-strands II through IV were more dynamic in beta-arrestin2 in the basal state, while the middle loop was more dynamic in beta arrestin1. With pre-activation, both beta-arrestin1 and beta-arrestin2 became more flexible, but broader regions of beta-arrestin1 became flexible compared to beta-arrestin2. The conformational differences between beta-arrestin1 and beta arrestin2 in both the basal and pre-activated states might determine their different receptor selectivities and different cellular functions. PMID- 25542151 TI - Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer. AB - The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P<0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P=0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression. PMID- 25542152 TI - MiRNA-125a-5p inhibits glioblastoma cell proliferation and promotes cell differentiation by targeting TAZ. AB - Glioblastoma (GBM) is the most lethal brain tumor due to the resistance to conventional therapies, such as radiotherapy and chemotherapy. TAZ, an important mediator of the Hippo pathway, was found to be up-regulated in diverse cancers, including in GBM, and plays important roles in tumor initiation and progression. However, little is known about the regulation of TAZ expression in tumors. In this study, we found that miR-125a-5p is an important regulator of TAZ in glioma cells by directly targeting the TAZ 3' UTR. MiR-125a-5p levels are inversely correlated with that of TAZ in normal astrocytes and a panel of glioma cell lines. MiR-125a-5p represses the expression of TAZ target genes, including CTGF and survivin, and inhibits cell proliferation and induces the differentiation of GBM cells; whereas over-expression of TAZ rescues the effects of miR-125a-5p. This study revealed a mechanism for TAZ deregulation in glioma cells, and also demonstrated a tumor suppressor role of miR-125a-5p in glioblastoma cells. PMID- 25542153 TI - A zebrafish (Danio rerio) bloodthirsty member 20 with E3 ubiquitin ligase activity involved in immune response against bacterial infection. AB - The tripartite motif (TRIM)-containing proteins exhibit various activities and play important roles in the immune system through regulating signaling pathways. Bloodthirsty gene is a multigene subset of TRIM genes. In this study we identified and characterized a new member of the bloodthirsty subset of TRIM genes, btr20, in zebrafish (Danio rerio). The gene is located on chromosome 19 and forms a cluster with btr18, btr21, btr22 and an E3 ubiquitin ligase TRIM39 like gene. Deduced btr20 represents a RBCC-B30.2 TRIM protein containing 544 amino acids. The mRNA expression level of btr20 was highest in intestine and gill, followed by in spleen and kidney. Challenge experiment with Aeromonas hydrophila strain NJ-1 showed that the levels of btr20 and NF-kappaB mRNA were remarkably upregulated in the four tissues mentioned above. btr20 was localized in the cytoplasm and formed aggregate in human embryonic kidney cell line 293T. In vitro self-ubiquitylation experiment demonstrated that btr20 has E3 ubiquitin ligase activity that can be self-ubiquitylated with most E2 enzymes, especially UbcH6. The results suggested that btr20 may involve in the anti-microbial activity in the immune system as an E3 ubiquitin ligase. PMID- 25542154 TI - 4'-CyanoPLP presents better prospect for the experimental detection of elusive cyclic intermediate radical in the reaction of lysine 5,6-aminomutase. AB - The results of our calculations suggest that the reaction of 4'-cyanoPLP with lysine 5,6-aminomutase offers better prospect for the experimental detection of elusive cyclic azacyclopropylcarbinyl radical (I), which is proposed to be a key intermediate in the reaction of pyridoxal-5'-phosphate dependent radical aminomutases. We have calculated the corresponding hyperfine coupling constants (HFCCs) for (14)N and (13)C of cyano group using several basis sets to help the characterization of 4'-cyanoI. PMID- 25542155 TI - A priority driven ABC approach to the emergency management of high energy pelvic trauma improves decision making in simulated patient scenarios. AB - INTRODUCTION: An ABC priority driven approach to the management of high energy pelvic injuries has been developed and applied as a teaching tool. A prospective study assessed whether trainees taught this ABC aide memoire gave better priority driven care in simulated patient scenarios. They were compared directly to colleagues undergoing the same pelvic training but without reference to the ABC concept. METHODS: Orthopaedic trainees were formally assessed by viva scenario upon their pelvic trauma management 6 weeks after a pelvic trauma teaching event. Trainees all received standard pelvic trauma teaching but were randomised into two groups. One group alone had an introduction to the ABC algorithm. Inclusion criteria were trainees belonging to the same deanery teaching group with similar levels of training and experience in pelvic trauma. Those completing a pelvic trauma post or teaching in pelvic trauma were excluded. RESULTS: There were 20 trainees included and three scenarios giving 60 scores. The mean year of training or the number of pelvic trauma cases experienced did not differ significantly between the groups (p=0.426 and p=0.347). The ABC teaching concept yielded significant improvements in several aspects: coagulopathy assessment and management (p=<0.001); urological injury (p=0.047), appropriate prioritisation (p=0.006) and bowel injury/open fracture assessment (p=0.007). A poorer response was seen in CT assessment (p=0.004). DISCUSSION AND CONCLUSION: The ABC priority driven approach to pelvic trauma management provides structure when decision making. This method improves clinician's recall, prioritisation and potentially clinical outcomes. PMID- 25542156 TI - Socioeconomic status and its association with the risk of developing hip fractures: a region-wide ecological study. AB - PURPOSE: To determine the association between socioeconomic deprivation (SES) and hip fracture risk. METHODS: Retrospective cohort study using a population-based database (primary care records) of over 5 million people. Eligibility: all living subjects registered during the period 2009-2012 and resident in an urban area. MEASURES: a validated SES composite index (proportion of unemployed, temporary workers, manual workers, low educational attainment and low educational attainment among youngsters) estimated for each area based on census data. OUTCOME: incident hip fracture rates as coded in medical records using ICD-10 codes. STATISTICS: zero-inflated Poisson models fitted to study the association between SES quintiles and hip fracture risk, adjusted for age, sex, obesity, smoking and alcohol consumption. RESULTS: Compared to the most deprived, wealthy areas had a higher hip fracture incidence (age- and sex-adjusted incidence 38.57 (37.14-40.00) compared to 34.33 (32.90-35.76) per 10,000 person-years). Similarly, most deprived areas had a crude and age- and sex-adjusted lower risk of hip fracture, RR of 0.71 (0.65-0.78) and RR of 0.90 (0.85-0.95), respectively, compared to wealthiest areas. The association was attenuated and no longer significant after adjustment for obesity: RR 0.96 (0.90-1.01). Further adjustment for smoking and high alcohol consumption did not make a difference. CONCLUSION: Wealthiest areas have an almost 30% increased risk of hip fracture compared to the most deprived. Differences in age-sex composition and a higher prevalence of obesity in deprived areas could explain this higher risk. PMID- 25542157 TI - Company reply to "Unexpected outbreak of Epstein-Barr virus post-transplantation lymphoproliferative disorder after hematopoietic stem cell transplantation conditioning with thymoglobulin". PMID- 25542158 TI - A retrospective analysis of treatment outcomes in adult T cell leukemia/lymphoma patients with aggressive disease treated with or without allogeneic stem cell transplantation: A single-center experience. AB - Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm with very poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been reported as a curative treatment modality for ATL. However, there are no reports comparing chemotherapy alone with allo-HSCT in ATL. In this report, we retrospectively analyzed data for patients treated with (n = 29, median age 55 years) or without allo-HSCT (n = 37, median age 58 years) for ATL in Kagoshima University Hospital, located in one of the most endemic areas of human T cell lymphotropic leukemia virus type 1 infection. Forty patients (61%) started coordination for allo-HSCT. Ten patients (34.4%) received allo-HSCT while in complete remission (CR), whereas the others were not in CR. Twenty-five patients (86.2%) received reduced-intensity conditioning, and the others received myeloablative conditioning. With a median follow-up period for survivors of 41 months (range, 5 to 125 months), the 3-year overall survival (OS) rate from first chemotherapy for all patients (with or without allo-HSCT) was 35.2%. The 3-year OS from first chemotherapy for patients who received allo-HSCT or only chemotherapy was 44.9% and 27.7%, respectively. Univariate analyses revealed that high serum soluble IL-2 receptor (sIL-2R) levels (>= 2000 U/mL) just before the conditioning regimen and progressive disease (PD) status at HSCT (according to Japan Clinical Oncology Group Study 0907 criteria) were significant risk factors for OS in the allo-HSCT group. Multivariate analyses revealed that PD status was a significant risk factor for OS in the allo-HSCT group. In the chemotherapy-only group, the 3-year OS rate was 61.5% (95% CI, 30.8% to 81.8%) in patients with serum sIL-2R levels < 2000 U/mL for > 3 months. In contrast, the 3-year OS rate was 5.7% (95% CI, .4% to 22.4%) in patients who did not achieve serum sIL-2R levels < 2000 U/mL for >3 months. Our single-center cohort experience indicates that chemosensitivity is the most important prognostic factor for OS in ATL patients and the use of allo-HSCT is limited in chemorefractory patients with aggressive ATL disease. In the chemosensitive patients, allo-HSCT demonstrated a tendency toward better OS. Further clinical studies are warranted to determine optimal treatments for patients who are less sensitive to conventional chemotherapy. PMID- 25542159 TI - A two-step approach to myeloablative haploidentical transplantation: low nonrelapse mortality and high survival confirmed in patients with earlier stage disease. AB - Haploidentical hematopoietic stem cell transplantation (HSCT) is an attractive alternative donor option based on the rapid availability of an acceptable donor for most patients and decreased cost compared with costs of other alternative donor strategies. The safety of haploidentical HSCT has increased in recent years, making it ethically feasible to offer to patients with earlier stage disease. We developed a 2-step approach to haploidentical HSCT that separates the lymphoid and myeloid portions of the graft, allowing fixed T cell dosing to improve consistency in outcome comparisons. In the initial 2-step trial, the subset of patients without morphologic disease at HSCT had high rates of disease free survival. To confirm these results, 28 additional patients without evidence of their disease were treated and are now 15 to 45 (median, 31) months past HSCT. To date, the 2-year cumulative incidence of nonrelapse mortality is 3.6%, with only 1 patient dying of nonrelapse causes, confirming the safety of this approach. Based on low regimen toxicity, the probabilities of disease-free and overall survival at 2 years are 74% and 77%, respectively, consistent with the findings in the initial trial and supporting the use of this approach in earlier stage patients lacking a matched related donor. PMID- 25542160 TI - Hyperbaric oxygen preconditioning attenuates hemorrhagic transformation through increasing PPARgamma in hyperglycemic MCAO rats. AB - Hyperbaric oxygen preconditioning (HBO-PC) has been demonstrated to attenuate hemorrhagic transformation (HT) after middle cerebral artery occlusion (MCAO) in hyperglycemic rats. However, the mechanisms remain to be illustrated. Recently, HBO-PC has been shown to activate peroxisome proliferator-activated receptor gamma (PPARgamma) by increasing 15d-PGJ2 in primary cultured neurons. We hypothesize that HBO-PC reduces HT by suppressing inflammation through increasing 15d-PGJ2 and activating PPARgamma in hyperglycemic MCAO rats. HBO (2.5ATA) was administered for 1h daily for 5 consecutive days. The PPARgamma inhibitor GW9662 was administered intraperitoneally to designated animals. Infarction volume, hemorrhage volume, neurological scores and mortality were analyzed. The levels of 15d-PGJ2, PPARgamma, TNF-alpha and IL-1beta, tight junction proteins as well as the activity of MMP-2 and MMP-9 were evaluated 24h after MCAO. HBO-PC reduced HT, improved neurological function, down-regulated inflammatory molecules and inhibited the activation of MMP-9 by increasing 15d-PGJ2 and PPARgamma at 24h after MCAO. The results suggested that HBO-PC might be an alternative measure to decrease HT in ischemic stroke. PMID- 25542161 TI - Impact of patent ductus arteriosus and subsequent therapy with ibuprofen on the release of S-100B and oxidative stress index in preterm infants. AB - BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) leads to injury in tissues/organs by reducing perfusion of organs and causing oxidative stress. The purpose of this study was to evaluate the oxidant/antioxidant status in preterm infants with hsPDA by measuring the total antioxidant capacity and total oxidant status and to assess neuronal damage due to oxidant stress related to hsPDA. MATERIAL AND METHODS: This prospective study included 37 low-birth weight infants with echocardiographically diagnosed hsPDA treated with oral ibuprofen and a control group of 40 infants without PDA. Blood samples were taken from all infants, and than the total antioxidant capacity (TAC), total oxidant status (TOS), and S-100B protein levels were assessed and oxidative stress index was calculated before and after therapy. RESULTS: The mean pre-therapy TOS level and oxidative stress index (OSI) value of the patients with hsPDA were significantly higher, but TAC level was lower than in the control group. There were no statistically significant differences in the mean post-therapy values of TOS, TAC, OSI, and S-100B protein between the two groups. CONCLUSIONS: hsPDA may cause cellular injury by increasing oxidative stress and damaging tissue perfusion; however the brain can compensate for oxidative stress and impaired tissue perfusion through well-developed autoregulation systems to decrease tissue injury. PMID- 25542163 TI - Molecular characterization and in vitro digestibility of normal maize starch hydrolyzed by maltotriohydrolase. AB - Normal maize starch was hydrolyzed by the glucan 1,4-alpha-maltotriohydrolase (AMTS), and the changes in molecular characteristics and digestibility of starch were evaluated. Upon hydrolysis, maltotriose purity could be modified via controlled AMTS action. The transglycosylation of AMTS possibly happened during the extensive hydrolysis of starch. No single linear association between the z average radius of gyration (Rz), conformation exponent (nu), apparent molecular density (rho) and weight average molar mass (Mw) of the starch molecules could be established in the entire process of AMTS hydrolysis. Under mild hydrolysis (<=240 min), Rz and rho displayed linear relationships with Mw. However, transitions of nu, Rz and rho appeared after extensive hydrolysis (>240 min), due to the increase in the amount of short chains [degree of polymerization (DP)<=5]. The spherical starch molecule tends toward less compact and a structure between sphere and random coil after extensive hydrolysis. And the increase in the amount of DP<=12 chains and reduction of molecular dimension after AMTS hydrolysis restrict the digestibility of starch. The results of this study suggest that normal maize starch can be modulated by AMTS to produce the desired maltotriose syrup, starch molecular characteristics, and starch digestibility. PMID- 25542164 TI - Extraction optimization, structure and antioxidant activities of Fortunella margarita Swingle polysaccharides. AB - The objective of this study was to maximize the yield of polysaccharides extracted from Fortunella margarita Swingle (FMPS) and investigate the relationship between the structure and antioxidant activities. The optimal conditions for ultrasonic-assisted extraction (UAE) of FMPS were ultrasonic power 171W, extraction temperature 50 degrees C, water volume to raw material weight (W/M) ratio 32 ml/g and extraction time 87 min. Under these conditions, the yield of FMPS was 4.15+/-0.11% (w/w), which was increased by 129.28% compared to hot water extraction. FMPS3, the main fraction of FMPS, was isolated by DEAE Sepharose CL-6B column chromatography. According to size-exclusion chromatography, multi-angle laser light-scattering and refractive index (SEC MALLS-RI), the molecular weight (Mw), polydispersity index (Mw/Mn) and root-mean square turning radius (Rg) of FMPS3 were 4.58*10(5) (+/-2.02%) Da, 1.08 (+/ 1.23%), 28.13 (+/-1.73%) nm, respectively. FMPS3, linked mainly by beta glycosidic bonds, consisted of galactose, galacturonic acid, glucose, mannose and rhamnose as shown by HPLC, FT-IR, 1H NMR and 13C NMR. Furthermore, FMPS3 displayed strong scavenging ability against hydroxyl, superoxide and DPPH radicals. The activity was affected by the monosaccharide composition, molecular weight and proportion of beta-glycosidic bonds and was a result of a combination of multiple structural factors. FMPS3 is potentially a novel natural antioxidant agent. PMID- 25542165 TI - Methanol-induced chain termination in poly(3-hydroxybutyrate) biopolymers: molecular weight control. AB - A systematic study was performed to demonstrate the impact of methanol (MeOH) on poly(3-hydroxybutyrate) (PHB) synthesis and molecular weight (MW). Glycerine was used as the primary carbon source with varying concentrations of MeOH. Methanol retarded but did not completely inhibit growth and PHB production in Pseudomonas oleovorans. Proton NMR analysis revealed that the PHB polymers were end-capped with methoxy chemical groups causing MW reductions. The MW decreases were contingent upon the initial MeOH media concentration and the duration of the fermentations. The largest impact occurred at an initial MeOH concentration of 0.10% (w/v) where the number average molecular weights (Mn) decreased by 39%, 55%, and 72% in the 48, 72 and 96 h cultures, respectively. Diffusion ordered NMR spectroscopy revealed a diffusivity (D) increase in the smaller molecular weight polymers with the PHB synthesized in the presence of 0.85% MeOH (72 h post inoculation) having a D value of 0.66*10(-10) m2/s. Diffusivity increases indicate a reduction in hydrodynamic radii (Rhz) consistent with shorter chain lengths. Crude glycerine from the biodiesel production process has been used as an inexpensive fermentation feedstock for polyhydroxyalkanoate (PHA) synthesis but its composition is facility-dependent. This information will be vital to tailor PHA properties to specific applications. PMID- 25542166 TI - Biosynthesis of hematite nanoparticles and its cytotoxic effect on HepG2 cancer cells. AB - Iron oxide nanoparticles were gaining significant importance in a variety of applications due to its paramagnetic properties and biocompatibility. Various chemical methods were employed for hematite nanoparticle synthesis which require special equipment or a complex production process. In this study, protein capped crystalline hexagonal hematite (alpha-Fe2O3) nanoparticles were synthesized by green approach using culture supernatant of a newly isolated bacterium, Bacillus cereus SVK1 at ambient conditions. The synthesized nanoparticles were characterized by electron microscopy, X-ray diffraction, UV-visible spectroscopy and Fourier transform infrared spectroscopic analysis. Nanoparticles were evaluated for its possible anticancer activity against HepG2 liver cancer cells by MTT assay. Hematite nanoparticles with an average diameter of 30.2 nm, exhibited a significant cytotoxicity toward HepG2 cells in a concentration dependent manner (CTC50=704 ng/ml). PMID- 25542167 TI - Effect of annealing on the thermal properties of poly (lactic acid)/starch blends. AB - A comparative study of the thermal behavior of PLA/starch blends annealed at different temperatures has been conducted. Annealing was found to be beneficial to weaken and even eliminate the enthalpy relaxation near Tg. The degree of crystallinity was evaluated by means of DSC, and the results showed that the crystallinity of the samples increased as the annealing temperatures were increased. It was observed that, during the annealing process, the disorder alpha (alpha') crystal modification tended to transform into the order alpha crystal modification. All of the PLA/starch blends showed a double melting behavior. With the increase of annealing temperatures, the lower Tm1 increased, while the Tm2 showed no evident change. The XRD patterns also showed that annealing was beneficial to the samples to form higher crystallinity. The TGA results indicated that the annealed samples did not show any higher thermal stability than the virgin samples. The activation energy calculated by the Flynn-Wall-Ozawa method at lower conversion degrees confirmed that the annealing slightly slowed the degradation. The activation energy did not show any dependence on the conversion degree, which indicated that there existed a complex degradation process of the PLA/starch blends. The average activation energy did not show obvious differences, indicating that the annealing treatment had little influence on the degradation activation energy. PMID- 25542162 TI - Cardiovascular function in large to small hibernators: bears to ground squirrels. AB - Mammalian hibernation has intrigued scientists due to extreme variations in normal seasonal physiological homeostasis. Numerous species manifest a hibernation phenotype although the characteristics of the hypometabolic state can be quite different. Ground squirrels (e.g., Sciuridae) are often considered the prototypical hibernator as individuals in this genus transition from an active, euthermic state (37 degrees C) to a nonresponsive hibernating state where torpid body temperature commonly falls to 3-5 degrees C. However, the hibernating state is not continuous as periodic warming and arousals occur. In contrast, the larger hibernators of genus Ursus are less hypothermic (body temperatures decline from approximately 37 degrees -33 degrees C), are more reactive, and cyclical arousals do not occur. Both species dramatically reduce cardiac output during hibernation from the active state (bears ~75 % reduction in bears and ~97 % reduction in ground squirrels), and both species demonstrate hypokinetic atrial chamber activity. However, there are several important differences in cardiac function between the two groups during hibernation. Left ventricular diastolic filling volumes and stroke volumes do not differ in bears between seasons, but increased diastolic and stroke volumes during hibernation are important contributors to cardiac output in ground squirrels. Decreased cardiac muscle mass and increased ventricular stiffness have been found in bears, whereas ground squirrels have increased cardiac muscle mass and decreased ventricular stiffness during hibernation. Molecular pathways of cardiac muscle plasticity reveal differences between the species in the modification of sarcomeric proteins such as titin and alpha myosin heavy chain during hibernation. The differences in hibernation character are likely to account for the alternative cardiac phenotypes and functional strategies manifested by the two species. Molecular investigation coupled with better knowledge of seasonal physiological alterations is dramatically advancing our understanding of small and large hibernators and their evolutionary differences. PMID- 25542168 TI - Improved removal of malachite green from aqueous solution using chemically modified cellulose by anhydride. AB - Cellulose modified with maleic (M) and phthalic (P) anhydride, to be named CMA and CPA, were tested as feasible adsorbents for the removal of malachite green from aqueous solution. At the same time, the uptake ability of natural cellulose was also studied for comparison. The structure of material was characterized by FT-IR and XRD. The effects of solution pH, initial dye concentration, contact time and temperature were investigated in detail by batch adsorption experiments. The kinetic and isotherm studies suggested that the adsorption followed the pseudo-second-order model and Langmuir isotherm. The maximum adsorption capacity on CMA and CPA were 370 mg g(-1) and 111 mg g(-1), respectively. Furthermore, the thermodynamics studies indicated the spontaneous nature of adsorption of malachite green on adsorbents. All the studied results showed that the modified cellulose could be used as effective adsorption material for the removal of malachite green from aqueous solutions. PMID- 25542169 TI - Effects of different crosslinking methods on the properties of collagen-calcium phosphate composite materials. AB - The purpose of this study is the preparation and characterization of porous collagen/calcium phosphates (Col/CaP) composites. Collagen scaffolds with high porosity were prepared by freeze-drying technique. Col/CaP scaffold were created by new method--by deposition of calcium phosphate within collagen matrix in two steps using freeze-drying process before immersing samples in calcium solution. To find the optimal preparative method, we prepared diverse Col/CaP scaffolds using different collagen concentration and various crosslinking method: crosslinking with carbodiimide (EDC/NHS) and dehydrothermal treatment (DHT). This study explores the effect of the different crosslinking method on the properties of scaffolds, such as: microstructure (porosity and density), dissolution, water uptake, mechanical properties and collagenase degradation. The results obtained showed that crosslinking the scaffolds by either EDC/NHS or DHT have good mechanical and morphological properties compatible with their potential application in bone regeneration. The results demonstrated that properties of Col/CaP scaffolds changed significantly with different crosslinking method. However, while EDC/NHS increased the scaffolds' resistance to dissolution and degradation by collagenase, DHT decreased the swelling ratio and resistance to dissolution in PBS solution. Based on our study, 2% collagen concentration and EDC/NHS as crosslinking reagent are recommended to design the scaffold for use in bone engineering. PMID- 25542170 TI - Biochemical and structural characterization of Cryptosporidium parvum Lactate dehydrogenase. AB - The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on glycolysis for energy production. Lactate dehydrogenase is a major regulator of glycolysis. This paper describes the biochemical characterization of C. parvum lactate dehydrogenase and high resolution crystal structures of the apo-enzyme and four ternary complexes. The ternary complexes capture the enzyme bound to NAD/NADH or its 3-acetylpyridine analog in the cofactor binding pocket, while the substrate binding site is occupied by one of the following ligands: lactate, pyruvate or oxamate. The results reveal distinctive features of the parasitic enzyme. For example, C. parvum lactate dehydrogenase prefers the acetylpyridine analog of NADH as a cofactor. Moreover, it is slightly less sensitive to gossypol inhibition compared with mammalian lactate dehydrogenases and not inhibited by excess pyruvate. The active site loop and the antigenic loop in C. parvum lactate dehydrogenase are considerably different from those in the human counterpart. Structural features and enzymatic properties of C. parvum lactate dehydrogenase are similar to enzymes from related parasites. Structural comparison with malate dehydrogenase supports a common ancestry for the two genes. PMID- 25542171 TI - Chitosan conjugated chloroquine: proficient to protect the induction of liver apoptosis during malaria. AB - Chitosan has impelled continuous motion by its unique physicochemical and biological characteristics. In our study, chitosan-tripolyphosphate (CS-TPP) particles was conjugated with an undervalued antimalarial drug, chloroquine to find out the proficiency against ROS mediated caspase activation and apoptosis in liver during Plasmodium berghei NK65 infection. The transmission electron microscopic image illustrated the size range of particle was less than 50 nm and the particle showed the blood compatibility. ROS generation, mitochondrial membrane potential, anti apoptotic and pro apoptotic protein level of CS-TPP conjugated chloroquine treated group revealed that CS-TPP conjugation amplified the protective capability of chloroquine. FACS study by annexin v-FITC and PI staining reveals chloroquine treatment reduces significantly (P<0.05) the apoptotic cells by 25.31%; whereas chitosan-tripolyphosphate conjugated nanochloroquine decreases by 61.56% apoptotic cell against P. berghei induced liver apoptosis. This study suggests that proficiency of conventional antimalarial drug may escalate by delivery with chitosan nanoparticles to portray defense possessions against malarial damage. PMID- 25542172 TI - Polyhydroxyalkanoates from Pseudomonas sp. using synthetic and olive mill wastewater under limiting conditions. AB - The present study aimed at investigating the ability of bacteria isolated from an enriched mixed culture to produce polyhydroxyalkanoates (PHAs) and examining the effect of nitrogen and dual nitrogen-oxygen limitation on PHAs production, by using both synthetic and olive mill wastewater (OMW). PHAs production was performed through batch experiments using both the enriched culture and the isolated strains (belonging to the genus of Pseudomonas) aiming to compare PHAs accumulation capacity, yields and rates. The use of enriched culture and synthetic wastewater under nitrogen limitation resulted in the highest PHA accumulation, i.e. 64.4%gPHAs/g of cell dry mass (CDM). However, when OMW was used, PHAs accumulation significantly decreased, i.e. 8.8%gPHAs/g CDM. The same trend was followed by the isolated strains, nevertheless, their ability to synthesize PHAs was lower. Although, dual nitrogen-oxygen limitation generally slowed down PHAs biosynthesis, in certain strains PHAs production was positively affected. PMID- 25542173 TI - Enhancing the thermal stability of inulin fructotransferase with high hydrostatic pressure. AB - The thermal stability of inulin fructotransferase (IFTase) subjected to high hydrostatic pressure (HHP) was studied. The value of inactivation rate of IFTase in the range of 70-80 degrees C decreased under the pressure of 100 or 200 MPa, indicating that the thermostability of IFTase under high temperature was enhanced by HHP. Far-UV CD and fluorescence spectra showed that HHP impeded the unfolding of the conformation of IFTase under high temperature, reflecting the antagonistic effect between temperature and pressure on IFTase. The new intramolecular disulfide bonds in IFTase were formed under a combination of HHP and high temperature. These bonds might be related to the stabilization of IFTase at high temperature. All the above results suggested that HHP had the protective effect on IFTase against high temperature. PMID- 25542174 TI - Development and characterization of biodegradable chitosan films containing two essential oils. AB - Active biodegradable films from chitosan containing 10% to 30% w/w of citronella essential oil (CEO) and cedarwood oil (CWO) were developed by casting and solvent evaporation method, and their physical, mechanical and thermal properties were investigated. Possible interactions between the chitosan chains and the essential oils were confirmed using Fourier-transform infrared spectroscopy (FTIR). Various amounts of CEO or CWO had significant effects on the films' mechanical properties, with the exception of 10% of CEO, which did not significantly affect the tensile strength of the films. The incorporation of the two tested oils provoked a remarkable reduction in the water-vapor permeability properties, with a decrease of about 63% when 30% CEO was added in chitosan films. Thermogravimetric analysis showed that degradation temperatures of the films containing CEO and CWO improved only slightly in comparison to control films without essential oils. FTIR spectra analysis provided some insights on the possible interactions between chitosan and the two essential oils used. This study suggests that active films can be developed by including CEO and CWO in a chitosan matrix. Such films can provide new formulation options for packaging industries in developing active packaging with potential food-technology applications. PMID- 25542175 TI - Approximated maximum adsorption of His-tagged enzyme/mutants on Ni2+-NTA for comparison of specific activities. AB - By approximating maximum activities of six-histidine (6His)-tagged enzyme/mutants adsorbed on Ni2+-NTA-magnetic-submicron-particle (Ni2+-NTA-MSP), a facile approach was tested for comparing enzyme specific activities in cell lysates. On a fixed quantity of Ni2+-NTA-MSP, the activity of an adsorbed 6His-tagged enzyme/mutant was measured via spectrophotometry; the activity after saturation adsorption (Vs) was predicted from response curve with quantities of total proteins from the same lysate as the predictor; Vs was equivalent of specific activity for comparison. This approach required abundance of a 6His-tagged enzyme/mutant over 3% among total proteins in lysate, an accurate series of quantities of total proteins from the same lysate, the largest activity generated by enzyme occupying over 85% binding sites on Ni2+-NTA-MSP and the minimum activity as absorbance change rates of 0.003 min(-1) for analysis. The prediction of Vs tolerated errors in concentrations of total proteins in lysates and was effective to 6His-tagged alkaline phosphatase and its 6His-tagged mutant in lysates. Notably, of those two 6His-tagged enzymes, Vs was effectively approximated with just one optimized quantity of lysates. Hence, this approach with Ni2+-NTA-MSP worked for comparison of specific activities of 6His-tagged enzyme/mutants in lysates when they had sufficient abundance among proteins and activities of adsorbed enzymes were measurable. PMID- 25542176 TI - Ultrasonic extraction optimization of L. macranthoides polysaccharides and its physicochemical properties. AB - The dried flower buds of L. macranthoides, belong to the item Shan Yin Hua, are widely used as raw materials for pharmaceutical, food additive, healthy food and cosmetic industry in China. To optimize the effects of the ultrasonic-assisted extraction (UAE) processing parameters on the yield of L. macranthoides polysaccharides (LMPs), a response surface methodology with a central composite rotatable design was employed. Four independent variables were investigated: ultrasonic power (X1), temperature (X2), time (X3), and the ratio of water volume to raw material weight (W/M ratio, X4). The experimental data were fitted to a quadratic polynomial equation using multiple regression analysis and also examined using appropriate statistical methods. The optimum conditions were: X1, 113.6 W; X2, 71.5 degrees C; X3, 54.7 min; and X4, 30.7 mL/g. Under the optimal conditions, the extraction yield of LMPs was (4.81+/-0.12)%, which is in close agreement with the value predicted by the statistical model. Further, LMPs were characterized by FT-IR, XRD, TGA/DSC and NMR. In vitro experiments indicated that LMPs had strong scavenging capacities towards the DPPH, hydroxyl and superoxide radicals. Overall, LMPs may have potential applications in the medical and food industries. PMID- 25542177 TI - Wheat bran feruloyl oligosaccharides modulate the phase II detoxifying/antioxidant enzymes via Nrf2 signaling. AB - The antioxidant activities of wheat bran feruloyl oligosaccharides (FOs) were determined in rats by determining the activities and mRNA expression levels of phase II detoxifying/antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and heme oxygenase-1 (HO-1) in rat organs. FOs was given by gavage at doses of 0.25, 0.5, and 0.75 mmol/kg body weight every day for 15 days. Compared with the control group, the activities of SOD, CAT, and GSH-Px in FOs treatment groups significantly (P<0.05) increased in heart, liver, and kidney. All the FOs treatment also significantly (P<0.05) increased the glutathione (GSH) contents in heart (28-58%), liver (32-71%), and kidney (31-73%) compared with the control. FOs up regulated the mRNA expression levels of SOD, CAT, and HO-1 in organs. Moreover, the immunoblot analysis revealed increased nuclear factor-E2-related factor (Nrf2) protein expression levels in organs and there were positive correlations between the mRNA expression of phase II detoxifying/antioxidant enzymes and the expressions of Nrf2 protein, which demonstrated FOs treatment could modulate the detoxifying/antioxidant enzymes via Nrf2 signaling. PMID- 25542179 TI - Structure and functional evaluation of porcine NANOG that is a single-exon gene and has two pseudogenes. AB - Nanog plays an important role in maintaining the pluripotency of murine and human embryonic stem cells. However, the molecular features and transcriptional regulation of the NANOG gene have not been well investigated in pig. Here, we report, for the first time, that porcine NANOG is encoded by a single exon gene (SEG) mapped on chromosome 1 and has two daughter genes, one pseudogene NANOGP1 on chromosome 5 and one tandem duplicate on chromosome 1. The duplicated pseudogene NANOGP2 has high sequence similarity to NANOG, but does not encode a functional protein due to deletions and in-frame stop codons. The NANOGP1 contains four exons and three introns, but is short of the homeodomain sequence. Transcriptome analysis confirmed that NANOG mRNA in porcine iPS cells is transcribed from the SEG NANOG, but not from NANOGP1, because the NANOGP1 promoter is highly methylated, as confirmed by global DNA methylation analysis. The NANOG protein encoded by NANOG retains N, H, and C1/W/C2 domains. The H domain is required for nuclear translocation, while the C1/W/C2 domain ensures the NANOG regulatory function. Overexpression of NANOG in porcine embryonic fibroblasts promoted upregulation of its target genes SOX2, KLF4, and c-MYC. In conclusion, the functional porcine NANOG that is different in chromosomal structure from mouse and human genes is a single exon gene and encodes the functional NANOG protein that can be specifically regulated by OCT4/SOX2, and can promote the activation of target pluripotent factors in vivo. PMID- 25542180 TI - Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. AB - The field of energy metabolism dramatically progressed in the last decade, owing to a large number of cancer studies, as well as fundamental investigations on related transcriptional networks and cellular interactions with the microenvironment. The concept of metabolic flexibility was clarified in studies showing the ability of cancer cells to remodel the biochemical pathways of energy transduction and linked anabolism in response to glucose, glutamine or oxygen deprivation. A clearer understanding of the large-scale bioenergetic impact of C MYC, MYCN, KRAS and P53 was obtained, along with its modification during the course of tumor development. The metabolic dialog between different types of cancer cells, but also with the stroma, also complexified the understanding of bioenergetics and raised the concepts of metabolic symbiosis and reverse Warburg effect. Signaling studies revealed the role of respiratory chain-derived reactive oxygen species for metabolic remodeling and metastasis development. The discovery of oxidative tumors in human and mice models related to chemoresistance also changed the prevalent view of dysfunctional mitochondria in cancer cells. Likewise, the influence of energy metabolism-derived oncometabolites emerged as a new means of tumor genetic regulation. The knowledge obtained on the multi-site regulation of energy metabolism in tumors was translated to cancer preclinical studies, supported by genetic proof of concept studies targeting LDHA, HK2, PGAM1, or ACLY. Here, we review those different facets of metabolic remodeling in cancer, from its diversity in physiology and pathology, to the search of the genetic determinants, the microenvironmental regulators and pharmacological modulators. PMID- 25542178 TI - Chitooligosaccharides attenuate Cu2+-induced cellular oxidative damage and cell apoptosis involving Nrf2 activation. AB - Alzheimer's disease (AD) is one of the common neurodegenerative diseases. Increase of labile copper pool plays an important role in the pathogenesis of AD. Nrf2(NF-E2-related factor-2)-ARE (antioxidant response element) signaling is an important intracellular manner to defend against oxidative stress. In this study, we used SH-SY5Y cells as a model of neuron to test the effect of chitooligosaccharides (COSs) on Cu(2+)-induced oxidative damage. SH-SY5Y cells were treated with different concentrations of COSs (100-800 mg/L) before incubated with Cu(2+). Cell viability and cell damage and apoptosis were assessed. Both extracellular H(2)O(2) and intracellular ROS were measured and the relative levels of Nrf2, phosphorylated Nrf2, and HO-1 were analyzed by Western blotting, and further HO-1 mRNA was relatively quantified by real-time quantitative PCR. The results indicated that Cu(2+)-induced decrease of cell viability and increase of LDH release. In cell-free solution, COSs alone or with Cu(2+) cannot scavenge O(2)(-); however, COSs downregulate the levels of cellular oxidative stress and activated Caspase-3 induced by Cu(2+). Further, the levels of pSer40-Nrf2 protein and both the transcription and the translation of HO-1 gene are dramatically increased in COSs-protective group compared with Cu(2+) damage group. Therefore, these results indicate that Nrf2 activation might be involved in the protection of COSs against Cu(2+)-induced cellular oxidative damage. COSs contribute to the attenuation of oxidative damage and could be used as a nutritional agent for AD treatment. PMID- 25542181 TI - A sustained increase in the intracellular Ca2+ concentration induces proteolytic cleavage of EAG2 channel. AB - Voltage-gated EAG2 channel is abundant in the brain and enhances cancer cell growth by controlling cell volume. The channel contains a cyclic nucleotide binding homology (CNBH) domain and multiple calmodulin-binding motifs. Here we show that a raised intracellular Ca(2+) concentration causes proteolytic digestion of heterologously expressed and native EAG2 channels. A treatment of EAG2-expressing cells with the Ca(2+) ionophore A23187 for 1h reduces the full length protein by ~80% with a concomitant appearance of 30-35-kDa peptides. Similarly, a treatment with the Ca(2+)-ATPase inhibitor thapsigargin for 3h removes 30-35-kDa peptides from ~1/3 of the channel protein. Moreover, an incubation of the isolated rat brain membrane with CaCl2 leads to the generation of fragments with similar sizes. This Ca(2+)-induced digestion is not seen with EAG1. Mutations in a C-terminal calmodulin-binding motif alter the degrees and positions of the cleavage. Truncated channels that mimic the digested proteins exhibit a reduced current density and altered channel gating. In particular, these shorter channels lack a rapid activation typical in EAG channels with more than 20-mV positive shifts in voltage dependence of activation. The truncation also eliminates the ability of EAG2 channel to reduce cell volume. These results suggest that a sustained increase in the intracellular Ca(2+) concentration leads to proteolytic cleavage at the C-terminal cytosolic region following the CNBH domain by altering its interaction with calmodulin. The observed Ca(2+)-induced proteolytic cleavage of EAG2 channel may act as an adaptive response under physiological and/or pathological conditions. PMID- 25542182 TI - The linker histone in Saccharomyces cerevisiae interacts with actin-related protein 4 and both regulate chromatin structure and cellular morphology. AB - Chromatin structure promotes important epigenetic mechanisms that regulate cellular fate by organizing, preserving and controlling the way by which the genetic information works. Our understanding of chromatin and its functions is sparse and not yet well defined. The uncertainty comes from the complexity of chromatin and is induced by the existence of a large number of nuclear proteins that influence it. The intricate interaction among all these structural and functional nuclear proteins has been under extensive study in the recent years. Here, we show that Saccharomyces cerevisiae linker histone physically interacts with Arp4p (actin-related protein 4) which is a key subunit of three chromatin modifying complexes - INO80, SWR1 and NuA4. A single - point mutation in the actin - fold domain of Arp4p together with the knock-out of the gene for the linker histone in S. cerevisiae severely abrogates cellular and nuclear morphology and leads to complete disorganizing of the higher levels of chromatin organization. PMID- 25542183 TI - A novel function for fibroblast growth factor 21: stimulation of NADPH oxidase dependent ROS generation. AB - Fibroblast growth factor 21 (FGF-21) is a major paracrine and endocrine regulator of metabolic homeostasis. Here we demonstrate that FGF-21 is also a potent mediator of innate immunity. Double-staining flow cytometry identified neutrophils and monocytes as the main sources of FGF-21 among circulating leukocytes. Functional assays showed that FGF-21 stimulates phagocytosis and production of reactive oxygen species in neutrophil-like HL-60 cells and monocytic THP-1 cells. The mechanism of action of FGF-21 was observed to involve FGF receptor activation, signal transduction through the PI3K/Akt pathway, and stimulation of NADPH oxidase activity. This study indicates that FGF-21 could be an attractive target for the management of inflammatory disorders. PMID- 25542184 TI - Pregnancy in acromegaly patients treated with pegvisomant. AB - To summarize all available data on pregnancy outcome of acromegaly patients exposed to the growth hormone receptor antagonist pegvisomant (PEGV) during pregnancy as present in the Pfizer's Global Safety Database. Pfizer's Global Safety Database contains adverse event data obtained from the following sources: spontaneous reports, health authorities, Pfizer-sponsored post-marketing surveillance program (ACROSTUDY), customer engagement programs, and clinical studies, reported regardless of outcome. The safety database was searched up to 10th March 2014. From the 35 pregnancy cases, 27 involved maternal [mean age (range) 33.3 years (23-41) and 8 paternal (33.7 years (32-38)] PEGV exposure. Two female patients were reported with two pregnancy cases each. Fetal outcome was normal in 14 (4 paternal) of the 18 reported as live birth, while 4 cases (1 paternal) did not specify the birth outcome. At conception, PEGV mean dose (range) was 15.3 mg/d (4.3-30). In 3 cases of maternal exposure of the 18 cases reporting live birth, PEGV was continued throughout the pregnancy in a dose of 12.1 mg/d (10-15). In 5 cases (all maternal) an elective termination of the pregnancy was performed with no reported fetal abnormalities, 2 cases (maternal) reported a non-PEGV-related spontaneous abortion and in 1 maternal case an ectopic pregnancy occurred. In 9 cases (3 paternal), the fetal outcome was not reported. Three women reported gestational diabetes; one woman continued PEGV treatment during pregnancy. Although the number of reported pregnancies with exposure to PEGV is very small, the presented data reflect the largest series of data available to date and do not suggest adverse consequences of PEGV on pregnancy outcome. Nevertheless, it should be stressed that PEGV should not be used during pregnancy unless absolutely necessary. PMID- 25542185 TI - Universal screening for hypothyroidism in pregnancy: time for a paradigm shift? PMID- 25542186 TI - The association with Turner syndrome significantly affects the course of Hashimoto's thyroiditis in children, irrespective of karyotype. AB - Only few studies have investigated to now whether the association with Turner syndrome (TS) may affect the course of Hashimoto's thyroiditis (HT) in children. Aim of this study was to ascertain whether the presentation and long-term course of HT in TS children may be characterized by a peculiar and atypical pattern. The clinical and biochemical findings at HT diagnosis in 90 TS children (group A) were compared with those recorded in 449 girls with HT but without TS (group B); in group A patients, thyroid function tests were re-evaluated after a median time interval of 4.9 years. At HT diagnosis median TSH levels and the rate of cases presenting with a thyroid dysfunction picture were significantly lower in group A, irrespective of karyotype abnormalities. In group A only 34.8 % of the girls who had initially presented with euthyroidism remained euthyroid even at re evaluation, whilst 67.7 % of those who had presented with subclinical hypothyroidism became overtly hypothyroid over time; also such evolutive pattern was irrespective of karyotype abnormalities. (1) In TS girls, HT presents with a milder hormonal pattern, which often deteriorates over time; (2) these biochemical features are not necessarily linked with a specific karyotype. PMID- 25542187 TI - Salivary testosterone measurement does not identify biochemical hypogonadism in aging men: a ROC analysis. PMID- 25542189 TI - Role of Mesenchymal Stem Cells Transfected With Vascular Endothelial Growth Factor in Maintaining Renal Structure and Function in Rats with Unilateral Ureteral Obstruction. AB - OBJECTIVES: Mesenchymal stem cells hold promise for renal disease treatment. Vascular endothelial growth factor may heal tubule-interstitial fibrosis in unilateral ureteral obstruction by inhibiting epithelial-mesenchymal transition. We investigated the protective effect of vascular endothelial growth factor in transfected mesenchymal stem cells in unilateral ureteral obstruction-induced renal injury in rats. MATERIALS AND METHODS: Male Wistar Albino rats (32 rats; weight, 250-300 g) were divided into 4 equal groups: group 1, control; group 2, unilateral ureteral obstruction; group 3, unilateral ureteral obstruction and mesenchymal stem cells; and group 4, unilateral ureteral obstruction and vascular endothelial growth factor-transfected mesenchymal stem cells. Vascular endothelial growth factor-transfected mesenchymal stem cells were administered intravenously before onset of unilateral ureteral obstruction. On day 14, the rats were killed and kidneys were retrieved. Tubular necrosis, mononuclear cell infiltration, and interstitial fibrosis were evaluated in paraffin blocks. We evaluated green fluorescent protein-positive and vascular endothelial growth factor-positive cells; anti-inflammatory (Prostaglandin E2 receptor) and interleukin 1 receptor antagonist), proinflammatory/anti-inflammatory (interleukin 6), and proinflammatory (MPO) cytokine expression levels; and levels of nitric oxide; transforming growth factor beta1, E-cadherin, and hydroxyproline. RESULTS: Green fluorescent protein-positive cells were negative in the renal parenchyma in groups 1 and 2 and positive in groups 3 and 4. Vascular endothelial growth factor levels were significantly higher in group 4. Transforming growth factor beta1, nitric oxide, and E-cadherin levels were significantly higher in the unilateral ureteral obstruction than control group; however, in the study groups, these values were not significantly different from the unilateral ureteral obstruction group. In stem cell-transplanted tissue samples, EP3, interleukin 1 receptor antagonist, and interleukin 6 levels were elevated, but MPO expression levels were low. Although there were significant differences for tubular necrosis and fibrosis in group 2, there were significant reductions in tubular injury and fibrosis in groups 3 and 4. CONCLUSIONS: Systemic stem cells transplanted into the kidney protected against unilateral ureteral obstruction-induced renal epithelial-mesenchymal transition and renal fibrosis. PMID- 25542188 TI - Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro. AB - Mitotane (1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane, o,p'-DDD) represents one of the most active drugs for the treatment of adrenocortical carcinoma. Its metabolites 1,1-(o,p'-dichlorodiphenyl) acetic acid (=o,p'-DDA) and 1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene (=o,p'-DDE) partly contribute to its pharmacological effects. Because mitotane has a narrow therapeutic index and causes pharmacokinetic drug-drug interactions, knowledge about these compounds' effects on drug metabolizing and transporting proteins is crucial. Using quantitative real-time polymerase chain reaction, our study confirmed the strong inducing effects of o,p'-DDD on mRNA expression of cytochrome P450 3A4 (CYP3A4, 30-fold) and demonstrated that other enzymes and transporters are also induced (e.g., CYP1A2, 8.4-fold; ABCG2 (encoding breast resistance cancer protein, BCRP), 4.2-fold; ABCB1 (encoding P-glycoprotein, P-gp) 3.4-fold). P-gp induction was confirmed at the protein level. o,p'-DDE revealed a similar induction profile, however, with less potency and o,p'-DDA had only minor effects. Reporter gene assays clearly confirmed o,p'-DDD to be a PXR activator and for the first time demonstrated that o,p'-DDE and o,p'-DDA also activate PXR albeit with lower potency. Using isolated, recombinant CYP enzymes, o,p'-DDD and o,p'-DDE were shown to strongly inhibit CYP2C19 (IC50 = 0.05 and 0.09 uM). o,p' DDA exhibited only minor inhibitory effects. In addition, o,p'-DDD, o,p'-DDE, and o,p'-DDA are demonstrated to be neither substrates nor inhibitors of BCRP or P-gp function. In summary, o,p'-DDD and o,p'-DDE might be potential perpetrators in pharmacokinetic drug-drug interactions through induction of drug-metabolizing enzymes or drug transporters and by potent inhibition of CYP2C19. In tumors over expressing BCRP or P-gp, o,p'-DDD and its metabolites should retain their efficacy due to a lack of substrate characteristics. PMID- 25542190 TI - Twitter and Health Science Research. AB - Twitter is a communication platform that can be used to conduct health science research, but a full understanding of its use remains unclear. The purpose of this narrative literature review was to examine how Twitter is currently being used to conduct research in the health sciences and to consider how it might be used in the future. A time-limited search of the health-related research was conducted, which resulted in 31 peer-reviewed articles for review. Information relating to how Twitter is being used to conduct research was extracted and categorized, and an explanatory narrative was developed. To date, Twitter is largely being used to conduct large-scale studies, but this research is complicated by challenges relating to collecting and analyzing big data. Conversely, the use of Twitter to conduct small-scale investigations appears to be relatively unexplored. PMID- 25542191 TI - Predictors of persistent pain after total knee arthroplasty: a systematic review and meta-analysis. AB - BACKGROUND: Several studies have identified clinical, psychosocial, patient characteristic, and perioperative variables that are associated with persistent postsurgical pain; however, the relative effect of these variables has yet to be quantified. The aim of the study was to provide a systematic review and meta analysis of predictor variables associated with persistent pain after total knee arthroplasty (TKA). METHODS: Included studies were required to measure predictor variables prior to or at the time of surgery, include a pain outcome measure at least 3 months post-TKA, and include a statistical analysis of the effect of the predictor variable(s) on the outcome measure. Counts were undertaken of the number of times each predictor was analysed and the number of times it was found to have a significant relationship with persistent pain. Separate meta-analyses were performed to determine the effect size of each predictor on persistent pain. Outcomes from studies implementing uni- and multivariable statistical models were analysed separately. RESULTS: Thirty-two studies involving almost 30 000 patients were included in the review. Preoperative pain was the predictor that most commonly demonstrated a significant relationship with persistent pain across uni- and multivariable analyses. In the meta-analyses of data from univariate models, the largest effect sizes were found for: other pain sites, catastrophizing, and depression. For data from multivariate models, significant effects were evident for: catastrophizing, preoperative pain, mental health, and comorbidities. CONCLUSIONS: Catastrophizing, mental health, preoperative knee pain, and pain at other sites are the strongest independent predictors of persistent pain after TKA. PMID- 25542193 TI - Re: Kadam RS and Kompella UB (2010) Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve. J Pharmacol Exp Ther 332:1107-1120; doi:10.1124/jpet.109.161570. PMID- 25542192 TI - When to Stop CPR and When to Perform Rhythm Analysis: Potential Confusion Among ACLS Providers. AB - BACKGROUND: Health care providers nationwide are routinely trained in Advanced Cardiac Life Support (ACLS), an American Heart Association program that teaches cardiac arrest management. Recent changes in the ACLS approach have de-emphasized routine pulse checks in an effort to promote uninterrupted chest compressions. We hypothesized that this new ACLS algorithm may lead to uncertainty regarding the appropriate action following detection of a pulse during a cardiac arrest. METHODS: We conducted an observational study in which a Web-based survey was sent to ACLS-trained medical providers at 4 major urban tertiary care centers in the United States. The survey consisted of 5 multiple-choice, scenario-based ACLS questions, including our question of interest. Adult staff members with a valid ACLS certification were included. RESULTS: A total of 347 surveys were analyzed. The response rate was 28.1%. The majority (53.6%) of responders were between 18 and 32 years old, and 59.9% were female. The majority (54.2%) of responders incorrectly stated that they would continue CPR and possibly administer additional therapies when a team member detects a pulse immediately following defibrillation. Secondarily, only 51.9% of respondents correctly chose to perform a rhythm check following 2 minutes of CPR. The other 3 survey questions were correctly answered an average of 89.1% of the time. CONCLUSION: Confusion exists regarding whether or not CPR and cardiac medications should be continued in the presence of a pulse. Education may be warranted to emphasize avoiding compressions and medications when a palpable pulse is detected. PMID- 25542194 TI - What would it take? Stakeholders' views and preferences for implementing a health care manager program in community mental health clinics under health care reform. AB - Health care manager interventions can improve the physical health of people with serious mental illness (SMI). In this study, we used concepts from the theory of diffusion of innovations, the consolidated framework for implementation research and a taxonomy of implementation strategies to examine stakeholders' recommendations for implementing a health care manager intervention in public mental health clinics serving Hispanics with SMI. A purposive sample of 20 stakeholders was recruited from mental health agencies, primary care clinics, and consumer advocacy organizations. We presented participants a vignette describing a health care manager intervention and used semistructured qualitative interviews to examine their views and recommendations for implementing this program. Interviews were recorded, professionally transcribed, and content analyzed. We found that a blend of implementation strategies that demonstrates local relative advantage, addresses cost concerns, and enhances compatibility to organizations and the client population is critical for moving health care manager interventions into practice. PMID- 25542195 TI - Trends in state regulation of nurse practitioners and physician assistants, 2001 to 2010. AB - Nurse practitioners and physician assistants can alleviate some of the primary care shortage facing the United States, but their scope-of-practice is limited by state regulation. This study reports both cross-sectional and longitudinal trends in state scope-of-practice regulations for nurse practitioners and physician assistants over a 10-year period. Regulations from 2001 to 2010 were compiled and described with respect to entry-to-practice standards, physician involvement in treatment/diagnosis, prescriptive authority, and controlled substances. Findings indicate that most states loosened regulations, granting greater autonomy to nurse practitioners and physician assistants, particularly with respect to prescriptive authority and physician involvement in treatment and diagnosis. Many states also increased barriers to entry, requiring high levels of education before entering practice. Knowledge of state trends in nurse practitioner and physician assistant regulation should inform current efforts to standardize scope of-practice nationally. PMID- 25542196 TI - A simple method for isolating chicken egg yolk immunoglobulin using effective delipidation solution and ammonium sulfate. AB - Chicken egg yolk immunoglobulin (IgY) is a superior alternative to mammalian immunoglobulin. However, the practical application of IgY in research, diagnostics, and functional food is limited due to complex or time-consuming purification procedures. The objective of this study was to develop a simple, safe, large-scale separation method for IgY from egg yolk. Egg yolk was diluted with 6-fold delipidation solutions made of different types (pectin, lambda carrageenan, carboxymethylcellulose, methylcellulose, and dextran sulfate) and concentrations (0.01, 0.05, 0.1, 0.15, and 0.2%) of polysaccharides, respectively. The yolk solution was adjusted to pH 5.0, and then kept overnight at 4 degrees C before being centrifuged at 4 degrees C. The resulting supernatant was added to 35% (w/v) (NH4)2SO4 and then centrifuged. The precipitant, which contained IgY, was dissolved in distilled water and then dialyzed. SDS-PAGE and Western blotting were utilized to conduct qualitative analysis of IgY; high performance liquid chromatography (HPLC) was used for quantitative analysis. The immunoreactivity of IgY was measured by ELISA. The results showed that yield, purity, and immunoreactivity varied with types and concentrations of polysaccharides. The optimal isolation of IgY for pectin, lambda-carrageenan, dextran sulfate, and carboxymethylcellulose was at the concentration of 0.1%; for methylcellulose, optimal isolation was at 0.15%. The best results were obtained in the presence of 0.1% pectin. In this condition, yield and purity can reach 8.36 mg/mL egg yolk and 83.3%, respectively, and the negative effect of IgY on immunoreactivity can be minimized. The procedure of isolation was simplified to 2 steps with a higher yield of IgY, avoiding energy- and time-consuming methods. Therefore, the isolation condition under study has a great potential for food industry production of IgY on a large scale. PMID- 25542197 TI - Protein source and nutrient density in the diets of male broilers from 8 to 21 d of age: Effects on small intestine morphology. AB - In a companion study, high amino acid (AA) or apparent metabolizable energy (AME) densities in the diets of broilers from 8 to 21 d of age were found to improve feed conversion. A total of 1,120 male Ross*Ross 708 chicks were randomly allocated to 80 pens (8 treatments, 10 replications per treatment, 14 chicks per pen). A 2*2*2 factorial arrangement of treatments was used to investigate the interaction among the protein source (high distillers dried grains with solubles diet [hDDGS] or high meat and bone meal diet [hMBM]), AA density (moderate or high), and AME density (2,998 or 3,100 kcal/kg) of diets on small intestine morphology. Duodenum, jejunum, and ileum samples from 2 chicks per pen were collected and measured individually at 21 d. Jejunum sections were processed for histological analysis. Chicks fed hDDGS diets exhibited longer small intestines than did chicks fed hMBM diets. Particularly, when chicks were fed high AA density diets, jejuna were longer in groups fed hDDGS diets than groups fed hMBM diets. Dietary treatments did not affect jejunum villus height, width, area, crypt depth, villus to crypt ratio, goblet cell size, or cell density. In birds fed diets containing a moderate AA and a high AME density, jejunum muscle layers of chicks fed hDDGS diets were thicker than those fed hMBM diets. Chicks exhibited a lower feed conversion ratio (FCR) and a higher BW gain when their crypts were shorter. In conclusion, an hDDGS diet may facilitate small intestine longitudinal growth in broilers, which may subsequently improve dietary nutrient absorption. In addition, broiler chicks with shallow intestinal crypts exhibited better growth performance. PMID- 25542198 TI - Framing of feedback impacts student's satisfaction, self-efficacy and performance. AB - Feedback is considered important to acquire clinical skills. Research evidence shows that feedback does not always improve learning and its effects may be small. In many studies, a variety of variables involved in feedback provision may mask either one of their effects. E.g., there is reason to believe that the way oral feedback is framed may affect its effect if other variables are held constant. In a randomised controlled trial we investigated the effect of positively and negatively framed feedback messages on satisfaction, self efficacy, and performance. A single blind randomised controlled between-subject design was used, with framing of the feedback message (positively-negatively) as independent variable and examination of hearing abilities as the task. First year medical students' (n = 59) satisfaction, self-efficacy, and performance were the dependent variables and were measured both directly after the intervention and after a 2 weeks delay. Students in the positively framed feedback condition were significantly more satisfied and showed significantly higher self-efficacy measured directly after the performance. Effect sizes found were large, i.e., partial eta (2) = 0.43 and eta (2) = 0.32 respectively. They showed a better performance throughout the whole study. Significant performance differences were found both at the initial performance and when measured 2 weeks after the intervention: effects were of medium size, respectively r = -.31 and r = -.32. Over time in both conditions performance and self-efficacy decreased. Framing the feedback message in either a positive or negative manner affects students' satisfaction and self-efficacy directly after the intervention be it that these effects seem to fade out over time. Performance may be enhanced by positive framing, but additional studies need to confirm this. We recommend using a positive frame when giving feedback on clinical skills. PMID- 25542201 TI - Training finger individuation with a mechatronic-virtual reality system leads to improved fine motor control post-stroke. AB - BACKGROUND: Dexterous manipulation of the hand, one of the features of human motor control, is often compromised after stroke, to the detriment of basic functions. Despite the importance of independent movement of the digits to activities of daily living, relatively few studies have assessed the impact of specifically targeting individuated movements of the digits on hand rehabilitation. The purpose of this study was to investigate the impact of such finger individuation training, by means of a novel mechatronic-virtual reality system, on fine motor control after stroke. METHODS: An actuated virtual keypad (AVK) system was developed in which the impaired hand controls a virtual hand playing a set of keys. Creation of individuated digit movements is assisted by a pneumatically actuated glove, the PneuGlove. A study examining efficacy of the AVK system was subsequently performed. Participants had chronic, moderate hand impairment resulting from a single stroke incurred at least 6 months prior. Each subject underwent 18 hour-long sessions of extensive therapy (3x per week for 6 weeks) targeted at finger individuation. Subjects were randomly divided into two groups: the first group (Keypad: N = 7) utilized the AVK system while the other group (OT: N = 7) received a similarly intensive dose of occupational therapy; both groups worked directly with a licensed occupational therapist. Outcome measures such as the Jebsen-Taylor Hand Function Test (JTHFT), Action research Arm Test (ARAT), Fugl-Meyer Upper Extremity Motor Assessment/Hand subcomponent (FMUE/FMH), grip and pinch strengths were collected at baseline, post-treatment and one-month post-treatment. RESULTS: While both groups exhibited some signs of change after the training sessions, only the Keypad group displayed statistically significant improvement both for measures of impairment (FMH: p = 0.048) and measures of task performance (JTHFT: p = 0.021). Additionally, the finger individuation index - a measure of finger independence - improved only for the Keypad group after training (p = 0.05) in the subset (Keypad: N = 4; OT: N = 5) of these participants for which it was measured. CONCLUSIONS: Actively assisted individuation therapy comprised of non task-specific modalities, such as can be achieved with virtual platforms like the AVK described here, may prove to be valuable clinical tools for increasing the effectiveness and efficiency of therapy following stroke. PMID- 25542199 TI - A Longitudinal Examination of Depression Among Gambling Inpatients. AB - Problem and pathological gamblers demonstrate high levels of depression, which may be related to coping styles, reactive emotional states, and/or genetics (Potenza et al., Arch Gen Psychiat 62(9):1015-1021, 2005; Getty et al., J Gambl Stud 16(4):377-391, 2000). Although depression impacts treatment outcomes (Morefield et al., Int J Men Healt Addict 12(3):367-379, 2013), research regarding depression among gamblers in residential treatment is particularly limited. This study attempts to address this deficit by examining the course of depressive symptoms among clients at a residential gambling program in the Western United States. Forty-four adults were administered a weekly measure of depression (Beck Depression Inventory-II, BDI-II) for eight consecutive weeks. Levels of depression were classified into three groups based on standard scoring criteria for the BDI-II: no/minimal, mild/moderate, and severe depression. Results from a mixed-model analysis indicated a main effect for group and time, as well as an interaction between group and time. Examination of the slopes for the rate of change for the three depression groups indicated no change in the non depressed group and a decrease in depression scores over time for both the mild/moderate and severely depressed groups. The slopes for the two symptomatic depression groups were not significantly different, indicating a similar rate of change. We speculate that reductions in depression symptoms may be related to feelings of self-efficacy, environmental containment/stabilization, and therapeutic effects of treatment. These results help to illuminate the role of significant processes in residential treatment, including initial stabilization, insight, self-efficacy, and termination. PMID- 25542200 TI - Genome-wide expression analysis of soybean NF-Y genes reveals potential function in development and drought response. AB - Nuclear factor-Y (NF-Y), a heterotrimeric transcription factor, is composed of NF YA, NF-YB and NF-YC proteins. In plants, there are usually more than 10 genes for each family and their members have been identified to be key regulators in many developmental and physiological processes controlling gametogenesis, embryogenesis, nodule development, seed development, abscisic acid (ABA) signaling, flowering time, primary root elongation, blue light responses, endoplasmic reticulum (ER) stress response and drought tolerance. Taking the advantages of the recent soybean genome draft and information on functional characterizations of nuclear factor Y (NF-Y) transcription factor family in plants, we identified 21 GmNF-YA, 32 GmNF-YB, and 15 GmNF-YC genes in the soybean (Glycine max) genome. Phylogenetic analyses show that soybean's proteins share strong homology to Arabidopsis and many of them are closely related to functionally characterized NF-Y in plants. Expression analysis in various tissues of flower, leaf, root, seeds of different developmental stages, root hairs under rhizobium inoculation, and drought-treated roots and leaves revealed that certain groups of soybean NF-Y are likely involved in specific developmental and stress responses. This study provides extensive evaluation of the soybean NF-Y family and is particularly useful for further functional characterization of GmNF-Y proteins in seed development, nodulation and drought adaptation of soybean. PMID- 25542203 TI - IncP-1beta Plasmids Are Important Carriers of Fitness Traits for Variovorax Species in the Mycosphere--Two Novel Plasmids, pHB44 and pBS64, with Differential Effects Unveiled. AB - The Laccaria proxima mycosphere strongly selects Variovorax paradoxus cells. Fifteen independent V. paradoxus strains, isolated from mycospheres sampled at two occasions, were investigated with respect to the occurrence of plasmids of sizes <60-100 kb. Two V. paradoxus strains, HB44 and BS64, were found to contain such plasmids, which were coined pHB44 and pBS64. Replicon typing using a suite of plasmid-specific PCR systems indicated that both plasmids belong to the IncP 1beta group. Also, both were able to mobilize selectable IncQ group plasmids into Escherichia coli as well as Pseudomonas fluorescens. Moreover, they showed stable replication in these organisms, confirming their broad host range. Strain BS64 was cured of pBS64 and plasmid pHB44 was subsequently moved into this cured strain by making use of the IncQ group tracer plasmid pSUP104, which was then removed at elevated temperature. Thus, both plasmids could be screened for their ability to confer a phenotype upon strain BS64. No evidence for the presence of genes for xenobiotic degradation and/or antibiotic or heavy metal resistances was found for either of the two plasmids. Remarkably, both could stimulate the production of biofilm material by strain BS64. Also, the population densities of pBS64-containing strain BS64 were temporarily raised in liquid as well as soil systems (versus the plasmid-cured strain), both in the presence of the fungal host Lyophyllum sp. strain Karsten. Strikingly, plasmid pHB44 significantly enhanced the fitness of strain BS64 in soil containing Lyophyllum sp. strain Karsten, but decreased its fitness in soil supplemented with extra FeCl3. The effect was noted both in separate (no inter-strain competition) and joint (competition) inoculations. PMID- 25542202 TI - Intramyocardial strain estimation from cardiac cine MRI. AB - PURPOSE: Functional strain is one of the important clinical indicators for the quantification of heart performance and the early detection of cardiovascular diseases, and functional strain parameters are used to aid therapeutic decisions and follow-up evaluations after cardiac surgery. A comprehensive framework for deriving functional strain parameters at the endocardium, epicardium, and mid wall of the left ventricle (LV) from conventional cine MRI data was developed and tested. METHODS: Cine data were collected using short TR-/TE-balanced steady state free precession acquisitions on a 1.5T Siemens Espree scanner. The LV wall borders are segmented using a level set-based deformable model guided by a stochastic force derived from a second-order Markov-Gibbs random field model that accounts for the object shape and appearance features. Then, the mid-wall of the segmented LV is determined based on estimating the centerline between the endocardium and epicardium of the LV. Finally, a geometrical Laplace-based method is proposed to track corresponding points on successive myocardial contours throughout the cardiac cycle in order to characterize the strain evolutions. The method was tested using simulated phantom images with predefined point locations of the LV wall throughout the cardiac cycle. The method was tested on 30 in vivo datasets to evaluate the feasibility of the proposed framework to index functional strain parameters. RESULTS: The cine MRI-based model agreed with the ground truth for functional metrics to within 0.30 % for indexing the peak systolic strain change and 0.29 % (per unit time) for indexing systolic and diastolic strain rates. The method was feasible for in vivo extraction of functional strain parameters. CONCLUSION: Strain indexes of the endocardium, mid wall, and epicardium can be derived from routine cine images using automated techniques, thereby improving the utility of cine MRI data for characterization of myocardial function. Unlike traditional texture-based tracking, the proposed geometrical method showed the ability to track the LV wall points throughout the cardiac cycle, thus permitting more accurate strain estimation. PMID- 25542204 TI - Genetic evidence for reproductive isolation among sympatric Epichloe endophytes as inferred from newly developed microsatellite markers. AB - Reproductive isolation is central to the maintenance of species, and especially in sympatry, effective barriers to prevent interspecific crosses are expected. Host specificity is thought to constitute an effective mechanism for the formation of barriers in different genera of Fungi, but evidence for endophytes is so far lacking. Sexual Epichloe species (Ascomycota, Clavicipitaceae) represent an ideal study system to investigate the mechanisms underlying speciation as mediated by host specificity because they include species complexes with several host-specific taxa. Here, we studied genetic differentiation of three host-specific Epichloe species using microsatellite markers that were newly in silico identified on the genome of Epichloe poae. Among these, 15 were experimentally tested and applied to study an extensive sampling of isolates representing Epichloe typhina infecting Dactylis glomerata and Epichloe clarkii infecting Holcus lanatus from a site with sympatric populations in Switzerland, as well as a reduced sampling of E. poae infecting Poa nemoralis to create a three-taxon dataset. Both principal coordinate analysis and Bayesian clustering algorithm showed three genetically distinct groups representing the three host specific species. High pairwise F ST values among the three species, as well as sequencing data of the tefA gene revealing diagnostic single nucleotide polymorphisms (SNPs), further support the hypothesis of genetic discontinuities among the taxa. These results provide genotypic evidence of the maintenance of reproductive isolation of the species in a context of sympatry. In silico testing of 885 discovered microsatellites on the genome of Epichloe festucae extend their applicability to a wider taxonomic range of Epichloe. PMID- 25542205 TI - Halotolerant PGPRs Prevent Major Shifts in Indigenous Microbial Community Structure Under Salinity Stress. AB - The resilience of soil microbial populations and processes to environmental perturbation is of increasing interest as alteration in rhizosphere microbial community dynamics impacts the combined functions of plant-microbe interactions. The present study was conducted to investigate the effect of inoculation with halotolerant rhizobacteria Bacillus pumilus (STR2), Halomonas desiderata (STR8), and Exiguobacterium oxidotolerans (STR36) on the indigenous root-associated microbial (bacterial and fungal) communities in maize under non-saline and salinity stress. Plants inoculated with halotolerant rhizobacteria recorded improved growth as illustrated by significantly higher shoot and root dry weight and elongation in comparison to un-inoculated control plants under both non saline and saline conditions. Additive main effect and multiplicative interaction ordination analysis revealed that plant growth promoting rhizobacteria (PGPR) inoculations as well as salinity are major drivers of microbial community shift in maize rhizosphere. Salinity negatively impacts microbial community as analysed through diversity indices; among the PGPR-inoculated plants, STR2-inoculated plants recorded higher values of diversity indices. As observed in the terminal restriction fragment length polymorphism analysis, the inoculation of halotolerant rhizobacteria prevents major shift of the microbial community structure, thus enhancing the resilience capacity of the microbial communities. PMID- 25542206 TI - Impact of resistant starch in three plantain (Musa AAB) products on glycaemic response of healthy volunteers. AB - BACKGROUND AND AIM OF THE STUDY: Plantains can be eaten in various forms providing a good opportunity to study the effect of starch type on glycaemic response, and so three products differing in their types of available carbohydrate and contents of resistant starch were tested. METHODS: Boiled unripe plantain (BUP), boiled unripe plantain crisps (BUPC), ripe raw plantain (RRP) and white bread as reference (all 25 g available carbohydrate portion) were given to ten pre-screened healthy individuals. Postprandial glycaemic responses and glycaemic indices (GI) were measured. RESULTS: Peak blood glucose for BUP, BUPC and RRP was at 45, 45 and 30 min post-meal time, respectively. The peak blood glucose concentrations for BUP, BUPC and RRP (1.8 +/- 0.8, 2.3 +/- 0.8, 1.9 +/- 0.7 mmol/L, n = 10, respectively) reflected the in vitro quantities/types of rapidly available glucose (RAG) in the samples. On the other hand, mean GI +/- SEM values obtained for the test products (BUP = 44.9 +/- 3.6, BUPC = 55.0 +/- 4.2, RRP = 38 +/- 4.4, n = 10) were neither significantly different nor directly correlated with RAG. CONCLUSIONS: The results show a potential link between RAG and GI, but the correlation is confounded by the presence of other constituents in the plantains. PMID- 25542207 TI - Pattern ERG in central serous retinopathy. AB - BACKGROUND: To evaluate the pattern electroretinogram (PERG) in central serous retinopathy. METHODS: In this prospective study, 20 patients with recent onset (<6 weeks) unilateral CSR were studied with the fellow eye acting as control. BCVA, psychophysical parameters, FFA, OCT, flash and pattern ERG were evaluated. RESULTS: The mean P50 amplitude in the affected eye at presentation was 2.36 +/- 0.8 MUv compared to 3.24 +/- 0.85 MUv in the normal eye. At 12 weeks, the mean P50 amplitude in the affected eye was 3.16 +/- 0.88 MUv compared to 3.63 +/- 0.82 MUv in the normal eye. The reduction of 27 % in P50 amplitude even after recovery was statistically significant (P < 0.001). A reduction of 19.77 % in the amplitude of N95 wave in the affected eye compared to the normal eye was seen, which was statistically significant (P < 0.001). In the affected eye, there was statistically significant improvement in the psychophysical tests at 12 weeks. CONCLUSIONS: This study reveals that P50 component of the PERG is reduced in cases of CSR, indicating functional disturbance of the macular photoreceptors. A normal flash ERG indicates that pathology is electrophysiologically localised to macula without affecting general retina. Residual deficit in the PERG explains poor quality of vision in spite of normal anatomical apposition and quantitative 6/6 visual acuity. PMID- 25542208 TI - Microarray analysis of long non-coding RNAs in COPD lung tissue. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) play an important role in the pathogenesis of many human diseases. In this study, we provide the description of genome-wide lncRNA expression in the lung tissue of non-smokers without Chronic obstructive pulmonary disease (COPD), of smokers without COPD and of smokers with COPD. METHODS: RNA was extracted from human lung tissue and analysed using an Agilent Human lncRNA + mRNA Array v2.0 system. RESULTS: 39,253 distinct lncRNA transcripts were detected in the lung tissues of all subjects. In smokers without COPD 87 lncRNAs were significantly up-regulated and 244 down-regulated compared to non-smokers without COPD with RNA50010|UCSC-9199-1005 and RNA58351| CombinedLit_316_550, the most over- and under-regulated, respectively. In contrast, in COPD patients 120 lncRNAs were over-expressed and 43 under-expressed compared with smokers without COPD with RNA44121|UCSC-2000-3182 and RNA43510|UCSC 1260-3754 being the most over- and under-regulated, respectively. Gene Ontology (GO) and pathway analysis indicated that cigarette smoking was associated with activation of metabolic pathways, whereas COPD transcripts were associated with 'hematopoietic cell lineage', intermediary metabolism and immune system processes. CONCLUSIONS: We conclude that the altered expression of lncRNAs might play partial role in pathways implicated in COPD onset and progression such as intermediary metabolism and the immune response. PMID- 25542209 TI - Structural implications of Dpy30 oligomerization for MLL/SET1 COMPASS H3K4 trimethylation. PMID- 25542210 TI - Late presenting congenital diaphragmatic hernia as tension gastrothorax. PMID- 25542211 TI - Influence of freshwater discharge on the microbial degradation processes of dissolved organic nitrogen in a subtropical estuary. AB - River bacterioplankton communities, influenced by watershed usage, are responsible for water purification. Bacterioplankton may be critical in the degradation of dissolved organic nitrogen (DON), the major nitrogen pool in the Caloosahatchee River, Florida. We investigated how freshwater discharge influences estuarine bacterioplankton and how the freshwater-originated DON is utilized by estuarine bacterioplankton. Microcosm experiments were conducted during low and high discharge using two upstream freshwater samples: one site primarily influenced by Lake Okeechobee and the other site moderately influenced by an agricultural watershed. These freshwater samples were filtered to eliminate indigenous microbial populations, then mixed with estuarine bacterioplankton. High-throughput sequencing revealed that bacterioplankton differed between low and high discharge and were influenced by salinity. Alphaproteobacteria and Bacteroidetes dominated in low discharge while Bacteroidetes and Cyanobacteria dominated during high discharge. In the microcosm experiment, DON concentration decreased with increasing cell densities, suggesting that the DON was utilized as a carbon and nitrogen source. Band signals in denaturing gradient gel electrophoresis corresponding to Alphaproteobacteria and Actinobacteria decreased while Gammaproteobacteria increased during the 1 month incubation. This data suggests that estuarine bacterioplankton communities are influenced by variations in discharge patterns and use freshwater-originated DON as demonstrated by a shift in community structure. PMID- 25542212 TI - Anti-inflammatory effects of kolaviron modulate the expressions of inflammatory marker genes, inhibit transcription factors ERK1/2, p-JNK, NF-kappaB, and activate Akt expressions in the 93RS2 Sertoli cell lines. AB - The anti-inflammatory effects of kolaviron (Kol-v) have been demonstrated in several experimental models. The ability of Kol-v to modulate the expressions of inflammatory genes in lipopolysaccharide (LPS)-stimulated Sertoli cell line, 93RS2 was investigated in this study. Kol-v decreased the expressions of inflammatory genes TNF-alpha, Tlr-4, and Nfkappab1 and has synergistic effect on LPS-induced COX-2 and iNOS expressions at high concentrations (25-100 MUM). At lower concentrations (5-15 uM), the expressions of TNF-alpha, IL-6, and IL-1alpha were down-regulated by Kol-v except Tgfbeta1 that was up-regulated. The LPS induced decrease in the expression of the anti-inflammatory genes IL-3, IL-4, and IL-10 was blocked by Kol-v at all concentrations of Kol-v tested. The LPS-induced phosphorylations of mitogen-activated protein kinase family members (ERK1/2, and p-JNK), decreased IkappaBalpha expression, and decreased Akt phosphorylation was blocked by Kol-v. Our results highlight the potential for Kol-v at lower concentration to ameliorate cellular damage caused by local inflammation. PMID- 25542213 TI - Cullin 4A and 4B ubiquitin ligases interact with gamma-tubulin and induce its polyubiquitination. AB - Regulated polyubiquitination is a key step for controlling protein degradation and maintaining proper balance between the proliferation of normal and uncontrolled cells. Addition of ubiquitin to the proteins by E3 ubiquitin ligases targets them for degradation by the 26S proteosome machinery. Discrepancies in ubiquitination and/or proteosome degradation might lead to multiple genetic disorders in humans. It is reported that CUL1 and BRCA1 ubiquitin ligases localize on centrosome region and regulate the centrosome duplication cycle for genomic stability. In the current study, we predicted the possible interaction of E3 ubiquitin ligase CUL4A complex with gamma-tubulin, a centrosome-specific protein, using bioinformatic protein-protein docking analysis. We also confirmed their interaction by performing co-immunoprecipitation studies using endogenous CUL4A/B and stable cell lines that overexpress Flag-CUL4A or Flag-CUL4B. We additionally noted that the gamma-tubulin was polyubiquitinated by CUL4A or 4B immune complex indicating that CUL4A or CUL4B may regulate the stability of gamma tubulin. Furthermore, the inhibition of proteosomal degradation pathway using MG132 or LLNV drugs resulted in accumulation and co-localization of CUL4A with gamma-tubulin in the centrosome region. Overall, our observation has identified gamma-tubulin as a novel target for E3 ubiquitin ligase CUL4 complex, and might lead to the establishment of a unique mechanism for controlling centrosome stability. PMID- 25542214 TI - Growth maximization trumps maintenance of leaf conductance in the tallest angiosperm. AB - Structural and physiological changes that occur as trees grow taller are associated with increased hydraulic constraints on leaf gas exchange, yet it is unclear if leaf-level constraints influence whole-tree growth as trees approach their maximum size. We examined variation in leaf physiology, leaf area to sapwood area ratio (L/S), and annual aboveground growth across a range of tree heights in Eucalyptus regnans. Leaf photosynthetic capacity did not differ among upper crown leaves of individuals 61.1-92.4 m tall. Maximum daily and integrated diurnal stomatal conductance (g s) averaged 36 and 34% higher, respectively, in upper crown leaves of ~60-m-tall, 80-year-old trees than in ~90-m-tall, 300-year old trees, with larger differences observed on days with a high vapor pressure deficit (VPD). Greater stomatal regulation in taller trees resulted in similar minimum daily leaf water potentials (Psi L) in shorter and taller trees over a broad range of VPDs. The long-term stomatal limitation on photosynthesis, as inferred from leaf delta (13)C composition, was also greater in taller trees. The delta (13)C of wood indicated that the bulk of photosynthesis used to fuel wood production in the main trunk and branches occurred in the upper crown. L/S increased with tree height, especially after accounting for size-independent variation in crown structure across 27 trees up to 99.8 m tall. Despite greater stomatal limitation of leaf photosynthesis in taller trees, total L explained 95% of the variation in annual aboveground biomass growth among 15 trees measured for annual biomass growth increment in 2006. Our results support a theoretical model proposing that, in the face of increasing hydraulic constraints with height, whole-tree growth is maximized by a resource trade-off that increases L to maximize light capture rather than by reducing L/S to sustain g s. PMID- 25542216 TI - Oral sodium and potassium binders in heart failure. AB - Significant improvements in the morbidity and mortality associated with chronic heart failure have been gained with the use ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. However, the use of these agents is often limited by their propensity to precipitate worsening renal function and hyperkalemia, particularly in patients with chronic kidney disease. Several pharmacologic agents have been developed in recent years that utilize the gastrointestinal tract as an alternate route for drug absorption, electrolyte exchange, and drug and electrolyte elimination. The existing data establishing the safety and efficacy of these novel agents will be the focus of this review. PMID- 25542215 TI - Constraint-induced movement therapy: trial sequential analysis applied to Cochrane collaboration systematic review results. AB - BACKGROUND: Trial sequential analysis (TSA) may establish when firm evidence about the efficacy of interventions is reached in a cumulative meta-analysis, combining a required information size with adjusted thresholds for conservative statistical significance. Our aim was to demonstrate TSA results on randomized controlled trials (RCTs) included in a Cochrane systematic review on the effectiveness of constraint-induced movement therapy (CIMT) for stroke patients. METHODS: We extracted data on the functional independence measure (FIM) and the action research arm test (ARAT) from RCTs that compared CIMT versus other rehabilitative techniques. Mean differences (MD) were analyzed using a random effects model. We calculated the information size and the cumulative Z-statistic, applying the O'Brien-Fleming monitoring boundaries. RESULTS: We included data from 14 RCTs. In the conventional meta-analysis (seven trials, 233 patients), the effect of CIMT on FIM was reported as significant (MD 2.88, 95% CI 0.08 to 5.68; P = 0.04). The diversity-adjusted required information size was 142 patients, and the cumulative Z-score did not cross the trial sequential monitoring boundary for benefit (adjusted 95% CI -0.02 to 5.78). The effect of CIMT on ARAT (nine trials, 199 patients) was reported as significant (MD 7.78, 95% CI 1.19 to 14.37; P = 0.02). However, the diversity-adjusted required information size was 252 patients, and the Z-score did not cross the trial sequential monitoring boundary for benefit (adjusted 95% CI -0.06 to 15.62). CONCLUSIONS: Although conventional meta-analyses of CIMT reached statistical significance, their overall results remain inconclusive and might be spurious. Researchers should not be overconfident on CIMT efficacy based on the results of meta-analyses and derived recommendations. PMID- 25542217 TI - Magnetic resonance elastography (MRE) in assessing hepatic fibrosis: performance in a cohort of patients with histological data. AB - PURPOSE: The purpose of this study was to compare fibrosis seen on liver biopsy to MR elastography (MRE) stiffness measurements in normal controls and patients with abnormal transaminases and chronic liver disease. METHODS: The control group consisted of 22 healthy liver transplant donors who by definition had normal transaminases. The patient group (32 patients) was recruited from the Mayo Clinic Arizona hepatobiliary clinic over a 3-year span. All subjects underwent a liver biopsy as part of their evaluation and agreed to MRE within 35 days of biopsy. Non-parametric tests were used to compare the MRE-predicted liver fibrosis to the fibrosis noted on liver biopsy. RESULTS: Analysis included 54 subjects (32 patients with chronic liver disease and 22 healthy liver donor candidates). MRE median liver stiffness measurements increased per histologic liver fibrosis stage (one-way ANOVA p = 0.001), with significant correlation between increasing fibrosis stage and stiffness values. Median MRE for control group (2.13 kPa; mean = 2.3 +/- 0.6 kPa) was significantly lower than for patient group (3.7 kPa; mean = 4.1 +/- 2.1 kPa) (p = 0.003). Significantly, lower median stiffness was seen in zero-to-moderate (F0-2, n = 22) vs. severe fibrosis stages (F3-4, n = 10) 2.80 vs. 5.9 kPa, respectively (p < 0.05). Using a 3.7-kPa cut-off value, the predicted sensitivity and specificity for detecting F0-2 from F3-4 were 91% and 80%, respectively. CONCLUSIONS: Our analysis supports previous findings that MRE is a non-invasive and effective method for detection and assessment of liver fibrosis, particularly for discrimination between F0-2 stages and F3-4 stages. MRE may represent a valuable tool to finely discern hepatic fibrosis non invasively. PMID- 25542218 TI - Diagnostic performance of CT findings for bowel ischemia and necrosis in closed loop small-bowel obstruction. AB - PURPOSE: The aim of this study was to investigate the diagnostic performance of contrast-enhanced CT (CECT) findings for bowel ischemia and necrosis in closed loop small-bowel obstruction (CL-SBO). MATERIALS AND METHODS: Thirty-five patients with CL-SBO confirmed by laparotomy (n = 34) or multiplanar reconstruction of thin slice CT images (n = 1) were included. Based on the surgical and clinical findings, these patients were classified into three groups: necrosis group (n = 16), ischemia without necrosis group (n = 11), and no ischemia group (n = 8). Two blinded radiologists retrospectively reviewed CECT including multiplanar reconstruction images and evaluated 12 CT findings. The sensitivity and specificity of each finding were compared among the three groups, and logistic regression analysis was performed. RESULTS: High attenuation of the bowel wall, intraperitoneal air, reduced enhancement of the mesenteric arteries, and small-bowel feces signs showed high specificities of 100%, 100%, 89%, and 89% but low sensitivities of 31%, 25%, 44%, and 31%, respectively, for the prediction of bowel necrosis in CL-SBO. According to multivariate logistic regression analysis, reduced bowel-wall enhancement, reduced enhancement of the mesenteric veins, and a lack of engorgement of the mesenteric veins were significant for predicting bowel ischemia or necrosis (P < 0.05). CONCLUSIONS: Reduced enhancements of bowel wall and mesenteric veins were good indicators of bowel ischemia or necrosis. On the contrary, engorgement of the mesenteric veins was a predictor of a viable bowel. PMID- 25542219 TI - Biliary strictures and masses: an expanded differential diagnosis. AB - Biliary strictures and masses are commonly a result of cholangiocarcinoma. However, there are several congenital, infectious, inflammatory, autoimmune, iatrogenic, and neoplastic etiologies that should also be considered in the differential diagnosis. Knowledge of the key imaging and clinical findings will aid in facilitating the diagnosis and treatment. PMID- 25542220 TI - New associate editor prof. Dr. Ivo Meinhold-Heerlein. PMID- 25542221 TI - Monitoring of progression of nonsurgically treated rotator cuff tears by magnetic resonance imaging. AB - BACKGROUND: Nonsurgically treated rotator cuff tears sometimes become irreparable in the lead up to surgical repair. The purposes of our study were to identify predictive factors in the progression of tear size, and determine the changes in tear location. METHODS: Eighty shoulders from 71 patients (mean age 69.4 years) diagnosed with rotator cuff tears by MRI were treated nonsurgically. MRI was repeated after more than 1 year of initial diagnosis. Tear size was measured from the edge of the tear to the lateral aspect of the greater tuberosity. Tears were classified into 5 groups based on tear size and 4 groups based on tear location. Changes in tear size and location were examined. RESULTS: The mean follow-up period was 22.3 months. The average progression of tear size was 5 mm during follow-up, averaging 3 mm per year. Tears that were initially <1 or >=4 cm were unlikely to progress in tear size. On the other hand, 1- to 2-cm tears on the initial MRI exhibited the greatest progression in tear size, followed by 2- to 3 cm tears. Furthermore, 62.5 % of localized tears in the posterior of the superior facet spread anteriorly, whereas 88.9 % of localized tears in the anterior of the superior facet did not change. CONCLUSIONS: Medium-sized tears are at high risk of tear progression. In contrast, there is little risk of early development of irreparable damage in partial tear or small full-thickness tears. In addition, typical tears may start in the posterior of the superior facet, and subsequently spread anteriorly. Our present findings may serve as a useful reference in determining the treatment course for rotator cuff tears. LEVEL OF EVIDENCE: Level IV, Case Series, Prognosis Study. PMID- 25542222 TI - Preliminary study of the patterns and physical risk factors of work-related musculoskeletal disorders among academicians in a higher learning institute. AB - BACKGROUND: Research has been conducted on the prevalence and physical risk factors of work-related musculoskeletal disorders (WMSDs) among occupations such as agriculture workers, office workers, school teachers, and health care professionals. However, a paucity of research exists on the patterns and physical risk factors of WMSDs among the academicians in a higher learning institution. This study was conducted to determine the patterns and physical risk factors of WMSDs among the academicians. METHODS: A cross-sectional study was conducted among 228 subjects with a mean age of participants of 32.3 +/- 7.8 for a period of 1 year from December 2011 until December 2012. An extended neordic musculoskeletal questionnaire (NMQ-E) was used to assess the patterns of work related musculoskeletal disorders. The short version of the Dutch musculoskeletal questionnaire (DMQ) was used to determine the physical risk factors of WMSDs among the academicians. Descriptive statistics and Pearson Chi square test were used for data analysis. RESULTS: The 1-year pattern of WMSDs among the academicians were neck pain (44.7 %), followed by shoulder pain (40.4 %), upper and lower back pain (33.3 %), and the least common region was elbow pain (3.5 %). Among 20 common physical activities in DMQ, 15 physical activities performed by the academicians in their workplace were considered as a physical risk factors for neck, shoulder, and back pain at p < 0.05. CONCLUSION: The preliminary study demonstrated that neck pain, shoulder pain, and back pain were the most common WMSDs among the academicians in a higher learning institution. PMID- 25542223 TI - Expression of tenocyte lineage-related factors in regenerated tissue at sites of tendon defect. AB - BACKGROUND: The healing mechanism of ruptured or injured tendons is poorly understood. To date, some lineage-specific factors, such as scleraxis and tenomodulin, have been reported as markers of tenocyte differentiation. Because few studies have focused on tenocyte lineage-related factors with respect to the repaired tissue of healing tendons, the aim of this study was to investigate their expression during the tendon healing process. METHODS: Defects were created in the patellar tendons of rats, and the patellae and patellar tendons were harvested at 3 days and at 1, 2, 3, 6, 12, and 20 weeks after surgery. They were studied using micro-computed tomography, and paraffin-embedded sections were then prepared for histological evaluation. Reverse transcription-polymerase chain reactions were performed to analyze the expression of genes related to the tenocyte lineage, chondrogenesis, and ossification. RESULTS: Repaired tissue became increasingly fibrous over time and contained a greater number of vessels than normal tendons, even in the later period. Safranin O staining revealed the existence of proteoglycan at 1 week and its persistence through 20 weeks. Ossification was detected in all tendons at 12 weeks. The expression of tenocyte lineage-related genes was high at 1 and 2 weeks. Chondrogenic genes were up regulated until 6 weeks. Runt-related transcription factor 2, an osteogenic gene, was up-regulated at 20 weeks. CONCLUSIONS: In our tendon defect model, cells participating in the tendon healing process appeared to differentiate toward tenocyte lineage only in the early phase, and chondrogenesis seemed to occur from the early phase onward. To improve tendon repair, it will be necessary to promote and maintain tenogenesis and to inhibit chondrogenesis, especially in the early phase, in order to avoid erroneous differentiation of stem cells. PMID- 25542224 TI - Care on demand in nursing homes: a queueing theoretic approach. AB - Nursing homes face ever-tightening healthcare budgets and are searching for ways to increase the efficiency of their healthcare processes without losing sight of the needs of their residents. Optimizing the allocation of care workers plays a key role in this search as care workers are responsible for the daily care of the residents and account for a significant proportion of the total labor expenses. In practice, the lack of reliable data makes it difficult for nursing home managers to make informed staffing decisions. The focus of this study lies on the 'care on demand' process in a Belgian nursing home. Based on the analysis of real life 'call button' data, a queueing model is presented which can be used by nursing home managers to determine the number of care workers required to meet a specific service level. Based on numerical experiments an 80/10 service level is proposed for this nursing home, meaning that at least 80 percent of the clients should receive care within 10 minutes after a call button request. To the best of our knowledge, this is the first attempt to develop a quantitative model for the 'care on demand' process in a nursing home. PMID- 25542225 TI - Catalytic models developed through social work. AB - The article develops the concept of catalytic processes in relation to social work with adolescents in an attempt to both reach a more nuanced understanding of social work and at the same time to develop the concept of catalytic processes in psychology. The social work is pedagogical treatment of adolescents placed in out of-home care and is characterised using three situated cases as empirical data. Afterwards the concept of catalytic processes is briefly presented and then applied in an analysis of pedagogical treatment in the three cases. The result is a different conceptualisation of the social work with new possibilities of development of the work, but also suggestions for development of the concept of catalytic processes. PMID- 25542226 TI - Virtual high throughput screening of carbapenem derivatives as new generation carbapenemase and penicillin binding protein inhibitors: a hunt to save drug of last resort. AB - The advent of carbapenem resistance by the production of beta-lectamases and mutated penicillin binding proteins (PBPs) has challenged the treatment of Enterobacteriaceae. Hence there is an urgent need to establish drugs that can fit in the pipeline by overcoming those situations. The working hypothesis of the work is based on two facts, i.e., i) design of inhibitors against mutated PBPs to which present drugs cannot bind efficiently to kill pathogen by inhibiting cell wall formation, ii) design of molecules that can bind with beta-lectamases with high affinity, so that they can supplement available drugs preventing their unwanted hydrolysis. In this work, over thousands of thienamycin (first natural carbapenem) derivatives were generated and out of which non-toxic 273 molecules were used for further study. Out of which, only few followed the first hypothesis and rest obeyed the second. Ligand L5 strictly followed the first hypothesis and L1-L4 followed to a satisfactory level. Molecular dynamic simulation was performed to check post-docking stability of the pharmacophores. PMID- 25542227 TI - Disparities in birth weight and gestational age by ethnic ancestry in South American countries. AB - OBJECTIVES: We examine disparities in birth weight and gestational age by ethnic ancestry in 2000-2011 in eight South American countries. METHODS: The sample included 60,480 singleton live births. Regression models were estimated to evaluate differences in birth outcomes by ethnic ancestry controlling for time trends. RESULTS: Significant disparities were found in seven countries. In four countries-Brazil, Ecuador, Uruguay, and Venezuela-we found significant disparities in both low birth weight and preterm birth. Disparities in preterm birth alone were observed in Argentina, Bolivia, and Colombia. Several differences in continuous birth weight, gestational age, and fetal growth rate were also observed. There were no systematic patterns of disparities between the evaluated ethnic ancestry groups across the study countries, in that no racial/ethnic group consistently had the best or worst outcomes in all countries. CONCLUSIONS: Racial/ethnic disparities in infant health are common in several South American countries. Differences across countries suggest that racial/ethnic disparities are driven by social and economic mechanisms. Researchers and policymakers should acknowledge these disparities and develop research and policy programs to effectively target them. PMID- 25542228 TI - Genetic polymorphisms of DNA repair pathways influence the response to chemotherapy and overall survival of gastric cancer. AB - We aimed to evaluate the clinical response to platinum-based chemotherapy and treatment outcome of gastric cancer patients in the present of ERCC1, ERCC2, NBN, RAD51, and XRCC3 gene polymorphisms. A number of 415 patients of gastric cancer that received platinum-based chemotherapy were enrolled in the present study. The presence of ERCC1 rs11615 and rs2298881, ERCC2 rs1799793 and rs13181, NBN rs1805794, rs709816, and RAD51 rs1801321 and XRCC3 rs1799794 were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method. Conditional regression analysis identified that CC genotype of ERCC1 rs11615 and AA genotype of ERCC2 rs1799793 was associated with a better response to chemotherapy in gastric cancer patients, and the odds ratio (ORs)(95% confidence interval (CI)) were 2.70(1.33-5.70) and 3.12(1.52-6.84), respectively. By the Cox analysis, the CC genotype of ERCC1 rs11615, AA genotype of ERCC2 rs1799793, and CC genotype of NBN rs1805794 were significantly associated with a longer overall survival (OS) of gastric cancer. In conclusion, our results suggest that ERCC1 rs11615, ERCC2 rs1799793, and NBN rs1805794 polymorphisms in the DNA repair pathways may influence the response to chemotherapy and OS of gastric cancer. PMID- 25542229 TI - Inhibitory effect of ibuprofen on tumor survival and angiogenesis in gastric cancer cell. AB - Numerous epidemiological studies have suggested effectiveness of long-term and regular use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, in preventing and treatment of certain cancers including prostate, colon, breast, lung, and gastric cancers. We have studied the potential anti turmeric effect of ibuprofen in adenocarcinoma gastric cell line (AGS). The effects of ibuprofen were investigated on cell proliferation, apoptosis, angiogenesis, and expression of stemness marker genes using real-time RT-PCR, DNA laddering, and tube formation assays via ECM gel and human umbilical vein endothelial cells (HUVECs). Annexin-V-FLUOS and propidium iodide (PI) were used to stain the apoptotic cells. Our findings indicate that ibuprofen at the concentrations of 100, 200, 300, 400, and 500 MUM is able to reduce the cancerous characteristics of the AGS cells by inducing apoptosis, inhibition of cell proliferation, and angiogenesis. Real-time RT-PCR showed that ibuprofen altered the expression of several genes including Akt, P53, PCNA, Bax, and Bcl2 in the AGS cells. In addition, reduction in CD44 and OCT3/4 transcript levels revealed that ibuprofen reduces the stemness of the AGS cells and therefore it could be used as a potential anti-tumor drug. PMID- 25542230 TI - The small-molecule compound BM-1197 inhibits the antiapoptotic regulators Bcl 2/Bcl-xL and triggers apoptotic cell death in human colorectal cancer cells. AB - Small molecule BH3 mimetics comprise a promising new chemotherapeutic strategy for treating relapsed or chemoresistant cancer. In this study, we investigated the cellular mechanism of action by which BM-1197, a Bcl-xL/Bcl-2 dual inhibitor, triggers apoptosis in a panel of colorectal cancer (CRC) lines. Using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, we determined that BM-1197 inhibited CRC cell growth in a concentration- and time-dependent manner. The 50 % inhibitory concentration (IC50) values for the most sensitive cell lines, SW620 and SW480, ranged from 0.07 to 1.10 MUM in response to a 72-h treatment. In CRC cells, BM-1197 induced apoptotic death without affecting the expression of Bcl-2 family proteins. However, BM-1197 effectively triggered a conformational change in Bax, releasing Bim from Bcl-xL by disrupting the interaction between Bcl-xL and Bak/Bax. Compared with the control group, BM-1197 treatment significantly increased the fraction of SW480 cells in the sub-G1 phase, the apoptosis rate, and cellular internucleosomal DNA fragmentation. The proapoptotic activity was associated with cytochrome c release, caspase-3 activation, and PARP-1 cleavage. Collectively, BM-1197 effectively suppressed the growth of the human CRC cell line SW480 by inducing mitochondria-dependent apoptotic cell death. These data have specific implications for the in vivo analysis and clinical evaluation of BM-1197 in CRC. PMID- 25542231 TI - Electrolyte disorders assessment in solid tumor patients treated with anti-EGFR monoclonal antibodies: a pooled analysis of 25 randomized clinical trials. AB - The role of anti-epithelial growth factor receptor monoclonal antibodies (anti EGFR MoAbs) in treatment-related electrolyte disorders is still controversial. Therefore, we conducted a meta-analysis of published randomized controlled trials (RCTs) to evaluate the incidences and overall risks of all-grade and grade 3/4 electrolyte disorder events. We searched relevant clinical trials from PubMed, EMBASE, and Web of Knowledge databases, meeting proceedings of American Society of Clinical Oncology and the European Society of Medical Oncology, as well as ClinicalTrials.gov. Eligible studies included phases II, III, and IV RCTs. Statistical analysis was performed to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) using fixed effects or random effects models based on the heterogeneity of included studies. A total of 16,411 patients from 25 RCTs were included in this meta-analysis. The all-grade incidence of hypomagnesemia related to anti-EGFR MoAbs was 34.0 % (95 % CI 28.0 40.5 %), and that for hypokalemia and hypocalcemia were 14.5 % (95 % CI 8.2-24.4 %) and 16.8 % (95 % CI 14.2-19.7 %), respectively. Compared with chemotherapy alone in colorectal cancer, addition of cetuximab increased the risk of grade 3/4 hypomagnesemia and grade 3/4 hypokalemia with RRs of 7.14 (95 % CI 3.13-16.27, p < 0.001) and 2.19 (95 % CI 1.14-4.23, p = 0.019). Additionally, colorectal cancer patients in panitumumab cases were more vulnerable to grade 3/4 hypomagnesemia and hypokalemia (RR 18.29, 95 % CI 7.29-48.41, p < 0.001, and RR 3.3, 95 % CI 1.32-8.25, p = .011). Treatment with anti-EGFR MoAbs is associated with significantly higher risks of electrolyte disorders such as hypomagnesemia, hypomagnesemia, and hypocalcemia, especially in colorectal cancer. Rigorous monitoring and early treatment of electrolyte disorders are proposed. PMID- 25542233 TI - The effect of benzyl isothiocyanate and its computer-aided design derivants targeting alkylglycerone phosphate synthase on the inhibition of human glioma U87MG cell line. AB - Benzyl isothiocyanate (BITC) has been shown to have inhibitory potential for human glioma U87MG cells; however, the effect and mechanism were not fully clear. In the present study, we found that BITC could inhibit U87MG cell proliferation, adhesion, invasion, and vasculogenic mimicry (VM) formation potential and induce oxidative stress, apoptosis, and cell cycle arrest. We also found that the expression of proliferation, invasion, VM oxidative stress, apoptosis, and cell cycle-related gene and the activity of tumor-related signaling pathways, including protein kinase C (PKC) zeta and Akt/nuclear factor-kappa B (NF-kappaB) pathways, were suppressed by BITC treatment. We also explored the anti-tumor potential of BITC in vivo, and we found that BITC also could regulate the expression of tumor-related gene and angiogenesis in nude mice model. Finally, we optimized the BITC construction targeting alkylglycerone phosphate synthase (AGPS) by computer-aided design, and the derivants also showed anti-tumor potential in vitro. PMID- 25542232 TI - Timosaponin AIII mediates caspase activation and induces apoptosis through JNK1/2 pathway in human promyelocytic leukemia cells. AB - Timosaponin AIII (TAIII) is a steroidal saponin isolated from Anemarrhena asphodeloides that has been shown to inhibit cell growth and induce apoptosis in cancer. However, the effect of TAIII on acute myeloid leukemia (AML) remains unclear. Here, the molecular mechanism by which TAIII-induced apoptosis affects human AML cells was investigated. The results showed that TAIII significantly inhibited cell proliferation of four AML cell lines (MV4-11, U937, THP-1, and HL 60). Furthermore, TAIII induced apoptosis of HL-60 cells through caspase-3, caspase-8, and caspase-9 activations and PARP cleavage in a dose- and time dependent manner. Moreover, Western blot analysis also showed that TAIII increased phosphorylation of JNK1/2 and p38 MAPK in a dose-dependent manner. Inhibition of JNK1/2 by specific inhibitors significantly abolished the TAIII induced activation of the caspase-8. Taken together, our results suggest that TAIII induces HL-60 cell apoptosis through JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML. PMID- 25542234 TI - N-cadherin mediates the migration of MCF-10A cells undergoing bone morphogenetic protein 4-mediated epithelial mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) of mammary epithelial cells is important in both normal morphogenesis of mammary glands and metastasis of breast cancer. Cadherin switching from E-cadherin to N-cadherin plays important roles in EMT. We found that cadherin switching is important in bone morphogenetic protein 4 (BMP4) induced EMT in MCF-10A cells. BMP4 increased the phosphorylation of SMAD proteins in MCF-10A cells. Canonical BMP4 signaling decreased the expression of E-cadherin and disrupted the polarity of the tight junction protein ZO-1 in MCF-10A cells. However, the expression of N-cadherin and SNAI2 was up-regulated in BMP4-treated MCF-10A cells. MCF-10A cells that expressed N-cadherin migrated into type I collagen gels in response to BMP4 when evaluated using three-dimensional culture assays. Thus, active canonical BMP4 signaling is important for the migration and EMT of mammary epithelial cells. Moreover, the decrease in E-cadherin and/or increase in N-cadherin may be required for BMP4-induced migration and EMT. PMID- 25542236 TI - Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in lung adenocarcinoma. AB - Prognosis in patients with lung cancer is poor. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) are proteins involved in the invasion and metastases of cancer. The objective of this study is to determine if there is a relationship between tumor expression of NGAL and MMP-9 in lung adenocarcinoma patients with prognosis and overall survival. Retrospective analysis was made of patients with lung adenocarcinoma treated at Medica Sur Hospital between 2005 and 2013. Tumor tissue was analyzed for NGAL and MMP-9 expression by immunohistochemistry. We identified 41 patients. Mean overexpression in tumoral tissue of NGAL was 70 % and 30 % for MMP-9. Univariate analysis revealed that prognostic factors associated with overall survival (OS) were NGAL expression and stage at diagnosis. Median OS for NGAL expression < 70 % was 45.7 months (95 % CI; 15.2-76.2) and for patients with >= 70 % 4.6 months (95 % CI; 0.5-18.8; P < 0.0001), and for stage at diagnosis (stages I and II mean not reached), stage III mean OS 15.57 months (95 % CI; 9.8-21.2) and stage IV 9.6 months (95 % CI; 0.8-18.4. P = 0.002). No differences in OS were found for expression of MMP-9. Multivariate analysis revealed significance for OS in NGAL expression (HR 5.01 [95 % CI; 1.68-14.93] P = 0.004) and stage at diagnosis (HR 2.05 [95 % CI 1.30-3.22] P = 0.002). Tumoral tissue expression of NGAL >= 70 % confers a worse prognosis compared to those who did not. NGAL is an independent prognostic factor of stage at diagnosis. PMID- 25542237 TI - Can Learning Collaboratives Support Implementation by Rewiring Professional Networks? AB - This study examined how a learning collaborative focusing on trauma-focused CBT (TF-CBT) impacted advice-seeking patterns between clinicians and three key learning sources: (1) training experts who share technical knowledge about TF CBT, (2) peers from other participating organizations who share their implementation experiences, and (3) colleagues from their own agency who provide social and professional support. Based on surveys administered to 132 clinicians from 32 agencies, participants' professional networks changed slightly over time by forming new advice-seeking relationships with training experts. While small, these changes at the clinician-level yielded substantial changes in the structure of the regional advice network. PMID- 25542235 TI - Curcumin reverses cisplatin resistance in cisplatin-resistant lung caner cells by inhibiting FA/BRCA pathway. AB - Cisplatin (DDP) is the most widely used chemotherapy agent for treatment of malignancies including lung cancer. However, the effectiveness of DDP is often weakened by acquired resistance of tumor cells. DDP kills cancer cells primarily by creating intrastrand and interstrand DNA cross-links, which block DNA replication. The Fanconi anemia (FA)/BRCA pathway is a DNA cross-link damage repair pathway, which regulates cellular resistance to DNA cross-link agents, such as DDP. Some study has shown that natural compound curcumin sensitize human ovarian and breast cancer cells to DDP. However, whether curcumin may reverse resistance to DDP in DDP-resistant lung cancer cells has not been understood. In this study, we showed that curcumin enhanced the proliferation inhibitory effect of DDP and promote DDP-induced apoptosis in A549/DDP cells (DDP-resistant lung adenocarcinoma cells). Moreover, we observed that FA/BRCA pathway DNA damage repair processes, such as DDP-induced FANCD2 monoubiquitination and nuclear foci formation were downregulated in the presence of curcumin, suggesting that curcumin enhanced sensitivity to DDP in A549/DDP cells through the inhibition of FA/BRCA pathway. Furthermore, the calculation of q value and apoptosis analyses revealed that curcumin in combination with DDP could exert a synergistic cytotoxic effect in A549/DDP cells, further demonstrating that curcumin can reverse cisplatin resistance of A549/DDP cells. In conclusion, by suppressing the FA/BRCA pathway DNA repair, curcumin potentiates DDP-induced proliferation inhibitory effect and apoptosis in A549/DDP cell, indicating that curcumin may serve as a chemosensitizer to cross-link-inducing anticancer drugs DDP. PMID- 25542239 TI - Comparison of different pretreatment strategies for ethanol production of West African biomass. AB - Pretreating lignocellulosic biomass for cellulosic ethanol production in a West African setting requires smaller scale and less capital expenditure compared to current state of the art. In the present study, three low-tech methods applicable for West African conditions, namely Boiling Pretreatment (BP), Soaking in Aqueous Ammonia (SAA) and White Rot Fungi pretreatment (WRF), were compared to the high tech solution of hydrothermal pretreatment (HTT). The pretreatment methods were tested on 11 West African biomasses, i.e. cassava stalks, plantain peelings, plantain trunks, plantain leaves, cocoa husks, cocoa pods, maize cobs, maize stalks, rice straw, groundnut straw and oil palm empty fruit bunches. It was found that four biomass' (plantain peelings, plantain trunks, maize cobs and maize stalks) were most promising for production of cellulosic ethanol with profitable enzymatic conversion of glucan (>30 g glucan per 100 g total solids (TS)). HTT did show better results in both enzymatic convertibility and fermentation, but evaluated on the overall ethanol yield the low-tech pretreatment methods are viable alternatives with similar levels to the HTT (13.4 15.2 g ethanol per 100 g TS raw material). PMID- 25542238 TI - Etanercept alleviates early brain injury following experimental subarachnoid hemorrhage and the possible role of tumor necrosis factor-alpha and c-Jun N terminal kinase pathway. AB - Cerebral inflammation plays a crucial role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effects of c-Jun N terminal kinase (JNK) inhibitor SP600125, acetylcholine (Ach), etanercept, and anti-TNF-alpha on cellular apoptosis in the cerebral cortex and the hippocampus, in order to establish the role of JNK and TNF-alpha in EBI. The SAH model was established using an endovascular puncture protocol. The reliability of the EBI model was determined by phosphorylated-Bad (pBad) immunohistochemistry. Neurological scores were recorded and western blot was used to detect the expression of JNK and TNF-alpha, and TUNEL assay was used to mark apoptotic cells. The results showed that pBad positive cells were evenly distributed in the cerebral cortex at different time points. The highest expression of pBad was reached 1 day after SAH, and pJNK and TNF-alpha reached their peak expression at 2 days after SAH. SP600125, Ach, and etanercept significantly decreased the level of pJNK and TNF-alpha in the cerebral cortex and the hippocampus. In addition, SP600125 and etanercept reduced cellular apoptosis in the cerebral cortex and the hippocampus and significantly improved neurological scores at 2 days after SAH potentially via inhibition of the JNK-TNF-alpha pathway. Ach reduced cellular apoptosis only in the cerebral cortex. It is possible that JNK induces TNF-alpha expression, which in turn enhances JNK expression in EBI after SAH, leading to increased apoptosis in the cerebral cortex and the hippocampus. Thus, our results indicate that that etanercept may be a potential therapeutic agent to alleviate EBI. PMID- 25542240 TI - Momordica charantia seed lectin: toxicity, bacterial agglutination and antitumor properties. AB - In last three decades, several studies were carried out on the D-galactose specific lectin of Momordica charantia seeds (MCL). In the present study, in vitro growth inhibition (8-23 %) at different concentrations (6-24 MUg/ml) of MCL was observed against Ehrlich ascites carcinoma (EAC) cells by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MCL also showed 28, 45, and 75 % growth inhibitions against EAC cells when administered 1.2, 2.0, and 2.8 mg/kg/day (i.p.), respectively for five consequent days in vivo in mice. After lectin treatment, the level of red blood cell and hemoglobin was increased significantly with the decrease of white blood cell and maintained the normal level when compared with EAC-bearing control and normal mice without EAC cells. Although MCL caused cell cycle arrest at G0/G1 phase of EAC cells, any irregular shape or apoptotic morphological alterations in the lectin-treated EAC cells was not observed by an optical and fluorescence microscope. Lectin showed toxicity against brine shrimp nauplii with an LC50 value of 49.7 MUg/ml. Four out of seven pathogenic bacteria were agglutinated by MCL in the absence of inhibitory sugar D-lactose/D-galactose. In conclusion, MCL showed strong cytotoxic effect and therefore can be used as a potent anticancer chemotherapeutic agent. PMID- 25542241 TI - Influence of azo dye concentration on activated sludge bacterial community in the presence of functionalized polyurethane foam. AB - Immobilized quinones exhibit good catalytic performance in the biodecolorization of azo dyes. However, in practical activated sludge systems, little is known about the effect of azo dye concentration on microbial communities in the presence of immobilized quinones. 454 Pyrosequencing was used to investigate structural changes and to determine the key microorganisms involved in Reactive Red X-3B decolorization in the presence of anthraquinone-2-sulfonate immobilized on polyurethane foam (AQS-PUF). Our results show that the AQS-PUF-supplemented system exhibited better stability and decolorization performance during a 30-day run than polyurethane-foam-only (PUF-supplemented) and control systems. Analysis of pyrosequencing data showed that the AQS-PUF-supplemented system had the highest bacterial diversity, followed by the control and PUF-supplemented systems during decolorization. Reactive Red X-3B and AQS-PUF significantly influenced bacterial communities at the class level: Erysipelotrichia and the most dominant Deltaproteobacteria showed significant positive correlations with Reactive Red X 3B, while unclassified Firmicutes were found to be significantly correlated with AQS-PUF. At the genus level, Desulfomicrobium, which represents 8-44 % of the total population, displayed a significant positive correlation with Reactive Red X-3B. Some bacteria, including Desulfovibrio, Shewanella, and Clostridium with relative abundances of less than 6 %, were positively correlated with AQS-PUF. These findings provide a novel insight into the changes that occur in the bacterial community during immobilized AQS-mediated decolorization. Less abundant quinone-reducing bacteria play important roles in accelerating the effect of AQS PUF on biodecolorization. PMID- 25542242 TI - Dipeptidase activity and growth of heat-treated commercial dairy starter culture. AB - Growing expectations of consumers of fermented dairy products urge the search for novel solutions that would improve their organoleptic properties and in the case of rennet cheeses-that would also accelerate their ripening process. The aim of this study was to determine the peptidolytic activities and growth of heat treated commercial culture of lactic acid bacteria. The analyzed culture was characterized by a relatively high peptidolytic activity. The growth of bacterial culture subjected to heat treatment at 50-80 degrees C for 15 s, 10 and 3 min was delayed by a few or 10-20 h compared to the control culture. Based on the results achieved, it may be concluded that in the production of rennet cheeses, the application of additional, fermentation-impaired starter cultures (via heating for ten or so minutes) may serve to accelerate their ripening and to improve their sensory attributes. PMID- 25542243 TI - Comparison of the driving forces of spring phenology among savanna landscapes by including combined spatial and temporal heterogeneity. AB - Understanding spatial and temporal dynamics of land surface phenology (LSP) and its driving forces are critical for providing information relevant to short- and long-term decision making, particularly as it relates to climate response planning. With the third generation Global Inventory Monitoring and Modeling System (GIMMS3g) Normalized Difference Vegetation Index (NDVI) data and environmental data from multiple sources, we investigated the spatio-temporal changes in the start of the growing season (SOS) in southern African savannas from 1982 through 2010 and determined its linkage to environmental factors using spatial panel data models. Overall, the SOS occurs earlier in the north compared to the south. This relates in part to the differences in ecosystems, with northern areas representing high rainfall and dense tree cover (mainly tree savannas), whereas the south has lower rainfall and sparse tree cover (mainly bush and grass savannas). From 1982 to 2010, an advanced trend was observed predominantly in the tree savanna areas of the north, whereas a delayed trend was chiefly found in the floodplain of the north and bush/grass savannas of the south. Different environmental drivers were detected within tree- and grass dominated savannas, with a critical division being represented by the 800 mm isohyet. Our results supported the importance of water as a driver in this water limited system, specifically preseason soil moisture, in determining the SOS in these water-limited, grass-dominated savannas. In addition, the research pointed to other, often overlooked, effects of preseason maximum and minimum temperatures on the SOS across the entire region. Higher preseason maximum temperatures led to an advance of the SOS, whereas the opposite effects of preseason minimum temperature were observed. With the rapid increase in global change research, this work will prove helpful for managing savanna landscapes and key to predicting how projected climate changes will affect regional vegetation phenology and productivity. PMID- 25542244 TI - Anatomical study for flexor hallucis longus tendon transfer in treatment of Achilles tendinopathy. AB - PURPOSE: The purpose of the study was to describe the anatomical variations of the connection between the flexor hallucis longus (FHL) and flexor digitorum longus (FDL) tendons in the knot of Henry in Asians, and quantify the length of FHL tendon graft with different incisions. METHODS: Sixty-four embalmed feet of 32 cadavers were analyzed anatomically with respect to the individual cross-links in the planta pedis. Single incision technique graft length was measured from the musculotendinous junction of FHL and the point at sustentaculum tali. Double incision technique was measured from musculotendinous junction of FHL and the level of the master knot of Henry. Additionally, minimally invasive incision technique was measured from musculotendinous junction of FHL to the first interphalangeal joint. These three techniques were then combined to determine the total potential tendon graft length obtainable using different approach. RESULTS: Only two different configurations were found. Type 1, a tendinous slip branched from the FHL to the FDL (62 of 64 feet). Type 2, a slip branched from the FHL to the FDL and another slip from the FDL to FHL (2 of 64). The average length of the FHL graft available from a single incision measured 5.08 cm (range 3.32-10.35, SD = 1.09), double incision technique measured 6.72 cm (range 4.69-12.09, SD = 1.03), and minimally invasive incision measured 17.49 cm (range 13.51-20.52, SD = 1.80). The difference between the lengths obtained from these three techniques was statistically significant (p < 0.001). CONCLUSION: The absence of no attachment and FDL tendon to the FHL between the two tendons in the foot may be more frequent than previously reported. Only two configurations of the anatomical relationship were found in this study. In over 96 % of the feet, a proximal to distal connection from the FHL to the FDL was found, which might contribute to the residual function of the lesser toes after FDL transfer. PMID- 25542245 TI - Do the radial head prosthesis components fit with the anatomical structures of the proximal radioulnar joint? AB - PURPOSE: The fitting accuracy of radial head components has been investigated in the capitulo-radial joint, and reduced contact after prosthetic replacement of the radial head has been observed. The kinematics of the proximal radioulnar joint (PRUJ) are affected by radial head arthroplasty as well, but have not yet been investigated in this regard. METHODS: The elbow joints of 60 upper extremities of formalin-fixed body donors were disarticulated to obtain a good view of the PRUJ. Each specimen was mounted on the examining table and radial head position in the native PRUJ was assessed in neutral position, full pronation, and full supination. Measurements were repeated after implantation of mono- and bi-polar prostheses. RESULTS: Analysis of the distribution of the joint contacts in the compartments showed significant differences after radial head replacement. In comparison to the native joint, after bipolar and monopolar radial head replacement, the physiological shift of the proximal radius was altered. DISCUSSION: The physiological shift of the joint contact of the radial head from anterior to posterior during forearm rotation that was found in the native joint in our cadaver model was not observed after prosthetic replacement. With higher conformity and physiological kinematic of radial head prostheses, possibly lower shear forces and lower contact pressures would be generated. CLINICAL RELEVANCE: The tested radial head prostheses do not replicate the physiological kinematics of the radial head. Further development in the prosthesis design has to be made. The meticulous reconstruction of the annular ligament seems to be of importance to increase joint contact. PMID- 25542246 TI - Movements of the double-lumen endotracheal tube due to lateral position with head rotation and tube fixation: a Thiel-embalmed cadaver study. AB - PURPOSE: Following successful double-lumen endotracheal tube (DLT) insertion for pulmonary surgery, the body position of a patient is changed from supine to lateral. This change occasionally leads to the malposition of the DLT and difficulty in differential lung ventilation. METHODS: In this study, we investigated movements of the DLT induced by change in body position from supine to lateral, using Thiel-embalmed cadavers. Thiel-embalmed cadavers retain full flexibility of the body and preservation of natural colours, using novel preservation techniques. After the tip of the DLT was directly fixed with forceps at the appropriate position in the bronchus, the DLT depth was measured at the lip in supine and lateral positions. RESULTS: The depth of DLT insertion measured at the lip in right (25.2 +/- 0.3 cm; mean +/- SEM) and left (25.1 +/- 0.3 cm) lateral positions was significantly increased compared to the supine position (24.7 +/- 0.3 cm). CONCLUSIONS: We recommend that the depth of DLT insertion should be advanced by approximately 0.5 cm from the best position, before changing from the supine to lateral position. PMID- 25542247 TI - Incidence trends in head and neck squamous cell carcinoma in Slovenia, 1983-2009: role of human papillomavirus infection. AB - An increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) was observed in several population-based registries and has been attributed to human papillomavirus (HPV) infection. In the present study, we aimed to assess the contribution of HPV infection to the burden of mucosal head and neck squamous cell carcinoma (HNSCC) in Slovenia. For this purpose, data from the nationwide Cancer Registry of Slovenia for cases diagnosed between 1983 and 2009 were analyzed to determine time trends of age-adjusted incidence rates and survival in terms of annual percentage change (APC) for HNSCC in potentially HPV-related and HPV-unrelated sites. In addition, determination of p16 protein, HPV DNA and E6/E7 mRNA was performed in a cohort of OPSCC patients identified from the prospective database for the years 2007-2008. In total, 2,862 cases of HNSCC in potentially HPV-related sites and 7,006 cases in potentially HPV-unrelated sites were identified with decreased incidence observed over the time period in both groups (-0.58; 95 % CI -1.28 to -0.13 and -0.90; 95 % CI -1.23 to -0.57). Regardless of the group, incidence trends for both genders showed a significant decrease in men and increase in women. In a cohort of 99 OPSCC patients diagnosed between 2007 and 2008, 20 (20.2 %) patients had HPV positive tumors and exhibited a superior outcome compared to HPV-negative patients. In conclusion, results of the epidemiologic and histopathologic study confirmed that HPV infection had no major impact on the incidence trends in the Slovenian patients with HNSCC and, specifically, OPSCC during the studied period. PMID- 25542248 TI - Management of different kinds of head and neck defects with the submental flap for reconstruction. AB - Head and neck surgeries often accompany with moderate-sized defects that require time-consuming reconstructions by free flaps. The submental flap is a versatile and time-effective option for reconstruction of orofacial defects providing acceptable cosmetic and functional results without requiring microsurgical techniques. A retrospective case series study of patients who underwent reconstruction with the submental flap between 2009 and 2013 was conducted. There were 36 patients (33 men and 3 women), with a mean age of 56.4 years, enrolled in this study. The primary lesion sites included oral cavity (24 patients), pharynx (8 patients), larynx (2 patients), neck (1 patient) as well as maxillary sinus (1 patient). All flaps were harvested as the myocutaneous flaps. All donor sites were closed primarily without the need of additional surgery. No complete loss of the flap was encountered and two cases developed marginal necrosis of the flap. The submental flap had a reliable pedicle and had minimal donor-site morbidity. It is an excellent flap option for patients with small- to medium-sized defects in head and neck region. PMID- 25542249 TI - Endoscopic stapedotomy: our view point. AB - Use of endoscope in middle ear surgery is not new, yet there is resistance to its use in stapedotomy. This is due to perceived long learning curve in shifting from conventional microscope to the endoscope and fear of one-handed work. (1) to present a case series of endoscopic stapedotomies and analyze the operative findings. (2) Discuss the merits and demerits of same. 20 patients with otosclerosis underwent stapedotomy over 5 years using 0 degrees , 4 mm nasal endoscope of 18 cm length. Visualization of middle ear structures, surgical steps, operative time, hearing results and complications were analyzed. In all 20 cases, (13 males, 7 females, age: 32.7 years) manipulation of endoscope within the canal was easy facilitating endomeatal incision and elevation of tympanomeatal flap. An optimum exposure of incudo-stapedial joint was obtained in 88.24 % cases. Adequate exposure of crura was obtained in 82.35 % and the footplate in 95 %. The removal of postero-superior bony wall was required in 30 % and chorda tympani mobilization in 25 % of cases. The average operative time was 31 min. Audiometry done at 6 weeks showed, complete air-bone gap closure in 55 %, mild conductive hearing loss (up to 20 dB) in 30 % and mixed hearing loss in 2 cases (BC up to 30 dB and air-bone gap up to 20 dB). In one patient who initially had hearing improvement post operatively, developed moderate conductive hearing loss at 10 weeks. Performing fully endoscopic stapedotomy using a 4 mm nasal endoscope is a feasible option giving excellent visualization with good results. PMID- 25542250 TI - Report on the VIIth International Symposium on Heat Shock Proteins in Biology & Medicine. AB - This seventh symposium in a series on heat shock proteins in biology and medicine was held November 1-5, 2014, at the Hilton Hotel in Old Town Alexandria, Virginia. Approximately 70 participants including principal investigators, postdoctoral fellows, and graduate students were in attendance. The major themes were: new properties of heat shock proteins (HSPs) and heat shock factor (HSF) and role in the etiology of cancer, molecular chaperones in aging, extracellular HSPs in inflammation and immunity, role of heat shock and the heat shock response in immunity and cancer, protein aggregation disorders and HSP expression, and Hsp70 in blood cell differentiation. The next meeting is planned for the fall of 2016 in the same venue. PMID- 25542252 TI - Reversible posterior leukoencephalopathy syndrome (RPLS): a report of two cases in adults. PMID- 25542251 TI - Single nucleotide polymorphisms in the Anti-Mullerian hormone (AMH Ile(49)Ser) and Anti-Mullerian hormone type II receptor (AMHRII -482 A>G) as genetic markers in assisted reproduction technology. AB - PURPOSE: The aim of the study was to evaluate whether the presence Antimullerian hormone (AMH) and Antimullerian hormone type II receptor (AMHRII) single nucleotide polymorphisms (SNPs) Ile(49)Ser and -482A>G respectively are related to the assisted reproduction outcome. METHODS: A prospective cross-sectional observational study was conducted in order to assess the distribution of AMH and AMHRII SNPs in two cohorts, one of healthy women (N = 100) and the control group and the IVF/ICSI group (N = 151) consisted of women undergoing IVF/ICSI treatment for infertility. Furthermore, a prospective longitudinal observational study was performed on the latter group to assess possible associations of these SNPs with patients' characteristics and controlled ovarian stimulation (COS) and pregnancy outcome. RESULTS: Among non-carriers of the AMH (Ile(49)Ser) polymorphism, basal FSH levels were lower in those with more than two of previous IVF attempts and fertilization rate was statistically higher in those with peak serum E2 levels below 1500 pg/ml, whereas among non-carriers of the AMHRII (-482 A>G) polymorphism, number of follicles was higher in those with more than two previous IVF attempts and total dose of gonadotropins was lower in those with peak serum E2 levels above 1500 pg/ml. CONCLUSIONS: There was evidence that in specific subgroups of women undergoing IVF/ICSI, AMH and AMHRII SNPs may be related to patients' characteristics and controlled ovarian stimulation and pregnancy outcome and thus may provide a means for the prediction of ovarian response in specific subgroups of women entering an IVF/ICSI program. PMID- 25542253 TI - Investigation of the possible association of NEDD4-2 (NEDD4L) gene with idiopathic photosensitive epilepsy. AB - NEDD4-2 alias NEDD4L (neural precursor cell expressed, developmentally downregulated) gene was reported as a candidate gene for epileptic photo sensitivity. We aimed to investigate this possible association of NEDD4-2 variants with idiopathic photosensitive epilepsy. Consecutive patients who had been followed up at our epilepsy center and diagnosed with idiopathic epilepsy according to ILAE criteria and clear-cut photoparoxysmal responses in their electroencephalograms and 100 ethnically matched healthy subjects were included in the study. The regions around previously reported three variants, namely, S233L, E271A and H515P were tracked with DHPLC and the samples showing variations were sequenced. 81 patients (63 females) aged between 12-63 years (45 had juvenile myoclonic epilepsy, 11 childhood absence epilepsy, 14 juvenile absence epilepsy, 7 late onset idiopathic generalized epilepsy, 1 unclassified idiopathic generalized epilepsy, and 3 patients with idiopathic photosensitive occipital lobe epilepsy) were included in this study. We found only one heterozygous S233L variant in a 23-year-old man who has photosensitive form of juvenile absence epilepsy and pattern sensitivity to striped carpets. Other two variants were not found in any of the other patients and controls. Our results suggest that three screened NEDD4-2 variants do not play a leading role in the pathogenesis of photosensitive epilepsy in the Turkish population. PMID- 25542254 TI - Use of a new enzyme extraction system to improve the sensitivity of SOS/umu test and application to environmental samples. AB - The purpose of this study was to find a better enzyme extraction reagent for the SOS/umu test to replace the conventional one (the combination of sodium dodecyl sulfate (SDS) and Z-buffer), which has the disadvantage of denaturing beta galactosidase leading to decreased measurement sensitivity. By adopting a microplate system, the performance of the umu test using BugBuster Master Mix, a commercially available enzyme extraction reagent, was compared with that using the conventional reagent for detecting the genotoxicity of known mutagens as well as environmental samples. BugBuster Master Mix was found to increase the detection sensitivities of the selected genotoxins and environmental water samples, due to the fact that it doesn't denature beta-galactosidase. The result of this study showed that BugBuster Master Mix could be a better enzyme extraction reagent for umu test. PMID- 25542256 TI - Myofibrillogenesis regulator-1 attenuated hypoxia/reoxygenation-induced apoptosis by inhibiting the PERK/Nrf2 pathway in neonatal rat cardiomyocytes. AB - The purpose of this study was to investigate the role of myofibrillogenesis regulator-1 (MR-1) in cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R), through protein kinase R-like ER kinase (PERK)/nuclear factor erythroid 2 related factor 2 (Nrf2) pathway. To address this aim, an H/R model of neonatal rat cardiomyocytes was used. MR-1 was overexpressed using an adenoviral vector system and knocked down using MR-1 specific siRNA. Apoptosis was assessed by using Annexin V/PI double staining, terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling assay, and the Bcl-2/Bax ratio. Western blotting was used to detect the protein levels of MR-1, glucose-regulated protein 78 (GRP78), total and phosphorylated PERK, Nrf2, activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), Bcl-2 and Bax. Immunofluorescence staining was used to assess the subcellular location of Nrf2. We found that H/R induced significant apoptosis in neonatal rat cardiomyocytes. MR-1 overexpression attenuated H/R-induced apoptosis, decreased GRP78 (P < 0.01) and CHOP expression (P < 0.05), and increased the Bcl-2/Bax ratio (P < 0.01). MR-1 overexpression suppressed H/R-induced PERK phosphorylation, Nrf2 nuclear translocation, and ATF4 expression (P < 0.01). While MR-1 knockdown aggravated H/R-induced apoptosis, increased expression of GRP78 and CHOP (P < 0.05), and decreased the Bcl-2/Bax ratio (P < 0.01). MR-1 knockdown significantly increased H/R-induced PERK phosphorylation (P < 0.05), Nrf2 nuclear translocation, and ATF4 expression (P < 0.01). These findings suggest that MR-1 alleviates H/R-induced cardiomyocyte apoptosis through inhibition of the PERK/Nrf2 pathway. PMID- 25542262 TI - Novel oral anticoagulants in patients undergoing cardioversion for atrial fibrillation. AB - Recent trials on novel oral anticoagulants (NOAC) in patients undergoing cardioversion showed that NOACs are as safe and effective as treatment with vitamin K antagonists in patients with atrial fibrillation undergoing electric or pharmacological cardioversion. We conducted an EMBASE and MEDLINE search for studies in which patients undergoing cardioversion were assigned to treatment with NOACs versus VKAs. We identified one prospective randomized study and three post hoc analysis of randomized trials which enrolled 2,788 controls that received NOACs and 1,729 patients that received VKAs. NOACs and VKAs had comparable effects on the rates of stroke/thromboembolism, major bleeding events and all-cause mortality. NOACs are safe and effective alternatives to VKA in patients with AF undergoing cardioversion. PMID- 25542255 TI - Analysis of the basal chordate Botryllus schlosseri reveals a set of genes associated with fertility. AB - BACKGROUND: Gonad differentiation is an essential function for all sexually reproducing species, and many aspects of these developmental processes are highly conserved among the metazoa. The colonial ascidian, Botryllus schlosseri is a chordate model organism which offers two unique traits that can be utilized to characterize the genes underlying germline development: a colonial life history and variable fertility. These properties allow individual genotypes to be isolated at different stages of fertility and gene expression can be characterized comprehensively. RESULTS: Here we characterized the transcriptome of both fertile and infertile colonies throughout blastogenesis (asexual development) using differential expression analysis. We identified genes (as few as 7 and as many as 647) regulating fertility in Botryllus at each stage of blastogenesis. Several of these genes appear to drive gonad maturation, as they are expressed by follicle cells surrounding both testis and oocyte precursors. Spatial and temporal expression of differentially expressed genes was analyzed by in situ hybridization, confirming expression in developing gonads. CONCLUSION: We have identified several genes expressed in developing and mature gonads in B. schlosseri. Analysis of genes upregulated in fertile animals suggests a high level of conservation of the mechanisms regulating fertility between basal chordates and vertebrates. PMID- 25542263 TI - Rapid normalization of vasculitis-induced left ventricular dysfunction related with multiple cardiac thrombi. AB - We present a young female patient admitted in the emergency department with pulmonary edema, severely impaired left ventricular function, and simultaneous intracardiac thrombi in left and right ventricle as well as in right atrium, at echocardiography. A magnetic resonance tomography showed excess myocardial tissue edema and diffuse gadolinium enhancement. Blood analysis showed an elevated eosinophils count. The patient showed a rapid normalization of left ventricular function as well as resolution of intracardiac thrombi and myocardial tissue edema 3 months after proper treatment with cyclophosphamide and steroids for Churg-Strauss syndrome. PMID- 25542264 TI - beta-Carotene ameliorates arsenic-induced toxicity in albino mice. AB - The present study evaluated the ameliorative potential of beta-carotene (BCT) against experimentally induced arsenic toxicity in Swiss albino mice. BCT (5 and 10 mg/kg) was administered orally to mice 30 min before oral administration of arsenic trioxide (3 mg/kg) for 14 consecutive days. On 15th day, the body weights, organ weights, hematological profiles, serum biochemical profile; hepatic and renal antioxidative parameters viz. lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase; and DNA fragmentation were evaluated. Co-treatment with BCT markedly and significantly normalized body weights, organ weights, hematological profiles, serum biochemical profile and significantly modulated all the hepatic and renal biochemical parameters and DNA fragmentation in arsenic-intoxicated mice. The present findings conclude that beta-carotene possessed remarkable ameliorative effect against arsenic-induced toxicity in albino mice mediated by its antioxidant and antigenotoxic properties. PMID- 25542266 TI - Novel FTS-diamine/cinnamic acid hybrids inhibit tumor cell proliferation and migration and promote apoptosis via blocking Ras-related signaling in vitro. AB - Novel FTS-diamine/cinnamic acid hybrids 7a-f were prepared, and their in vitro biological activities were evaluated. It was found that 7c showed the strongest anti-proliferation activities against cancer cells in vitro and significant growth inhibition of tumor in vivo, and more potential for inhibitory selectivity to tumor cells than intermediate 6 and FTS. Furthermore, the anti-proliferative effect of 7c in Lovo cell lines followed a similar pattern, which included a dose dependent induction of cell apoptosis via the up-regulation of Bax as well as activated caspase-3 and down-regulation of Bcl-2, and the inhibition of cancer cells migration and invasion in a concentration-dependent way. More importantly, 7c could significantly block Ras-related signaling pathways, which may contribute to its pro-apoptotic induction of the cancer cell lines and its inhibition of carcinoma cell proliferation, migration, and invasion. Therefore, our novel findings may provide a new framework for the discovery of new FTS hybrids for the intervention of human carcinoma cells. PMID- 25542265 TI - Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known as one of the most malignant potential diseases with poor neovascularization. By comparing PDAC to hepatocellular carcinoma (HCC), which is well vascularized, we investigated the mechanisms and tumor biological significance of the poor neovascularization in PDAC. METHODS: Surgical specimens from primary PDAC and HCC patients were immunohistologically stained to detect the expressions of CD105, CD44, HIF 1alpha, PHD3, and Siah2. We also used two PDAC and two HCC cell lines to compare the expressions of HIF-1alpha, PHD3, and CD44, as well as the production of VEGF in hypoxic condition. The role of PHD3 in regulating HIF-1alpha expression was further confirmed by siRNA knockdown in a PDAC cell line that highly expressed PHD3. RESULTS: There were significantly fewer microvessels but more cancer stem cells in PDAC specimens compared to HCC specimens. The expression of CD105 was reversely related to the expression of CD44 in PDAC and HCC specimens. PDAC specimens also showed higher expressions of PHD3 but lower expressions of HIF 1alpha. Similarly, the expression of PHD3 was observed clearly in PDAC cell lines, but was almost completely negative in HCC cell lines. Hypoxic stimulation clearly enhanced HIF-1alpha expression and VEGF secretion in both HCC cell lines, but did not significantly change in PDAC cell lines. The knockdown of PHD3 in PDAC cells restored the hypoxic-induced HIF-1alpha expression, which accordingly stimulated the cells' VEGF secretion. CONCLUSIONS: The enhanced expression of PHD3 might likely contribute to the poor neovascularization and affect the biological characterization in PDAC cancer cells. PMID- 25542267 TI - Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer. AB - PURPOSE: The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer. METHODS: Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV). Onartuzumab serum samples were collected pre- and post-dose on day 1 of cycles 1 4 and at the SDDV. Fridericia's correction was applied to QT recordings (QTcF), and change from baseline (DeltaQTcF) was calculated. Post-baseline measurements were reported as baseline-adjusted control arm (placebo plus bevacizumab plus paclitaxel)-corrected values (DeltaDeltaQTcF). Categorical ECG findings were noted. Linear mixed effects modeling evaluated a potential concentration DeltaQTcF relationship. RESULTS: Out of 185 enrolled patients, 165 patients had ECG-evaluable data for analyses. Similar DeltaQTcF and DeltaDeltaQTcF values were observed across all treatment arms, with mean increase <10 and <7 ms, respectively, across all time points. Similar changes in heart rate, PR interval, and QRS duration were noted across all treatment arms. Incidences of abnormal ECG findings of clinical interest were comparable in the onartuzumab-containing arms and the control arm. No concentration-DeltaQTcF relationship was evident at onartuzumab serum concentrations up to 1,200 MUg/ml. CONCLUSIONS: These data suggest that onartuzumab, at the dose and exposures studied in this clinical trial, does not meaningfully affect the QTcF interval. PMID- 25542268 TI - Prevalence and clinical significance of potential drug-drug interaction in hematopoietic stem cell transplantation. AB - Patients undergoing hematopoietic stem cell transplantation (HSCT) are at risk of developing potential drug-drug interactions (PDDIs). The aim of this study was to assess the prevalence of PDDIs that occur in HSCT patients on the day of hematopoietic stem cell infusion. We performed a cross-sectional study based on the evaluation of prescriptions to HSCT patients on the day of infusion (day 0). The PDDIs were analyzed using the DRUG-REAX((r)) system and classified according to the severity level, available scientific evidence, time of onset, and potential clinical impact. Forty patients undergoing HSCT were included in this study; 33 patients (82.5%) were exposed to at least one major and one contraindicated PDDI in a concomitant manner. All patients exposed to PDDIs had an increased risk of cardiotoxicity. Most cases of PDDIs were classified as being of major severity (80.9%), with time of onset not specified (61.9%), and with good or excellent scientific evidence (52.4%). HSCT patients have a high prevalence of clinically significant PDDIs. The management of PDDIs requires an approach that includes biochemical tests, installation of cardiac monitors, periodic electrocardiograms, implementation of electronic prescriptions with a PDDI alert system, and availability of the PDDI databases. PMID- 25542269 TI - Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study. AB - This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer. PMID- 25542270 TI - Thyroid hormone receptor alpha in breast cancer: prognostic and therapeutic implications. AB - We determined the expression of two transcriptional variants of thyroid hormone receptor alpha (THRalpha1 and THRalpha2) in samples from a cohort of breast cancer patients and correlated expression levels with survival. 130 women who were diagnosed with invasive breast carcinoma between 2007 and 2008 were included. Representative sections of their tumours were analyzed in triplicate on a tissue microarray for expression of THRalpha1 and THRalpha2 by immunohistochemistry. The prognostic significance of THRalpha1 and THRalpha2 expression was assessed using Kaplan-Meier survival analyses, adjusted for known prognostic factors. Seventy-four percent of tumours had high expression of THRalpha1 (Allred score >=6) and 40 % had high expression of THRalpha2. Expression of THRalpha2 correlated positively with ER expression (p < 0.001) and with PR expression (p < 0.001), but negatively with HER2 expression (p = 0.018). Patients with low THRalpha2 expression had inferior 5-year overall survival (75.3 %) compared to those with high expression (91.7 %; p = 0.06). In a multivariate model, high THRalpha2 expression was a significant and independent prognosticator of improved overall survival (HR = 0.84; 95 % CI 0.71-0.98). Many breast tumours express THRalpha2 at high levels and these patients experience improved survival. Thyroid hormone signalling may be important in a proportion of breast cancers and THRalpha2 expression may be a regulator of signalling in this pathway. PMID- 25542271 TI - HER2-family signalling mechanisms, clinical implications and targeting in breast cancer. AB - Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC. PMID- 25542272 TI - Increased pSmad2 expression and cytoplasmic predominant presence of TGF-betaRII in breast cancer tissue are associated with poor prognosis: results from the Shanghai Breast Cancer Study. AB - Perturbations of transforming growth factor-beta (TGF-beta) signaling are pivotal to tumorigenesis and tumor progression through their effects on cell proliferation and cell invasion. This study aims to evaluate the association of TGF-betaRII and pSmad2 protein expressions in breast tissue with clinicopathological factors and prognosis of breast cancer. Expression of the TGF betaRII and pSmad2 proteins was assessed in breast tissue of 1,045 breast cancer cases in the Shanghai Breast Cancer Study using a double immunofluorescence staining method, which was validated with standard single immunostains. TGF betaRII expression intensity was positively associated with younger age at diagnosis (P = 0.03), pre-menopausal status (P = 0.03), and lower TNM stage (P = 0.04). Cytoplasmic predominant expression pattern of TGF-betaRII was associated with older age at diagnosis (P = 0.04) and invasive histological type (P = 0.03). Increased pSmad2 expression was associated with higher breast cancer grade (P < 0.01). Higher pSmad2 expression [HR (95 % CI):1.48 (1.07-2.04), P = 0.02] and cytoplasmic predominant TGF-betaRII expression [HR (95 % CI): 1.80 (1.08-3.00), P = 0.02] were significantly associated with reduced cancer-free survival. Our data suggest that TGF-betaRII and pSmad2 expressions are associated with certain clinical and pathologic features of breast cancer. A cytoplasmic predominant TGF betaRII expression pattern and a higher pSmad2 expression were associated with decreased breast cancer survival. Our study provides additional evidence to support the important role of TGF-beta signaling in breast cancer prognosis. PMID- 25542273 TI - Preventing the spread of H1N1 influenza infection during a pandemic: autonomy supportive advice versus controlling instruction. AB - Wearing facemask is an effective strategy for preventing the spread of the H1N1 in enclosed public spaces. This quasi-experiment examined the effects of University professor 'autonomy support on students' motivation, social cognitive factors, and intention to wear facemasks in the lecture hall during a hypothetical H1N1 pandemic. University students (N = 705) completed self-report measures of motivation, social cognitive factors, and intention according to a hypothetical H1N1 pandemic scenario in which their professors asked them to wear facemasks in the lecture hall, using either an 'autonomy-supportive' interpersonal style or a 'controlling' style. The results showed that the manipulation of professors' autonomy support exerted a positive effect on students' perception of autonomy support, which positively predicted their self determined motivation, social cognitive factors, and intentions to wear facemasks. In conclusion, promoting self-determined motivation using autonomy supportive communication styles might be an effective means of fostering individuals' adaptive beliefs and motivation of H1N1 prevention. PMID- 25542275 TI - Stain on texture: perception of a dark spot having a blurred edge on textured backgrounds. AB - When distinguishing illumination from reflectance edges, both edge blurriness and textural continuity across an edge are generally used as cues to promote the illumination-edge interpretation. However, when these cues were combined, i.e., when a dark spot having a blurred edge was placed on textured backgrounds, we unexpectedly found that the spot appears stained or painted rather than differently illuminated ("stain on texture" phenomenon). This phenomenon suggests a disruptive interaction between the visual processing of blurred edges and background texture. Our experiments showed that middle spatial-frequency components of background texture play a critical role in producing this interaction. Specifically, when a textured background had relatively stronger energy in middle spatial-frequency bands, the dark spot having a blurred edge on the textured background was perceived as differing in reflectance. The findings are discussed in view of multiple levels of visual processes: one mainly concerns low-level features such as spatial-frequency components and another is a higher level process that takes into account the likelihood of spatial configurations in natural scenes, such as "spot shadow" in which the shadow is isolated and the shadow caster is out of sight. PMID- 25542274 TI - Material perception of a kinetic illusory object with amplitude and frequency changes in oscillated inducer motion. AB - The magnitude of the phase difference between inducers' oscillation of a kinetic illusory surface influences visual material impressions (Masuda et al., 2013). For example, impressions of bending or waving motions on a surface tend to occur at a 30- or 90-deg. phase difference, respectively. Here, we elucidate whether amplitude and frequency changes in an inducer's oscillation influence the visual impressions of an illusory surface's hardness, elasticity, and viscosity. Nine participants were asked to use an analog scale to judge their visual impressions relative to a standard pattern with no damping and no frequency change for each phase difference. Results revealed that hardness ratings were greater when amplitude decayed with time only in the 30-deg. phase difference. Elasticity ratings were greater when the frequency of oscillation had a large increase in the 90-deg. phase difference. In the 30-deg. phase difference, similar tendencies were only observed with no damping and ample damping. Viscosity ratings were greater when the frequency of oscillation decreased in both phase differences and when the amplitude decayed with time in the 30-deg. phase difference. These findings suggest that amplitude and frequency changes in an inducer's oscillation are significant factors for material perception derived from motion. PMID- 25542276 TI - Selective disinhibition: A unified neural mechanism for predictive and post hoc attentional selection. AB - The natural world presents us with a rich and ever-changing sensory landscape containing diverse stimuli that constantly compete for representation in the brain. When the brain selects a stimulus as the highest priority for attention, it differentially enhances the representation of the selected, "target" stimulus and suppresses the processing of other, distracting stimuli. A stimulus may be selected for attention while it is still present in the visual scene (predictive selection) or after it has vanished (post hoc selection). We present a biologically inspired computational model that accounts for the prioritized processing of information about targets that are selected for attention either predictively or post hoc. Central to the model is the neurobiological mechanism of "selective disinhibition" - the selective suppression of inhibition of the representation of the target stimulus. We demonstrate that this mechanism explains major neurophysiological hallmarks of selective attention, including multiplicative neural gain, increased inter-trial reliability (decreased variability), and reduced noise correlations. The same mechanism also reproduces key behavioral hallmarks associated with target-distracter interactions. Selective disinhibition exhibits several distinguishing and advantageous features over alternative mechanisms for implementing target selection, and is capable of explaining the effects of selective attention over a broad range of real-world conditions, involving both predictive and post hoc biasing of sensory competition and decisions. PMID- 25542277 TI - Do individuals with autism spectrum disorder process own- and other-race faces differently? AB - Individuals with autism spectrum disorder (ASD) process human faces in atypical ways according to previous literature. We investigated whether individuals with ASD can process face race information and respond to own- and other-race faces differentially. Chinese individuals with ASD (n=24), typically developing (TD) individuals (n=28), and individuals with intellectual disabilities (ID, n=26) were asked to recognize Chinese and Caucasian faces in an old-new face paradigm using eye tracking. In terms of recognition, the ASD and ID groups did not perform differently and displayed superior own-race recognition compared with other-race faces; TD participants displayed similar recognition of the two types of faces. In terms of eye tracking, the TD, ASD, and ID groups displayed more looking on the eyes and less looking on the nose and mouth of Caucasian faces relative to Chinese faces. Overall, individuals with ASD manifested a behavioral other-race effect and displayed the same type of cross-racial differentiation in face scanning observed in TD individuals. The findings suggest that as is the case with TD individuals, face processing of individuals with ASD is influenced by differences in visual experience with different face categories. PMID- 25542279 TI - Surgical education and training: how are they likely to change? PMID- 25542280 TI - Risk factors for unplanned readmissions in older adult trauma patients in Washington State: a competing risk analysis. AB - BACKGROUND: Hospital readmission is a significant contributor to increasing health care use related to caring for older trauma patients. This study was undertaken with the following aims: determine the proportion of older adult trauma patients who experience unplanned readmission, as well as risk factors for these readmissions and identify the most common readmission diagnoses among these patients. STUDY DESIGN: We conducted a retrospective cohort study of trauma patients age 55 years and older who survived their hospitalization at a statewide trauma center between 2009 and 2010. Linking 3 statewide databases, nonelective readmission rates were calculated for 30 days, 6 months, and 1 year after index discharge. Competing risk regression was used to determine risk factors for readmission and account for the competing risk of dying without first being readmitted. Subhazard ratios (SHR) are reported, indicating the relative risk of readmission by 30 days, 6 months, and 1 year. RESULTS: The cumulative readmission rates for the 14,536 participants were 7.9%, 18.9%, and 25.2% at 30 days, 6 months, and 1 year, respectively. In multivariable models, the strongest risk factors for readmission at 1 year (based on magnitude of SHR) were severe head injury (adjusted SHR = 1.47; 95% CI, 1.24-1.73) and disposition to a skilled nursing facility (SHR = 1.54; 95% CI, 1.39-1.71). The diagnoses most commonly associated with readmission were atrial fibrillation, anemia, and congestive heart failure. CONCLUSIONS: In this statewide study, unplanned readmissions after older adult trauma occurred frequently up to 1 year after discharge, particularly for patients who sustained severe head trauma and who could not be discharged home independently. Examining common readmission diagnoses might inform the development of interventions to prevent unplanned readmissions. PMID- 25542278 TI - Prenatal psychological distress and access to mental health care in the ELFE cohort. AB - BACKGROUND: Pregnant women are vulnerable to the deleterious impact of environmental stressors. The aims were to identify the environmental and pregnancy characteristics independently associated with prenatal psychological distress and access to mental health care. METHODS: We used data from the French cohort Etude Longitudinale Francaise depuis l'Enfance (ELFE), a nationally representative cohort of children followed-up from birth to adulthood. Information about prenatal psychological status and access to mental health care was collected during the maternity stay. Maternal/pregnancy characteristics independently associated with psychological distress and access to mental health care were explored using multivariate analyses. RESULTS: Of the 15,143 mothers included, 12.6% reported prenatal psychological distress. Prenatal distress was more frequent in women with very low economical status, alcohol/tobacco use, unplanned/unwanted pregnancy, late pregnancy declaration, multiparity and complicated pregnancy (high number of prenatal visits, prenatal diagnosis examination, obstetrical complications). Of the women reporting prenatal distress, 25% had a prenatal consultation with a mental health specialist and 11% used psychotropic drugs during pregnancy. Decreased likelihood to consult a mental health specialist was found in young women, with intermediate educational level and born abroad. LIMITATIONS: Causal inferences should be made cautiously as the questionnaire did not collect information on the temporal sequence between psychological distress and associated characteristics. CONCLUSIONS: Women with social and obstetrical vulnerabilities are at increased risk of poor mental health during pregnancy. Improving mental health care access during pregnancy is a public health priority. PMID- 25542281 TI - Is there hospital variation in long-term incisional hernia repair after abdominal surgery? AB - BACKGROUND: Currently, hospital benchmarking organizations are often limited to short-term surgical quality comparisons among hospitals. The goal of this study was to determine whether long-term rates of incisional hernia repair after common abdominal operations could be used to compare hospital long-term surgical quality. STUDY DESIGN: This was a cohort study with up to 4 years of follow-up. Patients who underwent 1 of 5 common inpatient abdominal operations were identified in 2005-2008 American College of Surgeons NSQIP data linked to Medicare inpatient records. The main outcomes included occurrence of an incisional hernia repair. A multivariable, shared frailty Cox proportional hazards regression was used to compare each hospital's incisional hernia rate with the overall mean rate for all hospitals and control for American College of Surgeons NSQIP preoperative clinical variables. RESULTS: A total of 37,134 patients underwent 1 of 5 common inpatient abdominal operations, including colectomy, small bowel resection, ventral hernia repair, pancreatic resection, or cholecystectomy, at 1 of 216 hospitals participating in American College of Surgeons NSQIP during the 4-year period. There were 1,474 (4.0%) patients who underwent an incisional hernia repair, at a median follow-up time of 16 months (interquartile range 8 to 25 months) after initial abdominal surgery. After risk adjustment, there was no significant difference in the ratio of any one hospital's adjusted hazard rate for incisional hernia repair vs the average hospital adjusted hazard rate. CONCLUSIONS: Risk-adjusted hospital rates of incisional hernia repair do not vary significantly from the average. This suggests that incisional hernia repair might not be sensitive enough as a long term quality metric for benchmarking hospital performance. PMID- 25542282 TI - A safe and valid procedure for pure laparoscopic partial hepatectomy of the most posterosuperior area: the top of segment 7. PMID- 25542283 TI - Treatment of an extensive unicystic ameloblastoma in a 7-year-old child: the best approach? AB - Ameloblastoma is a benign, slow-growing neoplasm of the jaw that arises from odontogenic epithelium. We present the case of a 7-year-old girl with a unicystic ameloblastoma of the mandible, and describe our approach to treatment. PMID- 25542284 TI - Subjective assessment of facial aesthetics after maxillofacial orthognathic surgery for obstructive sleep apnoea. AB - We aimed to evaluate the subjective perception of facial appearance by patients after maxillofacial surgery for obstructive sleep apnoea (OSA), and explored the possible correlation between satisfaction and surgical outcome. A total of 26 patients, 24 men and 2 women (mean (SD) age 45 (7) years), subjectively assessed their facial appearance before and after operation using a visual analogue scale (VAS). To investigate a possible association between postoperative facial appearance and surgical outcome, we analysed postoperative scores for the apnoea/hypopnoea index (AHI) and Epworth sleepiness scale (ESS). Postoperatively, 14 (54%) indicated that their facial appearance had improved, 4 (15%) recorded a neutral score, and 8 (31%) a lower score. The rating of facial appearance did not correlate with changes in the AHI or ESS following surgery. This study supports the view that most patients are satisfied with their appearance after maxillofacial orthognathic surgery for OSA. The subjective perception of facial aesthetics was independent of the surgical outcome. PMID- 25542285 TI - Pneumoparotid in "puffed cheek" computed tomography: incidence and relation to oropharyngeal conditions. AB - Pneumoparotid is common in patients with lesions of the oral cavity who have diagnostic computed tomography (CT) with the "puffed cheek" technique. Although such observations are often noted, we could find few papers about the incidence in relation to oropharyngeal conditions. We present a retrospective series of 47/300 patients who developed pneumoparotid during multidetector CT examination of the oropharyngeal region to assess the incidence and any possible correlation with regional disease. Patients were followed up for any symptoms and also for complications. In 14 patients the pneumoparotid was right-sided, in 17 left sided, and in 16 it was bilateral. There was a significant association between the incidence of pneumoparotid and the site of disease, it being stronger (p<0.001) with lesions in the oral cavity than with those in the oropharynx and hypopharynx. Apart from brief discomfort, none of the patients had any symptoms after the procedure. In summary, pneumoparotid developed in 47/300 (16%) of our patients after multidetector CT when the "puffed cheek" technique was used, and was more common in patients with lesions of the oral cavity and anterior tongue than among patients with lesions of the oropharyngeal, nasopharyngeal, and hypopharyngeal regions. Few patients experienced transient fullness immediately after the procedure. None of our patients had lasting or infective symptoms. PMID- 25542286 TI - Two different genotypes of H1N2 swine influenza virus isolated in northern China and their pathogenicity in animals. AB - During 2006 and 2007, two swine-origin triple-reassortant influenza A (H1N2) viruses were isolated from pigs in northern China, and the antigenic characteristics of the hemagglutinin protein of the viruses were examined. Genotyping and phylogenetic analyses demonstrated different emergence patterns for the two H1N2 viruses, Sw/Hebei/10/06 and Sw/Tianjin/1/07. Sequences for the other genes encoding the internal proteins were compared with the existing data to determine their origins and establish the likely mechanisms of genetic reassortment. Sw/Hebei/10/06 is an Sw/Indiana/9K035/99-like virus, whereas Sw/Tianjin/1/07 represents a new H1N2 genotype with surface genes of classic swine and human origin and internal genes originating from the Eurasian avian like swine H1N1 virus. Six-week-old female BALB/c mice infected with the Sw/HeB/10/06 and Sw/TJ/1/07 viruses showed an average weight loss of 12.8% and 8.1%, respectively. Healthy six-week-old pigs were inoculated intranasally with either the Sw/HeB/10/06 or Sw/TJ/1/07 virus. No considerable changes in the clinical presentation were observed post-inoculation in any of the virus inoculated groups, and the viruses effectively replicated in the nasal cavity and lung tissue. Based on the results, it is possible that the new genotype of the swine H1N2 virus that emerged in China may become widespread in the swine population and pose a potential threat to public health. PMID- 25542287 TI - A novel subpopulation of Salmonella enterica serovar Infantis strains isolated from broiler chicken organs other than the gastrointestinal tract. AB - Salmonella enterica subsp. enterica serovar Infantis strains were isolated from broiler chickens from six farms in Japan and the pathogenicity associated with the recently reported 280kbp mega plasmid was examined by possession of the plasmid and histopathology of tissues from these chickens. S. Infantis strains were isolated from 10 of 24 chickens. Phylogenetic, network and Bayesian cluster analyses were used to determine whether these strains were in the previously defined Clusters 1-5. Phylogenetic analysis classified the strains isolated in this study in two groups (Groups A and B). Both groups contained strains from gastrointestional contents, but only Group A also contained strains from spleen, liver, and lymphoid tissues. Histopathology showed suppurative splenitis in a spleen from which Group A strains were isolated. Although network and Bayesian cluster analyses were unable to differentiate Group A and B strains from the previously defined Clusters 1-5, population genetic analysis indicated that Group A was a different population from Cluster 5, indicating that Group A would be a subpopulation of Cluster 5. The irp2 gene, which is in the mega plasmid carried by a pathogenic S. Infantis strain recently isolated in Israel, was found in both Groups A and B strains and in the previously reported Clusters 4 and 5 strains. These results suggested that Group A would be a novel subpopulation of the previously defined Cluster 5, and presence of the mega plasmid may not be related whether S. Infantis strains can infect certain organs. PMID- 25542288 TI - Antibodies to ovine herpesvirus 2 glycoproteins decrease virus infectivity and prevent malignant catarrhal fever in rabbits. AB - Ovine herpesvirus-2 (OvHV-2) is the etiological agent of sheep-associated malignant catarrhal fever (SA-MCF), a fatal lymphoproliferative disease of many species in the order Artiodactyla. Development of a vaccine is critical to prevent mortality. Because OvHV-2 has not been cultured in vitro, SA-MCF research is hindered by the lack of in vitro tools to study viral constituents and specific host immune responses. As an alternative, in this study the neutralizing activity of antibodies against OvHV-2 glycoproteins gB and gH/gL was evaluated in vivo using rabbits. OvHV-2-specific antibodies were developed in rabbits by immunization using biolistic delivery of plasmids expressing the genes of interest. A lethal dose of OvHV-2 was incubated with the antisera and then nebulized into rabbits. Virus neutralization was assessed by measuring infection parameters associated with the virus infectious dose. Anti-gB or anti-gH/gL antibodies alone blocked infection in five out of six rabbits (83%), while a combination of anti-gB and anti-gH/gL antibodies protected all six rabbits (100%) from infection. These results indicate that antibodies to OvHV-2 gB and gH/gL are capable of neutralizing virions, and consequently, reduce virus infectivity and prevent SA-MCF in rabbits. Thus, OvHV-2 gB and gH/gL are suitable targets to be tested in a SA-MCF vaccine aimed at stimulating neutralizing antibody responses. PMID- 25542289 TI - Changes in peripheral blood leucocytes of sheep experimentally infected with Mycoplasma agalactiae. AB - Contagious agalactia is a serious disease of small ruminants affecting mainly mammary glands, joints and eyes. In sheep, the main aetiological agent is Mycoplasma agalactiae (Ma) whose abilities to persist in the target organs are known. Since there is no information on the effect of acute and chronic Ma infection on circulating leucocytes, the present study was designed to monitor granulocytes, monocytes, T and B lymphocytes, by flow cytometry, in female lactating sheep nasally infected with Ma. A profound depletion of leucocytes was observed from day 5 to day 34 post infection (p.i.). In particular, while the granulocytes returned to baseline levels by day 12 p.i., the monocytes remained significantly low until day 20 p.i. The infection caused a prolonged depletion of peripheral T lymphocytes (both CD4(+) and CD8(+)) while B lymphocytes remained unaltered throughout the study. Mycoplasma agalactiae was detected by real-time PCR in several anatomical sites (ear, nose and milk) from day 2-5 p.i. until the end of the study (i.e., day 50 p.i.) while a transient bacteraemia was observed from day 5 to day 12 p.i. The leucopenia observed following intranasal Ma infection is likely due to leucocyte infiltration within the target organs. PMID- 25542290 TI - Adaptive dynamic programming algorithms for sequential appointment scheduling with patient preferences. AB - OBJECTIVES: A well-developed appointment system can help increase the utilization of medical facilities in an outpatient department. This paper outlines the development of an appointment system that can make an outpatient department work more efficiently and improve patient satisfaction level. METHODS: A Markov decision process model is proposed to schedule sequential appointments with the consideration of patient preferences in order to maximize the patient satisfaction level. Adaptive dynamic programming algorithms are developed to avoid the curse of dimensionality. These algorithms can dynamically capture patient preferences, update the value of being a state, and thus improve the appointment decisions. RESULTS: Experiments were conducted to investigate the performance of the algorithms. The convergence behaviors under different settings, including the number of iterations needed for convergence and the accuracy of results, were examined. Bias-adjusted Kalman filter step-sizes were found to lead to the best convergence behavior, which stabilized within 5000 iterations. As for the effects of exploration and exploitation, it resulted in the best convergence behavior when the probability of taking a myopically optimal action equaled 0.9. The performance of value function approximation algorithm was greatly affected by the combination of basis functions. Under different combinations, errors varied from 2.7% to 8.3%. More preferences resulted in faster convergence, but required longer computation time. CONCLUSIONS: System parameters are adaptively updated as bookings are confirmed. The proposed appointment scheduling system could certainly contribute to better patient satisfaction level during the booking periods. PMID- 25542291 TI - Effect of acute arterial hypertension on morphine requirements and postsurgical pain. AB - STUDY OBJECTIVE: The study objective was to establish the impact of acute hypertension on morphine's requirements after laparoscopic cholecystectomy. DESIGN: The design was a randomized, simple blinded study. SETTING: The settings were operating room, postoperative recovery area, and first postoperative day. PATIENTS: There were 50 patients, American Society of Anesthesiologists I-II, aged 18-50 years, undergoing elective laparoscopic cholecystectomy with general anesthesia. INTERVENTIONS: Anesthetic management was standardized using propofol for induction, isoflurane for bispectral index (BIS) ranging between 40 and 60, and remifentanil maintained at a constant rate of 0.4 MUg kg per minute throughout surgery in all patients. Once intubated, patients were randomly allocated to 1 of 2 groups: hypertensive group: systolic arterial blood pressure was maintained with phenylephrine infusion 20%-30% over baseline; control group: systolic arterial blood pressure was maintained 20%-30% below baseline. All surgical incisions were infiltrated with bupivacaine 0.5%, and every patient received ketorolac 60 mg intravenous. Patient-controlled analgesia with morphine intravenous was used for postoperative analgesia. MEASUREMENTS: Pain visual analogue scale scores, arterial blood pressure, and hyperalgesia were assessed at recovery room every 15 minutes during the first 2 postoperative hours and then at 6, 12, and 24 postoperative hours. Cumulative morphine consumption was registered at 2 and 24 postoperative hours. MAIN RESULTS: The cumulative morphine consumption in the control group was around 18 mg compared with 6 mg in the hypertensive group (P = .019). During the first 75 minutes after surgery, the control group had higher visual analogue scale score pain compared with hypertensive group (P = .005). CONCLUSIONS: The intraoperative acute generation of mild hypertension with phenylephrine reduced postoperative morphine consumption and pain scores after laparoscopic cholecystectomy. PMID- 25542292 TI - Efficacy of betamethasone to prevent postoperative nausea and vomiting or pain. PMID- 25542293 TI - Intracranial hemorrhage during laparoscopic cholecystectomy due to unrecognized moyamoya disease. PMID- 25542294 TI - Assessment of cognitive dysfunction during migraine attacks: a systematic review. AB - Patients consistently report cognitive impairment during migraine attacks, yet the documentation of such dysfunction by neuropsychological evaluation has lacked similar consistency. This incongruence may be due to discrepant study designs, assessment tools and small samples sizes. To search for evidence of decline in cognitive functions during a migraine attack, compared to headache-free performance. The secondary objective was to determine if the eventual decline had a consistent neuropsychological pattern. Systematic review of the medical literature using PubMed and Cochrane library databases without limitations or restrictions from inception to March 2014, using the search terms "migraine", "cognition", "neuropsychological". We included studies in episodic migraine that had a neuropsychological evaluation performed during an attack. From 1,023 titles screened, a total of 10 articles met criteria for inclusion and were fully reviewed. Only five of these studies, comprising a total of 163 individuals, had enough data to allow an appraisal of the study question. All five studies were positive in documenting some type of reversible cognitive impairment during the migraine attack. The pattern of cognitive impairment most often documented was of executive dysfunction, but the presence of bias induced by the choice of tests and of small samples prevents this finding from being conclusive. This review supports the existence of reversible cognitive dysfunction during the migraine attack, corroborating patients' subjective descriptions. Further work is needed to establish the pattern of cognitive dysfunction, their underling pathophysiological mechanisms and the impact of these symptoms in migraine associated disability. PMID- 25542295 TI - Effect of glatiramer acetate three-times weekly on the evolution of new, active multiple sclerosis lesions into T1-hypointense "black holes": a post hoc magnetic resonance imaging analysis. AB - Conversion of active lesions to black holes has been associated with disability progression in subjects with relapsing-remitting multiple sclerosis (RRMS) and represents a complementary approach to evaluating clinical efficacy. The objective of this study was to assess the conversion of new active magnetic resonance imaging (MRI) lesions, identified 6 months after initiating treatment with glatiramer acetate 40 mg/mL three-times weekly (GA40) or placebo, to T1 hypointense black holes in subjects with RRMS. Subjects received GA40 (n = 943) or placebo (n = 461) for 12 months. MRI was obtained at baseline and Months 6 and 12. New lesions were defined as either gadolinium-enhancing T1 or new T2 lesions at Month 6 that were not present at baseline. The adjusted mean numbers of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a negative binomial model; adjusted proportions of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a logistic regression model. Of 1,292 subjects with complete MRI data, 433 (50.3 %) GA treated and 247 (57.2 %) placebo-treated subjects developed new lesions at Month 6. Compared with placebo, GA40 significantly reduced the mean number (0.31 versus 0.45; P = .0258) and proportion (15.8 versus 19.6 %; P = .006) of new lesions converting to black holes. GA significantly reduced conversion of new active lesions to black holes, highlighting the ability of GA40 to prevent tissue damage in RRMS. PMID- 25542296 TI - Protective effects of melatonin against oxidative damage induced by Egyptian cobra (Naja haje) crude venom in rats. AB - Naja haje envenomation is one of the leading causes of death due to snakebite. Antiserum therapy sometimes fails to provide enough protection against venom toxicity. In this study, we investigated the protective effects of melatonin against N. haje venom in rats. The animals were injected with venom (0.25mg/kg) and/or melatonin (10mg/kg) and compared with vehicle-treated rats. There was oxidative/nitrosative damage and apoptosis in the liver, heart, and kidneys of venom-injected rats. Melatonin counteracted the increased lipoperoxidation and nitric oxide, prevented decreased glutathione peroxidase and reductase activity, reduced the glutathione disulfide/glutathione (GSSG/GSH) ratio, and maintained the GSH pool. Furthermore, melatonin administration was associated with a reduction of apoptosis, which was increased in venom-injected rats. Overall, these results suggest that melatonin mitigates oxidative/nitrosative stress in venom-induced cardio-hepato-renal injury in rats. Our results suggest that melatonin treatment may ameliorate some of the effects of N. haje envenomation. PMID- 25542299 TI - Evolution of the active site of human glutathione transferase A2-2 for enhanced activity with dietary isothiocyanates. AB - BACKGROUND: Organic isothiocyanates (ITCs) are produced by plants, in which they are released from glucosinolates by myrosinase. ITCs are generally toxic and serve as a chemical defense against herbivorous insects and against infections by microorganisms. In mammalian tissues subtoxic concentrations of ITCs can provide protective effects against cancer and other diseases partially by induction of glutathione transferases (GSTs) and other detoxication enzymes. Thus, human consumption of edible plants rich in ITCs is presumed to provide health benefits. ITCs react with intracellular glutathione to form dithiocarbamates, catalyzed by GSTs. Formation of glutathione conjugates is central to the biotransformation of ITCs and leads to a route for their excretion. Clearly, the emergence of ITC conjugating activity in GSTs is essential from the biological and evolutionary perspective. METHODS: In the present investigation an active-site-focused mutant library of GST A2-2 has been screened for enzyme variants with enhanced ITC activity. RESULTS: Significantly superior activities were found in 34 of the approximately 2000 mutants analyzed, and the majority of the superior GSTs featured His and Gly residues in one of the three active-site positions subjected to mutagenesis. CONCLUSIONS: We explored the propensity of GSTs to obtain altered substrate selectivity and moreover, identified a specific pattern of mutagenesis in GST for enhanced PEITC detoxification, which may play an important role in the evolution of adaptive responses in organisms subjected to ITCs. GENERAL SIGNIFICANCE: The facile acquisition of enhanced ITC activity demonstrates that this important detoxication function can be promoted by numerous evolutionary trajectories in sequence space. PMID- 25542297 TI - Safety considerations with pharmacological treatment of gestational diabetes mellitus. AB - The number of women with gestational diabetes mellitus (GDM: diabetes first diagnosed in pregnancy) continues to grow, as do the associated risks of antenatal and postnatal complications and the chance of future diabetes and obesity in both mother and offspring. Recent randomised controlled trials have demonstrated clear benefits for intensive management of GDM using lifestyle modification, self blood glucose monitoring, close clinical supervision and, where glycaemia remains inadequately controlled, insulin therapy. More recently, metformin and glibenclamide have been shown to adequately reduce hyperglycaemia as part of a stepped approach to GDM management, with a switch to insulin therapy where necessary. Other oral medications have not been shown to be safe in pregnancy. Human insulin therapy is safe within the limits of hypoglycaemia and weight gain. Most insulin analogues are also now considered safe for use in pregnancy (insulin lispro, aspart and detemir). Metformin therapy is oral, and therefore preferred to insulin, but is associated with more gastrointestinal adverse effects, although not hypoglycaemia or weight gain. Conversely, glibenclamide is also an oral therapy but is associated with hypoglycaemia and weight gain. However, metformin crosses the placenta and it remains unclear whether glibenclamide crosses the placenta or not: long-term risks have not been shown, and are thought to be minimal, but further studies are needed. Metformin is seen by some as the treatment of choice where weight gain is an issue, providing that the unanswered questions over the long-term safety of oral agents have been discussed. PMID- 25542298 TI - High-fat diet decreases the expression of Kiss1 mRNA and kisspeptin in the ovary, and increases ovulatory dysfunction in postpubertal female rats. AB - BACKGROUND: Female reproductive health is noticeably compromised by obesity. The underlying mechanisms remain to be elucidated. Accumulating evidence indicates that the expression level of ovarian Kiss1 peaks in the afternoon during prooestrus, suggesting local regulatory roles for Kiss1 in the ovulatory process. We used a diet-induced model of obesity to evaluate whether the ovarian Kiss1 system is affected by obesity, and, to investigate the association of the Kiss1 system with ovulatory disorders in female rats. METHODS: Post-weaning, female, Sprague-Dawley rats were randomly fed either a high-fat diet (HFD) or a normal chow diet (NCD) until they reached postnatal day 30 (PND 30), PND 42, or PND 70. The timing of vaginal opening was recorded, and oestrous cyclicity was monitored for 2 consecutive weeks immediately post puberty and again at 8-9 weeks of age. Tissues from the left ovary were collected for determination of the levels of Kiss1 and G protein-coupled receptor 54 (GPR54) mRNA, and tissues from the right ovary were collected for assessment of the immunoreactivity (IR) of the corresponding protein products, kisspeptin and GPR54. RESULTS: The high-fat diet resulted in a significantly higher body weight and an earlier puberty onset. Oestrous cyclicity was disrupted by the HFD with significant reductions in the expression of ovulation-related genes. A marked suppression of ovarian Kiss1 mRNA levels was observed during prooestrus and oestrus at PND 42, and, during prooestrus, oestrus, and metoestrus at PND 70 in the HFD rats compared with the NCD controls. In the HFD group, the immunoreactivity of kisspeptin was significantly lower in theca cells from antral follicles during prooestrus and oestrus at PND 42, and, during prooestrus, oestrus at PND 70. At the prooestrus stage, in the HFD group the immunoreactivity of kisspeptin was also lower in the theca cells of preovulatory follicles at both PND 42 and PND 70. CONCLUSIONS: Exposure of female rats to an post-weaning, high-fat diet has long-term deleterious effects on ovulation, that may involve down-regulation of ovarian Kiss1 mRNA and kisspeptin. PMID- 25542300 TI - Control of protein function by prolyl isomerization. AB - BACKGROUND: Prolyl cis/trans isomerizations have long been known as critical and rate-limiting steps in protein folding. RESULTS: Now it is clear that they are also used as slow conformational switches and molecular timers in the regulation of protein activity. Here we describe several such proline switches and how they are regulated. CONCLUSIONS AND GENERAL SIGNIFICANCE: Prolyl isomerizations can function as attenuators and provide allosteric systems with a molecular memory. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25542301 TI - ROS-mediated redox signaling during cell differentiation in plants. AB - BACKGROUND: Reactive oxygen species (ROS) have emerged in recent years as important regulators of cell division and differentiation. SCOPE OF REVIEW: The cellular redox state has a major impact on cell fate and multicellular organism development. However, the exact molecular mechanisms through which ROS manifest their regulation over cellular development are only starting to be understood in plants. ROS levels are constantly monitored and any change in the redox pool is rapidly sensed and responded upon. Different types of ROS cause specific oxidative modifications, providing the basic characteristics of a signaling molecule. Here we provide an overview of ROS sensors and signaling cascades that regulate transcriptional responses in plants to guide cellular differentiation and organ development. MAJOR CONCLUSIONS: Although several redox sensors and cascades have been identified, they represent only a first glimpse on the impact that redox signaling has on plant development and growth. GENERAL SIGNIFICANCE: We provide an initial evaluation of ROS signaling cascades involved in cell differentiation in plants and identify potential avenues for future studies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25542302 TI - Role of genetic variants in ADIPOQ in human eating behavior. AB - The beneficial effects of adiponectin and its negative correlation with BMI are well described. Adiponectin serum levels are altered in eating disorders such as anorexia nervosa, bulimia nervosa or binge eating. Here, we tested the hypothesis that (1) adiponectin serum levels correlate with human eating behavior factors and (2) that genetic variants of the ADIPOQ locus influence both serum levels and eating behavior. We analyzed 11 SNPs within ADIPOQ and in the 5' UTR and measured serum adiponectin levels in 1,036 individuals from the German Sorbs population. The German version of the three-factor eating questionnaire (FEV) was completed by 548 Sorbs. For replication purposes, we included an independent replication cohort from Germany (N = 350). In the Sorbs, we observed positive correlations of restraint with adiponectin serum levels (P = 0.001; r = 0.148) which, however, did not withstand adjustment for covariates (P = 0.083; r = 0.077). In addition, four SNPs were nominally associated with serum adiponectin levels (all P < 0.05). Of these, two variants (rs3774261; rs1501229, all P < 0.05) were also related to disinhibition. Furthermore, three variants were exclusively associated with hunger (rs2036373, P = 0.049) and disinhibition (rs822396; rs864265, all P < 0.05). However, none of these associations withstood Bonferroni corrections for multiple testing (all P > 9.3 * 10(-4)). In our replication cohort, we observed similar effect directions at rs1501229 for disinhibition and hunger. A meta analysis resulted in nominal statistical significance P = 0.036 (Z score 2.086) and P = 0.017 (Z score 2.366), respectively. Given the observed relationship of the SNPs with adiponectin levels and eating behavior, our data support a potential role of adiponectin in human eating behavior. Whether the relationship with eating behavior is mediated by the effects of circulating adiponectin warrants further investigations. PMID- 25542303 TI - In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. AB - Red onions and low doses of the flavonoid, quercetin, increase insulin sensitivity and improve glucose tolerance. We hypothesized that dietary supplementation with red onion extract (RO) would attenuate high fat diet (HFD) induced obesity and insulin resistance similar to quercetin supplementation by increasing energy expenditure through a mechanism involving skeletal muscle mitochondrial adaptations. To test this hypothesis, C57BL/6J mice were randomized into four groups and fed either a low fat diet (LF), HFD (HF), HFD + quercetin (HF + Q), or HFD + RO (HF + RO) for 9 weeks. Food consumption and body weight and composition were measured weekly. Insulin sensitivity was assessed by insulin and glucose tolerance tests. Energy expenditure and physical activity were measured by indirect calorimetry. Skeletal muscle incomplete beta oxidation, mitochondrial number, and mtDNA-encoded gene expression were measured. Quercetin and RO supplementation decreased HFD-induced fat mass accumulation and insulin resistance (measured by insulin tolerance test) and increased energy expenditure; however, only HF + Q showed an increase in physical activity levels. Although quercetin and RO similarly increased skeletal muscle mitochondrial number and decreased incomplete beta oxidation, establishing mitochondrial function similar to that seen in LF, only HF + Q exhibited consistently lower mRNA levels of mtDNA encoded genes necessary for complexes IV and V compared to LF. Quercetin- and RO induced improvements in adiposity, insulin resistance, and energy expenditure occur through differential mechanisms, with quercetin-but not RO-induced energy expenditure being related to increases in physical activity. While both treatments improved skeletal muscle mitochondrial number and function, mtDNA encoded transcript levels suggest that the antiobesogenic, insulin-sensitizing effects of purified quercetin aglycone, and RO may occur through differential mechanisms. PMID- 25542304 TI - Oxytocin facilitates the extinction of conditioned fear in humans. AB - BACKGROUND: Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala-medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear. METHODS: Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo. RESULTS: Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases. CONCLUSIONS: Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders. PMID- 25542306 TI - Serum Levels of Hepatitis B Surface Antigen Predict Severity of Fibrosis in Patients With E Antigen-Positive Chronic Hepatitis B. AB - BACKGROUND & AIMS: Noninvasive techniques are needed to assess hepatic fibrosis in patients with chronic hepatitis B. We developed a scoring system to determine the degree of fibrosis in patients with genotype B or genotype C hepatitis B virus (HBV) infection and positive for the hepatitis B e antigen. METHODS: We performed a retrospective study to identify baseline variables associated with the severity of fibrosis (METAVIR scores, F0-F4) in a large phase 3 clinical trial of predominantly Asian patients (n = 710), using multivariate logistic regression analyses. Significant variables were used to construct predictive models using optimal cut-off values. The final model was validated in similar patients from a large phase 4 clinical trial (n = 465). RESULTS: We developed 2 prediction scoring systems (PSs). PS1 analyzed data on HBV genotype (B vs. C), patient age (<30 vs. >=30 y), level of hepatitis B surface antigen (<=17,500 vs. >17,500 IU/mL), and level of alanine aminotransferase (<=3-fold vs. >3-fold the upper limit of normal). PS2 analyzed data on only age and level of hepatitis B surface antigen. PS1 identified patients with F0 to F1 vs. F2 to F4 fibrosis with more than 87% specificity and a positive predictive value greater than 75; it identified patients with F0 to F2 vs. F2 to F4 fibrosis with approximately 95% specificity and a positive predictive value (PPV) of approximately 97%. PS2 identified patients with F0 to F1 fibrosis with less accuracy than PS1, but identified patients with F0 to F2 fibrosis with an almost identical level of sensitivity and PPV. CONCLUSIONS: We developed a simple scoring system to determine the severity of fibrosis in patients with genotypes B or C HBV infection who are hepatitis B e antigen positive. Our system differentiated patients with no or mild fibrosis (F0-F1) from those with marked or severe (F2 F4) fibrosis with a high PPV. The high level of specificity for the identification of nonsevere fibrosis (F0-F2) limits the risk of overlooking patients with severe fibrosis (F3-F4). PMID- 25542305 TI - Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons. AB - BACKGROUND: Where a neuron is positioned in the brain during development determines neuronal circuitry and information processing needed for normal brain function. When aberrations in this process occur, cognitive disorders may result. Patients diagnosed with schizophrenia have been reported to show altered neuronal connectivity and heterotopias. To elucidate pathways by which this process occurs and become aberrant, we have chosen to study the long isoform of nitric oxide synthase 1 adaptor protein (NOS1AP), a protein encoded by a susceptibility gene for schizophrenia. METHODS: To determine whether NOS1AP plays a role in cortical patterning, we knocked down or co-overexpressed NOS1AP and a green fluorescent protein or red fluorescent protein (TagRFP) reporter in neuronal progenitor cells of the embryonic rat neocortex using in utero electroporation. We analyzed sections of cortex (ventricular zone, intermediate zone, and cortical plate [CP]) containing green fluorescent protein or red fluorescent protein TagRFP positive cells and counted the percentage of positive cells that migrated to each region from at least three rats for each condition. RESULTS: NOS1AP overexpression disrupts neuronal migration, resulting in increased cells in intermediate zone and less cells in CP, and decreases dendritogenesis. Knockdown results in increased migration, with more cells reaching the CP. The phosphotyrosine binding region, but not the PDZ-binding motif, is necessary for NOS1AP function. Amino acids 181 to 307, which are sufficient for NOS1AP-mediated decreases in dendrite number, have no effect on migration. CONCLUSIONS: Our studies show for the first time a critical role for the schizophrenia-associated gene NOS1AP in cortical patterning, which may contribute to underlying pathophysiology seen in schizophrenia. PMID- 25542308 TI - Stereotactic ablative radiation therapy as first local therapy for lung oligometastases from colorectal cancer: a single-institution cohort study. AB - PURPOSE: To estimate stereotactic ablative radiation therapy (SABR) efficacy and its potential role as an alternative to surgery for the treatment of lung metastases from colorectal cancer. METHODS AND MATERIALS: Forty consecutive patients who received SABR as first local therapy at the time of lung progression were included, from 2004 to 2014. The primary study endpoint was overall survival. Secondary endpoints were progression-free survival and safety. RESULTS: A single nodule was treated in 26 patients (65%), 2 nodules in 10 patients (25%), 3 in 3 patients (7.5%), and 4 in 1 patient (2.5%), for a total of 59 lesions. The median delivered biological effective dose was 96 Gy, in 1 to 8 daily fractions. Median follow-up time was 20 months (range, 3-72 months). Overall survival rates at 1, 2, and 5 years were, respectively, 84%, 73%, and 39%, with 14 patients (35%) dead. Median overall survival was 46 months. Progression occurred in 25 patients (62.5%), at a median interval of 8 months; failure at SABR site was observed in 3 patients (7.5%). Progression-free survival rates were 49% and 27% at 1 and 2 years, respectively. DISCUSSION: The results of this retrospective exploratory analysis suggest safety and efficacy of SABR in patients affected with colorectal cancer lung oligometastases and urge inclusion of SABR in prospective clinical trials. PMID- 25542307 TI - Hyperglycemia enhances kidney cell injury in HIVAN through down-regulation of vitamin D receptors. AB - In the present study, we evaluated the effect of short term hyperglycemia on renal lesions in a mouse model (Tg26) of HIV-associated nephropathy (HIVAN). Control and Tg26 mice in groups (n=6) were administered either normal saline (FVBN or Tg) or streptozotocin (FVBN+STZ or Tg26+STZ). After two weeks, biomarkers were collected and kidneys were harvested. FVBN+ STZ and Tg26+STZ displayed elevated serum glucose levels when compared to FVBN and Tg26 respectively. Tg26+STZ displayed elevated (P<0.05) blood urea nitrogen (BUN) levels (P<0.05) and enhanced (P<0.01) proteinuria when compared to Tg26. Tg26+STZ displayed enhanced (P<0.001) number of sclerotic glomeruli and microcysts vs. Tg26. Renal tissues of Tg26 displayed down regulation of vitamin D receptor (VDR) expression and enhanced Ang II production when compared to FVBN mice. Hyperglycemia exacerbated down regulation of VDR and production of Ang II in FVBN and Tg mice. Hyperglycemia increased kidney cell reactive oxygen species (ROS) production and oxidative DNA damage in both FVBN and Tg26 mice. In in vitro studies, HIV down regulated podocyte VDR expression and also enhanced renin angiotensin system activation. In addition, both glucose and HIV stimulated kidney cell ROS generation and DNA damage and compromised DNA repair; however, tempol (superoxide dismutase mimetic), losartan (Ang II blocker) and EB1089 (VDR agonist) provided protection against DNA damaging effects of glucose and HIV. These findings indicated that glucose activated the RAS and inflicted oxidative stress-mediated DNA damage via down regulation of kidney cell VDR expression in HIV milieu both in vivo and in vitro. PMID- 25542309 TI - Clinical realization of sector beam intensity modulation for Gamma Knife radiosurgery: a pilot treatment planning study. AB - PURPOSE: To demonstrate the clinical feasibility and potential benefits of sector beam intensity modulation (SBIM) specific to Gamma Knife stereotactic radiosurgery (GKSRS). METHODS AND MATERIALS: SBIM is based on modulating the confocal beam intensities from individual sectors surrounding an isocenter in a nearly 2pi geometry. This is in contrast to conventional GKSRS delivery, in which the beam intensities from each sector are restricted to be either 0% or 100% and must be identical for any given isocenter. We developed a SBIM solution based on available clinical planning tools, and we tested it on a cohort of 12 clinical cases as a proof of concept study. The SBIM treatment plans were compared with the original clinically delivered treatment plans to determine dosimetric differences. The goal was to investigate whether SBIM would improve the dose conformity for these treatment plans without prohibitively lengthening the treatment time. RESULTS: A SBIM technique was developed. On average, SBIM improved the Paddick conformity index (PCI) versus the clinically delivered plans (clinical plan PCI = 0.68 +/- 0.11 vs SBIM plan PCI = 0.74 +/- 0.10, P=.002; 2 tailed paired t test). The SBIM plans also resulted in nearly identical target volume coverage (mean, 97 +/- 2%), total beam-on times (clinical plan 58.4 +/- 38.9 minutes vs SBIM 63.5 +/- 44.7 minutes, P=.057), and gradient indices (clinical plan 3.03 +/- 0.27 vs SBIM 3.06 +/- 0.29, P=.44) versus the original clinical plans. CONCLUSION: The SBIM method is clinically feasible with potential dosimetric gains when compared with conventional GKSRS. PMID- 25542310 TI - Assessment of national practice for palliative radiation therapy for bone metastases suggests marked underutilization of single-fraction regimens in the United States. AB - PURPOSE: To characterize temporal trends in the application of various bone metastasis fractionations within the United States during the past decade, using the National Cancer Data Base; the primary aim was to determine whether clinical practice in the United States has changed over time to reflect the published randomized evidence and the growing movement for value-based treatment decisions. PATIENTS AND METHODS: The National Cancer Data Base was used to identify patients treated to osseous metastases from breast, prostate, and lung cancer. Utilization of single-fraction versus multiple-fraction radiation therapy was compared according to demographic, disease-related, and health care system details. RESULTS: We included 24,992 patients treated during the period 2005-2011 for bone metastases. Among patients treated to non-spinal/vertebral sites (n=9011), 4.7% received 8 Gy in 1 fraction, whereas 95.3% received multiple-fraction treatment. Over time the proportion of patients receiving a single fraction of 8 Gy increased (from 3.4% in 2005 to 7.5% in 2011). Numerous independent predictors of single-fraction treatment were identified, including older age, farther travel distance for treatment, academic treatment facility, and non-private health insurance (P<.05). CONCLUSIONS: Single-fraction palliative radiation therapy regimens are significantly underutilized in current practice in the United States. Further efforts are needed to address this issue, such that evidence based and cost-conscious care becomes more commonplace. PMID- 25542311 TI - Patterns of relapse from a phase 3 Study of response-based therapy for intermediate-risk Hodgkin lymphoma (AHOD0031): a report from the Children's Oncology Group. AB - PURPOSE: The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. PATIENTS AND METHODS: From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. RESULTS: At 4 year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. CONCLUSION: Although response-based therapy has helped define treatment for selected RER patients, it has not improved outcome for SER patients or facilitated refinement of IFRT volumes or doses. PMID- 25542314 TI - If it looks like a duck and quacks like a duck .... AB - Be suspicious of emails soliciting papers from you if you do not know the editor who is requesting the article. If the message is effusively complimentary and offers rapid turnaround times for publication, be more suspicious. PMID- 25542312 TI - Fifteen forms of biodiversity trend in the Anthropocene. AB - Humans are transforming the biosphere in unprecedented ways, raising the important question of how these impacts are changing biodiversity. Here we argue that our understanding of biodiversity trends in the Anthropocene, and our ability to protect the natural world, is impeded by a failure to consider different types of biodiversity measured at different spatial scales. We propose that ecologists should recognize and assess 15 distinct categories of biodiversity trend. We summarize what is known about each of these 15 categories, identify major gaps in our current knowledge, and recommend the next steps required for better understanding of trends in biodiversity. PMID- 25542315 TI - Time can make a difference. AB - Through developing education, research, practice, and advocacy resources, the Oncology Nursing Society has supported and developed us as oncology nurses and as leaders. PMID- 25542316 TI - Oncology Nursing Society Position. Position statement on palliative care. PMID- 25542313 TI - Endogenous hydrogen sulfide production is essential for dietary restriction benefits. AB - Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine gamma-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation. PAPERFLICK: PMID- 25542318 TI - A qualitative exploration of the experience of men with prostate cancer involved in supervised exercise programs. AB - PURPOSE/OBJECTIVES: To provide an in-depth description of the experience of supervised exercise programs among men with prostate cancer and to identify elements critical to optimizing engagement and ongoing exercise participation. DESIGN: Descriptive, qualitative. SETTING: A tertiary exercise oncology center in Perth, Australia. SAMPLE: 12 men with prostate cancer participating in a structured, clinic-based group exercise program supervised by accredited exercise physiologists. METHODOLOGIC APPROACH: Participants completed a demographic and health history questionnaire and a semistructured interview. Thematic content analysis was performed. FINDINGS: Participants described physiological and psychological health benefits, which reduced treatment-related side effects and positively affected self-efficacy, and identified exercise physiologists as providing information about the importance of exercise, as well as practical, emotional, and social support. Peer support encouraged discussion of shared experiences and a sense of social connection. CONCLUSIONS: Results from the current study expand on existing quantitative data to provide evidence of psychosocial benefits among men with prostate cancer involved with supervised exercise programs. The data provide insight into the components of exercise programs that can form a framework for the development of effective supportive care programs. INTERPRETATION: Involvement in a structured, clinic-based group exercise program provides men with prostate cancer with considerable benefits. Supervision by qualified exercise physiologists and incorporation of a group approach are critical components of maximizing those benefits. PMID- 25542317 TI - Empowering Promotores de Salud as partners in cancer education and research in rural southwest Kansas. AB - PURPOSE/OBJECTIVES: To describe community-based participatory processes used to develop promotore training on cancer research, and to assess the feasibility of training promotores from rural communities to disseminate cancer research information. DESIGN: Prospective, cohort design. SETTING: Rural communities in the state of Kansas. SAMPLE: 34 Spanish-speaking promotores attended an information session; 27 enrolled and 22 completed training. METHODS: With input from a community advisory board, the authors developed a leadership and cancer curriculum and trained Spanish-speaking promotores to disseminate information on cancer research. Promotores completed pretraining and post-training surveys in Spanish to assess demographic characteristics and changes in knowledge of cancer, cancer treatment and cancer research studies, and intent to participate in cancer research. MAIN RESEARCH VARIABLES: Cancer knowledge, awareness of cancer clinical trials, interest in participating in cancer clinical research studies. FINDINGS: Compared to pretraining, after training, promotores were more likely to correctly define cancer, identify biopsies, describe cancer stages, and report ever having heard of cancer research studies. CONCLUSIONS: Completion rates of the training and willingness to participate in cancer research were high, supporting the feasibility of training promotores to deliver community-based education to promote cancer research participation. IMPLICATIONS FOR NURSING: Nursing professionals and researchers can collaborate with promotores to disseminate cancer education and research among underserved rural Latino communities in Kansas and elsewhere. Members of these communities appear willing and interested in improving their knowledge of cancer and cancer clinical trials. PMID- 25542319 TI - Communication difficulties and the experience of loneliness in patients with cancer dealing with fertility issues: a qualitative study. AB - PURPOSE/OBJECTIVES: To explore communication difficulties and the experience of loneliness among patients with cancer dealing with fertility issues. DESIGN: Qualitative study based on grounded theory principles. SETTING: One university hospital and two general hospitals in Flanders, Belgium. SAMPLE: 21 female and 7 male patients with cancer with potential fertility problems as a result of treatment. METHODS: Grounded theory approach using the constant comparison method; data collection (semistructured face-to-face interviews) and analysis occurred simultaneously. FINDINGS: Loneliness was a central theme in the experience of potential fertility loss among patients with cancer. Feelings of loneliness resulted from communication difficulties between the patient and members of his or her social environment or healthcare professionals because of several underlying processes and influencing factors. CONCLUSIONS: Loneliness was a strong and common feeling among patients with cancer. Patients, members of their social environment, and healthcare professionals experienced difficulties in communicating about fertility in the context of cancer, leading to patients' feelings of loneliness. IMPLICATIONS FOR NURSING: Healthcare professionals must be attentive to signs indicating loneliness regarding fertility concerns, and they should provide adequate information and appropriate guidance to support patients. Professionals need further training to improve knowledge and skills. PMID- 25542320 TI - Social support, self-rated health, and lesbian, gay, bisexual, and transgender identity disclosure to cancer care providers. AB - PURPOSE/OBJECTIVES: To describe factors related to diagnosis, identity disclosure, and social support among lesbian, gay, bisexual, and transgender (LGBT) patients with cancer, and to explore associations between these factors and self-rated health. DESIGN: Cross-sectional self-report survey design using descriptive and exploratory multivariate statistical approaches. SETTING: Online, Internet-based. SAMPLE: 291 LGBT patients (89% Caucasian; 50% gay, 36% lesbian, 7% bisexual, 3% transgender) with mixed cancers. METHODS: Participants completed a researcher-designed online survey assessing experiences of cancer diagnosis among LGBT patients at a single time point. MAIN RESEARCH VARIABLES: Demographics, which provider(s) delivered the patients' cancer diagnoses, to whom patients had disclosed their LGBT identity, how they disclosed, who was on their social support team at the time of diagnosis, and current self-rated health. FINDINGS: 79% of participants reported disclosing their identities to more than one cancer care provider. Participants most commonly introduced the topic of LGBT identity themselves, sometimes as a way to correct heterosexual assumptions (34%). Friends were the most common members of LGBT patients' support teams (79%). Four disclosure and support factors were consistently associated with better self-rated health. CONCLUSIONS: Disclosure of LGBT identity is a common experience in the context of cancer care, and disclosure and support factors are associated with better self-reported health among LGBT patients. IMPLICATIONS FOR NURSING: Creating safe environments for LGBT patients to disclose could improve cancer care delivery to this underserved population. Nurses and other providers should acknowledge and include diverse support team members in LGBT patients' care. PMID- 25542322 TI - Reliability and validity of a tool to assess oncology nurses' experiences with prognosis-related communication. AB - PURPOSE/OBJECTIVES: To establish the reliability and validity of a previously developed survey measuring nurses' experiences with prognosis-related communication. DESIGN: Psychometric testing of survey. SETTING: Mailed survey of Oncology Nursing Society (ONS) members. SAMPLE: 392 ONS members. METHODS: Reliability was analyzed using Cronbach's alpha. Total scale and subscale characteristics were evaluated through inter-item correlation matrices, average inter-item correlations, corrected item-to-total correlations, and Cronbach's alpha coefficients if the items were removed. Construct validity was assessed using exploratory factor analysis and contrasted group comparisons. MAIN RESEARCH VARIABLES: Measures of attitudes toward prognosis-related communication, demographic variables. FINDINGS: A three-factor structure emerged with acceptable reliability and validity. Contrasted group comparisons revealed differences in prognosis-related communication by nurses' years of experience with patients with cancer, level of education, and extent of education about prognosis-related communication. CONCLUSIONS: The final three-factor instrument, Prognosis-Related Communication in Oncology Nursing, was found to have acceptable reliability and validity. IMPLICATIONS FOR NURSING: The final instrument can serve as a tool to measure nurses' experiences with prognosis-related communication. Such measurements may guide interventions that aim to improve the process of prognostic disclosure and elucidate the role of the nurse in the process. PMID- 25542321 TI - Health behaviors in family members of patients completing cancer treatment. AB - PURPOSE/OBJECTIVES: To describe the impact of the cancer experience on the health behaviors of survivors' family members and to determine factors associated with family members' intentions for health behavior change. DESIGN: Descriptive, cross sectional, correlational. SETTING: A National Cancer Institute-designated comprehensive cancer center in the midwestern United States. SAMPLE: 39 family members and 50 patients with diagnoses of breast, colorectal, head and neck, lung, or prostate cancer who were completing definitive cancer treatment. METHODS: Patients and family members were approached in the clinic at three weeks or fewer before the completion of their course of treatment. Family members completed surveys and a structured interview in person or via telephone. MAIN RESEARCH VARIABLES: Intention, perceived benefit, and confidence about eating a healthful diet, physical activity, and smoking cessation; emotional distress; and family cohesion, conflict, and expressiveness. FINDINGS: Family members had high ratings for intention, perceived benefit, and confidence related to the behaviors of eating a healthful diet and performing 30 minutes of daily moderate-intensity physical activity. They also had high ratings for the extent to which the cancer experience had raised awareness of their cancer risk and made them consider undergoing screening tests for cancer; ratings were lower for making changes in their health behaviors. CONCLUSIONS: Family members expressed strong intentions to engage in health-promoting behaviors related to physical activity and nutrition at the post-treatment transition. IMPLICATIONS FOR NURSING: Oncology nurses are in a key position to engage family members and patients in behavior change. Nurses should assess family members at the completion of treatment for distress and provide interventions to influence the trajectory of distress in survivorship. PMID- 25542323 TI - Community respiratory virus infection in hematopoietic stem cell transplantation recipients and household member characteristics. AB - PURPOSE/OBJECTIVES: To determine if children or the number of contacts living in an immediate household increases the risk of community respiratory virus (CRV) acquisition in hematopoietic stem cell transplantation (HSCT) recipients. DESIGN: Retrospective, exploratory study. SETTING: National Cancer Institute-designated comprehensive cancer center located in the Southeast. SAMPLE: 720 adult outpatients post-autologous or allogeneic HSCT. METHODS: Data were gathered using a retrospective medical record review from July 1, 2006, to December 31, 2009. Summary statistics were used to describe sample characteristics. Binary logistic regression was used to determine whether the number of household member contacts or number of children in each age group was a significant predictor of CRV infection. Multivariate linear regression was used to investigate predictors of the number of CRV infections. MAIN RESEARCH VARIABLES: The dependent variable was acquisition of CRV infection. Independent variables included the number of children in the household and the number of household members. FINDINGS: Across all HSCT recipients, children aged 0-4 years (p = 0.01) and 5-12 years (p = 0.001) predicted CRV infection. The allogeneic group had the greatest incidence of CRV infection and was most sensitive to the presence of young children. The total number of household members was not a predictor of CRV infection. CONCLUSIONS: Households with children aged 12 years and younger more than doubled the risk of an HSCT recipient acquiring CRV infection. Additional studies are needed to test interventions designed to interrupt household transmission of CRV infection from children to vulnerable HSCT recipients. IMPLICATIONS FOR NURSING: Household contacts, particularly children, should be included in HSCT teaching. As indicated by the potentially high number of days from transplantation to acquisition of CRV infection, re-education and continuing focus on prevention of CRV infection should be reinforced throughout the lengthy transplantation period. PMID- 25542324 TI - Systematic reviews. AB - Systematic reviews are a type of literature review in which authors systematically search for, critically appraise, and synthesize evidence from several studies on the same topic (Grant & Booth, 2009). The precise and systematic method differentiates systematic reviews from traditional reviews (Khan, Kunz, Kleijnen, & Antes, 2003). In all types of systematic reviews, a quality assessment is done of the individual studies that meet inclusion criteria. These individual assessments are synthesized, and aggregated results are reported. Systematic reviews are considered the highest level of evidence in evidence-based health care because the reviewers strive to use transparent, rigorous methods that minimize bias. PMID- 25542325 TI - Two approaches to bridging the knowledge-practice gap in oncology nursing. AB - The field of oncology nursing is continually changing. New drugs to aid in the fight against cancer are being developed, complementary therapies to ease symptoms are gaining prominence, and survivorship care is becoming a welcome yet challenging area of subspecialty. For oncology nurses to provide quality care and to develop improved care delivery systems, they must not only have access to the most current knowledge in the field, but also be equipped with the skills necessary to integrate that knowledge into practice for the benefit of patients and families (LoBiondo-Wood et al., 2014). The importance of nursing research and its relationship to the practice of oncology nursing cannot be minimized (Moore & Badger, 2014). Oncology nurse researchers advance knowledge and, consequently, improve the quality of care for patients with cancer and their families. For example, the Oncology Nursing Society (ONS) regularly surveys its membership to identify key areas of research focus that then guide the work of nurse investigators (LoBiondo-Wood et al., 2014; ONS Research Agenda Team, 2009). Unfortunately, the shortage of nurse scientists, particularly in oncology nursing, continues to increase as senior doctoral faculty reach retirement age and doctoral education program development remains stagnant (Glasgow & Dreher, 2010; LoBiondo-Wood et al., 2014). This shortage has and will continue to lead to gaps in the generation and implementation of new knowledge, negatively affecting the quality of patient care. As a result, an urgent need exists for innovative and quality doctoral educational programs to develop nurse scientists (Moore & Badger, 2014). PMID- 25542326 TI - Management of malignancy-related ascites. AB - A 65-year-old Polish immigrant named T. J. was diagnosed with metastatic colon cancer in January 2012 when he presented with obstructing sigmoid colon cancer and liver metastases. A diverting colostomy as well as biopsy of his liver metastases was performed and chemotherapy with FOLFOX (5-fluorouracil [5-FU], leucovorin, oxaliplatin) and bevacizumab was initiated. After three months, he transitioned to maintenance therapy with infusional 5-FU and bevacizumab until he progressed in August 2012. Oxaliplatin was reintroduced and he responded until he developed progressive neuropathy in November and his therapy was changed to FOLFIRI (5-FU, leucovorin, irinotecan) and bevacizumab. T. J. developed liver progression after three months and, because he was Kras wild type, irinotecan and panitumumab were initiated. Liver-directed therapy also was pursued and he underwent radioembolization with yittrium-90 followed by chemoembolization with irinotecan-eluded beads. At the time of these procedures, T. J.'s portal and hepatic venous systems were patent (i.e., no thrombosis or obstruction causing portal hypertension). PMID- 25542327 TI - PALB2 and the risks for cancer: implications for clinical care. AB - Mutations in the PALB2 gene are responsible for a small but significant percentage of cancer risks in familial breast and pancreatic cancer families. PALB2 mutations may be associated with an increase in other cancer risks as well. This article will provide an overview of the PALB2 gene, cancer risks associated with carrying a PALB2 mutation, and implications for patient care. PMID- 25542328 TI - Emergence of stereotactic body radiation therapy. AB - Stereotactic body radiation therapy (SBRT) evolved from the application of stereotactic radiosurgery, which is focused intracranial radiation. SBRT offers high doses of specific radiation with oligofractions (five or less) to a specified target, providing local control to circumscribed tumors while sparing surrounding normal tissue. Commonly treated cancers include tumors of the lung and liver. The challenge with SBRT is to account for organ motion and the achievement of precise targeting. SBRT uses three-dimensional radiation therapy planning, intensity-modulated radiation therapy, as well as image-guided organ motion and gating. SBRT is based on the premise of geometric avoidance, targeting the tumor with the goal of complete avoidance of the surrounding normal tissues and critical organs. An SBRT course of treatment ranges from one to five treatments (hypofractionated) and, therefore, differs from conventional radiation, which is usually a prolonged course ranging from two to six weeks of daily treatment. PMID- 25542331 TI - Symptom distress and its association with traditional Chinese medicine use in Chinese American women with cancer. AB - PURPOSE/OBJECTIVES: To identify symptom distress related to cancer for a group of Chinese American women in treatment, and to examine their use of various forms of traditional Chinese medicine (TCM) and their relationships to specific symptoms they identified. DESIGN: Cross-sectional, correlational. SETTING: American Cancer Society Asian Initiatives support groups in the state of New York. SAMPLE: 97 Chinese American women residing in New York with a mean age of 57 years; the time since diagnosis of cancer ranged from two months to 24 years. The type of diagnosis for the majority of women was breast cancer. METHODS: A self-reported questionnaire including a demographic data form, a researcher-developed checklist for types of TCM, and the Memorial Symptom Assessment Scale Short Form (MSAS-SF) were administered. The MSAS-SF has three subscales: global distress index, psychological symptom distress scale, and physical symptom distress scale. MAIN RESEARCH VARIABLES: Symptoms, symptom distress, and types of TCM. The descriptive statistics and Mann-Whitney U tests were applied for data analysis. FINDINGS: Chinese American women with cancer in treatment reported multiple symptoms, and the three MSAS-SF distress subscale scores indicated moderate symptom distress. Symptoms were positively associated with the use of TCM. CONCLUSIONS: Chinese American women in treatment for cancer reported multiple symptoms and moderate symptom distress. Participants with specific symptoms tended to use specific forms of TCM. IMPLICATIONS FOR NURSING: High prevalence of psychological symptoms for Chinese American women with cancer suggests that oncology nurses should work with mental health providers for symptom management of this population. Oncology nurses also need to stay informed of the growing body of evidence on the benefits of TCM for patients with cancer. Future studies should include an emphasis on the improvement in methodologic quality for studies that investigate using TCM in participants with cancer. PMID- 25542330 TI - Women with breast cancer: self-reported distress in early survivorship. AB - PURPOSE/OBJECTIVES: To identify and compare levels of distress and sources of problems among patients with breast cancer in early survivorship. DESIGN: Descriptive, cross-sectional. SETTING: A National Cancer Institute-designated comprehensive cancer center. SAMPLE: 100 breast cancer survivors were selected to represent four time points in the cancer trajectory. METHODS: Distress was self reported using the Distress Thermometer and its 38-item problem list. Analysis of variance and chi-square analyses were performed as appropriate. MAIN RESEARCH VARIABLES: Distress scores, problem reports, and time groups. FINDINGS: Participants scored in range of the cutoff of more than 4 (range = 4.1-5.1) from treatment through three months post-treatment. At six months post-treatment, distress levels were significantly lower. Significant differences were found between groups on the total problem list score (p = 0.007) and emotional (p = 0.01) and physical subscale scores (p = 0.003). CONCLUSIONS: Comparison of groups at different points in the cancer trajectory found similar elevated levels from diagnosis through three months. Distress remained elevated in early survivorship but significantly decreased at six months post-treatment. IMPLICATIONS FOR NURSING: Interventions to reduce or prevent distress may improve outcomes in early survivorship. PMID- 25542332 TI - Resilience in adult cancer care: an integrative literature review. AB - PROBLEM IDENTIFICATION: In cancer care, empirical research and theory development on resilience has primarily been the domain of pediatric settings. This article aims to (a) describe current scientific perspectives on the concept of resilience, (b) summarize quantitative research on resilience in adult cancer care, and (c) identify implications for cancer nursing. LITERATURE SEARCH: An integrative literature review using PubMed, CINAHL(r), and PsycINFO databases was performed and full-text, peer-reviewed articles published since 2003 were included. DATA EVALUATION: To summarize quantitative research, 252 articles were retrieved yielding 29 eligible studies, of which 11 articles were evaluated and synthesized. Appropriate articles were reviewed and data were extracted and tabulated for synthesis. SYNTHESIS: Resilience is a dynamic process of facing adversity related to a cancer experience. It may be facilitated through nursing interventions after people affected by cancer have been confronted with the significant adversity posed by diagnosis, treatment, (long-term) symptoms, and distress. CONCLUSIONS: Resilience in adult cancer care is an under-researched area. Studies confirm the association with improved health outcomes (e.g., psychological well-being, mental and physical health). IMPLICATIONS FOR RESEARCH: Resilience is an important issue for adult cancer care. Researchers must carefully define a conceptual framework for developing nursing interventions aimed at furthering resilience in adult cancer care. PMID- 25542333 TI - The effectiveness of exercise interventions for improving health-related quality of life from diagnosis through active cancer treatment. AB - PURPOSE/OBJECTIVES: To evaluate the effectiveness of exercise interventions on overall health-related quality of life (HRQOL) and its domains among adults scheduled to, or actively undergoing, cancer treatment. DATA SOURCES: 11 electronic databases were searched through November 2011. In addition, the authors searched PubMed's related article feature, trial registries, and reference lists of included trials and related reviews. DATA SYNTHESIS: 56 trials with 4,826 participants met the inclusion criteria. At 12 weeks, people exposed to exercise interventions had greater improvement in overall HRQOL, physical functioning, role functioning, social functioning, and fatigue. Improvement in HRQOL was associated with moderate-to-vigorous intensity exercise interventions. CONCLUSIONS: Exercise can be a useful tool for managing HRQOL and HRQOL domains for people scheduled to, or actively undergoing, cancer treatment. More methodologically rigorous trials are needed to examine the attributes of exercise programs most effective for improving HRQOL. IMPLICATIONS FOR NURSING: Evidence from this review supports the incorporation of exercise programs of moderate-to vigorous intensity for the management of HRQOL among people scheduled to, or actively undergoing, cancer treatment into clinical guidelines through the Oncology Nursing Society's Putting Evidence Into Practice resources. PMID- 25542334 TI - The effects of age upon the expression of three miRNAs in muscle stem cells isolated from two different porcine skeletal muscles. AB - Aging is associated with a gradual loss of skeletal muscle mass and an impaired ability of this tissue to compensate for trauma. Studies in rodents and humans have also shown that resident stem cells within muscle have a reduced ability to proliferate and differentiate. In this study muscle stem cells have been isolated from two muscles, the diaphragm (DIA) and the semimembranosus (SM), from young and old pigs. The levels of three micro-RNAs (miRNAs) were measured when cells were in a proliferative phase and after 24 and 72h in differentiation medium. All three miRNAs are abundant in skeletal muscle with miR-1 and miR-206 known to regulate myogenic differentiation and miR-24 is involved in cell cycle regulation. The levels of expression of Pax7 and the myogenic regulatory factors MyoD and myogenin were also measured. There were marked differences in expression of all three miRNAs between the two age groups. Both miR-1 and miR-206 were reduced in the cells from the older animals. In contrast miR-24 expression was significantly higher in cells from older animals under differentiation conditions. There were also significant differences in the relative expression of all three miRNAs between cells from the SM and DIA in both young and old animals. The changes in miRNA expression described in this study that relate to age, may play a role in the impaired differentiation capacity of older muscle stem cells. PMID- 25542336 TI - [Etiology and clinical course of urinary tract infections in infants less than 3 months-old]. AB - BACKGROUND: Infants less than 3 months of age with urinary tract infection are usually hospitalized. Recent studies show that a less aggressive management for those patients aged >= 29 days may be feasible. OBJECTIVES: To determine the complication rate in infants<3 months of age with urinary tract infection, and to identify the causative agents and their antibiotic susceptibility. METHODS: A retrospective study was conducted on infants<3 months of age with positive urinalysis results, together with a positive urine culture from a catheterized specimen and seen in the Emergency Department from 2007 to 2012. Demographics, clinical and microbiology (microorganism isolated and antibiotic susceptibility) data were collected. The complications rate (bacteremia, bacterial meningitis, renal abscess, surgical intervention, Intensive Care Unit admission, or death) were calculated for the overall sample and for different age groups (<29, 29-60, and 61-90 days). RESULTS: A total of 460 patients are included; 137 (29.8%)<29, 166 (36.1%) 29-60, and 157 (34.1%) 61-90 days of age. Twenty four (5.4%; 95% CI: 3.6-7.8) had bacteremia; 15 (10.9%; 95% CI: 6.7-17.3) were<29 days; 8 (4.9%; 95% CI: 2.5-9.4) were 29-60 days, and one (0.7%; 95% CI: 0.1-3.7) was 61-90 days of age (P<.001). One neonate (0.8%; 95% CI: 0.1-4.1) had bacterial meningitis, and 2, renal abscess. Escherichia coli was the common pathogen identified (87.2%) in the urine culture, with a susceptibility to amoxicillin-clavulanate, gentamicin, and cefixime of 89.2, 97.0, and 96.0%, respectively. CONCLUSION: Complications are low in infants<3 months of age with UTI, especially in those >= 29 days of age. The identification of patients at very low risk for complications would allow a less aggressive management. Escherichia coli antibiotic susceptibility remains stable, but continuing careful surveillance is essential to optimize empirical antibiotic treatment. PMID- 25542337 TI - [Vaccination--General concepts. Systematic vaccination schedules for the child and adult in Spain. Impact of vaccination programs]. AB - One area of major importance in promoting health is the prevention of infectious diseases through vaccination. Vaccine is any preparation intended to generate immunity against a disease by stimulating the production of antibodies. There are two basic types: live attenuated and inactivated, with different characteristics that determine their use. The main properties of a vaccine are safety and protective efficacy. The vaccines can be administered based on individualized directions depending on various factors (personal, environmental...), or systematically as part of the immunization schedules. In Spain, the first childhood immunization schedule was implemented in 1975. The Autonomous Communities are currently responsible for establishing vaccine recommendations. The incidence of vaccine-preventable diseases and vaccination coverage are essential criteria for the evaluation of vaccination programs. In Spain the incidence of vaccine-preventable diseases is low. Vaccination coverage is high in childhood, but in adolescents, adults and groups at risk it is not always appropriate. PMID- 25542335 TI - [Serotypes and antibiotic resistance patterns in beta-hemolytic Streptococcus agalactiae isolates in colonized mothers and newborns with invasive disease]. AB - INTRODUCTION: Current preventive measures against neonatal disease caused by Streptococcus agalactiae (GBS) are prenatal screening and intrapartum antibiotic prophylaxis with appropriate antimicrobials. An alternative to this strategy would be the administration of a polysaccharide vaccine as the distribution of capsular serotypes of circulating strains needs to be known. METHODS: A study was made of 188 strains from pregnant women carrying GBS and 24 newborns with neonatal disease. Susceptibility testing was performed with penicillin, erythromycin and clindamycin following CLSI standards, and capsular serotype was determined by two methods: latex agglutination and PCR. RESULTS: Of the 188 strains of S.agalactiae from the pregnant women, there was 80.8% agreement in the results between the two techniques. Resistant to erythromycin and clindamycin was found in 16.5% and 10.1%, respectively. For neonatal strains, 95.8% of the results obtained by the two techniques were identical. The rates of resistance to erythromycin and clindamycin were 8.3% and 4.1%, respectively. In both groups, most frequently isolated serotype was iii, and the most related to antimicrobial resistance serotype was v. CONCLUSION: Epidemiological studies are necessary to continue surveillance of serotypes causing invasive disease and its antibiotic sensitivity patterns using sensitive and specific methods. PMID- 25542338 TI - [An unusual cause of cutaneous abscess to keep in mind]. PMID- 25542339 TI - [Purpura and necrosis of sudden onset in a patient with fever]. PMID- 25542340 TI - The extent of improvement of health-related quality of life as assessed by the SF36 and Paseika scales after parathyroidectomy in patients with primary hyperparathyroidism--a systematic review and meta-analysis. AB - BACKGROUND: Previous studies have shown that parathyroidectomy for primary hyperparathyroidism (PHPT) improve the function and quality of life of patients. The aim of this systematic review and meta-analysis is to determine the health related quality of life outcomes among those having surgical management for PHPT. METHODS: Several databases were searched (MEDLINE, EMBASE, PubMed, Current Contents) for studies in which health-related quality of life was measured by reliable and validated instruments (SF-36 and Paseika Questionnaire) before and after parathyroidectomy for patients with primary hyperparathyroidism (PHPT). For the SF-36, score differences greater than 5 points indicate clinically relevant changes. RESULTS: There were six studies with quality of life data. The SF-36 data was derived from 238 patients, with a mean age of 59 years and 71% were females. The range of follow up after surgery was 6 months to one year. The pre- and post-parathyroidectomy SF-36 quality of life scale scores were vitality (44 vs. 60, p<0.001), physical functioning (51 vs. 69, p<0.001), bodily pain (50 vs. 65, p<0.001), general health (54 vs. 64, p<0.001), role physical (34 vs. 52, p<0.001), role emotional (43 vs. 59, p<0.001), role social (60 vs. 74, p<0.001), and mental health (55 vs. 71, p<0.001). The Paseika data was derived from 203 patients, with a mean age of 54 years and 67% were females. The pre- and post parathyroidectomy Paseika scores were feeling tired (51 vs. 19, p<0.001), feeling thirsty (29 vs. 12, p<0.001), mood swings (33 vs. 12, p<0.001), joint pains (32 vs. 14, p<0.001), irritability (31 vs. 10, p<0.001), feeling blue (31 vs. 14, p<0.001), feeling weak (37 vs. 15, p<0.001), itchy (17 vs. 7, p<0.001), forgetful (27 vs. 16, p<0.001), headache (18 vs. 5, p<0.001), abdominal pain (19 vs. 8, p<0.001), bone pain (38 vs. 17, p<0.001), ability to move off chair (27 vs. 11, p<0.001). CONCLUSION: Parathyroidectomy significantly improves the short to medium-term health-related quality of life of patients suffering from primary hyperparathyroidism. PMID- 25542341 TI - IAPs: Modular regulators of cell signalling. AB - Members of the inhibitor of apoptosis (IAP) family are characterised by the presence of at least one baculoviral IAP repeat (BIR) domain. However, during the course of evolution, other globular modules have been adopted to perform distinct functions. Consequently, the IAP family is now recognised as consisting of members that perform critical functions in different aspects of cellular regulation. In this review, the structural diversity present within the IAP protein family is presented. Known structures of individual domains are discussed and their properties are described in light of recent data. In particular the plasticity of BIR domains and their ability to accommodate different binding partners is highlighted, as well as the importance of communication between the domains in regulating the covalent attachment of ubiquitin. PMID- 25542342 TI - Influence of residential segregation on survival after AIDS diagnosis among non Hispanic blacks. AB - PURPOSE: Non-Hispanic blacks (NHBs) are disproportionately affected by the AIDS epidemic. With the advent of highly active antiretroviral therapy (HAART), survival after AIDS diagnosis has increased dramatically, yet survival among NHBs is shorter compared with non-Hispanic whites. Racial residential segregation may be an important factor influencing observed racial disparities in survival. METHODS: We linked data on 30,813 NHBs from the Florida Department of Health HIV/AIDS Reporting system (1993-2004) with death records and applied segregation indices and poverty levels to the data. Weighted Cox models were used to examine the association between segregation measured on five dimensions and survival, controlling for demographic factors, clinical factors, and area-level poverty. Analyses were stratified by pre-HAART (1993-1995), early HAART (1996-1998), and late-HAART (1999-2004) eras. RESULTS: In the late-HAART era, adjusting for area level poverty, segregation remained a significant predictor of survival on two dimensions: Concentration (hazard ratio, 1.32; 95% confidence interval, 1.13 1.56) and centralization (hazard ratio, 1.44; 95% confidence interval, 1.12 1.84). Area-level poverty was an independent predictor of survival. CONCLUSIONS: These findings suggest that certain dimensions of segregation and poverty are associated with survival after AIDS diagnosis. PMID- 25542343 TI - Therapist differences in a randomised trial of the outcome of cognitive behaviour therapy for health anxiety in medical patients. AB - BACKGROUND: Health anxiety is common in medical settings and can be treated successfully by cognitive behaviour therapy. However it is not clear who might be best placed to deliver this therapy. OBJECTIVES: In a planned secondary analysis of data from a randomised trial of adapted cognitive behaviour therapy for health anxiety we compared outcomes of therapy delivered by nurses and other professional groups. DESIGN: A randomised controlled trial with two treatment arms, 5-10 sessions of cognitive behaviour therapy adapted health anxiety or standard care. SETTING: Cardiology, endocrine, gastroenterology, neurological and respiratory clinics in six general hospitals in the UK covering urban, suburban and rural areas. PARTICIPANTS: Medical patients attending the clinics who had pathological health anxiety and also scored for a diagnosis of hypochondriasis. METHODS: Patients were randomised to one of two treatment arms, 5-10 sessions of cognitive behaviour therapy adapted health anxiety or standard care delivered by naive therapists (not randomised) who were trained in advance before delivering the treatment. Independent assessment of outcomes by researchers masked to allocation status at 3m, 6m, 12m and 24m. RESULTS: 444 patients were randomised in the trial, 219 to cognitive behaviour therapy adapted health anxiety and 225 to standard care. 373 (84%) completed assessments after two years. Those treated by nurses (n=66) had improvement in health anxiety, generalised anxiety and depression outcomes that were significantly better and twice as great as those of the professional groups of assistant psychologists (n=87) and graduate workers (n=66) (P<0.01 over all time points). The number needed to treat to show superiority of nurse-delivered treatment over other treatment delivery was 4 at 6 months and 6 at one year. CONCLUSION: General nurses, after suitable training, are very effective therapists for patients with health anxiety in medical clinics and should be the therapists of choice for patients in these settings. PMID- 25542344 TI - Experimental and theoretical analysis of secondary Bjerknes forces between two bubbles in a standing wave. AB - Bubbles in an acoustic field are affected by forces such as primary and secondary Bjerknes forces, which have been shown to be influenced by acoustic pressure, frequency, bubble size and separation distance between bubbles. However, such studies are predominantly theoretical, and are mostly focused on the sign reversal of the secondary Bjerknes force. This study provides experimental data on the effect of a range of bubble sizes (8-30 MUm), distances (?0.2 mm), acoustic pressures (20-40 kPa) and frequencies (40-100 kHz) on the relative acceleration of two approaching bubbles. Under these conditions, only variations in the magnitude of the attractive force were observed. Using coupled equations of radial and translational motions, the acceleration and secondary Bjerknes force were calculated and compared to the experimental data. The variations in the magnitude of the secondary Bjerknes forces were explained by simulating bubble radius and coupled volume oscillation as a function of time. PMID- 25542345 TI - Hospital readmissions after cardiac surgery: is it a game worth playing? PMID- 25542347 TI - Histopathologic analysis of successful endothelial keratoplasty following multiple failed keratoplasties. AB - A 68-year-old woman with bilateral keratoconus presented with persistent visual acuity deficits following cataract extraction with a neodymium:YAG capsulotomy in the right eye 2 years earlier. Penetrating keratoplasty (PKP) had been performed for keratoconus in the right eye without complications until steroid drops were discontinued after 10 years because of persistent elevated intraocular pressure. The right eye experienced immunologic rejection and failure of 3 PKPs, 1 Descemet stripping endothelial keratoplasty (DSEK), and a trabeculectomy with an eventual anatomically successful DSEK before the patient died at 95 years of age. The left eye improved following a single PKP. Postmortem histopathologic analysis of the cornea showed an anatomically successful DSEK graft with intact donor Descemet membrane and viable graft endothelial cells. To our knowledge, this is the first histopathologic analysis of an anatomically successful DSEK after multiple failed PKPs and trabeculectomy. The course in this case supports early consideration of lamellar keratoplasty, especially in patients with ocular comorbidities. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25542348 TI - Bilateral capsule contraction syndrome-induced ciliary body detachment. AB - A 63-year-old woman experienced persistent hypotony in both eyes about 1 month after cataract surgery. Neodymium:YAG (Nd:YAG) laser capsulotomy was performed to enlarge the anterior capsule opening. Six days after the capsulotomy, an examination revealed reattached ciliary bodies and normal intraocular pressure. This case highlights a rare occurrence of ciliary detachment and secondary hypotony caused by capsule contraction after phacoemulsification surgery. Early detection and timely Nd:YAG laser anterior capsulotomy relaxes the capsule, alleviates the ciliary body detachment, and prevents serious complications. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25542346 TI - Field trial of GABA-fortified rice plants and oral administration of milled rice in spontaneously hypertensive rats. AB - Hypertension is one of the most critical risk factors accompanying cardiovascular diseases. gamma-Aminobutyric acid (GABA) is a non-protein amino acid that functions as a major neurotransmitter in mammals and also as a blood-pressure lowering agent. We previously produced GABA-fortified rice lines of a popular Japonica rice cultivar 'Koshihikari' by genetic manipulation of GABA shunt related genes. In the study reported here, we grew these same novel rice lines in a field trial and administered the milled rice orally to rats. The yield parameters of the transgenic rice plants were almost unchanged compared to those of untransformed cv. 'Koshihikari' plants, while the rice grains of the transgenic plants contained a high GABA content (3.5 g GABA/kg brown rice; 0.75 0.85 GABA g/kg milled rice) in a greenhouse trial. Oral administration of a diet containing 2.5% GABA-fortified rice, with a daily intake for 8 weeks, had an approximately 20 mmHg anti-hypertensive effect in spontaneous hypertensive rats but not in normotensive Wistar-Kyoto rats. These results suggest that GABA fortified rice may be applicable as a staple food to control or prevent hypertension. PMID- 25542349 TI - Interaction of ultraviolet light with the cornea: clinical implications for corneal crosslinking. AB - Understanding ultraviolet (UV) interaction with the human corneal tissue is of interest among corneal specialists given the widespread application of corneal crosslinking. This article reviews the current knowledge of light interaction with the cornea in the UV wavelength range. It also uses a novel experimental study to illustrate the role of 2 important corneal properties that have not yet been clarified: the epithelial contribution to overall UVA corneal absorbance and the regional anisotropy of UVA light transmittance. Finally, it presents the most recent insights into how different methods of UVA light irradiation and corneal soaking with riboflavin influence the outcome of corneal crosslinking. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25542352 TI - Low-intensity pulsed ultrasound-induced ATP increases bone formation via the P2X7 receptor in osteoblast-like MC3T3-E1 cells. AB - Low-intensity pulsed ultrasound (LIPUS) is used for bone healing in orthopedics and dentistry. It has been shown that LIPUS induces the secretion of extracellular adenosine triphosphate (ATP), a key mediator of osteoblast response to mechanical stimuli. However, the detailed mechanism of LIPUS-induced osteogenesis has been elusive. In this study, we investigated the role of the P2X7 receptor in LIPUS-induced osteogenesis. LIPUS induced the release of extracellular ATP, differentiation of osteoblasts and osteogenesis via the P2X7 receptor, without affecting the activity of alkaline phosphatase (ALPase). These results suggest that LIPUS-induced extracellular ATP promotes bone formation via the osteoblast P2X7 receptor independently of ALPase. PMID- 25542350 TI - Custom-fit radiolucent cranial implants for neurophysiological recording and stimulation. AB - BACKGROUND: Recording and manipulating neural activity in awake behaving animal models requires long-term implantation of cranial implants that must address a variety of design considerations, which include preventing infection, minimizing tissue damage, mechanical strength of the implant, and MRI compatibility. NEW METHOD: Here we address these issues by designing legless, custom-fit cranial implants using structural MRI-based reconstruction of the skull and that are made from carbon-reinforced PEEK. RESULTS: We report several novel custom-fit radiolucent implant designs, which include a legless recording chamber, a legless stimulation chamber, a multi-channel microdrive and a head post. The fit to the skull was excellent in all cases, with no visible gaps between the base of the implants and the skull. The wound margin was minimal in size and showed no sign of infection or skin recession. COMPARISON WITH EXISTING METHODS: Cranial implants used for neurophysiological investigation in awake behaving animals often employ methyl methacrylate (MMA) to serve as a bonding agent to secure the implant to the skull. Other designs rely on radially extending legs to secure the implant. Both of these methods have significant drawbacks. MMA is toxic to bone and frequently leads to infection while radially extending legs cause the skin to recede away from the implant, ultimately exposing bone and proliferating granulation tissue. CONCLUSIONS: These radiolucent implants constitute a set of technologies suitable for reliable long-term recording, which minimize infection and tissue damage. PMID- 25542353 TI - Rethinking 'academic' drug discovery: the Manchester Institute perspective. AB - The contraction in research within pharma has seen a renaissance in drug discovery within the academic setting. Often, groups grow organically from academic research laboratories, exploiting a particular area of novel biology or new technology. However, increasingly, new groups driven by industrial staff are emerging with demonstrable expertise in the delivery of medicines. As part of a strategic review by Cancer Research UK (CR-UK), the drug discovery team at the Manchester Institute was established to translate novel research from the Manchester cancer research community into drug discovery programmes. From a standing start, we have taken innovative approaches to solve key issues faced by similar groups, such as hit finding and target identification. Herein, we share our lessons learnt and successful strategies. PMID- 25542354 TI - Recent trends in analytical methods and separation techniques for drugs of abuse in hair. AB - Hair analysis of drugs of abuse has been a subject of growing interest from a clinical, social and forensic perspective for years because of the broad time detection window after intake in comparison to urine and blood analysis. Over the last few years, hair analysis has gained increasing attention and recognition for the retrospective investigation of drug abuse in a wide variety of contexts, shown by the large number of applications developed. This review aims to provide an overview of the state of the art and the latest trends used in the literature from 2005 to the present in the analysis of drugs of abuse in hair, with a special focus on separation analytical techniques and their hyphenation with mass spectrometry detection. The most recently introduced sample preparation techniques are also addressed in this paper. The main strengths and weaknesses of all of these approaches are critically discussed by means of relevant applications. PMID- 25542351 TI - Comprehensive chronic laminar single-unit, multi-unit, and local field potential recording performance with planar single shank electrode arrays. AB - BACKGROUND: Intracortical electrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications. In general, these electrode devices suffer from reliability and variability issues, which have led to comparative studies of existing and emerging electrode designs to optimize performance. Comparisons of different chronic recording devices have been limited to single-unit (SU) activity and employed a bulk averaging approach treating brain architecture as homogeneous with respect to electrode distribution. NEW METHOD: In this study, we optimize the methods and parameters to quantify evoked multi-unit (MU) and local field potential (LFP) recordings in eight mice visual cortices. RESULTS: These findings quantify the large recording differences stemming from anatomical differences in depth and the layer dependent relative changes to SU and MU recording performance over 6-months. For example, performance metrics in Layer V and stratum pyramidale were initially higher than Layer II/III, but decrease more rapidly. On the other hand, Layer II/III maintained recording metrics longer. In addition, chronic changes at the level of layer IV are evaluated using visually evoked current source density. COMPARISON WITH EXISTING METHOD(S): The use of MU and LFP activity for evaluation and tracking biological depth provides a more comprehensive characterization of the electrophysiological performance landscape of microelectrodes. CONCLUSIONS: A more extensive spatial and temporal insight into the chronic electrophysiological performance over time will help uncover the biological and mechanical failure mechanisms of the neural electrodes and direct future research toward the elucidation of design optimization for specific applications. PMID- 25542355 TI - One pot synthesis of poly(5-hydroxyl-1,4-naphthoquinone) stabilized gold nanoparticles using the monomer as the reducing agent for nonenzymatic electrochemical detection of glucose. AB - Monodispersed and highly stable gold nanoparticles with a diameter between 8 and 9 nm were synthesized in a weakly alkaline medium by chemical reduction of AuCl4( ) using 5-hydroxyl-1,4-naphthoquinone, and stabilized by the simultaneously formed poly(hydroxyl-1,4-naphthoquinone). The electrochemical properties of the resultant poly(hydroxyl-1,4-naphthoquinone) stabilized gold nanoparticles (AuNQ NPs) and its electrocatalytic activity for glucose oxidation in alkaline media were then investigated using a range of techniques, including dc cyclic, rotating disk electrode and Fourier transformed large amplitude ac voltammetry. The results demonstrate that these AuNQ NP modified electrodes exhibit excellent catalytic activity toward glucose oxidation in the potential region where the premonolayer oxidation process occurs. The overall catalytic glucose oxidation process was found to be mass transport controlled under the experimental conditions employed, allowing measurements to be conducted with a high reproducibility. The AuNQ NP modified electrodes showed a high sensitivity of 183 MUA mM(-1) cm(-2) with a wide linear dynamic range of 0.5-50 mM and a detection limit of 61 MUM. However, despite its excellent tolerance toward ascorbic acid, significant interference from uric acid was found with this AuNQ NP modified electrode. PMID- 25542356 TI - In vivo solid phase microextraction sampling of human saliva for non-invasive and on-site monitoring. AB - On-site sample preparation is an analytical approach based on direct sampling from the system under investigation. It has the advantage of combining sampling and sample preparation into a single step, thus generally is fast, minimizes the potential sources of error and eliminates the risks for analytes instability. For such analysis solid phase microextraction in thin film geometry (TF-SPME) can provide robust and convenient in vivo sampling, offering in the same time faster analysis and higher extraction recovery (i.e., better sensitivity) due to large surface to volume ratio. In this study, TF-SPME in coated blade and membrane formats with a single extraction phase were used for in vivo and ex vivo saliva extraction and separation by LC and GC, respectively. Due to applicability for wide range of polarity of analytes as well as thermal and solvent stability during the desorption, hydrophilic lipophilic balanced particles (HLB) were chosen as extraction phase and used for fast (5 min) in vivo and ex vivo sampling. The results of metabolomic profiling of the saliva are indicating that even 5 min in vivo sampling using TF-SPME followed by GC and LC analyses provides complementary coverage of wide range of analytes with different physical and chemical properties. To demonstrate the applicability of the method for doping analyses, the SPME-LC-MS/MS method was validated for simultaneous quantification of 49 prohibited substances with limit of quantification (LOQ) ranging between 0.004 and 0.98 ng mL(-1). Moreover, the method was also validated and successfully applied for determination of endogenous steroids in saliva where the concentrations of the analytes are substantially low. The developed assay offers fast and reliable multiresidue analysis of saliva as an attractive alternative to the standard analysis methods. PMID- 25542357 TI - Evaluation of atmospheric solid analysis probe ionization coupled to ion mobility mass spectrometry for characterization of poly(ether ether ketone) polymers. AB - Recently, the interest of the coupling between atmospheric solid analysis probe (ASAP) and ion mobility-mass spectrometry has been revealed in the field of polymers. This method associates a direct ionization technique with a bi dimensional separation method. Poly(ether ether ketones) (PEEK) belong to the family of the poly(aryl ether ketones) (PAEK) which are high performance aromatic polymers usually used in aerospace, electronics and nuclear industries. PEEK are important commercial thermoplastics with excellent chemical resistance and good mechanical properties. Because of their low solubility, few structural characterization studies of PEEK have been reported. In mass spectrometry, only MALDI-TOF analyses for polymer synthesis monitoring have been described with the use of strong acids such as sulfuric acid. This work demonstrates that ASAP is particularly efficient for analysis of PEEK in a solvent free approach with the production of intact small oligomers (n<=2). Five types of PEEK oligomers with different end-groups were evidenced. With MALDI-TOF, the same end-groups with almost the same relative abundance were obtained which support the hypothesis that the oligomers detected in ASAP are intact small oligomers and not fragments or pyrolysis products. This is particularly interesting as generally the ASAP analysis of polymers yields pyrolysis products with the loss of end-group information. The end-groups assignments have been confirmed by tandem mass spectrometry (MS/MS) experiments on the M(+) molecular ions, which allowed highlighting some specific neutral or radical losses as well as two diagnostic product ions. Thus, ASAP-IM/MS/MS proves to be a fast and efficient alternative way to characterize low solubility polymers such as PEEK. PMID- 25542358 TI - Reliability of veterinary drug residue confirmation: high resolution mass spectrometry versus tandem mass spectrometry. AB - Confirmation of suspected residues has been a long time domain of tandem triple quadrupole mass spectrometry (QqQ). The currently most widely used confirmation strategy relies on the use of two selected reaction monitoring signals (SRM). The details of this confirmation procedure are described in detail in the Commission Decision 93/256/EC (CD). On the other hand, high resolution mass spectrometry (HRMS) is nowadays increasingly used for trace analysis. Yet its utility for confirmatory purposes has not been well explored and utilized, since established confirmation strategies like the CD do not yet include rules for modern HRMS technologies. It is the focus of this paper to evaluate the likelihood of false positive and false negative confirmation results, when using a variety of HRMS based measurement modes as compared to conventional QqQ mass spectrometry. The experimental strategy relies on the chromatographic separation of a complex blank sample (bovine liver extract) and the subsequent monitoring of a number of dummy transitions respectively dummy accurate masses. The term "dummy" refers to precursor and derived product ions (based on a realistic neutral loss) whose elemental compositions (CxHyNzOdCle) were produced by a random number generator. Monitoring a large number of such hypothetical SRM's, or accurate masses inevitably produces a number of mass traces containing chromatographic peaks (false detects) which are caused by eluting matrix compounds. The number and intensity of these peaks were recorded and standardized to permit a comparison among the two employed MS technologies. QqQ performance (compounds which happen to produce a response in two SRM traces at identical retention time) was compared with a number of different HRMS(1) and HRMS(2) detection based modes. A HRMS confirmation criterion based on two full scans (an unfragmented and an all ion fragmented) was proposed. Compared to the CD criteria, a significantly lower probability of false positive and false negative findings is obtained by utilizing this criterion. PMID- 25542359 TI - Determination of dissolved methane in natural waters using headspace analysis with cavity ring-down spectroscopy. AB - Methane (CH4) is the third most abundant greenhouse gas (GHG) but is vastly understudied in comparison to carbon dioxide. Sources and sinks to the atmosphere vary considerably in estimation, including sources such as fresh and marine water systems. A new method to determine dissolved methane concentrations in discrete water samples has been evaluated. By analyzing an equilibrated headspace using laser cavity ring-down spectroscopy (CRDS), low nanomolar dissolved methane concentrations can be determined with high reproducibility (i.e., 0.13 nM detection limit and typical 4% RSD). While CRDS instruments cost roughly twice that of gas chromatographs (GC) usually used for methane determination, the process presented herein is substantially simpler, faster, and requires fewer materials than GC methods. Typically, 70-mL water samples are equilibrated with an equivalent amount of zero air in plastic syringes. The equilibrated headspace is transferred to a clean, dry syringe and then drawn into a Picarro G2301 CRDS analyzer via the instrument's pump. We demonstrate that this instrument holds a linear calibration into the sub-ppmv methane concentration range and holds a stable calibration for at least two years. Application of the method to shipboard dissolved methane determination in the northern Gulf of Mexico as well as river water is shown. Concentrations spanning nearly six orders of magnitude have been determined with this method. PMID- 25542360 TI - Label-free and direct protein detection on 3D plasmonic nanovoid structures using surface-enhanced Raman scattering. AB - In this paper we use surface-enhanced Raman spectroscopy (SERS) on 3D metallic structures for label-free detection and characterization of proteins of interest at low concentrations. The substrates are prepared via nanopatterning with latex nano/microparticles and Cr and Ag sputtering, yielding stable, tunable, and mechanically flexible plasmonic structures. The nanovoids generate a SERS signal of the proteins of interest that is background free and independent of the protein charge. Concentrations as low as 0.05 MUg mL(-1) could be detected for 4 different proteins. The proteins also exhibit significantly different SERS spectra on these substrates, which is an important feature for future label-free direct detection schemes. PMID- 25542361 TI - Doped zinc sulfide quantum dots based phosphorescence turn-off/on probe for detecting histidine in biological fluid. AB - We report a turn-on phosphorescence probe for detection of histidine based on Co(2+)-adsorbed N-acetyl-L-cysteine (NAC) capped Mn: ZnS quantum dots (QDs) which is directly synthesized by the hydrothermal method. The phosphorescence of NAC Mn: ZnS QDs is effectively quenched by Co(2+) attributing to the adsorption of Co(2+) onto the surface of QDs with a concomitant in suppressing the recombination process of hole and electron of QDs. The phosphorescence of Co(2+) adsorbed NAC-Mn: ZnS QDs can be recovered by binding of Co(2+) with histidine. The quenching and regeneration of the phosphorescence of NAC-Mn: ZnS QDs have been studied in detail. The as-prepared QDs-based probe is applied to determine histidine with a linear range of 1.25-30 MUM and a detection limit of 0.74 MUM. The relative standard deviation for eleven repeat detections of 20 MUM histidine is 0.65%. Co(2+)-adsorbed NAC-Mn: ZnS QDs show high sensitivity and good selectivity to histidine over other amino acids, metal ions and co-existing substances. The proposed QDs probe has been successfully applied to determination of histidine in human urine samples with good recoveries of 98.5-103%. PMID- 25542362 TI - A sensitive fluorescent assay for thiamine based on metal-organic frameworks with intrinsic peroxidase-like activity. AB - Metal-organic frameworks (MOFs) with tunable structures and properties have recently been emerged as very interesting functional materials. However, the catalytic properties of MOFs as enzymatic mimics remain to be further investigated. In this work, we for the first time demonstrated the peroxidase like activity of copper-based MOFs (HKUST-1) by employing thiamine (TH) as a peroxidase substrate. In the presence of H2O2, HKUST-1 can catalyze efficiently the conversion of non-fluorescent TH to strong fluorescent thiochrome. The catalytic activity of HKUST-1 is highly dependent on the temperature, pH and H2O2 concentrations. As a peroxidase mimic, HKUST-1 not only has the features of low cost, high stability and easy preparation, but also follows Michaelis-Menten behaviors and shows stronger affinity to TH than horseradish peroxidase (HRP). Based on the peroxidase-like activity of HKUST-1, a simple and sensitive fluorescent method for TH detection has been developed. As low as 1 MUM TH can be detected with a linear range from 4 to 700 MUM. The detection limit for TH is about 50 fold lower than that of HRP-based fluorescent assay. The proposed method was successfully applied to detect TH in tablets and urine samples and showed a satisfactory result. We believed that the present work could improve the understanding of catalytic behaviors of MOFs as enzymatic mimics and find out a wider application in bioanalysis. PMID- 25542363 TI - Synthetic multivalent DNAzymes for enhanced hydrogen peroxide catalysis and sensitive colorimetric glucose detection. AB - A peroxidase-mimic DNAzyme is a G-quadruplex (G4) DNA-hemin complex, in which the G4-DNA resembles an apoenzyme, and hemin is the cofactor for hydrogen peroxide (H2O2) catalysis. Twenty-one-mer CatG4 is a well-proven G4-DNA as well as a hemin binding aptamer for constituting a DNAzyme. This work studied if a multivalent DNAzyme with accelerated catalysis could be constructed using a multimeric CatG4 with hemin. We compared CatG4 monomer, dimer, trimer, and tetramer, which were prepared by custom oligo synthesis, for G4 structure formation. According to circular dichroism (CD) analysis, we found that a CatG4 multimer exhibited more active G4 conformation than the sum effect of equal-number CatG4 monomers. However, the DNAzyme kinetics was not improved monotonically along with the subunit number of a multimeric CatG4. It was the trivalent DNAzyme, trimeric CatG4:hemin, resulting in the rapidest H2O2 catalysis instead of a tetravalent one. We discovered that the trivalent DNAzyme's highest catalytic rate was correlated to its most stable hemin-binding G4 structure, evidenced by CD melting temperature analysis. Finally, a trivalent DNAzyme-based colorimetric glucose assay with a detection limit as low as 10 MUM was demonstrated, and this assay did not need adenosine 5'-tri-phosphate disodium salt hydrate (ATP) as a DNAzyme boosting agent. PMID- 25542364 TI - A DNA nanomachine based on rolling circle amplification-bridged two-stage exonuclease III-assisted recycling strategy for label-free multi-amplified biosensing of nucleic acid. AB - An autonomous DNA nanomachine based on rolling circle amplification (RCA)-bridged two-stage exonuclease III (Exo III)-induced recycling amplification (Exo III-RCA Exo III) was developed for label-free and highly sensitive homogeneous multi amplified detection of DNA combined with sensitive fluorescence detection technique. According to the configuration, the analysis of DNA is accomplished by recognizing the target to a unlabeled molecular beacon (UMB) that integrates target-binding and signal transducer within one multifunctional design, followed by the target-binding of UMB in duplex DNA removed stepwise by Exo III accompanied by the releasing of target DNA for the successive hybridization and cleavage process and autonomous generation of the primer that initiate RCA process with a rational designed padlock DNA. The RCA products containing thousands of repeated catalytic sequences catalytically hybridize with a hairpin reporter probe that includes a "caged" inactive G-quadruplex sequence (HGP) and were then detected by Exo III-assisted recycling amplification, liberating the active G-quadruplex and generating remarkable ZnPPIX/G-quadruplex fluorescence signals with the help of zinc(II)-protoporphyrin IX (ZnPPIX). The proposed strategy showed a wide dynamic range over 7 orders of magnitude with a low limit of detection of 0.51 aM. In addition, this designed protocol can discriminate mismatched DNA from perfectly matched target DNA, and holds a great potential for early diagnosis in gene-related diseases. PMID- 25542365 TI - MALDI-TOF mass spectrometric determination of eight benzodiazepines with two of their metabolites in blood. AB - A rapid and sensitive method was developed for the determination of benzodiazepines and benzodiazepine-like substances (BZDs) by matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS). In this method, alpha-cyano-4-hydroxy cinnamic acid was used as the matrix to assist the ionization of BZDs. Determination of 8 BZDs (with two of their metabolites) belonging to top 12 medical drugs detected in poisonous cases in Japan, was performed using diazepam-d5 as the internal standard. The limit of detection of zolpidem was 0.07ng/ml with its quantification range of 0.2-20ng/ml in blood, in the best case, and the limit of detection of flunitrazepam was 2ng/ml with its quantification range of 6-200ng/ml in blood, in the worst case. The spectra of zopiclone in MALDI-MS and MS/MS were different from those in electrospray ionization MS and MS/MS. Present method provides a simple and high throughput method for the screening of these BZDs using only 20MUl of blood. The developed method was successfully used for the determination of BZDs in biological fluids obtained from two victims. PMID- 25542366 TI - Molecular pathways associated with the intersex condition in rainbow darter (Etheostoma caeruleum) following exposures to municipal wastewater in the Grand River basin, ON, Canada. Part B. AB - Rainbow darter (Etheostoma caeruleum; RBD) is a small benthic fish found in North America. This species is sensitive to sewage effluent, and intersex is found in up to 80% of males in near-field areas in the Grand River, Ontario, Canada. To learn more about the molecular signaling cascades associated with intersex, a developed customized oligonucleotide microarray (4*180 K) using next generation sequencing was developed to characterize the transcriptome in the gonad of male and female RBD. Gene expression profiling was performed in males and females from both a reference site and a polluted site. Males with and without intersex condition from the areas closest to effluent outfalls were compared to males and females from a reference site. Microarray analysis revealed that there was increased mRNA abundance for genes associated with oogenesis in intersex males (i.e. the presence of eggs within the testis), and a decrease in mRNA abundance for genes associated with spermatid development. In females exposed to effluent, cell processes related with hatching and ovulation were down-regulated, and genes involved in immune responses were increased in abundance. In the non-intersex males exposed to effluent, cell processes such as sperm cell adhesion were decreased at the transcript level relative to males from the reference site. Microarray analysis revealed that heat shock proteins (HSP) were significantly increased in non-intersex males exposed to effluent; however, HSPs were not differentially expressed in intersex males exposed to the effluent. Genes involved in sex differentiation (sox9, foxl2 and dmrt1) and reproduction (esr1, esrb, ar, vtg, cyp19a1 and cyp11a) were measured in males, females, and intersex individuals. Consistent with the intersex condition, many transcripts showed an intermediate expression level in intersex males when compared to phenotypic males and females. This study improves our knowledge regarding the molecular pathways that underlie the intersex condition and develops a suite of qPCR bioassays in RBD that are able to discriminate pollutant-exposed males without intersex from those males with intersex. Part A of this study reports on the effects of municipal wastewater effluents (MWWEs) on RBD in the Grand River and demonstrates that there are disruptions in higher level endpoints that include altered steroid levels. Here we develop a new tool for assessing and monitoring the intersex condition in RBD in polluted natural environments and begin to characterize gene networks that are associated with the condition. PMID- 25542367 TI - Utilizing findings from a gender-based analysis to address chronic disease prevention and management among African-American women in a Michigan community. AB - This research note underscores the importance of including strategies to address gender-based disparities when planning and implementing community health improvement programs. Working in collaboration with the Inkster Partnership for a Healthier Community (IPHC), the National Kidney Foundation of Michigan conducted a gender-based analysis as part of its broader community health needs assessment efforts in Inkster, MI. The findings from these studies revealed significant challenges impacting women that were not being adequately addressed within the community. In response to these findings, the IPHC created a strategic action plan to respond to the highest priority needs by increasing community awareness of and linkages to resources that provide supportive services for low-income African-American women. PMID- 25542368 TI - Using gender-based analyses to understand physical inactivity among women in Yellowstone County, Montana. AB - Physical inactivity contributes to many health problems. Gender, the socially constructed roles and activities deemed appropriate for men and women, is an important factor in women's physical inactivity. To better understand how gender influences participation in leisure-time physical activity, a gender analysis was conducted using sex-disaggregated data from a county-wide health assessment phone survey and a qualitative analysis of focus group transcripts. From this gender analysis, several gender-based constraints emerged, including women's roles as caregivers, which left little time or energy for physical activity, women's leisure time activities and hobbies, which were less active than men's hobbies, and expectations for women's appearance that made them uncomfortable sweating in front of strangers. Gender-based opportunities included women's enjoyment of activity as a social connection, less rigid gender roles for younger women, and a sense of responsibility to set a good example for their families. The gender analysis was used to gain a deeper understanding of gender-based constraints and opportunities related to physical activity. This understanding is being used in the next step of our research to develop a gender-specific intervention to promote physical activity in women that addresses the underlying causes of physical inactivity through accommodation or transformation of those gender norms. PMID- 25542369 TI - MiR-200 Regulates Epithelial-Mesenchymal Transition in Anaplastic Thyroid Cancer via EGF/EGFR Signaling. AB - This study was set to study the molecular mechanism underlying how miR-200 regulates EGF/EGFR signaling to involve in epithelial-mesenchymal transition (EMT) in anaplastic thyroid cancer (ATC) cells. Loss-of-function experiments of EGFR silencing by siRNA transfection was performed. Transfection of pre-miR-200s or anti-miR-200s was used to increase or decrease miR-200 transcripts. Real-time PCR, Western blot, immunohistochemistry, and transwell experiments were performed to determine the role of miR-200s in EMT and its role in EGF/EGFR-mediated EMT in vitro and in vivo. EGF/EGFR signaling activation increased the expression of mesenchymal marker vimentin in Nthy-ori 3-1 cells and decreased the expression of endothelial maker E-cadherin. EGF stimulation led to increased RhoA expression in Nthy-ori 3-1 cells. EGFR silencing resulted in decreased RhoA expression in SW1736 and ARO cells. EGF stimulation led to down-regulation of miR-200s and EMT. Restoration of miR-200 expression by pre-miR-200a/c transfection reversed the process, including increased E-cadherin and decreased vimentin. Down-regulation of miR-200 by anti-miR-200 effectively reduced miR-200. Matrigel invasion assay proved that restoration of miR-200 expression counteracted invasiveness. EGFR silencing decreased invasiveness in SW1736 cells, while down-regulation of miR 200s restored invasiveness. Xenograft tumors of SW1736 cells with cotransfection of anti-miR-200s and EGFR siRNA which kept the similar E-cadherin and vimentin expression with the untransfected controls. In ATC cells, miR-200s play a central role in EGF/EGFR-mediated invasiveness in vitro and EMT in vivo. PMID- 25542370 TI - Infections Related to Totally Implantable Venous-Access Ports: Long-Term Experience in One Center. AB - The purpose of this study was to investigate the incidence and risk factors of infections associated with totally implantable venous-access ports (TIVAPs) in our hospital. From April 2007 through November 2013, a total of 1,026 patients with TIVAP were included in this study. We retrospectively analyzed the incidence of port-related infection, patient characteristics, and history. Risk factors for IVAP-related infection were determined statistically. Overall, 97 (9.59 %) of 1,026 infectious cases were reported. By reviewing the medical record of the patients, we found that younger age, hematogenous malignancy, and palliative chemotherapy were associated with higher infection incidence rate in patients who had implanted TIVAP (P < 0.05) in the subgroup analysis. In contrast, gender and insertion site were irrelevant factors in predicting the infection risk. Overall, TIVAP were proved to be safe and effective. Younger age, hematogenous malignancy, and palliative chemotherapy were associated with higher infection in patients who had implanted TIVAP. PMID- 25542372 TI - Reduced prefrontal activation during a verbal fluency task in Chinese-speaking patients with schizophrenia as measured by near-infrared spectroscopy. AB - Near-infrared spectroscopy (NIRS) has been applied to examine the possible functional alternations during the performance of cognitive tasks in schizophrenia. With this technique, previous studies have observed that patients with schizophrenia are often associated with reduced brain activation in the prefrontal cortex during the verbal fluency task (VFT) of the English version or the Japanese version. However, it remains unclear whether there is a brain functional impairment in Chinese-speaking patients with schizophrenia. In this study, we designed a Chinese version of the VFT and performed a multichannel NIRS study in a large group of patients with schizophrenia and healthy controls. We investigated brain activation during the task period of the Chinese version of the VFT within a schizophrenia group and a healthy group, respectively, and compared the relative changes between the two groups. Our results confirmed that Chinese-speaking patients with schizophrenia had significantly lower brain activation in the prefrontal cortex and superior temporal cortex when compared with healthy controls. Such findings based on the NIRS data provided us reliable evidences about brain functional deficits in the Chinese-speaking patients with schizophrenia. PMID- 25542371 TI - High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets. AB - The administration of estradiol-17beta (E) to animal models after loss of ovarian steroid production has many beneficial effects on neural functions, particularly in the serotonin system in nonhuman primates (NHPs). E also has anorexic effects, although the mechanism of action is not well defined. In the US, obesity has reached epidemic proportions, and blame is partially directed at the Western style diet, which is high in fat and sugar. This study examined the interaction of E and diet in surgically menopausal nonhuman primates with a 2*2 block design. Marmosets (Callithrix jacchus; n=4/group) were placed on control-low fat diet (LFD; 14%kcal from fat) or high fat diet (HFD; 28%kcal from fat) 1month prior to ovariectomy (Ovx). Empty (placebo) or E-filled Silastic capsules were implanted immediately following Ovx surgery. Treatments extended 6months. The established groups were: placebo+LFD, E+LFD, placebo+HFD, or E+HFD. At necropsy, the brain was flushed with saline and harvested. The midbrain was dissected and a small block containing the dorsal raphe nucleus was processed for qRT-PCR using Evagreen (Biotinum). Genes previously found to impact serotonin neural functions were examined. Results were compared with 2-way ANOVA followed by Bonferroni post hoc tests or Cohen's D analysis. There was a significant effect of treatment on tryptophan hydroxylase 2 (TPH2) across the groups (p=0.019). E stimulated TPH2 expression and HFD prevented E-stimulated TPH2 expression (p<0.01). Treatment differentially affected monoamine oxidase B (MAO-B) across the groups (p=0.05). E increased MAO-B with LFD, and this stimulatory effect was prevented by HFD (p<0.05). There was a significant difference between treatments in corticotrophin releasing factor-receptor 2 (CRF-R2) expression (p=0.012). E increased CRF-R2 and this stimulatory effect was blocked by HFD (p<0.01). Regardless of diet, E increased Fev mRNA (p=0.028) and decreased CRF-receptor 1 (CRF-R1) mRNA (p=0.04). HFD suppressed urocortin 1 (UCN1; stresscopin) expression (p=0.045) but E treatment had no effect. Monoamine oxidase A (MAO-A) was different due to treatment across the groups (p=0.028). MAO-A was increased in the E+HFD group (p<0.01) whereas previous studies showed E suppressed MAO-A in macaques. The serotonin reuptake transporter (SERT), the serotonin 1A receptor (5HT1A), estrogen receptor beta (ERbeta) and progestin receptor (PR) expressions were not different between groups. Estrogen receptor alpha (ERalpha) was undetectable. In summary, the data indicate that important actions of hormone therapy in the serotonin system may be lost in the context of a HFD. PMID- 25542373 TI - Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents. AB - BACKGROUND: Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities. METHODS: A series of heteroaryl phosphonicdiamide derivatives were designed as therapeutics to control and manage type2 diabetes. Initially defined Lipinski parameters encouraged them as safer drugs. Molecular docking of these compounds against Protein tyrosine phosphatase (PTP), the potential therapeutic target of type 2 diabetes, revealed their potential binding ability explaining their anti-diabetic activity in terms of PTP inhibition. Human intestinal absorption, Caco-2 cell permeability, MDCK cell permeability, BBB penetration, skin permeability and plasma protein binding abilities of the title compounds were calculated by PreADMET server. A convenient method has been developed for the synthesis of title compounds through the formation of 1-ethoxy-N,N'-bis(4-fluorobenzyl/pyridin-3-ylmethyl)phosphinediamine by the reaction of 4-fluorobenzylamine/ 3-picolylamine with ethyldichlorophosphite, subsequently reacted with heteroaryl halides using lanthanum(III) chloride as a catalyst. RESULTS: All the compounds exhibited significant in vitro anti-oxidant activity and in vivo evaluation in streptozotocin induced diabetic rat models revealed that the normal glycemic levels were observed on 12(th) day by 9a and 20(th) day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25(th) day. CONCLUSION: The results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes. Graphical Abstract Development of PTPs inhibitors. PMID- 25542374 TI - Role of monomer arrangement in the amyloid self-assembly. AB - Assembly of amyloid proteins into aggregates requires the ordering of the monomers in oligomers and especially in such highly organized structures as fibrils. This ordering is accompanied by structural transitions leading to the formation of ordered beta-structural motifs in proteins and peptides lacking secondary structures. To characterize the effect of the monomer arrangements on the aggregation process at various stages, we performed comparative studies of the yeast prion protein Sup35 heptapeptide (GNNQQNY) along with its dimeric form CGNNQQNY-(d-Pro)-G-GNNQQNY. The (d-Pro)-G linker in this construct is capable of adopting a beta-turn, facilitating the assembly of the dimer into the dimeric antiparallel hairpin structure (AP-hairpin). We applied Atomic Force Microscopy (AFM) techniques to follow peptide-peptide interactions at the single molecule level, to visualize the morphology of aggregates formed by both constructs, thioflavin T (ThT) fluorescence to follow the aggregation kinetics, and circular dichroism (CD) spectroscopy to characterize the secondary structure of the constructs. The ThT fluorescence data showed that the AP-hairpin aggregation kinetics is insensitive to the external environment such as ionic strength and pH contrary to the monomers the kinetics of which depends dramatically on the ionic strength and pH. The AFM topographic imaging revealed that AP-hairpins primarily assemble into globular aggregates, whereas linear fibrils are primary assemblies of the monomers suggesting that both constructs follow different aggregation pathways during the self-assembly. These morphological differences are in line with the AFM force spectroscopy experiments and CD spectroscopy measurements, suggesting that the AP-hairpin is structurally rigid regardless of changes of environmental factors. PMID- 25542375 TI - Characterization of recombinant biosynthetic precursors of the cysteine tryptophylquinone cofactors of l-lysine-epsilon-oxidase and glycine oxidase from Marinomonas mediterranea. AB - The lysine-epsilon-oxidase, LodA, and glycine oxidase, GoxA, from Marinomonas mediteranea each possesses a cysteine tryptophylquinone (CTQ) cofactor. This cofactor is derived from posttranslational modifications which are covalent crosslinking of tryptophan and cysteine residues and incorporation of two oxygen atoms into the indole ring of Trp. In this manuscript, it is shown that the recombinant synthesis of LodA and GoxA containing a fully synthesized CTQ cofactor requires coexpression of a partner flavoprotein, LodB for LodA and GoxB for GoxA, which are not interchangeable. An inactive precursor of LodA or GoxA which contained a monohydroxylated Trp residue and no crosslink to the Cys was isolated from the soluble fraction when they were expressed alone. The structure of LodA revealed an Asp residue close to the cofactor which is conserved in quinohemoprotein amine dehydrogenase (QHNDH), containing CTQ, and methylamine dehydrogenase (MADH) containing tryptophan tryptophylquinone (TTQ) as cofactor. To study the role of this residue in the synthesis of the LodA precursor, Asp-512 was mutated to Ala. When the mutant protein was coexpressed with LodB an inactive protein was isolated which was soluble and contained no modifications at all, suggesting a role for this Asp in the initial LodB-independent hydroxylation of Trp. A similar role had been proposed for this conserved Asp residue in MADH. It is noteworthy that the formation of TTQ in MADH from the precursor also requires an accessory enzyme for its biosynthesis but it is a diheme enzyme MauG and not a flavoprotein. The results presented reveal novel mechanisms of post-translational modification involved in the generation of protein-derived cofactors. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications. PMID- 25542376 TI - PtPLC, a pacifastin-related inhibitor involved in antibacterial defense and prophenoloxidase cascade of the swimming crab Portunus trituberculatus. AB - Pacifastin-related inhibitor is a new family of serine protease inhibitors that regulate the proteolytic cascade in multiple biological processes. Contrary to the knowledge on the structure and inhibitory mechanism of pacifastin-like members in locust, very little is known about their functions. Here, we report the inhibitory activities in relation to the structural characteristics of pacifastin light chain (PtPLC) gene identified from the swimming crab Portunus trituberculatus. The mature PtPLC and five PLD-related domains with critical residues were expressed in Escherichia coli, and assayed for their activities. The recombinant PtPLC (rPtPLC) displayed inhibitory activities against trypsin and chymotrypsin in a dose dependent manner, with a preference for trypsin. Except for rPtPLC-D4, the other four rPtPLC-related domains could inhibit at least one of serine proteases. The enzyme specificity of PtPLC domains generally corresponded to the nature of the P1 residue at the reactive site. rPtPLC was able to inhibit the growth of Gram-negative bacteria Vibrio alginolyticus and Pseudomonas aeruginosa, but not the Gram-positive bacterium and fungus tested. Further phenoloxidase (PO) assay showed the rPtPLC could depress the crab proPO system activation in vitro, and lead to 72.8% inhibition of PO activity at the concentration of 9.11 MUM. It also suppressed proPO activation induced by rPtcSP and rPtSPH1. As the first functional study of the recombinant PLC protein in crustaceans, the present results together indicate that PtPLC functions in the crab immune response possibly via inhibiting bacterial growth and regulating the proPO system. PMID- 25542377 TI - Identification of mud crab reovirus VP12 and its interaction with the voltage dependent anion-selective channel protein of mud crab Scylla paramamosain. AB - Mud crab reovirus (MCRV) is the causative agent of a severe disease in cultured mud crab (Scylla paramamosain), which has caused huge economic losses in China. MCRV is a double-stranded RNA virus with 12 genomic segments. In this paper, SDS PAGE, mass spectrometry and Western blot analyses revealed that the VP12 protein encoded by S12 gene is a structural protein of MCRV. Immune electron microscopy assay indicated that MCRV VP12 is a component of MCRV outer shell capsid. Yeast two hybrid cDNA library of mud crab was constructed and mud crab voltage dependent anion-selective channel (mcVDAC) was obtained by MCRV VP12 screening. The full length of mcVDAC was 1180 bp with an open reading frame (ORF) of 849 bp encoding a 282 amino acid protein. The mcVDAC had a constitutive expression pattern in different tissues of mud crab. The interaction between MCRV VP12 and mcVDAC was determined by co-immunoprecipitation assay. The results of this study have provided an insight on the mechanisms of MCRV infection and the interactions between the virus and mud crab. PMID- 25542378 TI - Identification and function of 11 Rab GTPases in giant freshwater prawn Macrobrachium rosenbergii. AB - Rab GTPases, members of the Ras-like GTPase superfamily, are central elements in endocytic membrane trafficking. However, little is known of the Rab genes in the giant freshwater prawn Macrobrachium rosenbergii. In this study, 11 Rab genes were identified from M. rosenbergii. All MrRabs have a RAB domain. Phylogenetic analysis showed that these 11 MrRabs were divided into different groups. The MrRab genes were ubiquitously expressed in heart, hemocytes, hepatopancreas, gills, stomach, and intestines. Real-time polymerase chain reaction revealed that the MrRab genes were significantly upregulated by white spot syndrome virus (WSSV) in the prawns, indicating that MrRabs might play an important role in innate immune response against WSSV. Moreover, after challenge with Vibrio parahaemolyticus, the expression levels of all MrRabs in the hepatopancreas were also upregulated, which might indicated the involvement of MrRabs in prawns antibacterial immunity. In all, these preliminary results showed that MrRabs were involved in innate immunity of M. rosenbergii. PMID- 25542379 TI - Evaluation of paraprobiotic applicability of Lactobacillus plantarum in improving the immune response and disease protection in giant freshwater prawn, Macrobrachium rosenbergii (de Man, 1879). AB - Paraprobiotics, also known as ghost probiotics, are non-viable microbial cells which, when administered in adequate amounts, confer a benefit on the host. However, the advantage of non-viable microbes over their viable counterparts is a much debated topic in aquaculture. Therefore, the present study was conducted to evaluate paraprobiotic effect of heat-killed Lactobacillus plantarum on giant freshwater prawn Macrobrachium rosenbergii. A 90-day feeding trial was conducted by feeding prawn juveniles (mean weight +/- SE: 0.54 +/- 0.03 g) with three experimental diets prepared by supplementing basal diet (Crude protein: 38%; Gross energy: 387 kcal 100 g(-1)) with different concentrations of heat-killed probiotics bacteria viz. HKPB1 (10(7) cfu g(-1) diet), HKPB2 (10(8) cfu g(-1) diet), HKPB3 (10(9) cfu g(-1) diet) and control diet (unsupplemented diet). In the present study, growth parameters viz. WG % and SGR and feed utilization parameters viz. FCE, FCR and PER, though improved marginally in all experimental groups, were found to be insignificant (P > 0.05) compared to the control. The immune parameters viz. total hemocyte count (THC), phenol oxidase (PO) activity, respiratory burst (RB) activity and clearance efficiency were significantly improved (P < 0.05) with concurrent decrease (P < 0.05) in cumulative mortality against Aeromonas hydrophila challenge in all the experimental groups except for HKPB1, where PO and RB activity did not improve significantly (P > 0.05) compared to the control. Among the experimental groups, though the improvement in immune parameters was higher (P < 0.05) in HKPB2 and HKPB3 compared to HKPB1 and the control, no significant difference (P > 0.05) was observed between HKPB2 and HKPB3. The results obtained from the present study indicate that the application of heat-killed L. plantarum at a concentration of 10(8) cfu g(-1) diet, though not effective in augmenting the growth and feed utilization parameters, can significantly improve immune parameters and disease resistance of M. rosenbergii in the laboratory condition. PMID- 25542380 TI - Comparative genomic of the BAFF and BAFF-like genes and immune response to bacteria of miiuy croaker (Miichthys miiuy). AB - As a member of the tumor necrosis factor (TNF) family, B cell activating factor (BAFF), also known as TNF ligand superfamily member 13B (TNF13B), playing a critical role in enhancing immune responses. BAFF is a central cytokine for B cell survival, proliferation, maturation and immunoglobulin secretion. In the present study, we describe the identification of the miiuy croaker BAFF (designed MmBAFF) and BAFF-like (designed MmBAFF-like) genes. The cDNA of MmBAFF contains an open reading frame (ORF) of 795 nucleotides that are translated into a predicted 264 amino acids. The ORF of MmBAFF-like consists of 705 bases encoding 234 amino acids. Amino acid sequence comparison indicated that MmBAFF and MmBAFF like possessed the TNF signatures, a predicted transmembrane domain, three conserved cysteine residues and a putative furin protease cleavage site, which were the typical characteristics of TNF gene in mammals and birds. The predicted three-dimensional (3D) structure of the MmBAFF and MmBAFF-like monomer analyzed by comparative protein modeling revealed that they were very similar to human counterpart. Comparative genomic analysis revealed that the locations of MmBAFF and MmBAFF-like genes are conserved among the bony fish. Phylogenetic analysis shows the MmBAFF is most closely related to other teleost BAFFs with the highest similarity to Epinephelus awoara. And BAFF-like cluster get together first to BAFF cluster than three closely related TNF superfamily (TNFSF) members. Real time quantitative PCR analysis shows the MmBAFF and MmBAFF-like transcripts are expressed in a wide range of tissues with the highest expression in skin and lymphoid tissue spleen. Upon induction by Vibrio anguillarum, their expressions are significantly upregulated in liver, spleen and kidney as compared to phosphate-buffered saline injected control fish. The association of increased BAFF expression after bacterial infection suggests that it plays a potentially important role in immune system of fish. PMID- 25542381 TI - Preliminary study on expression of antimicrobial peptides in European sea bass (Dicentrarchus labrax) following in vivo infection with Vibrio anguillarum. A time course experiment. AB - Antimicrobial polypeptides (AMPPs) are humoral components of the vertebrates and invertebrates innate immune system. Their potent broad spectrum antimicrobial activities have drawn the attention of the scientific community to their potential use not only as an alternative to antibiotics but also as functional targets for immunostimulants in order to enhance the host immunity. Fish synthesize a great number of these peptides but in European sea bass, an important fish species in the Mediterranean aquaculture, only a few AMPPs have been studied and these surveys have highlighted their functional role as predictive markers of stressful conditions. Many aspects concerning AMPP mode of action in the host during bacterial infections are still unknown. In this work a 72 h time course experiment, performed on juvenile sea bass intraperitoneally (i.p.) injected with a sub-lethal dose of Vibrio anguillarum, was aimed to investigate the mRNA expression of four specific AMPP genes and interleukin-1beta (IL-1beta) in skin, gills, spleen, and head kidney. AMPP genes were: dicentracin (DIC), histone-like protein 1 (HLP-1), histone-like protein 2 (HLP-2) and hemoglobin-like protein (Hb-LP). The delta-delta C(T) method in real-time RT-PCR allowed to gain more knowledge about temporal dynamics, preferential sites of expression as well as immunological and physiological role of these molecular markers. DIC was significantly up-regulated mainly in head kidney at 1.5-3 h post infection (p.i.). HLP-1 showed an extended-time overexpression in gills and a significant up-regulation in spleen. HLP-2 was interestingly overexpressed in gills at 24 h p.i., while Hb-LP showed a significant up-regulation in skin for all the 72 h trial as well as lower but always significant values either in gills or in spleen. Different was the response of IL-1beta that showed a dramatic up regulation in spleen and head kidney at 8 h p.i. whilst in gills it displayed a severe inhibition. During this survey the i.p. stimulus surely conditioned the AMPP expression in skin and gills, especially as regards the DIC that as piscidin related gene has an important defensive role in the mucosal tissues. However, two unconventional AMPP genes such as HLP-2 and Hb-LP, strictly related to the physiological mechanisms of fish, were less affected in terms of expression by the route of infection, being more evident in peripheral loci. These findings might suggest them as potential markers to be analyzed within plans of health survey in fish farms. PMID- 25542382 TI - Mitochondrial peroxiredoxin 3 (Prx3) from rock bream (Oplegnathus fasciatus): immune responses and role of recombinant Prx3 in protecting cells from hydrogen peroxide induced oxidative stress. AB - Pathogenic infections and environmental factors cause a variety of stresses in fish including oxidative stress by rapid elevation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Transcriptional activation and expression of antioxidant enzymes are essential for reducing the oxidative stress. In this study, we present the molecular characterization, immune responses and ROS scavenging activity of mitochondrial peroxiredoxin 3 from Oplegnathus fasciatus (RbPrx3). Coding sequence (CDS) of RbPrx3 contains 248 amino acids polypeptide which consists of highly conserved peroxiredoxin super family domain and two cysteine residues. Pairwise sequence comparison revealed that RbPrx3 has the greatest identity (94.8%) to Sparus aurata Prx3. Transcriptional analysis of RbPrx3 indicated the ubiquitously expressed mRNA in wide array of organs showing the highest expression in the liver of rock bream. Upon immune challenge of Edwardsiella tarda, Streptococcus iniae, rock bream iridovirus (RBIV) and lipopolysaccharide (LPS), RbPrx3 mRNA level was up regulated in immunocompetent liver tissues compared to unchallenged fish. Purified recombinant RbPrx3 treated THP-1 cells showed higher survival rate against H(2)O(2) induced oxidative stress and significantly reduced the level of intracellular ROS. Overall results from our study suggest that RbPrx3 may be involved in broader functions such as regulating oxidative stresses by scavenging ROS and activating immune responses in rock bream. PMID- 25542384 TI - Development and validation of a risk prediction model for tracheostomy in acute traumatic cervical spinal cord injury patients. AB - PURPOSE: Tracheostomy may become indispensable for patients with acute traumatic cervical spinal cord injuries. However, the early prediction of a tracheostomy is often difficult. Previous prediction models using the pulmonary function test (PFT) have limitations because some severely injured patients could not provide acceptable PFT results. We aim to develop an alternative model for predicting tracheostomy using accessible data obtained from the bedside. METHOD: Clinical, neurological and radiological data from 345 consecutive patients with acute tetraplegia were retrospectively reviewed. We applied multiple logistic regression analysis (MLRA) and classification and regression tree (CART) analysis to develop the prediction model for tracheostomy. By train-test cross-validation, we used the sensitivity, specificity, area under the receiver operating characteristics curve (AUC) and correction rate to evaluate the performance of these models. RESULTS: According to the American Spinal Injury Association (ASIA) standards, an admission ASIA motor score (AAMS) <= 22, ASIA grade A and presence of respiratory complications were identified as independent predictors of tracheostomy by both models. The model derived by CART suggested that the highest signal change (HSC) in the spinal cord on magnetic resonance imaging (MRI) also affected a patient's requirement for a tracheostomy, while MLRA demonstrated that tracheostomy was also influenced by the presence of an ASIA grade B injury. The CART model had a sensitivity of 73.7%, specificity of 89.7%, AUC of 0.909 and overall correction rate of 87.3%. The sensitivity, specificity, AUC and correction rate of the MLRA model were 81.8, 86.4, 0.889 and 85.7%, respectively. CONCLUSIONS: We suggest using the CART model in clinical applications. Patients with AAMS <= 1 exhibit an increased likelihood of requiring a tracheostomy. For patients with an AAMS in the range of 2-22, surgeons should consider giving these patients a tracheostomy once respiratory complications occur. Surgeons should be cautious to give a tracheostomy to patients with an AAMS >= 23, if the patient experiences an incomplete spinal cord injury and the HSC in the spinal cord is at C3 level or lower based on MRI. For other patients, close observation is necessary; generally, patients with complete SCI might require a tracheostomy more frequently. PMID- 25542383 TI - Complications, secondary interventions and long term morbidity after en bloc sacrectomy. AB - PURPOSE: En bloc sacrectomy is a demanding surgical procedure to remove tumors from the sacrum. Comprehensive data on readmissions for complications endured months to years after initial discharge are scant. The purpose of this study is to present the long-term complications, readmissions and secondary interventions for patients having undergone en bloc sacrectomy. METHODS: Patients were included if en bloc sacrectomy and follow-up were conducted in the authors institution. Correspondence from all specialties involved in the treatment of patients was retrieved. Predefined parameters were scored and assigned to five distinct phases: diagnostic phase; surgery; postoperative period to 1 year after surgery; second year after surgery until follow-up and last follow-up. RESULTS: Sixteen patients underwent anterior-posterior en bloc sacrectomy for a locally aggressive tumor (n=2); malignant tumor (n=13) or solitary metastasis (n=1). The type of resection was low (n=1); middle (n=3); high (n=4); total (n=3) and hemisacrectomy (n=5). The median surgical duration was 12.7 h and median blood lost was 12 l. A total of 73 major complications (average per patient 5; median 4; range 0-12) were recorded and 73 secondary interventions (average per patient 5; median 5; range 0-11) were performed in the first year postsurgery. From the second year until follow-up complications and secondary interventions markedly decreased. At final follow-up (65-266 months), considerable morbidity was found for the eleven patients still alive. CONCLUSIONS: En bloc sacrectomy is a procedure with a high rate of major complications, regardless of tumor histology, often necessitating readmissions and secondary interventions. Long-term survival is associated with considerable morbidity and extensive preoperative counseling should be conducted to discuss the risks and outcome of the procedure. PMID- 25542385 TI - Revision surgery for spinal tuberculosis with secondary deformity after treatment with debridement, instrumentation, and fusion. AB - PURPOSE: To discuss the cause and clinical efficacy of revision surgery for secondary deformity after treatment of spinal tuberculosis with debridement, instrumentation, and fusion. METHODS: From September 2007 to March 2013, 15 patients with postoperative secondary deformity after treatment of spinal tuberculosis were enrolled. Constitutional symptoms, laboratory findings, and radiographic evidence were used to evaluate the secondary deformity conditions and diagnose the recurrence of spinal tuberculosis. All patients underwent revision surgery. The clinical and radiographic data from before and after previous surgery, before and after revision surgery, and after a minimum follow up of 9 months were retrospectively reviewed. RESULTS: Among 15 cases of secondary deformity, there were 8 recurrences of spinal tuberculosis. Anterior instrumentation was used in 9 patients, and posterior instrumentation in 6. Regarding previous surgery, the mean number of involved segments was 2 vertebral bodies; a mean of 4 vertebral bodies were fused; the mean preoperative scoliosis of 14.5 degrees was corrected to 6.5 degrees (52.08 % correction); the mean preoperative kyphosis of 56.4 degrees was corrected to 28.9 degrees (44.8 % correction). Before revision surgery, the mean kyphotic angle increased to 58.6 degrees and the mean scoliosis angle increased to 19.6 degrees . New deformity occurred at the primary levels in 11 patients and at the level adjacent to fused segments in 4. After revision surgery, a mean of 8 vertebral bodies were fused; at final follow-up, the mean kyphotic angle was corrected to 26.7 degrees and the mean scoliosis angle was corrected to 2.4 degrees . No neurologic complications were observed during or after revision surgery. No complications with instrumentation and recurrence of spinal tuberculosis were found at final follow-up. CONCLUSIONS: Recurrence of spinal tuberculosis, incorrect choice of internal fixation strategy, unsuitable fused segments, and poor achievement of sagittal and coronal balance after surgery may lead to secondary deformity postoperatively. Good clinical outcomes were obtained by revision surgery to extend the fused segments, albeit with decreased spinal range of motion. PMID- 25542387 TI - Are scalar implicatures automatically processed and different for each individual? A mismatch negativity (MMN) study. AB - Scalar implicatures are ordinarily activated in human communication when the speaker uses a weak expression (e.g., some) from a set of stronger alternatives (e.g., many, all). It has been debated whether scalar inferences are generated by default. To clarify this issue and examine whether individual pragmatic ability will affect the mechanism of scalar inference processing, we performed experiment with an MMN paradigm to capture the neurophysiological indicators of automatic processing of spoken sentences and divided participants into high and low pragmatic ability groups. Experimental results showed that compared with the condition that an informative sentence ("Some animals have tails") is the deviant stimuli, when an underinformative sentence ("Some tigers have tails") is the deviant stimuli, the high pragmatic ability group induced mismatch negativity (MMN) and sustained negativity, while the low pragmatic ability group had no ERP effects. These results indicated that at least some people can automatically activate the scalar implicatures when encountering scalar trigger words, even in the inattentive status. PMID- 25542390 TI - Nucleophilic and electrophilic double aroylation of chalcones with benzils promoted by the dimsyl anion as a route to all carbon tetrasubstituted olefins. AB - Dimsyl anion promoted the polarity reversal of benzils in a Stetter-like reaction with chalcones to give 2-benzoyl-1,4-diones (double aroylation products), which, in turn, were converted into the corresponding tetrasubstituted olefins via aerobic oxidative dehydrogenation catalyzed by Cu(OAc)2. PMID- 25542388 TI - Modulatory potential of alpha-amyrin against hepatic oxidative stress through antioxidant status in Wistar albino rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: alpha-Amyrin (a pentacyclic triterpene widely distributed in nature and isolated from a variety of plant sources and pharmacologically shown a wide spectrum of activity including anti-inflammatory, anti-ulcer, anti-hyperlipidemic, anti-tumor, and hepatoprotective actions) explored as hepatomodulator from the ethanol extract of the stem bark of Alstonia scholaris Linn. against CCl4-induced hepatic oxidative stress through antioxidant status in wistar albino rats. MATERIALS AND METHODS: Experimental rats, hepato oxidatively stressed by CCl4 (0.2 ml/kg b wt/twice a week, intra-peritoneally), were concurrently received alpha-amyrin (20mg/kg body weight/day, orally) for 30 consecutive days. Hepatomodulatory potential was assessed by using the serum- markers like gamma-glutamyl transpeptidase (GGT), aspartate and alanine transaminases (AST, ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), acid phosphatase (ACP), sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GDH), and total bilirubin, total protein, glutathione reduced (GSH), ceruloplasmin, beta-carotene, vitamin C and vitamin E in serum concomitantly with the hepatic-antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s-transferase (GST), and 5'-nucleotidase, acid ribonuclease, glucose 6-phosphatase, succinic dehydrogenase and cytochrome-P-450 in liver tissue whereas lipid peroxidation (LPO) was estimated in both serum and liver contents. RESULTS: The assessment of all biochemical parameters registered a significant (P<0.001) hepatic oxidative stress in CCl4 treated rats, which was considerably recovered near to almost normal level in rats co-administered with alpha-amyrin at the dose level of 20mg/kg body weight/day for 30 consecutive days. The histoarchitectural examination of liver sections from treated groups further corroborated the hepatomodulatory potential of alpha-amyrin and compared with standard drug-silymarin. CONCLUSIONS: These findings indicate that the modulatory potential of alpha-amyrin against hepatic oxidative stress possibly involve mechanism related to its ability to block the P-450 mediated CCl4 bioactivation through selective inhibitors of ROS (reactive oxygen species) as antioxidants brought about significant inhibition of the formation of LPO suggesting possible involvement of O2(?-), HO2, HO2(?-), H2O2 and *OH. Therefore this study suggests that the use of alpha-amyrin as a hepatomodulatory potent to feasibility for a promising liver curative drug. PMID- 25542386 TI - Neurosteroid effects at alpha4betadelta GABAA receptors alter spatial learning and synaptic plasticity in CA1 hippocampus across the estrous cycle of the mouse. AB - Fluctuations in circulating levels of ovarian hormones have been shown to regulate cognition (Sherwin and Grigorova, 2011. Fertil. Steril. 96, 399-403; Shumaker et al., 2004. JAMA. 291, 2947-2958), but increases in estradiol on the day of proestrus yield diverse outcomes: In vivo induction of long-term potentiation (LTP), a model of learning, is reduced in the morning, but optimal in the afternoon (Warren et al., 1995. Brain Res. 703, 26-30). The mechanism underlying this discrepancy is not known. Here, we show that impairments in both CA1 hippocampal LTP and spatial learning observed on the morning of proestrus are due to increased dendritic expression of alpha4betadelta GABAA receptors (GABARs) on CA1 pyramidal cells, as assessed by electron microscopic (EM) techniques, compared with estrus and diestrus. LTP induction and spatial learning were robust, however, when assessed on the morning of proestrus in alpha4-/- mice, implicating these receptors in mediating impaired plasticity. Although alpha4betadelta expression remained elevated on the afternoon of proestrus, increases in 3alpha-OH-THP (3alpha-OH-5alpha-pregnan-20-one) decreased inhibition by reducing outward current through alpha4betadelta GABARs (Shen et al., 2007. Nat. Neurosci. 10, 469-477), in contrast to the usual effect of this steroid to enhance inhibition. Proestrous levels of 3alpha-OH-THP reversed the deficits in LTP and spatial learning, an effect prevented by the inactive metabolite 3beta-OH THP (10 mg/kg, i.p.), which antagonizes actions of 3alpha-OH-THP. In contrast, administration of 3alpha-OH-THP (10 mg/kg, i.p.) on the morning of proestrus improved spatial learning scores 150-300%. These findings suggest that cyclic fluctuations in ovarian steroids can induce changes in cognition via alpha4betadelta GABARs that are dependent upon 3alpha-OH-THP. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25542391 TI - Femoral intercondylar notch width size: a comparison between siblings with and without anterior cruciate ligament injuries. AB - PURPOSE: Anterior cruciate ligament (ACL) injuries in siblings are commonly observed in the clinic. One, possibly genetic, factor contributing to the pathogenesis of sibling injuries may be narrow intercondylar notches, which are well recognized as predisposing to ACL injury. This study aimed primarily to: (1) assess the incidence of ACL injuries in siblings within an existing study cohort, (2) compare intercondylar notch width size in injured compared to matched uninjured control siblings and (3) compare the number of injured versus control sibling pairs sharing a narrow notch. METHODS: Twenty-four ACL-injured siblings from 10 families were matched for age, gender, family composition and sports activity, with 24 uninjured siblings from another 10 families. Intercondylar radiographs were taken to calculate anterior and posterior notch width indices (NWI). Notch size and the number of narrow notches in sibling pairs were compared between groups. RESULTS: Thirteen of 72 ACL-study participants had siblings with torn ACLs. Mean anterior NWI was 0.18 and 0.24 (p < 0.001), and mean posterior NWI was 0.26 and 0.3 (p = 0.006) for injured and uninjured siblings, respectively. Sixty percent of injured sibling pairs shared a narrow notch, while no uninjured sibling pairs did so (p = 0.003). CONCLUSION: This study showed that siblings (and often sibling pairs) with injuries do have significantly narrower notches than those without. This could partly explain the prevalence of ACL injuries in siblings. To reduce ACL-injury rates, we advise that siblings of ACL injured athletes with narrow notches, be radiologically screened, and if necessary, cautioned and counselled regarding preventative training. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 25542392 TI - A Mediterranean-style diet and left ventricular mass (from the Northern Manhattan Study). AB - One mechanism linking diet, specifically the Mediterranean-style diet (DT), with cardiovascular disease prevention may be an association between a DT and left ventricular (LV) mass. However, there are little data on this relation. We hypothesized that adherence to a DT would be inversely associated with LV mass in the multiethnic population-based Northern Manhattan Study. The study included 1,937 participants with diet assessments and LV mass measured using echocardiography (mean age 67 +/- 9 years, 39% male, 58% Hispanic, 20% white, 20% black). A DT adherence score (range 0 to 9, 9 representing maximal adherence) was examined continuously and categorically (score 6 to 9 representing the top quartile vs 0 to 5). Multivariable-adjusted linear regression models were constructed to examine the cross-sectional association between a DT and LV mass. An inverse association was observed between the DT score and LV mass. In a model controlling for demographics, behavioral risk factors, diabetes, and blood pressure variables, LV mass was 1.98 g lesser for each 1-point greater DT score, and those with scores of 6 to 9 had an average LV mass that was 7.30 g less than those with scores of 0 to 5. The association was attenuated but remained statistically significant after additionally adjusting for body mass index. Results were similar when LV mass was corrected for height (LV mass). In conclusion, greater adherence to a DT is associated with decreased LV mass, an important risk factor for cardiovascular disease, and this association may be partly mediated by obesity. The association with LV mass may be involved in the protective effect of a DT on clinical vascular outcomes. PMID- 25542393 TI - Incidence and impact of totally occluded culprit coronary arteries in patients presenting with non-ST-segment elevation myocardial infarction. AB - The accuracy of the 12-lead electrocardiogram in detecting coronary artery occlusion is limited. We sought to determine the incidence, distribution, and outcomes of patients who have total occlusion of the culprit artery but present with non-ST-segment elevation myocardial infarction (NSTEMI). The randomized Acute Catheterization and Urgent Intervention Triage Strategy trial enrolled 13,819 patients presenting with non-ST-segment elevation acute coronary syndromes who underwent an early invasive strategy. The present study includes 1,319 patients with baseline biomarker elevation (NSTEMI) and no history of coronary artery bypass graft who underwent percutaneous coronary intervention of a single culprit vessel. We compared the baseline characteristics and outcomes according to whether the culprit vessel was occluded (baseline Thrombolysis In Myocardial Infarction [TIMI] 0 to 1) or patent (TIMI 2 to 3 flow) by angiographic core laboratory assessment. TIMI 0 to 1 flow in the culprit artery was present in 262 of 1,319 (19.9%) patients. The incidence of coronary occlusion was 28.4%, 19.3%, and 12.6% in patients with NSTEMI because of right coronary, left circumflex, and left anterior descending artery disease, respectively. Patients with an occluded culprit artery were more commonly men and had ST-segment deviation >=1 mm. One year outcomes, including death (3.5% vs 3.0%, p = 0.68) and myocardial infarction (8.4% vs 9.6%, p = 0.47), did not differ significantly between patients with versus without occluded culprit arteries, respectively. In conclusion, the present study demonstrates that the culprit artery is totally occluded in approximately 1 in 5 patients presenting with NSTEMI and single-vessel disease; however, the presence of total occlusion in NSTEMI was not associated with an incremental hazard of death or reinfarction at 1 year. PMID- 25542394 TI - Determinants of discrepancies in detection and comparison of the prognostic significance of left ventricular hypertrophy by electrocardiogram and cardiac magnetic resonance imaging. AB - Despite the low sensitivity of the electrocardiogram (ECG) in detecting left ventricular hypertrophy (LVH), ECG-LVH is known to be a strong predictor of cardiovascular risk. Understanding reasons for the discrepancies in detection of LVH by ECG versus imaging could help improve the diagnostic ability of ECG. We examined factors associated with false-positive and false-negative ECG-LVH, using cardiac magnetic resonance imaging (MRI) as the gold standard. We also compared the prognostic significance of ECG-LVH and MRI-LVH as predictors of cardiovascular events. This analysis included 4,748 participants (mean age 61.9 years, 53.5% females, 61.7% nonwhites). Logistic regression with stepwise selection was used to identify factors associated with false-positive (n = 208) and false-negative (n = 387), compared with true-positive (n = 208) and true negative (n = 4,041) ECG-LVH, respectively. A false-negative ECG-LVH status was associated with increased odds of Hispanic race/ethnicity, current smoking, hypertension, increased systolic blood pressure, prolongation of QRS duration, and higher body mass index and with lower odds of increased ejection fraction (model-generalized R(2) = 0.20). A false-positive ECG-LVH status was associated with lower odds of black race, Hispanic race/ethnicity, minor ST-T abnormalities, increased systolic blood pressure, and presence of any major electrocardiographic abnormalities (model-generalized R(2) = 0.29). Both ECG-LVH and MRI-LVH were associated with an increased risk of cardiovascular disease events (hazard ratio 1.51, 95% confidence interval 1.03 to 2.20 and hazard ratio 1.81, 95% confidence interval 1.33 to 2.46, respectively). In conclusion, discrepancy in LVH detection by ECG and MRI can be relatively improved by considering certain participant characteristics. Discrepancy in diagnostic performance, yet agreement on predictive ability, suggests that LVH by ECG and LVH by imaging are likely to be two distinct but somehow related phenotypes. PMID- 25542395 TI - Development and external validation of nomograms predicting disease-free and cancer-specific survival after radical cystectomy. AB - PURPOSE: To develop two nomograms predicting disease-free survival (DFS) and cancer-specific survival (CSS) and to externally validate them in multiple series. METHODS: Prospectively collected data from a single-centre series of 818 consecutive patients who underwent RC and PLND were used to build the nomogram. External validation was performed in 3,173 patients from 7 centres worldwide. Time to recurrence and to cancer-specific death were addressed with univariable and multivariable analyses. Nomograms were built to predict 2-, 5- and 8-year DFS and CSS probabilities. Predictive accuracy was quantified using the concordance index. RESULTS: Age, pathologic T stage, lymph-node density and extent of PLND were independent predictors of DFS and CSS (p < 0.05). Discrimination accuracies for DFS and CSS at 2, 5 and 8 years were 0.81, 0.8, 0.79 and 0.82, 0.81, 0.8, respectively, with a slight overestimation at calibration plots beyond 24 months. In the external series, predictive accuracies for DFS and CSS at 2, 5 and 8 years were 0.83, 0.82, 0.82 and 0.85, 0.85, 0.83 for European centres; 0.73, 0.72, 0.71 and 0.80, 0.74, 0.68 for African series; 0.76, 0.74, 0.71 and 0.79, 0.76, 0.73 for American series. CONCLUSIONS: These nomograms developed from a contemporary series are simple clinical tools and provide optimal oncologic outcome prediction in all external cohorts. PMID- 25542396 TI - Stabilization of microtubules by taxane diterpenoids: insight from docking and MD simulations. AB - Microtubules are formed from the molecules of tubulin, whose dynamics is important for many functions in a cell, the most dramatic of which is mitosis. Taxol is known to interact within a specific site on tubulin and also believed to block cell-cycle progression during mitosis by binding to and stabilizing microtubules. Along with the tremendous potential that taxol has shown as an anticancer drug, clinical problems exist with solubility, toxicity, and development of drug resistance. The crystal structure of taxane diterpenoids, namely, 10, 13-deacetyl-abeo-baccatin-IV (I), 5-acetyl-2-deacetoxydecinnamoyl taxinine-0.29hydrate (II), 7, 9-dideacetyltaxayuntin (III), and Taxawallin-K (IV), are very similar to the taxol molecule. Considerable attention has been given to such molecules whose archetype is taxol but do not posses long aliphatic chains, to be developed as a substitute for taxol with fewer side effects. In the present work, the molecular docking of these taxane diterpenoids has been carried out with the tubulin alpha-beta dimer (1TUB) and refined microtubule structure (1JFF) using Glide-XP, in order to assess the potential of tubulin binding of these cytotoxic agents. Results show that all the ligands dock into the classical taxol binding site of tubulin. Taxol shows the best binding capabilities. On the basis of docking energy and interactions, apart from taxol, molecule II has a better tendency of binding with 1TUB while molecule I shows better binding capability with bovine tubulin 1JFF. To validate the binding capabilities, molecular dynamics (MD) simulations of the best docked complexes of ligands with 1JFF have been carried out for 15.0 ns using DESMOND. Average RMSD variations and time line study of interactions and contacts indicate that these complexes remain stable during the course of the dynamics. However, taxol and molecule II prevail over other taxoids. PMID- 25542397 TI - Reference values for standardized tests of walking speed and distance: a systematic review. AB - OBJECTIVE: To provide an overview of the reference values and methodology used to obtain them for time- and distance-limited walk tests. METHODS: We performed a systematic review and searched PubMed, MEDLINE (Ovid), EMBASE, CINAHL, Scopus, PEDro, and The Cochrane Library from 1946 to May 2013. Full-text peer-reviewed articles written in English, French or Spanish were considered eligible. Two authors independently screened titles and abstracts. One author determined eligibility of full-text articles, appraised methodological quality, and extracted data. A second author independently verified the accuracy of extracted data. RESULTS: Of the 41 eligible studies reviewed, 25 failed to describe the method used to select participants and 10 had an inadequate sample size. Twenty five studies provided reference values for one time-limited walk test (6-min walk test (6 MWT)) and 18 studies provided reference values for 15 distance-limited walk tests. Across studies, walk test distances ranged from 3m to 40m. Descriptive values and reference equations for the 6 MWT were reported in 15 and 20 studies, respectively. Across 43 regression equations (median R(2)=0.46), age (98%) and sex (91%) were most frequently included. The equation yielding the maximum R(2) value (0.78) included age, height, weight and percentage of predicted maximum heart rate. Among six unique regression equations for distance limited walk tests (median R(2)=0.17), sex (83%), age (67%) and weight (67%) were most frequently included. The equation yielding the maximum R(2) value (0.25) included age and sex. CONCLUSIONS: Reference values reported for these tests provide a basis for classifying walking capacity as within normal limits, determining the magnitude of deficit, educating clients, setting rehabilitation goals, and planning studies. PMID- 25542398 TI - The effect of angle and moment of the hip and knee joint on iliotibial band hardness. AB - Although several studies have described kinematic deviations such as excessive hip adduction in patients with iliotibial band (ITB) syndrome, the factors contributing to increased ITB hardness remains undetermined, owing to lack of direct in vivo measurement. The purpose of this study was to clarify the factors contributing to an increase in ITB hardness by comparing the ITB hardness between the conditions in which the angle, moment, and muscle activity of the hip and knee joint are changed. Sixteen healthy individuals performed the one-leg standing under five conditions in which the pelvic and trunk inclination were changed in the frontal plane. The shear elastic modulus in the ITB was measured as an indicator of the ITB hardness using shear wave elastography. The three dimensional joint angle and external joint moment in the hip and knee joints, and muscle activities of the gluteus maximus, gluteus medius, tensor fasciae latae, and vastus lateralis, which anatomically connect to the ITB, were also measured. ITB hardness was significantly increased in the posture with pelvic and trunk inclination toward the contralateral side of the standing leg compared with that in all other conditions (increase of approximately 32% compared with that during normal one-leg standing). This posture increased both the hip adduction angle and external adduction moment at the hip and knee joint, although muscle activities were not increased. Our findings suggest that coexistence of an increased adduction moment at the hip and knee joints with an excessive hip adduction angle lead to an increase in ITB hardness. PMID- 25542399 TI - Visual feedback of the centre of gravity to optimize standing balance. AB - Force platform biofeedback training, whereby concurrent visual feedback of the centre of pressure (COP) is provided, has previously been used for balance training. Since the goal of balance is to maintain control of the centre of gravity (COG), specific feedback of the COG may be more likely than COP feedback to improve overall balance control. The purpose of this study was to compare the effect of concurrent visual feedback of the COP versus COG on postural control during a novel quiet standing task. Thirty-two young healthy adults (20-35 years old) were recruited. Participants were randomly assigned to receive concurrent visual feedback of either the COP or COG while standing on a foam pad. Training occurred over one session (20-30-second trials). Retention and transfer testing (i.e. without concurrent visual feedback) occurred after ~24h. Variability of the COG decreased, variability of COP-COG increased, and sample entropy increased with concurrent visual feedback. With practice, variability of COP, COG and COP COG decreased whereas sample entropy increased. The decrease in variability of COP-COG was greater for those who received COG feedback than those who received COP feedback. Training effects on COP, COG and COP-COG variability were not retained after 24h and removal of visual feedback. However, on retention and transfer testing, sample entropy was significantly higher than on baseline testing, indicating more 'automatic' postural control. These results suggest that concurrent visual feedback of neither the COP nor COG is superior for improving quiet standing balance control. PMID- 25542400 TI - A retrospective study to evaluate single agent methotrexate treatment in low risk gestational choriocarcinoma in the United Kingdom. AB - OBJECTIVE: To determine whether single agent chemotherapy with intramuscular methotrexate 50mg administered on days 1, 3, 5, and 7 and oral folinic acid 15mg administered on days 2, 4, 6, and 8 in 2 weekly cycles (IM MTX/FA) is an effective treatment regimen for patients with low risk gestational choriocarcinoma. METHOD: Electronic databases were searched to identify patients with gestational choriocarcinoma at the Sheffield and Charing Cross supra regional trophoblastic disease centres from January 2000 to December 2011. Clinical notes of low risk patients with FIGO score 0-6 were retrospectively reviewed to assess treatment outcomes and subsequent relapse. RESULTS: 65 patients were identified with low risk choriocarcinoma. Serum hCG levels normalised in 24 patients without the requirement of chemotherapy (19 with histological confirmation, 4 highly suspicious histology and 1 clinical diagnosis). Of 23 patients with histologically confirmed choriocarcinoma, 8 (35%) had a sustained complete response to IM MTX/FA and did not relapse. Both patients with FIGO score 6, and 1 patient with FIGO stage III metastatic disease developed resistance to IM MTX/FA and required further treatment. Despite the development of drug resistance or relapse all patients were successfully salvaged by subsequent treatments. CONCLUSIONS: Not all patients with low risk choriocarcinoma that have had primary intervention prior to staging, such as surgical resection or uterine evacuation will require chemotherapy, providing hCG levels continue to decline to normal. Low risk (FIGO 0-5) patients should initially receive IM MTX/FA due to its low toxicity, outpatient administration and reasonable efficacy. Patients with FIGO score 6 or FIGO stage III disease should make an informed choice between IM MTX/FA and combination chemotherapy. PMID- 25542401 TI - Pleural invasion by peripheral lung cancer: prediction with three-dimensional CT. AB - RATIONALE AND OBJECTIVES: To evaluate the clinical utility of three-dimensional (3D) computed tomography (CT) for predicting pleural invasion by peripheral lung cancer. MATERIALS AND METHODS: CT findings (tumor size, vertical diameter, length and area of the interface between tumor and the pleura, ratios of length and area [Rarea] of interface between tumor and the pleura to tumor size, angle between the tumor and adjacent pleura, presence or absence of pleural thickening, and originally developed 3D pleural patterns) in 201 consecutive patients with lung cancer of <=3 cm in contact with pleural surface were correlated with pathologic findings. Logistic modeling was used for determining the significant factors for prediction of pleural invasion, and receiver operating characteristic (ROC) curves were used for investigating diagnostic capability of significant factors, resulting in a recommendation to the optimal criteria for predicting pleural invasion and to the optimal threshold for differentiating parietal from visceral invasion. RESULTS: Sixty-one (30%) of the 201 patients had pathologically verified pleural invasion. Logistic modeling revealed that the 3D pleural pattern was the only significant factor (P < .001; relative risk of 7.34). Among every combination of the 3D patterns, skirt-like pattern showed the highest accuracy of 77% for predicting pleural invasion. In differentiating parietal from visceral pleural invasion, ROC analysis revealed that Rarea was optimal for differentiating parietal from visceral pleural invasion, and the highest accuracy of 77% was obtained with a cut-off value of 13.4 for this criterion. CONCLUSIONS: Computer-aided 3D CT analysis of the pleura was useful for predicting pleural invasion. PMID- 25542403 TI - Introduction: Toxicological assessment of kretek cigarettes. PMID- 25542402 TI - Potential method for gas production: high temperature co-pyrolysis of lignite and sewage sludge with vacuum reactor and long contact time. AB - Lignite and sewage sludge were co-pyrolyzed in a vacuum reactor with high temperature (900 degrees C) and long contact time (more than 2h). Beneficial synergetic effect on gas yield was clearly observed. Gas yield of blend fuel was evidently higher than that of both parent fuels. The gas volume yield, gas lower heating value (LHV), fixed carbon conversion and H2/CO ratio were 1.42 Nm(3)/kg(blend fuel), 10.57 MJ/Nm(3), 96.64% and 0.88% respectively, which indicated this new method a feasible one for gas production. It was possible that sewage sludge acted as gasification agents (CO2 and H2O) and catalyst (alkali and alkaline earth metals) provider during co-pyrolysis, promoting CO2-char and H2O char gasification which, as a result, invited the improvement of gas volume yield, gas lower heating value and fixed carbon conversion. PMID- 25542404 TI - Transcollation(r) technique in the thoracoscopic treatment of primary spontaneous pneumothorax. AB - OBJECTIVES: The already low invasiveness of the thoracoscopic treatment of spontaneous pneumothorax may be further reduced by the transcollation(r) technique. Herein, we report our further experience with a new device, to coagulate blebs and bullae, compared with contrast to endostapler resection. METHODS: Data of patients with recurrent or persistent spontaneous pneumothorax, who underwent thoracoscopic treatment, were prospectively collected and reviewed. Those with blebs or bullae (Stages III and IV in accordance with Vanderschueren's classification) were treated with a new device, based on coupling saline solution perfusion with radiofrequency energy. The combination of fluid with radiofrequency allows the sealing of tissue, avoiding charring or burning. Most operations were performed through two 1-cm incisions only. RESULTS: From 2005 to 2010, 73 patients were treated. These were 59 males (80.8%) and 14 females (19.2%), with a mean age of 27.9 years [standard deviation (SD): 11.7]. Forty three patients underwent general anaesthesia with selective intubation, 9 awake epidural anaesthesia and 21 spontaneous breathing anaesthesia with laryngeal mask. The mean operation time was 31 min (SD: 10.2). The median postoperative drainage period and hospital stay were 2 days (range of 1-11) and 3 days (range of 2-11), respectively. Prolonged air leak occurred in 1 patient (1.4%). Over a mean follow-up period of 60 months (SD: 22.5), two recurrences (2.7%) were reported. CONCLUSIONS: The transcollation(r) technique by cold coagulation of blebs and bullae seems to be effective in the treatment of primary spontaneous pneumothorax. Owing to its potential advantages, it appears to be particularly suitable to be associated with awake epidural and LMA anaesthesia. PMID- 25542405 TI - Evaluation and perceived results of moral case deliberation: A mixed methods study. AB - BACKGROUND: Moral case deliberation is increasingly becoming part of various Dutch healthcare organizations. Although some evaluation studies of moral case deliberation have been carried out, research into the results of moral case deliberation within aged care is scarce. RESEARCH QUESTIONS: How did participants evaluate moral case deliberation? What has moral case deliberation brought to them? What has moral case deliberation contributed to care practice? Should moral case deliberation be further implemented and, if so, how? RESEARCH DESIGN: Quantitative analysis of a questionnaire study among participants of moral case deliberation, both caregivers and team leaders. Qualitative analysis of written answers to open questions, interview study and focus group meetings among caregivers and team leaders. PARTICIPANTS AND RESEARCH CONTEXT: Caregivers and team leaders in a large organization for aged care in the Netherlands. A total of 61 moral case deliberation sessions, carried out on 16 care locations belonging to the organization, were evaluated and perceived results were assessed. ETHICAL CONSIDERATIONS: Participants gave informed consent and anonymity was guaranteed. In the Netherlands, the law does not prescribe independent ethical review by an Institutional Review Board for this kind of research among healthcare professionals. FINDINGS: Moral case deliberation was evaluated positively by the participants. Content and atmosphere of moral case deliberation received high scores, while organizational issues regarding the moral case deliberation sessions scored lower and merit further attention. Respondents indicated that moral case deliberation has the potential to contribute to care practice as relationships among team members improve, more openness is experienced and more understanding for different perspectives is fostered. If moral case deliberation is to be successfully implemented, top-down approaches should go hand in hand with bottom-up approaches. CONCLUSION: The relevance of moral case deliberation for care practice received wide acknowledgement from the respondents. It can contribute to the team's cohesion as mutual understanding for one another's views is fostered. If implemented well, moral case deliberation has the potential to improve care, according to the respondents. PMID- 25542406 TI - The association between sedentary behaviour, moderate-vigorous physical activity and frailty in NHANES cohorts. AB - OBJECTIVES: (1) To examine how sedentary behaviour and moderate-vigorous (MVPA) are each experienced during the day across different levels of frailty; (2) estimate and compare the extent to which high levels of sedentary behaviour and low levels of MVPA are associated with increased frailty and self-reported health, disability and healthcare utilization. METHODS: Community dwelling adults aged 50+ from the National Health and Nutrition Examination Survey (2003-2004; 2005-2006). Frailty was measured with the frailty index and physical activity was measured using ActiGraph accelerometers. RESULTS: On average, people engaged in about 8.5h of sedentary behaviour each day. The most frail individuals were more sedentary and less likely to meet weekly MVPA guidelines (9.57 h/day; 8.3%) than non-frail individuals (8.18 h/day; 1.1%; p<0.001). Frail individuals failed to demonstrate the patterns of the healthier individuals-higher levels of sedentary behaviour on Sundays and in the evenings and decreasing MVPA throughout the week. High sedentary behaviour and low MVPA were independently associated with higher levels of frailty, poor self-reported health, high ADL disability and higher healthcare usage. CONCLUSIONS: Many people over the age of 50, and most of those who are frail, were highly sedentary with very few meeting the recommended weekly levels of MVPA. Sedentary behaviour and MVPA were independently associated with frailty and adverse health outcomes in middle to older aged adults. Future research should focus on a longitudinal study to determine the temporal relationship between sedentary behaviour and frailty. PMID- 25542407 TI - Qualitative cross-cultural exploration of breast symptoms and impacts associated with hormonal treatments for menopausal symptoms to inform the development of new patient-reported measurement tools. AB - To explore cross-cultural experiences of women taking estrogen plus progestin therapies (EPT) and develop a symptom-based electronic diary and impact questionnaire for EPT-related breast symptoms. (1) Concept elicitation interviews were conducted with women in the US (n=14), Italy (n=15), Mexico (n=15) and China (n=15) to explore breast symptoms associated with EPT. Patients completed the Breast Sensitivity Questionnaire (BSQ) to evaluate understanding and comprehensiveness. (2) Based on concept elicitation, a 6-item eDiary (Breast Pain/Tenderness Daily Diary - BPT-DD) was generated and the BSQ modified forming the 18-item Breast Sensations Impact Questionnaire (BSIQ). (3) The measures were pilot-tested and then cognitively debriefed with US women receiving EPT. All qualitative data was subject to thematic analysis. Concept elicitation identified breast pain/tenderness, swollen breasts and sensitivity to contact as important symptoms, impacting women's emotional well-being, relationships with family/friends, social life, sleep, ability to move freely, contact, clothing and sexual activity. Experiences were relatively consistent across the country samples. Based on pilot testing and cognitive debriefing, the BPT-DD was reduced to 4 items (and renamed the Breast Pain Daily Diary - BP-DD) and the BSIQ was reduced to 13 items due to conceptual redundancy. Women taking EPT in the US, China, Mexico and Italy reported breast sensations that have a detrimental impact on quality of life. Two new measures were developed to assess the severity and impact of breast pain specific to EPT. This work highlights that EPT-related symptoms should be part of treatment decision-making, and treatments with less burdensome side effects are needed. PMID- 25542408 TI - Anticancer potential and mechanism of action of mango ginger (Curcuma amada Roxb.) supercritical CO2 extract in human glioblastoma cells. AB - Mango ginger (Curcuma amada Roxb.) is among the less-investigated species of Curcuma for anticancer properties. We have investigated the anticancer potential and the mechanism of action of a supercritical CO2 extract of mango ginger (CA) in the U-87MG human glioblastoma cell line. CA demonstrated higher cytotoxicity than temozolomide, etoposide, curcumin, and turmeric force with IC50, IC75, and IC90 values of 4.92 MUg/mL, 12.87 MUg/mL, and 21.30 MUg/mL, respectively. Inhibitory concentration values of CA for normal embryonic mouse hypothalamus cell line (mHypoE-N1) is significantly higher than glioblastoma cell line, indicating the specificity of CA against brain tumor cells. CompuSyn analysis indicates that CA acts synergistically with temozolomide and etoposide for the cytotoxicity with combination index values of <1. CA treatment also induces apoptosis in glioblastoma cells in a dose-dependent manner and downregulates genes associated with apoptosis, cell proliferation, telomerase activity, oncogenesis, and drug resistance in glioblastoma cells. PMID- 25542409 TI - Approach to the treatment of the infant with hyponatremia. AB - Hyponatremia is an electrolyte abnormality that occurs in infancy due to a variety of inherited and acquired disorders. Infants with hyponatremia can present with neurologic symptoms such as vomiting, weakness, and seizures. Common causes of hyponatremia in the infant population are excess ingestion or administration of hypotonic fluids and excessive gastrointestinal salt loss. Hyponatremia in infancy also can be a sign of less common disorders, such as mineralocorticoid deficiency or resistance, and disregulation of arginine vasopressin with impaired free-water removal. Treatment of infants with hyponatremia is dependent on the severity of symptoms and the cause of hyponatremia. In nephrogenic syndrome of inappropriate antidiuresis (NSIAD), fluid retention is due to a gain-of-function mutation in the arginine vasopressin receptor 2 (AVPR2) gene leading to low arginine vasopressin levels. We describe the case of an infant with hyponatremia due to NSIAD, whose mother also has a known mutation in the AVPR2 gene. We report the approach to the treatment of hyponatremia and its unique challenges in infancy. PMID- 25542410 TI - Approach to the diagnosis and treatment of hyponatremia in pregnancy. AB - Hyponatremia is the most commonly encountered electrolyte abnormality. Severe hyponatremia in pregnancy poses diagnostic and therapeutic challenges. Pregnancy involves changes in physiology that affect water and sodium homeostasis. Knowledge of these complex physiologic alterations during pregnancy is critical to managing dysnatremias in pregnancy. This teaching case describes a woman with chronic hyponatremia who presented during pregnancy with worsening hyponatremia. She had an activating vasopressin receptor mutation, which was passed on to her child, and her diagnostic workup is described. PMID- 25542411 TI - Estimated GFR and cystatin C for drug dosing: moving beyond proof of concept to clinical translation? PMID- 25542412 TI - Low-density lipoprotein apheresis for proteinuria in lupus nephritis with intraglomerular foam cells containing cholesterol crystals. AB - A 28-year-old woman with systemic lupus erythematosus was referred to our hospital due to nephrotic-level proteinuria despite approximately 1 year of treatment with 50 to 60 mg/d of prednisolone and 100 to 150 mg/d of cyclosporine with methylprednisolone pulse therapy. Kidney biopsy showed diffuse global lupus nephritis (World Health Organization class 4-G A/C) with many intraglomerular foam cells containing cholesterol crystals. Surprisingly, proteinuria diminished after only 5 low-density lipoprotein (LDL) cholesterol apheresis sessions. This case demonstrated the potential of LDL apheresis to exhibit a remarkable effect on not only focal segmental glomerulosclerosis, but also other types of nephritis, particularly nephritis with intraglomerular foam cells. PMID- 25542413 TI - Navigating toward research success in times of uncertainty: funding opportunities for early career investigators in nephrology. AB - There is considerable concern within the nephrology community about recent federal budget cuts and the decreasing availability of funds for research. This is especially difficult for junior investigators who are about to start a career as physician-scientists. Accordingly, it is imperative that resources other than federal funds be made available to these individuals during this most delicate yet crucial transition period. This commentary aims to provide an overview of nonfederal funding resources, focusing on the Norman S. Coplon Extramural Grant Program. This program emphasizes support of investigators at the most fragile period in their development of an academic career; it has provided >$11 million of research funds to more than 80 individuals since 2000. The outcome has been stellar, with more than 130 publications originating from these projects and >90% of awardees staying in academia. We hope these accomplishments will encourage similar activities by other entities and scientific programs in addition to ones that are ongoing. Ultimately, these collective efforts will inspire young researchers to use their knowledge, passion, and dedication to advance research into kidney diseases. PMID- 25542414 TI - Change in novel filtration markers and risk of ESRD. AB - BACKGROUND: Chronic kidney disease progression is a risk factor for end-stage renal disease (ESRD). A 57% decline in creatinine-based estimated glomerular filtration rate (eGFRcr) is an established surrogate outcome for ESRD in clinical trials, and a 30% decrease recently has been proposed as a surrogate end point. However, it is unclear whether change in novel filtration marker levels provides additional information for ESRD risk to change in eGFRcr. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Atherosclerosis Risk in Communities (ARIC) Study participants from 4 US communities. PREDICTORS: Percent change in levels of filtration markers (eGFRcr, cystatin C-based eGFR [eGFRcys], the inverse of beta2 microglobulin concentration [1/B2M]) over a 6-year period. OUTCOME: Incident ESRD. MEASUREMENTS: Cox proportional hazards regression with adjustment for demographics, kidney disease risk factors, and first measurement of eGFRcr. RESULTS: During a median follow-up of 13 years, there were 142 incident ESRD cases. In adjusted analysis, declines > 30% in eGFRcr, eGFRcys, and 1/B2M were associated significantly with ESRD compared with stable concentrations of filtration markers (HRs of 19.96 [95% CI, 11.73-33.96], 16.67 [95% CI, 10.27 27.06], and 22.53 [95% CI, 13.20-38.43], respectively). Using the average of declines in the 3 markers, >30% decline conferred higher ESRD risk than that for eGFRcr alone (HR, 31.97 [95% CI, 19.40-52.70; P=0.03] vs eGFRcr). LIMITATIONS: Measurement error could influence estimation of change in filtration marker levels. CONCLUSIONS: A >30% decline in kidney function assessed using novel filtration markers is associated strongly with ESRD, suggesting the potential utility of measuring change in cystatin C and B2M levels in settings in which improved outcome ascertainment is needed, such as clinical trials. PMID- 25542415 TI - Creatinine clearance, walking speed, and muscle atrophy: a cohort study. AB - BACKGROUND: Chronic kidney disease is associated with malnutrition and inflammation. These processes may lead to loss of skeletal muscle and reduced physical performance. Associations of kidney function with muscle composition and longitudinal measures of physical performance are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We evaluated 826 community dwelling older adults enrolled in the Invecchiare in Chianti (InCHIANTI) Study who were free of baseline stroke or activities of daily living disability. PREDICTOR: Baseline creatinine clearance (Clcr) based on 24-hour urine collection. OUTCOMES: Cross-sectional and longitudinal trajectories of physical performance measured by 7-m usual gait speed, 400-m fast gait speed, and knee extension strength using isometric dynamometry. Calf muscle composition assessed by quantitative computed tomography. RESULTS: Mean age of participants was 74 +/- 7 (SD) years, with 183 having Clcr < 60 mL/min/1.73 m(2). After adjustment, each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 0.01 (95% CI, 0.004 0.017) m/s slower 7-m usual walking speed and 0.008 (95% CI, 0.002-0.014) m/s slower 400-m walking speed. Each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 28 (95% CI, 0.8-55) mm(2) lower muscle area and 0.15 (95% CI, 0.04-0.26) mg/cm(3) lower muscle density. After adjustment, lower Clcr was associated with slower mean 7-m (P=0.005) and 400-m (P=0.02) walk and knee extension strength (P=0.001) during the course of follow-up. During a mean follow up of 7.1 +/- 2.5 years, each 10-mL/min/1.73 m(2) lower baseline Clcr was associated with 0.024 (95% CI, 0.01-0.037) kg/y greater decline in knee strength. LIMITATIONS: Single baseline measurement of Clcr and 3-year interval between follow-up visits may lead to nondifferential misclassification and attenuation of estimates. CONCLUSIONS: Among older adults, lower Clcr is associated with muscle atrophy, reduced walking speed, and more rapid declines in lower-extremity strength over time. PMID- 25542416 TI - Effects of 2 weeks of low-intensity cycle training with different pedaling rates on the work rate at lactate threshold. AB - PURPOSE: This study examined (1) the effects of a single bout of exercise at different pedaling rates on physiological responses, pedal force, and muscle oxygenation, and (2) the effects of 2 weeks of training with different pedaling rates on work rate at lactate threshold (WorkLT). METHODS: Sixteen healthy men participated in the study. An incremental exercise test involving pedaling a cycling ergometer at 50 rpm was conducted to assess maximal oxygen consumption and WorkLT. The participants performed constant workload, submaximal exercise tests at WorkLT intensity with three different pedaling rates (35, 50, and 75 rpm). Oxygen consumption ([Formula: see text]O2), blood pressure, heart rate (HR), blood lactate, and pedal force were measured and oxy-hemoglobin/myoglobin concentration (OxyHb/Mb) at vastus lateralis was monitored by near-infrared spectroscopy during exercise. The participants were then randomly assigned to cycling exercise training at WorkLT in either the low or high frequency pedaling rate (LFTr, 35 rpm or HFTr, 75 rpm) group. Each 60-min training session was performed five times/week. RESULTS: Despite maintaining the same work rate, [Formula: see text]O2 and HR were significantly lower at 35 than 75 rpm. Conversely, integrated pedal force was significantly higher at 35 than 75 rpm. Peripheral OxyHb/Mb was significantly lower at 35 than 75 rpm. After 2 weeks of training, WorkLT normalized to body mass significantly increased in the LFTr, but not the HFTr group. CONCLUSIONS: Pedaling rate and the corresponding pedal force and peripheral oxygenation during cycling exercise influence the effect of training at LT on WorkLT. PMID- 25542418 TI - Regulation of vascular endothelial genes by dietary flavonoids: structure expression relationship studies and the role of the transcription factor KLF-2. AB - Physiological concentrations (1 MUM) of 15 flavonoids were evaluated in human umbilical vein endothelial cells in the presence of hydrogen peroxide (H2O2) for their ability to affect endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression in order to establish the structural basis of their bioactivity. Flavonoid effects on eNOS transcription factor Krupple like factor-2 (KLF-2) expression were also evaluated. All studied flavonoids appeared to be effective compounds for counteracting the oxidative stress-induced effects on vascular gene expression, indicating that flavonoids are an excellent source of functional endothelial regulator products. Notably, the more effective flavonoids for KLF-2 up-regulation resulted in the highest values for eNOS expression, showing that the increment of eNOS expression would take place through KLF-2 induction. Structure-activity relationship studies showed that the combinations of substructures on flavonoid skeleton that regulate eNOS expression are made up of the following elements: glycosylation and hydroxylation of C-ring, double bond C2=C3 at C-ring, methoxylation and hydroxylation of B-ring, ketone group in C4 at C-ring and glycosylation in C7 of A-ring, while flavonoid features involved in the reduction of vasoconstrictor ET-1 expression are as follows: double bond C2=C3 at C-ring glycosylation in C7 of A-ring and ketone group in C4 of C-ring. PMID- 25542419 TI - Amphetamine sensitization is accompanied by an increase in prelimbic cortex activity. AB - Drug addiction is associated with dysfunction in the medial prefrontal cortex (mPFC). However, the modifications of neuronal activity in mPFC underlying the reinforcing properties of addictive drugs are still unclear. Here we carried out single-unit recording experiments to study the neuronal activity in the prelimbic (PL) cortex of anesthetized rats, after expression of locomotor sensitization to amphetamine. In control rats, an acute injection of amphetamine induced mainly an inhibitory effect on firing rate (FR) and this response was negatively correlated with the basal FR. Sensitized rats showed a higher proportion of excited neurons and the response to amphetamine was independent of basal FR. Moreover, in control rats, acute amphetamine decreased burst rate, whereas in sensitized rats acute amphetamine increased burst rate. These findings indicate that amphetamine sensitization renders mPFC neurons hyperexcitable. Taken together, these data support the hypothesis that early withdrawal is associated with an increase in the activity of the mPFC, which could strengthen the PL-Nucleus Accumbens connection, thus facilitating amphetamine-induced locomotor sensitization. PMID- 25542417 TI - Quantitation of secreted proteins using mCherry fusion constructs and a fluorescent microplate reader. AB - Traditional assays for secreted proteins include methods such as Western blot and enzyme-linked immunosorbent assay (ELISA) detection of the protein in the cell culture medium. We describe a method for the detection of a secreted protein based on fluorescent measurement of an mCherry fusion reporter. This microplate reader-based mCherry fluorescence detection method has a wide dynamic range of 4.5 orders of magnitude and a sensitivity that allows detection of 1 to 2fmol fusion protein. Comparison with the Western blot detection method indicated greater linearity, wider dynamic range, and a similar lower detection threshold for the microplate-based fluorescent detection assay of secreted fusion proteins. An mCherry fusion protein of matrix metalloproteinase-9 (MMP-9), a secreted glycoprotein, was created and expressed by transfection of human embryonic kidney (HEK) 293 cells. The cell culture medium was assayed for the presence of the fluorescent signal up to 32 h after transfection. The secreted MMP-9-mCherry fusion protein was detected 6h after transfection with a linear increase in signal intensity over time. Treatment with chloroquine, a drug known to inhibit the secretion of many proteins, abolished the MMP-9-mCherry secretion, demonstrating the utility of this method in a biological experiment. PMID- 25542420 TI - Using rats for vision research. AB - A wide variety of species are used for the study of visual neuroscience. This is beneficial because fundamental mechanisms and theoretical principles of vision are likely to be highly conserved, while different species exhibit different visual capacities and present different technical advantages for experiments. Eight years ago my laboratory adopted the hooded rat as our primary preparation for vision research. To some this may be surprising, as nocturnal rodents have often been presumed to have poor vision and weak visual behavior. This commentary will provide my personal perspective on how I came to work with rats; discuss an example research project for which rats have been advantageous; and comment on the opportunities and challenges of the preparation. PMID- 25542421 TI - Activation of GABA(B) receptors potentiates inward rectifying potassium currents in satellite glial cells from rat trigeminal ganglia: in vivo patch-clamp analysis. AB - In a previous study, we demonstrated that inflammation suppressed inward rectifying K(+) (Kir) currents in satellite glial cells (SGCs) from the trigeminal ganglia (TRGs) and that this impairment of glial potassium homeostasis in the trigeminal ganglion (TRG) contributed to trigeminal pain. The aim of the present study was to investigate whether activation of GABAB receptors modulates the Kir current in SGCs using in vivo patch-clamp and immunohistochemical techniques. Immunohistochemically, we found that immunoreactivity for glial specific Kir channel subunit Kir4.1 and the GABAB receptor was co-expressed in SGCs from the TRGs. In vivo whole-cell recordings were made using SGCs from the TRGs of urethane-anesthetized rats. Application of baclofen, a GABAB receptor agonist, significantly increased the mean peak amplitude of Kir currents in a concentration-dependent and reversible manner. Baclofen-induced potentiation of the Kir current was abolished by co-application of 3-amino-2-(4-chlorophenyl)-2 hydroxyprophylsulfonic acid (saclofen). In addition, baclofen significantly potentiated the density of the Ba(2+)-sensitive Kir current, and resulted in hyperpolarization of the mean membrane potential. These results suggest that activation of GABAB receptors potentiates the Kir current in SGCs and that GABA released from the TRG neuronal soma could contribute to buffering of extracellular K(+) concentrations following excitation of TRG neurons during the processing of sensory information, including the transmission of noxious stimuli. PMID- 25542422 TI - Disruption of medial prefrontal synchrony in the subchronic phencyclidine model of schizophrenia in rats. AB - Subchronic treatment with the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) produces behavioral abnormalities in rodents which are considered a reliable pharmacological model of neurocognitive deficits in schizophrenia. Alterations in prefrontal neuronal firing after acute PCP administration have been observed, however enduring changes in prefrontal activity after subchronic PCP treatment have not been studied. To address this we have recorded cortical oscillations and unit responses in putative cortical pyramidal cells in subchronic PCP-treated rats (2mg/kg twice daily for 7 days) under urethane anesthesia. We found that this regimen reduced theta oscillations in the medial prefrontal cortex. It further produced abnormal cortical synchronization in putative cortical pyramidal cells. These alterations in prefrontal cortex functioning may contribute to cognitive deficits seen in subchronic NMDA antagonist pre-treated animals in prefrontal-dependent tasks. PMID- 25542423 TI - Effects of electroacupuncture on the levels of retinal gamma-aminobutyric acid and its receptors in a guinea pig model of lens-induced myopia. AB - Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the retina and affects myopic development. Electroacupuncture (EA) is widely utilized to treat myopia in clinical settings. However, there are few reports on whether EA affects the level of retinal GABA during myopic development. To study this issue, in the present study, we explored the changes of retinal GABA content and the expression of its receptor subtypes, and the effects of EA stimulation on them in a guinea pig model with lens-induced myopia (LIM). Our results showed that the content of GABA and the expression of GABAA and GABAC receptors of retina were up-regulated during the development of myopia, and this up-regulation was inhibited by applying EA to Hegu (LI4) and Taiyang (EX-HN5) acupoints. Moreover, these effects of EA show a positional specificity. While applying EA at a sham acupoint, no apparent change of myopic retinal GABA and its receptor subtypes was observed. Taken together, our findings suggest that LIM is effective to up-regulate the level of retinal GABA, GABAA and GABAC receptors in guinea pigs and the effect may be inhibited by EA stimulation at LI4 and EX-HN5 acupoints. PMID- 25542424 TI - The miR-193a-3p regulated PSEN1 gene suppresses the multi-chemoresistance of bladder cancer. AB - Chemoresistance prevents the curative cancer therapy, our understanding of which remains inadequate. Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the gamma secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer. PMID- 25542425 TI - Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. AB - BACKGROUND: Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. METHODS: Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. RESULTS: Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration >=15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. CONCLUSION: SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses. PMID- 25542426 TI - An unusual long RP tachycardia: what is the mechanism? PMID- 25542427 TI - Single 3-minute freeze for second-generation cryoballoon ablation: one-year follow-up after pulmonary vein isolation. AB - BACKGROUND: The second-generation cryoballoon (CB-Adv) is effective in achieving pulmonary vein isolation (PVI) with encouraging results. The mid-term clinical efficacy of a single 3-minute freeze, without a routine bonus application, has been recently demonstrated. OBJECTIVE: The purpose of this study was to assess long-term clinical outcome after PVI with the CB-Adv using a single 3-minute application. METHODS: A total of 143 consecutive patients (93 male [65%], mean age 59.6 +/- 12.0 years) with paroxysmal atrial fibrillation (PAF; 113/143 [79%]) or early persistent atrial fibrillation (AF; 30/143 [21%]) underwent PVI using CB Adv with a single 3-minute freeze. Atrial tachyarrhythmia recurrences were defined as symptomatic or documented episodes >30 seconds. RESULTS: After a single freeze, isolation could be reached in 94.1% of all identified pulmonary veins. Complete PVI was successfully achieved with 1.1 +/- 0.4 mean freezes. Persistent phrenic nerve palsy occurred in 5 of 143 patients (3.5%). At a mean 12.1 +/- 4.4 months of follow-up, after a 3-month blanking period (BP), 80.4% (115/143) were in stable sinus rhythm (93/113 [82.3%] for PAF; 22/30 [73.3%] for early persistent AF). Fifteen patients underwent a second procedure with radiofrequency ablation showing reconnection in 7 of 15 right-sided (46.7%) and 6 of 15 left-sided (40%) pulmonary veins. Relapses during BP (P <.01), time to PVI (P = .02), and longer AF duration (P = .04) were independent predictors of recurrences. CONCLUSION: A single 3-minute freeze is highly effective, determining an atrial tachyarrhythmia freedom of 80.4% at 1-year follow-up. The incidence of persistent phrenic nerve palsy is 3.5%. Relapses during BP, time to PVI, and longer AF duration are predictors of recurrences. Routine use of an "insurance freeze" may not be needed. PMID- 25542428 TI - Bergenin decreases the morphine-induced physical dependence via antioxidative activity in mice. AB - Oxidative stress plays a role in the development of physical dependence induced by morphine. Bergenin, a polyphenol found in many Asian, African, and South American medicinal plants, is a potent antinarcotic agent with wide spectrum of pharmacological activities including antioxidant action. In the present study, we observed that bergenin decreased the development of physical dependence induced by morphine in mice and the antioxidant activity of bergenin plays a role in the antinarcotic effects through adapting to morphine-induced oxidative stress in the brain. The naloxone-precipitated withdrawal symptom (jumping frequency) was significantly ameliorated (50% of control group) by administration of bergenin (20 mg/kg) in morphine-treated mice. Furthermore, morphine-induced down regulation of glutathione (GSH) contents was reversed by bergenin administration in the frontal cortex and liver. Bergenin had no effects on the increased levels of nfr2-dependent antioxidant enzyme HO1 and NQO1 in the frontal cortex, striatum, and liver of morphine-treated mice. However, the morphine-induced increase in nrf2 nuclear translocation in the frontal cortex and striatum was inhibited by bergenin treatment. These results suggest that bergenin has a potential antinarcotic effect via regulation of GSH contents and oxidative stress. PMID- 25542429 TI - Isolation, characterization, and in rats plasma pharmacokinetic study of a new triterpenoid saponin from Dianthus superbus. AB - One new oleanolic acid triterpenoid saponin, 3-O-beta-D-glucopyranosyl olean-11, 13(18)-diene-23,28-dioic acid, (hereafter referred to as DS-1) was isolated from the traditional Chinese medicinal plant Dianthus superbus (D. superbus). DS-1 plays an important role in the bioactivity of D. superbus. Thus, a sensitive, reliable and accurate reversed-phased liquid chromatography with tandem mass spectrometry (LC-MS/MS) in negative ion mode was developed and validated for the quantification and pharmacokinetic study of DS-1 in rats plasma. The pharmacokinetic profile showed that DS-1 was rapidly absorbed and eliminated in plasma, indicating that significant accumulation of the compound in biological specimen is unlikely. In addition, poor absorption into systemic circulation was observed after oral administration of DS-1, resulting in low absolute bioavailability (0.92 %). PMID- 25542430 TI - Dual mini TightRope suspensionplasty for thumb basilar joint arthritis: a case series. AB - PURPOSE: To evaluate the efficacy of the technique of dual Mini TightRope suspensionplasty for treatment of trapeziometacarpal joint arthritis. METHODS: We conducted a retrospective study investigating the use of a dual Mini TightRope suspensionplasty technique from 2010 to 2013 at a single institution. We identified 11 patients (12 thumbs). Grip and pinch strength, thumb range of motion, and complications were reviewed. The trapezial space ratio was measured from the preoperative, postoperative, and follow-up radiographs. All patients completed the Disabilities of Arm, Shoulder, and Hand survey, Patient-Rated Wrist Evaluation, and the Michigan Hand Outcome Questionnaire at the latest follow-up. RESULTS: Dual Mini TightRope suspensionplasty resulted in reduced pain levels, increased grip and pinch strength, and preserved range of motion. Radiographs demonstrated maintenance of trapezial space height at an average of 17 months (range, 10-26 mo). There were no cases of impingement or fracture of the first and second metacarpal bases. CONCLUSIONS: Dual Mini TightRope suspensionplasty for the management of trapeziometacarpal joint arthritis yielded satisfactory results with improvement in strength and function. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25542431 TI - Preoperative electrocardiograms for nonsyndromic children with hand syndactyly. AB - PURPOSE: To examine the efficacy of preoperative electrocardiogram (EKG) screening for Timothy syndrome, a rare and fatal condition characterized by prolonged QT, in children referred for syndactyly release. METHODS: We reviewed the records of nonsyndromic syndactyly patients seen by a hand surgeon at our institution between 2007 and 2013. All underwent a preoperative screening EKG for Timothy syndrome. We reviewed the medical records for demographics, presentation, EKG results, and operative findings, and calculated median age at the time of EKG and surgery and frequency distributions for sex, side affected, EKG result, and clinical finding. The mean patient charge for EKG and interpretation was calculated. RESULTS: We identified 128 syndactyly patients, 72% of which were boys. Median age at the time of EKG testing and syndactyly release was 1 year. A total of 92% of patients had normal EKG results; one patient exhibited a prolonged QT. Ten patients (8%) had further cardiac evaluation because of the EKG result and were found to be normal on repeat testing. No patient met QT threshold for Timothy syndrome and all patients were cleared for surgery. The minimum patient charge for EKG testing was $183. CONCLUSIONS: To improve patient safety, some have advocated preoperative EKG testing for all children undergoing syndactyly release to rule out Timothy syndrome. Analysis of our experience failed to yield an instance of Timothy syndrome over a 7-year period. Although EKG charges were relatively low, costs resulting from additional testing, cardiology consultation, and provider and parent time should be considered. Our study does not support routine EKG testing for children referred for syndactyly release, and we have abandoned this practice. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 25542432 TI - The effect of humerus diaphyseal shortening on brachial plexus tension: a cadaver study. AB - PURPOSE: To assess the extent to which diaphyseal shortening of the humerus can allow direct suture in case of rupture or transection injuries of the brachial plexus. METHODS: The use of 3 fresh cadaver specimens allowed for the study of 6 brachial plexuses. Distance measurements were made between reference points placed on the clavicle and on different parts of the plexus. Those measurements were repeated after shortening the humerus by 2, 4, and 6 cm. RESULTS: None of the dissected plexuses had classic anatomy. A humeral shortening of 6 cm allowed for a statistically significant reduction of length between the supraclavicular part of the plexus and the terminal branches, which did not exceed 17 mm on average. The difference of length was much greater for the specimen in which the musculocutaneous nerve did not pierce the coracobrachialis muscle proximally. CONCLUSIONS: In clinical situations, nerve defects are usually larger than the gain observed when doing a 6-cm humeral shortening. Moreover, this procedure implies a large dissection, a functional loss of certain muscles, and a risk of humeral nonunion. CLINICAL RELEVANCE: In the absence of extensive nerve dissection, the observed change of length is insufficient in the most brachial plexus disruptions to allow for a direct suture instead of long nerve grafts. PMID- 25542433 TI - Biomechanical characteristics of hemi-hamate reconstruction versus volar plate arthroplasty in the treatment of dorsal fracture dislocations of the proximal interphalangeal joint. AB - PURPOSE: To compare stability and range of motion after hemi-hamate reconstruction versus volar plate arthroplasty in a biomechanical proximal interphalangeal (PIP) joint fracture-dislocation model. METHODS: Eighteen digits from 6 cadaver hands were tested. We created defects of 40%, 60%, and 80% in the palmar base of each digit's middle phalanx, simulating an acute PIP joint fracture-dislocation. Each defect scenario was reconstructed with a hemi-hamate arthroplasty followed by a volar plate arthroplasty. A computer-controlled mechanism was used to bring each digit's PIP joint from full extension to full flexion via the digital tendons in each testing state, and in the intact state. During each testing scenario we collected PIP joint cinedata in a true lateral projection using mini-fluoroscopy. A digital radiography program was used to measure the amount of middle phalanx dorsal translation (subluxation) in full PIP joint extension. We recorded the angle at which subluxation, if present, occurred during each testing scenario. RESULTS: Average dorsal displacement of the middle phalanx in relation to the proximal phalanx was 0.01 mm for the hemi-hamate reconstructed joints and -0.03 mm for the volar plate arthroplasty, compared with the intact state. Flexion contractures were noted in each of the specimens reconstructed with volar plate arthroplasty. Degree of contracture was directly correlated with defect size, averaging 20 degrees for 40% defects, 35 degrees for 60% defects, and 60 degrees for 80% defects. We observed no flexion contractures in the hemi-hamate reconstructions. CONCLUSIONS: Surgeons can use both hemi-hamate and volar plate arthroplasty to restore PIP joint stability following a fracture dislocation with a large middle phalanx palmar base defect. Use of volar plate arthroplasty led to an increasing flexion contracture as the middle phalanx palmar base defect increased. CLINICAL RELEVANCE: Clinicians can use the information from this study to help with surgical decision-making and patient education. PMID- 25542434 TI - The effect of using a cement gun with a narrow nozzle on cement penetration for total elbow arthroplasty: a cadaveric study. AB - PURPOSE: To compare the cement mantle characteristics associated with use of a narrow nozzle cement gun versus the use of a 60-mL catheter tip syringe. METHODS: Twelve cadaveric distal humeri were cemented with either a cement gun or a syringe without canal occlusion. The humeri were sectioned and photographed. The corticocancellous junction and the outer margin of the cement mantle were analyzed digitally. The corticocancellous junction defined the available area for cement penetration. The outline of the cement mantle defined the actual area of penetration. The ratio of penetration to the available area was recorded for each slice. The mean ratio for each humerus was multiplied by the number of slices in that sample containing cement to calculate a cement index. RESULTS: The cement penetration ratios observed in cross-sections at the same level and the cement index were significantly greater with the use of the cement gun than with the use of the syringe. There was no difference in the number of slices that contained cement. CONCLUSIONS: The use of a cement gun with a narrow nozzle improved cement mantle characteristics compared with the use of a syringe when measured in a cadaveric model in the absence of canal occlusion. CLINICAL RELEVANCE: Improving cement mantle characteristics may decrease the incidence of aseptic loosening after total elbow arythroplasty. PMID- 25542435 TI - The effect of an educational program on opioid prescription patterns in hand surgery: a quality improvement program. AB - PURPOSE: To assess the variability of opioid prescription patterns among hand surgeons in a single practice and to attempt to standardize postoperative prescription sizes based on the patient's surgical procedure. METHODS: We performed a preliminary chart review to assess the range of prescription sizes for 4 common hand surgery procedures. A group of hand surgeons agreed to write postoperative opioid prescriptions based on an evaluation of historical prescription patterns. An educational assist device (the pink card) was created to serve as a memory prompt and was given to physicians, midlevel practitioners, and trainees. Subsequent chart reviews of number of pills prescribed were done 3 and 15 months later. RESULTS: After implementation of the pink card, the average postoperative prescription size decreased for all 4 case types by 15% to 48%, reaching statistical significance for 2 of the procedures. Variability in prescription sizes decreased in all cases. There was a trend toward a decreasing number of prescription refills over the course of the study. There was no evidence that patients were obtaining refills from other sources within our multigroup practice. CONCLUSIONS: Although generalized opioid prescription guidelines exist, they lack specificity. Our multimodal approach using a simple educational-assist device and changes to postoperative order sets significantly affected surgeon behavior without evidence of inadequate treatment of pain. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 25542436 TI - Incipient malunion of an isolated humeral trochlea fracture treated with an elbow hemiarthroplasty: case report. AB - We report the case of a 49-year-old woman with severe elbow ankylosis 10 weeks after a trochlea fracture treated with open reduction and internal fixation. Imaging confirmed failure of open reduction and internal fixation with a displaced and severely damaged trochlea. We treated the nascent malunited trochlea and associated elbow ankylosis with a distal humeral hemiarthroplasty and circumferential elbow arthrolysis. The patient regained functional range of motion of the elbow and had minimal pain. Distal humeral hemiarthroplasty, which has been indicated for acute fractures involving the capitellum or the entire distal humerus, may also be indicated for certain isolated complex fractures of the trochlea. PMID- 25542437 TI - Computed tomography arthrography using a radial plane view for the detection of triangular fibrocartilage complex foveal tears. AB - PURPOSE: To classify triangular fibrocartilage complex (TFCC) foveal lesions on the basis of computed tomography (CT) arthrography using a radial plane view and to correlate the CT arthrography results with surgical findings. We also tested the interobserver and intra-observer reliability of the radial plane view. METHODS: A total of 33 patients with a suspected TFCC foveal tear who had undergone wrist CT arthrography and subsequent surgical exploration were enrolled. We classified the configurations of TFCC foveal lesions into 5 types on the basis of CT arthrography with the radial plane view in which the image slices rotate clockwise centered on the ulnar styloid process. Sensitivity, specificity, and positive predictive values were calculated for each type of foveal lesion in CT arthrography to detect foveal tears. We determined interobserver and intra observer agreements using kappa statistics. We also compared accuracies with the radial plane views with those with the coronal plane views. RESULTS: Among the tear types on CT arthrography, type 3, a roundish defect at the fovea, and type 4, a large defect at the overall ulnar insertion, had high specificity and positive predictive value for the detection of foveal tears. Specificity and positive predictive values were 90% and 89% for type 3 and 100% and 100% for type 4, respectively, whereas sensitivity was 35% for type 3 and 22% for type 4. Interobserver and intra-observer agreement was substantial and almost perfect, respectively. The radial plane view identified foveal lesion of each palmar and dorsal radioulnar ligament separately, but accuracy results with the radial plane views were not statistically different from those with the coronal plane views. CONCLUSIONS: Computed tomography arthrography with a radial plane view exhibited enhanced specificity and positive predictive value when a type 3 or 4 lesion was identified in the detection of a TFCC foveal tear compared with historical controls. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 25542438 TI - Anatomy of the flexor digitorum profundus insertion. AB - PURPOSE: To describe the anatomical insertion of the flexor digitorum profundus (FDP) on the distal phalanx. METHODS: The FDP insertion to the index, middle, ring, and little fingers were dissected in 10 fresh-frozen cadavers. The FDP tendon was dissected off the volar plate, which was elevated from proximal to distal, before the distal phalanx was disarticulated. The distal phalanx was then inked and the FDP was sharply dissected from bone. The insertion length, width, and distance of the insertion from the joint were measured and the insertion surface area and centroid of the FDP insertion were calculated. RESULTS: The average insertion length and width were 6.2 mm (range, 5.1-7.0 mm) and 7.9 mm (range, 6.9-8.4 mm), respectively. The average surface area of the distal phalanx occupied by the FDP tendon, for all fingers, was 20% (range, 15%-27%). The average distance from the most proximal insertion to the joint surface was 1.2 mm (range, 0.4-2.1 mm) and the calculated centroid of the FDP insertion from the distal interphalangeal joint was 3.6 mm (range, 2.5-5.1 mm) or approximately 20% of the distal phalangeal length. CONCLUSIONS: These findings may aid anatomical attachment of the FDP tendon in the treatment of zone I injuries. CLINICAL RELEVANCE: A better understanding of the anatomy of the FDP insertion may aid proper repair positioning in the treatment of zone I injuries. PMID- 25542439 TI - The effect of prosthetic radial head geometry on the distribution and magnitude of radiocapitellar joint contact pressures. AB - PURPOSE: To determine if radiocapitellar contact pressures would be elevated with nonanatomical (circular) prostheses over those mimicking native anatomy and if such pressures would be related to the depth and contour of the articular dish and to the pattern of prosthetic articulation against the lateral trochlear ridge. METHODS: Three commercially available circular radial head designs were compared with an anatomical radial head and 2 modified anatomical prototype radial head designs in 10 cadaveric specimens. Each prosthesis and specimen combination was loaded in neutral rotation and maximal extension with a custom testing apparatus while measuring contact areas and pressures using thin-film pressure sensors. RESULTS: Anatomical radial head prototype 2 had similar radiocapitellar contact areas and mean pressures as the native radial head; all other designs showed significant decreases in contact area and increased mean pressures. Peak contact pressures were also measured and were significantly elevated with all prostheses tested. Anatomical designs are statistically more likely to mimic normal contact with the lateral trochlear ridge and its adjacent sulcus than circular prostheses. They are also significantly less likely to have contact pressures above the 5 MPa threshold that is thought to be harmful to cartilage. The depth of the articular dish had a significant effect on contact area and pressure. CONCLUSIONS: Commercially available radial head prostheses demonstrated reduced radiocapitellar contact areas and elevated contact pressures during compressive loading. These were significantly greater with symmetrical circular prostheses than with asymmetrical elliptical designs. The prosthesis that best mimicked native contact behavior was the anatomical radial head prototype 2 owing to its design for articulating with the capitellum, the lateral trochlear ridge, and the sulcus between. CLINICAL RELEVANCE: Because radial head prostheses have the potential to cause capitellar erosion or arthritic change, those with lower contact pressures may lead to fewer such complications. PMID- 25542441 TI - [Late marginal recurrence of a choroidal melanoma after initially effective brachytherapy]. PMID- 25542440 TI - In Vivo kinematics of the trapeziometacarpal joint during thumb extension-flexion and abduction-adduction. AB - PURPOSE: The primary aim of this study was to determine whether the in vivo kinematics of the trapeziometacarpal (TMC) joint differ as a function of age and sex during thumb extension-flexion (Ex-Fl) and abduction-adduction (Ab-Ad) motions. METHODS: The hands and wrists of 44 subjects (10 men and 11 women with ages 18-35 y and 10 men and 13 women with ages 40-75 y) with no symptoms or signs of TMC joint pathology were imaged with computed tomography during thumb extension, flexion, abduction, and adduction. The kinematics of the TMC joint were computed and compared across direction, age, and sex. RESULTS: We found no significant effects of age or sex, after normalizing for size, in any of the kinematic parameters. The Ex-Fl and Ab-Ad rotation axes did not intersect, and both were oriented obliquely to the saddle-shaped anatomy of the TMC articulation. The Ex-Fl axis was located in the trapezium and the Ab-Ad axis was located in the metacarpal. Metacarpal translation and internal rotation occurred primarily during Ex-Fl. CONCLUSIONS: Our findings indicate that normal TMC joint kinematics are similar in males and females, regardless of age, and that the primary rotation axes are nonorthogonal and nonintersecting. In contrast to previous studies, we found Ex-Fl and Ab-Ad to be coupled with internal-external rotation and translation. Specifically, internal rotation and ulnar translation were coupled with flexion, indicating a potential stabilizing screw-home mechanism. CLINICAL RELEVANCE: The treatment of TMC pathology and arthroplasty design require a detailed and accurate understanding of TMC function. This study confirms the complexity of TMC kinematics and describes metacarpal translation coupled with internal rotation during Ex-Fl, which may explain some of the limitations of current treatment strategies and should help improve implant designs. PMID- 25542442 TI - [Apropos of 5 cases of optic nerve tumors diagnosed during a 6-year-period]. AB - INTRODUCTION: Optic nerve tumors are uncommon and rarely described. By way of five patients treated at the University Hospital of Clermont-Ferrand, France, over a six-year-period, we discuss their clinical and radiological characteristics, their treatment and their course. OBSERVATIONS: We report two cases of optic nerve glioma in small children, two cases of optic nerve sheath meningioma and a 57-year-old patient treated for lung cancer with an optic nerve metastasis and choroidal and brain metastases. The diagnosis was confirmed by imaging in all patients and histologically for the cases of optic nerve glioma. RESULTS: The children with glioma were exclusively treated with chemotherapy, the two women with meningioma exclusively with radiation therapy, and the man with the optic nerve metastasis by chemotherapy and radiotherapy. The tumors were stabilized in all cases except for a progression in one case of glioma, one year after treatment. DISCUSSION: Gliomas and meningiomas are the most frequent tumors; other tumors are rare. Through a literature review and many illustrations, we discuss epidemiologic, clinical and radiologic characteristics, treatment and course of these uncommon tumors. CONCLUSION: The diagnosis of optic nerve tumors must be considered in cases of anterior or posterior progressive optic neuropathy. Treatment must be a compromise between effective treatment of the tumor and preservation of visual function. Decisions are made through multidisciplinary consultations, in which the role of the ophthalmologist is crucial for the diagnosis and success of the treatment. PMID- 25542443 TI - [Extensive X-linked juvenile retinoschisis]. PMID- 25542444 TI - [Post-contusive subfoveolar hematoma in a pregnant women taking aspegic]. PMID- 25542445 TI - [Horizontal V-Y advancement flap for lower eyelid reconstruction in young patients]. AB - PURPOSE: The reconstruction of lower eyelid defects is a complex issue because of the thinness of eyelid tissues and the need for protection of the globe. The surgery must address two requirements: a functional goal, avoiding eyelid malposition, and a cosmetic goal, limiting aesthetic compromises. In young patients, direct closure is rarely possible if the defect is superior to 1cm. The horizontal V-Y advancement flap is a simple and reliable method but is hardly ever reported. The purpose of this study is to review the surgical technique and report our experience with this flap in the reconstruction of younger patients. PATIENTS AND METHODS: Nine patients, 5 men and 4 women, with a mean age of 54 years, underwent a lower eyelid reconstruction by horizontal V-Y advancement flap between 2011 and 2014. In every case, the initial pathology was a basal cell carcinoma and the surgical margins were uninvolved. The mean diameter of the surgical defect was 1.9 centimeters and the average procedure duration was 40 minutes. RESULTS: All patients were managed as outpatients. Functional and aesthetic results were judged satisfactory or very satisfactory by all the patients and their surgeon. No flap necrosis and no ectropion or scleral show were reported. In one patient, lower lid edema lasted until the third postoperative month. CONCLUSION: The horizontal V-Y advancement flap enables to repair lower eyelid defects using nearby skin of similar characteristics. Aesthetic results are very satisfactory, and scars, concealed in the eyelid creases, are nearly invisible in the long term. The lack of tension on the eyelid margin limits the risk of eyelid position. This simple and reliable one-step procedure, possible under local anesthesia, is appropriate for young, active patients, limiting the cosmetic sequelae and social ramifications. PMID- 25542446 TI - Management and interpretation of heterogeneous observational data: using insulin like growth factor-I data from the NordiNet(r) International Outcome Study. AB - OBJECTIVE: The NordiNet(r) International Outcome Study (IOS), a large-scale, non interventional, multi-centre, real-world study of Norditropin(r) treatment, registers insulin-like growth factor-I (IGF-I) values, as measured by different assays. This paper considers the potential biases introduced by using a single IGF-I reference data set in analysing NordiNet(r) IOS data. DESIGN: To evaluate possible biases from different IGF-I assays used across NordiNet(r) IOS, a mixed effect linear model was fitted to IGF-I data (analyses on log-transformed data). Pre-growth hormone treatment (pre-GHT) IGF-I values were assumed to depend on diagnosis, sex and age. During GHT, a treatment-effect dependent on these factors was added. Differences between assays were assumed multiplicative on the original scale. Individual measurements were scaled to a common level (Nichols Advantage) giving adjusted IGF-I standard deviation score (SDS) values. RESULTS: In total, 49 495 IGF-I measurements were available from 9481 paediatric patients. Mixed effect linear modelling showed a systematic difference between IGF-I levels measured by different assays. Differences were minimised when assessing change in IGF-I SDS from the start of GHT to 1-year follow-up. This applied to values adjusted for actual-assay used and for unadjusted delta IGF-I SDS values. Largest differences between unadjusted change in IGF-I SDS values were: for growth hormone deficiency 0.1 (girls) and 0.3 (boys); for small-for-gestational age 0.1; and for Turner syndrome 0.2. Similar magnitude differences were seen for data with unknown assay. CONCLUSIONS: Analysis and modelling suggest the current approach to IGF-I data collection and analyses in the NordiNet(r) IOS is sound: in a large cohort without assay-used information, potential bias is minimised by analysing changes in IGF-I SDS. PMID- 25542447 TI - Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy mediated metastatic melanoma phenotype. AB - Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2 positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy. SIGNIFICANCE: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. PMID- 25542449 TI - Central nervous system metastasis from breast cancer. PMID- 25542448 TI - EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma. AB - BRAF(V600E) is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EPHA2, a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin producing hepatocellular (EPH) receptors, and (ii) associated with a greater phenotypic dependence on EPHA2. Furthermore, we developed a series of first-in class EPHA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability, and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof of concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted. SIGNIFICANCE: In this study, we show that resistance to selective BRAF inhibitors can be mediated by the RTK EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance. PMID- 25542450 TI - Optimal cut points for quality of life questionnaire-core 30 (QLQ-C30) scales: utility for clinical trials and updates of prognostic systems in advanced hepatocellular carcinoma. AB - BACKGROUND: Health-related quality of life (QoL) has been validated as a prognostic factor for cancer patients; however, to be used in routine practice, QoL scores must be dichotomized. Cutoff points are usually based on arbitrary percentile values. We aimed to identify optimal cutoff points for six QoL scales and to quantify their added utility in the performance of four prognostic classifications in patients with hepatocellular carcinoma (HCC). METHODS: We reanalyzed data of 271 patients with advanced HCC recruited between July 2002 and October 2003 from 79 institutions in France in the CHOC trial, designed to assess the efficacy of long-acting octreotide. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30). The scores ranged from 0 to 100. Identification of optimal cutoff points was based on the method of Faraggi and Simon [Stat Med 1996;15:2203 2213]. Improvement in the performance of prognostic classifications was studied with Harrell's C-index, the net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: We found that optimal cutoff points were 50 for global health, 58.33 for physical functioning, 66.67 for role functioning, 66.67 for fatigue, 0 for dyspnea, and 33.33 for diarrhea. The addition of QoL and clinical factors improved the performance of all four prognostic classifications, with improvement in the range of 0.02-0.09 for the C index, 0.24-0.78 for 3-month NRI, and 0.02-0.10 for IDI. CONCLUSION: These cutoff values for QoL scales can be useful to identify HCC patients with very poor prognosis and thus improve design of clinical trials and treatment adjustment for these patients. PMID- 25542451 TI - [Pathological nighttime fears in children: Clinical specificities and effective therapeutics]. AB - OBJECTIVE: Pathological nighttime fears in children have been little studied. However, this disorder is commonly encountered in medical consultations and is discomforting and dysfunctional for both the child and the family. Most nighttime fears are part and parcel of normal development, and emanate from increasingly sophisticated cognitive development in the growing child. Thus, most children report a variety of coping strategies generally helpful in reducing their anxiety, which resolves spontaneously in the growing child. Nevertheless, in about 10% of children, nighttime fears are related to one or more anxiety disorders according to Diagnostic and Statistical Manual of Mental Disorders criteria. Then, it is estimated that severe nighttime fears and sleep problems occur in 20-30% of children. This problem is not transient and has to be treated. This study aims to review clinical features of nighttime fears and possible treatments for these patients and their families. METHOD: This systematic review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Two databases (Medline and Web of Science) were searched combining the search terms: nighttime fears AND children. English and French languages were imposed. There were no publication date or publication status limitations. RESULTS: Pathological nighttime fears are responsible for emotional (crying, panic, tantrums at bedtime, loss of confidence, self disparaging negative statements, and feeling of social embarrassment) and behavioral (wandering alone in the house at night, calls for parental or sibling comfort, bed sharing with parents or siblings, light source at night, refusal to go to the toilet alone at night) disturbances. This leads to a poor quality of sleep interfering with school learning, and also affects social development and family functioning. A full assessment has to be made to eliminate organic causes, have a baseline functioning, and search for comorbid anxiety diseases. The treatments which have proved effective are some cognitive-behavioral techniques: systematic desensitization (with relaxation or emotive imagery), reinforcement (gain of points and techniques of self statement), and cognitive techniques (reinforcing self-statements, reducing the aversive aspects of being in the dark, involving reality-testing statements, and active control are preferred in children older than 6 years, whereas the "anti-monster letter" and the techniques using a doll are preferred in children under 6 years old). The modelling technique seems to be appropriate at any age. CONCLUSION: We have explained the clinical features of pathological nighttime fears and the way to assess this disease, and we have pointed out the treatments whose effectiveness has been evaluated in this indication. PMID- 25542452 TI - Alvarado score: can it reduce unnecessary CT scans for evaluation of acute appendicitis? AB - OBJECTIVE: The objective of the study is to assess the utility of Alvarado score in the diagnosis of acute appendicitis and the utility of computed tomographic (CT) scan for evaluation of acute appendicitis when stratified by Alvarado scores. MATERIALS AND METHODS: Retrospective cohort study comprised adult patients who underwent abdominal CT for suspected acute appendicitis between January 2006 and December 2009. Two abdominal radiologists independently reviewed the CT scans; any discrepancies were resolved by a consensus review. Alvarado scores were calculated and categorized as low (0-3), equivocal (4-6), or high (7 10) probability for appendicitis. The diagnostic utility of CT scans and Alvarado score for acute appendicitis were compared with the criterion standard of combined medical chart review and pathology findings. RESULTS: In a cohort of 158 subjects, 73 (46.2%) had clinical diagnoses of acute appendicitis. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CT scan in the diagnosis of acute appendicitis were 97.5%, 98.6%, 96.5%, 96.0%, and 98.8%, respectively. The mean Alvarado score for subjects with complicated appendicitis was significantly higher (7.95) than subjects with uncomplicated appendicitis (6.67) and those with other diagnoses (5.95). Acute appendicitis was confirmed in 2 (13.3%) of 15 subjects with low probability Alvarado scores, 16 (30.8%) of 52 subjects with equivocal scores, and 55 (60.4%) of 91 subjects with high probability scores. CONCLUSION: The CT scan had high diagnostic utility for acute appendicitis. The Alvarado score was not a reliable independent predictive tool for acute appendicitis and could not replace CT scan. PMID- 25542453 TI - Clinical management of organophosphate poisoning in pregnancy. AB - BACKGROUND: Acute organophosphorus pesticide poisoning during pregnancy may lead to spontaneous abortion. Now, there is no definite strategy focused on maintaining pregnancy. METHOD: This is a retrospective analysis of 2 cases of organophosphorus poisoning during pregnancy. All patients received penehyclidine hydrochloride injection,until the tracheobronchial tree is cleared of the secretions, and most secretions were dried. In addition, magnesium sulfate was used in one woman for the correction of hyperdynamic uterine activity. RESULTS: Two women all survived, one fetus died of spontaneous abortion, and one fetus died of incoordinate uterine action. The 2 women had no significant complications during postpartum period. CONCLUSION: Penehyclidine hydrochloride and magnesium sulfate may be used to treat organophosphorus during pregnancy. However, futher study and new experimental need to be designed. PMID- 25542454 TI - Adjunctive analgesia with acupuncture for reduction of anterior shoulder dislocation: a pilot study. PMID- 25542455 TI - The significance of negative myeloperoxidase antineutrophil cytoplasmic antibodies and the role of cyclophosphamide in eosinophilic granulomatosis with polyangiitis. PMID- 25542456 TI - Pifithrin-alpha ameliorates resveratrol-induced two-cell block in mouse preimplantation embryos in vitro. AB - Treatment with resveratrol at concentrations greater than 0.5 MUmol/L resulted in the arrest of mouse embryo development at the two-cell stage. Resveratrol-induced cytotoxicity was investigated in embryos by evaluating morphologic features by using the bromodeoxyuridine assay and acridine orange and ethidium bromide double staining. Resveratrol was found to significantly increase the expressions of p53, p21, Atf3, smac/Diablo, Bax, Bak1, Bok, and Noxa mRNA in the embryos, whereas Cullin 3 and Cdk1 expressions were decreased. Furthermore, active p53 positive signal in embryos arrested at the two-cell stage was localized in the nucleus, whereas no active p53 signal was observed in control embryos. Pretreatment with pifithrin-alpha, a p53 inhibitor, downregulated active p53 in two-cell embryo nuclei and ameliorated approximately 50% of the embryonic developmental defect caused by resveratrol. The findings of the present study, therefore, suggest that pifithrin-alpha could be used as an effective cytoprotective agent against a reproductive toxin such as resveratrol. PMID- 25542457 TI - Effect of cushioned or single layer semen centrifugation before sex sorting on frozen stallion semen quality. AB - The aim of this study was to compare the effect of presorting centrifugation (cushioned [CC] or single-layer colloid [SLC]), with simple dilution (SD), on the quality of sex-sorted stallion semen before and after sorting and after freezing and thawing. Four ejaculates from each of two fertile stallions were collected 1 week apart and evaluated for percent total sperm motility (TM), percent viable acrosome-intact sperm (VAI), and DNA quality (percentage of DNA fragmentation index). Freezing caused, independently from CC and SLC treatments, a significant decrease of TM (P < 0.05) and VAI (P < 0.05) in both unsorted and sorted semen. On the other hand, sorting did not impair TM and VAI and, interestingly, improved DNA quality in all treatments only before freezing (28 vs 13, 28 vs 10, 22 vs 7 in SD, CC, and SLC for unsorted vs sorted groups, respectively; P < 0.05); this positive effect was lost in the same samples after freezing and thawing, suggesting that the freezing process reduces the DNA quality of sex-sorted sperm. Our results suggest that CC and SLC are not able to select those spermatozoa that possess a better ability to withstand sperm processing associated with sperm sorting and freezing. PMID- 25542458 TI - Survival of vitrified in vitro-produced bovine embryos after a one-step warming in-straw cryoprotectant dilution procedure. AB - Vitrification is an alternative to slow-rate freezing for cryopreserving bovine embryos. However, this technology requires simplification if it is to be used under field conditions. The main objective of this work was to develop a new system for the direct transfer of vitrified embryos to be used under farm conditions. For this, three objectives were set: (1) to compare the effect of vitrification, using the cryologic vitrification method (CVM), and slow-rate freezing on bovine embryo development and quality; (2) to develop a one-step warming procedure for bovine in vitro-produced (IVP) vitrified (by CVM) embryos; and (3) to assess the effects on embryo survival of a new method for the direct transfer of vitrified IVP bovine blastocysts. In vitro-produced blastocysts were initially either vitrified by CVM or subjected to slow freezing to compare embryo survival and quality (experiment 1). No differences were detected between these cryopreservation techniques in terms of the survival and quality variables at 24 hours or in terms of the proteins expressed. However, at 48 hours the vitrified embryos showed higher hatching rates, greater total cell numbers, and lower apoptotic indices (P < 0.05). In experiment 2, CVM-vitrified IVP blastocysts were warmed by the conventional two-step or one-step warming procedure by incubating them at 41 degrees C in 0.25 M sucrose for 10 minutes, 0.15 M sucrose for 10 minutes, or 0.25 M sucrose for 5 minutes. In addition, embryo transfer (ET) was performed using vitrified embryos warmed by the one-step procedure in 0.25 M sucrose solution for 5 minutes. As a control group, IVP fresh embryos were transferred to recipient females. No differences were observed in embryo survival or total cell number between any of the warming procedures. Moreover, no significant differences for pregnancy at 60 days were found between the ET groups. In experiment 3, expanded IVP blastocysts were then either vitrified using a conventional or a modified fiber plug designed to allow direct ET after in-straw cryoprotectant (CP) dilution. They were warmed using the one-step process (0.25 M sucrose, 5 minutes) in a 0.25 mL French straw. Embryo recovery associated with the modified fibreplug system was less reliable than with the conventional system. However, no differences were seen between the systems in terms of in vitro embryo survival among those finally recovered. Finally, IVP blastocysts were vitrified using conventional fibreplugs to maintain a high embryo recovery rate, and then warmed using the one-step warming in-straw CP dilution procedure, but using an adapter with a wider opening coupled to the French straw and a heated metal chamber to protect and keep the straw at 41 degrees C (experiment 4). No differences were seen in embryo survival rates between the two groups. The CVM combined with this new one-step warming in-straw CP dilution procedure could be used for direct ET under field conditions. PMID- 25542459 TI - Identification of heat shock protein 10 within the equine embryo, endometrium, and maternal peripheral blood mononuclear cells. AB - Early pregnancy factor has been identified as a 10-kDa extracellular homolog of heat shock protein 10 (Hsp10). Hsp10 has been detected during early pregnancy in serum of mice, sheep, pigs, horses, cows, and humans by the rosette inhibition test. Hsp10 has also been associated with several neoplastic and autoimmune diseases. The goal of the present study was to determine if Hsp10 could be detected in the early equine embryo through the use of immunohistochemistry and quantitative real-time PCR. Additionally, analysis of systemically harvested peripheral blood mononuclear cells (PBMCs) from both pregnant and nonpregnant mares was evaluated to determine expression levels of HSP10. Embryos were collected from Quarter Horse mares by uterine lavage at either 8 or 25 days after ovulation. Collection and separation of PBMCs occurred on Day 8 for both pregnant and nonpregnant mares. Immunohistochemistry revealed cytoplasmic localization of HSP10 throughout the single layer of ectodermal cells forming the trophoblast in Day-8 embryos. Day-25 embryos demonstrated intense localization focally along the apical border of ectodermal cells forming the trophoblast layer of the developing chorion. There was no nuclear staining in either embryonic population. Quantitative real-time PCR detected the presence of mRNA for HSP10 in both 8- and 25-day equine embryos. Day-25 embryos exhibited an elevated degree of expression (P = 0.006) compared with the 8-day embryos for HSP10. Endometrial samples did not display any significant difference in degree of expression for HSP10 (P = 0.10). Finally, PBMCs from pregnant mares demonstrated elevated (P = 0.03) expression of HSP10 compared to the nonpregnant mares on Day 8 of the estrous cycle. This study confirmed the presence of HSP10 protein and mRNA expression of HSP10 in equine embryos at two maturation stages. Additionally, the presence of increased gene expression within PBMCs of pregnant mares suggests communication, possibly leading to necessary immunomodulatory effects between the embryo and mare. PMID- 25542460 TI - Bovine embryo sex determination by multiplex loop-mediated isothermal amplification. AB - In cattle, the ability to determine the sex of embryos before embryo transfer is beneficial for increasing the number of animals with the desired sex. This study therefore developed a new modification of loop-mediated isothermal amplification in a multiplex format (multiplex LAMP) for highly efficient bovine embryo sexing. Two chromosomal regions, one specific for males (Y chromosome, S4 region) and the other common to both males and females (1.715 satellite DNA), were amplified in the same reaction tube. Each target was amplified by specifically designed inner primers, outer primers, and loop primers, where one of the S4 loop primers was labeled with the fluorescent dye 6-carboxyl-X-rhodamine (emitting a red color), whereas both satellite loop primers were labeled with the fluorescent dye fluorescein isothiocyanate (emitting a green color). After amplification at 63 degrees C for 1 hour, the amplified products were precipitated by a small volume of cationic polymer predispensed inside the reaction tube cap. Green precipitate indicated the presence of only control DNA without the Y chromosome, whereas orange precipitate indicated the presence of both target DNAs, enabling interpretation as female and male, respectively. Accuracy of the multiplex LAMP assay was evaluated using 46 bovine embryos with known sex (25 male and 21 female) generated by somatic cell nuclear transfer and confirmed by multiplex polymerase chain reaction. The multiplex LAMP showed 100% accuracy in identifying the actual sex of the embryos and provides a fast, simple, and cost-effective tool for bovine embryo sexing. PMID- 25542461 TI - The emergence of enterovirus D68 in a Dutch University Medical Center and the necessity for routinely screening for respiratory viruses. AB - BACKGROUND: Since August 2014, an increase in infections caused by enterovirus D68 (EV-D68) was reported in the USA and Canada, for the most part in children presenting with severe respiratory symptoms. OBJECTIVES: To determine whether an increase in severe EV-D68 respiratory infections was observed in our region. STUDY DESIGN: Samples from patients with respiratory symptoms were screened for viral pathogens, including rhinovirus and enterovirus. Subsequently, samples positive for rhinovirus and enterovirus were routinely sequenced for phylogenetic analysis. Furthermore, an additional method was used to detect EV-D68 specifically. RESULTS: During the first three quarters of the year 2014, 1896 respiratory samples were analyzed; 39 (2%) of them tested positive for enterovirus. Eighteen samples tested positive for EV-D68, obtained from 16 different patients admitted to our hospital. Eleven were children below the age of 18, of whom five children needed intensive care treatment. The remaining five samples were from adults, who all had an underlying disease; three were transplant patients (heart, lung and renal transplantation), the other two had an underlying lung condition (COPD, asthma). Phylogenetic analysis showed a close relationship with the strains circulating currently in the USA, all belonging to the known EV-D68 genetic subtypes. CONCLUSIONS: We observed an increase of EV-D68 infections in our population, both in children as well as in adult. In 2014 there have been 16 cases so far, compared to none in 2011 and 2013 and a single case in 2012. Phylogenetic analysis identified two similar clusters as shown in the USA and Canada. PMID- 25542462 TI - No evidence H10N8 avian influenza virus infections among poultry workers in Guangdong Province before 2013. PMID- 25542463 TI - Blood MxA protein as a marker for respiratory virus infections in young children. AB - BACKGROUND: Type I interferon induced MxA response can differentiate viral from bacterial infections, but MxA responses in rhinovirus or asymptomatic virus infections are not known. OBJECTIVE: To study MxA protein levels in healthy state and during respiratory virus infection of young children in an observational prospective cohort. STUDY DESIGN: Blood samples and nasal swabs were collected from 153 and 77 children with and without symptoms of respiratory infections, respectively. Blood MxA protein levels were measured by an enzyme immunoassay and PCR methods were used for the detection of respiratory viruses in nasal swabs. RESULTS: Respiratory viruses were detected in 81% of symptomatic children. They had higher blood MxA protein levels (median [interquartile range]) than asymptomatic virus-negative children (695 [345-1370] MUg/L vs. 110 [55-170] MUg/L; p < 0.001). Within asymptomatic children, no significant difference was observed in MxA responses between virus-positive and virus-negative groups. A cut off level of 175 MUg/L had 92% sensitivity and 77% specificity for a symptomatic respiratory virus infection. Rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, coronavirus, and human metapneumovirus infections were associated with elevated MxA responses. Asymptomatic virus negative children vaccinated with a live virus vaccine had elevated MxA protein levels (240 [120-540] MUg/L), but significantly lower than children with an acute respiratory infection, who had not received vaccinations (740 [350-1425] MUg/L; p<0.001). CONCLUSION: Blood MxA protein levels are increased in young children with symptomatic respiratory virus infections, including rhinovirus infections. MxA is an informative general marker for the most common acute virus infections. PMID- 25542464 TI - Mumps outbreak and laboratory diagnosis. AB - BACKGROUND: Several mumps outbreaks have been reported in Europe and in the United States among highly vaccinated populations. Biological diagnosis is classically based on the detection of mumps-specific IgM, but the ability of serological tests to confirm mumps infection seems to be limited among vaccinated patients. OBJECTIVES: We aim to report a mumps outbreak in an engineering school in Grenoble, France, from February to June 2013 and results of the biological testing. STUDY DESIGN: WHO definitions were used to define cases. Mumps--specific IgM and IgG were assessed by a commercially available EIA. Mumps RNA detection by real time reverse transcriptase polymerase chain reaction tests (RT-PCR) and mumps genotyping were performed by the French National Reference Centre for Paramyxoviridae. RESULTS: Sixty two mumps patient-cases were identified using WHO case definitions, 20 being biologically explored, of which 17 were confirmed by biological tests. Vaccination status was documented for 27 patients/62: 4 (14.8%) patients had received one dose of MMR vaccine, and 23 (85.2) two doses of MMR vaccine. Among the biologically explored patients, 83% had a positive RT PCR at the first sampling whereas only 45% had positive or equivocal IgM. All the genotyped strains were genotype G. CONCLUSIONS: Mumps laboratory diagnosis in a highly vaccinated population is challenging. Serological tests among vaccinated patients should be interpreted cautiously and confirmed by RT-PCR tests at the beginning of a mumps outbreak. PMID- 25542465 TI - Minority resistant HIV-1 variants and the response to first-line NNRTI therapy. AB - BACKGROUND: The presence of low-frequency HIV-1 variants with mutations making them resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) could influence the virological response to first-line NNRTI therapy. OBJECTIVES: This study was designed to describe the proportions and quantities of NRTI and NNRTI resistant variants in patients with successful first-line NNRTI therapy. STUDY DESIGN: We evaluated the presence of drug-resistance mutations (DRMs) prior to treatment initiation in 131 naive chronically HIV-1-infected patients initiating NNRTI-based first-line therapy. DRMs were detected by ultradeep pyrosequencing (UDPS) on a GS Junior instrument (Roche). RESULTS: The mean HIV RNA concentration was 4.78 +/- 0.74 log copies/mL and the mean CD4 cell count was 368 +/- 184 CD4 cells/mm(3). Patients were mainly infected with subtype B (68%) and 96% were treated with efavirenz. The sensitivity threshold for each mutation was 0.13 1.05% for 2000 reads. Major NRTI-resistant or NNRTI-resistant mutations were detected in 40 patients (33.6%). The median frequency of major NRTI-resistant mutations was 1.37% [IQR: 0.39-84.1], i.e.: a median of 556 copies/mL [IQR: 123 37,553]. The median frequency of major NNRTI-resistant DRMs was 0.78% [IQR: 0.67 7.06], i.e.: a median of 715 copies/mL [IQR: 391-3452]. The genotypic susceptibility score (GSS) of 9 (7.3%) patients with mutations to given treatment detected by UDPS was 1.5 or 2. CONCLUSIONS: First-line NNRTI-based treatment can produce virological success in naive HIV-1-infected patients harboring low frequency DRMs representing <1% of the viral quasispecies. Further studies are needed to determine the clinical cut-off of low-frequency resistant variants associated to virological failure. PMID- 25542467 TI - Coexistence of circulating HBsAg and anti-HBs antibodies in chronic hepatitis B carriers is not a simple analytical artifact and does not influence HBsAg quantification. AB - BACKGROUND: Presence at the same time of HBsAg and anti-HBs antibodies (HBsAg/Ab) is an entity sometimes encountered in chronic hepatitis B (CHB) carriers. OBJECTIVES: This study was designed to characterize such serological profiles and to assess the reliability of serological marker quantification by three commercially available assays in this setting. STUDY DESIGN: Among 2578 CHB identified patients, 129 (5%) had an HBsAg/Ab profile as determined by Abbott Architect. After exclusion of co-infections (HIV, HCV, HDV), HBV reactivation or HBIg treatment, 101 samples from 62 patients were tested for HBsAg and anti-HBs quantification using Architect, DiaSorin Liaison-XL and Roche Modular-Cobas. Influence of genotype and HBsAg variants was studied in 31 samples with HBV replication. RESULTS: HBsAg detection was confirmed with the 3 techniques for 98% (n = 99) of the samples while the HBsAg/Ab profile was concordant between all techniques for 65% of them. The overall correlation between the 3 HBsAg quantification techniques was good (R(2): 0.94-0.97). The median HBsAg concentration was comparable for the 99 samples whatever the used technique but a bias of -0.11 and 0.02 log IU/mL were noticed for DiaSorin and Roche compared to Abbott, respectively. Anti-HBs quantifications were poorly correlated between techniques with major discrepancies observed. Genotype and substitutions within the "a" determinant showed an impact on HBsAg quantification. CONCLUSIONS: The double HBsAg/Ab profile is not an analytical artifact and is confirmed on all commercially available techniques. While such profile does not influence HBsAg quantification, differences of HBsAg quantification were noticed according to HBV genotype or HBsAg variant. PMID- 25542466 TI - Molecular epidemiology of human rhinovirus infections in the pediatric emergency department. AB - BACKGROUND: Human rhinovirus (HRV) infections are highly prevalent, genetically diverse, and associated with both mild upper respiratory tract and more severe lower tract illnesses (LRTI). OBJECTIVE: To characterize the molecular epidemiology of HRV infections in young children seeking acute medical care. STUDY DESIGN: Nasal swabs collected from symptomatic children <3 years of age receiving care in the Emergency and Urgent Care Departments at Seattle Children's Hospital were analyzed by a rapid polymerase chain reaction (PCR) system (FilmArray((r))) for multiple viruses including HRV/enterovirus. HRV-positive results were confirmed by laboratory-developed real-time reverse transcription PCR (LD-PCR). Clinical data were collected by chart review. A subset of samples was selected for sequencing using the 5' noncoding region. Associations between LRTI and HRV species and genotypes were estimated using logistic regression analysis. RESULTS: Of 595 samples with HRV/enterovirus detected by FilmArray, 474 (80%) were confirmed as HRV by LD-PCR. 211 (96%) of 218 selected samples were sequenced; HRV species A, B, and C were identified in 133 (63%), 6 (3%), and 72 (34%), respectively. LRTI was more common in HRV-C than HRV-A illness episodes (adjusted OR [95% CI] 2.35[1.03-5.35). Specific HRV-A and HRV-C genotypes detected in multiple patients were associated with a greater proportion of LRTI episodes. In 18 patients with >1 HRV-positive illness episodes, a distinct genotype was detected in each. CONCLUSION: Diverse HRV genotypes circulated among symptomatic children during the study period. We found an association between HRV C infections and LRTI in this patient population and evidence of association between specific HRV genotypes and LRTI. PMID- 25542468 TI - Frequent hepatitis E in the Netherlands without traveling or immunosuppression. AB - BACKGROUND AND OBJECTIVE: In several Western countries, silent endemic hepatitis E virus (HEV) infection is common among blood donors. Immunocompromised persons may develop chronic hepatitis E, but the relevance of endemic HEV for immunocompetent persons remains largely unknown. We investigated the immune status and travel history in cases of hepatitis E in the Netherlands. STUDY DESIGN: Between January 2009 and May 2014, physicians throughout the Netherlands submitted samples from 4067 hepatitis patients to Sanquin Diagnostic Services for HEV antibody testing. For the 144 patients testing positive for HEV IgM and HEV RNA, travel behavior and immune status were assessed. Complete information was obtained for 81 patients. RESULTS: Surprisingly, the majority of patients (52/81, 64%) were immunocompetent and did not travel outside Europe. HEV genotyping was obtained for 47 non-traveling patients, all concerned HEV genotype 3. DISCUSSION: Our findings suggest that currently in Western countries the impact of hepatitis E for non-traveling, immunocompetent persons is underestimated. Historically cases of hepatitis A, B and C, but not cases of hepatitis E, are notifiable and warrant preventive measures. However, in parts of Western Europe HEV may have become the most important source of viral hepatitis, in immunocompetent and in immunosuppressed persons. Pending measures against the ongoing transmission of HEV genotype 3 in parts of Europe, physicians should consider hepatitis E in dealing with new hepatitis patients. PMID- 25542469 TI - Clinical characteristics and outcomes of severe rhinovirus-associated pneumonia identified by bronchoscopic bronchoalveolar lavage in adults: comparison with severe influenza virus-associated pneumonia. AB - BACKGROUND: Rhinoviruses (RVs) may cause pneumonia, but the characteristics of RV associated pneumonia have not been adequately evaluated. OBJECTIVE: We aimed to compare characteristics, complications, and outcomes between severe RV- and influenza virus (IFV)-associated pneumonia in adults. STUDY DESIGN: We used prospective cohort data of adult patients with severe pneumonia who had been admitted to the medical intensive care unit of a tertiary care hospital over a 4 year period. The clinical features and outcomes of 27 patients with RV-positive bronchoscopic bronchoalveolar lavage (BAL) fluid were compared to those of 51 pneumonia patients with IFV-positive BAL fluid or IFV-positive nasopharyngeal specimens. RESULTS: Of 356 patients who underwent bronchoscopic BAL and respiratory virus polymerase chain reaction (PCR), RV was the most commonly identified virus (8.1%) from BAL fluid. Patients with RV-associated pneumonia were more likely to be immunocompromised than patients with IFV-associated pneumonia (81.5% vs. 33.3%, p<0.001). Bacterial coinfection tended to be less common in the RV group (18.5% vs. 37.3%, p=0.09). Although septic shock was less common in the RV group (29.6% vs. 54.9%, p=0.03), other clinical manifestations, laboratory findings, and radiologic patterns were similar between the groups. The 28-day mortality of patients with severe RV- and IFV-associated pneumonia was similarly high (29.6% vs. 35.3% respectively, p=0.61). CONCLUSIONS: Severe RV associated pneumonia patients were more likely to be immunocompromised and less likely to present septic shock. Overall clinical features were similar and mortalities of both groups were comparably high. Studies of larger cohorts encompassing mild to moderate pneumonia patients are needed. PMID- 25542471 TI - Paradoxical response to intravenous immunoglobulin in a case of Parvovirus B19 associated chronic fatigue syndrome. AB - We describe a case of chronic fatigue syndrome (CFS) associated to Parvovirus B19 infection where administration of intravenous immunoglobulins (IVIG), previously reported as effective, induced a paradoxical clinical response and increased viral replication. The indication of IVIG administration in the treatment of Parvovirus B19-associated CFS should be carefully reconsidered. PMID- 25542470 TI - Next generation sequencing improves detection of drug resistance mutations in infants after PMTCT failure. AB - BACKGROUND: Next generation sequencing (NGS) allows the detection of minor variant HIV drug resistance mutations (DRMs). However data from new NGS platforms after Prevention-of-Mother-to-Child-Transmission (PMTCT) regimen failure are limited. OBJECTIVE: To compare major and minor variant HIV DRMs with Illumina MiSeq and Life Technologies Ion Personal Genome Machine (PGM) in infants infected despite a PMTCT regimen. STUDY DESIGN: We conducted a cross-sectional study of NGS for detecting DRMs in infants infected despite a zidovudine (AZT) and Nevirapine (NVP) regimen, before initiation of combination antiretroviral therapy. Sequencing was performed on PCR products from plasma samples on PGM and MiSeq platforms. Bioinformatic analyses were undertaken using a codon-aware version of the Smith-Waterman mapping algorithm and a mixture multinomial error filtering statistical model. RESULTS: Of 15 infants, tested at a median age of 3.4 months after birth, 2 (13%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs (K103N and Y181C) by bulk sequencing, whereas PGM detected 4 (26%) and MiSeq 5 (30%). NGS enabled the detection of additional minor variant DRMs in the infant with K103N. Coverage and instrument quality scores were higher with MiSeq, increasing the confidence of minor variant calls. CONCLUSIONS: NGS followed by bioinformatic analyses detected multiple minor variant DRMs in HIV-1 RT among infants where PMTCT failed. The high coverage of MiSeq and high read quality improved the confidence of identified DRMs and may make this platform ideal for minor variant detection. PMID- 25542472 TI - Rapid detection of enterovirus in cerebrospinal fluid by a fully-automated PCR assay is associated with improved management of aseptic meningitis in adult patients. AB - BACKGROUND: Enterovirus (EV) is the most frequent cause of aseptic meningitis (AM). Lack of microbiological documentation results in unnecessary antimicrobial therapy and hospitalization. OBJECTIVES: To assess the impact of rapid EV detection in cerebrospinal fluid (CSF) by a fully-automated PCR (GeneXpert EV assay, GXEA) on the management of AM. STUDY DESIGN: Observational study in adult patients with AM. Three groups were analyzed according to EV documentation in CSF: group A = no PCR or negative PCR (n=17), group B = positive real-time PCR (n = 20), and group C = positive GXEA (n = 22). Clinical, laboratory and health-care costs data were compared. RESULTS: Clinical characteristics were similar in the 3 groups. Median turn-around time of EV PCR decreased from 60 h (IQR (interquartile range) 44-87) in group B to 5h (IQR 4-11) in group C (p<0.0001). Median duration of antibiotics was 1 (IQR 0-6), 1 (0-1.9), and 0.5 days (single dose) in groups A, B, and C, respectively (p < 0.001). Median length of hospitalization was 4 days (2.5-7.5), 2 (1-3.7), and 0.5 (0.3-0.7), respectively (p < 0.001). Median hospitalization costs were $5458 (2676-6274) in group A, $2796 (2062-5726) in group B, and $921 (765-1230) in group C (p < 0.0001). CONCLUSIONS: Rapid EV detection in CSF by a fully-automated PCR improves management of AM by significantly reducing antibiotic use, hospitalization length and costs. PMID- 25542473 TI - Comparison of the Roche Cobas((r)) 4800 HPV assay to Digene Hybrid Capture 2, Roche Linear Array and Roche Amplicor for Detection of High-Risk Human Papillomavirus Genotypes in Women undergoing treatment for cervical dysplasia. AB - BACKGROUND: The recently FDA (U.S. food and drug administration) approved Roche Cobas((r)) 4800 (Cobas) human papillomavirus (HPV) has limited performance data compared to current HPV detection methods for test of cure in women undergoing treatment for high grade lesions. OBJECTIVE: Evaluation of Cobas HPV assay using historical samples from women undergoing treatment for cervical dysplasia. STUDY DESIGN: A selection of 407 samples was tested on the Cobas assay and compared to previous results from Hybrid Capture 2, HPV Amplicor and Roche Linear Array. RESULTS: Overall, a correlation between high-risk HPV positivity and high grade histological diagnosis was 90.6% by the Cobas, 86.1% by Hybrid Capture 2, 92.9% by HPV Amplicor and 91.8% by Roche Linear Array. CONCLUSION: The Cobas HPV assay is comparative to both the HPV Amplicor and Roche Linear Array assays and better than Hybrid capture 2 assay in the detection of High-Risk HPV in women undergoing treatment for cervical dysplasia. PMID- 25542474 TI - Severe viral hepatitis in a patient with chronic lymphocytic leukemia (CLL) complicated with autoimmune hemolytic anemia (AIHA), treated with steroids. AB - Infectious complications are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL) due to impaired immunity secondary to the disease itself and to the immunosuppressive therapies administered to these patients. We report a 78-year-old woman with CLL who was treated with steroids for autoimmune hemolytic anemia (AIHA). A few weeks later, she was admitted for severe acute hepatitis with disseminated intravascular coagulation (DIC). Despite the symptomatic treatment of DIC, standard reanimation and probabilistic antibiotics, the patient died within 24h with severe hepatic failure. Autopsy was in favor of a disseminated viral infection with esophageal, hepatic and pulmonary cytopathologic lesions with acidophilic intranuclear inclusions suggestive of herpes virus, even though HSV 1 and 2, CMV and HHV6 PCRs were negative. This case of severe viral hepatitis with esophagitis occurring three weeks after the introduction of high-dose steroid treatment for AIHA in a CLL patient calls for anti-herpetic prophylaxis in such patients, immunodepressed by their diseases and the treatment they receive. PMID- 25542475 TI - Successful recovery of MERS CoV pneumonia in a patient with acquired immunodeficiency syndrome: a case report. AB - Middle East Respiratory Syndrome Coronavirus (MERS CoV) may cause severe pneumonia with significant morbidity and mortality, particularly in patients with multiple comorbid condition. MERS CoV pneumonia has not been previously reported in patients with Human Immunodeficiency Virus (HIV). Herein, we report a case of MERS CoV pneumonia with a successful outcome in a patient recently diagnosed with HIV. PMID- 25542476 TI - Diffuse gastrointestinal bleeding and BK polyomavirus replication in a pediatric allogeneic haematopoietic stem cell transplant patient. AB - Patients undergoing haematopoietic stem cell transplantation (HSCT) are at high risk of severe gastrointestinal bleeding caused by infections, graft versus host disease, and disturbances in haemostasis. BK polyomavirus (BKPyV) is known to cause hemorrhagic cystitis, but there is also evidence of BKV shedding in stool and its association with gastrointestinal disease. We report putative association of BKPyV replication with high plasma viral loads in a pediatric HSCT patient developing hemorrhagic cystitis and severe gastrointestinal bleeding necessitating intensive care. The observation was based on chart review and analysis of BKPyV DNA loads in plasma and urine as well as retrospective BKPyV specific IgM and IgG measurements in weekly samples until three months post transplant. The gastrointestinal bleeding was observed after a >100-fold increase in the plasma BKPyV loads and the start of hemorrhagic cystitis. The BKPyV specific antibody response indicated past infection prior to transplantation, but increasing IgG titers were seen following BKPyV replication. The gastrointestinal biopsies were taken at a late stage of the episode and were no longer informative of BK polyomavirus involvement. In conclusion, gastrointestinal complications with bleeding are a significant problem after allogeneic HSCT to which viral infections including BKPyV may contribute. PMID- 25542478 TI - Circulating vaccine-derived polioviruses in the Extreme North region of Cameroon. AB - BACKGROUND: The World Health Organization (WHO) poliovirus eradication program includes careful surveillance of acute-flaccid paralysis (AFP) and mass and routine immunization with oral polio vaccine (OPV). In populations with low vaccine coverage, the live-attenuated Sabin strains, OPV types 1, 2 and 3, can evolve into virulent vaccine-derived polioviruses (VDPVs) and circulate in the community. Until recently, circulating VDPVs (cVDPVs) had not been reported in Cameroon despite the fact that VDPV2 outbreaks have occurred in nearby countries. OBJECTIVES: This study aimed to characterize virus isolates from four AFP patients infected with cVDPV2 in the Extreme North region of Cameroon in 2013. STUDY DESIGN: The complete VP1 region of the four VDPV strains was sequenced and the relationships with cVDPVs from neighboring countries were investigated. RESULTS: All four patients were infected by cVDPV2 strains showing 1.2-2.0% nucleotide difference compared to the reference Sabin 2 VP1 sequence. Phylogenetic analysis indicated that the VDPV strains were genetically linked to cVDPV2 lineages of the recent Chad cVDPV2 outbreak. CONCLUSIONS: The circulation of pathogenic VDPVs suggests that there are localized immunization gaps in some districts like Makary, Mada and Kolofata in Cameroon. To avoid poliomyelitis outbreaks in Cameroon, especially in the districts close to neighboring countries with ongoing cVDPV outbreaks, high polio vaccine coverage is essential. PMID- 25542477 TI - Performance of the fourth-generation Bio-Rad GS HIV Combo Ag/Ab enzyme immunoassay for diagnosis of HIV infection in Southern Africa. AB - BACKGROUND: Fourth-generation HIV assays detect both antigen and antibody, facilitating detection of acute/early HIV infection. The Bio-Rad GS HIV Combo Ag/Ab assay (Bio-Rad Combo) is an enzyme immunoassay that simultaneously detects HIV p24 antigen and antibodies to HIV-1 and HIV-2 in serum or plasma. OBJECTIVE: To evaluate the performance of the Bio-Rad Combo assay for detection of HIV infection in adults from Southern Africa. STUDY DESIGN: Samples were obtained from adults in Soweto and Vulindlela, South Africa and Dar es Salaam, Tanzania (300 HIV-positive samples; 300 HIV-negative samples; 12 samples from individuals previously classified as having acute/early HIV infection). The samples were tested with the Bio-Rad Combo assay. Additional testing was performed to characterize the 12 acute/early samples. RESULTS: All 300 HIV-positive samples were reactive using the Bio-Rad Combo assay; false positive test results were obtained for 10 (3.3%) of the HIV-negative samples (sensitivity: 100%, 95% confidence interval [CI]: 98.8-100%); specificity: 96.7%, 95% CI: 94.0-98.4%). The assay detected 10 of the 12 infections classified as acute/early. The two infections that were not detected had viral loads<400 copies/mL; one of those samples contained antiretroviral drugs consistent with antiretroviral therapy. CONCLUSIONS: The Bio-Rad Combo assay correctly classified the majority of study specimens. The specificity reported here may be higher than that seen in other settings, since HIV-negative samples were pre-screened using a different fourth generation test. The assay also had high sensitivity for detection of acute/early infection. False-negative test results may be obtained in individuals who are virally suppressed. PMID- 25542479 TI - Prevalence of HHV-8 in systemic autoimmune diseases. AB - BACKGROUND: Epidemiological data suggest that some viruses may be linked to the development of autoimmunity. OBJECTIVES: The objective of this work was to determine the presence of HHV-8 viral DNA in whole blood from patients suffering from different systemic autoimmune diseases (SAD). We also aimed at testing the prevalence of patients showing antibodies against an HHV-8 orfK8.1 peptide. STUDY DESIGN: Two hundred and eighty SAD patients and 50 healthy blood donor controls were included. Molecular analyses were performed by nested PCR from DNA obtained from whole blood and an enzyme immunoassay was developed in order to test for the presence of antibodies directed against a synthetic peptide derived from the HHV 8 orfK8.1 protein. RESULTS: Only 2 out of the 280 samples analyzed yielded the specific HHV-8 PCR product. Antibodies against orfK8.1 were detected in 2 SLE patients, 1 patient suffering from Sjogren's syndrome and 2 patients with vasculitis. CONCLUSIONS: We conclude that HHV-8 is usually not present in blood neither from autoimmune patients nor from healthy controls. Furthermore, HHV-8 antibodies against the HHV-8 orfK8.1 peptide were rarely detected. It leads us to infer that HHV-8 is not involved on the development of these disorders. It does not rule out the possibility that other environmental and microbiological triggers may account for their etiopathogenesis. PMID- 25542480 TI - Acute hepatitis B caused by a vaccine-escape HBV strain in vaccinated subject: sequence analysis and therapeutic strategy. AB - HBV vaccine contains the 'a' determinant region, the major immune-target of antibodies (anti-HBs). Failure of immunization may be caused by vaccine-induced or spontaneous 'a' determinant surface gene mutants. Here, we evaluate the possible lack of protection by HBV vaccine, describing the case of an acute hepatitis B diagnosed in a 55-year-old Caucasian male unpaid blood donor, vaccinated against HBV. Sequencing data for preS-S region revealed multiple point mutations. Of all the substitutions found, Q129H, located in the "a" determinant region of HBsAg, can alter antigenicity, leading to mutants. This mutant may cause vaccine failure especially when associated with high viremia of infecting source. PMID- 25542481 TI - Strokes and TIAs during and after carotid artery Doppler: cause or coincidence? AB - The aim of the present study was to explore the prevalence of acute cerebrovascular symptoms temporally related to carotid Doppler examination (DEx), in order to increase the awareness and recording of such events and to discuss possible mechanisms. All adult patients who complained of acute onset neurologic symptoms during or shortly after a carotid DEx, between 01/2003 and 12/2011 in the University Hospital of Lausanne were prospectively collected. We identified four consecutive patients with acute onset neurologic symptoms during or shortly after a carotid DEx among approximately 13,500 patients who underwent carotid DEx in our facility during the nine-year period (0.015% of all examined carotids). Clinical data, imaging reports and CTA (CT angiography) or/and ultrasound images are presented for each patient. Ischemic cerebrovascular events during or immediately after cervical Doppler could be due to chance or to several physical factors. They should be promptly recognized by Doppler personnel and properly treated, but do not put into question the overwhelming benefits of Doppler in cerebrovascular patients. PMID- 25542482 TI - Near real-time robust non-rigid registration of volumetric ultrasound images for neurosurgery. AB - Ultrasound images are acquired before and after the resection of brain tumors to help the surgeon to localize the tumor and its extent and to minimize the amount of residual tumor after the resection. Because the brain undergoes large deformation between these two acquisitions, deformable image-based registration of these data sets is of substantial clinical importance. In this work, we present an algorithm for non-rigid registration of ultrasound images (RESOUND) that models the deformation with free-form cubic B-splines. We formulate a regularized cost function that uses normalized cross-correlation as the similarity metric. To optimize the cost function, we calculate its analytic derivative and use the stochastic gradient descent technique to achieve near real time performance. We further propose a robust technique to minimize the effect of non-corresponding regions such as the resected tumor and possible hemorrhage in the post-resection image. Using manually labeled corresponding landmarks in the pre- and post-resection ultrasound volumes, we illustrate that our registration algorithm reduces the mean target registration error from an initial value of 3.7 to 1.5 mm. We also compare RESOUND with the previous work of Mercier et al. (2013) and illustrate that it has three important advantages: (i) it is fully automatic and does not require a manual segmentation of the tumor, (ii) it produces smaller registration errors and (iii) it is about 30 times faster. The clinical data set is available online on the BITE database website. PMID- 25542483 TI - Meshless bubble filter using ultrasound for extracorporeal circulation and its effect on blood. AB - A bubble filter with no mesh structure for extracorporeal circulation using ultrasound was developed. Hemolysis was evaluated by measuring free hemoglobin (FHb). FHb in 120 mL of bovine blood was measured in acoustic standing-wave fields. With a sound pressure amplitude of 60 kPa at driving frequencies of 1 MHz, 500 kHz and 27 kHz for 15 min. FHb values were 641.6, 2575 and 8903 mg/dL, respectively. Thus, hemolysis was inhibited with higher driving frequencies when the same sound pressure amplitude was applied. An ultrasound bubble filter with a resonance frequency of 1 MHz was designed. The filtering characteristics of the flowing microbubbles were investigated with a circulation system using bovine blood with a flow rate of 5.0 L/min. Approximately 99.1% of microbubbles were filtered with 250 kPa and a flow of 5.0 L/min. Hemolysis decreased as the sound pressure decreased; FHb values were 225.8 and 490.7 mg/dL when using 150 and 200 kPa, respectively. PMID- 25542484 TI - The role of viscosity estimation for oil-in-gelatin phantom in shear wave based ultrasound elastography. AB - Shear wave based ultrasound elastography utilizes mechanical excitation or acoustic radiation force to induce shear waves in deep tissue. The tissue response is monitored to obtain elasticity information about the tissue. During the past two decades, tissue elasticity has been extensively studied and has been used in clinical disease diagnosis. However, biological soft tissues are viscoelastic in nature. Therefore, they should be simultaneously characterized in terms of elasticity and viscosity. In this study, two shear wave-based elasticity imaging methods, shear wave dispersion ultrasound vibrometry (SDUV) and acoustic radiation force impulsive (ARFI) imaging, were compared. The discrepancy between the measurements obtained by the two methods was analyzed, and the role of viscosity was investigated. To this end, four types of gelatin phantoms containing 0%, 20%, 30% and 40% castor oil were fabricated to mimic different viscosities of soft tissue. For the SDUV method, the shear elasticity MU1 was 3.90 +/- 0.27 kPa, 4.49 +/- 0.16 kPa, 2.41 +/- 0.33 kPa and 1.31 +/- 0.09 kPa; and the shear viscosity MU2 was 1.82 +/- 0.31 Pa*s, 2.41 +/- 0.35 Pa*s, 2.65 +/- 0.13 Pa*s and 2.89 +/- 0.14 Pa*s for 0%, 20%, 30% and 40% oil, respectively in both cases. For the ARFI measurements, the shear elasticity MU was 7.30 +/- 0.20 kPa, 8.20 +/- 0.31 kPa, 7.42 +/- 0.21 kPa and 5.90 +/- 0.36 kPa for 0%, 20%, 30% and 40% oil, respectively. The SDUV results demonstrated that the elasticity first increased from 0% to 20% oil and then decreased for the 30% and 40% oil. The viscosity decreased consistently as the concentration of castor oil increased from 0% to 40%. The elasticity measured by ARFI showed the same trend as that of the SDUV but exceeded the results measured by SDUV. To clearly validate the impact of viscosity on the elasticity estimation, an independent measurement of the elasticity and viscosity by dynamic mechanical analysis (DMA) was conducted on these four types of gelatin phantoms and then compared with SDUV and ARFI results. The shear elasticities obtained by DMA (3.44 +/- 0.31 kPa, 4.29 +/- 0.13 kPa, 2.05 +/- 0.29 kPa and 1.06 +/- 0.18 kPa for 0%, 20%, 30% and 40% oil, respectively) were lower than those by SDUV, whereas the shear viscosities obtained by DMA (2.52 +/- 0.32 Pa.s, 3.18 +/- 0.12 Pa.s, 3.98 +/- 0.19 Pa.s and 4.90 +/- 0.20 Pa.s for 0%, 20%, 30% and 40% oil, respectively) were greater than those obtained by SDUV. However, the DMA results showed that the trend in the elasticity and viscosity data was the same as that obtained from the SDUV and ARFI. The SDUV results demonstrated that adding castor oil changed the viscoelastic properties of the phantoms and resulted in increased dispersion of the shear waves. Viscosity can provide important and independent information about the inner state of the phantoms, in addition to the elasticity. Because the ARFI method ignores the dispersion of the shear waves, namely viscosity, it may bias the estimation of the true elasticity. This study sheds further light on the significance of the viscosity measurements in shear wave based elasticity imaging methods. PMID- 25542485 TI - Fully automated carotid plaque segmentation in combined contrast-enhanced and B mode ultrasound. AB - Carotid plaque segmentation in B-mode ultrasound (BMUS) and contrast-enhanced ultrasound (CEUS) is crucial to the assessment of plaque morphology and composition, which are linked to plaque vulnerability. Segmentation in BMUS is challenging because of noise, artifacts and echo-lucent plaques. CEUS allows better delineation of the lumen but contains artifacts and lacks tissue information. We describe a method that exploits the combined information from simultaneously acquired BMUS and CEUS images. Our method consists of non-rigid motion estimation, vessel detection, lumen-intima segmentation and media adventitia segmentation. The evaluation was performed in training (n = 20 carotids) and test (n = 28) data sets by comparison with manually obtained ground truth. The average root-mean-square errors in the training and test data sets were comparable for media-adventitia (411 +/- 224 and 393 +/- 239 MUm) and for lumen-intima (362 +/- 192 and 388 +/- 200 MUm), and were comparable to inter observer variability. To the best of our knowledge, this is the first method to perform fully automatic carotid plaque segmentation using combined BMUS and CEUS. PMID- 25542486 TI - User-guided segmentation of preterm neonate ventricular system from 3-D ultrasound images using convex optimization. AB - A three-dimensional (3-D) ultrasound (US) system has been developed to monitor the intracranial ventricular system of preterm neonates with intraventricular hemorrhage (IVH) and the resultant dilation of the ventricles (ventriculomegaly). To measure ventricular volume from 3-D US images, a semi-automatic convex optimization-based approach is proposed for segmentation of the cerebral ventricular system in preterm neonates with IVH from 3-D US images. The proposed semi-automatic segmentation method makes use of the convex optimization technique supervised by user-initialized information. Experiments using 58 patient 3-D US images reveal that our proposed approach yielded a mean Dice similarity coefficient of 78.2% compared with the surfaces that were manually contoured, suggesting good agreement between these two segmentations. Additional metrics, the mean absolute distance of 0.65 mm and the maximum absolute distance of 3.2 mm, indicated small distance errors for a voxel spacing of 0.22 * 0.22 * 0.22 mm(3). The Pearson correlation coefficient (r = 0.97, p < 0.001) indicated a significant correlation of algorithm-generated ventricular system volume (VSV) with the manually generated VSV. The calculated minimal detectable difference in ventricular volume change indicated that the proposed segmentation approach with 3-D US images is capable of detecting a VSV difference of 6.5 cm(3) with 95% confidence, suggesting that this approach might be used for monitoring IVH patients' ventricular changes using 3-D US imaging. The mean segmentation times of the graphics processing unit (GPU)- and central processing unit-implemented algorithms were 50 +/- 2 and 205 +/- 5 s for one 3-D US image, respectively, in addition to 120 +/- 10 s for initialization, less than the approximately 35 min required by manual segmentation. In addition, repeatability experiments indicated that the intra-observer variability ranges from 6.5% to 7.5%, and the inter observer variability is 8.5% in terms of the coefficient of variation of the Dice similarity coefficient. The intra-class correlation coefficient for ventricular system volume measurements for each independent observer ranged from 0.988 to 0.996 and was 0.945 for three different observers. The coefficient of variation and intra-class correlation coefficient revealed that the intra- and inter observer variability of the proposed approach introduced by the user initialization was small, indicating good reproducibility, independent of different users. PMID- 25542488 TI - Changes in backscattered ultrasonic envelope statistics as a function of thrombus age: an in vitro study. AB - It is necessary to determine the age of thrombi in planning clinical treatment for thrombolysis. Ultrasound imaging can potentially be used to evaluate thrombus age in real time. The backscattered signals from thrombi may contain useful information regarding their age. On the basis of the randomness of ultrasound backscattering, this study explored changes in backscattered US statistics as a function of thrombus age. Porcine blood samples were used for the in vitro induction of fresh thrombi (day 0) with hematocrits ranging from 0%-40% and aged thrombi (days 0-8) with a hematocrit of 40%. Each thrombus was imaged using a pulse-echo ultrasound scanner equipped with a 7.5-MHz linear array transducer to acquire raw backscattered signals for B-mode and Nakagami imaging, by which the backscattered statistics were visualized. Hematoxylin and eosin staining and scanning electron microscopy were used to observe the histology of fresh and aged thrombi. The results indicated that a decrease in the number of red blood cells in the thrombus caused by the aging effect was observed in the in vitro model, indicating that the proposed model could simulate the structural changes in the thrombus during aging. Compared with fresh thrombi with various hematocrits, the aged thrombi exhibited a trend toward more substantial decreases in the Nakagami parameter with increasing thrombus age (the Nakagami parameter decreased from 1.1 to 0.6 as thrombus age increased from day 0 to day 8), indicating that thrombus aging causes the backscattered statistics to follow a pre-Rayleigh distribution to a high degree. This finding may be applied to the determination of thrombus age using conventional ultrasound imaging in the future. PMID- 25542487 TI - Treatment of microvascular micro-embolization using microbubbles and long-tone burst ultrasound: an in vivo study. AB - Despite epicardial coronary artery reperfusion by percutaneous coronary intervention, distal micro-embolization into the coronary microcirculation limits myocardial salvage during acute myocardial infarction. Thrombolysis using ultrasound and microbubbles (sonothrombolysis) is an approach that induces microbubble oscillations to cause clot disruption and restore perfusion. We sought to determine whether this technique could restore impaired tissue perfusion caused by thrombotic microvascular obstruction. In 16 rats, an imaging transducer was placed on the biceps femoris muscle, perpendicular to a single element 1-MHz treatment transducer. Ultrasound contrast perfusion imaging was performed at baseline and after micro-embolization. Therapeutic ultrasound (5000 cycles, pulse repetition frequency = 0.33 Hz, 1.5 MPa) was delivered to nine rats for two 10-min sessions during intra-arterial infusion of lipid-encapsulated microbubbles; seven control rats received no ultrasound-microbubble therapy. Ultrasound contrast perfusion imaging was repeated after each treatment or control period, and microvascular volume was measured as peak video intensity. There was a 90% decrease in video intensity after micro-embolization (from 8.6 +/ 4.8 to 0.7 +/- 0.8 dB, p < 0.01). The first and second ultrasound-microbubble sessions were respectively followed by video intensity increases of 5.8 +/- 5.1 and 8.7 +/- 5.7 dB (p < 0.01, compared with micro-embolization). The first and second control sessions, respectively, resulted in no significant increase in video intensity (2.4 +/- 2.3 and 3.6 +/- 4.9) compared with micro-embolization (0.6 +/- 0.7 dB). We have developed an in vivo model that simulates the distal thrombotic microvascular obstruction that occurs after primary percutaneous coronary intervention. Long-pulse-length ultrasound with microbubbles has a therapeutic effect on microvascular perfusion and may be a valuable adjunct to reperfusion therapy for acute myocardial infarction. PMID- 25542489 TI - Measurement of the Doppler power of flowing blood using ultrasound Doppler devices. AB - Measurement of the Doppler power of signals backscattered from flowing blood (henceforth referred to as the Doppler power of flowing blood) and the echogenicity of flowing blood have been used widely to assess the degree of red blood cell (RBC) aggregation for more than 20 y. Many studies have used Doppler flowmeters based on an analogue circuit design to obtain the Doppler shifts in the signals backscattered from flowing blood; however, some recent studies have mentioned that the analogue Doppler flowmeter exhibits a frequency-response problem whereby the backscattered energy is lost at higher Doppler shift frequencies. Therefore, the measured Doppler power of flowing blood and evaluations of RBC aggregation obtained using an analogue Doppler device may be inaccurate. To overcome this problem, the present study implemented a field programmable gate array-based digital pulsed-wave Doppler flowmeter to measure the Doppler power of flowing blood, in the aim of providing more accurate assessments of RBC aggregation. A clinical duplex ultrasound imaging system that can acquire pulsed-wave Doppler spectrograms is now available, but its usefulness for estimating the ultrasound scattering properties of blood is still in doubt. Therefore, the echogenicity and Doppler power of flowing blood under the same flow conditions were measured using a laboratory pulser-receiver system and a clinical ultrasound system, respectively, for comparisons. The experiments were carried out using porcine blood under steady laminar flow with both RBC suspensions and whole blood. The experimental results indicated that a clinical ultrasound system used to measure the Doppler spectrograms is not suitable for quantifying Doppler power. However, the Doppler power measured using a digital Doppler flowmeter can reveal the relationship between backscattering signals and the properties of blood cells because the effects of frequency response are eliminated. The measurements of the Doppler power and echogenicity of flowing blood were compared with those obtained in several previous studies. PMID- 25542491 TI - Role of shear wave sonoelastography in differentiation between focal breast lesions. AB - Our goal in this study was to evaluate the relevance of shear wave sonoelastography (SWE) in the differential diagnosis of masses in the breast with respect to ultrasound (US). US and SWE were performed (Aixplorer System, SuperSonic Imagine, Aix en Provence, France) in 76 women (aged 24 to 85) with 84 lesions (43 malignant, 41 benign). The study included BI-RADS-US (Breast Imaging Reporting and Data System for Ultrsound) category 3-5 lesions. In elastograms, the following values were calculated: mean elasticity in lesions (E(av.l)) and in fat tissue (E(av.f.)) and maximal (E(max.adj.)) and mean (E(av.adj.)) elasticity in lesions and adjacent tissues. The sensitivity and specificity of the BI-RADS category 4a/4b cutoff value were 97.7% and 90.2%. For an E(av.adj.) of 68.5 kPa, the cutoff sensitivity was 86.1% and the specificity was 87.8%, and for an E(max.adj.) of 124.1 kPa, 74.4% and 92.7%, respectively. For BI-RADS-US category 3 lesions, E(av.l), E(max.adj.) and E(av.adj.) were below cutoff levels. On the basis of our findings, E(av.adj.) had lower sensitivity and specificity compared with US. Emax.adj. improved the specificity of breast US with loss of sensitivity. PMID- 25542490 TI - An ultrasound-driven kinematic model for deformation of the infarcted mouse left ventricle incorporating a near-incompressibility constraint. AB - Mathematical models of varying complexity have proved useful in fitting and interpreting regional cardiac displacements obtained from imaging methods such as ultrasound speckle tracking or MRI tagging. Simpler models, such as the classic thick-walled cylinder model of the left ventricle (LV), can be solved quickly and are easy to implement, but they ignore regional geometric variations and are difficult to adapt to the study of regional pathologies like myocardial infarctions. Complex, anatomically accurate finite-element models work well, but are computationally intensive and require specialized expertise to implement. We developed a kinematic model that offers a compromise between these two traditional approaches, assuming only that displacements in the left ventricle are polynomial functions of initial position and that the myocardium is nearly incompressible, while allowing myocardial motion to vary spatially as would be expected in an ischemic or dyssynchronous LV. Model parameters were determined using an objective function with adjustable weights to account for confidence in individual displacement components and desired strength of the incompressibility constraint. The model accurately represented the motion of both normal and infarcted mouse LVs during the cardiac cycle, with normalized root mean square errors in predicted deformed positions of 8.2 +/- 2.3% and 7.4 +/- 2.1% for normal and infarcted hearts, respectively. PMID- 25542492 TI - Global and regional left ventricular strain indices in post-myocardial infarction patients with ventricular arrhythmias and moderately abnormal ejection fraction. AB - The aim of the study described here was to compare myocardial strains in ischemic heart patients with and without sustained ventricular tachycardia (VT) and moderately abnormal left ventricular ejection fraction (LVEF) to investigate which index could better predict VT on the basis of the analysis of global and regional left ventricular (LV) dysfunction. We studied 467 patients with previous myocardial infarction and LVEF >35%. Fifty-one patients had documented VT, and 416 patients presented with no VT. LV volumes and score index were obtained by 2 D echocardiography. Longitudinal, radial and circumferential strains were determined. Strains of the infarct, border and remote zones were also obtained. There were no differences in standard LV 2-D parameters between patients with and those without VT. Receiver operating characteristic values were -12.7% for global longitudinal strain (area under the curve [AUC] = 0.72), -4.8% for posterior inferior wall circumferential strain (AUC = 0.80), 61 ms for LV mechanical dispersion (AUC = 0.84), -10.1% for longitudinal strain of the border zone (AUC = 0.86) and -9.2% for circumferential strain of the border zone (AUC = 0.89). In patients with previous myocardial infarction and moderately abnormal LVEF, peri infarct circumferential strain was the strongest predictor of documented ventricular arrhythmias among all strain quantitative indices. Additionally, strain values from posterior-inferior wall infarctions had a higher association with arrhythmic events compared with global strain. PMID- 25542493 TI - Mammographic and sonographic features of triple-negative invasive carcinoma of no special type. AB - The aim of this study was to compare the mammography, ultrasound (US) and histologic features of triple-negative (TN) invasive carcinoma of no special type (NST) to non-TN invasive carcinoma of NST. The second aim was to assess whether the distinct imaging characteristics of TN breast cancer would persist after controlling for the histologic features. A total of 344 invasive carcinomas of NST in 337 patients from January 2007 to February 2008 were included in this study. Two radiologists retrospectively reviewed the mammography and US findings using the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicon and our institution's criteria. On mammography, TN invasive carcinoma of NST most commonly presented as a mass with round shape and non spiculated margin. On US, it was more likely to have internal hypoechogenicity, an abrupt boundary and posterior acoustic enhancement. TNBC lacked major suspicious imaging findings such as an irregular shape, spiculated margin and calcification. PMID- 25542494 TI - Effect of biological characteristics of different types of uterine fibroids, as assessed with T2-weighted magnetic resonance imaging, on ultrasound-guided high intensity focused ultrasound ablation. AB - The aims of this study were to assess the effects of the biological characteristics of different types of uterine fibroids, as assessed with T2 weighted magnetic resonance imaging (MRI), on ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation. Thirty-five patients with 39 symptomatic uterine fibroids who underwent myomectomy or hysterectomy were enrolled. Before surgery, the uterine fibroids were subdivided into hypo-intense, iso-intense, heterogeneous hyper-intense and homogeneous hyper-intense categories based on signal intensity on T2-weighted MRI. Tissue density and moisture content were determined in post-operative samples and normal uterine tissue, the isolated uterine fibroids were subjected to USgHIFU, and the extent of ablation was measured using triphenyltetrazolium chloride. Hematoxylin and eosin staining and sirius red staining were undertaken to investigate the organizational structure of the uterine fibroids. Estrogen and progesterone receptor expression was assayed via immunohistochemical staining. The mean diameter of uterine fibroids was 6.9 +/- 2.8 cm. For all uterine fibroids, the average density and moisture content were 10.7 +/- 0.7 mg/mL and 75.7 +/- 2.4%, respectively; and for the homogeneous hyper-intense fibroids, 10.3 +/- 0.5 mg/mL and 76.6 +/- 2.3%. The latter subgroup had lower density and higher moisture content compared with the other subgroups. After USgHIFU treatment, the extent of ablation of the hyper intense fibroids was 102.7 +/- 42.1 mm(2), which was significantly less than those of the hypo-intense and heterogeneous hyper-intense fibroids. Hematoxylin and eosin staining and sirius red staining revealed that the homogeneous hyper intense fibroids had sparse collagen fibers and abundant cells. Immunohistochemistry results revealed that estrogen and progesterone receptors were highly expressed in the homogeneous hyper-intense fibroids. This study revealed that lower density, higher moisture content, sparse collagen fibers, abundant cells and overexpression of estrogen and progesterone receptors are important biological characteristics that resulted in poor efficacy in the treatment of homogeneous hyper-intense fibroids. PMID- 25542495 TI - Defining the optimal age for focal lesioning in a rat model of transcranial HIFU. AB - This study aimed at determining the optimal age group for high-intensity focused ultrasound (HIFU) experiments for producing lesions in rats. Younger rats have thinner skulls, allowing for the acoustic waves to propagate easily through the skull without causing burns of the skin and brain surface. Younger rats however, have a smaller brain that can make HIFU focusing in the brain parenchyma challenging because of the focus size. In this study, we conducted transcranial HIFU sonications in rat pups of different ages (from 9 to 43 d) with a 1.5MHz MR compatible transducer. The electric power was selected to always reach a target temperature of at least 50 degrees C in the parenchyma. The thickness of the skull and of the brain parenchyma was measured using T2-weighted MR imaging. Results showed that the thickness of the brain parenchyma increased quickly from P9 to P12, reaching 8.5 mm at P16, and then increasing gradually along with age. The skull thickness increased gradually from P9 to P26, and then more quickly after P30. The ratio between brain parenchyma thickness and skull thickness decreased gradually with age. For the pups at 30 d, the temperature in the brain tissue adjacent to the skull increased to 48.9 degrees C, and those from the rodents older than 33 d reached 60 degrees C or higher, which can produce undesired irreversible damage in this location. We conclude that young rats aged 16-26 d are optimal for experiments producing transcranial HIFU lesions in rats with an intact skull. PMID- 25542497 TI - Hepatic angiomyolipomas: ultrasonic characteristics of 25 patients from a single center. AB - Twenty-five pathologically proven hepatic angiomyolipomas (AMLs) were included in the study. Ultrasonic features of hepatic AMLs were reviewed. Three types of echogenicity were observed on ultrasound examination: (i) strong hyper echogenicity, (ii) moderate hyper-echogenicity and (iii) hypo-echogenicity. Vascular signals within tumors could be detected in 22 (88.00%) tumors as multiple punctiform, filiform or dendriform signals by color Doppler flow imaging. Based on the enhancement patterns in the arterial, portal and late phases, the features of hepatic AMLs on contrast-enhanced ultrasound were divided into four subtypes: (i) "fast in slow out" (68.00%, n = 17); (ii) "fast in same out" (16%, n = 4); (iii) "fast in fast out" (12.00%, n = 3); and (iv) "fast in uneven out" (4.00%, n = 1). Contrast-enhanced ultrasound diagnosed 22 (88.00%) tumors as benign tumors and 13 (52.00%) as hepatic AMLs. Four cases were misdiagnosed as hepatic hemangioma, five cases as focal nodular hyperplasia (total = 36.00%). The rate of correct diagnosis of hepatic AMLs increased significantly from 24.00% for ultrasound alone to 52.00% for contrast-enhanced ultrasound. Therefore, information obtained from ultrasound, color Doppler flow imaging and contrast-enhanced ultrasound should be combined to improve diagnosis. PMID- 25542496 TI - Wall-less flow phantom for high-frequency ultrasound applications. AB - There are currently very few test objects suitable for high-frequency ultrasound scanners that can be rapidly manufactured, have appropriate acoustic characteristics and are suitably robust. Here we describe techniques for the creation of a wall-less flow phantom using a physically robust konjac and carrageenan-based tissue-mimicking material. Vessel dimensions equivalent to those of mouse and rat arteries were achieved with steady flow, with the vessel at a depth of 1.0 mm. We then employed the phantom to briefly investigate velocity errors using pulsed wave Doppler with a commercial preclinical ultrasound system. This phantom will provide a useful tool for testing preclinical ultrasound imaging systems. PMID- 25542498 TI - Atypical presentation of a distal cerebral aneurysm: Location and outcome in a young woman. PMID- 25542500 TI - Fatal outcome following thrombolysis for stroke secondary to infectious endocarditis. PMID- 25542499 TI - Applicability of the SPAN-100 index in a prospective and contemporary cohort of patients treated with intravenous rtPA in Catalonia. AB - BACKGROUND: Prognostic scales can be helpful for selecting patients for reperfusion treatment. This study aims to assess the prognostic ability of the recently published SPAN-100 index in a large cohort of stroke patients treated with intravenous thrombolysis (IV rtPA). METHODS: Using data from the prospective registery of all reperfusion treatments administered in Catalonia, we selected patients treated with IV rtPA alone between 2011 and 2012. The SPAN-100 index was calculated as the sum of age (years) and NIHSS score, and patients in the cohort were classified as SPAN-100 positive [>= 100] or SPAN-100 negative [< 100]. We measured raw and adjusted rates of symptomatic intracerebral haemorrhage (SICH), mortality, and 3-month functional outcome (mRS 0-2) for each SPAN-100 category. Area under the ROC curve was calculated to predict the main outcome measures. RESULTS: We studied 1685 rtPA-treated patients, of whom 1405 (83%) were SPAN-100 negative. The SICH rates adjusted for sex, pre-stroke mRS, hypertension, diabetes, dyslipidaemia, ischaemic heart disease, heart failure, atrial fibrillation, prior TIA/stroke and time to thrombolysis did not differ between groups, but likelihood of functional independence (mRS 0-2) at 3 months was nearly 8 times higher in the SPAN-100 negative group than in the positive group. Furthermore, the 3-month mortality rate was 5 times higher in the SPAN-100 positive group. ROC curve analysis showed high specificities for predicting both functional independence and 3-month mortality for a cut-off point of 100. CONCLUSION: The SPAN-100 index is a simple and straightforward method that may be useful for selecting candidates for rtPA treatment in doubtful cases, and for informing patients and their relatives about likely outcomes. PMID- 25542501 TI - Experience with Guillain-Barre syndrome in a neurological Intensive Care Unit. AB - INTRODUCTION: Guillain-Barre syndrome, an acute polyradiculoneuropathy that presents with weakness and areflexia, is the most common cause of acute flaccid paralysis. In certain patients, respiratory failure is secondary to this disorder, eventually causing patients to require mechanical ventilation and experience additional complications due to diminished respiratory support and related mobility limitations. Prognoses for most of these cases are positive; treatment consists of basic support combined with plasmapheresis or administration of immunoglobulins. OBJECTIVE: This study sought to describe the socio-demographic, clinical, laboratory and neurophysiological characteristics of patients with Guillain-Barre syndrome who were hospitalised in the Intensive Care Unit of the Neurological Institute of Colombia between 2006 and 2012. METHODOLOGY: This study presents a case series. RESULTS: We surveyed 25 patients (32% female and 68% male) with Guillain-Barre syndrome and an average age of 54 years. Sixty per cent of these patients were admitted between days 3 and 7 after symptom onset; 64% had a history of respiratory infection and 20% had a history of intestinal infection. In addition, 84% of the patients presented with albuminocytological dissociation. We observed the following clinical subtypes of Guillain-Barre syndrome: inflammatory demyelinating polyneuropathy in 32%, acute motor-sensory axonal neuropathy in 28%, acute motor axonal neuropathy in 28%, and Miller Fisher syndrome in 12%. CONCLUSIONS: In this descriptive study of a group of critical care patients with GBS, results depended on patients' clinical severity at time of admission. Our findings are similar to results published in the international literature. PMID- 25542502 TI - Analysis of in-hospital consultations between the emergency department and the on call neurologist due to headaches. PMID- 25542503 TI - Role of genes GSTM1, GSTT1, and MnSOD in the development of late-onset Alzheimer disease and their relationship with APOE*4. AB - INTRODUCTION: Several studies have reported increased oxidation of lipids, proteins and DNA in the brains of patients with Alzheimer disease (AD). Moreover, these patients display differences in the activity and polymorphisms of the genes encoding the enzymes GST (T1, M1) and MnSOD. For these reasons, we designed a study of the variability in GSTT1, GSTM1, and MnSOD genes in healthy and AD groups from a Venezuelan population. METHODS: We included 179 unrelated Venezuelan subjects classified as either AD patients (n=79) or healthy individuals (n=100). Presence or absence of the GSTT1/GSTM1 genes was determined using PCR-SSP, and polymorphisms of MnSOD and APOE genes were identified with PCR RFLP. RESULTS: The genotype GSTT1+/GSTM1- seems to favour development of AD (OR=2.06, P=.01). The risk level is higher when it is combined with the E4 allele of the APOE gene: GSTT1+/GSTM1-/E3E4 (OR=3.07, P=.05), GSTT1+/GSTM1-/E4E4 (OR=5.52, P=.02). The Ala-9Val polymorphism does not appear to be related to AD. However, the presence of the Ala/Ala genotype increases the risk provided by the E4 allele of the APOE gene: AlaAla/E3E4 (OR=3.47, P=.03), AlaAla/E4E4 (OR=6.3, P=.01). CONCLUSIONS: The results support the hypothesis that impaired mitochondrial function and increased oxidative damage are involved in the pathogenesis of AD. It is important to study other genes related to oxidative stress and antioxidant pathways which could be involved in susceptibility to AD. PMID- 25542504 TI - The potential use of salivary nitrite as a marker of NO status in humans. PMID- 25542505 TI - Alteration of Surface EMG amplitude levels of five major trunk muscles by defined electrode location displacement. AB - Exact electrode positioning is vital for obtaining reliable results in Surface EMG. This study aimed at systematically assessing the influence of defined electrode shifts on measured Surface EMG amplitudes of trunk muscles in a group of 15 middle aged healthy male subjects. The following leftsided muscles were investigated: rectus abdominis muscle, internal and external oblique abdominal muscles, lumbar multifidus muscle, and longissimus muscle. In addition to the recommended electrode positions, extra electrodes were placed parallel to these and along muscle fiber direction. Measurements were performed under isometric conditions in upright body position. Gradually changing, but defined loads were applied considering subject's upper body weight. For the abdominal muscles amplitude differences varied considerably depending on load level, magnitude, and direction. For both back muscles amplitudes dropped consistently but rather little for parallel electrode displacements. However, for the longissimus muscle a caudal electrode shift resulted in an amplitude increase of similar extent and independent from load level. Influence of electrode position variations can be proven for all trunk muscles but are more evident in abdominal than back muscles. Those muscle-specific effects confirm the necessity for an exact definition of electrode positioning to allow comparisons between individual subjects, groups of subjects, and studies. PMID- 25542506 TI - alpha-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects. AB - alpha-Lipoic acid (alpha-Lip) is a natural occurring antioxidant with beneficial anti-obesity properties. The aim of this study was to investigate the putative effects of alpha-Lip on mitochondrial biogenesis and the acquirement of brown like characteristics by subcutaneous adipocytes from overweight/obese subjects. Thus, fully differentiated human subcutaneous adipocytes were treated with alpha Lip (100 and 250MUM) for 24h for studies on mitochondrial content and morphology, mitochondrial DNA (mtDNA) copy number, fatty acid oxidation enzymes and brown/beige characteristic genes. The involvement of the Sirtuin1/Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (SIRT1/PGC-1alpha) pathway was also evaluated. Our results showed that alpha-Lip increased mitochondrial content in cultured human adipocytes as revealed by electron microscopy and by mitotracker green labeling. Moreover, an enhancement in mtDNA content was observed. This increase was accompanied by an up-regulation of SIRT1 protein levels, a decrease in PGC-1alpha acetylation and up-regulation of Nuclear respiratory factor 1 (Nrf1) and Mitochondrial transcription factor (Tfam) transcription factors. Enhanced oxygen consumption and fatty acid oxidation enzymes, Carnitine palmitoyl transferase 1 and Acyl-coenzyme A oxidase (CPT-1 and ACOX) were also observed. Mitochondria from alpha-Lip-treated adipocytes exhibited some morphological characteristics of brown mitochondria, and alpha-Lip also induced up-regulation of some brown/beige adipocytes markers such as cell death-inducing DFFA-like effector a (Cidea) and T-box 1 (Tbx1). Moreover, alpha Lip up-regulated PR domain containing 16 (Prdm16) mRNA levels in treated adipocytes. Therefore, our study suggests the ability of alpha-Lip to promote mitochondrial biogenesis and brown-like remodeling in cultured white subcutaneous adipocytes from overweight/obese donors. PMID- 25542507 TI - Metabolism and functions of lipids in myelin. AB - Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are lipid-rich and multilamellar membrane stacks. The lipid composition of myelin varies significantly from other biological membranes. Studies in mutant mice targeting various lipid biosynthesis pathways have shown that myelinating glia have a remarkable capacity to compensate the lack of individual lipids. However, compensation fails when it comes to maintaining long-term stability of myelin. Here, we summarize how lipids function in myelin biogenesis, axon-glia communication and in supporting long-term maintenance of myelin. We postulate that change in myelin lipid composition might be relevant for our understanding of aging and demyelinating diseases. This article is part of a Special Issue titled Brain Lipids. PMID- 25542508 TI - Brain membrane lipids in major depression and anxiety disorders. AB - Major depression and anxiety disorders have high prevalence rates and are frequently comorbid. The neurobiological bases for these disorders are not fully understood, and available treatments are not always effective. Current models assume that dysfunctions in neuronal proteins and peptide activities are the primary causes of these disorders. Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membrane's function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors. These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment. This article is part of a Special Issue entitled Brain Lipids. PMID- 25542509 TI - The capacity for long-chain polyunsaturated fatty acid synthesis in a carnivorous vertebrate: Functional characterisation and nutritional regulation of a Fads2 fatty acyl desaturase with Delta4 activity and an Elovl5 elongase in striped snakehead (Channa striata). AB - The endogenous production of long-chain polyunsaturated fatty acids (LC-PUFA) in carnivorous teleost species inhabiting freshwater environments is poorly understood. Although a predatory lifestyle could potentially supply sufficient LC PUFA to satisfy the requirements of these species, the nutrient-poor characteristics of the freshwater food web could impede this advantage. In this study, we report the cloning and functional characterisation of an elongase enzyme in the LC-PUFA biosynthesis pathway from striped snakehead (Channa striata), which is a strict freshwater piscivore that shows high deposition of LC PUFA in its flesh. We also functionally characterised a previously isolated fatty acyl desaturase cDNA from this species. Results showed that the striped snakehead desaturase is capable of Delta4 and Delta5 desaturation activities, while the elongase showed the characteristics of Elovl5 elongases. Collectively, these findings reveal that striped snakehead exhibits the genetic resources to synthesise docosahexaenoic acid (DHA; 22:6n-3) from eicosapentaenoic acid (EPA; 20:5n-3). Both genes are expressed at considerable levels in the brain and the liver. In liver, both genes were up-regulated by dietary C18 PUFA, although this increase did not correspond to a significant rise in the deposition of muscle LC PUFA. Brain tissue of fish fed with plant oil diets showed higher expression of fads2 gene compared to fish fed with fish oil-based diet, which could ensure DHA levels remain constant under limited dietary DHA intake. This suggests the importance of DHA production from EPA via the ?4 desaturation step in order to maintain an optimal reserve of DHA in the neuronal tissues of carnivores. PMID- 25542510 TI - Molecular cloning of a C-type lectin with one carbohydrate recognition domain from Fenneropenaeus merguiensis and its expression upon challenging by pathogenic bacterium or virus. AB - Lectins, one type of pattern recognition proteins, play important roles in an innate immunity of crustaceans including shrimp. A new C-type lectin designated FmLC1 was cloned from the hepatopancreas of banana shrimp Fenneropenaeus merguiensis by procedures of PCR and 5' and 3' rapid amplification of cDNA ends (RACE). The full-length cDNA is composed of 706bp with a single open reading frame of 477bp, encoding a peptide of 158 amino acid residues. Its deduced amino acid sequence comprises a putative signal peptide of 17 amino acids and has an estimated molecular mass of 17,934Da with a theoretical pI of 4.46. The primary sequence of FmLC1 contains a single carbohydrate recognition domain (CRD) with an EPS (Glu-Pro-Ser) motif and one Ca(2+) binding site, stabilized by two disulfide bonds. FmLC1 mRNA was detected to express specifically in the hepatopancreas, a master organ in shrimp. Its expression in the hepatopancreas was up-regulated to reach the maximum at 12 or 48h following challenge of shrimp with Vibrio harveyi or white spot syndrome virus, respectively. These results suggest that FmLC1 may participate in recognition of invading pathogens such as bacteria and viruses, and play roles in the immune response of shrimp even at different stages of the clearance of pathogens. PMID- 25542512 TI - Highly efficient syntheses of nano mixed-anions lead(II) thiocyanate/nitrate and lead(II) thiocyanate coordination polymers by sonochemical process. AB - Nanostructures of the three-dimensional coordination polymers with the ligand 2,5 bis(4-pyridyl)-3,4-diaza-2,4-hexadiene (4-bpdh), [Pb(4-bpdh)(NO3)(MU-NCS)]n (1) and [Pb(4-bpdh)(MU-NCS)2]n (2), have been synthesized by a sonochemical process at different concentrations and characterized by scanning electron microscopy, X ray powder diffraction, IR spectroscopy and elemental analyses. The solid state structural transformations of nano-compounds 1, 2 by anion-replacement processes under mechanochemical reaction, have been verified by IR and PXRD measurements. The SEM images showed that morphology change occurs on nanostructures during solid state anion-replacements. PMID- 25542511 TI - Comparative effects of intranasal neuropeptide Y and HS014 in preventing anxiety and depressive-like behavior elicited by single prolonged stress. AB - Stress triggered neuropsychiatric disorders are a serious societal problem. Prophylactic treatment or early intervention has great potential in increasing resilience to traumatic stress and reducing its harmful impact. Previously, we demonstrated proof of concept that intranasal administration of neuropeptide Y (NPY) or the melanocortin receptor four (MC4R) antagonist, HS014, prior to single prolonged stress (SPS) rodent post-traumatic stress disorder (PTSD) model, can prevent or attenuate many PTSD associated impairments. Here, we compare effects of NPY or HS014 given 30 min before or immediately after SPS stressors on development of anxiety, depressive-like behavior and associated biochemical abnormalities. SPS triggered anxiety on elevated plus maze (EPM) was reduced by intranasal administration of 100 MUg NPY and to even greater extent HS014 (3.5 ng or 100 MUg). The SPS-elicited depressive-like behavior on forced swim test was prevented with 100 MUg NPY or the high dose HS014. Combined administration of low HS014 and NPY, ineffective by themselves, prevented development of depressive like behavior. Reductions in stress triggered activation of locus coeruleus/noradrenergic system and HPA axis were observed with both HS014 and NPY. In contrast to NPY which has been showed earlier, infusion of HS014 immediately after SPS did not prevent the development of anxiogenic behavior on EPM. However, HS014 given after SPS stressors effectively even at very low dose, prevented development of depressive-like behavior. Thus, both MC4R antagonist and NPY, alone or combined, have potential for prophylactic treatment against traumatic stress triggered anxiety or depressive-like behaviors, while NPY has more widespread potential for early intervention. PMID- 25542514 TI - Cingulate and insula: the pain in the brain is not all the same. PMID- 25542513 TI - Ultrasound-assisted extraction and purification of taurine from the red algae Porphyra yezoensis. AB - The present study reports on the development of a method using ultrasound assisted extraction (UAE) during the purification of taurine from Porphyra yezoensis. The Box-Behnken design, which is a widely used form of response surface methodology, was used to investigate the effects of parameters on the UAE process. Three independent variables of taurine purification using UAE were studied including: extraction time, temperature, and ultrasonic power. The results showed that the highest taurine yield of 13.0mg/g was obtained with an extraction time of 38.3 min, the use of 300.0 W ultrasonic power, and an extraction temperature of 40.5 degrees C. A comparative study of taurine extraction was also conducted using either ultrasonication or mechanical agitation. The results indicated that the ultrasonic process required 9 times less time at 40 degrees C to obtain taurine with a similar yield as compared to the conventional extraction method. Therefore, UAE can used as an alternative to the conventional extraction method used during the recovery of taurine from P. yezoensis. The UAE method has several advantages, including that it uses lower extraction temperatures and has a shorter extraction time. The taurine present in the extract supernatant was efficiently separated and purified using a combination of 732 cation exchange chromatography and crystallization. The yield of purified taurine using this process was 1.1%. The structure of the purified taurine was confirmed by FTIR, MS, and NMR. Our findings suggest that P. yezoensis can be used as a taurine-rich food or food material. PMID- 25542515 TI - What can we learn about depression from gene expression in peripheral tissues? PMID- 25542516 TI - Hippocampal subfields and major depressive disorder. PMID- 25542517 TI - Differences between information in registries and articles did not influence publication acceptance. AB - OBJECTIVES: To assess whether journals are more likely to reject manuscripts with differences between information in registries and articles. We compared differences by sponsorship and assessed whether selective reporting favored publication of significant outcomes. STUDY DESIGN AND SETTING: Drug trials submitted to eight journals (January 2010-April 2012) were included. Publication status, primary outcomes, enrollment, and sponsorship were extracted. Primary outcomes and enrollment in registries and registration timing were reviewed. Prospective registration included registration before study start. Consistency between registered and reported information was evaluated. RESULTS: For 226 submitted manuscripts, primary outcomes were specified in both article and registry. Sixty six of 226 (29.2%) had primary outcome differences; 14 of 66 manuscripts with differences (21.2%) and 46 of 160 without differences (28.8%) were accepted. Fifty manuscripts (22.4%) had sample size differences; 10 of 50 with differences (20.0%) and 49 of 173 without differences (28.3%) were accepted. Industry-sponsored trials had less differences and were more often prospectively registered. After adjustment for sponsorship, differences and/or retrospective registration were not associated with decreased chance of acceptance (odds ratio 0.56; 95% confidence interval: 0.27, 1.13). Primary outcome differences favored significant outcomes in 49% of manuscripts. CONCLUSION: Differences between registered and reported information are not decisive for rejection. Editors should assess consistency between registries and articles to address selective reporting. PMID- 25542518 TI - Acute kidney injury in septic patients admitted to emergency clinical room: risk factors and outcome. AB - PURPOSE: Acute kidney injury (AKI) is a common source of morbidity in sepsis. We sought to determine risk factors for AKI, by acute kidney injury network (AKIN) criteria, in septic patients admitted in emergency clinical room (ER). MATERIALS AND METHODS: Prospective cohort study of 200 patients admitted to the ER of a University Hospital, followed for development of AKI over 5 days. RESULTS: AKI developed in 144/200 (72 %) patients. In multivariable regression analysis, independent risk factors for AKI included age over 65 years (OR 1.28; 95 % CI 1.12-1.89; p = 0.04), mean blood pressure (MBP) lower than 65 mmHg at moment of admission (OR 1.89; 95 % CI 1.43-2.64, p = 0.003) and diabetes mellitus (OR 1.66; 95 % CI 1.30-3.20; p = 0.012). Mortality rate was 51.4 % in AKI patients compared with 26.8 % for those without AKI (p = 0.002). Septic shock (OR = 1.83, 95 % CI 1.23-2.74, p = 0.007), AKIN 3 (OR = 1.64; 95 % CI 1.19-1.89, p = 0.02), APACHE 2 > 20 (OR 1.92, 95 % CI 1.34-2.02, p = 0.009) and need for dialysis (OR = 1.26, 95 % CI 1.13-1.75, p = 0.03) were identified as independent risk factors for death in multivariable regression analysis. CONCLUSIONS: AKI severity in septic patients admitted in ER is associated with mortality. Diabetes, age over 65 years, and low MBP are independent risk factors for AKI and deserve further study to prevent AKI and, consequently, decreasing mortality. PMID- 25542519 TI - Effects of corneal nerve density on the response to treatment in dry eye disease. AB - PURPOSE: To evaluate whether levels of corneal subbasal nerve fiber length (SNFL) in dry eye disease (DED) could prognosticate the level of improvement in signs and symptoms after treatment. DESIGN: Phase IV, double-masked, randomized clinical trial. PARTICIPANTS: Sixty patients with meibomian gland dysfunction associated DED and 27 age-matched controls. METHODS: Patients with DED were randomized to receive topical artificial tears, loteprednol etabonate 0.5%, or loteprednol etabonate 0.5%/tobramycin 0.3% twice daily for 4 weeks. At baseline, in vivo confocal microscopy of central cornea was performed in both eyes. Patients with DED were divided into 2 subgroups: those with low baseline SNFL and those with near-normal baseline SNFL for this purpose (the cutoff point: the mean SNFL in controls minus 2 standard deviations). Clinical signs and symptoms at baseline and after 4 weeks of treatment were compared between the subgroups with low and near-normal SNFL for all therapeutic groups. MAIN OUTCOME MEASURES: Symptom questionnaires, corneal fluorescein staining (CFS), conjunctival staining with lissamine green, tear break-up time, Schirmer's test, and SNFL. RESULTS: In patients with DED, baseline SNFL (17.06+/-5.78 mm/mm(2)) was significantly lower than in controls (23.68+/-3.42 mm/mm(2), P = 0.001). In the artificial tear and loteprednol groups, although no significant improvement in any sign or symptom was noted in patients with low baseline SNFL (<16.84 mm/mm(2)), subjects with near-normal baseline SNFL (>=16.84 mm/mm(2)) showed significant improvement in both symptoms and CFS score (all P < 0.05). In the loteprednol/tobramycin group, no significant change was evident for any sign or symptom in either subgroup of low or near-normal baseline SNFL. CONCLUSIONS: Significant improvements in CFS and patient symptomatology after DED treatment were evident only in the subgroup with near-normal corneal SNFL. Consideration of SNFL may assist in explaining the variability of patients' response to DED therapy. PMID- 25542522 TI - School-Based Victimization of Teachers in Korea: Focusing on Individual and School Characteristics. AB - Research has found that victimized teachers are more likely to suffer from psychological distress, experience impaired personal relationships, and report higher levels of fear, consequently yielding detrimental impacts on their job performance and relationships with students. However, limited empirical research has been conducted to understand the prevalence and predictors of violence against teachers. Using a nationally representative sample of 996 Korean teachers, the present study measured various types of victimization and examined predictors of teachers' victimization, focusing on teachers' socio-demographic characteristics, teachers' student-oriented approach/classroom atmosphere, and school characteristics. The results suggest that teacher victimization is widespread in South Korea and show significant effects of individual socio demographic factors (gender and being a homeroom teacher), classroom atmosphere, and school type on teachers' victimization. Policy implications are discussed in the conclusion. PMID- 25542520 TI - Growth of geographic atrophy in the comparison of age-related macular degeneration treatments trials. AB - PURPOSE: To evaluate the growth of geographic atrophy (GA) during anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Cohort within a clinical trial. PARTICIPANTS: Patients included in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). METHODS: Participants were randomly assigned to injections of ranibizumab or bevacizumab and to a 2-year dosing regimen of monthly or pro re nata (PRN) or to monthly for 1 year and PRN the following year. Digital color photographs and fluorescein angiograms at baseline and 1 and 2 years were evaluated for GA, and the total area of GA was measured by 2 graders masked to treatment; differences were adjudicated. Multivariate linear mixed models of the annual change in the square root of the area included baseline demographic, treatment, and ocular characteristics on imaging as candidate risk factors. MAIN OUTCOME MEASURES: Geographic atrophy growth rate. RESULTS: Among 1185 participants, 86 (7.3%) had GA at baseline, 120 (10.1%) developed GA during year 1, and 36 (3.0%) developed GA during year 2. Among 194 eyes evaluable for growth, the rate was 0.43 mm/yr (standard error [SE], +/-0.03 mm/year). In multivariate analysis, the growth rate was 0.37 mm/year in eyes receiving bevacizumab and 0.49 mm/year in eyes receiving ranibizumab (difference, 0.11 mm/yr; 95% confidence interval [CI], 0.01-0.22; P = 0.03). Growth rate did not differ between eyes treated monthly and PRN (P = 0.85). Eyes with subfoveal choroidal neovascularization (CNV) lesions had a lower growth rate than eyes with nonsubfoveal CNV lesions (difference, 0.12; 95% CI, 0.01-0.22; P = 0.03). Eyes with GA farther from the fovea had higher growth rates by 0.14 (95% CI, 0.01-27) mm/year for every millimeter farther from the fovea. The growth rate was 0.58 mm/year for eyes with predominantly classic lesions, 0.41 mm/year for eyes with minimally classic lesions, and 0.30 mm/year for eyes with occult only lesions (P < 0.01). The growth rate in eyes having a fellow eye with GA was higher by 0.13 mm/year (95% CI, 0.01-0.24; P = 0.03) than in eyes without GA in the fellow eye. Eyes with epiretinal membrane had a higher growth rate than eyes without epiretinal membrane (difference, 0.16; 95% CI, 0.03-0.30; P = 0.02). CONCLUSIONS: Geographic atrophy growth depends on several ocular factors. Ranibizumab may accelerate GA growth. PMID- 25542521 TI - Ophthalmologist-patient communication, self-efficacy, and glaucoma medication adherence. AB - OBJECTIVE: To examine the associations of provider-patient communication, glaucoma medication adherence self-efficacy, and outcome expectations with glaucoma medication adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Two hundred seventy-nine patients with glaucoma who were newly prescribed or taking glaucoma medications were recruited at 6 ophthalmology clinics. METHODS: Patients' visits were video recorded and communication variables were coded using a detailed coding tool developed by the authors. Adherence was measured using Medication Event Monitoring Systems for 60 days after their visits. MAIN OUTCOME MEASURES: The following adherence variables were measured for the 60-day period after their visits: whether the patient took 80% or more of the prescribed doses, percentage of the correct number of prescribed doses taken each day, and percentage of the prescribed doses taken on time. RESULTS: Higher glaucoma medication adherence self-efficacy was associated positively with better adherence with all 3 measures. Black race was associated negatively with percentage of the correct number of doses taken each day (beta = 0.16; P < 0.05) and whether the patient took 80% or more of the prescribed doses (odds ratio, 0.37; 95% confidence interval, 0.16-0.86). Physician education about how to administer drops was associated positively with percentage of the correct number of doses taken each day (beta = 0.18; P < 0.01) and percentage of the prescribed doses taken on time (beta = 0.15; P < 0.05). CONCLUSIONS: These findings indicate that provider education about how to administer glaucoma drops and patient glaucoma medication adherence self-efficacy are associated positively with adherence. PMID- 25542523 TI - Children With Disability Are More at Risk of Violence Victimization: Evidence From a Study of School-Aged Chinese Children. AB - Although research tends to focus on whether children with disability are more at risk of violence victimization, conclusive evidence on the association, especially in non-Western settings, is lacking. Using a large and representative sample of school-aged children in Hong Kong (N = 5,841, aged 9-18 years), this study aims to fill the research gap by providing reliable estimates of the prevalence of disability and the direct and indirect experiences of violence among children with disability. The study also compares the prevalence of child maltreatment, parental intimate partner violence (IPV), and in-law conflict to explore the factors related to the association between disability and violence victimization. The prevalence of disability among children was about 6%. Children with disability were more likely to report victimization than those without disability: 32% to 60% of the former had experienced child maltreatment, and 12% to 46% of them had witnessed IPV between parents or in-law conflict. The results of a logistic regression showed that disability increased the risk of lifetime physical maltreatment by 1.6 times. Furthermore, low levels of parental education and paternal unemployment were risk factors for lifetime child maltreatment. The risk of child maltreatment could have an almost sixfold increase when the child had also witnessed other types of family violence. Possible explanations and implications of the findings are discussed. PMID- 25542524 TI - Attitudes Toward Intimate Partner Violence and Associations With Condom Use Among Men in Haiti: An Analysis of the Nationally Representative Demographic Health Survey. AB - Although men have substantial decision-making power regarding condom use, the majority of HIV knowledge and prevention studies in the general Haitian population have been conducted among youth and women. We investigated attitudes toward intimate partner violence, knowledge of, and use of condoms among 9493 men in Haiti using data from the 2012 nationally representative Demographic and Health Survey. Only 36% of HIV-negative and 44% of HIV-positive men reported using a condom the last time they had had sex. Logistic regression revealed that believing it was justified for a man to hit or beat his wife if she refuses to have sex with him was associated with a lower odds of condom use. The odds of using a condom during last sex was higher among men who reported knowing condoms can prevent HIV and who had been tested for HIV. Given the low rate of condom use among men in Haiti, these findings suggest that interventions promoting HIV knowledge, HIV testing, and gender-violence prevention among men may also increase condom use. PMID- 25542525 TI - Comparing capture-recapture methods for estimation of the size of small and medium-sized populations using empirical data on commercial turkey farms in Canada. AB - The study objectives were (1) to conduct a systematic review of the performance of capture-recapture methods; (2) to use empirical data to estimate population size in a small-sized population (turkey breeder farms) and a medium-sized population (meat turkey farms) by applying two-source capture-recapture methods (the Lincoln-Petersen, the Chapman, and Chao's lower-bound estimators) and multi source capture-recapture methods (the log-linear modeling and sample coverage approaches); and (3) to compare the performance of these methods in predicting the true population sizes (2007 data). Our set-up was unique in that we knew the population sizes for turkey breeder farms (99) and meat turkey farms (592) in Canada in 2007, which we applied as our true population sizes, and had surveillance data from the Canadian Notifiable Avian Influenza Surveillance System (2008-2012). We defined each calendar year of sampling as a data source. We confirmed that the two-source capture-recapture methods were sensitive to the violation of the local independence assumption. The log-linear modeling and sample coverage approaches yielded estimates that were closer to the true population sizes than were the estimates provided by the two-source methods for both populations. The performance of both multi-source capture-recapture methods depended on the number of data sources analyzed and the size of the population. Simulation studies are recommended to better understand the limits of each multi source capture-recapture method. PMID- 25542526 TI - Testing a cumulative and aggregate exposure model using biomonitoring studies and dietary records for Italian vineyard spray operators. AB - The need for improved tools to estimate the cumulative and aggregate exposure to compounds such as plant protection products (PPPs) is recognised in the EU Regulation 1107/2009. A new model has been developed to estimate the exposure within a population to single compounds or compounds within a Cumulative Action Group, considering dietary and non-dietary sources and multiple exposure routes. To test the model a field study was carried out in Italy with operators applying tebuconazole fungicides, with measurements of dermal exposure collected. Whole urine samples were collected and analysed to provide values for the absorbed dose of tebuconazole, with duplicate diet samples collected and analysed as a measure of dietary exposures. The model provided predicted values of exposure for combined dietary and non-dietary routes of exposures which were compared to the measured absorbed dose values based on urinary analysis. The model outputs provided mean daily exposure values of 1.77 (+/- 1.96) ug a.s./kg BW which are comparable to measured mean values from the biomonitoring field study of 1.73 (+/ 1.31) ug a.s./kg BW. To supplement the limited measurement data available, comparisons against other models were also made and found to be comparable. PMID- 25542527 TI - Effects of soyasaponin I and soyasaponins-rich extract on the alternariol-induced cytotoxicity on Caco-2 cells. AB - Alternariol (AOH) is a mycotoxin produced by Alternaria spp. Soyasaponin I (Ss-I) is present naturally in legumes, and it has antioxidant properties. Cytotoxic and genotoxic effects of AOH have been demonstrated previously in vitro. In the present study, the cytotoxicity of AOH, Ss-I, and soyasaponins-rich extract from lentils was investigated; as well as, the cytoprotective effects of Ss-I and lentil extracts against AOH induced-cytotoxicity on Caco-2 cells. Cytotoxicity was carried out using MTT and PC assays (AOH: 3.125-100 uM, Ss-I: 3.125-50 uM, and lentil extracts: 1:0-1:32) during 24 h of exposure. Only AOH showed cytotoxic effect. The reduction in cell proliferation ranged from 25% to 47%. Simultaneous combination of Ss-I with AOH (1:1) increased cell proliferation (35%) compared to AOH tested alone. The Ss-I and extracts showed synergistic cytoprotective effects against cytotoxicity induced by AOH on Caco-2 cells. Food commodities containing Ss-I could contribute to diminish the toxicological risk that natural contaminant as AOH in diet can produce to humans. PMID- 25542528 TI - Antioxidant and DNA damage protection potentials of selected phenolic acids. AB - In this study, ten different phenolic acids (caffeic, chlorogenic, cinnamic, ferulic, gallic, p-hydroxybenzoic, protocatechuic, rosmarinic, syringic, and vanillic acids) were evaluated for their antioxidant and DNA damage protection potentials. Antioxidant activity was evaluated by using four different test systems named as beta-carotene bleaching, DPPH free radical scavenging, reducing power and chelating effect. In all test systems, rosmarinic acid showed the maximum activity potential, while protocatechuic acid was determined as the weakest antioxidant in beta-carotene bleaching, DPPH free radical scavenging, and chelating effect assays. Phenolic acids were also screened for their protective effects on pBR322 plasmid DNA against the mutagenic and toxic effects of UV and H2O2. Ferulic acid was found as the most active phytochemical among the others. Even at the lowest concentration value (0.002 mg/ml), ferulic acid protected all of the bands in the presence of H2O2 and UV. It is followed by caffeic, rosmarinic, and vanillic acids. On the other hand, cinnamic acid (at 0.002 mg/ml), gallic acid (at 0.002 mg/ml), p-hydroxybenzoic acid (at 0.002 and 0.004 mg/ml), and protocatechuic acid (at 0.002 and 0.004 mg/ml) could not protect plasmid DNA. PMID- 25542529 TI - New trend in non-invasive prenatal diagnosis. AB - The presence of fetal DNA in maternal plasma represents a source of genetic material which can be obtained non-invasively. To date, the translation of noninvasive prenatal diagnosis from research into clinical practice has been rather fragmented, and despite the advances in improving the analytical sensitivity of methods, distinguishing between fetal and maternal sequences remains very challenging. Thus, the field of noninvasive prenatal diagnosis of genetic diseases has yet to attain a routine application in clinical diagnostics. On the contrary, fetal sex determination in pregnancies at high risk of sex linked disorders, tests for fetal RHD genotyping and non-invasive assessment of chromosomal aneuploidies are now available worldwide. PMID- 25542530 TI - D-lactic acidosis mediated neuronal encephalopathy in acute lymphoblastic leukemia patient: an under diagnosis. AB - BACKGROUND: D-lactic acidosis, also referred as D-lactate encephalopathy, has been reported in patients with short bowl syndrome (SBS). CASE REPORT: The neurologic symptoms include altered mental status, slurred speech, and ataxia. Onset of neurological symptoms is accompanied by metabolic acidosis and high anion gap. We present here a case of D-lactic acidosis in a patient with acute lymphoblastic leukemia (ALL) who developed severe neurological symptoms and metabolic acidosis due to vancomycin-resistant enterococci (VRE) infection, and elevated D-lactic acid. PMID- 25542531 TI - Comparison by sex between thrombin generation and fibrin network characteristics in a healthy population. AB - BACKGROUND: The aim of the present work was to compare sex differences in thrombin generation and fibrin network characteristics in a young healthy population, and correlate thrombin generation parameters with fibrin network characteristics. METHODS: Sixty individuals aged 21 y (18-26), 50% men and 50% women were selected. Thrombin generation was performed with the Technothrombin TGA kit. Plasma fibrin formation kinetic was followed by turbidity at 350 nm, and the fibrin elastic modulus was measured with the Hemodyne. In addition, the prothrombin polymorphism G20210A was assessed. RESULTS: Thrombin generation in men was: lag time (LT): 12.5 +/- 3.0 min, peak thrombin: 257 +/- 135 nmol/l, and endogenous thrombin potential (ETP): 3459 +/- 449 nmol/l.min, while in women the LT was shortened (9.7 +/- 2.8 min, p<0.05) and thrombin formation increased (peak thrombin: 345 +/- 178 nmol/l and ETP: 4017 +/- 429 nmol/l.min, p<0.05). Prothrombin and fibrinogen plasma levels were similar between sexes, and the GG genotype of prothrombin G20210A polymorphism (rs1799963) had a frequency of 1. In women, fibrin formation was slightly faster and the elastic modulus was higher than men. CONCLUSIONS: The differences in thrombin generation between women and men were not related to prothrombin concentration, prothrombin polymorphism G20210A or fibrinogen concentration. PMID- 25542532 TI - Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients. AB - BACKGROUND: The expression of hepatic CYP3A decreases with inflammatory response but increases with glucocorticoid administration. The aim of this study was to evaluate the plasma concentration of voriconazole and itraconazole under inflammatory conditions and glucocorticoid therapy. METHODS: Forty-one voriconazole- and 42 itraconazole-treated immunocompromised patients were enrolled in this study. Plasma concentrations of triazoles and their major metabolites at 12h after dosing were determined. The relationships between C reactive protein (CRP), prednisolone dose, and plasma exposure parameters of triazole were evaluated. RESULTS: Plasma concentration of voriconazole was not correlated with that of its N-oxide. A higher CRP was correlated with a higher dose-normalized plasma concentration of voriconazole and a lower plasma concentration ratio of N-oxide to voriconazole. Prednisolone dose was weakly correlated with the plasma concentration ratio of N-oxide to voriconazole. Plasma concentration of itraconazole had a good correlation with that of its hydroxide. Parameters of itraconazole were not associated with CRP and prednisolone dose. CONCLUSIONS: An inflammatory state raised the plasma concentration of voriconazole through its metabolic reduction, while it did not have an effect on plasma concentration of itraconazole. Concomitant glucocorticoid administration slightly elevated the voriconazole metabolism, although it did not affect the plasma concentration of triazoles. PMID- 25542533 TI - Maintaining vs. enhancing motor sequence memories: respective roles of striatal and hippocampal systems. AB - It is now accepted that hippocampal- and striatal-dependent memory systems do not act independently, but rather interact during both memory acquisition and consolidation. However, the respective functional roles of the hippocampus and the striatum in these processes remain unknown. Here, functional magnetic resonance imaging (fMRI) was used in a daytime sleep/wake protocol to investigate this knowledge gap. Using a protocol developed earlier in our lab (Albouy et al., 2013a), the manipulation of an explicit sequential finger-tapping task, allowed us to isolate allocentric (spatial) and egocentric (motor) representations of the sequence, which were supported by distinct hippocampo- and striato-cortical networks, respectively. Importantly, a sleep-dependent performance enhancement emerged for the hippocampal-dependent memory trace, whereas performance was maintained for the striatal-dependent memory trace, irrespective of the sleep condition. Regression analyses indicated that the interaction between these two systems influenced subsequent performance improvements. While striatal activity was negatively correlated with performance enhancement after both sleep and wakefulness in the allocentric representation, hippocampal activity was positively related to performance improvement for the egocentric representation, but only if sleep was allowed after training. Our results provide the first direct evidence of a functional dissociation in consolidation processes whereby memory stabilization seems supported by the striatum in a time-dependent manner whereas memory enhancement seems linked to hippocampal activity and sleep dependent processes. PMID- 25542534 TI - Estimation of in vivo nonspecific binding in positron emission tomography studies without requiring a reference region. AB - Estimation of outcome measures in in vivo neuroreceptor mapping with positron emission tomography (PET) commonly depends on an assumption of uniform nondisplaceable binding throughout the brain. In many cases, this can be estimated based on data from a "reference region," an area of the brain devoid of the receptor of interest. However, often such a region does not exist, as there are some receptors everywhere throughout the brain. Erroneously designating a region as a "reference" can lead to biased estimation, and furthermore, if the level of specific binding in the purported reference region differs between comparison groups, the validity of resulting conclusions may be called into question. We present a method for estimation of all common PET outcome measures that can provide good estimates even when no reference region exists. Our aim is to use information from several regions simultaneously to estimate the information common to all regions. By not requiring specification (or validation) of a reference region, such an approach can provide an automated, objective approach for kinetic modeling of PET data. We illustrate the performance of these methods on simulated data, human [(11)C]WAY-100635 data, and [(11)C]CUMI-101 blocking data in baboons. We show close agreement between estimates obtained by using the proposed method (which does not require a reference region) and estimates based on either a reference region or a blocking study. PMID- 25542535 TI - In situ DOX-calcium phosphate mineralized CPT-amphiphilic gelatin nanoparticle for intracellular controlled sequential release of multiple drugs. AB - A co-delivery strategy has been developed to achieve the synergistic effect of a hydrophobic drug (camptothecin, CPT) and a hydrophilic drug (doxorubicin, DOX) by utilizing the unique structure of amphiphilic gelatin/camptothecin @calcium phosphate-doxorubicin (AG/CPT@CaP-DOX) nanoparticles as a carriers in order to replace double emulsions while preserving the advantages of inorganic materials. The hydrophobic agent (CPT) was encapsulated via emulsion with an amphiphilic gelatin core, and subsequently mineralized by CaP-hydrophilic drug (DOX) through precipitation to form a CaP shell on the CPT-AG amphiphilic gelatin core so that drug molecules with different characteristics (i.e. hydrophobic and hydrophilic) can be encapsulated in different regions to avoid their interaction. The existence of the CaP shell can protect the DOX against free release and cause an increased transfer of DOX across membranes, overcoming multidrug resistance. Release studies from core-shell carriers showed the possibility of achieving sequential release of more than one type of drug by controlling the pH-sensitive CaP shell and degradable AG core. The highly pH-responsive behavior of the carrier can modulate the dual-drug-release of DOX/CPT, specifically in acidic intracellular pH environments. The AG/CPT@CaP-DOX nanoparticles also exhibited higher drug efficiencies against MCF-7/ADR cells than MCF-7 cells, thanks to a synergistic cell cycle arrest/apoptosis-inducing effect between CPT and DOX. As such, this core-shell system can serve as a general platform for the localized, controlled, sequential delivery of multiple drugs to treat several diseases, especially for multidrug-resistant cancer cells. PMID- 25542536 TI - The care of the patient: field notes from a veteran. PMID- 25542537 TI - Should we test for genotype in deciding on age-related eye disease study supplementation? PMID- 25542538 TI - To intervene or not to intervene: that is the question. PMID- 25542539 TI - Author reply: To PMID 24491643. PMID- 25542540 TI - Author reply: To PMID 24794888. PMID- 25542541 TI - Author reply: To PMID 24321140. PMID- 25542542 TI - Re: Wang et al.: Quantitative measurements of the ciliary body in eyes with malignant glaucoma after trabeculectomy using ultrasound biomicroscopy (Ophthalmology 2014;121:862-9). PMID- 25542543 TI - Re: Oishi et al.: LAPTOP study: a 24-month trial of verteporfin versus ranibizumab for polypoidal choroidal vasculopathy (Ophthalmology 2014;121:1151 2). PMID- 25542544 TI - Author reply: To PMID 24484991. PMID- 25542545 TI - Re: Coster et al.: A comparison of lamellar and penetrating keratoplasty outcomes: a registry study (Ophthalmology 2014;121:979-87). PMID- 25542546 TI - Author reply: To PMID 24491643. PMID- 25542547 TI - Re: Coster et al.: A comparison of lamellar and penetrating keratoplasty outcomes: a registry study (Ophthalmology 2014;121:979-87). PMID- 25542548 TI - Nickel-catalyzed one-pot deoxygenation and reductive homocoupling of phenols via C-O activation using TCT reagent. AB - A new method for C-O bond activation of phenolic compounds has been achieved using 2,4,6-trichloro-1,3,5-triazine to utilize in one-pot Ni-catalyzed deoxygenation and reductive homocoupling reactions. With this simple method, phenolic compounds were converted to their corresponding arenes or biaryl compounds under mild conditions. The introduced methodology has a broad scope and demonstrates good functional group compatibility. PMID- 25542549 TI - Discovering the truth beyond the truth. AB - The question "What is truth?" is one of the oldest questions in philosophy. Truth within the field of medicine has gained relevance because of its fundamental relationship to the principle of patient autonomy. To fully participate in their medical care, patients must be told the truth-even in the most difficult of situations. Palliative care emphasizes patient autonomy and a patient-centered approach, and it is precisely among patients with chronic, life-threatening, or terminal illnesses that truth plays a particularly crucial role. For these patients, finding out the truth about their disease forces them to confront existential fears. As physicians, we must understand that truth, similar to the complexity of pain, is multidimensional. In this article, we discuss the truth from three linguistic perspectives: the Latin veritas, the Greek aletheia, and the Hebrew emeth. Veritas conveys an understanding of truth focused on facts and reality. Aletheia reveals truth as a process, and emeth shows that truth is experienced in truthful encounters with others. In everyday clinical practice, truth is typically equated with the facts. However, this limited understanding of the truth does not account for the uniqueness of each patient. Although two patients may receive the same diagnosis (or facts), each will be affected by this truth in a very individual way. To help patients apprehend the truth, physicians are called to engage in a delicate back-and-forth of multiple difficult conversations in which each patient is accepted as a unique individual. PMID- 25542550 TI - Differences in Performance Status Assessment Among Palliative Care Specialists, Nurses, and Medical Oncologists. AB - CONTEXT: The Eastern Cooperative Oncology Group performance status (ECOG PS) is one of the most commonly used assessments in oncology and palliative care (PC). However, the interobserver differences between medical oncologists and PC specialists have never been reported. OBJECTIVES: To determine the interobserver differences in ECOG PS assessment among PC specialists, PC nurses, and medical oncologists in patients with advanced cancer. METHODS: We retrospectively reviewed the medical records of all patients who had an outpatient PC consultation in 2013 and identified 278 eligible patients. We retrieved the ECOG PS scores and symptom burden assessed by the Edmonton Symptom Assessment System (ESAS). RESULTS: PC specialists (median +0.5, P < 0.0001) and nurses (median +1.0, P < 0.0001) rated the ECOG PS significantly higher than medical oncologists. The weighted kappa values were 0.26 between PC specialists and medical oncologists and 0.61 between PC specialists and nurses. PC specialists' assessments correlated with ESAS fatigue, dyspnea, anorexia, feeling of well being, and symptom distress score. The ECOG PS assessments by all three groups were significantly associated with survival (P < 0.001). However, patients with ECOG PS 2 and 3-4 rated by their medical oncologists had similar survival (P = 0.67). Predictors of discordance in ECOG PS assessments between PC specialists and medical oncologists were the presence of a potentially effective treatment (odds ratio [OR] 2.39; 95% CI 1.09-5.23) and poor feeling of well-being (>=4) (OR 2.38, 95% CI 1.34-4.21). CONCLUSION: ECOG PS assessments by PC specialists and nurses were significantly higher than those of medical oncologists. Systematic efforts to increase regular interdisciplinary communications may help to bridge this gap. PMID- 25542551 TI - Self- and Carer-Rated Pain in People With Dementia: Influences of Pain in Carers. AB - CONTEXT: Although pain is frequent in people with dementia (PwD), evidence on the prevalence and factors influencing ratings of pain in dementia is limited. Carer variables are often associated with bias in proxy ratings of pain, but few studies have examined the role of caregiver pain in influencing these ratings. OBJECTIVES: This study explored the prevalence of pain in PwD in a large U.K. SAMPLE: A secondary aim was to identify factors influencing ratings of pain in people with mild to moderate dementia and whether carer pain systematically influences proxy ratings. METHODS: This was a cross-sectional study of 488 caregiving dyads living in the community. Self- and carer-rated pain was assessed as part of the EuroQoL-5D (EQ-5D). Depression and anxiety for the PwD were measured by the Cornell Scale for Depression in Dementia and the Rating of Anxiety in Dementia Scale. The Hospital Anxiety and Depression Scale was used to measure anxiety and depressive symptoms in carers. Using logistic regression modeling, we examined the relationship between self- and carer-rated (proxy) pain in PwD and psychological distress, functional ability, and health status. Carer variables included self-rated health, strain, anxiety, depression, and caregiver pain. RESULTS: A total of 45% of PwD reported pain, whereas carer-rated pain was higher (59%). Self-rated pain was more frequent in those with lower self-rated health (adjusted odds ratio [AOR] 0.97; 95% CI 0.96-0.99, P <= 0.001) and higher anxiety (AOR 1.07; 95% CI 1.01-1.12, P = 0.013). Carer-rated (proxy) pain was additionally predicted by poor proxy-rated health in the PwD (AOR 0.98; 95% CI 0.96-0.99, P = 0.006) and carers' own experience of pain (AOR 0.36; 95% CI 0.21 0.63, P <= 0.001). CONCLUSION: Our results indicate that pain is very frequently reported in PwD and that the presence of pain is associated with high levels of anxiety. Caregiver pain affects carers' perceptions of pain in PwD. PMID- 25542552 TI - Advance Care Planning Does Not Adversely Affect Hope or Anxiety Among Patients With Advanced Cancer. AB - CONTEXT: Many physicians avoid advance care planning (ACP) discussions because they worry such conversations will lead to psychological distress. OBJECTIVES: To investigate whether engaging in ACP using online planning tools adversely affects hope, hopelessness, or anxiety among patients with advanced cancer. METHODS: Patients with advanced cancer and an estimated survival of two years or less (Intervention group) and a Control group were recruited at a tertiary care academic medical center (2007-2012) to engage in ACP using an online decision aid ("Making Your Wishes Known"). Pre/post and between-group comparisons were made, including hope (Herth Hope Index), hopelessness (Beck Hopelessness Scale), and anxiety (State Trait Anxiety Inventory). Secondary outcomes included ACP knowledge, self-determination, and satisfaction. RESULTS: A total of 200 individuals completed the study. After engaging in ACP, there was no decline in hope or increase in hopelessness in either the Control or Intervention group. Anxiety was likewise unchanged in the Control group but decreased slightly in the Intervention group. Knowledge of ACP (% correct answers) increased in both the groups, but more so in the Intervention group (13% increase vs. 4%; P<0.01). Self determination increased slightly in both groups, and satisfaction with the ACP process was greater (P<0.01) in the Intervention than Control group. CONCLUSION: Engaging in ACP with online planning tools increases knowledge without diminishing hope, increasing hopelessness, or inducing anxiety in patients with advanced cancer. Physicians need not avoid ACP out of concern for adversely affecting patients' psychological well-being. PMID- 25542553 TI - Management of thick submacular hemorrhage with subretinal tissue plasminogen activator and pneumatic displacement for age-related macular degeneration. PMID- 25542554 TI - Reply: To PMID 24531021. PMID- 25542555 TI - Reply: To PMID 24792107. PMID- 25542556 TI - Spectral-domain optical coherence tomography epithelial and flap thickness mapping in femtosecond laser-assisted in situ keratomileusis. PMID- 25542557 TI - Long-term increase in subfoveal choroidal thickness after surgery for senile cataracts. PMID- 25542558 TI - Reply: To PMID 24875000. PMID- 25542559 TI - Late-onset peripheral ulcerative sclerokeratitis associated with alkali chemical burn. PMID- 25542560 TI - Reply: To PMID 25194228. PMID- 25542561 TI - Tattoo-associated uveitis. PMID- 25542562 TI - Reply: To PMID 24874999. PMID- 25542563 TI - Bleb revision for resolution of hypotony maculopathy following primary trabeculectomy. PMID- 25542564 TI - Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative. AB - OBJECTIVE: We sought to analyze use of alternative treatments and pathology among women who underwent hysterectomy in the Michigan Surgical Quality Collaborative. STUDY DESIGN: Perioperative hysterectomy data including demographics, preoperative alternative treatments, and pathology results were analyzed from 52 hospitals participating in the Michigan Surgical Quality Collaborative from Jan. 1 through Nov. 8, 2013. Women who underwent hysterectomy for benign indications including uterine fibroids, abnormal uterine bleeding (AUB), endometriosis, or pelvic pain were eligible. Pathology was classified as "supportive" when fibroids, endometriosis, endometrial hyperplasia, adenomyosis, adnexal pathology, or unexpected cancer were reported and "unsupportive" if these conditions were not reported. Multivariable analysis was done to determine independent associations with use of alternative treatment and unsupportive pathology. RESULTS: Inclusion criteria were met by 56.2% (n = 3397) of those women who underwent hysterectomy (n = 6042). There was no documentation of alternative treatment prior to hysterectomy in 37.7% (n = 1281). Alternative treatment was more likely to be considered among women aged <40 years vs those aged 40-50 and >50 years (68% vs 62% vs 56%, P < .001) and among women with larger uteri. Unsupportive pathology was identified in 18.3% (n = 621). The rate of unsupportive pathology was higher among women age <40 years vs those aged 40-50 and >50 years (37.8% vs 12.0% vs 7.5%, P < .001), among women with an indication of endometriosis/pain vs uterine fibroids and/or AUB, and among women with smaller uteri. CONCLUSION: This study provides evidence that alternatives to hysterectomy are underutilized in women undergoing hysterectomy for AUB, uterine fibroids, endometriosis, or pelvic pain. The rate of unsupportive pathology when hysterectomies were done for these indications was 18%. PMID- 25542565 TI - Standardized processing of MALDI imaging raw data for enhancement of weak analyte signals in mouse models of gastric cancer and Alzheimer's disease. AB - Conventional mass spectrometry image preprocessing methods used for denoising, such as the Savitzky-Golay smoothing or discrete wavelet transformation, typically do not only remove noise but also weak signals. Recently, memory efficient principal component analysis (PCA) in conjunction with random projections (RP) has been proposed for reversible compression and analysis of large mass spectrometry imaging datasets. It considers single-pixel spectra in their local context and consequently offers the prospect of using information from the spectra of adjacent pixels for denoising or signal enhancement. However, little systematic analysis of key RP-PCA parameters has been reported so far, and the utility and validity of this method for context-dependent enhancement of known medically or pharmacologically relevant weak analyte signals in linear-mode matrix-assisted laser desorption/ionization (MALDI) mass spectra has not been explored yet. Here, we investigate MALDI imaging datasets from mouse models of Alzheimer's disease and gastric cancer to systematically assess the importance of selecting the right number of random projections k and of principal components (PCs) L for reconstructing reproducibly denoised images after compression. We provide detailed quantitative data for comparison of RP-PCA-denoising with the Savitzky-Golay and wavelet-based denoising in these mouse models as a resource for the mass spectrometry imaging community. Most importantly, we demonstrate that RP-PCA preprocessing can enhance signals of low-intensity amyloid-beta peptide isoforms such as Abeta1-26 even in sparsely distributed Alzheimer's beta amyloid plaques and that it enables enhanced imaging of multiply acetylated histone H4 isoforms in response to pharmacological histone deacetylase inhibition in vivo. We conclude that RP-PCA denoising may be a useful preprocessing step in biomarker discovery workflows. PMID- 25542566 TI - A public repository for mass spectrometry imaging data. PMID- 25542567 TI - A rapid microfluidic technique for integrated viability determination of adherent single cells. AB - Here, we report on a novel protocol for determining the viability of individual cells in an adherent cell culture, without adversely affecting the remaining cells in the sample. This is facilitated using a freestanding microfluidic perfusion device, the Multifunctional Pipette (MFP), which generates a virtual flow cell around selected single cells. We investigated the utility on four different cell lines, NG108-15, HEK 293, PC12, and CHO, and combined the assay with a cell poration experiment, in which we apply the pore-forming agent digitonin, followed by fluorescein diphosphate, a pre-fluorescent substrate for alkaline phosphatase, in order to monitor intracellular enzyme activity. The cell viability was instantly assessed through simultaneous perfusion with fluorescein diacetate (FDA) and propidium iodide (PI), both being dispensed through the same superfusion device used to porate and deliver the enzyme substrate. In this fluorescence assay, viable and non-viable cells were distinguished by their green and red emission, respectively, within 10 s. In addition, the enzyme activity was monitored over time as a secondary test for cellular activity. Our findings demonstrate that this microfluidic technology-assisted approach is a facile, rapid, and reliable means to determine the viability in single-cell experiments and that viability studies can be performed routinely alongside typical substrate delivery protocols. This approach would remove the need for global cell viability testing and would enable viability studies of only the cells under experimental analysis. PMID- 25542568 TI - Py-GC/MS applied to the analysis of synthetic organic pigments: characterization and identification in paint samples. AB - A collection of 76 synthetic organic pigments was analysed using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). The purpose of this work was to expand the knowledge on synthetic pigments and to assess characteristic pyrolysis products that could help in the identification of these pigments in paint samples. We analysed several classes of synthetic pigments not previously reported as being analysed by this technique: some metal complexes, beta-naphthol pigment lakes, BONA pigment lakes, disazopyrazolone, triarylcarbonium, dioxazine, anthraquinone, indanthrone, isoindoline and thioindigo classes. We also report for the first time the Py-GC/MS analysis of a number of naphthol AS, benzimidazolone, phthalocyanine and perylene pigments and other miscellaneous pigments including pigments with unpublished chemical structure. We successfully used the Py-GC/MS technique for the analysis of paints by artists Clyfford Still and Jackson Pollock to identify the synthetic organic pigments and the binding media. PMID- 25542569 TI - Comparison of sample preparation methods for the quantitative analysis of eicosanoids and other oxylipins in plasma by means of LC-MS/MS. AB - Oxylipins are potent lipid mediators. For the evaluation of their biological roles, several LC-MS based methods have been developed. While these methods are similar, the described sample preparation procedures for the extraction of oxylipins differ considerably. In order to deduce the most appropriate method for the analysis of non-esterified oxylipins in human plasma, we evaluated the performance of seven established sample preparation procedures. Six commonly used solid phase extraction (SPE) and one liquid-liquid extraction (LLE) protocol were compared based on the recovery of 13 added internal standards, extraction efficacy of oxylipins from plasma and reduction of ion-suppressing matrix. Dramatic differences in the performance in all three parameters were found. LLE with ethyl acetate was overall not a sufficient sample preparation strategy. The protocols using Oasis- and StrataX-material insufficiently removed interfering matrix compounds. Extraction efficacy of oxylipins on anion-exchanging BondElut cartridges was low, while removal of matrix was nearly perfect. None of the protocols led to a high extraction efficacy of analytes while removing all interfering matrix components. However, SPE on a C18-material with removal of matrix by water and n-hexane prior elution with methyl formate showed the best performance for the analysis of a broad spectrum of oxylipins in plasma. PMID- 25542570 TI - Ionic strength effect on molecular structure of hyaluronic acid investigated by flow field-flow fractionation and multiangle light scattering. AB - This study describes the effect of ionic strength on the molecular structure of hyaluronic acid (HA) in an aqueous solution using flow field-flow fractionation and multiangle light scattering (FlFFF-MALS). Sodium salts of HA (NaHA) raw materials (~2 * 10(6) Da) dispersed in different concentrations of NaCl prepared by repeated dilution/ultrafiltration procedures were examined in order to study conformational changes in terms of the relationship between the radius of gyration and molecular weight (MW) and molecular weight distribution (MWD) of NaHA in solution. This was achieved by varying the ionic strength of the carrier solution used in a frit-inlet asymmetrical FlFFF (FIAF4) channel. Experiments showed that the average MW of NaHA increased as the ionic strength of the NaHA solution decreased due to enhanced entanglement or aggregation of HA molecules. Relatively large molecules (greater than ~5 MDa) did not show a large increase in RMS radius value as the NaCl concentration decreased. Conversely, smaller species showed larger changes, suggesting molecular expansion at lower ionic strengths. When the ionic strength of the FlFFF carrier solution was decreased, the HA species in a salt-rich solution (0.2 M NaCl) underwent rapid molecular aggregation during FlFFF separation. However, when salt-depleted HA samples (I = 4.66~0.38 mM) were analyzed with FFF carrier solutions of a high ionic strength, the changes in both molecular structure and size were somewhat reversible, although there was a delay in correction of the molecular structure. PMID- 25542571 TI - Rapid on-site detection of ephedrine and its analogues used as adulterants in slimming dietary supplements by TLC-SERS. AB - Ephedrine and its analogues are in the list of prohibited substance in adulteration to botanical dietary supplements (BDS) for their uncontrollable stimulating side effects. However, they were always adulterated illegally in BDS to promote losing weight. In order to avoid detection, various kinds of ephedrine analogues were added rather than ephedrine itself. This has brought about great difficulties in authentication of BDS. In this study, we put forward for the first time a method which combined thin-layer chromatography (TLC) and surface enhanced Raman scattering (SERS) to directly identify trace adulterant. Ephedrine, pseudoephedrine, methylephedrine, and norephedrine were mixed and used in this method to develop an analytical model. As a result, the four analogues were separated efficiently in TLC analysis, and trace-components and low background SERS detection was realized. The limit of detection (LOD) of the four analogues was 0.01 mg/mL. Eight common Raman peaks (?upsilon = 620, 1003, 1030, 1159, 1181, 1205, 1454, 1603 cm(-1)) were extracted experimentally and statistically to characterize the common feature of ephedrine analogues. A TLC SERS method coupled with common-peak model was adopted to examine nine practical samples, two of which were found to be adulterated with ephedrine analogues. Identification results were then confirmed by UPLC-QTOF/MS analysis. The proposed method was simple, rapid, and accurate and can also be employed to trace adulterant identification even when there are no available reference derivatives on-site or unknown types of ephedrine analogues are adulterated. PMID- 25542572 TI - Monitoring metabolites from Schizophyllum commune interacting with Hypholoma fasciculare combining LESA-HR mass spectrometry and Raman microscopy. AB - Microbial competition for territory and resources is inevitable in habitats with overlap between niches of different species or strains. In fungi, competition is brought about by antagonistic mycelial interactions which alter mycelial morphology, metabolic processes, secondary metabolite release, and extracellular enzyme patterns. Until now, we were not able study in vivo chemical interactions of different colonies growing on the same plate. In this report, we developed a fast and least invasive approach to identify, quantify, and visualize co culture induced metabolites and their location of release within Schizophyllum commune. The pigments indigo, indirubin, and isatin were used as examples to show secondary metabolite production in the interaction zone with Hypholoma fasciculare. Using a combinatory approach of Raman spectroscopy imaging, liquid extraction surface analysis (LESA), and high-resolution mass spectrometry, we identified, quantified, and visualized the presence of indigo and indirubin in the interaction zone. This approach allows the investigation of metabolite patterns between wood degrading species in competition to gain insight in community interactions, but could also be applied to other microorganisms. This method advances analysis of living, still developing colonies and are in part not destructive as Raman spectroscopy imaging is implemented. PMID- 25542573 TI - Validation of a streamlined multiclass, multiresidue method for determination of veterinary drug residues in bovine muscle by liquid chromatography-tandem mass spectrometry. AB - Multiclass, multiresidue methods are becoming increasingly popular in regulatory monitoring programs due to their increased analytical scope and laboratory efficiency. In this work, we report the development and validation of a new high throughput analytical method to monitor up to 131 veterinary drug residues, representing at least 13 different classes, in bovine muscle. This novel method streamlined sample preparation to <15 min/sample/analyst, or a batch of 40-60 pre homogenized samples in <3 h/analyst, through the combination of dispersive solid phase extraction with in-vial filtration (a new technique known as filter-vial d SPE). The use of an enhanced sensitivity state-of-the-art tandem mass spectrometer led to <10 ng/g limits of quantification for nearly all drug analytes with injection of 0.17 mg of equivalent sample. Positive and negative switching in electrospray ionization was applied to cover all analytes in an 11 min liquid chromatographic separation. In the 3-day validation study, 100 of the drugs met quantification criteria of 70-120% recoveries and Horwitz Ratio <=1.0, and the remaining analytes could still be screened at regulatory target levels. In the validation study involving >11,400 analyte results for spiked samples, the rate of false negatives for identification purposes was <5%, and no false positives occurred at appreciable concentrations. PMID- 25542574 TI - Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases. AB - Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of the present study is to develop a quantitative turboflow LC-MS/MS method that can be used for rapid quantification of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) in serum and urine in emergency toxicological cases without time consuming extraction steps. The method was developed on an ion-trap LC-MS/MS instrument coupled to a turbulent-flow extraction system. The validation data showed no significant matrix effects and no ion suppression has been observed in serum and urine. Mean intraday accuracy and precision for LSD were 101 and 6.84%, in urine samples and 97.40 and 5.89% in serum, respectively. For O-H-LSD, the respective values were 97.50 and 4.99% in urine and 107 and 4.70% in serum. Mean interday accuracy and precision for LSD were 100 and 8.26% in urine and 101 and 6.56% in serum, respectively. For O-H-LSD, the respective values were 101 and 8.11% in urine and 99.8 and 8.35% in serum, respectively. The lower limit of quantification for LSD was determined to be 0.1 ng/ml. LSD concentrations in serum were expected to be up to 8 ng/ml. 2-Oxo-3-hydroxy LSD concentrations in urine up to 250 ng/ml. The new method was accurate and precise in the range of expected serum and urine concentrations in patients with a suspected LSD intoxication. Until now, the method has been applied in five cases with suspected LSD intoxication where the intake of the drug has been verified four times with LSD concentrations in serum in the range of 1.80-14.70 ng/ml and once with a LSD concentration of 1.25 ng/ml in urine. In serum of two patients, the O-H-LSD concentration was determined to be 0.99 and 0.45 ng/ml. In the urine of a third patient, the O-H-LSD concentration was 9.70 ng/ml. PMID- 25542575 TI - Quantitative evaluation of peptide-extraction methods by HPLC-triple-quad MS-MS. AB - In this study, the efficiency of five peptide-extraction methods-acetonitrile (ACN) precipitation, ultrafiltration, C18 solid-phase extraction (SPE), dispersed SPE with mesoporous carbon CMK-3, and mesoporous silica MCM-41-was quantitatively investigated. With 28 tryptic peptides as target analytes, these methods were evaluated on the basis of recovery and reproducibility by using high-performance liquid chromatography-triple-quad tandem mass spectrometry in selected-reaction monitoring mode. Because of the distinct extraction mechanisms of the methods, their preferences for extracting peptides of different properties were revealed to be quite different, usually depending on the pI values or hydrophobicity of peptides. When target peptides were spiked in bovine serum albumin (BSA) solution, the extraction efficiency of all the methods except ACN precipitation changed significantly. The binding of BSA with target peptides and nonspecific adsorption on adsorbents were believed to be the ways through which BSA affected the extraction behavior. When spiked in plasma, the performance of all five methods deteriorated substantially, with the number of peptides having recoveries exceeding 70% being 15 for ACN precipitation, and none for the other methods. Finally, the methods were evaluated in terms of the number of identified peptides for extraction of endogenous plasma peptides. Only ultrafiltration and CMK-3 dispersed SPE performed differently from the quantitative results with target peptides, and the wider distribution of the properties of endogenous peptides was believed to be the main reason. PMID- 25542576 TI - Capillary and microchip electrophoretic analysis of polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants which can reach the environment and food in different ways. Because of their high toxicity, two international regulatory institutions, the US Environmental Protection Agency and the European Food Safety Authority, have classified PAHs as priority pollutants, generating an important demand for the detection and identification of PAHs. Thus, sensitive, fast, and cheap methods for the analysis of PAHs in environmental and food samples are urgently needed. Within this context, electrophoresis, in capillary or microchip format, displays attractive features. This review presents and critically discusses the published literature on the different approaches to capillary and microchip electrophoresis analysis of PAHs. PMID- 25542577 TI - Electron microscopy of Staphylococcus epidermidis fibril and biofilm formation using image-enhancing ionic liquid. AB - We established an optimized biofilm observation method using a hydrophilic ionic liquid (IL), 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). In the present study, a biofilm was formed by Staphylococcus epidermidis. Using field emission (FE) scanning electron microscopy (SEM) and transmission electron microscopy (TEM), the colonization of assemblages formed by microbial cells was observed as a function of the cultivation time. FE-TEM analysis revealed that the fibril comprises three types of protein. In addition, the ultrastructure of each protein monomer was visualized. It was expected that the curly-structured protein plays an important role in extension during fibril formation. Compared to the conventional sample preparation method for electron microscopy, a fine structure was easily obtained by the present method using IL. This observation technique can provide valuable information to characterize the ultrastructure of the fibril and biofilm that has not been revealed till date. Furthermore, these findings of the molecular architecture of the fibril and the colonization behavior of microbial cells during biofilm formation are useful for the development of antibacterial drugs and microbial utilization. PMID- 25542578 TI - Determination of triazine herbicides in fresh vegetables by dynamic microwave assisted extraction coupled with homogeneous ionic liquid microextraction high performance liquid chromatography. AB - A novel extraction method, dynamic microwave-assisted extraction coupled with homogeneous ionic liquid microextraction, was developed for the determination of triazine herbicides, including desmetryn, terbumeton, propazine, terbuthylazine, dimethametryn, and dipropetryn in fresh vegetable samples by high performance liquid chromatography (HPLC). In the developed method, 120 MUL of 1-butyl-3 methylimidazolium tetrafluoroborate ([C4MIM][BF4]) was added to 10 mL of aqueous solution containing 0.3 g of NaCl to obtained the extraction solvent. Six triazines could be extracted completely within 4 min by the present method. Then, [NH4][PF6] was added into the extract to form a water-insoluble ionic liquid [C4MIM][PF6] via a simple metathesis reaction, and the analytes were enriched into the ionic liquid phase. After centrifugation and dilution with acetonitrile, the resulting solution was analyzed directly by HPLC. The effects of some experimental parameters, including type and volume of ionic liquid, volume of extraction solvent, amount of ion-pairing agent [NH4][PF6], salt concentration, microwave power, and flow rate of extraction solvent on the extraction efficiency were investigated and optimized. Under the optimum experimental conditions, the linearity for determining the analytes was in the range of 2.50-250.00 MUg kg( 1), with the correlation coefficients ranging from 0.9989 to 0.9999. When the present method was applied to the analysis of vegetable samples, satisfactory recoveries were obtained in the range of 76.8%-106.9%, and relative standard deviations were lower than 9.8%. PMID- 25542579 TI - Methods for characterization of organic compounds in atmospheric aerosol particles. AB - Atmospheric aerosol particles of primary or secondary, biogenic or anthropogenic origin are highly complex samples of changing composition in time and space. To assess their effects on climate or human health, the size-dependent chemical composition of these ubiquitous atmospheric constituents must be known. The development of novel analytical methods has enabled more detailed characterization of the organic composition of aerosols. This review gives an overview of the methods used in the chemical characterization of atmospheric aerosol particles, with a focus on mass-spectrometry techniques for organic compounds, either alone or in combination with chromatographic separation. Off line, on-site, and on-line methods are covered, and the advantages and limitations of the different methods are discussed. The main emphasis is on methods used for detailed characterization of the composition of the organic compounds in aerosol particles. We address and summarize the current state of analytical methods used in aerosol research and discuss the importance of developing novel sampling strategies and analytical instrumentation. Graphical Abstract Challenges in the atmospheric aerosol analytics. PMID- 25542580 TI - The case of triethylammonium cation loss during purification of certain nucleotide analogues: a cautionary note. AB - Nucleotides, their analogues, and other phosphate esters and phosphoramidates often contain the triethylammonium cation as a counterion. We found that this may be lost during chromatographic purification or concentration of solutions, yielding products in acidic forms or containing sub-stoichiometric amounts of the counterion. This in turn may be detrimental, e.g., due to possible decomposition of a compound or inaccurate sample preparation. Correlations between the structure of studied compounds and their susceptibility for cation loss were analyzed. Modifications in preparative techniques were developed to obtain the studied compounds with stoichiometric anion to cation ratios. PMID- 25542581 TI - Fabry disease: renal sphingolipid distribution in the alpha-Gal A knockout mouse model by mass spectrometric and immunohistochemical imaging. AB - Fabry disease is an X-linked lysosomal storage disease due to deficient alpha galactosidase A (alpha-Gal A) activity and the resultant lysosomal accumulation of globotriaosylceramide (Gb3) and related lipids primarily in blood vessels, kidney, heart, and other organs. The renal distribution of stored glycolipid species in the alpha-Gal A knockout mouse model was compared to that in mice to assess relative distribution and absolute amounts of accumulated sphingolipid isoforms. Twenty isoforms of five sphingolipid groups were visualized by mass spectrometry imaging (MSI), and their distribution was compared with immunohistochemical (IHC) staining of Gb3, the major stored glycosphingolipid in consecutive tissue sections. Quantitative bulk lipid analysis of tissue sections was assessed by electrospray ionization with tandem mass spectrometry (ESI MS/MS). In contrast to the findings in wild-type mice, all three analytical techniques (MSI, IHC, and ESI-MS/MS) revealed increases in Gb3 isoforms and ceramide dihexosides (composed mostly of galabiosylceramides), respectively. To our knowledge, this is the first report of the distribution of individual molecular species of Gb3 and galabiosylceramides in kidney sections in Fabry disease mouse. In addition, the spatial distribution of ceramides, ceramide monohexosides, and sphingomyelin forms in renal tissue is presented and discussed in the context of their biosynthesis. PMID- 25542582 TI - Organically modified silica nanoparticles doped with new acridine-1,2-dioxetane analogues as thermochemiluminescence reagentless labels for ultrasensitive immunoassays. AB - Doped organically modified silica nanoparticles (ORMOSIL NPs) with luminescent molecules represent a potent approach to signal amplification in biomolecule labeling. Herein, we report the synthesis of new ORMOSIL NPs incorporating thermochemiluminescent (TCL) 1,2-dioxetane derivatives to prepare TCL labels for ultrasensitive immunoassay, displaying a detectability comparable to those offered by other conventional luminescence-based systems. Amino-functionalized ORMOSIL NPs were synthesized for inclusion of acridine-containing 1,2-dioxetane derivatives with a fluorescence energy acceptor. The doped ORMOSIL NPs were further functionalized with biotin for binding to streptavidin-labeled species to be used as universal detection reagents for immunoassays. A quantitative non competitive immunoassay for streptavidin has been developed by immobilizing anti streptavidin antibody to capture streptavidin, then the antibody-bound streptavidin was detected by the biotinylated TCL ORMOSIL NPs. The analytical performance was similar to that obtained by chemiluminescent (CL) detection using horseradish peroxidase (HRP) as label, being the limits of detection 2.5-3.8 and 0.8 ng mL(-1) for TCL and CL detection, respectively. In addition, since the TCL emission is simply initiated by thermolysis of the label, chemical reagents were not required, thus allowing reagentless detection with a simplification of the analytical protocols. A compact mini dark box device based on the use of a cooled charge-coupled device (CCD) and a miniaturized heater has been developed and used to quantify the light emission after heat decomposition of the label at a temperature of 90-120 degrees C. These characteristics make TCL-doped ORMOSIL NPs ideal universal nanoprobes for ultrasensitive bioassays such as immuno- and DNA-based assay. PMID- 25542583 TI - Dried blood spot analysis of creatinine with LC-MS/MS in addition to immunosuppressants analysis. AB - In order to monitor creatinine levels or to adjust the dosage of renally excreted or nephrotoxic drugs, the analysis of creatinine in dried blood spots (DBS) could be a useful addition to DBS analysis. We developed a LC-MS/MS method for the analysis of creatinine in the same DBS extract that was used for the analysis of tacrolimus, sirolimus, everolimus, and cyclosporine A in transplant patients with the use of Whatman FTA DMPK-C cards. The method was validated using three different strategies: a seven-point calibration curve using the intercept of the calibration to correct for the natural presence of creatinine in reference samples, a one-point calibration curve at an extremely high concentration in order to diminish the contribution of the natural presence of creatinine, and the use of creatinine-[(2)H3] with an eight-point calibration curve. The validated range for creatinine was 120 to 480 MUmol/L (seven-point calibration curve), 116 to 7000 MUmol/L (1-point calibration curve), and 1.00 to 400.0 MUmol/L for creatinine-[(2)H3] (eight-point calibration curve). The precision and accuracy results for all three validations showed a maximum CV of 14.0% and a maximum bias of -5.9%. Creatinine in DBS was found stable at ambient temperature and 32 degrees C for 1 week and at -20 degrees C for 29 weeks. Good correlations were observed between patient DBS samples and routine enzymatic plasma analysis and showed the capability of the DBS method to be used as an alternative for creatinine plasma measurement. PMID- 25542584 TI - Direct, simultaneous quantification of fructooligosaccharides by FT-MIR ATR spectroscopy and chemometrics for rapid identification of superior, engineered beta-fructofuranosidases. AB - Fructooligosaccharides (FOS) are popular components of functional foods produced by the enzymatic transfer of fructose units to sucrose. Improving beta fructofuranosidase traits by protein engineering is restricted by the absence of a rapid, direct screening method for the fructooligosaccharide products produced by enzyme variants. The use of standard high-performance liquid chromatography (HPLC) methods involves time-consuming sample preparation and chromatographic and data analysis steps. To overcome these limitations, this work presents a rapid method for screening beta-fructofuranosidase variant libraries using Fourier transform mid-infrared attenuated total reflectance (FT-MIR ATR) spectroscopy and calibration using partial least squares (PLS) regression. The method offers notable improvements in terms of sample analysis times and cost, with the added benefit of the absence of toxic eluents. Wavenumber interval selection methods were tested to develop optimised PLS regression models that were successfully applied to quantify of glucose, fructose, sucrose, 1-kestose and nystose, the substrates and products of beta-fructofuranosidase activity. To the best of our knowledge, this is the first report on the use of infrared spectroscopy and PLS calibration for the quantification of 1-kestose and nystose. Independent test set validated results indicated that optimal wavenumber selection by interval PLS (iPLS) served to provide the best models for all sugars, bar glucose. Application of this screening method will facilitate the engineering of beta fructofuranosidases and other glycosyltransferase enzymes by random mutagenesis strategies, as it provides, for the first time, a rapid, direct assay for transferase products that may be adapted to a high-throughput set-up. PMID- 25542585 TI - Study of the distribution of actinides in human tissues using synchrotron radiation micro X-ray fluorescence spectrometry. AB - This study aims at evaluating the capabilities of synchrotron radiation micro X ray fluorescence spectrometry (SR micro-XRF) for qualitative and semi quantitative elemental mapping of the distribution of actinides in human tissues originating from individuals with documented occupational exposure. The investigated lymph node tissues were provided by the United States Transuranium and Uranium Registries (USTUR) and were analyzed following appropriate sample pre treatment. Semi-quantitative results were obtained via calibration by external standards and demonstrated that the uranium concentration level in the detected actinide hot spots reaches more than 100 MUg/g. For the plutonium hot spots, concentration levels up to 31 MUg/g were found. As illustrated by this case study on these unique samples, SR micro-XRF has a high potential for this type of elemental bio-imaging owing to its high sensitivity, high spatial resolution, and non-destructive character. PMID- 25542587 TI - Effects of chronic sodium alendronate on depression and anxiety in a menopausal experimental model. AB - OBJECTIVE: During menopause, lower levels of estrogen may induce bone resorption as well as anxiety and depression. Bisphosphonates represent the first choice in the treatment of osteoporosis and no data are available concerning their effects on comorbid behavior alterations. Therefore, in this study, we evaluated the effects of chronic alendronate (1 mg/kg/day) on depression and anxiety in an experimental animal model of menopause. METHODS: Female Wistar rats were ovariectomized or sham operated at 6-7 months of age. Two weeks after surgery, rats were randomized into four treatment (24 consecutive weeks) groups: (1) vehicle-treated SHAM group, (2) alendronate-treated SHAM group, (3) vehicle treated ovariectomized group, and (4) alendronate-treated ovariectomized group. After treatment, we evaluated both depressive- and anxiety-like behavior through forced swimming test (FST) and open-field test (OF). Finally, the inverted screen test was used to assess the incapacitating effects of ovariectomy in rats. RESULTS: We documented a significant and time-related increase in immobility times and in anxiety-like behavior in rats with ovariectomy in comparison to control sham group. Alendronate at 3 months, but not at 6 months, significantly decreased both immobility time and anxiety levels, but it significantly increased motor performance. Using the Pearson's test, we documented a significant correlation between behavior and motor performance. CONCLUSION: Despite the apparent effects of alendronate on animal behavior, in our experiments, such effects seem to be mediated by an increase in motor performance. PMID- 25542586 TI - Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking. AB - Alcohol binge-drinking during adolescence is a serious public health concern with long-term consequences. We used RNA sequencing to assess the effects of excessive adolescent ethanol binge-drinking on gene expression in the dorsal raphe nucleus (DRN) of alcohol preferring (P) rats. Repeated binges across adolescence (three 1h sessions across the dark-cycle per day, 5 days per week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5-3 g/kg/session) significantly altered the expression of approximately one-third of the detected genes. Multiple neurotransmitter systems were altered, with the largest changes in the serotonin system (21 of 23 serotonin-related genes showed decreased expression) and GABA-A receptors (8 decreased and 2 increased). Multiple neuropeptide systems were also altered, with changes in the neuropeptide Y and corticotropin-releasing hormone systems similar to those associated with increased drinking and decreased resistance to stress. There was increased expression of 21 of 32 genes for potassium channels. Expression of downstream targets of CREB signaling was increased. There were also changes in expression of genes involved in inflammatory processes, axonal guidance, growth factors, transcription factors, and several intracellular signaling pathways. These widespread changes indicate that excessive binge drinking during adolescence alters the functioning of the DRN and likely its modulation of many regions of the central nervous system, including the mesocorticolimbic system. PMID- 25542588 TI - Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges. AB - This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure. PMID- 25542589 TI - Multifunctional coumarin derivatives: monoamine oxidase B (MAO-B) inhibition, anti-beta-amyloid (Abeta) aggregation and metal chelation properties against Alzheimer's disease. AB - A series of coumarin derivatives were designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most of these compounds exhibited significant potency to inhibit hMAO B selectively and self-induced Abeta1-42 aggregation. In particular, compound 13 presented the greatest potential to inhibit hMAO-B (IC50=0.081MUM, SI >1234) and good inhibition of Abeta1-42 aggregation (52.9% at 20MUM). Moreover, compound 13 could function as a metal-chelator, penetrate the blood-brain barrier (BBB) and show low cell toxicity in rat pheochromocytoma (PC12) and SH-SY5Y cells. Taken together, these results suggested that compound 13 might be a promising multifunctional agent for AD treatment. PMID- 25542590 TI - Posterior reversible encephalopathy syndrome secondary to blood transfusion. AB - The appearance of posterior reversible encephalopathy syndrome (PRES) after blood transfusion is rare and has only been reported in three patients to our knowledge. We report a fourth patient with PRES secondary to blood transfusion. A 36-year-old woman with a history of menorrhagia presented to the emergency department with severe fatigue. She had a hemoglobin of 1.7 g/dl and received four units of red blood cells over 15 hours. On day 6 post-transfusion she returned with confusion, headache and a generalized tonic-clonic seizure. The MRI of her brain was consistent with PRES. The following day her confusion worsened, repeat MRI of the brain showed new T2-weighted lesions. Over next 10 days her mental status gradually improved close to her baseline. A repeat MRI of the brain showed resolution of the T2-weighted lesions. The clinical presentation, radiological findings and disease progression in our patient was consistent with PRES. Other than the blood transfusions, there were no apparent risk factors for PRES. The prior three patients with post-transfusion PRES have been reported in middle-aged women with uterine fibroids. It is suspected that these patients have a subacute to chronic anemic state due to ongoing menorrhagia. It is interesting to note that no cases of PRES post-transfusion have been reported in the setting of acute blood loss, such as from trauma. It is postulated that an abrupt increase in hemoglobin causes a rapid rise in blood viscosity and loss of hypoxic vasodilation. Subsequent endothelial damage and brain capillary leakage results in PRES. This constellation of changes may not occur after transfusion in patients with more acute blood loss. PMID- 25542592 TI - Finite element analysis in asymptomatic, symptomatic, and ruptured abdominal aortic aneurysms: in search of new rupture risk predictors. AB - OBJECTIVES: To compare biomechanical rupture risk parameters of asymptomatic, symptomatic and ruptured abdominal aortic aneurysms (AAA) using finite element analysis (FEA). STUDY DESIGN: Retrospective biomechanical single center analysis of asymptomatic, symptomatic, and ruptured AAAs. Comparison of biomechanical parameters from FEA. MATERIALS AND METHODS: From 2011 to 2013 computed tomography angiography (CTA) data from 30 asymptomatic, 15 symptomatic, and 15 ruptured AAAs were collected consecutively. FEA was performed according to the successive steps of AAA vessel reconstruction, segmentation and finite element computation. Biomechanical parameters Peak Wall Rupture Risk Index (PWRI), Peak Wall Stress (PWS), and Rupture Risk Equivalent Diameter (RRED) were compared among the three subgroups. RESULTS: PWRI differentiated between asymptomatic and symptomatic AAAs (p < .0004) better than PWS (p < .1453). PWRI-dependent RRED was higher in the symptomatic subgroup compared with the asymptomatic subgroup (p < .0004). Maximum AAA external diameters were comparable between the two groups (p < .1355). Ruptured AAAs showed the highest values for external diameter, total intraluminal thrombus volume, PWS, RRED, and PWRI compared with asymptomatic and symptomatic AAAs. In contrast with symptomatic and ruptured AAAs, none of the asymptomatic patients had a PWRI value >1.0. This threshold value might identify patients at imminent risk of rupture. CONCLUSIONS: From different FEA derived parameters, PWRI distinguishes most precisely between asymptomatic and symptomatic AAAs. If elevated, this value may represent a negative prognostic factor for asymptomatic AAAs. PMID- 25542591 TI - Epileptogenic focus localization in treatment-resistant post-traumatic epilepsy. AB - Pharmacologically intractable post-traumatic epilepsy (PTE) is a major clinical challenge for patients with penetrating traumatic brain injury, where the risk for this condition remains very high even decades after injury. Although over 20 anti-epileptic drugs (AED) are in common use today, approximately one-third of epilepsy patients have drug-refractory seizures and even more have AED-related adverse effects which compromise life quality. Simultaneously, there have been repeated recommendations by radiologists and neuroimaging experts to incorporate localization based on electroencephalography (EEG) into the process of clinical decision making regarding PTE patients. Nevertheless, thus far, little progress has been accomplished towards the use of EEG as a reliable tool for locating epileptogenic foci prior to surgical resection. In this review, we discuss the epidemiology of pharmacologically resistant PTE, address the need for effective anti-epileptogenic treatments, and highlight recent progress in the development of noninvasive methods for the accurate localization of PTE foci for the purpose of neurosurgical intervention. These trends indicate the current emergence of promising methodologies for the noninvasive study of post-traumatic epileptogenesis and for the improved neurosurgical planning of epileptic foci resection. PMID- 25542594 TI - Detection of major diarrheagenic bacterial pathogens by multiplex PCR panels. AB - Diarrheal diseases remain a major threat to the youngest population in low- and middle-income countries. The main bacterial pathogens causing diarrhea are diarrheagenic Escherichia coli (DEC) that consists of enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enterohemorrhagic EHEC and enteroinvasive E. coli (EIEC), Salmonella, Shigella spp. (S. dysenteria, S. sonnei, S. flexneri) Campylobacter (C. coli, C. jejuni), Vibrio (V. vulnificus, V. parahaemolyticusm, V. cholerae), Yersinia enterocolitica and Aeromonas hydrophila. The aim of this study was to set up rapid multiplex PCR (mPCR) panels to identify these diarrheagenic pathogens based on their specific virulence genes. Primers against specific target genes were combined into three mPCR panels: one for diarrheal E. coli, one for pathogens causing mainly bloody diarrhea, and the third for the remaining pathogens. The panels were tested against a set of stool samples from Swedish children with diarrhea and controls and the analysis identified bacterial pathogens in 14/54 (26%) of the samples. These results show that our three developed mPCR panels can detect main bacterial diarrheagenic pathogens in clinical samples. PMID- 25542593 TI - Fate of patients unwilling or unsuitable to undergo surgical intervention for a ruptured abdominal aortic aneurysm. AB - INTRODUCTION: The primary objective of this study was to assess the duration of in-hospital survival in 57 patients with ruptured abdominal aortic aneurysms (RAAA) who did not undergo surgical intervention. REPORT: Two hours after registration in the emergency room, 58% (95% CI 45-71) of patients were still alive. The median survival was 2.2 hours (interquartile range 1-18). In a subgroup including 26 haemodynamically stable patients, survival after 2 hours was 96% (95% CI 89-100). CONCLUSION: In patients with an RAAA without surgical intervention, the duration of in-hospital survival is limited. However, a group of haemodynamically stable patients can be identified in whom survival is much longer. PMID- 25542595 TI - Identification of ethylparaben as the antimicrobial substance produced by Brevibacillus brevis FJAT-0809-GLX. AB - In this study, crude antimicrobial extract from the culture supernatant of Brevibacillus brevis FJAT-0809-GLX was extracted, and its antimicrobial activity was investigated with the agar diffusion method. The results showed that the antimicrobial activity of the culture supernatant of B. brevis FJAT-0809-GLX increased with the extension of the incubation time of B. brevis FJAT-0809-GLX. The antimicrobial spectrum assays showed that this crude antimicrobial extract from culture supernatant of B. brevis FJAT-0809-GLX could inhibit the growth of both bacteria and fungi. A heat stability test was performed, and different temperatures (30 degrees C, 50 degrees C and 70 degrees C) did not affect the antibiotic activity of this crude antimicrobial extract. The crude antimicrobial extract was also tolerable to changes in pH levels. Its antibiotic activity against Escherichia coli was stable at pH 1 to pH 11, with zone sizes ranging from 18.46mm to 22.19mm. Almost all of the crude extracts extracted using different solvents showed variable degrees of inhibition zones against E. coli, with zone sizes ranging from 17.29mm to 19.62mm, except petroleum ether and butanol extracts, which were found to be completely inactive. Purification of the antimicrobial components was carried out using a column chromatographic technique with column chromatography grade silica gel and analyzed by an Agilent 7890A Network GC system. The separated compound was identified as ethylparaben, with a retention time of 21.980min and a relative amount of 95.50%. The antimicrobial activity of ethylparaben on different types of bacteria and fungi was investigated, and ethylparaben was shown to inhibit different types of microbes to different extents. To the best of our knowledge, this is the first report demonstrating that the bacterium B. brevis could produce ethylparaben. PMID- 25542596 TI - Searching hidden truth behind clinical trials. PMID- 25542597 TI - Essential rules and requirements for global clinical trials in rare lung diseases: a sponsor's standpoint. AB - International multicenter trials have the advantage of being able to recruit many patients within a short period. This is particularly useful for rare diseases. Ideally, conclusions drawn from the results of a global clinical trial apply to all study centers and countries involved, potentially expediting drug development and facilitating approval in foreign markets. However, several challenges must be overcome to ensure optimal trial conduct and coordinate trial sites working under different regulations and technical and cultural conditions. Thus, standardizing these trial elements is essential and may include training courses for the medical and technical staff at the study sites. Considering a rare disease, such as idiopathic pulmonary fibrosis (IPF), it is the trial sponsor's responsibility to seek consensus among clinical experts and regulatory agencies about fundamental questions, including a consistent diagnosis. In cross-cultural studies, it is important to use hard (objective) efficacy endpoints rather than patient-reported (subjective) measures, such as quality of life. A quality assurance program should be implemented, including the central review of diagnostic findings. Careful safety monitoring and an external independent data monitoring committee that periodically assesses a study treatment's risk-benefit ratio are required to protect trial patients from potential harm. Over the past few years, Boehringer Ingelheim has conducted two large-scale global clinical trials for the treatment of IPF (INPULSISTM-1 and INPULSISTM-2). These studies have just been completed and, as a result of careful planning, have successfully complied with the standards and needs of an international, cross-cultural study. PMID- 25542598 TI - Usefulness of a disease severity staging classification system for IPF in Japan: 20 years of experience from empirical evidence to randomized control trial enrollment. AB - Since 1991, the severity of idiopathic pulmonary fibrosis (IPF) has been classified into 4 stages-stage I (characterized by a resting PaO2 >= 80 Torr), stage II (70-79 Torr), stage III (60-69 Torr), or stage IV (<60 Torr)-to aid decisions on medical care subsidization in Japan. Among patients with stage II/III IPF, the severity should be increased by one stage if the lowest oxygen saturation on pulse oximetry (SpO2) is <90% during a 6-min walk test. Patients with stage III/IV IPF receive Japanese government subsidies for incurable diseases. This classification system highly correlates with serial changes in the percentage of vital capacity (%VC), the diffusing capacity for carbon monoxide, the incidence of acute exacerbation, and survival. A phase III trial of pirfenidone showed that IPF patients with an SpO2 on exertion of <90% and either a %VC >= 70% or a PaO2 >= 70 Torr (which includes most patients with stage III disease) at baseline would benefit from pirfenidone treatment. Recent post marketing surveillance of 1370 patients--67.3% of whom had stage III/IV IPF- showed that pirfenidone was well-tolerated among those treated for longer than 6 months (63% of patients). A Japanese randomized controlled trial (RCT) demonstrated that inhaled N-acetylcysteine monotherapy benefitted patients with early IPF (stage I/II, with no desaturation on exertion). Thus, N-acetylcysteine monotherapy is suitable for early IPF, and pirfenidone is indicated for advanced disease. The classification of IPF severity is important in identifying clinically responsive patients and those suitable for RCT enrollment. PMID- 25542599 TI - Utility of immunological tests for bird-related hypersensitivity pneumonitis. AB - BACKGROUND: The reaction of specific antibodies and sensitized lymphocytes to antigens is important in hypersensitivity pneumonitis (HP). However, there are no known studies evaluating the utility of the lymphocyte proliferation test (LPT) or specific antibodies to avian antigens in diagnosing bird-related HP. In this study, we examined the sensitivity and specificity of these two tests. METHODS: Patients with acute bird-related HP (n=10), chronic bird-related HP (n=35), acute summer-type HP (n=14), and other interstitial pneumonia (IP) (n=76) were evaluated. The optimal cutoff values were determined by receiver operating curve (ROC) analyses of specific antibodies in serum and bronchoalveolar lavage fluid (BALF), and by conducting the LPT on mononuclear cells in peripheral blood and BALF. RESULTS: The sensitivity and specificity of the antibodies were 80-100% and 92-100% in acute bird-related HP, and 26-79% and 73-93% in chronic bird-related HP, respectively. The sensitivity and specificity of the LPT were 50-100% and 100% in acute bird-related HP, and 46% and 91% in chronic bird-related HP, respectively. CONCLUSIONS: Specific antibodies and the LPT are quite useful for diagnosing acute bird-related HP. The presence of specific antibodies in BALF and the results of LPT with peripheral blood mononuclear cells are particularly useful for diagnosing chronic bird-related HP. PMID- 25542601 TI - Efficacy and long-term clinical outcome of bronchial occlusion with endobronchial Watanabe spigots for persistent air leaks. AB - BACKGROUND: We reviewed our clinical experience and examined the efficacy and long-term outcome of bronchial occlusion with endobronchial Watanabe spigots (EWSs). METHODS: We retrospectively reviewed the clinical charts of patients who had undergone endoscopic bronchial occlusion with EWSs between July 2002 and July 2004. The affected bronchi were identified by chest computed tomography, pleurography, and balloon occlusion test. RESULTS: Of the 21 patients, 18 had underlying pulmonary complications, including chronic obstructive lung disease (n=14), cancer (n=4), pneumoconiosis (n=3), and pneumonia (n=1). Six (29%) achieved complete resolution and 12 (57%) experienced a reduction in air leaks after the first EWS insertion. Of the 12 patients with reduced air leaks, 10 subsequently underwent chemical pleurodesis and 5 (24%) achieved complete resolution after the procedure. A second EWS insertion procedure was performed for 8 patients: 2 achieved complete resolution and 5 achieved a further reduction in air leaks with complete resolution after chemical pleurodesis. Eighteen of the 21 patients were followed up at an outpatient clinic after discharge: 13 for more than 12 months and 4 for more than 84 months. During the follow-up period, most patients did not show any obvious pulmonary complications. CONCLUSIONS: We showed that bronchial occlusion with EWSs was effective in stopping or reducing air leaks and that 86% of our patients finally achieved complete resolution, some when the occlusion was combined with chemical pleurodesis. The rate of complications was acceptable, even after long-term placement. PMID- 25542600 TI - Prevalence of asthma with airflow limitation, COPD, and COPD with variable airflow limitation in older subjects in a general Japanese population: the Hisayama Study. AB - BACKGROUND: Elucidating the prevalence of asthma and chronic obstructive pulmonary disease (COPD) is important for designing a public health strategy. Recent studies have discriminated a phenotype of COPD with variable airflow limitation (COPD-VAL) associated with asthma-COPD overlap syndrome. Its prevalence remains uncertain. The age and occupational distributions in the town of Hisayama and in Japan are nearly identical. Each disease's prevalence was estimated for the town's residents. METHODS: In 2008, town residents (>= 40 years) were solicited to participate in a health checkup. Individuals with abnormal spirometry (forced expiratory volume in 1s/forced vital capacity [FEV1/FVC]<70% and/or %FVC<80%) were recommended for further evaluations. Two pulmonologists in a blinded fashion reviewed their medical records, including bronchodilator reversibility. Individuals with airflow limitation were classified as having asthma, COPD, COPD-VAL, or other diseases. The prevalence of each disease was then estimated. RESULTS: A total of 2100 residents (43.4% of residents in the age group) completed spirometry. In 455 residents with abnormal spirometry, 190 residents had further evaluations, and the medical records of 174 residents were reviewed. The prevalence of asthma with airflow limitation, COPD, and COPD-VAL, were 2.0%, 8.4%, and 0.9%, respectively. The prevalence of COPD and COPD-VAL were higher in men and smokers than in women and never-smokers. The prevalence of COPD, but not COPD-VAL or asthma, increased with age. CONCLUSION: The prevalence of asthma with airflow limitation, COPD, and COPD-VAL were estimated in a population of residents (>= 40 years) in Hisayama. PMID- 25542602 TI - An analysis of etiology, causal pathogens, imaging patterns, and treatment of Japanese patients with bronchiectasis. AB - BACKGROUND: Bronchiectasis (BE), a syndrome that presents with persistent or recurrent bronchial sepsis related to irreversibly damaged and dilated bronchi, has not been well-characterized in Asians. This study aims to review the etiology, causal pathogens, imaging patterns, and treatment of BE and to define the prognostic factors for acute exacerbation in a Japanese population. METHODS: We performed a retrospective cohort study of 147 patients (104 women; median age, 73 years; range, 30-95 years) with BE at our institution using high-resolution computed tomography to identify imaging patterns and the area of pulmonary involvement. RESULTS: Common BE etiologies were idiopathic (N=50 [34%]), sinobronchial syndrome (N=37 [25%]), non-tuberculous mycobacteriosis (NTM; N=26 [18%]), and previous respiratory infection (N=21[14%]). Pseudomonas aeruginosa was the most common causal pathogen (24%). Common imaging patterns were cylindrical (66%) and mixed including cylindrical pattern (47%). The median number of involved lobes was 2; 49% of the patients had >= 3 involved lobes, and 49% had middle lobe and left lingula dominant BE. Patients with predominantly lower lobe BE comprised 4% of the NTM group and 48% of the non-NTM group (P<0.001). In multivariate analysis, cystic BE was a predictor for frequent exacerbations in non-NTM patients (OR=7.947; P=0.004) which led to increased hospital admissions (OR=4.691; P=0.004). CONCLUSIONS: Idiopathic and sinobronchial syndrome were common causes of BE. Etiology did not contribute to imaging pattern or predictors of exacerbations. Cystic BE was a predictor for frequent exacerbations in the non-NTM BE patients. PMID- 25542603 TI - Efficacy of combined corticosteroid and pirfenidone for acute exacerbation of idiopathic pulmonary fibrosis after surgery for lung cancer: a case report. PMID- 25542604 TI - Effect of low-level laser therapy on adolescents with temporomandibular disorder: a blind randomized controlled pilot study. AB - PURPOSE: The aim of this pilot study was to evaluate the effect of low-level laser therapy on pain, mandibular movements, and occlusal contacts in adolescents and young adults with temporomandibular disorder. MATERIALS AND METHODS: Individuals aged 14 to 23 years were evaluated. The Research Diagnostic Criteria for Temporomandibular Disorders were used for the diagnosis of temporomandibular disorders. Pain was assessed with a visual analog scale. Occlusal contacts were recorded using the T-Scan III program (Tekscan, Boston, MA). The participants were randomly allocated to 2 groups: active or placebo laser treatment. The laser parameters were as follows: wavelength of 780 nm, energy density of 33.5 J/cm(2), power of 50 mW, power density of 1.67 W/cm(2), and 20-second exposure time. The Kolmogorov-Smirnov test was used to determine the normality of the data distribution. The paired t test was used for the comparisons of the pretreatment and post-treatment results. The SPSS program for Windows (version 15.0; SPSS, Chicago, IL) was used for all analyses, with the level of significance set at 5% (P < .05). RESULTS: No statistically significant differences between groups were found for the right and left anterior temporal muscles (P = .3801 and P = .5595, respectively), superior masseter muscles (P = .087 and P = .1969, respectively), medial masseter muscles (P = .2241 and P = .076, respectively), or inferior masseter muscles (P = .5589 and P = .3268, respectively) after treatment. CONCLUSIONS: No statistically significant differences were found regarding pain, mandibular range of motion, or the distribution of occlusal contacts after treatment with low-level laser therapy. These preliminary results need to be verified in a larger sample of patients to confirm the lack of response to low level laser therapy. PMID- 25542605 TI - Preliminary results of fixed, fiber-reinforced resin bridges on four 4- * 5-mm ultrashort implants in compromised bony sites: a pilot study. AB - PURPOSE: To determine the effectiveness of fixed, fiber-reinforced resin bridges on 4 ultrashort implants with a sufficient implant survival success rate of at least 90% in highly atrophic jaws. MATERIALS AND METHODS: A prospective temporal cohort study was designed, with the inclusion of 10 patients. Of the 10 patients, 8 had atrophic jaws (7 women, 1 man; mean age at implant placement 58.5 years, range 40.7 to 73.9) and 2 had fibula-mandibular transplants (1 woman, aged 76.5 years; and 1 man, aged 69.3 years). All 10 patients had their dentition restored with 4 ultrashort implants. The implant dimensions were 4 mm in diameter and 5 mm long, with a locking taper abutment connection supporting a fixed, fiber reinforced and composite resin-facetted bridge. The postoperative follow-up period averaged 19.5 months (range 9.1 to 33.1). RESULTS: The survival and success rate was 97.25%. The average mesial and distal bone level was 0.2 +/- 0.3 mm in the atrophic mandibles and 0.4 +/- 1.2 mm in the fibula transplants at the last follow-up visit. Prosthetic-related patient issues were limited to decementation events. No chipping or fracturing of the prostheses was observed. CONCLUSION: Retention of fixed prosthetic restorations using 4 ultrashort implants showed promising short-term cumulative survival and success rates. PMID- 25542606 TI - The toolbox of Auricularia auricula-judae dye-decolorizing peroxidase - Identification of three new potential substrate-interaction sites. AB - Dye-decolorizing peroxidases (DyPs) such as AauDyPI from the fungus Auricularia auricula-judae are able to oxidize substrates of different kinds and sizes. A crystal structure of an AauDyPI-imidazole complex gives insight into the binding patterns of organic molecules within the heme cavity of a DyP. Several small N containing heterocyclic aromatics are shown to bind in the AauDyPI heme cavity, hinting to susceptibility of DyPs to azole-based inhibitors similar to cytochromes P450. Imidazole is confirmed as a competitive inhibitor with regard to peroxide binding. In contrast, bulky substrates such as anthraquinone dyes are converted at the enzyme surface. In the crystal structure a substrate analog, 4 (2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), binds to a tyrosine rich hollow harboring Y25, Y147, and Y337. Spin trapping with a nitric oxide donor uncovers Y229 as an additional tyrosine-based radical center in AauDyPI. Multi-frequency EPR spectroscopy further reveals the presence of at least one intermediate tryptophanyl radical center in activated AauDyPI with W377 as the most likely candidate. PMID- 25542607 TI - Genomic and proteomic fingerprints of acute rejection in peripheral blood and urine. AB - Acute dysfunction of a kidney transplant can be the result of many different etiologies and an allograft biopsy is frequently necessary to diagnose acute rejection. This invasive procedure, while generally safe, is time consuming, costly and inconvenient. We summarize recent advances in genomic and proteomic techniques using peripheral blood and urine for the diagnosis of acute rejection. While much progress has been made, validation of these new molecular tests in the clinical setting is still required. PMID- 25542609 TI - Efficacy of antioxidants as a Complementary and Alternative Medicine (CAM) in combination with the chemotherapeutic agent doxorubicin. AB - INTRODUCTION: Although doxorubicin (Dox)-induced cardiac toxicity and pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) were reported to be correlated with reactive oxygen species (ROS) generation, there is no effective preventive treatment at present. Therefore, the aim of this study was to investigate whether antioxidants-resveratrol (RSVL), tetrahydroxystilbene glucoside (THSG), curcumin, and the ethanolic extract of Antrodia cinnamomea (EEAC)-have the ability to reduce Dox-induced ROS and have a synergistic anticancer effect with Dox that could prevent those side effects and enhance the efficacy of cancer treatment. METHODS: 3T3 normal cells were used as a model to evaluate the effects of these antioxidants in reducing ROS accumulation. Furthermore, the synergistic anticancer effect of antioxidants with Dox on the MCF-7 breast cancer model was also evaluated. RESULTS: Pretreatment of cells with RSVL, curcumin, and EEAC increased the cell antioxidant ability by improving the activity of superoxide dismutase (SOD), prevented or limited intracellular damage, and ameliorated the harmful effects of ROS. Additionally, RSVL, curcumin, and EEAC had synergistic effects with Dox against MCF-7 breast cancer cells. CONCLUSION: RSVL, curcumin, and EEAC have the potential to be clinically applied to prevent cardiac toxicity and HFS and enhance the anticancer efficiency of Dox. PMID- 25542610 TI - Prediction of blood-brain barrier permeation of alpha-adrenergic and imidazoline receptor ligands using PAMPA technique and quantitative-structure permeability relationship analysis. AB - Imidazoline receptor ligands are a numerous family of biologically active compounds known to produce central hypotensive effect by interaction with both alpha2-adrenoreceptors (alpha2-AR) and imidazoline receptors (IRs). Recent hypotheses connect those ligands with several neurological disorders. Therefore some IRs ligands are examined as novel centrally acting antihypertensives and drug candidates for treatment of various neurological diseases. Effective Blood Brain Barrier (BBB) permeability (P(e)) of 18 IRs/alpha-ARs ligands and 22 Central Nervous System (CNS) drugs was experimentally determined using Parallel Artificial Membrane Permeability Assay (PAMPA) and studied by the Quantitative Structure-Permeability Relationship (QSPR) methodology. The dominant molecules/cations species of compounds have been calculated at pH = 7.4. The analyzed ligands were optimized using Density Functional Theory (B3LYP/6 31G(d,p)) included in ChemBio3D Ultra 13.0 program and molecule descriptors for optimized compounds were calculated using ChemBio3D Ultra 13.0, Dragon 6.0 and ADMET predictor 6.5 software. Effective permeability of compounds was used as dependent variable (Y), while calculated molecular parametres were used as independent variables (X) in the QSPR study. SIMCA P+ 12.0 was used for Partial Least Square (PLS) analysis, while the stepwise Multiple Linear Regression (MLR) and Artificial Neural Networks (ANN) modeling were performed using STASTICA Neural Networks 4.0. Predictive potential of the formed models was confirmed by Leave-One-Out Cross- and external-validation and the most reliable models were selected. The descriptors that are important for model building are identified as well as their influence on BBB permeability. Results of the QSPR studies could be used as time and cost efficient screening tools for evaluation of BBB permeation of novel alpha-adrenergic/imidazoline receptor ligands, as promising drug candidates for treatment of hypertension or neurological diseases. PMID- 25542611 TI - Promoting clinical research to medically underserved communities: current practices and perceptions about clinical trial recruiting strategies. AB - INTRODUCTION: Although clinical trials have the potential to provide the most advanced medical treatments and screening options, accrual rates remain low among medically underserved populations. Strategies to enhance clinical trial recruitment are frequently undertaken without developing, implementing, and evaluating communication and educational activities. This study assesses the current clinical trial recruiting efforts taking place at academic medical centers in a southeastern state and explores principal investigators' attitudes and beliefs about how to successfully recruit for clinical trials, in the general population, and in African American and rural communities. METHODS: An online survey was used to collect responses from clinical trial principal investigators working in a southeastern state's five main academic medical centers. Respondents were asked about their experience with recruitment and recruiting strategies, in general, and in the African American and rural communities. RESULTS: Respondents said that it was most difficult to find rural residents to participate in clinical trials (M=3.60, SD=.93), followed by the general public (M=3.30, SD=.99) and African American residents (M=3.15, SD=.99). Investigators most often reported personally recruiting their patients (M=3.50, SD=1.34) and through local doctors (M=2.80, SD=1.20). Principal investigators rarely recruit through faith based organizations (M=1.74, SD=1.05), or by using radio (M=1.62, SD=.90), or television ads (M=1.42, SD=.75). CONCLUSION: Clinical trial investigators rarely communicate about clinical research outside of the medical setting or partner with community organizations or local doctors to reach individuals in medically underserved communities. Study implications describe the importance of educating research teams about how best to promote clinical trial awareness and knowledge. PMID- 25542612 TI - Sensitivity to model geometry in finite element analyses of reconstructed skeletal structures: experience with a juvenile pelvis. AB - Biomechanical analysis of juvenile pelvic growth can be used in the evaluation of medical devices and investigation of hip joint disorders. This requires access to scan data of healthy juveniles, which are not always freely available. This article analyses the application of a geometric morphometric technique, which facilitates the reconstruction of the articulated juvenile pelvis from cadaveric remains, in biomechanical modelling. The sensitivity of variation in reconstructed morphologies upon predicted stress/strain distributions is of particular interest. A series of finite element analyses of a 9-year-old hemi pelvis were performed to examine differences in predicted strain distributions between a reconstructed model and the originally fully articulated specimen. Only minor differences in the minimum principal strain distributions were observed between two varying hemi-pelvic morphologies and that of the original articulation. A Wilcoxon rank-sum test determined there was no statistical significance between the nodal strains recorded at 60 locations throughout the hemi-pelvic structures. This example suggests that finite element models created by this geometric morphometric reconstruction technique can be used with confidence, and as observed with this hemi-pelvis model, even a visual morphological difference does not significantly affect the predicted results. The validated use of this geometric morphometric reconstruction technique in biomechanical modelling reduces the dependency on clinical scan data. PMID- 25542613 TI - Metrology test object for dimensional verification in additive manufacturing of metals for biomedical applications. AB - Additive manufacturing continues to increase in popularity and is being used in applications such as biomaterial ingrowth that requires sub-millimeter dimensional accuracy. The purpose of this study was to design a metrology test object for determining the capabilities of additive manufacturing systems to produce common objects, with a focus on those relevant to medical applications. The test object was designed with a variety of features of varying dimensions, including holes, cylinders, rectangles, gaps, and lattices. The object was built using selective laser melting, and the produced dimensions were compared to the target dimensions. Location of the test objects on the build plate did not affect dimensions. Features with dimensions less than 0.300 mm did not build or were overbuilt to a minimum of 0.300 mm. The mean difference between target and measured dimensions was less than 0.100 mm in all cases. The test object is applicable to multiple systems and materials, tests the effect of location on the build, uses a minimum of material, and can be measured with a variety of efficient metrology tools (including measuring microscopes and micro-CT). Investigators can use this test object to determine the limits of systems and adjust build parameters to achieve maximum accuracy. PMID- 25542614 TI - Cleaning and disinfection of patient care items, in relation to small animals. AB - Patient care involves several medical and surgical items, including those that come into contact with sterile or other high-risk body sites and items that have been used on other patients. These situations create a risk for infection if items are contaminated, and the implications can range from single infections to large outbreaks. To minimize the risk, proper equipment cleaning, disinfection/sterilization, storage, and monitoring practices are required. Risks posed by different items; the required level of cleaning, disinfection, or sterilization; the methods that are available and appropriate; and how to ensure efficacy, must be considered when designing and implementing an infection control program. PMID- 25542608 TI - Mathematical and computational modeling in biology at multiple scales. AB - A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas of epidemiology, cell physiology and cancer are surveyed. The technique of molecular dynamics is covered, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. The utility of quantum mechanical methods in biophysical and biochemical modeling is explored. The field of computational enzymology is examined. PMID- 25542615 TI - Fighting surgical site infections in small animals: are we getting anywhere? AB - A diverse array of pathogen-related, patient-related, and caretaker-related issues influence risk and prevention of surgical site infections (SSIs). The entire surgical team involved in health care settings in which surgical procedures are performed play a pivotal role in the prevention of SSIs. In this article, current knowledge of SSI risk factors and prevention methods is reviewed. Although new avenues that can be explored in the prevention of SSIs in veterinary medicine are described, the main conclusion drawn is that the best method for prevention of SSI is to adhere to what we already know. PMID- 25542616 TI - Comparative study of the efficacy of different treatment options in patients with chronic blepharitis. AB - OBJECTIVE: To compare the efficacy of 3 treatment options in patients with chronic blepharitis. METHODOLOGY: An experimental, randomized, controlled study was conducted on 45 patients (female 67%; Mean age: 40.5 years) diagnosed with chronic blepharitis, in order to compare the effectiveness of three treatment options. Group 1: eyelid hygiene with neutral shampoo three times/day; group 2: neutral shampoo eyelid hygiene plus topical metronidazole gel 0.75% twice/day; group 3: neutral eyelid hygiene with shampoo plus neomycin 3.5% and polymyxin 10% antibiotic ointment with 0.5% dexamethasone 3 times/day. The symptoms and signs were assessed by assigning scores from 0: no symptoms and/or signs; 1: mild symptoms and/or signs, 2: moderate symptoms and/or signs; and 3: severe symptoms and/or signs. RESULTS: A significant improvement was observed in the signs and symptoms in all 3 treatment groups. While groups 1 and 2 had more improvement in all variables studied (P<.05), Group 3 showed no clinical improvement for itching (P=.16), dry eye (P=.29), eyelashes falling (P=.16), and erythema at the eyelid margin (P=.29). CONCLUSIONS: Shampoo eyelid hygiene neutral and neutral shampoo combined with the use of metronidazole gel reported better hygiene results than neutral shampoo lid with antibiotic ointment and neomycin and polymyxin dexamethasone. PMID- 25542618 TI - Prognosis of critical limb ischemia patients with tissue loss after achievement of complete wound healing by endovascular therapy. AB - OBJECTIVE: Critical limb ischemia (CLI) patients with tissue loss have been recognized to have a poor survival rate. In this study, we aimed to determine whether the prognosis of CLI patients with tissue loss improves after complete wound healing is achieved by endovascular therapy. METHODS: We treated 187 CLI patients with tissue loss by endovascular therapy from April 2007 to December 2012. Among these patients, 113 patients who achieved complete wound healing were enrolled. The primary end point was survival rate at 3 years. The secondary end points were limb salvage rate and recurrence rate of CLI at 3 years. RESULTS: The mean follow-up period after achievement of complete wound healing was 32 +/- 18 months. At 1 year, 2 years, and 3 years, the survival rates were 86%, 79%, and 74%; the limb salvage rates were 100%, 100%, and 100%; the recurrence rates of CLI were 2%, 6%, and 9%, respectively. On multivariate Cox proportional hazard analysis, age >75 years (hazard ratio, 3.18; 95% confidence interval, 1.23-8.24; P = .017) and nonambulatory status (hazard ratio, 2.46; 95% confidence interval, 1.08-5.65; P = .035) were identified as independent predictors of death for CLI patients with tissue loss even after complete wound healing was achieved. The Kaplan-Meier curve for the overall survival rate at 3 years showed that CLI patients of older age (>75 years) had a significantly decreased survival rate compared with CLI patients of younger age (<=75 years) (58% vs 87%; log-rank test, P < .001). In addition, nonambulatory CLI patients had a significantly poor survival rate relative to ambulatory CLI patients (40% vs 93%; log-rank test, P < .001). CONCLUSIONS: The overall survival rate of CLI patients was acceptable and the recurrence rate of CLI was extremely low once complete wound healing was achieved. Nonambulatory status and age >75 years can serve as predictors of death even after complete wound healing is achieved. PMID- 25542617 TI - Mitochondrial Disease Sequence Data Resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities. AB - Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. PMID- 25542619 TI - Surgery for Crohn's disease: look harder, act faster. PMID- 25542621 TI - Health sciences rated highly in UK's research assessment. PMID- 25542620 TI - Crohn's disease management after intestinal resection: a randomised trial. AB - BACKGROUND: Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS: In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score >=i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS: Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION: Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING: AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council. PMID- 25542622 TI - The data show a U-shaped association of sodium intake with cardiovascular disease and mortality. PMID- 25542623 TI - Response to "The data show a U-shaped association of sodium intake with cardiovascular disease and mortality". PMID- 25542624 TI - Aldosterone Levels, Aortic Stiffness, and Wave Reflection in Essential Hypertensive Patients. AB - BACKGROUND: The aim of the present study was to evaluate the grade of arterial stiffening, in relation to aldosterone (ALDO) and plasma renin activity (PRA) levels, in essential never-treated hypertensive patients. MATERIALS AND METHODS: We studied 1,330 consecutive patients without clinical and/or laboratory findings of primary or secondary aldosteronism. Arterial stiffness indices Aix75 and carotid-femoral pulse wave velocity (PWVc-f) were measured and a 24-hour urine collection for ALDO was carried out to classify patients with low ALDO <12 mcg/24 hours and high ALDO >12 but <24 mcg/24 hours. Patients were divided according to PRA (high PRA > 1ng/ml/hour, low PRA < 1ng/ml/hour) and ALDO levels (high ALDO > 12 but <24 mcg/24 hours, low ALDO < 12 mcg/24 hours) in four groups. Also patients were grouped according to serum ALDO quartiles, 24-hour urine ALDO quartiles, PRA quartiles, and serum ALDO/PRA quartiles. RESULTS: Patients were classified in 4 groups: group I (high ALDO and low PRA), group II (high ALDO and high PRA), group III (low ALDO and low PRA), and finally group IV (low ALDO and high PRA). PWVc-f and AoAIx75 were significantly higher in group I followed by group II, III, and IV (P < 0.001). Comparison of arterial stiffness indices according to PRA quartiles and PWVc-f and AoAIx75 showed significantly higher in the 1st quartile compared to 2nd, 3rd, and 4th, respectively (P < 0.001). PWVc-f and AoAIx75 were also compared among the four quartiles of aldosterone-renin ratio and they were significantly higher (P < 0.001) in the 4th quartile followed by the 3rd, 2nd, and 1st, respectively. CONCLUSIONS: Arterial stiffness indices are higher among essential hypertensive patients with high normal serum and urine ALDO levels, pointing to a causal relationship between renin-angiotensin aldosterone system activation and large artery properties. PMID- 25542625 TI - Hypertension in Reproductive-Aged Women With Polycystic Ovary Syndrome and Association With Obesity. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common disorder with metabolic complications, yet the prevalence of hypertension is unclear. We aim to assess hypertension prevalence and the impact of obesity in women reporting PCOS compared to those not reporting PCOS. METHODS: This is a cross-sectional analysis of data from a large longitudinal study, the Australian Longitudinal Study on Women's Health (ALSWH). Women from the general community were randomly selected from the national health insurance database. Standardized data collection occurred at 6 survey time points. Data from Survey 4 in 2006 (n = 8,612, age: 28 33 years) were examined for this study. The main outcome measures studied were self-reported PCOS and hypertension. RESULTS: Reported PCOS prevalence was 5.8% (95% confidence interval (CI): 5.3%-6.4%). Women with PCOS had higher body mass index (BMI). Hypertension prevalence was 5.5% (95% CI: 3.3-7.7) in women reporting PCOS and 2.0% (95% CI: 1.6-2.3) in women not reporting PCOS (P < 0.001). Hypertension was associated with BMI (odds ratio: 1.07, 95% CI: 1.05 1.10, P < 0.001) with a trend towards an association with PCOS (P = 0.09). On subgroup analysis, hypertension was not associated with BMI in women reporting PCOS but was associated in those not reporting PCOS. CONCLUSIONS: In this large community-based cohort, we note increased prevalence of hypertension and higher BMI in young women reporting PCOS. BMI association with hypertension appeared clear in women not reporting PCOS. Yet in women with PCOS, hypertension appeared to not be associated with BMI, akin to observations on diabetes risk in PCOS, suggesting that metabolic abnormalities in PCOS may be independent of BMI. PMID- 25542626 TI - Heir to the throne or young pretender: can targeted therapy added to gemcitabine cisplatin doublet therapy improve outcomes for advanced urothelial cancer? PMID- 25542627 TI - Toward personalizing the use of androgen deprivation therapy to maximize benefit and minimize harm. PMID- 25542629 TI - Transurethral resection of the prostate for benign prostatic obstruction: will it remain the gold standard? PMID- 25542628 TI - Acute epididymitis revisited: impact of molecular diagnostics on etiology and contemporary guideline recommendations. AB - BACKGROUND: Acute epididymitis is a common infectious disease of unknown etiology in about 30% of cases with guidelines based on studies published >15 yr ago. OBJECTIVE: To investigate the etiology of acute epididymitis using state-of-the art methods and to provide rational data for antimicrobial therapy and clinical management. DESIGN, SETTING, AND PARTICIPANTS: Between 2007 and 2013, 237 patients (150 antimicrobially naive and 87 antibiotically pretreated) with acute epididymitis underwent comprehensive investigation comprising microbiologic cultures, polymerase chain reaction (PCR) for sexually transmitted infections (STIs), 16S ribosomal DNA (rDNA) analysis, and PCR detection of 23 viruses. Clinical management followed international guidelines. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Etiology, clinical management, and outcome after 3 mo were assessed. RESULTS AND LIMITATIONS: A causative pathogen, predominantly Escherichia coli (56%), was identified in 132 antibiotic-naive patients (88%) and 44 pretreated patients (51%); 16S rDNA analysis increased the detection rate by 10%. STIs were present in 34 cases (14%) (25 patients with Chlamydia trachomatis) and were not restricted to a specific age group. Enteroviruses were found in only two patients (1%). In naive patients, cultured bacteria were susceptible to fluoroquinolones and group 3 cephalosporins in >85% of cases (preateted patients: 42% and 67%, respectively). Primary empirical therapy was continued in 88% of naive patients for 11 d and in 77% of pretreated patients for 13 d with indwelling urinary catheters, rendering patients as high risk for switching. Only six patients (2.5%) underwent semicastration. Prostate-specific antigen levels halved within 3 mo, except in patients who were antibiotic naive and without detected pathogens. Study limitations included a lack of susceptibility testing in cases of STIs. CONCLUSIONS: Even in antimicrobially pretreated patients, acute epididymitis is mainly of bacterial origin. STIs are not limited to patients aged <35 yr. Viral epididymitis seems a rare condition. Current guideline recommendations on empirical antimicrobial therapy are adequate. PATIENT SUMMARY: Patients with acute epididymitis should receive appropriate diagnostics and antimicrobial therapy for safe conservative management. PMID- 25542630 TI - Transcriptomic response of the hydrothermal mussel Bathymodiolus azoricus in experimental exposure to heavy metals is modulated by the Pgm genotype and symbiont content. AB - Hydrothermal vent mussels belonging to the genus Bathymodiolus dominate communities at hydrothermal sites of the Mid-Atlantic Ridge. The mussel Bathymodiolus azoricus harbors thiotrophic and methanotrophic symbiotic bacteria in its gills and evolves in naturally highly metal contaminated environments. In the context of investigations on metal tolerance/effect in B. azoricus, we focused our work on the short-term adaptive response (15days) of mussels to different metals exposure at a molecular level using metal concentrations chosen to mimic natural situations at three vents sites. The expression of a set of 38 genes involved in different steps of the metal uptake, detoxication and various metabolisms was analysed by qPCR. Mussels were also genotyped at 10 enzyme loci to explore the relationships among natural genetic variation and gene expression. Relation between symbiont content (both sulfur-oxidizing and methanogen bacteria) and gene expression was also analysed. Our study demonstrated the influence of metal cocktail composition and time exposure on the transcriptome regulation with a specific pattern of regulation observed for the three metal cocktail tested. We also evidenced the significant influence of some specific Pgm genotype on the global gene expression in our experimental populations and a general trend of a higher gene expression in individuals carrying a high symbiont content. PMID- 25542631 TI - [Atherogenic indices in workers of different occupational sectors of the Spanish Mediterranean area]. AB - INTRODUCTION: Atherogenic indices predict cardiovascular disease, as they provide a good reflection of the clinical and metabolic interactions of lipid fractions. MATERIAL AND METHOD: A descriptive cross-sectional study was conducted on 60,798 workers in the Spanish Mediterranean area on whom different atherogenic indices (cholesterol/HDL, LDL/HDL, triglycerides/HDL) were determined, and the influence they have in the different productive work sectors. RESULTS: In women, the mean values of the different atherogenic indices are better in the health sector, while they are better in men in the primary sector. The percentage of working women with low values is also greater in the healthcare sector, while in men there is no clear predominant sector, with the best values being shown in the hospitality and primary sector. CONCLUSION: The distribution of cardiovascular risk factors and the values of the different atherogenic indices analyzed vary in different industrial sectors. PMID- 25542632 TI - [Intima-media thickness in a middle-old age sample of the Spanish general population]. AB - OBJECTIVES: To ascertain reference values of carotid intima-media thickness (cIMT) in a middle and old-aged sample of the Spanish general population and to establish the 75(th) percentile above which it is necessary to control more strictly other cardiovascular risk factors. To determine cIMT values and the number of carotid plaques in age and sex subgroups, and whether there are differences between them. MATERIAL AND METHODS: Lipids, apolipoproteins, number of carotid atherosclerotic plaques if any, and cIMT of both common carotid arteries were determined in 171 individuals, representative of the adult general population of Burgos (Spain). RESULTS: The median age of the patients was 63 years (interquartile range = 20) and the 75th percentile of carotid IMT was 0,88 mm and 0,81 mm in men and women, respectively. This study shows that the values of cIMT median increase with age and are higher in men than in women in all age groups, except in individuals over 74 years where cIMT median values are similar. The presence or absence of atherosclerotic plaques was not statistically different between men and women at different ages. CONCLUSIONS: This population study shows the reference values of cIMT in a middle and old-aged sample of the Spanish population and shows that age, male gender, systolic blood pressure (SBP) and personal history of coronary heart disease are the main determinants of increased cIMT. PMID- 25542633 TI - Reduced resistance to oxidative stress during reproduction as a cost of early life stress. AB - Stress exposure during early-life development can have long-term consequences for a variety of biological functions including oxidative stress. The link between early-life stress and oxidative balance is beginning to be explored and previous studies have focused on this link in adult non-breeding or immature individuals. However, as oxidative stress is considered as the main physiological mechanism underlying the trade-off between self-maintenance and investment in reproduction, it is necessary to look at the consequences of early-life stress on oxidative status during reproduction. Here, we investigated the effects of exposure to pre- and/or post-natal stress on oxidative balance during reproduction under benign or stressful environmental conditions in an avian model species, the Japanese quail. We determined total antioxidant status (TAS), total oxidant status (TOS) and resistance to a free-radical attack in individual exposed to pre-natal stress, post-natal stress or both and in control individuals exposed to none of the stressors. TAS levels decreased over time in all females that reproduced under stressful conditions. TOS decreased between the beginning and the end of reproductive period in pre-natal control females. In all females, resistance to a free-radical attack decreased over the reproductive event but this decrease was more pronounced in females from a pre-natal stress development. Our results suggest that pre-natal stress may be associated with a higher cost of reproduction in terms of oxidative stress. These results also confirm that early life stress can be associated with both benefits and costs depending of the life history stage or environmental context. PMID- 25542635 TI - Paclitaxel-coated versus plain balloon angioplasty for dysfunctional arteriovenous fistulae: one-year results of a prospective randomized controlled trial. AB - PURPOSE: To report 1-year results of a single-center randomized controlled trial comparing paclitaxel-coated balloon (PCB) versus high-pressure plain balloon angioplasty for the treatment of failing arteriovenous fistulae (AVFs). MATERIALS AND METHODS: Forty patients (26 men; mean age, 61 y +/- 14.63) were randomized at 1:1 to undergo PCB (n = 20) or high-pressure balloon (HPB; n = 20) angioplasty of dysfunctional AVFs. There were no significant differences in baseline demographics between groups. Enrollment required a clinical diagnosis of a dysfunctional AVF attributed to a single stenotic lesion verified with digital subtraction angiography. Primary endpoints included device success, anatomic success, clinical success, and target lesion revascularization (TLR)-free survival. Secondary endpoints included dialysis circuit primary patency and procedure-related complication rates. RESULTS: Device success rates were 100% in the HPB group and 35% in the PCB group (P < 0001): further dilation with an HPB was needed to achieve anatomic success in 13 of 20 cases in the PCB group (65%). Anatomic and clinical success rates were 100% in both groups. TLR-free survival (PCB, 308 d; HPB, 161 d; hazard ratio [HR], 0.478; 95% confidence interval [CI], 0.236-0.966; P = .03) and access circuit primary patency (PCB, 270 d; HPB, 161 d; HR, 0.479; 95% CI, 0.237-0.968; P = .04) were significantly in favor of PCB angioplasty. No minor or major procedure-related complications occurred. CONCLUSIONS: In this single-center study, the use of PCBs resulted in superior TLR-free survival and dialysis access circuit primary patency of dysfunctional AVFs. However, additional HPB postdilation was required in the majority of cases. PMID- 25542634 TI - Retargeting T cells to GD2 pentasaccharide on human tumors using Bispecific humanized antibody. AB - Anti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g., neuroblastoma) by relying on Fc dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single-chain Fv fragment (ScFv) was linked to the carboxyl end of the anti GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunologic synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with >105-fold selectivity over normal tissues, releasing Th1 cytokines (TNFalpha, IFNgamma, and IL2) when GD2+ tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8 BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells. PMID- 25542637 TI - Acute effect of erythromycin on metabolic transformations of volatile fatty acid mixture under anaerobic conditions. AB - The study explored the acute inhibitory impact of erythromycin on the methanogenic activity of acclimated biomass fed with a volatile fatty acid mixture and acetate alone. Parallel batch reactors were operated for six days, with increasing erythromycin dosing in the range of 1-1000 mg L(-1). Substrate removal was monitored by means of soluble COD and volatile fatty acid (VFA) measurements together with parallel observations on biogas and methane generation. The inhibitory impact was variable with the initial erythromycin dose: At lower doses, the VFA mixture was completely removed but partially utilized, leading to reduced biogas and methane generation, suggesting the analogy of uncompetitive inhibition. At higher doses, propionate utilization was totally impaired and butyrate removal was reduced, but acetate was still fully removed. Remaining VFAs were partly converted to new VFA compound through isomerization and polymerization reactions. High erythromycin doses induced total inactivation of microbial metabolism with negligible methane generation. PMID- 25542636 TI - Parasympathetic reactivity in fibromyalgia and temporomandibular disorder: associations with sleep problems, symptom severity, and functional impairment. AB - Despite evidence of autonomic disturbances in chronic multisymptom illnesses such as temporomandibular disorder (TMD) and fibromyalgia, additional work is needed to characterize the role of parasympathetic reactivity in these disorders. Given the high levels of comorbidity with psychiatric disorders characterized by stronger parasympathetic decline than controls in safe contexts (leading to higher arousal), it was hypothesized that individuals with TMD and fibromyalgia would respond similarly. In this preliminary investigation, 43 women with TMD (n = 17), TMD + fibromyalgia (n = 11), or neither (controls; n = 15) completed a baseline assessment of respiratory sinus arrhythmia (a measure of parasympathetic activity) followed by ongoing parasympathetic assessment during a questionnaire period. As predicted, patients showed greater parasympathetic decline during psychosocial assessment, suggesting an autonomic stance that supports defensive rather than engagement behaviors. Individual differences in parasympathetic reduction during the questionnaire period were related to a variety of physical and psychosocial variables. Although this study has a number of key limitations, including a convenience sampling approach and small group sizes, if replicated in larger samples, the findings would have important implications for the treatment of patients with these disorders. PERSPECTIVE: Compared to controls, individuals with TMD or TMD and fibromyalgia demonstrated greater parasympathetic decline during psychosocial assessment, and individual differences in parasympathetic decline predicted negative patient outcomes. Such parasympathetic decline may demonstrate a tendency to readily perceive danger in safe environments. PMID- 25542638 TI - Dechlorane Plus in paired hair and serum samples from e-waste workers: correlation and differences. AB - Dechlorane Plus (DP) and a dechlorinated product of DP were measured in 34 matched human hair and serum samples (19 males and 15 females) collected from e waste recycling workers in South China. The DP (sum of syn- and anti-DP) concentrations in hair and serum samples ranged from 6.3 to 1100 ng g(-1) dry weight and from 22 to 1400 ng g(-1) lipid weight (lw). The levels of anti-Cl11-DP ranged from 0.02 to 1.8 ng g(-1) in hair and from not detected to 7.9 ng g(-1) lw in serum. Significant positive correlations for both DP and anti-Cl11-DP concentrations between hair and serum samples were found (p<0.05), indicating hair to be a suitable matrix for human DP exposure. However, a significant difference was found in the DP isomer composition between hair and serum, suggesting stereoselective bioaccumulation during the absorption of DP into hair. A sharp gender difference was found in the levels of DP in hair. Moreover, syn DP, anti-DP and anti-Cl11-DP in hair significantly correlated with those in serum for male samples, but not for female samples. The observed gender differences in the present study may be, in part, ascribed to the much longer hair exposure time for females than males due to the difference in sampling distance from the scalp. PMID- 25542639 TI - Determination of (4-methylcyclohexyl)methanol isomers by heated purge-and-trap GC/MS in water samples from the 2014 Elk River, West Virginia, chemical spill. AB - A heated purge-and-trap gas chromatography/mass spectrometry method was used to determine the cis- and trans-isomers of (4-methylcyclohexyl)methanol (4-MCHM), the reported major component of the Crude MCHM/DowanolTM PPh glycol ether material spilled into the Elk River upriver from Charleston, West Virginia, on January 9, 2014. The trans-isomer eluted first and method detection limits were 0.16-MUg L(-1)trans-, 0.28-MUg L(-1)cis-, and 0.4-MUg L(-1) Total (total response of isomers) 4-MCHM. Estimated concentrations in the spill source material were 491-g L(-1)trans- and 277-g L(-1)cis-4-MCHM, the sum constituting 84% of the source material assuming its density equaled 4-MCHM. Elk River samples collected?3.2 km downriver from the spill on January 15 had low (?2.9 MUg L(-1) Total) 4-MCHM concentrations, whereas the isomers were not detected in samples collected 2 d earlier at the same sites. Similar 4-MCHM concentrations (range 4.2 5.5 MUg L(-1) Total) occurred for samples of the Ohio River at Louisville, Kentucky, on January 17, ~630 km downriver from the spill. Total 4-MCHM concentrations in Charleston, WV, office tap water decreased from 129 MUg L(-1) on January 27 to 2.2 MUg L(-1) on February 3, but remained detectable in tap samples through final collection on February 25 indicating some persistence of 4 MCHM within the water distribution system. One isomer of methyl 4 methylcyclohexanecarboxylate was detected in all Ohio River and tap water samples, and both isomers were detected in the source material spilled. PMID- 25542640 TI - Context-specific selection of algorithms for recursive feature tracking in endoscopic image using a new methodology. AB - In minimally invasive surgery, the tracking of deformable tissue is a critical component for image-guided applications. Deformation of the tissue can be recovered by tracking features using tissue surface information (texture, color,...). Recent work in this field has shown success in acquiring tissue motion. However, the performance evaluation of detection and tracking algorithms on such images are still difficult and are not standardized. This is mainly due to the lack of ground truth data on real data. Moreover, in order to avoid supplementary techniques to remove outliers, no quantitative work has been undertaken to evaluate the benefit of a pre-process based on image filtering, which can improve feature tracking robustness. In this paper, we propose a methodology to validate detection and feature tracking algorithms, using a trick based on forward-backward tracking that provides an artificial ground truth data. We describe a clear and complete methodology to evaluate and compare different detection and tracking algorithms. In addition, we extend our framework to propose a strategy to identify the best combinations from a set of detector, tracker and pre-process algorithms, according to the live intra-operative data. Experimental results have been performed on in vivo datasets and show that pre process can have a strong influence on tracking performance and that our strategy to find the best combinations is relevant for a reasonable computation cost. PMID- 25542641 TI - Experiments on individual strategy updating in iterated snowdrift game under random rematching. AB - How do people actually play the iterated snowdrift games, particularly under random rematching protocol is far from well explored. Two sets of laboratory experiments on snowdrift game were conducted to investigate human strategy updating rules. Four groups of subjects were modeled by experience-weighted attraction learning theory at individual-level. Three out of the four groups (75%) passed model validation. Substantial heterogeneity is observed among the players who update their strategies in four typical types, whereas rare people behave like belief-based learners even under fixed pairing. Most subjects (63.9%) adopt the reinforcement learning (or alike) rules; but, interestingly, the performance of averaged reinforcement learners suffered. It is observed that two factors seem to benefit players in competition, i.e., the sensitivity to their recent experiences and the overall consideration of forgone payoffs. Moreover, subjects with changing opponents tend to learn faster based on their own recent experience, and display more diverse strategy updating rules than they do with fixed opponent. These findings suggest that most of subjects do apply reinforcement learning alike updating rules even under random rematching, although these rules may not improve their performance. The findings help evolutionary biology researchers to understand sophisticated human behavioral strategies in social dilemmas. PMID- 25542642 TI - Recent advances in virtual screening for drug discovery. PMID- 25542643 TI - Clinical guidelines in transfusion medicine. PMID- 25542644 TI - Simvastatin prodrug micelles target fracture and improve healing. AB - Simvastatin (SIM), a widely used anti-lipidemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug's hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles' therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing. PMID- 25542646 TI - The role of RNase R in trans-translation and ribosomal quality control. AB - Gene expression not only depends on the rate of transcription but is also largely controlled at the post-transcriptional level. Translation rate and mRNA decay greatly influence the final protein levels. Surveillance mechanisms are essential to ensure the quality of the RNA and proteins produced. Trans-translation is one of the most important systems in the quality control of bacterial translation. This process guarantees the destruction of abnormal proteins and also leads to degradation of the respective defective RNAs through the action of Ribonuclease R (RNase R). This exoribonuclease hydrolyzes RNAs starting from their 3' end. Besides its involvement in trans-translation, RNase R also participates in the quality control of rRNA molecules involved in ribosomal biogenesis. RNase R is thus emerging as a key factor in ensuring translation accuracy. This review focuses on issues related to the quality control of translation, with special emphasis on the role of RNase R. PMID- 25542645 TI - Esterase-activatable beta-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. AB - Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, beta lapachone (beta-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of beta-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of beta-lap prodrug nanotherapeutics consisting of diester derivatives of beta-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of beta lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered beta-lap-dC3 and -dC6 prodrugs were converted to beta-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H: quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of beta-lap dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over beta-lap-dC6 micelles or beta-lap HPbetaCD complexes. Improved therapeutic efficacy of beta-lap-dC3 micelles correlated with higher area under the concentration-time curves of beta-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, gammaH2AX, and ATP depletion). beta-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy. PMID- 25542648 TI - Higher-level phylogeny of the Hymenoptera inferred from mitochondrial genomes. AB - Higher-level hymenopteran relationships remain unresolved in both morphological and molecular analyses. In this study, we present the most comprehensive analyses of hymenopteran relationships based on 48 mitochondrial (mt) genomes. One complete and two nearly complete mt genomes representing three hymenopteran superfamilies were newly sequenced. We assessed the influence of inclusion/exclusion of 3rd codon positions, alignment approaches, partition schemes and phylogenetic approaches on topology and nodal support within the Hymenoptera. The results showed that the topologies were sensitive to the variation of dataset and analytical approach. However, some robust and highly supported relationships were recovered: the Ichneumonomorpha was monophyletic; the Trigonalyoidea+Megalyroidea and the Diaprioidea+Chalcidoidea were consistently recovered; the Cynipoidea was generally recovered as the sister group to the Diaprioidea+Chalcidoidea. In addition, the monophyletic Aculeata and Proctotrupomorpha were recovered in some analyses. Several gene rearrangements were detected in each of the three newly sequenced mt genomes. Specifically, the Ibalia leucospoides mt genome harbors a large inversion of a gene block from trnE to trnS2. Inverted, duplicated A+T rich regions were detected in the Ibalia leucospoides mt genome, which probably played an important role during the formation of the large gene block inversion via recombination. PMID- 25542649 TI - A species-level phylogeny of all extant and late Quaternary extinct mammals using a novel heuristic-hierarchical Bayesian approach. AB - Across large clades, two problems are generally encountered in the estimation of species-level phylogenies: (a) the number of taxa involved is generally so high that computation-intensive approaches cannot readily be utilized and (b) even for clades that have received intense study (e.g., mammals), attention has been centered on relatively few selected species, and most taxa must therefore be positioned on the basis of very limited genetic data. Here, we describe a new heuristic-hierarchical Bayesian approach and use it to construct a species-level phylogeny for all extant and late Quaternary extinct mammals. In this approach, species with large quantities of genetic data are placed nearly freely in the mammalian phylogeny according to these data, whereas the placement of species with lower quantities of data is performed with steadily stricter restrictions for decreasing data quantities. The advantages of the proposed method include (a) an improved ability to incorporate phylogenetic uncertainty in downstream analyses based on the resulting phylogeny, (b) a reduced potential for long branch attraction or other types of errors that place low-data taxa far from their true position, while maintaining minimal restrictions for better-studied taxa, and (c) likely improved placement of low-data taxa due to the use of closer outgroups. PMID- 25542650 TI - Long-term disease control and toxicity outcomes following surgery and intensity modulated radiation therapy (IMRT) in pediatric craniopharyngioma. AB - PURPOSE: To report long-term progression-free survival (PFS) and late-toxicity outcomes in pediatric craniopharyngioma patients treated with IMRT. PATIENTS AND METHODS: Twenty-four children were treated with IMRT to a median dose of 50.4Gy (range, 49.8-54Gy). The clinical target volume (CTV) was the gross tumor volume (GTV) with a 1cm margin. The planning target volume (PTV) was the CTV with a 3 5mm margin. Median follow-up was 107.3months. RESULTS: The 5- and 10-year PFS rates were 65.8% and 60.7%. The 5- and 10-year cystic PFS rates were 70.2% and 65.2% while the 5- and 10-year solid PFS were the same at 90.7%. Endocrinopathy was seen in 42% at initial diagnosis and in 74% after surgical intervention, prior to IMRT. Hypothalamic dysfunction and visual deficits were associated with increasing PTV and number of surgical interventions. CONCLUSIONS: IMRT is a viable treatment option for pediatric craniopharyngioma. Despite the use of IMRT, majority of the craniopharyngioma patients experienced long-term toxicity, many of which present prior to radiotherapy. Limitations of retrospective analyses on small patient cohort elicit the need for a prospective multi-institutional study to determine the absolute benefit of IMRT in pediatric craniopharyngioma. PMID- 25542647 TI - Heterogeneity of the translational machinery: Variations on a common theme. AB - In all organisms the universal process of protein synthesis is performed by the ribosome, a complex multi-component assembly composed of RNA and protein elements. Although ribosome heterogeneity was observed already more than 40 years ago, the ribosome is still traditionally viewed as an unchangeable entity that has to be equipped with all ribosomal components and translation factors in order to precisely accomplish all steps in protein synthesis. In the recent years this concept was challenged by several studies highlighting a broad variation in the composition of the translational machinery in response to environmental signals, which leads to its adaptation and functional specialization. Here, we summarize recent reports on the variability of the protein synthesis apparatus in diverse organisms and discuss the multiple mechanisms and possibilities that can lead to functional ribosome heterogeneity. Collectively, these results indicate that all cells are equipped with a remarkable toolbox to fine tune gene expression at the level of translation and emphasize the physiological importance of ribosome heterogeneity for the immediate implementation of environmental information. PMID- 25542651 TI - Cryopreservation of Escherichia coli K12TG1: protection from the damaging effects of supercooling by freezing. AB - Injuries in living cells caused by water freezing during a freeze-thaw process have been extensively reported. In particular, intracellular water freezing has long been incriminated in cell death caused by a high cooling rate, but this supposition could not always be demonstrated. This work aims to discriminate the role of water freezing, dehydration and cold-induced injuries in cellular damage occuring during cryopreservation. For this purpose, Escherichia coli K12TG1 suspensions were maintained in a supercooled or frozen state at -20 degrees C for times ranging from 10 min to 5 h. The supercooled state was maintained for a long period at -20 degrees C by applying a non-injurious isostatic pressure (P<40 MPa). Next, viability and membrane damage were determined by agar plating and fluorescence staining with propidium iodide and bis-oxonol. It was clear that keeping the cell suspensions in the supercooled state had a detrimental effect on both viability and plasma membrane permeability. Conversely, when cells were subjected to cold stress by freezing, the survival rate remained high throughout the experiment, and the cell membranes suffered little damage. Moreover, cells subjected to 5h of osmotic treatments at -20 degrees C, conditions that mimic cryoconcentration upon freezing, and subsequently diluted and thawed suffered little damage. Dehydration due to cryoconcentration upon freezing protects the cells against the deleterious effects of supercooling, especially in the plasma membranes. The decrease in membrane leakage upon dehydration at low temperatures could be linked to differences in the gel state of the membrane revealed by a higher Laurdan general polarization (GP) value. PMID- 25542653 TI - Stability indicating RP-HPLC method development and validation for the simultaneous determination of aminexil and minoxidil in pharmaceutical dosage form. AB - The objective of the present work is to develop stability indicating high performance liquid chromatographic method for the simultaneous determination of aminexil and minoxidil in pharmaceutical dosage form. The chromatographic separation was achieved with BDS Hypersil C18 column (250 mm*4.6 mm*5 MU) as stationary phase and phosphate buffer and acetonitrile (78:22) as mobile phase. The method was employed by using a flow rate of 1.1 mL/min kept at 30 degrees C. The detection wavelength was kept at 238 nm by using photo-diode array detector. The retention times of the aminexil and minoxidil were found to be 2.3 min and 3.9 min, respectively. The method developed was validated in accordance with ICH guidelines with respect to the stability indicating capacity of the method including system suitability, accuracy, precision, linearity, range, limit of detection, limit of quantification and robustness. The linearity responses of aminexil and minoxidil were found to be in the concentration ranges of 18.75 112.5 MUg/mL and 25-150 MUg/mL, respectively. The LOD and LOQ values for aminexil were found to be 0.31 and 0.92 MUg/mL and minoxidil were found to be 0.03 and 0.10 MUg/mL respectively. The percentage recoveries for both the drugs were found in the range of 98-101%. This method is accurate, precise and sensitive; hence, it can be employed for routine quality control of aminexil and minoxidil in pharmaceutical industries and drug testing laboratories. PMID- 25542652 TI - Deoxynivalenol-induced cytokines and related genes in concanavalin A-stimulated primary chicken splenic lymphocytes. AB - Deoxynivalenol (DON) immunotoxicity and its induction of cytokines and related genes in the splenic lymphocytes of chickens have not been completely elucidated. In the present study, we aimed to evaluate the effects of 48 h of different DON treatments (0 MUg/mL, 0.2 MUg/mL, 0.8 MUg/mL, 3.2 MUg/mL, 12.5 MUg/mL, and 50 MUg/mL) on the secretion and the mRNA expressions of some cytokine genes, such as interleukin-1beta (IL-1beta), IL-1RI, IL-2, IL-4, IL-6, IL-10, IL-12beta, and IFN gamma in chicken splenic lymphocytes. The concentrations of IL-1RI, IL-6, IL-10, and IFN-gamma were increased with the DON concentrations increasing (P<0.05 or P<0.01). However, the concentrations of IL-1beta, IL-2, IL-4, and IL-12beta were decreased with the DON concentrations increasing (P<0.05 or P<0.01). Except IL 1beta, the mRNA expressions of the other cytokines were up-regulated by DON. The highest mRNA expressions values of IL-1RI, IL-4, IL-10, IL-12beta, and IFN-gamma were at 50 MUg/mL DON treatment groups (P<0.05 or P<0.01), while the highest mRNA expressions values of IL-2 and IL-6 were at 12.5 MUg/mL DON treatment groups (P<0.05 or P<0.01). Our data revealed that the potent effects of DON in affecting the secretion and the mRNA expression of the related cytokines in chicken splenic lymphocytes in vitro. PMID- 25542654 TI - [Positive aspects of aging]. PMID- 25542655 TI - [Impact of the economic crisis on the activity of a clinical research ethics committee]. AB - PURPOSE: Analyze the impact of economic and social crisis in volume and funding of clinical trials (CT) and observational studies (ES) from the activity of an Research Ethics Committee (REC). METHOD: REC memories 2003-2012 were reviewed. Financing of evaluated projects, CT and OS were analyzed classifying them into four groups: 1) promoted by pharmaceutical industry, 2) by scientific societies with industry support, 3) by scientific societies with government support and 4) unfunding.Two periods were compared: pre-crisis (2003-2007) and crisis (2008 2012). RESULTS: During 10 studied years, 744 protocols were evaluated: a 71% of group 1, a 9% of group 2, a 3% of group 3 and a 17% was no funding. Regarding OS, 40%, 5,4%, 8,6% and 46% were the groups 1, 2, 3 and 4 respectively. Analyzing crisis versus pre-crisis period, statistically significant differences were observed in the decreasing of number of CT phase 2 and 3 and in the rising EO. Comparing crisis related to the pre-crisis period, the Group 4 increased statistically significantly. CONCLUSIONS: Evolution of total number of studies evaluated by REC tends to be maintained and even increased over time. REC maintains its activity and even increased at the expense of financing and unfunded OS. PMID- 25542656 TI - [Parenteral administration medicines: recommendations of preparation, administration and stability]. AB - OBJECTIVE: To develop recommendations for the preparation of parenteral drugs (MAP), to assess the transferability of their preparation, from nursing units in the hospital ward to the pharmacy service (SF). METHOD: A table of stabilities of parenteral drugs included in the pharmacotherapeutic guideline was developed using the american and spanish guidelines. Information about MAP was collected (method of preparation, support, maintenance, validity, administration specifications and packaging) by consulting product technical sheets, pharmaceutical industries, literature review and databases. RESULTS: After reviewing 209 drugs, a list of recommendations was developed. According to the data, MAP will be prepared as follows: 89 drugs will be prepared from SF, 62 drugs at nursing units because of its immediate administration requirement and 58 are already packed for its administration by the industry. Of these 62 drugs prepared a nursing units, 14 of them will be prepared in the following doses by the SF. Therefore, 48 drugs will be prepared at nursing units from the 209 parenteral drugs reviewed. CONCLUSIONS: A standardized method of preparation, storage, administration and validity of MAP was established by the SF. The preparation of MAP in the SF extends its shelf life, by considering physicochemical stability, level of risk and product vulnerability to microbiological contamination. The information provided will contribute to a reduction of errors associated with the preparation and administration of MAP. PMID- 25542657 TI - [Dapagliflozin, a novel oral antidiabetic with an uncertain future]. AB - OBJECTIVE: Diabetes mellitus type 2 (DM2) is one of the main sociosanitary problems; there are many treatments for it. Recently, it has been approved the first drug of a new family of oral hypoglycemic agents (OHA): dapagliflozin. We aimed to review the available scientific evidence on dapagliflozin, in order to analyze its effectiveness, safety and cost and to estimate its role in the current pharmacotherapy of DM2. METHODS: Effectiveness and safety of dapagliflozin were analyzed by an evaluation of the scientific evidence. The cost of different OHA was calculated based on the defined daily dose (DDD) and their ex-factory prices. RESULTS: Seven randomized clinical trials were identified: 2 monotherapy (840 patients) and 5 in combination with other hypoglycemic agents (3184 patients). In the seven trials, dapagliflozin reduced HbA1c; all were compared with placebo, unless in a trial of combination therapy in which was compared with an active drug (glipizide). The most common side effects were genitourinary infections and hypotension, although it should be taken into consideration the increase of the bladder cancer. Besides the DPP-4 inhibitors, dapagliflozin is one of the OHA more expensive (annual cost of DDD= 729.3 euros). CONCLUSIONS: Dapagliflozin does not provide advantages over pharmacotherapy for DM2. Its lack of experience of use, the absence of significant clinical benefits and its high cost make it necessary to restrict its use. PMID- 25542658 TI - [Adherence to oral antineoplastic therapy]. AB - BACKGROUND: Oral chemotherapy agents offer advantages including cost, patient comfort and potential improvement in quality of life versus intravenous drugs. However ensuring adherence and monitoring adverse effects is more difficult. The aim of this study was to examine the real adherence in patients with oral chemotherapy agents in our hospital, to assess the influence of patient and treatment characteristics, to identify reasons for non adherence, to identify opportunities for improvement pharmaceutical care and to assess the potential relation between adherence and treatment outcomes. METHOD: observational, prospective study for a period of four month, in the patients who were dispensing oral chemotherapy agents in outpatient setting. The medical prescriptions, medical history and patient interviews were used to collect data. RESULTS: 141 patients were assessing. 72% were considered as fully adherent, while 28% reported some kind of non adherence. Adherence was influenced by time from diagnosis and adverse effects. No relationship between adherence and treatment outcomes was found. CONCLUSIONS: Adherence to oral chemotherapy was 72%, identifing opportunities for improvement pharmaceutical care to prevent adverse effects and to improve our patient adherence. PMID- 25542659 TI - [Economic perspectives of the research on advanced therapies]. AB - Since a new advanced therapy medicinal product is discovered until finally allowed its sale in the domestic market, it has to overcome a series of stages. Biomedical research is the first phase, currently its situation is encouraging to the increase in the number of clinical trials in Spain and in the rest of the world, despite the economic situation and the various difficulties that have faced the pharmaceutical laboratories. The next phase consists in obtaining the authorization of marketing of the European Medicines Agency. After authorization, will attempt to set a fair and moderate price for inclusion in the list of health provision of Social Security. A price for a drug that provides added value to health and society, a price that is generated profits for the pharmaceutical companies that hope to make up for the years of work and investment. Commitment to advanced therapy must be clear and forceful, to fund ongoing research projects and encouraging their creation with economic aid. PMID- 25542660 TI - Resistant hypertension in pediatric end stage renal disease. PMID- 25542661 TI - [L-Arginine pill induced esophageal ulcer: causes not reported previously esophagitis for pills]. PMID- 25542662 TI - [Update in the treatment of dermatomyositis; a case study]. PMID- 25542663 TI - [Use of pertuzumab and docetaxel desensitization in oncological patient; apropos of a case]. PMID- 25542664 TI - [Magnesium in drugs: do we have enough information?]. PMID- 25542665 TI - [Suspected itchy rash secondary to lenalidomide]. PMID- 25542666 TI - [Response to clinical case report: treatment with urea as an alternative to tolvaptan for the syndrome of inappropriate secretion of antidiuretic hormone]. PMID- 25542668 TI - Abnormal proliferation and spontaneous differentiation of myoblasts from a symptomatic female carrier of X-linked Emery-Dreifuss muscular dystrophy. PMID- 25542670 TI - Predictors of support among students, faculty and staff for a smoke-free university campus. AB - OBJECTIVES: Students, faculty, and staff at a Pacific Northwest public university were surveyed one year after enactment of a smoke-free campus policy. Objectives were to assess levels of support for a smoke-free campus, ascertain exposure levels to outdoor tobacco smoke, and identify correlates of policy support. METHOD: A 2013 Web-based survey included 5691 students (response rate 26%) and 2051 faculty/staff (response rate 43%). Measures included support for a smoke free campus, smoking status, exposure to secondhand smoke, and perceptions of levels of policy support and campus smoking. Logistic regression was used to examine predictors of support. RESULTS: Seventy-two percent of students and 77% of faculty/staff supported a smoke-free campus. Respondents reported limited exposure to smoke near building entrances, but exposure near campus boundaries was reported by majorities of students (77%) and faculty/staff (55%). Predictors of students' policy support included never-smoker status, perceived support by peers, perceived student smoking prevalence, campus smoke exposure, and female gender, among others. Predictors of faculty/staff support included never-smoker status, perceived policy support by students and peers, campus smoke exposure, female gender, and age. CONCLUSION: Students, faculty, and staff were strongly supportive of the existing smoke-free campus policy. However, the policy led to smoking activity shifting to the campus periphery. PMID- 25542669 TI - (125)I-Labelled 2-Iodoestrone-3-sulfate: synthesis, characterization and OATP mediated transport studies in hormone dependent and independent breast cancer cells. AB - INTRODUCTION: Organic Anion Transporting Polypeptides (OATP) are a family of membrane associated transporters that facilitate estrone-3-sulphate (E3S) uptake by hormone dependent, post-menopausal breast cancers. We have established E3S as a potential ligand for targeting hormone dependent breast cancer cells, and in this study sought to prepare and investigate radioiodinated E3S as a tool to study the OATP system. METHODS: 2- and 4-Iodoestrone-3-sulfates were prepared from estrone via aromatic iodination followed by a rapid and high yielding sulfation procedure. The resulting isomers were separated by preparative HPLC and verified by (1)H NMR and analytical HPLC. Transport studies of 2- and 4-[(125)I] E3S were conducted in hormone dependent (i.e. MCF-7) and hormone independent (i.e. MDA-MB-231) breast cancer cells in the presence or absence of the specific transport inhibitor, bromosulfophthalein (BSP). Cellular localization of OATP1A2, OATP2B1, OATP3A1 and OATP4A1 were determined by immunofluorescence analysis using anti-Na(+)/K(+) ATPase-alpha (1:100 dilution) and DAPI as plasma membrane and nuclear markers, respectively. RESULTS: Significantly (p<0.01) higher total accumulation of 2-[(125)I]-E3S was observed in hormone dependent MCF-7 as compared to hormone independent MDA-MB-231 breast cancer cells. In contrast 4 [(125)I]-E3S did not show cellular accumulation in either case. The efficiency of 2-[(125)I]-E3S transport (expressed as a ratio of Vmax/Km) was 2.4 times greater in the MCF-7 as compared to the MDA-MB-231 breast cancer cells. OATP1A2, OATP3A1 and OATP4A1 expression was localized in plasma membranes of MCF-7 and MDA-MB-231 cells confirming the functional role of these transporters in radioiodinated E3S cellular uptake. CONCLUSION: An efficient method for the preparation of 2- and 4 [(125)I]-E3S was developed and where the former demonstrated potential as an in vitro probe for the OATP system. The new E3S probe can be used to study the OATP system and as a platform to create radiopharmaceuticals for imaging breast cancer. PMID- 25542671 TI - Monitoring the evolution of crystallization processes by in-situ solid-state NMR spectroscopy. AB - Crystallization processes play a crucial role in many aspects of biological and physical sciences. Progress in deepening our fundamental understanding of such processes relies, to a large extent, on the development and application of new experimental strategies that allow direct in-situ monitoring of the process. In this paper, we give an overview of an in-situ solid-state NMR strategy that we have developed in recent years for monitoring the time-evolution of different polymorphic forms (or other solid forms) that arise as the function of time during crystallization from solution. The background to the strategy is described and several examples of the application of the technique are highlighted, focusing on both the evolution of different polymorphs during crystallization and the discovery of new polymorphs. PMID- 25542673 TI - Bilateral dystrophic ossification of the thyroid cartilage. PMID- 25542672 TI - [Evaluation of performance of BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) in a Brazilian cohort of 1,492 patients with spondyloarthritis: data from the Brazilian Registry of Spondyloarthritides (RBE)]. AB - OBJECTIVE: To analyze the results of the application of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in a large series of Brazilian patients with the diagnosis of SpA and establish its correlations with specific variables into the group. METHODS: A common protocol of investigation was prospectively applied to 1492 Brazilian patients classified as SpA according to the European Spondyoarthropathies Study Group (ESSG), attended at 29 referral centers of Rheumatology in Brazil. Clinical and demographic variables, and disease indices (BASDAI, Basfi, Basri, Mases, ASQol) were applicated. The total values of BASDAI were compared to the presence of the different variables. RESULTS: The mean score of BASDAI was 4.20 +/- 2.38. The mean scores of BASDAI were higher in patients with the combined (axial + peripheral + entheseal) (4.54 +/- 2.38) clinical presentation, compared to the pure axial (3.78 +/- 2.27) or pure peripheral (4.00 +/- 2.38) clinical presentations (p<0.001). BASDAI also presented higher scores associated with the female gender (p<0.001) and patients who did not practice exercises (p < 0.001). Regarding the axial component, higher values of BASDAI were significantly associated with inflammatory low back pain (p<0.049), alternating buttock pain (p<0.001), cervical pain (p<0.001) and hip involvement (p<0.001). There was also statistical association between BASDAI scores and the peripheral involvement, related to the lower (p=0.004) and upper limbs (p=0.025). The presence of enthesitis was also associated to higher scores of BASDAI (p=0.040). Positive HLA-B27 and the presence of cutaneous psoriasis, inflammatory bowel disease, uveitis and urethritis were not correlated with the mean scores of BASDAI. Lower scores of BASDAI were associated with the use of biologic agents (p<0.001). CONCLUSION: In this heterogeneous Brazilian series of SpA patients, BASDAI was able to demonstrate "disease activity" in patients with axial as well as peripheral disease. PMID- 25542674 TI - Effect of comanagement with internal medicine on hospital stay of patients admitted to the Service of Otolaryngology. AB - INTRODUCTION AND OBJECTIVES: Patients admitted to the Department of Otolaryngology (ENT) are increasing in age, comorbidity and complexity, leading to increased consultations/referrals to Internal Medicine (IM). An alternative to consultations/referrals is co-management. We studied the effect of co-management on length of stay (LoS) in hospital for patients admitted to ENT. METHODS: This was a retrospective observational study including patients >=14 years old discharged from ENT between 1/1/2009 and 30/06/2013, with co-management from May/2011. We analysed age, sex, type of admission, whether the patient was operated, administrative weight associated with DRG, total number of discharge diagnoses, Charlson comorbidity index (CCI), deaths, readmissions and LoS. RESULTS: There were statistically significant differences between both groups in age (4.5 years; 95% confidence interval [95% CI] 2.8-6.3), emergency admissions (odds ratio [OR] 1.4; 95% CI 1.1-1.8), administrative weight (0.3637; 95% CI 0.0710-0.6564), number of diagnoses (1.3; 95% CI 1-1.6), CCI (0.4; 95% CI 0.2 0.6) and deaths (OR 4.1; 95% CI 1.1-15.7). On adjustment, co-management reduced ENT LoS in hospital by 28.6%, 0.8 days (95% CI 0.1-1.6%; P=.038). This reduction represents an ENT savings of at least ?165,893. CONCLUSIONS: Co-management patients admitted to ENT are increasing in age, comorbidity and complexity. Co management is associated with reduced LoS and costs in ENT, similar to those observed in other surgical services. PMID- 25542675 TI - Hierarchical neurocomputations underlying concurrent sound segregation: connecting periphery to percept. AB - Natural soundscapes often contain multiple sound sources at any given time. Numerous studies have reported that in human observers, the perception and identification of concurrent sounds is paralleled by specific changes in cortical event-related potentials (ERPs). Although these studies provide a window into the cerebral mechanisms governing sound segregation, little is known about the subcortical neural architecture and hierarchy of neurocomputations that lead to this robust perceptual process. Using computational modeling, scalp-recorded brainstem/cortical ERPs, and human psychophysics, we demonstrate that a primary cue for sound segregation, i.e., harmonicity, is encoded at the auditory nerve level within tens of milliseconds after the onset of sound and is maintained, largely untransformed, in phase-locked activity of the rostral brainstem. As then indexed by auditory cortical responses, (in)harmonicity is coded in the signature and magnitude of the cortical object-related negativity (ORN) response (150-200 ms). The salience of the resulting percept is then captured in a discrete, categorical-like coding scheme by a late negativity response (N5; ~500 ms latency), just prior to the elicitation of a behavioral judgment. Subcortical activity correlated with cortical evoked responses such that weaker phase-locked brainstem responses (lower neural harmonicity) generated larger ORN amplitude, reflecting the cortical registration of multiple sound objects. Studying multiple brain indices simultaneously helps illuminate the mechanisms and time-course of neural processing underlying concurrent sound segregation and may lead to further development and refinement of physiologically driven models of auditory scene analysis. PMID- 25542676 TI - Postacute rehabilitation quality of care: toward a shared conceptual framework. AB - There is substantial interest in mechanisms for measuring, reporting, and improving the quality of health care, including postacute care (PAC) and rehabilitation. Unfortunately, current activities generally are either too narrow or too poorly specified to reflect PAC rehabilitation quality of care. In part, this is caused by a lack of a shared conceptual understanding of what construes quality of care in PAC rehabilitation. This article presents the PAC-rehab quality framework: an evidence-based conceptual framework articulating elements specifically pertaining to PAC rehabilitation quality of care. The widely recognized Donabedian structure, process, and outcomes (SPO) model furnished the underlying structure for the PAC-rehab quality framework, and the International Classification of Functioning, Disability and Health (ICF) framed the functional outcomes. A comprehensive literature review provided the evidence base to specify elements within the SPO model and ICF-derived framework. A set of macrolevel outcomes (functional performance, quality of life of patient and caregivers, consumers' experience, place of discharge, health care utilization) were defined for PAC rehabilitation and then related to their (1) immediate and intermediate outcomes, (2) underpinning care processes, (3) supportive team functioning and improvement processes, and (4) underlying care structures. The role of environmental factors and centrality of patients in the framework are explicated as well. Finally, we discuss why outcomes may best measure and reflect the quality of PAC rehabilitation. The PAC-rehab quality framework provides a conceptually sound, evidence-based framework appropriate for quality of care activities across the PAC rehabilitation continuum. PMID- 25542678 TI - Case report: fibrous dysplasia of the navicular bone treated with excision of navicular and talo-cuneiform arthrodesis. AB - Fibrous dysplasia is an uncommon beningn disorder of bone. It usually affects the long bones, and is uncommon in the navicular. We describe a case of fibrous dysplasia of the navicular successfully treated with navicular excision and talo cuneiform arthrodesis. PMID- 25542679 TI - Quantum dot agglomerates in biological media and their characterization by asymmetrical flow field-flow fractionation. AB - The molecular composition of the biological environment of nanoparticles influences their physical properties and changes their pristine physicochemical identity. In order to understand, or predict, the interactions of cells with specific nanoparticles, it is critical to know their size, shape, and agglomeration state not only in their nascent state but also in biological media. Here, we use asymmetrical flow field-flow fractionation (AF4) with on-line multiangle light scattering (MALS), dynamic light scattering (DLS) and UV-Visible absorption detections to determine the relative concentration of isolated nanoparticles and agglomerates in the case of three types of semi-conductor quantum dots (QDs) dispersed in Dulbecco's Modified Eagle Media (DMEM) containing 10% of fetal bovine serum (DMEM-FBS). AF4 analysis also yielded the size and size distribution of the agglomerates as a function of the time of QDs incubation in DMEM-FBS. The preferred modes of internalization of the QDs are assessed for three cell-types, N9 microglia, human hepatocellular carcinoma cells (HepG2) and human embryonic kidney cells (Hek293), by confocal fluorescence imaging of live cells, quantitative determination of the intracellular QD concentration, and flow cytometry. There is an excellent correlation between the agglomeration status of the three types of QDs in DMEM-FBS determined by AF4 analysis and their preferred mode of uptake by the three cell lines, which suggests that AF4 yields an accurate description of the nanoparticles as they encounter cells and advocates its use as a means to characterize particles under evaluation. PMID- 25542677 TI - Effects of emotionally charged auditory stimulation on gait performance in the elderly: a preliminary study. AB - OBJECTIVES: To evaluate the effect of a novel divided attention task-walking under auditory constraints-on gait performance in older adults and to determine whether this effect was moderated by cognitive status. DESIGN: Validation cohort. SETTING: General community. PARTICIPANTS: Ambulatory older adults without dementia (N=104). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: In this pilot study, we evaluated walking under auditory constraints in 104 older adults who completed 3 pairs of walking trials on a gait mat under 1 of 3 randomly assigned conditions: 1 pair without auditory stimulation and 2 pairs with emotionally charged auditory stimulation with happy or sad sounds. RESULTS: The mean age of subjects was 80.6+/-4.9 years, and 63% (n=66) were women. The mean velocity during normal walking was 97.9+/-20.6cm/s, and the mean cadence was 105.1+/-9.9 steps/min. The effect of walking under auditory constraints on gait characteristics was analyzed using a 2-factorial analysis of variance with a 1 between factor (cognitively intact and minimal cognitive impairment groups) and a 1-within factor (type of auditory stimuli). In both happy and sad auditory stimulation trials, cognitively intact older adults (n=96) showed an average increase of 2.68cm/s in gait velocity (F1.86,191.71=3.99; P=.02) and an average increase of 2.41 steps/min in cadence (F1.75,180.42=10.12; P<.001) as compared with trials without auditory stimulation. In contrast, older adults with minimal cognitive impairment (Blessed test score, 5-10; n=8) showed an average reduction of 5.45cm/s in gait velocity (F1.87,190.83=5.62; P=.005) and an average reduction of 3.88 steps/min in cadence (F1.79,183.10=8.21; P=.001) under both auditory stimulation conditions. Neither baseline fall history nor performance of activities of daily living accounted for these differences. CONCLUSIONS: Our results provide preliminary evidence of the differentiating effect of emotionally charged auditory stimuli on gait performance in older individuals with minimal cognitive impairment compared with those without minimal cognitive impairment. A divided attention task using emotionally charged auditory stimuli might be able to elicit compensatory improvement in gait performance in cognitively intact older individuals, but lead to decompensation in those with minimal cognitive impairment. Further investigation is needed to compare gait performance under this task to gait on other dual-task paradigms and to separately examine the effect of physiological aging versus cognitive impairment on gait during walking under auditory constraints. PMID- 25542680 TI - TPGS-chitosome as an effective oral delivery system for improving the bioavailability of Coenzyme Q10. AB - This study aimed to design the chitosan coated TPGS liposome to enhance the bioavailability of Coenzyme Q10 (CoQ10). Optimization of formulation variables for the preparation of the liposome was performed and then three liposomal formulations (TPGS-liposome, TPGS-chitosome, chitosome) were prepared with narrow size distribution and high encapsulation efficiency. All of three liposomal formulations were stable at pH 1.2 and 7.0 for 24h without any significant drug leakage. Furthermore, chitosan-coated liposomes showed the strong mucoadhesive properties. All the tested liposomal formulations significantly enhanced the cellular uptake of CoQ10 as compared to the untreated drug. Particularly, TPGS chitosome appeared to be most effective in improving the cellular uptake of CoQ10 in Caco-2 cells (about 30-folds greater than the untreated powder formulation). In oral pharmacokinetic studies, TPGS-chitosome enhanced the systemic exposure of CoQ10 by 3.4 folds as compared to the untreated powder and also displayed the extended drug release profile for up to 24h in rats. Compared to the untreated powder CoQ10, TPGS-chitosome significantly improved the antioxidant effect of CoQ10 and reduced the intracellular ROS level. In conclusion, TPGS-chitosome significantly enhanced the oral bioavailability of CoQ10 and prolonged drug release profile in rats, suggesting that TPGS-chitosome could be an effective oral delivery platform to improve the oral bioavailability of poorly absorbable drugs. PMID- 25542681 TI - Fabrication, solid state characterization and bioavailability assessment of stable binary amorphous phases of Ritonavir with Quercetin. AB - In the current study, Quercetin (QRT) was characterized for thermodynamic and kinetic parameters and found as an excellent glass former. QRT was paired with Ritonavir (RTV) (BCS class-IV antiretroviral) to form stable amorphous form and pharmacologically relevant combination. Binary amorphous forms of RTV and QRT in molar ratios 1:1, 1:2 and 2:1 were prepared by solvent evaporation technique and characterized by XRPD, DSC and FTIR. The prepared binary phases were found to become amorphous after solvent evaporation which was confirmed by disappearance of crystalline peaks from X-ray diffractograms and detecting single Tg in DSC studies. The physical stability studies at 40 degrees C for 90 days found RTV:QRT 1:2 and RTV:QRT 2:1 phases stable, while trace crystallinity was detected for 1:1M ratio. The temperature stability of RTV:QRT 1:2 and RTV:QRT 2:1 amorphous forms can be attributed to phase solubility of both components where the drug in excess acts as a crystallization inhibitor. Except for RTV:QRT 1:2 ratio, there was no evidence of intermolecular interactions between two components. Almost 5 fold increase in the saturation solubility was achieved for RTV, compared to crystalline counterpart. While for QRT, the solubility advantage was not achieved. In vivo oral bioavailability study was conducted for 1:2 binary amorphous form by using pure RTV as a control. Cmax was improved by 1.26 fold and Tmax was decreased by 2h after comparing with control indicating improved absorption. However no significant enhancement of oral bioavailability (1.12 fold after comparing with control) was found for RTV. PMID- 25542682 TI - A galloylated dimeric proanthocyanidin from grape seed exhibits dentin biomodification potential. AB - Grape seeds are a rich source of polyphenols, especially proanthocyanidins (PACs), and are also known for the presence of galloylated oligomeric PACs (OPACs). The present study focuses on the phytochemical methodology for grape seed (O)PACs and their potential role as dentin biomodifiers to be used in restorative and reparative dentistry. A new method using centrifugal partition chromatography (CPC) was developed for the preparative separation of the grape seed (O)PACs. Orthogonal phytochemical profiling of the resulting CPC fractions was performed using C18 and diol HPLC, normal phase HPTLC, and IT-TOF MS analysis. A galloylated procyanidin dimer (1) was isolated from a CPC fraction in order to evaluate its potential to enhance dentin bio-mechanical properties. Moreover, it helped to evaluate the impact of the galloyl moiety on the observed bioactivity. Structure elucidation was performed using ESI-MS, 1D and 2D NMR analyses. For the first time, (1)H iterative full spin analysis (HiFSA) was performed on this type of molecule, enabling a detailed proton chemical shift and coupling constant assignment. The CPC fractions as well as 1 showed promising results in the dentin stiffness bioassay and indicate that they may be used as dental intervention biomaterial. PMID- 25542683 TI - Antimicrobial and cytotoxic isopimarane diterpenoid glycosides from Microlepia pilosissima Ching. AB - A phytochemical investigation of the EtOH extract of the dry fronds of Microlepia pilosissima Ching afforded four new isopimarane diterpene glycosides, 3alpha-O alpha-L-rhamnopyranosyl-7beta-O-beta-D-fucopyranosyl-ent-iospimara-8(14),15-diene (1), 3alpha-O-[2-O-acetyl-alpha-L-rhamnopyranosyl]-7beta-O-beta-D-fucopyranosyl ent-iospimara-8(14),15-diene (2), 3alpha-O-[beta-D-glucopyranosyl-(1->2)-alpha-L rhamnopyranosyl]-7beta-O-beta-D-fucopyranosyl-ent-iospimara-8(14),15-diene (3) and 3alpha-O-[beta-D-fucopyranosyl-(1->2)-alpha-L-rhamnopyranosyl]-7beta-O-beta-D fucopyranosyl-ent-iospimara-8(14),15-diene (4) as well as their aglycone, 3alpha,7beta-dihydroxy-ent-iospimara-8(14),15-diene (5). Their structures were characterized by spectroscopic methods, including 1D-NMR, 2D-NMR, and HR-ESI-MS. The isolated compounds were evaluated in vitro for antimicrobial properties against three pathogen fungi and two oral pathogens and cytotoxicities against eight tumor cell lines. As a result, compounds 1-4 appeared to be promising antimicrobial potential and possessed moderate cytotoxic activities against the tested tumor cell lines. PMID- 25542684 TI - Identification of evodiamine as the bioactive compound in evodia (Evodia rutaecarpa Benth.) fruit extract that activates human peroxisome proliferator activated receptor gamma (PPARgamma). AB - The dried unripe fruit from Evodia rutaecarpa Benth., known as Wu zhu yu in China, has long been used in traditional Chinese medicine. In this research, we provide evidence that evodia fruit extract activates peroxisome proliferator activated receptor gamma (PPARgamma) and, as identified through HPLC fractionation and mass spectroscopy, the activating phytochemical is evodiamine. Evodiamine was shown to bind to and activate PPARgamma. It was also shown to activate PPARgamma-regulated gene expression in human hepatoma cells similar to known PPARgamma ligands and that the expression was blocked by a PPARgamma specific antagonist. PMID- 25542685 TI - New alkylresorcinols from a lipophilic extract of Urginea indica L. bulbs showing experimental trauma healing activity. AB - Several alkylresorcinols presenting the substitution pattern of structures I (3 methyl ether of 5-alkyl-2-methylresorcinol) and II (1,3-dimethyl ether of 5 alkylresorcinol), were isolated from the dichloromethane extract of the air-dried bulbs of Urginea indica L. Compounds of structure I with 15, 17 and 20 carbon atoms in the alkyl chain as well as compounds of structure II with 20, 22, 24 carbon atoms in the alkyl chain are new. The structures of the new compounds were elucidated on the basis of their NMR and MS data. The exact number of homologues in each series I and II and the exact length of the side chain were found using GC-MS analysis. The dichloromethane extract of the bulbs was evaluated for its trauma healing properties after local application and a statistically significant tendency to trauma remodeling was observed in comparison to control groups. PMID- 25542686 TI - Triterpenoids from Inonotus obliquus and their antitumor activities. AB - Three new lanostane-type triterpenes, inonotusanes A-C (1-3), and a new naturally occurring one, 3beta-hydroxy-25,26,27-trinorlanosta-8,22E-dien-24-oic acid (4), together with sixteen known triterpenoids (5-20), including 13 lanostane derivatives, 2 lupanes and 1 oleanane-type triterpene were isolated from the sclerotia of Inonotus obliquus. Their structures were elucidated by 1D and 2D NMR spectroscopy and HRMS. Compounds 6, 8, 18 and 20 exhibited strong cytotoxicity against A549 tumor cell lines, with IC50 values of 2.34, 1.63, 8.39 and 5.39MUM, respectively. Seven compounds (3, 9, 10, 12, 18-20) exhibited moderate cytotoxicity against A549, HT29, Hela or L1210 tumor cell lines. PMID- 25542688 TI - Making sense of OA. PMID- 25542687 TI - Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers. AB - BACKGROUND: Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses. METHODS: We used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawberries and/or a less pleasant strawberry taste) using functional magnetic resonance imaging. Volunteers rated pleasantness, intensity, and wanting for each stimulus. RESULTS: There were no significant differences between groups in subjective ratings. However, tetrahydrocannabivarin increased responses to chocolate stimuli in the midbrain, anterior cingulate cortex, caudate, and putamen. Tetrahydrocannabivarin also increased responses to aversive stimuli in the amygdala, insula, mid orbitofrontal cortex, caudate, and putamen. CONCLUSIONS: Our findings are the first to show that treatment with the CB1 neutral antagonist tetrahydrocannabivarin increases neural responding to rewarding and aversive stimuli. This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects. PMID- 25542690 TI - Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care. AB - Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21(st) century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos, Switzerland. In this context Professor Barbara Sahakian recently made a formal presentation at the World Economic Forum (see Barbara Sahakian Blog from April 11, 2014, at https://forumblog.org/people/barbara-sahakian/) Full details of the discussions that formed the bases for these actions are presented in the main body of this document. PMID- 25542689 TI - PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13. AB - BACKGROUND: VGF (nonacryonimic) and phosphatidylinositol 3-kinase (PI3K)/AKT (also known as protein kinase B, PKB)/mammalian target of rapamycin (mTOR) signaling play pivotal roles in depression. However, whether phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF participates in rapid-acting antidepressant-like actions of GLYX-13 is unclear. METHODS: Herein, we evaluated the effects of acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) in the forced swim test. In addition, we assessed whether the acute treatment with GLYX 13 reverses the depressive-like behaviors induced by chronic unpredictable mild stress. Furthermore, we determined whether the Vgf knockdown in hippocampus of mice blocks the effects of GLYX-13. Moreover, we also demonstrated the effects of intra-hippocampus infusion of LY294002 (10 nmol/side), a specific phosphatidylinositol 3-kinase inhibitor prior to the treatment of GLYX-13 in the forced swim test. Lastly, whether alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor and mTOR activation involves in the antidepressant-like effects of GLYX-13 was examined. RESULTS: Our results shown that GLYX-13 dose-dependently reversed the depressive-like behaviors in forced swim test. Additionally, GLYX-13 significantly reversed the downregulation of phosphorylation of AKT, mTOR, and eukaryotic elongation factor 2 as well as VGF induced by chronic unpredictable mild stress in hippocampus. Further, Vgf knockdown in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and upregulation on phosphatidylinositol 3 kinase/AKT/mTOR/VGF signaling of GLYX-13. Moreover, intra-hippocampus infusion of LY294002 significantly abolished the antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Finally, antidepressant-like effects of GLYX-13 required AMPA receptor and mTOR activation, as evidenced by the ability of NBQX and rapamycin to block the effects of GLYX-13, respectively. CONCLUSIONS: Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13. PMID- 25542692 TI - Preliminary results: ethanol sclerotherapy after ultrasound-guided fine needle aspiration without anesthesia in the management of simple ovarian cysts. AB - STUDY OBJECTIVE: To investigate the feasibility of ultrasound-guided, fine-needle aspiration and ethanol sclerotherapy of simple ovarian cysts in an office setting without anesthesia. We also describe the rate of cyst recurrence in patients treated with this technique and explore the associated risk factors. DESIGN: Prospective follow-up of patients after ethanol sclerotherapy of simple adnexal cysts in a single center trial (Canadian Task Force classification II-1). SETTING: The study was conducted at Bellvitge Teaching Hospital in Barcelona, Spain. PATIENTS: Ethanol sclerotherapy was performed on 60 simple adnexal cysts between 2009 and 2012. INTERVENTIONS: Ultrasound-guided fine-needle aspiration and ethanol sclerotherapy. MEASUREMENTS AND MAIN RESULTS: Patient demographics and cyst characteristics were collected for all patients. Potential risk factors for recurrence were analyzed by univariate and multivariate analyses. All the procedures, except 1, were performed without anesthesia. The only major complication was a case of self-limiting hem peritoneum that was managed expectantly. Moderate abdominal pain occurred in 26.7% of patients during the procedure. Fifty-five patients completed at least 6 months of follow-up and were included in the statistical recurrence analyses. Cyst recurrence was recorded in 9.1% of the patients and was managed in the usual manner in all the cases. Univariate analyses indicated that a larger cyst diameter and a higher estimated cyst volume were significantly associated with recurrence. In the multivariate analysis, recurrence was only significantly associated with estimated cyst volume. CONCLUSION: Ethanol sclerotherapy of simple ovarian cysts in an office setting without anesthesia is a feasible technique associated with a low rate of complications and recurrence, although larger randomized studies are necessary to assess the predictive factors for cyst recurrence. PMID- 25542693 TI - [How to improve the visibility of Spanish research in nursing? Reference journals and quality indexes]. AB - Research ends when the results are shared in the academic and professional community, and for this reason they need to be published in scientific journals of reference. But the question is where should the results of nursing research be published? Taking into account the expanding context and scientific consolidation of the discipline. To answer this question, an analysis will be made of the benefits and the most common criticisms of the two most important multidisciplinary literature data bases, as well as examining the context of the Spanish nursing journals in these data bases. A description will also be made of the indexing systems, as well as making proposals to contribute to improved visibility of Spanish nursing research through the positioning of its journals. PMID- 25542694 TI - [Did the patients with chronic obstructive pulmonary disease in Primary Care center Anton de Borja correctly utilize inhalers?]. AB - OBJECTIVE: To determine the percentage of patients with Pulmonary Obstructive Chronic Disease who doing of incorrect form the inhaler technique. METHOD: Descriptive transversal study made in the Primary Care Center "Anton de Borja" of Rubi (in Barcelona) during the period between May and December 2013, where it was studied a representative sample of 200 patients. To assess the inhaler technique was performed a personal interview with the patient in which it was requested him to carry out a demonstration of how he was using his inhaler regularly evaluating his inhaler technique by means of the regulations established by Spanish Society of Pneumology and Thoracic Surgery. RESULTS: 43% of the patients carry out inhaler technique incorrectly. The percentage of inadequate use of inhalers of dry powder was 26%, of the pressurized cartridge 38% and the inhaler chamber 10%. 82% of patients >= 65 years who have prescribed a pressurized inhaler cartridge do not perform accompanied by an inhaler chamber. CONCLUSIONS: A high percentage of patients do not correctly carry out inhaler technique, pointing the rare use made of the inhaler chamber despite its proven efficacy and the high number of patients with pressurized inhaler cartridge. These results reflect the need for the implementation of an educational program in our Primary Care Center to teach patients to use inhaler devices. PMID- 25542695 TI - The bone marrow microenvironment is a critical player in the NK cell response against acute myeloid leukaemia in vitro. AB - Immune therapy for acute myeloid leukaemia (AML) has been largely disappointing. One possible explanation might lie in the microenvironment of the bone marrow, comprising cellular (e.g. mesenchymal stromal cells, MSC) and non-cellular components (e.g. hypoxia). The purpose of this study was to investigate the effects of these components in the immune response against AML in vitro. In vitro exposure of lymphocytes to hypoxia resulted in an increased expression of CD69 as an activation marker in NK cells only, with subsequently enhanced cell lysis of K 562 cell line by NK cells but not in lysis of primary blast. However, co-culture of AML cells with MSC significantly protected leukemic blasts from NK cell mediated lysis, mainly in a specific manner requiring cell-to-cell contact with supportive MSC. These data imply a relevant but unequivocal role of hypoxia and MSC the immune response against AML blasts. PMID- 25542696 TI - Tolerability of induction chemotherapy dosing practices in acute myeloid leukemia patients. AB - For patients with high body surface areas (BSA), differing chemotherapy dosing strategies have been utilized in attempts to reduce toxicity. In a retrospective evaluation, we compared the effects of chemotherapy dosing in acute myeloid leukemia patients with high BSA (>2m(2)) who received capped doses (n=12) to those who received uncapped doses (n=24), and to patients with BSA<=2m(2) (n=42). There were no statistically significant differences among groups (BSA<=2m(2), BSA>2m(2) capped, and BSA>2m(2) uncapped) in the incidences of febrile neutropenia (85.7, 66.7, and 75.0%, respectively, p=0.29), bacteremia (19.0, 8.3, and 16.7%, respectively, p=0.68), mucositis (42.8, 50.0, and 41.7%, respectively, p=0.88) or nausea/vomiting (47.6, 33.3, and 37.5, respectively, p=0.57). Results suggest delivery of unadjusted chemotherapy based on actual body weight is likely safe in hematological malignancies. PMID- 25542697 TI - The ratio of absolute lymphocyte count at interim of therapy to absolute lymphocyte count at diagnosis predicts survival in childhood B-lineage acute lymphoblastic leukemia. AB - Absolute lymphocyte count (ALC) after therapy has been reported to be an independent prognostic factor for clinical outcome in leukemia. This study mainly analyzed ALC at interim of therapy on day 22 (ALC-22) and the ratio of ALC-22 to ALC at diagnosis (ALC-0) on the impact of survival and the relation of ALC to lymphocyte subsets in 119 pediatric B-lineage acute lymphoblastic leukemia (B ALL) patients. Univariate analysis revealed that ALC-22/ALC-0 ratio <10% was significantly associated with inferior overall survival (OS) (hazard ratio (HR)=12.24, P=0.0014) and event-free survival (EFS) (HR=3.3, P=0.0046). In multivariate analysis, ALC-22/ALC-0 ratio remained an independent prognostic factor for OS (HR=6.92, P=0.0181) and EFS (HR=2.78, P=0.0329) after adjusting for age, white blood cell (WBC) count and minimal residual disease (MRD) status. A Spearman correlation test showed that CD3+ T cells had a negative correlation with ALC-0 (r=-0.7204, P<0.0001) and a positive correlation with ALC-22 (r=0.5061, P=0.0071). These data suggest that ALC-22/ALC-0 ratio may serve as a more effective biomarker to predict survival in pediatric B-ALL and ALC is mainly associated with CD3+ T cells. PMID- 25542698 TI - Quantitative analysis of CDKN2A methylation, mRNA, and p16(INK4a) protein expression in children and adolescents with Burkitt lymphoma: biological and clinical implications. AB - CDKN2A is a tumor suppressor gene critical in the cell cycle regulation. Little is known regarding the role of CDKN2A methylation in the pathogenesis of Burkitt lymphoma (BL). CDKN2A methylation was investigated using pyrosequencing in 51 tumor samples. p16(INK4a) mRNA and protein levels were measured using real-time PCR and immunohistochemistry, respectively. CDKN2A methylation was detectable in 72% cases. Nuclear expression of p16(INK4a) was not detected in 41% cases. There was an association between methylation and absence of CDKN2A mRNA (P=0.003). In conclusion, CDKN2A methylation occurs at a high frequency suggesting a role in BL pathogenesis and potential therapeutic implications. PMID- 25542699 TI - Exploring the attitudes and knowledge of support workers towards individuals with intellectual disabilities. AB - BACKGROUND: The aim of this study is to explore support workers' attitudes and knowledge towards individuals with intellectual disabilities (IDs) to see whether a new attitude scale needs to be developed. METHOD: Support workers from a charitable organization located in the West Midlands in the United Kingdom participated in one of four focus groups conducted in late 2013. Thematic analysis was then conducted which identified the emergent themes from the focus groups. RESULTS: Five themes emerged from the analysis, namely, discrimination of people with IDs, attitude change, impacts of integration, their role as a carer and the impact of training. Only one theme, 'the impacts of integration', is clearly represented in current attitude scales; 'their role as a carer' and 'discrimination of people with IDs' are partially represented. CONCLUSION: These results suggest that current attitude scales do not accurately measure the attitudes of support workers; therefore, a modified attitude scale could be developed to incorporate findings from this study. PMID- 25542700 TI - A community support program for children with autism and their typically developing siblings: Initial investigation. AB - Siblings are a critical part of lifelong support for individuals with autism spectrum disorder (ASD). But siblings face their own social-emotional adjustment needs. These needs may be addressed through programs that include support groups specifically for the siblings. This study examined the effects of a community program on typical siblings' depression, anxiety, ASD knowledge, and peer network as well as reciprocal interactions between the typical sibling and sibling with ASD. The program provided a sibling support group, a skills intervention for children with ASD, and an inclusive recreation time. Siblings reported significant decreases in depression and physiological anxiety and improvements in their peer network. Autism knowledge increased but only approached significance. Direct observations revealed improvement in reciprocal interactions by most children that did not reach statistical significance. Parents, typical siblings, and interventionists indicated positive reactions to the program and its goals and outcomes. Findings are discussed in terms of the need to continue to explore interventions for siblings of children with ASD. PMID- 25542701 TI - 'It's my life': autonomy and people with intellectual disabilities. AB - This article discusses autonomy in the lives of adults with intellectual disabilities. The article draws on inclusive research in Iceland with 25 women and 16 men and employs ideas of relational autonomy from the perspectives of the Nordic relational approach to disability. In this article, we examine autonomy in relation to private life, that is, homes and daily activities. The article demonstrates how practices have improved with time and seem less paternalistic. However, the article also demonstrates that the assistance people with intellectual disabilities receive in their homes often has institutional qualities, and they are often met with belittling perspectives from staff and family members. Furthermore, many did not have access to important information needed to develop individual autonomy and independence, including making their own choices. The research findings suggest that people with intellectual disabilities can with appropriate support develop individual autonomy and make their own choices. PMID- 25542702 TI - Perovskite for the highly selective enrichment of phosphopeptides. AB - Selective and effective enrichment of phosphopeptides from complex samples is essential in phosphoproteome study by mass spectrometry (MS). In this work, we compared perovskites (MgTiO3, CaTiO3, SrTiO3, BaTiO3 and CaZrO3) with metal oxides (ZrO2 and TiO2) in their capability for the selective enrichment of phosphopeptides. It was found here that perovskites exhibited higher selectivity towards phosphopeptides than commonly used ZrO2 and TiO2, even though they all have high affinity to phosphopeptides. As for perovskites, CaTiO3 exhibited better selectivity for enrichment of phosphopeptides than SrTiO3, MgTiO3, BaTiO3 and CaZrO3, which might be ascribed to their crystal structures and electrophilic abilities. Moreover, to further confirm the performance of CaTiO3, CaTiO3 and TiO2 were applied to the enrichment of phosphopeptides from tryptic digest of proteins of human Jurkat-T cell lysate, respectively. The results showed CaTiO3 has much higher selectivity than TiO2 in the enrichment of phosphopeptides from the complex biological sample. Taken together, here we show that CaTiO3 is an excellent material for the highly selective enrichment of phosphopeptides and it could be potentially used in the large-scale phosphoproteome study. PMID- 25542703 TI - Fast agitated directly suspended droplet microextraction technique for the rapid analysis of eighteen organophosphorus pesticides in human blood. AB - A new sample preparation technique named as fast agitated directly suspended droplet microextraction (FA-DSDME) was proposed as an improved version of directly suspended droplet microextraction (DSDME) for the extraction and pre concentration of wide-range organophosphorus pesticides (OPPs) from human blood prior to liquid chromatography tandem mass spectrometric (LC-MS/MS) analysis. In this method, instead of protecting the unwanted rupturing of extraction droplet (organic solvent), it was deliberately splintered into fine droplets by providing automated high-speed agitation to the biphasic extraction system (extraction solvent and sample solution). Fine organic droplets were then recollected into one, not by using a centrifuge machine but just by giving a very slow stirring to the bottom of the extraction system. The present method has surmounted the problem of prolonged extraction time associated with old DSDME. Under optimum extraction conditions, the method showed good sensitivity with low detection limits ranging from 0.0009 to 0.122MUgL(-1). Mean recoveries were achieved in the range of 86-109% at three levels of spiking concentration (low, middle and high) from linearity range of individual analyte. Intra-day and inter-day precisions were <=4.68 and <=9.57 (%RSD) respectively. Enrichment factor (EF) for each analyte varied from 30 to 132 which prove the ability of this technique to pre concentrate the extracted analytes up to a good extent. The sample matrices have shown an insignificant influence on method's sensitivity. The proposed method may find immense use in epidemiological, toxicological, regulatory and forensic laboratories. PMID- 25542704 TI - Qualitative and quantitative evaluation of solvent systems for countercurrent separation. AB - Rational solvent system selection for countercurrent chromatography and centrifugal partition chromatography technology (collectively known as countercurrent separation) studies continues to be a scientific challenge as the fundamental questions of comparing polarity range and selectivity within a solvent system family and between putative orthogonal solvent systems remain unanswered. The current emphasis on metabolomic investigations and analysis of complex mixtures necessitates the use of successive orthogonal countercurrent separation (CS) steps as part of complex fractionation protocols. Addressing the broad range of metabolite polarities demands development of new CS solvent systems with appropriate composition, polarity (pi), selectivity (sigma), and suitability. In this study, a mixture of twenty commercially available natural products, called the GUESSmix, was utilized to evaluate both solvent system polarity and selectively characteristics. Comparisons of GUESSmix analyte partition coefficient (K) values give rise to a measure of solvent system polarity range called the GUESSmix polarity index (GUPI). Solvatochromic dye and electrical permittivity measurements were also evaluated in quantitatively assessing solvent system polarity. The relative selectivity of solvent systems were evaluated with the GUESSmix by calculating the pairwise resolution (alphaip), the number of analytes found in the sweet spot (Nsw), and the pairwise resolution of those sweet spot analytes (alphasw). The combination of these parameters allowed for both intra- and inter-family comparison of solvent system selectivity. Finally, 2-dimensional reciprocal shifted symmetry plots (ReSS(2)) were created to visually compare both the polarities and selectivities of solvent system pairs. This study helps to pave the way to the development of new solvent systems that are amenable to successive orthogonal CS protocols employed in metabolomic studies. PMID- 25542705 TI - Continuous enrichment of circulating tumor cells using a microfluidic lateral flow filtration chip. AB - The isolation and characterization of circulating tumor cells (CTC) is of great importance in cancer diagnosis and prognosis. Highly sensitive detection of CTCs can be very difficult because they are extremely rare (i.e., 1-5 CTCs per 10(9) erythrocytes) in blood. Recently, various devices have been developed that exploit biochemical (affinity-based) and physical (size or density) methods. Antibody-based isolation has its own limitations, as the expression level of the epitopes for an antibody varies due to the heterogeneity of cancer cells. Harsh conditions associated with physical methods can cause the deformation and damage of CTCs during the isolation process. Here, we propose a microfluidic lateral flow filtration (MU-LaFF) chip in which lateral flow was combined with vertical flow into the filter to capture the CTCs gently. The CTCs experienced weak shear flow owing to the lateral flow and traveled alongside the filter channel until finally being captured. The vertical flow in the filter held the captured cells tightly and served as an exit for uncaptured hematological cells (white and red blood cells). From our MU-LaFF chip we obtained a high capture efficiency (95%) and purity (99%), minimizing any damage to the CTCs. Our MU-LaFF technology is expected to be useful in the diagnosis and prognosis of various cancers. PMID- 25542706 TI - Determination of atmospheric amines by on-fiber derivatization solid-phase microextraction with 2,3,4,5,6-pentafluorobenzyl chloroformate and 9 fluorenylmethoxycarbonyl chloride. AB - Alkylamines play an important role in atmospheric chemistry and are of concern for human health. Determining them from the vapor phase is challenging owing to their high polarity and volatility, water solubility, low concentrations, and poor chromatographic properties. We propose on-fiber derivatization solid-phase microextraction (SPME) to increase sensitivity and selectivity for the determination of alkylamines in air samples. SPME fibers coated in head-space with 2,3,4,5,6-pentafluorobenzyl chloroformate (PFBCF, 10min) or 9 fluorenylmethoxycarbonyl (FMOC) chloride (5min) were exposed to the sample for 5 120min, after which the derivatized alkylamines were thermally desorbed in the GC injection port and analyzed by GC-MS. The specific focus of the research was dimethylamine (DMA) but, as well as secondary amines, both coating agents readily react with primary and tertiary amines and with ammonia at ambient temperatures. The fiber coating procedures, sampling times, and analytical conditions were optimized, and methods were tested with natural samples. PFBCF was more selective and almost an order of magnitude more sensitive than FMOC chloride. Both reagents are applicable, however, depending on the requirements. With scan mode and use of molecular ion for quantification, the limit of quantification for DMA was 0.17MUgL(-1) when derivatized with PFBCF and 3.4MUgL(-1) when derivatized with FMOC chloride. When selected ion monitoring was used with the most abundant ion, the limit of quantification for DMA was 2.8ngL(-1). Intermediate reproducibility expressed as relative standard deviation was around 30% with PFBCF and less than 20% with FMOC chloride. Fibers coated with PFBCF could be used at least up to 24h when stored at 4 degrees C and for 5 to 7h when stored at room temperature. After sampling/derivatization, storage time before analysis should not exceed 48h at 4 degrees C or 24h at room temperature. At maximum, the PFBCF-coated fiber can be used in 100 coating/sampling/analysis cycles. PMID- 25542707 TI - The relative importance of the adsorption and partitioning mechanisms in hydrophilic interaction liquid chromatography. AB - We propose an original model of effective diffusion along packed beds of mesoporous particles for HILIC developed by combining Torquatos model for heterogeneous beds (external eluent+particles), Landauers model for porous particles (solid skeleton+internal eluent), and the time-averaged model for the internal eluent (bulk phase+diffuse water (W) layer+rigid W layer). The new model allows to determine the analyte concentration in rigid and diffuse W layer from the experimentally determined retention factor and intra-particle diffusivity and thus to distinguish the retentive contributions from adsorption and partitioning. We apply the model to investigate the separation of toluene (TO, as a non retained compound), nortriptyline (NT), cytosine (CYT), and niacin (NA) on an organic ethyl/inorganic silica hybrid adsorbent. Elution conditions are varied through the choice of a third solvent (W, ethanol, tetrahydrofuran (THF), acetonitrile (ACN), or n-hexane) in a mobile phase (MP) of ACN/aqueous acetate buffer (pH 5)/third solvent (90/5/5, v/v/v). Whereas NA and CYT retention factors increase monotonously from W to n-hexane as third solvent, NT retention reaches its maximum with polar aprotic third solvents. The involved equilibrium constants for adsorption and partitioning, however, do not follow the same trends as the overall retention factors. NT retention is dominated by partitioning and NA retention by adsorption, while CYT retention is controlled by adsorption rather than partitioning. Our results reveal that the relative importance of adsorption and partitioning mechanisms depends in a complex way from analyte properties and experimental parameters and cannot be predicted generally. PMID- 25542708 TI - [Intravascular large B-cell lymphoma revealed by a cerebral infarct and a mesenteric ischemia]. PMID- 25542709 TI - [Blood components and good practices in transfusion]. AB - Each year, more than three millions of blood components are transfused to more than five hundred thousand patients in France. The optimal use of blood components requires that physicians prescribing blood components master the clinical indications of red blood cells concentrates, platelet concentrates and fresh frozen plasma. In addition, physicians in charge of blood component prescription should provide adequate pre- and post-transfusion information to their patients. Compliance of blood components administration in patients with safety guidelines contributes as well to their optimal use. In addition, for each blood component transfused, a proper evaluation of its safety and its efficacy should be done. Finally, a regular evaluation of transfusion practice in hospital services were blood components are used, through audits made in cooperation with their blood component provider, either blood transfusion centre or the hospital blood bank, enables to appreciate the level of compliance with safety and clinical guidelines, and more globally how the transfusion process is mastered. PMID- 25542710 TI - [Management of the traumatic aortic blunt injury in 2014]. AB - Diagnosis of blunt thoracic aortic injury (BAI) should be considered in any serious polytrauma. The diagnosis is mainly based on the CT scan at baseline. Life-threatening lesions are often associated with BAI. Hospital mortality is mainly due to associated lesions. Except the complete rupture of the aorta, treatment should be initiated after hemodynamic and respiratory stabilization of the patient and after the treatment of a lesion involving the immediate prognosis. Endovascular treatment of BAI became the treatment of choice, especially for patients with severe associated injuries and bleeding risk. Additional data on the long-term stents are necessary in these young patients. Conventional surgical treatment is always indicated for young subjects with stable hemodynamic, low risk of bleeding and when surgery may be delayed several hours. PMID- 25542711 TI - [Antiphosphatidylethanolamine antibody as a marker of antiphospholipid syndrome?]. AB - Antibody to phosphatidylethanolamine (aPE) are observed in thrombotic or obstetric manifestations suggestive of antiphospholipid syndrome (APS). aPE seem to be markers of thrombotic risk independent of conventional antiphospholipid antibodies (aPL). aPE assays are not standardized. There is no therapeutic recommendation for isolated aPE patients with thrombotic or obstetric events. Prospective studies have to be carried to better define the therapeutic management of these patients. Value of aPE in APS criteria is still not established. PMID- 25542712 TI - Message from the president. PMID- 25542713 TI - The ECG in left bundle branch block and heart failure. PMID- 25542714 TI - In memoriam: Pablo A. Chiale, MD. PMID- 25542715 TI - Bilateral false-positive tube thoracostomy in helicopter emergency medical service. PMID- 25542716 TI - Solving the problem of the transport of twin newborns. PMID- 25542718 TI - A 26-year-old man struck by lightning. PMID- 25542719 TI - Lessons from the military. PMID- 25542720 TI - Watch me pull a rabbit out of my hat. PMID- 25542721 TI - Articles that may change your practice: crystalloid and blood products. PMID- 25542722 TI - What's SAFE Look Like? PMID- 25542724 TI - Increased enforcement action likely on the horizon for ambulance providers. PMID- 25542725 TI - Family-centered care in pediatric critical care transport. AB - OBJECTIVE: Family-centered care (FCC) in medicine highlights mutually beneficial partnerships among providers, patients, and families. In the field of specialty pediatric critical care transport (SPCCT), FCC includes family presence during transport. We sought to describe family presence and family/staff perspectives of FCC in transport. METHODS: This institutional review board-approved study established family presence rates among 5 SPCCT teams. At the top-performing family presence team, parents of transported children were interviewed. A staff survey measured perspectives on FCC using SurveyMonkey (Palo Alto, CA). Statistical tests including chi-square and Fisher exact tests for comparative data were applied using SPSSv17.0 software (SPSS Inc, Chicago, IL). RESULTS: The cohort-wide range of family presence was 23% to 66%. Parents were 4 times more likely to accompany their child if transported by ground versus air (ground: 26 [59%] vs. air: 6 [26%]). Sex, race, travel distance from referral hospital, and child's age did not influence the rate of family accompaniment. Most staff (76%) received education on FCC. CONCLUSIONS: This study informs how transport factors and parent/staff perceptions influence parental presence on transport at a single center. Opportunities to optimize transport FCC include defining protocols for ground and air transport, establishing a more welcoming attitude toward parents, and designing an FCC educational module specific for transport staff. PMID- 25542726 TI - Rural trauma patients cannot wait: tranexamic Acid administration by helicopter emergency medical services. AB - OBJECTIVE: Tranexamic acid (TXA) administration has been shown to reduce mortality in bleeding trauma patients if given in the hospital within 3 hours of injury. Its use has been theorized to be of benefit in the prehospital environment. This study evaluates the timing of TXA administration in a critical care helicopter emergency medical service (HEMS) versus that of the destination trauma hospital. METHODS: We performed a retrospective chart review of consecutive trauma patients who were given TXA during HEMS transfer. The time of injury to HEMS arrival, TXA administration, and hospital arrival was collected. RESULTS: Twenty complete records were identified in which TXA was administered by HEMS: 11 scene calls and 9 interfacility transfers. The median time in minutes from the time of injury to HEMS arrival, TXA administration, and receiving hospital arrival was 90, 114, and 171, respectively, for scene calls and 134, 173, and 224, respectively, for interfacility transfers. CONCLUSION: TXA must be administered before arrival at a trauma hospital to meet the recommendation of administration within 3 hours of injury for all patients transferred between facilities and for many patients transported from a trauma scene. PMID- 25542727 TI - Prehospital use of blood and plasma in pediatric trauma patients. AB - OBJECTIVE: Our rural trauma center uses packed red blood cells (PRBCs) and plasma onboard our helicopter to offset the delay of transport. We summarize our initial experience with prehospital blood use in pediatric trauma patients. METHODS: Our air ambulance service began carrying PRBCs in 1987 and plasma in 2009. We performed a 9-year retrospective review including patients (< 18 years) who received blood during helicopter transports. Only patients transported to our level 1 trauma center were included to ensure complete follow-up. RESULTS: Sixteen patients (6 females) were identified with a mean age of 13 years. The mean transport time was 30 minutes with 75% transferred in from a referring center. Injuries were blunt in 9 patients and penetrating in 2 patients. The mean Injury Severity Score was 30. Fifteen patients received an average of 1.5 units of PRBCs during flight. Indications for PRBCs were severe anemia (6), known blood loss (5), and nonresponder to intravenous fluids (4). Average hemoglobin improved from 9.4 to 11.4 mg/dL at our center. Base deficit improved from -7 to -5.7 at arrival. Five patients received a mean of 1.4 units of plasma. The arrival international normalized ratio was 1.4. The average length of stay was 9.3 days. Four patients died. Trauma Related Injury Severity Score showed 3 patients were unexpected survivors (0.24, 0.24, and 0.38). CONCLUSION: Prehospital use of blood in injured children is rare. However, when indicated, this initial review of our protocol showed increased hemoglobin, decreased acidosis, and unexpected survivors with our program. Because of the rarity of prehospital blood use in children, administration triggers require continued review and refinement. PMID- 25542728 TI - Factors associated with mode of transport decision making for pediatric-neonatal interfacility transport. AB - OBJECTIVE: Transport professionals must routinely engage in complex decision making. One challenging decision is the determination of mode of transport. This study explores the decisional factors involved in the determination of mobilizing ground ambulance versus helicopter for pediatric-neonatal interfacility transport. The aim was to gather initial qualitative data to aid in the development of an objective scoring tool that would be used to guide the mode of transport decision for pediatric and neonatal interfacility transport. The focus of the study was to elicit the factors that influence the mode of transport decision among professionals who are involved in this decision. METHODS: This study was conducted in an urban, freestanding children's hospital with a dedicated pediatric/neonatal transport team. Subjects were given written scenarios that represented a phone call requesting transport from a referring hospital. Subjects were asked to choose between 2 modes of transport: ambulance or helicopter. Weather was assumed to be clear. Decision-making factors were gathered and tallied. For group comparison, the Fisher exact, Pearson chi-square, Student t, or Wilcoxon rank sum tests for scale data was used. A multivariate logistic regression was performed to assess factors associated with the mode of transport decision. RESULTS: Responses were received from a total of 19 subjects. Nurses represented 58% (11) of the respondents, and physicians represented 42% (8). The nurses were all either currently employed on the transport team or had left the team within the past 2 years. The physicians were all critical care or emergency medicine fellows and attending physicians who serve in the medical control role for the transport team. All subjects reported a minimum of five years in their respective professions. The decision to mobilize a helicopter for interfacility transport was significantly associated with the provider's level of clinical concern in conjunction with the perceived distance and if neurovascular or respiratory status was in question in both univariate tests and the multivariate logistic regression. The decision to mobilize a helicopter did not differ significantly between professional roles (nurse vs. physician) or concerns about hemodynamic status such as blood pressure and heart rate. Physicians were significantly more likely to overestimate perceived ground travel time to the outside facility. CONCLUSIONS: Health care providers responsible for directing and conducting the interfacility transport of critically ill children are more likely to mobilize a helicopter for transport in the face of neurovascular or respiratory clinical concerns in conjunction with a prolonged transport distance. When the provider's level of concern is lower, then a ground ambulance is consistently chosen even if out of hospital time is prolonged. PMID- 25542729 TI - Improving accessibility to lung transplantation for children through air transport. AB - INTRODUCTION: There are a limited number of pediatric lung transplant programs in the United States; therefore, geographical barriers limit critically ill children who may be good candidates for lung transplantation. MATERIALS AND METHODS: With advancements in technology, extracorporeal membrane oxygenation (ECMO) is becoming an option to bridge children requiring advanced life support to lung transplantation and offers the opportunity to transport critically ill children to pediatric lung transplant centers. RESULTS: Air transport services with rotor wing and fixed-wing aircraft were successfully developed and quickly became as a vital component of our pediatric lung transplant program offering ECMO for both transport and as a bridge to lung transplantation to children throughout the United States. CONCLUSION: Air transport services can be an important component of pediatric lung transplant programs to offer this advanced treatment to children. PMID- 25542730 TI - Racial and ethnic diversity of the U.S. national nurse workforce 1988-2013. AB - The objective of this article is to examine the racial and ethnic diversity profile of the nurse workforce over time and by geographic region. We conducted survey analysis using the National Sample Survey of Registered Nurses from 1988 to 2008, and further supplemented our trend analysis using published findings from the 2013 National Workforce Survey of Registered Nurses. The gap in racial/ethnic minority representation between the RN workforce and the population has been persistent and has widened over time. This diversity gap is primarily due to underrepresentation of Hispanics and Blacks in the RN workforce, which varied across states and regions, with the largest gaps occurring for Hispanics in the South and West and for Blacks in the South. Greater levels of sustained and targeted support to increase nurse workforce diversity are needed and should be geared not only to specific underrepresented groups but also to the regions and states with the greatest needs. PMID- 25542731 TI - Gaining independent prescriptive practice: one state's experience in adoption of the APRN Consensus Model. AB - Nurses are increasingly encouraged to be active participants in health policy. This article provides an exemplar of how nurse practitioners (NPs) in one state, North Dakota, used strategic policy actions to obtain independent prescriptive privileges. Consistent and clear communication among NPs and with key stakeholders, including legislators, contributed to a positive policy outcome. North Dakota nurse leaders in this initiative have shared their experiences with a variety of audiences including other state boards of nursing and NP organizations in states such as New York, South Dakota, and Louisiana. In addition, a webinar sponsored by the Center to Champion Nursing in America at AARP featured several of the North Dakota NP leaders, who shared their reflections of this experience and the strategies they used. Regulatory environments and public policies will continue to significantly influence the future of all nurses. This case study of one state can be useful to NPs and other nurses seeking meaningful policy change through laws or regulations with regard to scope of practice or other health policy issues. PMID- 25542732 TI - Intrinsically radiopaque polyurethanes with chain extender 4,4'-isopropylidenebis [2-(2,6-diiodophenoxy)ethanol] for biomedical applications. AB - Radiopaque polyurethanes are used for medical applications as it allows post operative assessment of the biomaterial devices using X-ray. Inherently, radiopaque polyurethanes based on polytetramethylene glycol (PTMG), polypropylene glycol, 4,4'-methylenebis(phenyl isocyanate), and a new iodinated chain extender 4,4'-isopropylidenebis[2-(2,6-diiodophenoxy)ethanol] with flexible spacers were synthesized and characterized. The iodinated polyurethanes were clear, optically transparent, and had high molecular weights. The polyurethanes also possessed excellent radiopacity and high thermal stability. The biocompatibility of the most promising iodinated polyurethane was evaluated both in vitro (cytotoxicity evaluation by direct contact and MTT assay, using L929 mouse fibroblast cells) and in vivo (toxicology studies in rabbits and subcutaneous implantation in rats). The material was nontoxic and well tolerated by the animals. Thus, these radiopaque and transparent polyurethanes are expected to have potential for various biomedical applications. PMID- 25542733 TI - New horizon in dialysis depuration: Characterization of a polysulfone membrane able to break the 'albumin wall'. AB - The uremic syndrome is attributed to the progressive retention of a large number of toxins, which under normal conditions are excreted by the healthy kidneys. Standard dialytic membranes do not purify middle-high molecular weight toxins. Haemodiafiltration with endogenous reinfusion coupled with a highly permeable membrane could break the limit of the 'albumin wall' improving the dialytic depuration without loss of important nutrients. The aim of this study was to evaluate the performance of a new polysulfone membrane, Synclear 0.2, to remove uremic molecules. Surface Enhanced Laser Desorption Ionization-Time of Flight was employed to evaluate the proteomic profile of ultrafiltrate and Electrospray Ionization-Quadruple-ToF coupled with on-chip elution was used for proteins identification. A high and specific permeability for middle-high molecular weight molecules was revealed by mass spectrometry for the investigated membrane. The identified proteins are mostly uremic toxins: their relative abundance, estimated in the ultrafiltrate by exponentially modified protein abundance index, showed a high purification efficiency of the new membrane when compared with conventional ones. In conclusion, Synclear 0.2, used as convective membrane in hemodiafiltration with endogenous reinfusion treatment, permits to break the 'albumin wall', clearing middle-high molecular weight uremic toxins, improving the dialytic treatment purification efficiency. PMID- 25542734 TI - Environmental disruption of the circadian clock leads to altered sleep and immune responses in mouse. AB - In mammals, one of the most salient outputs of the circadian (daily) clock is the timing of the sleep-wake cycle. Modern industrialized society has led to a fundamental breakdown in the relationship between our endogenous timekeeping systems and the solar day, disrupting normal circadian rhythms. We have argued that disrupted circadian rhythms could lead to changes in allostatic load, and the capacity of organisms to respond to other environmental challenges. In this set of studies, we apply a model of circadian disruption characterized in our lab in which mice are housed in a 20h long day, with 10h of light and 10h of darkness. We explored the effects of this environmental disruption on sleep patterns, to establish if this model results in marked sleep deprivation. Given the interaction between circadian, sleep, and immune systems, we further probed if our model of circadian disruption also alters the innate immune response to peripheral bacterial endotoxin challenge. Our results demonstrate that this model of circadian disruption does not lead to marked sleep deprivation, but instead affects the timing and quality of sleep. We also show that while circadian disruption does not lead to basal changes in the immune markers we explored, the immune response is affected, both in the brain and the periphery. Together, our findings further strengthen the important role of the circadian timing system in sleep regulation and immune responses, and provide evidence that disrupting the circadian clock increases vulnerability to further environmental stressors, including immunological challenges. PMID- 25542735 TI - TNFalpha G308A polymorphism is associated with resilience to sleep deprivation induced psychomotor vigilance performance impairment in healthy young adults. AB - Cytokines such as TNFalpha play an integral role in sleep/wake regulation and have recently been hypothesized to be involved in cognitive impairment due to sleep deprivation. We examined the effect of a guanine to adenine substitution at position 308 in the TNFalpha gene (TNFalpha G308A) on psychomotor vigilance performance impairment during total sleep deprivation. A total of 88 healthy women and men (ages 22-40) participated in one of five laboratory total sleep deprivation experiments. Performance on a psychomotor vigilance test (PVT) was measured every 2-3h. The TNFalpha 308A allele, which is less common than the 308G allele, was associated with greater resilience to psychomotor vigilance performance impairment during total sleep deprivation (regardless of time of day), and also provided a small performance benefit at baseline. The effect of genotype on resilience persisted when controlling for between-subjects differences in age, gender, race/ethnicity, and baseline sleep duration. The TNFalpha G308A polymorphism predicted less than 10% of the overall between subjects variance in performance impairment during sleep deprivation. Nonetheless, the differential effect of the polymorphism at the peak of performance impairment was more than 50% of median performance impairment at that time, which is sizeable compared to the effects of other genotypes reported in the literature. Our findings provided evidence for a role of TNFalpha in the effects of sleep deprivation on psychomotor vigilance performance. Furthermore, the TNFalpha G308A polymorphism may have predictive potential in a biomarker panel for the assessment of resilience to psychomotor vigilance performance impairment due to sleep deprivation. PMID- 25542736 TI - Alcohol-induced sedation and synergistic interactions between alcohol and morphine: a key mechanistic role for Toll-like receptors and MyD88-dependent signaling. AB - Increasing evidence demonstrates induction of proinflammatory Toll-like receptor (TLR) 2 and TLR4 signaling by morphine and, TLR4 signaling by alcohol; thus indicating a common site of drug action and a potential novel innate immune dependent hypothesis for opioid and alcohol drug interactions. Hence, the current study aimed to assess the role of TLR2, TLR4, MyD88 (as a critical TLR-signaling participant), NF-kappaB, Interleukin-1beta (IL-1beta; as a downstream proinflammatory effector molecule) and the MU opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5g/kg) and alcohol (2.5g/kg) interaction with morphine (5mg/kg) by assessing the loss of righting reflex (LORR) as a measure of sedation. Wild-type male Balb/c mice and matched genetically-deficient TLR2, TLR4, and MyD88 strains were utilized, together with pharmacological manipulation of MOR, NF-kappaB, TLR4 and Interleukin-1beta. Alcohol induced significant LORR in wild-type mice; this was halved by MyD88 and TLR4 deficiency, and surprisingly nearly completely eliminated by TLR2 deficiency. In contrast, the interaction between morphine and alcohol was found to be MOR-, NF-kappaB-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1beta. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-kappaB-p65 positive cells in the motor cortex in concordance with wild-type and TLR2 deficient mouse behavioral data, implicating neuroimmunopharmacological signaling as a pivotal mechanism in this clinically problematic drug-drug interaction. PMID- 25542738 TI - Comparative study of two thioredoxins from common cutworm (Spodoptera litura): cloning, expression, and functional characterization. AB - Thioredoxins (Trxs) are a ubiquitous family of antioxidant enzymes that are involved in protecting organisms against various oxidative stresses. Here, we cloned and characterized two thioredoxins, named SlTrx1 and SlTrx2, from the common cutworm Spodoptera litura. SlTrx1 and SlTrx2, respectively, consist of 988 and 606 bp full-length cDNA with 318 and 447 bp open reading frames encoding 106 and 149 amino acid residues. Furthermore, the N-terminal region of SlTrx2 contains a predicted mitochondrial localization signal (33 amino acids). A phylogenetic relationship analysis revealed that SlTrx1 is in the cytosolic thioredoxin Trx1 cluster, whereas SlTrx2 is in the mitochondrial thioredoxin Trx2 cluster. Recombinant SlTrx1 (14 kDa) and SlTrx2 (16 kDa), expressed in baculovirus-infected insect Sf9 cells, demonstrated insulin disulfide reductase activity at the same optimum temperature and pH value of 35 degrees C and 7.0, respectively, in vitro. During S. litura development, we found that SlTrx1 and SlTrx2 had similar transcript expression patterns and were constitutively expressed in the epidermis, fat body, and midgut, with the highest expression occurring in the sixth-instar larval stage in the epidermis and midgut. In addition, both SlTrx1 and SlTrx2 mRNA were up-regulated in S. litura after injection with H2O2, cumene hydroperoxide, indoxacarb, and metaflumizone. These results suggest that SlTrx1 and SlTrx2 function as potent antioxidant enzymes, and provide a molecular basis for the roles SlTrx1 and SlTrx2 during development and the oxidative stress response of S. litura. PMID- 25542737 TI - Total and differential white blood cell counts, high-sensitivity C-reactive protein, and cardiovascular risk in non-affective psychoses. AB - Schizophrenia is associated with increased cardiovascular disease morbidity and mortality. Schizophrenia is also associated with immune and inflammatory abnormalities, including aberrant blood levels of lymphocytes, cytokines and high sensitivity C-reactive protein (hsCRP). The purpose of this study is to investigate the relationship between total and differential white blood cell (WBC) counts, hsCRP, and indices of cardiovascular disease risk in patients with schizophrenia and related non-affective psychoses. 108 inpatients and outpatients age 18-70 with non-affective psychoses and 44 controls participated in this cross sectional study. Subjects had a fasting blood draw between 8 and 9am for glucose, lipids, total and differential WBC counts, and hsCRP. Vital signs and medical history were obtained. Patients with non-affective psychosis had significantly higher hsCRP levels than controls (p=0.04). In linear regression analyses, lymphocyte and monocyte counts were a significant predictor of the total-to-HDL cholesterol ratio in subjects with non-affective psychosis (p?0.02 for each). In binary logistic regression analyses, total WBC count was a significant predictor of an elevated 10-year estimated risk of myocardial infarction and cardiovascular disease in subjects with non-affective psychosis (p?0.03 for each). Associations between total and differential WBC counts and cardiovascular disease risk indices were stronger in males than females with non-affective psychosis. Our findings provide further evidence that measurement of total and differential WBC counts may be germane to the clinical care of patients with schizophrenia and related disorders, and support an association between inflammation and cardiovascular disease risk in these patients. PMID- 25542739 TI - Economic burden and cost determinants of coronary heart disease in rural southwest China: a multilevel analysis. AB - OBJECTIVES: To estimate the economic burden of coronary heart disease (CHD) in a given year (2010), including direct and indirect costs, and examine the impact of contextual and individual socio-economic (SES) predictors on the costs of CHD among adults in rural southwest China. STUDY DESIGN: Cross-sectional community survey. METHODS: In total, 4595 adults (aged >=18 years) participated in this study. A prevalence-based cost-of-illness approach was used to estimate the economic burden of CHD. Information on demographic characteristics of the study population and the economic consequences of CHD was obtained using a standard questionnaire. Multilevel linear regression was used to model the variation in costs of CHD. RESULTS: In the study population, the overall prevalence of CHD was 2.9% (3.5% for males, 2.3% for females). The total cost of CHD was estimated to be US$17 million. Inpatient hospitalizations represented the main component of direct costs of CHD, and direct costs accounted for the greatest proportion of the economic burden of CHD. Males were more likely to have a higher economic burden of CHD than females. A positive association was found between the individual's level of education and the economic burden of CHD. Residence in a higher-income community was associated with higher costs related to CHD. CONCLUSIONS: This study found that both contextual and individual SES were closely associated with the costs of CHD. Future strategies for CHD interventions and improved access to affordable medications to treat and control CHD should focus on less-educated individuals and communities with lower SES. PMID- 25542740 TI - Standardised (plain) cigarette packaging increases attention to both text-based and graphical health warnings: experimental evidence. AB - OBJECTIVE: To investigate whether standardised cigarette packaging increases the time spent looking at health warnings, regardless of the format of those warnings. STUDY DESIGN: A factorial (two pack styles x three warning types) within-subject experiment, with participants randomised to different orders of conditions, completed at a university in London, UK. METHODS: Mock-ups of cigarette packets were presented to participants with their branded portion in either standardised (plain) or manufacturer-designed (branded) format. Health warnings were present on all packets, representing all three types currently in use in the UK: black & white text, colour text, or colour images with accompanying text. Gaze position was recorded using a specialised eye tracker, providing the main outcome measure, which was the mean proportion of a five second viewing period spent gazing at the warning-label region of the packet. RESULTS: An opportunity sample of 30 (six male, mean age = 23) young adults met the following inclusion criteria: 1) not currently a smoker; 2) <100 lifetime cigarettes smoked; 3) gaze position successfully tracked for > 50% viewing time. These participants spent a greater proportion of the available time gazing at the warning-label region when the branded section of the pack was standardised (following current Australian guidelines) rather than containing the manufacturer's preferred design (mean difference in proportions = 0.078, 95% confidence interval 0.049 to 0.106, p < 0.001). There was no evidence that this effect varied based on the type of warning label (black & white text vs. colour text vs. colour image & text; interaction p = 0.295). CONCLUSIONS: During incidental viewing of cigarette packets, young adult never-smokers are likely to spend more time looking at health warnings if manufacturers are compelled to use standardised packaging, regardless of the warning design. PMID- 25542741 TI - Health care expenses in relation to obesity and smoking among U.S. adults by gender, race/ethnicity, and age group: 1998-2011. AB - OBJECTIVES: Obesity and smoking are two leading health risk factors and consume substantial health care resources. This study estimates and tracks annual per capita health care expenses associated with obesity and smoking among U.S. adults aged 18 years and older from 1998 to 2011. STUDY DESIGN: Retrospective data analysis. METHODS: Individual-level data came from the National Health Interview Survey 1996-2010 waves and the Medical Expenditure Panel Survey 1998-2011 waves. Annual per-capita health care expenses associated with obesity and smoking were estimated in two-part models, accounting for individual characteristics and sampling design. RESULTS: Obesity and smoking were associated with an increase in annual per-capita total health care expenses (2011 US$) by $1360 (95% confidence interval: $1134-$1587) and $1046 ($846-$1247), out-of-pocket expenses by $143 ($110-$176) and $70 ($37-$104), hospital inpatient expenses by $406 ($283-$529) and $405 ($291-$519), hospital outpatient expenses by $164 ($119-$210) and $95 ($52-$138), office-based medical provider service expenses by $219 ($157-$280) and $117 ($62-$172), emergency room service expenses by $45 ($28-$63) and $57 ($44-$71), and prescription expenses by $439 ($382-$496) and $251 ($199-$302), respectively. From 1998 to 2011, the estimated per-capita expenses associated with obesity and smoking increased by 25% and 30% for total health care, 41% and 48% for office-based medical provider services, 59% and 66% for emergency room services, and 62% and 70% for prescriptions but decreased by 16% and 15% for out of-pocket health care expenses, 3% and 0.3% for inpatient care, and 6% and 2% for outpatient care, respectively. Health care expenses associated with obesity and smoking were considerably larger among women, Non-Hispanic whites, and older adults compared with their male, racial/ethnic minority, and younger counterparts. CONCLUSIONS: Health care costs associated with obesity and smoking are substantial and increased noticeably during 1998-2011. They also vary significantly across gender, race/ethnicity and age. PMID- 25542742 TI - Response to short communication 'Management of prediabetes through lifestyle modification in overweight and obese African-American women: the fitness, relaxation and eating to stay health (FRESH) randomized controlled trial'. PMID- 25542743 TI - Gang involvement among street-involved youth in a Canadian setting: a gender based analysis. PMID- 25542744 TI - Response to letter: 'Why it is important to consider contextual factors in public health'. PMID- 25542745 TI - A consensus on men's health status and policy in Asia: a Delphi survey. AB - OBJECTIVE: There is currently no documentation on the availability and implementation of policies related to men's health in Asia. This Delphi study aimed to achieve an Asian consensus on men's health policy based on the opinions and recommendations from men's health key opinion leaders. STUDY DESIGN: A two phase Delphi online survey was used to gather information from men's health stakeholders across Asian countries. METHODS: All stakeholders were invited to participate in the survey through men's health conferences, personal contacts, recommendations from international men's health organizations and snowballing method. Stakeholders were asked about their concerns on 17 men's health key issues as well as their opinion on the availability and recommendations on men's health policies and programmes in their countries. RESULTS: There were a total of 128 stakeholders (policy makers, clinicians, researchers and consumers), from 28 Asian countries, who responded in the survey. Up to 85% of stakeholders were concerned about various men's health issues in Asia and in their respective country, particularly in smoking, ischaemic heart disease and high blood pressure. There is a lack of men's health policies and programmes in Asia (availability = 11.6-43.5%) and up to 92.9% of stakeholders recommended that these should be developed. CONCLUSIONS: These findings call for policy change and development, and more importantly a concerted effort to elevate men's health status in Asia. PMID- 25542746 TI - Why it is important to consider contextual factors in public health. PMID- 25542747 TI - Exploring the process when developing a lifestyle intervention in primary care for type 2 diabetes: a longitudinal process evaluation. AB - OBJECTIVES: A thorough understanding of the processes involved in lifestyle interventions is needed in order to close the gap between research and daily practice. This study explored the processes involved in the provision of a lifestyle intervention to patients with type 2 diabetes mellitus (T2DM) by health care professionals in primary care. STUDY DESIGN: Mixed methods. METHODS: Health care professionals were asked to intensify lifestyle interventions for patients with T2DM in a routine care setting. Data were collected by serial interviews with health care professionals and patients, recorded consultations, an activity questionnaire and biomedical information. Qualitative data were analysed using a framework analysis with a phenomenological approach. RESULTS: The lifestyle intervention developed by the health care professionals included motivational interviewing, a nutrition and physical activity diary, and a multidisciplinary approach [physiotherapist, dietician, general practitioner and diabetes practice nurse (DPN)]. Participants and health care professionals were positive about the intervention, and patients were more active (P = 0.027), lost weight (P = 0.031) and had lower levels of glycated haemoglobin (P = 0.012). However, qualitative data showed that patients were passive during the consultation, and did not ask questions about ways to improve their lifestyle. DPNs did not use motivational interviewing optimally; provided patients with information that was difficult to understand; and were easily satisfied with the efforts of the patients. CONCLUSIONS: Lifestyle intervention for patients with T2DM is difficult in routine primary care. DPNs should adapt to the knowledge level of the patients, and patients must be stimulated to take an active role in their treatment. Patients and health care professionals should become equal partners in determining mutually agreeable treatment plans and goals. PMID- 25542749 TI - Neurofibrosarcoma of the lumbar spine with a misleading onset. PMID- 25542750 TI - Diffuse idiopathic skeletal hyperosteosis leading to snoring and dysphagia. PMID- 25542751 TI - Isolated spinal sarcoidosis. PMID- 25542752 TI - Seminal megavesicle in autosomal dominant polycystic kidney disease. AB - Retrospective analysis of 99 male autosomal dominant polycystic kidney disease (ADPKD) patients compared to an age-matched control population showed seminal vesicle ectasia >10 mm (megavesicle) in 23% (23/99) of ADPKD patients that was not present in any controls (P<.0001). Median (range) seminal vesicle convoluted tubule diameter in ADPKD patients was 4.2 (1.7-30) mm compared to 3.1 (1.7-6.8) mm in controls (P<.0001). Discrete cysts were identified in four ADPKD patients but in none of the control population (P=.12). Seminal megavesicles may explain the infertility sometimes observed in male ADPKD patients. PMID- 25542753 TI - Use of multidetector computed tomography 3D reconstructions in assessing lower tracheal-bronchial pathology and subsequent surgical interventions. AB - PURPOSE: To evaluate the contribution of 3D reconstruction in assessing lower tracheobronchial pathology and surgical interventions. METHODS: Twenty patients fit our criteria of lower tract tracheobronchial pathologies for a total of 25 abnormalities. Studies were reviewed by two board certified pediatric radiologists. Diagnostic value of 3D reconstruction in assessing surgical findings was evaluated. RESULTS: Three-dimensional (3D) reconstruction was perceived to add specific information in seven cases: three cases clarifying how attempting surgical intervention would be helpful, and in four cases, 3D reconstruction gave added information that aided surgical planning. CONCLUSIONS: Three-dimensional reconstructions can be a helpful tool in planning surgical interventions. PMID- 25542748 TI - INS-gene mutations: from genetics and beta cell biology to clinical disease. AB - A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved. PMID- 25542754 TI - MR-based trabecular bone microstructure is not altered in subjects with indolent systemic mastocytosis. AB - Subjects with indolent systemic mastocytosis (ISM) have an increased risk for osteoporosis. It has been demonstrated that trabecular bone microstructure analysis improves the prediction of bone strength beyond dual-energy X-ray absorptiometry-based bone mineral density. The purpose of this study was to obtain Magnetic Resonance (MR)-based trabecular bone microstructure parameters as advanced imaging biomarkers in subjects with ISM (n=18) and compare them with those of normal controls (n=18). Trabecular bone microstructure parameters were not significantly (P>.05) different between subjects with ISM and controls. These findings revealed important pathophysiological information about ISM-associated osteoporosis and may limit the use of trabecular bone microstructure analysis in this clinical setting. PMID- 25542755 TI - Left ovarian vein dilation or pelvic congestion syndrome secondary to abdominal aortic dissection: incidental findings on CT angiography. AB - BACKGROUND: In the study, we describe eight cases in which pelvic congestion syndrome (PCS) was a direct complication of abdominal aortic dissection (AD). METHODS: We recorded computed tomographic (CT) details of the AD and PCS. The patterns of pelvic varices and reflux were identified as well. RESULTS: All eight had abdominal AD (diameter, 23.44-33.98 mm). The compressed left renal vein revealed stenosis in situ (diameter, 1.17-2.69 mm). CT also revealed dilation of left ovarian vein with left pelvic varices in all cases. CONCLUSIONS: Some cases of PCS and dilation of the left ovarian vein can be directly correlated with abdominal AD. PMID- 25542756 TI - Ameliorative effect of nicorandil on high fat diet induced non-alcoholic fatty liver disease in rats. AB - Nonalcoholic fatty liver disease (NAFLD) is an accumulation of excessive amounts of fats in the liver that is not caused by alcohol consumption. It is considered as the most common liver disease in Western societies. The aim of this study is to investigate the possible protective effects of nicorandil and pioglitazone, the benefits of their combination and the possible mechanism underlie these effects in NAFLD. Rats were fed a high-fat diet (HFD) for eight weeks to induce NAFLD. In the next eight weeks, rats were fed the HFD along with pioglitazone (4 mg/kg) or nicorandil in two dose levels (3 or 15 mg/kg), alone or in combination. Chronic HFD administration resulted in significant elevations in serum levels of liver enzymes, total cholesterol, triglycerides, glucose, insulin and HOMA-IR index as compared with the control group. This was coupled with significant increments in liver triglycerides, MDA content and TNF-alpha as well as a significant reduction in liver GSH content. In comparison with the control group; liver expression of NF-kappaB was significantly elevated while liver eNOS expression and nitric oxide content were significantly decreased in HFD group. Treatment with pioglitazone or nicorandil either alone or in combination successfully ameliorated the deleterious effects of HFD on the all previous parameters. In conclusion, this investigation indicates a novel role of nicorandil in rats with NAFLD. This effect is mediated through, nitric oxide donor, antioxidant and anti-inflammatory properties, leading to improvement of insulin resistance. It is worth mentioning that the combinations were more effective than the individual drugs. PMID- 25542757 TI - Differential regulation of epidermal growth factor receptor by hydrogen peroxide and flagellin in cultured lung alveolar epithelial cells. AB - In previous studies, we found that stimulation of Toll-like receptor 5 (TLR5) by flagellin induced the activation of mitogen-activated protein kinase (MAPK) activated protein kinase-2 (MAPKAPK-2) through activation of the p38 MAPK pathway in cultured alveolar epithelial A549 cells. Our studies strongly suggested that MAPKAPK-2 phosphorylated epidermal growth factor receptor (EGFR) at Ser1047. It has been reported that phosphorylation of Ser1047 after treatment with tumor necrosis factor alpha (TNFalpha) induced the internalization of EGFR. In the present study, we first found that treatment of A549 cells with hydrogen peroxide induced the activation of MAPKAPK-2 and phosphorylation of EGFR at Ser1047 within 30 min. This was different from flagellin treatment because hydrogen peroxide treatment induced the phosphorylation of EGFR at Tyr1173 as well as Ser1047, indicating the activation of EGFR. We also found that KN93, an inhibitor of CaM kinase II, inhibited the hydrogen peroxide-induced phosphorylation of EGFR at Ser1047 through inhibition of the activation of the p38 MAPK pathway. Furthermore, we examined the internalization of EGFR by three different methods. Flow cytometry with an antibody against the extracellular domain of EGFR and biotinylation of cell surface proteins revealed that flagellin, but not hydrogen peroxide, decreased the amount of cell-surface EGFR. In addition, activation of extracellular signal-regulated kinase by EGF treatment was reduced by flagellin pre-treatment. These results strongly suggested that hydrogen peroxide activated the p38 MAPK pathway via activation of CaM kinase II and that flagellin and hydrogen peroxide regulate the functions of EGFR by different mechanisms. PMID- 25542758 TI - Clathrin-dependent internalization of the angiotensin II AT1A receptor links receptor internalization to COX-2 protein expression in rat aortic vascular smooth muscle cells. AB - The major effects of Angiotensin II (AngII) in vascular tissue are mediated by AngII AT1A receptor activation. Certain effects initiated by AT1A receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC), AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by beta-arrestin-dependent receptor internalization and NF-kappaB activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization of activated AT1A receptor mediates NF kappaB activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2's effects on AT1 receptor/GFP internalization in HEK-293 cells and p65 NF-kappaB nuclear localization in RASMC. Pitstop-2 significantly inhibited internalization of AT1A receptor (44.7% +/- 3.1% Control vs. 13.2% +/- 8.3% Pitstop-2; n=3) as determined by radioligand binding studies in RASMC. Studies utilizing AT1A receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NF-kappaB phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNFalpha signaling. Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through beta arrestin mediated internalization of G protein-coupled receptors, such as AT1A receptors. PMID- 25542759 TI - Growth models of dyadic synchrony and mother-child vagal tone in the context of parenting at-risk. AB - We used multilevel modeling to examine dynamic changes in respiratory sinus arrhythmia (RSA) and observer-coded interactive synchrony for mother-child dyads engaged in a laboratory interaction, to characterize parenting-at-risk. Seventy nine preschooler-mother dyads including a subset with documented child maltreatment (CM; n=43) were observed completing a joint puzzle task while physiological measures were recorded. Dyads led by CM mothers showed decreases in positive synchrony over time, whereas no variation was observed in non-CM dyads. Growth models of maternal RSA indicated that mothers who maintained high levels of positive interactive synchrony with their child evidenced greater RSA reactivity, characterized by an initial withdrawal followed by augmentation as the task progressed, after accounting for CM group status. These results help to clarify patterns of RSA responding in the context of caregiver-child interactions, and demonstrate the importance of modeling dynamic changes in physiology over time in order to better understanding biological correlates of parenting-at-risk. PMID- 25542760 TI - Does exposure to flame retardants increase the risk for preterm birth? AB - During the past 40 years, polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants and nearly all women have some level of exposure. PBDEs have been isolated from amniotic fluid and cord plasma indicating vertical transmission; however, their effects on pregnancy outcome are largely unknown. Therefore, we quantified PBDE-47, the most common congener in maternal plasma samples collected at the time of labor from women who subsequently had term or preterm birth (PTB). Women were then scored based on whether or not they had very low, low, medium, high or very high peripheral plasma concentrations of PBDE-47. Probit regression analysis suggested that women in the PTB group had a greater chance of scoring higher on this scale (P<0.001). Women with high (OR=3.8, CI: 1.6, 9.7; P=0.003) or very high PBDE-47 concentrations were at greater odds (OR=5.6, CI: 2.2, 15.2; P<0.001) for PTB than women with very low levels of PBDE 47. Results became even more significant after adjustment for maternal race, age, and marital status. These findings suggest that high levels of maternal exposure to PBDEs might increase the risk for PTB. PMID- 25542761 TI - Academic year-end changeover and stroke outcomes. AB - BACKGROUND: Lower quality of care and poorer outcomes are suspected when new trainees (eg, residents) start in July in teaching hospitals, the so-called "the July effect." We evaluated outcomes and processes of care among patients with an acute ischemic stroke (AIS) admitted in July versus other 11 months of the year. METHODS: We evaluated AIS patients admitted to 11 tertiary stroke centers in Ontario, Canada between July 1, 2003, and March 31, 2008, identified from the Registry of the Canadian Stroke Network. The main outcomes were death at 30 days and poor functional outcome defined as death at 30 days or a modified Rankin Scale 3-5 at discharge. RESULTS: Of 10,319 eligible AIS patients, 882 (8.5%) were admitted in July and 9437 during the remaining months. There was no difference in baseline characteristics or stroke severity between the 2 groups. Patients admitted in July were less likely to receive thrombolysis (12% vs. 16%; odds ratio (OR), .72; 95% confidence interval (CI), .59-.89), dysphagia screening (64% vs. 68%; OR, .86; 95% CI, .74-.99), and stroke unit care (62% vs. 68%; OR, .78; 95% CI, .68-.90). July admission was not associated with either of higher death at 30 days (adjusted OR, .88; 95% CI, .74-1.03) or poor functional outcome (adjusted OR, .92; 95% CI, .74-1.14). Results remained consistent in the sensitivity analysis by including both July and August as part of the "July effect." CONCLUSIONS: AIS patients admitted to tertiary stroke centers during July had similar outcomes despite slightly less frequent thrombolysis and stroke unit care. PMID- 25542762 TI - Poststroke fatigue: hints to a biological mechanism. AB - BACKGROUND: Poststroke fatigue (PSF) is common, but the biological basis of this fatigue is unknown. We explored the possibility that PSF is related to systemic inflammation by investigating polymorphisms in 2 genes that affect the immune response. METHODS: In a substudy of a larger trial that evaluated the role of the immune response on stroke outcome, fatigue was assessed at 30, 90, 180, and 365 days after ischemic stroke using the Fatigue Assessment Scale. Subjects were genotyped for 3 single nucleotide polymorphisms, one in the interleukin-1 receptor antagonist gene (IL1RN; rs4251961, a T/C substitution) and two in the in toll-like receptor-4 (TLR4) gene (1063 A/G [Asp299Gly] rs4986790 and 1363 C/T [Thr399Ile] rs4986791). RESULTS: Of the 39 participants, 22 (56%) endorsed fatigue during the study. The degree of fatigue was remarkably constant over time and independent of stroke outcome. The C allele of the rs4251961 single nucleotide polymorphism (SNP) in IL1RN was associated with self-reported fatigue (P = .03), whereas the cosegregating polymorphisms in TLR4 were associated with lower levels of fatigue (P= .04). CONCLUSIONS: SNPs in 2 genes with opposing effects on inflammatory immune responses were significantly, but differentially, associated with PSF. These findings suggest a direct link between immune signaling dysregulation and PSF. PMID- 25542763 TI - Teleneurosonology: a novel application of transcranial and carotid ultrasound. AB - BACKGROUND: To demonstrate the technical feasibility of interfacing transcranial Doppler (TCD) and carotid "duplex" ultrasonography (CUS) peripherals with telemedicine end points to provide real-time spectral waveform and duplex imaging data for remote review and interpretation. METHODS: We performed remote TCD and CUS examinations on a healthy, volunteer employee from our institution without known cerebrovascular disease. The telemedicine end point was stationed in our institution's hospital where the neurosonology examinations took place and the control station was in a dedicated telemedicine room in a separate building. The examinations were performed by a postgraduate level neurohospitalist trainee (M.N.R.) and interpreted by an attending vascular neurologist, both with experience in the performance and interpretation of TCD and CUS. RESULTS: Spectral waveform and duplex ultrasound data were successfully transmitted from TCD and CUS instruments through a telemedicine end point to a remote reviewer at a control station. Image quality was preserved in all cases, and technical failures were not encountered. CONCLUSIONS: This proof-of-concept study demonstrates the technical feasibility of interfacing TCD and CUS peripherals with a telemedicine end point to provide real-time spectral waveform and duplex imaging data for remote review and interpretation. Medical diagnostic and telemedicine devices should be equipped with interfaces that allow simple transmission of high-quality audio and video information from the medical devices to the telemedicine technology. Further study is encouraged to determine the clinical impact of teleneurosonology. PMID- 25542764 TI - CD34+/CD144+ circulating endothelial cells as an indicator of carotid atherosclerosis. AB - BACKGROUND: The relationships between the number of circulating endothelial cells (CECs) or endothelial progenitor cells (EPCs) and indicators of carotid atherosclerosis, such as the intima-media thickness (IMT) and plaque score are not well characterized in patients with chronic ischemic stroke. The objective of this study was to investigate these relationships in patients with chronic ischemic stroke and in patients with risk factors for stroke. METHODS: A total of 58 patients (69.6 +/- 10.0 years, 21 females) with chronic ischemic stroke or with risk factors for stroke were included in this study. IMT was measured using an IntimaScope, and the numbers of CECs and EPCs were measured using flow cytometry. CECs and EPCs were defined as CD34+/CD144+ and CD34+/CD133+ cells, respectively. RESULTS: The number of CECs in patients with large artery atherosclerosis was higher than that in patients with cardioembolism or small vessel occlusion (P < .05). In contrast, there were no significant differences in the number of EPCs between groups. A positive correlation was also observed between the plaque score and the number of CECs (r(2) = .139, P < .05, n = 36). Moreover, the number of CECs in patients with moderate and severe atherosclerosis (.32 +/- .11/MUL, n = 22) was higher than that in patients with no plaque and mild atherosclerosis (.25 +/- .07/MUL, n = 34, P < .05). CONCLUSIONS: The number of CECs was high in patients with large artery atherosclerosis who experienced chronic ischemic stroke. And this number may reflect severity of carotid atherosclerosis. PMID- 25542765 TI - Rupture of a concealed aneurysm after intravenous thrombolysis of a thrombus in the parent middle cerebral artery. AB - BACKGROUND: Management of ischemic stroke in the presence of aneurysmal brain disease is controversial. Recent retrospective evidence suggests that in selected patients, intravenous thrombolysis (IVT) remains a safe approach for reperfusion. METHODS: We document a case of post-thrombolysis aneurysmal rupture. Supported by additional scientific literature we postulate that acute aneurysmal thrombosis leading to stroke in the culprit artery may be an ominous sign of rupture and should be considered separately from fortuitously discovered distant aneurysmal disease. RESULTS: A 71-year-old female presented with an acute right middle cerebral artery stroke syndrome. IVT allowed vessel reperfusion and revealed a previously concealed, juxtaposed non-giant M1 segment saccular aneurysm. Secondary aneurysmal rupture ensued. The aneurysm was secured by surgical clipping. Postoperative course was uneventful. CONCLUSIONS: This case shows that despite reports of thrombolysis safety in the presence of brain aneurysms, thrombolysis remains potentially hazardous and hints toward an increased risk when the stroke arises on the parent vessel itself. PMID- 25542766 TI - N-Bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders. AB - The search for novel heterobicyclic compounds within the drug-like chemical space continues to be an area of interest in medicinal chemistry. Unsaturated N bridgehead heterocycles are well represented in marketed drugs for a variety of therapeutic areas, and continue to play an important role in central nervous system (CNS) drug discovery programs. Examples of medicinal chemistry strategies that make use of N-bridged 5,6-bicyclic pyridines are discussed here in this Minireview, which covers the literature from 2010 up to 2014. B1-class imidazopyridines and B3-class pyrazolopyridines have proven to be at the forefront of molecular prototypes that are capable of interacting with disease relevant targets in neurodegeneration and neuropsychiatry. PMID- 25542767 TI - Maternal and infant factors associated with infancy-onset hydrocephalus in Washington State. AB - OBJECTIVE: Hydrocephalus, a complex condition characterized by progressive accumulation of cerebrospinal fluid within the ventricular system of the brain, affects ~ 6 in 10,000 infants and is heterogeneous in nature. Previous investigations of risk factors have not considered etiologic heterogeneity. METHODS: We conducted a case-control study of 1748 children with hydrocephalus identified through birth certificate check boxes and ICD-9 codes of linked hospital discharge records through the first year of life. Control infants were identified from birth records (N = 19,700), frequency matched to cases by year of birth. Three mutually exclusive, nonexhaustive subgroups were identified: hydrocephalus associated with a neural tube defect (n = 332); prenatal-onset hydrocephalus (n = 402); and hydrocephalus associated with intracranial hemorrhage (n = 446). Within each group, we examined associations with maternal age, race/ethnicity, parity, diabetes and hypertension, and infant sex and gestation. We used logistic regression to calculate odds ratios and 95% confidence intervals. RESULTS: Asian ethnicity was independently associated with an inverse risk of all subtypes of hydrocephalus (hydrocephalus associated with a neural tube defect: odds ratio, 0.44; 95% confidence interval, 0.23 to 0.84; prenatal-onset hydrocephalus: odds ratio, 0.47; 95% confidence interval, 0.27 to 0.83; hydrocephalus associated with intracranial hemorrhage: odds ratio, 0.59; 95% confidence interval, 0.33 to 1.07) compared with whites. Pre-existing diabetes was associated to varying degrees with all three subtypes (hydrocephalus associated with a neural tube defect: odds ratio, 1.94; 95% confidence interval, 0.61 to 6.17; prenatal-onset hydrocephalus: odds ratio, 5.20; 95% confidence interval, 2.60 to 10.40; hydrocephalus associated with intracranial hemorrhage: odds ratio, 5.26; 95% confidence intervals, 2.85 to 9.69). Hypertension had a positive association with hydrocephalus associated with intracranial hemorrhage (odds ratio, 1.91; 95% confidence interval, 1.46 to 2.52) but an inverse association with hydrocephalus associated with a neural tube defect (odds ratio, 0.59; 95% confidence interval, 0.36 to 0.98). Gestation <= 30 weeks was associated with all three subgroups, most notably hydrocephalus associated with intracranial hemorrhage (odds ratio, 443.56; 95% confidence intervals, 326.34 to 602.87); nearly two-thirds (64%) of hydrocephalus associated with intracranial hemorrhage infants were born <= 30 weeks. Male gender was independently associated only with hydrocephalus associated with intracranial hemorrhage (odds ratio, 1.82; 95% confidence interval, 1.40 to 2.39). No associations were observed with advanced or young maternal age or with parity. CONCLUSIONS: The different risk profiles seen among these three subgroups support the biologically heterogeneous nature of infantile hydrocephalus. Future research should take specific etiologic subtypes into account. PMID- 25542768 TI - The effects of early life lead exposure on the expression of P2X7 receptor and synaptophysin in the hippocampus of mouse pups. AB - The present study was undertaken to investigate the effects of maternal lead exposure on expression of P2X7 receptor and synaptophysin in the hippocampus of mice offspring. Lead exposure initiated from beginning of gestation to weaning. Lead acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.5% and 1% groups, respectively. On the 21st postnatal day, the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of P2X7 receptor and synaptophysin in hippocampus was examined by immunohistochemistry and Western blotting. The lead levels in blood and hippocampus of all lead exposure groups were significantly higher than that of the control group (P<0.05). Compared with the control group, the expression of P2X7 receptor was increased in lead exposed groups (P<0.05), but the expression of synaptophysin was decreased (P<0.05). The high expression of P2X7 receptor and low expression of synaptophysin in the hippocampus of pups may contribute to the neurotoxicity associated with maternal Pb exposure. PMID- 25542769 TI - Prevalence of Mycobacterium tuberculosis strain genotypes in Taiwan reveals a close link to ethnic and population migration. AB - Taiwan is a relatively isolated island, serving as a mixing vessel for colonization by different waves of ethnic and migratory groups over the past 4 centuries. The potential transmission pattern of Mycobacterium tuberculosis in different ethnic and migratory populations remains to be elucidated. By using mycobacterial tandem repeat sequences as genetic markers, the prevalence of M. tuberculosis strains in Taiwan revealed a close link to the historical migration. Interestingly, the M. tuberculosis strain in the aborigines of Eastern and Central Taiwan had a dominance of the Haarlem (Dutch) strain while those in Southern Taiwan had a dominance of the East-African Indian (EAI) strain. The prevalence of different M. tuberculosis strains in specific ethnic populations suggests that M. tuberculosis transmission is limited and restricted to close contact. The prevalence of the Beijing modern strain in the young population causes a concern for M. tuberculosis control, because of high virulence and drug resistance. Furthermore, our data using molecular genotyping should provide valuable information on the historical study of the origin and migration of aborigines in Taiwan. PMID- 25542770 TI - SOX2, OTX2 and PAX6 analysis in subjects with anophthalmia and microphthalmia. AB - Anophthalmia (A) and microphthalmia (M) are rare developmental anomalies that have significant effects on visual activity. In fraction of A/M subjects, single genetic defects have been identified as causative. In this study we analysed 65 Italian A/M patients, 21 of whom are syndromic, for mutations in SOX2, OTX2 and PAX6 genes. In syndromic patients the presence of genome imbalances through array CGH was also investigated. No mutations were found for OTX2 and PAX6 genes. Three causative SOX2 mutations were found in subjects with syndromic A. In a subject with syndromic signs and monolateral M, two de novo 6.26 Mb and 1.37 Mb deletions in 4q13.2q13.3 have been identified. A SOX2 missense (p.Ala161Ser) mutation was found in 1 out of 39 a subject with non-syndromic monolateral M. Alanine at position 161 is conserved along phylogeny and the p.Ala161Ser mutation is estimated pathogenic by in silico analysis. However, this mutation was also present in the unaffected patient's daughter. PMID- 25542771 TI - Case of mild Schmid-type metaphyseal chondrodysplasia with novel sequence variation involving an unusual mutational site of the COL10A1 gene. AB - Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait. MCDS is a relatively common form of MCD. Most mutations that cause MCDS occur within the carboxyl-terminal non-collagenous domain (NC1) of the COL10A1 gene. We performed mutational analysis of the COL10A1 genes in 4 unrelated Korean patients with diagnosed MCDS. Mutational analysis of COL10A1 identified c.1904_1915delinsT (p.Gln635LeufsX10) and c.1969dupG (p.Ala657GlyfsX10), 2 novel frameshift mutations, and c.2030T>A (p.Val677Glu) and c.862G>C (p.Gly288Arg) at unusual mutational sites, which could be pathogenic. We present the first report of the molecular characteristics of MCDS in 4 Korean patients. Our findings suggest that a novel sequence variation involving an unusual mutational site of the COL10A1 gene can cause mild MCDS. PMID- 25542774 TI - Stuck in a vicious circle of stress. Parental concerns and barriers to changing children's dietary and physical activity habits. AB - INTRODUCTION: Dietary habits and physical activity are often the focus of obesity prevention programmes and involving parents in such programmes has proven to be effective. The aims of this study were to describe parents' concerns about their children's diet and physical activity habits and to describe barriers to change. RESULTS: The study used archival data gathered unobtrusively in the form of memos taken after sessions of Motivational Interviewing as part of the parental support programme, A Healthy School Start. The 74 MI-sessions were conducted from October 2010 to April 2011 with either a mother or father or both, all with children in pre-school class. Thematic analysis was applied. Three themes were identified regarding children's dietary habits: amount of food consumed influenced by behaviour in the family, eating situations influenced by stressful everyday life and family interplay, and food choices influenced by stressful everyday life and family interplay. One theme appeared regarding physical activity: physical activity influenced by stressful everyday life and family interplay. CONCLUSION: Family interplay appears to be an important link between the work-life stress perceived by parents and less healthy food and physical activity habits in the home. Both lack of parental cooperation and negative parent-child interactions may act as barriers to healthy eating and physical activity and should be addressed in future intervention studies on health-related behaviours of children. PMID- 25542772 TI - A novel nonhuman primate model of cigarette smoke-induced airway disease. AB - Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD. PMID- 25542773 TI - A spontaneous deletion within the desmoglein 3 extracellular domain of mice results in hypomorphic protein expression, immunodeficiency, and a wasting disease phenotype. AB - Desmoglein 3 is a transmembrane component of desmosome complexes that mediate epidermal cell-to-cell adhesion and tissue integrity. Antibody blockade of desmoglein 3 function in pemphigus vulgaris patients leads to skin blistering (acantholysis) and oral mucosa lesions. Desmoglein 3 deficiency in mice leads to a phenotype characterized by cyclic alopecia in addition to the dramatic skin and mucocutaneous acantholysis observed in pemphigus patients. In this study, mice that developed an overt squeaky (sqk) phenotype were identified with obstructed airways, cyclic hair loss, and severe immunodeficiency subsequent to the development of oral lesions and malnutrition. Single-nucleotide polymorphism based quantitative trait loci mapping revealed a genetic deletion that resulted in expression of a hypomorphic desmoglein 3 protein with a truncation of an extracellular cadherin domain. Because hypomorphic expression of a truncated desmoglein 3 protein led to a spectrum of severe pathology not observed in mice deficient in desmoglein 3, similar human genetic alterations may also disrupt desmosome function and induce a disease course distinct from pathogenesis of pemphigus vulgaris. PMID- 25542775 TI - Motives for consumer choice of traditional food and European food in mainland China. AB - The demand for European (-style) foods in mainland China has been increasing dramatically during the last decade. Nevertheless, European food producers often appear to be not capable to fully exploit this huge market potential, partially due to the competition with traditional (Chinese) foods. This study examines the determinants of mainland Chinese consumers' choice of traditional food and European food. A web-based survey was administered with 541 consumers from two cities: Shanghai and Xi'an. Thereby, the Food Choice Motives model, predominantly used thus far in a European or developed context, is applied to mainland China in order to address the lack of knowledge on food motives of its consumer market and to detect associations between these motives, attitudes, and purchase intentions. Factor analysis resulted in a new Food Choice Motive construct that is considered more appropriate within the context of mainland Chinese consumers, encompassing six dimensions: Health concern, Time or money saving, Sensory appeal, Availability and familiarity, Mood and Food safety concern. Path analysis demonstrated that Time or money saving was negatively associated with attitude toward traditional food on the one hand and purchase intentions toward European food on the other hand. Availability and familiarity had a positive association with attitude toward traditional food. Mood was a positive factor driving attitude toward European food. For both food types, Sensory appeal and Attitude were positively linked to purchase intentions. Furthermore, Mood was negatively linked to the purchase intention toward traditional food in Shanghai. Food safety concern was positively associated with attitudes toward traditional food in Xi'an. PMID- 25542776 TI - Hidden osteophyte formation on plain X-ray is the predictive factor for development of knee osteoarthritis after 48 months--data from the Osteoarthritis Initiative. AB - OBJECTIVE: To examine whether the detection of osteophytes anywhere in the knee could serve as a pre-radiographic biomarker for osteoarthritis (OA) development. METHODS: Baseline magnetic resonance imaging (MRIs) of 132 participants in the Osteoarthritis Initiative (OAI) were studied. Based on radiographs, 66 knees were assessed as osteoarthritis-free (no-osteoarthritis [NOA], or Kellgren/Lawrence [K/L] severity grade 0/1 both at baseline and 48 months), and another 66 knees were assessed as having radiographic OA changes (pre-radiographic osteoarthritis [PROA], or with K/L grade 0/1 at baseline and grade >= 2 at 48 months). Using baseline MRI data, we examined eight sites of osteophyte formation: the medial and lateral femoral condyle (MFC and LFC, respectively); medial and lateral tibial plateau (MTP and LTP, respectively); medial and lateral facets of the patellofemoral joint (PM and PL, respectively); tibial spine (TS); and femoral intercondylar notch (IC). Knee joint osteophyte size was assessed via the 8-point marginal osteophytes item of the whole-organ magnetic resonance imaging score (WORMS). The frequencies and distributions of osteophytes were compared between groups. RESULTS: Mild-size osteophytes (defined as score >= 2) were observed more frequently at the MFC (P = 0.00278), MTP (P = 0.0046), TS (P = 0.0146), PM (P < 0.0001), PL (P = 0.0012), and IC (P < 0.0001) in PROA knees than in NOA knees. Moderate-size osteophytes (defined as score >= 4) were more frequently observed in PROA knees than in NOA knees only at the IC (P < 0.0001). CONCLUSION: Knees with osteophyte formation at the IC, even those of K/L severity grade 0/1, are at risk for the development of radiographic OA by 48 months. PMID- 25542777 TI - Use-dependent cortical processing from fingertips in touchscreen phone users. AB - Cortical activity allotted to the tactile receptors on fingertips conforms to skilful use of the hand. For instance, in string instrument players, the somatosensory cortical activity in response to touch on the little fingertip is larger than that in control subjects. Such plasticity of the fingertip sensory representation is not limited to extraordinary skills and occurs in monkeys trained to repetitively grasp and release a handle as well. Touchscreen phones also require repetitive finger movements, but whether and how the cortex conforms to this is unknown. By using electroencephalography (EEG), we measured the cortical potentials in response to mechanical touch on the thumb, index, and middle fingertips of touchscreen phone users and nonusers (owning only old technology mobile phones). Although the thumb interacted predominantly with the screen, the potentials associated with the three fingertips were enhanced in touchscreen users compared to nonusers. Within the touchscreen users, the cortical potentials from the thumb and index fingertips were directly proportional to the intensity of use quantified with built-in battery logs. Remarkably, the thumb tip was sensitive to the day-to-day fluctuations in phone use: the shorter the time elapsed from an episode of intense phone use, the larger the cortical potential associated with it. Our results suggest that repetitive movements on the smooth touchscreen reshaped sensory processing from the hand and that the thumb representation was updated daily depending on its use. We propose that cortical sensory processing in the contemporary brain is continuously shaped by the use of personal digital technology. PMID- 25542779 TI - Mutagenesis during plant responses to UVB radiation. AB - We tested an idea that induced mutagenesis due to unrepaired DNA lesions, here the UV photoproducts, underlies the impact of UVB irradiation on plant phenotype. For this purpose we used protonemal culture of the moss Physcomitrella patens with 50% of apical cells, which mimics actively growing tissue, the most vulnerable stage for the induction of mutations. We measured the UVB mutation rate of various moss lines with defects in DNA repair (pplig4, ppku70, pprad50, ppmre11), and in selected clones resistant to 2-Fluoroadenine, which were mutated in the adenosine phosphotrasferase gene (APT), we analysed induced mutations by sequencing. In parallel we followed DNA break repair and removal of cyclobutane pyrimidine dimers with a half-life tau = 4 h 14 min determined by comet assay combined with UV dimer specific T4 endonuclease V. We show that UVB induces massive, sequence specific, error-prone bypass repair that is responsible for a high mutation rate owing to relatively slow, though error-free, removal of photoproducts by nucleotide excision repair (NER). PMID- 25542778 TI - Diet-induced obesity attenuates endotoxin-induced cognitive deficits. AB - Activation of the immune system can impair cognitive function, particularly on hippocampus dependent tasks. Several factors such as normal aging and prenatal experiences can modify the severity of these cognitive deficits. One additional factor that may modulate the behavioral response to immune activation is obesity. Prior work has shown that obesity alters the activity of the immune system. Whether diet-induced obesity (DIO) influences the cognitive deficits associated with inflammation is currently unknown. The present study explored whether DIO alters the behavioral response to the bacterial endotoxin, lipopolysaccharide (LPS). Female C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for a total of five months. After consuming their respective diets for four months, mice received an LPS or saline injection and were assessed for alterations in spatial learning. One month later, mice received a second injection of LPS or saline and tissue samples were collected to assess the inflammatory response within the periphery and central nervous system. Results showed that LPS administration impaired spatial learning in the control diet mice, but had no effect in DIO mice. This lack of a cognitive deficit in the DIO female mice is likely due to a blunted inflammatory response within the brain. While cytokine production within the periphery (i.e., plasma, adipose, and spleen) was similar between the DIO and control mice, the DIO mice failed to show an increase in IL-6 and CD74 in the brain following LPS administration. Collectively, these data indicate that DIO can reduce aspects of the neuroinflammatory response as well as blunt the behavioral reaction to an immune challenge. PMID- 25542780 TI - Ultraviolet-B radiation stimulates downward leaf curling in Arabidopsis thaliana. AB - Plants are very well adapted to growth in ultraviolet-B (UV-B) containing light. In Arabidopsis thaliana, many of these adaptations are mediated by the UV-B receptor UV resistance locus 8 (UVR8). Using small amounts of supplementary UV-B light, we observed changes in the shape of rosette leaf blades. Wild type plants show more pronounced epinasty of the blade edges, while this is not the case in uvr8 mutant plants. The UVR8 effect thus mimics the effect of phytochrome (phy) B in red light. In addition, a meta-analysis of transcriptome data indicates that the UVR8 and phyB signaling pathways have over 70% of gene regulation in common. Moreover, in low levels of supplementary UV-B light, mutant analysis revealed that phyB signaling is necessary for epinasty of the blade edges. Analysis of auxin levels and the auxin signal reporter DR5::GUS suggest that the epinasty relies on altered auxin distribution, keeping auxin at the leaf blade edges in the presence of UV-B. Together, our results suggest a co-action of phyB and UVR8 signaling, with auxin as a downstream factor. PMID- 25542781 TI - The uptake of HIV Tat peptide proceeds via two pathways which differ from macropinocytosis. AB - Cell penetrating peptides (CPPs) have been extensively studied as vectors for cellular delivery of therapeutic molecules, yet the identity of their uptake routes remained unclear and is still under debate. In this study we provide new insights into CPP entry routes by quantitatively measuring the intracellular uptake of FAM-labeled Tat-peptide under rigorous kinetic and thermal conditions. The uptake of Tat-peptide between 4 and 15 degrees C corresponds to Q10=1.1, proceeding through a prompt (<5 min), temperature-independent process, suggesting direct membrane translocation. At longer durations, Tat rate of uptake shows linear dependence on temperature with Q10=1.44, accompanied by activation energy Ea=4.45 Kcal/mole. These values are significantly lower than those we found for the macropinocytosis probe dextran (Q10=2.2 and Ea=7.2 Kcal/mole) which possesses an exponential dependence on temperature, characteristic of endocytosis processes. Tat-peptide and dextran do not interfere with each other's uptake rate and the ratio of Tat-peptide uptake to its extracellular concentration is ~15 times higher than that for dextran. In addition, Phloretin, a modulator of cell membrane dipole potential, is shown to increase dextran uptake but to reduce that of Tat. We conclude that the uptake of Tat differs from that of dextran in all parameters. Tat uptake proceeds by dual entry routes which differ by their energy dependence. PMID- 25542782 TI - Structure of the N-terminal segment of human retinol dehydrogenase 11 and its preferential lipid binding using model membranes. AB - Retinol dehydrogenase 11 (RDH11) has been postulated to be anchored to membranes by means of its N-terminal segment in retinal pigment epithelial (RPE) cells where it participates to the visual cycle. The analysis of the primary sequence of RDH11 revealed that its N-terminal hydrophobic segment could be involved in the anchoring of this enzyme to membranes. However, no information is yet available on the properties of this N-terminal segment to support this role. The secondary structure and membrane binding of two N-terminal peptides of RDH11 with different lengths have thus been investigated to provide this information. Online tools allowed predicting an alpha-helical secondary structure for both peptides. Infrared spectroscopy and circular dichroism have shown that the alpha-helix of the Long-peptide (35 amino acids) is longer and more rigid than that of the Short peptide (25 amino acids) regardless of the type of solvent. Langmuir monolayers have been used as a model membrane to study lipid-peptide interactions. Values of maximum insertion pressure and synergy suggested a preferential binding of the Long-peptide to lipids with a phosphoethanolamine polar head group, which are abundant in the RPE. Furthermore, infrared spectroscopy in monolayers has shown that the alpha-helical structure of the Long-peptide is more stable in the presence of saturated phospholipids whereas the structure of the Short-peptide is mainly disordered. Altogether, the present data demonstrate that the alpha helical hydrophobic core of the N-terminal segment of RDH11 displays properties typical of transmembrane domains, in agreement with its postulated role in the membrane anchoring of this protein. PMID- 25542783 TI - Ion channel expression as promising cancer biomarker. AB - Cancer is a disease with marked heterogeneity in both response to therapy and survival. Clinical and histopathological characteristics have long determined prognosis and therapy. The introduction of molecular diagnostics has heralded an explosion in new prognostic factors. Overall, histopathology, immunohistochemistry and molecular biology techniques have described important new prognostic subgroups in the different cancer categories. Ion channels and transporters (ICT) are a new class of membrane proteins which are aberrantly expressed in several types of human cancers. Besides regulating different aspect of cancer cell behavior, ICT can now represent novel cancer biomarkers. A summary of the data obtained so far and relative to breast, prostate, lung, colorectal, esophagus, pancreatic and gastric cancers are reported. Special emphasis is given to those studies aimed at relating specific ICT or a peculiar ICT profile with current diagnostic methods. Overall, we are close to exploit ICTs for diagnostic, prognostic or predictive purposes in cancer. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25542784 TI - Can conceptual congruency effects between number, time, and space be accounted for by polarity correspondence? AB - Conceptual congruency effects have been interpreted as evidence for the idea that the representations of abstract conceptual dimensions (e.g., power, affective valence, time, number, importance) rest on more concrete dimensions (e.g., space, brightness, weight). However, an alternative theoretical explanation based on the notion of polarity correspondence has recently received empirical support in the domains of valence and morality, which are related to vertical space (e.g., good things are up). In the present study we provide empirical arguments against the applicability of the polarity correspondence account to congruency effects in two conceptual domains related to lateral space: number and time. Following earlier research, we varied the polarity of the response dimension (left-right) by manipulating keyboard eccentricity. In a first experiment we successfully replicated the congruency effect between vertical and lateral space and its interaction with response eccentricity. We then examined whether this modulation of a concrete-concrete congruency effect can be extended to two types of concrete abstract effects, those between left-right space and number (in both parity and magnitude judgment tasks), and temporal reference. In all three tasks response eccentricity failed to modulate the congruency effects. We conclude that polarity correspondence does not provide an adequate explanation of conceptual congruency effects in the domains of number and time. PMID- 25542785 TI - Tumor control probability and the utility of 4D vs 3D dose calculations for stereotactic body radiotherapy for lung cancer. AB - Four-dimensional (4D) dose calculations for lung cancer radiotherapy have been technically feasible for a number of years but have not become standard clinical practice. The purpose of this study was to determine if clinically significant differences in tumor control probability (TCP) exist between 3D and 4D dose calculations so as to inform the decision whether 4D dose calculations should be used routinely for treatment planning. Radiotherapy plans for Stage I-II lung cancer were created for 8 patients. Clinically acceptable treatment plans were created with dose calculated on the end-exhale 4D computed tomography (CT) phase using a Monte Carlo algorithm. Dose was then projected onto the remaining 9 phases of 4D-CT using the Monte Carlo algorithm and accumulated onto the end exhale phase using commercially available deformable registration software. The resulting dose-volume histograms (DVH) of the gross tumor volume (GTV), planning tumor volume (PTV), and PTVsetup were compared according to target coverage and dose. The PTVsetup was defined as a volume including the GTV and a margin for setup uncertainties but not for respiratory motion. TCPs resulting from these DVHs were estimated using a wide range of alphas, betas, and tumor cell densities. Differences of up to 5Gy were observed between 3D and 4D calculations for a PTV with highly irregular shape. When the TCP was calculated using the resulting DVHs for fractionation schedules typically used in stereotactic body radiation therapy (SBRT), the TCP differed at most by 5% between 4D and 3D cases, and in most cases, it was by less than 1%. We conclude that 4D dose calculations are not necessary for most cases treated with SBRT, but they might be valuable for irregularly shaped target volumes. If 4D calculations are used, 4D DVHs should be evaluated on volumes that include margin for setup uncertainty but not respiratory motion. PMID- 25542786 TI - Dosimetric experience with 2 commercially available multilumen balloon-based brachytherapy to deliver accelerated partial-breast irradiation. AB - The purpose of this work was to report dosimetric experience with 2 kinds of multilumen balloon (MLB), 5-lumen Contura MLB (C-MLB) and 4-lumen MammoSite MLB (MS-MLB), to deliver accelerated partial-breast irradiation, and compare the ability to achieve target coverage and control skin and rib doses between 2 groups of patients treated with C-MLB and MS-MLB brachytherapy. C-MLB has 5 lumens, the 4 equal-spaced peripheral lumens are 5 mm away from the central lumen. MS-MLB has 4 lumens, the 3 equal-spaced peripheral lumens are 3 mm away from the central lumen. In total, 43 patients were treated, 23 with C-MLB, and 20 with MS-MLB. For C-MLB group, 8 patients were treated with a skin spacing < 7 mm and 12 patients with rib spacing < 7 mm. For MS-MLB group, 2 patients were treated with a skin spacing < 7 mm and 5 patients with rib spacing < 7 mm. The dosimetric goals were (1) >= 95% of the prescription dose (PD) covering >= 95% of the target volume (V(95%) >= 95%), (2) maximum skin dose <= 125% of the PD, (3) maximum rib dose <= 145% of the PD (if possible), and (4) the V(150%) <= 50 cm(3) and V(200%) <= 10 cm(3). All dosimetric criteria were met concurrently in 82.6% of C-MLB patients, in 80.0% of MS-MLB patients, and in 81.4% of all 43 patients. For each dosimetric parameter, t-test of these 2 groups showed p > 0.05. Although the geometric design of C-MLB is different from that of MS-MLB, both applicators have the ability to shape the dose distribution and to provide good target coverage, while limiting the dose to skin and rib. No significant difference was observed between the 2 patient groups in terms of target dose coverage and dose to organs at risk. PMID- 25542787 TI - Shortening a Carrel Patch in a Graft With Multiple Arteries: A Step-By-Step Technical Analysis. AB - OBJECTIVES: Multiple renal arteries in donor kidneys are not a rare entity. Whenever encountered, they pose a surgical challenge in renal transplant because they require a more complicated back table vascular reconstruction and implant technique. We developed a unique step-by-step in vivo illustration of the application of shortening a Carrel (aortic) patch to address multiple arteries in deceased-donor renal transplant. MATERIALS AND METHODS: Case report. RESULTS: We present the case of a 63-year-old man who received a left kidney from a deceased donor with 2 arteries on a Carrel patch that were anastomosed in a neopatch model. CONCLUSIONS: A donor kidney with multiple arteries is a challenge before arterial anastomosis. Various anastomotic patterns have been described for this situation. Treatment of multiple arteries depends mainly on the donor source (living or deceased), the characteristics of multiple arteries, and the transplant surgeon's preference. When the length of the aortic patch of a deceased donor is > 2.5 cm, the surgeon may shorten it and form a neopatch to facilitate a single arterial anastomosis to the recipient. PMID- 25542788 TI - Protein composition alters in vivo resorption of PEG-based hydrogels as monitored by contrast-enhanced MRI. AB - We report on the use of magnetic resonance imaging (MRI)-based non-invasive monitoring to document the role of protein adjuvants in hydrogel implant integration in vivo. Polyethylene glycol (PEG) hydrogels were formed with different protein constituents, including albumin, fibrinogen and gelatin. The hydrogels were designed to exhibit similar material properties, including modulus, swelling and hydrolytic degradation kinetics. The in vivo resorption properties of these PEG-based hydrogels, which contained a tethered gadolinium contrast agent, were characterized by MRI and histology, and compared to their in vitro characteristics. MRI data revealed that PEG-Albumin implants remained completely intact throughout the experiments, PEG-Fibrinogen implants lost about 10% of their volume and PEG-Gelatin implants underwent prominent swelling and returned to their initial volume by day 25. Fully synthetic PEG-diacrylate (PEG DA) control hydrogels lost about half of their volume after 25 days in vivo. Transverse MRI cross-sections of the implants revealed distinct mechanisms of the hydrogel's biodegradation: PEG-Fibrinogen and PEG-Albumin underwent surface erosion, whereas PEG-Gelatin and PEG-DA hydrogels mainly underwent bulk degradation. Histological findings substantiated the MRI data and demonstrated significant cellular response towards PEG-DA and PEG-Gelatin scaffolds with relatively low reaction towards PEG-Fibrinogen and PEG-Albumin hydrogels. These findings demonstrate that PEG-protein hydrogels can degrade via a different mechanism than PEG hydrogels, and that this difference can be linked to a reduced foreign body response. PMID- 25542789 TI - A combined biomaterial and cellular approach for annulus fibrosus rupture repair. AB - Recurrent intervertebral disc (IVD) herniation and degenerative disc disease have been identified as the most important factors contributing to persistent pain and disability after surgical discectomy. An annulus fibrosus (AF) closure device that provides immediate closure of the AF rupture, restores disc height, reduces further disc degeneration and enhances self-repair capacities is an unmet clinical need. In this study, a poly(trimethylene carbonate) (PTMC) scaffold seeded with human bone marrow derived mesenchymal stromal cells (MSCs) and covered with a poly(ester-urethane) (PU) membrane was assessed for AF rupture repair in a bovine organ culture annulotomy model under dynamic load for 14 days. PTMC scaffolds combined with the sutured PU membrane restored disc height of annulotomized discs and prevented herniation of nucleus pulposus (NP) tissue. Implanted MSCs showed an up-regulated gene expression of type V collagen, a potential AF marker, indicating in situ differentiation capability. Furthermore, MSCs delivered within PTMC scaffolds induced an up-regulation of anabolic gene expression and down-regulation of catabolic gene expression in adjacent native disc tissue. In conclusion, the combined biomaterial and cellular approach has the potential to hinder herniation of NP tissue, stabilize disc height, and positively modulate cell phenotype of native disc tissue. PMID- 25542790 TI - Biological adhesive based on carboxymethyl chitin derivatives and chitin nanofibers. AB - Novel biological adhesives made from chitin derivatives were prepared and evaluated for their adhesive properties and biocompatibility. Chitin derivatives with acrylic groups, such as 2-hydroxy-3-methacryloyloxypropylated carboxymethyl chitin (HMA-CM-chitin), were synthesized and cured by the addition of an aqueous hydrogen peroxide solution as a radical initiator. The adhesive strength of HMA CM-chitin increased when it was blended with chitin nanofibers (CNFs) or surface deacetylated chitin nanofibers (S-DACNFs). HMA-CM-chitin/CNFs or HMA-CM-chitin/S DACNFs have almost equal adhesive strength compared to that of a commercial cyanoacrylate adhesive. Moreover, quick adhesion and induction of inflammatory cells migration were observed in HMA-CM-chitin/CNF and HMA-CM-chitin/S-DACNF. These findings indicate that the composites prepared in this study are promising materials as new biological adhesives. PMID- 25542791 TI - Synergism through combination of chemotherapy and oxidative stress-induced autophagy in A549 lung cancer cells using redox-responsive nanohybrids: a new strategy for cancer therapy. AB - A combination of various therapeutic approaches has emerged as a promising strategy for cancer treatment. A safe and competent nano-delivery system is thus in urgent demand to facilitate the simultaneous transport of various therapeutic agents to cancer cells and a tumor region to achieve synergistic effect. Gold nanoparticles (GNPs) and mesoporous silica nanoparticle (MSNs) were fabricated herein as potential candidates for drug delivery. Serving as gatekeepers, GNPs (5 nm in diameter) were attached onto the amino-functionalized MSNs (denoted as NMSNs) via a relatively weak gold-nitrogen bonding. The resulting nanohybrids (denoted as GCMSNs) were uptaken by cells, and the detachment of GNPs and subsequent intracellular drug release from NMSNs were achieved by competitive binding of intracellular glutathione to GNPs. In addition to the function of gatekeeping, GNPs also play another role as the oxidative stress elicitor. Our in vitro studies revealed that GCMSNs induced higher oxidative stress in lung cancer cells (A549) than in normal cells (3T3-L1). This growth inhibitory effect found in the cancer cells was likely induced by mitochondria dysfunction originated from the GCMSN-induced, oxidative stress-triggered mitochondria-mediated autophagy. The redox-responsive nanohybrids were further loaded with camptothecin and the intensified synergistic therapeutic effects were observed associated with combined chemotherapy and oxidative stress strategy. The results clearly demonstrate that such unique nanohybrids hold great promise for selective and effective cancer treatments. PMID- 25542793 TI - The use of alpha-conotoxin ImI to actualize the targeted delivery of paclitaxel micelles to alpha7 nAChR-overexpressing breast cancer. AB - Alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the alpha7 nAChR-overexpressing tumors, herein, alpha-conotoxin ImI, a disulfide-rich toxin with highly affinity for alpha7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of alpha7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the alpha7 nAChR-targeted nanomedicines could deliver more specifically and faster into alpha7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca(2+) transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, alpha7 nAChR is also a promising target for anti-tumor drug delivery and in this case, alpha-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting alpha7 nAChR-overexpressing tumors. PMID- 25542792 TI - Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells. AB - A major limitation in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14 positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets. PMID- 25542794 TI - Graphene oxide-BaGdF5 nanocomposites for multi-modal imaging and photothermal therapy. AB - By using a solvothermal method in the presence of polyethylene glycol (PEG), BaGdF5 nanoparticles are firmly attached on the surface of graphene oxide (GO) nanosheets to form the GO/BaGdF5/PEG nanocomposites. The resulting GO/BaGdF5/PEG shows low cytotoxicity, positive magnetic resonance (MR) contrast effect and better X-ray attenuation property than Iohexol, which enables effective dual modality MR and X-ray computed tomography (CT) imaging of the tumor model in vivo. The enhanced near-infrared absorbance, good photothermal stability and efficient tumor passive targeting of GO/BaGdF5/PEG result in the highly efficient photothermal ablation of tumor in vivo after intravenous injection of GO/BaGdF5/PEG and the following 808-nm laser irradiation (0.5 W/cm(2)). The histological and biochemical analysis data reveal no perceptible toxicity of GO/BaGdF5/PEG in mice after treatment. These results indicate potential application of GO/BaGdF5/PEG in dual-modality MR/CT imaging and photothermal therapy of cancers. PMID- 25542795 TI - Evaluation of the influence of fullerenol on aging and stress resistance using Caenorhabditis elegans. AB - Fullerene derivatives have attracted extensive attention in biomedical fields and polyhydroxyl fullerene (fullerenol), a water-soluble fullerene derivative, is demonstrated as a powerful antioxidant. To further assess their anti-aging and anti-stress potential, we employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the effects of fullerenol on the growth, development, behavior and anti-stress ability in vivo. The data show that fullerenol has no obviously toxic effect on nematodes and can delay C. elegans aging progress under normal condition. Further studies demonstrate that fullerenol attenuates endogenous levels of reactive oxygen species and provides protection to C. elegans under stress conditions by up-regulating stress-related genes in a DAF-16 depend manner and improving lifespan. In summary, our data suggest that fullerenol might be a safe and reasonable anti-aging candidate with great potential in vivo. PMID- 25542796 TI - The effect of transplantation of nasal mucosal epithelial cell sheets after middle ear surgery in a rabbit model. AB - Postoperative regeneration of the middle ear mucosa and pneumatization of the middle ear cavity are of great importance after middle ear surgery. This study developed a new method to transplant autologous nasal mucosal epithelial cell sheets into the damaged middle ear cavity. The aim of this study was to evaluate postoperative healing after the transplantation of the cell sheets. Rabbit nasal mucosal epithelial cell sheets were fabricated on a temperature-responsive culture dish, and transplanted into the damaged middle ear of rabbit, which was surgically created. The healing of middle ears was evaluated by histology and X ray computed tomography after transplantation. Functional evaluation was performed by measuring the maximum middle ear total pressure reflecting a trans mucosal gas exchange function. Two control groups were used: the normal control group and the mucosa-eliminated control group. Transplantation of cell sheets suppressed the bone hyperplasia and the narrowing of pneumatic space in the middle ear cavity compared with the mucosa-eliminated control group. The mucosal gas exchange function was also better in the cell sheet-transplanted group. Nasal mucosal epithelial cell sheet was confirmed to be useful as an effective graft material after middle ear surgery and hopefully become a novel therapy in the future. PMID- 25542798 TI - In vivo tumor-targeted dual-modal fluorescence/CT imaging using a nanoprobe co loaded with an aggregation-induced emission dye and gold nanoparticles. AB - As an intensely studied computed tomography (CT) contrast agent, gold nanoparticle has been suggested to be combined with fluorescence imaging modality to offset the low sensitivity of CT. However, the strong quenching of gold nanoparticle on fluorescent dyes requires complicated design and shielding to overcome. Herein, we report a unique nanoprobe (M-NPAPF-Au) co-loading an aggregation-induced emission (AIE) red dye and gold nanoparticles into DSPE PEG(2000) micelles for dual-modal fluorescence/CT imaging. The nanoprobe was prepared based on a facile method of "one-pot ultrasonic emulsification". Surprisingly, in the micelles system, fluorescence dye (NPAPF) efficiently overcame the strong fluorescence quenching of shielding-free gold nanoparticles and retained the crucial AIE feature. In vivo studies demonstrated the nanoprobe had superior tumor-targeting ability, excellent fluorescence and CT imaging effects. The totality of present studies clearly indicates the significant potential application of M-NPAPF-Au as a dual-modal non-invasive fluorescence/X ray CT nanoprobe for in vivo tumor-targeted imaging and diagnosis. PMID- 25542800 TI - Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis. AB - Protein therapeutics targeting inflammatory mediators have shown great promise for the treatment of autoimmunities such as rheumatoid arthritis (RA). However, a significant challenge in this area has been their low in vivo stability and consequently their severely compromised therapeutic efficacy. One such therapeutic molecule IL-1 receptor antagonist (IL-1ra), used in the treatment of rheumatoid arthritis, has displayed only modest efficacy in human clinical trials owing to its short biological half-life. Herein, we report a novel approach to conglomerate individual protein entities into a drug depot by incorporation of an amyloidogenic motif Lys-Phe-Phe-Glu (KFFE) thereby dramatically improving their systemic persistence and in turn their therapeutic efficacy in a mice model of autoimmune arthritis. PMID- 25542799 TI - Keratin films for ocular surface reconstruction: evaluation of biocompatibility in an in-vivo model. AB - Amniotic membrane (AM) transplantation is the clinical standard for ocular surface reconstruction, however recently keratin film (KF) has been proposed as an alternative material. Aim of the current study was to evaluate corneal biocompatibility of KF in a rabbit model. Forty-six New Zealand white rabbits underwent dissection of a corneal intrastromal pocket in which an AM or KF implant was inserted and observed for 10 days and for 4 weeks. Half of animals received topical steroids, while the other half were left without. At the end of the follow-up clinical and histology examinations were performed to evaluate transparency, inflammation and degradation. After 10 days the clinical and the histology results appeared to be comparable in KF implanted eyes treated with and without steroids. After 4 weeks, comparable clinical results were observed in all KF implanted eyes, while the inflammation score was lower in non-steroid compared to steroid treated eyes along with a higher degradation rate of the keratin films. In conclusion, keratin films from human hair show a good biocompatibility and transparency in vivo. The administration of topical steroids seems to slow down implant degradation which might be important for the modulation of tissue integration and matrix regeneration. PMID- 25542797 TI - Enhanced fluorescence imaging guided photodynamic therapy of sinoporphyrin sodium loaded graphene oxide. AB - Extensive research indicates that graphene oxide (GO) can effectively deliver photosensitives (PSs) by pi-pi stacking for photodynamic therapy (PDT). However, due to the tight complexes of GO and PSs, the fluorescence of PSs are often drastically quenched via an energy/charge transfer process, which limits GO-PS systems for photodiagnostics especially in fluorescence imaging. To solve this problem, we herein strategically designed and prepared a novel photo-theranostic agent based on sinoporphyrin sodium (DVDMS) loaded PEGylated GO (GO-PEG-DVDMS) with improved fluorescence property for enhanced optical imaging guided PDT. The fluorescence of loaded DVDMS is drastically enhanced via intramolecular charge transfer. Meanwhile, the GO-PEG vehicles can significantly increase the tumor accumulation efficiency of DVDMS and lead to an improved PDT efficacy as compared to DVDMS alone. The cancer theranostic capability of the as-prepared GO-PEG-DVDMS was carefully investigated both in vitro and in vivo. Most intriguingly, 100% in vivo tumor elimination was achieved by intravenous injection of GO-PEG-DVDMS (2 mg/kg of DVDMS, 50 J) without tumor recurrence, loss of body weight or other noticeable toxicity. This novel GO-PEG-DVDMS theranostics is well suited for enhanced fluorescence imaging guided PDT. PMID- 25542801 TI - Human astrocytes develop physiological morphology and remain quiescent in a novel 3D matrix. AB - Astrocytes are the most abundant glial cells in the brain and are responsible for diverse functions, from modulating synapse function to regulating the blood-brain barrier. In vivo, these cells exhibit a star-shaped morphology with multiple radial processes that contact synapses and completely surround brain capillaries. In response to trauma or CNS disease, astrocytes become activated, a state associated with profound changes in gene expression, including upregulation of intermediate filament proteins, such as glial fibrillary acidic protein (GFAP). The inability to recapitulate the complex structure of astrocytes and maintain their quiescent state in vitro is a major roadblock to further developments in tissue engineering and regenerative medicine. Here, we characterize astrocyte morphology and activation in various hydrogels to assess the feasibility of developing a matrix that mimics key aspects of the native microenvironment. We show that astrocytes seeded in optimized matrix composed of collagen, hyaluronic acid, and matrigel exhibit a star-shaped morphology with radial processes and do not upregulate GFAP expression, hallmarks of quiescent astrocytes in the brain. In these optimized gels, collagen I provides structural support, HA mimics the brain extracellular matrix, and matrigel provides endothelial cell compatibility and was found to minimize GFAP upregulation. This defined 3D microenvironment for maintaining human astrocytes in vitro provides new opportunities for developing improved models of the blood-brain barrier and studying their response to stress signals. PMID- 25542802 TI - Label-free imaging of gelatin-containing hydrogel scaffolds. AB - Composite hyaluronic acid (HA) hydrogels containing gelatin are used in regenerative medicine as tissue-mimicking scaffolds for improving stem cell survival. Once implanted, it is assumed that these biomaterials disintegrate over time, but at present there is no non-invasive imaging technique available with which such degradation can be directly monitored in vivo. We show here the potential of chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) as a label-free non-invasive imaging technique to monitor dynamic changes in scaffold composition in vivo. The CEST properties of the three individual hydrogel components (HA, GelinS, and polyethylene glycol diacrylate) were first measured in vitro. The complete hydrogel was then injected into the brain of immunodeficient rag2(-/-) mice and CEST MR images were obtained at day 1 and 7 post-transplantation. In vitro, GelinS gave the strongest CEST signal at 3.6 ppm offset from the water peak, originating from the amide protons present in gelatin. In vivo, a significant decrease in CEST signal was observed at 1 week post-implantation. These results were consistent with the biodegradation of the GelinS component, as validated by fluorescent microscopy of implanted hydrogels containing Alexa Fluor 488-labeled GelinS. Our label-free imaging approach should be useful for further development of hydrogel formulations with improved composition and stability. PMID- 25542803 TI - Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres. AB - Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres. PMID- 25542804 TI - Delta-like ligand 4-targeted nanomedicine for antiangiogenic cancer therapy. AB - Tumor angiogenesis is a multistep process involved with multiple molecular events in cancer microenvironment. Several molecular-targeted agents aiming to suppress tumor angiogenesis have been successfully translated into cancer clinic. However, new strategies are still urgently desired to be excavated to overcome the poor response and resistance in some antiangiogenic therapies. Recently, Delta-like ligand 4 (Dll4) is identified to be specifically over-expressed on tumor vascular endothelial cells (EC), and the Dll4-Notch pathway serves as a critical regulator in the development and maintenance of tumor angiogenesis. The intensively up regulated phenotype of Dll4 on the membrane of tumor vascular EC implies that Dll4 may act as a targetable address for drug delivery system (DDS) to achieve targeted antiangiogenic cancer therapy. Here, a nano-DDS, GD16 peptide (H2N GRCTNFHNFIYICFPD-CONH2, containing a disulfide bond between Cys3 and Cys13) conjugated nanoparticles loading paclitaxel (GD16-PTX-NP), which can specifically target the angiogenic marker Dll4, was fabricated for the investigation of antiangiogenic therapeutic efficacy in human head and neck cancer FaDu (Dll4 negative) xenograft in nude mice. The results demonstrate that GD16-PTX-NP achieved controlled drug release and exhibited favorable in vivo long-circulating feature. GD16-PTX-NP exerted enhanced antiangiogenic activity in the inhibition of human umbilical vein endothelial cell (HUVEC) viability, motility, migration, and tube formation, and in the Matrigel plug model as well, which can be definitely ascribed to the active internalization mediated by the interaction of GD16 and the over-expressed Dll4 on EC. GD16-PTX-NP showed accurate in vivo tumor neovasculature targeting property in FaDu tumor, where the paclitaxel was specifically delivered into the tumor vascular EC, leading to significant apoptosis of tumor vascular EC and necrosis of tumor tissues. The antiangiogenic activity of GD16-PTX-NP significantly contributed to its in vivo anticancer efficacy in Fadu tumor; moreover, no overt toxicity to the mice was observed. Our research firstly presents the potency and significance of a Dll4-targeted nanomedicine in antiangiogenic cancer therapy. PMID- 25542805 TI - Size-dependent long-term tissue response to biostable nanowires in the brain. AB - Nanostructured neural interfaces, comprising nanotubes or nanowires, have the potential to overcome the present hurdles of achieving stable communication with neuronal networks for long periods of time. This would have a strong impact on brain research. However, little information is available on the brain response to implanted high-aspect-ratio nanoparticles, which share morphological similarities with asbestos fibres. Here, we investigated the glial response and neuronal loss in the rat brain after implantation of biostable and structurally controlled nanowires of different lengths for a period up to one year post-surgery. Our results show that, as for lung and abdominal tissue, the brain is subject to a sustained, local inflammation when biostable and high-aspect-ratio nanoparticles of 5 MUm or longer are present in the brain tissue. In addition, a significant loss of neurons was observed adjacent to the 10 MUm nanowires after one year. Notably, the inflammatory response was restricted to a narrow zone around the nanowires and did not escalate between 12 weeks and one year. Furthermore, 2 MUm nanowires did not cause significant inflammatory response nor significant loss of neurons nearby. The present results provide key information for the design of future neural implants based on nanomaterials. PMID- 25542806 TI - Variants of CYP27B1 are associated with both multiple sclerosis and neuromyelitis optica patients in Han Chinese population. AB - Multiple sclerosis (MS) and neuromyelitis optica (NMO) are chronic demyelinating diseases of the central nervous system (CNS). Recently, variants of vitamin D metabolizing genes, including rs12368653, rs10876994, rs118204009 and rs703842 in CYP27B1, and rs2248359 in CYP24A1 have been identified to be associated with the pathogenicity of MS in Caucasian populations. However, these results have not been replicated in Han Chinese population. Here we investigated the association of these variants with MS and NMO susceptibility in 149 MS patients, 110 NMO patients and 294 healthy controls using MassARRAY system and Sanger sequencing. We found that the frequencies of the A allele of rs703842 were higher in MS patients than controls (p=0.032), and statistical differences were observed in the genotypes of both rs703842 (p=0.013) and rs10876994 (p=0.001) between NMO patients and controls. In addition, we found difference in the genotype of rs12368653 between MS patients and controls (p=0.008). However, no difference was found in rs2248359 among these three groups. The reported rare mutation p.R389H (rs118204009) was not found in our study. In conclusion, our study suggested that variants of CYP27B1 were associated with both MS and NMO patients in Han Chinese population. PMID- 25542807 TI - Genetic polymorphisms of CYP2C19 2 and ABCB1 C3435T affect the pharmacokinetic and pharmacodynamic responses to clopidogrel in 401 patients with acute coronary syndrome. AB - BACKGROUNDS AND OBJECTIVES: Clopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied. METHODS AND RESULTS: 401 acute coronary syndrome (ACS) patients received either a 300 mg loading dose following 75 mg maintenance dose daily or a 75mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P<0.05 vs. non-carriers) and thus decreased platelet inhibition (P<0.05 vs. non-carriers). Notably, the carriers of ABCB1 C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P<0.05 vs. non carriers) which also correlated with subsequently decreased platelet inhibition (P<0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel. CONCLUSIONS: CYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1 C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation. PMID- 25542808 TI - Comparison of the complete mitochondrial genome of the stonefly Sweltsa longistyla (Plecoptera: Chloroperlidae) with mitogenomes of three other stoneflies. AB - The complete mitochondrial genome of the stonefly, Sweltsa longistyla Wu (Plecoptera: Chloroperlidae), was sequenced in this study. The mitogenome of S. longistyla is 16,151bp and contains 37 genes including 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and a large non-coding region. S. longistyla, Pteronarcys princeps Banks, Kamimuria wangi Du and Cryptoperla stilifera Sivec belong to the Plecoptera, and the gene order and orientation of their mitogenomes were similar. The overall AT content for the four stoneflies was below 72%, and the AT content of tRNA genes was above 69%. The four genomes were compact and contained only 65-127bp of non-coding intergenic DNAs. Overlapping nucleotides existed in all four genomes and ranged from 24 (P. princeps) to 178bp (K. wangi). There was a 7-bp motif ('ATGATAA') of overlapping DNA and an 8-bp motif (AAGCCTTA) conserved in three stonefly species (P. princeps, K. wangi and C. stilifera). The control regions of four stoneflies contained a stem-loop structure. Four conserved sequence blocks (CSBs) were present in the A+T-rich regions of all four stoneflies. PMID- 25542809 TI - Common variations in the FTO gene and obesity in Thais: a family-based study. AB - Several studies have revealed the association between single nucleotide polymorphisms (SNPs) in the first intron of fat mass and obesity-associated (FTO) gene and obesity. To date, more than 100 SNPs in the FTO gene have been identified in various populations. Nevertheless, this association has not yet been confirmed in Thai populations. The aim of this study was to investigate whether FTO variants are associated with obesity in Thais. We analyzed ten variants in the FTO gene (rs9939609, rs9926289, rs8050136, rs9930501, rs9930506, rs9940646, rs9940128, rs1421085, rs17817449, and rs8043757) in 12 families (83 persons); composed of 12 proband cases and 71 associated family members. All participants were genotyped using polymerase chain reaction (PCR) method and DNA sequencing assay. We found significant associations between three SNPs located in the first intron of FTO gene (rs1421085, rs17817449, and rs8043757) and obesity. The odds ratios were 2.82 (95% CI, 1.16-6.90, p=0.02) for rs1421085 and rs17817449, and 3.15 (95% CI, 1.28-7.76, p=0.01) for rs8043757. Strong linkage disequilibrium among ten SNPs was observed (D'>0.8). Haplotype analysis (combination of rs1421085 (T/C), rs17817449 (T/G), and rs8043757 (A/T)) showed that the CGT haplotype is associated with an increased risk of obesity (OR, 2.42; 95% CI, 1.18-4.97; p=0.018) when compared to the reference haplotype (TTA). The SNPs rs1421085, rs17817449 and rs8043757 in the first intron of the FTO gene are associated with increasing risk of obesity in Thais. PMID- 25542810 TI - Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) +49 A>G gene polymorphism in Egyptian cases with rheumatoid arthritis. AB - BACKGROUND: The gene encoding cytotoxic T lymphocyte associated antigen-4 (CTLA 4) has been reported to be associated with rheumatoid arthritis (RA) in several ethnic populations. The aim of this work is to assess the association of this polymorphism with the susceptibility, activity and functional disability of RA in Egyptian subjects. SUBJECTS AND METHODS: This study included 112 unrelated RA Egyptian patients who were compared to 122 healthy controls from the same locality. For all subjects, DNA was genotyped for CTLA-4 +49 A>G (rs231775) polymorphism using the PCR-RFLP technique. Antibodies to cyclic citrullinated peptides (anti-CCP) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequency of the CTLA-4 G allele was significantly higher among cases compared to controls (37.1% vs. 23.4%, OR=1.93; 95% CI=1.29-2.89, p=0.002). Also, the frequency of CTLA-4 +49 G allele carriage (AG+GG genotypes) was significantly higher among cases with RA compared to controls (61.6% vs. 41.8%, OR=2.23, 95% CI=1.32-3.77, p=0.003). Logistic regression analysis showed that cases positive to the G allele (GA+GG genotypes) had less frequency of rheumatoid deformities and also a lower DAS28-CRP score, yet with a higher visual analogue scale (VAS) i.e. more functional disability than other cases. CONCLUSIONS: CTLA-4 +49 G allele carriage was associated with increased susceptibility and functional disability of RA in Egyptian patients. PMID- 25542811 TI - The effect of genetic polymorphisms of TLR2 and TLR4 in Turkish patients with coronary artery disease. AB - Coronary artery disease (CAD), being a multifactorial disease process, has been suggested to be associated by the interaction of both environmental and genetic risk factors. Toll-like receptors (TLRs) are related to the receptors of the innate immune system which serves as the recognition of the conserved pathogen motifs and the activation of the signals that stimulate inflammatory genes. In this study, we investigated the relationship between the polymorphisms in the TLR2-Arg753Gly, TLR4-Asp299Gly and Thr399Ile gene and CAD. The study population consisted of 300 patients (149 men, 151 women) with angiographically documented CAD. The polymorphisms were genotyped by real time PCR. No association between TLR2-Arg677Trp or TLR4-Asp299Gly and -Thr399Ile gene polymorphisms and the presence or the severity of CAD was observed. On the other hand, the TLR2 Arg753Arg genotype seemed to have a protective effect against development of CAD (OR=0.17; 95% CI=0.04-0.83). Our findings suggest that TLR2-Arg753Gly polymorphism is associated with CAD susceptibility in Turkish patients. PMID- 25542812 TI - Comparative transcriptomic analysis provides insights into the molecular basis of brachyurization and adaptation to benthic lifestyle in Eriocheir sinensis. AB - The development of Eriocheir sinensis from the megalopa to the first juvenile crab undergoes brachyurization and a habitat transition from pelagic to benthic lifestyle. However, the molecular mechanism of this process is poorly understood in crabs. Using next-generation RNA sequencing, we identified 22,622 annotated unigenes and 1016 differentially expressed genes especially involved in metamorphosis, sensory perception and immunity in the two stages. Among 22,622 unigenes, 169 unigenes were assigned to morphogenic pathways (i.e., Wnt, Hedgehog and hormone biosynthesis). For metamorphosis, 38 up-regulated genes in megalopae were associated with cytoskeleton construction, while, 52 up-regulated genes in juvenile were related to cuticle development and protein degradation. Several crucial genes involved in phototransduction and two olfactory-related genes were significantly up-regulated in megalopae. Moreover, 44 immunity-related genes were highly expressed in megalopae. This study provides a comprehensive view of brachyurization and benthic adaptation mechanisms in E. sinensis. PMID- 25542813 TI - Galectin-1 in injured rat spinal cord: implications for macrophage phagocytosis and neural repair. AB - Galectin (Gal)-1 is a small carbohydrate-binding protein and immune modulatory cytokine that is synthesized locally at the site of peripheral nerve injury. In this environment, Gal1 can promote regeneration of injured peripheral axons, in part by modifying the function of macrophages recruited to the site of injury. Unlike in injured peripheral nerves, macrophages do not promote axon regeneration in the injured central nervous system (CNS), perhaps because Gal1 levels are not regulated appropriately. Because the dynamics and cellular localization of endogenous Gal1 have not been rigorously characterized after CNS injury, we examined the spatio-temporal distribution of Gal1 in rat spinal cords subjected to a standardized contusion injury. Whereas Gal1 was not expressed in uninjured spinal cord, it was significantly upregulated after SCI, especially within the lesion core. Gal1 was expressed in ~40% of lesion-localized macrophages at 3-28 days post-injury (dpi), and in ~45% of astrocytes in the lesion border at 7-28 dpi. Most lesion-localized Gal1+ macrophages did not express the phagocytosis marker ED1, and Gal1+ cells contained less phagocytosed lipids. These data suggest that time- and location-dependent regulation of Gal1 by macrophages (and astrocytes) could be important for modulating phagocytosis, inflammation/gliosis, and axon growth after SCI. PMID- 25542815 TI - Does a Restricted Fluid Resuscitation Strategy Decrease Mortality in Trauma Patients? PMID- 25542814 TI - Influence of interleukin 10 polymorphisms -592 and -1082 to the HIV, HBV and HCV serostatus among intravenous drug users. AB - BACKGROUND: Interleukin 10 (IL-10) is a multifunctional cytokine produced by macrophages, monocytes, and T-helper cells. Two polymorphisms at positions -592 and -1082 have been associated with HIV susceptibility. However, their associations with susceptibility to HIV and its co-infections among intravenous drug users (IDUs) are largely unknown. METHODS: A total of 345 IDUs were recruited. Of the 173 HIV negative IDUs, 20 were classified as highly exposed HIV seronegative subjects (HESNs). A control group consisted of 496 blood donors; all HIV, HCV, and HBV negative. The IL-10-592C/A and -1082A/G were determined using TaqMan allelic discrimination assay. RESULTS: Of the IDUs, 50% were HIV positive, 89% HCV positive, 67% HBV positive and 41% had triple infection. IL-10-592C allele and -1082A allele were the most common and the -1082AG/-592CC was the most common genotype pair. All HESNs exhibited -1082A allele as compared to 81.4% of the HIV positive IDUs and 79% of donors (p=0.029 and p=0.019, respectively). None of HESNs had GG/CC genotype pair compared with 18.6% of HIV positive IDUs and 21.0% of donors (p=0.029 and p=0.019, respectively). The possession of -592AC and genotype pair AG/AC were associated with the decreased odds of HBV infection (OR=0.28; 95% CI 0.09-0.87; p=0.028 and OR=0.19; 95% CI 0.06-0.61; p=0.052, respectively). CONCLUSIONS: The presence of low producing IL-10-1082A and -592A alleles and their containing genetic variants protect highly exposed IDUs against acquisition of HIV and HBV infections. PMID- 25542816 TI - Is there any difference between the early age myocardial infarction and late age myocardial infarction in terms of psychiatric morbidity in patients who have survived acute myocardial infarction? AB - OBJECTIVE: We aimed to compare the rates of psychiatric morbidity in patients who had early age and late age MI in patients who have survived acute myocardial infarction? METHODS: One hundred sixteen patients who were hospitalized in the coronary care unit were included in the study. Psychiatric assessment of the patients was carried out within 1-6months post-MI. Psychiatric interviews were conducted with the Structured Clinical Interview for DSM-IV (SCID-I). Also used were the Beck Depression Inventory (BDI), Spielberger State-Trait Anxiety Inventory (STAI), and Health Anxiety Inventory (HAI). RESULTS: A total of 116 patients were divided into two groups according to age as an early age myocardial infarction group (EA-MI) and a late age myocardial infarction group (LA-MI). The EA-MI group included 24 patients 45years of age and under. The LA-MI group included 92 patients over 45years of age. Current psychiatric disorders, lifetime psychiatric disorders and lifetime depressive disorders were significantly more frequent in the EA-MI group than in the LA-MI group. CONCLUSION: EA-MI patients have experienced a depressive episode prior to the onset of the MI, whereas in the LA-MI group, the patients typically experienced depressive episodes after MI. Our findings suggest that depression may increase the risk of MI at an early age. PMID- 25542817 TI - Sex difference in using the SCOFF questionnaire to identify eating disorder patients at a psychiatric outpatient clinic. AB - OBJECTIVE: Patients with eating disorder (ED) often remain unrecognized in many settings. Few studies have explored the use of eating measures in an adult male population. This study aimed to examine the comparative validity of the SCOFF questionnaire for detecting ED cases in men and women in the psychiatric outpatient setting. METHOD: Psychiatric outpatients, including 605 men and 936 women, aged 18-45years, completed the paper form SCOFF and were interviewed using the ED Module of the Structured Clinical Interview for the DSM-IV-TR. A subgroup of patients completed several additional self-reported questionnaires concerning eating and general psychopathology. RESULTS: Scores of 2 and 3 on the SCOFF were the optimal cutoff values for determining ED among men (sensitivity 86% and specificity 74%) and women (sensitivity 80% and specificity 86%), respectively. While age did not significantly affect the validity indices, the SCOFF as a screening tool for ED in obese men was underperformed. CONCLUSIONS: The Mandarin Chinese version of the SCOFF is a potentially valid tool to detect ED in both genders in the psychiatric outpatient settings. By helping to detect hidden ED morbidity, the SCOFF can enhance diagnostic accuracy and facilitate comprehensive treatment among psychiatric outpatients. PMID- 25542818 TI - [Risk of rectal perforation during intention to treat laser photovaporization of prostate with transrectal ultrasound guidance: a report of 4 cases]. PMID- 25542819 TI - Long-term cryopreservation of human oocytes does not increase embryonic aneuploidy. AB - OBJECTIVE: To determine if long-term cryopreservation of human oocytes affects oocyte developmental competence, blastocyst euploidy, or live-birth rates. DESIGN: Retrospective cohort study. SETTING: University-based fertility center. PATIENT(S): A total of 33 patients with cryopreserved oocytes underwent oocyte thaw, blastocyst culture, trophectoderm biopsy, and 24-chromosome preimplantation genetic screening (PGS) with array comparative genomic hybridization between December 2011 and July 2014; subjects were compared with 2:1 age-matched controls with fresh oocytes whose embryos underwent trophectoderm biopsy and PGS during the same period. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of fertilization, blastulation, euploidy, implantation, and live birth. RESULT(S): Thirty-three patients (mean age 36.2 +/- 3.8 y) thawed 475 oocytes that had been cryopreserved for a median of 3.5 years. Compared with 66 age-matched controls who underwent in vitro fertilization and PGS with fresh oocytes, embryos derived from cryopreserved oocytes demonstrated compromised blastocyst formation (54.5% vs. 66.2%) despite no impairment in fertilization (72.8% vs. 73.2%). Results showed no difference in the number of euploid blastocysts (1.7 +/- 1.9 vs. 2 +/- 2.5), percentage of euploid blastocysts (44.5% vs. 47.6%), rate of implantation (65% vs. 65%), or rate of live birth and ongoing pregnancy (62.5% vs. 55%) after 24-chromosome PGS with cryopreserved or fresh oocytes. CONCLUSION(S): Embryos derived from cryopreserved oocytes demonstrate impaired blastulation but equivalent rates of euploidy, implantation, and live birth compared with blastocysts derived from fresh oocytes, supporting the safety and efficacy of oocyte cryopreservation. PMID- 25542820 TI - Frozen-thawed day 5 blastocyst transfer is associated with a lower risk of ectopic pregnancy than day 3 transfer and fresh transfer. AB - OBJECTIVE: To determine the ectopic pregnancy rate with fresh versus frozen thawed embryo transfers, and factors associated with ectopic pregnancy in patients undergoing IVF-ET. DESIGN: Retrospective analysis. SETTING: Institutional IVF center. PATIENT(S): A total of 3,183 patients who received 3,340 blastocysts transfers: 1,994 fresh transfers and 1,346 frozen-thawed transfers. INTERVENTION(S): Patients received fresh day 3 embryos (F-D3 group), fresh day 5 blastocysts (F-D5 group), frozen-thawed day 3 embryos (T-D3 group), or frozen-thawed day 5 or 6 blastocysts (T-D5 and T-D6 groups). MAIN OUTCOME MEASURE(S): Ectopic pregnancy rate. RESULT(S): The ectopic pregnant rates were 2.4% in the F-D3 group, 1.7% in F-D5, 1.9% in T-D3, 0.3% in T-D5, and 0.5% in T D6. The ectopic pregnant rate of the T-D3 group was significantly greater than that of the T-D5 and T-D6 groups (1.9% vs. 0.3% and 0.5%). The ectopic pregnancy rate of the F-D5 group was significantly greater than that of the T-D5 group (1.7% vs. 0.3%). CONCLUSION(S): Frozen-thawed day 5 blastocyst transfer is associated with a lower ectopic pregnancy rate than frozen-thawed day 3 transfer and fresh transfer in patients undergoing IVF-ET. PMID- 25542821 TI - Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. AB - OBJECTIVE: To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily of ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. DESIGN: Double-blind, randomized administration of two 12-week courses of ulipristal acetate. SETTING: Gynecology centers. PATIENT(S): A total of 451 patients with symptomatic uterine fibroid(s) and heavy bleeding. INTERVENTION(S): Two repeated 12-week treatment courses of daily 5 or 10 mg of ulipristal acetate. MAIN OUTCOME MEASURE(S): Amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), pain. RESULT(S): In the 5- and 10-mg treatment groups (62% and 73% of patients, respectively) achieved amenorrhea during both treatment courses. Proportions of patients achieving controlled bleeding during two treatment courses were >80%. Menstruation resumed after each treatment course and was diminished compared with baseline. After the second treatment course, median reductions from baseline in fibroid volume were 54% and 58% for the patients receiving 5 and 10 mg of ulipristal acetate, respectively. Pain and QoL improved in both groups. Ulipristal acetate was well tolerated with less than 5% of patients discontinuing treatment due to adverse events. CONCLUSION(S): Repeated 12-week courses of daily oral ulipristal acetate (5 and 10 mg) effectively control bleeding and pain, reduce fibroid volume, and restore QoL in patients with symptomatic fibroids. CLINICAL TRIAL REGISTRATION NUMBER: NCT01629563 (PEARL IV). PMID- 25542822 TI - MicroRNA-451 plays a role in murine embryo implantation through targeting Ankrd46, as implicated by a microarray-based analysis. AB - OBJECTIVE: To determine the potential microRNA (miRNA) regulators of embryo implantation, as a continuation of genomic and proteomic research. DESIGN: Laboratory animal research. SETTING: University hospital laboratory. ANIMAL(S): Adult healthy female C57BL6/J mice (age 6-8 weeks, nonfertile, weighing 18-20 g each). INTERVENTION(S): Female mice were mated naturally with fertile males to produce pregnancy. Luminal epithelium was collected by laser-capture microdissection during the implantation period. Mouse models of pseudopregnancy, delayed implantation, and artificial decidualization were established. MAIN OUTCOME MEASURE(S): The miRNA profile in luminal epithelium was clarified by microarray analysis and validated by real-time reverse transcription polymerase chain reaction (qRT-PCR) in a series of models. Target genes were predicted and confirmed by luciferase activity assay. The role of miRNA in implantation was examined by loss-of-function and gain-of-function of miRNA in vitro and in vivo. RESULT(S): A total of 29 and 15 miRNAs were up- and down-regulated, respectively, during the implantation period; 11 of these miRNAs were validated by qRT-PCR. The profile of miR-451 was clarified in a series of models. A dual-luciferase activity assay showed that Ankrd46 was a target gene of miR-451. Loss-of-function by LV-miR-451 sponge or miR-451 inhibitor led to a reduced number of embryo implantations, but had little effect on fertilization. CONCLUSION(S): miR-451 was specifically up-regulated during the implantation period, and it may play a major role in embryo implantation by targeting Ankrd46. PMID- 25542823 TI - Characterization of primary cultures of adult human epididymis epithelial cells. AB - OBJECTIVE: To establish cultures of epithelial cells from all regions of the human epididymis to provide reagents for molecular approaches to functional studies of this epithelium. DESIGN: Experimental laboratory study. SETTING: University research institute. PATIENT(S): Epididymis from seven patients undergoing orchiectomy for suspected testicular cancer without epididymal involvement. INTERVENTION(S): Human epididymis epithelial cells harvested from adult epididymis tissue. MAIN OUTCOME MEASURE(S): Establishment of a robust culture protocol for adult human epididymal epithelial cells. RESULT(S): Cultures of caput, corpus, and cauda epithelial cells were established from epididymis tissue of seven donors. Cells were passaged up to eight times and maintained differentiation markers. They were also cryopreserved and recovered successfully. Androgen receptor, clusterin, and cysteine-rich secretory protein 1 were expressed in cultured cells, as shown by means of immunofluorescence, Western blot, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The distribution of other epididymis markers was also shown by means of qRT-PCR. Cultures developed transepithelial resistance (TER), which was androgen responsive in the caput but androgen insensitive in the corpus and cauda, where unstimulated TER values were much higher. CONCLUSION(S): The results demonstrate a robust in vitro culture system for differentiated epithelial cell types in the caput, corpus, and cauda of the human epididymis. These cells will be a valuable resource for molecular analysis of epididymis epithelial function, which has a pivotal role in male fertility. PMID- 25542825 TI - Maternal and paternal indoor or outdoor smoking and the risk of asthma in their children: a nationwide prospective birth cohort study. AB - BACKGROUND: Little is known about the differential impact of combinations of parental smoking behavior (indoor or outdoor smoking, or not smoking) on preventing childhood asthma. Our objective was to examine the association between parental smoking behavior and children's asthma. METHODS: A nationally representative population-based birth cohort of 40,580 babies, aged 0.5 years in 2001 (response rate, 87.8%), was studied to estimate adjusted odds ratios of combinations of maternal and paternal indoor or outdoor smoking at home for physician visits and hospitalization for childhood asthma up to 8-years-old, and population attributable fractions. RESULTS: Odds of hospitalization for asthma among children whose father alone smokes indoors at home did not largely increase (up to 20%). However, if the mother also smokes indoors at home, the odds strongly increased. After adjusting for demographic, perinatal and socioeconomic factors, the increase in odds for children whose father and mother both smoke indoors compared to children with non-smoking parents was 54% (95% confidence interval: 21-96%), 43% (8-90%) and 72% (22-143%) for children aged 0.5<-2.5, 2.5< 4.5 and 4.5<-8 years-old, respectively. The odds ratios of smoking outdoors did not largely differ from those of smoking indoors. Our estimation of population attributable fractions revealed that if all parents in Japan quit smoking, hospitalization of children for asthma could be reduced by 8.3% (2.2-14.3%), 9.3% (0.9-17.6%) and 18.2% (7.7-28.8%), respectively. CONCLUSIONS: Parental indoor smoking at home increased and exacerbated children's asthma. Smoking at home, whether it is indoors or outdoors, may increase the risks for asthma attacks of their children. PMID- 25542824 TI - Mediators of a smoking cessation intervention for persons living with HIV/AIDS. AB - BACKGROUND: Cigarette smoking among persons living with HIV (PLWH) is a pressing public health concern, and efforts to evaluate cessation treatments are needed. The purpose of the present study was to assess potential mechanisms of a cell phone-delivered intervention for HIV-positive smokers. METHODS: Data from 350 PLWH enrolled in a randomized smoking cessation treatment trial were utilized. Participants were randomized to either usual care (UC) or a cell phone intervention (CPI) group. The independent variable of interest was treatment group membership, while the dependent variable of interest was smoking abstinence at a 3-month follow-up. The hypothesized treatment mechanisms were depression, anxiety, social support, quit motivation and self-efficacy change scores. RESULTS: Abstinence rates in the UC and CPI groups were 4.7% (8 of 172) and 15.7% (28 of 178), respectively. The CPI group (vs. UC) experienced a larger decline in depression between baseline and the 3-month follow-up, and a decline in anxiety. Self-efficacy increased for the CPI group and declined for the UC group. Quit motivation and social support change scores did not differ by treatment group. Only self-efficacy met the predefined criteria for mediation. The effect of the cell phone intervention on smoking abstinence through change in self-efficacy was statistically significant (p<0.001) and accounted for 17% of the total effect of the intervention on abstinence. CONCLUSIONS: The findings further emphasize the important mechanistic function of self-efficacy in promoting smoking cessation for PLWH. Additional efforts are required to disentangle the relationships between emotional, distress motivation, and efficacious smoking cessation treatment. PMID- 25542826 TI - Baseline serum beta-carotene concentration and mortality among long-term asbestos exposed insulators. AB - BACKGROUND: Although interventional trials demonstrated that moderate-dose beta carotene supplementation increases lung cancer mortality in smokers and asbestos exposed workers, differences in serum concentrations in absence of supplementation have not been studied in asbestos-exposed workers. METHODS: A mortality analysis was performed to assess the relationship of nonsupplemented serum beta-carotene to all-cause and cancer mortalities using 1981 to 1983 serum beta-carotene concentration measurements from 2,646 U.S. white male insulators (mean age, 57.7 years). Multivariable-adjusted Cox proportional hazard models that included terms for age, duration of asbestos exposure, smoking, season, and region were fitted to estimate mortality HRs and 95% confidence intervals (CI) according to serum beta-carotene concentrations. RESULTS: Median follow-up was 12.8 years and 984 (33.8%) subjects died during the follow-up period, including 415 deaths from overall cancer and 219 deaths from lung cancer. The overall mortality HR for a serum beta-carotene increase of 10 MUg/dL was 0.97 (95% CI, 0.96-0.99). Compared with the lowest quartile, HRs were 0.90 (95% CI, 0.76-1.07) for the second (38-65 MUg/dL), 0.80 (95% CI, 0.67-0.96) for the third (66-104 MUg/dL), and 0.63 (95% CI, 0.51-0.77) for the highest serum beta-carotene quartile (>=105 MUg/dL). There was no association between serum beta-carotene and overall cancer mortality (HR, 1.00; 95% CI, 0.97-1.02) or lung cancer mortality (HR, 0.99; 95% CI, 0.96-1.02). CONCLUSIONS: Higher nonsupplemented serum beta carotene concentrations were negatively associated with all-cause mortality among asbestos-exposed individuals. IMPACT: Serum beta-carotene can be a marker of one or more determinants of reduced mortality in asbestos-exposed workers. Cancer Epidemiol Biomarkers Prev; 24(3); 555-60. (c)2014 AACR. PMID- 25542827 TI - Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. AB - BACKGROUND: Results of the Multiethnic Cohort (MEC) study demonstrated that, for the same quantity of cigarettes smoked, African Americans and Native Hawaiians have a higher risk of lung cancer compared with whites, whereas Latinos and Japanese Americans have a lower risk. We hypothesize that the uptake and/or metabolism of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) could explain the differences in lung cancer risk. METHODS: We measured urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides and their sum (total NNAL), biomarkers of NNK uptake, in 2,252 smokers from the MEC. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, creatinine and total nicotine equivalents, a marker of total nicotine uptake. RESULTS: African Americans had the highest median total NNAL levels (1.80 pmol/mL urine) and Japanese Americans had the lowest (0.914 pmol/mL urine), with intermediate values in the other three groups. Geometric mean of total NNAL in African Americans was also highest, and in Japanese Americans it was lowest; Japanese American geometric mean was statistically different from whites (P = 0.004). CONCLUSIONS: African Americans had higher levels of total NNAL per mL urine than whites, while Japanese Americans had lower levels, consistent with lung cancer risk among smokers in these groups. However, our data were not consistent with the high and low lung cancer risks of Native Hawaiian and Latino smokers, respectively. IMPACT: The higher lung cancer susceptibility of African-American smokers and the lower susceptibility of Japanese-American smokers compared with whites can be explained in part by exposure to the potent lung carcinogen NNK. Cancer Epidemiol Biomarkers Prev; 24(3); 561-9. (c)2014 AACR. PMID- 25542828 TI - Vitamin D-associated genetic variation and risk of breast cancer in the breast and prostate cancer cohort consortium (BPC3). AB - BACKGROUND: Two recent genome-wide association studies (GWAS) identified SNPs in or near four genes related to circulating 25-hydroxyvitamin D [25(OH)D] concentration. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. METHODS: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. RESULTS: We found no association between any of the four SNPs or their polygenic score and breast cancer risk. CONCLUSIONS: Our findings do not support an association between vitamin D status, as reflected by 25(OH)D-related genotypes, and breast cancer risk. IMPACT: These findings may contribute to future meta-analyses and scientific review articles, and provide new data about the association between vitamin D-related genes and breast cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 627-30. (c)2014 AACR. PMID- 25542829 TI - Lag times between lymphoproliferative disorder and clinical diagnosis of chronic lymphocytic leukemia: a prospective analysis using plasma soluble CD23. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is a chronic disease that often progresses slowly from a precursor stage, monoclonal B-cell lymphocytosis (MBL), and that can remain undiagnosed for a long time. METHODS: Within the European Prospective Investigation into Cancer cohort, we measured prediagnostic plasma sCD23 for 179 individuals who eventually were diagnosed with CLL and an equal number of matched control subjects who remained free of cancer. RESULTS: In a very large proportion of CLL patients' plasma sCD23 was clearly elevated 7 or more years before diagnosis. Considering sCD23 as a disease predictor, the area under the ROC curve (AUROC) was 0.95 [95% confidence interval (CI), 0.90-1.00] for CLL diagnosed within 0.1 to 2.7 years after blood measurement, 0.90 (95% CI, 0.86-0.95) for diagnosis within 2.8 to 7.3 years, and 0.76 (95% CI, 0.65-0.86) for CLL diagnosed between 7.4 and 12.5 years. Even at a 7.4-year and longer time interval, elevated plasma sCD23 could predict a later clinical diagnosis of CLL with 100% specificity at >45% sensitivity. CONCLUSIONS: Our findings provide unique documentation for the very long latency times during which measurable B cell lymphoproliferative disorder exists before the clinical manifestation of CLL. IMPACT: Our findings have relevance for the interpretation of prospective epidemiologic studies on the causes of CLL in terms of reverse causation bias. The lag times indicate a time frame within which an early detection of CLL would be theoretically possible. Cancer Epidemiol Biomarkers Prev; 24(3); 538-45. (c)2014 AACR. PMID- 25542831 TI - Plasma isoflavones and risk of primary liver cancer in Japanese women and men with hepatitis virus infection: a nested case-control study. AB - BACKGROUND: Evidence suggests that estrogen plays a preventive role in primary liver cancer development, and it might be thought that isoflavones, which are structurally similar to estrogens and bind to estrogen receptors, are associated with the risk of liver cancer. We investigated this suspected association by measuring plasma concentrations of isoflavones in a nested case-control study of a population-based prospective cohort in Japan. METHODS: From 18,628 target participants ages 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B or hepatitis C virus infection at baseline (n = 1,544). Among these, 90 (28 women and 62 men) were newly diagnosed with primary liver cancer from 1993 through 2006; they were matched with 175 controls (54 women and 121 men). Plasma concentrations of isoflavones (genistein, daidzein, glycitein, and equol) were measured using triple quadrupole tandem liquid chromatography-mass spectrometry. The ORs of liver cancer development based on plasma concentrations were estimated with a conditional logistic regression model. RESULTS: Basically, distributions of plasma isoflavone concentrations did not differ between the cases and controls. No statistically significant associations of genistein, daidzein, glycitein, and equol with primary liver cancer risk were found in either women or men. CONCLUSIONS: In middle-aged Japanese women and men with hepatitis virus infection, plasma isoflavones were unassociated with the occurrence of primary liver cancer. IMPACT: The role of isoflavones in liver carcinogenesis merits further study using both biomarkers and data on dietary intake of isoflavones. Cancer Epidemiol Biomarkers Prev; 24(3); 532-7. (c)2014 AACR. PMID- 25542832 TI - Child sexual abuse as reported by Israeli adolescents: social and health related correlates. AB - The objectives of the study were to assess the prevalence of child sexual abuse (CSA) in a nation-wide representative sample of 14-17 year old Israeli adolescents, and to examine the associations between CSA, socio-demographic correlates and various measures of physical and mental health. The study population consisted of 906 mother-adolescent dyads, belonging to a community based, representative sample of Israeli 14-17 year olds, interviewed in 2004-5. Response rate was 68%. Subjects provided demographic data, and information about CSA, physical symptoms, body image, well-being and use of mental health services. DAWBA was used to obtain information regarding mental disorders and suicidality. SDQ was used to obtain data on bullying. Statistical analyses were conducted using an SPSS-17 complex sample analysis module and multivariate analyses were conducted to assess the associations between CSA and risk factors and social and health related correlates. Findings show that CSA was reported by 3.3% of adolescents. Higher risk of exposure to CSA was found among girls, among adolescents living in a one-parent household and among adolescents with a chronic disability. In multivariate models adjusting for gender, learning disabilities and depression, CSA was associated with suicidal attempts, stomach ache, dizziness, sleep problems, well being at home and bullying behaviors. No association was found with suicidal ideation or other physical symptoms. Our findings confirm that the associations between CSA and different outcomes vary depending on the socio-psychological context, and underline the importance of addressing the complexity of variables associated with CSA. PMID- 25542830 TI - Enterolignan-producing phenotypes are associated with increased gut microbial diversity and altered composition in premenopausal women in the United States. AB - BACKGROUND: Lignans in plant foods are metabolized by gut bacteria to the enterolignans, enterodiol (END) and enterolactone (ENL). Enterolignans have biologic activities important to the prevention of cancer and chronic diseases. We examined the composition of the gut microbial community (GMC) as a contributor to human enterolignan exposure. METHODS: We evaluated the association between the GMC in stool, urinary enterolignan excretion, and diet from a 3-day food record in 115 premenopausal (ages 40-45 years) women in the United States. Urinary enterolignans were measured using gas chromatography-mass spectroscopy. The GMC was evaluated using 454 pyrosequencing of the 16S rRNA gene. Sequences were aligned in SILVA (www.arb-silva.de). Operational taxonomic units were identified at 97% sequence similarity. Taxonomic classification was performed and alpha and beta diversity in relationship to ENL production were assessed. Multivariate analysis and regression were used to model the association between enterolignan excretion and the GMC. Bacteria associated with ENL production were identified using univariate analysis and ridge regression. RESULTS: After adjusting for dietary fiber intake and adiposity, we found a significant positive association between ENL excretion and either the GMC (P = 0.0007), or the diversity of the GMC (P = 0.01). The GMC associated with high ENL production was distinct (UNIFRAC, P < 0.003, MRPP) and enriched in Moryella spp., Acetanaerobacterium spp., Fastidiosipila spp., and Streptobacillus spp. CONCLUSION: Diversity and composition of the GMC are associated with increased human exposure to enterolignans. IMPACT: Differences in gut microbial diversity and composition explain variation in gut metabolic processes that affect environmental exposures and influence human health. Cancer Epidemiol Biomarkers Prev; 24(3); 546-54. (c)2014 AACR. PMID- 25542833 TI - Is intra-articular hyaluronic acid effective in treating osteoarthritis of the hip joint? AB - Hyaluronic acid (HA) injections are used to treat osteoarthritis of the hip but their efficacy has not been clearly established. The purpose of this meta analysis was to determine the effect of HA injections on hip pain. There were twenty-three studies that met our criteria and the mean decrease in visual analog scores (VAS) was -1.97 (95% CL, 2.83 to -1.12, P<0.0001). However, the clinical relevance of this change is difficult to determine since the decrease in VAS was only -0.27 in the six randomized trials in the study and the duration of follow up in most studies was less than six months. Multicenter randomized trials are needed to determine the true efficacy of HA injections in decreasing pain associated with hip osteoarthritis. PMID- 25542834 TI - Intra-sample heterogeneity of sperm DNA methylation. AB - The study of sperm epigenetics is challenging and limited largely to sperm population estimates rather than individual spermatozoa. While this type of approach is likely sufficient for most somatic cell lines, it is problematic in a tissue where a single cell is disproportionality influential. Furthermore, we know very little about the epigenetic variability between different sperm from the same ejaculate. Thus, it is essential that we better understand the heterogeneity of sperm epigenetic marks within an ejaculate. In this study, we have performed sperm genome-wide DNA methylation analyses on single ejaculates from 20 individuals. Sperm samples were subjected to gradient separation, following which the 90% layer ('high-quality sperm') and the 35% layer ('low quality sperm') were isolated and analyzed separately using the Illumina 450K methylation array. We did not identify any single CpG that was differentially methylated between the two fractions. In contrast, we did identify 772 significant regional methylation alterations between the two layers. Coefficient of variance analysis also revealed that, in addition to having multiple sites that appear to be differentially methylated, the 35% layer sperm population, as a whole, displayed significantly higher variability in DNA methylation than did the 90% layer. In conclusion, while the two sperm populations analyzed here do not appear to be entirely distinct, those sperm that are generally considered to be of 'poor-quality' display some consistent regions of alteration and, more strikingly, demonstrate more heterogeneity than sperm considered to be of more normal quality. PMID- 25542835 TI - Identification of a human subcortical maternal complex. AB - Maternal effect genes play essential roles in early embryonic development. However, the mechanisms by which maternal effect genes regulate mammalian early embryonic development remain largely unknown. Recently, we identified a subcortical maternal complex (SCMC) that is composed of at least four proteins encoded by Mater, Floped, Tle6 and Filia and is critical for mouse preimplantation development. The present study demonstrates that human SCMC homologous genes (NLRP5, OOEP, TLE6 and KHDC3L) are specifically expressed in the oocytes of human fetal ovaries. The proteins of this complex co-localize in the subcortex of human oocytes and early embryos. Furthermore, the SCMC proteins physically interact with each other when they are co-expressed in cell lines. These results indicate that human NLRP5, OOEP, TLE6 and KHDC3L function as a complex in the oocytes and early embryos of Homo sapiens. Considering the important roles of the SCMC in mouse early embryogenesis, the characterization of the human SCMC will provide a basis for investigating human early embryonic development and will have clinical implications in human female infertility or recurrent spontaneous abortion. PMID- 25542837 TI - What's in a Name? Evaluating the Effects of the "Sex Offender" Label on Public Opinions and Beliefs. AB - Particularly over the past two decades, the terms sex offender and juvenile sex offender (JSO) have attained increasingly common usage in media and public policy discourse. Although often applied as factual descriptors, the labels may evoke strong subconscious associations with a population commonly presumed to be compulsive, at high risk of re-offense, and resistant to rehabilitation. Such associations, in turn, may exert considerable impact on expressions of support for certain policies as well as public beliefs and opinions about adults and youth who have perpetrated sexual offenses. The current study systematically evaluated the impact of the "sex offender" and "JSO" labels through series of items administered to a nationally stratified and matched sample from across the United States. The study employed an experimental design, in which one group of participants (n = 498) ranked their levels of agreement with a series of statements utilizing these labels, and a control group (n = 502) responded to a matched set of statements substituting the labels with more neutral descriptive language. Findings support the hypothesis that use of the "sex offender" label strengthens public support for policies directed at those who have perpetrated sexual crimes, including public Internet disclosure, residency restrictions, and social networking bans. The "JSO" label is demonstrated to produce particularly robust effects, enhancing support for policies that subject youth to public Internet notification and affecting beliefs about youths' propensity to re-offend as adults. Implications for public policy, media communication, and research are explored and discussed. PMID- 25542836 TI - Overexpression of the truncated form of High Mobility Group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation. AB - The pathogenesis of uterine leiomyomas, the most common benign tumor in women, is still unknown. This lack of basic knowledge limits the development of novel non invasive therapies. Our group has previously demonstrated that leiomyoma side population (SP) cells are present in tumor lesions and act like putative tumor initiating stem cells in human leiomyoma. Moreover, accumulated evidence demonstrates that these benign tumors of mesenchymal origin are characterized by rearrangements of the High Mobility Group A proteins (HMGA). In this work, we tested the hypothesis that leiomyoma development may be due to overexpression of HMGA2 (encoding high mobility group AT-hook2) in myometrial stem cells using in vitro and in vivo approaches. Our work demonstrates that the truncated/short form of HMGA2 induces myometrial cell transformation toward putative tumor-initiating leiomyoma cells and opens up new possibilities to understand the origin of leiomyomas and the development of new therapeutic approaches. PMID- 25542839 TI - Rapid detection of diagnostic targets using isothermal amplification and HyBeacon probes--a homogenous system for sequence-specific detection. AB - Isothermal amplification is a rapid, simple alternative to PCR, with amplification commonly detected using fluorescently labelled oligonucleotide probes, intercalating dyes or increased turbidity as a result of magnesium pyrophosphate generation. SNP identification is possible but requires either allele-specific primers or multiple dye-labelled probes, but further downstream processing is often required for allelic identification. Here we demonstrate that modification of common isothermal amplification methods by the addition of HyBeacon probes permits homogeneous sequence detection and discrimination by melting or annealing curve analysis. Furthermore, we demonstrate that isothermal amplification and sequence discrimination is possible directly from a crude sample such as an expressed buccal swab. PMID- 25542838 TI - Impact of Comorbidities on Prostate Cancer Stage at Diagnosis in Florida. AB - To examine the association of major types of comorbidity with late-stage prostate cancer, a random sample of 11,083 men diagnosed with prostate cancer during 2002 2007 was taken from the Florida Cancer Data System. Individual-level covariates included demographics, primary insurance payer, and comorbidity following the Elixhauser Index. Socioeconomic variables were extracted from Census 2000 data and merged to the individual level data. Provider-to-case ratio at county level was alsocomputed. Multilevel logistic regression was used to assess associations between these factors and late-stage diagnosis of prostate cancer. Higher odds of late-stage diagnosis was significantly related to presence of comorbidities, being unmarried, current smoker, uninsured, and diagnosed in not-for-profit hospitals. The study reported that the presence of certain comorbidities, specifically 10 out of the 45, was associated with late-stage prostate cancer diagnosis. Eight out of 10 significant comorbid conditions were associated with greater risk of being diagnosed at late-stage prostate cancer. On the other hand, men who had chronic pulmonary disease, and solid tumor without metastasis, were less likely to be diagnosed with late-stage prostate cancer. Late-stage diagnosis was associated with comorbidity, which is often associated with increased health care utilization. The association of comorbidity with late-stage prostate cancer diagnosis suggests that individuals with significant comorbidity should be offered routine screening for prostate cancer rather than focusing only on managing symptomatic health problems. PMID- 25542840 TI - LNA probe-based assay for the detection of Tomato black ring virus isolates. AB - Tomato black ring virus (TBRV) infects a wide range of economically important plant species worldwide. In the present study we developed a locked nucleic acid (LNA) real-time RT-PCR assay for accurate detection of genetically diverse TBRV isolates collected from different hosts. The assay based on the LNA probe has a wide detection range, high sensitivity, stability and amplification efficiency. The assay amplified all tested TBRV isolates, but no signal was observed for the RNA from other nepoviruses and healthy plant species. Under optimum reaction conditions, the detection limit was estimated around 17 copies of the TBRV target region in total RNA. Real-time RT-PCR with the LNA probe described in this paper will serve as a valuable tool for robust, sensitive and reliable detection of TBRV isolates. PMID- 25542841 TI - Selection of lactic acid bacteria from Brazilian kefir grains for potential use as starter or probiotic cultures. AB - Brazilian kefir is a homemade fermented beverage that is obtained by incubating milk or a brown sugar solution with kefir grains that contribute their different microbiological compositions. It is highly important to isolate and characterize microorganisms from Brazilian kefir grains to obtain starter cultures for the industrial production of a standardized commercial kefir. Thus, the present study aimed to isolate lactic acid bacteria from eight kefir grains that were propagated in milk or sugar solutions from five different locations in Brazil and to select Lactobacillus isolates based on desirable in vitro probiotic properties. One hundred eight isolates from both substrates were identified by amplified ribosomal DNA restriction analysis and/or 16S rRNA gene sequencing and were determined to belong to the following 11 species from the genera: Lactococcus, Leuconostoc, Lactobacillus (L.), and Oenococcus. Leuconostoc mesenteroides, Lactobacillus kefiri, and Lactobacillus kefiranofaciens were isolated only from milk grains, whereas Lactobacillus perolens, Lactobacillus parafarraginis, Lactobacillus diolivorans, and Oenococcus oeni were isolated exclusively from sugar water grains. When the microbial compositions of four kefir grains were evaluated with culture-independent analyses, L. kefiranofaciens was observed to predominant in milk grains, whereas Lactobacillus hilgardii was most abundant in sugar water kefir. Unfortunately, L. hilgardii was not isolated from any grain, although this bacteria was detected with a culture-independent methodology. Fifty-two isolated Lactobacilli were tested for gastric juice and bile salt tolerance, antagonism against pathogens, antimicrobial resistance, and surface hydrophobicity. Three Lactobacillus strains (L. kefiranofaciens 8U, L. diolivorans 1Z, and Lactobacillus casei 17U) could be classified as potential probiotics. In conclusion, several lactic acid bacteria that could be used in combination with yeasts as starter cultures for both milk kefir and sugar water kefir were characterized, and the functional properties of several of the lactobacilli isolated from the kefir grains were suggestive of their possible use as probiotics in both kefir and other dairy products. PMID- 25542843 TI - Adrenal cortex tissue homeostasis and zonation: A WNT perspective. AB - The adrenal cortex plays essential roles in the control of sodium and water homeostasis, stress response, inflammation and metabolism, through secretion of glucocorticoids and mineralocorticoids. Coordinated production of these hormones relies on functional zonation of the cortex, characterised by expression of Cyp11b2 under the control of angiotensin II and plasma potassium level in zona glomerulosa (ZG) and Cyp11b1 under the control of ACTH in zona fasciculata (ZF). The mechanisms involved in the establishment of functional zonation and its maintenance during centripetal cortex cell renewal are still poorly understood. Here, we hypothesise that the hormonal and signalling pathways that control adrenal cortex function are also involved in cortical zonation. In particular, we summarise evidence on the role of WNT/beta-catenin signalling in ZG differentiation and how tight control of its activity is required to shape the adult cortex. In this context, we discuss the potential role of known WNT regulators and the possibility of a reciprocal cross-talk between PKA and WNT signalling. PMID- 25542842 TI - Induction of apoptosis in Caco-2 cells by exogenously added O2- produced by a nanodevice. AB - The effects of reactive oxygen species on cells have attracted considerable attention in relation to oxidative stress and related disorders. Superoxide (O2( )) is the primary reactive oxygen species formed in animals as a byproduct or purposeful product of enzymes. We recently established an O2(-)-generating nanodevice that produces O2(-) continuously even in culture medium, by improving an original nanodevice. The new nanodevice, named Device II, efficiently induced cell death in Caco-2 cells in a time- and dose-dependent manner. Catalase largely recovered the cell viability, while superoxide dismutase rather lowered the viability. Flow cytometric and fluorescence microscopic analyses revealed that phosphatidylserine was exposed on the cells and that caspase-3 was activated in the cells after treatment with Device II. These findings indicated that exogenously added O2(-) caused apoptosis in Caco-2 cells through its derivative H2O2. PMID- 25542844 TI - Introduction to the 2014 Adrenal Cortex Conference Keith L. Parker Memorial Lecturer: Bernard Schimmer, Ph.D. PMID- 25542845 TI - 11beta-Hydroxyandrostenedione: Downstream metabolism by 11betaHSD, 17betaHSD and SRD5A produces novel substrates in familiar pathways. AB - 11beta-Hydroxyandrostenedione (11OHA4), a major C19 steroid produced by the adrenal, was first reported in the 1950s. Initially the subject of numerous studies, interest dwindled due to the apparent lack of physiological function and, by the end of the century, 11OHA4 was no longer considered as an adrenal C19 steroid. Our recent studies, however, showed that 11OHA4 is the precursor to novel active androgens which include 11-ketodihydrotestosterone (11KDHT) which has been implicated in prostate cancer, thereby renewing interest in 11OHA4. In this paper we review the biosynthesis and downstream metabolism of 11OHA4. We discuss the extra-adrenal biosynthesis of 11OHA4 in humans and in other species, highlighting the well-documented role of 11OHA4 in the testes of male fish in which the steroid functions as an active androgen. Finally, we discuss the physiological relevance of 11OHA4 metabolism in castration resistant prostate cancer and outline future prospects. PMID- 25542846 TI - The binding site specificity of STARD4 subfamily: Breaking the cholesterol paradigm. AB - Steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain proteins display diverse expression patterns and cellular localisations. They bind a large variety of lipids and sterols and are involved in lipid metabolism, lipid transfer and cell signalling. The START domain tertiary structure is an alpha-helix/beta-grip fold module of approximately 210 amino acids delimiting an internal cavity forming the binding site. However, the determinants that dictate ligand specificity and the mechanism of ligand entry and exit are ill-defined. Herein, we review and discuss the current knowledge on ligand specificity and binding mechanism of START domains. More specifically, we highlight that the conserved residues of STARD1, STARD3, STARD4, STARD5 and STARD6 START domains binding sterol play an important structural role for the global protein fold, whereas the residues forming the cavity that fits the shape of their respective ligand are divergent, suggesting their participation in ligand specificity. We also explore the potential binding of steroids to STARD6 in the context of ligand selectivity. PMID- 25542847 TI - Differential regulation of kit ligand A (kitlga) expression in the zebrafish ovarian follicle cells--evidence for the existence of a cyclic adenosine 3', 5' monophosphate-mediated binary regulatory system during folliculogenesis. AB - Kit ligand (Kitl) is an important paracrine factor involved in the activation of primordial follicles from the quiescent pool and in the maintenance of meiotic arrest before germinal vesicle breakdown (GVBD). It has been reported that follicle-stimulating hormone (FSH) stimulates but luteinizing hormone (LH) suppresses the expression of Kitl in the granulosa cells in mammals. Considering that both gonadotropins signal in the follicle cells mainly by activating cyclic adenosine 3', 5'-monophosphate (cAMP) pathway, we are intrigued by how cAMP differentially regulates Kitl expression. In the present study, we demonstrated that both human chorionic gonadotropin (hCG) and pituitary adenylate cyclase activating polypeptide (PACAP) inhibited insulin-like growth factor I (IGF-I) induced Akt phosphorylation and kitlga expression in the zebrafish follicle cells. Further experiments showed that cAMP was involved in regulating the expression of kitlga. However, two cAMP-activated effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), had converse effects. PKA promoted whereas Epac inhibited the expression of kitlga, as demonstrated by the respective activators. Interestingly, cAMP also appeared to exert differential effects on kitlga expression at different stages of follicle development during folliculogenesis, significantly stimulating kitlga expression at the early growth stage but suppressing it at the full-grown stage before final oocyte maturation, implying a potential mechanism for differential effects of the same pathway at different stages. The inhibitory effect of forskolin (activator of adenylate cyclase) and H89 (inhibitor of PKA) on IGF-I-induced expression of kitlga suggested cross-talk between the cAMP and IGF-I-activated PI3K-Akt pathways. This study, together with our previous findings on IGF-I regulation of kitlga expression, provides important clues to the underlying mechanism that regulates Kit ligand expression during folliculogenesis in the ovary. PMID- 25542848 TI - Obesity and cardiopulmonary bypass-associated acute kidney injury: authors' reply. PMID- 25542849 TI - Design of homo-organic acid producing strains using multi-objective optimization. AB - Production of homo-organic acids without byproducts is an important challenge in bioprocess engineering to minimize operation cost for separation processes. In this study, we used multi-objective optimization to design Escherichia coli strains with the goals of maximally producing target organic acids, while maintaining sufficiently high growth rate and minimizing the secretion of undesired byproducts. Homo-productions of acetic, lactic and succinic acids were targeted as examples. Engineered E. coli strains capable of producing homo-acetic and homo-lactic acids could be developed by taking this systems approach for the minimal identification of gene knockout targets. Also, failure to predict effective gene knockout targets for the homo-succinic acid production suggests that the multi-objective optimization is useful in assessing the suitability of a microorganism as a host strain for the production of a homo-organic acid. The systems metabolic engineering-based approach reported here should be applicable to the production of other industrially important organic acids. PMID- 25542850 TI - Characterizing metabolic pathway diversification in the context of perturbation size. AB - Cell metabolism is an important platform for sustainable biofuel, chemical and pharmaceutical production but its complexity presents a major challenge for scientists and engineers. Although in silico strains have been designed in the past with predicted performances near the theoretical maximum, real-world performance is often sub-optimal. Here, we simulate how strain performance is impacted when subjected to many randomly varying perturbations, including discrepancies between gene expression and in vivo flux, osmotic stress, and substrate uptake perturbations due to concentration gradients in bioreactors. This computational study asks whether robust performance can be achieved by adopting robustness-enhancing mechanisms from naturally evolved organisms-in particular, redundancy. Our study shows that redundancy, typically perceived as a ubiquitous robustness-enhancing strategy in nature, can either improve or undermine robustness depending on the magnitude of the perturbations. We also show that the optimal number of redundant pathways used can be predicted for a given perturbation size. PMID- 25542852 TI - Circulating tumor cell enumeration by the CellSearch system: the clinician's guide to breast cancer treatment? AB - Circulating tumor cells (CTCs) are cancer cells that are present in the blood of patients with solid cancers and are shed from existing tumor lesions into the blood stream. The enumeration of CTCs has long been considered to hold great promise in guiding treatment decision-making in breast cancer patients. However, guidelines on how to use CTC enumeration in clinical decision-making in primary breast cancer and metastatic breast cancer are lacking. Here, we set out to review the most relevant literature to date, to ultimately come to general recommendations regarding the use of CTC enumeration in primary breast cancer and metastatic breast cancer. PMID- 25542851 TI - Dynamic knockdown of E. coli central metabolism for redirecting fluxes of primary metabolites. AB - Control of native enzyme levels is important when optimizing strains for overproduction of heterologous compounds. However, for many central metabolic enzymes, static knockdown results in poor growth and protein expression. We have developed a strategy for dynamically modulating the abundance of native enzymes within the host cell and applied this to a model system for myo-inositol production from glucose. This system relies on controlled degradation of a key glycolytic enzyme, phosphofructokinase-I (Pfk-I). Through tuning Pfk-I levels, we have been able to develop an Escherichia coli strain with a growth mode close to wild type and a production mode with an increased glucose-6-phosphate pool available for conversion into myo-inositol. The switch to production mode is trigged by inducer addition, allowing yield, titer, and productivity to be managed through induction time. By varying the time of Pfk-I degradation, we were able to achieve a two-fold improvement in yield and titers of myo-inositol. PMID- 25542853 TI - Clinical information systems end user satisfaction: the expectations and needs congruencies effects. AB - Prior research on information systems (IS) shows that users' attitudes and continuance intentions are associated with their satisfaction with information systems. As such, the increasing amount of investments in clinical information systems (CIS) signifies the importance of understanding CIS end users' (i.e., clinicians) satisfaction. In this study, we develop a conceptual framework to identify the cognitive determinants of clinicians' satisfaction formation. The disconfirmation paradigm serves as the core of the framework. The expectations and needs congruency models are the two models of this paradigm, and perceived performance is the basis of the comparisons in the models. The needs and expectations associated with the models are also specified. The survey methodology is adopted in this study to empirically validate the proposed research model. The survey is conducted at a public hospital and results in 112 and 203 valid responses (56% and 98% response rates) from doctors and nurses respectively. The partial least squares (PLS) method is used to analyze the data. The results of the study show that perceived CIS performance is the most influential factor on clinicians' (i.e., doctors and nurses) satisfaction. Doctors' expectations congruency is the next significant determinant of their satisfaction. Contrary to most previous findings, nurses' expectations and expectations congruency do not show a significant effect on their satisfaction. However, the needs congruency is found to significantly affect nurses' satisfaction. PMID- 25542854 TI - Insights into the molecular foundations of electrical excitation. PMID- 25542855 TI - Transplantation: a brief history. AB - Developments in transplantation have progressed dramatically over the past century. Current research is underway to optimize immune modulation, genetically engineering animals for xenografting, and breakthroughs are occurring in regenerative medicine. However, pioneering live-donor transplantation has transformed transplantation in the organ shortage, and these contribute an increased proportion of transplanted organs. Live-donor transplantation is associated with better long-term outcomes, and techniques to recover organs have become less invasive. We set out to examine the evolution of transplantation from its historic beginnings to the developments that make it successful today. PMID- 25542856 TI - Cohesin modulates transcription of estrogen-responsive genes. AB - The cohesin complex has essential roles in cell division, DNA damage repair and gene transcription. The transcriptional function of cohesin is thought to derive from its ability to connect distant regulatory elements with gene promoters. Genome-wide binding of cohesin in breast cancer cells frequently coincides with estrogen receptor alpha (ER), leading to the hypothesis that cohesin facilitates estrogen-dependent gene transcription. We found that cohesin modulates the expression of only a subset of genes in the ER transcription program, either activating or repressing transcription depending on the gene target. Estrogen responsive genes most significantly influenced by cohesin were enriched in pathways associated with breast cancer progression such as PI3K and ErbB1. In MCF7 breast cancer cells, cohesin depletion enhanced transcription of TFF1 and TFF2, and was associated with increased ER binding and increased interaction between TFF1 and its distal enhancer situated within TMPRSS3. In contrast, cohesin depletion reduced c-MYC mRNA and was accompanied by reduced interaction between a distal enhancer of c-MYC and its promoters. Our data indicates that cohesin is not a universal facilitator of ER-induced transcription and can even restrict enhancer-promoter communication. We propose that cohesin modulates transcription of estrogen-dependent genes to achieve appropriate directionality and amplitude of expression. PMID- 25542857 TI - Empowerment an essential ingredient in the clinical environment: a review of the literature. AB - Empowerment is an important concept worthy of attention in healthcare. The merits of empowerment are irrefutable including benefits to the organisation and to the individual nurse. Empowered nurses contribute to the clinical learning environment in a positive way. There is a dearth of literature on how or indeed if nursing students are empowered. The process of empowering registered staff/nursing students is not clear. Ward environment and culture are important contributors to patient care, patient safety and staff well-being. It is therefore necessary to address how empowerment can contribute positively to improving the environment in which care is provided. PMID- 25542858 TI - Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens. AB - Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5 mg/kg), the 5-HT2C antagonist SB 242084 (SB, 2 mg/kg), or Cit + SB, and the effect on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis. In a separate experiment, animals were treated with vehicle, Cit (20 mg/kg/d), SB (2 mg/kg/d) or Cit + SB for a period of 2 days (s.c.), and the impact on the release of 5-HT and DA in the ventral tegmental area (VTA) and NAcc was studied. On the day of microdialysis, 5-HT2C receptor sensitivity was assessed with an SB challenge. Acutely administered Cit + SB increased 5-HT release in the NAcc more than Cit alone. SB alone increased DA release in the NAcc (not in the VTA), but when administered together with Cit, this effect was abolished. A 2-day treatment with Cit or Cit + SB increased 5-HT release in both VTA and NAcc. Combining Cit with SB augmented the effect of Cit in the VTA. DA release in VTA and NAcc was only significantly increased after 2 days of treatment with Cit + SB. In conclusion, Cit + SB had synergistic effects on 5-HT and DA release after 2-days of treatment, probably related to a decreased tonic inhibition of DA release via 5-HT2C receptors. Regional differences occur and future studies should elucidate if this augmentation strategy is beneficial at the behavioral level. PMID- 25542859 TI - Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia: a (1)H MRS study. AB - This is a (1)H MR spectroscopy (MRS) study of glutamate (Glu), measured as Glx, levels in temporal and frontal lobe regions in patients with schizophrenia compared with a healthy control group with the objective of revealing aspects of the underlying neurochemistry of auditory hallucinations. We further compared and correlated Glu(Glx) levels for the patients-only against frequency and severity of auditory hallucinations and the sum of Positive symptoms, and also for frequency and severity of emotional withdrawal, and sum of Negative symptoms. The sample included 23 patients with an ICD-10 and DSM-IV diagnosis of schizophrenia, and 26 healthy control subjects without any known psychiatric or neurological disorders. Symptom scores were obtained from the Positive and Negative Syndrome Scale (PANSS). (1)H MRS data were acquired on a 3T MR scanner from two temporal and two frontal voxels, using standard sequences and analysis parameters. The results showed that schizophrenia patients as a group had reduced Glu(Glx) levels in the voxels of interest compared to the healthy control subjects, while increased levels were found for patients with frequent and severe auditory hallucinations, relative to patients with less frequent and severe hallucination. We further found significant positive correlations between frequency and severity of auditory hallucinations, and for sum Positive symptoms, and Glu(Glx) levels in all regions, not seen when the analysis was done for negative symptoms. It is concluded that the results show for the first time that glutamate may be a mediating factor in auditory hallucinations in schizophrenia. PMID- 25542861 TI - Accelerated tumor progression in mice lacking the ATP receptor P2X7. AB - The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1beta and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. PMID- 25542863 TI - Oronasal fistula repair using the alveolar ridge approach. AB - OBJECTIVES: Use the alveolar ridge approach operation to repair anterior palate oronasal fistulae. METHODS: In this study, oronasal communication defects were covered with in situ mucosal flaps, resulting in reduced palatal leakage bilaterally. This treatment approach not only provides good esthetic appearance results, but also prevents food and liquid leakage into nose. RESULTS: 25 patients were considered in this study. The alveolar ridge approach for the complication of anterior palate oronasal fistula was a good alternative for these patients; no incision scars were created, and the physiological state after surgery is optimized, with the resulting outcome most closely approximating true anatomic repair. Mucosal and gingival lateral palatal mucosa post-surgical healing results also were good, with return to a natural position. CONCLUSION: Oronasal fistula repair with the alveolar ridge approach is an easy and perhaps ideal method, with a high success rate. PMID- 25542860 TI - Diffusion tensor imaging in first degree relatives of schizophrenia and bipolar disorder patients. AB - OBJECTIVES: White matter (WM) abnormalities are one of the most widely and consistently reported findings in schizophrenia (SZ) and bipolar disorder (BD). If these abnormalities are inherited determinants of illness, suitable to be classified as an endophenotype, relatives of patients must also have them at higher rate compared to the general population. In this review, we evaluate published diffusion tensor imaging (DTI) studies comparing first degree relatives of SZ and BD patients and healthy control subjects. METHODS: We searched PubMed, Embase and PsychInfo for DTI studies which included an unaffected relative and a healthy comparison group. RESULTS: 22 studies fulfilled the inclusion criteria. WM abnormalities were found in many diverse regions in relatives of SZ patients. Although the findings were not completely consistent across studies, the most implicated areas were the frontal and temporal WM regions and the corpus callosum. Studies in relatives of BD patients were fewer in number with less consistent findings reported across studies. CONCLUSIONS: Our review supports the concept of WM abnormalities as an endophenotype in SZ, with somewhat weaker evidence in BD, but larger and higher quality studies are needed to make a definitive comment. PMID- 25542864 TI - Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011. AB - The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0-14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0-14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families. PMID- 25542865 TI - Preparing to provide MTM services. AB - Medication Therapy Management (MTM) has been a way for pharmacist to enhance their position as an integral member of the health care team as the need for improved clinical and economic outcomes in relation to the US health care system became apparent. MTM Certificate training programs are provided by numerous organizations. Collaboration Practice Agreements (CPA) are gaining significance as the role of the pharmacist is expanding in the care of patients as part of a multidisciplinary health care team. One major hurdle that many pharmacists are faced with is receiving reimbursement for the services provided. The Medicare Modernization Act of 2003 recognized that pharmacists play an important role in the management of patient care and that pharmacists bring an expertise and knowledge that will help to identify and resolve patient medication therapy problems. PMID- 25542862 TI - HOXB7 promotes malignant progression by activating the TGFbeta signaling pathway. AB - Overexpression of HOXB7 in breast cancer cells induces an epithelial-mesenchymal transition and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here, we report that phosphorylation of SMAD3 was detected in a higher percentage in primary mammary tumor tissues from double transgenic MMTV-Hoxb7/Her2 mice than tumors from single-transgenic Her2/neu mice, suggesting activation of TGFbeta/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFbeta2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFbeta2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFbeta2 promoter in luciferase and chromatin immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells were reversed by knockdown of TGFbeta2 or pharmacologic inhibition of TGFbeta signaling. Furthermore, knockdown of TGFbeta2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor-associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGFbeta2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFbeta2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell-autonomous and non-cell-autonomous manner through activation of the TGFbeta signaling pathway. PMID- 25542866 TI - Advances in the Care of Adults With Congenital Heart Disease. AB - The significant decline in mortality among children and adolescents with congenital heart disease (CHD) is associated with an increasing prevalence of CHD in adults, particularly those with moderate to severe defects. As a significant percentage of adolescents and young adults are lost to follow-up in the transition from pediatric to adult care, they may present for elective procedures with substantial CHD-associated morbidity. In addition to the specific cardiac defect, the procedures performed, and the current pathophysiological status, several factors should be considered when managing the adult with CHD. These include the type of setting (adult vs pediatric institution); surgeon (pediatric vs adult cardiac surgeon); coexisting diseases associated with CHD, such as coronary artery disease, hepatic dysfunction, renal dysfunction, cerebrovascular accidents, myopathy, and coagulation disorders; acquired diseases of aging; pregnancy; and psychosocial functioning. The current status of the management of common and important congenital cardiac defects is also described. PMID- 25542867 TI - [In Process Citation]. PMID- 25542868 TI - [Efficacy of initial antiretroviral therapy based on lopinavir/ritonavir plus 2 nucleoside/nucleotide analogs in patients with human immunodeficiency virus type 1 infection]. AB - Triple combination regimens consisting of lopinavir/ritonavir (LPV/r) plus 2 nucleoside/nucleotide analogs continue to be a valid option in initial antiretroviral therapy. Other protease inhibitors boosted with ritonavir (and in future with cobicistat) have been introduced, as well as other non-nucleoside analogs (rilpivirin) and 3 integrase inhibitors. None of the new regimens have shown superiority over LPV/r or comparisons are lacking. Therefore, regimens including LPV/r continue to be recommended as initial first-line or alternative strategies in most treatment guidelines. Dual combinations with LPV/r (plus raltegravir or lamivudine) are described in another article and can provide a similar response rate to triple combinations, better tolerance, and an improved cost-efficacy ratio, both for initial therapy and in simplification strategies. In contrast, LPV/r or darunavir/r monotherapy does not seem an acceptable option in treatment-naive patients and is becoming increasingly less acceptable in simplification strategies. PMID- 25542869 TI - [Lopinavir/ritonavir in new initial antiretroviral treatment strategies]. AB - According to evidence from randomized controlled trials and epidemiological data, the antiretroviral treatment (ART) of choice has consisted of the combination of 2 nucleoside analog reverse-transcriptase inhibitors (NRTI) plus 1 non-nucleoside analog reverse-transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) for more than 17 years. There are several unresolved issues, notably the toxocity associated with NRTI, especially thymidine analogs, and the possibility of cross resistance, which may affect subsequent treatment. The development of new antiretroviral drugs with simpler dosing regimens and lower toxicity has led to evaluation of innovative strategies such as dual therapy for initial ART in treatment-naive, with the aim of preventing long-term toxicity and increasing treatment adherence. Despite encouraging results, some combinations have proven unsatisfactory. The strategies with favorable results to date consist of twice daily lopinavir/ritonavir (LPV/r)-based regimens, those in the PROGRESS (LPV/r + raltegravir) and GARDEL (LPV/r + lamivudine) trials, and the combination of darunavir and raltegravir (NEAT 001 trial), although the latter observed a higher tendency (statistically nonsignificant) to virological failure in the dual combination arm. These trials were based on the use of NRTI-sparing regimens consisting of 2-3 fully- active agents for highly-active ART in treatment-naive HIV-positive patients. Recent studies provide evidence supporting the use of NRTI sparing regimens in HIV-infected patients with failure to an initial NNRTI-based ART regimen. The present review will discuss only LPV/r-based innovative strategies in initial ART regimens. PMID- 25542870 TI - [Lopinavir/ritonavir in new simplification strategies in antiretroviral therapy]. AB - Interest in simplification arises from the need to dispense with nucleoside analogs due to their long-term toxicity. Since the first trials analyzing the safety and effectiveness of the strategy with lopinavir/ritonavir (LPV/r) emerged more than 10 years ago, simplification continues to arouse scientific, clinical and economic interest. At present, there is no consensus on recommendations; interpretations of results are discordant: while some emphasize the greater risk of loss of virologic control, others indicate that the possible virological rebound with this strategy is unrelated to a loss of therapeutic options or to the emergence of resistance to ritonavir-boosted protease inhibitors. This scenario governs the recommendations that can be made in clinical practice; almost all groups agree that candidates should be selected for a simplification strategy with fewer drugs. PMID- 25542871 TI - [Lopinavir/ritonavir in patients with human immunodeficiency virus infection in special situations]. AB - Ritonavir-boosted lopinavir (LPV/r) is a protease inhibitor used for the treatment of human immunodeficiency virus (HIV) infection in both normal patients and in certain situations. In patients with renal failure, LPV/r does not require dosage adjustment because it is metabolized in the liver. Cohort studies have shown that the incidence of varying degrees of renal disease and/or crystalluria related to combination antiretroviral therapy with tenofovir and some protease inhibitors (PI) does not appear with LPV/r or that the incidence is much lower with this combination. Neurocognitive impairments are described in a high proportion of patients with HIV infection and viral replication or related inflammatory activity in the subarachnoid space. In these patients, LPV/r is one of the therapeutic options. A score has been published that rates antiretroviral drugs according to the concentration attained in the cerebrospinal fluid (CSF). LPV/r levels reached in CSF exceed the IC50 of wild-type HIV and has a valuable score (score 3) of the drugs currently used. The most important comorbid condition is chronic hepatitis, due to its frequency and because the biotransformation of LPV/r occurs in the liver. In these circumstances, it is important to evaluate the influence of liver failure on blood drug levels and how these values may cause liver toxicity. LPV/r dose modification has not been established in the presence of liver failure. LPV/r-induced liver toxicity has only been reported with a certain frequency when liver enzymes were elevated at baseline or in patients with chronic hepatitis C, although most cases of liver toxicity were mild. PMID- 25542872 TI - [Lopinavir/ritonavir in human immunodeficiency virus-infected women]. AB - There are clear sex-related biological differences between men and women. Diseases that affect the two sexes differently are studied separately. However, some diseases affect both men and women, but their incidence or outcome are clearly different. In human immunodeficiency virus infection, the potential differences in the effects of antiretroviral therapy are poorly characterized and few studies have been designed to elucidate these differences. Moreover, women are usually poorly represented in clinical trials of antiretroviral drugs. PMID- 25542873 TI - [Challenges of lopinavir/ritonavir in the chronicity of human immunodeficiency virus infection]. AB - Combination antiretroviral therapy (ART) has increased patient survival, which is currently similar to that of the general population in western countries. However, ART is unable to completely restore normal health, given the persistence of chronic immune activation. Human immunodeficiency virus (HIV) infection has become a chronic disease and 50% of patients will soon be older than 50 years. Currently, there is a debate on the possibility of accelerated aging in the HIV infected population. An overlap has been observed between chronic inflammation, age-related comorbidities, lifestyle, and the long-term toxicity of ART. ART related toxicity can encourage the development of comorbidities, especially cardiovascular and renal complications, while toxicity-especially that of thymidine analogs-can also contribute to inflammation and aging. Evidence is available on simplification strategies with boosted protease inhibitor monotherapy aiming to avoid or reduce potential or demonstrated toxicity. Currently, studies are underway of dual therapy strategies with lopinavir/ritonavir (LPV/r) with distinct antiretroviral agents. The studies with the largest samples are those with raltegravir and lamivudine. The GARDEL trial has demonstrated that dual therapy with LPV/r plus a generic drug such as lamivudine is non-inferior to triple therapy in treatment- naive patients. All of the above indicates the response to the challenge posed to LPV/r by the chronic phase of the disease and by the need to reduce costs. PMID- 25542874 TI - [Positioning of lopinavir/ritonavir in antiretroviral treatment schemes]. AB - Lopinavir/ritonavir (LPV/r) was approved for use in the treatment of human immunodeficiency virus (HIV) infection in 2001 and is the protease inhibitor that has been most widely studied in clinical trials. Despite the time interval since its approval, all the evidence accumulated in the last 14 years indicates that LPV/r continues to occupy an important position among antiretroviral drugs. Firstly, LPV/r plus 2 nucleoside/nucleotide analogs is still considered a good option for initial antiretroviral therapy (ART). Secondly, numerous studies have evaluated the efficacy and safety of new initial ART strategies based on LPV/r in dual therapy. The results obtained suggest that LPV/r plus lamivudine (3TC) or raltegravir can be as effective in initial ART as standard triple therapy and justify their consideration as alternative regimens in this scenario. Thirdly, LPV/r is a pioneer drug, as well as being the agent with the largest amount of evidence from clinical trials on simplification to monotherapy (LPV/r) or dual therapy (LPV/r + 3TC). Lastly, LPV/r is highly useful is special situations. It has a low risk of liver toxicity in patients with chronic liver disease, its use is preferred in the treatment of patients with HIV-2, and it is safe and effective in preventing vertical HIV transmission. PMID- 25542875 TI - Significant role of Mn(III) sites in e(g)(1) configuration in manganese oxide catalysts for efficient artificial water oxidation. AB - Development of efficient bio-inspired water oxidation system with transition metal oxide catalyst has been considered as the one of the most challenging task in the recent years. As the oxygen evolving center of photosystem II consists of Mn4CaO5 cluster, most of the water oxidation study was converged to build up manganese oxide based catalysts. Here we report the synthesis of efficient artificial water oxidation catalysts by transferring the inactive manganese monooxide (MnO) under highly oxidizing conditions with ceric ammonium nitrate (CAN) and ozone (O3). MnO was partially oxidized to form mixed-valent manganese oxide (MnOx) with CAN whereas completely oxidized to mineral phase of epsilon MnO2 (Akhtenskite) upon treatment of O3 in acidic solution, which we explore first time as a water oxidation catalyst. Chemical water oxidation, as well as the photochemical water oxidation in the presence of sacrificial electron acceptor and photosensitizer with the presented catalysts were carried out that followed the trends: MnOx>MnO2>MnO. Structural and activity correlation reveals that the presence of larger extent of Mn(III) in MnOx is the responsible factor for higher activity compared to MnO2. Mn(III) species in octahedral system with eg(1) configuration furnishes and facilitates the Mn-O and Mn-Mn bond enlargement with required structural flexibility and disorder in the manganese oxide structure which indeed facilitates water oxidation. PMID- 25542876 TI - Challenges of the WEB Device for Intracranial Aneurysms: How to Widen the Spectrum and Compare Favorably. PMID- 25542877 TI - Viewpoints on the ARUBA trial. PMID- 25542878 TI - The maze-making and solving technique for coil embolization of large and giant aneurysms. AB - BACKGROUND AND PURPOSE: Despite major progress in treating aneurysms by coil embolization, the complete occlusion of aneurysms of >10 mm in diameter (large/giant aneurysms) remains challenging. We present a novel endovascular treatment method for large and giant cerebral aneurysms called the "maze-making and solving" technique and compare the short-term follow-up results of this technique with those of conventional coil embolization. MATERIALS AND METHODS: Eight patients (65 +/- 11.5 years of age, 7 women) with large/giant unruptured nonthrombosed cerebral aneurysm (mean largest aneurysm dimension, 19 +/- 4.4 mm) were treated by the maze-making and solving technique, a combination of the double-catheter technique and various assisted techniques. The coil-packing attenuation, postoperative courses, and recurrence rate of this maze group were compared with 30 previous cases (conventional group, 65.4 +/- 13.0 years of age; 22 women; mean largest aneurysm dimension, 13.4 +/- 3.8 mm). RESULTS: Four maze group cases were Raymond class 1; and 4 were class 2 as indicated by immediate postsurgical angiography. No perioperative deaths or major strokes occurred. Mean packing attenuation of the maze group was significantly higher than that of the conventional group (37.4 +/- 5.9% versus 26.2 +/- 5.6%). Follow-up angiography performed at 11.3 +/- 5.4 months revealed no recurrence in the maze group compared with 39.2% in the conventional group. CONCLUSIONS: The maze-making and solving technique achieves high coil-packing attenuation for efficient embolization of large and giant cerebral aneurysms with a low risk of recurrence. PMID- 25542879 TI - Arterial spin-labeling perfusion MRI stratifies progression-free survival and correlates with epidermal growth factor receptor status in glioblastoma. AB - BACKGROUND AND PURPOSE: Glioblastoma is a common primary brain tumor with a poor but variable prognosis. Our aim was to investigate the feasibility of MR perfusion imaging by using arterial spin-labeling for determining the prognosis of patients with glioblastoma. MATERIALS AND METHODS: Pseudocontinuous arterial spin-labeling with 3D background-suppressed gradient and spin-echo was acquired before surgery on 53 patients subsequently diagnosed with glioblastoma. The calculated CBF color maps were visually evaluated by 3 independent readers blinded to patient history. Pathologic and survival data were correlated with CBF map findings. Arterial spin-labeling values in tumor tissue were also quantified by using manual fixed-size ROIs. RESULTS: Two perfusion patterns were characterized by visual evaluation of CBF maps on the basis of either the presence (pattern 1) or absence (pattern 2) of substantial hyperperfused tumor tissue. Evaluation of the perfusion patterns was highly concordant among the 3 readers (kappa = 0.898, P < .001). Pattern 1 (versus pattern 2) was associated with significantly shorter progression-free survival by Kaplan-Meier analysis (median progression-free survival of 182 days versus 485 days, P < .01) and trended with shorter overall survival (P = .079). There was a significant association between pattern 1 and epidermal growth factor receptor variant III expression (P < .01). CONCLUSIONS: Qualitative evaluation of arterial spin labeling CBF maps can be used to stratify survival and predict epidermal growth factor receptor variant III expression in patients with glioblastoma. PMID- 25542880 TI - Reply: To PMID 24948502. PMID- 25542881 TI - Predictive value of calvarial fracture for delayed epidural hematoma following decompressive craniectomy. PMID- 25542882 TI - Plasma D-dimer levels and clinical response to ciclosporin in severe chronic spontaneous urticaria. PMID- 25542884 TI - Phagocyte nicotinamide adenine dinucleotide phosphate oxidase activity in patients with inherited IFN-gammaR1 or IFN-gammaR2 deficiency. PMID- 25542885 TI - Matrix metalloproteinase 12 is produced by M2 macrophages and plays important roles in the development of contact hypersensitivity. PMID- 25542883 TI - Suppression of the immunologic response to peanut during immunotherapy is often transient. AB - BACKGROUND: Studies suggest that oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) for food allergy hold promise; however, the immunologic mechanisms underlying these therapies are not well understood. OBJECTIVE: We sought to generate insights into the mechanisms and duration of suppression of immune responses to peanut during immunotherapy. METHODS: Blood was obtained from subjects at baseline and at multiple time points during a placebo-controlled trial of peanut OIT and SLIT. Immunologic outcomes included measurement of spontaneous and stimulated basophil activity by using automated fluorometry (histamine) and flow cytometry (activation markers and IL-4), measurement of allergen-induced cytokine expression in dendritic cell (DC)-T-cell cocultures by using multiplexing technology, and measurement of MHC II and costimulatory molecule expression on DCs by using flow cytometry. RESULTS: Spontaneous and allergen-induced basophil reactivity (histamine release, CD63 expression, and IL 4 production) were suppressed during dose escalation and after 6 months of maintenance dosing. Peanut- and dust mite-induced expression of TH2 cytokines was reduced in DC-T-cell cocultures during immunotherapy. This was associated with decreased levels of CD40, HLA-DR, and CD86 expression on DCs and increased expression of CD80. These effects were most striking in myeloid DC-T-cell cocultures from subjects receiving OIT. Many markers of immunologic suppression reversed after withdrawal from immunotherapy and in some cases during ongoing maintenance therapy. CONCLUSION: OIT and SLIT for peanut allergy induce rapid suppression of basophil effector functions, DC activation, and TH2 cytokine responses during the initial phases of immunotherapy in an antigen-nonspecific manner. Although there was some interindividual variation, in many patients suppression appeared to be temporary. PMID- 25542886 TI - Prednisone for acute virus-associated wheeze in children: Panacea or one more brick in the wall? PMID- 25542887 TI - Participation of NMDA receptors in the lateral hypothalamus in gastric erosion induced by cold-water restraint. AB - The present study investigated whether neurons in the lateral hypothalamus (LH) play a role in the occurrence of gastric ulcerations induced by cold-water restraint. The first experiment indicated that bilateral N-methyl-d-aspartate (NMDA) lesions of the LH (20MUg/1MUl per side) reduced the amount of gastric ulceration induced by cold-water restraint. In the second experiment, the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV; 2.5MUg/0.5MUl per side) or its vehicle was microinjected bilaterally into the LH prior to the cold-water restraint procedure. APV did not induce gastric ulcerations but reduced the amount of ulceration induced by cold-water restraint. These results indicate that NMDA receptors in the LH play an important role in the occurrence of gastric ulceration induced by cold-water restraint. The participation of the LH and possible neuronal circuitry involved in stress-induced ulceration are discussed. PMID- 25542888 TI - Alterations of cognitive function and 5-HT system in rats after long term microwave exposure. AB - The increased use of microwaves raises concerns about its impact on health including cognitive function in which neurotransmitter system plays an important role. In this study, we focused on the serotonin system and evaluated the long term effects of chronic microwave radiation on cognition and correlated items. Wistar rats were exposed or sham exposed to 2.856GHz microwaves with the average power density of 5, 10, 20 or 30mW/cm(2) respectively for 6min three times a week up to 6weeks. At different time points after the last exposure, spatial learning and memory function, morphology structure of the hippocampus, electroencephalogram (EEG) and neurotransmitter content (amino acid and monoamine) of rats were tested. Above results raised our interest in serotonin system. Tryptophan hydroxylase 1 (TPH1) and monoamine oxidase (MAO), two important rate-limiting enzymes in serotonin synthesis and metabolic process respectively, were detected. Expressions of serotonin receptors including 5-HT1A, 2A, 2C receptors were measured. We demonstrated that chronic exposure to microwave (2.856GHz, with the average power density of 5, 10, 20 and 30mW/cm(2)) could induce dose-dependent deficit of spatial learning and memory in rats accompanied with inhibition of brain electrical activity, the degeneration of hippocampus neurons, and the disturbance of neurotransmitters, among which the increase of 5-HT occurred as the main long-term change that the decrease of its metabolism partly contributed to. Besides, the variations of 5-HT1AR and 5-HT2CR expressions were also indicated. The results suggested that in the long-term way, chronic microwave exposure could induce cognitive deficit and 5-HT system may be involved in it. PMID- 25542889 TI - Is sensory-specific satiety for a bitter-sweet infusion modulated by context? AB - The sensory-affective attributes of beverages have an important influence on a given intake and successive consumptions because of sensory-specific satiety (SSS; defined as a decrease in pleasantness ratings of a food eaten relative to uneaten foods). No studies have, however, investigated how multiple sessions of SSS for familiar drinks over a period of several days up to a week may change their pleasantness and how these hedonic-related judgments are affected by the context during SSS testing. With twenty-six participants, the present study explored the medium lasting and contextual effects of repeated SSS sessions for a bitter-sweet infusion on olfactory and flavour pleasantness over the course of three exposures in either a laboratory or a cafeteria setting. The results showed olfactory and flavour SSS for the infusion following each consumption in both the artificial and the natural setting. More interestingly, despite the failure to detect medium-term SSS (i.e., a greater decrease in pleasantness ratings of a food eaten relative to uneaten foods after repeated SSS sessions over several days as compared to the first SSS session), a contextual modulation of olfactory SSS was observed with a lesser overall magnitude in the cafeteria compared to the laboratory setting. To the best of our knowledge, the impact of eating location on the development of satiation and the differential contextual sensitivity of SSS for orthonasal odours and flavours has not been reported previously. The implications of potential environmental control of SSS are considered in this study. PMID- 25542891 TI - Effects of temperature and feeding frequency on ingestion and growth for rare minnow. AB - Water temperature and feeding frequency are two important components in feeding strategy that directly affect the growth and physiology of fishes. The rare minnow (Gobiocypris rarus) has been cultured for decades in the laboratory as an experimental fish and is widely used in environmental science research. An 8-week factorial feeding experiment was conducted on juvenile rare minnows to investigate the interaction between water temperature (ambient, 20, 24, 28 degrees C) and feeding frequency (one, two, three meals per day) on growth performance, feed utilization, gut evacuation and adaptability to variable environmental conditions. Groups fed three times a day at 28 degrees C attained the maximum final body weight, followed by those fed two times a day at 24 degrees C. There was an obvious curvilinear relationship between specific growth rate and temperature. Increased temperature significantly promoted food consumption and growth rate, but there were no benefits on growth by feeding multiple times at temperatures of 18 degrees C or lower. Temperature and feeding frequency also affected gut evacuation rates: high temperature and frequency lead to fast evacuation. These results show that the optimal temperature and feeding frequency for rare minnow is 24 degrees C and two meals a day for maximal growth, feeding efficiency, and daily management. The findings also suggest that the rare minnow has the ability to rapidly adapt to changing culture conditions by adjusting physiological activities in the short term. PMID- 25542890 TI - Using the context preexposure facilitation effect to study long-term context memory in preweanling, juvenile, adolescent, and adult rats. AB - The present study used the context preexposure facilitation effect (CPFE) to examine long-term retention of incidental context learning in periweanling, adolescent and adult rats. The CPFE is a variant of contextual fear conditioning in which encoding the context representation, associating this representation with shock, and expressing the context-shock association each occur on separate occasions. Experiment 1 manipulated the retention interval-1d, 8d, 15d, or 22d between context preexposure and training with immediate shock to determine how long the encoded context could be remembered (testing always occurred 24h following training). The other factors were age-postnatal day (PND) 24 vs 31-and training group-Preexposed to the training context (Pre) vs. an alternate context (Alt-Pre). At both ages, significantly more freezing was evident in the Pre vs. Alt Pre Groups at the 24h, 8d and 15d retention intervals but not at the 22d interval, indicating that juvenile-adolescent rats remember the context for up to 15d. In contrast, context memory persists for 22days in adult rats (Experiment 2); and is not evident after 24h, 8d, or 15d retention intervals in PND 17 rats (Experiment 3). The present study illustrates the value of the CPFE paradigm for investigations of long-term context memory in developing rats. Implications for the neurobiology of infantile amnesia are discussed. PMID- 25542892 TI - Simultaneous determination of 11 beta-agonists in human urine using high performance liquid chromatography/tandem mass spectrometry with isotope dilution. AB - The misuse of beta-agonists constitutes a potential risk to public health and has been forbidden in many countries. In this study, we describe a method for specific, sensitive and rapid detection of beta-agonists in human urine. Urine samples were extracted with ethyl acetate, without any additional purification step, and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) with Clenbuterol-D9 and Salbuterol-D3 as internal standards. The intra- and interday precision values of the method were all <5.60% and the accuracy ranged from 94.5 to 109%. Extraction recovery for 11 beta agonists varied from 66.7 to 108%. One UPLC-MS-MS analysis could be completed within 12 min and the limits of detection for 11 beta-agonists were 0.1 ng/mL in the experiment. beta-Agonists in human urines from 24 volunteers were analyzed by our validated method and 1.70 ng/mL salbutamol was detected in one volunteer. The application of UPLC-MS-MS method in beta-agonists detection of human urine will be helpful in veterinary control of beta-agonists and for studying the effect of beta-agonists on human health. PMID- 25542893 TI - Comparison of different urine pretreatments for biological monitoring of pyrethroid insecticides. AB - During a cross-validation practice of urinary analysis of pyrethroid insecticide metabolite (3-phenoxybenzoic acid, 3-PBA) by two laboratories (Lab A and Lab B), difference in 3-PBA concentration was noticed. The analytical methods used in the exercise were enzymatic deconjugation (glucuronidase/sulfatase) followed by solid phase extraction and isotope dilution LC-MS-MS determination (Lab A) and acidic deconjugation followed by liquid-liquid extraction and gas chromatography-mass spectrometry determination (Lab B). A significant difference was found for one of the five samples: lower value was obtained in Lab A. Use of acidic deconjugation in Lab A resulted in comparable value with the analytical result for this sample originally obtained in Lab B. The comparison was extended to 42 urine samples taken from Japanese males in Lab A by using the two different deconjugation methods and LC-MS-MS determination. Significantly lower value was obtained for enzymatic deconjugation in some of the 42 urine samples. The results suggested the presence of other conjugated species of 3-PBA than glucuronide and sulfate in human urine. Although the overall agreement between the values obtained by the deconjugation methods was fair, it appears that urine samples should be pretreated by acidic deconjugation for the analysis in biological monitoring of pyrethroid exposure. PMID- 25542894 TI - Expression of glypican 3 enriches hepatocellular carcinoma development-related genes and associates with carcinogenesis in cirrhotic livers. AB - Glypican-3 (GPC3) protein expression was determined by immunohistochemical analysis from 29 normal livers, 80 cirrhotic livers sample taken near hepatocellular carcinoma (HCC), and 87 cirrhotic livers without HCC. The levels for miR-657 and HCC-related gene mRNAs were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Also, a published microarray dataset was used for gene set enrichment analysis (GSEA) to investigate the relationship between GPC3- and HCC-related gene signatures. Kaplan-Meier analysis was used to evaluate the relationship between GPC3 and HCC recurrence. GPC3 protein expression was not detected in any of the 29 (0%) normal livers, but was detected in 32 of 87 (37%) cirrhotic livers without HCC, and 51 of 80 (64%) cirrhotic liver samples taken near HCC sites (P < 0.001). The GPC3-positive rate in cirrhotic livers of viral origin was 68% (27/40), which was significantly higher than for non-viral cirrhotic livers (11%, 5/47) (P < 0.001). Also, GPC3 expression positively correlated with mRNA expression of HCC-related genes in the qRT-PCR and GSEA evaluations. Furthermore, HCC recurrence in cirrhotic liver samples taken near HCC sites was significantly higher in the GPC3-positive group than the GPC3-negative group (Log-rank P = 0.02, HR = 3.26; 95% CI = 1.20-10.29). This study demonstrated that highly expression of GPC3 could enrich HCC-related genes' mRNA expression and positive associate with dysplasia in cirrhotic livers. Therefore, GPC3 may serve as a precancerous biomarker in cirrhotic livers. PMID- 25542895 TI - Antibiotic usage and the development of resistance. PMID- 25542896 TI - A consensus development conference model for establishing health policy for surveillance and screening of antimicrobial-resistant organisms. AB - The Canadian Consensus Development Conference on Surveillance and Screening for Antimicrobial-Resistant Organisms (AROs) was sponsored by the Alberta Ministry of Health to provide evidence to update policies for ARO screening in acute care settings. A rigorous evidence-based literature review completed before the conference concluded that that neither universal nor targeted screening of patients was associated with a reduction in hospital-acquired ARO colonization, infection, morbidity, or mortality. Leading international clinicians, scientists, academics, policy makers, and administrators presented current evidence and clinical experience, focusing on whether and how hospitals should screen patients for AROs as part of broader ARO control strategies. An unbiased and independent "jury" with a broad base of expertise from complementary disciplines considered the evidence and released a consensus statement of 22 recommendations. Policy highlights included developing an integrated "One Health" strategy, fully resourcing basic infection control practices, not performing universal screening, and focusing original research to determine what works. PMID- 25542897 TI - How eco-evolutionary principles can guide tree breeding and tree biotechnology for enhanced productivity. AB - Tree breeding and biotechnology can enhance forest productivity and help alleviate the rising pressure on forests from climate change and human exploitation. While many physiological processes and genes are targeted in search of genetically improved tree productivity, an overarching principle to guide this search is missing. Here, we propose a method to identify the traits that can be modified to enhance productivity, based on the differences between trees shaped by natural selection and 'improved' trees with traits optimized for productivity. We developed a tractable model of plant growth and survival to explore such potential modifications under a range of environmental conditions, from non-water limited to severely drought-limited sites. We show how key traits are controlled by a trade-off between productivity and survival, and that productivity can be increased at the expense of long-term survival by reducing isohydric behavior (stomatal regulation of leaf water potential) and allocation to defense against pests compared with native trees. In contrast, at dry sites occupied by naturally drought-resistant trees, the model suggests a better strategy may be to select trees with slightly lower wood density than the native trees and to augment isohydric behavior and allocation to defense. Thus, which traits to modify, and in which direction, depend on the original tree species or genotype, the growth environment and wood-quality versus volume production preferences. In contrast to this need for customization of drought and pest resistances, consistent large gains in productivity for all genotypes can be obtained if root traits can be altered to reduce competition for water and nutrients. Our approach illustrates the potential of using eco-evolutionary theory and modeling to guide plant breeding and genetic technology in selecting target traits in the quest for higher forest productivity. PMID- 25542898 TI - Retbindin is an extracellular riboflavin-binding protein found at the photoreceptor/retinal pigment epithelium interface. AB - Retbindin is a novel retina-specific protein of unknown function. In this study, we have used various approaches to evaluate protein expression, localization, biochemical properties, and function. We find that retbindin is secreted by the rod photoreceptors into the inter-photoreceptor matrix where it is maintained via electrostatic forces. Retbindin is predominantly localized at the interface between photoreceptors and retinal pigment epithelium microvilli, a region critical for retinal function and homeostasis. Interestingly, although it is associated with photoreceptor outer segments, retbindin's expression is not dependent on their presence. In vitro, retbindin is capable of binding riboflavin, thus implicating the protein as a metabolite carrier between the retina and the retinal pigment epithelium. Altogether, our data show that retbindin is a novel photoreceptor-specific protein with a unique localization and function. We hypothesize that retbindin is an excellent candidate for binding retinal flavins and possibly participating in their transport from the extracellular space to the photoreceptors. Further investigations are warranted to determine the exact function of retbindin in retinal homeostasis and disease. PMID- 25542899 TI - Crystal structure of DNA cytidine deaminase ABOBEC3G catalytic deamination domain suggests a binding mode of full-length enzyme to single-stranded DNA. AB - APOBEC3G (A3G) is a DNA cytidine deaminase (CD) that demonstrates antiviral activity against human immunodeficiency virus 1 (HIV-1) and other pathogenic virus. It has an inactive N-terminal CD1 virus infectivity factor (Vif) protein binding domain (A3G-CD1) and an actively catalytic C-terminal CD2 deamination domain (A3G-CD2). Although many studies on the structure of A3G-CD2 and enzymatic properties of full-length A3G have been reported, the mechanism of how A3G interacts with HIV-1 single-stranded DNA (ssDNA) is still not well characterized. Here, we reported a crystal structure of a novel A3G-CD2 head-to-tail dimer (in which the N terminus of the monomer H (head) interacts with the C terminus of monomer T (tail)), where a continuous DNA binding groove was observed. By constructing the A3G-CD1 structural model, we found that its overall fold was almost identical to that of A3G-CD2. We mutated the residues located in or along the groove in monomer H and the residues in A3G-CD1 that correspond to those seated in or along the groove in monomer T. Then, by performing enzymatic assays, we confirmed the reported key elements and the residues in A3G necessary to the catalytic deamination. Moreover, we identified more than 10 residues in A3G essential to DNA binding and deamination reaction. Therefore, this dimer structure may represent a structural model of full-length A3G, which indicates a possible binding mode of A3G to HIV-1 ssDNA. PMID- 25542901 TI - Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models. AB - PURPOSE: ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/kappa ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic. EXPERIMENTAL DESIGN: We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models. RESULTS: A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models. CONCLUSIONS: NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203. PMID- 25542902 TI - Hand function and performance of daily activities in systemic lupus erythematosus: a clinical study. AB - This clinical study was performed to investigate hand problems in individuals with systemic lupus erythematosus (SLE) in comparison with healthy controls, and to explore problems in the performance of daily activities related to these hand problems, in order to objectify findings from a previous mail survey. We also investigated whether a simple hand test could detect hand problems in SLE. All individuals, 71 with SLE and 71 healthy controls, were examined for manifestations in body structures and body functions of the hands with a study specific protocol. The simple hand test was performed by all the individuals and the arthritis impact measurement scale (AIMS 2) questionnaire was completed by the SLE individuals. In the SLE group, 58% had some kind of difficulty in the simple hand test, compared with 8% in the control group. Fifty percent of the SLE individuals experienced problems in performing daily activities due to hand deficits. Pain in the hands, reduced strength and dexterity, Raynaud's phenomenon and trigger finger were the most prominent body functions affecting the performance of daily activities. Deficits in hand function are common in SLE and affect the performance of daily activities. The simple hand test may be a useful tool in detecting hand problems. PMID- 25542900 TI - Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin. AB - PURPOSE: We have previously demonstrated that ritonavir targeting of glycolysis is growth inhibitory and cytotoxic in a subset of multiple myeloma cells. In this study, our objective was to investigate the metabolic basis of resistance to ritonavir and to determine the utility of cotreatment with the mitochondrial complex I inhibitor metformin to target compensatory metabolism. EXPERIMENTAL DESIGN: We determined combination indices for ritonavir and metformin, impact on myeloma cell lines, patient samples, and myeloma xenograft growth. Additional evaluation in breast, melanoma, and ovarian cancer cell lines was also performed. Signaling connected to suppression of the prosurvival BCL-2 family member MCL-1 was evaluated in multiple myeloma cell lines and tumor lysates. Reliance on oxidative metabolism was determined by evaluation of oxygen consumption, and dependence on glutamine was assessed by estimation of viability upon metabolite withdrawal in the context of specific metabolic perturbations. RESULTS: Ritonavir treated multiple myeloma cells exhibited increased reliance on glutamine metabolism. Ritonavir sensitized multiple myeloma cells to metformin, effectively eliciting cytotoxicity both in vitro and in an in vivo xenograft model of multiple myeloma and in breast, ovarian, and melanoma cancer cell lines. Ritonavir and metformin effectively suppressed AKT and mTORC1 phosphorylation and prosurvival BCL-2 family member MCL-1 expression in multiple myeloma cell lines in vitro and in vivo. CONCLUSIONS: FDA-approved ritonavir and metformin effectively target multiple myeloma cell metabolism to elicit cytotoxicity in multiple myeloma. Our studies warrant further investigation into repurposing ritonavir and metformin to target the metabolic plasticity of myeloma to more broadly target myeloma heterogeneity and prevent the reemergence of chemoresistant aggressive multiple myeloma. PMID- 25542903 TI - Validity and reliability of the Lupus QoL index in Turkish systemic lupus erythematosus patients. AB - BACKGROUND: Systemic lupus erythematosus (SLE) patients have seriously impaired quality of life (QoL). In addition to activity and damage indices used in the past, tools to evaluate QoL in SLE have been developed in recent years. In this study, we test the validity of the Turkish version of the Lupus-QoL (LupusQoL-TR) score, and investigate its association with clinical findings and activity indices. METHODS: A total of 132 patients diagnosed with SLE according to ACR 1997 criteria were included. The clinical and demographic features, and biochemical data were retrieved from hospital records. SLE Disease Activity Index (SLEDAI) and damage score (SLICC-ACR) were determined at the time of administration of Lupus-QoL questionnaire. The Lupus-QoL includes 34 questions divided into eight domains. We reevaluated the LupusQoL-TR and pretested its understandability. SLE patients were concomitantly administered the LupusQoL-TR and generic SF-36. Internal consistency, test-retest reliability, convergent and discriminant validity were calculated. RESULTS: The mean age of our SLE patients was 37.9 +/- 12.8 years. Internal consistency reliability ranged from 0.88 to 0.93, and test-retest reliability from 0.84 to 0.94. LupusQoL-related domains in SF-36 were correlated (from 0.66 to 0.74). Most LupusQoL-TR domains, except planning, were able to discriminate between active and inactive SLE groups. Scores in all domains of the LupusQoL-TR were found to be discriminative for patients with and without damage according to SLICC-ACR score. CONCLUSION: The LupusQoL-TR was found to be a valid patient-reported outcome measure method when evaluating QoL in Turkish SLE patients. PMID- 25542904 TI - Vascular- and pregnancy-related outcomes in patients with systemic lupus erythematosus with positive antiphospholipid profile and thrombocytopenia. AB - This study aimed to investigate whether patients with lupus and a positive antiphospholipid profile with thrombocytopenia are at a higher risk for obstetric complications or thrombotic events than patients without thrombocytopenia. We conducted a case-control study matched 3:1 by sex, age of systemic lupus erythematosus diagnosis, age at study start, disease duration and length of follow-up time. Time to first event following study start was compared using Kaplan-Meier curves and log-rank tests and it was not statistically significant. In this study setting and population, thrombocytopenia was not associated with a higher risk for obstetrical complications or thrombotic events. PMID- 25542905 TI - Increased DNA double-strand breaks and enhanced apoptosis in patients with lupus nephritis. AB - OBJECTIVE: DNA double-strand breaks (DSBs) lead to mutations, genomic instability and apoptotic death, whereas accumulation of apoptotic cells results in excessive autoantigen presentation and autoantibody formation. We aimed to measure DSB levels in lupus nephritis, a severe complication of the prototypic systemic autoimmune disease. METHODS: The intrinsic DNA damage and the apoptosis induction/DSB levels were evaluated in peripheral blood mononuclear cells of six patients and 10 healthy controls following exposure to genotoxic agents (melphalan, cisplatin) ex vivo. DSBs were assessed using immunofluorescence quantification of gammaH2AX foci and comet assay. RESULTS: Intrinsic DNA damage was increased in lupus versus control cells in both assays (Olive Tail Moment units of 15.8 +/- 2.3 versus 3.0 +/- 1.4 in comet, p < 0.01; % gammaH2AX-positive cells: 13.6 +/- 1.8 versus 4.6 +/- 0.9, p < 0.01, respectively). Melphalan or cisplatin doses as low as 9.9 +/- 4.8 or 29.8 +/- 8.3 ug/ml, respectively, were sufficient to induce apoptosis in lupus cells; control cells required doses of 32.3 +/- 7.7 and 67.7 +/- 5.5 ug/ml, respectively. Drug-induced DSB levels were increased in lupus versus control cells, with the area under the curve (AUC) for melphalan-induced DSBs being 3050 +/- 610 (% gammaH2AX-positive staining cells) * (drug dose) in patients and 1580 +/- 350 in controls (p < 0.05); the corresponding values for cisplatin-induced AUC were 13900 +/- 1800 for lupus and 4500 +/- 750 for controls (p < 0.01). Interestingly, within either lupus patients or controls examined, the accumulation of DSBs correlated with apoptosis degrees (all p < 0.01). Results in lupus cells were not associated with individual disease activity level or treatment modalities at the time of the study. CONCLUSION: These findings suggest a novel mechanism by which increased accumulation of DSBs may render cells more sensitive to apoptosis, thus contributing to the induction of systemic autoimmunity. PMID- 25542906 TI - Biomarkers of kidney injury and klotho in patients with atherosclerotic renovascular disease. AB - BACKGROUND AND OBJECTIVES: Occlusive renovascular disease and hypertension may progress to CKD. Circulating levels of several biomarkers, including fibroblast growth factor (FGF)-23, Klotho, and soluble urokinase plasminogen activator receptor (suPAR), are altered in patients with CKD, but their role in essential hypertension (EH) and renovascular hypertension (RVH) remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Levels of FGF-23, Klotho, suPAR, plasminogen activator inhibitor (PAI)-1, tissue factor, and tissue factor pathway inhibitor (TFI) were measured in the inferior vena cava and renal vein of hypertensive patients with atherosclerotic renal artery stenosis (n=12) or age matched participants with EH (n=12) and relatively preserved renal function. Single-kidney blood flow was measured to calculate renal release of markers. For control, peripheral vein levels were measured in healthy volunteers (HVs; n=12). RESULTS: FGF-23 levels did not differ among the groups, whereas Klotho levels were lower in participants with RVH and EH than in HVs, and suPAR levels were elevated in patients with RVH compared with HVs and patients with EH (6.1+/-1.5 versus 4.4+/-1.9 and 3.2+/-1.2 ng/ml, P<0.05). PAI-1 levels were higher in patients with RVH than in patients with EH, but tissue factor and TFI levels were not statistically significantly different. After adjustment for GFR, Klotho levels remained decreased in both RVH and EH, and suPAR and PAI-1 levels remained elevated in RVH. eGFR correlated inversely with systemic and renal vein suPAR levels, and directly with systemic Klotho levels. CONCLUSIONS: Klotho levels are low in hypertensive patients, whereas suPAR and PAI-1 levels are specifically elevated in RVH, correlating with GFR. Klotho, PAI-1, and suPAR may be markers of kidney injury in hypertensive patients. PMID- 25542907 TI - A longitudinal study of inflammation, CKD-mineral bone disorder, and carotid atherosclerosis after renal transplantation. AB - BACKGROUND AND OBJECTIVES: The role of reversibility of nontraditional risk factors, like inflammation and CKD-mineral bone disorder, in the reduction of cardiovascular risk after renal transplantation is still scarcely defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The longitudinal relationship between C-reactive protein, CKD-mineral bone disorder biomarkers, and intima media thickness was investigated in a series of 178 patients (age=32+/-10 years) with stage 5 CKD maintained on chronic dialysis who underwent echo-color Doppler studies of the carotid arteries before and after renal transplantation. Smokers and patients with diabetes were excluded from the study. In all patients, immunosuppression was performed by a standard regimen on the basis of calcineurin inhibitors. Healthy controls were specifically selected to match the age and sex distribution of the patients. Biochemical and intima media thickness assessments were repeated 6 months after transplantation. RESULTS: Before transplantation, intima media thickness in patients with stage 5 CKD on dialysis (average=0.9+/ 0.2 mm) was higher (P<0.001) than in well matched healthy controls (0.6+/-0.1 mm) and reduced substantially (-22%; 95% confidence interval, -24% to -20%) after transplantation (P=0.001). GFR (multivariable-adjusted beta=0.23; P<0.001), C reactive protein (beta=0.15; P<0.001), and fibroblast growth factor 23 (beta=0.28; P<0.001) were the strongest independent correlates of intima media thickness before transplantation. Similarly, longitudinal changes in the same biomarkers were the sole independent correlates of simultaneous changes in intima media thickness (C-reactive protein: beta=0.25; fibroblast growth factor 23: beta=0.26; P<0.001 for both) after renal transplantation. The evolution of intima media thickness after transplantation was largely independent of classic risk factors, including BP, LDL cholesterol, and insulin resistance, as measured by homeostatic model assessment. CONCLUSIONS: Intima media thickness improves after renal transplantation. Such an improvement associates with parallel changes in serum C-reactive protein and fibroblast growth factor 23. These observations are in keeping with the hypothesis that the decline in cardiovascular risk after transplantation, in part, depends on partial resolution of nontraditional cardiovascular risk factors, like inflammation and CKD-mineral bone disorder. PMID- 25542908 TI - Mapping novel immunogenic epitopes in IgA nephropathy. AB - BACKGROUND AND OBJECTIVES: IgA plays a key role in IgA nephropathy (IgAN) by forming immune complexes and depositing in the glomeruli, leading to an inflammatory response. However, the antigenic targets and functional characterization of IgA have been incompletely defined in this disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study was performed in sera from patients who were studied as part of a prospective, observational study of IgAN. These patients (n=22) all had biopsy-proven IgAN within 3 years of study initiation, complete clinical data, annual urinary inulin clearance for GFRs, and at least 5 years of follow-up. Progression was defined as loss of >5 ml/min per 1.73 m(2) per year of inulin clearance measured over at least 5 years. A protein microarray was used for detection of IgAN-specific IgA autoantibodies in blood across approximately 9000 human antigens to specifically identify the most immunogenic protein targets that drive IgA antibodies in IgAN (n=22), healthy controls (n=10), and non-IgAN glomerular diseases (n=17). Results were validated by ELISA assays in sera and by immunohistochemistry in IgAN kidney biopsies. IgA specific antibodies were correlated with clinical and histologic variables to assess their effect on disease progression and prognosis. RESULTS: Fifty-four proteins mounted highly significant IgA antibody responses in patients with IgAN with a false discovery rate (q value) of <=10%; 325 antibodies (P<=0.05) were increased overall. Antitissue transglutaminase IgA was significantly elevated in IgAN (P<0.001, q value of 0%). IgA antibodies to DDX4 (r=-0.55, P=0.01) and ZADH2 (r=-0.48, P=0.02) were significantly correlated with the decline of renal function. Specific IgA autoantibodies are elevated in IgAN compared with normal participants and those with other glomerular diseases. CONCLUSIONS: In this preliminary study, IgA autoantibodies target novel proteins, highly expressed in the kidney glomerulus and tubules. These IgA autoantibodies may play important roles in the pathogenesis of IgAN. PMID- 25542909 TI - Estimation of GFR using beta-trace protein in children. AB - BACKGROUND AND OBJECTIVES: Sex may affect the performance of small molecular weight proteins as markers of GFR because of differences in fat mass between the two sexes. The hypothesis was that the diagnostic performance of beta-trace protein, a novel marker of GFR, would be significantly better in boys than in girls. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: GFR, height, weight, serum creatinine, and beta-trace protein were measured in 755 children and adolescents (331 girls) undergoing (99)technetium diethylenetriamine penta-acetic acid renal scans from July of 1999 to July of 2006. Boys and girls were separated into formula generation cohorts (284 boys and 220 girls) and formula validation cohorts (140 boys and 111 girls). GFR-estimating formulas on the basis of beta trace protein, creatinine, and height were derived using stepwise linear regression analysis of log-transformed data. The slope of the regression lines of the sex-specific eGFRs were compared. Bland-Altman analysis was used for testing agreement between (99)technetium diethylenetriamine penta-acetic acid GFR and calculated GFR both with this equation in boys and girls as well as previously established Benlamri, White, and Schwartz formulas. RESULTS: In the stepwise regression analysis, beta-trace protein (R(2)=0.73 for boys and R(2)=0.65 for girls) was more important than creatinine (which increased R(2) to 0.81 for boys and R(2) to 0.75 for girls) and height (which increased R(2) to 0.88 for boys and R(2) to 0.80 for girls) in the data generation groups. GFR can be calculated using the following formulas:[Formula: see text]and[Formula: see text]Bland Altman analysis showed better performance in boys than in girls. The new formulas performed significantly better than the previous Benlamri, White, and Schwartz formulas with respect to bias, precision, and accuracy. CONCLUSIONS: Improved and sex-specific formulas for the estimation of GFR in children on the basis of beta trace protein, serum creatinine, and height are now available. PMID- 25542910 TI - Significant reduction in ventilator-associated pneumonia with the Venner-PneuX System in high-risk patients undergoing cardiac surgery: the Low Ventilator Associated-Pneumonia study. AB - OBJECTIVES: This study assessed whether the Venner-PneuX endotracheal tube (ET) system, which has sub-glottic suction as well as irrigation ports and continuous cuff-pressure monitoring, is associated with a reduction in ventilator-associated pneumonia (VAP) when compared with the standard ET in high-risk patients undergoing cardiac surgery. METHODS: This was a single-institution, prospective, randomized control trial. Patients were categorized as either Group A (Venner PneuX ET tube, n = 120) or Group B (Standard ET tube, n = 120). Inclusion criteria included patients over the age of 70 years and/or impaired left ventricular function (LVEF <50%) undergoing cardiac surgery. Patients were monitored for VAP for up to 48 h post extubation and the diagnosis of VAP was according to the centres for disease control definition. RESULTS: There were no significant differences in the patients' demographics. The mean (SD) ages for the two groups were 72.4 (8.2) and 72.1 (7.4) years (P = 0.6), respectively. The mean EuroSCORE was 6.39 (2.2) for Group A and 6.48 (2.6) for Group B (P = 0.9). The median intubation times were 14.7 (7.3, 2927.2) h and 13 (2.5, 528.7) h, respectively. VAP incidence was significantly lower in the Venner-PneuX ET group, being 10.8% when compared with 21% in the standard ET group (P = 0.03). There was no significant difference between the two groups in terms of intensive care unit stay (P = 0.2) and in-hospital mortality (P = 0.2). A binary logistic regression analysis (type of ET tube, age, LVEF, history of lung disease, smoking history, surgical procedure, EuroSCORE, cardiopulmonary bypass time, blood transfusion, intubation duration among others) confirmed that the Venner-PneuX ET tube was associated with significant VAP reduction (Odds ratio 0.45, P = 0.03). CONCLUSIONS: The Venner-PneuX VAP prevention system is associated with a significant reduction in VAP. This can potentially lead to significant cost reductions and should be implemented as part of the VAP reduction bundle. PMID- 25542911 TI - E-Cigarettes and Smoking Cessation: Insights and Cautions From a Secondary Analysis of Data From a Study of Online Treatment-Seeking Smokers. AB - BACKGROUND: Evidence from observational studies regarding the association between electronic cigarette (e-cigarette) use and cessation is mixed and difficult to interpret. Utilizing 2 analytic methods, this study illustrates challenges common in analyses of observational data, highlights measurement challenges, and reports associations between e-cigarette use and smoking cessation. METHODS: Data were drawn from an ongoing web-based smoking cessation trial. The sample was comprised of 2,123 participants with complete 3-month follow-up data. Logistic regression models with and without entropy balancing to control for confounds were conducted to evaluate the association between e-cigarette use and 30-day cigarette smoking abstinence. RESULTS: At follow-up, 31.7% of participants reported using e cigarettes to quit in the past 3 months. E-cigarette users differed from nonusers on baseline characteristics including cigarettes per day, Fagerstrom score, quit attempt in the past year, and previous use of e-cigarettes to quit. At follow-up, e-cigarette users made more quit attempts and employed more cessation aids than smokers who did not use e-cigarettes to quit. E-cigarette use was negatively associated with abstinence after adjustment for baseline characteristics; however, the association was not significant after additional adjustment for use of other cessation aids at 3 months. CONCLUSIONS: The magnitude and significance of the estimated association between e-cigarette use and cessation in this study were dependent upon the analytical approach. Observational studies should employ multiple analytic approaches to address threats to validity. Future research should employ better measures of patterns of and reasons for e-cigarette use, frequency of e-cigarette use, and concurrent use of cessation aids. PMID- 25542912 TI - Predictors of pregnant quitters' intention to return to smoking postpartum. AB - INTRODUCTION: Although many pregnant women quit smoking, most return to smoking postpartum. Returning to smoking is strongly related to women's stated intention about smoking during pregnancy. We examined factors related to women's intention to return to smoking to improve intervention trials. METHODS: We report cross sectional baseline data from a randomized controlled trial to prevent postpartum return to smoking. Women (n = 382; 98% consent rate) were English-speaking women who smoked at least 100 cigarettes in their lifetimes and at least 5 cigarettes a day prior to becoming pregnant. We fit logistic regression models to test whether women's intention to return to smoking was associated with demographic and smoking factors such as race, parity, and smoker self-identity. RESULTS: Forty three percent of women had a strong intention of returning to smoking. Factors independently associated with intending to return to smoking were: stating they did not want to be currently pregnant (OR = 2.1, CI = 1.1-3.9), reporting being abstinent for fewer days (OR = 0.8, CI = 0.7-0.9), being less concerned about the harmful effects of smoking to themselves (OR = 1.6, CI = 0.9-2.8), viewing quit as temporary (OR = 2.1, CI = 1.2-3.6), and self-identifying selves as smokers (OR = 8.7, CI = 5.0-15.2). CONCLUSIONS: Although some factors related to intention to return to smoking were unchangeable, it might be possible to attempt to change women's attribution of why they quit to be more permanent and to have them change their self-identity to be a "nonsmoker" from a "smoker who is not currently smoking." Helping women have stronger intentions to stay quit could promote less return to smoking postpartum. PMID- 25542914 TI - SRNT Trainee Network Spotlight: Trainee Network Advisory Board. PMID- 25542913 TI - Correlates of Converted and Native Nondaily Smoking. AB - OBJECTIVES: Nondaily smokers represent a growing proportion of current smokers in the United States. However, little is known about which characteristics are important in distinguishing between nondaily smokers who are former daily smokers (converted nondaily) and nondaily smokers who never smoked daily (native nondaily). This study contrasts converted and native nondaily smokers on demographic, psychosocial, tobacco-related characteristics and quit intentions and behaviors in a tri-ethnic sample (Blacks, Whites, and Latinos) of smokers. METHODS: Smokers were recruited for a web-based survey using an online panel survey company. Participants were 1,201 nondaily smokers (904 converted nondaily smokers and 297 native nondaily smokers). A multivariable logistic regression was conducted to assess the associations between demographic, smoking-related, and psychosocial variables with converted versus native nondaily smoking. RESULTS: Logistic regression indicated that number of years smoking, years as a nondaily smoker, number of days smoked in a month, smoking dependence, identity as a smoker, and number of smoking cessation methods used were correlates of being converted nondaily smokers versus native nondaily smokers. CONCLUSIONS: Clinicians and researchers should consider characteristic variations in nondaily smokers when designing and implementing intervention efforts targeting this smoking population. PMID- 25542915 TI - Knowledge About E-Cigarette Constituents and Regulation: Results From a National Survey of U.S. Young Adults. AB - OBJECTIVES: To examine young adults' knowledge of e-cigarette constituents and regulation and its association with product use and self-reported exposure to marketing. METHODS: Young adults (18-34 years, N = 1,247) from a U.S. web panel were surveyed in March 2014. Using multinomial logistic regressions, self reported exposure to marketing was examined as a predictor of whether participants responded correctly (reference category), incorrectly, or "don't know" to four knowledge items-whether e-cigarettes contain nicotine, contain toxic chemicals, are regulated by government for safety, and are regulated for use as a cessation aid. Analyses adjusted for demographics and smoking status and were weighted to match the U.S. young adult population. RESULTS: Most respondents did not know if e-cigarettes, contain toxic chemicals (48%), are regulated for safety (61%), and are regulated as cessation aids (68%); fewer than 37% answered all of these items correctly. Current users of e-cigarettes (past 30 days) had a lower likelihood of being incorrect about safety testing (p = .006) and being regulated as a cessation aid (p = .017). Higher exposure to e-cigarette marketing was associated with a lower likelihood of responding "don't know" than being correct, and with a higher likelihood of being incorrect as opposed to correct about e-cigarettes containing nicotine. CONCLUSIONS: Knowledge about e-cigarette constituents and regulation was low among young adults, who are the largest consumer group for these products. Interventions, such as warning labels or information campaigns, may be necessary to educate and correct misinformation about these products. PMID- 25542916 TI - Associations of Weight Concerns With Self-Efficacy and Motivation to Quit Smoking: A Population-Based Study Among Finnish Daily Smokers. AB - INTRODUCTION: Concerns about weight gain occurring after smoking cessation may affect motivation and self-efficacy towards quitting smoking. We examined associations of smoking-specific weight concerns with smoking cessation motivation and self-efficacy in a population-based cross-sectional sample of daily smokers. METHODS: Six-hundred biochemically verified (blood cotinine) current daily smokers comprising 318 men and 282 women aged 25-74 years, were studied as part of the National FINRISK (Finnish Population Survey on Risk Factors on Chronic, Noncommunicable Diseases) study and its DIetary, Lifestyle and Genetic factors in the development of Obesity and Metabolic syndrome (DILGOM) sub-study that was conducted in Finland in 2007. Self-reported scales were used to assess weight concerns, motivation and self-efficacy regarding the cessation of smoking. Multiple regression analyses of concerns about weight in relation to motivation and self-efficacy were conducted with adjustments for sex, age (years), body mass index (BMI, [kg/m(2)]), physical activity (times per week), and further controlled for nicotine dependence (Fagerstrom Test for Nicotine Dependence). RESULTS: Higher levels of weight concerns were associated with lower self-efficacy (beta = -0.07, p < .001) after adjusting for sex and age. The association remained after additional adjustment for BMI and physical activity (beta = -0.07, p < .001). After further controlling for nicotine dependence the association became weaker but remained significant (beta = -0.04, p = .02). There were no statistically significant associations between concerns about weight and motivation for smoking cessation (beta = 0.02, p = 0.16). CONCLUSIONS: These cross-sectional population-based data do not support earlier findings that suggest that smokers with high levels of weight concerns are less motivated to quit smoking. Our data suggest that daily smokers who are highly concerned about weight may have lower self-efficacy for cessation of smoking. PMID- 25542918 TI - E-Cigarette Market Trends in Traditional U.S. Retail Channels, 2012-2013. AB - INTRODUCTION: E-cigarette sales continue to increase in the United States. To date, little surveillance research has documented the specific product attributes driving growth. This study uses national market scanner data to describe sales trends in traditional U.S. tobacco retail channels between 2012 and 2013 and identifies product features associated with sales increases. METHODS: Data on e cigarette sales in convenience stores, drug stores, grocery stores, and mass merchandisers in the United States were obtained from the Nielsen Company. Each product was coded for attributes such as brand, flavor, and unit size. Total sales volume, market share, and percent growth were calculated for various product attributes. RESULTS: E-cigarette sales more than doubled between 2012 and 2013, from $273.6 million to $636.2 million, respectively. Growth was particularly strong in the convenience store channel. Blu eCigs quickly emerged as the best-selling brand and in 2013 constituted nearly half (44.1%) of overall sales. Although fruit-flavored and other flavored products experienced marked growth, unflavored and menthol e-cigarettes overwhelmingly dominated the market. Sales of single unit products (likely disposable e-cigarettes) increased by 216.4%, a much faster rate than multi-unit packs and cartridge refills. CONCLUSIONS: In traditional U.S. retail channels, particularly the convenience store channel, sales of e-cigarettes continue to grow, with brands like blu and disposable products as the likely drivers. Given the rapidly-changing market, expanded surveillance is needed to monitor sales not only in traditional retail locations, but sales online and in specialty "vape shops," as well. PMID- 25542917 TI - Relationships of PROP Taste Phenotype, Taste Receptor Genotype, and Oral Nicotine Replacement Use. AB - INTRODUCTION: Recommended dosage of oral nicotine replacement therapy (NRT) product is often not achieved in smoking cessation attempts. n-6-propylthiouracil (PROP) bitter taste phenotype may be a potential risk factor for non-adherence to oral NRT products due to their bitter taste. There is limited literature on this phenotype in the context of smoking and none in relation to oral NRT pharmacotherapy. METHODS: The association of PROP taste phenotype with NRT usage and sensory response to products was examined. In a cross-over experimental design, 120 participants received a 1 week supply of nicotine inhalers and 1 week of nicotine lozenges with random assignment to order. Mixed effects linear model analyses were conducted. RESULTS: PROP taste phenotype and taste receptor genotype were not associated with NRT usage or sensory response to NRT, after adjusting for other factors. However, PROP non-tasters used a higher number of lozenges per day (continuous exposure) than nicotine cartridges (intermittent exposure). Unexpectedly, half of baseline PROP non-tasters shifted to taster phenotype 2 weeks after smoking cessation or reduction. Menthol cigarette smokers identified higher NRT strength of sensation scores than nonmenthol smokers. Taste receptor genotype was related to PROP taste phenotype (Kendall tau = .591, p = .0001). CONCLUSIONS: A nonsignificant relationship of PROP phenotype and NRT usage may be associated with NRT under-dosing and limited variance in the outcome variable. PROP non-tasters' greater use of lozenges is consistent with nicotine exposure being less aversive to non-tasters. Further research of this and other factors impacting NRT usage are warranted to effectively inform smoking cessation pharmacotherapy. PMID- 25542919 TI - Reduced Influence of Monetary Incentives on Go/NoGo Performance During Smoking Abstinence. AB - INTRODUCTION: Smokers may experience decreased sensitivity to nondrug incentives during acute smoking deprivation. This decreased sensitivity may undermine attempts to encourage continued abstinence by enhancing cognitive processes through the use of monetary incentives. This study assessed whether the capacity for monetary incentives to enhance cognitive performance was compromised in nicotine-deprived smokers. METHOD: Eighteen smokers performed an incentivized Go/NoGo task on 2 occasions, once after smoking as usual prior to the session, and once after undergoing 12-hr abstinence. Participants could earn up to $5.00 ($2.50 per session) based on their performance on reward blocks of the Go/NoGo task. RESULTS: Performance was significantly more accurate on incentivized NoGo, frequent-Go, and infrequent-Go trials relative to neutral trials during the smoke as usual session. Participants also produced fewer premature, impulsive responses on rewarded versus neutral blocks during the smoke as usual session. No significant difference between reward and neutral blocks was observed on any of the 4 performance indices during the abstinent session. CONCLUSIONS: The ability for monetary incentives to enhance inhibitory control may be compromised during acute abstinence in smokers. These findings may have implications for contingency management treatment programs which are thought to promote continued abstinence partly by facilitating the allocation of cognitive resources to processes that encourage continued abstinence by increasing the value associated with continued abstinence. PMID- 25542920 TI - Change in Body Weight Does Not Mediate the Relationship Between Exercise and Smoking Cessation Among Weight-Concerned Women Smokers. AB - INTRODUCTION: Exercise has received attention as a method to prevent or reduce postcessation weight gain. However, little is known about how weight changes following quit attempts contribute to the relationship between exercise and smoking cessation. The present study assessed how exercise relates to cessation and whether initial changes in exercise after quitting smoking promote cessation through attenuated weight gain. METHODS: Weight-concerned women smokers (N = 342) receiving cessation treatment provided biochemical validation of cessation, reported weekly exercise activities, and were weighed at 1, 3, and 6 months following treatment initiation. Survival analyses were used to determine time to and risk of relapse among women who reported engaging in varied levels of exercise at baseline. A mediation analysis was used to examine whether the effect of initial changes in exercise on longer-term cessation was driven by change in weight. All analyses were adjusted for relevant covariates. RESULTS: Women smokers who reported high levels of exercise at baseline were less likely to relapse and returned to smoking more gradually than did women who reported low levels of exercise. Change in weight did not mediate the relationship between exercise and cessation. CONCLUSIONS: Cessation interventions utilizing an exercise component may have to develop exercise regimens of either higher duration or greater intensity to produce beneficial cessation outcomes, particularly when targeting sedentary smokers. Given that change in weight did not mediate the relationship between exercise and cessation, it is likely that other mediational processes are involved. PMID- 25542921 TI - On-Line Chemical Composition Analysis of Refillable Electronic Cigarette Aerosol Measurement of Nicotine and Nicotyrine. AB - INTRODUCTION: Electronic cigarettes (e-cigs) generate aerosols that users inhale. Analyses of e-liquids inconsistently report nicotyrine, a nicotine analog that could impede nicotine metabolism, raising questions about nicotyrine formation. METHODS: E-cig aerosols were analyzed on-line using a Thermal Desorption Aerosol Gas Chromatograph. Three e-liquids were tested: an unflavored solution in propylene glycol (PG); an unflavored solution in PG and vegetable glycerin (VG), and a flavored solution in PG and VG. A heating duration experiment determined the nicotyrine to nicotine ratio (NNR) in particle phase as a function of the duration of e-cig activation. An aging experiment determined the NNR in e-liquids and aerosols as a function of time since initial exposure to air and storage condition. RESULTS: Nicotine and nicotyrine were quantified in all 3 e-liquids and aerosols. Duration of e-cig activation was inversely related to NNR (NNR = 0.04 with 3-s activation, 0.26 with 0.5 s). Aging influenced both e-liquid NNR and aerosol NNR. On average, the e-liquid NNR increased from 0.03 at 11 days after opening to 0.08 after 60 days. For similar heating durations, aerosol NNR increased from 0.05 at 11 days to 0.23 after 60 days. Storage conditions had little effect on NNR. CONCLUSIONS: E-cig aerosols have variable nicotyrine quantities. Aerosol NNR depends on vaping technique and time elapsed since the e liquid was exposed to air. It is hypothesized that aerosolized nicotyrine could facilitate nicotine absorption, inhibit the metabolism of nicotine, and reduce a user's urge to smoke. PMID- 25542923 TI - Novel therapeutic approaches for neglected infectious diseases. PMID- 25542922 TI - Assessing and Predicting Susceptibility to Waterpipe Tobacco Use Among College Students. AB - INTRODUCTION: College youth susceptible to waterpipe tobacco smoking (WTS) represent an important target to intervene upon in order to prevent their uptake of this product. This study examined the performance of a 4-item susceptibility measure to WTS to predict future waterpipe use and correlates of susceptibility. METHODS: A cohort of college students from 11 university campuses in North Carolina and Virginia completed an online survey in 2012 and again in 2013 that assessed WTS susceptibility and subsequent waterpipe use. Tobacco use, marijuana use, binge drinking, and sensation seeking were also assessed. RESULTS: Overall, 964 students who reported having never used waterpipe tobacco in 2012 completed the online surveys both years. Overall, about 27% of college youth were susceptible to WTS each year. Participants susceptible in 2012 were 2.5 times more likely to report having used waterpipe tobacco the subsequent year than non susceptible participants after controlling for significant correlates of waterpipe use. Correlates of susceptibility were: being male, past 30 day cigarette smoking, use of other tobacco products, binge drinking and marijuana use, as well as higher sensation seeking. CONCLUSIONS: A 4-item WTS susceptibility measure predicts future WTS. This measure can be used to identify and intervene upon susceptible college youth to curb further exploration of WTS. Indeed, a nontrivial proportion of college students found susceptible go on to use waterpipe tobacco within a year. PMID- 25542924 TI - Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study. AB - BACKGROUND: Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation wide, population-based study. PATIENTS AND METHODS: A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. RESULTS: In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. CONCLUSIONS: Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS. PMID- 25542925 TI - Expression of estrogen receptors in non-malignant mammary tissue modifies the association between insulin-like growth factor 1 and breast cancer risk. AB - BACKGROUND: Several studies have reported that the insulin-like growth factor 1 (IGF-1) is positively associated with estrogen receptor-positive [ER(+)] breast cancer risk, whereas there is little or no association with respect to ER(-) breast cancer. All comparisons of ER(+) breast cancer cases, however, have been made versus healthy controls, for whom there is no information about the ER expression in their mammary gland. PATIENTS AND METHODS: In the context of a case control investigation conducted in Athens, Greece, we studied 102 women with incident ERalpha(+) breast cancer and compared their IGF-1 blood levels with those of 178 ERalpha(+) and 83 ERalpha(-) women with benign breast disease (BBD) who underwent biopsies in the context of their standard medical care. Data were analysed using multiple logistic regression and controlling for potential confounding variables. RESULTS: ERalpha(+) breast cancer patients had higher IGF 1 levels compared with women with BBD [odds ratio (OR) 1.36, 95% confidence interval (CI): 0.95-1.94, per 1 standard deviation (SD) increase in IGF-1 levels]. When ERalpha status of women with BBD was taken into account, the difference in IGF-1 levels between ERalpha(+) breast cancer patients and women with BBD was clearly driven by the comparison with BBD women who were ERalpha(+) (OR = 1.95, 95% CI: 1.31-2.89 per 1 SD increase in IGF-1 levels), whereas there was essentially no association with IGF-1 levels when ERalpha(+) breast cancer patients were compared with ERalpha(-) BBD women. These contrasts were particularly evident among post/peri-menopausal women. CONCLUSIONS: We found evidence in support of an interaction of IGF-1 with the expression of ERalpha in the non-malignant mammary tissue in the context of breast cancer pathogenesis. This is in line with previous evidence suggesting that IGF-1 increases the risk of ER(+) breast cancer. PMID- 25542926 TI - Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis. AB - BACKGROUND: New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin alpha, epoetin beta, darbepoetin alpha, biosimilars). PATIENTS AND METHODS: A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. RESULTS: Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. CONCLUSIONS: After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data. PMID- 25542928 TI - Constants in an era of change. PMID- 25542927 TI - Modified screening and ranking algorithm for copy number variation detection. AB - MOTIVATION: Copy number variation (CNV) is a type of structural variation, usually defined as genomic segments that are 1 kb or larger, which present variable copy numbers when compared with a reference genome. The screening and ranking algorithm (SaRa) was recently proposed as an efficient approach for multiple change-points detection, which can be applied to CNV detection. However, some practical issues arise from application of SaRa to single nucleotide polymorphism data. RESULTS: In this study, we propose a modified SaRa on CNV detection to address these issues. First, we use the quantile normalization on the original intensities to guarantee that the normal mean model-based SaRa is a robust method. Second, a novel normal mixture model coupled with a modified Bayesian information criterion is proposed for candidate change-point selection and further clustering the potential CNV segments to copy number states. Simulations revealed that the modified SaRa became a robust method for identifying change-points and achieved better performance than the circular binary segmentation (CBS) method. By applying the modified SaRa to real data from the HapMap project, we illustrated its performance on detecting CNV segments. In conclusion, our modified SaRa method improves SaRa theoretically and numerically, for identifying CNVs with high-throughput genotyping data. AVAILABILITY AND IMPLEMENTATION: The modSaRa package is implemented in R program and freely available at http://c2s2.yale.edu/software/modSaRa. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25542934 TI - Sonographic and cytopathologic correlation of papillary thyroid carcinoma variants. AB - Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and constitutes more than 70% of thyroid malignancies. Although TNM staging is the most widely used parameter for determination of therapeutic plans, recent studies have suggested that different histopathologic variants of PTC can also have different clinical courses and patient prognoses. Sonographic criteria for PTC are well established and include a taller-than-wide shape, an irregular margin, microcalcifications, and marked hypoechogenicity. The role of sonography has expanded to enable the characterization of PTC variants based on their sonographic features. Tall cell and diffuse sclerosing variants appear to have more aggressive clinical courses with unfavorable prognoses, whereas the more recently described cribriform-morular and Warthin-like variants have relatively indolent clinical courses. The prognoses of patients with follicular, solid, columnar cell, and oncocytic variants are still controversial and may be similar to the prognosis of conventional PTC. Understanding the sonographic characteristics of PTC variants with clinicopathologic correlation may be helpful for suggesting an appropriate treatment plan. PMID- 25542935 TI - A taller-than-wide shape is a good predictor of papillary thyroid carcinoma in small solid nodules. AB - OBJECTIVES: The purpose of this study was to evaluate whether a nodule with a taller-than-wide shape (ie, an anteroposterior diameter that is longer than the transverse diameter on a transverse or longitudinal plane [anteroposterior-to transverse ratio] >1) is a good predictor of papillary thyroid carcinoma (PTC) according to nodule size. METHODS: We retrospectively examined 207 thyroid nodules in our hospital from September 2011 to February 2013. Nodules were divided into groups by size: small (<=0.5 cm; group A), medium (0.5-1 cm; group B), and large (>1 cm; group C). Sonographic features were defined as an anteroposterior-to-transverse ratio greater than 1, microcalcifications, blurred margins, and hypoechogenicity. RESULTS: An anteroposterior-to-transverse ratio greater than 1 was the most accurate sonographic feature for predicting PTC in small nodules, with high sensitivity (81.4%) and specificity (96.8%), but it was not accurate in large nodules (>1 cm). Microcalcifications showed higher sensitivity (P< .05) in large nodules (60.0%) than in small ones (27.9%). Hypoechogenicity and blurred margins showed high sensitivity (95.3% and 97.7%, respectively) but low specificity (19.4% and 29.9%) for diagnosis of PTC in small thyroid nodules. An anteroposterior-to-transverse ratio greater than 1 in conjunction with another sonographic feature achieved the highest diagnostic accuracy in small nodules. CONCLUSIONS: The predictive values of sonographic features depend on nodule size. An anteroposterior-to-transverse ratio greater than 1, especially in conjunction with another sonographic risk factor, showed superior performance for PTC diagnosis in small nodules. PMID- 25542932 TI - Asymmetrical macromolecular complex formation of lysophosphatidic acid receptor 2 (LPA2) mediates gradient sensing in fibroblasts. AB - Chemotactic migration of fibroblasts toward growth factors relies on their capacity to sense minute extracellular gradients and respond to spatially confined receptor-mediated signals. Currently, mechanisms underlying the gradient sensing of fibroblasts remain poorly understood. Using single-particle tracking methodology, we determined that a lysophosphatidic acid (LPA) gradient induces a spatiotemporally restricted decrease in the mobility of LPA receptor 2 (LPA2) on chemotactic fibroblasts. The onset of decreased LPA2 mobility correlates to the spatial recruitment and coupling to LPA2-interacting proteins that anchor the complex to the cytoskeleton. These localized PDZ motif-mediated macromolecular complexes of LPA2 trigger a Ca(2+) puff gradient that governs gradient sensing and directional migration in response to LPA. Disruption of the PDZ motif mediated assembly of the macromolecular complex of LPA2 disorganizes the gradient of Ca(2+) puffs, disrupts gradient sensing, and reduces the directional migration of fibroblasts toward LPA. Our findings illustrate that the asymmetric macromolecular complex formation of chemoattractant receptors mediates gradient sensing and provides a new mechanistic basis for models to describe gradient sensing of fibroblasts. PMID- 25542936 TI - A novel approach to patient self-monitoring of sonographic examinations using a head-mounted display. AB - OBJECTIVES: Patients' use of a head-mounted display during their sonographic examinations could provide them with information about their diseases in real time and might help improve "patient-centered care." We conducted this prospective study to evaluate the feasibility of a modern head-mounted display for patient self-monitoring of sonographic examinations. METHODS: In November and December 2013, 58 patients were enrolled. Patients wore a head-mounted display (HMZ-T2; Sony Corporation, Tokyo, Japan) during their sonographic examinations and watched their own images in real time. After the sonographic examinations, the patients completed a questionnaire, in which they evaluated the utility of the head-mounted display, their understanding of their diseases, their satisfaction with using the head-mounted display, and any adverse events. Until November 26, 2013, patients' names were requested on the questionnaire; after that date, the questionnaire was changed to be anonymous. RESULTS: Of the 58 patients, 56 (97%) elected to participate in this study. The head-mounted display was reported to have good image quality by 42 patients (75%) and good wearability by 39 (70%). Thirty-six patients (64%) reported they had deepened their understanding of their diseases. There were no major complications, and only 2 patients (4%) had mild eye fatigue. There was no significant association between questionnaire results and patient characteristics. None of the questionnaire results changed significantly after the questionnaire was made anonymous. CONCLUSIONS: The use of a modern head-mounted display by patients during sonographic examinations provided good image quality with acceptable wearability. It could deepen their understanding of their diseases and help develop patient centered care. PMID- 25542937 TI - Differentiation of metastatic cervical lymph nodes with ultrasound elastography by virtual touch tissue imaging: preliminary study. AB - OBJECTIVES: The purpose of this study was to investigate the clinical usefulness of acoustic radiation force impulse elastography for the differential diagnosis of cervical lymph nodes. METHODS: Virtual touch tissue imaging (Siemens Medical Solutions, Mountain View, CA) was analyzed in 81 patients (mean age, 46.6 years; range, 5-82 years) with 81 lymph nodes (45 metastatic nodes and 36 benign nodes). RESULTS: Most benign lymph nodes were slightly darker or the same in brightness compared with surrounding tissue, whereas most metastatic nodes were obviously darker. The mean area ratio of benign lymph nodes +/- SD (1.05 +/- 0.15) was statistically lower than the mean area ratio of metastatic lymph nodes (1.39 +/- 0.20; P < 0.001). The area ration cutoff level for metastatic lymph nodes was estimated to be 1.16. With the use of a receiver operating characteristic curve with this cutoff value, the area ratio predicted malignancy with sensitivity of 91.1%, specificity of 83.3%, and an area under the curve of 0.925. CONCLUSIONS: Acoustic radiation force impulse imaging is feasible for cervical lymph nodes. The Virtual Touch tissue imaging technique can complement conventional sonography, thereby making it easier to diagnose cervical lymph nodes. PMID- 25542938 TI - Effects of ultrasound implementation on physical examination learning and teaching during the first year of medical education. AB - OBJECTIVES: Increasing emphasis has been placed on point-of-care ultrasound in medical school. The overall effects of ultrasound curriculum implementation on the traditional physical examination skills of medical students are still unknown. We studied the effects on the Objective Standardized Clinical Examination (OSCE) scores of year 1 medical students before and after ultrasound curriculum implementation. METHODS: An ultrasound curriculum was incorporated into the physical diagnosis course for year 1 medical students in the 2012-2013 academic year. We performed a prospective observational study comparing traditional OSCE scores of year 1 medical students exposed to the ultrasound curriculum (post-ultrasound) versus historic year 1 medical student controls (pre ultrasound) with no ultrasound exposure. Questionnaire data were also obtained from year 1 medical students and physical diagnosis faculty to assess attitudes toward ultrasound implementation. RESULTS: The final overall OSCE scores were graded with a 5-point Likert-type scale from unsatisfactory to outstanding. There was a significant increase in outstanding scores in the post-ultrasound compared to the pre-ultrasound group (27.0% versus 10.9%; P< .001). The post-ultrasound group had significantly (P< .05) increased first-time pass rates on blood pressure measurements, the abdominal examination, and professionalism. Student and physical diagnosis faculty questionnaire data showed an overall positive response, with most agreeing or strongly agreeing that ultrasound should be included in the future year 1 medical student curriculum. CONCLUSIONS: Ultrasound implementation into a physical diagnosis curriculum for year 1 medical students is feasible and may improve their overall traditional physical examination skills. PMID- 25542939 TI - Benefits of sonography in diagnosing suspected uncomplicated acute diverticulitis. AB - OBJECTIVES: Despite evidence demonstrating equivalent accuracy of sonography and computed tomography (CT) in the workup of mild/uncomplicated acute diverticulitis, CT is overwhelmingly performed as the initial diagnostic test, particularly in the acute setting. Our study evaluated potential radiation and turnaround time savings associated with performing sonography instead of CT as the initial diagnostic examination in the workup of suspected uncomplicated acute diverticulitis. METHODS: We retrospectively reviewed medical records from January 2010 to December 2012 for patients presenting with clinical symptoms of acute diverticulitis. Patients were categorized as a whole and subgrouped by age (>40 and <40 years). A modified Hinchey classification (Am Surg 1999; 65:632-636) was used to stage the severity of the disease. The effective radiation dose was calculated by multiplying the dose length product from the scanner by the standard conversion coefficient (k= 0.0021 mSv/mGy * cm). The turnaround time for patients was calculated as the time the examination was ordered by the emergency department physician or staff to the time the report was finalized. RESULTS: Our study included 253 patients (172 male and 81 female; mean age +/- SD, 50.2 +/- 11.7 years; 132 >40 years and 121 <40 years). The distribution of patients by the modified Hinchey classification was 210 (stages 0 and 1a), 26 (stages 1b and 2), 17 (stages 3 and 4), 0 (fistula), and 0 (obstruction). The estimated CT radiation dose per patient was 21 +/- 5.2 mSv. Mean turnaround times for CT and sonography were 138.5 +/- 76.9 and 51.3 +/- 44 minutes, respectively. CONCLUSIONS: Sonography is a lower-cost, faster, and radiation-free alternative that measures up to the diagnostic standards of CT for management of suspected mild or uncomplicated acute diverticulitis. PMID- 25542940 TI - Nonsurgical management of childhood intussusception: retrospective comparison between sonographic and fluoroscopic guidance. AB - OBJECTIVES: The purpose of this study was to compare the effectiveness of sonography and fluoroscopy in guiding intussusception reduction and evaluate possible complications for each procedure. METHODS: A retrospective analysis was performed by reviewing 31 cases of intussusception diagnosed and managed between January 2009 and January 2014 at the University of California, Davis Children's Hospital, after obtaining approval from the Institutional Review Board. To eliminate other confounding factors related to technique and experience, only cases performed by 2 pediatric radiologists who exclusively used either fluoroscopy or sonography were compared. RESULTS: Fourteen patients (age range, 6 35 months) were treated by sonographic guidance using saline, and another 17 patients (age range, 2-57 months) were treated by fluoroscopy using either air or a water-soluble contrast agent. All 14 patients (100%) who underwent sonographically guided reduction were successfully treated without complications. Fourteen of the 17 patients (82%) who underwent fluoroscopic guidance had successful reductions. One complication of perforation was documented. CONCLUSIONS: Sonography and fluoroscopy are equally effective in the nonsurgical management of childhood intussusception. The absence of ionizing radiation and better visualization of possible pathologic lead points makes sonography the ideal method. PMID- 25542941 TI - A new simple technique for 3-dimensional sonographic assessment of the pelvic floor muscles. AB - OBJECTIVES: The purpose of this study was to assess the reproducibility of a new technique for 3-dimensional (3D) pelvic floor sonography: OmniView combined with Volume Contrast Imaging (VCI; GE Healthcare, Kretz Ultrasound, Zipf, Austria) for pelvic hiatal area measurement. In addition, we aimed to study the intermethod agreement between the new technique and the standard 3D rendering method. METHODS: We acquired a static 3D sonographic transperineal volume from 124 nulliparous asymptomatic women and 118 women with symptoms of pelvic floor dysfunction. Each 3D data set was analyzed by the OmniView-VCI technique to measure the pelvic hiatal area twice by one operator and once by another to assess intraobserver and interobserver reproducibility. The first operator later measured the hiatal area using the 3D rendering method to evaluate intermethod agreement. Reproducibility and intermethod agreement were studied by the intraclass correlation coefficient and Bland-Altman method. RESULTS: Hiatal area measurements by the OmniView-VCI technique showed high intraobserver and interobserver reproducibility in both asymptomatic and symptomatic women. In addition, high agreement was shown between the new technique and 3D rendering in both groups. No systematic differences were noted in any of the reliability studies performed. The new technique took slightly less time to calculate the hiatal area than the standard rendering method in both asymptomatic and symptomatic women. CONCLUSIONS: OmniView-VCI is a reliable method for pelvic hiatal area measurement. Further studies are needed to assess its reliability under contraction and the Valsalva maneuver and to evaluate its usefulness and reproducibility for diagnosis of levator ani lesions. PMID- 25542942 TI - Dynamic high-resolution sonography compared to magnetic resonance imaging for diagnosis of temporomandibular joint disk displacement. AB - OBJECTIVES: The purpose of this study was to determine the value of dynamic high resolution sonography for evaluation of temporomandibular joint (TMJ) disk displacement compared to magnetic resonance imaging (MRI) with the mouth closed and during the maximal mandibular range of motion. METHODS: Dynamic high resolution sonography with the mouth closed and during the maximal mandibular range of motion was performed on 39 consecutive patients (78 joints; 13 male and 26 female; age range, 18-77 years; mean age +/- SD, 37.23 +/- 16.26 years) with TMJ disorders. A TMJ MRI study was performed 1 to 7 days after sonography. We searched for signs of disk displacement and findings compatible with degenerative joint disease. Both studies were performed and interpreted independently by blinded operators. RESULTS: Magnetic resonance imaging depicted 22 normal joints (28.2%), 21 (26.9%) with anterior disk displacement with reduction, 15 (19.2%) with anterior disk displacement without reduction, and 20 (25.6%) with degenerative disease. Sonography depicted 30 normal joints (38.5%), 22 (28.2%) with anterior disk displacement with reduction, 12 (15.4%) with anterior disk displacement without reduction, and 14 (17.9%) with degenerative disease. The overall sensitivity, specificity, and accuracy of sonography for diagnosis of disk displacement were 74.3%, 84.2%, and 77.7%, respectively. The sensitivity, specificity, and accuracy for diagnosis of disk displacement with reduction were 78.6%, 66.7%, and 73.0%, and the values for diagnosis of disk displacement without reduction were 66.7%, 78.6%, and 73.0%. CONCLUSIONS: Dynamic high resolution sonography is a potential imaging method for diagnosis of TMJ disk displacement and degenerative diseases. Further studies are needed to make dynamic high-resolution sonography the first-line test for diagnosis of TMJ disk displacement. PMID- 25542943 TI - Sonographically guided posterior subtalar joint injections via the sinus tarsi approach. AB - OBJECTIVES: To determine the feasibility and accuracy of sonographically guided posterior subtalar joint (PSTJ) injections performed through the sinus tarsi. METHODS: A single experienced operator completed 10 sonographically guided PSTJ injections via the sinus tarsi on 10 unembalmed cadaveric ankle-foot specimens. Injections were performed using a 17-5-MHz linear transducer, a 25-gauge, 50-mm needle, and an out-of-plane, anterior-to-posterior needle trajectory parallel to the calcaneal surface. Sonographic assessment for fluid in the posterior and lateral PSTJ recesses, sinus tarsi, and peroneal tendon sheath was performed before and after injections of 2 and 4 mL of tap water. Two additional specimens were injected with a contrast agent: 1 via the sonographically guided approach and another by a computed tomographically guided approach. RESULTS: All 10 sonographically guided PSTJ tap water injections were accurate, distending both the posterior and lateral PSTJ recesses. In addition, all 10 specimens showed posterior recess distension by 2 mL, whereas only 2 specimens (20%) showed lateral recess distension at this volume. By 4 mL, both recesses were clearly distended in all specimens. Both contrast agent injections produced similar PSTJ computed tomographic arthrograms and patterns of recess distension similar to the sonographically guided tap water injections. No sonographically guided PSTJ injection placed fluid in the peroneal tendon sheath. CONCLUSIONS: Sonographically guided PSTJ injections via the sinus tarsi can accurately and specifically deliver injectate into the PSTJ while monitoring injectate flow within the posterior recess. The sinus tarsi approach may be used as an alternative technique to perform sonographically guided PSTJ injections when clinically appropriate. PMID- 25542944 TI - Quantitative assessment of mitral inflow and aortic outflow stroke volumes by 3 dimensional real-time full-volume color flow doppler transthoracic echocardiography: an in vivo study. AB - OBJECTIVES: Noninvasive quantification of left ventricular (LV) stroke volumes has an important clinical role in assessing circulation and monitoring therapeutic interventions for cardiac disease. This study validated the accuracy of a real-time 3-dimensional (3D) color flow Doppler method performed during transthoracic echocardiography (TTE) for quantifying volume flows through the mitral and aortic valves using a dedicated offline 3D flow computation program compared to LV sonomicrometry in an open-chest animal model. METHODS: Forty-six different hemodynamic states in 5 open-chest pigs were studied. Three-dimensional color flow Doppler TTE and 2-dimensional (2D) TTE were performed by epicardial scanning. The dedicated software was used to compute flow volumes at the mitral annulus and the left ventricular outflow tract (LVOT) with the 3D color flow Doppler method. Stroke volumes by 2D TTE were computed in the conventional manner. Stroke volumes derived from sonomicrometry were used as reference values. RESULTS: Mitral inflow and LVOT outflow derived from the 3D color flow Doppler method correlated well with stroke volumes by sonomicrometry (R = 0.96 and 0.96, respectively), whereas correlation coefficients for mitral inflow and LVOT outflow computed by 2D TTE and stroke volumes by sonomicrometry were R = 0.84 and 0.86. Compared to 2D TTE, the 3D method showed a smaller bias and narrower limits of agreement in both mitral inflow (mean +/- SD: 3D, 2.36 +/- 2.86 mL; 2D, 10.22 +/- 8.46 mL) and LVOT outflow (3D, 1.99 +/- 2.95 mL; 2D, 4.12 +/- 6.32 mL). CONCLUSIONS: Real-time 3D color flow Doppler quantification is feasible and accurate for measurement of mitral inflow and LVOT outflow stroke volumes over a range of hemodynamic conditions. PMID- 25542945 TI - Echocardiographic evaluation of aortic atheromas in patients with aortic stenosis. AB - OBJECTIVES: The association of aortic atheromas in patients with isolated aortic stenosis has recently been acknowledged, probably because the pathogenic mechanisms are similar. Therefore, this study evaluated the extent and severity of thoracic aortic atheromas in patients with different grades of aortic stenosis using transesophageal echocardiography. METHODS: We retrospectively evaluated transesophageal echocardiographic examinations of 686 consecutive patients with a diagnosis of aortic stenosis. The prevalence and morphologic characteristics of atheromas in 3 segments of the thoracic aorta were assessed. Plaque thickness was measured at each segment, and the thickest plaque was used to establish severity. Atheromas were graded as mild, moderate, or severe according to plaque thickness (<2, 2-4, or >4 mm, respectively). Aortic stenosis was graded as mild, moderate, or severe on the basis of the gradient and anatomic aortic valve area (>1.5, 1.0 1.5, or <1.0 cm(2)). RESULTS: A total of 382 patients were men, and 304 were women (mean age +/- SD, 74 +/- 15 years); 86% of the patients had aortic atheromas. The severe stenosis group had a significantly higher rate of atheromas (95% versus 40%; P < .001) than the mild stenosis group, with more complex atheromas (52% versus 22%; P< .001). There was no significant difference in the atheroma grades between the severe and moderate stenosis groups, but moderate cases had more moderate and severe atheromas than mild cases (45% and 15% versus 19% and 3%; P < .01). CONCLUSIONS: This study showed a correlation in the extent of aortic atheromas across several degrees of aortic stenosis. Patients with moderate and severe stenosis had more extensive atherosclerotic atheromas than those with mild stenosis. PMID- 25542946 TI - Noninvasive imaging of aortic atherosclerosis by ultrasound biomicroscopy in a mouse model. AB - OBJECTIVES: The noninvasive and accurate evaluation of vessel characteristics in mouse models has become an intensive focus of vascular medicine. This study aimed to apply ultrasound biomicroscopy to evaluate aortic atherosclerotic progression in a low-density lipoprotein receptor (LDL-R) knockout mouse model of atherosclerosis. METHODS: Ten male LDL-R(-/-)C57BL/6 mice aged 16 and 24 weeks and 8 male wild-type C57BL/6 mice aged 16 and 24 weeks were used as experimental and control groups, respectively. Ultrasound biomicroscopy was applied to detect the morphologic characteristics of the aortic root, ascending aorta, aortic arch, and carotid artery and to measure the aortic root intima-media thickness and carotid artery bifurcation. RESULTS: Ultrasound biomicroscopy showed a significant increase in the aortic root intima-media thickness from 0.10 +/- 0.03 mm in 16-week-old mice to 0.16 +/- 0.04 mm in 24-week-old mice (P < .01). The ultrasound biomicroscopically measured intima-media thickness was highly correlated with the histologic measurement (r = 0.81). CONCLUSIONS: Ultrasound biomicroscopy could be used for a noninvasive, accurate, and dynamic analysis of aortic atherosclerosis in LDL-R knockout mice. PMID- 25542947 TI - Differentiation of benign and malignant sub-1-cm breast lesions using contrast enhanced sonography. AB - OBJECTIVES: The purpose of this study was to prospectively assess the diagnostic efficacy of contrast-enhanced sonography for differential diagnosis of sub-1-cm breast lesions. METHODS: Contrast-enhanced sonography was performed in 46 women with 46 sub-1-cm breast lesions scheduled for surgery or biopsy. Histologic results were used as a reference standard. The contrast enhancement pattern, enhancement degree, direction, margin, radial vessels surrounding the lesion, and lesion size discrepancy between contrast-enhanced and conventional sonography were evaluated. RESULTS: The detection rates for increased size, radial vessels surrounding the lesion, and hyperenhancement on contrast-enhanced sonography were significantly higher in the malignant than the benign group (P < .05). The sensitivity, specificity, and accuracy for increased size were 72.7%, 80.0%, and 78.2%, respectively. The sensitivity, specificity, and accuracy for radial vessels surrounding the lesion were 54.5%, 97.1%, and 87.0%. The sensitivity, specificity, and accuracy for hyperenhancement were 81.8%, 60.0%, and 65.0%. No significant difference was found for the enhancement pattern, direction, and margin between the groups. CONCLUSIONS: Contrast-enhanced sonographic features of sub-1-cm breast lesions included increased size on contrast-enhanced sonography, radial vessels surrounding the lesion, and hyperenhancement. Identification of these features is useful for differentiation of small breast lesions. PMID- 25542948 TI - Comparison of lesion detection in the transverse and coronal views on automated breast sonography. AB - OBJECTIVES: The purpose of our study was to compare the accuracy of detection of lesions in the coronal and transverse views on automated breast sonography. METHODS: Three breast radiologists independently interpreted automated breast sonograms from 113 women: 14 with negative findings and 99 with known breast lesions (99 benign and 53 malignant findings). The readers were asked to detect the presence or absence of the abnormalities using the transverse and coronal views in different reading sessions. If a lesion was detected, we evaluated its location, sonographic features, including shape, orientation, margin, boundary type, and echo pattern, and final American College of Radiology Breast Imaging Reporting and Data System assessment category. The reading time was also evaluated. RESULTS: Of 456 potential detections (152 lesions with 3 readers), 80.5% of the detections were made with the transverse view, and 67.3% were made with the coronal view. The detection rates for both malignant and benign lesions were significantly higher for the transverse view than for the coronal view (P < .001). The reading time for the coronal view was less than that for the transverse view (mean +/- SD, 3.83 +/- 1.71 versus 5.57 +/- 2.21 minutes). The intraclass correlation coefficient values for lesion location, distance from the nipple, and lesion size for both views all exceeded 0.7. CONCLUSIONS: Although the coronal view on automated breast sonography showed comparable reliability and a shorter reading time, the detection rate for the coronal view was significantly lower than that for the transverse view in both benign and malignant lesions. It is preferable to reserve the coronal view as an additional method to the transverse view. PMID- 25542949 TI - Chorionic bump on first-trimester sonography: not necessarily a poor prognostic indicator for pregnancy. AB - OBJECTIVES: The purpose of this study was to determine the live birth rate of pregnancies with a diagnosis of a chorionic bump, a convex bulge from the choriodecidual surface into the first-trimester gestational sac. METHODS: Pregnant patients at least 18 years old with the finding of a chorionic bump on first-trimester sonography were included in this prospective observational study. The independent variables were chorionic bump size and number and presence or absence of a history of infertility or coagulation disorder. The primary end point was pregnancy outcome. RESULTS: During the 4-year study period, 52 pregnancies had a diagnosis of a chorionic bump. Overall, 34 resulted in live births, corresponding to an absolute live birth rate of 65%, and 18 were nonviable. Forty-one chorionic bump pregnancies were otherwise normal (ie, pregnancies in which a gestational sac, yolk sac, and embryo with heartbeat were seen at some point), and in this subset, the live birth rate was 83% (34 of 41). All pregnancies with more than 1 chorionic bump (4) ended in demise (100%). The average maximum dimension of the chorionic bump was 1.3 cm (range, 0.5-3.8 cm); however there was not a statistically significant correlation between chorionic bump size and pregnancy outcome (P = .5866; odds ratio, 0.54; 95% confidence interval, 0.06-5.01). Nine patients (17%) had a history of infertility treatment, and 4 (8%) had a history of coagulation disorder. Only 1 chorionic bump pregnancy was associated with a birth defect. CONCLUSIONS: The live birth rate in our chorionic bump cohort was 65% overall and even higher (83%) if the pregnancy was otherwise normal. The clinical implication is that a chorionic bump on first trimester sonography is not necessarily associated with a guarded prognosis. PMID- 25542950 TI - Detailed transabdominal fetal anatomic scanning in the late first trimester versus the early second trimester of pregnancy. AB - OBJECTIVES: To compare visualization rates for early targeted organ scanning at gestational ages ranging from 11 weeks 3 days to 13 weeks 2 days versus 14 weeks 3 days to 16 weeks 2 days. METHODS: We conducted a prospective longitudinal study of patients who presented for nuchal translucency (NT) screening and targeted organ scanning. Extended targeted organ scanning, including the central nervous system, face and neck, chest, heart (including complete echocardiography), digestive system, abdominal wall, urinary system, skeleton, and umbilical cord with its insertion and placenta, was performed on gravidas in 2 age ranges. Uterine artery Doppler mapping was performed during the second scan. All cases were examined twice: once at NT screening (up to 13 weeks 2 days) and again in the early second trimester. RESULTS: A total of 408 women were recruited and scanned twice. Three abnormalities were diagnosed in the second scan that were not seen in the first: dysplastic long bones, tricuspid stenosis, and cleft lip (without palate involvement). None had chromosomal anomalies. Successful visualization rates in all organ systems exceeded 94% in the second trimester. At the first-trimester scan, some systems had high success rates, whereas others were very low; eg, in the brain, the cerebellum and posterior fossa were visualized successfully approximately 50% of the time and the upper lip only approximately 10%. On fetal echocardiography, the 4-chamber view and outflow tracts were imaged successfully approximately 40% of the time, and the kidneys approximately 35%. Uterine artery Doppler mapping was possible in all patients on at least one side. On third-trimester follow-up, we diagnosed 1 mild pulmonary stenosis, 1 autosomal recessive polycystic kidney disease, and 1 ventricular septal defect. CONCLUSIONS: The early second-trimester scan was much more productive than targeted organ scanning performed during the NT window. When counseling women regarding the optimal time for early transabdominal targeted organ scanning, successful visualization rates for various organ systems should be considered. PMID- 25542951 TI - Shear wave elastography in placental dysfunction: comparison of elasticity values in normal and preeclamptic pregnancies in the second trimester. AB - OBJECTIVES: The aim of this study was to determine whether shear wave elastography of the placenta differs between normal pregnancies and pregnancies complicated by preeclampsia between 20 and 23 weeks' gestation. METHODS: A prospective study was performed with 204 consecutive singleton pregnancies that had routine anomaly scanning between 20 and 23 weeks' gestation. One hundred twenty-nine of these patients were examined with shear wave elastography; 101 women who had clinically normal pregnancies with normal fetal biometric measurements and normal deliveries without any perinatal complications formed group A, and 28 women who had a clinical diagnosis of early-onset preeclampsia before anomaly scanning formed group B. Women with either posterior placentations (n = 63) or other obstetric disorders (n = 12) were excluded from the study. RESULTS: Shear wave elastographic values for group B were significantly higher than those for group A (P < .05). No statistically significant difference was found between the elasticity values measured at the center or edge of the placenta (P > .05). CONCLUSIONS: Shear wave elastography differentiates between the placental elasticity of normal pregnancies and pregnancies complicated by preeclampsia when performed during the second trimester. As a new method for tissue characterization, shear wave elastography is useful for evaluation of placental function and can be used as a supplement to existing methods for prediction of preeclampsia. PMID- 25542952 TI - Factors affecting the feasibility of routine first-trimester fetal echocardiography. AB - OBJECTIVES: The purpose of our study was to assess the factors that may improve the feasibility of routine fetal echocardiography at the time of the first trimester scan. METHODS: In this prospective study, we included 616 healthy singleton fetuses. Examinations were performed transabdominally by a single sonographer at the beginning of his training in first-trimester screening. The fetal heart was examined by high-definition color Doppler imaging to obtain the 4 chamber view, right and left ventricular outflow tracts, and 3-vessel and trachea view. Logistic regression was used to investigate the effect on the ability to visualize different cardiac structures. RESULTS: The frequency of successful heart examinations increased significantly with the number of scans performed (P < .05). The sonographer needed 180 examinations before he could successfully examine the heart in at least 80% of cases. Significant factors that increased the probability of adequate echocardiography were the length of the heart examination and the experience of the sonographer (P< .05) but not transducer heart distance, maternal body mass index, fetal crown-rump length, placenta interposition, or restrictive fetal position. Visualization of the left ventricular outflow tract could be improved by increasing the experience of the sonographer and decreasing the transducer-heart distance. Also, visualization of the 3-vessel and trachea view depended on the length of the heart examination, the experience of the sonographer, an anterior position of the placenta, and a restrictive fetal position. CONCLUSIONS: Competence in color flow mapping assessment of the fetal heart at gestational ages of 11 weeks to 13 weeks 6 days is achieved only after extensive supervised training. PMID- 25542953 TI - Usefulness of sonography for diagnosis of siliconomas mimicking metastatic lymphadenopathy on computed tomography. PMID- 25542954 TI - Prenatal diagnosis of Aicardi-Goutieres syndrome: a sonographic mimicry of cytomegalovirus fetopathy. PMID- 25542955 TI - Point-of-care ultrasound: not a stethoscope-a separate clinical entity. PMID- 25542956 TI - Accessory head of the biceps tendon versus aponeurotic expansion of the supraspinatus tendon. PMID- 25542957 TI - Clarification of terminology: sonographic appearance of the pronator quadratus muscle in healthy volunteers. PMID- 25542959 TI - Editorial: Another successful year for the Japanese Journal of Clinical Oncology. PMID- 25542958 TI - High Transmissibility During Early HIV Infection Among Men Who Have Sex With Men San Francisco, California. AB - We estimate the relative transmission rate in early versus later infection among men who have sex with men (MSM) in San Francisco, California, by studying the characteristics of a sample of transmitters, recruited through newly diagnosed, recently infected MSM between 1996 and 2009. Of 36 transmitters identified, 9 were determined on the basis of testing history and serologic testing to have been recently infected. The unadjusted odds ratio of transmitting during early infection was 15.2 (95% confidence interval [CI], 6.3-33.4; P < .001); the odds ratio was 8.9 (95% CI, 4.1-19.4) after adjustment for self-reported antiretroviral treatment. This high transmissibility could be due to both high infectiousness and high rates of sex partner change or concurrent partnerships. PMID- 25542961 TI - Ulcerative skin metastases of primary lung cancer. PMID- 25542962 TI - Five-year relative survival rate of kidney and renal pelvis cancer in the USA, Europe and Japan. PMID- 25542963 TI - Mission (im)possible - mapping the brain becomes a reality. AB - Charting and understanding the full wiring diagram of complex neuronal structures such as the central nervous system or the brain (Connectomics) is one of the big remaining challenges in life sciences. Although at first it appears nearly impossible to map out a full diagram of, e.g., a mouse brain with sufficient resolution to identify each and every connection between neurons, recent technological advances move such an ambitious undertaking into the realms of possibility without spending decades at a microscope. However there are still many challenges to address in order to pave the way for fast and systematic neurobiological understanding of whole networks. These challenges range from a more robust and reproducible sample preparation to automated image data acquisition, more efficient data storage strategies and powerful data analysis tools. Here we will review novel imaging techniques developed for the challenge of mapping out the full connectome of a nervous system, brain or eye to name just a few examples. The imaging techniques reviewed cover light sheet illumination methods, single and multi-beam scanning electron microscopy, and we will briefly mention the possible combination of both light and electron microscopy. In particular we will review 'clearing' and in vivo methods that can be performed with light sheet fluroescence microscopes such as the ZEISS Lightsheet Z.1. We will then focus on scanning electron microscopy with single and multi-beam instruments including methods such as serial blockface imaging and array tomography methods. PMID- 25542964 TI - RE: reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. PMID- 25542965 TI - RE: Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. PMID- 25542966 TI - Response. PMID- 25542968 TI - The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride. AB - It is widely recognized that the phenotype of familial hyperkalemic hypertension is mainly a consequence of increased activity of the renal Na(+)-Cl(-) cotransporter (NCC) because of altered regulation by with no-lysine-kinase 1 (WNK1) or WNK4. The effect of WNK4 on NCC, however, has been controversial because both inhibition and activation have been reported. It has been recently shown that the long isoform of WNK1 (L-WNK1) is a chloride-sensitive kinase activated by a low Cl(-) concentration. Therefore, we hypothesized that WNK4 effects on NCC could be modulated by intracellular chloride concentration ([Cl( )]i), and we tested this hypothesis in oocytes injected with NCC cRNA with or without WNK4 cRNA. At baseline in oocytes, [Cl(-)]i was near 50 mM, autophosphorylation of WNK4 was undetectable, and NCC activity was either decreased or unaffected by WNK4. A reduction of [Cl(-)]i, either by low chloride hypotonic stress or coinjection of oocytes with the solute carrier family 26 (anion exchanger)-member 9 (SLC26A9) cRNA, promoted WNK4 autophosphorylation and increased NCC-dependent Na(+) transport in a WNK4-dependent manner. Substitution of the leucine with phenylalanine at residue 322 of WNK4, homologous to the chloride-binding pocket in L-WNK1, converted WNK4 into a constitutively autophosphorylated kinase that activated NCC, even without chloride depletion. Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC. These observations suggest that WNK4 can exert differential effects on NCC, depending on the intracellular chloride concentration. PMID- 25542967 TI - Considerations and challenges in defining optimal iron utilization in hemodialysis. AB - Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population. PMID- 25542970 TI - Valproic acid prevents NMDA-induced retinal ganglion cell death via stimulation of neuronal TrkB receptor signaling. AB - Valproic acid (VPA) is widely prescribed for treatment of epilepsy, mood disorders, migraines, and neuropathic pain. It exerts its therapeutic benefits through multiple mechanisms, including enhancement of GABAergic activity, activation of prosurvival protein kinases, and inhibition of histone deacetylase. Increasing evidence suggests that VPA possesses neuroprotective properties. We examined neuroprotective effects of VPA in an N-methyl-d-aspartate (NMDA) excitotoxicity model, which mimics some of the pathological features of glaucoma. In vivo retinal imaging using optical coherence tomography revealed that NMDA induced retinal degeneration was suppressed in the VPA-treated retina, and histological analyses confirmed that VPA reduced retinal ganglion cell death. In vivo electrophysiological analyses demonstrated that visual impairment was prevented in the VPA-treated retina, clearly establishing both histological and functional effects of VPA. Brain-derived neurotrophic factor (BDNF) expression was up-regulated in Muller glial cells, and neuroprotective effects of VPA on retinal ganglion cells were significantly reduced in a conditional knockout mouse strain with deletion of tropomyosin receptor kinase B (TrkB), a receptor for BDNF from retinal ganglion cells. The results show that VPA stimulates BDNF up regulation in Muller glial cells and provides direct evidence that neuronal TrkB is important in VPA-mediated neuroprotection. Also, VPA suppresses oxidative stress induced by NMDA in the retina. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be useful for treatment of glaucoma. PMID- 25542971 TI - Nonlinear dynamics of the CAM circadian rhythm in response to environmental forcing. AB - Crassulacean acid metabolism (CAM) photosynthesis functions as an endogenous circadian rhythm coupled to external environmental forcings of energy and water availability. This paper explores the nonlinear dynamics of a new CAM photosynthesis model (Bartlett et al., 2014) and investigates the responses of CAM plant carbon assimilation to different combinations of environmental conditions. The CAM model (Bartlett et al., 2014) consists of a Calvin cycle typical of C3 plants coupled to an oscillator of the type employed in the Van der Pol and FitzHugh-Nagumo systems. This coupled system is a function of environmental variables including leaf temperature, leaf moisture potential, and irradiance. Here, we explore the qualitative response of the system and the expected carbon assimilation under constant and periodically forced environmental conditions. The model results show how the diurnal evolution of these variables entrains the CAM cycle with prevailing environmental conditions. While constant environmental conditions generate either steady-state or periodically oscillating responses in malic acid uptake and release, forcing the CAM system with periodic daily fluctuations in light exposure and leaf temperature results in quasi periodicity and possible chaos for certain ranges of these variables. This analysis is a first step in quantifying changes in CAM plant productivity with variables such as the mean temperature, daily temperature range, irradiance, and leaf moisture potential. Results may also be used to inform model parametrization based on the observed fluctuating regime. PMID- 25542972 TI - Automatic cell counting with ImageJ. AB - Cell counting is an important routine procedure. However, to date there is no comprehensive, easy to use, and inexpensive solution for routine cell counting, and this procedure usually needs to be performed manually. Here, we report a complete solution for automatic cell counting in which a conventional light microscope is equipped with a web camera to obtain images of a suspension of mammalian cells in a hemocytometer assembly. Based on the ImageJ toolbox, we devised two algorithms to automatically count these cells. This approach is approximately 10 times faster and yields more reliable and consistent results compared with manual counting. PMID- 25542969 TI - Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy. AB - Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy. PMID- 25542973 TI - The processivity factor complex of feline herpes virus-1 is a new drug target. AB - Feline herpes virus-1 (FHV-1) is ubiquitous in the cat population and is a major cause of blindness for which antiviral drugs, including acyclovir, are not completely effective. Recurrent infections, due to reactivation of latent FHV-1 residing in the trigeminal ganglia, can lead to epithelial keratitis and stromal keratitis and eventually loss of sight. This has prompted the medical need for an antiviral drug that will specifically inhibit FHV-1 infection. A new antiviral target is the DNA polymerase and its associated processivity factor, which forms a complex that is essential for extended DNA strand synthesis. In this study we have cloned and expressed the FHV-1 DNA polymerase (f-UL30) and processivity factor (f-UL42) and demonstrated that both proteins are required to completely synthesize the 7249 nucleotide full-length DNA from the M13 primed-DNA template in vitro. Significantly, a known inhibitor of human herpes simplex virus-1 (HSV 1) processivity complex was shown to inhibit FHV-1 processive DNA synthesis in vitro and block infection of cells. This validates using f-UL42/f-UL30 as a new antiviral drug target to treat feline ocular herpes infection. PMID- 25542974 TI - Characterization of novel respiratory syncytial virus inhibitors identified by high throughput screen. AB - Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory tract infections with no effective treatment available. Finding novel inhibitors of RSV is an important first step towards developing an efficacious RSV therapy. Here we report the characterization of three novel classes of RSV replication inhibitors identified through a high throughput RSV replicon screen of ~1million compounds in the AstraZeneca compound collection. These inhibitors, cpd 1, 2, and 3, specifically targeted RSV and were not active against other viruses tested. Resistance selection in RSV A2 with cpd 1 identified escape viruses with mutations mapped to the RSV L protein, an RNA-dependent RNA polymerase (Y1631C and I1413T). Recombinant RSV containing the L Y1631C substitution conferred resistance towards cpd 1, suggesting that the RSV polymerase is the target of this inhibitor. Interestingly, cpd 3, a nucleoside analog, induced a single resistant mutation in the P protein (D231V), indicating a novel mode of action not previously reported. cpd 2 affected host cell cycle and no frequent mutation was isolated following resistance selection, suggesting its possible involvement of a host-targeted mechanism. Taken together, we have identified three novel RSV inhibitors with different modes of action, providing new chemistry starting points for the discovery and development of future RSV therapeutic treatment. PMID- 25542975 TI - Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PL(pro)) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS CoV PL(pro). Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PL(pro) and these can now be used as lead compounds for further antiviral drug development. PMID- 25542977 TI - The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model. AB - Neuromyelitis optica (NMO) is causally linked to autoantibodies (ABs) against aquaporin 4 (AQP4). Here, we focused on the pathogenic effects exclusively mediated by human ABs to AQP4 in vivo. We performed cell-free intrathecal (i.th.) passive transfer experiments in Lewis rats using purified patient NMO immunoglobulin G (IgG) and various recombinant human anti-AQP4 IgG-ABs via implanted i.th. catheters. Repetitive application of patient NMO IgG fractions and of recombinant human anti-AQP4 ABs induced signs of spinal cord disease. Magnetic resonance imaging (MRI) revealed longitudinal spinal cord lesions at the site of application of anti-AQP4 IgG. Somatosensory evoked potential amplitudes were reduced in symptomatic animals corroborating the observed functional impairment. Spinal cord histology showed specific IgG deposition in the grey and white matter in the affected areas. We did not find inflammatory cell infiltration nor activation of complement in spinal cord areas of immunoglobulin deposition. Moreover, destructive lesions showing axon or myelin damage and loss of astrocytes and oligodendrocytes were all absent. Immunoreactivity to AQP4 and to the excitatory amino acid transporter 2 (EAAT2) was markedly reduced whereas immunoreactivity to the astrocytic marker glial fibrillary acid protein (GFAP) was preserved. The expression of the NMDA-receptor NR1 subunit was downregulated in areas of IgG deposition possibly induced by sustained glutamatergic overexcitation. Disease signs and histopathology were reversible within weeks after stopping injections. We conclude that in vivo application of ABs directed at AQP 4 can induce a reversible spinal cord disease in recipient rats by inducing distinct histopathological abnormalities. These findings may be the experimental correlate of "penumbra-like" lesions recently reported in NMO patients adjacent to effector-mediated tissue damage. PMID- 25542979 TI - Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis. AB - Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody mediated diseases that are now recognized. PMID- 25542978 TI - Differential subcellular Ca2+ signaling in a highly specialized subpopulation of astrocytes. AB - Recent evidence suggests that astrocytes do not serve a mere buffering function, but exhibit complex signaling pathways, disturbance of which contributes significantly to the pathophysiology of CNS diseases. Little is known regarding the intracellular signaling pathways in the specialized optic nerve head astrocytes (ONHAs), the major glia cell type in non-myelinated optic nerve head. Here we show the differential subcellular expression of intracellular Ca(2+) channels in ONHAs. Expression of type 1 and type 3 inositol-1-4-5,-trisphosphate receptors (IP3Rs) in the endoplasmic reticulum and type 2 IP3Rs in the nuclear envelope causes differential Ca(2+) release from intracellular stores in nuclear vs. cytosolic compartments. Our study identifies differential distribution and activity of Ca(2+) channels as molecular substrate and mechanism by which astrocytes independently regulate Ca(2+) transients in both cytoplasm and nucleoplasm, thereby controlling genomic and non-genomic cellular signaling, respectively. This provides excellent targets for therapeutics restoring pathological disturbances of intracellular Ca(2+) signaling present in glaucoma and other neurodegenerative disorders with astrocyte involvement. PMID- 25542981 TI - Activation of either the ETA or the ETB receptors is involved in the development of electrographic seizures following intrahippocampal infusion of the endothelin 1 in immature rats. AB - The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40pmol/MUl) was infused either alone or co administered with selective antagonists of ETA (BQ123; 70nmol/MUl) or ETB receptors (BQ788; 70nmol/1MUl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40pmol/1MUl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10mM PBS or 0.01% DMSO-PBS solution; pH7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24h after ET-1 infusion. Infusion of ET-1 or ET 1+ETB receptor antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizure duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET 1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures following the application of ET-1 in immature rats. The dissociation between the ischemic-producing and seizure-producing processes suggests that damage is not necessary to induce seizures, although it may exacerbate them. PMID- 25542980 TI - Voltage-gated Ca2+ entry promotes oligodendrocyte progenitor cell maturation and myelination in vitro. AB - We have previously shown that the expression of voltage-operated Ca(++) channels (VOCCs) is highly regulated in the oligodendroglial lineage and is essential for proper oligodendrocyte progenitor cell (OPC) migration. Here we assessed the role of VOCCs, in particular the L-type, in oligodendrocyte maturation. We used pharmacological treatments to activate or block voltage-gated Ca(++) uptake and siRNAs to specifically knock down the L-type VOCC in primary cultures of mouse OPCs. Activation of VOCCs by plasma membrane depolarization increased OPC morphological differentiation as well as the expression of mature oligodendrocyte markers. On the contrary, inhibition of L-type Ca(++) channels significantly delayed OPC development. OPCs transfected with siRNAs for the Cav1.2 subunit that conducts L-type Ca(++) currents showed reduce Ca(++) influx by ~75% after plasma membrane depolarization, indicating that Cav1.2 is heavily involved in mediating voltage-operated Ca(++) entry in OPCs. Cav1.2 knockdown induced a decrease in the proportion of oligodendrocytes that expressed myelin proteins, and an increase in cells that retained immature oligodendrocyte markers. Moreover, OPC proliferation, but not cell viability, was negatively affected after L-type Ca(++) channel knockdown. Additionally, we have tested the ability of L-type VOCCs to facilitate axon-glial interaction during the first steps of myelin formation using an in vitro co-culture system of OPCs with cortical neurons. Unlike control OPCs, Cav1.2 deficient oligodendrocytes displayed a simple morphology, low levels of myelin proteins expression and appeared to be less capable of establishing contacts with neurites and axons. Together, this set of in vitro experiments characterizes the involvement of L-type VOCCs on OPC maturation as well as the role played by these Ca(++) channels during the early phases of myelination. PMID- 25542982 TI - Distinguishing mild cognitive impairment from Alzheimer's disease with acrolein metabolites and creatinine in urine. AB - BACKGROUND: We previously reported that the level of urinary 3-hydroxypropyl mercapturic acid (3-HPMA)/creatinine (Cre) was reduced following stroke. The aim of this study was to determine whether the level of 3-HPMA/Cre in urine was reduced in subjects with dementia. METHODS: The level of 3-HPMA was measured by LC-MS/MS, and that of amino acid conjugated acrolein (AC-Acro) was by ELISA. The study included 128 elderly subjects divided into 74 non-demented (control), 22 mild cognitive impairment (MCI) and 32 Alzheimer's disease (AD) subjects. RESULTS: The urinary 3-HPMA/Cre and AC-Acro/Cre in MCI plus AD subjects were significantly lower than those in control subjects. In addition, urinary Cre in AD subjects was significantly higher than that in MCI subjects, and 3-HPMA/Cre and AC-Acro/Cre in AD subjects were significantly lower than that in MCI subjects. Among these three markers, the lower 3-HPMA/Cre ratio was most strongly correlated with the decline of MMSE (Mini-Mental State Examination) and the increase in CDRsob (Clinical Dementia Rating Scale Sum of Boxes Scores). Furthermore, reduction in 3-HPMA/Cre in urine was well correlated with increase in Abeta40/42 in plasma in demented subjects. CONCLUSION: The results indicate that 3-HPMA/Cre in urine is the most reliable biochemical marker to distinguish AD subjects from MCI subjects among three markers. PMID- 25542976 TI - Natural history of beta-cell adaptation and failure in type 2 diabetes. AB - Type 2 diabetes mellitus (T2D) is a complex disease characterized by beta-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the beta-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of beta-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, beta-cell adaptation and beta-cell failure, and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of beta-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against beta-cell failure. PMID- 25542983 TI - Evaluation of two methods to measure hemoglobin concentration among women with genetic hemoglobin disorders in Cambodia: a method-comparison study. AB - BACKGROUND: Genetic hemoglobin (Hb) E variants are common in Cambodia and result in an altered and unstable Hb molecule. We evaluated two methods to measure Hb concentration among individuals with and without Hb variants using a hemoglobinometer (HemoCue) and a hematology analyzer (Sysmex XT-1800i). METHODS: We determined the bias and concordance between the methods among 420 Cambodian women (18-45 y). RESULTS: Bias and concordance appeared similar between methods among women with no Hb disorders (n=195, bias=2.5, rhoc=0.68), women with Hb E variants (n=133, bias=2.5, rhoc=0.78), and women with other Hb variants (n=92, bias=2.7, rhoc=0.73). The overall bias was 2.6g/l, resulting in a difference in anemia prevalence of 11.5% (41% using HemoCue and 29.5% using Sysmex, p<0.001). Based on visual interpretation of the concordance plots, the HemoCue device appears to underestimate Hb concentrations at lower Hb concentrations and to overestimate Hb concentrations at higher Hb concentrations (in comparison to the Sysmex analyzer). CONCLUSIONS: Bias and concordance were similar across groups, suggesting the two methods of Hb measurement were comparable. We caution field staff, researchers and policy makers in the interpretation of data and the impact that bias between methods can have on anemia prevalence rates. PMID- 25542984 TI - Solid lipid nanoparticles as non-viral vector for the treatment of chronic hepatitis C by RNA interference. AB - RNA interference (RNAi) is a promising strategy to treat the chronic infection by hepatitis C virus (HCV). The objective of this work was to develop a non-viral vector based on solid lipid nanoparticles (SLN) and RNAi to inhibit the internal ribosome entry site (IRES) mechanism of the HCV. The vectors were prepared with SLN, protamine, hylauronic acid (HA) or dextran (DX), and a short-hairpin RNA expression plasmid targeted to the stem loop II of the 5' UTR (shRNA74). The particle size, surface charge, and capacity to bind, release and protect the shRNA74 against nucleases were evaluated. Cell uptake, silencing capacity and cell viability were evaluated in HepG2 cells. All the vectors presented particle size in the range of nanometers and positive surface charge, and they were able to protect the shRNA74 against DNase. An effective and rapid uptake into the cells was observed. Silencing capacity ranged from 3% to 67% depending on the presence of DX or HA in the vector, the shRNA74 to SLN ratio, and the shRNA74 dose. Vectors prepared with HA showed to be twice more effective than those prepared with DX. Differences in the intracellular trafficking may justify the higher efficacy of the HA-prepared vectors. PMID- 25542985 TI - Anti-inflammatory effects of a novel ricinoleic acid poloxamer gel system for transdermal delivery. AB - Our previous study showed that the use of ricinoleic acid as an oil phase resulted in the formation of a stable pluronic lecithin organogel (PLO gel) with better thixotropic properties and higher permeation of ketoprofen than the isopropyl palmitate PLO gel. This study aims to evaluate and compare the in vitro and in vivo anti-inflammatory effects of the ricinoleic acid PLO gel system with isopropyl palmitate PLO gel. Ketoprofen was used as a model drug. In vitro anti inflammatory activity and cell viability tests were performed in human rheumatoid arthritis synovial fibroblast cell line using a blank ricinoleic acid PLO gel and compared to that of the isopropyl palmitate PLO gel. In vivo anti-inflammatory activity of ricinoleic acid PLO gel containing 10% ketoprofen was evaluated and compared with the isopropyl palmitate PLO gel in a carrageenan-induced rat paw edema model. The results from the in vitro study showed that the blank ricinoleic acid PLO gel possessed significantly higher anti-inflammatory activity than isopropyl palmitate PLO gel at 1 mM concentration (p<0.05), while both the gel formulations had no significant cytotoxic activity. Further in vivo testing of the formulation showed that the ricinoleic acid PLO gel formulation was significantly more effective in reducing pain and edema when compared to the isopropyl palmitate PLO gel. In addition, the ricinoleic acid PLO gel formulation markedly inhibited the synthesis of prostaglandin E2. In conclusion, the efficacy of PLO gels used in pain management may be enhanced by using ricinoleic acid instead of isopropyl palmitate as an oil phase. PMID- 25542986 TI - Effect of monoacyl phosphatidylcholine content on the formation of microemulsions and the dermal delivery of flufenamic acid. AB - The choice of appropriate excipients is crucial for the success of a dermal drug delivery system. Especially surfactants should be chosen carefully, because of their possible interactions with the skin or the applied drug. Since monoacyl phosphatidylcholine (MAPL) exhibits great emulsification properties and can be derived from natural sources, it is of great interest as surfactant in microemulsions. Therefore, the aim of the present study was to investigate the effect of the MAPL content on the formation of microemulsions. The great emulsification power of MAPL was confirmed by increased isotropic areas with increasing MAPL content. Moreover, a decrease in particle size, particle size distribution and viscosity with increasing MAPL content was determined. Besides its effects on microemulsion structure, MAPL exhibited a significant influence on the skin permeation of flufenamic acid. Interestingly, the higher the MAPL content, the lower was the skin permeation of flufenamic acid. A possible explanation might be that the hydrophilic MAPL could hinder the permeation of the lipophilic drug. In contrast, the skin permeation enhancing effects of the microemulsion with the lowest MAPL content might be attributed to formation of a patch-like structure and therefore better contact between the formulation and the skin. PMID- 25542989 TI - Effects of coformers on phase transformation and release profiles of carbamazepine cocrystals in hydroxypropyl methylcellulose based matrix tablets. AB - The aim of this study was to investigate the effects of coformers on phase transformation and release profiles of carbamazepine (CBZ) cocrystals in hydroxypropyl methylcellulose (HPMC) based matrix tablets. It has been found that selection of different coformers of saccharin (SAC) and cinnamic acid (CIN) can affect the stability of CBZ cocrystals in solution, resulting in significant differences in the apparent solubility of CBZ. The dissolution advantage of CBZ SAC cocrystals can only be shown for a short period during dissolution because of the fast conversion to its dihydrate form (DH). HPMC can partially inhibit the crystallisation of CBZ DH during dissolution of CBZ-SAC cocrystal. However, the increased viscosity of HPMC dissolution medium reduced the dissolution rate of CBZ-SAC cocrystals. Therefore the CBZ-SAC cocrystal formulation did not show any significant advantage in CBZ release rate. In contrast the improved CBZ dissolution rate of CBZ-CIN cocrystal can be realised in both solution and formulation due to its high stability. In conclusion, exploring and understanding the mechanisms of the phase transformation of pharmaceutical cocrystals in aqueous medium for selection of lead cocrystals is the key for success of product development. PMID- 25542988 TI - Formulation and characterization of inhalable magnetic nanocomposite microparticles (MnMs) for targeted pulmonary delivery via spray drying. AB - Targeted pulmonary delivery facilitates the direct application of bioactive materials to the lungs in a controlled manner and provides an exciting platform for targeting magnetic nanoparticles (MNPs) to the lungs. Iron oxide MNPs remotely heat in the presence of an alternating magnetic field (AMF) providing unique opportunities for therapeutic applications such as hyperthermia. In this study, spray drying was used to formulate magnetic nanocomposite microparticles (MnMs) consisting of iron oxide MNPs and d-mannitol. The physicochemical properties of these MnMs were evaluated and the in vitro aerosol dispersion performance of the dry powders was measured by the Next Generation Impactor((r)). For all powders, the mass median aerosol diameter (MMAD) was <5MUm and deposition patterns revealed that MnMs could deposit throughout the lungs. Heating studies with a custom AMF showed that MNPs retain excellent thermal properties after spray drying into composite dry powders, with specific absorption ratios (SAR)>200W/g, and in vitro studies on a human lung cell line indicated moderate cytotoxicity of these materials. These inhalable composites present a class of materials with many potential applications and pose a promising approach for thermal treatment of the lungs through targeted pulmonary administration of MNPs. PMID- 25542987 TI - Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles. AB - Fenretinide is an effective anti-cancer drug with high in vitro cytotoxicity and low in vivo systemic toxicity. In clinical trials, fenretinide has shown poor therapeutic efficacy following oral administration - attributed to its low bioavailability and solubility. The long term goal of this project is to develop a formulation for the oral delivery of fenretinide. The purpose of this part of the study was to prepare and characterize hydrophilic nanoparticle formulations of fenretinide. Three different ratios of polyvinyl pyrrolidone (PVP) to fenretinide were used, namely, 3:1, 4:1, and 5:1. Both drug and polymer were dissolved in a mixture of methanol and dichloromethane (2:23 v/v). Rotary evaporation was used to remove the solvents, and, following reconstitution with water, a high pressure homogenizer was used to form nanoparticles. The particle size and polydispersity index were measured before and after lyophilization. The formulations were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The effectiveness of the formulations was assessed by release studies and Caco-2 cell permeability assays. As the PVP content increased, the recovered particle size following lyophilization became more consistent with the pre-lyophilization particle size, especially for those formulations with less lactose. The DSC scans of the formulations did not show any fenretinide melting endotherms, indicating that the drug was either present in an amorphous form in the formulation or that a solid solution of the drug in PVP had formed. For the release studies, the highest drug release among the formulations was 249.2+/-35.5ng/mL for the formulation with 4:1 polymer-to-drug. When the permeability of the formulations was evaluated in a Caco-2 cell model, the mean normalized flux for each treatment group was significantly higher (p<0.05) from the fenretinide control. The formulation containing 4:1 polymer-to-drug ratio and 6:5 lactose-to-formulation ratio emerged as the optimal choice for further evaluation as a potential oral delivery formulation for fenretinide. PMID- 25542990 TI - Robust and versatile pectin-based drug delivery systems. AB - Pectin-based resistant, interactive and versatile hydrogel vehicles for oral administration have been prepared. These systems are thought to be versatile enough to allow the inclusion of substances (such as the surfactants tested: Pluronic, Tween, Na Lauryl sulphate) that may contribute to tailor the drug release patterns. Tolbutamide, that shows a discrete and pH-dependent solubility in water, has been employed as a model drug to test the capability of these matrices to overcome such drug-imposed restraints. The incorporation of different surfactants produced pectin-based hydrogels of difficult manipulation. In order to improve this drawback, two different strategies have been developed: blending with agarose or freeze-drying. The presence of agarose yields robust systems that can be handled and tested as prepared, in the fresh state. Freeze-drying not only allows to shape pure pectin and blend systems, but also generates a porous structure whose microstructure, determined by the different components included, influences on the drug release behavior. Tolbutamide release kinetics from freshly prepared matrices can be fitted to the Higuchi model while the freeze dried ones adjust to the Korsmeyer-Peppas model; hence the hydrogel chains rearrangement processes rule the release during the rehydration process. PMID- 25542991 TI - Molecular interactions of rifabutin with membrane under acidic conditions. AB - This work focuses on the interaction of the anti-tuberculosis (anti-TB) drug, rifabutin (RFB) with cell membrane models formed by 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC). The experiments were performed under acidic conditions (i.e., pH 5.0) taking into account the pH conditions that RFB may find in the course of its in vivo pharmacological activity. The partition of the drug to the membrane was quantified through the partition coefficient (Kp). Fluorescence quenching studies were performed to predict the drug's location across the cell membrane model. The effect of RFB on the biophysical parameters of the cell membrane model was studied by steady-state anisotropy and small-angle X-ray scattering (SAXS). The overall results point to a marked interaction of RFB with cell membranes under acidic pH, which may be related with its pharmacological effects. The in vivo success of RFB may be associated with the drug's disordering effect of the membranes under acidic pH values environments, and consequently drug accumulation in the gastric infected tissues and inside phagolysosomes. On the other hand, the present study allowed establishing important correlations with the gastrointestinal side effects caused by RFB. PMID- 25542992 TI - Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway. AB - The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free beta-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoate (10mg/kg/week, I.M.), taurine (100mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3beta-HSD, and 17beta-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF alpha, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats. PMID- 25542994 TI - Comparison of mupirocin-based media for selective enumeration of bifidobacteria in probiotic supplements. AB - An international standard already exists for the selective enumeration of bifidobacteria in milk products. This standard uses Transgalactosylated oligosaccharides (TOS) propionate agar supplemented with mupirocin. However, no such standard method has been described for the selective enumeration of bifidobacteria in probiotic supplements, where the presence of bifidobacteria is much more variable than in milk products. Therefore, we enumerated bifidobacteria by colony count technique in 13 probiotic supplements using three media supplemented with mupirocin (Mup; 100mg/l): TOS, Bifidobacteria selective medium (BSM) and modified Wilkins-Chalgren anaerobe agar with soya peptone (WSP). Moreover, the potential growth of bifidobacterial strains often used in probiotic products was performed in these media. All 13 products contained members of the genus Bifidobacterium, and tested mupirocin media were found to be fully selective for bifidobacteria. However, the type strain Bifidobacterium bifidum DSM 20456 and collection strain B. bifidum DSM 20239 showed statistically significant lower counts on TOS Mup media, compared to BSM Mup and WSP Mup media. Therefore, the TOS Mup medium recommended by the ISO standard cannot be regarded as a fully selective and suitable medium for the genus Bifidobacterium. In contrast, the BSM Mup and WSP Mup media supported the growth of all bifidobacterial species. PMID- 25542993 TI - Characteristics and concepts of dynamic hub proteins in DNA processing machinery from studies of RPA. AB - DNA replication, damage response and repair require the coordinated action of multi-domain proteins operating within dynamic multi-protein machines that act upon the DNA substrate. These modular proteins contain flexible linkers of various lengths, which enable changes in the spatial distribution of the globular domains (architecture) that harbor their essential biochemical functions. This mobile architecture is uniquely suited to follow the evolving substrate landscape present over the course of the specific process performed by the multi-protein machinery. A fundamental advance in understanding of protein machinery is the realization of the pervasive role of dynamics. Not only is the machine undergoing dynamic transformations, but the proteins themselves are flexible and constantly adapting to the progression through the steps of the overall process. Within this dynamic context the activity of the constituent proteins must be coordinated, a role typically played by hub proteins. A number of important characteristics of modular proteins and concepts about the operation of dynamic machinery have been discerned. These provide the underlying basis for the action of the machinery that reads DNA, and responds to and repairs DNA damage. Here, we introduce a number of key characteristics and concepts, including the modularity of the proteins, linkage of weak binding sites, direct competition between sites, and allostery, using the well recognized hub protein replication protein A (RPA). PMID- 25542996 TI - GABAA alpha5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085. AB - GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABAA-alpha2 and -alpha3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABAA-alpha5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABAA-alpha2/alpha3/alpha5 receptors) with TP003 (a reportedly GABAA-alpha3 selective PAM) against spinal sensitization. However, in-house electrophysiology studies designed to confirm the selectivity of TPA023 and TP003 for human GABAA receptors did not corroborate published data, with TP003 displaying considerable GABAA-alpha5 receptor efficacy. Therefore, we identified a novel PAM, NS16085, which possesses negligible efficacy at GABAA-alpha5 receptors, but with GABAA alpha2/alpha3 efficacy equivalent to NS11394. At the GABAA-alpha1 receptor the compound gives low level of negative modulation further separating it from the other compounds. Rat pups with carrageenan-induced hindpaw inflammatory hyperalgesia were used to make ex vivo spinal dorsal root-evoked ventral root recordings. Some spontaneous activity and large numbers of spikes to repetitive stimulation of dorsal roots at C-fibre intensity, indicative of wind-up and sensitization were observed. Equimolar concentrations of NS11394, TP003 and NS16085 all attenuated wind-up to a similar degree; TPA023 was clearly less effective. In adult rats, NS16085 (3-30 mg/kg, p.o.) dose-dependently reduced formalin-induced hindpaw flinching with efficacy comparable to NS11394. Thus, potentiation of GABAA-alpha2 and-alpha3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABAA-alpha5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function. PMID- 25542997 TI - Functional G-protein-coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus. AB - The G-protein-coupled receptor 35 (GPR35) was de-orphanized after the discovery that kynurenic acid (KYNA), an endogenous tryptophan metabolite, acts as an agonist of this receptor. Abundant evidence supports that GPR35 exists primarily in peripheral tissues. Here, we tested the hypothesis that GPR35 exists in the hippocampus and influences the neuronal activity. Fluorescence immunohistochemical staining using an antibody anti-NeuN (a neuronal marker), an antibody anti-GFAP (a glial marker), and an antibody anti-GPR35 revealed that neurons in the stratum oriens, stratum pyramidale, and stratum radiatum of the CA1 field of the hippocampus express GPR35. To determine the presence of functional GPR35 in the neurocircuitry, we tested the effects of various GPR35 agonists on the frequency of spontaneous action potentials recorded as fast current transients (CTs) from stratum radiatum interneurons (SRIs) under cell attached configuration in rat hippocampal slices. Bath application of the GPR35 agonists zaprinast (1-10 MUM), dicumarol (50-100 MUM), pamoic acid (500-1000 MUM), and amlexanox (3 MUM) produced a concentration- and time-dependent reduction in the frequency of CTs. Superfusion of the hippocampal slices with the GPR35 antagonist ML145 (1 MUM) increased the frequency of CTs and reduced the inhibitory effect of zaprinast. Bath application of phosphodiesterase 5 inhibitor sildenafil (1 or 5 MUM) was ineffective, whereas a subsequent application of zaprinast was effective in reducing the CT frequency. The present results demonstrate for the first time that functional GPR35s are expressed by CA1 neurons and suggest that these receptors can be molecular targets for controlling neuronal activity in the hippocampus. PMID- 25542995 TI - Nephron proximal tubule patterning and corpuscles of Stannius formation are regulated by the sim1a transcription factor and retinoic acid in zebrafish. AB - The mechanisms that establish nephron segments are poorly understood. The zebrafish embryonic kidney, or pronephros, is a simplified yet conserved genetic model to study this renal development process because its nephrons contain segments akin to other vertebrates, including the proximal convoluted and straight tubules (PCT, PST). The zebrafish pronephros is also associated with the corpuscles of Stannius (CS), endocrine glands that regulate calcium and phosphate homeostasis, but whose ontogeny from renal progenitors is largely mysterious. Initial patterning of zebrafish renal progenitors in the intermediate mesoderm (IM) involves the formation of rostral and caudal domains, the former being reliant on retinoic acid (RA) signaling, and the latter being repressed by elevated RA levels. Here, using expression profiling to gain new insights into nephrogenesis, we discovered that the gene single minded family bHLH transcription factor 1a (sim1a) is dynamically expressed in the renal progenitors first marking the caudal domain, then becoming restricted to the proximal segments, and finally exhibiting specific CS expression. In loss of function studies, sim1a knockdown expanded the PCT and abrogated both the PST and CS populations. Conversely, overexpression of sim1a modestly expanded the PST and CS, while it reduced the PCT. These results show that sim1a activity is necessary and partially sufficient to induce PST and CS fates, and suggest that sim1a may inhibit PCT fate and/or negotiate the PCT/PST boundary. Interestingly, the sim1a expression domain in renal progenitors is responsive to altered levels of RA, suggesting that RA regulates sim1a, directly or indirectly, during nephrogenesis. sim1a deficient embryos treated with exogenous RA formed nephrons that were predominantly composed of PCT segments, but lacked the enlarged PST observed in RA treated wild-types, indicating that RA is not sufficient to rescue the PST in the absence of sim1a expression. Alternately, when sim1a knockdowns were exposed to the RA inhibitor diethylaminobenzaldehyde (DEAB), the CS was abrogated rather than expanded as seen in DEAB treated wild-types, revealing that CS formation in the absence of sim1a cannot be rescued by RA biosynthesis abrogation. Taken together, these data reveal previously unappreciated roles for sim1a in zebrafish pronephric proximal tubule and CS patterning, and are consistent with the model that sim1a acts downstream of RA to mitigate the formation of these lineages. These findings provide new insights into the genetic pathways that direct nephron development, and may have implications for understanding renal birth defects and kidney reprogramming. PMID- 25542998 TI - Impact of earliest activation site location in the septal right ventricular outflow tract for identification of left vs right outflow tract origin of idiopathic ventricular arrhythmias. AB - BACKGROUND: The earliest activation site (EAS) location in the septal right ventricular outflow tract (RVOT) could be an additional mapping data predictor of left ventricular outflow tract (LVOT) vs RVOT origin of idiopathic ventricular arrhythmias (VAs). OBJECTIVE: The purpose of this study was to assess the impact of EAS location in predicting LVOT vs RVOT origin. METHODS: Macroscopic and histologic study was performed in 12 postmortem hearts. Electroanatomic maps (EAMs) from 37 patients with outflow tract (OT) VA with the EAS in the septal RVOT were analyzed. Pulmonary valve (PV) was defined by voltage scanning after validation of voltage thresholds by image integration. EAM measurements were correlated with those of macroscopic/histologic study. RESULTS: A cutoff value of 1.9 mV discriminated between subvalvular and supravalvular positions (90% sensitivity, 96% specificity). EAS >=1 cm below PV excluded RVOT site of origin (SOO). According to anatomic findings (distance PV-left coronary cusp = 5 +/- 3 vs PV-right coronary cusp = 11 +/- 5 mm), EAS-PV distance was significantly shorter in VAs arising from left coronary cusp than from the other LVOT locations (4.2 +/- 5.4 mm vs 9.2 +/- 7 mm; P = .034). The 10-ms isochronal longitudinal/perpendicular diameter ratio was higher in the RVOT vs the LVOT SOO group (1.97 +/- 1.2 vs 0.79 +/- 0.49; P = .001). An algorithm based on EAS-PV distance and the 10-ms isochronal longitudinal/perpendicular diameter ratio predicted LVOT SOO with 91% sensitivity and 100% specificity. CONCLUSION: An algorithm based on the EAS-PV distance and the 10-ms isochronal longitudinal/perpendicular diameter ratio accurately predicts LVOT vs RVOT SOO in outflow tract VAs with EAS in the septal RVOT. PMID- 25542999 TI - Association of personality traits with oral health-related quality of life independently of objective oral health status: a study of community-dwelling elderly Japanese. AB - OBJECTIVES: Oral health-related quality of life (OHRQoL) is being increasingly used in epidemiologic studies of dentistry. However, patient-reported OHRQoL does not always coincide with clinical measures. Previous studies have shown a relationship between OHRQoL and personality, but did not concomitantly investigate oral function. We aimed to examine the association among personality traits, oral function, and OHRQoL using a large sample of community-dwelling Japanese elderly. METHODS: The participants (n = 938; age, 69-71 years) were drawn from a complete enumeration of an urban area and a rural area of both the Tokyo metropolitan area and Hyogo Prefecture. The self-perceived impact of OHRQoL was measured using the Geriatric Oral Health Assessment Index (GOHAI). The oral status and socioeconomic characteristics were recorded in each participant, and personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) were assessed with the NEO-five-factor inventory. Multiple linear regression analysis was performed to examine the relationships between OHRQoL and other factors, with p < 0.05 considered to be statistically significant. RESULTS: Neuroticism was negatively associated with the GOHAI score in bivariate analyses (Spearman rank-order correlation coefficient (rs )= -0.20), whereas extraversion was positively associated (rs = 0.17). In the regression analyses, neuroticism (standardized partial regression coefficient (beta) = -0.179) and extraversion (beta=0.094) were significantly associated with the GOHAI scores independently of the number of teeth, maximal occlusal force, and financial status. CONCLUSIONS: Personality traits are associated with OHRQoL independently of objective measures of oral health status in community-dwelling elderly Japanese. CLINICAL SIGNIFICANCE: This study showed personality traits are associated with OHRQoL independently of dental status and oral function in old Japanese people. As elderly patients undergo increasingly complex dental treatments, there is a need to evaluate patient personality traits prior to dental treatment and predict patient expectations and responses to planned treatment. This is advantageous in determining the most appropriate therapy. PMID- 25543000 TI - A neutral lipid envelope-type nanoparticle composed of a pH-activated and vitamin E-scaffold lipid-like material as a platform for a gene carrier targeting renal cell carcinoma. AB - A renal cell carcinoma (RCC) is one of the refractory tumors, since it readily acquires resistance against chemotherapy. Thus, alternative therapeutic approaches such as obstructing the neovasculature are needed. We previously reported on the development of a plasmid DNA (pDNA)-encapsulating liposomal nanoparticle (LNP) as a hepatic gene delivery system that is applicable to systemic administration. The key molecular component is a SS-cleavable and pH activated lipid-like material (ssPalm) that mounts dual sensing motifs (ternary amines and disulfide bonding) that are responsive to the intracellular environment. The main purpose of the present study was to expand its application to a tumor-targeting gene delivery system in mice bearing tumors established from a RCC (OS-RC-2). When the modification of the surface of the particle is optimized for the polyethyleneglycol (PEG), stability in the blood circulation is improved, and consequently tumor-selective gene expression can be achieved. Furthermore, gene expression in the tumor was increased slightly when the hydrophobic scaffold of the ssPalm was replaced from the conventionally used myristic acid (ssPalmM) to alpha-tocopherol succinate (ssPalmE). Moreover, tumor growth was significantly suppressed when the completely CpG-free pDNA encoding the solute form of VEGFR (fms-like tyrosine kinase-1: sFlt-1) was used, especially when it was delivered by the LNP formed with ssPalmE (LNP(ssPalmE)). Thus, the PEG-modified LNP(ssPalmE) is a promising gene carrier for the cancer gene therapy of RCC. PMID- 25543001 TI - The Black cells phenotype is caused by a point mutation in the Drosophila pro phenoloxidase 1 gene that triggers melanization and hematopoietic defects. AB - Melanization contributes to arthropod-specific innate immunity through deposition of melanin at wound sites or around parasites, with concomitant release of microbicidal reactive oxygen species. Melanization requires sequential activation of proteolytic enzymes in the hemolymph, including the final enzyme pro phenoloxidase. Black cells (Bc) is a mutation causing spontaneous melanization of Drosophila crystal cells, a hemocyte cell type producing phenoloxidases. Bc individuals exhibit circulating black spots but fail to melanize upon injury. Although Bc is widely used as a loss-of-function mutant of phenoloxidases, the mutation causing Bc remained unknown. Here, we identified a single point mutation in the pro-phenoloxidase 1 (PPO1) gene of Bc flies causing an Alanine to Valine change in the C-terminal domain of PPO1, predicted to affect the conformation of the N-terminal pro-domain cleavage site at a distance and causing uncontrolled catalytic activity. Genomic insertion of a PPO1(A480V) transgene phenocopies Black cells, proving that A480V is indeed the causal mutation of the historical Bc phenotype. PMID- 25543003 TI - Improved profiling of estrogen metabolites by orbitrap LC/MS. AB - Estrogen metabolites are important biomarkers to evaluate cancer risks and metabolic diseases. Due to their low physiological levels, a sensitive and accurate method is required, especially for the quantitation of unconjugated forms of endogenous steroids and their metabolites in humans. Here, we evaluated various derivatives of estrogens for improved analysis by orbitrap LC/MS in human serum samples. A new chemical derivatization reagent was applied modifying phenolic steroids to form 1-methylimidazole-2-sulfonyl adducts. The method significantly improves the sensitivity 2-100 fold by full scan MS and targeted selected ion monitoring MS over other derivatization methods including, dansyl, picolinoyl, and pyridine-3-sulfonyl products. PMID- 25543004 TI - Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases. AB - The naturally occurring mammalian endocannabinoids possess biological attributes that extend beyond interaction with cannabinoid receptors. These extended biological properties are the result of oxidative metabolism of the principal mammalian endocannabinoids arachidonoyl ethanolamide (anandamide; A-EA) and 2 arachidonoylglycerol (2-AG). Both endocannabinoids are oxidized by cyclo oxygenase-2 (COX-2), but not by COX-1, to a series of prostaglandin derivatives (PGs) with quite different biological properties from those of the parent substrates. PG ethanolamides (prostamides, PG-EAs) and PG glyceryl esters (PG-Gs) are not only pharmacologically distinct from their parent endocannabinoids, they are distinct from the corresponding acidic PGs, and are differentiated from each other. Ethanolamides and glyceryl esters of the major prostanoids PGD2, PGE2, PGF2alpha, and PGI2 are formed by the various PG synthases, and thromboxane ethanolamides and glyceryl esters are not similarly produced. COX-2 is also of interest by virtue of its corollary central role in modulating endocannabinoid tone, providing a new therapeutic approach for treating pain and anxiety. Other major oxidative conversion pathways are provided for both A-EA and 2-AG by several lipoxygenases (LOXs), resulting in the formation of numerous hydroxyl metabolites. These do not necessarily represent inactivation pathways for endocannabinoids but may mimic or modulate the endocannabinoids or even display alternative pharmacology. Similarly, A-EA and 2-AG may be oxidized by P450 enzymes. Again a very diverse number of metabolites are formed, with either cannabinoid-like biological properties or an introduction of disparate pharmacology. The biological activity of epoxy and hydroxyl derivatives of the endocannabinoids remains to be fully elucidated. This review attempts to consolidate and compare the findings obtained to date in an increasingly important research area. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". PMID- 25543005 TI - Progress in cell-based therapies for tendon repair. AB - The last decade has seen significant developments in cell therapies, based on permanently differentiated, reprogrammed or engineered stem cells, for tendon injuries and degenerative conditions. In vitro studies assess the influence of biophysical, biochemical and biological signals on tenogenic phenotype maintenance and/or differentiation towards tenogenic lineage. However, the ideal culture environment has yet to be identified due to the lack of standardised experimental setup and readout system. Bone marrow mesenchymal stem cells and tenocytes/dermal fibroblasts appear to be the cell populations of choice for clinical translation in equine and human patients respectively based on circumstantial, rather than on hard evidence. Collaborative, inter- and multi disciplinary efforts are expected to provide clinically relevant and commercially viable cell-based therapies for tendon repair and regeneration in the years to come. PMID- 25543006 TI - Non-genetic engineering of cells for drug delivery and cell-based therapy. AB - Cell-based therapy is a promising modality to address many unmet medical needs. In addition to genetic engineering, material-based, biochemical, and physical science-based approaches have emerged as novel approaches to modify cells. Non genetic engineering of cells has been applied in delivering therapeutics to tissues, homing of cells to the bone marrow or inflammatory tissues, cancer imaging, immunotherapy, and remotely controlling cellular functions. This new strategy has unique advantages in disease therapy and is complementary to existing gene-based cell engineering approaches. A better understanding of cellular systems and different engineering methods will allow us to better exploit engineered cells in biomedicine. Here, we review non-genetic cell engineering techniques and applications of engineered cells, discuss the pros and cons of different methods, and provide our perspectives on future research directions. PMID- 25543002 TI - This old heart: Cardiac aging and autophagy. AB - Autophagy, a cellular housekeeping process, is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Autophagic activity declines with age and may explain many features of age-related cardiac dysfunction. In this review we summarize the current state of knowledge regarding age-related changes in autophagy in the heart. Recent findings from studies in human hearts are presented, including evidence that the autophagic response is intact in the aged human heart. Impaired autophagic clearance of protein aggregates or deteriorating mitochondria will have multiple consequences including increased arrhythmia risk, decreased contractile function, reduced tolerance to ischemic stress, and increased inflammation; thus autophagy represents a potentially important therapeutic target to mitigate the cardiac consequences of aging. This article is part of a Special Issue entitled CV Aging. PMID- 25543007 TI - Preclinical assessments of vaginal microbicide candidate safety and efficacy. AB - Sexually transmitted infections like HIV, HPV, and HSV-2, as well as unplanned pregnancy, take a huge toll on women worldwide. Woman-initiated multipurpose prevention technologies that contain antiviral/antibacterial drugs (microbicides) and a contraceptive to simultaneously target sexually transmitted infections and unplanned pregnancy are being developed to reduce these burdens. This review will consider products that are applied topically to the vagina. Rectally administered topical microbicides in development for receptive anal intercourse are outside the scope of this review. Microbicide and microbicide/contraceptive candidates must be rigorously evaluated in preclinical models of safety and efficacy to ensure that only candidates with favorable risk benefit ratios are advanced into human clinical trials. This review describes the comprehensive set of in vitro, ex vivo, and in vivo models used to evaluate the preclinical safety and antiviral efficacy of microbicide and microbicide/contraceptive candidates. PMID- 25543009 TI - Specific PCR and real-time PCR assays for detection and quantitation of 'Candidatus Phytoplasma phoenicium'. AB - Almond witches' broom (AlmWB) is a fast-spreading lethal disease of almond, peach and nectarine associated with 'Candidatus Phytoplasma phoenicium'. The development of PCR and quantitative real-time PCR (qPCR) assays for the sensitive and specific detection of the phytoplasma is of prime importance for early detection of 'Ca. P. phoenicium' and for epidemiological studies. The developed qPCR assay herein uses a TaqMan((r)) probe labeled with Black Hole Quencher Plus. The specificity of the PCR and that of the qPCR detection protocols were tested on 17 phytoplasma isolates belonging to 11 phytoplasma 16S rRNA groups, on samples of almond, peach, nectarine, native plants and insects infected or uninfected with the phytoplasma. The developed assays showed high specificity against 'Ca. P. phoenicium' and no cross-reactivity against any other phytoplasma, plant or insect tested. The sensitivity of the developed PCR and qPCR assays was similar to the conventional nested PCR protocol using universal primers. The qPCR assay was further validated by quantitating AlmWB phytoplasma in different hosts, plant parts and potential insect vectors. The highest titers of 'Ca. P. phoenicium' were detected in the phloem tissues of stems and roots of almond and nectarine trees, where they averaged from 10(5) to 10(6) genomic units per nanogram of host DNA (GU/ng of DNA). The newly developed PCR and qPCR protocols are reliable, specific and sensitive methods that are easily applicable to high-throughput diagnosis of AlmWB in plants and insects and can be used for surveys of potential vectors and alternative hosts. PMID- 25543008 TI - Silver nanoparticles: synthesis, properties, and therapeutic applications. AB - Silver nanoparticles (AgNPs) have been widely used in biomedical fields because of their intrinsic therapeutic properties. Here, we introduce methods of synthesizing AgNPs and discuss their physicochemical, localized surface plasmon resonance (LSPR) and toxicity properties. We also review the impact of AgNPs on human health and the environment along with the underlying mechanisms. More importantly, we highlight the newly emerging applications of AgNPs as antiviral agents, photosensitizers and/or radiosensitizers, and anticancer therapeutic agents in the treatment of leukemia, breast cancer, hepatocellular carcinoma, lung cancer, and skin and/or oral carcinoma. PMID- 25543010 TI - Plasma-sprayed titanium coating to polyetheretherketone improves the bone-implant interface. AB - BACKGROUND CONTEXT: Rapid and stable fixation at the bone-implant interface would be regarded as one of the primary goals to achieve clinical efficacy, regardless of the surgical site. Although mechanical and physical properties of polyetheretherketone (PEEK) provide advantages for implant devices, the hydrophobic nature and the lack of direct bone contact remains a limitation. PURPOSE: To examine the effects of a plasma-sprayed titanium coated PEEK on the mechanical and histologic properties at the bone-implant interface. STUDY SETTING: A preclinical laboratory study. METHODS: Polyetheretherketone and plasma sprayed titanium coated PEEK implants (Ti-bond; Spinal Elements, Carlsbad, CA, USA) were placed in a line-to-line manner in cortical bone and in a press-fit manner in cancellous bone of adult sheep using an established ovine model. Shear strength was assessed in the cortical sites at 4 and 12 weeks, whereas histology was performed in cortical and cancellous sites at both time points. RESULTS: The titanium coating dramatically improved the shear strength at the bone-implant interface at 4 weeks and continued to improve with time compared with PEEK. Direct bone ongrowth in cancellous and cortical sites can be achieved using a plasma-sprayed titanium coating on PEEK. CONCLUSIONS: Direct bone to implant bonding can be achieved on PEEK in spite of its hydrophobic nature using a plasma sprayed titanium coating. The plasma-sprayed titanium coating improved mechanical properties in the cortical sites and the histology in cortical and cancellous sites. PMID- 25543011 TI - Indirect foraminal decompression after anterior lumbar interbody fusion: a prospective radiographic study using a new pedicle-to-pedicle technique. AB - BACKGROUND CONTEXT: A frequently quoted advantage of anterior lumbar interbody fusion (ALIF) is indirect foraminal decompression, although there are few studies substantiating this statement. Also, there are no clinical studies using a standardized method to measure the foraminal area (FA) and the correlation with disc height (DH) parameters. This study is proposed to measure the degree of indirect foraminal decompression radiologically using a standardized method and correlate with the intervertebral disc parameters. PURPOSE: To standardize the foramen measurement technique. To measure indirect neural foraminal decompression in surgically operated patients after ALIF using radiographic measurement and elucidate factors affecting foraminal restoration. STUDY DESIGN: A prospective cohort study. PATIENT SAMPLE: A continuous cohort of patients undergoing ALIF surgery. OUTCOME MEASURES: It included FA, foraminal height (FH), and foraminal width. METHODS: This is a prospective analysis of a single surgeon series of consecutive patients undergoing an ALIF from 2011 to 2013. Pre- and postoperative computed tomography scans were used to obtain a standardized foramen snapshot using the pedicle-to-pedicle (P-P) technique, and measurements were obtained using image j software. Radiologic parameters such as DH, local disc angle (LDA), and lumbar lordosis (LL) were measured using radiographs and Surgimap software. RESULTS: One-hundred forty patients with 184 levels were operated. Anterior lumbar interbody fusion resulted in a statistically significant (p<.01) improvement in foraminal dimensions (area=67%, height=21%, and width=38%). Other parameters also significantly improved, including anterior DH (90%), posterior DH (77%), LDA, and LL (6%). Posterior DH correlated significantly with FH improvement. Statistically, the P-P technique presented with high intra- and interclass reliabilities. CONCLUSIONS: Anterior lumbar interbody fusion results in significant indirect foraminal decompression based on the new P-P technique. Posterior DH is a significant factor in the restoration of the FH. PMID- 25543012 TI - Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome. AB - Multiple synostoses syndrome 2 (SYNS2) is a rare genetic disease characterized by multiple fusions of the joints of the extremities, like phalangeal joints, carpal and tarsal joints or the knee and elbows. SYNS2 is caused by point mutations in the Growth and Differentiation Factor 5 (GDF5), which plays an essential role during skeletal development and regeneration. We selected one of the SYNS2 causing GDF5 mutations, p.N445T, which is known to destabilize the interaction with the Bone Morphogenetic Protein (BMP) antagonist NOGGIN (NOG), in order to generate the superagonistic GDF5 variant GDF5(N445T). In this study, we tested its capacity to support regeneration in a rat critical-sized defect model in vivo. MicroCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5(wt)) treated defects. Microarray-based gene expression and quantitative PCR analyses from callus tissue point to a specific acceleration of the early phases of bone healing, comprising the inflammation and chondrogenesis phase. These results support the concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities. PMID- 25543013 TI - Fundamental differences in axial and appendicular bone density in stress fractured and uninjured Royal Marine recruits--a matched case-control study. AB - Stress fracture is a common overuse injury within military training, resulting in significant economic losses to the military worldwide. Studies to date have failed to fully identify the bone density and bone structural differences between stress fractured personnel and controls due to inadequate adjustment for key confounding factors; namely age, body size and physical fitness; and poor sample size. The aim of this study was to investigate bone differences between male Royal Marine recruits who suffered a stress fracture during the 32 weeks of training and uninjured control recruits, matched for age, body weight, height and aerobic fitness. A total of 1090 recruits were followed through training and 78 recruits suffered at least one stress fracture. Bone mineral density (BMD) was measured at the lumbar spine (LS), femoral neck (FN) and whole body (WB) using Dual X-ray Absorptiometry in 62 matched pairs; tibial bone parameters were measured using peripheral Quantitative Computer Tomography in 51 matched pairs. Serum C-terminal peptide concentration was measured as a marker of bone resorption at baseline, week-15 and week-32. ANCOVA was used to determine differences between stress fractured recruits and controls. BMD at the LS, WB and FN sites was consistently lower in the stress fracture group (P<0.001). Structural differences between the stress fracture recruits and controls were evident in all slices of the tibia, with the most prominent differences seen at the 38% tibial slice. There was a negative correlation between the bone cross sectional area and BMD at the 38% tibial slice. There was no difference in serum CTx concentration between stress fracture recruits and matched controls at any stage of training. These results show evidence of fundamental differences in bone mass and structure in stress fracture recruits, and provide useful data on bone risk factor profiles for stress fracture within a healthy military population. PMID- 25543014 TI - HLA-E polymorphism and clinical outcome after allogeneic hematopoietic stem cell transplantation in Egyptian patients. AB - Human leukocyte antigen-E (HLA)-E in a non-classical major histocompatibility complex (MHC) class I (Ib) molecule. HLA-E-peptide complex acts as a ligand for natural killer (NK) cells and CD8+ T lymphocytes playing a dual role in natural and acquired immune responses. The difference in expression levels between HLA-E alleles was suggested to have impact on transplantation outcome. The aim of the study is to evaluate the clinical effect of HLA-E alleles on transplantation in a group of Egyptian patients. HLA-E genotyping was analyzed in eighty-eight recipients of stem cell transplantation using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). HLA-E*01:03 allele showed a trend towards lower cumulative incidence of relapse at 2 years compared to homozygous HLA-E*01:01 genotype (8% versus 21.5%, p=0.09, HR: 0.30, 95% CI: 0.91 1.69). HLA-E was the only factor showing near significant association with relapse incidence. HLA-E polymorphism did not affect the cumulative incidence of acute GVHD grades II-IV at 100 days, the 2-year cumulative incidence of extensive chronic GVHD, transplant related mortality (TRM) or overall survival (OS). CONCLUSION: the suggested association of HLA-E polymorphism with reduced risk of relapse needs verification in a larger cohort. However, its proposed role in GVL helps better understanding of alloreactivity of T cells and NK cells and their implication in immunotherapy post allogeneic hematopoietic stem cell transplantation. PMID- 25543015 TI - Impact of three Illumina library construction methods on GC bias and HLA genotype calling. AB - Next-generation sequencing (NGS) is increasingly recognized for its ability to overcome allele ambiguity and deliver high-resolution typing in the HLA system. Using this technology, non-uniform read distribution can impede the reliability of variant detection, which renders high-confidence genotype calling particularly difficult to achieve in the polymorphic HLA complex. Recently, library construction has been implicated as the dominant factor in instigating coverage bias. To study the impact of this phenomenon on HLA genotyping, we performed long range PCR on 12 samples to amplify HLA-A, -B, -C, -DRB1, and -DQB1, and compared the relative contribution of three Illumina library construction methods (TruSeq Nano, Nextera, Nextera XT) in generating downstream bias. Here, we show high GC% to be a good predictor of low sequencing depth. Compared to standard TruSeq Nano, GC bias was more prominent in transposase-based protocols, particularly Nextera XT, likely through a combination of transposase insertion bias being coupled with a high number of PCR enrichment cycles. Importantly, our findings demonstrate non uniform read depth can have a direct and negative impact on the robustness of HLA genotyping, which has clinical implications for users when choosing a library construction strategy that aims to balance cost and throughput with data quality. PMID- 25543016 TI - The failure of medical education to develop moral reasoning in medical students. AB - OBJECTIVE: The goal of this study was to determine differences in moral judgment among students in medical school. METHODS: This cross-sectional study involved students currently enrolled in undergraduate medical education. Recruited via email, 192 students took an online version of the Defining Issues Test to determine their current stage of moral judgment, as well as their percentage of postconventional thought. Independent variables included year of graduation, which indicated curriculum completion as well as participation in a professionalism course. Data was analyzed primarily using One-Way Analysis of Variance. RESULTS: Of the 192 participants, 165 responses were utilized. ANOVA showed no significant differences in moral judgment between or among any of the student cohorts, which were grouped by year of matriculation. Comparisons included students in the four years of medical school, divided by graduation year; students about to graduate (n=30) vs. those still in school (n=135); and students who had participated in a course in professionalism (n=91) vs. those who had not (n=74). CONCLUSIONS: These results demonstrate a lack of evolution in the moral reasoning of medical students and raise the issue of what might stimulate positive changes in moral judgment during the medical school experience. PMID- 25543017 TI - Characterizing the human equivalent dose of herbal medicines in animal toxicity studies. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicines have been generally believed to be safe. With the increasing use of herbal medicine worldwide, however, the safety of traditional herbal drugs frequently becomes a medical issue. AIM OF THE STUDY: This study was aimed to characterize the safe dose of herbal medicines through the systematic review for "human equivalent dose (HED)" from animal-based toxicity studies. METHODS AND MATERIALS: A literature search for animal-based toxicity studies of herbal medicines in eight databases, including PubMed and Embase, was performed without language restriction. From the "no observed adverse effect level (NOAEL)" of each animal study, HED values were then calculated according to the composition (single or multiple herbs) and indication of the medicines. RESULTS: Among 729 relevant articles identified in the initial screening, 112 (233 studies comprising 105 single-herb and 128 multiple-herb studies) that met our inclusion criteria were finally reviewed. The total average HED value (from mouse, rat, rabbit and dog) was 278.1+/-358.0 mg/kg, and the values for single- and multiple-herb studies were 322.7+/-488.4 mg/kg and 241.5+/ 189.2 mg/kg, respectively. When the studies were analyzed according to herbal drug indication, drugs used for revitalization had the highest HED value (433.0+/ 265.2 mg/kg), while those for infectious diseases had the lowest (110.6+/-118.6 mg/kg). CONCLUSIONS: Our results provide important information regarding the safe dose of herbal medicines; thus, these data offer researchers and practitioners information critical for drug development or clinical application. PMID- 25543018 TI - Oroxylum indicum (L.) Kurz, an important Asian traditional medicine: from traditional uses to scientific data for its commercial exploitation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Oroxylum indicum? (L.) Kurz has been used for centuries as a traditional medicine in Asia in ethnomedicinal systems for the prevention and treatment of several diseases, such as jaundice, arthritic and rheumatic problems, gastric ulcers, tumors, respiratory diseases, diabetes, and diarrhea and dysentery, among others. The present review provides scientific evidence supporting the therapeutic potency of the plant for ethnomedicinal uses and identifies gaps for future research to facilitate commercial exploitation. METHODS: This review is based on available information on traditional uses and phytochemical, pharmacological, clinical and toxicity data for Oroxylum indicum that was collected from electronic (SciFinder, PubMed, Science Direct, and ACS, among others) and library searches. KEY FINDING: A variety of traditional medicinal uses of Oroxylum indicum in different Southeast and South Asian countries have been reported in books describing the uses of these plants. Phytochemical investigations of the different parts of the plant resulted in identification of approximately 111 compounds, among which flavonoids, naphthalenoids and cyclohexylethanoids are the predominant groups. The crude extracts and their isolates exhibit a wide spectrum of in vitro and in vivo pharmacological activities involving antimicrobial, anti-inflammatory, anti arthritic, anticancer, anti-ulcer, hepatoprotective, antidiabetic, antidiarrheal and antioxidant activities. Flavonoids are the major constituents of all parts of the plant. From a toxicity perspective, only aqueous and ethanolic extracts of stem bark, root bark and fruits have been assessed and found to be safe. The major flavonoids of the stem bark, such as baicalein, chrysin and oroxylin A, were reported for the first time as natural flavonoids with potent inhibitory activity against endoprotease enzymes and proprotein convertases, which play a key role in the growth of cancer and in viral and bacterial infections. Flavonoids are the active components of bioactive extracts. Several Ayurvedic medicines have been formulated either singly using this plant or along with other herbs for the treatment of different diseases. CONCLUSIONS: Pharmacological results have supported some traditional medicinal uses of Oroxylum indicum. Several extracts and their isolates have been reported to exhibit interesting pharmacological properties. These components could be useful as sources of modern medicines following future detailed studies to elucidate their underlying mechanisms, toxicity, synergistic effects and clinical trials. Attention should also be focused on pharmacological studies investigating the traditional uses of the plant, which have not been yet addressed, as well as clinical studies investigating commercial Ayurvedic medicines and other ethnomedicinal preparations in human subjects based on this plant to confirm the safety and quality of the preparations. PMID- 25543019 TI - Efficacy of the saponin component of Impatiens capensis Meerb.in preventing urushiol-induced contact dermatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Many different tribes of American Indians used jewelweed, Impatiens capensis Meerb, as a plant mash to reduce development of poison ivy dermatitis. Saponins are a natural soapy constituent found within plants. A 2012 study suggested that saponins may be present in jewelweed which could be responsible for its efficacy in preventing rash development following contact with Toxicodendron radicans (L.) Kuntze (poison ivy). This study validated this hypothesis and demonstrated additional biological activity of the jewelweed saponin containing extract. MATERIALS AND METHODS: Fresh I. capensis leaves were extracted with methanol and further partitioned between ethyl acetate and water, with a final separation between water and n-butanol, to obtain a saponin containing extract. The presence of saponins in the extract was demonstrated by the observation of foaming and using a vanillin colorimetric assay for total saponins. Efficacy of the saponin containing extracts in rash reduction was tested by brushing poison ivy (PI) onto the forearms of volunteers (N=23) in six locations and treating these PI exposed areas with distilled water (control), saponin containing extracts, fresh plant mashes, and soaps made with and without plant extracts. Saponin containing extracts were further tested for biological activity against both gram negative and gram positive bacteria and against cancer cell lines A-375, HT-29, and MCF-7. Additionally, because saponins have been shown to have a stimulatory effect in cardiac muscle 2 ul saponin extract was applied superficially to black worms, Lumbriculus variegatus (N=5). RESULTS, AND CONCLUSIONS: Both saponin containing extracts and all soaps tested were effective in reducing poison ivy dermatitis; thus, saponin content correlates with PI rash prevention. No apparent antibiosis was observed against any bacteria tested; however, dose response cytotoxicity was documented against MCF-7 breast cancer cells and cytostatic activity was seen against the HT-29 colon cancer cell lines. Lumbriculus variegatus exhibited a 138% increase in heart rate over baseline rate five minutes post treatment implying a possible positive chronotropic effect. PMID- 25543020 TI - The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis. AB - Sepsis and septic shock in response to bacterial or viral infections remain the major health problem worldwide. Despite decades of intensive research and improvements in medical care, severe sepsis is associated with high mortality. Rapid activation of the adrenal gland glucocorticoid and catecholamine production is a fundamental component of the stress response and is essential for survival of the host. However, in many critically ill patients this homeostatic function of the adrenal gland is often impaired. In these patients, plasma levels of adrenocorticotropic hormone (ACTH) and cortisol are often dissociated. This has been attributed to the stimulatory action of non-ACTH factors within the adrenal gland such as cytokines, and recently with decreased cortisol metabolism and suppressed ACTH synthesis. Regulation of the hypothalamus-pituitary-adrenal (HPA) axis function during sepsis is a complex process which involves various immune and neuroendocrine interactions occurring at the levels of the central nervous system (CNS) and the adrenal gland. A coordinated interaction of numerous cell types and systems within the adrenal gland is involved in the sustained adrenal glucocorticoid production. This review article describes and discusses recent experimental findings regarding the role of adrenal gland microenvironment including the adrenal vasculature and the immune-adrenal crosstalk in the disregulated HPA axis during sepsis conditions. In summary, in addition to the reduced cortisol breakdown and related ACTH suppression, sepsis-mediated chronic activation of the immune-adrenal crosstalk and vascular dysfunction may contribute to the HPA axis dysregulation found in septic patients. PMID- 25543021 TI - Regulation of androgen biosynthesis - A short review and preliminary results from the hyperandrogenic starvation NCI-H295R cell model. AB - Regulation of androgen production is poorly understood. Adrenarche is the physiologic event in mid-childhood when the adrenal zona reticularis starts to produce androgens through specific expression of genes for enzymes and cofactors necessary for androgen synthesis. Similarly, expression and activities of same genes and products are deregulated in hyperandrogenic disorders such as the polycystic ovary syndrome (PCOS). Numerous studies revealed involvement of several signaling pathways stimulated through G-protein coupled receptors or growth factors transmitting their effects through cAMP- or non-cAMP-dependent signaling. Overall a complex network regulates androgen synthesis targeting involved genes and proteins at the transcriptional and post-translational levels. Newest players in the field are the DENND1A gene identified in PCOS patients and the MAPK14 which is the kinase phosphorylating CYP17 for enhanced lyase activity. Next generation sequencing studies of PCOS patients and transcriptome analysis of androgen producing tissues or cell models provide newer tools to identify modulators of androgen synthesis. PMID- 25543022 TI - Modulation of corticospinal excitability by reward depends on task framing. AB - Findings from previous transcranial magnetic stimulation (TMS) experiments suggest that the primary motor cortex (M1) is sensitive to reward conditions in the environment. However, the nature of this influence on M1 activity is poorly understood. The dopamine neuron response to conditioned stimuli encodes reward probability and outcome uncertainty, or the extent to which the outcome of a situation is known. Reward uncertainty and probability are related: uncertainty is maximal when probability is 0.5 and minimal when probability is 0 or 1 (i.e., certain outcome). Previous TMS-reward studies did not examine these factors independently. Here, we used single-pulse TMS to measure corticospinal excitability in 40 individuals while they performed a simple computer task, making guesses to find or avoid a hidden target. The task stimuli implied three levels of reward probability and two levels of uncertainty. We found that reward probability level interacted with the trial search condition. That is, motor evoked potential (MEP) amplitude, a measure of corticospinal neuron excitability, increased with increasing reward probability when participants were instructed to "find" a target, but not when they were instructed to "avoid" a target. There was no effect of uncertainty on MEPs. Response times varied with the number of choices. A subset of participants also received paired-pulse stimulation to evaluate changes in short-intracortical inhibition (SICI). No effects of SICI were observed. Taken together, the results suggest that the reward-contingent modulation of M1 activity reflects reward probability or a related aspect of utility, not outcome uncertainty, and that this effect is sensitive to the conceptual framing of the task. PMID- 25543023 TI - Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer's disease (APP/PS1) transgenic mice. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease. Post-mortem examination and brain imaging studies indicate that neurodegeneration is evident in the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Here, we investigated the effects of exercise (running) on the neuronal structure and function of the hippocampus and amygdala in APP/PS1 transgenic (Tg) mice. At 4-months-old, an age before amyloid deposition, the amygdala-associated, but not the hippocampus-associated, long-term memory was impaired in the Tg mice. The dendritic complexities of the amygdalar basolateral neurons, but not those in the hippocampal CA1 and CA3 neurons, were reduced. Furthermore, the levels of BDNF/TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala, but not in the hippocampus of the 4-month-old Tg mice. The concentrations of Abeta40 and Abeta42 in the amygdala were higher than those in the hippocampus. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-AKT and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Abeta in the amygdala and hippocampus. Exercise training did not change the levels of APP or RAGE, but significantly increased the levels of LRP-1 in both brain regions of the Tg mice. In conclusion, our results suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Abeta clearance. Physical exercise may serve as a means to delay the onset of AD. PMID- 25543024 TI - Inactivating the infralimbic but not prelimbic medial prefrontal cortex facilitates the extinction of appetitive Pavlovian conditioning in Long-Evans rats. AB - The infralimbic medial prefrontal cortex (IL) has been posited as a common node in distinct neural circuits that mediate the extinction of appetitive and aversive conditioning. However, appetitive extinction is typically assessed using instrumental conditioning procedures, whereas the extinction of aversive conditioning is customarily studied using Pavlovian assays. The role of the IL in the extinction of appetitive Pavlovian conditioning remains underexplored. We investigated the involvement of the IL and prelimbic medial prefrontal cortex (PrL) in appetitive extinction in Pavlovian and instrumental conditioning assays in male, Long-Evans rats. Following acquisition, a gamma-aminobutyric acid agonist solution (0.03 nmol muscimol; 0.3 nmol baclofen; 0.3 MUl/side) was bilaterally microinfused into the IL or PrL to pharmacologically inactivate each region before the first extinction session. Compared to saline, PrL inactivation did not affect the acquisition of extinction or the recall of extinction memory 24-h later. IL inactivation caused a more rapid extinction of Pavlovian conditioning, but had no effect on the extinction of instrumental conditioning or extinction recall. IL inactivation during a Pavlovian conditioning session in which conditioned stimulus (CS) trials were paired with sucrose did not affect CS elicited behaviour, but increased responding during intervals that did not contain the CS. The same manipulation did not impact lever pressing for sucrose. These findings suggest that the IL may normally maintain Pavlovian conditioned responding when an anticipated appetitive CS is unexpectedly withheld, and that this region has distinct roles in the expression of Pavlovian conditioning when an appetitive unconditioned stimulus is either presented or omitted. PMID- 25543025 TI - Stronger learning recruits additional cell-signaling cascades: c-Jun-N-terminal kinase 1 (JNK1) is necessary for expression of stronger contextual fear conditioning. AB - Increased training often results in stronger memories but the neural changes responsible for these stronger memories are poorly understood. It is proposed here that higher levels of training that result in stronger memories recruit additional cell signaling cascades. This study specifically examined if c-Jun N terminal kinase 1 (JNK1) is involved in the formation of stronger fear conditioning memories. Wildtype (WT), JNK1 heterozygous (Het), and JNK1 knockout (KO) mice were fear conditioned with 1 trial, 2 trials, or 4 trials. All mice learned both contextual (hippocampus-dependent) and cued (hippocampus independent) fear conditioning but for contextual fear conditioning only, the JNK1 KO mice did not show higher levels of learning with increased trials. That is, WT mice showed a significant linear increase in contextual fear conditioning as training trials increased from 1 to 2 to 4 trials whereas KO mice showed the same level of contextual fear conditioning as WT mice for 1 trial training but did not have increased levels of contextual fear conditioning with additional trials. These data suggest that JNK1 may not be critical for learning but when higher levels of hippocampus-dependent learning occur, JNK1 signaling is recruited and is necessary for stronger hippocampus-dependent memory formation. PMID- 25543026 TI - An update to polyketide synthase and non-ribosomal synthetase genes and nomenclature in Fusarium. AB - Members of the genus Fusarium produce a plethora of bioactive secondary metabolites, which can be harmful to humans and animals or have potential in drug development. In this study we have performed comparative analyses of polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) from ten different Fusarium species including F. graminearum (two strains), F. verticillioides, F. solani, F. culmorum, F. pseudograminearum, F. fujikuroi, F. acuminatum, F. avenaceum, F. equiseti, and F. oxysporum (12 strains). This led to identification of 52 NRPS and 52 PKSs orthology groups, respectively, and although not all PKSs and NRPSs are assumed to be intact or functional, the analyses illustrate the huge secondary metabolite potential in Fusarium. In our analyses we identified a core collection of eight NRPSs (NRPS2-4, 6, 10-13) and two PKSs (PKS3 and PKS7) that are conserved in all strains analyzed in this study. The identified PKSs and NRPSs were named based on a previously developed classification system (www.FusariumNRPSPKS.dk). We suggest this system be used when PKSs and NRPSs have to be classified in future sequenced Fusarium strains. This system will facilitate identification of orthologous and non-orthologous NRPSs and PKSs from newly sequenced Fusarium genomes and will aid the scientific community by providing a common nomenclature for these two groups of genes/enzymes. PMID- 25543027 TI - Hypoxia switches episodic breathing to singlet breathing in red-eared slider turtles (Trachemys scripta) via a tropisetron-sensitive mechanism. AB - Hypoxia-induced changes in the chelonian breathing pattern are poorly understood. Thus, breathing was measured in freely swimming adult red-eared slider turtles breathing air prior to breathing nitrogen for 4h. Ventilation increased 10-fold within 10min due to increased breath frequency and tidal volume. Breaths/episode decreased by ~50% within after 1h of hypoxia while the number of singlet breaths increased from 3.1+/-1.6singlets/h to a maximum of 66.1+/-23.5singlets/h. Expiratory and inspiratory duration increased during hypoxia. For doublet and triplet breaths, expiratory duration increased during the first breath only, while inspiratory duration increased for all breaths. Tropisetron (5-HT3 receptor antagonist, 5mg/kg) administration prior to hypoxia attenuated the hypoxia induced increase in singlet breath frequency. Along with results from previous in vitro studies, this study suggests that 5-HT3 receptor activation may be required for the hypoxia-induced increase in singlet breathing pattern in red-eared slider turtles. PMID- 25543028 TI - Ferulic acid attenuates the down-regulation of MEK/ERK/p90RSK signaling pathway in focal cerebral ischemic injury. AB - Ferulic acid provides neuroprotective effects against a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia. Mitogen-activated protein kinases can regulate extensive intracellular processes including cell differentiation, growth, and death. This study further investigated whether ferulic acid modulates a protective mechanism through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad during cerebral ischemic injury. Male Sprague-Dawley rats were treated with ferulic acid (100mg/kg) or vehicle after the onset of MCAO and brain tissues were collected 24h after MCAO. These results indicated that ferulic acid decreases the volume of the infarct area and the number of cells positive in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Although MCAO injury induces a decrease in the phosphorylation of Raf-1, MEK1/2, and ERK1/2, ferulic acid treatment prevents the injury-induced decrease in these phosphorylation levels. Ferulic acid also attenuates the injury-induced decrease in p90RSK and Bad phosphorylation levels. These findings suggest that ferulic acid prevents MCAO induced neuronal cell death and that the MEK-ERK-p90RSK-Bad signaling pathway is involved in these neuroprotective effects. PMID- 25543029 TI - Is a neuronal chain between the pineal body and the retina in rats and hamsters? Transneural tracing studies. AB - Neuronal chains between the retina and the pineal body were investigated. Transneuronal tracers, retrograde spreading pseudorabies virus (labeled with green fluorescent protein, memGreen-RV) and virus spreading in both ante- and retrograde directions (labeled with red fluorescent protein, Ka-VHS-mCherry-A-RV) were injected into the right eye of vitreous body of intact or bilaterally sympathectomized Wistar male rats. Intact golden hamsters also received memGreen RV into the eye and Ka-VHS-mCherry-A-RV into the pineal body. Four-five days later the animals were sacrificed. Frozen sections were prepared from the removed structures. In intact rats memGreen-RV resulted in green fluorescent labeling in the trigeminal and the superior cervical ganglia, the lateral horn of the spinal cord, the paraventricular and the suprachiasmatic nuclei, the perifornical region, the ventrolateral medulla, the locus ceruleus, and the raphe nuclei. In sympathectomized rats the labeling was missing from the brainstem but further existed in the hypothalamus. This observation indicates that the hypothalamic labeling is not mediated by the sympathetic system. One labeled neuron in the pineal body was only observed in 2/13 rats. It was independent from the sympathectomy. When the animals received Ka-VHS-mCherry-A-RV the distribution of the labeling was very similar to that of the intact group receiving retrograde virus. In golden hamsters the memGreen-RV labeled structures were seen in similar places as in rats, but virus labeled nerve cell bodies were always seen in the pineal body. Injection of Ka-VHS-mCherry-A-RV into the pineal body of hamsters resulted in labeling of the retina at both sides. It was concluded that the retinopetal neuronal chain in golden hamsters is always present but in rats it is stochastic. PMID- 25543030 TI - The change of circulating insulin like growth factor binding protein 7 levels may correlate with postoperative cognitive dysfunction. AB - Insulin-like growth factor binding protein (IGFBP) 7 may be a critical regulator of memory consolidation. This study was performed to assess the relationship between circulating IGFBP7 levels and postoperative cognition dysfunction (POCD) in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. Among one hundred and two patients included in this study, forty-four patients completed collection of all four blood samples and thirty-five patients were diagnosed with POCD. The results of Mini-Mental State Examination (MMSE) test and enzyme-linked immunosorbent assay showed that postoperative MMSE score and circulating insulin-like growth factor (IGF)-1 level were lower and circulating IGFBP7 level was higher than preoperative level. Circulating IGF-1 level was significantly lower and D-value of preoperative and postoperative day 1 circulating IGFBP7 levels (DeltaIGFBP7(1)) was significantly higher in the POCD group. Age preoperative MMSE, IGF-1 level and DeltaIGFBP7(1) significantly correlated with POCD, but preoperative IGFBP7 level not. Logistic regression analysis revealed that older patients, lower preoperative MMSE score, IGF-1 level and higher IGFBP7 level significantly increased the risk of POCD, but DeltaIGFBP7(1) not. Hence, circulating IGF-1 and IGFBP7 levels and their changes during operation under general anesthesia may correlate with POCD, but further investigation in larger samples is needed. PMID- 25543031 TI - Oxygen-glucose deprivation inducing B1 RNA inhibits neuronal cells metabolic activity by NLRP3 and associated proinflammatory cytokines production. AB - Cerebral ischemia occurs when blood flow to part of the brain is obstructed, which can result in oxygen and glucose deprivation (OGD) and neuronal damage. However, the mechanisms remain poorly understood. The present study investigated the production and effects of double-stranded RNA (dsRNA) induced by OGD in neuronal cells. By confocal microscopy, dsRNA containing B1 and B2 RNA, was found accumulating in HT22 cells under OGD treatment. The sequence of B1 RNA was identified and transfected into HT22 cells. Interestingly, B1 RNA induced transcription and expression of NLRP3, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, which was similar to the effects of OGD treatment. Moreover, HT22 cell growth inhibition and proinflammatory cytokines production induced by OGD and B1 RNA treatment were down-regulated by NLRP3 knock-down. These findings suggest that B1 RNA induced by OGD forms as dsRNA and inhibits neuronal cell metabolic activity by regulating the NLRP3 and associated proinflammatory cytokines production. PMID- 25543032 TI - Amplification-free sequencing of cell-free DNA for prenatal non-invasive diagnosis of chromosomal aberrations. AB - Cell-free DNA has been used for fetal rhesus factor and sex determination, fetal aneuploidy screening, cancer diagnostics and monitoring, and other applications. However current methods of using cell free DNA require amplification, which leads to allelic dropout and bias especially when starting with small amounts of DNA. Here we describe an amplification-free method for sequencing of cell-free DNA, even from low levels of starting material. We evaluated this method in the context of prenatal diagnosis of fetal aneuploidy and compared it with a PCR based library preparation method as well as a recently described method using unique molecular identifiers (UMI). All methods performed well, however coverage was increased by the amplification-free method and GC-induced bias was reduced by both the amplification-free method and the UMI method. Future diagnostic applications including whole genome sequencing of cell-free DNA will benefit from amplification-free sequencing. PMID- 25543033 TI - Transcriptome analysis revealed changes of multiple genes involved in immunity in Cynoglossus semilaevis during Vibrio anguillarum infection. AB - Half-smooth tongue sole (Cynoglossus semilaevis) is one of the most valuable marine aquatic species in Northern China. Given to the rapid development of aquaculture industry, the C. semilaevis was subjected to disease-causing bacteria Vibrio anguillarum. It therefore is indispensable and urgent to understand the mechanism of C. semilaevis host defense against V. anguillarum infection. In the present study, the extensively analysis at the transcriptome level for V. Anguillarum disease in tongue sole was carried out. In total, 94,716 high quality contigs were generated from 75,884,572 clean reads in three libraries (HOSG, NOSG, and CG). 22,746 unigenes were identified when compared with SwissProt, an NR protein database and NT nucleotide database. 954 genes exhibiting the differentially expression at least one pair of comparison in all three libraries were identified. GO enrichment for these genes revealed gene response to biotic stimulus, immune system regulation, and immune response and cytokine production. Further, the pathways such as complement and coagulation cascades and Vibrio cholerae infection pathways were enriched in defensing of pathogen. Besides, 13,428 SSRs and 118,239 SNPs were detected in tongue sole, providing further support for genetic variation and marker-assisted selection in future. In summary, this study identifies several putative immune pathways and candidate genes deserving further investigation in the context of development of therapeutic regimens and lays the foundation for selecting resistant lines of C. semilaevis against V. anguillarum. PMID- 25543034 TI - Grouper (Epinephelus coioides) IL-34/MCSF2 and MCSFR1/MCSFR2 were involved in mononuclear phagocytes activation against Cryptocaryon irritans infection. AB - MCSF and its well-known receptor MCSFR had been well studied in humans, regulating the differentiation, proliferation, and survival of the mononuclear phagocyte system. IL-34, which is an alternative ligand of MCSF receptor, was recently identified as a novel cytokine and functionally overlaps with MCSF. However, the functional study of these receptors and their ligands in fish are largely unknown. In the present study, the cDNA of two potential grouper MCSFR ligands have been cloned, EcIL-34 (657 bp) and EcMCSF2 (804 bp), as well as an additional copy of grouper MCSFR, EcMCSFR2 (3141 bp). Sequence analysis showed that these three molecules had higher identities with other fish counterparts compared to mammals and their conserved structures and important functional residues were also analyzed. Tissue distribution analysis showed that EcIL-34 is dominant in brain, gill and spleen compared to EcMCSF2, which is dominant in head kidney, trunk kidney, skin, heart and muscle. EcMCSFR1 was dominant in the most tissues except head kidney and liver compared to EcMCSFR2. The different tissue distribution patterns of these two grouper MCSF receptors and their two ligands indicate the different mononuclear phagocyte differentiation and activation modes in different tissues. In Cryptocaryon irritans infected grouper, EcIL-34 and EcMCSFR2 were the most strongly up-regulated ligand and receptor in the infected sites, gill and skin. Their up-regulation confirmed the proliferation and activation of phagocytes in C. irritans infected sites, which would improve the antigen presentation and elicit the host local specific immune response. In C. irritans infected grouper head kidney, both ligands EcIL-34 and EcMCSF2 (especially EcMCSF2) were up-regulated, but both receptors EcMCSFR1 and EcMCSFR2 were down-regulated, which indicated that the phagocytes differentiation and proliferation may have occurred in this hemopoietic organ, and after that they migrated to the infected cites. The down-regulation of EcIL-34 and EcMCSF2 and no significant change of EcMCSFR1 and EcMCSFR2 in most time point of grouper spleen showed it was less involved in phagocytes response to C. irritans infection. PMID- 25543035 TI - Impact of age at onset of cannabis use on cannabis dependence and driving under the influence in the United States. AB - BACKGROUND AND AIMS: There is growing evidence that driving under the influence of cannabis is associated with a higher risk of motor vehicle crash. Cannabis dependence has been reported to be associated with a three-fold increased risk of motor vehicle crash. The impact of the age at onset of cannabis use on the risk of both cannabis dependence and driving under the influence of cannabis has not been evaluated so far. METHODS: Data were drawn from the 2001-2002 National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a survey of 43,093 adults aged 18 years and older. We limited our analyses to the sample of participants who reported having ever used cannabis (n=8172), of whom 8068 had a known age at onset of cannabis use. RESULTS: Of the 8068 participants included, 5.15% reported having driven under the influence of cannabis. Among those, only a minority (14.46%) were diagnosed with cannabis dependence. Compared to those who start using cannabis at age 21 years or after, participants who used cannabis before the age of 14 years were 4 times more likely to have a history of cannabis dependence and 3 times more likely to reported having driven under the influence of cannabis. An inverse relationship between the age at onset of cannabis use and driving under the influence and risk of cannabis dependence was found. CONCLUSIONS: Starting to smoke cannabis younger than 21 years is associated with both cannabis dependence and driving under the influence of cannabis. PMID- 25543036 TI - Update of cytokines and genes in asthma and allergic rhinitis. PMID- 25543037 TI - The linkage of allergic rhinitis and obstructive sleep apnea. AB - Rhinitis can be divided into allergic and non-allergic rhinitis. Rhinitis, particularly allergic rhinitis, has been shown to be associated with obstructive sleep apnea; a condition characterized by repetitive upper airway obstruction during sleep. Allergic rhinitis increases the risk of developing obstructive sleep apnea by two major mechanisms: 1) increase in airway resistance due to higher nasal resistance and 2) reduction in pharyngeal diameter from mouth breathing that moves the mandible inferiorly. Other inflammatory mediators including histamine, CysLTs, IL 1beta and IL-4 found in high levels in allergic rhinitis, have also been shown to worsen sleep quality in obstructive sleep apnea. Prior studies have shown that treatment of allergic rhinitis, particularly when intranasal steroid are used, improved obstructive sleep apnea. Leukotriene receptor antagonists were also associated with positive results on obstructive sleep apnea in adult patients with concomitant allergic rhinitis but current data are limited in the case of children. PMID- 25543038 TI - Prevalence of asthma, level of control and factors associated with asthma control in Thai elementary school students in Bangkok. AB - BACKGROUND: Little is known about the level of asthma control in Thai elementary school students living in the inner city of Bangkok. Our study aimed to evaluate the prevalence of asthma, level of asthma control and factors associated with asthma control in Thai students. METHODS: We conducted a cross-sectional descriptive study in students aged between 6-12 years at 3 public schools and 3 private schools in Bangkok. The parent-completed questionnaire used to assess the prevalence of asthma and asthma symptoms was translated from the Phase I ISAAC (The International Study of Asthma and Allergies in Childhood) questionnaire. Univariate analysis was used to identify possible risk factors related to partly and uncontrolled asthma. RESULTS: A population of 1,428 students was recruited by screening questionnaires (66.1% of response rate). The mean age was 9.5 years. Prevalence of physician-diagnosed asthma was 9% and the most common asthma symptom was night cough (23.8%). The level of asthma control was assessed in students with current asthma and classified as controlled (46.7%), partly controlled (43.3%) and uncontrolled (10%). Around 27% of students with current asthma in this study use controller medications. Factors associated with asthma control were analyzed but none approached significance. CONCLUSIONS: The prevalence of asthma in elementary school students living in Bangkok has decreased since the previous survey and the use of controller medications has increased. Asthma management strategies should focus on encouraging awareness among physicians and parents about the importance of using controller medications to achieve better control of asthma. PMID- 25543039 TI - Investigation of dermatology life quality index and serum prolactin and serum dehydroepiandrosterone sulphate levels in patients with chronic urticaria. AB - BACKGROUND: Chronic urticaria (CU) is known to be one of the most disturbing diseases which significantly affect the quality of life. Prolactin (PRL) and DHEA S (dehydroepiandrosterone sulfate) are stress-associated hormones in chronic urticaria. OBJECTIVE: In the present study, we measured DHEA-S and prolactin levels of CU patients, compared them with healthy subjects and evaluated the association between disease status and serum levels. METHODS: Plasma DHEA-S and serum PRL concentrations were measured in 48 CU patients and 31 healthy subjects. CU activity was assessed with the use of the symptom scores recommended with EAACI/GALEN/EDF guidelines. All the patients participating in this study were evaluated by means of Dermatology Life Quality Index (DLQI). With respect to DLQI and clinical activity scores, plasma DHEA-S and serum prolactin levels were compared. RESULTS: Median plasma concentration of DHEA-S was significantly lower in CU patients as compared with healthy subjects (p = 0.026). DHEA-S levels of females were significantly lower than males (p = 0.001). Mean PRL values of the patients were higher than the controls, but not statistically significant (p = 0.619) and there was a statistically signifcant inverse correlation with DHEA-S levels (p = 0.04, r = -0.298). Therewas a significant correlation between DLQI and clinical disease activity (p < 0.001, r = 0.748). CONCLUSIONS: The exact relation of hormones to CU pathogenesis remains to be determined by further clinical studies. In addition, therapies aiming to increase DHEA-S and decrease PRL may be subject to trial in CU. PMID- 25543040 TI - Allergen induced Treg response in the peripheral blood mononuclear cells (PBMCs) of patients with nasal polyposis. AB - BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease of the nasal cavity and sinuses regulated by T cells. Regulatory T (Treg) cells are involved in controlling immune responses and inhibiting the allergen-specific effector cell response. The aim of this study was to evaluate whether NP patients had defects in Treg cells after specific allergen exposure and the possible correlation between atopy and Treg cells. METHODS: Peripheral blood mononuclear cells (PBMCs), isolated from NP patients and controls, were cultured with allergen+phytohemagglutinin (PHA) or PHA stimulation for 48h. The frequency of CD4+CD25+Foxp3+ cells was measured by flow cytometry. The level of Foxp3 was measured by Real-time PCR. Concentrations of Interferon-gamma (IFN-gamma), Interleukin-4 (IL-4), Interleukin-5 (IL-5), Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) in culture supernatants were determined by ELISA. RESULTS: Both atopic and non-atopic NP patients had a significantly decreased frequency of Treg cells and Foxp3 level in allergen stimulated PBMCs, also significantly decreased TGF-beta level in culture supernatants. The decrease was even more striking in the atopic group. Also, there were significantly negative correlations between Treg cells and IFN-gamma, IL-4, IL-5. Moreover, inthe atopic group, allergen stimulation downregulated Treg cells and increased IFN-gamma, IL-4, IL-5 levels, while upregulating Treg cells and decreasing IFN-gamma, IL-4, IL-5 levels in controls. CONCLUSIONS: Patients with NP have a defective Treg cell response after allergen stimulation which is related to excessive Th1 and Th2 responses to specific allergens. Atopy may increase the impairment of Treg and exacerbate NP through the defective suppression of Treg on Th1 and Th2. PMID- 25543041 TI - H2-Eb1 expression is upregulated in the nasal mucosa of allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) is one of the most common allergic diseases. The results of recent studies of HLA-DRB1 suggest that HLA-DRB1 plays an important role in allergic disease. OBJECTIVE: The aim of the present study was to investigate the relationship between the H2-Eb1 (orthologous gene of human HLA DRB1 in mice) gene and AR pathogenesis in AR mice. METHODS: Female 129/sv mice were sensitized with ovalbumin (OVA) to establish an AR mouse model. After successful induction, the nasal mucosa was fixed and stained for pathologic analysis, such as eosinophil (EOS) evaluation and mast cell infiltration etc. The Th1 and Th2 cytokines IFN-gamma, IL-2, IL-4, IL-10 and the OVA-specific IgE levels were detected using the ELISA method. The H2-Eb1 and GATA-3 (GATA-binding protein-3) and T-bet (T-box expressed in T-cells) protein expression in the nasal mucosa were detected by the western blot or immune-histochemistry, immunofluorescence technique. The expression of H2-Eb1 mRNA in nasal mucosa was analyzed by quantitative real time PCR. RESULTS: Compared with the control group, the cilia layer in nasal mucosa of the experimental group was found to be partially desquamated; eosinophil (EOS) and mast cell infiltration was found in submucosal layer; serum OVA-IgE and IL-4, IL-10 levels were found to be significantly increased, together with a decrease of IFN-gamma and IL-2 levels. The expression of H2-Eb1 mRNA and H2-Eb1 protein, as well as the ratio of GATA 3/T-bet expression, were upregulated in the nasal mucosa of the experimental group as compared to controls. CONCLUSION: H2-Eb1 expression, accompanied by an increased GATA-3/T-bet ratio were significantly upregulated in the nasal mucosa of our successfully established AR mouse model, suggesting that HLA-DRB1 may play an important role in the pathogenesis of AR and in Th1/Th2 balance regulation. PMID- 25543042 TI - The correlation between IL-20 and the Th2 immune response in human asthma. AB - BACKROUND: Interleukin-20 (IL-20) belongs to the IL-10 family, which has been shown to be crucial in immune responses, regulation of inflammatory responses, hemopoiesis, and epidermal cell and keratinocyte differentiation. However, the role of IL-20 in asthma remains unclear. Here, our aim is to evaluate the correlation between IL-20 and the Th2 immune response in human. METHODS: In this study, we recruited 100 asthma patients and 100 control subjects for collection of serum samples and biopsy material. Firstly, We observed the expression of IL 20 in the airway epithelium of asthma patients by immuno-histochemical analysis, and then used an enzyme-linked immune-sorbent assay (ELISA) to analyze the serum levels of IL-20, IL-4, IL-5 and IL-13 in patients with asthma. RESULTS: We found high levels of expression of IL-20 in the airway epithelium of asthma patients. We also found that the concentrations of IL-20 and the Th2 cytokines, IL-4, IL-5 and IL-13, were significantly higher in patients with asthma and a positive correlation were found between IL-20 and Th2 cytokines (IL-4, IL-5, and IL-13). Furthermore, levels of IL-20 gradually increased according to the severity of the asthma. CONCLUSIONS: IL-20 levels are increased in the epithelium and serum of asthmatic patients. The correlation between IL-20 levels and Th2 cytokines suggests that IL-20 may play a patho-physiologic role in the Th2 immune response in human asthma and may be a potential biomarker of asthma severity. PMID- 25543043 TI - Hyper-IgE syndrome with a novel STAT3 mutation-a single center study from India. AB - BACKGROUND: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by the triad of elevated IgE and eosinophilia, eczema and recurrent skin and pulmonary infections. Mutation in the STAT3 gene accounts for majority of the autosomal dominant and sporadic forms of HIES. OBJECTIVE: To report clinical and molecular analyses of patients with Hyper IgE syndrome from a single tertiary care center in India. METHODS: Four patients with suspected HIES were studied. Flowcytometry for T(H)17 cell numbers and phosphoSTAT3, and STAT3 gene sequencing were performed. RESULTS: T(H)17 cells were significantly reduced. Mutations were found in the DNA-binding domain in three and a mutation in the transactivation domain in one patient. One of the mutations detected was a novel mutation (g54792 c.1018A> C p.K340Q) in the DNA binding domain. Mycobacterial infection, which is usually not commonly associated with HIES was found in two of our cases, one with a cutaneous abscess in the shoulder, and the other with BCG site reactivation. CONCLUSIONS: A novel mutation in the STAT3 is reported. Mycobacterial infections can be seen in the spectrum of HIES related infections. PMID- 25543044 TI - Crude ethanolic extracts of Zingiber cassumunar ROXB. inhibit PMA-induced MUC2 and MUC5AC expression via ERK inhibition in human airway epithelial cells. AB - BACKGROUND: Over expression of mucin often leads to serious airway pathologies. The rhizome of Zingiber cassumunar Roxb. ("Phlai" in Thai) has been used as an anti-asthmatic drug in Thai traditional medicine. However, the effect of this plant on mucin production has not been reported. OBJECTIVE: The aim of the present study was to investigate whether crude ethanolic extracts of Zingiber cassumunar (CEZE) suppress phorbol12-myristate 13-acetate (PMA)-induced mucin production and gene expression in human airway epithelial cells and if so, to examine whether the suppression of mucin gene expression is mediated via the mitogen-activated protein kinase (MAPK) signal transduction pathways. METHODS: Confluent NCI-H292 cells were pretreated with CEZE for 2 hours and then stimulated with 100 or 200 nmol/l PMA for 8 h. The levels of MUC2 and MUC5AC mRNA were determined by RT-PCR and real-time PCR. Levels of total mucin; MUC2 and MUC5AC inculture supernatants were measured using ELLA and ELISA assays, respectively. Extracellular signal-regulated kinase (ERK), JNK, p38 MAPK protein levels were analyzed by Western blotting. RESULTS: CEZE (5-100?g/ml) significantly inhibited total mucin production, including MUC2 and MUC5AC mRNA and proteins induced by PMA in NCI-H292 cells. The extracts obviously inhibited the phosphorylation of ERK, but not JNK and p38 in PMA-stimulated NCI-H292 cells. Our results suggest that Z. cassumunar-mediated suppression of PMA-induced MUC2 and MUC5AC mRNA operates via ERK inhibition. CONCLUSION: Z. cassumunar suppresses PMA-induced MUC2 and MUC5AC gene expression in human airway epithelial cells via inhibition of ERK MAPK-dependent pathway. PMID- 25543045 TI - IL-33 promotes mouse keratinocyte-derived chemokine, an IL-8 homologue, expression in airway smooth muscle cells in ovalbumin-sensitized mice. AB - BACKGROUND: Although it is recognized that IL-33 plays a key role in the onset of asthma, it is currently unclear whether IL-33 acts on any other target cells besides mast cells and Th2 cells in asthma. We investigated that whether airway smooth muscle cells (ASMCs) could contribute to asthma via stimulation with IL 33. METHODS: To create a mouse model of acute asthma, murine ASMCs were isolated and cultured in vitro with IL-33. The ASMCs were divided into two groups, ASMCs from normal mice and ASMCs from ovalbumin-sensitized mice. The release of mouse KC was analyzed by PCR and ELISA. Immunocytochemical Staining of murine ASMCs for ST2 and IL-1RAcP was performed. RESULTS: IL-33 promoted KC expression, both in terms of mRNA and protien levels, in ASMCs from ovalbumin-sensitized mice. ST2 and IL-1RAcP were expressed in the membrane of ASMCs in ovalbumin-sensitized mice. CONCLUSION: IL-33 may contribute to the inflammation in the airways by acting on airway smooth muscle cells. IL-33 and ST2 may play important roles in allergic bronchial asthma. PMID- 25543046 TI - Food allergens affect the intestinal tight junction permeability in inducing intestinal food allergy in rats. AB - BACKGROUND: The intestinal tract plays an important role in food allergy and the intestinal mucosa barrier is critical for maintenance of its function. The underlying mechanisms of how food allergens modulate the intestinal permeability in inducing intestinal food allergy remain elusive. OBJECTIVE: The aim of this study was to explore the mechanism of how food allergens influence the function of intestinal barrier and induce intestinal food allergy. METHODS: Ovalbumin (OVA) was chosen to establish intestinal food allergy models in juvenile and adult rats that were confirmed by IgE and IgG assay. Intestinal tissue morphology was analyzed by HE staining. Intestinal permeability was dynamically monitored using a Lactulose (L)-Mannitol (M) assay. The morphology of the tight junctions in the intestinal mucosa barrier were analyzed under TEM. The expression of key molecules in tight junction regulation was evaluated by Real-time PCR. RESULTS: We found: 1) The sensitization rate in juvenile rats was higher than in adult rats; 2) Intestine fluff erosion was more serious in juvenile rats than in adult rats in the duodenum and ileum; 3) Intestinal permeability was severely damaged, according to the results of the Lactulose (L)-Mannitol (M) assay; 4) Tight junction damage on the mucosal barrier was observed; Real-time PCR results showed that the expression of some key molecules that are involved in tight junction regulation was also affected. CONCLUSIONS: Our data suggested that the allergy sensitization rate of Ovalbumin (OVA) in the juvenile group is higher than in adults and food allergens may increase intestinal mucosal permeability through intestinal tight junction regulation in inducing intestinal food allergy. PMID- 25543047 TI - Bullous cutaneous mastocytosis, a rarely reported disease in Asian children. AB - Diffuse cutaneous mastocytosis, the most rare form of cutaneous mastocytosis, often manifests as bullous lesions. Although cutaneous mastocytosis should be included in a differential diagnosis for pruritic skin lesions in children, early diagnosis of the disease is not easy due to its rare occurrence. A 17-month-old boy presented with recurrent itchy bullous skin lesions. He had been treated as atopic dermatitis at other hospitals for about one year, however, he was eventually diagnosed with diffuse cutaneous mastocytosis through skin biopsy. Unlike adults, children with cutaneous mastocytosis usually improve with age and do not develop systemic mastocytosis. Therefore, early and accurate diagnosis of cutaneous mastocytosis in children is essential for appropriate care. PMID- 25543048 TI - An automatic tool to analyze and cluster macromolecular conformations based on self-organizing maps. AB - MOTIVATION: Sampling the conformational space of biological macromolecules generates large sets of data with considerable complexity. Data-mining techniques, such as clustering, can extract meaningful information. Among them, the self-organizing maps (SOMs) algorithm has shown great promise; in particular since its computation time rises only linearly with the size of the data set. Whereas SOMs are generally used with few neurons, we investigate here their behavior with large numbers of neurons. RESULTS: We present here a python library implementing the full SOM analysis workflow. Large SOMs can readily be applied on heavy data sets. Coupled with visualization tools they have very interesting properties. Descriptors for each conformation of a trajectory are calculated and mapped onto a 3D landscape, the U-matrix, reporting the distance between neighboring neurons. To delineate clusters, we developed the flooding algorithm, which hierarchically identifies local basins of the U-matrix from the global minimum to the maximum. AVAILABILITY AND IMPLEMENTATION: The python implementation of the SOM library is freely available on github: https://github.com/bougui505/SOM. CONTACT: michael.nilges@pasteur.fr or guillaume.bouvier@pasteur.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25543050 TI - Effect of high-oxygen and oxygen-free modified atmosphere packaging on the spoilage process of poultry breast fillets. AB - A comparison was made of the effect of atmospheres containing high oxygen (70% O2 and 30% CO2) or high nitrogen (70% N2 and 30% CO2) on the spoilage process during storage (at 4 degrees C) of poultry fillets. Four samples of each gas atmosphere were analyzed at 7 sample points during storage. For this analysis, the growth of typical spoilage organisms (Brochothrix thermosphacta, Pseudomonas spp., Enterobacteriaceae, and Lactobacilli spp.) and total viable count (TVC) were analyzed and modeled by using the Gompertz function. Sensory analyses of the poultry samples were carried out by trained sensory panelists to analyze color, odor, texture, drip loss, and general appearance. The composition of the spoilage flora differed between the oxygen-free atmosphere and the high-oxygen atmosphere. Anaerobic conditions favored the growth of Lactobacilli spp., whereas aerobic gas composition favored the growth of B. thermosphacta. However, no significant difference (P<0.05) in TVC and sensory parameters were observed for poultry samples stored under a high-oxygen atmosphere in comparison to a high-nitrogen atmosphere. These results indicate that high-oxygen packaging has no additional beneficial effect on the quality maintenance and shelf life of fresh poultry fillets. PMID- 25543049 TI - Comprehensive transcriptome analysis reveals accelerated genic evolution in a Tibet fish, Gymnodiptychus pachycheilus. AB - Elucidating the genetic mechanisms of organismal adaptation to the Tibetan Plateau at a genomic scale can provide insights into the process of adaptive evolution. Many highland species have been investigated and various candidate genes that may be responsible for highland adaptation have been identified. However, we know little about the genomic basis of adaptation to Tibet in fishes. Here, we performed transcriptome sequencing of a schizothoracine fish (Gymnodiptychus pachycheilus) and used it to identify potential genetic mechanisms of highland adaptation. We obtained totally 66,105 assembled unigenes, of which 7,232 were assigned as putative one-to-one orthologs in zebrafish. Comparative gene annotations from several species indicated that at least 350 genes lost and 41 gained since the divergence between G. pachycheilus and zebrafish. An analysis of 6,324 orthologs among zebrafish, fugu, medaka, and spotted gar identified consistent evidence for genome-wide accelerated evolution in G. pachycheilus and only the terminal branch of G. pachycheilus had an elevated Ka/Ks ratio than the ancestral branch. Many functional categories related to hypoxia and energy metabolism exhibited rapid evolution in G. pachycheilus relative to zebrafish. Genes showing signature of rapid evolution and positive selection in the G. pachycheilus lineage were also enriched in functions associated with energy metabolism and hypoxia. The first genomic resources for fish in the Tibetan Plateau and evolutionary analyses provided some novel insights into highland adaptation in fishes and served as a foundation for future studies aiming to identify candidate genes underlying the genetic bases of adaptation to Tibet in fishes. PMID- 25543052 TI - The Impact of Noninvasive Prenatal Testing on the Practice of Maternal-Fetal Medicine-Podcast #7. PMID- 25543051 TI - Suppression of human B cell activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin involves altered regulation of B cell lymphoma-6. AB - The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces marked suppression of the primary humoral immune response in virtually every animal species evaluated thus far. In addition, epidemiological studies performed in areas of dioxin contamination have identified an association between TCDD exposure and an increased incidence of non-Hodgkin's lymphoma (NHL). Recent studies using an in vitro CD40 ligand model of human B cell differentiation have shown that TCDD impairs both B cell activation and differentiation. The present study extends these findings by identifying B cell lymphoma-6 [BCL-6] as a putative cellular target for deregulation by TCDD, which may contribute to suppression of B cell function as well as NHL. BCL-6 is a multifunctional transcriptional repressor frequently mutated in NHLs and known to regulate critical events of B cell activation and differentiation. In the presence of TCDD, BCL-6 protein levels were elevated and concurrently the same population of cells with high BCL-6 levels showed decreased CD80 and CD69 expression indicative of impaired cellular activation. The elevated BCL-6 levels resulted in a concomitant increase in BCL-6 DNA binding activity at its cognate binding site within an enhancer region for CD80. Furthermore, a small molecule inhibitor of BCL-6 activity reversed TCDD-mediated suppression of CD80 expression in human B cells. In the presence of a low-affinity ligand of the aryl hydrocarbon receptor (AHR), suppression of B cell activation and altered BCL-6 regulation were not observed. These results provide new mechanistic insights into the role of BCL-6 in the suppression of human B cell activation by TCDD. PMID- 25543053 TI - Serine phosphorylation of vasodilator-stimulated phosphoprotein (VASP) regulates colon cancer cell survival and apoptosis. AB - AIMS: In colon cancer, disease recurrence and death are associated with abnormal tumor cell survival. Vasodilator-stimulated phosphoprotein (VASP) is an actin binding protein regulating cell shape and polarity through the F-actin cytoskeleton, whose activity is controlled by cAMP-dependent phosphorylation at Ser157 and cGMP-dependent phosphorylation at Ser239. This study examined the role of differential VASP Ser phosphorylation in regulating cell survival and apoptosis in human colon carcinoma cells. MAIN METHODS: Selective inhibition of VASP Ser157 or Ser239 phosphorylation in colon cancer cells was performed with specific phosphomutant constructs. F-actin organization was examined by confocal microscopy, and the balance of cell survival and death assessed by measuring acridine orange and ethidium bromide staining, caspase-3 and BAD-pS112 expression and DNA fragmentation. KEY FINDINGS: In human colon carcinoma cells suppression of VASP Ser157 phosphorylation reduced F-actin content and survival and increased apoptosis, while inhibition of VASP Ser239 phosphorylation increased F-actin content and survival and reduced cell death. Also, while 8Br-cAMP induced VASP Ser157 phosphorylation and reduced cell death, treatments with 8CPT-cGMP elevated VASP Ser239 phosphorylation and promoted apoptosis. SIGNIFICANCE: These findings suggest that differential VASP Ser phosphorylation represents a unique therapeutic target to control cell survival and death behavior in colon cancer. In particular, pharmacological manipulation of VASP Ser phosphorylation could be exploited to affect the malignant actin cytoskeleton and induce apoptosis in colorectal cancer cells. PMID- 25543054 TI - Protective effects of systemic treatment with methylprednisolone in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION). AB - This study investigated the protective effects of the administration of steroids on optic nerves (ON) and retinal ganglion cells (RGCs) in a rodent model of non arteritic anterior ischemic optic neuropathy (rAION). We induced rAION using rose bengal and argon laser irradiation in a photodynamic procedure on the optic discs of rats. The treated groups received methylprednisolone (MP) via peritoneal injection for 2 weeks. The control group received intraperitoneal injections of phosphate-buffered saline (PBS) post-rAION. At the 4th week post-infarct, MP treatments significantly rescued the RGCs (mm(2)) in the central retinas (1920 +/ 210, p < 0.001) and mid-peripheral retinas (950 +/- 240, respectively, p = 0.018) compared with those of the PBS-treated rats (central: 900 +/- 210 and mid peripheral: 440 +/- 180). Functional assessment with flash visual-evoked potentials demonstrated that P1 latency (ms) was shortened in the MP group compared to the PBS group (108 +/- 14 and 147 +/- 9, respectively, p < 0.001). In addition, the P1 amplitude (uV) was enhanced in the MP group compared to the PBS group (55 +/- 12 and 41 +/- 13, respectively, p < 0.05). TUNEL assays showed a decrease in the number of apoptotic cells in the RGC layers of MP-treated retinas compared to the PBS-treated group (p < 0.05). ED1 positive cells (/HPF) were significantly decreased in the ONs of the MP group compared to the PBS group (p < 0.001). In conclusion, systemic administration of MP had neuroprotective effects on RGC survival and ON function in the rAION animal model. PMID- 25543055 TI - Reply: To PMID 24907494. PMID- 25543056 TI - IgG and EoE: too soon for a paradigm shift away from IgE. PMID- 25543057 TI - The comparison of antioxidative and hepatoprotective activities of Codonopsis pilosula polysaccharide (CP) and sulfated CP. AB - Codonopsis pilosula polysaccharide (CP) was extracted, purified and modified by chlorosulfonic acid-pyridine method to obtain a sulfated CP (sCP). Their antioxidative activities in vitro were compared through the free radical scavenging test. The results demonstrated that the scavenging capabilities of sCP were significantly stronger than those of CP. In vivo test, the mice hepatic injury model was prepared by BCG/LPS method, then administrated respectively with sCP and CP at three dosages, the biochemical indexes in serum, antioxidative indexes in liver homogenate and histopathological change in liver of the mice were compared. The results showed that in high (200mg/kg) and middle (150mg/kg) dosages of sCP groups, the contents of ALT, AST and TNF-alpha in serum and MDA in liver homogenate were significantly lower than those in the model group and numerically lower than those in the CP groups, the activities of SOD and GSH-Px in liver homogenate were significantly higher than those in the model group and numerically higher than those in the CP groups. In the model group there were obvious pathological changes in the liver, while in the sCP groups were near normal. These results indicate that sCP and CP possess antioxidative activity in vitro and in vivo, the activity of sCP is stronger than that of CP and sulfation modification can enhance the antioxidative and hepatoprotective activities of Codonopsis pilosula polysaccharide. PMID- 25543058 TI - Dental pulp stem cells differentiation into retinal ganglion-like cells in a three dimensional network. AB - The loss of retinal ganglion cells (RGCs) in majority of retinal degenerative diseases is the first seen pathological event. A lot of studies aim to discover suitable cell sources to replace lost and damaged RGCs. Among them dental pulp stem cells (DPSCs) have a great potential of differentiating into neuronal lineages as well as RGCs. Moreover, three-dimensional (3D) networks and its distribution for growing and differentiation of stem cells as much as possible mimic to native tissue holds great potential in retinal tissue engineering. In this study, we isolate DPSCs from rat incisors and validate them with flow cytometry. Briefly, we differentiated cells using DMEM/F12 containing FGF2, Shh and 0.5% FBS into retinal ganglion-like cells (RGLCs) in two conditions; 3D state in biocompatible fibrin hydrogel and two-dimensional (2D) or conventional culture in polystyrene plates. Immuncytochemical and gene expression analysis revealed the expression of Pax6, Atoh7 and BRN3B increased in 3D fibrin culture compared to 2D conventional culture. In combination, these data demonstrate that using 3D networks can resemble near natural tissue properties for effective generating RGCs which used to treat neurodegenerative diseases such as glaucoma. PMID- 25543059 TI - The smallest natural high-active luciferase: cloning and characterization of novel 16.5-kDa luciferase from copepod Metridia longa. AB - Coelenterazine-dependent copepod luciferases containing natural signal peptide for secretion are a very convenient analytical tool as they enable monitoring of intracellular events with high sensitivity, without destroying cells or tissues. This property is well suited for application in biomedical research and development of cell-based assays for high throughput screening. We report the cloning of cDNA gene encoding a novel secreted non-allelic 16.5-kDa isoform (MLuc7) of Metridia longa luciferase, which, in fact, is the smallest natural luciferase of known for today. Despite the small size, isoform contains 10 conservative Cys residues suggesting the presence of up to 5 SS bonds. This hampers the efficient production of functionally active recombinant luciferase in bacterial expression systems. With the use of the baculovirus expression system, we produced substantial amounts of the proper folded MLuc7 luciferase with a yield of ~3 mg/L of a high purity protein. We demonstrate that MLuc7 produced in insect cells is highly active and extremely thermostable, and is well suited as a secreted reporter when expressed in mammalian cells ensuring higher sensitivity of detection as compared to another Metridia luciferase isoform (MLuc164) which is widely employed in real-time imaging. PMID- 25543060 TI - Use of 1-4 interaction scaling factors to control the conformational equilibrium between alpha-helix and beta-strand. AB - 1-4 interaction scaling factors are used in AMBER forcefields to reduce the exaggeration of short-range repulsion caused by the 6-12 Lennard-Jones potential and a nonpolarizable charge model and to obtain better agreements of small molecule conformational energies with experimental data. However, the effects of these scaling factors on protein secondary structure conformations have not been investigated until now. This article reports the finding that the 1-4 interactions among the protein backbone atoms separated by three consecutive covalent bonds are more repulsive in the alpha-helix conformation than in two beta-strand conformations. Therefore, the 1-4 interaction scaling factors of protein backbone torsions phi and psi control the conformational equilibrium between alpha-helix and beta-strand. Molecular dynamics simulations confirm that reducing the phi and psi scaling factors readily converts the alpha-helix conformation of AcO-(AAQAA)3-NH2 to a beta-strand conformation, and the reverse occurs when these scaling factors are increased. These results suggest that the phi and psi scaling factors can be used to generate the alpha-helix or beta strand conformation in situ and to control the propensities of a forcefield for adopting secondary structure elements. PMID- 25543062 TI - Biomaterials mediated microRNA delivery for bone tissue engineering. AB - Bone tissue engineering is an alternative strategy to overcome the problems associated with traditional treatments for bone defects. A number of bioactive materials along with new techniques like porous scaffold implantation, gene delivery, 3D organ printing are now-a-days emerging for traditional bone grafts and metal implants. Studying the molecular mechanisms through which these biomaterials induce osteogenesis is an equally hot field. Biomaterials could determine the fate of a cell via microRNAs (miRNAs). miRNAs are short non-coding RNAs that act as post-transcriptional regulators of gene expression and play an essential role for regulation of cell specific lineages including osteogenesis. Thus, this review focuses the recent trends on establishing a link of biomaterials with miRNAs and their delivery for bone tissue engineering applications. PMID- 25543061 TI - Anti-group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection. AB - BACKGROUND: HIV-exposed uninfected infants have increased infection risk and mortality compared to HIV-unexposed infants. HIV-exposed infants may be at increased risk of invasive GBS disease due to reduced maternal antibody against GBS. METHODS: We quantified antibodies that bind to the surface of whole Group B Streptococcus (GBS) of serotypes Ia, Ib, II, III and V using novel flow cytometry assays in South African HIV-infected and non-infected mothers and their uninfected infants. Antibody-mediated complement C3b/iC3b deposition onto GBS of these serotypes was also quantified by a novel flow cytometry assay. RESULTS: Geometric mean concentration (GMC) of both surface-binding anti-GBS antibody and antibody-mediated complement deposition onto GBS were reduced in HIV-infected women (n=46) compared to HIV-uninfected women (n=58) for ST1a (surface-binding: 19.3 vs 29.3; p=0.003; complement deposition: 2.9 vs 5.3 SU/mL; p=0.003), STIb (24.9 vs 47.6; p=0.003; 2.6 vs 4.9 SU/mL; p=0.003), STII (19.8 vs 50.0; p=0.001; 3.1 vs 6.2 SU/mL; p=0.001), STIII (27.8 vs 60.1; p=0.001; 2.8 vs 5.3 SU/mL; p=0.001) and STV (121.9 vs 185.6 SU/mL; p<0.001) and in their infants for STIa (complement deposition 9.4 vs 27.0 SU/mL; p=0.02), STIb (13.4 vs 24.5 SU/mL; p=0.02), STII (14.6 vs 42.7 SU/mL; p=0.03), STIII (26.6 vs 62.7 SU/mL; p=0.03) and STV (90.4 vs 165.8 SU/mL; p=0.04). Median transplacental transfer of antibody from HIV-infected women to their infants was reduced compared to HIV-uninfected women for GBS serotypes II (0.42 [IQR 0.22-0.59] vs 1.0 SU/mL [0.42-1.66]; p<0.001), III (0.54 [0.31-1.03] vs 0.95 SU/mL [0.42-3.05], p=0.05) and V (0.51 [0.28-0.79] vs 0.75 SU/mL [0.26-2.9], p=0.04). The differences between infants remained significant at 16 weeks of age. CONCLUSIONS: Maternal HIV infection was associated with lower anti-GBS surface binding antibody concentration and antibody-mediated C3b/iC3b deposition onto GBS bacteria of serotypes Ia, Ib, II, III and V. This may render these infants more susceptible to early and late onset GBS disease. PMID- 25543063 TI - K153R polymorphism in myostatin gene increases the rate of promyostatin activation by furin. AB - Recent studies demonstrated an association between the K153R polymorphism in the myostatin gene with extreme longevity, lower muscle strength and obesity but the molecular basis of these associations has not been clarified. Here, we show that the K153R mutation significantly increases the rate of proteolysis of promyostatin by furin, but has no effect on the activity of the latent complex or the cleavage of the latent complex by bone morphogenetic protein 1 (BMP-1). The increased rate of activation of K153R mutant promyostatin may explain why this polymorphism is associated with obesity, lower muscle strength and extension of lifespan. PMID- 25543064 TI - Anatomy and history of an external quality assessment program for interpretative comments in clinical biochemistry. AB - The provision of clinical interpretation of results, either verbally or in the printed report, may be considered an integral part of clinical biochemistry diagnostic service. Proficiency testing or external quality assessment (EQA) of such activity may be useful in education, training, continuing professional development and ensuring the quality of such service. Details of the Patient Report Comments Program (RPCProgram) developed by the Royal College of Pathologists of Australasia (RCPA) Chemical Pathology Quality Assurance Programs Pty Ltd (QAP) is described in this review. The program is aimed at pathologists, clinical scientists and trainees. Registered participants are provided a report with case details and a set of clinical biochemistry results at monthly intervals and submit an interpretative comment for the report. Comments received are broken up into components that are translated into common key phrases. An expert panel evaluates the key phrases, classifies them according to appropriateness and drafts a suggested comment, a case summary and a rationale, which are included in a summary report returned to participants. There is considerable diversity in the quality of interpretative comments received from participants of the PRCProgram. The primary purpose of EQA of interpretative commenting is educational self assessment, and they are recognized as a continuing professional development activity. Whilst there is some evidence for the utility of interpretative comments in improving patient outcomes, evidence for the utility of EQA in improving quality of comments is awaited. PMID- 25543065 TI - A family history of Type 1 alcoholism differentiates alcohol consumption in high cortisol responders to stress. AB - BACKGROUND: The differentiation between high and low cortisol responders to stress is of interest in determining the risk factors which may, along with genetic vulnerability, influence alcohol intake. STUDY 1: METHODS: Thirty-two healthy volunteers, family history positive to alcoholism (FHP, n = 16) and family history negative (FHN, n = 16) attended two laboratory sessions during which alcohol or placebo was offered. RESULTS: There were no differences in consumption of alcohol or placebo between FHP and FHN subjects. STUDY 2: METHODS: Fifty-eight healthy social drinkers, FHP (n = 27) and FHN (n = 31) attended two laboratory sessions. They were administered either alcohol or placebo in both sessions they attended. All subjects underwent either a stress task (the Trier Social Stress Test, TSST) or a stress-free period, at two separate occasions, before being offered beverage. After the salivary cortisol analysis, subjects in each group were divided into high (HCR) or low (LCR) cortisol responders. RESULTS: After stress, subjects who were FHP-HCR consumed more alcohol than FHN HCR. There were no differences in the placebo intake between FHP and FHN subjects regardless of their cortisol response. CONCLUSIONS: This result indicates that stress promotes alcohol consumption only in subjects with a family history of Type 1 alcoholism who show an increase in cortisol response to stress. This behaviour is similar to that previously observed in alcohol dependent individuals after stress and thus could represent an endophenotype posing a risk for future development of alcohol use disorders. PMID- 25543066 TI - Histone methylation codes involved in stemness, multipotency, and senescence in budding tunicates. AB - We examined the dynamics of nuclear histone H3 trimethylation related to cell differentiation and aging in a budding tunicate, Polyandrocarpa misakiensis. Throughout zooidal life, multipotent epithelial and coelomic cell nuclei showed strong trimethylation signals at H3 lysine27 (H3K27me3), consistent with the results of western blotting. Epidermal H3K27me3 repeatedly appeared in protruding buds and disappeared in senescent adult zooids. The budding-specific cytostatic factor TC14-3 allowed aging epidermal cells to restore H3K27me3 signals and mitochondrial gene activities via mitochondrial transcription factor a, all of which were made ineffective by an H3K27me3 inhibitor. Chromatin immunoprecipitation showed that TC14-3 enhances H3K27me3 of transdifferentiation related genes and consequently downregulates the expression of these genes. In contrast, trimethylation signals at H3 lysine4 (H3K4me3) appeared transiently in transdifferentiating bud cells and stably lasted in undifferentiated adult cells without affecting H3K27me3. A transdifferentiation-related gene external signal regulated kinase heavily underwent H3K4me3 in developing buds, which could be reproduced by retinoic acid. These results indicate that in P. misakiensis, TC14 3-driven H3K27 trimethylation is a default state of bud and zooid cells, which serves as the histone code for cell longevity. H3K27me3 and H3K4me3 double positive signals are involved in cell stemness, and absence of signals is the indication of senescence. PMID- 25543067 TI - Effects of perceived efficacy and prospect of success on detection in the Guilty Actions Test. AB - Two experiments were conducted in order to examine factors that might influence the motivation of guilty and informed innocent examinees to either cope or cooperate with the Guilty Actions Test. Guilty participants committed a mock crime and informed innocent participants handled the critical items of the crime in an innocent context. In Experiment 1 the participants were led to believe that the prospects of being found innocent on the test were either high or low. In Experiment 2 the participants were led to believe that the test was either highly accurate or of questionable validity. Results indicated that for both guilty and informed innocent participants low prospects of success and low detection efficacy of the test were associated with enhanced physiological responses to the critical information, whereas high prospects of success and high detection efficacy were associated with attenuated physiological responses. Theoretical and practical implications of the results are discussed. PMID- 25543068 TI - Comparison of two simulation systems to support robotic-assisted surgical training: a pilot study (Swine model). AB - OBJECTIVE: To compare the efficacy of simulation-based training between the Mimic dV- Trainer and traditional dry lab da Vinci robot training. DESIGN: A prospective randomized study analyzing the performance of 20 robotics-naive participants. Participants were enrolled in an online da Vinci Intuitive Surgical didactic training module, followed by training in use of the da Vinci standard surgical robot. Spatial ability tests were performed as well. Participants were randomly assigned to 1 of 2 training conditions: performance of 3 Fundamentals of Laparoscopic Surgery dry lab tasks using the da Vinci or performance of 4 dV Trainer tasks. Participants in both groups performed all tasks to empirically establish proficiency criterion. Participants then performed the transfer task, a cystotomy closure using the daVinci robot on a live animal (swine) model. The performance of robotic tasks was blindly assessed by a panel of experienced surgeons using objective tracking data and using the validated Global Evaluative Assessment of Robotic Surgery (GEARS), a structured assessment tool. RESULTS: No statistically significant difference in surgeon performance was found between the 2 training conditions, dV-Trainer and da Vinci robot. Analysis of a 95% confidence interval for the difference in means (-0.803 to 0.543) indicated that the 2 methods are unlikely to differ to an extent that would be clinically meaningful. CONCLUSION: Based on the results of this study, a curriculum on the dV- Trainer was shown to be comparable to traditional da Vinci robot training. Therefore, we have identified that training on a virtual reality system may be an alternative to live animal training for future robotic surgeons. PMID- 25543069 TI - Glial fibrillary acidic protein is a body fluid biomarker for glial pathology in human disease. AB - This review on the role of glial fibrillary acidic protein (GFAP) as a biomarker for astroglial pathology in neurological diseases provides background to protein synthesis, assembly, function and degeneration. Qualitative and quantitative analytical techniques for the investigation of human tissue and biological fluid samples are discussed including partial lack of parallelism and multiplexing capabilities. Pathological implications are reviewed in view of immunocytochemical, cell-culture and genetic findings. Particular emphasis is given to neurodegeneration related to autoimmune astrocytopathies and to genetic gain of function mutations. The current literature on body fluid levels of GFAP in human disease is summarised and illustrated by disease specific meta-analyses. In addition to the role of GFAP as a diagnostic biomarker for chronic disease, there are important data on the prognostic value for acute conditions. The published evidence permits to classify the dominant GFAP signatures in biological fluids. This classification may serve as a template for supporting diagnostic criteria of autoimmune astrocytopathies, monitoring disease progression in toxic gain of function mutations, clinical treatment trials (secondary outcome and toxicity biomarker) and provide prognostic information in neurocritical care if used within well defined time-frames. PMID- 25543070 TI - The motirod: a novel physical skill task that enhances motivation to learn and thereby increases neurogenesis especially in the female hippocampus. AB - Males and females perform differently on a variety of training tasks. In the present study we examined performance of male and female rats while they were trained with a gross motor skill in which they learn to maintain their balance on an accelerating rotating rod (the accelerating rotarod). During training, many animals simply step off the rod, thus terminating the training. This problem was addressed by placing cold water below the rod. We termed the new training procedure "motirod" training because the trained animals were apparently motivated to remain on the rod for longer periods of time. Groups of male and female adult Sprague-Dawley rats were trained on either the standard accelerating rotarod or the motirod for four trials per day on four consecutive days. Latency to fall from the rod (in seconds) was recorded. The motivating feature increased performance especially in females (p=.001). As a consequence of enhanced performance, females retained significantly more new cells in the dentate gyrus of the hippocampus than those trained on the accelerating rotarod or those that received no training. In addition, individuals that learned well retained more new cells, irrespective of sex or task conditions. Previous studies have established that new cells rescued from death by learning remain in the hippocampus for months and mature into neurons (Leuner et al., 2004a; Shors, 2014). These data suggest that sex differences in physical skill learning can arise from sex differences in motivation, which thereby influence how many new neurons survive in the adult brain. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25543071 TI - Hidden in plain view: degeneracy in complex systems. AB - Degeneracy is a word with two meanings. The popular usage of the word denotes deviance and decay. In scientific discourse, degeneracy refers to the idea that different pathways can lead to the same output. In the biological sciences, the concept of degeneracy has been ignored for a few key reasons. Firstly, the word "degenerate" in popular culture has negative, emotionally powerful associations that do not inspire scientists to consider its technical meaning. Secondly, the tendency of searching for single causes of natural and social phenomena means that scientists can overlook the multi-stranded relationships between cause and effect. Thirdly, degeneracy and redundancy are often confused with each other. Degeneracy refers to dissimilar structures that are functionally similar while redundancy refers to identical structures. Degeneracy can give rise to novelty in ways that redundancy cannot. From genetic codes to immunology, vaccinology and brain development, degeneracy is a crucial part of how complex systems maintain their functional integrity. This review article discusses how the scientific concept of degeneracy was imported into genetics from physics and was later introduced to immunology and neuroscience. Using examples of degeneracy in immunology, neuroscience and linguistics, we demonstrate that degeneracy is a useful way of understanding how complex systems function. Reviewing the history and theoretical scope of degeneracy allows its usefulness to be better appreciated, its coherency to be further developed, and its application to be more quickly realized. PMID- 25543073 TI - Analysis of personal and cultural values as key determinants of novel food acceptance. Application to an ethnic product. AB - This paper sets out to analyse whether the complexity and the type of benefits and values pursued in the consumer choice process for a novel food product (couscous) varies with the consumer's ethnic origin (Spanish and Arab). A qualitative study was used to explore these issues in an application of the "means-end chain" theory. The hierarchical value maps obtained point to the presence of an important emotional dimension in the consumption of the selected product, particularly Arab consumers, suggesting that greater familiarity with the product results in a more complex choice process. Some cross-cultural variation can also be observed. Arab consumers attach more importance to issues such as the geographic origin of the product, cultural identification, and fulfilment of family duty. Spanish couscous consumers, meanwhile, claim that it is a way to follow the latest trends, and be more cosmopolitan and more successful within their environment. PMID- 25543072 TI - Developmental PCB exposure increases susceptibility to audiogenic seizures in adulthood. AB - Developmental exposure to polychlorinated biphenyls (PCBs) causes auditory deficits. Thus, we recently conducted a study to investigate if developmental PCB exposure would exacerbate noise-induced hearing loss in adulthood. Unexpectedly, some PCB-exposed rats exhibited seizure-like behaviors when exposed to loud noise. Therefore, we conducted the current experiment to determine if adult rats perinatally exposed to PCBs are more susceptible to audiogenic seizures when tested in a standard audiogenic seizure paradigm. Adult male and female rats exposed to PCBs during gestation and lactation (0, 1, 3 or 6 mg/kg/day) and previously tested in the noise-induced hearing loss study were presented with a 100 dB noise stimulus. If they did not exhibit clonus in response to the 100 dB noise, they were exposed to a 105 dB stimulus 24-48 h later. This was followed by an 110 dB stimulus 24-48 h later if they did not exhibit clonus at 105 dB. Female and male rats exposed to either 3 or 6 mg/kg PCBs exhibited a significantly higher incidence of audiogenic seizures, shorter latency to onset of seizures, and greater severity of seizures compared to controls. Thyroxine measured in littermates at weaning was significantly lower in all PCB groups compared to controls, suggesting a potential mechanism for the increased incidence of audiogenic seizures. This is the first study to show that developmental PCB exposure increases the susceptibility to audiogenic seizures in adulthood. PMID- 25543074 TI - 'Food addiction'. What happens in childhood? PMID- 25543075 TI - Metabolic and feeding behavior alterations provoked by prenatal exposure to aspartame. AB - The use of artificial sweeteners has increased together with the epidemic growth of obesity. In addition to their widespread use in sodas, artificial sweeteners are added to nearly 6000 other products sold in the US, including baby foods, frozen dinners and even yogurts. It has been suggested that the use of nonnutritive sweeteners can lead to body weight gain and an altered metabolic profile. However, very few studies have evaluated the effects of maternal consumption of artificial non-caloric sweeteners on body weight, feeding behavior or the metabolism of offspring in adult life. In this study, we found that animals exposed to aspartame during the prenatal period presented a higher consumption of sweet foods during adulthood and a greater susceptibility to alterations in metabolic parameters, such as increased glucose, LDL and triglycerides. These effects were observed in both males and females, although they were more pronounced in males. Despite the preliminary nature of this study, and the need for further confirmation of these effects, our data suggest that the consumption of sweeteners during gestation may have deleterious long-term effects and should be used with caution. PMID- 25543076 TI - Reprint of: Eating like you are overweight: the effect of overweight models on food intake in a remote confederate study. AB - There is consistent evidence that people model the eating behaviour of others. The extent to which people model the amount of food consumed by other people of different weight statuses has received less attention. Here we tested the effect on food consumption of exposing female participants to information about the food consumption of either normal/healthy weight or overweight individuals. Eighty female participants took part in a between-subjects experiment, in which we used a remote-confederate design and manipulated whether participants saw intake information about normal/healthy weight or overweight previous participants (remote confederates). Regardless of the weight-status of the remote confederates, participants ate more food when they believed that previous participants had eaten a large amount of food, in comparison with when they believed previous participants had eaten a smaller amount of food. These findings indicate that women may model the food intake of other women, even when they believe they are of a different weight status to themselves. PMID- 25543077 TI - Slave to habit? Obesity is associated with decreased behavioural sensitivity to reward devaluation. AB - The motivational value of food is lower during satiety compared to fasting. Dynamic changes in motivational value promote food seeking or meal cessation. In obesity this mechanism might be compromised since obese subjects ingest energy beyond homeostatic needs. Thus, lower adaptation of eating behaviour with respect to changes in motivational value might cause food overconsumption in obesity. To test this hypothesis, we implemented a selective satiation procedure to investigate the relationship between obesity and the size of the behavioural devaluation effect in humans. Lean to obese men (mean age 25.9, range 19-30 years; mean BMI 29.1, range 19.2-45.1 kg/m(2)) were trained on a free operant paradigm and learned to associate cues with the possibility to win different food rewards by pressing a button. After the initial training phase, one of the rewards was devalued by consumption. Response rates for and wanting of the different rewards were measured pre and post devaluation. Behavioural sensitivity to reward devaluation, measured as the magnitude of difference between pre and post responses, was regressed against BMI. Results indicate that (1) higher BMI compared to lower BMI in men led to an attenuated behavioural adjustment to reward devaluation, and (2) the decrease in motivational value was associated with the decrease in response rate between pre and post. Change in explicitly reported motivational value, however, was not affected by BMI. Thus, we conclude that high BMI in men is associated with lower behavioural adaptation with respect to changes in motivational value of food, possibly resulting in automatic overeating patterns that are hard to control in daily life. PMID- 25543078 TI - Immunomodulatory effects of chitin microparticles on Leishmania major-infected BALB/c mice. AB - Chitin and its some derivatives are known to be non-allergic and non-toxic substances. It has been shown that chitin microparticles have immunomodulatory activities. In the present study, we investigated the in vivo immunomodulatory activities of chitin microparticles (CMPs) on Leishmania major-infected BALB/c mice. BALB/c mice were infected with L. major promastigotes at their base of the tail. CMPs (100MUg/100MUl) were injected into the site of infection from 3days before to 2 or 8 weeks after infection at two-day intervals. Cytokine concentrations (TNF-alpha, IFN-gamma, IL-5 and IL-10) were measured using ELISA assays. Compared to the untreated group, production of TNF-alpha was significantly elevated in the CMPs-treated group. Moreover, the IFN-gamma/IL-5 ratio was significantly elevated in CMPs-treated infected mice (P=0.023). Notably, the concentration of IL-10 was higher in CMPs-treated mice. These results showed that CMPs have in vivo immunomodulatory effects via the production of IFN-gamma and IL-10. We also measured the onset and size of lesions in both treated and untreated mice. The average times taken for the onset of the lesion formation were 35 and 29days for CMPs-treated and untreated mice (P=0.023), respectively. The mean size of the lesions was smaller in CMPs-treated group. Our study serves as a basis for future investigations on the application of CMPs as a prophylactic (vaccine adjuvant) and/or therapeutic modality against leishmaniasis. PMID- 25543079 TI - Molecular identification of Hysterothylacium aduncum specimens isolated from commercially important fish species of Eastern Mediterranean Sea using mtDNA cox1 and ITS rDNA gene sequences. AB - The presence of a Raphidascarid parasitic nematode Hysterothylacium aduncum (Rudolphi, 1802) in two sparid fish (Sparus aurata and Diplodus vulgaris) and one soleid fish (Solea solea) was investigated in this study. A total of 868 individuals; 385 S. aurata, 437 D. vulgaris and 46 S. solea were collected from the Mersin Bay between February 2013 and January 2014 and examined. Variations in the prevalence, mean intensity, and mean abundance of the parasite were 14.55%, 2.05, and 0.30 for S. aurata, 4.12%, 2.44, and 0.10 for D. vulgaris, and 15.22%, 3.29, and 0.50 for S. sole respectively. Nucleotide sequences of 1398 base pair long fragment of 18S rRNA-ITS1-5.8S rRNA-ITS2-28S rRNA region and 641 base pair long fragment of mtDNA cytochrome c oxidase I (cox1) gene were used in molecular identification of isolated parasites at species level. All the parasite samples were identified as H. aduncum based on nucleotide sequence comparisons. Both ITS rDNA and mtDNA cox1 sequences revealed a genetic variation among H. aduncum specimens isolated from different fish species, while only mtDNA cox1 sequences were indicating a mean genetic distance of 0.010 among H. aduncum specimens of the same host species. PMID- 25543080 TI - Prognostic value of skin perfusion alterations in cirrhotic patients with septic shock. PMID- 25543081 TI - Corticosteroids can be used to treat alcoholic hepatitis after a recent upper gastrointestinal bleed. PMID- 25543082 TI - Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol induced hepatic steatosis and cell death in mice. AB - BACKGROUND & AIMS: Effective therapies for alcoholic liver disease are currently unavailable. The present study tested the efficacy of Alda-1, a specific aldehyde dehydrogenase 2 (ALDH2) activator, in treating alcoholic liver disease. METHODS: Male C57BL/6J mice were exposed to alcohol for a time-course study on aldehyde metabolism. The specificity and efficacy of Alda-1 on activating hepatic ALDH2 and aldehyde clearance were determined by acute treatments. Then, mice were fed alcohol for 8 weeks with Alda-1 administration for the last 10 days to test the therapeutic potential of Alda-1. Lastly, H4IIEC3 cells were treated with ethanol, acetaldehyde, or 4-hydroxynonenal to define the link between aldehydes and hepatotoxicity. RESULTS: Alcohol feeding for 8 weeks induced hepatic ALDH2 dysfunction and aldehyde accumulation. One dose of Alda-1 administration elevated hepatic ALDH activity, which was blocked by the specific ALDH2 inhibitor, daidzin. Alda-1 accelerated acetaldehyde clearance after acute alcohol intoxication. Alda-1 treatment in the 8-week alcohol feeding model reversed liver damage along with reduction of hepatic aldehydes. Alda-1 re-activated transcription factors, upregulated fatty acid oxidation enzymes, and reversed steatosis. Alcohol-induced endoplasmic reticulum stress and apoptotic cell death were also attenuated by Alda-1. Acetaldehyde or 4-hydroxynonenal treatment to H4IIEC3 cells inactivated transcription factors and induced endoplasmic reticulum stress and apoptosis, while ethanol per se showed limited effects. CONCLUSIONS: Pharmacological activation of ALDH2 by Alda-1 reversed alcoholic steatosis and apoptosis through accelerating aldehyde clearance. This study indicates that ALDH2 is a promising molecular target and Alda-1 has therapeutic potential for treating alcoholic liver disease. PMID- 25543083 TI - Phosphomimetic mutation of the N-terminal lid of MDM2 enhances the polyubiquitination of p53 through stimulation of E2-ubiquitin thioester hydrolysis. AB - Mouse double minute 2 (MDM2) has a phosphorylation site within a lid motif at Ser17 whose phosphomimetic mutation to Asp17 stimulates MDM2-mediated polyubiquitination of p53. MDM2 lid deletion, but not Asp17 mutation, induced a blue shift in the lambda(max) of intrinsic fluorescence derived from residues in the central domain including Trp235, Trp303, Trp323, and Trp329. This indicates that the Asp17 mutation does not alter the conformation of MDM2 surrounding the tryptophan residues. In addition, Phe235 mutation enhanced MDM2 binding to p53 but did not stimulate its ubiquitination function, thus uncoupling increases in p53 binding from its E3 ubiquitin ligase function. However, the Asp17 mutation in MDM2 stimulated its discharge of the UBCH5a-ubiquitin thioester adduct (UBCH5a is a ubiquitin-conjugating enzyme E2D 1 UBC4/5 homolog yeast). This stimulation of ubiquitin discharge from E2 was independent of the p53 substrate. There are now four known effects of the Asp17 mutation on MDM2: (i) it alters the conformation of the isolated N-terminus as defined by NMR; (ii) it induces increased thermostability of the isolated N-terminal domain; (iii) it stimulates the allosteric interaction of MDM2 with the DNA-binding domain of p53; and (iv) it stimulates a novel protein-protein interaction with the E2-ubiquitin complex in the absence of substrate p53 that, in turn, increases hydrolysis of the E2 ubiquitin thioester bond. These data also suggest a new strategy to disrupt MDM2 function by targeting the E2-ubiquitin discharge reaction. PMID- 25543084 TI - Differential role of base pairs on gal promoters strength. AB - Sequence alignments of promoters in prokaryotes postulated that the frequency of occurrence of a base pair at a given position of promoter elements reflects its contribution to intrinsic promoter strength. We directly assessed the contribution of the four base pairs in each position in the intrinsic promoter strength by keeping the context constant in Escherichia coli cAMP-CRP (cAMP receptor protein) regulated gal promoters by in vitro transcription assays. First, we show that base pair frequency within known consensus elements correlates well with promoter strength. Second, we observe some substitutions upstream of the ex-10 TG motif that are important for promoter function. Although the galP1 and P2 promoters overlap, only three positions where substitutions inactivated both promoters were found. We propose that RNA polymerase binds to the -12T base pair as part of double-stranded DNA while opening base pairs from 11A to +3 to form the single-stranded transcription bubble DNA during isomerization. The cAMP-CRP complex rescued some deleterious substitutions in the promoter region. The base pair roles and their flexibilities reported here for E. coli gal promoters may help construction of synthetic promoters in gene circuitry experiments in which overlapping promoters with differential controls may be warranted. PMID- 25543085 TI - Expression, purification, and characterization of galactose oxidase of Fusarium sambucinum in E. coli. AB - A gene encoding a galactose oxidase (GalOx) was isolated from Fusarium sambucinum cultures and overexpressed in Escherichia coli yielding 4.4mg enzyme per L of growth culture with a specific activity of 159Umg(-1). By adding a C-terminal His tag the enzyme could be easily purified with a single affinity chromatography step with high recovery rate (90%). The enzyme showed a single band on SDS-PAGE with an apparent molecular mass of 68.5kDa. The pH optimum for the oxidation of galactose was in the range of pH 6-7.5. Optimum temperature for the enzyme activity was 35 degrees C, with a half-life of 11.2min, 5.3min, and 2.7min for incubation at 40 degrees C, 50 degrees C, and 60 degrees C, respectively. From all tested substrates, the highest relative activity was found for 1-methyl-beta galactopyranoside (226Umg(-1)) and the highest catalytic efficiency (kcat/Km) for melibiose (2700mM(-1)s(-1)). The enzyme was highly specific for molecular oxygen as an electron acceptor, and showed no appreciable activity with a range of alternative acceptors investigated. Different chemicals were tested for their effect on GalOx activity. The activity was significantly reduced by EDTA, NaN3, and KCN. PMID- 25543086 TI - SOX2, a predictor of survival in gastric cancer, inhibits cell proliferation and metastasis by regulating PTEN. AB - Inconsistent results of SOX2 expression have been reported in gastric cancer (GC). Here, we demonstrated that SOX2 was progressively downregulated during GC development via immunochemistry in 755 human gastric specimens. Low SOX2 levels were associated with pathological stage and clinical outcome. Multivariate analysis indicated that SOX2 protein expression served as an independent prognostic marker for GC. Gain-and loss-of function studies showed the anti proliferative, anti-metastatic, and pro-apoptotic effects of SOX2 in GC. PTEN was selected as SOX2 targets by cDNA microarray and ChIP-DSL, further identified by luciferase assays, EMSA and ChIP-PCR. PTEN upregulation in response to SOX2 enforced expression suppressed GC malignancy via regulating Akt dephosphorylation. PTEN inhibition reversed SOX2-induced anticancer effects. Moreover, concordant positivity of SOX2 and PTEN proteins in nontumorous tissues but lost in matched GC specimens predicted a worse patient prognosis. Thus, SOX2 proved to be a new marker for evaluating GC outcome. PMID- 25543087 TI - Neuropilin-2 mediates lymphangiogenesis of colorectal carcinoma via a VEGFC/VEGFR3 independent signaling. AB - Lymphangiogenesis critically contributes to the lymphatic metastasis of colorectal carcinomas (CRCs), but the underlying mechanism of CRC lymphangiogenesis remains largely elusive. We have previously demonstrated that Semaphorin-3F (SEMA3F) is critically involved in CRC metastasis, and the receptor of SEMA3F, neuropilin-2 (NRP2), originally described as an axon guiding chemorepulsant implicated in nerve development, has been suggested in promoting lymphangiogenesis via acting as an obligate co-receptor of VEGFR3 cooperatively enhancing the activity of VEGF-C. Our present study revealed that in colorectal carcinomas, NRP2 expression levels of tumor-associated lymphatic endothelial cells (LECs) are significantly correlated with the density of tumor lymphatic vessels. In vitro, activation of NRP2 in LECs substantially facilitates their migration, sprouting, and tubulogenesis capacity via regulating the rearrangement of cytoskeleton polarity. In vivo model further showed that in the xenografts generated from SEMA3F knockdown CRC cells, NRP2 is substantially activated in tumor-associated LECs, resulting in a significantly increased tumor lymphangiogenesis. Further evidence demonstrated that CRC cell induces the activation of NRP2 in LECs to promote tumor lymphangiogenesis via integrinalpha9beta1/FAK/Erk pathway independent VEGF-C/VEGFR3 signaling. Our study for the first time revealed the novel molecular mechanism of NRP2-mediated lymphangiogenesis in CRCs, suggesting NRP2 as a potential therapeutic target in preventing lymphatic metastasis of CRCs. PMID- 25543088 TI - Regulation and function of Myb-binding protein 1A (MYBBP1A) in cellular senescence and pathogenesis of head and neck cancer. AB - Myb-binding protein 1A (MYBBP1A) is a nucleolar protein implicated in stress response and carcinogenesis; however, its functional contribution to senescence remains elusive. In this study we show decreased MYBBP1A protein levels in tumor cells after treatment with etoposide, a potent inducer of DNA damage. Although silencing of MYBBP1A expression was not sufficient to induce senescence, it significantly increased the relative abundance of senescent cells after DNA damage. We found an inverse regulation of MYBBP1A and AKT phosphorylation (pAKT(Ser473)), which was characteristic for the pre-senescent state after etoposide administration in vitro. Tissue microarrays with tumor specimens from primary oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 61) by immunohistochemistry revealed a significant correlation between MYBBP1A(low)pAKT(Ser473)(high) staining pattern and shorter progression-free (p = 0.007) or overall survival (p < 0.001). Multivariate analysis showed that MYBBP1A(low)pAKT(Ser473)(high) staining pattern is an independent prognosticator for OPSCC. Taken together, our study points to a critical role of MYBBP1A in the regulation of senescence under genotoxic stress and that a MYBBP1A(low)AKT(Ser473)(high) staining pattern serves not only as a marker for the pre-senescent stage but also as an indicator of OPSCC patients at high risk for treatment failure. PMID- 25543089 TI - Antibody dissociation rates are predictive of neutralizing antibody (NAb) course: a comparison of interferon beta-1b-treated Multiple Sclerosis (MS) patients with transient versus sustained NAbs. AB - A proportion of multiple sclerosis (MS) patients treated with interferon-beta (IFNbeta) develop neutralizing antibodies (NAbs), which can reduce therapeutic efficacy. In the Betaseron/Betaferon in Newly Emerging MS for Initial Treatment (BENEFIT) study, 88/277 patients developed NAbs, 48 having transient positivity and 29 having sustained positivity. This study aimed to investigate the antibody binding characteristics of serial sera in a subset of these two patient groups. Using BiacoreTM, a surface plasmon resonance-based technology that monitors biomolecular interactions in real time, we immobilized pure IFNbeta-1b and analyzed antibody binding responses and dissociation rates of these sera. NAb titers correlated directly with binding responses and inversely with dissociation rates, and sera from sustained NAb patients demonstrated significantly higher binding responses and slower dissociation rates than sera from transient NAb patients. Thus, transient and sustained NAbs are quantitatively and qualitatively different, and interestingly, binding responses and dissociation rates at month 12 could predict the NAb course. PMID- 25543090 TI - Change in the hedonic value of an aversive stimulus in the presence of a pre exposed odor. AB - Rats exhibit a sensitive period from the time of birth until postnatal day 10 during which they develop preferences for odors even if those odors are paired with a moderately aversive stimulus. It is still unknown whether pre-exposure to an odor produces alterations on intake responses of basic tastants, and on other patterns that indicate a change in the hedonic value of reward, such as nipple grasping behavior. The current study assessed the effect of pre-exposure to an odor immediately after birth on intake responses of appetitive and aversive tastants. The objectives were to assess if 3-hour-old rats adjust their behaviors to obtain different values of appetitive and aversive rewards in the presence of a familiar odor. Specifically we wanted to determine whether the intake of saccharin or quinine, administered through the artificial nipple, increases in the presence of the familiar odor. Results showed that 3-hour-old rats differentially respond to two different concentrations of saccharin and two concentrations of quinine. In the presence of the pre-exposed odor newborn rats increased intake and grasp responses to the artificial nipple containing quinine. This effect disappeared with a higher concentration of quinine. These results suggest that the pre-exposed odor generated a change in the hedonic value of the aversive reward. PMID- 25543091 TI - Neurodevelopment and phenotype-modulating functions of S100B protein: a pilot study. AB - The importance of certain neurotrophic proteins found in maternal blood and milk for breastfed infants has remained ambiguous. This study was conducted to present evidence of the impact of an induced deficit of active S100B protein on neonate development. Newborn mice from two groups of mothers, immunized or sham-immunized against S100B, were subjected to various behavioral tests, and the development of their morphological characteristics was recorded from birth until weaning. Morphological problems, including weight gain and fur coating, a delay in the maturation of neurobehavioral systems and a deficit in neuromotor functions, including visual abilities, somato-sensory and posture reactions, muscular strength, locomotion, and fear/orienting processes, were observed in pups of immunized mothers. The S100B protein of external or internal origin in infants may be considered to be a specific factor that determines neuro- and morphological development and a risk-avoidance ('homeward-bent' or fearful) phenotype. The suppression of activity of the S100B protein results in a slower neonatal development and the formation of a risk-tolerant (fearless) phenotype of the offspring. This study thus considers the mechanism of neuroplastic regulation on the extent of sensation-seeking or risk-taking (homeless-like or fearless) and sensation- or risk-avoidance (home-bound or fearful) features in individual phenotypes. PMID- 25543092 TI - CD161(+) T cells as predictive markers for acute graft-versus-host disease. AB - CD161 is a type II transmembrane glycoprotein with characteristics of the C-type lectin superfamily, which has recently been shown to promote T cell expansion. In this study, the role of T cells expressing CD161 as a predictor for the occurrence of acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (SCT) was investigated. Sixty-one patients who underwent first allogeneic SCT were enrolled. At engraftment, the expression of CD3, CD4, CD8, CD161, CD16, and CD56 was analyzed by flow cytometry. After adjusting for potential variables by univariate analysis, we performed a multivariate analysis, which revealed a low frequency of CD8(+)CD161(+) cells (P = .034) and a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+) cells (P = .001) were associated with the occurrence of aGVHD with a grade of >= II. Moreover, the frequency of CD8(+)CD161(+) T cells was negatively correlated with aGVHD grade. A separate analysis for visceral aGVHD showed similar results, with a low frequency of CD8(+)CD161(+) T cells (P = .031) or a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+)cells (P < .001), indicating a high risk. Also, the predictive role of serum IL-17 levels for the occurrence of aGVHD was identified, and RORgammaT was more highly expressed in CD4(+)CD161(+) T cells than in CD8(+)CD161(+) T cells after allogeneic SCT (P = .032). Although our study was limited by the heterogeneity and small number of patients, these results suggest that the CD8(+) subset of CD161(+) T cells may have regulatory effects and that they provide a basis for predicting the occurrence of aGVHD after allogeneic SCT. PMID- 25543093 TI - Acute cholecystitis is a common complication after allogeneic stem cell transplantation and is associated with the use of total parenteral nutrition. AB - The incidence and risk factors for acute cholecystitis after allogeneic hematopoietic stem cell transplantation (HSCT) are not well defined. Of 644 consecutive adult transplants performed at our institution between 2001 and 2011, acute cholecystitis occurred in the first year of transplant in 32 patients (5.0%). We conducted 2 retrospective case-control studies of this population to determine risk factors for cholecystitis after HSCT and to evaluate the performance of different methods of imaging to diagnosis cholecystitis in patients undergoing HSCT compared with non-HSCT patients. In the HSCT population, development of cholecystitis was associated with an increased 1-year overall mortality rate (62.5% versus 19.8%, P < .001). The risk of developing cholecystitis was higher in patients who received total parenteral nutrition (TPN) (adjusted odds ratio, 3.41; P = .009). There was a trend toward more equivocal abdominal ultrasound findings in HSCT recipients with acute cholecystitis compared with nontransplant patients (50.0% versus 30.6%, P = .06). However, hepatobiliary iminodiacetic acid (HIDA) scans were definitively positive for acute cholecystitis in most patients in both populations (80.0% of HSCT recipients versus 77.4% of control subjects, P = .82). In conclusion, acute cholecystitis is a common early complication of HSCT, the risk is increased in patients who receive TPN, and it is associated with high 1-year mortality. In HSCT recipients with findings suggestive of acute cholecystitis, especially those receiving TPN, early use of HIDA scan may be considered over ultrasound. PMID- 25543095 TI - Long-range dispersal, stochasticity and the broken accelerating wave of advance. AB - Rare long distance dispersal events are thought to have a disproportionate impact on the spread of invasive species. Modelling using integrodifference equations suggests that, when long distance contacts are represented by a fat-tailed dispersal kernel, an accelerating wave of advance can ensue. Invasions spreading in this manner could have particularly dramatic effects. Recently, various authors have suggested that demographic stochasticity disrupts wave acceleration. Integrodifference models have been widely used in movement ecology, and as such a clearer understanding of stochastic effects is needed. Here, we present a stochastic non-linear one-dimensional lattice model in which demographic stochasticity and the dispersal regime can be systematically varied. Extensive simulations show that stochasticity has a profound effect on model behaviour, and usually breaks acceleration for fat-tailed kernels. Exceptions are seen for some power law kernels, K(l)?|l|-beta with beta<3, for which acceleration persists despite stochasticity. Such kernels lack a second moment and are important in 'accelerating' phenomena such as Levy flights. Furthermore, for long-range kernels the approach to the continuum limit behaviour as stochasticity is reduced is generally slow. Given that real-world populations are finite, stochastic models may give better predictive power when long-range dispersal is important. Insights from mean-field models such as integrodifference equations should be applied with caution in such circumstances. PMID- 25543094 TI - Effect of cord blood processing on transplantation outcomes after single myeloablative umbilical cord blood transplantation. AB - Variations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P = .001) or plasma and red cell reduced (odds ratio, .54; P = .05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P = .04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery. PMID- 25543098 TI - Vancomycin intermediate-resistant Staphylococcus aureus (VISA) isolated from a patient who never received vancomycin treatment. AB - BACKGROUND: With the abuse of antibiotics, the methicillin-resistant Staphylococcus aureus (MRSA) strain became prevalent. Furthermore, Staphylococcus aureus with a character of vancomycin intermediate-resistance (VISA) has been found globally since the first report in Japan. The main objectives of this study were to report a case of VISA isolated from a Chinese patient who had never undergone Vancomycin treatment, and to determine its molecular character. METHODS: A total of 9 strains were recovered from a patient during the therapeutic process. Antimicrobial susceptibility testing was performed to determine their antibiotic susceptibility patterns. To detect the VISA strain's molecular epidemiological features, growth and morphological characters, we used multilocus sequence typing, autolysis assay and transmission electric microscope tests. Pulsed-field gel electrophoresis (PFGE) was performed to characterize the heterogeneities of all isolates. RESULTS: One isolate was found to exhibit vancomycin intermediated-resistant with MIC of 8 MUg/ml. It was ST239-T030-agr-1, had thickened cell wall, and displayed a slower growth rate and reduced susceptibility to Triton X-100-induced autolysis than other strains. All 9 strains exhibited the same PFGE pattern. CONCLUSION: This is the first report of VISA found in central China from a patient who had never received vancomycin treatment. PMID- 25543097 TI - Emergence and spread of tetracycline resistant Vibrio cholerae O1 El Tor variant during 2010 cholera epidemic in the tribal areas of Odisha, India. AB - OBJECTIVES: The epidemics of cholera were reported in the Kashipur, K.singhpur, B cuttack blocks of Rayagada district and Mohana block of Gajapati district of Odisha during 2010. The present study was carried out to isolate the bacterial pathogen, its drug sensitivity pattern and to describe the spread of the disease in those areas. METHODS: A total of 68 rectal swabs collected from patients with severe diarrhea, admitted to different health centers and diarrhea affected villages were bacteriologically analyzed. Similarly 22 water samples collected from different villages from nala, chua, etc were tested for the presence of V cholerae. RESULTS: Out of 68 rectal swabs tested 35 (51.5%) were V cholerae O1 Ogawa and 14(20.6%) were E coli; which might be commensals. All water samples were negative for V cholerae. The V cholerae strains were sensitive to gentamicin, norfloxacin, ciprofloxacin, azithromycin and ofloxacin; but were resistant to ampicillin, tetracycline, nalidixic acid, furazolidone, streptomycin, erythromycin, co-trimoxazole, neomycin and chloramphenicol. All V cholerae strains were 100% resistant to tetracycline and they were El Tor variants harboring ctxB gene of classical strain. CONCLUSIONS: The present study indicated the emergence and spread of tetracycline resistant V cholerae O1 El Tor variant in the tribal areas which needs close monitoring. PMID- 25543099 TI - Feasibility of a cost-effective, video analysis software-based mobility protocol for objective spine kinematics and gait metrics: a proof of concept study. AB - The purpose of this study was to investigate the potential of a high-throughput, easily implemented, cost-effective, video analysis software-based mobility protocol to quantify spine kinematics. This prospective cohort study of clinical biomechanics implemented 2-dimensional (2D) image processing at a tertiary-care academic institution. Ten healthy, able-bodied volunteers were recruited for 2D videography of gait and functional motion. The reliability of a 2D video analysis software program for gait and range of motion metrics was evaluated over 2 independent experimental sessions, assessing for inter-trial, inter-session, and inter-rater reliability. Healthy volunteers were evaluated for simple forward and side bending, rotation, treadmill stride length, and more complex seated-to standing tasks. Based on established intraclass correlation coefficients, results indicated that reliability was considered good to excellent for simple forward and side bending, rotation, stride length, and more complex sit-to-standing tasks. In conclusion, a cost-effective, 2D, video analysis software-based mobility protocol represents a feasible and clinically useful approach for objective spine kinematics and gait metrics. As the complication rate of operative management in the setting of spinal deformity is weighed against functional performance and quality of life measures, an objective analysis tool in combination with an appropriate protocol will aid in clinical assessments and lead to an increased evidence base for management options and decision algorithms. PMID- 25543096 TI - Alteration of mammary gland development and gene expression by in utero exposure to arsenic. AB - Early life exposure to estrogens and estrogen like contaminants in the environment is thought to contribute to the early onset of puberty and consequently increases the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERalpha) that was due to the increased and altered response of the ERalpha transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer. PMID- 25543100 TI - An example of the usefulness of joinpoint trend analysis for assessing changes in traffic safety policies. AB - AIM: To show the usefulness of joinpoint trend analysis for assessing changes in traffic safety policies. METHODS: Trends in driver death rates from traffic injury stratified by alcohol involvement in Spain during 2001-2011 were characterized with joinpoint regression to observe how changes in these rates match in time with the implementation of traffic regulations and interventions. RESULTS: Both alcohol-related (blood alcohol concentration >0.3g/l) and non alcohol-related rates decreased similarly (10-11% annually) during 2001-2011, although the former showed an earlier (2003 joinpoint) acceleration of the downward trend than the latter (2006 joinpoint); both joinpoints matched in time with relevant road safety interventions. CONCLUSIONS: These results, which are consistent with results from previous analytical studies, show that joinpoint trend analysis, although not valid for causal inference, is useful for assessing changes in traffic safety policies. This methodology can be easily extended to other risk factors, such as excessive speeding or not wearing a seat belt. PMID- 25543101 TI - Evaluating changes in driver behaviour: a risk profiling approach. AB - New road safety strategies continue to be devised by researchers and policy makers with pay-as-you-drive (PAYD) schemes gaining increasing attention. However, empirically measuring the effectiveness of these strategies is challenging due to the influence of the road environment and other factors external to the driver. The analysis presented here applies Temporal and Spatial Identifiers to control for the road environment and Driver Behaviour Profiles to provide a common measure of driving behaviour based on the risk of a casualty crash for assessing the effectiveness of a PAYD scheme on reducing driving risks. The results show that in many cases personalised feedback alone is sufficient to induce significant changes, but the largest reductions in risk are observed when drivers are also awarded a financial incentive to change behaviour. Importantly, the more frequent the exposure to the speeding information, the greater the magnitude of the change. However, the changes are disproportionately associated with those that were already safer drivers in the baseline period suggesting that some drivers may be predisposed to changing their behaviour. These results suggest that it would be beneficial to provide real-time or daily feedback on speeding behaviour in conjunction with a financial reward scheme, potentially as a component of insurance premiums. PMID- 25543102 TI - Development of adjustment functions to assess combined safety effects of multiple treatments on rural two-lane roadways. AB - Numerous studies have attempted to evaluate the safety effectiveness of specific single treatment on roadways by estimating crash modification factors (CMFs). However, there is a need to also assess safety effects of multiple treatments since multiple treatments are usually simultaneously applied to roadways. Due to the lack of sufficient CMFs of multiple treatments, the Highway Safety Manual (HSM) provides combining method for multiple CMFs. However, it is cautioned in the HSM and related sources that combined safety effect of multiple CMFs may be over or under estimated. Moreover, the literature did not evaluate the accuracy of the combining method using CMFs obtained from the same study area. Thus, the main objectives of this research are: (1) to estimate CMFs and crash modification functions (CM Functions) for two single treatments (shoulder rumble strips, widening (1-9ft) shoulder width) and combination (installing shoulder rumble strips+widening shoulder width) using the observational before-after with empirical Bayes (EB) method and (2) to develop adjustment factors and functions to assess combined safety effects of multiple treatments based on the accuracy of the combined CMFs for multiple treatments estimated by the existing combining method. Data was collected for rural two-lane roadways in Florida and Florida specific safety performance functions (SPFs) were estimated for different crash types and severities. The CM Functions and adjustment functions were developed using linear and nonlinear regression models. The results of before-after with EB method show that the two single treatments and combination are effective in reducing total and SVROR (single vehicle run-off roadway) crashes. The results indicate that the treatments were more safety effective for the roadway segments with narrower original shoulder width in the before period. It was found that although the CMFs for multiple treatments (i.e., combination of two single treatments) were generally lower than CMFs for single treatments, they were getting similar to the roadway segments with wider shoulder width. The findings indicate that the combined safety effects of multiple treatments using HSM combining method are mostly over-estimated and the accuracy of HSM combining method vary based on crash types and severity levels. Therefore, it is recommended to develop and apply the adjustment factors and functions to predict the safety effects of multiple treatments when the HSM combining method is used. PMID- 25543103 TI - Does Human Papillomavirus Cause Esophageal Adenocarcinoma? PMID- 25543104 TI - Diffuse Gastric Wall Thickening: Appearances Can Be Deceptive. PMID- 25543105 TI - Endotoxin tolerance induction in human periodontal ligament fibroblasts stimulated with different bacterial lipopolysaccharides. AB - OBJECTIVE: Human periodontal ligament fibroblasts (hPDLFs) may play an important role in immune responses in the periodontal microenvironment by secreting proinflammatory cytokines. The present study aimed to explore the reaction of hPDLFs to a secondary lipopolysaccharide (LPS) challenge by examining cytokines and innate sensors. METHODS: Primary cultures of hPDLFs were obtained and identified by immunochemistry. Cells were treated with a secondary LPS challenge followed by a primary LPS or no LPS as a control. The levels of cytokines were assayed using cytometric bead array (CBA) kits, and the protein levels of Toll like receptors (TLRs) were determined using flow cytometry. The messenger RNA (mRNA) levels of TLRs were determined using real-time polymerase chain reaction (PCR). RESULTS: We show that the initial LPS exposure significantly induced hPDLFs to produce cytokines interleukin-8 (IL-8) and IL-6, whereas the secondary LPS challenge dramatically diminished the levels of cytokines IL-8 and IL-6. The mRNA and protein levels of TLRs were increased by the initial LPS stimulus but decreased by the secondary LPS challenge. CONCLUSION: An LPS stimulus induces immune responses in hPDLFs, whereas an LPS challenge exerts endotoxin tolerance by downregulating proinflammatory cytokines and TLR mRNA and protein expression. This process may confer hPDLFs with their essential functions for maintaining oral mucosal immunity homeostasis. PMID- 25543106 TI - In vitro effect of Paullinia cupana (guarana) on hydrophobicity, biofilm formation, and adhesion of Candida albicans' to polystyrene, composites, and buccal epithelial cells. AB - OBJECTIVE: In vitro evaluation of the effect of guarana (GUAR) on cell surface hydrophobicity (CSH), on biofilm formation, and on adhesion of C. albicans to polystyrene, to composite resins, and to buccal epithelial cells (BEC). MATERIALS AND METHODS: Lyophilised aqueous extract of GUAR was tested on C. albicans ATCC (90028). The effect of GUAR was evaluated by examining the CSH of C. albicans, as determined by microbial adhesion to hydrocarbons test, by assessing biofilm production and through adhesion assays (microplates of polystyrene, BEC and composites). One nanoparticle (Z350((r))) and two microhybrid (LLis((r)), Opallis((r))) composites were tested. Scanning electron microscopy (SEM) was used to analyse adhesion of C. albicans composites. Assays were performed in triplicate and the results analysed by Chi-square test, Kruskal-Wallis test and Dunn's Multiple Comparison post hoc test at 5% significance level. RESULTS: GUAR did not inhibit growth of C. albicans at any concentration, but it reduced adhesion to polystyrene surface (p < 0.001). Exposure to GUAR did not change CSH and biofilm formation, but it increased adhesion of C. albicans to the nanoparticle composite (p = 0.042) and reduced its adhesion to BEC (p < 0.001). SEM confirmed an aggregatory pattern of adhesion of C. albicans to composites. CONCLUSION: GUAR increased the adhesion of C. albicans to the surface of the nanoparticle composite. However, it reduced the adhesion of C. albicans to BEC and to polystyrene, which reveals its potential use in prevention of oral diseases. PMID- 25543107 TI - Mechanistic investigations of the hydrolysis of amides, oxoesters and thioesters via kinetic isotope effects and positional isotope exchange. AB - The hydrolysis of amides, oxoesters and thioesters is an important reaction in both organic chemistry and biochemistry. Kinetic isotope effects (KIEs) are one of the most important physical organic methods for determining the most likely transition state structure and rate-determining step of these reaction mechanisms. This method induces a very small change in reaction rates, which, in turn, results in a minimum disturbance of the natural mechanism. KIE studies were carried out on both the non-enzymatic and the enzyme-catalyzed reactions in an effort to compare both types of mechanisms. In these studies the amides and esters of formic acid were chosen because this molecular structure allowed development of methodology to determine heavy-atom solvent (nucleophile) KIEs. This type of isotope effect is difficult to measure, but is rich in mechanistic information. Results of these investigations point to transition states with varying degrees of tetrahedral character that fit a classical stepwise mechanism. This article is part of a special issue entitled: Enzyme Transition States from Theory and Experiment. PMID- 25543108 TI - Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition. AB - A number of biomonitoring surveys have been performed for chlorpyrifos (CPF) and its metabolite (3,5,6-trichloro-2-pyridinol, TCPy); however, there is no available guidance on how to interpret these data in a health risk assessment context. To address this gap, Biomonitoring Guidance Values (BGVs) are developed using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. The PBPK/PD model is used to predict the impact of age and human variability on the relationship between an early marker of cholinesterase (ChE) inhibition in the peripheral and central nervous systems [10% red blood cell (RBC) ChE inhibition] and levels of systemic biomarkers. Since the PBPK/PD model characterizes variation of sensitivity to CPF in humans, interspecies and intraspecies uncertainty factors are not needed. Derived BGVs represent the concentration of blood CPF and urinary TCPy associated with 95% of the population having less than or equal to 10% RBC ChE inhibition. Blood BGV values for CPF in adults and infants are 6100 ng/L and 4200 ng/L, respectively. Urinary TCPy BGVs for adults and infants are 2100 MUg/L and 520 MUg/L, respectively. The reported biomonitoring data are more than 150-fold lower than the BGVs suggesting that current US population exposures to CPF are well below levels associated with any adverse health effect. PMID- 25543109 TI - Octreotide for control of bleeding peristomal varices in palliative care. PMID- 25543111 TI - Controlled drug release from melt-extrudates through processing parameters: a chemometric approach. AB - The objective of this study was to tailor a drug release profile through the adjustment of some key processing parameters involved in melt-extrusion: die temperature, shear rate, die length and drug particle size. Two experimental designs were selected, namely a 2-level full factorial design to examine the effects and significance of the processing factors, and a central composite design of the surface responses to find the best set of factor levels to obtain given specifications of drug release. Extrudates of poly(ethylene-co-vinyl acetate) and phenylpropanolamine hydrochloride were prepared using a ram extruder. Drug release profiles from the matrix systems were fitted using a power law, for which a new mathematical expression of a burst release was provided. The burst release and exponent were selected as the responses. The processing factors had a drastic influence on the drug release. Within the domain that was investigated, the burst release and the exponent varied from 6 to 54% and 0.1 to 0.4, respectively, resulting in a time requires for 50% drug release extending from hours to weeks. These results demonstrated the possibilities of modulating the release profile by means of the processing parameters rather than through the classical approach of altering the formulation. PMID- 25543112 TI - Transdermal baicalin delivery using diethylene glycol monoethyl ether-mediated cubic phase gel. AB - This study investigated the transdermal permeability of baicalin, a hydrophobic and readily hydrolyzed drug, delivered by glyceryl monooleate (GMO)-based cubic phase gel (CPG) mediated with Transcotol((r)) P (TP, diethylene glycol monoethyl ether). A range of CPGs was produced by varying GMO, water, and TP levels. Examination of their physicochemical properties revealed that the optically isotropic CPG showed higher viscosity than lamellar phase gels (LPG), and the baicalin cargo increased CPG viscosity. The GMO:TP ratio and water content also altered viscosity. CPG-mediated delivery increased baicalin's skin permeation, with 76.65- to 200.24-fold higher (p<0.05) transdermal flux than that of a Carbopol((r))-based hydrogel (HDG), and 6.72- to 17.55-fold (p<0.05) higher than that of LPG, with the same water content. Rat in vivo microdialysis showed that CPG produced sustained baicalin release, with superior pharmacokinetic parameters to those of HDG. Furthermore, cutaneous drug absorption was more efficient on rat abdominal skin, compared to that in the chest or scapular region. Effective fusion between the CPG lipid matrix and the stratum corneum may explain this enhancement of transdermal permeation. CPG containing TP therefore, achieved excellent transdermal drug delivery and good baicalin stability, indicating that this system represents a promising transdermal delivery vehicle. PMID- 25543113 TI - Informal caregiving for elderly people with mental illnesses and the mental health of the informal caregivers. AB - OBJECTIVES: Caring for a person often imposes a significant burden on informal caregivers, which is a possible threat to their own health and well-being. The aim of this study is twofold: (i) We analyze whether the risk of the mental burden due to informal caregiving increases when the dependent person suffers from mental disorders. (ii) We investigate if the utilization of formal care assistance reduces this burden. METHOD: Routine data from a sickness fund regarding informal caregivers of frail elderly persons aged more than 65 years is analyzed by estimating pooled logit models. RESULTS: We find evidence for a significant difference of the risk of mental disturbance in informal caregivers when caring for impaired elderly with and without certain mental disorders. However, claiming formal care services in addition to the informal care provision decreases the disturbance. DISCUSSION: There are political implications that arise from our results: First, the already existing system of formal in-home services should be enlarged. Second, special attention should be paid to the health status of the person in need of care when deciding which form of care is appropriate and the least burdensome for the informal caregiver. PMID- 25543110 TI - Measuring Experience With End-of-Life Care: A Systematic Literature Review. AB - CONTEXT: Increasing interest in end-of-life care has resulted in many tools to measure the quality of care. An important outcome measure of end-of-life care is the family members' or caregivers' experiences of care. OBJECTIVES: To evaluate the instruments currently in use to inform next steps for research and policy in this area. METHODS: We conducted a systematic review of PubMed, PsycINFO, and PsycTESTS((r)) for all English-language articles published after 1990 using instruments to measure adult patient, family, or informal caregiver experiences with end-of-life care. Survey items were abstracted and categorized into content areas identified through an iterative method using three independent reviewers. We also abstracted information from the most frequently used surveys about the identification of proxy respondents for after-death surveys, the timing and method of survey administration, and the health care setting being assessed. RESULTS: We identified 88 articles containing 51 unique surveys with available content. We characterized 14 content areas variably present across the 51 surveys. Information and care planning, provider care, symptom management, and overall experience were the most frequent areas addressed. There was also considerable variation across the surveys in the identification of proxy respondents, the timing of survey administration, and in the health care settings and services being evaluated. CONCLUSION: This review identified several comprehensive surveys aimed at measuring the experiences of end-of-life care, covering a variety of content areas and practical issues for survey administration. Future work should focus on standardizing surveys and administration methods so that experiences of care can be reliably measured and compared across care settings. PMID- 25543114 TI - The adoption of pharmaceutical innovation and its impact on the treatment costs for Alzheimer's disease in Taiwan. AB - BACKGROUND: As the population ages, the number of people living with Alzheimer's disease (AD) has been increasing over time. Between 1999 and 2006, four new AD drugs were approved for insurance coverage in Taiwan. AIMS OF THE STUDY: We investigate the heterogeneous influences of adopting these new drugs on healthcare expenditures. We also evaluate whether the adoption of pharmaceutical innovation creates any "offsetting" effect in the sense that an increase in one component of the health care costs is offset by the decrease in the other components of health care costs. METHODS: AD patients are defined in this study as those who are diagnosed with ICD-9-CM code 331.0. Based on longitudinal insurance claims data, we identify 1,088 AD patients whose first diagnosis occurred between 1997 and 2007. After excluding the period before each patient's AD diagnosis, 4,629 patient-year observations are found to constitute an unbalanced panel data set used in this study. We employ the correlated-random effects quantile regression (CREQR) method to explicitly control for the unobserved heterogeneity and to consider the heterogeneous influences of adopting new drugs on different points of the conditional distribution function of health expenditures. RESULTS: Our empirical findings are consistent with previous evidence that the adoption of pharmaceutical innovation is costly. To be specific, the expenditure-increasing effect is mainly reflected by the increase in expenditure on drugs in the outpatient sector. In addition, we find evidence of a significant offsetting effect in the sense that new-drug users tend to make less use of inpatient services. As a result, the net effect of adopting pharmaceutical innovation is heterogeneous across AD patients: the use of new drugs is expenditure-increasing for patients whose health care costs are distributed below the 75th quantile; by contrast, the use of new drugs is expenditure-neutral above the 75th quantile, that is, the increase in the drug costs is almost completely offset by the decrease in the inpatient expenditure. DISCUSSION: The adoption of pharmaceutical innovation for treating AD is associated with a significant offsetting effect for higher cost patients. Our results also show that the CREQR method supplements the traditional ordinary least squares (OLS) method to provide interesting information beyond the conditional mean of the distribution. In our study, CREQR estimates suggest that the marginal impact of adopting pharmaceutical innovation on health care costs is heterogeneous across AD patients. IMPLICATIONS FOR HEALTH POLICIES: Given that the impact of adopting new AD drugs on health care costs is not uniform among patients, current payment regulations that impose simple clinical criteria to decide the eligibility of using new drugs, that is, a policy that adopts one size to fit for all, may become an access barrier to realizing the potential benefits of pharmaceutical innovation. IMPLICATIONS FOR FUTURE RESEARCH: Another potential source of the offsetting effect is that adopting new AD drugs may be beneficial to the reduction in the cost of long-term care. This is an important avenue for future research. PMID- 25543115 TI - Association between quality of life and treatment response in children with attention Deficit Hyperactivity Disorder and their parents. AB - BACKGROUND: It has been shown that Attention Deficit Hyperactivity Disorder (ADHD) lowers the Quality of Life (QoL) of patients and their families. Medication as part of the treatment has a favourable effect on symptoms as well as functioning. Evidence on the impact of pharmacological treatment on symptoms of ADHD and the QoL of the patient and their family is still limited. There is a need for further research on QoL in ADHD as well as the relationship between ADHD and the impact on families rather than solely on patients. AIMS OF THE STUDY: Measure QoL of children with ADHD and their parents and explore the association of QoL with treatment response. METHODS: A cross-sectional survey was performed using an online questionnaire to collect QoL data of children with ADHD (based on proxy reporting of parents) and their parents in a sample of members of an ADHD parent association. QoL was measured by EQ-5D and KIDSCREEN-10. Treatment response was based on descriptions by experts, based on compliance and functioning. RESULTS: Analyses were based on 618 questionnaires (treatment responder n=428, treatment non-responder n=190). Mean age of the children was 11.8 years (82.4% male). QoL according to EQ-5D utility was 0.83 and 0.74 for responders and non-responders, respectively (p<0.001). For KIDSCREEN-10 the index was 42.24 and 40.33 for responders and non-responders, respectively (p<0.001). EQ 5D utility scores of the parents were 0.83 on average; no association with their child's treatment response could be established. A significant positive correlation between EQ-5D utility of the children and EQ-5D utility of the parents (R2=0.207, p<0.001) was found. The association between treatment response and children's QoL was significantly influenced by age category, having a sibling with ADHD, and presence of comorbidity. DISCUSSION: Strengths of this study are its sample size and the inclusion of QoL of parents, which has not been reported simultaneously before. The facts that data were derived from members of the ADHD parent association, the data for children were based on parents' report, and lack of possibility for confirmation of the clinical diagnosis are the main study limitations. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: QoL of children with ADHD was shown to be significantly positively associated with response to treatment and negatively affected by comorbidity. In determining the treatment effects in ADHD, QoL and family overall well-being should be a standard consideration as well as an integrated part of health policy discussions on ADHD. IMPLICATIONS FOR HEALTH POLICIES: Policymakers in the field of ADHD should focus on QoL of the patient, but also on the broader effects of effective treatment on the well-being of the parents. IMPLICATIONS FOR FURTHER RESEARCH: Suggestions for further research include the repetition of this study including a control group and obtaining children's self-report on QoL and clinicians report on diagnosis. PMID- 25543116 TI - A roadmap to parity in mental health financing: the case of Lebanon. AB - BACKGROUND: Inadequate access to mental health (MH) services in Lebanon, where prevalence is noteworthy, is a concern. Although a multitude of factors affects access to services, lack of financial coverage of MH services is one that merits further investigation. AIM OF THE STUDY: This study aims at providing a systematic description of MH financing systems with a special focus on Lebanon, presenting stakeholder viewpoints on best MH financing alternatives/strategies and recommending options for enhancing financial coverage. METHODS: A comprehensive review of existing literature on MH financing systems was conducted, with a focus on the system in Lebanon. In addition, key stakeholders were interviewed to assess MH organizational and financing arrangements. Finally, a national round table was organized with the aim of discussing findings (from the review and interviews) and developing an action roadmap. RESULTS: Taxation and out-of-pocket payments are the most common MH financing sources worldwide and in the Eastern Mediterranean Region. In Lebanon, all funding entities, except private insurance and mutual funds, cover inpatient and outpatient MH services, albeit with inconsistencies in levels of coverage. The national roundtable recommended two main MH financing enhancements: (i) creating a knowledge-sharing committee between insurers and MH specialists, and (ii) convincing labor unions/representatives to lobby for MH coverage as part of the negotiated benefit package. DISCUSSION: There are concerns regarding the equity, effectiveness and efficiency of the MH financing system in Lebanon. The fragmented system in Lebanon leads to differences in MH coverage across different financing intermediaries, which is inequitable. The fact that one out of four Lebanese suffer a mental disorder throughout their lives and very low percentages of those obtain treatment signals a problem in effectiveness. As for efficiency, the inefficient fragmentation of MH financing among seven intermediaries is a problematic characteristic of the healthcare financing system as a whole. Moreover, the orientation of the general healthcare system towards curative rather than preventive care is reflected in MH financing as well. Limitations of the study include the lack of access to data about the MH expenditure of every financing intermediary in Lebanon; therefore it was not possible to calculate a total annual MH spending on a country level. Another limitation was the inability to map the sources of funding with the MH service provision sector, as more extensive data about the MH services provided by each of the public, private, voluntary and informal sectors is needed. IMPLICATIONS FOR HEALTH POLICIES: Providing a clear description of the current MH financing system helps policymakers recognize the disparities present in the coverage of MH, guiding them into making informed decisions on allocation of funds. This study therefore constitutes the first step towards achieving more equitable and socially just coverage, advances knowledge and provides well-needed locally relevant research. Findings are expected to inform policymaking and have already contributed to influencing a change in the policy of the Internal Security Forces Health Fund. As a result of the roundtable discussion and follow up that ensued, the fund has removed the suicide attempt exclusion from its insurance policy. PMID- 25543117 TI - Selection on meiosis genes in diploid and tetraploid Arabidopsis arenosa. AB - Meiotic chromosome segregation is critical for fertility across eukaryotes, and core meiotic processes are well conserved even between kingdoms. Nevertheless, recent work in animals has shown that at least some meiosis genes are highly diverse or strongly differentiated among populations. What drives this remains largely unknown. We previously showed that autotetraploid Arabidopsis arenosa evolved stable meiosis, likely through reduced crossover rates, and that associated with this there is strong evidence for selection in a subset of meiosis genes known to affect axis formation, synapsis, and crossover frequency. Here, we use genome-wide data to study the molecular evolution of 70 meiosis genes in a much wider sample of A. arenosa. We sample the polyploid lineage, a diploid lineage from the Carpathian Mountains, and a more distantly related diploid lineage from the adjacent, but biogeographically distinct Pannonian Basin. We find that not only did selection act on meiosis genes in the polyploid lineage but also independently on a smaller subset of meiosis genes in Pannonian diploids. Functionally related genes are targeted by selection in these distinct contexts, and in two cases, independent sweeps occurred in the same loci. The tetraploid lineage has sustained selection on more genes, has more amino acid changes in each, and these more often affect conserved or potentially functional sites. We hypothesize that Pannonian diploid and tetraploid A. arenosa experienced selection on structural proteins that mediate sister chromatid cohesion, the formation of meiotic chromosome axes, and synapsis, likely for different underlying reasons. PMID- 25543119 TI - Identification of MANF as a protein interacting with RTN1-C. AB - Reticulons (RTNs) constitute a family of endoplasmic reticulum (ER)-associated proteins with a reticular distribution. Recently, evidence has shown that they exert a cancer-specific proapoptotic function via interaction or modulation of specific proteins. Such evidence is particularly associated with the RTN1-C family members. In order to explore proteins that interact with RTN1-C, the yeast two-hybrid system and regular molecular biological techniques were used to screen the human fetal brain cDNA library. As a result, seven RTN1-C interacting proteins including Homo sapiens mesencephalic astrocyte-derived neurotrophic factor (MANF) were obtained. The interactions between RTN1-C and its interacting proteins were confirmed by beta-galactosidase assay and growth test in selective media. Moreover, the MANF/RTN1-C interaction was verified in vitro by glutathione S-transferase pull-down assay and in vivo by immunoprecipitation assay. By immunofluorescence assay, it was found that MANF co-localized with RTN1-C in the ER. Knockdown of RTN1-C reduced the localization of MANF in the ER. These results provide clues to further explore the function of RTN1-C and MANF in neurodegenerative diseases and cancer. PMID- 25543120 TI - New methods for determining proton pumping ability and electron transfer activity of the cytochrome bc1 complex. AB - It is important to determine the electron transfer activity and proton pumping ability of the cytochrome bc1 complex for better understanding its structure and function. In this study, several methods for determining the electron transfer and proton pumping of the bc1 complex, including the traditional and the new methods, are presented and evaluated. For determining the proton pumping ability of the bc1 complex, the new stopped-flow method has a higher accuracy than the traditional pH meter method, and the new spectrophotometer method is more convenient than the traditional pH meter method. In measuring the electron transfer activity of the bc1 complex, the new stopped-flow method is more accurate and has a higher separating capacity than the traditional spectrophotometer method. PMID- 25543118 TI - Hemispheric language asymmetry in first episode psychosis and schizotypy: the role of cannabis consumption and cognitive disorganization. AB - Cannabis use has been related to an elevated psychosis risk and attenuated cognitive functioning. Cannabis-related cognitive impairments are also observed in populations along the psychosis dimension. We here investigated whether a potential behavioral marker of the psychosis dimension (attenuated functional hemispheric asymmetry) is even further attenuated in individuals using cannabis (CU) vs those not using cannabis (nCU). We tested 29 patients with first-episode psychosis (FEP; 11 CU) and 90 healthy controls (38 CU) on lateralized lexical decisions assessing left-hemisphere language dominance. In patients, psychotic symptoms were assessed by Positive & Negative Symptom Scale (PANSS). In controls, self-reported schizotypy was assessed (The Oxford-Liverpool Inventory of Feelings and Experiences: O-LIFE). Results indicated that nCU FEP patients had a relative reduced hemispheric asymmetry, as did controls with increasing cognitive disorganization (CogDis) scores, in particular when belonging to the group of nCU controls. Positive, disorganized and negative PANSS scores in patients and negative and positive schizotypy in controls were unrelated to hemispheric asymmetry. These findings suggest that cannabis use potentially balances rather than exacerbates uncommon hemispheric laterality patterns. Moreover, in healthy populations, the potential stabilization of typical hemispheric asymmetry in CU might be most relevant to individuals with elevated CogDis. We discuss the potential beneficial and harmful effects of cannabis use along the psychosis dimension together with propositions for future studies that should account for the mediating role of additional substances (eg nicotine), cannabis composition (eg cannabidiol content), and individual differences (eg physical health, or absence of significant polysubstance use). PMID- 25543123 TI - Treatment of leishmaniasis: a review and assessment of recent research. AB - Leishmaniasis is a diverse group of neglected diseases caused by protozoan parasite of genus Leishmania and transmitted by the bite of a female phlebotomine sand fly. These diseases stand as a major health problem worldwide, especially in their visceral form. Despite innumerable studies on leishmaniasis, many questions are still unanswered. One of the main challenges is the presence of different Leishmania species and various clinical manifestations, complicating the therapeutic approach. There are many available antileishmanial agents, but the drug of choice is still out of reach, since almost all available drugs share several limitations and many of them are expensive with severe side effects or have a markedly reduced effectiveness. Immunosuppressed patients should also be given a special attention which represents an additional challenge. In the meantime, the combination of local and parenteral therapies with existing drugs remain a priority to improve the efficacy and to shorten the duration of the treatment. This review was undertaken to highlight the chemotherapeutic strategies, their mechanisms of action and main limitations. PMID- 25543121 TI - To be an ally or an adversary in bladder cancer: the NF-kappaB story has not unfolded. AB - Signaling and regulation of transcription factor nuclear factor-kappaB (NF kappaB) has been an area of extensive research since its first discovery nearly three decades ago. Members of the NF-kappaB family have been reported to critically mediate a multitude of responses in normal cells. Therefore, it is not surprising that NF-kappaB function can go awry and result in pathological conditions including cancer. Despite its critical importance, the functional role of NF-kappaB has not received the same attention in cancers of all tissue types. In the case of cancer of the urinary bladder, which is the second most common urologic cancer, the involvement of NF-kappaB in the development of superficial or muscle invasive disease and during cancer recurrence is rudimentary at best. Nuclear expression of p65/RelA is seen in bladder cancer patients and has been found to negatively affect survival of patients with superficial and muscle invasive disease. Despite these observations, the exact mechanism of NF-kappaB upregulation and function remains unknown. Furthermore, the emergence of a tumor suppressive role for NF-kappaB in recent years suggests that the family may play the role of a double-edged sword in cancer, which remains unexplored in bladder cancer. The challenge now is to delineate the increasing complexity of this pathway in the development and progression of bladder cancer. Here, we review key aspects of the current knowledge of signaling and regulation by the NF-kappaB family focusing on its controversial role in cancer and highlight the importance of studying NF-kappaB in bladder cancer in particular. PMID- 25543122 TI - SATB1 and 2 in colorectal cancer. AB - The special AT-rich sequence-binding proteins 1 and 2 (SATB1/2) are nuclear matrix associated proteins that are transcription factors involved in chromatin remodeling and gene regulation. Expression of the SATB2 gene is tissue-specific, and the only epithelial cells expressing SATB2 are the glandular cells of the lower gastrointestinal tract where its expression is regulated by microRNA-31 (miR-31) and miR-182. SATB2, along with its homolog SATB1, are thought to be involved in various cancers with their roles in this disease being specific to the type of cancer. Colorectal cancer (CRC) provides the largest association of SATB2 with cancer and the roles of SATB2 are better defined and more studied in CRC than in any other cancer type. SATB1 displays a negative association with SATB2 in CRC. The various studies that have investigated the involvement of SATB1 and 2 in CRC have produced consistent findings. Here, we form four major conclusions regarding the role of these proteins in CRC and their potential clinical value: (i) SATB2 is a sensitive marker to distinguish CRC from other cancer types, (ii) Reduced expression of SATB2 in CRC is associated with poor prognosis, (iii) High levels of SATB1 expression facilitate CRC and are associated with poor prognosis and (iv) Overexpression of miR-31 and -182 in CRC leads to more aggressive cancer. This review will describe several of the key investigations that established these conclusions and highlight results that offer opportunities for future research in the treatment and diagnosis of CRC. PMID- 25543125 TI - Inhibition of intracerebral glioblastoma growth by targeting the insulin-like growth factor 1 receptor involves different context-dependent mechanisms. AB - BACKGROUND: Signaling by insulin-like growth factor 1 receptor (IGF-1R) can contribute to the formation and progression of many diverse tumor types, including glioblastoma. We investigated the effect of the IGF-1R blocking antibody IMC-A12 on glioblastoma growth in different in vivo models. METHODS: U87 cells were chosen to establish rapidly growing, angiogenesis-dependent tumors in the brains of nude mice, and the GS-12 cell line was used to generate highly invasive tumors. IMC-A12 was administered using convection-enhanced local delivery. Tumor parameters were quantified histologically, and the functional relevance of IGF-1R activation was analyzed in vitro. RESULTS: IMC-A12 treatment inhibited the growth of U87 and GS-12 tumors by 75% and 50%, respectively. In GS 12 tumors, the invasive tumor extension and proliferation rate were significantly reduced by IMC-A12 treatment, while apoptosis was increased. In IMC-A12-treated U87 tumors, intratumoral vascularization was markedly decreased, and tumor cell proliferation was moderately reduced. Flow cytometry showed that <2% of U87 cells but >85% of GS-12 cells expressed IGF-1R. Activation of IGF-1R by IGF-1 and IGF-2 in GS-12 cells was blocked by IMC-A12. Both ligands stimulated GS-12 cell proliferation, and IGF-2 also stimulated migration. IMC-A12 inhibited these stimulatory effects and increased apoptosis. In U87 cells, stimulation with either ligand had no functional effect. CONCLUSIONS: IGF-1R blockade can inhibit glioblastoma growth by different mechanisms, including direct effects on the tumor cells as well as indirect anti-angiogenic effects. Hence, blocking IGF-1R may be useful to target both the highly proliferative, angiogenesis-dependent glioblastoma core component as well as the infiltrative periphery. PMID- 25543124 TI - Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients. AB - Despite multimodal treatment, the prognosis of high-grade gliomas is grim. As tumor growth is critically dependent on new blood vessel formation, antiangiogenic treatment approaches offer an innovative treatment strategy. Bevacizumab, a humanized monoclonal antibody, has been in the spotlight of antiangiogenic approaches for several years. Currently, MRI including contrast enhanced T1-weighted and T2/fluid-attenuated inversion recovery (FLAIR) images is routinely used to evaluate antiangiogenic treatment response (Response Assessment in Neuro-Oncology criteria). However, by restoring the blood-brain barrier, bevacizumab may reduce T1 contrast enhancement and T2/FLAIR hyperintensity, thereby obscuring the imaging-based detection of progression. The aim of this review is to highlight the recent role of imaging biomarkers from MR and PET imaging on measurement of disease progression and treatment effectiveness in antiangiogenic therapies. Based on the reviewed studies, multimodal imaging combining standard MRI with new physiological MRI techniques and metabolic PET imaging, in particular amino acid tracers, may have the ability to detect antiangiogenic drug susceptibility or resistance prior to morphological changes. As advances occur in the development of therapies that target specific biochemical or molecular pathways and alter tumor physiology in potentially predictable ways, the validation of physiological and metabolic imaging biomarkers will become increasingly important in the near future. PMID- 25543127 TI - Brief intervention in the workplace for heavy drinkers: a randomized clinical trial in Japan. AB - AIMS: To investigate the effectiveness of brief intervention (BI) conducted in the workplace for heavy drinkers. METHODS: A randomized controlled trial was conducted at six companies in Japan. Participants were heavy drinkers who met the inclusion criteria and were randomized into three groups: the BI group, BI with diary group and a control group. Outcomes (total drinks, binge drinking episodes and alcohol-free days) were evaluated at 3 and 12 months. RESULTS: The 304 participants recruited were allocated to the three groups and 277 participated in all follow-up evaluations. Dropout rates in the respective groups were 7.0, 14.9 and 5.5%. Some improvements were observed in all the groups. In particular, alcohol-free days in the BI group were significantly increased by 93.0% at 12 months. Total drinks at 12 months were reduced by 41 g per week in the BI group compared with the control group, although the intergroup difference was not significant. CONCLUSION: BI in the workplace is effective for increasing the number of alcohol-free days. However, the effectiveness on decreasing alcohol consumption was unclear, which could be explained by alcohol screening itself causing a reduction in drinking. PMID- 25543126 TI - Image-guided, intensity-modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes. AB - BACKGROUND: We report our preliminary outcomes following high-dose image-guided intensity modulated radiotherapy (IG-IMRT) for skull base chordoma and chondrosarcoma. METHODS: Forty-two consecutive IG-IMRT patients, with either skull base chordoma (n = 24) or chondrosarcoma (n = 18) treated between August 2001 and December 2012 were reviewed. The median follow-up was 36 months (range, 3-90 mo) in the chordoma cohort, and 67 months (range, 15-125) in the chondrosarcoma cohort. Initial surgery included biopsy (7% of patients), subtotal resection (57% of patients), and gross total resection (36% of patients). The median IG-IMRT total doses in the chondrosarcoma and chordoma cohorts were 70 Gy and 76 Gy, respectively, delivered with 2 Gy/fraction. RESULTS: For the chordoma and chondrosarcoma cohorts, the 5-year overall survival and local control rates were 85.6% and 65.3%, and 87.8% and 88.1%, respectively. In total, 10 patients progressed locally: 8 were chordoma patients and 2 chondrosarcoma patients. Both chondrosarcoma failures were in higher-grade tumors (grades 2 and 3). None of the 8 patients with grade 1 chondrosarcoma failed, with a median follow-up of 77 months (range, 34-125). There were 8 radiation-induced late effects-the most significant was a radiation-induced secondary malignancy occurring 6.7 years following IG-IMRT. Gross total resection and age were predictors of local control in the chordoma and chondrosarcoma patients, respectively. CONCLUSIONS: We report favorable survival, local control and adverse event rates following high dose IG IMRT. Further follow-up is needed to confirm long-term efficacy. PMID- 25543128 TI - Physical activity and risk of alcohol use disorders: results from a prospective cohort study. AB - AIMS: To examine the effect of physical activity on risk of developing alcohol use disorders in a large prospective cohort study with focus on leisure-time physical activity. METHODS: Data came from the four examinations of the Copenhagen City Heart Study (CCHS), performed in 1976-1978, 1981-1983, 1991-1994 and 2001-2003. Information on physical activity (classified as Moderate/high, low or sedentary) and covariates was obtained through self-administered questionnaires, and information on alcohol use disorders was obtained from the Danish Hospital Discharge Register, the Danish Psychiatric Central Research Register and the Winalco database. In total, 18,359 people participated in the study, a mean follow-up time of 20.9 years. Cox proportional hazards model with delayed entry was used. Models were adjusted for available covariates (age, smoking habits, alcohol intake, education, income and cohabitation status) including updated time-dependent variables whenever possible. RESULTS: A low or moderate/high leisure-time physical activity was associated with almost half the risk of developing alcohol use disorder compared with a sedentary leisure-time physical activity. This translates into a 1.5- to 2-fold increased risk of developing alcohol use disorder (Hazard ratios for men 1.64; 95% CI 1.29-2.10 and women 1.45; 1.01-2.09) in individuals with a sedentary leisure-time physical activity, compared with a moderate to high level. However, when stratifying by presence of other psychiatric disorders, no association was observed in women with psychiatric comorbidity. Residual confounding may have been present in this study, especially according to rough measures of income and education. CONCLUSIONS: In both men and women, being sedentary in leisure time was a risk factor for developing an alcohol use disorder. PMID- 25543130 TI - Diagnostic reference levels in digital mammography: a systematic review. AB - This study aims to review the literature on existing diagnostic reference levels (DRLs) in digital mammography and methodologies for establishing them. To this end, a systematic search through Medline, Cinahl, Web of Science, Scopus and Google scholar was conducted using search terms extracted from three terms: DRLs, digital mammography and breast screen. The search resulted in 1539 articles of which 22 were included after a screening process. Relevant data from the included studies were summarised and analysed. Differences were found in the methods utilised to establish DRLs including test subjects types, protocols followed, conversion factors employed, breast compressed thicknesses and percentile values adopted. These differences complicate comparison of DRLs among countries; hence, an internationally accepted protocol would be valuable so that international comparisons can be made. PMID- 25543131 TI - Mathematical study of the thermoluminescence process in K2YF5:Tb(3+). AB - This paper presents results of studying the simulated thermoluminescence (TL) glow curve in potassium-yttrium double fluoride doped with trivalent optically active Tb(3+) ions (K2YF5:Tb(3+)). Samples have been irradiated with different doses (0.24, 2.4 and 24 Gy) of beta particles. Four trapping states and one kind of recombination-centre model have been used in this simulation. The activation energy and order of kinetics are determined using the general-order kinetic model. The results obtained using the authors' proposed models were tested and compared with the experimental glow curve of K2YF5:Tb(3+). The comparison has shown that the proposed model can predict more accurately and easily the behaviour of the TL glow curve at three different doses. PMID- 25543129 TI - Relationship between emotional processing, drinking severity and relapse in adults treated for alcohol dependence in Poland. AB - AIMS: Growing data reveals deficits in perception, understanding and regulation of emotions in alcohol dependence (AD). The study objective was to explore the relationships between emotional processing, drinking history and relapse in a clinical sample of alcohol-dependent patients. METHODS: A group of 80 inpatients entering an alcohol treatment program in Warsaw, Poland was recruited and assessed at baseline and follow-up after 12 months. Baseline information about demographics, psychopathological symptoms, personality and severity of alcohol problems was obtained. The Schutte Self-Report Emotional Intelligence (EI) Test and Toronto Alexithymia Scale (TAS) were utilized for emotional processing assessment. Follow-up information contained data on drinking alcohol during the last month. RESULTS: At baseline assessment, the duration of alcohol drinking was associated with lower ability to utilize emotions. Patients reporting more difficulties with describing feelings drank more during their last episode of heavy drinking, and had a longer duration of intensive alcohol use. A longer duration of the last episode of heavy drinking was associated with more problems identifying and regulating emotions. Poor utilization of emotions and high severity of depressive symptoms contributed to higher rates of drinking at follow up. CONCLUSIONS: These results underline the importance of systematic identification of discrete emotional problems and dynamics related to AD. This knowledge has implications for treatment. Psychotherapeutic interventions to improve emotional skills could be utilized in treatment of alcohol-dependent patients. PMID- 25543133 TI - Patient exposure levels in radiotherapy CT simulations in Finland. AB - Computed tomography (CT)-based simulation is an essential part of the radiotherapy treatment process. Patient exposure levels in CT simulations were collected from 15 CT systems from all 13 Finnish radiation therapy centres. A large standard deviation up to 56 % in dose levels between CT systems was noticed. Average volumetric CT dose indexes (in body phantom) were 24, 18 and 29 mGy for prostate, resection breast and head and neck treatment targets, respectively, and 70 mGy (in head phantom) for whole brain. These average dose indexes were much higher than those in corresponding diagnostic imaging in Finland. Dose levels in simulations with some devices were even over 3-fold higher than the diagnostic reference level for the same area of interest. Moreover, large variations in other exposure parameters, such as pitch and slice thickness, were seen. The results were discussed nationally, and general guidance to optimise dose levels was shared. PMID- 25543132 TI - EURADOS intercomparison on emergency radiobioassay. AB - Nine laboratories participated in an intercomparison exercise organised by the European Radiation Dosimetry Group (EURADOS) for emergency radiobioassay involving four high-risk radionuclides ((239)Pu, (241)Am, (90)Sr and (226)Ra). Diverse methods of analysis were used by the participating laboratories for the in vitro determination of each of the four radionuclides in urine samples. Almost all the methods used are sensitive enough to meet the requirements for emergency radiobioassay derived for this project in reference to the Clinical Decision Guide introduced by the NCRP. Results from most of the methods meet the requirements of ISO 28218 on accuracy in terms of relative bias and relative precision. However, some technical gaps have been identified. For example, some laboratories do not have the ability to assay samples containing (226)Ra, and sample turnaround time would be expected to be much shorter than that reported by many laboratories, as timely results for internal contamination and early decisions on medical intervention are highly desired. Participating laboratories are expected to learn from each other on the methods used to improve the interoperability among these laboratories. PMID- 25543134 TI - Mono(2-ethylhexyl)phthalate accumulation disturbs energy metabolism of fat cells. AB - Phthalates are lipophilic and tend to accumulate in adipose tissue, an important regulator of energy balance and glucose homeostasis. The study aimed to determine whether cellular phthalate accumulation influenced fat cell energy metabolism. Following a 3-day treatment with adipogenesis-inducing medium and a 2-day treatment with adipogenesis-maintaining medium, 3T3-L1 cells differentiated into adipocytes in the presence of a phthalate at a clinically relevant concentration (30-300 MUM) for another 6 days. Two phthalates, di(2-ethylhexyl)phthalate and di n-butylphthalate, and their metabolites, mono(2-ethylhexyl)phthalate (MEHP) and mono-n-butylphthalate, were used here. The phthalate treatments caused no marked effect on cytotoxicity and adipogenesis. Only the MEHP-treated adipocytes were found having smaller lipid droplets; MEHP accumulated in cells in a dose- and time-dependent manner. The MEHP-treated adipocytes exhibited significant increases in lipolysis and glucose uptake; quantitative real-time polymerase chain reaction (qPCR) analysis revealed correlated changes in expression of marker genes involved in adipogenesis, lipid metabolism, and glucose uptake. Analysis of oxygen consumption rate (a mitochondrial respiration indicator) and extracellular acidification rate (a glycolysis indicator) indicated a higher energy metabolism in the adipocytes. qPCR analysis of critical genes involved in mitochondrial biogenesis and/or energy metabolism showed that expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha, sirtuin 3, and protein kinase A were significantly enhanced in the MEHP-treated adipocytes. In vitro evidence of MEHP impacts on lipolysis, glucose uptake/glycolysis, and mitochondrial respiration/biogenesis demonstrates that MEHP accumulation disturbs energy metabolism of fat cells. PMID- 25543135 TI - Role of silver nanoparticles (AgNPs) on the cardiovascular system. AB - With the advent of nanotechnology, the use and applications of silver nanoparticles (AgNPs) have increased, both in consumer products as well as in medical devices. However, little is known about the effects of these nanoparticles on human health, more specific in the cardiovascular system, since this system represents an important route of action in terms of distribution, bioaccumulation and bioavailability of the different circulating substances in the bloodstream. A collection of studies have addressed the effects and applications of different kinds of AgNPs (shaped, sized, coated and functionalized) in several components of the cardiovascular system, such as endothelial cells, isolated vessels and organs as well as integrative animal models, trying to identify the underlying mechanisms involved in their actions, to understand their implication in the field of biomedicine. The purpose of the present review is to summarize the most relevant studies to date of AgNPs effects in the cardiovascular system and provide a broader picture of the potential toxic effects and exposure risks, which in turn will allow pointing out the directions of further research as well as new applications of these versatile nanomaterials. PMID- 25543137 TI - Dicer and Hsp104 function in a negative feedback loop to confer robustness to environmental stress. AB - Epigenetic mechanisms can be influenced by environmental cues and thus evoke phenotypic variation. This plasticity can be advantageous for adaptation but also detrimental if not tightly controlled. Although having attracted considerable interest, it remains largely unknown if and how environmental cues such as temperature trigger epigenetic alterations. Using fission yeast, we demonstrate that environmentally induced discontinuous phenotypic variation is buffered by a negative feedback loop that involves the RNase Dicer and the protein disaggregase Hsp104. In the absence of Hsp104, Dicer accumulates in cytoplasmic inclusions and heterochromatin becomes unstable at elevated temperatures, an epigenetic state inherited for many cell divisions after the heat stress. Loss of Dicer leads to toxic aggregation of an exogenous prionogenic protein. Our results highlight the importance of feedback regulation in building epigenetic memory and uncover Hsp104 and Dicer as homeostatic controllers that buffer environmentally induced stochastic epigenetic variation and toxic aggregation of prionogenic proteins. PMID- 25543136 TI - p53 mutations change phosphatidylinositol acyl chain composition. AB - Phosphatidylinositol phosphate (PIP) second messengers relay extracellular growth cues through the phosphorylation status of the inositol sugar, a signal transduction system that is deregulated in cancer. In stark contrast to PIP inositol head-group phosphorylation, changes in phosphatidylinositol (PI) lipid acyl chains in cancer have remained ill-defined. Here, we apply a mass spectrometry-based method capable of unbiased high-throughput identification and quantification of cellular PI acyl chain composition. Using this approach, we find that PI lipid chains represent a cell-specific fingerprint and are unperturbed by serum-mediated signaling in contrast to the inositol head group. We find that mutation of Trp53 results in PIs containing reduced-length fatty acid moieties. Our results suggest that the anchoring tails of lipid second messengers form an additional layer of PIP signaling in cancer that operates independently of PTEN/PI3-kinase activity but is instead linked to p53. PMID- 25543138 TI - In vivo single-cell detection of metabolic oscillations in stem cells. AB - Through the use of bulk measurements in metabolic organs, the circadian clock was shown to play roles in organismal energy homeostasis. However, the relationship between metabolic and circadian oscillations has not been studied in vivo at a single-cell level. Also, it is unknown whether the circadian clock controls metabolism in stem cells. We used a sensitive, noninvasive method to detect metabolic oscillations and circadian phase within epidermal stem cells in live mice at the single-cell level. We observe a higher NADH/NAD+ ratio, reflecting an increased glycolysis/oxidative phosphorylation ratio during the night compared to the day. Furthermore, we demonstrate that single-cell metabolic heterogeneity within the basal cell layer correlates with the circadian clock and that diurnal fluctuations in NADH/NAD+ ratio are Bmal1 dependent. Our data show that, in proliferating stem cells, the circadian clock coordinates activities of oxidative phosphorylation and glycolysis with DNA synthesis, perhaps as a protective mechanism against genotoxicity. PMID- 25543139 TI - The thymus-specific serine protease TSSP/PRSS16 is crucial for the antitumoral role of CD4(+) T cells. AB - In cancer, immune cells can play conflicting roles, either protective, by elimination of tumor cells during immune surveillance, or detrimental, by promoting carcinogenesis during inflammation. We report here that the thymus specific serine protease (TSSP), which is involved in CD4(+) T cell maturation in the thymus, exerts a tumor suppressor activity. Mice genetically deficient for TSSP are highly prone to spontaneous cancer development. The absence of TSSP also increases the rate of induced colitis-associated colorectal (CAC) tumor formation, through exacerbated colon inflammation. Adoptive transfer of T cells in various combinations (CD4(+) and CD8(+) from wild-type and/or knockout mice) into T cell-deficient mice showed that the TSSP-deficient CD4(+) T cell compartment promotes tumor development, associated with high levels of the cytokine IL-17A. Inhibition of IL-17A during CAC tumor formation prevents the increased carcinogenesis and colic immune disequilibrium observed in TSSP deficient mice. Therefore, our data demonstrate that antitumoral immune surveillance requires thymic TSSP-driven production of CD4(+) T cells contributing to inflammatory balance. PMID- 25543140 TI - HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion. AB - The E3 ubiquitin ligase HUWE1, deregulated in carcinoma, has been implicated in tumor formation. Here, we uncover a role for HUWE1 in cell migration and invasion through degrading the RAC activator TIAM1, implying an additional function in malignant progression. In MDCKII cells in response to HGF, HUWE1 catalyzes TIAM1 ubiquitylation and degradation predominantly at cell-cell adhesions, facilitating junction disassembly, migration, and invasion. Depleting HUWE1 or mutating the TIAM1 ubiquitylation site prevents TIAM1 degradation, antagonizing scattering, and invasion. Moreover, simultaneous depletion of TIAM1 restores migration and invasion in HUWE1-depleted cells. Significantly, we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas. Thus, we elucidate a critical role for HUWE1 in regulating epithelial cell-cell adhesion and provide additional evidence that ubiquitylation contributes to spatiotemporal control of RAC. PMID- 25543141 TI - An autoregulatory mechanism imposes allosteric control on the V(D)J recombinase by histone H3 methylation. AB - V(D)J recombination is initiated by a specialized transposase consisting of the subunits RAG-1 and RAG-2. The susceptibility of gene segments to DNA cleavage by the V(D)J recombinase is correlated with epigenetic modifications characteristic of active chromatin, including trimethylation of histone H3 on lysine 4 (H3K4me3). Engagement of H3K4me3 by a plant homeodomain (PHD) in RAG-2 promotes recombination in vivo and stimulates DNA cleavage by RAG in vitro. We now show that H3K4me3 acts allosterically at the PHD finger to relieve autoinhibition imposed by a separate domain within RAG-2. Disruption of this autoinhibitory domain was associated with constitutive increases in recombination frequency, DNA cleavage activity, substrate binding affinity, and catalytic rate, thus mimicking the stimulatory effects of H3K4me3. Our observations support a model in which allosteric control of RAG is enforced by an autoinhibitory domain whose action is relieved by engagement of active chromatin. PMID- 25543142 TI - Input- and cell-type-specific endocannabinoid-dependent LTD in the striatum. AB - Changes in basal ganglia plasticity at the corticostriatal and thalamostriatal levels are required for motor learning. Endocannabinoid-dependent long-term depression (eCB-LTD) is known to be a dominant form of synaptic plasticity expressed at these glutamatergic inputs; however, whether eCB-LTD can be induced at all inputs on all striatal neurons is still debatable. Using region-specific Cre mouse lines combined with optogenetic techniques, we directly investigated and distinguished between corticostriatal and thalamostriatal projections. We found that eCB-LTD was successfully induced at corticostriatal synapses, independent of postsynaptic striatal spiny projection neuron (SPN) subtype. Conversely, eCB-LTD was only nominally present at thalamostriatal synapses. This dichotomy was attributable to the minimal expression of cannabinoid type 1 (CB1) receptors on thalamostriatal terminals. Furthermore, coactivation of dopamine receptors on SPNs during LTD induction re-established SPN-subtype-dependent eCB LTD. Altogether, our findings lay the groundwork for understanding corticostriatal and thalamostriatal synaptic plasticity and for striatal eCB-LTD in motor learning. PMID- 25543144 TI - Exon circularization requires canonical splice signals. AB - Circular RNAs (circRNAs), an abundant class of noncoding RNAs in higher eukaryotes, are generated from pre-mRNAs by circularization of adjacent exons. Using a set of 15 circRNAs, we demonstrated their cell-type-specific expression and circular versus linear processing in mammalian cells. Northern blot analysis combined with RNase H cleavage conclusively proved a circular configuration for two examples, LPAR1 and HIPK3. To address the circularization mechanism, we analyzed the sequence requirements using minigenes derived from natural circRNAs. Both canonical splice sites are required for circularization, although they vary in flexibility and potential use of cryptic sites. Surprisingly, we found that no specific circRNA exon sequence is necessary and that potential flanking intron structures can modulate circularization efficiency. In combination with splice inhibitor assays, our results argue that the canonical spliceosomal machinery functions in circRNA biogenesis, constituting an alternative splicing mode. PMID- 25543143 TI - TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells. AB - TRIM28 is a corepressor that mediates transcriptional silencing by establishing local heterochromatin. Here, we show that deletion of TRIM28 in neural progenitor cells (NPCs) results in high-level expression of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. We find that NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription and silencing of ERVs, which is in contrast to other somatic cell types using DNA methylation. We also show that derepression of ERVs influences transcriptional dynamics in NPCs through the activation of nearby genes and the expression of long noncoding RNAs. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs. Our results warrant future studies on the role of ERVs in the healthy and diseased brain. PMID- 25543146 TI - Development of a multi-VOC reference material for quality assurance in materials emission testing. AB - Emission test chamber measurement is necessary to proof building materials as sources of volatile organic compounds (VOCs). The results of such measurements are used to evaluate materials and label them according to their potential to emit harmful substances, polluting indoor air. If only labelled materials were installed indoors, this would improve indoor air quality and prevent negative impacts on human health. Because of the complex testing procedure, reference materials for the quality assurance are mandatory. Currently, there is a lack of such materials because most building products show a broad variation of emissions even within one batch. A previous study indicates lacquers, mixed with volatile organic pollutants, as reproducible emission source for a wide range of substances. In the present study, the curing of the lacquer-VOC mixture inside micro-chambers was optimised. Therefore, the humidity and the chamber flow were varied. Typical indoor air pollutants with a wide range of volatilities, for example, styrene, n-hexadecane, dimethyl and dibutyl phthalate were selected. It turned out that, under optimised curing parameters inside the micro-chamber, their emission can be reproduced with variations of less than 10 %. With this, a next important step towards a reference material for emission testing was achieved. PMID- 25543147 TI - Ultra-high-performance liquid chromatography-tandem mass spectrometry for the analysis of free and conjugated natural estrogens in cow milk without deconjugation. AB - A sensitive liquid chromatography/electrospray ionization-tandem mass spectrometry method for the determination of free and conjugated estrogens in cow milk is described. Milk samples were diluted with water and then extracted and cleaned up by solid-phase extraction using graphitized carbon black as adsorbent material, without any enzymatic cleavage, derivatization, and/or protein precipitation step. Two fractions were collected (free and conjugated estrogens) and analyzed separately. Mass spectrometry analysis was performed in negative ion mode using selected reaction monitoring acquisition mode. For all compounds, the coefficients of determination (R(2)) ranged between 0.9892 and 0.9997. Analytical recoveries were in the range of 86-109% for free estrogens and 85-118% for conjugates, with relative standard deviations below 10%, and the method detection limit ranged between 3 and 80 ng L(-1). Finally, the developed method was used to determine the presence of free and conjugated estrogens in six retail milk samples (five cow milk samples and one goat milk sample) and one goat milk sample provided by a local shepherd. Estrone was found to be the major free estrogen present in commercial milk samples, and estrone 3-sulfate showed the highest concentration among the target conjugated estrogens. Estriol was also observed in some analyzed milk samples, but the concentrations were always below the limit of quantification. PMID- 25543145 TI - An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. AB - Estrogen-receptor alpha (ERalpha) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERalpha VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERalpha and Tac1 signaling. Disrupting the development of Nkx2 1(+) VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons coexpressing ERalpha and Tac1. Unexpectedly, two responses controlled by ERalpha(+) neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERalpha, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses. PMID- 25543148 TI - Preparation of a novel weak cation exchange/hydrophobic interaction chromatography dual-function polymer-based stationary phase for protein separation using "thiol-ene click chemistry". AB - A novel dual-function mixed-mode stationary phase based on poly(glycidyl methacrylate-co-ethylene dimethacrylate) microspheres was synthesized by thiol ene click chemistry and characterized by infrared spectroscopy and elemental analysis. The new system displays both hydrophobic interaction chromatography (HIC) character in a high salt concentration mobile phase, and weak cation exchange (WCX) chromatography character in a low salt concentration mobile phase. It can be used to separate proteins in both ion-exchange chromatography (IEC) mode and HIC mode. The resolution and selectivity of the stationary phase were evaluated in both HIC mode and IEC mode using protein standards. In comparison with the conventional WCX and HIC columns, the results were satisfactory and acceptable. Protein mass and bioactivity recoveries of more than 96% can be achieved in both HIC mode and IEC mode using this column. The results indicate that the novel dual-function mixed-mode column in many cases can replace the use of two individual WCX and HIC columns. In addition, the effects on protein separation of different ligand structures in the dual-function stationary phase and the pH of the mobile phase used were also investigated in detail. The results show that electrostatic interaction of the ligand with proteins must match the hydrophobicity of the ligand, which is an important factor to prepare the dual function stationary phase. On the basis of this dual-function mixed-mode chromatography column, a new two-dimensional liquid chromatography technology with a single column system was also developed in this study, and was used to renature and purify recombinant human interferon-gamma from inclusion bodies. The mass recovery, purity, and specific bioactivity obtained for the purified recombinant human interferon-gamma were 87.2%, 92.4%, and 2.8 * 10(7) IU/mg, respectively, in IEC mode, and 83.4%, 95.2%, and 4.3 * 10(7) IU/mg, respectively, in HIC mode. The results indicate that the dual-function mixed-mode stationary phase prepared in this study may aid in the development of new two-dimensional liquid chromatography technology with a single column for intensive proteomic studies, and it may also find applications in recombinant protein drug production since it can save column costs and simplify the biotechnological processes. PMID- 25543149 TI - Retroperitoneal ganglioneuroma revealed as an "incidentaloma" in a healthy volunteer. PMID- 25543150 TI - Effects of titanium dioxide nanoparticles isolated from confectionery products on the metabolic stress pathway in human lung fibroblast cells. AB - Titanium dioxide (TiO2) is a common additive in many foods, pigments, personal care products, and other consumer products used in daily life. Despite the widespread use of nanoscale TiO2 and composites of nanoscale TiO2 in the food industry, there is a serious lack of awareness of the toxicity of TiO2 nanoparticles (NPs) among consumers and manufacturers. There is an urgent need for toxicological studies of TiO2 NPs. TiO2 food additives separated from marketed foods were characterized by transmission electron microscopy. In addition, the effects of TiO2 NPs on metabolic stress in WI-38 cells were analyzed. Cell viability, total ROS, mitochondrial transmembrane potential (DeltapsiM), cell cycle, and metabolism-related gene expression were analyzed. The results indicate that TiO2 NPs have a significant concentration-dependent toxic effect in lung cells. The DeltapsiM, the intracellular ROS level, and the stages of the WI-38 cell cycle were altered by increasing TiO2 concentrations after exposure for 24 and 48 h relative to the control. Cytochrome P450 1A, GSTM3, and glutathione S-transferase A4 upregulation in response to the TiO2 NPs was observed. These findings suggest that the toxicity of TiO2 from confectionery products in WI-38 cells may be mediated through an increase in oxidative stress. The results of this study clearly demonstrate the nanotoxicological effects of TiO2 on WI-38 cells and will be useful for nanotoxicological indexing. PMID- 25543151 TI - Spatial distribution of perfluoroalkyl substances in surface sediments of five major rivers in China. AB - Perfluoroalkyl substances (PFASs) have received great attention from the public and scientific community due to their potential adverse impacts on the ecosystem and human health. We investigated the occurrence and distribution of 16 PFASs from 2 classes of PFASs-perfluoroalkyl carboxylic acids and perfluoroalkane sulfonic acids-in the archived surface sediments of five major rivers (Yellow River, Hai River, Liao River, Zhujiang River, and Dongjiang River) in northern and southern China. The study was also performed during the wet and dry seasons. Perfluorooctanoic acid and perfluorooctane sulfonic acid were the most frequently detected (detection frequency = 100 and 63 %, respectively) in the sediments of the five rivers; the concentrations ranged from 0.08 to 0.99 ng/g dry weight (dw) and were lower than the limit of detection ( 0.05) during estrus (n = 5) and diestrus (n = 5); 5.9 and 7.2 mL/min/100g, respectively. Uterine perfusion in subfertile/infertile mares affected by elastosis was lower than that of control mares during both estrus (P < 0.01) and diestrus (P < 0.01). The differences in baseline levels of perfusion between the control and elastosis groups indicate that elastosis of the uterine vasculature is associated with decreased uterine perfusion during both phases of the estrous cycle. In the uterus, a compromise in UBF could have implications in endometrial glandular development, postbreeding endometritis, uterine clearance, development of the conceptus, and overall fertility. PMID- 25543152 TI - SOX17 is a critical specifier of human primordial germ cell fate. AB - Specification of primordial germ cells (PGCs) marks the beginning of the totipotent state. However, without a tractable experimental model, the mechanism of human PGC (hPGC) specification remains unclear. Here, we demonstrate specification of hPGC-like cells (hPGCLCs) from germline competent pluripotent stem cells. The characteristics of hPGCLCs are consistent with the embryonic hPGCs and a germline seminoma that share a CD38 cell-surface marker, which collectively defines likely progression of the early human germline. Remarkably, SOX17 is the key regulator of hPGC-like fate, whereas BLIMP1 represses endodermal and other somatic genes during specification of hPGCLCs. Notable mechanistic differences between mouse and human PGC specification could be attributed to their divergent embryonic development and pluripotent states, which might affect other early cell-fate decisions. We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information. PMID- 25543153 TI - Activated type 2 innate lymphoid cells regulate beige fat biogenesis. AB - Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Ralpha in PDGFRalpha(+) APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PAPERCLIP: PMID- 25543155 TI - Early development and function of the corpus luteum and relationship to pregnancy in the buffalo. AB - A detailed study on the structure and function of the CL in the Day-5 to Day-10 window of development, and relationship to the likelihood of pregnancy, was undertaken in Italian Mediterranean buffaloes. In experiment 1, buffaloes underwent synchronization of estrus and fixed-time artificial insemination (n = 23). Features of the CL were measured from Days 5 to 10 after fixed-time artificial insemination, and pregnancy was confirmed on Day 70. Buffaloes that established a pregnancy (n = 14) had a larger CL area (1.31 +/- 0.1 vs. 1.09 +/- 0.1 cm(2); P < 0.01) and greater progesterone (P4) concentrations (1.90 +/- 0.1 vs. 1.48 +/- 0.1 ng/mL; P < 0.01) during Days 5 to 10 compared with nonpregnant buffaloes. In the same period, blood flow measured as time average medium velocity tended to be greater (P = 0.059) in buffaloes that were subsequently pregnant versus nonpregnant buffaloes (10.8 +/- 0.8 vs. 8.4 +/- 0.9). There was a relationship (R(2) = 0.136; P < 0.05) between CL area, P4, and time average medium velocity from Days 5 to 10. Logistic regression analysis showed that P4 concentration on Day 10 had a significant influence on pregnancy (odds ratio, 19.337; P < 0.01). In experiment 2, highly vascularized CLs (HVCLs, n = 3) and lowly vascularized CLs (LVCLs, n = 3) on Day 5 were examined by contrast-enhanced ultrasonography and then subjected to histologic investigation. Blood flow was greater in HVCLs than in LVCLs. Highly vascularized CLs showed intense staining for factor VIII and had many small, irregular-shaped blood vessels, whereas LVCLs had low factor VIII staining and relatively few large, regular-shaped vessels. Luteal cell expression of vascular EGF was greater for HVCLs compared with LVCLs. The study has shown that greater development and function of the CL from as early as Day 5 is related to an increased likelihood of pregnancy in the buffalo. Corpus lutea that show early development at Day 5 have greater expression of vascular EGF and factor VIII, increased vascularization, and higher blood flow. PMID- 25543156 TI - The "dilution effect" in stallion sperm. AB - Dilution of semen to less than 20 * 10(6) sperm/mL has been reported to decrease sperm quality in multiple species, a phenomenon known as the semen "dilution effect." Critical evaluation of stallion semen diluted to these concentrations, however, has not been reported. This study evaluated sperm motion characteristics (percent total motility [TMOT], percent progressive motility [PMOT], curvilinear velocity [MUm/s], and percent straightness) and plasma membrane integrity (percent plasma membrane intact [PMI]) in semen samples diluted to 2.5 * 10(6) sperm/mL with the addition of 0%, 7.5%, or 25% seminal plasma (groups T-2.5/0, T 2.5/7.5, and T-2.5/25, respectively), or after simple dilution to 30 * 10(6) sperm/mL (group T-30), or simple dilution to a ratio of 3:1 (extender:semen; group T-3:1SD). Evaluations were performed immediately after semen collection (T0), and after 24 and 48 hours of cooled storage (T24 and T48, respectively). The PMI and TMOT were the highest in group T-3:1SD at T0. At T24, the PMI in groups T-30, T3:1SD and T3:1/30, and T-2.5/0 were higher than that in the other groups (P < 0.05), whereas TMOT in group T-3:1SD was higher (P < 0.05) than that in all other groups except T-30. By T48, no difference was detected for PMI among groups T-3:1SD, T-30, and T-2.5/0; for TMOT among groups T-3:1SD, T-30, and T 2.5/0, and T-2.5/7.5 (P > 0.05), whereas PMOT was the highest in groups T-2.5/0 and T-2.5/7.5 (P < 0.05). These findings revealed that treatments in which semen was diluted to a concentration of 2.5 * 10(6) sperm/mL had lower initial PMI, TMOT, and PMOT, but semen quality did not decline after 24 and 48 hours of cooled storage. In this study, TMOT and PMI in dilute semen were less than those in more concentrated semen at T0. This effect, while significant, was small and less apparent after cooled storage. PMID- 25543157 TI - Survival capacity of Mycoplasma agalactiae and Mycoplasma mycoides subsp capri in the diluted semen of goat bucks and their effects on sperm quality. AB - This study examines the viability of Mycoplasma agalactiae (Ma) and Mycoplasma mycoides subsp capri (Mmc) during 150 minutes of incubation at 37 degrees C in contaminated diluted semen (DS) doses. The effects of the presence of both microorganisms on sperm viability, motility, and morphology were also examined. In a second experiment, the viability of Ma and its effects on sperm viability were determined in ejaculate samples and skimmed milk semen extender samples. Ma and Mmc were able to survive in DS at concentrations considered infectious, and no significant differences in mean concentrations were detected (7.1 log colony forming units [CFU]/mL). However, initial concentration of Ma declined (P < 0.05) from 7.5 to 6.9 log CFU/mL and Mmc declined (P < 0.05) from 7.7 to 7.1 log CFU/mL after incubation. Conversely, ejaculate concentrations of Ma increased significantly (from 7.1 to 7.4 log CFU/mL, P < 0.05). These observations suggest that the natural breeding medium is more suitable for Ma than the medium used for artificial insemination (AI). The presence of Mmc slightly reduced sperm viability in the DS (from 21.7% to 16.6%, P < 0.05). The absence of major effects on sperm quality could lead to the unnoticed use of semen contaminated with Ma and Mmc for AI. As both bacteria were able to survive the conditions of ejaculates and semen doses, these findings suggest a risk of venereal transmission of contagious agalactia and support the use of mycoplasma-free semen samples for (AI). PMID- 25543158 TI - Effect of pyrochar and hydrochar amendments on the mineralization of the herbicide isoproturon in an agricultural soil. AB - Carbon (C)-rich, solid products from pyrolysis (pyrochars) and hydrothermal carbonization (HTC, hydrochars) are expected to reduce the bioavailability and bioaccessibility of pesticides as side effect of soil addition. To compare effects of different feedstocks (digestate, miscanthus, woodchips) and production processes (pyrolysis at 750 degrees C, HTC at 200 degrees C and 250 degrees C), (14)C-labeled isoproturon (IPU) was applied at 0.75 kg ha(-)(1) to loamy sand amended either with 0.5% or 5% pyrochars or hydrochars, which was then incubated for 50d. Mineralization of IPU was measured as (14)C-CO2 released from soil-char composites. Pore-water and methanol extractable (14)C-IPU was quantified as well as non-extractable (14)C-residues (NER). Furthermore, C mineralization of pyrochars, hydrochars and feedstocks was studied to assess the relationship between IPU bioaccessibility and char decomposability. In pure soil, 8.1% of applied IPU was mineralized after 50d. This was reduced more strongly in pyrochar treatments (81 +/- 6% reduction) than in hydrochar treatments (56 +/- 25% reduction). Different feedstocks had no significantly different effect when 5% char was added, but their effect was significant and dependent on the production process in 0.5% amendments. Pesticide binding can occur by surface sorption as well as by diffusion and subsequent occlusion in micropores. The latter can be expected to result in high amounts of NER, as it was observed in the pyrochar treatments. Hydrochars were less stable than pyrochars and contained lower amounts of NER. Thus, in hydrochar amended soils, better accessibility of IPU to microbial degradation may be a result of full char decomposition within decades ensuring controlled pesticide degradation. PMID- 25543159 TI - Polycyclic aromatic hydrocarbons (PAHs) and their derivatives (alkyl-PAHs, oxygenated-PAHs, nitrated-PAHs and azaarenes) in urban road dusts from Xi'an, Central China. AB - Urban road dusts are carriers of polycyclic aromatic compounds (PACs) and are therefore considered to be a major source of contamination of other environmental compartments and a source of exposure to PACs for urban populations. We determined the occurrence, composition pattern and sources of several PACs (29 alkyl- and parent-PAHs, 15 oxygenated-PAHs (OPAHs), 4 azaarenes (AZAs), and 11 nitrated-PAHs (NPAHs)) in twenty urban road dusts and six suburban surface soils (0-5cm) from Xi'an, central China. The average concentrations of ?29PAHs, ?4AZAs, ?15OPAHs, and ?11NPAHs were 15767, 673, 4754, and 885 n gg(-1) in road dusts and 2067, 784, 854, and 118 ng g(-1) in surface soils, respectively. The concentrations of most individual PACs were higher in street dusts than suburban soils, particularly for PACs with molecular weight>192 g mol(-1). The enrichment factors of individual PACs were significantly positively correlated with log KOA and log KOW, indicating an increasing deposition and co-sorption of the PACs in urban dusts with decreasing volatility and increasing hydrophobicity. Significant correlations between the concentrations of individual and sum of PACs, carbon fractions (soot and char), and source-characteristic PACs (combustion-derived PAHs and retene, etc.), indicated that PAHs, OPAHs and AZAs were mostly directly emitted from combustion activities and had similar post-emission fates, but NPAHs were possibly more intensely photolyzed after deposition as well as being emitted from vehicle exhaust sources. The incremental lifetime cancer risk (ILCR) resulting from exposure to urban dust bound-PACs was higher than 10(-6), indicating a non-negligible cancer risk to residents of Xi'an. PMID- 25543160 TI - Primary pulmonary hyalinizing clear cell carcinoma of bronchial submucosal gland origin. AB - Hyalinizing clear cell carcinoma (HCCC) has only been described in salivary glands of the head and neck. We report a 38-year-old man with a 2.6-cm lung tumor that was growing in a peribronchial location and had morphologic features of HCCC. The tumor cells expressed cytokeratin 7 and keratin AE1/AE3, and the vast majority of tumor cells marked also with p63 and p40. They were negative for cytokeratin 20, S-100, smooth muscle actin, napsin A, and thyroid transcription factor-1. Fluorescence in situ hybridization revealed Ewing Sarcoma Breakpoint Region 1 (EWSR1) rearrangement, and reverse-transcription polymerase chain reaction confirmed the presence of the EWSR1-Activating Transcription Factor 1 (ATF1) fusion transcript, which was subsequently sequenced. The morphologic, immunophenotypic, cytogenetic, and molecular findings together with the patient's history and location of the tumor support a diagnosis of primary pulmonary HCCC of bronchial submucosal gland origin. It is our understanding that this is the first report of HCCC arising as a primary tumor outside the head and neck region. PMID- 25543162 TI - Pullout wire fixation together with distal interphalangeal joint Kirschner wire stabilization for acute combined tendon and bone (double level) mallet finger injury. AB - This article describes a previously unclassified type of combined tendon/bone mallet finger. This supplements the conventional Doyle classification. The article also describes the technique for surgical treatment of such mallet fingers, which involves the use of a pullout wire with K-wire stabilization of the distal interphalangeal joint. PMID- 25543163 TI - Nager syndrome. PMID- 25543164 TI - How and why researchers use the number needed to vaccinate to inform decision making--a systematic review. AB - BACKGROUND: The number needed to vaccinate (NNV) is a measure that has been widely used in the scientific literature to draw conclusions about the usefulness and cost-effectiveness of various immunization programmes. The main objective of this review is to examine how and why the NNV has been used and reported in the published literature. METHODS: Electronic databases were searched and records were screened against the eligibility criteria by two independent authors. We included papers that reported and interpreted NNV. RESULTS: We identified 27 studies, the designs including observational studies, economic analyses, systematic reviews, and commentaries. The NNV has been used in the literature to describe three main themes: potential benefits of vaccination programmes, cost effectiveness, and economic analyses, and modelling studies to compare different vaccination strategies. CONCLUSIONS: NNV has been used in a wide variety of ways in the literature, yet there are no defined thresholds for what is a favourable NNV. Furthermore, the generalizability of the NNV is usually limited. Further work is required to determine the most appropriate use of this measure. PMID- 25543161 TI - Fondaparinux in the initial and long-term treatment of venous thromboembolism. AB - BACKGROUND: Even in the absence of evidence on its long-term efficacy and safety, a number of patients with venous thromboembolism (VTE) receive long-term therapy with fondaparinux alone in everyday practice. METHODS: We used the Registro Informatizado de Enfermedad Tromboembolica (RIETE) registry to compare the rate of VTE recurrences and major bleeding at 10 and 90 days in patients with and without cancer. For long-term therapy, fondaparinux was compared with vitamin K antagonists (VKA) in patients without cancer and with low-molecular-weight heparin (LMWH) in those with cancer. RESULTS: Of 47,378 patients recruited, 46,513 were initially treated with heparin, 865 with fondaparinux. Then, 263 patients (78 with cancer) were treated for at least 3 months with fondaparinux. After propensity-score matching, there were no differences between patients receiving initial therapy with heparin or fondaparinux. Among patients with cancer, there were no differences between fondaparinux and LMWH. Among patients without cancer, the long-term use of fondaparinux was associated with an increased risk of major bleeding (3.24 % vs. 0.95 %, p<0.05). CONCLUSIONS: An unexpected high rate of major bleeding was observed in non-cancer patients treated with long-term fondaparinux. Our small sample does not allow to derive relevant conclusions on the use of fondaparinux in cancer patients. PMID- 25543166 TI - Anemia attributed to vitamin B6 deficiency in post-pancreaticoduodenectomy patients. AB - Micronutrient deficiencies such as vitamin A, iron, zinc, and selenium have been known to occur as a consequence of pancreaticoduodenectomy (PD), but vitamin B6 deficiency has not been previously reported. We report two post-PD patients who developed anemias attributed to vitamin B6 deficiency. Oral supplementations of vitamin B6 significantly improved anemias in both cases. Micronutrients including vitamin B6 should be monitored in post-PD patients, and supplementations should be carried out when necessary. PMID- 25543165 TI - Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells. AB - Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention. PMID- 25543167 TI - Illicit use of opioid substitution drugs: prevalence, user characteristics, and the association with non-fatal overdoses. AB - BACKGROUND AND AIMS: Diversion of opioid substitution drugs (OSD) is of public concern. This study examined the prevalence, frequency, and predictors of illicit OSD use in a group of injecting drug users (IDUs) and assessed if such use was associated with non-fatal overdoses. METHODS: Semi-annual cross-sectional interviews conducted in Oslo, Norway (2006-2013), from 1355 street-recruited IDUs. Hurdle, logistic, and multinomial regression models were employed. RESULTS: Overall, 27% reported illicit OSD use in the past four weeks; 16.8% methadone, 12.5% buprenorphine, and 2.9% both drugs. Almost 1/10 reported at least one non fatal overdose in the past four weeks, and roughly 1/3 reported such experience in the past year. Use of additional drugs tended to be equally, or more prevalent among illicit OSD users than other IDUs. In terms of illicit OSD use being a risk factor for non-lethal overdoses, our results showed significant associations only for infrequent buprenorphine use (using once or less than once per week). Other factors associated with non-fatal overdoses included age, education, homelessness, as well as the benzodiazepines, stimulants, and heroin use. CONCLUSIONS: Users of diverted OSD may represent a high-risk population, as they used more additional drugs and used them more frequently than other IDUs. However, illicit OSD use may be less harmful than previously assumed. After accounting for an extensive set of covariates, only infrequent illicit buprenorphine use, but not methadone use, was associated with non-fatal overdoses. PMID- 25543168 TI - Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms is strongly associated with depression and anxiety in Japanese employees. AB - BACKGROUND: Although alcohol-related disorders (ARD) have been shown to be accompanied by comorbid depressive and anxiety disorders, and alcohol metabolic enzyme genes, ADH1B and ALDH2 polymorphisms, have been associated with an increased risk of ARD, no studies have been conducted to evaluate the associations between these genetic polymorphisms and anxiety or depression. METHOD: A total of 1944 Japanese workers were interviewed regarding their depressive and anxiety disorders, including suicidality, by a brief psychiatric structured interview (MINI). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphism combinations with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and anxiety/depressive disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of two enzyme genotypes (Group I-V, in order from the lowest alcohol sensitivity). RESULTS: Those with ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1 were likely to be at an increased risk of depressive and anxiety disorders as well as ARD. This tendency was more apparent among non-drinkers (OR 9.20, 95% CI 1.66 50.89). No adverse effects of ALDH2 or ADH1B alone were observed with mental disorder risks. Likewise, analyses conducted combining job rank and genetic alcohol sensitivity showed no material associations with such risks. CONCLUSIONS: Genetic alcohol sensitivity, especially that with the genotype combination of ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1, was significantly associated with an increased risk of depressive and anxiety disorders as well as ARD. PMID- 25543169 TI - Developmental toxicity of perfluorononanoic acid in mice. AB - Perfluorononanoic acid (PFNA) is a ubiquitous and persistent environmental contaminant. Although its levels in the environment and in humans are lower than those of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA), a steady trend of increases in the general population in recent years has drawn considerable interest and concern. Previous studies with PFOS and PFOA have indicated developmental toxicity in laboratory rodent models. The current study extends the evaluation of these adverse outcomes to PFNA in mice. PFNA was given to timed-pregnant CD-1 mice by oral gavage daily on gestational day 1-17 at 1, 3, 5 or 10mg/kg; controls received water vehicle. Dams given 10mg/kg PFNA could not carry their pregnancy successfully and effects of this dose group were not followed. Similar to PFOS and PFOA, PFNA at 5mg/kg or lower doses produced hepatomegaly in the pregnant dams, but did not affect the number of implantations, fetal viability, or fetal weight. Mouse pups were born alive and postnatal survival in the 1 and 3mg/kg PFNA groups was not different from that in controls. In contrast, although most of the pups were also born alive in the 5mg/kg PFNA group, 80% of these neonates died in the first 10 days of life. The pattern of PFNA-induced neonatal death differed somewhat from those elicited by PFOS or PFOA. A majority of the PFNA-exposed pups survived a few days longer after birth than those exposed to PFOS or PFOA, which typically died within the first 2 days of postnatal life. Surviving neonates exposed to PFNA exhibited dose dependent delays in eye opening and onset of puberty. In addition, increased liver weight seen in PFNA-exposed offspring persisted into adulthood and was likely related to the persistence of the chemical in the tissue. Evaluation of gene expression in fetal and neonatal livers revealed robust activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) target genes by PFNA that resembled the responses of PFOA. Our results indicate that developmental toxicity of PFNA in mice is comparable to that of PFOS and PFOA, and that these adverse effects are likely common to perfluoroalkyl acids that persist in the body. PMID- 25543170 TI - Stress-triggered signaling affecting survival or suicide of Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a major human pathogen that can survive to stress conditions, such as the acidic environment of inflammatory foci, and tolerates lethal pH through a mechanism known as the acid tolerance response. We previously described that S. pneumoniae activates acidic-stress induced lysis in response to acidified environments, favoring the release of cell wall compounds, DNA and virulence factors. Here, we demonstrate that F(0)F(1)-ATPase is involved in the response to acidic stress. Chemical inhibitors (DCCD, optochin) of this proton pump repressed the ATR induction, but caused an increased ASIL. Confirming these findings, mutants of the subunit c of this enzyme showed the same phenotypes as inhibitors. Importantly, we demonstrated that F(0)F(1)-ATPase and ATR are necessary for the intracellular survival of the pneumococcus in macrophages. Alternatively, a screening of two-component system (TCS) mutants showed that ATR and survival in pneumocytes were controlled in contrasting ways by ComDE and CiaRH, which had been involved in the ASIL mechanism. Briefly, CiaRH was essential for ATR (ComE represses activation) whereas ComE was necessary for ASIL (CiaRH protects against induction). They did not regulate F0F1-ATPase expression, but control LytA expression on the pneumococcal surface. These results suggest that both TCSs and F(0)F(1)-ATPase control a stress response and decide between a survival or a suicide mechanism by independent pathways, either in vitro or in pneumocyte cultures. This biological model contributes to the current knowledge about bacterial response under stress conditions in host tissues, where pathogens need to survive in order to establish infections. PMID- 25543171 TI - Neurotransmitter-mediated anxiogenic action of PACAP-38 in rats. AB - The action of PACAP-38 was studied by measuring the anxiogenic-anxiolytic behavior of rats in an elevated plus maze. PACAP-38 was administered into the lateral brain ventricle and the behavior of the animals was measured 3h later. The possible involvement of transmitters was measured by pretreating the animals with receptor blockers which alone did not influence the task, but in the doses used were effective with other neuropeptides. The receptor antagonist PACAP 6-38 (a PAC 1/VPAC2 receptor antagonist of PACAP-38 receptor), haloperidol (a non selective dopamine receptor antagonist), phenoxybenzamine (an alpha1/alpha2beta adrenergic receptor antagonist), propranolol(a beta-adrenergic receptor antagonist), bicuculline (a gamma-aminobutyric acid subunit A receptor antagonist), methysergide (a nonselective 5-HT2 serotonergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), naloxone (a nonselective opioid receptor antagonist) and nitro-l arginine which acts by blocking the enzyme nitric oxide synthase, thereby blocking the nitric oxide synthesis, were tested. The following parameters were measured: the time spent in open arms/the time spent in total entries. PACAP-38 decreased the ratio of time spent in open arms to the time spent in total entries, indicating anxiogenic action. The total number of entries was not altered significantly either by PACAP-38 or by the receptor blockers. The following receptor blockers diminished the action of PACAP-38: PACAP 6 38,haloperidol, methysergide, naloxone and nitro-l-arginine. Pretreatment with atropine, phenoxybenzamine, propranolol and bicuculline did not influence the action of PACAP-38 on the time spent in open arms. The results demonstrate that PACAP-38 administered into the lateral brain ventricle exerted anxiogenic action at 3 h following treatment. Pretreatment of the animals with various receptor blockers indicated that a nonselective dopaminergic receptor antagonist, 5HT2 serotonergic and opioid receptors, nitric oxide and PAC1 receptors are involved in the anxiogenic action induced by PACAP-38. PMID- 25543172 TI - Whole organism responses and intersex severity in rainbow darter (Etheostoma caeruleum) following exposures to municipal wastewater in the Grand River basin, ON, Canada. Part A. AB - Municipal wastewater effluents (MWWEs) contain anthropogenic substances that can exhibit endocrine-disrupting activity. These complex mixtures have been observed to exert adverse effects on fish. Rainbow darter (Etheostoma caeruleum, RBD) is a small benthic fish that is widespread throughout the Grand River, Ontario, Canada, and has been previously shown to be adversely affected by MWWE exposure in this watershed. The objectives of this study were to quantify biological responses in this sentinel species and intersex severity in male fish, in relation to the area of urbanization. It focused on RBD populations adjacent to wastewater outfalls in the Grand River watershed. In May 2011, nine sites across the urban gradient were selected to evaluate the impact of MWWEs. Endpoints for energy storage (i.e. condition factor, k; liversomatic index, LSI) as well as reproductive endpoints (i.e. gonadosomatic index, GSI; gonad development, hormone production), and intersex were assessed in the fish. Rainbow darter showed a high incidence of intersex downstream of the wastewater outfalls, especially below the largest treatment plant outfall at Kitchener (~85%). We applied an intersex index (score from 0 to 7) that considers the number of eggs within the testis and the stage of maturation of the egg. RBD exposed downstream of the largest wastewater outfall at Kitchener had a score of 3.81+/-0.37 compared to upstream to the urban areas where there were no intersex males found other than a single individual with a score 1 (average intersex score of site 0.06+/-0.06). In addition, several fish associated with the Kitchener outfall had macroscopic vitellogenic eggs in the testes (intersex scores 5 and 6). The sub-population of fish located at the wastewater outfall also showed a tendency towards skewed sex ratios (greater proportion of females to male fish) compared to the population at the reference sites. Male fish inhabiting the urbanized area of the Grand River also showed reduced levels of testosterone (T) and 11-ketotestosterone (11KT). Intersex males had the lower levels of 11KT relative to the upstream reference fish but could not be distinguished from normal males collected at the exposed sites. Despite the high levels of intersex at these sites, no relationships were evident among intersex severity and other measured endpoints such as GSI, LSI or in vitro steroid production. The effects observed appear to be associated with urbanization and exposure to treated MWWEs in the watershed. Although intersex incidence and severity was a very good indicator of wastewater exposure, intersex could not be directly linked to other effects in this wild population. The effects of MWWEs on transcriptional changes in adult RBD exposed to the effluents are reported in the corresponding report (Part B). PMID- 25543173 TI - Investigation of inflammatory response of decellularized porcine aortic tissue in mice: can we rely on this experimental setting? PMID- 25543175 TI - Re: Histology of a Marfan aorta 4.5 years after personalized external aortic root support. PMID- 25543174 TI - Pitfalls and premature failure of the Freedom SOLO stentless valve. AB - OBJECTIVES: This study reports a series of pitfalls, premature failures and explantation of the third-generation Freedom SOLO (FS) bovine pericardial stentless valve. METHODS: A total of 149 patients underwent aortic valve replacement using the FS. Follow-up was 100% complete with an average observation time of 5.5 +/- 2.3 years (maximum 8.7 years) and a total of 825 patient-years. Following intraoperative documentation, all explanted valve prostheses underwent histological examination. RESULTS: Freedom from structural valve deterioration (SVD) at 5, 6, 7, 8 and 9 years was 92, 88, 80, 70 and 62%, respectively. Fourteen prostheses required explantation due to valve-independent dysfunction (n = 5; i.e. thrombus formation, oversizing, aortic dilatation, endocarditis and suture dehiscence) or valve-dependent failure (acute leaflet tears, n = 4 and severe stenosis, n = 5). Thus, freedom from explantation at 5, 6, 7, 8 and 9 years was 95, 94, 91, 81 and 72%, respectively. An acute vertical tear along the non-coronary/right coronary commissure to the base occurred at a mean of 6.0 years (range 4.3-7.3 years) and affected size 25 and 27 prostheses exclusively. Four FS required explantation after a mean of 7.5 years (range 7.0-8.3 years) due to severe functional stenosis and gross calcification that included the entire aortic root. CONCLUSIONS: The FS stentless valve is safe to implant and shows satisfying mid-term results in our single institution experience. Freedom from SVD and explantation decreased markedly after only 6-7 years, so that patients with FS require close observation and follow-up. Exact sizing, symmetric positioning and observing patient limitations are crucial for optimal outcome. PMID- 25543176 TI - Evaluation of the efficacy of a haemostatic matrix for control of intraoperative and postoperative bleeding in major lung surgery: a prospective randomized study. AB - OBJECTIVES: This prospective randomized study was designed to assess the safety and efficacy of a haemostatic matrix in intraoperative bleeding control and prevention of postoperative bleeding after major lung surgery. METHODS: One hundred and twenty patients undergoing major lung resection and presenting with intraoperative persistent active bleeding have been prospectively enrolled and randomly assigned to receive [Floseal(r) group (FG)] or not (control group) the application of Floseal(r) to the bleeding site and to the site of the hilar dissection. To evaluate the efficacy of the product, several intraoperative and postoperative data were compared between the two groups. RESULTS: No adverse event related to the haemostatic matrix application occurred. The intraoperative haemostasis rate at 3 (primary end-point), 6 and 10 min was significantly higher and the mean time to haemostasis was significantly shorter in the FG. The quantity of chest drain fluids did not show significant differences at 24, 48 and 72 h between the two groups. Postoperative haemoglobin-level variation was significantly lower in patients of the FG (-0.7 +/- 0.66 vs -2.3 +/- 5.87 g/dl; P = 0.04). Similarly, haematocrit variation was lower in the haemostatic group ( 2.6 +/- 2.19 vs -4.2 +/- 3.71; P = 0.006). The chest drain duration resulted significantly shorter in the FG (10.3 +/- 5.05 vs 13.3 +/- 6.28 days; P = 0.005). In-hospital stay was shorter in the FG (6.4 +/- 2.9 vs 8.1 +/- 5.42 days; P = 0.044). CONCLUSIONS: In conclusion, the application of Floseal(r) in major lung resections proved safe and effective in increasing the intraoperative successful haemostasis rate and in reducing postoperative variation in haemoglobin and haematocrit levels. The sealant use was also related with a significantly shorter chest drain duration and hospitalization. PMID- 25543177 TI - Platelet dysfunction and acquired von Willebrand syndrome in patients with left ventricular assist devices. AB - OBJECTIVES: Unexplained bleeding events are a severe complication in patients with left ventricular assist devices (LVADs). Platelet dysfunction and acquired von Willebrand syndrome (AVWS) may contribute to bleeding tendencies. Yet, comprehensive data with respect to platelet function and AVWS in LVAD patients in terms of bleeding events are scarce. METHODS: Thirty-nine HeartMate II patients were included in this study. Data of at least two time points were available for each patient. Platelet function was analysed via light transmission aggregometry in 19 patients without LVAD, 28 in early (<=14 days) and 30 in late postimplantation states (>=30 days). Von Willebrand factor (VWF) antigen, VWF collagen binding capacity and VWF multimeric analyses were performed in 26 patients without LVAD, 39 in early and 33 in late postimplantation states to diagnose AVWS. Bleeding complications were recorded for 39 patients in the early and 33 in the late postoperative period. RESULTS: Platelet dysfunction was detectable in 18 of 19 without LVAD and in all patients following LVAD implantation. Platelet aggregation values did not change over time (without early, P = 0.27, n = 14; early-late, P = 0.17, n = 21). AVWS was not diagnosed in patients without LVAD, except for one. On LVAD, 33 of 39 patients had AVWS in the early and all in the late period (n = 33). Bleeding events occurred in 44% of patients in the early and in 64% of patients in the late period. CONCLUSIONS: According to our data, platelet aggregation is often impaired in LVAD patients even without an implanted LVAD. Additionally, appearance of AVWS seems to be closely linked to LVAD implantation. PMID- 25543178 TI - To sew or to staple? PMID- 25543179 TI - Results of comparing transthoracic device closure and surgical repair with right infra-axillary thoracotomy for perimembranous ventricular septal defects. AB - OBJECTIVES: Transthoracic device closure (TTDC) and surgical repair with right infra-axillary thoracotomy (SRRIAT) are two main alternative minimally invasive approaches for restrictive perimembranous ventricular septal defect (VSD); however, few studies have compared them with each other in terms of effectiveness and cost. METHODS: Patients with perimembranous VSD undergoing TTDC or SRRIAT from January 2012 to July 2013 were reviewed in a comparative investigation between the two procedures. RESULTS: Success from the procedures was achieved in 30 TTDC (30/33, 91%) and 96 SRRIAT patients (100%). Operation duration in the TTDC group was significantly shorter than that of the SRRIAT group (115.8 +/- 43.8 vs 175.6 +/- 41.3 min, P < 0.01). The total perioperative drainage, use of red blood cells, mechanical ventilation time, stay in the intensive care unit and hospital stay for the TTDC group were significantly less than those in the SRRIAT group. No deaths or complete atrioventricular block occurred in either group. One SRRIAT patient accepted a second surgery for residual shunt. TTDC costs slightly more than SRRIAT (40270.6 +/- 2741.3 renmingbi [RMB] vs 32964.5 +/- 8221.6 RMB, P < 0.01). CONCLUSIONS: Both TTDC and SRRIAT showed excellent outcomes and cosmetic appearance for suitable VSD candidates. Although its costs were higher, TTDC had the advantages over SRRIAT of a short operation duration and intensive care unit stay and fewer days in the hospital. PMID- 25543180 TI - Possibility of high-resolution ptychographic iterative imaging with low energy electrons: dynamical calculations. AB - Ptychographic iterative engine (PIE), a form of coherent diffractive imaging in which the phase of both low-angle and high-angle diffraction data is used to form an image without a lens, can in principle deliver wavelength-limited resolution. Working at low accelerating voltages (30 keV) reduces specimen knock-on damage, increases high-resolution contrast and allows a scanning electron microscope to be used as a transmission electron microscopy. However, electrons are very strongly scattered at low energy. To that end, the effect of dynamical scattering on PIE at low accelerating voltages is calculated to illustrate the possibility of generating high-resolution images with low energy electrons. PMID- 25543182 TI - Exercise can improve physical self perceptions in adolescents with low motor competence. AB - Adolescents with low motor competence have diminished perceptions of their physical self and tend to avoid physical activities. This study examined the outcomes of an exercise intervention that focused on improving aerobic fitness, strength, and self-perceptions in the physical domain in adolescents with poor motor coordination. The sample included 35 adolescents with low motor competence, comprising boys (n = 25) and girls (n = 10) ranging in age from 13 to 17 years, who attended two sessions per week in the 13 week exercise intervention study (AMP it up). Physical self-perceptions were measured before and after the intervention using the Physical Self Perception Profile and Perceived Importance Profile. Significant improvements in perceived Physical Condition, Attractive Body and Physical Strength sub domain scores were identified between pre and post test. Adjusting for age, gender, BMI and attendance, regression analyses revealed that Attractive Body was the strongest predictor of Physical Self Worth at pre test, joined by Physical Condition at post-test. This exercise intervention had a positive impact on adolescent physical self-perceptions, in particular males, with improvements in those sub domains specifically related to the exercise program. Changes in specific aspects of Physical Self Worth can be facilitated by exercise interventions, after a relatively short period of time, in adolescents with poor motor coordination. PMID- 25543181 TI - Premenopausal plasma 25-hydroxyvitamin D, mammographic density, and risk of breast cancer. AB - Epidemiologic evidence for an association between plasma 25-hydroxyvitamin D [25(OH)D] and breast cancer is inconsistent. Data are especially limited for premenopausal women and for associations with mammographic density. To test the hypothesis that plasma concentration of 25(OH)D is associated with mammographic density, we conducted a cross-sectional study among 835 premenopausal women in the Nurses' Health Studies. We measured 25(OH)D in blood samples and used multivariable linear regression to quantify the association of average percent density by quartile of plasma 25(OH)D. In a nested case-control analysis including 493 breast cancer cases, we evaluated risk of breast cancer associated with vitamin D status within tertiles of mammographic density. Women in the top quartile of plasma 25(OH)D levels had an average percent breast density 5.2 percentage points higher than women in the bottom quartile (95 % confidence interval: 1.8, 8.7; P trend <0.01), after adjusting for predictors of 25(OH)D and established breast cancer risk factors. Plasma 25(OH)D concentration was significantly inversely associated with breast cancer risk among women with high mammographic density (P trend < 0.01) but not among women in lower tertiles of mammographic density (P-interaction < 0.01). These results do not support the hypothesis that vitamin D is inversely associated with percent mammographic density in premenopausal women. There was evidence that the association between premenopausal 25(OH)D and breast cancer risk varies by mammographic density, with an inverse association apparent only among women with high mammographic density. PMID- 25543183 TI - Long-term sensorimotor and therapeutical effects of a mild regime of prism adaptation in spatial neglect. A double-blind RCT essay. AB - Spatial neglect (SN) is commonly associated with poor functional outcome. Adaptation to a rightward optical deviation of vision has been shown to benefit to SN rehabilitation. The neurophysiological foundations and the optimal modalities of prism adaptation (PA) therapy however remain to be validated. This study is aimed at exploring the long-term sensory-motor, cognitive and functional effects produced by weekly PA sessions over a period of four weeks. A double blind, monocentric randomized and controlled trial (RCT) was carried out. Twenty patients with left SN secondary to stroke were included, 10 in the "prism" group and 10 in the "control" group. The sensory-motor effects of PA were evaluated by measurement of manual and visual straight-ahead, and also by precision of pointing without visual feedback before and after each PA session. The functional independence measure (FIM) was evaluated before and at 1, 3 and 6 months after PA, while SN severity was assessed using the Behavioural Inattention Test (BIT) before and 6 months after PA. Before the intervention, only manual straight-ahead pointing constituted a reproducible sensory-motor measurement. During prism exposure, a questionnaire showed that not a single patient were aware of the direct effects of optical deviation on pointing movement performance. The sensory motor after-effects produced by the PA produced a more rapid reduction of the rightward manual straight-ahead, which was secondarily followed by visual straight-ahead. These sensory-motor effects helped to clarify the action mechanisms of PA on SN. At the conclusion of the 6-month follow-up, the two groups showed similar improvement, indicating that a weekly PA session over 4 weeks was not sufficient to produce long-term functional benefit. This improvement was correlated with the evolution of visual straight-ahead, which can be proposed as a marker for patients outcome. PMID- 25543184 TI - Sweat chloride levels in asthma. PMID- 25543185 TI - Lisfranc injuries. AB - Lisfranc injuries are commonly asked about in FRCS Orthopaedic trauma vivas. The term "Lisfranc injury" strictly refers to an injury where one or more of the metatarsals are displaced from the tarsus. The term is more commonly used to describe an injury to the midfoot centred on the 2nd tarsometatarsal joint. The injury is named after Jacques Lisfranc de St. Martin (1790-1847), a French surgeon and gynaecologist who first described the injury in 1815. 'Lisfranc injury' encompasses a broad spectrum of injuries, which can be purely ligamentous or involve the osseous and articular structures. They are often difficult to diagnose and treat, but if not detected and appropriately managed they can cause long-term disability. This review outlines the anatomy, epidemiology, classification, investigation and current evidence on management of this injury. PMID- 25543186 TI - Development and validation of a short-version checklist for patients undergoing hemodialysis based on the International Classification of Functioning, Disability and Health. AB - BACKGROUND: In 2009, we developed a "100-category checklist" for patients undergoing hemodialysis (HD) based on the International Classification of Functioning, Disability and Health, and we confirmed its validity. However, we found that for patients' daily assessment, 100 categories were too many. The purpose of the present study was to develop and validate a short version of the "100-category checklist." METHODS: A total of 100 outpatients undergoing HD were recruited. They were interviewed using the "100-category checklist" and asked whether they had experienced problems after starting HD. From the "100-category checklist," we extracted categories that had greater than a 50 % rate of "yes" responses. Content validity was evaluated using the frequency of patients who had a problem in each category. Criterion validity was evaluated based on the correlation of the score from the "short-version checklist" categories with that from the Kidney Disease Quality of Life (KDQOLTM) questionnaire. Construct validity was evaluated using Spearman correlation coefficients between the number of problem categories and the presence of HD-related complications. Cronbach's coefficient alpha was calculated to evaluate internal consistency. RESULTS: Twenty-two categories were identified as problem categories. Criterion validity showed that 12 categories were significantly correlated with subscales of the KDQOLTM. Construct validity showed that the presence of complications contributed to an increased number of problems associated with HD. Cronbach's coefficient alpha of this checklist was 0.79. CONCLUSION: The "short-version checklist" had a certain degree of validity, suggesting its usefulness in a simplified assessment of patients undergoing HD. PMID- 25543187 TI - Exploring urinary biomarkers in autosomal dominant polycystic kidney disease. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, is a progressive disease characterized by a bilateral proliferation and enlargement of renal cysts. Recent reports have shown that tolvaptan, a vasopressin V2 receptor antagonist, has been effective in inhibiting renal cyst proliferation and enlargement in ADPKD patients, although no biomarker has identified to predict the effects of tolvaptan. We explored the effective urinary biomarkers in ADPKD in human and in an animal model. METHODS: We measured 28 biomarkers in urine taken from ADPKD patients to compare with that of healthy subjects. Next, a gene expression analysis of the kidney from DBA/2FG-pcy mice (ADPKD model animals) was performed to identify prospective biomarkers. Additionally, we investigated the DBA/2FG-pcy mouse urine samples to determine the biomarkers' efficacy. RESULTS: There were statistically significant differences in 12 of the 28 prospective urinary biomarkers between urine from ADPKD patients and that from healthy subjects. Six of these matched with highly expressed gene products of DBA/sFG-pcy mouse kidneys. Among those 6 biomarkers, NGAL, M-CSF, and MCP-1 showed significantly higher values in the urine of DBA/2FG pcy mice than that of wild type. CONCLUSIONS: This study suggests that NGAL, M CSF, MCP-1 are potential candidates of urinary biomarkers in ADPKD. PMID- 25543188 TI - Sirtuin 6 is essential for sodium sulfide-mediated cytoprotective effect in ischemia/reperfusion-stimulated brain endothelial cells. AB - BACKGROUND: Our recent data demonstrated that hydrogen sulfide (H2S), the third gaseous transmitter, had a protective effect on stroke. The purpose of this study was to investigate the protective effect of H2S in oxygen glucose deprivation and reperfusion (OGD/R)-stimulated brain endothelial cells and its association with sirtuin 6 (SIRT6). METHODS: Cultured bEnd.3 brain endothelial cells were exposed to OGD/R. The effects of sodium sulfide (Na2S, an exogenous H2S donor) on cell death, lactate dehydrogenase release, intracellular reactive oxygen species (ROS) production, superoxide dismutase (SOD) and catalase (CAT) activities, H2S level, cystathionine gamma-lyase (CSE) expression, and sirtuin 6 (SIRT6) expression/activity were tested to elucidate the protective mechanisms of H2S. RESULTS: Application of Na2S concentration dependently reduced OGD/R-induced cell death, accompanying with decreasing intracellular ROS production and increasing activities of SOD and CAT. In addition, Na2S also enhanced H2S level and CSE expression associated with upregulation of SIRT6 expression and activity in OGD/R stimulated brain endothelial cells, whereas CSE inhibitor DL-propargylglycine further deteriorated the decrease of SIRT6 expression and activity as well as the reduction of H2S level and CSE expression caused by OGD/R. Furthermore, SIRT6 knockdown abolished Na2S-mediated CSE expression and cytoprotection action in OGD/R-stimulated cells. CONCLUSIONS: Na2S protected brain endothelial cells against simulated ischemic injury through SIRT6-dependent mechanisms. PMID- 25543189 TI - Practice variation in long-term secondary stroke prevention in The Netherlands. AB - BACKGROUND: Stroke guidelines emphasize the importance of adequate vascular risk factor assessment and management in transient ischemic attack (TIA) and ischemic stroke patients, but it is not clear how these guidelines are applied in routine clinical practice. The limited data that are available indicate that TIA and ischemic stroke patients often do not receive the recommended interventions. The aim of this study was to investigate practice variations in long-term secondary stroke prevention in The Netherlands. METHODS: Between June and December 2013, an invitation for a web-based survey was sent to 90 Dutch neurologists with a special interest in stroke neurology. This web-based survey contained questions regarding the organization of outpatient care for TIA and ischemic stroke patients after initial hospital assessment, pharmacologic treatment, and nonpharmacologic strategies for long-term secondary prevention. RESULTS: In total, 84 (93%) neurologists completed the survey. Although nearly all respondents reported that they follow-up TIA and ischemic stroke patients after initial hospital assessment, the number of follow-up visits and the follow-up duration were variable. A similar variation was found in treatment targets levels for both blood pressure and low-density lipoprotein cholesterol. Regarding nonpharmacologic strategies for long-term secondary stroke prevention, most respondents inform their TIA and ischemic stroke patients about the importance of smoking cessation. There is considerably less attention for the other lifestyle risk factors. CONCLUSIONS: We found considerable practice variation in long-term secondary stroke prevention. These variations may have an impact on the risk for stroke recurrence and cardiovascular disease in general. PMID- 25543190 TI - Parkinsonism after external ventricular drainage in a patient with intraventricular hemorrhage. AB - We report a patient who presented with Parkinsonism after external ventricular drainage (EVD) for an intraventricular hemorrhage (IVH). We also demonstrate dopaminergic system dysfunction using (18)F-florinated-N-3-fluoropropyl-2-beta carboxymethoxy-3-beta-(4-lodophenyl) nortropane ((18)F-FP-CIT) positron emission tomography (PET) scanning. A 50-year-old woman presented with manifestations of Parkinsonism, including severe rigidity and 3-Hz resting tremor, immediately after EVD for IVH. (18)F-FP-CIT PET images at 6 months after onset showed dysfunction of the bilateral caudate nuclei and putamen after EVD that seemed to have induced Parkinsonism, although no lesion was observed in those areas on either conventional computed tomography or magnetic resonance imaging. With a dose of 300/1200 mg/day carbidopa/levodopa, the rigidity of both upper and lower extremities was significantly reduced, and the tremor completely disappeared. The decreased rigidity also improved the activities of daily living performance. In summary, a patient developed Parkinsonism after EVD for IVH, and we demonstrated dopaminergic system dysfunction on (18)F-FP-CIT PET images. Clinicians should pay particular attention to the occurrence of Parkinsonism when performing procedures that can reduce intraventricular pressure. PMID- 25543191 TI - Expression of estrogen and progesterone receptors across human malignancies: new therapeutic opportunities. AB - Estrogen and progesterone receptors (ERs and PRs) are known for their prognostic as well as treatment predictive value in breast cancer. Although these receptors are differentially expressed in some other malignancies, and likely participate in the biology of those cancer types, the relevance to outcome and therapy is not well established. The use of ER as a highly effective therapeutic target in oncology was pioneered in breast cancer, and the lessons learned from its success could potentially benefit patients with several other malignancies in which hormone receptors are highly expressed. Indeed, there are several potent drugs available that target hormone receptors. These agents show incontrovertible evidence of benefit in patients with hormone receptor-positive breast cancer. It is conceivable that these drugs may have salutary effects in a variety of cancers other than those originating in the breast, based on the overexpression of hormone receptors in some patients, and the preclinical and clinical reports showing responses to these drugs in diverse cancers, albeit in small series or anecdotally. We therefore undertook a literature review in order to summarize the current data regarding the biologic and clinical implications of expression of estrogen and progesterone receptors in various malignancies and the possibilities for deployment of hormone manipulation beyond breast cancer. PMID- 25543192 TI - Exploring alternative ovarian cancer biomarkers using innovative nanotechnology strategies. AB - Our increased understanding of ovarian cancer's blueprints (mediated by DNA and RNA) and behavior (mediated by proteins) points to wide differences across patients that cannot be depicted by histology alone. Conventional diagnosis usually entails an adequate tissue biopsy, which limits serial testing. There is thus a motivation to shift towards easier to obtain clinical samples (e.g., ascites or blood). In response, investigators are increasingly leveraging alternative circulating biomarkers in blood or proximal fluids and harnessing novel profiling platforms to help explore treatment-related effects on such biomarkers in serial fashion. In this review, we discuss how new nanotechnologies we developed intersect with alternative ovarian cancer biomarkers for improved understanding of metastases and therapeutic response. PMID- 25543194 TI - Could serum pentraxin 3 levels and IgM deposition in skin biopsies predict subsequent renal involvement in children with Henoch-Schonlein purpura? AB - BACKGROUND: The aim of this study was to evaluate the potential of serum pentraxin 3 (PTX3) values as an early predictor of subsequent renal involvement in patients with Henoch-Schonlein purpura (HSP) with no abnormalities on urinary examination and in renal function tests at disease onset. METHODS: This was a prospective cohort study which included 60 pediatric patients with HSP (age range 3-15 years) who were diagnosed between February 2011 and October 2012 and 60 age- and sex-matched healthy controls. The patients were followed up for at least 18 months. Clinical findings were recorded for all patients at first examination, and blood samples for routine laboratory parameters and PTX3 value as well as skin biopsy specimens were obtained from each subject. RESULTS: Of the 60 patients with HSP, 29 (48.3 %) developed subsequent renal involvement, of whom four underwent kidney biopsy. The mean serum PTX3 level of patients with subsequent renal involvement was significantly higher than those of patients without renal involvement and of the controls (2.20 +/- 1.30 vs. 1.36 +/- 0.85 and 1.03 +/- 0.7 ng/ml, respectively; p = 0.004). Immunofluorescence evaluation of skin biopsy revealed that in addition to immunoglobulin A (IgA) deposition, the IgM deposition was significantly associated with subsequent renal involvement (p = 0.008). CONCLUSIONS: A high PTX3 level and IgM staining in skin biopsies from HSP patients may be harbingers of subsequent renal involvement. PMID- 25543193 TI - The demise of calcium-based phosphate binders-is this appropriate for children? AB - In children with chronic kidney disease (CKD) optimal control of mineral and bone disorder (MBD) is essential not only for the prevention of debilitating skeletal complications and for achieving adequate growth, but also for preserving long term cardiovascular health. The growing skeleton is particularly vulnerable to the effects of CKD, and bone pain, fractures and deformities are common in children on dialysis. Defective bone mineralisation has been linked with ectopic calcification, which in turn leads to significant morbidity and mortality. Despite national and international guidelines for the management of CKD-MBD, the management of mineral dysregulation in CKD can be extremely challenging, and a significant proportion of patients have calcium, phosphate or parathyroid hormone levels outside the normal ranges. Clinical and experimental studies have shown that, in the setting of CKD, low serum calcium levels are associated with poor bone mineralisation, whereas high serum calcium levels can lead to arterial calcification, even in children. The role of calcium in CKD-MBD is the focus of this review. PMID- 25543195 TI - Synthesis and characterization of carboxymethyl cellulose from office waste paper: a greener approach towards waste management. AB - In the present study, functionalization of mixed office waste (MOW) paper has been carried out to synthesize carboxymethyl cellulose, a most widely used product for various applications. MOW was pulped and deinked prior to carboxymethylation. The deinked pulp yield was 80.62 +/- 2.0% with 72.30 +/- 1.50% deinkability factor. The deinked pulp was converted to CMC by alkalization followed by etherification using NaOH and ClCH2COONa respectively, in an alcoholic medium. Maximum degree of substitution (DS) (1.07) of prepared CMC was achieved at 50 degrees C with 0.094 M and 0.108 M concentrations of NaOH and ClCH2COONa respectively for 3h reaction time. The rheological characteristics of 1-3% aqueous solution of optimized CMC product showed the non-Newtonian pseudoplastic behavior. Fourier transform infra red (FTIR), nuclear magnetic resonance (NMR) and scanning electron microscope (SEM) study were used to characterize the CMC product. PMID- 25543197 TI - Commentary from the editor. PMID- 25543196 TI - Mechanosensation circuitry in Caenorhabditis elegans: A focus on gentle touch. AB - Forward or reverse movement in Caenorhabditis elegans is the result of sequential contraction of muscle cells arranged along the body. In larvae, muscle cells are innervated by distinct classes of motorneurons. B motorneurons regulate forward movement and A motorneurons regulate backward movement. Ablation of the D motor neurons results in animals that are uncoordinated in either direction, which suggests that D motorneurons regulate the interaction between the two circuits. C. elegans locomotion is dictated by inputs from interneurons that regulate the activity of motorneurons which coordinate muscle contraction to facilitate forward or backwards movement. As C. elegans moves through the environment, sensory neurons interpret chemical and mechanical information which is relayed to the motor neurons that control locomotory direction. A mechanosensory input known as light nose touch can be simulated in the laboratory by touching the nose of the animal with a human eyebrow hair. The recoil reaction that follows from light nose touch appears to be primarily mediated by glutamate release from the polymodal sensory neuron ASH. Numerous glutamate receptor types are found in different neurons and interneurons which suggest that several pathways may regulate the aversive response. Based on the phenotypes of mutants in which neuropeptide processing is abolished, neuropeptides play a role in circuit regulation. The light touch response is also regulated by transient receptor channel proteins and degenerin/epithelial sodium channels which modulate the activity of sensory neurons involved in the nose touch response. PMID- 25543198 TI - Image-guided radiation therapy for prostate cancer: A computed tomography-based assessment of fiducial marker migration between placement and 7 days. AB - PURPOSE: This study was conducted to determine whether clinically significant fiducial marker migration occurs immediately after prostatic implantation. METHODS AND MATERIALS: One hundred patients with transperineal (n = 39) or transrectal (n = 61) placement of 3 gold fiducial markers underwent computed tomography scans on day 0 (after placement) and day 7 (at radiation planning). Each marker was marked as a point of interest in a treatment planning system. An automated point-based algorithm was then used to coregister the day 0 and day 7 images by matching the markers through rigid translations and rotations. The mean distance between fiducial pairs (d-) was recorded to assess the degree of seed migration. Prostate contours were delineated, and the day 0 prostate volumes were uniformly expanded by 1, 3, and 5 mm. The percentage of the day 7 prostate volume covered by each day 0 prostate with expansion was calculated to assess whether prostate contours, if performed on day 0, would adequately cover the prostate on day 7. RESULTS: The average d- for all patients was 0.78 +/- 0.45 mm; only 1 patient had d- > 2 mm. Placement technique, hormonal therapy, prostate size, and marker distance from the capsule were not associated with d- (P > .05). The mean percentages of day 7 prostate volumes covered by the day 0 prostate plus 1, 3, and 5 mm were 98.3%, 99.8%, and 100%, respectively. With an expansion of 3 mm, 98% of men had >95% of day 0 volume covered; with an expansion of 5 mm, 100% of men had 100% of the day 0 volume covered. CONCLUSIONS: There is minimal change in the relative positions of fiducial markers (average d- < 1.0 mm) 1 week after placement. A 1- to 3-mm expansion would account for the variation in seed position for the vast majority of cases. These results suggest that planning could be performed on the day of implantation without adverse consequence. PMID- 25543199 TI - Prevention of needle displacement in multifraction high-dose-rate prostate brachytherapy: A prospective volumetric analysis and technical considerations. AB - PURPOSE: We conducted a prospective study to evaluate needle displacements between prostate high-dose-rate (HDR) brachytherapy fractions and offer technical recommendations to help prevent displacements from the outset. METHODS AND MATERIALS: Planning computed tomography and verification computed tomography scans were obtained at 1-mm slice thickness and prospectively assessed for interfraction needle movement for each fraction of a 2-fraction HDR prostate boost. For both the planning and verification CTs, distances from each needle tip to the centroid of 3 implanted prostate gold seeds were measured. We determined the mean and range of the displacement distances. RESULTS: Thirty-three consecutive patients (66 fractions, 540 needle-pair positions for a total of 1080 needles) were evaluated for changes in the length between the needle tip and centroid displacement. Overall, only 0.2% of the needles had any change greater than 3.5 mm between the needle tip and centroid. The mean amount of displacement was 0.97 mm, with a standard deviation of 0.76 mm. Among the patients, no fraction had more than 1 needle with a variation greater than 3.0 mm. CONCLUSIONS: Needle displacements in HDR prostate brachytherapy have been reported by numerous institutions using various techniques. We report the first study to demonstrate needle displacement of less than 1 mm on average, and we describe our process of care surrounding the implantation. PMID- 25543200 TI - Nurse-led ED support for residential aged care facility staff: an evaluation study. AB - OBJECTIVES: To evaluate the impact of a nurse-led telephone support service to Residential Aged Care Facilities (RACFs) on a range of measures relating to the transfer of acutely unwell residents to the Emergency Department (ED) of a large tertiary referral hospital in New South Wales, Australia over a 9 month period. METHODS: A pre- and post-intervention design determined the impact of the telephone service, associated clinical guidelines and education. Data from 4 intervention RACFs using the nurse-led telephone service were compared with 8 control RACFs. Data included the older patient's triage category, presenting problem(s), transfer rates from RACFs, ED admissions, and overall hospital length of stay. Interviews and focus groups with staff from RACFs and EDs were conducted to ascertain their experiences. RESULTS: Reduced presentations of older people to the ED from the 4 pilot RACFs occurred. High levels of satisfaction among staff in RACFs were reported. PMID- 25543201 TI - The organizational culture of emergency departments and the effect on care of older adults: a modified scoping study. AB - How does the organizational micro culture in emergency departments (EDs) impact the care of older adults presenting with a complaint or condition perceived as non-acute? This scoping study reviews the literature and maps three levels of ED culture (artifacts, values and beliefs, and assumptions). Findings on the artifact level indicate that EDs are poorly designed for the needs of older adults. Findings on the ED value and belief level indicate that EDs are for urgent cases (not geriatric care), that older adults do not receive the care and respect they should be given, that older adults require too much time, and that the basic nursing needs of older adults are not a priority for ED nurses. Finally, finding on the assumptions level underpinning ED behaviors suggest that older adults do not belong in the ED, most older adults in the ED are not critically ill and therefore can wait, and staff need to be available for acute cases at all times. A systematic review on the effect of ED micro culture on the quality of geriatric care is warranted. PMID- 25543202 TI - A comparison of the cardiometabolic profile of black South Africans with suspected non-alcoholic fatty liver disease (NAFLD) and excessive alcohol use. AB - Excessive alcohol use and non-alcoholic fatty liver disease (NAFLD) are putative cardiovascular disease risk factors. In order to ease the identification of these conditions on primary health care level, we aimed to determine and compare the demographic and cardiometabolic characteristics of excessive alcohol users and those with suspected NAFLD in black South Africans. In the Prospective Urban Rural Epidemiology study (North West Province, South Africa, N = 2021, collected in 2005) we selected 338 participants, namely: 1) alcohol users (N = 143) reporting 'yes' to alcohol intake, with high gamma-glutamyl transferase (GGT) >=80 U/L and a percentage carbohydrate deficient transferrin (%CDT) >=2%; 2) non alcohol users (N = 127) self-reporting 'no' to alcohol intake with GGT <=30 U/L and %CDT <=2%; and 3) NAFLD group (N = 68) who were non-drinkers with GGT levels >=60 U/L and %CDT <= 2%. The demographics indicated that the alcohol users were mostly men (73%) with a body mass index (BMI) of 19.8 (15.2-27.3) kg/m(2), 90% of which were smokers. Systolic blood pressure (SBP) of alcohol users significantly correlated with high-density lipoprotein cholesterol (HDL-C) (beta = 0.24; p = 0.003) and waist circumference (WC) (beta = 0.22; p = 0.006). Non-alcohol users were mostly women (84%) with a BMI of 26.0 (18.0-39.2) kg/m(2) and blood pressure in this group related positively with triglycerides. The NAFLD group were also mostly women (72%) with a comparatively larger WC (p < 0.001) and an adverse metabolic profile (total cholesterol: 5.55 +/- 1.69 mmol/L; glycosylated hemoglobin: 6.03 (4.70-9.40) %). Diastolic blood pressure in the NAFLD group associated positively with WC (beta = 0.27; p = 0.018). We therefore found disparate gender and cardiometabolic profiles of black South Africans with suspected NAFLD and excessive alcohol use. The described profiles may aid health care practitioners in low resource settings when using these crude screening measures of gender, obesity indices (and self-reported alcohol use) to identify individuals at risk. PMID- 25543203 TI - The use of circular external fixators in the management of lower limb trauma in Dublin: a single surgeon's 20-year experience. AB - INTRODUCTION: It has been estimated that approximately 520,000 injury presentations are made to Irish accident and emergency departments each year. Fractures account for 20 % of these injuries. Circular external fixators (frames) have been shown to be a safe and effective method of treatment for long bone fractures where internal fixation is impossible or in-advisable. We present the outcomes of all frames applied at our institution for stabilisation of acute fractures over a 20-year period. METHODS AND METHODS: We retrospectively reviewed a prospectively compiled database of all frames applied in our institution and identified all frames which were applied for acute lower limb trauma. RESULTS: We identified 68 fractures in 63 patients. There were 11 femoral fractures and 57 tibial fractures. All fractures were classified using the AO Classification system, and most fractures were Type C fractures. We used an Ilizarov frame for 53 fractures and a Taylor Spatial Frame for 15 fractures. The mean time in frame was 365 days for a femoral fracture and 230 days for a tibial fracture. There were five tibial non-unions giving an overall union rate of 93 %. Factors associated with non-union included high-energy trauma and cigarette smoking. CONCLUSION: The vast majority of lower limb fractures can be treated using 'conventional' methods. Complex fractures which are not amenable to open reduction and internal fixation or cast immobilisation can be treated in a frame with excellent results. The paucity of published reports regarding the use of frames for complex trauma reflects the under-utilisation of the technique. PMID- 25543204 TI - CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs. AB - CDH13 encodes T-cadherin, a receptor for high molecular weight (HMW) adiponectin and low-density lipoprotein, promoting proliferation and migration of endothelial cells. Genome-wide association studies have mapped multiple variants in CDH13 associated with cardiometabolic traits (CMT) with variable effects across studies. We hypothesized that this heterogeneity might reflect interplay with DNA methylation within the region. Resequencing and EpiTYPERTM assay were applied for the HYPertension in ESTonia/Coronary Artery Disease in Czech (HYPEST/CADCZ; n = 358) samples to identify CDH13 promoter SNPs acting as methylation Quantitative Trait Loci (meQTLs) and to investigate their associations with CMT. In silico data were extracted from genome-wide DNA methylation and genotype datasets of the population-based sample Estonian Genome Center of the University of Tartu (EGCUT; n = 165). HYPEST-CADCZ meta-analysis identified a rare variant rs113460564 as highly significant meQTL for a 134-bp distant CpG site (P = 5.90 * 10(-6); beta = 3.19%). Four common SNPs (rs12443878, rs12444338, rs62040565, rs8060301) exhibited effect on methylation level of up to 3 neighboring CpG sites in both datasets. The strongest association was detected in EGCUT between rs8060301 and cg09415485 (false discovery rate corrected P value = 1.89 * 10(-30)). Simultaneously, rs8060301 showed association with diastolic blood pressure, serum high-density lipoprotein and HMW adiponectin (P < 0.005). Novel strong associations were identified between rare CDH13 promoter meQTLs (minor allele frequency <5%) and HMW adiponectin: rs2239857 (P = 5.50 * 10(-5), beta = -1,841.9 ng/mL) and rs77068073 (P = 2.67 * 10(-4), beta = -2,484.4 ng/mL). Our study shows conclusively that CDH13 promoter harbors meQTLs associated with CMTs. It paves the way to deeper understanding of the interplay between DNA variation and methylation in susceptibility to common diseases. PMID- 25543206 TI - Differences in survival between patients with systemic lupus erythematosus from a public and a private center. PMID- 25543205 TI - Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans. AB - Invasive fungal disease constitutes a growing health burden and development of novel antifungal drugs with high potency and selectivity against new fungal molecular targets are urgently needed. Previously, an aminothiazole derivative, designated as 41F5, was identified in our laboratories as highly active against Histoplasma yeast (MIC50 0.4-0.8 MUM) through phenotypic high-throughput screening of a commercial library of 3600 purine mimicking compounds (Antimicrob. Agents Chemother.2013, 57, 4349). Consequently, 68 analogues of 41F5 were designed and synthesized or obtained from commercial sources and their MIC50s of growth inhibition were evaluated in Histoplasma capsulatum to establish a basic structure-activity-relationship (SAR) for this potentially new class of antifungals. The growth inhibiting potentials of smaller subsets of this library were also evaluated in Cryptococcus neoformans and human hepatocyte HepG2 cells, the latter to obtain selectivity indices (SIs). The results indicate that a thiazole core structure with a naphth-1-ylmethyl group at the 5-position and cyclohexylamide-, cyclohexylmethylamide-, or cyclohexylethylamide substituents at the 2-position caused the highest growth inhibition of Histoplasma yeast with MIC50s of 0.4 MUM. For these analogues, SIs of 92 to >100 indicated generally low host toxicity. Substitution at the 3- and 4-position decreased antifungal activity. Similarities and differences were observed between Histoplasma and Cryptococcus SARs. For Cryptococcus, the naphth-1-ylmethyl substituent at the 5 position and smaller cyclopentylamide- or cyclohexylamide groups at the 2 position were important for activity. In contrast, slightly larger cyclohexylmethyl- and cyclohexylethyl substituents markedly decreased activity. PMID- 25543207 TI - Louping ill virus (LIV) in the Far East. AB - This study focused on finding, culturing, and identifying the biological and genetic characteristics of three louping ill virus (LIV) strains in the south of the Russian Far East. The Primorye-155-77 and Primorye-20-79 virus strains were isolated from Ixodes persulcatus ticks, and the Primorye-185-91 strain was isolated from the blood of a person after a tick bite. According to the hemagglutination and neutralization tests, Primorye-155-77, Primorye-20-79 and Primorye-185-91 had weak reactivity with antibodies in an antiserum against tick borne encephalitis virus. In Primorye-155-77 and Primorye-20-79, the sequences of the 5' ends of the 2456-nucleotide-long viral RNA including the 5' untranslated region (UTR) and genes of the capsid protein, prM protein and envelope E protein were determined. The complete genome sequence of Primorye-185-91 was determined. The E protein gene of the Negishi strain differed from those of three analyzed strains, as there were mutations resulting in the replacement of three amino acids: Ala163Thr, Asp193Asn and Ala313Thr. The homology of Primorye-185-91 to LIV 369/T2 was 97.57 %, and to the Penrith strain, it was 98.36 %. Phylogenetic analysis showed that Primorye-155-77, Primorye-20-79 and Primorye-185-91 are related to LI/A and LI/K strains isolated in England and Scotland and to the Negishi strain; these strains have a common progenitor. Negishi-like strains were represented by one subtype of louping ill virus, i.e. the British subtype (LIV Brit). The possibility is discussed of a single introduction of the virus to the Far Eastern region (Japan and Primorsky Krai) from a single natural locus more than 50 years ago. PMID- 25543209 TI - Lower urinary tract symptoms, erectile dysfunction, and their correlation in men aged 50 years and above: a cross-sectional survey in Beijing, China. AB - BACKGROUND: The aim of this study was to investigate the correlation between incidence of lower urinary tract symptoms and erectile dysfunction in men aged >=50 years. MATERIAL AND METHODS: A cross-sectional study was performed in 1644 men aged >50 years in Beijing. The International Index of Erectile Function (IIEF)-5 and International Prostate Symptom Score were recorded for each patient. Pearson's chi-square test and Spearman correlation coefficients were used to analyze the International Prostate Symptom Scores and lower urinary tract symptoms, and their correlations with erectile dysfunction. RESULTS: The incidence rates of erectile dysfunction among men with mild, moderate, and severe lower urinary tract symptoms were 85.7, 93.7, and 97.9%, respectively. Interestingly, the total IIEF-5 score significantly correlated with the total International Prostate Symptom Score (r=-0.335; P<0.01), obstructive symptoms (r= 0.276; P<0.01), and irritative symptoms (r=-0.326; P<0.01). The correlation between the severity of lower urinary tract symptoms and that of erectile dysfunction was consistently maintained (r=0.304; P<0.01). Age significantly correlated with International Prostate Symptom Score (r=0.388; P<0.01), lower urinary tract symptoms severity (r=0.457; P<0.01), total IIEF-5 score (r=-0.533; P<0.01), and erectile dysfunction severity (r=0.529; P<0.01). CONCLUSIONS: The incidence of lower urinary tract symptoms and erectile dysfunction in aging men increase with age, and the severity of erectile dysfunction is positively correlated with the severity of lower urinary tract symptoms. PMID- 25543208 TI - Prenatal maternal blood triglyceride and fatty acid levels in relation to exposure to di(2-ethylhexyl)phthalate: a cross-sectional study. AB - OBJECTIVES: The hypolipidemic effects of di(2-ethylhexyl)phthalate (DEHP) exposure in humans have not been investigated. And the influences of maternal prenatal DEHP exposure on birth outcomes are not well-known. We aimed to estimate prenatal DEHP exposure in maternal blood, and evaluate its relationships to maternal blood triglyceride (TG) and fatty acid (FA) levels and to birth outcomes. METHODS: We studied 318 mother-newborn pairs residing in Sapporo, Japan. Blood was taken one time during pregnancy for each mother. Maternal and infant characteristics were obtained from medical records and questionnaire survey. We measured DEHP metabolite, mono(2-ethylhexyl) phthalate (MEHP), along with TG and 9 FAs using maternal blood, and analyzed associations of MEHP level with maternal blood TG/FA levels and infant birth dimensions. RESULTS: Maternal blood TG and palmitoleic/oleic acid levels were higher, but stearic/docosahexaenoic acids and MEHP were lower during late pregnancy. Maternal blood MEHP levels inversely correlated with TG and palmitic/palmitoleic/oleic/linoleic/alpha-linolenic acids. After adjustment for confounders, we found that a tenfold increase in blood MEHP levels correlated with a decrease in TG of 25.1 mg/dl [95% confidence interval (CI) 4.8-45.3 mg/dl], and similar relations in palmitic (beta = -581.8; 95 % CI -906.5, 257.0), oleic (beta = -304.2; 95% CI -518.0, -90.5), linoleic (beta = -348.6; 95% CI -510.6, -186.6), and alpha-linolenic (beta = -6.3; 95% CI -9.5, -3.0) acids. However, we observed no correlations between maternal blood MEHP levels and infant birth weight, length, chest circumference, or head circumference. CONCLUSIONS: Ambient DEHP exposure during pregnancy inversely correlated with maternal blood TG and 4 FA levels, but not birth outcomes. PMID- 25543210 TI - [Drug treatment of inpatients with chronic kidney disease in the acute care ward of a Swiss regional hospital]. AB - INTRODUCTION: Optimal drug treatment may slow down the progression of chronic kidney disease (CKD) and reduce the associated complications. We conducted a study to assess the drug treatment of inpatients with CKD at their discharge. METHODS: We retrospectively collected patient data from the electronic medical record of a Swiss regional hospital for two non-consecutive months. Patients were eligible if their glomerular filtration rate at discharge ranged between 15 and 60 mL/min/1.73 m2. Primary outcome was optimal CKD management, defined by drug treatment conforming to the following 3 criteria: (i) appropriate medication dosage relative to kidney function, (ii) absence of contraindicated medication, and (iii) treatment of any comorbidity/complication related to CKD; or alternatively by the recommendation of a kidney-specific follow-up. RESULTS: The primary outcome was achieved by 45.1% of the 71 patients included. A total of 29.6% had at least one inappropriate medication dosage at discharge, 9.9% left with a drug contraindicated in case of CKD, and 73.2% presented at least one untreated comorbidity/complication at discharge. The most common untreated comorbidity was anaemia. A proposition for a specific follow-up was lacking in 39 of the 56 patients discharged with a non-optimal treatment. CONCLUSION: Drug treatment of patients with CKD may be improved in our setting, especially the treatment of comorbidities/complications related to CKD and the specific ambulatory follow-up. PMID- 25543211 TI - Influence of the carbamate fungicide benomyl on the gene expression and activity of aromatase in the human breast carcinoma cell line MCF-7. AB - The carbamate fungicide benomyl reportedly inhibited the growth of the human breast cancer cell line MCF-7 by inducing apoptosis. However, influence of benomyl on the expression and activity of aromatase of MCF-7 cells remains to be examined, since benomyl was identified as an endocrine disruptor. We here confirmed through cell cycle analysis and immunofluorescence staining that benomyl damaged microtubules and caused apoptosis. We also found that benomyl inhibited histone deacetylase (HDAC) 1 and accumulated acetylated histone H3 in MCF-7 cells. Additionally, benomyl enhanced the levels of aromatase protein and mRNA, albeit at high concentrations. It is thus likely that benomyl enhanced the promoter activity of the aromatase gene via acetylation of histone H3 as does the HDAC inhibitor Vorinostat. In conclusion, benomyl remains to be a risk factor as an endocrine disruptor for breast cancer. PMID- 25543212 TI - Digital gene expression profiling (DGE) of cadmium-treated Drosophila melanogaster. AB - Cadmium is highly toxic and can cause oxidative damage, metabolic disorders, and reduced lifespan and fertility in animals. In this study, we investigated the effects of cadmium in Drosophila melanogaster, performing transcriptome analysis by using tag-based digital gene expression (DGE) profiling. Among 1970 candidate genes, 1443 were up-regulated and 527 were down-regulated following cadmium exposure. Using Gene Ontology analysis, we found that cadmium stress affects three processes: transferase activity, stress response, and the cell cycle. Furthermore, we identified five differentially expressed genes (confirmed by real time PCR) involved in all three processes: Ald, Cdc2, skpA, tefu, and Pvr. Pathway analysis revealed that these genes were involved in the cell cycle pathway and fat digestion and absorption pathway. This study reveals the gene expression response to cadmium stress in Drosophila, it provides insights into the mechanisms of this response, and it could contribute to our understanding of cadmium toxicity in humans. PMID- 25543213 TI - RNA-seq based on transcriptome reveals differ genetic expressing in Chlamys farreri exposed to carcinogen PAHs. AB - The effects of a mixture of carcinogen polycyclic aromatic hydrocarbons (BaP, BaA, BbF and CHR) on transcriptional responses in the digestive gland of scallop, Chlamys farreri, were investigated by high-throughput RNA-sequencing (RNA-seq) technologies. In total, 209 and 260 genes were identified as significantly up- or down-regulated, respectively. Functional analysis based on gene ontology (GO) classification system and the Kyoto encyclopedia of genes and genomes (KEGG) database revealed that PAHs significantly altered the expression of genes involved in stress response, detoxication, antioxidation which were extensively discussed. In particular, CYP450 2P1 and QO mRNA expression were found to be up regulated by exposure to PAHs mixture, suggesting that CYP450 2P1 and QO mRNA expression can be a potential marker for prediction of the biological effects of a mixture of PAHs on scallops. PMID- 25543214 TI - Antibiotic prophylaxis by teicoplanin and risk of acute kidney injury in cardiac surgery. AB - OBJECTIVE: To investigate the risk of acute kidney injury (AKI) associated with antibiotic prophylaxis with teicoplanin in cardiac surgery. DESIGN: Observational cohort study. Data were gathered from patient charts and national registers. SETTING: University hospital. PARTICIPANTS: All adult patients who underwent cardiac surgery at the authors' institution between January 1, 2010 and July 31, 2013 were eligible for the study. INTERVENTIONS: The risk for AKI associated with teicoplanin prophylaxis was estimated by multivariate logistic regression. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, AKI, was defined according to the Acute Kidney Injury Network criteria stage 1, as an increase of postoperative serum creatinine by >=26 MUmol/L (>=0.3 mg/dL) or a relative increase of >=50% compared to the preoperative value. The authors included 2,809 patients, and 1,056 (38%) received a combination of teicoplanin and cloxacillin for antibiotic prophylaxis. The remaining 1,753 (62%) patients received only cloxacillin and constituted the control group. AKI occurred in 32% (n = 343) in the teicoplanin group compared to 29% (n = 517) in the control group. There was a significant association between antibiotic prophylaxis with teicoplanin and AKI; multivariate adjusted odds ratio (OR): 1.41 (95% confidence interval [CI] 1.18 1.70). There was a dose-dependent relationship; 600 mg OR: 1.48 (95% CI 1.17 1.87), and 400 mg OR: 1.34 (95% CI 1.06-1.71). The findings were confirmed in several subgroup analyses; men (OR: 1.27; 95% CI 1.03-1.56); women (OR: 1.90; 95% CI 1.30-2.80); normal renal function (OR: 1.31; 95% CI 1.07-1.60), and reduced renal function (OR: 1.80; 95% CI 1.13-2.85). CONCLUSIONS: Antibiotic prophylaxis with teicoplanin was associated with an increased risk of AKI after cardiac surgery. The relative risk of AKI was higher in women and in patients with impaired renal function. PMID- 25543215 TI - Echocardiographic Evaluation of LVAD Flow During Intra-Aortic Balloon Pump Support. PMID- 25543216 TI - Use of a McGrath Videolaryngoscope to assist transesophageal echocardiography probe insertion in anesthetized patients. PMID- 25543217 TI - Venoarterial extracorporeal membrane oxygenation for cardiogenic shock and cardiac arrest: a meta-analysis. AB - OBJECTIVE: To evaluate the effect of extracorporeal membrane oxygenation (ECMO) on survival and complication rates in adults with refractory cardiogenic shock or cardiac arrest. DESIGN: Meta-analysis. SETTING: University hospitals. PARTICIPANTS: One thousand one hundred ninety-nine patients from 22 observational studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Observational studies published from the year 2000 onwards, examining at least 10 adult patients who received ECMO for refractory cardiogenic shock or cardiac arrest were included. Pooled estimates with 95% confidence intervals were calculated based on the Freeman-Tukey double-arcsine transformation and DerSimonian-Laird random-effect model. Survival to discharge was 40.2% (95% confidence intervals [CI], 33.9-46.7), while survival at 3, 6, and 12 months was 55.9% (95% CI, 41.5 69.8), 47.6% (95% CI, 25.4-70.2), and 54.4% (95% CI, 36.6-71.7), respectively. Survival up to 30 days was higher in cardiogenic shock patients (52.5%, 95% CI, 43.7%-61.2%) compared to cardiac arrest (36.2%, 95% CI, 23.1%-50.4%). Concurrently, complication rates were particularly substantial for neurologic deficits (13.3%, 95% CI, 8.3-19.3), infection (25.1%, 95%CI, 15.9-35.5), and renal impairment (47.4%, 95% CI, 30.2-64.9). Significant heterogeneity was detected, although its levels were similar to previous meta-analyses that only examined short-term survival to discharge. CONCLUSIONS: Venoarterial ECMO can improve short-term survival in adults with refractory cardiogenic shock or cardiac arrest. It also may provide favorable long-term survival at up to 3 years postdischarge. However, ECMO also is associated with significant complication rates, which must be incorporated into the risk-benefit analysis when considering treatment. These findings require confirmation by large, adequately controlled and standardized trials with long-term follow-up. PMID- 25543218 TI - Low Concentration of Dezocine in Combination With Morphine Enhance the Postoperative Analgesia for Thoracotomy. AB - OBJECTIVE: When morphine and dezocine are mixed together, the clinical interactions with analgesic effects and adverse events remain unknown. The authors aimed to investigate the efficacy of low concentrations of dezocine in combination with morphine for postoperative pain. DESIGN: A prospective, randomized, double-blinded clinical trial. SETTING: Cancer Institute and Hospital, National Cancer Center, China. PARTICIPANTS: Sixty patients undergoing thoracotomy were randomized into 3 groups to investigate the analgesic efficacy of different ratios of morphine and dezocine. INTERVENTIONS: The morphine group (Group M) received morphine (1 mg/mL) alone for patient-controlled analgesia (PCA); the morphine+dezocine 1 group (Group MD1) received morphine (1 mg/mL) combined with dezocine (0.05 mg/mL) at a ratio of 20:1 for PCA; the morphine+dezocine 2 group (Group MD2) received morphine (1 mg/mL) combined with dezocine (0.1 mg/mL) at a ratio of 10:1 for PCA. Cumulative morphine consumption, verbal rating scores (VRS), and adverse events were evaluated throughout a 48 hour postoperative period. MEASUREMENTS AND MAIN RESULTS: Cumulative morphine requirements were (1) statistically higher in Group M than in Group MD2 at 24 and 48 hours after surgery and (2) statistically higher in Group M than Group MD1 at 48 hours after surgery. Postoperative VRS for evaluating pain were similar among the 3 groups. The incidence of postoperative nausea and pruritus was statistically higher in Group M than in Groups MD1 and MD2. The incidence of dizziness was not significantly different among groups. CONCLUSIONS: The combination of morphine and dezocine at the concentrations [morphine (mg/mL)]/[dezocine (mg/mL)] of 1/0.05 (ratio 20:1) and 1/0.1 (ratio 10:1) may enhance postoperative analgesia after thoracotomy. PMID- 25543219 TI - [Reply]. PMID- 25543220 TI - [Clinical significance of molecular analysis of the chromosomal cassette SCCmecA in methicillin-resistant strains of Staphylococcus aureus]. PMID- 25543221 TI - Pulmonary arterial hypertension and portal hypertension in a patient with hereditary hemorrhagic telangiectasia. AB - BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare disease that could be inherited with an autosomal dominant pattern. Mutations in BMPR2 gene are described in over 70% of cases, although other genes are involved in lesser extend in PAH. Hereditary hemorrhagic telangiectasia (HHT) is another rare autosomal dominant disease. PAH is a rare complication of HHT that occurs in less than 1% of cases. Liver cirrhosis with portal hypertension is also associated with the presence of PAHs in 1-2% of cases. PATIENTS: We present here a patient with HHT who developed PAH shortly after showing portal hypertension. RESULTS: Some genes (BMPR2, ACVRL1, ENG) seem to play an important role in PAH pathogenesis. We analyzed these genes, detecting mutations in BMPR2 gene (c.1021G>A (V341L), c.327G>A (p.Q109Q)), ACVRL1 (c.313+20C>A, c.1502+7A>G) and ENG (c.498G>A (Q166Q)). The patient also had 3 polymorphisms in the TRPC6 gene (c.1-361A>T, c.1-254C>G, c.1-218C>T). CONCLUSIONS: The study of these genes will help us to identify and track individuals susceptible for developing PAH associated with other diseases. PMID- 25543222 TI - [Lower doses of tolvaptan in hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion]. PMID- 25543223 TI - [Vaccinal calendar]. PMID- 25543224 TI - [Pruriginous lesion in the corner of the mouth]. PMID- 25543226 TI - [Worldwide variations over the years in etiology of iliopsoas abscess. Reality or a selection bias?]. PMID- 25543225 TI - [Homozygous familial hypercholesterolemia. First case in Spain treated with lomitapide, an inhibitor of the synthesis of lipoproteins with apolipoprotein B]. PMID- 25543227 TI - [Miliary tuberculosis with pulmonary, meningeal and bone involvement]. PMID- 25543228 TI - [Hospital admission: An opportunity for diabetes screening]. PMID- 25543229 TI - [A neonate with aprosopia, monomelia and celosomy]. AB - The specimen of which it is a matter here takes part of the heritage of the Museum of Anatomy and Embryology of the Faculty of Medicine of the Universite Libre de Bruxelles. Its medical history is completely unknown, because it takes part of an ancient collection of pathological anatomy saved from destruction and recovered by the laboratory of Anatomy and Embryology. The specimen is strongly folded up on itself ("in extension"), its length so arranged is about 25 cm; unfolded, it develops to 45 cm. Cranial perimeter is of 31 cm. Unfortunately, the brain was removed during the initial analysis, and only the examination of the braincase allows to draw some conclusions on the probable state of the encephalon. The face is rudimentary, without any orbit, and the oral cavity is limited to a vertical slit, revealing small strongly tipped up maxillary bones. A double proboscis is present. The trunk is characterised by a rather broad celosomy, with exhibition of the intestines, the liver and the pancreas. Anal atresia is observed, and the external sexual organs are hypoplastic and ambiguous. The whole left lower limb is absent, including the left half of the pelvis, corresponding to a left unilateral complete ectromelia. The neck is in hyperextension, so that the occipital region seems extremely welded in the cervical spine. However, CT examination does not confirm the presence of such fusion, but on the other hand, reveals a severe axial diversion of the spine with hyperextension. Extremely rare in humans, the aprosopia is more readily present in some animals (sheep). Its association with a monomelia and a celosomy seems not yet described. PMID- 25543230 TI - [Alfred-Louis-Dominique Richet (1816-1891): education, anatomy and surgery]. AB - Alfred-Louis-Dominique Richet was an anatomist and surgeon born in Dijon, France in 1816. He defended the teaching of clinical anatomy instead of descriptive anatomy, judged inappropriate to learn operative medicine. His name is associated with several anatomical structures that we cite in the present article. PMID- 25543231 TI - Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. AB - Nonreplicating and metabolically quiescent bacteria are implicated in latent tuberculosis infections and relapses following "sterilizing" chemotherapy. However, evidence linking bacterial dormancy and persistence in vivo is largely inconclusive. Here we measure the single-cell dynamics of Mycobacterium tuberculosis replication and ribosomal activity using quantitative time-lapse microscopy and a reporter of ribosomal RNA gene expression. Single-cell dynamics exhibit heterogeneity under standard growth conditions, which is amplified by stressful conditions such as nutrient limitation, stationary phase, intracellular replication, and growth in mouse lungs. Additionally, the lungs of chronically infected mice harbor a subpopulation of nongrowing but metabolically active bacteria, which are absent in mice lacking interferon-gamma, a cytokine essential for antituberculosis immunity. These cryptic bacterial forms are prominent in mice treated with the antituberculosis drug isoniazid, suggesting a role in postchemotherapeutic relapses. Thus, amplification of bacterial phenotypic heterogeneity in response to host immunity and drug pressure may contribute to tuberculosis persistence. PMID- 25543232 TI - Risk factors for acute compartment syndrome of the leg associated with tibial diaphyseal fractures in adults. AB - BACKGROUND: We sought to examine the occurrence of acute compartment syndrome (ACS) in the cohort of patients with tibial diaphyseal fractures and to detect associated risk factors that could predict this occurrence. MATERIALS AND METHODS: A total of 1,125 patients with tibial diaphyseal fractures that were treated in our centre were included into this retrospective cohort study. All patients were treated with surgical fixation. Among them some were complicated by ACS of the leg. Age, gender, year and mechanism of injury, injury severity score (ISS), fracture characteristics and classifications and the type of fixation, as well as ACS characteristics in affected patients were studied. RESULTS: Of the cohort of patients 772 (69 %) were male (mean age 39.60 +/- 15.97 years) and the rest were women (mean age 45.08 +/- 19.04 years). ACS of the leg occurred in 87 (7.73 %) of all tibial diaphyseal fractures. The mean age of those patients that developed ACS (33.08 +/- 12.8) was significantly lower than those who did not develop it (42.01 +/- 17.3, P < 0.001). No significant difference in incidence of ACS was found in open versus closed fractures, between anatomic sites and following IM nailing (P = 0.67). Increasing pain was the most common symptom in 71 % of cases with ACS. CONCLUSIONS: We found that younger patients are definitely at a significantly higher risk of ACS following acute tibial diaphyseal fractures. Male gender, open fracture and IM nailing were not risk factors for ACS of the leg associated with tibial diaphyseal fractures in adults. LEVEL OF EVIDENCE: Level IV. PMID- 25543234 TI - Interacting personalities: behavioural ecology meets quantitative genetics. AB - Behavioural ecologists increasingly study behavioural variation within and among individuals in conjunction, thereby integrating research on phenotypic plasticity and animal personality within a single adaptive framework. Interactions between individuals (cf. social environments) constitute a major causative factor of behavioural variation at both of these hierarchical levels. Social interactions give rise to complex 'interactive phenotypes' and group-level emergent properties. This type of phenotype has intriguing evolutionary implications, warranting a cohesive framework for its study. We detail here how a reaction-norm framework might be applied to usefully integrate social environment theory developed in behavioural ecology and quantitative genetics. The proposed emergent framework facilitates firm integration of social environments in adaptive research on phenotypic characters that vary within and among individuals. PMID- 25543233 TI - Effect of PNPLA3 rs738409 variant (I148 M) on hepatic steatosis, necroinflammation, and fibrosis in Japanese patients with chronic hepatitis C. AB - BACKGROUND: Host genetic factors have been suspected to influence histological liver damage in chronic liver disease. The nonsynonymous single-nucleotide polymorphism rs738409 C > G in the patatin-like phospholipase domain-containing 3 gene (PNPLA3, also known as adiponutrin), encoding the I148 M protein variant, has been identified as a novel genetic marker for hepatic steatosis and fibrosis in nonalcoholic fatty liver disease and alcoholic liver disease. We aimed to determine whether the PNPLA3 rs738409 variant was associated with hepatic steatosis, necroinflammation, and fibrosis in Japanese patients with chronic hepatitis C. METHODS: In a cross-sectional study in Japan, we analyzed 276 patients with chronic hepatitis C who underwent liver biopsy. Genotyping for rs738409 was performed using the TaqMan genotyping assay. RESULTS: The frequencies of the rs738409 CC, CG, and GG genotypes were 32.6, 46.4, and 21.0 %, respectively. Multivariate analysis revealed that the GG genotype was independently associated with the presence of steatosis [odds ratio (OR) 2.58, 95 % confidence interval (CI) 1.37-4.84, p = 0.003], severe necroinflammatory activity (OR 2.16, 95 % CI 1.12-4.16, p = 0.02), and advanced fibrosis (OR 2.10, 95 % CI 1.07-4.11, p = 0.03), after adjustment for age, sex, body mass index, and diabetes. CONCLUSIONS: The PNPLA3 rs738409 variant influences histological liver damage in Japanese patients with chronic hepatitis C. The G allele homozygotes are at higher risk for hepatic steatosis, severe necroinflammation, and advanced fibrosis. PMID- 25543236 TI - Safety of early enrollment into outpatient cardiac rehabilitation after open heart surgery. AB - The safety of early enrollment (<2 weeks after hospital discharge) into cardiac rehabilitation (CR) after recent coronary artery bypass graft (CABG) surgery or heart valve surgery (HVS) has not previously been assessed and has important policy implications. Consequently, we performed a detailed review of all clinical adverse events within 6 months of hospital discharge. We compared early and late attendees for patients undergoing CABG surgery or HVS and included patients with myocardial infarction (MI) as an additional control group. We analyzed 112 patients undergoing CABG surgery, 69 patients undergoing HVS, and 59 patients with MI. Median time (interquartile range) from hospital discharge to CR enrollment was 10.5 (8 to 15), 12 (8.5 to 21), and 9 days (7 to 14), respectively. There was no difference in major event rates between early and late enrollees (17% vs 17%, respectively, log-rank p = 0.98) or by diagnosis (15%, 16%, and 22% for CABG surgery, HVS, and MI, respectively; log-rank p = 0.50). Sternal instability and wound infection rates were similar. CR-related adverse events trended toward increased event rates in surgical and early enrollees, but of 44 events, only 3 were exercise related, none resulted in permanent harm, and 41 (93%) were managed in CR without need for emergency services. In conclusion, it appears that a policy of encouraging early enrollment into CR in patients with a recent open heart surgery seems unlikely to harm patients when careful individualized assessment and exercise prescription take place within the bounds of an established CR program. PMID- 25543235 TI - Comparison of outcomes of balloon aortic valvuloplasty plus percutaneous coronary intervention versus percutaneous aortic balloon valvuloplasty alone during the same hospitalization in the United States. AB - The use of percutaneous aortic balloon balvotomy (PABV) in high surgical risk patients has resurged because of development of less invasive endovascular therapies. We compared outcomes of concomitant PABV and percutaneous coronary intervention (PCI) with PABV alone during same hospitalization using nation's largest hospitalization database. We identified patients and determined time trends using the International Classification of Diseases, Ninth Revision, Clinical Modification, procedure code for valvulotomy from Nationwide Inpatient Sample database 1998 to 2010. Only patients >60 years with aortic stenosis were included. Primary outcome included in-hospital mortality, and secondary outcomes included procedural complications, length of stay (LOS), and cost of hospitalization. Total 2,127 PABV procedures were identified, with 247 in PABV + PCI group and 1,880 in the PABV group. Utilization rate of concomitant PABV + PCI during same hospitalization increased by 225% from 5.1% in 1998 to 1999 to 16.6% in 2009 to 2010 (p <0.001). Overall in-hospital mortality rate and complication rates in PABV + PCI group were similar to that of PABV group (10.3% vs 10.5% and 23.4% vs 24.7%, respectively). PABV + PCI group had similar LOS but higher hospitalization cost (median [interquartile range] $30,089 [$21,925 to $48,267] versus $18,421 [$11,482 to $32,215], p <0.001) in comparison with the PABV group. Unstable condition, occurrence of any complication, and weekend admission were the main predictors of increased LOS and cost of hospital admission. Concomitant PCI and PABV during the same hospitalization are not associated with change in in hospital mortality, complications rate, or LOS compared with PABV alone; however, it increases the cost of hospitalization. PMID- 25543237 TI - Pseudo-first-order reaction of chemically and biologically formed green rusts with HgII and C15H15N3O2: effects of pH and stabilizing agents (phosphate, silicate, polyacrylic acid, and bacterial cells). AB - The kinetics of Hg(II) and methyl red (MR) reduction by hydroxycarbonate green rust (GR1) and by hydroxysulfate green rust (GR2) were studied in the presence of naturally occurring organic and inorganic ligands (phosphate, polyacrylic acid, bacterial cells, silicate). The reducing ability of biogenic hydroxycarbonate green rust (GR1bio), obtained after microbial reduction of lepidocrocite by Shewanella putrefaciens, was also investigated and compared to those of chemically synthesized GR1 and GR2 (GR1ab and GR2ab). Pseudo first-order rate constants (kobs) of Hg(II) reduction (at pH 7.0, 8.2, and 9.5) and MR reduction (at pH 7.0) were determined and were normalized to the structural Fe(II) content of GRs (kFeII) and to the estimated concentration of surface Fe(II) sites (kS). The kS values ranged from 0.3 L mmol(-1) min(-1) to 43 L mmol(-1) min(-1) for the Hg reduction, and from 0.007 L mmol(-1) min(-1) to 3.4 L mmol(-1) min(-1) for the MR reduction. No significant discrepancy between GRab and GRbio was observed in term of reactivity. However, the reduction kinetics of MR was generally slower than the Hg(II) reduction kinetics for all tested GRs. While a slight difference in Hg(II) reduction rate was noted whatever the pH values (7.0, 8.2, or 9.5), the reduction of MR was significantly affected in the presence of ligands. A decrease by a factor of 2-200, depending on the type of ligand used, was observed. These data give new insights into the reactivity of GRs in the presence of co-occurring organic and inorganic ligands, and have major implications in the characterization of contaminated systems as well as water treatment processes. PMID- 25543238 TI - A novel and simple treatment for control of sulfide induced sewer concrete corrosion using free nitrous acid. AB - Improved technologies are currently required for mitigating microbially induced concrete corrosion caused by the oxidation of sulfide to sulfuric acid in sewer systems. This study presents a novel strategy for reducing H2S oxidation on concrete surfaces that accommodate an active corrosion biofilm. The strategy aims to reduce biological oxidation of sulfide through treating the corrosion biofilm with free nitrous acid (FNA, i.e. HNO2). Two concrete coupons with active corrosion activity and surface pH of 3.8 +/- 0.3 and 2.7 +/- 0.2 were sprayed with nitrite. For both coupons, the H2S uptake rates were reduced by 84%-92% 15 days after the nitrite spray. No obvious recovery of the H2S uptake rate was observed during the entire experimental period (up to 12 months after the spray), indicating the long-term effectiveness of the FNA treatment in controlling the activity of the corrosion-causing biofilms. Live/Dead staining tests on the microorganisms on the concrete coupon surfaces demonstrated that viable bacterial cells decreased by > 80% 39 h after the nitrite spray, suggesting that biofilm cells were killed by the treatment. Examination of a corrosion layer within a suspended solution, containing the corrosion-causing biofilms, indicated that biological activity (ATP level and ratio of viable bacterial cells) was severely decreased by the treatment, confirming the bactericidal effect of FNA on the microorganisms in the biofilms. While field trials are still required to verify its effectiveness, it has been demonstrated here that the FNA spray is potentially a very cheap and effective strategy to reduce sewer corrosion. PMID- 25543239 TI - Degradation of aqueous and soil-sorbed estradiol using a new class of stabilized manganese oxide nanoparticles. AB - Manganese oxide (MnO2) was reported to be effective for degrading aqueous pharmaceutical chemicals. However, little is known about its potential use for degrading soil-sorbed contaminants. To bridge this knowledge gap, we synthesized, for the first time, a class of stabilized MnO2 nanoparticles using carboxymethyl celluloses (CMC) as a stabilizer, and tested their effectiveness for degrading aqueous and soil-sorbed estradiol. The most desired particles (highest reactivity and soil deliverability) were obtained at a CMC/MnO2 molar ratio of 1.39 * 10( 3), which yielded a mean hydrodynamic size of 39.5 nm and a narrow size distribution (SD = 0.8 nm). While non-stabilized MnO2 particles rapidly aggregated and were not transportable through a soil column, CMC-stabilized nanoparticles remained fully dispersed in water and were soil deliverable. At typical aquatic pH (6-7), CMC-stabilized MnO2 exhibited faster degradation kinetics for oxidation of 17beta-estradiol than non-stabilized MnO2. The reactivity advantage becomes more evident when used for treating soil-sorbed estradiol owing to the ability of CMC to complex with metal ions and prevent the reactive sites from binding with inhibitive soil components. A retarded first order rate model was able to interpret the oxidation kinetics for CMC-stabilized MnO2. When used for degrading soil-sorbed estradiol, several factors may inhibit the oxidation effectiveness, including desorption rate, soil-MnO2 interactions, and soil-released metals and reductants. CMC-stabilized MnO2 nanoparticles hold the potential for facilitating in situ oxidative degradation of various emerging contaminants in soil and groundwater. PMID- 25543240 TI - Improved method for measuring transparent exopolymer particles (TEP) and their precursors in fresh and saline water. AB - Transparent exopolymer particles (TEP) and their precursors produced by phyto /bacterio-planktons in fresh and marine aquatic environments are increasingly considered as a major contributor to organic/particulate and biological fouling in micro-/ultra-filtration and reverse osmosis membrane (RO) systems. However, currently established methods which are based on Alcian blue (AB) staining and spectrophotometric techniques do not measure TEP-precursors and have the tendency to overestimate concentration in brackish/saline water samples due to interference of salinity on AB staining. Here we propose a new semi-quantitative method which allows measurement of both TEP and their colloidal precursors without the interference of salinity. TEP and their precursors are first retained on 10 kDa membrane, rinsed with ultra-pure water, and re-suspended in ultra-pure water by sonication and stained with AB, followed by exclusion of TEP-AB precipitates by filtration and absorbance measurement of residual AB. The concentration is then determined based on the reduction of AB absorbance due to reaction with acidic polysaccharides, blank correction and calibration with Xanthan gum standard. The extraction procedure allows concentration of TEP and their pre-cursors which makes it possible to analyse samples with a wide range of concentrations (down to <0.1 mg Xeq/L). This was demonstrated through application of the method for monitoring these compounds in algal cultures and a full-scale RO plant. The monitoring also revealed that concentrations of the colloidal precursors were substantially higher than the concentration of TEP themselves. In the RO plant, complete TEP removal was observed over the pre-treatment processes (coagulation-sedimentation-filtration and ultrafiltration) but the TEP precursors were not completely removed, emphasising the importance of measuring this colloidal component to better understand the role of TEP and acidic polysaccharides in RO membrane fouling. PMID- 25543241 TI - Distribution of platinum and other traffic related metals in sediments and clams (Corbicula sp.). AB - Platinum is part of traffic-emitted metals since the introduction of automotive catalyst converters. Still, automobile emissions are one of the major sources for metals in European river systems. However, field data on Pt is scarce and there is a lack of knowledge concerning the distribution and biological availability of Pt. Therefore, the distribution of traffic related metals (Cd, Cr, Cu, Ni, Pb, Pt, and Zn) was analyzed in sediment samples and in the Asian clam Corbicula sp. Samples were taken from three transects following road runoff inlets. Pt was introduced into the river by road runoff. The highest Pt concentrations in sediments were analyzed in the silt/clay fraction (45 ng/g), while the highest total Pt burden was obtained for the sand fraction, that makes up more than 60% of the sediment. Metal concentrations were related to the area of the drained street section as well as to their distance from the discharge point, and to grain size distribution within the sediment. Pt and other traffic related metals were accumulated by clams. Due to the feeding behavior of the freshwater mussel Corbicula sp. Pt concentrations in the soft tissue remain relatively low (max Pt concentration: 1.3 ng/g freeze dried soft tissue) and acute lethal or toxic effects therefore appear to be unlikely. Nonetheless, chronic exposure effects still have to be examined. PMID- 25543242 TI - Benthic community recovery from brine impact after the implementation of mitigation measures. AB - In many regions, seawater desalination is a growing industry that has its impact on benthic communities. This study analyses the effect on benthic communities of a mitigation measure applied to a brine discharge, using polychaete assemblages as indicator. An eight-year study was conducted at San Pedro del Pinatar (SE Spain) establishing a grid of 12 sites at a depth range of 29-38 m during autumn. Brine discharge started in 2006 and produced a significant decrease in abundance, richness and diversity of polychaete families at the location closest to the discharge, where salinity reached 49. In 2010, a diffuser was deployed at the end of the pipeline in order to increase the mixing, to reduce the impact on benthic communities. After implementation of this mitigation measure, the salinity measured close to discharge was less than 38.5 and a significant recovery in polychaete richness and diversity was detected, to levels similar to those before the discharge. A less evident recovery in abundance was also observed, probably due to different recovery rates of polychaete families. Some families like Paraonidae and Magelonidae were more tolerant to this impact. Others like Syllidae and Capitellidae recovered quickly, although still affected by the discharge, while some families such as Sabellidae and Cirratulidae appeared to recover more slowly. PMID- 25543243 TI - Droplet digital PCR for simultaneous quantification of general and human associated fecal indicators for water quality assessment. AB - Despite wide application to beach water monitoring and microbial source identification, results produced by quantitative PCR (qPCR) methods are subject to bias introduced by reliance on quantitative standards. Digital PCR technology provides direct, standards-free quantification and may potentially alleviate or greatly reduce other qPCR limitations such as difficulty in multiplexing and susceptibility to PCR inhibition. This study examined the efficacy of employing a duplex droplet digital PCR (ddPCR) assay that simultaneously quantifies Enterococcus spp. and the human fecal-associated HF183 marker for water quality assessment. Duplex ddPCR performance was evaluated side-by-side with qPCR and simplex ddPCR using reference material and 131 fecal and water samples. Results for fecal and water samples were highly correlated between ddPCR and simplex qPCR (coefficients > 0.93, p < 0.001). Duplexing Enterococcus and HF183 in qPCR led to competition and resulted in non-detection or underestimation of the target with low concentration relative to the other, while results produced by simplex and duplex ddPCR were consistent and often indistinguishable from one another. ddPCR showed greater tolerance for inhibition, with no discernable effect on quantification at inhibitor concentrations one to two orders of magnitude higher than that tolerated by qPCR. Overall, ddPCR also exhibited improved precision, higher run-to-run repeatability, similar diagnostic sensitivity and specificity on the HF183 marker, but a lower upper limit of quantification than qPCR. Digital PCR has the potential to become a reliable and economical alternative to qPCR for recreational water monitoring and fecal source identification. Findings from this study may also be of interest to other aspects of water research such as detection of pathogens and antibiotic resistance genes. PMID- 25543244 TI - Sulfide and methane production in sewer sediments. AB - Recent studies have demonstrated significant sulfide and methane production by sewer biofilms, particularly in rising mains. Sewer sediments in gravity sewers are also biologically active; however, their contribution to biological transformations in sewers is poorly understood at present. In this study, sediments collected from a gravity sewer were cultivated in a laboratory reactor fed with real wastewater for more than one year to obtain intact sediments. Batch test results show significant sulfide production with an average rate of 9.20 +/- 0.39 g S/m(2).d from the sediments, which is significantly higher than the areal rate of sewer biofilms. In contrast, the average methane production rate is 1.56 +/- 0.14 g CH4/m(2).d at 20 degrees C, which is comparable to the areal rate of sewer biofilms. These results clearly show that the contributions of sewer sediments to sulfide and methane production cannot be ignored when evaluating sewer emissions. Microsensor and pore water measurements of sulfide, sulfate and methane in the sediments, microbial profiling along the depth of the sediments and mathematical modelling reveal that sulfide production takes place near the sediment surface due to the limited penetration of sulfate. In comparison, methane production occurs in a much deeper zone below the surface likely due to the better penetration of soluble organic carbon. Modelling results illustrate the dependency of sulfide and methane productions on the bulk sulfate and soluble organic carbon concentrations can be well described with half-order kinetics. PMID- 25543245 TI - Assessing outcomes in individuals undergoing fasciotomy for chronic exertional compartment syndrome of the leg. AB - PURPOSE: The purposes of this study were to evaluate patient-reported outcomes after fasciotomy of the leg for chronic exertional compartment syndrome (CECS) and to determine the rate at which revision surgery was required and the prognostic value of intracompartmental pressure (ICP) testing. METHODS: This was a retrospective consecutive case series of patients with CECS who underwent preoperative ICP testing and surgical fasciotomy for treatment of CECS of the leg between September 2001 and January 2012. RESULTS: Of 69 eligible patients, 46 were evaluated at a mean follow-up time of 54.9 months (range, 3.9 to 127.3 months). Forty-two patients met the Pedowitz criteria for CECS diagnosis. Mean score on the Lower Extremity Functional Scale (LEFS) was 70.4 (standard deviation [SD] +/- 11.2) at follow-up and 72.3 (SD +/- 11.2) at the patient-perceived time of best outcome. Best outcome was reported at a mean time of 14.3 months (range, 0.5 to 84 months). Five of 46 (11%) patients required a revision fasciotomy. Thirty-six of 46 (78%) patients reported being either satisfied (n = 14) or very satisfied (n = 22) at follow-up. The Pedowitz criteria were highly sensitive (97%) but not specific (10%) and had a positive predictive value (PPV) of 79%. CONCLUSIONS: Functional outcomes after fasciotomy for CECS were favorable. ICP testing was shown to be sensitive but not specific. Revision surgery was required for 5 of the 46 patients (11%). Patient satisfaction rates, return to sport, return to preoperative activity levels, and LEFS scores were all high. This case series confirms that fasciotomy is a safe and effective surgical treatment for CECS. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25543246 TI - Surgical Treatment Options for Glenohumeral Arthritis in Young Patients: A Systematic Review and Meta-analysis. AB - PURPOSE: The aim of this study was to compare surgical treatment options for young patients with glenohumeral arthritis. METHODS: A systematic review of the English-language literature was conducted by searching PubMed, EMBASE, and Scopus with the following term: "(shoulder OR glenohumeral) AND (arthritis OR osteoarthritis) AND (young OR younger)." Studies that reported clinical or radiological outcomes of nonbiologic surgical treatment of generalized glenohumeral arthritis in patients younger than 60 years of age were included. Data were extracted to include study and patient characteristics, surgical technique, outcome scores, pain relief, satisfaction, functional improvement, return to activity, health-related quality of life, complications, need for and time to revision, range of motion, and radiological outcomes. Study quality was assessed with the Modified Coleman Methodology Score. RESULTS: Thirty-two studies containing a total of 1,229 shoulders met the inclusion criteria and were included in the review. Pain scores improved significantly more after total shoulder arthroplasty (TSA) than after hemiarthroplasty (HA) (P < .001). Patient satisfaction was similar after HA and TSA. Revision surgery was equally likely after HA, TSA, and arthroscopic debridement (AD). Complications were significantly less common after AD than after HA (P = .0049) and TSA (P < .001). AD and TSA afforded better recovery of active forward flexion and external rotation than did HA. At radiological follow-up, subluxation was similarly common after HA and TSA. CONCLUSIONS: According to current Level IV data, TSA provides greater improvement of pain and range of motion than does HA in the surgical treatment of young patients with glenohumeral arthritis. AD is an efficacious and particularly safe alternative in the short term for young patients with concerns about arthroplasty. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 25543247 TI - How much arthritis is too much for hip arthroscopy: a systematic review. AB - PURPOSE: The purpose of this study was to determine the extent of preoperative osteoarthritis (OA) that precludes benefit from hip arthroscopy by systematically reviewing the literature on hip arthroscopy in the setting of OA. METHODS: We searched the Medline and PubMed databases using the following Medical Subject Heading terms: arthritis, osteoarthritis, chondral damage, chondral injury, chondral delamination, and hip arthroscopy. Two authors independently reviewed the literature and included articles if they were in the English language; commented on preoperative factors, parameters, physical examination, or diagnostic testing that may be evidence of cartilage damage and/or arthritis; contained outcome data on patients undergoing hip arthroscopy; and had a sample size of at least 10 patients with arthritic changes in the hip. We excluded review articles, technique articles, articles with overlapping patient populations, articles with hip arthroscopy used as an adjunct to an open procedure, articles with inflammatory and septic arthritis, and articles with a mean age younger than 18 years. RESULTS: Our search identified 518 articles, of which 15 met the inclusion and exclusion criteria. Two thousand fifty-one hips underwent arthroscopy at a mean patient age of 40.2 years. Of these, 1,195 hips had signs of OA. There were 345 conversions to total hip arthroplasty/surface replacement arthroplasty. Of these patients, 274 had OA. Eight patient-reported outcome instruments were used. Factors influencing outcomes were preoperative OA, age, chondral damage, femoroacetabular impingement, and duration of symptoms. CONCLUSIONS: Current evidence is insufficient to define a cutoff for how much arthritis is too much for hip arthroscopy. However, this analysis shows that patients with a Tonnis grade of 1 or greater or a joint space of 2 mm or less are less likely to benefit from hip arthroscopy and more likely to require conversion to total hip arthroplasty/surface replacement arthroplasty. Postoperative scores on patient-reported outcome instruments are lower in the arthritic population at follow-up compared with their nonarthritic counterparts. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 25543248 TI - Arthroscopic treatment of posterior shoulder instability: a systematic review. AB - PURPOSE: We performed a systematic review of the literature to determine the early and midterm outcomes of arthroscopic stabilization for posterior shoulder instability. METHODS: We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for related articles published in the English language. The 2 authors selected studies for inclusion or exclusion. The inclusion criteria included a minimum of 1 year of follow-up, with at least 20 patients in the study population. RESULTS: We included 6 studies, with a total of 387 patients (396 shoulders). All studies were retrospective, Level IV studies, except for 1 prospective study (Level II). In 81.06% of cases, patients reported a significant traumatic episode. The mean follow-up period was 44.4 months, and the mean recurrence rate was 5.37%. Most of the patients were able to return to sport (mean, 92.5%). CONCLUSIONS: The early and midterm results of arthroscopic stabilization of the shoulder for posterior instability are promising. Most of the patients were satisfied with the results of surgery and were able to return to sport. Larger studies and more prospective randomized trials are needed to confirm these findings. LEVEL OF EVIDENCE: Level IV, systematic review of 1 Level II study and 5 Level IV studies. PMID- 25543249 TI - Quadriceps tendon autograft for anterior cruciate ligament reconstruction: a comprehensive review of current literature and systematic review of clinical results. AB - PURPOSE: The autograft of choice for anterior cruciate ligament (ACL) reconstruction remains controversial. Recently, there has been an increase in interest in the quadriceps tendon as an autologous graft option for ACL reconstruction. The purposes of this study were to provide an in-depth review of quadriceps tendon anatomy, histology, and biomechanics and to synthesize reported clinical outcomes of ACL reconstructions using quadriceps tendon autografts. We hypothesize that (1) published studies on the anatomic, histologic, and biomechanical data regarding the quadriceps tendon support its use as a graft option for ACL reconstruction and (2) clinical outcomes of ACL reconstruction using quadriceps tendon autograft have similar clinical outcomes to bone-patellar tendon-bone autografts with less donor-site morbidity. METHODS: We performed a comprehensive review of the literature regarding the anatomy, histology, and biomechanical studies of the quadriceps tendon, as well as a systematic review of clinical studies (Level of Evidence I-III) evaluating outcomes after ACL reconstruction using quadriceps tendon autograft. Stability outcomes, functional outcomes, range of motion, patient satisfaction, morbidity, and complications were comprised. RESULTS: Fourteen studies were included in the review of clinical results, including 1,154 ACL reconstructions with quadriceps tendon autograft. Six studies directly compared quadriceps tendon autografts (n = 383) with bone patellar tendon-bone autografts (n = 484). Stability outcomes (Lachman, pivot shift, and instrumented laxity testing), functional outcomes (International Knee Documentation Committee and Lysholm scores), overall patient satisfaction, range of motion, and complications were similar between quadriceps tendon and other graft options. Less donor-site morbidity was seen in patients who underwent quadriceps tendon ACL reconstructions. CONCLUSIONS: Use of the quadriceps tendon autograft for ACL reconstruction is supported by current orthopaedic literature. It is a safe, reproducible, and versatile graft that should be considered in future studies of ACL reconstruction. LEVEL OF EVIDENCE: Level III, systematic review of Level I, II, and III studies. PMID- 25543250 TI - Complications after arthroscopic coracoclavicular reconstruction using a single adjustable-loop-length suspensory fixation device in acute acromioclavicular joint dislocation. AB - PURPOSE: The purpose of this study was to evaluate clinical and radiological outcomes after arthroscopically assisted coracoclavicular (CC) fixation using a single adjustable-loop-length suspensory fixation device for acute acromioclavicular dislocation and to report intraoperative and postoperative complications. METHODS: Eighteen consecutive patients with acute acromioclavicular dislocation underwent arthroscopically assisted CC fixation using a single TightRope (Arthrex, Naples, FL). Using the Rockwood classification, 3 patients had grade III dislocations, one patient had a grade IV dislocation, and 14 patients had grade V dislocations. RESULTS: The preoperative CC distance of the injured shoulder was 16.1 +/- 2.7 mm (range, 11.2 to 21.0 mm), and it increased by 99% +/- 36% (range, 17% to 153%) on average compared with the contralateral shoulder. The average CC distance was 10.5 +/- 2.5 mm (range, 7.7 to 15.5 mm), and it increased by 30% +/- 30% (range, -9.4% to 90%) at the final follow-up. Compared with immediate postoperative radiographs, the CC distance was maintained in 12 patients, increased between 50% and 100% in 4 patients, and increased more than 100% in 2 patients at final follow-up. However, there was no statistical difference in Constant scores between 6 patients with reduction loss (95.6 +/- 4.5) and 12 patients with reduction maintenance (98.4 +/- 2.5; P = .17). Perioperative complications occurred in 8 patients, including one case of acromioclavicular arthritis, one case of delayed distal clavicular fracture at the clavicular hole of the device, 3 cases of clavicular or coracoid button failures, and 3 cases of clavicular bony erosion. CONCLUSIONS: Satisfactory clinical outcomes were obtained after CC fixation using the single adjustable loop-length suspensory fixation device for acute acromioclavicular joint dislocation. However, CC fixation failure of greater than 50% of the unaffected side in radiological examinations occurred in 33% of the patients within 3 months after the operation. Additionally, 8 patients (44%) had complications associated with the adjustable-loop-length suspensory fixation device and surgical technical problems. Despite acceptable shoulder function restoration, adequate care should be exercised in surgical treatment of acute acromioclavicular dislocation with a single adjustable-loop-length suspensory fixation device for optimal radiological outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25543251 TI - Diurnal rhythms of plasma GLP-1 levels in normal and overweight/obese subjects: lack of effect of weight loss. AB - Food intake is regulated by not only neurohormonal, but also social, educational, and even cultural factors. Within the former, there is a complex interaction between orexigenic (ghrelin) and anorexigenic (glucagon-like peptide-1 (GLP-1)) factors in order to adjust the food intake to caloric expenditure; however, the number of subjects that are unable to properly balance appetite and body weight is increasing continuously. A loss of circadian or diurnal coordination of any of these factors may be implied in this situation. Special attention has retrieved GLP-1 due to its usefulness as a therapeutic agent against obesity and related alterations. Thus, the objective of the present study was to compare GLP-1 diurnal synthesis between normal weight and overweight/obese subjects, and to evaluate whether weight loss can restore the synthesis rhythms of GLP-1. Three groups of 25 subjects were divided attending to their body mass index (BMI) in normal weight, overweight, or obese subjects. Diurnal (5 points) GLP-1 levels were analyzed. Secondly, an intervention (behavioral-dietary treatment) study was conducted to analyze the effect of weight loss on plasma GLP-1 concentrations. Our results showed that baseline GLP-1 level was significantly lower in normal weight subjects (p = 0.003); furthermore, our cosinor analysis revealed a higher amplitude (p = 0.040) and daily GLP-1 variation (47%) in these subjects. In fact, our ANOVA data showed a lack of rhythmicity in overweight/obese patients. Weight loss was not able to restore a diurnal rhythm of plasma GLP-1 levels. In summary, the present work shows a disruption of diurnal GLP-1 levels in overweight/obese subjects, which worsen as body fat progresses. The attenuation of the GLP-1 synthesis rhythms may be important to understand the impairment of food intake regulation in overweight/obese subjects. PMID- 25543252 TI - Interocular asymmetries in axial length and refractive error in 4 cohorts. PMID- 25543253 TI - Reduced curvature of ligand-binding domain free-energy surface underlies partial agonism at NMDA receptors. AB - NMDA receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Partial agonists elicit submaximal channel activation, but crystal structures of the ligand-binding domains (LBDs) bound with partial and full agonists show little difference. To uncover the molecular mechanism for partial agonism, here we computed the free-energy surfaces of the GluN1 (an obligatory subunit of NMDA receptors) LBD bound with a variety of ligands. The free-energy minima are similarly positioned for full and partial agonists, but the curvatures are significantly reduced in the latter case, indicating higher probabilities for sampling conformations with a not fully closed domain cleft. The free-energy surfaces for antagonists have both shifted minima and further reduced curvatures. Reduced curvature of free-energy surface appears to explain well the partial agonism at NMDA receptors and may present a unique paradigm in producing graded responses for receptors in general. PMID- 25543254 TI - Two pathways mediate interdomain allosteric regulation in pin1. AB - Allostery is an essential means for regulating biomolecular functions and provides unique opportunities for drug design, yet our ability to elucidate allosteric mechanisms remains limited. Here, based on extensive molecular dynamics simulations, we present an atomistic picture of the pathways mediating the allosteric regulation of the PPIase domain of Pin1 by its WW domain. Two pathways jointly propagate the action of substrate-WW binding to produce closure and rigidification of three PPIase catalytic-site loops. One pathway preexists in the apo protein, but remains dormant until substrate-WW binding completes the second. The reduction in conformational entropy and preorganization of the catalytic-site loops observed here may explain why substrate-WW binding enhances ligand affinity and catalytic activity of the PPIase domain and suggest a combination drug therapy for Pin1-related diseases. Whereas the traditional view of allostery has emphasized conformational transition, our study identifies a distinct role of conformational dynamics in eliciting allostery. PMID- 25543255 TI - Amyloidogenesis of bacterial prionoid RepA-WH1 recapitulates dimer to monomer transitions of RepA in DNA replication initiation. AB - Most available structures of amyloids correspond to peptide fragments that self assemble in extended cross beta sheets. However, structures in which a whole protein domain acts as building block of an amyloid fiber are scarce, in spite of their relevance to understand amyloidogenesis. Here, we use electron microscopy (EM) and atomic force microscopy (AFM) to analyze the structure of amyloid filaments assembled by RepA-WH1, a winged-helix domain from a DNA replication initiator in bacterial plasmids. RepA-WH1 functions as a cytotoxic bacterial prionoid that recapitulates features of mammalian amyloid proteinopathies. RepA are dimers that monomerize at the origin to initiate replication, and we find that RepA-WH1 reproduces this transition to form amyloids. RepA-WH1 assembles double helical filaments by lateral association of a single-stranded precursor built by monomers. Double filaments then associate in mature fibers. The intracellular and cytotoxic RepA-WH1 aggregates might reproduce the hierarchical assembly of human amyloidogenic proteins. PMID- 25543256 TI - Structure of the Kti11/Kti13 heterodimer and its double role in modifications of tRNA and eukaryotic elongation factor 2. AB - The small, highly conserved Kti11 alias Dph3 protein encoded by the Kluyveromyces lactis killer toxin insensitive gene KTI11/DPH3 is involved in the diphthamide modification of eukaryotic elongation factor 2 and, together with Kti13, in Elongator-dependent tRNA wobble base modifications, thereby affecting the speed and accuracy of protein biosynthesis through two distinct mechanisms. We have solved the crystal structures of Saccharomyces cerevisiae Kti13 and the Kti11/Kti13 heterodimer at 2.4 and 2.9 A resolution, respectively, and validated interacting residues through mutational analysis in vitro and in vivo. We show that metal coordination by Kti11 and its heterodimerization with Kti13 are essential for both translational control mechanisms. Our structural and functional analyses identify Kti13 as an additional component of the diphthamide modification pathway and provide insight into the molecular mechanisms that allow the Kti11/Kti13 heterodimer to coregulate two consecutive steps in ribosomal protein synthesis. PMID- 25543257 TI - Modeling an in-register, parallel "iowa" abeta fibril structure using solid-state NMR data from labeled samples with rosetta. AB - Determining the structures of amyloid fibrils is an important first step toward understanding the molecular basis of neurodegenerative diseases. For beta-amyloid (Abeta) fibrils, conventional solid-state NMR structure determination using uniform labeling is limited by extensive peak overlap. We describe the characterization of a distinct structural polymorph of Abeta using solid-state NMR, transmission electron microscopy (TEM), and Rosetta model building. First, the overall fibril arrangement is established using mass-per-length measurements from TEM. Then, the fibril backbone arrangement, stacking registry, and "steric zipper" core interactions are determined using a number of solid-state NMR techniques on sparsely (13)C-labeled samples. Finally, we perform Rosetta structure calculations with an explicitly symmetric representation of the system. We demonstrate the power of the hybrid Rosetta/NMR approach by modeling the in register, parallel "Iowa" mutant (D23N) at high resolution (1.2A backbone rmsd). The final models are validated using an independent set of NMR experiments that confirm key features. PMID- 25543258 TI - Rhizobium-legume symbioses: the crucial role of plant immunity. AB - New research results have significantly revised our understanding of the rhizobium-legume infection process. For example, Nod factors (NFs), previously thought to be absolutely essential for this symbiosis, were shown to be dispensable under particular conditions. Similarly, an NF receptor, previously considered to be solely involved in symbiosis, was shown to function during plant pathogen infections. Indeed, there is a growing realization that plant innate immunity is a crucial component in the establishment and maintenance of symbiosis. We review here the factors involved in the suppression of plant immunity during rhizobium-legume symbiosis, and we attempt to place this information into context with the most recent and sometimes surprising research results. PMID- 25543259 TI - Mammography and breast cancer screening. PMID- 25543260 TI - Selenium effect on ischemia-reperfusion injury of gastrocnemius muscle in adult rats. AB - Selenium is a trace element that has antioxidant and neuroprotective effects. The aim of this study is to investigate the effects of selenium in reducing ischemia reperfusion injury of the gastrocnemius muscle. In this experimental study, 80 adult male Wistar rats weighing 250-300 g were divided into ten groups (N = 8 per group). Group 1 is control group (without ischemia-reperfusion). Group 2 received 0.2 mg/kg selenium. Group 3 received ischemia + 3 d reperfusion + 0.2 mg/kg selenium, group 4 received ischemia + 3 d reperfusion + 0.2 mg/kg placebo, group 5 received ischemia + 7 d reperfusion + 0.2 mg/kg selenium, group 6 received ischemia + 7 d reperfusion + 0.2 mg/kg placebo, group 7 received ischemia + 14 d reperfusion + 0.2 mg/kg selenium, group 8 received ischemia + 14 d reperfusion + 0.2 mg/kg placebo, group 9 received ischemia + 28 d reperfusion + 0.2 mg/kg selenium and group 10 received ischemia + 3 d reperfusion + 0.2 mg/kg placebo. External iliac artery blocked for 3 h. After reperfusion, rats killed and gastrocnemius muscle removed, fixed, and tissue processing performed. Samples stained with hematoxylin-eosin for edema evaluation, toluidine blue for mast cell infiltration evaluation and immunohistochemistry for detection TNF-alpha and NF kappa B proteins. Comparison of mast cell infiltration, edema of the interstitial fluid on the tissue, expression of TNF-alpha protein, and expression of NF-kappa B protein in the groups that received selenium with corresponding placebo group showed that selenium can reduce edema, mast cell infiltration, and TNF-alpha expression and inactivated NF-kappa B. The use of selenium simultaneously with creating ischemia can reduce ischemia-reperfusion injury of the gastrocnemius muscle. PMID- 25543261 TI - miR-21 is overexpressed in NPM1-mutant acute myeloid leukemias. AB - MicroRNAs (miRs) play a key role in the pathogenesis of human malignancies and particularly in acute myeloid leukemias (AMLs) and are increasingly recognized as potential biomarkers and therapeutic targets. miR-21 is dysregulated in several types of cancers, including some hematologic malignancies, and plays a key role in carcinogenesis, disease recurrence and metastasis. However, no studies have specifically investigated the role of miR-21 in AMLs. In this study we analyzed the expression of miR-21 and of its target PDCD4 (Programmed Cell Death 4) during normal hematopoietic differentiation and in AMLs. Our results showed that: (i) miR-21 expression is strongly up-modulated during normal granulo/monocytic differentiation, while PDCD4 protein level is concomitantly downmodulated; (ii) miR-21 is frequently overexpressed in AML blasts, in association with a marked PDCD4 protein downmodulation; (iii) miR-21 expression level is particularly elevated in NPM1mutant AMLs. Together, these findings suggest that deregulated miR-21 expression may contribute to disease pathogenesis in NPM1-mutated AMLs. PMID- 25543262 TI - Characterization of Pseudomonas monteilii CCM 3423 and its physiological potential for biodegradation of selected organic pollutants. AB - Pseudomonas monteilii CCM 3423 bacterial strain, deposited at the Czech Collection of Microorganisms, was originally isolated by Halama and Augustin (1980) as a bacterium degrading aromatic hydrocarbons and derivates. A detailed study supported by a molecular genetics method of sequence analyses of rrs and rpoD genes was used to reclassify the strain, originally stored as 'Pseudomonas putida'. The physiological characteristics of the strain are complemented with research in the capacity to utilize selected organic pollutants (anthracene, benz[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, fluorene, naphthalene, phenanthrene). The obtained results point at very good biodegradation properties of the strain. Already after 7 days of the bacterial strain's action, there was a decrease in all the organic contaminants to 79.8 +/- 2.6 %. In 14 days, the amount of organic contaminants dropped to 59.3 +/- 2.8 %. After 21 days of biodegradation experiments, the overall quantity of the observed organic substances fell below the half limit to 45.7 +/- 2.5 % of residuals. Finally, after 28 days, the residue was 35.4 +/- 2.2 %, and after 35 days of the action of P. monteilii, the tested samples contained mere 27.8 +/- 2.8 % of organic pollutants. The results imply that Pseudomonas monteilii CCM 3423 is a prospective strain in terms of further biotechnological application in contaminated environment. PMID- 25543263 TI - Elucidating sex and gender differences in diabetes: a necessary step toward personalized medicine. PMID- 25543264 TI - Improving the acidic stability of Staphylococcus aureus alpha-acetolactate decarboxylase in Bacillus subtilis by changing basic residues to acidic residues. AB - The alpha-acetolactate decarboxylase (ALDC) can reduce diacetyl fleetly to promote mature beer. A safe strain Bacillus subtilis WB600 for high-yield production of ALDC was constructed with the ALDC gene saald from Staphylococcus aureus L3-15. SDS-PAGE analysis revealed that S. aureus alpha-acetolactate decarboxylase (SaALDC) was successfully expressed in recombinant B. siutilis strain. The enzyme SaALDC was purified using Ni-affinity chromatography and showed a maximum activity at 45 degrees C and pH 6.0. The values of K m and V max were 17.7 MUM and 2.06 mM min(-1), respectively. Due to the unstable property of SaALDC at low pH conditions that needed in brewing process, site-directed mutagenesis was proposed for improving the acidic stability of SaALDC. Homology comparative modeling analysis showed that the mutation (K52D) gave rise to the negative-electrostatic potential on the surface of protein while the numbers of hydrogen bonds between the mutation site (N43D) and the around residues increased. Taken together the effect of mutation N43D-K52D, recombinant SaALDCN43D-K52D showed dramatically improved acidic stability with prolonged half life of 3.5 h (compared to the WT of 1.5 h) at pH 4.0. In a 5-L fermenter, the recombinant B. subtilis strain that could over-express SaALDCN43D-K52D exhibited a high yield of 135.8 U mL(-1) of SaALDC activity, about 320 times higher comparing to 0.42 U mL(-1) of S. aureus L3-15. This work proposed a strategy for improving the acidic stability of SaALDC in the B. subtilis host. PMID- 25543265 TI - The NR4A nuclear receptors as potential targets for anti-aging interventions. AB - The development of innovative anti-aging strategy is urgently needed to promote healthy aging and overcome the occurrence of age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. Genomic instability, deregulated nutrient sensing and mitochondrial dysfunction are established hallmark of aging. Interestingly, the orphan nuclear receptors NR4A subfamily (NR4A1, NR4A2 and NR4A3) are nutrient sensors that trigger mitochondria biogenesis and improve intrinsic mitochondrial function. In addition, NR4A receptors are components of DNA repair machinery and promote DNA repair. Members of the NR4A subfamily should also be involved in anti-aging properties of hormesis since these receptors are induced by various form of cellular stress and stimulate protective cells response such as anti-oxidative activity and DNA repair. Previous studies reported that NR4A nuclear receptors subfamily is potential therapeutic targets for the treatment of age related disorders (e.g. metabolic syndromes, diabetes and neurodegenerative diseases). Consequently, we propose that targeting NR4A receptors might constitute a new approach to delay aging and the onset of diseases affecting our aging population. PMID- 25543266 TI - Bitter correlationship between autoimmune hepatitis and smoking. AB - Cigarette smoke contains numerous toxic, carcinogenic and mutagenic chemicals, stable and unstable free radicals and reactive oxygen species (ROS) which cause biological oxidative damage. Continuous exposure to those chemicals leads to immense amount of damage to the human health either directly or indirectly. A hypothesis is advanced here that a possible explanation for developing autoimmune hepatitis (AIH) is due to regular smoking for long years of time. To examine this hypothesis, I relied on an experience of a case of a patient, as well as critical reading of the literature on smoking and different autoimmune disorders. Among the autoimmune diseases, rheumatoid arthritis (RA), multiple sclerosis (MS), thyroid disease, primary biliary cirrhosis (PBC) are reported mostly among tobacco-exposed animals. The observational and theoretical knowledge strengthen the hypothesis that smoking can be one of the causes of generating autoimmune hepatitis. This hypothesis could lead to a new diagnostic category, as well as therapeutic approaches for changing the regular smoking behavior. PMID- 25543268 TI - Biological features of biofilm-forming ability of Acinetobacter baumannii strains derived from 121 elderly patients with hospital-acquired pneumonia. AB - This study is to investigate a biological activity of Acinetobacter baumannii isolates from sputum specimens of 121 elderly patients with hospital-acquired pneumonia. The ability of the isolates to form biofilms was quantitatively assessed by crystal violet staining, and adhesive property was examined using Giemsa staining. Biofilm-forming ability by the isolates was employed to test antimicrobial resistance and examine sources and clinical manifestations. The isolates grew as biofilm on abiotic surface at the indicated temperatures after a 48 h of incubation. 27.3 % of the isolates were strongly biofilm-positive in the samples, and 84.8 % displayed high adhesion ability (P < 0.05). All of the isolates showed antibiotic resistance at different levels, and the isolates produced strong biofilm exhibited low-level resistance to gentamicin, minocycline and ceftazidime (P < 0.05). The patients' experience in ICU, use of antibiotics and estimation of APACHE II (<17) were related to incidence of strong biofilm formation with no clinical manifestations found in the study. All clinical isolates are able to form biofilms which refer to adhesive efficiency and antibiotic resistance. Patient experiences in ICU surveillance, use of antibiotics and APACHE II scores are involved in biofilm-forming ability by the nosocomial pathogen derived from the hospitalized patients. PMID- 25543267 TI - Consensus statement on a framework for the management of comorbidity and extra articular manifestations in rheumatoid arthritis. AB - The objective of the study was to develop evidence-based and practical recommendations for the detection and management of comorbidity in patients with rheumatoid arthritis (RA) in daily practice. We used a modified RAND/UCLA methodology and systematic review (SR). The process map and specific recommendations, based on the SR, were established in discussion groups. A two round Delphi survey permitted (1) to prioritize the recommendations, (2) to refine them, and (3) to evaluate their agreement by a large group of users. The recommendations cover: (1) which comorbidities should be investigated in clinical practice at the first and following visits (including treatments, risk factors and patient's features that might interfere with RA management); (2) how and when should comorbidities and risk factors be investigated; (3) how to manage specific comorbidities, related or non-related to RA, including major adverse events of RA treatment, and to promote health (general and musculoskeletal health); and (4) specific recommendations to assure an integral care approach for RA patients with any comorbidity, such as health care models for chronic inflammatory patients, early arthritis units, relationships with primary care, specialized nursing care, and self-management. These recommendations are intended to guide rheumatologists, patients, and other stakeholders, on the early diagnosis and management of comorbidity in RA, in order to improve disease outcomes. PMID- 25543270 TI - Low-income minority patient engagement with automated telephonic depression assessment and impact on health outcomes. AB - PURPOSE: We investigated dimensions of low-income minority patient engagement in the context of diabetes-depression care-management with automated telephone assessment (ATA) calls as a facilitator. METHODS: Mixed method analyses (including regression analyses and coding of interviews) were used to examine patient engagement with technology, assess its impact on health outcomes and satisfaction with care, and analyze barriers to engagement. Patient engagement was measured by analyzing patient's ATA call response rates. We then evaluated those results in the context of the outcomes of the broader clinical trial, which compared three study arms. RESULTS: Average completed call rate throughout the study is about 50 % and decreases after 6 months. The biggest barrier to patient engagement is timing. Patient engagement levels differ by baseline depression status and have no significant effect on health outcomes and satisfaction with care at 6, 12, and 18 months. However, from the preliminary clinical trial results, the arm in which the ATA system is implemented has higher satisfaction with depression care than the two control arms. Thus, it is more likely that technology positively affects satisfaction with depression care outcomes through provider engagement rather than patient engagement. CONCLUSIONS: The study's patient engagement results and identified barriers would be useful to aid the design and implementation of future automated screening and monitoring systems to optimize patient engagement. The results also suggest that implementing a technology-supported care-management might not result in outcome disparities among patients with different levels of patient engagement. PMID- 25543269 TI - Syk is indispensable for CpG-induced activation and differentiation of human B cells. AB - B cells are efficiently activated by CpG oligodeoxynucleotides (ODNs) to produce pro-inflammatory cytokines and antibody (Ab). Here, we describe a so far unidentified, spleen tyrosine kinase (Syk)-dependent pathway, which is indispensable for CpG-induced human B cell activation. We show that triggering of B cells by CpG results in Syk and src kinase phosphorylation, proliferation, as well as cytokine and Ab production independent of the BCR. Notably, all these functions are abrogated when Syk is inhibited. We demonstrate that CpG-induced Syk activation originates from the cell surface in a TLR9-dependent manner. While inhibition of Syk does not influence the uptake of CpG ODNs, activation of the kinase is a prerequisite for the delivery of CpG into TLR9-containing endolysosomes and for the CpG-induced up-regulation of TLR9 expression. Our results reveal an alternative, Syk-dependent pathway of CpG-induced B cell stimulation, which is initiated at the plasma membrane and seems to be an upstream requirement for endosomal TLR9-driven B cell proliferation and differentiation. PMID- 25543271 TI - Valuing EQ-5D health states for Sri Lanka. AB - PURPOSE: The aim of this study was to derive an algorithm to estimate utility values for the EQ-5D-3L health states based on the preferences of a population sample from Sri Lanka. METHODS: The time trade-off method was used to directly value 198 EQ-5D-3L health states in a general population sample (n = 780) from Sri Lanka. Stratified cluster sampling with random selection within clusters was used to select the sample from four districts. Each participant valued 15 health states via face-to-face interviews. The best fit model was selected using consistency, parsimony, and goodness of fit. Based on logical inconsistency, numerous sub-samples were also used for model specification. For each model, the numbers of illogical orderings in the resulting value set were also examined. RESULTS: Generalised least squares with random effects were found to be the best specification. The sub-sample consisting of participants with less than seven logical inconsistent observations produced no illogical ordering in the final value set and is considered the preferred model. Compared to value sets in other countries, a high disutility is associated with level 3 deficits in the mobility dimension. More than 50 % of health states in the Sri Lankan value set are deemed worse than death health states. CONCLUSIONS: Sri Lankan utility values for EQ-5D 3L states deviate markedly from existing values for upper middle and high-income countries. It is important to have country-specific utility values to conduct cost-utility analysis. PMID- 25543272 TI - Nephrotic syndrome in a patient with Pfeifer-Weber-Christian disease. PMID- 25543273 TI - Atypical fracture in a child with osteogenesis imperfecta. PMID- 25543274 TI - Antinuclear autoantibody profile in systemic sclerosis patients who are negative for anticentromere and anti-topoisomerase I specificities. PMID- 25543275 TI - Ultrasound in gout: a useful tool for following urate-lowering therapy. AB - OBJECTIVE: We aimed to determine the ability of ultrasonography (US) to show decrease or disappearance of urate deposits in gouty patients requiring urate lowering therapy (ULT). METHODS: To be included in this prospective single-centre study, patients needed toexhibit (1) proven gout by monosodic urate (MSU) crystals in synovial fluid and (2) US-evidenced urate deposits (double contour [DC] sign and/or tophi) before starting ULT (allopurinol [n=4], febuxostat [n=12]). At baseline and after six months of ULT, one trained ultrasonographer assessed the knee and first metatarsophalangeal (MTP1s) joints. Serum uric-acid (SUA) level was assessed at baseline and at three and six months after ULT initiation. Correlation between US findings and achievement of SUA level objective (< 360MUmol/L) was estimated by the kappa coefficient (kappa). RESULTS: We studied 16 patients (all males, mean age 61.0+/-18.3 years). The mean disease duration was 7.1+/-6.2 years. Tophi were found at clinical examination in 56% of patients. Baseline SUA levels were 688+/-153MUmol/L. At baseline, US revealed tophi or a DC sign among 62.5 to 75% of patients in knees and 87.5% in MTP1s. After six months of ULT, none of the four patients, not achieving the SUA level objective, had disappearance of US features. Among the remaining 12 patients, US features (tophi or DC sign) disappeared or decreased in all but one with a stable DC sign in one MTP1. The correlation between the whole US examination and SUA level was excellent (kappa=0.875). CONCLUSIONS: US could show disappearance of urate deposits after ULT and appears to be well correlated with efficacy of ULT. PMID- 25543276 TI - Acute crystal-induced arthritis and rheumatoid factor seropositivity. PMID- 25543277 TI - A 3D model of thrombus formation in a stent-graft after implantation in the abdominal aorta. AB - Here we present a 3D kinetic model of thrombus formation in an endovascular prosthesis after implantation in an abdominal aorta with an aneurysm. The computational fluid dynamic technique (CFD) was used to determine the process of thrombus formation and growth in the stent-graft on the basis of the medical data from computed tomography angiography and Doppler ultrasound examination of 10 patients. The Quemada model was used to describe rheological properties of blood. Results of the CFD simulations were validated based on actual data from patients with diagnosed thrombi in aortic implants. The results show that the elaborated CFD model correctly predicted thrombus formation, shape and deposition site in an endovascular prosthesis. The developed CFD model of thrombus growth can be applied to predict the risk of thrombus formation in stent-grafts and assist in selection of geometry of the endovascular prosthesis to reduce possible complications after stent-graft implantation using only basic medical data. PMID- 25543278 TI - Bone adaptation to cyclic loading in murine caudal vertebrae is maintained with age and directly correlated to the local micromechanical environment. AB - The ability of the skeleton to adapt to mechanical stimuli (mechanosensitivity) has most often been investigated at the whole-bone level, but less is known about the local mechanoregulation of bone remodeling at the bone surface, especially in context of the aging skeleton. The aim of this study was to determine the local and global mechanosensitivity of the sixth caudal vertebra during cyclic loading (8 N, three times per week, for six weeks) in mice aged 15, 52, and 82 weeks at the start of loading. Bone adaptation was monitored with in vivo micro-computed tomography. Strain energy density (SED), assumed as the mechanical stimulus for bone adaptation, was determined with micro-finite element models. Mechanical loading had a beneficial effect on the bone microstructure and bone stiffness in all age groups. Mineralizing surface was on average 13% greater (p<0.05) in loaded than control groups in 15- and 82-week-old mice, but not for 52-week-old mice. SED at the start of loading correlated to the change in bone volume fraction in the following 6 weeks for loaded groups (r(2)=0.69-0.85) but not control groups. At the local level, SED was 14-20% greater (p<0.01) at sites of bone formation, and 15-20% lower (p<0.01) at sites of bone resorption compared to quiescent bone surfaces for all age groups, indicating SED was a stimulus for bone adaptation. Taken together, these results support that mechanosensitivity is maintained with age in caudal vertebrae of mice at a local and global level. Since age-related bone loss was not observed in caudal vertebrae, results from the current study might not be translatable to aged humans. PMID- 25543279 TI - On the relationship between tibia torsional deformation and regional muscle contractions in habitual human exercises in vivo. AB - The mechanical relationship between bone and muscle has been long recognized. However, it still remains unclear how muscles exactly load on bone. In this study, utilizing an optical segment tracking technique, the in vivo tibia loading regimes in terms of tibia segment deformation in humans were investigated during walking, forefoot and rear foot stair ascent and running and isometric plantar flexion. Results suggested that the proximal tibia primarily bends to the posterior aspect and twists to the external aspect with respect to the distal tibia. During walking, peak posterior bending and peak torsion occurred in the first half (22%) and second half (76%) of the stance phase, respectively. During stair ascent, two noticeable peaks of torsion were found with forefoot strike (38% and 82% of stance phase), but only one peak of torsion was found with rear foot strike (78% of stance phase). The torsional deformation angle during both stair ascent and running was larger with forefoot strike than rear foot strike. During isometric plantar flexion, the tibia deformation regimes were characterized more by torsion (maximum 1.35 degrees ) than bending (maximum 0.52 degrees ). To conclude, bending and torsion predominated the tibia loading regimes during the investigated activities. Tibia torsional deformation is closely related to calf muscle contractions, which further confirm the notion of the muscle-bone mechanical link and shift the focus from loading magnitude to loading regimes in bone mechanobiology. It thus is speculated that torsion is another, yet under-rated factor, besides the compression and tension, to drive long bone mechano-adaptation. PMID- 25543280 TI - Beware of docking! AB - Docking is now routine in virtual screening or lead optimization for drug screening and design. The number of papers related to docking has dramatically increased over the past decade. However, there are many issues to consider when undertaking a docking study. Frequent problems or issues arise, such as the wrong binding site of the target protein, screening using an unsuitable small-molecule database, the choice of docking pose, high dock score but failed in molecular dynamics (MD) simulation, and lack of clarity over whether the compound is an inhibitor or agonist. These problems should be cause for caution and concern before performing docking. Some papers show comprehensive biochemistry experiments but only a simple docking figure. This review presents some evidence to show that the docking might be questionable, despite a high score. In some cases, the accuracy of docking can even change from 0% to 92.66%. Thus, please beware of docking! PMID- 25543281 TI - Profilin-1 serves as a gatekeeper for actin assembly by Arp2/3-dependent and independent pathways. AB - Cells contain multiple F-actin assembly pathways, including the Arp2/3 complex, formins, and Ena/VASP, which have largely been analyzed separately. They collectively generate the bulk of F-actin from a common pool of G-actin; however, the interplay and/or competition between these pathways remains poorly understood. Using fibroblast lines derived from an Arpc2 conditional knockout mouse, we established matched-pair cells with and without the Arp2/3 complex. Arpc2(-/-) cells lack lamellipodia and migrate more slowly than WT cells but have F-actin levels indistinguishable from controls. Actin assembly in Arpc2(-/-) cells was resistant to cytochalasin-D and was highly dependent on profilin-1 and Ena/VASP but not formins. Profilin-1 depletion in WT cells increased F-actin and Arp2/3 complex in lamellipodia. Conversely, addition of exogenous profilin-1 inhibited Arp2/3 complex actin nucleation in vitro and in vivo. Antagonism of the Arp2/3 complex by profilin-1 in cells appears to maintain actin homeostasis by balancing Arp2/3 complex-dependent and -independent actin assembly pathways. PMID- 25543283 TI - Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice. AB - Syntenin-1 is an intracellular PDZ protein that binds multiple proteins and regulates protein trafficking, cancer metastasis, exosome production, synaptic formation, and IL-5 signaling. However, the functions of Syntenin-1 have not yet been clearly characterized in detail, especially in vivo. In this study, we generated a Syntenin-1 knock out (KO) mouse strain and analyzed the role(s) of Syntenin-1 in IL-5 signaling, because the direct interaction of Syntenin-1 with the cytoplasmic domain of the IL-5 receptor alpha subunit and the regulation of IL-5 signaling by Syntenin-1 have been reported. Unexpectedly, the number of IL-5 responding cells was normal and the levels of fecal immunoglobulins were rather higher in the Syntenin-1 KO mice. We also found that IgA and IgM production of splenic B cells stimulated in vitro was increased in Syntenin-1 KO mice. In addition, we showed that a distribution of intestinal microbial flora was influenced in Syntenin-1 KO mice. Our data indicate that Syntenin-1 negatively regulates the intestinal immunoglobulin production and has a function to maintain the intestinal homeostasis in vivo. The analysis of Syntenin-1 KO mice may provide novel information on not only mucosal immunity but also other functions of Syntenin-1 such as cancer metastasis and neural development. PMID- 25543282 TI - Profilin regulates F-actin network homeostasis by favoring formin over Arp2/3 complex. AB - Fission yeast cells use Arp2/3 complex and formin to assemble diverse filamentous actin (F-actin) networks within a common cytoplasm for endocytosis, division, and polarization. Although these homeostatic F-actin networks are usually investigated separately, competition for a limited pool of actin monomers (G actin) helps to regulate their size and density. However, the mechanism by which G-actin is correctly distributed between rival F-actin networks is not clear. Using a combination of cell biological approaches and in vitro reconstitution of competition between actin assembly factors, we found that the small G-actin binding protein profilin directly inhibits Arp2/3 complex-mediated actin assembly. Profilin is therefore required for formin to compete effectively with excess Arp2/3 complex for limited G-actin and to assemble F-actin for contractile ring formation in dividing cells. PMID- 25543284 TI - Simultaneous determination of ten alkaloids of crude and wine-processed Rhizoma Coptidis aqueous extracts in rat plasma by UHPLC-ESI-MS/MS and its application to a comparative pharmacokinetic study. AB - Rhizoma coptidis (R.C.), a widely used traditional Chinese medicine, has been used for centuries in the treatment of hypertension, inflammation, dysentery and liver diseases, etc. Wine-processing is a specialized technology by sauteing crude herbal medicine using Chinese rice wine. This paper was designed to establish a simultaneous quantitative method of ten alkaloids (berberine, coptisine, palmatine, jatrorrhizine, epiberberine, magnoflorine, columbamine, noroxyhydrastinine, oxyberberine and 8-oxocoptisine) in rat plasma. Furthermore, the pharmacokinetics of those alkaloids after administration of crude and wine processed R.C. aqueous extracts was compared. As a result, a ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) method was developed and validated for the first time. Chromatographic separation was achieved on a C18 column using gradient elution with the mobile phase consisting of acetonitrile and water (containing 0.2% formic acid) at a flow rate of 0.2 ml/min. The validated method showed good linearity over a wide concentration range (r>0.99), and lower limits of quantification less than 5.46 ng/ml for the each analyte. The intra- and inter day assay variability was below 9.9% and 10.5% for all analytes, respectively. The extraction recovery of those alkaloids and I.S. ranged from 65.3% to 90.7%. The validated method has been successfully applied to pharmacokinetic comparison after administration of crude and wine-processed R.C. aqueous extracts. Pharmacokinetic comparative study showed that Cmax of coptisine and 8 oxocoptisine and AUC0-t of coptisine, palmatine and 8-oxocoptisine were increased significantly (p<0.05) after wine-processing, while other compounds didn't show significant difference, which suggested that wine-processing exerted limited effects on the absorption of alkaloids. These results might be helpful for R.C.' clinical reasonable application and further studies on its wine-processing mechanism. PMID- 25543285 TI - Identification of the major degradation pathways of ticagrelor. AB - Ticagrelor is a direct-acting and reversible P2Y12-adenosine diphosphate (ADP) receptor blocker used as antiplatelet drug. Forced degradation under various stress conditions was carried out. The degradation products have been detected and identified by high-pressure liquid chromatography multistage mass spectrometry (LC-MS(n)) along with high-resolution mass spectrometry. C18 XTerra MS column combined with a linear gradient mobile phase composed of a mixture of 10 mM acetate ammonium/acetonitrile was shown suitable for drug and impurity determinations and validated as a stability indicating method. Structural elucidation of the degradation products relied on MS(n) studies and accurate mass measurements giving access to elemental compositions. Up to nine degradation products resulting from oxidation/auto-oxidation, S-dealkylation and N dealkylation have been identified, covering a range of possible degradation pathways for derivatives with such functional groups. Kinetics was also studied in order to assess the molecule's shelf-life and to identify the most important degradation factors. PMID- 25543286 TI - An UPLC-MS-based metabolomics investigation on the anti-fatigue effect of salidroside in mice. AB - An ultra-performance liquid chromatography-quadrupole time-of-flight-based metabolomic approach was developed to study influence of salidroside, an anti fatigue ingredient from Rhoiola rosea, on urinary metabolic profiling of rats to a single dose of 180 mg/kg per day. Unsupervised principal component analysis (PCA) and supervised orthogonal pre-projection to latent structures discriminate analysis (OPLS-DA) on metabolite profiling revealed obvious differentiation between the salidroside treated groups and controls in both positive and negative ion modes. Eleven urinary metabolites contributing to the differentiation were identified as anti-fatigue biomarkers: N-acetylserotonin, 2-Methoxyestrone 3 glucuronide, Taurine, Melatonin, Sorbitol, Geranyl diphosphate, Z-nucleotide, Cortisone, Dihydrocortisol, Sebacic acid, Pregnenolone sulfate. The physiological significance of these biomarkers is discussed. The work showed that metabolomics is a powerful tool in studying the anti-fatigue effects of natural compound salidroside on multiple targets in vivo. PMID- 25543287 TI - Application of chemometric algorithms to MALDI mass spectrometry imaging of pharmaceutical tablets. AB - During drug product development, the nature and distribution of the active substance have to be controlled to ensure the correct activity and the safety of the final medication. Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), due to its structural and spatial specificities, provides an excellent way to analyze these two critical parameters in the same acquisition. The aim of this work is to demonstrate that MALDI-MSI, coupled with four well known multivariate statistical analysis algorithms (PCA, ICA, MCR-ALS and NMF), is a powerful technique to extract spatial and spectral information about chemical compounds from known or unknown solid drug product formulations. To test this methodology, an in-house manufactured tablet and a commercialized Coversyl((r)) tablet were studied. The statistical analysis was decomposed into three steps: preprocessing, estimation of the number of statistical components (manually or using singular value decomposition), and multivariate statistical analysis. The results obtained showed that while principal component analysis (PCA) was efficient in searching for sources of variation in the matrix, it was not the best technique to estimate an unmixing model of a tablet. Independent component analysis (ICA) was able to extract appropriate contributions of chemical information in homogeneous and heterogeneous datasets. Non-negative matrix factorization (NMF) and multivariate curve resolution-alternating least squares (MCR-ALS) were less accurate in obtaining the right contribution in a homogeneous sample but they were better at distinguishing the semi-quantitative information in a heterogeneous MALDI dataset. PMID- 25543288 TI - Geoherbalism evaluation of Radix Angelica sinensis based on electronic nose. AB - Radix Angelica sinensis (Danggui, DG), derived from the dry root of Angelicae sinensis, is popularly used for its antioxidant, hematinic and immuno enhancement. However, DG from different origins possess different quality, and difficult to identity. In this study, we used electronic nose technique to investigate DG from different producing areas for monitoring the correlation of origin and quality. The electronic nose was employed to establish classification model of DG originated from four main producing areas of Gansu, Yunnan, Sichuan and Hubei in China. Principal component analysis (PCA) and discriminant function analysis (DFA) were performed to differentiate DG samples from four main producing areas. The content of phthalides of DG were determined to confirm the quality changes and investigate its correlation with the odor response values by Gas Chromatography-Mass Spectrometer (GC-MS). The results of PCA and DFA analysis showed that the electronic nose could accurately distinguish DG from four main producing areas. The method of electronic nose for identification could be verified by GC-MS technology, and the main ingredient content was consistent with its odor of DG. In conclusion, electronic nose could effectively identify different origins of DG, and could be applied for rapid identification and quality control of genuine Angelica herbs. PMID- 25543289 TI - Localization of ginsenosides in the rhizome and root of Panax ginseng by laser microdissection and liquid chromatography-quadrupole/time of flight-mass spectrometry. AB - The root and rhizome of Panax ginseng C.A. Mey, known as ginseng, is a commonly used medicinal plant. Ginsenosides are the major active components responsible for the tonic effects of this herb. Here, the combination of laser microdissection and ultra-high performance liquid chromatography quadrupole/time of flight-mass spectrometry (UHPLC-QTOF-MS) was applied to investigate the localization of ginsenosides in root and rhizome of P. ginseng. Five kinds of tissue cells were separated from the rhizome, main root and branch root of ginseng. Fifty-nine ginsenosides were identified and the results showed that the cork contained more kinds of ginsenosides than did the cortex, phloem, xylem and resin canals. It is interesting that the phloem, xylem and resin canals from branch root contained a greater number of ginsenosides than did from main root. This study provides solid evidence on the accumulation of ginsenosides in cork, cortex, phloem and xylem. PMID- 25543290 TI - Role of brachytherapy for advanced prostate cancer. PMID- 25543291 TI - Advanced prostate cancer. Introduction. PMID- 25543292 TI - Correlations between peroxisome proliferator activator receptor gamma, Cystatin C, or advanced oxidation protein product, and atherosclerosis in diabetes patients. AB - We aimed to explore the relationship between peroxisome proliferator activator receptor gamma (PPAR gamma), Cystatin C or advanced oxidation protein product (AOPP) and atherosclerosis (AS), and identify their diagnostic values for AS. Eighty AS patients above the age of 75 with type 2 diabetes were screened by brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI). The baseline level of patients was firstly analyzed, and then the expression of PPAR gamma was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Meanwhile, a double-antibody sandwich enzyme-linked immunosorbent assay was performed to analyze the concentration of AOPP, and immunonephelometry was carried out to detect the concentration of Cystatin C. The baseline level of patients was basically consistent. The expression of PPAR gamma was significantly higher in severe AS than mild AS patients (P < 0.05), while no differences were found in serum Cystatin C and AOPP between severe AS and mild AS patients (P > 0.05). Thus, PPAR gamma exhibited a high diagnostic value for severe AS (AUC = 0.850), but not Cystatin C and AOPP (AUC = 0.553, AUC = 0.4780). Moreover, the combination of PPAR gamma, Cystatin C and AOPP exhibited a quite high diagnostic value in AS (AUC = 0.961, Sen = 0.9, Spe = 0.975), which was also higher than PPAR gamma alone. In conclusion, the contents of PPAR gamma, Cystatin C and AOPP were closely related to AS in diabetes, indicating a potential clinical diagnostic value of PPAR gamma, Cystatin C and AOPP in diabetes with AS. PMID- 25543294 TI - Is there truly an oncologic indication for interval appendectomy? AB - BACKGROUND: The rate of recurrent appendicitis is low following nonoperative management of complicated appendicitis. However, recent data suggest an increased rate of neoplasms in these cases. METHODS: The study was a retrospective review of patients with acute appendicitis at 2 university-affiliated community hospitals over a 12-year period. The primary outcome measure was the incidence of appendiceal neoplasm following interval appendectomy. RESULTS: Six thousand thirty-eight patients presented with acute appendicitis. Appendectomy was performed in 5,851 (97%) patients at the index admission. Of the 188 patients treated with initial nonoperative management, 89 (47%) underwent interval appendectomy. Appendiceal neoplasms were identified in 11 of the 89 (12%) patients. These included mucinous neoplasms (n = 6), carcinoid tumors (n = 4), and adenocarcinoma (n = 1). The rate of neoplasm in patients over age 40 was 16%. CONCLUSIONS: There is a significant rate of neoplasms identified in patient over age 40 undergoing interval appendectomy. This should be considered following nonoperative management of complicated appendicitis. PMID- 25543293 TI - Metabolic regulation and energy homeostasis through the primary Cilium. AB - Obesity and diabetes represent a significant healthcare concern. In contrast to genome-wide association studies that, some exceptions notwithstanding, have offered modest clues about pathomechanism, the dissection of rare disorders in which obesity represents a core feature have highlighted key molecules and structures critical to energy regulation. Here we focus on the primary cilium, an organelle whose roles in energy homeostasis have been underscored by the high incidence of obesity and type II diabetes in patients and mouse mutants with compromised ciliary function. We discuss recent evidence linking ciliary dysfunction to metabolic defects and we explore the contribution of neuronal and nonneuronal cilia to these phenotypes. PMID- 25543295 TI - Effects of the antimicrobial peptide cathelicidin (LL-37) on immortalized gingival fibroblasts infected with Porphyromonas gingivalis and irradiated with 625-nm LED light. AB - Porphyromonas gingivalis causes chronic inflammatory diseases (periodontal diseases) that destroy the periodontal ligament and alveolar bone. Antimicrobial peptides are crucial components of the host defense response required to maintain cellular homeostasis during microbial invasion. Because light-emitting diode (LED) irradiation influences the host defense response against bacterial infections, we investigated its effect on immortalized gingival fibroblasts (IGFs) infected with P. gingivalis. IGFs were incubated with P. gingivalis following LED irradiation at 425, 525, and 625 nm. The dark 1 group comprised noninfected, nonirradiated IGFs, and the dark 2 group comprised nonirradiated IGFs infected with P. gingivalis. These groups served as controls. Infected cells and controls were assayed for reactive oxygen species (ROS) and were subjected to RT-PCR and Western blotting analyses to determine the levels of expression of antimicrobial peptides. LED irradiation enhanced the bactericidal effects of the antimicrobial peptide LL-37 in cells infected with P. gingivalis. Irradiation at 625 nm decreased inflammatory responses involving the release of prostaglandin E2 induced by ROS in P. gingivalis-infected IGFs. LED irradiation at 625 nm induces an anti-inflammatory response that elicits the production of antimicrobial peptides, providing an efficacious method of treatment for periodontal diseases. PMID- 25543296 TI - Longitudinal effect of curcumin-photodynamic antimicrobial chemotherapy in adolescents during fixed orthodontic treatment: a single-blind randomized clinical trial study. AB - White spot lesions are one of the concerns during the fixed orthodontic treatment. Thus, the aim of the present study was to evaluate the antimicrobial/anti-inflammatory effect of curcumin-photodynamic antimicrobial chemotherapy (c-PACT) and chlorhexidine varnish on the plaque accumulation and gingival bleeding in adolescents under fixed orthodontic treatment. A randomized clinical trial was performed with an initial number of 45 patients being distributed into three groups: group I-chlorhexidine varnish 2%, group II-placebo varnish, and group III-c-PACT (curcumin at 1.5 mg.mL(-1)) exposed to blue Light emitting diode (LED) light at 450 nm (power density = 165 mW.cm(-2), fluency = 96 J.cm(-2), total dose = 150.7 J). The treatments were performed for four consecutive times with an interval of 1 week each. After the interventions, two calibrated examiners (Kappa value = 0.75) analyzed the dental plaque accumulation by plaque index (PI) and gingivitis condition by gingival bleeding index (GBI) with 1 and 3 months of follow-up after the treatments comprised a final sample of 35 patients. No significant difference was found to PI between the groups during baseline and 1-month period. Group III (1.52 +/- 0.51) presented significance difference from group I (0.91 +/- 0.75) and group II (1.03 +/- 0.51) at 3 months of follow-up. In this same period, there was more plaque accumulation with significant statistical difference (P <= 0.05) in comparison to the other periods to all studied groups. There was a GBI reduction statistically significant to groups I and III at 1-month follow-up in comparison to other periods. No effect was verified to dental plaque accumulation after the photodynamic application mediated with curcumin activated with a blue LED light. PMID- 25543297 TI - Complete genome of a Puumala virus strain from Central Europe. AB - Puumala virus (PUUV) is one of the predominant hantavirus species in Europe causing mild to moderate cases of haemorrhagic fever with renal syndrome. Parts of Lower Saxony in north-western Germany are endemic for PUUV infections. In this study, the complete PUUV genome sequence of a bank vole-derived tissue sample from the 2007 outbreak was determined by a combined primer-walking and RNA ligation strategy. The S, M and L genome segments were 1,828, 3,680 and 6,550 nucleotides in length, respectively. Sliding-window analyses of the nucleotide sequences of all available complete PUUV genomes indicated a non-homogenous distribution of variability with hypervariable regions located at the 3'-ends of the S and M segments. The overall similarity of the coding genome regions to the other PUUV strains ranged between 80.1 and 84.7 % at the level of the nucleotide sequence and between 89.5 and 98.1 % for the deduced amino acid sequences. In comparison to the phylogenetic trees of the complete coding sequences, trees based on partial segments revealed a general drop in phylogenetic support and a lower resolution. The Astrup strain S and M segment sequences showed the highest similarity to sequences of strains from geographically close sites in the Osnabruck Hills region. In conclusion, a primer-walking-mediated strategy resulted in the determination of the first complete nucleotide sequence of a PUUV strain from Central Europe. Different levels of variability along the genome provide the opportunity to choose regions for analyses according to the particular research question, e.g., large-scale phylogenetics or within-host evolution. PMID- 25543298 TI - Application of capillary electrophoresis in determination of acid dissociation constant values. AB - The chemical groups undergoing protonation or deprotonation in solution are described by the acid dissociation constant value, the key parameter for physicochemical characterization of biologically- and pharmacologically-important compounds. Capillary electrophoresis (CE) proved to be suitable technique for its determination: it enables automated and accurate measurements even for minute amount of sample, does not require the information about concentration, and handle both the impure and complex samples. In this review, a number of contributions reporting on the application of CE in pKa prediction has been summarized and critically discussed. The reader will find herein the brief introduction of theory, summary of all works published in the last decade, considerations on the most important innovations and achievements, and the discussion of pKa-related issues as e.g. the role of pKa-shifts in the chiral separation mechanism or the elucidation of migration order reversals observed during CE-mediated separations. PMID- 25543299 TI - Determination of tranexamic acid in various matrices using microwave-assisted derivatization followed by dispersive liquid-liquid microextraction. AB - Tranexamic acid (TA) is widely used to treat medical hemorrhagic conditions and as a whitening agent in cosmetic products. The aim of this study was to develop a micro-analytical method of determining TA in widely varying sample matrices, including pharmaceuticals, cosmetics, extracts of the stratum corneum, human keratinocyte cells, and human plasma. Using dansyl chloride as the derivatizing reagent in the pretreatment reduced the reaction time to within 4min in combined microwave-assisted reaction. To prevent excess dansyl chloride and sample matrices from damaging the column, 4MUL chloroform was used to remove excess derivatizing agent and interference through dispersive liquid-liquid microextraction (DLLME) method. After pretreatment, 1MUL of sample solution was injected in capillary liquid chromatography coupled with ultraviolet detector (CapLC-UV). By coupling the proposed method with cylinder-sampling method, TA was successfully extracted from the stratum corneum. The calibration curves for the standard solution and human plasma were in the ranges of 0.1-50MUM and 5-500MUM, respectively. Both calibration curves had correlation coefficients (r(2)) of 0.999. The limits of detection were 0.03pmol in standard solution and 3pmol in plasma. Compared to non-derivatized TA, the use of CapLC-UV for detecting derivatized TA provides a 1000-fold sensitivity improvement. PMID- 25543300 TI - Identification of two novel brominated contaminants in water samples by ultra high performance liquid chromatography-Orbitrap Fusion Tribrid mass spectrometer. AB - Tetrabromobisphenol A mono(2-hydroxyethyl ether) (TBBPA-MHEE) and TBBPA mono(glycidyl ether) (TBBPA-MGE), two impurities of TBBPA derivatives, were hypothesized to be novel brominated contaminants with potential toxicity. However, due to lacking of analytical method and pure standards, their environmental behavior and toxicity have not been studied. Herein we developed a sensitive method based on ultra-high performance liquid chromatography-Orbitrap Fusion Tribrid mass spectrometer (UHPLC-Orbitrap Fusion TMS) for simultaneous detection of TBBPA-MHEE and TBBPA-MGE in water samples. The sample pretreatment method and the experimental conditions of UHPLC and Orbitrap Fusion TMS, were optimized in detail. The instrument detection limits (IDLs) for TBBPA-MHEE and TBBPA-MGE were 0.5pg and 0.6pg, respectively. The method detection limits (MDLs) for TBBPA-MHEE and TBBPA-MGE in river water samples were 0.9 and 0.8ng/L. With the proposed method, we were able to detect TBBPA-MHEE and TBBPA-MGE for the first time in water samples and technical products of TBBPA derivatives. Therefore, UHPLC-Orbitrap Fusion TMS is a simple and effective tool for identification and quantification of novel contaminants in the environment. PMID- 25543301 TI - Determination of nonpolar and polar lipid classes in human plasma, erythrocytes and plasma lipoprotein fractions using ultrahigh-performance liquid chromatography-mass spectrometry. AB - A novel normal-phase (NP) ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC/MS) method is developed for a separation and quantitation of nonpolar lipid classes occurring in human plasma, erythrocytes and plasma lipoprotein fractions. The baseline class separation of cholesteryl esters (CE), cholesterol, triacylglycerols (TG), regioisomers of 1,2- and 1,3-diacylglycerols (DG) and 1-monoacylglycerols (1-MG) is achieved using an optimized hexane - 2 propanol-acetonitrile mobile phase within 18min for all nonpolar lipid classes or only 9min excluding monoacylglycerols not detected in studied samples. The determination of individual nonpolar lipid classes is performed by the response factor approach and the use of dioleoyl ethylene glycol as a single internal standard. Polar lipid classes, such as phosphatidylglycerols (PG), phosphatidylethanolamines (PE), phosphatidylcholines (PC), sphingomyelins (SM) and lysophosphatidylcholines (LPC), are separated by hydrophilic interaction liquid chromatography (HILIC) using 5mmol/L aqueous ammonium acetate-methanol acetonitrile gradient within 13minutes. The quantitation of polar lipid classes is done by a similar approach as for nonpolar lipid classes, but a different internal standard (sphingosyl PE d17:1/12:0) is used. The complementary information on fatty acyl profiles after the transesterification of the total lipid extract is obtained by gas chromatography with flame ionization detection (GC/FID). The applicability of developed methodology for fast and comprehensive characterization of blood lipidome is illustrated on samples of human plasma, erythrocytes, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) fractions. PMID- 25543302 TI - Optimisation of chromatographic resolution using objective functions including both time and spectral information. AB - The optimisation of the resolution in high-performance liquid chromatography is traditionally performed attending only to the time information. However, even in the optimal conditions, some peak pairs may remain unresolved. Such incomplete resolution can be still accomplished by deconvolution, which can be carried out with more guarantees of success by including spectral information. In this work, two-way chromatographic objective functions (COFs) that incorporate both time and spectral information were tested, based on the peak purity (analyte peak fraction free of overlapping) and the multivariate selectivity (figure of merit derived from the net analyte signal) concepts. These COFs are sensitive to situations where the components that coelute in a mixture show some spectral differences. Therefore, they are useful to find out experimental conditions where the spectrochromatograms can be recovered by deconvolution. Two-way multivariate selectivity yielded the best performance and was applied to the separation using diode-array detection of a mixture of 25 phenolic compounds, which remained unresolved in the chromatographic order using linear and multi-linear gradients of acetonitrile-water. Peak deconvolution was carried out using the combination of orthogonal projection approach and alternating least squares. PMID- 25543303 TI - Facile construction of macroporous hybrid monoliths via thiol-methacrylate Michael addition click reaction for capillary liquid chromatography. AB - A facile approach based on thiol-methacrylate Michael addition click reaction was developed for construction of porous hybrid monolithic materials. Three hybrid monoliths were prepared via thiol-methacrylate click polymerization by using methacrylate-polyhedral oligomeric silsesquioxane (POSS) (cage mixture, n=8, 10, 12, POSS-MA) and three multi-thiol crosslinkers, 1,6-hexanedithiol (HDT), trimethylolpropane tris(3-mercaptopropionate) (TPTM) and pentaerythritol tetrakis(3-mercaptopropionate) (PTM), respectively, in the presence of porogenic solvents (n-propanol and PEG 200) and a catalyst (dimethylphenylphosphine, DMPP). The obtained monoliths possessed high thermal and chemical stabilities. Besides, they all exhibited high column efficiencies and excellent separation abilities in capillary liquid chromatography (cLC). The highest column efficiency could reach ca. 195,000N/m for butylbenzene on the monolith prepared with POSS-MA and TPTM (monolith POSS-TPTM) in reversed-phase (RP) mode at 0.64mm/s. Good chromatographic performance were all achieved in the separations of polycyclic aromatic hydrocarbons (PAHs), phenols, anilines, EPA 610 as well as bovine serum albumin (BSA) digest. The high column efficiencies in the range of 51,400 117,000N/m (achieved on the monolith POSS-PTM in RP mode) convincingly demonstrated the high separation abilities of these thiol-methacrylate based hybrid monoliths. All the results demonstrated the feasibility of the phosphines catalyzed thiol-methacrylate Michael addition click reaction in fabrication of monolithic columns with high efficiency for cLC applications. PMID- 25543304 TI - A validated liquid chromatographic method for the determination of polycyclic aromatic hydrocarbons in honey after homogeneous liquid-liquid extraction using hydrophilic acetonitrile and sodium chloride as mass separating agent. AB - In the present report, a simple and cost-effective method for the determination of twelve US EPA priority polycyclic aromatic hydrocarbons (PAHs) in honey samples after salting-assisted liquid-liquid extraction and UHPLC with fluorescence detection is proposed. The sample treatment is based on the usage of hydrophilic acetonitrile as extraction solvent and its phase separation under high salinity conditions. Due to the high sugar content of the samples the phase separation is promoted effortlessly. Several parameters affecting the extraction efficiency and method sensitivity including the concentration of the honey samples, the type and volume of the extraction solvent, the type and quantity of the inorganic salt, extraction time and centrifugation time was systematically investigated. The method was validated in-house according to the Commission Decision 2002/657/EC guidelines. The limit of detection (LOD) of the method lay between 0.02 and 0.04ngmL(-1) (corresponding to 0.08 and 0.16ngg(-1)) which are close to the quality criteria established by European Regulation (EC) 836/2011 concerning the PAHs in foodstuffs. The mean analytical bias (expressed as relative recoveries) in all spiking levels was acceptable being in the range of 54-118% while the relative standard deviation (RSD) was lower than 19%. The proposed method has been satisfactorily applied for the analysis of the selected PAHs residues in various honey samples obtained from Greek region. PMID- 25543305 TI - High-resolution three-dimensional diffusion-weighted MRI/CT image data fusion for cholesteatoma surgical planning: a feasibility study. AB - The aim of the study was to assess the feasibility of high-resolution three dimensional diffusion-weighted images (HR3D-DWIs)/multi-detector row CT (MDCT) images' data fusion for surgical planning for cholesteatoma. A total of 12 patients (7 male and 5 female; age range 11-72 years; mean 38.1 years) with cholesteatoma underwent preoperative MRI using a 3.0-T clinical unit and an 8 channel array-head coil. For each subject, HR3D-DWIs were obtained using a turbo field-echo with diffusion-sensitized driven-equilibrium preparation with 1.5 mm iso-voxel dimension. These patients also underwent MDCT with a slice thickness of 0.5 mm. Fusion of the HR3D-DWIs and MDCT images was performed using an automated rigid registration and subsequent manual fine-tuning by a board-certified neuroradiologist on a workstation. Fused images were compared to CT and findings confirmed based on operation reports. On the fused images, the extent of the cholesteatoma, which was depicted as a conspicuous high-intensity lesion could be easily evaluated with background bony structures. In all patients, the location and extent of the cholesteatoma on the fused images corresponded well with the intraoperative findings. Image fusion between HR3D-DWIs and MDCT images is feasible, and provides valuable preoperative information for surgical planning to otorhinolaryngologists. PMID- 25543306 TI - Oesophageal duplication cysts, a rare cause of neck lump treated by ultrasound guided drainage: case report and review of the literature. AB - Oesophageal duplication cysts are a rare congenital anomaly of the foregut which usually present in infancy with respiratory symptoms, recurrent pneumonia and feeding difficulty. Other presenting symptoms depend on the location of the cyst and can include dysphagia, chest pain, arrhythmias and features of mediastinal compression. Treatment is usually surgical resection, recommended for complete resolution of symptoms, histological diagnosis and exclusion of malignancy. Here, we present a case of infected oesophageal duplication cyst which presents as a neck lump in a 43-year-old female with a background of Goltz syndrome, azygos fissure and congenital aortic stenosis. Surgical resection was decided against owing to the patient's high risk secondary to co-morbidities and instead ultrasound guided drainage was carried out successfully. The patient was symptom free and well at 1-year follow-up. Oesophageal duplication is an unusual presentation of a neck lump in an adult and whilst the usual treatment is surgical resection, we present here a case treated in an entirely different manner. PMID- 25543307 TI - Sharp neck injuries in suicidal intention. AB - Sharp neck injuries in suicidal intention often present as serious emergency situations with the need for an immediate diagnosis and treatment. We report our study of the clinical evolution of this emergency condition. This study investigates the cases of sharp neck injuries in suicidal intention treated at our institution between 2000 and 2010. Patient records were collected in a retrospectively reviewed and analyzed database. The current literature was compared to our findings. We found 36 cases (10 female and 26 male). The neck injuries were superficial and profound in 16 and 20 patients, respectively. Twenty-two patients were seen by the Head and Neck surgeon. A surgical neck exploration was necessary in 19 cases. Tracheal, laryngeal, pharyngeal and vascular injuries were found in one, five, three and three cases, respectively. The hospital stay ranged from 1 to 47 days. All the patients underwent emergency psychiatric assessment and were subsequently referred for psychiatric treatment. One patient died in the emergency room from an additional arterial injury to the wrist. Sharp neck injuries in suicidal intention treated with an interdisciplinary medical, surgical and psychiatric emergency assessment and treatment have low mortality and morbidity. PMID- 25543308 TI - Comment on: Robotic single-site cholecystectomy in the obese: outcomes from a single institution. PMID- 25543309 TI - Single-anastomosis duodenoileal bypass as a second step after sleeve gastrectomy. AB - BACKGROUND: After sleeve gastrectomy, many surgical options are available in patients with insufficient weight loss. Duodenal switch is typically considered the operation that results in higher weight loss, although it is, perhaps unjustly, considered technically difficult and may be accompanied by severe side effects. Single-anastomosis duodenoileal bypass with sleeve gastrectomy is a simplification of the duodenal switch that may behave as a standard biliopancreatic diversion but is easier and quicker to perform. Given its effectiveness as a primary surgery we hypothesized that it would be successful as a second-step operation. The objective of this study was to analyze the weight loss and co-morbidities resolution after a single-anastomosis duodenoileal bypass (SADI) performed as a second step after sleeve gastrectomy. METHODS: Sixteen patients with an initial body mass index of 56.4 kg/m(2) and a mean excess weight loss of 39.5% after a sleeve gastrectomy were submitted to a single-anastomosis duodenoileal bypass with a 250-cm common channel. RESULTS: There were no postoperative complications. The mean excess weight loss was 72% 2 years after the second-step surgery. The complete remission rate was 88% for diabetes, 60% for hypertension, and 40% for dyslipidemia. The mean number of daily bowel movements was 2.1. One patient suffered an isolated episode of clinical hypoalbuminemia. CONCLUSION: SADI is a safe operation that offers a satisfactory weight loss for patients subjected to a previous sleeve gastrectomy. The side effects are well tolerated, and complications are minimal. PMID- 25543310 TI - Effects of a very low calorie diet in the preoperative stage of bariatric surgery: a randomized trial. AB - BACKGROUND: Preoperative bariatric patients can follow very low calorie diets (VLCD), reducing surgical risks. However, possible advantages of a liquid diet over one of normal consistency are controversial. This study investigated the effect of a liquid VLCD compared with one of normal consistency considering visceral fat (VF) loss and metabolic profile in preoperative clinically severe obese patients. METHODS: This was a randomized, open-labeled, controlled clinical trial. Patients were divided into 2 groups: liquid diet and normal diet. Data were collected at baseline and 7 and 14 days after intervention. Information gathered was analyzed for loss of weight and VF, biochemical data, anthropometric data, and energy intake. RESULTS: Fifty-seven patients consumed the liquid diet and 47 consumed the normal consistency diet. The liquid diet group lost significantly more weight (P<.0290) and VF (P<.0410) than the normal diet group. An inverse correlation occurred between VF loss and surgical time among the liquid diet group (r2=-.1302, P=.001). Additionally, there was a positive correlation between the percentage of excess weight loss and ketonuria (P=.0070). No between-group difference occurred regarding calorie intake. CONCLUSION: Patients that consumed a liquid diet presented a positive effect on reducing VF and greater weight loss than the normal diet group. Both VLCDs presented benefits offering a protective effect during the preoperative stage. PMID- 25543311 TI - Safe and effective performance of endoscopy in obese patients: are we adequately prepared to provide the best outcomes. PMID- 25543312 TI - Gastric sleeve leak: a single institution's experience with early combined laparoendoscopic management. AB - BACKGROUND: Sleeve gastrectomy is an effective weight loss procedure that is technically less complex than Roux-en-Y gastric bypass. However, staple line leak (SLL) remains a significant complication of this procedure with reported incidence ranging from 1%-7%. Multiple treatment strategies for SLL are reported including surgical re-exploration, percutaneous drainage, and endoscopic stenting. Our objective was to review the results of our experience with combined laparoendoscopic procedures in managing SLL. METHODS: A retrospective review of patients with SLL after laparoscopic sleeve gastrectomy (LSG) between June 2008 and October 2013 was performed. Patient characteristics, operative details, and postoperative management strategies were reviewed. All patients were managed with a combination of early laparoscopic washout and endoscopic stenting. RESULTS: One hundred sixty-five patients underwent LSG with SLL identified in 4 patients (2.4%). One patient was transferred from an outside institution for SLL. Average time to SLL diagnosis was postoperative day 3 (range 1-7). After diagnosis patients underwent laparoscopic washout and initial endoscopic stenting. Three patients required additional endoscopic procedures to manage stent migration, and 2 required additional procedures for peri-stent leak. Complications were managed endoscopically with stent adjustment or replacement. Patients had indwelling stents for an average of 29 days (range 15-56). Mean hospital length of stay was 30 days (range 20-42). CONCLUSION: SLL after LSG can confer a high morbidity and mortality. Endoscopic management of SLL with stenting has been advocated because it successfully manages the leaks and avoids additional invasive procedures. Based on our experience, successful management of SLL can be achieved with an early combined laparoendoscopic approach. PMID- 25543313 TI - Comment on: Laparoscopic adjustable gastric banding with gastric placation: short term results and comparison with LAGB alone and sleeve gastrectomy. PMID- 25543314 TI - Comment on: Prevalence and characteristics of individuals without diabetes and hypertension who underwent bariatric surgery: lessons learned about metabolically healthy obese. PMID- 25543315 TI - Comment on: Duodenal diverted sleeve gastrectomy with ileal interposition does not cause biliary salt malabsorption. PMID- 25543316 TI - Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene. PMID- 25543317 TI - Led astray: MELAS initially misdiagnosed as herpes simplex encephalitis. PMID- 25543318 TI - Intraluminal carotid artery thrombus on gadolinium-enhanced MRA. PMID- 25543319 TI - Stratifying patients at the risk of heart failure hospitalization using existing device diagnostic thresholds. AB - BACKGROUND: Heart failure hospitalizations (HFHs) cost the US health care system ~$20 billion annually. Identifying patients at risk of HFH to enable timely intervention and prevent expensive hospitalization remains a challenge. Implantable cardioverter defibrillators (ICDs) and cardiac resynchronization devices with defibrillation capability (CRT-Ds) collect a host of diagnostic parameters that change with HF status and collectively have the potential to signal an increasing risk of HFH. These device-collected diagnostic parameters include activity, day and night heart rate, atrial tachycardia/atrial fibrillation (AT/AF) burden, mean rate during AT/AF, percent CRT pacing, number of shocks, and intrathoracic impedance. There are thresholds for these parameters that when crossed trigger a notification, referred to as device observation, which gets noted on the device report. We investigated if these existing device observations can stratify patients at varying risk of HFH. METHODS: We analyzed data from 775 patients (age: 69 +/- 11 year, 68% male) with CRT-D devices followed for 13 +/- 5 months with adjudicated HFHs. HFH rate was computed for increasing number of device observations. Data were analyzed by both excluding and including intrathoracic impedance. HFH risk was assessed at the time of a device interrogation session, and all the data between previous and current follow-up sessions were used to determine the HFH risk for the next 30 days. RESULTS: 2276 follow-up sessions in 775 patients were evaluated with 42 HFHs in 37 patients. Percentage of evaluations that were followed by an HFH within the next 30 days increased with increasing number of device observations. Patients with 3 or more device observations were at 42* HFH risk compared to patients with no device observation. Even after excluding intrathoracic impedance, the remaining device parameters effectively stratified patients at HFH risk. CONCLUSION: Available device observations could provide an effective method to stratify patients at varying risk of heart failure hospitalization. PMID- 25543320 TI - Victims of lethal hypothermia have decreased levels of thrombomodulin in myocardium and urine. AB - Severe cold stress has been shown to cause changes in the expression and secretion of thrombomodulin (TM), an endothelial protein regulating haemostasis and inflammation. To further evaluate TM as a cold stress indicator, relative TM mRNA and TM protein levels in the myocardium and the concentrations of TM in serum and urine were analysed in different causes of death (hypothermia main cause, n = 80; hypothermia contributory cause, n = 26; cardiovascular disease (CVD) main cause, n = 94; trauma main cause, n = 45; other main cause, n = 25). Urinary catecholamine concentrations and myocardial heat shock factor 1 (HSF1) transcript levels were also studied. The TM mRNA and the TM protein levels in myocardium and urine were significantly lower in hypothermia deaths than those in the controls. Post-mortem interval did not correlate with urinary TM concentration. The sensitivity and specificity of urinary TM assay to detect hypothermia deaths were 70.8 and 70.3 %, respectively. Catecholamine concentrations in urine correlated significantly with TM concentration in urine and TM mRNA levels in all groups excluding CVD deaths. There were no differences in the HSF1 transcript levels and no correlation to TM levels. These findings provide further evidence that cold stress and hypothermia affect TM expression and secretion and that they are possibly linked to catecholamine action. Thus, measuring post-mortem TM levels may provide additional support to diagnosing hypothermia in medico-legal examination. The results may also provide additional knowledge for the treatment of hypothermic patients and the use of hypothermia for medical purposes. PMID- 25543321 TI - Schizophrenia Patient or Spiritually Advanced Personality? A Qualitative Case Analysis. AB - Many aspects of spiritual experience are similar in form and content to symptoms of psychosis. Both spiritually advanced people and patients suffering from psychopathology experience alterations in their sense of 'self.' Psychotic experiences originate from derangement of the personality, whereas spiritual experiences involve systematic thinning out of the selfish ego, allowing individual consciousness to merge into universal consciousness. Documented instances and case studies suggest possible confusion between the spiritually advanced and schizophrenia patients. Clinical practice contains no clear guidelines on how to distinguish them. Here we use a case presentation to help tabulate clinically useful points distinguishing spiritually advanced persons from schizophrenia patients. A 34-year-old unmarried male reported to our clinic with four main complaints: lack of sense of self since childhood; repeated thoughts questioning whether he existed or not; social withdrawal; and inability to continue in any occupation. Qualitative case analysis and discussions using descriptions from ancient texts and modern psychology led to the diagnosis of schizophrenia rather than spiritual advancement. PMID- 25543322 TI - [Disseminated mucormycosis in immunocompetent patients: A disease that also exists]. AB - Mucormycosis is usually an acute angioinvasive infections, which leads to non suppurative necrosis and significant tissue damage. It represents 1.6% of all the invasive fungal infections and predominates in immunosuppressed patients with risk factors. Incidence has been significantly increased even in immunocompetent patients. Due to finding a case of disseminated mucormycosis caused by Rhizomucor pusillus in a young immunocompetent patient, a systematic review was carried out of reported cases in PubMed of mucormycosis in immunocompetent adults according to the main anatomic locations, and especially in disseminated cases. A review of the main risk factors and pathogenicity, clinical manifestations, techniques of early diagnosis, current treatment options, and prognosis is presented. Taxonomy and classification of the genus Mucor has also been reviewed. PMID- 25543323 TI - Using LigasureTM or Harmonic Ace(r) in Laparoscopic Sleeve Gastrectomies? A Prospective Randomized Study. AB - BACKGROUND: Laparoscopic sleeve gastrectomy is one of the most recent advances of surgery for treating morbid obesity. Many laparoscopic devices have evolved to provide vascular control and tissue dissection. METHODS: This is a prospective randomized study comparing the intraoperative and postoperative complications and operative time of two groups of patients who underwent laparoscopic sleeve gastrectomy. In the first group after randomization, sleeve gastrectomy was performed using LigasureTM and in the second group Harmonic Ace(r) was used. RESULTS: In total, 94 patients were enrolled in the study allocated in two groups. In group 1, 43 patients were operated using LigasureTM, and in group 2, 51 patients were operated using Harmonic Ace(r). No significant differences were highlighted between these two groups with regards to operative time (45.0 +/- 15.0 vs 40.0 +/- 20.0 min, p = 0.199), intraoperative complications (32.6 vs 15.7 %, p = 0.054) and postoperative complications (4.7 vs 17.6 %, p = 0.051). CONCLUSIONS: Both LigasureTM and Harmonic Ace(r) provide surgeons ergonomy, and no significant differences were shown in operative time and complications. Safety and efficacy in such demanding operations is of critical importance. Choice between these two shears lies with surgeon's preference. PMID- 25543324 TI - The prevalence of orthorexia nervosa among eating disorder patients after treatment. AB - BACKGROUND: The pursuit for healthy food consumption is considered a laudable habit. This attitude can turn into pathological when cognitions and worries about healthy nutrition lead to such an accurate food selection that correct diet becomes the most important part of one's own life leading to important dietary restrictions, stereotyped eating or impairment in important areas of functioning. This behaviour is coined orthorexia nervosa (ON) and can share common characteristics with anorexia nervosa (AN) and bulimia nervosa (BN). The purpose of the present study was to examine the frequency of ON among women with eating disorders (EDs) and to evaluate if it changed after treating the ED. METHODS: Thirty-two patients with AN or BN were evaluated by means of the ORTO-15, the Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS) and the Eating Attitude Test (EAT-26) before (t0) and 3 years after the treatment of their ED (t1), and compared to 32 female healthy controls (HC) matched by gender, age, and BMI at t1. RESULTS: A significantly higher percentage of patients either at t0 (28 %) or t1 (58 %) resulted positive to ORTO-15 compared to controls (6 %). YBC-EDS and EAT-26 scores were higher among ED patients than in HC, but they decreased from t0 to t1. CONCLUSIONS: Orthorexia nervosa symptoms are highly prevalent among patients with AN and BN, and tend to increase after treatment. ON seems associated both with the clinical improvement of AN and BN and the migration towards less severe forms of EDs. It is necessary to clarify if ON residual symptomatology can be responsible for a greater number of relapses and recurrences of EDs. PMID- 25543325 TI - Acute effect of high-intensity cycling exercise on carotid artery hemodynamic pulsatility. AB - PURPOSE: Investigate the effects of acute high-intensity exercise on common carotid artery (CCA) dimensions, stiffness, and wave intensity. METHODS: Fifty five healthy men and women (22 +/- 5 year; 24.5 +/- 2.7 kg m(-2)) underwent 30 s of high-intensity cycling (HIC; Wingate anaerobic test). CCA diameter, stiffness [beta-stiffness, Elastic Modulus (E p)], pulsatility index (PI), forward wave intensities [due to LV contraction (W 1) and LV suction (W 2)], and reflected wave intensity [negative area (NA)] were assessed using a combination of Doppler ultrasound, wave intensity analysis, and applanation tonometry at baseline and immediately post-HIC. RESULTS: CCA beta-stiffness, E p, PI and pulse pressure increased significantly immediately post-HIC (p < 0.05). CCA diameter decreased acutely post-HIC (p < 0.05). There were also significant increases in W 1 and NA and a significant decrease in W 2 (p < 0.05). A significant correlation was found between change in W 1 and PI (r = 0.438, p < 0.05), from rest to recovery as well as a significant inverse correlation between W 2 and PI (r = -0.378, p < 0.05). Change in PI was not associated with change in CCA stiffness or NA (p > 0.05). CONCLUSIONS: Acute HIC results in CCA constriction and increases in CCA stiffness along with increases in hemodynamic pulsatility. The increase in pulsatility may be due to a combination of increased forward wave intensity from increased LV contractility into a smaller vessel (i.e. impaired matching of diameter and flow) coupled with reduced LV suction. PMID- 25543326 TI - [Coping with suffering, dying and death: challenges for care in the 21st century]. PMID- 25543327 TI - [Smoking at work. Health professionals and the smoke-free law]. PMID- 25543328 TI - Down-Regulation of MRP1 Expression in C6/VP16 Cells by Chitosan-MRP1-siRNA Nanoparticles. AB - High expression of multidrug resistance-associated protein 1 (MRP1) in tumor cells reduces effectiveness of chemotherapy drugs. In this study, we screened MRP1 interfering RNA (MRP1-siRNA) molecules that are able to reverse etoposide (VP16) resistance in multidrug resistance rat glioma cell line C6/VP16, and identified one siRNA molecule that is able to effectively deplete the expression of MRP1 gene and reverse tumor cells resistance to etoposide. Since siRNA instability limits its application in treatment of diseases, we next tested silencing effect of chitosan-MRP1-siRNA nanoparticles and found that the nanoparticles with N:P ratio 175 are able to effectively inhibit MRP1 mRNA and protein expression. Our data demonstrate that chitosan can be used as siRNA carrier for high efficient gene silencing in tumor cells. PMID- 25543329 TI - Breast Cancer: Epidemiology and Etiology. AB - Breast cancer, the most frequently occurring cancer in women, is a major public health problem, with 1,384,155 estimated new cases worldwide with nearly 459,000 related deaths. Breast cancer is highly heterogeneous in its pathological characteristics, some cases showing slow growth with excellent prognosis, while others being aggressive tumors. Current predictions and statistics suggest that both worldwide incidence of breast cancer and related mortality are on the rise. According to 2012 GLOBOCAN statistics, nearly 1.7 million women were diagnosed with breast cancer with 522,000 related deaths-an increase in breast cancer incidence and related mortality by nearly 18 % from 2008. According to American Cancer Society, one in eight women in the United States will develop breast cancer in her lifetime. It has been predicted that the worldwide incidence of female breast cancer will reach approximately 3.2 million new cases per year by 2050. These numbers reflect the magnitude of breast cancer incidence, its effect on society worldwide and the need for urgency for preventive and treatment measures. While technological advances in medical sciences and health care have made it possible to detect the disease early and to start the treatment early on to prevent the progress of the disease into a metastatic state, there are several unanswered questions with regard to the molecular mechanisms that underlie the aggressiveness of certain forms of this disease. Epidemiological studies suggest that addressing socio economical issues is utmost important, so that all women have equal access to medical care from screening to advanced treatment, and only such decisive action can help reduce the worldwide burden of breast cancer. PMID- 25543330 TI - Advantages, Disadvantages, and Trend of Integrative Medicine in the Treatment of Heart Failure. AB - Integrative medicine therapy using traditional Chinese medicine (TCM) combined with western medicine has shown some advantages in treating heart failure (HF), such as holistic concept; multi-target treatment; dialectical logic; personalized therapy; formulae compatibility; and reduction of side effects of western medicine. However, problems still exist in TCM treatment of HF, including non uniformed categorization of TCM, lack of standardized syndrome differentiation and lack of an evidence base. The future of treatment of HF seems to be focused on reversing ventricular remodeling, improving cardiac rehabilitation, and accelerating experimental research and drug discovery in TCM. PMID- 25543331 TI - Marketing to Develop the Premier Medical Brand in the Huaihai Economic Zone. AB - Based on the practices at Xuzhou Central Hospital, the authors analyzed the improvements in the healthcare quality and economic efficiency after implementing a brand marketing strategy. Using methods including questionnaires and business controlling means, we summarized that the improvements to the healthcare quality and economic efficiency after strategies were implemented in the areas of network, reputation, academic research, and public welfare. After the implementation of a brand marketing campaign, the medical service quality and brand reputation have been greatly improved. Meanwhile, a central hospital group was formed and gradually became the central healthcare provider in the Huaihai Economic Zone. The new marketing facilitated the drastic increase of medical service and brand reputation. PMID- 25543332 TI - Emotion processing in schizophrenia is state and trait dependent. AB - BACKGROUND: Substantial evidence exists about emotion processing (EP) impairments in schizophrenia patients. However, whether these deficits are present primarily during psychosis (i.e., state dependent) or an integral part of the disorder (i.e., trait dependent) remains unclear. METHODS: EP was assessed with the degraded facial affect recognition task in schizophrenia patients (N=521) and healthy controls (N=312) at baseline (T1) and after a three year follow-up (T2). In schizophrenia patients symptomatic remission was assessed with the Positive and Negative Syndrome Scale (PANSS) remission tool. Patients were divided into four groups: remission T1 and remission T2 (RR); remission T1 and non-remission T2 (RN); non-remission T1 and non-remission T2 (NN) and non-remission T1 and remission T2 (NR). Factorial repeated measures ANCOVA was used to compare EP performance over time between groups. Age, gender and general cognition were included as covariates. RESULTS: Schizophrenia patients performed worse than healthy controls on EP at T1 (p=0.001). The patients that were in symptomatic remission at both time points (the RR group) performed worse than the healthy controls at T2 (p<0.001). Significant group*time interactions were found between RR and RN (p=0.001), and between NR and RN (p=0.04), indicating a differential EP performance over time. No group*time interaction was found between NN and NR. CONCLUSION: The results show relatively poor EP performance in schizophrenia patients compared to healthy controls. EP performance in schizophrenia patients was associated with symptomatic remission. The results provide support for the hypothesis that EP deficits in schizophrenia are both state and trait dependent. PMID- 25543333 TI - Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have essential roles in synaptic plasticity which is involved in pathogenesis and treatment of psychiatric disorders. However, it is not clear whether they act simultaneously during illness states in major psychiatric disorders. METHODS: BDNF and GDNF serum levels were measured concomitantly by enzyme-linked immunosorbent assay (ELISA) method in 171 patients diagnosed with schizophrenia (n=33), bipolar disorder-manic episode (n=39), bipolar/unipolar depression (n=64, 24/40) and obsessive-compulsive disorder (n=35) according to DSM-IV, and 78 healthy volunteers. SCID-I and SCID non patient version were used for clinical evaluation of the patients and healthy volunteers, respectively. Correlations between the two trophic factor levels, and illness severity scores, duration of illness and medication dosages were studied across different illnesses. RESULTS: While patients had equally lower BDNF levels in all diagnoses, GDNF levels were significantly higher in mania and lower in schizophrenia compared to healthy controls. BDNF levels were negatively correlated to illness severity scores in affective episodes (mania and depression). Longer duration of illness (>5 years) had an impact on lower GDNF levels in schizophrenia. BDNF levels and antipsychotic drug dosages in schizophrenia, and GDNF levels and antidepressant drug dosages in obsessive compulsive disorder were positively correlated. CONCLUSION: Our data confirmed the evidence of equally deficient neuronal support by BDNF in all major psychiatric illnesses, but suggested a diverse glial functioning between schizophrenia and mania. PMID- 25543335 TI - Non-invasive cardiac output monitoring during sinus surgery. PMID- 25543334 TI - Pattern of secretion of pregnancy-associated plasma protein-A (PAPP-A) during pregnancies complicated by fetal aneuploidy, in vivo and in vitro. AB - BACKGROUND: Pregnancy-associated placental protein-A (PAPP-A) is a metalloprotease which circulates as an hetero-tetramer in maternal blood. Its maternal serum concentration in fetal trisomy 21 is decreased during the first trimester, so that PAPP-A is a useful screening biomarker. However, the regulation of PAPP-A placental secretion is unclear. We therefore investigated the secretion of PAPP-A in pregnancies complicated by fetal aneuploidies, both in vivo and in vitro. METHODS: Maternal serum collected between 10 WG and 33 WG during 7014 normal pregnancies and 96 pregnancies complicated by fetal trisomy 21, 18, and 13 were assayed for PAPP-A using the Immulite 2000xpi system(r). The pregnancies were monitored using ultrasound scanning, fetal karyotyping and placental analysis. Villous cytotrophoblasts were isolated from normal and trisomic placenta and cultured to investigate PAPP-A secretion in vitro (n=6). RESULTS: An increased nuchal translucency during the first trimester is a common feature of many chromosomal defect but each aneuploidy has its own syndromic pattern of abnormalities detectable at the prenatal ultrasound scanning and confirmed at the fetal examination thereafter. PAPP-A levels rise throughout normal pregnancy whereas in trisomy 21, PAPP-A levels were significantly decreased, but only during the first trimester. PAPP-A levels were decreased in trisomy 13 and sharply in trisomy 18, whatever the gestational age. In vitro, PAPP-A secretion was decreased in aneuploidy, and associated with decreased hCG secretion in Trisomy 21 and 18. These biochemical profiles did not appear to be linked to any specific histological lesions affecting the placenta. CONCLUSIONS: These profiles may reflect different quantitative and qualitative placental dysfunctions in the context of these aneuploidies. PMID- 25543337 TI - Viva questions from the IJDVL. PMID- 25543338 TI - High-resolution manometry in diagnosis and treatment of achalasia: help or hype. AB - High-resolution manometry (HRM) with 36 pressure transducers spanning the esophagus has revolutionized the diagnosis and treatment of esophageal motility disorders, especially with respect to achalasia. The three major contributions of HRM are as follows: (a) Integrated relaxation pressure (IRP) at the esophagus gastric junction (EGJ) >15 mmHg has a sensitivity of 97 % for the diagnosis of achalasia; (b) there are three distinct subtypes of achalasia - type 1 (no distal pressurization), type II (panesophageal pressurization), and type III (spastic contractions); and (c) subtypes predict the success of treatment with type II patients doing the best and type III being the most difficult to treat. Recent studies also suggest that HRM is superior to conventional manometry for diagnosis of achalasia. Other useful observation from HRM is the recognition of EGJ outflow obstruction (type IV achalasia) with normal peristalsis which may be due to mechanical or functional impairment at the EGJ. Finally, after successful treatment of achalasia, the IRP falls to less than 15 mmHg and the achalasia pressurization pattern resolves sometimes with the return of weak peristalsis. This complements well with the information obtained by the timed barium esophagram. PMID- 25543336 TI - Pathway activation profiling reveals new insights into age-related macular degeneration and provides avenues for therapeutic interventions. AB - Age-related macular degeneration (AMD) is a major cause of blindness in older people and is caused by loss of the central region of the retinal pigment epithelium (RPE). Conventional methods of gene expression analysis have yielded important insights into AMD pathogenesis, but the precise molecular pathway alterations are still poorly understood. Therefore we developed a new software program, "AMD Medicine", and discovered differential pathway activation profiles in samples of human RPE/choroid from AMD patients and controls. We identified 29 pathways in RPE-choroid AMD phenotypes: 27 pathways were activated in AMD compared to controls, and 2 pathways were activated in controls compared to AMD. In AMD, we identified a graded activation of pathways related to wound response, complement cascade, and cell survival. Also, there was downregulation of two pathways responsible for apoptosis. Furthermore, significant activation of pro mitotic pathways is consistent with dedifferentiation and cell proliferation events, which occur early in the pathogenesis of AMD. Significantly, we discovered new global pathway activation signatures of AMD involved in the cell based inflammatory response: IL-2, STAT3, and ERK. The ultimate aim of our research is to achieve a better understanding of signaling pathways involved in AMD pathology, which will eventually lead to better treatments. PMID- 25543339 TI - Pisacano Leadership Foundation names 2014 Pisacano Scholars. PMID- 25543340 TI - Clinical informatics as an option for American Board of Family Medicine Diplomates. PMID- 25543342 TI - [Retraction: Effects of an integrated self-management program on self-management, glycemic control, and maternal identity in women with gestational diabetes mellitus]. PMID- 25543341 TI - Asymmetric Coulomb fluids at randomly charged dielectric interfaces: anti fragility, overcharging and charge inversion. AB - We study the distribution of multivalent counterions next to a dielectric slab, bearing a quenched, random distribution of charges on one of its solution interfaces, with a given mean and variance, both in the absence and in the presence of a bathing monovalent salt solution. We use the previously derived approach based on the dressed multivalent-ion theory that combines aspects of the strong and weak coupling of multivalent and monovalent ions in a single framework. The presence of quenched charge disorder on the charged surface of the dielectric slab is shown to substantially increase the density of multivalent counterions in its vicinity. In the counterion-only model (with no monovalent salt ions), the surface disorder generates an additional logarithmic attraction potential and thus an algebraically singular counterion density profile at the surface. This behavior persists also in the presence of a monovalent salt bath and results in significant violation of the contact-value theorem, reflecting the anti-fragility effects of the disorder that drive the system towards a more "ordered" state. In the presence of an interfacial dielectric discontinuity, depleting the counterion layer at the surface, the charge disorder still generates a much enhanced counterion density further away from the surface. Likewise, the charge inversion and/or overcharging of the surface occur more strongly and at smaller bulk concentrations of multivalent counterions when the surface carries quenched charge disorder. Overall, the presence of quenched surface charge disorder leads to sizable effects in the distribution of multivalent counterions in a wide range of realistic parameters and typically within a distance of a few nanometers from the charged surface. PMID- 25543343 TI - Obituary: Susan Lim Lee Hong: February 14, 1952 - August 2, 2014. PMID- 25543344 TI - [Bleeding tumor of the lower lip. It was not there weeks ago!]. PMID- 25543345 TI - [Eating disorders. Physical activity in treatment of anorexia nervosa]. PMID- 25543346 TI - [Framework for the next generation. The thorny path to a rural physician's life]. PMID- 25543347 TI - [My practice is probably a wellness oasis]. PMID- 25543348 TI - [A fine little boy with a panicked mother]. PMID- 25543349 TI - [Revision to 1. July 2014. Two chronic illness codes are now side by side]. PMID- 25543350 TI - [Geriatric care. Barthel index is not part of GOP 03242]. PMID- 25543351 TI - [Starting 2015 new non-medical assistants flood health care practice]. PMID- 25543352 TI - [MFA during a home visit may do more than just hold a hand]. PMID- 25543353 TI - [23 million affected persons. These patients need better pain management]. PMID- 25543354 TI - [Uncomplicated respiratory tract infections. "As needed prescriptions are almost never filled"]. PMID- 25543355 TI - [Rare lung diseases. Not everyone who wheezes has COPD]. PMID- 25543356 TI - [Lung, heart, eye, skin. Sarcoidosis is a chameleon]. PMID- 25543357 TI - [Young man with obstructive long disease. It is not due to smoking!]. PMID- 25543358 TI - [Sudden fever attacks in a young Crohn disease patient. Would you have considered the heart here?]. PMID- 25543359 TI - [Patient with colon carcinoma and venous thrombosis. What anticoagulation would you prescribe for him?]. PMID- 25543360 TI - [Comorbidity in rheumatic diseases. Check the heart and kidneys of your arthritis patient!]. PMID- 25543361 TI - [Confusion states. The schizophrenia spectrum is unexpectedly large]. PMID- 25543362 TI - [Intestinal cancer early detection. Better not to rely on the guaiac test]. PMID- 25543363 TI - [During therapy with metformin pay attention to TSH!]. PMID- 25543364 TI - [Colistin inhalation helps against Pseudomonas aeruginosa,]. PMID- 25543365 TI - [Ironically, athletes often have bad teeth]. PMID- 25543367 TI - [Too much salt impairs the heart - too little as well!]. PMID- 25543366 TI - [Protein rich diet boosts training effects]. PMID- 25543369 TI - [Ablate thyroid nodules with radio frequency]. PMID- 25543368 TI - [The bones are suddenly vanishing in this man]. PMID- 25543370 TI - [Image of the anatomy of the skin]. PMID- 25543371 TI - [The new EU and US hypertension guidelines. Implication for practice]. PMID- 25543372 TI - [ACE inhibitors or ARBs for first-line treatment of arterial hypertension--who goes for the victory?]. PMID- 25543373 TI - [What means walking limitation by pain in the calf?]. PMID- 25543374 TI - [Update gout: what has changed in diagnosis and treatment?]. PMID- 25543375 TI - [Physician's role in "medical drama"--pitfall?]. PMID- 25543376 TI - [Microscopic hematuria]. PMID- 25543377 TI - [Smoking cessation improves quality of life]. PMID- 25543378 TI - [Symptomatic coronary heart diseases. Combination therapy is successful in general practice]. PMID- 25543379 TI - [Long-term oral anticoagulation. Self monitoring optimizes vitamin K antagonist therapy]. PMID- 25543380 TI - [Interview with Dr. Christoph Soppa, consultant physician, Munich. No additional budget burden]. PMID- 25543381 TI - [Looking to the future: treatment for retinal vascular disease]. PMID- 25543382 TI - [Inhibition of stress-responsive signaling pathway prevents neural cell death following optic nerve injury]. AB - Optic nerve injury (ONI) induces retinal ganglion cell (RGC) death and optic nerve atrophy that lead to visual loss. Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase (MAPKKK) and plays an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 MAPK activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 MAPK inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 (MCP-1) production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS) in microglia were decreased when the ASK1-p38 MAPK pathway was blocked by inhibitor of ASK1 or p38 MAPK. ONI-induced expression of TNF and iNOS in the retina were absent in ASK1-deficient mice. These results suggest that ASK1 activation in both neural and glial cells is involved in neural cell death, and that pharmacological interruption of ASK1-p38 MAPK pathways could be beneficial in the treatment of ONI. PMID- 25543383 TI - [(Pro) renin receptor in the pathogenesis of proliferative diabetic retinopathy]. AB - The renin-angiotensin system (RAS), originally regarded as an important controller of systemic blood pressure (circulatory RAS), plays a pivotal role in pathological vascular conditions including inflammation and angiogenesis (tissue RAS). (Pro) renin receptor [(P) RR] is known to bind with prorenin causing the dual activation of tissue renin-angiotensin system (RAS) together with RAS independent intracellular signaling pathways and contributes to the molecular pathogenesis of end-organ damage. In this review, we investigated localization and expression of (P)RR in fibrovascular tissues and vitreous fluids from patients with proliferative diabetic retinopathy and evaluated the molecular mechanisms in vitro in order to confirm the conclusions regarding (P) RR from animal studies. (P)RR immunoreactivity was detected in vascular endothelial cells, co-localized with prorenin, phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor (VEGF). Protein levels of soluble (P) RR in the vitreous fluids were higher in proliferative diabetic retinopathy (PDR) eyes than in non-diabetic control eyes, and were significantly correlated with vitreous VEGF levels and the vascular density of fibrovascular tissues. We herein report the first evidence that shows the close association of (P) RR with angiogenic activity in human PDR. The present data suggest the validity of (P) RR as a molecular target for the treatment of PDR. PMID- 25543384 TI - [Polypoidal choroidal vasculopathy: new observations and therapeutic implications]. AB - Polypoidal choroidal vasculopathy (PCV) is a subtype of neovascular age-related macular degeneration characterized by peculiar polypoidal lesions seen on indocyanine green angiography (IA). However, precise pathogenesis of PCV has yet to be clearly elucidated. In addition to the conventional diagnostic tools, we evaluated the clinical characteristics of PCV by means of relatively new and noninvasive imaging methods, namely, fundus autofluorescence photography and enhanced depth imaging optical coherence tomography, and found novel observations. This article focuses especially on the relationship between the clinical characteristics of PCV and choroidal vascular hyperpermeability. Choroidal vascular hyperpermeability, which is visualized as multifocal hyperfluorescence in the middle and late phases on IA, was originally described as a characteristic finding in, central serous chorioretinopathy (CSC). Of the 89 patients with PCV in our case series, 31 patients (34.8%) demonstrated choroidal vascular hyperpermeability. The patients with PCV associated with choroidal vascular hyperpermeability demonstrated more frequently bilateral occurrence of neovascular membrane, a history of CSC, a thickened choroid and poor responses to ranibizumab therapy than those without choroidal vascular hyperpermeability. Our results provide further understanding of PCV and new therapeutic implications. PMID- 25543385 TI - [Impact of anti-VEGF therapy on the cellular microenvironment in retinal angiogenesis]. AB - Various large-scale studies show the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in treatment of retinal diseases. Based on the evidence, it is expected that this therapeutic strategy will be used widely for various retinal vascular diseases including diabetic retinopathy and retinal vein occlusion. Leukocyte infiltration is an important step that occurs during angiogenesis in inflammatory diseases. Various studies report that infiltrated leukocytes are a prerequisite for retinal angiogenesis, including diabetic retinopathy. Furthermore, the fibrovascular membrane (FVM) microenvironment consists of stromal components (extracellular matrix, myofibroblasts and leukocytes) supported by angiogenesis (endothelial cells and pericytes). The activity of proliferative diabetic retinopathy (PDR) is thought to be determined by the angiogenesis-assisted FVM microenvironment status. Recently, we investigated whether intravitreal anti-VEGF therapy modulates leukocyte infiltration in retinal angiogenesis using the surgically obtained FVM in pars plana vitrectomy with or without pretreatment with bevacizumab. The effect of anti-VEGF therapy on leukocyte infiltration was also examined with a mouse model of oxygen-induced retinopathy. Moreover, the impact of anti-VEGF therapy on endothelial cells, pericytes and myofibroblasts was also examined using the FVM. We could observe that anti-VEGF therapy blocked leukocyte infiltration as well as re-entry from the retina. The therapy also could induce the contraction of blood vessels, increasing the pericyte ratio and transforming growth factor-beta expression in the FVM. Our data indicate anti-VEGF therapy could attain anti inflammation, vessel contraction and vessel maturation, resulting in the resolution of retinal edema as well as the prevention of intraoperative hemorrhage. PMID- 25543386 TI - [The macrophage contribution for maintaining lymphatic vessel in cornea]. AB - The presence of antigen-presenting cells and hem- and lymphangiogenesis in the cornea are risk factors for the rejection of corneal transplants. We previously reported that antigen-presenting cells such as macrophages (MPs) play an important role in the induction of lymphatic endothelial cells during inflammation. This prompted us to inquire whether the existence of lymphatic vessels in the cornea is associated with the activation of MPs during inflammation. To investigate this question, we performed suture placement on the cornea to induce inflammation. We found that a large number of MPs were recruited and that lymphatic vessels were formed in response. Next, as C57BL/6 mice have a higher rejection rate after corneal transplantation than BALB/c mice, we compared the corneas of C57BL/6 and BALB/c mice under normal and inflamed conditions. We found that the number of spontaneously formed lymphatic vessels in the C57BL/6 corneas was significantly greater than in the BALB/c corneas, and that there were more activated MPs in the C57BL/6 corneas than in the BALB/c corneas. Additionally, to confirm that activated MPs induced and maintained lymphatic vessels in the cornea, we depleted the number of MPs in C57BL/6 mice via clodronate liposomes. We found that MP depletion reduced the spontaneous formation of lymphatic vessels and reduced inflammation-induced lymphangiogenesis relative to control mice. Finally, we found that mice deficient in MP markers had fewer spontaneously formed lymphatic vessels and less lymphangiogenesis than control C57BL/6 mice. The evidence gathered in this study leads us to conclude that activated MPs appear to play an important role in the formation of new lymphatic vessels and in their maintenance. PMID- 25543387 TI - [Problems of visual field disturbance criteria in visual impairment grade 5]. AB - PURPOSE: In 1995, the Act on Welfare of Physically Disabled Persons was revised and the visual impairment grading methods were modified. In this revision, the target size for peripheral visual field measurements was changed from V/4 to I/4. We compared the area of I/4 and V4 visual fields in normal eyes and evaluated its influence on the decision of the visual impairment grade 5. SUBJECTS AND METHODS: Goldmann kinetic perimetry results obtained from 137 eyes of 137 subjects (age 10 79, average +/- SD: 47.0 +/- 17.5) at Kinki University Hospital were retrospectively evaluated. The V/4 and I/4 isopter areas were calculated using Image J and compared with the normal visual field range in the visual impairment criteria. RESULTS: The V/4 isopter area decreased from age 70 and the I/4 isopter area decreased significantly from age 50. The aging slope of the isopter areas were significantly larger in I/4 than in V/4. In age 60 to 69, 19% showed a smaller I/4 isopter area than that of the grade 5 criteria. In age 70 to 79, 75% showed a smaller I/4 isopter area than that of the grade 5 criteria. CONCLUSION: In some elderly people, the binocular I/4 isopter area is smaller than the visual impairment grade 5 criteria. PMID- 25543388 TI - [Adenoid cystic carcinoma of the lacrimal gland: clinicopathological study]. AB - PURPOSE: To clarify the clinicopathologic features including outcome of adenoid cystic carcinoma arising from the lacrimal gland. SUBJECTS AND METHODS: Background of patients, TNM classification, treatments, histopathological findings and the outcome were examined for 10 patients with adenoid cystic carcinoma of the lacrimal gland diagnosed at Tokyo Medical University Hospital. RESULTS: Patients included 6 men and 4 women and the average age was 49.5 years old. Four patients (40%) developed distant metastases and 5 patients (50%) showed local recurrence. Three patients died or progressed to palliative care, and the 5 year survival rate was 55.5% (Kaplan-Meier). The patients with progression of more than T3 in TNM classification and solid pattern in histopathological findings suggested poor outcome. Although heavy ion radiotherapy was performed in 4 patients, 2 patients died or progressed to palliative care. CONCLUSION: Prognosis of patients with adenoid cystic carcinoma of the lacrimal gland is related to TNM classification and histological type. Medical treatment including heavy ion radiotherapy was performed, the outcome was poor. PMID- 25543389 TI - [Equipment for digital mammography]. PMID- 25543390 TI - [X-ray diagnosis and its role in the treatment process]. PMID- 25543391 TI - [Diagnostic capability of microfocus roentgenography]. PMID- 25543392 TI - [The effect of scattered X-ray radiation on the imaging quality and techniques for its suppression]. PMID- 25543393 TI - [Monitoring of performance of diagnostic X-ray apparatuses under working conditions]. PMID- 25543394 TI - [Upgrade of the calculation method for determining the effective energy of X-ray radiation at its experimental verification]. PMID- 25543395 TI - [Spatial resolution in the scanning direction in detectors based on signal accumulation with time delay?]. PMID- 25543396 TI - [A technique for X-ray protection monitoring in electron accelerators with regard for the activity mode]. PMID- 25543397 TI - [The influence of X-ray generation conditions on reduced scattering coefficients in anode voltage measurements]. PMID- 25543399 TI - [Software for assessment of detective quantum efficiency of digital X-ray detectors]. PMID- 25543398 TI - [Technical monitoring of the state of body and its systems in patents with acute leukemia subjected to chemoradiotherapy and bone marrow transplantation]. PMID- 25543400 TI - [Assessment of detective quantum efficiency of digital X-ray detectors under conditions of clinics]. PMID- 25543401 TI - [X-ray imaging of microcalcinations on the basis of dual-energy dividing and subtraction mammography]. PMID- 25543402 TI - [Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers]. AB - OBJECTIVE: To determine the genetic forms of follicular cell thyroid carcinoma (FCTC) (papillary and follicular thyroid carcinoma (PTC and FTC)), to identify criteria to individually predict the development of the same disease for relatives, and to assess the role of molecular markers in the diagnosis, prognosis, and treatment of this disease. SUBJECTS AND METHODS: One hundred and ninety adult patients aged 20 to 84 years with histologically verified PTC and FTC and 20 children (12 patients with PTC and 8 with benign thyroid tumors) aged 2 to 16 years were examined. To assess the role of the BRAF gene as a molecular marker for thyroid carcinoma, DNA was isolated from the thyroid tumor tissue of 29 patients, which had been obtained by fine-needle aspiration biopsy (FNAB) and scraping and swabbing the cytological specimen previously showing an area containing tumor cells. A BRAF c.1799T>A (p.V600E) mutation in the FNAB specimens was tested by allele-specific ligation, followed by PCR amplification. RESULTS: The examinees' families were found to have a segregation of benign thyroid tumor and nontumor diseases (13.6%). Neoplasias of different sites were observed in 15% of the patients' relatives. Multiple primary tumors were detected in 6.1% of the patients and in 25% of the examined children (3/12). PTC was ascertained to accumulate as two clinical forms in the families. One form belongs to familial PTC (FPTC) in which two or three generations of relatives in the family are afflicted by only PTC and have a more severe phenotype of the disease. The other includes an association of FPTC with papillary kidney cancer. Furthermore, FPTC and PTC may be a component of multitumor syndromes, such as multiple endocrine neoplasia type 1, Cowden syndrome, and familial adenomatous polyposis. The familial hereditary forms of FCTC were generally revealed in 4.2% of the patients. BRAF v600E mutations were found in only 3 patients with Stages II and III PTC and were not in all the 12 children with PTC. CONCLUSION: The found clinical manifestation of the hereditary forms of FCTC permits the identification of people at high risk for this disease. No correlation between somatic BRAF mutations with a less favorable course in PTC can be noticed because there are few observations. Analysis of published data on the role of molecular markers in FCTC has shown that the existing specific somatic changes complement information in the differential cytological diagnosis when examining FNAB specimens. PMID- 25543403 TI - [Morphological characteristics of recurrent papillary thyroid carcinoma]. AB - Papillary thyroid carcinoma is generally characterized by a favorable prognosis in patients after timely and adequate treatment. However, local tumor growth recurrences and regional and distant metastases may occur in 5-20% of cases posttreatment. OBJECTIVE: To comparatively analyze the morphology and cellular composition of papillary thyroid carcinoma in two patient groups with comparable clinical and morphological characteristics, but different in the long-term results of treatment. MATERIAL AND METHODS: Histological specimens from 17 papillary thyroid carcinoma cases with recurrent tumor growth after treatment and resurgery (an experimental group) and 18 control cases without recurrences were selected from the database of the Chernobyl bank. The morphological features of primary tumors were studied in both groups; the morphology of recurrent tumors was also investigated in the experimental group. RESULTS: The higher incidence of tumors with papillary structure and a focal component from high-columnar, clear, and oxyphilic tumor cells was found in a group with a poor prognosis (a local relapse and metastases in the regional lymph nodes after thyroidectomy, hormonal and radioiodine therapy. CONCLUSION: The found morphological features of recurrent papillary thyroid carcinoma may serve as a starting point for further establishing criteria for tumor resistance to radioiodine therapy and for substantiating indications for other high-technology treatments, including targeted therapy. PMID- 25543404 TI - [Comparative clinical and morphological analysis of technogenic and cryptogenic papillary thyroid carcinoma in children and adolescents]. AB - OBJECTIVE: To make a comparative retrospective clinical and morphological analysis of cases of post-Chernobyl (technogenic) and sporadic (cryptogenic) papillary thyroid carcinoma (PTC) in children and adolescents in the Republic of Belarus. MATERIAL AND METHODS: Nine hundred and thirty-six patients aged less than 19 years, operated on in 1990-2005, when cancer incidence in this age group was directly related to the consequences of the Chernobyl accident (technogenic carcinoma) were examined. A comparison group included their 140 peers who were born after March 1987 and treated in 2005-2010 for PTC (cryptogenic carcinoma). The Kruskal-Wallis test was used to compare quantitative variables; the Fisher, Pearson, and Fisher-Freeman-Halton tests were employed to compare categorical variables. All calculations were made using the R package version 2.15.0. The results were considered to be statistically significant at p<0.05. RESULTS: Comparison of cases of cryptogenic carcinoma and those of technogenic carcinomas diagnosed in 1990-1995 and 1996-2001 revealed substantial differences in the clinical and morphological patterns of the disease. In both mentioned periods, the patients with technogenic PTC were younger than those with cryptogenic PTC (p<0.0001 and p=0.0014, respectively). The proportion of male patients in the technogenic carcinoma group was much higher than that in the cryptogenic carcinoma one (p=0.0006 and p=0.0031). The patients with technogenic carcinoma were also more frequently observed to have infiltrative tumor growth (p=0.0003 and p=0.0169) and lung metastastic involvement (p=0.0001 and p=0.0008). What is more, the architectonics of technogenic versus cryptogenic carcinoma more often contained a solid component (p<0.0001 and p<0.0001), marked intratumoral fibrosis (p=0.0008 and p=0.0266), mononuclear infiltration (p<0.0001 and p<0.0001), and no baseline abnormality (p<0.0001 and p<0.0001). CONCLUSION: In spite of its age similarity, technogenic carcinoma proved to be more clinically aggressive than cryptogenic carcinoma: the extent of organ invasion and the infiltrative growth of carcinoma were more frequently observed. PMID- 25543405 TI - [An expert system for differential diagnosis of medullary and oxyphilic cell thyroid carcinoma]. AB - OBJECTIVE: To reveal the quantitative regularities of pathological changes in the nuclei and aggregates of C and B cells and to build an expert system on their basis for the differential diagnosis of medullary and oxyphilic cell thyroid carcinoma. MATERIAL AND METHODS: Puncture smears with histologically verified medullary (C cell) carcinoma and oxyphilic cell (B cell) carcinoma were investigated. The nuclei and aggregates of C cells and B cells (Hurthle cells, oncocytes) were morphometrically examined with a computer color image analyzer on the basis of a light microscope and a digital photo camera. RESULTS: The quantitative regularities of the degree of C and B cell aggregation in medullary and oxyphilic cell thyroid carcinoma were found by morphometry. The threshold values for the aggregates in the comparison groups and their weight coefficients formed the basis for the expert system to differentially diagnose medullary and oxyphilic cell carcinoma at the initial stages of patient examination. The clinical trials showed the high efficiency of the developed expert system. PMID- 25543406 TI - [The morphological characteristics of HIV-associated tuberculosis in relation to blood CD4+ lymphocyte counts]. AB - OBJECTIVE: To investigate the morphological features of HIV-associated tuberculosis with different peripheral blood CD4 lymphocyte counts. MATERIAL AND METHODS: Intraoperative and biopsy specimens from 148 patients with HIV associated tuberculosis were examined. Group 1 included 16 (10.8%) patients having a CD4+ lymphocyte count above 350 cells/MUl; Group 2 comprised 38 (25.7%) patients having 200 to 349 cells/MUl; Group 3 consisted of 94 (63.5%) patients with a CD4+ lymphocyte count below 200 cells/MUl. Histological and immunohistochemical studies and a polymerase chain reaction assay were used. RESULTS: According to the predominant inflammatory phase, all analyzed cases were divided into 4 patterns of tissue responses: 1) typical productive granulomatous tuberculous inflammation; 2) obscure productive granulomatous inflammation; 3) a predominant alterative phase with the formation of pyonecrotic foci; 4) a predominant exudative tissue response with the development of amorphofunctional pattern typical of nonspecific inflammation. A relationship was found between the count of CD4+ lymphocytes and the predominant pattern of a tissue inflammatory response. A productive component of inflammation prevailed in Group 1; a mild productive response with the significantly obscure features of a granulomatous process was dominant in Group 2; alterative phenomena were noted in Group 3. Most patients (n=132, 89.2%) were stated to have an obscure granulomatous response (n=61, 41.2%), and a preponderance of an alternative (n=48, 32.4%) and vascular (n=23, 15.6%) components of inflammation. CONCLUSION: The magnitude of alterative and exudative components in the foci of tuberculous inflammation suggested that there was a change-over from a delayed hypersensitivity reaction that was typical of tuberculosis to an immediate hypersensitivity reaction and reflected severe immune system dysfunction. PMID- 25543407 TI - [BRAF V600E mutation detection in melanoma patients: clinical and morphological features]. AB - OBJECTIVE: To estimate the frequency of BRAF V600E mutation in melanoma patients and to assess an association of this type of mutation with the clinical and morphological characteristics of the disease. MATERIAL AND METHODS: The mutation of BRAF V600E was analyzed using an allele-specific real-time PCR assay in 71 melanoma patients treated at the Krasnoyarsk Territorial Oncology Dispensary. Before DNA isolation, the glasses containing the material obtained from the patients and stained with hematoxylin and eosin were tested for the content of tumor cells in the sections. Later on, genomic DNA was isolated with a FFPET DNA Extraction kit (Biolink, Russia) and the real-time PCR assay was carried out. RESULTS: The BRAF V600E mutation was observed in 40.84% of the patients and was not in 59.16%. There were specific features in tumor location and histotype in relation to the status of BRAF. CONCLUSION: To detect whether the V600E mutation is present or absent in the BRAF gene in melanoma patients is an important component in the evaluation of the biological behavior of tumor cells and their performance of biologically significant functions, such as tumor invasion and dissemination and neoangiogenesis, which is important for the further assessment of tumor progression and disease prognosis. PMID- 25543408 TI - [Solid pseudopapillary tumors of the pancreas: clinical and morphological characteristics, specific features of their immunophenotype, and diagnostic problems]. AB - OBJECTIVE: To analyze 60 cases of solid pseudopapillary tumors (SPTs) of the pancreas, to reveal their most characteristic clinical and morphological features, and to study their possible histogenesis. MATERIAL AND METHODS: Sixty cases of SPTs of the pancreas underwent clinical, morphological, and immunohistochemical (IHC) examinations; a comparison group consisted of 86 pancreatic tumors of other histogenesis. RESULTS: It has been shown for the first time that SPTs are characterized by the nuclear expression of claudin 3 and the cytoplasmic expression of claudin 7. It has been also ascertained that the aberrant perinuclear (dot-like) expression of CD99 is a unique feature of these tumors. CONCLUSION: SPTs of the pancreas are distinguished by a diversity of clinical manifestations and morphological features, but have a unique immunophenotype, which can differentiate them from other types of pancreatic tumors. PMID- 25543409 TI - Immunohistochemical characteristics of uveal melanoma assording to the age at diagnosis, histological type and extension of the tumor. AB - The purpose of this study was to investigate the relationship between MMP9 expression and tumour invasion in different structures of the eye. We also examined whether there was any correlation between the growth factors (TGFb and EGF), onco-suppressor proteins (p16 and p53) and Ki-67, and the tumour histological subtypes, atypia level and age at diagnosis. Tumour specimens were obtained from 42 primary uveal melanomas immediately after enucleation at The Helmholtz Moscow Research Institute of Eye Diseases. The patients were not treated with radio- or thermotherapy. During our systematic study, we exclusively employed 10%-formalin fixed, paraffin-wax-embedded tissue sections of UM for histological diagnosis and immunohistochemistry. According to our data the hyperexpression of MMP9 and EGFR correlates with a high proportion of spindle cells in a tumour (Kruskal-Wallis test p=0,1 for each). Moreover, we have demonstrated the association between the level of EGFR, TGFb and MMP9 expression and the initial invasion stage (Spearman's test p=0,1). In addition, we have revealed the significant correlation between TGFb hyperexpression and atypia level (Spearman's test p=0,059). Our data reflect that the diagnoses at an advanced age correlate with hyperexpression of p16 (Kruskal-Wallis test p=0,068). An interesting result is that p16 level reduced in inverse proportion to that of TGFb. On the basis of our data and previous studies, we reached the conclusion that after the lapse of time the level of p16 rises significantly in order to inhibit proliferating activity of melanocytes in the normally functioning pigmented layer. However, although the probability of UM diagnoses in elderly is increasing, we have no reliable data for the relationship with high atypia levels. PMID- 25543410 TI - [The morphofunctional state of the liver and the possibilities of pharmacotherapy for its disease in small bowel obstruction]. AB - OBJECTIVE: To study the results of liver morphological studies in 40 Vietnamese pot belly pigs with simulated small bowel obstruction. MATERIALS AND METHODS: Liver morphofunctional changes in acute strangulation ileus were investigated in an experiment on 40 Vietnamese pot belly pigs weighing 15-20 kg. Five animals were used as a control. RESULTS: In simulated acute ileus, the found morphofunctional changes in hepatocytes were characterized by toxic dystrophy of the organ with the signs of secondary hepatitis. CONCLUSION: During the experiment, the course of the disease and surgical restoration of small bowel patency have been found to be accompanied by significant histological and ultrafine structural disorders of the liver, which is a rationale for intensive antihypoxant, antioxidant, and hepatoprotective therapy in the pre- and postoperative periods. PMID- 25543411 TI - [Small cell lung carcinoma metastasis to clear cell renal cell carcinoma]. AB - The paper describes an anatomical pathology case of synchronous multiple primary carcinoma in a 75-year-old man with a tumor-to-tumor phenomenon of small cell lung carcinoma metastasis to clear cell renal cell carcinoma (tumor-to-tumor). PMID- 25543412 TI - [Nontraumatic chylopericardium and chylothorax in premature neonates]. AB - Deaths of extremely premature babies undiagnosed as having spontaneous chylopericardium (CP) and chylothorax (CT) are analyzed. The specific features of these death cases are the polyetiology of CP/CT and the similarity of their pathogenesis in the absence of specific clinical symptomatology. PMID- 25543413 TI - [A case of hypertrophic cardiomyopathy in an 8-month-old baby]. AB - The paper analyzes a death due to undiagnosed asymmetric hypertrophic cardiomyopathy in an 8-month-old baby. The peculiarities of this case are the extent of myocardial damage, the irreversibility of structural injuries in the absence of clinical symptoms, and a concurrence of hypertrophic cardiomyopathy and severe pneumonia and meningoencephalitis. PMID- 25543414 TI - [Primary cardiomyopathies]. AB - The paper provides a review of literature on primary cardiomyopathy yet referring to as an inadequately studied abnormality that is diagnosed with difficulty by clinicians and frequently missed by pathologists at autopsy. PMID- 25543415 TI - [Impacts of electroacupuncture on constipation of intestine and lung syndromes and its correlative study]. AB - OBJECTIVE: To observe the improvements in constipation differentiated as intestine system syndrome and lung system syndrome treated with electroacupuncture (EA) and explore their correlation. METHODS: Seventy cases of severe functional constipation were randomized into an EA group and a pseudo-EA group, 35 cases in each one. In the EA group, the needles were inserted deeply at Tianshu (ST 25) and Fujie (SP 14) on bilateral sides, and directly went to parietal peritoneum. EA was attached to the needles, dense-disperse wave, 2 Hz/15 Hz, and 0.1 to 1.0 mA. The perpendicular insertion was done at Shangjuxu (ST 37), 25 mm in depth. After qi arrival, the needle was lifted, thrusted and rotated once every 10 min, for 3 times totally. The needles were retained for 30 min. In the pseudo-EA group, the pseudo-points lateral to Tianshu (ST 25), Fujie (SP 14) and Shangjuxu (ST 37) on bilateral sides were punctured shallowly. The electric stimulation was pretended to connect but with the electric wire cutting off. The needles were retained for 30 min. The treatment was given 5 times weekly in the first two weeks and 3 times weekly in the later 6 weeks. Totally, 28 treatments were required. TCM intestine and lung syndrome scale was used for evaluation. The changes in TCM syndromes were observed before and after treatment in the patients of the two groups. RESULTS: The total score of intestine and lung syndrome and the score of individual syndrome were all reduced after treatment as compared with those before treatment in the two groups (both P<0.01). The improvements of the EA group in the total score of intestine system syndrome, the scores of large. intestine syndrome and stomach syndrome, the total score of lung system syndrome and the score of lung dysfunction in dispersing and descending syndrome were superior to those of the pseudo-EA group (P<0.01, P<0.05). The differences in the scores of lung qi deficiency syndrome and throat syndrome were not significant between the two groups (all P>0.05). Simultaneously, the very strong positive correlation (P<0.01) and positive linear correlation (P<0.01) were presented in the total score of intestine and lung syndrome of the two groups. CONCLUSION: EA obviously improves in intestine system syndrome (including large intestine syndrome and stomach syndrome), as well as lung system syndrome (lung dysfunction in dispersing and descending) in the treatment of constipation. But the improvements are not apparent in the treatment of lung qi deficiency and throat disorder. Additionally, the obvious correlation is displayed in the improvements in intestine and lung syndrome. PMID- 25543416 TI - [Bloodletting at Touwei(ST 8) for 32 cases of premenstural headache]. PMID- 25543417 TI - [Case of edema in lower extremity after surgery of ovarian cancer]. PMID- 25543418 TI - [Acupuncture at "Siguan" combined with Gallbladder Meridian acupoints for migraine: a randomized controlled trial]. AB - OBJECTIVE: To observe and evaluate the clinical effect of acupuncture at "Siguan" combined with the Gallbladder Meridian acupoints on migraine. METHODS: With randomized controlled trial design, 87 patients were randomly divided into an observation group (42 cases) and a control group (45 cases). The observation group was treated with acupuncture at "Siguan" including Hegu (LI 4) and Taichong (LR 3), combined with the Gallbladder Meridian acupoints including Fengchi (GB 20), Shuaigu (GB 8), Qiuxu (GB 40) and Zulinqi (GB 41), while the control group was treated with acupuncture at the Gallbladder Meridian acupoints, including Fengchi (GB 20), Shuaigu (GB 8), Qiuxu (GB 40), Zulinqi (GB 41), Yanglingquan (GB 34) and Hanyan (GB 4). The treatment was given every other day in two groups, 3 times per week for totally 6 weeks. The migraine intensity, migraine frequency and lasting time of each migraine were observed before and after treatment, and 3 month follow-up was performed after treatment. The clinical efficacy in two groups was evaluated. RESULTS: Compared with those before treatment, the migraine intensity, frequency and lasting time were all reduced significantly after treatment in the two groups (all P<0.01), which were more obvious in the observation group (all P<0.05). At the end of the treatment, the total effective rate was 95.2% (40/42) in the observation group and 80.0% (36/45) in the control group, which had statistical difference (P<0.05). After 3-month follow-up, the total effective rate was 88.1% (37/42) in the observation group and 75.6% (34/45) in the control group, which had no statistical difference (P>0.05). CONCLUSION: The "Siguan" combined with the Gallbladder Meridian acupoints could significantly relieve the migraine intensity, frequency and lasting time, and its improvement of symptoms and short-term efficacy are superior to those of the Gallbladder Meridian acupoints alone. PMID- 25543419 TI - [Case of spasmodic torticollis with Gilles de La Tourette syndrome]. PMID- 25543420 TI - [Efficacy on chronic obstructive pulmonary disease at stable stage treated with cutting method and western medication]. AB - OBJECTIVE: To compare the difference in clinical efficacy on chronic obstructive pulmonary disease (COPD) at stable stage in the patients among the combined therapy of cutting method and western medication (combined therapy), simple cutting method and simple western medication. METHODS: One hundred and twenty cases of COPD were randomized into three groups, 40 cases in each one. In the cutting method group, for excessive phlegm pattern/syndrome, Feishu (BL 13), Danzhong (CV 17), Dingchuan (EX-B 1) and Yuji (LU 10) were selected as the main acupoints, and Lieque (LU 7) and Pianli (LI 6) were as the supplementary acupoints. For the pattern/syndrome of failure to consolidate kidney primary, Shenshu (BL 23), Pishu (BL 20), Guanyuan (CV 4) and Yuji (LU 10) were selected as main acupoints, and Jueyinshu (BL 14) and Zusanli (ST 36) were as the supplementary acupoint. Three acupoints were selected alternatively in each treatment and the cutting method was applied once every 10 days. Three treatments made one session. Two sessions of treatment were required. In the western medication group, salbutamol sulfate aerosol, one press (200 MUg/press) was used each night, as well as salmeterol xinafoate and fluticasone propionate powder for inhalation, one inhalation each night. The treatment of 1 month made one session. Two sessions were required. In the combined therapy group, the cutting method and western medication were applied in combination. The results of clinical symptom score, lung function test, arterial blood gas analysis, degree of inflation as well as clinical efficacy were observed before and after treatment in each group. RESULTS: Except the degree of lung inflation, the clinical symptom score, indices of lung function test, partial pressure of arterial blood gas (PaO2) and partial pressure of carbon dioxide (PaCO2) were all obviously improved after treatment as compared with those before treatment in each group (all P<0.05). They were apparently improved after treatment in the combined therapy group and the cutting method group as compared with those in the western medication group (all P<0.05). The total effective rate was 77.5% (31/40) in the combined therapy group and was 75.0% (30/40) in the cutting method group, both better than 60.0% (24/40) in the western medication group (both P<0.05). CONCLUSION: The simple cutting method based on syndrome differentiation and the combined therapy with western medication achieve the superior efficacy on COPD at stable stage as compared with the simple western medication. The effect mechanism is possibly related to the improvement of bronchial airway function through constant acupoint stimulation. PMID- 25543421 TI - [Efficacy on depression in breast cancer treated with acupuncture and auricular acupressure]. AB - OBJECTIVE: To compare the efficacy difference in treatment of depression in breast cancer between the combined therapy of acupuncture and auricular acupressure and western medication. METHODS: Sixty patients were randomized into an observation group and a control group, 30 cases in each one. In the observation group, the combined therapy of acupuncture and auricular acupressure was adopted. The main acupoints of acupuncture were Hegu (LI 4), Tai-chong (LR 3), Baihui (GV 20), Zusanli (ST 36), Qihai (CV 6), etc. The supplementary acupoints were combined according to the syndrome differentiation. The treatment was given once every day, 5 treatments a week, at the interval of 2 days among weeks. The auricular acupressure was applied to gan (CO12, liver), pi (CO13, spleen), neifenmi (CO18, endocrine), etc., once every 4 days, on each side in one treatment. In the control group, fluoxetine hydrochloride capsules were prescribed for oral administration, 20 mg, once a day. The Hamilton depression rating scale (HAMD) was used to assess the disease severity and efficacy before treatment, in 4 and 8 weeks of treatment separately. HAMD factor changes were observed before treatment and at the end of the 8th week. The Asberg antidepressants scale (SERS) was applied to safety assessment. RESULTS: The total effective rate was 86.7% (26/30) in the observation group, better than 63.3% (19/30) in the control group (P<0.05). At the end of the 4th and 8th weeks, HAMD scores were all reduced apparently in the two groups (all P<0.01). At the end of the 8th week, the scores of the HAMD factor 1 (anxiety/somatic system), factor 5 (retardation) and factor 6 (sleep disturbance) were all reduced as compared with those before treatment in the two groups (all P<0.01); the results in the observation group were better than those in the control group (P<0.05, P<0.01). SERS score in the observation group was lower obviously than that in the control group (P<0.01). CONCLUSION: The combined therapy of acupuncture and auricular acupressure achieves the antidepression effect in treatment of depression in breast cancer and has less side effects and high safety. The efficacy is superior to fluoxetine hydrochloride capsules. PMID- 25543422 TI - [Case of Raynaud's disease]. PMID- 25543423 TI - [Acupoint catgut embedding for perimenopausal syndrome: a clinical controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy differences between acupoint catgut embedding and Kuntai capsule for perimenopausal syndrome, so as to provide an effective treatment method for perimenopausal syndrome. METHODS: Thirty-three cases in the embedding group were treated with acupoint catgut embedding at back shu points and front-mu points of liver, spleen and kidney combined with syndrome differentiation and disease differentiation, ten days per times; the Kuntai group was treated with oral administration of Kuntai capsule, 4 capsules each time, three times per day. The Kupperman index (KI) was observed in the two groups before treatment after 10 days, 30 days and 60 days of treatment, respectively; the efficacy was evaluated according to the ratio of KI. RESULTS: After the treatment, as treatment proceeded, the score of KI and ratio of KI were gradually reduced in two groups; the score of KI and ratio of KI in the embedding group after 10 days of treatment was lower than those in the Kuntai group (both P<0.05); after 10 days of treatment, the total effective rate was 36.4% (12/33) in the embedding group, which was superior to 3.0% (1/33) in the Kuntai group (P<0.05); however, after 30 days and 60 days of treatment, the differences of each index between two groups were not statistically significant (all P>0.05). CONCLUSION: Both the acupoint catgut embedding and Kuntai capsule could reduce the score of KI and improve clinical symptoms, and the acupoint catgut embedding has certain advantage on the early stage of treatment. PMID- 25543424 TI - [Acupoint catgut embedding combined with moxibustion for 42 cases of infertility with blood stasis type]. PMID- 25543425 TI - [Clinical observation of dog days moxibustion plaster therapy in treatment of allergic rhinitis of different patterns/syndromes]. AB - OBJECTIVE: To explore the efficacy and feasibility of dog days moxibustion plaster therapy in treatment of allergic rhinitis of different patterns/syndromes. METHODS: Allergic rhinitis of lung deficiency and invasion of cold, spleen qi deficiency and kidney yang deficiency, 56 patients for each pattern/syndrome were randomized into a plaster therapy group and a nasal spray group, 28 cases in each one. In the plaster therapy group, according to the pattern/syndrome differentiation, with literature retrieval method, 3 acupoints of high frequency utility in clinic were selected as one group in acupoint plaster therapy. For lung deficiency and invasion of cold pattern/syndrome, Feishu (BL 13), Fengmen (BL 12) and Hegu (LI 4) were selected. For spleen qi deficiency pattern/syndrome, Pishu (BL 21), Zusanli (ST 36) and Dazhui (GV 14) were selected. For kidney yang deficiency pattern/ syndrome, Shenshu (BL 23), Dingchuan (EX-B 1) and Bailao (EX-HN 15) were selected. Separately, on July 13, 2013, July 23, 2013, August 2, 2013 and August 12, 2013, the aucpoint plaster therapy was applied, 2 to 4 h (1 to 2 h for children) each time. In the nasal spray group, beclometasone dipropionate aqueous nasal spray, 2 presses one nostril each time, 2 to 3 times a day, continuously for 4 weeks. The symptom score and efficacy were compared before and after treatment in the patients of the two groups. RESULTS: The symptom scores of 3 patterns/syndromes were all apparently improved after treatment as compared with those before treatment in the patients of the two groups (all P<0.05), and the result in the plaster therapy group was better than that of the nasal spray group (P<0.05, P<0.01). For lung deficiency and invasion of cold pattern/syndrome, the total effective rate was 87.3% (20/24) in the plaster therapy group, better than 84.6% (22/26) in the nasal spray group (P<0.05). For spleen qi deficiency pattern/syndrome, the total effective rate was 83.3% (20/24) in the plaster therapy group, obviously better than 76.9% (22/26) in the nasal spray group (P<0.05). For kidney yang deficiency pattern/syndrome, the total effective rate was 79.2% (19/24) in the plaster therapy group, better than 76.9% (22/26) in the nasal spray group (P<0.05). CONCLUSION: The dog days moxibustion plaster therapy achieves definite efficacy on allergic rhinitis at the acupoints selected based on the differentiation of different patterns/syndromes and the efficacy is better than beclometasone dipropionate aqueous nasal spray. PMID- 25543426 TI - [Prevention of procedural pain in dressing changes of burn wounds by auricular injection of small-dose fentanyl]. AB - OBJECTIVE: To explore the effective method of the prevention and treatment of procedural pain in dressing changes of burn wounds. METHODS: Ninety patients of burn injury were randomized into 3 groups, 30 cases in each one. In the group A, fentanyl citrate injection was used at corresponding injury area, jiaogan (AH6a, sympathetic nerve), fei (CO14, lung), neifenmi (CO18, endocrine) on ear, 0.25 mL at each point. In the group B, fentanyl citrate injection was applied subcutaneously in the deltoid muscle, 1 mL. In the group C, 0.9% sodium chloride injection was applied subcutaneously in the deltoid muscle, 1 mL. The visual analogue scale (VAS) was used to evaluate the analgesic effect before, during and 10 min after dressing change in the patients of the three groups separately. RESULTS: It was not different in VAS score before dressing change among the three groups (P> 0.05). Compared with that before dressing change, the pain was not significant and VAS score was not different during and after dressing change in the patients of the group A (both P>0.05), but the score in the patients of the group B and C was different significantly (all P<0.05). The VAS score during and after dressing change in the group A was lower than that in the group B and C (all P<0.05), and the score in the group B was lower than that in the group C (P<0.05). CONCLUSION: Fentanyl injection of small dose at auricular points achieves definite analgesic effect on procedural pain in dressing changes of burn wounds, superior to subcutaneous injection of fentanyl. PMID- 25543427 TI - [Elongated needling at perigastric skin with needle-sticking method for 23 cases of chronic gastric volvulus]. PMID- 25543428 TI - [Penetration needling and interactive method for 30 cases of palpitation]. PMID- 25543429 TI - [The two-step location method of acupoint in Internal Canon of Medicine and its clinical application]. AB - An accurate location of acupoint is one of the key factors for improving clinical therapeutic effect of acupuncture and moxibustion. From the theoretical basis, operation method, principle discussion and clinical application, the clinical practicability of the two-step location method of acupoint in Internal Canon of Medicine is discussed. This two-step location method is in accord with the original connotation of acupoint, and focuses on the function state of acupoint. As is suggested in clinical researches, the acupoint location that is acquired by using the two-step location method, as a treated area, could obviously improve the therapeutic effect of acupuncture and moxibustion. Therefore, the two-step location method of acupoint in Internal Canon of Medicine should be considered as guideline of clinical acupoint location. PMID- 25543430 TI - [Acupuncture combined with kinetic needling for 80 cases of acute lumbar sprain]. PMID- 25543432 TI - [Acupoint combination and acupuncture-moxibustion prescription]. AB - The modern physicians have different views on acupoint combination and acupuncture-moxibustion prescription and confuse them in clinical practice. It is significant to clarify the conception, connotation and relationship between them so as to normalize the therapeutic program of acupuncture and moxibustion and promote the standardization of acupuncture and moxibustion. Through the collection of relevant literature and analysis on the differences in the understandings among physicians, the conception, connotation and relationship between acupoint combination and acupuncture-moxibustion prescription are summarized. It is viewed that the acupoint combination is based on TCM theory. Under the guide of acupoint selection, in combination of the characters of clinical practice and acupoint indications, two or more than two acupoints of the same function are combined to enhance the collaborative effects of acupoints so as to achieve specific efficacy and improve clinical efficacy. Regarding acupuncture-moxibustion prescription, on the basis of disorder and syndrome differentiation of patients, the concrete therapeutic program is put forward, including acupoint composition and therapeutic method. Acupoint combination is the basic element of acupuncture-moxibustion prescription. Acupuncture moxibustion prescription is the specific application of acupoint combination. PMID- 25543431 TI - [Innovative application of Yingxiang (LI 20) and Neiyingxiang (EX-HN 9) in acupuncture verses]. AB - The ancient discussion and modern clinical application regarding Yingxiang (LI 20) and Neiyingxiang (EX-HN 9) in acupuncture verses are explored. Acupuncture verses are the summary of clinical experiences of acupuncture scholars in the past dynasties, of which the records on application of Yingxiang (LI 20) and Neiyingxiang (EX-HN 9) mainly focused on nasal, facial and head-eye diseases, which is characterized with overall summarization, brilliant exposition, simple language, and distinctive characteristics. Nowadays, based on the ancient usage, the clinical application about these two acupoints is continuously developing. If the ancient acupuncture verses could be understood thoroughly, the clinical practice could be better guided and its effects could be improved. PMID- 25543433 TI - [Acupoint catgut embedding for 50 cases of gastrocnemius spasm]. PMID- 25543434 TI - [Effects of electroacupuncture with branch-foundation acupoint combination on the pituitary-target gland axis in aging rats with yang deficiency]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) with branch foundation acupoint combination on the indices regarding pituitary-target gland axis in aging rats with yang deficiency, so as to explore its regulating mechanism on aging rats with yang deficiency. METHODS: Forty healthy Sprague Dawley female rats were randomly divided into a normal control group, a model group, an EA group and an EA control group, 10 rats in each group. Except the normal control group, the rats in the rest 3 groups were all treated with subcutaneous injection of D-galactose for 40 d, followed by intramuscular injection of hydrocortisone for 7 d to establish aging model with yang deficiency. After the successful establishment of model, the EA group was treated with EA at "Guanyuan" (CV 4), "Housanli" (ST 36) and "Baihui "(GV 20) while the EA control group was treated with EA at "Zhongji" (CV 3) "Yinlingquan" (SP 9) and "Yintang" (GV 29); the rats in the normal control group and model group were immobilized and fixed during the same time period. The treatments were given 6 times per week totally for 4 weeks. With radiation immunity analysis method, the 8 biological indices of pituitary-target gland axis, including thyroid stimulating hormone (TSH), triiodothyronine (T3), tetraiodothyronine-4 (T4), adrenocorticotropic hormone (ACTH), corticosterone (CORT), estradiol (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were detected to observe the changes of their content. RESULTS: Compared with the normal control group, the serum level of TSH, T3, T4 and E2 were reduced in the model group (P<0.05, P< 0.01) while those of ACTH, CORT, FSH and LH were increased (P<0.05, P<0.01). Compared with the model group, the serum level of TSH, T3, T4 and E2 were increased in the EA group (P<0.05, P<0.01) while those of ACTH, CORT, FSH and LH were significantly reduced (P<0.05, P<0.01). Compared with the EA control group, the content of TSH was increased in the EA group without statistical significance (P>0.05), that of T3, T4 and E2 was increased (all P<0.05) and that of ACTH, CORT, FSH and LH was significantly reduced (all P<0.05). CONCLUSION: The electroacupuncture with branch-foundation acupoint combination has benign regulating effects on the key hormones of pituitary-target gland axis, which could effectively improve the dysfunction of pituitary-target gland axis that is caused by aging with yang deficiency; the efficacy of electroacupuncture with branch-foundation acupoint combination is superior to that of adjacent control acupoint combination. PMID- 25543435 TI - [Regulation effects of electroacupuncture at "Sanyinjiao" (SP 6) on bladder function in rats with overactive bladder after cystostomy]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) at "Sanyinjiao" (SP 6) on urodynamics indices in rats with overactive bladder (OAB) after cystostomy, and to explore its regulation mechanism on bladder function. METHODS: Forty-eight Sprague-Dawley female rats which received cystostomy were randomly divided into a blank group (group A), a blank Sanyinjiao group (group B), a blank non-acupoint group (group C), a model group (group D), a model Sanyinjiao group (group E) and a model non-acupoint group (group F), 8 rats in each one. The model of OAB was established with 1% acetic acid solution perfused into the bladder in the group D, group E and group F. No treatment was given to the group A and group D. Acupuncture was applied at bilateral "Sanyinjiao" (SP 6) in the group B and group E, followed by EA after the arrival of qi. Acupuncture was applied at bilateral non-acupoint in the group C and group F, followed by EA with continuous wave, 2 Hz of frequency for 30 min. The treatment was given for continuous 5 urination cycles. The BL-420 E+ biological function experiment system was used to measure and record the changes of indices of bladder pressure and urodynamics. RESULTS: Compared with the group A, the bladder capacity and urine output in the group B were significantly increased (both P<0.05), and the urination rate was increased in the group C (P<0.05); the differences of each index between group C and group B were not statistically significant (all P>0.05). Compared with the group D, the capacity pressure, bladder capacity, detrusor pressure, urinary output and urination rate in the group E were all increased (all P<0.05). Compared with the group F, the capacity pressure and detrusor pressure in the group E were increased (both P<0.05). CONCLUSION: The EA at "Sanyinjiao" (SP 6) could significantly improve urine function in rats with OAB after cystostomy, but its regulation effect on urination is not obvious in rats with non-OAB. PMID- 25543436 TI - [Abdominal acupuncture combined with abdominal massage for 30 cases of lumbar intervertebral disc]. PMID- 25543437 TI - [Professor ZHOU Yun-xian's experience of acupuncture combined with Chinese material medica for xerophthalmia]. AB - Professor ZHOU Yun-xian's clinical experience of acupuncture combined with Chinese material medica for xerophthalmia is introduced. Her treatment for xerophthalmia is firstly focused on syndrome differentiation, indicating that different syndrome has different treatment of acupuncture and Chinese material medica. It is emphasized that by following the holistic concept of TCM, the local acupoints and whole-body acupoints cooperate closely, forming her special combination method of acupoints. In clinic, attention is focused on the application of many acupuncture techniques and extra points. With the combination of acupuncture and Chinese material medica, the treatment is flexible with superior clinical efficacy. PMID- 25543438 TI - [Practice and diversion of acupuncture-moxibustion scientization in modern times: taking ZHU Lian as the center]. AB - By following the acupuncture scholar ZHU Lian's academic thought in modern times, and comparing with other contemporary acupuncture scholars, it is found that since the Republic of China, there has been an obvious practice tendency of scientization among academic thoughts of acupuncture, especially in ZHU Lian. This tendency of scientization continues until the early stage of New China. Accompanied with the process of acupuncture high education, academic thoughts represented by acupuncture-moxibustion textbook are different from scientization that is represented by ZHU Lian, and the basic path of acupuncture-moxibustion education and academic theory changed from here. PMID- 25543439 TI - [Case of serious weary syndrome in spring]. PMID- 25543440 TI - [Rules for acupoint selection in treatment of perimenopausal syndrome based on data mining technology]. AB - OBJECTIVE: To analyze the rules for acupoint selection of acupuncture and moxibustion in domestic clinical treatment of perimenopausal syndrome based on data mining technology in modern times. METHODS: The relevant literature were retrieved from Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wanfang database on this disease treated with clinical acupuncture and moxibustion in China from 1978 to 2013. The database of acupuncture-moxibustion prescription was set up. The relevant regulations of data mining technology were used to analyze the rules for acupoint selection. RESULTS: Totally, 211 papers, 254 acupuncture-moxibustion prescriptions and 130 acupoints were included. The total frequency of acupoints application was 2193 times, with 14 meridians involved. The utilization of the acupoints in the lower limbs and on the back were 33.0% (723/2193) and 23.8% (521/2193) and those of yin and yang meridians were 51.8% (1136/2193) and 44.0% (965/2193), respectively. The utilization of the specific acupoints accounted for 88.7% (1946/2193). CONCLUSION: In clinical treatment of perimenopausal syndrome with acupuncture and moxibustion in modern times, the acupoint selection from involved meridians is the basis, associated with multiple methods of acupoint combination; yin and yang meridians are equally important and the specific acupoints are considered particularly critical in application. PMID- 25543441 TI - [Analysis on the adverse events of cupping therapy in the application]. AB - The deep analysis has been done on the cases of adverse events and common injury of cupping therapy encountered in recent years in terms of manipulation and patient's constitution. The adverse events of cupping therapy are commonly caused by improper manipulation of medical practitioners, ignoring contraindication and patient's constitution. Clinical practitioners should use cupping therapy cautiously, follow strictly the rules of standard manipulation and medical core system, pay attention to the contraindication and take strict precautions against the occurrence of adverse events. PMID- 25543442 TI - [Misdiagnosis of 1 case of injury of femoral adductor muscle]. PMID- 25543443 TI - [Case of superficial thrombophlebitis due to improper manipulation of pricking blood]. PMID- 25543444 TI - [The development of World Federation of Acupuncture-Moxibustion Societies]. AB - From cooperation between World Federation of Acupuncture-Moxibustion Societies (WFAS) and World Health Organization, works of academics and standardization, acupuncture-moxibustion education, technique service, organization development, etc., the 27-year development of WFAS since 1987 was summarized and reviewed in details. The growth of WFAS witnesses and promotes the development of acupuncture and moxibustion in the world, so by learning the experience and lessons, WFAS could have a wider path, becoming a core organization for communicating and promoting the development of acupuncture, even the traditional medicine in the world. PMID- 25543445 TI - [How to establish a good acupuncture-moxibustion standard?]. AB - At the beginning of a standard item, the standardized objects and involved contents should be demonstrated thoroughly, which is the precondition of establishing a good standard. After the proposal of this standard, a high-level drafting group should be built, led by top specialists who also draft the standard, which is essential to guarantee the quality of the standard. Before drafting the standard, literature regarding this standard should be searched completely, and Directives for Standardization should be learned to understand the basic requirements of establishing a standard; in the meanwhile, selections on standardized contents and quantitative boundaries of technical indices should be comprehensively and deeply studied. At the stage of consultation, focus should be paid on the scope of the consultation departments, level and personnel quality. As for standard review, it should be precise and truth-seeking. At the stage of submitting and authorization, it is necessary to have timely communication. Only by full cooperations of all parties, and by strictly following the procedure, method and rule of standard establishment, can a high quality acupuncture-moxibustion standard be established. PMID- 25543446 TI - [Penetration needling at special points for 40 cases of stopping lactation]. PMID- 25543447 TI - [Study on "Hegu (LI 4) regulates face and mouth" based on palmomental reflex]. AB - OBJECTIVE: To explore the correlation between hand and face-mouth, so as to provide nerve reflex basis for the theory "Hegu (LI 4) regulates face and mouth". METHODS: Seven hundred and sixty-three participants who met the inclusive criteria were divided into different age groups. The skin around participants' thenar eminence was gently scraped to be observed whether there was an involuntary movement around the face or mouth, which was palmomental reflex. The results of palmomental reflex were recorded. RESULTS: The total occurrence rate of palmomental reflex was 46.26%. For those who were 0 to 1 years old, the palmomental reflex was all positive; for those who were 21 to 36 years old, the positive rate was 20.45%, which was the lowest; for those who were 65 to 85 years old, more than half of them were positive. The majority of those who were 0 to 2 years old were bilateral positive palmomental reflex, while the majority of those who were 65 to 85 years old were unilateral positive palmomental reflex. CONCLUSION: There is a certain connection between hand and face-mouth. The occurrence rate of palmomental reflex changes from high to low over age increasing, and then changes from low to high with the aging, presenting a "high low-high" U-shaped curve, which is possible related to the growth and recession of nervous system. PMID- 25543448 TI - [Case of primary hyperhidrosis]. PMID- 25543449 TI - [Trace to source of nail pressing needle-inserting method]. PMID- 25543450 TI - [Research progress on the effects of acupuncture-moxibustion serum]. AB - The acupuncture-moxibustion serum has received wide attention as a new idea and method. Its application on researches in vivo and the treatment of disease not only has an important theory value, but also provides new ideas for overcoming the limitations of researches in vivo and some disease's treatment. Literature regarding the basic research of acupuncture-moxibustion serum for last more than 10 years is reviewed, and the effects of acupuncture-moxibustion serum on respiratory system, digestive system, cardiovascular system, nervous system, immune system, anti-aging, bone metabolism and anti-cancer are summarized, hoping to provide references for clinical treatment and evidence-based medicine. PMID- 25543453 TI - Aminomethylation reaction of ortho-pyridyl C-H bonds catalyzed by group 3 metal triamido complexes. AB - Tris[N,N-bis(trimethylsilyl)amido] complexes of group 3 metals, especially yttrium and gadolinium, served as catalysts for ortho-C-H bond addition of pyridine derivatives and N-heteroaromatics into the C?N double bond of nonactivated imines to afford the corresponding aminomethylated products. Addition of catalytic amounts of secondary amines, such as dibenzylamine, dramatically improved the catalytic activity through the formation of a mixed ligated complex such as [(Me3Si)2N]2Y(NBn2)(THF) (4). Furthermore, kinetic studies using the isolated complex 4 provided a plausible reaction mechanism by which coordination of two pyridine derivatives afforded a penta-coordinated species as a key step. PMID- 25543452 TI - The influence of surface modification on bacterial adhesion to titanium-based substrates. AB - This study examines bacterial adhesion on titanium-substrates used for bone implants. Adhesion is the most critical phase of bacterial colonization on medical devices. The surface of titanium was modified by hydrothermal treatment (HT) to synthesize nanostructured TiO2-anatase coatings, which were previously proven to improve corrosion resistance, affect the plasma protein adsorption, and enhance osteogenesis. The affinity of the anatase coatings toward bacterial attachment was studied by using a green fluorescent protein-expressing Escherichia coli (gfp-E. coli) strain in connection with surface photoactivation by UV irradiation. We also analyzed the effects of surface topography, roughness, charge, and wettability. The results suggested the dominant effects of the macroscopic surface topography, as well as microasperity at the surface roughness scale, which were produced during titanium machining, HT treatment, or both. Macroscopic grooves provided a preferential site for bacteria deposit within the valleys, while the microscopic roughness of the valleys determined the actual interaction surface between bacterium and substrate, resulting in an "interlocking" effect and undesired high bacterial adhesion on nontreated titanium. In the case of TiO2-coated samples, the nanocrystals reduced the width between the microasperities and thus added nanoroughness features. These factors decreased the contact area between the bacterium and the coating, with consequent lower bacterial adhesion (up to 50% less) in comparison to the nontreated titanium. On the other hand, the pronounced hydrophilicity of one of the HT coated discs after pre-irradiation seemed to enhance the attachment of bacteria, although the increase was not statistically significant (p > 0.05). This observation may be explained by the acquired similar degree of wetting between gfp-E. coli and the coating. No correlation was found between the bacterial adhesion and the zeta-values of the samples in PBS, so the effect of surface charge was considered negligible in this study. PMID- 25543454 TI - Monomer conversion and shrinkage force kinetics of low-viscosity bulk-fill resin composites. AB - OBJECTIVE: To investigate the subsurface degree of conversion (DC) and shrinkage force formation of low-viscosity (flowable) bulk-fill composite materials. MATERIALS AND METHODS: Three flowable bulk-fill resin composites [SureFil SDR flow (SDR; Dentsply DeTrey), Venus Bulk Fill (VB; Heraeus Kulzer) and x-tra base (XB; VOCO)] and one conventional flowable control composite material [EsthetX flow (EX; Dentsply DeTrey)] were tested. The materials were photoactivated for 20 s at an irradiance of 1170 mW/cm2 and the DC (n=5) was recorded at 0.1-, 1.5- and 4-mm depth using Fourier transform infrared spectroscopy. Shrinkage forces (n=5) of 1.5-mm-thick specimens were continuously recorded for 15 min using a custom made stress analyzer. Data were statistically analyzed by ANOVA, Tukey's HSD and Bonferroni's post-hoc tests (alpha=0.05). RESULTS: SDR generated the significantly lowest shrinkage forces (22.9+/-1.4 N), but also attained the significantly lowest DC at 1.5-mm depth (67.5+/-0.8%). The conventional flowable composite EX generated the significantly highest shrinkage forces (40.7+/-0.7 N) and reached a significantly higher DC (74.4+/-1.3%) compared to SDR and XB at 1.5 mm depth. The shrinkage force values of VB (29.4+/-1.1 N) and XB (28.3+/-0.6 N) were similar (p>0.05). All materials attained significantly higher DC at 4-mm depth than at the near-surface. CONCLUSION: The tested low-viscosity bulk-fill materials show lower shrinkage force formation than a conventional flowable resin composite at high levels of degree of conversion up to 4-mm incremental thickness. PMID- 25543455 TI - Craniofacial and pharyngeal airway morphology in patients with acromegaly. AB - OBJECTIVE: The aim of this study was to assess differences in craniofacial characteristics, upper spine and pharyngeal airway morphology in patients with acromegaly compared with healthy individuals. MATERIALS AND METHODS: Twenty-one patients with acromegaly were compared with 22 controls by linear and angular measurements on cephalograms. The differences between the mean values of cephalometric parameters were analyzed with Mann-Whitney U-test. RESULTS: With respect to controls, anterior (p<0.05), middle (p<0.01) and posterior (p<0.05) cranial base lengths were increased, sella turcica was enlarged (p<0.001) and upper spine morphology demonstrated differences in the height of atlas (p<0.01) and axis (p<0.05) in patients with acromegaly. Craniofacial changes were predominantly found in the frontal bone (p<0.01) and the mandible (p<0.05). As for the airway, patients with acromegaly exhibited diminished dimensions at nasal (p<0.001), uvular (p<0.01), mandibular (p<0.01) pharyngeal levels and at the narrowest point of the pharyngeal airway space (p<0.001) compared to healthy controls. Soft palate width was significantly higher (p<0.001) and the hyoid bone was more vertically positioned (p<0.01) in patients with acromegaly. CONCLUSIONS: Current results point to the importance of the reduced airway dimensions and that dentists and/or orthodontists should be aware of the cranial or dental abnormalities in patients with acromegaly. PMID- 25543456 TI - Vesicular release statistics and unitary postsynaptic current at single GABAergic synapses. AB - The existence of vesicular docking sites in central synapses is supported by morphological and biochemical evidence, but their functional role remains elusive. To investigate this role we have studied single depressing GABAergic synapses where multivesicular release and postsynaptic receptor saturation have been documented. We used failure/success patterns to estimate the number of vesicular docking sites, which varied from one to six among synapses. Variations of docking site numbers account for differences in release probability, as well as in the amplitude and decay kinetics of unitary postsynaptic currents. Upon repetitive stimulation, decreasing docking site occupancy likewise accounts for changes both in presynaptic and postsynaptic parameters. Finally steady-state docking site occupancy during train stimulations can be modulated by applying subthreshold presynaptic conditioning potential steps. The results suggest that differences in docking site numbers determine intersynaptic variability and that docking site occupancy is a key parameter controlling single synapse signaling. PMID- 25543457 TI - Distinct limb and trunk premotor circuits establish laterality in the spinal cord. AB - Movement coordination between opposite body sides relies on neuronal circuits capable of controlling muscle contractions according to motor commands. Trunk and limb muscles engage in distinctly lateralized behaviors, yet how regulatory spinal circuitry differs is less clear. Here, we intersect virus technology and mouse genetics to unravel striking distribution differences of interneurons connected to functionally distinct motor neurons. We find that premotor interneurons conveying information to axial motor neurons reside in symmetrically balanced locations while mostly ipsilateral premotor interneurons synapse with limb-innervating motor neurons, especially those innervating more distal muscles. We show that observed distribution differences reflect specific premotor interneuron subpopulations defined by genetic and neurotransmitter identity. Synaptic input across the midline reaches axial motor neurons preferentially through commissural axon arborization, and to a lesser extent, through midline crossing dendrites capturing contralateral synaptic input. Together, our findings provide insight into principles of circuit organization underlying weighted lateralization of movement. PMID- 25543459 TI - Surface charge control through the reversible adsorption of a biomimetic polymer on silica particles. AB - The control of the physicochemical properties of silica particles is of paramount importance to achieve full functionality in specific applications. A novel facile method of silica particle synthesis, requiring only two reactants, was developed. Control of the surface charge of these newly synthesized silica particles was achieved via the rapid electrostatic adsorption and acidic desorption of the branched, biomimetic polymer, polyethylenimine (PEI). Successful adsorption/desorption of PEI was supported by ATR-FTIR spectra, an adsorption isotherm, and zeta-potential curves. PEI adsorption above a threshold PEI concentration was determined to categorically change the topography of the silica particles' zeta-potential curve. The results from our study convey a rapid, reversible, and reliable method of silica particle surface charge control. This may be of particular use in tailoring surface interactions of silica or silica coated particles for applications in drug delivery, biomedical technologies, catalysis, and coatings. PMID- 25543458 TI - In vivo measurement of cell-type-specific synaptic connectivity and synaptic transmission in layer 2/3 mouse barrel cortex. AB - Intracellular recordings of membrane potential in vitro have defined fundamental properties of synaptic communication. Much less is known about the properties of synaptic connectivity and synaptic transmission in vivo. Here, we combined single cell optogenetics with whole-cell recordings to investigate glutamatergic synaptic transmission in vivo from single identified excitatory neurons onto two genetically defined subtypes of inhibitory GABAergic neurons in layer 2/3 mouse barrel cortex. We found that parvalbumin-expressing (PV) GABAergic neurons received unitary glutamatergic synaptic input with higher probability than somatostatin-expressing (Sst) GABAergic neurons. Unitary excitatory postsynaptic potentials onto PV neurons were also faster and more reliable than inputs onto Sst neurons. Excitatory synapses targeting Sst neurons displayed strong short term facilitation, while those targeting PV neurons showed little short-term dynamics. Our results largely agree with in vitro measurements. We therefore demonstrate the technical feasibility of assessing functional cell-type-specific synaptic connectivity in vivo, allowing future investigations into context dependent modulation of synaptic transmission. PMID- 25543461 TI - Spatial-temporal clustering of companion animal enteric syndrome: detection and investigation through the use of electronic medical records from participating private practices. AB - There is interest in the potential of companion animal surveillance to provide data to improve pet health and to provide early warning of environmental hazards to people. We implemented a companion animal surveillance system in Calgary, Alberta and the surrounding communities. Informatics technologies automatically extracted electronic medical records from participating veterinary practices and identified cases of enteric syndrome in the warehoused records. The data were analysed using time-series analyses and a retrospective space-time permutation scan statistic. We identified a seasonal pattern of reports of occurrences of enteric syndromes in companion animals and four statistically significant clusters of enteric syndrome cases. The cases within each cluster were examined and information about the animals involved (species, age, sex), their vaccination history, possible exposure or risk behaviour history, information about disease severity, and the aetiological diagnosis was collected. We then assessed whether the cases within the cluster were unusual and if they represented an animal or public health threat. There was often insufficient information recorded in the medical record to characterize the clusters by aetiology or exposures. Space-time analysis of companion animal enteric syndrome cases found evidence of clustering. Collection of more epidemiologically relevant data would enhance the utility of practice-based companion animal surveillance. PMID- 25543460 TI - Greenhouse gas emission of diets in the Netherlands and associations with food, energy and macronutrient intakes. AB - OBJECTIVE: To evaluate the greenhouse gas emission (GHGE) of diets in Dutch girls, boys, women and men and to explore associations with diet composition. DESIGN: Descriptive analyses for the total population as well as stratified for gender, age and dietary environmental load. SETTING: The Netherlands. SUBJECTS: Dutch children and adults aged 7-69 years (n 3818). RESULTS: The GHGE of daily diets was on average 3.2 kg CO2-equivalents (CO2e) for girls, 3.6 kg CO2e for boys, 3.7 kg CO2e for women and 4.8 kg CO2e for men. Meat and cheese contributed about 40 % and drinks (including milk and alcoholic drinks) 20 % to daily GHGE. Considerable differences in environmental loads of diets existed within age and gender groups. Persons with higher-GHGE diets consumed more (in quantity of foods and especially drinks) than their counterparts of a similar sex and age with low GHGE diets. Major differences between high- and low-GHGE diets were in meat, cheese and dairy consumption as well as in soft drinks (girls, boys and women) and alcoholic drinks (men). Of those, differences in meat consumption determined the differences in GHGE most. Diets with higher GHGE were associated with higher saturated fat intake and lower fibre intake CONCLUSIONS: GHGE of daily diets in the Netherlands is between 3 and 5 kg CO2e, with considerable differences between individuals. Meat, dairy and drinks contribute most to GHGE. The insights of the study may be used in developing (age- and gender-specific) food-based dietary guidelines that take into account both health and sustainability aspects. PMID- 25543462 TI - Modeling in-situ transport of uranine and colloids in the fracture network in KURT. AB - An in-situ dipole migration experiment was conducted using the conservative tracer uranine and latex colloids in KAERI (Korea Atomic Energy Research Institute) Underground Research Tunnel (KURT). The location and dimensions of the fractures between the two boreholes were estimated using the results of a borehole image processing system (BIPS) investigation, and the connectivity of the fractures was evaluated by a packer test. To investigate the flow and transport of uranine and colloids through an in-situ fracture network, a fracture network transport model was newly developed. The model consists of a series of one-dimensional advection-dispersion-matrix diffusion equations for each channel of the fracture network. Using the fracture network transport model, the most probable representation and the hydrologic parameters of the fracture network can be estimated by fitting the breakthrough of uranine. While the fracture network might not be unique, the representation chosen was adequate to describe the breakthrough of uranine and it represents a reasonable approach to modeling transport in the fracture network. An additional evaluation showed that the colloid transport in this study was influenced by filtration on the fracture surface rather than the enhancement of the colloid velocity. Overall, the model can explain successfully the in-situ experimental results of uranine and colloid transports through the fracture network. PMID- 25543463 TI - Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-beta oligomer-treated hippocampal neurons. AB - Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AbetaOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3beta. By this mechanism, AbetaOs may also impair axonal transport before tau-induced cytoskeletal collapse and cell death. Here, we demonstrate that a constitutively active form of protein kinase B/AKT prevents brain-derived neurotrophic factor (BDNF) transport defects in AbetaO-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3beta rescues BDNF transport defects independent of tau. Furthermore, exendin-4, an anti-diabetes agent, restores normal BDNF axonal transport by stimulating the glucagon-like peptide-1 receptor to activate the insulin pathway. Collectively, our findings indicate that normalized insulin signaling can both prevent and reverse BDNF transport defects in AbetaO-treated neurons. Ultimately, this work may reveal novel therapeutic targets that regulate BDNF trafficking, promote its secretion and uptake, and prolong neuronal survival during AD progression. PMID- 25543464 TI - [Changes of ADAMTS13 activity and vWF antigen level in patients with acute myelogenous leukemia and their significance]. AB - This study was purposed to investigate the changes of von Willebrand factor cleaving protease (ADAMTS13) activity and vWF antigen level in patients with acute myelogenous leukemia (AML) before and after treatment and evaluate their clinical significance. Seventy-three AML patients were enrolled in this study, the sodium citrate anticoagulated plasma was collected before and after their induction chemotherapy. Fluorescence resonance energy transfer substrate vWF73 (FRETS-vWF73) assay was established to detect the plasma ADAMTS13 activity while vWF antigen level was measured by ELISA. The results showed that the ADAMTS13 activity in newly diagnosed patients with AML before induction therapy was obviously lower than that in normal controls (63.3 +/- 25.5)% vs (105.1 +/- 37.7)(P < 0.01), while the vWF antigen level was higher than that in normal controls (226.6 +/- 127.0)% vs (111.4 +/- 39.7)% (P < 0.01). After standard induction chemotherapy, the ADAMTS13 activity of AML patients in complete remission period was higher than that in AML patients before therapy (P < 0.01), and was not significant difference with that in normal controls; the vWF antigen was significantly lower than that in AML patients before therapy (P < 0.01), but it still was higher than that in controls (P < 0.05). The ADAMTS13 activity in newly diagnosed AML patients complicated with infection before therapy was obviously lower than that in AML patients without infection (52.2 +/- 20.6)% vs (73.9 +/- 24.7)% (P < 0.01), while the vWF antigen level was significantly higher than that in AML patients without infection (262.2 +/- 135.7)% vs (193.8 +/- 110.2)% (P < 0.05). The ADAMTS13 activity in AML patients with disseminated intravascular coagulation (DIC) was significantly lower than that in AML patients without DIC (42.0 +/- 14.5)% vs (73.4 +/- 22.7)% (P < 0.01), while the vWF antigen level was obviously higher that in AML patients without DIC (274.2 +/- 140.0)% vs (204.7 +/- 115.5)% (P < 0.01). It is concluded that the ADAMTS13 activity in newly diagnosed AML patients befor induction therapy has been confiremed to be lower and the vWF antigen level to be higher, especially in AML patients with infection or DIC. The ADAMTS13 and vWF antigen may play a role in the pathogenesis of AML and the formation of infection and DIC. PMID- 25543465 TI - [Correlation between expression of SIL-TAL1 fusion gene and deletion of 6q in T cell acute lymphoblastic leukemia]. AB - The present study was designed to investigate the prevalence and clinical significance of SIL-TAL1 rearrangements in T-cell acute lymphoblastic leukemia (T ALL). The incidence of SIL-TAL1 rearrangements was analyzed by nest real-time quantitative polymerase chain reaction (RT-PCR) in 68 patients with T-ALL. Karyotypic analysis was performed by conventional R-banding assay and array-based comparative genomic hybridization (array-CGH). The results showed that SIL-TAL1 rearrangements were identified in 10/26 (38.5%) pediatric and 2/42 (4.8%) adult T ALL cases, which indicate a pediatric preference for SIL-TAL1 rearrangements in T ALL. Two different transcripts were detected in 6/12(50%) T-ALL samples. Abnormal karyotypes were detected in 6 out of 11 cases (54.5%) and a deletion of the long arm of chromosome 6 was observed in 4 cases. Array-CGH results of 2 T-ALL cases with SIL-TAL1 rearrangement revealed that this fusion gene was resulted from a cryptic deletion of 1p32, and the overlap region of 6q deletion was 6q14.1-16.3. These cases with SIL-TAL1 fusion had a higher white blood cell (WBC) count and higher serum levels of lactate dehydrogenase (LDH) than cases without SIL-TAL1 fusion. It is concluded that SIL-TAL1 rearrangements are associated with loss of heterozygosity of chromosomal 6q, and SIL-TAL1-positive patients are younger than SIL-TAL1-negative patients. In contrast to the cases without SIL-TAL1 fusion, there are many adverse prognostic factors in the cases with SIL-TAL1 fusion, such as higher WBC count and higher LDH levels. PMID- 25543466 TI - [Construction of lentiviral vector carrying human OCT4A gene and establishment of leukemic cell line K562 stably expressing OCT4A]. AB - This study was purposed to construct a lentiviral vector carrying human OCT4A gene and green fluorescent protein (GFP) , and infect the leukemic cell line K562, observe the expression of OCT4A in K562 cells. According to the sequence of OCT4A mRNA which was found in GenBank, the special primer sequences were synthesized. The OCT4A gene was amplified by RT-PCR, and then cloned into the pCR Blunt vector. The OCT4A DNA fragment was subcloned into the lentiviral vector pLVX-IRES-ZsGreen1 which was restricted by EcoR1 to generate a lentiviral vector pLVX-OCT4A-ZsGreen1. The sequence of the recombinant plasmid was identified by DNA sequencing. Recombinant lentivirus was generated by co-transfection of three plasmids into 293FT cells using lipofectamine 2000 and transfected into K562 cells. Real-time PCR and Western blot were applied to detect the expression of OCT4A mRNA and protein, CCK-8 and colony formation assay were performed to evaluate the effects of OCT4A on proliferation of K562 cells. The results showed that the recombinant lentiviral vector pLVX-OCT4A-ZsGreen1 was successfully constructed. The virus titers were (1.43 +/- 0.25) * 10(8) U/ml. After infection of K562 cells with the lentivirus, the recombinant plasmid could stably up regulate the expression of OCT4A gene and protein according the real-time PCR and Western blot detection results. CCK-8 and colony formation assay showed that exogenous OCT4A gene could significantly promote cell growth and the colony formation of K562 cells. It is concluded that the recombinant lentiviral vector pLVX-OCT4A- ZsGreen1 carrying human OCT4A gene is successfully constructed; K562 cells which stably up-regulates the expression of OCT4A mRNA are obtained, the results of this study provide fundamental basis for further study on mechanism of OCT4A in human leukemia development. PMID- 25543467 TI - [Clinical significance of detecting peripheral T cell subsets in children with leukemia]. AB - This study was purposed to investigate the changes of peripheral blood T cells in children with acute leukemia at different stages and understand the immune status of children with leukemia. The CD4+, CD8+, CD4+/ CD8+ ratio, CD3+ and NK cells in 42 children with acute leukemia and 50 cases of normal children (as control group) were determined by flow cytometry at different periods after complete remission. The results showed that the CD3+ CD4+, CD8+ rate and CD4+/CD8+ ratio in newly diagnosed ALL and AML children were significantly lower than those in control group (P < 0.05). The NK cell count in newly diagnosed children with acute leukemia was significantly lower than that in control group (P < 0.05). Although the NK cell count in ALL and AML children gradually rose at 3, 6, 12 months after complete remission, but it still was statistically different from normal control group (P < 0.05). It is concluded that children with acute leukima have cellular immune disfunction at onset and during treatment, but the cell immune function gradually recovered after complete remission achieved. However, its recovery rate is slow. The results of this study can provided a basis for subsequently use of immunomodulations in leukemia children. PMID- 25543468 TI - [Analysis and significance of hematopoietic progenitor B cells in patients with acute leukemia]. AB - Normal hematopoietic B progenitor cells are similar with acute B lymphoblastic leukemia (ALL) cells in terms of morphology and immunophenotypes which easily result in misdiagnosis of diseases. This study was purposed to explore the importance of B progenitor cell (BPC) level in differential diagnosis of hematologic diseases. A total of 664 specimens including 87 specimens from patients with non-malignant hematologic diseases as control and 577 specimens from AL patients in different progressive stage were analyzed. Out of 577 specimens 26 were collected from ALL patients, 261 were collected from B-ALL, 290 were collected from AML. The relation of different clinical status (new diagnosis, remission, relapse), age and degree of leukemia cell involvement with hematopoietic BPC level were analyzed through identification of CD34/CD10/CD19/CD45 antibody combination and quantification of hematopoietic BPC. The results indicated that (1) CD45 distributed from positive to weak positive, and with very low side scatter. The early hematopoietic BPC expressed CD34+, along with increasing of cell maturation, the CD34 expression gradually disappeared, while CD19 and CD10 showed positive in whole stage of hemaropoietic BPC, and early CD10 highly was expressed. (2) the mean percentage of hematopoietic BPC was 1.36% in control group, 0.60% in T-ALL, 1.39% in B-ALL and 0.80% in AML; the detected rate of hematopoietic BPC in control, T-ALL, B-ALL and AML were 87.4%, 61.5%, 83.5%, 75.9%, respectively; the mean percentage of hematopoietic BPC was 0.37% at new diagnosis, 1.66% in remission and 0.55% in relapse. (3) along with increase of age, the hematopoietic BPC level generally disclined. (4) specimens >5% hematopoietic BPC were mainly found in remission stage of leukemia patients. It is concluded that the hematopoietic BPC are present in malignant and non-malignant hematologic diseases. The changes of hematopoietic BPC level correlate with disease state, age and leukemia cell involvement. The increased hematopoietic BPC level are observed most often in the patients with remission after themotherapy. It should be carefully to diagnose and discriminate between malignant and benign cells with double positive CD19 and CD10. Use of multiparametric flow cytometry and optimal antibody combination are important for discriminating hematopoietic BPC from minor residual disease and accuratly diagnosing diseases and evaluating curative effectiveness. PMID- 25543469 TI - [Expression characteristics of CD200 in acute myeloid leukemia and its clinical significance]. AB - This study was aimed to investigate the relationship between expression of CD200 antigen and clinical characteristics in AML patients and to analyse the value of CD200 in evaluation of AML prognosis. The CD200 and immunophenotypes were detected by flow cytometry, the chromosome karyotypes were determined by R banding, the FISH was used to measure the AML1/ETO, PML/RARa and inv(16), and PCR technique was used to detect the fusion genes AML1/ETO and PML/RARalpha. The results showed that the positive rate of CD200 antigen expression in 54 patients was 57.4% (31/54), the CD200 antigen expression between sex and age of patients was no significant different (P > 0.05). There was significant difference of CD200 expression between CD34 and CD117 (P < 0.05), but the difference of CD200 expression in chromosome karyotypes was no significant difference(P > 0.05). Moreover, there was significant difference of CD200 expression in CD34 and CD117 of CBF positive AML patients (P < 0.05). It is concluded that the CD200 antigen expression in AML may associate with a poor prognosis of patients. PMID- 25543470 TI - [Effects of emodin on apoptosis and cell cycle related genes in U937 cells]. AB - This study was aimed to observe the effects of emodin on apoptosis and cell cycle related genes in human myeloid leukemia cell line U937 cells. U937 cells were exposed to 60 umol/L emodin for 24, 48, 72 h. The expressions of C-MYC, h-TERT, PIM-2, Survivin, wild type P53, P21, TGF beta-1 and MCL-1 genes before and after treatment with emodin were determined and quantitated by using reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that the expressions of C-MYC, h-TERT, PIM-2, Survivin in treated U937 cells decreased, but the expressions of WTp53, P21 and TGFbeta1 increased, while the expression of MCL-1 gene had no obvious change. It is concluded that multiple pathways may be involved in the processes of emodin-induced U937 cell apoptosis. PMID- 25543471 TI - [Effect of aurora inhibitor VX-680 on proliferation and apoptosis of CML cells]. AB - This study was aimed to explore the effect of VX-680, an aurora inhibitor, on proliferation and apoptosis of K562, KCL22 cell lines and CD34+ cells from chronic myeloid leukemia (CML) patients in vitro. The proliferation of K562 and KCL22 cell was detected by CCK-8 method. Apoptosis of cells was detected by Annexin V-PI labeling and flow cytometry. The colony forming ability of bone marrow CD34+ cells derived from CML patients and donors was determined by the colony forming test. The results showed that the treatment of K562, KCL22 and CML CD34+ cells with VX-680 of 20-100 nmol/L for 3 days could obviously inhibit the cell proliferation in a concentration-dependent manner (P < 0.01). VX-680 treatment significantly induced apoptosis of K562 and KCL22 cells. Compared to bone marrow CD34+ cells derived from the healthy donors, the colony forming ability of CML CD34+ cells derived from bone marrow of CML patients was remarkably reduced (P < 0.01). It is concluded that VX-680, an aurora inhibitor, can inhibit the proliferation and induce apoptosis of CML cells in vitro. PMID- 25543472 TI - [Nilotinib treatment for patients with imatinib-resistant or intolerant chronic myeloid leukemia]. AB - This study was purposed to evaluate the efficacy and safety of nilotinib for treating patients with imatinib-resistant or intolerant chronic myeloid leukemia (CML). A total of 23 patients with imatinib-resistant or intolerant CML were enrolled in this study. These patients received nilotinib orally 600-800 mg every day, their curative efficacy, tolerance and overal survival were evaluated. The results showed that all the patients treated with nilotinib obtained complete hematologic remission (CHR), out of them 82.6% patients achieved complete cytogenetic remission (CCyR) and 56.5% patients achieved complete molecular remission (CMR), their adverse events mostly were mild to moderate, generally were transient and easily cured; the median treatment time with nilotinib was 13.5 (1-44) months, and the median follow-up time was 40 (12-102) months. It is concluded that nilotinib has been confirmed to be effective for patients with imatinib-resistant or intolerant CML, and may be selected as a second generation of tyrosine kinase inhibitor (TKI). PMID- 25543473 TI - [Efects of Inhibiting miR-155 Expression on the Proliferation and Apoptosis of Leukemia THP-1 Cells]. AB - The aim of this study was to investigate the effects of miR-155 inhibitor transfection on the proliferation and apoptosis of THP-1 cells. The miR-155 inhibitor was transfected into THP-1 cells (THP-1I) by using X-treme GENE siRNA transfection reagent. Cells without transfection (THP-1C) and cells with negative transfection (THP-1IC) were used as controls. Quantitative real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of miR-155 and relative expression of SHIP1 mRNA in the cells. Cell proliferation was assayed using CCK-8 method. Cell apoptosis were detected by flow cytometry. The expression of SHIP1, TAKT and pAKT in THP-1 cells were detected by Western blot. The results indicated that compared with THP-1C and THP-1IC, the expression of miR-155 in THP-1I cells was significantly reduced; miR-155 inhibition significantly increased apoptosis rate in THP-1 cells (P < 0.05) ; miR-155 inhibition in THP-1 cells caused no significant alteration in SHIP1 mRNA level but significantly increased its protein content, indicating some post transcriptional modulations might exist underlying the modulation of miR-155 to SHIP1, the miR-155 caused significantly reduced protein level of pAKT (P < 0.05) without interfering TAKT protein content. It is concluded that the miR-155 inhibition may promote THP-1 cell apoptosis through increasing SHIP1 protein content and impairing its downstream PI3K/AKT signaling pathway. This study suggests that miR-155 inhibition may be a promising therapy strategy for treating acute myeloid leukemia (AML). PMID- 25543474 TI - [Quercetin enhances the anti-leukemic effect of adriamycin]. AB - This study was purposed to explore the anti-leukemic mechanism of quercetin (Que) in vivo and it enhancing chemotherapeutic effect of adriamycin (ADR) by establishing the quercetin-treated P388 transplanted nude mouse model. The P388 leukemic cells in logarithmic growth phase were taken and injected subcutaneously into BALB/c nude mice so as to establish the leukemia-transplanted nude mouse model. The model mice were treated by quercetin, ADR and their combination, and the survival changes of model mice were observed, the hemogram and peripheral blood cell count examination were performed regularly; the cell cycle was detected and the influence of quercetin on cell proliferation was analyzed by flow cytometry; the caspase-3 protein expression level was detected by ELISA; the mRNA and protein changes of NF-kappaB, BCL-2, BAX were measured by real-time quantitative flourascence PCR and Western blot respectively. The results indicated that the quercetin and adriamycin could significantly prolong the survival of P388 leukemia nude mice, and their combination displayed significantly prolonged effect. Quercetin and adriamycin alone or in their combination could reduce the ratio of G0/G1 phase in mice, the cell ratio in S phase and G2/M phase increased, and the effects of the combination group were more significant than that of the single agent groups. Quercetin could activate caspase-3 and promote leukemic cell apoptosis. Meanwhile, quercetin could down regulate the expression of BCL-2 and NF-kappaB gene, and up-regulate the expression of BAX gene. It is concluded that through modulating the expression of apoptosis-related genes, the quercetin can inhibit leukemia cell proliferation, promote apoptosis, and enhance the chemotherapeutic effects of adriamycin. These results provide some valuable data for further research and development of quercetin as a new and effective anti-leukemic drug. PMID- 25543475 TI - [Effects of H3K27 methylation inhibitor EPZ005687 on apoptosis, proliferation and cell cycle of U937 cells and normal CD34 positive cells]. AB - The aim of this study was to investigate the effects of H3K27 methylation inhibitor EPZ005687 on the apoptosis, proliferation and cell cycle of U937 cells and normal CD34+ cells. The U937 cells and normal CD34+ cells were treated with different concentration of EPZ005687 at different time points. The apoptosis rate was determined by Annexin V/PI staining. The cell proliferation and cell cycle was determined using WST-1 assay and 7-AAD assay, respectively. The activity of H3K27 methylation was detected by chemiluminescent immunoassay. The results showed that the EPZ005687 induced an obvious apoptosis of U937 cells. The apoptotic rate was 3.96% +/- 0.79%,5.74% +/- 0.73%,13.34% +/- 1.77% and 25.24% +/ 2.55% in U937 cells treated with 0.5, 1, 5 and 10 umol/L EPZ005687 for 48 hours, respectively. However, EPZ005687 had rare effect on normal bone marrow(NBM) CD34+ cells. The apoptotic rate was 3.64% +/- 0.62%,4.28% +/- 0.99%,6.18% +/- 1.19% and 7.56% +/- 1.34% after U937 cells were treated with 0.5, 1, 5 and 10 umol/L EPZ005687 for 48 hours, respectively. EPZ005687 inhibited obviously the proliferation of U937 cells but had weak effect on the proliferation of NBMCD34+ cells. The inhibitory effect of EPZ005687 on U937 cells was time-dependent after treated with 0.5, 1, 5 and 10 umol/L EPZ005687 from 12 to 96 hours. EPZ005687 induced G1 phase blocking (G1%, 64.18% +/- 13.27% vs 49.43% +/- 12.54%) and decreased the percentage of cells in S phase (9.67% +/- 2.61% vs15.26% +/- 5.58%) in U937 cells. However, EPZ005687 had no effect on the cell cycle of NBMCD34+ cells. In addition, EPZ005687 produced obviously depletion of H3K27 methylation in U937 cells (P < 0.05), but hardly had effect on the H3K27 methylation of NBMCD34+ cells. It is concluded that the EPZ005687 inhibites proliferation, induces apoptosis and cell cycle blocking in G1 phase in leukemia cells. This agent may have potential value in clinical application. PMID- 25543476 TI - [Clinical study of 32 patients with adult Philadelphia chromosome-positive acute lymphoblastic leukemia]. AB - This study was aimed to evaluate the efficacy and safety of imatinib in the treatment of patients with adult Ph chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). A total of 32 diagnosed adult Ph(+)ALL patients from July 2007 to February 2014 in our hospital were retrospectively analyzed and were divided into two groups: imatinib plus chemotherapy group and traditional chemotherapy group. The differences between two groups were analysed in disease free survival time (DFS), overall survival time (OS) and toxicity. The G banding technigue was used to analyse the karyotype, and the flow cytometry was applyed to detect the immune markers on surface of cells. The results showed that all patients expressed B cell and hematopietic stem/progenitor cell immune markers, out of them 21 patients (65.6%) were with myeloid antigens, 27 patients with simple Ph (+) phenotype and 5 patients with additional chromosome abnormality. The DFS and OS of the imatinib group were statistically longer than those of the traditional chemotherapy group (14.3 +/- 4.7 months vs 10.7 +/- 3.8 months) (P < 0.05) and 22.6 +/- 6.8 months vs 10.7 +/- 3.8 months) (P < 0.05)). There was no significant difference in toxic effects between two groups (P > 0.05)). It is concluded that the all cases of adult Ph(+)ALL are with B cell phenotype and express hematopietic stem/progenitor cell antigen. They often accompanied by expression of myeloid antigens and additonal chromosome abnormality in genetics. The combination of imatinib with chemotherapy can prolong remission time and survival time for patients of non-hematopietic stem cell transplantation on the basis of no notably increasing the toxic effects. PMID- 25543477 TI - [Effect of 5-aza-CdR demethylation on expression of SHP-1 and C-kit genes in leukemia HL-60 cells]. AB - This study was aimed to investigate the expression level of SHP-1 and C-kit genes in acute leukemia HL-60 cells and effect of 5-aza-CdR demethylation on expression of SHP-1 and C-kit genes. RT-PCR was used to detect the mRNA expression level of SHP-1 and C-kit mRNA in HL-60 cells of the drug-treated group and control group.The methylation specific PCR (MSP) was applied to measure the methylation status of SHP-1 and C-kit genes in HL-60 cells.The results showed that after being treated with 5-aza-CdR, the recovery of SHP-1 gene expression was observed in HL-60 cells in which SHP-1 mRNA originally was not expressed. Meanwhile, the high expression level of C-kit mRNA in HL-60 cells was decreased. When HL-60 cells were treated with 0, 0.5, 1.0, 2.0 umol/L 5-aza-CdR, the demethylation effect was enhanced, the expression of SHP-1 mRNA displayed an ascending tendency, and the expression of C-kit mRNA showed an descending tendency in dose dependent manner (P < 0.05) . It is concluded that the absence of SHP-1 mRNA expression in HL-60 cells and recovery of expression after treatment with 5-aza CdR suggest that the hypermethylation of SHP-1 gene relates with pathogenesis of leukemia, and the abnormal increase of C-kit mRNA expression maybe exist in formation of leukemia. The effect of 5-aza-CdR on expression of SHP-1 and C-kit shows dose-dependency, the higher the 5-aza-CdR concentration, the higher the SHP 1 expression and the lower the C-kit expression, moreover, the effect of 5-aza CdR shows time-dependency in specific concentration.The SHP-1 mRNA expression negatively correlates with C-kit mRNA expression, suggesting that the decrease or absence of SHP-1 expression in leukemia cells weakens the negative regulation on C-kit signaling pathway, thus plays a role in the formation of leukemia. PMID- 25543478 TI - [Effect of honokiol on proliferation and apoptosis in HL-60 cells and its potential mechanism]. AB - This study was aimed to investigate the effect of Honokiol (HNK) on proliferation and apoptosis of acute myeloid leukemia HL-60 cells and its potential mechanism. Inhibitory effect of HNK on the HL-60 cell proliferation was detected by MTT assay. Flow cytometry was used to detect the change of cell cycle and AnnexinV/PI staining was used to detect apoptosis. Western blot was applied to analyze the cell cycle protein (cyclins), cyclin-dependent kinase (CDK), P53, P21, P27, BCL 2, BCL-XL, Bax, caspase-3/9 and proteins for MAPK signal pathway. The results showed that HNK could inhibit the proliferation of HL-60 cells in time- and dose dependent ways. HNK arrested HL-60 cells in G0/G1 phase, and S phase cells decreased significantly (P < 0.05). The expression of cyclin D1, cyclin A, cyclin E and CDK2/4/6 were significantly down-regulated (P < 0.05), the expression of P53 and P21 was significantly upregulated after treating for 24 h with HNK (P < 0.05). After 24 h treatment with HNK, HL-60 cell apoptosis increased significantly with the upregulation of activated caspase-3, -9, BAX expression and the downregulation of BCL-2, BCL-XL expression. The MAPK subfamily, P38 and JNK were not significantly changed, but the expression of MEK1/2-ERK1/2 was significantly downregulated (P < 0.05). It is concluded that HNK arrestes the cells at G0/G1 phase and induces HL-60 cell apoptosis through the intervention of MEK1/2-ERK1/2 signaling pathway. PMID- 25543479 TI - [Investigation of lymphoma patients' EBV infection status]. AB - This study was purposed to investigate the EBV infection status of lymphoma patients from January 2008 to April 2012 in the First Hospital of Peking University. All the candidates have been detected for EBV which was either peripheral blood EBV DNA or ISH EBER in pathology from January 2008 to April 2012. The information on their sex, age, pathological type, peripheral blood EBV DNA and ISH EBER was collected, the positive rate of different EBV tests was studied, and the different characteristics of the EBV(+) and EBV(-) group were also explored. And Kaplan-Meier and Cox survival analysis was applied to investigate the EBV's effect on overall survival of these patients. The results showed that among 169 lymphoma patients, the positive rates of EBV EBER in extranodal NK/T cell lymphoma, angioimmunoblastic T cell lymphoma and peripheral T-cell lymphoma were 84.8%, 72.7% and 40.0%, respectively, and were ranged as the top three. The positive rate of EBV in DLBCL was relatively lower (16.7%) than that in above three types of lymphoma. The positive rate of peripheral blood EBV DNA of the elderly EBV(+) DLBCL was 50%. One out of 10 HL patients was subjected to EBER detection, the result of which was positive. The positive rate of peripheral blood EBV DNA of HL was 10%. Both the T cell lymphoma proportion and the rate of B symptom were higher in EBV(+) group than in EBV(-) group. In all the EBER(+) cases, the difference of OS between EBV(+) and EBV(-) patients was statistically significant. In multiple-factor survival analysis, peripheral blood EBV DNA positive was an independent risk factor for poor prognosis in the patients with lymphoma. It is concluded that EBV is closely related to extranodal NK/T cell lymphoma, angioimmunoblastic T cell lymphoma and peripheral T-cell lymphoma. Peripheral blood EBV DNA positive is an independent risk factor for poor prognosis in lymphoma patients. PMID- 25543480 TI - [Retrospective analysis of 23 patients with angioimmunoblastic T cell lymphoma]. AB - This study was aimed to investigate the therapy and prognostic factors of angioimmunoblastic T cell lymphoma (AITL). The clinical data of 23 patients with AITL were collected and the clinical features, laboratorial data, survival and prognostic factor were retrospectively analyzed. The results indicated that the median age of the patients was 62 years. Out of them 21 (91.3%) patients were with intermediate high and high risk according to the international prognostic index (IPI), 14 (60.9%) patients had extranodal disease and 5 (21.7%) patients had autoimmune disease. The overall response rate(ORR) for the whole group was 68.2%, the estimated 3-year and 5-year survival rates were 38.3% and 28.7% respectively. High-dose chemotherapy combined with auto-HSCT improved the outcome of young patients. Immunosuppressive therapy were used in replace/refractory patients. Age more than 65 years, IPI score, LDH level, the number of lymph node involvement, short-term effect, fibrinogen level, beta2-MG level and bone marrow involvement were prognostic factors with statistical significance. Cox multivariate analysis showed that the level of LDH, beta2-MG and bone marrow involevment were independent prognostic factors, IPI, PIT and mPIT were useful for stratified patients into different prognostic risk groups. It is concluded that AITL is aggressive disease occurred in older patients, and autoimmune dysfunction with infectibility, often appears in AITL patients with poor prognosis. The young patients can be benefited from initial intensive chemotherapy. High-dose chemotherapy combined with auto-HSCT may be a better choice for those patients. Immunosuppressive therapy can be used in replase/refractory patients. PMID- 25543482 TI - [Expression of MiRNA-21 in diffuse large B cell lymphoma and its significance]. AB - MicroRNA-21 (miR-21) is considered to play a key role in many cellular processes, affecting tumorigenesis by inhibiting target gene expression. However, its role in diffuse large B-cell lymphoma (DLBCL) is still unclear, and there are no in depth studies on relationship between miR-21 and cellular phenotype. This study was aimed to investigated the expression and role of miR-21 in the regulation of cell biological behavior in DLBCL. The expressions of miR-21 in three DLBCL cell lines were detected by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The possible roles of miR-21 in the biological and behavioral properties of DLBCL were explored by transfection of anti-miR-21 for miR-21 knockdown. In addition, PDCD4 and PTEN were assessed by luciferase reporter assay, qRT-PCR and Western blot. The results revealed that miR-21 expression was significantly upregulated in activated B-cell-like DLBCL cells as compared to germinal centre-like DLBCL cells. The inhibition of miR-21 could induce suppression of proliferation and invasion, as well as increase apoptosis in DLBCL. Moreover, knockdown of miR-21 increased the expressions of PDCD4 and PTEN at the protein level but not at the mRNA level. It is concluded the miR-21 can regulate proliferation, invasion, and apoptosis, so it has a potential therapeutic application in DLBCL. PMID- 25543481 TI - [Clinical characteristics and long-term follow-up of 29 patients with primary mediastinal large B cell lymphoma]. AB - This study was aimed to investigate the clinical manifestation, pathological features, treatment and related prognosis factors of primary mediastinal large B cell lymphoma (PMLBCL). The clinical data of 29 PMLBCL patients admitted in Peking University First Hospital were summarized and the related factors were analyzed retrospectively from January 2000 to November 2013. The results showed that 29 patients with the median age 32 were all pathologically diagnosed as PMLBCL. The main clinical features included mediastinal bulk mass (72.4%), superior vena caval syndrome (51.7%), dyspnea (62.1%), serous membrane fluid (48.3%), with 62.1% extranodal invasion and 62.1% extra-thoracic involvement. According to Ann-Arbor stage, 16 patients (55.1%) were classified to stage I/II and 13 patients (44.9%) to stage III/IV, 12 patients (41.4%) had B symptoms. Among the 29 patients, 2 patients failed to be followed and the others were followed for the median time of 29 months, 17 patients achieved CR, 5 patients achieved PR, 1 patient replaced and 4 patients died of disease progression. The 5 year overall survival rate (OS) was 85.2%, in which RCHOEP regimen group patients had OS 94.4% and CHOEP group patients had OS 75%; 8 patients underwent auto-HSCT and 1 patients underwent allo-HSCT who kept in CR state. Univariate analysis by log-rank test showed albumin level and LDH >= 2ULN, the initial therapy response and IPI score were prognostic factors , but neither were independent prognostic factors by Cox Regression Model. It is concluded that PMLBCL has distinct clinical features. RCHOEP chemotherapy regimen can achieve satisfactory results, but needs to be explored by further clinical trials. PMID- 25543483 TI - [Inhibitory effect of bone marrow mesenchymal stem cells on lymphoma cell proliferation]. AB - Growing evidences show that mesenchymal stem cells (MSC) home to tumorgenesis and inhibit tumor cells, however, their molecular mechanisms are unclear. The purpose of this study was to explore the effect of B7-H4 in the influence of the mouse MSC on the proliferation of lymphoma cell line EL-4. The expression of B7-H4 on the MSC cell line C3H10T1/2 (C3H10) was detected by using immunofluorescence. FAM siRNA was synthesized and transfected into C3H10 cells by INTERFER in (TM) siRNA Transfection Reagent. The transfection efficiency was determined by fluorescent microscopy and flow cytometry. The mRNA expression of B7-H4 was detected by RT PCR after transfection of siRNA-B7-H4 into C3H10 cell line. The EL-4 was co cultured with C3H10 siRNA-NC or C3H10 siRNA-B7-H4 for 48 hours, then was compared with EL-4 cultured alone, after 48 hours the cells were harvested under the confocal microscopy and measured by means of CCK-8 Kit. The results showed that the siRNA transfection efficiency in C3H10 cells reached to 72.43%, B7-H4 expressed highly on C3H10, the B7-H4 mRNA expression was down-regulated by transfection with different concentrations of siRNA into C3H10 cells. The proliferation of EL-4 was inhibited by C3H10 cells, and the effects were weakened and even disappeared after down-regulation of B7-H4. It is concluded that C3H10 can inhibit the proliferation of EL-4 through the expression of B7-H4, and this study provides new targets for the clinical treatment of lymphoma. PMID- 25543484 TI - [Effect of silencing NOTCH1 gene by shRNA interference on AKT/mTOR pathway in mantle cell lymphoma]. AB - The study was purposed to investigate the effect of silencing NOTCH1 gene by shRNA interference on the proliferation, apoptosis and the expression of AKT signaling pathway-related proteins in mantle cell lymphoma Jeko-1 cell line. The hairpin-like oligonucleotide sequences targeting NOTCH1 gene were designed and transfected into Jeko-1 cells by lipofectamine (TM) 2 000. NOTCH1 mRNA and protein were detected respectively by RT-PCR and Western blot. Cell growth was determined by MTT. Cell apoptosis was analyzed by flow cytometry. The expressions of BCL-2, BAX, procaspase-3, procaspase-9, Akt, p-Akt, p-mTOR, p-P70S6K were detected by Western blot. The results showed that NOTCH1 mRNA expression was markedly suppressed by the shRNA targeting NOTCH1. NOTCH1 shRNA suppressed the proliferation of Jeko-1 cells and induced apoptosis of these cells. The cell apoptotic rate was (34.5 +/- 3.4)%, (2.4 +/- 1.3) %, (1.7 +/- 0.6) % in NOTCH1 shRNA, Neg-shRNA and blank groups, respectively, and the difference between them was statistically significant (P < 0.01). NOTCH1 shRNA down-regulated the expression of BCL-2, procaspase-3, procaspase 9, p-Akt, p-mTOR and p-70S6K, up regulated the expression of BAX, but no change protein expression of Akt was observed. It is concluded that the silencing NOTCH1 gene expression by shRNA interference may inhibit Jeko-1 proliferation, induce the cell apoptosis, and the mechanisms may be associated with the inhibition of Akt/mTOR signaling pathway by dephosphorylation. PMID- 25543485 TI - [Clinical efficacy of idarubicin combined with methotrexate for treatment of patients with central nervous system diffuse large B cell lymphoma]. AB - This study was aimed to investigate the clinical efficacy of idarubicin combined with methotrexate for treatment of patients with central nervous system diffuse large B-cell lymphoma. A total of 88 patients with central nervous system diffuse large B-cell lymphoma was selected, out of them 54 patients received idarubicin combined with methotrexate and were selected as A group, other 34 patients received only methotrexate and were selected as B group (control group). Clinical efficacy and safety were compared after treatment. The results showed that in A group 84 patients achieved complete remission (CR), 5 patients archived partial remission (PR), the total remission rate of A group was 72.2%; in B group 10 patients achieved complete remission (CR), 4 patients archived partial remission (PR), the total remission rate of B group was 41.2%; the average survival time of A group was 33.172 months, and the average survival time of B group was 26.305 months, the former was significantly higher than latter (P < 0.05). It is concluded that idarubicin combined with methotrexate for the patients with central nervous system diffuse large B-cell lymphoma is effective and safe, and may be used in clinic. PMID- 25543486 TI - [Immunophenotype characteristics of patients with multiple myeloma in different risk stratification]. AB - This study assessed the immunophenotype characteristics of newly diagosised patients with multiple myeloma (MM) in different risk stratification in order to find the relationship between the immunophenotype and prognosis of MM. The expressions of CD45, CD38, CD138, CD56, CD19, CD117, CD13, CD20, CD22, CD34, Kappa, Lambda in bone marrow samples from 62 newly diagnosed MM patients were detected by using flow cytometric multiparametric direct immunofluorescence technique, CD45/SSC and CD38/SSC combination gating, then the immumophemotypic characteristics of patients in different risk stratification groups were analyzed and compared. The new risk stratification of all patients was carried out according to ISS stages (Interuational Staging System) and cytogenetic characteristics. The results indicated that all the malignant plasma cells commonly expressed CD38 (100%) and CD138 (100%); CD19+ (6.5%) ,CD45+ (22.6%), CD56+ (59.6%) and monoclonal light chain (82%); but the expressions of CD117+ (27.4%) , CD13+ (17.7%) , CD20+ (16.1%) were diverse. According to risk stratification, it is found that the standard-risk and high-risk groups had lower expression of CD56 (P = 0.022) and higher expression of CD117 (P = 0.011), compared with the low-risk group. It is concluded that the immunophenotype of MM is heterogeneity, the lower expression of CD56 and higher expression of CD117 may be associate with poor prognosis. PMID- 25543487 TI - [Clinical characteristics and therapeutic efficacy of immunoglobin D multiple myeloma]. AB - This study was aimed to evaluate the clinical characteristics of immunoglobin D multiple myeloma (IgD MM) and its curative efficacy. The clinical data of 15 cases of newly diagnosed IgD MM from April 1993 to June 2013 were analyzed retrospectively. Among 15 cases received induction treatment, the traditional chemotherapy was carried out in 9 cases, bortezomib-based therapy was performed in 6 cases. The diagnostic criteria and disease response criteria of MM were based on International Myeloma Working Group (IMWG) criteria,survival time was analyzed by using Kaplan-Meier method, the median age of patients was 57 years (range 40-72), the ratio of male to female was 2:1, the MM patients in Durie Salmon stage III accounted for 100% (15/15) , the MM patients with lambda light chain accounts for 80% (12/15) , with bone lesion 86.7% (13/15), with pleural effusion 26.7% (4/15) , with renal impairment (RI) 86.7% (13/15) ,with anemia 93.3% (14/15) , with serum album<35 g/L 26.7% (4/15). The median creatinine clearance rate (Ccr) of patients was 23.1 (6-44) ml/min, and median hemoglobin level was 82 (43-131) g/L. The results showed that in followed-up 11 cases, 8 cases died, 3 cases survived; the average duration of follow-up for these cases was 20 (0.5-138) months, the median progression-free survival time (PFS) was 7 (95%CI4.6-9.4) months, and the median overall survival (OS) time was 15 (95%CI6.6 27.4 ) months. Compared traditional chemotherapy with bortezomib regimen therapy,median OS time was 17 (95%CI6.1-28.0) months vs 15 (95%CI 0.0-33.3) months (P = 0.90) . Assessable curative effect of 14 cases was as follows: CR 33.3% (5/15); VGPR 13.3% (2/15); PR 20% (3/15); SD 20% (3/15); PD 6.7% (1/15). It is concluded that IgD MM is a rare type of MM and has a poor prognosis. Bortezomib may be beneficial for some patients with extramedullary infiltration. Autologous hematopoietic stem cell transplantation may improve survival time. PMID- 25543488 TI - [Effect of mitoxantrone on proliferation and apoptosis of human multiple myeloma cell RPMI8226]. AB - This study was aimed to investigate the effects of mitoxantrone on proliferation and apoptosis of human multiple myeloma cell line RPMI-8226 and its mechanism. The inhibitory rate of RPMI8226 cells proliferation was assayed by MTT, the morphological changes of RPMI-8226 cells were observed by inverted flurescent microscopy and transmission electron microscopy, the apoptosis rate and the cell cycle distribution of RPMI-8226 cells were detected by flow cytometry. The effects of mitoxantrone on the expression of BCL-2, BAX, caspase-3 mRNA were detected by RT-PCR, the BCL-2, BAX, caspase-3 protein expression of RPMI-8226 cells was analyzed by Western blot. The results showed that mitoxantrone could inhibit the proliferation of RPMI-8226 cells in time- and dose-dependent manners. Light microscopy showed that the cell number in mitoxantrone group was significantly less than that in control group and the cell growth arrangement was irregular, apoptotic cells could be seen. Under electron microscope, typical apoptotic morphological and ultrastructural changes could be observed, these results confirmed that the mitoxantrone could induce apoptosis of RPMI-8226 cells, the difference have statistical significance (P < 0.05). The 1.0 ug/ml low concentration of mitoxantrone mainly arrested RPMI-8226 cells in the G2/M phase(P < 0.05), and the 2.0 ug/ml high concentration of mitoxantrone mainly arrested RPMI-8226 cells in the S phase (P < 0.05). The expression of BCL-2 mRNA decreased (P < 0.05),while the expression of BAX, caspase-3 mRNA increased (P < 0.05). Western blot indicated that BCL-2 protein expression also decreased (P < 0.05) and BAX, caspase-3 protein expression increased. It is concluded that the mitoxantrone can inhibit the proliferation of RPMI-8226 cells by inducing cell apoptosis. Activation of the mitochondrial and death receptor pathways of apoptosis may be involved in the mitoxantrone-induced apoptosis, the cell cycle arrest may also play an important role in the apoptosis mechanism. PMID- 25543489 TI - [Effect of free light chain ratio normalization after treatment on prognosis of patients with multiple myeloma]. AB - This study was aimed to investigate the normalization of serum free light chain ratio (sPLCR) after treatment of multiple myeloma (MM) and its influence on the prognosis of MM patients. The clinical data of 42 patients with MM were analyzed retrospectively from January 2009 to November 2013 in out department. According to sPLCR consecutive normalization for more 4 weeks or not after treatment, the patients were classified in patients with mormalized sPLCR and patients with abnormalized sPLCR, then the influence of traditional prognostic factors of MM on sPLCR and effect of sPLCR on overall survival (OS) time of MM patients were analyzed. The results showed that the influence of age, ISS stage displayed statistical difference between sFLCR normalization group and abnormalization group, the age >= 65 years and ISS stage III negatively impacted on sFLCR normalization (P < 0.05). The response rates of patients with normalized sFLCR were as follows: CR - 60%, VGPR - 38.89%; PR - 28.57%; 17 patients (40.48%) with sFLCR normalization showed superior OS, as compared with patients with sPLCR abnormalization (P < 0.01). It is concluded that the sFLCR normalization is the independent prognostic factor for MM, suggesting that the MM patients with sPLCR normalization after treatment have superior prognosis. PMID- 25543490 TI - [Mechanisms of cladribine-inducing apoptosis of multiple myeloma RPMI 8226 cells in vitro]. AB - This study was purposed to explore the mechanisms of cladribine (2-CdA)-inducing apoptosis of multiple mycloma RPMI 8226 cells. The MTT method was used to determine cell proliferation after being treated with 2-CdA. Apoptosis and cell cycle progression were examined by flow cytometry. Transmission electron microscopy was used to observe ultrastructural changes of RPMI 8226 cells. RT-PCR and Western blot were used to analyze the mRNA and protein expression levels of BCL-2, MCL-2 and caspase-3 respectively. The results showed that the 2-CdA inhibited proliferation of RPMI 8226 cells in time and dose-dependent manner. Typical apoptotic morphological and ultrastructure changes could be observed by electron microscopy. Flow cytometry showed that 2-CdA induced myeloma cell apoptosis and arrested myeloma cells in the G2/M phase. The mRNA expression of BCL-2 and MCL-1 decreased but that of caspase-3 not apparently changed. Western blot results suggested that the change trend of BCL-2 MCL-1 and caspase-3 was the same as result of RT-PCR. It is concluded that 2-CdA exhibits inhibitory effects on RPMI 8226 cells in vitro. Activating the mitochondrial and death receptor pathways of apoptosia may be the potential mechanism, meanwhile, the cell cycle arrest may also play a critical role in apoptosis. PMID- 25543491 TI - MNPs-Fe3O4mediates malignant Hematolpoectic cell apoptosis. AB - This study was purposed to evaluate whether the safe concentration of magnetic nanoparticles of Fe3O4(MNPs-Fe3O4) for monocytes could induce the SKM-1 cell apoptosis. The average size and Zeta potential of MNPs-Fe3O4were determined by transmission electron microscopy and the Malvern Zetasizer 3000 HS, respectively. The cell viability after being exposed to MNPs-Fe3O4for 12, 24, 48, and 72 hours was detected by using cell count Kit-8. The cell apoptosis was evaluated by flow cytometry with Annexin V/PI double staining and Wright-Giemsa staining. The cell cycle was measured by flow cytometry. The levels of active caspase-3, survivin and bcl-rambo in cells treated with MNPs-Fe3O4and/or trolox for 48 hours were detected with Western blot. The results showed that the cell viability decreased in SKM-1 cells after exposure to 50 umol/L and 100 umol/L MNPs-Fe3O4(P < 0.05), but did not in monocytes (P > 0.05), compared with that of each non-MNPs-Fe3O4 treated group. This exposure also induced the SKM-1 cells to be arrested in G0/G1. Annexin V/PI staining assay showed that cell apoptotic rate induced by 100 umol/L MNPs-Fe3O4was significantly high in SKM-1 cells while not so high in monocytes, and the pretreatment with trolox could attenuate the apoptosis. Moreover, the active caspase-3 increased in SKM-1 cells after the exposure to MNPs-Fe3O4, while that was not in monocytes, and the increased expression of BCL rambo and the decreased expression of survivin involved in the process were also observed. It is concluded that MNPs-Fe3O4can induce the caspase 3-dependent SKM-1 cell apoptosis by increasing the BCL-rambo expression and decreasing the survivin expression, but this cytotoxic effect can not be observed in monocyte's. PMID- 25543492 TI - [mRNA expression of notch ligand-delta-like-1 and jagged-1 in mesenchymal stem cells of MDS patients]. AB - This study was aimed to investigated the mRNA expression levels of Notch ligands- Delta-like-1 and Jagged-1 in bone marrow mesenchymal stem cells of patients with myelodysplastic syndrome (MDS), and to explore their relation with onset of MDS. Bone marrow mesenchymal stem cells of 38 patients with MDS and 16 normal subjects as control were collected to detect mRNA expression of Delta-like-1 and Jagged-1 by using real-time quantitative polymerase chain reaction. The results showed that the expression levels of Delta-like-1 and Jagged-1 in mesenchymal stem cells of MDS patients were significantly higher than that in normal controls (P < 0.05). According to WHO criteria, the mRNA expression of Delta-like-1 in RA/RAS, RCMD and RAEB groups were significantly higher than that in normal controls (P < 0.05), the mRNA expression of Jagged-1 in RAEB group was also significantly higher than that in normal controls (P < 0.05). The mRNA expression of Delta-like 1 was significantly correlated with the proportion of blasts in the bone marrow of MDS patients (r = 0.502, P < 0.05). The expression levels of Delta-like-1 and Jagged-1 in MDS patients with abnormal karyotypes were significantly higher than those in MDS patients with normal karyotypes (P < 0.05). The mRNA expression of Delta-like-1 in higher risk group according to International Prognostic Scoring System was significantly higher than that in lower risk group (P < 0.05), there was no significant difference in Jagged-1 expression levels between higher risk group and lower risk group (P > 0.05). It is concluded that the changes of Delta like-1 and Jagged-1 expression level in MSC may play a role in the pathogenesis of myelodysplastic syndrome. PMID- 25543494 TI - [Regulatory effect of As2O3on imbalance between adipogenic and osteogenic differentiation of BM-MSC from patients with aplastic anemia]. AB - This study was aimed to explore the regulation of arsenic trioxide (As2O3) on imbalance between adipogenic and osteogenic differentiation of BM-MSC from patients with aplastic anemia(AA). The BM-MSC from AA patients were separated and purified, placed into the adipogenic and osteogenic differentiation culture system, then added the As2O3, CsA, As2O3combined with CsA were added to corresponding differentiation culture system, the concentration of As2O3and CsA were set at 0.001 umol/ml and 2.5 mmol/ml respectively, the cells were divided into As2O3group, the CsA group, combined group and control group (no drug). The cell morphological observation, oil red 'O' staining, Von-Kossa staining, and RT PCR were used to detect corresponding differentiation marks. The results indicated that in respect to adipogenic differentiation, cellular morphology observing and oil red 'O' staining showed that the rate of adipocyte differentiation in As2O3group was (18.3 +/- 1.9)%, which was lower than the (91.8 +/- 2.7)% in the CsA group and (92.1 +/- 1.2)% in control group (P < 0.05), there was no significant difference in comparison with (8.3 +/- 1.9)% in the combined group (P > 0.05), but the rate of differentiation in CsA group was higher than that in combined group (P < 0.05), and there was no significant difference in comparison wtih control group. RT-PCR showed that the LPL-mRNA expression level in As2O3group were significantly lower than that in the CsA group and the control group (P < 0.05), no difference was observed while compared with the combined group (P > 0.05), but the LPL-mRNA expression level in CsA group was significantly higher than that in the combined group (P < 0.05). In terms of osteogenetic differentiation, the calcium deposition in As2O3group and combined group was obviously observed while rarely in the CsA group and the control group when detected by the Von-Kossa staining. OST-mRNA expression level in As2O3group were higher than that in CsA group and the control group (P < 0.05), while compared with the combined group, there was no significant difference (P > 0.05), but the OST-mRNA expression level in the CsA group was lower than that in the combined group (P < 0.05). It is concluded that As2O3can significantly enhance the ability of BM-MSC from AA patients to differentiate into osteoblast, also can inhibit the adipogenic differentiation, in contrast, the CsA can not promote the osteoblast differentiation of BM-MSC from AA patients. PMID- 25543493 TI - [Comparison between two different dose of r-ATG combined with CsA for treating children with severe aplastic anemia]. AB - This study was purposed to compare the efficacy and safety of two different doses of rabbit anti-thymocyte globulin (r-ATG) combined with cyclosporine (CsA) for treating children with severe aplastic anemia (SAA). From January 2005 to July 2010, a total of 95 children with SAA accepted intensive immunosuppressive therapy (IIST) in our department, out of them 55 cases were treated with r-ATG 2.5 mg/(kg.d) for 5 days in combination with CsA (group I) and other 40 cases were treated with r-ATG 3.5 mg/(kg.d) for 5 days in combination with CsA (group II). The responsive rate, adverse reactions, early mortality, relapse and clonal disease were analyzed retrospectively and results between the two groups were compared. Out of 95 patients 43 were boys and 52 were girls, their ages were from 1 to 16 years. The sex, age, severity and course of the disease were comparable between the two groups. The results showed that after treating for 3 and 6 months, the response of patients in group II was higher than that of patients in group I (50% vs 32.1%, P = 0.08 and 65% vs 45.3%, P = 0.059), at 9 and 12 months the response rate of patients in group II and group I did not show significant difference (70.0% vs 71.1%,P = 0.904 and 82.5% vs 80.8%,P = 0.832); at 12 months of treatment, the complete response rate of patients in group II was significantly higher than that of patients in group I (40.0% vs 23.1%,P = 0.08); at 3, 6, 9 months of treatment, the complete response rate of 2 groups showed no obvious difference. The incidence of serum disease, early infection and early mortality did not show statistical difference between two groups. There was no statistical difference in 2 year overall survival rate of two groups. In group I 39 patients were followed-up for more than 2 years, among them 3 patients relapsed, 1 patient died and 1 patient was diagnosed as acute monocytic leukemia (M5). In group II 15 patients were followed up for more than 2 years, there were no relapse, death and clonal disease. It is concluded that the r-ATG combined with CsA is an effective and safe therapeutic regimen for the SAA children. The effect of r-ATG 3.5 mg/(kg.d) is better than the 2.5 mg/(kg.d). The early safety is comparable between the two groups. However, the long-term effect, complications and survival rate need longer follow-up study to evaluate. PMID- 25543495 TI - [Anti-mouse CD122 antibody promotes the hematopoietic repopulating capacity of cord blood CD34+ cells in NOD/SCID mice]. AB - The study was aimed to investigate the effect of anti-mouse CD122 antibody on the hematopoietic repopulating capacity of cord blood CD34+ cells in a humanized murine model-non obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After sublethal irradiation with gamma-ray, NOD/SCID mice were intraperitoneally injected with 200 ug mouse isotype control antibody or anti-mouse CD122 antibody. Human cord blood CD34+ cells or phosphate-buffered saline (PBS) were injected via the tail vein at 6-8 hours later. Cohort of the mice injected with anti-mice CD122 antibody or control antibody alone were sacrificed at different time point (at week 2, 3, and 4 weeks) after the injection, and the percentage of NK cells in the peripheral blood was analyzed by flow cytometry. To evaluate the effect of anti-mouse CD122 antibody on the repopulating capacity of cord blood CD34+ cells in the recipient mice, phenotype analysis was performed in the bone marrow at 6 and 8 weeks after the transplantation. The results showed that the proportion of NK cells in the peripheral blood were (4.6 +/- 0.6)% and (5.7 +/- 1.7)% at week 2 and 3 after anti-CD122 antibody injection respectively,which decreased by 60%, compared with the mice injected with isotype control antibody. After 6 and 8 weeks of cord blood CD34+ cell transplantation,the percentage of human CD45+ in the bone marrow of the recipient mice treated with anti-mice CD122 antibody was (63.0 +/- 12.2)% and (53.2 +/- 16.3)%,respectively,which were dramatically higher than that in the mice treated with isotype control antibody (7.7 +/- 3.6)% and (6.1 +/- 2.4)%. Moreover,at 8 weeks after transplantation,human CD34+ cells appeared significantly in the recipients treated with anti-CD122 antibody. It is concluded that the anti-mouse CD122 antibody enhances the hematopoietic repopulating capacity of cord blood CD34+ cells in the NOD/SCID mice through decreasing the proportion of NK cells. PMID- 25543496 TI - [Efficacy analysis of haploidentical allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia]. AB - This study was aimed to explore the effect and feasibility of related haploidentical allogeneic hematopoietic stem cell transplantation (hi-HSCT) used in the treatment of patients with Ph+ ALL. A total of 22 patients with Ph+ ALL received related hi-HSCT from March 2008 to August 2013. The clinical data of all cases were retrospectively analyzed.There were 15 cases of CR1, 3 cases of CR2, 1 case of CR3 and 3 cases of relapse. The bone marrow and peripheral blood stem cells of related haplotype donors were used for transplantation. All patients were subjected to pretreatment consisting of cytarabine, busulfan (Bu), cyclophosphamide and tota1 body irradiation (TBI), etc. GVHD was prevented by combining variety of immunosuppressants including CsA, MTX, MMF and ATG, etc. The results showed that all of 22 patients acquired hematopoietic reconstitution, and the median time of granulocytes exceeding 0.5 * 109/L and platelets exceeding 20 * 109/L which were transplanted by donors were 13 days and 23 days respectively. The mean follow-up period was 13 months. Ten patients had experience of aGVHD, and 8 patients had experience of cGVHD. Two patients died of infection, 3 died of GVHD and 3 died of relapse,and the rest patients were alive in disease-free situation at lase follow-up. The 2-year disease-free surviva1 rate was 57%. It is concluded that related hi-HSCT can prolong disease-free survival of Ph(+)ALL patients and even cure. PMID- 25543497 TI - [Analysis of the efficiency and influence factors of PBSC collection with AutoPBSC and MNC procedure of cell separator]. AB - This study was aimed to analyze the efficiency and influence factors of PBSC collection by an automatic (AutoPBSC procedure) and a semiautomatic apheresis procedure ( MNC procedure) of COBE Spectra cell separators. According to the different objects, A total of 109 apheresis cases were divided into autologous cohort (patient) and allogeneic cohort (donor). The quantity and quality of the collections and the characteristics of apheresis procedure were compared, the yields and influence factors of two cohorts with two kinds of procedures were analyzed respectively. The results showed that the collections of two procedure in patients and donors which processed the similar blood volumes were insignificantly different in MNC%, CD34+ %, CD34+ cell counts and Hb concentration (P > 0.05) ; the collections by AutoPBSC procedure had got fewer platelets, less product volumes whereas more ACD-A used, longer apheresis time in comparison with MNC procedure (P < 0.05). Correlation analysis indicated that MNC (r = 0.314,P = 0.015) , CD34+ cell counts (r = 0.922, P = 0.000) in collections were positively correlated with preahperesis in the autologus cohort by two procedures, CD34+ cell counts were correlated with WBC (r = 0.369, P = 0.004) and MNC (r = 0.495,P = 0.000) in collections; MNC (r = 0.896, P = 0.000) was positive correlated with preahperesis by AutoPBSC procedures and CD34+ cell counts also (r = 0.666,P = 0.000) by MNC procedure in the allogeneic cohort. Male had got more MNC and CD34+ cell counts than female (P < 0.05), age <= 40 had got more MNC and CD34+ cell counts than age>40 (P < 0.05) in patients by AutoPBSC procedure; age > 40 had got more CD34+ cell counts than age <= 40 by MNC procedure(P < 0.05). Only male had got more MNC and CD34+ cell counts than female (P < 0.05) by MNC procedure in donors. It is concluded that with same amount of blood processing, the PBSC collections from autologous patients and allogeneic donors had got a high degree of uniformly in purity of MNC and purity and concentration of CD34(+) cell counts by two procedure, whereas sex and age imposed more influence on PBSC collection in autologous. PMID- 25543498 TI - [Protective effect of HS-6101 on rhesus monkeys with severe hematopoietic acute radiation sickness]. AB - This study was purposed to investigate the protective effects of lipoprotein HS 6101(6101) on rhesus monkey total body irradiated with 7.0 Gy 60Cogamma-ray. A total of 30 health adult rhesus monkeys were randomly divided into symptomatic therapy (ST), WR2721 and HS-6101 30, 90 and 270 mg/kg groups (n = 6), the rhesus monkeys of each groups were injected with physiological saline 0.3 ml/kg, WR-2721 30 mg/kg, or HS-6101 30, 90 and 270 ug/kg, respectively. All agents were once intramuscularly injected at 1 hr prior irradiation. General observation, peripheral blood cell counts, colony forming unite assay of bone marrow hemopoietic progenitor cells, and histopathological examination were performed. The results showed that animals in symptomatic therapy group begin to die on the 13(th) day and 4 animals died within 24 days, the average survival time was 18.2 +/- 4.3 days; 2 animals in WR-2717 groups died on day 15.8 and day 18.5 post irradiation respectively. 1 animal in HS-6101 270 mg/kg group died on day 35.8, all other animals survived. Nadirs of peripheral blood white blood cells, neutrophils and platelets of animals in HS-6101 treatment groups were significantly higher than those in other 2 groups including ST and WR-2721 groups, and the hemopoietic recovery were also significantly speeding up(P < 0.05 and 0.01). In vitro results showed that HS-6101 obviously promoted 7.0 Gy 60Cogamma irradiated monkey's bone marrow mononuclear cells to form various hematopoietic progenitor cell colonies (P < 0.05 and 0.01) . Compared with symptomatic therapy and WR-2717 groups, bone marrow histopathological changes in HS-6101 treatment groups showed more active hemopoietic cell proliferation and higher density structure. It is concluded that HS-6101 90 ug/kg treatment can promote the bone marrow recovery of 7.0 Gy 60Cogamma irradiated monkey, alleviate their animal symptom, simplify the treatment measures and improve the animal survival rate. The HS-6101 shows remarkable radioprotective effects as compared with the currently internationally acknowledged radioprotectant of WR-2721. PMID- 25543499 TI - [The clinical value of F-18 FDG PET/CT in patients with secondary hemophagocytic syndrome]. AB - The aim of this study was to investigate the role of F-18 fluoro-2-deoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in diagnosis and prognostic evaluation of secondary hemophagocytic syndrome (HPS). A total of 11 secondary HPS patients examined with 18F-FDG-PET/CT were retrospectively analyzed. The diagnostic value of F-18 FDG PET/CT for malignancy detection was assessed. The values of maximum standardized uptake value (SUV(max)) in spleen (SUVS(p)) and in bone marrow (SUVBM) were measured to analyze their relationship with various laboratorial parameters and clinical outcome of secondary HPS patients. The results showed that 4 out of the 11 patients had malignancies, the sensitivity, specificity and diagnostic accuracy of F-18 FDG PET/CT for malignancy detection were 100%, 66.7% and 75% respectively, the SUV(max) of spleen and bone marrow showed no significant correlation with laboratorial parameters, a maximum SUVS(p) of 3.10 and a maximum SUVBM of 3.47 were the optimal cutoffs for predicting patients' outcome, the increased uptake of F-18 FDG in the BM and spleen were significantly associated with shorter survival time according to univariate analysis. It is concluded that 18F-FDG PET/CT may especially play an important role in diagnosis and predicting outcome of secondary HPS for the small sample size. PMID- 25543500 TI - [Effects of rhG-CSF Stimulation in vitro on the Adhesion and Polarization of Human CD4+T Lymphocytes]. AB - The adhesion and polarization of T lymphocytes involved in the adhesive interaction of lymphocyte function-associated antigen 1 (LFA-1) with its ligand intercellular adhesion molecule 1 (ICAM-1). This study was aimed to investigate the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) stimulation in vitro on the adhesion and polarization of CD4+ T cells of healthy human in peripheral blood. The peripheral blood mononuclear cells were collected from 12 healthy volunteers. The CD4+ T cells were sorted by miniMACS. The sorted CD4+ T cells were incubated with rhG-CSF for 24 h, then the adhesion and polarization of CD4+ T cells activated by stroma cell-derived factor -1alpha (SDF 1alpha) and ICAM-1 were detected by ELISA and inverted microscope. The results showed that the percentage of adhesion CD4+T cells in the experimental group (rhG CSF acting on the healthy adult volunteers) (61.9 +/- 5.9)% was lower than that in the control group (healthy adult volunteers without rhG-CSF stimulation) (68.3 +/- 7.3)% (P < 0.05). The percentage of polarized CD4+T cells in the experimental group (24.3 +/- 4.3)% was also lower than that in control group (47.1 +/- 5.1)% (P < 0.05). It is concluded that the adhesion and polarization of CD4+T lymphocytes can be inhibited after rhG-CSF stimulation. PMID- 25543501 TI - [Kinetics of Cu crossing human erythrocyte membrane]. AB - This study was aimed to investigate various factors influencing the proceduction of Cu(II) crossing human erythrocyte membrane, including concentration of Cu2+, pH value of the medium, temperature and time of incubation, and to derive kinetic equation of Cu(II) crossing human erythrocyte membrane. Suspension red blood cells were incubated by Cu2+, then content of Cu2+ crossed human erythrocyte membrane was determined by atomic absorption spectrometry under various conditions after digestion. The results showed that content of Cu2+ crossed human erythrocyte membrane increased with the increase of extracellular Cu2+ and enhancement of incubation temperature, and the content of Cu2+ crossed human erythrocyte membrane showed a increasing tendency when pH reached to 6.2-7.4, and to maximum at pH 7.4, then gradually decreased at range of pH 7.4-9.2. It is concluded that the Cu2+ crossing human erythrocyte has been confirmed to be the first order kinetics characteristics within 120 min, and the linear equation is 103 * Y = 0.0497t +6.5992. PMID- 25543502 TI - [Isolation, culture and characterization of outgrowth endothelial cells from the human peripheral blood]. AB - Compared with endothelial progenitor cells, outgrowth endothelial cells (BOECs) from peripheral blood are rich in protein for blood angiogenesis and cell adhesion, similar to mature endothelial cells in biological characteristics. Moreover, they are now replacing human umbilical vein endothelial cells for the latter's limited life span and drift of phenotype, and might become a new tool for exploring the vascular abnormalities. This study was aimed to establish the protocol of producing BOECs, and then analyze the cell phenotype and function of BOECs. Mononuclear cells were collected from peripheral blood by gradient centrifugation and then seeded on plates and cultivated in EGM-2 medium for 4 weeks. The morphological changes of cells were observed and cell phenotype was examined by flow cytometry. VWF multimers were used to analyse the distribution of vWF multimers in superment of BOECs and the storage of vWF in BOECs, and the secretion of vWF in BOECs under stimulation was detected by confocal fluorescence microscopy. The results showed that after 4-week-culture in vitro, the cell colonies and characteristic cobblestone-like morphology of BOECs were found in plates. For another three weeks of expansion, BOECs expressed CD31, CD34, and EPCR, without the expression of CD14, CD45 and CD133. The vWF from BOECs cell supernatant shared the same multimer pattern as that in normal plasma. By confocal fluorescence microscopy, vWFs were observed in BOECs. The amount of vWF increased in cells, and vWF strings were formed on cell surface by the stimulation of phorbol-12-myristate-13-acetate(PMA). It is concluded that the BOECs are first successfully established, and the phenotype and function of BOECs are analyzed. They are the native cell models for the pathogenesis of von Willebrand diseases (vWD), and may be used as new gene therapy tools for vWD. PMID- 25543503 TI - [Blood matching and transfusion for 12 acute autoimmune hemolytic anemia patients by extracorporal hemolysis test]. AB - In order to screen the compatible red cells by using extracorporal hemolysis test for acute autoimmune hemolytic anemia (AIHA) patients who were difficult to be matched by automatic microcolumn gel indirect antiglobulin test. Twenty-six cases of AIHA were chosen as control group, to whom the same type of donor red blood cells were infused with the weakest blood agglutination; 12 cases of acute AIHA patients were chosen as test group, these patients were difficult to be matched by automatic microcolumn gel indirect antiglobulin test, and the donor red cells without hemolysis by extracoral hemolysis test were transfused for them. The results showed that compared with the control group,the effect of transfusion was better in test group (P < 0.01), with 2.26 U leukocyte-depleted erythrocyte suspension in average, whose hemoglobin, reticulocyte and total bilirubin levels were changed significantly compared with those before blood transfusion (P < 0.01) . It is concluded that the compatible red blood cells for the acute AIHA patients can be screened by the extracorporal hemolysis test, when it is difficult to screen by the automatic microcolumn gel indirect antiglobulin test. PMID- 25543504 TI - [Influence of reagent storage in Sysmex CA7000 for different time on 4 test RESULTS: of the plasma coagulation]. AB - The purpose of this study was to investigate the influence of blood coagulation reagents stored for different time on test results of the specimens prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (Fib). A total of 21 patient plasma specimens was taken and measured for homeostasis by Sysmex CA7000 automated blood coagulation analyzer and supporting reagent. The PT, APTT, TT and Fib of specimens were measured with the reagents stored in Sysmex CA7000 for different time. The differences of PT, APTT, TT and Fib were analyzed between values measured of the reagents stored for 0 hour and different time (TS:12, 24, 36,48, 60, 72 h; DA:24, 48, 72, 96, 120 h; TT:2, 4, 6, 8, 10, 12 h; TR:4, 8, 12, 16, 20, 24 h; OVB:1, 2, 3, 4, 5 ,6 h), respectively. The results showed that when coagulation reagent TS were stored for more than 48 h , DA 96 h, TT 10 h, TR 16 h and OVB 4 h, the values of PT, APTT, TT and Fib of samples were statistically different from the values measured with fresh coagulation reagent (P < 0.01), respectively. Compared 0 h with TS stored for 48-72, DA 96-120, TT 10-12, TR 16-24 and OVB 4-6 h, the percentage difference of PT, APTT, TT and Fib is in -2.6% ~ 10.8%, -3.44% ~ 4.8%, -3.9% ~ 5.52%, -10.8% ~ 3.3% and -17.2% ~ 0.5%, the PT and Fib changes were more significant. Accordingly, the result of PT, APTT and TT had a uptrend as the reagent stored in Sysmex CA7000 analyzer for a long time, while Fib downtrend. It is concluded that the reagents showed be timely replaced when the plasma coagulation test is performed so as to obtain accurate results of examination. PMID- 25543505 TI - [Establishment of real-time fluorescent quantitative polymerase chain reaction for rapid detection of M244V mutation in kinase domain of BCR-ABL fusion gene]. AB - The present study was aimed to establish a high sensitive and specific method for detecting M244V mutation in kinase domain of BCR-ABL(fusion gene) by using real time quantitative PCR technology. The specific primer of the mutational site was designed, and then the PCR reaction system and condition were optimized to establish the new real-time PCR method for detecting M244V mutation. The results showed that a method of detecting M244V mutation has been successfully established. The detection results indicated that this method possessed high sensitivity, specificity and accuracy. It is concluded that the method based on fluorescent quantitative polymerase chain reaction for detecting M244V mutation can be used to detect the M244V mutation in CML patients successfully. PMID- 25543506 TI - [Analysis of gene expression profiles to improve the treatment of leukemia]. AB - In clinical practice, acute myelocytic leukemia (AML) has been classified into favorable risk type, intermediate risk type and unfavorable risk type in order to take a proper treatment and good prognosis. Unfortunately, the majority of AML patients are defined as an intermediated risk and they have diverse responses to standard therapy. Some of them should accept the allogeneic hematopoietic stem cell transplantation after first induction remission to improve prognosis, but others can survive through the chemotherapy based on consolidation regimens. However, with the advanced high-throughput sequencing technology, people tend to view the complex interplay as a whole instead of investigating the abnormality independently. The gene expression profile consisting of variation of methylation, mRNA, microRNA and other information contribute to further specify the leukemia subtype and improve the treatment and prognosis of leukemia. Moreover, the gene expression profile can help to know more about the essential of the disease and to develop the new drug which is more effective and specific. PMID- 25543507 TI - [Significance of chromosome 7 abnormalities in myeloid malignancies]. AB - Chromosome 7 abnormalities are the most common cytogenetic alterations found in myeloid malignancies. Myeloid malignancies exhibiting monosomy 7/del (7q) have been confirmed to associate with high susceptibility to infections, poor response to chemotherapy, and short survival time, so speculating that chromosome 7 has important tumor suppressor genes. Commonly deleted segments (such as 7q22) of chromosome 7 have been identified by FISH and other technologies. Genes (EZH2, MLL5, DOCK4, SAMD9L/SAMD9) located in commonly deleted segments of 7q have been cloned and characterized along with the advance of molecular biology.This review summaries the current advancement about myeloid malignancies associated with monosomy7/del(7q). PMID- 25543509 TI - [Progress of study on drug therapy in adults patients with acute myeloid leukemia (non APL) after remission]. AB - Acute myeloid leukemia (non APL) is a group of highly heterogeneous hematologic malignancy.In recent years, after the standard "3+7" regimen, the complete remission rate of adult patients with AML (non-APL) can be as high as 70%-80%. However, due to the existence of minimal residual disease after remission, the recurrence of the disease still inevitable, only approximately 20% to 30% of the patients enjoy longterm disease-free survival. Currently only allogeneic hematopoietic stem cell transplantation is one of the most effective treatment ways for AML. The number of transplant patients is limited, because of various reasons, such as the physical condition of patients, donor sources or economic reason. After transplantation, patients also have the possibility of recurrence, therefore, drug treatment is still important after AML remission. At present, NCCN (National Comprehensive Cancer Network) recommended high-dose cytarabine as first-line postremission therapy for patients of good prognosis group and as second-line therapy for intermediate risk group. In recent years, researchers have explored other drugs, such as the nucleoside analogues, methyltransferase inhibitors and protease inhibitors or other drugs for the treatment of adult AML patients who is in remission.In this article, the treatment of conventional medicine for the treatment of AML after complete remission is summarized. PMID- 25543508 TI - [Expression and Significance of PTPL1 in Hematological Malignancies]. AB - PTPL1 is a protein with a predicted MW of 270 kD, and plays a major role in many cellular functions, including cell survival, proliferation, differentiation and motility. Evidence has demonstrated that PTPL1 is associated with tumor. Although many conflicting results suggested that PTPL1 has two contradictory effects (supressing or promoting ) on tumor, the real effect depends on the involved substrate and the cellular context. Expression of PTPL1 is low in lymphoma, while it is high in myeloid leukemia. PTPL1 has been regarded as a tumor suppressor in lymphoma, the methylation of PTPL1 promoter leads to gene expression reduced or disappeared, playing a lymphoma tumor suppressor role. This review focuses on PTPL1 domain and its interacting proteins, the relationship between PTPL1 and hematological malignancies. PMID- 25543510 TI - [Treatment of lymphoblastic leukemia with CD19-specific modified chimeric antigen receptor T cells]. AB - Bioengineered T cells, which are the genetically manipulated T cells to express chimeric antigen receptor T Cell (CAR T) against leukemia-associated specific antigens, were applied to treat acute and chronic lymphocytic leukemia with CAR T. CAR T cells combined with cell-surface binding site and anti-CD19 chimeric antigen receptor can treat diseases through T cells transfection. CAR T cells can recognize the CD19 antigen on B cells with specific cell-surface loci. CAR T cells can proliferate by 1000 times and differentiate in vivo by the CD19 antigen stimulation, therefore, kill the acute and chronic lymphocytic leukemia cells effectively. This article briefly reviews the CAR T cells and the effect of CAR T cells on acute and chronic lymphoblastic leukemia. PMID- 25543511 TI - [Recent advances of studies on the therapy-related myelodysplastic syndromes/acute myeloid leukemia]. AB - Therapy-related myelodysplasia syndromes/acute myeloid leukemia (t-MDS/AML) is a clinical syndrome occurring as a late complication after chemotherapy and (or) radiotherapy, attracting much more attention owing to the improved treatment agents and longer survival of many treated patients. According to the WHO classification of 2008, t-MDS/AML is a serious complication of chemotherapy or radiotherapy given to a malignant or nonmalignant condition consisting of t-AML, t-MDS and t-MDS/myeloproliferative diseases (t-MDS/MPD). This review mainly focuses on the pathogenesis, relationship with primary tumour, treatment and prognosis of t-MDS/AML. PMID- 25543512 TI - [Research advance on frozen injury and protective mechanisms of cryopreservated platelets]. AB - Platelets are important component in the blood which play vital role in physiological hemostasis. In clinic, platelets are usually transfused to patients suffered from idiopathic thrombocytopenic purpura,thrombocytopenia after chemotherapy and radiotherapy,or hemorrhagic thrombocytopenia caused by other reasons. Storage time for platelet concentrates is limited to five days at room temperature, leading to an increasing number of scrap rate, therefore the prolonging the storage time is important for clinical application. Storage at -80 degrees C is an ideal long-term cryopreservation method for platelet concentrates. In this article, platelets cryopreservation,the mechanism of frozen injury and the protective mechanisms of platelets were reviewed. PMID- 25543513 TI - [Advance of researches on relation of Th17 cells with immuno-associatied hematologic diseases]. AB - Th17 cells are a newly discovered subsets of T cells. It can specifically secrete IL-17. The RORgammat and STAT3 are specific transcription factors of Th17 cells. In recent researches, it has been found that Th17 cells and their proportion increased in a variety of autoimmune diseases. This article briefly reviews Th17 cells and its relationship with the occurrence and severity of several immune related blood diseases, including aplastic anemia, autoimmune hemolytic anemia, immune thrombo-cytopenia and immune-related pancytopenia. PMID- 25543514 TI - [Relationship between platelet specific antibodies and the onset, clinical manifestation, treatment and prognosis of ITP]. AB - Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease. It is considered that production of platelet auto-antibodies was one of the pathogenesis of ITP, first-line therapy including corticosteroid and immunoglobulin could reduce destruction of platelets by inhibiting production of auto-antibodies and blocking Fc-receptor of reticuloendothelial system, but some of the patients were refractory to first-line therapy and have persistent duration of the disease, having worse prognosis and developing into chronic/refractory ITP(C/RITP) . Platelet membrane glycoprotein like GPIIb/IIIa and GPIbalpha are the most common antigen targets, but first-line therapy was less effective to patients whose anti-GPIbalpha antibodies are positive. Further studies revealed that the way causing platelet destruction by anti-GPIIb/IIIa antibodies and anti-GPIbalpha antibodies are different: the former is mainly dependent to Fc-pathway, and the latter mainly cleared platelet by Fc-independent way. Results above indicated that detection of type of platelet auto-antibodies maybe potential to treatment and prognosis of ITP. This article summarizes relationship between platelet specific antibodies and the onset, clinical manifestation, treatment and prognosis of ITP. PMID- 25543515 TI - [Research progress on epstein-barr virus and its related lymphoma]. AB - Epstein-Barr virus (EBV) belongs to r-DNA herpes virus family and the first discovered virus associated with human tumors. Numerous studies have found that EBV infection is related to the occurrence of a variety of lymphomas, such as Hodgkin's lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, HIV-related lymphoma and diffuse large B-cell lymphoma. Recent studies indicated that the gene expression products of EBV latent infections play an important role in the lymphoma, and these findings provide the theoretical basis for the treatment of EBV-related lymphoma. This review mainly discusses the progress in the mechanism and the therapy of EBV-related lymphoma. PMID- 25543516 TI - [Research advances on caspase-independent cell death of K562 cells]. AB - Caspase independent cell death (CICD) is defined as death that ensues when a signal that normally induces apoptosis fails to activate caspases,it can be activated by PARP-1, Calpains, Bax and AIF, possessing distinctive biologic characteristic differed from apoptosis and necrosis. Recent researchs have found that the molecular mechanisms governing CICD of K562 is opposite from that of the traditional medicine killing leukemia cells, which may have the potential pharmaceutical point for new drugs. This article reviews the newly acquaintance of molecular mechanisms for CICD and recent studies concerning the induction death of K562 cells via CICD, so as to provide some reference for the research of new drug point. PMID- 25543518 TI - Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies. AB - BACKGROUND: Studies have reported inconsistent results concerning the existence of associations of folate intake and serum folate levels with prostate cancer risk. This study sought to summarise the evidence regarding these relationships using a dose-response meta-analysis approach. METHODS: In January 2014, we performed electronic searches of PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate on the incidence of prostate cancer. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of the incidence of prostate cancer for more than 2 categories of folate were included. RESULTS: Overall, we included 10 prospective studies reporting data on 202,517 individuals. High dietary folate intake had little or no effect on prostate cancer risk (risk ratio [RR] = 1.02; 95% CI = 0.95-1.09; P = 0.598). The dose-response meta-analysis suggested that a 100 MUg per day increase in dietary folate intake has no significant effect on the risk of prostate cancer (RR = 1.01; 95% CI = 0.99-1.02; P = 0.433). However, high serum folate levels were associated with an increased risk of prostate cancer (RR = 1.21; 95% CI = 1.05-1.39; P = 0.008). The dose-response meta-analysis indicated that a 5 nmol/L increment of serum folate levels was also associated with an increased risk of prostate cancer (RR = 1.04; 95% CI = 1.00-1.07; P = 0.042). CONCLUSIONS: Our study indicated that dietary folate intake had little or no effect on prostate cancer risk. However, increased serum folate levels have potentially harmful effects on the risk of prostate cancer. PMID- 25543517 TI - Accuracy of genome-wide imputation in Braford and Hereford beef cattle. AB - BACKGROUND: Strategies for imputing genotypes from the Illumina-Bovine3K, Illumina-BovineLD (6K), BeefLD-GGP (8K), a non-commercial-15K and IndicusLD-GGP (20K) to either Illumina-BovineSNP50 (50K) or to Illumina-BovineHD (777K) SNP panel, as well as for imputing from 50K, GGP-IndicusHD (90iK) and GGP-BeefHD (90tK) to 777K were investigated. Imputation of low density (<50K) genotypes to 777K was carried out in either one or two steps. Imputation of ungenotyped parents (n = 37 sires) with four or more offspring to the 50K panel was also assessed. There were 2,946 Braford, 664 Hereford and 88 Nellore animals, from which 71, 59 and 88 were genotyped with the 777K panel, while all others had 50K genotypes. The reference population was comprised of 2,735 animals and 175 bulls for 50K and 777K, respectively. The low density panels were simulated by masking genotypes in the 50K or 777K panel for animals born in 2011. Analyses were performed using both Beagle and FImpute software. Genotype imputation accuracy was measured by concordance rate and allelic R(2) between true and imputed genotypes. RESULTS: The average concordance rate using FImpute was 0.943 and 0.921 averaged across all simulated low density panels to 50K or to 777K, respectively, in comparison with 0.927 and 0.895 using Beagle. The allelic R(2) was 0.912 and 0.866 for imputation to 50K or to 777K using FImpute, respectively, and 0.890 and 0.826 using Beagle. One and two steps imputation to 777K produced averaged concordance rates of 0.806 and 0.892 and allelic R(2) of 0.674 and 0.819, respectively. Imputation of low density panels to 50K, with the exception of 3K, had overall concordance rates greater than 0.940 and allelic R(2) greater than 0.919. Ungenotyped animals were imputed to 50K panel with an average concordance rate of 0.950 by FImpute. CONCLUSION: FImpute accuracy outperformed Beagle on both imputation to 50K and to 777K. Two-step outperformed one-step imputation for imputing to 777K. Ungenotyped animals that have four or more offspring can have their 50K genotypes accurately inferred using FImpute. All low density panels, except the 3K, can be used to impute to the 50K using FImpute or Beagle with high concordance rate and allelic R(2). PMID- 25543519 TI - Symptoms of anxiety on both sides of the US-Mexico border: the role of immigration. AB - Home to about 15 million people, the US-Mexico border area has suffered stresses from increased border security efforts and a costly drug war in Mexico. Whether immigration patterns add to increasing levels of anxiety for the Mexican population and the Mexican-origin individuals living in the US-Mexico border and near the border is unknown. We used the US-Mexico Study on Alcohol and Related Conditions (UMSARC), a cross-sectional survey (2011-2013) of individuals living in border and non-border cities of the US (n = 2336) and Mexico (n = 2460). In Mexico respondents were asked if they ever migrated to the US or have a family member living in the US (328) or not (2124), while in the US respondents were asked if they were born in Mexico (697), born in the US with no US-born parents (second generation, 702) or born in the US with at least one US-born parent (third generation, 932). The prevalence and risk factors for symptoms of anxiety using the Beck Anxiety Inventory (>=10) were obtained. Mexicans with no migrant experience had a prevalence of anxiety and adjusted prevalence ratio (PR) within the last month of 6.7% (PR = reference), followed by Mexicans with migration experience of 13.1% (PR = 1.8), Mexican-born respondents living in the US of 17.3% (PR = 2.6), US born Mexican-Americans of 2nd generation of 18.6% (PR = 3.3) and finally US born 3rd + generation of 25.9% (PR = 3.8). Results help to identify regions and migration patterns at high risk for anxiety and may help to unravel causal mechanisms that underlie this risk. PMID- 25543520 TI - ABCB1 gene polymorphisms and violent suicide attempt among survivors. AB - INTRODUCTION: Those suicide attempters that choose violent methods dramatically diminish the possibility of survival. Completed suicide using violent means, which is common among first-time suicide attempters, was recently found to be more likely among T allele carriers in the three most common ABCB1 SNPs, encoding for P-gp. Thus, this study examined, for the first time, whether these ABCB1 SNPs were associated with the use of violent means among survivors of a suicide attempt. MATERIAL AND METHODS: Suicide attempters (n = 578, 87.4% women; of whom 16.6% committed a violent intent) were genotyped for exonic SNPs in the ABCB1 (C1236T, G2677T/A, C3435T). The relations of the three genotypes and of the TTT haplotype with the use of a violent suicide method were evaluated separately. The impact of confounds on these variables was controlled. RESULTS: A higher frequency (p = 0.02) of suicide attempters using violent methods was found among those carrying the ABCB1 haplotype (1236TT-2677TT-3435TT). Since gender and number of previous suicide attempts were identified as confounds, the relation was tested in the subset of women who were first-time attempters or second- and more-time attempters. The ABCB1 haplotype increased the risk more than three times in those women attempting a violent suicide for the first time (OR = 3.6; CI95%: 1.08-12.09; p = 0.04). DISCUSSION: The ABCB1 haplotype (1236TT-2677TT 3435TT) was related to the use of a violent suicide attempt method. Genotyping for these three ABCB1 SNPs may be helpful to detect people at risk of first suicide intents using violent methods. PMID- 25543521 TI - miR-744 is a potential prognostic marker in patients with hepatocellular carcinoma. AB - Identification of new biomarkers for aggressiveness of hepatocellular carcinoma (HCC) to supplement the current group of prognosis algorithms is a significant clinical need. To clarify expression levels of microRNA-744 (miR-744) in HCC tissues and to explore its clinicopathological significance in HCC patients following liver transplantation (LT), we quantified miR-744 using real-time quantitative reverse transcription polymerase chain reaction in 96 paired cancerous tissues and para-cancerous normal liver tissues. We investigated relationships among miR-744 expression, clinicopathological parameters, and overall survival (OS). Of 96 paired samples, 68 cancer tissues expressed low miR 744 compared with their matched normal liver tissues. Patients with microvascular invasion or multi-tumor nodules showed significantly lower miR-744 expression; miR-744 was further decreased in patients with post-LT HCC recurrence compared with non-recurring patients. Patients with lower miR-744 expression showed significantly poorer recurrence-free survival and OS than individuals with higher miR-744 levels. Multivariate analysis revealed that lower miR-744 was an independent predictor of poor prognosis. Our results associate decreased miR-744 expression with HCC recurrence and prognosis, and also suggest that miR-744 is an independent predictor of survival in HCC patients after LT and may therefore be a potential biomarker for their prognosis. PMID- 25543522 TI - Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: Is it different? AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of insulin resistance [IR]. However, a significant proportion of NAFLD patients are devoid of IR. Is NAFLD sans IR a different entity? The aim of the study was to compare the anthropometric, metabolic, biochemical, ultrasonography, and histological profile of NAFLD patients with and without IR. METHODS: Retrospective analyses of 336 NAFLD patients diagnosed during the last two years was done. Patients without IR were compared with those with IR. RESULTS: Out of 336 patients, 153 [45.53%] were without IR. Although age, gender, BMI and transaminase levels were comparable, significantly higher proportion of patients in non-IR group were non-obese [43.14% vs. 25/14%; P=0.0005], and had mild fatty change on ultrasonography; [78.43% vs. 67.21%; P=0.022]. Higher proportion of them had elevated transaminases; [67.97% vs. 56.83%; P=0.036]. Serum triglyceride [178.52+/-78.78 vs. 204.86+/-94.72 mg/dl; P=0.02], FBG [85.39+/-13.80 vs. 98.93+/-31.56 mg/dl; P=0.00], PGBG [123.76+/ 36.77 vs. 148.07+/-64.67m g/dl; P=0.00], and serum insulin [6.33+/-2.18 vs. 15.39+/-12.56 MUIU/ml; P=0.00] were significantly lower in patients without IR. Although there was no difference in histology, interestingly fibrosis was seen in one third of patients despite absence of IR. CONCLUSION: Nearly half of our NAFLD population was without IR; one third of them had significant fibrosis. NAFLD is probably a heterogeneous disease and IR is not the sole factor responsible for NAFLD; further studies are needed to find out other possible etiological factors. PMID- 25543523 TI - Risk of donor-site lymphatic vessel dysfunction after microvascular lymph node transfer. AB - BACKGROUND: Microvascular lymph node transfer has been used to improve lymphatic function in patients with lymphoedema. We previously reported changes in the lymphatic function of the donor limb after lymph node transfer. For this reason, we modified our surgical method to be more conservative. SUBJECTS AND METHODS: Microvascular lymph node transfer was performed in 13 patients using the previously reported original method. Sixteen patients were operated upon using the more conservative modified method. Lymphatic function in the donor limb was evaluated using volumetry, lymphoscintigraphy and tissue water percentage. RESULTS: In the original method group, the donor-limb volume was on average greater (199 +/- 540 ml) than in the non-operated control limb. The volume difference between the limbs was smaller (151 +/- 463 ml) in the modified method group. Two patients in the original method group had abnormal transport index (Ti) values in lymphoscintigraphy indicating decreased lymphatic function of the donor limb. In the modified method group, the Ti-values remained normal. The tissue water percentage of the donor limb was on average 40% +/- 4% in the original method group and 40% +/- 3% in the modified method group. Importantly, none of the patients in either group developed clinical lymphoedema in the donor limb during the 11-84-month follow-up. CONCLUSIONS: Even with the more conservative lymph node transfer method, we can observe slight, subclinical signs of lymphatic dysfunction in the donor limb. These results highlight the importance of minimizing the surgical exploration in the inguinal area and avoiding damage to the lymphatic vessels or sentinel nodes draining the lower limb. PMID- 25543524 TI - Activation of oxidative stress and inflammatory factors could account for histopathological progression of aflatoxin-B1 induced hepatocarcinogenesis in rat. AB - Aflatoxin-B1 (AFB1) intoxication is known to develop hepatocellular carcinoma (HCC). However, pathogenesis and diagnosis of AFB1-induced HCC remain undefined. This article describes histopathological progression versus kinetics of the placental glutathione S-transferase (GST-pi) expression and profiles of the antioxidant enzymes, pro-inflammatory cytokines, and proliferative cell nuclear antigen (PCNA) in the liver from the rats administered with two doses of 1 mg AFB1/kg b.w. Histopathologically, hepatocytes necrosis could be observed after 4 weeks of the AFB1 treatment, which subsequently developed into the well-defined foci of altered hepatocytes (FAH) at 10 weeks post-treatment stage. This was consistent with an increasing trend of GST-pi immunostaining especially in the liver foci as a function of FAH progression and thus, suggesting that GST-pi over expression may serve as a marker for AFB1-induced hepatocarcinogenesis. The liver from AFB1-treated rats showed significantly enhanced level of reactive oxygen species coinciding with the declined immunostaining for superoxide dismutase-1, a committed enzyme of the antioxidant pathway, in the FAH regions and also with declined activity of the other antioxidant enzymes. Concordantly, the liver from the AFB1-treated rats showed over expression of pro-inflammatory cytokines; TNF alpha & IL-1alpha and a cell proliferative marker PCNA. These findings present histological characterization of AFB1-induced HCC development and provide evidence for activation of oxidative stress-pro-inflammatory pathway during hepatocarcinogenesis induced by AFB1 toxicity. PMID- 25543525 TI - CCAAT-enhancer binding protein (C/EBP) beta regulates insulin-like growth factor (IGF) 1 expression in porcine liver during prenatal and postnatal development. AB - IGF1 expression regulation attracts numerous interests because of its important role during mammalian growth and development. Domestic pig can be used as a valuable animal model to investigate human development since they share the high similarity in general physiology and metabolism. In this study, we examined the expression pattern of IGF1 and found it associated with liver C/EBP beta expression pattern in porcine liver during embryonic and postnatal development. Both IGF1 and C/EBP beta expression in liver maintained at low levels before birth and increased after birth. Correspondingly, C/EBP beta demonstrated high binding activity to two sites at IGF1 promoter region in liver after birth. Additionally, IGF1 expression can be activated by C/EBP beta overexpression in porcine primary hepatocytes. These results indicated that C/EBP beta can activate IGF1 expression after birth by binding to IGF1 promoter. Our study may contribute to a better understanding of mammalian development and bring a novel anti-aging pathway in human. PMID- 25543526 TI - Arterial stiffness is increased in young women with endometriosis. AB - Endometriosis is a chronic gynaecological disorder that is accompanied by inflammation and oxidative stress. Atherosclerosis has a long subclinical progression in arteries of children and young adults decades before overt clinical manifestations of the disease. In this study, we determined arterial stiffness by measuring brachial-ankle pulse wave velocity (baPWV) in women with endometriosis to assess the presence of subclinical atherosclerosis. We also measured markers of inflammation and oxidative stress in women with endometriosis. baPWV in women with endometriosis aged over 30 years was significantly higher than that in women without endometriosis aged over 30 years (p < 0.05), but not in women aged less than 30. Serum high-sensitivity C-reactive protein level in women with endometriosis was significantly higher than that in controls (p < 0.05). Young women with endometriosis show significantly increased arterial stiffness, suggesting that women with endometriosis need to be cautious of the future onset of atherosclerosis. PMID- 25543527 TI - Foetal axillary lymphangioma with ipsilateral pes equinovarus: pitfalls in sonographic differential diagnosis (axillary lymphangioma & pes equinovarus). AB - Lymphangiomas are rare congenital malformations of the lymphatic system. Despite the benign histology, they are likely to grow rapidly and invade the surrounding tissues. In contrast to the cystic hygromas, lymphangiomas at the axillary region tend to have normal karyotype. However, associated hydrops makes the prognosis poor. Due to isolated few cases in the literature, the true incidence of foetal axillary lymphangiomas is not known. We present here a pre-natal ultrasonographic diagnosis of a 15-week foetus with rapidly growing axillary lymphangioma with ipsilateral foot abnormality which had normal karyotype. PMID- 25543528 TI - Cervical uterine cancer in a virgin young woman - Case report. PMID- 25543529 TI - A Novel early pregnancy assessment unit/Gynaecology assessment unit dashboard: An experience from a UK district general hospital. AB - The establishment of early pregnancy assessment units (EPAUs)/Gynaecology assessment units (GAUs) started more than 20 years ago in the UK to decrease hospital admissions of patients with early pregnancy problems. However, there are still wide variations in the quality of services provided by these units. The objective of this study was to create a method that can be used for continuous assessment of these units on a regular basis. We designed a dashboard covering all aspects of EPAU/GAU activities depending upon the early pregnancy unit association guidelines, and the department of health data and statistics. The EPAU/GAU dashboard has been used successfully in the early assessment pregnancy unit of Yeovil District hospital for few years and is still implemented until now. It is an excellent tool for continuous audit. It is a simple method that should be adopted by different EPAUs/GAUs for their objective assessment in order to improve the services provided by these units. PMID- 25543530 TI - Evaluation of human chaperonin 10 and high-sensitivity C-reactive protein levels of infertile women who underwent ovulation induction and intra-uterine insemination. AB - INTRODUCTION: The implantation of embryo is one of the crucial steps of a successful pregnancy. The foetus should be protected from maternal immune system, for the appropriate implantation and modification in maternal immunity is crucial. We investigated high-sensitivity C-reactive protein (hs CRP), which is an indicator of low-grade inflammation and Cp10 that has immunosuppressant and growth-promoting capabilities at embryo levels in ovulation induction and intra uterine insemination (IUI)applied in infertile women. The ovulation induction was maintained by clomiphene citrate or gonadotropins for 42 infertile patients. After successful ovulation induction, IUI was carried out. The blood samples were taken 2 and 8 days after IUI to evaluate Cp10 and hs CRP levels. The pregnant and non-pregnant groups' results were analyzed. The Cp10 levels 8 days after IUI were higher in pregnant group, whereas there was no difference for the 2 days after levels between pregnant and non-pregnant group. The hs CRP levels were similar for both 2nd and 8th days when we compared pregnant and non-pregnant groups. The Cp10 levels increased from day 2 to day 8 in pregnant group. In contrast, the Cp10 levels decreased in non-pregnant group. The change in hs CRP levels from day 2 to day 8 was not significant in pregnant and non-pregnant groups. The Cp10 levels were higher in early phases of fertilisation and elevated through the preceding days of conception in pregnant patients, while it decreased in non pregnant patients with failed cycles. PMID- 25543531 TI - Injectable biodegradable hydrogels from vitamin D-functionalized polycarbonates for the delivery of avastin with enhanced therapeutic efficiency against metastatic colorectal cancer. AB - Humanized vascular endothelial growth factor (VEGF) antibody (bevacizumab; Avastin) is a highly effective monoclonal antibody against metastatic colorectal cancer and several other advanced late stage cancers. However, limited aqueous solubility and short circulation half-life of the antibody result in long infusion time (30-90 min) and frequent injections. Such direful medical procedures often cause considerable patient inconvenience and prolonged pharmacy preparation. Subcutaneous delivery of Avastin using injectable hydrogels can continuously provide Avastin to treat the malignancy and mitigate antibody degradation. In this study, ABA triblock copolymers of vitamin D-functionalized polycarbonate and poly(ethylene glycol), that is, VDm-PEG-VDm were synthesized and employed to form physically cross-linked injectable hydrogels for encapsulation and subcutaneous delivery of Avastin in a sustained fashion. Antitumor studies were performed using two different HCT116 xenograft mouse models: a subcutaneous and an intraperitoneal metastatic tumor models. The therapeutic efficacy of Avastin-loaded hydrogel injected subcutaneously (s.c.) was compared to an Avastin solution injected via either intravenous (i.v.) or intraperitoneal (i.p.) route. In the subcutaneous tumor model, the Avastin-loaded hydrogel resulted in greater tumor suppression as compared to i.v. and i.p. administration of Avastin solution. The biodistribution pattern of the hydrogel delivery system was also different from the other formulations as there was significantly higher accumulation in the tumor tissue and lesser accumulation within the liver and kidneys as compared to Avastin delivered through i.v. and i.p. administration. Furthermore, in vivo studies carried out on mice with peritoneal metastasis demonstrated that Avastin-loaded hydrogel and weekly administration of Avastin solution resulted in higher survival (87 and 77% over 62 days, respectively) when compared to the control, blank hydrogel and bolus Avastin solution (i.v.; 50-60%). The antimetastatic activity of Avastin delivered using a one-time injection of the hydrogel was as effective as that of 4* weekly injections (i.v.) of Avastin. The reduced injection frequency provided by the subcutaneous formulation may enhance patient convenience and compliance for metastatic cancer therapy. PMID- 25543532 TI - Can digit ratio (2D:4D) studies be helpful in explaining the aetiology of idiopathic gynecomastia? AB - BACKGROUND: Aetiology of idiopathic form of gynecomastia is unknown and it has not been established if it is related to factors present at the prenatal period or if it is caused by yet unidentified environmental conditions. OBJECTIVE: The aim of this study is to compare digit ratio (2D:4D) in men with idiopathic gynecomastia and unaffected male and female controls from the general population. METHODS: The study involved 250 subjects (50 men with idiopathic gynecomastia, 100 control men and 100 control women). Eight measurements were taken: body height, waist and hip circumferences, II and IV digits' lengths (right and left), and body weight, and 4 indices were calculated: BMI, WHR, and 2D:4D for the right and left hand. RESULTS: 2D:4D in men with gynecomastia ([median (I-III quartiles)]: 1.03 (1.01-1.04) for right hand and 1.03 (1.01-1.03) for left hand) was significantly different than the ratio in control men [0.97 (0.95-0.99)] for right and left hand) (p<0.0001) and similar to the ratio found in control women [1.02 (1-1.03)] for right and left hand) (p=1). Men with gynecomastia were characterized with higher values of the following variables: weight, waist and hip circumferences, BMI and WHR. Their body height was significantly greater than in women (p<0.0001) but similar to the values observed in control men (p=0.2687). CONCLUSION: The findings presented in this study may influence the aetiology related classification of gynecomastia and justify introducing the new group: "gynecomastia related to the prenatal sex hormones disturbances". PMID- 25543533 TI - Primordial follicle activation in the ovary of Ames dwarf mice. AB - BACKGROUND: The insulin receptor substrate 1 (IRS1), phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt1), Forkhead Box O3a (FOXO3a) pathway is directly involved in aging and ovarian activation of follicle growth. Therefore, the aim of this work was to measure the expression of genes related to the ovarian pathway for activation of primordial follicles and FOXO3a protein phosphorylation between young and old female Ames dwarf (df/df) and normal (N) mice. METHODS: For this study ovaries from N (n = 10) and df/df (n = 10) female mice were collected at 5-6 months of age and at 21-22 months of age. For immunohistochemistry ovaries from 12 month-old and df/df mice were used. RESULTS: The expression of Irs1, Pi3k, Akt1, mammalian target of rapamycin (Mtor), suppressor of cytokine signaling -2 (Socs2), Socs3 was lower (P < 0.05) in older than younger N mice and not different (P > 0.05) between young and old df/df mice. The expression of Foxo3a was also lower (P < 0.05) in old than younger N and df/df mice and was higher (P < 0.05) in old df/df than N mice. Expression of Amh was lower (P < 0.05) in old than young N and df/df mice and was higher (P = 0.0009) in df/df than N mice. Imunnostaining for p-FOXO3 was lower in df/df than N mice (P < 0.001), although FOXO3 immunostaining was not different (P > 0.05) between df/df and N mice. CONCLUSIONS: In sum, the present study indicates that lower expression of Irs1, Socs2, Socs3, Akt1, Pi3k, Mtor and Foxo3a mRNA in the ovaries of older mice of both genotypes is associated to a reduced ovarian activity revealed by lower expression of Amh mRNA. At the same time, ovaries of old df/df mice maintained higher expression of Foxo3a mRNA, which was associated to higher ovarian activity. We have shown that df/df females have a lower level of p-FOXO3 in oocytes from primordial/primary follicles, an important activator of follicular growth. Therefore, this study strongly indicates that Prop1(df) mutation causes delayed ovarian aging. PMID- 25543534 TI - Mobilization of heavy metals from urban contaminated soils under water inundation conditions. AB - A microcosm experiment was conducted to investigate heavy metal release from the urban soils heavily contaminated by past industrial activities. The aim was to assess the mobility of various heavy metals under inundation with water. The results show that reductive dissolution of iron and manganese compounds was markedly enhanced by organic matter. However, mobilization of Fe and Mn was affected by the abundance of these metals in the soils. The dissolution of Fe and Mn oxides led to the release of As and Zn that were bound to them. However, mixed temporal variation patterns were observed for As, suggesting complication of As mobility by other factors. It is likely that the added organic matter played a role in the formation of organic matter-Fe(III)-arsenic association, leading to partial re-immobilisation of the liberated As at the latter stage of the experiment. Zn showed a consistent trend where it was initially released with reductive dissolution of Fe and Mn compounds and then re-immobilised, possibly through hydrolysis to form insoluble zinc hydroxide. In spite of abundant presence, release of Pb was limited due to its low solubility under less acidic conditions. It appears that anaerobic environment stabilized the soil-borne Cr by forming insoluble Cr(OH)3. PMID- 25543535 TI - The cytokines of pulmonary fibrosis: Much learned, much more to learn. AB - Organ fibrosis, the result of exaggerated, persistent, and often irreversible accumulation of extracellular matrix, complicates numerous diseases in all organs and tissues and has particularly serious consequences in the lungs. Abnormally accumulating scar tissue both replaces normally functioning parenchyma and distorts the architecture of unaffected tissue. In the lungs, the fibrotic process often leads to rapid and severe abnormalities in respiratory mechanics and gas exchange properties. There is no confirmed cure, and better therapies are required for treating fibrosis. The development of therapeutic strategies compels a better understanding of the cellular and molecular mechanisms of fibrosis, which are diverse, complex, and redundant. Epithelial injury, oxidative stress, coagulation disturbances, and inflammation are engaged in a complex interplay leading to augmented transformation of several cell types into myofibroblasts and prolonged survival of these extracellular matrix-producing cells. Cytokines are centrally engaged in the homeostatic and pathophysiologic regulation of connective tissue. Furthermore, it appears that identical cytokines are utilized by inflammation, profibrotic mechanisms, and the fibrotic process itself, suggesting that specific targeting or utilization of these cytokines holds therapeutic promise. In this article, we review the wealth of recent knowledge on major cytokines involved in the fibrotic process. PMID- 25543536 TI - Novel 5.712 kb mitochondrial DNA deletion in a patient with Pearson syndrome: a case report. AB - Pearson marrow-pancreas syndrome (PS) is a progressive multi-organ disorder caused by deletions and duplications of mitochondrial DNA (mtDNA). PS is often fatal in infancy, and the majority of patients with PS succumb to the disease before reaching three-years-of-age, due to septicemia, metabolic acidosis or hepatocellular insufficiency. The present report describes the case of a four month-old infant with severe normocytic normochromic anemia, vacuolization of hematopoietic precursors and metabolic acidosis. After extensive clinical investigation, the patient was diagnosed with PS, which was confirmed by molecular analysis of mtDNA. The molecular analysis detected a novel large-scale (5.712 kb) deletion spanning nucleotides 8,011 to 13,722 of mtDNA, which lacked direct repeats at the deletion boundaries. The present report is, to the best of our knowledge, the first case reported in South Korea. PMID- 25543538 TI - Implementation of an enhanced probation program: evaluating process and preliminary outcomes. AB - Supervision, Monitoring, Accountability, Responsibility, and Treatment (SMART) is Kentucky's enhanced probation pilot program modeled after Hawaii's Opportunity Probation with Enforcement (HOPE). SMART is proposed to decrease substance use, new violations, and incarceration-related costs for high-risk probationers by increasing and randomizing drug testing, intensifying supervision, and creating linkages with needed resources (i.e., mental health and substance use). SMART adopts a holistic approach to rehabilitation by addressing mental health and substance abuse needs as well as life skills for fostering deterrence of criminal behavior vs. punitive action only. A mixed methods evaluation was implemented to assess program implementation and effectiveness. Qualitative interviews with key stakeholders (i.e., administration, judges, attorneys, and law enforcement/corrections) suggested successful implementation and collaboration to facilitate the pilot program. Quantitative analyses of secondary Kentucky Offender Management System (KOMS) data (grant Year 1: 07/01/2012-06/30/2013) also suggested program effectiveness. Specifically, SMART probationers showed significantly fewer: violations of probation (1.2 vs. 2.3), positive drug screens (8.6% vs. 29.4%), and days incarcerated (32.5 vs. 118.1) than comparison probationers. Kentucky's SMART enhanced probation shows preliminary success in reducing violations, substance use, and incarceration. Implications for practice and policy will be discussed. PMID- 25543537 TI - The suppression of ghrelin signaling mitigates age-associated thermogenic impairment. AB - Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms.Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis. PMID- 25543539 TI - Genetic and environmental components of family history in type 2 diabetes. AB - Family history of diabetes is a major risk factor for type 2 diabetes (T2D), but whether this association derives from shared genetic or environmental factors is unclear. To address this question, we developed a statistical framework that models four components of variance, including known and unknown genetic and environmental factors, using a liability threshold model. Focusing on parental history, we simulated case-control studies with two first-degree relatives for each individual, assuming 50 % genetic similarity and a range of values of environmental similarity. By comparing the association of parental history with T2D in our simulations to case-control studies of T2D nested in the Nurses' Health Study and Health Professionals Follow-up Study, we estimate that first degree relatives have a correlation of 23 % (95 % CI 15-27 %) in their environmental contribution to T2D liability and that this shared environment is responsible for 32 % (95 % CI 24-36 %) of the association between parental history and T2D, with the remainder due to shared genetics. Estimates are robust to varying model parameter values and our framework can be extended to different definitions of family history. In conclusion, we find that the association between parental history and T2D derives from predominately genetic but also environmental effects. PMID- 25543540 TI - Photosynthetic light reactions increase total lipid accumulation in carbon supplemented batch cultures of Chlorella vulgaris. AB - Microalgae are an attractive biofuel feedstock because of their high lipid to biomass ratios, lipid compositions that are suitable for biodiesel production, and the ability to grow on varied carbon sources. While algae can grow autotrophically, supplying an exogenous carbon source can increase growth rates and allow heterotrophic growth in the absence of light. Time course analyses of dextrose-supplemented Chlorella vulgaris batch cultures demonstrate that light availability directly influences growth rate, chlorophyll production, and total lipid accumulation. Parallel photomixotrophic and heterotrophic cultures grown to stationary phase reached the same amount of biomass, but total lipid content was higher for algae grown in the presence of light (an average of 1.90 mg/mL vs. 0.77 mg/mL over 5 days of stationary phase growth). PMID- 25543541 TI - Predicting gaseous emissions from small-scale combustion of agricultural biomass fuels. AB - A prediction model of gaseous emissions (CO, CO2, NOx, SO2 and HCl) from small scale combustion of agricultural biomass fuels was developed in order to rapidly assess their potential to be burned in accordance to current environmental threshold values. The model was established based on calculation of thermodynamic equilibrium of reactive multicomponent systems using Gibbs free energy minimization. Since this method has been widely used to estimate the composition of the syngas from wood gasification, the model was first validated by comparing its prediction results with those of similar models from the literature. The model was then used to evaluate the main gas emissions from the combustion of four dedicated energy crops (short-rotation willow, reed canary grass, switchgrass and miscanthus) previously burned in a 29-kW boiler. The prediction values revealed good agreement with the experimental results. The model was particularly effective in estimating the influence of harvest season on SO2 emissions. PMID- 25543542 TI - A self-sustaining advanced lignocellulosic biofuel production by integration of anaerobic digestion and aerobic fungal fermentation. AB - High energy demand hinders the development and application of aerobic microbial biofuel production from lignocellulosic materials. In order to address this issue, this study focused on developing an integrated system including anaerobic digestion and aerobic fungal fermentation to convert corn stover, animal manure and food wastes into microbial lipids for biodiesel production. Dairy manure and food waste were first anaerobically digested to produce energy and solid digestate (AD fiber). AD fiber and corn stover were then processed by a combined alkali and acid hydrolysis, followed by fungal lipid accumulation. The integrated process can generate 1L biodiesel and 1.9 kg methane from 12.8 kg dry dairy manure, 3.1 kg dry food wastes and 12.2 kg dry corn stover with a positive net energy of 57 MJ, which concludes a self-sustaining lignocellulosic biodiesel process and provides a new route to co-utilize corn stover and organic wastes for advanced biofuel production. PMID- 25543544 TI - Phytoremediation potential of cadmium-contaminated soil by Eucalyptus globulus under different coppice systems. AB - The objective of this research was to determine the phytoremediation potential of Eucalyptus globulus in Cd contaminated soil through two different harvest methods. Although replanting is more expensive than coppicing and produces less aboveground biomass, more Cd can be removed from the soil with roots removal at each harvest as the E. globulus absorbs vast majority of heavy metals in non metabolically active parts like roots. Despite the higher cost of replanting in a single harvest, when phytoremediation efficiency and total duration are considered as important factors, the replanting treatment should be recommended as an appropriate method which can decrease the phytoremediation time obviously. PMID- 25543543 TI - TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves' disease and Graves' ophthalmopathy. AB - PURPOSE: Intronic thyroid-stimulating hormone receptor polymorphisms have been associated with the risk for both Graves' disease and Graves' ophthalmopathy, but results have been inconsistent among different populations. We aimed to investigate the influence of thyroid-stimulating hormone receptor intronic polymorphisms in a large well-characterized population of GD patients. METHODS: We studied 279 Graves' disease patients (231 females and 48 males, 39.80 +/- 11.69 years old), including 144 with Graves' ophthalmopathy, matched to 296 healthy control individuals. Thyroid-stimulating hormone receptor genotypes of rs179247 and rs12885526 were determined by Real Time PCR TaqMan((r)) SNP Genotyping. RESULTS: A multivariate analysis showed that the inheritance of the thyroid-stimulating hormone receptor AA genotype for rs179247 increased the risk for Graves' disease (OR = 2.821; 95 % CI 1.595-4.990; p = 0.0004), whereas the thyroid-stimulating hormone receptor GG genotype for rs12885526 increased the risk for Graves' ophthalmopathy (OR = 2.940; 95 % CI 1.320-6.548; p = 0.0083). Individuals with Graves' ophthalmopathy also presented lower mean thyrotropin receptor antibodies levels (96.3 +/- 143.9 U/L) than individuals without Graves' ophthalmopathy (98.3 +/- 201.9 U/L). We did not find any association between the investigated polymorphisms and patients clinical features or outcome. CONCLUSION: We demonstrate that thyroid-stimulating hormone receptor intronic polymorphisms are associated with the susceptibility to Graves' disease and Graves' ophthalmopathy in the Brazilian population, but do not appear to influence the disease course. PMID- 25543545 TI - Lung cancer risk from PAHs emitted from biomass combustion. AB - This study deals with the assessment of the cancer risk attributable to PAH exposure, attributable to the increased use of biomass for space heating in Greece in the winter of 2012-2013. Three fractions of particulates (PM1, PM2.5 and PM10) were measured in two sampling sites (urban/residential and traffic influenced) followed by chemical analysis of 19 PAHs and levoglucosan (used as a biomarker tracer). PAH-induced lung cancer risk was estimated by a comprehensive methodology that incorporated human respiratory tract deposition modelling in order to estimate the toxic equivalent concentration (TEQ) at each target tissue. This allowed us to further differentiate internal exposure and risk by age groups. Results showed that all PM fractions are higher in Greece during the cold months of the year, mainly due to biomass use for space heating. PAH and levoglucosan levels were highly correlated, indicating that particles emitted from biomass combustion are more toxic than PM emitted from other sources. The estimated lung cancer risk was non-negligible for residents close to the urban background monitoring site. Higher risk was estimated for infants and children, due to the higher bodyweight normalized dose and the human respiratory tract (HRT) physiology. HRT structure and physiology in youngsters favor deposition of particles that are smaller and more toxic per unit mass. In all cases, the estimated risk (5.7E-07 and 1.4E-06 for the urban background site and 1.4E-07 to 5.0E-07 for the traffic site) was lower to the one estimated by the conventional methodology (2.8E-06 and 9.7E-07 for the urban background and the traffic site respectively) that is based on Inhalation Unit Risk; the latter assumes that all PAHs adsorbed on particles are taken up by humans. With the methodology proposed herein, the estimated risk presents a 5-7 times difference between the two sampling sites (depending on the age group). These differences could not have been identified had we relied only on conventional risk assessment method. Consequently, the actual cancer risk attributable to PAHs on PM emitted from biomass burning would have been significantly underestimated. PMID- 25543547 TI - The influence of season and living environment on children's urinary 1 hydroxypyrene levels in Ulaanbaatar, Mongolia. AB - BACKGROUND: Heating indoor living environments elevates air pollution in Ulaanbaatar, Mongolia. OBJECTIVE: This study was conducted to investigate the influence of season and living environment on children's urinary 1-hydroxypyrene (1-OHP) levels in Ulaanbaatar, Mongolia. METHODS: Our study subjects were 320 children aged 11-15 years living in gers, brick houses and apartments, in ger and non-ger areas of Ulaanbaatar. Spot urine samples and questionnaires were collected three times from each subject in three seasons, September (warm) and December (cold) in 2011 and March (moderate) in 2012. Urinary 1-OHP was analyzed by high-performance liquid chromatography with fluorescent detection (HPLC/FLD). Generalized estimating equation (GEE) models were applied to estimate the seasonal and residential effects on 1-OHP levels, adjusting for demographic and environmental factors. RESULTS: Children's urinary 1-OHP levels showed significant seasonal differences with 0.30 +/- 0.57 MUmol/mol creatinine in cold season, 0.14 +/- 0.12 MUmol/mol creatinine in moderate season, and 0.14 +/- 0.21 MUmol/mol creatinine in warm season. After controlling confounding factors, the GEE model showed that season, living area, and housing type had significant influence on children's urinary 1-OHP levels. Urinary 1-OHP levels in the cold and moderate seasons were, respectively 2.13 and 1.37 times higher than the warm season. Urinary 1-OHP levels for children living in ger areas were 1.27 times higher than those living in non-ger areas. Children who lived in gers or brick houses had 1.58 and 1.34 times higher 1-OHP levels, respectively, compared with those living in apartments. Children's urinary 1-OHP levels were associated with either estimated NO2 or SO2 concentrations at their home addresses in Ulaanbaatar. CONCLUSION: Mongolian children's urinary 1-OHP levels were significantly elevated during the cold season, and for those living in ger areas, gers, or brick houses in Ulaanbaatar. Children's urinary 1-OHP levels were associated PAH co-pollutants SO2 and NO2, suggesting elevated 1-OHP levels may be attributable to PAH emissions from coal burning and traffic respectively, with indoor emissions from stoves further contributing to elevated 1-OHP in some children. PMID- 25543546 TI - Megacities air pollution problems: Mexico City Metropolitan Area critical issues on the central nervous system pediatric impact. AB - The chronic health effects associated with sustained exposures to high concentrations of air pollutants are an important issue for millions of megacity residents and millions more living in smaller urban and rural areas. Particulate matter (PM) and ozone (O3) concentrations close or above their respective air quality standards during the last 20 years affect 24 million people living in the Mexico City Metropolitan Area (MCMA). Herein we discuss PM and O3 trends in MCMA and their possible association with the observed central nervous system (CNS) effects in clinically healthy children. We argue that prenatal and postnatal sustained exposures to a natural environmental exposure chamber contribute to detrimental neural responses. The emerging picture for MCMA children shows systemic inflammation, immunodysregulation at both systemic and brain levels, oxidative stress, neuroinflammation, small blood vessel pathology, and an intrathecal inflammatory process, along with the early neuropathological hallmarks for Alzheimer and Parkinson's diseases. Exposed brains are briskly responding to their harmful environment and setting the bases for structural and volumetric changes, cognitive, olfactory, auditory and vestibular deficits and long term neurodegenerative consequences. We need to improve our understanding of the PM pediatric short and long term CNS impact through multidisciplinary research. Public health benefit can be achieved by integrating interventions that reduce fine PM levels and pediatric exposures and establishing preventative screening programs targeting pediatric populations that are most at risk. We fully expect that the health of 24 million residents is important and blocking pediatric air pollution research and hiding critical information that ought to be available to our population, health, education and social workers is not in the best interest of our children. PMID- 25543548 TI - Photocatalytic treatment of pharmaceutical wastewater using new multiwall-carbon nanotubes/TiO2/SiO2 nanocomposites. AB - For the photocatalytic removal of bisphenol A (BPA) and carbamazepine (CBZ) from water solution a new multiwall-carbon nanotubes and TiO2/SiO2 nanocomposites (MWCNT-TiO2-SiO2) were applied. Nanocomposites with the addition of 0.15-17.8 wt% MWCNT show high potential for the removal of both pollutants. The starting concentration of each contaminant was halved during 20 min of UVA irradiation. The decomposition process of CBZ over investigated nanocomposites proceeded differently than it was observed for the classical photocatalyst P25. The kinetics of the removal followed as a pseudo-first order regime with the k1 in range 0.0827-0.1751 min(-1) for BPA and 0.0131-0.0743 min(-1) for CBZ. Toxicity to Vibrio fischeri and Daphnia magna was significantly reduced indicating formation of non-toxic products of photooxidation of tested contaminants. PMID- 25543549 TI - Characterization of the chemical diversity of glycosylated mycosporine-like amino acids in the terrestrial cyanobacterium Nostoc commune. AB - Mycosporine-like amino acids (MAAs) are UV-absorbing pigments, and structurally unique glycosylated MAAs are found in the terrestrial cyanobacterium Nostoc commune. In this study, we examined two genotypes of N.commune colonies with different water extract UV-absorption spectra. We found structurally distinct MAAs in each genotype. The water extract from genotype A showed a UV-absorbing spectrum with an absorption maximum at 335nm. The extract contained the following compounds: 7-O-(beta-arabinopyranosyl)-porphyra-334 (478Da), pentose-bound shinorine (464Da), hexose-bound porphyra-334 (508Da) and porphyra-334 (346Da). The water extract from genotype B showed a characteristic UV-absorbing spectrum with double absorption maxima at 312 and 340nm. The extract contained hybrid MAAs (1050Da and 880Da) with two distinct chromophores of 3-aminocyclohexen-1-one and 1,3-diaminocyclohexen linked to 2-O-(beta-xylopyranosyl)-beta-galactopyranoside. A novel 273-Da MAA with an absorption maximum at 310nm was also identified in genotype B. The MAA consisted of a 3-aminocyclohexen-1-one linked to a gamma aminobutyric acid chain. These MAAs had potent radical scavenging activities in vitro and the results confirmed that the MAAs have multiple roles as a UV protectant and an antioxidant relevant to anhydrobiosis in N. commune. The two genotypes of N. commune exclusively produced their own characteristic glycosylated MAAs, which supports that MAA composition could be a chemotaxonomic marker for the classification of N. commune. PMID- 25543551 TI - Identifying differentially expressed genes in trophozoites and cysts of Acanthamoeba T4 genotype: Implications for developing new treatments for Acanthamoeba keratitis. AB - Acanthamoeba T4 genotype is the most prevalent genotype associated with amoebic keratitis. Acanthamoeba keratitis therapy is difficult due to transformation of trophozoite to cyst stage, which hinders the treatment of the disease. Although encystation assists the organism to survive against the chemotherapeutic compounds, the precise mechanism of encystation remains poorly understood. The purpose of this work was to identify differentially expressed genes in Acanthamoeba T4 genotype which might be useful for understanding of the encystment process and may thus help develop more efficient treatment. The mRNA profile of trophozoite and cyst of Acanthamoeba T4 genotype isolated from a soft contact lens wearer were analyzed using a cDNA amplified fragment length polymorphism (cDNA-AFLP) technique. Subsequently, a real time reverse transcriptase-PCR was performed to validate the cDNA-AFLP results. Three genes, heat shock protein70 (hsp70), actin-I and elongation factor-1alpha (EF-1alpha) were differentially expressed during Acanthamoeba differentiation. An in silico result predicted that transformation of trophozoite to cyst could be mediated through their cooperation with the protein partners interaction. Taken together, our experimental and bioinformatics findings suggested potential functions of hsp70, EF-1alpha and actin-I in differentiation of Acanthamoeba T4 genotype which may be useful in the design of an efficient therapeutic strategy in AK. PMID- 25543552 TI - An annotated catalogue of the Membracidae types in the Museu de Zoologia da Universidade de Sao Paulo, Brazil (Hemiptera: Auchenorrhyncha: Cicadomorpha). AB - Here presented is an annotated catalogue of the Membracidae types deposited at the Museu de Zoologia da Universidade de Sao Paulo (MZSP), with information on 106 primary types and 171 secondary types. These type specimens represent 82 nominal species currently classified in 8 treehopper subfamilies and 17 tribes. According to our estimates, at least 10 primary types and 44 secondary types are missing in the collection. A comprehensive list of literature sources, taxonomic remarks, label data and descriptions on the state of preservation of specimens are given. PMID- 25543550 TI - State transitions and fluorescence quenching in the cyanobacterium Synechocystis PCC 6803 in response to changes in light quality and intensity. AB - State transition and non-photochemical fluorescence quenching in cyanobacteria are short-term adaptations of photosynthetic apparatus to changes in light quality and intensity, however, the kinetic details and relationship are still not clear. In this work, time-dependent 77K fluorescence spectra were monitored for cyanobacterium Synechocystis PCC 6803 cells under blue, orange and blue-green light in a series of intensities. The characteristic fluorescence signals indicated state transition taking place exclusively under 430-450 or 580-600nm light or 480-550nm light at the intensities ?150MUEm(-2)s(-1) to achieve a conserved level with variable rate constant. Under 480-500nm or 530-550nm light at the intensities ?160MUEm(-2)s(-1), state transition took place at first but stopped as soon as the fluorescence quenching appeared. The dependence of appearance, induction period, level and rate constant for the quenching on light intensity suggests that a critical concentration of photo-activated OCPs is necessary and may be achieved by a dynamic equilibrium between the activation and deactivation under light. PMID- 25543553 TI - A new synonym for Pristimantis luscombei (Duellman and Mendelson 1995) and the description of a new species of Pristimantis from the upper Amazon basin (Amphibia: Craugastoridae). AB - We consider Pristimantis achuar as junior synonym of P. luscombei, based on morphological and genetic evidence. Paratype specimens of P. luscombei are part of a new species, which lead to taxonomic confusion regarding the identity of P. luscombei. We describe and name this new species as Pristimantis miktos sp. nov. from Juyuintza, Pastaza province, eastern lowlands of Ecuador. Morphological diagnostic characters used to distinguish the new species from other brownish Amazonian Pristimantis are: (1) skin of dorsum shagreen with scattered tubercles or pustules; (2) tympanum prominent; (3) a thick X-shaped scapular dermal ridge in males; and (4) an orange iris in life. Pristimantis miktos is an inhabitant of the lowlands forests of the Pastaza and Napo drainages in eastern Ecuador and northern Loreto in Peru, reaching elevations of up to 350 m; P. luscombei is widely distributed in the upper Amazon Basin of Ecuador, northern Peru and extreme western Brazil, up to 1000 m. Phylogenetic analyses reveals that P. luscombei and the new species are not closest relatives, as also deduced from morphological evidence. PMID- 25543554 TI - Review of the Lutrochidae (Coleoptera) of the Guianas and Lesser Antilles, with description of four new species. AB - The species of Lutrochidae from the Guianas, and the Lesser Antilles are reviewed, including the first reports of the family from Guyana, Suriname, and Grenada. Four species are described as new: Lutrochus funkae n. sp. and L. wao n. sp. from Guyana and French Guiana, L. grenadensis n. sp. from Grenada, and L. leeanneae n. sp. from Suriname. Photographs, genitalia illustrations, and distribution maps are provided for all species, and habitat photos and notes are presented for the species for which they are available. PMID- 25543555 TI - A new species of the Gekko japonicus group (Squamata: Gekkonidae) from central Laos. AB - A new species of the Gekko japonicus group is described from Khammouane Province, central Laos, based on distinct morphological and molecular features. Gekko thakhekensis sp. nov. is distinguished from the remaining congeners by a combination of the following characters: size moderate (SVL 67.6-79.2 mm); nares in contact with rostral; internasals absent; postmentals enlarged; interorbital scales between anterior corners of the eyes 22-26; dorsal tubercles absent; ventral scales between mental and cloacal slit 165-174; midbody scale rows 110 116; ventral scale rows 32-40; subdigital lamellae on first toe 11-13, on fourth toe 14-15; finger and toe webbing present at base, about one fifth of length of digits; tubercles on upper surface of fore and hind limbs absent; precloacal pores 1-5 in males; postcloacal tubercles two; tubercles absent on dorsal surface of tail base; subcaudals enlarged; dorsal surface of body with greyish brown blotches. In molecular analyses, the new species is recovered as a sister taxon to G. scientiadventura, but the two species are separated by approximately 12% divergence as shown by the partial mitochondrial ND2 gene. PMID- 25543556 TI - A missing geographic link in the distribution of the genus Echinotriton (Caudata: Salamandridae) with description of a new species from southern China. AB - Disjunct geographic distribution of a species or a group of species is the product of long-term interaction between organisms and the environment. Filling the distributional gap by discovery of a new population or a species has significant biogeographic implications, because it suggests a much wider past distribution and provides evidence for the route of range expansion/contraction. The salamandrid genus Echinotriton (commonly known as spiny salamanders, spiny newts, or crocodile newts) has two species that are restricted to two widely separated areas, one in eastern Zhejiang province, China and the other in the Ryukyu Archipelago of Japan. It has been hypothesized that Echinotriton was once continuously distributed between the two areas through a historical land bridge that connected mainland China, Taiwan, and the archipelago. Finding fossils or relic populations along the postulated distribution are strong evidence for the hypothesis. Hundred-twenty-two years after the description of E. andersoni and eight-one years after that of E. chinhaiensis, we discover a third species of Echinotriton in southern China, which fills the distributional gap of the former two species. Species status of the new species is confirmed through molecular phylogenetic analysis and morphological comparison. Mitochondrial DNA indicates that the new species is sister to E. chinhaiensis, while nuclear DNA does not support this relationship. The new species has a very large quadrate projection, a single line of lateral warts pierced by distal rib extremities, normally developed 5th toes, and conical skin tubercles. Our discovery supports the hypothesis that there was a continuous distribution of Echinotriton from eastern coastal China to the Ryukyu Archipelago. We suggest that other species of this genus may also be found in Taiwan. Due to the rarity of this new species, we urge all hobbyists to refrain themselves from collecting this salamander or leaking locality information if encountered, and boycott any trading. PMID- 25543557 TI - Analysis of plumage, morphology, and voice reveals species-level differences between two subspecies of Prevost's Ground-sparrow Melozone biarcuata (Prevost and Des Murs) (Aves: Emberizidae). AB - Melozone biarcuata (Prevost's Ground-sparrow) has traditionally been divided into two allopatric groups based on differences in vocalizations and plumage characteristics: M. b. cabanisi in Costa Rica and M. b. biarcuata/M. b. hartwegi in northern Central America. However, the relationship between these subspecies has not been studied using a modern taxonomic approach. In this study, our objective was to provide the first detailed taxonomic comparison between these three subspecies using an integrative multi-trait analysis. We analyzed morphometric features, qualitative plumage patterns, and quantitative plumage measurements using spectral reflectance from all three subspecies, and we analyzed vocalizations for subspecies M. b. biarcuata and M. b. cabanisi. Our results show that M. b. cabanisi can be readily distinguished from the two other subspecies on the basis of morphometrics (M. b. cabanisi are smaller), plumage patterns (M. b. cabanisi have different facial markings and plumage patches), color differences (M. b. cabanisi have plumage patches that differ in color and brightness), and vocalizations (M. b. cabanisi have songs and calls that are acoustically distinct from those of M. b. biarcuata). By contrast, the two northern subspecies M. b. biarcuata and M. b. hartwegi were very similar for most traits, supporting previous suggestions that the two northern subspecies should be considered a single subspecies. Our data reveal that the differentiation in phenotypic characteristics between M. b. cabanisi versus M. b. biarcuata and M. b. hartwegi is similar to that reported for other complexes of subspecies where species status has been recognized. We argue that M. b. cabanisi should be treated as a species separate from M. biarcuata and propose that it be called Melozone cabanisi, White-faced Ground-sparrow. Our findings will contribute to the conservation efforts of the White-faced Ground-sparrow, which is endemic to Costa Rica's Central Valley and Turrialba Valley, by bringing focus to conservation policies that preserve ground-sparrow habitat (thickets, shade coffee plantations, and young secondary forest). PMID- 25543558 TI - New species of small scaly crickets of genus Micrornebius (Orthoptera: Mogoplistidae; Mogoplistinae) from Singapore. AB - The small and cryptic scaly crickets of the genus Micrornebius from Singapore are reviewed. The Henningian species concept was applied and morphology was used to estimate species boundaries. Three new species are described: Micrornebius distinctus sp. n., Micrornebius eclipsus sp. n. and Micrornebius mandai sp. n. This increases the number of species Micrornebius from Singapore to five. A tentative key to the species of Micrornebius from Singapore is provided. PMID- 25543559 TI - Species of the genus Aragara Walker (Diptera: Chloropidae: Chloropinae: Mindini) from China with key to species of the world. AB - The genus Aragara Walker is newly recorded from China. The following two species are described new to science: A. flavaristata sp. nov. and A. menglaensis sp. nov. One species, A. trilineata Cherian, is newly recorded from China, and one new combination, A. sinensis (Yang & Yang), is proposed. A key to world species of genus Aragara is given. PMID- 25543560 TI - Hexanchorus bifurcatus sp. nov., a new tepui riffle beetle (Coleoptera: Elmidae: Larainae) from Tafelberg, Suriname. AB - Here we present the first published record of a laraine elmid from Suriname, which represents a new species - Hexanchorus bifurcatus sp. nov. Specimens were collected from the summit of Tafelberg, a table mountain near the Wilhelmina Range of Suriname. This species can be distinguished from all other Hexanchorus by the bifurcate elytral apices and median projection of the third abdominal ventrite of the female, as well as the distinctive male genitalia. Habitus photos, illustrations of the genitalia, a distribution map, notes on habitat, and comparative diagnoses are provided. PMID- 25543561 TI - Two new species of Oxytrechus Jeannel, 1927 from Ecuador (Coleoptera, Carabidae). AB - Two new species of Oxytrechus Jeannel 1927 are described from the paramos of the Ecuadorian Andes in Pichincha province (Ecuador: Northern Sierra): O. osellai n. sp. from Cangahua at 3375 m a.s.l. and O. belloi n. sp. from Paso de la Virgen at 3515 m a.s.l. PMID- 25543562 TI - Studies of Madagascan Ptiliidae (Coleoptera) 4: The genus Bambara including eight new species and the first account of blindness and aptery in the genus . AB - This is the fourth report detailing Ptiliidae collected from forest litter by the Moravian Museum (Brno, Czech Republic) expeditions to Madagascar 2010-2013. Eight new species are described and figured: B. edwardi sp. n.; B. lanquidula sp. n.; B. merina sp.n.; B. opaca sp. n.; B. problematica sp. n.; B. secubita sp. n.; B. thomasi sp. n. and B. verecunda sp. n., and new data recorded for B. dybasi Johnson. Problems concerning the genital morphology and species determination of the parthenogenetic members of the genus are discussed in relation to the findings, and the first blind and apterous species reported.A key to the known species from the island is provided. PMID- 25543563 TI - Post larval stages of Tanytydeus beyzavii sp. nov. (Acari: Paratydeidae) from Iran. AB - A new species Tanytydeus beyzavii sp. nov. (Acari: Paratydeidae) is described and illustrated from soil under plants in Iran. Leg setation is presented for the genus, as is a key to species. The genus Hexatydeus syn. nov. is synonymised with Tanytydeus because the former represent nymphal stages of Tanytydeus. PMID- 25543564 TI - A comparative morphological analyses of four species of Camptocercus Baird,1843 (Cladocera: Anomopoda: Chydoridae). AB - Study of four poorly known cladocera species of the genus Camptocercus Baird,1843 (Anomopoda: Chydoridae): North American C. oklahomensis Mackin, 1930, and three Palearctic species, C. uncinatus Smirnov, 1971, C. fennicus Stenroos, 1898, and C. lilljeborgi Schoedler, 1862, revealed strong differences between them in both outer morphology and morphology of appendages. C. oklahomensis lacks a head keel, typical for the most species of the genus, and has numerous characters confirming its basal position within the genus, namely less elongated postabdomen with groups of elementary marginal denticles and less specialized morphology of the thoracic limbs. C. uncinatus and C. fennicus have similar limb morphology, these species form a monophyletic clade with South-East Asian species C. vietnamensis Thanh, 1980. C. lilljeborgi have a straight ventral margin of valves with specially dense setation, similar to the species of the genus Graptoleberis Sars, 1862. C. lilljeborgi also has most derived appendages, i.e. exopodites of limbs III-V have seta 4 reduced to a state of a small stub, and seta 3 with extremely wide basal portion. The level of differences in thoracic limb morphology in Camptocercus is unusual for the subfamily Aloninae, where in most genera limb morphology is relatively uniform. Morphology and phylogenetic relationships of the studied species are discussed. PMID- 25543565 TI - The mitochondrial phylogeography and intraspecific taxonomy of the Steppe Racerunner, Eremias arguta (Pallas) (Lacertidae: Sauria, Reptilia), reflects biogeographic patterns in Middle Asia. AB - Steppe racerunner, Eremias (Eremias) arguta, is one of the most widespread species of the Asian racerunners (genus Eremias). Several subspecies were traditionally recognized however, morphological variability is so high that delimitation of these subspecies was always problematic. Here we present a phylogenetic hypothesis for this species based on cytochrome b sequences (55 samples from 35 populations, 900 bp partial sequences), infer it biogeography and the revise its subspecific structure. Six major phylogenetic lineages were revealed. The southernmost populations (E. a. uzbekistanica) from Uzbekistan form a clade together with the Issyk-Kul Lake subspecies (E. a. darevskii) based on both molecular and morphological evidence. Within more northern populations, there is a split between populations from Northern Caucasus, Europe and Western Kazakhstan (E. a. deserti) and Central and Eastern Kazakhstan populations (E. a. arguta). Transcaucasian (E. a. transcaucasica) steppe racerunners are grouped with Middle Asian populations. Finally, the easternmost samples, assigned to "E. a. potanini" are nested within the E. a. arguta clade. Populations from the Ili River Valley form a separate lineage sister to the clade joining all other E. arguta lineages and might represent a yet undescribed taxon. Species distribution in relation to historical biogeography of Middle Asia is discussed. PMID- 25543566 TI - A new species of the genus Norops from Darien, Panama, with comments on N. sulcifrons (Cope 1899) (Reptilia, Squamata, Dactyloidae). AB - We describe the new species Norops triumphalis sp. nov. from Darien, Panama. Norops triumphalis differs from all congeners by having a combination of (1) smooth, bulging, subimbricate ventral scales; (2) a short tail, ratio tail length/SVL 1.54; (3) short hind legs, longest toe of adpressed hind leg reaching to ear opening, ratio shank length/SVL 0.24; (4) a lichenous body pattern; and (5) a very large yellowish orange dewlap in males. In external morphology, N. triumphalis is most similar to the species of the N. pentaprion group. Norops triumphalis differs from the other species in the N. pentaprion group, except N. sulcifrons, by having a very large orange male dewlap (vs. a large red or pink dewlap) and an unpigmented throat lining. Norops triumphalis differs from N. sulcifrons by having the supracaudal scales not forming a serrated crest (vs. a distinct serrated caudal crest present in N. sulcifrons), 4 supracaudal scales per segment (vs. 3 supracaudal scales per segment in N. sulcifrons), greatly enlarged outer postmental scales, about four times the size of adjacent medial scales (vs. moderately enlarged outer postmental scales, about twice the size of adjacent medial scales, in N. sulcifrons), and no enlarged postcloacal scales in males (vs. a pair of moderately enlarged postcloacal scales present in male N. sulcifrons). We further provide a standardized description and illustrations of the holotype of N. sulcifrons. PMID- 25543567 TI - Taxonomy, host-plant associations and phylogeny of African Crotalaria-feeding seed beetles (Coleoptera, Chrysomelidae, Bruchinae): the Conicobruchus strangulatus (Fahraeus) species group. AB - A small group of six morphologically related seed beetles (Coleoptera: Chrysomelidae: Bruchinae) belonging to the Conicobruchus genus is reviewed. Species in this group for which host-plants are known feed on various species of Crotalaria (Fabaceae, Crotalarieae). Here we provide diagnoses and a dichotomous key for all six species. The following synonymies are proposed: Conicobruchus cicatricosus (Fahraeus, 1839) (= Bruchus cicatricosus pallidioripennis Pic, 1941) syn. nov.; Conicobruchus strangulatus (Fahraeus, 1839) (= Bruchus hargreavesi Pic, 1933) syn. nov. The corresponding Conicobruchus strangulatus species group is hereby designated. New host-plant data are also included, which correspond to the results of recent collections of legume pods in East Africa. In addition we carried out molecular phylogenetic analyses on a representative sampling of Conicobruchus species (including the six species of interest). The latter allow us to assess the monophyly of the group of interest and to unravel their evolutionary relationships. Molecular phylogenetic analyses also indicate that at least two lineages of Conicobruchus successfully shifted toward Crotalarieae during the course of their diversification. PMID- 25543568 TI - A revision of the genus Herminella Spaeth (Chrysomelidae: Cassidinae: Notosacanthini), with a description of a new related genus and species from Madagascar. AB - The genus Herminella Spaeth from southern Africa is revised. It comprises four species: Herminella liliputana Spaeth and H. marshalli Spaeth are redescribed and two species are described as new-H. quadrimaculata from South Africa and H. flavocostata from Nambia and South Africa. A new related genus and species Hermosacantha madagascarica from Madagascar is described. Members of both genera belong to the smallest world cassids. PMID- 25543569 TI - Three new species of Eurypon Gray, 1867 from Northeastern Brazil (Poecilosclerida; Demospongiae; Porifera). AB - Three new species of Eurypon from Northeastern Brazil are described: Eurypon clavilectuarium sp. nov.; Eurypon suassunai sp. nov. and Eurypon distyli sp. nov. Samples were collected from the continental shelf of Rio Grande do Norte, Bahia and Paraiba States. While the majority of Atlantic Eurypon species have been described from deep water, two of three new species described in this study were collected from shallow depths. The three new species from Brazil were compared with all other eighteen Eurypon species described from the Atlantic. PMID- 25543570 TI - A new species of Sinacroneuria (Plecoptera: Perlidae) from China with a provisional key to species. AB - Sinacroneuria dabieshana sp. nov. is proposed from Henan and Hubei provinces, China and the new species is compared with related congeners. The discovery of this species represents the northernmost distribution of the genus in China. A provisional key to the males of known species of Sinacroneuria is also presented. PMID- 25543571 TI - Electribius relictus, a new extant species of Artematopodidae (Coleoptera: Elateroidea) from Veracruz, Mexico. AB - Electribius relictus sp. nov. (Artematopodidae) is described from a cloud forest fragment in central Veracruz, Mexico. This species is distinguished from the other extant species known, E. crowsoni Lawrence (Mexico) and E. similis Lawrence (El Salvador), by the pronotum and elytra completely black, pronotum with margins crenulate at base, fifth abdominal ventrite with distinct median ridge, and the shape of aedeagus. The new species is illustrated and a key for the identification of extant species of the genus and ecological data for the collecting site are provided. PMID- 25543572 TI - New findings of Eurycercus Baird, 1843 (Cladocera: Anomopoda) in the Eastern Palaearctic. AB - Information on the cladocerans of Eastern Palaerctic is limited, and remote islands of Arctic and Subarctic in this region are among inadequately studied territories, i.e. due to a very limited access to them. "Nearctic" Eurycercus longirostris is reported here for the first time from Bering Island and Wrangel Island. Also E. macracanthus is found to be common in Kamchatka Peninsula, while previously only a single population was known. We concluded that the Beringian land bridge played, together with glaciation in North America, important role in the evolutionary history of Eurycercus (Eurycercus), as it was earlier demonstrated for other cladocerans and other animals. PMID- 25543573 TI - Geographical distribution of pelagic decapod shrimp in the Atlantic Ocean. AB - Ninety-one species of pelagic decapod shrimp were identified in 938 midwater trawl collections taken between 1963 and 1974 from the North and South Atlantic. Distributional maps are provided for the most frequently occurring species. Nighttime abundance of most species was greatest within the upper 200 m. Degree of geographical overlap was estimated using the geometric mean of the proportion of joint occurrences with a value >= 0.5 deemed significant. Geographical distributions tended to be unique, and only 31 species had values >= 0.5 with one or more other species. Species within genera and within phylogenetic subgroups of Sergia were generally parapatric or partially overlapping in distribution. Five geographical groupings of co-occurring species across genera were identified: Subpolar-Temperate, Southern Hemisphere, Central, Tropical, Eastern Tropical and Western Tropical. The two species of the Southern Hemisphere group are circumpolar at temperate latitudes. The 12 species of the Central group occurred throughout the subtropical and tropical North and South Atlantic. The eight species of the Tropical group occurred broadly across the equatorial Atlantic and Caribbean with ranges usually extending into the Gulf of Mexico and northward in the Gulf Stream. The two species of the Western Tropical group occurred most often in the western tropics, but there were scattered occurrences at subtropical latitudes. The four species of the Eastern Tropical group were endemic to the Mauritanian Upwelling and the Angola-Benguela Frontal zones off western Africa. Two of the three species in the Subpolar-Temperate group had bipolar distributions, and all three occurred in the Mediterranean and in the Mauritanian Upwelling zone. Most Central, Tropical and Western Tropical species were present in the in the Gulf of Mexico. The 10 species from the Mediterranean were a mixture of Subpolar-Temperate, Central and benthopelagic species. Patterns of distribution in Atlantic pelagic decapods closely parallel those of other pelagic taxa, but myctophid fishes from the same collections appear to partition subtropical regions more finely. PMID- 25543574 TI - Two new species of the genus Wellsopsyllus (Copepoda; Harpacticoida; Paramesochridae) from the Yellow Sea. AB - A study of benthic harpacticoids from the intertidal zone of Gosapo Beach, on the west (Yellow Sea) coast of Korea, resulted in the discovery of two species of Wellsopsyllus Kunz, 1981. The first new species, Wellsopsyllus (Wellsopsyllus) egregius sp. nov., was allocated to the nominotypical subgenus by a combination of three characters: 1) a 3-segmented P4 exopod, 2) 1-segmented P2-P3 endopods, and 3) a P1 endopod-2 with one apical seta. However, it can be clearly distinguished from its congeners by the following characters: 1) a caudal rami with two blunt setae and the seta VII located sub-distally, 2) a P2 and P3 endopod represented by a small blunt process, and 3) the semioval shape of P5. The second new species was placed in the subgenus Scottopsyllus Apostolov & Marinov, 1988 according to the 3-segmented exopod and 2-segmented endopod of P4. Wellsopsyllus (S.) koreanus sp. nov. exhibits a unique combination of characters: 1) a dimpled distal margin of the female P5 endopodal lobe armed with two subequal setae, 2) a caudal seta V consisting of a stout spine-like base with a long cylindrical seta-like portion arising subdistally, and 3) a distinct bundle of five long inner setules on the P1 basis. We present a summary of the characters of all species in the genus Wellsopsyllus and propose an updated key for their identification. PMID- 25543575 TI - Review of Psorodonotus Specularis Group (Orthoptera, Tettigoniidae, Tettigoniinae): two new species from North-east Anatolia. AB - The Anatolio-Caucasio-Balkan genus Psorodonotus (Orthoptera, Tettigoniidae) presently includes 13 species belonging to three species groups. In the present study we review the Specularis group and describe two new species-P. rize Kaya & Ciplak sp. n. and P. giresun Kaya & Ciplak sp. n.. Data obtained of 21 different populations from the North-eastern Anatolia and the Caucasus are used for descriptive and analytical purposes. Morphology of this group has been studied both qualitatively and quantitatively using linear metric data of the hind femur and geometric data of male and female pronotum, male cerci and ovipositor. Male calling songs are described and statistically analysed. Qualitative and/or quantitative morphology and male calling song suggested seven taxonomic units: P. specularis specularis, P. specularis inermis, P. inflatus, P. davisi, P. soganli, P. rize sp. n., P. giresun sp. n.. Our results suggest closest relationships of P. rize sp. n. with P. davisi and of P. giresun sp. n. with P. soganli. PMID- 25543576 TI - A new species of Meharia Chretien, 1915 (Lepidoptera, Cossidae) from the United Arab Emirates, with a world catalogue of the genus. AB - Meharia breithaupti sp. nov. is described from the United Arab Emirates. PMID- 25543577 TI - Two new species of Acroceratitis Hendel (Diptera: Tephritidae) and an updated key for the species from India. AB - Two new species of genus Acroceratitis Hendel, namely A. parastriata David & Hancock , sp. nov. and A. breviscapa David, Ramani & Hancock, sp. nov., are described from India. A. histrionica (de Meijere) is recorded for the first time from India. An updated key to Indian species of Acroceratitis is also provided. PMID- 25543578 TI - Two new quill mites of the family Syringophilidae (Acari: Prostigmata) parasitising the tapaculos (Passeriformes: Rhinocryptidae) in South America. AB - Two new species of syringophilid mites (Acari: Prostigmata: Syringophilidae) associated with passeriform birds of the family Rhinocryptidae in South America are described: Syringophiloidus teledromas sp. nov. from Teledromas fuscus (Sclater and Salvin) in Argentina and Aulonastus pteroptochos sp. nov. from Pteroptochos tarnii (King) in Chile. The genus Aulonastus Kethley, 1970 is recorded from the tapaculos for the first time, and the new species of Syringophiloidus Kethley, 1970 described here is the second record of this genus on rhinocryptid birds. PMID- 25543579 TI - Nyctomyia biunguiculata, a new cavernicolous species of tribe Aedini (Diptera: Culicidae) from southern Thailand. AB - Nyctomyia biunguiculata, sp. n., is described from a unique male reared from a pupa (exuviae partially decomposed and over cleared) collected from a rimstone pool deep inside Wat Sumano cave located in Phatthalung Province of southern Thailand. The genitalia of the holotype are illustrated, and the species is compared with Nc. pholeocola, the type species of the genus described from a cave in another province of southern Thailand. The species has not been found outside the cave and appears to be a true troglobite. PMID- 25543580 TI - Partial revision of Japanese Pectinariidae (Annelida: Polychaeta), including redescriptions of poorly known species. AB - Eight species of Pectinariidae de Quatrefages, 1866 were recorded from Japan and adjacent waters. We studied four species of the family and redescribe the poorly known species from the Seto Inland Sea and Ariake Sound, Kyushu based on recently collected material. The species covered in this study are Amphictene japonica (Nilsson, 1928), Lagis bocki (Hessle, 1917), Pectinaria okudai (Imajima & Hartman, 1964) and Pectinaria hiuchiensis Kitamori, 1965. PMID- 25543581 TI - Towards resolving a problem of the identity of the Aethus species (Hemiptera: Heteroptera: Cydnidae) occurring in Cambodia. AB - The genus Aethus in Cambodia is known only from a single species collected in the 1950s that was originally identified as A. indicus. However, what was regarded as A. indicus in the Oriental and Australian regions appeared to consist of three sibling species, recognizable only on the basis of male genital structures, i.e., A. philippinensis, A. pseudindicus, and true A. indicus. To date, the lack of males representing this genus from Cambodia made it impossible to verify which species actually occur in this country. The present study, based on eight males collected at the same locality in Cambodia where the specimens were originally identified as A. indicus more than 50 years ago (i.e., Siem Reap), confirmed the occurrence of A. pseudindicus, not A. indicus, as previously reported. Male genitalia, i.e. the paramere, the opening of genital capsule, and the apex of aedeagus, are described and their photographs are provided for both species. PMID- 25543582 TI - Provisional revision of American snapping shrimp allied to Alpheus floridanus Kingsley, 1878 (Crustacea: Decapoda: Alpheidae) with notes on A. floridanus africanus. AB - Alpheus floridanus Kingsley, 1878 has been previously treated as a single, morphologically diverse species with a broad distribution in the eastern and western Atlantic Ocean and eastern Pacific Ocean. However, variations in morphology and color patterns, in addition to genetic evidence, have prompted futher investigation. Morphological characters, including curvature and length of the scaphocerite, number teeth on the incisor process of the mandible, number of pereopodal spines, proportions of the major chela, as well as color patterns, support recognition of several species in the Alpheus floridanus complex. Alpheus floridanus sensu stricto (s.s.) is redescribed based upon a lectotype selected from the former syntypic pair. The mutilated second specimen of the syntypic pair is identified as A. platycheirus Boone, 1927, which is fully redescribed. Three species are described as new: A. hephaestus sp. nov. from the eastern Pacific, and A. roblesi sp. nov. and A. ulalae sp. nov. from the western Atlantic. Morphological comparisions to the eastern Atlantic A. floridanus africanus Balss, 1916 are discussed, however a formal treatment of this subspecies is not the objective of this study. Our proposed taxonomic revisions of the A. floridanus complex are supported in a companion molecular genetic analysis (following paper, this volume). PMID- 25543583 TI - Molecular phylogenetics of American snapping shrimps allied to Alpheus floridanus Kingsley, 1878 (Crustacea: Decapoda: Alpheidae). AB - Widely distributed populations of the snapping shrimp, Alpheus floridanus Kinglsey, 1878, from the eastern Pacific and western and eastern Atlantic Ocean have long been suspected to represent different species due to extreme morphological variation among conspecifics. A companion study (Bracken-Grissom & Felder 2014) contains redescriptions of two western Atlantic species (A. floridanus Kingsley 1878 sensu stricto and A. platycheirus Boone, 1927), assignments of the original syntypes for A. floridanus, descriptions of three new species from the Atlantic and eastern Pacific (A. hephaestus Bracken-Grissom & Felder, 2014; A. roblesi Bracken-Grissom & Felder, 2014; A. ulalae Bracken Grissom & Felder, 2014), and discussion of the relationship of the eastern Atlantic A. floridanus africanus Balss, 1916. The present study underpins all these findings by application of molecular phylogenetic techniques. Analysis of partial sequences of the 16S, 12S, and COI mitochondrial genes separate species throughout the eastern Pacific and the eastern and western Atlantic. Morphological comparisons suggested that the two syntypes of A. floridanus belong to different species, and molecular results in this study confirm this separation. Genetic data suggest a strong affinity between the western Atlantic A. platycheirus and the eastern Pacific A. hephaestus. Close relationships are evident between trans-Atlantic species, A. floridanus africanus and A. floridanus, a pattern also seen for other cryptic and pseudocryptic species of Alpheus. Alpheus roblesi and A. ulalae represent early-branching lineages within the complex. In some cases, molecular phylogenetic relationships between members of the A. floridanus complex can be reconciled with postulated biogeographic history. PMID- 25543584 TI - Two new species of ghost shrimp assigned to the genus Cheramus Spence Bate, 1888 (Crustacea: Decapoda: Axiidea: Callianassidae) from the Ryukyu Islands, Japan. AB - Two new species of the callianassid ghost shrimp are described and illustrated on the basis of specimens from the Ryukyu Islands, Japan. These are provisionally assigned to the genus Cheramus Spence Bate, 1888, and appear closest to Callianassa acutirostella Sakai, 1988, also provisionally transferred to Cheramus herewith. These three species can be differentiated by characters of the telson, third maxilliped, chelipeds and uropod. The taxonomic status of Cheramus is briefly discussed. PMID- 25543585 TI - Revision of the Australian species of Gonatopus group 5 (Hymenoptera: Dryinidae), with description of a new species from the Society Islands, French Polynesia. AB - Eleven Australian species of Gonatopus Ljungh, 1810 group 5 are revised. A new species is described from the Leeward Islands: G. perraulti Olmi, Marletta & Guglielmino, sp. nov. (French Polynesia: Society Islands). New combination is proposed for G. levis (Olmi, 1991), comb. nov. (from Dicondylus). A new key to the Australian species of Gonatopus group 5 is presented. PMID- 25543586 TI - New species of Uropodina from Madagascar (Acari: Mesostigmata). AB - Seven new species and one new genus of Uropodina are described from Madagascar. The third Afrotropical species of Polyaspis is described (Polyapis (Polyaspis) madagascarensis sp. nov.), with a key to the Afrotropical species of the genus. The first species of Dinychus from the Afrotropical region is described, as Dinychus lepus sp. nov.. An unusual new species of Trichouropoda species is described as Trichouropoda madagascarica sp. nov.. A new genus (Malagana gen. nov.) is described, with type species Malagana rotunda sp. nov.. The genus Pulchellaobovella is recorded from the Afrotropical Region for the first time, on the basis of Pulchellaobovella madagascarica sp. nov., with nomenclatural notes on the genera Pulchellaobovella and Janetiella. Uroobovella graeca Kontschan, 2010 is moved into the genus Pulchellaobovella, as Pulchellaobovella graeca (Kontschan, 2010b) comb. nov. Two new species of Rotundabaloghia (Circobaloghia) are described, Rotundabaloghia (Circobaloghia) ermilovi sp. nov. and Rotundabaloghia (Circobaloghia) kaydani sp. nov. PMID- 25543587 TI - Description of two new genera and two new species of Metarbelidae (Lepidoptera, Cossoidea) from the Northeastern Congolian Lowland Forests Ecoregion (Central Africa). AB - The genera Dianfosseya gen. nov. and Janegoodallia gen. nov. and their single species D. leakeyi sp. nov. and J. davenporti sp. nov. are both described from Isiro, north-eastern Democratic Republic of the Congo, Central Africa (Afrotropical Region). Wing pattern and male genitalia of the new species are depicted and notes on the habitat are presented. PMID- 25543588 TI - Laetosphecia, a new genus of clearwing moths from south-eastern China, with a brief review of the Sesiini from China (Lepidoptera, Sesiidae). AB - In this study, a new genus of Sesiini, Laetosphecia Kallies & Arita gen. nov., is described. The type species, Laetosphecia variegata (Walker, 1865) comb. nov., and a new species, Laetosphecia brideliana Kallies & Arita spec. nov., occur in south-eastern China (Province of Guangdong and Hong Kong). The larvae of both species cause galls in small branches of Bridelia tomentosa Blume (Phyllanthaceae). Furthermore, Laetosphecia leucozona (Hampson, 1919) comb. nov. from north-eastern India is transferred to the new genus. Additionally, we briefly review the Sesiini fauna of Mainland China and present an updated checklist for this region. Trilochana caseariae Yang & Wang, 1989 syn. nov. is established as a junior synonym of Trilochana scolioides Moore, 1879. Lenyra ashtaroth (Westwood, 1848) and Sphecosesia rhodites Kallies & Arita, 2004 are reported from China for the first time. PMID- 25543589 TI - Two new species of Paraneseuthia Franz (Coleoptera, Staphylinidae, Scydmaeninae) from West Malaysia. AB - Two new species of Paraneseuthia are described from peninsular Malaysia: P. joeparkeri sp. n. from Bukit Larut (Maxwell Hill) and P. titiwangsana sp. n. from the Genting Highlands. The new species are morphologically allied to species known so far only from Sumatra; they all share emarginate apex of the aedeagus bordered at each side by a subtriangular projection and a pair of setae. This is the first record of this eutheiine genus from the Malay Peninsula and extends the known diversity of Paraneseuthia species within the historical Sundaland area. PMID- 25543590 TI - Pentamyrmecini, a new tribe for Pentamyrmex spinosus, a remarkable new genus and species of Pentatomidae (Hemiptera: Heteroptera) from Thailand. [Corrected]. AB - Pentamyrmex spinosus new genus, new species is described, and a new tribe is erected for this remarkable insect. This is the first report of ant mimicry in the Pentatomidae. PMID- 25543591 TI - [Effect of TGF-beta1 expression on periodontal tissue reconstruction for rapid teeth movement through reducing resistance and distraction]. AB - PURPOSE: To investigate the role of transforming growth factor-beta1 (TGF-beta1) in periodontal tissue reconstruction during rapid teeth movement through reducing resistance and distraction. METHODS: Twenty Beagle dogs were randomly divided into five groups according to time points: distraction for 5 days, 10 days, 15 days, retaining 10 days after distraction for 15 days, and retaining 90 days after distraction for 15 days. The mandibular first premolar was moved by using reducing resistance and distraction (experimental group) or conventional distraction (control group) randomly. For each group, tooth movement distance was measured and first premolar periodontal tissue pieces were obtained in scheduled time. Hematoxylin-eosin stain, Picric acid-Sirius red, and immunohistochemistry were performed. The data was analyzed by using SPSS 18.0 software package. RESULTS: The speed of tooth movement and periodontal reconstruction of the experimental group were significantly faster than the control group. TGF-beta1 positive expression in two groups had similar distribution area, and reached peak at most active stage of osteogenesis in both groups. But in different stages of distraction, the positive expression in the experimental group was significantly higher than the control group(P<0.05). CONCLUSIONS: Compared with conventional orthodontic method, reducing resistance and distraction can obviously increase the expression of TGF-beta1 of tension side of the distracted tooth, and accelerate periodontal tissue reconstruction. PMID- 25543592 TI - [Effect of fluoride on the viability and apoptosis of ameloblasts in vitro]. AB - PURPOSE: To evaluate the effect of fluoride on viability of rat ameloblasts in vitro. METHODS: The ameloblasts of rat was exposed to different concentrations of NaF (0, 0.4, 0.8, 1.6, 3.2, 6.4 mmol/L) for 24, 48 and 72 hours. CCK-8 assays were performed to measure the cells proliferation; The morphology of apoptosis was observed by Hoechst 33258 staining and the rate of apoptosis was determined by flow cytometry. The data was analyzed using SPSS 13.0 software package. RESULTS: (1)The proliferation of ameloblasts was increased when concentrations of NaF between 0.4 mmol/L and 0.8 mmol/L, whereas inhibited at 1.6 mmol/L NaF and above. The effects were in time-dependent manner.(2)Cells in the 1.6 mmol/L NaF groups showed unclear karyorrhexis and apoptotic cell morphology. The effects were in concentration-dependent manner. CONCLUSIONS: (1)Fluoride has two-phase effects to ameloblasts: At low doses, it promoted cell proliferation while at high doses it had negative effects. (2)1.6 mmol/L NaF could induce apoptosis of ameloblasts. PMID- 25543593 TI - [The effects of ADAM28 AS-ODN on biological function of human gingival fibroblasts]. AB - PURPOSE: To study the effects of a disintegrin and metalloproteinase 28 (ADAM28) antisense oligodeoxynucleotide (AS-ODN) on proliferation, differentiation and apoptosis of human gingival fibroblasts (HGFs), and analyze the possible mechanism. METHODS: Cell culture, gene transfection, MTT chromatometry, enzyme dynamics, and flow cytometry (FCM) techniques were used to detect the effects of ADAM28 AS-ODN on biological characteristics of HGFs after transfected into HGFs. The statistical differences were evaluated by SNK test with SPSS 16.0 software package. RESULTS: In ADAM28 AS-ODN group, the proliferation activity of HGFs decreased significantly. Cell percentage in S phase in AS-ODN group was notably lower than that of S-ODN and untransfected groups, and cell percentage in G2+M phase was remarkably lower than that of untransfected group. Cell proliferation index (PI=S+G2M) in AS-ODN group was significantly lower than that of the other two groups. There was a significant difference between the groups. In AS-ODN group, alkaline phosphatase (ALP) secretion activity and percentage of apoptotic cell notably increased. CONCLUSIONS: ADAM28 AS-ODN could inhibit HGFs proliferation significantly and influence the changes of cell cycle, promote HGFs differentiation and induce HGFs apoptosis remarkably. PMID- 25543594 TI - [Effect of CORM-2 on atherosclerosis in experimental periodontitis of rats]. AB - PURPOSE: To evaluate the effect of CORM-2 (carbon monoxide releasing molecule-2) on atherosclerosis in experimental periodontitis of rats. METHODS: Forty Wistar rats were divided into four groups randomly. Rats in control group did not receive any procedure; animals in the carbon monoxide group (CO group) and the chronic periodontitis group (CP group) were induced experimental periodontitis and treated with CORM-2 (10mg/kg per day), or normal saline solution (NaCl 0.9%), respectively; animals in the solvent group (DMSO group) received dimethylsulfoxide solution (DMSO 0.05%) only. Blood samples were collected after 1, 3, 7, 14 and 28 days from all animals for analysis of C react protein (CRP), oxidized low density lipoprotein (ox-LDL), soluble vascular cell adhesion molecule-1, (sVCAM-1) and interleukin-10 (IL-10) by enzyme-linked immunosorbent assay (ELISA). Rats were sacrificed after 28 days. Lipid deposition was checked by means of oil red staining in the descending aorta. Changes in alveolar bone levels were measured and periodontal tissues were histopathologically examined to assess the infiltration of inflammatory cells. SPSS17.0 software package was used to analyse the experimental data. RESULTS: The serum levels of CRP, ox-LDL and sVCAM-1 in CP group were significantly higher than that in CO and the other two groups (P<0.05). The level of IL-10 in CP group was significantly lower (P<0.05). Lipid deposition in the descending aorta was observed in CP group. The alveolar bone loss and the ratio of presence of inflammatory cell infiltration (ICI) in CP group were significantly higher compared with CO groups (P<0.05). CONCLUSIONS: This study demonstrated that CORM-2 can not only reduce the inflammatory response in periodontal tissues in rats with experimental periodontitis, but also inhibit atherosclerosis-associated cytokines and lipid deposition in descending aorta, which suggests a favorable potential in treatment of periodontitis and atherosclerosis. PMID- 25543595 TI - [Electrochemical impedance spectroscopic study of titanium in physiological environment with blood-serum protein]. AB - PURPOSE: Electrochemical impedance spectroscopy (EIS) was employed to study the corrosion behaviour of titanium in dummy environment with blood-serum protein. METHODS: EIS of titanium in PBS and cell culture fluid was acquired by advanced electrochemical system. The characteristic of EIS-Nyquist and EIS-Bode were investigated and the equivalent circuit was used to analyze the EIS results. The data was analyzed using SPSS 11.0 software package. RESULTS: The corrosion resistance of the titanium in cell culture fluid was significantly higher than that in PBS (P<0.05). The phase angle of TiO2-based passive film at low frequency decreased to 55 degrees when titanium was in PBS, but 75 degrees when in cell culture fluid. CONCLUSIONS: The blood-serum protein plays an important role in the corrosion behaviour of titanium in physiological environment. PMID- 25543596 TI - [Coculture of stem cells from the apical papilla and human umbilical vein endothelial cells enhances the angiogenic potential of dental pulp tissues]. AB - PURPOSE: To observe the effect of coculture of stem cells from the apical papilla (SCAPs) and human umbilical vein endothelial cells (HUVECs) on the angiogenic potential of dental pulp tissues. METHODS: SCAPs were incubated in osteo/odontogenic, adipogenic, neurogenic induction medium and alpha-MEM medium, whose multilineage differentiation capacities were confirmed using alizarin red staining, oil red O staining and betaIII-tubulin immunofluorescent staining. The tubular length, branching points number and junctional areas were detected after 3, 6, 9 h since cells were seeded onto matrigel, and the data was analyzed using SPSS 16.0 software package. RESULTS: SCAPs in the experimental groups were detected having more lipid droplets, mineralization nodules and neuron-like cells. Coculture of SCAPs and HUVECs formed more vessel-like structures in tubular formation assay. CONCLUSIONS: SCAPs are capable of differentiating into fat, bone, and nerve-like cells in vitro. Coculture of SCAPs and HUVECs can enhance the angiogenic potential of dental pulp tissues. PMID- 25543597 TI - [Study of relationship between different contents of zinc and antibacterial activity on calcium phosphate coating modified by plasma electrolytic oxidation method]. AB - PURPOSE: Calcium phosphate activity coating containing different contents of zinc was deposited onto the surface of pure titanium modified by plasma electrolytic oxidation. The physical and chemical properties of different contents of zinc were compared among three groups, and the influence on antibacterial activity of P.gingivalis (Pg) and A.actinomycetemcomitans (Aa) was evaluated. METHODS: Pure titanium samples were treated in the electrolyte of plasma electrolytic oxidation with 0.08 mol/L calcium and 0.06 mol/L phosphorus, and 0.01, 0.03, 0.05 zinc was added to each group in order to deal with pure titanium plate. Titanium samples were divided into three groups: low, middle and high group according to zinc contents. The group without zinc was as control. The binding force of coating and titanium was tested by electric universal test machine. The topography of surfaces was observed under scanning electron microscope (SEM). The crystalline structure of surfaces was determined by XRD. The chemistry and elements of surfaces were determined by XPS. Pg and Aa were seeded onto samples surfaces, and the antibacterial properties of four kinds of materials were evaluated by using scanning electron microscopy and the paster method. Statistical analysis was performed using SPSS 13.0 software package. RESULTS: It was found that the aperture and roughness were increased with the increase of content of zinc. The crystallization of low zinc group was superior to high zinc group. The content of HA and Zn3P2 in low zinc group was more, but ZnO in high zinc group was more. Scanning electron microscope demonstrated that the number of Pg and Aa decreased on the surface with the increase of the content of zinc, while the bacteria of high zinc group underwent lysis and necrosis. By using the paster method, the number of Pg and Aa decreased on the surface with the increase of the content of zinc, and there was significant difference among the four groups. CONCLUSIONS: The change of zinc content will change the physical and chemical properties of the coating; at the same time, the antimicrobial property of calcium phosphate coating with high content zinc was the best. PMID- 25543598 TI - [Experimental evaluation of pure traditional Chinese medical mouth rinse on skin and mucosa stimulation and bacteriostatic-bactericidal effect]. AB - PURPOSE: To observe the stimulating effect of pure traditional Chinese medical mouth rinse (PTCMMR) on skin and mucosa and to evaluate the efficacy of PTCMMR on inhibiting and killing oral common bacteria. METHODS: PTCMMR and normal saline (NS) were separately dripped onto 14 five-month rabbits' left and right eyes for 7 days, and were smeared on the left and right side of buttocks, abdomens, back of 10 seven-month guinea pigs (after hair removal) once a day for comparison between the two sides. Five animals were sacrificed after 3 and 7 days of smearing to make pathological sections. Bacterium suspension with Staphylococcus aureus, Escherichia coli, Candida albicans, Pseudomonas aeruginosa and Streptococcus B were dropped to nutrient solution containing different concentrations of PTCMMR or compound Borax solution to observe the growth situation of bacteria. Inhibition zone diameters were measured after 18h of incubation within 37 degrees centigrade incubator. The data was statistically analyzed using SPSS 17.0 software package. RESULTS: There was no obvious change such as redness, dermatitis between rabbits' left eye conjunctiva and the control group. The bacteriostatic and bactericidal effect of anaerobe and aerobe with dropping of PTCMMR was stronger than that of control group. CONCLUSIONS: PTCMMR has no stimulation to skin and mucosa, while it has strong efficacy to inhibit and kill oral common bacteria. PMID- 25543599 TI - [A study on the development of TMPT-contained trial dentin sealant]. AB - PURPOSE: To investigate the effect of resin curing system formulations of TMPT contained trial dentin sealant on its bonding and polymerization properties. METHODS: Commercially available Hybrid Coat (HyC) and previously trial TMPT contained dentin sealant T33 as control groups, adjusting camphorquinone (CQ) content to make CQ trial dentin sealants. Their dentin shear bond strength was tested to find the strongest group named CQn as the next test substrate. N phenylglycine (NPG) content of original sponges was adjusted to make NC trial sponges. Bond strength and degree of conversion of CQn were tested using each NC trial sponges. The data was analyzed by SPSS13.0 software package. RESULTS: CQ3 showed the biggest bond strength in the group of CQ trial sealants of about 12.99 MPa. When CQ3 was used with every NPG trial sponges, NPG4.4 and NPG7.3 groups showed the statistically greatest bond strength of about 14.68 and 14.69 MPa (P<0.05). And NPG7.3 also showed the maximum degree of conversion of about 83.2%. CONCLUSIONS: The bonding strength and degree of conversion of trial TMPT contained dentin sealant were the biggest when molar ratio of CQ and NPG was 1:4.4 or 7.3, but the material properties need to be tested in subsequent experiments. PMID- 25543600 TI - [Effects of 5-aza-2-deoxycytidine on methylation status of RECK gene and cancer cell invasion in tongue cancer SCC-4 cells]. AB - PURPOSE: To investigate the effects of 5-aza-2-deoxycytidine on methylation status and invasion ability of RECK gene in tongue cancer SCC-4 cells. METHODS: Tongue cancer cell line SCC-4 cells were treated with 5-aza-dC at different concentrations for 72 h. Methylation status of RECK gene of SCC-4 cells was detected by methylation specific PCR (MSP), the expression of RECK gene mRNA was detected by real-time quantitative PCR. The expression of RECK protein was detected by Western blot, and the invasion ability of SCC-4 cell was examined by Transwell assay. SPSS13.0 software package was used for statistical analysis. RESULTS: RECK gene of SCC-4 cells was in high methylation status in untreated group, abnormal methylation was effectively reversed by 5-aza-dC treatment. After treatment with different concentration of 5-aza-dC for 72 h, relative mRNA expression level increased gradually (P<0.05). The relative expression level of RECK protein in 5-aza-dC treated group was significantly higher than that in the control group,the invasion ability of SCC-4 cell was decreased gradually. CONCLUSIONS: 5-aza-dC treatment for tongue cancer SCC-4 cells can successfully reverse high methylation status of RECK gene and restore the expression of RECK gene mRNA and protein, and reduced the invasion ability. PMID- 25543601 TI - [Correlation analysis of EphA7 expression with clinico-pathological parameters and prognosis in tongue squamous cell carcinoma]. AB - PURPOSE: To evaluate the relationship between the expression of EphA7 and its clinical correlation and function with tongue squamous cell carcinoma (TSCC). METHODS: The expression of EphA7 was determined in 54 pairs of human TSCC tissues and pair-matched adjacent noncancerous tissues by immunohistochemistry. Furthermore, association between EphA7 expression and patients' clinicopathological characteristics, overall and disease-free survival were evaluated. Invasion and metastasis of SCC9 cell were detected before and after down regulation of EphA7 expression. Differences in measurement data were compared with paired-t test, and survival analysis was made by Kaplan-Meier method using SPSS17.0 software package. RESULTS: EphA7 was positive in all examined specimens. Significant associations were noted between high EphA7 expression and absence of lymph node metastasis, absence of vascular invasion, dense stromal inflammatory reaction and female gender. TSCC patients with higher EphA7 expression presented longer overall and disease-free survival compared with low EphA7 expression. The invasion and metastasis of SCC9 cell increased significantly after down regulation of EphA7. CONCLUSIONS: The study indicated that EphA7 may participate in the malignant transformation of TSCC, reinforcing their utility as targets for potential therapeutic intervention. PMID- 25543602 TI - [Clinical effect of functional repair of bilateral cleft lip in 66 patients]. AB - PURPOSE: To explore the clinical effect of functional repair for bilateral cleft lip using modified Mulliken method. METHODS: Sixty-six patients with bilateral cleft lip were selected and assigned to receive modified Mulliken method. During the operation, the prolabium was kept as narrow "tie" shape, the orbicularis oris was anatomically repositioned, and the orbicularis oris ring was re-built. Vermilion tubercle was reconstructed with the lateral red vermillion. The nasal deformity was preliminarily repaired. and the nasal columella was elongated at the same time. RESULTS: All the patients were followed-up for 0.5-2 years, there was no "trisection upper lip". The symmetry and natural shape of Cupid's bow were obtained in more than 80% patients. The width of philtrum was similar to normal children. Full vermilion of the lips, moderate-size vermilion tubercles and good dynamic and static shape were obtained without whistle deformities. Normal width of nasal base and nostril symmetry were gained. The columella was elongated. Satisfactory contour of the nasal tip was achieved. CONCLUSIONS: Modified Mulliken method could functionally repair bilateral cleft lip and effectively correct nasolabial deformities. It is worthy of wide clinical application. PMID- 25543603 TI - [Evaluation of facial aesthetics in young population with beautiful faces in Nanchang city]. AB - PURPOSE: To analyze the full-face and lateral aesthetical standards among fine looking young people in Jiangxi province, in order to provide reference for orthodontic treatment. METHODS: Fourteen young males and fifteen young females from universities in Nanchang city were selected through audition of young beauty within Jiangxi province. Their full-face and lateral pictures were then taken. Ten orthodontists and 85 non-orthodontists in different ages and sexuality who were randomly selected were asked to rank all of the selected pictures in descending order of attractiveness independently and also pick out the most beautiful male and female photos according to their own judgments. Comparisons were carried out to select the universally recognized beautiful males and females and analyze their soft tissue facial profile. RESULTS: Orthodontists held significantly different opinions on the facial esthetic profile for males and females, especially for males. On the other hand, although the non-professionals also had different views on the profiles, the evaluations for males were quite consistent. To be specific, young people selected No.13 male and No.1 female while the old people preferred to select No.7 male and the No.9 female. At the same time, men selected No.7 and No.13 male, and No.1 and No.9 female while women selected No.13 male and No.1 female. CONCLUSIONS: Both orthodontists and non orthodontists have different opinions on the facial esthetic profile for young males and females. During orthodontic treatments, orthodontists should respect the opinions of the patients and their family members on the matter of facial improvements. PMID- 25543604 TI - [Study on articulation characteristics of patients after cleft palate repair in Henan province]. AB - PURPOSE: To establish the pathological speech characteristic of patients after cleft plate repair in Henan province by unusual speech frequency and vowel formants. METHODS: One hundred normal speech patients and 121 patients after cleft palate repair were selected, their formant frequency of vowels/ a,o,e,i,u,u/ were obtained. The pathological speech frequency was collected in 121 postoperative patients. The acoustic features of the vowel were compared by SPSS17.0 software package with two independent sample t test. RESULTS: According to articulation position, 21.9% of misarticulation of postoperative patients occurred in dental consonants, 5.2% in retroflex consonants, 21.6% in alveolar consonants, 19.2% in palatal consonants, 12.9% in velar consonants and 6.6% in dorsum consonants. The average value of F2 of/a, o, e, u/did not show significant difference between the two groups (P>0.05).The difference of average value of F2 of /i,u/ was significant (P<0.05). The average value of F1 of/a, o, e, I, u/did not show significant difference between the two groups (P>0.05).Except /a/,the average value of F3 of vowel /o, e, i, u, u/showed significant difference between the two groups (P<0.05). CONCLUSIONS: Misarticulation of patients after cleft palate repair in Henan province mainly occurred in dental consonants, alveolar consonants and palatal consonants; tongue over curly can be observed in operated patients with cleft palate. There was no significant difference between the two groups in mouth opening. PMID- 25543605 TI - [An analysis of soft tissue profile features of beautiful men and women with polar coordinates]. AB - PURPOSE: To analyze the profile features of soft tissues of beautiful young men and women with Han nationality by polar coordinates. METHODS: Sixty-two beautiful college students (aged 18-23 years, average 20.1 years, 31 men, 31 women) were chosen according to inclusion criteria as study samples. The lateral cephalograms of the samples were taken in natural head position. The polar system was established with the Bolton (Bo) point as the pole, and the Bo-N line as the polar axis. The polar coordinates were measured of the mark points on the soft tissues of the samples' maxillofacial regions respectively. The measured data were statistically analyzed with SPSS 17.0 software package. RESULTS: There were no significant differences among the polar angles of the marking points on the soft tissues (P>0.05), the results were not statistically significant; there were significant differences among the measured data of line distances (P<0.01); the ratios of the polar radius of each mark point and Bo-N were not significantly different (P>0.05); there were significant differences among the values of Bo Pos/ Bo-Sn, Bo-LL/Bo-Pos between men and women, which was statistically significant (P<0.05). CONCLUSIONS: Polar coordinates can be applied to cephalometry to accurately and integrally describe maxillofacial profile features. There are minor differences between the profile features of beautiful men and women, and the differences are mainly shown in mandible and the fullness of lips. PMID- 25543606 TI - [Efficacy evaluation of fixed Twin-block appliance and tooth extraction in skeletal Class II malocclusion]. AB - PURPOSE: To evaluate the skeletal and dentoalveolar effects of Twin-Block combined with straight wire appliances and tooth extraction in the treatment of skeletal Class II malocclusion with mandibular retrognathia in growing individuals. METHODS: The sample comprised 31 growing individuals with skeletal Class II and mandibular retrognathia, divided into 2 groups. One group (18 patients) was treated with fixed Twin-block combined with fixed appliance; the other group (13 patients) was only treated with fixed appliance after tooth extraction. Lateral cephalograms pretreatment and posttreatment were taken before and after Twin-block treatment and after all fixed appliance treatment. Pancherz's cephalometric measurements were analyzed statistically. Intragroup and intergroup changes of the two groups were evaluated by test using SPSS 15.0 software package. RESULTS: According to Pancherz's analysis, mandibular length increased, point Pg, mandibular incisors and first molars moved forward, maxillary incisors moved backward, overjet decreased (P<0.05) after treatment with Twin-block and fixed appliance. Within the rectification of anterior overjet, proportion of dentofacial factor was 39.5%, skeletal factor was 60.5%. Within the rectification of posterior relationship, proportion of dentofacial factor was 44.9%, skeletal factor was 55.1%. CONCLUSIONS: Twin-block combined with fixed appliance treatment can efficiently promote mandibular growth, restrict forward growth of maxilla to some extent, correct incisor and molar relationship and improve skeletal profile in growing skeletal Class II individuals with mandibular retrognathia. PMID- 25543607 TI - [Study of the root canal characteristics of mandibular central incisors in 150 patients using cone-beam computed tomography]. AB - PURPOSE: To investigate the root canal characteristics of mandibular central incisors using a cone-beam computed tomography (CBCT) technique. METHODS: One hundred and fifty patients (79 males and 71 females) receiving CBCT scan at Shanghai Ninth People's Hospital were recruited into this study. A total of 295 image samples of mandibular central incisors were obtained and analyzed in terms of the number and type of root canals. RESULTS: The majority of mandibular central incisors had a single canal (61% possessed a Type I canal system). Although 39% of the roots possessed two canals, only 8.8%had two separate apical foramina. CONCLUSIONS: The prevalence of two canals of mandibular central incisors in this case series was 39% and is within the range reported by previous studies on case series of different racial origin. PMID- 25543608 TI - [Oral candida species distribution in patients receiving radiotherapy for head and neck cancer]. AB - PURPOSE: To investigate the distribution of oral candida species in head and neck cancer (HNC) patients treated with radiation therapy, and provide the basis for planning of clinical preventive measures. METHODS: Saliva was sampled from 60 HNC patients before, during and after radiation. Concomitantly, 60 healthy individuals whose age and sex matched that of the patient group were selected as control group. Oral candida carriages were quantitatively detected and the different candida species were identified by multiple measures such as CHROMagar candida culture medium and API 20C AUX yeast identification system. Then the differences between the two groups in terms of the candida detection rate and the distribution of each species of candida were analyzed with SPSS 17.0 software package. RESULTS: Xerostomia and dysphagia was found in 54 HNC patients during radiotherapy, radiation-induced oral mucotitis(RIOM) was found in 50 HNC patients,and oral candidiasis was found in 18 HNC patients; In radiation group, the detection rate of candida colonization during radiation was 56.7%, 63.3% postradiation, which showed significant differences compared with pre-radiation (X2 =18.320,P<0.001 ); Among the 54 identified clinical isolates, candida albicans (n=42) was the most frequent, followed by candida parapsilosis (n=6), candida tropicalis (n=4) and candida glabrata (n=2). In radiation group, the oral candida pathogens detection rate was 30%, and candida colonization was 46.7%. CONCLUSIONS: The oral candida colonization rate was significantly higher in HNC patients after radiotherapy, which indicated that the candida infection may be closely related to RIOM. PMID- 25543609 TI - [Correlation between anxiety, depression and pefectionistic tendencies in patients before orthodontic treatment]. AB - PURPOSE: To discuss the relationships between the level of anxiety, depression and perfectionism in dental patients before orthodontic treatment. METHODS: A modified Corah Dental Anxiety Scale (MDAS), Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS) and Chinese Frost Multidimensional Perfectionism Scale (CFMPS) were used in 170 patients before orthodontic treatment. The data was analyzed by independent sample t test, correlation and multiple regression analysis using SPSS16.0 software package. RESULTS: 24.71% of the patients had obvious dental anxiety with MDAS scores>=11, there was significant difference in the scores of SAS, SDS between dental anxiety group and non-dental anxiety group (P<0.01), the scores of concern over mistakes (CM), personal standards (PS), doubts about actions (DA) and organization (OR) of dental anxiety patients were of significant difference compared with that in the non-dental anxiety group (P<0.05). Concern over mistakes (CM), personal standards (PS) and doubts about actions (DA) had significant positive correlations with the scores of SAS and SDS (P<0.01); while organization (OR) had negative correlation with the scores of SDS (P<0.05); Regression analysis showed that the scores of concern over mistakes (CM), organization (OR) and age seemed to be a strong predictor of the scores of SAS and SDS. CONCLUSIONS: The level of anxiety and depression of dental anxiety patients before orthodontic treatment is higher than non-dental anxiety group, and it has significant correlation with perfectionistic tendencies, for dental anxiety of patients with early intervention should be combined with different age and perfectionism personality characteristics. PMID- 25543610 TI - [A clinical evaluation on the stability of orthodontic mini-implants using resonance frequency analysis]. AB - PURPOSE: To evaluate the stability of mini-implant by resonance frequency analysis and to determine the optimal loading timing of orthodontic force. METHODS: Fourteen orthodontic patients who had upper first premolars extraction and needed mini-implants to reinforce the anchorage were enrolled in this study. The patients were divided into 2 groups: delay-loading group and selective loading group. A joined head mini-implant was inserted in the buccal interradicular area on each side of maxilla for each patient and 28 mini-implants in total were used. Osstell resonance frequency device was used to measure the ISQ (implant stability quotients) value. The measurements were performed immediately after the implant insertion and weekly afterwards until week 16. After the ISQ value was stable, orthodontic force of 150g was loaded on the mini implants in selective-loading group. The same level of force was applied in delay loading group at week 12. The data was analyzed by one-way ANOVA and t test using SPSS 19.0 software package. RESULTS: Twenty-three mini-implants were stable during the study. Twelve unloading mini-implants in delay-loading group showed maximal ISQ values immediately after insertion and at week 1 (21.48 +/- 5.25). The ISQ values decreased gradually from week 2 to week 5 and reached a plateau after week 6 (11.26 +/- 3.36). Eleven mini-implants survived in selective-loading group were then loaded at week 6. There were no significant differences of ISQ values in loading and unloading mini-implants after 6 weeks. The remaining 5 mini implants were loosing during the first 4 weeks, which showed a significant lower initial ISQ values compared to the successful implants. CONCLUSIONS: The stability of mini-implants decreases 1 week after insertion and maintains after 6 weeks. Orthodontic loading after week 6 has no influence on the stability. Lower initial stability is an important factor for the failure of mini-implants. PMID- 25543611 TI - [Correlation analysis of VEGF and PTEN expression in gingival carcinoma]. AB - PURPOSE: To study the expression of vascular endothelial growth factor (VEGF) and phosphatase and tensin homolog (PTEN) in gingival carcinoma and their correlation in order to provide reference for clinical treatment. METHODS: Sixty-six gingival cancer patients were determined by pathological examination, among which 31 were well-differentiated, 20 were moderately differentiated and 15 were poorly differentiated. 15 adjacent normal tissues were chosen as control group. The expression of VEGF and PTEN was examined by immunohistochemical method. Correlation analysis was performed with SPSS13.0 software package. RESULTS: The positive rate of PTEN in control group was significantly higher than other groups (P<0.05). The expression of VEGF in poorly differentiated group was significantly higher than other groups (P<0.05). Correlation analysis showed that the expression of VEGF was positively correlated to recurrence and lymph node metastasis (P<0.05); PTEN was negatively correlated to recurrence and lymph node metastasis (P<0.05); VEGF and PTEN in gingival carcinoma was negatively correlated (P<0.05). CONCLUSIONS: The increased expression of VEGF and decreased expression of PTEN in gingival carcinoma may play a mutual role in the development of gingival cancer. PMID- 25543612 TI - [Application of sonic endo-instruments in combination with Mtwo Ni-Ti files in root canal preparation of molars]. AB - PURPOSE: To evaluate the clinical outcome of sonic endo-instruments in combination with Mtwo Ni-Ti files in root canal preparation of molars. METHODS: One hundred patients (118 first molars, 428 root canals) were included in this study, they were randomly assigned into 2 groups (n=50).Group 1 was shaped with sonic endo-instruments in combination with Mtwo Ni-Ti files,while group 2 was treated with stainless-steel files, both groups were obturated with lateral condensation technique. The time of root canal shaping, acute post-operative pain, the quality of the root canal filling and the success rate after 1 year were recorded and analyzed using SPSS 11.0 software package. RESULTS: The average preparation time in group 1 was (5.3+/-0.6)min/canal and (12.7+/-0.9) min/canal in group 2 (t=100.89,P<0.001). The rate of acute postoperative pain was significantly lower X(2)=4.87, P<0.05,in group 1 (8.20%) than in group 2 (22.81%); in group 1, 92.86% root canals were filled adequately while only 78.92% in group 2, the difference was significant (X(2)=17.45, P<0.05);higher success rate (X(2)=3.95, P<0.05) after 1 year was achieved in group 1 (91.80%) compared with group 2 (78.95%). CONCLUSIONS: Compared with stainless-steel files, sonic endo instruments in combination with Mtwo Ni-Ti files in root canal preparation of molars seem more effective, cause less postoperative pain and offer higher success rates. PMID- 25543613 TI - [Effectiveness of acellular dermal matrix and parotid fascia in preventing Frey's syndrome: meta analysis]. AB - PURPOSE: To evaluate and compare the effectiveness of acellular dermal matrix (ADM) and parotid fascia in preventing Frey's syndrome. METHODS: A literature research was performed using Wanfang Database, Chinese Biological Literature Database, China National Knowledge Infrastructure and Chinese Scientific Journals database of VIP from 2001 to 2013. Relative ratio (RR) was calculated and meta analysis was performed by Review Manager 5.2. RESULTS: A total of 16 controlled studies were included. Meta analysis showed that the use of ADM and preservation of the parotid fascia could significantly reduce the risk of Frey's syndrome. The subjective incidence was decreased by 71% and 87%, and objective incidence was reduced by 64% and 85%, respectively. Significant difference was found between ADM and parotid fascia in reducing subjective incidence, in which ADM seemed to be more effective. CONCLUSIONS: The present study suggested that parotid fascia should be adopted as an effective method to reduce Frey's syndrome in most circumstances for patients with benign parotid tumors. For those whose parotid fascia could not be preserved, ADM might be another good choice. PMID- 25543614 TI - [Application of role-play simulation in pre-clinical practice of the fourth grade students in department of endodontics]. AB - PURPOSE: To apply role- play simulation in pre-clinical practice of the fourth grade students in department of endodontics. METHODS: Thirty-two students were randomly divided into 2 groups, there were 16 students in each group. Students in one group were taught with role-play simulation while the other group with lecture-based learning method. The teaching effect was measured with examination and questionnaire survey. The data was analyzed by using SPSS 17.0 software package. RESULTS: There were no significant differences in basic knowledge, case analysis and oral examination between 2 groups (P>0.05), but there was significant difference in history taking and medical records writing, practical examination and total scores between 2 groups (P<0.05). The role-play simulation was generally approved by both teachers and students in experimental group. CONCLUSIONS: The abilities of the fourth grade students can be developed by role play simulation in different aspects. Role-play simulation can be applied in pre clinical practice of the fourth grade students in department of endodontics. PMID- 25543615 TI - [Treatment of mandibular first premolars with complex root canals: report of 2 cases]. AB - Mandibular first premolars have complex root canals. Double root canals and three root canals usually happen. Clinicians should be aware of the normal anatomy of root canal system and vigilant about the possibility of canal variation. In this paper, two cases of mandibular first premolars with double (2-2,Verlucci) and three(1-3,Verlucci) root canals were reported. The root canal type and its incidence were discussed. Clinicians should carefully explore to confirm the existence of variation and avoid missed canals, which are necessary for a successful root canal therapy. PMID- 25543616 TI - Apristurus breviventralis, a new species of deep-water catshark (Chondrichthyes: Carcharhiniformes: Scyliorhinidae) from the Gulf of Aden. AB - A new deep-water catshark of the genus Apristurus Garman, 1913 is described based on nine specimens from the Gulf of Aden in the northwestern Indian Ocean. Apristurus breviventralis sp. nov. belongs to the 'brunneus group' of the genus and is characterized by having pectoral-fin tips reaching beyond the midpoint between the paired fin bases, a much shorter pectoral-pelvic space than the anal fin base, a low and long-based anal fin, and a first dorsal fin located behind pelvic-fin insertion. The new species most closely resembles the western Atlantic species Apristurus canutus, but is distinguishable in having greater nostril length than internarial width and longer claspers in adult males. Apristurus breviventralis sp. nov. represents the sixth species of Apristurus from the western Indian Ocean and the 38th species globally. PMID- 25543617 TI - Description of immatures and association with adults of three species of Anacroneuria Klapalek (Plecoptera: Perlidae) of the Brazilian Amazon. AB - Nymphs of three species of the genus Anacroneuria Klapalek, 1909, A. marlieri Froehlich, 2001; A. minuta Klapalek, 1922, and A. manauensis Ribeiro-Ferreira, 2001 are described. The associations of nymphs with adults were made by rearing. The known geographical distribution in Brazil of these three species was expanded. PMID- 25543618 TI - Acanthaleyrodes elevatus sp. n. (Hemiptera: Aleyrodidae) from India, with key to species and discussion of tuberculate setae. AB - The genus Acanthaleyrodes Takahashi is reported for the first time from India. Acanthaleyrodes elevatus sp. n. is described from Bridelia retusa in Kerala, India, with a key to puparia of Acanthaleydes species. The new species differs in its exceptionally elevated eighth abdominal tergite, circular vasiform orifice and eight pairs of subdorsal setae. The generic characteristics of Acanthaleyrodes are redefined and distinguished from those of Tuberaleyrodes Takahashi. A. styraci Takahashi is re-described in detail with illustrations of puparia and immatures from Hong Kong. A lectotype puparium is designated for A. callicarpae Takahashi. The development of tuberculate setae is discussed, in whitefly puparia and earlier nymphal instars, and considered to be subject to environmental modification. PMID- 25543619 TI - Revision of the Afrotropical Pimentelia Laboissiere, 1939 (Coleoptera, Chrysomelidae, Galerucinae). AB - We redescribe two of the valid species of the Afrotropical galerucine genus Pimentelia Laboissiere, 1939. This group forms a distinct monophyletic group, characterized by several external and genitalic characters. It is closer related to Galerudolphia Hincks, 1949 and Neobarombiella Bolz & Wagner, 1912. The revision is based on the examination of 30 specimens from continental Africa, and contains two valid species: the type of the genus, Pimentelia kuanduensis Laboissiere, 1939, and Pimentelia maculata (Jacoby, 1885) comb. nov. (= Sermyloides unifasciata Jacoby, 1900 syn. nov.). A further species originally described, Pimentelia ochracea Laboissiere, 1939 is unknown to us, type material could not be found. Another species, Pimentelia hertigi (Laboissiere, 1931), has to be transferred to another group since external characters show that it is not closely related to Pimentelia and does not belong to this genus. Pimentelia is described in detail, redescriptions are provided for the two known species, including figures of external and genitalic characters, and distribution maps. A key is provided to facilitate species identification. PMID- 25543620 TI - Re-description of three species of the genus Sectonema Thorne, 1930 (Nematoda: Dorylaimida: Aporcelaimidae) originally studied by E. Altherr. AB - Three species of the genus Sectonema, namely S. demani, S. heynsi and S. macrospiculum, originally described by E. Altherr, are re-described on the basis of type material. Detailed descriptions, morphometrics and illustrations, including line drawings and/or LM pictures, diagnoses and remarks about their identity and later reports are provided for each species. Sectonema demani is characterized by its 6.78-7.24 mm long body, lip region 27-28 um broad, mural tooth 19-20 um long at its ventral side, pharyngeal expansion 834-875 um long or 68-69% of total neck length, uterus a simple tube-like structure 2.1-2.2 times the corresponding body diameter, V = 49-52, tail short and rounded conoid (51-55 um, c = 123-143, c' = 0.7-0.8), and male unknown. Sectonema heynsi is distinguished by its body 6.45 mm long, lip region 28 MUm broad, circumoral area bearing cilia- or seta-like structures, mural tooth-like structure 20 MUm long, pharyngeal expansion 856 MUm long or 68% of total neck length, uterus a tube-like structure ?1.7 times the corresponding body diameter, V = 50, tail short and rounded to conoid (54 MUm, c = 120, c' = 0.7), and male unknown. And S. macrospiculum is characterized by its 4.07-5.06 mm long body, lip region 27-28 MUm broad, ventral side of the odontostyle 15 MUm long, pharyngeal expansion 555 640 MUm long or 67-68% of total neck length, uterus a simple tube-like structure 1.9-2.1 times the corresponding body diameter, V = 53, female tail short and convex conoid with rounded terminus (62 MUm, c = 82, c' = 0.7), male tail more conoid than that of female and with the ventral side visibly more straight (58 MUm, c = 71, c' = 0.8), spicules 107 MUm long, and eight irregularly spaced ventromedian supplements bearing hiatus. PMID- 25543621 TI - Two new species of fanged frogs from Peninsular Malaysia (Anura: Dicroglossidae). AB - Taxonomic status of fanged frogs from the Peninsular Malaysia, previously assigned to Limnonectes kuhlii, is assessed using genetic and morphological approaches. Phylogenetic relationships inferred from sequences of the mitochondrial and nuclear genes revealed that the fanged frogs from the Peninsula form a monophyletic group and are clearly divergent from other species previously, or even now, assigned to L. kuhlii from Mainland Southeast Asia. In both mtDNA and nuDNA phylogeny, the Malay Peninsula clade diverges into two lineages, one from north (Larut Hill, Perak, and Hulu Terengganu, Terengganu) and another from south (Genting Highlands, Pahang, and Gombak, Selangor). These lineages are separated by large genetic distances, comparable with those observed between some other species of L. kuhlii-like frogs. Although the two lineages are very similar morphologically, they are distinguishable in several morphological traits and are considered heterospecific. We therefore describe them as L. utara sp. nov. and L. selatan sp. nov. These new species differ from all other species of kuhlii-like frogs from Mainland Southeast Asia by the surface of tibia, which is densely covered by large warts. PMID- 25543622 TI - Pseudoceros astrorum, a new species of Polycladida (Cotylea, Pseudocerotidae) from Northeastern Brazil. AB - Pseudoceros astrorum n. sp. is characterized by a smooth dorsal surface with a brown ground colour, and with net-like pattern of small black granules, white spots of different sizes uniformly distributed, a thin black sub-marginal band, and a white marginal rim. The pseudotentacles are dark brown with white tips and the anterior margin and cerebral region is devoid of pigmentation. The male system is characterised by conspicuous spermiducal bulbs, a conical curved penis stylet, and the sucker lies more or less posterior. With this contribution, the number of known species from Brazil is now 72, and has created new interest in the lesser-known polyclad fauna from the northeast coast of Brazil. PMID- 25543623 TI - First record of Lucilia bufonivora Moniez, 1876 (Diptera: Calliphoridae) from North America and key to North American species of the L. bufonivora species group. AB - The obligate anuran myiasis blow fly Lucilia bufonivora Moniez is reported from North America for the first time. The L. bufonivora species group is defined on the basis of the aedeagus and the history and biology of the North American species (L. bufonivora, L. elongata Shannon and L. silvarum (Meigen)) are discussed. A key is provided to separate the three North American species of this group. The North American species L. thatuna Shannon, a member of the L. sericata (Meigen) species group, is also treated because it is likely a parasite of anurans and is poorly known. The male abdominal sternites, aedeagus (L. elongata only), pregonites, postgonites, bacilliform sclerites, ejaculatory sclerites, and female ovipositors and spermathecae of L. elongata and L. thatuna are illustrated for the first time. PMID- 25543624 TI - Sabellaria and Lygdamis (Polychaeta: Sabellariidae) from reefs off northeastern Brazil including a new species of Sabellaria. AB - Members of the polychaete taxon Sabellariidae Johnston, 1865 are known to live in sand tubes cemented onto rocky substrata, mollusk shells, or sea grasses. Of 37 known Sabellaria species, only nine were reported for the Brazilian coast, in all cases being associated with aggregates of other species. The genus is considered cosmopolitan. Herein we describe for the first time an aggregate of sabellariids composed by Sabellaria nanella and Sabellaria wilsoni. In addition, we describe a new species of Sabellaria. Lygdamis are represented by solitary species. None of the 17 known species were previously reported from the southwestern Atlantic Ocean. We report Lygdamis rayrobertsi for the first time in the South Atlantic. PMID- 25543625 TI - Korean species of the genus Perlomyia Banks, 1906 (Plecoptera: Leuctridae). AB - Eight species of the genus Perlomyia (Plecoptera: Leuctridae) are reported from Korea, six are new records for the Korean Peninsula. Two species, known only as unassociated females are described under informal unnamed designations. Previous Korean records are discussed, taxonomic characters of the Korean specimens and Korean distribution are presented for these species. Zoogeographic notes on the Asian Perlomyia are also given. PMID- 25543626 TI - Musserakis sulawesiensis gen. et sp. n. (Nematoda: Heterakidae) collected from Echiothrix centrosa (Rodentia: Muridae), an old endemic rat of Sulawesi, Indonesia. AB - Musserakis sulawesiensis gen. et sp. n. (Nematoda: Heterakidae) is described from the large-bodied shrew rat, Echiothrix centrosa, one of the old endemic rats of Sulawesi, Indonesia. Musserakis is readily distinguished from other heterakid genera by having non-recurrent and non-anastomosing cephalic cordons, by lacking papillae between papillae groups around precloacal sucker and cloacal aperture and by lacking teeth in the pharyngeal portion. The spicules are equal but with marked dimorphism among individuals. Heterakids collected from other old endemic murids examined, i.e., Crunomys celebensis, Tateomys macrocercus and Tateomys rhinogradoides, and the new endemic rats of Sulawesi, were Heterakis spumosa Schneider, 1866, a cosmopolitan nematode of various murids. It is suggested that M. sulawesiensis is specific to Echiothrix. PMID- 25543627 TI - A new species of Forcipomyia Meigen (Diptera: Ceratopogonidae) described with immature stages from India. AB - Life stages of Forcipomyia parasecuris sp. n. is described, illustrated and photomicrograph based on examination with scanning electron microscope and binocular microscope. The larvae were collected from rotting banana stump of a banana garden at lower Gangetic plain area in India. Absence of ocular sensillum and campaniform sensillum in ocular area of pupa, a synapomorphic character of this proposed new species exhibits its uniqueness in genus Forcipomyia. This is also the first life stage of any Forcipomyia described from India. PMID- 25543628 TI - Illustrated checklist of mileewine leafhoppers (Hemiptera: Cicadellidae: Mileewinae) of China, with descriptions of four new species. AB - Four new species of Mileewini, Mileewa houhensis Yang, Meng & He, sp. nov., M. xiaofeiae Yang, Meng & He, sp. nov., M. yangi Yang, Meng & He, sp. nov. and Ujna liangae Yang, Meng & He, sp. nov. are described and illustrated. Mileewa nigricauda Yang & Li, 1999 is placed as a junior synonym of M. dorsimaculata (Melichar, 1902); three of the previously described Chinese Mileewa are transferred to the genus Ujna. These are Ujna harpa (Yang & Li, 2004) comb. nov., U. nigrimaculata (Yang & Li, 2004) comb. nov., and U. puerana (Yang & Meng, 2010) comb. nov. M. lynchi (Distant, 1918) is recorded as new for China. A checklist of Mileewini leafhoppers of China along with photograph of their dorsal habitus is provided. PMID- 25543629 TI - A new species of porcelain crab, Petrolisthes tuerkayi n. sp. (Crustacea: Anomura: Porcellanidae), from the Persian Gulf. AB - A new species of porcellanid crab, Petrolisthes tuerkayi n. sp., is described from the Persian Gulf. The new species is closely related to P. rufescens Heller, 1861, but is easily distinguishable by having three or four large spines distally on the posterior margin of the carpus of chelipeds, whereas the posterior margin of the cheliped merus in P. rufescens is unarmed. PMID- 25543630 TI - The breeding behaviour, advertisement call and tadpole of Limnonectes dabanus (Anura: Dicroglossidae). AB - Fanged frogs (Limnonectes) are a group of dicroglossid frogs from Asia that often have reversed sexual dimorphism with larger males. Limnonectes dabanus is a poorly known species of fanged frog from forested habitats in southern Vietnam and eastern Cambodia. Adult males exhibit an extreme degree of megacephaly and possess bizarre head ornamentation. L. dabanus breeds in shallow, non-flowing or very slow-flowing pools, puddles, and drainage ditches. Eggs are laid as a widely spaced array, and the larvae have a morphology typical of pond-dwelling tadpoles. Although males of the species lack vocal sacs, they produce a low-pitched (0.4 0.6 kHz), single-note advertisement call that sounds like a drop of water falling into water. Given the spacing of calling males, presence of multiple females near breeding sites, and reversed sexual dimorphism, the mating system of L. dabanus may be an example of resource-defense polygyny, and the massive head of the male is likely used in male combat. PMID- 25543631 TI - Integrative taxonomy and phylogeny-based species delimitation of Philippine water monitor lizards (Varanus salvator Complex) with descriptions of two new cryptic species. AB - We describe two new species of morphologically cryptic monitor lizards (genus Varanus) from the Philippine Archipelago: Varanus dalubhasa sp. nov. and V. bangonorum sp. nov. These two distinct evolutionary lineages are members of the V. salvator species complex, and historically have been considered conspecific with the widespread, northern Philippine V. marmoratus. However, the new species each share closer phylogenetic affinities with V. nuchalis (and potentially V. palawanensis), than either does to one another or to V. marmoratus. Divergent from other recognized species within the V. salvator Complex of water monitors by as much as 3.5% pairwise genetic distance, these lineages are also distinguished by unique gular coloration, metrics of body size and scalation, their non monophyly with "true" V. marmoratus, and insular allopatric distributions, suggesting biogeographically distinct and unique evolutionary histories. We compare the new species with the most geographically proximate and phenotypically relevant lineages. Although we show that these new taxa are nearly indistinguishable morphologically from V. marmoratus, both species can be readily distinguished from their closest relatives (each's respective sister taxon, V. palawanensis and V. nuchalis) by traditional morphological characters. Our findings underscore the high herpetological diversity and biogeographical complexity of vertebrates in the Philippines, and further emphasize the need for detailed study of species-level diversity, mechanisms of reproductive isolation, gene flow, and biologically relevant boundaries between taxa within the V. salvator Complex. PMID- 25543632 TI - Simulium ledangense, a new species of the Simulium feuerborni species-group of the subgenus Nevermannia (Diptera: Simuliidae) from Mount Ledang, Peninsular Malaysia. AB - Simulium (Nevermannia) ledangense sp. nov. is described from females, males, pupae and mature larvae from Peninsular Malaysia. This new species is assigned to the Simulium feuerborni species-group of the subgenus Nevermannia, and is characterized by the pupa having a very long stalk of the ventral paired gill filaments, which is almost five times longer than the interspiracular trunk and female tergites of segments 2 and 5 to 7 shiny. Taxonomic notes are given to distinguish this new species from three known species of the S. feuerborni species-group from Malaysia. PMID- 25543633 TI - A new Australian genus and five new species of Rogadinae (Hymenoptera: Braconidae), one reared as a gregarious endoparasitoid of an unidentified limacodid (Lepidoptera) . AB - Teresirogas Quicke & Shaw gen. nov. (type species T. australicolorus Quicke & Shaw sp. nov.) is described and illustrated, based on a series recently reared gregariously from a cocooned mummy of an unidentified species of Limacodidae collected under loose Eucalyptus bark in New South Wales, Australia. Older reared and unreared congeneric specimens represent four additional species, T. billbrysoni Quicke & van Achterberg sp. nov., T. nolandi Quicke & Butcher sp. nov., T. prestonae Quicke & van Achterberg sp. nov., and T. williamsi Quicke & van Achterberg sp. nov., which are also described and illustrated. Three of these additional species have also been reared from Limacodidae cocoons on Eucalyptus, with one, perhaps erroneous, record suggesting a saturniid host. Molecular analysis confirms the placement of the new type species of Teresirogas in the tribe Rogadini, as inferred initially from the claws with pointed basal lobe and host relationships of some of the species, but one species has the claw character poorly developed which had made its affinities uncertain before the more recently reared and sequenceable material became available. PMID- 25543634 TI - Four new species of Cichlidogyrus (Monogenea, Ancyrocephalidae) from Sarotherodon mvogoi and Tylochromis sudanensis (Teleostei, Cichlidae) in Cameroon. AB - The four Cichlidogyrus species (Monogenea, Ancyrocephalidae) found on the gills of Sarotherodon mvogoi and Tylochromis sudanensis (Teleostei, Cichlidae) in Cameroon are considered new and are described herein. Cichlidogyrus mvogoi n. sp. from Sarotherodon mvogoi, characterised by a long (> 100 um), thin and spirally coiled penis and a short marginal hook pair I. Cichlidogyrus sigmocirrus n. sp. from Tylochromis sudanensis, characterised by a short marginal hook pair I, a slightly spirally coiled penis with reduced heel, an accessory piece being a spirally coiled band wrapped round the penis and attached to the penis basal bulb by a very thin filament. Cichlidogyrus chrysopiformis n. sp. from Tylochromis sudanensis, characterised by an marginal hook pair I of medium size, a thin spirally coiled penis (1.5 turn) with a developed flared heel, an accessory piece being a large gutter shaped band, ending in a narrow complex extremity, and linked to the basal bulb of the penis by a very thin filament, a short, straight and slightly ringed vagina. Cichlidogyrus djietoi n. sp. from Tylochromis sudanensis, characterised by a slightly spirally coiled penis (2 turns) with developed heel, an accessory piece being a large gutter shaped band, ending in a narrow folded back extremity, a short funnel shaped vagina. The three latter species are also remarkable by the morphology of their auricles implanted on the anterior side of the dorsal transverse bar which make them (together with the other species described from Tylochromis hosts) a homogeneous and original group within Cichlidogyrus, this distinctive feature seems to be ancestral compared to other Cichlidogyrus species. PMID- 25543635 TI - Two new troglobitic Newportia (Newportia) from Brazil (Chilopoda: Scolopendromorpha). AB - Newportia (Newportia) spelaea n. sp. and Newportia (N.) potiguar n. sp. are here described from Bahia and Rio Grande do Norte State, respectively. These two species show highly troglomorphic traits, such as elongation of antennae, legs, ultimate legs, tergites, pronounced depigmentation and reduced sclerotization of the cuticle. Both species occur in caves located in a semi-arid biome (Caatinga) and can be considered troglobites. PMID- 25543636 TI - The maculosus group of the genus Celaenorrhinus Hubner, 1819 from China, with discovery of female C. kuznetsovi Devyatkin, 2000 (Lepidoptera: Hesperiidae: Pyrginae). AB - The maculosus group of the genus Celaenorrhinus from China is reviewed, in which 7 species are treated. Taiwanese maculosus taiwanus is reinstated to full species rank. The hitherto unknown female of C. kuznetsovi, as well as the female genitalia of C. maculosus and C. major are described. Adults and genitalia are illustrated, and a brief description of each species is given. A Key to the Chinese species of the maculosus group is provided. PMID- 25543637 TI - A new species of Euptychia Hubner, 1818 (Lepidoptera: Nymphalidae: Satyrinae: Satyrini) from Mount Roraima, Guyana. AB - A new nymphalid species in the subtribe Euptychiina, Euptychia roraima Nakahara, Fratello & Harvey n. sp., is described from Mount Roraima, Guyana. Both internal and external morphology of E. roraima are compared against several Euptychia species and the relationship between E. roraima and congeners is briefly discussed. A strong case is put forth for further and extensive exploration of the Pantepui region concerning its poorly known butterfly fauna. PMID- 25543638 TI - Revision of the genus Metallesthes Kraatz and description of Metallesthes anneliesae, a new species of Cetoniinae (Coleoptera: Scarabaeidae) from Queensland and New South Wales, Australia. AB - The endemic Australian flower chafer genus Metallesthes Kraatz, 1880 (Coleoptera: Scarabaeidae: Cetoniinae) is revised. Metallesthes anneliesae Moeseneder & Hutchinson new species is described from southern Queensland and New South Wales. Metallesthes unicolor (Macleay, 1863) revised status is raised from synonymy with Metallesthes metallescens (White, 1859). Metallesthes metallescens and Metallesthes unicolor are redescribed and their holotypes are figured. A specimen bearing a Nonfried type label is designated as the lectotype of Metallesthes subpilosa Nonfried, 1891. Metallesthes subpilosa new synonymy is synonymised with Pseudoclithria ruficornis (Westwood, 1874). A key to the species of the genus is provided. Distribution maps are shown and known host plants are listed. PMID- 25543639 TI - A new species of the cardinalfish genus Siphamia (Perciformes, Apogonidae) from West Papua, Indonesia. AB - A new species of the cardinalfish genus Siphamia is described from specimens collected in the Province of West Papua, Indonesia, at depths of 50-72 m. Siphamia papuensis n. sp. has a striated light organ which makes it a member of the S. tubifer species group. Within this group it is closely related to S. argentea, sharing with the latter 13 pectoral-fin rays, 9 developed gill rakers and an irregular pattern of yellowish green bars on the body. It differs from S. argentea in having an incomplete lateral line and in lacking dark marks on the head, and at the origin and end of the dorsal-fin and anal-fin bases, as well as the absence of red spots along the light organ and along the back. Japanese records of S. tubulata are reidentified as S. argentea, and new locality records for S. argentea and S. stenotes are reported. Analysis of sequence data from a 16S rDNA fragment revealed the clear separation of S. papuensis n. sp., S. argentea and other included Siphamia species (S. jebbi, S. tubifer and S. stenotes). PMID- 25543640 TI - A new "Bat-Voiced" species of Dendropsophus Fitzinger, 1843 (Anura, Hylidae) from the Amazon Basin, Brazil. AB - We describe Dendropsophus ozzyi sp. nov., a new species of treefrog, tentatively included in the Dendropsophus microcephalus Group and most notably diagnosed by the presence of pointed fingers and an advertisement call with a very high dominant frequency. The new species is known from three localities in the Brazilian Amazon forest, two on western State of Para and one (the type locality) in eastern State of Amazonas (03 degrees 56'50"S and 58 degrees 26'36"W, 45 m a.s.l.). PMID- 25543641 TI - Description of the second and third instars of Aspidytes wrasei Balke, Ribera & Beutel, 2003, with comments on the identification of larvae of Aspidytes Ribera, Beutel, Balke & Vogler, 2002 (Coleoptera: Aspidytidae), and phylogenetic considerations. AB - The second- and third instar larvae of the cliff water beetle Aspidytes wrasei Balke, Ribera & Beutel, 2003 are studied for the first time with special emphasis on morphometry and chaetotaxy. A review of the characters useful in the identification of larvae of Aspidytes Ribera, Beutel, Balke & Vogler, 2002 is presented. Confirming previous findings, larvae of this genus are unique within Hydradephaga in the dorsally oriented spiracles on the abdominal segment VIII of instars II and III. The inclusion of Aspidytidae within the superfamily Dytiscoidea is reinforced by the following putative synapomorphies: presence of pore PAp, proximal insertion of pore ANg, apical or subapical insertion of seta MX8, presence of pore LAd, and distal insertion of seta CO6. Larvae of A. wrasei differ from those of A. niobe Ribera, Beutel, Balke & Vogler, 2002 in several significant characters that may indicate that both species have a long history of independent evolution. PMID- 25543642 TI - Horabagrus melanosoma: a junior synonym of Horabagrus brachysoma (Teleostei: Horabagridae). AB - Horabagrus melanosoma was described from West Venpala in the lower reaches of the Manimala River, in the state of Kerala, India. It was distinguished from its nearest congener, H. brachysoma based on a combination of characters including darker body colour, shorter pelvic fin and greater number of anal fin rays. Examination of the type material revealed significant morphometric and meristic discrepancies with the original description. Based on multivariate morphometric, and genetic analysis of topotypical specimens, we propose that H. melanosoma should be treated as a junior synonym of H. brachysoma. PMID- 25543643 TI - Discovery of the twisted-wing parasite family Myrmecolacidae (Insecta: Strepsiptera) from China, with description of two new species of the genus Myrmecolax Westwood, 1861. AB - The twisted-wing parasite family Myrmecolacidae is recorded from China for the first time based on the discovery of the genus Myrmecolax Saunders. Two species of Myrmecolax are described as new to science, Myrmecolax pachygnathus sp. nov. and Myrmecolax arcuatus sp. nov.. PMID- 25543644 TI - A new species of Zonana DeLong & Freytag (Hemiptera: Cicadellidae: Iassinae: Gyponini) from Peru with a key to species of the genus. AB - A new species of the genus Zonana DeLong & Freytag, 1963 from Peru is described and illustrated: Z. petalacea sp. nov. This species is easily distinguished from other species of the genus by its peculiar aedeagus with a pair of slender ventral processes and a unique flattened petal-shaped dorsal process. A taxonomic key to the now four known species of Zonana is provided. PMID- 25543645 TI - New species of Pheretima (Oligochaeta: Megascolecidae) from the Mt. Malindang Range, Mindanao Island, Philippines. AB - We provide descriptions, with illustrations of internal structures, for 18 new species of Pheretima from Mt. Malindang, Misamis Occidental Province, Mindanao Island, Philippines. Among the 18 species, 11 belong to the P. sangirensis species group, characterized by having a pair of spermathecal pores in the intersegmental furrow of 7/8 and lacking penial sheaths in the copulatory bursae: P. maculodorsalis n. sp., P. tigris n. sp., P. immanis n. sp., P. lago n. sp., P. nunezae n. sp., P. boniaoi n. sp., P. malindangensis n. sp., P. misamisensis n. sp., P. wati n. sp., P. longiprostata n. sp., and P. nolani n. sp. One species, P. longigula n. sp., belongs to the P. montana species group, characterized by having a pair of spermathecal pores in the intersegmental furrow of 7/8 and penial sheaths in the copulatory bursae. Two species, P. vergrandis n. sp. and P. concepcionensis n. sp., are monothecal. Three species, P. adevai n. sp., P. lluchi n. sp., and P. potonganensis n. sp., belong to the P. darnleiensis species group, characterized by having either four or five pairs of spermathecae from vi to ix, with a fifth pair variably present in segment v. One species, P. subanensis n. sp., is athecate. All species described here from the Mt. Malindang Range are probably native rather than introduced, and probably do not represent range extensions of species known from neighboring islands in Southeast Asia. We provide an identification key to the Pheretima species from Mt. Malindang. PMID- 25543647 TI - Anostracan (Crustacea: Branchiopoda) zoogeography III. Australian bioregions . AB - Anostracan bioregions were identified for Australia. These regions were quantitatively defined using species distributions compared through Jaccard's Coefficient of Community Similarity, and qualitatively defined using regional soils data. Community assemblages are quantified using Fager's Index of Recurring Species Groups. Substrate geochemistry was used to investigate additional relationships, but was limited by the constraints of available data. However, the highly salinized soils directly relate to Australia bearing the highest diversity of halophilic anostracan taxa. Three anostracan biogeographical regions are defined for Australia: Western, Eastern and Southern. PMID- 25543646 TI - New species and new record of hadzioids (Amphipoda: Senticaudata, Hadzioidea) from the Persian Gulf, Iran. AB - New record and new species of the families Melitidae Bousfield, 1973 and Maeridae Krapp-Schickel, 2008 are described from the Iranian shorelines of the Persian Gulf. Melita persia sp. nov. is differentiated from other members of M. zeylanica Stebbing, 1904 group by: the presence of two setae on inner ramus of third uropod, the setal arrangement on the telson, and a recurved proximal lobe of sixth coxa in females. Also, Elasmopus menurte Barnard, 1974 previously described from Western Australia and Mauritius is recorded, for the first time, from Persian Gulf in the north-western Indian Ocean. PMID- 25543648 TI - Heterodera guangdongensis n. sp. (Nematoda: Heteroderinae) from bamboo in Guangdong Province, China--a new cyst nematode in the Cyperi group. AB - Heterodera guangdongensis n. sp. is described from bamboo (Phyllostachys pubescens Mazel) based on morphology and molecular analyses of rRNA D2D3 expansion domains of large subunit (LSU D2D3) and internal transcribed spacer (ITS) sequences. This new species can be classified in the Cyperi group. Cysts are characterized by a prominent, ambifenestrate vulval cone with weak underbridge, a vulva-anus distance of 28.9-35.9 MUm and a vulval slit of 31.1 41.0 MUm, but without bullae. Females are characterized by a 25.1-27.6 MUm stylet with rounded knobs sloping slightly posteriorly. Males are characterized by a 21.5-23.0 MUm stylet with knobs slightly projecting or flat anteriorly, lateral field with four lines, and a 22.0-26.0 MUm spicule with bifurcate tip. Second stage juveniles are characterized by a 19.3-21.3 stylet with slightly projecting or anteriorly flattened knobs, lateral field with three lines, a 41.7-61.3 MUm tail with finely rounded terminus and hyaline portion forming 43.0-57.1% of the tail length. Molecular analyses show that the species has unique D2D3 and ITS rRNA sequences and RFLP-ITS-rRNA profiles. PMID- 25543649 TI - A new species of Parapinnanema (Nematoda, Chromadoridae) from Dr Theodor Mortensen's Pacific Expedition 1914-16 with an identification key to the genus. AB - A new species from the family Chromadoridae is described from samples collected during Dr Mortensen's Pacific Expedition 1914-16 to Honolulu, Hawaii. Parapinnanema hawaiiensis sp. nov. is characterized by a low c' ratio and especially by a peculiar complex morphology of the median part of the gubernaculum. An updated and modified key to all the valid species of Parapinnanema is proposed. PMID- 25543650 TI - Two new species of Coryogalops (Perciformes: Gobiidae) from the Red Sea . AB - Two new species of the gobiid genus Coryogalops, C. guttatus sp. nov. and C. pseudomonospilus sp. nov., are described from the Red Sea. Coryogalops guttatus sp. nov. is distinguished from its congeners by having dorsal-fin rays VI + I,12; anal-fin rays I,10-11; pectoral-fin rays 17, three upper rays with free tips; pelvic fins I,5, joined to form a disc, weakly emarginate, with pelvic frenum reduced; longitudinal scale series 33-35; transverse scale rows 9-10; circumpeduncular scales 10-11; seven transverse suborbital rows of sensory papillae on cheek; no tentacle above upper eye margin; anterior nostril tubular, with triangular lappet extending from posterior rim, posterior nostril slightly raised; dark orange spots on many of the scales below body midline form a longitudinal pattern, each spot covering one scale; two distinct dark spots behind edge of preopercle, and similar pair of spots at pectoral-fin base. Coryogalops pseudomonospilus sp. nov. is distinguished from congeners by having dorsal-fin rays VI + I,11; anal-fin rays I,10; pectoral-fin rays 16-17, two upper rays with free tips; pelvic fins I,5, joined to form a disc, moderately emarginate, with pelvic frenum well-developed; longitudinal scale series 33-35; transverse scales rows 9; circumpeduncular scales 12; seven transverse suborbital rows of sensory papillae on cheek; no tentacle above upper eye margin; anterior nostril tubular, without lappet from posterior rim, posterior nostril slightly raised; and irregular dark maroon mark covering lower part of the first three membranes between spines of first dorsal fin. The distribution of species restricted to the western Indian Ocean is discussed, and a key to the species of the genus is provided. PMID- 25543651 TI - The phylogenetic position and taxonomic status of the Rainbow Tree Snake Gonyophis margaritatus (Peters, 1871) (Squamata: Colubridae) . AB - Molecular phylogenies have provided strong evidence for clarifying the taxonomy of groups with ambiguous morphological traits, thus avoiding potentially misleading conclusions based on evolutionary convergence of these traits. For snakes, established molecular databases along with new sequences from rare species allows us to estimate phylogenies, to clarify the phylogenetic relationships and test the monophyly of most taxonomic groups. Using one mitochondrial gene and five nuclear loci, we evaluate the taxonomic status of a rare Southeast Asian serpent, the Rainbow Tree Snake Gonyophis margaritatus (Squamata: Colubridae) by inferring a molecular phylogeny of 101 snake species. Both maximum likelihood and time- calibrated Bayesian inference phylogenies demonstrate that G. margaritatus is sister to Rhadinophis prasinus, previously considered to be part of a radiation of Old World ratsnakes. This group is in turn sister to a group containing Rhadinophis frenatus and Rhynchophis boulengeri with the entire clade originating in the mid-Miocene (~16 Ma) in Southeast Asia. This group is sister to the genus Gonyosoma and together originated in the early Miocene (~20 Ma). We discuss three potential solutions towards eliminating polyphyly of the genus Rhadinophis, but recommend using the genus name Gonyosoma for all species within this clade, which currently contains all of the species within the genera Gonyosoma, Gonyophis, Rhadinophis, and Rhynchophis. PMID- 25543652 TI - New species of Hercostomus baishanzuensis group from Tibet (Diptera: Dolichopodidae, Dolichopodinae). AB - Previously only ten species of Hercostomus Loew were known to occur in Tibet, of which only two belong to the H. baishanzuensis group. Here the following six species of the H. baishanzuensis group are described as new to science: Hercostomus bisetus sp. nov., H. deltodontus sp. nov., H. flavus sp. nov., H. galonglaensis sp. nov., H. nuciformis sp. nov. and H. pailongensis sp. nov. A key to the species of the H. baishanzuensis group from Tibet is provided. PMID- 25543653 TI - A new species of Chironius Fitzinger, 1826 from the state of Bahia, Northeastern Brazil (Serpentes: Colubridae). AB - We describe a new species of Chironius Fitzinger, 1826 from the highlands of Chapada Diamantina, state of Bahia, Brazil. The new species is distinguished from all currently recognized congeners by a unique combination of states of characters on coloration, scale counts, scale ornamentation, and hemipenis. The new species closely resembles Chironius flavolineatus (Jan, 1863) in color pattern, but differs from the later taxon by the presence of two to four posterior temporal scales; cloacal shield entire; six to ten rows of keeled dorsal scales at midbody; ventral scales with posterior dark edges forming conspicuous transverse bars along almost the entire venter; conspicuous dark longitudinal stripes (in "zigzag") in the midventral portion of subcaudals; region of medial constriction of hemipenis slightly covered with spinules separating calyces of apex from spines below region of constriction; and sulcus spermaticus situated on convex face of hemipenis in lateral view. The new species is apparently restricted to Chapada Diamantina, corroborating the biological importance of this region from a conservational perspective. PMID- 25543654 TI - Aradidae from Vietnam IV. Review of the Oriental flat bug genus Lissonotocoris Usinger & Matsuda, 1959 (Hemiptera: Heteroptera: Aradidae). AB - To date, only the type species Lissonotocoris membranaceus Usinger & Matsuda 1959 is known and recorded from Vietnam and China, Hainan Island. Four new species of the previously monotypic genus Lissonotocoris are described and figured: loebli n.sp. (Thailand), glabronotus n.sp. (N.Vietnam), pachycerus n.sp. (Malaysia) and siamensis n.sp. (Thailand). A key for the identification of all 5 species is provided. PMID- 25543655 TI - The immatures of Culicoides lacustris Ronderos (Diptera: Ceratopogonidae). AB - Larva and pupa of the Patagonian species Culicoides lacustris Ronderos are described in detail with phase-contrast microscope at oil immersion and scanning electron microscope. Studied specimens were collected in a wetland, alongside to the Provincial Route 12, between the cities of Esquel and Gualjaina in the Chubut Province. They are compared with the more similar congener, Culicoides venezuelensis Ortiz & Mirsa. PMID- 25543656 TI - A second discovery of Diapontonia maranulus Bruce, 1986 (Crustacea: Decapoda: Palaemonidae) in the Caribbean. AB - A second discovery of the echinoid associated shrimp species Diapontonia maranulus Bruce, 1986 is recorded from deep water off Curacao, Leeward Islands of the Dutch Caribbean. The material is compared with the type description and paratypic material as well as with material of closely related species. A mtDNA COI barcode was obtained from the material. The systematic position of the genus is discussed. PMID- 25543657 TI - Description of Pella sichuanensis sp. n. (Coleoptera: Staphylinidae: Aleocharinae) from Micang Mountain, Sichuan, China. AB - Pella sichuanensis Zheng & Zhao, sp. n. of the P. cognata group is described, illustrated, and distinguished from similar congeners. PMID- 25543659 TI - Colonic tuberculosis mimicking Crohn's disease: an exceptional cause of massive surgical rectal bleeding. PMID- 25543660 TI - Hydrophilic polymer embolism and associated vasculopathy of the lung: prevalence in a retrospective autopsy study. AB - Hydrophilic polymers are commonly applied as surface coatings on vascular devices and have been shown to dissociate during endovascular use, causing hydrophilic polymer embolism (HPE). Adverse effects related to this phenomenon have been recognized and reported. The prevalence of this complication is unknown. We conducted a retrospective study to determine the prevalence of HPE among hospital autopsies over a 29-month period. Postmortem tissue was histologically evaluated for the presence, location(s) and extent of HPE. HPE findings were correlated with documented clinical and laboratory data and patient outcome. Of 136 hospital autopsies examined, 18 (13%) showed evidence of HPE involving the lungs (n = 18), heart (n = 1) or central nervous system (n = 1). Localized pulmonary HPE was seen in 12 patients (9%). Multifocal pulmonary HPE was found in 6 patients (4%) and was associated with clinical vasculitis (33%; P < .0001), suspected pulmonary ischemia (50%; P = .008), coagulopathy (67%; P = .002), and constitutional disease (83%; P = .01). Within affected lung, associated histopathologic changes included occlusive intravascular or perivascular inflammation (89%), intravascular fibrous response (56%), microthrombus formation (44%), vasculitis (28%), and/or pulmonary microinfarction (28%). Statistically significant differences in hospital days (P = .008) and number of vascular interventions (P = .01) were noted between affected and unaffected patients. We conclude that HPE is an underdiagnosed phenomenon with primary involvement of the lungs, where secondary vascular changes are common. Additional studies may be needed to clarify risks and to identify preventative strategies for this iatrogenic complication of catheterizations and "minimally invasive" endovascular techniques. PMID- 25543661 TI - Low intensity pulse ultrasound stimulate chondrocytes growth in a 3-D alginate scaffold through improved porosity and permeability. AB - A 3-D scaffold culture system has been used to promote in producing functional chondrocytes for repairing damaged cartilage. In the present study, the low intensity pulse ultrasound (LIPUS) (P(-)=0, 0.055, 0.085 and 0.11 MPa) was applied to improve the porosity and permeability of a 3-D alginate scaffold which was beneficial for the nutrition supply and metabolism during cell growth in 3-D alginate scaffold. The porosity and permeability of the scaffold was quantitatively analyzed based on scanning electron microscopy examination and fluorescence image observation. The results suggest that, for the scaffold exposed to LIPUS, its porosity and permeability could be significantly enhanced by the increasing LIPUS amplitude, which might be induced by the microstreaming shear stress generated by ultrasound-driven microbubble oscillations. Furthermore, the assessments of cell proliferation and collagen II expression confirmed that chondrocytes growth could be effectively promoted in 3-D alginate scaffolds treated by LIPUS, because of the improved scaffold porosity and permeability might benefit cell growth space and nutrition supply. It should also be noticed that appropriate LIPUS driving parameters should be adapted to achieve optimized chondrocytes culture effect in 3-D alginate scaffold. PMID- 25543662 TI - Individual macromolecule motion in a crowded living cell. AB - The application of the general model of the law of mass action itself, of the achievement of dynamic, statistical equilibria, has led to great successes in describing the theory of single-molecule biophysics and biochemistry based on individually and freely diffusing molecules in dilute liquid and crowded living cells. For example, anomalous diffusion is a general phenomenon in living cells. There is solid evidence for analyzing fluorescence correlation and dual color fluorescence crosscorrelation spectroscopy data (FCS and dual color FCCS) in cellular applications by equations based on anomalous subdiffusion. Using equations based on normal diffusion causes artifacts of the fitted biological system response parameters and of the interpretations of the FCS and dual color FCCS data in the crowded environment of living cells. Equations based on normal diffusion are not valid in living cells. The original article embraces the status of the experimental situation and touches obstacles that still hinder the applications of single molecules in the cellular environment. PMID- 25543663 TI - Novel synthetic pharmacophores inducing a stabilization of cellular microtubules. AB - Microtubule drugs have been widely used in cancer chemotherapies. Although microtubules are subject to regulation by signal transduction mechanisms, their pharmacological modulation has so far relied on compounds that bind to the tubulin subunit. Using a cell-based assay designed to probe the microtubule polymerization status, we identified two pharmacophores, CM09 and CM10, as cell permeable microtubule stabilizing agents. These synthetic compounds do not affect the assembly state of purified microtubules in vitro but they profoundly suppress microtubule dynamics in vivo. Moreover, they exert cytotoxic effects on several cancer cell lines including multidrug resistant cell lines. Therefore, these classes of compounds represent novel attractive leads for cancer chemotherapy. PMID- 25543665 TI - Epidemic characteristics and spatio-temporal patterns of scrub typhus during 2006 2013 in Tai'an, Northern China. AB - Tai'an, a famous cultural tourist district, is a new endemic foci of scrub typhus in northern China. Frequent reports of travel-acquired cases and absence of effective vaccine indicated a significant health problem of scrub typhus in Tai'an. Thus, descriptive epidemiological methods and spatial-temporal scan statistics were used to describe the epidemic characteristics and detect the significant clusters of the high incidence of scrub typhus at the town level in Tai'an. Results of descriptive epidemiological analysis showed a total of 490 cases were reported in Tai'an with the annual average incidence ranging from 0.48 to 2.27/100 000 during 2006-2013. Females, the elderly and farmers are the high risk groups. Monthly changes of scrub typhus cases indicated an obvious epidemic period in autumn. Spatial-temporal distribution analysis, showed significant clusters of high incidence mainly located in eastern and northern Tai'an. Our study suggests that more effective, targeted measures for local residents should be implemented in the eastern and northern areas of Tai'an in autumn. Meanwhile, it may prove beneficial for health policy makers to advise travellers to take preventive measures in order to minimize the risk of infection of scrub typhus in Tai'an. PMID- 25543664 TI - Clinical evaluation of CEA, CA19-9, CA72-4 and CA125 in gastric cancer patients with neoadjuvant chemotherapy. AB - BACKGROUND: In the clinical practice of neoadjuvant chemotherapy, response markers are very important. We aimed o investigate whether tumor markers CEA(carcino-embryonic antigen), CA19-9(carbohydrate antigen 19-9), CA72 4(carbohydrate antigen 72-4), and CA125(carbohydrate antigen 125) can be used to evaluate the response to neoadjuvant chemotherapy, and to evaluate the diagnosis and prognosis value of four tumor markers in the patients of gastric cancer. METHODS: A retrospective review was performed of 184 gastric cancer patients who underwent a 5-Fu, leucovorin, and oxaliplatin (FOLFOX) neoadjuvant chemotherapy regimen, followed by surgical treatment. Blood samples for CEA, CA19-9, CA72-4, and CA125 levels were taken from patients upon admission to the hospital and after neoadjuvant chemotherapy. Statistical analysis was performed to identify the clinical value of these tumor markers in predicting the survival and the response to neoadjuvant chemotherapy. RESULTS: Median overall survival times of pretreatment CA19-9-positive and CA72-4-positive patients (14.0 +/-2.8 months and 14.8 +/-4.0 months, respectively) were significantly less than negative patients (32.5 +/-8.9 months and 34.0 +/-10.1 months, respectively) (P = 0.000 and P = 0.002, respectively). Pretreatment status of CA19-9 and CA72-4 were independent prognostic factors in gastric cancer patients (P = 0.029 and P = 0.008, respectively). Pretreatment CEA >50 ng/ml had a positive prediction value for clinical disease progression after neoadjuvant chemotherapy according to the ROC curve (AUC: 0.694, 95% CI: 0.517 to 0.871, P = 0.017). The decrease of tumor markers CEA, CA72-4, and CA125 was significant after neoadjuvant chemotherapy (P = 0.030, P = 0.010, and P = 0.009, respectively), especially in patients with disease control (including complete, partial clinical response, and stable disease) (P = 0.012, P = 0.020, and P = 0.025, respectively). A decrease in CA72 4 by more than 70% had a positive prediction value for pathologic response to neoadjuvant chemotherapy according to the ROC curve (AUC: 0.764, 95% CI: 0.584 to 0.945, P = 0.020). CONCLUSIONS: Our results suggest that high preoperative serum levels of CA72-4 and CA19-9 are associated with higher risk of death, high pretreatment CEA levels (>50 ng/ml) may predict clinical disease progression after neoadjuvant chemotherapy, and a decrease (>70%) of CA72-4 may predict pathologic response to neoadjuvant chemotherapy. PMID- 25543666 TI - Evaluation of the Balanced Menus Challenge: a healthy food and sustainability programme in hospitals in Maryland. AB - OBJECTIVE: The Balanced Menus Challenge (BMC) is a national effort to bring the healthiest, most sustainably produced meat available into health-care settings to preserve antibiotic effectiveness and promote good nutrition. The present study evaluated the outcomes of the BMC in the Maryland/Washington, DC region. DESIGN: The BMC is a cost-effective programme whereby participating hospitals reduce meat purchases by 20 % of their budget, then invest the savings into purchasing sustainably produced meat. A mixed-methods retrospective assessment was conducted to assess (i) utilization of the BMC 'implementation toolkit' and (ii) achievement of the 20 % reduction in meat purchases. Previous survey data were reviewed and semi-structured interviews were conducted. SETTING: Hospitals located in the Maryland/Washington, DC region, USA, that adopted the BMC. SUBJECTS: Twelve hospitals signed the BMC in the Maryland/Washington, DC region and six were available for interview. RESULTS: Three hospitals in the Maryland/Washington, DC region that signed the BMC tracked their progress and two achieved a reduction in meat procurement by >=20 %. One hospital demonstrated that the final outcome goal of switching to a local and sustainable source for meat is possible to achieve, at least for a portion of the meal budget. The three hospitals that reduced meat purchases also received and used the highest number of BMC implementation tools. There was a positive correlation between receipt and usage of implementation tools (r=0.93, P=0.005). CONCLUSIONS: The study demonstrates that hospitals in the Maryland/Washington, DC region that sign the BMC can increase the amount of sustainably produced meat purchased and served. PMID- 25543669 TI - Effects of Lycium barbarum polysaccharides on oxidative stress in hyperlipidemic mice following chronic composite psychological stress intervention. AB - Chronic composite psychological stress intervention is the accumulation of factors which may induce psychological stress, including food deprivation, water deprivation and swimming in cold water. Approximately 40% of cases of atherosclerosis are associated with chronic composite psychological stress. The aim of the present study was to explore the effects of Lycium barbarum polysaccharides (LBP) on blood lipid levels and oxidative stress in hyperlipidemic mice, following chronic composite psychological stress. A hyperlipidemic mouse model was generated, and the mice were subjected to chronic composite psychological stress and treated with LBP for 30 days. After 30 days the triglyceride (TG) and total cholesterol (TC) levels were measured in the serum, and the mRNA expression levels of cholesterol 7alpha-hydroxylase (CYP7A1) were determined in the liver, in order to observe any changes to lipid metabolism. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured in the liver to evaluate the effects of LBP on oxidative stress. The blood serum levels of interleukin-6 (IL-6) and heat shock protein 70 (HSP-70) were measured to evaluate the extent of the aortic inflammatory response, and to determine the protective effects of LBP. The levels of TG, TC, MDA and IL-6 were significantly higher in the mice subjected to chronic composite psychological stress (HS), as compared with the mice treated with LBP alone (HL), or treated with LBP and subjected to stress (HLS). In addition, SOD and HSP-70 levels, and the mRNA expression levels of CYP7A1 were significantly lower in the HS group, as compared with that in the HL and HLS groups. These results suggest that chronic composite psychological stress may promote the occurrence and development of atherosclerosis, by inducing the aortic inflammatory response and lipid peroxidation. Furthermore, treatment with LBP significantly inhibited oxidative stress and the aortic inflammatory response. PMID- 25543671 TI - Annotated catalogue of Australian weevils (Coleoptera: Curculionoidea). AB - This catalogue presents the first-ever complete inventory of all described taxa of Australian weevils, including both valid and invalid names. The geographical scope spans mainland Australia and its continental islands as well as the subantarctic Heard and McDonald Islands, the Pacific Lord Howe and Norfolk Islands and the Indian-Ocean Christmas Island. 4111 species in 832 genera (including one extinct species and one fossil) are recognised as occurring in this territory, distributed over seven families, 20 subfamilies and 94 tribes. The families and subfamilies are arranged in a currently accepted phylogenetic sequence but the tribes, genera and species in alphabetical order. Introductory chapters outline the discovery and composition of the Australian weevil fauna, the burden of synonymy, the format and conventions of the catalogue and the taxonomic and nomenclatural changes proposed. Sixteen new genera and six new species are described, two new names and 25 new generic and 72 new species synonymies and 189 new combinations are proposed and 46 type species designations are effected. The records of 356 taxa are annotated to justify or explain various taxonomic and nomenclatural acts and issues, covering descriptions of new taxa, new synonymies and generic combinations, artificial taxon concepts, changes in classification and a number of nomenclatural matters. The catalogue of the taxa present in Australia is followed by a list of 19 species incorrectly recorded from Australia or introduced as biocontrol agents but not established, and by one species inquirenda. All these records are also annotated. Two appendices list the 102 species introduced into Australia, both accidental and deliberate (as weed control agents). A bibliography with full references of all original descriptions and pertinent other citations from the literature is provided, and an index to all names concludes the catalogue. PMID- 25543670 TI - Phylogenetic and structural analysis of the phospholipase A2 gene family in vertebrates. AB - The phospholipase A (PLA)2 family is the most complex gene family of phospholipases and plays a crucial role in a number of physiological activities. However, the phylogenetic background of the PLA2 gene family and the amino acid residues of the PLA2G7 gene following positive selection gene remain undetermined. In this study, we downloaded 49 genomic data sets of PLA from different species, including the human, house mouse, Norway rat, pig, dog, chicken, cattle, African clawed frog, Sumatran orangutan and the zebrafish species. Phylogenetic relationships were determined using the neighbor-joining (NJ), minimum evolution (ME) and maximum parsimony (MP) methods, as well as the Bayesian information criterion. The results were then presented as phylogenetic trees. Positive selection sites were detected using site, branch and branch-site models. These methods led us to the following assumptions: i) closer lineages were observed between PLA2G16 and PLA2G6, PLA2G7 and PLA2G4, PLA2G3 and PLA2G12, as well as among PLA2G10, PLA2G5 and PLA2G15; ii) PLA2G5 appeared to be the origin of the PLA2 family, and PLA2G7 was one of the most evolutionarily distant PLA2 proteins; iii) 16 positive-selection sites were detected and were marked in the PLA2G7 protein sequence as 327D, 257Q, 276G, 34s, 66G, 67C, 319S, 28N, 50S, 54T, 58R, 75T, 88Q, 92R, 179H and 191K. PMID- 25543672 TI - A review of the physonect siphonophore genera Halistemma (Family Agalmatidae) and Stephanomia (Family Stephanomiidae). AB - Re-descriptions are given for all the known species in the siphonophore physonect genera Halistemma (Family Agalmatidae) and Stephanomia (Family Stephanomiidae fam. nov.) based almost entirely on specimens collected by submersibles or ROVs. A new Halistemma species, H. maculatum sp. nov., is also described. Until now two of the Halistemma species were known only from incomplete specimens, such that for one, H. cupulifera Lens & van Riemsdijk, only the tentilla had been described, while for the other, H. striata Totton, only the nectophores were known. The species Stephanomia amphytridis Lesueur & Petit, originally established on the basis of only an illustration of part of the siphosome, is poorly known and several descriptions in the past have been based on further siphosomal material that actually belonged to a species of Halistemma. A specimen of that species, which included the nectosome, was recently described by Mapstone (2004) as H. amphytridis, but Pugh (2006) considered that it actually belonged to H. foliacea Quoy & Gaimard. That specimen has been re-examined for this study. The taxonomic position of the two genera is discussed. Although only distantly related the species of the two genera have a post-larval form referred to as the Nectalia stage. Haeckel (1888b) originally described a specimen at this stage as a separate species, Nectalia loligo. Nectalia stage specimens of two Halistemma species and of S. amphytridis were present in the material and their relationship with Haeckel's specimen is discussed. PMID- 25543668 TI - Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging. AB - During aging, progressive deleterious changes increase the risk of disease and death. Prominent molecular hallmarks of aging are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication. Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes, including age-related diseases like cancer, cardiovascular pathologies, and neurodegenerative disorders. Evidence is emerging that lncRNAs influence the molecular processes that underlie age-associated phenotypes. Here, we review our current understanding of lncRNAs that control the development of aging traits. PMID- 25543667 TI - Genetic diversity is a predictor of mortality in humans. AB - BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease. RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%. CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival. PMID- 25543673 TI - Fifteen from one: a revision of the Galaxias olidus Gunther, 1866 complex (Teleostei, Galaxiidae) in south-eastern Australia recognises three previously described taxa and describes 12 new species. AB - The systematics of the Galaxias olidus hyper-species complex from freshwater habitats in south-eastern, mainland Australia is revised. Galaxias olidus Gunther 1866 is redescribed, Galaxias fuscus Mack 1936 and Galaxias ornatus Castelnau 1873, previously synonymised with G. olidus (sensu lato), are reinstated as valid taxa and redescribed, and 12 taxa are described as new: Galaxias aequipinnis sp. nov., Galaxias arcanus sp. nov., Galaxias brevissimus sp. nov., Galaxias gunaikurnai sp. nov., Galaxias lanceolatus sp. nov., Galaxias longifundus sp. nov., Galaxias mcdowalli sp. nov., Galaxias mungadhan sp. nov., Galaxias oliros sp. nov., Galaxias supremus sp. nov., Galaxias tantangara sp. nov., and Galaxias terenasus sp. nov. These species are morphologically similar and, whilst there is extensive overlap in meristic counts and morphometric characters, each can be diagnosed by unique combinations of characters, including allozyme loci and colour pattern; morphological diagnosis is improved greatly if based on freshly formalin-fixed material. Galaxias schomburgkii Peters 1868, Galaxias bongbong Macleay 1881, Galaxias kayi Ramsay & Ogilby 1886 and Galaxias oconnori Ogilby 1912 are retained as junior synonyms of G. olidus (sensu stricto). The types for Galaxias findlayi Macleay 1882 are lost and no specimens matching its description were collected or examined from the Mt. Kosciuszko region; it is also currently retained as a junior synonym of Galaxias olidus s.s. The species G. terenasus sp. nov. and G. arcanus sp. nov. are the most morphologically specialised in the complex and G. olidus s.s remains the most morphologically variable species. It also remains the most widespread taxon, though its previously known distribution is reduced, particularly in the south-west of its range. Nine species are narrow range endemics, known from one, or only a few, locations, and these restricted distributions most probably reflect the fragmentation and reduction of former ranges caused by the effects of alien salmonids. Eleven species are of conservation concern, most are considered critically endangered. PMID- 25543675 TI - Family-group names of Recent fishes. AB - The family-group names of animals (superfamily, family, subfamily, supertribe, tribe and subtribe) are regulated by the International Code of Zoological Nomenclature. Family names are particularly important because they are among the most widely used of all technical animal names. Apart from using the correct family-group name according to the Code, it is also important to use one unique universal name (with a fixed spelling) to avoid confusion. We have compiled a list of family-group names for Recent fishes, applied the rules of the Code and, if possible, tried to conserve the names in prevailing recent practice. We list all of the family-group names found to date for Recent fishes (N=2625), together with their author(s) and year of publication. This list can be used in assigning the correct family-group name to a genus or a group of genera. With this publication we contribute to the usage of correct, universal family-group names in the classification of, and for communication about, Recent fishes. PMID- 25543674 TI - On the Miocene Cyprideis species flock (Ostracoda; Crustacea) of Western Amazonia (Solimoes Formation): Refining taxonomy on species level. AB - The Miocene mega-wetland of western Amazonia holds a diverse, largely endemic ostracod fauna. Among them, especially the genus Cyprideis experienced a remarkable radiation. Micropalaeontologic investigations of a 400 m long sediment core (~62 km SW Benjamin Constant, Amazonia, Brazil) permitted a taxonomic revision of about two-thirds of hitherto described Cyprideis species. We evaluate the diagnostic value of shell characters and provide an extensive illustration of the intraspecific variability of species. Based on comparative morphology, the 20 recorded Cyprideis species are arranged in groups and subgroups. The "smooth" group comprises C. amazonica, C. kotzianae, C. kroemmelbeini, C. machadoi, C. multiradiata, C. olivencai, C. paralela and C. simplex; the "ornate" group C. curucae nom. nov., C. cyrtoma, C. aff. graciosa, C. inversa, C. ituiae n. sp., C. matorae n. sp., C. minipunctata, C. munoztorresi nom. nov., C. pebasae, C. reticulopunctata, C. schedogymnos and C. sulcosigmoidalis. Five species have been revalidated, two renamed, two synonymised and two are new descriptions. Along with 10 further formally established species, for which a review is pending, Cyprideis keeps at least 30 endemic species in that region during Miocene times. Up to 12 Cyprideis species have been found to occur sympatrically, representing >90% of the entire ostracod fauna. Ostracod index species enable a biostratigraphic allocation of the well succession to the Cyprideis minipunctata to Cyprideis cyrtoma biozones, corresponding to a late Middle to early Late Miocene age (late Serravallian-early Tortonian). PMID- 25543676 TI - The cicadas of Argentina with new records, a new genus and fifteen new species (Hemiptera: Cicadoidea: Cicadidae). AB - The Argentine cicada fauna is determined. A total of 108 species belonging to 37 genera, eight tribes, and three subfamilies of cicadas are represented in the Argentine cicada fauna. One genus and 15 species are described as new to science: Torresia Sanborn & Heath gen. n., Fidicinoides ferruginosa Sanborn & Heath sp. n., Proarna alalonga Sanborn & Heath sp. n., Proarna parva Sanborn & Heath sp. n., Prasinosoma medialinea Sanborn & Heath sp. n., Dorisiana noriegai Sanborn & Heath sp. n., Guyalna platyrhina Sanborn & Heath sp. n., Herrera humilastrata Sanborn & Heath sp. n., Herrera umbraphila Sanborn & Heath sp. n., Parnisa lineaviridia Sanborn & Heath sp. n., Parnisa viridis Sanborn & Heath sp. n., Alarcta micromacula Sanborn & Heath sp. n., Torresia lariojaensis Sanborn & Heath sp. n., Torresia sanjuanensis Sanborn & Heath sp. n., Chonosia longiopercula Sanborn & Heath sp. n., and Chonosia septentrionala Sanborn & Heath sp. n. Adusella signata Haupt, 1918 rev. stat. is determined to be a valid species, removed as a junior synonym of Tettigades lebruni Distant, 1906 and reassigned to the genus Odopoea Distant to become Odopoea signata comb. n. Fidicina vinula Stal, 1854 rev. stat. is determined to be a valid species, removed as a junior synonym of Fidicinoides pronoe (Walker, 1850) and assigned to the genus Fidicinoides Boulard & Martinelli to become Fidicinoides vinula comb. n. Proarna capistrata Distant, 1885 rev. stat. is determined to be a valid species, removed as a junior synonym of Proarna montividensis Berg, 1882. Chonosia papa (Berg, 1882) rev. stat. is determined to be a valid species and removed as a junior synonym of Chonosia crassipennis (Walker, 1858). Chonosia crassipennis var. metequei nom. nud. Deletang, 1919 syn. n. is considered natural variation in C. crassipennis. Dorisia bonaerensis var. bergi nom. nud. Deletang, 1919 syn. n. and Dorisia bonaerensis var. dominiquei nom. nud. Deletang, 1919 syn. n. are considered to be natural variation within Guyalna bonaerensis (Berg, 1879). Derotettix proseni Torres, 1945 is determined to be a junior synonym of Derotettix wagneri Distant, 1905 syn. n. Dorisiana metcalfi nom. nov. pro Cicada viridis Olivier, 1790 nec Cicada viridis Linnaeus, 1758 is proposed. Tettigades lizeriana Deletang, 1919 is shown to be an invalid name for the purposes of zoological nomenclature. The first records for Argentina of Fidicinoides determinata (Walker, 1858), Fidicinoides vinula (Stal, 1854) comb. n., rev. stat., Prasinosoma fuembuenai Torres, 1963, Ariasa bilaqueata (Uhler, 1903), Ariasa colombiae (Distant, 1892), Carineta boliviana Distant, 1905, Carineta gemella Boulard, 1986, Calyria stigma (Walker, 1850), Selymbria pandora Distant, 1911, Taphura hastifera (Walker, 1858), Taphura misella (Stal, 1854), and Tettigades angularis Torres, 1958 are provided. Ten species are removed from the Argentine cicada fauna. The new records and new species represent a 36% increase in the known cicada fauna. Fifty-eight species (54%) and 10 genera (27%) are currently endemic to Argentina. PMID- 25543679 TI - Clinical efficacy of subgingival debridement with adjunctive erbium:yttrium aluminum-garnet laser treatment in patients with chronic periodontitis: a randomized clinical trial. AB - BACKGROUND: The efficacy of erbium:yttrium-aluminum-garnet (Er:YAG) laser application as an adjunct to subgingival debridement in the treatment of chronic periodontitis (CP) is controversial. This study assesses the efficacy of combining full-mouth subgingival debridement with Er:YAG laser application in the treatment of patients with CP. METHODS: In this 12-month, single-masked, parallel group clinical trial, 40 patients with moderate CP were selected and randomly assigned to a test group (one session of full-mouth ultrasonic subgingival debridement followed 1 week later by Er:YAG application in sites with initial probing depths [PDs] of >=4.5 mm) and a control group (two sessions of ultrasonic debridement within 1 week). The main outcome variable was change in PD; the secondary outcomes were change in clinical attachment level and proportion of sites with bleeding on probing. Outcomes were assessed at baseline and after 3, 6, and 12 months. Data were analyzed as intention to treat using analysis of variance to assess intergroup differences. RESULTS: Both treatments resulted in significant clinical improvements. The test group achieved, in comparison with the control, a significantly lower percentage of sites with PD >=4.5 mm (17.44% versus 22.83%, respectively; P = 0.004) and a tendency for a lower percentage of sites with PD >=4.5 mm and bleeding on probing (9.78% versus 12.69%; P = 0.052). CONCLUSION: This limited added clinical effect may justify the use of a protocol combining full-mouth ultrasonic debridement with laser therapy in the treatment of initial moderate CP. PMID- 25543680 TI - Discovery of anti-malarial agents through application of in silico studies. AB - Among the various parasitic diseases, malaria is the deadliest one. Due to the emergence of high drug resistance to the existing drug candidates there is a global need for development of new drug candidates which will be effective against resistant strains of malaria parasite. In silico molecular modeling approaches have been playing an important role in the discovery of novel lead molecules having antimalarial activity. Present review is an effort to cover all the developments related to the application of computational techniques for the design and discovery of novel antimalarial compounds since the year 2011 onwards. PMID- 25543678 TI - Advances in pharmacotherapy for primary biliary cirrhosis. AB - INTRODUCTION: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive. AREAS COVERED: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids. EXPERT OPINION: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA. PMID- 25543681 TI - The current status of antimalarial drug research with special reference to application of QSAR models. AB - Malaria, the most virulent parasitic disease, has become a devastating health problem in tropical and subtropical regions, especially in Africa, due to favorable temperature and rainfall conditions for the development of the causative vector. Due to the spread of multidrug resistance to the marketed antimalarial drugs including the "magic bullet" artemisinin, discovery and development of new antimalarial drugs is one of the utmost challenges. Different government and non-government chemical regulatory authorities have recommended the application of non-animal, alternative techniques and in particular, in silico, methods in order to provide information about the basic physicochemical properties as well as the ecological and human health effects of chemicals before they reach into the market for public use. In this aspect, application of chemometric methods along with structure-based approaches may be useful for the design and discovery of new antimalarial compounds. The quantitative structureactivity relationship (QSAR) along with molecular docking and pharmacophore modeling techniques play a crucial role in the field of drug design. QSAR focuses on the chemical attributes influencing the activity and thereby allows synthesis of selective potential candidate molecules. In this communication, we have reviewed the QSAR reports along with some pharmacophore modeling and docking studies of antimalarial agents published during the year 2011 to 2014 and attempted to focus on the importance of physicochemical properties and structural features required for antimalarial activity of different chemical classes of compounds. Note that this is not an exhaustive review and all the given examples should be considered as the representative ones. The reader will gain an insight of the current status of QSAR and related in silico models developed for different classes of antimalarial compounds. This review suggests that combination of both ligand and structure-based drug designing approaches may be a promising tool for the discovery and development of new molecules with potential antimalarial activity. PMID- 25543682 TI - New horizons in antimalarial drug discovery in the last decade by chemoinformatic approaches. AB - Antimalarial drug discovery process is progressively carried out by a combination of innovation and knowledge based methods that include computational and experimental approaches to achieve potent leads. Among the various computational approaches, chemoinformatics plays a critical role in the discovery of new leads or drug candidates. Chemoinformatics provides researchers tools to derive information on substructures, chemical space, similarity and diversity. It also helps to manage and store chemical data, study important molecular properties and filter libraries with regard to specified criteria in the database. To accomplish these ends it uses various tools amongst which are docking, 3D-QSAR, similarity search, virtual screening, database mining and pharmacophore mapping. This review is a perspective of the utility of chemoinformatic approaches in antimalarial drug design. It covers various facets such as targets that have been exploited for antimalarial drug discovery by chemoinformatic methods; potential antimalarial targets that have not yet been explored; the challenges faced in antimalarial drug discovery, and future directions for discovery of novel antimalarial agents. PMID- 25543684 TI - Understanding the structural requirements in diverse scaffolds for the inhibition of P. falciparum dihydroorotate dehydrogenase (PfDHODH) using 2D-QSAR, 3D pharmacophore and structure-based energy- optimized pharmacophore models. AB - P. falciparum dihydroorotate dehydrogenase (PfDHODH) of the pyrimidine biosynthetic pathway offers a promising target for the development of antimalarial drugs in the scenario of widespread P. falciparum resistance. In this background, we have made an effort to decipher the structural requirements for the inhibition of PfDHODH using regression-based 2DQSAR, 3D-pharmacophore modeling and energy-based pharmacophoric (e-pharmacophore) studies. The 2D-QSAR and 3D-pharmacophore models were built from a structurally diverse set of 38 dihydrothiophenone derivatives, while the e-pharmacophore models were developed from two different co-crystal structures (PDB ID: 3O8A, 3I68) with varied scaffolds (benzimidazole, IC50: 22 nM and triazolopyrimidine, IC50: 56 nM) showing an inhibitory activity against the PfDHODH. The 2D-QSAR modeling study depicted the contribution of constitutional (number of oxygen atoms), spatial (molar volume), structural (number of rotatable bonds), and electronic (dipole moment) descriptors in predicting the PfDHODH inhibitory activity. The regression model showed the maximum contribution of constitutional descriptor (number of oxygen atoms representing the hydrogen bond acceptor feature) in determining the inhibitory activity. The best 3D-pharmacophore model (Hypo-1) with a correlation coefficient of 0.960 showed two hydrogen bond acceptor (HBA) and one ring aromatic (RA) features as the essential structural requirements for predicting the inhibitory activity. The e-pharmacophores derived from two different co crystal structures highlighted the energy-based contribution of one hydrogen bond acceptor (e-HBA), one hydrogen bond donor (e-HBD) and three/four ring aromatic (e RA) features for the inhibitory activity. The screening of external sets by the e pharmacophores showed that both the models are capable of identifying the structurally diverse and potent compounds. PMID- 25543683 TI - 3D-QSAR studies on Plasmodium falciparam proteins: a mini-review. AB - 3D-QSAR has become a very important tool in the field of Drug Discovery, especially in important areas like malarial research. The 3D-QSAR is principally a ligand-based drug design but the bioactive conformation of the ligand can also be taken into account in constructing a 3D-QSAR model. The induction of receptor based 3D-QSAR has been proven to give more robust statistical models. In this review, we have discussed the various 3D-QSAR works done so far which were aimed at combating malaria caused by Plasmodium falciparam. We have also discussed the various enzymes/receptors (targets) in Plasmodium falciparam for which the 3D QSAR had been generated. The enzymes - wild and mutated dihydrofolate reductase, enoyl acyl protein carrier protein reductase, farnesyltransferase, cytochrome bc1, and falcipains were the major targets for pharmacophore-based drug design. Apart from the above-mentioned targets there were many scaffolds for which the target macromolecule was undefined and could have single/multiple targets. The generated 3D-QSAR model can be used to identify hits by screening the pharmacophore against a chemical library. In this review, the hits identified against various targets of plasmodium falciparam that have been discussed along with their basic scaffold. The various software programs and chemical databases that have been used in the generation of 3D-QSAR and screening were given. From this review, we understand that there is a considerable need to develop novel scaffolds that are different from the existing ligands to overcome cross resistance. PMID- 25543685 TI - Molecular modelling based target identification for endo-peroxides class of antimalarials. AB - The emerging cases of artemisinin and endoperoxide drug resistance are becoming a challenge to antimalarial drug discovery and therapy. The exact mode of action of this class of antimalarials is still unknown which presents a bottleneck for the understanding of drug resistance as well as designing new lead molecules of this class. To address this issue, the molecular docking and scoring studies of a homogeneous and structurally diverse dataset of artemisinin derived trioxanes have been performed on each of the two plausible targets of this class viz. heme and PfATP6. Since the crystal structure of PfATP6 is unknown, its homology model was built utilizing the human SERCA1 protein crystallized structure as a template. The binding energies of the heme binding site of the docked artemisinin derivatives showed very good correlation with the antimalarial activity (r(2) = 0.69), whereas the same study with the binding site of pfATP6 showed a very poor correlation (r(2) = 0.12), suggesting heme to be the possible target of artemisinin derived endoperoxides. PMID- 25543686 TI - Discovery of new potential antimalarial compounds using virtual screening of ZINC database. AB - Falcipain-3 (FP-3) is a cysteine protease of the malaria parasite Plasmodium falciparum which is a promising and attractive target enzyme for antiparasitic chemotherapy. In this study, a support vector machine (SVM) model based on fingerprint-based descriptors was developed on a dataset of 239 FP-3 inhibitors to identify the most active antimalarial compounds among the active compounds provided from similarity search. The satisfactory classification performance achieved by the SVM model shows its ability to use it as a further filter to distinguish the most active compounds. The accuracy in prediction for the training, test and external validation sets were 97.39%, 94.74% and 90.6%, respectively. Furthermore, the performance of the model was examined by plotting the receiver operating characteristic (ROC) curve, and the area under the ROC curve was 0.96 for the modeling set. The ability of a virtual screening scheme to scaffold hopping or lead hopping is known as a key ability of an effective method for virtual screening. Three diverse reference FP-3 structures were chosen as active antimalarial compounds to search the lead-like database of ZINC and retrieve the most similar compounds. Compounds having Tanimoto similarity coefficient above 0.8 were extracted for further analysis by classification model. The SVM model rendered five most active compounds and they were also analyzed by ADME/Tox and diversity measures. Maximum property-based distance between extracted compounds was found to be 0.70, which shows the importance of applying multiple diverse reference compounds in the similarity searching. PMID- 25543687 TI - Exploring MIA-QSARs' for antimalarial quinolon-4(1H)-imines. AB - A series of quinolon-4(1H)-imines have been recently discovered as antimalarials, targeting both the exoerythrocytic and erythrocytic stages of the parasite's development stages, which correspond to the phase of clinical symptoms. Endowed with chemical and metabolic stability, the quinolon-4(1H)- imines are thus presented as promissory dual-stage antimalarials. Three versions of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) methods, namely traditional MIA-QSAR, augmented MIA-QSAR (aug-MIA-QSAR) and color encoded aug-MIA-QSAR (aug- MIA-QSARcolor), were applied to model the antimalarial activities in this series of compounds. The multiple linear regression models indicated that the aug-MIA-QSAR method is more predictive and reliable than the others (R(2) = 0.8079, R(2)cv = 0.6647 and R(2)pred = 0.9691) for this series of compounds. The selected aug- MIA-QSAR descriptors were used for pattern recognition using discriminant analysis by partial least squares (PLS-DA), in order to separate compounds with low, moderate and high bioactivities. PMID- 25543689 TI - The effect of Apium Nodiflorum in experimental osteoporosis. AB - Treatment of osteoporosis remains a therapeutic challenge. The effect of Apium Nodiflorum extract on development of experimental osteoporosis, pain thresholds and carrageenan-induced inflammation has been studied in ovariectomized osteoporotic Wistar rats. After osteoporosis verification rats were randomized and received vehicle only, HPLC-standardized Apium extract (equal to 2.4 mg/kg Quercetin) or Genistein (2.5 mg/kg) for 8 weeks. To verify the effect of Apium on the development of osteoporosis, bone mineral density (BMD) and bone mineral content (BMC), bone histology and plasma levels of IL-6 and RANKL were measured 6 months after ovariectomy and 8 weeks after treatment with Apium extract or Genistein as comparator. Inflammatory hyperalgesia was induced by intraplantar injection of 1% Carrageenan. Apium extract and Genistein impeded the development of osteoporosis (significant differences were shown for BMC and BMD levels in drug vs. vehicle treated rats) and improved bone histology and histological score. Apium and Genistein decreased IL-6 level. Both treatments alleviated mechanical hyperalgesia, decreased exudative reaction and lowered inflammatory pain threshold. The results suggested that Apium extract could be an alternative therapy for post-menopausal osteoporosis. PMID- 25543690 TI - Lipid based nanocapsules: a multitude of biomedical applications. AB - Lipid nanocapsules with their unique composition represent a promising biocompatible drug delivery platform in nanometer range with narrow size distribution. They are highly stable in comparison to other nano-vectors and were found to impart very desirable characteristics to the therapeutic molecule being delivered within. The current review sheds the light on the methods of preparation of lipid nanocapsules, which are simple and easily scalable, in addition to providing examples of post insertion of some compounds for prolonging vascular circulation, protection, and targeting several diseases. In addition, the review discusses the vast in vitro and in vivo applications of lipid nanocapsules when administered via different routes such as oral, parenteral and transdermal routes. Promising use of nanocapsules in treatment of cancer, Alzheimer's disease, dermatological conditions and other miscellaneous applications are highlighted. PMID- 25543688 TI - Efficacy of GP referral of insufficiently active patients for expert physical activity counseling: protocol for a pragmatic randomized trial (The NewCOACH trial). AB - BACKGROUND: Physical inactivity is fourth in the list of risk factors for global mortality. General practitioners are well placed to offer physical activity counseling but insufficient time is a barrier. Although referral to an exercise specialist is an alternative, in Australia, these allied health professionals are only publicly funded to provide face-to-face counseling to patients who have an existing chronic illness. Accordingly, this trial aims to determine the efficacy of GP referral of insufficiently active patients (regardless of their chronic disease status) for physical activity counseling (either face-to-face or predominately via telephone) by exercise specialists, based on patients' objectively assessed physical activity levels, compared with usual care. If the trial is efficacious, the equivalence and cost-effectiveness of face-to-face counseling versus telephone counseling will be assessed. METHODS: This three arm pragmatic randomized trial will involve the recruitment of 261 patients from primary care clinics in metropolitan and regional areas of New South Wales, Australia. Insufficiently active (less than 7000 steps/day) consenting adult patients will be randomly assigned to: 1) five face-to-face counseling sessions, 2) one face-to-face counseling session followed by four telephone calls, or 3) a generic mailed physical activity brochure (usual care). The interventions will operationalize social cognitive theory via a behavior change counseling framework. Participants will complete a survey and seven days of pedometry at baseline, and at three and 12 months post-randomization. The primary analyses will be based on intention-to-treat principles and will compare: (i) mean change in average daily step counts between baseline and 12 months for the combined intervention group (Group 1: face-to-face, and Group 2: telephone) and usual care (Group 3); (ii) step counts at 3 months post-randomization. Secondary outcomes include: self-reported physical activity, sedentary behavior, quality of life, and depression. DISCUSSION: If referral of primary care patients to exercise specialists increases physical activity, this process offers the prospect of systematically and sustainably reaching a large proportion of insufficiently active adults. If shown to be efficacious this trial provides evidence to expand public funding beyond those with a chronic disease and for delivery via telephone as well as face-to-face consultations. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000884909 . PMID- 25543692 TI - Seroepidemiology and risk factors of Toxoplasma gondii infection in undergraduate university female students in Jordan. AB - This study estimated the seroprevalence and risk factors for acquiring Toxoplasma gondii infection by undergraduate female university students in Jordan. A cross sectional study from September 2013 to July 2014 analysed 202 blood samples for IgG and IgM antibodies by enzyme-linked immunosorbent assay and a semi constructed questionnaire was completed by participants to gather information about Toxoplasma infection risk factors. T. gondii IgG antibodies were detected in 66.5% of the females. Only one sample was positive for both IgG and IgM. Using chi2 test, six factors showed significant association with T. gondii infection (P ? 0.01). The multivariate logistic regression model showed that female students living in houses, wet areas, with income >US $750/month and using spring (untreated) water were 47.42, 10.20, 5.00, 3.25 more times at risk to be seropositive for T. gondii, respectively, compared to female students living in apartments, dry areas, with income <= US $750/month and using treated water, respectively. This study concluded that T. gondii infection in female university students in Jordan is high and most women become infected before marriage; however, congenital toxoplasmosis is still likely to occur in Jordan. Thus, dissemination of protective measures and knowledge by healthcare professionals is essential especially for pregnant women. PMID- 25543694 TI - 'It's just so much waste.' A qualitative investigation of food waste in a universal free School Breakfast Program. AB - OBJECTIVE: To understand stakeholders' perspectives on food waste in a universal free School Breakfast Program implementing a Breakfast in the Classroom model. DESIGN: Semi-structured focus groups and interviews were conducted with school district stakeholders. Inductive methods were used to code resulting transcripts, from which themes were identified. The analysis provides a thematic analysis of stakeholders' perspectives on food waste in the School Breakfast Program. SETTING: Ten elementary schools in a large urban school district implementing a universal free Breakfast in the Classroom model of the US national School Breakfast Program. SUBJECTS: Elementary-school students (n 85), parents (n 86), teachers (n 44), cafeteria managers (n 10) and school principals (n 10). RESULTS: Stakeholders perceived food waste as a problem and expressed concern regarding the amount of food wasted. Explanations reported for food waste included food related (palatability and accessibility), child-related (taste preferences and satiation) and programme-related (duration, food service policies, and coordination) factors. Milk and fruit were perceived as foods particularly susceptible to waste. Several food waste mitigation strategies were identified by participants: saving food for later, actively encouraging children's consumption, assisting children with foods during mealtime, increasing staff support, serving smaller portion sizes, and composting and donating uneaten food. CONCLUSIONS: Stakeholders recognized food waste as a problem, reported myriad contributing factors, and have considered and employed multiple and diverse mitigation strategies. Changes to the menu and/or implementation logistics, as well as efforts to use leftover food productively, may be possible strategies of reducing waste and improving the School Breakfast Program's economic, environmental and nutritional impact. PMID- 25543695 TI - [Second-generation tyrosine kinase inhibitors: the first-line treatment strategy of chronic myeloid leukemia patients?]. PMID- 25543693 TI - Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins. AB - In the menstrual cycle, the mid-cycle surge of gonadotropins (both luteinising hormone [LH] and follicle-stimulating hormone [FSH]) signals the initiation of the periovulatory interval, during which the follicle augments progesterone production and begins to luteinise, ultimately leading to the rupture of the follicle wall and the release of an oocyte. The administration of gonadotropins in controlled ovarian stimulation (COS) leads to supraphysiological steroid concentrations of a very different profile compared with those seen during natural cycles. It has been suggested that these high steroid concentrations cause alterations in endometrial development, affecting oocyte viability in assisted reproductive technology. Furthermore, it has been proposed that elevated progesterone levels have a negative effect on the reproductive outcome of COS. This may arise from an asynchrony between embryo stage and endometrium status at the window of implantation. The regulation of progesterone production by the developing follicles during COS is a complicated interplay of hormonal systems involving the theca and granulosa cells, and the effect of the actions of both LH and FSH. The present paper reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis. Based on current evidence, it is not clear whether the high levels of progesterone produced during COS have detrimental effects on fertility. PMID- 25543696 TI - [Cellular immune function and its clinical implications in 45 patients with multiple myeloma]. AB - OBJECTIVE: To investigate cellular immune function and its clinical significance in patients with multiple myeloma (MM). METHODS: 45 MM patients were divided into three groups:newly diagnosed (n=18), stable stage (n=17) and relapsed/refractory (n=10). The frequencies of T cell subtypes, natural killer (NK) cells, dendritic cells (DC), helper T cells (including Th1 and Th2), regulatory T cells(Treg) and Th17 cells in peripheral blood were detected by flow cytometry. Serum concentrations of beta2 microglobulin (beta2-MG), lactate dehydrogenase (LDH) and hemoglobin (Hb) were also detected, respectively. RESULTS: Compared with controls and stable stage group, the ratios of CD4+/CD8+, DC1/DC2, and Th1/Th2, the numbers of Treg and NK cells were significantly lower in newly diagnosed group. However, the ratio of IL-17A/Treg was significantly higher in newly diagnosed group (P<0.05). Compared with stable stage group, the ratios of CD4+/CD8+, DC1/DC2 and Th1/Th2 were significantly lower, and the ratio of IL-17A/Treg was significantly higher in relapsed/refractory group (P<0.05). In higher ISS stages, the ratios of CD4+/CD8+ and Th1/Th2 were significantly lower and the ratio of IL 17A/Treg was significantly higher (P<0.05). There were negative correlations between the ratios of CD4+/CD8+, DC1/DC2, Th1/Th2 and the levels of beta2-MG and LDH, respectively (P<0.05). The ratio of IL-17A/Treg was positively correlated with the levels of beta2-MG and LDH (P<0.05). They were no correlated with the level of Hb (P>0.05). CONCLUSION: The abnormal ratios of CD4+/CD8+, DC1/DC2, Th1/Th2 and IL-17A/Treg were closely related with disease condition stages, treatment outcomes, progression and prognosis in MM patients. PMID- 25543698 TI - [Diagnostic performance and clinical correlation of serum vascular endothelial growth factor levels in patients with newly diagnosed POEMS syndrome]. AB - OBJECTIVE: To evaluate the diagnostic performance and clinical correlation of serum vascular endothelial growth factor (VEGF) in patients with newly diagnosed POEMS syndrome. METHODS: We recruited 104 patients with POEMS syndrome who diagnosed at Peking Union Medical College Hospital during October 2010 to April 2014 in the current study. Clinical data and serum samples were collected. Serum VEGF levels were measured, comparing to both disease and healthy controls, and its correlation with clinical features were analyzed. RESULTS: Patients with newly diagnosed POEMS syndrome showed markedly elevated levels of serum VEGF (median 3503 ng/L, P<0.01). A cut-off value of 1 200 ng/L had a specificity of 90.2%, with a sensitivity of 83.7%, in support of a POEMS diagnosis. Further analyses indicated that patients with higher serum VEGF level (>2 000 ng/L) had more prevalent osteosclerosis (61.0% vs 37.0%, P=0.031) and papilledema (70.1% vs 44.4%, P=0.017). CONCLUSION: Serum VEGF level was useful in differentiating POEMS syndrome from other disorders with overlapping clinical presentations, and its levels correlated with several disease features. PMID- 25543697 TI - [Characteristics and treatment outcomes in 822 adult patients with acute myeloid leukemia:a single center experience]. AB - OBJECTIVE: To investigate the characteristics and the short- or long-term treatment outcomes of the adult patients with acute myeloid leukemia (AML) in China. METHODS: From 1999 to 2010, 822 adult cases with AML were enrolled, diagnosed and classified by the FAB and WHO criteria, respectively. The treatment outcomes and prognostic factors were analyzed retrospectively. RESULTS: In all patients with a median age of 38.5(15-83) years, acute monoblastic and monocytic leukemia (M5), AML with t(15;17)/PML-RARalpha (APL) and AML with t(8;21)/AML1 ETO(M2b) were the most common subtypes, accounting for 29.7%, 20.9% and 14.6% respectively. In APL patients, CR was achieved in 95.2%, with an early death (ED) rate of 4.8%. And the estimated overall survival (OS) and disease-free survival (DFS) at 5 year was 87.5% and 88.8%, respectively. Patients with other AML subtype (Non-APL) revealed a CR rate of 82.0%, ED of 4.3%, and estimated 5-year OS and DFS both of 48.8%. The OS rate of Non-APL patients at 3-year varied significantly (P<0.01) among three prognostic groups by cytogenetic risk stratification:favorable, 69.5%; intermediate, 52.8%; unfavorable, 29.8%. The prognostic factors for OS among Non-APL included age, cytogenetic abnormalities, courses of the median/high-dose cytarabine and allogeneic hematopoietic stem cell transplantation. CONCLUSION: When compared with the previous reports, the AML patients in our study were younger and showed a different subtype distribution. Treatment outcomes of APL and Non-APL were just the same as those in international leukemia centers. Chemotherapy by risk stratification, after diagnosis and classification according to the WHO criteria, is a key point to improve the outcomes in AML. PMID- 25543699 TI - [CSF3R, ASXL1,SETBP1, JAK2 V617F and CALR mutations in chronic neutrophilic leukemia]. AB - OBJECTIVE: To observe the CSF3R, ASXL1, SETBP1, JAK2 V617F and CALR mutations in patients with chronic neutrophilic leukemia (CNL). METHODS: Twelve suspected "CNL" patients were retrospectively reviewed according the WHO criteria (2008). CSF3R,ASXL1,SETBP1 and CALR mutations were sequenced, and JAK2 V617F was tested by allele specific (AS)-PCR. RESULTS: 6 of 12 cases were diagnosed as CML, and all of the 6 carried. 4 of 6 patients also had ASXL1 and SETBP1 mutations and one had a CALR mutation (c.1154-1155insTTGTC). Two patients with monoclonal gammopathy with uncertain significance (MGUS) combined with CNL-like symptoms had no CSF3R, ASXL1, SETBP1, JAK2 V617F or CALR mutation. The same results were also seen in other 4 cases with secondary neutrophilic leukocytosis. CONCLUSION: CSF3R, ASXL1 and SETBP1 mutations differential diagnosis of CNL, and should be included in the diagnostic protocol so as to improve diagnostic accuracy for CNL. PMID- 25543700 TI - [SHP-1 gene in the disease progression of chronic myeloid leukemia]. AB - OBJECTIVE: To investigate the profile of promoter methylation and expression of SHP-1 gene in the progression of chronic myeloid leukemia (CML). METHODS: The expression level of SHP-1 mRNA and protein in bone marrow or peripheral blood mononuclear cells from CML patients were detected by Western blot and SYBR Green based qRT-PCR. The methylation status of SHP-1 were assessed by methylation specific polymerase chain reaction (MSP) assay. K562 cells were infected with the lentiviral plasmids pEX-SHP-1-puro-Lv105 (K562-SHP-1) or pEX-EGFP-puro-Lv105 (K562-EGFP). The levels of proteins and phosphorylated proteins were detected by Western blot. qRT-PCR assay was used to test the level of BCR-ABL mRNA. RESULTS: The relative levels of SHP-1 mRNA were sharply decreased in advanced stages CML compared to chronic phase (CP)-CML (0.79+/-0.37 vs 1.18+/-0.64, P= 0.009). The level of SHP-1 protein was lower in advanced stages CML compared to CP-CML (0.57+/-0.02 vs 1.02+/-0.04, P=0.039). The frequency of SHP-1 gene promoter methylation at selected loci in CP-CML was 23.8% (10/42), and the methylated regions were detected in all advanced CML samples (P<0.01). SHP-1 was stably transfected into K562 cells and selected with puromycin. Overexpression of SHP-1 inhibited the proliferation and induced the apoptosis of K562 cells, meanwhile leaded to G0/G1 phase arrest. After transfection, the level of BCR-ABL mRNA was not affected in K562-SHP-1 cells (1.32+/-0.34) compared to K562-EGFP cells (1.18+/-0.20, P=0.644), but overexpression of SHP-1 caused a slight decrease in BCR-ABL protein in K562-SHP-1 cells compared to K562 -EGFP cells (0.78+/-0.15 vs 1.27+/-0.24, P=0.040). Overexpression of SHP-1 resulted in a remarkable decrease in MYC protein, phosphorylated forms of JAK2, STAT5, Akt and MAPK. However, the un-phosphorylated forms of these molecules were not significantly affected. CONCLUSION: Decreased expression of SHP-1 caused by aberrant promoter hypermethylation may play a key role in the progression of CML by dysregulation of BCR-ABL, Akt, MAPK, MYC, JAK2 and STAT5 signaling. PMID- 25543701 TI - [Clinical analysis of lower doses rituximab for children primary immune thrombocytopenia]. AB - OBJECTIVE: To evaluate the efficacy and safety of lower doses rituximab(375 mg/m2*1) in primary children immune thrombocytopenia (ITP). METHODS: Fifty children [23 male and 27 female, the median age was 9.5 years (rage 3.5-17.0 years)]with persistent and chronic ITP were treated with lower doses rituximab from January 2009 to January 2013 in our hospital. Efficacy and side effects of lower doses rituximab was studied, and factors related to the outcomes were analyzed. RESULTS: Among fifty patients, 17/50(34%) achieved a complete response (CR) and 15/50 (30%) patients got response (R). Patients with CR continued to maintain a platelet count above 50*109/L at a median 12.3 (6-40) months. Patents with R continued to maintain a platelet count above 30*109/L at a median 6 (2-12) months. The overall response (OR) in 3 and 6 months were 58% (29/50), 64% (32/50) respectively. Six patients have mild and transient side effects, including urticarial rash and fever, which were promptly resolved with appropriate therapy. Sex, age at diagnosis, interval from diagnosis to initial treatment with rituximab, platelet count at treatment and CD19+B cell count did not influence the overall response and complete response (P>0.05). Patients with anti GPIIb/IIIa autoantibody had a better OR (P<0.05). CONCLUSION: Children with persistent and chronic ITP treated by lower doses rituximab had better therapeutic effects. Patients with anti-GPIIb/IIIa autoantibody had better response. Rituximab was well tolerated and no related serious side effects were recorded in the study. PMID- 25543702 TI - [Outcomes of modified NHL-BFM-90 protocol for children and adolescents with lymphoblastic lymphoma]. AB - OBJECTIVE: To evaluate the long-term survival of children and adolescents with lymphoblastic lymphoma (LBL) treated by a modified NHL-BFM-90 protocol. METHODS: From March 1998 to November 2010, 107 untreated patients with LBL (age <18 years) were enrolled and stratified into three groups (R1, R2 and R3), according to the stage of disease and response to induction chemotherapy. All patients received different intensive chemotherapy regimens based on a modified NHL-BFM-90 protocol. Total treatment duration was 2 years. RESULTS: Of the 107 patients, 79 were boys and 28 were girls, with a median age of 10 years (range 2.5-18 years). Six patients (5.6%) were stage I/II, 101 (94.4%) stage III/IV. The R1, R2 and R3 groups accounted for 5.6%, 71.0% and 23.4%, respectively. 75.7% of the patients had T-LBL, and 24.3% was B-LBL. At a median follow-up duration of 60 months (range 1-186 months), 24 patients died. The 5-year event-free survival (EFS) and overall survival (OS) were 75.5% and 77.8 % for all patients, 100.0% and 100.0% for group R1, 84.5% and 87.5 % for R2, 44.0% and 44.0% for R3, 72% and 73.5% for T-LBL, 86.4% and 88.5% for B-LBL, respectively. Myleosuppression was the major toxicity and need aggressive management. CONCLUSION: The modified NHL-BFM-90 protocol is an effective therapy for children and adolescents with LBL in low and intermediate risk. T-LBL had the similar outcomes as B-LBL did. The patients in high-risk group had a poor survival and new protocols are needed. PMID- 25543703 TI - [A comparable analysis of IPSS and IPSS-R for evaluating prognosis of myelodysplastic syndrome]. AB - OBJECTIVE: To investigate the patients' characteristics and efficacy of prognosis evaluation by International Prognosis Scoring System (IPSS) and Revised International Prognosis Scoring System (IPSS-R) in patients with myelodysplastic syndrome (MDS). METHODS: Prognostic value of IPSS and IPSS-R was evaluated on clinical data from 159 MDS patients, according to WHO classification. RESULTS: With a median age of 44 years (range:15-80 years), MDS patients had the frequency of 38.56% with abnormal karyotype, including the most common abnormality +8 (20/153, 12.6%). 34 of 142 patients transformed into leukemia. Age and the level of beta2 micro-globulin were the prognostic factors by multivariate analysis and IPSS-R had a better prognostic significance. The differences in cumulative survival between IPSS subgroups were significant (P<0.05) except that between low and intermediate I-risk group (P>0.05). There were statistical differences for IPSS-R low risk group vs high or very high risk group, and intermediate risk group vs high or very high risk group (P<0.05). IPSS-R enables IPSS subgroups re stratification and split IPSS intermediate I-risk group into two subgroups with different prognosis. CONCLUSION: There were significant differences in age of onset, distribution of prognosis scoring system subgroups and abnormal karyotype compared with those in Europe and America. The proportion of higher risk (worse than good karyotype) in IPSS-R was higher than that in Europe and America. Age and the level of beta2 micro-globulin were prognostic factors. Both IPSS and IPSS R were applicable in Chinese MDS patients and the latter performed better. Applying IPSS-R to re-stratify IPSS subgroups helps evaluate prognosis more accurately and improve treatment outcomes. PMID- 25543704 TI - [Residual hematopoiesis is an important prognostic factor of immunosuppressive therapy in severe aplastic anemia]. AB - OBJECTIVE: To evaluate the prognostic value of residual bone marrow hematopoiesis in severe aplastic anemia (SAA) patients with immunosuppressive therapy (IST). METHODS: Clinical data and hematologic responses of 38 SAA patients treated with IST regimen (antithymocyte globulin combined with cyclosporine) in our hospital were retrospectively analyzed. Correlation of pre-IST baseline reticulocyte (Ret), absolute neutrophils count (ANC), soluble transferrin receptor (sTfR) concentration, corrected TPO value and hematologic response rate were statistically analyzed and receiver operating characteristic (ROC) curve was used to estimate the value of Ret, ANC, sTfR, and corrected TPO in predicting early IST response. RESULTS: Responders to IST had significantly higher pre-IST baseline Ret, ANC, sTfR concentration [19.9(2.7-84.4)*109/L, 0.59(0.12 2.67)*109/L, 0.82(0.22-1.58) mg/L] and lower corrected TPO value [142.9(31.8-1 035.0)] than non-responders [5.1(1.5-23.1)*109/L, 0.20(0.04-1.33)*109/L, 0.45(0.19-0.72)mg/L and 2 335.0(1 308.3-7 771.2)](P<0.05). Optimizing parameter cutoff levels obtained from ROC curve was Ret 6.75*109/L, ANC 0.30*109/L, sTfR 0.76 mg/L and corrected TPO 148.6, respectively. Combining the four parameters to predict 6 month hemotologic response showed that all the 7 patients with high Ret, ANC, sTfR and low corrected TPO, while only 1 among those 9 with low Ret, ANC, sTfR and high corrected TPO. CONCLUSION: Such parameters evaluating residual bone marrow hematopoiesis as Ret, ANC, sTfR, corrected TPO are practical in predicting early IST response in SAA. PMID- 25543705 TI - [Chronic lymphocytic leukemia with concomitant chronic myeloid leukemia: a case report]. PMID- 25543707 TI - [Clinical implications of tumor necrosis factor-alpha in lymphomas]. AB - OBJECTIVE: To investigate the levels of tumor necrosis factor-alpha (TNF-alpha) in tissue or plasma and its clinical implications in different types of lymphoma. METHODS: The levels of TNF-alpha in paraffin tissue or plasma samples were detected by immunohistochemistry or ELISA assay in 88 lymphoma patients and 88 healthy controls. Univariate and multivariate Cox regression analysis were used to identify the correlation between Ann Ardor stage, blood cells count, bone marrow abnormalities, erythrocyte sedimentation rate (ESR), serum ferritin and TNF-alpha expression. RESULTS: The levels of TNF-alpha had significant difference in different types of lymphoma (P<0.05). High positive and levels in Hodgkin lymphoma [HL, 72.72% and (43.12+/-15.28) ng/L], aggressive non-HL [NHL, 67.86% and (40.73+/-16.65) ng/L], and indolent NHL [57.14% and (53.18+/-20.47) ng/L]. Cox regression analysis showed that Ann Ardor stage, bone marrow abnormalities, ESR, and the levels of TNF-alpha were independent risk factors for lymphoma with poor prognosis. CONCLUSION: As an independent factor, TNF-alpha may play a role in the development of lymphoma and is an important prognostic factor. PMID- 25543708 TI - [Evaluation of the immune target effects of corticosteroids, rituximab or gamma globulin for treatment of immune thrombocytopenia]. PMID- 25543706 TI - [Clinical features and risk factors analysis of acute graft-versus-host disease in patients with related HLA-haploidentical non T cell-depleted in vitro peripheral hematopoietic stem cell transplantation]. AB - OBJECTIVE: To study the clinical features of acute graft-versus-host disease (aGVHD) and its risk factors for the related HLA-haploidentical non T cell depleted in vitro peripheral hematopoietic stem cell transplantation (RHNT PBSCT). METHODS: From July 2002 to December 2012, 104 patients who underwent the RHNT-PBSCT were enrolled to analyze the incidences, location and its risk factors of aGVHD, compared with those of the 103 patients who received the HLA-matched sibling non T cell-depleted in vitro PBSCT (MSNT-PBSCT) in the same period. RESULTS: (1)The cumulative incidence of aGVHD in the RHNT-PBSCT group was significantly higher than the MSNT-PBSCT group [(56.2+/-4.7)% vs (34+/-3.6)%, P<0.05], but the cumulative incidences of II-IV and III-IVgrade aGVHD had no significant difference between the two groups[(39.5+/-2.9)% vs (21.2+/-5.4)%, P>0.05; (12.6+/-4.1)% vs (10.8+/-2.4)%, P>0.05]. (2)The cumulative incidence of cutaneous aGVHD was significantly higher in RHNT-PBSCT group than that in MSNT PBSCT group [(42.3+/-3.2)% vs (17.5+/-2.3)%, P<0.05]. The cumulative incidences of liver and gastrointestinal aGVHD between the two groups had no significant difference [(7.7+/-2.1)% vs (12.6+/-3.4)%, P>0.05; (16.3+/-4.5)% vs (10.3+/ 2.5)%, P>0.05]. (3)The 3-year disease free survival (DFS) and overall survival(OS) of RHNT-PBSCT group and MSNT-PBSCT group were (63+/-5.5)%, (65.2+/ 4.7)% and (74.2+/-5.4)%, (77.4+/-5)% respectively, without significance (P=0.078, P=0.052). (4)aGVHD occurrence with HLA haplotype (P=0.003) and matched loci (P=0.002) were significantly correlated by univariate analysis. Multivariate analysis showed that only the HLA typing is a risk factor for aGVHD (HR=1.891, P=0.03). CONCLUSION: Although the incidence of total aGVHD in RHNT-PBSCT protocol is higher than that in MSNT-PBSCT, but there was no significance in severe aGVHD and cutaneous aGVHD was the common type, which indicates that RHNT-PBSCT protocol is feasible. PMID- 25543709 TI - [Clinical implications of immune paresis in symptomatic multiple myeloma patients]. PMID- 25543710 TI - [Reduced intensive chemotherapy for children with Down syndrome-associated acute leukemia: two cases report and literature review]. PMID- 25543711 TI - [Essential thrombocythemia with JAK2 V617F mutation transformed into acute myeloid leukemia without JAK2 V617F mutation:case report and literature review]. PMID- 25543712 TI - [Blastic plasmacytoid dentritic cell neoplasm:two cases report and literature review]. PMID- 25543713 TI - [Current outlook on mutations of myeloproliferative neoplasms]. PMID- 25543714 TI - [Advances in immunotherapy for relapsed-refractory diffuse large B cell lymphoma]. PMID- 25543715 TI - [Myeloma cancer stem cells:the new target for multiple myeloma]. PMID- 25543716 TI - Insight into core-shell dependent anoxic Cr(VI) removal with Fe@Fe2O3 nanowires: indispensable role of surface bound Fe(II). AB - In this study, we investigated the anoxic Cr(VI) removal with core-shell Fe@Fe2O3 nanowires. It was found the surface area normalized Cr(VI) removal rate constants of Fe@Fe2O3 nanowires first increased with increasing the iron oxide shell thickness and then decreased, suggesting that Fe@Fe2O3 nanowires possessed an interesting core-shell structure dependent Cr(VI) removal property. Meanwhile, the Cr(VI) removal efficiency was positively correlated to the amount of surface bound Fe(II). This result revealed that the core-shell structure dependent Cr(VI) removal property of Fe@Fe2O3 nanowires was mainly attributed to the reduction of Cr(VI) by the surface bound Fe(II) besides the reduction of Cr(VI) adsorbed on the iron oxide shell via the electrons transferred from the iron core. The indispensable role of surface bound Fe(II) was confirmed by Tafel polarization and high-resolution X-ray photoelectron spectroscopic depth profiles analyses. X ray diffraction patterns and scanning electron microscope images of the fresh and used Fe@Fe2O3 nanowires revealed the formation of Fe(III)/Cr(III)/Cr(VI) composite oxides during the anoxic Cr(VI) removal process. This study sheds a deep insight into the anoxic Cr(VI) removal mechanism of core-shell Fe@Fe2O3 nanowires and also provides an efficient Cr(VI) removal method. PMID- 25543717 TI - Immobilizing highly catalytically active noble metal nanoparticles on reduced graphene oxide: a non-noble metal sacrificial approach. AB - In this work, we have developed a non-noble metal sacrificial approach for the first time to successfully immobilize highly dispersed AgPd nanoparticles on reduced graphene oxide (RGO). The Co3(BO3)2 co-precipitated with AgPd nanoparticles and subsequently sacrificed by acid etching effectively prevents the primary AgPd particles from aggregation. The resulted ultrafine AgPd nanoparticles exhibit the highest activity (turnover frequency, 2739 h(-1) at 323 K) among all the heterogeneous catalysts for the dehydrogenation of formic acid to generate hydrogen without CO impurity. The sacrificial approach opens up a new avenue for the development of high-performance metal nanocatalysts. PMID- 25543718 TI - Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells. AB - Radiation-induced heart disease (RIHD) is becoming an increasing concern for patients and clinicians alike due to the use of radiotherapy for the treatment of breast cancer, Hodgkin's lymphoma, pediatric cancer and tumors of the thorax. However, the mechanisms underlying this phenomenon remain largely unknown. As the senescent cell fraction following irradiation is known to increase, in the present study, we investigated whether ionizing radiation (IR) causes the onset of heart disease by inducing cellular senescence in cardiomyocytes. In the present study, we evaluated the effects of IR on HL-1 and H9C2 cells, cells predominantly used in in vitro myocardial cell models. We found that the exposure of the HL-1 and H9C2 cells to IR induced reactive oxygen species (ROS)-mediated cellular senescence, as shown by staining of senescence-associated beta galactosidase (SA-beta-gal). The levels of ROS in irradiated cells were determined using the fluorescent dye, 2', 7'-dichlorodihydrofluorescein diacetate (DCF-DA). Notably, the expression of corin, a cardiac protease that is essential for the proteolytic cleavage of natriuretic peptides, was significantly decreased following the exposure of the cells to IR. Importantly, the knockdown of corin by RNA interference enhanced IR-induced senescence. On the contrary, the overexpression of natriuretic peptides reversed the IR-induced senescence. Taken together, our data suggest that defects in corin function and the inhibition of natriuretic peptides following exposure to IR may contribute to the development of RIHD through the acceleration of cellular senescence. PMID- 25543720 TI - C-H bond functionalization via [1,5]-hydride shift/cyclization sequence: approach to spiroindolenines. AB - A concise synthesis of spiroindolenines from 2-substituted (Me, Et) indoles and 2 (pyrrolidin-1-yl)benzaldehydes has been developed via a [1,5]-hydride shift/cyclization sequence. This method features a wide substrate scope and an operationally simple procedure, affording the spiroindolenines in good to excellent yields and moderate diastereoselectivity (3.5/1 dr). When the inseparable mixture of spiroindolenine isomers were washed with isopropyl ether after flash chromatography, the major isomers could be obtained in up to >20/1 dr. PMID- 25543721 TI - Prolixus (Acari: Trombidiformes: Tenuipalpidae) newly recorded from New Zealand: A new species from Cyperaceae and its ontogenetic patterns in chaetotaxy. AB - The genus Prolixus (Acari: Tenuipalpidae) was represented by two species from Australian sedges prior to this study. A new species, Prolixus meyerae sp. nov., is here described and illustrated from leaves of Gahnia (Cyperaceae) in Auckland, New Zealand. In this paper, we present the ontogenetic additions in idiosomal and leg chaetotaxy from larva to adult. A key to world species of Prolixus is also proposed. PMID- 25543722 TI - The trypanorhynch cestode fauna of Borneo. AB - Borneo is considered a centre for biodiversity in both the terrestrial and aquatic environments. However, information on the diversity of parasites and trypanorhynch cestodes infecting sharks and rays in particular is rather limited at present. During a large-scale study focusing on the parasite diversity of elasmobranchs from Malaysian and Indonesian Borneo a total of 520 spiral intestines of elasmobranchs were collected during seven years of extensive sampling. Trypanorhynch cestodes were discovered in 163 specimens belonging to 43 different elasmobranch species (i.e. 17 species of sharks and 26 species of rays). Overall, 50 species of trypanorhynchs were recovered from the hosts' spiral intestines, some of which represented new species and genera that have been subsequently described. Numerous new host records are added for previously described species. Of the 50 trypanorhynch species present in waters off Borneo 30 (= 60%) were recovered from rays, while 20 species (= 40%) were found in sharks. The geographical distribution of these cestode species was dominated by taxa that occur in the Indo-west Pacific (= 30%) followed by species endemic to Borneo (= 28%). Nine species (= 18%) are found both in Borneo and Australia or have a cosmopolitan distribution. The present study also assessed the host specificity for 16 species belonging to three prominent trypanorhynch genera recovered from elasmobranchs from Borneo (i.e. Dollfusiella Campbell & Beveridge, 1994, Prochristianella Dollfus, 1946 and Parachristianella Dollfus, 1946). Most species (= 63%) were euryxenous utilizing hosts from different orders or even classes, with only a single species (i.e. Dollfusiella imparispinis Schaeffner & Beveridge, 2013) being oioxenous utilizing a single host species. The remaining species (= 31%) were mesostenoxenous utilizing different host species from a single genus. The least host specific taxa were the three representatives of Parachristianella and Prochristianella clarkeae Beveridge, 1990. PMID- 25543723 TI - Development sites, feeding modes and early stages of seven European Palloptera species (Diptera, Pallopteridae). AB - Two hundred and ninety-eight rearing records and 87 larvae and puparia were obtained of seven species of Palloptera Fallen (Diptera, Pallopteridae), mainly in Scotland during 2012-2013. The third stage larva and puparium of each species were assessed morphologically and development sites and feeding modes investigated by rearing, observation and feeding tests. Early stages appear to be distinguished by the swollen, apico-lateral margins of the prothorax which are coated in vestiture and a poorly developed anal lobe with few spicules. Individual pallopteran species are separated by features of the head skeleton, locomotory spicules and the posterior respiratory organs. Five species can be distinguished by unique character states. Observations and feeding tests suggest that the frequently cited attribute of zoophagy is accidental and that saprophagy is the primary larval feeding mode with autumn/winter as the main period of development. Food plants were confirmed for flowerhead and stem developing species and rain is important for maintaining biofilms on which larvae feed. Due to difficulties in capturing adults, especially males, the distribution and abundance of many pallopteran species is probably underestimated. Better informed estimates are possible if early stages are included in biodiversity assessments. To facilitate this for the species investigated, a key to the third stage larva and puparium along with details on finding them, is provided. PMID- 25543724 TI - Description of a new leech species of Helobdella (Clitellata: Glossiphoniidae) from Mexico with a review of Mexican congeners and a taxonomic key. AB - To date, six species of the leech genus Helobdella have been recorded from Mexico: Helobdella atli, Helobdella elongata, Helobdella octatestisaca, Helobdella socimulcensis, Helobdella virginiae and Helobdella temiscoensis n. sp. This new species is characterized by a lanceolate body, the presence of a nuchal scute, uniform brown pigment on both dorsal and ventral surfaces, the absence of papillae, well-separated eyespots, six pairs of testisacs and five pairs of crop caeca, the last of which forms posterior caeca. In addition, we provide new geographic records for Helobdella species from Mexico resulting from our own collections, vouchers deposited at the Coleccion Nacional de Helmintos from the Instituto de Biologia, UNAM, Mexico and vouchers at the Invertebrate Zoology Collection of the Smithsonian's National Museum of Natural History (USNM) Washington D.C., USA. We present a comprehensive review of Mexican Helobdella species, including the new species, with notes on the characteristic morphology and geographic distribution of each species with 91 new records from 20 states. In addition, we provide a taxonomic key for the identification of the Mexican species. PMID- 25543725 TI - A contribution to the fauna of raspy crickets (orthoptera: gryllacrididae: gryllacridinae) in Korea. AB - The little known raspy cricket subfamily Gryllacridinae is reviewed for Korea. Three species are confirmed through material examination and are taxonomically considered as follows: Eugryllacris japonica (Matsumura et Shiraki, 1908) comb. nov. is transferred from Prosopogryllacris japonica (Matsumura et Shiraki, 1908), Nippancistroger testaceus (Matsumura et Shiraki, 1908) has a newly proposed junior synonym Nippancistroger koreanus Storozhenko & Paik, 2003 syn. nov., and Metriogryllacris tigris sp. nov. is newly described from the far southern Yeoseo do Island. PMID- 25543726 TI - Two new cleistocheliferous species of Clathria of sciophilous habitats from
Northeastern Brazil (Poecilosclerida: Demospongiae: Porifera). AB - We describe two new species of Clathria (Microciona) Bowerbank, 1862: C. (M.) crassitoxa sp. nov. and C. (M.) trairae sp. nov. from Paraiba State (Northeastern Brazil). All are sciophilous species and are represented by small fragments removed from the substrate. Both new species have cleistochelae, and are compared with their cleistocheliferous congeners, differing from all of them by the possession of different combinations of other megascleres and microscleres. PMID- 25543727 TI - New species of Antocha Osten Sacken, 1860 crane flies (Diptera: Limoniidae) for South Korea. AB - New species Antocha (Antocha) koreana from South Korea is described and illustrations of the distinguishing morphological features, including wing venation, male and female genitalia and male antenna, are provided with a discussion on distinguishing newly described species from other similar species. Habitat information for new species is presented. Antocha (Antocha) subconfluenta Alexander, 1930 is new record for Korean fauna and first record from outside Japan. PMID- 25543728 TI - A new species of Acledra s. str. (Hemiptera: Heteroptera: Pentatomidae)
from the highlands of Argentina and Bolivia, with a checklist and key to the species of the nominate subgenus. AB - Acledra (Acledra) bichromocornis n. sp. from the highlands of Argentina and Bolivia is described. A checklist of the species of Acledra s. str. is provided, including the distribution by country. A key to the species of Acledra s. str. is included. PMID- 25543730 TI - The discovery of a second species of Mallophthiria Edwards (Diptera, Bombyliidae, Crocidiinae) from Chile. AB - The Neotropical genus Mallophthiria Edwards is restricted to Chile (Concepcion and Choapa) and comprises M. lanata Edwards, 1930 and M. elguetai sp. nov. The new species is described and illustrations of the external morphology of adults and male and female terminalia are also included. PMID- 25543729 TI - Satyrichthys kikingeri Pogoreutz, Vitecek & Ahnelt, 2013, a junior synonym of Satyrichthys laticeps (Schlegel, 1852) (Actinopterygii: Teleostei: Peristediidae). AB - Satyrichthys kikingeri Pogoreutz, Vitecek & Ahnelt, 2013 was described as a new species based on a single dried specimen from the Maldives, Indian Ocean. Although this species was considered to differ from the most similar species of the genus, S. laticeps (Schlegel, 1852), by numbers of barbels and anal fin rays, and several morphometric characters, it is clear that both species are inseparable as these characters were misinterpreted in the holotype in the original description of S. kikingeri. Therefore, S. kikingeri is a junior synonym of S. laticeps. PMID- 25543731 TI - Dakotaseps gen. nov., a replacement name for the lizard genus Dakotasaurus Nydam 2013, a junior homonym of the ichnotaxon Dakotasaurus Branson and Mehl 1932. PMID- 25543732 TI - Fleas (Insecta-Siphonaptera) of Chile: a review. AB - This study presents a revision of the fleas (Siphonaptera) in Chile, gathered from 1993-2013 in response to a request to update our knowledge of the fauna of this country, as catalogued by Beaucournu & Gallardo in 1991 and 1992. For each taxon we give the depository of the type, the main references concerning it, its general distribution, particularly in Chile, and its known hosts, mainly in this country. Our review of the existing literature on fleas of Chile gives information on a total of 8 families, 11 subfamilies, 31 genera, 9 subgenera and 112 species (with 11 subspecies). The hosts are represented by 21 families of mammals (91 species) and 16 of birds (27 species). In addition we present 21 new reports of fleas for Chile and 165 new localities. PMID- 25543733 TI - A new genus and species of Serpulidae (Annelida, Polychaeta, Sabellida) from the Caribbean Sea. AB - A new genus and species of Serpulidae (Annelida, Polychaeta) from the Caribbean Sea. Turbocavus secretus (gen. nov. and sp. nov.) is described from shallow hard substrates (0.5-3 m) in wind-sheltered bays of St. John, U.S. Virgin Islands and Curacao, as well as from diving depths (46-49 m) around Bonaire (Leeward Antilles), Caribbean Sea. The new taxon, which has from 7 to 19 thoracic chaetigers and up to 335 abdominal chaetigers, bears a unique type of thoracic chaeta which is multifolded at the base and continues with a groove tapering to the capillary tip. The new serpulid has unique 18S rRNA sequences and genetic analysis of the 18S rRNA gene situates the new genus at the basis of the serpulid cladogram, well separated from other genera, and close to Filograna/Salmacina and Protula. PMID- 25543734 TI - A new colorful species of Pristimantis (Anura: Craugastoridae) from the eastern flank of the Cordillera Central in Colombia . AB - We describe a new species of Pristimantis from the humid forests on the eastern flank of the northern Cordillera Central in Colombia (6o 23' 19.3554" N, 75o 1' 24.0594" W; ca. 1150 m.a.s.l.). Pristimantis jaguensis sp. nov. is characterized by an extraordinary variation in color and is readily distinguished from congeneric species by lacking nuptial pads, discoidal fold and conical calcar tubercles; flanks and belly white to cream without blotches as well as iris yellow ocher to copper with thick brown reticulation and cream sclera. Molecular phylogenetic analyses recovered the new species in a clade with species mostly distributed in Ecuador. Our finding suggests that new taxa can still be discovered in the Middle Magdalena River valley of Colombia despite the extensive sampling this region has received during the last decades. PMID- 25543735 TI - On some sea cucumbers from Ghana (Echinodermata: Holothuroidea) with descriptions of a new genus and one new species. AB - This paper reports on some sea cucumbers (Holothuroidea) in the collections of the NHMUK, taken off the coast of Ghana. Most result from collections around Accra during the years 1949-52. A couple of other species are included. Altogether six species are here reported, viz. Holothuria (Holothuria) dakarensis Panning, 1939; Holothuria (Semperothuria) imitans Ludwig, 1875; Holothuria (Vaneyothuria) lentiginosa lentiginosa (von Marenzeller,1893); Stereoderma congoana (Heding, 1935); Ocnus cruciformis Thandar n. sp. and Leptopentacta cabindaensis (Cherbonnier, 1949) herein transferred to a new genus Cherbocnus Thandar erected for this purpose. Another West African species, Cladodactyla monodi Cherbonnier, 1950 is referred to Stereoderma. All cucumariids are West African forms whereas the holothuriids are shared with the North-West Atlantic Ocean. PMID- 25543736 TI - A new genus of the tribe Caliscelini (Hemiptera, Fulgoroidea, Caliscelidae) from Vietnam. AB - A new genus Annamatissus Gnezdilov et Bourgoin gen. nov., including the new species, Annamatissus tami Gnezdilov et Soulier-Perkins sp. nov. is described in the family Caliscelidae from the Bi-Doup massif in Lam Dong Province of Vietnam. The new taxon represents only the second genus of the tribe Caliscelini known from Vietnam. An identification key to separate Gelastissus Kirkaldy from Annamatissus gen. nov. is provided together with a check list of the Caliscelidae of Vietnam and their distribution. New distribution data in Vietnam are given for Cicimora sicildia Emeljanov, 1998 and Gelastissus hokutonis (Matsumura, 1916). PMID- 25543737 TI - Eriophyoid mites (Acari: Prostigmata: Eriophyoidea) from Hungary: a new species on Agrimonia eupatoria (Rosaceae) and new record on Convolvulus arvensis (Convolvulaceae). AB - A new species of eriophyoid mite, Aculus castriferrei n. sp., associated with Agrimonia eupatoria (Rosaceae) is described and illustrated from Hungary. Morphological differences distinguishing this vagrant species from other rosaceous inhabiting congeners are discussed. Aceria malherbae Nuzzaci is a new record for the eriophyoid fauna of Hungary after it was found causing severe damage symptoms to Convolvulus arvensis L. (Convolvulaceae). PMID- 25543738 TI - A new species of Dasineura Rondani (Diptera: Cecidomyiidae) in flower galls of Camassia (Asparagaceae: Agavoideae) in the Pacific Northwest, USA. AB - A new species, Dasineura camassiae Gagne (Diptera: Cecidomyiidae), is described, illustrated and compared to some of its congeners from related hosts and western North America. The new species causes flower galls on Camassia (Agavoideae; Asparagaceae) in the Pacific Northwest. Its current known distribution is Oregon and Washington, USA. Larvae develop in spring in flowers of Camassia spp., causing the young ovaries to enlarge prematurely and eventually abort, without forming seeds or mature fruit. Full-grown larvae crawl out of the gall in rapid succession and drop to the soil where they pupate; they remain there until spring of the following year when the adults emerge and lay eggs. The galls they induce in camas lily buds represent the first known association of the cosmopolitan genus Dasineura with the group of plants that includes Agave and its relatives. PMID- 25543739 TI - Leptophlebiidae (Ephemeroptera) of the Serra do Tepequem, Roraima State, Brazil: new records and description of two new species. AB - Miroculis (Miroculis) eldorado sp. nov. and Ulmeritoides passorum sp. nov. are described based on material from Serra do Tepequem, Roraima State, Brazil. Additional records of Leptophlebiidae genera and species are made. Askola Peters, 1969, Farrodes Peters, 1971, Microphlebia Savage & Peters, 1983, Hydrosmilodon Flowers & Dominguez, 1992, Hagenulopsis minuta Spieth, 1943 and Simothraulopsis demerara (Traver, 1947) are recorded for the first time in Roraima State. Simothraulopsis janae Mariano, 2010 is recorded for the first time in the Northern Brazil. PMID- 25543740 TI - First record of the genus Caenophanes Foerster (Hymenoptera: Braconidae: Doryctinae) for America north of Mexico with a description of a new species from Wyoming USA . AB - The first species of Caenophanes Foerster recorded from America north of Mexico is described: Caenophanes harlowi Haimowitz and Marsh, and a key to distinguish the two described New World species is provided. We discuss evidence that suggests that Caenophanes is likely to have cosmopolitan distribution and may be more common than might be anticipated from the current number of described species. PMID- 25543741 TI - Taxonomic consequences of cryptic speciation in the Golden Whistler Pachycephala pectoralis complex in mainland southern Australia. AB - The Golden Whistler (Aves: Passeriformes: Pachycephalidae) Pachycephala pectoralis sensu lato has long played a key role in the development of the theory of allopatric speciation (Mayr 1932a, b; Mayr 1942; Galbraith 1956). The P. pectoralis species complex formerly comprised 60-70 nominal subspecies and so had a distribution spanning the Indo-Pacific (Boles 2007). More recent taxonomic treatments consider the complex as multiple species-level taxa largely circumscribed by geography (Dickinson and Christidis 2014; Gill and Donsker 2014). In Australia, the endemic species P. pectoralis sensu stricto is sympatric with the closely related Mangrove Golden Whistler P. melanura. However, as the latter's English name suggests, P. melanura is closely tied to mangroves in Australia, southeast New Guinea, and islets in the Bismarck Archipelago. Diagnostic plumage traits separating the two species are subtle: males of P. melanura have more extensively black tails and a greyer upper surface to the remiges, and females are usually yellower ventrally. All Pachycephala species, especially those in the P. pectoralis-melanura species complex, have recently become the focus of DNA sequence-based studies (Jonsson et al. 2008, 2014; Andersen et al. 2014). Data from most populations have now been analysed phylogenetically to better understand relationships and thus the history of evolution and speciation processes within and between both species. This has also been used in studies of the group's historical biogeography to provide information as to the age of taxa and their spread across oceanic archipelagos and continents (Jonsson et al. 2014). Here we discuss the taxonomic implications of a result that has emerged consistently and independently in these studies, concerning the systematics of the southern Australian populations in south eastern and south-western Australia, both of which have been ascribed to P. p. fuliginosa since Galbraith (1956), and we show that the name P. occidentalis Ramsay, 1878 is available for the western population and should be used for it. PMID- 25543742 TI - A checklist of the snake fauna of Guinea, with taxonomic changes in the genera Philothamnus and Dipsadoboa (Colubridae) and a comparison with the snake fauna of some other West African countries. AB - We present here the results of a study of 4,906 snakes from Guinea belonging to 95 species collected from 2002 to 2013 at 54 localities in all administrative regions of the country. We resurrect Dipsadoboa guineensis from the synonymy of D. brevirostris and consider the latter species a junior synonym of D. duchesnei. In addition we resurrrect Philothamnus pobeguini and P. belli from the synonymy of P. heterodermus. 19 species were not previously collected in this country, including Letheobia coecata, Tricheilostoma bicolor, Myriopholis rouxestevae, Rhinoleptus koniagui, Python regius, Grayia tholloni, Natriciteres fuliginoides, Philothamnus heterolepidotus, Thrasops aethiopissa, Amblyodipsas unicolor, Gonionotophis granti, Mehelya crossi, Prosymna gregeirti, Prosymna meleagris, Rhamphiophis oxyrhynchus, Elapsoidea trapei, Naja katiensis, Naja senegalensis and Echis jogeri. Based on a critical review of literature and our own data, we compare the currently known snake fauna of Guinea (104 species) with that of Sierra Leone (65 species), Liberia (63 species), Ivory Coast (101 species), Ghana (102 species), Togo (93 species), Benin (72 species) and Nigeria (118 species). PMID- 25543743 TI - Contribution to a revision of the genus Pratylenchoides Winslow, 1958 (Nematoda: Merliniidae), with redescription of P. erzurumensis Yuksel, 1977 from Iran. AB - Morphological and morphometric studies were conducted on the populations and paratypes of 14 species of the genus Pratylenchoides, including P. alkani, P. acuticauda, P. arenarius, P. arenicola, P. bacilisemenus, P. crenicauda, P. erzurumensis, P. heathi, P. laticauda, P. ritteri, P. rivalis, P. sheri, P. utahensis and P. variabilis. In addition, P. erzurumensis was redescribed based on a bisexual population from western Iran. The conoid head of males is an additional diagnostic character of this species distinguishing it from the closely related P. laticauda and P. camachoi. Based on detailed study of the main characters, synonymies of P. arenarius with P. bacilisemenus and P. variabilis with P. crenicauda are proposed. Synonymy of P. alkani with P. ritteri is supported also by morphological and biological evidence. Some taxonomic notes are made on some other species of the genus. Finally, a diagnostic compendium and key is provided for species identification. PMID- 25543744 TI - A review of the legged mealybugs on bamboo (Hemiptera: Coccoidea: Pseudococcidae) occurring in China. AB - Twenty-two species of legged mealybugs occur on bamboo (Poaceae: Bambusoideae) in China. These species are reviewed and two of them are described for the first time: Dysmicoccus luoyangensis Li & Wu, sp. nov. and Trionymus indocalamus Li & Wu, sp. nov. Two new combinations are established: Pseudococcus bambusicola Takahashi and Kaicoccus bambusus Wu are transferred to genus Formicococcus Takahashi as F. bambusicola (Takahashi) comb. nov. and F. bambusus (Wu) comb. nov., respectively. Formicococcus bambusicola, Heliococcus bambusae (Takahashi), Neoripersia miscanthicola Takahashi and Trionymus formosanus Takahashi are redescribed and reillustrated based on type specimens. Brief notes are provided for Balanococcus kwoni Pellizari & Danzig, B. zhejiangensis Li & Wu, Dysmicoccus dengwuensis Ferris, D. indocalamus Wu, Eumyrmococcus smithii Silvestri, Ferrisicoccus angustus Ezzat & McConnell, Heliococcus lingnaniae Wang, H. takae (Kuwana), Heterococcus abludens Borchsenius, Miscanthicoccus miscanthi (Takahashi), Palmicultor lumpurensis (Takahashi), Paraporisaccus guizhouensis Lu & Wu, Paraserrolecanium fargesii Wu, Pseudantonina magnotubulata Borchsenius and Trionymus bambusae (Green). A key to the species of legged mealybugs on bamboo occurring in China is given. A list of bamboo mealybugs worldwide is also provided. PMID- 25543745 TI - Grasshoppers of the Mascarene Islands: new species and new records (Orthoptera, Caelifera). AB - The grasshopper fauna of Mascarene Islands (Mauritius, Rodrigues and La Reunion), in South Western Indian ocean is examined. Numerous field surveys and examination of museum specimens recorded twenty species of Grasshoppers on the archipelago. Five of them are new records, including a new species: Odontomelus ancestrus n. sp. restricted to Round Island, a 2 km2 islet North to Mauritius. Despite intensive searching, five of the non endemic species once recorded on the archipelago have not been recorded again and might correspond to temporary settlements/introductions. A key to Mascarene grasshoppers is given. PMID- 25543747 TI - The genus Epidapus Haliday (Diptera, Sciaridae) in New Caledonia, with the description of four new species. AB - The following species of the genus Epidapus Haliday, 1851 are recognized from New Caledonia: Epidapus (s. str.) aciculatus sp. n., E. (Pseudoaptanogyna) angulatus sp. n., E. (s. str.) formosus sp. n., E. (Zuhalia) primus Mohrig, 2004 and E. (s. str.) triquetrus sp. n. The new species are described, and a key to the local species is given. PMID- 25543746 TI - A survey of Euphorinae (Hymenoptera: Braconidae) of southern Iran, with description of a new species. AB - A faunistic survey of Euphorinae (Hym., Braconidae) in southern Iran, as well as an updated checklist of the genera and species in Iran, are presented. Sampling was performed using Malaise traps at different locations of Hormozgan province and Qeshm Island in Persian Gulf during 2011-2013. In total, 38 species belonging to 10 genera are listed from Iran. The recorded species belong to the following genera: Allurus Forster, 1862 (two species), Chrysopophthorus Goidanich 1948 (one species), Dinocampus Forster, 1862 (one species), Ecclitura Kokujev, 1902 (one species), Leiophron Nees von Esenbeck, 1819 (10 species), Meteorus Haliday, 1835 (12 species), Perilitus Nees von Esenbeck, 1819 (five species), Syntretus Forster 1862 (three species), Wesmaelia Foerster, 1862 (one species) and Zele Curtis, 1832 (two species). Allurus lituratus (Haliday 1835), Dinocampus coccinellae (Schrank, 1802), Leiophron (Peristenus) grandiceps (Thomson 1892), Meteorus rubens (Nees, 1811) and Wesmaelia petiolata (Wollaston, 1858) are new records for Hormozgan province and Leiophron (Peristenus) grandiceps (Thomson 1892) is recorded for the first time from Iran. In addition, Meteorus breviterebratus Ameri, Talebi & Beyarslan sp. n. is newly described and illustrated. PMID- 25543748 TI - A new species of Paracaprella Mayer, 1890 (Amphipoda: Caprellida: Caprellidae) from southern Brazil. AB - A new species of the genus Paracaprella is described based on the specimens associated with the algae Sargassum cymosum and Laurencia obtusa that were collected from infralittoral depths (0.5 to 3.0 m) at Sepultura Beach, Bombinhas and Paciencia Beach, Penha, Santa Catarina State, Brazil. This new species differs from the others of the genus by the unique morphology of the males' gnathopod 2: its propodus has a grasping margin provided with a deep groove. An identification key for Paracaprella species is also presented. PMID- 25543749 TI - A new species of Spongilla-fly from Western Africa (Neuroptera: Sisyridae). AB - A new species of spongilla-fly (Neuropterida, Neuroptera, Sisyridae: Sisyra) is described from Western Africa (Guinea and Ivory Coast). This new Sisyra species differs from all other known African species both in its morphology and genitalia, and it seems to be most closely related to a species in Thailand. PMID- 25543751 TI - Revision of the stick insect genus Clitarchus Stal (Phasmatodea: Phasmatidae): new synonymies and two new species from northern New Zealand. AB - We describe two new species of Clitarchus Stal from Northland, New Zealand. Clitarchus rakauwhakanekeneke sp. nov. is described from the Poor Knights Islands and Clitarchus tepaki sp. nov. is described from the Te Paki / North Cape area and the Karikari Peninsula at the northernmost tip of New Zealand. Two new synonymies are proposed including Clitarchus multidentatus Brunner (syn. nov.) and Clitarchus tuberculatus Salmon (syn. nov.) as synonyms of Clitarchus hookeri (White). Clitarchus magnus Brunner, recorded from Thailand, is transferred to Ramulus Saussure and given the replacement name Ramulus changmaiense nom. nov. The holotype of C. multidentatus was recorded as being collected from New Caledonia; however we believe this is a labelling error and the specimen was collected from New Zealand. These taxonomic changes render Clitarchus endemic to New Zealand and consisting of three species; C. hookeri, C. rakauwhakanekeneke and C. tepaki. Keys to the adult males and females of Clitarchus species are given in addition to notes on host plants, ecology and geographic distributions. PMID- 25543752 TI - Palaearctic species of the Spathius exarator species group (Hymenoptera: Braconidae: Doryctinae) with entirely sculptured mesopleuron. AB - The Palaearctic species of the S. exarator species group of the genus Spathius Nees with entirely sculptured mesopleuron are discussed. Four new species, Spathius austriacus sp. nov., S. intercontinentalis sp. nov., S. pseudodentatus sp. nov., and S. sculptipleurum sp. nov., are described and illustrated. Spathius curvicaudis Ratzeburg, 1944 treated here as junior synonym of S. erythrocephalus Wesmael, 1838 (syn. nov.) The key for determination of the Palaearctic species of this group with constantly or temporary sculptured mesopleuron is provided. PMID- 25543753 TI - Two new species and a new record of Comesomatidae (Nematoda, Araeolaimida) from Southern Hikurangi Margin, New Zealand. AB - We describe two new species and provide one new species record of the family Comesomatidae from a submarine canyon habitat on the Southern Hikurangi margin, New Zealand. Vasostoma hexodontium n. sp. is characterized by having an amphideal fovea with three turns, buccal cavity with six teeth and gubernaculum with long and straight caudal apophyses. Sabatieria dispunctata n. sp. is characterized by the absence of cuticle punctations, large amphideal fovea with 4.5 turns, pharynx with posterior bulb, absence of pre-cloacal supplements, strongly arcuate and cuticularized spicules, simple gubernaculum with short caudal apophyses, and vulva opening directed posteriorly. Laimella subterminata Chen & Vincx, 2000, which was originally described from the Beagle Channel and the Magellan Strait (Chile), is recorded from the Southwest Pacific for the first time. PMID- 25543754 TI - Five new species of Disepyris Kieffer, 1905 (Hymenoptera: Bethylidae), with emended generic diagnosis. AB - Five new species of Disepyris Kieffer (Hymenoptera: Bethylidae) are described and illustrated: D. kenyaensis Lim & Azevedo, sp. nov. (Kenya), D. fessus Lim & Azevedo, sp. nov., D. mongoliaensis Lim & Azevedo, sp. nov., D. prolatatus Lim & Azevedo, sp. nov. (Mongolia), D. niveus Lim & Azevedo, sp. nov. (United Arab Emirates) and the genus is first recorded from Yemen, based on a female of D. guigliae (Benoit). The diagnosis of Disepyris is emended by a combination of following characteristics: head with palpal formula 6:3; ventral surface of antennal flagellomeres III-XI with one pair of parallel basiconic sensillae; clypeus with median lobe distinctly wider than lateral lobe; eyes with sparse, very minute hairs; occipital carina present; mesonotum with notauli weakly carinate, present on anterior half of mesoscutum, median area without transverse foveolate or punctate groove; propodeal spiracle present antero-dorsally on propodeal disc, lateral surface of propodeum strigate; forewing without postmarginal vein, long radial flexion line present, medial flexion line divided into two apical lines. Legs polished without sculpture, appressed pubescence absent; mesotibia with sparse, short spines on apical half; hind basitarsus with one row of comb ventrally. PMID- 25543755 TI - Cambarus (Puncticambarus) callainus, a new species of crayfish (Decapoda: Cambaridae) from the Big Sandy River basin in Kentucky, Virginia, and West Virginia, USA. AB - Cambarus (Puncticambarus) callainus, new species, is a stream-dwelling crayfish endemic to the Big Sandy River basin in Kentucky, Virginia, and West Virginia. Within the basin, C. callainus occurs in the Levisa, Tug, and Russell fork watersheds. The new species is morphologically and genetically most similar to Cambarus veteranus, which is endemic to the Upper Guyandotte River basin of West Virginia. The new species can be differentiated from C. veteranus by its more lanceolate rostrum (width less than 50% length), slightly more obtuse suborbital angle, and less well-defined lateral impression at the base of the chelae. PMID- 25543756 TI - Hiding in plain sight: a new species of bent-toed gecko (Squamata: Gekkonidae: Cyrtodactylus) from West Timor, collected by Malcolm Smith in 1924. AB - We describe a new species of bent-toed gecko from a single specimen initially collected in 1924 by Malcolm Smith on Timor Island in the Lesser Sunda Archipelago of Indonesia. Cyrtodactylus celatus sp. nov. is distinguished from all other congeners by the following combination of characters: small adult size; without spinose tubercles on the ventrolateral body fold and along the lateral margin of the tail; 16 longitudinal rows of tubercles at midbody; 42 ventral scales between the ventrolateral folds at midbody; no transversely enlarged, median subcaudal scales; 17 subdigital lamellae (seven basal + ten distal) under the fourth toe; no abrupt transition between postfemoral and ventral femoral scale series. The specimen is the earliest confirmed record of the genus Cyrtodactylus for Timor, and it is the first putatively endemic gecko species described from this island. PMID- 25543757 TI - Reappraisal of the Javanese Bullfrog complex, Kaloula baleata (Muller, 1836) (Amphibia: Anura: Microhylidae), reveals a new species from Peninsular Malaysia. AB - A new species of Narrow-mouthed frog of the genus Kaloula is described from northern Peninsular Malaysia. Kaloula latidisca sp. nov. is genetically and morphologically most similar to K. baleata and K. indochinensis but differs from those and other congeners by the unique combination of the following characters: (1) adult males SVL 49.2-56.2 mm (x=53.5 +/- 3.0; N=4); (2) finger tips expanded into large, transversely expanded discs (disc width 2.8-3.1 mm, x=3.0 +/- 0.1); (3) inner metatarsal tubercle large, oval, distinctly raised, slightly shorter than first toe; (4) three subarticular tubercles on fourth toe; (5) toe webbing formula: I 1-2 II 1-3 III 2-3.5 IV 4-2 V; and (6) yellow to orange irregularly shaped patch on the axillary, inguinal and posterior region of thigh. PMID- 25543758 TI - Leptohelia flexibilis gen. nov. et sp. nov., a remarkable deep-sea stylasterid (Cnidaria: Hydrozoa: Stylasteridae) from the southwest Pacific. AB - Leptohelia flexibilis gen. nov. et sp. nov., the first stylasterid with a combined calcified and non-calcified skeleton, is described from seamounts and the slope off the islands of New Caledonia, in the southwestern Pacific. The new species is distinguished from all other species of the family Stylasteridae by having a non-calcified organic axis, internal to the basal portion of the calcified corallum. The internal axis is flexible and enclosed by a series of up to 10 calcified annuli, allowing passive lateral bending of the colony. Molecular phylogenetic analyses confirm that Leptohelia flexibilis is a stylasterid coral and reveal that the species is closely related to Leptohelia microstylus comb. nov., a southwestern Pacific stylasterid that lacks an internal axis. PMID- 25543759 TI - Ladies in stripes: taxonomic confusion in a potential mimicry complex among Wallacean Coccinellidae (Coleoptera: Coccinellidae). AB - Two species of ladybird beetles, one belonging to Phrynocaria Timberlake (Coccinellni) and the second to Chilocorus Leach (Chilocorini) collected by R.A. Wallace in the Maluku Islands (Indonesia) have identical body size and colour pattern with longitudinal stripes on elytra. Their external features were so similar that G.R. Crotch included both of them in the type series of Chilocorus wallacii Crotch, 1874. The specimen designated as the lectotype of Chilocorus wallacii belongs to Phrynocaria. Coelophora wallacii Crotch, 1874 is also transferred to Phrynocaria (new comb.) and becomes senior homonym and Phrynocaria crotchi new name is proposed for the secondary junior homonym. Chilocorus crotchi sp. nov. is described for the taxon misidentified as Chilocorus wallacii Crotch. PMID- 25543760 TI - Inulin-D-alpha-tocopherol succinate (INVITE) nanomicelles as a platform for effective intravenous administration of curcumin. AB - The aim of this work was to evaluate the potential of INVITE-based nanomicelles, an amphiphilic polymer constituted by inulin (INU) and vitamin E (VITE), as a platform for improving the biopharmaceutical properties of hydrophobic drugs. For this purpose, curcumin was selected as a model and curcumin-INVITE nanomicelles were prepared. This drug delivery system was characterized both in vitro for what concerns the physicochemical properties, blood compatibility, and cellular uptake, and in vivo for the evaluation of the pharmacokinetic profile. It was found that these nanomicelles released curcumin in a controlled manner, and they were able to penetrate cellular membrane. Moreover, they showed an improved pharmacokinetic profile after intravenous administration. In conclusion, INVITE micelles might constitute promising nanocarriers for improving the biopharmaceutical performance of hydrophobic drugs. PMID- 25543762 TI - Study of the genus Opius Wesmael (Hymenoptera: Braconidae: Opiinae) in Southern Iran, with eleven new records. AB - This study was carried out to determine the species of the genus Opius Wesmael, 1835 in Hormozgan province (Southern Iran). Malaise traps and sweep nets were used to obtain adult specimens from various habitats in Hormozgan province during 2011-2013. Fifteen species from the genus Opius belonging to ten subgenera were collected. The subgenera Merotrachys Fischer, 1972 and Opiostomus Fischer, 1972 and eleven species are recorded for the first time from Iran: Opius (Agnopius) nowakowskii Fischer, 1959; Opius (Agnopius) novosimilis Fischer, 1989, Opius (Allophlebus) staryi Fischer, 1958; Opius (Allotypus) damnosus Papp, 1980; Opius (Opiostomus) riphaeus Tobias, 1986; Opius (Opiothorax) minusculae Fischer, 1967; Opius (Pendopius) bajariae Fischer, 1989; Opius (Merotrachys) penetrator Fischer 1966; Opius (Hypocynodus) flavipes Szepligeti, 1898; Opius (Hypocynodus) latidens Fischer, 1990 and Opius (Hypocynodus) latipediformis Fischer 2004. A key for identification of Opius species from southern Iran is provided. PMID- 25543761 TI - Expression of cluster of differentiation-95 and relevant signaling molecules in liver cancer. AB - The present study investigated the protein expression levels of cluster of differentiation (CD)95, caspase-8, caspase-3 and poly(ADP-ribose) polymerase 1 (PARP1) in liver cancer and its association with clinical pathological parameters. The results demonstrated that the expression of CD95 correlated with histological differentiation, liver cirrhosis, lymph node metastasis and distant metastasis (P<0.05), however, no correlations with gender, age, quantity of tumor nodules or T stage were observed (P>0.05). The expression of CD95 was upregulated using a plasmid, which led to an increase in the expression levels of caspase-8 and caspase-3 and a decrease in the expression of PARP1. Upregulation of CD95 also promoted the apoptosis of the liver cancer cells. These results indicated that CD95 was associated with liver cancer and promoted the apoptosis of liver cancer cells by caspase-8, caspase-3 and PARP1. PMID- 25543763 TI - A revision of the genus Ora Clark, 1865 (Coleoptera: Scirtidae) in Argentina (part I)--descriptions of new species. AB - Three new species of the genus Ora Clark are described from Argentina: O. brevieminentia sp. n., O. megadepressa sp. n. and O. sigmoidea sp. n. All the species are characterized by a pair of frontoclypeal foveae, dorsal surface of mandible covered with setae, third labial palpomere arising from the inner margin of second palpomere, anterior pronotal angles distinctly projected anteriorly, a pair of glabrous areas on abdominal ventrites 2-5, ventrite 5 emarginate, with a pair of foveae in females, and tegmen with an apical digitiform lobe. Ora brevieminentia is similar externally to O. gamma Champion and O. platensis Brethes, but it differs in having a more convex body, a smaller total length/elytral width ratio, coarser elytral punctation and a shorter lateral protuberance on the penis. Ora megadepressa is similar externally to O. depressa Fabricius, but differs in that the body is wider, the tegmen is laterally spiny with the lobe less narrowed basally, and the penis is straight with the base and the longer subapical process directed to the right-hand. Ora sigmoidea is similar in body color and shape to O. brevenotata Pic, and the aedeagus resembles that of O. texana Champion. However, the lobe of the tegmen is less protruding, the laminar dorsal piece of the penis is broadened, the apex is truncate, and the S shaped ventral piece is distinctly curved. PMID- 25543764 TI - Lectotype designation for Murex nebula Montagu 1803 (Mangeliidae) and its implications for Bela Leach in Gray 1847. AB - Bela Leach in Gray is a misapplied and broadly defined genus within the family Mangeliidae Fischer, 1883. Examination of material from the Montagu collection at the Royal Albert Memorial Museum & Art Gallery (RAMM) in Exeter (UK) led to the discovery of six specimens of Murex nebula Montagu 1803 (the type species of Bela). This material is considered to belong to the original lot used by Montagu to define his species. We selected the best-preserved specimen as a lectotype. The lectotype and paralectotypes deposited at the RAMM are fully described and illustrated. Furthermore, diagnostic characters for recognizing B. nebula specimens are presented: protoconch shows weak ornamentation; teleoconch is fusiform with slightly convex whorls characterized by broad, suture-to-suture ribs and dense but weak spiral elements; outer lip is thin; anal sinus is shallow, placed on the shoulder ramp. These key features are of basic importance for: i) restricting the usage of the genus Bela and promoting its stability and consistent usage in literature and ii) separating two allied (and sometimes interchanged) genera: Bela and Mangelia Risso 1826. PMID- 25543765 TI - Description of a new species of Microstoma (Pisces, Microstomatidae) from the southwestern Pacific Ocean. AB - A new species of the microstomatid genus Microstoma is described from specimens collected in the SW Pacific Ocean off New Zealand and Australia. Microstoma australis n. sp. differs from M. microsotma of the Mediterranean and Atlantic Ocean in having a higher number of gill rakers and vertebrae. Both species are compared with available data for NE Pacific specimens. PMID- 25543766 TI - A new genus and species of freshwater crab from Madagascar (Decapoda, Brachyura, Potamoidea, Potamonautidae). AB - A new genus and species of freshwater crab is described from Madagascar. The new species is morphologically closest to the three species of the genus Foza Reed & Cumberlidge, 2006, but can easily be distinguished by having a completely smooth carapace with an unarmed anterolateral margin and a mandible with a distinctly shortened anterior lobe. This unusual suite of characters is sufficient to warrant the recognition of a new monotypic genus to accommodate this species. PMID- 25543767 TI - Three new species of Spiladarcha Meyrick, 1913 (Lepidoptera: Urodidae) from Costa Rica. AB - Three new species of Spiladarcha are described from Costa Rica, including S. puravida n. sp., S. septifera n. sp., and S. tuberculata n. sp. The genus Spiladarcha is reported from Costa Rica for the first time. Synapomorphies of Spiladarcha are revised. Photos of adult habitus and genitalia of known sexes are provided. PMID- 25543768 TI - Taxonomic revision of the Nippostrongylinae (Nematoda, Heligmonellidae) arasitic in Oriental Muridae. The genus Paraheligmonelloides Fukumoto, Kamiya & Suzuki, 1980. AB - The genus Paraheligmonelloides Fukumoto, Kamiya and Suzuki, 1980 (Nippostrongylinae) is revised and split into four genera, mainly based on characters of the synlophe not previously considered at the supraspecific level. These characters mainly include the homology of the left ridge with ridge 1', the relative size of the right ridge to the left ridge and to ridge 1' and the distribution of the largest ridges. Paraheligmonelloides sensu stricto, characterized by the homology of the left ridge with ridge 1', contains only the type species, Paraheligmonelloides kenyensis Fukumoto, Kamiya and Suzuki, 1980, parasitic in a lagomorph from Kenya. Krishnasamyos n. gen., characterized by ridge 1' forming a comarete, two minute left ventral ridges and ridge 1 larger than other dorsal ridges, only includes the species Krishnasamyos triangulus n. comb., parasitic in Malaysian murids. Hughjonestrongylus n. gen., characterized by numerous ridges markedly unequal in size, with the largest ridges grouped in relation to the lateral fields, includes Hughjonestrongylus ennisae n. comb., Hughjonestrongylus amplicaudae n. comb., Hughjonestrongylus mirzai n. comb., and Hughjonestrongylus singauwaensis n. comb., all parasitic in murids from Papua Indonesia and Papua New Guinea. Syafruddinema n. gen., characterized by ridge 1 as long as other dorsal ridges and a gap associated with the left lateral field, between ridges 2' and 3', includes Syafruddinema paruromyos n. comb., Syafruddinema annandalei n. comb., and Syafruddinema eropeplios n. comb., parasitic in murids from Malaysia and Indonesia. A key to the proposed genera is provided. PMID- 25543769 TI - Description of the final instar larva of Limnetron antarcticum Forster and notes on its female (Anisoptera: Aeshnidae). AB - The final instar larva of Limnetron antarcticum Forster is described and illustrated for the first time based on one specimen collected in Misiones Province, Argentina. It is compared with L. debile (Karsch). Color pattern and ovipositor morphology of the female imago are described. PMID- 25543770 TI - First New Zealand record of the Australian species Hemiodoecus leai China, 1924 (Hemiptera: Peloridiidae); a hitchhiker on moss. AB - The Australian mossbug Hemiodoecus leai China, 1924, is recorded for the first time in New Zealand based on repeated sampling from a self-sustaining population at Opoho Creek, Dunedin (South Island) since 2011. The history of the discovery of H. leai, probably accidentally introduced with moss used to transport fish ova from Tasmania, is summarised. A brief taxonomic treatment accompanied by illustrations and data on distribution, puts this discovery in context with the 2011 taxonomic review of New Zealand Peloridiidae published in the Fauna of New Zealand series. Biological notes based on field and laboratory observations are also provided. PMID- 25543771 TI - Three new monotypic genera of Trichopolydesmidae from Croatia, Balkan Peninsula (Diplopoda, Polydesmida). AB - Three new monotypic genera are described from underground habitats in Croatia: Balkanodesmus biokovensis gen. n., sp. n., Solentanodesmus insularis gen. n., sp. n. and Velebitodesmus cavernicolus gen. n., sp. n. In all three new genera the prefemoral part of the gonopods is orientated transversely to the main body axis, and all three new genera possess numerous metatergal setae arranged in a few transverse irregular rows, a condition observed in several European trichopolydesmids. These three new genera are very close to the genus Verhoeffodesmus. A distribution map and a brief discussion about the relationship with congeners are provided. PMID- 25543772 TI - Review of the genus Lesteva Latreille, 1797 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini) of Iran and adjacent territories. AB - The type and additional material from adjacent territories of species of the genus Lesteva Latreille, 1797 of Iran are revised. Eight species are recognized, three of which are described as new: L. (s.str.) frischi sp.n. (Iran, Esfahan), L. (s.str.) schawalleri sp.n. (Iran, Elburs) and L. (s.str.) antennata sp.n. (Iran, Golestan). Two synonyms are proposed: L. (s.str.) binotata Reitter, 1901 = L. (s.str.) syriaca Luze, 1903, syn. n., L. (s.str.) longoelytrata longoelytrata (Goeze, 1777) = L. (s.str.) soror Smetana, 1967, syn. n. A key to species known from Iran and new provincial records for L. (s.str.) binotata Reitter, L. (s.str.) longoelytrata longoelytrata (Goeze), L. (s.str.) maculipennis Luze, 1903 and L. (Lestevidia) punctata Erichson, 1839 are provided. L. (s.str.) binotata Reitter and L. (s.str.) maculipennis are redescribed. Aedeagi of all new species, L. (s.str.) binotata, L. (s.str.) longoelytrata longoelytrata and L. (s.str.) maculipennis, as well as the antennae of all species and the variability of elytral maculae for two redescribed species are illustrated. PMID- 25543773 TI - New and little known Coptotriche and Tischeria species (Lepidoptera: Tischeriidae) from Primorskiy Kray, Russian Far East. AB - The paper provides data on two new and two little known Coptotriche Walsingham and Tischeria Zeller species from Primorskiy Kray (=Primorskiy Territory), Russian Far East: Coptotriche minuta Diskus & Stonis, sp. nov., Tischeria unca Diskus & Stonis, sp. nov. are described, T. decidua siorkionla Kozlov and T. sichotensis Ermolaev are redescribed. Currently, together with the described new species, the fauna of Tischeridae of Far Eastern Russia comprises three Coptotriche species and seven Tischeria species. A neotype, replacing the missing type series of T. sichotensis, is designated here. For the first time all four species treated from Russian Far East are illustrated with photographs of the adults and genitalia (T. sichotensis also with photographs of the leaf-mines). PMID- 25543774 TI - Ptyctimous mites (Acari, Oribatida) from the Joint Russian-Vietnamese Biological Expedition (October 2013-April 2014). AB - An annotated checklist of ptyctimous mite taxa, collected from the Joint Russian Vietnamese Biological expedition (October 2013-April 2014) in four forest zones (Dong Nai Biosphere Reserve, Dong Nai Culture and Nature Reserve, Bu Gia Map National Park, Bi Dup-Nui Ba National Park) is provided. It includes 28 species, 16 genera and six families. One new subgenus, Euphthiracarus (Parapocsia) Niedbala subgen. nov., and five new species, Acrotritia paragranulata Niedbala sp. nov., Hoplophthiracarus clavatus Niedbala sp. nov., Steganacarus (Rhacaplacarus) spinus Niedbala sp. nov., Euphthiracarus (Euphthiracarus) quasitakahashii Niedbala sp. nov. and Euphthiracarus (Parapocsia) medius Niedbala sp. nov., are described. Supplementary descriptions of Apoplophora minuscula Niedbala, 2013 (see Niedbala & Ermilov 2013), Arphthicarus parasentus Niedbala, 2000 and Atropacarus (Hoplophorella) stilifer (Hammer, 1961) are presented. PMID- 25543775 TI - Species boundaries of Pardosa concinna and P. lapponica (Araneae: Lycosidae) in the northern Nearctic: morphology and DNA barcodes. AB - The Holarctic Pardosa lapponica (Thorell, 1872) and the Nearctic P. concinna (Thorell, 1877) are the only North American members of the Pardosa lapponica species-group. The morphological similarity between the two species raises the question of whether or not they should be treated as separate species. To examine the boundary between P. lapponica and P. concinna, morphological and genetic variation within and between the species was analysed. Copulatory organ characters of Nearctic specimens were analysed to determine if additional diagnostic characters exist, and the mtDNA COI region was sequenced to look for species-specific variation. Morphometric analysis of copulatory characters in females (e.g. length of median septum) and males (e.g. embolus length) of both species did not reveal diagnostic characters other than the terminal apophysis. No species-specific genetic patterns were found between the two species. The interspecific similarities in morphology and low genetic divergence between Nearctic specimens of P. lapponica and P. concinna contrasts with high genetic divergence between Palearctic and Nearctic specimens of P. lapponica. The results suggest a comprehensive taxonomic revision is necessary for the P. lapponica species-group. PMID- 25543776 TI - The identity of Hyla leucotaenia Burmeister, 1861 (Anura: Hylidae). AB - The German naturalist Carl Hermann Conrad Burmeister (1807-1892) had a prolific scientific career, spanning multiple taxa from diverse insect groups and trilobites to temnospondyls, birds, and extant and fossil mammals (see Berg, 1895). His contributions to anuran taxonomy are concentrated in two books, "Erlauterungen zur Fauna Brasiliensis..." (Burmeister, 1856) and "Reise durch die La Plata-Staaten..." (Burmeister, 1861). The latter is an account of his travels in Argentina and Uruguay from 1857-1860 and includes descriptions of three new species of frogs: Leiuperus nebulosus, Cystignathus mystacinus, and Hyla leucotaenia. While the first two names currently designate valid species, with the combinations Pleurodema nebulosum and Leptodactylus mystacinus respectively, the last name has had a more complex taxonomic history. It involves confusions involving a homonym, its consideration as a junior synonym of Hypsiboas pulchellus (Dumeril & Bibron, 1841)-a widely distributed species in eastern Argentina, southeastern Brazil, and Uruguay (Frost, 2014)-and its actual identity corresponding to another widespread species in the same geographic area, with which it has never before been associated: Scinax squalirostris (A. Lutz, 1925). All these issues are discussed in this paper. PMID- 25543777 TI - New data on Empis Linnaeus (Diptera: Empididae) from Iran, with description of a new species of the subgenus Lissempis Bezzi. AB - Fourteen species of the genus Empis Linnaeus were collected and identified from Iran. Empis (Lisssempis) guilanensis Kazerani & Shamshev sp. nov. is described and illustrated from Guilan province in north central Iran. The following seven species were recorded from Iran for the first time: E. (Euempis) tessellata Fabricius, 1794; E. (Pachymeria) mediterranea (Loew, 1864); E. (P.) obscuripes (Loew, 1873); E. (Polyblepharis) dedecor Loew, 1869; E. (P.) engeli Chvala, 1999; E. (P.) soror Collin, 1937; E. (P.) spirifera Bezzi, 1909. An identification key to the subgenera and species of Empis from Iran are provided. PMID- 25543778 TI - Polyphyly of Hylophilus and a new genus for the Tawny-crowned Greenlet (Aves: Passeriformes: Vireonidae). AB - Once a catch-all taxon for various small, greenish passerines (Sclater 1881), today the genus Hylophilus Temminck contains 15 species of Neotropical greenlets in the avian family Vireonidae (Clements et al. 2013). Although Hylophilus species do share some common anatomical proportions and plumage features (Baird 1866; Ridgway 1904), some striking and concordant differences in habitat, voice, and iris color led Ridgely and Tudor (1989) to posit that the genus might contain sufficient diversity to warrant splitting into multiple genera. PMID- 25543779 TI - A new species of Taeniothrips (Thysanoptera: Thripidae) from India. AB - Taeniothrips bharokariiensis sp. n. is described from specimens collected on ferns from Himachal Pradesh state of India. This is the third species in which S2 setae on abdominal sternite VII are positioned marginally. Partial sequence data of mitochondrial cytochrome c oxidase (mtCOI) from holotype and paratypes is provided. PMID- 25543780 TI - The identity of Pethia punctata, a senior synonym of P. muvattupuzhaensis (Teleostei: Cyprinidae). AB - Francis Day described Pethia punctata from Cochin, on the Malabar (south western) coast of India. Although, the species is now recovered from its synonymy with P. ticto, an accurate diagnosis and description have been lacking. A redescription of P. punctata based on external morphology, osteology and genetics is provided, which revealed that P. muvattupuzhaensis, described from Muvattupuzha River, Ernakulam District, Kerala, India, is its junior synonym. Pethia punctata can be diagnosed from other known species in the genus by a combination of characters including lateral line complete, with 23-25 pored scales; 8 predorsal scales; 1/24/1/31/2 scales in transverse line; dorsal fin originating almost opposite to, or slightly before pelvic-fin origin; gill rakers 7 on first ceratobranchial; 4+26 total vertebrae; a small black humeral spot covering anterior half of the fourth scale of the row below the lateral-line row; two minute dark spots below the humeral spot; a prominent spot on the caudal peduncle, surrounded by a golden hoop covering scales 19-21 of the lateral-line row; and dorsal fin with 2-3 longitudinal rows of black spots, third row occupying only anterior portion of the fin. PMID- 25543781 TI - Revision of the Afrotropical Lycorininae (Ichneumonidae; Hymenoptera) II. Three new Lycorina species and additional distribution records. AB - Three new Afrotropical Lycorina species are described: L. horstmanni sp. nov., L. jacksonfive sp. nov. and L. riftensis sp. nov. The description of L. globiceps is expanded to include the large variability of the colour pattern. New distribution records are provided for L. fici and L. globiceps. An illustrated dichotomous key, and an online interactive matrix key available on www.waspweb.org, are provided for the identification of the seven known Afrotropical Lycorininae species. PMID- 25543782 TI - Biology, early stages and description of a new species of Adelognathus Holmgren (Hymenoptera: Ichneumonidae: Adelognathinae). AB - Adelognathus leucotrochi Shaw & Wahl sp. nov. is described from Britain where it is a univoltine slightly gregarious koinobiont ectoparasitoid of late stage larvae of the tenthredinid sawfly Nematus leucotrochus Hartig feeding on Ribes uva-crispa. Defensive reactions by the host to prospecting females are described. The developmental biology of A. leucotrochi is described in detail: the host is only temporarily paralysed by the injection of a venom that has no other effect on the host, and eggs are laid on the host's dorsum without involvement of the ovipositor-that is, the egg issues direct from the genital opening. Prior to oviposition the adult female parasitoid prepares the site by spreading an adhesive substance from her ovipositor. Host-feeding by adult females occurs on haemolymph and sometimes also other tissues obtained at the site of a wound made always by the mandibles, but appears not to be obligatory. It may be concurrent or non-concurrent with oviposition; in the latter case, it may be either destructive or non-destructive. Larval development is very rapid, taking about 70 hr at 18-22oC, and the host continues to feed for approximately the first half of this period. Five larval instars were detected, and their cephalic sclerites are described and illustrated, as are those of the final instars of a further three species of Adelognathus for comparison. The rather featureless final instar larva is also figured, as is the tough cocoon in which the winter is passed as a prepupa. The biology of some idiobiont Adelognathus species is discussed in comparison with that of A. leucotrochi, and several other instances of eggs not issuing from the ovipositor in non-aculeate ectoparasitoid Hymenoptera, whether koinobionts or idiobionts, are briefly reviewed. It is concluded that this habit seems to arise rather easily when there is direct bodily contact between the adult and the host/prey, as indeed is the case in all carnivorous aculeates that do not practice continuous provisioning. PMID- 25543783 TI - An advanced, new long-legged bird from the Early Cretaceous of the Jehol Group (northeastern China): insights into the temporal divergence of modern birds. AB - We describe a new ornithuromorph bird species, Gansus zheni from the Lower Cretaceous lacustrine deposits of the Jiufotang Formation (Jehol Group), Liaoning Province, China. A cladistic analysis resolves Gansus zheni as the sister taxon of the roughly contemporaneous Gansus yumenensis (Xiagou Formation, Gansu Province), and together as the most immediate outgroup to Ornithurae. Gansus zheni is the most advanced bird known today for the Jehol Biota. Its discovery provides the best-documented case of inter-basinal correlations (Jehol and Changma basins of Liaoning and Gansu provinces, respectively) using low-taxonomic clades of fossil birds. The existence of close relatives of Ornithurae in deposits formed at about 120 million years ago helps to mitigate the long standing controversy between molecular and paleontological evidence for the temporal divergence of modern birds (Neornithes). PMID- 25543784 TI - Description of the final instar larva of Rhionaeschna vigintipunctata (Ris, 1918) (Odonata: Aeshnidae). AB - The final instar larva of Rhionaeschna vigintipunctata (Ris) (Odonata, Aeshnidae) is described for the first time. The description is based on a series of mature female larvae collected in Tucuman (NW Argentina) and reared to imago. It shares the U-shaped distal excision of epiproct with other larvae of the Marmaraeschna group (only R. pallipes and R. brevicercia known from this stage); but the minute tubercle at each side of the cleft of ligula is absent. Other characters unique to R. vigintipunctata include: open ligula (vs. closed in other "Marmaraeschna"), and mandibular formula. A table to distinguish the larvae of the three species of "Marmaraeschna" and biological and distributional data of R. vigintipunctata are included. PMID- 25543785 TI - New species of Elaphidiini (Coleoptera, Cerambycidae) from Bolivia. AB - Five new Elaphidiini species are described from Bolivia including Anelaphus maculatus sp. nov. from Tarija and Mephritus bonasoi sp. nov., M. meyeri, sp. nov., M. punctulatus sp. nov. and M. eleandroi sp. nov. from Santa Cruz. A revised key to all 22 South American Mephritus species is provided. PMID- 25543786 TI - Review of the Eisenia muganiensis (Michaelsen, 1910) species group with description of two new species (Oligochaeta: Lumbricidae). AB - The Eisenia muganiensis species group is established, consisting of a set of Asian earthworm species characterized by elongate, backward placed clitellum and tubercles: Eisenia malevici Perel, 1962; Eisenia muganiensis (Michaelsen, 1910); Eisenia patriciae Szederjesi, Pavlicek, Coskun & Csuzdi, 2014 and Eisenia transcaucasica (Perel, 1967). The species are shortly reviewed and furthermore, two new species of the E. muganiensis group are described, E. kontschani sp. nov. from Turkey and E. malekae sp. nov. from Iran. PMID- 25543787 TI - New species and new record of the rare genera Xynotingis Drake, 1948 and Zeiratingis Drake & Ruhoff, 1961 (Hemiptera: Tingidae) from China. AB - Xynotingis hoytana Drake, 1948 and Zeiratingis hainanensis sp. nov. are recorded from China (Hainan Island). Species of both genera are very rarely collected. This represents the first record of both genera in this country. The new species is described. Illustrations of the involved species are provided as well as a key to the species of the genus Zeiratingis. PMID- 25543788 TI - A new species of Hoplognathoca Suarez, 1962 from Central America and description of male of Hoplognathoca costarricensis Suarez, 1962 (Hymenoptera: Mutillidae). AB - Hoplognathoca jinotega Cambra, Quintero & Brothers, sp. nov., female, from Nicaragua and Guatemala and the male of H. costarricensis Suarez, 1962 are described and illustrated. The genus Hoplognathoca is reported for the first time from Nicaragua. PMID- 25543789 TI - Sawflies of the genus Emphytopsis (Hymenoptera, Tenthredinidae) associated with Stewartia (Theaceae) in Japan. AB - Japanese species of the sawfly genus Emphytopsis Wei & Nie, 1998, are reviewed and the following four species are recognized and keyed: E. flatoserrula Wei, 2011, from Kyushu, E. nigromaculata (Takeuchi, 1952) from Honshu, Shikoku and Kyushu, E. shinoharai Wei & Niu, 2011, from Honshu and Shikoku, and E. vernalis Shinohara, n. sp., from Honshu and Kyushu. Stewartia pseudocamellia Maxim. (Theaceae) is recorded as a host plant for E. nigromaculata and E. vernalis and the larvae of these two species are briefly described. The life history of these two species is discussed based on field observations and rearing records. PMID- 25543790 TI - Redescription of the sun-spider Mummucina titschacki Roewer, 1934 (Solifugae, Mummuciidae) with notes on the taxonomy of the genus. AB - Mummucina Roewer, 1934 is the second largest genus in the South American sun spider family Mummuciidae. The limits of this and other genera are largely unexplored, and the traditional classification system is controversial. In the present contribution, the type species Mummucina titschacki Roewer, 1934 is redescribed, aided by scanning electron micrographs and the examination of a series of 72 specimens (including males) from the type locality in Ecuador. Some taxonomic remarks are made. PMID- 25543791 TI - Taxonomic revision of Pseudorhopalia Wilcox & Papavero, 1971 (Insecta, Diptera, Mydidae, Rhopaliinae), with description of a new species from the Brazilian Amazon . AB - The previously monotypic genus Pseudorhopalia Wilcox & Papavero, 1971 is here revised, with description of a new species, Pseudorhopalia manauara, sp. n. The type-species, P. mirandai (d'Andretta & Carrera, 1951), is only found in northeastern Brazil, in the semiarid Caatinga biome. On the other hand, the new species is found in the humid Brazilian Amazonia, within dense ombrophilous forest and campina (scleromorphic scrub vegetation associated with white sand). PMID- 25543792 TI - Descriptions and key to the larvae of the Tasmanian endemic genus Hoplogonus Parry (Coleoptera: Lucanidae), and comparison with the sympatric Lissotes rudis Lea. AB - The stag beetle (Coleoptera: Lucaindae) genus Hoplogonus Parry is endemic to northeastern Tasmania and contains three recognised species. Descriptions of the imagines have been published previously, but not the larvae. Descriptions of the larvae of the three Hoplogonus species and the sympatric Lissotes rudis Lea (also Lucanidae) are presented and discussed, and a key to aid identification of Hoplogonus larvae is included. The classification of Hoplogonus within the tribe Platycerini is proposed, alongside Lissotes. PMID- 25543793 TI - A new species of Limatulichthys Isbrucker & Nijssen (Loricariidae, Loricariinae) from the western Guiana Shield . AB - Limatulichthys nasarcus n. sp. is described as a new species based on 15 specimens from the Ventuari and Caura Rivers in Southern Venezuela. The new species can be distinguished from its only congener, L. griseus, by the presence of anterior abdominal plates half the size of those at center of abdomen (vs. plates similar in size); distinct spots less than half of diameter of naris across entire dorsum, including snout and head (vs. indistinct dorsal spots larger or equal than diameter of naris); lateral portions of head and opercle with dark well-defined spots larger than those on dorsum (vs. spots on lateral portions of head and opercle equal in size to those on remainder of body); snout profile in dorsal view broadly rounded (vs. acutely triangular); head longer (21.4-24.2 SL vs. 17.7-21.0%); and anal fin longer (15.7-18.0 SL vs. 13.7-15.6%). Distinctiveness of the two species is further supported by their non-overlapping distribution in multivariate morphospace. The disjunct distribution of L. nasarcus across both the Caura and Ventuari rivers exclusive of the main Orinoco River channel contributes to a growing body of evidence supporting the historical connection between headwaters of these drainages. The hypothesized existence of a 'proto-Berbice' paleodrainage provides one explanation for such a connection. PMID- 25543794 TI - A new species of the genus Bathylagichthys (Pisces, Bathylagidae) from New Zealand. AB - Bathylagichthys kobylianskyi n. sp. is described from specimens collected during fisheries surveys of the Exclusive Economic Zone of New Zealand. It was previously misidentified as B. problematicus, from which it differs in having fewer vertebrae (43-45 versus 49-51) and more gill rakers (usually 27-31 versus 25-28). Bathylagichthys kobylianskyi n. sp. is closely related to B. greyae of the Atlantic Ocean as both have two branchiostegal rays and a short supraorbital. The latter species differs from B. kobylianskyi n. sp. in having a more slender body, fewer gill rakers and modally higher number of vertebrae and anal-fin rays. PMID- 25543795 TI - One new species of the Genus Apotrechus (Orthoptera: Gryllacrididae), with provided morphological photographs for five Chinese species. AB - One new species of the genus Apotrechus from China is described, i.e. Apotrechus trilobus Bian & Shi sp. nov.. Meanwhile, a key to the species and the morphological photographs for five Chinese known species are provided in this paper. All material is deposited in the Museum of Hebei University. PMID- 25543796 TI - The larva of Aphylla protracta (Hagen, 1859), and a redescription of the larva of A. angustifolia Garrison, 1986 (Odonata: Gomphidae). AB - The larva of Aphylla protracta is described and figured. It is characterized by 3rd antennomere subcylindrical, flattened on ventral surface, 4.2 times longer than its widest part. Abdomen with dorsal protuberances well developed on S2-4, reduced on S5, vestigial or absent on S6-9; lateral spines lacking entirely, tergites 5-8 with minute reddish setae, tergite 9 with abundant, small, reddish setae on most of its surface and the whole posterior margin; S10 cylindrical, very long, five times longer than its base, much longer than S6+7+8+9. Also, a redescription and figures of A. angustifolia are provided, and a comparison of both species is made. Mainly differences between both species were found in abdominal dorsal protuberances and the presence/absence of small setae on abdominal tergites. PMID- 25543797 TI - Thestral incognitus, a new genus and species of Pentatomidae from Chile (Heteroptera: Pentatomidae: Pentatominae: Carpocorini). AB - Thestral incognitus, new genus and species of Pentatomidae (Pentatominae: Carpocorini) is described from central Chile. The relationships among this new genus and other South American genera are discussed. Also, similarities are noted between Thestral and the Australian genus Poecilotoma. Poecilotoma is tentatively placed in the Carpocorini. A key to aid in the recognition of the genera of Chilean Carpocorini is provided. PMID- 25543798 TI - A review of the zumpti species group of the genus Harpyrhynchoides (Acariformes: Harpirhynchidae)--ectoparasites of passerines. AB - The zumpti species group of the genus Harpyrhynchoides (Harpirhynchidae), parasites of passerines, is revised. A key to the species of this group is provided and data on host associations and geographic distribution of its constituent species are summarized. This group includes six previously recognized species: Harpyrhynchoides alaudinus Bochkov, 2000, H. brevis (Ewing, 1911) comb. nov., H. heatherae Bochkov and Galloway, 2013, H. rubeculinus (Cherny and Sixl, 1971), H. vulgaris Bochkov and Galloway, 2004, and H. zumpti (Fain, 1972). Three species from North American passerines are described as new: H. setophaga sp. nov. from Setophaga ruticilla (Parulidae), H. xanthocephalus sp. nov. from Xanthocephalus xanthocephalus (Icteridae), and H. spizella sp. nov. from Spizella passerina (Emberizidae). Additionally, H. brevis is redescribed based on samples from Coccothraustes vespertinus (type host) and Loxia curvirostra (Passeriformes: Fringillidae) from North America. Harpyrhynchoides kirgizorum Fain et al. 1999 syn. nov. is synonymized with H. zumpti. PMID- 25543799 TI - Taxonomic notes on Australian species of Sciacharis (Magellanoconnus) (Coleoptera: Staphylinidae: Scydmaeninae). AB - Two species of Australian Cyrtoscydmini were placed in the subgenus Magellanoconnus Franz of Sciacharis Broun: S. carinifrons (Franz) and S. kangarouana (Franz) (both originally described in Neuraphoconnus, a junior synonym of Magellanoconnus Franz). Examination of type specimens revealed that these species names, published in the same paper, are synonymous and S. carinifrons is here selected as a valid name. This species is redescribed and its morphological details are illustrated. Possible relationships of Australian Magellanoconnus with Sciacharis s. str. and Euconnus s. str. are discussed. PMID- 25543800 TI - A new species of Boca Lowry & Stoddart, 1997 (Amphipoda: Lysianassoidea: Aristiidae) from a mesophotic coral ecosystem off Puerto Rico, Caribbean Sea. AB - A new species of the genus Boca Lowry & Stoddart, 1997 is described from a mesophotic coral ecosystem off southwestern Puerto Rico, in the Caribbean Sea. The new species is easily recognized from the others in the genus mainly by the following characters: (1) maxilliped, inner plate with 2 long apical simple setae; palp, articles slender, subequal in length; (2) gnathopod 1, propodus slightly elongate, about 2.5 * longer than wide, and palm extremely acute, quite long and distinctly demarked by a robust seta at the palmar corner; (3) gnathopod 2, carpus slightly elongate, about 3.7 * longer than wide; (4) pereopod 5, basis widely expanded posteriorly, posterior margin rounded and smooth, and posteroventral lobe weakly developed. We also present a key to world species of Boca. This is the fifth species of Boca from world's oceans and the first record of the genus from Puerto Rico. PMID- 25543801 TI - Clarias serniosus, a new walking catfish (Teleostei: Clariidae) from Laos. AB - Clarias serniosus, a new Southeast Asian walking-catfish species, is described from the Bolavens Plateau in southern Laos. The new species is a member of the C. batrachus species complex, and can be distinguished from congeners in the complex in having a combination of: occipital process length 15-17 % HL, head length 28.2 28.6% SL, head width 18.5-19.2% SL, head depth 13.0-13.7% SL, distance between the occipital process and the base of the first dorsal-fin ray 8.5% SL, smooth anterior edge of pectoral spine, 67 dorsal-fin rays, body depth at anus 16.2 16.5% SL, and 57 total vertebrae. PMID- 25543802 TI - A review of the Polystira clade--the Neotropic's largest marine gastropod radiation (Neogastropoda: Conoidea: Turridae sensu stricto). AB - The Polystira clade (here comprising Polystira and Pleuroliria) is a poorly known but hyper-diverse clade within the neogastropod family Turridae (sensu stricto). It has extensively radiated within the tropics and subtropics of the Americas, to which it is endemic. In this paper we present a synthetic overview of existing information on this radiation together with new information on estimated species diversity, systematic relationships, a species-level molecular phylogenetic analysis and preliminary macroecological and diversification analyses, to serve as a platform for further study. We currently estimate that about 300 species (122 extant) are known from its 36 million year history but this number will undoubtedly increase as we extend our studies. We discuss the relationships of Polystira to other Neotropical Turridae (s.s.) and examine the taxonomy and systematics of the geologically oldest described members of the clade. To aid taxonomic description of shells we introduce a new notation for homologous major spiral cords. Focusing on key publications, we discuss in detail the changing historical understanding of the taxonomy of the clade and the relationships of its component genus-level taxa: Polystira Woodring, 1928, Pleuroliria de Gregorio, 1890, Josephina Gardner, 1945 and Oxytropa Glibert, 1955. We designate a neotype for Pleurotoma (Pleuroliria) supramirifica de Gregorio, 1890, to stabilize our understanding of this, the type species of Pleuroliria. Application of the name Oxytropa is restricted to the type species. The genus Polystira is conchologically re-described and for the first time we synthesize available information on the anatomy, feeding and toxinology, reproduction and life history, larval modes and life habits, and geographic and bathymetric ranges of its species. We give an updated list of the 19 formally described living species and present the pitfalls of the currently poor species-level taxonomy of Polystira using case examples. We present a molecular phylogenetic analysis of 22 extant species using three mitochondrial gene fragments (COI, 12S rRNA and 16S rRNA). This reveals undescribed species and indicates that Recent genetic clades ('biospecies') are consistent with finely divided conchological 'morphospecies'. Historically, there has been a slow realisation of the high species diversity of the Polystira clade and we consider that this may be due to inadequate precision of morphological description of shells and a lack of clear homology statements. We suggest how these both might be improved. Finally, using a data compilation based on museum specimens we examine species range-size distributions and species abundance distributions for 85 of the 112 extant western Atlantic species that we have delimited to date. Our results indicate that the majority of species are rare and have short geographic ranges; only a few are wide-ranging and abundant. This has important implications for surveys of biodiversity. PMID- 25543803 TI - New species of Potamocoris Hungerford (Heteroptera, Potamocoridae) from Costa Rica and a key to the species . AB - A new potamocorid species, Potamocoris sitesi NEW SPECIES, with its two wing morphs (coleopteroid and macropterous) are described from Costa Rica. Descriptions are supported with photographs and illustrations. Parameres become progressively narrower, ending in a sharp needle-like point. This is the third species of Potamocoris known from Central America. A key to the species of the genus is provided. PMID- 25543804 TI - A new species of Lissodendoryx (Anomodoryx) Burton, 1934 (Porifera: Demospongiae: Poecilosclerida) from deeper waters off the Atlantic coast of Brazil. AB - The members of Lissodendoryx Topsent, 1892a are recognized by a spicule combination of ectosomal tylotes or strongyles, isodictyal reticulate architecture, arcuate isochelae and sigmas (Hofman & Van Soest 1995; Van Soest 2002). Five subgenera of Lissodendoryx, are recognized (Van Soest 2002): Lissodendoryx (Acanthodoryx) Levi, 1961, L. (Anomodoryx) Burton, 1934, L. (Ectyodoryx) Lundbeck, 1909, L. (Lissodendoryx) Topsent, 1892a, and L. (Waldoschmittia) de Laubenfels, 1936. Lissodendoryx (Anomodoryx) is defined by the presence of a single megasclere type (Van Soest 2002). Currently has six recognized species (Van Soest et al. 2014) including two from Brazil (Muricy et al. 2011): L. (A.) recife (Boury-Esnault, 1973) and L. (A.) tylota (Boury Esnault, 1973). In this paper, a new species of L. (Anomodoryx) is described from the mesophotic zone off Bacia Potiguar (Rio Grande do Norte State, Northeastern Brazil). The specimen was preserved in ethanol 80% and deposited in the Porifera Collection of the Universidade Federal de Pernambuco (UFPEPOR). PMID- 25543805 TI - Brachiopods from Late Jurassic-Early Cretaceous hydrocarbon seep deposits, central Spitsbergen, Svalbard. AB - Late Jurassic-Early Cretaceous (Late Volgian-latest Ryazanian) rhynchonellate brachiopods are described from eight out of 15 hydrocarbon seep deposits in the Slottsmoya Member of the Agardhfjellet Formation in the Janusfjellet to Knorringfjellet area, central Spitsbergen, Svalbard. The fauna comprises rhynchonellides, terebratulides (terebratuloids and loboidothyridoids) and a terebratellidine. The rhynchonellides include: Pseudomonticlarella varia Smirnova; Ptilorhynchia mclachlani sp. nov.; and Ptilorhynchia obscuricostata Dagys. The terebratulides belong to the terebratuloids: Cyrtothyris? sp.; Cyrtothyris aff. cyrta (Walker); Praelongithyris? aff. borealis Owen; and the loboidothyridoids: Rouillieria cf. michalkowii (Fahrenkohl); Rouillieria aff. ovoides (Sowerby); Rouillieria aff. rasile Smirnova; Uralella? cf. janimaniensis Makridin; Uralella? sp.; Pinaxiothyris campestris? Dagys; Placothyris kegeli? Harper et al.; and Seductorithyris septemtrionalis gen. et sp. nov. The terebratellidine Zittelina? sp. is also present. Age determinations for all but one of the brachiopod-bearing seeps are based on associated ammonites. Five of the seep carbonates have yielded Lingularia similis?, and it is the only brachiopod species recorded from two of the seeps. Other benthic invertebrate taxa occurring in the seeps include bivalves, gastropods, echinoderms, sponges, and serpulid and non-serpulid worm tubes. The brachiopod fauna has a strong Boreal palaeobiogeographic signature. Collectively, the Spitsbergen seep rhynchonellate brachiopods exhibit high species richness and low abundance (<100 specimens from 8 seeps). This contrasts markedly with other Palaeozoic---Mesozoic brachiopod-dominated seep limestones where brachiopods are of low diversity (typically monospecific) with a super-abundance of individuals. The shallow water environmental setting for the Spitsbergen seeps supported a diverse shelf fauna, compared to enigmatic Palaeozoic-Mesozoic brachiopod-dominated seeps. PMID- 25543806 TI - New Oppiidae (Acari: Oribatida) from the Golden Gate Highlands National Park in South Africa. AB - A checklist of Oppiidae sampled at Golden Gate Highlands National Park in central South Africa is provided. Twelve genera and 17 species were recorded of which one species, Arcoppia fenestralis, is recorded from South Africa for the first time. One new subgenus and six new species were identified and are described. The new species are Brachioppia louwi sp. nov., Brachioppiella (B.) dawidi sp. nov., Brachioppiella (B.) goblina sp. nov., Kokoppia mandelai sp. nov., Lanceoppia (L.) scytheae sp. nov., Oppiella (Q.) goldengatensis sp. nov.. Oppiella (Quattoppiella) subgen. nov. is characterized by the absence of costulae on the prodorsum and having four pairs of genital setae. PMID- 25543807 TI - A new species of Lophophysema (Porifera, Hexactinellida, Hyalonematidae) from the South China Sea. AB - We describe Lophophysema eversa sp. nov. (Porifera, Hexactinellida, Hyalonematidae) based on a single specimen collected from the South China Sea at a depth of 3683 m. The new species can be distinguished from the three known congeners by its unusual body shape with basalia on the side of the body, the lack of macramphidiscs, the combination of the pinular pentactins having spiny tangential rays and the pinular ray of atrialia longer than dermalia and canalaria. This is the first record of the genus Lophophysema from the South China Sea. We also use a partial sequence of the 16S rRNA gene to confirm the family assignment of the new specimen. PMID- 25543808 TI - Description and DNA barcoding of Ochetostethomorpha secunda, a new species of the South African endemic burrower bug genus (Hemiptera: Heteroptera: Cydnidae) from Namibia. AB - Ochetostethomorpha secunda sp. nov. from Namibia, the second species of the South African endemic genus is described, illustrated, and compared with O. nollothensis Schumacher, 1913. The new species is the third of the subfamily Sehirinae known from Namibia. Moreover, a DNA barcode sequence was generated for this new species (827 bp of cytochrome oxidase I) and was deposited in GenBank. PMID- 25543809 TI - A New Species of Corynoneura Winnertz from Oriental China (Diptera: Chironomidae: Orthocladiinae). AB - A new species of Corynoneura Winnertz (1846) from Oriental China, C. ecphora sp. n. is described and illustrated as male. A distribution map of adult males in Oriental China is given. A key to known males of Oriental China is provided. PMID- 25543810 TI - An annotated checklist of the bush katydids (Orthoptera: Phaneropteridae: Phaneropterinae) from Singapore, including an illustrated key to species. AB - The Phaneropterinae, or commonly known as the bush katydids, are among the most speciose katydids in the world. The bush katydids have interesting life histories but little is known about species from Southeast Asia. The source of problem may lie in the lack of sampling and revised taxonomic knowledge. The paper reports a species checklist of Phaneropterinae from Singapore. In total, 30 species were recorded from Singapore, eight of which may be locally extinct. Each species was also annotated with known life history information or taxonomic remarks, whenever possible. The female of Phaulula malayica was also described for the first time. An illustrated key to species from Singapore was also provided to assist in species identification. PMID- 25543811 TI - The genus Sitothrips (Thysanoptera: Thripidae) with a new grass-living species from southern Iran. AB - One of the generic characters given by zur Strassen (2003) for species of the genus Sitothrips Priesner (1931) is the presence of 2-segmented maxillary palps. In contrast, a new species of this genus is described below from Iran in which the maxillary palps are clearly 3-segmented (Fig. 5). The genus was erected for arabicus Priesner from Egypt, a species now recorded widely among countries around the Mediterranean, from Morocco to southern Russia. Three further species are listed in Sitothrips: almargeniensis Titschack from Spain and Portugal, lindbergi zur Strassen from the Canary Islands and Morocco, and calcaratus (Savenko) from southern Russia. The identity of the latter species remains in some doubt as, in contrast to the other species, it was described as wingless and lacking ocelli (Savenko 1944), but zur Strassen (2003) provided an illustrated key to the other three species. PMID- 25543812 TI - A new genus to accommodate three skinks currently assigned to Menetia (Lacertilia: Scincidae). AB - Menetia timlowi Ingram 1977 has had a chequered generic history due to ambiguity in interpreting its various character states. Ingram (1977) assigned this species to Menetia on the strength of "the long narrow obliquely oriented first supraocular" and "enlarged upper circumoculars". In doing so, he admitted the possibility that M. timlowi "may in fact be a Carlia" but because "all Carlia, except burnetti, lack fused lower eyelids and have a typically anvil shaped presubocular", allocating timlowi to Menetia seemed the best available option. Ingram and Covacevich (1988) revisited the generic status of this species when resurrecting Lygisaurus from the synonymy of Carlia to accommodate a group of small leaf-litter dwelling skinks. In proposing the new combination L. timlowi (Ingram 1977), they considered the supraoculars to be transverse whereas Ingram had stated them to be oblique in his original species description. PMID- 25543815 TI - The effect of psychoeducation on anxiety and pain in patients with mastalgia. AB - BACKGROUND: Mastalgia is a debilitating disorder, which has serious effects on one's daily life and causes significant medical costs. AIM: Mastalgia patients determine the overall approach and improve the quality of life of patients. METHODS: In this study, the outcomes of psychoeducation on anxiety and pain in a group of patients with mastalgia without an organic etiology have been investigated. 88 patients were included in this study. The socio-demographic data form, the Symptom Checklist 90 (SCL-90), the Toronto Alexithymia Scale-20 (TAS 20), the Hamilton Anxiety Scorer (HAM-A), the State-Trait Anxiety Inventory (STAI I, STAI-2) and the Visual Analogue Scale (VAS) were all applied to the patients. 64 randomly selected patients (Group 1) were given psychoeducation while the remaining 24 (Group 2) were not. All patients were called back after 1 month for repeats of the HAM-A, STAI-I, STAI-2 and VAS tests. RESULTS: The results of this study demonstrated that psychoeducation has positive impacts on the perception of pain besides stationary, contemporary and total anxiety scores. CONCLUSIONS: It is concluded that the administration of psychoeducation is a good choice in the degradation of anxiety symptoms and pain. PMID- 25543816 TI - Evaluation of the eZono 4000 with eZGuide for ultrasound-guided procedures. AB - Ultrasound-guided procedures are increasingly common in a variety of acute care settings, such as the operating room, critical care unit and emergency room. However, accurate judgment of needle tip position using traditional ultrasound technology is frequently difficult, and serious injury can result from inadvertently advancing beyond or through the target. Needle navigation is a recent innovation that allows the clinician to visualize the needle position and trajectory in real time as it approaches the target. A novel ultrasound machine has recently been introduced that is portable and designed for procedural guidance. The eZono 4000TM features an innovative needle navigation technology that is simple to use and permits the use of a wide range of commercially available needles, avoiding the inconvenience and cost of proprietary equipment. This article discusses this new ultrasound machine in the context of other currently available ultrasound machines featuring needle navigation. PMID- 25543817 TI - New Year resolutions. PMID- 25543818 TI - Evaluation of bactericidal effect of three antiseptics on bacteria isolated from wounds. AB - OBJECTIVE: Antiseptics are widely used in wound management to prevent or treat wound infections due to their proven wound healing properties regardless of their cytotoxicity. The objective of this study was to determine the bactericidal effects of three antiseptics on pathogens known to cause wound infections. METHOD: The study was carried out at a tertiary care hospital and a university microbiology laboratory in Sri Lanka in 2013. The three acids (acetic acid, ascorbic acid and boric acid) in increasing concentration (0.5%, 0.75% and 1%) were tested against bacterial suspensions equivalent to 0.5 McFarland standard. The Bacteria isolates used were isolated from wound and standard strains of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. RESULTS: There were 33 (68.8%) Coliforms, 10 (20.8%) Pseudomonas species, and 5 (10.4%) strains of Staphylococcus aureus. Acetic acid at concentration of 0.5% inhibited growth of 37 (77%) and 42 (87.5%) of tested isolates when exposed for 30 and 60 minutes, respectively. However 100% inhibition was achieved at four hours. At a concentration of 0.75%, 40 (83.3%) and 44 (91.7%) were inhibited when exposed for 30 and 60 minutes, respectively, with 100% inhibition at 4 hours. At concentration of 1%, 46 (95.8%) inhibition was seen at 30 minutes and 100% inhibition at 60 minutes. Ascorbic acid, at 0.5% and 0.75 % concentrations, inhibited growth of 45(93.7%) and 47(97.9%) of isolates respectively when exposed for 30 minutes. At these two concentrations, 100% inhibition was achieved when exposed for one hour. At 1% concentration, 100% inhibition was achieved at 30 minutes. Boric acid did not show bactericidal effect at concentrations of 0.5%, 0.75 % and 1%. Pseudomonas species were inhibited at 30 minutes by 0.5% acetic acid. Bactericidal effect against all the standard strains was seen with three acids at each concentration tested from 30 minutes onwards CONCLUSION: Ascorbic acid was bactericidal for all organisms tested within the shortest exposure time at the lowest concentration compared to other two acids. Despite promising bactericidal effects, further studies warrant, as ongoing debates on toxicity of acids on tissue epithelialisation. Application of antiseptics for a shorter duration could overcome this problem without losing bactericidal activity. DECLARATION OF INTEREST: The authors have no conflict of interest and no funding was received for this study. PMID- 25543819 TI - A real-life clinical evaluation of a next-generation antimicrobial dressing on acute and chronic wounds. AB - OBJECTIVE: To assess the effectiveness of a new, next-generation antimicrobial dressing (AQUACEL Ag+ dressing) in facilitating healing in a variety of hard-to heal wounds that may have been compromised by infection and/or biofilm. METHOD: This was an international, multi-centred, real-life, non-randomised evaluation involving patients with a wide variety of slow-, non-healing or deteriorating chronic and acute wounds. There were no strict inclusion or exclusion criteria and the clinicians were asked to use their discretion in the selection of patients. The clinicians continued to use their standard protocol of care but replaced their existing primary wound-contact dressing with the next-generation antimicrobial dressing (NGAD) for up to 4 weeks. Clinicians could extend the treatment period if this was deemed clinically appropriate. Baseline assessments included wound bed characteristics, exudate level, indicators of wound biofilm, and signs and symptoms of infection. At the final assessment, the investigators reported the wound size, wound bed characteristics, and exudate level. RESULTS: A total of 121 patients were recruited into the original evaluation, of which eight were excluded for incomplete data sets. Most wounds (73; 64%) were either venous leg ulcers (59; 52%) or diabetic foot ulcers (14; 12%). At baseline, the wounds of (26; 23%) patients were slowly improving, 65 were stagnant (58%) and 22 (19%) were deteriorating. Just under three-quarters (74%) of the wounds had suspected biofilm (criteria including failure of a wound to heal, lack of response to topical and systemic antimicrobial agents, or the presence of slimy substances on the wound surface). Following the evaluations, the average wound closure achieved for all wounds was 72.6%, 19 (17%) wounds healed, 47 (42%) achieved at least 90% wound closure, and 71 (63%) achieved at least 75% closure. The average treatment period was 4.1 weeks; 35 wounds were treated with the dressing for more than 4 weeks. Cost analysis indicated that potential antimicrobial dressing cost reductions of approximately 30% were realised using the NGAD. CONCLUSION: This real-life, non-randomised evaluation provides encouraging evidence that the NGAD may have a role to play in facilitating wound progression towards healing by helping to eliminate the biofilm barrier. DECLARATION OF INTEREST: M. Walker, D. Metcalf, D. Parsons and P. Bowler are all employees of ConvaTec Ltd. Aysha Mendes da Mata is an independent writer and Annemarie Brown is an independent clinician, both received a fee and support from MA Healthcare to write up the evaluation using data supplied by ConvaTec. PMID- 25543820 TI - Measurement of microelectric potentials in a bioelectrically-active wound care device in the presence of bacteria. AB - OBJECTIVE: Wound healing is enhanced in the presence of an external electrical field. The purpose of this study was first to investigate whether microelectric potentials (EPs) can be generated when the innovative design of a silver (Ag)- and zinc (Zn)-printed wound care device was exposed to saline solution which is commonly used to clean wound sites; and second to measure the generated EPs while the device was exposed to bacterial culture suspensions to mimic infection. METHOD: An Ag/Zn-printed test specimen as a wound care device was designed to accommodate Ag and Zn half-cell potentials by alternatively printing them on a woven polyester material in a well-characterised dot matrix pattern. A well calibrated high impedance EPs measuring system was used to measure any EPs generated. Ultrasensitive inductively coupled plasma analysis was performed to determine whether the device induced any increase in trace metals in rabbit blood following implantation for 2-4 weeks. RESULTS: EPs were consistently generated under various conductive solutions at the levels of 120.4+/-26.3mV (average+/ standard deviation) on Ag dots and -506.5+/-76.3mV over Zn dots to form microcircuits with EPs of 626.7+/-86.3mV between the Ag and Zn metallic elements of the dressing. Interestingly, the patterns of EPs generated with stable polarities were consistent when the device was exposed to bacterial suspensions for mimicking wound infection. Implantation of the device did not cause any increase in Ag or Zn in rabbit blood. CONCLUSION: The Ag/Zn-printed wound device generated sustained EPs successfully in the presence of various conductive fluids without changing EPs including polarities. Consistently generated EPs at each battery couple with Ag/Zn-based wound device would restore disrupted physiologic bioelectric signals on wound sites, which could lead to improved wound healing. DECLARATION OF INTEREST: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army, the US Department of Defense, the Department of Veterans Affairs, or the Henry M. Jackson Foundation for Advancement of Military Medicine. The research was supported by the US Air Force medical support agency (AFMSA), office of the Air Force Surgeon General, USA. PMID- 25543821 TI - Use of HBOT and a living bilayer skin substitute for a compromised flap with chronic steroid use: a case report. AB - Wound healing in a degloving injury can be compromised due to mechanical compression, increased length-to-width ratio, and time to treatment. Chronic steroid use is also a known risk factor for poor wound healing in wounds of any type. We report the first known case of hyperbaric oxygen therapy and Apligraf, a living bilayer skin substitute, for non-operative salvage of a traumatic degloving injury in 70-year-old female on chronic steroids for sarcoidosis. DECLARATION OF INTEREST: The authors have received no financial support for the material presented in this study outside of the scope of standard patient care reimbursement. The authors do not have any financial conflict of interest to disclose. PMID- 25543822 TI - The effect of concentration of tackifying agent on adhesive and skin-protective properties of ceramide 2-containing hydrocolloid dressings. AB - OBJECTIVE: In the treatment of pressure ulcers and leg ulcers it is necessary to achieve an effective balance between adhesive and skin-protective properties. We speculated that addition of a tackifying agent (TA) to ceramide 2-containing hydrocolloid dressings would increase their adhesiveness under dry conditions and reduce their adhesiveness under wet conditions because dry tack converts to wet tack after water absorption. METHOD: We prepared ceramide 2-containing hydrocolloid dressings with varying amounts of TA. Basic characteristics of the test ceraminde dressings, such as initial tack force and peeling force, were evaluated using standard methods. Peeling force and stratum corneum (SC) removal on healthy human skin were also evaluated at 20 minutes, 7 hours, and 72 hours. In addition, the effect of 10 repeated applications on transepidermal water loss (TEWL) was investigated on the skin of hairless mice under dry and wet conditions. Statistical analyses were performed using one-way analysis of variance followed by Dunnett's multiple comparison test. A p-value of <0.05 was considered statistically significant. RESULTS: On a stainless steel substrate, initial tack force and 180 degrees peeling force increased as TA content increased. Twenty minutes after application on human skin, peeling force and SC removal increased with increasing TA content. When TA contents were over 10%, significant differences in peeling force and SC removal were obtained compared with ceramide 2-containing hydrocolloid dressings without TA (p<0.05). However, a TA content-dependent increase in peeling force was not evident 7 hours and 72 hours after application. Under dry conditions, TEWL increased with repeated application and peeling. Conversely, no significant increases in TEWL were evident under wet conditions after 10 repeated applications and peelings. CONCLUSION: Our data demonstrate that the initial attachment of ceramide 2 containing hydrocolloid dressings to the skin increases with addition of TA. Skin damage can be avoided by conversion of the adhesive system to wet tack with water absorption. DECLARATION OF INTEREST: Masushi Kohta and Tetsuji IwasakI are employees of ALCARE Co., Ltd., Japan. This project was supported by an unrestricted grant from ALCARE. PMID- 25543824 TI - 'Sustainability does not quite get the attention it deserves': synergies and tensions in the sustainability frames of Australian food policy actors. AB - OBJECTIVE: The development of food policy is strongly influenced by the understanding and position actors adopt in their 'framing' of sustainability. The Australian Government developed a National Food Plan (2010-2013). In public consultations on the National Food Plan Green Paper, the government sought stakeholders' views on sustainability. The present study examined the way in which the food industry and civil society organizations framed sustainability in their submissions to the Green Paper. DESIGN: Submissions by food industry actors and civil society organizations were analysed using a framing matrix that examined positioning, drivers, underlying principles and policy solutions related to sustainability. Submissions were open coded and subsequently organized based on themes within the framing matrix. SETTING: Australia. SUBJECTS: One hundred and twenty-four written submissions (1420 pages). RESULTS: While submissions from industry and civil society organizations often framed sustainability similarly, there were also major differences. Civil society organizations were more likely to make the link between the food supply and population health, while industry was more likely to focus on economic sustainability. Both viewed consumer demand as a driver of sustainability, welcomed the idea of a whole-of-government approach and stressed the need for investment in research and development to improve productivity and sustainable farming practices. CONCLUSIONS: The meaning of sustainability shifted throughout the policy process. There are opportunities for creating shared value in food policy, where the health, environment and economic dimensions of sustainability can be compatible. However, despite pockets of optimism there is a need for a shared vision of sustainability if Australia is to have a food policy integrating these dimensions. PMID- 25543823 TI - Comparison of growth factor adsorbed scaffold and conventional scaffold with growth factor supplemented media for primary human articular chondrocyte 3D culture. AB - BACKGROUND: Cartilage tissue engineering offers new strategies in repairing damaged cartilage. Scaffolds have been used for the in vitro and in vivo procedures for this application, which demonstrates the compatible biological and physical properties that mimic natural tissues. Several types of scaffolds were used and had different effects on cell functions. The study was designed to develop a functional gelatin scaffold by adsorption of hyaluronan (HA) and the transforming growth factor beta3 (TGF-beta3) in a commercially available gelatin scaffold. RESULTS: The biological properties of human articular chondrocytes were investigated during a 21-day cultivation embedded in either HA + TGF-beta3 adsorbed scaffolds or the conventional supplemented method. The rising of proliferation of chondrocytes embedded in adsorbed scaffolds was observed at day 17 and 21 of cultivation (1.27 and 1.28 fold, respectively). The chondrogenic gene expression of the chondrocytes embedded in HA + TGF-beta3 adsorbed scaffolds significantly increased: SOX-9 (1.65 fold), ACAN (7.65 fold) and COL2A1 (1.83 fold). Remarkably, over the 21 days of cultivation, HA + TGF-beta3 adsorbed scaffolds promoted the extracellular matrix molecules production with higher accumulation of HA (1.2 fold), collagen (1.42 fold) and uronic acid (1.41 fold). Moreover, the cell population and extracellular matrix production, which were examined by a histological analysis and a scanning electron microscope, were correlated with the biochemical analysis. CONCLUSION: A small amount of HA and TGF-beta3 initially adsorbed in the scaffolds (70 MUg and 10 ng, respectively) was consumed over the 21-day cultivation. The HA + TGF-beta3 adsorbed gelatin scaffold is effective and more suitable than the conventional supplemented method for the in vitro assessment of human chondrocyte 3D culture. PMID- 25543830 TI - Nanodiamonds as a new horizon for pharmaceutical and biomedical applications. AB - A palpable need for the optimization of therapeutic agents, due to challenges tackled by them such as poor pharmacokinetics and chemoresistance, has steered the journey towards novel interdisciplinary scientific field for emergence of nanostructure materials as a carrier for targeted delivery of therapeutic agents. Amongst various nanostructures, nanodiamonds are rapidly rising as promising nanostructures that are suited especially for various biomedical and imaging applications. Advantage of being biocompatible and ease of surface functionalization for targeting purpose, besides safety which are vacant by nanodiamonds made them a striking nanotool compared to other nonmaterials which seldom offer advantages of both functionality as well as safety. This review outlines the summary of nanodiamonds, regarding their types, methods of preparation, and surface modification. It also portrays the potential applications of nanodiamond as targeted drug delivery of various bioactive agents. Based on photoluminescent and optical property, nanodiamonds are envisioned as an efficient bioimaging nanostructure. Nanodiamonds as a novel platform hold great promise for targeting cancer cells and in-vivo cell imaging. Based upon their inimitable properties and applications nanodiamonds propose an exciting future in field of therapeutics and thus possess vibrant opportunities. PMID- 25543831 TI - In situ Raman spectroscopy of sulfur speciation in lithium-sulfur batteries. AB - In situ Raman spectroscopy and cyclic voltammetry were used to investigate the mechanism of sulfur reduction in lithium-sulfur battery slurry cathodes with 1 M lithium bis(trifluoromethane sulfonyl)imide (LiTFSI) and tetraethylene glycol dimethyl ether (TEGDME)/1,3-dioxolane (DIOX) (1/1, v/v). Raman spectroscopy shows that long-chain polysulfides (S8(2-)) were formed via S8 ring opening in the first reduction process at ~2.4 V vs Li/Li(+) and short-chain polysulfides such as S4(2-), S4(-), S3(*-), and S2O4(2-) were observed with continued discharge at ~2.3 V vs Li/Li(+) in the second reduction process. Elemental sulfur can be reformed in the end of the charge process. Rate constants obtained for the appearance and disappearance polysulfide species shows that short-chain polysulfides are directly formed from S8 decomposition. The rate constants for S8 reappearance and polysulfide disappearance on charge were likewise similar. The formation of polysulfide mixtures at partial discharge was found to be quite stable. The CS2 additive was found to inhibit the sulfur reduction mechanism allowing the formation of long-chain polysulfides during discharge only and stabilizing the S8(2-) product. PMID- 25543825 TI - Role of Chlamydia trachomatis and emerging Chlamydia-related bacteria in ectopic pregnancy in Vietnam. AB - In this case-control study, we investigated the seroprevalence and molecular evidence of Chlamydia trachomatis and Waddlia chondrophila in ectopic pregnancies (EP) and uneventful control pregnancies in 343 women from Vietnam. Whereas presence of C. trachomatis IgG was strongly associated with EP [adjusted odds ratio (aOR) 5.41, 95% confidence interval (CI) 2.58-11.32], its DNA remained undetected in all tubal lesions. We confirmed an independent association between antibodies against Waddlia and previous miscarriage (aOR 1.87, 95% CI 1.02-3.42). Further investigations are needed to understand the clinical significance of Waddlia's high seroprevalence (25.9% in control pregnancies) in this urban population. PMID- 25543832 TI - Plasmon-enhanced formic acid dehydrogenation using anisotropic Pd-Au nanorods studied at the single-particle level. AB - Plasmonic bimetal nanostructures can be used to drive the conventional catalytic reactions efficiently at low temperature with the utilization of solar energy. This work developed Pd-modified Au nanorods, which work as the light absorber and the catalytically active site simultaneously, and exhibit efficient plasmon enhanced catalytic formic acid dehydrogenation even when below room temperature (5 degrees C). Plasmon-induced interface interaction and photoreaction dynamics of individual nanorods were investigated by single-particle photoluminescence measurement, and a complete quenching phenomenon at the LSPR region was observed for the first time. More importantly, the spatial distribution of the SPR-induced enhancement, analyzed by the finite difference time domain (FDTD) simulation, shows that only tip-coated Pd can be affected for the occurrence of plasmon resonance energy transfer. This finding provides a route to decrease the amount of Pd species by the selective deposition only at the field-enhanced sites. PMID- 25543833 TI - Synthesis of fluorenes via tandem copper-catalyzed [3 + 2] cycloaddition and rhodium-catalyzed denitrogenative cyclization in a 5-exo mode from 2 ethynylbiaryls and N-sulfonyl azides in one pot. AB - An efficient synthetic method of fluorenes having an enamine moiety at C-9 methylene bridge is developed from N-sulfonyl-4-biaryl-1,2,3-triazole derivatives via Rh-catalyzed denitrogenative cyclization in a 5-exo mode. Rh-catalyzed denitrogenative cyclization followed by catalytic hydrogenation produces N tosylaminomethyl-substituted fluorenes in one pot. Moreover, fluorenes are synthesized via tandem Cu-catalyzed [3 + 2] cycloaddition and Rh-catalyzed denitrogenative cyclization in a 5-exo mode starting from 2-ethynylbiaryls and N sulfonyl azides in one pot. PMID- 25543834 TI - Histologic considerations about a rare case of recurrent incisional hernia on McBurney incision. AB - AIM: Incisional hernias are often related to longitudinal or transverse laparotomy with an incidence that rises from to 2 to 23 %. The oblique incision often used to surgically treat acute appendicitis has little probability to develop incisional hernia with an estimated incidence less than 2%. Some series report 0.1 - 0.9% of it. Anatomic, physiologic and histologic factors have been implicated in herniation development, such as intra-abdominal pressure or alteration on tissue components; many different risk factors can be taken into account to justify this rare condition such as female gender, diabetes, peritonitis, abscess or appendiceal phlegmon as the cause of the first operation, wound infection, seroma, use of cutgut to suture aponeurosis, interrupted suture to the aponeurotic layer. MATERIAL OF STUDY: We present the rare case of young man who underwent surgical operation of acute appendicitis. Mc Burney incision was performed. Successively he underwent re-operation for incisional hernia developed upon McBurney incision and then "recurrence" of the same one. DISCUSSION AND CONCLUSION: Histological analysis of scar tissue was done. Alteration on histological pattern protein expression was discovered. PMID- 25543835 TI - Tougu Xiaotong formula induces chondrogenic differentiation in association with transforming growth factor-beta1 and promotes proliferation in bone marrow stromal cells. AB - Indian hedgehog (Ihh), one of the hedgehog gene families, is indicated in the regulation of chondrocyte differentiation. Tougu Xiaotong formula (TXF), a traditional Chinese medicinal compound, has been used for the treatment of bone and joint disease. However, the underlying molecular mechanisms of TXF on the function of bone marrow stromal cells (BMSCs) remain unclear. In the present study, the affect of TXF on proliferation and chondrogenic differentiation was investigated in primary BMSCs from four-week-old Sprague Dawley rats. The cell viability in BMSCs treated with TXF was higher compared to the untreated cells. Additionally, the percentage of G(0)/G(1) phase cells was significantly decreased, whereas that of the S phase cells was significantly increased. Furthermore, following TXF treatment, cyclin D1, cyclin-dependent kinase 4 (CDK4) and CDK6 expression in BMSCs was significantly enhanced. The results showed that TXF had no cytotoxicity to BMSCs. To explore the effect of TXF on the differentiation in BMSCs, whether TXF induced chondrogenic differentiation of BMSCs by the regulation of Ihh signaling pathway was investigated. The protein expression of Ihh, Patched and Smoothened in the induction group were significantly increased when compared to those in the control group, and the highest protein level of Ihh was in the induction group that was treated with the combination of TXF and transforming growth factor-beta1 (TGF-beta1). In addition, TXF combined with TGF-beta1 significantly induced the protein expression of cartilage oligomeric matrix protein and collagen II compared to the TGF-beta1 group. Taken together, these results indicate that TXF promotes the proliferation via accelerating the G(1)/S transition, and induces chondrogenic differentiation in BMSCs by activation of the Ihh signaling pathway in association with TGF beta1. PMID- 25543836 TI - Proteomic studies of pediatric medulloblastoma tumors with 17p deletion. AB - CNS tumors are the leading cause of cancer-related death in children. Medulloblastoma is the commonest pediatric CNS malignancy, wherein, despite multimodal therapy with surgery, radiation, and chemotherapy, 5 year survival rates merely approach 60%. Until present, gene expression and cytogenetic studies have produced contradicting findings regarding the molecular background of the specific disease. Through integration of genomics, bioinformatics, and proteomics, the current study aims to shed light at the proteomic-related molecular events responsible for MBL pathophysiology, as well as to provide molecular/protein/pathway answers concerning tumor-onset. Experiments were performed on tissues collected at surgery. With 17p loss being the commonest chromosomal aberrance observed in our sample set, array-CGH were employed to first distinguish for 17p-positive cases. 2-DE coupled to mass spectrometry identification exposed the MBL-specific protein profile. Protein profiles of malignant tissues were compared against profiles of normal cerebellar tissues, and quantitative protein differences were determined. Bioinformatics, functional and database analyses, characterization, and subnetwork profiling generated information on MBL protein interactions. Key molecules of the PI3K/mTOR signaling network were identified via the techniques applied herein. Among the findings IGF2, PI3K, Rictor, MAPKAP1, S6K1, 4EBP1, and ELF4A, as part of the IGF network (implicating PI3K/mTOR), were founded to be deregulated. PMID- 25543837 TI - In vivo evaluation of folate decorated cross-linked micelles for the delivery of platinum anticancer drugs. AB - The biodistribution of micelles with and without folic acid targeting ligands were studied using a block copolymer consisting of acrylic acid (AA) and polyethylene glycol methyl ether acrylate (PEGMEA) blocks. The polymers were prepared using RAFT polymerization in the presence of a folic acid functionalized RAFT agent. Oxoplatin was conjugated onto the acrylic acid block to form amphiphilic polymers which, when diluted in water, formed stable micelles. In order to probe the in vivo stability, a selection of micelles were cross-linked using 1,8-diamino octane. The sizes of the micelles used in this study range between 75 and 200 nm, with both spherical and worm-like conformation. The effects of cross-linking, folate conjugation and different conformation on the biodistribution were studied in female nude mice (BALB/c) following intravenous injection into the tail vein. Using optical imaging to monitor the fluorophore labeled polymer, the in vivo biodistribution of the micelles was monitored over a 48 h time-course after which the organs were removed and evaluated ex vivo. These experiments showed that both cross-linking and conjugation with folic acid led to increased fluorescence intensities in the organs, especially in the liver and kidneys, while micelles that are not conjugated with folate and not cross-linked are cleared rapidly from the body. Higher accumulation in the spleen, liver, and kidneys was also observed for micelles with worm-like shapes compared to the spherical micelles. While the various factors of cross-linking, micelle shape, and conjugation with folic acid all contribute separately to prolong the circulation time of the micelle, optimization of these parameters for drug delivery devices could potentially overcome adverse effects such as liver and kidney toxicity. PMID- 25543838 TI - Preventive effects of 125I seeds on benign restenosis following esophageal stent implantation in a dog model. AB - The present study aimed to evaluate the effects of iodine-125 (125I) seeds on the proliferation of primary esophageal fibroblasts in dogs, and to assess the safety and preventive efficacy of 125I seed-pre-loaded esophageal stents in benign restenosis following implantation. Primary fibroblasts were cultured with various 125I seed activities, which were then evaluated using cell proliferation and apoptosis assays as well as cell cycle analysis using Annexin V/propidium iodide (PI) double staining and PI staining. Prior to sacrification, animals were submitted to esophageal radiography under digital subtraction angiography. Esophageal tissues were collected and examined for macroscopic, microscopic and pathological alterations. The results demonstrated a significant and dose dependent inhibition of fibroblast proliferation and increased apoptosis following exposure to 125I seeds. G0/G1 fibroblast populations increased in a dose-dependent manner following treatment with 125I seeds, in contrast to cells in S phase. Four weeks following implantation, alpha-smooth muscle actin and proliferating cell nuclear antigen expression levels in the experimental group were significantly lower compared with those in the control group; in addition, eight weeks following implantation, esophageal inner diameters were increased in the experimental group. 125I seeds inhibited proliferation of dog esophageal fibroblasts via cell cycle arrest and apoptosis. In conclusion, 125I seed-pre loaded esophageal stents inhibited benign hyperplasia in the upper edge of the stent to a certain extent, which relieved benign restenosis following implantation with a good safety profile. PMID- 25543839 TI - New species of Centroderes (Kinorhyncha: Cyclorhagida) from the Northwest Atlantic Ocean, life cycle, and ground pattern of the genus. AB - Four new species of Centroderes are described from the Northwest Atlantic Ocean based on light microscopical observations of 153 adult and 26 juvenile specimens and on SEM investigations of 54 adult and 3 juvenile specimens. Centroderes barbanigra n. sp. and C. bonnyae n. sp. can be distinguished from all other species by the existence of a short lateroventral tube on segment 7. The latter species can be separated from the former by an acicular spine in the lateral accessory position on segment 8. The female of both C. readae n. sp. and C. spinosus possesses a female-specific, modified gland cell outlet on segments 7-9, but such an outlet is missing on segment 7 of all other species. The latter species is distinguished from the former by its robust lateroventral spine on segment 8 and by its lack of a laterodorsal sensory spot on segment 4, whereas the former species shows a midlateral sensory spot on segment 8. Centroderes drakei n. sp. agrees with the remaining American species in the possession of a laterodorsal sensory spot on segment 4; the former species can be distinguished from C. readae n. sp. by the lack of a sensory spot sublaterally on segment 1 and midlaterally on segment 8 as well as by the lack of a female-specific, modified gland cell outlet on segment 7; C. drakei n. sp. can be separated from C. barbanigra n. sp. and C. bonnyae n. sp. by its lack of a lateroventral tube on segment 7. We report anomalies rarely noticed for Kinorhyncha, such as different developmental artifacts in several specimens and a potential tumour in one individual. Evidence is provided that species of Centroderes develop via at least two adult life history stages, but three or more adult stages exist in C. drakei n. sp.; this represents the first record of a more complicated life cycle in Kinorhyncha. This paper also contains the first report of spermatophores in cyclorhagid Kinorhyncha and in both female and male specimens. In addition, characters in the ground pattern of Centroderes are summarized. PMID- 25543841 TI - Review of the Neotropical scale insects formerly assigned to Coelostomidiidae and here transferred to a new tribe within the Monophlebidae (Hemiptera: Sternorrhyncha: Coccoidea). AB - This study reviews the status of all Neotropical genera and species of Coelostomidiidae (Hemiptera: Coccoidea) and transfers them to the family Monophlebidae in the Cryptokermesini Foldi & Gullan tribe n. (the tribe Cryptokermini Tao & Hao is recognised here as a nomen nudum). This change of family placement for Neotropical taxa is based on the morphology of adult males, as supported by the phylogenetic study of Hodgson & Hardy (2013), and by unpublished DNA data. New diagnoses are provided for each of the four recognised genera of Cryptokermesini: Cryptokermes Hempel, Mimosicerya Cockerell, Neocoelostoma Hempel and Paracoelostoma Morrison. The genus Nautococcus Vayssiere is considered here to be a junior synonym (syn. n.) of Mimosicerya and the type species of Nautococcus, N. schraderae Vayssiere, thus becomes M. schraderae (Vayssiere) comb. n. Cryptokermes mexicanus Morrison is transferred to Mimosicerya as M. mexicana (Morrison) comb. n. Also Cryptokermes mimosae Foldi does not fit the morphological concept of Cryptokermes and is excluded from this genus and revision, and from the new tribe; its taxonomic position is uncertain and requires further study. All type species of the Cryptokermesini, including N. schraderae (as M. schraderae), are redescribed and illustrated based on most female instars and available adult males, examined using optical and scanning electron microscopes. Adult males are described and illustrated only for M. schraderae and N. xerophila. Keys are provided to distinguish the Neotropical monophlebid tribes Cryptokermesini and Llaveiini and to recognise each cryptokermesine genus based on female instars and first-instar nymphs. The included species of Cryptokermesini and their known distributions are: Cryptokermes brasiliensis Hempel from Brazil and C. oaxaensis Foldi from Mexico; Mimosicerya hempeli (Cockerell) from Brazil, M. mexicana from Mexico, M. schraderae from Panama and M. williamsi Foldi from Venezuela; Neocoelostoma xerophila Hempel from Argentina, Bolivia, Brazil, Paraguay and Uruguay; and Paracoelostoma peruvianum Morrison from Peru. All these insects live exposed on their host plant, either inside a secreted test (as for female and immature male instars of Cryptokermes, Neocoelostoma and Paracoelostoma) or the strongly sclerotised derm of the preadult female protects the adult (as for all species of Mimosicerya). Adult females of Mimosicerya are pupillarial, remaining within the exuviae of the previous instar, whereas adult females of the other three genera either remain within their test (and some species may be pupillarial) or escape the test to oviposit. The morphology of the adult female and often the preadult female is strongly modified, with reduction of antennae and legs, and with legs lacking in some species. PMID- 25543840 TI - A supplement to the revision of the Scirtes flavoguttatus species-group (Coleoptera: Scirtidae: Scirtinae). AB - New species of the Scirtes flavoguttatus species-group are described from SE Asia. Altogether 34 species are newly described, including Scirtes beccus sp. nov. (Malaysia), S. bocakorum sp. nov. (Indonesia), S. crockerensis sp. nov. (Malaysia), S. decorus sp. nov. (Malaysia), S. dumogensis sp. nov. (Indonesia), S. gunongmulensis sp. nov. (Malaysia), S. ishikawai sp. nov. (Vietnam), S. kinabalensis sp. nov. (Malaysia), S. kundasangensis sp. nov. (Malaysia), S. lambriensis sp. nov. (Indonesia), S. leuserensis sp. nov. (Indonesia), S. luteus sp. nov. (Malaysia), S. malaisei sp. nov. (Myanmar), S. melinauensis sp. nov. (Malaysia), S. noonadan sp. nov. (Philippines), S. pallicolor sp. nov. (Malaysia), S. penampangensis sp. nov. (Malaysia), S. phoupanensis sp. nov. (Laos), S. prodigiosus sp. nov. (Malaysia), S. punctatus sp. nov. (Philippines), S. quasibalehensis sp. nov. (Malaysia), S. ranauensis sp. nov. (Malaysia), S. sarawakensis sp. nov. (Malaysia), S. seblatensis sp. nov. (Indonesia), S. sibayensis sp. nov. (Indonesia), S. sibolangitensis sp. nov. (Indonesia), S. sulawesicus sp. nov. (Indonesia), S. sulcigeroides sp. nov. (Malaysia), S. talinisensis sp. nov. (Philippines), S. ulukimanisensis sp. nov. (Malaysia), S. velutinus sp. nov. (Malaysia), S. vietnamicus sp. nov. (Vietnam), S. wallacei sp. nov. (Indonesia), S. yangsinensis sp. nov. (Vietnam). New localities of six species are provided. An updated identification key, checklist and a summary of distributional data are included. Probability of the occurrence of the Scirtes flavoguttatus species-group was evaluated with an analysis in MaxEnt software. It is highly plausible that members of the group occur in most mountainous rainforests of SE Asia. PMID- 25543842 TI - Revision of the Western Palaearctic species of the genus Dinotrema Foerster, 1862 (Hymenoptera, Braconidae, Alysiinae). AB - The first comprehensive revision of the Western Palaearctic species of the genus Dinotrema Foerster, 1862 is provided. 174 species of this genus are redescribed and illustrated. Ten species are described as new, viz, D. acompressum sp. nov., D. cahitum sp. nov., D. collybiae sp. nov., D. digitatum sp. nov., D. glabrideum sp. nov., D. helote sp. nov., D. lepiotae sp. nov., D. norwegicum sp. nov., D. oxybellum sp. nov. and D. torpi sp. nov. The following new combinations are suggested: Dinotrema adventum (Fischer), comb. nov., D. aurelianum (Fischer), comb. nov., D. cetiusmonte (Fischer), comb. nov., D. converginerve (Fischer), comb. nov., D. intermissum (Fischer), comb. nov., D. leptocorne (Fischer), comb. nov., D. longicarinatum (Fischer), comb. nov., and D. thurnense (Fischer), comb. nov. The following names are synonymised: Dinotrema naeviformis (Fischer) with D. costulatum (Thomson), Dinotrema aequale Tobias with D. tarbagataicum Tobias, D. alua (Stelfox et Graham) with D. tauricum (Telenga), D. isometricum (Fischer) with D. cruciatum (Fischer), D. isosoma (Fischer) with D. cruciforme (Fischer), and D. ovalisignum (Fischer) with D. catharinae (Fischer) (syn. nov.). A key to all Western Palaearctic species of Dinotrema is provided for the first time. PMID- 25543843 TI - Revision of Pherusa Oken, 1807(Polychaeta: Flabelligeridae). AB - Pherusa Oken, 1807 was the first genus of flabelligerids to be described and was regarded as having over 40 species. Following revision of all available material two morphological patterns are recognized: Pherusa is restricted to those species with eight branchial filaments of similar width, and anchylosed falcate neurohooks, shorter than body width. Species with the same number of branchial filaments but with neurochaetae mostly straight, distally foliose and often as long as body width are transferred to a new genus: Lamispina n. gen. Pherusa contains 14 species, including six newly described: P. plumosa (Muller, 1776), type-species, restricted, from Greenland, P. affinis (Leidy, 1855) from the NW Atlantic, P. andersonorum n. sp. from the NE Pacific (California), P. aspera (Stimpson, 1854) from the NW Atlantic, P. hobsonae n. sp. from the NE Pacific (Washington), P. incrustata Quatrefages, 1866, reinstated from the Mediterranean Sea, P. mikacae n. sp. from the Adriatic Sea, P. moorei n. sp. from the NW Pacific (Japan), P. neopapillata Hartman, 1961 from the NE Pacific (California), P. nipponica n. sp. from the NW Pacific (Japan), P. obscura Quatrefages, 1866 reinstated from the NE Atlantic (France), P. papillata (Johnson, 1901) from the NE Pacific (Washington), P. rullieri n. sp. from the Eastern tropical Atlantic (Benin), and Pherusa sibogae (Caullery, 1944) n. comb. from Western Timor, Indonesia. Lamispina n. gen. has 10 species with five newly described: L. schmidtii (Annenkova-Chlopina, 1924) n. comb., type-species from the Japan Sea (incl. P. negligens (Berkeley & Berkeley, 1950)), L. amoureuxi n. sp. from the NE Atlantic (off SW Ireland), L. carrerai n. sp. from the NE Pacific (Mexico), L. chilensis n. sp. from the SE Pacific (Chile), L. falcata (Stop-Bowitz, 1948) n. comb. from the Norwegian Sea, L. gymnopapillata (Hartmann-Schroder, 1965) n. comb. from the SE Pacific (Chile), L. horsti (Haswell, 1892) n. comb. from Southern Australia, L. keeli n. sp. from the Gulf of Mexico (Florida), L. kerguelarum (Grube, 1877) n. comb. from the Southern Indian Ocean (Kerguelen Islands), and L. milligani n. sp. from the NW Atlantic (Florida). Keys to identify these two genera and all species in each genus are also included. PMID- 25543845 TI - Belimumab for the treatment of systemic lupus erythematosus. AB - Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management of SLE. PMID- 25543846 TI - Protein surface charge of trypsinogen changes its activation pattern. AB - BACKGROUND: Trypsinogen is the inactive precursor of trypsin, a serine protease that cleaves proteins and peptides after arginine and lysine residues. In this study, human trypsinogen was used as a model protein to study the influence of electrostatic forces on protein-protein interactions. Trypsinogen is active only after its eight-amino-acid-long activation peptide has been cleaved off by another protease, enteropeptidase. Trypsinogen can also be autoactivated without the involvement of enteropeptidase. This autoactivation process can occur if a trypsinogen molecule is activated by another trypsin molecule and therefore is based on a protein-protein interaction. RESULTS: Based on a rational protein design based on autoactivation-defective guinea pig trypsinogen, several amino acid residues, all located far away from the active site, were changed to modify the surface charge of human trypsinogen. The influence of the surface charge on the activation pattern of trypsinogen was investigated. The autoactivation properties of mutant trypsinogen were characterized in comparison to the recombinant wild-type enzyme. Surface-charged trypsinogen showed practically no autoactivation compared to the wild-type but could still be activated by enteropeptidase to the fully active trypsin. The kinetic parameters of surface charged trypsinogen were comparable to the recombinant wild-type enzyme. CONCLUSION: The variant with a modified surface charge compared to the wild-type enzyme showed a complete different activation pattern. Our study provides an example how directed modification of the protein surface charge can be utilized for the regulation of functional protein-protein interactions, as shown here for human trypsinogen. PMID- 25543847 TI - siRNA delivery to lung-metastasized tumor by systemic injection with cationic liposomes. AB - CONTEXT: Cationic liposomes can efficiently deliver siRNA to the lung by intravenous injection of cationic liposome/siRNA complexes (lipoplexes). OBJECTIVE: The aim of this study was to examine a formulation of cationic liposomes for siRNA delivery to lung metastasis of breast tumor. MATERIALS AND METHODS: For the preparation of cationic liposomes, 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP) or dimethyldioctadecylammonium bromide (DDAB) as a cationic lipid and cholesterol (Chol) or 1,2-dioleoyl-L-alpha-glycero-3 phosphatidylethanolamine (DOPE) as a neutral lipid were used. In vitro and in vivo gene silencing effects by cationic lipoplexes were evaluated after transfection into stably luciferase-expressing human breast tumor MCF-7-Luc cells and after intravenous injection into mice with lung MCF-7-Luc metastasis, respectively. Intracellular localization of siRNA after transfection into MCF-7 cells by cationic lipoplexes and biodistribution of siRNA after intravenous injection of cationic lipoplexes into the mice with lung metastasis were examined by confocal and fluorescent microscopy analyses, respectively. RESULTS: In in vitro transfection, DOTAP/DOPE and DDAB/DOPE lipoplexes of luciferase siRNA strongly suppressed luciferase activity in MCF-7-Luc cells, but DOTAP/Chol and DDAB/Chol lipoplexes did not, although DOTAP/Chol and DDAB/Chol lipoplexes exhibited higher cellular uptake than DOTAP/DOPE and DDAB/DOPE lipoplexes. When their cationic lipoplexes were intravenously injected into mice with lung MCF-7 Luc metastasis, siRNAs were mainly accumulated in the lungs; however, the reduced luciferase activities in the lung-metastasized tumors were observed only by injections of DOTAP/Chol and DOTAP/DOPE lipoplexes, but not by DDAB/Chol and DDAB/DOPE lipoplexes. CONCLUSIONS: DOTAP-based liposomes might be useful as an in vivo siRNA delivery carrier that can induce gene silencing in lung-metastasized tumors. PMID- 25543848 TI - Quercetin promotes neuronal and behavioral recovery by suppressing inflammatory response and apoptosis in a rat model of intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is a common and devastating disease affecting millions of people worldwide annually. Exaggerated inflammation and apoptosis are two pivotal pathological processes for secondary brain injury after ICH. Quercetin, a flavonoid widely distributed in various herbs, fruits and vegetables, has been proved to improve neuronal functional recovery in spinal cord injury rats. However, the efficacy of quercetin in caring for post-ICH brain injury has not been investigated. In the present study, we established an ICH model by injecting type VII bacterial collagenase (0.5U) into the central striatum of male Sprague-Dawley rats. The animals were randomized to four groups: sham-operation group; ICH + vehicle group; ICH + 5 mg/kg quercetin group; and ICH + 50 mg/kg quercetin group. The expression levels of IL-1beta, IL-4, IL-6 and TNF alpha in the brain tissue were assayed by Real-time PCR, ELISA and Western Blot, and cell apoptosis was assayed by TUNEL and caspase-3 staining 3 days after model establishment. It was found that the lesion volume, the brain water content, the expression levels of the four inflammation markers and the number of apoptotic cells were reduced significantly in ICH rats receiving quercetin, especially in 50 mg/kg quercetin group. These results confirmed the therapeutic efficacy of quercetin in repairing brain injury, probably by inhibiting inflammatory response and apoptosis, thus promoting nerve functional restoration. PMID- 25543850 TI - Interactions between abiotic constraint, propagule pressure, and biotic resistance regulate plant invasion. AB - With multiple species introductions and rapid global changes, there is a need for comprehensive invasion models that can predict community responses. Evidence suggests that abiotic constraint, propagule pressure, and biotic resistance of resident species each determine plant invasion success, yet their interactions are rarely tested. To understand these interactions, we conducted community assembly experiments simulating situations in which seeds of the invasive grass species Phragmites australis (Poaceae) land on bare soil along with seeds of resident wetland plant species. We used structural equation models to measure both direct abiotic constraint (here moist vs. flooded conditions) on invasion success and indirect constraint on the abundance and, therefore, biotic resistance of resident plant species. We also evaluated how propagule supply of P. australis interacts with the biotic resistance of resident species during invasion. We observed that flooding always directly reduced invasion success but had a synergistic or antagonistic effect on biotic resistance depending on the resident species involved. Biotic resistance of the most diverse resident species mixture remained strong even when abiotic conditions changed. Biotic resistance was also extremely effective under low propagule pressure of the invader. Moreover, the presence of a dense resident plant cover appeared to lower the threshold at which invasion success became stable even when propagule supply increased. Our study not only provides an analytical framework to quantify the effect of multiple interactions relevant to community assembly and species invasion, but it also proposes guidelines for innovative invasion management strategies based on a sound understanding of ecological processes. PMID- 25543851 TI - Age-specific reproductive success and cost in female Alpine ibex. AB - In female mammals, reproduction requires high energy expenditure because of gestation and lactation, possibly leading to a fitness cost. Several studies, however, failed to find the expected negative correlation between current and future reproductive success, likely because of individual heterogeneity in reproductive potential. We compared reproductive performance and costs of reproduction for 40 female Alpine ibex in one established population with 29 females translocated from the same population to a new colony. We investigate factors affecting pregnancy, fecundity and overwinter survival of juveniles, after accounting for individual heterogeneity. In both populations, prime-aged females experienced a strong reproductive cost. Senescent females, however, showed no evidence of reproductive costs. The colonizing population showed lower reproductive cost and better age-specific reproductive performance than the established population. We found a general pattern of low age-specific fecundity and reproductive success that was affected by environmental constraints. Age specific reproductive success was unrelated to longevity. Although about 84% of adult females appeared to conceive, independently of environmental constraints, energy was allocated to reproduction in a highly conservative manner, leading to low age-specific fecundity (only 36 and 21% of prime-aged and senescent females were seen with a kid) but high kid survival (100% to weaning and 92% to 1 year). Our results suggest that females embarked on lactation only if they had a very high probability of raising their offspring. Our study highlights how reproductive performance and costs in this species vary with age and environment, and are the result of a highly conservative reproductive tactic. PMID- 25543852 TI - DNA left on browsed twigs uncovers bite-scale resource use patterns in European ungulates. AB - Fine-scale resource use by large herbivores is often difficult to quantify directly. This is particularly true for browsing ungulates due to the challenges in observing shy subjects in forested environments of low visibility. As a consequence we know relatively little about resource use by diverse browsing ungulates. When browsing, ungulates leave behind saliva on the browsed twig that includes their DNA, which can be used to identify the species that was responsible for browsing the twig. We used this method, which we term "biteDNA", to study bite-scale browsing patterns in a temperate ungulate community. This approach provides a level of detail in browsing patterns across species that was previously very hard to attain. We found that all deer species largely overlapped in terms of the tree species they used. Moose browsed larger diameters than red deer and roe deer, but these latter two species did not differ. Moose browsed at higher heights than red deer, and red deer higher than roe deer. Although the deer species differed in mean browsing height, species were comparable in terms of their minimum browsing height of ~20 cm. This means that height and diameter ranges of the smaller species were found to be completely inside the ranges of the larger species. Hence, while moose may access exclusive food resources in terms of browse height and diameter, red and roe deer cannot. PMID- 25543849 TI - Effects of circadian disruption on methamphetamine consumption in methamphetamine exposed rats. AB - RATIONALE: A substantial number of clinical studies indicate associations between sleep abnormalities and drug abuse; however, the role played by the circadian system in the development of addiction is largely unknown. OBJECTIVE: The aim of this study was to examine the effects of experimentally induced chronic jet lag on methamphetamine consumption in a rat model of methamphetamine drinking. METHODS: Male Sprague-Dawley rats (n = 32) were housed in running wheel cages in a 12:12 h light:dark cycle. One group of rats (n = 16) was given 2 weeks of forced methamphetamine consumption (0.01 % in drinking water; meth pre-exposed) while a second group (n = 16, not pre-exposed) received water only. This was followed by a 2-week abstinence period during which half of the animals from each group were exposed to four consecutive 6-h advancing phase shifts of the light:dark cycle, while the other half remained on the original light:dark cycle. Methamphetamine consumption was assessed in all rats following the deprivation period using a two-bottle choice paradigm. RESULTS: Methamphetamine consumption was initially lower in methamphetamine pre-exposed versus not pre-exposed rats. However, during the second week following abstinence, consumption was significantly higher in phase-shifted rats of the methamphetamine pre-exposed group compared to all other groups. CONCLUSIONS: These data reveal an effect of circadian rhythm disturbance on methamphetamine consumption and suggest that dysregulation of the circadian system be considered in the etiology of relapse and addiction. PMID- 25543853 TI - Heterocyclic cyclohexanone monocarbonyl analogs of curcumin can inhibit the activity of ATP-binding cassette transporters in cancer multidrug resistance. AB - Curcumin (CUR) is a phytochemical that inhibits the xenobiotic ABC efflux transporters implicated in cancer multidrug resistance (MDR), such as P glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5). The use of CUR in the clinic however, is complicated by its instability and poor pharmacokinetic profile. Monocarbonyl analogs of CUR (MACs) are compounds without CUR's unstable beta-diketone moiety and were reported to have improved stability and in vivo disposition. Whether the MACs can be used as MDR reversal agents is less clear, as the absence of a beta-diketone may negatively impact transporter inhibition. In this study, we investigated 23 heterocyclic cyclohexanone MACs for inhibitory effects against P-gp, BCRP, MRP1 and MRP5. Using flow cytometry and resistance reversal assays, we found that many of these compounds inhibited the transport activity of the ABC transporters investigated, often with much greater potency than CUR. Overall the analogs were most effective at inhibiting BCRP and we identified three compounds, A12 (2,6-bis((E)-2,5-dimethoxy benzylidene)cyclohexanone), A13 (2,6-bis((E)-4-hydroxyl-3-methoxybenzylidene) cyclohexanone) and B11 (3,5-bis((E)-2-fluoro-4,5-dimethoxybenzylidene)-1 methylpiperidin-4-one), as the most promising BCRP inhibitors. These compounds inhibited BCRP activity in a non-cell line, non-substrate-specific manner. Their inhibition occurred by direct transporter interaction rather than modulating protein or cell surface expression. From these results, we concluded that MACs, such as the heterocyclic cyclohexanone analogs in this study, also have potential as MDR reversal agents and may be superior alternatives to the unstable parent compound, CUR. PMID- 25543855 TI - Effect of the Dutch school-based education programme 'Taste Lessons' on behavioural determinants of taste acceptance and healthy eating: a quasi experimental study. AB - OBJECTIVE: To assess the effect of the Dutch school-based education programme 'Taste Lessons' on children's behavioural determinants towards tasting unfamiliar foods and eating healthy and a variety of foods. DESIGN: In a quasi-experimental study design, data on behavioural determinants were collected at baseline, four weeks and six months after the intervention in both the intervention and control group. Children completed consecutively three questionnaires in which knowledge, awareness, skills, attitude, emotion, subjective norm and intention towards the two target behaviours were assessed. Teachers implemented on average a third of the programme activities. Multilevel regression analyses were conducted to compare individual changes in the determinants in the intervention group with those in the control group, corrected for children's gender and age. Effect sizes were expressed as Cohen's d. SETTING: Dutch elementary schools. SUBJECTS: Forty nine classes (1183 children, 9-12 years old) in grades 5-8 of twenty-one elementary schools. RESULTS: The intervention group showed a higher increase in knowledge (d=0.26, P<0.01), which persisted after six months (d=0.23, P<0.05). After four weeks, the intervention group showed a higher increase in number of foods known (d=0.22, P<0.05) and tasted (d=0.21, P<0.05), subjective norm of the teacher (d=0.17, P<0.05) and intention (d=0.16, P<0.05) towards the target behaviours. CONCLUSIONS: Partial implementation of Taste Lessons during one school year showed small short-term effects on increasing behavioural determinants in relation to tasting unfamiliar foods and eating healthy and a variety of foods. Full and repeated implementation of Taste Lessons in subsequent years might result in larger effects. PMID- 25543854 TI - A web-based support for pregnant women and new mothers with type 1 diabetes mellitus in Sweden (MODIAB-Web): study protocol for a randomized controlled trial. AB - BACKGROUND: Women with type 1 diabetes face particular demands in their lives in relation to childbearing. During pregnancy, in order to optimize the probability of giving birth to a healthy child, their blood glucose levels need to be as normal as possible. After childbirth, they experience a 'double stress': in addition to the ordinary challenges they face as new mothers, they also need to focus on getting their blood glucose levels normal. To improve self-management of diabetes and overall well-being in women with type 1 diabetes, a person-centered web-based support was designed to be tested in a randomized controlled trial (RCT) to be used during pregnancy and early motherhood. This protocol outlines the design of this RCT, which will evaluate the effectiveness of the specially designed web-based support for mothers with type 1 diabetes in Sweden. METHODS/DESIGN: The study is designed as an RCT. The web support consists of three parts: 1) evidence-based information, 2) a self-care diary, and 3) communication with peers. The primary outcome is general well-being evaluated with the Well-Being Questionnaire short version (W-BQ12) and diabetes management evaluated with the Diabetes Empowerment Scale, short version (SWE-DES). Women attending six hospital-based antenatal care centers in Sweden are invited to participate. The inclusion period is November 2011 to late 2014. The allocation of participants to web support (intervention group) and to usual care (control group) is equal (1:1). In total, 68 participants in each group will be needed to reach a statistical power of 80% with significance level 0.05. DISCUSSION: The web support is expected to strengthen the women's personal capacity and autonomy during pregnancy, breastfeeding, and early motherhood, leading to optimal well being and diabetes management. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01565824 (registration date March 27th 2012). PMID- 25543856 TI - A barcode-free combinatorial screening platform for matrix metalloproteinase screening. AB - Application of droplet microfluidics to combinatorial screening applications remains elusive because of the need for composition-identifying unique barcodes. Here we propose a barcode-free continuous flow droplet microfluidic platform to suit the requirements of combinatorial screening applications. We demonstrate robust and repeatable functioning of this platform with matrix metalloproteinase activity screening as a sample application. PMID- 25543857 TI - Left ventricular to coronary connections in newborns with a hypoplastic left heart. AB - We present images and brief clinical summaries of four infants with prominent left ventricular to coronary arterial connections in the setting of hypoplastic left heart, mitral stenosis, and aortic atresia. PMID- 25543858 TI - Concerns and worries in people living with inflammatory bowel disease (IBD): A mixed methods study. AB - OBJECTIVE: This mixed-methods study aimed to explore concerns and worries related to living with inflammatory bowel disease (IBD). METHODS: Overall, 294 patients with a clinically established diagnosis of IBD were enrolled in this cross sectional study. Concerns and worries were measured with one open-ended question. Measures of anxiety and depressive symptoms and disease activity were also administered. A thematic analysis was conducted and thematic map created. Spearman's rho was used to identify univariate correlations between predictors and the main themes. Binary logistic regression was used to test the predictors of the main themes. RESULTS: Despite the majority of study participants being in IBD remission (74%, n=217), all but 11 reported significant IBD-related concerns. Twenty two percent reported symptoms of depression and 41% of anxiety. Four themes were identified: Quality of life (51%); Unpredictability (35%); Symptoms (34%) and Treatments (19%). Males and older people were less concerned about Quality of life (OR=.597, 95% CI: .363-.980 and OR=.980, 95% CI: .965-.995, respectively). Those in remission were less concerned about Symptoms (OR=.510, 95% CI: .281- .926) while those with longer disease duration worried more about the Symptoms (OR=1.035, 95% CI: 1.010-1.061). Males were less concerned about Treatments (OR=.422, 95% CI: .229-.777). CONCLUSION: IBD patients report significant disease-related concerns even when in remission. Further exploration of what predicts patient concerns may help in shaping health-care delivery so that it better addresses patient needs. PMID- 25543859 TI - [Sigmoid volvulus in the puerperium]. PMID- 25543860 TI - [Internal hernia through a broad ligament defect]. PMID- 25543861 TI - Modulation of alternative oxidase to enhance tolerance against cold stress of chickpea by chemical treatments. AB - The alternative oxidase (AOX) is the enzyme responsible for the alternative respiratory pathway. This experiment was conducted to examine the influence on cold tolerance ability of chickpea (Cicer aurentium cv. Mufitbey) seedlings of AOX activator (pyruvate), AOX inhibitor (salicylhydroxamic acid (SHAM)) and an inhibitor of the cytochrome pathway of respiration (antimycin A) treatments. 5mM pyruvate, 2MUM antimycin A and 4mM SHAM solutions were exogenously applied to thirteen-day-old chickpea leaves and then the seedlings were transferred to a different plant growth chamber arranged to 10/5 degrees C (day/night) for 48h. Cold stress markedly increased the activities of antioxidant enzymes compared to controls. Pyruvate and antimycin A significantly increased the cold-induced increase in antioxidant activity but SHAM decreased it. Cold-induced increases in superoxide anion, hydrogen peroxide, and lipid peroxidation levels were significantly reduced by pyruvate and antimycin A, but increased by SHAM treatment. Pyruvate and antimycin A application increased both the activity and protein expression of AOX in comparison to cold stress alone. However, SHAM significantly decreased activity of AOX but did not affect its expression. Total cellular respiration values (TCRV) supported the changes in activity and expression of AOX. While TCRV were increased by cold and pyruvate, they were significantly reduced by SHAM and especially antimycin A. These results indicate that pyruvate and antimycin A applications were effective in reducing oxidative stress by activating the alternative respiratory pathway as well as antioxidant activity. Furthermore, direct activation of AOX, rather than inhibition of the cytochrome pathway, was the most effective way to mitigate cold stress. PMID- 25543862 TI - Role of dioxygenase alpha-DOX2 and SA in basal response and in hexanoic acid induced resistance of tomato (Solanum lycopersicum) plants against Botrytis cinerea. AB - Resistance of tomato (Solanum Lycopersicum) to the fungal pathogen Botrytis cinerea requires complex interplay between hormonal signalling. In this study, we explored the involvement of new oxylipins in the tomato basal and induced response to this necrotroph through the functional analysis of the tomato alpha dioxygenase2 (alpha-DOX2)-deficient mutant divaricata. We also investigated the role of SA in the defence response against this necrotrophic fungus using SA deficient tomato nahG plants. The plants lacking dioxigenase alpha-DOX2, which catalyses oxylipins production from fatty acids, were more susceptible to Botrytis, and hexanoic acid-induced resistance (Hx-IR) was impaired; hence alpha DOX2 is required for both tomato defence and the enhanced protection conferred by natural inducer hexanoic acid (Hx) against B. cinerea. The divaricata plants accumulated less pathogen-induced callose and presented lower levels of jasmonic acid (JA) and 12-oxo-phytodienoic acid (OPDA) upon infection if compared to the wild type. Glutathion-S-transferase (GST) gene expression decreased and ROS production significantly increased in Botrytis-infected divaricata plants. These results indicate that absence of alpha-DOX2 influences the hormonal changes, oxidative burst and callose deposition that occur upon Botrytis infection in tomato. The study of SA-deficient nahG tomato plants showed that the plants with low SA levels displayed increased resistance to Botrytis, but were unable to display Hx-IR. This supports the involvement of SA in Hx-IR. NaghG plants displayed reduced callose and ROS accumulation upon infection and an increased GST expression. This reflects a positive relationship between SA and these defensive mechanisms in tomato. Finally, Hx boosted the pathogen-induced callose in nahG plants, suggesting that this priming mechanism is SA-independent. Our results support the involvement of the oxylipins pathway and SA in tomato response to Botrytis, probably through complex crosstalk of the hormonal balance with callose and ROS accumulation, and reinforce the role of the oxidative stress in the outcome of the plant-Botrytis interaction. PMID- 25543863 TI - Hydrogen-rich water enhances cadmium tolerance in Chinese cabbage by reducing cadmium uptake and increasing antioxidant capacities. AB - The aim of the present paper was to understand the specific mechanism of hydrogen rich water (HRW) in alleviating cadmium (Cd) toxicity in Chinese cabbage (Brassica campestris spp. chinensis L.). Our results showed that the addition of 50% saturation HRW significantly alleviated the Cd toxic symptoms, including the improvement of both root elongation and seedling growth inhibition. These responses were consistent with a significant decrease of Cd accumulation in roots and shoots, which was further confirmed by the histochemical staining. Molecular evidence illustrated that Cd-induced up-regulations of IRT1 and Nramp1 genes, responsible for Cd absorption, were blocked by HRW. By contrast, Cd-induced up regulation of the HMA3 gene, which regulates Cd sequestration into the root vacuoles, was substantially strengthened by HRW. Furthermore, compared with those in Cd stress alone, the expressions of HMA2 and HMA4, which function in the transportation of Cd to xylem, were repressed by co-treatment with HRW. HRW enhanced the activities of antioxidant enzymes, including superoxide dismutase, guaiacol peroxidase, catalase and ascorbate peroxidase. These results were further confirmed by the alleviation of oxidative damage, as indicated by the decrease of thiobarbituric acid reactive substances (TBARS) and reactive oxygen species (ROS) production. Taken together, these results suggest that the improvement of Cd tolerance by HRW was associated with reduced Cd uptake and increased antioxidant defense capacities. Therefore, the application of HRW may be a promising strategy to improve Cd tolerance of Chinese cabbage. PMID- 25543864 TI - Prevalence of diabetic foot disorders and related risk factors among Egyptian subjects with diabetes. AB - INTRODUCTION: Multiple pathologies including diabetic neuropathy, peripheral vascular disease (PVD) and infection contribute to lower extremities amputation in diabetes. AIM: We examined the prevalence of diabetic foot problems and related risk factors in Egypt. SUBJECTS AND METHODS: Between July 2008 and December 2009, 1000 male and 1000 female consecutive adult patients with diabetes (>= 18-year-old) attending the Alexandria University Diabetic Foot Screening Clinic were surveyed for history/presence of foot ulcers and/or amputations, skin/nail changes, joint mobility, sensory neuropathy (10 g-Semmes-Weinstein Monofilament) and peripheral vascular disease (PVD) using Ankle Brachial Index (ABI). RESULTS: The majority of patients had type 2 diabetes (96.75%) with a mean age of 57.30 +/- 10.47 years and a mean disease duration of 11.76 +/- 8.26 years. The mean body mass index was 32.84 +/- 6.31 kg/m(2) with 29.55% being current or ex-smokers. In these subjects, 4.4% had a past history of non-traumatic amputation (male:female: 6.2% vs. 2.6%, p < 0.001); 6.1% had past history (10.3% vs. 7%, p = 0.009) and 8.7% had active foot ulceration (8.1% vs. 4.1% p < 0.001) with a male preponderance. The prevalence of sensory neuropathy was 29.3% (M:F: 30.7%: 27.9%) and peripheral vascular disease (PVD) was 11% (M:F 11.8%:10.2%). Diabetic foot complications were associated with disease duration (p < 0.001), history of coronary artery disease (p = 0.001), stroke (p = 0.009), PVD (p < 0.001), laser photocoagulation (p < 0.001), sensory neuropathy (p < 0.001) and renal replacement therapy (p < 0.001). On multivariate analysis, diabetes duration, foot fissures, Charcot's foot, limited joint mobility, PVD and sensory neuropathy remained independently associated with diabetic foot disorders. CONCLUSION: In Egypt, a mosaic of risk factors contributes to the high prevalence of diabetic foot disease in type 2 diabetes. These findings call for regular assessment of vascular, neuropathic and skin status to prevent these serious foot complications. PMID- 25543865 TI - Uterine remnant: An uncommon finding after transvaginal hysterectomy. PMID- 25543866 TI - Primary neuroendocrine tumors of the gallbladder: Ultrasonographic and MDCT features with pathologic correlation. PMID- 25543867 TI - About chemodectomas occurring concurrently in two sites: in the mediastinum and the lungs. PMID- 25543868 TI - Vascular steal from right ventricular metastasis of renal tumor: insight from single source dual energy cardiac CT. PMID- 25543869 TI - Warthin's tumor of parotid gland: Surgery or follow-up? Diagnostic value of a decisional algorithm with functional MRI. AB - PURPOSE: Warthin's tumor is the second most frequent benign tumor of the parotid gland, with no risk of malignant evolution. That is why surgery should be avoided if the preoperative diagnosis is certain. The aim of the study was to assess the added value of a decisional algorithm for the preoperative diagnosis of Warthin's tumor. MATERIALS AND METHODS: This retrospective IRB-approved study included 75 patients who underwent standardised MRI with conventional sequences (T1- and T2 weighted images, and T1 post-contrast sequences with fat saturation) and functional sequences: diffusion (b0, b1000) and perfusion MR. Two independent readers reviewed the images using the decisional algorithm. The conclusion of each reader was: the lesion is or is not a Warthin's tumor. The MRI conclusion was compared with histology or with cytology and follow-up. We calculated the Cohen's kappa coefficient between the two observers and the sensitivity and specificity of the algorithm-helped-reading for the diagnosis of Warthin's tumor. RESULTS: Seventy-five patients; histology (n=61) or cytology and follow-up (n=14) results revealed 20 Warthin's tumors and 55 other tumors. Using the algorithm, sensitivity and specificity were 80-96%, and 85-100%, respectively for readers 1 and 2. The Cohen's kappa coefficient between the two observers was 0.79 (P<0.05) for the diagnosis of Warthin's tumor. CONCLUSION: Our decisional algorithm helps the preoperative diagnosis of Warthin's tumor. The specificity of the technique is sufficient to avoid surgery if a parotid gland tumor presents all the MRI characteristics of a Warthin's tumor. PMID- 25543870 TI - Use of an automatic recording system for CT doses: evaluation of the impact of iterative reconstruction on radiation exposure in clinical practice. AB - OBJECTIVE: Despite the obligatory recording of doses administered to patients during CT scans, this data is not easily accessible. The objective of this study was to implement and validate a computerised automated dose-recording system for CT scans, for a single radiology department. MATERIAL AND METHODS: Every patient undergoing a CT scan in our department over a one-year period was included in the study. The CT scanner was upgraded after eight months (installation of iterative reconstruction and choice of an additional voltage of 100 kV). The system recorded, from DICOM image headers, the patient data and technical acquisition parameters. The statistical analysis compared the dose length products (DLP) before and after the upgrade, and compared them with the diagnostic reference levels (DRL). RESULTS: Four thousand seven hundred and ninety-five CT scans were included (2141 before the upgrade and 2654 after). For all of the acquisition protocols tested, there was a reduction in DLP after the upgrade. The mean reduction was 30%, with a range of 17% to 44% depending on the protocol. After the upgrade, all of the mean DLPs were under the DRL thresholds (P<0.0001). CONCLUSION: The proposed tool enabled systematic recording of the doses of radiation used in CT scans. It confirmed the significant reduction in the dose resulting from the implementation of iterative reconstruction, and enabled an exhaustive and rapid control of the respect of DRLs. PMID- 25543872 TI - Board certification in internal medicine and cardiology: Historical success and future challenges. AB - Board certification is at a critical juncture. As physicians face increased regulation and pressures from both inside and outside the profession, board certification and Maintenance of Certification (MOC) are coming under increased scrutiny from the public and the medical community. At this challenging time, it is important to remind ourselves what board certification is (and what it is not) and revisit the origins of this tangible expression of professional self regulation, even as we contemplate how it needs to improve. Board certification has evolved over time and must continue to evolve; it is our collective responsibility as physicians that peer-developed standards meet the needs of both the profession and the public. In this article, we will reflect on the history of the American Board of Internal Medicine (ABIM), especially which related to Cardiology, and describe some of ABIM's challenges and new directions. PMID- 25543873 TI - Colchicine and beyond: new options for the treatment of pericarditis. PMID- 25543874 TI - Endocrine sensitivity is decisive for patient outcome in small node-negative breast cancers (BC) (pT1a,b) - results from the Munich Cancer Registry. AB - PURPOSE: In clinical routine, adjuvant systemic therapy in small node-negative (N0) BC is controversial, in particular in HER2-positive disease. We aimed to evaluate outcome of consecutive patients with small N0 BC in a population-based cancer registry and thus consequently substantiate indications for chemotherapy in those patient subgroups at increased relapse risk or poor survival. METHODS: From 2002 to 2009 (median follow-up 6 years), 9707 primary breast cancer patients with N0 tumors <2 cm (pTis, pT1N0M0) were reported to the Munich Cancer Registry. Patients with pTis tumors (n = 1870) served as internal comparator. Time to progression, observed (OS) and relative survival rates (Kaplan-Meier estimates) are presented. Cox regression analysis was used to assess the influence of tumor size, age, HR-, and HER2-status. RESULTS: 10-year-OS for pTis was 94.0%. In HR positive tumors it was 91.9% in pT1a, 90.6% in pT1b, and 86.8% in pT1c. In HR negative tumors, rates were 91.7%, 86.8%, and 86.8%, respectively. In HER2 positive tumors it was 81.2%, 88.1%, and 86.7%, in HER2-negative 93.1%, 90.6%, and 86.0%, respectively. In the multivariate model, age, tumor size, and HR status showed a significant impact on OS (HRneg. vs. HRpos.: hazard ratio 1.50 (95% CI; 1.12-1.99), while HER2-status was not an independent prognostic factor. CONCLUSION: Prognosis of N0 tumors <1 cm is excellent, especially if they are HR positive, even in HER2-positive cases. Weighing potential benefits vs. side effects, there seems to be no need for chemotherapy in tumors <0.5 cm. In pT1b chemotherapy may be considered, if tumors are triple negative or HER2-positive and HR-negative. In pT1c guideline-based adjuvant therapy using all therapeutic options seems to be warranted. PMID- 25543876 TI - Liquid metal/metal oxide frameworks with incorporated Ga2O3 for photocatalysis. AB - Solvothermally synthesized Ga2O3 nanoparticles are incorporated into liquid metal/metal oxide (LM/MO) frameworks in order to form enhanced photocatalytic systems. The LM/MO frameworks, both with and without incorporated Ga2O3 nanoparticles, show photocatalytic activity due to a plasmonic effect where performance is related to the loading of Ga2O3 nanoparticles. Optimum photocatalytic efficiency is obtained with 1 wt % incorporation of Ga2O3 nanoparticles. This can be attributed to the sub-bandgap states of LM/MO frameworks, contributing to pseudo-ohmic contacts which reduce the free carrier injection barrier to Ga2O3. PMID- 25543875 TI - Optimal time following fluorescein instillation to evaluate rigid gas permeable contact lens fit. AB - PURPOSE: To examine the optimum time at which fluorescein patterns of gas permeable lenses (GPs) should be evaluated. METHODS: Aligned, 0.2mm steep and 0.2mm flat GPs were fitted to 17 patients (aged 20.6 +/- 1.1 years, 10 male). Fluorescein was applied to their upper temporal bulbar conjunctiva with a moistened fluorescein strip. Digital slit lamp images (CSO, Italy) at 10* magnification of the fluorescein pattern viewed with blue light through a yellow filter were captured every 15s. Fluorescein intensity in central, mid peripheral and edge regions of the superior, inferior, temporal and nasal quadrants of the lens were graded subjectively using a +2 to -2 scale and using ImageJ software on the simultaneously captured images. RESULTS: Subjectively graded and objectively image analysed fluorescein intensity changed with time (p < 0.001), lens region (centre, mid-periphery and edge: p < 0.05) and there was interaction between lens region with lens fit (p < 0.001). For edge band width, there was a significant effect of time (F = 118.503, p < 0.001) and lens fit (F = 5.1249, p = 0.012). The expected alignment, flat and steep fitting patterns could be seen from approximately after 30 to 180 s subjectively and 15 to 105 s in captured images. CONCLUSION: Although the stability of fluorescein intensity can start to decline in as little as 45 s post fluorescein instillation, the diagnostic pattern of alignment, steep or flat fit is seen in each meridian by subjective observation from about 30s to 3 min indicating this is the most appropriate time window to evaluate GP lenses in clinical practice. PMID- 25543877 TI - All solution-processed lead halide perovskite-BiVO4 tandem assembly for photolytic solar fuels production. AB - The quest for economic, large-scale hydrogen production has motivated the search for new materials and device designs capable of splitting water using only energy from the sun. Here we introduce an all solution-processed tandem water splitting assembly composed of a BiVO4 photoanode and a single-junction CH3NH3PbI3 hybrid perovskite solar cell. This unique configuration allows efficient solar photon management, with the metal oxide photoanode selectively harvesting high energy visible photons, and the underlying perovskite solar cell capturing lower energy visible-near IR wavelengths in a single-pass excitation. Operating without external bias under standard AM 1.5G illumination, the photoanode-photovoltaic architecture, in conjunction with an earth-abundant cobalt phosphate catalyst, exhibits a solar-to-hydrogen conversion efficiency of 2.5% at neutral pH. The design of low-cost tandem water splitting assemblies employing single-junction hybrid perovskite materials establishes a potentially promising new frontier for solar water splitting research. PMID- 25543878 TI - Effect of alloy elements on the morphology transformation of TiB2 particles in Al matrix. AB - To reveal the effect of alloy element on the morphology of in situ TiB2 particles, a series of TiB2 particles with various morphology were obtained via controlling synthesis process. Si and Cu can affect the morphology transformation of TiB2 particles significantly. Si preferentially adsorbed on (101-1), (112-0) and (12-13-) planes resulting in the polyhedron morphology of TiB2. Cu adsorbed on (101-0) preferentially leading to the minimum aspect (the ratio of the diameter and thickness). PMID- 25543879 TI - Ultrastructural changes and programmed cell death of trophocytes in the gonad of Isohypsibius granulifer granulifer Thulin, 1928 (Tardigrada, Eutardigrada, Isohypsibiidae). AB - The studies on the fates of the trophocytes, the apoptosis and autophagy in the gonad of Isohypsibius granulifer granulifer have been described using transmission electron microscope, light and fluorescent microscopes. The results presented here are the first that are connected with the cell death of nurse cells in the gonad of tardigrades. However, here we complete the results presented by Weglarska (1987). The reproductive system of I. g. granulifer contains a single sack-like hermaphroditic gonad and a single gonoduct. The gonad is composed of three parts: a germarium filled with proliferating germ cells (oogonia); a vitellarium that has clusters of female germ cells (the region of oocytes development); and a male part filled with male germ cells in which the sperm cells develop. The trophocytes (nurse cells) show distinct alterations during all of the stages of oogenesis: previtello-, vitello- and choriogenesis. During previtellogenesis the female germ cells situated in the vitellarium are connected by cytoplasmic bridges, and form clusters of cells. No ultrastructural differences appear among the germ cells in a cluster during this stage of oogenesis. In early vitellogenesis, the cells in each cluster start to grow and numerous organelles gradually accumulate in their cytoplasm. However, at the beginning of the middle of vitellogenesis, one cell in each cluster starts to grow in order to differentiate into oocyte, while the remaining cells are trophocytes. Eventually, the cytoplasmic bridges between the oocyte and trophocytes disappear. Autophagosomes also appear in the cytoplasm of nurse cells together with many degenerating organelles. The cytoplasm starts to shrink, which causes the degeneration of the cytoplasmic bridges between trophocytes. Apoptosis begins when the cytoplasm of these cells is full of autophagosomes/autolysosomes and causes their death. PMID- 25543880 TI - Antibiotic prophylaxis in elective laparoscopic cholecystectomy is useless. A prospective multicenter study. AB - AIM: We performed a prospective study to evaluate the effect of antibiotic prophylaxis (AP) on the incidence of infection in elective laparoscopic cholecystectomy (LC). MATERIAL OF STUDY: All patients were at low-medium anesthetic and infectious risk and underwent LC for benign disease. At induction of anesthesia 41 patients received ampicillin-sulbactam 3g, 40 patients received ciprofloxacin 400mg intravenously, and 53 patients received no AP. RESULTS: Postoperative infection was observed in 11 patients (8.2%) in the entire study group. All ob served infections were superficial surgical site infections (SSIs), always located at the umbilical incision. Infection occurred in 3 patients (7.3%) in ampicillin-sulbactam group, in 3 patients (7.5%) in ciprofloxacin group and in 5 patients (9.4%) in nonantibiotic group (p=0.916). Univariate analysis showed that duration of operation, placement of a drain and postoperative hospital stay were significantly associated with the development of SSIs. At multivariate analysis, only duration of operation was statistically significant in predicting SSIs. DISCUSSION: The present study did not show any advantage in the use of AP, although in case of difficult surgery the risk of SSIs is increased, in particular in the umbilical incision. In all patients, the bile culture was sterile, then the infection of the umbilical site is not due to bacterial infection from the gallbladder. CONCLUSIONS: AP in elective LC should not be routinely performed. A particular attention to the preoperative cleaning and topical antibiotic therapy of the umbilical area is advised. PMID- 25543881 TI - Long-term survivor of primary malignant melanoma of the esophagus treated with surgical resection. AB - INTRODUCTION: Primary malignant melanoma of the esophagus is a rare diagnosis with only a few hundred cases reported in the literature. Due to the aggressive nature of this disease, long-term survivors are exceedingly rare with only a handful of case reports. PRESENTATION OF CASE: We report the case of a 38 year old man who presented with chest and back pain. Workup revealed a mediastinal mass and the patient was diagnosed with primary malignant melanoma of the esophagus and treated with radical resection. Despite the poor prognosis associated with primary malignant melanoma of the esophagus, he remains disease free for over 7 years. DISCUSSION: Initially primary malignant melanoma of the esophagus was a controversial diagnosis until the demonstration of normal melanocytes in healthy patients. It is an aggressive disease that is nearly uniformly fatal. Review of the literature shows that treatment with radical surgical resection extends prognosis by months while treatment with adjuvant chemotherapy is controversial. CONCLUSION: Primary malignant melanoma of the esophagus is a rare and aggressive disease that should be treated with surgical resection when feasible. We report the rare case of a long term survivor over 7 years since diagnosis. PMID- 25543882 TI - Upper G.I. hemorrhage from glass fragments' ingestion in a patient with jejunal diverticula - Case report. AB - INTRODUCTION: Acute upper gastrointestinal bleeding is a common emergency. The ingestion of foreign bodies represents a less frequent cause of bleeding, but it is equally life-threatening, especially if the patient does not report the incident. PRESENTATION OF CASE: We are reporting the case of a 77-year-old patient with a bleeding caused by ingestion of glass fragments with co-existing jejunal diverticula. DISCUSSION: The ingestion of foreign bodies is a rare, mostly accidental event. Another possible source of upper G.I. bleeding is jejunal diverticula; in this case, the examination of the specimens showed evidence of glass ingestion fragments as the likely cause of bleeding. CONCLUSION: Surgeons should be aware that patients may fail to report correctly on the possible causes of bleeding, misleading the diagnosis, and delaying the diagnostic routes. PMID- 25543883 TI - Touching anatomy: On the handling of preparations in the anatomical cabinets of Frederik Ruysch (1638-1731). AB - This paper argues that the anatomical Cabinets of Dutch anatomist Frederik Ruysch must be understood as an early modern workshop in which preparations were continuously handled. It is claimed that preparations actively appealed to anatomists and visitors to handle, re-dissect, touch, and even kiss them. Touching anatomy, therefore, not only refers to the physical handling of objects, but also to the ways preparations impacted on visitors and touched them emotionally. PMID- 25543884 TI - Comments on the Ananterinae Pocock, 1900 (Scorpiones: Buthidae) and description of a new remarkable species of Ananteris from Peru. AB - New comments are proposed for the subfamily Ananterinae (sensu Pocock). The worldwide pattern of distribution of the elements associated with this subfamily, as well as aspects of their ecology, are discussed. The biogeographic patterns presented by extant and fossil elements of this subfamily confirm not only the characteristics of a group presenting a typical Gondwanian distribution, but also correspond to older Pangaean patterns. One new remarkable species is described in the genus Ananteris Thorell. This new species is also the first record of the genus for Peru. PMID- 25543886 TI - Allosteric ACTion: the varied ACT domains regulating enzymes of amino-acid metabolism. AB - Allosteric regulation of enzyme activity plays important metabolic roles. Here we review the allostery of enzymes of amino-acid metabolism conferred by a discrete domain known as the ACT domain. This domain of 60-70 residues has a betaalphabetabetaalphabeta topology leading to a four-stranded beta4beta1beta3beta2 antiparallel sheet with two antiparallel helices on one face. Extensive sequence variation requires a combined sequence/structure/function analysis for identification of the ACT domain. Common features include highly varied modes of self-association of ACT domains, ligand binding at domain interfaces, and transmittal of allosteric signals through conformational changes and/or the manipulation of quaternary equilibria. A recent example illustrates the relatively facile adoption of this versatile module of allostery by gene fusion. PMID- 25543885 TI - Interaction of recombinant octameric hemoglobin with endothelial cells. AB - Hemoglobin-based oxygen carriers (HBOCs) may generate oxidative stress, vasoconstriction and inflammation. To reduce these undesirable vasoactive properties, we increased hemoglobin (Hb) molecular size by genetic engineering with octameric Hb, recombinant (r) HbbetaG83C. We investigate the potential side effects of rHbbetaG83C on endothelial cells. The rHbbetaG83C has no impact on cell viability, and induces a huge repression of endothelial nitric oxide synthase gene transcription, a marker of vasomotion. No induction of Intermolecular-Adhesion Molecule 1 and E-selectin (inflammatory markers) transcription was seen. In the presence of rHbbetaG83C, the transcription of heme oxygenase-1 (oxidative stress marker) is weakly increased compared to the two other HBOCs (references) or Voluven (control). This genetically engineered octameric Hb, based on a human Hb betaG83C mutant, leads to little impact at the level of endothelial cell inflammatory response and thus appears as an interesting molecule for HBOC development. PMID- 25543887 TI - Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: comparison of three methods. AB - OBJECTIVE: To compare signal intensity (SI) correction using scale and rescale slopes with SI correction using SIs of spleen and muscle for quantifying multiphase hepatic contrast enhancement with Gd-EOB-DTPA by assessing their correlation with T1 values generated from Look-Locker turbo-field-echo (LL-TFE) sequence data (ER-T1). MATERIALS AND METHODS: Thirty patients underwent Gd-EOB DTPA-enhanced magnetic resonance imaging (MRI) in this prospective clinical study. For each patient, breath-hold T1-weighted fat-suppressed three-dimensional (3D) gradient echo sequences (e-THRIVE) were acquired before and 2 (first phase), 10 (second phase), and 20min (third phase) after intravenous Gd-EOB-DTPA. Look Locker turbo-field-echo (LL-TFE) sequences were acquired before and 1.5 (first phase), 8 (second phase), and 18min (third phase) postcontrast. The liver parenchyma enhancement ratios (ER) of each phase were calculated using the SI from e-THRIVE sequences (ER-SI) and the T1 values generated from LL-TFE sequence data (ER-T1) respectively. ER-SIs were calculated in three ways: (1) comparing with splenic SI (ER-SI-s), (2) comparing with muscle SI (ER-SI-m), (3) using scale and rescale slopes obtained from DICOM headers (ER-SI-c), to eliminate the effects of receiver gain and scaling. For each of the first, second and third phases, correlation and agreement were assessed between each ER-SI and ER-T1. RESULTS: In the first phase, all ER-SIs correlated weakly with ER-T1. In the second and third phases, ER-SI-c showed a stronger linear correlation with ER-T1 (r(2)=0.71-0.72, p<0.01) than did ER-SI-s (r(2)=0.37-0.39, p<0.01) or ER-SI-m (r(2)=0.30-0.41, p<0.01). CONCLUSION: SI correction using scale and rescale slopes from DICOM data is the most acceptable algorithm for evaluating delayed phase Gd-EOB-DTPA hepatic enhancement. PMID- 25543888 TI - GATA5 loss-of-function mutation in familial dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is an important cause of sudden cardiac death and heart failure and is the leading indication for heart transplantation in children and adults worldwide. Recent studies have revealed a strong genetic basis for idiopathic DCM, with many distinct genes causally implicated. Nevertheless, DCM is a genetically heterogeneous disorder and the genetic determinants underlying DCM in a substantial proportion of patients remain unclear. In this study, the whole coding exons and flanking introns of the GATA binding protein 5 (GATA5) gene, which codes for a zinc-finger transcription factor essential for cardiovascular development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as the controls were genotyped for GATA5. The functional characteristics of the mutant GATA5 were analyzed in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.G240D, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional analyses revealed that the GATA5 mutant was associated with significantly diminished transcriptional activity. This study firstly links GATA5 mutation to DCM, which provides novel insight into the molecular mechanisms of DCM, suggesting a potential molecular target for the prenatal prophylaxis and allele-specific treatment of DCM. PMID- 25543890 TI - Acute abdominal pain accompanied by high creatinine in a female patient with schizophrenia. PMID- 25543889 TI - Array heterogeneity prevents catastrophic forgetting in infants. AB - Working memory is limited in adults and infants. But unlike adults, infants whose working memory capacity is exceeded often fail in a particularly striking way: they do not represent any of the presented objects, rather than simply remembering as many objects as they can and ignoring anything further (Feigenson & Carey, 2003, 2005). Here we explored the nature of this "catastrophic forgetting," asking whether stimuli themselves modulate the way in which infants' memory fails. We showed 13-month old infants object arrays that either were within or that exceeded working memory capacity--but, unlike previous experiments, presented objects with contrasting features. Although previous studies have repeatedly documented infants' failure to represent four identical hidden objects, in Experiments 1 and 2 we found that infants who saw four contrasting objects hidden, and then retrieved just two of the four, successfully continued searching for the missing objects. Perceptual contrast between objects sufficed to drive this success; infants succeeded regardless of whether the different objects were contrastively labeled, and regardless of whether the objects were semantically familiar or completely novel. In Experiment 3 we explored the nature of this surprising success, asking whether array heterogeneity actually expanded infants' working memory capacity or rather prevented catastrophic forgetting. We found that infants successfully continued searching after seeing four contrasting objects hidden and retrieving two of them, but not after retrieving three of them. This suggests that, like adults, infants were able to remember up to, but not beyond, the limits of their working memory capacity when representing heterogeneous arrays. PMID- 25543894 TI - AN EVALUATION OF AMALGAM SEPARATORS. PMID- 25543891 TI - Performance of a zero valent iron-based anaerobic system in swine wastewater treatment. AB - In this paper, short-term exposure experiments with different ZVI concentrations were conducted to research the effects of ZVI adding on the anaerobic system for treating swine wastewater. Increasing the ZVI dose had a stimulatory effect on COD removal and CH4 production possibly due to a higher corrosion-induced H2 and dissolved ferrous ions, which could stimulate the methanogenesis and thus the biodegradation. In addition, the abiotic corrosion reactions such as flocculation, adsorption and precipitation were inevitable to removal some suspended COD. However, high ZVI doses had a potential risk on microorganism due to the present of large numbers of solid iron species in sludge, which likely encapsulated the cells and even damaged the cellular structure. Taken as a whole, the most enhancing effect induced by ZVI was observed at the rZVI/VSS of 2.63, and the maximum efficiency of per ZVI adding occurred at the rZVI/VSS of 0.74. But the ZVI concentration of 50 g/L (the rZVI/VSS was 5.26) was proved too high to facilitate microorganism activity, considering the higher LDH leakage and lower intracellular ATP level than the only sludge system. PMID- 25543896 TI - Lipid-dependent regulation of the unfolded protein response. AB - Protein folding homeostasis in the lumen of the endoplasmic reticulum is defended by signal transduction pathways that are activated by an imbalance between unfolded proteins and chaperones (so called ER stress). Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6. These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER. However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review. PMID- 25543898 TI - Physical activity and diabetic cardiomyopathy: myocardial adaptation depending on exercise load. AB - Diabetes mellitus (DM), an increasing health problem worldwide, is associated with severe cardiovascular complications. To date, the beneficial effects of physical activity in both prevention and treatment of DM and its complications are well established. Nevertheless, it appears that exercise training, depending on the load, exerts differential effects on the myocardium. Hence, in this review, the impact of exercise training, focusing on exercise modalities and adaptations in response to load, on diabetic cardiovascular function, are discussed. Molecular mechanisms that may be involved in these adaptions to exercise training are also addressed. PMID- 25543897 TI - The mitochondrial unfolded protein response-synchronizing genomes. AB - Maintenance of the mitochondrial proteome is performed primarily by chaperones, which fold and assemble proteins, and by proteases, which degrade excess damaged proteins. Upon various types of mitochondrial stress, triggered genetically or pharmacologically, dysfunction of the proteome is sensed and communicated to the nucleus, where an extensive transcriptional program, aimed to repair the damage, is activated. This feedback loop, termed the mitochondrial unfolded protein response (UPR(mt)), synchronizes the activity of the mitochondrial and nuclear genomes and as such ensures the quality of the mitochondrial proteome. Here we review the recent advances in the UPR(mt) field and discuss its induction, signaling, communication with the other mitochondrial and major cellular regulatory pathways, as well as its potential implications on health and lifespan. PMID- 25543899 TI - Recent Advances in Optimal Adjunctive Antithrombotic Therapy in STEMI Patients Undergoing Primary Angioplasty: An Overview. AB - There has been a considerable effort to improve adjunctive antithrombotic therapies to reperfusion strategies in the treatment of ST-segment elevation Myocardial Infarction (STEMI). Therefore, the aim of this article is to provide a critical and updated overview of recent advances on adjunctive antithrombotic therapies in patients undergoing primary angioplasty for STEMI. Due to very low costs, early Unfractionated Heparin (UFH) plus additional periprocedural administration should still be regarded as the gold standard in antithrombotic therapy, whereas subsequent subcutaneous administration of Low Molecular Weight Heparins (LMWHs) or fondaparinux should be considered, especially in patients at higher risk of thromboembolic complications. Periprocedural bivalirudin should be considered instead of a strategy of combined UFH and Glycoprotein (Gp) IIb/IIIa inhibitors, especially among patients at higher risk of bleeding complications. New oral ADP antagonists should be administrated as early as possible soon after diagnosis, whereas the use of clopidogrel should be limited to the cases when the new ADP antagonists are not available or contraindicated. However, rivaroxaban has obtained indication for Acute Coronary Syndromes (ACS), and therefore its combination with aspirin and clopidogrel will gain recognition especially among STSegment Elevation Myocardial Infarction (STEMI) patients. Future trials are needed to compare different possible strategies with oral antithrombotic therapies and in particular optimal duration, especially in the era of new DES that have been shown to reduce the risk of stent thrombosis. Early Gp IIb/IIIa inhibitor use may be considered as upstream therapy especially in high-risk patients, whereas the choice of periprocedural administration may be based on thrombus burden or in case of impaired haemodynamic conditions that may compromise oral drug absorption. Overall, a more aggressive antithrombotic approach should be considered within the first hours from symptom onset, when the considerable viability justifies aggressiveness. The use of radial approach and potential protamine administration should be considered in order to minimize the risk of bleeding complications. Due to the very low mortality currently achieved by primary angioplasty and stenting, a further reduction in short or mediumterm mortality would be not easy to demonstrate. Therefore, additional endpoints, such as infarct size and myocardial perfusion, may be considered in future randomized trials especially for the evaluation of new periprocedural antithrombotic therapies among patients undergoing mechanical revascularization for STEMI. PMID- 25543900 TI - Molecular assembly of Schiff Base interactions: construction and application. PMID- 25543901 TI - Marked elevation of hepatic transaminases in recipients of an orthotopic liver transplant from a brain-dead donor receiving extracorporeal membrane oxygenation. AB - BACKGROUND: Hemodynamic instability can lead to failure of donor organ procurement in brain-dead donors. Extracorporeal membrane oxygenation (ECMO) has been used in non-heart-beating donors to increase the donor pool, but the use of ECMO to salvage donor organs has been rarely used. We aimed to analyze postoperative liver function test results in patients receiving orthotopic liver transplants from ECMO-supported brain-dead donors. MATERIAL AND METHODS: We retrospectively reviewed the records of 43 recipients of orthotopic liver transplantation from May 2009 to June 2012. Six recipients received liver grafts from ECMO-maintained donors designated as the ECMO group (n=6). The remaining patients were assigned to the non-ECMO group (n=37). Complication and mortality rates and liver function test results on postoperative days 1, 3, 5, 7, and 14 were compared between the 2 groups. RESULTS: Serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase levels were significantly elevated on postoperative Day 1 in the ECMO group. There were no significant differences in the complication and overall survival rates between the 2 groups (P=0.411). CONCLUSIONS: Although serum transaminases markedly elevated on postoperative Day 1, ECMO successfully preserved potential liver grafts in hemodynamically unstable brain-dead donors. PMID- 25543902 TI - Removal of the residual roots of mandibular wisdom teeth in the lingual space of the mandible via endoscopy. AB - In this study, we aimed to evaluate the reliability of the use of endoscopy for removal of the residual roots of mandibular wisdom teeth in the lingual space of the mandible. Seven patients with residual roots of the mandibular wisdom teeth remaining in the lingual space were treated via endoscopy, and the results of their treatments were reviewed retrospectively. The study found that the residual roots of the mandibular wisdom teeth in the lingual space were removed successfully via endoscopy. The average duration of surgery for each case was 5 min, and no complications were observed in any case. There is little risk involved with removing the residual roots of mandibular wisdom teeth in the lingual space via endoscopy and the procedure is safe and fast. We conclude that it is worth promoting this clinical procedure for current and future use. PMID- 25543903 TI - Controversies in orbital reconstruction--I. Defect-driven orbital reconstruction: a systematic review. AB - In the 1980s, computed tomography was introduced as an imaging modality for diagnosing orbital fractures. Since then, new light has been shed on the field of orbital fracture management. Currently, most surgeons are likely to repair orbital fractures based on clinical findings and particularly on data obtained from computed tomography scans. However, an important but unresolved issue is the fracture size, which dictates the extent and type of reconstruction. In other fields of trauma surgery, an increasing body of evidence is stressing the importance of complexity-based treatment models. The aim of this study was to systematically review all articles on orbital reconstruction, with a focus on the indication for surgery and the defect size and location, in order to identify the reconstruction methods that show the best results for the different types of orbital fractures. PMID- 25543904 TI - Controversies in orbital reconstruction--II. Timing of post-traumatic orbital reconstruction: a systematic review. AB - The timing of orbital reconstruction is a determinative factor with respect to the incidence of potential postoperative orbital complications. In orbital trauma surgery, a general distinction is made between immediate (within hours), early (within 2 weeks), and late surgical intervention. There is a strong consensus on the indications for immediate repair, but clinicians face challenges in identifying patients with minimal defects who may actually benefit from delayed surgical treatment. Moreover, controversies exist regarding the risk of late surgery-related orbital fibrosis, since traumatic ocular motility disorders sometimes recover spontaneously and therefore do not necessarily require surgery. In this study, all currently available evidence on timing as an independent variable in orbital fracture reduction outcomes for paediatric and adult patients was systematically reviewed. Current evidence supports guidelines for immediate repair but is insufficient to support guidelines on the best timing for non immediate orbital reconstruction. PMID- 25543905 TI - Endostar inhibits hypoxia-induced cell proliferation and migration via the hypoxia-inducible factor-1alpha/vascular endothelial growth factor pathway in vitro. AB - Endostar, a recombinant human endostatin, is recognized as one of the most effective angiogenesis inhibitors. The angiogenesis inhibitory effects of Endostar suggest a possible beneficial role of Endostar in choroidal neovascularization (CNV), which is predominantly induced by hypoxia. In our previous study, it was reported that Endostar may inhibit the proliferation and migration of RF/6A choroid-retinal endothelial cells. However, the inhibitory effect of Endostar on hypoxia-induced cell proliferation and migration in RF/6A cells has not yet been elucidated. Therefore, the present study investigated the effect of Endostar on hypoxia-induced cell proliferation and migration in RF/6A cells and the possible mechanisms underlying this effect. Under chemical hypoxia conditions, cell viability was increased to 114.9+/-10.1 and 123.6+/-9.6% in cells treated with 100 and 200 um CoCl2, respectively, compared with the control (P<0.01). Pretreatment with 10-100 ug/ml Endostar significantly inhibited CoCl2 induced cell proliferation (P<0.05), and pre-treatment with 10 ug/ml Endostar for 24, 48 and 96 h attenuated CoCl2-promoted cell migration by 60.5, 48.3 and 39.6%, respectively, compared with the control (P<0.001). In addition, pretreatment with 10 ug/ml Endostar reversed the cell cycle arrest at S phase and the increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) mRNA in RF/6A cells treated with 200 uM CoCl2. These data indicate that Endostar inhibited CoCl2-induced hypoxic proliferation and migration, and limited cell cycle progression in vitro possibly through the HIF-1alpha/VEGF pathway. PMID- 25543906 TI - Incorporating sign-dependence in health-related social welfare functions. AB - It is important to measure people's preferences regarding the trade-off between efficiency and equity in health to make public decisions that are in a society's best interests. This article demonstrates the usefulness of social welfare functions to obtain these measurements. Insights from individual decision making, in particular, prospect theory, turn out to be helpful to estimate societal preferences more accurately. The author shows how one can disentangle the effects of loss aversion in this estimation. The presented approach also allows for sign dependent societal utility and equity weighting functions. Recent empirical studies that used this approach with choices concerning quality of life of other people reported the presence of substantial inequity aversion both for gains and for losses, as well as loss aversion. Several examples demonstrate the relevance of these insights for preference elicitations and health economic evaluations. PMID- 25543909 TI - PHDs inhibitor DMOG promotes the vascularization process in the AV loop by HIF-1a up-regulation and the preliminary discussion on its kinetics in rat. AB - BACKGROUND: The Arterovenous Loop (AV Loop) model is a vascularization model in tissue engineering research, which is capable of generating a three dimensional in vivo unit with cells as well as the supporting vessels within an isolation chmaber. In our previous studies the AV loop in the isolation chamber was discovered to undergo hypoxia, characterized by Hypoxia Inducible Factor (HIF) up regulation. The vascularization followed the increase of HIF-alpha temporally, while it was spatially positively correlated with the HIF-alpha level, as well. This study aims to prove that HIF-1a up-regulation is the stimulus for vascularization in the AV loop model. METHOD: The AV loop model in rats was created by interposing a femoral vein graft into the distal ends of the contralateral femoral artery and vein, and the loop was embeded in fibrin matrix and fixed in isolation chamber. PHD (prolyl hydroxylases) inhibitor DMOG (Dimethyloxallyl Glycine) was applied systemically in the rats in 40 mg/KG at day 0 and day 3 (DMOG-1), or in 15 mg/KG at day 8, day10 and day12 (DMOG-2). Two weeks later the specimens were explanted and underwent morphological and molecular evaluations. RESULTS: Compared to the control group, in the DMOG-2 group the HIF-1alpha positive rate was siginicantly raised as shown in immunohistochemistry staining, accompanied with a smaller cross section area and greater vessel density, and a HIF-1alpha accumulation in the kidney. The mRNA of HIF-1alpha and its angiogenic target gene all increased in different extends. Ki67 IHC demostrate more positive cells. There were no significant change in the DMOG-1 group. CONCLUSION: By applying DMOG systemically, HIF-1alpha was up regulated at the protein level and at the mRNA level, acompanied with angiogenic target gene up-regulateion, and the vascularization was promoted correspondingly. DMOG given at lower dosage constantly after one week tends to have better effect than the group given at larger dosage in the early stage in this model, and promotes cell proliferation, as evidenced by Ki67 IHC. Thus, this study proves that HIF-1a up-regulation is the stimulus for vascularization in the AV loop model and that the process of the vessel outgrowth can be controlled in the AV Loop model utilizing this mechanism. PMID- 25543911 TI - Guy Sebag, adieu mon ami. PMID- 25543910 TI - Spirotetronate antibiotics with anti-Clostridium activity from Actinomadura sp. 2EPS. AB - The rare actinomycetes strain 2EPS was isolated from soil and analysis of cultural, morphological characteristics, diaminopimelic acid content of its cell wall, and 16S rRNA gene sequence indicates that 2EPS belongs to genus Actinomadura. In addition, neighbor-joining phylogenetic tree also confirmed the relationships of this strain to other members of Actinomadura. A butanol extract with antibacterial activity was purified by reversed-phase chromatography to obtain three bioactive compounds, designated as compounds 1, 2 and 3. The structures of these compounds were determined using spectroscopic analysis ((1)H NMR and (13)C-NMR) and mass spectrometric analysis (HR-TOF-MS). Compounds 1-3 were identified and found to be the same as those included in the Japanese patent number JP 09227587 for spirotetronate antibiotics and are BE-45722A (1), BE 45722B (2) and BE-45722C (3), respectively. All compounds were active against Gram-positive bacteria (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, and B. subtilis ATCC 6633) with low MIC values between 0.08 and 5.0 ug/ml. Moreover, both 1 and 3 also exhibited strong activity, with similar MIC values, against Clostridium perfringens S107 at 0.63 ug/ml and C. difficile 630 at 0.08 ug/ml. These results suggest the identified spirotetronate compounds may have potential in the treatment of Clostridium infections. Overall, this analysis demonstrates that rare actinomycetes are a promising source for discovery of antimicrobial compounds. PMID- 25543912 TI - Complete mitochondrial genome of the Sharpnose stingray Himantura gerrardi (Myliobatiformes: Dasyatidae). AB - In this study, we presented the complete mitochondrial genome of the Sharpnose stingray Himantura gerrardi for the first time, which was 17,685 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a putative control region. The overall nucleotide composition was 30.1% A, 27.5% C, 14.5% G and 28.0% T. A total of 22 bp overlaps and 83 bp short intergenic spaces were found in the mitogenome. Two start codons (ATG and GTG) and two stop codons (TAG and TAA/T) were used in the protein-coding genes. The origin of L-strand replication (OL) sequence formed a hairpin structure between the tRNA-Asn and tRNA-Cys genes. The termination associated sequence (TAS) formed a hairpin structure near the tRNA-Pro in the control region. PMID- 25543914 TI - DNA barcoding and molecular phylogeny in Ranidae. AB - The family Ranidae has the widest distribution compared with other frog family. The phylogeny of the Ranidae is still a matter of dispute. In the present study, we analyzed the COI barcodes of 29 species from six genera belonging to the family Ranidae. Twenty-seven species (93.10% of all the species) were correctly identified by their DNA barcodes. Pelophylax lessonae and Pelophylax ridibundus shared the same one barcode sequence. Kimura two-parameter distances were calculated between barcodes. Pair-wise comparisons among-species were distributed from 0.16% (between Pelophylax lessonae and Pelophylax esculenta) to 29.13% (between Rana warszewitschii and Rana dybowskii). The average genetic distance between species was 28 times higher than the average genetic distance within species. The neighbor-joining method was used to construct a phylogenetic tree, which grouped all the genera into two divergent clades. The results indicated that some currently recognized genera of Ranidae may not be monophyletic. COI gene data supported the hypothesis of polyphyly for Rana, Amolops, Babina, and Hylarana. DNA barcoding is an effective molecular tool for Ranidae species identification and phylogenetic inference. PMID- 25543913 TI - The complete mitochondrial genome of the bass yabby Trypaea australiensis Dana 1852, (Crustacea; Decapoda; Callianassidae) - a new gene order for the Decapoda. AB - The complete mitochondrial genome of the Bass yabby Trypaea australiensis was obtained from a partial genome scan using the MiSeq sequencing system. The T. australiensis mitogenome is 16,821 bp in length (70.25% A + T content) made up of 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs and a putative 1977 bp non-coding AT-rich region. This Trypaea mitogenome sequence is the 5th for the family Callianassidae and represents a new gene order for the Decapoda involving protein-coding, rRNA and tRNA genes and the control region. PMID- 25543915 TI - The complete mitochondrial genome of Temnopleurus hardwickii (Camarodonta: Temnopleuridae). AB - The complete mitochondrial genome of Temnopleurus hardwickii was sequenced using long-PCR and primer walking methods. The complete mitochondrial genome is a 15,696 bp circular molecule which contains 22 tRNAs, 2 rRNAs, 13 protein-coding genes as well as a non-coding control region as in other urchin. The genome was composed of 32.9% A, 29.3% T, 21.4% C and 16.4% G, showing a slight AT bias (62.3%). The control region is 156 bp. Twelve of the 13 mitochondrial protein coding genes use ATG as their start codon while the ATP8 gene starts with GTG. All the 13 mitochondrial protein-coding genes use TAG or TAA as their complete stop codon. PMID- 25543918 TI - An acute abdominal syndrome reveals a postoperative ilio-iliac arteriovenous fistula: about one case. AB - INTRODUCTION: Postoperative ilio-iliac arteriovenous fistula is an unusual but known complication after lumbar surgery. CASE REPORT: We report the case of a 74 year-old patient consulted at the emergency department for intense acute abdominal syndrome revealing a post-operative common ilio-iliac arteriovenous fistula 5 years after a lumbosacral arthrodesis L3-S1. The patient was treated with an endovascular arterial stent-graft with immediate vascular and clinical results. CONCLUSION: Arteriovenous fistula is a possible etiology of acute abdominal syndrome in patients with lumbar or abdominopelvic surgery history. PMID- 25543916 TI - Motion preservation in type II odontoid fractures using temporary pedicle screw fixation: a preliminary study. AB - PURPOSE: To assess the feasibility of temporary pedicle screw fixation for motion preservation of type II odontoid fractures unsuitable for anterior screw. METHODS: Between 2012 and 2013, temporary pedicle screw fixation was performed in 13 patients with type II odontoid fractures unsuitable for anterior screw. The patients were 10 men and 3 women with an average age of 40. The implant was removed after fracture union. Dynamic CT was performed >= 1 month after implant removal to evaluate atlantoaxial rotation and axial neck rotation. Literature data on axial neck rotation were obtained as a historical control. RESULTS: Fifty two pedicle screws were placed successfully with satisfactory fracture reduction achieved in all patients. The average follow-up period was 14.2 months. At a mean of 9 months after the initial operation, fracture union was confirmed and implants were removed. The average total axial neck rotation was 116.5 degrees +/- 25.8 degrees (78.2 +/- 14.8 % of the historical controls). The average total atlantoaxial rotation was 34.2 degrees +/- 22.0 degrees (27.3 +/- 13.8 % of total axial neck rotation). CONCLUSIONS: Temporary pedicle screw fixation is a feasible technique for motion preservation of type II odontoid fractures unsuitable for anterior screw. PMID- 25543919 TI - Answer to the letter to editor of N. Todd concerning "symptomatic epidural hematoma after lumbar decompression surgery" by Kao FC et al., Eur Spine J (2014), doi:10.1007/s00586-014-3297-8. PMID- 25543917 TI - Endplate changes following discectomy: natural history and associations between imaging and clinical data. AB - PURPOSE: Some patients will experience post-operative back pain following lumbar discectomy, and the potential sources for that pain are poorly understood. One potential source is the vertebral endplates. The goal of this study was to document the changes that occur in lumbar endplates following discectomies, and to assess associations between endplate changes and clinical outcomes. METHODS: Changes in lumbar endplates and discs were assessed from X-rays, CT and MRI exams by comparing preoperative imaging with imaging obtained at yearly intervals up to 5 years. 260 endplates in 137 patients with single-level herniation and discectomy were analyzed. The geometry of osseous defects in the endplates was measured from the CT exams, and marrow and disc changes adjacent to endplates were assessed from the MRI exams. Clinical outcome assessments were collected at each time point. Descriptive statistics were used to describe endplate defect sizes, and logistic regression and analysis of variance were used to identify potential associations between endplate and vertebral body changes and clinical outcomes. RESULTS: Approximately 14 % of the endplates had osseous defects prior to surgery. After surgery, 24 % of inferior and 43 % of superior endplates had defects. Change occurred within the first year and remained relatively constant over the next few years. Disc signal intensity worsened and disc height decreased following surgery. New Modic changes were also observed. None of these changes were associated with having achieved a clinically significant improvement in outcome scores. The follow-up rates were low at the later time points and significant associations cannot be ruled out. CONCLUSIONS: This study documents lesion characteristics in detail and supports that osseous defects in the endplates at the level of a lumbar discectomy may be a relatively common finding following surgery, along with disc height loss, loss of disc signal intensity, and Modic changes. The clinical significance of these imaging findings could not be conclusively determined in this study. PMID- 25543920 TI - Metabolite identification for mass spectrometry-based metabolomics using multiple types of correlated ion information. AB - Metabolite identification remains a bottleneck in mass spectrometry (MS)-based metabolomics. Currently, this process relies heavily on tandem mass spectrometry (MS/MS) spectra generated separately for peaks of interest identified from previous MS runs. Such a delayed and labor-intensive procedure creates a barrier to automation. Further, information embedded in MS data has not been used to its full extent for metabolite identification. Multimers, adducts, multiply charged ions, and fragments of given metabolites occupy a substantial proportion (40-80%) of the peaks of a quantitation result. However, extensive information on these derivatives, especially fragments, may facilitate metabolite identification. We propose a procedure with automation capability to group and annotate peaks associated with the same metabolite in the quantitation results of opposite modes and to integrate this information for metabolite identification. In addition to the conventional mass and isotope ratio matches, we would match annotated fragments with low-energy MS/MS spectra in public databases. For identification of metabolites without accessible MS/MS spectra, we have developed characteristic fragment and common substructure matches. The accuracy and effectiveness of the procedure were evaluated using one public and two in-house liquid chromatography mass spectrometry (LC-MS) data sets. The procedure accurately identified 89% of 28 standard metabolites with derivative ions in the data sets. With respect to effectiveness, the procedure confidently identified the correct chemical formula of at least 42% of metabolites with derivative ions via MS/MS spectrum, characteristic fragment, and common substructure matches. The confidence level was determined according to the fulfilled identification criteria of various matches and relative retention time. PMID- 25543921 TI - A revision of the New Zealand species of Howickia Richards. AB - Howickia Richards 1951 is redefined to include all wingless or strongly brachypterous Sphaeroceridae in New Zealand as well as two newly described fully winged species, H. oliveri and H. lepidostylus. Biroina Richards 1973 is newly treated as a junior subjective synonym of Howickia. The following new flightless species are described from New Zealand: H. bicolor, H. cordata, H. exasperata, H. harrisoni, H. mercurialis, H. nigrilegula, H. nigriventer, H. nudistylus, H. omamari, H. palmai, H. regalis, H. tangata, H. wahaika and H. zonula. PMID- 25543922 TI - Two new species of the South Asian catfish genus Pseudolaguvia from northeastern India (Teleostei: Sisoridae). AB - Two new species of sisorid catfish, Pseudolaguvia magna and P. jiyaensis, are described from the upper Brahmaputra River basin in Arunachal Pradesh, northeastern India. Pseudolaguvia magna differs from its congeners by its much larger size (47.0 mm standard length vs. a maximum of 35.6 mm), by having a broader rhomboid thoracic adhesive apparatus, two pale-brown or cream patches on the mid-dorsal region across the dorsal midline: one rectangular to elliptic patch on the mid-interdorsal region, and another indistinct elliptic to irregular patch between the adipose and caudal-fins; and a small, round, pale-brown to cream spot on the lateral side of the head; and except for P. inornata, P. austrina, P. virgulata, and P. assula, in lacking pale to cream cross-bands on the body. Another syntopic new species, Pseudolaguvia jiyaensis, is distinguished from its congeners by having the thoracic adhesive apparatus almost reaching the pelvic-fin origin, and by having fewer vertebrae (25-27 vs. 28-34; except in P. tenebricosa and P. tuberculata). Details of the combination of characters differentiating each of the new species from its congeners are provided in the respective diagnoses. PMID- 25543923 TI - Spelaeogammarus titan, a new troglobitic amphipod from Brazil (Amphipoda: Bogidielloidea: Artesiidae). AB - A new troglobitic species of the amphipod family Artesiidae Holsinger, 1980 is described from a cave in the municipality of Santa Maria da Vitoria, in the Brazilian state of Bahia, northeastern Brazil. Spelaeogammarus titan sp. nov. differs from the others in the genus by its body length, rising up to 18.3 mm, the antenna 1 with accessory flagellum 6-articulate, propodus of the first gnathopod 1.8 X longer than basis, the largest in the genus, coxa 5 with posterior lobe slightly concave, inner ramus of pleopods with 10 to 13 setae, outer ramus of uropod 3 with 22 simple setae, and telson with 1 apical plus 3 subapical stout setae in each lobe. With this study, the knowledge of Spelaeogammarus is improved to 5 species, all of them exclusive to caves in the northeastern Brazilian state of Bahia. A comparative table with the diagnostic characters of the species of Spelaeogammarus is provided. PMID- 25543924 TI - First record of the genus Kuwaita (Annelida: Lumbrineridae) in Europe with the description of a new species and new ultramorphological data for the genus. AB - A new species of the genus Kuwaita Mohammad, 1973, collected intertidally from a northern Spain estuary (Bay of Biscay), is described. Kuwaita hanneloreae sp. nov. constitutes the first evidence of this genus in European waters and is characterised by: prostomium with three small antennae protruding from nuchal fold, lack of eyes; simple multidentate hooded hooks with long hood in anterior chaetigers, and short hood in posterior ones with well defined proximal and distal teeth with several teeth between them; posterior chaetigers with very small nephridial papillae; branchiae reduced to little knobs in posterior parapodia; maxillary apparatus with five pairs of maxillae, MIII bidentate with distal tooth bigger than proximal one. We present brief notes on its ecology and remarks on the presence and ultrastructure of a notopodial sense organ newly recorded for the genus. Furthermore, an updated key of the genus Kuwaita is included. PMID- 25543925 TI - Description of new species of Surimyia Reemer and Carreramyia Doesburg (Diptera: Syrphidae) from the Brazilian Amazon. AB - Surimyia reemeri sp. n. and Carreramyia jatai sp. n. are described from the Brazilian Amazon. The diagnosis of Surimyia Reemer is emended to include S. reemeri sp. n. that differs from other species of the genus mainly by the shape of male terminalia and basoflagellomere length. In addition, S. rolanderi Reemer is recorded for Brazil for the first time. The key to species of Carreramyia Doesburg by Reemer (2008) is modified to include C. jatai sp. n., and a key to species of Surimyia is provided. PMID- 25543926 TI - The correct name of the endemic Dasypus (Cingulata: Dasypodidae) from northwestern Argentina. AB - We show that Dasypus mazzai Yepes 1933 is a senior synonym of Dasypus yepesi Vizcaino 1995. We present morphological evidence that the holotype of D. mazzai is not a juvenile of Dasypus novemcinctus or any other species of this genus, but a distinct endemic species from northwestern Argentina undistinguishable from D. yepesi. Therefore, the correct name for the long-nosed armadillo of intermediate size occurring in the Argentinean provinces of Jujuy and Salta is Dasypus mazzai Yepes 1933. PMID- 25543927 TI - A new species of Sinocorophium from the Yangtze estuary (Crustacea: Amphipoda: Corophiidae: Corophiinae: Corophiini), China. AB - Amphipods collected from the Yangtze estuary, Shanghai, China are described as a new species, Sinocorophium dongtanense. It is closely allied to Sinocorophium homoceratum Yu, 1938 but differs markedly in the inner lateral side of peduncular article 4 of male antenna 2 having two rows of teeth. PMID- 25543928 TI - The species of the Chthonius heterodactylus group (Arachnida, Pseudoscorpiones, Chthoniidae) from the eastern Alps and the Carpathians. AB - The species of the subgenus Chthonius (Chthonius) C.L. Koch, 1843 displaying a sigmoid fixed chelal finger from the Eastern Alps and the Carpathians, assigned to the informal heterodactylus species-group, are revised and a key given for their identification. The following species are present in this area: Chthonius cavernarum Ellingsen, 1909 (Italy, Romania, Slovenia), C. heterodactylus Tomosvary, 1882 (Czech Republic, Hungary, Germany, Poland, Romania, Slovakia, Ukraine), C. hungaricus Mahnert, 1981 (Hungary, Romania, Slovakia), C. lessiniensis Schawaller, 1982 (Italy), C. pusillus Beier, 1947 (Austria, Slovenia) and C. raridentatus Hadzi, 1930 (Austria, Croatia, Italy, Slovenia). The following synonymies are proposed: Chthonius diophthalmus Daday, 1889, C. (C.) orthodactylus gracilis Beier, 1935, C. (C.) ksenemani Hadzi, 1939 and C. (C.) leruthi Beier, 1939 are junior subjective synonyms of C. heterodactylus Tomosvary, 1882 (n. syn.); C. (C.) pivai Gardini, 1991 is a junior subjective synonym of C. (C.) lessiniensis Schawaller, 1982 (n. syn.); C. (C.) ellingseni Beier, 1939, C. (C.) brandmayri Callaini, 1986 and C. (C.) jalzici Curcic, 1988 are junior subjective synonyms of C. (C.) raridentatus Hadzi, 1930 (n. syn.). Lectotypes are designated for C. cavernarum Ellingsen, 1909 and C. (C.) ellingseni Beier, 1939. Chthonius (C.) pusillus is newly recorded from Slovenia, C. (C.) hungaricus and Mundochthonius carpaticus Rafalski, 1948 are newly recorded from Romania, and the presence of C. (C.) cavernarum in Italy is confirmed. PMID- 25543930 TI - New observations on Myxozoa of the goldline sea bream Sarpa salpa L. 1758 (Teleostei : Sparidae) from the Mediterranean coast of Tunisia. AB - A member of the Sparidae family, the goldline sea bream Sarpa salpa (Linnaeus, 1758) collected from the Gulf of Tunis and the Bay of Bizerte in Northeast Tunisia, Western Mediterranean, were examined for the myxozoan parasites. During the parasitological exposure, a total of 7 myxosporean are found including 6 coelozoic species belong to the genus Ceratomyxa Thelohan, 1892 infected the gallbladder of their host of which 3 known species have been previously described, C. arcuata Thelohan, 1892, C. pallida Thelohan, 1895 and C. herouardi Georgevitch, 1916 and 3 species seem different in morphology to Ceratomyxa spp already known from Mediterranean Sea or from other localities in the wide world. These species are Ceratomyxa sp. 1, Ceratomyxa sp. 2 and Ceratomyxa sp. 3. Only one histozoic species belongs to the genus Henneguya Thelohan, 1892, Henneguya sp. identified for the first time infecting the mesentery vessels of S. salpa. The myxosporean parasite C. arcuata Thelohan, 1892 is reported for the first time in Tunisian waters from the goldline sea bream which represents as new host records. In addition to the Monoparasitism, the phenomenon of Polyparasitism was observed between the current species in both sampling sites with two types: Biparasitism and Triparasitism. The most frequent Polyparasitism was a Biparasitism-type between C. herouardi and C. pallida with frequency 16.97%. For all the species, no serious pathogenic changes have been recorded in the host organ or in the outward appearance of the fish. Morphological features, site of infection into the host, parasite prevalence and mean intensity of each myxosporean found during this survey are determined and their taxonomic affinities to other species are discussed. PMID- 25543929 TI - A re-description of the fossil damselfly Eolestes syntheticus Cockerell, 1940 (Odonata: Zygoptera: Eolestidae n. fam.) with description of new taxa from the Eocene of North America. AB - The enigmatic species Eolestes syntheticus Cockerell, 1940, from the Early Eocene of North America, previously attributed to the lestoid family Synlestidae, is re examined in light of the discovery of new material from the Middle Eocene Kishenehn Formation in northwestern Montana. E. syntheticus and a new species, Eolestes ramosus sp. n., are attributed to a new family Eolestidae fam. n.. In addition, a new genus and species very closely related to Lestidae but assigned to family unknown, Lutetialestes uniformis sp. n., is described from the Kishenehn Formation. PMID- 25543931 TI - The deepwater demersal ichthyofauna of the western Coral Sea. AB - The highly diverse deepwater demersal ichthyofauna of the western Coral Sea was first systematically surveyed in two exploratory voyages in 1985 and 1986, and these fish assemblages have not been investigated at the same level since. Only recently have catch data and specimens, obtained from these first voyages almost 3 decades ago, been rigorously investigated and analysed. Some 393 species of fishes from 125 families were collected during the 1985 voyage which surveyed the northeastern Australian continental margin, and the Saumarez and Queensland Plateaus. A checklist of the species caught is provided. Levels of endemicity of deepwater fishes in the western Coral Sea are very high with about 50% of well studied groups, such as sharks and rays, confined to this relatively small geographic region. A very high proportion of species caught during this voyage were either undescribed (78 species or 20%) or new Australian records (96 species or 24%) at the time of the survey. Another 68 species (17%) are the subject of further taxonomic investigation or are currently undergoing formal description. The fauna exhibits some intraregional differences in structure. Biogeographically informative fishes such as skates appear to be cryptically partitioned within the region, differing in composition to other Australian regions and those of French territories to the east. Strong depth-related partitioning of the fauna is also evident, and its structure follows zonation patterns observed across the wider Australian region. Given the high level of micro-endemicity and regional uniqueness of the fauna, there is a compelling argument for the existence of a faunal gyre in the Coral Sea. New gap-filling surveys are needed to better define the structure of this fauna and determine its distribution. PMID- 25543932 TI - Mites of the genus Paracoroptes Lavoipierre, 1955 (Acariformes: Psoroptidae)- skin parasites of the African monkeys of the family Cercopithecidae (Primates). AB - Two new species of Paracoroptes Lavoipierre, 1955 (Acariformes: Psoroptidae: Paracoroptinae) are described: Paracoroptes miopithecus sp. n. from Miopithecus talapoin (Schreber) and Paracoroptes piliocolobus sp. n. from Piliocolobus badius (Kerr) (Primates: Cercopithecidae)--both are from the Democratic Republic of the Congo. A key to all 6 species of the genus is provided and host-parasite relationships of its representatives are discussed. PMID- 25543933 TI - Canines make the difference: a new species of Hypsugo (Chiroptera: Vespertilionidae) from Laos and Vietnam. AB - Hypsugo was regarded as a subgenus of Pipistrellus by many authors, but its generic distinctiveness is now widely accepted. According to recent taxonomic arrangements, nine species are known to occur in Southeast Asia. During the investigation of material recently collected from Lao PDR and Vietnam we identified an additional species and hence describe it here as Hypsugo dolichodon n. sp. It resembles H. pulveratus, but is larger with conspicuously long canines and differs considerably in the DNA barcode gene sequence. PMID- 25543934 TI - Descriptions of the immature stages of Dampfomyia (Coromyia) beltrani (Vargas & Diaz-Najera) (Diptera: Psychodidae), with notes on morphology and chaetotaxy nomenclature. AB - All immature stages of the phlebotomine sandfly Dampfomyia (Coromyia) beltrani (Vargas & Diaz-Najera) [= Lutzomyia (Coromyia) beltrani, sensu Young & Duncan 1994] are described and illustrated based on reared specimens from founder females collected from the type-locality in Veracruz, Mexico. These represent the first description of egg, and the third of larva instars and pupa of a species of the subgenus Coromyia, only preceded by Da. vespertilionis (Fairchild & Hertig) and Da. isovespertilionis (Fairchild & Hertig). Some morphological nomenclature clarifications are suggested toward the standardization of immature descriptions, which, in turn, would allow detection of homologies for future integration of these developmental stages characters into a phylogenetic analyses. PMID- 25543935 TI - A contribution to the aphid fauna (Hemiptera: Aphididae) of Wrangel Island. AB - Five aphid species collected on Wrangel Island (Russia) are presented. One species, Aphis polaris sp. nov., feeding on Astragalus alpinus L. and Oxytropis sp., is described, and the fundatrix morph of two others, Pterocomma groenlandicum Hille Ris Lambers, 1952 and Metopolophium sabihae Prior, 1976., is described for the first time. PMID- 25543936 TI - Ten new species from the Patagonian Andes (Argentina and Chile), mostly belonging to a newly designated Stigmella purpurimaculae group (Lepidoptera: Nepticulidae). AB - Ten new Stigmella Schrank species are described: Stigmella purpurimaculae Remeikis & Stonis, sp. nov., S. cana Remeikis & Stonis, sp. nov., S. truncata Remeikis & Stonis, sp. nov., S. sceptra Remeikis & Stonis, sp. nov., S. concreta Remeikis & Stonis, sp. nov., S. pseudoconcreta Remeikis & Stonis, sp. nov., S. quadrata Remeikis & Stonis, sp. nov. (all belonging to the newly designated S. purpurimaculae group), and S. semilactea Remeikis & Stonis, sp. nov., S. brutea Remeikis & Stonis, sp. nov., S. pseudodigitata Remeikis & Stonis, sp. nov. (not attributed to a species group) are described from the Andes (Patagonia: Argentina and Chile). For the species of the purpurimaculae group, a partial reduction of phallus, dentate cornuti, and strong development of utriculus (which can be equal or longer of the corpus bursae) are characteristic. Some of the species of the purpurimaculae group were collected near Nothofagus pumilio (Poepp. & Endl.) Krasser, Nothofagaceae, but there is still no confirmation that Nothofagus is a host-plant. All new Stigmella species are illustrated with photographs and drawings of the adults and genitalia. PMID- 25543937 TI - Review of the Chinese species of the genus Coelostoma Brulle, 1835 (Coleoptera: Hydrophilidae: Sphaeridiinae). AB - The Chinese species of the genus Coelostoma Brulle, 1835 are revised and diagnosed. Five new species are described: Coelostoma bifidum sp. nov. (Jiangxi, Guangdong, Hong Kong), C. hajeki sp. nov. (Guangdong, Guangxi), C. hongkongense sp. nov. (Hong Kong), C. huangi sp. nov. (Guangxi, Jiangxi), and C. gentilii sp. nov. (Xizang). Coelostoma coomani Orchymont, 1932, C. orbiculare (Fabricius, 1775) and C. vividum Orchymont, 1936 are reported for the first time from China. Coelostoma sulcatum Pu, 1963, syn. nov. is synonymized with C. stultum (Walker, 1858). Additional faunistic data from China are provided for C. phallicum Orchymont, 1940, C. vagum Orchymont, 1940, C. turnai Hebauer, 2006, C. wui Orchymont, 1940, C. stultum (Walker, 1858), C. vitalisi Orchymont, 1923, C. fallaciosum Orchymont, 1936 and C. horni (Regimbart, 1920). Coelostoma fabricii (Montrouzier, 1860) is not considered as member of Chinese fauna as all previous records are dubious and no new material was found during our study. The distribution of C. horni in China is discussed in detail, with records from Hong Kong here considered dubious. An updated identification key to the Chinese species of Coelostoma is provided. PMID- 25543938 TI - Rebuttal to Koeda et al. (2014) on the Red Sea fishes of the perciform genus Pempheris. AB - Koeda et al. (2014) published a review of fishes of the genus Pempheris of the Red Sea. They concluded that there are four species: P. adusta Bleeker, P. mangula Cuvier, P. nesogallica Cuvier, and a new species, P. tominagai. We show that the first three species they cite are not present in the Red Sea, as follows. 1) P. adusta is a western Pacific species (type locality Ambon), described only from the holotype, and without a dark border on the anal fin. Koeda et al. (2014) mistakenly apply that name to P. flavicycla which is a widespread Indian Ocean species characterized by a prominent broad black border along the anal fin. Koeda et al. (2014) also redescribe P. adusta, using Indian Ocean specimens of P. flavicycla, despite the coloration difference and a 2.5% difference in the mtDNA sequence (COI) between Indian Ocean and W. Pacific populations. 2) P. mangula is a species from the east coast of India (type locality Visakhapatnam), clearly distinct in both gill-raker counts and a 1.1% sequence divergence in COI from its Red Sea relative P. rhomboidea. Pempheris mangula is not found west of India, and Koeda et al. (2014) mistakenly use DNA from Oman and Madagascar to represent P. mangula, instead of genetic material available from the type locality. 3) Pempheris nesogallica (type locality Mauritius) is unknown from the Red Sea. Koeda et al. (2014) separate P. nesogallica from P. rhomboidea (their "P. mangula") by eye size; we fail to find any difference (and they use their purported eye-size difference to erroneously rename one of the two syntypes of P. nesogallica as "P. mangula"). 4) Their new species P. tominagai is referred to as the Indian Ocean sister species of "P. schwenkii of the Pacific"; however, the type locality of P. schwenkii is the Batu Islands off the SW coast of Sumatra in the Indian Ocean. They mistakenly include specimens of a distant South African species as paratypes of P. tominagai. We have determined that P. tominagai is a valid species endemic to the Red Sea and Gulf of Aden. They misidentify one lot of P. rhomboidea in the collection of the Hebrew University of Jerusalem as their record of P. nesogallica from the Red Sea. They misidentify the specimen in their photograph of Fig. 1B as P. adusta and use it as material for their redescription of the species, but it is now shown to be a paratype of Pempheris bexillon Mooi & Randall, 2014. Additionally, they regard P. malabarica Cuvier as a junior synonym of P. molucca Cuvier, but the name P. molucca is based on a fanciful painting and is unavailable as a nomen dubium. They treat Pempheris russellii Day as a junior synonym of P. mangula; however, it is distinct in having longer pectoral fins, a larger eye, and more gill rakers. Their key to the species of Pempheris of the Red Sea is incorrect. We present a new key and conclude that only three species of Pempheris are presently known from the Red Sea: P. flavicycla, P. rhomboidea, and P. tominagai. PMID- 25543939 TI - Synopsis of the Japanese species of Aleocharinae (Coleoptera: Staphylinidae), with review of the type specimens I. Tribes Himalusini and Leucocraspedini. AB - The Japanese species of the tribes Himalusini and Leucocraspedini are reviewed. The tribe Sinanarchusini Pace, 2013 is synonymized with Himalusini in which the genera Protinodes Sharp, 1888, Himalusa Pace, 2006 and Sinanarchusa Pace, 2013 are recognized. Protinodes and Sinanarchusa have been placed in Hygronomini and Sinanarchusini respectively. Only a single species Leucocraspedum rufotestaceum Bernhauer, 1927 is recognized in Japanese fauna of Leucocraspedini. Two other known species, Leucocraspedum pallidum Cameron, 1933 and L. parvum Cameron, 1949 are synonymized with L. rufotestaceum. PMID- 25543940 TI - Revision of the genus Metoisops (Hemiptera: Heteroptera, Miridae, Isometopinae) from late Eocene European amber. AB - Metoisops akingbohungbei, M. groehni, M. punctatodiffusus, M. intergerivus, M. grabenhorsti, M. variabilis, and M. consimilis are described as new species from the late Eocene Baltic, Ukrainian, (Rovno) and Saxonian (Bitterfeld) amber. The new diagnosis of the genus Metoisops and also all species of this genus presented, along with illustrations. An analysis of all studied specimens referring to of Metoisops from different Eocene European amber demonstrates the great variability of their features, and allows for differentiation of species. Ratios of the width and length of body, eye, vertex, antennal and rostral segments, pronotum, mesoscutum and scutellum, claval commissura, length of hind femur, tibia and tarsus, corium and cuneus length, as well as ratio of membrane cell's width and length of all 9 species of the genus Metoisops are presented. PMID- 25543941 TI - A checklist of stag beetles (Coleoptera: Scarabaeoidea: Lucanidae) from Iran. AB - An updated checklist of the Lucanidae (Coleoptera) from Iran is given. New locality records are listed and some dubious distributional records are discussed. Dorcus vavrai Nonfried, 1905 is placed in synonymy with Dorcus peyronis Reiche and Saulcy, 1856 (new synonymy) The female of Lucanus xerxes Kral, 2004 is described. A key for the identification of the Iranian stag beetle species is also provided and all the species are figured. PMID- 25543942 TI - Nematocarcinus Milne Edwards, 1881 (Crustacea, Decapoda) from Southwestern Atlantic, including the Southern Mid-Atlantic Ridge area. AB - The deep sea shrimp genus Nematocarcinus Milne Edwards, 1881 includes 47 species, ten of them have been recorded from the Atlantic Ocean. Herein, material sampled during three scientific projects (REVIZEE Central Fishery project; Campos Basin Deep Sea Environmental Project; Evaluation of Environmental Heterogeneity in the Campos Basin) made in the Southwestern Atlantic, off Brazil, is examined. In addition, material sampled from the South Mid Atlantic Ridge (MAR-ECO Project) was also examined. Four species are recorded for the first time to the southwestern Atlantic Ocean including Mid Atlantic Ridge area: Nematocarcinus faxoni Burukovsky, 2001; N. gracilipes Filhol, 1884; N. rotundus Crosnier & Forest, 1973 and N. tenuipes Spence-Bate, 1888. PMID- 25543943 TI - A new species of Psychrophrynella (Anura: Craugastoridae) from the Cordillera Real, Department La Paz, Bolivia. AB - We describe a new species of Psychrophrynella from a single locality in the Cordillera Real, in the Andes of Department of La Paz, Bolivia. Psychrophrynella teqta sp. nov. is highly variable in color pattern and differs from the species geographically closer mostly by presenting yellow or red blotches, usually absent in other species. In addition, the new species differs from all species in the genus because the males have a pulsed call. Males of this species show parental care, and the high number of eggs per nest suggest that perhaps more than one clutch might be attended by a single male. As other species in the genus, the new species is infected by Batrachochytrium dendrobatidis, and thus, a conservation threat is already present upon its discovery. PMID- 25543944 TI - Two new water beetles from the Hantamsberg, an inselberg in the Northern Cape of South Africa (Coleoptera, Hydraenidae). AB - Mesoceration hantam sp. nov. and Parhydraena faeni sp. nov., are described from the Hantamsberg plateau, an inselberg in the Northern Cape of South Africa. The new species are so far known only from temporary waters on the Hantamsberg summit, where they were both abundant. Sampling in these mountains also revealed an interesting accompanying water beetle fauna, including the northernmost known record of Hydropeplus montanus Omer-Cooper, a species characteristic of mountain fynbos further south in the region. PMID- 25543945 TI - A new Lampromyia Macquart from Europe (Diptera: Vermileonidae). AB - Lampromyia bellasiciliae sp. n. is described from Sicily, Italy. The new species belongs to the pallida subgroup and is differentiated from related taxa in a dichotomous identification key. DNA barcodes for eight of the currently recognised ten Palaearctic species of Lampromyia are provided, and the calculated genetic distances between the taxa and species groups/subgroups are discussed. New distributional data for additional species of Lampromyia are presented and the occurrence of the Palaearctic taxa is depicted in a distribution map. PMID- 25543946 TI - A review of the genus Heterodina Kensley & Schotte, 2005 (Crustacea: Isopoda: Sphaeromatidae) with description of a new species from Iran. AB - Heterodina Schotte & Kensley, 2005 is revised with Heterodina qeshmensis sp. nov., described from the subtidal zone of the Qeshm Island, southern Iran. Heterodina qeshmensis sp. nov. is characterized by: unornamented dorsal surfaces, wide and anteriorly concave epistome, and the appendix masculina with sub parallel margins and not extending beyond the distal margin of the endopod. A key to the species is provided. The penial processes of Heterodina mccaini Schotte & Kensley, 2005 is also re-illustrated. PMID- 25543947 TI - The bees of the genus Sphecodes Latreille 1804 of the Russian Far East, with key to species (Hymenoptera: Apoidea: Halictidae). AB - Eighteen species of the bee genus Sphecodes are recorded from the Russian Far East. Sphecodes orientalis Astafurova & Proshchalykin, sp. nov. is described from Primorskiy Territory, Jewish Autonomous Province, Khabarovsk Territory and Sakhalin. Five species: S. laticaudatus Tsuneki 1983, S. nippon Meyer 1922, S. okuyetsu Tsuneki 1983, S. simillimus Smith 1873, and S. tanoi Tsuneki 1983 are recorded for the first time from Russia. Six species: S. albilabris (Fabricius 1793), S. cristatus Hagens 1882, S. longulus Hagens 1882, S. miniatus Hagens 1882, S. monilicornis (Kirby 1802), and S. puncticeps Thomson 1870 are newly recorded from the Russian Far East. New synonymy has been established for S. crassus Thomson 1870 (=S. dyozankeanus Tsuneki 1983, syn. nov.; =S. ohdeyamanus Tsuneki 1984, syn. nov.); S. ferruginatus Hagens 1882 (=S. koikensis Tsuneki 1983, syn. nov.; =S. hanedai Tsuneki 1983, syn. nov.); S. geoffrellus (Kirby 1802) (=S. silvicola Tsuneki 1983, syn. nov.); S. tanoi Tsuneki 1983 (=S. coptis Tsuneki 1983, syn. nov.); S. longulus Hagens 1882 (=S. amakusensis Yasumatsu et Hirashima 1951, syn. nov.); S. scabricollis Wesmael 1835 (=S. sibiricus Cockerell, 1924, syn. nov.). Illustrated key to males and females of all species known from the Russian Far East are provided. PMID- 25543948 TI - A revision of the genus Solter Navas, 1912 for Maghreb and West Africa with descriptions of five new species (Neuroptera, Myrmeleontidae). AB - The Solter species of the Maghrebian and sub-Saharan West African Regions are revised. Nine species are recorded, S. bouyeri nov. sp., S. dogon nov. sp., S. francoisi nov. sp., S. leopardalis nov. sp., S. liber Navas, S. lucretii nov. sp., S. naevipennis Navas, S. neglectus Navas stat. rev. and S. rothschildi Navas. A lectotype is designated for the last species. A tenth species, S. ardens (Navas), is classified as incertae sedis. Solter virgilii Navas is removed from the species present in the area covered by this study. The larva of S. leopardalis is described. All species are illustrated including habitus, morphological characters and male genitalia. An identification key is provided. PMID- 25543949 TI - A new annelid species from whalebones in Greenland and aquaculture sites in Newfoundland: Ophryotrocha cyclops, sp. nov. (Eunicida: Dorvilleidae). AB - A new species of Ophryotrocha was discovered on whalebones in Greenland (120 m depth) and at finfish aquaculture sites in Newfoundland (30-70 m depth), where it is considered to be a bioindicator of aquaculture-related organic enrichment. Phylogenetic analyses based on three genes (COI, 16S mitochondrial and H3 nuclear genes) show close affinities with O. lobifera and O. craigsmithi, two species also found on both whalebones and at aquaculture sites (North Sea), and with O. shieldsi from aquaculture sites in Tasmania. The new species is named Ophryotrocha cyclops sp. nov. due to the juxtaposed, quasi-fused central eyes that give the impression of a single eye in live specimens. PMID- 25543950 TI - Aphanius marassantensis, a new toothcarp from the Kizilirmak drainage in northern Anatolia (Cyprinodontiformes: Cyprinodontidae). AB - Aphanius marassantensis, new species, is described from the Kizilirmak River drainage in northern Anatolia based on colouration, meristic and morphometric characters, and the mtDNA COI barcode region. It is distinguished from other Anatolian Aphanius by one or several of the following characters: a stout body shape (BD/SL 28.2-39.6%), complete scale cover, and 25-28 scales along the lateral line. Males have 8-13 dark-brown lateral bars, of which the antepenultimate bar anterior to the caudal-fin base is 0.9-1.8 times wider than the anterior white interspace, 2-3 vertical rows of spots on the caudal fin, a black dorsal fin, sometimes with a narrow whitish-grey base, a white anal fin with 1-3 rows of black spots, in some individuals with a black margin, and hyaline pelvic fins. Females do not have vertical rows of dark-brown spots on caudal or anal fins, but numerous dark-brown spots on the flanks, arranged in 1-3 lateral rows behind a vertical from the dorsal-fin base. Their dorsal fin is hyaline with tiny dark-brown spots on rays and membranes; pectoral fins, caudal and anal fins are hyaline, and one prominent large dark-brown blotch is situated in mid-lateral position on the hypural plate. The new species is also distinguished by 11 fixed, diagnostic nucleotide substitutions in the mtDNA COI barcode region. The description of this new species, which brings the number of Anatolian Aphanius species to 12, underlines the character of Anatolia as a region of extraordinarily high biodiversity. PMID- 25543951 TI - Re-examination of Hemidactylus tenkatei van Lidth de Jeude, 1895: Populations from Timor provide insight into the taxonomy of the H. brookii Gray, 1845 complex (Squamata: Gekkonidae). AB - Recent herpetofaunal investigations in Timor-Leste revealed populations similar to Hemidactylus brookii Gray, 1845 in four of 13 districts. In order to properly identify these populations, we examined their relationships to other H. brookii complex populations, notably those from nearby Roti Island, Indonesia (to which the name H. tenkatei van Lidth de Jeude, 1895 has been applied) and topotypic Bornean samples. We evaluated both meristic and mensural data from a set of specimens that included the type material of H. brookii and H. tenkatei, and we generated nuclear (RAG1) and mitochondrial (ND2) DNA sequence data for Timor Leste specimens and a topotypical Bornean specimen presumed to represent H. brookii sensu stricto. Morphologically, Timorese geckos are clearly distinct from H. brookii and identical to H. tenkatei. Our molecular data show that the Bornean specimen thought to be H. brookii is genetically congruent with Timor-Leste specimens, and this specimen is therefore identified as H. tenkatei. Our data also reveal that the Burmese species H. subtriedroides Annandale, 1905 is distinct from both H. tenkatei and H. brookii. While the current data do not allow us to determine with certainty whether H. tenkatei is the oldest available name for these widespread forms, it is the only name that can be reliably applied at this time. PMID- 25543952 TI - MATUS HYZNY & ROK GASPARIC (2014) Ghost shrimp Calliax de Saint Laurent, 1973 (Decapoda: Axiidea: Callianassidae) in the fossil record: systematics, palaeoecology and palaeobiogeography. Zootaxa, 3821 (1): 37-57. PMID- 25543953 TI - Oxidative stress associated with rootstock-scion interactions in pear/quince combinations during early stages of graft development. AB - Exposing a plant to stress situations, such as grafting, generally triggers antioxidant defense systems. In fruit tree grafting, quince (Cydonia oblonga) is widely used as a rootstock for pear (Pyrus communis L.), but several economically important pear cultivars are incompatible with available quince rootstocks. In this study, grafts were established using an in vitro callus graft system mimicking the events taking place in fruit trees. In vitro grown callus from pear [P. communis L. cv. 'Conference' (Co) and cv. 'William' (Wi)] and quince (C. oblonga Mill. clone 'BA29') was used to establish the compatible homografts 'Co/Co', 'Wi/Wi' and 'BA29/BA29', the compatible heterograft 'Co/BA29' and the incompatible heterograft 'Wi/BA29'. The main objective was to determine whether specific isoforms of genes involved in oxidative stress [superoxide dismutase (SOD), ascorbate peroxidase (APX) and catalase (CAT)] are differentially expressed at the graft interface from compatible and incompatible unions throughout 3 weeks after grafting. Reactive oxygen species (ROS) levels and programmed cell death were also evaluated in the course of graft development. Genes differentially expressed between compatible and incompatible heterografts were identified. Transcript levels of six antioxidant genes (SOD1, SOD3, APX3, APX6, CAT1 and CAT3) were down-regulated 10 days after grafting (DAG) in the incompatible heterograft in comparison to the compatible one. Likewise, SOD enzymatic activities were significantly higher at 1 and 10 days after wounding in the compatible cultivar 'Co' than in the incompatible one 'Wi'. These findings, together with live cell imaging of ROS-specific probes, ultrastructural mitochondrial changes and DNA fragmentation related to apoptotic processes, give indications that within incompatible rootstock/scion interfaces, either the level of ROS is increased or there is a less efficient detoxification system. PMID- 25543954 TI - A nuclear-localized histone-gene binding protein from rice (OsHBP1b) functions in salinity and drought stress tolerance by maintaining chlorophyll content and improving the antioxidant machinery. AB - Plants have evolved a number of molecular strategies and regulatory mechanisms to cope with abiotic stresses. Among the various key factors/regulators, transcription factors (TFs) play critical role(s) towards regulating the gene expression patterns in response to stress conditions. Altering the expression of the key TFs can greatly influence plant stress tolerance. OsHBP1b (accession no. KM096571) is one such TF belonging to bZIP family, localized within the Saltol QTL, whose expression is induced upon salinity treatment in the rice seedlings. qRT-PCR based expression studies for OsHBP1b in seedlings of contrasting genotypes of rice showed its differential regulation in response to salinity stress. A GFP based in vivo study showed that the OsHBP1b protein is nuclear localized and possesses the trans-activation activity. As compared to the WT tobacco plants, the transgenic plants ectopically expressing OsHBP1b showed better survival and favourable osmotic parameters (such as germination and survival rate, membrane stability, K(+)/Na(+) ratio, lipid peroxidation, electrolyte leakage and proline contents) under salinity and drought stress. Under salinity conditions, the transgenic plants accumulated lower levels of reactive oxygen species as compared to the WT. It was also accompanied by higher activities of antioxidant enzymes (such as ascorbate peroxidase and superoxide dismutase), thereby demonstrating that transgenic plants are physiologically better adapted towards the oxidative damage. Taken together, our findings suggest that OsHBP1b contributes to abiotic stress tolerance through multiple physiological pathways and thus, may serve as a useful 'candidate gene' for improving multiple stress tolerance in crop plants. PMID- 25543955 TI - Retinoic acid receptors: from molecular mechanisms to cancer therapy. AB - Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARalpha, RARbeta and RARgamma, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported. PMID- 25543956 TI - Pericranial nerve blockade as a preventive treatment for migraine: Experience in 60 patients. AB - INTRODUCTION: Anaesthetic blockade of pericranial nerves is frequently used to treat headache disorders. There is no evidence on indication of this treatment for migraine. We aim to evaluate its effectiveness as a preventive treatment for migraine using specific indication criteria. METHODS: Between January 2009 and May 2013 we offered pericranial nerve blockade to migraine patients with a history of preventive drug intolerance or failure. We selected patients with tenderness to palpation of at least one greater occipital nerve (GON) or supraorbital nerve (SON). Responses at 3 months were categorised as complete response (no pain), partial response (reduction of at least 50% in severity or frequency of headache episodes), or no response. RESULTS: Anaesthetic blockade was performed in 60 patients (52 females, 8 males; mean age 40.6 +/- 12.4 years, range 19-76). The most common procedure was blockade of GON and SON on both sides. Complete response lasting at least 2 weeks was recorded in 23 patients (38.3%), with partial response in 24 patients (40%), and no response in 13 (21.7%). In the group presenting complete response, age and length of history of migraine were significantly lower. No severe side effects were detected. Response time ranged from 2 weeks to 3 months. CONCLUSIONS: Pericranial nerves blockade using tenderness to palpation as an inclusion criterion is safe and potentially effective as prophylactic treatment for migraine. The best responses in our series were observed in younger patients with shorter histories of migraine. PMID- 25543957 TI - Alpha blocker and angiotensin-converting enzyme inhibitor in the management of severe pulmonary valve stenosis: from bench to bedside. AB - INTRODUCTION: Neonates with severe pulmonary valve stenosis tend to remain oxygen dependent, despite resolution of the transpulmonary gradient. Alpha 2 blockers - phentolamine - and angiotensin-converting enzyme inhibitors - captopril - were reported to improve oxygen saturation. OBJECTIVE: To describe the role of phentolamine and captopril in the treatment of these patients. METHODS: In a retrospective cohort study, 28 neonates with severe pulmonary valve stenosis underwent balloon valvuloplasty. Among them, 20 remained oxygen or prostaglandin dependent after intervention, and were treated with phentolamine or captopril. Oxygen saturation was monitored before and after intervention and following treatment with these medications. Mean duration of hospitalisation was recorded. RESULTS: Mean age and weight were 25.2 days and 3.1 kg, respectively. Before balloon dilation, 18/20 (90%) neonates were on prostaglandin, whereas after the procedure only 6/18 patients required it. All 20 patients required oxygen after the procedure, and nine patients (45%) were started on phentolamine. Among them, one patient with severe infundibular stenosis did not respond favourably, and 11 patients (55%) were started on captopril. After starting phentolamine or captopril treatment, prostaglandin could be discontinued after a mean time of 15.86 hours. Within <2 days, there was an increase in mean oxygen saturation from 76.6 to 93.0%. CONCLUSION: Phentolamine and captopril seem to have therapeutic roles in neonates with severe pulmonary valve stenosis who remain oxygen dependent after balloon dilation. Both drugs led to vasodilation of the pulmonary and systemic vascularisation and facilitated inflow to the right ventricle. Right to-left shunt across a patent foramen ovale or atrial septal defect decreased and saturation improved, leading to a significant reduction in the length of hospitalisation. PMID- 25543958 TI - "Running Water Won't Freeze": How people with advanced Parkinson's disease experience occupation. AB - OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative condition often resulting in significant disability and impacting on one's ability to participate in an occupation. The present study aimed to explore how people with advanced Parkinson's disease experience the phenomenon of occupation in their daily lives in order to inform the practice of occupational therapy in palliative care. METHOD: Using a phenomenological approach, in-depth interviews were undertaken with a purposive sample of 10 people in the advanced stages of Parkinson's disease. These interviews were audiotaped, transcribed verbatim, and subsequently analyzed using a thematic content analysis approach. The study received approval from the relevant university ethics committee, as well as the research network of Parkinson's UK. RESULTS: The experience of occupation emerged as being physical, psychological, social, and spiritual with related subthemes. Within each of these themes, participants described their experience of occupation that they valued and that were important to their daily lives. They also identified the strategies they employed to continue participating in certain occupations and described others they were no longer able to engage in and the impact of that loss. SIGNIFICANCE OF RESULTS: Participants' experiences crossed the domains of palliative care and suggest that adopting a palliative care approach would enhance an enhanced quality of life, experienced in terms of meaningful and valuable occupation. Disruption to participation in occupation caused them distress and frustration, suggesting that access to occupation focused therapy would significantly improve quality of life for people with PD. As there is a strong link between the ethos of occupational therapy and palliative care, it is proposed that there is a valuable role for occupational therapy intervention to play within palliative care. PMID- 25543959 TI - Long-term fate of the aortic valve after an arterial switch operation. AB - OBJECTIVE: To evaluate long-term performance of the aortic valve after an arterial switch operation (ASO), in terms of regurgitation and reoperation. METHODS: A longitudinal analysis of patients who underwent an ASO between 1988 and 1998 at the Birmingham Children's Hospital. Any type of aortic valve surgery after ASO was censored. To determine progression of aortic valve regurgitation, cardiology follow-up and echocardiograms from the operation until 2012 were reviewed. RESULTS: A total of 362 patients underwent ASO; median age was 8 days. Ventricular septal defect was present in 151, aortic coarctation in 39, and interrupted aortic arch in 6 patients. The trap door technique was used for coronary translocation when possible; 4.1% had intramural coronaries. There were 331 alive patients; follow-up was complete at 93%; median duration was 16 years (interquartile range, 12-18.2 years). Overall survival at 10 and 20 years was 97.6% and 95.2%, respectively. Aortic valve reoperation occurred in 5 patients, giving freedom from aortic surgery of 99.3% and 97.7% at 10 and 20 years, respectively. Reoperations were aortic valve replacement (3), Bentall operation (1), and aortic valve repair (1). Freedom from >=moderate regurgitation at 10 with 20 years was 97% to 80%, respectively. Degree of regurgitation immediately after ASO was strongly predictive of late aortic valve function: patients discharged with mild regurgitation had a significantly increased risk of progression compared with those with no regurgitation (20 years of freedom from >=moderate regurgitation, 50% vs 96%, P = .0000). CONCLUSIONS: Reoperation on the aortic valve is rarely necessary, even late after an ASO, but a significant number of patients do have late aortic regurgitation and continue to need observation. PMID- 25543960 TI - Auditory-perceptual analysis of voice in abused children and adolescents. AB - INTRODUCTION: Abused children and adolescents are exposed to factors that can trigger vocal changes. OBJECTIVE: This study aimed to analyze the prevalence of vocal changes in abused children and adolescents, through auditory-perceptual analysis of voice and the study of the association between vocal changes, communication disorders, psychiatric disorders, and global functioning. METHODS: This was an observational and transversal study of 136 children and adolescents (mean age 10.2 years, 78 male) who were assessed by a multidisciplinary team specializing in abused populations. Speech evaluation was performed (involving the aspects of oral and written communication, as well as auditory-perceptual analysis of voice, through the GRBASI scale). Psychiatric diagnosis was performed in accordance with the DSM-IV diagnostic criteria and by applying the K-SADS; global functioning was evaluated by means of the C-GAS scale. RESULTS: The prevalence of vocal change was 67.6%; of the patients with vocal changes, 92.3% had other communication disorders. Voice changes were associated with a loss of seven points in global functioning, and there was no association between vocal changes and psychiatric diagnosis. CONCLUSION: The prevalence of vocal change was greater than that observed in the general population, with significant associations with communication disorders and global functioning. The results demonstrate that the situations these children experience can intensify the triggering of abusive vocal behaviors and consequently, of vocal changes. PMID- 25543961 TI - Preservation of cardiac function in left ventricle cardiac hypertrophy using an AAV vector which provides VEGF-A expression in response to p53. AB - Here we present the application of our adeno-associated virus (AAV2) vector where transgene expression is driven by a synthetic, p53-responsive promoter, termed PG, used to supply human vascular endothelial growth factor-A165 (VEGF-A). Thus, p53 is harnessed to promote the beneficial expression of VEGF-A encoded by the AAVPG vector, bypassing the negative effect of p53 on HIF-1alpha which occurs during cardiac hypertrophy. Wistar rats were submitted to pressure overload induced by thoracic aorta coarctation (TAC) with or without concomitant gene therapy (intramuscular delivery in the left ventricle). After 12 weeks, rats receiving AAVPG-VEGF gene therapy were compared to those that did not, revealing significantly improved cardiac function under hemodynamic stress, lack of fibrosis and reversal of capillary rarefaction. With these functional assays, we have demonstrated that application of the AAVPG-VEGF vector under physiologic conditions known to stimulate p53 resulted in the preservation of cardiac performance. PMID- 25543962 TI - Genetics of critical contacts and clashes in the DNA packaging specificities of bacteriophages lambda and 21. AB - The cos sites in lambda and 21 chromosomes contain binding sites that recruit terminase to initiate DNA packaging. The small subunits of terminase, gpNu1 (lambda) and gp1 (21), have winged helix-turn-helix DNA binding domains, where the recognition helixes differ in four of nine residues. To initiate packaging, the small subunit binds three R sequences in the cosB subsite. lambda and 21 cannot package each other's DNA, due to recognition helix and R sequence differences. In lambda and 21 cosBs, two bp, tri1 and tri2, are conserved in the R sequences yet differ between the phages; they are proposed to play a role in phage-specific packaging by lambda and 21. Genetic experiments done with mixed and matched terminase and cosB alleles show packaging specificity depends on favorable contacts and clashes. These interactions indicate that the recognition helixes orient with residues 20 and 24 proximal to tri2 and tri1, respectively. PMID- 25543964 TI - Infection of the upper respiratory tract of hamsters by the bovine parainfluenza virus type 3 BN-1 strain expressing enhanced green fluorescent protein. AB - Bovine parainfluenza virus type 3 (BPIV3) is an important pathogen associated with bovine respiratory disease complex (BRDC). We have generated a recombinant BPIV3 expressing enhanced green fluorescent protein (rBPIV3-EGFP) based on the BN 1 strain isolated in Japan. After intranasal infection of hamsters with rBPIV3 EGFP, EGFP fluorescence was detected in the upper respiratory tract including the nasal turbinates, pharynx, larynx, and trachea. In the nasal turbinates, rBPIV3 EGFP attained high titers (>10(6) TCID50/g of tissue) 2-4 days after infection. Ciliated epithelial cells in the nasal turbinates and trachea were infected with rBPIV3-EGFP. Histopathological analysis indicated that mucosal epithelial cells in bronchi were shed by 6 days after infection, leaving non-ciliated cells, which may have increased susceptibility to bacterial infection leading to the development of BRDC. These data indicate that rBPIV3-EGFP infection of hamsters is a useful small animal model for studying the development of BPIV3-associated BRDC. PMID- 25543963 TI - Nonhuman primate infants have an impaired respiratory but not systemic IgG antibody response following influenza virus infection. AB - Respiratory infection of young infants results in increased morbidity and mortality compared to infection of adults. In spite of the significance of this health issue, our understanding of the immune response elicited in infants especially in the respiratory tract is highly limited. We developed a nonhuman primate model to probe the virus-specific antibody response in infants following infection with influenza virus. Infection of infants resulted in more pulmonary damage and higher viral loads compared to adults. While the systemic IgG antibody response was similar in infant and adult animals, the response in the upper respiratory tract of the infant was compromised. This lower response was associated with an increased prevalence of Treg cells and low levels of BALT. These data suggest a defect in the ability to produce effective virus-specific antibody responses at the local infection site is a contributor to increased pulmonary damage in the at-risk infant population. PMID- 25543965 TI - Actin-myosin network is required for proper assembly of influenza virus particles. AB - Actin filaments are known to play a central role in cellular dynamics. After polymerization of actin, various actin-crosslinking proteins including non-muscle myosin II facilitate the formation of spatially organized actin filament networks. The actin-myosin network is highly expanded beneath plasma membrane. The genome of influenza virus (vRNA) replicates in the cell nucleus. Then, newly synthesized vRNAs are nuclear-exported to the cytoplasm as ribonucleoprotein complexes (vRNPs), followed by transport to the beneath plasma membrane where virus particles assemble. Here, we found that, by inhibiting actin-myosin network formation, the virus titer tends to be reduced and HA viral spike protein is aggregated on the plasma membrane. These results indicate that the actin-myosin network plays an important role in the virus formation. PMID- 25543966 TI - Association of VPg and eIF4E in the host tropism at the cellular level of Barley yellow mosaic virus and Wheat yellow mosaic virus in the genus Bymovirus. AB - Barley yellow mosaic virus (BaYMV) and Wheat yellow mosaic virus (WYMV) are separate species in the genus Bymovirus with bipartite plus-sense RNA genomes. In fields, BaYMV infects only barley and WYMV infects only wheat. Here, we studied the replicative capability of the two viruses in barley and wheat mesophyll protoplasts. BaYMV replicated in both barley and wheat protoplasts, but WYMV replicated only in wheat protoplasts. The expression of wheat translation initiation factor 4E (eIF4E), a common host factor for potyviruses, from the WYMV genome enabled WYMV replication in barley protoplasts. Replacing the BaYMV VPg gene with that of WYMV abolished BaYMV replication in barley protoplasts, whereas the additional expression of wheat eIF4E from BaYMV genome restored the replication of the BaYMV mutant in barley protoplasts. These results indicate that both VPg and the host eIF4E are involved in the host tropism of BaYMV and WYMV at the replication level. PMID- 25543967 TI - Compartment syndrome secondary to acute pectoralis major tendon rupture. PMID- 25543968 TI - Patients with heart failure with reduced ejection fraction have exaggerated reductions in cerebral blood flow during upright posture. PMID- 25543969 TI - Primary prevention implantable cardioverter-defibrillators and survival in older women. AB - OBJECTIVES: The purpose of this study was to assess the benefit of primary prevention implantable cardioverter defibrillators (ICDs) in women. BACKGROUND: Clinical trials of primary prevention ICDs enrolled a limited number of women. METHODS: Using a propensity score method, we matched 490 women >=65 years of age who received an ICD during a hospitalization for heart failure in the National Cardiovascular Data Registry ICD Registry from January 1, 2006, through December 31, 2007, to 490 ICD-eligible women without an ICD hospitalized for heart failure in the Get With The Guidelines for Heart Failure database from January 1, 2006, through December 31, 2009. The primary endpoint was all-cause mortality obtained from the Medicare Claims Database. An identical analysis was conducted in men. RESULTS: Median follow-up for patients with an ICD was 4.6 years versus 3.2 years for patients with no ICD. Compared with women with no ICD, those with an ICD were younger and less frequently white. In the matched cohorts, the survival of women with an ICD was significantly longer than that of women without an ICD (adjusted hazard ratio: 0.79, 95% confidence interval: 0.66 to 0.95; p = 0.013). Similarly, men with an ICD had longer survival than men without an ICD (adjusted hazard ratio: 0.73, 95% confidence interval: 0.65 to 0.83; p < 0.0001). There was no interaction between sex and the presence of an ICD with respect to survival (p = 0.44). CONCLUSIONS: Among older women with left ventricular dysfunction, a primary prevention ICD was associated with a significant survival benefit that was nearly identical to that seen in men. These findings support the use of primary prevention ICDs in eligible patients regardless of sex. PMID- 25543970 TI - Cerebral hypoperfusion is exaggerated with an upright posture in heart failure: impact of depressed cardiac output. AB - OBJECTIVES: The purpose of this study was to examine cerebral blood flow (CBF) supine and during upright sitting in HF patients and control subjects to test the hypothesis that patients with HF will have a greater reduction in CBF from supine to seated compared with the control group. BACKGROUND: Reduced CBF has been reported in patients with heart failure (HF). However, previous work has only examined CBF while supine, although an upright posture common to daily living may lead to further reductions. METHODS: In 22 HF patients and 22 age- and sex matched control subjects, continuous heart rate, mean arterial pressure, and end tidal carbon dioxide readings were collected while supine and seated upright. Cardiac output was estimated from pulse contour analysis and was corrected for body size (cardiac index). The right internal carotid artery was imaged by using ultrasound to estimate CBF. RESULTS: Heart rate increased less in response to the upright posture in HF patients versus control subjects (p = 0.006). Mean arterial pressure was unchanged, whereas end-tidal carbon dioxide decreased in response to position (p = 0.004) but did not differ between groups. Cardiac index was lower in patients with HF (p < 0.001) and decreased in both groups in response to the upright posture (p = 0.025), with a trend for a greater decrease in the HF group (p = 0.065). CBF decreased more in response to the upright posture in the HF group than in the control group (p = 0.007). CONCLUSIONS: The reduction in CBF was exaggerated in the upright posture in HF patients and may increase the risk for subsequent cognitive impairment. PMID- 25543971 TI - Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. AB - OBJECTIVES: The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers. BACKGROUND: HCM is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. METHODS: In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. RESULTS: Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end diastolic diameter improved toward normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. -0.5; p < 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (-0.02 vs. +0.15; p = 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group. CONCLUSIONS: Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982). PMID- 25543973 TI - Advanced care planning: care to plan in advance. PMID- 25543974 TI - Renin-Angiotensin-aldosterone system activation during decongestion in acute heart failure: friend or foe? PMID- 25543972 TI - Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure. AB - OBJECTIVES: The purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes. BACKGROUND: High-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation. METHODS: This study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes. RESULTS: Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5). CONCLUSIONS: High-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491). PMID- 25543975 TI - Why should cardiologists consider genetic testing for hypertrophic cardiomyopathy? PMID- 25543976 TI - Advance directives among hospitalized patients with heart failure. AB - OBJECTIVES: The purpose of this study was to assess the frequency and correlates of documented advance directives (ADs) among patients hospitalized for heart failure (HF). BACKGROUND: Discussing ADs with patients with HF is critical for identifying treatment goals consistent with patients' values and preferences and for facilitating health care team communication. METHODS: We retrospectively identified electronic medical records of adult patients admitted to 2 large tertiary care hospitals with either the primary or secondary discharge diagnosis of HF from September 2008 to August 2013 to assess the presence of ADs in electronic medical records. We performed analyses including HF as either the primary or secondary admission diagnosis and HF as the primary admission diagnosis only. Multivariable models were constructed to investigate independent predictors of documented ADs. RESULTS: Data included 44,768 admissions from 24,291 individual patients over 5 years. Mean age of patients at admission was 64.8 +/- 15.9 years; 47.9% of these patients were female, 51.8% were black. The median length of stay for all admissions was 5 (3 to 10) days; 12.7% of patients had documented ADs. Older age, female sex, white race, higher socioeconomic status, higher risk for adverse in-hospital outcomes, length of stay >=5 days, hospice discharge, palliative care consultation, and a do-not-resuscitate order were all associated with a significantly higher chance of having documented ADs. A significant increase in ADs over time was noted, but more than 80% of patients did not have ADs in medical records at the end of the study period. CONCLUSIONS: In a diverse population of hospitalized patients with HF, most did not have a documented AD in the medical records. Although several factors were associated with a higher probability, major opportunities exist for all subgroups of patients with HF to improve documentation of ADs. PMID- 25543977 TI - The effect of footwear and foot orthoses on transverse plane knee motion during running - A pilot study. AB - OBJECTIVES: This study aimed to determine the immediate effects of footwear and foot orthoses on transverse plane rotation of the knee joint during the stance phase of jogging gait. DESIGN: An experimental, within subjects, repeated measures design. METHODS: Three-dimensional knee kinematics were estimated in the transverse plane by surface-mounted markers as 14 asymptomatic participants ran in four randomised conditions; neutral shoe, neutral shoe with customised orthoses, neutral shoe with prefabricated orthoses, and a stability shoe. Peak internal/external rotation joint angles and ranges of motion (ROM) during loading response, midstance and propulsion were determined. Immediate subjective comfort was also recorded for each condition using a 100 mm visual analogue scale. RESULTS: Significant main effects of condition were observed for all outcomes except transverse plane knee ROM during loading response (p < 0.05). All significant differences occurred between the stability shoe and another condition, with less knee internal rotation in the stability shoe (mean differences ranged between 1.7 degrees and 6.1 degrees ) (p < 0.05). The neutral shoe with prefabricated orthoses was reported as more uncomfortable than all other testing conditions. CONCLUSIONS: The stability shoe reduced peak knee internal rotation throughout stance phase of jogging more than any other condition. Importantly, it was subjectively as comfortable as the other conditions. These results identify the ability for footwear alone to induce immediate proximal kinematic effects. The use of the kinematic theory behind foot orthoses therapy is also questioned. PMID- 25543978 TI - Ca(2+) binding protein S100A1 competes with calmodulin and PIP2 for binding site on the C-terminus of the TPRV1 receptor. AB - Transient receptor potential vanilloid 1 ion channel (TRPV1) belongs to the TRP family of ion channels. These channels play a role in many important biological processes such as thermosensation and pain transduction. The TRPV1 channel was reported to be also involved in nociception. Ca(2+) ions are described to participate in the regulation of TRP channels through the interaction with Ca(2+) binding proteins, such as calmodulin or S100A1. Calmodulin is involved in the Ca(2+)-dependent regulation of TRPV1 via its binding to the TRPV1 C-terminal region. However, the role of the Ca(2+)-binding protein S100A1 in the process of TRP channel regulation remains elusive. Here we characterized a region on the TRPV1 C-terminus responsible for the interaction with S100A1 using biochemical and biophysical tools. We found that this region overlaps with previously identified calmodulin and PIP2 binding sites and that S100A1 competes with calmodulin and PIP2 for this binding site. We identified several positively charged residues within this region, which have crucial impact on S100A1 binding, and we show that the reported S100A1-TRPV1 interaction is calcium-dependent. Taken together, our data suggest a mechanism for the mutual regulation of PIP2 and the Ca(2+)-binding proteins S100A1 and calmodulin to TRPV1. PMID- 25543979 TI - Fabrication of a novel scaffold of clotrimazole-microemulsion-containing nanofibers using an electrospinning process for oral candidiasis applications. AB - Clotrimazole (CZ)-loaded microemulsion-containing nanofiber mats were developed as an alternative for oral candidiasis applications. The microemulsion was composed of oleic acid (O), Tween 80 (T80), and a co-surfactant such as benzyl alcohol (BzOH), ethyl alcohol (EtOH) or isopropyl alcohol (IPA). The nanofiber mats were obtained by electrospinning a blended solution of a CZ-loaded microemulsion and a mixed polymer solution of 2% (w/v) chitosan (CS) and 10% (w/v) polyvinyl alcohol (PVA) at a weight ratio of 30:70. The nanofiber mats were characterized using various analytical techniques. The entrapment efficiency, drug release, antifungal activity and cytotoxicity were investigated. The average diameter of the nanofiber mats was in the range of 105.91-125.56 nm. The differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) results revealed the amorphous state of the CZ-loaded microemulsions incorporated into the nanofiber mats. The entrapment efficiency of CZ in the mats was approximately 72.58-98.10%, depended on the microemulsion formulation. The release experiment demonstrated different CZ release characteristics from nanofiber mats prepared using different CZ-loaded microemulsions. The extent of drug release from the fiber mats at 4h was approximately 64.81-74.15%. The release kinetics appeared to follow Higuchi's model. In comparison with CZ lozenges (10mg), the nanofiber mats exhibited more rapid killing activity. Moreover, the nanofiber mats demonstrated desirable mucoadhesive properties and were safe for 2h. Therefore, the nanofiber mats have the potential to be promising candidates for oral candidiasis applications. PMID- 25543980 TI - Polymeric nanoassemblies entrapping curcumin overcome multidrug resistance in ovarian cancer. AB - The increasing emergence of multidrug-resistant (MDR) cells presents a challenge to effective cancer therapy. Curcumin (CUR) has multifunctional anticancer properties, but its clinical use has been limited by poor solubility. We developed biodegradable polymeric micelles entrapping CUR in order to improve its antitumor activity and to explore whether it could treat MDR cells. This delivery system produced small micelles with a high encapsulation efficiency, good stability, and slow release of CUR. CUR micelles showed cytotoxic effects in wild type drug-sensitive A2780s and in paclitaxel-resistant A2780t ovarian adenocarcinoma cells. The concentration of free CUR that reduced cell viability by 50% (IC50) was 1.5 fold and 1.2 fold higher than that of CUR micelles in A2780s and A2780t cells, respectively. Cellular uptake studies indicated that delivery by micelles improved CUR uptake into both cell lines. Cell cycle analysis suggested that CUR micelles induced apoptosis and enhanced G2/M arrest. Overall, CUR micelles may provide a novel strategy to improve the clinical management of MDR ovarian cancer. PMID- 25543981 TI - Injectable in situ forming xylitol-PEG-based hydrogels for cell encapsulation and delivery. AB - Injectable in situ crosslinking hydrogels offer unique advantages over conventional prefabricated hydrogel methodologies. Herein, we synthesize poly(xylitol-co-maleate-co-PEG) (pXMP) macromers and evaluate their performance as injectable cell carriers for tissue engineering applications. The designed pXMP elastomers were non-toxic and water-soluble with viscosity values permissible for subcutaneous injectable systems. pXMP-based hydrogels prepared via free radical polymerization with acrylic acid as crosslinker possessed high crosslink density and exhibited a broad range of compressive moduli that could match the natural mechanical environment of various native tissues. The hydrogels displayed controlled degradability and exhibited gradual increase in matrix porosity upon degradation. The hydrophobic hydrogel surfaces preferentially adsorbed albumin and promoted cell adhesion and growth in vitro. Actin staining on cells cultured on thin hydrogel films revealed subconfluent cell monolayers composed of strong, adherent cells. Furthermore, fabricated 3D pXMP cell-hydrogel constructs promoted cell survival and proliferation in vitro. Cumulatively, our results demonstrate that injectable xylitol-PEG-based hydrogels possess excellent physical characteristics and exhibit exceptional cytocompatibility in vitro. Consequently, they show great promise as injectable hydrogel systems for in situ tissue repair and regeneration. PMID- 25543982 TI - Exploring a new SPION-based MRI contrast agent with excellent water dispersibility, high specificity to cancer cells and strong MR imaging efficacy. AB - Advances in contrast agents have greatly enhanced the sensitivity of magnetic resonance imaging (MRI) technique for early diagnosis of cancer. However, the commercial superparamagnetic iron oxide nanoparticles (SPION)-based contrast agents synthesized by co-precipitation method are not monodisperse with irregular morphologies and ununiform sizes. Other reported SPION-based contrast agents synthesized by solvothermal method or thermal decomposition method are limited by the bad water-dispersibility and low specificity to cancer cells. Herein, we propose a new strategy for exploring SPION-based MRI contrast agents with excellent water-dispersibility and high specificity to cancer cells. The SPION was synthesized by a polyol method and then entrapped into albumin nanospheres (AN). After that, a ligand folic acid (FA) was conjugated onto the surface of the AN to construct a SPION-AN-FA composite. The transmission electron microscope (TEM) and dynamic light scattering (DLS) results indicate that the SPION-AN-FA has a spherical shape, a uniform size and an excellent water-dispersibility (polydispersity index (PDI) <0.05). The results of laser scanning confocal microscope (LSCM) and flow cytometry demonstrate that the SPION-AN-FA nanoparticles are highly specific to MCF-7 and SPC-A-1 cells due to the recognition of ligand FA and folate receptor alpha (FRalpha). The r2/r1 value of SPION-AN-FA is around 40, which is much higher than that of Resovist((r)) indicating that our SPION-AN-FA has a stronger T2 shortening effect. The T2 weighted images of MCF-7 cells incubated with SPION-AN-FA are significantly darker than those of MCF-7 cells incubated with AN, indicating that our SPION-AN FA has a strong MR imaging efficacy. In view of the excellent water dispersibility, the high specificity to cancer cells and the strong MR imaging efficacy, our SPION-AN-FA can be used as a negative MR contrast agent. PMID- 25543983 TI - Evaluation of characteristics and in vitro antioxidant properties of RSV loaded hyaluronic acid-DPPC microparticles as a wound healing system. AB - Resveratrol (RSV) was incorporated into microparticles by spray drying to treat chronic wounds such as diabetic ulcers. RSV was chosen due to its defense mechanisms as the formation of free radicals delays the healing process. RSV was loaded into microparticles consisting of dipalmitoylphosphatidylcholine (DPPC) and hyaluronic acid (HA), a polysaccharide naturally present within the skin, known to contribute to the healing process. Microparticles were evaluated in terms of production yield, size distribution, encapsulation efficiency, morphology, specific surface area, thermal properties and water content. Spherical and homogenous microparticles (span <= 2) in a size range between 20 and 30 MUm were obtained with high encapsulation efficiency (>= 97%). The effect of enzymes (hyaluronidase, phospholipase and lipase) on RSV release showed a dose dependent pattern followed by a slow release stage. Cytotoxicity/proliferation and oxidative stress parameters (glutathione, oxidized glutathione, glutathione peroxidase, malondialdehyde, superoxide dismutase) obtained from human dermal fibroblast cell cultures revealed that formulations increased cell proliferation and the presence of RSV decreased oxidation in cells. RSV-loaded HA-DPPC microparticles appear as a promising formulation for wound healing due to synergistic effect of the ingredients. PMID- 25543984 TI - Adsorption properties of an activated carbon for 18 cytokines and HMGB1 from inflammatory model plasma. AB - The ability of an activated carbon (AC) to adsorb 18 different cytokines with molecular weights ranging from 8 kDa to 70 kDa and high mobility group box-1 (HMGB1) from inflammatory model plasma at 310 K and the mechanisms of adsorption were examined. Porosity analysis using N2 gas adsorption at 77K showed that the AC had micropores with diameters of 1-2 nm and mesopores with diameters of 5-20 nm. All 18 cytokines and HMGB1 were adsorbed on the AC; however, the shapes of the adsorption isotherms changed depending on the molecular weight. The adsorption isotherms for molecules of 8-10 kDa, 10-20 kDa, 20-30 kDa, and higher molecular weights were classified as H-2, L-3, S-3, and S-1 types, respectively. These results suggested that the adsorption mechanism for the cytokines and HMGB1 in the mesopores and on the surface of the AC differed as a function of the molecular weight. On the basis of these results, it can be concluded that AC should be efficient for cytokine adsorption. PMID- 25543985 TI - Cell response to single-walled carbon nanotubes in hybrid porous collagen sponges. AB - Three-dimensional (3D) porous collagen sponges incorporated with single-walled carbon nanotubes (SWCNTs) were prepared and used for 3D culture of bovine articular chondrocytes (BACs). The pore structures of the sponges were controlled by using ice particulates as a porogen material. The responses of cells to SWCNTs were investigated in this 3D cell culture system by evaluation of cell functions and cellular uptake of SWCNTs. The results showed that cells adhered and spatially distributed in the porous sponges. The incorporation of SWCNTs in the porous sponges promoted cell proliferation and production of sulfated glycosaminoglycans (sGAG). Confocal Raman imaging revealed that SWCNTs could be internalized by cells. The hybrid porous sponges not only provided nanostructured pore surfaces to facilitate cell proliferation and extracellular matrix (ECM) secretion but also supplied nanomaterials for cellular uptake which may be useful for biomedical applications. PMID- 25543986 TI - Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz. AB - Efavirenz is a lipophilic non-nucleoside reverse transcriptase inhibitor used in the first-line pediatric therapeutic cocktail. Due to its high lipophilicity (logP = 5.4) and poor aqueous solubility (intrinsic water solubility = 8.3 MUg/mL) efavirenz has low bioavailability. A 30 mg/mL solution in a medium-chain triglyceride vehicle is the only pediatric formulation available with an oral bioavailability 20% lower than the solid form. The current work was aimed at formulating and characterizing liquid crystal nanoparticles for oral delivery of efavirenz to improve oral bioavailability, provide sustained release, minimize side effects and drug resistance. Formulation of cubosomes was done by two methods; sonication and spray drying. Sonication gave highest entrapment efficiency and least particle size. Further, monoolein was substituted with phytantriol as monoolein gets degraded in the presence of lipase when administered orally with consequent loss of liquid crystalline structure. It was confirmed that there was no difference in particle size, entrapment efficiency and nature of product formed by using monoolein or phytantriol. The best formulation was found to be F9, having particle size 104.19 +/- 0.21 nm and entrapment efficiency 91.40 +/- 0.10%. In vitro release at the end of 12h was found to be 56.45% and zeta potential to be -23.14 mV which stabilized the cubic phase dispersions. It was further characterized for TEM, small angle X-ray scattering (SAXS), DSC and stability studies. SAXS revealed Pn3m space group, indicating a diamond cubic phase which was further confirmed by TEM. Pharmacokinetics of EFV was studied in male Wistar rats. EFV-loaded cubosome dispersions exhibited 1.93 and 1.62-fold increase in peak plasma concentration (Cmax) and 1.48 and 1.42-fold increase in AUC in comparison to that of a suspension prepared with the contents of EFV capsules suspended in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in medium-chain triglyceride respectively. Thus, stable cubosomes of efavirenz with increased bioavailability providing sustained release effect could be prepared successfully using phytantriol and poloxamer 407. PMID- 25543987 TI - Mechanistic approaches on the antibacterial activity of poly(acrylic acid) copolymers. AB - The availability of polymeric antimicrobially active surfaces, which are mainly based on cationic surface effects, is limited. We have previously reported the discovery that, in addition to cationic surfaces, anionic surfaces based on poly(acrylic acid) (PAA) copolymers have a bactericidal effect. In this study, poly(styrene)-poly(acrylic acid)-diblock copolymers (PS-b-PAA) are used to describe the major variables causing the material to have a bactericidal effect on Escherichia coli ATCC 25922 in aqueous suspensions. Upon contact with water, the surface structure of the copolymer changes, the pH value decreases, and the PAA-block migrates toward the surface. Systematically modified antimicrobial tests show that the presence of acid-form PAA provides maximum antimicrobial activity of the material in slightly acidic conditions, and that an ion-exchange effect is the most probable mechanism. Antimicrobially inactive counter-ions inhibit the bactericidal activity of the copolymers, but the material can be regenerated by treatment with acids. PMID- 25543988 TI - Assessment of 2,2,6,6-tetramethyl-4-piperidinol-based amine N-halamine-labeled silica nanoparticles as potent antibiotics for deactivating bacteria. AB - Novel potent antibiotics, amine N-halamine-labeled silica nanoparticles (ANHLS NPs) based on 2,2,6,6-tetramethyl-4-piperidinol (TMP), were skillfully synthesized via the encapsulation of silica nanoparticles with amine N-halamine polymer for effective killing pathogenic bacteria. The particle size and coating thickness of amine N-halamine of ANHLS NPs were well controlled by tuning size of silica NPs and polymer encapsulation period, respectively. Effect of chlorination time on the oxidative chlorine content in ANHLS NPs was well elucidated by the aid of the modified iodometric/thiosulfate technique. Antimicrobial action of the ANHLS NPs on bacterial strain was evaluated using Staphylococcus aureus and Escherichia coli as model pathogenic bacteria. Bactericidal assessment showed that the ANHLS NPs exerted powerful bactericidal capability toward both two model bacteria. Time-kill assay demonstrated the significance of the oxidative chlorine content and contact time on antibacterial behavior. Size effect experiment displayed the decisive role of the size in controlling the biocidal activity. Plausible antibacterial mechanism of the ANHLS NPs against pathogenic bacteria was also discussed. Such a systematic investigation of the ANHLS NPs provides us a novel idea of making them the promising candidates for deactivating bacteria or even disease control. PMID- 25543989 TI - Titanium-based nanocomposite materials: a review of recent advances and perspectives. AB - This article explains recent advances in the synthesis and characterization of novel titanium-based nanocomposite materials. Currently, it is a pressing concern to develop innovative skills for the fabrication of hybrid nanomaterials under varying experimental conditions. This review generally focuses on the adsorption behavior of nanocomposites for the exclusion of organic and inorganic pollutants from industrial effluents and their significant applications in various fields. The assessment of recently published articles on the conjugation of organic polymers with titanium has revealed that these materials may be a new means of managing aquatic pollution. These nanocomposite materials not only create alternative methods for designing novel materials, but also develop innovative industrial applications. In the future, titanium-based hybrid nanomaterials are expected to open new approaches for demonstrating their outstanding applications in diverse fields. PMID- 25543990 TI - Gold-gold bonding: the key to stabilizing the 19-electron ternary phases LnAuSb (Ln = La-Nd and Sm). AB - We report a new family of ternary 111 hexagonal LnAuSb (Ln = La-Nd, Sm) compounds that, with a 19 valence electron count, has one extra electron compared to all other known LnAuZ compounds. LaAuSb, CeAuSb, PrAuSb, NdAuSb, and SmAuSb crystallize in the YPtAs-type structure, and have a doubled unit cell compared to other LnAuZ phases as a result of the buckling of the Au-Sb honeycomb layers to create interlayer Au-Au dimers. The dimers accommodate the one excess electron per Au and thus these new phases can be considered Ln2(3+)(Au-Au)(0)Sb2(3-). Band structure, density of states, and crystal orbital calculations confirm this picture, which results in a nearly complete band gap between full and empty electronic states and stable compounds; we can thus present a structural stability phase diagram for the LnAuZ (Z = Ge, As, Sn, Sb, Pb, Bi) family of phases. Those calculations also show that LaAuSb has a bulk Dirac cone below the Fermi level. The YPtAs-type LnAuSb family reported here is an example of the uniqueness of gold chemistry applied to a rigidly closed shell system in an unconventional way. PMID- 25543991 TI - Perceiving a story outside of conscious awareness: When we infer narrative attributes from subliminal sequential stimuli. AB - Perceiving a story behind successive movements plays an important role in our lives. From a general perspective, such higher mental activity would seem to depend on conscious processes. Using a subliminal priming paradigm, we demonstrated that such story perception occurs without conscious awareness. In the experiments, participants were subliminally presented with sequential pictures that represented a story in which one geometrical figure was chased by the other figure, and in which one fictitious character defeated the other character in a tug-of-war. Although the participants could not report having seen the pictures, their automatic mental associations (i.e., associations that are activated unintentionally, difficult to control, and not necessarily endorsed at a conscious level) were shifted to line up with the story. The results suggest that story perception operates outside of conscious awareness. Implications for research on the unconscious were also briefly discussed. PMID- 25543992 TI - The forgotten remindings: Personal remindings examined through self-probed retrospection during reading and writing. AB - Remindings are spontaneously arising recollections of past personal experiences that are instrumental in that they occur in response to an ongoing task to which they are perceived as being related. While related areas of research have found the number of off-task thoughts to decrease with the difficulty of the on-going task, task difficulty has yet to be examined in remindings. Here we present a series of studies examining the effects of task difficulty on remindings as well as further examining the phenomenological characteristics of remindings. Experiments 1-3 provide evidence that the frequency of remindings during different types of reading and writing task decreases with increasing difficulty associated with the parallel task. Experiment 4 shows that the content of remindings varies systematically with characteristics of the parallel task, indicating their context dependency and potential instrumentality. Findings are discussed in relation to research on mind wandering and involuntary autobiographical memories. PMID- 25543993 TI - Effects of context on recollection and familiarity experiences are task dependent. AB - The influence of test context on reports of recollection and familiarity depends on how these subjective recognition experiences are conceptualized and measured. Bodner and Lindsay (2003) found that critical items elicited more remember judgments but fewer know judgments in a less (vs. more) memorable context. In contrast, Tousignant and Bodner (2012) found that independent ratings of recollection and familiarity were both higher in a less memorable context. We replicated the dissociative pattern with judgments using recollect/familiar labels (Experiment 1), and in a novel R/F/B task that added a "both" option to eliminate the mutual exclusivity between the recollect and familiar options (Experiment 2). Adding a "guess" option eliminated these context effects (Experiment 3), however whether allowing guesses "cleans up" or "desensitizes" recollection and familiarity judgments remains unclear. Determining which task variants provide appropriate measures of subjective recognition experiences will require an examination of additional dissociations and triangulation with other measures. PMID- 25543994 TI - Retracted: chronic recurrent multifocal osteomyelitis with concomitant features of juvenile idiopathic arthritis. AB - [This retracts the article DOI: 10.1155/2011/210795.]. PMID- 25543995 TI - [Bilateral foreign body in chest x-ray]. PMID- 25543996 TI - An analysis of challenging behavior, comorbid psychopathology, and Attention Deficit/Hyperactivity Disorder in Fragile X Syndrome. AB - The present study sought to investigate the relationship between challenging behavior, comorbid psychopathology, and Attention-Deficit/Hyperactivity Disorder (AD/HD) in Fragile X Syndrome (FRAX). Additionally, this study sought to examine how such disorders are predicted by gender, presence of autism spectrum disorder (ASD), and presence of intellectual disability (ID). A total of 47 children and adolescents with FRAX were assessed. Results revealed high levels of challenging behavior and AD/HD symptoms within the sample, with some participants exhibiting symptoms of comorbid psychopathology. Further analysis revealed that challenging behavior and comorbid psychopathology were positively correlated, with stereotypy correlating most strongly with comorbid psychopathology. In addition, ASD was found to predict challenging behavior, and gender was found to predict AD/HD symptoms. The implications of these findings are discussed. PMID- 25543997 TI - Defining social inclusion of people with intellectual and developmental disabilities: an ecological model of social networks and community participation. AB - Social inclusion is an important goal for people with intellectual and developmental disabilities, families, service providers, and policymakers; however, the concept of social inclusion remains unclear, largely due to multiple and conflicting definitions in research and policy. We define social inclusion as the interaction between two major life domains: interpersonal relationships and community participation. We then propose an ecological model of social inclusion that includes individual, interpersonal, organizational, community, and socio political factors. We identify four areas of research that our ecological model of social inclusion can move forward: (1) organizational implementation of social inclusion; (2) social inclusion of people with intellectual and developmental disabilities living with their families, (3) social inclusion of people along a broader spectrum of disability, and (4) the potential role of self-advocacy organizations in promoting social inclusion. PMID- 25543998 TI - MicroRNA expression profiles in human adipose-derived stem cells during chondrogenic differentiation. AB - The aim of the present study was to examine the microRNA (miRNA or miR) expression profiles during the chondrogenic differentiation of human adipose derived stem cells (hADSCs) and identify the potential mechanisms through which miRNAs may affect the process of chondrogenesis. hADSCs were isolated and cultured. The expression levels of chondrogenic markers was detected by FACS analysis and immunohistochemistry. The miRNA expression profiles were then obtained through a miRNA array and confirmed through northern blot analysis. Putative targets of the miRNAs were predicted and validated through a luciferase reporter assay. The comparison of hADSCs following the induction of chondrogenic differentiation with undifferentiated hADSCs revealed 20 miRNAs that were differentially expressed by at least 2-fold, and these miRNAs included 12 upregulated miRNAs and 8 downregulated miRNAs. Northern blot analysis further confirmed the miRNA expression levels. Of these miRNAs, the expression of miR-490 5p was gradually downregulated following the induction of chondrogenic differentiation. The overexpression of miR-490-5p increased the expression of the chondrogenic markers, collagen, type II, alpha 1 (Col2A1), collagen, type X, alpha 1 (Col10A1) and aggrecan. Furthermore, it was confirmed that miR-490-5p directly targets bone morphogenetic protein receptor type 2 (BMPR2). In conclusion, in this study, we identified a set of miRNAs that may play key roles in the regulation of the chondrogenic differentiation of hADSCs. Our results may provide a basis for the further investigations into the molecular mechanisms of action of miRNAs in hADSC chondrogenesis. PMID- 25543999 TI - Thoracic spinal manipulation for musculoskeletal shoulder pain: Can an instructional set change patient expectation and outcome? AB - STUDY DESIGN: Planned secondary analysis of a randomized clinical trial. OBJECTIVES: To examine: 1) patients' baseline expectations for treatment outcome of thoracic high velocity low amplitude thrust manipulations (HVLATM) to the thoracic spine for shoulder pain; 2) if the message conveyed by the clinician changed the patients' expectation; 3) any differences in outcome based on expectation independent of messaging.; and 4) any differences in outcome for those patients whose expectations significantly changed as a result of the messaging. BACKGROUND: Thoracic HVLATM may be an effective intervention for patients suffering from musculoskeletal shoulder pain. The role of expectation in the treatment effectiveness of this intervention has not been established. METHODS: Subjects' expectations regarding the effectiveness of HVLATM on shoulder pain were recorded at baseline. This was reassessed immediately following the provision of positive or neutral instructional set. The subjects then received a thoracic or scapular HVLATM. The Shoulder Pain and Disability Index (SPADI) and the numeric pain rating scale (NPRS) were used as outcomes measures. RESULTS: There was a 10 subject change (23%) in positive expectation that was statistically significant (p = 0.019) following a positive message. There was no statistically significant difference in pain and function when these subjects were compared to all other subjects. CONCLUSION: Although patients' expectations of positive outcome significantly changed when providing a positive instructional set, these changes did not translate into clinically significant short term changes in shoulder pain and function. LEVEL OF EVIDENCE: 1b. PMID- 25544000 TI - A new causative bacteria of infective endocarditis, Bergeyella cardium sp. nov. AB - The first cases of infective endocarditis due to a new species of Bergeyella, Bergeyella cardium sp. nov., are reported. Two strains, 13-07(T) (= JCM 30115(T) = NCCP 15908(T)) and 13-16, were independently isolated from 2 patients in different hospitals in Korea. Initially, the isolates were identified as Brevundimonas spp.; however, their 16S rRNA gene sequences shared a similarity of 94.9% with Bergeyella zoohelcum, implying that they are a new species belonging to of the genus Bergeyella. The organisms might be susceptible to many commonly used antibiotics, including penicillin. The first case was successfully treated with ceftriaxone, and the second, with piperacillin/tazobactam plus amikacin. PMID- 25544008 TI - Fast separation and quantification of steroid hormones Delta4- and Delta7 dafachronic acid in Caenorhabditis elegans. AB - Separation of isomeric molecular species, e.g. double bond position isomers, is a challenging task for liquid chromatography. The two steroid hormones Delta4- and Delta7-dafachronic acid (DA) represent such an isomeric pair. DAs are 3 ketosteroids found in the nematode Caenorhabditis elegans and generated from cholesterol. Delta4- and Delta7-DA have important biological activities and are produced by two different biological pathways in C. elegans. Here we have described a fast separation method for these two isomers using a 1.3 MUm core shell particle in less than 10 min together with a simple MeOH extraction. Using this method we were able to independently quantify Delta4- and Delta7-DA in C. elegans independently from each other and limits of detection of about 5 ng/ml for each isomer were achieved with a good day-to-day reproducibility. As proof-of principle the method has been applied to the quantification of DAs in worms fed ad libitum or under bacterial deprivation. PMID- 25544009 TI - Optimization and application of headspace-solid-phase micro-extraction coupled with gas chromatography-mass spectrometry for the determination of volatile compounds in cherry wines. AB - A simple, rapid and solvent-free multi-residue method has been developed and applied to confirm and quantify a series of volatile compounds in five cherry wines by gas chromatography coupled with mass spectrometry (GC-MS). Four parameters (e.g., coating material of fiber, temperature and time of extraction, and addition of sodium chloride in the solution) of headspace solid-phase micro extraction (HS-SPME) were optimized, resulting in the best extraction condition including 50/30 MUm DVB/CAR/PDMS fiber, 45 min and 50 degrees C of SPME, and 2g of sodium chloride addition in the wine during the extraction. The SPME had LODs and LOQs ranging from 0.03 to 7.27 MUg L(-1) and 0.10 to 24.24 MUg L(-1) for analytic compounds, respectively. Repeatability and reproducibility values were all below 19.8%, with mean values of 12.7% and 10.5%, respectively. Regression coefficients (R(2)) of detective linearity of the standard curves was higher than 0.9852. Moreover, relative recoveries of analytical targets were achieved in a range of 60.7-125.6% with good relative standard deviation values (<=20.6%). In addition, a principal component analysis (PCA) was used to analyze the aroma profiles of the wines, which indicated that five samples were distinctly divided into two groups based on their different geographical origins and volatile compounds. PMID- 25544001 TI - International variation in place of death of older people who died from dementia in 14 European and non-European countries. AB - OBJECTIVES: The objective of this study was to examine variation in place of death of older people dying from dementia in countries across 4 continents. DESIGN: Study of death certificate data. METHODS: We included deaths of older (65 + years) people whose underlying cause of death was a dementia-related disease (ICD-10: F01, F02, F03, G30) in Belgium, the Netherlands, England, Wales, France, Italy, Spain, Czech Republic, Hungary, New Zealand, United States, Canada, Mexico and South Korea. We examined associations between place of death and sociodemographic factors, social support, and residential and health care system factors. RESULTS: Overall, 4.8% of all deaths were from a dementia-related disease, ranging from 0.4% in Mexico to 6.9% in Canada. Of those deaths, the proportion occurring in hospital varied from 1.6% in the Netherlands to 73.6% in South Korea. When controlling for potential confounders, hospital death was more likely for men, those younger than 80, and those married or living in a region with a higher availability of long-term care beds, although this could not be concluded for each country. Hospital death was least likely in the Netherlands compared with other countries. CONCLUSIONS: Place of death of older people who died from a dementia-related disease differs substantially between countries, which might point to organizational differences in end-of-life care provision. Increasing the availability of long-term care beds might be important to reduce the number of hospital deaths, while focusing specialized end-of-life care services on married people or those aged 65 to 79 might be crucial for achieving home death. However, proper end-of-life care needs to be ensured in hospitals, should this be the most appropriate end-of-life care setting. PMID- 25544010 TI - A sensitive method for digoxin determination using formate-adduct ion based on the effect of ionization enhancement in liquid chromatograph-mass spectrometer. AB - A sensitive and rapid method based on formate-adduct ion detection was developed and fully validated for digoxin determination in rat plasma. For LC/MS/MS detection with formate-adducts as precursor ions, transitions of m/z 825.5->779.9 for digoxin and m/z 809.5->763.4 for the internal standard (digitoxin) were monitored in negative mode. To investigate the impact of formic acid on the mass response and method sensitivity, a formic acid concentration range of 0-0.1% (0, 0.0005%, 0.002%, 0.01%, 0.1%, v/v) was evaluated. A concentration of 0.002% gave the highest sensitivity, which was 16- to 18-fold higher than deprotonated ions, and was designated as the contribution giving the strongest ionization enhancement and adduction. A number of parameters were then varied in order to optimize the method, and a limit of quantitation (LOQ) at 0.2 ng/mL was reached with an injection volume of 5 MUL, a total run time of 3 min, and 0.1 mL of rat plasma. A calibration curve was plotted over the range 0.2-50 ng/mL (R(2)=0.9998), and the method was successfully applied to study pharmacokinetics in rat following a single oral administration of digoxin (0.05 mg/kg). Four additional steroid saponins (digitoxin, deslanoside, ginsenoside Rg1 and Rb1) were investigated to assess the impact of formic acid on the mass response of steroid saponins. Compounds with a conjugated lactonic ring in their structures such as digoxin, digitoxin and deslanoside tended to form stable formate-adduct ions more easily. The LC/MS/MS method developed here is therefore well suited for the quantification of steroid saponins that are difficult to deprotonate using other MS approaches. PMID- 25544011 TI - Optimization of supercoiled HPV-16 E6/E7 plasmid DNA purification with arginine monolith using design of experiments. AB - The progress of DNA vaccines is dependent on the development of suitable chromatographic procedures to successfully purify genetic vectors, such as plasmid DNA. Human Papillomavirus is associated with the development of tumours due to the oncogenic power of E6 and E7 proteins, produced by this virus. The supercoiled HPV-16 E6/E7 plasmid-based vaccine was recently purified with the arginine monolith, with 100% of purity, but only 39% of recovery was achieved. Therefore, the present study describes the application of experimental design tools, a newly explored methodology in preparative chromatography, in order to improve the supercoiled plasmid DNA recovery with the arginine monolith, maintaining the high purity degree. In addition, the importance and influence of pH in the pDNA retention to the arginine ligand was also demonstrated. The Composite Central Face design was validated and the recovery of the target molecule was successfully improved from 39% to 83.5%, with an outstanding increase of more than double, while maintaining 100% of purity. PMID- 25544012 TI - Microscale and miniscale fermentation and screening. AB - Small-scale bioreactors in the microliter and milliliter range gained more importance in recent years. For the characterization of mass transfer, the volumetric mass transfer coefficient kLa and the oxygen transfer rate OTRmax are considered. kLa values up to 1440 hour(-1) are reported for small-scale bioreactors. The OTRmax is strongly influenced by the liquid film thickness and, finally, by the liquid viscosity. Optical on-line methods, such as fluorescence and scattered light measurements, are applied to monitor pH, dissolved oxygen tension (DOT), product formation and biomass. Recently, single cell microfluidics are used to obtain new insights into microbial behavior at changing operating conditions. Finally, novel fed-batch techniques are applied to assimilate the cultivation conditions between screening and production scale. PMID- 25544013 TI - Production of natural products through metabolic engineering of Saccharomyces cerevisiae. AB - Many high-value metabolites are produced in nature by organisms that are not ideal for large-scale production. Therefore, interest exists in expressing the biosynthetic pathways of these compounds in organisms that are more suitable for industrial production. Recent years have seen developments in both the discovery of various biosynthetic pathways, as well as development of metabolic engineering tools that allow reconstruction of complex pathways in microorganisms. In the present review we discuss recent advances in reconstruction of the biosynthetic pathways of various high-value products in the yeast Saccharomyces cerevisiae, a commonly used industrial microorganism. Key achievements in the production of different isoprenoids, aromatics and polyketides are presented and the metabolic engineering strategies underlying these accomplishments are discussed. PMID- 25544014 TI - Declines in polybrominated diphenyl ether contamination of San Francisco Bay following production phase-outs and bans. AB - California has implemented unique consumer product flammability standards. Polybrominated diphenyl ether (PBDE) flame retardants were once widely incorporated into products to meet these standards, but concerns regarding toxicity and accumulation in humans and biota led to nationwide phase-outs and state bans. A decade of PBDE monitoring in San Francisco Bay has resulted in a data set that covers periods during and after PBDE use and consists of hundreds of measurements of water, sediment, and biota. While PBDEs remain widely detected in biota, levels have declined by nearly half in sport fish and 74-95% in bivalves and bird eggs. Concentrations of BDE-47 in sediment have dropped by over one-third from 2002 to 2012; in water, a decline is not yet evident. The dominant congener in sediment, DecaBDE component BDE-209, showed no temporal trend. U.S. production of DecaBDE ended in 2013; future monitoring may reveal declines. Overall, the data indicate that reduced production can result in relatively rapid reductions in the concentrations of some hydrophobic contaminants in biota and sediment, particularly when implemented after only a few decades of heavy use. Recent changes to California's flammability standards may lessen the use of other flame retardants and similarly reduce Bay contamination. PMID- 25544015 TI - Ultrasound monitoring of childhood linear morphea. PMID- 25544016 TI - Malignant acanthosis nigricans, florid cutaneous and mucosal papillomatosis, and tripe palms in a man with gastric adenocarcinoma. PMID- 25544017 TI - LEOPARD syndrome without hearing loss or pulmonary stenosis: a report of 2 cases. AB - LEOPARD syndrome is an autosomal dominant disease caused by germline mutations in the RAS-MAPK (mitogen-activated protein kinase) pathway. LEOPARD is an acronym for the main manifestations of the syndrome, namely, multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. None of these characteristic features, however, are pathognomonic of LEOPARD syndrome, and since they are highly variable, they are often not present at the time of diagnosis. We describe 2 cases of LEOPARD syndrome without hearing loss or pulmonary stenosis in which diagnosis was confirmed by identification of a mutation in the PTPN11 gene. Regular monitoring is important for the early detection of complications, as these can occur at any time during the course of disease. PMID- 25544018 TI - Skeletal muscle metastases as initial presentation of gastric carcinoma. AB - BACKGROUND: Gastric carcinoma is one of the most common malignancies in the world. Skeletal muscle metastases from gastric carcinoma are rare. CASE REPORT: We report a case of a 67-year-old man patient with skeletal muscle metastasis developing from gastric carcinoma. He had a painful swelling of the left thigh. A chest computed tomography (CT) scan with enhancement showed pulmonary thromboembolism. Despite heparin therapy, edema and pain of the lower limbs increased bilaterally, so the patient underwent pelvic magnetic resonance imaging (MRI), which documented an altered signal intensity in the upper third of his thighs bilaterally. Furthermore, the examination of the ultrasound (US)-guided biopsy specimen of the left gluteal muscle showed signet ring cell adenocarcinoma metastasis. An upper gastrointestinal tract endoscopy confirmed a gastric ulceration, with a biopsy positive for signet ring cell adenocarcinoma. Because of the advanced stage of disease, the patient underwent only supportive care and died 74 days after admission. CONCLUSIONS: Skeletal muscle metastasis may be the initial presentation of gastric carcinoma and diagnosis could be difficult. Biopsy is mandatory for diagnosis. PMID- 25544019 TI - Targeting ENaC as a Molecular Suspect in Cystic Fibrosis. AB - Cystic fibrosis (CF) is the most common life shortening autosomal inherited disorder, affecting 1 in 2500 newborns in the Caucasian population. In CF the lung pathology is associated with dehydration of the airways epithelial surface which in part results from Na(+) hyperabsorption via the epithelial sodium channel (ENaC). The molecular mechanisms of this Na(+) hyperabsorption and its correlation with the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) are not fully understood. However, it is obvious that a reduced Cl(-) secretion by CFTR and an enhanced Na+ absorption through ENaC lead to the so far incurable disease. Therefore, it could be indicated to pursue a double-tracked strategy in that way enabling Cl(-) secretion by a reconstitution of the defect CFTR as well as blocking ENaC to prevent Na(+) hyperabsorption. Since the cloning of CFTR great efforts have been done in delivery of CFTR for the correction of the reduced Cl(-) secretion. Positive benefits for the inhibition of the CF related Na(+) hyperabsorption offer technologies using small molecule inhibitors like ASOs or siRNA, which target translation and knockdown of ENaC, respectively. In this review we discuss possible CFTR/ENaC interactions in the context of CF, describe ENaC structure as well as some of the numerous attempts that were performed to prevent the Na(+) hyperabsorption in CF related lung disease. Thus, we give a short summary of e.g. amiloride therapy approaches and focus on inventive blocking efforts using ASOs and siRNA. PMID- 25544020 TI - The association between the chronic use of non-steroidal anti- inflammatory drugs and oxidative and inflammatory markers in the elderly. AB - OBJECTIVES: Investigate the association between the chronic or occasional use of nonsteroidal anti-inflammatory drugs (NSAIDs) and plasma levels of oxidative and inflammatory markers in elderly at the Family Health Strategy in Brazil. METHODS: It was a cross-sectional study of data collected from random elderly volunteers. A questionnaire including sociodemographic, health and medicine use data was administered. The blood levels of FRAP (ferric reducing ability of plasma), AOPP (plasma advanced oxidation protein products), MDA (malondialdehyde) and insulin were measured. RESULTS: The study sample comprised 758 elderly patients, of which 121 (15.96%) used NSAIDs. The mean age was 68.53 years and 68.41 for individuals who used NSAIDs occasionally and chronically, respectively. Gastric problems may be associated with the chronic or occasional use of NSAIDs (P = 0.042). Which indicates mean plasma levels of Insulin and HOMA-IR (Homeostasis Model Assessment Insulin Resistance) are increased in chronic use of NSAIDs and describes a statistical trend (P = 0.065) for the association of chronic NSAIDs use with the BMI (body mass index) of the subjects studied. CONCLUSION: This study suggests that there is no association between the chronic or occasional use of NSAIDs and oxidative and inflammatory markers. It is known that NSAIDs have innumerable adverse effects, but they can have some benefits. So, additional studies are needed to clarify whether NSAIDs are associated with these markers and whether they are related with their real consequences. PMID- 25544021 TI - Progress in measuring family spillover effects for economic evaluations. AB - Despite considerable progress in measuring family spillover effects for economic evaluations, much work remains. This editorial describes recent advances in the field and identifies areas for future research. In particular, we point out the need to clarify the potential for double-counting from including spillover effects related to caregiver time and spillover effects related to family quality of life outcomes in Reference Case analyses. We believe that research on family spillover effects has the potential to increase interest in the field of economic evaluation and its use as a tool for decision making. PMID- 25544022 TI - Finding benefit in stressful uncertain circumstances: relations to social support and stigma among women with unexplained illnesses. AB - Living with a chronic illness can be challenging, but the ability to derive benefits and grow from this experience may enhance well-being. However, the possibility of obtaining such benefits may be dependent on the levels of stigmatization and lack of social support experienced by an individual as a result of the illness. Chronic fatigue syndrome (CFS) and fibromyalgia are chronic conditions that remain largely unexplained and those with these conditions must often contend with stigma and skepticism from others. Individuals with CFS/fibromyalgia often display stress-related biological alterations and the experience of stressful life events has been associated with illness development. The present study demonstrated that women with CFS/fibromyalgia (n = 40) as well as community participants who were depressed/anxious (n = 37), reported higher stigma levels than healthy women (n = 33). Moreover, women with CFS/fibromyalgia and those with depression/anxiety also reported greater levels of stigma than women with a chronic yet more widely accepted condition (n = 35; rheumatoid arthritis, osteoarthritis and multiple sclerosis). Secrecy related to stigma among those with CFS/fibromyalgia declined with increased social support, but this was not apparent among those with other chronic conditions. In addition, posttraumatic growth was lower among women with CFS/fibromyalgia compared to those with other chronic conditions. Qualitative analysis examining both negative impacts and positive changes stemming from illness experience revealed many similarities between women with CFS/fibromyalgia and those with other chronic conditions, including elevated appreciation for life, personal growth and compassion for others. However, women with CFS/fibromyalgia tended to report less positive change regarding interpersonal relationships compared to women with other chronic conditions. In general, unexplained illnesses were also accompanied by stigmatization which might ultimately contribute to women's lower ability to derive positive growth from their illness experience. PMID- 25544023 TI - Suppression of choroidal neovascularization by Endostar in rats. AB - Choroidal neovascularization (CNV) is common in various retinal and choroidal diseases, and may result in severe and irreversible loss of vision. Our previous studies suggested that Endostar, a novel recombinant endostatin, is able to inhibit the proliferation and migration of choroid-retinal endothelial cells. To further evaluate the effect of Endostar on the formation of CNV in vivo, a rat model of laser-induced CNV was constructed and Endostar or phosphate-buffered saline treatment was administered intravitreally every other day. Using fluorescein angiography (FA), reduced CNV incidence and leakage grade was observed in the Endostar group. In addition, CNV area and maximal thickness were prominently reduced in the Endostar group measured by choroid flat mounts and sections. Furthermore, vascular endothelial growth factor (VEGF), hypoxia inducible factor 1alpha and chemokine C-X-C motif ligand 1 were markedly reduced in the Endostar group as determined by quantitative polymerase chain reaction and downregulation of VEGF was also verified by western blot analysis at the protein level. This study demonstrates that Endostar suppressed CNV in a rat model, which may be largely mediated by the downregulation of VEGF and other angiogenic molecules. PMID- 25544024 TI - Aberrant amygdala intrinsic functional connectivity distinguishes youths with bipolar disorder from those with severe mood dysregulation. AB - It remains unclear the degree to which youths with episodic mania (bipolar disorder; BD) vs. those with chronic, severe irritability (severe mood dysregulation, SMD) should be placed in similar or distinct diagnostic groups. Addressing this clinically meaningful question requires greater understanding of the neural alterations underlying both disorders. We evaluated resting state functional magnetic resonance imaging data of 53 youths (14 BD, 20 healthy volunteers (HV), and 19 SMD, ages 9-18.5 years). Seed regions of interest were the bilateral basolateral, superficial and centromedial amygdala, defined using the Juelich probabilistic atlas. We found a significant between-group difference in functional connectivity between the left basolateral amygdala and the medial aspect of the left frontal pole plus the posterior cingulate/precuneus. This finding was driven by hyperconnectivity among BD vs. HV or SMD youths. As with earlier data, these findings suggest that the pathophysiology of BD and SMD may differ. PMID- 25544028 TI - Breast cancer metastatic to the kidney with renal vein involvement. AB - The common sites of breast cancer metastases include bones, lung, brain, and liver. Renal metastasis from the breast is rare. We report a case of breast cancer metastatic to the kidney with extension into the renal vein. A 40-year-old woman had undergone left mastectomy for breast cancer at the age of 38. A gastric tumor, which was later proved to be metastasis from breast cancer, was detected by endoscopy. Computed tomography performed for further examination of the gastric tumor revealed a large left renal tumor with extension into the left renal vein. It mimicked a primary renal tumor. Percutaneous biopsy of the renal tumor confirmed metastasis from breast cancer. Surgical intervention of the stomach and the kidney was avoided, and she was treated with systemic chemotherapy. Breast cancer metastatic to the kidney may present a solitary renal mass with extension into the renal vein, which mimics a primary renal tumor. PMID- 25544027 TI - Enhancing outreach for persons with serious mental illness: 12-month results from a cluster randomized trial of an adaptive implementation strategy. AB - BACKGROUND: Few implementation strategies have been empirically tested for their effectiveness in improving uptake of evidence-based treatments or programs. This study compared the effectiveness of an immediate versus delayed enhanced implementation strategy (Enhanced Replicating Effective Programs (REP)) for providers at Veterans Health Administration (VA) outpatient facilities (sites) on improved uptake of an outreach program (Re-Engage) among sites not initially responding to a standard implementation strategy. METHODS: One mental health provider from each U.S. VA site (N = 158) was initially given a REP-based package and training program in Re-Engage. The Re-Engage program involved giving each site provider a list of patients with serious mental illness who had not been seen at their facility for at least a year, requesting that providers contact these patients, assessing patient clinical status, and where appropriate, facilitating appointments to VA health services. At month 6, sites considered non responsive (N = 89, total of 3,075 patients), defined as providers updating documentation for less than <80% of patients on their list, were randomized to two adaptive implementation interventions: Enhanced REP (provider coaching; N = 40 sites) for 6 months followed by Standard REP for 6 months; versus continued Standard REP (N = 49 sites) for 6 months followed by 6 months of Enhanced REP for sites still not responding. Outcomes included patient-level Re-Engage implementation and utilization. RESULTS: Patients from sites that were randomized to receive Enhanced REP immediately compared to Standard REP were more likely to have a completed contact (adjusted OR = 2.13; 95% CI: 1.09-4.19, P = 0.02). There were no differences in patient-level utilization between Enhanced and Standard REP sites. CONCLUSIONS: Enhanced REP was associated with greater Re-Engage program uptake (completed contacts) among sites not responding to a standard implementation strategy. Further research is needed to determine whether national implementation of Facilitation results in tangible changes in patient-level outcomes. TRIAL REGISTRATION: ISRCTN: ISRCTN21059161. PMID- 25544029 TI - Applicability of the EORTC/MSG criteria for IFD in clinical practice. AB - Invasive fungal disease (IFD) is a feared complication in patients with hematological malignancies. In 2008, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG) published updated criteria for the diagnostic workup within clinical studies for immunosuppressed patients with suspected fungal infection. We applied these criteria in a routine clinical setting with regard to their feasibility for bedside practice at our institution in a 1-year period. One hundred seventy consecutive patients with a recent history of chemotherapy-induced neutropenia (n = 100) or allogeneic stem cell recipients (n = 70) who had received a CT scan of the chest in search of pulmonary IFD were examined. We analyzed all available radiological and microbiological data according to the EORTC/MSG criteria. The quality of images was good in 94.7%, microbiological diagnostics performed in 94.1% patients. Five patients had histopathologic-proven IFD, 18 patients were classified as "probable," 55 patients as "possible" IFD, and 92 patients did not fulfill any criteria ("no IFD"). Microbiology revealed suggestive findings in 29 patients. These were either galactomannan antigen (Gm-AG) in serum (n = 18) and/or broncho-alveolar lavage (BAL) (n = 5). CT scan showed pulmonary infiltrates in 106 patients; 78 were classified as typical for IPA, further discriminated by morphology and number of nodules, as well as additional signs (halo, air crescent, cavity). We observed a better overall survival in patients without infiltrates compared to those with any type of infiltrate (p = 0.042) and a trend toward favorable survival in patients who had micronodular lesions (p = 0.058). We also found a higher probability of Gm-AG positivity in the group of allogeneic stem cell transplantation (allo-SCT) patients (p = 0.001) and a trend toward an association of Gm-AG positivity and positive findings on CT (p = 0.054). The applicability of criteria was good, both with regard to radiological and mycological evidence and sufficient for the categorization of IFD according to EORTC/MSG in the clinical setting. However, our findings suggest that feasibility improves with stringency of mycological workup, which is reflected in the two subgroups. Radiology harvests by far more suggestive findings which can only partly be correlated with mycological evidence. Although feasible, whether the EORTC/MSG criteria are the appropriate tool for early identification of IFD remains open for discussion. PMID- 25544030 TI - Late-onset hemophagocytic lymphohistiocytosis (HLH) in an adult female with Griscelli syndrome type 2 (GS2). PMID- 25544031 TI - Patterns of monocyte subpopulations and their surface expression of HLA-DR during adverse events after hematopoietic stem cell transplantation. AB - Human leukocyte antigen DR surface expression in "classical" CD14++CD16- (M1), "intermediate" CD14++CD16+ (M2), and "non-classical" CD14+CD16++ (M3) monocytes reflects the activation state of these cells. The full spectrum of monocyte and its function is still unknown. The present pilot study describes the monocyte subpopulations and their human leukocyte antigen DR expression during the post transplant period as well as during transplant-related adverse events of 30 pediatric patients and young adults with hemato-oncological malignancies and immunodeficiency disorders in comparison to healthy children and young adults. A significant change of the human leukocyte antigen DR expression in all three monocyte subpopulations during the period after bone marrow transplantation depending on the time after transplantation and adverse events could be recognized. Prior to and during sepsis or bacterial infection, a significant decrease in human leukocyte antigen DR expression occurred. A significant increase on CD14++CD16- monocytes could be observed during graft-versus-host disease. The alterations of human leukocyte antigen DR expression on the monocyte subpopulations during adverse events after hematopoietic stem cell transplantation may be a sign of changes in the capacity of these subpopulations. Moreover, human leukocyte antigen DR expression in monocyte subpopulations may be used to monitor treatment responses in these entities. PMID- 25544032 TI - Mavridis' area as a target for either selective or combined accumbens/ventral internal capsule deep brain stimulation. PMID- 25544033 TI - HR-MAS NMR spectroscopy: an innovative tool for the characterization of iron oxide nanoparticles tracers for molecular imaging. AB - The development of molecular imaging by MRI requires the use of contrast agents able to recognize specifically a peculiar target at the molecular level. Iron oxide nanoparticles grafted with small organic molecules represent an interesting platform for molecular imaging. The characterization of the surface of these nanoparticles is an important step in the development of these molecular agents, and HR-MAS NMR spectroscopy appears to be a very interesting tool. The use of 1D and 2D NMR spectra is indeed very helpful to investigate the covalent grafting of organic molecules at the nanoparticle surface. DOSY spectra could also be very helpful, but we will show here that it is not possible to obtain accurate DOSY spectra on iron oxide nanoparticles. PMID- 25544034 TI - Head and otolith morphology of the genera Hymenocephalus, Hymenogadus and Spicomacrurus (Macrouridae), with the description of three new species. AB - The fishes of the genus Hymenocephalus live over continental slope terrain, chiefly between 300 and 1000 m water depths, in all tropical oceans, except the eastern Pacific. They are characterized by an elongated light organ with two lenses, striations on jugular and thorax, and by an extraordinary development of sensory reception organs: strongly enlarged eyes, exceptionally large and specialized sagittal otoliths and extremely wide and deep head canals resembling caverns and housing the cephalic sensory organ for motion reception (lateral line system). The purpose of this study is to evaluate the potential that a detailed analysis of the head and otolith morphology can offer for distinguishing the various species and assessment of their interrelationships. About 500 specimens were investigated, representing all 22 nominal species of the genus Hymenocephalus, except for H. barbatulus (specimens of which could not be located), the two species of the related genus Hymenogadus and three of the four species of Spicomacrurus. Because of the delicate and thin nature of the head bones and head skin typical for the fishes of the genus Hymenocephalus and the deteriorating effects of formalin to the aragonitic otoliths, only a fraction of the studied specimens actually contributed useful data, although that fraction represented all species studied. Otoliths in particular and aspects of the cephalic canal system were found to contribute additional characters that help to verify the status of certain controversial species such as H. heterolepis, H. nascens and species within the H. striatissimus and H. grimaldii Groups. Hymenocephalus longiceps is revised to represent a junior synonym of H. longibarbis. Eight species groups are defined within the genus Hymenocephalus. Three new species are being described in the course of this review: H. iwamotoi from off northwestern Australia, H. sazonovi from the Sala y Gomez and Nazca Ridges, and H. punt from northern Somalia and the Gulf of Aden, now raising the count of valid species in the genus to a total of 24. The specializations of the sensory reception organs show a variety of developments with well-expressed phylogenetic polarities that are discussed in the context of their evolution and interrelationships. A well-documented case of polarity reversal of certain characters in the H. aterrimus Group is interpreted as a functional adaptation to migration of these fishes into a deeper water environment that favors different specializations of the sensory reception. PMID- 25544035 TI - [Self-rated health in adults: influence of poverty and income inequality in the area of residence]. AB - OBJECTIVE: To evaluate the influence of income inequality and poverty in the towns of Bogota, Colombia, on poor self-rated health among their residents. METHODS: The study was based on a multipurpose survey applied in Bogota-Colombia. A hierarchical data structure (individuals=level1, locations=level 2) was used to define a logit-type multilevel logistic model. The dependent variable was self perceived poor health, and local variables were income inequality and poverty. All analyses were controlled for socio-demographic variables and stratified by sex. RESULTS: The prevalence of self-reported fair or poor health in the study population was 23.2%. Women showed a greater risk of ill health, as well as men and women with a low educational level, older persons, those without work in the last week and persons affiliated to the subsidized health system. The highest levels of poverty in the city increased the risk of poor health. Cross-level interactions showed that young women and men with a low education level were the most affected by income inequality in the locality. CONCLUSIONS: In Bogota, there are geographical differences in the perception of health. Higher rates of poverty and income inequality were associated with an increased risk of self-perceived poor health. Notable findings were the large health inequalities at the individual and local levels. PMID- 25544036 TI - N-terminal pro-brain natriuretic peptide in acute Kawasaki disease correlates with coronary artery involvement. AB - BACKGROUND: We have lately documented the importance of N-terminal pro-brain natriuretic peptide in aiding the diagnosis of Kawasaki disease. OBJECTIVES: We sought to investigate the potential value of N-terminal pro-brain natriuretic peptide pertaining to the prediction of coronary artery dilatation (Z-score>2.5) and/or of resistance to intravenous immunoglobulin therapy. We hypothesised that increased serum N-terminal pro-brain natriuretic peptide level correlates with increased coronary artery dilatation and/or resistance to intravenous immunoglobulin. METHODS: We carried out a prospective study involving newly diagnosed patients treated with 2 g/kg intravenous immunoglobulin within 5-10 days of onset of fever. Echocardiography was performed in all patients at onset, then weekly for 3 weeks, then at month 2, and month 3. Coronary arteries were measured at each visit, and coronary artery Z-score was calculated. All the patients had N-terminal pro-brain natriuretic peptide serum level measured at onset, and the Z-score calculated. RESULTS: There were 109 patients enrolled at 6.58+/-2.82 days of fever, age 3.79+/-2.92 years. High N-terminal pro-brain natriuretic peptide level was associated with coronary artery dilatation at onset in 22.2 versus 5.6% for normal N-terminal pro-brain natriuretic peptide levels (odds ratio 4.8 [95% confidence interval 1.05-22.4]; p=0.031). This was predictive of cumulative coronary artery dilatation for the first 3 months (p=0.04-0.02), but not during convalescence at 2-3 months (odds ratio 1.28 [95% confidence interval 0.23-7.3]; p=non-significant). Elevated N-terminal pro-brain natriuretic peptide levels did not predict intravenous immunoglobulin resistance, 15.3 versus 13.5% (p=1). CONCLUSION: Elevated N-terminal pro-brain natriuretic peptide level correlates with acute coronary artery dilatation in treated Kawasaki disease, but not with intravenous immunoglobulin resistance. PMID- 25544037 TI - Gelsolin is a potential cellular target for cotinine to regulate the migration and apoptosis of A549 and T24 cancer cells. AB - In the present work, we have investigated the effect of cotinine, the major metabolite of nicotine on the A549 and T24 cell lines in the context of structural and quantitative changes of F-actin, gelsolin and vimentin. The chosen cell lines constitute the established experimental models for lung and bladder cancers, respectively, in the case of which, smoking cigarettes is one of the key factor increasing their incidence rate significantly. In order to evaluate the impact of cotinine on the viability and proliferation of A549 and T24 cells, the MTT assay was performed. The organization and distribution of F-actin, gelsolin and vimentin were examined using conventional and confocal fluorescence microscopy. The levels of F-actin and gelsolin as well as the percentages of apoptotic and dead cells were assessed using the image-based cytometer. The ultrastructural changes of cotinine-treated A549 and T24 cells were visualized under the transmission electron microscopy. We have shown here that cotinine enhances the survival and proliferation rate of A549 and T24 cells. We have also found that in A549 cells, but not in T24 cell line, cotinine acted stimulating on the vimentin filament network. Furthermore, the increase in the fluorescence intensity of gelsolin upon the addition of cotinine to the T24 cells was found to be correlated with the lack of apoptosis induction as well as the increase of migration potential of these cells. On the other hand, the cotinine-induced decrease in the fluorescence intensity of gelsolin was associated with the increase in the percentages of apoptotic A549 cells and the decreased migratory ability of these cells. Based on the obtained results, we propose that the gelsolin is an important cellular target for cotinine, through which this compound influences on the basic processes involved in neoplastic transformation and metastasis, such as migration and apoptosis. PMID- 25544038 TI - Sire effect on early and late embryonic death in French Holstein cattle. AB - We investigated the effect of maternal sire on early pregnancy failure (between D0, day of insemination and D90) in their progeny during the first and second lactations (n=3508) in the Holstein breed. The estimated breeding value (EBV) for cow fertility of 12 bulls (reliability?0.95) was used to create the following three groups: low, medium and high EBV (EBV from -0.7 to 1 expressed as genetic standard deviation relative to the mean of the breed). In their daughters (93 to 516 per bull), progesterone measurement was carried out on the day of artificial insemination (AI; D0) to check whether the cows were in the follicular phase and on D18 to 25 to assess non-fertilisation-early embryonic mortality (NF-EEM). Late embryonic mortality (LEM) and early foetal death (FD) were determined by ultrasonography on D45 and D90 and by the return to oestrus after the first AI. Frequencies of NF-EEM, LEM, FD and pregnancy were 33.3%, 11.7%, 1.4% and 48.5% and incidences were 35.1, 19.0, 2.7 and 51.1, respectively. Sire EBV was significantly related to the incidences of pregnancy failure between D0 and D90, fertilisation failure-early embryonic mortality (FF-EEM) and LEM but not to the incidence of FD between D45 and D90 of pregnancy. The relative risk (RR) of FF EEM was significantly higher (RR=1.2; P<0.05) for the progeny group of low EBV bulls when compared with high EBV bulls. The same effect was observed when comparing LEM of the progeny groups from the low EBV bulls to those from moderate and high EBV bulls (RR, respectively, of 1.3 and 1.4; P<005). The incidence of FF EEM was significantly higher when cows were inseminated before 80 days postpartum compared with later, and for the extreme values of the difference between milk fat and protein content measured during the first 3 months of lactation. FF-EEM was also significantly related to the year of observation. The incidence of LEM was higher for the highest producing cows and was influenced by interaction between milk yield*lactation rank and milk yield*milk protein content. In conclusion, this study showed large differences in early pregnancy failure between progeny groups and highlights the interest of accurate characterisation of embryonic death in order to identify potential candidate genes for female fertility. PMID- 25544039 TI - Characterization of angiotensin I-converting enzyme from anterior gills of the mangrove crab Ucides cordatus. AB - Angiotensin I-converting enzyme (ACE) is a well-known metallopeptidase that is found in vertebrates, invertebrates and bacteria. We isolated from the anterior gill of the crab Ucides cordatus an isoform of ACE, here named crab-ACE, which presented catalytic properties closely resembling to those of mammalian ACE. The enzyme was purified on Sepharose-lisinopril affinity chromatography to apparent homogeneity and a band of about 72 kDa could be visualized after silver staining and Western blotting. Assays performed with fluorescence resonance energy transfer (FRET) selective ACE substrates Abz-FRK(Dnp)P-OH, Abz-SDK(Dnp)P-OH and Abz-LFK(Dnp)-OH, allowed us to verify that crab-ACE has hydrolytic profile very similar to that of the ACE C-domain. In addition, we observed that crab-ACE can hydrolyze the ACE substrates, angiotensin I and bradykinin. The enzyme was strongly inhibited by the specific ACE inhibitor lisinopril (Ki of 1.26 nM). However, in contrast to other ACE isoforms, crab-ACE presented a very particular optimum pH, being the substrate Abz-FRK(Dnp)-P-OH hydrolyzed efficiently at pH 9.5. Other interesting characteristic of crab-ACE was that the maximum hydrolytic activity was reached at around 45 degrees C. The description of an ACE isoform in Ucides cordatus is challenging and may contribute to a better understanding of the biochemical function of this enzyme in invertebrates. PMID- 25544040 TI - Injectable alginate-O-carboxymethyl chitosan/nano fibrin composite hydrogels for adipose tissue engineering. AB - Injectable, biodegradable scaffolds are required for soft tissue reconstruction owing to its minimally invasive approach. Such a scaffold can mimic the native extracellular matrix (ECM), provide uniform distribution of cells and overcome limitations like donor site morbidity, volume loss, etc. So, here we report two classes of biocompatible and biodegradable hydrogel blend systems namely, Alginate/O-carboxymethyl chitosan (O-CMC) and Alginate/poly (vinyl alcohol) (PVA) with the inclusion of fibrin nanoparticles in each. The hydrogels were prepared by ionic cross-linking method. The developed hydrogels were compared in terms of its swelling ratio, degradation profile, compressive strength and elastic moduli. From these preliminary findings, it was concluded that Alginate/O-CMC formed a better blend for tissue engineering applications. The potential of the formed hydrogel as an injectable scaffold was revealed by the survival of adipose derived stem cells (ADSCs) on the scaffold by its adhesion, proliferation and differentiation into adipocytes. Cell differentiation studies of fibrin incorporated hydrogel scaffolds showed better differentiation was confirmed by Oil Red O staining technique. These injectable gels have potential in soft tissue regeneration. PMID- 25544041 TI - Hemagglutinin glycosylation modulates the pathogenicity and antigenicity of the H5N1 avian influenza virus. AB - The location and number of glycosylation in HA proteins exhibit large variations among H5 subtype avian influenza viruses (AIVs). To investigate the effect of glycosylation in the globular head of HA on the pathogenicity and antigenicity of H5N1 AIVs, seven rescued AIVs differing in their glycosylation patterns (144N, 158N and 169N) within the HA globular head of A/Mallard/Huadong/S/2005 were generated using site directed mutagenesis. Results showed that loss of glycosylation 158N was the prerequisite for H5 AIV binding to the alpha2,6-linked receptor. Only in conjunction with the removal of the 158N glycosylation, the H5 AIVs harboring both 144N and 169N glycosylations obtained an optimal binding preference to the alpha2,6-linked receptor. Compared with the wild-type virus, growth of viruses lacking glycosylation at either 158N or 169N was significantly reduced both in MDCK and A549 cells, while replication of viruses with additional glycosylation 144N was significantly promoted. Mutant viruses with loss of 158N or 169N glycosylation sites showed increased pathogenicity, systemic spread and pulmonary inflammation in mice compared to the wild-type H5N1 virus. In addition, chicken studies demonstrated that inactivated de-glycosylation 169N mutant induced cross-reaction HI and neutralization antibody against various clades of H5N1 AIVs. Moreover, this type of glycan pattern vaccine virus provided better cross-protection in chickens compared to wild-type vaccine virus. Thus, the glycosylation alteration of HA should be considered in the global surveillance and vaccine design of H5 subtype AIVs. PMID- 25544042 TI - Birth defects in the newborn population: race and ethnicity. AB - BACKGROUND: Racial variability in certain prenatal risk factors, such as prenatal vitamin supplementation and termination of pregnancy for fetal anomaly, has altered the racial prevalence of birth defects. Analysis of a single large representative population is required to analyze current racial differences in the prevalence of birth defects in the United States. METHODS: This is a population-based cross-sectional study to analyze racial differences in the prevalence of birth defects. We reviewed all live births in the 2008 Nationwide Inpatient Sample (NIS) database and determined birth prevalence of 55 selected birth defects in Caucasians. We then calculated the relative risk of these birth defects in African-Americans, Hispanics, and Asians relative to Caucasians. RESULT: Overall birth defect prevalence was 29.2 per 1000 in a cohort of 1,048,252 live births, of which 51% were Caucasians. Compared with Caucasians, the risk of overall birth defects was lower in African-Americans (relative risk = 0.9, confidence interval 0.8-0.9) and Hispanics (relative risk = 0.9, confidence interval 0.8-0.9). The risk of overall birth defects was similar in Caucasians and Asians. Relative to the Caucasians, African-Americans had a lower risk of cardiac, genitourinary, and craniofacial malformations but a higher risk of musculoskeletal malformations. Hispanics had a lower risk of genitourinary and gastrointestinal malformation. Asians had a higher risk of craniofacial and musculoskeletal malformations. CONCLUSION: This is a comprehensive description of racial differences in the risk of birth defects in the United States. Observed racial differences in the risk of birth defects may be related to genetic susceptibilities, to cultural or social differences that could modify exposures, or to the many potential combinations between susceptibilities and exposures. PMID- 25544043 TI - Topological models of heteromeric protein assemblies from mass spectrometry: application to the yeast eIF3:eIF5 complex. AB - Describing, understanding, and modulating the function of the cell require elucidation of the structures of macromolecular assemblies. Here, we describe an integrative method for modeling heteromeric complexes using as a starting point disassembly pathways determined by native mass spectrometry (MS). In this method, the pathway data and other available information are encoded as a scoring function on the positions of the subunits of the complex. The method was assessed on its ability to reproduce the native contacts in five benchmark cases with simulated MS data and two cases with real MS data. To illustrate the power of our method, we purified the yeast initiation factor 3 (eIF3) complex and characterized it by native MS and chemical crosslinking MS. We established substoichiometric binding of eIF5 and derived a model for the five-subunit eIF3 complex, at domain level, consistent with its role as a scaffold for other initiation factors. PMID- 25544044 TI - Attachment of cell-binding ligands to arginine-rich cell-penetrating peptides enables cytosolic translocation of complexed siRNA. AB - Cell-penetrating peptides (CPPs), such as nona-arginine (9R), poorly translocate siRNA into cells. Our studies demonstrate that attaching 9R to ligands that bind cell surface receptors quantitatively increases siRNA uptake and importantly, allows functional delivery of complexed siRNA. The mechanism involved accumulation of ligand-9R:siRNA microparticles on the cell membrane, which induced transient membrane inversion at the site of ligand-9R binding and rapid siRNA translocation into the cytoplasm. siRNA release also occurred late after endocytosis when the ligand was attached to the L isoform of 9R, but not the protease-resistant 9DR, prolonging mRNA knockdown. This critically depended on endosomal proteolytic activity, implying that partial CPP degradation is required for endosome-to-cytosol translocation. The data demonstrate that ligand attachment renders simple polycationic CPPs effective for siRNA delivery by restoring their intrinsic property of translocation. PMID- 25544045 TI - The novolactone natural product disrupts the allosteric regulation of Hsp70. AB - The highly conserved 70 kDa heat shock proteins (Hsp70) play an integral role in proteostasis such that dysregulation has been implicated in numerous diseases. Elucidating the precise role of Hsp70 family members in the cellular context, however, has been hampered by the redundancy and intricate regulation of the chaperone network, and relatively few selective and potent tools. We have characterized a natural product, novolactone, that targets cytosolic and ER localized isoforms of Hsp70 through a highly conserved covalent interaction at the interface between the substrate-binding and ATPase domains. Biochemical and structural analyses indicate that novolactone disrupts interdomain communication by allosterically inducing a conformational change in the Hsp70 protein to block ATP-induced substrate release and inhibit refolding activities. Thus, novolactone is a valuable tool for exploring the requirements of Hsp70 chaperones in diverse cellular contexts. PMID- 25544046 TI - The complex mechanism of antimycobacterial action of 5-fluorouracil. AB - A combination of chemical genetic and biochemical assays was applied to investigate the mechanism of action of the anticancer drug 5-fluorouracil (5-FU), against Mycobacterium tuberculosis (Mtb). 5-FU resistance was associated with mutations in upp or pyrR. Upp-catalyzed conversion of 5-FU to FUMP was shown to constitute the first step in the mechanism of action, and resistance conferred by nonsynonymous SNPs in pyrR shown to be due to derepression of the pyr operon and rescue from the toxic effects of FUMP and downstream antimetabolites through de novo production of UMP. 5-FU-derived metabolites identified in Mtb were consistent with the observed incorporation of 5-FU into RNA and DNA and the reduced amount of mycolyl arabinogalactan peptidoglycan in 5-FU-treated cells. Conditional depletion of the essential thymidylate synthase ThyX resulted in modest hypersensitivity to 5-FU, implicating inhibition of ThyX by fluorodeoxyuridylate as a further component of the mechanism of antimycobacterial action of this drug. PMID- 25544047 TI - [Editor's commentary. Greetings to Professor Attila Horvath on the occasion of his 75. birthday by his colleagues at the Institute of Skin and Sexually Transmitted Diseases and Cutaneous Cancers, Semmelweis University, Budapest, Hungary]. PMID- 25544048 TI - [Sexually transmitted coinfections. HIV coinfections]. AB - Coinfections of sexually transmitted infections are frequent due to the same transmission routes which may facilitate the transmission of other sexually transmitted infections. Sexually transmitted coinfections are associated with atypical and generally more severe clinical features, more complications, resistency to treatment, unfavourable outcome, and worse prognosis. Sexually transmitted infections may increase the likelihood of acquiring and transmission of HIV infection. The authors summarize the most important characteristics of sexually transmitted infections (such as HIV and hepatitis B virus, HIV and hepatitis C virus, HIV and syphilis, HIV and gonorrhoeae, HIV and chlamydia coinfections). These infections are more frequent in HIV infected patients than in the normal population. The shared transmission routes, impairment of the immune response, elevated cytokine levels and the associated inflammatory milieu produce local tissue damage, breaches in mucosal epithelium, which increases the risk of human immunodeficiency virus infection. Regular screening for sexually transmitted infections, use of more sensitive diagnostic methods, improved reporting and avoidance of unsafe sexual behaviour among certain subpopulations as well as education are essential in the prevention of sexually transmitted coinfections. PMID- 25544050 TI - [Genitourethral infections caused by D-K serotypes of Chlamydia trachomatis]. AB - Sexually transmitted infections of the urogenital tract are most commonly caused by the intracellular bacteria Chlamydia trachomatis worldwide, resulting the clinical picture of acute urethritis in men as well as urethritis and endocervicitis in women. As women often present with few symptoms only or a completely symptom-free disease course, one of the most important long-term complications is chronic pelvic inflammatory disease often followed by the development of infertility caused by chronic scar formation. Well-organized screening programs are considered to have a leading role in the prevention of disease spreading and long lasting unwanted complications. Antibiotic treatment options are often influenced by special circumstances, such as pregnancy and several complicated clinical forms. The aims of the authors are to give a concise review on the current knowledge regarding Chlamydia trachomatis infections and summarize typical clinical signs, modern diagnostic techniques as well as accepted treatment protocols and basic aspects of screening. PMID- 25544049 TI - [Skin symptoms associated with human immunodeficiency virus infection]. AB - The recently observed accelerated increase of human immunodeficiency virus infection in Hungary poses a major public concern for the healthcare system. Given the effective only but not the curative therapy, prevention should be emphasized. Current statistics estimate that about 50% of the infected persons are not aware of their human immunodeficiency virus-positivity. Thus, early diagnosis of the infection by serological screening and timely recognition of the disease-associated symptoms are crucial. The authors' intention is to facilitate early infection detection with this review on human immunodeficiency virus associated skin symptoms, and highlight the significance of human immunodeficiency virus care in the everyday medical practice. PMID- 25544051 TI - [Anal cytology]. AB - INTRODUCTION: The incidence of anal cancer has increased in recent decades, particularly among human immunodeficiency virus infected men who have sex with men. Anal intraepithelial neoplasia is a potential precursor lesion of anal cancer. Anal cytology is the primary screening test for anal intraeptithelial neoplasia. AIM: The authors aimed to analyze the results of anal cytology of patients with human immunodeficiency virus infection at the National Centre of STD, Department of Dermatology, Dermatooncology and Venereology, Semmelweis University. METHOD: 155 anal cytological examinations were performed in 140 patients between November 1, 2012 and August 31, 2014. RESULTS: 44% of patients were found to have anal dysplasia, and only 1.6% of patients had high-grade lesions. This rate is lower as compared to published studies including larger number of patients. CONCLUSIONS: The study underlines the necessity of screening for anal lesions in the population at-risk. PMID- 25544052 TI - [Yeast species in vulvovaginitis candidosa]. AB - INTRODUCTION: Vulvovaginal candidiasis is the most common mycosis, however, the available information about antifungal susceptibilities of these yeasts is limited. AIM: To compare the gold standard fungal culture with a new molecular identification method and report the incidence of yeast species in vulvovaginitis candidosa. METHOD: The authors studied 370 yeasts isolated from vulvovaginal candidiasis and identified them by phenotypic and molecular methods. RESULTS: The most common species was Candida albicans (85%), followed by Candida glabrata, and other Candida species. CONCLUSION: At present there are no recommendations for the evaluation of antifungal susceptibility of pathogenic fungal species occurring in vulvovaginal candidiasis and the natural antifungal resistance of the different species is known only. Matrix Assisted Laser Desorption Ionization Time of Flight identification can be used to differentiate the fluconazole resistant Candida dubliniensis and the sensitive Candida albicans strains. PMID- 25544053 TI - [Syphilitic glomerulonephritis: case report and review of the literature]. AB - The authors report the history of a patient with syphilitic glomerulonephritis, a rare complication of syphilis. The patient was admitted to the hospital with clinical symptoms of neurosyphilis. During his hospital stay urine analysis revealed an extremely high proteinuria, that had not been known before. Intravenous penicillin treatment improved the renal protein loss, but it took a total of six months until complete resolution was achieved. The serology that confirmed the syphilis, the concomitant nephrotic syndrome and the improvement after penicillin therapy met the criteria of syphilitic glomerulonephritis. This case prompted the authors to review the literature about this rare complication of syphilis that has a great clinical significance. PMID- 25544054 TI - [Lymphogranuloma venereum: the first Hungarian cases]. AB - Lymphogranuloma venereum is a sexually transmitted infection caused by the Chlamydia trachomatis serovars L1-3. It has been found to be endemic in tropical countries. In the last decades several cases have been reported in Western Europe, particularly in men who have sex with men population infected with human immunodeficiency virus. The authors present three cases of lymphogranuloma venereum infections, observed at their department in 2013 and 2014. The three human immunodeficiency virus infected patients who belonged to men who have sex with men population had casual sexual contacts in Western Europe. The symptoms included urethral discharge, discomfort and inguinal lymphadenomegaly in two patients, and rectal pain, discharge and perianal ulceration in one patient. The diagnosis was confirmed by nucleic acid amplification test performed in samples obtained from urethral discharge and exudate of perianal ulcer; lymphogranuloma venereum 2b serovars were demonstrated in two patients and serovar 2 in one patient. Doxycyclin (daily dose of two times 100 mg for 21 days) resolved the symptoms in all cases. The authors conclude that lymphogranuloma venereum is a diagnostic challenge in Hungary, too. It is important to be aware of the altered clinical features of this disease to prevent complications and spreading. PMID- 25544055 TI - Emergency percutaneous aortic valve replacement in a patient with a cervical spine fracture secondary to critical aortic stenosis. AB - An 81 year-old female with severe aortic stenosis was admitted electively to determine her anatomic suitability for trans-catheter aortic valve implantation (TAVI). Transthoracic echocardiogram prior to referral confirmed critical aortic stenosis with a mean transaortic valve gradient of 106mmHg, aortic valve area (AVA) 0.6cm(2) and dimensionless index (DI) 0.18. She reported a significant symptom burden with New York Heart Association Class III dyspnoea, four episodes of syncope in the month prior to admission and exertional chest pain. PMID- 25544057 TI - Corrigendum: The complex becomes more complex: protein-protein interactions of SnRK1 with DUF581 family proteins provide a framework for cell- and stimulus type specific SnRK1 signaling in plants. AB - [This corrects the article on p. 54 in vol. 5, PMID: 24600465.]. PMID- 25544056 TI - Benzodiazepinone derivatives protect against endoplasmic reticulum stress mediated cell death in human neuronal cell lines. AB - Endoplasmic reticulum (ER) stress causes neuronal dysfunction followed by cell death and is recognized as a feature of many neurodegenerative diseases. Using a phenotypic screen, we recently identified benzodiazepinone derivatives that reduce ER stress-mediated apoptosis in a rat neuronal progenitor cell line (CSM14.1). Herein we describe how structure-activity relationship (SAR) studies around these screening hits led to compounds that display robust cytoprotective activity against thapsigargin-induced ER stress in SH-SY5Y and H4 human neuronal cell lines. We demonstrate that the most potent of these derivatives, compound 4hh, inhibits the activation of p38 MAP kinase (p38) and c-Jun N-terminal kinase (JNK), protein kinases that are downstream signal effectors of the unfolded protein response (UPR). Compound 4hh specifically protects against thapsigargin induced cell death and displays no protection against other insults known to induce cellular stress or activate p38. However, compound 4hh provides moderate inhibition of p38 activity stimulated by compounds that disrupt calcium homeostasis. Our data indicate that probe compound 4hh is a valuable small molecule tool that can be used to investigate the effects of ER stress on human neurons. This approach may provide the basis for the future development of therapeutics for the treatment of neurodegenerative diseases. PMID- 25544058 TI - The Kantian brain: brain dynamics from a neurophenomenological perspective. AB - Current research on spontaneous, self-generated brain rhythms and dynamic neural network coordination cast new light on Immanuel Kant's idea of the 'spontaneity' of cognition, that is, the mind's capacity to organize and synthesize sensory stimuli in novel, unprecedented ways. Nevertheless, determining the precise nature of the brain-cognition mapping remains an outstanding challenge. Neurophenomenology, which uses phenomenological information about the variability of subjective experience in order to illuminate the variability of brain dynamics, offers a promising method for addressing this challenge. PMID- 25544060 TI - Clinical and diagnostic problems of desmoid-type fibromatosis of the mesentery: case report and review of the literature. AB - BACKGROUND: Desmoid-type fibromatosis (DTF) is a "locally aggressive, but not metastasizing" proliferation of soft tissues that is difficult to diagnose pre operatively. Surgical en bloc resection of abdominal DTF can be difficult or an overtreatment. The diagnosis is therefore crucial for the decision making to minimize unnecessary morbidity. CASE REPORT: A 33-year old female patient with an incidental intra-operative diagnosis of a 20 cm mesenteric mass involving the duodenum, jejunum, ileum and right colon underwent extended resection for a DTF. A review of the literature, limited only to mesenteric localization of DTF, was performed for the diagnosis, treatment and outcome. RESULTS: Twentyfive cases of DTF have been analyzed. Pre-operative diagnosis was suspected in 20% but 95,2% of all the patients underwent resection without pre-operative diagnosis. In two cases, intra-operative, frozen section diagnosis was unsuccessfully attempted. Complications were reported in 12%, recurrence in 4%, and mortality in 0% of the patients. CONCLUSION: Pre-operative diagnosis of mesenteric DTF is challenging in most cases, but it can avoid unnecessary extended surgery. Efforts should be made to achieve a correct pre-operative diagnosis based on more reliable imaging and pathological features, to help in decision making. PMID- 25544059 TI - Substoichiometric hydroxynonenylation of a single protein recapitulates whole cell-stimulated antioxidant response. AB - Lipid-derived electrophiles (LDEs) that can directly modify proteins have emerged as important small-molecule cues in cellular decision-making. However, because these diffusible LDEs can modify many targets [e.g., >700 cysteines are modified by the well-known LDE 4-hydroxynonenal (HNE)], establishing the functional consequences of LDE modification on individual targets remains devilishly difficult. Whether LDE modifications on a single protein are biologically sufficient to activate discrete redox signaling response downstream also remains untested. Herein, using T-REX (targetable reactive electrophiles and oxidants), an approach aimed at selectively flipping a single redox switch in cells at a precise time, we show that a modest level (~34%) of HNEylation on a single target is sufficient to elicit the pharmaceutically important antioxidant response element (ARE) activation, and the resultant strength of ARE induction recapitulates that observed from whole-cell electrophilic perturbation. These data provide the first evidence that single-target LDE modifications are important individual events in mammalian physiology. PMID- 25544061 TI - Tailoring the properties of surface-immobilized azobenzenes by monolayer dilution and surface curvature. AB - Photoswitching in densely packed azobenzene self-assembled monolayers (SAMs) is strongly affected by steric constraints and excitonic coupling between neighboring chromophores. Therefore, control of the chromophore density is essential for enhancing and manipulating the photoisomerization yield. We systematically compare two methods to achieve this goal: First, we assemble monocomponent azobenzene-alkanethiolate SAMs on gold nanoparticles of varying size. Second, we form mixed SAMs of azobenzene-alkanethiolates and "dummy" alkanethiolates on planar substrates. Both methods lead to a gradual decrease of the chromophore density and enable efficient photoswitching with low-power light sources. X-ray spectroscopy reveals that coadsorption from solution yields mixtures with tunable composition. The orientation of the chromophores with respect to the surface normal changes from a tilted to an upright position with increasing azobenzene density. For both systems, optical spectroscopy reveals a pronounced excitonic shift that increases with the chromophore density. In spite of exciting the optical transition of the monomer, the main spectral change in mixed SAMs occurs in the excitonic band. In addition, the photoisomerization yield decreases only slightly by increasing the azobenzene-alkanethiolate density, and we observed photoswitching even with minor dilutions. Unlike in solution, azobenzene in the planar SAM can be switched back almost completely by optical excitation from the cis to the original trans state within a short time scale. These observations indicate cooperativity in the photoswitching process of mixed SAMs. PMID- 25544062 TI - A primary fish gill cell culture model to assess pharmaceutical uptake and efflux: evidence for passive and facilitated transport. AB - The gill is the principle site of xenobiotic transfer to and from the aqueous environment. To replace, refine or reduce (3Rs) the large numbers of fish used in in vivo uptake studies an effective in vitro screen is required that mimics the function of the teleost gill. This study uses a rainbow trout (Oncorhynchus mykiss) primary gill cell culture system grown on permeable inserts, which tolerates apical freshwater thus mimicking the intact organ, to assess the uptake and efflux of pharmaceuticals across the gill. Bidirectional transport studies in media of seven pharmaceuticals (propranolol, metoprolol, atenolol, formoterol, terbutaline, ranitidine and imipramine) showed they were transported transcellularly across the epithelium. However, studies conducted in water showed enhanced uptake of propranolol, ranitidine and imipramine. Concentration equilibrated conditions without a concentration gradient suggested that a proportion of the uptake of propranolol and imipramine is via a carrier-mediated process. Further study using propranolol showed that its transport is pH dependent and at very low environmentally relevant concentrations (ng L(-1)), transport deviated from linearity. At higher concentrations, passive uptake dominated. Known inhibitors of drug transport proteins; cimetidine, MK571, cyclosporine A and quinidine inhibited propranolol uptake, whilst amantadine and verapamil were without effect. Together this suggests the involvement of specific members of SLC and ABC drug transporter families in pharmaceutical transport. PMID- 25544063 TI - Evaluation of the toxic effects of brominated compounds (BDE-47, 99, 209, TBBPA) and bisphenol A (BPA) using a zebrafish liver cell line, ZFL. AB - The toxic effects of three polybrominated diphenyl ether (PBDE) congeners (BDE 47, -99, and -209), tetrabromobisphenol A (TBBPA) and bisphenol A (BPA), were evaluated by determining their 24h and 96 h median lethal concentrations using a zebrafish liver cell line, ZFL. It was found that BDE-47, BDE-99 and TBBPA showed comparative cytotoxicity within the range of 1.2-4.2 MUM, and were more toxic than BPA (367.1 MUM at 24 h and 357.6 MUM at 96 h). However, BDE-209 induced only 15% lethality with exposures up to 25 MUM. The molecular stresses of BDE-47, -99, TBBPA and BPA involved in thyroid hormone (TH) homeostasis and hepatic metabolism were also investigated. Using a reporter gene system to detect zebrafish thyroid hormone receptor beta (zfTRbeta) transcriptional activity, the median effective concentration of triiodothyronine (T3) was determined to be 9.2*10(-11) M. BDE 47, BDE-99, TBBPA and BPA alone, however, did not exhibit zfTRbeta agonistic activity. BPA displayed T3 (0.1 nM) induced zfTRbeta antagonistic activity with a median inhibitory concentration of 19.3 MUM. BDE-47, BDE-99 and TBBPA displayed no antagonistic effects of T3-induced zfTRbeta activity. Target gene expressions were also examined under acute exposures. The significant inhibition of different types of deiodinases by all of the test chemicals indicated TH circulation disruption. All four chemicals, especially BPA, were able to affect transcripts of phase II hepatic metabolizing enzymes (UGT2A1, SULT1) in vitro. In conclusion, the zfTRbeta reporter gene system developed here helps delineate an in vitro model to enable the analysis of the TH disruption effects of environmental pollutants in fish. BPA and the brominated compounds tested were able to disrupt the TH system at the gene expression level, probably through the deiodination pathways. PMID- 25544064 TI - Who accesses complementary therapies and why?: An evaluation of a cancer care service. AB - INTRODUCTION: Advances in cancer diagnosis and treatment have resulted in longer survival, meaning patients are living with a chronic-type condition. Therefore the needs of such patients have changed placing greater emphasis on survivorship, such as impact on quality of life and sleep patterns. Evidence suggests complementary therapies positively impact not only on the cancer patient's quality of life but also on family members and friends. METHODOLOGY: This service evaluation examines self-reported benefits following a course of complementary therapy offered by a local cancer charity. RESULTS: Analysis of self-reported sleep scores and perceived quality of life experiences confirmed a number of trends relating to the demographics of people accessing the complementary therapy service. CONCLUSION: Results suggest the complementary therapies provided by Action Cancer significantly improved clients' quality of life. Based on these findings the authors make a number of recommendations in relation to the use of complementary therapies by cancer patients. PMID- 25544065 TI - Assessing the potential risk of rupture of abdominal aortic aneurysms. AB - Abdominal aortic aneurysms (AAAs) involve complex interplays between inflammatory and biomechanical factors that can be elucidated with anatomical and functional imaging. Although AAA size has been well-established in the literature to correlate with risk of rupture (and subsequent need for vascular intervention), there are other less-well-known characteristics about AAAs that also contribute to higher risk of rupture. This review focuses on biomechanical, radiological, and epidemiological characteristics of AAAs that are associated with higher rupture risk. For clinicians, knowing and considering a wide variety of risk factors in addition to AAA size is important to initiate early and proper intervention for AAA repair. Although there is no official quantitative risk score of AAA rupture risk that takes other non-size-related variables into account, if clinicians are aware of these other parameters, it is hoped that intervention can be appropriately performed for higher-risk AAAs that have not met the size-threshold for elective repair. PMID- 25544066 TI - IGFBP-2: The dark horse in metabolism and cancer. AB - The ubiquitous nature of the IGF system, expressed early in embryonic development throughout postnatal and adult life, indicates a key role for this system in human biology. Studies of transgenic mice over-expressing components of the IGF system or mice with disruptions of the same genes have clearly shown that the IGF system plays an important role in vivo. The activity of the IGF ligands, elicited via their receptors and transduced by various intracellular signal pathways, is modulated by the IGFBPs. Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in the nervous system, peripheral tissue and organs. Besides binding to IGFs in the circulation, these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix and cell surface proteoglycans and integrin receptors. In addition to these "local" peri cellular activities of IGFBP-2, it became evident that IGFBP-2 exerts other key functions within the cell. In the cytoplasm IGFBP-2, most likely in the absence of the IGFs, interacts with regulatory proteins including transcription factors and cytoplasm-nuclear transporters. Within the nucleus IGFBP-2, directly or indirectly, promotes transcriptional activation of specific genes. These intrinsic activities of IGFBP-2 are mediated via specific functional domains. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumor growth and metastasis. PMID- 25544067 TI - Three new species of Ammonicera from the Eastern Pacific coast of North America, with redescriptions and comments on other species of Omalogyridae (Gastropoda, Heterobranchia). AB - The family Omalogyridae comprises some of the smallest known marine snails. Like all micromolluscs, they have been historically neglected and are underrepresented in faunistic surveys. Based on a few focused studies of the family, 15 valid omalogyrid species were previously recognised in the Indian and Pacific Oceans. To these, we add 3 new species based on a morphological analysis of material in the dry collection of the Natural History Museum of Los Angeles County, applying light and scanning electron microscopies. The new species, Ammonicera mcleani, A. mexicana and A. sleursi, are the first omalogyrid species described from the Eastern Pacific coast of North America. Redescriptions of the Australian omalogyrids Ammonicera sucina (Laseron, 1954) and Omalogyra liliputia (Laseron, 1954) are also presented, detailing for the first time ultrastructural aspects of their shell morphology. Additionally, we present here the first record of Ammonicera binodosa Sleurs, 1985b in Sri Lanka, introduce the new combination Ammonicera vangoethemi (Sleurs, 1985c) for Omalogyra vangoethemi, and formally remove Transomalogyra Palazzi & Gaglini, 1979 from Omalogyridae by fixing its type species as Homalogyra densicostata Jeffreys, 1884. Finally, we present lists, geographic records and a bibliography of all currently recognised omalogyrid species in the Indian, Pacific and Antarctic Oceans, as well as an update to a previously published compilation of the Atlantic and Mediterranean representatives of the family. PMID- 25544068 TI - Two new species of dark Neoperla (Plecoptera: Perlidae) from Oriental Realm of China. AB - Two new species of the perlid genus Neoperla, N. tadpolata Li & Muranyi, sp. nov. and N. yunnana Li & Wang, sp. nov. are proposed from Guangxi Zhuang Autonomous Region and Yunnan Province of China, respectively. They are both typical members of the N. montivaga species group and the taxonomic relationships are discussed with related congeners of the group. PMID- 25544069 TI - Rhinobatos whitei, a new shovelnose ray (Batoidea: Rhinobatidae) from the Philippine Archipelago. AB - A new shovelnose ray, Rhinobatos whitei sp. nov., is described from material collected at fish markets of the southern Philippines. This ray was first formally indentified as an undescribed species more than a decade ago as part of a WWF funded survey of sharks and rays of the Philippines. It was considered to be most closely related to another shovelnose ray found nearby in the western North Pacific, R. schlegelii, but differs from that species in body shape and aspects of coloration, meristics and morphometry. It differs from all other shovelnose rays of the region in its NADH2 sequence, clustering together with an Indonesian species R. jimbaranensis, and another undescribed species from Borneo. PMID- 25544070 TI - A new species of Triepeolus (Hymenoptera: Apidae), with comments on T. utahensis (Cockerell) and T. melanarius Rightmyer. AB - Triepeolus matildae Rightmyer, sp. nov., from Mexico (Baja California) and USA (California) is described and both genders are differentiated from the closely related species T. utahensis (Cockerell) using morphological characters. The synonymy of T. utahensis and T. heterurus was established in Rightmyer (2008); however, the younger name was used in that treatment, an error that is corrected herein. Males of both T. matildae and T. utahensis are additionally differentiated from T. melanarius Rightmyer, which is morphologically similar in that gender only. DNA barcoding evidence supporting the recognition of the new species is additionally presented. PMID- 25544071 TI - A review of the genus Litinium Cobb, 1920 (Nematoda: Enoplida: Oxystominidae) with descriptions of four new species from two contrasting habitats. AB - Four new species of the genus Litinium are described from mangroves and from deep sea. The genus Litinium now includes ten valid species. An emended generic diagnosis and a pictorial guide for species identification are given. Litinium quangi sp. n. and L. curticauda sp. n., both found in mangroves of South Vietnam, are morphologically similar and differ from other congeneric species in body size, having short anterior setae, ovoid amphideal fovea and a short rounded tail. Litinium quangi differs from L. curticauda in the number of midventral preanal supplementary setae (one in L. quangi and two in L. curticauda) and relative tail length (c' 1.12-1.63 in L. quangi and 0.83-0.94 in L. curticauda). Litinium abyssorum sp. n. and L. profundorum sp. n., both collected from the Angola Basin, South-East Atlantic Ocean, at depth 5400 m, are also morphologically similar and differ from other species of the genus by having a smaller body and relatively large amphideal fovea with deep invagination of the anterior edge. Litinium abyssorum differs from L. profundorum in the number of midventral preanal setae (two in L. abyssorum, one in L. profundorum), relative tail length (c' 3.61 in L. abyssorum and 1.17 in L. profundorum) and L. abyssorum has unequal spicules. PMID- 25544072 TI - Redescription of Vertigo (Vertigo) nitidula (Mousson, 1876) (Gastropoda: Vertiginidae) from the Caucasus region. AB - A revision of material of a minute land snail species from the Caucasus region usually named Vertigo (Vertigo) sieversi (Boettger, 1879) (Pilsbry 1919; Schileyko 1984; Sysoev & Schileyko 2005; Egorov 2008; Sysoev & Schileyko 2009), including types of all described varieties revealed that adjustments of the delimitation and the nomenclature of this insufficiently known taxon are necessary. We reinstate the oldest available name, Vertigo (Vertigo) nitidula (Mousson, 1876), for this species, redescribe it, and discuss its distinction from Vertigo (Vertigo) substriata (Jeffreys, 1833) as well as its geographical range. PMID- 25544073 TI - New record of the bush cricket, Zvenella yunnana Gorochov (Orthoptera: Gryllidae: Podoscirtinae) from India. AB - The first record of a known species of bush cricket, Zvenella yunnana (Gryllidae: Podoscirtinae), collected from the North-eastern province, Meghalaya (India) is reported. Previously, the species was reported from Thailand and the Indo-China region (Gorochov, 1985, 1988). The other congeneric species reported is Zvenella geniculata (Chopard) from Thailand. The morphological characterization of Z. yunnana has been presented with suitable illustrations. PMID- 25544074 TI - Calyptraeotheres sp. nov. (Crustacea: Decapoda: Pinnotheridae), symbiont of the slipper shell Crepidula striolata Menke, 1851 (Mollusca: Gastropoda: Calyptraeidae) from the Gulf of California, Mexico. AB - Calyptraeotheres camposi sp. nov. is described from the Gulf of California, Mexico. The new species is close to C. granti (Glassell, 1933) and C. pepeluisi Campos & Hernandez-Avila, 2010 from the Mexican Pacific and to C. hernandezi Hernandez-Avila & Campos 2006 from the Western Atlantic. These four species feature a third maxilliped with a 2-segmented endopod palp and the exopod with unsegmented flagellum. Calyptraeotheres camposi sp. nov. differs from C. granti and C. hernandezi by having the eyes visible in dorsal view, the carapace with arcuate anterolateral margins, the dorsal, longitudinal depressions connected with the transversal depression, and the propodus of pereiopod 2 equal or slightly longer than the carpus. From C. pepeluisi it is distinguished by the absence of a transversal depression on the carapace and the longitudinal depressions not connecting, the carpus and propodus of the third maxilliped being sub-trapezoidal and sub-conical, respectively, in lieu of subrectangular, and the inner surface of the fixed finger nude instead of bearing short setae near the cutting edge and ventral margin. PMID- 25544075 TI - Gasteruption youngi sp. nov. (Hymenoptera: Evanioidea: Gasteruptiidae) from South Australia; an unusual species with trichoid sensilla on the ovipositor sheaths. AB - Gasteruption youngi, sp. nov. (Evanioidea: Gasteruptiidae) is described based on several female specimens from South Australia. The new species is unusual in that it has stout trichoid sensilla on the ovipositor sheaths and long, thin trichoid sensilla on metasomal tergites T3-T8. The likely host is the colletid bee Euryglossula microdonta (Rayment, 1934). PMID- 25544076 TI - A review of the family Clenchiellidae (Mollusca: Caenogastropoda: Truncatelloidea). AB - The truncatelloidean family Clenchiellidae, previously treated as a tribe or subfamily of Hydrobiidae, is diagnosed as a distinct family including Clenchiella and three new genera, Coliracemata, Colenuda and Coleglabra. The family is characterised by the discoidal shell with spiral keels or cords, and a wide umbilicus. All species are found in mangrove swamps or adjacent habitats in tropical estuaries, with the exception of one riverine and one lacustrine species. Clenchiella includes the type species, C. victoriae Abbott, from the Philippines, the widespread C. minutissima (Wattebled) (= C. papuensis Benthem Jutting) from Vietnam, Singapore, Thailand, Papua New Guinea and tropical Australia, and three new species, C. bicingulata n. sp. from Singapore and Thailand, C. varicosa n. sp. from Hong Kong and Taiwan, and C. iriomotensis n. sp. from Okinawa, Japan. Coliracemata n. gen. includes C. mortoni n. sp. (type of the genus) from Hong Kong, C. katurana n. sp. from Okinawa, C. clarkae n. sp. from northeastern Australia, and tentatively C. microscopica (Nevill) and C. innocens (Preston) from India. Colenuda n. gen. consists of a single species, C. kessneri n. sp., from Northern Territory, Australia. Coleglabra n. gen. includes C. nordaustralis n. sp. (type of the genus) from Northern Territory and C. sentaniensis (Benthem Jutting) from a freshwater lake in Irian Jaya. Anatomical characters are described for nine of the twelve species. The Clenchiellidae is shown to be more closely related to Calopiidae, Tornidae, and Iravadiidae, than to Hydrobiidae. PMID- 25544077 TI - Notes on the genus Pseudokuzicus Gorochov, 1993 (Orthoptera: Tettigoniidae: Meconematinae: Meconematini) from China. AB - Two new species of the genus Pseudokuzicus are described: Pseudokuzicus (Pseudokuzicus) trianglus sp. nov. and Pseudokuzicus (Pseudokuzicus) platynus sp. nov. from China. In addition, morphological structures, a distribution map for known species distributed in China and a key to the species are provided. All specimens are deposited in the Museum of Hebei University, Baoding, P. R. China. PMID- 25544078 TI - A new Hyphessobrycon (Ostariophysi: Characiformes: Characidae) from the middle Amazon basin, Brazil. AB - Hyphessobrycon montagi, new species, is described from tributaries of the Rio Arapiuns, a left margin affluent of the lower Rio Tapajos, Amazon basin, Para, Brazil. The new species can be diagnosed from all its congeners by the possession of a combination of two well-defined humeral blotches, connected by a narrow stripe, and a caudal peduncle blotch. A putatively monophyletic Hyphessobrycon heterorhabdus species-group, restricted to H. heterorhabdus, H. amapaensis, and H. eschwartzae, is herein proposed based on shared derived features of color pattern. Alternative proposals of a "Hyphessobrycon heterorhabdus group" presented in the recent literature are evaluated and criticized. PMID- 25544079 TI - Description of Cyclocephala distincta Burmeister (Coleoptera: Scarabaeidae: Dynastinae: Cyclocephalini) immatures and identification key for third instars of some Cyclocephala species. AB - The larval instars and pupa of Cyclocephala distincta Burmeister (Coleoptera: Scarabaeidae: Dynastinae: Cyclocephalini) are described and compared to those of other known congenerics. Adult C. distincta, specialized flower visitors of Neotropical palms (Arecaceae), were collected in an area of native Atlantic Forest cover in the northeastern coast of Brazil and reared in captivity. The larvae of C. distincta diff---er from those of the other congenerics because of a distinctive pattern and arrangement of the setae on the raster. PMID- 25544080 TI - The first Pan-Podocnemididae turtle egg from the Presidente Prudente Formation (Late Cretaceous, Bauru Group), Brazil. AB - Pan-Podocnemididae turtles are ubiquitous in Late Cretaceous rocks of the Bauru Group in southeastern Brazil. This group of side-necked turtles is particularly abundant in a turtle-bearing site of the Presidente Prudente Formation known as Tartaruguito. Here, we describe the first turtle egg (LPRP-USP 0052) from the Tartaruguito site. LPRP-USP 0052 is nearly complete but misses a pole and measures 5,1 and 2,9-2,2 centimeters due to its flattened minor axis. The egg morphology and microstructure were analyzed by observations performed with CT, Optic Microscopy, Scanning Electronic Microscopy and Wave Dispersion Energy analyses. The eggshell ranges from 145 to160 micrometers thick. Considering the matching morphology of the new specimen and its provenance from the stratigraphic horizon that yielded only the podocnemidids Bauruemys and Roxochelys, it is most likely that LPRP-USP 0052 was produced by a podocnemidid turtle. PMID- 25544081 TI - A review of the genus Bullanga Navas, 1917 (Neuroptera: Myrmeleontidae). AB - A review of genus Bullanga Navas, 1917 is presented. All three species of Bullanga are redescribed and illustrated in detail. The female of Bullanga florida is described for the first time. A key to Bullanga species is also provided. PMID- 25544082 TI - Synopsis of Epipleoneura (Zygoptera, Coenagrionidae, "Protoneuridae"),
with emphasis on its Brazilian species. AB - A revision of the known species of Epipleoneura is presented. Material of all Brazilian species was examined. Two new species are described: E. ottoi (Holotype: Brazil, Goias State, Sao Bartolomeu river) and E. susanae (Holotype: Brazil, Mato Grosso State, Sao Lorenzo river), and the male of E. humeralis and the female of E. kaxuriana are described for the first time. With the exception of E. protostictoides, diagnoses, morphological characterizations, and illustrations of all species including known females are presented. The genital ligula of 25 species is described or redescribed. Morphological intraspecific variation is presented for E. machadoi, E. metallica, and E. venezuelensis. PMID- 25544083 TI - A review of the genus Magadha Distant, 1906 (Hemiptera: Fulgoromorpha: Achilidae). AB - Three new species of the planthopper genus Magadha, M. basimaculata sp. nov., M. densimaculosa sp. nov. and M. intumescentia sp. nov., are described and illustrated from China. The male of M. taibaishanensis Wang, 1989 is described for the first time. Illustrations of M. pinnata Chen, Yang & Wilson, 1989 and M. redunca Chen, Yang & Wilson, 1989 and a key to all species of the genus are given. PMID- 25544084 TI - Revision of the genus Achmonia of Africa south of the Sahara (Coleoptera: Staphylinidae: Staphylininae). AB - A redescription of the genus Achmonia Bordoni, 2004 is presented. Based on a revision of types and of additional material, seven species are recognized in Africa south of the Sahara and placed into two species groups. All species are described or redescribed and illustrated, four of them for the first time: Achmonia carinata sp. nov., A. kapangana sp. nov., A. knirschi sp. nov., and A. simulator sp. nov. A lectotype is designated for Xantholinus amabilis Boheman, 1848, Eulissus flavomarginatus Bernhauer, 1929 and E. congoensis Bernhauer, 1932. These species are transferred to Achmonia. A lectotype is designated for Eulissus semiflavus Bernhauer, 1913, and E. gerardi Bernhauer, 1929 and the following synonymy is proposed: Achmonia amabilis (Boheman, 1848) = Eulissus semiflavus Bernhauer, 1913, syn. nov. = Eulissus gerardi Bernhauer, 1929, syn. nov. The distribution of the genus in Africa south of Sahara is mapped and a key to species is presented. PMID- 25544085 TI - Remarkable morphological features of taxonomic interest in the female genitalia of five Erythrogonia species (Hemiptera: Cicadomorpha: Cicadellidae). AB - The female genitalia of the Cicadellidae (leafhoppers) are usually considered more morphologically conservative (i.e., less variable) than the male genitalia at the generic and specific levels. However, various recent publications on the Cicadellinae (sharpshooters) have demonstrated the existence of useful characters in the female genitalia for the recognition of genera and species. Here we describe, illustrate, compare, and discuss peculiar processes, sclerites, and other features of the first pair of valvifers, sternite VIII, and ovipositor valvulae I and II of five species of the sharpshooter genus Erythrogonia (E. calva (Taschenberg, 1884), E. hertha Medler, 1963, E. phoenicea (Signoret, 1853), E. proterva Melichar, 1926, and E. sexguttata (Fabricius, 1803)). This genus includes currently the highest species diversity among the New World Cicadellinae, an agriculturally important subfamily. Comparative notes on other genera of the Cicadellini are added. In agreement with other recent publications, our results challenge the view that the morphology of the female genitalia is almost always conservative in the Cicadellidae. PMID- 25544086 TI - Two new species of Atractus from Colombia (Reptilia, Squamata, Dipsadidae). AB - We describe two new species of Atractus from Colombia: one from the Serrania de la Lindosa, south of San Jose de Guaviare in the province Guaviare, and another from Punta de Betin in the province Magdalena, close to the Caribbean coast. The first new species differs from all congeners by having a combination of 17 smooth dorsal scale rows; loreal present, approximately as long as high; temporals 1+2; seven supralabials; seven infralabials; five maxillary teeth; four gular scale rows; four pre-ventrals; 187 ventrals in single male; 29/31 subcaudals in single male; dorsum of body with longitudinal stripes; venter uniformly dark gray. The second new species differs from all congeners by having a combination of 17 smooth dorsal scale rows; loreal absent; temporals 1+2; seven supralabials; six or seven infralabials; eight maxillary teeth; three gular scale rows; three pre ventrals; 146 ventrals in single male; 31/32 subcaudals in single male; dorsum of body and tail reddish brown with paired, occasionally slightly alternating lateral vertical cream blotches, approximately one dorsal scale broad, not contacting in vertebral region; venter cream with reddish brown blotches, forming two parallel series on anterior body and a checkered pattern on the rest of body. PMID- 25544087 TI - Observations on the biology of Afrotropical Hesperiidae (Lepidoptera). Part 7. Hesperiinae incertae sedis: grass and bamboo feeders. AB - Partial life histories for 17 Hesperiinae incertae sedis that feed on grasses or bamboos (Poaceae) are described and illustrated. The genera dealt with are: Astictopterus (from Evans' (1937) Astictopterus group), Prosopalpus, Kedestes (from Evans' (1937) Ampittia group), Ceratrichia, Pardaleodes, Ankola (From Evans' (1937) Ceratrichia and Acleros groups), Perrotia (part), Chondrolepis, and Monza (part) (all from Evans' Ploetzia genera group). The Poaceae-feeders comprise a relatively small proportion of the Afrotropical Hesperiinae fauna, particularly the mainland Afrotropical fauna. The caterpillars shown here are fairly homogeneous, with the head wider nearer the base, and lacking obvious setae on the body. Wax glands have been noted over most of the ventral surface A1 A8 in the final instar of Ceratrichia, Pardaleodes and Monza, but are absent in Chondrolepis, and either absent or not documented for other genera. The short double frontal projection of Tsitana uitenhaga is unusual, but pupae of the congeneric species have not been documented. The pupae of Kedestes spp. generally have extensive black or dark areas. The pupae of Pardaleodes and Ankola are very flimsy and collapse after emergence. All known pupae of Chondrolepis spp. have a short, blunt downturned frontal projection, not seen for any other Afrotropical genera, although Semalea spp. may have a short blunt projection. The remaining pupae are all generally similar and undistinguished. These are not substantial differences, but suggest that pupal characters may be useful in grouping some of the genera of Afrotropical Hesperiinae incertae sedis. PMID- 25544088 TI - Morphological redescription and DNA barcoding of Linevitshia prima Makarchenko, 1987 (Diptera: Chironomidae: Diamesinae) from Amur River basin (Russian Far East), with notes on systematics of the genus. AB - Additions and corrections to the diagnosis of the genus Linevitshia for male adult, pupa and larva are given, and systematic position of the genus is discussed. Illustrated redescription of adult male and first description of 4th instar larva of L. prima Makarchenko from Amur River basin are provided. Comparison of data based on a new material with those of L. yezoensis Endo showed that the latter name is a junior synonym of L. prima. The species specificity of L. prima COI sequences is analyzed and the sequences are presented as diagnostic characters-molecular markers of L. prima. PMID- 25544089 TI - Revision of the Neotropical genus Marbenia Malloch (Diptera: Periscelididae). AB - The Neotropical genus Marbenia Malloch is revised and now includes 3 species: Marbenia cinerea, sp. nov., Marbenia pallida, sp. nov. and Marbenia peculiaris Malloch, 1931. The genus is herein recorded from the amazonian region of South America (Bolivia, Brazil and Ecuador), and characters of male and female terminalia are illustrated for the first time. PMID- 25544090 TI - Pseudoamphicteis sinensis sp. nov., a new species of Ampharetidae (Polychaeta) from China. AB - A new species of the ampharetid genus Pseudoamphicteis, P. sinensis sp. nov., is described based on material deposited in the Marine Biological Museum of the Chinese Academy of Sciences (Qingdao). The new species is widely distributed from depths of 7-103 m in the Yellow Sea and the East China Sea. It is distinguished from the only other known species of this genus Pseudoamphicteis papillosa Hutchings, 1977 by its grooved branchiae. The genus has not previously been reported from China. PMID- 25544091 TI - Two new species of Willowsia from New Caledonia (Collembola: Entomobryidae). AB - The genus Willowsia is reported for the first time from New Caledonia. Two new species, W. neocaledonica sp. nov. and W. nigra sp. nov., are described based on material deposited at the Museum National d'Histoire Naturelle, Paris. The new species can be distinguished from other members of the genus by coloration and characters of the dorsal chaetotaxy of the head and terga. PMID- 25544092 TI - Phthiria sharafi sp. nov., a new record of the subfamily Phthiriinae (Bombyliidae, Diptera) from Saudi Arabia. AB - This new species (Phthiria sharafi sp. nov.) represents the first record of the subfamily Phthiriinae (Bombyliidae, Diptera) from Saudi Arabia. The species was collected from Garf Raydah Protected Area, Abha, Asir Province, south-western part of Saudi Arabia, using a Malaise trap erected in a site rich in olive, cactus and Juniper trees. The type locality has an Afrotropical influence, with the Afrotropical elements predominant, and a closer affiliation to the Afrotropical region than to the Palearctic region or the Eremic zone. PMID- 25544093 TI - Paramosina, a new genus of high Andean Limosininae (Diptera: Sphaeroceridae). AB - Paramosina, a new genus of Sphaeroceridae, is described on the basis of one abundant new species, Paramosina hirsuta Marshall, from the Ecuadorian Andes. PMID- 25544094 TI - The status of Crossopalpus obscuripes (Adams), a new junior synonym of Crossopalpus aenescens (Wiedemann) (Diptera: Hybotidae: Tachydromiinae). AB - Adams (1905) described a new species, Stilpon obscuripes, from two female specimens collected near Salisbury, Rhodesia (now Harare, Zimbabwe) by Frank L. Snow. Although Smith (1969) briefly treated this species under the genus Stilpon Loew in his monograph on the Empididae of southern Africa, it is evident that he had not seen the type material. The species remained little known until Cumming & Cooper (1992) examined the syntypes and transferred the species to Crossopalpus Bigot, indicating that C. obscuripes (Adams) was allied to C. aenescens (Wiedemann). During preparation of the Hybotidae chapter for the Manual of Afrotropical Diptera (Sinclair & Cumming, accepted), C. obscuripes was re examined and discovered to be identical to C. aenescens, which was originally described from South Africa. The Crossopalpus aenescens-group was previously studied by Collin (1960), who recognized four included species, and Smith (1967), who provided a key to the species and illustrations of the male terminalia (i.e., right surstylus) of this complex. PMID- 25544095 TI - A new species of Chleuastochoerus (Artiodactyla: Suidae) from the Linxia Basin, Gansu Province, China. AB - The Linxia Basin, Gansu Province, China, is known for its abundant and well preserved fossils. Here a new species, Chleuastochoerus linxiaensis sp. nov., is described based on specimens collected from the upper Miocene deposits of the Linxia Basin, distinguishable from C. stehlini by the relatively long facial region, more anteromedial-posterolaterally compressed upper canine and more complicated cheek teeth. A cladistics analysis placed Chleuastochoerus in the subfamily Hyotheriinae, being one of the basal taxa of this subfamily. Chleuastochoerus linxiaensis and C. stehlini are considered to have diverged before MN 10. C. tuvensis from Russia represents a separate lineage of Chleuastochoerus, which may have a closer relationship to C. stehlini but bears more progressive P4/p4 and M3. PMID- 25544096 TI - The orb-weaving spider genus Eustala Simon, 1895 (Araneae, Araneidae): eight new species, redescriptions, and new records. AB - Eight new species of Eustala Simon, 1895 are described from southern Brazil. Eustala guarani n. sp., from Parana and E. catarina n. sp., from Santa Catarina, are based on males and females. Six species are described from Rio Grande do Sul: E. ericae n. sp., E. cidae n. sp., E. lisei n. sp., E. cuia n. sp., E. farroupilha n. sp., based on males and females, and E. eldorado n. sp., based only on males. Eustala mourei Mello-Leitao, 1947, from Parana and E. ulecebrosa (Keyserling, 1892), described from Rio Grande do Sul are redescribed and illustrated. New records are given for Eustala albiventer (Keyserling, 1884), E. taquara (Keyserling, 1892), E. minuscula (Keyserling, 1892), E. itapocuensis Strand, 1916, E. photographica Mello-Leitao, 1944, E. levii Poeta, Marques & Buckup, 2010, and E. palmares, Poeta, Marques & Buckup, 2010. Eustala perfida Mello-Leitao, 1947, described from Parana, and E. belissima Poeta, Marques & Buckup, 2010, from Rio Grande do Sul, are newly recorded from Uruguay. Distribution maps are provided. PMID- 25544097 TI - The subgenus Andrena (Micrandrena) (Hymenoptera: Andrenidae) in the Iberian Peninsula. AB - This work presents the results obtained after a revision of the current species of the subgenus Andrena (Micrandrena) Ashmead, 1899 that appear in the Iberian Peninsula. It provides a key to the species, diagnosis, biological data, and comments about the 19 species and 5 subspecies. Additionally, it includes a redescription of five species because their original descriptions were inadequate. Newly reported for the Iberian Peninsula are Andrena floricola Eversmann, 1852 and Andrena strohmella Stockhert, 1928. This study is the first contribution to resolve certain taxonomic problems in the subgenus Andrena (Micrandrena); however, the use of additional tools like morphometric and molecular characters are recommended in the future to confirm the taxonomic status of Andrena spreta Perez, 1895. PMID- 25544098 TI - A new genus and two new species of Luzarinae cricket from the Atlantic Forest of Northeast Brazil (Orthoptera, Grylloidea). AB - A new genus and two new species of Luzarinae crickets (Grylloidea, Phalangopsidae) are described from the Atlantic Forest of Northeast Brazil. Marcgraviella muriciensis Souza-Dias n. gen., n. sp. and M. christianae Desutter Grandcolas & Souza-Dias n. gen., n. sp. are described using characters of morphology and male genitalia. The new genus is characterized by male genitalia singularities, presenting elongated and inflatable pseudepiphallic parameres, which lies in vertical or almost vertical position, and long and tubular pseudepiphallic arms associated to phallic glands. We provide a discussion about the morphology of male genitalia and the function of the phallic glands and pseudepiphallic arms in Marcgraviella n. gen. and related taxa. An identification key for Marcgraviella n. gen. and related genera is proposed. These genera, which bear phallic glands, are placed in the newly named group, the Aracambiae. PMID- 25544099 TI - One new species of Micronephthys Friedrich, 1939 and one new species of Nephtys Cuvier, 1817 (Polychaeta: Phyllodocida: Nephtyidae) from eastern Australia with notes on Aglaophamus australiensis (Fauchald, 1965) and a key to all Australian species. AB - There are currently over 130 described species of Nephtyidae worldwide, with 18 species known from Australian waters belonging to four genera. Two new species are described, Micronephthys derupeli n. sp., and Nephtys triangula n. sp., from Eastern Australia. Descriptions are provided for all species examined. Comments are given about the recent transfer of Nephtys australiensis to Aglaophamus. A key to all Australian species of nephtyids is provided. PMID- 25544100 TI - Morphological and molecular analysis of the genus Culicoides (Diptera: Ceratopogonidae) in Slovakia with five new records. AB - The biodiversity of Culicoides from eastern Slovakia was investigated by light trapping. An integrative taxonomy approach combining DNA barcode sequence and morphological analyses was used to accurately identify specimens. Five species were newly recorded from Slovakia: Culicoides picturatus Kremer & Deduit, C. gejgelensis Dzhafarov, C. clastrieri Callot et al., C. griseidorsum Kieffer and C. odiatus Austen. The checklist of the Culicoides species recorded from SK has been updated to 63 species and barcode sequence data is provided for 8 species not previously available on GenBank. Conflict between results from molecular and morphological analyses resulted in the discovery of some potentially new cryptic species and the inability of DNA barcodes to distinguish C. festivipennis Kieffer from C. clastrieri, C. salinarius Kieffer from C. manchuriensis Tokunaga and C. pallidicornis Kieffer from C. subfasciipennis Kieffer. These conflicts suggest further study is required to clarify the status of these species. PMID- 25544101 TI - Description and conservation status of a new species of Australotomurus (Collembola: Entomobryidae: Orchesellinae) from urban Perth remnant bushland. AB - A new species of the Australian endemic genus Australotomurus Stach, 1947 A. morbidus sp. nov., is described from four urban remnants in Perth. Australotomurus morbidus sp. nov. is the first species in the genus found to possess male secondary sexual characters on antennal segment III as well as I. The males of all other described species in the genus occurring in south-eastern Australia have secondary sexual characters on antennal segments I and II rather than I and III. Typical habitats for Australotomurus species are long undisturbed native grasslands and heathland at low and high elevations. The new species extends the known distribution of the genus ca. 2,000 km west. Australotomurus morbidus sp. nov. is the only species in the genus currently vulnerable to extinction because of its restricted distribution to only four localities, all of which are subject to considerable human disturbance. This species was listed as critically endangered when it was known (but not yet described) from only one locality but was delisted a few years later when three other locations for the species were found. The history and records of A. morbidus sp. nov. suggest that listing species using current Western Australian legislation does not necessarily protect vulnerable species. The new species is described here and new records for some other Australian species of Orchesellinae provided, including the first Australian record of Heteromurus major (Moniez, 1889). PMID- 25544102 TI - Marine macrostomorpha (platyhelminthes, rhabditophora) from the algarve (southern portugal). AB - Ten species of Macrostomorpha were found in marine environments of the Algarve (Portugal). Six of them were found in the Ria Formosa, a vast intertidal euryhaline lagoon system that dominates the most Eastern coast of the Algarve: two unidentified species of Microstomum Schmidt, 1848, Macrostomum cf. rubrocinctum Ax, 1951 and two unidentified species of Macrostomum Schmidt, 1848, Paromalostomum dubium (de Beauchamps, 1927), Paromalostomum minutum Rieger, 1971 and Cylindromacrostomum faroensis n.sp.. Comparison of this species with C. mediterraneum (Ax, 1955) and the species from Venice, considered to be C. mediterraneum by Rieger (1977), leads to the conclusion that the individuals studied by Rieger are in fact representatives of a separate species, C. riegeri n.sp.. Acanthomacrostomum spiculiferum Papi & Swedmark, 1959 was found in the Atlantic, 10-15 m deep, near the western coast of the Algarve. Haplopharynx papii n. sp. occurs on the beach exposed to the Atlantic as well as in the Ria Formosa. All identified and previously known (marine) species found in the Algarve had been found before, either in the Atlantic or in the Mediterranean basin. PMID- 25544103 TI - Description of a new species of Anomala Samouelle (Coleoptera: Scarabaeidae: Rutelinae) from Northern Territory, Australia. AB - A new species of Anomala Samouelle (Coleoptera: Scarabaeidae: Rutelinae) is described from the Northern Territory of Australia. The new species is diagnosed by the single tooth along the external margin of protibia, medially interrupted marginal bead on pronotal base and the clypeus weakly reflexed anteriorly. The illustrated diagnoses of the remaining Australian species and the key to their identification is also provided. PMID- 25544104 TI - A comparison of stresses in molar teeth restored with inlays and direct restorations, including polymerization shrinkage of composite resin and tooth loading during mastication. AB - Polymerization shrinkage of composites is one of the main causes of leakage around dental restorations. Despite the large numbers of studies there is no consensus, what kind of teeth reconstruction--direct or indirect composite restorations are the most beneficial and the most durable. OBJECTIVE: The aim was to compare equivalent stresses and contact adhesive stresses in molar teeth with class II MOD cavities, which were restored with inlays and direct restorations (taking into account polymerization shrinkage of composite resin) during simulated mastication. METHOD: The study was conducted using the finite elements method with the application of contact elements. Three 3D models of first molars were created: model A was an intact tooth; model B--a tooth with a composite inlay, and model C--a tooth with a direct composite restoration. Polymerization linear shrinkage 0.7% of a direct composite restoration and resin luting cement was simulated (load 1). A computer simulation of mastication was performed (load 2). In these 2 situations, equivalent stresses according to the modified von Mises criterion (mvM) in the materials of mandibular first molar models with different restorations were calculated and compared. Contact stresses in the luting cement-tooth tissue adhesive interface around the restorations were also assessed and analyzed. RESULTS: Equivalent stresses in a tooth with a direct composite restoration (the entire volume of which was affected by polymerization shrinkage) were many times higher than in the tooth restored with a composite inlay (where shrinkage was present only in a thin layer of the luting cement). In dentin and enamel the stress values were 8-14 times higher, and were 13 times higher in the direct restoration than in the inlay. Likewise, contact stresses in the adhesive bond around the direct restoration were 6.5-7.7 times higher compared to an extraorally cured restoration. In the masticatory simulation, shear contact stresses in the adhesive bond around the direct composite restoration reached the highest values 32.8 MPa and significantly exceeded the shear strength of the connection between the resin luting cement and the tooth structure. SIGNIFICANCE: Equivalent stresses in the tooth structures restored with inlays and in the restoration material itself and contact stresses at the tooth-luting cement adhesive interface are many times lower compared to teeth with direct composite restorations. Teeth with indirect restorations are potentially less susceptible to damage compared to those with direct restorations. Composite inlays also ensure a better seal compared to direct restorations. Polymerization shrinkage determines stress levels in teeth with direct restorations, while its impact on adhesion in indirectly restored teeth is insignificant. PMID- 25544105 TI - Precisely detecting atomic position of atomic intensity images. AB - We proposed a quantitative method to detect atomic position in atomic intensity images from experiments such as high-resolution transmission electron microscopy, atomic force microscopy, and simulation such as phase field crystal modeling. The evaluation of detection accuracy proves the excellent performance of the method. This method provides a chance to precisely determine atomic interactions based on the detected atomic positions from the atomic intensity image, and hence to investigate the related physical, chemical and electrical properties. PMID- 25544106 TI - Genetic analysis of schizophrenia and bipolar disorder reveals polygenicity but also suggests new directions for molecular interrogation. AB - Over the last few years, genetics research has made significant strides in identifying many risk factors for schizophrenia and bipolar disorder. These risk factors include inherited common single nucleotide polymorphisms, copy number variants, and rare single nucleotide variants, as well as rare de novo variants. For all variants, the common theme has been that of polygenicity, meaning that many small genetic risk factors influence risk in the population and that no gene or variant on its own has been shown to be fully deterministic of schizophrenia or bipolar. When taken together, biological themes that have emerged including the importance of synaptic function and calcium signaling. This has implications for our understanding of the biological underpinnings of these diseases. PMID- 25544107 TI - What is the oligoadenylate synthetases-like protein and does it have therapeutic potential for influenza? AB - Besides its pandemic potential, seasonal influenza infection is associated with an estimated 250,000 to 500,000 deaths worldwide every year. Part of this virulence of influenza virus can be attributed to its ability to evade the host innate immune response. Here, we discuss the possibility of using a recently described mechanism of boosting the innate immunity by oligoadenylate synthetase like protein, to combat influenza infections. PMID- 25544108 TI - What makes gambling cool? Images of agency and self-control in fiction films. AB - The study is a qualitative film analysis. It seeks to determine the semiotic and cinematic structures that make gambling appealing in films based on analysis of 72 film scenes from 28 narrative fiction films made from 1922 to 2003 about gambling in North American and West European mainstream cinema. The main game types include card games, casino games, and slot machines. The theme of self control and competence was identified as being central to gambling's appeal. These images are strongly defined by gender. The study was funded by ELOMEDIA, financed by the Finnish Ministry of Education and Culture as well as the Finnish Foundation for Alcohol Studies. The limitations of the study are noted. PMID- 25544109 TI - Medical and Psychiatric Effects of Long-Term Dependence on High Dose of tramadol. AB - BACKGROUND: Tramadol dependence has been studied recently after large-scale exposure. Although tramadol dependence has increased rapidly in Egypt since 2004, no studies have evaluated the effect of high dose long-term tramadol dependence. OBJECTIVES: To address the chronic sequel of tramadol dependence over at least 5 years duration with a large dose (more than 675 mg/day, three tablets or more, each tablet of 225 mg). The study was aimed to check the physical and psychiatric status during tramadol dependence and 3 months after complete treatment. METHODS: The present study was applied on 79 patients with single tramadol-dependence dose of 675 mg or more for 5 years or more. We examined the physical and psychological impact of tramadol abuse before and after 3 months of stoppage of the drug. RESULTS: The blood chemistry was nearly within normal parameters, although slight nonsignificant rise in liver enzymes was reported in some cases. Patients during tramadol dependence period were angry, hostile, and aggressive. On the other hand, after treatment the main problem observed was the significant increase in comorbid anxiety, depressive, and obsessive-compulsive symptoms, but no increase was found in psychotic symptoms. Tramadol-dependence dose was more important than duration of use in psychiatric illness. CONCLUSIONS: Tramadol dependence on high dose could be physically safe to some limit, but psychiatrically it has many side effects. PMID- 25544110 TI - Isolation and phenotypic characterization of side population cells in oral squamous cell carcinoma. AB - A subset of cancer stem cells termed 'side population' (SP) cells has been identified in several types of solid tumor and is known to be responsible for the failure of chemotherapy and for cancer relapse. In the present study, the oral squamous cell carcinoma (OSCC) cell line SCC-55 was used for analysis of the SP cells based on Hoechst 33342 exclusion, via the ATP-binding cassette (ABC) transporter, with and without verapamil using fluorescence activated cell sorting. The results demonstrated that the presence of SP cells in the SCC-55 cell line was 2.8%, which was reduced to 0.6% in the presence of verapamil, an inhibitor of the ABC transporter. In addition, following exposure to the chemotherapeutic drug 5-fluorouracil, a high survival rate was observed in the SP cells due to overexpression of the ABCG2 and B-cell lymphoma 2 proteins. In addition, overexpression of stem cell surface markers, including CD44 and CD147 was observed in the SP cells. Therefore, these findings suggested that OSCC contains SP cells, which share certain characteristics with stem cells. The coexpression of ABC transporters and stem cell surface markers in SP cells may be associated with resistance to chemotherapeutic agents and also supports a role for these cells in tumor recurrence, metastasis and invasion. PMID- 25544111 TI - ABCB1 gene polymorphisms and glucocorticoid-induced avascular necrosis of the femoral head susceptibility: a meta-analysis. AB - BACKGROUND: The results of studies on association between ABCB1 gene polymorphisms and glucocorticoid-induced avascular necrosis of the femoral head (GANFH) are controversial. This study aimed to assess the association of ABCB1 gene polymorphisms with the risk of GANFH by conducting a meta-analysis. MATERIAL AND METHODS: The PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between ABCB1 polymorphisms and GANFH risk. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity. RESULTS: A total of 5 studies and 833 patients were included in the final analysis. Significant differences were found for rs1045642 polymorphism in the comparisons of CC vs. CT+TT (OR, 1.462; 95% CI, 1.066-2.007; P=0.019), and rs2032582 polymorphism in the comparisons of GG vs. G(TA)+(TA)(TA) (OR, 1.548; 95% CI,1.063-2.255; P=0.023). CONCLUSIONS: The study demonstrated that the ABCB1 polymorphisms (rs1045642 and rs2032582) significantly reduced the risk of GANFH. PMID- 25544112 TI - Corrigendum: Antibacterial activities of bacteriocins: application in foods and pharmaceuticals. AB - [This corrects the article on p. 241 in vol. 5, PMID: 24904554.]. PMID- 25544113 TI - Effect of phytic acid, tannic acid and pectin on fasting iron bioavailability both in the presence and absence of calcium. AB - OBJECTIVE: To determine the effect of phytic acid, tannic acid and pectin on fasting non-heme iron bioavailability in both the presence and absence of calcium. RESEARCH METHODS: Twenty-eight apparently healthy adult females participated in two iron absorption studies using radioactive iron isotopes ((59)Fe and (55)Fe). One group received 5mg of iron (as FeSO4) alone (control), together with 10mg of phytic acid, 100mg of tannic acid and 250mg of pectin (study A), on different days. The second group received the same iron doses and compounds as the other group, plus 800mg of calcium (CaCl2) (study B). The compounds were administered after an overnight fast, and no food or beverages were consumed for the following 3h. Iron status and circulating radioactivity were measured in venous blood samples. RESULTS: The geometric means of iron bioavailability (range+/-1SD) for iron alone, iron with phytic acid, iron with tannic acid, and iron with citrus pectin were 25.0% (11.9-52.0); 18.9% (9.9 35.8); 16.8% (8.7-32.3); and 21.1% (10.2-43.9), respectively (repeated-measures ANOVA, p<0.02 (Dunnett's post hoc: control vs tannic acid p<0.05). When 800mg of calcium was added (study B), iron bioavailability was 16.7% (10.1-27.5); 13.2% (7.1-24.6); 14.8% (8.8-25.1); and 12.6% (5.5-28.8), respectively (repeated measures ANOVA, NS). CONCLUSIONS: Tannic acid decreases the fasting bioavailability of non-heme iron, however this effect did not exist in the presence of calcium. No effect was observed by phytic acid or citrus pectin on fasting non-heme iron bioavailability in both the presence and absence of calcium. PMID- 25544114 TI - Scabies. AB - INTRODUCTION: Scabies is a common public health problem. In many resource-poor settings, scabies is an endemic problem; whereas in industrialised countries, it is most common in institutionalised communities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of topical treatments for scabies? What are the effects of systemic treatments for scabies? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found five studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: benzyl benzoate (topical), crotamiton (topical), ivermectin (oral), malathion (topical), permethrin (topical), and sulfur compounds (topical). PMID- 25544115 TI - Monoamine Oxidase Inhibition and Molecular Modeling Studies of Piperidyl-thienyl and 2-Pyrazoline Derivatives of Chalcones. AB - A series of piperidyl-thienyl & 2-pyrazoline derivatives of quinolyl-thienyl chalcones were tested to observe the structural characteristics for the monoamine oxidase inhibitory (MAO) activity. In both these series, a diverse range of substituted thiophenes are used which enable the structure activity relationship. The compounds showed enhanced inhibition against MAO-A & B as compared to reference compounds. Compound 1c exhibited most potent MAO-A inhibition having IC50 value of 0.062 uM, while 1j showed excellent inhibitory potency against MAO B having IC50 value of 0.088 uM. The present investigation demonstrated that among piperidyl-thienyl chalcones, almost all the compounds exhibit significant MAO-A inhibition, thus may have antidepressant activity. Whereas among the 2 pyrazoline derivatives of chal-cones, many compounds revealed MAOB inhibition and hence may be applied in the control of senile dementia. Molecular docking studies were carried out against human MAO-A and MAO-B to rationalize important binding site interactions. PMID- 25544116 TI - Beta-Blockers and Nitrates: Pharmacotherapy and Indications. AB - Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina. PMID- 25544117 TI - Old and New Drugs for Treatment of Stable Angina: New Anti-Anginal Drugs and Coronary Revascularization. AB - Since the first human catheterization performed by Forssman in 1929 angioplasty equipment and medical therapies have undergone considerable evolution and technical improvement allowing interventionalists to perform more complex procedures and solving most of the percutaneous limitations. While percutaneous coronary intervention (PCI) has dramatically changed the outcome in the Acute Coronary Syndrome (ACS) setting, its role in the treatment of chronic stable angina is still debated. Stable coronary artery disease (SCAD) is a major public health issue and its prevalence is still increasing in the industrialized world. The correct treatment sees a multi-strategy approach aimed to a relief of symptoms, prevention of future cardiac events and survival improvement. In so forth, treatment strategies include optimal medical therapy (OMT) alone or combined with percutaneous or surgical coronary revascularization. Despite this, angina remains poorly controlled in the vast majority of CAD patients. Traditional agents such Beta-blockers or Calcium channel blockers or short and long acting nitrates have been used as first-line anti-anginal therapy for several years. Nowadays newer and more effective drugs usually used on top of older medical treatment have become available. PMID- 25544118 TI - New Anti-Anginal Drugs: Ranolazine. AB - Chronic angina represents a condition that impairs quality of life and is associated with decreased life expectancy in the industrialized countries. Current therapies that reduce angina frequency include old drugs such as nitrates, beta -blockers and calcium antagonists. Several new investigational drugs are being tested for the treatment of chronic angina. This review will focus on ranolazine, a drug approved by the US Food and Drug Administration (FDA) in 2006 for patients with chronic angina who continue to be symptomatic despite optimized therapies. The main molecular mechanism underlying ranolazine-mediated beneficial effects has been identified as inhibition of the late Na+ current during the action potential, which potentially improves oxygen consumption, diastolic dysfunction and coronary blood flow. The aim of this review is to update the evidence for ranolazine treatment in chronic angina and discuss its therapeutic perspectives based on the most recent clinical and experimental studies. PMID- 25544119 TI - Pathophysiology of Atherosclerotic Plaque Development. AB - Cardiovascular diseases and in particular coronary atherosclerotic disease are the leading cause of mortality and morbidity in the industrialized countries. Coronary atherosclerosis has been recognized for over a century and it was the subject of various studies. Pathophysiological studies have unravelled the interactions of molecular and cellular elements involved in atherogenesis; during the last decades the basic research has focused on the study of the instability of atherosclerotic plaque. Plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes including ST - segment elevation myocardial infarction and non ST - segment elevation myocardial infarction. This is a brief review of the pathophysiology of atherosclerotic plaque development. PMID- 25544120 TI - Ivabradine for Treatment of Coronary Artery Disease: From Last Chance Resort to Mainstem of a Reasoned Therapy. AB - Heart rate is a fundamental determinant of cardiac oxygen consumption and plays a pivotal role in the pathophysiology of chronic stable angina (CSA). Ivabradine selectively and specifically inhibits the sino-atrial If current, slowing selectively heart rate without other significant haemodynamic effects. The consequent clinical effects are a sinus rate reduction similar to that obtained with beta-blockers, but without the related haemodynamic side effects. Ivabradine clinical benefits have been demonstrated both in patients with stable coronary artery disease (CAD) with associated systolic left ventricular dysfunction or in patients with congestive heart failure (HF). In this review we focused on the pharmacology and clinical research about ivabradine in the context of anti ischemic therapy for CAD patients. Actually most guidelines suggest ivabradine therapy as last resort antianginal drugs in patients with uncontrolled symptoms or excessive heart rate despite maximum tolerated beta-blockade. However, the peculiar pharmacologic effects of the drug suggest that most patients with CAD might benefit from adding ivabradine to their therapeutic schemata. In fact, even if the recently released main analysis of the SIGNIFY study seems not to support an employ of ivabradine in primary prevention, it is easy to imagine a future wider use of this drug in elderly patients with incomplete myocardial revascularization and in patients with total chronic coronary occlusions and failure or unacceptable risk for percutaneous or surgical coronary revascularization. PMID- 25544124 TI - Local politico-administrative perspectives on quality improvement based on national registry data in Sweden: a qualitative study using the Consolidated Framework for Implementation Research. AB - BACKGROUND: Through a national policy agreement, over 167 million Euros will be invested in the Swedish National Quality Registries (NQRs) between 2012 and 2016. One of the policy agreement's intentions is to increase the use of NQR data for quality improvement (QI). However, the evidence is fragmented as to how the use of medical registries and the like lead to quality improvement, and little is known about non-clinical use. The aim was therefore to investigate the perspectives of Swedish politicians and administrators on quality improvement based on national registry data. METHODS: Politicians and administrators from four county councils were interviewed. A qualitative content analysis guided by the Consolidated Framework for Implementation Research (CFIR) was performed. RESULTS: The politicians' and administrators' perspectives on the use of NQR data for quality improvement were mainly assigned to three of the five CFIR domains. In the domain of intervention characteristics, data reliability and access in reasonable time were not considered entirely satisfactory, making it difficult for the politico-administrative leaderships to initiate, monitor, and support timely QI efforts. Still, politicians and administrators trusted the idea of using the NQRs as a base for quality improvement. In the domain of inner setting, the organizational structures were not sufficiently developed to utilize the advantages of the NQRs, and readiness for implementation appeared to be inadequate for two reasons. Firstly, the resources for data analysis and quality improvement were not considered sufficient at politico-administrative or clinical level. Secondly, deficiencies in leadership engagement at multiple levels were described and there was a lack of consensus on the politicians' role and level of involvement. Regarding the domain of outer setting, there was a lack of communication and cooperation between the county councils and the national NQR organizations. CONCLUSIONS: The Swedish experiences show that a government supported national system of well-funded, well-managed, and reputable national quality registries needs favorable local politico-administrative conditions to be used for quality improvement; such conditions are not yet in place according to local politicians and administrators. PMID- 25544125 TI - Individual trans 18:1 isomers are metabolised differently and have distinct effects on lipogenesis in 3T3-L1 adipocytes. AB - The objective of this research was to study the metabolism of individual trans fatty acids (FAs) that can be found in ruminant fat or partially hydrogenated vegetable oils (PHVO) and determine their effects on FA composition and lipogenic gene expression in adipocytes. Differentiated 3T3-L1 adipocytes were treated with 200 uM of either trans-9-18:1, trans-11-18:1, trans-13-18:1, cis-9-18:1 or BSA vehicle control for 120 h. Trans-9-18:1 increased total cell FA content (umole/well) compared to other FA treatments, which was mainly related to the accumulation of trans-9-18:1 in the cells. Adipocytes were able to desaturate a significant proportion of absorbed trans-11-18:1 and trans-13-18:1 (~20 and 30% respectively) to cis-9,trans-11-18:2 and cis-9,trans-13-18:2, whereas trans-9 18:1 was mostly incorporated intact resulting in a greater lipophilic index (i.e. decreased mean FA fluidity) of adipocytes. Trans-9-18:1 up-regulated (P < 0.05) the expression of lipogenic genes including acetyl-CoA carboxylase (1.65 fold), FA synthase (1.45 fold), FA elongase-5 (1.52 fold) and stearoyl-CoA desaturase-1 (1.49 fold), compared to the control, whereas trans-11-18:1 and trans-13-18:1 did not affect the expression of these genes compared to control. Our results suggest that the metabolism and lipogenic properties of trans-11-18:1 and trans-13-18:1, typically the most abundant trans FA in beef from cattle fed forage-based diets, are similar and are different from those of trans-9-18:1, the predominant trans FA in PHVO. PMID- 25544126 TI - Phase I/II study of docetaxel, cisplatin, and 5-fluorouracil combination chemoradiotherapy in patients with advanced esophageal cancer. AB - PURPOSE: This phase I/II study was aimed to determine the recommended dose (RD) of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF RT) for patients with esophageal cancer and to evaluate the efficacy and safety of this protocol. METHODS: Fourteen patients with esophageal cancer enrolled in this dose escalation study to determine the RD for a phase III trial. Efficacy and toxicity in DCF-RT of RD were evaluated in 37 patients with esophageal cancer. RESULTS: The RD for DCF-RT for esophageal cancer in the present study was 50 mg/m(2) docetaxel plus 60 mg/m(2) cisplatin on day 1 and day 29 plus 600 mg/m(2) 5-FU on days 1-4 and days 29-32 and concurrent radiation of 60 Gy/30 fractions/6 weeks. The main toxicities were myelotoxicity and radiation esophagitis. In this phase I/II study, we could have safety and feasibility by RD, because there was low mortality and most toxicities were manageable level. The complete response (CR) rate and response rate were 54.1 and 83.8 %, respectively, in the phase II study. In patients with a classification of clinical T4, the CR rate and response rate were 47.6 and 85.7 %, respectively. The 2-year overall survival rate, 2-year progression-free survival rate, and median survival time (MST) were 52.9, 50.0 %, and 24.7 months, respectively. In patients with clinical T4 classification, the 2-year overall survival rate, 2 year progression-free survival rate, and MST were 43.5, 44.9 %, and 21.6 months respectively. CONCLUSIONS: DCF-RT keeps safety and feasibility by management of myelotoxicity adequately in RD. This protocol might produce a high CR rate and favorable prognosis compared with standard chemoradiotherapy for advanced esophageal cancer. PMID- 25544127 TI - Cks1 proteasomal degradation is induced by inhibiting Hsp90-mediated chaperoning in cancer cells. AB - PURPOSE: Cks1, a conformationally heterogenous 9 kDa protein, is markedly overexpressed in cancer cells and contributes to tumor development. Cks1 is an essential component of the SCF-Skp2 ubiquitin ligase complex that targets the Cdk inhibitors p27(Kip1) and p21(Cip1). Cks1 is known to interact with the Hsp90 Cdc37 chaperone machinery, although whether this facilitates its conformational maturation and stability is not known. To test whether abrogating the chaperone function of Hsp90 could destabilize Cks1, we examined the effects of treating different cancer cell lines with the benzoquinone ansamycin 17-allylamino geldanamycin (17-AAG), a compound that selectively binds Hsp90 and potently inhibits its ATP-dependent chaperone activity. METHODS: The effect of Hsp90 inhibition using 17-AAG on Cks1 protein and associated cell cycle proteins including Skp2, p27(Kip1), p21(Cip1), and Cdk1 in cancer cells was determined by Western blotting. Ubiquitination analysis was carried out by transfecting cells with an HA-ubiquitin plasmid and specifically immunoprecipitating Cks1 to examine polyubiquitinated species. Flow cytometry was utilized to examine the effects of Hsp90 inhibition on cell cycle profiles. RESULTS: Here, we demonstrate for the first time that inhibition of Hsp90 utilizing 17-AAG destabilizes Cks1 in cancer cells by promoting its ubiquitination and proteasomal degradation. 17-AAG-induced Cks1 depletion was accompanied by concomitant decreases in Skp2 and Cdk1. 17-AAG treatment also induced G2/M accumulation in MCF-7 breast carcinoma cells, and G1 accumulation in the colon carcinoma lines HCT116 and SW620. CONCLUSIONS: We conclude that perturbing the Hsp90 pathway could provide a useful therapeutic strategy in tumors driven by Cks1 overexpression. PMID- 25544128 TI - R0 resection, not surgical technique, is the key consideration in pelvic exenteration surgery. PMID- 25544129 TI - Combined analysis of the tobacco metabolites cotinine and 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanol in human urine. AB - Two of the most widely measured compounds in the urine of people who use tobacco products are cotinine, a major metabolite of the addictive constituent nicotine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the powerful lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Thousands of analyses have been reported in the literature, carried out exclusively, to the best of our knowledge, by separate methods. In the study reported here, we have developed a sensitive, accurate, and precise liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring method for the combined analysis of total cotinine (the sum of cotinine and its glucuronide) and total NNAL (the sum of NNAL and its glucuronide). The new method quantifies naturally occurring [(13)C]cotinine to minimize problems associated with the vast differences in concentration of total cotinine and total NNAL in urine. This method should greatly facilitate future determinations of these important compounds. PMID- 25544130 TI - Descriptions and records of Cladiopsocidae and Dolabellopsocidae (Insecta: Psocodea: 'Psocoptera') from Valle del Cauca and National Natural Park Gorgona, Colombia. AB - The results of a survey on the species diversity of the families Cladiopsocidae and Dolabellopsocidae (Psocodea: 'Psocoptera': Psocomorpha: Epipsocetae) in Valle del Cauca and in the National Natural Park (NNP) Gorgona, Colombia, are presented. The specimens studied were collected in the context of two scientific projects, in which 12 species in the two families were identified, five in Cladiopsocidae and seven in Dolabellopsocidae. In the first family, Cladiopsocus presented a new record in the country and four new species; in the latter, two genera were identified, Dolabellopsocus, with three new species and two new records, and Isthmopsocus, with two new species. This study presents the description of the nine new species from Valle del Cauca and NNP Gorgona, the new records for Colombia and identification keys to the neotropical species of both families. PMID- 25544131 TI - New and little known species of ptyctimous mites (Acari, Oribatida) from Cameroon. AB - Altogether 24 species of ptyctimous mites were found in sifting litter samples from the Cameroon. Twelve new species of the ptyctimous mites, Indotritia montkoupensis sp. nov., Acrotritia furca sp. nov., Acrotritia quasidivida sp. nov., Hoplophthiracarus kumboensis sp. nov., Hoplophthiracarus reticulatus sp. nov., Hoplophthiracarus spinus sp. nov., Steganacarus (Rhacaplacarus) quaternarius sp. nov., Austrophthiracarus bicarinatus sp. nov., Protophthiracarus diatropos sp. nov., Protophthiracarus korupensis sp. nov., Protophthiracarus preptos sp. nov., Atropacarus (Hoplophorella) gibbus sp. nov., from the Cameroon are described and figured. Seven species are recorded for the first time for the Cameroon oribatid mite fauna. A comparison of morphological similarities with the most closely related species is presented. Taxonomical notes and additional information for two ptyctimous species: Acrotritia ardua (C.L.Koch, 1841), Arphthicarus sculptilis (Niedbala, 1988), were added. Keys for Afrotropical species of genera Hoplophthiracarus and Protophthiracarus are presented. PMID- 25544132 TI - Three new species of the bee genus Ruizantheda sensu lato (Hymenoptera: Halictidae: Caenohalictina). AB - Males of Ruizantheda Moure sensu lato differ from males of other Caenohalictina in having the outer gonostylar plate with a large membranous region that extends to the ventral region, and the ventral gonostylus in the form of a retrorse lobe. These features permit the placement of three new species described here in the genus in this broader sense. However, despite having simple mandibles, they do not have the traits considered as apomorphies of Ruizantheda s. str. or Ruizantheda + Oragapostemon Cure by earlier authors, and neither do they possess features of Ruizanthedella Moure. Moreover, in the new species, the outer gonostylar plate is short, ending before the apex of the main gonostylar lobe and has long setae on its dorsal surface, while in other Ruizantheda, the outer gonostylar plate extends beyond the apex of the main gonostylar lobe and lacks setae. Additionally, two of the new species have a distribution different from those of most Ruizantheda-Ruizantheda inca n. sp. is found in Ancash, Peru and R. aerugineus n. sp. in the state of Minas Gerais, Brazil. Instead of including the three species in a new genus, we believe that it is more reasonable to maintain the status of Ruizantheda sensu Michener and until a new phylogenetic analysis of the entire subtribe, inclusive of the species newly established here, is completed. The three new species, known only by the male, are described and illustrated, and a key to the species of Ruizantheda s. l. is provided. The homologies between the gonostylar structures, mainly those related to the dorsal gonostylar process, of males of Ruizantheda, Caenohalictus Cameron, and Pseudagapostemon Schrottky are discussed. PMID- 25544133 TI - Review of the genus Cystomutilla Andre, 1896 (Hymenoptera: Mutillidae: Sphaeropthalminae: Sphaeropthalmini), with description of the new genus Hemutilla gen. nov. and four new species from China. AB - The species of the genus Cystomutilla Andre, 1896 are reviewed. A new genus Hemutilla Lelej, Tu et Chen, gen. nov. (type species Hemutilla granulata Tu, Lelej et Chen, sp. nov.) and four new species: H. tuberculata Tu, Lelej et Chen, sp. nov. (China: Henan, Shaanxi), H. ferrugineipes Tu, Lelej et Chen, sp. nov. (China: Hunan), H. granulata Tu, Lelej et Chen, sp. nov. (China: Zhejiang), and H. cheni Tu et Lelej, sp. nov. (China: Fujian) are described and illustrated. New combinations are proposed for Hemutilla hoozana (Zavattari, 1913), comb. nov. and H. bifurcata (Chen, 1957), comb. nov. A key to males and females of two species of Cystomutilla Andre and six species of Hemutilla gen. nov. is given. PMID- 25544134 TI - Gastrointestinal helminths (Cestoda, Chabertiidae and Heligmonellidae) of Pogonomys loriae and Pogonomys macrourus (Rodentia: Muridae) from Papua Indonesia and Papua New Guinea with the description of a new genus and two new species. AB - Pieces of cestode, not indentified further, and 12 species of nematode including 1 new genus, 3 new species and 7 putative new species from the Families Chabertiidae and Heligmonellidae were collected from the digestive tracts of 16 Pogonomys loriae and 19 P. macrurous (Murinae: Hydromyini) from Papua, Indonesia and Papua New Guinea. The chabertiid Cyclodontostomum purvisi and the heligmonellid Odilia mackerrasae have been described previously from endemic murids. Hasanuddinia pogonomyos n. sp. can be distinguished from its congeners by the number of ridges in the synlophe, length of spicules and having a vagina with a dorsal diverticulum. Odilia dividua n. sp. is larger than its congeners, has a longer oesophagus, relatively shorter spicules and larger eggs. Pogonomystrongylus domaensis n. gen., n. sp. differs from all other genera in the Heligmonellidae in the characters of the synlophe, 7-10 ridges oriented sub frontally with a single left ventral ridge hypertrophied. Species richness of the nematode assemblages of P. loriae and P. macrourus are comparable to those of Abeomelomys sevia, Chiruromys vates and Coccymys rummleri when numbers of hosts examined are considered. Species composition was distinctive with 12, including the 7 putative species, of 14 species presently known only from species of Pogonomys. Similarities between the nematode fauna of endemic rodent hosts from Indonesia and Papua New Guinea were noted. PMID- 25544135 TI - The Liothrips-lineage of thrips (Thysanoptera: Phlaeothripidae) from Iran with the first record of micropterous morph of a Liothrips species. AB - A key is provided to the three Phlaeothripinae genera of the Liothrips-lineage known from Iran, Cephalothrips, Liothrips, and Liophloeothrips. Ataliothrips is placed as a new synonym of Liothrips, and the micropterous morph of L. reuteri described, this morph being unique among species of Liothrips. Illustrated keys are provided to the species of these genera recorded from Iran, all of which are considered to be leaf-feeding. In addition, a key is provided to the three species of Liophloeothrips from Europe, because L. hungaricus has been recorded from Iran although with no known voucher specimens. PMID- 25544136 TI - A further new species of Sarcofahrtiopsis Hall (Diptera: Sarcophagidae) associated with faeces of the disk-winged bat (Thyroptera Spix: Chiroptera) in Brazil and the redescription of the female terminalia of S. cuneata (Townsend). AB - The male, female and puparium are described for Sarcofahrtiopsis cupendipe sp. nov., whose larvae live in the roosts of disk-winged bats (Thyroptera species). Sarcofahrtiopsis cupendipe and S. thyropteronthos Pape, Dechmann & Vonhof are both associated with the faeces of the disk-winged bat and are the only species of Sarcofahrtiopsis with wing vein R1 fully setose dorsally and a short parameral apodeme in the male terminalia. In addition, the female terminalia of S. cuneata (Townsend) is redescribed. PMID- 25544137 TI - Aspidochirotida (Echinodermata: Holothuroidea) from the northeast coast of Brazil. AB - This is a taxonomic work on the aspidochirotid sea cucumbers from shallow waters in Northeast Brazil. We studied 165 specimens, classified into 2 families, 3 genera, 7 subgenera and 9 species. Descriptions, illustrations and literature data are included for each species, in addition to ecological notes and information on their distribution in the northeast coast of Brazil. A taxonomic key is provided for the identification of the species. PMID- 25544138 TI - To "bee" or not to be-on some ornamental shrimp from Guangdong Province, Southern China and Hong Kong SAR, with descriptions of three new species. AB - Several atyid specimens were collected from hill streams in Guangdong Province, Southern China and Hong Kong during fieldtrips between 2004 and 2013. Some of these species, most of them also sold as ornamental pet shrimp in the international aquarium trade, proved to be new to science by morphological observation and analysis of mtDNA sequences. Three new species, Caridina logemanni n. sp., Caridina mariae n. sp. and Caridina conghuensis n. sp., all of them members of the so called Caridina serrata species group (Cai & Ng 1999) are described in detail below. Caridina tumida Wang, Liang & Li, 2008 is synonymised with Caridina venusta Wang, Liang & Li, 2008. Caridina meridionalis Wang, Liang & Li, 2008 is moved to the genus Paracaridina Liang, Guo & Tang, 1999 and synonymised with Paracaridina zijinica Liang, 2002. New records for Caridina trifasciata Yam & Cai, 2003 and Caridina serrata Stimpson, 1860 are recorded. All species are compared to their morphologically closest congeners and the phylogenetic relationships between atyid shrimps from Southern China are shown. PMID- 25544139 TI - A Checklist of the Gyrinidae (Coleoptera: Adephaga) of Brazil. AB - A checklist of all known species of the water beetle family Gyrinidae (whirligig beetles) recorded from Brazil is assembled. This checklist is based on literature published prior to 2012. A total of 206 species and subspecies are cited for Brazil, distributed among three genera (Enhydrus Laporte, 1834, Gyrinus Geoffroy, 1762 and Gyretes Brulle, 1835). For each species we also include a complete account of its nomenclature including synonyms and historical combinations. The geographical distribution of each species both inside and outside of Brazil is provided. PMID- 25544140 TI - Nematodes from galls on Myrtaceae. IX. Fergusobia rosettae n. sp. on Melaleuca quinquenervia and F. tolgaensis n. sp. on Syzygium luehmannii, from Queensland. AB - Two new species of Fergusobia, collected from 'rosette' shoot bud galls on Melaleuca quinquenervia, and from leaf, stem, leaf and flower bud galls on Syzygium luehmannii, both from the Cairns region of Queensland, Australia, are described. Fergusobia rosettae Davies n. sp. is characterised by the combination of a small, arcuate parthenogenetic female having a short conoid tail with a bluntly rounded tip, an arcuate, relatively slender, infective female with an almost hemispherical tail tip, and arcuate males with arcuate to angular (not heavily sclerotised) spicules and leptoderan bursa arising at 40-50% of body length from tail tip. Fergusobia tolgaensis Davies n. sp. is characterised by the combination of a small open C-shaped parthenogenetic female with a broadly conoid tail, an arcuate infective female with a broadly rounded tail tip, and arcuate males with angular (not heavily sclerotised) spicules and short to mid-length leptoderan bursa. These two species of nematodes are associated with fly larvae that have dorsal shields comprising bars of raised cuticular ridges and spicules, similar to that of fly larvae from the M. leucadendra species group. The shield morphologies of these fly larvae and their possible genetic relationships are discussed. Possible evolutionary relationships of the Fergusobia nematodes from these galls are discussed, considering their morphology, DNA sequences, and the relationships of the associated Fergusonina flies and host plants. PMID- 25544142 TI - A new species of the Scinax catharinae Group (Anura: Hylidae) from Northeastern Brazil. AB - We describe a new species of the Scinax catharinae Group from Municipality of Porto Seguro, State of Bahia northeastern Brazil. The new species is mainly characterized by its small size, nuptial pad dark colored, and compound pectoral fold. Additionally, we describe the structure of its nuptial pad and compare it with that of S. agilis. We also briefly discuss its phylogenetic relationships within Scinax. PMID- 25544141 TI - Nematodes from galls on Myrtaceae. X. Fergusobia from galls on narrow-leaved Melaleuca spp. in Australia, with descriptions of three new species . AB - Three new species of Fergusobia, respectively collected from shoot bud galls on narrow-leaved Melaleuca spp. in Australia, are described. Fergusobia armillarisae n. sp. Davies is characterised by the combination of an arcuate to open C-shaped parthenogenetic female with an extensile uterus and a short, conoid tail, an arcuate infective female with a broadly rounded tail tip, and an arcuate male with an angular spicule and bursa arising at 50-80% of body length. Fergusobia decorae n. sp. Davies has an arcuate parthenogenetic female with a non-extensile uterus and a broadly conoid tail, an arcuate infective female with most curvature behind the vulva and a short tail with a broadly rounded tip, and an arcuate male with an arcuate spicule and bursa arising at 40-50% of body length. Fergusobia linariifoliae n. sp. Davies is characterised by the combination of an arcuate parthenogenetic female with an extensile uterus and a short, conoid tail with a bluntly rounded tip, a barely arcuate infective female with a broadly rounded tail tip, and an arcuate male with an angular spicule and bursa arising at 40-50% of body length. Earlier molecular analyses inferred from DNA sequencing of 28S rDNA D2/D3 domains and a portion of mitochondrial DNA cytochrome oxidase subunit I (mtCOI) are further discussed. PMID- 25544143 TI - Review of the species of the genus Marthogryllacris (Orthoptera, Gryllacrididae, Gryllacridinae) . AB - A review of the genus Marthogryllacris Karny, 1937 was presented. The genus Borneogryllacris should be regarded as a subgenus of Marthogryllacris. Five new species were described: M. (M.) rufonotata sp. nov., M. (B.) nanlingensis sp. nov., M. (B.) bimaculata sp. nov., M. (B.) spinosa sp. nov. and M. (B.) elongata sp. nov.. A key to the species of Marthogryllacris and the distributional data were provided. PMID- 25544144 TI - A new species of the genus Dulichiella Stout, 1912 (Crustacea: Amphipoda: Melitidae) from Pecem Harbor, Ceara state, Brazil. AB - A new species of the genus Dulichiella Stout, 1912 is described for the Northeastern Brazilian coast. The new species is recognized from the others in the genus by presenting (1) the accessory flagellum 5-articulate, (2) distolateral crown of gnathopod 2 of males with 4 spines, (3) Maxilla 1 inner plate, outer plate and palp distally enlarged and rounded, and (4) Pereopods 6 and 7 without bunches of long setae. This is the second species of Dulichiella recorded from South Atlantic and Brazilian waters. PMID- 25544145 TI - Mass-casualty Response to the Kiss Nightclub in Santa Maria, Brazil. AB - On January 27, 2013, a fire at the Kiss Nightclub in Santa Maria, Brazil led to a mass-casualty incident affecting hundreds of college students. A total of 234 people died on scene, 145 were hospitalized, and another 623 people received treatment throughout the first week following the incident.1 Eight of the hospitalized people later died.1 The Military Police were the first on scene, followed by the state fire department, and then the municipal Mobile Prehospital Assistance (SAMU) ambulances. The number of victims was not communicated clearly to the various units arriving on scene, leading to insufficient rescue personnel and equipment. Incident command was established on scene, but the rescuers and police were still unable to control the chaos of multiple bystanders attempting to assist in the rescue efforts. The Municipal Sports Center (CDM) was designated as the location for dead bodies, where victim identification and communication with families occurred, as well as forensic evaluation, which determined the primary cause of death to be asphyxia. A command center was established at the Hospital de Caridade Astrogildo de Azevedo (HCAA) in Santa Maria to direct where patients should be admitted, recruit staff, and procure additional supplies, as needed. The victims suffered primarily from smoke inhalation and many required endotracheal intubation and mechanical ventilation. There was a shortage of ventilators; therefore, some had to be borrowed from local hospitals, neighboring cities, and distant areas in the state. A total of 54 patients1 were transferred to hospitals in the capital city of Porto Alegre (Brazil). The main issues with the response to the fire were scene control and communication. Areas for improvement were identified, namely the establishment of a disaster-response plan, as well as regularly scheduled training in disaster preparedness/response. These activities are the first steps to improving mass-casualty responses. PMID- 25544146 TI - Thiazole: a promising heterocycle for the development of potent CNS active agents. AB - Thiazole is a valuable scaffold in the field of medicinal chemistry and has accounted to display a variety of biological activities. Thiazole and its derivatives have attracted continuing interest to design various novel CNS active agents. In the past few decades, thiazoles have been widely used to develop a variety of therapeutic agents against numerous CNS targets. Thiazole containing drug molecules are currently being used in treatment of various CNS disorders and a number of thiazole derivatives are also presently in clinical trials. A lot of research has been carried out on thiazole and their analogues, which has proved their efficacy to overcome several CNS disorders in rodent as well as primate models. The aim of present review is to highlights diverse CNS activities displayed by thiazole and their derivatives. SAR of this nucleus has also been well discussed. This review covers the recent updates present in literature and will surely provide a greater insight for the designing and development of potent thiazole based CNS active agents in future. PMID- 25544147 TI - [Proteomics, a new tool for an accurate typing of amyloidosis]. AB - Amyloidosis is a rare group of diseases related to extracellular deposition of proteins in an insoluble beta-pleated sheet structure presenting a characteristic apple-green birefringence under polarized light after Congo red staining. Thirty types of proteins are known to cause amyloidosis. The accurate identification of the amyloid protein is of paramount importance since it is a key step for the clinical management and personalized treatment. Amyloid typing is usually based on immunohistochemistry and immunofluorescence on tissular sections. This approach has several limits leading to a subtyping failure rate of 15 to 58% of cases. To overcome these difficulties, proteomic methods have been developed to characterize directly the amyloid protein. The most advanced technique carried out on fixed and paraffin-embedded tissue consists of laser microdissection followed by mass spectrometry. The type of amyloidosis can be determined in more than 95% of cases. However, the experience for this technique is very limited apart from the Mayo Clinic (Rochester, United States). In France, a very close proteomic assay has been implemented in the department of pathology of Foch Hospital with similar results. The introduction of proteomics in clinical practice represents a major improvement for typing amyloidosis. In this article, we discuss the benefits and limits of the different techniques used for amyloid classification and we briefly report our proteomic results. PMID- 25544148 TI - [Lower limb edema during valpromide treatment: case report and literature review]. AB - INTRODUCTION: Valpromide and sodium divalproate are indicated in the treatment of maniac episodes of bipolar disorder. These drugs are metabolized into valproic acid. The occurrence of peripheral edema has been described as a very rare adverse reaction of those drugs. CASE REPORT: We report the case of a patient treated with valpromide who presented edema of the lower limbs. The increase in furosemide dose allowed regression of edema, and valpromide discontinuation resulted in rapid normalization. Recurrence of mood disorders led to the reintroduction of valpromide, which was associated with recurrence of edema. The definitive withdrawal of valpromide resulted in resolution of edema. CONCLUSION: Edema of the lower limbs can be induced by valproate. The mechanism of this reaction is unknown. These edema appear to be reversible upon discontinuation of the drug. Clinicians should be aware of a possible relationship between valproate derived drugs and peripheral edema. PMID- 25544149 TI - Multiple births in sub-saharan Africa: epidemiology, postnatal survival, and growth pattern. AB - The study endeavored to assess the epidemiology, postnatal survival, and growth pattern of multiple births in Sub-Saharan Africa (SSA). It was based on the data of 25 demographic health surveys conducted in the subcontinent since 2008. The records of 213,889 children born in the preceding 59 months of the surveys were included. The multiple birth rate was computed as the number of multiple confinements per 1,000 births. Factors associated with multiple births were identified using logistic regression and their survival pattern was assessed using the Kaplan-Meier method. The multiple birth rate was 17.1 (95% confidence interval: 17.7-16.6) and showed considerable variation across the 25 countries included in the study. Odds of multiple births were significantly increased with advanced maternal age, parity, and maternal height but not with wealth index, age at first birth, and month of birth. At the end of the fourth year of age, the cumulative survival probability was as low as 0.77 in multiple births as compared to 0.93 in their counterparts. The odds of neonatal, infant and under-five mortality were 5.55, 4.39, and 3.72 times increased in multiple births, respectively. Multiple births tend to be malnourished than singletons and the odds of wasting, stunting, and underweight were 1.31, 1.83, and 1.73 times raised, consecutively. Nevertheless, multiple births regain their weight-for-age (WFA) and height-for-age (HFA) deficits by the end of the fourth year of age. Counseling pregnant mothers with multiple gestation to give birth at a health institution and providing close medical follow-up during and after the neonatal period can improve the survival of multiple births. PMID- 25544150 TI - Prescription drug use during pregnancy and risk of childhood cancer - is there an association? AB - In economically developed countries up to 90% of women are prescribed medications, including vitamins and supplements, during pregnancy. Whilst a number of adverse health outcomes in their offspring have been related to prescription drug use, associations with childhood cancer are less clear and most investigations have been reliant on maternal self-report. With a view to providing new insight we investigated maternal prescription drug use and risk of childhood cancer primary care medical records collected as part of the United Kingdom Childhood Cancer Study, a national population-based case-control study conducted between 1991 and 1996. There was evidence that mothers of children with acute lymphoblastic leukaemia (OR 1.36, 95% CI 1.14-1.63), medulloblastoma (OR 1.79, 95% CI 1.00-3.22) and Wilms tumour (OR 1.79; 95% CI 1.05-3.04) were more likely to have been prescribed iron when compared to mothers of controls. In addition, systemic anti-infectives were positively associated with acute myeloid leukaemia (OR 1.58, 95% CI: 1.05-2.38) and rhabdomyosarcoma (OR 1.80, 95% CI 1.03 3.16), and analgesic use (NO2B) was positively associated with Hodgkin lymphoma (OR 5.02, 95% CI 2.16-11.82) and neuroblastoma (OR 1.99, 95% CI 1.07-3.69). Whilst our findings suggest that maternal use of antibiotics, iron, and nervous system drugs during pregnancy may be associated with some childhood cancer subtypes these associations need to be confirmed elsewhere. Unravelling the mechanisms that may underpin these associations is complex and research is needed to determine whether they are directly related to the drugs themselves, or the illnesses for which they were prescribed. PMID- 25544151 TI - Roots of a social brain: developmental models of emerging animacy-detection mechanisms. AB - Here, we review evidence of unlearned predispositions to orient toward visual and auditory cues associated with the presence of animate creatures. We concentrate on studies on chicks of galliform species, whose behavioural preferences for social partners are analyzed in a comparative perspective with respect to the human developmental literature. The emerging nature of chicks' social predispositions is discussed in relation to the underlying physiological mechanisms and to the role of genetic and environmental factors in their development. In the second part of the review, we summarize evidence on the neural substrate of the animacy detectors, again focusing on our animal model of election, the domestic chick. On the basis of a substantial amount of indirect evidence, subpallial structures, among which the optic tectum (homologous to the mammalian superior colliculus), seem to comprise the most probable candidates. We also discuss some preliminary evidence of different brain activity, measured by IEG expression, in chicks exposed to predisposed or a non-predisposed stimulus. PMID- 25544152 TI - alpha-Linolenic acid supplementation in BioXcell(r) extender can improve the quality of post-cooling and frozen-thawed bovine sperm. AB - The present study was conducted to determine the effects of supplementing alpha linolenic acid (ALA) into BioXcell((r)) extender on post-cooling, post-thawed bovine spermatozoa and post thawed fatty acid composition. Twenty-four semen samples were collected from three bulls using an electro-ejaculator. Fresh semen samples were evaluated for general motility using computer assisted semen analyzer (CASA) whereas morphology and viability with eosin-nigrosin stain. Semen samples extended into BioXcell((r)) were divided into five groups to which 0, 3, 5, 10 and 15 ng/ml of ALA were added, respectively. The treated samples were incubated at 37 degrees C for 15 min for ALA uptake by sperm cells before being cooled for 2 h at 5 degrees C. After evaluation, the cooled samples were packed into 0.25 ml straws and frozen in liquid nitrogen for 24 h before thawing and evaluation for semen quality. Evaluation of cooled and frozen-thawed semen showed that the percentages of all the sperm parameters improved with 5 ng/ml ALA supplement. ALA was higher in all treated groups than control groups than control group. In conclusion, 5 ng/ml ALA supplemented into BioXcell((r)) extender improved the cooled and frozen-thawed quality of bull spermatozoa. PMID- 25544153 TI - Targeted therapies in germ cell tumors. PMID- 25544154 TI - Income inequality and treatment of African American men with high-risk prostate cancer. PMID- 25544155 TI - Skills for nursing practice: development of clinical skills in pre-registration nurse education. AB - Rapid changes during the past two decades have seen a growing challenge to prepare newly qualified nurses who are clinically competent and confident to meet the demands of contemporary healthcare. Recent publications emphasise the need to prioritise clinical skills in nurse education (DH 2012a, Francis, 2012). This discussion reports on a project scoping the clinical skills required within pre registration nursing curricula and considers how this has influenced curriculum development at one Higher Education Institution in the UK. This paper reports on the project analysis of nursing and healthcare policy, identifying six core themes of skills relevant for nursing practice. Furthermore it explores the findings of a series of focus groups with nursing practitioners and managers identifying priorities for clinical skills in the pre-registration curriculum. These highlighted a broad range of skills required of newly qualified practitioners, which pose a challenge for integration within nurse education. How this challenge has been addressed through the incorporation of these skills themes throughout a new pre-registration curriculum is also examined. PMID- 25544156 TI - U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor. AB - U0126 is a potent and selective inhibitor of MEK1 and MEK2 kinases. It has been widely used as an inhibitor for the Ras/Raf/MEK/ERK signaling pathway with over 5000 references on the NCBI PubMed database. In particular, U0126 has been used in a number of studies to show that inhibition of the Raf/MEK/ERK pathway protects neuronal cells against oxidative stress. Here, we report that U0126 can function as an antioxidant that protects PC12 cells against a number of different oxidative-stress inducers. This protective effect of U0126 is independent of its function as a MEK inhibitor, as several other MEK inhibitors failed to show similar protective effects. U0126 reduces reactive oxygen species (ROS) in cells. We further demonstrate that U0126 is a direct ROS scavenger in vitro, and the oxidation products of U0126 exhibit fluorescence. Our finding that U0126 is a strong antioxidant signals caution for its future usage as a MEK inhibitor and for interpreting some previous results. PMID- 25544157 TI - High enantiomeric excess of the flavor relevant 4-alkyl-branched Fatty acids in milk fat and subcutaneous adipose tissue of sheep and goat. AB - Volatile 4-alkyl-branched fatty acids are characteristic flavor compounds of sheep and goat. Due to the methyl branch, the carbon C-4 represents a stereogenic center with the possible presence of one or both enantiomers in the respective samples. In this study, we used enantioselective gas chromatography to study the enantiomeric composition of 4-methyloctanoic acid (4-Me-8:0) and 4-ethyloctanoic acid (4-Et-8:0) in milk and dairy products from sheep and goat as well as in goat subcutaneous tissue. Different columns coated with modified cyclodextrins were tested to resolve racemic 4-alkyl-branched fatty acid methyl ester standards. The best enantiomer resolution was obtained on 25% octakis(2,3,6-tri-O-ethyl)-gamma cyclodextrin (gamma-TECD) diluted in OV-1701. For analysis of the food samples, the lipids were extracted and fatty acids in the extracts were converted into fatty acid methyl esters. Non-aqueous reversed-phase high-performance liquid chromatography was used to fractionate the samples in order to gain one solution enriched in 4-Me-8:0 methyl ester and one solution enriched with 4-Et-8:0 methyl ester. Subsequent analysis by enantioselective gas chromatography with mass spectrometry allowed only the detection of one enantiomer of 4-Me-8:0 and 4-Et 8:0 in the samples. By means of a non-racemic standard of 4-Me-8:0, it was found that the predominant enantiomer was (R)-4-Me-8:0. PMID- 25544159 TI - [Multiple special formed titanium mesh cages in the treatment of lumbo-sacral spinal tuberculosis via posterior approach only]. AB - OBJECTIVE: To determine the clinical efficacy and feasibility of multiple special formed titanium mesh cages (TMCs) to treat lumbo-sacral spinal tuberculosis via posterior approach. METHODS: From July, 2007 to June, 2013, 25 patients with lumbo-sacral spinal tuberculosis underwent one-stage posterior debridement, internal fi xation, and interbody fusion using multiple special formed titanium meshes. We compared the parameters as follow: the pre- and post-operative American Spinal Injury Association (ASIA) score, lumbo-sacral angle, the height of intervertebral space, visual analogue scale (VAS), and erythrocyte sedimentation rate (ESR), and observed operation time, intraoperative blood loss, and time of bone graft fusion. RESULTS: Operation time ranged from 90 to 180 min, (128+/-24) min in average. Blood loss in the operation ranged from 100 to 800 mL, (310+/-125) mL in average. The patients were followed up for 24 to 59 months, (43+/-7) months in average. One patient delayed healing of wound. ASIA score was improved in a certain degree in patients with neurological dysfunctions. The lumbo-sacral angle and the height of intervertebral space in the post-operation were significantly higher than those in the preoperation (P< 0.001). VAS was reduced obviously after 2 weeks of operation. The ESR recovered to the normal level 6 months after operation in all the patients. Solid fusion was achieved within 4 to 8 months, 6 months in average. No sinus tract, cerebrospinal meningitis, tuberculosis recurrence and titanium mesh subsidence were found. CONCLUSION: For lumbo-sacral tuberculosis, multiple special formed titanium mesh cages via posterior approach is safe and effective, which is good to the stability in spine reconstruction. PMID- 25544158 TI - White matter damage of the brain is associated with poor outcome in vascular surgery patients with claudication: a pilot study. AB - OBJECTIVE: Peripheral arterial disease (PAD) is a systemic atherosclerotic syndrome with high post-operative morbidity and mortality. Fractional anisotropy (FA), an index measured by magnetic resonance diffusion tensor imaging (DTI), has been shown to be exceedingly sensitive to microstructural damage in brain white matter tracts. It is hypothesized that pre-operative white matter damage is more extensive in PAD patients scheduled for vascular surgery who experience an adverse long-term outcome. METHODS: Preoperative FA values were obtained in 24 consecutive PAD patients (age >40 years) scheduled for elective infrainguinal revascularization surgery and in 15 healthy age matched participants. All patients had their clinical history taken and underwent physical examination and laboratory tests. After surgery, patients were followed for a median of 52 months (range 40-63) and major adverse cardiovascular and cerebrovascular events (MACCE) were recorded. RESULTS: There were no statistically significant differences in baseline demographic or clinical variables between the MACCE group and the non MACCE group. During follow up, eight PAD patients suffered a MACCE and they had lower FA values than patients without MACCE or healthy controls (mean +/- SD 0.370 +/- 0.017 vs. 0.392 +/- 0.023 vs. 0.412 +/- 0.018, p = .036 and p = .00007, respectively). Voxelwise analysis of the FA data revealed diffuse spatial distribution of white matter damage in PAD patients. There was no statistically significant association between the FA values and other clinical variables. CONCLUSION: Microstructural white matter damage was associated with poor outcome in PAD patients with claudication requiring surgical revascularization, and its extent may have clinical value in risk stratification. PMID- 25544160 TI - [Effects of tumor necrosis factor-alpha converting enzyme on mucous hypersecretion in inflammatory airway]. AB - OBJECTIVE: To investigate the effect of tumor necrosis factor-alpha converting enzyme (TACE) on mucous hypersecretion in inflammatory airway. METHODS: Mucous hypersecretion model of human lung adenocarcinoma cells A549 was induced by human neutrophil elastase (HNE), and TNF-alpha converting enzyme inhibitor-1 (TAPI-1), an inhibitor of TACE, was chosen for the inference study. The expression of MUC5AC and TACE was examined. Th e cells were divided into 5 groups: a negative control group, HNE1 (15 nmol/L) group, HNE2 (25 nmol/L) group, HNE3 (50 nmol/L) group and TAPI-1 group. RT-PCR was used to examine MUC5AC and TACE mRNA expression. The protein expression of TACE and MUC5AC was examined by Western blot and ELISA, respectively. RESULTS: HNE induced the TACE and MUC5AC mRNA and protein expression in a dose-dependent manner. Compared with the control group, the increases were all significantly increased in the three dosages of HNE group (P< 0.01). The HNE-induced TACE and MUC5AC mRNA and protein expression were dramatically attenuated in the presence of TAPI-1, an inhibitor of TACE (P< 0.01). CONCLUSION: TACE participated cell signalling pathway of airway mucous hypersecretion, and could down regulation the level of inflammation airway mucous hypersecretion. PMID- 25544161 TI - [Correlation between eIF3a and HE4 expression and ovarian cancer]. AB - OBJECTIVE: To investigate the correlation between eukaryotic translation initiation factor 3, subunit A (eIF3a) and human epididymis protein 4 (HE4) expression and ovarian cancer. METHODS: RT-PCR or immunohistochemistry was used to examine eIF3a and HE4 mRNA or protein expression in ovarian tissues from patients with ovarian cancer (n=181) or benign ovarian tumors, or from the healthy women. RESULTS: There were significant differences in mRNA and protein expression of eIF3a and HE4 among normal ovarian tissues, benign ovarian tumor tissues, and ovarian cancer tissues (P< 0.05). There were significant differences in mRNA expression of eIF3a and HE4 between the normal tissues and the ovarian cancer tissues, or between the benign ovarian tumor tissues and the normal tissues (P< 0.001). The mRNA expression of eIF3a in the normal ovarian tissues was significantly higher than that in the benign ovarian tumor tissues or that in the ovarian cancer tissues. The mRNA expression of HE4 was gradually increased from the normal ovarian tissues, the benign ovarian tumor tissues to the ovarian cancer tissues. The mRNA expression of HE4 in the ovarian cancer tissues was significantly higher than that in the benign ovarian tumor tissues (P< 0.001). Positive expression rates for eIF3a or HE4 protein in normal, benign tumor, and cancer tissues were 0, 66.7%, and 81.0% or 0, 27.8%, and 56.2%, respectively. There were significant differences in positive expression rates of eIF3a protein and HE4 protein between the ovarian tumor tissues and benign ovarian tumor tissues, between the ovarian cancer tissues and the normal ovarian tissues, or between the benign ovarian tumor tissues and the normal ovarian tissues (P< 0.001). The eIF3a protein expression was positively correlated with HE4 protein expression (r=0.575, P< 0.05). CONCLUSION: The expressions of eIF3a and HE4 are associated with ovarian cancer, and extracellular regulated protein kinases may play a role in the interaction between eIF3a and HE4. PMID- 25544162 TI - [Effect of chronic high-fat diet on predation behavior in rats]. AB - OBJECTIVE: To observe the eff ect and mechanism of chronic high-fat diet on predation behavior in rats. METHODS: Ten female SD rats with 4-week-old were randomly divided into a normal control group (NC group, n=5) and a chronic high fat diet group (HF group, n=5). The rats in the NC group received the regular diet while rats in the HF group were fed with high-fat diet. Fift een weeks later, the predation behavior of rats was evaluated by open fi eld test and food foraging tests. At the end of experiments, the rats were killed and brain tissues were collected for evaluation of c-Fos protein expression in anterior cingulate cortex by immunohistochemical assay. RESULTS: Th e predation behavior of rats in the HF group was signifi cantly impaired in the competitive or non-competitive food foraging test compared with the control rats (P< 0.001). Th e c-fos protein expression in anterior cingulate cortex of rats from the HF group was signifi cantly decreased (P< 0.001). CONCLUSION: Long time high-fat diet can aff ect the predation behavior of rats, which is related to dysfunction of neuron in anterior cingulate cortex. PMID- 25544163 TI - [Knowledge, attitude and behavior on blood lipid among people participated in health examination in Changsha and the influential factors]. AB - OBJECTIVE: To evaluate the knowledge, attitude and behavior on blood lipid among people in Changsha and to provide evidences for prevention and control of blood lipid abnormality. METHODS: A total of 400 cases were randomly selected on the questionnaire of the knowledge, attitude and behavior on blood lipid in ordinary adults who participate in health examination in Xiangya Hospital. Blood lipid related physical examination was conducted at the same time. The health examination participants were divided into several groups according to their sex, age, degree of education, marriage and family income. The influential factors for knowledge, attitude and behavior were analyzed. RESULTS: The knowledge score of blood lipid for health examination participants was 18.33+/-8.67 (total score 37), the attitude score was 6.63+/-2.45 (total score 9) and the behavior score was 8.32+/-2.65 (total score 16). The scores of female was higher than that of male in the terms of knowledge and behavior (both P< 0.05); the scores in the 40 49 age group were lower than those in the other age groups (all P< 0.05); the scores in the junior high school group were lower than those in the other education groups (all P< 0.05); the scores in the family group with less than 2 000 yuan income were lower than those in other family groups with different income (all P< 0.05). The multiple stepwise regression analysis showed that: 1) the knowledge on blood lipid score was influenced by ages and education background (both P< 0.05); 2) while the attitude of blood lipid was influenced by four factors such as education background, systemic blood pressure, blood sugar and triglyceride(all P< 0.05); 3) the behavior on blood lipid was influenced by five factors such education background, triglyceride, systemic blood pressure, blood sugar and ages (all P< 0.05). CONCLUSION: The knowledge, attitude and behavior on blood lipid among health examination participants were mostly influenced by education background, gender and ages. Thus, clinical medical staff should prevent the blood lipid abnormality through the health education and improve the knowledge in normal people. The group of 40-49 age male should be thought as the primary intervention subjects. The knowledge, attitude and behavior on blood lipid among the general population is also related to individual's blood pressure, blood sugar and triglyceride. So the clinical medical staff should also improve the knowledge of blood lipid, blood pressure and blood sugar in general population for improving their attitude and unhealthy habits. In addition, the active control of blood sugar and blood pressure can enhance the overall health status of the general population. PMID- 25544164 TI - [Effect of puncture-related pain on the quality of life in patients undergoing maintenance hemodialysis through internal arteriovenous fistula]. AB - OBJECTIVE: To investigate the effect of puncture-related pain on the quality of life in patients undergoing maintenance hemodialysis through internal arteriovenous fi stula. METHODS: A total of 180 hemodialysis patients with the arteriovenous fistula were surveyed by the kidney disease quality of life short form(KDQOL-SF1.3), demographic data questionnaire, visual analogue scale and pain self-efficacy questionnaire. RESULTS: The median score of puncture-related pain was 5 and the score of pain self-efficacy was (31.42+/-14.59). The quality of life in the patients undergoing maintenance hemodialysis is poor. KDQOL-SF1.3 was (69.45+/-24.19), SF-36 was (49.82+/-19.17) and ESRD-targeted was (55.46+/-18.37). Multivariate analysis demonstrated that the quality of life was positively correlated with the patient gender (beta=0.152, P< 0.05, OR=1.638, 95% CI 1.241 1.954), working position (beta=0.307, P< 0.05, OR=2.069, 95% CI 1.206--3.148), using time of arteriovenous fistula (beta=-0.815, P< 0.05, OR=0.223, 95% CI 0.095 0.741), the score of pain (beta=-0.017, P< 0.05, OR=1.004, 95% CI 0.886-1.431) and pain self-efficacy (beta=-0.409, P< 0.05, OR=0.803, 95% CI 0.710-0.984). There existed negative correlation between the quality of life score and the puncture-related pain score in these patients (r=-0.472, -0.465, -0.381, P< 0.01), positive correlation between the quality of life score and the score of pain self-efficacy (r=0.647, 0.203, 0.518, P< 0.05), and negative correlation between the puncture-related pain score and the score of pain self-efficacy(r= 0.745, P< 0.01). CONCLUSION: Puncture-related pain is a crucial influential factor on the quality of life in the patients undergoing maintenance hemodialysis through internal arteriovenous fistula. PMID- 25544165 TI - [Single-incision laparoscopic appendectomy versus conventional laparoscopic appendectomy for adult acute appendicitis: a Meta-analysis for randomized controlled trials]. AB - OBJECTIVE: To evaluate the efficiency and safety for single-incision laparoscopic appendectomy (SILA) and conventional laparoscopic appendectomy (CLA). METHODS: The literature of randomized controlled trials (RCTs) concerning SILA versus CLA was retrieved by searching the electronic databases from the inception date to May 2014. Methodological quality of the included trials was assessed by using the Cochrane Reviewers' Handbook criteria, and the data were extracted and subjected to Meta-analysis by using RevMan 5.1 analysis software. RESULTS: A total of 1 183 patients were finally selected after the screening. Among them, 582 cases underwent SILA and 601 cases underwent CLA. Meta-analysis results demonstrated that SILA was associated with higher conversion rate (RR=4.38, 95% CI 1.96-9.79, Z=3.59, P=0.0003), longer operative time (RR=4.83, 95% CI 1.57-8.09, Z=2.90, P=0.004), shorter length of hospital stay (WMD=?0.11, 95%CI ?0.21-?0.01, Z=2.02, P=0.04), and better scores for the postoperative appearance of incision (WMD=0.94, 95%CI 0.49-1.40, Z=4.06, P< 0.001) compared with CLA; no significant difference was observed in postoperative complications and postoperative pain scores (RR=1.03, 95% CI 0.74-1.45, Z=0.18, P=0.86; WMD=?0.19, 95%CI ?0.59-0.20, Z=0.95, P=0.34) between the 2 groups. CONCLUSION: For patients under the conditions of the strict selection, SILA is a safe and effective procedure for the treatment of adult acute appendicitis, especially apply to those who care about incision appearance. PMID- 25544166 TI - [Treatment of multi-segmental cervical spondylosis by long or segmented anterior cervical decompression and fixation surgery]. AB - OBJECTIVE: To investigate the clinical efficacy of two different anterior cervical surgeries in treatment of multi-segmental cervical spondylosis. METHODS: A total of 86 patients with multi-segmental cervical spondylosis were treated by anterior cervical surgery procedure. Among them, 62 and 24 cases were involved in three and four gap, respectively. Each patient underwent the surgery of long or segmented anterior cervical decompression and fixation. Preoperative and postoperative cervical curvature change, internal fixation stability, fusion rate and nerve function were evaluated. RESULTS: All patients were successfully completed the operation, segmented surgery showed better cervical lordosis recovery, but there were no significant difference between long and segmented anterior cervical surgery in blood loss and recovery of neurological function (P> 0.05). CONCLUSION: The segmented anterior cervical surgery has advantages in the treatment of multisegmental cervical spondylosis. PMID- 25544167 TI - [Therapeutic effect of extracorporeal shock wave combined with orthopaedic insole on plantar fasciitis]. AB - OBJECTIVE: To observe the therapeutic effect of extracorporeal shock wave combined with orthopaedic insole on plantar fasciitis. METHODS: A total of 153 plantar with plantar fasciitis were randomly divided into a combined group (n=51), an extracorporeal shock wave group (n=53) and an orthopaedic group (n=49). The combined group received treatment of both extracorporeal shock wave and orthopaedic insole while the extracorporeal shock wave or the orthopaedic group only received the treatment of extracorporeal shock wave or orthopaedic insole. The therapeutic parameters such as visual analogue scale (VAS) scores, continued walking time and thickness of the plantar fascia were monitored before and aft er the treatment for 2 weeks, 1 month and 3 months, respectively. RESULTS: The VAS scores in the 3 groups were all reduced after the treatment compared with the corresponding scores before the therapy (P< 0.05). The VAS score in the extracorporeal shock wave group was greater than that in the orthopedic group after the treatment for 2 weeks. The VAS score in the combined group was smaller than that in the orthopedic group after the treatment for 2 weeks and 3 months (P< 0.05). The VAS scores in the orthopedic group and the combined group were smaller than those in the extracorporeal shock wave group after the treatment for 1 month or 3 months (P< 0.05). The continued walking time and thickness of the plantar fascia was improved after the treatment (P< 0.05). The cure rate and total effective rate in the combination group were obviously greater than those in the two other groups. The cure rate in the orthopedic group was greater than that in the extracorporeal shock wave group (P< 0.05). CONCLUSION: Extracorporeal shock wave combined with orthopaedic insole therapy is an effective method to treat plantar fasciitis. It is recommended to spread in clinic. PMID- 25544168 TI - [Suppression of hepatocellular carcinoma invasion and metastasis by Rho-kinase inhibitor Fasudil through inhibition of BTBD7-ROCK2 signaling pathway]. AB - OBJECTIVE: To explore the eff ect of Fasudil on the invasion and metastatic abilities of human high metastatic liver cancer cells (HCCLM3) and the underlying mechanisms. METHODS: HCCLM3 cells were incubated with 100 MUmol/L Fasudil. Fluorescence staining for F-actin and Transwell assay were performed to observe the invasion ability of HCCLM3 cells. HCCLM3 cells were divided into 3 groups: a negative control group, a Fasudil group and a BTB/ POZ domain containing 7 (BTBD7)-siRNA group. Western blot assay was performed to detect the expression levels of BTBD7, ras homolog family member C (RhoC) and Rho-associated, coiled coil containing protein kinase 2 (ROCK2), matrix metalloproteinases 2 (MMP2) and MMP9. Zymogram analysis method was performed to detect the expression activities of MMP2 and MMP9. The BTBD7-siRNA group was served as a positive control. RESULTS: In HCCLM3 cells treated with Fasudil, the invasion ability was significant decreased compared with the control group, concomitant with the down regulated expression levels of BTBD7, RhoC and ROCK2 protein as well as the decreased activities of MMP2 and MMP9. CONCLUSION: Fasudil plays an important role in interfering BTBD7-ROCK2 signaling pathway and suppressing the invasion and metastasis of hepatocellular carcinoma. PMID- 25544169 TI - [Correlation between the expression of C-terminal tensin-like protein and the prognosis of hepatocellular carcinoma]. AB - OBJECTIVE: To explore the correlation between the expression of C-terminal tensin like protein (CTEN) and the prognosis of hepatocellular carcinoma (HCC). METHODS: Using immunohistochemistry, we detected CTEN protein level in samples of primary lesion and adjacent non-tumor lesion collected from 240 patients with HCC. The relationship between CTEN expression and clinicopathology, 5 year recurrent-free survival, or overall survival was evaluated by Chi-square test, Kaplan-Meier, or Cox regression analysis. RESULTS: High CTEN expression was detected in 55% of hepatocellular carcinoma tissues and 20% of adjacent carcinoma tissues (P< 0.001). CTEN expression was positively correlated with tumor diameter (P=0.022), venous invasion (P=0.007) or TNM stages (P=0.022). Five-year recurrence-free survival time (P< 0.001) and overall survival time (P< 0.001) in patients with high CTEN expression were significantly less than those in patients with low CTEN expression. Multivariate Cox regression analysis revealed that the CTEN expression was an independent prognostic marker for HCC (all P< 0.05). CONCLUSION: CTEN protein may play a role in the genesis and development of HCC, and it can function as a prognostic marker. PMID- 25544170 TI - [Contrastive study on conventional ultrasound, compression elastography and acoustic radiation force impulse imaging in the differential diagnosis of benign and malignant breast tumors]. AB - OBJECTIVE: To evaluate the diagnostic performance of conventional ultrasound, compression elastography (CE) and acoustic radiation force impulse imaging (ARFI) in differential diagnosis of benign and malignant breast tumors. METHODS: A total of 98 patients with liver lesions were included in the study. The images of conventional ultrasound, CE and the values of virtual touch tissue quantification (VTQ) of breast lesions were obtained. The diagnostic performance of conventional ultrasound, CE and ARFI were assessed by using pathology as the gold standard, and then evaluate the diagnosis efficiency of these three approaches in differential diagnosing benign and malignant breast tumors. RESULTS: The specificity, sensitivity and accuracy in the diagnosis of malignant breast tumors for conventional ultrasound were 80.0%, 81.1% and 81.7%, respectively, whereas for CE elastic score were 85.7%, 86.7% and 86.3%, respectively. With a cutoff value of 3.71 for the SR, the sensitivity, specificity, accuracy in diagnosis of malignant breast tumors were 97.1%, 83.3% and 88.4%, respectively. With a cutoff value of 3.78 m/s for VTQ, the sensitivity, specificity, accuracy in diagnosis of malignant breast tumors were 94.3%, 91.7% and 92.6%, respectively. The difference in diagnosis efficiency among ARFI, CE and conventional ultrasound in differential diagnosis of benign and malignant breast tumors was significant (P< 0.05). CONCLUSION: Conventional ultrasound, CE and ARFI are all useful for the differential diagnosis of benign and malignant breast tumors. But the diagnosis efficiency of ARFI is superior to CE and conventional ultrasound. The three approaches can help each other in differential diagnosis of benign and malignant breast tumors. PMID- 25544171 TI - [Effect of high glucose on NADPH oxidase expression and reactive oxygen species generation in human umbilical vein endothelial cells]. AB - OBJECTIVE: To explore the effect of high glucose on NADPH oxidase (NOX) expression and intracellular reactive oxygen species (ROS) generation in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were divided into a control group, a mannite group, a glucose group and a glucose plus diphenylene iodonium (DPI) group. Intracellular ROS was detected by flow cytometry. RNA and protein expression of NOX in HUVECs was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. RESULTS: 1) Compared with the control group, the intracellular ROS were significantly increased in the glucose group (P< 0.05, n=3), but there were no significant change in the glucose plus DPI group (P> 0.05, n=3); 2) Compared with the control group, the mRNA and protein expression of NOX4 in the glucose group were significantly increased (P< 0.05), but there were no significant change in the mRNA and protein expression of NOX2, p22phox, p67phox and rac (all P> 0.05); 3) there were no significant difference in the mRNA and protein expression of NOX2, NOX4, p22phox, p67phox and rac between the glucose plus DPI group and the control group (all P> 0.05). CONCLUSION: High glucose may increases intracellular ROS generation by increasing the expression of NOX4 in HUVECs, which might mediate the oxidative stress. PMID- 25544172 TI - [Resveratrol improves intestinal injury in hemorrhagic shock rats by protection of mitochondria and reduction of oxidative stress]. AB - OBJECTIVE: To explore whether resveratrol can reduce intestinal damage in hemorrhagic shock rats and the underlying mechanism. METHODS: A total of 24 Sprague-Dawley rats of specifi c pathogen free (SPF) were randomly divided into a control group(n=8), a resveratrol group (SR group, n=8) and a vehicle group (SS group, n=8). Th e mean arterial pressure was recorded. Two hours aft er hemorrhagic shock, 15 mg/kg resveratrol or 0.3 mL equal volume of vehicle and autologous blood were given, respectively. The intestinal specimens were collected for hematoxylin-eosin (HE) staining and calculated the pathological score. The superoxide dismutase 2 (SOD2) and cytochrome C (Cyt C) protein expression was examined by immunohistochemistry and/or Western blot. ATP level, activities of glutathione peroxidase (GXH-px), catalase (CAT) and SOD were also detected. RESULTS: Two hours after autologous blood transfusion, the mean arterial pressure in the SR group was significantly higher than that in the SS group (P< 0.01). Compared with the SS group, the pathological injury was significantly alleviated and pathological scores were dramatically reduced in the SR group (P< 0.05). The activities of GXH-px, CAT, SOD and the ATP levels in the SR group were significantly higher than those in the SS group (all P< 0.01). Compared with the SS group, the SOD2 expression was significantly higher while the Cyt C expression was dramatically lower in the SR group (both P< 0.01). CONCLUSION: Resveratrol could alleviate the intestinal injury in hemorrhagic shock rats, which might be associated with its effects on reduction of oxidative stress and protection of mitochondria. PMID- 25544173 TI - [Associations of blood pressure, glucose or lipids with stroke in different age or gender]. AB - OBJECTIVE: To investigate the relationship between blood pressure, blood glucose or blood lipids and patients with cerebral infarction (CI) or intracerebral hemorrhage (ICH) in different age or gender. METHODS: Th e case-control study consecutively recruited patients with fi rst-ever-in-a-lifetime CI (n=358) and ICH (n=230) and community-acquired pneumonia (n=165) as controls between January 2010 and December 2013 at the Second Xiangya Hospital of Central South University. The patients with CI or ICH were divided into the young group, the middle-aged group and the older group, and the risk factors were compared between the 3 groups. The patients with CI or ICH were respectively further divided into the male group and the female group. The blood pressure, glucose and lipids were measured. RESULTS: Data from logistic regression models showed that CI was closely associated with high blood pressure, hypertension, diabetes mellitus (DM) or fasting plasma glucose (FPG) (P< 0.05), and ICH was closely related to high blood pressure, hypertension, low density lipoproteincholesterol (LDL-C), FPG, serum creatinine (SCr) or alcohol drinking (P< 0.05); hypertension was the main risk factor for stroke. The odds ratios for the young, the middle-aged and older group were 10.43, 4.74 and 7.39 respectively (P< 0.05). Systolic blood pressure (OR=28.74) was the important risk factor for the young stroke, and the OR is 2.81 for the middle-aged stroke. Diastolic blood pressure (OR=2.96) and DM (OR=6.25) were the risk factor for the middle-aged stroke. LDL-C (OR=2.87) was a risk factor for the older stroke; the mean levels of diastolic blood pressure in males were significantly increased compared with that in females with CI, while the mean levels of TC, HDL-C or LDL-C in females were significantly higher than that in males with ICH (P< 0.05). CONCLUSION: Hypertension, systolic blood pressure in particular, is the most common risk factor for young stroke patients. DM and hypertension are the risk factors for the middle-aged patients, while hypertension, DM, LDL-C and alcohol consuming are the risk factors for the aged patients. PMID- 25544174 TI - [A study on loneliness among people who lost their children in disaster area of 5.12 Earthquake]. AB - OBJECTIVE: To evaluate the status of loneliness, the influential factors and the relationship between loneliness and family function among bereaved parents in disaster area of 5.12 Earthquake and to provide basis for mental and family reconstruction for those people suffering from the Earthquake. METHODS: A total 190 bereaved parents in disaster area of 5.12 Earthquake were enrolled for an across-sectional study. A face-to-face survey was conducted by following scales: General Data Scale, University of California at Los Angels Loneliness Scale, Emotional and Social Loneliness Scale and Family APGAR Index. RESULTS: The score of loneliness ranged from 24 to 69 (mean=43.58, SD=9.61), the score of emotional loneliness ranged from 5 to 24 (mean=11.95, SD=3.60) while the social loneliness ranged from 6 to 24 (mean=13.99, SD=3.69). The scores of loneliness, social loneliness and emotional loneliness were all increased among bereaved parents compared to people without loss of their child. The results of multivariate analysis showed that family function and status of fertility significantly impacted the loneliness (P< 0.05). Furthermore, there was negative correlation between family function and the loneliness, social loneliness and emotional loneliness (P< 0.05). CONCLUSION: The bereaved parents in disaster area of 5.12 Earthquake showed higher level of loneliness. The better of family function indicated the less of loneliness in bereaved parents. Measures should be taken to promote mental and family reconstruction for such people, including providing effective skills to improve emotional communication and family function and offering technical support for having another baby. PMID- 25544175 TI - [Therapeutic effect of gamma knife on intracranial cavernous angioma]. AB - OBJECTIVE: To evaluate the therapeutic effect of gamma knife on patients with intracranial cavernous angioma (CA). METHODS: The medical records of 122 patients (134 lesions) who underwent radiosurgery were reviewed retrospectively. RESULTS: Th e average follow-up period was 43 months. No patient died. One patient underwent CA resection. In patients with epilepsy, 83% patients showed alleviation of seizures. About 44% of the lesions shrank in size after treatment with gamma knife radiosurgery (59/134). Seven cases had hemorrhage again after radiosurgery, and the overall annual hemorrhage rate was 1.6%. Edema was found in 11.5% patients (14/122) and all patients showed improvement aft er treatment. CONCLUSION: Gamma knife is a safe treatment for CA, which could obviously improve the symptoms of epilepsy. Gamma knife radiosurgery is the fi rst option for the treatment of cavernous sinus angiomas. PMID- 25544177 TI - Prognostic value of coronary computed tomography angiography in stroke patients. AB - OBJECTIVE: The predictive value of coronary computed tomography angiography (CCTA) in stroke patients has not yet been established. We investigated the prognostic value of coronary artery disease (CAD) detection by CCTA, and determined the incremental risk stratification benefit of CCTA findings as compared to coronary artery calcium scores (CACS) in ischemic stroke patients without chest pain. METHODS: Among 914 consecutive ischemic stroke patients, 317 (68.5% were male with a mean age of 64 years) who had at least one clinical risk factor for CAD without chest pain were prospectively enrolled to undergo CCTA. CT images were assessed for CAC, presence of CAD and extent of CAD. The primary endpoint was major adverse cardiac events (MACEs) defined as cardiac death, non fatal myocardial infarction, unstable angina requiring hospitalization, or revascularization after 90 days from index CCTA. RESULTS: The prevalence of CAC >=1 was 73.1% (232/317) and the average CACS was 346.6 +/- 693.5 (Agatston unit). During the median follow-up period of 409 days, there were a total of 26 MACEs. Both CACS [CAC (101-400, and >400)] and CCTA findings [presence of obstructive CAD, 1-vessel disease (VD), 2-VD, and 3-VD] independently stratified risk of future MACEs (all p < 0.05). The time-dependent receiver operating characteristic curve analysis revealed that CAD findings (presence of obstructive CAD and number of involved vessels) based on CCTA improved risk stratification beyond clinical risk factors and CACS (iAUC: 0.863 vs 0.752, p < 0.05). CONCLUSION: In ischemic stroke patients without chest pain, CCTA findings of CAD provide additional risk discrimination over CACS. PMID- 25544176 TI - On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects. AB - Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins. The effect of PCSK9 on LDLR is being successfully utilized toward the development of anti-PCSK9 therapies to reduce plasma LDL-C levels. Current biochemical research has uncovered additional mechanisms of action and interacting partners for PCSK9, and this opens the way for a more thorough understanding of the regulation, metabolism, and effects of this interesting protein. PMID- 25544178 TI - Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice. AB - Regulatory T-Cells (Tregs) play a protective role against the development of atherosclerosis. Moreover, thymic stromal lymphopoietin (TSLP)/thymic stromal lymphopoietin receptor (TSLPR) signaling in myeloid dendritic cells (DCs) promote Treg differentiation. Here, we examined the potential role of TSLP/TSLPR on Treg homeostasis in atherosclerosis. The frequencies of both latency-associated peptide (LAP)(+) and Foxp3(+) Tregs were reduced in the thymus and spleen of ApoE(-/-) mice compared with C57BL/6 mice, and this effect was associated with decreased thymic output. The tolerogenic function of DCs obtained from ApoE(-/-) mice was compromised compared with those from C57BL/6 mice. The expression of TSLP and TSLPR was also inhibited in ApoE(-/-) mice. In addition, we found that ox-LDL attenuated TSLP expression in cultured thymic epithelial cells (TECs) through the activation of retinoid X receptor alpha (RXRA) and IL-1beta and decreased LAP and PD-L1 expression in oxLDL-activated DCs while both were up regulated in TSLP-activated DCs. We also observed that the TSLP-DCs mediated differentiation of Tregs was abrogated through LAP neutralization. Furthermore, TSLP injection rescued Treg defects in ApoE(-/-) mice. These findings suggest that Treg defects in ApoE(-/-) mice might partially be attributed to the disruption of TSLP-TSLPR-LAP signaling in epithelial cells (ECs) and DCs. PMID- 25544179 TI - Expression of anaphylatoxin receptors on platelets in patients with coronary heart disease. AB - OBJECTIVE: Inhibition of components of the complement system or of its receptors has been postulated as a concept for primary and secondary prevention in atherosclerosis and was applied in clinical trials. Although the anaphylatoxin receptors C3aR and C5aR are commonly associated with inflammatory cells, in vitro studies suggested their expression also on platelets. METHODS AND RESULTS: Expression levels of C3aR and C5aR were measured by flow cytometry in a collective of 302 patients with documented coronary artery disease (CAD) including patients with stable CAD (n = 152), unstable angina (n = 54), acute myocardial infarction (AMI; Non-ST elevation myocardial infarction, n = 70, ST elevation MI, n = 26) or healthy controls (n = 21). Patients with stable CAD, unstable angina or AMI had significantly higher expression of C5aR on platelets in comparison to healthy controls (MFI 14.68 (5.2), 14.56 (5.18) and 13.34 (4.52) versus 10.68 (3.1)); p < 0.001). In contrast, the expression of C3aR on platelets was significantly enhanced in patients with stable and unstable CAD but not in patients with AMI compared to controls. While there was a strong correlation between the soluble ligands of these receptors C3a and C5a, we observed only a weak correlation with their receptors on platelets. Similarly, agonist induced aggregation (MEA, ADP, and TRAP) showed only a weak correlation with the expression level of anaphylatoxin - receptors on platelets. Of note, the expression of both anaphylatoxin-receptors on platelets strongly correlated with platelet activation as assessed with the surface activation marker P-selectin (r = 0.47, p > 0.001 for C3aR, r = 0.76 for C5aR, p < 0.001). Likewise, we observed a positive correlation of C3aR with other molecules associated with platelet activation such as SDF-1. CONCLUSION: In summary, we observed a positive correlation between the expression of anaphylatoxin-receptors C3aR and C5aR with platelet activation in patients with CAD. Further investigations are needed to study the clinical and mechanistic relevance of these findings. PMID- 25544180 TI - Iron status and its association with coronary heart disease: systematic review and meta-analysis of prospective studies. AB - BACKGROUND: Observations in the past have hypothesized an association between body iron status and coronary heart disease (CHD). Epidemiological studies to date have however been inconclusive without the existence of strongly positive or strongly negative associations between iron status and coronary heart disease. OBJECTIVES: To investigate the association between iron status and coronary heart disease. DATA SOURCES: A systematic review was performed using the databases PubMed and Cochrane Library. Search terms included iron, ferritin, transferrin, total iron binding capacity, coronary heart disease and angina. STUDY SELECTION: Only prospective studies investigating the association of body iron status and coronary heart disease were included. All participants were free from coronary heart disease at baseline. There were no language or geographic restrictions imposed on the search strategy. DATA EXTRACTION: Independent extraction of articles by 2 authors using predefined data fields. DATA SYNTHESIS: All pooled analyses were based on random-effects models. A total of 17 studies were identified for analysis, involving a total of 9236 cases of coronary heart disease and 156,427 participants. Several studies reported more than 1 marker of iron status. For serum ferritin, comparison of individuals in the top third versus the bottom third of baseline measurements yielded a combined risk ratio of 1.03 (95%CI, 0.87-1.23) for CHD/MI. For transferrin saturation, the combined risk ratio for CHD/MI was 0.82 (95% CI, 0.75-0.89) for individuals in the top third versus the bottom third of baseline measurements. Comparison of individuals in top and bottom thirds of baseline measurements yielded non-significant risk ratios of studies involving total iron-binding capacity (combined risk ratio, 0.99; 95% CI 0.86-1.13) and serum iron (combined risk ratio, 0.87; 95% CI 0.73 1.04). For serum iron, the combined risk ratio for CHD/MI after excluding the study by Morrisson et al. [1] was 0.80 (95% CI, 0.73-0.87). CONCLUSIONS: The results suggest that there is a negative association of transferrin levels and coronary heart disease with high transferrin saturations being associated with a lower risk of CHD/MI. There was also a negative association of serum iron and CHD/MI after one study [1] was excluded. There is no significant association between the other markers of iron status and CHD. It is however difficult to infer causality from these findings due to limitations in terms of reverse causality bias and residual confounding. PMID- 25544181 TI - Involvement of ERK pathway in interferon alpha-mediated antiviral activity against hepatitis C virus. AB - Interferon alpha (IFN-alpha) is the key component of the therapy for hepatitis C virus (HCV) infection. IFN-alpha exerts anti-HCV activity by targeting certain signaling pathways. Using infectious HCV culture system in human hepatoma Huh7.5.1 cells, we analyzed functional relevance of extracellular signal regulated kinase (ERK) pathway for IFN-alpha-mediated anti-HCV activity. IFN alpha treatment resulted in activation of ERK pathway by increasing phosphorylation of c-Raf, MEK, and ERK1/2 in Huh7.5.1 cells, whereas HCV impaired such activation. IFN-alpha-dependent ERK1/2 phosphorylation was blocked by MEK inhibitor U0126. Pharmacological inhibition of ERK1/2 by U0126 or siRNA-mediated knockdown of ERK1/2 resulted in suppressive effects on HCV RNA levels and expression of HCV nonstructural protein 3 and envelope protein 2, establishing an important role for ERK pathway in HCV replication. Moreover, induction of a set of antiviral genes by IFN-alpha was enhanced in HCV-infected Huh7.5.1 cells due to the ERK1/2 knockdown, suggesting that impairment of ERK signaling may potentiate HCV inhibition by IFN-alpha. These results demonstrate that ERK pathway is involved in IFN-alpha-mediated antiviral activity against HCV. PMID- 25544182 TI - Genetic variation in the promoter region of pro-inflammatory cytokine TNF-alpha in perinatal HIV transmission from Mumbai, India. AB - Various host factors such as cytokines and HLA, regulate the immune system and influence HIV transmission to infants exposed to HIV-1 through their mothers. Tumor Necrosis Factor Alpha (TNF-alpha) is a strong pro-inflammatory mediator and thought to influence vulnerability to HIV infection (and/or) transmission. Polymorphisms in regulatory regions are known to govern the production of this cytokine. However, the association of these variations in perinatal HIV transmission is yet to be established. Present study aimed to evaluate if polymorphisms in promoter region of TNF-alpha gene is associated with perinatal HIV transmission. With informed consent from parents, infants' blood was collected for HIV screening and SNPs analysis at 2 loci: TNF (rs1800629) and TNF (rs361525) using PCR-SSP method. HIV positive (n = 27) and negative (n = 54) children at the end of 18th month follow up were considered for this study. GG genotype, responsible for low expression of TNF (rs1800629) was significantly (p = 0.005) higher in uninfected children, while higher GA genotype frequency was observed in infected children. The 'G' allele frequency was significantly higher in negative children (p = 0.016). We conclude that genotypic variants of TNF (rs1800629) are a likely contributor to perinatal HIV transmission. This provides new insights in markers of differential susceptibility to perinatal HIV transmission. PMID- 25544183 TI - Anti-proliferative effect of fungal taxol extracted from Cladosporium oxysporum against human pathogenic bacteria and human colon cancer cell line HCT 15. AB - Cladosporium oxysporum a new taxol producing endophytic fungus was identified and production of taxol were characterized using UV-visible spectroscopy (UV-vis), high-performance liquid chromatography (HPLC), infrared (IR) nuclear magnetic resonance spectroscopy (NMR ((13)C and (1)H)) and liquid chromatography-mass spectrometry (LC-MS). The taxol biosynthetic gene (dbat) was evaluated for new taxol producing fungus. Antibacterial activity against six different human pathogenic bacteria was done by agar well diffusion method. The anticancer efficacy of isolated fungal taxol were also evaluated in human colon cancer cell HCT 15 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cytotoxicity and nuclear morphology analysis. The isolated fungal taxol showed positive towards biosynthetic gene (dbat) and effective against both Gram positive as well as Gram negative. The fungal taxol suppress growth of cancer cell line HCT 15 with an IC50 value of 3.5MUM concentration by 24h treatment. Thus, the result reveals that C. oxysporum could be a potential alternative source for production of taxol and have antibacterial as well as anticancer properties with possible clinical applications. PMID- 25544184 TI - Antibacterial potential of rutin conjugated with thioglycolic acid capped cadmium telluride quantum dots (TGA-CdTe QDs). AB - Quantum dots not only act as nanocarrier but also act as stable and resistant natural fluorescent bio markers used in various in vitro and in vivo photolabelling and biological applications. In this study, the antimicrobial potential of TGA-CdTe QDs and commercial phenolics (rutin and caffeine) were investigated against Escherichiacoli. UV absorbance and fluorescence quenching study of TGA-CdTe QDs with rutin and caffeine complex was measured by spectroscopic technique. QDs-rutin conjugate exhibited excellent quenching property due to the -OH groups present in the rutin structure. But the same time caffeine has not conjugated with QDs because of lacking of -OH group in its structure. Photolabelling of E. coli with QDs-rutin and QDs-caffeine complex was analyzed by fluorescent microscopic method. Microbe E. coli cell membrane damage was assessed by atomic force (AFM) and confocal microscopy. Based on the results obtained, it is suggested that QDs-rutin conjugate enhance the antimicrobial activity more than the treatment with QDs, rutin and caffeine alone. PMID- 25544185 TI - Vibrational spectroscopic study of pure and silica-doped sulfonated poly(ether ether ketone) membranes. AB - We report the vibrational properties of sulfonated poly(ether ether ketone) (SPEEK) membranes, used as electrolytes in proton exchange membrane (PEM) fuel cells, studied by Fourier transform infrared (FTIR) spectroscopy. We discuss the changes in the vibrational modes of the functional groups present in the polymer arising due to the sulfonation process and the subsequent incorporation of silica particles functionalized with sulfonic acid group. From the infrared spectra, we confirm the incorporation of sulfonic acid group in the polymer chain as well as in the functionalized silica particles. We have also measured the variations in the peak area ratio of the characteristic out-of-plane vibrations of the aromatic rings in the PEEK polymer at 1280cm(-1) with respect to a reference peak at 1305cm(-1). These values were correlated to the crystallinity (XC) values experimentally determined by DSC technique, providing a non-destructive means to calculate the crystallinity of polymer membranes. The calculated XC values were in good agreement with the experimental values. The crystallinity was observed to decrease with increasing degree of sulfonation (DS), indicating the crystalline to-amorphous phase modification of the polymer by sulfonation, which along with the enhanced ion-exchange capacity and water uptake, is responsible for the improved ionic conductivity at higher DS values. PMID- 25544186 TI - Chemometric analysis of correlations between electronic absorption characteristics and structural and/or physicochemical parameters for ampholytic substances of biological and pharmaceutical relevance. AB - Forty ampholytic compounds of biological and pharmaceutical relevance were subjected to chemometric analysis based on unsupervised and supervised learning algorithms. This enabled relations to be found between empirical spectral characteristics derived from electronic absorption data and structural and physicochemical parameters predicted by quantum chemistry methods or phenomenological relationships based on additivity rules. It was found that the energies of long wavelength absorption bands are correlated through multiparametric linear relationships with parameters reflecting the bulkiness features of the absorbing molecules as well as their nucleophilicity and electrophilicity. These dependences enable the quantitative analysis of spectral features of the compounds, as well as a comparison of their similarities and certain pharmaceutical and biological features. Three QSPR models to predict the energies of long-wavelength absorption in buffers with pH=2.5 and pH=7.0, as well as in methanol, were developed and validated in this study. These models can be further used to predict the long-wavelength absorption energies of untested substances (if they are structurally similar to the training compounds). PMID- 25544187 TI - Density functional theory studies on molecular structure, vibrational spectra and electronic properties of cyanuric acid. AB - The present work has been carried out a combined experimental and theoretical study on molecular structure, vibrational spectra and NBO analysis of cyanuric acid. The FT-IR (100-4000cm(-1)) and FT-Raman spectra (400-4000cm(-1)) of cyanuric acid were recorded. In DFT methods, Becke's three parameter exchange functional (B3) combined with gradient-corrected correlation functional of Lee, Yang and Parr (LYP) by implementing the split-valence polarized 6-31G(d,p) and 6 31++G(d,p) basis sets have been considered for the computation of the molecular structure optimization, vibrational frequencies, thermodynamic properties and energies of the optimized structures. The density functional theory (DFT) result complements the experimental findings. The electronic properties, such as HOMO LUMO energies and molecular electrostatic potential (MESP) are also performed. Mulliken population analysis on atomic charges is also calculated. The first order hyperpolarizability (betatotal) of this molecular system and related properties (beta, MU and Deltaalpha) are calculated using DFT/B3LYP/6-31G (d,p) and B3LYP/6-311++G(d,p) methods. The thermodynamic functions (heat capacity, entropy and enthalpy) from spectroscopic data by statistical methods were also obtained for the range of temperature 50-1000K. PMID- 25544188 TI - Quantum chemical computations, vibrational spectroscopic analysis and antimicrobial studies of 2,3-Pyrazinedicarboxylic acid. AB - Density Functional Theory (DFT) calculations at B3PW91 level with 6-311G (d) basis sets were carried out for 2,3-Pyrazinedicarboxylic acid (PDCA) to analyze in detail the equilibrium geometries and vibrational spectra. Calculations reveal that the optimized geometry closely resembles the experimental XRD data. Vibrational spectra were analyzed on the basis of potential energy distribution (PED) of each vibrational mode, which provides quantitative as well as qualitative interpretation of IR and Raman spectra. Information about size, shape, charge density distribution and site of chemical reactivity of the molecule were obtained by mapping electron density isosurface with the electrostatic potential surface (ESP). Based on optimized ground state geometries, NBO analysis was performed to study donor-acceptor (bond-antibond) interactions. TD-DFT analysis was also performed to calculate energies, oscillator strength of electronic singlet-singlet transitions and the absorption wavelengths. The (13)C and (1)H nuclear magnetic resonance (NMR) chemical shifts of the molecule in the ground state were calculated by gauge independent atomic orbital (GIAO) method and compared with the experimental values. PDCA was screened for its antimicrobial activity and found to exhibit antifungal and antibacterial effects. Molecular docking was also performed for the different receptors. PMID- 25544189 TI - Extractive liquid-liquid spectrofluorometric determination of trace and ultra concentrations of bromate in water samples by the fluorescence quenching of tetraphenylphosphonium iodide. AB - A low cost and selective spectrofluorimetric method has been developed for trace determination of bromate ions in water. The method has been based upon complete extraction of the produced yellow colored ion associate of the reagent tetraphenylphosphonium iodide (TPP(+) I(-)) and bromate ions from aqueous media into chloroform and measuring the fluorescence quenching at lambdaex/em=242/305nm. The composition, stability and the most probable mechanism of the produced associate have been determined. The plot of fluorescence intensity of TPP(+) I(-)vs. bromate concentration was linear in the range 0.86 150.0MUgL(-1). The limits of detection (LOD) and quantification (LOQ) of BrO3(-) were 0.24 and 0.76MUgL(-1), respectively. The method was found free from most of the interferences present in chromatographic, spectrofluorometric and spectrophotometric methods. Intra and inter-day laboratory accuracy and precision for analysis of bromate in water were determined. The method provides better performance compared to the international standard method recently issued (ISO 11206:2011). The method was applied satisfactorily for analysis of 1.0MUgL(-1) bromate in the presence of high excess of chloride (50mg/L) without pretreatment with a relative standard deviation (RSD) of +/-2.9%. The method was applied for analysis of bromate in various water samples. Statistical comparison of the results of the proposed method with those obtained by the standard method revealed no significant differences in the accuracy and precision. PMID- 25544190 TI - DFT electronic structure calculations, spectroscopic studies, and normal coordinate analysis of 2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl acetate. AB - The solid phase FTIR and FT-Raman spectra of 2-[(5-nitro-1,3-thiazol-2 yl)carbamoyl]phenyl acetate (25N2LCPA) have been recorded 450-4000cm(-1) and 100 4000cm(-1) respectively. The normal coordinate analysis was carried out to confirm the precision of the assignments. DFT calculations have been performed giving energies, optimized structures, harmonic vibrational frequencies and IR intensities. The structure of the molecule was optimized and the structural characteristics were determined by density functional theory (DFT) using B3LYP method with 6-31+G(d,p) basis set. The detailed interpretation of the vibrational spectra has been carried out with aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology. The Vibrational frequencies are calculated in the above method and are compared with experimental frequencies which yield good agreement between observed and calculated frequencies. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. In addition, Frontiers molecular orbital and molecular electrostatic potential were computed by using Density Functional Theory (DFT) B3LYP/6-31+G(d,p) basis set. The calculated HOMO and LUMO energies show that charge transfer occurs in the molecule. PMID- 25544191 TI - A strong NH...Br vibrational behaviour studied through X-ray, vibrational spectra and quantum chemical studies in an isomorphous crystal: 2-Nitroanilinium bromide. AB - A needle shaped transparent light brown crystals of 2-nitroanilinium bromide were successfully synthesized and crystallized from an aqueous mixture by slow evaporation technique. Single crystal XRD studies confirm the crystalline phase of this isomorphous compound which contains a positively charge 2-nitroanilinium cation and a negatively charged bromide anion. The solid phase FT-IR and FT-Raman spectra of the compound have been recorded in the range of 4000-400cm(-1). The observed modes are correlated by the factor group theory analysis and different IR and Raman active species were identified. Geometrical optimisations were carried out and harmonic vibrational wave numbers were computed for the minimum energy molecular structure at RHF level invoking 6-311++G(d,p) and SDD basis sets. Optimised molecular geometry was compared with the crystallographic data. The calculated wavenumbers were compared with the experimental values. The NH vibrational bands are shifted from its normal range and the shifting is associated with the influence of the intermolecular hydrogen bonds in the crystal. A strong intensity peak in theoretical and corresponding band in experimental confirms the presence of NH...Br interaction as predicted in crystalline state. PMID- 25544192 TI - Temperature and high pressure effects on the structural features of catalytic nanocomposites oxides by Raman spectroscopy. AB - Structural characterizations of nanostructured oxides were studied by X-ray diffraction (XRD), Raman and infrared spectroscopy. The oxides catalysts namely, SnO2, ZrO2, CeO2, MnOx, Al2O3 and TiO2 were prepared by a nanocasting route and the effect of the temperature and pressure on the stability of the solids was evaluated. Raman spectra showed that ZrO2 and TiO2 exhibited phase transitions at moderate temperatures whereas CeO2, SnO2 and MnOx had an effective creation of defects in their structures upon annealing at elevated temperatures. The results suggested also that the effect of the temperature on the particles growth is related to the type of oxide. In this regard, phase transition by up to 600 degrees C accelerated the sintering of ZrO2 and CeO2 grains compared to TiO2, SnO2 and MnOx counterparts. Under hydrostatic pressures lower than 10GPa, rutile TiO2 and tetragonal ZrO2 exhibited pressure induced phase transition whereas CeO2 and SnO2 were stable at pressures close to 15GPa. The experiments revealed that the nanostructured SnO2 oxide exhibited stable performance at relatively high temperatures without phase transition or sintering, being suitable to be used as catalysts in the range of temperature and pressure studied. PMID- 25544193 TI - Synthesis, conformational structure and spectroscopic properties of trans diazidobis(2,2-dimethyl-1,3-propanediamine)chromium(III) perchlorate. AB - A new complex trans-anti-[Cr(Me2tn)2(N3)2]ClO4.2H2O, where Me2tn=2,2-dimethyl-1,3 propanediamine was synthesized and characterized, and its molecular structure was established by single-crystal X-ray diffraction at 95K. The complex crystallized in the space group C2/c of the monoclinic system with four mononuclear formula units in a cell of dimensions a=16.600 (3), b=7.709 (2), c=16.865 (3)A, and beta=99.07 (3) degrees . The chromium(III) atom was in a distorted octahedral coordination with four N atoms of two chelating Me2tn ligands and two N atoms of the azido group in the trans axial position. The two six-membered rings in the complex adopted only anti chair-chair conformations with respect to each other The important bond lengths are CrN(azide) 2.007 (2), CrN(Me2tn) 2.081 (2), 2.082 (2), NN(azide) 1.184 (2) and 1.156 (2)A, respectively. The crystal lattice is stabilized by hydrogen bonding interactions among the ClO4(-), hydrate molecule, N3(-), and NH groups of the Me2tn ligand. The ligand field analysis as well as the IR and electronic spectral properties were described. PMID- 25544194 TI - Synthesis, DNA interactions and antibacterial PDT of Cu(II) complexes of phenanthroline based photosensitizers via singlet oxygen generation. AB - Cu(II) complexes [Cu(mqt)(B)H2O]ClO4(1-3) of 2-thiol 4-methylquinoline and phenanthroline bases (B), viz 1,10-phenanthroline (phen in 1), Dipyrido[3,2 d:2',3'-f]quinoxaline (dpq in 2) and Dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3) have been prepared and characterized by elemental analysis, IR, UV-Vis, magnetic moment values, EPR spectra and conductivity measurements. The spectral data reveal that all the complexes exhibit square-pyramidal geometry. The DNA-binding behaviors of the three complexes were investigated by absorption spectra, viscosity measurements and thermal denaturation studies. The DNA binding constants for complexes (1), (2) and (3) were determined to 2.2*10(3), 1.3*10(4) and 8.6*10(4)M(-1) respectively. The experimental results suggest that these complexes interact with DNA through groove-binding mode. The photo induced cleavage studies shows that the complexes possess photonuclease property against pUC19 DNA under UV-Visible irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. Antimicrobial photodynamic therapy was studied using photodynamic antimicrobial chemotherapy (PACT) assay against Escherichiacoli and all complexes exhibited significant reduction in bacterial growth on photoirradiation. PMID- 25544195 TI - Association between physician beliefs regarding assigned treatment and clinical response: re-analysis of data from the Hypericum Depression Trial Study Group. AB - BACKGROUND: We have previously shown an association between patient belief and treatment response in the Hypericum Depression Trial Study Group's 2002 study. We re-examined these data to determine whether clinical improvement was associated with physician belief about assigned therapy. METHODS: Three hundred and forty adults with major depression and baseline scores >=20 on the 17-item Hamilton Depression Scale (HDRS-17) were randomized to Hypericum 900-1500mg/day, sertraline 50-100mg/day, or placebo for 8 weeks. At week 8, physicians guessed their patients' treatment. We analyzed 277 subjects with at least one post baseline visit and physician guess data. We examined association between guess and improvement in HDRS-17 and whether treatment assignment moderated the effect of belief on remission (final HDRS-17 score <8). RESULTS: Patient and doctor guesses agreed at 53% for sertraline, 68% for Hypericum, and 52% for placebo (kappa=0.37). Doctors guessed placebo correctly (38%) more than sertraline (18%) or Hypericum (19%) (p=0.001). Adverse event scores were significantly greater among subjects for which the clinicians guessed Hypericum (p<0.001) or sertraline (p=0.005) compared to placebo. Significant improvements in HDRS-17 score were found when comparing the Hypericum-guess (p<0.001) or the sertraline-guess group (p<0.001) against the placebo-guess group. Remission rates were significantly greater for subjects whose clinicians guessed sertraline (p<0.001) or Hypericum (p<0.001) versus placebo. CONCLUSION: Doctors tended to guess placebo more easily than Hypericum or sertraline, and their guesses tended to favor active therapies when improvement was more robust. Results show association but not causation, and merit more careful investigation. PMID- 25544197 TI - Recurrent intraventricular thrombus following myocardial infarction. PMID- 25544196 TI - Synthesis of 5,6-dihydropyrazolo[1,5-c]quinazolines through gold-catalyzed chemoselective bicyclization of N-propargylic sulfonylhydrazones. AB - An efficient method for the preparation of 5,6-dihydropyrazolo[1,5-c]quinazolines via gold(I)-catalyzed chemoselective bicyclization of N-propargylic sulfonylhydrazones has been developed. This process relies on the chemoselective cyclization of the hydrazone nitrogen instead of the usually favored aniline nitrogen onto the alkyne. The synthetic utility of the current strategy is demonstrated through the synthesis of a potential Eg5/Kinesin spindle protein inhibitor. PMID- 25544198 TI - Dante and cardiology: Physiopathology and clinical features of cardiovascular diseases in the Middle Ages. AB - Ancient non-medical texts can unexpectedly provide useful information on the development of knowledge about the heart and its diseases throughout history. The 750th anniversary of the birth of the Italian poet Dante Alighieri (1265-1321) provides a timely opportunity to analyze medical references in his works, in particular, focusing on literary descriptions that may be attributed to cardiovascular disorders. Dante's high level of medical knowledge, probably derived from his academic studies, is testified by his affiliation to the Florentine Guild of physicians and pharmacists. In all his works, the poet shows a deep interest for the heart. However, his anatomical and physiological knowledge of the circulatory system appears to be poor, probably due to it being based on theories and concepts brought forth by Aristotle and Galen, which were taught in medieval universities. Despite this, accurate descriptions of some symptoms (emotional syncope, orthopnea, dyspnea on exertion) and signs (ascites, paleness), which may be attributed to cardiovascular disorders, can be easily found in Dante's works, particularly in his masterpiece, the Divine Comedy. The literary and historical analysis of cardiovascular signs and symptoms allows us to assume that clinical features due to alterations of heart function were probably known by medieval physicians, but their etiology and pathophysiological mechanisms were not completely understood in that period. Historians of cardiology and clinicians should consider analysis of non-medical texts (including poetry) as an opportunity to better investigate the evolution of their discipline throughout the ages. PMID- 25544199 TI - Exercise-induced left-ventricular hypertrabeculation in athlete's heart. PMID- 25544201 TI - Benfluorex: An active toxin for the development of aortic valve stenosis. PMID- 25544200 TI - Utility of graded exercise tolerance tests for prediction of cardiovascular mortality in old age: The Rancho Bernardo Study. AB - BACKGROUND: Exercise electrocardiography in asymptomatic adults has been criticized because of relatively poor accuracy predicting future heart disease risk, but studies may have been too short. We investigated if integrated analysis of graded exercise tolerance tests (GXT) predicted long-term coronary heart disease (CHD) and all-cause mortalities among community-dwelling older adults. METHODS AND RESULTS: From 1972 to 1974, 1789 adult residents of a predominantly Caucasian, middle- to upper-middle-class southern California community participated in a clinical evaluation that included a GXT; 52.4% (N=939) of those who had baseline GXT were followed up to 2010-up to 36years-for vital status, CHD and all-cause mortality. Multiply adjusted hazard ratios of an abnormal graded GXT were 1.65 (95% CI 0.78-3.49) and 1.56 (95% CI 1.15-2.11) for CHD and all cause mortality, respectively. An integrated analysis hazard ratio was calculated based on the following GXT findings: significant ST change, inability to achieve target heart rate [THR], abnormal heart rate recovery [HRR], and chronotropic incompetency [ChI]. Compared to those with 0 or 1 abnormality, participants with 2 or more positive findings had significantly higher CHD (HR 2.18) and all-cause (HR 1.92) mortalities. Participants with 3 or more positive findings showed even higher hazard ratios-CHD (HR 6.16) and all-cause (HR 2.49) mortalities. When adjusted for any of 3 Framingham risk models, the integrated electrocardiographic model correlated well with CHD and all-cause mortalities. CONCLUSIONS: An integrated analysis of electrocardiographic and non-electrocardiographic measures of GXT is useful in predicting long-term CHD and all-cause mortalities in an asymptomatic middle-aged population. PMID- 25544202 TI - Geographic variation and phylogenetic relationships of Myiopagis olallai (Aves: Passeriformes; Tyrannidae), with the description of two new taxa from the Northern Andes. AB - Geographic variation in vocalizations, morphology and plumage patterns in New World flycatchers is little understood, particularly in rare species with disjunct distributions. We discovered a distinct new flycatcher of the genus Myiopagis from cloud forests of the northern Central Andes in Antioquia, Colombia. Comparisons of vocalizations and external morphology, and molecular phylogenetic analyses, demonstrate that the "Antioquia Myiopagis" is a unique lineage of the M. caniceps-olallai group. We show that three specimens collected in 1940-1951 from cloud forests of Serrania de Perija in Venezuela, and traditionally assigned to M. caniceps, represent another distinct taxon that is closer to the "Antioquia Myiopagis" and M. olallai. Both new taxa, from Antioquia and Perija, are described as subspecies of M. olallai. We present a phylogenetic hypothesis for the M. caniceps-olallai group, in which M. olallai and the "Antioquia Myiopagis" are phylogenetically nested within the polytypic M. caniceps, which consists of at least four distinct lineages, indicating that species diversity in this group could be underestimated. PMID- 25544203 TI - A new species of mealybug in the genus Paracoccus Ezzat & McConnell from North America (Insecta: Coccoidea: Pseudococcidae). AB - A probably adventive mealybug species, Paracoccus gillianae sp. n. is described from North America. Its entry into the United States was likely to have been via the horticultural trade of Agave spp. (Liliales: Agavaceae) and other host plants in the family Agavaceae. Illustrations of the adult female and male, and diagnosis from congeners in the New World and from other Paracoccus species known to feed on Agavaceae, are provided. PMID- 25544204 TI - Sinocyclocheilus brevifinus (Teleostei: Cyprinidae), a new species of cavefish from Guangxi, China. AB - Sinocyclocheilus brevifinus sp. nov. is described from a subterranean river at Maohedong Village, Guangxi Zhuang Autonomous Region, Southern China. The new species can be distinguished from all congeners in having functional eyes, last simple dorsal fin ray soft and without serrations along posterior margin, eye diameter small (3.4-5.0 %SL), tip of depressed dorsal fin not reaching vertical at anal fin origin, tip of depressed pelvic fin far from anus, maxillary barbel not reaching anterior edge of operculum, rostral barbel not reaching posterior edge of operculum, scales of lateral line row significantly larger than those of scale rows immediately above and below lateral line, and flanks with distinct black spots and blotches. PMID- 25544205 TI - A new species of Velvet Gecko (Oedura: Diplodactylidae) from the limestone ranges of the southern Kimberley, Western Australia. AB - We describe a new species of large Oedura from the Oscar Range on the southern edge of the Kimberley Craton in north-western Australia. Oedura murrumanu sp. nov. can be distinguished from all congeners by the combination of large size (snout-vent length to 103 mm), moderately long and slightly swollen tail, tiny scales on the dorsum, fringe of laterally expanded lamellae on each digit, and 6 7 paired distal subdigital lamellae on the fourth toe. The new species is the first endemic vertebrate known from the limestone ranges of the southern Kimberley; however, this area remains poorly surveyed and further research (particularly wet season surveys and genetic analyses) is required to better characterise regional biodiversity values. PMID- 25544206 TI - A new species of the genus Paravillersia (Acari: Prostigmata: Stigmaeidae) from Western Siberia, with supplementary description of Paravillersia grata Kuznetsov, 1978. AB - A new species of the genus Paravillersia Kuznetsov, 1978 (Acari: Stigmaeidae), P. jamaliensis Khaustov sp. nov. is described from mosses on fen in Western Siberia, Russia. The supplementary description of Paravillersia grata Kuznetsov, 1978 is provided based on the type material. PMID- 25544207 TI - A review of genus-group names in Diptera (Insecta) that J.C. Fabricius
"borrowed" from other dipterists and proposed as new in his systematic works from 1775 to 1805. AB - It is shown that a total of eight pre-existing genus-group names in Diptera were "borrowed" and deliberately given new identities in the systematic works of J.C. Fabricius: Bibio Fabricius, 1775, Ceria Fabricius, 1794, Hirtea Fabricius, 1798, Mulio Fabricius, 1798, Scatophaga Fabricius, 1805, Sicus Fabricius, 1798, Thereva Fabricius, 1798 and Voluccella Fabricius, 1794. These names are reviewed from the standpoint that they are nomenclaturally available as intentional homonymous proposals of names for new genus-group taxa. New type-species designations are made for Bibio Fabricius, Mulio Fabricius, and Scatophaga Fabricius. Bibio Fabricius, 1775 is recognized as a senior synonym of Thereva Latreille, 1797, syn. n., but is invalid as it is a junior homonym of Bibio Geoffroy, 1762. Scatophaga Fabricius, 1805 is recognized as a junior synonym of Psila Meigen, 1803, syn. n. The nominal species Musca suilla Fabricius, 1794 has been misinterpreted as a species of Scathophaga Meigen, 1803 by subsequent authors. Scathophaga spurca Meigen, 1826 is revived as the valid name for Scathophaga suilla auct. nec (Fabricius, 1794), stat. rev. A lectotype is designated for Musca suilla Fabricius and it is shown to belong to the scathophagid Norellisoma spinimanum (Fallen, 1819), syn. n. In order to maintain stability of nomenclature and prevailing usage, reversal of precedence is invoked to declare Cordylura spinimana Fallen, 1819 as a nomen protectum and Musca suilla Fabricius, 1794 as a nomen oblitum. PMID- 25544208 TI - A revision of the endemic South African sac spider genus Lessertina Lawrence, 1942 (Araneae: Eutichuridae). AB - The endemic South African sac spider genus Lessertina Lawrence, 1942, previously known only from the type species (L. mutica Lawrence, 1942), is revised. Both sexes of L. mutica are redescribed and the species is recorded from the Eastern Cape, KwaZulu-Natal and Limpopo Provinces. A new species, L. capensis sp. nov., is described from the Eastern and Western Cape Provinces. PMID- 25544209 TI - Elaphopsocoides, a new genus of Psocidae (Psocodea: 'Psocoptera') from Valle del Cauca, Colombia. AB - Two new species of Elaphopsocoides n. gen. from Valle del Cauca, Colombia, are here described and illustrated. The new genus is related to Elaphopsocus Roesler, but differs from it mostly in the hypandrial projections and in phallosome structure. The female subgenital plate has a distinct, median, posterior projection. The types are deposited in the Entomology Museum, Universidad del Valle (MUSENUV), Santiago de Cali, Colombia. PMID- 25544210 TI - Revision of the spider genus Mystaria Simon, 1895 (Araneae: Thomisidae) and the description of a new genus from the Afrotropical region. AB - The spider genera Mystaria Simon, 1895 and Paramystaria Lessert, 1919 are revised (Mystarini: Thomisidae). About 400 individuals were studied. The approach followed was classical taxonomy using illustrated sexual dimorphic copulatory characters and described morphological characters, photographed or measured. Paramystaria is considered a junior synonym of Mystaria, based on similarity to the type M. rufolimbata Simon, 1895 but with the exclusion of M. unicolor Simon, 1895, a species last studied in 1895. Mystaria unicolor is re-described and placed in a new genus, Leroya gen. n., together with L. silva sp. n. (??, DRC) which is recognised as the type species. Mystaria now contains 13 well-defined species, four of which are in new generic combinations. Four males are described for the first time, and eight new species. Re-described species include M. flavoguttata Lawrence, 1952, M. lata Lawrence, 1927, M. rufolimbata and M. variabilis Lessert, 1919. Subspecies elevated to species level include M. occidentalis Millot, 1942 and new species descriptions include M. budongo sp. n. (?, Rwanda, DRC, Uganda), M. irmatrix sp. n. (??, Mozambique, South Africa) M. lindaicapensis sp. n. (??, South Africa), M. mnyama sp. n. (??, South Africa), M. oreadae sp. n. (?, Rwanda, DRC), M. savannensis sp. n. (??, Botswana, South Africa, Zambia, Zimbabwe), M. soleil sp. n. (??, Uganda, Kenya) and M. stakesbyi sp. n. (??, Ghana, DRC, Kenya, Rwanda, Tanzania, Uganda). The insufficiently known taxa Paramystaria decorata Lessert, 1919 and P. variabilis delesserti Caporiacco, 1949 are also transferred to Mystaria. Keys are provided to species and related tribal genera, with geographic distributions of species recorded. Revisions of more genera are needed, in particular of those genera related to Mystarini, before phylogenetic relationships can be considered. PMID- 25544211 TI - Cheirimedon foscae sp. nov. (Amphipoda: Lysianassidae: Tryphosinae) from the deep sea Campos Basin, Southwestern Atlantic Ocean. AB - A new species of lysianassid amphipod belonging to the genus Cheirimedon was collected on the continental slope of the Campos Basin, the largest oil reserve in Brazilian waters. This is the first record of the genus Cheirimedon from the Atlantic Ocean, which was previously restricted to the Antarctic and Tasmanian sea. The new species is fully illustrated and compared with related species. Additionally, a world key to the Cheirimedon species is provided. PMID- 25544212 TI - Two new species of Paraphilopterus Mey, 2004 (Phthiraptera: Ischnocera: Philopteridae) from New Guinean bowerbirds (Passeriformes: Ptilonorhynchidae) and satinbirds (Passeriformes: Cnemophilidae). AB - Two new species of Paraphilopterus Mey, 2004 are described and named. Paraphilopterus knutieae n. sp. is described from two subspecies of Macgregor's bowerbirds: Amblyornis macgregoriae nubicola Schodde & McKean, 1973 and A. m. kombok Schodde & McKean, 1973, and Sanford's bowerbird: Archboldia sanfordi (Mayr & Gilliard, 1950) (Ptilonorhynchidae). Paraphilopterus meyi n. sp. is described from two subspecies of crested satinbirds: Cnemophilus macgregorii macgregorii De Vis, 1890 and C. m. sanguineus Iredale, 1948 (Cnemophilidae). These new louse species represent the first records of the genus Paraphilopterus outside Australia, as well as from host families other than the Corcoracidae. The description of Paraphilopterus is revised and expanded based on the additional new species, including the first description of the male of this genus. Also, we provide a key to the species of Paraphilopterus. PMID- 25544213 TI - Two new species and new records of Syndicus Motschulsky (Coleoptera, Staphylinidae, Scydmaeninae) from SE Asia and Australia. AB - Two new species of the cyrtoscydmine ant-like stone beetle genus Syndicus are described: S. (s. str.) birmanicus sp. n. (from Myanmar) and S. (Semisyndicus) chiangmaianus sp. n. (from Thailand). A previously unknown male of S. (s. str.) puncticollis Jaloszynski is described, and for the first time the spermatheca of S. (Semisyndicus) sumatrensis Schaufuss is illustrated. Syndicus puncticollis, S. (s. str.) difficilis Jaloszynski, and S. (s. str.) saketianus Jaloszynski, all previously known only from Thailand, are recorded for the first time from Myanmar. Additionally new records are given for S. (s. str.) lamdongianus Jaloszynski (from Laos), S. (s. str.) kingii (King) (from Australia), S. (s. str.) malandae Franz (from Australia), and S. (Semisyndicus) leai ranongianus Jaloszynski (from Thailand). PMID- 25544214 TI - Notocrater christofferseni n. sp. (Vetigastropoda: Pseudococculinidae): first record of the genus in the South Atlantic Ocean. AB - This paper reports the genus Notocrater Finlay, 1926 from the South Atlantic Ocean based on the description of a new species, Notocrater christofferseni n. sp. from deep waters off northeastern Brazil. Notocrater christofferseni n. sp. is compared with N. houbricki McLean & Harasewych, 1995 and N. youngi McLean & Harasewych, 1995. The new species differs from these congeners mainly by the anterior region, which comprises about 95% of shell length and has double pustule rows (about 50) arranged concentrically from the anterior margin to the center of the shell. The present study extends knowledge of the latitudinal and bathymetric distribution of Notocrater from the Bahamas (26 degrees N; 518 m) to the Southeastern Atlantic (northeastern Brazil: 10 degrees S; 720 m). PMID- 25544215 TI - Two new species of Aphidini Latreille, 1802 (Hemiptera: Aphididae) from Turkey. AB - Apterous and alate viviparous females of Protaphis kvavadzei sp. n. on Eryngium campestre (Apiaceae) and Aphis matricariae sp. n. on Matricaria sp. (Asteraceae) from Turkey are described. The new species are differentiated from other aphids colonising these host plants and from species with similar morphology. PMID- 25544216 TI - A new species of Canace Haliday from Portugal, with a revised key to species (Diptera: Canacidae: Canacinae). AB - A new species of Canace Haliday, in Curtis, 1837 from Portugal is described. This species, related to C. actites Mathis, 1982, is known so far from a single maritime locality near Lisbon. A key to species of the genus is also provided. PMID- 25544217 TI - The rare subgroup C1 of Marphysa (Polychaeta, Eunicidae): re-description of species and first records in the Mediterranean Sea. AB - Marphysa is one of the largest genera in the family Eunicidae, containing 76 valid species. However, among them there are only five species that share the diagnostic characters of having only composite falcigers in inferior setae and branchiae confined in the anterior body. These species are relatively rare and less described while in their original descriptions their differentiation is mainly based on features believed to be age-specific today. In this study, the type-materials of M. adenensis, M. purcellana and M. gemmata have been re examined and re-described with illustrations. For M. adenensis, new material from the Mediterranean Sea was also examined, where this group has not been recorded up to date. The above species were compared to each other and new differential characters are being highlighted. A revised key for the Marphysa species found in the Mediterranean is also provided. PMID- 25544218 TI - Epimeria rafaeli sp. nov. (Crustacea, Amphipoda, Epimeriidae) from Western Australia. AB - Members of the family Epimeriidae are reported in Australian waters for the first time and Epimeria rafaeli sp. nov. is described from deep water just south of the Abrolhos Island, Western Australia. PMID- 25544219 TI - The first well-preserved coelophysoid theropod dinosaur from Asia. AB - Coelophysoid dinosaurs represent the earliest major radiation of neotheropods. These small-to-medium-sized agile bipeds lived throughout much of Pangaea during the Late Triassic-arly Jurassic. Previously reported coelophysoid material from Asia (excluding the Gondwanan territory of India) is limited to two specimens that comprise only limb fragments. This paper describes a new genus and species of coelophysoid, Panguraptor lufengensis, from the Lower Jurassic Lufeng Formation of Yunnan Province, China. The new taxon is represented by a well preserved skeleton, including the skull and lower jaw, the presacral vertebral column and partial ribs, the right scapula, a partial forelimb, part of the pelvic girdle, and an almost complete hind limb. It is distinguished from other coelophysoid theropods by the unique combination of the following three character states: 1) diagonal (rostrodorsal-caudoventral) ridge on lateral surface of maxilla, within antorbital fossa, 2) elliptical, laterally facing fenestra caudodorsal to aforementioned diagonal ridge, and 3) hooked craniomedial corner of distal tarsal IV. Cladistic analysis recovers Panguraptor lufengensis deeply nested within Coelophysoidea as a member of Coelophysidae, and it is more closely related to Coelophysis than to "Syntarsus". Panguraptor represents the first well preserved coelophysoid theropod dinosaur from Asia, and provides fresh evidence supporting the hypothesis that terrestrial tetrapods tended to be distributed pan continentally during the Early Jurassic. PMID- 25544220 TI - A new Orussus species from South Korea, and a key to the East Asian Orussidae (Hymenoptera). AB - Orussus melanosoma Lee & Wei, sp. nov. from South Korea is described and illustrated. Phylogenetic analyses place the new species basally in Orussus, together with other species from the Far East. A key to species of Orussidae from the eastern Palaearctic is provided. PMID- 25544221 TI - A new species of Western Atlantic sea lily in the family Bathycrinidae (Echinodermata: Crinoidea), with a discussion of relationships between crinoids with xenomorphic stalks. AB - A new species in the family Bathycrinidae is described from abyssal depths from the Bahamas. It is referred to the recently established genus Discolocrinus, which formerly comprised a single species D. thieli Mironov, 2008 from the Eastern Pacific. Discolocrinus iselini n. sp. is characterized by large body size, high tegmen with tube-like upper region, extremely elongated IBr1 and IBr2, large knobby processes on primibrachials, and overgrowth of soft tissue on the pinnules, the tissue containing numerous perforated or imperforate ossicles of varying size and form. Differences between Discolocrinus and other bathycrinids may seem to be of taxonomic importance at the family level, but knowledge of the morphology and variability of both species of Discolocrinus is incomplete and, until a richer material becomes available, the genus should remain in family Bathycrinidae. Representatives of five families with xenomorphic stalks were examined to characterize the genera on the basis of number or form of knobby processes. These processes occur in two families with differing external morphology: ten-armed Bathycrinidae and five-armed Bourgueticrinidae. They also occur in the comatulid family Atelecrinidae. This similarity might seem to indicate a close relationship between the three families. However, morphological analysis supports the separation of the families Caledonicrinidae and Septocrinidae from Bathycrinidae despite the fact that they share a xenomorphic stalk and IBr2ax. These conclusions are in agreement with results of recent molecular studies. PMID- 25544222 TI - An annotated checklist of the aquatic Polyphaga (Coleoptera) of Egypt I. Family Hydraenidae. AB - Data from previous literature were used to compile a checklist of the Egyptian fauna of Hydraenidae (Coleoptera). The checklist includes data on the type localities, type specimens, descriptors, distributions and previous literature for 15 valid species belonging to 3 genera (Hydraena, Limnebius and Ochthebius). Ochthebius was represented by 13 species, while Hydraena and Limnebius were represented only by a single species for each of them. The present study provides a summary that can serve as the basis for future progress in the knowledge of the Egyptian Hydraenidae. PMID- 25544223 TI - On the genus Calyptobates Polhemus & Polhemus (Hemiptera: Heteroptera: Gerridae) from India with description of a new species and a key to the species of World. AB - Calyptobates rajani sp. nov. is described from Great Nicobar Island, Andaman and Nicobar Islands, India. This new species is closely related to C. andaman Polhemus & Polhemus, 1994, described from Andaman Islands, India. Two species of Calyptobates Polhemus & Polhemus including the new species are presently known from India. A key to the species of Calyptobates from world and the distribution map of Indian species are also provided. PMID- 25544224 TI - New or interesting Peritelini of the west-palaearctic fauna. XXV. A novel Italian species of the genus Meira Jacquelin Du Val (Coleoptera, Curculionidae, Entiminae). AB - A new species of Meira Jacquelin du Val from Island of Elba, M. tedeschii sp. n., is described. Some taxonomically important characters, which allow for the separation of this new taxon from other closely related species, are illustrated. PMID- 25544225 TI - A new mycophagous species of the genus Gaurax Loew, 1863 (Diptera: Chloropidae) from Benin, Africa. AB - A special survey was undertaken to study the insects living in the sporophores of Basidiomycota in Benin, Africa. Three specimens of Chloropidae, which are described here as a new species of Gaurax Loew, were reared from two fruiting bodies of different species of fungi: Amanita subviscosa Beeli and a species of Boletaceae. The fungi were collected from Miombo woodlands in Central Benin. Fruiting bodies were placed in plastic containers covered with nylon gauze, while sawdust was used as a pupariation substrate. Details of collecting localities and the method of insect rearing have also been described by Disney et al. (2013). The new species belongs to the worldwide genus Gaurax Loew, which includes 157 known species, the majority of which are from the Australasian region (Pape & Evenhuis 2013, Nartshuk & Andersson 2013). Only three species are so far recorded from the Afrotropical region (Sabrosky 1980, Pape & Evenhuis 2013). PMID- 25544226 TI - Turbo-taxonomy: 21 new species of Myzostomida (Annelida). AB - An efficient protocol to identify and describe species of Myzostomida is outlined and demonstrated. This taxonomic approach relies on careful identification (facilitated by an included comprehensive table of available names with relevant geographical and host information) and concise descriptions combined with DNA sequencing, live photography, and accurate host identification. Twenty-one new species are described following these guidelines: Asteromyzostomum grygieri n. sp., Endomyzostoma scotia n. sp., Endomyzostoma neridae n. sp., Mesomyzostoma lanterbecqae n. sp., Hypomyzostoma jasoni n. sp., Hypomyzostoma jonathoni n. sp., Myzostoma debiae n. sp., Myzostoma eeckhauti n. sp., Myzostoma hollandi n. sp., Myzostoma indocuniculus n. sp., Myzostoma josefinae n. sp., Myzostoma kymae n. sp., Myzostoma laurenae n. sp., Myzostoma miki n. sp., Myzostoma pipkini n. sp., Myzostoma susanae n. sp., Myzostoma tertiusi n. sp., Protomyzostomum lingua n. sp., Protomyzostomum roseus n. sp., Pulvinomyzostomum inaki n. sp., and Pulvinomyzostomum messingi n. sp.. PMID- 25544227 TI - Updating the description and taxonomic status of Brachionus sessilis Varga, 1951 (Rotifera: Brachionidae) based on detailed morphological analysis and molecular data. AB - Brachionus sessilis Varga, 1951 is an epizoic rotifer living exclusively on cladocerans of the genus Diaphanosoma. Current taxonomic knowledge relies solely on limited morphological information, whereas there is no type material. Here, we aim to resolve issues concerning its morphology and taxonomy using both morphological and genetic characters on material sampled from Lake Balaton (Hungary), as well as Lake Doirani (Greece) that was selected for comparison purposes. Biometrical analysis was based on extensive lorica measurements. Phylogenetic reconstruction was based on DNA sequence information of the mitochondrial cytochrome c oxidase subunit I (COI) and 16S rRNA gene regions as well as of the nuclear internal transcribed spacer 1 (ITS1). Well-supported evidence for substantial differentiation of B. sessilis from its closest phylogenetic relatives supports its species-rank status. Our phylogenetic analysis suggests a highly supported clade encompassing B. sessilis and another epizoic rotifer, namely B. rubens. PMID- 25544228 TI - Phylogenetic relationships and taxonomic revision of Paranoplocephala Luhe, 1910 sensu lato (Cestoda, Cyclophyllidea, Anoplocephalidae). AB - An extensive phylogenetic analysis and genus-level taxonomic revision of Paranoplocephala Luhe, 1910-like cestodes (Cyclophyllidea, Anoplocephalidae) are presented. The phylogenetic analysis is based on DNA sequences of two partial mitochondrial genes, i.e. cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1), and includes 51 cestode isolates. The revision concerns all 34 Paranoplocephala-like species considered valid, of which 21 species could be included in the molecular phylogenetic analysis. Based on the phylogenetic relationships and main morphological features, with emphasis on the structure of the scolex, suckers and neck, length of the vagina (relative to the cirrus sac) and distribution of testes, 12 new genera are proposed for cestodes traditionally assigned to Paranoplocephala s. l. This results in 23 new combinations. The new genera are: Gulyaevia n. g., Chionocestus n. g., Microticola n. g., Beringitaenia n. g., Arctocestus n. g., Rauschoides n. g., Eurotaenia n. g., Douthittia n. g., Lemminia n. g., Tenoraia n. g., Rodentocestus n. g. and Cookiella n. g. In addition, Paranoplocephala (s. s.) and Parandrya Gulyaev & Chechulin, 1996 are redescribed; the latter genus is considered valid, although it has been earlier synonymized with Paranoplocephala. A new species (Beringitaenia nanushukensis n. sp.) from Microtus miurus is described. Based on the DNA sequence data, several additional lineages probably representing independent species are identified, but not described as new taxa because of lack of good-quality specimens or absence of reliable morphological differences. The study also presents the first evidence for the phylogenetic position of the monotypic genus Gallegoides Tenora & Mas-Coma, 1978 based on DNA sequence data. A key for the Paranoplocephala-like genera is presented. The patterns of diversity and zoogeography of cestodes representing the "arvicoline clade" (72 species) are complex, involving mechanisms of dispersal, geographic colonization and host switching linking faunas across Eurasia and North America. PMID- 25544229 TI - New species and subspecies of Rhyacophila (Trichoptera: Rhyacophilidae) from Asia. AB - New species and subspecies of the genus Rhyacophila (Trichoptera, Rhyacophilidae), i.e. Rhyacophila mikusi n. sp. in the R. yosiiana Group from Taiwan (Republic of China), Rhyacophila wichardi n. sp. in the R. curvata Group, Rhyacophila chayulpa ghunsa new subspecies in the R. chayulpa Group, and Rhyacophila chembo bigu new subspecies in the R. khimbarpa Group from Nepal are described and illustrated with drawings of the genitalia. PMID- 25544230 TI - A taxonomic revision of the Asian keelback snakes, genus Amphiesma (Serpentes: Colubridae: Natricinae), with description of a new species. AB - The Asian keelback snakes (genus Amphiesma) are a widely distributed group of Old World natricines, inhabiting a variety of niches and exhibiting significant morphological variation. Recent molecular phylogenies suggest that this genus is not monophyletic, and that additional cryptic diversity is also likely present. We conducted a phylogenetic analysis of the group based on 3162 bp of one mitochondrial gene (Cyt. b) and three nuclear genes (C-mos, Rag1, NT3), sampling 18 species in addition to those sequenced in previous works. All analyses consistently show that Amphiesma consists of three distinct, monophyletic lineages with strong support. We divide Amphiesma into three genera, Amphiesma, Hebius, and Herpetoreas. The genus Amphiesma is monotypic, Herpetoreas contains three species, and Hebius comprises the remaining 39 species. On the basis of a combination of molecular analyses and external morphological comparisons, we describe a new species in the Herpetoreas group from China as H. burbrinki sp. nov. Several other species are shown to be non-monophyletic or contain significant levels of intraspecific genetic diversity. Another Old World natricine genera, Xenochrophis is also found to be non-monophyletic. Our results indicate that further taxonomic revisions are needed in Natricinae, at multiple levels. PMID- 25544231 TI - Note on the genus Morimospasma Ganglbauer with description of two new species from China (Coleoptera: Cerambycidae: Lamiinae). AB - The genus Morimospasma Ganglbauer, 1890 is reviewed. Two new species, M. jiangi sp. nov. and M. dalaolingensis sp. nov., are described and illustrated. M. paradoxum Ganglbauer is newly recorded from Anhui, China. Taxonomic status of M. nitidituberculatus Hua is discussed. The Chinese names of M. jiangi sp. nov. and M. dalaolingensis sp.nov. are designated, respectively, as Jiangshi Juliutianniu and Dalaoling Juliutianniu in Chinese phonetic alphabet. A key to all six species of Morimospasma is provided. PMID- 25544232 TI - Taxonomic relationship between two Gammarus species, G. nipponensis and G. sobaegensis (Amphipoda: Gammaridae), with description of a new species. AB - To assess the taxonomic relationship between G. nipponensis and G. sobaegensis, morphological features and molecular phylogenetic relationships using the nuclear 28S rRNA and the mitochondrial COI genes were examined. Detailed morphological observations revealed that G. nipponensis and G. sobaegensis were clearly distinguishable. In addition to the morphological differences, these two species were genetically diverged. In the course of this study, an undescribed species was found from Tsushima and Iki Islands and described here as G. mukudai. In the molecular phylogenetic analyses, monophyletic relationships of G. nipponensis, G. sobaegensis, and G. mukudai were shown but relationships among three species were unclear due to low statistical supports. Phylogeography of G. nipponensis, G. sobaegensis, and G. mukudai were discussed. PMID- 25544233 TI - Morphological variation in the Cinnamon Tanager Schistochlamys ruficapillus Aves: Thraupidae). AB - The Cinnamon Tanager Schistochlamys ruficapillus inhabits semi-open grassy country, primarily in Brazil south of Amazonia. Three subspecies are currently recognized, one of which, S. r. sicki, is poorly known and endemic to the central Brazilian savannas (Cerrado). This paper analyses individual and geographic variation in this species on the basis of body measurements and plumage coloration. Larger birds are usually found farther south and at higher elevations, while smaller birds are found farther north and at lower elevations, as predicted by Bergmann's rule. Nevertheless, some unexpectedly small individuals (referable to S. r. sicki) can be found in central Brazil. Individual and geographical variation in plumage coloration is substantial, but it is not closely tied to variation in body size. Therefore, given the large number of specimens intermediate between the three subspecies, we propose to consider the Cinnamon Tanager a monotypic but highly variable species. The recognition of three subspecies by previous taxonomists was due to small sample sizes associated with large gaps in sampling. PMID- 25544234 TI - Taxonomy of Cotylea (Platyhelminthes: Polycladida) from Cabo Frio, southeastern Brazil, with the description of a new species. AB - Polyclads are free-living Platyhelminthes with a simple, dorsoventrally flattened body and a much ramified intestine. In Brazil, 66 species are reported; only three from Rio de Janeiro State (RJ). The main objective of this study is to describe and illustrate coloration pattern, external morphology, reproductive system morphology and, when possible, biological and ecological aspects of species of the suborder Cotylea found in Cabo Frio, RJ. Of the 13 cotylean polyclad species found, Pseudobiceros pardalis, Cycloporus variegatus and Eurylepta aurantiaca are new records from the Brazilian coast and one species is new to science, Pseudoceros juani sp. nov. Feeding observations were made of four species. It is the first time that Lurymare utarum, Cycloporus gabriellae, C. variegatus and E. aurantiaca are illustrated with digital photographs of live specimens and histological preparations. This study increases to 70 the number of Brazilian Polycladida and to 14 the number of species known from Rio de Janeiro State. However, the knowledge about Polycladida in Brazil still has gaps, with great parts of the coast remaining unsampled. PMID- 25544235 TI - New records of Bodotriidae (Crustacea: Cumacea) from Puerto Rico with descriptions of three new species. AB - In a continuing effort to describe the cumacean fauna of Puerto Rico we describe three new species of Bodotriidae, a family that has never been reported from Puerto Rico before. While finding and describing new microcrustacean species may not be an impossible task, if there is available taxonomic expertise, the currently described species were found in large numbers within a short distance from the Marine Laboratories of the University of Puerto Rico where the local reefs have been studied for over half a century, highlighting the large gaps that exist in our estimates of Caribbean marine diversity. The three new species, Cyclaspis gurui sp. nov., Cyclaspis mariae sp. nov. and Vaunthompsonia budaii sp. nov. are reported from a fringing reef off La Parguera, southwest coast of Puerto Rico and Vaunthompsonia cristata Bate, 1858 represents a new record for Puerto Rico from the mesophotic reefs. PMID- 25544236 TI - Revised species definitions and nomenclature of the rose colored Cithaerias butterflies (Lepidoptera, Nymphalidae, Satyrinae). AB - This study provides updated species definitions for five rose-colored Cithaerias butterflies, starting with a historical overview of their taxonomy. Given their mostly transparent wings, genitalia morphology yielded the most reliable characters for species definition and identification. Genitalic divergence is more pronounced when multiple species occur in sympatry than between parapatric taxa. Cithaerias aurorina is granted full species status, C. cliftoni is reinstated as a full species, and one new combination is proposed, i.e. C. aurora tambopata. Two new synonyms are proposed, Callitaera phantoma and Callitaera aura = Cithaerias aurora. PMID- 25544237 TI - Microlepidogaster discus, a new species of Hypoptopomatinae (Siluriformes: Loricariidae) from the rio Jequitinhonha basin, southeastern Brazil. AB - A new Hypoptopomatinae is described from the upper rio Jequitinhonha basin. The new species is distinguished from all congeners by having the ventral laminar expansions of cleithrum and coracoid bearing only 1-30 odontodes, restricted to the area near the pectoral-fin insertion; the anterior plates of mid-ventral lateral series reduced, not ventrally elongated, the first or the second markedly round; pectoral-fin unbranched ray distinctly divided distally, with 7-15 ossified segments, reaching almost half of its length; and accessory process on first epibranchial present. Microlepidogaster discus is further distinguished from its congeners by several other osteological features. The problems concerning the taxonomy of Microlepidogaster, as well as the pattern of distribution of the genus, are discussed. PMID- 25544238 TI - New species of Helpis Simon, 1901 from Australia (Araneae: Salticidae), with a new definition of the genus. AB - Five new species of Helpis Simon, 1901 from Queensland and New South Wales are diagnosed, described and illustrated: H. foelixi sp. nov. (?); H. merriwa sp. nov. (?); H. staregai sp. nov. (?); H. wanlessi sp. nov. (?) and H. wisharti sp. nov. (?). The male of H. kenilworthi Zabka, 2002 is described for the first time, Helpis gracilis Gardzinska, 1996 is illustrated to show intraspecific variation and Astia colemani Wanless, 1988 is redescribed and transferred to the genus Helpis. Remarks on relationships of described species are provided and maps with distributional records are given. PMID- 25544239 TI - New additions to the Honduran fauna of spider wasps (Hymenoptera: Pompilidae) with the description of two species. AB - Two new species of pepsine spider wasps, Calopompilus setaerotundus Waichert & Pitts, sp. nov. and Priocnemis (Umbripennis) wasbaueri Waichert & Pitts, sp. nov., are described and illustrated. Calopompilus Ashmead, Priocnemis Schiodte and sixteen additional species are newly reported from Honduras. A new combination is proposed for Ageniella fragilis (Fox), comb. nov., which is transferred from Agenia Schiodte. PMID- 25544241 TI - Taking contrast coverage seriously. PMID- 25544240 TI - A cisplatin-incorporated liposome that targets the epidermal growth factor receptor enhances radiotherapeutic efficacy without nephrotoxicity. AB - Radiotherapy (RT) is one of the major modalities for non-small cell lung cancer (NSCLC), but its efficacy is often compromised by cellular resistance caused by various mechanisms including the overexpression of epidermal growth factor receptor (EGFR). Although cis-diamminedichloroplatinum(II) (cisplatin, CDDP) has been well characterized as an effective radiosensitizer, its clinical application is limited by its severe nephrotoxic effects. In our current study, we developed a CDDP-incorporated liposome (LP) conjugated with EGFR antibodies (EGFR:LP-CDDP) and evaluated its potential to radiosensitize EGFR-overexpressing cells without exerting nephrotoxic effects. EGFR:LP-CDDP showed higher cytotoxicity than non targeting liposomal CDDP (LP-CDDP) in the cells expressing EGFR in vitro. In an A549 cell-derived xenograft tumor mouse model, increased delays in tumor growth were observed in the mice treated with a combination of EGFR:LP-CDDP and radiation. Notably, the EGFR:LP-CDDP-treated animals showed no differences in body weight loss, survival rates of nephrotoxicity compared with untreated control mice. In contrast, the use of CDDP caused lower body weights and poorer survival outcomes accompanied by a significant level of nephrotoxicity [e.g., decreased kidney weight, increased blood urea nitrogen (BUN) and creatinine, and pathological change]. These findings suggest the feasibility of using EGFR:LP CDDP to radiosensitize cells in a targeted manner without inducing nephrotoxic effects. This compound may therefore have clinical potential as part of a tailored chemoradiotherapy strategy. PMID- 25544242 TI - When a report is both more and less than a report. PMID- 25544243 TI - Combat Radiology: Imaging 3.0 in Faraway Places. PMID- 25544244 TI - Ethical analysis as a tool for addressing treatment controversies: radiotherapy timing in children with orbital rhabdomyosarcoma as a case example. AB - PURPOSE: The treatment of orbital rhabdomyosarcoma is a topic of debate between North American and European clinicians, with the utility of radiation therapy as part of initial management in question. Despite differences in philosophy, the dominant North American approach of upfront radiation and the dominant European approach of radiation only in the event of recurrence yield a similar rate of overall survival. We sought to identify the ethical arguments for each approach. METHODS: Established moral principles and appeals in contemporary medical ethics were utilized to identify the ethical arguments supporting each treatment approach. The potential for technologic advances to alter the analysis was considered. RESULTS: Emphasizing the principle of beneficence, the North American approach seeks to reduce recurrence rates. In contrast, the European approach seeks to avoid radiation-induced sequelae, emphasizing the principle of nonmaleficence. Both approaches are based on well-established ethical principles, evidence, and clinical experience. Thus, both approaches currently appear to have legitimacy and should be included in the informed consent process. However, if treatment-related toxicity is reduced through improvements in radiation delivery, the North American approach could emerge as ethically superior. CONCLUSIONS: Ethical analysis can aid in addressing challenges that arise when professional practices and perspectives differ in the management of cancer patients. PMID- 25544245 TI - "But it's just paracetamol": Caregivers' ability to administer over-the-counter painkillers to children with the information provided. AB - OBJECTIVE: To determine whether caregivers are able to make informed decisions about their families' use of over-the-counter (OTC) painkillers through access to and use of three mechanisms of information provision. METHODS: A cross sectional, face-to-face questionnaire was administered to 60 caregivers and seven pharmacists in Cape Town, South Africa. Caregivers answered questions related to paracetamol (acetaminophen) labels, inserts and Patient Information Leaflets (PIL). RESULTS: Most study caregivers received labels with the painkillers they purchased. Many pharmacists (43%) felt that the information provided was ineffective in preventing overdosing. Study caregivers found it difficult to understand the scientific terms in all three mechanisms of information provision. Most respondents (80%) found the PIL easiest to understand, yet few had received PILs with their purchase. Ten percent of literate respondents were unable to understand the dosage requirements for children. CONCLUSION: Most caregivers are not able to make informed decisions from the information provided with OTC painkillers. This is mostly attributable to limited provision of information and low health literacy. PRACTICE IMPLICATIONS: Written information with OTC medications in simple language and verbal counselling at dispensaries would play a significant role in increasing the health literacy of especially at risk populations of over-dosing their children. PMID- 25544246 TI - Adsorption of water from aqueous acetonitrile on silica-based stationary phases in aqueous normal-phase liquid chromatography. AB - Excess adsorption of water from aqueous acetonitrile mobile phases was investigated on 16 stationary phases using the frontal analysis method and coulometric Karl-Fischer titration. The stationary phases include silica gel and silica-bonded phases with different polarities, octadecyl and cholesterol, phenyl, nitrile, pentafluorophenylpropyl, diol and zwitterionic sulfobetaine and phosphorylcholine ligands bonded on silica, hybrid organic-silica and hydrosilated matrices. Both fully porous and core-shell column types were included. Preferential uptake of water by the columns can be described by Langmuir isotherms. Even though a diffuse rather than a compact adsorbed discrete layer of water on the adsorbent surface can be formed because of the unlimited miscibility of water with acetonitrile, for convenience, the preferentially adsorbed water was expressed in terms of a hypothetical monomolecular water layer equivalent in the inner pores. The uptake of water strongly depends on the polarity and type of the column. Less than one monomolecular water layer equivalent was adsorbed on moderate polar silica hydride-based stationary phases, Ascentis Express F5 and Ascentis Express CN column at the saturation capacity, while on more polar stationary phases, several water layer equivalents were up taken from the mobile phase. The strongest affinity to water was observed on the ZIC cHILIC stationary phases, where more than nine water layer equivalents were adsorbed onto its surface at its saturation capacity. Columns with bonded hydroxyl and diol ligands show stronger water adsorption in comparison to bare silica. Columns based on hydrosilated silica generally show significantly decreased water uptake in comparison to stationary phases bonded on ordinary silica. Significant correlations were found between the water uptake and the separation selectivity for compounds with strong polarity differences. PMID- 25544248 TI - Usefulness of endoscopic papillary balloon dilation for removal of common bile duct stones as compared to endoscopic sphincterotomy. PMID- 25544247 TI - Pharmacokinetic properties of single- and repeated-dose sufentanil sublingual tablets in healthy volunteers. AB - PURPOSE: Sufentanil is a MU-opioid agonist with a high therapeutic index in preclinical studies and no active metabolites, and it is highly lipophilic, thereby enabling a transmucosal route of administration. Rapid distribution from the plasma after IV sufentanil administration results in a short duration of action requiring excessive repeated dosing if used for postoperative analgesia. The sufentanil sublingual tablet system (SSTS) is a handheld, preprogrammed, patient-controlled analgesia system designed to allow patients to self-administer sufentanil 15-MUg tablets under their tongue with a 20-minute lockout. The pharmacokinetic (PK) characteristics of sufentanil, administered by different routes of delivery and after single and repeated sublingual (SL) administration, were examined in 2 studies. METHODS: A randomized, open-label, crossover study in healthy subjects evaluated the PK profile of sufentanil 15 MUg administered by different routes: IV, SL, buccal (BU), and PO. A second open-label, crossover study in healthy subjects evaluated the PK parameters after single and repeated doses (full SSTS drug cartridge of 40 consecutive SL doses administered every 20 minutes) of a sufentanil 15-MUg SL tablet. Doses were self-administered using the SSTS. FINDINGS: In the route of administration study (n = 25), mean Cmax values were highest with IV administration, and bioavailability values were: SL, 59%; BU, 78%; and PO, 9%. The absorption across the oral mucosa was associated with a median plasma half-time (time from Cmax to 50% of Cmax) that was 25-fold longer (2.5 hours) with SL versus IV administration (0.1 hours). In the single- and repeated-dose study (n = 38), mean AUC0-infinity was 125.5 h . pg/mL, and Cmax was 35.0 pg/mL, with a median Tmax of 0.8 hours after the administration of a single sufentanil SL tablet. With 40 consecutive doses, Cmax was 8-fold higher compared with that of a single dose, and steady state was achieved after the 13th dose. Median plasma half-time after the 40th dose was not statistically longer than that after a single dose (2.7 vs 2.2 hours, respectively), and the median Tmax was 0.3 hours after the last repeated dose. IMPLICATIONS: These study results support the viability of the SSTS for use in patient-controlled analgesia. The wide range of mean drug concentrations achieved after repeated dosing at 20-minute intervals compared with those with a single dose suggests the flexibility of patient-controlled dosing to meet individual analgesic requirements. The prolonged plasma half-time with SL administration is expected to provide a more appropriate duration of analgesia compared with that of IV administration, and the PK properties of repeated-dose administration support a 20-minute lockout interval. PMID- 25544249 TI - Progesterone-to-follicle index is better correlated with in vitro fertilization cycle outcome than blood progesterone level. AB - OBJECTIVE: To investigate the impact of late follicular phase progesterone (P) elevation in relation to ovarian response on cycle outcome. DESIGN: Cohort study. The progesterone-to-follicle index (PFI) was calculated by dividing the blood P by the number of follicles >=14 mm. The clinical pregnancy rate was calculated against the range of PFI values and blood P levels. SETTING: In vitro fertilization unit. PATIENT(S): A heterogenous population undergoing IVF with pituitary suppression and gonadotropin stimulation resulting in 3-15 follicles >=14 mm and blood P<=10 nmol/L on hCG day and resulting in fresh embryo transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Association of blood P and PFI with clinical pregnancy rate. RESULT(S): Data were retrieved for 8,649 IVF cycles in normal responders. The (reverse) odd ratios for pregnancy were 1.112 (95% confidence interval [CI], 1.077-1.165) for blood P and 4.104 (95% CI, 3.188 5.284) for the PFI. Elevated P levels were associated with a lower pregnancy rate only when they reached the >93rd percentile. The PFI was inversely and linearly related to the pregnancy rate for the whole range of values. CONCLUSION(S): A late increase in P level is detrimental if it is a consequence of increased P production per follicle (high PFI) but not if it is a consequence of additional follicular recruitment. The PFI enables clinicians to differentiate these conditions. PMID- 25544250 TI - Spatial and temporal variation in de facto wastewater reuse in drinking water systems across the U.S.A. AB - De facto potable reuse occurs when treated wastewater is discharged into surface waters upstream of potable drinking water treatment plant (DWTP) intakes. Wastewater treatment plant (WWTP) discharges may pose water quality risks at the downstream DWTP, but additional flow aids in providing a reliable water supply source. In this work de facto reuse is analyzed for 2056 surface water intakes serving 1210 DWTPs across the U.S.A. that serve greater than 10,000 people, covering approximately 82% of the nation's population. An ArcGIS model is developed to assess spatial relationships between DWTPs and WWTPs, with a python script designed to perform a network analysis by hydrologic region. A high frequency of de facto reuse occurrence was observed; 50% of the DWTP intakes are potentially impacted by upstream WWTP discharges. However, the magnitude of de facto reuse was seen to be relatively low, where 50% of the impacted intakes contained less than 1% treated municipal wastewater under average streamflow conditions. De facto reuse increased greatly under low streamflow conditions (modeled by Q95), with 32 of the 80 sites yielding at least 50% treated wastewater, this portion of the analysis is limited to sites where stream gauge data was readily available. PMID- 25544251 TI - Modeling water quality in an urban river using hydrological factors--data driven approaches. AB - Contrasting seasonal variations occur in river flow and water quality as a result of short duration, severe intensity storms and typhoons in Taiwan. Sudden changes in river flow caused by impending extreme events may impose serious degradation on river water quality and fateful impacts on ecosystems. Water quality is measured in a monthly/quarterly scale, and therefore an estimation of water quality in a daily scale would be of good help for timely river pollution management. This study proposes a systematic analysis scheme (SAS) to assess the spatio-temporal interrelation of water quality in an urban river and construct water quality estimation models using two static and one dynamic artificial neural networks (ANNs) coupled with the Gamma test (GT) based on water quality, hydrological and economic data. The Dahan River basin in Taiwan is the study area. Ammonia nitrogen (NH3-N) is considered as the representative parameter, a correlative indicator in judging the contamination level over the study. Key factors the most closely related to the representative parameter (NH3-N) are extracted by the Gamma test for modeling NH3-N concentration, and as a result, four hydrological factors (discharge, days w/o discharge, water temperature and rainfall) are identified as model inputs. The modeling results demonstrate that the nonlinear autoregressive with exogenous input (NARX) network furnished with recurrent connections can accurately estimate NH3-N concentration with a very high coefficient of efficiency value (0.926) and a low RMSE value (0.386 mg/l). Besides, the NARX network can suitably catch peak values that mainly occur in dry periods (September-April in the study area), which is particularly important to water pollution treatment. The proposed SAS suggests a promising approach to reliably modeling the spatio-temporal NH3-N concentration based solely on hydrological data, without using water quality sampling data. It is worth noticing that such estimation can be made in a much shorter time interval of interest (span from a monthly scale to a daily scale) because hydrological data are long-term collected in a daily scale. The proposed SAS favorably makes NH3-N concentration estimation much easier (with only hydrological field sampling) and more efficient (in shorter time intervals), which can substantially help river managers interpret and estimate water quality responses to natural and/or manmade pollution in a more effective and timely way for river pollution management. PMID- 25544252 TI - Quantifiler(r) Trio Kit and forensic samples management: a matter of degradation. AB - DNA collected from crime scenes may have experienced different levels of degradation. This is mainly due to sample exposure to different environmental factors. The impact of DNA degradation on short tandem repeat (STR) profiling can lead to partial or null information and in some cases, the identification of the trace may fail. The availability of a system enabling the assessment not only of the quantity of the DNA but also of its quality in terms of degradation would result in shorter time for sample processing, more reliable identifications and cost reduction by predicting the quality of the DNA profiles prior to STR analysis. We report here a study on 181 selected degraded DNA samples extracted from real crime scene evidence. The selected samples were processed by combining the use of a new commercial quantification kit (Quantifiler(r) Trio) with a new 24 marker multiplex PCR amplification kit (Globalfiler(r) Kit). Applying different statistical analyses we investigated the reliability of the Degradation Index provided by the Quantifiler(r) Trio in determining the level of DNA degradation in a forensic sample. This useful information can be used to predict the quality of the profile obtained after STR amplification. The combination of such a quantification kit with different PCR protocols allowed us to define practical guidelines for processing degraded forensic DNA samples with a simplified and comprehensive approach. PMID- 25544253 TI - Population genetics of 17 Y-STR loci in Xibe ethnic minority from Liaoning Province, Northeast China. PMID- 25544254 TI - Theoretical perspectives on nonnative interactions and intrinsic disorder in protein folding and binding. AB - The diverse biological functions of intrinsically disordered proteins (IDPs) have markedly raised our appreciation of protein conformational versatility, whereas the existence of energetically favorable yet functional detrimental nonnative interactions underscores the physical limitations of evolutionary optimization. Here we survey recent advances in using biophysical modeling to gain insight into experimentally observed nonnative behaviors and IDP properties. Simulations of IDP interactions to date focus mostly on coupled folding-binding, which follows essentially the same organizing principle as the local-nonlocal coupling mechanism in cooperative folding of monomeric globular proteins. By contrast, more innovative theories of electrostatic and aromatic interactions are needed for the conceptually novel but less-explored 'fuzzy' complexes in which the functionally bound IDPs remain largely disordered. PMID- 25544255 TI - The structure of fibrils from 'misfolded' proteins. AB - Recent developments in solid-state NMR have opened the way to the structural analysis of protein fibrils, with the power of studying them at atomic resolution. Solid-state NMR is a relatively new player in the field of structural biology, and reliable approaches to successfully tackle 3D structures have been developed and applied recently. Here we discuss a number of applications to selected fibrils, including prions, alpha-synuclein and Amyloid-beta (Abeta). The latter is, as for its small monomer size, accessible to full 3D structure determination by solid-state NMR. In addition, chemical-shift assignments, from which secondary structure can be directly be determined, is possible for much larger proteins, and has provided important insight in the structural organization of prions and other amyloids playing a central role in disease. PMID- 25544256 TI - A gap in science's and the media images of people who use drugs and sex workers: research on organizations of the oppressed. AB - This paper discusses organizations of the oppressed, such as drug user and sex worker groups, and the images of themselves that they construct. We suggest that analysis of these organizationally-produced collective self-images -frequently overlooked in scholarly research -is crucial to understanding the complex internal dynamics of users' and sex workers' organizations and struggles they engage in when defining their collective (organizational) identities and course of action. PMID- 25544257 TI - Portraying the alcoholic: images of intoxication and addiction in American alcoholism movies, 1931-1962. PMID- 25544258 TI - MicroRNA-33a inhibits lung cancer cell proliferation and invasion by regulating the expression of beta-catenin. AB - MicroRNAs (miRNAs) are short, non-coding RNAs that are aberrantly expressed in tumors. miRNA-33a (miR-33a) is closely associated with cholesterol metabolism and is essential for cellular growth. The aim of the present study was to explore the role of miR-33a and identify its clinical significance in lung cancer cells. miR 33a was observed to be overexpressed in the lung cancer cell lines A549 and NCI H460. MTT assay results demonstrated that the overexpression of miR-33a significantly inhibited the proliferation of A549 cells, and similar results were obtained from the colony formation assay. This suggests that transfection of miR 33a may suppress the growth of lung cancer cells. Overexpression of miR-33a was also observed to result in marked G1/S phase cell cycle arrest in A549 and NCI H460 cell lines using fluorescence-activated cell sorting analysis. Western blot analysis revealed that overexpression of miR-33a significantly reduced the expression of beta-catenin in A549 and NCI-H460 cells, suggesting a direct or indirect regulation of beta-catenin by miR-33a in lung cancer cells. In conclusion, the current study may provide strategies for the treatment of lung cancer and clarify the mechanism of its progression. PMID- 25544259 TI - Association between expression of MMP-2 and MMP-9 genes and pathogenesis of intracranial hemorrhage in severe coagulation factor XIII deficiency. AB - Background Matrix metalloproteinases (MMPs) play a key role in the degradation of basement membrane and extracellular matrix in tissue remodeling, and are involved in pathogenesis of intracranial hemorrhage (ICH). Despite replacement therapy, ICH is by far the main cause of bleeding-related death among patients with severe factor XIII deficiency (FXIIID). The aim of this study is to evaluate the association between MMP-2 and MMP-9 genes expression and ICH in these patients. Materials and methods Quantitative real-time reverse transcription (RT)-PCR assay was used to quantify MMP-2 and MMP-9 mRNAs in 42 specimens of patients with FXIIID including 18 case and 24 control groups. The comparative method of relative quantification (2-Delta-Delta-cCt) was utilized to analyze the expression level of each target gene. The expression level of glyceraldehyde-3 phosphate dehydrogenase was used to standardize the expression levels of MMPs. Results Umbilical bleeding was the most common clinical manifestation among all patients. We found expression upregulation of MMP-9 gene in 13 patients (72.2%) in case and 3 patients (12.5%) in control group, indicating a significant difference between cases and controls for MMP-9 gene expression level (P = 0.001%)(CI 2.8-95.3). Conclusions Our patients present with a wide spectrum of clinical symptoms, which are important in screening and diagnosis of patients with FXIIID. We hypothesized that the overexpression of MMP-9 due to polymorphisms or inflammation was associated with pathogenesis of ICH in FXIIID. This effect can be attenuated by nonspecific MMP inhibition to reduce hospitalization and death rates in these patients. PMID- 25544260 TI - Methylenetetrahydrofolate reductase 677TT genotype may be associated with an increased lung cancer risk in North China: an updated meta-analysis. AB - BACKGROUND: Although many epidemiology studies have investigated the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and their associations with lung cancer (LC), definite conclusions cannot be drawn. To clarify the effects of MTHFR polymorphisms on the risk of LC, we performed a meta analysis in Chinese populations. MATERIAL/METHODS: Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) until 16 February 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. RESULTS: A total of 11 studies with 2487 LC cases and 3228 controls were included in this meta-analysis. Overall, no significant association was found between MTHFR C677T polymorphism and LC risk when all studies in Chinese populations were pooled into this meta-analysis. In subgroup analyses stratified by geographical location and source of controls, significantly increased risk was found in North China (T vs. C: OR=1.28, 95% CI: 1.14-1.44; TT vs. CC: OR=1.67, 95% CI: 1.33 2.10; TT + CT vs. CC, OR=1.39, 95% CI=1.15-1.69; TT vs. CC + CT: OR=1.46, 95% CI: 1.03-2.06) and in population-based studies (TT vs. CC: OR=1.37, 95% CI: 1.14 1.65; TT vs. CC + CT: OR=1.25, 95% CI: 1.07-1.45). CONCLUSIONS: This meta analysis provides evidence that MTHFR C677T polymorphism may contribute to LC development in North China. Studies with larger sample sizes and wider spectrum of populations are warranted to verify this finding. PMID- 25544261 TI - Whose deceleration is it? PMID- 25544262 TI - Hemodynamic instability in patients undergoing pulmonary embolectomy: institutional experience. AB - OBJECTIVES: Acute pulmonary embolism is a major cause of morbidity and mortality in patients presenting for emergent cardiac surgery with overall mortality ranging from 6% to as high as 85%. While the initial focus of treatment is nonsurgical or percutaneous interventions, surgical treatment continues to be a treatment for patients with refractory thrombus burden or cardiogenic shock. Our institution regularly performs surgical pulmonary embolectomy with improved outcomes compared to current reports. We thus performed a retrospective analysis of outcomes of pulmonary embolectomy patients and anesthetic management. DESIGN: A retrospective review of 40 patients undergoing emergent pulmonary embolectomy over a 4 year period (2008-2012) at our institution was performed to assess for a 2nd period of critical instability. SETTING: The study was conducted at a tertiary, level 1, trauma university medical center. PARTICIPANTS: The study was performed through chart review of patient hospital records. INTERVENTIONS: No interventions were performed. MEASUREMENTS: Anesthetic records were reviewed along with echocardiographic records and surgical reports to assess cardiac function, need for emergent cardiopulmonary bypass, and degree of patient morbidity. CONCLUSIONS: A total of 40 patients were studied. Hemodynamic instability occurred in 12.5% of patients at time of induction requiring emergent cardiopulmonary bypass. Another 17% of patients who remained stable following induction developed subsequent instability requiring emergent cardiopulmonary bypass during pericardial opening or manipulation which has not been previously reported. One patient died during hospitalization. Patients who required emergent bypass following induction of general anesthesia tended to receive higher doses of induction drugs than the other groups. In patients who needed emergent bypass during pericardial manipulation there were no identifiable factors suggesting that these patients remain at risk despite a stable post-induction course. PMID- 25544264 TI - End-tidal anesthetic concentration audible alert setup to minimize intraoperative awareness. PMID- 25544263 TI - Comparison of sugammadex and conventional reversal on postoperative nausea and vomiting: a randomized, blinded trial. AB - STUDY OBJECTIVE: To determine whether the new selective binding agent sugammadex causes less postoperative nausea and vomiting (PONV) than the cholinesterase inhibitor neostigmine. DESIGN: Prospective, randomized, double-blinded study. SETTING: University-affiliated hospital. PATIENTS: One hundred American Society of Anesthesiologists physical status 1 and 2 patients scheduled for extremity surgery. INTERVENTIONS: Patients were randomly assigned to neostigmine (70 MUg/kg) and atropine (0.4 mg per mg neostigmine) or sugammadex 2 mg/kg for neuromuscular antagonism at the end of anesthesia, when 4 twitches in response to train-of-four stimulation were visible with fade. MEASUREMENTS: We recorded PONV, recovery parameters, antiemetic consumption, and side effects. MAIN RESULTS: Nausea and vomiting scores were lower in the sugammadex patients upon arrival in the postanesthesia care unit (med: 0 [min-max, 0-3] vs med: 0 [min-max, 0-3]; P < .05), but thereafter low and comparable. Postoperative antiemetic and analgesic consumption were similar in each group. Extubation (median [interquartile range], 3 [1-3.25] vs 4 [1-3.25]; P < .001) first eye opening (4 [3-7.25] vs 7 [5-11]; P < .001), and head lift (4 [2-7.25] vs 8 [11-25]; P < .001) in minutes were shorter in patients given sugammadex. Postoperative heart rates were significantly lower in all measured times patients given neostigmine. CONCLUSIONS: Nondepolarizing neuromuscular blocking antagonism with sugammadex speeds recovery of neuromuscular strength but only slightly and transiently reduces PONV compared with neostigmine and atropine. PMID- 25544265 TI - Effect of genotype imputation on genome-enabled prediction of complex traits: an empirical study with mice data. AB - BACKGROUND: Genotype imputation is an important tool for whole-genome prediction as it allows cost reduction of individual genotyping. However, benefits of genotype imputation have been evaluated mostly for linear additive genetic models. In this study we investigated the impact of employing imputed genotypes when using more elaborated models of phenotype prediction. Our hypothesis was that such models would be able to track genetic signals using the observed genotypes only, with no additional information to be gained from imputed genotypes. RESULTS: For the present study, an outbred mice population containing 1,904 individuals and genotypes for 1,809 pre-selected markers was used. The effect of imputation was evaluated for a linear model (the Bayesian LASSO - BL) and for semi and non-parametric models (Reproducing Kernel Hilbert spaces regressions - RKHS, and Bayesian Regularized Artificial Neural Networks - BRANN, respectively). The RKHS method had the best predictive accuracy. Genotype imputation had a similar impact on the effectiveness of BL and RKHS. BRANN predictions were, apparently, more sensitive to imputation errors. In scenarios where the masking rates were 75% and 50%, the genotype imputation was not beneficial. However, genotype imputation incorporated information about important markers and improved predictive ability, especially for body mass index (BMI), when genotype information was sparse (90% masking), and for body weight (BW) when the reference sample for imputation was weakly related to the target population. CONCLUSIONS: In conclusion, genotype imputation is not always helpful for phenotype prediction, and so it should be considered in a case-by-case basis. In summary, factors that can affect the usefulness of genotype imputation for prediction of yet-to-be observed traits are: the imputation accuracy itself, the structure of the population, the genetic architecture of the target trait and also the model used for phenotype prediction. PMID- 25544266 TI - Nasopharyngeal airway stenting devices for obstructive sleep apnoea: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review outcomes of adults with obstructive sleep apnoea treated with nasopharyngeal airway stenting devices. METHODS: Medline, Scopus, Web of Science and the Cochrane Library databases were searched, and data on device use and tolerability, sleepiness, oxygen saturation, apnoea index, apnoea-hypopnoea index, and sleep quality were collected. RESULTS: Of 573 potential studies, 29 were retrieved for detailed evaluation and 16 met the study criteria. Polysomnography data for patients treated with nasal trumpets as an isolated therapy were pooled for meta-analysis. The mean apnoea index +/- standard deviation, for 53 patients, decreased from 32.4 +/- 15.9 to 9.0 +/- 7.2 episodes per hour (p < 0.00001). The mean apnoea-hypopnoea index, for 193 patients, decreased from 44.1 +/- 18.9 to 22.7 +/- 19.3 episodes per hour (p < 0.00001). The mean lowest oxygen saturation, for 193 patients, increased from 66.5 +/- 14.2 to 75.5 +/- 13.9 per cent (p < 0.00001). CONCLUSION: Some studies have demonstrated limited effectiveness and low tolerability of nasopharyngeal airway stenting devices, while other studies have shown a significant benefit in treating obstructive sleep apnoea, with a high level of patient acceptance. Nasal trumpets have been successful in decreasing airway obstruction in the short term. PMID- 25544269 TI - Malignant glomus tumor of the thyroid gland where is heretofore an unreported organ: a case report and literature review. AB - Glomus tumors are relatively uncommon clinically benign tumors. Malignant glomus tumors are rare, and only a small number develop metastatic foci. The usual location is deep dermis or subcutis, but it has been reported in various locations. A 55-year-old man presented with an incidentally found thyroid mass. Neck ultrasound showed a mass with a heterogeneous hypoechoic calcific mass in the right lobe. Right lobectomy specimen showed the 3.6-cm-sized calcified mass composed of sheets of uniform round to polygonal cells and intervening staghorn shaped vessels. Occasional cellular atypism and necrosis with increased mitotic activity (up to 7 per 10 high-power fields) were found. Infiltration to the residual thyroid parenchyma, vessel, thyroidal capsule, and strap muscle was found. These tumor cells were strongly positive for smooth muscle actin, collagen type IV, and vimentin with pericellular reticulin-cuffing. Ultrastructurally, closely packed oval-shaped tumor cells having cytoplasmic mitochondria, rough endoplasmic reticulums with pinocytotic vesicles along the plasmalemmal surface and thin filaments of 6 nm in diameter were surrounded by thick basal lamina. That mass was diagnosed as a malignant glomus tumor. Incidentally, a 0.5-cm-sized papillary carcinoma was found through entire embedding. Complete thyroidectomy with chemotherapy was done. Thirty months later, multiple metastases developed in the brain and lung, and he expired. To our knowledge, neither benign nor malignant thyroid glomus tumor has been previously described. Here, we describe the first case of a malignant glomus tumor in the thyroid gland. PMID- 25544270 TI - Stochastic dynamics of adaptive trait and neutral marker driven by eco evolutionary feedbacks. AB - How the neutral diversity is affected by selection and adaptation is investigated in an eco-evolutionary framework. In our model, we study a finite population in continuous time, where each individual is characterized by a trait under selection and a completely linked neutral marker. Population dynamics are driven by births and deaths, mutations at birth, and competition between individuals. Trait values influence ecological processes (demographic events, competition), and competition generates selection on trait variation, thus closing the eco evolutionary feedback loop. The demographic effects of the trait are also expected to influence the generation and maintenance of neutral variation. We consider a large population limit with rare mutation, under the assumption that the neutral marker mutates faster than the trait under selection. We prove the convergence of the stochastic individual-based process to a new measure-valued diffusive process with jumps that we call Substitution Fleming-Viot Process (SFVP). When restricted to the trait space this process is the Trait Substitution Sequence first introduced by Metz et al. (1996). During the invasion of a favorable mutation, a genetical bottleneck occurs and the marker associated with this favorable mutant is hitchhiked. By rigorously analysing the hitchhiking effect and how the neutral diversity is restored afterwards, we obtain the condition for a time-scale separation; under this condition, we show that the marker distribution is approximated by a Fleming-Viot distribution between two trait substitutions. We discuss the implications of the SFVP for our understanding of the dynamics of neutral variation under eco-evolutionary feedbacks and illustrate the main phenomena with simulations. Our results highlight the joint importance of mutations, ecological parameters, and trait values in the restoration of neutral diversity after a selective sweep. PMID- 25544268 TI - Technical guidelines for head and neck cancer IMRT on behalf of the Italian association of radiation oncology - head and neck working group. AB - Performing intensity-modulated radiotherapy (IMRT) on head and neck cancer patients (HNCPs) requires robust training and experience. Thus, in 2011, the Head and Neck Cancer Working Group (HNCWG) of the Italian Association of Radiation Oncology (AIRO) organized a study group with the aim to run a literature review to outline clinical practice recommendations, to suggest technical solutions and to advise target volumes and doses selection for head and neck cancer IMRT. The main purpose was therefore to standardize the technical approach of radiation oncologists in this context. The following paper describes the results of this working group. Volumes, techniques/strategies and dosage were summarized for each head-and-neck site and subsite according to international guidelines or after reaching a consensus in case of weak literature evidence. PMID- 25544271 TI - Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress mediated apoptosis via toll-like receptor 2/4. AB - Endoplasmic reticulum (ER) stress responses play critical roles in the pathogenesis of tuberculosis. To investigate the regulatory role of the ER stress response in 38-kDa antigen-induced apoptosis, we examined the relationship between the ER stress response and apoptosis in bone marrow-derived macrophages (BMDMs) stimulated with Mycobacterium tuberculosis antigen (38-kDa Ag). The expression of ER molecular chaperones, including C/EBP homologous protein (CHOP), glucose-regulated protein (Bip) and phosphorylated alpha subunit of eukaryotic initiation factor 2, was induced in BMDMs stimulated with the 38-kDa Ag. Interestingly, 38-kDa Ag-stimulation induced apoptosis via activation of caspase 12, -9 and -3. However, 38-kDa Ag-induced apoptosis was significantly reduced in TLR2- and TLR4-deficient macrophages. Because toll-like receptors (TLRs) initiate the activation of mitogen-activated protein kinase (MAPK) signaling cascades, we evaluated the effect of MAPK activation on ER stress. The 38-kDa Ag activated Jun N-terminal kinase, extracellular signal-regulated kinase and p38 phosphorylation. MAPK signaling induced the secretion of proinflammatory cytokines such as MCP-1, TNF-alpha and IL-6. The 38-kDa Ag-induced MCP-1 was especially associated with the induction of MCP-1-induced protein (MCPIP), which increased the generation of reactive oxygen species (ROS) and ER stress. To investigate the role of MCPIP in ROS-induced ER stress by 38-kDa Ag stimulation, we transfected MCPIP siRNA into RAW264.7 cells before 38-kDa Ag stimulation, and measured the generation of ROS and expression of ER molecular chaperones. ROS production and CHOP expression were decreased by the silencing of MCPIP induction. Our results demonstrate that the expression of MCPIP by 38-kDa Ag stimulation is increased through a TLR-MAPK dependent signaling pathway, and leads to ER stress-induced apoptosis. In conclusion, MCPIP is important for host defense mechanisms in mycobacterial pathogenesis. PMID- 25544272 TI - 5-HT2B receptor blockade attenuates beta-adrenergic receptor-stimulated myocardial remodeling in rats via inhibiting apoptosis: role of MAPKs and HSPs. AB - Recent studies have proposed the potential role of 5-HT2B receptor (5-HT2BR) blockade in alleviating myocardial dysfunction; hitherto, the regulatory pathway for its protective effect has remained enigmatic. In the present study, we sought to investigate the role of SB-204741, a 5-HT2BR blocker in isoproterenol-induced myocardial remodeling in rats and its cross-talk with apoptosis and mitogen activated protein kinase (MAPKs)/heat shock proteins (HSPs) pathway. To assess this hypothesis, we measured the effect of SB-204741 (0.25-1.0 mg/kg/day, i.p.) in isoproterenol (85 mg/kg/day, s.c.)-induced myocardial remodeling in rats. SB 204741 dose dependently improved hemodynamic and ventricular functions following isoproterenol-induced myocardial injury. This amelioration was well substantiated with reduced expression of 5-HT2B, inflammatory proteins (NF-kappaBp65, IKK-beta, TNF-alpha, IL-6, and Cox-2), MAPKs (p-p38/p38 and p-JNK/JNK ratio) accompanied with increased protein expression of HSPs (alphaB-crystallin, Hsp27 and Hsp70), autophagy (LC3 and Beclin-1) and p-ERK/ERK ratio. Additionally, SB-204741 inhibited apoptotic signaling pathway as there was decreased DAPI/TUNEL positivity and protein expression of cytochrome c, Bax, and caspase-3 along with increased Bcl-2 expression. Preservation of histopathological and ultrastructural components, normalization of nitric oxide level, endogenous antioxidants and myocyte injury marker enzymes were also observed. In conclusion, inhibition of apoptosis via modulation of MAPKs/HSPs is essential for 5-HT2BR blockade mediated cardioprotective effect. PMID- 25544273 TI - Revision of Phaenocora Ehrenberg, 1836 (Rhabditophora, Typhloplanidae, Phaenocorinae) with the description of two new species. AB - A morphological and taxonomical account of the taxon Phaenocora is provided. An effort was made to locate and study all available material and, where possible, species are briefly re-described. We also describe two new species: Phaenocora gilberti sp. nov. from Cootes Paradise, Ontario, Canada and Phaenocora aglobulata sp. nov. from Prairie Grove, Alabama, USA. Species recognition is based on a combination of both male and female morphology. A comparison of and discussion on all species is given, resulting in a total of 28 valid species, three species inquirendae, five species dubiae, and one nomen nudum. An identification key is provided. PMID- 25544274 TI - A new species of Allobates (Anura: Aromobatidae) from the Tapajos River basin, Para State, Brazil. AB - We describe a new species of Allobates from the south of eastern Amazonia, Brazil. This species inhabits fluvial springs and the banks of small streams in terra-firme forests along the Tapajos River basin. Average snout-to-vent length is 17.78 mm (range 16.09-19.59 mm) among males and 19.50 mm (range 17.97-20.84 mm) among females. Surface of dorsum is marked by a distinct dark color pattern, with three convex areas, triangle and diamond-shaped. The species has a diffuse pale dorsolateral line (absent in some specimens), while the oblique lateral bar is defined. Dark-brown transversal stripes are present on femoral and tibial dorsal surfaces, which align with each other in live specimens when at rest. Tadpoles have short papillae on anterior (8-10 papillae on each side) and posterior labium (>30 papillae). Posterior labium is projected to the front, hiding posterior tooth rows. Eggs are deposited in nests on rolled or cranked dead leaves on the forest floor. Egg membranes and jelly-nests are transparent. Advertisement calls are mainly characterized by the continuous emission of single notes that might shift sporadically to note-pairs, emitted during short periods. Notes are split by regular silent intervals, with peak frequency ranging between 4273-4867 Hz. PMID- 25544275 TI - A review of the orientalis group of the Otostigmus subgenus Otostigmus Porat, 1876 (Chilopoda: Scolopendromorpha: Scolopendridae). AB - The Otostigmus subgenus Otostigmus, which currently comprises 58 species, was subdivided by Lewis (2010a) into nine species groups based on Attems' (1930a) monograph. The orientalis group comprising 19 species and two subspecies is the subject of this paper. In most cases, the type material is redescribed and variation discussed. The following species are valid: O. ateles Chamberlin, 1920, O. australianus Attems, 1930, O. brevidentatus Verhoeff, 1937, O. foveolatus Verhoeff, 1937, O. kashmiranus Lewis, 1992, O. metallicus Haase, 1887, O. multidens multidens Haase, 1887, O. oatesi Kraepelin, 1903, O. orientalis Porat, 1876, O. ruficeps Pocock, 1890, and O. striolatus Verhoeff, 1937. O. seychellarum Attems, 1900, is reinstated as a valid species and O. niasensis Silvestri, 1895, and O. sucki Krae-pelin, 1903 which may be O. metallicus are regarded as valid pro tem. O. greggi Chamberlin, 1944, is a junior subjective synonym of O. astenus (Kohlrausch, 1881), and O. loriae Silvestri, 1895, and O. multidens carens Attems, 1938, junior subjective synonyms of O. multidens. O. loriae nordicus Schileyko, 1995, becomes O. multidens nordicus comb. nov. O. nemorensis Silvestri, 1895, O. poonamae Khanna & Tripathi, 1986, and O. telus Chamberlin, 1939, are nomina dubia. A key to the species is provided. PMID- 25544276 TI - A review of the Hexactinellida (Porifera) of Chile, with the first record of Caulophacus Schulze, 1885 (Lyssacinosida: Rossellidae) from the Southeastern Pacific Ocean. AB - All records of the 15 hexactinellid sponge species known to occur off Chile are reviewed, including the first record in the Southeastern Pacific of the genus Caulophacus Schulze, 1885, with the new species Caulophacus chilense sp. n. collected as bycatch in the deep water fisheries of the Patagonian toothfish Dissostichus eleginoides Smitt, 1898 off Caldera (27oS), Region of Atacama, northern Chile. All Chilean hexactinellid species occur in bathyal to abyssal depths (from 256 up to 4142 m); nine of them are reported for the Sala y Gomez and Nazca Ridges, with one species each in the Juan Fernandez Archipelago and Easter Island. The Chilean hexactinellid fauna is still largely unknown, consisting of only 2.5 % of the known hexactinellid extant species. Further studies and deep water sampling are essential to assess their ecology and distribution, particularly in northern Chile. PMID- 25544277 TI - Two new species of tarsonemid mites (Acari: Tarsonemidae) from northeastern Brazil. AB - Two new species of tarsonemid mites, Daidalotarsonemus annonae sp. nov. and Fungitarsonemus setillus sp. nov. found on Annonaceae leaves collected in northeastern Brazil are described and illustrated. Females of D. annonae are similar to those of D. serissae, but differ by having setae c2 setiform, and seta 1a distant from apodeme 1. F. setillus is similar to F. pereregrinus, but females can be distinguished by having the prodorsal shield fused to tergite C, dorsal setae h and d short, and setae c1 longer than c2. PMID- 25544278 TI - First record of the family Pseudochiridiidae (Arachnida, Pseudoscorpiones) from continental South America--a Pseudochiridium from a Brazilian cave. AB - The small pseudoscorpion family Pseudochiridiidae Chamberlin, 1923 comprises two genera and 12 extant species recorded from Asia (Burma, Christmas Island, Indonesia, India, Nepal, Malaysia, New Guinea, Philippines, Nicobars and Sumba), eastern, central and southern Africa (Chad, D.R. Congo, Kenya, South Africa, Tanzania), Madagascar, Seychelles (Aldabra), North America (Florida) and the Caribbean Islands of Dominican Republic and Cuba (Harvey 2013, Barba & Barroso 2013); one unidentified species is mentioned for the fauna of Mexico (Ceballos 2004). A fossil species has been described from Dominican amber by Judson (2007), who predicted the presence of this family in South America. PMID- 25544279 TI - Description of two new cases of gynandromorphism in Paratrigona Schwarz and Augochlora Smith (Hymenoptera: Apidae and Halictidae). AB - Two new records of gynandromorphism in bees are described and illustrated for Paratrigona glabella and Augochlora amphitrite. The specimens show a mixture of male and female features, complete in Augochlora and on head and mesosoma in Paratrigona. Including the specimen described herein, gynandromorphs are now known for a total of three species in Meliponini bees and three species in Augochlorini bees. PMID- 25544280 TI - Ogyges Kaup, a flightless genus of Passalidae (Coleoptera) from Mesoamerica: nine new species, a key to identify species, and a novel character to support its monophyly. AB - Nine new species of Ogyges Kaup (Coleoptera: Passalidae) from the mountainous cloud forests of Mesoamerica are described: O. handali new species and O. menchuae new species from Guatemala; O. cavei new species, O. laurae new species, O. llama new species, O. mutenroshii new species, O. ratcliffei new species, and O. toriyamai new species from Honduras; and O. sandinoi new species from Nicaragua, the first objective record of the genus for this country. A key to the adult Ogyges is included. The work also shows that Ogyges possesses an exclusive autapomorphy: a trituberculate suprainternal tooth of each mandible (one long and wide apical tubercle and two connected, small, almost conical, basal tubercles). This character state is found in all known Ogyges species and is proposed as a synapomorphy that supports the monophyly of the genus. PMID- 25544281 TI - Ctenostomatous Bryozoa from Sao Paulo, Brazil, with descriptions of twelve new species. AB - This paper describes 21 ctenostomatous bryozoans from the state of Sao Paulo, Brazil, based on specimens observed in vivo. A new family, Jebramellidae n. fam., is erected for a newly described genus and species, Jebramella angusta n. gen. et sp. Eleven other species are described as new: Alcyonidium exiguum n. sp., Alcyonidium pulvinatum n. sp., Alcyonidium torquatum n. sp., Alcyonidium vitreum n. sp., Bowerbankia ernsti n. sp., Bowerbankia evelinae n. sp., Bowerbankia mobilis n. sp., Nolella elizae n. sp., Panolicella brasiliensis n. sp., Sundanella rosea n. sp., Victorella araceae n. sp. Taxonomic and ecological notes are also included for nine previously described species: Aeverrillia setigera (Hincks, 1887), Alcyonidium hauffi Marcus, 1939, Alcyonidium polypylum Marcus, 1941, Anguinella palmata van Beneden, 1845, Arachnoidella evelinae (Marcus, 1937), Bantariella firmata (Marcus, 1938) n. comb., Nolella sawayai Marcus, 1938, Nolella stipata Gosse, 1855 and Zoobotryon verticillatum (delle Chiaje, 1822). PMID- 25544282 TI - A cladistic re-analysis of the Gadiformes (Teleostei, Paracanthopterygii) using three-item analysis. AB - In the present paper, we describe LisBeth, a newly published phylogenetic program. LisBeth implements the cladistic three-item analysis for systematics and biogeography. We show how LisBeth handles character representation, character analysis, exact search functions, reconstruction of the intersection tree and other features, such as retention index, completeness index, character history and link with other programs such as PAUP*, version 4.0b10, TNT and Xper2. Using LisBeth, we reanalyze the phylogeny based on morphological characters of the order Gadiformes (Teleostei, Paracanthopterygii) published by Endo (2002) and compare our results. We also describe the generation of hypotheses of homology following Endo's guidelines versus 3ia representation schemes. We compare the topologies of all results and show the implications of the interpretation of character history. PMID- 25544283 TI - Afroleius floridus (Mahunka, 1985) comb. nov. and three new Afroleius Mahunka, 1984 species (Acari: Oribatida: Mycobatidae) from South Africa. AB - Three new species of the genus Afroleius Mahunka, 1984 are described: A. amieae sp. nov. with round notogastral foveae and long rostral and lamellar setae, A. inae sp. nov. with long lamellae and rostral and lamellar setae of similar length, and A. valerieae sp. nov. with ventrally directed bothridium and octotaxic system consisting of porose areas. Magyaria florida Mahunka, 1985 is recombined in the genus Afroleius as A. floridus comb. nov. Juvenile instars of A. floridus comb. nov. are described. PMID- 25544284 TI - Two new species of Encarsia Forster (Hymenoptera, Aphelinidae) and first description of the male E. plana Viggiani & Ren from China. AB - Two new species of Encarsia Forster (Hymenoptera: Aphelinidae) are described from China, Encarsia floralis Wang, Huang & Polaszek, sp. nov. and Encarsia maculiformis Wang, Huang & Polaszek, sp. nov., and the male of Encarsia plana Viggiani & Ren (1987) is newly described. PMID- 25544285 TI - Two new species of the feather mite genus Analloptes (Trouessart, 1885) Acariformes: Astigmata: Xolalgidae) from passerines (Aves: Passeriformes) in Brazil. AB - Two new feather mite species of the genus Analloptes Trouessart, 1885 (Acariformes: Xolalgidae) are described from suboscine passerines (Passeriformes) in Brazil: Analloptes giganteus sp. n. from Conopophaga lineata (Wied) (Conopophagidae) and A. cnemotricci sp. n. from Cnemotriccus fuscatus (Wied) (Tyrannidae). These are the first Analloptes species described from passerine hosts. Within the genus Analloptes, the two described species constitute a distinct species group characterized by the presence of setae ve and c1 in both sexes and by having the paragenital apodeme free from coxal structures in males. PMID- 25544286 TI - Diagnostic recognition of Escherichia coli septicemia in in vivo vascular blood. AB - A method of detecting Escherichia coli (EC) in in vivo blood with septicemia was sought using a handmade macro three-electrode (ME) system. Towards this end, an analytical ME probe was prepared using mercury immobilized on a carbon nanotube working electrode, and two graphite pencils were used as counter and reference electrodes instead of the expensive Ag/AgCl standard and Pt counter electrode. Under the optimum conditions, the cyclic potential was obtained at a 0.05 V anodic, then the square-wave stripping working range was obtained at 0.5-3.5 ml (3x10(2)~4x10(2)CFU/1ml) EC. Also under the optimum conditions, the statistic stability was examined in 1 ml EC 15(th) repeat anodic, with a relative standard deviation of RSD=0.98x10(-2). The developed method was applied to non treated blood, using only one drop. The patient blood with septicemia had a fast accumulation time (30 sec). A diagnostic detection limit of 0.06 ml EC was obtained. The recognition methods can be applied to in vivo vascular blood and real organic fluids, and can be used for poisoning control. PMID- 25544287 TI - Treatment of hypertension in heart failure with preserved ejection fraction. AB - Prevalence of Heart Failure with Preserved Ejection (HFPEF) has been rising steadily in the recent past. Studies have shown that at least half of patients presenting with symptoms and signs of heart failure (HF) have preserved left ventricular ejection fraction, i.e. HFPEF, and that this portion of the HF population consists predominantly of women, older age group, and people with hypertension and other cardiovascular risk factors. The morbidity and mortality associated with HFPEF are much higher than the normal population. Chronic hypertension is the most common cause in addition to age, with suggestion of up to 60% of patients with HFPEF being hypertensive. Addressing the specific aetiology and aggressive risk factor modification remain the mainstay in the treatment of HFPEF. Current guidelines recommend the management should involve treatment of hypertension, control of heart rate, venous pressure reduction, and prevention of myocardial ischemia. This review aims to discuss the role of hypertension in the pathophysiology, risk stratification and prognosis of HFPEF, as well as the current available data on various antihypertensive options in this population. PMID- 25544288 TI - Molecular mechanism of aggravation of hypertensive organ damages by short-term blood pressure variability. AB - There is increasing evidence that not only the elevation of systolic and diastolic blood pressure (BP) but also the increase in BP variability (or fluctuation) are associated with hypertensive organ damages and the morbidity and mortality of cerebrovascular and cardiovascular events. However, the molecular mechanism whereby the increase in BP variability aggravates hypertensive organ damages remains unknown. Thus, we created a rat chronic model of a combination of hypertension and large BP variability by performing bilateral sino-aortic denervation in spontaneously hypertensive rat. A series of our studies using this model revealed that large BP variability induces chronic myocardial inflammation by activating local angiotensin II and mineralocorticoid receptor systems and thereby aggravates cardiac hypertrophy and myocardial fibrosis, leading to systolic dysfunction, in hypertensive hearts. In addition, large BP variability induces the aggravation of arteriolosclerotic changes and ischemic cortical fibrosis in hypertensive kidney via local angiotensin II system. PMID- 25544289 TI - Hypertension in Egypt: a systematic review. AB - BACKGROUND: With 29% of the world's adult population projected to have hypertension by the year 2025, prevention and management of hypertension have become a public health priority. Hypertension also referred to as high blood pressure, in which the arteries have persistent high blood pressure. This results in a condition where the heart has to work harder than normal to flow blood through the vessels. A few years ago, there was no sufficient information about the epidemiology of hypertension, treatment protocols and its consequences in Egypt. Lately, there has been a major change in health system in Egypt, including research development. OBJECTIVES: To evaluate the existing data on prevalence, levels of awareness, treatment and control of hypertension in Egypt with a view of suggestive actions that could enhance control of hypertension and improve quality of life of the patients. METHODS: Six databases (Pub Med, Cochrane, MEDLINE, Sciencedirect, MedEase, Embase) were searched in November 2013, applying the following criteria: published from January 1995 to November 2013 written in English and carried out on human subjects. RESULTS: 21 studies were included in the systematic review of the prevalence, awareness, and control of hypertension in Egypt. The sample size ranged from 27 subjects to 12008 subjects, and the age range from 6-95 years. Every study had both male and female representatives. In most of the studies, the women were more than the men. CONCLUSION: There are declines in the levels of awareness of hypertension and even lower levels of control. Research is required to reveal reasons behind these near to the ground levels of control and treatment, and especially awareness, in order to put in the picture policy for the improvement of quality of life of hypertensive patients in Egypt. PMID- 25544290 TI - Analyzing the impact of severe tropical cyclone Yasi on public health infrastructure and the management of noncommunicable diseases. AB - INTRODUCTION: Traditionally, post disaster response activities have focused on immediate trauma and communicable diseases. In developed countries such as Australia, the post disaster risk for communicable disease is low. However, a "disease transition" is now recognized at the population level where noncommunicable diseases (NCDs) are increasingly documented as a post disaster issue. This potentially places an extra burden on health care resources and may have implications for disaster-management systems. With increasing likelihood of major disasters for all sectors of global society, there is a need to ensure that health systems, including public health infrastructure (PHI), can respond properly. Problem There is limited peer-reviewed literature on the impact of disasters on NCDs. Research is required to better determine both the impact of NCDs post disaster and their impact on PHI and disaster-management systems. METHODS: A literature review was used to collect and analyze data on the impact of the index case event, Australia's Severe Tropical Cyclone Yasi (STC Yasi), on PHI and the management of NCDs. The findings were compared with data from other world cyclone events. The databases searched were MEDLINE, CINAHL, Google Scholar, and Google. The date range for the STC Yasi search was January 26, 2011 through May 2, 2013. No time limits were applied to the search from other cyclone events. The variables compared were tropical cyclones and their impacts on PHI and NCDs. The outcome of interest was to identify if there were trends across similar world events and to determine if this could be extrapolated for future crises. RESULTS: This research showed a tropical cyclone (including a hurricane and typhoon) can impact PHI, for instance, equipment (oxygen, syringes, and medications), services (treatment and care), and clean water availability/access that would impact both the treatment and management of NCDs. The comparison between STC Yasi and worldwide tropical cyclones found the challenges faced were linked closely. These relate to communication, equipment and services, evacuation, medication, planning, and water supplies. CONCLUSION: This research demonstrated that a negative trend pattern existed between the impact of STC Yasi and other similar world cyclone events on PHI and the management of NCDs. This research provides an insight for disaster planners to address concerns of people with NCDs. While further research is needed, this study provides an understanding of areas for improvement, specifically enhancing protective PHI and the development of strategies for maintaining treatment and alternative care options, such as maintaining safe water for dialysis patients. PMID- 25544293 TI - Environmental and socioeconomic data do not improve the Predicting Asthma Risk in Children (PARC) tool. PMID- 25544291 TI - The zebrafish period2 protein positively regulates the circadian clock through mediation of retinoic acid receptor (RAR)-related orphan receptor alpha (Roralpha). AB - We report the characterization of a null mutant for zebrafish circadian clock gene period2 (per2) generated by transcription activator-like effector nuclease and a positive role of PER2 in vertebrate circadian regulation. Locomotor experiments showed that per2 mutant zebrafish display reduced activities under light-dark and 2-h phase delay under constant darkness, and quantitative real time PCR analyses showed up-regulation of cry1aa, cry1ba, cry1bb, and aanat2 but down-regulation of per1b, per3, and bmal1b in per2 mutant zebrafish, suggesting that Per2 is essential for the zebrafish circadian clock. Luciferase reporter assays demonstrated that Per2 represses aanat2 expression through E-box and enhances bmal1b expression through the Ror/Rev-erb response element, implicating that Per2 plays dual roles in the zebrafish circadian clock. Cell transfection and co-immunoprecipitation assays revealed that Per2 enhances bmal1b expression through binding to orphan nuclear receptor Roralpha. The enhancing effect of mouse PER2 on Bmal1 transcription is also mediated by RORalpha even though it binds to REV-ERBalpha. Moreover, zebrafish Per2 also appears to have tissue specific regulatory roles in numerous peripheral organs. These findings help define the essential functions of Per2 in the zebrafish circadian clock and in particular provide strong evidence for a positive role of PER2 in the vertebrate circadian system. PMID- 25544292 TI - An alternative retinoic acid-responsive Stra6 promoter regulated in response to retinol deficiency. AB - Cellular uptake of vitamin A (retinol) is essential for many biological functions. The Stra6 protein binds the serum retinol-binding protein, RBP4, and acts in conjunction with the enzyme lecithin:retinol acyltransferase to facilitate retinol uptake in some cell types. We show that in embryonic stem (ES) cells and in some tissues, the Stra6 gene encodes two distinct mRNAs transcribed from two different promoters. Whereas both are all-trans-retinoic acid (RA) responsive in ES cells, the downstream promoter contains a half-site RA response element (RARE) and drives an ~ 13-fold, RA-associated increase in luciferase reporter activity. We employed CRISPR-Cas9 genome editing to show that the endogenous RARE is required for RA-induced transcription of both Stra6 isoforms. We further demonstrate that in ES cells, 1) both RARgamma and RXRalpha are present at the Stra6 RARE; 2) RA increases co-activator p300 (KAT3B) binding and histone H3 Lys-27 acetylation at both promoters; 3) RA decreases Suz12 levels and histone H3 Lys-27 trimethylation epigenetic marks at both promoters; and 4) these epigenetic changes are diminished in the absence of RARgamma. In the brains of WT mice, both the longer and the shorter Stra6 transcript (Stra6L and Stra6S, respectively) are highly expressed, whereas these transcripts are found only at low levels in RARgamma(-/-) mice. In the brains of vitamin A-deficient mice, both Stra6L and Stra6S levels are decreased. In contrast, in the vitamin A-deficient kidneys, the Stra6L levels are greatly increased, whereas Stra6S levels are decreased. Our data show that kidneys respond to retinol deficiency by differential Stra6 promoter usage, which may play a role in the retention of retinol when vitamin A is low. PMID- 25544294 TI - Effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans: a crossover double-blind study. AB - PURPOSE: Recently, attention has been paid to dexmedetomidine, a selective alpha 2 adrenoceptor agonist, as a possible additive for local anesthesia. However, the effect of locally injected dexmedetomidine on the anesthetic action in humans has not fully been clarified. Thus, the purpose of the present study was to evaluate the effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans. MATERIALS AND METHODS: Twenty healthy volunteers were included in the present crossover double-blinded study. Lidocaine solution or lidocaine plus dexmedetomidine solution was submucosally injected into the alveolar mucosa in a crossover and double-blinded manner. The local anesthetic effect of the solutions was evaluated by measuring the current perception threshold (CPT) in the oral mucosa for 120 minutes after injection. Furthermore, the sedation level, blood pressure, and heart rate of the volunteers were evaluated. For statistical analysis, the Wilcoxon signed rank test and 2-way repeated measures analysis of variation were used. RESULTS: The CPT was increased with the 2 solutions and peaked 10 minutes after injection. CPT values 10 and 20 minutes after injection of lidocaine plus dexmedetomidine solution were considerably higher than those with lidocaine solution. The duration of an important increase in the CPT after injection with lidocaine plus dexmedetomidine solution was longer than that with lidocaine. Furthermore, the area under the time curve of CPT was considerably higher with lidocaine plus dexmedetomidine solution than with lidocaine solution. No volunteer showed a change in sedation level, blood pressure, or heart rate after injection with either test solution throughout the experiment. CONCLUSION: The present study showed that a combination of dexmedetomidine plus lidocaine considerably enhances the local anesthetic potency of lidocaine without any major influences on the cardiovascular system when locally injected into the oral mucosa. PMID- 25544295 TI - Panton-Valentine leukocidin positive Staphylococcal aureus infections of the head and neck: case series and brief review of literature. AB - Panton-valentine leukocidin (PVL) is a pore-forming cytotoxin produced by some clones of Staphylococcus aureus that is associated with infections ranging from uncomplicated skin and soft tissue infections to life-threatening necrotizing pneumonia. PVL S aureus-associated maxillofacial infections are rarely reported; therefore, a high degree of clinical suspicion is warranted and close liaison with microbiologists and appropriate samples are required for optimal management. This report discusses the management and learning points from 3 such cases managed by the Greater Glasgow and Clyde National Health Service maxillofacial surgical teams. PMID- 25544296 TI - Monitoring for periodontal inflammatory disease in the third molar region. AB - PURPOSE: To assess changes at 2-year intervals in the periodontal status of the third molar region in participants enrolled with asymptomatic third molars and no clinical evidence of third molar region periodontal pathology. PARTICIPANTS AND METHODS: The included participants who presented with a healthy periodontal status (all probing depths [PDs], <4 mm) in the third molar region, defined as distal of second molars and around adjacent third molars, were from a larger longitudinal study of participants with asymptomatic third molars. Full-mouth periodontal PD data from 6 sites per tooth were obtained clinically at enrollment and at subsequent 2-year intervals. Data were aggregated to the patient level. Outcome variables were the presence or absence of periodontal pathology, defined as at least 1 PD of at least 4 mm in the third molar region. RESULTS: One hundred twenty-nine participants had a third molar region PD shallower than 4 mm at enrollment. Most participants were Caucasian (85%), women (60%), younger than 25 years (62%), educated beyond high school (84%), and with good oral health habits. At 6 years, excluding the 61 participants lost to follow-up, 47% participants had had third molars removed, 21% had developed at least 1 PD of at least 4 mm in the third molar region since enrollment, and 32% retained the periodontal status at enrollment (all PDs in third molar region, <4 mm). Demographic characteristics were not statistically different for participants followed for 6 years compared with those lost to follow-up. CONCLUSIONS: Although not all participants could be followed for 6 years after enrollment or chose to retain third molars, one third of participants maintained the third molar region periodontal status assessed at baseline for 6 years after enrollment; no clinical evidence of pathology developed over time. PMID- 25544297 TI - Does smoking affect the Ki67 and p53 expressions in asymptomatic fully impacted lower third molar follicles? AB - PURPOSE: Ki67 and p53 protein expressions are the most widely used markers to show the pathologic proliferation and early-stage tumoral alterations in vital tissues. The aim of this study was to compare Ki67 and p53 protein expressions in smokers' and nonsmokers' pericoronal follicles of asymptomatic impacted lower third molars (ILTMs). MATERIALS AND METHODS: A cross-sectional study was planned. The study sample was derived from a population of patients who presented for evaluation and operative treatment of asymptomatic ILTMs. The predictor variable was smoking status, defined as smoker or nonsmoker. Outcome variables were Ki67 and p53 protein expressions in ILTM follicles. Other study variables were age, gender, tooth position, cigarette pack-year, epithelial layer staining, and inflammation. Independent-samples t test analyses were conducted with SPSS 10.0 (SPSS, Inc, Chicago, IL), with statistical significance set at a P value equal to .05. RESULTS: The study sample was composed of 70 patients (35 in the smoker group) who contributed 60 follicles. There were statistical differences between the 2 groups for variables Ki67 and p53. Mean expression levels of Ki67 were 3.93 +/- 2.17 and 2.48 +/- 2.09, respectively, for smokers and nonsmokers (P = .011). Mean expression levels of p53 were 5.32 +/- 1.98 and 3.06 +/- 2.34, respectively, for smokers and nonsmokers (P = .000). CONCLUSION: The present study showed that dental follicles of smokers have higher Ki67 and p53 protein expressions than nonsmokers' follicles. PMID- 25544298 TI - Interfragmentary screw fixation of the zygomatic arch in complex midface and zygomaticomaxillary fractures. AB - Zygomatic arch reduction and fixation is a key point in the treatment of complex midface and zygomaticomaxillary fractures. High-impact frontal trauma can cause posterior displacement of zygomatic bone, with a sagittal fracture of the root of the zygomatic arch extending posteriorly to the glenoid fossa. Miniplate and screw fixation of this fracture requires a large detachment of soft tissue, thus being technically more difficult for proper fixation and increasing the risk of soft tissue damage. This report describes an operative approach for fixation of this type of fracture using an adaptation of the lag screw technique. After the initial reduction of zygomatic bone, the proximal segment of the zygomatic arch containing the sagittal fracture is anatomically reduced and a 2.0-mm titanium screw is placed with an inferior inclination of 10 degrees to 15 degrees into the mastoid cells of the temporal bone, thus avoiding intracranial screw placement. This technique showed excellent results in reduction and long-term stability. It facilitates the surgical procedure, decreases the risk of soft tissue damage, and can lower costs compared with conventional miniplate and screw fixation. PMID- 25544299 TI - Cone-beam computed tomography education and exposure in oral and maxillofacial surgery training programs in the United States. AB - PURPOSE: The purpose of this study was to estimate the penetration of cone-beam computed tomography (CBCT) in oral and maxillofacial surgery (OMS) residency programs in the United States. In addition, this study was designed to assess the education and training, relevance, and image interpretation responsibility of CBCT as experienced by OMS residents. MATERIALS AND METHODS: The authors performed a cross-sectional study of all 102 US-based OMS program directors (PDs) from January 1, 2014 through April 30, 2014. Study variables included questions about 4 key factors in CBCT in OMS programs: access, education and training, relevance, and image interpretation responsibility. Data analysis was a product of the percentage of positive responses to each question. RESULTS: Fifty-four PDs participated in the study. The results showed that 87% of responding OMS programs have access to CBCT and that CBCT is used primarily for dental implant-related procedures. CONCLUSION: OMS residents are actively involved in CBCT use in their residency. OMS residents' access to CBCT is increasing, and their education, training, and image interpretation responsibility is increasing. PMID- 25544300 TI - Sialendoscopy-assisted treatment for radioiodine-induced sialadenitis. AB - PURPOSE: Chronic sialadenitis is a common complication of radioactive iodine for the treatment of thyroid disease. The aim of this study was to describe the authors' experience with interventional sialendoscopy for the management of radioiodine-induced sialadenitis. MATERIALS AND METHODS: Twelve patients with radioiodine-induced sialadenitis treated with sialendoscopy from January 2013 through December 2013 at the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University were retrospectively reviewed. Age, gender, and time to development of radioiodine-induced sialadenitis were obtained from the hospital database. All patients were asked to undergo visual analog scale (VAS) and salivary gland scintigraphy (SGS) examinations before and 6 months after surgery. A paired t test was conducted, and a P value less than .05 was considered statistically significant. RESULTS: Twelve patients (15 parotid glands and 4 submandibular glands) successfully underwent interventional sialendoscopy under local anesthesia. Ductal stenosis was the most common feature identified by endoscopy. Among the 12 patients, swelling occurred in 91.7%. Compared with the preoperative score of 6, the mean VAS score 6 months after sialendoscopy was 3; 15 glands (78.9%) showed improved uptake and excretion by SGS. The postoperative VAS score was significantly lower than the preoperative VAS score (P < .05), and the postoperative SGS result was significantly higher than the preoperative SGS result (P < .05). CONCLUSIONS: Interventional sialendoscopy could be an effective technique for the treatment of sialadenitis caused by radioactive iodine. PMID- 25544301 TI - Coronectomy of the mandibular third molar: a retrospective study of 185 procedures and the decision to repeat the coronectomy in cases of failure. AB - PURPOSE: A prevalent complication associated with mandibular third molar extraction is inferior alveolar nerve (IAN) injury. This study evaluated the success rate of coronectomy and, in the event of failure of the procedure, retreatment. PATIENTS AND METHODS: One hundred seventy-three patients underwent 185 coronectomy procedures of the mandibular third molar to prevent IAN injury. The coronectomy was performed along the cementoenamel junction. Residual roots were trimmed 3 to 4 mm below the crest margin. No pulp treatment was performed and the roots were left vital. A postoperative orthopantogram was recorded immediately after the procedure or at follow-up 1 month later. Two additional orthopantographic views were taken at 6- and 12-month follow-up appointments. Statistical analyses were performed to assess differences in root migration, pain, wound healing and failure by age, gender, and time elapsed from coronectomy. Statistical data were considered significant at a P value less than .05. RESULTS: Statistical differences in the migration of residual roots from 6 to 12 months were found. Migration of the roots was found in younger patients. In a total of 10 cases of failure, 4 were treated with repeat coronectomy. The other 6 cases were treated with reoperation (ie, removal of residual roots). CONCLUSION: Immediate postoperative radiographic imaging is recommended, as well as, follow-up evaluation 12 months after surgery. In addition, repeat coronectomy is recommended for cases in which enamel retention is diagnosed to prevent residual roots from becoming infected. PMID- 25544302 TI - Pedicled buccal fat pad flap as a reliable surgical strategy for the treatment of medication-related osteonecrosis of the jaw. AB - PURPOSE: The purpose of this study was to evaluate the coverage of the pedicled buccal fat pad flap (PBFP) and the long-term results of this treatment in patients with medication-related osteonecrosis of the jaw (MRONJ). PATIENTS AND METHODS: Ten patients (2 men and 8 women; average age, 72.9 yr old) diagnosed with MRONJ were selected. Patients were treated with a PBFP. Data from patients regarding MRONJ stage, defect size, bone exposure after surgery, operation time, admission period, duration of antibiotic therapy, recurrence of disease, and postoperative complications were analyzed retrospectively. RESULTS: Six patients were diagnosed with MRONJ stage 2, and 4 patients were diagnosed with MRONJ stage 3. The maximum defect in the study was 62 * 18 mm. Among the 10 patients, there was only 1 bony exposure, which occurred on postoperative day 2 after receiving the PBFP. This exposure might have been due to an incomplete resection of the affected bone. There were no severe donor site morbidities, and all patients showed satisfactory healing without incident. CONCLUSIONS: According to this evaluation, the PBFP effectively covered a relatively large surgical defect. Complications were minimal, and there was no recurrence of bony exposure during follow-up. In conclusion, using the PBFP was a reliable treatment option for the management of denuded bone in patients with MRONJ. PMID- 25544303 TI - Microbial biofilms are able to destroy hydroxyapatite in the absence of host immunity in vitro. AB - PURPOSE: It is widely thought that inflammation and osteoclastogenesis result in hydroxyapatite (HA) resorption and sequestrum formation during osseous infections, and microbial biofilm pathogens induce the inflammatory destruction of HA. We hypothesized that biofilms associated with infectious bone disease can directly resorb HA in the absence of host inflammation or osteoclastogenesis. Therefore we developed an in vitro model to test this hypothesis. MATERIALS AND METHODS: Customized HA discs were manufactured as a substrate for growing clinically relevant biofilm pathogens. Single-species biofilms of Streptococcus mutans, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans and mixed-species biofilms of C albicans plus S mutans were incubated on HA discs for 72 hours to grow mature biofilms. Three different non-biofilm control groups also were established for testing. HA discs were then evaluated by means of scanning electron microscopy, micro-computed tomography metrotomography, x-ray spectroscopy, and confocal microscopy with planimetric analysis. In addition, quantitative cultures and pH assessment were performed. Analysis of variance was used to test for significance between treatment and control groups. RESULTS: All investigated biofilms were able to cause significant (P < .05) and morphologically characteristic alterations in HA structure as compared with controls. The highest number of alterations observed was caused by mixed biofilms of C albicans plus S mutans. S mutans biofilm incubated in medium with additional sucrose content was the most detrimental to HA surfaces among single-species biofilms. CONCLUSIONS: Our findings suggest that direct microbial resorption of bone is possible in addition to immune-mediated destruction, which has important translational implications for the pathogenesis of chronic bone infections and for targeted antimicrobial therapeutics. PMID- 25544304 TI - Treatment of severe infantile hemangiomas with propranolol: an evaluation of the efficacy and effects of cardiovascular parameters in 25 consecutive patients. AB - PURPOSE: The aim of this study was to investigate the therapeutic results and effects of propranolol on cardiovascular parameters in infants receiving systemic propranolol for complicated infantile hemangiomas (IHs), as well as to evaluate the adverse effects of propranolol throughout the course of treatment. MATERIALS AND METHODS: Twenty-five consecutive patients who presented with complicated IHs were prospectively recruited into this study between April 2012 and June 2013. All patients were treated with systemic propranolol at a dose of 1.0 to 1.5 mg/kg, and the drug was taken once per day. The length of treatment was 8.2 months on average and ranged from 6 to 12 months. The follow-up visits were scheduled monthly after discharge. Changes were recorded during the 3-day hospitalization, including systolic and diastolic blood pressures, heart rate, and blood glucose level. The treatment responses were scored according to a 4 point scale system as very good, good, mild, or no response. The adverse effects after medication administration were evaluated and managed accordingly. RESULTS: Of the 25 patients, 8 (32%) had a very good response, 11 (44%) had a good response, and 6 (24%) had a mild response. When pretreatment and post-treatment values were compared, there was no significant decrease in mean systolic and diastolic blood pressures and mean heart rate (all P > .05). The decreases in the cardiovascular parameters were not commonly associated with observable clinical symptoms. No major collateral effects were observed, and no infants were withdrawn from treatment because of side effects. CONCLUSIONS: Fluctuations from the normal ranges of cardiovascular parameters occurred frequently with the initiation of propranolol, but were clinically asymptomatic. Therefore oral propranolol was an effective and safe treatment for IHs, particularly for early intervention suitable for severe IHs. PMID- 25544305 TI - Transfer of anterolateral thigh flaps in elderly oral cancer patients: complications in oral and maxillofacial reconstruction. AB - PURPOSE: Although a promising approach, the use of anterolateral thigh (ALT) free flaps has been limited in the reconstruction of oral and maxillofacial defects in elderly patients. The aim of this study was to estimate the frequency of postoperative complications and identify factors associated with complications. PATIENTS AND METHODS: The authors designed and implemented a retrospective study on the frequency of postoperative complications in elderly patients. They enrolled a sample composed of patients who underwent ALT free flap transfers for the repair of defects created during oral and maxillofacial cancer surgery from February 2002 to March 2013. The chi(2) test, t test, and multivariate regression model were used. RESULTS: A total of 1,100 patients were studied (859 men and 241 women). One hundred four patients (9.5%) were at least 70 years old (elderly group) at the time of surgery; the other 996 patients were younger than 70 years (younger group). The overall success rate of ALT free flap transfer was 97.2% (97.0% in the younger group, 99.0% in the elderly group; P > .05). The overall complication rate was 27.5% (27.2% in the younger group, 29.8% in the elderly group; P = .572). Multivariate analysis showed that operation time, American Society of Anesthesiologists class, and comorbidity were independent risk factors for postoperative complications in elderly patients. CONCLUSIONS: Oral and maxillofacial reconstruction using ALT free flaps in elderly patients can achieve outcomes similar to those obtained in younger patients. Limiting the operation time is important for improving surgical outcomes. PMID- 25544306 TI - Favipiravir: a new medication for the Ebola virus disease pandemic. AB - The purpose of this report is to advocate speedy approval and less stringent regulations for the use of experimental drugs such as favipiravir in emergencies. Favipiravir is a new antiviral medication that can be used in emerging viral pandemics such as Ebola virus, 2009 pandemic influenza H1N1 virus, Lassa fever, and Argentine hemorrhagic fever. Although favipiravir is one of the choices for the treatment of patients with Ebola virus, several concerns exist. First, a clinical trial of favipiravir in patients infected with the Ebola virus has not yet been conducted, and further studies are required. Second, favipiravir has a risk for teratogenicity and embryotoxicity. Therefore, the Ministry of Health, Welfare and Labor of Japan has approved this medication with strict regulations for its production and clinical use. However, owing to the emerging Ebola virus epidemic in West Africa, on August 15, 2014, the Minister of Health, Welfare and Labor of Japan approved the use of favipiravir, if needed. PMID- 25544307 TI - Co-transmission of the non-transmissible South African Babesia bovis S24 vaccine strain during mixed infection with a field isolate. AB - The South African Babesia bovis live blood vaccine, originating from a field isolate attenuated by 23 serial syringe passages in splenectomized calves, has lost the ability to infect the natural vector Rhipicephalus (Boophilus) microplus. In this study, infection with mixed parasites from the vaccine strain and a field isolate, resulted in transmission of both genotype populations. Comparing the field isolate and transmitted combination indicated no significant difference in their virulence, while challenge of vaccinated cattle with these isolates showed the ability of the vaccine to protect against both. Limiting dilution of the transmitted combination, followed by infection of splenectomized cattle (n=34) yielded no single infections for the vaccine strain genotype, seven clonal lines of the field isolate and one mixture of vaccine strain and field isolate. Only one of two field isolate clonal lines selected for vector transmission study was transmitted. Showing that B. bovis isolates can contain both tick transmissible and non-transmissible subpopulations. The findings of this study also indicate the probability of vaccine co-infection transmission occurring in the field, which may result in new genotype populations of B. bovis. However, the impact of this recombination with field isolates is considered negligible since a genotypically diverse population of B. bovis is already present in South Africa. PMID- 25544308 TI - Rickettsia infection in Amblyomma tonelliae, a tick species from the Amblyomma cajennense complex. AB - The present study was performed to evaluate the Rickettsia infection in Amblyomma tonelliae ticks from Argentina. All ticks were subjected to DNA extraction and tested by a battery of PCRs to amplify fragments of four rickettsial genes, 23S 5S, gltA, ompA and htrA. Two ticks were positive. The Rickettsia detected in one tick represents a new lineage which is named Rickettsia sp. strain El Tunal. This new strain belongs to the canadensis group because it is closely related to Rickettsia monteiroi, Rickettsia canadensis and Candidatus "Rickettsia tarasevichiae". They clustered together on a high supported clade with both gltA and htrA genes. The other positive tick was infected with Candidatus "Rickettsia amblyommii". The results presented in this study constitute the first records of Rickettsia infection in A. tonelliae ticks. However, the medical relevance of these findings should be considered cautiously because the pathogenicity of Rickettsia sp. strain El Tunal and Candidatus "R. amblyommii" remains undetermined. PMID- 25544309 TI - Exposure to hazardous air pollutants and the risk of amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a serious and rapidly fatal neurodegenerative disorder with an annual incidence of 1-2.6/100,000 persons. Few known risk factors exist although gene-environment interaction is suspected. We investigated the relationship between suspected neurotoxicant hazardous air pollutants (HAPs) exposure and ALS. METHODS: A case-control study involving sporadic ALS cases (n = 51) and matched controls (n = 51) was conducted from 2008 to 2011. Geocoded residential addresses were linked to U.S. EPA NATA data (1999, 2002, and 2005) by census tract. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: Residential exposure to aromatic solvents significantly elevated the risk of ALS among cases compared to controls in 2002 (OR = 5.03, 95% CI: 1.29, 19.53) and 1999 (OR = 4.27, 95% CI: 1.09, 16.79) following adjustment for education, smoking, and other exposure groups. Metals, pesticides, and other HAPs were not associated with ALS. CONCLUSIONS: A potential relationship is suggested between residential ambient air aromatic solvent exposure and risk of ALS in this study. PMID- 25544310 TI - Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen. AB - Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative condition of the central nervous system that preferentially afflicts women more than men. Low estrogen states such as menopause and the postpartum period favor exacerbations of multiple sclerosis in women with the disease. Existing and emerging evidence suggests a role for estrogen in the alleviation of symptoms and reversal of pathology associated with MS. While clinical evidence is sparse regarding the benefit of estrogen therapy for women at risk for MS exacerbations, scientific data demonstrates that estrogen potentiates numerous neuroprotective effects on the central nervous system (CNS). Estrogens play a wide range of roles involved in MS disease pathophysiology, including increasing antiinflammatory cytokines, decreasing demyelination, and enhancing oxidative and energy producing processes in CNS cells. PMID- 25544311 TI - Toll-like receptor 1(TLR1) Gene SNP rs5743618 is associated with increased risk for tuberculosis in Han Chinese children. AB - Toll-like receptor 1 (TLR1) recognizes lipopeptides with TLR2, and affects immune response to Mycobacterium tuberculosis infection. Here, we report results of the first case-control pediatric study of the TLR1 single-nucleotide polymorphisms and susceptibility to tuberculosis (TB). A pediatric case-control study enrolled 340 TB patients and 366 healthy controls, all Han Chinese from North China. Significant differences of the allelic and genotypic distributions of rs5743618 in TLR1 gene were observed between TB group and control group and, G allele of rs5743618 was associated with increased risk for TB (OR: 2.40, 95%CI: 1.41-4.07, P = 0.0009). TLR1 rs5743618 -GT genotype was related to reduction in surface expression of TLR1 in monocytes and granulocytes regardless of stimulation with inactivated H37Rv. In addition, after stimulated with inactivated lysate of M. tuberculosis strain H37Rv, samples of peripheral blood mononuclear cells (PBMCs) from children with the rs5743618 GT genotypes showed a decreased level of Tumor Necrosis Factor-a (TNF-a) and CXC chemokine ligand 10 (CXCL10) production, invariable production of interleukin-6 (IL-6) and IL-8 and increased production of IL-10 ex vivo. To conclude, TLR1 rs5743618 G allele was found associated to susceptibility to TB in Han Chinese pediatric population. TLR1 rs5743618-GT genotype carriers may have reduced immune response to MTB infection although further study is warranted to test this conclusion. PMID- 25544313 TI - The vascular surgery workforce: a survey of consultant vascular surgeons in the UK, 2014. AB - OBJECTIVE: The purpose of this study was to describe the demographics, training, and practice characteristics of consultant vascular surgeons across the UK to provide an assessment of current, and inform future prediction of workforce needs. METHODS: A questionnaire was developed using a modified Delphi process to generate questionnaire items. The questionnaire was emailed to all consultant vascular surgeons (n = 450) in the UK who were members of the Vascular Society of Great Britain & Ireland. RESULTS: 352 consultant vascular surgeons from 95 hospital trusts across the UK completed the survey (78% response rate). The mean age was 50.6 years old, the majority (62%) were mid-career, but 24% were above the age of 55. Currently, 92% are men and only 8% women. 93% work full-time, with 60% working >50 hours, and 21% working >60 hours per week. The average team was 5 to 6 (range 2-10) vascular surgeons, with 23% working in a large team of >=8. 17% still work in small teams of <=3. Over 90% of consultant vascular surgeons perform the major index vascular surgery procedures (aneurysm repair, carotid endarterectomy, infra-inguinal bypass, amputation). While 84% perform standard endovascular abdominal aortic aneurysm repair (EVAR), <50% perform more complex endovascular aortic therapy. The majority of vascular surgeons "like their job" (85%) and are "satisfied" (69%) with their job. 34% of consultant vascular surgeons indicated they were "extremely likely" to retire within the next 10 years. CONCLUSIONS: This study provides the first detailed analysis of the new specialty of vascular surgery as practiced in the UK. There is a need to plan for a significant expansion in the consultant vascular surgeon workforce in the UK over the next 10 years to maintain the status quo. PMID- 25544314 TI - Commentary on "Three-dimensional CT reconstruction of the carotid artery: identifying the high bifurcation". PMID- 25544312 TI - Arabinosylated lipoarabinomannan (Ara-LAM) mediated intracellular mechanisms against tuberculosis infection: involvement of protein kinase C (PKC) mediated signaling. AB - Tuberculosis causes severe immunosuppression thereby ensuring the loss of the host protective immune responses. During Mycobacterium tuberculosis infection, the pathogen modulates TLR-2 receptor down-stream signaling, indicating the possible involvement of TLR-2 in the regulation of the host immune response. Moreover, different PKC isoforms are also involved in the course of infection. Arabinosylated lipoarabinomannan (Ara-LAM) possesses immuno-modulatory properties which induce the pro-inflammatory responses via induction of TLR-2-mediated signaling. Here, we found that pretreatment of M. tuberculosis-infected macrophages with Ara-LAM caused a significant increase in the conventional PKC expression along with their active association with TLR-2. This association activated the TLR-2 -mediated downstream signaling, facilitating the activation of MAP kinase P38. All these events culminated in the up-regulation of proinflammatory response, which was abrogated by treatment with PKC-alpha and P38 inhibitors. Moreover, pretreatment of macrophages with Ara-LAM abrogated the IL 10 production while restored MHC-II expression in the infected macrophages. This study demonstrates that Ara-LAM confers protection against tuberculosis via TLR 2/PKC signaling crosstalk which is responsible for the induction of host protective immune response against tuberculosis. PMID- 25544315 TI - Controlled intracellular self-assembly and disassembly of 19F nanoparticles for MR imaging of caspase 3/7 in zebrafish. AB - Compared to (1)H MRI, (19)F MRI provides higher selectivity but lower sensitivity. Therefore, the need to inject high doses of the (19)F probe to improve its sensitivity for in vivo diagnosis remains a challenge. A "smart" strategy is needed that could locally concentrate a low-dose (19)F probe while avoiding the fast transverse relaxation of the probes. Locally self-assembling and disassembling (19)F nanoparticles may be an optimal measure to achieve this goal. Herein, we report a dual-functional probe 1 for glutathione (GSH) controlled self-assembly and subsequent caspase 3/7 (Casp3/7)-controlled disassembly of formed nanoparticles (i.e., 1-NPs). Consecutive assembly and disassembly of 1-NPs translate to "off" and "on" (19)F magnetic resonance (MR) signal states, respectively. Employing this smart strategy, we successfully used 1 for the consecutive detection of GSH and Casp3/7 activity in vitro and in cells and imaging Casp3/7 activity in cells and in zebrafish at low doses with a 14.1 T magnetic field. PMID- 25544316 TI - Fruit of Ziziphus jujuba (Jujube) at two stages of maturity: distinction by metabolic profiling and biological assessment. AB - The fruit of Ziziphus jujuba, named as jujube or Chinese date, is used as a health supplement worldwide. Two kinds of jujubes are commonly found in the market: immature jujubes eaten as fruits, and mature jujubes employed as medicinal herbs. To study the variation of jujubes at two developmental stages, we investigated their chemical and biological properties by metabolic profiling and cellular assays. In NMR profiling, the levels of 11 metabolites were measured. Statistically differences in the levels of threonine, alanine, acetate, creatine, glucose, sucrose, and formate were found between mature and immature jujubes. In parallel, their neuro-protecting and erythropoietic activities were compared. The water extract of mature jujube possessed better effect in inducing neurofilament expression than that of the immature one, while immature jujube extract performed better in activating HRE-mediated transcriptional activity. These findings suggest the maturity of jujube has to be considered when it is being used for health food products. PMID- 25544317 TI - Eating in moderation and the essential role of awareness. A Dutch longitudinal study identifying psychosocial predictors. AB - BACKGROUND: Eating in moderation, i.e. the attempt to monitor and limit the intake of energy-dense foods, is a promising strategy in the prevention of weight gain. The purpose of this study was to examine which psychosocial factors derived from the I-Change Model (ICM) were associated with eating in moderation, and whether these factors differed between adults with a correct (aware) or incorrect (unaware) perception of their dietary behaviour. METHODS: This study used a longitudinal design with measurements at baseline (N = 483) and six-month follow up (N = 379). Eating in moderation was defined as the average daily energy intake from energy-dense food products and was measured by a validated food frequency questionnaire. Linear regression analyses were used to assess the associations between the ICM factors and eating in moderation. The moderating role of awareness was examined by including interactions between awareness and the ICM factors in the regression analyses using the pick-a-point approach to further examine the associations for aware and unaware participants. RESULTS: Participants who were aware of their dietary behaviour had a significantly lower average daily energy intake compared to those who were unaware. Eating in moderation was predicted by awareness, risk perception, social influence and intention. Among the aware participants, eating in moderation was predicted by risk perception, attitude, social influence and intention. Among the unaware participants, only risk perception and self-efficacy were significantly associated with eating in moderation. CONCLUSIONS: Our findings show that psychosocial factors may only predict eating in moderation when people are aware of their risk behaviour. Therefore, interventions aimed at promoting complex behaviours, such as eating in moderation, should first focus on improving individuals' awareness of their risk behaviour before targeting motivational factors. PMID- 25544318 TI - Hydrothermal synthesis of hydroxyapatite nanorods in the presence of sodium citrate and its aqueous colloidal stability evaluation in neutral pH. AB - In this paper, colloidal hydrophilic hydroxyapatite nanorods were synthesized in the presence of sodium citrate via thermal-decomplexing method. The influence of sodium citrate/Ca ions molar ratio (CT/CM) on the synthesis of HA nanorods was characterized in term of structure, size, morphology, and colloidal stability through TEM, XRD, Zeta potential, DLS and long-term standing test. The results show that increasing CT/CM would evidently facilitate high aspect ratio and enhance colloidal stability of nanorods. When the CT/CM is above 1/3, well crystallized HA nanorods with mean aspect ratio up to 5 would be obtained and kept colloidally stable for over two months in neutral pH (7.3-7.5). The origin responding to the results is that increasing CT/CM would enhance the inhibiting growth effect of sodium citrate and increasing absorption density of citrate ions on the particle surface. This work provides new insights into the role of citrate on both the crystallization and tailoring of colloidal stability. Moreover, the synthesized HA nanorods are promising materials for use as carriers for local targeted drug delivery systems as well as building blocks for the preparation of nanostructured scaffolds for cells in bone tissue engineering. PMID- 25544319 TI - Assembly of polystyrene-coated gold nanoparticles at the air-water interface. AB - Gold nanoparticles (NPs) coated with thiol-terminated polystyrene chains of varying molar mass were added to polystyrene-b-polymethylmethacrylate (PS-b-PMMA) block copolymer monolayers at the air-water interface. Composite films were transferred to solid substrates by the Langmuir-Blodgett technique. For most of the investigated systems, TEM micrographs and AFM images reveal the formation of 2D island-like aggregates of particles organized on a close-packed hexagonal lattice. This characteristic aggregate formation is lost when PS ligands are within the same length regime as the PS block from the copolymer. The results are compared with those obtained for analogous systems containing no copolymer where NPs are deposited on either a bare water surface or bare glass. Interparticle distance between NPs is found to depend on the surface on which they are deposited, the presence or not of the copolymer monolayer, and ligand length. PMID- 25544320 TI - Polystyrene-graphene oxide (GO) nanocomposite synthesized by interfacial interactions between RAFT modified GO and core-shell polymeric nanoparticles. AB - Here we report simple and robust one-pot method for the preparation of polystyrene (PS)/graphene oxide (GO) nanocomposite using reversible addition fragmentation chain transfer (RAFT) modified GO in surfactant free emulsion polymerization (SFEP). The results suggested that ionic comonomer, styrene sulfonate sodium salt (SS-Na), concentration plays vital role in forming PS/GO nanocomposite. X-ray and electron diffraction studies suggest that there is no recombination of GO sheets when moderate SS-Na concentration is used, resulting complete exfoliation of GO sheets in the PS/GO nanocomposite. The formation of core-shell particles in which PS is the core and polystyrene sulfonate sodium salt (PSS-Na) is the shell, and the specific interactions between functional groups of GO and PSS-Na are attributed as the driving forces for the PS/GO nanocomposite formation. PMID- 25544321 TI - Protein adsorption on electrospun zinc doped hydroxyapatite containing nylon 6 membrane: kinetics and isotherm. AB - Surface modification of electrospun polymeric membrane surfaces is a critical step towards the separation process including protein adsorption. In this study, the electrospun Nylon fibers was incorporated with positively charged zinc doped hydroxyapatite (HAp) nanoparticles to study the adsorption of negatively charged proteins, namely bovine serum albumin (BSA). Effects of zinc amount within the atomic structure of HAp (nZH; n=0, 4, 8 At.%) was evaluated on produced scaffolds and consequently protein adsorption. The results showed that the ability of Nylon membrane to adsorb BSA increased with incorporation of nZH nanoparticles within the nylon structure. This phenomenon is appeared to be relate to different electrostatic charge and not to physical characteristic of scaffolds. The incorporated membrane (N-4ZH) by nanoparticles with highest zeta (xi) potential adsorbed the maximum amount of protein. The adsorption of BSA was best fitted with pseudo-second order kinetic model. The experimental isotherm data were further analyzed by using Langmuir and Freundlich equations. By comparing the correlation coefficients obtained for each linear transformation of isotherm analysis, it was found that the Langmuir equation was the best fit equilibrium model that described the adsorption of BSA on these membranes. PMID- 25544322 TI - Analysis of ionic strength effects on the adsorption of simple amino acids. AB - HYPOTHESIS: Amino acid adsorption by metals and/or oxide surfaces is important in many biomedical and industrial processes, however limited information exists discussing ionic strength influences on the mechanism of adsorption. A comparison of pure water solution and added 1:1 electrolyte should highlight the effects of electrolyte on amount adsorbed. ATR spectroscopy of the adsorbed phase should demonstrate the effects on the mechanism of adsorption. EXPERIMENTS: Low solution concentration adsorption isotherms for glycine, lysine and glutamic acid on Aerosil 200 silica were generated in pure water and 10 and 100 mmol/L sodium chloride solutions. A systematic study of the adsorption isotherms as well as adsorbent and adsorptive solution properties was performed. ATR-IR spectroscopy was used to analyse the adsorbed phase in solution. FINDINGS: Glycine adsorbs primarily through electrostatic interactions; lysine also adsorbs through electrostatic interactions in a parallel conformation with the surface. Glutamic acid adsorbs via hydrogen bonding and forms intermolecular clusters around an adsorbed nucleus. ATR-IR spectrum deconvolution shows a peak shift for glycine and lysine associated with the delta(ad)NH3(+) vibration, indicating interaction through the amino moieties. Amount adsorbed was decreased significantly by the addition of 10 mmol/L sodium chloride and completely inhibited by the addition of 100 mmol/L sodium chloride. PMID- 25544323 TI - Reflections on ancestral haplotypes: medical genomics, evolution, and human individuality. AB - The major histocompatibility complex (MHC), once labelled the "sphinx of immunology" by Jan Klein, provides powerful challenges to evolutionary thinking. This essay highlights the main discoveries that established the block ancestral haplotype structure of the MHC and the wider genome, focusing on the work by the Perth (Australia) group, led by Roger Dawkins, and the Boston group, led by Chester Alper and Edmond Yunis. Their achievements have been overlooked in the rush to sequence the first and subsequent drafts of the human genome. In Caucasoids, where most of the detailed work has been done, about 70% of all known allelic MHC diversity can be accounted for by 30 or so ancestral haplotypes (AHs), or conserved sequences of many mega-bases, and their recombinants. The block haplotype structure of the genome, as shown for the MHC (and other genetic regions), is a story that needs to be understood in its own right, particularly given the promotion of the "HapMap" project and single nucleotide polymorphism (SNP) linkage disequilibrium (LD) analysis, which has been wrongly touted as the only way to pinpoint those genes that are important in genetic disorders or other desired (qualitative) characteristics. PMID- 25544324 TI - Of mice and men: lyme disease and biodiversity. AB - The current rapid rate of species extinction and loss of biodiversity occurring throughout the world has the potential to exact far-reaching adverse impacts on human health in many ways, including increasing the risk of infectious disease transmission. Here, we use Lyme disease as a model to illustrate how loss of biodiversity in the community of vertebrates may lead to increased transmission of zoonotic pathogens in humans. We also illustrate how preserving biodiversity has the potential to reduce the prevalence of human infectious disease more generally. PMID- 25544325 TI - Parts and wholes: the human microbiome, ecological ontology, and the challenges of community. AB - The early results of the Human Microbiome Project, released in June 2012, add to the overwhelming data that show that there are literally trillions of microbes that live in and on each human individual. This research raises profound questions about what it means to be an individual organism, human or otherwise. In this paper, we ask two broad questions: (1) how might we conceive of an individual organism, given these results? and (2) in light of this emerging conception of the individual organism, what are the implications for how humans conceive of their own self-sufficiency and interact with other members of the living world? We highlight the ontological and political presuppositions animating this research and return to Aristotle for insights into how to conceive of and how to behave towards and within a diverse community of interdependent living parts that function together as one. PMID- 25544326 TI - Comparative effectiveness research: decision-based evidence. AB - In the clinical research context, comparative effectiveness research (CER) refers to the comparison of several health-care interventions administered under real world conditions to individuals representative of the day-to-day clinical practice target population. We provide a brief history of CER and argue that CER can be used to deliver useful, but currently lacking information. Three study designs that can accomplish this are discussed, and incorporating CER into cost benefit analyses is examined. The relationships between CER and evidence-based and personalized medicine are also considered, as is the challenge of implementing CER results into routine clinical practice. PMID- 25544327 TI - "Case Neisser": experimental design, the beginnings of immunology, and informed consent. AB - In 1892, Albert L. Neisser (1855-1916), the professor of dermatology and venereology at the University of Breslau (Prussia), undertook two series of clinical experiments: one to test whether serum from syphilitic patients had a prophylactic value against contracting syphilis, and the other to test whether such serum had a therapeutic value for syphilitic patients. The first experiment was based on the erroneous scientific hypothesis called "Colles's law," which posited that a fetus that was syphilitic due to the father's disease could in utero immunize its mother against syphilis. Neisser acknowledged that neither experiment achieved its goal. However, when his work was published, Neisser was criticized not for the various errors of experimental design that should have been recognizable to him, but because of his failure to obtain the consent of his non-syphilitic subjects. The political furor that followed led to the first governmental edict to require informed consent of participants in clinical research. This essay examines how Neisser's generally forgotten investigation into therapies for syphilis led to some of the first regulations about informed consent. PMID- 25544328 TI - Targeted chemotherapy, the medical ecosystem, and the future of American health care. AB - In light of the difficulties experienced by the pharmaceutical industry in developing important new drugs, the rapid design and introduction of the targeted chemotherapeutic agent, crizotinib, is a significant achievement. Understanding the roles of the patient, the physician, the regulator (FDA), health insurance companies, and the manufacturer (Pfizer) in the development of this drug can shed light on the prospects for future drugs and on the workings of the complicated health-care ecosystem. Patients were eager for an effective drug against lung cancer with minimal toxicity but were reluctant to enroll in clinical trials. Oncologists were enthusiastic about the new drug but have a financial incentive favoring intravenous medicines over oral agents. The FDA was under pressure to approve new drugs quickly. The drug manufacturer modified its corporate structure and developed collaborations with academics and international partners, but was pressured by stockholders to maximize short-term profitability. Insurance companies balked at the price of the drug and used tiered pricing to limit their costs. The successful design, development, and diffusion of crizotinib may signal a new departure for the pharmaceutical industry, but whether such successes are replicated in the future will depend on the delicately balanced ecosystem that constitutes American health care. PMID- 25544329 TI - The heartfelt music of Ludwig van Beethoven. AB - Musicologists, historians, and physicians have speculated that Beethoven experienced cardiac arrhythmias, and that they manifest in specific compositions. Based on what is known about Beethoven's medical issues, this seems a reasonable assumption to make. This essay strengthens the hypothesis that Beethoven suffered from cardiac arrhythmias by placing Beethoven's music in its historical context, and by identifying several compositions that may reflect Beethoven's experience of an arrhythmia. PMID- 25544331 TI - Concise synthesis of the C15-C38 fragment of okadaic acid: application of the Suzuki-Miyaura reaction to spiroacetal synthesis. AB - A concise synthetic entry to the C15-C38 fragment of okadaic acid by exploiting a Suzuki-Miyaura reaction for the rapid assembly of the spiroacetal substructures has been developed. The present synthesis was completed in 19 linear steps from a commercially available material, showcasing the efficiency of our synthetic strategy. PMID- 25544332 TI - Medical student experience in surgery influences their career choices: a systematic review of the literature. AB - OBJECTIVES: Student experiences during surgical rotations may dictate interest in future surgical careers. The objective of this study was to systematically examine the effect of surgical experience (SE) on student attitudes toward surgical careers and also to identify variables influencing the educational value of SE. METHODS: A systematic review of the available literature was conducted by 2 independent researchers searching Medline, EMBASE, Google Scholar, and Cochrane databases, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses recommendations. Studies assessing SE during the students' surgical rotations were identified. The quality of the included studies was assessed using a validated quality index. Factors affecting student surgical rotation experience and perceptions of surgical careers were recorded. RESULTS: Overall, 204 studies were identified; 20 unique studies met the inclusion criteria with a median cohort size of 169 (interquartile range: 107-262) respondents. Most were cross-sectional surveys (n = 16/20) and administered to clinical students (n = 16/20). All studies investigating the effect of SE on career choices (n = 8) found that positive experiences during the surgical placement were associated with an increased interest in surgical careers. The operating theater experience was identified as a defining feature of overall SE. Involvement in operative procedures, a welcoming environment, and avoidance of syncopal events positively influenced the SE, particularly in those who actively sought educational opportunities. Study limitations included single-center and single-year cohort designs (70%) with the use of nonvalidated research tools (95%). CONCLUSIONS: A systematic review of the literature highlights a number of factors associated with a positive surgical rotation, which may lead to more students deciding to pursue a career in surgery. Understanding the factors that contribute to these decisions through multicenter studies using validated research tools may lead to more effective surgical rotations, ultimately improving the delivery of the surgical education. PMID- 25544333 TI - Spatial distribution of perfluoroalkyl acids in surface sediments of the German Bight, North Sea. AB - Perfluoroalkyl acids (PFAAs) have been determined in the environment globally. However, studies on the occurrence of PFAAs in marine sediment remain limited. In this study, 16 PFAAs are investigated in surface sediments from the German Bight, which provided a good overview of the spatial distribution. The concentrations of SigmaPFAAs ranged from 0.056 to 7.4 ng/g dry weight. The highest concentration was found at the estuary of the River Ems, which might be the result of local discharge source. Perfluorooctane sulfonic acid (PFOS) was the dominant compound, and the enrichment of PFOS in sediment might be strongly related to the compound structure itself. The geographical condition of the German Bight influenced the movement of water and sediment, resulting in complex distribution. Following normalization according to total organic carbon (TOC) content, PFAA distributions showed a different picture. Significant linear relationships were found between total PFAA concentrations and TOC (R2=0.50, p<0.01). Compared with a previous study conducted in the same area, a declining trend was presented for the concentrations of PFOS and perfluorooctanoic acid (PFOA). Compound structure, geographical condition, and organic carbon in the sediment influence the distribution of PFAAs in the German Bight. Environmental risk assessment indicated that the risk from PFOA is negligible, whereas PFOS in marine sediment may present a risk for benthic organisms in the German Bight. PMID- 25544334 TI - Pharmaceuticals in the freshwater invertebrate, Gammarus pulex, determined using pulverised liquid extraction, solid phase extraction and liquid chromatography tandem mass spectrometry. AB - The development, characterisation and application of a new analytical method for multi-residue PPCP determination in the freshwater amphipod, Gammarus pulex are presented. Analysis was performed using pulverised liquid extraction (PuLE), solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Qualitative method performance offered excellent limits of detection at <20 ng g(-1) for 18 out of 29 compounds. For quantitative application, linearity and precision were considered acceptable for 10 compounds across the ng MUg g(-1) range (R2>=0.99; <=20% relative standard deviation respectively). The method was applied to the analysis of G. pulex and river water sourced from six tributaries of the River Thames. Carbamazepine, diazepam, nimesulide, trimethoprim and warfarin were determined in G. pulex samples at low ng g(-1) (dry weight) concentrations across these sites. Temazepam and diclofenac were also detected, but were not quantifiable. Six pharmaceuticals were quantified in surface waters across the eight sites at concentrations ranging from 3 to 344 ng L(-1). The possibility for confirmatory detection and subsequent quantification of pharmaceutical residues in benthic organisms such as G. pulex will enable further understanding on the susceptibility and ecological effects of PPCPs in the aquatic environment. PMID- 25544335 TI - Quantifying the link between crop production and mined groundwater irrigation in China. AB - In response to increasing demand for food, Chinese agriculture has both expanded and intensified over the past several decades. Irrigation has played a key role in increasing crop production, and groundwater is now an important source of irrigation water. Groundwater abstraction in excess of recharge (which we use here to estimate groundwater mining) has resulted in declining groundwater levels and could eventually restrict groundwater availability. In this study we used a hydrological model, WBMplus, in conjunction with a process based crop growth model, DNDC, to evaluate Chinese agriculture's recent dependence upon mined groundwater, and to quantify mined groundwater-dependent crop production across a domain that includes variation in climate, crop choice, and management practices. This methodology allowed for the direct attribution of crop production to irrigation water from rivers and reservoirs, shallow (renewable) groundwater, and mined groundwater. Simulating 20 years of weather variability and circa year 2000 crop areas, we found that mined groundwater fulfilled 20%-49% of gross irrigation water demand, assuming all demand was met. Mined groundwater accounted for 15% 27% of national total crop production. There was high spatial variability across China in irrigation water demand and crop production derived from mined groundwater. We find that climate variability and mined groundwater demand do not operate independently; rather, years in which irrigation water demand is high due to the relatively hot and dry climate also experience limited surface water supplies and therefore have less surface water with which to meet that high irrigation water demand. PMID- 25544336 TI - Plutonium as a tracer for soil erosion assessment in northeast China. AB - Soil erosion is one of the most serious environmental and agricultural problems faced by human society. Assessing intensity is an important issue for controlling soil erosion and improving eco-environmental quality. The suitability of the application of plutonium (Pu) as a tracer for soil erosion assessment in northeast China was investigated by comparing with that of 137Cs. Here we build on preliminary work, in which we investigated the potential of Pu as a soil erosion tracer by sampling additional reference sites and potential erosive sites, along the Liaodong Bay region in northeast China, for Pu isotopes and 137Cs. 240Pu/239Pu atomic ratios in all samples were approximately 0.18, which indicated that the dominant source of Pu was the global fallout. Pu showed very similar distribution patterns to those of 137Cs at both uncultivated and cultivated sites. 239+240Pu concentrations in all uncultivated soil cores followed an exponential decline with soil depth, whereas at cultivated sites, Pu was homogenously distributed in plow horizons. Factors such as planted crop types, as well as methods and frequencies of irrigation and tillage were suggested to influence the distribution of radionuclides in cultivated land. The baseline inventories of 239+240Pu and 137Cs were 88.4 and 1688 Bq m(-2) respectively. Soil erosion rates estimated by 239+240Pu tracing method were consistent with those obtained by the 137Cs method, confirming that Pu is an effective tracer with a similar tracing behavior to that of 137Cs for soil erosion assessment. PMID- 25544337 TI - Responses of 20 lake-watersheds in the Adirondack region of New York to historical and potential future acidic deposition. AB - Critical loads (CLs) and dynamic critical loads (DCLs) are important tools to guide the protection of ecosystems from air pollution. In order to quantify decreases in acidic deposition necessary to protect sensitive aquatic species, we calculated CLs and DCLs of sulfate (SO4(2-))+nitrate (NO3-) for 20 lake watersheds from the Adirondack region of New York using the dynamic model, PnET BGC. We evaluated lake water chemistry and fish and total zooplankton species richness in response to historical acidic deposition and under future deposition scenarios. The model performed well in simulating measured chemistry of Adirondack lakes. Current deposition of SO4(2-)+NO3-, calcium (Ca2+) weathering rate and lake acid neutralizing capacity (ANC) in 1850 were related to the extent of historical acidification (1850-2008). Changes in lake Al3+ concentrations since the onset of acidic deposition were also related to Ca2+ weathering rate and ANC in 1850. Lake ANC and fish and total zooplankton species richness were projected to increase under hypothetical decreases in future deposition. However, model projections suggest that lake ecosystems will not achieve complete chemical and biological recovery in the future. PMID- 25544338 TI - Effect of 17beta-estradiol on stability and mobility of TiO2 rutile nanoparticles. AB - Contaminants including titanium dioxide nanoparticles (n-TiO2), as well as organic wastewater contaminants (OWCs), have been detected in wastewater treatment plant effluents, however, no information is yet available on how OWCs may modify the surface properties of TiO2 nanoparticles, or influence their stability in water and subsequent mobility in porous media. In this study, 17beta estradiol (E2) was chosen as a representative OWC to investigate the interaction between OWCs and n-TiO2. Batch and kinetic sorption experiments and Fourier Transform Infrared (FTIR) Spectrometer measurements confirmed that E2 was quickly sorbed onto the surface of n-TiO2 aggregates in water. Aggregation experiments showed that the presence of E2 has a minor influence on the size of n-TiO2 aggregates under lower ionic strength conditions at natural pH. In high ionic strength solution, the presence of E2 led to an increased average hydrodynamic diameter and a wider distribution of n-TiO2 aggregate sizes. Interaction energy analyses indicated that steric repulsion likely contributed to the stability of the n-TiO2 suspension in the presence of E2. Mobility analysis based on the clean bed filtration theory indicated that the impact of E2 on the mobility of n-TiO2 in porous media is minimal in comparison to the influence of solution ionic strength. PMID- 25544339 TI - Erratum: Dopaminergic therapy affects learning and impulsivity in Parkinson's disease. AB - [This corrects the article on p. 833 in vol. 1, PMID: 25493274.]. PMID- 25544340 TI - Effect of whole body vibration on the postural control of the spine in sitting. AB - Stability is defined by the ability to return to the initial (or unperturbed) state following a perturbation and hence can be assessed by quantifying the post perturbation response. This response may be divided into two phases: an initial passive response phase, dependent upon both the steady state of the system and the system's intrinsic mechanical properties; and a recovery phase, dependent upon active control and reflexes. These two phases overlap and interact with each other. Whole body vibration (WBV) is assumed to influence neuro-sensory functions and perhaps both response stages. The current study observed the effect of WBV on several novel response factors that quantify the two phases in response to an external perturbation. The results indicate a significant effect of vibration exposure on: (1) the normalized maximum distance traveled by center of pressure (COP) from the neutral seated posture, and (2) the normalized time to maximum distance (tau), such that B and tau increased after WBV exposure and decreased after sitting without WBV. These changes may be indicative of passive visco elastic changes caused by WBV exposure on the spinal tissues which has been indicated as a creep deformation of tissues post-exposure. This change may make the spine vulnerable to injury. Similar trends were noticed in the variables calculated from center of mass data. PMID- 25544341 TI - Is effective mass in combat sports punching above its weight? AB - The segmental and muscular complexity of the human body can result in challenges when examining the kinetics of impacts. To better understand this complexity, combat sports literature has selected effective mass as a measure of an athlete's inertial contribution to the momentum transfer during the impact of strikes. This measure helps to clarify the analysis of striking kinetics in combat sports. This paper will review: (1) effective mass as a concept and its usage as a measure of impact intensity in combat sports, (2) the neuromuscular pattern known as "double peak muscle activation" which has been theorized to help enhance initial hand velocity upon impact and joint stiffening during impact, (3) the methods and equations used to calculate effective mass, and (4) practitioner recommendations based on the literature. We will argue in this manuscript that the act of punching presents unique challenges to the current understanding of effective mass due to additional force application during impact. This review will improve the understanding of effective mass and its roles in effective striking serving to underpin future research into performance enhancement in striking based combat sports. PMID- 25544342 TI - Studies on the systematics and taxonomy of the genus Hylaeus F. (8) Revision of the Afrotropic subgenus Hylaeus (Deranchylaeus) Bridwell (Hymenoptera: Anthophila, Colletidae). AB - The Afrotropic subgenus Deranchylaeus; of the colletid bee genus Hylaeus is revised for the first time on the basis of all the available type material. Here, 28 new synonymies were detected: Prosopis flaviscutum Alfken and Hylaeus graaffi Cockerell = H. curvicarinatus (Cameron); H. microstictus Cockerell = dregei (Strand); H. bequaertianus Bridwell and H. ogilviei Cockerell = H. gabonicus (Vachal); P. immarginata Alfken and H. abjunctus Cockerell = H. krebsianus (Strand); H. absonulus Cockerell and H. reditus Cockerell = H. lightfooti Bridwell; H. subreditus Cockerell = H. lineaticeps (Friese); H. tinctulus extensicornis Cockerell = H. perater Cockerell; P. corpana Warncke and H. rhodognathus Cockerell = H. promontorii Meade-Waldo; P. atriceps Friese, P. atriceps var. major Strand, H. sanctus Cockerell, H. sublucens Cockerell, H. varians Cockerell, H. tenuis var. dominae Cockerell, H. punctiferus Cockerell, P. totana Warncke and H. multifarius Eardley & Urban = H. robertianus (Cameron); H. simulans Cockerell = H. rugipunctus (Alfken); H. simplex (Bingham), H. simplior Meade-Waldo, H. perdensus Cockerell and P. postica Warncke = H. tenuis (Alfken); H. kasindensis Cockerell = H. xanthostoma (Alfken). Lectotypes were designated for Prosopis alfkeni Friese, P. atriceps Friese, P. curvicarinata Cameron, P. flaviscutum Alfken, P. gabonica Vachal, P. rugipuncta Alfken, P. tenuis Alfken and P. xanthostoma Alfken. The following 12 new species are described: H. (Deranchylaeus) amharicus sp. n. ?; bernhardi sp. n. ?; camerunensis sp. n. ??; chimani sp. n. ?; eardleyi sp. n. ??; gessianus sp. n. ??; izikosalis sp. n. ?; nottoni sp. n. ?; oromialis sp. n. ??; pamelae sp. n. ?; paulyi sp. n. ?? and venustus sp. n. ?. Keys for the identification of males and females of all species are provided. PMID- 25544343 TI - A synopsis of the scolytine ambrosia beetles of Thailand (Coleoptera: Curculionidae: Scolytinae). AB - The present state of knowledge of the scolytine ambrosia beetles of Thailand is summarised to provide a basis for future studies of the fauna and its economic importance in forestry, timber production and crop tree plantations. A checklist of the fauna is provided with information on local and world distribution, host trees, biology and taxonomy. Six faunal elements based on geographical distribution, and the host tree and altitudinal preferences of species are discussed. One hundred and sixty-one species are recorded from Thailand, 67 of them for the first time. The following new synonym is proposed: Euwallacea wallacei (Blandford) (= Xyleborus barbatomorphus Schedl n.syn.). The following new combinations are given: Ambrosiophilus cristatulus (Schedl), Ambrosiophilus latisulcatus (Eggers), Beaverium dihingensis (Eggers), Beaverium lantanae (Eggers) and Immanus desectus (Eggers) are transferred from their present position in Ambrosiodmus; Ancipitis depressus (Eggers) and Ancipitis punctatissimus (Eichhoff) are transferred from Leptoxyleborus; Cyclorhipidion armipenne (Schedl), Cyclorhipidion inarmatum (Eggers), Euwallacea semiermis (Schedl), Fortiborus macropterus (Schedl), Microperus nudibrevis (Schedl) and Wallacellus minutus (Blandford) are transferred from Xyleborus. PMID- 25544344 TI - Water mites from Mount Kinabalu and the Crocker Range, Borneo, Malaysia (Acari: Hydrachnidia), with the description of 34 new species. AB - Descriptions are presented of new species of water mites from two mountains in the Malaysian part of Borneo. A new subgenus of the genus Javalbia (Hygrobatidae), i.e. Megapes n. subgen., and 34 new species are described: Limnocharidae: Limnochares (Limnochares) spinosa n. sp.; Oxidae: Oxus (Oxus) fuscus n. sp.; Hydryphantidae: Protzia borneoensis n. sp.; Sperchontidae: Sperchon kinabaluensis n. sp., Sperchonopsis orientalis n. sp.; Hygrobatidae: Hygrobates (Hygrobates) acutipalpis n. sp., H. (Hygrobates) hamatoides n. sp., H. (Hygrobates) striatus n. sp., Atractides (Atractides) neospatiosus n. sp., A. (Atractides) sabahensis n. sp., A. (Atractides) crockerensis n. sp., A. (Atractides) curtisetus n. sp., A.(Tympanomegapus) borneoensis n. sp.; Frontipodopsidae: Frontipodopsis suturalis n. sp.; Aturidae: Javalbia (Javalbia) montana n. sp., J. (Javalbia) solitaria n. sp., J. (Javalbiopsis) borneoensis n. sp., J. (Javalbiopsis) kinabaluensis n. sp., J. (Javalbiopsis) magniseta n. sp., J. (Javalbiopsis) reticulata n. sp., J. (Megapes) uncinata n. sp., Albaxona mahuaensis n. sp., Axonopsis (Axonopsis) longigenitalis n. sp., A. (Axonopsis) rugosa n. sp., A. (Paraxonopsis) truncata n. sp., A. (Brachypodopsis) latipalpis n. sp., A. (Vicinaxonopsis) caeca n. sp., Erebaxonopsis kipungitensis n. sp., Ljania inconspicua n. sp., L. obliterata n. sp., Albia (Albiella) crocker n. sp., Aturus borneoensis n. sp.; Athienemanniidae: Africasia acuticoxalis n. sp.; Arrenuridae: Thoracophoracarus uniacetabulatus n. sp. A key is presented for the Javalbia species of Borneo. New records are given for 10 further species. In the course of revisional work, lectotypes are designated for the following species: Atractides cognatus (K. Viets) and A. propatulus (K. Viets). PMID- 25544345 TI - Revision of the taxonomy of Polycirrus Grube, 1850 (Annelida: Terebellida: Polycirridae). AB - The large polychaete genus Polycirrus (Terebellida: Polycirridae) is revised based on a morphological study of the type material of most of the approximately 74 nominal species; 59 species, including a new species, P. coibensis n.sp., from the Pacific coast of Panama, are accepted as valid. All characters are reanalysed and discussed in the light of recent phylogenetic studies of terebellomorph taxa, and a standard set of characters is developed. Most of the 59 accepted species are redescribed and illustrations provided in order to facilitate future identifications of members of the genus. We designate a neotype for the type species of the genus, Polycirrus medusa Grube, 1850, and a lectotype for P. elisabethae McIntosh, 1915, in order to stabilize the concept and type locality of these taxa. A replacement name is proposed for Polycirrus kerguelensis McIntosh, 1885, which is a secondary junior homonym of Ereutho kergulenesis McIntosh, 1885, viz. Polycirrus macintoshi new name. Two species are newly synonymised: Polycirrus insignis Gravier, 1907 (senior synonym P. antarcticus (Willey, 1902)) and Polycirrus habitats Carrerette & Nogueira, 2013 (senior synonym, P. clavatus (Kinberg, 1867)). In addition, several previously synonymised species are reinstated. All available names in the genus are tabulated with type species and type localities and their taxonomic status is assessed. A key to all valid species is provided. PMID- 25544347 TI - [Rectal tuberculosis in HIV patient]. PMID- 25544346 TI - Overexpression of miR-145 in U87 cells reduces glioma cell malignant phenotype and promotes survival after in vivo implantation. AB - In the present study, we sought to elucidate the effect of miR-145 on glioma cell progression and its mechanisms of action. We examined the effects of miR-145 on proliferation and invasion of U87 glioma cells and on capillary tube formation. Our data show that restoration of miR-145 in U87 glioma cells significantly reduced their in vitro proliferation, invasion and angiogenesis. However, decreased miR-145 expression promoted U87 glioma cell proliferation, invasion and angiogenesis, and reduced-expression of miR-145 increased ADAM17 and EGFR expression in U87 cells. Overexpression of miR-145 reduced ADAM17 and EGFR expression. VEGF secretion and VEGF expression were decreased by increased miR 145 expression in U87 cells and were reversed by miR-145 downregulation in vitro. Nude mice with intracerebral implantation of U87 overexpressing miR-145 cells exhibited significantly reduced tumor growth and promoted survival compared with control groups. Taken together, these results suggest a role for miR-145 as a tumor suppressor which inhibits glioma cell proliferation, invasion and angiogenesis in vitro and reduces glioma growth in vivo. PMID- 25544348 TI - [Improving functional outcome of schizophrenia with cognitive remediation]. AB - The functional outcome of schizophrenia is partly conditioned by cognitive disorders associated with this disease. The functional outcome of schizophrenia depends not only on psychotropic medications, but also on non-pharmacological measures and in particular on cognitive remediation. All patients suffering from schizophrenia should benefit from a multidisciplinary functional evaluation including neuropsychological assessment. The restitution of the functional evaluation's results values preserved skills rather than deficits. Cognitive remediation should be considered when cognitive disorders have a functional impact. It reduces the impact of the patient's cognitive disorders and improves the success of his/her concrete projects. PMID- 25544349 TI - Bioelectrochemical analyses of the development of a thermophilic biocathode catalyzing electromethanogenesis. AB - The use of thermophilic microorganisms as biocatalysts for electromethanogenesis was investigated. Single-chamber reactors inoculated with thermophiles and operated at 55 degrees C showed high CH4 production rates (max. 1103 mmol m(-2) day(-1) at an applied voltage of 0.8 V) with current-capture efficiencies >90%, indicating that thermophiles have high potential as biocatalysts. To improve the electromethanogenic activity, the developed biocathode was transferred to a two chamber reactor and operated at a poised potential of -0.5 V vs SHE. The CH4 production rates of the biocathode were enhanced approximately 6-fold in 160 h of poised-potential incubation, indicating that the acclimation of the biocathode resulted in performance improvement. Compositional alteration of the cathodic microbiota suggested that a Methanothermobacter-related methanogen and synergistetes- and thermotogae-related bacteria were selected during the acclimation. Cyclic voltammetry of the "acclimated" biocathode showed an augmented cathodic catalytic wave with a midpoint potential at ca. -0.35 V vs SHE. Moreover, the biocathode was able to catalyze electromethanogenesis at -0.35 V vs SHE. These results suggested that the ability of the biocathode to catalyze electromethanogenesis via direct electron transfer was enhanced by the acclimation. This study provides new technological and fundamental information on electromethanogenic bioelectrochemical systems (BESs) that may be extended to other BESs. PMID- 25544351 TI - Coagulation abnormalities in sepsis. AB - Although the pathophysiology of sepsis has been elucidated with the passage of time, sepsis may be regarded as an uncontrolled inflammatory and procoagulant response to infection. The hemostatic changes in sepsis range from subclinical activation of blood coagulation to acute disseminated intravascular coagulation (DIC). DIC is characterized by widespread microvascular thrombosis, which contributes to multiple organ dysfunction/failure, and subsequent consumption of platelets and coagulation factors, eventually causing bleeding manifestations. The diagnosis of DIC can be made using routinely available laboratory tests, scoring algorithms, and thromboelastography. In this cascade of events, the inhibition of coagulation activation and platelet function is conjectured as a useful tool for attenuating inflammatory response and improving outcomes in sepsis. A number of clinical trials of anticoagulants were performed, but none of them have been recognized as a standard therapy because recombinant activated protein C was withdrawn from the market owing to its insufficient efficacy in a randomized controlled trial. However, these subgroup analyses of activated protein C, antithrombin, and thrombomodulin trials show that overt coagulation activation is strongly associated with the best therapeutic effect of the inhibitor. In addition, antiplatelet drugs, including acetylsalicylic acid, P2Y12 inhibitors, and glycoprotein IIb/IIIa antagonists, may reduce organ failure and mortality in the experimental model of sepsis without a concomitant increased bleeding risk, which should be supported by solid clinical data. For a state-of the-art treatment of sepsis, the efficacy of anticoagulant and antiplatelet agents needs to be proved in further large-scale prospective, interventional, randomized validation trials. PMID- 25544350 TI - Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. AB - Circularization was recently recognized to broadly expand transcriptome complexity. Here, we exploit massive Drosophila total RNA-sequencing data, >5 billion paired-end reads from >100 libraries covering diverse developmental stages, tissues, and cultured cells, to rigorously annotate >2,500 fruit fly circular RNAs. These mostly derive from back-splicing of protein-coding genes and lack poly(A) tails, and the circularization of hundreds of genes is conserved across multiple Drosophila species. We elucidate structural and sequence properties of Drosophila circular RNAs, which exhibit commonalities and distinctions from mammalian circles. Notably, Drosophila circular RNAs harbor >1,000 well-conserved canonical miRNA seed matches, especially within coding regions, and coding conserved miRNA sites reside preferentially within circularized exons. Finally, we analyze the developmental and tissue specificity of circular RNAs and note their preferred derivation from neural genes and enhanced accumulation in neural tissues. Interestingly, circular isoforms increase substantially relative to linear isoforms during CNS aging and constitute an aging biomarker. PMID- 25544353 TI - Evaluating implicit drinking identity as a mediator of drinking motives and alcohol consumption and craving. AB - INTRODUCTION: Implicit drinking identity (i.e., cognitive associations between the self and drinking) is a reliable predictor of drinking. However, whether implicit drinking identity might mediate the relationship between other robust predictors of drinking and drinking outcomes is unknown. We hypothesized that implicit drinking would mediate the relationship between drinking motives and alcohol consumption and craving. METHOD: We assessed drinking motives at Time 1, implicit drinking identity at Time 2 (on average, 11 days later) and self reported alcohol consumption and craving at Time 3 (on average, 6 days later) in a sample of 194 US undergraduates (54% women) who reported at least one heavy drinking episode (4 drinks for women, 5 for men) in the past month. Participants completed self-report measures of drinking motives, daily alcohol consumption, and current craving. RESULTS: Implicit drinking identity uniquely mediated the relationship between social motives and alcohol consumption. It did not, however, mediate the relationship between motives and craving. Time 2 implicit drinking identity was positively associated with greater alcohol consumption and craving at Time 3, even after controlling for drinking motives. Subsequent analyses indicated significant indirect effects between social, enhancement, and coping motives (but not conformity) and consumption and craving when each motive was evaluated individually. CONCLUSIONS: Implicit drinking identity continues to have promise as a predictor of drinking outcomes and as a target for interventions. Future experimental and prospective studies will be critical to establish the circumstances under which implicit drinking identity is strengthened and/or activated and the resulting effects on hazardous drinking. PMID- 25544354 TI - Chronic non-fatal Datura abuse in a patient of paranoid schizophrenia: a case report. AB - INTRODUCTION: A range of psychoactive substances used by patients suffering from schizophrenia varies and may include those which are fatal and may cause serious toxicity leading to death. We here present a case report of a patient suffering from paranoid schizophrenia, who was abusing Datura stramonium over a prolonged period. CASE SUMMARY: A 32 year old male presented with aggressive behaviour, irritability for 6 years and regular intake of Datura seeds for 3 years. After taking detailed history and mental status examination (MSE), diagnoses of paranoid schizophrenia and mental and behavioral disorder due to use of hallucinogen were made. He had shown improvement on standard treatment with antipsychotics. CONCLUSION: D. stramonium is recognized among emerging new psychoactive substances being used across the world. Among various theories we discuss self-medication hypothesis as a mediating factor for this case. Though D. stramonium is notorious for its life threatening sequelae, clinicians should be aware of its chronic abuse as self-medication. PMID- 25544352 TI - Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. AB - Gene expression and regulation is an important sculptor of the behavior of organisms. Epigenetic mechanisms regulate gene expression not by altering the genetic alphabet but rather by the addition of chemical modifications to proteins associated with the alphabet or of methyl marks to the alphabet itself. Being dynamic, epigenetic mechanisms of gene regulation serve as an important bridge between environmental stimuli and genotype. In this review, we outline epigenetic mechanisms by which gene expression is regulated in animals and humans. Using fear learning as a framework, we then delineate how such mechanisms underlie learning and stress responsiveness. Finally, we discuss how epigenetic mechanisms might inform us about the transgenerational inheritance of behavioral traits that are being increasingly reported. PMID- 25544355 TI - The Journal of Comparative PathologyEducational Trust 2014 awards. PMID- 25544356 TI - Targeted next generation sequencing reveals a novel intragenic deletion of the LAMA2 gene in a patient with congenital muscular dystrophy. AB - Mutations in the LAMA2 gene cause laminin alpha-2 (merosin)-deficient congenital muscular dystrophies, which are autosomal recessive muscle disorders. Laminin alpha-2 is widely expressed in the basement membrane of skeletal muscle, the myotendinous junctions and extra-synaptically at neuromuscular synapses. In the present study, target next-generation sequencing was used for mutation detection, and polymerase chain reaction (PCR) analysis and Sanger sequencing were used in the identification of small deletions. Subsequently, quantitative PCR (qPCR) was performed to characterize the identified deletion encompassing exon five of the LAMA2 gene. Two causative mutations were identified using target region sequencing which provided the additional information required to facilitate clinical diagnosis. One heterozygous mutation (p. Lys682LysfsX22) was identified and confirmed by Sanger sequencing, and another heterozygous mutation (Exon5del) was found and validated by qPCR. Co-segregation analysis indicated that the Exon5del mutation originated from the proband's mother and the previously reported frameshift mutation (p. Lys682LysfsX22) was inherited from the proband's father. To the best of our knowledge, the present study was the first to report an entire exon five deletion in the LAMA2 gene. PMID- 25544357 TI - The biogeography of viral emergence: rice yellow mottle virus as a case study. AB - Rice yellow mottle virus (RYMV) exemplifies the key role in plant virus emergence of the early steps of crop extension and intensification in traditional agriculture. In East Africa, RYMV emerged in the 19(th) century after rice intensification along the Indian Ocean coast, and later spread inland concomitantly with rice introduction. In West Africa, the contrasted history of rice cultivation among regions differently shaped RYMV populations. A biogeographical approach - which jointly considers the spatial distribution of the virus and its hosts over time - was applied to reach these conclusions. We linked the evolution of RYMV over the past two centuries to a geographical map of the history of rice cultivation in Africa. PMID- 25544358 TI - A long-term follow-up of children and adolescents referred for assessment of auditory processing disorder. AB - OBJECTIVE: This study investigated whether young adults (between 18 and 30 years at the time of the project) who were assessed for auditory processing disorder (APD) in childhood (between 7 and 16 years) experience persistence of listening and communication difficulties. DESIGN: Participants completed a mixed methods questionnaire focusing on common areas of complaint in APD and two open-ended questions exploring participants' past and present experiences with listening and communication difficulties. STUDY SAMPLE: Ninety-seven of the 722 potential participants returned completed questionnaires, of whom 66 had been diagnosed with APD (APD group) at the time of their auditory processing assessment and 31 had not met diagnostic criteria (NAPD group) at that time. RESULTS: Substantial commonality was noted in the reported listening and communication difficulties between the APD and NAPD participants. Volunteered comments aggregated into four major content themes which included: listening and communication difficulties; participants' sense of self; change; and participation. Members of the APD group reported greater communication difficulty than NAPD group members, irrespective of environmental listening conditions. CONCLUSIONS: Young adults with a prior referral for, and in some cases a diagnosis of, APD as children continue to experience auditory processing difficulties across a range of daily situations. PMID- 25544359 TI - The antidepressant bupropion exerts alleviating properties in an ovariectomized osteoporotic rat model. AB - AIM: Depression is a risk factor for impaired bone mass and micro-architecture, but several antidepressants were found to increase the incidence of osteoporotic fractures. In the present study we used ovariectomized (OVX) rats as a model of osteoporosis to investigate the effects of the antidepressant bupropion on the femoral bones. METHODS: OVX animals were treated with bupropion (30, 60 mg.kg( 1).d(-1)) for six weeks. Bone turnover biomarkers (urinary DPD/Cr ratio, serum BALP, OC, TRAcP 5b, CTX and sRANKL levels) and inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) were determined using ELISA. Inductively coupled plasma mass spectroscopy (ICP-MS) was used to determine the femoral bone mineral concentrations. The cortical and trabecular morphometric parameters of femoral bones were determined using micro-CT scan and histopathology. RESULTS: In OVX rats, the levels of bone turnover biomarkers and inflammatory cytokines were significantly elevated and femoral bone Ca(2+) and PO4(3-) concentrations were significantly reduced. Moreover, cortical and trabecular morphometric parameters and histopathology of femoral bones were severely altered by ovariectomy. Bupropion dose-dependently inhibited the increases in bone turnover biomarkers and inflammatory cytokines. OVX rats treated with the high dose of bupropion showed normal mineral concentrations in femoral bones. The altered morphometric parameters and histopathology of femoral bones were markedly attenuated by the treatment. CONCLUSION: Bupropion exerts osteo-protective action in OVX rats through suppressing osteoclastogenesis-inducing factors and inflammation, which stabilize the osteoclasts and decrease bone matrix degradation or resorption. PMID- 25544360 TI - Tanshinone IIA therapeutically reduces LPS-induced acute lung injury by inhibiting inflammation and apoptosis in mice. AB - AIM: To study the effects of tanshinone IIA (TIIA) on lipopolysaccharide (LPS) induced acute lung injury in mice and the underlying mechanisms. METHODS: Mice were injected with LPS (10 mg/kg, i.p.), then treated with TIIA (10 mg/kg, i.p.). Seven hours after LPS injection, the lungs were collected for histological study. Protein, LDH, TNF-alpha and IL-1beta levels in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in lungs were measured. Cell apoptosis and Bcl-2, caspase-3, NF-kappaB and HIF-1alpha expression in lungs were assayed. RESULTS: LPS caused marked histological changes in lungs, accompanied by significantly increased lung W/D ratio, protein content and LDH level in BALF, and Evans blue leakage. LPS markedly increased neutrophil infiltration in lungs and inflammatory cytokines in BALF. Furthermore, LPS induced cell apoptosis in lungs, as evidenced by increased TUNEL-positive cells, decreased Bcl-2 content and increased cleaved caspase-3 content. Moreover, LPS significantly increased the expression of NF-kappaB and HIF-1alpha in lungs. Treatment of LPS-injected mice with TIIA significantly alleviated these pathological changes in lungs. CONCLUSION: TIIA alleviates LPS-induced acute lung injury in mice by suppressing inflammatory responses and apoptosis, which is mediated via inhibition of the NF kappaB and HIF-1alpha pathways. PMID- 25544361 TI - Nutlin-3-induced redistribution of chromatin-bound IFI16 in human hepatocellular carcinoma cells in vitro is associated with p53 activation. AB - AIM: Interferon-gamma inducible protein 16 (IFI16), a DNA sensor for DNA double strand break (DSB), is expressed in most human hepatocellular carcinoma cell (HCC) lines. In this study we investigated the re-localization of chromatin-bound IFI16 by Nutlin-3, a DNA damage agent, in HCC cells in vitro, and the potential mechanisms. METHODS: Human HCC SMMC-7721 (wild-type TP53), Huh-7 (mutant TP53), Hep3B (null TP53) and normal fetal liver L02 cell lines were examined. DSB damage in HCC cells was detected via gammaH2AX expression and foci formation assay. The expression of IFI16 and IFNB mRNA was measured using RT-PCR, and subcellular localization and expression of the IFI16 protein were detected using chromatin fractionation, Western blot analysis, and fluorescence microscopy. RESULTS: Treatment of SMMC-7721 cells with Nutlin-3 (10 MUmol/L) or etoposide (40 MUmol/L) induced significant DSB damage. In SMMC-7721 cells, Nutlin-3 significantly increased the expression levels of IFI16 and IFNB mRNA, and partially redistributed chromatin-bound IFI16 protein to the cytoplasm. These effects were blocked by pretreatment with pifithrin-alpha, a p53 inhibitor. Furthermore, Nutlin-3 did not induce ectopic expression of IFI16 protein in Huh-7 and Hep3B cells. Moreover, the association of IFI16 with chromatin and Nutlin-3-induced changes in localization were not detected in L02 cells. CONCLUSION: Nutlin-3 regulates the subcellular localization of IFI16 in HCC cells in vitro in a p53 dependent manner. PMID- 25544362 TI - Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation. AB - AIM: Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine. METHODS: Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection. The cells were treated with sanguinarine (1 MUmol/L) or its analogue berberine (1 MUmol/L) for 4 d. Cell proliferation was evaluated by counting cell numbers and with a BrdU incorporation assay. The levels of cleaved PARP-89 (an apoptosis marker) and cyclin-D1 (a proliferative index) were measured using Western blotting. RESULTS: In 10% serum-containing media, overexpressing either Rac1 or Rac1b did not significantly change the cell proliferation. In the serum starved media, however, the survival rate of Rac1b cells was significantly increased, whereas that of Rac1 cells was moderately increased. The level of cleaved PARP-89 was significantly increased in serum-starved Rac1 cells, but markedly reduced in serum-starved Rac1b cells. The level of cyclin-D1 was significantly increased in both serum-starved Rac1 and Rac1b cells. Treatment with sanguinarine, but not berberine, inhibited the proliferation of Rac1b cells, which was accompanied by significantly increased the level of PARP-89, and decreased both the level of cyclin-D1 and the percentage of BrdU positive cells. CONCLUSION: Rac1b enhances the cell proliferation under a growth-limiting condition via both anti-apoptotic and pro-proliferative mechanisms. Sanguinarine, as the specific inhibitor of Rac1b, is a potential therapeutic agent for malignant tumors with up-regulated Rac1b. PMID- 25544364 TI - Unusual case of primary adenocarcinoma of the small bowel and lung occurring in a patient: a case report and review of literature. PMID- 25544363 TI - Regulatory networks between neurotrophins and miRNAs in brain diseases and cancers. AB - Neurotrophins are involved in many physiological and pathological processes in the nervous system. They regulate and modify signal transduction, transcription and translation in neurons. It is recently demonstrated that the neurotrophin expression is regulated by microRNAs (miRNAs), changing our views on neurotrophins and miRNAs. Generally, miRNAs regulate neurotrophins and their receptors in at least two ways: (1) miRNAs bind directly to the 3' untranslated region (UTR) of isoform-specific mRNAs and post-transcriptionally regulate their expression; (2) miRNAs bind to the 3' UTR of the regulatory factors of neurotrophins and regulate their expression. On the other hand, neurotrophins can regulate miRNAs. The results of BNDF research show that neurotrophins regulate miRNAs in at least three ways: (1) ERK stimulation enhances the activation of TRBP (HIV-1 TAR RNA-binding protein) and Dicer, leading to the upregulation of miRNA biogenesis; (2) ERK-dependent upregulation of Lin28a (RNA-binding proteins) blocks select miRNA biogenesis; (3) transcriptional regulation of miRNA expression through activation of transcription factors, including CREB and NF kappaB. These regulatory processes integrate positive and negative regulatory loops in neurotrophin and miRNA signaling pathways, and also expand the function of neurotrophins and miRNAs. In this review, we summarize the current knowledge of the regulatory networks between neurotrophins and miRNAs in brain diseases and cancers, for which novel cutting edge therapeutic, delivery and diagnostic approaches are emerging. PMID- 25544367 TI - Next generation haplotyping to decipher nuclear genomic interspecific admixture in Citrus species: analysis of chromosome 2. AB - BACKGROUND: The most economically important Citrus species originated by natural interspecific hybridization between four ancestral taxa (Citrus reticulata, Citrus maxima, Citrus medica, and Citrus micrantha) and from limited subsequent interspecific recombination as a result of apomixis and vegetative propagation. Such reticulate evolution coupled with vegetative propagation results in mosaic genomes with large chromosome fragments from the basic taxa in frequent interspecific heterozygosity. Modern breeding of these species is hampered by their complex heterozygous genomic structures that determine species phenotype and are broken by sexual hybridisation. Nevertheless, a large amount of diversity is present in the citrus gene pool, and breeding to allow inclusion of desirable traits is of paramount importance. However, the efficient mobilization of citrus biodiversity in innovative breeding schemes requires previous understanding of Citrus origins and genomic structures. Haplotyping of multiple gene fragments along the whole genome is a powerful approach to reveal the admixture genomic structure of current species and to resolve the evolutionary history of the gene pools. In this study, the efficiency of parallel sequencing with 454 methodology to decipher the hybrid structure of modern citrus species was assessed by analysis of 16 gene fragments on chromosome 2. RESULTS: 454 amplicon libraries were established using the Fluidigm array system for 48 genotypes and 16 gene fragments from chromosome 2. Haplotypes were established from the reads of each accession and phylogenetic analyses were performed using the haplotypic data for each gene fragment. The length of 454 reads and the level of differentiation between the ancestral taxa of modern citrus allowed efficient haplotype phylogenetic assignations for 12 of the 16 gene fragments. The analysis of the mixed genomic structure of modern species and cultivars (i) revealed C. maxima introgressions in modern mandarins, (ii) was consistent with previous hypotheses regarding the origin of secondary species, and (iii) provided a new picture of the evolution of chromosome 2. CONCLUSIONS: 454 sequencing was an efficient strategy to establish haplotypes with significant phylogenetic assignations in Citrus, providing a new picture of the mixed structure on chromosome 2 in 48 citrus genotypes. PMID- 25544370 TI - An amidation/cyclization approach to the synthesis of N-hydroxyquinolinones and their biological evaluation as potential anti-plasmodial, anti-bacterial, and iron(II)-chelating agents. AB - A 26-member library of novel N-hydroxyquinolinone derivatives was synthesized by a one-pot Buchwald-type palladium catalyzed amidation and condensation sequence. The design of these rare scaffolds was inspired from N-hydroxypyridones and 2 quinolinones classes of compounds which have been shown to have rich biological activities. The synthesized compounds were evaluated for their anti-plasmodial and anti-bacterial properties. In addition, these compounds were screened for their iron(II)-chelation properties. Notably, four of these compounds exhibited anti-plasmodial activities comparable to that of the natural product cordypyridone B. PMID- 25544372 TI - Supplements to species groups of the subgenus Homoneura in China (Diptera: Lauxaniidae: Homoneura), with descriptions of twenty new species . AB - The following twenty species are new to science: Homoneura (Homoneura) longifurcata sp. nov. and H. (H.) triprocessa sp. nov. in the H. (H.) abnormis group; H. (H.) quadristriata sp. nov. in the H. (H.) bistriata group; H. (H.) subulifera sp. nov. and H. (H.) triangulata sp. nov. in the H. (H.) formosae group; H. (H.) dadongshanica sp. nov., H. (H.) denticulata sp. nov., H. (H.) simigrandis sp. nov., H. (H.) tianjingshanica sp. nov. and H. (H.) zhangjiajiensis sp. nov. in the H. (H.) henanensis group; H. (H.) hamata sp. nov. in the H. (H.) lii group; H. (H.) degenerata sp. nov. in the H. (H.) sauteri group; H. (H.) falcata sp. nov., H. (H.) fengyangshanica sp. nov., H. (H.) hongmaoensis sp. nov. and H. (H.) zhejiangensis sp. nov. in the H. (H.) singularis group; H. (H.) shunxica sp. nov. in the H. (H.) striatifrons group; H. (H.) bicuspidata sp. nov. and H. (H.) noticomata sp. nov. in the H. (H.) trispina group; H. (H.) jianlingensis sp. nov. in the H. (H.) unguiculata group. The H. (H.) interrupta Sasakawa, 2001 and H. (H.) strigata (Mejere, 1910) are recorded for the first time in China. Two synonyms are proposed, including H. (H.) beijingensis Gao & Yang, in Wang, Gao & Yang, 2012 as a junor synonym of H. (H.) henanensis Yang, Zhu & Hu, 1999, H. (H.) trunciformis Shi & Yang, 2009 as a junor synonym of H. (H.) ornatifrons (Kertesz, 1913). PMID- 25544371 TI - Hypericum perforatum and neem oil for the management of acute skin toxicity in head and neck cancer patients undergoing radiation or chemo-radiation: a single arm prospective observational study. AB - BACKGROUND: Radiation dermatitis is common in patients treated with combined radiotherapy and chemotherapy for head and neck malignancies. Its timely and adequate management is of uttermost importance for both oncological outcomes and global quality of life. We prospectively evaluated the role of hypericum perforatum and neem oil (Holoil(r); RIMOS srl, Mirandola, Italy) in the treatment of acute skin toxicity for patients undergoing radiotherapy or chemo-radiotherapy for head and neck cancer. METHODS: A consecutive series of 28 head and neck cancer patients submitted to radiotherapy (RT) was enrolled onto this mono institutional single-arm prospective observational study. Patients undergoing both definitive or post-operative radiotherapy were allowed, either as exclusive modality or combined with (concomitant or induction) chemotherapy. We started Holoil treatment whenever bright erythema, moderate oedema or patchy moist desquamation were observed. Holoil(r) was used during all RT course and during follow up time, until acute skin toxicity recovery. RESULTS: The maximum detected acute skin toxicity was Grade 1 in 7% of patients, Grade 2 in 68%, Grade 3 in 25%, while at the end of RT was Grade 0 in 3.5%, Grade 1 in 32%, Grade 2 in 61%, Grade 3 in 3.5%. For patients having G2 acute skin toxicity, it mainly started at weeks 4-5; for those having G3, it began during weeks 5-6. Median times spent with G2 or G3 toxicity were 17.5 and 11 days. Patients having G2 acute skin toxicity had a dermatitis worsening in 27% of case (median occurrence time: 7 days). G3 events were reconverted to a G2 profile in all patients (median time: 7 days). Those experiencing a G2 skin event were converted to a G1 score in 23% of cases (median time: 14 days). Time between maximum acute skin toxicity and complete skin recovery after RT was 27 days. CONCLUSIONS: Holoil(r) proved to be a safe and active option in the management of acute skin toxicity in head and neck cancer patients submitted to RT or chemo-radiotherapy. A prophylactic effect in the prevention of moist desquamation may be hypothesized for hypericum and neem oil and need to be tested within a prospective controlled study. PMID- 25544373 TI - The species of Botanochara Dejean, 1836 (Coleoptera: Chrysomelidae) from Argentina: an identification key, new host plant records and list of Cassidinae found in birds' nests and other protected places. AB - The genus Botanochara Dejean, 1836 comprises 43 species distributed in the Neotropical Region, among which 26 (57%) are known from Argentina. Botanochara praefica (Spaeth, 1940) is synonymized with B. macularia (Boheman, 1850). Botanochara missionea (Spaeth, 1915) and B. tessellata (Burmeister, 1870) are illustrated for the first time. Botanochara duodecimnotata (Boheman, 1850) and Botanochara segnis (Boheman, 1862) are new country records. Six species are shared with Bolivia, 21 with Brazil, 15 with Paraguay, one with Peru, and 7 with Uruguay. The known geographic distributions, synonymies, hybrids, chromosome numbers, and host plants in Argentina and adjacent countries are summarized. New localities and host plants, and some corrections of misidentified species from Argentina are given. Distribution maps of all species in Argentina with known localities superimposed with biogeographic provinces are provided. The southern limits of Botanochara in western, central and eastern Argentina are established and correlates with the known distributions of Ipomoea L. species (Convolvulaceae). A total of 12,815 specimens of Cassidinae were found inside birds' nests from Argentina, from which 11,538 (90.03%) belong to 8 species of Botanochara; 9,331 (80.87%) were found during Autumn (21th March to 20th June) and Winter (21th June to 20th September) (diapause), and 2,207 (19.13%) during Spring (21 th September to 20 th December) and Summer (21 th December to 20 th March) (aseasonal quiescence). Additional records of two other Cassidinae found in birds' nests and other protected places, Carlobruchia tricostata (Spaeth, 1907) and Stolas lacordairei (Boheman, 1850), are also provided. PMID- 25544368 TI - Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches. AB - Resistance to chemotherapy is among the most important issues in the management of ovarian cancer. Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous. Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy. Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways. Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment. In addition, hypoxia induced by anti angiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy. Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance. Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies. PMID- 25544374 TI - Revision of the genus Acanthaspis Amyot & Serville (Hemiptera: Heteroptera: Reduviidae: Reduviinae) from China, with new records of species to adjacent countries. AB - The assassin bugs of the genus Acanthaspis Amyot & Serville (Reduviinae) from China are revised. Fourteen species are recognized, described or redescribed and illustrated. Three species, A. fulviconnexa, A. melanota, and A. octoguttata, are described as new to science. Acanthaspis subinermis Hsiao 1976 is synonymized with A. laoensis Distant 1919. A key for the identification of Chinese species of Acanthaspis is provided. The biology of A. cincticrus Stal is briefly noted. The following species are newly recorded from adjacent countries: A. collaris Hsiao from Laos and Thailand, A. geniculata Hsiao from Vietnam, A. picta Hsiao from Laos, Myanmar and Thailand, A. quinquespinosa (Fabricius) from Nepal, A. ruficeps Hsiao from Laos, Thailand and Vietnam, and A. laoensis Distant from Thailand. PMID- 25544375 TI - Who wants to go further has to know the past: A comment upon: Ultrasonography versus computed tomography for suspected nephrolithiasis-R. Smith-Bindman et al. N Engl J Med. 2014 Sep 18;371(12):1100-1110. PMID- 25544369 TI - Targeted immune therapy of ovarian cancer. AB - Clinical outcomes, such as recurrence-free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy, and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathological network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies. PMID- 25544377 TI - Evidence-based Effective Triage Operation During Disaster: Application of Human trajectory Data to Triage Drill Sessions. AB - INTRODUCTION: Though many governmental and nongovernmental efforts for disaster prevention have been sought throughout Japan since the Great East Japan Earthquake on March 11, 2011, most of the preparation efforts for disasters have been based more on structural and conventionalized regulations than on scientific and objective grounds. Problem There has been a lack of scientific knowledge for space utilization for triage posts in disaster drill sessions. This report addresses how participants occupy and make use of the space within a triage post in terms of areas of use and occupied time. METHOD: The trajectories of human movement by using Ubiquitous Stereo Vision (USV) cameras during two emergency drill sessions held in 2012 in a large commercial building have been measured. The USV cameras collect each participant's travel distance and the wait time before, during, and after undergoing triage. The correlation between the wait time and the space utilization of patients at a triage post has been analyzed. RESULTS: In the first session, there were some spaces not entirely used. This was caused largely by a patient who arrived earlier than others and lingered in the middle area, which caused the later arrivals to crowd the entrance area. On the other hand, in the second session, the area was used in a more evenly-distributed manner. This is mainly because the earlier arrivals were guided to the back space of the triage post (ie, the opposite side of the entrance), and the late arrivals were also guided to the front half, which was not occupied by anyone. As a result, the entire space was effectively utilized without crowding the entrance. CONCLUSION: This study has shown that this system could measure people's arrival times and the speed of their movements at the triage post, as well as where they are placed until they receive triage. Space utilization can be improved by efficiently planning and controlling the positioning of arriving patients. Based on the results, it has been suggested that for triage operation, it is necessary to efficiently plan and control the placement of patients in order to use strategically limited spatial resources. PMID- 25544376 TI - Differential expression of the multidrug resistance 1 (MDR1) protein in prostate cancer cells is independent from anticancer drug treatment and Y box binding protein 1 (YB-1) activity. AB - PURPOSE: The development of a drug-resistant phenotype is the major challenge during treatment of castration-resistant prostate cancer (PC). In solid cancer entities, one of the major contributors to chemoresistance is the multidrug resistance 1 (MDR1) protein. Believed to be involved in the induction of MDR1 expression is the presence of anticancer drugs as well as the Y box binding protein 1 (YB-1). METHODS: Basal as well as drug-induced expression of MDR1 in established PC cell lines was assessed by Western blotting and mass spectrometry. Subsequently, the influence of YB-1 on MDR1 expression was examined via transient overexpression of YB-1. RESULTS: While LNCaP and PC-3 cells showed no detectable amounts of MDR1, the resistance factor was found to be expressed in 22Rv1 cells. Despite this difference, all three cell lines demonstrated similar growth behavior in the presence of the first-line chemotherapeutic agent docetaxel. Incubation of 22Rv1 cells with docetaxel, cabazitaxel, and abiraterone did not significantly alter MDR1 expression levels. Furthermore, overexpression of the MDR1 controlling factor YB-1 showed no impact on MDR1 expression levels. CONCLUSIONS: MDR1 was detectable in the PC cell line 22Rv1. However, this study suggests that MDR1 is of less importance for drug resistance in PC cells than in other types of solid cancer. Furthermore, in contrast to YB-1 properties in other malignancies, MDR1 regulation through YB-1 seems to be unlikely. PMID- 25544378 TI - Modulating the serotonin system in the treatment of major depressive disorder. AB - LEARNING OBJECTIVE: Discuss the theory of modulation of receptor activity or the blockade of the reuptake of multiple neurotransmitter systems for the future treatment of MDD. Major depressive disorder (MDD) is a serious and often crippling psychiatric illness with a high risk of relapse and treatment resistance. In this article, we discuss the role of the serotonergic system in MDD including our current understanding of how various serotonin (5HT) receptors modulate monoamine neurotransmission and behavior. We also discuss how pharmacologic interventions, including novel and existing antidepressants and atypical antipsychotics, may be utilized to adjust serotonergic neurotransmission and provide more effective treatments for patients with MDD. PMID- 25544379 TI - [Medaillon-like dermal dendrocyte hamartoma: A case report]. AB - Medaillon-like dermal dendrocyte hamartomas are rare congenital cutaneous lesions. They are present at birth as asymptomatic, benign, round, erythematous, well-circumscribed, atrophic patches. Typically, they have characteristic pliable, wrinkled surface; subtle telangiectases may also be appreciated. They are localized on the upper trunk or the neck. They may be misdiagnosed as atrophoderma, cutis aplasia, or anetoderma. Characteristic histologic findings include epidermal atrophy and the presence of CD34-positive spindle cell proliferation in the dermis. Little is known about the pathophysiology of medaillon-like dermal dendrocyte hamartomas. The main diagnosis pitfall is atrophic congenital dermatofibrosarcoma protuberance due to clinical and histological similarities. We emphasize that molecular studies to eliminate the t(17;22)(q22;q13) translocation of dermatofibrosarcomas may provide determinant elements for diagnosis in order to avoid unnecessary mutilating surgery. We present a case of medaillon-like dermal dendrocyte hamartoma with a local recurrence. PMID- 25544380 TI - Decision-making and cancer screening: a qualitative study of older adults with multiple chronic conditions. AB - OBJECTIVE: To understand how older persons with multiple chronic conditions (MCC) approach decisions about cancer screening. MATERIALS AND METHODS: We conducted interviews with adults >65 years old with at least two chronic conditions who were taking >=five medications daily. Patients were first asked how age and multimorbidity influence their cancer screening decisions. After showing them an educational prompt that explained the relationship between life expectancy and the benefits of cancer screening, respondents were then asked about screening in the context of specific health scenarios. Using grounded theory, three independent readers coded responses for salient themes. Sample size was determined by thematic saturation. RESULTS: Most respondents (26 of 28) initially indicated that their overall health or medical conditions do not influence their cancer screening decisions. After viewing the educational prompt, respondents described two broad approaches to cancer screening in the setting of increasing age or multi-morbidity. The first was a "benefits versus harms" approach in which participants weighed direct health benefits (e.g. reducing cancer incidence or mortality) and harms (e.g. complications or inconvenience). The second was a heuristic approach. Some heuristics favored screening, such as a persistent belief in unspecified benefits from screening, value of knowledge about cancer status, and not wanting to "give up", whereas other heuristics discouraged screening, such as fatalism or a reluctance to learn about their cancer status. CONCLUSIONS: When considering cancer screening, some older persons with MCC employ heuristics which circumvent the traditional quantitative comparison of risks and benefits, providing an important challenge to informed decision making. PMID- 25544381 TI - Berberine exhibits antitumor effects in human ovarian cancer cells. AB - BACKGROUND: Berberine is an extract of a traditional Chinese herbal medicine and has been shown to inhibit the proliferation and induce apoptosis in a wide variety of tumour cells. However, the effects of Berberine in ovarian cancer cells are unknown. AIMS: To investigate the potential anti-cancer effects of Berberine in human ovarian cancer cells. METHODS: Cell proliferation was evaluated by a MTT assay. Apoptosis was determined by using Annexin V/PI staining and transmission electron microscopy. The methylation status of the hMLH1 promoter CpG islands was analysed by using methylation-specific polymerase chain reaction (MSP). mRNA expression of BCLM-2, BAX, survivin and HMLH1 was quantified by real-time fluorescence quantitative RT-PCR. RESULTS: Berberine significantly inhibited the proliferation of SKOV3 cells in a dose- and time-dependent manner. It also dose-dependently induced apoptosis, possibly through down-regulating the anti-apoptotic genes BCL-2 and survivin, and up-regulating the pro-apoptotic gene BAX. When combined with cisplatin, Berberine showed a strong synergistic anticancer effect against ovarian cancer cells. In addition, Berberine was found to restore the demethylation status of the hMLH1 promoter and up-regulate the mRNA expression of hMLH1. CONCLUSION: Berberine possesses antitumor effect via inhibition of cell proliferation and induction of apoptosis in ovarian cancer cells. Berberine could synergistically enhance the cell killing effect of other antitumor agents such as cisplatin. Further studies are essential to explore the therapeutic potential of Berberine either alone or in combination with other anticancer agents in patients with ovarian cancer. PMID- 25544382 TI - 5-Benzylidene-3,4-dihalo-furan-2-one derivatives inhibit human leukemia cancer cells through suppression of NF-kappaB and GSK-3beta. AB - It has been demonstrated that PPARgamma agonists effectively inhibit proliferation, metastasis as well as induce apoptosis in human cancer cell lines. In this study, twenty-two rosiglitazone analogues, 5-benzylidene-3,4- dihalo furan-2-one derivatives, which have been identified as PPARgamma agonists in our previous work, were evaluated for their antitumor effects. Among these compounds, (Z)-3,4-dibromo-5-(3-methoxy-4-((3,5,6-trimethylpyrazin-2- yl)methoxy)benzylidene)furan-2(5H)-one (6w) shows the best antitumor activity, especially against the leukemia cell line U937, resulting in significant cytotoxicity, increased apoptosis and changes in mitochondrial membrane potential. Up-regulation of pro-apoptosis-associated proteins (Bax, caspase-3 and caspase-9) and cleaved PARP as well as down-regulation of anti-apoptosis protein Bcl-2 are observed in 6w-treated U937 cells. It was shown that the antitumor effect of 6w stems from its ability to inhibit the PPARgamma-dependent expression of NF-kappaB and GSK-3beta. PMID- 25544383 TI - Scaling up nutrition in fragile and conflict-affected states: the pivotal role of governance. AB - Acute and chronic undernutrition undermine conditions for health, stability and socioeconomic development across the developing world. Although fragile and conflict-affected states have some of the highest rates of undernutrition globally, their response to the multilateral 'Scaling Up Nutrition' (SUN) initiative in its first two-year period was ambivalent. The purpose of this research was to investigate factors affecting fragile and conflict-affected states' engagement with SUN, and to examine what differentiated those fragile states that joined SUN in its first phase from those that did not. Drawing on global databases (Unicef, World Bank, UNDP), and qualitative country case studies (Afghanistan, the Democratic Republic of Congo, Sierra Leone, Pakistan and Yemen) we used bivariate logistic regressions and principal component analysis to assess social, economic and political factors across 41 fragile states looking for systematic differences between those that had signed up to SUN before March 2013 (n = 16), and those that had not (n = 25). While prevalence of malnutrition, health system functioning and level of citizen empowerment had little or no impact on a fragile state's likelihood of joining SUN, the quality of governance (QOG) strongly predicted accession. SUN-signatory fragile states scored systematically better on the World Bank's Country Policy and Institutional Assessment (CPIA) and the Worldwide Governance Indicators 'effectiveness of government' indices. We conclude that strengthening governance in fragile states may enhance their engagement with initiatives such as SUN, but also (recognising the potential for endogeneity), that the way aid is structured and delivered in fragile states may be an underlying determinant of whether and how governance in such contexts improves. The research demonstrates that more nuanced analysis of conditions within and among countries classed as 'fragile and conflict-affected' is both possible and necessary if aid policies are to be shaped in ways that support rather than undermine growth in governance capacity. PMID- 25544384 TI - Auditory agnosia as a clinical symptom of childhood adrenoleukodystrophy. AB - OBJECTIVE: To investigate detailed auditory features in patients with auditory impairment as the first clinical symptoms of childhood adrenoleukodystrophy (CSALD). SUBJECTS AND METHODS: Three patients who had hearing difficulty as the first clinical signs and/or symptoms of ALD. Precise examination of the clinical characteristics of hearing and auditory function was performed, including assessments of pure tone audiometry, verbal sound discrimination, otoacoustic emission (OAE), and auditory brainstem response (ABR), as well as an environmental sound discrimination test, a sound lateralization test, and a dichotic listening test (DLT). The auditory pathway was evaluated by MRI in each patient. RESULTS: Poor response to calling was detected in all patients. Two patients were not aware of their hearing difficulty, and had been diagnosed with normal hearing by otolaryngologists at first. Pure-tone audiometry disclosed normal hearing in all patients. All patients showed a normal wave V ABR threshold. Three patients showed obvious difficulty in discriminating verbal sounds, environmental sounds, and sound lateralization and strong left-ear suppression in a dichotic listening test. However, once they discriminated verbal sounds, they correctly understood the meaning. Two patients showed elongation of the I-V and III-V interwave intervals in ABR, but one showed no abnormality. MRIs of these three patients revealed signal changes in auditory radiation including in other subcortical areas. CONCLUSION: The hearing features of these subjects were diagnosed as auditory agnosia and not aphasia. It should be emphasized that when patients are suspected to have hearing impairment but have no abnormalities in pure tone audiometry and/or ABR, this should not be diagnosed immediately as psychogenic response or pathomimesis, but auditory agnosia must also be considered. PMID- 25544385 TI - Is hydroxyethyl starch necessary for sedimentation of bone marrow? AB - Hydroxyethyl starch (HES) is used to separate hematopoietic progenitor cells after bone marrow (BM) collection from red blood cells. The aims were to study alternatives for HAES-steril (200 kDa; not available anymore) and to optimize the sedimentation process. Using WBC-enriched product (10 * 10(9) WBC/L), instead of BM, sedimentation at 10% hematocrit using final 0.6 or 0.39% Voluven (130 kDa) or without HES appeared to be good alternatives for 0.6% HAES-steril. MNC recovery >80% and RBC depletion >90% was reached. Optimal sedimentation was reached using 110-140 mL volume. Centrifugation appeared not suitable for sedimentation. Additional testing with BM might be necessary to confirm these results. PMID- 25544386 TI - Prognostic factors and complication rates for double-filtration plasmapheresis in patients with Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an acute immune-mediated demyelinating polyradiculoneuropathy that could lead to disabilities if not properly treated. There are only limited data on the prognostic factors and complications when using double-filtration plasmapheresis in these patients. We reviewed the medical records of 60 GBS patients who underwent double-filtration plasmapheresis as the first-line therapy at a tertiary care teaching hospital. The severity of disease was evaluated at different time points using disability scores. Functional outcome was defined as good (GBS disability score 0 to 2) or poor (GBS disability score 3 to 6) at 28 days after admission. The cohort included 22 women and 38 men with a mean age of 50 +/- 18 years. In univariate logistic regression analysis, potential factors associated with poor outcome include an older age (P = 0.101), the absence of preceding respiratory tract infection (P = 0.043), mechanical ventilation (P = 0.016), a lower hematocrit (p = 0.072), a lower serum sodium level (P = 0.153) and a higher disability score on admission (P < 0.001). In multivariate analysis, a higher disability score on admission was associated with a poorer outcome (OR, 5.61; 95% CI, 2.34 to 13.43; P < 0.001), whereas the presence of prodromal upper respiratory tract infection correlated with a better outcome (OR, 0.13; 95% CI, 0.03-0.59; P = 0.009). Among 60 patients, eleven (18.3%) have various complications attributed to plasmapheresis treatment. Six patients (10.0%) developed deep vein thrombosis and two experienced catheter related infection (3.3%). Hypotension, allergy and hemolysis occurred in one patient each (1.7%). In conclusion, we describe our experiences of using DFPP in the treatment of GBS. The pretreatment severity score was the most significant predictor of treatment outcome, suggesting that early referral and timely treatment are important. Potential complications such as catheter-related infection and deep vein thrombosis should be monitored carefully. PMID- 25544387 TI - Transfer-free synthesis of doped and patterned graphene films. AB - High-quality and wafer-scale graphene on insulating gate dielectrics is a prerequisite for graphene electronic applications. For such applications, graphene is typically synthesized and then transferred to a desirable substrate for subsequent device processing. Direct production of graphene on substrates without transfer is highly desirable for simplified device processing. However, graphene synthesis directly on substrates suitable for device applications, though highly demanded, remains unattainable and challenging. Here, we report a simple, transfer-free method capable of synthesizing graphene directly on dielectric substrates at temperatures as low as 600 degrees C using polycyclic aromatic hydrocarbons as the carbon source. Significantly, N-doping and patterning of graphene can be readily and concurrently achieved by this growth method. Remarkably, the graphene films directly grown on glass attained a small sheet resistance of 550 Omega/sq and a high transmittance of 91.2%. Organic light emitting diodes (OLEDs) fabricated on N-doped graphene on glass achieved a current density of 4.0 mA/cm(2) at 8 V compared to 2.6 mA/cm(2) for OLEDs similarly fabricated on indium tin oxide (ITO)-coated glass, demonstrating that the graphene thus prepared may have potential to serve as a transparent electrode to replace ITO. PMID- 25544388 TI - Rational design of hyper-glycosylated interferon beta analogs: a computational strategy for glycoengineering. AB - Glycoengineering has been successfully used to improve the physicochemical and pharmaceutical properties of therapeutics. One aspect of glycoengineering is to introduce new N-linked glycosylation consensus sequences (Asn, X, Thr/Ser) into desirable positions in the peptide backbone by mutational insertion to generate proteins with increased sialic acid content. In the current work, human interferon beta (huIFN-beta) was used as a model to identify the potential positions for the addition of new N-glycosylation sites. A computational strategy was employed to predict the structural distortions and functional alterations that might be caused by the change in amino acid sequence. Accordingly, three dimensional (3D) structures of the designed huIFN-beta analogs were generated by comparative modeling. Molecular dynamics (MD) simulation was carried out to assess the molecular stability and flexibility profile of the structures. Subsequently, for the purpose of glycoengineering huIFN-beta, analogs with 3D structures more similar to the wild-type huIFN-beta and exposed Asn residue in the new N-glycosylation site were identified. These modeling procedures indicated that the addition of the new N-glycosylation site in the loop regions had lower constraining effects on the tertiary structure of the protein. This computational strategy can be applied to avoid alterations in the 3D structure of proteins caused by changes in the amino acid sequences, when designing novel hyper glycosylated therapeutics. This in turn reduces labor-intensive experimental analyses of each analog. PMID- 25544389 TI - Structural basis for cooperative binding of azoles to CYP2E1 as interpreted through guided molecular dynamics simulations. AB - CYP2E1 metabolizes a wide array of small, hydrophobic molecules, resulting in their detoxification or activation into carcinogens through Michaelis-Menten as well as cooperative mechanisms. Nevertheless, the molecular determinants for CYP2E1 specificity and metabolic efficiency toward these compounds are still unknown. Herein, we employed computational docking studies coupled to molecular dynamics simulations to provide a critical perspective for understanding a structural basis for cooperativity observed for an array of azoles from our previous binding and catalytic studies (Hartman et al., 2014). The resulting 28 CYP2E1 complexes in this study revealed a common passageway for azoles that included a hydrophobic steric barrier causing a pause in movement toward the active site. The entrance to the active site acted like a second sieve to restrict access to the inner chamber. Collectively, these interactions impacted the final orientation of azoles reaching the active site and hence could explain differences in their biochemical properties observed in our previous studies, such as the consequences of methylation at position 5 of the azole ring. The association of a second azole demonstrated significant differences in interactions stabilizing the bound complex than observed for the first binding event. Intermolecular interactions occurred between the two azoles as well as CYP2E1 residue side chains and backbone and involved both hydrophobic contacts and hydrogen bonds. The relative importance of these interactions depended on the structure of the respective azoles indicating the absence of specific defining criteria for binding unlike the well-characterized dominant role of hydrophobicity in active site binding. Consequently, the structure activity relationships described here and elsewhere are necessary to more accurately identify factors impacting the observation and significance of cooperativity in CYP2E1 binding and catalysis toward drugs, dietary compounds, and pollutants. PMID- 25544390 TI - A comparative study on the therapeutic effects of silymarin and silymarin-loaded solid lipid nanoparticles on D-GaIN/TNF-alpha-induced liver damage in Balb/c mice. AB - Nanostructure-mediated drug delivery is known to have a potential to improve drug bioavailability, apart from fostering release deviation of drug molecules and enabling precision drug targeting. Solid lipid nanoparticles (SLNs) have drawn great deal of the attention of scientists in finding a solution to minimize pharmaceutic limitations of the drugs used. Silymarin (Sm) has so far been used for treating diverse liver and gallbladder disorders, such as cirrhosis, hepatitis, and jaundice, and for protecting the liver against poisoning from chemical and environmental toxins on account of its antihepatotoxic and antioxidative properties. The present study aims to develop a novel silymarin loaded solid lipid nanoparticle (Sm-loaded SLN) system with enhanced bioavailability and with an ability to provide excellent hepatic protection for poorly water-soluble drugs. Based upon our investigation results with apoptotic markers, PCNA and lightmicroscopic findings, it can be concluded that Sm-loaded SLN significantly reduced D-GaIN/TNF-alpha-induced hepatotoxicity, which suggested improved bioactivity compared to Sm. In conclusion, Sm-loaded SLN could be a useful system for the delivery of poorly water-soluble Sm, apart from providing favourable hepatic protection. PMID- 25544391 TI - Structural and biomechanical changes in the Achilles tendon after chronic treatment with statins. AB - Cases of tendinopathy and tendon ruptures have been reported as side effects associated with statin therapy. This work assessed possible changes in the structural and biomechanical properties of the tendons after chronic treatment with statins. Wistar rats were divided into the following groups: treated with atorvastatin (A-20 and A-80), simvastatin (S-20 and S-80) and the group that received no treatment (C). The doses of statins were calculated using allometric scaling, based on the doses of 80 mg/day and 20 mg/day recommended for humans. The morphological aspect of the tendons in A-20, S-20 and S-80 presented signals consistent with degeneration. Both the groups A-80 and S-80 showed a less pronounced metachromasia in the compression region of the tendons. Measurements of birefringence showed that A-20, A-80 and S-80 groups had a lower degree of organization of the collagen fibers. In all of the groups treated with statins, the thickness of the epitenon was thinner when compared to the C group. In the biomechanical tests the tendons of the groups A-20, A-80 and S-20 were less resistant to rupture. Therefore, statins affected the organization of the collagen fibers and decreased the biomechanical strength of the tendons, making them more predisposed to ruptures. PMID- 25544392 TI - GATA3 expression in morphologic subtypes of breast carcinoma: a comparison with gross cystic disease fluid protein 15 and mammaglobin. AB - GATA3 is a transcription factor, which is involved in the growth and differentiation of several human tissues. Immunohistochemical staining for this marker has proven to be useful in recognizing a number of tumors, most notably those in the urinary tract and breasts. To date, no study has specifically assessed the distribution of GATA3 among different histomorphologic subtypes of breast carcinoma. The surgical pathology archive at our institution was searched, to retrieve cases of breast carcinomas of the following microscopic types-ductal, lobular, mucinous, metaplastic, medullary, apocrine, signet-ring cell, and micropapillary. Tissue microarrays were created, with four 0.6-mm punch specimens from each case. The tissue microarrays were cut at a 5-MUm thickness and stained with monoclonal antibodies to GATA3 (Biocare Medical Inc, Concord, CA), mammaglobin (Dako, Carpinteria, CA), and gross cystic disease fluid protein 15 (Dako). Tumors were considered to be positive for those markers if more than 5% of the cells were labeled. Of 55 ductal adenocarcinomas, 51 (92.7%) expressed GATA3. All 4 GATA3-negative tumors were Nottingham grade III lesions that were also nonreactive for estrogen receptor protein. GATA3 was present in 28 (96.6%) of 29 lobular adenocarcinomas, 10 (90.9%) of 11 apocrine adenocarcinomas, 10 (83.3%) of 12 medullary carcinomas, 5 (55.5%) of 9 metaplastic carcinomas, and 1 of 2 signet-ring cell carcinomas. Mucinous carcinomas (23 cases) and micropapillary carcinomas (12 cases) uniformly and strongly labeled for GATA3. GATA3 equaled or surpassed the sensitivity of mammaglobin and gross cystic disease fluid protein 15 in all histologic subgroups of breast cancer in the study. Although most ductal adenocarcinomas were labeled for GATA3, it was absent in high-grade tumors that also lacked estrogen receptor protein. Favorable prognosis types of breast carcinoma (eg, mucinous carcinoma) and aggressive variants such as micropapillary carcinoma were equally reactive for this marker. A proportion of medullary and metaplastic carcinomas was GATA3 negative (17% and 44%, respectively). Thus, those pathologic entities cannot be excluded diagnostically by an absence of GATA3 immunoreactivity. PMID- 25544393 TI - What you get is what you believe: eighteen-month-olds demonstrate belief understanding in an unexpected-identity task. AB - Based on recent findings of implicit studies, researchers have claimed that even infants can understand others' false beliefs. However, it is unclear whether infants are able to understand others' belief about an object's identity when this object can be represented in different ways. In a novel interactive unexpected-identity task derived from the appearance-reality paradigm, 18-month olds helped an adult to achieve her goal based on the adult's belief about an object's identity. To do so, they needed to understand how this adult represented this object--according to its appearance or its real identity--and to generalize these representations to a category of objects. The results suggest that infants' false-belief understanding is as sophisticated as that of preschool children. PMID- 25544394 TI - Preschoolers perform more informative experiments after observing theory violating evidence. AB - This study investigated the effect of evidence conflicting with preschoolers' naive theory on the patterns of their free exploratory play. The domain of shadow size was used--a relatively complex, ecologically valid domain that allows for reliable assessment of children's knowledge. Results showed that all children who observed conflicting evidence performed an unconfounded informative experiment in the beginning of their play, compared with half of the children who observed confirming evidence. Mainly, these experiments were directed at investigating a dimension that was at the core of children's initial theory. Thus, preschoolers were flexible in the type of experiments they performed, but they were less flexible in the content of their investigations. PMID- 25544395 TI - Process dissociation of familiarity and recollection in children: response deadline affects recollection but not familiarity. AB - According to dual-process theories, recollection (slow and associated with contextual details) and familiarity (fast and automatic) are two independent processes underlying recognition memory. An adapted version of the process dissociation paradigm was used to measure recognition memory in 5-, 7-, and 11 year-olds and adults. In Experiment 1, it was found that 5-year-olds already recollect details of items (i.e., number). Recollection increased particularly between 5 and 7 years. Familiarity differed between 5 years and adulthood. In Experiment 2, under limited response time during retrieval, recollection was eliminated in 5-year-olds and reduced across all ages, whereas familiarity was left unaffected. Together, these findings are consistent with dual-process theories of recognition memory and provide support for two processes underlying recognition memory from a developmental perspective. PMID- 25544396 TI - Consonant/vowel asymmetry in early word form recognition. AB - Previous preferential listening studies suggest that 11-month-olds' early word representations are phonologically detailed, such that minor phonetic variations (i.e., mispronunciations) impair recognition. However, these studies focused on infants' sensitivity to mispronunciations (or omissions) of consonants, which have been proposed to be more important for lexical identity than vowels. Even though a lexically related consonant advantage has been consistently found in French from 14 months of age onward, little is known about its developmental onset. The current study asked whether French-learning 11-month-olds exhibit a consonant-vowel asymmetry when recognizing familiar words, which would be reflected in vowel mispronunciations being more tolerated than consonant mispronunciations. In a baseline experiment (Experiment 1), infants preferred listening to familiar words over nonwords, confirming that at 11 months of age infants show a familiarity effect rather than a novelty effect. In Experiment 2, which was constructed using the familiar words of Experiment 1, infants preferred listening to one-feature vowel mispronunciations over one-feature consonant mispronunciations. Given the familiarity preference established in Experiment 1, this pattern of results suggests that recognition of early familiar words is more dependent on their consonants than on their vowels. This adds another piece of evidence that, at least in French, consonants already have a privileged role in lexical processing by 11 months of age, as claimed by Nespor, Pena, and Mehler (2003). PMID- 25544397 TI - Endothelin receptors, renal effects and blood pressure. AB - The endothelin system has emerged as a key player in the renal control of salt and water homeostasis, exerting profound effects on both the renal vasculature and tubular epithelial cells. Recent advances include new actions of endothelins in the glomerulus, an emerging role for the ETA receptor in chronic kidney disease (CKD) progression and in tubular function, and a more detailed understanding of the tubular response to high salt intake. A large body of evidence also implicates dysfunction of the endothelin system in hypertension, particularly salt-sensitive hypertension, although recent data suggests important sex-differences may exist. Finally, clinical trials indicate that antagonists of endothelin receptors hold great promise in treating resistant hypertension and proteinuric renal disease. PMID- 25544398 TI - Micro-marketing healthier choices: effects of personalized ordering suggestions on restaurant purchases. AB - We study the effects of the Nutricate receipt, which makes personalized recommendations to switch from unhealthy to healthier items at a restaurant chain. We find that the receipts shifted the mix of items purchased toward the healthier alternatives. For example, the share of adult main dishes requesting "no sauce" increased by 6.8 percent, the share of kids' meals with apples (instead of fries) rose by 7.0 percent and the share of breakfast sandwiches without sausage increased by 3.8 percent. The results illustrate the potential of emerging information technologies, which allow retailers to tailor product marketing to individual consumers, to generate healthier choices. PMID- 25544399 TI - Inequity in long-term care use and unmet need: two sides of the same coin. AB - We investigate the determinants of several LTC services and unmet need using data from a representative sample of the non-institutionalised disabled population in Spain in 2008. We measure the level of horizontal inequity and compare results using self-reported versus a more objective indicator of unmet needs. Evidence suggests that after controlling for a wide set of need variables, there is not an equitable distribution of use and unmet need of LTC services in Spain; formal services are concentrated among the better-off, while intensive informal care is concentrated among the worst-off. The distribution of unmet needs for LTC services depends on the service considered and on whether we focus on subjective or objective measures. In 2008, only individuals with the highest dependency level had universal coverage. Our results show that inequities in most LTC services and unmet needs among this group either remain or even increase for formal services. PMID- 25544400 TI - Competition, gatekeeping, and health care access. AB - We study gatekeeping physicians' referrals of patients to specialty care. We derive theoretical results when competition in the physician market intensifies. First, due to competitive pressure, physicians refer patients to specialty care more often. Second, physicians earn more by treating patients themselves, so refer patients to specialty care less often. We assess empirically the overall effect of competition with data from a 2008-2009 Norwegian survey, National Health Insurance Administration, and Statistics Norway. From the data we construct three measures of competition: the number of open primary physician practices with and without population adjustment, and the Herfindahl-Hirschman index. The empirical results suggest that competition has negligible or small positive effects on referrals overall. Our results do not support the policy claim that increasing the number of primary care physicians reduces secondary care. PMID- 25544401 TI - Access to health insurance and the use of inpatient medical care: evidence from the Affordable Care Act young adult mandate. AB - The Affordable Care Act of 2010 expanded coverage to young adults by allowing them to remain on their parent's private health insurance until they turn 26 years old. While there is evidence on insurance effects, we know very little about use of general or specific forms of medical care. We study the implications of the expansion on inpatient hospitalizations. Given the prevalence of mental health needs for young adults, we also specifically study mental health related inpatient care. We find evidence that compared to those aged 27-29 years, treated young adults aged 19-25 years increased their inpatient visits by 3.5 percent while mental illness visits increased 9.0 percent. The prevalence of uninsurance among hospitalized young adults decreased by 12.5 percent; however, it does not appear that the intensity of inpatient treatment changed despite the change in reimbursement composition of patients. PMID- 25544402 TI - The influence of thought control on the experience of persecutory delusions and auditory hallucinations in daily life. AB - Attempts to control or suppress thoughts are often unsuccessful and may even lead to an increase in the unwanted content. Intrusive thoughts and thought control are influential in the experience of psychosis, although recent findings have arisen from non-clinical samples and data tend to be retrospective in nature. The current study utilised repeated momentary assessments (experience sampling methodology) delivered as part of participants' daily routine to examine the associations between thought control and the experience of persecutory delusions and auditory hallucinations. The findings revealed that thought control was related to the subsequent severity and distress in relation to psychotic symptoms. Moreover, most of these effects persisted over two subsequent monitoring timepoints, although their size was diminished. These findings add weight to models of psychosis that include a role for thought control, and also highlight opportunities for targeted momentary interventions. Future work might seek to elucidate which specific aspects of thought control are important, alongside the use of more multifaceted measures of psychotic experiences. PMID- 25544403 TI - Mechanisms of change in cognitive therapy for obsessive compulsive disorder: role of maladaptive beliefs and schemas. AB - The present study aimed to identify mechanisms of change in individuals with moderately severe obsessive-compulsive disorder (OCD) receiving cognitive therapy (CT). Thirty-six adults with OCD received CT over 24 weeks. At weeks 0, 4/6, 12, 16/18, and 24, independent evaluators assessed OCD severity, along with obsessive beliefs and maladaptive schemas. To examine mechanisms of change, we utilized a time-varying lagged regression model with a random intercept and slope. Results indicated that perfectionism and certainty obsessive beliefs and maladaptive schemas related to dependency and incompetence significantly mediated (improved) treatment response. In conclusion, cognitive changes in perfectionism/certainty beliefs and maladaptive schemas related to dependency/incompetence precede behavioral symptom reduction for OCD patients. Targeting these mechanisms in future OCD treatment trials will emphasize the most relevant processes and facilitate maximum improvement. PMID- 25544404 TI - Oral ulceration associated with concurrent herpes simplex virus, cytomegalovirus, and Epstein-Barr virus infection in an immunocompromised patient. AB - In immunocompromised patients, oral ulcerations are common and have a wide spectrum of causes, including herpesvirus infection. We report on a case in which an oral ulcer was simultaneously infected by herpes simplex (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in a kidney-pancreas transplant recipient. A 46-year-old woman presented with a clinically nonspecific dorsal tongue ulcer of 3 months duration. Histopathologic evaluation indicated keratinocytes exhibiting herpetic viral cytopathic effect. Nuclear and cytologic alterations suggestive of CMV infection were found in endothelial cells subjacent to the ulcer. Immunohistochemistry testing for HSV and CMV was positive in these cells. Large atypical mononuclear cells were also evident in the ulcer bed's inflammatory infiltrate, which had intense nuclear positivity for Epstein-Barr encoding region in situ hybridization. We believe this is the first well documented report of the definitive concomitant presence of HSV, CMV, and EBV in an immunocompromised patient. Although the pathogenesis of coinfected ulcers remains unknown, a synergistic effect is possible. PMID- 25544405 TI - Microscopic analysis of molar--incisor malformation. AB - OBJECTIVE: Molar-incisor malformation (MIM) is a newly discovered type of dental anomaly that involves a characteristic root malformation of the permanent first molars. The aim of this study was to reveal the microstructure of MIM teeth in order to determine their origin. STUDY DESIGN: Four MIM teeth were extracted from a 9-year-old girl due to severe mobility. The detailed microstructure of the teeth was determined by examinations with micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, immunohistochemical staining, and scanning electron microscopy to reveal the detailed microstructure. RESULTS: Micro-CT and H&E staining revealed the pulpal floor comprising three layers: upper, middle, and lower. Amorphous hard tissues and hyperactive cells were observed in the middle layer of the pulpal floor, and the cells stained positively for dentin sialoprotein and osteocalcin, but not for collagen XII. CONCLUSION: The results of the present study imply that MIM-affected molars probably result from inappropriate differentiation of the apical pulp and dental follicle. PMID- 25544406 TI - Obesity-related non-alcoholic fatty liver disease (NAFLD): A multifactorial process. PMID- 25544407 TI - Effect of necrosectomy and vacuum-assisted closure (VAC) on mitochondrial function and oxidative stress markers in severe acute pancreatitis. AB - BACKGROUND: Severe acute pancreatitis (SAP) is associated with high morbidity and mortality. OBJECTIVE: To evaluate whether necrosectomy, alone or combined with vacuum-assisted closure (VAC), has any additional beneficial effects on mitochondrial function and/or oxidative stress markers in SAP. METHODS: Patients with SAP, APACHE II score > 8, and inadequate response to management in an intensive care unit were included in a prospective observational study. Sixteen underwent necrosectomy and 24 underwent necrosectomy plus VAC every 48 h. Patients were then categorized as survivors or deceased. Submitochondrial membrane fluidity of platelets and F0F1-ATPase hydrolysis were measured to represent mitochondrial function. Oxidative/nitrosative stress was measured using lipoperoxides (LPOs), nitric oxide (NO), erythrocyte membrane fluidity, and total antioxidant capacity (TAC). RESULTS: Membrane fluidity in submitochondrial particles of platelets remained significantly increased throughout the study, and then eventually rised in deceased patients managed with necrosectomy + VAC vs. survivors (p < 0.041). Hydrolysis was significantly increased from baseline to endpoint in all patients, predominating in those who died after management with necrosectomy (p < 0.03). LPO increased in all patients, and necrosectomy was more efficient for the eventual decrease in survivors (p < 0.039). NO was found to be increased for the baseline-endpoint result among both survivors and deceased patients with both management options. Erythrocyte membrane fluidity was increased in survivors managed with necrosectomy + VAC, and eventually returned to normal (p < 0.045). TAC was found to be consumed in all patients for the duration of the study. CONCLUSIONS: Mitochondrial dysfunction and oxidative/ nitrosative stress with significant systemic antioxidant consumption were found. Necrosectomy was more efficient and better cleared LPOs. Necrosectomy + VAC improved erythrocyte membrane fluidity and increased survival. PMID- 25544408 TI - Value of a step-up diagnosis plan: CRP and CT-scan to diagnose and manage postoperative complications after major abdominal surgery. AB - Postoperative complications frequently follow major abdominal surgery and are associated with increased morbidity and mortality. Early diagnosis and treatment of complications is associated with improved patient outcome. In this study we assessed the value of a step-up diagnosis plan by C-reactive protein and CT-scan (computed tomography-scan) imaging for detection of postoperative complications following major abdominal surgery.An observational cohort study was conducted of 399 consecutivepatients undergoing major abdominal surgery between January 2009 and January 2011. Indication for operation, type of surgery, postoperative morbidity, complications according to the Clavien-Dindo classification and mortality were recorded. Clinical parameters were recorded until 14 days postoperatively or until discharge. Regular C-reactive protein (CPR) measurements in peripheral blood and on indication -enhanced CT-scans were performed.Eighty three out of 399 (20.6 %) patients developed a major complication in the postoperative course after a median of seven days (IQR 4-9 days). One hundred and thirty two patients received additional examination consisting of enhanced CT scan imaging, and treatment by surgical reintervention or intensive care observation. CRP levels were significantly higher in patients with postoperative complications. On the second postoperative dayCRP levels were on average 197.4 mg/L in the uncomplicated group, 220.9 mg/L in patients with a minor complication and 280.1 mg/L in patients with major complications (p < 0,001).CT-scan imaging showed a sensitivity of 91.7 % and specificity of 100 % in diagnosis of major complications. Based on clinical deterioration and the increase of CRP, an additional enhanced CT-scan offered clear discrimination between patients with major abdominal complications and uncomplicated patients. Adequate treatment could then be accomplished. PMID- 25544409 TI - Insulin resistance and metabolic syndrome are related to non-alcoholic fatty liver disease, but not visceral adiposity index, in severely obese patients. AB - The visceral adiposity index (VAI) is a marker of visceral fat distribution and dysfunction. Visceral adiposity is related to nonalcoholic fatty liver disease (NAFLD); however, there is some controversy regarding the association between VAI and NAFLD.The aim of this study was to analyse the relationship between VAI and NAFLD and to describe the related factors in severely obese patients. A total of 139 patients who underwent bariatric surgery were included in this cross sectional study. Liver biopsy was performed during surgery. Univariate and multivariate analysis were conducted to study the features related to VAI. A univariate analysis was conducted to identify which factors were associated with liver histology. In the univariate analysis, steatosis, liver inflammation, non alcoholic steatohepatitis (NASH) and fibrosis were associated with VAI. In the multivariate analysis, only HOMA (Beta: 0.06; p < 0.01) and metabolic syndrome (Beta: 1.23; p < 0.01) were related to VAI. HOMA, the presence of metabolic syndrome, and waist circumference (WC) were statistically related to the NAFLD activity score (NAS score): HOMA: 0-2: 5.04; 3-4: 7.83; > or = 5: 11,32; p < 0.01; MS: 0-2: 37 %; 3-4: 33.3 %; > or = 5: 76%; p < 0.01; WC: 0-2: 128.7 cm; 3 4: 130.7; > or = 5: 140.6; p < 0.01). For the prediction of NASH (NAS score > or = 5), the AUROC curve were 0.71 (CI 95 %: 0.63-0.79) for VAI and 0.7 (CI 95 %: 0.62-0.78) for WC. In conclusion, HOMA, WC and metabolic syndrome are related to liver histology in patients with severe obesity. In the multivariate analysis, VAI was associated with HOMA and metabolic syndrome, but not with liver histology. PMID- 25544410 TI - Percutaneous endoscopic gastrostomy: An update on its indications, management, complications, and care. AB - BACKGROUND: Numerous disorders impairing or diminishing a patient's ability to swallow may benefit from a PEG tube placement. This is considered the elective feeding technique if a functional digestive system is present. METHODS: A PubMed based search restricted to the English literature from the last 20 years was conducted. References in the results were also reviewed to identify potential sources of information. RESULTS: PEG feeding has consistently demonstrated to be more effective and safe than nasogastric tube feeding, having also replaced surgical and radiological gastrostomy techniques for long term feeding. PEG is considered a minimally invasive procedure to ensure an adequate source for enteral nutrition in institutionalized and at home patients. Acute and chronic conditions associated with risk of malnutrition and dysphagia benefit from PEG placement: Beyond degenerative neuro-muscular disorders, an increasing body of evidence supports the advantages of PEG tubes in patients with head and neck cancer and in a wide range of situations in pediatric settings.The safety of PEG placement under antithrombotic medication is discussed. While antibiotic prophylaxis reduces peristomal wound infection rates, co-trimoxazole solutions administered through a newly inserted catheter constitutes an alternative to intravenous antibiotics. Early feeding (3-6 hours) after PEG placement firmly supports on safety evidences, additionally resulting in reduced costs and hospital stays. Complications of PEG are rare and the majority prevented with appropriated nursing cares. CONCLUSIONS: PEG feeding provides the most valuable access for nutrition in patients with a functional gastrointestinal system. Its high effectiveness, safety and reduced cost underlie increasing worldwide popularity. PMID- 25544411 TI - Usefulness of Tc-99m labelled heat-denatured red blood cell scintigraphy for diagnosis of peritoneal splenosis in a patient with hepatocellular cancer: A case report. PMID- 25544412 TI - Necrotic left colitis due to hot water enema. PMID- 25544413 TI - LPAC syndrome associated with deletion of the full exon 4 in a ABCB4 genetic mutation in a patient with hepatitis C. AB - Low-phospholipid-associated cholelithiasis syndrome (LPAC) is associated with ABCB4 genetic mutation. ABCB4 encodes MDR3 protein, involved in biliary phosphatidylcholine excretion.Higher prevalence in women, biliary symptoms in young adults and ursodesoxycholic acid (UDCA) response are the main features. We report the case of a 48-year-old man with hepatitis C, genotype 1b, fibrosis F3, null responder to Peg-IFN-alpha-2b/ribavirin and nephritic colic. In 2011 he developed jaundice, pruritus and epigastric pain.He showed increased serum levels of AST, ALT, GGT, bilirubin and alpha-fetoprotein, and viral load (14,600,000 IU/mL). Pancreatic- CT, endoscopic ultrasonography and echo-Doppler showed noncirrhotic chronic liver disease. The episode resolved spontaneously and one year later he suffered a similar episode. UDCA was started with excellent response. An immunohistochemistry study and sequencing of ABCB4 did not find alteration. MLPA(r) technique detected heterozygous deletion of the full exon 4 confirming LPAC syndrome diagnosis. PMID- 25544414 TI - Peritoneal tuberculosis. Radiographic diagnosis. AB - Peritoneal tuberculosis (TB) is an extrapulmonary form of presentation of tuberculosis. HIV infection is a primary risk factor for this condition. Diagnosis requires microbiological or histopathological confirmation in addition to supporting radiological imaging studies. Abdominal ultrasonography and CT are useful to obtain a radiographic diagnosis, with typical findings including diffuse peritoneal thickening, presence of ascites in varying volumes, adenopathies, and caseating nodes. We report 2 cases of patients with ascites and nodular peritoneal thickening on diagnostic images, as well as high CA-125 levels in laboratory tests. In both patients, a diagnosis of peritoneal tuberculosis was reached following a US-guided peritoneal biopsy. PMID- 25544415 TI - Three cases of liver toxicity with a dietary supplement intended to stop hair loss. AB - Liver toxicity associated with herbal remedies and dietary supplements is an increasing concern. Several toxic hepatitis cases have been reported in the literature in association with products intended for weight loss where green tea extracts are an ingredient.Three hepatotoxicity cases are reported below in association with the use of Inneov masa capilar(r), a dietary supplement intended to stop hair loss whose primary component is green tea catechins. In all of them, other potential causes of acute hepatitis were ruled out.We highlight the importance of awareness regarding these substances at history taking in order to identify and report hepatic adverse reactions secondary to apparently safe herbs as described in the present manuscript. PMID- 25544416 TI - [Foreign bodies of the upper gastrointestinal tract]. PMID- 25544417 TI - Ectopic pancreas as a rare cause of obstructive jaundice. PMID- 25544418 TI - Neuroendocrine carcinoma of the common bile duct. PMID- 25544419 TI - Carcinoid tumor of the common bile duct. PMID- 25544420 TI - Absence of HLA-DQ2 and HLA-DQ8 does not exclude celiac disease in Brazilian patients. PMID- 25544421 TI - Dermatitis herpetiformis in Brazilan male celiac disease patients: A case series. PMID- 25544422 TI - Tetany and convulsions: Onset symptoms in Crohn's disease. PMID- 25544425 TI - International note: awareness and context of cyber-harassment among secondary school students in Oyo state, Nigeria. AB - We determined the awareness and context of cyber-harassment among secondary school students (653 survey respondents and 18 in-depth interviewees) in Oyo state, Nigeria. Respondents' mean age was 14.2 +/- 2.2 years and 53.9% were aware of cyber-harassment occurring in their school or among their friends. Cyber harassment was often perpetrated via phone calls (62.5%), text messaging (36.9%), chat rooms (28.7%), through pictures or video clips sent via mobile phones (11.9%), emails (6.8%) or websites (5.9%). Cyber-harassment behaviours mentioned were the use of abusive words (25.4%), saying mean things or making fun of the victim (13.9%), solicitations for relationships (7.9%) or sex (6.8%) and spreading rumours about the victim (6.8%). In-depth interviewees recounted experiences of cyber-harassment suffered by their friends. Many were relationship related, sexual solicitations and threats and corroborated quantitative findings. Respondents are aware of cyber-harassment occurring among students in the study area. Comprehensive interventions to address the problem need to be instituted. PMID- 25544426 TI - Is co-ruminating with friends related to health problems in victimized adolescents? AB - Co-rumination, or the tendency to revisit and endlessly discuss problems and negative events, has been linked to depression and other emotional difficulties (Rose, Carson, & Waller, 2007). The current study examined the moderating effect of co-rumination on the relationship between peer victimization and depression, anxiety, PTSD symptoms, and health problems in 108 adolescents aged 10-15 years. Adolescents and a parent completed measures of adolescents' peer victimization, co-rumination, depression, and health problems. Results indicate that adolescents who are both peer victimized and engaged in high levels of co-rumination were at highest risk for psychological problems. Co-rumination also moderated the relationship between peer victimization and physical health problems via general depressive symptoms (i.e., moderated mediation). PMID- 25544427 TI - Inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resistance in ovarian cancer cells. AB - Ovarian cancer is the number one cause of death from gynaecological malignancy. Platinum-based and taxol-based chemotherapy has been used as a standard therapy, but intrinsic and acquired resistance to chemotherapy is a major obstacle to treat the disease. In the present study, we found that in the chemoresistant ovarian cancer SKOV3/TR cells, interleukin-6 (IL-6), IL-6 receptor and signal transducers and activators of transcription 3 (STAT3) expression as well as STAT3 phosphorylation were upregulated compared to those in parental cells. Silencing of IL-6 using IL-6 siRNA was found to suppress IL-6 production, STAT3 and phosphoSTAT3 levels, which eventually reduced proliferation and clonogenicity of taxol-resistant SKOV3/TR cells. In addition, stattic, a STAT3 inhibitor, was found to result in decrease of cell viability and clonogenicity of these cells, indicating that the elevated IL-6 and STAT3, phosphoSTAT3 levels are associated with the development of taxol resistance. Next, we found anti-proliferative effect of apigenin on both SKOV3 and SKOV3/TR cells. RT-PCR and western blot results showed that apigenin significantly reduced the expression of Axl and Tyro3 receptor tyrosine kinases (RTKs) at mRNA and protein level, which account for its cytotoxic activity. We further found that apigenin decreased Akt phosphorylation and the level of B-cell lymphoma-extra large (Bcl-xl or BCL2-like 1 isoform 1), an inhibitor of apoptosis. On the contrary to these results, apigenin had no effect on IL-6 production, STAT3 and phosphoSTAT3 protein levels, suggesting that apigenin exerts its anti-proliferative activity via downregulation of Axl and Tyro3 expression, Akt phosphorylation and Bcl-xl expression, but not modulation of IL-6/STAT3 axis. Taken together, our data suggest that inhibition of IL-6/STAT3 signaling pathway and downregulation of Axl and Tyro3 RTKs expression might be a therapeutic strategy to overcome taxol resistance in ovarian cancer cells. PMID- 25544428 TI - Promoting Shared Decision Making to strengthen outcome of young children with Autism Spectrum Disorders: the role of staff competence. AB - Little is known on how the conceptual description of Shared Decision Making (SDM) accomplishes clinical practice in the context of lifetime disabilities as in particular Autism Spectrum Disorders (ASD), when intervention is long-lasting and requires constant family involvement. This study aimed mainly to investigate to what extent the staff's competence in SDM contributes to positive child and parent improvement when involving parents in Early Intensive Behavior Interventions (EIBI). It was also geared to verify whether SDM staff competence contributes to a child's treatment responsiveness. A total of 25 young children with ASD (23 male, 3 female, age range 34-92 months, mean age 51.4+/-13.6) were included in the study. Of these, nine children were allocated to a Parent Involvement condition accompanied by SDM Staff Training (PI-SDM), and eight children to a Parent Inclusion in Treatment Delivery Only condition without SDM Staff Training (PI-DO). Nine months treatment outcomes of severity, developmental and adaptive measures were compared to Treatment As Usual (n=8). PI-SDM was associated with improvement of autistic symptoms (p<=.05), adaptive functioning (p<=.01) and developmental outcome (p<=.01), as well as parent (p<=.05) and staff competence (p<=.001). The magnitude of outcome was inferior in the PI-PO and TAU group. A Reliable Change was identified in more than 40% of children included in PI-SDM, while PI-PO (>20%) and TAU (>12%) let to little Reliable Change and partially skill deterioration. Staff's SDM skill competence predicts reduced parental stress (beta=-.500, p<=.05) and contributes significantly to a positive treatment responder trajectory (p<=.01), besides lower severity (p<=.05), higher adaptive (p<=.01) and communication skills (p<=.05). The study indicates that parent inclusion should be conceptualized as a collaborative partnership model rather than as adherence in treatment provision, based on a target SDM staff training that may constitute an external contributor to treatment responsiveness and positive child as well as parent outcome. PMID- 25544429 TI - Erratum. AB - [This corrects the article on p. 166 in vol. 4, PMID: 25215193.]. PMID- 25544430 TI - Review of the genus Eotilla Schuster, 1949 (Hymenoptera: Bradynobaenidae: Typhoctinae: Eotillini) and description of new species from Argentina. AB - Diagnoses for the genus Eotilla Schuster, 1949 based on males and females, new generic and specific characters, descriptions of two new Argentinian species (Eotilla schusteri Torrens, Fidalgo, Roig-Alsina & Brothers, sp. nov. and E. medanito Torrens, Fidalgo, Roig-Alsina & Brothers, sp. nov., based on both sexes), a description of the female of E. superba Brothers, 1974 and redescriptions of the males of E. mickeli Schuster, 1949 and E. superba are provided. A key to the species of Eotilla is presented. PMID- 25544431 TI - A new species of Eumops (Chiroptera: Molossidae) from southwestern Peru. AB - The genus Eumops is the most diverse genera of molossid bats in the Neotropics. In Peru this genus is widely distributed and represented by nine species: E. auripendulus, E. delticus, E. hansae, E. maurus, E. nanus, E. patagonicus, E. perotis, E. trumbulli, and E. wilsoni. After several years of mammalian diversity surveys in the coastal desert and western slopes of southwestern Peru, a specimen of Eumops was collected whose unique set of traits allows us to assert that deserves to be described as a new species. Based on molecular and morphological evidence, the new species is related to medium-large sized species (i.e. E. glaucinus, E. auripendulus, and E. perotis). Cytochrome b genetic divergence between the new species and the other species of the genus was high (> 12%) and it is consistent with morphological divergence presented for this new species. This new species, endemic to Peru, increases the diversity of Eumops to 16 species. PMID- 25544432 TI - A new phasmid gecko (Squamata: Diplodactylidae: Strophurus) from the Arnhem Plateau: more new diversity in rare vertebrates from northern Australia. AB - The Arnhem Plateau is a rugged expanse of sandstone escarpment in the Australian Monsoonal Tropics with a highly endemic biota. Here we describe a new species of small spinifex dwelling Strophurus (phasmid gecko) that also appears to be endemic to this region. Strophurus horneri sp. nov. can be diagnosed from all congeners by aspects of size, coloration and scalation. Even with the description of this new species, however, levels of morphological and genetic diversity within Strophurus from the stone country of the Northern Territory suggest additional divergent lineages are present. A number of recent studies have now provided preliminary evidence of evolutionary diversity within the Arnhem Plateau, but data remains scant and almost nothing is known about how topography and historical processes have shaped the endemic biota of this region. PMID- 25544433 TI - Contributions to the genus Ulonemia Drake and Poor (Hemiptera: Heteroptera: Tingidae) from China, with descriptions of three new species. AB - The genus Ulonemia Drake and Poor, 1937 from China is treated. Three species are described as new to science, namely Ulonemia jingae sp. nov., U. angusta sp. nov., and U. magna sp. nov., as well as a redescription of the known species U. assamensis (Distant, 1903a). Illustrations of habitus and diagnostic characters of these species are provided, together with a key to the species of Ulonemia occurring in the Oriental region. PMID- 25544434 TI - Description of female nymphal instars and adult female of Kermes echinatus Balachowsky (Hemiptera, Coccoidea, Kermesidae) based on specimens from Crete and mainland Greece, with a discussion on geographical variation. AB - The first-instar nymph, second- and third-instar female nymphs and the adult female of Kermes echinatus Balachowsky (Hemiptera, Coccoidea, Kermesidae) are described and illustrated; micrographs of morphological details are also provided. The species was collected on the island of Crete (Greece) and on mainland Greece, new localities for this species, and are compared with Israeli specimens from where it was originally described. PMID- 25544435 TI - Five new species of Hypseloecus Reuter (Hemiptera: Miridae) on hemiparasitic Santalales from India. AB - Five new species of Hypseloecus viz., Hypseloecus acutus sp. nov., Hypseloecus articulatus sp. nov., Hypseloecus belli sp. nov., Hypseloecus orientale sp. nov. and Hypseloecus spinosus sp. nov. are described from India. The genus is recorded for the first time from India collected on hemiparasitic plants of the genera Dendrophthoe and Viscum (Santalales). A key to identification of the five species has been provided with descriptions of the male genital structures, digital microscopic images and also photographic images of live individuals. PMID- 25544436 TI - Taxonomic revision of Calamister Kirkaldy, 1906 (Fulgoromorpha: Cixiidae) with the description of a new species. AB - Calamister obscurus Kirkaldy, 1906 is redescribed, illustrated and a lectotype designated from the type series. A new species, C. cougalensis, is added to the genus. An identification key is provided and morphological characters discussed. Doubts are raised about a specimen published as C. obscurus by Jacobi (1928). PMID- 25544437 TI - Key to species of the leafhopper genus Membranacea Qin & Zhang (Hemiptera, Cicadellidae, Typhlocybinae, Empoascini), with a new species from China. AB - A new species Membranacea distincta sp. nov. is described and illustrated from China. A key, based on the male genitalia, is given to separate all six species of the genus. The type specimens of the new species are deposited in the Institute of Entomology, Guizhou University, Guiyang, China (GUGC). PMID- 25544438 TI - Redescriptions of six species of Ilyodromus Sars, 1894 (Crustacea, Ostracoda, Cyprididae) from New Zealand and Eastern Australia. AB - In this paper, we redescribe six species of the genus Ilyodromus Sars, 1894: I, stanleyanus (King, 1855), I. varrovillius (King, 1855), I. smaragdinus Sars, 1894, I. obtusus Sars, 1894, I. substriatus Sars, 1894 and I. viridulus (Brady, 1886) using materials stored in the Oslo museum (Norway) and (re-) described by G.O. Sars. For each species examined, we have identified a number of additional diagnostic characters to those used by Sars and earlier authors. In particular, the length of setae, claws and segments of the antennule, antenna, sixth limb, and caudal ramus appear to be important for species delineation in the genus, as does the internal structure of the valves. PMID- 25544439 TI - The host plants of the Telamonini treehoppers (Hemiptera: Membracidae: Smiliinae) and the first diagnoses of nymphs for 14 species. AB - Recent research on the treehopper tribe Telamonini has focused on their classification and Nearctic distribution but little has been published on their biology, including detailed information on their host plants as well as data on their nymphal stage. Any studies including host plant data have emphasized adult records (often unreliable due to their movements), largely ignoring the nymphs, which are the predominant feeding stage. This work provides the first comprehensive summary of Telamonini host plants, it documents the first positive identification of the nymphs for several telamonine species (and the genus Helonica), and it provides the first morphological diagnoses for 14 species, thus filling in major gaps in the life history of many species. Host plant records were determined based on accounts in the literature (adults and nymphs), from rearings of nymphs on host plants to the adult stage, and from label data on museum specimens. The Telamonini are known from 22 families, 41 genera, and 80 species of mostly woody, deciduous trees (of which, six species are new host plant records). Nearly half of all telamonines have been collected from more than one plant genus and only 12 species are known from a single host plant species. Telamonine nymphs were reared to the adult stage on 15 plant species. Of 68 telamonine species, 45 have been found on oak (Quercus), and white oak (Q. alba) is the most common telamonine host plant. Telamona monticola has the most recorded host plants with 29. The work includes 23 color illustrations showing both live and preserved nymphs, representing 15 species, all illustrated for the first time (eight are positively identified for the first time). Differences in nymphal morphology among species within Archasia, Glossonotus, Heliria, and Telamona suggest current generic definitions need revision. This study highlights the need for an increased emphasis on nymphal collections when determining treehopper host plants and inferring classifications. PMID- 25544440 TI - Foa yamba, a new species of cardinalfish (Percomorpha: Apogonidae: Apogonichthyini) from the tidal region of the Clarence River, Australia and redescriptions of the West Pacific Foa longimana and Foa hyalina. AB - Foa yamba, a new species is described from an eastern Australian tidal estuary. This species differs from other West Pacific Foa by having many small spots on the body. Foa longimana, known only from the holotype, is presently an unidentifiable larval stage from Indonesia and is redescribed, but not allocated to a different genus. Foa hyalina, a West Pacific species is reviewed and its known distribution expanded. It is distinguished by five reddish or brownish-red bars on the body from nape to the level of middle portion of the second dorsal fin and lacks markings on caudal fin. PMID- 25544441 TI - Description of Dirrhagofarsus ernae n. sp. with a key to the known Dirrhagofarsus species (Coleoptera: Eucnemidae). AB - The adult and the larva of Dirrhagofarsus ernae n. sp. are described from the Eastern United States. The genus Dirrhagofarsus is diagnosed and a key to all known species of the genus is provided. PMID- 25544442 TI - First record of the caridean shrimp genus Bresilia Calman, 1896 (Crustacea: Decapoda: Bresiliidae) from the East Pacific and description of a new species. AB - A new species of Bresilia Calman, 1896, representing the first record of this genus for the East Pacific, is described from deep water off the Pacific coast of Mexico. The new species is close to B. atlantica Calman, 1896, the type species of the genus with which it shares the general shape of the carapace and rostrum, the latter with a reduced number of small dorsal teeth, and the shape and relative size of the first pereiopod. It also shares with B. atlantica a similar antennular peduncle and a distally very wide scaphocerite. The first maxilliped has a long crescent-shaped exopod, without a flagellum and a strongly reduced caridean lobe, two characters found in B. atlantica and in only one other known species of Bresilia, i.e., B. corsicana Forest & Cals, 1977. The new species can be distinguished from the other seven species of Bresilia by the armature of the rostrum (few, very small spines) and a much wider scaphocerite, with an anterior margin twice as wide as the proximal margin. PMID- 25544443 TI - A new species of Xylota Meigen (Diptera: Syrphidae) from the Far East. AB - Xylota danieli Mutin & Ichige spec. nov. is proposed as the new name for Xylota amamiensis Shiraki sensu Mutin & Gilbert (1999), from the Russian Far East and Japan, which is described and figured. New synonymy is proposed for Xylota coquilletti Herve-Bazin, 1914 (= X. coquilletti amamiensis Shiraki, 1968 syn. nov.; = X. vulgaris Yang & Cheng in Cheng & Yang, 1993 syn. nov.). PMID- 25544444 TI - The bees of the genus Colletes Latreille 1802 of the European part of Russia, with keys to species (Hymenoptera: Apoidea: Colletidae). AB - For the European part of Russia 30 species of the bee genus Colletes are recorded. Colletes subnitens Noskiewicz 1936, C. wacki Kuhlmann 2002 and C. warnckei Kuhlmann 2002 were found in Russia for the first time and C. kozlovi Friese 1913 is newly recorded from the European part of Russia. For Colletes kozlovi, C. subnitens and C. wacki this is the first record for Europe. The female of C. subnitens Noskiewicz is here described for the first time. Illustrated keys to males and females of all species known from European part of Russia are provided. PMID- 25544445 TI - Description of a new genus and species of Cerophytidae (Coleoptera: Elateroidea) from Africa with a cladistic analysis of the family. AB - The family Cerophytidae is revised to include Afrocerophytum vix gen. nov. and sp. nov., from the tropical rainforest of western Africa. Afrocerophytum and A. vix (type locality: Ivory Coast, Tai Region, neighborhood of Gouleako village) are described and illustrated. A key to the Cerophytidae genera is provided. The new genus is distinguished by four autapomorphies: anterior edge of phallobase rounded and not emarginate, base of tergite IX not fused at middle with the base of sternite IX, basal region of penis weakly constricted, and coxites divided into proximal and distal lobes. A cladistic analysis was conducted including all 22 species of known Cerophytidae and using representatives of the families Eucnemidae, Throscidae, Brachypsectridae and Elateridae as outgroups. The strict consensus cladogram produced from the resulting eighteen most parsimonious trees is (Cerophytum (Afrocerophytum (Brachycerophytum, Phytocerum))). Cerophytum, the Holarctic clade, is the sister group of the Gondwanian clade (Afrocerophytum (Brachycerophytum, Phytocerum)); the Ethiopian clade Afrocerophytum is the sister group of the Neotropical clade (Brachycerophytum, Phytocerum). PMID- 25544446 TI - Ulyxes, a new Australopapuan mite genus associated with arboreal nests (Acari: Laelapidae). AB - As part of a survey of mammal and bird nests, new species, new male stages, and some feeding observations have been collected from what was formerly called the Androlaelaps ulysses group. As many features of this group are consistently different from Androlaelaps, and also from Haemolaelaps where it was formerly placed, this group is here elevated to Ulyxes new genus, and U. autolycus, U. euryclea, and U. theoclymenus are described as new species. This genus has a broad range of feeding behaviour spanning intranasal parasitism, nidicolous parasitism, and at least one species is a nidicolous predator. Its host range is broad; two new species are shown here to cohabit with parrots while most remaining species associate with mammals. In contrast to the variation in feeding behaviour, Ulyxes spp are associated with a narrow range of nest types, being confined to arboreal nests, usually tree hollows (rarely fallen logs), and on the parrot or mammal hosts that use them. Ulyxes spp show a remarkable variability in male cheliceral development, which assorts according to feeding behaviour. There is a strong contrast between male chelicerae of predatory and parasitic species that has not been previously observed in such a compact dermanyssine genus. Previously male cheliceral morphology was thought to be conservative enough to provide diagnostic characters at suprageneric rank. For systematics, these findings complicate previous attempts to recognise male mouthparts as reliable features marking higher-level natural groups that include dermanyssoid vertebrate parasites. For evolutionary studies, this may be relevant in seeking examples of transitions to, or away from, parasitism. PMID- 25544447 TI - A new combination for the bembicine genus Selman Parker, 1929 (Hymenoptera: Crabronidae). AB - The identity of Monedula diana Handlirsch, 1890 is reassessed and the species is transferred to the monotypic genus Selman, which now includes two species, S. diana n. comb. and S. notatus (Taschenberg, 1870). The main differences between the two species are presented. Photographs of the holotype of Monedula diana are provided and its putative type locality is discussed. Also new distribution records are provided for S. notatus. PMID- 25544448 TI - First record of the Genus Lichnofugia from India with description of a new species (Orthoptera: Tettigoniidae; Conocephalinae; Agraeciini; Liarina). AB - The genus Lichnofugia is reported for the first time from India with a description of Lichnofugia umshingensis sp. nov. from Shillong, Meghalaya. The distribution of Lichnofugia thus extends eastward from Peninsular Malaysia and Thailand to north- eastern India. PMID- 25544449 TI - A revision of the Annulariidae of Central America (Gastropoda: Littorinoidea). AB - Twenty annulariid taxa are reviewed from Central America, including three new species and one new genus. One species is regarded as an incertae sedis and two as mislabeled lots of Cuban origin. Many species are highly endemic. Although not speciose, Central America has a high diversity of conchological forms and may represent the ancestral source of annulariids in general. PMID- 25544450 TI - Mitochondrial DNA reveals a new species of parachuting frog (Rhacophoridae: Rhacophorus) from Sumatra. AB - The Indonesian island of Sumatra contains several endemic species of parachuting frog of the genus Rhacophorus. Most of these are known from small type series collected from only a few localities, and consequently, many Sumatran Rhacophorus species are poorly understood. Using mitochondrial DNA (mtDNA), we investigated relationships among a group of Rhacophorus species from southern Sumatra. Our molecular analysis was based on a fragment of the 16S ribosomal subunit gene (16S) and included data derived from type specimens of two species endemic to Sumatra: R. barisani and R. catamitus. Our analyses of these data reveal that the only known female specimen of R. catamitus possesses a divergent 16S sequence compared to male specimens (8.82%; uncorrected "p" distance). Based on phylogenetic reconstructions, we found that this female specimen belongs to an unnamed taxon related to R. margaritifer from Java. Consequently, we remove the specimen from R. catamitus and describe it as R. bengkuluensis sp. nov., a medium sized slender tree frog with extensive brown hand webbing. We identified additional specimens referable to the new species using mtDNA and morphology. These specimens originate from low to intermediate elevations (ca. 600-1600 m) in the provinces of Bengkulu and Lampung, suggesting that R. bengkuluenis is widely distributed across the southwestern versant of the Bukit Barisan. PMID- 25544451 TI - New psallopinous plant bugs (Hemiptera: Heteroptera, Miridae, Psallopinae) from the New Hebrides and Nigeria. AB - The paper presents descriptions and illustrations of two new species from the genus Psallops: P. schmitzi from New Hebridae and P. webbi from Nigeria. Photographs and line drawings general habitus and male genitalia are provided. A short review of the subfamily Psallopinae and two other related subfamilies Isometopinae and Cylapinae is given. PMID- 25544452 TI - A new species of Forcipomyia (Microhelea) Meigen (Insecta: Diptera: Ceratopogonidae) from the Neotropical region. AB - We describe and illustrate a new species of biting midge belonging to the subgenus Forcipomyia (Microhelea), from the Estacao Biologica de Boraceia, Sao Paulo State, Brazil. We include illustrations of the mouthparts, head, thorax, legs, abdominal setae, and habitus. The new species is similar to the few other recorded Neotropical species of biting midges, such as Forcipomyia (Microhelea) alleni, Forcipomyia (Microhelea) castneri, Forcipomyia (Microhelea) grandcolasi, and Forcipomyia (Microhelea) tettigonaris. However, it can be distinguished by the combination of external characters, such as the number of plates on the maxilla, the number of denticles on the mandible, the size of the labellum, and the morphology of the palpus. The two female specimens examined were found biting on a female stick bug, Paraphasma paulense (Phasmida: Pseudophasmatidae), which was attracted to a light trap. PMID- 25544453 TI - Nomenclature and taxonomy of Telmatoscopus Eaton and Seoda Enderlein; with a discussion of parameral evolution in Paramormiini and Pericomaini (Diptera: Psychodidae, Psychodinae). AB - Historically, Telmatoscopus Eaton, 1904 has been a nomenclaturally and taxonomically problematic taxon as different authors have used different type species to define their concepts of the genus. Here it is shown that Pericoma advena Eaton, 1893 is the valid type species rather than Pericoma morula Eaton, 1893. Furthermore, the genus Seoda Enderlein, 1935 is revived for the genus comprising Pericoma labeculosa Eaton, 1893, P. morula and their relatives. The differences between Telmatoscopus and Seoda are described in detail based on historical and freshly collected material of the three putative type species. Four new synonymies are proposed: Panimerus havelkai Wagner, 1975 and Telmatoscopus seguyi Vaillant, 1990 are synonymized with Telmatoscopus advena, and Telmatoscopus incanus Nielsen, 1964 and Telmatoscopus vaillanti Withers, 1986 are synonymized with Seoda morula. A potential phylogenetic pattern in the male genital sclerites is discussed in detail. In Telmatoscopus, the jointed appendages of the gonocoxally derived parameral complex are separate small sclerites found near the bases of the distiphallic lobes of the aedeagus. In Seoda, they are fused medially to form a small, moveable triangular or arrow shaped sclerite. Medial parameral sclerite fusion in Psychodinae is otherwise known to occur only in Pericomaini and the paramormiine genus Psychomasina Jezek, 2004; however, many genera of Paramormiini show an apparently intermediate condition where the parameres are fused in one end to form a V- or U-shaped "furca". It is hypothesized that Paramormiini is paraphyletic with respect to Pericomaini, as suggested in a previous phylogenetic hypothesis based on molecular data. PMID- 25544454 TI - Deep-water sponges (Porifera) from Bonaire and Klein Curacao, Southern Caribbean. AB - Four submersible dives off the coast of Bonaire (Caribbean Netherlands) and Klein Curacao (Curacao) to depths of 99.5-242 m, covering lower mesophotic and upper dysphotic zones, yielded 52 sponge specimens belonging to 31 species. Among these we identified 13 species as new to science. These are Plakinastrella stinapa n. sp., Pachastrella pacoi n. sp., Characella pachastrelloides n. sp., Geodia curacaoensis n. sp., Caminus carmabi n. sp., Discodermia adhaerens n. sp., Clathria (Microciona) acarnoides n. sp., Antho (Acarnia) pellita n. sp., Parahigginsia strongylifera n. sp., Calyx magnoculata n. sp., Neopetrosia dutchi n. sp., Neopetrosia ovata n. sp. and Neopetrosia eurystomata n. sp. We also report an euretid hexactinellid, which belongs to the rare genus Verrucocoeloidea, recently described (2014) as V. liberatorii Reiswig & Dohrmann. The remaining 18 already known species are all illustrated by photos of the habit, either in situ or 'on deck', but only briefly characterized in an annotated table to confirm their occurrence in the Southern Caribbean. The habitat investigated-steep limestone rocks, likely representing Pleistocene fossil reefs--is similar to deep-water fossil reefs at Barbados of which the sponges were sampled and studied by Van Soest and Stentoft (1988). A comparison is made between the two localities, showing a high degree of similarity in sponge composition: 53% of the present Bonaire-Klein Curacao species were also retrieved at Barbados. At the level of higher taxa (genera, families) Bonaire-Klein Curacao shared approximately 80% of its lower mesophotic and upper dysphotic sponge fauna with Barbados, despite a distance between them of 1000 km, indicating high faunal homogeneity. We also preliminarily compared the shallow-water (euphotic) sponge fauna of Curacao with the combined data available for the Barbados, Bonaire and Klein Curacao mesophotic and upper dysphotic sponges, which resulted in the conclusion that the two faunas show only little overlap. PMID- 25544455 TI - Grimaldinia pronotalis n.gen., n.sp. from Mid-Cretaceous Burmese Amber (Hemiptera: Heteroptera, Leptopodidae, Leptosaldinae). AB - A new genus and species of leptopodid bug, Grimaldinia pronotalis Popov & Heiss is described and illustrated from Burmese Middle Cretaceous (Albian-Cenomanian) amber originating from the northern Myanmar's Kachin State. This is the second finding of Leptosaldinae (Leptopodidae), after Poinar published on Palaeoleptus burmanicus from Burmese amber in 2009. PMID- 25544456 TI - Two new species of Martintella Artigas, 1996 (Diptera, Asilidae, Asilinae) from Costa Rica. AB - Two new species of Martintella Artigas, 1996, Martintella aurata sp. nov. and Martintella fernandoi sp. nov., from Costa Rica are described and illustrations of species of the genus are provided. PMID- 25544457 TI - New archaeorthopteran insects from the Late Carboniferous of the Nord and Pas-de Calais basins in northern France (Insecta: Cnemidolestodea, Panorthoptera). AB - New polyneopteran insects are described from Pennsylvanian (Bashkirian, Moscovian) compressed fossils from the North of France (Insecta: Archaeorthoptera). Discovery of wing apex with distinct venation, e.g., apical fusion of RA with RP, numerous parallel posterior branches of RP with transversal crossveins, can be assigned to cf. Tococladus sp. (Cnemidolestodea: Tococladidae). It represents the second record of Cnemidolestodea from the Avion locality apart from Aviocladus pectinatus Prokop et al., 2014. Bruaylogus magnificus gen. et sp. nov., based on forewing venation, is attributed to Panorthoptera nec Orthoptera having some distinct characters for the placement either close to Oedischiidae or a more basal position possibly with affinities to genus Heterologus. Aviologus duquesnei gen. et sp. nov., based on forewing venation, differs from Oedischiidae by the presence of basal fork of M far from point of separation between M and Cu and fusion of MA with first posterior branch of RP. Aviologus share a long stem of M and simple CuPabeta with Heterologus duyiwuer and H. langfordorum, but both differ in well separated median and radial veins. These new fossils demonstrate that the archaeorthopterid insect fauna from the North of France was rather diverse with links to late Carboniferous and early Permian assemblages in Euramerica such as the Mazon Creek, Carbondale Formation or Elmo, Wellington Formation (Illinois, Kansas, USA) entomofaunas. PMID- 25544458 TI - Incisitermes nishimurai, a new drywood termite species (Isoptera: Kalotermitidae) from the highlands of Central America. AB - Incisitermes nishimurai is described from soldiers and winged imagos collected in the highlands of Honduras. It is distinguished from all other Incisitermes species by the dark rugosity of the soldier frons and by the rather large, uniformly very dark, imago. PMID- 25544459 TI - Somatochlora shennong sp. nov. from Hubei, China (Odonata: Corduliidae). AB - A new species, Somatochlora shennong sp. nov. (holotype ?, Dajiuhu National Wetland Park in Shennongjia National Nature Reserve, Hubei Province, China, 9 August 2012) is described, illustrated, and compared with the related species S. dido Needham and S. taiwana Inoue & Yokota. PMID- 25544460 TI - A new species of freshwater crab of the genus Sodhiana Yeo & Ng, 2012 (Decapoda: Brachyura: Gecarcinucidae) from southern Iran. AB - A new species of freshwater crab, Sodhiana iranica n. sp. (Decapoda: Brachyura: Gecarcinucidae), is described from Bastak, Iran. This is fourth species of Sodhiana Yeo & Ng, 2012, described, and is the second one known from Iran. It can be distinguished from congeners by the form of its carapace and the structure of the male first gonopod. PMID- 25544461 TI - A new species of Furculanurida (Collembola: Neanuridae) from Ivory Coast, with comments on related genera. AB - A new species of Pseudachorutinae, Furculanurida emucronata sp. nov., is described from Lamto in the Ivory Coast. It differs from all known Pseudachorutinae species by the presence of a strong lateral tooth on the claw of leg I, and from other species of the genus Furculanurida by the absence of a mucro. It is provisionally assigned to the genus Furculanurida which is redefined accordingly. The heterogeneity of the genus is stressed, and its relationships with Arlesiella, Kenyura, Pseudachorutes and Stachorutes are discussed. PMID- 25544462 TI - The types, publication date, and validity of Nucella elongata Golikov & Kussakin (Mollusca, Ocenebrinae). AB - The name Nucella heyseana var. elongata Golikov & Kussakin, 1962 was proposed for a 'form of uncertain taxonomic level', found in Kunashir and Sakhalin islands. However, this entity was previously recorded as Thais lamellosa (non Gmelin, 1791) (Kussakin 1956: 105-106, 108). In this description, the individual collected from southern shore of Kunashir Island was verbally described in the text and illustrated with a photographic image (Golikov & Kussakin 1962: 312-315, pl. 2, fig. 2c ['v' in Russian]). N. heyseana var. elongata was expressly proposed as an infrasubspecific entity, as a variation of N. heyseana (Dunker, 1882) specific to particular habitats. Therefore it is not an available name according the provisions of International Code of Zoological Nomenclature Articles 45.5 and 45.6.3 (ICZN 1999; hereafter the Code). According to Article 1.3.4 it should be excluded from the species group as not regulated by the Code. In 1974, Golikov & Kussakin described this form as the species Nucella elongata Golikov and Kussakin, 1962, mentioning the same entity (Golikov & Kussakin 1974: 295). This verbal description is identical with their previous text published in 1962, although the new species was not illustrated. However, the same specimen from Kunashir Island was clearly designated as the holotype repeating the same shell measurements and collecting location. In this and following publications N. elongata was reported from Kurile Islands and Sakhalin (Golikov & Kussakin 1978: 190-191, fig. 132; Golikov & Scarlato 1985: 426). In 1978, they repeated their texts dated 1962 and 1974 confirming the same specimen from Kunashir Island as the holotype preserved in Zoological Institute, Russian Academy of Sciences, St. Petersburg (ZIN) collection, although they illustrated different shell (presumably a paratype, which we did not find in ZIN) obtained from southeastern Sakhalin. PMID- 25544463 TI - Synopsis of bakeriella kieffer, 1910 (hymenoptera, bethylidae). AB - Thirty valid species and their junior synonymous were investigated. Neotropical species of Epyrinae were also examined in order to find possible misclassified species of Bakeriella. Diagnoses and illustrations of all valid species are provided. Male genitalia of 14 previously described species are first described and illustrated. The lectotypes of Bakeriella flavicornis Kieffer, 1910 and Epyris montivagus Kieffer, 1910 are designated. The status of Bakeriella lindigi (Kieffer, 1910), stat. resurr. is resurrected from the synonyms of Bakeriella montivaga (Kieffer, 1910). The new synonymy is proposed for Bakeriella polita Evans 1964 =Bakeriella vicina Azevedo & Moreira, 2005, syn. nov.; Bakeriella lindigi Kieffer, 1910 =Epyris bogotensis Kieffer, 1910, syn. nov.; Bakeriella flavicornis Kieffer, 1910 =Bakeriella depressa Kieffer, 1910, syn. nov. Keys to males and females of Bakeriella are also provided. Twelve species had their distribution broadened. PMID- 25544464 TI - Seguenziidae (Gastropoda: Vetigastropoda) from SE Brazil collected by the Marion Dufresne (MD55) expedition . AB - The present work deals with the vetigastropods of the family Seguenziidae collected by the Marion Dufresne (MD55) expedition in SE Brazil, reporting the occurrence of eight species. The following species have their geographical range extended: Ancistrobasis costulata, Carenzia carinata, Carenzia trispinosa, Hadroconus altus, Seguenzia elegans and Seguenzia formosa. Two new species, Halystina umberlee sp. nov. and Seguenzia triteia sp. nov., are described. PMID- 25544465 TI - Revision of Chinese Dilaridae (Insecta: Neuroptera) (Part II): Species of the genus Dilar Rambur from Tibet. AB - Three species of the genus Dilar Rambur, 1838, are recorded and described from Tibet in southwestern China, including Dilar geometroides H. Aspock & U. Aspock, 1968, Dilar harmandi (Navas, 1909), and Dilar tibetanus Yang, 1987, with the former two species recorded in Tibet for the first time. All three species are redescribed. Dilar aspersus Yang, 1988, and Dilar pusillus Yang, 1992, are synonymized with Dilar geometroides Aspock & Aspock, 1968, and Dilar tibetanus Yang, 1987, respectively. A key to the Dilar species from Tibet is provided. PMID- 25544466 TI - Overview and key to the New Zealand Cynipoidea (Hymenoptera). AB - An overview of Cynipoidea (Hymenoptera) in New Zealand is presented with information on families, genera, and when available, species. Notes on their distribution, biology, and a taxonomic key are provided. The New Zealand cynipoid fauna is very poorly known, with only 11 described species, and five genus-only taxa. The fauna is dominated by introduced species; two species have been deliberately introduced as biological control agents, and at least 12 taxa are definitely or probably adventives. Many of these species are widespread and collected from modified and non-native habitats. New generic records of Figitidae for New Zealand include: Xyalaspis (Anacharitinae), Ganaspis, (Eucoilinae), and Thoreauella (Emargininae), all of which are considered adventives. There are no native species of gall forming wasps (Cynipidae) in New Zealand, and only two native species of Figitidae are present: Anacharis zealandica Ashmead, 1900 and Kleidotoma subantarcticana Yoshimoto, 1964. PMID- 25544467 TI - Clathria (Thalysias) (Poecilosclerida: Demospongiae: Porifera) from Brazil:
New species and redescription of Clathria (Thalysias) basiarenacea (Boury Esnault, 1973). AB - The subgenus Clathria (Thalysias) Duchassaing & Michelotti, 1864 has 97 valid species, of which 27 are recorded in the Atlantic Ocean. However, only three species are known from Brazil so far. Here we provide the redescription of Clathria (Thalysias) basiarenacea (Boury- Esnault, 1973), based on the discovery of new characters (additional category of auxiliary styles, and details of spicules), and describe a new species of Clathria (Thalysias) repens sp. nov., that differs from sister species in having a live orange color, a massively encrusting repent growth form with lamellate folds and anastomosed projections, and three categories of structural styles, of which the two auxiliary styles have microspined heads. We also invalidate the record of Clathria (Thalysias) procera (Ridley, 1884) for Brazil. PMID- 25544468 TI - Advertisement call of Dendropsophus studerae (Carvalho-e-Silva, Carvalho-e-Silva and Izecksohn, 2003) (Anura: Hylidae), with new record and geographic distribution extension. AB - The treefrog genus Dendropsophus Fitzinger comprises 95 species, with geographic distribution from northern Argentina and Uruguay north through tropical South and Central America to tropical southern Mexico (Frost 2014). Dendropsophus studerae was included in the D. microcephalus clade by Faivovich et al. (2005), which currently consists of 39 species (Frost 2014). The species that most resembles D. studerae is D. bipunctatus (Spix), as already stated in the original description of the former (Carvalho-e-Silva et al. 2003). Thus far, Dendropsophus studerae was only known from its type locality, in the municipality of Quebrangulo (09o19'08"S, 36o28'16"W), State of Alagoas, northeastern Brazil. The original description of the species also included data on its eggs, tadpole (oral disc and external morphology) and some natural history information of adults and larvae, but its advertisement call remains undescribed. PMID- 25544469 TI - A new species and additional records of Pseudolathra Casey (Coleoptera: Staphylinidae: Paederinae) from southern China. AB - Material of the paederine genus Pseudolathra Casey, 1905 from the Chinese provinces of Zhejiang, Shanghai, Hunan, Guizhou, Guangxi and Hainan is examined. Six species are identified, one of which is described: P. glabra Peng & Li sp. n. (Guizhou: Mayanghe). The genus is now represented in the Oriental and eastern Palaearctic regions by 29 species. PMID- 25544470 TI - A quantitative exposure model simulating human norovirus transmission during preparation of deli sandwiches. AB - Human noroviruses (HuNoVs) are a major cause of food borne gastroenteritis worldwide. They are often transmitted via infected and shedding food handlers manipulating foods such as deli sandwiches. The presented study aimed to simulate HuNoV transmission during the preparation of deli sandwiches in a sandwich bar. A quantitative exposure model was developed by combining the GoldSim(r) and @Risk(r) software packages. Input data were collected from scientific literature and from a two week observational study performed at two sandwich bars. The model included three food handlers working during a three hour shift on a shared working surface where deli sandwiches are prepared. The model consisted of three components. The first component simulated the preparation of the deli sandwiches and contained the HuNoV reservoirs, locations within the model allowing the accumulation of NoV and the working of intervention measures. The second component covered the contamination sources being (1) the initial HuNoV contaminated lettuce used on the sandwiches and (2) HuNoV originating from a shedding food handler. The third component included four possible intervention measures to reduce HuNoV transmission: hand and surface disinfection during preparation of the sandwiches, hand gloving and hand washing after a restroom visit. A single HuNoV shedding food handler could cause mean levels of 43+/-18, 81+/-37 and 18+/-7 HuNoV particles present on the deli sandwiches, hands and working surfaces, respectively. Introduction of contaminated lettuce as the only source of HuNoV resulted in the presence of 6.4+/-0.8 and 4.3+/-0.4 HuNoV on the food and hand reservoirs. The inclusion of hand and surface disinfection and hand gloving as a single intervention measure was not effective in the model as only marginal reductions of HuNoV levels were noticeable in the different reservoirs. High compliance of hand washing after a restroom visit did reduce HuNoV presence substantially on all reservoirs. The model showed that good handling practices such as washing hands after a restroom visit, hand gloving, hand disinfection and surface disinfection in deli sandwich bars were an effective way to prevent HuNoV contamination of the prepared foods, but it also demonstrated that further research is needed to ensure a better assessment of the risk of HuNoV transmission during preparation of foods. PMID- 25544471 TI - Wet-lab tested microRNA assays for qPCR studies with SYBR(r) Green and DNA primers in pig tissues. AB - MicroRNAs are key post-transcriptional regulators of gene expression that are involved in several biological processes including those that mediate disease pathophysiology. Hence, quantifying microRNA expression levels can provide important and novel insights into disease biology. In recent years, the pig has emerged as an excellent large animal model for studying human diseases and conditions (e.g. obesity) due to similarities in organ size, gastro-intestinal tract, metabolism, immune response, genetics and the availability of relevant tissues that are not normally easily available in humans. We have previously developed two useful tools in the field of microRNA quantitative real time PCR (qPCR): 1) a very specific, sensitive and simple qPCR method based on DNA primers, MiR-specific qPCR; and 2) the free primer-design software miRprimer. The present study integrates in a publicly accessible database all available information on validated porcine microRNA qPCR assays that have utilized these tools. Due to the high phylogenetic conservation in microRNA sequence between pig, humans and other domestic species this database is a very valuable resource for the broader scientist community who are working on microRNAs and want to use readily tested qPCR assays in a simple and cost-effective manner. PMID- 25544472 TI - Factorial validity, measurement equivalence and cognitive performance of the Cambridge Neuropsychological Test Automated Battery (CANTAB) between patients with first-episode psychosis and healthy volunteers. AB - BACKGROUND: The purpose of this study was to use selected Cambridge Neuropsychological Test Automated Battery (CANTAB) tests to examine the dimensional structure of cognitive dysfunction in first episode of psychosis (FEP) patients compared with cognition in healthy subjects. METHOD: A total of 109 FEP patients and 96 healthy volunteers were administered eight CANTAB tests of cognitive function. Principal components analysis (PCA) was used to estimate dimensionality within the test results. The dimensions identified by the PCA were assumed to reflect underlying cognitive traits. The plausibility of latent factor models was estimated using confirmatory factor analysis (CFA). Multi-group CFA (MGCFA) was used to test for measurement invariance of factors between groups. The nature and severity of cognitive deficits amongst patients as opposed to controls were evaluated using a general linear model. RESULTS: Amongst subjects PCA identified two underlying cognitive traits: (i) a broad cognitive domain; (ii) attention/memory and executive function domains. Corresponding CFA models were built that fitted data well for both FEP patients and healthy volunteers. As in MGCFA latent variables appeared differently defined in patient and control groups, differences had to be ascribed using subtest scores rather than their aggregates. At subtest score level the patients performed significantly worse than healthy subjects in all comparisons (p < 0.001). CONCLUSIONS: Results of this study demonstrate that the structure of underlying cognitive abilities as measured by a selection of CANTAB tests is not the same for healthy individuals and FEP patients, with patients displaying widespread cognitive impairment. PMID- 25544473 TI - Acute effects of viral respiratory tract infections on sputum bacterial density during CF pulmonary exacerbations. AB - BACKGROUND: Airway proliferation of Pseudomonas aeruginosa bacteria is thought to trigger CF exacerbations and may be affected by the presence of viral infections. METHODS: A 2-year prospective study was conducted on 35 adults with CF. P. aeruginosa sputum density was analyzed during stable, exacerbation and post exacerbation assessments. Upon exacerbation, samples were sent for PCR detection of respiratory viruses and the sputum density of P. aeruginosa in patients with a viral infection versus those without was compared. RESULTS: Twenty-two patients experienced 30 exacerbations during the study period; 50% were associated with a viral infection. There was no change in sputum density of P. aeruginosa from the stable to exacerbation state when measured by quantitative culture or by PCR. Virus-associated exacerbations did not result in significant increases in P. aeruginosa sputum density compared to non-viral exacerbations. CONCLUSION: Sputum density of P. aeruginosa was not increased at the time of CF exacerbation and was not influenced by the presence of viral infection. PMID- 25544474 TI - Alcohol addiction: a molecular biology perspective. AB - Alcohol misuse represents worldwide an important risk factor for death and disability. Excessive alcohol consumption is widely diffused in different ethnicities and alcohol use is part of the lifestyle of both young and old people. The genetic basis of alcohol dependence concerning ethanol metabolism and the pathways of reward circuits are well known. The role of genetic variants in the neurobiology of addiction as well as in response to medication in alcoholism therapy still represents an intriguing argument that needs to be deeply analyzed and explained. The molecular approach to the study of these aspects could be difficult because of the large number of genes and variations involved. Our work is intended to offer an overview of genes and variants involved in alcohol addiction and pharmacogenetics. Our aim is to delineate a molecular approach strategy to look at alcohol dependence from a genetic and applicative point of view. The indications provided in this work should be of help for those who wish to undertake a molecular study of this multifactorial disease. PMID- 25544475 TI - How cryo-EM is revolutionizing structural biology. AB - For many years, structure determination of biological macromolecules by cryo electron microscopy (cryo-EM) was limited to large complexes or low-resolution models. With recent advances in electron detection and image processing, the resolution by cryo-EM is now beginning to rival X-ray crystallography. A new generation of electron detectors record images with unprecedented quality, while new image-processing tools correct for sample movements and classify images according to different structural states. Combined, these advances yield density maps with sufficient detail to deduce the atomic structure for a range of specimens. Here, we review the recent advances and illustrate the exciting new opportunities that they offer to structural biology research. PMID- 25544476 TI - Modularity, context-dependence, and insulation in engineered biological circuits. AB - The ability to link systems together such that they behave as predicted once they interact with each other is an essential requirement for the forward-engineering of robust synthetic biological circuits. Unfortunately, because of context dependencies, parts and functional modules often behave unpredictably once interacting in the cellular environment. This paper reviews recent advances toward establishing a rigorous engineering framework for insulating parts and modules from their context to improve modularity. Overall, a synergy between engineering better parts and higher-level circuit design will be important to resolve the problem of context-dependence. PMID- 25544478 TI - Evaluation of techniques to prevent colorectal anastomotic leakage. AB - BACKGROUND: Anastomotic leakage is a major complication after anterior resection for rectal cancer. The double-stapling technique (DST) is the main method for creating a colorectal anastomosis. However, the rate of anastomotic leakage after DST remains high, and the technical risk factors have not been well established. MATERIALS AND METHODS: Five methods of colorectal anastomosis were performed on the porcine rectum and colon: single-stapled double-purse-string (SSDP), DST, side-to-side with a linear stapler (SS-L), side-to-side with a circular stapler (SS-C), and SS-C with hand-sewn reinforcement (n = 6 for each method). In each group, burst pressures were tested, paying special attention to the locations of the first disruptions. The anastomosis line, including staples, was embedded in polyester resin, and polished sections were examined histologically. RESULTS: Burst pressures were significantly higher in the SS-L and SS-C than those in the SSDP and DST groups (P < 0.001) and were higher in the SS-C with hand-sewn reinforcement than those in the SS-L and SS-C groups (P < 0.001). Remarkably, in the SSDP, DST, and SS-C groups, the first disruptions occurred on the staple line created by the circular stapler. CONCLUSIONS: The experimentally strongest colorectal anastomosis created with instruments currently in use was a SS-C. This anastomosis does not overlap staple lines and does not require a purse-string suture. Hand-sewn reinforcement was effective in increasing the anastomotic strength. PMID- 25544479 TI - Small bowel stricture as a late sequela of superior mesenteric vein thrombosis. AB - INTRODUCTION: The increasing frequency of use of CT in patients with acute abdomen is likely to improve the diagnosis of rarely occurring conditions/causes such as superior mesenteric vein thrombosis (MVT). Despite its severe consequences, MVT often presents with nonspecific clinical features. PRESENTATION OF CASE: AD, a 64-year-old man was an emergency admission with vague abdominal discomfort of two weeks duration, acute upper abdominal pain, loose stools, fresh rectal bleeding and vomiting. A contrast enhanced abdominal CT showed thrombosis of the proximal portal vein and the entire length of the superior mesenteric vein (SMV) with small bowel ischaemia extending from the terminal ileum to the mid jejunal loops. Tests for paroxysmal nocturnal haemoglobinuria and Janus kinase 2 mutation yielded negative results. AD was readmitted seven months later with small bowel obstruction requiring segmental small bowel resection with end-to-end anastomosis. Abdominal CT had shown complete resolution of MVT but a small bowel stricture. DISCUSSION: Thrombosis limited to mesenteric veins results in earlier and more frequent development of infarction compared to portal combined with mesenteric venous thrombosis. Most patients may be successfully treated with anti coagulation therapy alone. However, surgery may be required to deal with intestinal infarction or late sequela of MVT. CONCLUSION: This case demonstrates that MVT can be reversed by effective anticoagulation. However, the price paid for a mild to moderate effect on the bowel may be significant stricture later on. Patients escaping early bowel resection due to massive MVT leading to bowel infarction may still require resection later due to stricture. PMID- 25544477 TI - Prokaryotically and eukaryotically expressed interleukin-24 induces breast cancer growth suppression via activation of apoptosis and inhibition of tumor angiogenesis. AB - Melanoma differentiation-associated-7 (mda-7)/interleukin-24 (IL-24), a unique cytokine-tumor suppressor, exerts tumor-selective killing activity in numerous types of cancer cell. Although eukaryotically and prokaryotically expressed recombinant human (rh)IL-24 proteins have been previously shown to produce potent antitumor effects, to the best of our knowledge, no side-by-side study has been conducted that compares the two proteins directly. In the present study, rhIL-24 protein was expressed in BL21 Escherichia coli transformed with the pET-21a(+) hIL-24 plasmid by isopropyl-beta-D-1-thiogalactopyranoside induction. Following a denaturing and renaturing process, the soluble rhIL-24 was purified using a Q Sepharose column. rhIL-24 protein was also expressed in Chinese hamster ovary mammalian cells stably transfected with the pcDNA3-hIL-24 plasmid. The in vitro antitumor efficacies of the two treatments were compared using the MDA-MB-231 human breast cancer cell line. Furthermore, the therapeutic efficacies of the bacteria-derived rhIL-24 protein and the liposome-coated pcDNA3-hIL-24 naked plasmid were evaluated in athymic nude mice with subcutaneously xenografted MDA MB-231 cell tumors. The prokaryotically expressed/purified rhIL-24 protein and the eukaryotically expressed rhIL-24 in the cell supernate were revealed to be capable of efficiently suppressing MDA-MB-231 tumor growth in vitro. Similarly, the administration of bacteria-derived rhIL-24 protein and pcDNA3-hIL-24 naked plasmid also provided therapeutic benefits in the treatment of in vivo MDA-MB-231 xenografted tumors. The retarded in vitro and in vivo breast cancer growth elicited by rhIL-24 was closely associated with the upregulation of the ratio of anti-apoptotic B cell lymphoma 2 (Bcl-2) to pro-apoptotic Bcl-2-associated X protein (Bax), as well as the activation of caspase-3 followed by marked induction of apoptosis, and the notable inhibition of tumor angiogenesis. Thus, the results of the present study indicate that prokaryotically expressed rhIL-24 protein may be an alternate and promising antitumor agent in human breast cancer or other types of cancer. PMID- 25544480 TI - A novel approach using liquid embolic agent for the treatment of pancreatic cutaneous fistulas: Report of a case. AB - Pancreatic fistula formation remains one of the most dreadful complications after pancreaticoduodenectomies, resulting in extended hospital stays, increased healthcare costs, along with significantly increased morbidity and mortality. Little is mentioned in the literature about the use of percutaneous techniques to resolve this complication when conservative treatments fail. Thus, we developed a novel technique for treating pancreatic-cutaneous fistulas that develop post pancreaticoduodenectomy. This work describes a novel approach of using a liquid embolic agent to treat a high-output pancreatic-cutaneous fistula after a Whipple procedure, which to the best of our knowledge after extensive literature searches, has not been performed before. PMID- 25544481 TI - Richter-type Spigelian hernia: A case report and review of the literature. AB - INTRODUCTION: Abdominal wall hernias through the arcuate line termed Spigelian hernias are uncommon. These hernias presenting as a Richter-type, with strangulation of part of the circumference of the bowel wall is very rare. PRESENTATION OF CASE: We report a 27-year-old male patient who presented with a Richter-type Spigelian hernia. LITERATURE REVIEW: A MEDLINE literature search of this rare entity yielded six publications presenting Richter-type Spigelian hernias. All of these articles and accompanying references were thoroughly reviewed. There was no gender or anatomical side predominance among the patients. All except our patient presented here were elderly. Pain was the most common symptom and was present in all patients. All patients underwent surgical repair and none reported recurrence of their hernia afterwards. DISCUSSION AND CONCLUSION: Richter-type Spigelian hernia is rare and has been reported infrequently in the existing literature. Clinical diagnosis is challenging and CT scan is the diagnostic study of choice. Surgical repair is the definitive treatment and involves primary or mesh repair of the defect as appropriate. Necrotic bowel should be resected and we recommend biologic mesh repair in these cases if the defect is large. PMID- 25544482 TI - Pyoderma gangrenosum after cardiac surgery masquerading as a fulminant sternal wound infection. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a rare, ulcerative inflammatory skin pathology frequently associated with systemic inflammatory disease. While rare after surgery, recognition of this disease in the post-surgical setting is important as it can mimic wound infection. There have been ten case reports to date of PG occurring immediately after cardiac surgery, with all of them presenting within the first week post-operatively. PRESENTATION OF CASE: We herein present a delayed and dramatic presentation of PG nine days after mitral valve replacement and repair of patent foramen ovale, two days after being discharged with a seemingly normal healing wound. Diagnosis of this disease in the postoperative period requires high suspicion when the characteristic ulcerative lesions are seen diffusely in all surgical wounds and show minimal improvement with antibiotic treatment or debridement. DISCUSSION/CONCLUSION: Our case highlights the importance of recognizing this disease in the postoperative period, even in a delayed presentation and initially limited to one of the surgical sites. This case calls for an awareness of this disease entity amongst cardiac surgeons as well as intensivists. PMID- 25544483 TI - Gastrointestinal stromal tumor (GIST) presenting as a groin mass mimicking and incarcerated hernia. AB - INTRODUCTION: The contents of a hernial sac can harbor preperitoneal fat, epiploon or some hollow viscera, with a malignant lesion in its interior being an unusual finding. PRESENTATION OF CASE: We present the case of a 59 year-old male who arrived in the Emergency Department with an irreducible inguinal hernia, with no local signs of vascular compromise. The diagnosis was made after examining the hernia sac, using an inguinal approach, showing evidence of a largely necrosed gelatinous mass, which was resected by mid-line infraumbilical laparotomy. The mass was diagnosed as a high risk gastrointestinal stromal tumor. DISCUSSION: GIST are characterized by the absence of symptoms in most cases. The unusual presentation, as incarcerated hernia, allowed the diagnosis of this disease. The tumor measured 6cm with a mitotic index greater than 5/50 CGA tumor is classified as high risk. The finding of a thickened peritoneum proceeded to opening. The exploration of the sac is critical. CONCLUSIONS: Exploring the hernia sac in any complicated hernia, especially when the sac has macroscopic alterations and presence of areas of bleeding inside is essential. PMID- 25544484 TI - Selective agenesis of pancreatic isthmus parenchyma with preservation of main pancreatic duct continuity, a very rare entity: Case report. AB - CONTEXT: Agenesis of the dorsal pancreas is a rare anomaly, mostly associated with other medical conditions. It may be complicated with pancreatic neoplasms. CASE REPORT: We report the case of a 51-year-old male with selective agenesis of pancreatic isthmus with preservation of main pancreatic duct and branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) with suspicious features of the pancreas. CONCLUSION: This is probably the first report of isolated agenesis of pancreatic isthmus with conservation of main pancreatic duct. PMID- 25544485 TI - Takotsubo cardiomyopathy - An unexpected complication in spine surgery. AB - INTRODUCTION: Takotsubo cardiomyopathy is an apical ballooning syndrome, which can be triggered by stress. Only few case reports describe the onset of Takotsubo as a complication of neurosurgery procedures. CLINICAL PRESENTATION: A case of a 53 year-old female with a spinal neurinoma and surgery-associated Takotsubo cardiomyopathy is demonstrated. The patient developed typical signs of a myocardial infarction with circulation depression and ST elevation, but normal cardiac enzymes at the end of surgery. Cardiac catheterization and levocardiography confirmed the absence of any critical coronary disease but the presence of a typical apical ballooning and midventricular hypokinesis. The patient recovered completely under supportive conservative and cardiological therapy, showing regular left ventricular pump function. CONCLUSION: Interventions in neurosurgery and perioperative care should be kept as stress free as possible. Due to the possibility of neurogenic mechanisms related to cardiomyopathy, Takotsubo cardiomyopathy as an entity of stress-induced complications should be taken into consideration. PMID- 25544486 TI - Metachronous adenocarcinoma of the anal canal after anterior resection for sporadic primary rectal adenocarcinoma: A rare case report. AB - INTRODUCTION: Anal canal adenocarcinoma is an extremely rare malignancy with poorly defined diagnostic and treatment criteria. PRESENTATION OF CASE: A 42-year old women was diagnosed with primary anal canal adenocarcinoma 11 months after undergoing anterior resection for primary sporadic rectal adeocarcinoma. Transanal excision was performed and additional adjuvant chemotherapy was given. Immunohistology showed positivity for cytokeratin (CK) 20 and CDX2, and negative CK7, which is compatible with colorectal subtype anal adenocarcinoma. At 6 months follow-up the patient has no evidence of recurrent or metastatic disease. DISCUSSION: Diagnosis of primary anal adenocarcinoma is typically delayed because of its rarity, and vague clinical presentation. Exact histologic criteria remain poorly defined but the use of immunohistology has improved the overall diagnostic accuracy of anal adenocarcinoma and it also helps define its correct origin. Reports on the management and outcomes of this cancer consist mainly of retrospective studies with no consistent treatment strategy and limited comparison data. Most authors currently recommend neoadjuvant chemoradiotherapy and radical resection. Despite aggressive therapy, rates of local failure and distant recurrence remain high. CONCLUSION: Diagnosis of adenocarcinoma of the anal canal is difficult but specific immunohistolgic patterns help to correctly identify its correct origin and subtype. Defining the correct subtype of anal adenocarcinoma may impact treatment strategies of this rare cancer. PMID- 25544487 TI - An unusual cause of mass localized on vastus lateralis muscle in childhood: Hydatid cyst. AB - INTRODUCTION: Musculoskeletal hydatid disease is a rare pathology and its diagnosis is often delayed because of slowly growing mass without inflammation. It is critical to suspicious clinical diagnosis in rural endemic areas and for preoperative diagnosis of this disease. PRESENTATION OF CASE: We present a 9-year old boy referred with mass located on the anterolateral part of distal thigh. Diagnosis was verified with MRI histopathologically for the presence of hydatid cyst located in vastus lateralis muscle. Magnetic resonance imaging (MRI) was performed for further imaging. MRI showed an oval cystic mass approximately 77*20*18mm in the left vastus lateralis muscle, containing round-shaped daughter cysts. Patients were treated with surgical excision and medical therapy. Clinical, radiological and serologic tests showed no recurrence after treatment. DISCUSSION: The muscle is considered an unfavorable site for hydatidosis because of its high lactic acid level that creates an unfavorable milieu for growth. The detachment of the germinative membrane from pericyst (water-lily sign) is considered to be pathognomonic and is reported in locations other than the liver and lung in magnetic resonance imaging. Surgery is the most effective way to treat hydatid cysts. Complete surgical resection and medical therapy are the preferred treatment for isolated echinococcosis. CONCLUSION: Hydatid cyst in vastus lateralis is a very rare disease. Hydatid cyst should be kept in mind when observing soft tissue mass of the extremities in patients from areas endemic of Echinococcus granulosus. PMID- 25544488 TI - Endoscopic closure of persistent gastric leak and fistula following laparoscopic sleeve gastrectomy. AB - INTRODUCTION: Conservative management for gastric leak and fistulae after laparoscopic sleeve gastrectomy (LSG) often results in prolonged hospitalization as well as requirement of TPN or recurrent surgery (Casella et al., 2009) [1]. Endoscopically-placed stents are an additional non-invasive method, but are associated with the complication of stent migration in up to 50% of cases (Casella and co-workers, 2009) [1,4]. As other non-invasive means of treatment are absent, we believe this case demonstrates a new technique for multiple gastric leaks following LSG in patients without sepsis or peritonitis. PRESENTATION OF CASE: A patient developed a staple line gastric leak that persisted for 10 weeks following LSG despite multiple modalities of treatment. She refused to undergo stent placement, so via esophagogastroduodenoscopy (EGD), fistula margins were cauterized with argon plasma coagulation and a fibrin sealant was injected to include the surrounding area. Endoclips were placed along the fistula tracts. A repeat procedure was required. Follow up imaging confirmed resolution of gastric leak and patient did not experience additional complications. DISCUSSION: The patient was able to discontinue TPN and return to an oral diet. Both procedures were well tolerated and did not require hospitalization. CONCLUSION: Endoscopic management of multiple gastric leaks and fistulae using fibrin seal, endoclips, and cauterization appears to be a promising noninvasive form of treatment with a lower associated morbidity and shortened hospitalization. PMID- 25544489 TI - Video assisted thoracoscopic surgery cases with right-sided aortic arch aneurysm and complete vascular ring: Case report. AB - INTRODUCTION: Right-sided aortic arch with aberrant left subclavian artery and ligamentum arteriosum, after double aortic arch, is the second most common complete vascular ring. It was traditionally treated by open surgical thoracotomy and recently video assisted thoracoscopic surgery (VATS) has been used in some cases. PRESENTATION OF CASE: We describe the cases of two infants who presented with gastroesophageal reflux, dyspnea, dysphagia secondary to aneurysmal dilatation of the retroesophageal arch confirmed by imaging data. VATS procedure was performed through a left thoracoscopic approach. Ligamentum arteriosus compressed esophagus was clipped, sectioned and then released the esophagus in one case; also, In the second case, we clipped and sectioned aorta, distal to the origin of aberrant left subclavian artery. DISCUSSION: CT angiography and MRI are known to be the most effective available imaging methods for vascular ring detection. Also, there are several surgical approaches to vascular rings such as, thoracotomy and thoracoscopy. There is a large body of evidence confirming the safety, efficacy and convenience of VATS as a therapeutic option for congenital heart disease including right-sided aortic arch and aberrant left subclavian artery. CONCLUSION: VATS is a less invasive and safe strategy for management of right-sided aortic arch with aberrant left subclavian artery and ligamentum arteriosum. PMID- 25544490 TI - Ipsilateral olecranon and distal radius fracture: A case report. AB - INTRODUCTION: Concomitant ipsilateral olecranon and distal radius fracture are rare injuries. Their clinical presentation is unusual and investigation and management is poorly described. PRESENTATION OF CASE: We present a 55-year-old woman patient who fell off sustaining a concomitant distal radius and olecranon fracture in the same extremity. On examination, there was gross swelling of the proximal and distal forearm and no neurovascular deficit. Radiographs confirmed distal radius and olecranon fracture. Patient was treated with open reduction and anatomic locking plate for olecranon and a closed reduction percuteneous K wire fixation with penning fixator for distal radius fracture. After physical therapy program, functional results were good and DASH score was 60. DISCUSSION: Several different combinations of fracture with dislocation have been described, but, to our knowledge, concurrent ipsilateral olecranon and distal radius fracture has not been reported before. In the literature review there are two similar cases in the English literature. CONCLUSION: Ipsilateral olecranon and distal radius fracture is a very rare injury due to different trauma mechanisms. However we should keep in mind that there may be adjacent joints and structures for concomitant injuries. PMID- 25544491 TI - Unusual presentation of a giant benign inflammatory polyp in the upper esophagus. AB - INTRODUCTION: Benign inflammatory fibroid polyps (IFP) are rare submucosal tumors of the upper gastrointestinal tract. Rarely, they can develop in the esophagus, usually in the lower third. There are only 12 cases of giant IFP of the esophagus reported in literature and little is known about their origin, biological behavior and operative management. We present a patient with a giant benign IFP of the esophagus that originated from the upper esophagus. CASE PRESENTATION: The patient is a 59-year-old male who presented with dysphagia. Upper endoscopy and esophagram revealed a giant intraluminal esophageal mass with a pedicle in the upper esophagus. Resection of this mass was performed through a left cervical esophagotomy. Pathology confirmed IFP, On 2 year follow up, there was no recurrence of the mass. DISCUSSION: A giant IFP is defined as an IFP greater than 4cm, commonly present in the distal esophagus. Pathology usually reveals vascularized fibrous stroma with elements of inflammatory infiltrate. This mass is slow-growing and asymptomatic until it grows to a large size. Common diagnostic studies include barium esophagram, upper endoscopy, and CT imaging. A key pre-operative work-up is to identify the location of the pedicle to plan out surgical approach and to avoid injuring the rich blood supply thus preventing a life threatening hemorrhage during the operation. CONCLUSION: Giant IFPs are infrequent in clinical practice. Resection is indicated and usually performed by a surgical intervention or endoscopic removal. The pathogenesis of these polyps remains poorly understood due to the rarity of these lesions. PMID- 25544492 TI - Pneumatic colon injury following high pressure blow gun dust cleaner spray to the perineum. AB - INTRODUCTION: A pneumatic tool or air tool such as blow gun dust cleaner is a tool driven by compressed air and spraying of the perineum can insufflate the colon due to its high pressure and high flow rate. PRESENTATION OF CASE: We present a case of 4 year old boy who developed sudden onset of tense abdominal distention and developed peritonitis. Patient's family initially denied a history of trauma. Radiologic examination showed pneumoperitoneum and colon dilatation. Exploratory laparotomy revealed a tension pneumoperitoneum, bloody ascitic fluid, multiple site of ecchymosis and serosal tear of the colon and a minute perforation of transverse colon. Postoperative reinvestigation revealed that the patient's perineum was sprayed, using blow gun dust cleaner. DISCUSSION: Air from pneumatic tools produces column of air at pressure of 3.5-8.8kg/cm(2) and pressure greater than the resting anal pressure of 0.109kg/cm(2) force air to enter the colon when the perineum is sprayed. Different degree of colon injury results when airflow is greater than 1.46L/m, and/or intraluminal pressure greater than 0.109kg/cm(2). In most children, initial anxiety to tell the truth result in difficulty to obtain good history. CONCLUSION: Spraying of the perianal with excessive pneumatic force of greater than the resting anal pressure and high air flow rate causes multiple site colon injury and tension pneumoperitoneum due to colon perforation. Parent should be caution in children playing with high pressure pneumatic tool, and the importance of history is emphases for early correct diagnosis. PMID- 25544494 TI - New insights into atrazine degradation by cobalt catalyzed peroxymonosulfate oxidation: kinetics, reaction products and transformation mechanisms. AB - The widespread occurrence of atrazine in waters poses potential risk to ecosystem and human health. In this study, we investigated the underlying mechanisms and transformation pathways of atrazine degradation by cobalt catalyzed peroxymonosulfate (Co(II)/PMS). Co(II)/PMS was found to be more efficient for ATZ elimination in aqueous solution than Fe(II)/PMS process. ATZ oxidation by Co(II)/PMS followed pseudo-first-order kinetics, and the reaction rate constant (k(obs)) increased appreciably with increasing Co(II) concentration. Increasing initial PMS concentration favored the decomposition of ATZ, however, no linear relationship between k(obs) and PMS concentration was observed. Higher efficiency of ATZ oxidation was observed around neutral pH, implying the possibility of applying Co(II)/PMS process under environmental realistic conditions. Natural organic matter (NOM), chloride (Cl(-)) and bicarbonate (HCO3(-)) showed detrimental effects on ATZ degradation, particularly at higher concentrations. Eleven products were identified by applying solid phase extraction-liquid chromatography-mass spectrometry (SPE-LC/MS) techniques. Major transformation pathways of ATZ included dealkylation, dechlorination-hydroxylation, and alkyl chain oxidation. Detailed mechanisms responsible for these transformation pathways were discussed. Our results reveal that Co(II)/PMS process might be an efficient technique for remediation of groundwater contaminated by ATZ and structurally related s-triazine herbicides. PMID- 25544493 TI - Distribution of uranium and thorium in dolomitic gravel fill and shale saprolite. AB - The objectives of this study were to examine (1) the distribution of U and Th in dolomitic gravel fill and shale saprolite, and (2) the removal of uranium from acidic groundwater by dolomitic gravel through precipitation with amorphous basaluminite at the U.S. DOE Oak Ridge Integrated Field Research Challenge (ORIFRC) field site west of the Oak Ridge Y-12 National Security Complex in East Tennessee. Media reactivity and sustainability are a technical concern with the deployment of any subsurface reactive media. Because the gravel was placed in the subsurface and exposed to contaminated groundwater for over 20 years, it provided a unique opportunity to study the solid and water phase geochemical conditions within the media after this length of exposure. This study illustrates that dolomite gravel can remove U from acidic contaminated groundwater with high levels of Al(3+), Ca(2+), NO(3-), and SO4(2-) over the long term. As the groundwater flows through high pH carbonate gravel, U containing amorphous basaluminite precipitates as the pH increases. This is due to an increase in groundwater pH from 3.2 to ~6.5 as it comes in contact with the gravel. Therefore, carbonate gravel could be considered as a possible treatment medium for removal and sequestration of U and other pH sensitive metals from acidic contaminated groundwater. Thorium concentrations are also high in the carbonate gravel. Thorium generally shows an inverse relationship with U from the surface down into the deeper saprolite. Barite precipitated in the shallow saprolite directly below the dolomitic gravel from barium present in the acidic contaminated groundwater. PMID- 25544495 TI - Application of glyco-blotting for identification of structures of polysaccharides causing membrane fouling in a pilot-scale membrane bioreactor treating municipal wastewater. AB - A new approach for the analysis of polysaccharides in membrane bioreactor (MBR) is proposed in this study. Enrichment of polysaccharides by glyco-blotting, in which polysaccharides are specifically collected via interactions between the aldehydes in the polysaccharides and aminooxy groups on glycoblotting beads, enabled MALDI-TOF/MS analysis at a high resolution. Structures of polysaccharides extracted from fouled membranes used in a pilot-scale MBR treating municipal wastewater and those in the supernatant of the mixed liquor suspension in the MBR were investigated. It was found that the overlap between polysaccharides found in the supernatants and those extracted from the fouled membrane was rather limited, suggesting that polysaccharides that dominate in supernatants may not be important in membrane fouling in MBRs. Analysis using a bacterial carbohydrate database suggested that capsular polysaccharides (CPS) and/or lipo polysaccharides (LPS) produced by gram-negative bacteria are key players in the evolution of membrane fouling in MBRs. PMID- 25544496 TI - Effect of algae growth on aerobic granulation and nutrients removal from synthetic wastewater by using sequencing batch reactors. AB - The effect of algae growth on aerobic granulation and nutrients removal was studied in two identical sequencing batch reactors (SBRs). Sunlight exposure promoted the growth of algae in the SBR (Rs), forming an algal-bacterial symbiosis in aerobic granules. Compared to the control SBR (Rc), Rs had a slower granulation process with granules of loose structure and smaller particle size. Moreover, the specific oxygen uptake rate was significantly decreased for the granules from Rs with secretion of 25.7% and 22.5% less proteins and polysaccharides respectively in the extracellular polymeric substances. Although little impact was observed on chemical oxygen demand (COD) removal, algal bacterial symbiosis deteriorated N and P removals, about 40.7-45.4% of total N and 44% of total P in Rs in contrast to 52.9-58.3% of TN and 90% of TP in Rc, respectively. In addition, the growth of algae altered the microbial community in Rs, especially unfavorable for Nitrospiraceae and Nitrosomonadaceae. PMID- 25544497 TI - Prolonged exposure of mixed aerobic cultures to low temperature and benzalkonium chloride affect the rate and extent of nitrification. AB - The combined effect of benzalkonium chloride (BAC) and prolonged exposure to low temperature on nitrification was investigated. Ammonia oxidation at 22-24 degrees C by an enriched nitrifying culture was inhibited at increasing BAC concentrations and ceased at 15 mg BAC/L. The non-competitive inhibition coefficient was 1.5+/-0.9 mg BAC/L. Nitrification tests were conducted without and with BAC at 5mg/L using an aerobic, mixed heterotrophic/nitrifying culture maintained at a temperature range of 24-10 degrees C. Maintaining this culture at 10 degrees C for over one month in the absence of BAC, resulted in slower nitrification kinetics compared to those measured when the culture was first exposed to 10 degrees C. BAC was degraded by the heterotrophic population, but its degradation rate decreased significantly as the culture temperature decreased to 10 degrees C. These results confirm the negative impact of quaternary ammonium compounds on the nitrification process, which is further exacerbated by prolonged, low temperature conditions. PMID- 25544498 TI - Differences in nutrient uptake capacity of the benthic filamentous algae Cladophora sp., Klebsormidium sp. and Pseudanabaena sp. under varying N/P conditions. AB - The N/P ratio of wastewater can vary greatly and directly affect algal growth and nutrient removal process. Three benthic filamentous algae species Cladophora sp., Klebsormidium sp. and Pseudanabaena sp. were isolated from a periphyton bioreactor and cultured under laboratory conditions on varying N/P ratios to determine their ability to remove nitrate and phosphorus. The N/P ratio significantly influenced the algal growth and phosphorus uptake process. Appropriate N/P ratios for nitrogen and phosphorus removal were 5-15, 7-10 and 7 20 for Cladophora sp., Klebsormidium sp. and Pseudanabaena sp., respectively. Within these respective ranges, Cladophora sp. had the highest biomass production, while Pseudanabaena sp. had the highest nitrogen and phosphorus contents. This study indicated that Cladophora sp. had a high capacity of removing phosphorus from wastewaters of low N/P ratio, and Pseudanabaena sp. was highly suitable for removing nitrogen from wastewaters with high N/P ratio. PMID- 25544500 TI - Characterization of MT-2 cells as a human regulatory T cell-like cell line. PMID- 25544501 TI - CD4(+) T-cell dependence of primary CD8(+) T-cell response against vaccinia virus depends upon route of infection and viral dose. AB - CD4(+) T-cell help (CD4 help) plays a pivotal role in CD8(+) T-cell responses against viral infections. However, the role in primary CD8(+) T-cell responses remains controversial. We evaluated the effects of infection route and viral dose on primary CD8(+) T-cell responses to vaccinia virus (VACV) in MHC class II(-/-) mice. CD4 help deficiency diminished the generation of VACV-specific CD8(+) T cells after intraperitoneal (i.p.) but not after intranasal (i.n.) infection. A large viral dose could not restore normal expansion of VACV-specific CD8(+) T cells in i.p. infected MHC II(-/-) mice. In contrast, dependence on CD4 help was observed in i.n. infected MHC II(-/-) mice when a small viral dose was used. These data suggested that primary CD8(+) T-cell responses are less dependent on CD4 help in i.n. infection compared to i.p. infection. Activated CD8(+) T cells produced more IFN-gamma, TNF-alpha and granzyme B in i.n. infected mice than those in i.p. infected mice, regardless of CD4 help. IL-2 signaling via CD25 was not necessary to drive expansion of VACV-specific CD8(+) T cells in i.n. infection, but it was crucial in i.p. infection. VACV-specific CD8(+) T cells underwent increased apoptosis in the absence of CD4 help, but proliferated normally and had cytotoxic potential, regardless of infection route. Our results indicate that route of infection and viral dose are two determinants for CD4 help dependence, and intranasal infection induces more potent effector CD8(+) T cells than i.p. infection. PMID- 25544502 TI - Nasopharyngeal cancer-derived microRNA-21 promotes immune suppressive B cells. AB - The prevalence of nasopharyngeal cancer (NPC) is high in the southern area of China and some other districts in the world. The pathogenesis of NPC is unclear. It is reported that some microRNAs (miR) are involved in the progression of NPC. This study aims to investigate the role of miR-21 in the induction of immune tolerance of NPC. In this study, NPC tissue was collected from patients with NPC. Assessment of miR was performed with real time quantitative RT-PCR. Western blotting was used to assess proteins of interleukin 10 and nuclear factor I-A (NFI-A). Immune cells were analyzed by flow cytometry. The results showed that NPC cell line C666-1 and surgically removed NPC tissue expressed miR-21, which was upregulated by the presence of the Toll-like receptor 3 ligand, Poly I: C. Exposure to miR-21 increased the expression of NFI-A and interleukin (IL)-10 in naive B cells. High frequency of IL-10(+) B cells was detected in the NPC tissue. The NPC- or miR-21-primed B cells suppressed cytotoxic CD8(+) T cell activities. We conclude that NPC-derived miR-21 induces IL-10(+) B cells; the latter is capable of suppressing CD8(+) T-cell activities. miR-21 may be a potential target in the treatment of NPC. PMID- 25544505 TI - Retaining Low-Income Minority Cancer Patients in a Depression Treatment Intervention Trial: Lessons Learned. AB - Previously published work finds significant benefit from medical and behavioral health team care among safety-net patients with major depression. This qualitative study assessed clinical social worker, psychiatrist and patient navigator strategies to increase depression treatment among low-income minority cancer patients participating in the ADAPt-C clinical depression trial. Patient care retention strategies were elicited through in-depth, semi-structured interviews with nine behavioral health providers. Using grounded theory, concepts from the literature and dropout barriers identified by patients, guided interview prompts. Retention strategies clustered around five dropout barriers: (1) informational, (2) instrumental, (3) provider-patient therapeutic alliance, (4) clinic setting, and (5) depression treatment. All strategies emphasized the importance of communication between providers and patients. Findings suggest that strong therapeutic alliance and telephone facilitates collaborative team provider communication and depression treatment retention among patients in safety-net oncology care systems. PMID- 25544499 TI - Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection. AB - Infection with hepatitis C virus (HCV), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma. HCV infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. Upon HCV infection, the host induces the interferon (IFN)-mediated frontline defense to limit virus replication. Conversely, HCV employs diverse strategies to escape host innate immune surveillance. Type I IFN elicits its antiviral actions by inducing a wide array of IFN-stimulated genes (ISGs). Nevertheless, the mechanisms by which these ISGs participate in IFN-mediated anti HCV actions remain largely unknown. In this review, we first outline the signaling pathways known to be involved in the production of type I IFN and ISGs and the tactics that HCV uses to subvert innate immunity. Then, we summarize the effector mechanisms of scaffold ISGs known to modulate IFN function in HCV replication. We also highlight the potential functions of emerging ISGs, which were identified from genome-wide siRNA screens, in HCV replication. Finally, we discuss the functions of several cellular determinants critical for regulating host immunity in HCV replication. This review will provide a basis for understanding the complexity and functionality of the pleiotropic IFN system in HCV infection. Elucidation of the specificity and the mode of action of these emerging ISGs will also help to identify novel cellular targets against which effective HCV therapeutics can be developed. PMID- 25544506 TI - The effects of attention deficit hyperactivity disorder on clothing selection and habits among Turkish University students. AB - The purpose of this study was to identify the factors that influence the shopping attitudes of college students with and without ADHD. This study also examined the effects of ADHD on the academic and social lives of college students. The sample consisted of 219 university students. These students were interviewed by a psychiatrist with regard to ADHD symptoms according to the DSM-IV. The Adult ADHD Self Report Scale (ASRS), the Teen Interpersonal Influence Scale, and a demographic information form were used as measurement devices. The ADHD and control groups were classified in three different ways: (1) met the ADHD criteria for both Clinical Diagnosis and the ASRS; (2) met only the criteria for Clinical Diagnosis; or (3) met only the criteria of the ASRS. Our research shows that individuals with ADHD experience more problems with money management and are more affected by the media, friends, and brands compared with individuals without ADHD. Smoking and alcohol use disorders, accidents, being held back, and disciplinary actions often accompany ADHD in college students. To the best of our knowledge, the shopping attitudes of young adults with ADHD and the influence of the media, peers, family, and brands have not been studied until now. PMID- 25544503 TI - The immunological underpinnings of vaccinations to prevent cytomegalovirus disease. AB - A universal cytomegalovirus (CMV) vaccination promises to reduce the burden of the developmental damage that afflicts up to 0.5% of live births worldwide. An effective vaccination that prevents transplacental transmission would reduce CMV congenital disease and CMV-associated still births and leave populations less susceptible to opportunistic CMV disease. Thus, a vaccination against this virus has long been recognized for the potential of enormous health-care savings because congenital damage is life-long and existing anti-viral options are limited. Vaccine researchers, industry leaders, and regulatory representatives have discussed the challenges posed by clinical efficacy trials that would lead to a universal CMV vaccine, reviewing the links between infection and disease, and identifying settings where disrupting viral transmission might provide a surrogate endpoint for disease prevention. Reducing the complexity of such trials would facilitate vaccine development. Children and adolescents are the targets for universal vaccination, with the expectation of protecting the offspring of immunized women. Given that a majority of females worldwide experience CMV infection during childhood, a universal vaccine must boost natural immunity and reduce transmission due to reactivation and re-infection as well as primary infection during pregnancy. Although current vaccine strategies recognize the value of humoral and cellular immunity, the precise mechanisms that act at the placental interface remain elusive. Immunity resulting from natural infection appears to limit rather than prevent reactivation of latent viruses and susceptibility to re-infection, leaving a challenge for universal vaccination to improve upon natural immunity levels. Despite these hurdles, early phase clinical trials have achieved primary end points in CMV seronegative subjects. Efficacy studies must be expanded to mixed populations of CMV-naive and naturally infected subjects to understand the overall efficacy and potential. Together with CMV vaccine candidates currently in clinical development, additional promising preclinical strategies continue to come forward; however, these face limitations due to the insufficient understanding of host defense mechanisms that prevent transmission, as well as the age-old challenges of reaching the appropriate threshold of immunogenicity, efficacy, durability and potency. This review focuses on the current understanding of natural and CMV vaccine-induced protective immunity. PMID- 25544504 TI - IL-17 induces radiation resistance of B lymphoma cells by suppressing p53 expression and thereby inhibiting irradiation-triggered apoptosis. AB - p53 is a well-known tumor suppressor. However, the regulatory mechanism(s) for p53 expression in B lymphoma cells, and the possible role of p53 in the development of the radioresistance in tumor cells are largely unknown. A human B lymphoma cell line, Karpas1106 (k1106), was used as a model of radioresistance. Apoptosis of k1106 cells was determined using flow cytometry. Expression of p53 was assessed using real time RT-PCR and western blotting. The results showed that irradiation at 8 Gy induced apoptosis in up to 40% of k1106 cells. At the same time, the irradiation markedly increased IL-6 production of the k1106 cells. When k1106 cells were cocultured with regulatory T cells (Tregs) and irradiated, the rate of apoptotic k1106 cells was significantly reduced, indicating an acquired resistance to irradiation. IL-6 derived from the irradiation-treated k1106 cells induced IL-17 expression in Tregs. The IL-17(+)Foxp3(+) T cells suppressed p53 expression in k1106 cells. Collectively, irradiated k1106 cells induce the expression of IL-17 in Tregs, which interferes with the expression of p53 protein in k1106 cells and thereby represses irradiation-triggered apoptosis in k1106 cells. PMID- 25544507 TI - A novel GBE1 mutation and features of polyglucosan bodies autophagy in adult polyglucosan body disease. AB - We report the clinical, neuro-imaging, pathological and biochemical features of an Italian family in which two siblings have the Adult Polyglucosan Body Disease (APBD). APBD is a rare autosomal recessive disorder characterized by a gradually progressive involvement of both the central and peripheral nervous systems caused by the deficiency of the glycogen branching enzyme (GBE1). The two affected siblings, a 64-year-old man and his 67-year-old sister who had complained of urinary urgency and sporadic incontinence and also progressive gait difficulty for 6 and 7 years respectively, had severely impaired deep sensations on direct examination and a moderately severe symmetrical, axonal sensory-motor neuropathy on electrophysiological testing. GBE1 activity was below 25% of the normal rate in leukocytes and sural nerves. The siblings were homozygous for the novel GBE1 mutation p.N541D. All other members of the pedigree are heterozygous and manifest no symptoms, even in the very elderly. The affected siblings showed polyglucosan bodies (PBs) included within non-myelinating Schwann cells and within lymphocyte vesicles, which were positive for the autophagy markers P62 and LC3-II at immunofluorescence microscopy. PMID- 25544508 TI - Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population. AB - BACKGROUND: Several pathogenesis and genetic factors influence predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) especially for isoniazid (INH). However, the major susceptibility genes for ATDH are N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). NAT2 gene determines the individual's acetylator status (fast, intermediate or slow) to metabolize drugs and xenobiotics, while CYP2E1 c1/c1 genotype carriers had an increased risk of ATDH. Polymorphisms of the NAT2 and CYP2E1 genes vary remarkably among the populations of different ethnic origins. The aim of this study was to determine, for the first time, the frequency of slow acetylators in Moroccan population by genotyping of NAT2 gene variants and determining the genotype c1/c1 for CYP2E1 gene, in order to predict adverse effects of Tuberculosis treatment, particularly hepatotoxicity. RESULTS: The frequencies of specific NAT2 alleles were 53%, 25%, 2% and 4% for NAT2*5, NAT2*6, NAT2*7 and NAT2*14 respectively among 163 Moroccan studied group. Genotyping of CYP2E1 gene, by real-time polymerase chain reaction using TaqMan probes, revealed frequencies of 98.5% for c1/c1 and 1.5% for c1/c2 among 130 Moroccan studied group. CONCLUSION: The most prevalent genotypes of NAT2 gene in Moroccans are those which encode slow acetylation phenotype (72.39%), leading to a high risk of ATDH. Most Moroccans are homozygous for c1 allele of CYP2E1 gene which aggravates hepatotoxicity in slow acetylators. This genetic background should be taken into account in determining the minimum dose of INH needed to treat Moroccan TB patients, in order to decrease adverse effects. PMID- 25544510 TI - The genus Leucophenga (Diptera, Drosophilidae), part IV: the ornata species group from the East Asia, with morphological and molecular evidence (II). AB - Twenty-one species of the Leucophenga ornata species group are surveyed (including 12 new species): L. atrinervis Okada, 1968; L. digmasoma Lin & Wheeler, 1972; L. multipunctata Chen & Aotsuka, 2003; L. nigrinervis Duda, 1924; L. pectinata Okada, 1968; L. pentapunctata Panigrahy & Gupta, 1982; L. quadripunctata (de Meijere, 1908); L. regina Malloch, 1935; L. trivittata Okada, 1990; L. acutifoliacea sp. nov.; L. albiterga sp. nov.; L. angustifoliacea sp. nov.; L. baculifoliacea sp. nov.; L. cornuta sp. nov.; L. hirticeps sp. nov.; L. latifascia sp. nov.; L. pinguifoliacea sp. nov.; L. retihirta sp. nov. L. securis sp. nov.; L. sinupenis sp. nov.; L. villosa sp. nov.; these species (except for L. baculifoliacea sp. nov.) having pubescence on the distal portion of aedeagus. A key to all the examined species of the ornata group in this study is provided. We try to improve our species delimitation by integrating the DNA sequences data with morphological information. The intra- and interspecific pairwise K-2P (Kimura's two-parameter) distances are summarized. PMID- 25544509 TI - Use of alpha-1 adrenoceptor antagonists in patients who underwent low-dose-rate brachytherapy for prostate cancer - a randomized controlled trial of silodosin versus naftopidil. AB - BACKGROUND: To evaluate the effect of two different alpha-1 adrenoceptor antagonists on lower urinary tract symptoms in patients who underwent LDR brachytherapy. METHODS: A total of 141 patients who had been clinically diagnosed with localized prostate cancer and underwent LDR-brachytherapy were enrolled. Patients were randomized and allocated to two groups (silodosin 8 mg vs. naftopidil 75 mg). The primary endpoint was a change in the international prostate symptom score (IPSS) at 3 months after seed implantation. Secondary endpoints included the recovery rate of IPSS at 12 months after seed implantation, the change in IPSS and overactive bladder symptom score, uroflowmetric parameters, and frequency volume chart (FVC). To determine independent variables that can predict IPSS recovery, logistic regression analysis was carried out. RESULTS: The mean change in the IPSS at 3 months after seed implantation in both groups was ?10.6 (naftopidil) and ?10.4 (silodosin), respectively. There was not a significant difference between the two groups (p=0.728). An increase in urinary frequency and a decrease in total urinated volume and mean voided volume were observed in FVC for 12 months after seed implantation. Multivariate analysis revealed that the urethral dose (UD30) was an independent predictive parameter of IPSS recovery. Patients with UD30 < 200Gy showed a higher recovery rate of IPSS at 12 months after seed implantation. CONCLUSION: There was no significant difference of serial change in IPSS between silodosin and naftopidil during the first year after seed implantation. A lower dose on the urethra was an independent predictor of IPSS recovery at 12 months after seed implantation. PMID- 25544511 TI - Male secondary sexual characters resolve taxonomic uncertainty: five new species and a review of the formerly monotypic rove beetle genus Mimosticus Sharp (Coleoptera: Staphylinidae: Staphylininae). AB - The hitherto poorly known Neotropical rove beetle genus Mimosticus is reviewed. Five new species are described from the Andes, Mimosticus aeneipennis sp. n., Mimosticus latens sp. n., Mimosticus pseudosharpi sp. n., Mimosticus sharpi sp. n. and Mimosticus tenuiformis sp. n. The widely distributed type species of the genus, Mimosticus viridipennis Sharp, 1884, is redescribed. Aedeagal characters traditionally used to delimit species in Staphylinidae exhibited only subtle inter-specific differences in Mimosticus but were corroborated by distinct differences in male secondary sexual characters. A modern description and morphological diagnosis of the genus are provided, distribution and bionomic data are summarized, and the placement of Mimosticus in the Staphylinini subtribe Amblyopinina is justified in the context of recent, character-based phylogenetic hypotheses. PMID- 25544512 TI - A review of the ectoparasitic mites (Acari: Dermanyssoidea) associated with birds and their nests in Slovakia, with notes on identification of some species. AB - We review the parasitic mites of the superfamily Dermanyssoidea found in the nests of Slovakian domestic and wild birds (and a few mammals), compiled from new data and literature sources. Three mite genera are included, namely Dermanyssus Duges (Dermanyssidae), Ornithonyssus Sambon and Pellonyssus Clark & Yunker (Macronyssidae), in which we recognised nine reliably documented species. Pellonyssus is represented by one species, Dermanyssus by five species, and Ornithonyssus by three species. We compiled information on the ecological requirements and host preferences of these mite species, including data on geographic distribution, altitudinal distribution, and occurrence in different habitats and nest types. An identification key to the species occurring in Slovakia is provided, together with taxonomic remarks on the identification and external morphology of some selected species. Parasitic mites have been reported from 119 taxa of Slovakian vertebrates (including man), of which 108 belong to 17 orders of birds. Dermanyssus americanus Ewing and Ornithonyssus bursa (Berlese) are reported from Slovakia for the first time. Examination of older voucher material collected in Slovakia revealed many misidentified specimens: the name Dermanyssus hirundinis (Hermann) has been widely used for misidentified specimens of Dermanyssus carpathicus Zeman; D. americanus was confused with D. hirundinis; while O. bursa has been confused with Ornithonyssus sylviarum (Canestrini & Fanzago). Slovakia is the second country in Europe with known occurrence of the genus Pellonyssus. PMID- 25544513 TI - First record and a new species of Alvinocaris Williams & Chace, 1982 (Crustacea: Decapoda: Caridea: Alvinocarididae) from the Indian Ocean. AB - A new species of the alvinocaridid shrimp genus Alvinocaris Williams & Chace, 1982 is described from the Solitaire hydrothermal vent field at 2606 m depth on the Central Indian Ridge. Alvinocaris solitaire sp. nov., the first species of the genus to be recorded from the Indian Ocean, is morphologically most similar to A. lusca Williams & Chace, 1982 from the Galapagos Rift, East Pacific Rise. The new species is distinguished from A. lusca by the less produced pterygostomial angle of the carapace, the presence of small teeth on the posterolateral margin of the third pleuron, and the lack of short plumose setae on the posteromedian margin of the telson. The genetic divergence of the mitochondrial cytochrome c oxidase subunit I (COI) gene (600 bp) among the nine Alvinocaris species analyzed clearly indicates that the new taxon is distinct from the congeneric species for which genetic data are available. PMID- 25544514 TI - On the genus Hermippus Simon, 1893 (Araneae: Zodariidae, Zodariinae) in India with the description of three new species from the Western Ghats and proposing a new biogeographical hypothesis for the distribution of the genus. AB - Three new species of the ant-eating spider genus Hermippus Simon, 1893, H. globosus sp. nov., H. inflexus sp. nov. and H. gavi sp. nov. are described and illustrated from the Western Ghats in the Kerala region of southern India. The genus is redefined and two species groups are recognized: the cruciatus-group with all the five described Oriental species including H. cruciatus Simon, 1905, H. arjuna Gravely, 1921, H. inflexus sp. nov., H. globosus sp. nov. and H. gavi sp. nov. and the loricatus-group representing all the seven described Afrotropical species including H. loricatus Simon, 1893, H. affinis Strand, 1906, H. schoutedeni Lessert, 1938, H. septemguttatus Lawrence, 1942, H. minutus Jocque, 1986, H. tenebrosus Jocque, 1986 and H. arcus Jocque, 1989. The biogeographic distribution and possible migratory route of Hermippus spp. from Africa to the Oriental region are given. PMID- 25544515 TI - Two new species of feather mites (Acarina: Psoroptidia) from the Great Barbet, Psilopogon virens (Piciformes: Megalaimidae). AB - The paper describes two new species of feather mites collected on Psilopogon virens (Boddaert) (Piciformes: Megalaimidae) in India (Meghalaya): Megalaimobius massarae sp. nov. (Analgoidea: Pteronyssidae) and Picalgoides arbenzi sp. nov. (Psoroptoidea: Psoroptoididae). Males of M. massarae sp. nov. differ from the other three species of the genus by the shape of the transventral sclerite which is much deeper concave. The female of the new species has the external copulatory tub with an acute apex (this structure has a truncated apex in females of other species). Males of Picalgoides arbenzi sp. nov. differ from the closest species P. capitonis Cerny, 1974 mainly by the shape of adanal apodemes which are fused into a large arch encircling the anal field. Females of the new species have the hysteronotal shield with acute posterior angles and setae d2 situated on the lateral margins of this shield (in females of P. capitonis the hysteronotal shield has the posterior angles rounded and setae d2 situated at a short distance from the lateral margins of this shield). PMID- 25544516 TI - Laubieriopsis petersenae n. sp. and L. cf. cabiochi (Amoureux, 1982) (Polychaeta: Fauveliopsidae) from dredge disposal sites off Honolulu, Hawaii. AB - Fauveliopsid polychaetes have been collected at dredge disposal sites off Honolulu from 397-507 m depth. We report and describe the first Pacific record of Laubieriopsis cf. cabiochi (Amoureux, 1982), originally described from the North Atlantic. A new species, Laubieriopsis petersenae, n. sp. is described as being the species in the genus with the lowest number of body segments (15). Other distinctive features are the presence of bidentate aciculars on thoracic chaetigers, and unpaired genital papilla present on the right side of chaetiger 6/7. The new species is most similar to the L. brevis complex from the Atlantic and L. hartmanae and L. brevis japonica from the Pacific Ocean, but differs on the combination of the characters cited above. We provide an emended diagnosis for this genus to include the ultrastructure of the acicular with rows of spines, and a key to all described species. PMID- 25544517 TI - Taxonomic revision of Scopocira Simon, 1900 (Araneae: Salticidae). AB - The genus Scopocira Simon, 1900 is revised and six valid species are redescribed and illustrated: S. carinata Crane, 1945, S. dentichelis Simon, 1900, S. fuscimana (Mello-Leitao, 1941), S. histrio Simon, 1900, S. melanops (Taczanowski, 1871) and S. tenella Simon, 1900. The following synonymies are established: S. vivida (Peckham & Peckham, 1901) = S. histrio Simon, 1900 syn. nov.; S. panamena Chamberlin & Ivie, 1936 = S. dentichelis Simon, 1900 syn. nov. The males of S. fuscimana (Mello-Leitao, 1941) and S. melanops (Taczanowski, 1871) are described and illustrated for the first time. Both sexes of S. abaporu sp. nov., S. bicornia sp. nov., S. cepa sp. nov., S. cyrili sp. nov. and S. kunai sp. nov., and males of S. crotalica sp. nov., S. pterodactyla sp. nov. and S. sciosciae sp. nov., all eight from South America, are described and illustrated, increasing the present member list up to 14 species. Record maps are given. Scopocira atypica Mello-Leitao, 1922 is considered species inquirenda. PMID- 25544518 TI - Revision of the genus Arotes Gravenhorst (Hymenoptera: Ichneumonidae: Acaenitinae) from Japan. AB - Three Japanese species of the genus Arotes Gravenhorst, 1829 are revised. A new species, A. japonicus Ito & Watanabe, sp. nov., is described from the four main islands of Japan. This species can easily be distinguished from congeneric species by the black body without yellow markings and the entirely black hind tibia. Arotes sugiharai Uchida, 1934 is newly recorded from the islands of Kyushu and Tsushima, and the males of this species are described for the first time. The synonymy of A. moiwanus (Matsumura, 1912) and its color variant alboannulatus Uchida, 1928 are confirmed by DNA sequence analysis of the mitochondrial COI gene. The key to the world's species of Arotes proposed by Castillo et al. (2011) is updated and a key to the Japanese species is provided. PMID- 25544519 TI - Neotropical Hemerodromia Meigen (Diptera: Empididae), a world of discovery I: new generic record and new species from Brazilian Amazon Basin. AB - Ten new species of Hemerodromia Meigen, 1822 are described and illustrated from the Brazilian state of Amazonas: H. amazonensis sp. nov., H. breviradia sp. nov., H. cercusdilatata sp. nov., H. collini sp. nov., H. epandriocurvialis sp. nov., H. jauensis sp. nov., H. lamellata sp. nov., H. longilamellata sp. nov., H. maturaca sp. nov., H. smithi sp. nov. This is the first record of the genus from the Brazilian Amazon Basin. PMID- 25544520 TI - Taxonomy of Eumenes punctatus-complex (Hymenoptera: Vespidae: Eumeninae) from Korea with DNA barcoding and key to Far Eastern species of the genus Eumenes Latreille, 1802. AB - Based on DNA barcoding analysis and morphological comparison, new synonymy is proposed for Eumenes punctatus de Saussure, 1852 =E. asioboreus Kim & Sk. Yamane, 2001, syn. nov. Independent status of the Far Eastern species E. rubrofemoratus Giordani Soika, 1941 from the transpalearctic E. coarctatus (Linnaeus, 1758) is supported, suggesting their recent origin with comparatively low genetic divergence. A revised key to the Far Eastern species of the genus Eumenes is provided. Distribution of E. quadratus Smith, 1852 is corrected and E. rubrofemoratus Giordani Soika, 1941 is newly recorded from South Korea. For future taxonomic comprehension of the Far Eastern Eumenes, problematic species pairs requiring additional molecular tests are hereby suggested and discussed. PMID- 25544521 TI - Zoogeography of epigean freshwater Amphipoda (Crustacea) in Romania: fragmented distributions and wide altitudinal variability. AB - Inland epigean freshwater amphipods of Romania are diverse and abundant for this region has a favourable geographical position between the Balkans and the Black Sea. Excluding Ponto-Caspian species originating in brackish waters and freshwater subterranean taxa, there are 11 formally recognized epigean freshwater species recorded from this country. They belong to 3 genera, each representing a different family: Gammarus (Gammaridae, 8 species or species complexes), Niphargus (Niphargidae, 2 epigean species) and Synurella (Crangonyctidae, one species). Their large-scale distribution patterns nevertheless remain obscure due to insufficient data, consequently limiting biogeographical interpretations. We provide extensive new data with high resolution distribution maps, thus improving the knowledge of the ranges of these taxa. Gammarus species display substantial altitudinal variability and patchy, fragmented distribution patterns. They occur abundantly, particularly in springs and streams, from lowlands to sub-mountainous and mountainous regions. In the light of recent molecular research, we hypothesize that the complex geomorphological dynamics of the Carpathian region during the Late Tertiary probably contributed to their allopatric distribution pattern. Contrasting with Gammarus, the genera Niphargus and Synurella exhibit low altitudinal variability, broad ecological valences and overlapping distributions, being widespread throughout the lowlands. The current distribution of N. hrabei and N. valachicus seems to be linked to the extent of the Paratethys during the Early Pliocene or Pleistocene. We further discuss the taxonomic validity of two synonymized and one apparently undescribed taxon, and provide an updated pictorial identification key that includes all taxa and forms discussed in our study. The mosaic distribution of epigean freshwater amphipod species in Romania shows that this region is particularly suitable for phylo- and biogeographical analyses of this group. PMID- 25544522 TI - Redescription and molecular characterisation of Dujardinascaris madagascariensis and a note on D. dujardini (Nematoda: Heterocheilidae), parasites of Crocodylus niloticus, with a key to Dujardinascaris spp. in crocodilians. AB - An examination of one specimen of Nile crocodile, Crocodylus niloticus (Laurenti, 1768), from Lake Turkana (Kenya), revealed the presence of two ascaridoid nematodes belonging to the genus Dujardinascaris Baylis, 1947. Dujardinascaris madagascariensis Chabaud & Caballero, 1966 was studied by scanning electron microscopy, redescribed, and differentiated from D. dujardini (Travassos, 1920). Dujardinascaris madagascariencsis is the second of the genus to be sequenced. An internal fragment of the small ribosomal subunit and nuclear ribosomal DNA internal transcribed spacer 2 region were amplified--the slowly evolving 18S gene region was used for phylogenetic analysis. Molecular data confirmed affinity of D. madagascariensis to the family Heterocheilidae and revealed its closest relationship with D. waltoni. A key to the species of Dujardinascaris parasitizing crocodiles is provided. PMID- 25544523 TI - On the identity of Prochyliza nigrimana (Meigen) and Prochyliza nigricornis (Meigen) (Diptera: Piophilidae), with a synopsis of Prochyliza Walker and description of a new species. AB - With representatives distributed throughout the Holarctic and Neotropical regions, the genus Prochyliza Walker (Diptera: Piophilidae) is known from eight species. There has been, however, considerable controversy over the identity of two of them: the common, synanthropic species Prochyliza nigrimana (Meigen), and the rarely collected Prochyliza nigricornis (Meigen). The described differences between both species were only based on body colouration but, since a wide colour variation has been documented among P. nigrimana individuals, several authors had suggested that both taxa might be just extreme colour variants of the same species. Recent collections from central Spain showed that the colouration characters described for P. nigricornis certainly apply to dark P. nigrimana individuals, but also to other Prochyliza specimens showing distinct morphological characters and genitalia. In order to solve this controversy, the holotypes of both P. nigrimana and P. nigricornis were studied, concluding that both specimens are conspecific and instating P. nigricornis as a subjective junior synonym (syn. nov.). A new species, Prochyliza georgekaplani sp. nov., is described from specimens collected in central Spain. A synopsis and an updated identification key to the known species of the genus Prochyliza are also provided. PMID- 25544524 TI - Two new species of the genus Dasybasis Macquart, 1847, from Chile (Diptera: Tabanidae: Diachlorini). AB - The females of Dasybasis antillanca and Dasybasis collagua, new species, are described from specimens collected in Osorno and Iquique Provinces, south and north Chile, respectively. Their relationships to other Dasybasis species are discussed. PMID- 25544525 TI - Alien bryozoans in the eastern Mediterranean Sea--new records from the coast of Lebanon. AB - The Levant Basin (SE Mediterranean) is the most exposed to the introduction of non-indigenous species. The current assessment of exotic bryozoans present along the coast of Lebanon has been completed by the recording of fourteen cheilostome species (one cryptogenic) collected by diving in 17 localities (2-42 m). This set of exotic bryozoans comprises ten genera, including four (Akatopora Davis, 1934, Drepanophora Harmer, 1957, Mucropetraliella Stach, 1936 and Predanophora Tilbrook, 2006) not previously reported in the Mediterranean, while Celleporaria is the most successful extra-Mediterranean genus with four species in the survey collection. A new Celleporina species, C. bitari n. sp., also collected in the Red Sea, is described. Although lessepsian migration through the Suez Canal is the main pathway for exotic bryozoans in this region, the geographic origin of some species suggests that shipping through Gibraltar Strait is also responsible to a large extent. PMID- 25544526 TI - The Cylindrobulla/Ascobulla complex--unraveling problems in identification and adding to Cylindrobulla diversity (Gastropoda, Heterobranchia, Sacoglossa) by describing a new species. AB - Sacoglossa (Gastropoda: Heterobranchia) are generally considered a monophyletic group, previously associated within the now defunct "Opisthobranchia", but now basally located within Panpulmonata. In the light of this new phylogenetic hypothesis, detailed knowledge of the most basal groups within Sacoglossa is of paramount importance. This study focuses on the genus Cylindrobulla, which is usually considered the most basal group within the Sacoglossa from a morphological point of view, because it does not share the typical elongate radula teeth of all other Sacoglossa. We describe a new species, Cylindrobulla schuppi sp. nov., and provide data on its food. We reexamined and clarify the radula of the type species C. beauii, review the genus with all other valid species, provide new characters to aid in the proper identification of species within this genus, compare it to the very similar genus Ascobulla, present a determination key using external characters to ensure proper identification of the two similar genera, and discuss phylogenetic relationships within the shelled sacoglossan, the Oxynoacea. PMID- 25544527 TI - A new species of Eostyloceros (Cervidae, Artiodactyla) from the Late Miocene of the Linxia Basin in Gansu, China. AB - A new species, Eostyloceros hezhengensis sp. nov., is established based on a skull with its cranial appendages collected from the Late Miocene Liushu Formation of the Linxia Basin in Gansu Province, northwestern China. It is a large-sized muntjak with a distinct longitudinal ridge along the lateral margin of the frontal bone that joins the antler pedicle. The pedicle is short, cylindrical, robust, and extends posteriorly from the rear of the orbit. The anterior and posterior branches arise from the burr and diverge at an angle of 30 degrees . The posterior branch is relatively long, and its tip is strongly curved posteriorly. The anterior branch is straight and situated anteromedially from the posterior branch. The posterior branch is lateromedially compressed, and the anterior branch has a circular cross section. The morphological observation together with a cladistic and a principal component analysis indicate that E. hezhengensis is more basal than any known species of the genus Eostyloceros in having shorter pedicles, a lower position of the fork above the burr, more slender anterior branches, and a small angle between the anterior and posterior branches. Its age is the middle Late Miocene, corresponding to the late Bahean. PMID- 25544528 TI - Characithecium (Monogenoidea: Dactylogyridae) parasitic on the Neotropical fish Oligosarcus jenynsii (Teleostei: Characidae) from the Pampasic region, Argentina, with the emendation of the genus. AB - Presently, only 2 species of dactylogyrid monogeneans have been reported Characidae inhabiting lakes and streams from the Pampasic region (central Argentina). During a parasitological survey on the characid Oligosarcus jenynsii, from Nahuel Ruca Lake (Buenos Aires province, Argentina), dactylogyrids were found on the gills. Specimens were identified as members of Characithecium: C. chascomusensis n. comb, C. longianchoratum n. sp., C. robustum n. sp., C. quadratum n. sp. and C. chelatum n. sp. These species can be distinguished from each other mainly by differences in the shape of the accessory piece of the male copulatory organ, morphology of anchors and ventral bars as well as position of vaginal aperture. The observation of some additional features present in all species studied, such as the vaginal aperture position (as midventral, lateroventral or lateromarginal) and the variability in the morphology of ventral bar (posteromedial projection present or absent) justified an emended diagnosis of Characithecium. PMID- 25544529 TI - Redescription of Leptohyphes cornutus Allen, 1967 (Ephemeroptera: Leptohyphidae) and description of three related new species. AB - Leptohyphes cornutus Allen from Brazil (Santa Catarina) and Misiones, Argentina is re-studied from new material and newly diagnosed as follows: tubercles on head (two pairs), pronotum (two pairs, anterior pair very small), and mesonotum (two pairs), abdominal terga without paired tubercles, nor remnants of them; fore femur length/maximum width, 1.4-1.8; tarsal claws denticulation 4-11+1; hind wing pads present in females; gill formula 3/10/8/8/5. Three new species are described from the nymphal stage: 1) Leptohyphes airuoca sp. nov. from Minas Gerais and Rio de Janeiro (Brazil) characterized by: i) two paired tubercles on head, two pairs on pronotum, and one pair on mesonotum, abdominal terga VI-IX with single medial tubercle projecting from hind margin; ii) fore femur length/maximum width, 1.7 2.0; iii) tarsal claws denticulation 4+0; iv) hind wing pads absent in female; v) gill formula 3/9/9/7/6. 2) Leptohyphes cornutillus sp. nov. from Espirito Santo (Brazil), with: i) paired tubercles on head (two pairs), pronotum (two pairs, anterior pair very small), and mesonotum (three pairs), abdominal terga with remnants of paired tubercles on hind margin (blunt and short undulations in dorsal view); ii) fore femur length/maximum width, 2.1-2.3; iii) tarsal claws denticulation 6+1; iv) hind wing pads present in females; v) gill formula 3/11/9/9/6. And 3) Leptohyphes nebulosus sp. nov. from Espirito Santo (Brazil), with: i) two paired tubercles on head, one pair on pronotum, and one pair on mesonotum, abdominal terga VI-VII with paired submedian tubercles on hind margin; ii) fore femur length/maximum width, 1.6; iii) tarsal claws denticulation 5+1; iv) hind wing pads present in females; v) gill formula 3/9/9/9/6. PMID- 25544530 TI - The immature stages of Polypedilum (Pentapedilum) nodosum (Johannsen) and Polypedilum (Tripodura) masudai (Tokunaga) (Diptera, Chironomidae, Chironominae). AB - Based on associated material collected from Macau and Guangxi, the pupae and larvae of Polypedilum (Pentapedilum) nodosum Johannsen and P. (Tripodura) masudai Tokunaga are described completely for the first time. Both species are newly recorded from China. Characters for distinguishing the immature stage of these species from other allied Polypedilum species are noted. The previously recorded Polypedilum (Pentapedilum) 'K1' of Cranston (1996) is shown to be P. nodosum. Information is provided on distribution and ecological tolerances. PMID- 25544531 TI - A survey of the Cape Floristic Region of South Africa for the presence of cyst nematodes (Nematoda: Heteroderidae). AB - A survey was performed to detect the presence of cyst nematodes in the Cape Floristic Region of South Africa. Soil was collected in the rhizosphere of the dominant plant species within blocks of indigenous vegetation and cysts were extracted from them. A total of 81 blocks of indigenous vegetation were sampled as described. Cysts were detected in 7 of these samples, representing 6 different vegetation types. One set of primers was used to amplify the ITS regions from these cysts, including the 5.8S ribosomal gene, as well as short parts of the 18S and 28S ribosomal genes. ITS-rDNA sequences from the indigenous isolates were aligned with selected sequences of other species from the Heteroderidae. Phylogenetic analyses to resolve the relationships between indigenous isolates and selected representatives of the Heteroderidae were conducted using the Maximum Parsimony method. The consensus tree resulting from alignment of the circumfenestrate cysts revealed that isolates SK18, WK1 and WK26 are included in a clade of Globodera species that parasitise non-solanaceous plants, forming a monophyletic group with G. millefolii, G. artemisiae, and an unidentified Globodera sp. from Portugal. In a tree resulting from the alignment of the Heterodera spp., isolates OK14 and WK2 are included in the Afenestrata group, forming a monophyletic group with H. orientalis.This survey unearthed at least four potentially new species of cyst nematodes, which may prove invaluable for the study of the evolution and biogeography of the group. PMID- 25544532 TI - Description of Helicoconis tatricus sp. n. (Neuroptera, Coniopterygidae) from Slovakia (Central Europe) and key for determination of all Palaearctic species of subgenus Helicoconis. AB - A new species of dustywings, Helicoconis tatricus sp. n., is described from the foothills of the Tatra Mountains in Slovakia. The new species differs from other species of the subgenus Helicoconis by structure of male genitalia-unfurcated styli and wide and short apophyses. The key for determination of all Palaearctic species of the subgenus Helicoconis is added and the distribution of Palaearctic species is discussed. PMID- 25544533 TI - A new species of the genus Mygdonia (Hemiptera: Heteroptera: Coreidae) from Madagascar with a key to species. AB - A new species, Mygdonia milivoji sp. nov. (Coreidae: Coreinae: Mictini) from south-west Madagascar is described, illustrated and compared with widely distributed M. elongata Distant, 1879. A key to Mygdonia species based on females is given and distribution of both Madagascan species is briefly discussed. PMID- 25544534 TI - Lineage delimitation and description of nine new species of bush frogs (Anura: Raorchestes, Rhacophoridae) from the Western Ghats Escarpment. AB - Bush frogs of the genus Raorchestes are distributed mainly in the Western Ghats Escarpment of Peninsular India. The inventory of species in this genus is incomplete and there is ambiguity in the systematic status of species recognized by morphological criteria. To address the dual problem of taxon sampling and systematic uncertainty in bush frogs, we used a large-scale spatial sampling design, explicitly incorporating the geographic and ecological heterogeneity of the Western Ghats. We then used a hierarchical multi-criteria approach by combining mitochondrial phylogeny, genetic distance, geographic range, morphology and advertisement call to delimit bush frog lineages. Our analyses revealed the existence of a large number of new lineages with varying levels of genetic divergence. Here, we provide diagnoses and descriptions for nine lineages that exhibit divergence across multiple axes. The discovery of new lineages that exhibit high divergence across wide ranges of elevation and across the major massifs highlights the large gaps in historical sampling. These discoveries underscore the significance of addressing inadequate knowledge of species distribution, namely the "Wallacean shortfall", in addressing the problem of taxon sampling and unknown diversity in tropical hotspots. A biogeographically informed sampling and analytical approach was critical in detecting and delineating lineages in a consistent manner across the genus. Through increased taxon sampling, we were also able to discern a number of well-supported sub clades that were either unresolved or absent in earlier phylogenetic reconstructions and identify a number of shallow divergent lineages which require further examination for assessment of their taxonomic status. PMID- 25544535 TI - Systematics of the Monomorium rothsteini Forel species complex (Hymenoptera: Formicidae), a problematic ant group in Australia. AB - A recent molecular, morphological and distributional analysis of Monomorium rothsteini demonstrated that it comprises many separately evolving lineages that could be recognised morphologically and/or genetically based on mitochondrial DNA sequences. Based on these results M. rothsteini is revised, resulting in four species being brought out of synonymy (M. bogischi Wheeler, M. leda Forel, M. humilior Forel and M. subapterum Wheeler) and 18 new species recognised: M. broschorum n. sp., M. capeyork n. sp., M. eremoides n. sp., M. eremum n. sp., M. geminum n. sp., M. hertogi n. sp., M. hoffmanni n. sp., M. kidman n. sp., M. maryannae n. sp., M. merepah n. sp., M. mitchell n. sp., M. oodnadatta n. sp., M. pilbara n. sp., M. speculum n. sp., M. stagnum n. sp., M. tenebrosum n. sp., M. topend n. sp., M. torrens n. sp. Monomorium rothsteini v. doddi Santschi is recognised as a valid synonomy of M. rothsteini s.str. Along with M. rothsteini Forel s. str., there are now 23 described species in the complex, however it likely comprises many more species given the number of additional CO1 lineages and morphotypes that remain unresolved due to incomplete data. Biological notes are provided as well as a key to workers, descriptions, images and distribution maps for each species. PMID- 25544536 TI - Three new Prothemenops species (Araneae: Idiopidae) from central Thailand. AB - Prothemenops irineae sp. n., P. khirikhan sp. n. and P. phanthurat sp. n. are described from males and females collected in the Thai provinces of Prachuap Khiri Khan and Phetchaburi. The diagnosis of the genus Prothemenops is emended to include these three species and others to be described later. Notes on variation of morphological characters, biology and phenology are given. PMID- 25544537 TI - A revision of the genus Bombyciella Draudt, 1950, with description of a new species and a new genus (Lepidoptera, Noctuidae: Xyleninae). AB - The small Noctuidae genus Bombyciella Draudt, 1950, is revised, based on type material of its only two known species, Bombyciella talpa Draudt, 1950 and Bombyciella sericea Draudt, 1950. Bombyciella antra sp. n. from southwest China is described as a new species close to B. talpa, the type-species of Bombyciella. B. sericea is found to be different in most characters, not congeneric with B. talpa, and most closely related to the genus Euplexia Stephens and Chandata Moore. Therefore a new genus, Maxiana gen. n., is described for its inclusion. These genera belong to two different tribus in the subfamily Xyleninae, Xylenini (Bombyciella) and Phlogophorini (Maxiana gen. n.). The systematic placement within the two subfamilies is also discussed. Lectotypes for B. talpa and B. sericea are designated. PMID- 25544538 TI - Torneuma penaensis sp. n. from the Algarve, Portugal (Coleoptera, Curculionidae). AB - A new species of the genus Torneuma Wollaston, 1860 is described from the Algarve region in Portugal. It is the third species of the genus known from Portugal besides T. longipenne Pic, 1910 and T. serpentinum Stuben, 2007. PMID- 25544539 TI - Description of the female and notes on distribution, habitat, nymphal development, song and chromosomes of Tropidonotacris grandis Ragge (Orthoptera: Phaneropteridae). AB - The female of Tropidonotacris grandis is described and information on distribution, habitat, song, chromosomes and nymphal development of this species given. The populations of northern Tanzania all occur in deciduous dry forest, a habitat highly endangered by destruction and therefore T. grandis must be regarded at least as a vulnerable species according to the IUCN red list. PMID- 25544540 TI - A review of the Tychobythinus algiricus species group from North Africa (Coleoptera: Staphylinidae: Pselaphinae). AB - The species belonging to the Tychobythinus algiricus group are revised and the group is characterized and defined. Tychobythinus algiricus (Raffray, 1871) is redescribed, illustrated and its distribution and its synonymic framework discussed, establishing that Tychobythinus occidentalis Besuchet, 1962 is a junior synonym of Tychobythinus algiricus (syn. nov.). A key for species identification is provided. PMID- 25544541 TI - Three new species in the leafhopper genus Angustuma (Hemiptera: Cicadellidae: Evacanthinae) from Thailand. AB - The genus Angustuma Xing & Li, 2013 of the subfamily Evacanthinae is recorded from Thailand for the first time. Three new species, Angustuma basinigra sp. nov., Angustuma flavinigra sp. nov. and Angustuma flavimacula sp. nov., are described and illustrated. Their diagnostic characteristics are compared with close relatives. A key to all known species of Angustuma is provided. PMID- 25544542 TI - Absence of consistent genetic differentiation among several morphs of Actinia (Actiniaria: Actiniidae) occurring in the Portuguese coast. AB - Actinia equina, the beadlet sea anemone, is a very labile species, displaying variable colour patterns, broad habitat choice and diverse modes of reproduction. Historically, studies using genetic markers such as allozymes and differences in habitat choice lead several authors to propose that different colour morphs could represent different species. One of the species defined was A. fragacea. In this paper, the relationships between brown, red and green colour morphs of A. equina and A. fragacea were studied, using two DNA fragments (one mitochondrial and one nuclear). Individuals were sampled from three different areas in Portugal separated by a maximum distance of 500 km. This is the first study applying direct sequencing of selected gene fragments to approach the validity of Actinia morphs as different genetic entities. The results show that, at least in the Portuguese coast, these colour morphs do not correspond to the two valid species recognized in the literature. The existence of cryptic species is discussed. PMID- 25544543 TI - Role of the mitochondrial alternative oxidase pathway in hydrogen photoproduction in Chlorella protothecoides. AB - MAIN CONCLUSION: The AOX pathway in C. protothecoides plays an important role in the photoprotection of PSII by alleviating the inhibition of the repair of the photodamaged PSII during H2 photoproduction. We had demonstrated that nitrogen limitation (LN) substantially enhanced H2 photoproduction in Chlorella protothecoides. In the present study, the mitochondrial alternative oxidase (AOX) pathway capacity was found to increase significantly during H2 photoproduction under LN or under LN simultaneously with sulfur deprivation (LNS) conditions. The purpose of this study was to clarify the role of the AOX pathway during H2 photoproduction in C. protothecoides. The AOX pathway can affect H2 photoproduction in the following ways: (1) consuming O2, which is favorable for the establishment of anaerobiosis; (2) consuming NADPH and competing with hydrogenase for photosynthetic electrons, which would decrease the H2 photoproduction; (3) protecting photosystem (PS) II, which is a direct electron source for H2 photoproduction, from photoinhibition. In LN and LNS cultures, the inhibition of the AOX pathway reduced the H2 photoproduction significantly, and did not increase the amount of O2. But, the inhibition of the AOX pathway decreased the maximal photochemical efficiency of PSII (F v/F m) and the actual photochemical efficiency of PSII (Phi PSII) significantly, leading to photoinhibition, which would decrease the photosynthetic electrons transferred to hydrogenase. And, the inhibition of the AOX pathway did not change the level of photoinhibition in the presence of D1 protein synthesis inhibitor chloramphenicol, indicating that the inhibition of the AOX pathway did not accelerate the photodamage to PSII directly but inhibited the repair of the photodamaged PSII. Therefore, the mitochondrial AOX pathway in C. protothecoides plays an important role in the photoprotection of PSII by alleviating the inhibition of the repair of the photodamaged PSII during H2 photoproduction, which is thus able to supply more electrons to hydrogenase under LN and LNS conditions. PMID- 25544545 TI - Disaster Metrics: Evaluation of de Boer's Disaster Severity Scale (DSS) Applied to Earthquakes. AB - INTRODUCTION: Quantitative measurement of the medical severity following multiple casualty events (MCEs) is an important goal in disaster medicine. In 1990, de Boer proposed a 13-point, 7-parameter scale called the Disaster Severity Scale (DSS). Parameters include cause, duration, radius, number of casualties, nature of injuries, rescue time, and effect on surrounding community. Hypothesis This study aimed to examine the reliability and dimensionality (number of salient themes) of de Boer's DSS scale through its application to 144 discrete earthquake events. METHODS: A search for earthquake events was conducted via National Oceanic and Atmospheric Administration (NOAA) and US Geological Survey (USGS) databases. Two experts in the field of disaster medicine independently reviewed and assigned scores for parameters that had no data readily available (nature of injuries, rescue time, and effect on surrounding community), and differences were reconciled via consensus. Principle Component Analysis was performed using SPSS Statistics for Windows Version 22.0 (IBM Corp; Armonk, New York USA) to evaluate the reliability and dimensionality of the DSS. RESULTS: A total of 144 individual earthquakes from 2003 through 2013 were identified and scored. Of 13 points possible, the mean score was 6.04, the mode = 5, minimum = 4, maximum = 11, and standard deviation = 2.23. Three parameters in the DSS had zero variance (ie, the parameter received the same score in all 144 earthquakes). Because of the zero contribution to variance, these three parameters (cause, duration, and radius) were removed to run the statistical analysis. Cronbach's alpha score, a coefficient of internal consistency, for the remaining four parameters was found to be robust at 0.89. Principle Component Analysis showed uni-dimensional characteristics with only one component having an eigenvalue greater than one at 3.17. The 4-parameter DSS, however, suffered from restriction of scoring range on both parameter and scale levels. CONCLUSION: Jan de Boer's DSS in its 7-parameter format fails to hold statistically in a dataset of 144 earthquakes subjected to analysis. A modified 4-parameter scale was found to quantitatively assess medical severity more directly, but remains flawed due to range restriction on both individual parameter and scale levels. Further research is needed in the field of disaster metrics to develop a scale that is reliable in its complete set of parameters, capable of better fine discrimination, and uni-dimensional in measurement of the medical severity of MCEs. PMID- 25544544 TI - Heteromerization of ligand binding domains of N-methyl-D-aspartate receptor requires both coagonists, L-glutamate and glycine. AB - NMDA receptors (NMDAR) are voltage- and glutamate-gated heteromeric ion channels found at excitatory neuronal synapses, the functions of which are to mediate the mechanisms of brain plasticity and, thereby, its higher order functions. In addition to Glu, the activation of these heteromeric receptors requires Gly or d Ser as a coagonist. However, it is not fully known as to why coagonism is required for the opening of NMDAR ion channels. We show herein that the ligand binding domains (LBD) of the GluN1 and GluN2A subunits of the NMDAR heterodimerize only when both coagonists, Glu and Gly/d-Ser, bind to their respective sites on GluN2 and GluN1. In the agonist-free state, these domains form homomeric interactions, which are disrupted by binding of their respective agonists. Also, in a heteromer formed by the LBDs, GluN2A is more sensitized to bind Glu, while the affinity of Gly for GluN1 remains unchanged. We thus provide direct evidence to show that coagonism is necessary for heteromeric pairing of LBDs, which is an essential step in forming functional ion channels in NMDARs. PMID- 25544546 TI - Resolution of severe cardiomyopathy in infantile Pompe disease. AB - Infantile Pompe disease is a rare inborn error of metabolism characterized by severe hypertrophic cardiomyopathy and generalised hypotonia occurring in infancy. We present a case of an infant with severe hypertrophic cardiomyopathy that resolved after treatment with enzyme replacement therapy. PMID- 25544547 TI - Bronchial Schwannoma: An Uncommon Tumor. PMID- 25544548 TI - Professions and Working Conditions Associated With Community-Acquired Pneumonia. AB - INTRODUCTION: Community-acquired pneumonia (CAP) is not considered a professional disease, and the effect of different occupations and working conditions on susceptibility to CAP is unknown. The aim of this study is to determine whether different jobs and certain working conditions are risk factors for CAP. METHODOLOGY: Over a 1-year period, all radiologically confirmed cases of CAP (n=1,336) and age- and sex-matched controls (n=1,326) were enrolled in a population-based case-control study. A questionnaire on CAP risk factors, including work-related questions, was administered to all participants during an in-person interview. RESULTS: The bivariate analysis showed that office work is a protective factor against CAP, while building work, contact with dust and sudden changes of temperature in the workplace were risk factors for CAP. The occupational factor disappeared when the multivariate analysis was adjusted for working conditions. Contact with dust (previous month) and sudden changes of temperature (previous 3 months) were risk factors for CAP, irrespective of the number of years spent working in these conditions, suggesting reversibility. CONCLUSION: Some recent working conditions such as exposure to dust and sudden changes of temperature in the workplace are risk factors for CAP. Both factors are reversible and preventable. PMID- 25544549 TI - Status of the ban on asbestos use in Spain and Latin America. PMID- 25544550 TI - Quality of life in schizophrenia spectrum disorders: associations with insight and psychopathology. AB - Therapeutic interventions in chronic mental illness face the important challenge to pursuit the quality of life (QOL) of patients. Insight into chronic mental illness, though a prerequisite for treatment adherence and a positive therapeutic outcome, has shown adverse associations with subjective QOL. This study aims to explore the contribution of psychopathological symptoms on the ambiguous role of insight on QOL. Seventy-two outpatients with schizophrenia spectrum disorders were assessed using the positive and negative syndrome scale, the scale to assess unawareness of mental disorder, and the WHOQOL-100 instrument for the assessment of quality of life. Insight was found to associate inversely with quality of life. Among psychopathological symptoms, depressive symptoms were the strongest negative contributor on QOL. Mediation analysis revealed that the effects of awareness of the consequences of illness on QOL were largely mediated by depressive symptoms (full mediation for the effect on physical and psychological domain and partial mediation for the effect on independence and environment domain of the QOL). Our results suggest that the inverse relationship between insight and subjective quality of life is partially mediated by depressive symptoms. We discuss theoretical and therapeutic implications of the findings, in conjunction with similar recent research data. PMID- 25544551 TI - Prediction-driven matched molecular pairs to interpret QSARs and aid the molecular optimization process. AB - BACKGROUND: QSAR is an established and powerful method for cheap in silico assessment of physicochemical properties and biological activities of chemical compounds. However, QSAR models are rather complex mathematical constructs that cannot easily be interpreted. Medicinal chemists would benefit from practical guidance regarding which molecules to synthesize. Another possible approach is analysis of pairs of very similar molecules, so-called matched molecular pairs (MMPs). Such an approach allows identification of molecular transformations that affect particular activities (e.g. toxicity). In contrast to QSAR, chemical interpretation of these transformations is straightforward. Furthermore, such transformations can give medicinal chemists useful hints for the hit-to-lead optimization process. RESULTS: The current study suggests a combination of QSAR and MMP approaches by finding MMP transformations based on QSAR predictions for large chemical datasets. The study shows that such an approach, referred to as prediction-driven MMP analysis, is a useful tool for medicinal chemists, allowing identification of large numbers of "interesting" transformations that can be used to drive the molecular optimization process. All the methodological developments have been implemented as software products available online as part of OCHEM (http://ochem.eu/). CONCLUSIONS: The prediction-driven MMPs methodology was exemplified by two use cases: modelling of aquatic toxicity and CYP3A4 inhibition. This approach helped us to interpret QSAR models and allowed identification of a number of "significant" molecular transformations that affect the desired properties. This can facilitate drug design as a part of molecular optimization process. Graphical AbstractMolecular matched pairs and transformation graphs facilitate interpretable molecular optimisation process. PMID- 25544552 TI - Quantitative evaluation of radiation oncologists' adaptability to lower reimbursing treatment programs. AB - PURPOSE: Rapid development of sophisticated modalities has challenged radiation oncologists to evaluate workflow and care delivery processes. Our study assesses treatment modality use and willingness to alter management with anticipated limitations in reimbursement and resources. METHODS AND MATERIALS: A web-based survey was sent to 43 radiation oncologists in a National Cancer Institute designated comprehensive cancer center network. The survey contained 7 clinical cases with various acceptable treatment options based on our institutional clinical pathways. Each case was presented in 3 modules with varying situations: (1) unlimited resources with current reimbursement, (2) restricted reimbursement (bundled payment), and (3) both restricted reimbursement and resources. Reimbursement rates were based on the 2013 Medicare fee schedule. Adoption of lower reimbursing options (LROs) was defined as the percentage of scenarios in which a respondent selected an LRO compared with baseline. RESULTS: Forty-three physicians completed the survey, 11 (26%) at academic and 32 (74%) at community facilities. When bundled payment was imposed (module 1 vs 2), an increase in willingness to adopt LROs was observed (median 11.1%). When physicians were limited to both bundled payment and resource restriction, adoption of LROs was more pronounced (module 1 vs 3; median 22.2%, P < .01). There was a trend to selecting LROs between module 1 and 2 that reached significance when transitioning from module 1 to 3. A positive correlation between years in clinical practice and adoption of LROs was demonstrated (r(2) = 0.181, P<.01). This association remained significant when stratifying respondents by experience (<=25 vs >25 years, P = .02). CONCLUSIONS: Radiation oncologists were more likely to choose lower reimbursing treatment options when both resource restriction and bundled payment were presented. Those with fewer years of clinical practice were less inclined to alter management, perhaps reflecting modern residency training. Future cost-utility analyses may help to better guide radiation oncologists in selection of LROs. PMID- 25544554 TI - Pregnancy-like hyperplasia with focal atypia arising within a gynecomastic male breast: a case report. PMID- 25544553 TI - Prospective observer and software-based assessment of magnetic resonance imaging quality in head and neck cancer: Should standard positioning and immobilization be required for radiation therapy applications? AB - PURPOSE: The purpose of this study was to investigate the potential of a head and neck magnetic resonance simulation and immobilization protocol on reducing motion induced artifacts and improving positional variance for radiation therapy applications. METHODS AND MATERIALS: Two groups (group 1, 17 patients; group 2, 14 patients) of patients with head and neck cancer were included under a prospective, institutional review board-approved protocol and signed informed consent. A 3.0-T magnetic resonance imaging (MRI) scanner was used for anatomic and dynamic contrast-enhanced acquisitions with standard diagnostic MRI setup for group 1 and radiation therapy immobilization devices for group 2 patients. The impact of magnetic resonance simulation/immobilization was evaluated qualitatively by 2 observers in terms of motion artifacts and positional reproducibility and quantitatively using 3-dimensional deformable registration to track intrascan maximum motion displacement of voxels inside 7 manually segmented regions of interest. RESULTS: The image quality of group 2 (29 examinations) was significantly better than that of group 1 (50 examinations) as rated by both observers in terms of motion minimization and imaging reproducibility (P < .0001). The greatest average maximum displacement was at the region of the larynx in the posterior direction for patients in group 1 (17 mm; standard deviation, 8.6 mm), whereas the smallest average maximum displacement was at the region of the posterior fossa in the superior direction for patients in group 2 (0.4 mm; standard deviation, 0.18 mm). Compared with group 1, maximum regional motion was reduced in group 2 patients in the oral cavity, floor of mouth, oropharynx, and larynx regions; however, the motion reduction reached statistical significance only in the regions of the oral cavity and floor of mouth (P < .0001). CONCLUSIONS: The image quality of head and neck MRI in terms of motion-related artifacts and positional reproducibility was greatly improved by use of radiation therapy immobilization devices. Consequently, immobilization with external and intraoral fixation in MRI examinations is required for radiation therapy application. PMID- 25544555 TI - Evaluation of MR issues for the latest standard brands of orthopedic metal implants: plates and screws. AB - PURPOSE: The study was performed to evaluate magnetic resonance (MR) issues for the latest standard brands of plates and screws used in orthopedic surgery at a 1.5-T MR system, including the safety and metallic artifacts. METHODS: The plates and screws (made of titanium alloy and stainless steel materials, according to the latest standard brands) were assessed for displacement in degrees, MRI related heating and artifacts at a 1.5-T MR system. The displacement in degrees of the plates and screws was evaluated on an angel-measurement instrument at the entrance of the MR scanner. The MRI-related heating was assessed on a swine leg fixed with a plate by using a "worst-case" pulse sequence. A rectangular water phantom was designed to evaluate metallic artifacts of a screw on different sequences (T1/T2-weighted FSE, STIR, T2-FSE fat saturation, GRE, DWI) and then artifacts were evaluated on T2-weighted FSE sequence by modifying the scanning parameters including field of view (FOV), echo train length (ETL) and bandwidth to identify the influence of parameters on metallic artifacts. 15 volunteers with internal vertebral fixation (titanium alloy materials) were scanned with MR using axial and sagittal T2-FSE, sagittal T2-FSE fat suppression and STIR with conventional and optimized parameters, respectively. Then all images were graded by two experienced radiologists having the experience of more than 7 years under double-blind studies that is neither of them knew which was conventional parameter group and optimized parameter group. RESULTS: The average deflection angle of titanium alloy and stainless steel implants were 4.3 degrees and 7.7 degrees , respectively, (less than 45 degrees ) which indicated that the magnetically induced force was less than the weight of the object. The deflection angle of the titanium alloy implants was less than the stainless steel one (t=9.69, P<0.001). The average temperature changes of titanium alloy before and after the scan was 0.48 degrees C and stainless steel implants was 0.74 degrees C, respectively, with the background temperature changes of 0.24 degrees C. The water phantom test indicated that the DWI sequence produced largest artifacts, while FSE pulse sequence produced smallest artifacts. And T2-weighted FSE fat saturation sequence produced larger artifacts than STIR sequence. The influence of the scanning parameters on metallic artifacts was verified that metallic artifacts increased with longer echo train length and bigger FOV, while decreased with larger bandwidth. The interreader agreement was good or excellent for each set of images graded with Cohen's Kappa statistic. Image grading of axial and sagittal T2-FSE with optimized parameters were significantly superior to that with conventional parameters (grade, 3.3+/-0.5 vs 2.7+/-0.6, P=0.003; 3.2+/-0.4 vs 1.9+/-0.7, P=0.001) and image of STIR sequence received a better grade than T2 FSE FS sequence (grade, 3.4+/-0.5 vs 1.7+/-0.6, P<0.001). CONCLUSIONS: The latest standard plates and screws used in orthopedic surgery do not pose an additional hazard or risk to patients undergoing MR imaging at 1.5-T or less. Though artifacts caused by them cannot be ignored because of their relatively large size, it is possible to be minimized by choosing appropriate pulse sequences and optimizing scanning parameters, such as FSE and STIR sequence with large bandwidth, small FOV and appropriate echo train length. PMID- 25544556 TI - Evaluation of high-pitch dual-source CT angiography for evaluation of coronary and carotid-cerebrovascular arteries. AB - OBJECTIVES: To explore the feasibility and diagnostic accuracy of a combined one step high-pitch dual-source computed tomography angiography (CTA) technique for evaluation of coronary and carotid-cerebrovascular arteries. MATERIALS AND METHODS: 85 symptomatic patients suspected of coronary artery and cerebrovascular disease referred for simultaneous coronary and carotid-cerebrovascular CTA were included. Additional invasive angiography of the coronary and cerebral arteries was performed within 30 days in 23 and 13 patients, respectively. The objective parameters of image quality, the mean CT attenuations, image noise, signal-to noise ratio (SNR), and contrast-to-noise ratio (CNR) were evaluated. The subjective image quality of vessels was also assessed by 2 independent radiologists blinded to the patients' medical history and scan protocols. The diagnostic performance of CTA including sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the detection or exclusion of significant artery stenosis was calculated using the chi-squared test of contingency and correlated with the results of invasive angiography representing the standard of reference. RESULTS: Image quality was rated excellent (score 1) in 95.3% (1074/1127), good (score 2) in 3.3% (37/1127), adequate (score 3) in 1.0% (11/1127), and non-diagnostic (score 4) in 0.4% (5/1127) of coronary segments. Image quality of carotid and cerebral vessels was rated mostly excellent (score 1, 95.12% [78/82]; score 2, 3.66% [3/82]; score 3, 1.22% [1/82]). The sensitivity, specificity, PPV and NPV for the detection of coronary stenosis were 92.2% (81.1-97.7%), 95.2% (91.7-97.5%), 79.6% (67.1-89.1%) and 98.3% (95.8-99.5%), respectively. For the detection of carotid and cerebral artery stenosis, CTA demonstrated a sensitivity of 92.8% (80.5-98.4%), a specificity of 93.5% (88.3-96.8%), a PPV of 79.6% (65.6-89.7%) and a NPV of 97.9% (94.1-99.5%). The effective radiation dose was 1.42+/-0.44mSv (range, 0.88 3.35mSv). CONCLUSION: Dual-source CT with a one-step high-pitch scan protocol for combined coronary and carotid-cerebrovascular CTA provides good image quality and a high diagnostic accuracy for the simultaneous evaluation of coronary, carotid and cerebral artery stenosis and may be a useful examination with relatively low radiation exposure in patients with suspected coronary and carotid cerebrovascular disease. PMID- 25544557 TI - Computed tomographic features of lymphangioleiomyomatosis: evaluation in 138 patients. AB - PURPOSE: The aim was to characterize the computed tomographic (CT) findings from Japanese patients with lymphangioleiomyomatosis (LAM). MATERIALS AND METHODS: CT scans of the chest, abdomen, and pelvis from 124 patients with sporadic LAM (S LAM, mean age, 37.4 years) and 14 patients with tuberous sclerosis complex (TSC) LAM (mean age, 35.6 years) were analyzed. RESULTS: Pulmonary nodules (18.8%) and hepatic angiomyolipoma (AML, 24.3%) were more common in our patients than those in previous reports. Compared with TSC-LAM, S-LAM group had a higher frequency of pulmonary nodules (28.6% vs 32.3%, P<0.01) and lower frequencies of air-space consolidation (21.4% vs 2.4%, P<0.01), pneumothorax (28.6% vs 8.1%, P=0.02), pulmonary hilar lymphadenopathy (14.3% vs 0.8%, P<0.01), renal AML (85.7% vs 17.4%, P<0.01), hepatic AML (71.4% vs 17.4%, P<0.01), and retrocrural lymphadenopathy (14.3% vs 1.4%, P=0.04). Axial lymphatic abnormalities (i.e., thoracic duct dilatation, lymphadenopathy, and lymphangioleiomyoma) were most common in the pelvis and tended to decrease in incidence with increased distance from the pelvis. CONCLUSION: The incidence of some CT findings in Japanese patients differed from those in previous reports. Axial lymphatic abnormalities noted here suggest that the origin of LAM cells may be the pelvis. PMID- 25544558 TI - Reference database of lung volumes and capacities in wistar rats from 2 to 24 months. AB - This study determines the effects of growing and aging on lung physiological volumes and capacities and the incidence of inflammation in the small airways with age in rats. A reference database comprising of body weight gain, lung physiological volumes and capacities and an anatomopathological study of lung lesions over 240 Wistar rats from two to 24 -mo, is described. Tidal volume (TV), minute respiratory volume (MRV), and forced vital capacity (FVC) decreased during the first six months of life and then remain constant until 24 -mo of age. The respiratory frequency (Rf) and dynamical compliance (Cdyn) maintain at constant values from 2 to 24- mo of age; the functional residual capacity (FRC) increases in the first 6 -mo and then remains constant up to 24 -mo. It was verified a less intensive inflammation in the small airways with age, when compared with the median and large airways. IN CONCLUSION: This study showed the normal parameters for lung volumes and capacities and the incidence of infections for growing and aging male and female rats. The age-related data on these main respiratory parameters in rats would be useful in studies of aging-related disorders using this model and for safety pharmacology studies necessary for the development of drugs. PMID- 25544559 TI - Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. AB - The protein LC3 is indispensible for the cellular recycling process of autophagy and plays critical roles during cargo recruitment, autophagosome biogenesis, and completion. Here, we report that LC3 is phosphorylated at threonine 50 (Thr(50)) by the mammalian Sterile-20 kinases STK3 and STK4. Loss of phosphorylation at this site blocks autophagy by impairing fusion of autophagosomes with lysosomes, and compromises the ability of cells to clear intracellular bacteria, an established cargo for autophagy. Strikingly, mutation of LC3 mimicking constitutive phosphorylation at Thr(50) reverses the autophagy block in STK3/STK4 deficient cells and restores their capacity to clear bacteria. Loss of STK3/STK4 impairs autophagy in diverse species, indicating that these kinases are conserved autophagy regulators. We conclude that phosphorylation of LC3 by STK3/STK4 is an essential step in the autophagy process. Since several pathological conditions, including bacterial infections, display aberrant autophagy, we propose that pharmacological agents targeting this regulatory circuit hold therapeutic potential. PMID- 25544560 TI - Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease. AB - Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease. PMID- 25544561 TI - ELAV links paused Pol II to alternative polyadenylation in the Drosophila nervous system. AB - Alternative polyadenylation (APA) has been implicated in a variety of developmental and disease processes. A particularly dramatic form of APA occurs in the developing nervous system of flies and mammals, whereby various developmental genes undergo coordinate 3' UTR extension. In Drosophila, the RNA binding protein ELAV inhibits RNA processing at proximal polyadenylation sites, thereby fostering the formation of exceptionally long 3' UTRs. Here, we present evidence that paused Pol II promotes recruitment of ELAV to extended genes. Replacing promoters of extended genes with heterologous promoters blocks normal 3' extension in the nervous system, while extension-associated promoters can induce 3' extension in ectopic tissues expressing ELAV. Computational analyses suggest that promoter regions of extended genes tend to contain paused Pol II and associated cis-regulatory elements such as GAGA. ChIP-seq assays identify ELAV in the promoter regions of extended genes. Our study provides evidence for a regulatory link between promoter-proximal pausing and APA. PMID- 25544562 TI - Adaptive regulation of testis gene expression and control of male fertility by the Drosophila hairpin RNA pathway. [Corrected]. AB - Although endogenous siRNAs (endo-siRNAs) have been described in many species, still little is known about their endogenous utility. Here, we show that Drosophila hairpin RNAs (hpRNAs) generate an endo-siRNA class with predominant expression in testes. Although hpRNAs are universally recently evolved, we identify highly complementary protein-coding targets for all hpRNAs. Importantly, we find broad evidence for evolutionary divergences that preferentially maintain compensatory pairing between hpRNAs and targets, serving as first evidence for adaptive selection for siRNA-mediated target regulation in metazoans. We demonstrate organismal impact of hpRNA activity, since knockout of hpRNA1 derepresses its target ATP synthase-beta in testes and compromises spermatogenesis and male fertility. Moreover, we reveal surprising male-specific impact of RNAi factors on germ cell development and fertility, consistent with testis-directed function of the hpRNA pathway. Finally, the collected hpRNA loci chronicle an evolutionary timeline that reflects their origins from prospective target genes, mirroring a strategy described for plant miRNAs. PMID- 25544563 TI - Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. AB - Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi's sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 virus-host interactions. KSHV causes AIDS-associated cancers, and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. We found that the conserved KSHV protein ORF24 binds to RNA polymerase II and brings it to viral late promoters by mimicking and replacing cellular TATA-box-binding protein (TBP). This is required for herpesviral late gene expression, a complex and poorly understood phase of the viral lifecycle. PMID- 25544565 TI - Induction of rhabdomyosarcoma by embedded military-grade tungsten/nickel/cobalt not by tungsten/nickel/iron in the B6C3F1 mouse. AB - Continued improvements in the ballistic properties of military munitions have led to metal formulations for which little are known about the long-term health effects. Previously we have shown that a military-grade tungsten alloy comprised of tungsten, nickel, and cobalt, when embedded into the leg muscle of F344 rats to simulate a fragment wound, induces highly aggressive metastatic rhabdomyosarcomas. An important follow-up when assessing a compound's carcinogenic potential is to test it in a second rodent species. In this study, we assessed the health effects of embedded fragments of 2 military-grade tungsten alloys, tungsten/nickel/cobalt and tungsten/nickel/iron, in the B6C3F1 mouse. Implantation of tungsten/nickel/cobalt pellets into the quadriceps muscle resulted in the formation of a rhabdomyosarcoma around the pellet. Conversely, implantation of tungsten/nickel/iron did not result in tumor formation. Unlike what was seen in the rat model, the tumors induced by the tungsten/nickel/cobalt did not exhibit aggressive growth patterns and did not metastasize. PMID- 25544566 TI - Re: genotype and phenotype frequencies of paraoxonase 1 in fertile and infertile men. PMID- 25544564 TI - The strength and cooperativity of KIT ectodomain contacts determine normal ligand dependent stimulation or oncogenic activation in cancer. AB - The receptor tyrosine kinase KIT plays an important role in development of germ cells, hematopoietic cells, and interstitial pacemaker cells. Oncogenic KIT mutations play an important "driver" role in gastrointestinal stromal tumors, acute myeloid leukemias, and melanoma, among other cancers. Here we describe the crystal structure of a recurring somatic oncogenic mutation located in the C terminal Ig-like domain (D5) of the ectodomain, rendering KIT tyrosine kinase activity constitutively activated. The structural analysis, together with biochemical and biophysical experiments and detailed analyses of the activities of a variety of oncogenic KIT mutations, reveals that the strength of homotypic contacts and the cooperativity in the action of D4D5 regions determines whether KIT is normally regulated or constitutively activated in cancers. We propose that cooperative interactions mediated by multiple weak homotypic contacts between receptor molecules are responsible for regulating normal ligand-dependent or oncogenic RTK activation via a "zipper-like" mechanism for receptor activation. PMID- 25544569 TI - Two-dimensional near ultraviolet (2DNUV) spectroscopic probe of structural dependent exciton dynamics in a protein. AB - Understanding the exciton dynamics in biological systems is crucial for the manipulation of their function. We present a combined quantum mechanics (QM) and molecular dynamics (MD) simulation study that demonstrates how coherent two dimensional near-ultraviolet (2DNUV) spectra can be used to probe the exciton dynamics in a mini-protein, Trp-cage. The 2DNUV signals originate from aromatic transitions that are significantly affected by the couplings between residues, which determine exciton transport and energy relaxation. The temporal evolution of 2DNUV features captures important protein structural information, including geometric details and peptide orientations. PMID- 25544568 TI - Notch1 induces epithelial-mesenchymal transition and the cancer stem cell phenotype in breast cancer cells and STAT3 plays a key role. AB - Breast cancer is the most common malignancy in women. The Notch signaling pathway has been shown to be associated with the development and progression of many human cancers, including breast cancer, but the precise mechanism remains unknown. Here, the influence of Notch1 signaling in mammary epithelial cells was studied. We showed that Notch1 promotes proliferation in MCF7 and MCF10A cells. Transwell assay indicated that Notch1 overexpression promotes cell migration and the invasion of breast cancer cells. We showed that MCF7 and MCF10A cells overexpressing Notch1 acquired features of epithelial-mesenchymal transition (EMT) and displayed a cancer stem cell (CSC) phenotype. The expression levels of the epithelial markers E-cadherin and occludin were decreased, while the expression levels of the mesenchymal markers N-cadherin, vimentin and fibronectin were increased in cells overexpressing Notch1. We demonstrated that Notch1 induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) in breast cancer cells and increased the expression of p65 and interleukin (IL)-1beta. Inhibition of STAT3 activity by JSI124 reduced the expression of p65 and IL-1. Treatment of MCF7-notch1 and MCF10A-notch1 cells with JSI124 also reduced the expression of N-cadherin, markers of epithelial mesenchymal transition and increased the expression of E-cadherin. Our results suggest that Notch1 promotes EMT and the CSC phenotype through induction of STAT3. PMID- 25544567 TI - Endogenous WNT signals mediate BMP-induced and spontaneous differentiation of epiblast stem cells and human embryonic stem cells. AB - Therapeutic application of human embryonic stem cells (hESCs) requires precise control over their differentiation. However, spontaneous differentiation is prevalent, and growth factors induce multiple cell types; e.g., the mesoderm inducer BMP4 generates both mesoderm and trophoblast. Here we identify endogenous WNT signals as BMP targets that are required and sufficient for mesoderm induction, while trophoblast induction is WNT independent, enabling the exclusive differentiation toward either lineage. Furthermore, endogenous WNT signals induce loss of pluripotency in hESCs and their murine counterparts, epiblast stem cells (EpiSCs). WNT inhibition obviates the need to manually remove differentiated cells to maintain cultures and improves the efficiency of directed differentiation. In EpiSCs, WNT inhibition stabilizes a pregastrula epiblast state with novel characteristics, including the ability to contribute to blastocyst chimeras. Our findings show that endogenous WNT signals function as hidden mediators of growth factor-induced differentiation and play critical roles in the self-renewal of hESCs and EpiSCs. PMID- 25544570 TI - The pupae of the biting midges of the world (Diptera: Ceratopogonidae), with a generic key and analysis of the phylogenetic relationships between genera. AB - The pupae of species in each of the 45 genera of Ceratopogonidae known in this stage are diagnosed and described. A standard set of terms is provided, with a glossary, for all pertinent structures of the pupal stage within a context of other Culicomorpha. The variety of terms provided by previous authors are synonymized. Some pupal structures are directly related to developing adult structures and these are discussed. A key to the genera (and to the subgenera of Forcipomyia Meigen) allows for their identification. Pupation and pupal behaviour is summarized. A table of all previous descriptions of each stage of the immatures (egg, larva, pupa) is provided, showing that 13% of all validly named extant Ceratopogonidae are known as pupae. This study examined 45% of these species. All species known as fossil pupae are discussed. A phylogenetic analysis based primarily on pupal characters confirms the relationships between the subfamilies as well as the relationships between the genera in Leptoconopinae, Forcipomyiinae and Dasyheleinae. The question of the monophyly of the Culicoidini remains unresolved. Results confirm the paraphyly of the Ceratopogonini and, for the first time, the Sphaeromiini sensu lato, which is divided into Hebetulini (new tribe), Johannsenomyiini Crampton (new status) and Sphaeromiini sensu novum. Sphaeromiini sensu novum includes Sphaeromias Curtis, Leehelea Debenham, Homohelea Kieffer and Xenohelea Kieffer and forms the sister group of the Palpomyiini. Other genera in Sphaeromiini sensu lato not known as pupae are discussed. The genus Mallochohelea Wirth is shown to be polyphyletic and one group of species is therefore recognized as members of the new genus Anebomyia (type species = Mallochohelea atripes Wirth). A number of species previously placed in Stilobezzia Kieffer are shown to belong to Schizonyxhelea Clastrier. Study of the type species of the monotypic genus Nemoromyia Liu and Yu showed it to be a member of the Palpomyia distincta species group and the generic name is therefore a new junior synonym of Palpomyia. Examination of pupae showed that the following species were misplaced and are now in other genera as follows: Schizonyxhelea brevicostalis (Das Gupta & Wirth), 1968: 28 (Stilobezzia) new combination, Schizonyxhelea bulla (Thomsen), 1935: 289 (Stilobezzia) new combination, Schizonyxhelea caribe (Lane & Forattini), 1958: 208 (Stilobezzia) new combination, Schizonyxhelea diminuta (Lane & Forattini), 1958: 209 (Stilobezzia) new combination, Schizonyxhelea obscura (Lane & Forattini), 1958: 216 (Stilobezzia) new combination, Schizonyxhelea panamensis (Lane & Forattini), 1958: 218 (Stilobezzia) new combination, Schizonyxhelea thomsenae (Wirth), 1953: 83 (Stilobezzia) new combination, Schizonyxhelea scutata (Lane & Forattini), 1961: 92 (Stilobezzia) new combination, Pellucidomyia geari (de Meillon & Wirth), 1981: 547 (Macropeza) new combination, Dibezzia prominens (Johannsen) 1932: 435 (Johannsenomyia) new combination, Nilobezzia theileri (de Meillon & Wirth, 1981:552) (Sphaeromias) new combination, Anebomyia atripes (Wirth, 1962: 281) (Mallochohelea) new combination, Anebomyia fluminea (de Meillon & Wirth), 1981: 550 (Mallochohelea) new combination, Anebomyia siricis (de Meillon), 1961: 50 (Sphaeromias) new combination, Anebomyia texensis (Wirth), 1962: 283 (Mallochohelea) new combination, Anebomyia yunnana (Yu & Zou), in Yu et al. 2005: 1503 (Mallochohelea) new combination, Bezzia goezii (Schrank), 1803: 72 (Tipula) new combination (also a nomen nudum), Palpomyia nemorosa (Liu & Yu), 1991: 26 (Nemoromyia) new combination. Bezzia xanthogaster (Kieffer), 1919: 130 (Probezzia) is a junior homonym of Probezzia xanthogaster (Kieffer), 1917: 329 (Bezzia) and is here given the new name Bezzia gilvigaster Borkent. The fossil genus Paraculicoides Pierce, 1966: 94 and its type species Paraculicoides rouseae Pierce, 1966: 94 are removed from the Ceratopogonidae and likely belong in the Psychodidae. PMID- 25544571 TI - Statins do not improve lung function decline in COPD? PMID- 25544572 TI - Simulation of risk of tuberculosis infection in healthcare workers in hospitals of an intermediate incidence country. AB - We simulated the frequency of tuberculosis infection in healthcare workers in order to classify the risk of TB transmission for nine hospitals in Medellin, Colombia. We used a risk assessment approach to estimate the average number of infections in three risk groups of a cohort of 1082 workers exposed to potentially infectious patients over 10- and 20-day periods. The risk level of the hospitals was classified according to TB prevalence: two of the hospitals were ranked as being of very high priority, six as high priority and one as low priority. Consistent results were obtained when the simulation was validated in two hospitals by studying 408 healthcare workers using interferon gamma release assays and tuberculin skin testing. The latent infection prevalence using laboratory tests was 41% [95% confidence interval (CI) 34.3-47.7] and 44% (95% CI 36.4-51.0) in those hospitals, and in the simulation, it was 40.7% (95% CI 32.3 49.0) and 36% (95% CI 27.9-44.0), respectively. Simulation of risk may be useful as a tool to classify local and regional hospitals according to their risk of nosocomial TB transmission, and to facilitate the design of hospital infection control plans. PMID- 25544573 TI - Postoperative Radiotherapy Alone Versus Chemoradiotherapy in Stage I-II Endometrial Carcinoma: An Investigational and Propensity Score Matching Analysis. AB - PURPOSE: The purpose of this study was to compare the results of postoperative adjuvant radiotherapy (RT) and concurrent chemoradiotherapy (CRT) in stage I-II endometrial carcinoma. MATERIALS AND METHODS: We analyzed a total of 64 patients with surgically staged I-II endometrial carcinoma who were treated with postoperative adjuvant RT or concurrent CRT between March 1999 and July 2013. Thirty-two patients who received postoperative RT alone were matched with those who received postoperative CRT (n=32) in accordance to age, stage, and tumor histology. Overall survival and relapse-free survival, as well as toxicity of the RT and CRT arms were evaluated and compared. RESULTS: The 5-year overall survival rate was 90.0% for the RT arm and 91.6% for the CRT arm. There was no significant difference in overall survival between the two treatment arms (p=0.798). The 5 year relapse-free survival rate was 87.2% in the RT arm and 88.0% in the CRT arm. Again, no significant difference in relapse-free survival was seen between the two arms (p=0.913). In a multivariate analysis, tumor histology was an independent prognostic factor for relapse-free survival (hazard ratio, 3.67; 95% of CI, 2.34 to 7.65; p=0.045). Acute grade 3 or 4 hematologic toxicities in the CRT arm were significantly higher than in the RT alone arm (6.2% vs. 31.2%, p=0.010). CONCLUSION: Adjuvant pelvic concurrent chemoradioherapy did not show superior results in overall survival and relapse-free survival compared to RT alone in stage I-II endometrial carcinoma. PMID- 25544574 TI - Prognostic value of splenic artery invasion in patients undergoing adjuvant chemoradiotherapy after distal pancreatectomy for pancreatic adenocarcinoma. AB - PURPOSE: The purpose of this study was to evaluate the outcome of adjuvant chemoradiotherapy (CRT) after distal pancreatectomy (DP) in patients with pancreatic adenocarcinoma, and to identify the prognostic factors for these patients. MATERIALS AND METHODS: We performed a retrospective review of 62 consecutive patients who underwent curative DP followed by adjuvant CRT between 2000 and 2011. There were 31 men and 31 women, and the median age was 64 years (range, 38 to 80 years). Adjuvant radiotherapy was delivered to the tumor bed and regional lymph nodes with a median dose of 50.4 Gy (range, 40 to 55.8 Gy). All patients received concomitant chemotherapy, and 53 patients (85.5%) also received maintenance chemotherapy. The median follow-up period was 24 months. RESULTS: Forty patients (64.5%) experienced relapse. Isolated locoregional recurrence developed in 5 patients (8.1%) and distant metastasis in 35 patients (56.5%), of whom 13 had both locoregional recurrence and distant metastasis. The median overall survival (OS) and disease-free survival (DFS) were 37.5 months and 15.4 months, respectively. On multivariate analysis, splenic artery (SA) invasion (p=0.0186) and resection margin (RM) involvement (p=0.0004) were identified as significant adverse prognosticators for DFS. Also, male gender (p=0.0325) and RM involvement (p=0.0007) were associated with a significantly poor OS. Grade 3 or higher hematologic and gastrointestinal toxicities occurred in 22.6% and 4.8% of patients, respectively. CONCLUSION: Adjuvant CRT may improve survival after DP for pancreatic body or tail adenocarcinoma. Our results indicated that SA invasion was a significant factor predicting inferior DFS, as was RM involvement. When SA invasion is identified preoperatively, neoadjuvant treatment may be considered. PMID- 25544575 TI - Breast Cancer-Related Lymphedema after Neoadjuvant Chemotherapy. AB - PURPOSE: The risk for lymphedema (LE) after neoadjuvant chemotherapy (NCT) in breast cancer patients has not been fully understood thus far. This study is conducted to investigate the incidence and time course of LE after NCT. MATERIALS AND METHODS: A total of 313 patients with clinically node-positive breast cancer who underwent NCT followed by surgery with axillary lymph node (ALN) dissection from 2004 to 2009 were retrospectively analyzed. All patients received breast and supraclavicular radiation therapy (SCRT). The determination of LE was based on both objective and subjective methods, as part of a prospective database. RESULTS: At a median follow-up of 5.6 years, 132 patients had developed LE: 88 (28%) were grade 1; 42 (13%) were grade 2; and two (1%) were grade 3. The overall 5-year cumulative incidence of LE was 42%. LE first occurred within 6 months after surgery in 62%; 1 year in 77%; 2 years in 91%; and 3 years in 96%. In a multivariate analysis, age (hazard ratio [HR], 1.66; p < 0.01) and the number of dissected ALNs (HR, 1.68; p < 0.01) were independent risk factors for LE. Patients with both of these risk factors showed a significantly higher 5-year cumulative incidence of LE compared with patients with no or one risk factor (61% and 37%, respectively; p < 0.001). The addition of adjuvant chemotherapy did not significantly correlate with LE. CONCLUSION: LE after NCT, surgery, and SCRT developed early after treatment, and with a high incidence rate. More frequent surveillance of arm swelling may be necessary in patients after NCT, especially during the first few years of follow-up. PMID- 25544576 TI - TGF-beta Suppresses COX-2 Expression by Tristetraprolin-Mediated RNA Destabilization in A549 Human Lung Cancer Cells. AB - PURPOSE: Overexpression of cyclooxygenase 2 (COX-2) is thought to promote survival of transformed cells. Transforming growth factor beta (TGF-beta) exerts anti-proliferative effects on a broad range of epithelial cells. In the current study, we investigated whether TGF-beta can regulate COX-2 expression in A549 human lung adenocarcinoma cells, which are TGF-beta-responsive and overexpress COX-2. MATERIALS AND METHODS: Western blotting, Northern blotting, and mRNA stability assays were performed to demonstrate that COX-2 protein and mRNA expression were suppressed by TGF-beta. We also evaluated the effects of tristetraprolin (TTP) on COX-2 mRNA using RNA interference. RESULTS: We demonstrated that COX-2 mRNA and protein expression were both significantly suppressed by TGF-beta. An actinomycin D chase experiment demonstrated that COX-2 mRNA was more rapidly degraded in the presence of TGF-beta, suggesting that TGF beta-induced inhibition of COX-2 expression is achieved via decreased mRNA stability. We also found that TGF-beta rapidly and transiently induced the expression of TTP, a well-known mRNA destabilizing factor, before suppression of COX-2 mRNA expression was observed. Using RNA interference, we confirmed that increased TTP levels play a pivotal role in the destabilization of COX-2 mRNA by TGF-beta. Furthermore, we showed that Smad3 is essential to TTP-dependent down regulation of COX-2 expression in response to TGF-beta. CONCLUSION: The results of this study show that TGF-beta down-regulated COX-2 expression via mRNA destabilization mediated by Smad3/TTP in A549 cells. PMID- 25544577 TI - Nomogram for predicting breast conservation after neoadjuvant chemotherapy. AB - PURPOSE: The ability to accurately predict the likelihood of achieving breast conservation surgery (BCS) after neoadjuvant chemotherapy (NCT) is important in deciding whether NCT or surgery should be the first-line treatment in patients with operable breast cancers. MATERIALS AND METHODS: We reviewed the data of 513 women, who had stage II or III breast cancer and received NCT and surgery from a single institution. The ability of various clinicopathologic factors to predict the achievement of BCS and tumor size reduction to <= 3 cm was assessed. Nomograms were built and validated in an independent cohort. RESULTS: BCS was performed in 50.1% of patients, with 42.2% of tumors reduced to <= 3 cm after NCT. A multivariate logistic regression analysis showed that smaller initial tumor size, longer distance between the lesion and the nipple, absence of suspicious calcifications on mammography, and a single tumor were associated with BCS rather than mastectomy (p < 0.05). Negative estrogen receptor, smaller initial tumor size, higher Ki-67 level, and absence of in situ component were associated with residual tumor size <= 3 cm (p < 0.05). Two nomograms were developed using these factors. The areas under the receiver operating characteristic curves for nomograms predicting BCS and residual tumor <= 3 cm were 0.800 and 0.777, respectively. The calibration plots showed good agreement between the predicted and actual probabilities. CONCLUSION: We have established a model with novel factors that predicts BCS and residual tumor size after NCT. This model can help in making treatment decisions for patients who are candidates for NCT. PMID- 25544578 TI - Diagnostic and Prognostic Implications of Spine Magnetic Resonance Imaging at Diagnosis in Patients with Multiple Myeloma. AB - PURPOSE: The aim of this study is to determine the diagnostic and prognostic role of baseline spinal magnetic resonance imaging (MRI) in patients with multiple myeloma. MATERIALS AND METHODS: We enrolled patients newly diagnosed with multiple myeloma from 2004-2011 at a single center. Abnormal MRI findings that were not detected in radiographs have been analyzed and categorized as malignant compression fractures or extramedullary plasmacytoma. The bone marrow (BM) infiltration patterns on MRI have been classified into five categories. RESULTS: A total of 113 patients with a median age of 65 years (range, 40 to 89 years) were enrolled in the study. Malignant compression fractures not detected in the bone survey were found in 26 patients (23.0%), including three patients (2.6%) with no related symptoms or signs. Extramedullary plasmacytoma was detected in 22 patients (19.5%), including 15 (13.3%) with epidural extension of the tumor. Of these 22 patients, 11 (50.0%) had no relevant symptoms or signs. The presence of malignant compression fractures did not influence overall survival; whereas non epidural extramedullary plasmacytoma was associated with poor overall survival in the multivariate analysis (hazard ratio, 3.205; 95% confidence interval [CI], 1.430 to 9.845; p=0.042). During the follow-up for a median of 21 months (range, 1 to 91 months), overall survival with the mixed BM infiltrative pattern (median, 24.0 months; 95% CI, 22.9 to 25.1 months) was shorter than those with other patterns (median 56 months; 95% CI, 48.9 to 63.1 months; p=0.030). CONCLUSION: These results indicate that spine MRI at the time of diagnosis is useful for detecting skeletal lesions and predicting the prognosis in patients with multiple myeloma. PMID- 25544579 TI - Incidence of primary spinal cord, spinal meninges, and cauda equina tumors in Korea, 2006-2010. AB - PURPOSE: Primary spinal cord and appendage tumors (PSCAT) originating from the spinal cord, spinal meninges, and cauda equina are uncommon. Worldwide, population-based cancer registry data are mostly based on malignant tumors only, which means few data are available on PSCATs, including non-malignant tumors. Therefore, the objective of this study was to provide information regarding the incidence of both non-malignant and malignant PSCATs in Korea on a national level. MATERIALS AND METHODS: Incidence of PSCATs was estimated from cases diagnosed between 2006 and 2010 using the National Cancer Incidence Database in Korea. Age-adjusted rates were calculated using the world standard population, and male-to-female rate ratios were calculated by histology type. RESULTS: Of all PSCATs registered (n=3,312), 86.6% were non-malignant. The overall age-adjusted incidence of PSCATs was 1.08 per 100,000 person-years, with an incidence of 0.99 per 100,000 in females and 1.15 in males. The most common site of PSCATs was the spinal cord (83.4%), followed by spinal meninges (16.1%) and cauda equina (0.5%). The most common histological type was neurilemmoma (41.3%), followed by meningiomas (20.1%) and ependymomas (7.6%). Men had significantly higher rates than women for ependymomas and lymphomas but had lower rates for meningiomas. CONCLUSION: This study provides the first population-based analysis of PSCATs in Korea. PMID- 25544580 TI - Oxaliplatin-Induced Immune-Mediated Thrombocytopenia: A Case Report. AB - Oxaliplatin is a third-generation platinum derivative used for metastatic or advanced colorectal cancer treatment. Although myelosuppression is the most common cause of oxaliplatin-induced thrombocytopenia, rare cases of oxaliplatin induced immune-mediated thrombocytopenia are reported. We report a case of a 57 year-old woman with colon cancer who developed gum bleeding and petechiae after oxaliplatin infusion. Laboratory tests revealed grade 4 thrombocytopenia and grade 4 neutropenia. She recovered from the thrombocytopenia and accompanying neutropenia within 4 days with no recurrence following discontinuation of oxaliplatin. Physicians need to be aware of the risk of severe acute thrombocytopenia following oxaliplatin administration. PMID- 25544582 TI - Metachronous double primary cancer after treatment of breast cancer. AB - PURPOSE: The pattern of double primary cancer after treatment for breast cancer is important for patient survival. MATERIALS AND METHODS: We analyzed 108 cases of metachronous double primary cancer in breast cancer patients treated from 1999 to 2012. RESULTS: Metachronous double primary cancers occurred in 108 of 2,657 patients (4.1%) with breast cancer. The median time to the occurrence of second cancer after diagnosis of the first was 58.4+/-41.2 months (range, 6.9 to 180.2 months). The most common cancer was thyroid cancer, which occurred in 45 patients (41.7%). This was followed by gastric cancer in 16 patients (14.8%), endometrial cancer in 10 patients (9.3%), and cervical cancer in seven patients (6.5%). The relative risk showed a significant increase in endometrial (4.78; 95% confidence interval [CI], 1.66 to 13.79), gastric (2.61; 95% CI, 1.68 to 4.06), and thyroid cancer (1.95; 95% CI, 1.37 to 2.79). At 5 years after diagnosis of breast cancer, secondary cancer occurred in 48 patients (44.4%), with 50.0% of the endometrial, 56.3% of the stomach, and 37.8% of the thyroid cancer cases being diagnosed after 5 years. Median survival after diagnosis of the second cancer was 123.9+/-11.2 months. The prognosis was mainly influenced by the anatomic site. CONCLUSION: The incidence of endometrial, stomach, and thyroid cancer increased significantly after treatment with primary breast cancer, and survival was dependent on early detection and the type of second primary cancer. A prolonged follow-up examination for metachronous double primary cancer is needed to provide early detection and improve survival time in patients with breast cancer. PMID- 25544581 TI - Treatment Outcomes of Rituximab Plus Hyper-CVAD in Korean Patients with Sporadic Burkitt or Burkitt-like Lymphoma: Results of a Multicenter Analysis. AB - PURPOSE: This study was conducted to evaluate outcomes in adult patients with Burkitt lymphoma (BL) or Burkitt-like lymphoma treated with an rituximab plus hyper-CVAD (R-hyper-CVAD) regimen by focusing on tolerability and actual delivered relative dose intensity (RDI). MATERIALS AND METHODS: Patients >= 20 years of age and pathologically diagnosed with BL or Burkitt-like lymphoma were treated with at least one cycle of R-hyper-CVAD as the first-line treatment in this study. Eligible patients' case report forms were requested from their physicians to obtain clinical and laboratory data for this retrospective study. RESULTS: Forty-three patients (median age, 51 years) from 14 medical centers in Korea were analyzed, none of which were infected with human immunodeficiency virus. The majority of patients had advanced diseases, and 24 patients achieved a complete response (75.0%). After a median follow-up period of 20.0 months, 2-year event-free and overall survival rates were 70.9% and 81.4%, respectively. Eleven patients (25.6%) were unable to complete the R-hyper-CVAD regimen, including six patients due to early death. The RDIs of adriamycin, vincristine, methotrexate, and cytarabine were between 60% and 65%, which means less than 25% of patients received greater than 80% of the planned dose of each drug. Poor performance status was related to the lower RDIs of doxorubicin and methotrexate. CONCLUSION: R-hyper-CVAD showed excellent treatment outcomes in patients who were suitable for dose-intense chemotherapy. However, management of patients who are intolerant to a dose-intense regimen remains problematic due to the frequent occurrence of treatmentrelated complications. PMID- 25544583 TI - The efficacy of external beam radiotherapy for airway obstruction in lung cancer patients. AB - PURPOSE: The objective of this study was to evaluate external beam radiotherapy (EBRT) in lung cancer patients who suffer from airway obstruction. MATERIALS AND METHODS: Medical data of 95 patients with a lung mass that obstructed the airway and received EBRT for it were analyzed. Fifty-nine patients (62.1%) had non-small cell lung cancer and 36 patients (37.9%) had small cell lung cancer. Radiotherapy was given at 8 to 45 Gy (median, 30 Gy) in 1 to 15 fractions (median, 10 fractions). The response to EBRT was assessed through changes in radiographic findings and/or subjective symptoms between before and after EBRT. The median follow-up duration was 124 days. The primary end point was the airway-obstruction resolving rate after EBRT. The secondary end points were patient survival and toxic effects of EBRT. RESULTS: Improvement of airway obstruction after EBRT on chest X-ray was achieved in 75 of 95 patients (78.9%). The median time for resolving the radiologic findings and/or symptoms of airway obstruction after EBRT was 7 days (range, 1 to 76 days). The 1-year survival rate was significantly higher in responders than non-responders (12.5% vs. 0.0%, p < 0.001). The biologically effective dose of >= 39 Gyalpha/beta=10 (p < 0.01) and the longest obstructive lesion of < 6 cm (p=0.04) were significantly associated with a good response to EBRT in resolving the airway obstruction. No one had grade 3 or higher acute and chronic toxicities. CONCLUSION: EBRT is an effective treatment in relieving airway obstruction without severe toxicities in lung cancer patients. PMID- 25544585 TI - Diffuse Large B-Cell Lymphoma with Involvement of the Breast and Testis in a Male Patient. AB - Here we report a case of a 76-year-old man with diffuse large B-cell lymphoma (DLBCL) with simultaneous involvement of the right breast and left testicle. The patient underwent complete resection of the involved testis, followed by immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and prophylactic radiotherapy to the contralateral testis. Following this multimodal therapy, he achieved a complete response. This is a rare case of DLBCL involving both the breast and the testis in a male patient. PMID- 25544584 TI - The Impact of Molecularly Targeted Treatment on Direct Medical Costs in Patients with Advanced Non-small Cell Lung Cancer. AB - PURPOSE: To investigate the impact of targeted treatment on direct medical costs of patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Medical records of 108 stage IIIB/IV NSCLC patients treated in Seoul National University Hospital between 2003 and 2009, were reviewed to collect medical resources utilization data from the diagnosis of stage IIIB/IV NSCLC to the end of active anti-cancer treatment. The direct medical costs were calculated by multiplying the number of medical resources used by the unit price. All costs were expressed in US dollars for each patient. RESULTS: The mean total direct medical costs were $34,732 (standard deviation, 21,168) in the study cohort. The mean total direct medical costs were higher in epidermal growth factor receptor ( EGFR ) mutation (EGFR MT)-positive patients than EGFR wild-type (EGFR WT) patients ($41,403 vs. $30,146, p=0.005). However, the mean monthly direct medical costs did not differ significantly between EGFR MT-positive patients and EGFR WT patients ($2,120 vs. $2,702, p=0.119) because of the longer duration of active anti-cancer treatment in EGFR MT-positive patients. This discrepancy was mainly attributable to EGFR MT-positive patients' lower non-chemotherapy costs ($948 vs. $1,522, p=0.007). The total and monthly direct medical costs of ALK fusion positive patients who did not receive ALK inhibitors did not differ from WT/WT patients. CONCLUSION: This study suggests that the availability of targeted agents for EGFR MT-positive patients lowers the mean monthly medical costs by prolonging survival and diminishing the use of other medical resources, despite the considerable drug costs. PMID- 25544586 TI - Repolarization Lability Measured by Spatial TT' Angle. AB - AIMS: Increased T peaks cloud volume is associated with increased risk of ventricular arrhythmias (VA) in cardiomyopathy (CM) patients. T peaks cloud volume is formed, as a result, of (1) the angle between consecutive T-vectors and (2) temporal variability in T-vector amplitude. This study compares association of these two factors with VA. METHODS: Baseline orthogonal ECGs were recorded during 5 min at rest in 414 patients with structural heart disease [mean age 59.4+/-12.0; 68% whites; 73% men; 45% non-ischemic CM] before implantation of implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death. The spatial TT' angle between consecutive spatial T vectors was calculated using the definition of the inner product. RESULTS: During a median 14 months of follow-up, 61 patients experienced sustained VA with appropriate ICD therapies. In a multivariable Cox regression model after adjustment for age, sex, race, spatial TT' angle was associated with VA (HR 1.03; 95%CI 1.0-1.05; P=0.034). Interaction with CM type was found: TT' angle was strongly associated with polymorphic VT/VF in non-ischemic CM (HR 1.04; 95%CI 1.0-1.05; P=0.033). CONCLUSION: Increased spatial TT' angle is associated with increased risk of VA. PMID- 25544587 TI - Fermentation and alternative oxidase contribute to the action of amino acid biosynthesis-inhibiting herbicides. AB - Acetolactate synthase inhibitors (ALS-inhibitors) and glyphosate (GLP) are two classes of herbicide that act by the specific inhibition of an enzyme in the biosynthetic pathway of branched-chain or aromatic amino acids, respectively. The physiological effects that are detected after application of these two classes of herbicides are not fully understood in relation to the primary biochemical target inhibition, although they have been well documented. Interestingly, the two herbicides' toxicity includes some common physiological effects suggesting that they kill the treated plants by a similar pattern despite targeting different enzymes. The induction of aerobic ethanol fermentation and alternative oxidase (AOX) are two examples of these common effects. The objective of this work was to gain further insight into the role of fermentation and AOX induction in the toxic consequences of ALS-inhibitors and GLP. For this, Arabidopsis T-DNA knockout mutants of alcohol dehydrogenase (ADH) 1 and AOX1a were used. The results found in wild-type indicate that both GLP and ALS-inhibitors reduce ATP production by inducing fermentation and alternative respiration. The main physiological effects in the process of herbicide activity upon treated plants were accumulation of carbohydrates and total free amino acids. The effects of the herbicides on these parameters were less pronounced in mutants compared to wild-type plants. The role of fermentation and AOX regarding pyruvate availability is also discussed. PMID- 25544588 TI - Characterization of the salt stress vulnerability of three invasive freshwater plant species using a metabolic profiling approach. AB - The effects of salt stress on freshwater plants has been little studied up to now, despite the fact that they are expected to present different levels of salt sensitivity or salt resistance depending on the species. The aim of this work was to assess the effect of NaCl at two concentrations on three invasive freshwater species, Elodea canadensis, Myriophyllum aquaticum and Ludwigia grandiflora, by examining morphological and physiological parameters and using metabolic profiling. The growth rate (biomass and stem length) was reduced for all species, whatever the salt treatment, but the response to salt differed between the three species, depending on the NaCl concentration. For E. canadensis, the physiological traits and metabolic profiles were only slightly modified in response to salt, whereas M. aquaticum and L. grandiflora showed great changes. In both of these species, root number, photosynthetic pigment content, amino acids and carbohydrate metabolism were affected by the salt treatments. Moreover, we are the first to report the salt-induced accumulation of compatible solutes in both species. Indeed, in response to NaCl, L. grandiflora mainly accumulated sucrose. The response of M. aquaticum was more complex, because it accumulated not only sucrose and myo-inositol whatever the level of salt stress, but also amino acids such as proline and GABA, but only at high NaCl concentrations. These responses are the metabolic responses typically found in terrestrial plants. PMID- 25544589 TI - Tolerance to clomazone herbicide is linked to the state of LHC, PQ-pool and ROS detoxification in tobacco (Nicotiana tabacum L.). AB - In this study, plantlets of two tobacco (Nicotiana tabacum L.) varieties that are clomazone-tolerant (cv. Xanthi) and clomazone-sensitive (cv. Virginie vk51) were subjected to low concentration of clomazone herbicide. The oxygen-evolving rate of isolated chloroplasts, chlorophyll a fluorescence transients, JIP-test responses, hydrogen peroxide contents, antioxidant enzyme activities, cytohistological results and photosynthetic pigment contents were recorded. The results indicated that the carotenoid content was 2-fold higher in Virginie, which had greater clomazone sensitivity than Xanthi. Virginie exhibited noticeable decreases in the LHC content (Chl a/b ratio), the maximum photochemical quantum efficiency of PSII (Fv/Fm), the performance index on the absorption basis (PIabs), and the electron flux beyond the first PSII QA evaluated as (1-VJ) with VJ=(FJ-F0)/(Fm-F0) as well as increases in the rate of photon absorption (ABS/RC) and the energy dissipation as heat (DI0/RC). These results suggest that PSII photoinhibition occurred as a consequence of more reduced PQ-pool and accumulated QA(-). The oxygen evolution measurements indicate that PSI electron transport activity was not affected by clomazone. The more significant accumulation of H2O2 in Virginie compared to Xanthi was due to the absence of ROS-scavenging enzymes, and presumably induced programmed cell death (PCD). The symptoms of PCD were observed by cytohistological analysis, which also indicated that the leaf tissues of clomazone-treated Virginie exhibited significant starch accumulation compared to Xanthi. Taken together, these results indicate that the variable tolerance to clomazone observed between Virginie and Xanthi is independent of the carotenoid content and could be related to the state of the LHC, the redox state of the PQ-pool, and the activity of detoxification enzymes. PMID- 25544590 TI - Intrinsic stability of Brassicaceae plasma membrane in relation to changes in proteins and lipids as a response to salinity. AB - Changes in plasma membrane lipids, such as sterols and fatty acids, have been observed as a result of salt stress. These alterations, together with modification of the plasma membrane protein profile, confer changes in the physical properties of the membrane to be taken into account for biotechnological uses. In our experiments, the relationship between lipids and proteins in three different Brassicaceae species differing in salinity tolerance (Brassica oleracea, B. napus and Cakile maritima) and the final plasma membrane stability were studied. The observed changes in the sterol (mainly an increase in sitosterol) and fatty acid composition (increase in RUFA) in each species led to physical adaptation of the plasma membrane to salt stress. The in vitro vesicles stability was higher in the less tolerant (B. oleracea) plants together with low lipoxygenase activity. These results indicate that the proteins/lipids ratio and lipid composition is an important aspect to take into account for the use of natural vesicles in plant biotechnology. PMID- 25544591 TI - A possible role of an anthocyanin filter in low-intensity light stress-induced flowering in Perilla frutescens var. crispa. AB - The red-leaved form of Perilla frutescens var. crispa was induced to flower by low-intensity light stress. The leaves of this form are normally red, but turned green under low-intensity light due to anthocyanin depletion in the epidermis. Flowering did not occur when plants were grown under light passed through a red colored cellophane paper, which has an absorption spectrum similar to that of anthocyanins. High-concentration anthocyanins may play the role of a red-colored optical filter under normal light conditions, and this filter effect may be lost under low-intensity light, causing a change in the wavelength characteristics of the light with which the mesophyll cells are irradiated. This change may induce a photobiological effect leading to flowering. The gene expression and enzyme activity of phenylalanine ammonia-lyase (PAL), the key enzyme for anthocyanin biosynthesis, decreased under low-intensity light. L-2-aminooxy-3-phenylpropionic acid (AOPP), which is widely used as a PAL inhibitor, inhibited low-intensity light stress-induced flowering and increased PAL activity and anthocyanin content. The inhibition of flowering by AOPP in P. frutescens may be through different mechanisms than PAL inhibition. PMID- 25544592 TI - Magainin-related peptides stimulate insulin-release and improve glucose tolerance in high fat fed mice. AB - Earlier peptidomic analysis of the skin secretion of Xenopus amieti led to the identification of orthologs of magainins and other peptides. This study investigated the degradation, in vitro insulin-releasing and acute metabolic effects of magainin-AM1 (GIKEFAHSLGKFG KAFVGGILNQ) and magainin-AM2 (GVSKILHSAGKFGKAFLGEIMKS). Plasma degradation was investigated using reversed phase HPLC and MALDI-TOF mass spectroscopy. Insulin-releasing effects were determined using BRIN-BD11 clonal beta cells and mouse islets. Effects of magainin peptides on cytosolic enzyme lactate dehydrogenase release, membrane potential and intracellular Ca(2+) concentration were assessed using BRIN-BD11 cells while their in vivo effects on glucose tolerance and insulin release were assessed in obese, insulin-resistant Swiss National Institute of Health (NIH) mice. Both peptides were resistant to degradation by plasma enzymes in vitro for up to 8 h. Though magainin-AM1 elicited non-toxic, concentration-dependent stimulation of insulin-release from clonal BRINBD11 cells at concentrations >= 100nM, magainin-AM2 produced a higher stimulation of insulin-release from BRIN BD11 cells and isolated mouse islets. Membrane depolarization and intracellular [Ca(2+)]i in BRIN-BD11 cells were significantly (P<0.05) induced by both peptides and chelation of extracellular Ca(2+), addition of diazoxide or verapamil significantly (P<0.01) reduced the insulinotropic actions of the peptides. Administration of magainin-AM2 (75 nmol/kg body weight) to high-fat fed mice significantly enhanced insulin-release (P<0.01) and improved glucose tolerance (P<0.05). These data indicate magainin-AM2 peptides have potential for development into agents for treatment of type 2 diabetes. PMID- 25544593 TI - Postpartum metabolic control in a cohort of women with type 1 diabetes. AB - BACKGROUND AND OBJECTIVE: Pregnancy in women with type 1 diabetes (T1D) involves greater risks as compared to non-diabetic women, but less information is available about blood glucose and weight control after delivery. Our aim was to evaluate the postpartum metabolic profile (blood glucose and weight control) of women with T1D and the factors related to those metabolic outcomes. METHODS: A retrospective, observational study of 36 women with T1D during pregnancy and for up to one year after delivery. RESULTS: Fifty percent of patients attended a preconceptional planning program (PPP), and 44.4% of women were treated with continuous subcutaneous insulin infusion. Mean preconceptional HbA1c and body mass index (BMI) were 7.2+/-1.2% and 23.8+/-5.0 respectively. In the total cohort, blood glucose control significantly worsened one year after delivery (HbA1c: 7.2+/-1.2 vs 7.6+/-1.2%, P<0.001). Lower preconceptional HbA1c values were found in patients who attended PPP (6.6+/-0.5 vs. 7.8+/-1.4%; P=0.02), and were maintained for one year after delivery. No differences were found in body mass index (BMI) from the pregestational period to one year after delivery in any of two groups (No PPP 22.5+/-4.6 vs 23.2+/-4.8, P=0.078; PPP 25.4+/-3.4 vs 25.5+/ 3.4 kg/m(2), P=0.947). Preconceptional HbA1c was shown to be the most important determinant of metabolic control (beta=0.962, p<0.001) and weight one year after delivery (beta=0.524, p=0.025) and weight gain during pregnancy (beta=0.633, p=0.004). CONCLUSIONS: Pregnant women with T1D return to prepregnancy body weight one year after delivery, especially those with lower HbA1c levels and BMI before pregnancy. However, blood glucose control deteriorates after delivery, suggesting the need for changes in clinical practice after delivery. PMID- 25544594 TI - Acceptability of the aquatic environment for exercise training by people with chronic obstructive pulmonary disease with physical comorbidities: Additional results from a randomised controlled trial. AB - OBJECTIVES: Water-based exercise training is a relatively new concept in the management of people with COPD. This study aimed to examine the acceptability of the aquatic environment as a medium for exercise training in people with COPD with physical comorbidities. DESIGN: Following a supervised eight week, three times a week, water-based exercise training programme conducted in a hospital hydrotherapy pool as part of a randomised controlled trial, participants completed a questionnaire about their experience with exercise training in the pool including adverse events, barriers and factors enabling exercise programme completion, satisfaction with the aquatic environment and their preference for an exercise training environment. RESULTS: All 18 participants (mean (SD) age 72 (10) years; FEV1% predicted 60 (10) %) who commenced the water-based exercise training programme completed the questionnaire. Three participants withdrew from training. High acceptability of the water and air temperature, shower and change room facilities, staff assistance and modes of pool entry was reported (94% to 100%). Six factors were highly rated as enabling exercise programme adherence and completion: staff support (chosen by 93% of participants), enjoyment (80%), sense of achievement (80%), noticeable improvements (73%), personal motivation (73%) and participant support (53%). Eighty-nine percent of the participants indicated they would continue with water-based exercise. CONCLUSIONS: This study provides the first insight into the acceptability of the aquatic environment for exercise training in people with COPD and indicates water-based exercise and the aquatic environment is well accepted. PMID- 25544595 TI - Taxol stabilizes gap junctions and reduces ischemic ventricular arrhythmias in rats in vivo. AB - The dynamic movements of connexin 43 (Cx43) are regulated by microtubules and their associated proteins. Dysfunction of Cx43 in the ischemic myocardium is correlated with ventricular arrhythmias (VAs). The present study aimed to determine the effects of microtubules on Cx43 expression and distribution in myocardial tissue, as well as to examine the susceptibility of the heart to VAs during acute myocardial ischemia and reperfusion. Rats were subject to left coronary artery occlusion for 20 min followed by 20 min reperfusion and received taxol at different concentrations (0.1, 0.3 and 0.9 umol.kg-1 in 0.5 ml saline) intraperitoneally. Monophasic action potentials at the epicardium were recorded and analyzed using an electrocardiogram. Immunoblots and immunofluorescence staining were used to detect tubulin polymerization and Cx43 expression and distribution. Taxol pretreatment significantly ameliorated the depolymerization of microtubules, improved Cx43 expression and redistribution, reduced the occurrence of VAs, ameliorated shortening of 90% repolarization action potential durations (APD)90 and improved APD dispersion during myocardial ischemia reperfusion. The present study demonstrated that taxol reduced ischemic VAs and its mechanism may be correlated with the preservation of Cx43 by stabilizing microtubules. PMID- 25544596 TI - Volume-sensitive outwardly rectifying Cl(-) channels contribute to butyrate triggered apoptosis of murine colonic epithelial MCE301 cells. AB - Butyrate is a fatty acid with an important role in the maintenance of colonic homeostasis. It induces apoptosis in colonic epithelial cells and contributes to the pathogenesis of ulcerative colitis. However, just how how butyrate triggers apoptosis is poorly understood. In our model system of mouse colonic epithelial MCE301 cells, whole-cell patch-clamp recordings revealed the presence of swelling activated outwardly rectifying chloride ion (Cl(-)) currents. These currents exhibited time-dependent inactivation upon strong depolarization, a low field strength anion selectivity (I(-) > Br(-) > Cl(-) > F(-)), and a sensitivity to 4 (2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl)oxybutyric acid (DCPIB), a specific blocker of volume-sensitive outwardly rectifying (VSOR) Cl(-) channels. The results of flow cytometric analysis and caspase 3/7 assays demonstrated that exposure of MCE301 cells to sodium butyrate for 16 h triggered apoptotic cell shrinkage, phosphatidylserine exposure, and caspase 3/7 activation. Importantly, the VSOR Cl(-) channel blocker was able to inhibit sodium butyrate-induced apoptotic processes. These results suggest that activation of the VSOR Cl(-) channel is essential for sodium butyrate-triggered apoptosis in MCE301 cells. PMID- 25544597 TI - Autophagic regulation of smooth muscle cell biology. AB - Autophagy regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (patho)physiology. PMID- 25544598 TI - Is outcome of differentiated thyroid carcinoma influenced by tumor stage at diagnosis? AB - BACKGROUND: There is no international consensus on surveillance strategies for differentiated thyroid carcinoma (DTC) after radiotherapy for childhood cancer. Ultrasonography could allow for early detection of DTC, however, its value is yet unclear since the prognosis of DTC is excellent. We addressed the evidence for the question: 'is outcome of DTC influenced by tumor stage at diagnosis?'. METHODS: A multidisciplinary working group answered the sub-questions: 'is recurrence or mortality influenced by DTC stage at diagnosis? Does detection of DTC at an early stage contribute to a decline in adverse events of treatment?' The literature was systematically reviewed, and conclusions were drawn based on the level of evidence (A: high, B: moderate to low, C: very low). RESULTS: In children, level C evidence was found that detection of DTC at an early stage is associated with lower recurrence and mortality rates. No evidence was found that it influences morbidity rates. In adults, clear evidence was found that less advanced staged DTC is a favorable prognostic factor for recurrence (level B) and mortality (level A). Additionally, it was found that more extensive surgery increases the risk to develop transient hypoparathyroidism (level A) and that higher doses of radioiodine increases the risk to develop second primary malignancies (level B). CONCLUSION: Identification of DTC at an early stage is beneficial for children (very low level evidence) and adults (moderate to high level evidence), even considering that the overall outcome is excellent. These results are an important cornerstone for the development of guidelines for childhood cancer survivors at risk for DTC. PMID- 25544600 TI - Platelet derivatives in regenerative medicine: an update. AB - Prior preclinical and clinical studies support the use of platelet-derived products for the treatment of soft and hard tissue lesions. These regenerative effects are controlled by autocrine and paracrine biomolecules including growth factors and cytokines contained in platelet alpha granules. Each growth factor is involved in a phase of the healing process, such as inflammation, collagen synthesis, tissue granulation, and angiogenesis collectively promoting tissue restitution. Platelet derivatives have been prepared as platelet-rich plasma, platelet gel, platelet-rich fibrin, and platelet eye drops. These products vary in their structure, growth factors, composition, and cytokine concentrations. Here, we review the current use of platelet-derived biological products focusing on the rationale for their use and the main requirements for their preparation. Variation in the apparent therapeutic efficacy may have resulted from a lack of reproducible, standardized protocols for preparation. Despite several individual studies showing favorable treatment effects, some randomized controlled trials as well as meta-analyses have found no constant clinical benefit from the application of platelet-derived products for prevention of tissue lesions. Recently, 3 published studies in dentistry showed an improvement in bone density. Seven published studies showed positive results in joint regeneration. Five published studies demonstrated an improvement in the wound healing, and an improvement of eye epithelial healing was observed in 2 reports. Currently, at least 14 ongoing clinical trials in phase 3 or 4 have been designed with large groups of treated patients (n > 100). Because the rationale of the therapy with platelet-derived compounds is still debated, a definitive insight can be acquired only when these large randomized trials will be completed. PMID- 25544601 TI - Strategies for oral delivery and mitochondrial targeting of CoQ10. AB - Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a powerful, endogenously produced, intracellularly existing lipophilic antioxidant. It combats reactive oxygen species (ROS) known to be responsible for a variety of human pathological conditions. Its target site is the inner mitochondrial membrane (IMM) of each cell. In case of deficiency and/or aging, CoQ10 oral supplementation is warranted. However, CoQ10 has low oral bioavailability due to its lipophilic nature, large molecular weight, regional differences in its gastrointestinal permeability and involvement of multitransporters. Intracellular delivery and mitochondrial target ability issues pose additional hurdles. To maximize CoQ10 delivery to its biopharmaceutical target, numerous approaches have been undertaken. The review summaries the current research on CoQ10 bioavailability and highlights the headways to obtain a satisfactory intracellular and targeted mitochondrial delivery. Unresolved questions and research gaps were identified to bring this promising natural product to the forefront of therapeutic agents for treatment of different pathologies. PMID- 25544599 TI - Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents. AB - We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-IIalpha, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence. PMID- 25544602 TI - Development, optimization and evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of drug resistance lung cancer using Box-Behnken design. AB - In the present study, nanostructured lipid carriers (NLCs) along with various surfactants loaded with paclitaxel (PTX) were prepared by an emulsification technique using a Box-Behnken design. The Box-Behnken design indicated that the most effective factors on the size and PDI were at high surfactant concentration (1.5%), low lipids ratio (6:4) and medium homogenization speed (6000 rpm). Among all the formulations, Tween 20-loaded NLCs show least particle size compared to Tween 80 and Tween 60. Entrapment efficiency of Tween 20, Tween 80 and Tween 60 loaded formulations were 82.40, 85.60 and 79.78%, respectively. Drug release of Tween 80, Tween 20 and Tween 60-loaded NLCs is 64.9, 62.3 and 59.7%, respectively (within 72 h). Maximum cellular uptake was observed with Tween 20 formulation on Caco-2 cell lines. Furthermore, spray drying of resultant NLCs was showed good flow properties and was selected for drug delivery to deeper airways. In-vivo studies demonstrated the better localization of drug within the lungs using different surfactant-based pulmonary delivery systems. From this study, we have concluded that delivering drugs through pulmonary route is advantageous for local action in lungs as maximum amount of drug concentration was observed in lungs. The surfactants could prove to be beneficial in treating drug resistance lung cancer by inhibiting P-gp efflux in the form of nano lipidic carriers. PMID- 25544603 TI - Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery. AB - CONTEXT: The study was aimed to develop a polymeric nanoparticle formulation of anticancer drug carboplatin using biodegradable polymer polycaprolactone (PCL). The formulation is intended for intranasal administration to treat glioma anticipating improved brain delivery as nasal route possess direct access to brain and nanoparticles have small size to overcome the mucosal and blood-brain barrier. OBJECTIVE: Development and evaluation of carboplatin-PCL nanoparticles for brain delivery by nasal route. METHODOLOGY: Carboplatin-loaded PCL nanoparticles (CPCs) were prepared by double emulsion-solvent evaporation technique and characterized by particle size, zeta potential, entrapment efficiency, scanning electron microscopy and differential scanning calorimetry. The CPCs were assessed for in vitro release kinetics, ex vivo permeation and in situ nasal perfusion. Cytotoxic potential of CPCs in vitro was evaluated on LN229 human glioblastoma cells. RESULTS AND DISCUSSION: The optimized formulation of carboplatin-PCL nanoparticle CPC-08 with particle size of 311.6 +/- 4.7 nm and zeta potential -16.3 +/- 3.7 mV exhibited percentage entrapment efficiency of 27.95 +/- 4.21. In vitro drug release showed initial burst release followed by slow and continues release indicating biphasic pattern. The ex vivo permeation pattern through sheep nasal mucosa also exhibited a similar release pattern as for in vitro release studies. In situ nasal perfusion studies in Wistar rats demonstrate that CPCs show better nasal absorption than carboplatin solution. In vitro cytotoxicity studies on LN229 cells showed an enhancement in cytotoxicity by CPCs compared to carboplatin alone. CONCLUSION: CPC-08 effectively improves nasal absorption of carboplatin and can be used for intranasal administration of carboplatin for improved brain delivery. PMID- 25544604 TI - Novel drug delivery system: an immense hope for diabetics. AB - CONTEXT: Existing medication systems for the treatment of diabetes mellitus (DM) are inconvenient and troublesome for effective and safe delivery of drugs to the specific site. Therefore, investigations are desired to deliver antidiabetics using novel delivery approaches followed by their commercialization. OBJECTIVE: The present review aims to provide a compilation on the latest development in the field of novel drug delivery systems (NDDSs) for antidiabetics with special emphasis on particulate, vesicular and miscellaneous systems. METHODS: Review of literature (restricted to English language only) was done using electronic databases like Pubmed(r) and Scirus, i.e. published during 2005-2013. The CIMS/MIMS India Medical Drug Information eBook was used regarding available marketed formulation of antidiabetic drugs. Keywords used were "nanoparticle", "microparticle", "liposomes", "niosomes", "transdermal systems", "insulin", "antidiabetic drugs" and "novel drug delivery systems". Single inclusion was made for one article. If in vivo study was not done then article was seldom included in the manuscript. RESULTS: The curiosity to develop NDDSs of antidiabetic drugs with special attention to the nanoparticulate system followed by microparticulate and lipid-based system is found to emerge gradually to overcome the problems associated with the conventional dosage forms and to win the confidence of end users towards the higher acceptability. CONCLUSION: In the current scientific panorama when the area of novel drug delivery system has been recognized for its palpable benefits, unique potential of providing physical stability, sustained and site-specific drug delivery for a scheduled period of time can open new vistas for precise, safe and quality treatment of DM. PMID- 25544605 TI - Maternal serum vitamin D levels in pregnancies complicated by neural tube defects. AB - OBJECTIVE: The association between vitamin D deficiency and abnormal neural development has been proposed previously. We aimed to evaluate maternal serum vitamin D levels in pregnancies complicated by neural tube defects (NTDs) and compared them with healthy pregnant women. METHODS: A total of 60 pregnant women were included in this controlled cross-sectional study. Thirty of the patients whose pregnancies were complicated by meningocele, meningomyelocele, encephalocele, anencephaly and fetal acrania constituted the study group, whereas 30 normal pregnant women constituted the control group. The main parameters recorded for each woman were as follows: age, body mass index (BMI), gestational week (GW), gravidity, abortion, co-morbidities, dressing style, consumption of milk and dairy products and serum levels of 25(OH)VitD3, calcium, albumin and total protein. RESULTS: The mean maternal serum 25(OH)VitD3 level was 6.2 +/- 5.0 ng/ml in the study group and 9.1 +/- 7.3 ng/ml in the control group (p: 0.071). The mean maternal serum calcium level was statistically significantly higher in the control group, and calcium-rich dietary intake was also more common in this group (p < 0.05). There was no statistically significant difference between groups in terms of age, BMI, GW, dressing style and serum levels of albumin and total protein. CONCLUSIONS: Vitamin D deficiency is common among pregnant women, and maternal serum calcium levels were lower in pregnancies complicated by NTD than healthy pregnant women. Larger further studies are required to evaluate the effects of calcium-rich dietary sources or vitamin D and calcium in the development of NTDs. PMID- 25544608 TI - Dynamic visualization of alpha-catenin reveals rapid, reversible conformation switching between tension states. AB - The cytosolic protein alpha-catenin is a postulated force transducer at cadherin complexes. The demonstration of force activation, identification of consequent downstream events in live cells, and development of tools to study these dynamic processes in living cells are central to elucidating the role of alpha-catenin in cellular mechanics and tissue function. Here we demonstrate that alpha-catenin is a force-activatable mechanotransducer at cell-cell junctions by using an engineered alpha-catenin conformation sensor based on fluorescence resonance energy transfer (FRET). This sensor reconstitutes alpha-catenin-dependent functions in alpha-catenin-depleted cells and recapitulates the behavior of the endogenous protein. Dynamic imaging of cells expressing the sensor demonstrated that alpha-catenin undergoes immediate, reversible conformation switching in direct response to different mechanical perturbations of cadherin adhesions. Combined magnetic twisting cytometry with dynamic FRET imaging revealed rapid, local conformation switching upon the mechanical stimulation of specific cadherin bonds. At acutely stretched cell-cell junctions, the immediate, reversible conformation change further reveals that alpha-catenin behaves like an elastic spring in series with cadherin and actin. The force-dependent recruitment of vinculin-a principal alpha-catenin effector-to junctions requires the vinculin binding site of the alpha-catenin sensor. In cells, the relative rates of force dependent alpha-catenin conformation switching and vinculin recruitment reveal that alpha-catenin activation and vinculin recruitment occur sequentially, rather than in a concerted process, with vinculin accumulation being significantly slower. This engineered alpha-catenin sensor revealed that alpha-catenin is a reversible, stretch-activatable sensor that mechanically links cadherin complexes and actin and is an indispensable player in cadherin-specific mechanotransduction at intercellular junctions. PMID- 25544609 TI - Cell-size control and homeostasis in bacteria. AB - How cells control their size and maintain size homeostasis is a fundamental open question. Cell-size homeostasis has been discussed in the context of two major paradigms: "sizer," in which the cell actively monitors its size and triggers the cell cycle once it reaches a critical size, and "timer," in which the cell attempts to grow for a specific amount of time before division. These paradigms, in conjunction with the "growth law" [1] and the quantitative bacterial cell cycle model [2], inspired numerous theoretical models [3-9] and experimental investigations, from growth [10, 11] to cell cycle and size control [12-15]. However, experimental evidence involved difficult-to-verify assumptions or population-averaged data, which allowed different interpretations [1-5, 16-20] or limited conclusions [4-9]. In particular, population-averaged data and correlations are inconclusive as the averaging process masks causal effects at the cellular level. In this work, we extended a microfluidic "mother machine" [21] and monitored hundreds of thousands of Gram-negative Escherichia coli and Gram-positive Bacillus subtilis cells under a wide range of steady-state growth conditions. Our combined experimental results and quantitative analysis demonstrate that cells add a constant volume each generation, irrespective of their newborn sizes, conclusively supporting the so-called constant Delta model. This model was introduced for E. coli [6, 7] and recently revisited [9], but experimental evidence was limited to correlations. This "adder" principle quantitatively explains experimental data at both the population and single-cell levels, including the origin and the hierarchy of variability in the size-control mechanisms and how cells maintain size homeostasis. PMID- 25544610 TI - Peters plus syndrome mutations disrupt a noncanonical ER quality-control mechanism. AB - BACKGROUND: O-fucose is added to cysteine-rich domains called thrombospondin type 1 repeats (TSRs) by protein O-fucosyltransferase 2 (POFUT2) and is elongated with glucose by beta3-glucosyltransferase (B3GLCT). Mutations in B3GLCT result in Peters plus syndrome (PPS), an autosomal recessive disorder characterized by eye and other developmental defects. Although 49 putative targets are known, the function of the disaccharide and its role in PPS remain unexplored. RESULTS: Here we show that while POFUT2 is required for secretion of all targets tested, B3GLCT only affects the secretion of a subset, consistent with the observation that B3GLCT mutant phenotypes in PPS patients are less severe than embryonic lethal phenotypes of Pofut2-null mice. O-glycosylation occurs cotranslationally, as TSRs fold. Mass spectral analysis reveals that TSRs from mature, secreted protein are stoichiometrically modified with the disaccharide, whereas TSRs from protein still folding in the ER are partially modified, suggesting that O-glycosylation marks folded TSRs and promotes ER exit. In vitro unfolding assays demonstrate that fucose and glucose stabilize folded TSRs in an additive manner. In vitro refolding assays under redox conditions showed that POFUT2 recognizes, glycosylates, and stabilizes the folded form of TSRs, resulting in a net acceleration of folding. CONCLUSIONS: While known ER quality-control machinery rely on identifying and tagging unfolded proteins, we find that POFUT2 and B3GLCT mediate a noncanonical ER quality-control mechanism that recognizes folded TSRs and stabilizes them by glycosylation. Our findings provide a molecular basis for the defects observed in PPS and potential targets that contribute to the pathology. PMID- 25544612 TI - Twin plants from supernumerary egg cells in Arabidopsis. AB - Sexual reproduction of flowering plants is distinguished by double fertilization the two sperm cells delivered by a pollen tube fuse with the two gametic cells of the female gametophyte, the egg and the central cell-inside the ovule to give rise to the embryo and the nutritive endosperm, respectively. The pollen tube is attracted by nongametic synergid cells, and how these two cells of the female gametophyte are specified is currently unclear. Here, we show that ALTERED MERISTEM PROGRAM 1 (AMP1), encoding a protein associated with the endoplasmic reticulum, is required for synergid cell fate during Arabidopsis female gametophyte development. Loss of AMP1 function leads to supernumerary egg cells at the expense of synergids, enabling the generation of dizygotic twins. However, if twin embryos are formed, endosperm formation is prevented, eventually resulting in ovule abortion. The latter can be overcome by the delivery of supernumerary sperm cells in tetraspore (tes) pollen, enabling the formation of twin plants. Thus, both primary and supernumerary egg cells are fully functional in amp1 mutant plants. Sporophytic AMP1 expression is sufficient to prevent cell fate change of synergids, indicating that one or more AMP1-dependent mobile signals from outside the female gametophyte can contribute to its patterning, in addition to the previously reported lateral inhibition between gametophytic cells. Our results provide insight into the mechanism of synergid fate specification and emphasize the importance of specifying only one egg cell within the female gametophyte to ensure central-cell fertilization by the second sperm cell. PMID- 25544611 TI - Rac1-dependent phosphorylation and focal adhesion recruitment of myosin IIA regulates migration and mechanosensing. AB - BACKGROUND: Cell migration requires coordinated formation of focal adhesions (FAs) and assembly and contraction of the actin cytoskeleton. Nonmuscle myosin II (MII) is a critical mediator of contractility and FA dynamics in cell migration. Signaling downstream of the small GTPase Rac1 also regulates FA and actin dynamics, but its role in regulation of MII during migration is less clear. RESULTS: We found that Rac1 promotes association of MIIA with FA. Live-cell imaging showed that, whereas most MIIA at the leading edge assembled into dorsal contractile arcs, a substantial subset assembled in or was captured within maturing FA, and this behavior was promoted by active Rac1. Protein kinase C (PKC) activation was necessary and sufficient for integrin- and Rac1-dependent phosphorylation of MIIA heavy chain (HC) on serine1916 (S1916) and recruitment to FA. S1916 phosphorylation of MIIA HC and localization in FA was enhanced during cell spreading and ECM stiffness mechanosensing, suggesting upregulation of this pathway during physiological Rac1 activation. Phosphomimic and nonphosphorylatable MIIA HC mutants demonstrated that S1916 phosphorylation was necessary and sufficient for the capture and assembly of MIIA minifilaments in FA. S1916 phosphorylation was also sufficient to promote the rapid assembly of FAs to enhance cell migration and for the modulation of traction force, spreading, and migration by ECM stiffness. CONCLUSIONS: Our study reveals for the first time that Rac1 and integrin activation regulates MIIA HC phosphorylation through a PKC-dependent mechanism that promotes MIIA association with FAs and acts as a critical modulator of cell migration and mechanosensing. PMID- 25544613 TI - Individual differences in alpha frequency drive crossmodal illusory perception. AB - Perception routinely integrates inputs from different senses. Stimulus temporal proximity critically determines whether or not these inputs are bound together. Despite the temporal window of integration being a widely accepted notion, its neurophysiological substrate remains unclear. Many types of common audio-visual interactions occur within a time window of ~100 ms. For example, in the sound induced double-flash illusion, when two beeps are presented within ~100 ms together with one flash, a second illusory flash is often perceived. Due to their intrinsic rhythmic nature, brain oscillations are one candidate mechanism for gating the temporal window of integration. Interestingly, occipital alpha band oscillations cycle on average every ~100 ms, with peak frequencies ranging between 8 and 14 Hz (i.e., 120-60 ms cycle). Moreover, presenting a brief tone can phase-reset such oscillations in visual cortex. Based on these observations, we hypothesized that the duration of each alpha cycle might provide the temporal unit to bind audio-visual events. Here, we first recorded EEG while participants performed the sound-induced double-flash illusion task and found positive correlation between individual alpha frequency (IAF) peak and the size of the temporal window of the illusion. Participants then performed the same task while receiving occipital transcranial alternating current stimulation (tACS), to modulate oscillatory activity either at their IAF or at off-peak alpha frequencies (IAF+/-2 Hz). Compared to IAF tACS, IAF-2 Hz and IAF+2 Hz tACS, respectively, enlarged and shrunk the temporal window of illusion, suggesting that alpha oscillations might represent the temporal unit of visual processing that cyclically gates perception and the neurophysiological substrate promoting audio-visual interactions. PMID- 25544618 TI - Honouring Seppo Koponen on the occasion of this 70th Birthday. PMID- 25544614 TI - Molecular-genetic analysis is essential for accurate classification of renal carcinoma resembling Xp11.2 translocation carcinoma. AB - Xp11.2-translocation renal carcinoma (TRCC) is suspected when a renal carcinoma occurs in young patients, patients with a prior history of exposure to chemotherapy and when the neoplasm has morphological features suggestive of that entity. We retrieved 20 renal tumours (from 17,500 archival cases) of which morphology arose suspicion for TRCC. In nine cases, TFE3 translocation was confirmed by fluorescence in situ hybridisation analysis. In 9 of the remaining 11 TRCC-like cases (7 male, 4 female, aged 22-84 years), material was available for further study. The morphological spectrum was diverse. Six tumours showed a mixture of cells with eosinophilic or clear cytoplasm in tubular, acinar and papillary architecture. One case was high grade with epithelioid, spindle cell and sarcomatoid areas. Another showed tubular, solid, and papillary areas and foci containing spindle cells reminiscent of mucinous tubular and spindle cell carcinoma. The third showed dyscohesive nests of large epithelioid and histiocytoid cells in a background of dense lymphoplasmacytic infiltrate. By immunohistochemistry, keratin AE1/AE3 was diffusely positive in three tumours, while CK7 strongly stained one tumour and another focally and weakly. CD10 and Pax8 were expressed by eight, AMACR and vimentin by seven, CA-IX by four and TFE3 and cathepsin K by two tumours. Of the two TFE3-positive tumours, one showed polysomy of chromosome 7 and the other of 17; they were VHL normal and diagnosed as unclassifiable RCC. Of the seven TFE3-negative tumours, three showed polysomy of 7/17 and VHL abnormality and were diagnosed as combined clear cell RCC/papillary RCC. One TFE3-negative tumour with normal 7/17 but LOH 3p (VHL abnormality) was diagnosed as clear cell RCC. One TFE3-negative tumour with polysomy 7/17 but normal VHL was diagnosed as papillary RCC, and two with normal chromosomes 7/17 and VHL gene were considered unclassifiable. As morphological features and IHC are heterogeneous, TRCC-like renal tumours can only be sub classified accurately by multi-parameter molecular-genetic analysis. PMID- 25544615 TI - Human papilloma virus status of penile squamous cell carcinoma is associated with differences in tumour-infiltrating T lymphocytes. AB - Meta-analyses show that approximately half of all squamous cell carcinomas (SCCs) of the penis are associated with a human papillomavirus (HPV) infection. As data about the tumour microenvironment of HPV-positive and HPV-negative penile carcinomas is scarce and conflicting, we examined tumour-infiltrating lymphocyte populations in such cases. The HPV status of 28 penile SCCs was determined by polymerase chain reaction, while the number and distribution of different lymphocyte populations were analysed by immunohistochemistry on whole sections of paraffin-embedded tumour specimens. The average number of tumour-infiltrating T cells in HPV-associated SCC was higher than in HPV-negative SCC, and their phenotype showed strong polarization towards a T helper 1 and cytotoxic immune response. In addition, we identified more tumour-infiltrating regulatory T cells in HPV-positive carcinomas, which might represent a mechanism of immune evasion. The present study provides further evidence that the tumour microenvironment of HPV-positive carcinomas differs from that of HPV-negative carcinomas. PMID- 25544619 TI - A survey of East Palaearctic Gnaphosidae (Araneae). 3. On new and poorly known Gnaphosa Latreille, 1804. AB - Two new species, Gnaphosa koponeni sp. n. (??, Tuva, Russia) and G. tunevae sp. n. (?, Mongolia) are described. New figures and distribution data are provided for G. gracilior Kulczynski, 1901, G. kansuensis Schenkel, 1963, G. mandschurica Schenkel, 1963, G. sticta Kulczynski, 1908, G. stoliczkai O. Pickard-Cambridge, 1885 and G. wiehlei Schenkel, 1963. Additional morphological evidence is provided that G. similis Kulczynski, 1926 is not a synonym of G. muscorum (L. Koch, 1866). Gnaphosa stoliczkai is reported from Mongolia for the first time. The synonymy of Gnaphosa potanini Simon, 1895 with G. silvicola Kamura, 1988 is discussed and is likely to be incorrect. PMID- 25544620 TI - Studies on species of Holarctic Pardosa groups (Araneae, Lycosidae). VIII. The Palearctic species of the Pardosa nigra group. AB - The eight Palearctic species of the Pardosa nigra group are reviewed, illustrated and keyed. Two of them are redescribed: Pardosa lyrata (Odenwall, 1901) and P. paramushirensis (Nakatsudi, 1937). The former is widespread in Siberia and has also been found in Mongolia while the latter has been recorded from Japan (Honshu and Hokkaido) and Russia: the Kuril Islands (a neotype is designated from topotypic material from Paramushir Island). Pardosa fomichevi sp. n. is described from the Maritime Province (Primorye) in Russia, based on both sexes. Pardosa arctica (Kulczynski, 1916) is placed as a synonym to P. eiseni (Thorell, 1875). PMID- 25544621 TI - A revision of the Holarctic genus Larinioides Caporiacco, 1934 (Araneae: Araneidae). AB - All known species of Larinioides Caporiacco, 1934 are revised. Seven species are recognised, of which one is transferred from Araneus Clerck, 1757 as a new combination, Larinioides jalimovi (Bakhvalov, 1981) comb. n. The first description of a male of L. jalimovi is given. The following four new synonyms are proposed: Epeira gracilis Menge, 1878 syn. n. and Aranea dumetorum islandicola Strand, 1906 syn. n. = L. patagiatus (Clerck, 1757); Araneus cungei Bakhvalov, 1974, syn. n. = Larinioides folium (Schrank, 1803); and Araneus sclopetarius Clerck, 1757 syn. n. = L. cornutus (Clerck, 1757). Detailed illustrations of habitus, copulatory organs, and identification keys of males and females of all Larinioides species are provided. PMID- 25544622 TI - Two new species of Euscorpius (Scorpiones: Euscorpiidae) from Bulgaria, Serbia, and Greece. AB - Two new species of Euscorpius Thorell, 1876 (subgenus Euscorpius s.str.) (Scorpiones: Euscorpiidae) are described based on morphology and the COI DNA barcoding marker: E. deltshevi sp. n. from northern Bulgaria and neighbouring Serbia (formerly reported as E. carpathicus) and E. solegladi sp. n. from southwestern Bulgaria and neighbouring Greece (formerly reported as E. hadzii). PMID- 25544623 TI - A revision of the Neotropical genus Austrohahnia Mello-Leitao (Araneae, Hahniidae). AB - The Neotropical genus Austrohahnia Mello-Leitao, 1942 is revised, comprising four species from Argentina. The genus is here transferred to the subfamily Hahniinae Bertkau, 1878 from Cybaeolinae Lehtinen, 1967. Austrohahnia is diagnosed by a single synapomorphy, short setae ventrally on the abdomen, in immature as well as adult stages. The type species A. praestans Mello-Leitao, 1942 is redescribed. Austrohahnia catleyi new species is described and illustrated based both sexes from the alder forests of northwestern Argentina. Austrohahnia melloleitaoi (Schiapelli & Gerschman, 1942) new combination was transferred from Hahnia C.L. Koch, 1841, the male is described and illustrated for the first time, and the female is redescribed. Austrohahnia isophthalma (Mello-Leitao, 1941) new combination is also transferred from Hahnia and considered a nomen dubium. New geographic records of studied species are provided. PMID- 25544624 TI - Two new species of the Polysphincta genus-group (Hymenoptera: Ichneumonidae: Pimplinae) reared from their spider (Araneae) hosts in Europe. AB - Flacopimpla barathrica sp. n. and Zatypota flamma sp. n., belonging to the Polysphincta genus-group, are described, the former from Fennoscandia and the latter from Hungary. Like other species of this group for which the natural history is known, the new species are koinobiont ectoparasitoids of spiders. They have been reared from the theridiid spiders Thymoites bellissimus (L. Koch) and Parasteatoda sp. Archer respectively. The host records support the hypothesis of Flacopimpla being parasitoids of the spider family Theridiidae. The results also indicate that F. barathrica sp. n. has a very narrow host range consisting of a single species in Fennoscandia. The genus Flacopimpla was previously only known from the New World, and F. barathrica sp. n. is thus the first species of its genus in the Palaearctic. It is also the first troglophilic species of the Polysphincta genus-group. Zatypota albicoxa (Walker) is reported as new to Hungary. PMID- 25544625 TI - A new species of Scytodes from Algeria (Araneae: Scytodidae), with a review of the species from the Maghreb. AB - Four spitting spider species in the genus Scytodes are recorded from the Maghreb: Scytodes annulipes Simon, 1907, stat. n. (elevated to species rank), S. major Simon, 1885, S. velutina Heineken & Lowe, 1832 and Scytodes seppoi Bosmans & Van Keer, sp. n. The male and female of the latter are described and illustrated. No recent records of the commonly cited S. thoracica (Latreille, 1804) can be provided, so earlier citations are considered to be erroneous. Images, illustrations and new distribution data of the other three known species in the Maghreb are given. PMID- 25544626 TI - Koponenius gen. nov., a new genus of the millipede family Haplodesmidae from the Himalayas of India and Nepal (Diplopoda: Polydesmida). AB - The first, apparently westernmost indigenous representatives of Haplodesmidae are reported, from the Himalayas of Nepal and India. Both new species belong to a new genus, Koponenius gen. nov., with K. unicornis sp. nov., the type species from Darjeeling District, NE India, and K. biramus sp. nov., from Nepal. The new genus is superficially very similar to Prosopodesmus Silvestri, 1910, most species of which seem to be native to tropical Australia, partly also to southern Japan. However, Koponenius gen. nov. is easily distinguished in showing only 19 body segments, a special ozopore formula (5, 7-18), 4 transverse rows of setigerous isostictic tubercles per postcollum metatergum, and a clearly helicoid, twisted prefemoral portion of the gonopod so that the seminal groove runs mostly laterally, not mesally. PMID- 25544627 TI - A new species of Alopecosa (Araneae: Lycosidae) from Canada: a morphological description supported by DNA barcoding of 19 congeners. AB - A new species, Alopecosa koponeni sp. n., is described from the Arctic part of Manitoba. Individuals of A. koponeni most resemble those of A. pictilis (Emerton, 1885), but are smaller than the latter and differ in the epiginum and in colour pattern in both sexes. DNA barcode results show an interspecific distance of 0.93 between A. koponeni sp. n. and A. pictilis, a shallow genetic divergence that suggests a recent separation. PMID- 25544628 TI - The first fossil spider (Araneae: Palpimanoidea) from the Lower Jurassic (Grimmen, Germany). AB - The first Lower Jurassic (Lias) spider is described as Seppo koponeni n. gen. & n. sp. from a single female specimen from Grimmen, Germany. It most likely belongs to the Palpimanoidea, on account of the presence of cheliceral peg teeth and other features consistent with palpimanoid families, though its familial placement is uncertain. Its presence in the region at that time concurs with ideas about the more widespread presence of palpimanoids across the world in the early Mesozoic, before the break-up of Pangaea. PMID- 25544629 TI - On a new Agyneta species from Ukraine related to A. suecica Holm, 1950 (Araneae: Linyphiidae). AB - Agyneta pinicola sp.n. is described from Northeastern Ukraine. Agyneta suecica Holm, 1950 is redescribed and a complete comparison of the two species is given. PMID- 25544630 TI - Two new species of Pharta Thorell, 1891 with the description of Ibana senagang gen. et sp. nov. (Araneae: Thomisidae). AB - Two new species of Pharta, P. sudmannorum sp. nov. (??, Borneo) and P. koponeni sp. nov. (?, Thailand) are described. Furthermore, Ibana senagang gen. nov. & sp. nov. from Malaysia is described based on its exceptional palp, which has a reduced, movable conductor and thick-long spines on the distal, ventral surface of the tibia, reminiscent of Epidius Thorell, 1877. PMID- 25544631 TI - Description of a new species of Uroballus Simon, 1902 (Araneae: Salticidae) from Malaysia, with the longest spinnerets of any known jumping spider. AB - A new species Uroballus koponeni sp. n. (?) from Malaysia (Borneo) is diagnosed, illustrated and described. The genus is unusual for jumping spiders in having extremely long spinnerets. PMID- 25544632 TI - Serum paraoxonase type-1 activity in pigs: assay validation and evolution after an induced experimental inflammation. AB - Paraoxonase 1 (PON1) is a serum enzyme synthesised and secreted primarily by the liver. It possesses anti-inflammatory properties limiting the production of pro inflammatory mediators. The objectives of this study were to validate three spectrophotometric assays for the quantification of PON1 activity in pig serum, and to determine if PON1 activity in porcine behaves as a negative acute phase protein (APP), decreasing in inflammatory conditions. An analytical validation using three different substrates - 5-thiobutil butyrolactone (TBBL), phenylacetate (PA) and 4-(p)-nitrophenyl acetate (pNA) - was performed. In addition, inflammation was experimentally induced in five pigs by subcutaneous injection of turpentine oil, while five control pigs were left untreated. The treated pigs showed significant increases in CRP and decreases in albumin, indicating an inflammatory condition. The three substrates used would be suitable for PON1 activity measurements in serum samples, since they offer adequate precision (coefficients of variation<10%), sensitivity (0.01, 0.15, 0.02 U/mL for TBBL, pNA and PA respectively) and accuracy (r=0.99). In addition, PON1 behaves as a negative APP in pigs since a significant decrease (P<0.05) in its activity after 72 h of the induction of the inflammation was observed with all substrates. PMID- 25544633 TI - Simple Prostatectomy: A Step Too Far for Laparoscopy? PMID- 25544634 TI - Observed Advantages of the STAMPEDE Study Design. PMID- 25544635 TI - Location of prosthodontic treatment and oral health-related quality of life--an exploratory study. AB - PURPOSE: Prosthodontic treatment has a positive effect on oral health-related quality of life (OHRQoL); however, there is a paucity of studies assessing the impact of OHRQoL based on where in the mouth ("location") the treatment is performed. This exploratory study investigated the association of the location (anterior, posterior region) of prosthodontic treatment with magnitude and nature of OHRQoL changes. METHODS: In this non-randomized prospective clinical study, 190 adult patients (17-83 years) were recruited at baseline and 104 were available for the follow-up analyses. Of those, 50 patients received treatment only in the posterior segment and 54 patients in both anterior and posterior regions. Treatment included conventional fixed partial prostheses, removable prostheses or a combination of both. OHRQoL was assessed with the German language version of the 49-item Oral Health Impact Profile (OHIP) at baseline and the questionnaire was repeated 4-6 weeks post-treatment. Magnitude and effect size of changes in summary and sub-scale scores were calculated and data analyzed. RESULTS: Patients experienced a substantially impaired OHRQoL (mean OHIP score: 32.3 points) at baseline and an improvement in OHRQoL of 6.8 OHIP points following treatment. This study showed a greater improvement in OHRQoL in patients treated in both regions compared to those treated in the posterior region alone, especially in the function and aesthetic domains. CONCLUSIONS: This explorative study suggests that OHRQoL improvement is affected by where prosthodontic treatment is performed in the mouth. Greater understanding of qualitative aspects of reconstructive therapies is needed for improved treatment planning and patient consent. PMID- 25544638 TI - Speech hastening during electrical stimulation of left premotor cortex. AB - Cortical and axonal electrical stimulation of left premotor cortex and SMA during awake brain surgery yielded unique behavioral responses. In two patients, there was involuntary acceleration of speech (i.e., speech hastening) during a counting or picture naming task. In one patient, stimulation led to a deceleration of the rate with which three different tasks were performed (arm movements, finger tapping and counting). Possible explanatory mechanisms are discussed, and the literature on so-called "negative motor areas" is shortly reviewed. It is argued that the function of loops between cortex and basal ganglia were modulated via stimulation of frontostriatal and/or fronto-opercular pathways. PMID- 25544637 TI - Measurement of PIP3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specific inhibitors in luminal breast cancer. AB - BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110alpha inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110beta isoform. Importantly, the reactivation of PI3K mediated by p110beta does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110beta inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers. PMID- 25544639 TI - Mass spectrometric characterization of human serum albumin dimer: A new potential biomarker in chronic liver diseases. AB - Human serum albumin (HSA) undergoes several structural alterations affecting its properties in pro-oxidant and pro-inflammatory environments, as it occurs during liver cirrhosis. These modifications include the formation of albumin dimers. Although HSA dimers were reported to be an oxidative stress biomarker, to date nothing is known about their role in liver cirrhosis and related complications. Additionally, no high sensitive analytical method was available for HSA dimers assessment in clinical settings. Thus the HSA dimeric form in human plasma was characterized by mass spectrometry using liquid chromatography tandem mass spectrometry (LC-ESI-Q-TOF) and matrix assisted laser desorption time of flight (MALDI-TOF) techniques. N-terminal and C-terminal truncated HSA, as well as the native HSA, undergo dimerization by binding another HSA molecule. This study demonstrated the presence of both homo- and hetero-dimeric forms of HSA. The dimerization site was proved to be at Cys-34, forming a disulphide bridge between two albumin molecules, as determined by LC-MS analysis after tryptic digestion. Interestingly, when plasma samples from cirrhotic subjects were analysed, the dimer/monomer ratio resulted significantly increased when compared to that of healthy subjects. These isoforms could represent promising biomarkers for liver disease. Additionally, this analytical approach leads to the relative quantification of the residual native HSA, with fully preserved structural integrity. PMID- 25544636 TI - Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta. AB - In PTEN-mutated tumors, we show that PI3Kalpha activity is suppressed and PI3K signaling is driven by PI3Kbeta. A selective inhibitor of PI3Kbeta inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kbeta only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kalpha and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kalpha and PI3Kbeta. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions. PMID- 25544640 TI - [Elective partial nephrectomy: how far should we go?]. PMID- 25544641 TI - Caffeine as a lead compound for the design of therapeutic agents for the treatment of Parkinson's disease. AB - The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson's disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson's disease. PMID- 25544642 TI - Predictive model and optimization of a combined treatment of caprylic acid and citric acid for the reduction of Escherichia coli O157:H7 using the response surface methodology. AB - Our recent previous study reported the outstanding synergistic bactericidal activity of a combination of two natural antimicrobials: caprylic acid (CA) and citric acid (CTA). In the present study, the response surface methodology was used with the central composite design to build a model based on four factors, i.e., the CA concentration, CTA concentration, temperature, and treatment time, for the reduction of Escherichia coli O157:H7. This model was used to determine the optimum conditions for desirable responses and to evaluate the effects of experimental factors. The ranges of the four variables used in the design were as follows: CA concentration (0.25, 0.50, 0.75, 1.00, and 1.25 mM), CTA concentration (0.25, 0.50, 0.75, 1.00, and 1.25 mM), temperature (25, 30, 35, 40, and 45 degrees C), and time (1, 3, 5, 7, and 9 min). A second-order quadratic model of the effect of four variables was constructed and the experimental values agreed well with the values derived from model equation (R(2)=0.954). The adequacy of this model for predicting the magnitude of bacterial reduction was verified based on the validation data (R(2)=0.946). The optimum conditions for the combined treatment for microbial reduction were determined by ridge analysis, which were 1.0mM CA and 0.8mM CTA at 39.6 degrees C for 5.4 min. The CA concentration and temperature were the most significant variables. This study provides a comprehensive understanding of the bactericidal effects of the combined CA and CTA treatment. A distinct advantage of the proposed method is its cost-effectiveness. This treatment could be used as a preservative in the food industry because the two components are natural products. PMID- 25544643 TI - ALSUntangled: introducing The Table of Evidence. PMID- 25544644 TI - Semantic deficits in amyotrophic lateral sclerosis. AB - Our objective was to investigate, and establish neuroanatomical correlates of, semantic deficits in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD), compared to semantic dementia (SD) and controls. Semantic deficits were evaluated using a naming and semantic knowledge composite score, comprising verbal and non-verbal neuropsychological measures of single-word processing (confrontational naming, comprehension, and semantic association) from the Sydney Language Battery (SYDBAT) and Addenbrooke's Cognitive Examination - Revised (ACE-R). Voxel based morphometry (VBM) analysis was conducted using the region of interest approach. In total, 84 participants were recruited from a multidisciplinary research clinic in Sydney. Participants included 17 patients with ALS, 19 with ALS-FTD, 22 with SD and 26 age- and education-matched healthy controls. Significant semantic deficits were observed in ALS and ALS-FTD compared to controls. The severity of semantic deficits varied across the clinical phenotypes: ALS patients were less impaired than ALS-FTD patients, who in turn were not as impaired as SD patients. Anterior temporal lobe atrophy significantly correlated with semantic deficits. In conclusion, semantic impairment is a feature of ALS and ALS-FTD, and reflects the severity of temporal lobe pathology. PMID- 25544645 TI - Systematics and natural history of Southeast Asian Rock Geckos (genus Cnemaspis Strauch, 1887) with descriptions of eight new species from Malaysia, Thailand, and Indonesia. AB - A well-supported and well-resolved phylogeny based on a concatenated data set from one mitochondrial and two nuclear genes, six morphological characters, and nine color pattern characters for 44 of the 50 species of the Southeast Asian Rock Geckos (genus Cnemaspis Strauch, 1887) is consistent with the previous taxonomy of Cnemaspis based solely on morphology and color pattern. Cnemaspis is partitioned into four major clades that collectively contain six species groups. The monophyly of all clades and species groups is strongly supported and they are parapatrically distributed across well-established, biogeographical regions ranging from southern Vietnam westward through southern Indochina, southward through the Thai-Malay Peninsula, then eastward to Borneo. Eight new species (Cnemaspis omari sp. nov. from the Thai-Malaysian border; C. temiah sp. nov. from Cameron Highlands, Pahang, Malaysia; C. stongensis sp. nov. from Gunung Stong, Kelantan, Malaysia; C. hangus sp. nov. from Bukit Hangus, Pahang, Malaysia; C. sundagekko sp. nov. from Pulau Siantan, Indonesia; C. peninsularis sp. nov. from southern Peninsular Malaysia and Singapore, and C. mumpuniae sp. nov. and C. sundainsula sp. nov. from Pulau Natuna Besar, Indonesia) are described based on morphology and color pattern and all but C. sundagekko sp. nov. are included in the phylogenetic analyses. Cnemaspis kendallii is polyphyletic and a composite of six species. An updated taxonomy consistent with the phylogeny is proposed for all 50 species and is based on 25 morphological and 53 color pattern characters scored across 594 specimens. Cladogenetic events and biogeographical relationships within Cnemaspis were likely influenced by this group's low vagility and the cyclical patterns of geographical and environmental changes in Sundaland over the last 25 million years and especially within the last 2.5 million years. The phylogeny indicates that nocturnality, diurnality, substrate preferences, and the presence of ocelli in the shoulder regions have evolved independently multiple times. PMID- 25544646 TI - Folding of a beta-sheet miniprotein: probability fluxes, streamlines, and the potential for the driving force. AB - In this work we continue the study of the first-passage folding of an antiparallel beta-sheet miniprotein (beta3s) that was initiated in the previous work [Kalgin et al. J. Phys. Chem. B, 2014, 118, 4287]. We consider a larger ensemble of folding trajectories, which allows us to gain a closer insight into the folding dynamics. In particular, we calculate the potential for the driving force of folding in a reduced space of collective variables. The potential has two components. One component (Phi) is responsible for the source and sink of the folding flow, which are formed, respectively, in the regions of the unfolded and native states of the protein, and the other (Psi) accounts for the flow vorticity inherently generated at the sides of the reaction channel and provides the canalization of the folding flow between the source and sink. We show that both components obey Poisson's equations with the corresponding source/sink terms. The resulting components have a very simple form: the Phi-surface consists of two well-defined peaks of different signs, which correspond, respectively, to the source and sink of the folding flow, and the Psi-surface consists of two ridges of different signs that connect the source and sink of the flow. PMID- 25544647 TI - Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. AB - BACKGROUND AND PURPOSE: HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/p16 status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPV-associated p16 expression in a cohort of patients with stage III-IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/p16 also extends to tumors of non-oropharyngeal origin. MATERIAL AND METHODS: 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by p16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells. RESULTS: Thirty-eight percent (490/1294) of the tumors were p16 positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p<.0001. In OPC p16-positivity significantly improved loco-regional control (LRC) (adjusted HR [95% CI]: 0.43 [0.32-0.57]), event-free survival (EFS) (HR 0.44 [0.35-0.56]), and overall survival (OS) (HR: 0.38 [0.29-0.49]), respectively, compared with p16-negativity. In non-OPC no prognostic impact of p16-status was found for either endpoint: LRC (HR: 1.13 [0.75-1.70]), EFS (HR: 1.06 [0.76-1.47]), and OS (HR: 0.82 [0.59-1.16]). CONCLUSIONS: The independent influence of HPV-associated p16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor p16-status, indicating that the prognostic impact may be restricted to OPC only. PMID- 25544648 TI - Dosimetric analysis of urethral strictures following HDR (192)Ir brachytherapy as monotherapy for intermediate- and high-risk prostate cancer. AB - BACKGROUND AND PURPOSE: To evaluate dosimetric parameters related to urethral strictures following high dose-rate brachytherapy (HDRBT) alone for prostate cancer. MATERIAL AND METHODS: Ten strictures were identified in 213 patients treated with HDRBT alone receiving 34Gy in four fractions, 36Gy in four fractions, 31.5Gy in 3 fractions or 26Gy in 2 fractions. A matched-pair analysis used 2 controls for each case matched for dose fractionation schedule, pre treatment IPSS score, number of needles used and clinical target volume. The urethra was divided into membranous urethra and inferior, mid and superior thirds of the prostatic urethra. RESULTS: Stricture rates were 3% in the 34Gy group, 4% in the 36Gy group, 6% in the 31.5Gy group and 4% in the 26Gy group. The median time to stricture formation was 26months (range 8-40). The dosimetric parameters investigated were not statistically different between cases and controls. No correlation was seen between stricture rate and fractionation schedule. CONCLUSIONS: Urethral stricture is an infrequent complication of prostate HDRBT when used to deliver high doses as sole treatment, with an overall incidence in this cohort of 10/213 (4.7%). In a matched pair analysis no association with dose schedule or urethral dosimetry was identified, but the small number of events limits definitive conclusions. PMID- 25544649 TI - Potential anti-cancer drugs commonly used for other indications. AB - An increasing resistance of mammalian tumor cells to chemotherapy along with the severe side effects of commonly used cytostatics has raised the urgency in the search for new anti-cancer agents. Several drugs originally approved for indications other than cancer treatment have recently been found to have a cytostatic effect on cancer cells. These drugs could be expediently repurposed as anti-cancer agents, since they have already been tested for toxicity in humans and animals. The groups of newly recognized potential cytostatics discussed in this review include benzimidazole anthelmintics (albendazole, mebendazole, flubendazole), anti-hypertensive drugs (doxazosin, propranolol), psychopharmaceuticals (chlorpromazine, clomipramine) and antidiabetic drugs (metformin, pioglitazone). All these drugs have a definite potential to be used especially in combinations with other cytostatics; the chemotherapy targeting of multiple sites now represents a promising approach in cancer treatment. The present review summarizes recent information about the anti-cancer effects of selected drugs commonly used for other medical indications. Our aim is not to collect all the reported results, but to present an overview of various possibilities. Advantages, disadvantages and further perspectives regarding individual drugs are discussed and evaluated. PMID- 25544650 TI - Phytochemicals for breast cancer therapy: current status and future implications. AB - Breast cancer is one of the most common malignancies among women, representing nearly 30% of newly diagnosed cancers every year. Till date, various therapeutic interventions, including surgery, chemotherapy, hormonal therapy, and radiotherapy are available and are known to cause a significant decline in the overall mortality rate. However, therapeutic resistance, recurrence and lack of treatment in metastasis are the major challenges that need to be addressed. Increasing evidence suggests the presence of cancer stem cells (CSCs) in heterogeneous population of breast tumors capable of selfrenewal and differentiation and is considered to be responsible for drug resistance and recurrence. Therefore, compound that can target both differentiated cancer cells, as well as CSCs, may provide a better treatment strategy. Due to safe nature of dietary agents and health products, investigators are introducing them into clinical trials in place of chemotherapeutic agents.This current review focuses on phytochemicals, mainly flavonoids that are in use for breast cancer therapy in preclinical phase. As phytochemicals have several advantages in breast cancer and cancer stem cells, new synthetic series for breast cancer therapy from analogues of most potent natural molecule can be developed via rational drug design approach. PMID- 25544651 TI - Assessment of metal(loid)s phytoavailability in intensive agricultural soils by the application of single extractions to rhizosphere soil. AB - The influence of soil properties on the phytoavailability of metal(loid)s in a soil-plant system was evaluated. The content of extractable metal(loid)s obtained by using different extraction methods was also compared. To perform this study, a test plant (Lactuca sativa) and rhizosphere soil were sampled at 5 different time points (2, 4, 6, 8 and 10 weeks of plant growth). Four extraction methods (Mehlich 3, DTPA, NH4NO3 and CaCl2) were used. Significant positive correlations between the soil extractable content and lettuce shoot content were obtained for several metal(loid)s. The extraction with NH4NO3 showed the higher number of strong positive correlations indicating the suitability of this method to estimate metal(loid)s phytoavailability. The soil CEC, OM, pH, texture and oxides content significantly influenced the distribution of metal(loid)s between the phytoavailable and non-phytoavailable fractions. A reliable prediction model for Cr, V, Ni, As, Pb, Co, Cd, and Sb phytoavailability was obtained considering the amount of metal(loid) extracted by the NH4NO3 method and the main soil properties. This work shows that the analysis of rhizosphere soil by single extractions methods is a reliable approach to estimate metal(loid)s phytoavailability. PMID- 25544652 TI - Antioxidative responses in zebrafish liver exposed to sublethal doses Aphanizomenon flos-aquae DC-1 aphantoxins. AB - Aphanizomenon flos-aquae secretes paralytic shellfish poisons (PSPs), termed aphantoxins, and endangers environmental and human health via eutrophication of water worldwide. Although the molecular mechanism of neuronal PSP toxicity has been well studied, several issues remain unresolved, notably the in vivo hepatic antioxidative responses to this neurotoxin. Aphantoxins extracted from a natural isolate of A. flos-aquae DC-1 were resolved by high performance liquid chromatography. The primary components were gonyautoxins 1 and 5 and neosaxitoxin. Zebrafish (Danio rerio) were treated intraperitoneally with either 5.3 or 7.61 (low and high doses, respectively) MUg saxitoxin (STX) equivalents (eq)/kg of A. flos-aquae DC-1 aphantoxins. Antioxidative responses in zebrafish liver were examined at different timepoints 1-24h post-exposure. Aphantoxin administration significantly enhanced hepatic malondialdehyde (MDA) content 1-12h post-exposure, indicative of oxidative stress and lipid peroxidation. By contrast, levels of reduced glutathione (GSH) in zebrafish liver declined significantly after 3-24h exposure, suggesting that GSH participates in MDA metabolism. A significant upregulation of the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was observed, suggesting that aphantoxins induce lipid peroxidation in zebrafish liver and are likely to be hepatotoxic. Hepatic levels of MDA and GSH, and of the three enzymes (SOD, CAT, and GPx), therefore provide potential biomarkers for studying environmental exposure to aphantoxins/PSPs from cyanobacterial blooms. PMID- 25544653 TI - Multi-exposure cancer and non-cancer risk assessment of trihalomethanes in drinking water supplies - A case study of Eastern region of India. AB - The lifetime cancer risk and the hazard index of trihalomethanes (THMs) through oral ingestion, dermal absorption, and inhalation exposure from supply water of five WTPs were analysed. THMs concentration varied from plant to plant and was found to be in the range of 274-511ug/l, which is much higher than the prescribed USEPA standards of 80ug/l. Chloroform was the most dominant THM followed by bromodichloromethane (BDCM), and dibromochloromethane (DBCM). Cancer risk analysis through multi-pathways exposure reveals that residents had a higher cancer risk through oral ingestion than other two routes of exposure. The lifetime cancer risks of THMs from supply water were 100 times higher than prescribed USEPA guidelines. The higher cancer risk found for Indian context than those reported for other countries like USA, UK, Japan, Australia, is mainly due to the higher concentration level of THMs, water intake and average body weight. The study also revealed that amongst different THMs, chloroform is the major THMs causing cancer risk through both oral and dermal route of exposure whereas in case of inhalation it was mainly because of BDCM. Average lifetime cancer risk analysis indicated that females are more prone to cancer risk than males. Oral ingestion is a major route indicating the potential impact of non-cancer risk while it was insignificant through dermal exposure. Sensitivity analysis of THMs revealed that chloroform is the predominant parameter followed by body weight and exposure duration influencing cancer risk. PMID- 25544654 TI - Dynamics of neural networks over undirected graphs. AB - In this paper we study the dynamical behavior of neural networks such that their interconnections are the incidence matrix of an undirected finite graph G=(V,E) (i.e., the weights belong to {0,1}). The network may be updated synchronously (every node is updated at the same time), sequentially (nodes are updated one by one in a prescribed order) or in a block-sequential way (a mixture of the previous schemes). We characterize completely the attractors (fixed points or cycles). More precisely, we establish the convergence to fixed points related to a parameter alpha(G), taking into account the number of loops, edges, vertices as well as the minimum number of edges to remove from E in order to obtain a maximum bipartite graph. Roughly, alpha(G')<0 for any G' subgraph of G implies the convergence to fixed points. Otherwise, cycles appear. Actually, for very simple networks (majority functions updated in a block-sequential scheme such that each block is of minimum cardinality two) we exhibit cycles with non-polynomial periods. PMID- 25544655 TI - Antioxidant response and carboxylate metabolism in Brassica rapa exposed to different external Zn, Ca, and Mg supply. AB - Zinc (Zn), calcium (Ca), and magnesium (Mg) malnutrition are common deficiencies in many developed and developing countries, resulting in a widespread health problem. Biofortification of food crops is an agricultural strategy that can be used to increase the levels of these elements in the edible portions of crops. Deficiency or toxicity of these cations in soils reduces plant growth, crop yield, and the quality of plant foodstuff. The aim of this study was to investigate the effect of external Zn, Ca, and Mg supply on accumulation and distribution of this elements as well as antioxidant response and organic acid composition of Brassica rapa ssp. trilocularis line R-o-18. Plants were grown at low Zn (0.05 MUM Zn) and high Zn (500 MUM Zn), low Ca (0.4 mM) and high Ca (40 mM), and low Mg (0.2 mM), and high Mg (20 mM) to simulate deficiency and toxicity conditions. Larger shoot biomass reductions were observed under high Zn, Ca and Mg treatments, and superoxide dismutase (SOD), ascorbate peroxidase (APX), H2O2, malondialdehyde (MDA), and total ascorbate (AA) showed a marked increase in these treatments. Therefore, Brassica plants might be more sensitive to excess of these elements in the nutrient solution. The translocation factor (TF) and distribution coefficient (DC) values of Zn, Ca, and Mg indicated higher translocation and accumulation in deficient conditions. High biosynthesis and citrate content in Brassica plants may be associated mainly with a high-nutrient solution extraction ability of these plants. These results provide background data, which will be used to characterize TILLING mutants to study the effects of mutations in genes involved in regulating Zn, Ca, and Mg distribution and accumulation in plants. PMID- 25544656 TI - Hepatitis C virus RNA levels at week-2 of telaprevir/boceprevir administration are predictive of virological outcome. AB - BACKGROUND: Triple therapy with telaprevir/boceprevir + pegylated interferon+ribavirin can achieve excellent antiviral efficacy, but it can be burdened with resistance development at failure. AIMS: To evaluate kinetics of hepatitis C virus (HCV) RNA decay and early resistance development, in order to promptly identify patients at highest risk of failure to first generation protease inhibitors. METHODS: HCV-RNA was prospectively quantified in 158 patients receiving pegylated-interferon+ribavirin+telaprevir (N = 114) or+boceprevir (N = 44), at early time-points and during per protocol follow-up. Drug resistance was contextually evaluated by population sequencing. RESULTS: HCV RNA at week-2 was significantly higher in patients experiencing virological failure to triple-therapy than in patients with sustained viral response (2.3 [1.9-2.8] versus 1.2 [0.3-1.7]log IU/mL, p < 0.001). A 100 IU/mL cut-off value for week-2 HCV-RNA had the highest sensitivity (86%) in predicting virological success. Indeed, 23/23 (100%) patients with undetectable HCV-RNA reached success, versus 26/34 (76.5%) patients with HCV-RNA<100 IU/mL, and only 11/31 (35.5%) with HCV-RNA > 100 IU/mL (p < 0.001). Furthermore, differently from failing patients, none of the patient with undetectable HCV-RNA at week-2 had baseline/early resistance. CONCLUSIONS: With triple therapy based on first generation protease inhibitors, suboptimal HCV-RNA decay at week-2 combined with early detection of resistance can help identifying patients with higher risk of virological failure, thus requiring a closer monitoring during therapy. PMID- 25544658 TI - Preliminary results of an attempt to predict over apron occupational exposure of cardiologists from cardiac fluoroscopy procedures based on DAP (dose area product) values. AB - This study is an effort to propose a mathematical relation between the occupational exposure measured by a dosimeter worn on a lead apron in the chest region of a cardiologist and the dose area product (DAP) recorded by a meter attached to the X-ray tube. We aimed to determine factors by which DAP values attributed to patient exposure could be converted to the over-apron entrance surface air kerma incurred by cardiologists during an angiographic procedure. A Rando phantom representing a patient was exposed by an X-ray tube from 77 pre defined directions. DAP value for each exposure angle was recorded. Cardiologist exposure was measured by a Radcal ionization chamber 10X5-180 positioned on a second phantom representing the physician. The exposure conversion factor was determined as the quotient of over apron exposure by DAP value. To verify the validity of this method, the over-apron exposure of a cardiologist was measured using the ionization chamber while performing coronary angiography procedures on 45 patients weighing on average 75 +/- 5 kg. DAP values for the corresponding procedures were also obtained. Conversion factors obtained from phantom exposure were applied to the patient DAP values to calculate physician exposure. Mathematical analysis of our results leads us to conclude that a linear relationship exists between two sets of data: (a) cardiologist exposure measured directly by Radcal & DAP values recorded by the X-ray machine system (R (2) = 0.88), (b) specialist measured and estimated exposure derived from DAP values (R (2) = 0.91). The results demonstrate that cardiologist occupational exposure can be derived from patient data accurately. PMID- 25544657 TI - Liver fibrosis, microbial translocation and immune activation markers in HIV and HCV infections and in HIV/HCV co-infection. AB - BACKGROUND: Liver fibrosis is accelerated in patients co-infected with human immunodeficiency virus and hepatitis C viruses. AIMS: We investigated the correlation between liver fibrosis, immune activation and microbial translocation. METHODS: This cross-sectional study included patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) mono-infections, HIV/HCV co-infection, and healthy controls (20 subjects/group). Peripheral blood was analysed to determine the levels of Forkhead box 3 (Foxp3) T cells, TGF beta1, CD14 (soluble and surface isoforms), IL-17 and bacterial translocation products. These measurements were correlated to the severity of liver fibrosis, measured with the FIB-4 score and transient elastography. RESULTS: Foxp3T cell levels were significantly elevated in HIV mono-infected and co-infected groups (p<0.0005). FIB-4 and liver stiffness values inversely correlated with TGF-beta1 (p=0.0155 and p=0.0498). Bacterial DNA differed significantly in the HIV-positive compared to the other groups: HIV/HCV co-infected subjects had significantly higher serum levels of bacterial translocation products, CD14, and IL-17 levels (p<0.001). CONCLUSIONS: Fibrosis stage in HIV/HCV co-infection may be influenced by immune activation due either by viral infections or to bacterial translocation. PMID- 25544659 TI - Efficacy of vaccination against HPV infection to prevent cervical cancer in France. PMID- 25544661 TI - "That's not what we do": evidence that normative change is a mechanism of action in group interventions. AB - Group interventions for mental health have proved very effective, but there is little consensus on their mechanism of action. In the present study, we posit that normative change is a plausible mechanism and provide a test of this in an eating disorder prevention group program. Participants were 112 women aged 15-25 years with body, shape or weight concerns who completed five questionnaires across the four session group-based intervention. Results indicated that participants experienced a significant reduction in thin-ideal internalization, body dissatisfaction and dieting intentions across the course of the program. These decrements were preceded by changes in group norms. Changes in both descriptive norms and injunctive norms in the first half of the program predicted improvement in thin-ideal internalization, body dissatisfaction and dieting intentions in the second half. Implications for theoretical models of attitude change are discussed, as well as implications for group interventions more generally. PMID- 25544660 TI - Ozone inhalation modifies the rat liver proteome. AB - Ozone (O3) is a serious public health concern. Recent findings indicate that the damaging health effects of O3 extend to multiple systemic organ systems. Herein, we hypothesize that O3 inhalation will cause downstream alterations to the liver. To test this, male Sprague-Dawley rats were exposed to 0.5ppm O3 for 8h/day for 5 days. Plasma liver enzyme measurements showed that 5 day O3 exposure did not cause liver cell death. Proteomic and mass spectrometry analysis identified 10 proteins in the liver that were significantly altered in abundance following short-term O3 exposure and these included several stress responsive proteins. Glucose-regulated protein 78 and protein disulfide isomerase increased, whereas glutathione S-transferase M1 was significantly decreased by O3 inhalation. In contrast, no significant changes were detected for the stress response protein heme oxygenase-1 or cytochrome P450 2E1 and 2B in liver of O3 exposed rats compared to controls. In summary, these results show that an environmentally relevant exposure to inhaled O3 can alter the expression of select proteins in the liver. We propose that O3 inhalation may represent an important unrecognized factor that can modulate hepatic metabolic functions. PMID- 25544663 TI - Application of the Monte Carlo efficiency transfer method to an HPGe detector with the purpose of environmental samples measurement. AB - Monte Carlo efficiency transfer method was used to determine the full energy peak efficiency of a coaxial n-type HPGe detector. The efficiencies calibration curves for three Certificate Reference Materials were determined by efficiency transfer using a (152)Eu reference source. The efficiency values obtained after efficiency transfer were used to calculate the activity concentration of the radionuclides detected in the three materials, which were measured in a low-background gamma spectrometry system. Reported and calculated activity concentration show a good agreement with mean deviations of 5%, which is satisfactory for environmental samples measurement. PMID- 25544662 TI - Challenges in the management of Neisseria gonorrhoeae keratitis. AB - We describe the presentation and subsequent management of a case of keratitis caused by Neisseria gonorrhoeae. A thirty-nine year old gentleman presented with a purulent ocular discharge. Corneal melt with corneal perforation occurred. Neisseria gonorrhoeae was cultured. Systemic and topical antibiotics were given. Deep lamellar keratoplasty was performed for corneal perforation. At three months post treatment no recurrence of infection was noted. The possibility of Neisseria gonorrhoeaea keratitis should always be considered in patients with a purulent ocular discharge even if the case history is not immediately suggestive of the same. Severe gonococcal keratitis may be unilateral. Deep lamellar keratoplasty can be considered as a therapeutic option in patients with severe gonococcal keratitis. PMID- 25544664 TI - Reset charge sensitive amplifier for NaI(Tl) gamma-ray spectrometer. AB - The time constant of the output signal of the front-end readout circuit of a traditional gamma-ray spectrometer with a NaI(Tl)+PMT structure is affected by temperature, measurement environment and the signal transmission cable, so it is difficult to get a good resolution spectrum, especially at higher counting rates. In this paper, a reset charge sensitive amplifier (RCSA) is designed for the gamma-ray spectrometer with a NaI(Tl)+PMT structure. The designed RCSA outputs a step signal, thus enabling the acquisition of double-exponential signals with a stable time constant by using the next stage of a CR differentiating circuit. The designed RCSA is mainly composed of a basic amplifying circuit, a reset circuit and a dark current compensation circuit. It provides the output step signal through the integration of the PMT output charge signal. When the amplitude of the step signal exceeds a preset voltage threshold, it triggers the reset circuit to generate a reset pulse (about 5us pulse width) to reset the output signal. Experimental results demonstrated that the designed RCSA achieves a charge sensitivity of 4.26*10(10)V/C, with a zero capacitance noise of 51.09fC and a noise slope of 1.98fC/pF. Supported by the digital shaping algorithm of the digital multi-channel analyzer (DMCA), it can maintain good energy resolution with high counting rates up to 150kcps and with a temperature range from -19 degrees C to 50 degrees C. PMID- 25544665 TI - Comparison of results of the manual and automated scoring of micronucleus frequencies in (60)Co-irradiated peripheral blood lymphocytes for triage dosimetry. AB - Scoring micronuclei in the peripheral blood lymphocytes of individuals exposed to ionizing radiation is a rapid biodosimetry assay. Peripheral blood lymphocytes from five individuals were exposed in vitro to 0-5Gy of (60)Co gamma-radiation at a dose rate of 0.76Gy/min. The blood cultures were initiated with RPMI-1640 (80%) supplemented with FBS (20%), stimulated with mitogen and incubated at 37 degrees C for 44h. At the 44th hour, cytochalasin-B (6ug/mL) was added, and the cultures were incubated for 28h more. The cells were harvested with a pre-chilled hypotonic solution (0.075M) and fixed with a Carnoy's solution (methanol/acetic acid 5:1). Giemsa- and propidium-iodide-stained cells affixed to slides for microscopy were scored manually and automatically with the micronucleus scoring software from MetaSystems. The micronucleus frequencies determined in the Giemsa stained cells by manual and automated scoring were 23.6% different (P<0.0001) with an efficiency of 24.9%. Slides stained with propidium iodide are a better choice for automated scoring than Giemsa-stained ones. PMID- 25544666 TI - Filtered epithermal quasi-monoenergetic neutron beams at research reactor facilities. AB - Filtered neutron techniques were applied to produce quasi-monoenergetic neutron beams in the energy range of 1.5-133keV at research reactors. A simulation study was performed to characterize the filter components and transmitted beam lines. The filtered beams were characterized in terms of the optimal thickness of the main and additive components. The filtered neutron beams had high purity and intensity, with low contamination from the accompanying thermal emission, fast neutrons and gamma-rays. A computer code named "QMNB" was developed in the "MATLAB" programming language to perform the required calculations. PMID- 25544667 TI - Targeting of gamma-tubulin complexes to microtubule organizing centers: conservation and divergence. AB - Organisms with closed or open mitosis have differentially evolved various gamma tubulin complex (gamma-TuC) recruiting factors to organize diverse cellular microtubule (MT) arrays, including the mitotic spindle. gamma-TuC recruiting factors not only target the gamma-TuC to MT nucleation sites, but also regulate MT nucleation activity by generating the template for MT nucleation or promoting the MT nucleation activity of pre-existing gamma-tubulin ring complexes (gamma TuRCs). Here we outline the current understanding of MT nucleator assembly and its regulation by gamma-tubulin small complex (gamma-TuSC) receptors. Moreover, we discuss the emergence of gamma-TuC recruiting factors through evolution with augmented complexity and diversity and propose a hypothesis to account for the evolution of these factors in cooperative spindle assembly. PMID- 25544668 TI - Inhibition of vascular endothelial growth factor A and hypoxia-inducible factor 1alpha maximizes the effects of radiation in sarcoma mouse models through destruction of tumor vasculature. AB - PURPOSE: To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1alpha (HIF-1alpha) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. METHODS AND MATERIALS: Hypoxia-inducible factor 1alpha was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1alpha binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. RESULTS: In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm(3) within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1alpha inhibition kept tumors at <250 mm(3) for up to 30 days. Trimodality therapy on tumors reduced HIF-1alpha activity as measured by expression of nuclear HIF-1alpha by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formation and increases in DNA damage (as measured by Comet assay and gammaH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. CONCLUSIONS: Inhibition of HIF-1alpha is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature. PMID- 25544669 TI - Characterization of Tako-tsubo Cardiomyopathy in Spain: Results from the RETAKO National Registry. AB - INTRODUCTION AND AIMS: The etiology and epidemiology of tako-tsubo cardiomyopathy remain uncertain. The symptoms of this condition are often similar to those of myocardial infarction and, although it usually has a good prognosis, it is not without complications. Our aim was to characterize this disease in our setting using a dedicated registry (Spanish REgistry for TAKOtsubo cardiomyopathy). METHODS: The prospective registry included 202 incident patients in 23 hospitals from 2012 to 2013. The patients' clinical characteristics and analytical, echocardiographic, and imaging results were recorded, as were the events during follow-up. Patients were included when the attending physician considered the case proven, and incidence was calculated relative to the catheterizations requested for a presumptive diagnosis of acute coronary syndrome. RESULTS: The patients were predominantly women (90%), with a mean age of 70 years, and many had cardiovascular risk factors, such as hypertension (67%), dyslipidemia (41%), diabetes mellitus (15%), and smoking (15%). The incidence of tako-tsubo cardiomyopathy was 1.2%, and there was no clear weekly or seasonal distribution pattern. Chest pain was the predominant symptom, a triggering factor (emotional, physical, or both) was present in 72%, and most patients consulted within the first 6h after symptom onset. The median duration of hospitalization was 7 days. There were heart failure symptoms in 34.0%, arrhythmia in 26.7%, and 2.4% of patients died. CONCLUSIONS: The incidence of tako-tsubo cardiomyopathy is low. This disease primarily affects postmenopausal women, and occurs after a situation of emotional stress in more than half of affected individuals. It is characterized by anginal pain, shows no seasonal distribution, and has a good prognosis, although it is not without morbidity and mortality. PMID- 25544670 TI - Synergistic enhancement of anticancer effects on numerous human cancer cell lines treated with the combination of EGCG, other green tea catechins, and anticancer compounds. AB - PURPOSE: In 2008, we reported that 10 Japanese-size cups of green tea daily, supplemented with tablets of green tea extract (GTE), reduced the recurrence of colorectal adenoma by 51.6% in patients after polypectomy. Based on these results, we paid special attention to Japanese cancer patients, who consume green tea every day and are administered anticancer drugs. This encouraged us to study whether the combination of green tea catechins and anticancer drugs has the potential to enhance the efficacy of the drugs. RESULTS AND DISCUSSION: The combination of GTE and NSAIDs synergistically inhibited tumor development in rodents through the activation of the GADD153-DR5-TRAIL apoptotic pathway. Since then, this study was further extended by various investigators to the combinations of EGCG and other green tea catechins with anticancer compounds, the latter of which include NSAIDs, phytochemicals, and anticancer drugs. In order to demonstrate whether diversity of the combinations would generally induce synergistic anticancer effects on numerous human cancer cell lines, we studied the results of 42 in vitro combination experiments and the synergistic inhibition of tumor volume of 13 combination experiments using xenograft mouse models, which were previously reported by other investigators. The various combinations of EGCG and anticancer compounds induced similar synergistic anticancer effects for both in vitro and in vivo experiments, and showed an average reduction in tumor volume by 70.3%. Considering the evidence showing that treatment with EGCG inhibited self-renewal of cancer stem cells, the combination shows a great advantage. CONCLUSION: Green tea is a cancer preventive for humans, showing a new trend of green tea catechins as synergists with anticancer compounds. PMID- 25544671 TI - HER2 positivity in gastric and esophageal adenocarcinoma: clinicopathological analysis and comparison. AB - PURPOSE: Primary tumor classification of gastric or esophageal cancer has changed significantly with recent alterations of the tumor-node-metastasis (TNM) staging system. Considering these alterations, human epidermal growth factor receptor 2 (HER2) positivity rates were determined and compared in gastric and esophageal adenocarcinoma. Additionally, HER2 positivity in relation to other clinicopathological characteristics was evaluated. METHODS: A total of 321 patients with histologically confirmed invasive gastric or esophageal adenocarcinoma were examined for HER2 by immunohistochemy (IHC) and chromogenic in situ hybridization (CISH). IHC 3+ or IHC 2+/CISH-positive tumors were considered HER2 positive. Clinicopathological characteristics were retrospectively retrieved from the patient records. RESULTS: HER2 positivity was found in 50 of 321 patients (15.6 %). In univariate and multivariate logistic models, HER2 positivity rates were significantly higher in esophageal primary tumors (esophageal 25.0 % vs. gastric 7.4 %) and in intestinal histological tumor type (intestinal 22.6 % vs. diffuse/mixed 5.7 %). No significant differences in HER2 positivity were found between males and females, age below and above 65 years, biopsies and surgical specimens or advanced and early-stage disease. Using the 7th TNM edition, many tumors (30.5 % of all included tumors and 64.5 % of all esophageal primary tumors) previously classified as gastric cancer are now classified as esophageal cancer. CONCLUSIONS: HER2 positivity occurs in 15.6 % of invasive gastroesophageal adenocarcinoma in Western patients, of which the majority is esophageal primary tumors and of the intestinal tumor type. With the introduction of the 7th TNM edition, a large number of tumors previously classified as gastric are now classified as esophageal tumors instead, with relatively high HER2 positivity rates in these esophageal primary tumors. PMID- 25544672 TI - Circulating MACC1 as a novel diagnostic and prognostic biomarker for nonsmall cell lung cancer. AB - PURPOSE: Metastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that plays an important role in cancer progression and metastasis. MACC1 has important functions in the differentiation, invasion, and metastasis of nonsmall cell lung cancer (NSCLC). However, the value of circulating MACC1 as a potential diagnostic and prognostic biomarker for NSCLC remains unknown. METHODS: Plasma MACC1 mRNA levels were examined in 272 patients with NSCLC, 61 with benign lung disease, and 80 healthy volunteers using reverse transcription quantitative real time polymerase chain reaction. RESULTS: MACC1 was more highly expressed in NSCLC patients than in patients with benign disease (P < 0.001) or in healthy volunteers (P < 0.001). High MACC1 expression was significantly associated with NSCLC stage (P = 0.013) and lymph node metastasis (P = 0.016). The area under the receiver operating characteristic curve was 0.766, and the optimal cutoff value was 0.105, providing a sensitivity of 71.4 % and a specificity of 89.1 %. The diagnostic capability of circulating MACC1 mRNA was higher than that of carcinoembryonic antigen (P = 0.025) or cytokeratin-19 (P = 0.010). Furthermore, high MACC1 expression was associated with poor overall survival (OS) and disease free survival (DFS) and predicted poor survival in NSCLC patients. Consequently, MACC1 mRNA was an independent prognostic factor of OS and DFS. CONCLUSION: We concluded that circulating MACC1 mRNA represents a potential noninvasive, diagnostic and prognostic marker for NSCLC. PMID- 25544673 TI - Regulation of the Renin-Angiotensin System Pathways in the Human Decidua. AB - Pregnancy outcome is influenced, in part, by the sex of the fetus. Decidual renin messenger RNA (REN) abundance is greater in women carrying a female fetus than a male fetus. Here, we explore whether the sex of the fetus also influences the regulation of decidual RAS expression with a known stimulator of renal renin and cyclic adenosine monophosphate (cAMP). Cyclic adenosine monophosphate had no affect on decidual REN expression, since REN abundance was still greater in decidual explants from women carrying a female fetus than a male fetus after cAMP treatment. Cyclic adenosine monophosphate decreased prorenin levels in the supernatant if the fetus was female (ie, prorenin levels were no longer sexually dimorphic) and altered the fetal sex-specific differences in other RAS genes seen in vitro. Therefore, fetal sex influences the decidual renin-angiotensin system response to cAMP. This may be related to the presence of fetal cells in the maternal decidua. PMID- 25544674 TI - Polymorphisms of Genes Involved in the Folate Metabolic Pathway Impact the Occurrence of Unexplained Recurrent Pregnancy Loss. AB - Low levels of folate combined with high levels of homocysteine may cause unexplained recurrent pregnancy loss (URPL). However, the relationships between polymorphisms in genes of the folate metabolic pathway and URPL remain controversial. We conducted a case-control study to explore polymorphisms of the major folate pathway genes, including methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G and reduced folate carrier 1 (RFC-1) 80A>G, and their associations with URPL. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the distributions of MTHFR, MTR and RFC-1 polymorphisms, and the results were validated using direct sequencing. The polymorphisms in MTRR were determined using direct sequencing. Haplotypes were analyzed using SHEsis, an online tool for biological analysis. We found that the MTHFR 677T allele and the 677T/1298A/2756A/66A/80G haplotype were risk factors for URPL, while the MTR 2756G allele and the 677C/1298A/2756A/66A/80A haplotype exhibited protective effects on susceptibility to URPL in a Chinese Han population from the Hangzhou area. PMID- 25544676 TI - Autophagy in Normal and Abnormal Early Human Pregnancies. AB - Autophagy is an inducible catabolic process by which cells degrade and recycle materials to survive stress, starvation, and hypoxia. The aim of this study was to evaluate autophagy at the fetal-maternal interface, to assess autophagy involvement during the early phase of human gestation, and to explore autophagic modification in case of early abnormal pregnancy outcome. Specimens were collected from first-trimester normal gestations undergoing legal termination of pregnancy and first-trimester sporadic spontaneous miscarriages. Autophagy was studied in villous and decidual samples by transmission electron microscopy, immunohistochemistry, immunofluorescence, and Western blotting. Autophagy markers were found in cytotrophoblast, syncytiotrophoblast, extravillous trophoblast, and decidual stromal cells. Autophagy is physiologically involved in early normal gestation. Compared with normal pregnancy, spontaneous miscarriage presents an increase in autophagy expression in villous specimens due to an increment in concentration of autophagic vacuole in syncytiotrophoblast, suggesting a cytoprotective mechanism of the cells to respond to microenvironmental challenge. PMID- 25544675 TI - The Effect of an Obesogenic Maternal Environment on Expression of Fetal Umbilical Cord Blood miRNA. AB - OBJECTIVE: Exposure to maternal obesity in utero predisposes offspring to obesity and metabolic disease. This study investigated whether maternal obesity is associated with alterations in expression of fetal microRNA (miRNA). STUDY DESIGN: A cohort study of women with body mass index (BMI) >=35 kg/m(2) (n = 16) versus those with normal BMI 20 to 24.9 (n = 20) was performed. All participants had normal glucose tolerance (1-hour glucose challenge test <130) and normally grown neonates (2700-3500 g). Umbilical cord samples were collected immediately after delivery. Expression of miRNA was assessed using Affymetrix GeneChip miRNA 3.0 Arrays. Differential miRNA expression was determined using Student t tests with Benjamini-Hocherg correction. RESULTS: For 1733 human mature miRNAs, the expression levels were not statistically different in umbilical cord blood samples from pregnancies of obese women compared to controls. CONCLUSION: Expression of fetal miRNA is not altered in umbilical cord blood in response to in utero exposure to obesity. Alternate mechanisms underlying the fetal effects of maternal obesity should be explored. PMID- 25544677 TI - Expanding TAVI options: elective rotational atherectomy during trans-catheter aortic valve implantation. AB - Aortic valve stenosis (AVS) in the elderly is frequently associated to coronary artery disease (CAD). In patients with significant coronary stenosis surgical valve replacement is associated to coronary bypass grafting, but whether coronary angioplasty is needed in patients receiving trans-catheter aortic valve implantation (TAVI) is unknown. Given the frequent complexity of CAD in the elderly with calcific AVS, rotational atherectomy (RA) may be needed in some cases. No data are available about feasibility and safety of RA during TAVI. The need for myocardial revascularization in TAVI candidates is discussed, and a series of RA cases performed during TAVI is described. PMID- 25544678 TI - Optical imaging beyond the diffraction limit by SNEM: effects of AFM tip modifications with thiol monolayers on imaging quality. AB - Tip-enhanced nanoscale optical imaging techniques such as apertureless scanning near-field optical microscopy (a-SNOM) and scanning near-field ellipsometric microscopy (SNEM) applications can suffer from a steady degradation in performance due to adhesion of atmospheric contaminants to the metal coated tip. Here, we demonstrate that a self-assembled monolayer (SAM) of ethanethiol (EtSH) is an effective means of protecting gold-coated atomic force microscopy (AFM) probe tips from accumulation of surface contaminants during prolonged exposure to ambient air. The period over which they yield consistent and reproducible results for scanning near-field ellipsometric microscopy (SNEM) imaging is thus extended. SNEM optical images of a microphase separated polystyrene-block-poly (methylmethacrylate) (PS-b-PMMA) diblock copolymer film, which were captured with bare and SAM-protected gold-coated AFM probes, both immediately after coating and following five days of storage in ambient air, were compared. During this period the intensity of the optical signals from the untreated gold tip fell by 66%, while those from the SAM protected tip fell by 14%. Additionally, gold coated AFM probe tips were modified with various lengths of alkanethiols to measure the change in intensity variation in the optical images with SAM layer thickness. The experimental results were compared to point dipole model calculations. While a SAM of 1-dodecanethiol (DoSH) was found to strongly suppress field enhancement we find that it can be locally removed from the tip apex by deforming the molecules under load, restoring SNEM image contrast. PMID- 25544679 TI - Automated CBED processing: sample thickness estimation based on analysis of zone axis CBED pattern. AB - An automated processing of convergent beam electron diffraction (CBED) patterns is presented. The proposed methods are used in an automated tool for estimating the thickness of transmission electron microscopy (TEM) samples by matching an experimental zone-axis CBED pattern with a series of patterns simulated for known thicknesses. The proposed tool detects CBED disks, localizes a pattern in detected disks and unifies the coordinate system of the experimental pattern with the simulated one. The experimental pattern is then compared disk-by-disk with a series of simulated patterns each corresponding to different known thicknesses. The thickness of the most similar simulated pattern is then taken as the thickness estimate. The tool was tested on [0 1 1] Si, [0 1 0] alpha-Ti and [0 1 1] alpha-Ti samples prepared using different techniques. Results of the presented approach were compared with thickness estimates based on analysis of CBED patterns in two beam conditions. The mean difference between these two methods was 4.1% for the FIB-prepared silicon samples, 5.2% for the electro-chemically polished titanium and 7.9% for Ar(+) ion-polished titanium. The proposed techniques can also be employed in other established CBED analyses. Apart from the thickness estimation, it can potentially be used to quantify lattice deformation, structure factors, symmetry, defects or extinction distance. PMID- 25544680 TI - Tri-peptide reference structures for the calculation of relative solvent accessible surface area in protein amino acid residues. AB - Relative amino acid residue solvent accessibility values allow the quantitative comparison of atomic solvent-accessible surface areas in different residue types and physical environments in proteins and in protein structural alignments. Geometry-optimised tri-peptide structures in extended solvent-exposed reference conformations have been obtained for 43 amino acid residue types at a high level of quantum chemical theory. Significant increases in side-chain solvent accessibility, offset by reductions in main-chain atom solvent exposure, were observed for standard residue types in partially geometry-optimised structures when compared to non-minimised models built from identical sets of proper dihedral angles abstracted from the literature. Optimisation of proper dihedral angles led most notably to marked increases of up to 54% in proline main-chain atom solvent accessibility compared to literature values. Similar effects were observed for fully-optimised tri-peptides in implicit solvent. The relief of internal strain energy was associated with systematic variation in N, C(alpha) and C(beta) atom solvent accessibility across all standard residue types. The results underline the importance of optimisation of 'hard' degrees of freedom (bond lengths and valence bond angles) and improper dihedral angle values from force field or other context-independent reference values, and impact on the use of standardised fixed internal co-ordinate geometry in sampling approaches to the determination of absolute values of protein amino acid residue solvent accessibility. Quantum chemical methods provide a useful and accurate alternative to molecular mechanics methods to perform energy minimisation of peptides containing non-standard (chemically modified) amino acid residues frequently present in experimental protein structure data sets, for which force field parameters may not be available. Reference tri-peptide atomic co-ordinate sets including hydrogen atoms are made freely available. PMID- 25544681 TI - Cell Signaling Mechanisms by which Geniposide Regulates Insulin- Degrading Enzyme Expression in Primary Cortical Neurons. AB - An increasing number of studies have demonstrated that insulin-degrading enzyme (IDE) plays an essential role in both the degradation and its activity of beta amyloid (Abeta). Therefore, the regulation of IDE expression and/or modification of IDE-dependent actions are two emerging strategies for the treatment of Alzheimer's disease (AD). We previously observed that geniposide, a novel agonist of glucagon-like peptide 1 receptor (GLP-1R), could attenuate Abeta-induced neurotoxicity by regulating the expression of IDE in primary cortical neurons. However, the signal transduction mechanisms underlying this effect were not elucidated. The present study, therefore examined and explored the cell signaling transduction and molecular mechanisms by which geniposide induces the expression of IDE in primary cortical neurons. The current study revealed that LY294002 (an inhibitor for phosphatidyl inositol 3-kinase, PI3K), PP1 (inhibitor for c-Src), GW9662 (antagonist for peroxisome proliferator-activated receptor gamma, PPARgamma), H89 (an inhibitor for protein kinase A, PKA) and AG1478 (an antagonist for epidermal growth factor receptor, EGFR) prohibited the up regulation of IDE induced by geniposide in primary cortical neurons. Further, geniposide also enhanced the phosphorylation of PPARgamma and accelerated the release of phosphorylated FoxO1 (forkhead box O1) from nuclear fraction to the cytosol. Moreover, geniposide directly activated the activity of IDE promoter in PC12 cells, which confirmed the presence of the GLP-1 receptor. Taken together, our findings reveal for the first time the cell signaling transduction pathway of geniposide regulating the expression of IDE in neurons. PMID- 25544682 TI - Type 2 diabetes mellitus in France in 2012: results from the ObEpi survey. AB - AIM: This analysis estimates the prevalence of type 2 diabetes mellitus (T2DM) in French adults participating in the ObEpi (obesity epidemiology) 2012 survey and also proposes a description of that population, according to comorbidities, treatments and sociodemographic factors related to the disease. METHODS: A self administered questionnaire was posted to 20,000 households from the Kantar Health panel. In total, 25,714 adults aged>=18 years and representative of the French population completed the survey between January and March 2012. RESULTS: The prevalence of T2DM was 5.5+/-0.3% (95% CI) in this representative sample of the adult French population. Average age of patients was 65.9 years; 55% were men. Mean body mass index was 29.9kg/m(2) (men: 29.4kg/m(2), women: 30.6 kg/m(2); P<0.01); the prevalence of obesity was 43.1% (men: 39.9%, women: 47.1%; P<0.01). Patient-reported treatments for comorbidities were frequent: high blood pressure, 59.1%; dyslipidaemia, 59.9%; myocardial infarction/angina pectoris, 9.7%; revascularization, 7.8%; heart failure, 7.4%; sleep apnoea, 8.3%; and osteoarthritis, 10.7%. With regards to known treatments, 81.4% of patients were taking oral antidiabetic drugs (OADs), and 15.3% were using insulin therapy. Also, 18.8% of diabetic respondents reported financial hardship. CONCLUSION: T2DM remains a disease of major concern: compared with the non-diabetic population, all parameters surveyed showed unfavourable ratings, particularly for women. PMID- 25544683 TI - Young femoral neck fractures: are we measuring outcomes that matter? AB - INTRODUCTION: Femoral neck fractures in younger aged patients are particularly devastating injuries with profound impairments of quality of life and function. As there are multiple differences in patient and injury characteristics between young and elderly femoral neck fracture patients, the geriatric hip fracture literature is unlikely to be generalisable to patients under age 60. We conducted a systematic review to determine if clinically relevant outcome measures have been used in previously published clinical studies of internal fixation in young adults with femoral neck fractures. METHODS: We conducted a comprehensive literature search using multiple electronic databases and conference proceedings to identify studies which used internal fixation for the management of femoral neck fractures in patients between the ages of 15 to 60. Eligibility screening and data abstraction were performed in duplicate. We classified the reported outcomes into the following categories: operative and hospital outcomes, radiographic outcomes, clinical outcomes, and functional outcomes and health related quality of life. We calculated the frequencies of reported outcomes. RESULTS: Fort-two studies met our inclusion criteria. Operative and hospital outcomes were poorly reported with less than one-quarter of studies reporting relevant data. Important radiographic outcomes were also inadequately reported with only one-third of studies reporting the quality of the fracture reduction, and methods for assessment were highly variable. The assessment of avascular necrosis was reported in almost all the included studies (95.2%); however, the assessment of nonunion was only reported in three-quarters of the studies. Re operations were reported in 73.8% of the included studies and the assessment of fracture healing was only reported in two-thirds of the studies. Less than half of the studies reported functional outcomes or health-related quality of life (overall patient evaluation scales and systems (45.2%), patient functional outcomes (30.9%), and health-related quality of life (4.8%). DISCUSSION: Our systematic review found that the assessment of clinically relevant outcomes in the young femoral neck fracture literature is lacking, which makes utilising the literature to guide clinical practice challenging. Future studies should aim to include important radiographic measures, fracture-healing complications, functional outcomes, and health-related quality of life during any assessment of young femoral neck fracture treatment. PMID- 25544684 TI - Longitudinally extensive transverse myelitis in systemic lupus erythematosus: case report and review of the literature. AB - OBJECTIVE: To report a case of longitudinally extensive transverse myelitis (LETM), a rare but disabling condition defined as a lesion of the spinal cord that extends over four or more vertebrae on MRI, in association with systemic lupus erythematosus (SLE). METHODS: We present a rare case of LETM involving the cervical and thoracic spinal cord in a patient with SLE and review the existing literature on the association of lupus-associated myelitis. RESULTS: LETM is included within the diagnostic criteria for Neuromyelitis Optica (NMO), but is also known to be associated with a wide range of auto-immune diseases. Only 37 cases of LETM in patients with SLE have been previously described. We performed an updated review on epidemiology, pathophysiology, clinical features, diagnosis, management, and prognosis of LETM in the setting of SLE. CONCLUSION: Due to the generally poor prognosis of LETM in SLE patients, prompt diagnosis and treatment is of critical importance for a positive clinical outcome. We provide a comprehensive perspective of past and current literature in order to aid diagnosis and management of this rare phenomenon. PMID- 25544685 TI - Synthesis, characterization and in vitro photodynamic antimicrobial activity of basic amino acid-porphyrin conjugates. AB - Photodynamic antimicrobial chemotherapy (PACT), as a novel and effective modality for the treatment of infection with the advantage of circumventing multidrug resistance, receives great attention in recent years. The photosensitizer is the crucial element in PACT, and cationic porphyrins have been demonstrated to usually be more efficient than neutral and negatively charged analogues towards bacteria in PACT. In this work, three native basic amino acids, l-lysine, l histidine and l-arginine, were conjugated with amino porphyrins as cationic auxiliary groups, and 13 target compounds were synthesized. This paper reports their syntheses, structural characterizations, oil-water partition coefficients, singlet oxygen generation yields, photo-stability, as well as their photo inactivation efficacies against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa in vitro. The preliminary structure-activity relationship was discussed. Compound 4i, with porphyrin bearing four lysine moieties, displays the highest photo inactivation efficacy against the tested bacterial strains at 3.91 MUM with a low light dose (6 J/cm(2)), and it is stable in serum and lower cytotoxicity to A929 cells. These basic amino acid-porphyrin conjugates are potential photosensitizers for PACT. PMID- 25544686 TI - Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach. AB - Phospholipidosis (PLD) is an undesirable potential side-effect of drugs, and cationic amphiphilic drugs (CADs) represent the main class of PLD inducers. A CADs toxicophore has been recently proposed, although the CADs definition is far from being trivial. In this work we derive a three-dimensional CADs toxicophore (here named PLD-phore) using a molecular interaction field approach, and test its suitability to discriminate between PLD inducers and non-inducers in a virtual screening approach. Ten commercially available compounds predicted to be PLD inducers and non-inducers based on their similarity to the PLD-phore were experimentally tested for PLD induction using two cell-based in vitro assays (fluorescent lipid uptake, activity of secreted lysosomal beta-hexosaminidase). When a positive effect was observed, the PLD induction was also confirmed by transmission electron microscopy. Two exceptions to the general statement about CADs and PLD induction were detected and discussed, and for one compound the cell based in-vitro assays lead to different outcomes. PMID- 25544688 TI - Identification and optimization of Escherichia coli GlmU inhibitors: an in silico approach with validation thereof. AB - Bacterial infections are causing havoc on the populace. Continuous rising of antibiotic resistance in bacteria causes pressing requirement of new drugs and drug therapies that are effective against these multidrug resistance bacteria. GlmU, which is a bifunctional acetyltransferase/uridyltransferase enzyme, is novel target to treat bacterial infections. An effort has been made to identify and develop novel inhibitors of acetyltransferase activity of Escherichia coli (Ec) GlmU protein. In silico approach has been applied to screen chemical library of 50,000 drug-like compounds procured from ChemBridge and ChemDiv databases. This chemical library was screened by using a combination of ligand guided and structure guided techniques. In vitro evaluation of the in silico identified hits helped in the discovery of 8 promising inhibitors of acetyltransferase activity of Ec GlmU. Structure guided lead optimization strategy was adopted based on the acetyltransferase binding site analysis, that presented the scope of modification around three different structural moieties identified through in vitro hits. In addition, molecular dynamics studies revealed the stability of the protein inhibitor complexes of the two most promising inhibitors identified in this study. PMID- 25544689 TI - Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via intermediate (3 pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines and evaluation of their antiplasmodial and antifungal activity. AB - (3-Pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines were prepared via cyclization of diallylaminoquinolines and 4-chloro-N-quinolinylbutanamides, respectively, as novel synthetic intermediates en route to N-functionalized 3-, 5 , 6- and 8-aminoquinolines with potential biological activity. (3-Pyrrolin-1 yl)quinolines were subjected to bromination reactions, and the reactivity of (2 oxopyrrolidin-1-yl)quinolines toward lithium aluminum hydride and methyllithium was assessed, providing an entry into a broad range of novel functionalized (pyrrolidin-1-yl)- and (hydroxyalkylamino)quinolines. Antiplasmodial evaluation of these novel quinolines and their functionalized derivatives revealed moderate micromolar potency against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum, and the two most potent compounds also showed micromolar activity against a chloroquine-resistant strain of P. falciparum. Antifungal assessment of (hydroxyalkylamino)quinolines revealed three compounds with promising MIC values against Rhodotorula bogoriensis and one compound with potent activity against Aspergillus flavus. PMID- 25544687 TI - Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics. AB - A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt D-Arg-Aba-Gly-(3',5'-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt D-Arg-Aba-beta-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat. PMID- 25544691 TI - Disentangling multimodal processes in social categorization. AB - The current work examines the role of sensorimotor processes (manipulating whether visual exposure to hard and soft stimuli encourage sensorimotor simulation) and metaphor processes (assessing whether participants have understanding of a pertinent metaphor: "hard" Republicans and "soft" Democrats) in social categorization. Using new methodology to disassociate these multimodal processes (i.e., semantic, metaphoric, and sensorimotoric), the current work demonstrates that both sensorimotor and metaphor processes, combined, are needed to find an effect upon conceptual processing, providing evidence in support of the combined importance of these two theorized components. When participants comprehended the metaphor of hard Republicans and soft Democrats, and when encouraged to simulate sensorimotor experiences of hard and soft stimuli, those stimuli influenced categorization of faces as Republican and Democrat. PMID- 25544690 TI - Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2 ol-based potential Selective Estrogen Receptor Modulators for breast cancer. AB - In a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1 yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERalpha. Two representative compounds were also evaluated for in vitro membrane permeability, plasma stability as well as in-vivo toxicity in mice. The compounds displayed well-acceptable drug-like in vitro membrane permeability as well as plasma stability and were well-tolerated in experimental mice at 300 mg/kg dose. PMID- 25544692 TI - Reliability and validity of an accelerometry based measure of static and dynamic postural stability in healthy and active individuals. AB - Postural stability is an important measure in both research and clinical practice. A portable, easy to use device that can provide higher resolution than current clinical tests may allow for better identification of patients or athletes with postural stability deficits. The purpose of this study was to evaluate the ability of a tri-axial accelerometer to quantify postural stability in a healthy athletic population. Ten subjects were recruited to determine the reliability of the accelerometer to measure dynamic postural stability and thirteen were recruited to compare the accelerometer measures across tasks of varying difficulty. Subjects were asked to complete four static postural stability tasks with eyes open and eyes closed and two dynamic postural stability tasks for a total of ten tasks. During each task postural stability was measured using a tri-axial accelerometer and force platform. Differences between postural stability scores between tasks and the correlation between the two measures were assessed. The accelerometer demonstrated moderate to good test-retest reliability (ICC=0.732 to 0.899). Only the medial-lateral axis of the accelerometer showed significant differences between static tasks but all directions were able to show significant differences between static and dynamic tasks. Additionally, Spearman's ranked correlations showed little to no correlation between the accelerometer and force platform scores. Accelerometers are a reliability tool for postural stability that measure low difficulty tasks best in the medial lateral direction. Low correlation between the accelerometer and force platform suggest that these two methods are not measuring the same components of postural stability. PMID- 25544693 TI - Nitrous oxide, methane and carbon dioxide dynamics from experimental pig graves. AB - Twelve pig carcasses were buried in single, shallow and deep (30 and 90 cm, respectively) graves at an experimental site near Ottawa, Ontario, Canada, with three shallow and three deep wrapped in black plastic garbage bags. An additional six carcasses were left at the surface to decompose, three of which were bagged. Six reference pits without remains were also dug. The objective of this three year study was to examine the biogeochemistry and utility of nitrous oxide (N2O), methane (CH4) and carbon dioxide (CO2) in grave detection and whether grave depth or cadaver condition (bagged versus bare) affected soil pore air concentrations and emission of the three gases. Graves showed significantly higher (alpha=0.05) concentrations and surface fluxes of N2O and CO2 than reference pits, but there was no difference in CH4 between graves and reference pits. While CH4 decreased with depth in the soil profiles, N2O and CO2 showed a large increase compared to reference pits. Shallow graves showed significantly higher emissions and pore air concentrations of N2O and CO2 than deep graves, as did bare versus bagged carcasses. PMID- 25544694 TI - Analysis of cocaine and its adulterants in drugs for international trafficking seized by the Brazilian Federal Police. AB - Here, gas chromatography with nitrogen phosphorous detector (GC-NPD) method was developed and validated for the quantification of cocaine and adulterants (caffeine, 4-dimethylaminoantipyrine, levamisole, lidocaine and phenacetin) in illicit samples. The method was based on direct dilution of samples in methanol, sonication for 5 min and centrifugation. After appropriate dilution, an aliquot was injected into GC-MS in order to identify the active compounds and into GC-NPD for the analytes quantification. Bupivacaine was used as an internal standard. The method showed to be precise, accurate and linear over a range of 0.5-100% (weight/weight percentages) for all analytes, except phenacetin which showed a linear range between 2% and 100%. The method was successfully applied to 54 samples seized by the Brazilian Federal Police in the International Airport of Sao Paulo and mailing services during the year 2011. All the samples were associated with international trafficking and were apprehended while leaving the country. The purity of cocaine ranged from 16.5% to 91.4%. Cocaine was the only detected active compound in 29.6% of total samples. Among the identified cutting agents, levamisole was the most abundant (55.6% of the total samples) and relative concentrations (weight/weight percentages) ranged from 0.7% to 23%. Lidocaine, caffeine, phenacetin and 4-dimethylaminoantipyrine were also identified in these samples in minor concentrations. In contrast with what we initially hypothesized, drugs intended to international trafficking did not present high cocaine purity and most of the samples were laced with adulterants before leaving Brazil. PMID- 25544695 TI - Molecular characterization of RNA binding motif protein 3 (RBM3) gene from Pashmina goat. AB - Pashmina goat inhabits the high altitude cold arid desert of Ladakh, India. This goat is known for its finest and costliest under fiber. Though the under fiber may be a part of its complex thermoregulation mechanism, the genetics of its adaptability under cold conditions is not known. As an attempt to understand its adaptive genetics, and the role of RNA-binding proteins at the cellular response, this study was conducted to characterize the RBM3 gene in Pashmina goat and its expression during hypothermia. The ORF of Pashmina RBM3 gene was 273 bp. Phylogenetic analysis revealed that Pashmina RBM3 is closely related to Bos taurus RBM3. Pashmina RBM3 was characterized by comparative modeling studies. The final 3-D model contained two alpha-helices and four beta-sheets. qRT-PCR data showed that Pashmina RBM3 gene expression was significantly higher (P < 0.05) at moderate (30 degrees C) hypothermic stress conditions as compared with deep (15 degrees C) hypothermia. PMID- 25544696 TI - Dietary conjugated linoleic acid and its effect on immune response in pigs infected with the porcine reproductive and respiratory syndrome virus. AB - The aim of this study was to evaluate the effects of dietary conjugated linoleic acid (CLA) on immune response in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). A total of 18 pigs 4 weeks of age were allocated to 3 treatments, 6 per treatment: 0% CLA, 1% CLA, and 2% CLA. Serum IL 1beta, IL-6 and TNF-alpha; lymphocyte proliferation; and IL-2, IFN-gamma, IL-10, IL-4 and IL-12 in PBMCs were evaluated. NF-kappaB, COX2, iNOS and PPAR-gamma mRNA were also evaluated. No differences were observed among treatment groups in most of the in vivo cytokine profiles; only TNF-alpha production was increased in infected pigs in the CLA-supplemented groups. The cytokine profile in vitro was not affected by CLA supplementation. CLA decreased the proliferation of PBMCs stimulated with PRRSVs. Inflammation mediators and PPAR-gamma were not affected by CLA in infected pigs. CLA did not improve the immune response of PRRSV infected pigs. PMID- 25544697 TI - Recombinant transferrin binding protein A (rTbpA) fragments of Pasteurella multocida serogroup B:2 provide variable protection following homologous challenge in mouse model. AB - Transferrin binding protein A (TbpA), an iron acquisition surface protein that also acts as virulence factor, is widely distributed among strains of Pasteurella multocida. In the present study, a total of seven clones of TbpA fragments (39D to F777; 39D to Q697; 188V to F777; 188V to Q697; 39D to P377; 188V to P377 and 39D to F187) belonging to P. multocida B:2 were constructed, over-expressed and purified as recombinant fusion proteins from Escherichia coli using affinity chromatography. Immunization of mice with rTbpA fragments resulted in a significant (p < 0.05) rise in antigen specific serum total IgG and subtypes (IgG1 and IgG2a) tires. All immunized mice challenged with 8 LD50 of P. multocida B:2 resulted in a variable protective efficacy up to 50%. The study indicated the potential possibilities to incorporate full length TbpA in subunit vaccine formulation composed of synergistic subunit antigens against haemorrhagic septicaemia (HS) in cattle and buffalo. PMID- 25544698 TI - Adrenocorticotrophic hormone causes an increase in cortisol, but not parathyroid hormone, in dogs. AB - Dogs with spontaneous disorders of glucocorticoid production often have marked disturbances in calcium homeostasis. For example, hypercalcaemia is frequently observed in dogs with hypoadrenocorticism and secondary hyperparathyroidism is a common feature of canine hyperadrenocorticism. The mechanism(s) by which glucocorticoids modulate calcium homeostasis in dogs remains ill-defined. The hypothesis of this study is that a marked increase in serum cortisol concentrations would lead to an immediate negative calcium balance state which would drive a compensatory increase in parathyroid hormone (PTH) concentrations. This hypothesis was investigated by measuring serum cortisol and plasma PTH concentration in 19 dogs before and after administration of adrenocorticotrophic (ACTH) hormone. Post ACTH administration, there was a significant increase in serum cortisol, but not PTH, concentrations. The results of this study do not support the hypothesis that an increase in endogenous glucocorticoids influences calcium balance sufficiently to cause an immediate, compensatory increase in parathyroid hormone concentration. PMID- 25544699 TI - Effect of rCaIFN-gamma pretreatment on propofol-isoflurane suppression of NK cytotoxic activity in the peripheral blood of dogs. AB - In dogs, natural killer (NK) cell cytotoxic activity, which is an index of antitumor immunity, decreases after general anesthesia. In this study, we examined whether the decrease in NK cytotoxic activity can be controlled with interferon-gamma (IFN-gamma) treatment. Beagles were divided into 2 groups: a treated group (n = 6) that received recombinant canine IFN-gamma (rCaIFN-gamma) and an untreated control group (n = 6). Blood samples were taken before and at 24, 120, and 192 hours after anesthesia. NK cytotoxic activity toward canine thyroid cancer cells was measured in isolated lymphocytes with the Rose Bengal assay. The decrease in NK cytotoxic activity after anesthesia was significantly inhibited by administration of rCaIFN-gamma before propofol-isoflurane anesthesia. Further studies are necessary to evaluate the clinical implications of rCaIFN-gamma treatment in tumor recurrence and morbidity. PMID- 25544701 TI - Coevolution between Contracaecum (Nematoda, Anisakidae) and Austrolebias (Cyprinodontiformes, Rivulidae) host-parasite complex from SW Atlantic coastal basins. AB - In recent years, molecular studies in host-parasite interactions in terms of coevolution have become important. Larvae (L3) of two species of Contracaecum were found parasitizing species of Rivulidae in the Atlantic coastal basins from Uruguay. The aim of this study is to determine the patterns of differentiation of this host-parasite complex in order to clarify possible coevolutionary events in such interaction throughout phylogeographic approach using both nuclear and mitochondrial molecular markers (internal transcribed spacers (ITS) and cytochrome oxidase subunit 1 (cox-1)). Based on both markers, intraspecific variation in Contracaecum species was lower than 2 %, while interspecific variation was greater than 10 %. Both species of Contracaecum constitute monophyletic groups. Contracaecum resulted in a paraphyletic genus when incorporating other Contracaecum species and closely related nematode sequences from GenBank. ITS regions showed that Contracaecum sp. 1 is more closely related to other species of the same genus than with their counterparts from Atlantic coastal basins in Uruguay. Haplotype network for both markers corroborate the existence of two distinct taxa. While ITS pairwise FST comparisons and the indirect estimate of gene flow confirm the existence of two distinct Contracaecum species, mitochondrial gene detected low levels of migrants between some of the populations from both species. Our results suggest that coevolution in this host parasite complex species is plausible. Parasite cladogenetic events occur almost simultaneously with the separation of the hypothetical ancestors of each species complex of Austrolebias during Pliocene. Additionally, the two lineages of Contracaecum colonize differently the species within each of the Austrolebias complexes. PMID- 25544700 TI - Prostate adenocarcinoma associated with prostatic infection due to Schistosoma haematobium. Case report and systematic review. AB - Schistosomiasis affects more than 240 million people worldwide, an infection which may cause urogenital manifestations including, among others, squamous bladder cancer and prostate involvement. We describe the first case of a prostate adenocarcinoma associated with prostatic Schistosoma haematobium infection occurring in Angola. Prostate carcinoma was suspected because of high levels of prostate-specific antigen. This observation prompted us to review the literature on schistosomiaisis with respect to genital pathology and prostate cancer. Described genital manifestations in men include funiculitis, epididymitis, granulomata of the seminal vesicles, testicular masses, and prostate lesions which may cause haematospermia and infertility. In contrast to bladder cancer, only 12 reports including the present case on 17 cases on prostate carcinoma associated with schistosomiasis have been published worldwide. The rarity of reports on prostate carcinoma associated with schistosomiasis is partly due to diagnostic constraints, and its incidence is underestimated. However, in emerging countries, the incidence of prostate cancer appears to increase mainly as a result of urbanization and improved access to health care where schistosomiasis prevalence is decreasing. PMID- 25544702 TI - Current surveys on the prevalence and distribution of Dirofilaria spp. and Acanthocheilonema reconditum infections in dogs in Romania. AB - During the last decades, Dirofilaria spp. infection in European dogs has rapidly spread from historically endemic areas towards eastern and northeastern countries, but little or no information is available from these geographical regions. The present study provides a picture of filarial infections in dogs from Romania and compares two tests for the diagnosis of Dirofilaria immitis. From July 2010 to March 2011, blood samples were collected from 390 dogs from nine counties of Romania and serological SNAP tests were performed for the detection of D. immitis antigen. The remaining blood clots were subsequently used for DNA extraction followed by multiplex PCR for assessing filarioid species diversity (i.e. D. immitis, Dirofilaria repens and Acanthocheilonema reconditum). Based on molecular detection, an overall prevalence of 6.92 % (n = 27; 95 % confidence interval (CI) 4.70-10.03 %) for D. repens, 6.15 % (n = 24; 95 % CI 4.07-9.14 %) for D. immitis and 2.05 % (n = 8; 95 % CI 0.96-4.16 %) for A. reconditum was recorded, with significant variations according to sampling areas. Coinfections of D. immitis and D. repens were recorded in 23.91 % (n = 11) positive dogs. A slightly higher prevalence for D. immitis was detected at the SNAP test (n = 28, 7.17 %; 95 % CI 4.91-10.33 %), but this difference was not statistically significant (p = 0.66). However, only 53.57 % (n = 15) of antigen-positive dogs were confirmed by PCR, while other dogs (n = 9) PCR positive for D. immitis were negative at the serology. The present study shows that Dirofilaria species are endemic in the southern and southeastern areas of Romania, This article also provides, for the first time, an epidemiological picture of the distribution of A. reconditum in Romania. PMID- 25544703 TI - Mosquito larvicidal potential of silver nanoparticles synthesized using Chomelia asiatica (Rubiaceae) against Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus (Diptera: Culicidae). AB - Mosquitoes transmit serious human diseases, causing millions of deaths every year. Mosquito control is to enhance the health and quality of life of county residents and visitors through the reduction of mosquito populations. Mosquito control is a serious concern in developing countries like India due to the lack of general awareness, development of resistance, and socioeconomic reasons. Today, nanotechnology is a promising research domain which has a wide ranging application in vector control programs. These are nontoxic, easily available at affordable prices, biodegradable, and show broad-spectrum target-specific activities against different species of vector mosquitoes. In the present study, larvicidal activity of aqueous leaf extract and silver nanoparticles (AgNPs) synthesized using C. asiatica plant leaves against late third instar larvae of Anopheles stephensi, Aedes aegypti, and Cx. quinquefasciatus. The range of varying concentrations of synthesized AgNPs (8, 16, 24, 32, and 40 MUg/mL) and aqueous leaf extract (40, 80, 120, 160, and 200 MUg/mL) were tested against the larvae of An. stephensi, Ae. aegypti, and Cx. quinquefasciatus. The synthesized AgNPs from C. asiatica were highly toxic than crude leaf aqueous extract in three important vector mosquito species. The results were recorded from UV-Vis spectrum, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy analysis (EDX). Considerable mortality was evident after the treatment of C. asiatica for all three important vector mosquitoes. The LC50 and LC90 values of C. asiatica aqueous leaf extract appeared to be effective against An. stephensi (LC50, 90.17 MUg/mL; LC90, 165.18 MUg/mL) followed by Ae. aegypti (LC50, 96.59 MUg/mL; LC90, 173.83 MUg/mL) and Cx. quinquefasciatus (LC50, 103.08 MUg/mL; LC90, 183.16 MUg/mL). Synthesized AgNPs against the vector mosquitoes of An. stephensi, Ae. aegypti, and Cx. quinquefasciatus had the following LC50 and LC90 values: An. stephensi had LC50 and LC90 values of 17.95 and 33.03 MUg/mL; Ae. aegypti had LC50 and LC90 values of 19.32 and 34.87 MUg/mL; and Cx. quinquefasciatus had LC50 and LC90 values of 20.92 and 37.41 MUg/mL. No mortality was observed in the control. These results suggest that the leaf aqueous extracts of C. asiatica and green synthesis of silver nanoparticles have the potential to be used as an ideal eco-friendly approach for the control of An. stephensi, Ae. aegypti, and Cx. quinquefasciatus. This is the first report on the mosquito larvicidal activity of the plant extracts and synthesized AgNPs. PMID- 25544704 TI - Antimicrobial and mosquitocidal activity of microbial synthesized silver nanoparticles. AB - Microbial synthesis of nanoparticles is a green approach that interconnects nanotechnology and microbial biotechnology. Here, we synthesized the silver nanoparticles (AgNPs) using bacterial strains of Listeria monocytogenes, Bacillus subtilius and Streptomyces anulatus. We tested the efficacy of AgNPs against the larvae, pupae and adults of Anopheles stephensi and Culex quinquefasciatus. We have also investigated the antifungal activity of AgNPs against the soil keratinophilic fungus of Chrysosporium keratinophilum. The efficacy tests were then performed at different concentrations and varying numbers of hours by probit analysis. The results were obtained using a UV-visible spectrophotometer, and the images were recorded with a transmission electron microscope (TEM). The synthesized AgNPs were in varied shape and sizes. The larvae and pupae of Cx. quinquefasciatus were found highly susceptible to AgNPs synthesized using the L. monocytogenes, B. subtilius and S. anulatus than the An. stephensi, while the adults of An. stephensi were found more susceptible to the AgNPs synthesized using the L. monocytogenes, B. subtilius and S. anulatus the Cx. quinquefasciatus. Further, these nanoparticles have also been tested as antifungal activity against the entomopathogenic fungus C. keratinophilum. The higher zone of inhibition occurred at the concentration level of 50 MUl. This study gives an innovative approach to develop eco-friendly AgNPs which act as an effective antifungal agent/fungicide and insecticide. PMID- 25544705 TI - Leucocytozoon pterotenuis sp. nov. (Haemosporida, Leucocytozoidae): description of the morphologically unique species from the Grallariidae birds, with remarks on the distribution of Leucocytozoon parasites in the Neotropics. AB - We describe morphologically unique Leucocytozoon pterotenuis sp. nov. (Haemosporida, Leucocytozoidae), the first reported leucocytozoid species developing in fusiform host cell found in a Neotropical passeriform bird. The type host of this parasite is the Chestnut-crowned Antpitta (Grallaria ruficapilla, Grallariidae), an elusive native passerine bird whose natural history remains, to a large degree, unexplored. This bird was captured in Palacio forest in the damping zone of Chingaza National Natural Park, Cundinamarca, Colombia, at 2900 m above sea level (asl). Gametocytes of the new species develop both in roundish and fusiform host cells. This parasite is readily morphologically distinguishable from the described Leucocytozoon species because its host cells possess the narrow (needle-like) spindle-shaped processes, which length markedly exceeds their width. Additionally, the host cell nucleus markedly extends into the processes. Phylogenetic relationships were constructed based on a fragment of the mitochondrial cytochrome b gene and the complete mitochondrial genome. Phylogenetic analysis placed the lineage of L. pterotenuis in different positions depending on the length of the sequence analyzed that is likely due to poor sampling of Leucocytozoon species, especially from rare or non-passerine hosts, as well as a paucity of complete mitochondrial sequences of these parasites. Available data indicate that Leucocytozoon parasites are distributed mainly in mountain regions of the Neotropics where unique morphological forms have been recently discovered. To a better knowledge of the diversity of Leucocytozoon spp. and their host-vector-parasite interactions in Neotropical countries, additional deep and intensive samplings are needed, particularly in orders different to Passeriformes. PMID- 25544706 TI - Host specificity, pathogenicity, and mixed infections of trypanoplasms from freshwater fishes. AB - This work summarizes the results of the 8-year study focused on Trypanoplasma sp. parasitizing freshwater fishes in the vicinity of Kyiv, Ukraine. Out of 570 fish specimens of 2 different species analyzed, 440 individuals were found to be infected. The prevalence of infection ranged from 24 % in Abramis brama Linnaeus (freshwater bream) to 100 % in Cobitis taenia Linnaeus (spined loach). The level of parasitemia also varied between moderate in freshwater bream and very high in spined loach. Interestingly, no clinical manifestations of trypanoplasmosis were observed even in extremely heavily infected C. taenia. We hypothesize that different species may differ in evolutionary timing allowing for reciprocal adaptation of the members of the "host-parasite" system. Molecular analysis of the 18S rRNA sequences revealed that several specimens were simultaneously infected with at least two different trypanoplasm species. To the best of our knowledge, this is the first report of the mixed infection with fish trypanoplasms. PMID- 25544708 TI - Correlation between squamous cell carcinoma of the lung and human papillomavirus infection and the relationship to expression of p53 and p16. AB - The number of non-small-cell lung cancer (NSCLC) patients reported as infected with human papillomavirus (HPV) varies among countries and by race and geographical location. Furthermore, the relationship between HPV and the expressions of p53 and p16 remains unclear. A large cohort of NSCLC patients from Shanghai was studied. Paraffin sections from 128 cases of lung adenocarcinoma (ADC) and 134 cases of squamous cell carcinoma (SQC) were collected from the Shanghai Chest Hospital. Samples were analyzed by polymerase chain reaction (PCR) and reverse dot blot for detection of HPV DNA and by immunohistochemistry for detection of p53 and p16 expressions. The rate of HPV infection in SQC cases was significantly higher than in ADC cases (12.69 versus 3.91%). Females with SQC had a significantly higher rate of HPV infection compared to males with SQC (18.75 versus 7.14%, p = 0.044). HPV infection was correlated with gender and age in SQC but not with the degree of tumor differentiation, TNM stage, or smoking. Koilocytosis was significantly correlated to the tumor differentiation grade, regardless of age and TNM stage. The expressions of p53 and p16 were correlated with HPV infection and the tumor histological type but not with the degree of tumor differentiation, TNM stage, smoking, gender, or age. p53-positive expression was significantly higher in HPV-infected SQC cases than in those not infected with HPV. There was no statistically significant difference in the expression of p16 between the two groups. Data showed that HPV infection may be an important virulence factor in SQC, particularly in female patients. HPV infection appears to be involved in cancer progression in SQC by promoting the expression of p53; however, p16 cannot be used as a surrogate marker for HPV infection in SQC. PMID- 25544709 TI - Histopathological characterization of ulcerated breast cancer and comparison to their non-ulcerated counterparts. AB - Approximately 6-15 % of breast cancer patients are diagnosed with primary ulcerated breast cancer (ULBC). ULBC is known to be associated with short recurrence free and poor overall survival. Therefore, the purpose of this study was to characterize ULBC and compare the histopathological findings with those of non-ulcerative breast cancer (NULBC). A total of 152 ULBCs were evaluated and compared to 304 consecutive non-ulcerated, age-matched breast malignancies. Patients mean age was 65 years (SD = 13.0 ULBC, SD = 14.0 NULBC). ULBC was associated with a higher rate of poorly differentiated tumors (p = < 0.001), as well as larger tumor sizes (p = < 0.001). As expected, the rate of axillary lymph node involvement was higher in ULBC patients (p = <0.001). In addition to that, ULBC was associated with a higher rate of triple negative breast cancer (p = 0.002), and higher Ki67 expression (p = < 0.001). ULBC showed more aggressive histopathological features in comparison to NULBC which may contribute to the generally known poorer prognosis of women with ULBC. PMID- 25544710 TI - Overexpression of ETV4 is associated with poor prognosis in prostate cancer: involvement of uPA/uPAR and MMPs. AB - ETS gene fusions involving ERG, ETV1, ETV4, ETV5, and FLI1 define a distinct class of prostate cancer (PCa), and this might have a bearing on diagnosis, prognosis, and rational therapeutic targeting. In the current study, we focused on the clinicopathological significance of ETV4 in Chinese PCa patients and the mechanisms whereby ETV4 overexpression mediates tumor invasion in the prostate. Overall, ETV4 overexpression was identified in 30.4 % (45/148) of PCa cases by immunohistochemistry. Accordingly, ETV4 was rearranged in only 1.6 % (2/128) of PCa patients. Clinically, ETV4 overexpression was significantly correlated with Gleason score (P = 0.045) and pathological tumor stage (P = 0.041). Multivariate Cox regression analysis indicated that ETV4 is an unfavorable independent prognostic factor (P = 0.040). Functional studies further showed that small interfering RNA (siRNA) knockdown of ETV4 significantly decreases proliferation and invasion of PC-3 cell and partially reverses epithelial-mesenchymal transition in vitro. Notably, ETV4 knockdown significantly downregulated expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) at messenger RNA (mRNA) and protein levels. Chromatin immunoprecipitation assay demonstrated that ETV4 regulates uPA expression through direct binding to its promoter region. Additionally, ETV4 knockdown was also observed to significantly inhibit expression of matrix metalloproteinase (MMP)-2 and MMP-9. In conclusion, for the first time, our study suggested that ETV4 is an independent poor prognostic factor in Chinese PCa patients. Silencing of ETV4 suppresses invasion of PCa cells by inhibiting the expression of uPA/uPAR as well as MMPs. Further studies will be needed to determine whether ETV4 could be regarded as a potential target for the management and prevention of PCa. PMID- 25544707 TI - The HER2 Signaling Network in Breast Cancer--Like a Spider in its Web. AB - The human epidermal growth factor receptor 2 (HER2) is a major player in the survival and proliferation of tumour cells and is overexpressed in up to 30 % of breast cancer cases. A considerable amount of work has been undertaken to unravel the activity and function of HER2 to try and develop effective therapies that impede its action in HER2 positive breast tumours. Research has focused on exploring the HER2 activated phosphoinositide-3-kinase (PI3K)/AKT and rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathways for therapies. Despite the advances, cases of drug resistance and recurrence of disease still remain a challenge to overcome. An important aspect for drug resistance is the complexity of the HER2 signaling network. This includes the crosstalk between HER2 and hormone receptors; its function as a transcription factor; the regulation of HER2 by protein-tyrosine phosphatases and a complex network of positive and negative feedback-loops. This review summarises the current knowledge of many different HER2 interactions to illustrate the complexity of the HER2 network from the transcription of HER2 to the effect of its downstream targets. Exploring the novel avenues of the HER2 signaling could yield a better understanding of treatment resistance and give rise to developing new and more effective therapies. PMID- 25544711 TI - Urodynamic evaluation and anorectal manometry pre- and post-operative bowel shaving surgical procedure for posterior deep infiltrating endometriosis: a pilot study. AB - STUDY OBJECTIVE: To analyze bowel and urinary function in patients with posterior deep infiltrating endometriosis (DIE) >30 mm in largest diameter at transvaginal ultrasound before and after surgical nerve-sparing excision. DESIGN: Prospective observational study (Canadian Task Force classification III). SETTING: Tertiary care university hospital in Bologna, Italy. PATIENTS: Twenty-five patients with posterior DIE were included in the study between June 2011 and December 2012. Patients did not receive hormone therapy for at least 3 months before and 6 months after surgery. INTERVENTIONS: Patients underwent urodynamic studies and anorectal manometry before and after nerve-sparing laparoscopic excision of the posterior DIE nodule. MEASUREMENTS AND MAIN RESULTS: Intestinal and urinary function was evaluated in patients with bulky posterior DIE using urodynamic and anorectal manometry. Results of urodynamic studies and anorectal manometry were similar before and after nerve-sparing surgical excision of the posterior DIE nodule. Urodynamic studies demonstrated a high prevalence of voiding dysfunction, whereas anorectal manometry showed no reduction in rectoanal inhibitory reflex and hypertone of the internal anal sphincter. CONCLUSIONS: Patients with posterior DIE >30 mm in greatest diameter demonstrate preoperative dysfunction at urodynamic study and anorectal manometry, probably due to DIE per se. The nerve sparing surgical approach seems not to influence the motility or sensory capacity of the bladder and the rectosigmoid colon. PMID- 25544713 TI - Is pigment patterning in fish skin determined by the Turing mechanism? AB - More than half a century ago, Alan Turing postulated that pigment patterns may arise from a mechanism that could be mathematically modeled based on the diffusion of two substances that interact with each other. Over the past 15 years, the molecular and genetic tools to verify this prediction have become available. Here, we review experimental studies aimed at identifying the mechanism underlying pigment pattern formation in zebrafish. Extensive molecular genetic studies in this model organism have revealed the interactions between the pigment cells that are responsible for the patterns. The mechanism discovered is substantially different from that predicted by the mathematical model, but it retains the property of 'local activation and long-range inhibition', a necessary condition for Turing pattern formation. Although some of the molecular details of pattern formation remain to be elucidated, current evidence confirms that the underlying mechanism is mathematically equivalent to the Turing mechanism. PMID- 25544712 TI - Self-assessed efficacy of a clinical musculoskeletal anatomy workshop: A preliminary survey. AB - OBJECTIVE: To survey the efficacy of a practical workshop on clinical musculoskeletal anatomy held in five American countries. METHODS: A self assessment competence questionnaire sent to participants 1-3 months after the workshop. Results were compared to the results of a practical, instructor assessed, pre-workshop test. RESULTS: The response rate of participants was 76.4%. The overall, self-assessed competence score for anatomical items that had been included in the pre-test was 76.9 (scale 0-100) as compared to an overall score of 48.1 in the practical, pre-workshop test (p<0.001). For items that were addressed in the workshop, but not included in the pre-test, self-assessed competence was rated at 62.9. Differences in anatomical knowledge between individuals from different countries and professional groups noted in the practical pre-test were no longer present in the post-test self-assessment. CONCLUSIONS: From this preliminary data and supporting evidence from the literature we believe that our anatomy workshop provides an effective didactic tool for increasing competence in musculoskeletal anatomy. PMID- 25544714 TI - Thyroid dysfunction after intra-arterial chemotherapy for hypopharyngeal and laryngeal cancer. AB - OBJECTIVE: Hypothyroidism is a late side effect after curative radiotherapy in the head and neck region. Superselective intra-arterial chemotherapy (SSIAC), when combined with radiation (SSIAC-R), shows higher control potential for locally advanced head and neck cancers, which is attributable to a delivery of higher concentrations of chemotherapeutic agents. However, it could enhance damages in the normal tissues. Hypothyroidism is a late adverse effect after curative radiotherapy in the head and neck region. This study focuses on the toxic effect of treatment modality for thyroid function. METHODS: A retrospective analysis was performed to examine patients' thyroid function after SSIAC-R for laryngeal and hypopharyngeal cancer. RESULTS: Hypothyroidism was observed in 21 (77.8%) of 27 patients receiving SSIAC-R, 4 (33.3%) of 12 patients treated with radiation alone, and 7 (41.1%) of 17 who underwent systemic chemoradiotherapy. The number of administered vessels significantly correlated with the incidence of developing hypothyroidism among SSIAC-R treated patients (P=0.03). CONCLUSION: Concurrent setting of SSIAC with radiation significantly raises the possibility of hypothyroidism. Therefore, monitoring late complications of therapeutic procedures is essential during follow-up visits. PMID- 25544715 TI - Distension test in passive external rotation: Validation of a new clinical test for the early diagnosis of shoulder adhesive capsulitis. AB - OBJECTIVE: The aim of this study is to evaluate the internal validity of a clinical test for the early diagnosis of shoulder adhesive capsulitis, called the Distension Test in Passive External Rotation (DTPER). MATERIAL AND METHOD: The DTPER is performed with the patient standing up, the arm adducted, and the elbow bent at 90 degrees . From this position, a smooth passive external rotation is started, the affected arm being supporting at the wrist with one hand of the examiner and the other maintaining the adducted elbow until the maximum painless point of the rotation is reached. From this point of maximum external rotation with the arm in adduction and with no pain, an abrupt distension movement is made, increasing the external rotation, causing pain in the shoulder if the test is positive. This term was performed on a group of patients with shoulder pain of many origins, in order to analyse the predictive values, sensitivity, specificity, and the likelihood ratio. RESULTS: The DTPER showed a sensitivity of 100% (95% CI; 91.8 to 100%) and a specificity of 90% (95% CI; 82.4 to 94.8%). The positive predictive value was 0.62 and a likelihood ratio of 10.22 (95% CI; 5.5 to 19.01). False positives were only found in patients with subscapular tendinopathies or glenohumeral arthrosis. DISCUSSION: The DTPER has a high sensitivity for the diagnosis of adhesive capsulitis, and is excluded when it is practically negative. False positives can easily be identified if there is external rotation with no limits (subscapular tendinopathy) or with a simple shoulder X-ray (glenohumeral arthrosis). PMID- 25544717 TI - Examining elite Parasport athletes with sport involvement and sports equipment. AB - Elite athletes require the most advanced sports equipment to maintain their competitive edge, but manufacturers cannot always satisfy these athletes' specific equipment needs. Sport involvement can influence sports-equipment selections and is described as the process by which individuals rely on attitudes and belief systems to make sports-related consumption decisions. This study involved semistructured interviews with 5 elite Parasport athletes to identify and analyze the role of sport involvement in their selection of sports equipment. The results revealed that the athletes identified product limitations, created a collaborative environment, and promoted a culture of innovation to develop new sports products and address existing limitations. Theoretical and practical implications are discussed. PMID- 25544716 TI - Stepping Stones and Creating Futures intervention: shortened interrupted time series evaluation of a behavioural and structural health promotion and violence prevention intervention for young people in informal settlements in Durban, South Africa. AB - BACKGROUND: Gender-based violence and HIV are highly prevalent in the harsh environment of informal settlements and reducing violence here is very challenging. The group intervention Stepping Stones has been shown to reduce men's perpetration of violence in more rural areas, but violence experienced by women in the study was not affected. Economic empowerment interventions with gender training can protect older women from violence, but microloan interventions have proved challenging with young women. We investigated whether combining a broad economic empowerment intervention and Stepping Stones could impact on violence among young men and women. The intervention, Creating Futures, was developed as a new generation of economic empowerment intervention, which enabled livelihood strengthening though helping participants find work or set up a business, and did not give cash or make loans. METHODS: We piloted Stepping Stones with Creating Futures in two informal settlements of Durban with 232 out of school youth, mostly aged 18-30 and evaluated with a shortened interrupted time series of two baseline surveys and at 28 and 58 weeks post-baseline. 94/110 men and 111/122 women completed the last assessment, 85.5% and 90.2% respectively of those enrolled. To determine trend, we built random effects regression models with each individual as the cluster for each variable, and measured the slope of the line across the time points. RESULTS: Men's mean earnings in the past month increased by 247% from R411 (~$40) to R1015 (~$102, and women's by 278% R 174 (~$17) to R 484 (about $48) (trend test, p < 0.0001). There was a significant reduction in women's experience of the combined measure of physical and/or sexual IPV in the prior three months from 30.3% to 18.9% (p = 0.037). This was not seen for men. However both men and women scored significantly better on gender attitudes and men significantly reduced their controlling practices in their relationship. The prevalence of moderate or severe depression symptomatology among men and suicidal thoughts decreased significantly (p < 0.0001 and p = 0.01). CONCLUSIONS: These findings are very positive for an exploratory study and indicate that the Creating Futures/Stepping Stones intervention has potential for impact in these difficult areas with young men and women. Further evaluation is needed. PMID- 25544718 TI - Public attitudes toward people with intellectual disabilities after viewing Olympic or Paralympic performance. AB - Despite some changes to the way that people with intellectual disabilities (ID) are viewed in society, negative attitudes prevail. One of the aspirations of the 2012 Paralympic games was to influence the public's attitudes toward people with disabilities. The aim of this study was to investigate whether stimuli depicting people with ID performing at Paralympic level of competition change attitudes toward ID. A mixed randomized comparison design was employed comparing 2 groups: those who viewed Paralympic-level ID sport footage and information and those who viewed Olympic footage and information. One hundred fourteen students, mean age 25 yr, were administered measures of implicit (subconscious) attitudes toward disability and explicit (belief-based) attitudes toward ID. Implicit attitudes significantly changed in a positive direction for both groups. The findings provide evidence that both Paralympic (ID) and Olympic media coverage may have at least a short-term effect on attitudes toward people with disabilities. PMID- 25544719 TI - "We can talk while we're walking": seeking the views of adults with intellectual disability to inform a walking and social-support program. AB - To better understand how physical activity programs may contribute to improved health and social-support outcomes for people with intellectual disability, the authors conducted semistructured interviews with 11 people with intellectual disability and community-based volunteers in Brisbane, Australia. Three broad themes emerged: individual factors that generally facilitated activity, external factors that posed barriers to participation, and broader normative factors that directed participation. A key reflection arising out of the thematic analysis was that participants with intellectual disability and volunteers highlighted subtle but pervasive differences in barriers and facilitators to being active. Recommendations are provided for interventions aiming to improve physical activity and social support among those with intellectual disability. The authors' research process demonstrates the utility of seeking the views of potential participants before program rollout to inform implementation and demonstrates the usefulness of a qualitative, actively inclusive approach to health interventions. PMID- 25544720 TI - Preservice physical educators' self-efficacy beliefs toward inclusion: the impact of coursework and practicum. AB - The purpose of this study was to investigate the effect of completion of an adapted physical education (APE) course with an associated on-campus practicum on preservice physical educators' self-efficacy beliefs toward the inclusion of individuals with specific disabilities (autism, intellectual disabilities, physical disabilities, and visual impairments). Preservice students in physical education teacher education (N = 98) at a large U.S. Midwestern university enrolled in 1 of 2 separate 15-wk APE courses with an associated 9-wk practicum experience were surveyed at the beginning, middle, and conclusion of each course. Results of 4 separate 2-factor fixed-effect split-plot ANOVAs revealed significant improvements in self-efficacy beliefs from Wk 1 to Wk 8 and from Wk 1 to Wk 15 across all disability categories. Significant differences between courses were found only for autism in Time 1. PMID- 25544721 TI - Physical activity and school-age individuals with visual impairments: a literature review. AB - The purpose of this article was to review published research literature on physical activity for school-age individuals with visual impairments by describing study characteristics and major findings. Keyword searches were used to identify articles from electronic databases published from 1982 to June 2013. Eighteen articles met all inclusion criteria, and relevant data such as participants, visual-impairment levels, theory, measurement, and dependent variables were extracted from them. Of the 18 studies, 5 were descriptive, 6 correlational, and 7 were interventions. Only 4 studies explicitly stated a theoretical or conceptual framework. Major findings suggest that low physical activity levels of school-age individuals with visual impairments may be related to perceived participation barriers including the availability of appropriate opportunities rather than visual acuity or educational setting. PMID- 25544724 TI - Recording of brain activity across spatial scales. AB - Brain activity reveals exquisite coordination across spatial scales, from local microcircuits to brain-wide networks. Understanding how the brain represents, transforms and communicates information requires simultaneous recordings from distributed nodes of whole brain networks with single-cell resolution. Realizing multi-site recordings from communicating populations is hampered by the need to isolate clusters of interacting cells, often on a day-to-day basis. Chronic implantation of multi-electrode arrays allows long-term tracking of activity. Lithography on thin films provides a means to produce arrays of variable resolution, a high degree of flexibility, and minimal tissue displacement. Sequential application of surface arrays to monitor activity across brain-wide networks and subsequent implantation of laminar arrays to target specific populations enables continual refinement of spatial scale while maintaining coverage. PMID- 25544725 TI - Using percentage of sarcomatoid differentiation as a prognostic factor in renal cell carcinoma. AB - BACKGROUND: The objective of this study was to determine if the percentage of sarcomatoid differentiation (%Sarc) in renal cell carcinoma (RCC) can be used for prognostic risk stratification, because sarcomatoid RCC (sRCC) is an aggressive variant of kidney cancer. PATIENTS AND METHODS: We performed a retrospective analysis of patients who underwent surgery for RCC at our institution between 1999 and 2012. Pathology slides for all sRCC cases were reexamined by a single pathologist and %Sarc was calculated. %Sarc was analyzed as a continuous variable and as a categorical variable at cut points of 5%, 10%, and 25%. Potential prognostic factors associated with overall survival (OS) were determined using the Cox regression model. OS curves were generated using Kaplan-Meier methods and survival differences compared using the log-rank test. RESULTS: One thousand three hundred seven consecutive cases of RCC were identified, of which 59 patients had sRCC (4.5%). As a continuous variable %Sarc was inversely associated with OS (P = .023). Predictors of survival on multivariable analysis included pathologic (p) T status, tumor size, clinical (c) M status and %Sarc at the 25% level. OS was most dependent on the presence of metastatic disease (4 months vs. 21.2 months; P = .001). In cM0 patients with locally advanced (>= pT3) tumors, OS was significantly diminished in patients with > 25 %Sarc (P = .045). However, %Sarc did not influence OS in patients with cM1 disease. CONCLUSION: Patients with sRCC have a poor overall outcome as evidenced by high rates of recurrence and death, indicating the need for more effective systemic therapies. In nonmetastatic patients, the incorporation of %Sarc in predictive nomograms might further improve risk stratification. PMID- 25544726 TI - A bilateral analysis scheme for false positive reduction in mammogram mass detection. AB - In this paper, a bilateral image analysis scheme is developed for the purpose of reducing false positives (FPs) in the detection of masses in dense mammograms. It consists of two steps: a region matching step for determining the correspondence between a pair of mammograms, and a bilateral similarity analysis step for discarding FPs in the detection. For the first step, a matching cost is defined to quantify the credibility of the corresponding region in a pair of bilateral mammograms. For the second step, a similarity measurement is introduced to discriminate between mass and normal for a pair of bilateral regions based on both global and local image appearances. The proposed scheme is tested on a set of 332 mammograms. The results show that the proposed scheme could obtain better performance when compared with several existing bilateral analysis schemes. With detection sensitivity at 85%, the proposed bilateral scheme could reduce the FP rate of a unilateral scheme from 3.64 to 2.39 per image, a 34% reduction. PMID- 25544727 TI - Microfluidic platform towards point-of-care diagnostics in infectious diseases. AB - Rapid and timely diagnosis of infectious diseases is a critical determinant of clinical outcomes and general public health. For the detection of various pathogens, microfluidics-based platforms offer many advantages, including speed, cost, portability, high throughput, and automation. This review provides an overview of the recent advances in microfluidic technologies for point-of-care (POC) diagnostics for infectious diseases. The key aspects of such technologies for the development of a fully integrated POC platform are introduced, including sample preparation, on-chip nucleic acid analysis and immunoassay, and system integration/automation. The current challenges to practical implementation of this technology are discussed together with future perspectives. PMID- 25544728 TI - [Anatomy of the levator ani muscle and implications for obstetrics and gynaecology]. AB - Pelvic floor disorders include urogenital and anorectal prolapse, urinary and faecal incontinence. These diseases affect 25% of patients. Most of time, treatment is primarily surgical with a high post-operative risk of recurrence, especially for pelvic organ prolapse. Vaginal delivery is the major risk factor for pelvic floor disorders through levator ani muscle injury or nerve damage. After vaginal delivery, 20% of patients experiment elevator ani trauma. These injuries are more common in case of instrumental delivery by forceps, prolonged second phase labor, increased neonatal head circumference and associated anal sphincter injuries. Moreover, 25% of patients have temporary perineal neuropathy. Recently, pelvic three-dimensional reconstructions from RMI data allowed a better understanding of detailed levator ani muscle morphology and gave birth to a clear new nomenclature describing this muscle complex to be developed. Radiologic and anatomic studies have allowed exploring levator ani innervation leading to speculate on the muscle and nerve damage mechanisms during delivery. We then reviewed the levator ani muscle anatomy and innervation to better understand pelvic floor dysfunction observed after vaginal delivery. PMID- 25544729 TI - A climatology of 7Be in surface air in European Union. AB - This study presents a European-wide analysis of the spatial and temporal distribution of the cosmogenic isotope (7)Be in surface air. This is the first time that a long term database of 34 sampling sites that regularly provide data to the Radioactivity Environmental Monitoring (REM) network, managed by the Joint Research Centre (JRC) in Ispra, is used. While temporal coverage varies between stations, some of them have delivered data more or less continuously from 1984 to 2011. The station locations were considerably heterogeneous, both in terms of latitude and altitude, a range which should ensure a high degree of representativeness of the results. The mean values of (7)Be activity concentration presented a spatial distribution value ranging from 2.0 to 5.4 mBq/m(3) over the European Union. The results of the ANOVA analysis of all (7)Be data available indicated that its temporal and spatial distributions were mainly explained by the location and characteristic of the sampling sites rather than its temporal distribution (yearly, seasonal and monthly). Higher (7)Be concentrations were registered at the middle, compared to high-latitude, regions. However, there was no correlation with altitude, since all stations are sited within the atmospheric boundary layer. In addition, the total and yearly analyses of the data indicated a dynamic range of (7)Be activity for each solar cycle and phase (maximum or minimum), different impact on stations having been observed according to their location. Finally, the results indicated a significant seasonal and monthly variation for (7)Be activity concentration across the European Union, with maximum concentrations occurring in the summer and minimum in the winter, although with differences in the values reached. The knowledge of the horizontal and vertical distribution of this natural radionuclide in the atmosphere is a key parameter for modelling studies of atmospheric processes, which are important phenomena to be taken into account in the case of a nuclear accident. PMID- 25544730 TI - Human adipose-derived stem cells attenuate inflammatory bowel disease in IL-10 knockout mice. AB - Inflammatory bowel disease (IBD) is a complex immunological disorder characterized by chronic inflammation caused mainly by unknown factors. The interleukin-10 knockout (IL-10 KO) mouse is a well-established murine model of IBD which develops spontaneous intestinal inflammation that resembles Crohn's disease. In the present study, human adipose-derived mesenchymal stem cells (hAMSCs) were administrated to IL-10 KO mice to evaluate the anti-inflammatory effects of hAMSCs that may attenuate the progress of or treat IBD. After IBD was induced by feeding the IL-10 KO mouse a 125-250 ppm piroxicam mixed diet for 1 week, 2*10(6) hAMSCs were injected into the peritoneum and the mice were switched to a normal diet. After 1 week, the mice were sacrificed and tissue samples were harvested. Tissue scores for inflammation and inflammation-related genes expression were determined. The hAMSC-treated group showed significantly reduced inflammatory changes in histological analysis. Reverse transcription-PCR analysis showed that RANTES, Toll-like receptor 9, and IL-4 expression levels were not significantly different between the groups while IL-12, INF-gamma, and TNF-alpha levels were significantly decreased in the hAMSC treated group. hAMSC attenuated IBD in the IL-10 KO mice by suppressing inflammatory cytokine expression, was mediated by the type 1 helper T cell pathway. Even though only a single injection of hAMSCs was delivered, the effect influenced chronic events associated with inflammatory changes and demonstrated that hAMSCs are a powerful candidate for IBD therapy. PMID- 25544731 TI - Editorial overview: Virus replication in animals and plants. PMID- 25544732 TI - Ketofol for procedural sedation revisited: pro and con. PMID- 25544734 TI - Are antibiotics effective in the treatment of acute bronchitis? AB - In patients without underlying lung disease, antibiotics in acute bronchitis appear to decrease cough, but the clinical significance of this decrease is uncertain. Their use should be weighed against the cost and potential adverse effects for treatment of a self-limiting disease. PMID- 25544733 TI - Factors Associated With Successful Resuscitation After Out-of-Hospital Cardiac Arrest and Temporal Trends in Survival and Comorbidity. AB - STUDY OBJECTIVE: Out-of-hospital cardiac arrest has an overall poor prognosis. We sought to identify what temporal trends and influencing factors existed for this condition in one region. METHODS: We studied consecutive out-of-hospital cardiac arrest patients from 2007 to 2011 with attempted resuscitation in Copenhagen. From an Utstein database, we assessed survival to admission and comorbidity with the Charlson comorbidity index from the National Patient Registry and employment status from the Danish Rational Economic Agents Model database. We used logistic regression analyses to identify factors associated with outcome. RESULTS: Of a total of 2,527 attempted resuscitations in out-of-hospital cardiac arrest patients, 40% (n=1,015) were successfully resuscitated and admitted to the hospital. The strongest independent factors associated with successful resuscitation were shockable primary rhythm (multivariate odds ratio [OR]=3.9; 95% confidence interval [CI] 3.1 to 5.0), witnessed arrest (multivariate OR=3.5; 95% CI 2.7 to 4.6), and out-of-hospital cardiac arrest in a public area (multivariate OR=2.1; 95% CI 1.6 to 2.8), whereas no comorbidity (multivariate OR=1.1; 95% CI 0.8 to 1.45), sex (multivariate OR=1.14; 95% CI 0.91 to 1.44), and employment status (multivariate OR=1.17; 95% CI 0.89 to 1.56) were not independently associated with outcome. The number of patients with a high comorbidity burden (Charlson comorbidity index >=3) increased during the study period (P trend <.001), from 18% to 31% (P trend <.001), whereas the percentage of out-of-hospital cardiac arrest patients with successful resuscitation to hospital admission increased by 3% per year during the study period, from 37% in 2007 to 43% in 2011 (P trend <.001). CONCLUSION: Our observations confirm the importance of key features that influence out-of-hospital cardiac arrest survival to hospital admission but are not highly influenced by public health actions. Despite increased illness burden, this short term outcome from cardiac arrest improved as care system efforts matured. PMID- 25544735 TI - The Diagnosis of Ectopic Pregnancy. PMID- 25544736 TI - Overcoming the 911 fear factor. PMID- 25544738 TI - Longitudinal effects of the SSRI paroxetine on salivary cortisol in Major Depressive Disorder. AB - Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation is a prominent finding in more severe Major Depressive Disorder (MDD), and is characterized by increased baseline cortisol levels at awakening (BCL), blunted cortisol awakening response (CAR) and increased area under the cortisol curve (AUC). Selective serotonin reuptake inhibitors (SSRIs) appear to normalize HPA-axis dysfunction, but this is hardly investigated longitudinally. We studied salivary BCL, CAR and AUC at awakening and 30min thereafter. We compared measurements in initially drug-free MDD-patients with healthy controls (HCs) at study-entry. In patients, we repeated measures after 6 and 12 weeks' treatment with the SSRI paroxetine. Non-responding patients received a randomized dose-escalation after six weeks' treatment. We found no significant study-entry differences in BLC, CAR or AUC between MDD patients (n=70) and controls (n=51). In MDD-patients, we found general decreases of BCL and AUC during paroxetine treatment (p<=0.007), especially in late and non responders. Importantly, while overall CAR did not change significantly over time, it robustly increased over 12 weeks especially when patients achieved remission (p<=0.041). The dose-escalation intervention did not significantly influence CAR or other cortisol parameters. In conclusion, paroxetine seems to interfere with HPA-axis dysregulation, reflected in significant overall decreases in BCL and AUC during treatment. Paroxetine appears to decrease HPA-axis set point in MDD, which might result in increased HPA-axis activity over time, which is further improved when patients achieve remission (ISRCTN register nr. ISRCTN44111488). PMID- 25544737 TI - Maternal postnatal depression predicts altered offspring biological stress reactivity in adulthood. AB - The offspring of depressed parents have been found to show elevated basal levels of the stress hormone cortisol. Whether heightened cortisol stress reactivity is also present in this group has yet to be clearly demonstrated. We tested whether postnatal maternal depression predicts subsequent increases in offspring biological sensitivity to social stress, as indexed by elevated cortisol reactivity. Participants (mean age 22.4-years) derived from a 22-year prospective longitudinal study of the offspring of mothers who had postnatal depression (PND group; n=38) and a control group (n=38). Salivary cortisol response to a social evaluative threat (Trier Social Stress Test) was measured. Hierarchical linear modelling indicated that PND group offspring showed greater cortisol reactivity to the stress test than control group participants. Group differences were not explained by offspring depressive or anxiety symptoms, experiences of negative life events, elevated basal cortisol at age 13-years, subsequent exposure to maternal depression, or other key covariates. The findings indicate that the presence of early maternal depression can predict offspring biological sensitivity to social stress in adulthood, with potential implications for broader functioning. PMID- 25544739 TI - High fat feeding is associated with stimulation of the hypothalamic-pituitary adrenal axis and reduced anxiety in the rat. AB - Previous studies have shown that diet-induced obesity is associated with insulin resistance and impaired feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to test the hypothesis that hyper secretion of glucocorticoid, evoked by feeding rats a high fat (HF) diet for 12 weeks, also influences behavioural and neural responses to the elevated plus-maze (EPM) test of anxiety. HF-fed animals exhibited anxiolytic-like behaviour in the EPM but were also hyperactive in this test. Covariant analysis established that the anxiolytic-like behaviour was not secondary to the increase in activity. The HF diet significantly increased basal levels of plasma corticosterone. The groups exposed to the EPM also displayed increased plasma corticosterone levels compared to the relevant control group, although the increment was smaller in the HF-fed animals. Glucocorticoid receptor (GR) immunoreactivity in the cytoplasmic fraction of parietal cortex and hypothalamus and the particulate fraction of the parietal cortex were increased by HF feeding. The behavioural changes evoked by HF feeding did not correlate significantly with changes in GR immunoreactivity in each treatment group or 5-HT turnover in the brain areas studied. It is concluded that anxiolytic properties evoked in the EPM by high fat feeding are unlikely to be related to the changes in HPA function seen in animals fed this diet. PMID- 25544740 TI - Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans. AB - Pre-clinical and clinical evidence indicates that opioid drugs have stress dampening effects. In animal models, opioid analgesics attenuate responses to isolation distress, and in humans, opioids reduce stress related to anticipation of physical pain. The stress-reducing effects of opioid drugs may contribute to their abuse potential. Despite this evidence in laboratory animals, the effects of opioids on responses to psychosocial stress have not been determined in humans. Here we examined the effects of buprenorphine, a MU-opioid partial agonist used to treat opioid dependence and pain, on subjective and physiological responses to a stressful public speaking task in healthy adults. We hypothesized that buprenorphine would reduce subjective and physiological stress responses. Healthy adult volunteers (N=48) were randomly assigned to receive placebo, 0.2mg sublingual buprenorphine, or 0.4mg sublingual buprenorphine in a two-session study with a stressful speaking task (Trier Social Stress Test; TSST) and a non stressful control task. During the sessions, the participants reported on their mood states, provided subjective appraisals of the task, and measures of salivary cortisol, heart rate, and blood pressure at regular intervals. Stress produced its expected effects, increasing heart rate, blood pressure, salivary cortisol, and subjective ratings of anxiety and negative mood. In line with our hypothesis, both doses of buprenorphine significantly dampened salivary cortisol responses to stress. On self-report ratings, buprenorphine reduced how threatening participants found the tasks. These results suggest that enhanced opioid signaling dampens responses to social stress in humans, as it does in laboratory animals. This stress-dampening effect of buprenorphine may contribute to the non medical use of opioid drugs. PMID- 25544741 TI - Minimally important change values of a measurement instrument depend more on baseline values than on the type of intervention. AB - OBJECTIVES: Multi-item questionnaires are frequently used to measure outcomes in randomized controlled trials (RCTs) in patients with sciatica. Knowing the minimaly important change (MIC) values for these instruments will facilitate interpretation of change scores. MIC values have been shown to be dependent on baseline values. The question is whether they also depend on the type of intervention. To estimate the MIC of the Roland Morris Disability Questionnaire (modified 23 item version) (RMDQ) and of intensity of leg pain measured by a Visual Analogue Scale (VAS) in patients with sciatica and to assess to what extent MIC values depend on type of intervention and on baseline values. STUDY DESIGN AND SETTING: This is a secondary analysis of RCT data of the effects of early surgery vs. prolonged conservative treatment in patients with sciatica. Baseline and 8-week data were used to assess MIC of the RMDQ-23 and VAS leg pain. We used the receiver operator characteristic (ROC) method to assess the MIC. Global Perceived Recovery (rated 8 weeks after baseline) was used as anchor. Subgroups were created based on type of treatment and baseline severity. RESULTS: The MIC value of the RMDQ-23 for the total group of sciatica patients was 7.5. The values were 8.1 and 6.9 for surgery and conservative treatment, respectively. For high and low baseline values, the MICs were 9.0 and 4.9, respectively, irrespective of treatment received. The MIC values of the VAS leg pain were 34.4 for the total group. For surgery and conservative treatment, the MIC values were 38.5 and 30.4, respectively, whereas for groups with high and low baseline values, MIC values of 53.5 and 17.2 were found. CONCLUSION: The MIC values of the RMDQ-23 and VAS leg pain were found to be highly dependent on their baseline values, although the type of intervention appeared to influence the MIC value only slightly. PMID- 25544742 TI - Metabolic syndrome and discrepancy between actual and self-identified good weight: Aerobics Center Longitudinal Study. AB - This study examined whether the discrepancy between measured and self-identified good weight (weight discrepancy) predicts metabolic syndrome (MetSyn). This study included 6,413 participants enrolled in the Aerobics Center Longitudinal Study (mean follow-up: 4.8+/-3.8 years). Weight discrepancy was defined as measured weight minus self-identified good weight. MetSyn was defined using standard definitions. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident MetSyn, by weight discrepancy category, were estimated using Cox proportional hazards regression. The multivariable-adjusted HR for MetSyn was 3.48 (95% CI=2.48-4.86) for those who maintained higher weight discrepancy over time compared to individuals with lower weight discrepancy. Additional adjustment for body mass index did not change this interpretation (HR=3.44; 95% CI=2.46 4.82). Weight discrepancy may be a useful screening characteristic and target for future interventions to further reduce the risk of chronic weight-related disorders, included MetSyn. PMID- 25544743 TI - Effects of television exposure on developmental skills among young children. AB - BACKGROUND: Literature addressing the effects of television exposure on developmental skills of young children less than 36 months of age is scarce. This study explored how much time young children spend viewing television and investigated its effects on cognitive, language, and motor developmental skills. METHODS: Data were collected from the Pediatric Clinics at University Medical Center in Southern Taiwan. The participants comprised 75 children who were frequently exposed to television and 75 children who were not or infrequently exposed to television between 15 and 35 months old. The age and sex were matched in the two groups. The Bayley Scales of Infant Development-second edition and Peabody Developmental Motor Scales-second edition were used to identify developmental skills. Independent t-tests, chi(2) tests, and logistic regression models were conducted. RESULTS: Among 75 children who were frequently exposed to television, young children watched a daily average of 67.4 min of television before age 2, which was excessive according to the American Academy of Pediatrics. Viewing television increased the risk of delayed cognitive, language, and motor development in children who were frequently exposed to television. Cognitive, language, and motor delays in young children were significantly associated with how much time they spent viewing television. The type of care providers was critical in determining the television-viewing time of children. CONCLUSION: We recommend that pediatric practitioners explain the impacts of television exposure to parents and caregivers to ensure cognitive, language, and motor development in young children. Advocacy efforts must address the fact that allowing young children to spend excessive time viewing television can be developmentally detrimental. PMID- 25544745 TI - Role of vitamin D and sFlt-1/PlGF ratio in the development of early- and late onset preeclampsia. AB - BACKGROUND: The imbalanced production of placental biomarkers and vitamin D deficiency have been proposed as risk factors for the development of preeclampsia (PE). However, little is known about the relationship between them and their role in early- versus late-onset PE. The objectives were to assess the role of 25 hydroxyvitamin D [25(OH)D] concentrations and the soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio in the development of early- and late-onset PE; and to evaluate the relationship between 25(OH)D and the biomarkers. METHODS: A retrospective, full-blinded cohort study was conducted at the Obstetric Emergency Service of a tertiary care hospital. Pregnant women (n=257) attending obstetric triage with suspicion of PE were included. sFlt-1, PlGF and 25(OH)D concentrations were measured by electrochemoluminescence (ECLIA) immunoassay and pregnancy outcome (development of PE) was registered from patients records. RESULTS: PE women showed lower 25(OH)D concentrations at clinical presentation than non-PE women (median: 35.0 nmol/L and 39.6 nmol/L, respectively; p=0.027). Women with 25(OH)D levels <50 nmol/L experienced an increased risk of developing late-onset PE [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.4-15], but no association was found for early-onset PE. However, a sFlt-1/PlGF ratio above the corresponding cutpoints increased the risk of developing both early- and late-onset PE [ORs 58 (95% CI 11-312) and 12 (95% CI 5.0-27), respectively]. No association was found between 25(OH)D levels and sFlt 1/PlGF ratio. CONCLUSIONS: Low vitamin D status in women with suspected late onset PE increases the risk of imminent development of the disease. PMID- 25544744 TI - Plant-microorganism-soil interactions influence the Fe availability in the rhizosphere of cucumber plants. AB - Iron (Fe) is a very important element for plants, since it is involved in many biochemical processes and, often, for the low solubility of the natural Fe sources in soil, plants suffer from Fe - deficiency, especially when grown on calcareous soils. Among the numerous plant growth-promoting rhizobacteria (PGPR) that colonize the rhizosphere of agronomically important crops, Azospirillum brasilense has been shown to exert strong stimulating activities on plants, by inducing alterations of the root architecture and an improvement of mineral nutrition, which could result from an enhancement of ion uptake mechanisms as well as by increased bioavailability of nutrients. Some studies have also established that A. brasilense can act as biocontrol agent, by preventing the growth and/or virulence of phytopathogens, most likely through the production of microbial siderophores that sequester Fe from the soil. Despite microbial siderophores complexed with Fe could be an easily accessible Fe source for plants, the possible involvement of A. brasilense in improving Fe nutrition in plants suffering from the micronutrient deficiency has not been investigated yet. Within the present research, the characterization of the physiological and biochemical effects induced by Fe starvation and PGPR inoculation in cucumber plants (Cucumis sativus L. cv. Chinese Long) was carried out. The analyses of root exudates released by hydroponically grown plants highlighted that cucumber plants respond differently depending on the nutritional status. In addition, following the cultivation period on calcareous soil, also the root exudates found in the extracts suggested a peculiar behaviour of plants as a function of the treatment. Interestingly, the presence of the inoculum in soil allowed a faster recovery of cucumber plants from Fe-deficiency symptoms, i.e. increase in the chlorophyll content, in the biomass and in the Fe content of leaves. These observations might suggest a feasible application of A. brasilense in alleviating symptoms generated by Fe-limiting growth condition in cucumber plants. PMID- 25544746 TI - Faecal haemoglobin concentrations do vary across geography as well as with age and sex: ramifications for colorectal cancer screening. PMID- 25544747 TI - Co-treatment with therapeutic neural stem cells expressing carboxyl esterase and CPT-11 inhibit growth of primary and metastatic lung cancers in mice. AB - In this study, neural stem cells (NSCs)-derived enzyme/prodrug therapy (NDEPT) was used to treat primary lung cancer or metastatic lung cancer in the brain. To confirm the anti-tumor effect of NSCs expressing carboxyl esterase (CE), A549 lung cancer cells were treated with HB1.F3.CE cells and CPT-11. A significant decrease in the viability/proliferation of lung cancer cells was observed compared to negative controls or cells treated with CPT-11 alone. To produce a mouse model of primary lung cancer or lung cancer metastasis to the brain, A549 cells were implanted in the dorsal area of the mouse or right hemisphere. CM-DiI pre-stained stem cells were implanted near the primary lung cancer tumor mass or in the contralateral brain. Two days after stem cells injection, mice were inoculated with CPT-11 (13.5 kg/mouse/day) via intraperitoneal injection. In the primary lung cancer mouse models, tumor mass was 80% lower in response to HB1.F3.CE in conjunction with CPT-11, while it was only reduced by 40% in the group treated with CPT-11 alone. Additionally, therapeutic efficacy of co treatment with stem cells and CPT-11 was confirmed by detection of apoptosis and necrosis in primary and metastatic lung cancer tissues. By secreting VEGF, tumor cells modulate Erk1/2 and Akt signaling and migration of stem cells. This further increased tumor-selectivity of stem cell/prodrug co-therapy. Overall, these results indicate that NSCs expressing the therapeutic gene may be a powerful tool for treatment of primary lung cancer or metastasis of lung cancer to the brain. PMID- 25544749 TI - DEPTOR has growth suppression activity against pancreatic cancer cells. AB - DEPTOR was reported as a naturally occurring inhibitor of mTORC1 and mTORC2. The role of DEPTOR in the growth and survival of pancreatic cancer cells has not previously been determined. Here we report that while DEPTOR shows a cytoplasmic expression in both normal pancreatic acinar and islet cells in a patchy manner, its expression is reduced in PanIN1 and PanIN2 and completely lost in 100 out of 101 pancreatic ductal adenocarcinoma (PDAC) tissues. Ectopic DEPTOR expression in two pancreatic cancer cell lines, Panc-1 and Miapaca-2, caused a significant 1) suppression of anchorage-dependent growth in monolayer culture, particularly under conditions with growth factor deprivation; 2) decreased clonogenic survival, and 3) suppressed anchorage-independent growth in soft agar. These effects are attributable to moderate induction of apoptosis and growth arrest at the S and G2/M phases, in a cell line dependent manner. Furthermore, ectopic DEPTOR expression moderately inhibited mTORC1 activity, as demonstrated by reduced phosphorylation of S6K, S6, and 4E-BP1. Taken together, these data suggest that DEPTOR has a tumor suppressive activity against pancreatic cancer cells, and its loss of expression may contribute to pancreatic tumorigenesis. PMID- 25544748 TI - A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy. AB - Mesoderm Inducer in Xenopus Like1 (MIXL1), a paired-type homeobox transcription factor induced by TGF-beta family of ligands is required for early embryonic specification of mesoderm and endoderm. Retrovirally transduced Mixl1 is reported to induce acute myelogenous leukemia (AML) with a high penetrance. But the mechanistic underpinnings of MIXL1 mediated leukemogenesis are unknown. Here, we establish the protooncogene c-REL to be a transcriptional target of MIXL1 by genome wide chromatin immune precipitation. Accordingly, expression of c-REL and its downstream targets BCL2L1 and BCL2A2 are elevated in MIXL1 expressing cells. Notably, MIXL1 regulates c-REL through a zinc finger binding motif, potentially by a MIXL1-Zinc finger protein transcriptional complex. Furthermore, MIXL1 expression is detected in the cancer genome atlas (TCGA) AML samples in a pattern mutually exclusive from that of HOXA9, CDX2 and HLX suggesting the existence of a core, yet distinct HOX transcriptional program. Finally, we demonstrate MIXL1 to be induced by BMP4 and not TGF-beta in primary human hematopoietic stem and progenitor cells. Consequently, MIXL1 expressing AML cells are preferentially sensitive to the BMPR1 kinase inhibitor LDN-193189. These findings support the existence of a novel MIXL1-c REL mediated survival axis in AML that can be targeted by BMPR1 inhibitors. (MIXL1- human gene, Mixl1- mouse ortholog, MIXL1- protein). PMID- 25544750 TI - Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process. AB - Low doses of radiation may have profound effects on cellular function. Individuals may be exposed to low doses of radiation either intentionally for medical purposes or accidentally, such as those exposed to radiological terrorism or those who live near illegal radioactive waste dumpsites.We studied the effects of low dose radiation on human bone marrow mesenchymal stromal cells (MSC), which contain a subpopulation of stem cells able to differentiate in bone, cartilage, and fat; support hematopoiesis; and contribute to body's homeostasis.The main outcome of low radiation exposure, besides reduction of cell cycling, is the triggering of senescence, while the contribution to apoptosis is minimal. We also showed that low radiation affected the autophagic flux. We hypothesize that the autophagy prevented radiation deteriorative processes, and its decline contributed to senescence.An increase in ATM staining one and six hours post irradiation and return to basal level at 48 hours, along with persistent gamma H2AX staining, indicated that MSC properly activated the DNA repair signaling, though some damages remained unrepaired, mainly in non-cycling cells. This suggested that the impaired DNA repair capacity of irradiated MSC seemed mainly related to the reduced activity of a non-homologous end-joining (NHEJ) system rather than HR (homologous recombination). PMID- 25544751 TI - SWI/SNF complexes are required for full activation of the DNA-damage response. AB - SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated in ~20% of all human primary tumors. Yet our knowledge of their tumor-suppressor mechanism is limited. To investigate the role of SWI/SNF complexes in the DNA-damage response (DDR), we used shRNAs to deplete BRG1 and BRM and then exposed these cells to a panel of 6 genotoxic agents. Compared to controls, the shRNA knockdown cells were hypersensitive to certain genotoxic agents that cause double-strand breaks (DSBs) associated with stalled/collapsed replication forks but not to ionizing radiation-induced DSBs that arise independently of DNA replication. These findings were supported by our analysis of DDR kinases, which demonstrated a more prominent role for SWI/SNF in the activation of the ATR-Chk1 pathway than the ATM-Chk2 pathway. Surprisingly, gammaH2AX induction was attenuated in shRNA knockdown cells exposed to a topoisomerase II inhibitor (etoposide) but not to other genotoxic agents including IR. However, this finding is compatible with recent studies linking SWI/SNF with TOP2A and TOP2BP1. Depletion of BRG1 and BRM did not result in genomic instability in a tumor-derived cell line but did result in nucleoplasmic bridges in normal human fibroblasts. Taken together, these results suggest that SWI/SNF tumor-suppressor activity involves a role in the DDR to attenuate replicative stress and genomic instability. These results may also help to inform the selection of chemotherapeutics for tumors deficient for SWI/SNF function. PMID- 25544752 TI - Phosphorylation of Tip60 by p38alpha regulates p53-mediated PUMA induction and apoptosis in response to DNA damage. AB - Tip60 is a multifunctional acetyltransferase involved in multiple cellular functions. Acetylation of p53 at K120 by Tip60 promotes p53-mediated apoptosis after DNA damage. We previous showed that Tip60 activity is induced by phosphorylation at T158 by p38. In this study, we investigated the role of p38 mediated Tip60 phosphorylation in p53-mediated, DNA damage-induced apoptosis. We found that DNA damage induces p38 activation, Tip60-T158 phosphorylation, and p53 K120 acetylation with similar kinetics. p38alpha is essential for DNA damage induced Tip60-T158 phosphorylation. In addition, both p38alpha and Tip60 are essential for p53-K120 acetylation, binding of p53 to PUMA promoter, PUMA expression and apoptosis induced by DNA damage. Moreover, DNA damage induces protein kinase activity of p38alpha towards Tip60-T158, and constitutive activation of p38 in cells leads to increases in Tip60-T158 phosphorylation, p53 K120 acetylation, PUMA expression and apoptosis. Furthermore, the Tip60-T158A mutant that cannot be phosphorylated by p38 fails to mediate p53-K120 acetylation, PUMA induction, and apoptosis following DNA damage. These results establish that Tip60-T158 phosphorylation by p38 plays an essential role in stimulating Tip60 activity required for inducing the p53-PUMA pathway that ultimately leads to apoptosis in response to DNA damage, which provides a mechanistic basis for the tumor-suppressing function of p38 and Tip60. PMID- 25544754 TI - Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment. AB - Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment. PMID- 25544753 TI - Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma. AB - The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (gammaH2AX), marker of DNA damage and genomic instability. Constitutive gammaH2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF 0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL. PMID- 25544755 TI - MicroRNA-130a associates with ribosomal protein L11 to suppress c-Myc expression in response to UV irradiation. AB - The oncoprotein c-Myc is essential for cell growth and proliferation while its deregulated overexpression is associated with most human cancers. Thus tightly regulated levels and activity of c-Myc are critical for maintaining normal cell homeostasis. c-Myc is down-regulated in response to several types of stress, including UV-induced DNA damage. Yet, mechanism underlying UV-induced c-Myc reduction is not completely understood. Here we report that L11 promotes miR-130a targeting of c-myc mRNA to repress c-Myc expression in response to UV irradiation. miR-130a targets the 3'-untranslated region (UTR) of c-myc mRNA. Overexpression of miR-130a promotes the Ago2 binding to c-myc mRNA, significantly reduces the levels of both c-Myc protein and mRNA and inhibits cell proliferation. UV treatment markedly promotes the binding of L11 to miR-130a, c myc mRNA as well as Ago2 in cells. Inhibiting miR-130a significantly suppresses UV-mediated c-Myc reduction. We further show that L11 is relocalized from the nucleolus to the cytoplasm where it associates with c-myc mRNA upon UV treatment. Together, these results reveal a novel mechanism underlying c-Myc down-regulation in response to UV-mediated DNA damage, wherein L11 promotes miR-130a-loaded miRISC to target c-myc mRNA. PMID- 25544756 TI - Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis. AB - Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe. PMID- 25544757 TI - Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma. AB - The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor 1alpha (HIF-1alpha) pathway and up-regulation of the drug efflux transporter P glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down regulated the Ras/ERK1/2/HIF-1alpha/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID- 25544758 TI - Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. AB - Multidrug resistance (MDR) is a primary hindrance to curative cancer chemotherapy. In this respect, lysosomes were suggested to play a role in intrinsic MDR by sequestering protonated hydrophobic weak base chemotherapeutics away from their intracellular target sites. Here we show that intrinsic resistance to sunitinib, a hydrophobic weak base tyrosine kinase inhibitor known to accumulate in lysosomes, tightly correlates with the number of lysosomes accumulating high levels of sunitinib in multiple human carcinoma cells. Furthermore, exposure of cancer cells to hydrophobic weak base drugs leads to a marked increase in the number of lysosomes per cell. Non-cytotoxic, nanomolar concentrations, of the hydrophobic weak base chemotherapeutics doxorubicin and mitoxantrone triggered rapid lysosomal biogenesis that was associated with nuclear translocation of TFEB, the dominant transcription factor regulating lysosomal biogenesis. This resulted in increased lysosomal gene expression and lysosomal enzyme activity. Thus, treatment of cancer cells with hydrophobic weak base chemotherapeutics and their consequent sequestration in lysosomes triggers lysosomal biogenesis, thereby further enhancing lysosomal drug entrapment and MDR. The current study provides the first evidence that drug-induced TFEB associated lysosomal biogenesis is an emerging determinant of MDR and suggests that circumvention of lysosomal drug sequestration is a novel strategy to overcome this chemoresistance. PMID- 25544759 TI - Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin. AB - Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer for which there is no effective treatment. Previously, we and others demonstrated that CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in breast cancer. In this study, we investigated the effects of CXCR4 gene silencing on cisplatin chemosensitivity in human triple-negative breast cancer cell lines. We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin. Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin treated CXCR4 knockdown cells was significantly higher than control cells. Furthermore, we demonstrated CXCR4 knockdown cells showed lower levels of mutant p53 and Bcl-2 protein than the control group, while also having higher levels of caspase-3 and Bax. However overexpression of CXCR4 had the reverse effect. In vivo experiments confirmed that downregulation of CXCR4 enhanced cisplatin anticancer activity in tumor-bearing mice, and that this enhanced anticancer activity is attributable to tumor cell apoptosis. Thus, this study indicates that CXCR4 can modulate cisplatin sensitivity in TNBC cells and suggests that CXCR4 may be a therapeutic target for TNBC. PMID- 25544760 TI - Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma. AB - Melanoma is often caused by mutations due to exposure to ultraviolet radiation. This study reports a recurrent somatic C > T change causing a P131L mutation in the RQCD1 (Required for Cell Differentiation1 Homolog) gene identified through whole exome sequencing of 20 metastatic melanomas. Screening in 715 additional primary melanomas revealed a prevalence of ~4%. This represents the first reported recurrent mutation in a member of the CCR4-NOT complex in cancer. Compared to tumors without the mutation, the P131L mutant positive tumors were associated with increased thickness (p = 0.02), head and neck (p = 0.009) and upper limb (p = 0.03) location, lentigo maligna melanoma subtype (p = 0.02) and BRAF V600K (p = 0.04) but not V600E or NRAS codon 61 mutations. There was no association with nodal disease (p = 0.3). Mutually exclusive mutations of other members of the CCR4-NOT complex were found in ~20% of the TCGA melanoma dataset suggesting the complex may play an important role in melanoma biology. Mutant RQCD1 was predicted to bind strongly to HLA-A0201 and HLA-Cw3 MHC1 complexes. From thirteen patients with mutant RQCD1, an anti-tumor CD8+ T cell response was observed from a single patient's peripheral blood mononuclear cell population stimulated with mutated peptide compared to wildtype indicating a neoantigen may be formed. PMID- 25544761 TI - Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer. AB - Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naive prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naive prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC. PMID- 25544762 TI - Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling. AB - One challenge in biology is signal transduction monitoring in a physiological context. Intravital imaging techniques are revolutionizing our understanding of tumor and host cell behaviors in the tumor environment. However, these deep tissue imaging techniques have not yet been adopted to investigate the second messenger calcium (Ca2+). In the present study, we established conditions that allow the in vivo detection of Ca2+ signaling in three-dimensional tumor masses in mouse models. By combining intravital imaging and a skinfold chamber technique, we determined the ability of photodynamic cancer therapy to induce an increase in intracellular Ca2+ concentrations and, consequently, an increase in cell death in a p53-dependent pathway. PMID- 25544763 TI - Claudin-1 enhances tumor proliferation and metastasis by regulating cell anoikis in gastric cancer. AB - Claudin-1 (CLDN1) is overexpressed in gastric cancer and correlated with tumor invasion, metastasis and poor outcome. Here, we both down and up regulated CLDN1 expression in gastric cancer cells to elucidate its role in gastric carcinogenesis and tumor progression. We found that deficiency of CLDN1 inhibited cells migration, invasion, and colony formation in vitro and tumorigenicity, metastasis in vivo. Also, CLDN1 promoted cell aggregation and increased anoikis resistance. Down or up regulation of CLDN1 was accompanied with changes of membrane beta-catenin expression as well as Akt and Src activities. When beta catenin was up-regulated in CLDN1-KD cells, cell aggregation and anoikis resistance were restored, and Akt and Src signal pathways were re-activated. Taken together, these findings suggest that CLDN1 is oncogenic in gastric cancer and its malignant potential may be attributed in part to regulation of anoikis, by mediating membrane beta-catenin-regulated cell-cell adhesion and cell survival. PMID- 25544765 TI - The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells. AB - Metastatic colorectal cancer (mCRC) remains a major public health problem, and diagnosis of metastatic disease is usually associated with poor prognosis. The multi-kinase inhibitor regorafenib was approved in 2013 in the U.S. for the treatment of mCRC patients who progressed after standard therapies. However, the clinical efficacy of regorafenib is quite limited. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may lead to synergistic enhancement of antitumor efficacy and overcome cellular drug resistance. Protein kinase D (PKD), a family of serine/threonine kinases, mediates key signaling pathways implicated in multiple cellular processes. Herein, we evaluated the combination of regorafenib with a PKD inhibitor in several human CRC cells. Using the Chou-Talalay model, the combination index values for this combination treatment demonstrated synergistic effects on inhibition of cell proliferation and clonal formation. This drug combination resulted in induction of apoptosis as determined by flow cytometry, increased PARP cleavage, and decreased activation of the anti-apoptotic protein HSP27. This combination also yielded enhanced inhibition of ERK, AKT, and NF kappaB signaling. Taken together, PKD inhibition in combination with regorafenib appears to be a promising strategy for the treatment of mCRC. PMID- 25544764 TI - Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe. AB - Hypoxia-inducible genes may contribute to therapy resistance in glioblastoma (GBM), the most aggressive and hypoxic brain tumours. It has been recently reported that erythropoietin (EPO) and its receptor (EPOR) are involved in glioma growth. We now investigated whether EPOR signalling may modulate the efficacy of the GBM current treatment based on chemotherapy (temozolomide, TMZ) and radiotherapy (X-rays). Using RNA interference, we showed on glioma cell lines (U87 and U251) that EPOR silencing induces a G2/M cell cycle arrest, consistent with the slowdown of glioma growth induced by EPOR knock-down. In vivo, we also reported that EPOR silencing combined with TMZ treatment is more efficient to delay tumour recurrence and to prolong animal survival compared to TMZ alone. In vitro, we showed that EPOR silencing not only increases the sensitivity of glioma cells to TMZ as well as X-rays but also counteracts the hypoxia-induced chemo- and radioresistance. Silencing EPOR on glioma cells exposed to conventional treatments enhances senescence and induces a robust genomic instability that leads to caspase-dependent mitotic death by increasing the number of polyploid cells and cyclin B1 expression. Overall these data suggest that EPOR could be an attractive target to overcome therapeutic resistance toward ionising radiation or temozolomide. PMID- 25544766 TI - Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferating in vivo. AB - Chronic lymphocytic leukemia (CLL) cells residing in the bone marrow (BM) and in secondary lymphoid tissues receive survival and proliferative signals from the microenvironment, resulting in persistence of residual disease after treatment. In this study, we characterized primary CLL cells cultured with BM stromal cells, CD40 ligand and CpG ODN to partially mimic the microenvironment in the proliferative centers. This co-culture system induced proliferation and chemoresistance in primary CLL cells. Importantly, co-cultured primary CLL cells shared many phenotypical features with circulating proliferative CLL cells, such as upregulation of ZAP-70 and CD38 and higher CD49d and CD62L expression. This indicates aggressiveness and capability to interact with surrounding cells, respectively. In addition, levels of CXCR4 were decreased due to CXCR4 internalization after CXCL12 stimulation by BM stromal cells. We suggest that this co-culture system can be used to test drugs and their combinations that target the proliferative and drug resistant CLL cells. PMID- 25544767 TI - TGF-beta1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma. AB - TGF-beta1, a potent EMT (epithelial-mesenchymal transition) inducer present in the tumor microenvironment, is involved in the metastasis and progression of various carcinomas, including esophageal squamous cell carcinoma (ESCC). TIP30 (30kDa HIV-1 Tat interacting protein) is a putative tumor metastasis suppressor. Here, we found TIP30 was decreased in cells undergoing EMT induced by TGF-beta1, an occurrence that was related to promoter hypermethylation. TGF-beta1 induced TIP30 hypermethylation via increasing DNMT1 and DNMT3A expression, which could be restored by TGF-beta antibodies. In our in vitro and in vivo studies, we showed that silence of TIP30 led to EMT, enhanced migrative and invasive abilities of ESCC cells, promoted tumor metastasis in xenografted mice; alternatively, overexpression of TIP30 inhibited TGF-beta1-induced EMT, and metastatic abilities of ESCC cells. Mechanically, TIP30 silencing induced the nuclear translocation and transcriptional activation of beta-catenin in an AKT-dependent manner, which further resulted in the initiation of EMT. Consistently, TIP30 was frequently methylated and downregulated in ESCC patients. Loss of TIP30 correlated with nuclear beta-catenin and aberrant E-cadherin expression. TIP30 was a powerful marker in predicting the prognosis of ESCC. Taken together, our results suggest a novel and critical role of TIP30 involved in TGF-beta1-induced activation of AKT/beta-catenin signaling and ESCC metastasis. PMID- 25544768 TI - Hypoxia up-regulates SERPINB3 through HIF-2alpha in human liver cancer cells. AB - SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells. Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2alpha (not HIF-1alpha) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2alpha-mediated SERPINB3 up-regulation under hypoxic conditions required intracellular generation of ROS. Immuno-histochemistry (IHC) and transcript analysis, performed in human HCC specimens, revealed co-localization of the two proteins in liver cancer cells and the existence of a positive correlation between HIF-2alpha and SERPINB3 transcript levels, respectively. Hypoxia, through HIF-2alpha-dependent and redox sensitive mechanisms, up-regulates the transcription, synthesis and release of SERPINB3, a molecule with a high oncogenic potential. PMID- 25544769 TI - betaIII-tubulin: a novel mediator of chemoresistance and metastases in pancreatic cancer. AB - Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, beta tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of beta-tubulins in pancreatic cancer are unknown. We measured the expression of different beta-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence betaIII-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of betaIII-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that betaIII-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing betaIII-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of betaIII-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that betaIII-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients. PMID- 25544770 TI - Inhibition of HIF-1alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all the malignancies. Now, gemcitabine (Gem) is the first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem is usually ineffective to the PDAC because of high degree of drug resistance. Hypoxia and immune suppressive milieu are the best-described hallmarks of PDAC; therefore, we investigated the impact of hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with Gem on the induction of immunogenic cell death (ICD). We verified that combined treatment with Gem/PX-478 significantly enhanced the anti-tumor effect and increased proportion of tumor infiltrating T-lymphocytes in Panc02-bearing immune competent but not in immune-deficient mice. Vaccination using Panc02 cell line treated with single agent or in combination showed significant anti-tumor effects. Pancreatic cell lines treated with Gem and PX-478 can induce an increase in eIF2alpha phosphorylation was correlated with down-regulation of HIF-1alpha and elicited exposure of CRT and release of HMGB1 and ATP. Only co-treated cells induced DC maturation/phagocytosis and IFN-gamma secretion by cytotoxic T lymphocytes. Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization. We propose that inhibition HIF-1alpha elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD. PMID- 25544771 TI - Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival. AB - Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival. PMID- 25544772 TI - A microRNA signature profile in EBV+ diffuse large B-cell lymphoma of the elderly. AB - Currently, there is no characteristic microRNA (miRNA) expression pattern in Epstein-Barr virus+ diffuse large B-cell lymphoma of the elderly (EBV+DLBCLe). This study aims to characterize a signature profile and identify miRNAs that can be used as biomarkers and alternative therapeutic targets for EBV+DLBCLe. Seventy one DLBCL patients aged 50 years and older were included and four EBV+ and four EBV- samples were analyzed in two miRNA array platforms (pilot study). A larger multicenter cohort (29 EBV+DLBCLe and 65 EBV-DLBCL patients) was used to validate the results by real-time polymerase chain reaction. In the pilot study, 9% of DLBCL were EBV+DLBCLe by in situ hybridization. In multicenter study, EBV+DLBCLe group showed a predominance of non-germinal center B-cell origin. Overall survival duration of EBV+DLBCLe was significantly inferior to that of EBV-DLBCL patients. We found 10 deregulated miRNAs in the two groups, but only seven were statistically different. We confirmed overexpression of hsa-miR-126, hsa-miR 146a, hsa-miR-146b, hsa-miR-150, and hsa-miR-222 and underexpression of hsa-miR 151 in EBV+DLBCLe cases compared to EBV-DLBCL cases. Hsa-miR-146b and hsa-miR-222 showed high specificity for identifying EBV+DLBCLe. The present study proposed a miRNA signature for EBV+DLBCLe and our findings suggest that hsa-miR-146b and hsa miR-222 could be biomarkers and therapeutic targets. PMID- 25544773 TI - Targeting the microRNA-21/AP1 axis by 5-fluorouracil and pirarubicin in human hepatocellular carcinoma. AB - MicroRNAs function as oncomiRs and tumor suppressors in diverse cancers. However, the utility of specific microRNAs in predicting the clinical benefit of chemotherapy has not been well-established. Here, we investigated the correlation between microRNA-21 expression and hepatic arterial infusion chemotherapy with 5 fluorouracil and pirarubicin (HAIC) for hepatocellular carcinoma (HCC). We found that HCC patients with low microRNA-21 levels in tumors tended to have a longer time to recurrence and disease-free survival. We demonstrated that microRNA-21 suppression in combination with 5-fluorouracil and pirarubicin treatment inhibited tumor growth in subcutaneous xenograft mice models. Mechanistically, the AP-1 and microRNA-21-mediated axis was verified to be a therapeutic target of cytotoxic drugs and deregulation of this axis led to an enhanced cell growth in HCC. Taken together, our findings demonstrate that microRNA-21 is a chemotherapy responsive microRNA and can serve as a prognostic biomarker for HCC patients undergoing HAIC. Targeting microRNA-21 enhances the effect of chemotherapeutic drugs, thereby suggesting that microRNA-21 suppression in combination with HAIC may be a novel approach for HCC treatment. PMID- 25544775 TI - The antimicrobial peptide pardaxin exerts potent anti-tumor activity against canine perianal gland adenoma. AB - Pardaxin is an antimicrobial peptide of 33 amino acids, originally isolated from marine fish. We previously demonstrated that pardaxin has anti-tumor activity against murine fibrosarcoma, both in vitro and in vivo. In this study, we examined the anti-tumor activity, toxicity profile, and maximally-tolerated dose of pardaxin treatment in dogs with different types of refractory tumor. Local injection of pardaxin resulted in a significant reduction of perianal gland adenoma growth between 28 and 38 days post-treatment. Surgical resection of canine histiocytomas revealed large areas of ulceration, suggesting that pardaxin acts like a lytic peptide. Pardaxin treatment was not associated with significant variations in blood biochemical parameters or secretion of immune-related proteins. Our findings indicate that pardaxin has strong therapeutic potential for treating perianal gland adenomas in dogs. These data justify the veterinary application of pardaxin, and also provide invaluable information for veterinary medicine and future human clinical trials. PMID- 25544776 TI - The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway. AB - B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti leukemic activity in p53wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53mutated B-CLL cells and in p53mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53wild-type and p53mutated B-CLL patient cell cultures, as well as in p53mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53mutated leukemic cells, by acting through the induction of a p53 independent pathway. PMID- 25544777 TI - Reconciling solvent effects on rotamer populations in carbohydrates - A joint MD and NMR analysis. AB - The rotational preferences of the hydroxymethyl group in pyranosides is known to depend on the local environment, whether in solid, solution, or gas phase. By combining molecular dynamics (MD) simulations with NMR spectroscopy the rotational preferences for the omega angle in methyl 2,3-di-O-methyl-alpha-D glucopyranoside (3) and methyl 2,3-di-O-methyl-alpha-D-galactopyranoside (6) in a variety of solvents, with polarities ranging from 80 to 2.3 D have been determined. The effects of solvent polarity on intramolecular hydrogen bonding have been identified and quantified. In water, the internal hydrogen bonding networks are disrupted by competition with hydrogen bonds to the solvent. When the internal hydrogen bonds are differentially disrupted, the rotamer populations associated with the omega angle may be altered. In the case of 3 in water, the preferential disruption of the interaction between HO6 and O4 destabilizes the tg rotamer, leading to the observed preference for gauche rotamers. Without the hydrogen bond enhancement offered by a low polarity environment, both 3 and 6 display rotamer populations that are consistent with expectations based on the minimization of repulsive intramolecular oxygen-oxygen interactions. In a low polarity environment, HO6 prefers to interact with O4, however, in water these interactions are markedly weakened, indicating that HO6 acts as a hydrogen bond donor to water. PMID- 25544774 TI - The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. AB - Tspan8 and CD151 are metastasis-promoting tetraspanins and a knockdown (kd) of Tspan8 or CD151 and most pronounced of both tetraspanins affects the metastatic potential of the rat pancreatic adenocarcinoma line ASML. Approaching to elaborate the underlying mechanism, we compared ASMLwt, -CD151kd and/or Tspan8kd clones. We focused on tumor exosomes, as exosomes play a major role in tumor progression and tetraspanins are suggested to be engaged in exosome targeting. ASML-CD151/Tspan8kd cells poorly metastasize, but regain metastatic capacity, when rats are pretreated with ASMLwt, but not ASML-CD151kd and/or -Tspan8kd exosomes. Both exosomal CD151 and Tspan8 contribute to host matrix remodelling due to exosomal tetraspanin-integrin and tetraspanin-protease associations. ASMLwt exosomes also support stroma cell activation with upregulation of cytokines, cytokine receptors and proteases and promote inflammatory cytokine expression in hematopoietic cells. Finally, CD151-/Tspan8-competent exosomes support EMT gene expression in poorly-metastatic ASML-CD151/Tspan8kd cells. These effects are not seen or are weakened using ASML-CD151kd or -Tspan8kd exosomes, which is at least partly due to reduced binding/uptake of CD151- and/or Tspan8 deficient exosomes. Thus, CD151- and Tspan8-competent tumor exosomes support matrix degradation, reprogram stroma and hematopoietic cells and drive non metastatic ASML-CD151/Tspan8kd cells towards a motile phenotype. PMID- 25544779 TI - Influence of non-reactive solvent on optical performance, photopolymerization kinetics and morphology of nanoporous polymer gratings. AB - A study of nanoporous polymer gratings, with controllable nanostructured porosity, as a function of grating performance, photopolymerization kinetics and morphology is presented. Modifying the standard holographic polymer dispersed liquid crystal (H-PDLC) system, by including a non-reactive solvent, results in a layered, nanoporous morphology and produces reflective optical elements with excellent optical performance of broadband reflection. The addition of the non reactive solvent in the pre-polymer mixture results in a morphology typified by void/polymer layer-by-layer structures if sufficient optical energy is used during the holographic writing process. The duration and intensity of optical exposure necessary to form well-aligned nanoporous structures can only be obtained in the modified system by (a) illumination under longer time of holographic interference patterning (30 min) or (b) illumination under very short time of holographic interference patterning (30 s) and followed by post-curing using homogeneous optical exposure for 60 min. Comparatively, a typical H-PDLC is formed in less than 1 min. To further understand the differences in the formation of these two analogous materials, the temporal dynamics of the photoinitiation and polymerization (propagation) kinetics were examined. It is shown herein that the writing exposure gives a cross-linked polymer network that is denser in the bright regions. With 60% (or even 45%) acrylate conversion, almost no free monomer would be left after the writing. Continued exposure serves primarily to add cross-links. This has the tendency to collapse the network, especially the less dense portions, which in effect get glued down to the more dense parts. To the extent that the solvent increases the mobility of the polymer network, this process will be aided. Equally important, the size of the periodic nanopores can be varied from 10 to 50 nm by controlling either the LC concentration in the pre polymer mixture or by controlling the time of the homogeneous post-cure. PMID- 25544778 TI - Adaptation of a Psycho-Oncology Intervention for Black Breast Cancer Survivors: Project CARE. AB - Black women are traditionally underserved in all aspects of cancer care. This disparity is particularly evident in the area of psychosocial interventions where there are few programs designed to specifically meet the needs of Black breast cancer survivors. Cognitive-behavioral stress management intervention (CBSM) has been shown to facilitate adjustment to cancer. Recently, this intervention model has been adapted for Black women who have recently completed treatment for breast cancer. We outline the components of the CBSM intervention, the steps we took to adapt the intervention to meet the needs of Black women (Project CARE) and discuss the preliminary findings regarding acceptability and retention of participants in this novel study. PMID- 25544780 TI - (m.n)-Homorubins. Syntheses and Structures. AB - Five new homorubin analogs of bilirubin with their two dipyrrinone components conjoined to (CH2)2, (CH2)3, and (CH2)4 units were synthesized with propionic acid chains shortened to acetic and elongated to butyric, and examined by spectroscopy and molecular mechanics computations for an ability to form conformation-determining hydrogen bonds. With m designating the number of conjoining CH2 units and n indicating the number of CH2 units of the alkanoic acid chains of (m.n)-homorubins, (2.1), (3.2), (4.2), and (4.3) homorubins were prepared and compared with previously synthesized (2.2) and (2.3), which adopt intramolecularly hydrogen bonded conformations in CHCl3. PMID- 25544782 TI - Family Socioeconomic Status, Peers, and The Pathto College. AB - Drawing on the primary/secondary effects perspective of educational inequality, this mixed methods study investigated connections between high school students' trajectories through college preparatory coursework and their relationships with parents and peers as a channel in the intergenerational transmission of socioeconomic inequality. Growth curve and multilevel analyses of national survey and transcript data revealed that having college-educated parents differentiated students' enrollment in advanced coursework at the start of high school and that this initial disparity was stably maintained over subsequent years. During this starting period of high school, exposure to school-based peer groups characterized by higher levels of parent education appeared to amplify these coursework disparities between students with and without college-educated parents. Ethnographic data from a single high school pointed to possible mechanisms for these patterns, including the tendency for students with college educated parents to have more information about the relative weight of grades, core courses, and electives in college-going and for academically-relevant information from school peers with college-educated parents to matter most to students' coursework when it matched what was coming from their own parents. PMID- 25544783 TI - Diversity and the Civic Spirit in British Neighbourhoods: An Investigation with MCDS and EMBES 2010 Data. AB - Recently, there has been a proliferation of studies investigating the relationship between diversity and outcomes such as social cohesion and civic mindedness. This article addresses several common problems in this field and, using data for British neighbourhoods, elaborates on the experiences of both white British and ethnic minority respondents. We conclude that, if anything, diversity should be encouraged to cement the integration progress of migrants and foster stronger identification with Britain in the second generation. Deprivation at the neighbourhood level along with individual factors such as fear of crime is a much stronger predictor of deterioration of the civic spirit than diversity. Bridging contacts have the expected strong positive association with cohesion outcomes; and contrary to policy concerns no strong negative impact is observed for associational bonding among minority ingroupers. PMID- 25544781 TI - Neurological and psychiatric disorders as a neuroglial failure. AB - Neuroglia are a diverse non-neuronal population of cells in the central and peripheral nervous system. These cells have a variety of functions that can all be summed up as the maintenance of homeostasis of the nervous system. It is the loss of homeostasis that represents the culprit of all disorders. Thus, neuroglia can be envisioned as the pivotal element in all neural disorders, be that neurological or psychiatric. In this review, we discuss the role of glia in homeostasis and defence of the nervous system as well as changes in the morpho functional characteristics of these cells in various disorders. PMID- 25544784 TI - On the definition of a confounder. AB - The causal inference literature has provided a clear formal definition of confounding expressed in terms of counterfactual independence. The causal inference literature has not, however, produced a clear formal definition of a confounder, as it has given priority to the concept of confounding over that of a confounder. We consider a number of candidate definitions arising from various more informal statements made in the literature. We consider the properties satisfied by each candidate definition, principally focusing on (i) whether under the candidate definition control for all "confounders" suffices to control for "confounding" and (ii) whether each confounder in some context helps eliminate or reduce confounding bias. Several of the candidate definitions do not have these two properties. Only one candidate definition of those considered satisfies both properties. We propose that a "confounder" be defined as a pre-exposure covariate C for which there exists a set of other covariates X such that effect of the exposure on the outcome is unconfounded conditional on (X, C) but such that for no proper subset of (X, C) is the effect of the exposure on the outcome unconfounded given the subset. A variable that helps reduce bias but not eliminate bias we propose referring to as a "surrogate confounder." PMID- 25544785 TI - OPTIMAL COMPUTATIONAL AND STATISTICAL RATES OF CONVERGENCE FOR SPARSE NONCONVEX LEARNING PROBLEMS. AB - We provide theoretical analysis of the statistical and computational properties of penalized M-estimators that can be formulated as the solution to a possibly nonconvex optimization problem. Many important estimators fall in this category, including least squares regression with nonconvex regularization, generalized linear models with nonconvex regularization and sparse elliptical random design regression. For these problems, it is intractable to calculate the global solution due to the nonconvex formulation. In this paper, we propose an approximate regularization path-following method for solving a variety of learning problems with nonconvex objective functions. Under a unified analytic framework, we simultaneously provide explicit statistical and computational rates of convergence for any local solution attained by the algorithm. Computationally, our algorithm attains a global geometric rate of convergence for calculating the full regularization path, which is optimal among all first-order algorithms. Unlike most existing methods that only attain geometric rates of convergence for one single regularization parameter, our algorithm calculates the full regularization path with the same iteration complexity. In particular, we provide a refined iteration complexity bound to sharply characterize the performance of each stage along the regularization path. Statistically, we provide sharp sample complexity analysis for all the approximate local solutions along the regularization path. In particular, our analysis improves upon existing results by providing a more refined sample complexity bound as well as an exact support recovery result for the final estimator. These results show that the final estimator attains an oracle statistical property due to the usage of nonconvex penalty. PMID- 25544786 TI - Bayesian Multiscale Modeling of Closed Curves in Point Clouds. AB - Modeling object boundaries based on image or point cloud data is frequently necessary in medical and scientific applications ranging from detecting tumor contours for targeted radiation therapy, to the classification of organisms based on their structural information. In low-contrast images or sparse and noisy point clouds, there is often insufficient data to recover local segments of the boundary in isolation. Thus, it becomes critical to model the entire boundary in the form of a closed curve. To achieve this, we develop a Bayesian hierarchical model that expresses highly diverse 2D objects in the form of closed curves. The model is based on a novel multiscale deformation process. By relating multiple objects through a hierarchical formulation, we can successfully recover missing boundaries by borrowing structural information from similar objects at the appropriate scale. Furthermore, the model's latent parameters help interpret the population, indicating dimensions of significant structural variability and also specifying a 'central curve' that summarizes the collection. Theoretical properties of our prior are studied in specific cases and efficient Markov chain Monte Carlo methods are developed, evaluated through simulation examples and applied to panorex teeth images for modeling teeth contours and also to a brain tumor contour detection problem. PMID- 25544787 TI - Generalized Ordinary Differential Equation Models. AB - Existing estimation methods for ordinary differential equation (ODE) models are not applicable to discrete data. The generalized ODE (GODE) model is therefore proposed and investigated for the first time. We develop the likelihood-based parameter estimation and inference methods for GODE models. We propose robust computing algorithms and rigorously investigate the asymptotic properties of the proposed estimator by considering both measurement errors and numerical errors in solving ODEs. The simulation study and application of our methods to an influenza viral dynamics study suggest that the proposed methods have a superior performance in terms of accuracy over the existing ODE model estimation approach and the extended smoothing-based (ESB) method. PMID- 25544788 TI - SENSORIMOTOR DEVELOPMENT IN COCAINE-EXPOSED INFANTS. AB - This study investigated effects of prenatal cocaine exposure on infant sensorimotor development. One hundred and sixty-seven 12-month-olds (74 cocaine exposed and 93 unexposed) were assessed using the Bayley Scales of Infant Development (BSID). Ninety-seven had previously been evaluated on the Movement Assessment of Infants and the Test of Sensory Functions in Infants at age 4 months. On the BSID, the cocaine-exposed infants performed less well on the Mental portion and were more frequently rated as behaviorally suspect. Cocaine exposed infants also performed less well at four months on the motor and sensory measures. Early motor performance predicted 12 month BSID mental, motor and behavioral outcomes. Cocaine exposure had an effect independent from confounders on general cognitive and specific motor and behavioral outcomes. PMID- 25544789 TI - MATERNAL ROLE CONFUSION: RELATIONS TO MATERNAL ATTACHMENT AND MOTHER-CHILD INTERACTION FROM INFANCY TO ADOLESCENCE. AB - Self-reports of role confusion with the parent in childhood are associated with a variety of adverse outcomes. However, role-confusion has been studied primarily from the point of view of the child. The current study evaluated an instrument for assessing role confusion from maternal interviews rather than from child observations or self-reports in adulthood. Fifty-one mothers participating in a longitudinal study since their own child's infancy were administered the Experiences of Caregiving Interview (C. George & J. Solomon, 1996) when the child was age 20. Interviews were coded using the newly developed Parental Assessment of Role Confusion (PARC; L. Vulliez-Coady & K. Lyons-Ruth, 2009). Maternal PARC scores were related to observational measures of role-confusion in interaction with the child both in infancy and late adolescence. PARC scores also were related to mothers' hostile-helpless states of mind on the Adult Attachment Interview (C. George, N. Kaplan, & M. Main, 1984, 1985, 1986) and to the extent of Unresolved loss, but not Unresolved Trauma. PARC scores also were related to mothers' self-reports of helplessness experienced in the parenting role. Discriminant validity of the PARC was demonstrated in that role confusion on the PARC was not related to hostile or disoriented forms of parent-child interaction. Implications for clinical assessment of role confusion are discussed. PMID- 25544790 TI - Parenthood and Leaving Home in Young Adulthood. AB - With increases in nonmarital fertility, the sequencing of transitions in early adulthood has become even more complex. Once the primary transition out of the parental home, marriage was first replaced by nonfamily living and cohabitation; more recently, many young adults have become parents before entering a coresidential union. Studies of leaving home, however, have not examined the role of early parenthood. Using the Young Adult Study of the 1979 National Longitudinal Survey of Youth (n = 4,674), we use logistic regression to analyze parenthood both as a correlate of leaving home and as a route from the home. We find that even in mid-adolescence, becoming a parent is linked with leaving home. Coming from a more affluent family is linked with leaving home via routes that do not involve children rather than those that do, and having a warm relationship with either a mother or a father retards leaving home, particularly to nonfamily living, but is not related to parental routes out of the home. PMID- 25544791 TI - A Longitudinal Examination of the Bi-Directional Links between Academic Achievement and Parent-Adolescent Conflict. AB - We examined reciprocal associations between parent-adolescent conflict and academic achievement over a two-year period. Participants were mothers, fathers, and adolescents from predominantly White, working and middle class families (N = 168). After accounting for previous academic achievement, parent-adolescent conflict predicted relative declines in academic achievement two years later. After controlling for relationship quality at Time 1, lower math grades predicted relative increases in parent-adolescent conflict two years later among families with less education. PMID- 25544792 TI - Genetic polymorphisms involved in folate metabolism and maternal risk for down syndrome: a meta-analysis. AB - Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I (2) statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS. PMID- 25544793 TI - ZEB1 expression in endometrial biopsy predicts lymph node metastases in patient with endometrial cancer. AB - PURPOSE: The purpose of this study was to analyze the expression of zinc-finger E box-binding homeobox 1 (ZEB1) in endometrial biopsy and its correlation with preoperative characteristics, including lymph node metastases in patient with endometrial cancer. METHODS: Using quantitative RT-PCR, ZEB1 expressions in endometrial biopsy from 452 patients were measured. The relationship between ZEB1 expression and preoperative characteristics was analyzed. RESULTS: ZEB1 expressions were significantly associated with subtype, grade, myometrial invasion, and lymph node metastases. Lymph node metastases could be identified with a sensitivity of 57.8% at specificity of 74.1% by ZEB1 expression in endometrial biopsy. Based on combination of preoperative characteristics and ZEB1 expression, lymph node metastases could be identified with a sensitivity of 62.1% at specificity of 96.2% prior to hysterectomy. CONCLUSION: ZEB1 expression in endometrial biopsy could help physicians to better predict the lymph node metastasis in patients with endometrial cancer prior to hysterectomy. PMID- 25544794 TI - What patterns of postpartum psychological distress are associated with maternal concerns about their children's emotional and behavioural problems at the age of three years? AB - Mothers experiencing psychological distress in the postpartum period may have difficulties parenting their children. Inconsistent and unresponsive parenting may increase the risk of later emotional and behavioural problems in children. The purpose of this study was to identify how maternal psychological characteristics cluster at eight weeks postpartum, and whether these clusters were associated with maternal-reported child emotional and behavioural problems at the age of three years, as measured by the Parents' Evaluation of Developmental Status (PEDS) questionnaire. In a longitudinal pregnancy cohort (N = 647), three clusters of postpartum psychological characteristics were identified. Contrary to expectations, mothers with the greatest psychological distress did not report concerns about their child's emotional and behavioural problems; rather, they reported concerns about global developmental delay. These findings suggest that infants of mothers experiencing postpartum psychological distress should receive additional follow-up to reduce the risk for global developmental delay. PMID- 25544795 TI - Determination of the flavonoid components of cashew apple (Anacardium occidentale) by LC-DAD-ESI/MS. AB - Liquid chromatography, with diode array detection and electrospray ionization mass spectrometry (LC-DAD-ESI/MS), was used to identify and quantify flavonoids in cashew apple. One anthocyanin and thirteen glycosylated flavonols were detected in a methanol-water extract. Among them, the 3-O-galactoside, 3-O glucoside, 3-O-rhamnoside, 3-O-xylopyranoside, 3-O-arabinopyranoside and 3-O arabinofuranoside of quercetin and myricetin, as well as kaempferol 3-O-glucoside were identified by direct comparison with standards or positively identified flavonoids in cranberry. The anthocyanin was the 3-O-hexoside of methyl-cyanidin. Trace amounts of delphinidin and rhamnetin were detected in the hydrolyzed extract, suggesting their glycosides were present, but undetectable, in the original extract. The concentrations of the 14 flavonoids in the tested sample were determined. This is the first report of these flavonoids in cashew apple. PMID- 25544796 TI - The polyphenolic profiles of common bean (Phaseolus vulgaris L.). AB - Based on the phenolic profiles obtained by high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-DAD-ESI/MS), 24 common bean samples, representing 17 varieties and 7 generic off-the-shelf items, belonging to ten US commercial market classes can be organized into six different groups. All of them contained the same hydroxycinnaminic acids, but the flavonoid components showed distinct differences. Black beans contained primarily the 3-O glucosides of delphinidin, petunidin and malvidin, while pinto beans contained kaempferol and its 3-O-glycosides. Light red kidney bean contained traces of quercetin 3-O-glucoside and its malonates, but pink and dark red kidney beans contained the diglycosides of quercetin and kaempferol. Small red beans contained kaempferol 3-O-glucoside and pelargonidin 3-O-glucoside, while no flavonoids were detected in alubia, cranberry, great northern, and navy beans. This is the first report of the tentative identification of quercetin 3-O-pentosylhexoside and flavonoid glucoside malonates, and the first detailed detection of hydroxycinnamates, in common beans. PMID- 25544797 TI - Polyphenol content and antioxidant activity of California almonds depend on cultivar and harvest year. AB - The polyphenol content and antioxidant activity of Nonpareil, Carmel, Butte, Sonora, Fritz, Mission, and Monterey almond cultivars harvested over three seasons in California were examined. LC-MS was employed to quantify 16 flavonoids and two phenolic acids in acidified methanol extracts of almond skins. The 3-year mean polyphenol content of cultivars ranged from 4.0 to 10.7 mg/100 g almonds. Isorhamnetin-3-O-rutinoside was the most abundant flavonoid, present at 28-49% of total polyphenols among cultivars. Almonds from 2006 and 2007 had 13% fewer polyphenols than 2005, but FRAP and total phenols were comparable. Cultivar, but not season, had a differential impact on individual polyphenol synthesis. Using the results of polyphenol, total phenol, and FRAP, multivariate analysis distinguished harvest years and most cultivars with 80% confidence. Flavonoid content and antioxidant activity of almonds may be more dependent on cultivar than on seasonal differences. PMID- 25544798 TI - Tentative identification, quantitation, and principal component analysis of green pu-erh, green, and white teas using UPLC/DAD/MS. AB - Tea (Camellia sinensis L.), an important drink and a natural medicine for thousands of years, contains many health beneficial compounds. Growing season, geographical region, and fermentation methods create many variations in tea compositions, which contribute to each tea's uniqueness. In this study, a simple, rapid, and efficient ultra-performance liquid chromatography (UPLC) method combined with diode array detector (DAD) and mass spectroscopic (MS) detection and chemometrics analysis was used to analyse three different types of teas (green pu-erh, green tea, white tea). Using the developed method, 68 compounds were identified and 54 were quantified based on retention times, UV spectra, and MS spectra by referencing to available standards and data in the literatures. The results showed the chemical differences between the tested teas. Principal component analysis (PCA) was applied to classify and distinguish between tea samples. PMID- 25544799 TI - The role of male harassment on female fitness for the dengue vector mosquito Aedes aegypti. AB - Sexual harassment studies in insects suggest that females can incur several kinds of costs from male harassment and mating. Here, we examined direct and indirect costs of male harassment on components of female fitness in the predominantly monandrous mosquito Aedes aegypti. To disentangle the costs of harassment versus the costs of mating, we held females at a low or high density with males whose claspers were modified to prevent insemination, and compared these to females held with normal males and to those held with females or alone. A reduced longevity was observed when females were held under high density conditions with males or females, regardless if male claspers had been modified. There was no consistent effect of harassment on female fecundity. Net reproductive rate (R0) was higher in females held at low density with normal males compared to females held with males in the other treatments, even though only a small number of females showed direct evidence of remating. Indirect costs and benefits that were not due to harassment alone were observed. Daughters of females held with normal males at high density had reduced longevity compared to daughters from females held without conspecifics. However, their fitness (R0) was higher compared to females in all other treatments. Overall, our results indicate that A. aegypti females do not suffer a fitness cost from harassment of males when kept at moderate densities, and they suggest the potential for benefits obtained from ejaculate components. PMID- 25544800 TI - Age Differences in Adaptive Decision Making: The Role of Numeracy. AB - The primary purposes of the present study were to examine age differences in adaptive decision making and to evaluate the role of numeracy in mediating the relationship between age and adaptive decision making. Adaptive decision making was assessed by the Cups task (Levin, Weller, Pederson, & Harshman, 2007). Forty six younger (18 to 24 years old) and 37 older adults (61 to 89 years old) completed the Cups task. In addition, the Numeracy Scale (Lipkus, Samsa, & Rimer, 2001) was used to measure individual numeric ability. Adaptive decision making was operationalized by the Expected Value sensitivity (i.e., the product of probability and outcome magnitudes) across the gain and the loss domains. Older adults had significantly lower Expected Value sensitivity than young adults. In addition, older adults demonstrated significantly lower numeracy than younger adults. Finally, numeracy partially mediated the relationship between age and adaptive decision making. It is suggested that older adults' declined decision making may be partially due to their declined numeric abilities. Implications were discussed in numeracy education and public policies concerning older adults. PMID- 25544801 TI - The Tunicate CIONA: A Model System for Understanding the Relationship Between Regeneration and Aging. AB - The use of the tunicate Ciona intestinalis as a model system to study the relationship between regeneration and aging is reviewed. Ciona has powerful regeneration capacities, which fade with age. Some additional benefits are-, a relatively short life span, the ability to study regeneration in vitro, the close phylogenetic relationship between tunicates and vertebrates, and the host of molecular tools already established in this system. The neural complex (NC), the oral siphon (OS), and the oral siphon pigment organs (OPO) have high capacities for regeneration. However, these organs show an inverse relationship between rate of regeneration and age. The ability to regenerate a complete OS disappears in the oldest animals of a natural population, probably due to the inability to form a blastema at the wound site. Effects on blastema formation could also be involved in the reduction of NC regeneration capacity. The fidelity of OPO restoration is also compromised by excess differentiation of precursor cells in local siphon niches in the oldest animals. The Ciona model provides a pathway to understand the molecular basis of these phenomena. PMID- 25544803 TI - Reinvestigation of the Cd-Gd phase diagram. AB - The complete Cd-Gd equilibrium phase diagram was investigated by a combination of powder-XRD, SEM and DTA. All previously reported phases, i.e., CdGd, Cd2Gd, Cd3Gd, Cd45Gd11, Cd58Gd13, and Cd6Gd, could be confirmed. In addition, a new intermetallic compound with a stoichiometric composition corresponding to "Cd8Gd" was found to exist. It was obtained that "Cd8Gd" decomposes peritectically at 465 degrees C. Homogeneity ranges of all intermetallic compounds were determined at distinct temperatures. In addition, the maximum solubilities of Cd in the low- and high-temperature modifications of Gd were determined precisely as 4.6 and 22.6 at.%, respectively. All invariant reaction temperatures (with the exception of the formation of Cd58Gd13) as well as liquidus temperatures were determined, most probably, Cd58Gd13 is formed in a peritectoid reaction from Cd45Gd11 and Cd6Gd at a temperature below 700 degrees C. PMID- 25544802 TI - Personality and Psychopathology: A Stagnant Field in Need of Development. AB - A dominant paradigm in psychopathology research proposes that individual differences in personality are centrally involved in the origins and manifestations of psychopathology, and structural models of personality and psychopathology have been extremely useful in helping to organize associations among many traits and disorders. However, these models merely describe patterns of covariation; they do not explain the processes by which these patterns emerge. We argue that the field is stagnated, as it is overly focused on the demonstration of concurrent associations and on confirming a spectrum model that proposes traits and disorders are manifestations of the same underlying constructs. We contend that if the field is to move toward an understanding of causal processes, it must integrate knowledge and principles of personality development and developmental psychopathology. To begin this integration, we review (1) normative trends in personality change, (2) age-related changes in the prevalence of disorders, and (3) the impact of onset and chronicity on the severity of disorders. We propose several developmental processes that may contribute to the co-development of personality and psychopathology. We then present novel empirical findings to illustrate how a developmental perspective on traits and disorders can inform new hypotheses, and propose principles and hypotheses that should guide future research. PMID- 25544804 TI - Prefronto-cerebellar transcranial direct current stimulation improves sleep quality in euthymic bipolar patients: a brief report. AB - INTRODUCTION: Sleep problems are common in bipolar disorder (BD) and may persist during the euthymic phase of the disease. The aim of the study was to improve sleep quality of euthymic BD patients through the administration of prefronto cerebellar transcranial direct current stimulation (tDCS). METHODS: 25 euthymic outpatients with a diagnosis of BD Type I or II have been enrolled in the study. tDCS montage was as follows: cathode on the right cerebellar cortex and anode over the left dorsolateral prefrontal cortex (DLPFC); the intensity of stimulation was set at 2 mA and delivered for 20 min/die for 3 consecutive weeks. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality at baseline and after the tDCS treatment. RESULTS: PSQI total score and all PSQI subdomains, with the exception of "sleep medication," significantly improved after treatment. DISCUSSION: This is the first study where a positive effect of tDCS on the quality of sleep in euthymic BD patients has been reported. As both prefrontal cortex and cerebellum may play a role in regulating sleep processes, concomitant cathodal (inhibitory) stimulation of cerebellum and anodal (excitatory) stimulation of DLPFC may have the potential to modulate prefrontal thalamic-cerebellar circuits leading to improvements of sleep quality. PMID- 25544805 TI - Peer Influences on Adolescent Decision Making. AB - Research efforts to account for elevated risk behavior among adolescents have arrived at an exciting new stage. Moving beyond laboratory studies of age differences in "cool" cognitive processes related to risk perception and reasoning, new approaches have shifted focus to the influence of social and emotional factors on adolescent neurocognition. We review recent research suggesting that adolescent risk-taking propensity derives in part from a maturational gap between early adolescent remodeling of the brain's socio emotional reward system and a gradual, prolonged strengthening of the cognitive control system. At a time when adolescents spend an increasing amount of time with their peers, research suggests that peer-related stimuli may sensitize the reward system to respond to the reward value of risky behavior. As the cognitive control system gradually matures over the course of the teenage years, adolescents grow in their capacity to coordinate affect and cognition, and to exercise self-regulation even in emotionally arousing situations. These capacities are reflected in gradual growth in the capacity to resist peer influence. PMID- 25544806 TI - Marital quality and health: Implications for marriage in the 21st century. AB - Being in a happy marriage is related to better psychological and physical health. This paper describes current approaches to conceptualizing and measuring marital quality and physical health, and results from a recent meta-analysis examining associations between marital quality and physical health outcomes. To illustrate the practical significance of these findings, this paper also illustrates how the magnitude of the marital quality - physical health association is similar in size to associations between health behaviors (diet, physical activity) and health outcomes, and briefly reviews the state of the science regarding plausible biobehavioral pathways that explain how marital functioning influences health. After describing the current state of research on factors that might modify the association between marital quality and health, particularly individual differences and gender, the paper concludes with implications of the past 50 years of research on marital quality and health for marriage in the 21st century. PMID- 25544808 TI - How important is pharmacognosy for doctors and dentists? PMID- 25544807 TI - Prediction of Gene Activity in Early B Cell Development Based on an Integrative Multi-Omics Analysis. AB - An increasingly common method for predicting gene activity is genome-wide chromatin immuno-precipitation of 'active' chromatin modifications followed by massively parallel sequencing (ChIP-seq). In order to understand better the relationship between developmentally regulated chromatin landscapes and regulation of early B cell development, we determined how differentially active promoter regions were able to predict relative RNA and protein levels at the pre pro-B and pro-B stages. Herein, we describe a novel ChIP-seq quantification method (cRPKM) to identify active promoters and a multi-omics approach that compares promoter chromatin status with ongoing active transcription (GRO-seq), steady state mRNA (RNA-seq), inferred mRNA stability, and relative proteome abundance measurements (iTRAQ). We demonstrate that active chromatin modifications at promoters are good indicators of transcription and steady state mRNA levels. Moreover, we found that promoters with active chromatin modifications exclusively in one of these cell states frequently predicted the differential abundance of proteins. However, we found that many genes whose promoters have non-differential but active chromatin modifications also displayed changes in abundance of their cognate proteins. As expected, this large class of developmentally and differentially regulated proteins that was uncoupled from chromatin status used mostly post-transcriptional mechanisms. Strikingly, the most differentially abundant protein in our B-cell development system, 2410004B18Rik, was regulated by a post-transcriptional mechanism, which further analyses indicated was mediated by a micro-RNA. These data highlight how this integrated multi-omics data set can be a useful resource in uncovering regulatory mechanisms. This data can be accessed at: https://usegalaxy.org/u/thereddylab/p/prediction-of-gene-activity-based-on-an integrative-multi-omics-analysis. PMID- 25544810 TI - CBCT imaging - A boon to orthodontics. AB - The application of innovative technologies in dentistry and orthodontics has been very interesting to observe. The development of cone-beam computed tomography (CBCT) as a preferred imaging procedure for comprehensive orthodontic treatment is of particular interest. The information obtained from CBCT imaging provides several substantial advantages. For example, CBCT imaging provides accurate measurements, improves localization of impacted teeth, provides visualization of airway abnormalities, it identifies and quantifies asymmetry, it can be used to assess periodontal structures, to identify endodontic problems, to plan placement sites for temporary skeletal anchorage devices, and to view condylar positions and temporomandibular joint (TMJ) bony structures according to the practitioner's knowledge at the time of orthodontic diagnosis. Moreover, CBCT imaging involves only a minimal increase in radiation dose relative to combined diagnostic modern digital panoramic and cephalometric imaging. The aim of this article is to provide a comprehensive overview of CBCT imaging, including its technique, advantages, and applications in orthodontics. PMID- 25544809 TI - Therapeutic applications of botulinum neurotoxins in head and neck disorders. AB - OBJECTIVE: The aim of this article is to review the mechanism of action, physiological effects, and therapeutic applications of botulinum neurotoxins in the head and neck area. STUDY DESIGN: An extensive literature search was performed using keywords. The resulting articles were analyzed for relevance in four areas: overview on botulinum neurotoxins, the role of botulinum neurotoxins in the management of salivary secretory disorders, the role of botulinum neurotoxins in the management of facial pain, and the role of botulinum neurotoxins in head and neck movement disorders. Institutional review board approval was not needed due the nature of the study. RESULTS: Botulinum neurotoxin therapy was demonstrated to be a valuable alternative to conventional medical therapy for many conditions affecting the head and neck area in terms of morbidly, mortality, and patient satisfaction with treatment outcomes. CONCLUSION: Botulinum neurotoxin therapy provides viable alternatives to traditional treatment modalities for some conditions affecting the head and neck region that have neurological components. This therapy can overcome some of the morbidities associated with conventional therapy. More research is needed to determine the ideal doses of botulinum neurotoxin to treat different diseases affecting the head and neck regions. PMID- 25544811 TI - Enhancement of orthodontic anchorage and retention by the local injection of strontium: An experimental study in rats. AB - OBJECTIVES: To examine the clinical and histological effects of locally injected strontium on the anchoring unit of a rat model of an experimental relapsed tooth movement. MATERIALS AND METHODS: Thirty-six 10-week-old male Wister rats were randomly divided into two groups of 18 animals that were then randomly divided into three subgroups of six animals corresponding to three observation periods: T1 = 1 week, T2 = 2 weeks, and T3 = 3 weeks. In the first experiment, both the right and left maxillary first molars were moved buccally with a standardized expansive spring. Strontium chloride solution was injected every 2 days into the subperiosteal area buccal to the left maxillary first molar (the experimental side). The right-sided first molar was injected with distilled water as a control. In the second experiment, maxillary first molars were moved buccally with the spring. After 3 weeks, the spring was removed. Two days before the spring removal, strontium chloride was injected into the palatal side of left sided maxillary first molar and distilled water was injected into the palatal side of the right-sided maxillary first molar as in experiment 1. RESULTS: At the end of the experimental period, significant levels of inhibition were noted in terms of both tooth movement and relapse movement in strontium-injected sides. Histological examinations showed that strontium enhanced the number of osteoblasts and reduced the number of osteoclasts. CONCLUSION: The local injection of strontium can inhibit the degree of experimental and relapsed tooth movement in a rat model. PMID- 25544812 TI - Orthodontic treatment and referral patterns: A survey of pediatric dentists, general practitioners, and orthodontists. AB - OBJECTIVE: This study aims to assess the orthodontic diagnostic skills, referral patterns, and the perceptions of orthodontic benefits of pediatric and general dentists in comparison with orthodontists. MATERIALS AND METHODS: Two online surveys were e-mailed to pediatric dentists, general dentistry practitioners, and orthodontists registered as members of the Saudi Dental Society and the Saudi Orthodontic Society. The surveys included questions about the type of orthodontic treatment provided, referral trends, and timing; presumed benefits associated with successful orthodontic treatment; and diagnosis and treatment plans of seven cases representing different malocclusions. RESULTS: In total, 25 orthodontists, 18 pediatric dentists, and 14 general practitioners completed the survey. Only 38.8% of pediatric dentists and 7.1% of general practitioners reported that they practiced orthodontics clinically. The perceptions of the three groups toward the benefits of orthodontic treatment were comparable in the psychosocial areas. However, the orthodontists perceived significantly lesser effects of orthodontic treatment on the amelioration of temporomandibular disorder (TMD) symptoms. Pediatric dentists tended to rate the need and urgency of treatment higher, while general practitioners tended to rate the need of treatment lower. The selected treatment plans for three early malocclusion cases showed the greatest discrepancies between the orthodontists and the other two groups. CONCLUSIONS: The orthodontists consistently and significantly downplayed the perceived benefit of orthodontic treatment to reduce TMD symptoms. Also, while there was a similarity in the diagnosis, there were notable differences in the proposed treatment approaches, perceived treatment need, and timing of intervention between the three groups of practitioners. PMID- 25544813 TI - The association between dental and periodontal diseases and sickle cell disease. A pilot case-control study. AB - OBJECTIVE: This is a pilot case-control study conducted to investigate the prevalence of dental caries and periodontal disease and examine the possible association between oral health deterioration and SCD severity in a sample of Saudi SCD patients residing in the city of Al-Qatif, Eastern Province, Saudi Arabia. MATERIALS AND METHODS: Dental examination to determine the Decayed, Missing and Filled Teeth index (DMFT), Community Periodontal Index (CPI), and plaque index system were recorded for 33 SCD patients and 33 age and sex-matched controls in the Al-Qatif Central Hospital, Qatif, Saudi Arabia. Self-administered surveys used to assess socio-economic status; oral health behaviors for both SCD patients and controls were recorded. In addition, the disease severity index was established for all patients with SCD. SPSS data analysis software package version 18.0 was used for statistical analysis. Numerical variables were described as mean with a standard deviation. RESULTS: Decayed teeth were significantly more in individuals with ages ranging from 18 to 38 years with SCD compared to the control group (p = 0.036) due to oral hygiene negligence. The mean number of filled teeth was significantly lower in individuals with SCD when compared to the control group (p = 0.015) due to the lack of appropriate and timely treatment reflected in the survey responses of SCD patients as 15.2% only taking oral care during hospitalization. There were differences between the cases and controls in the known caries risk factors such as income level, flossing, and brushing habit. The DMFT, CPI, and plaque index systems did not differ significantly between the SCD patients and the control group. CONCLUSION: Data suggest that patients with SCD have increased susceptibility to dental caries, with a higher prevalence of tooth decay and lower prevalence of filled teeth. Known caries risk factors influenced oral health more markedly than did factors related to SCD. PMID- 25544814 TI - Women with more severe degrees of temporomandibular disorder exhibit an increase in temperature over the temporomandibular joint. AB - AIM: The purpose of the present study was to correlate the degree of temporomandibular disorder (TMD) severity and skin temperatures over the temporomandibular joint (TMJ) and masseter and anterior temporalis muscles. MATERIALS AND METHODS: This blind cross-sectional study involved 60 women aged 18 40 years. The volunteers were allocated to groups based on Fonseca anamnestic index (FAI) score: no TMD, mild TMD, moderate TMD, and severe TMD (n = 15 each). All volunteers underwent infrared thermography for the determination of skin temperatures over the TMJ, masseter and anterior temporalis muscles. The Shapiro Wilk test was used to determine the normality of the data. The Kruskal-Wallis test, followed by Dunn's test, was used for comparisons among groups according to TMD severity. Spearman's correlation coefficients were calculated to determine the strength of associations among variables. RESULTS: Weak, positive, significant associations were found between FAI score and skin temperatures over the left TMJ (rs = 0.195, p = 0.009) and right TMJ (rs = 0.238, p = 0.001). Temperatures over the right and left TMJ were significantly higher in groups with more severe TMD (p < 0.05). CONCLUSION: FAI score was associated with skin temperature over the TMJ, as determined by infrared thermography, in this sample. Women with more severe TMD demonstrated a bilateral increase in skin temperature. PMID- 25544815 TI - Determinant factors of Yemeni maxillary arch dimensions. AB - OBJECTIVE: Information about maxillary arch and palatal dimensions in human populations is important for clinical orthodontics. This study was conducted to assess the determinants of maxillary arch dimensions in a sample of Yemeni individuals aged 18-25 years. MATERIALS AND METHODS: The study sample comprised 214/765 adults (101 women, 113 men) who underwent clinical examination and fulfilled the study criteria. Study models were constructed and evaluated to measure maxillary arch and palatal dimensions. RESULTS: The majority of mean maxillary arch dimensions were significantly greater in men than in women, with inter-second molar distance showing the greatest difference and palatal depth showing the least difference. CONCLUSION: Measurements of palatal depth and relationships of the canines to one another and to other teeth thus had the widest ranges, implying that these dimensions are the strongest determinants of maxillary arch size. PMID- 25544816 TI - Epidemiological and evolutionary characteristics of heart failure in patients with left bundle branch block - A Moroccan center-based study. AB - BACKGROUND: In patients with heart failure, left bundle branch block (LBBB) seems to be associated with an increased risk of cardiovascular mortality. PURPOSE: The purpose of this study is to determine the in-hospital outcome of congestive heart failure patients with LBBB versus those without. METHODS: We conducted a prospective observational study at the Department of Intensive Care and Rhythmology at the Mohammed V Military Hospital of Rabat, where 330 patients were admitted for heart failure between January 2008 and September 2012. Screening out patients with missing data yielded a cohort of 274 patients. Among the 274 patients, only 110 had LBBB and a left ventricular ejection fraction lower than 50%. We randomly selected a subset of 110 patients diagnosed as non-LBBB to ensure a significant statistical comparison between LBBB and non-LBBB patients. We therefore considered two groups in our analysis: 110 heart failure (HF) patients with LBBB and 110 HF patients without LBBB. Patients with incomplete records were excluded. RESULTS: Male gender was dominant in both groups (82.7% vs. 66.7%, p = 0.005). Patients with LBBB had a higher prevalence of idiopathic dilated cardiomyopathy (39.1% vs. 4.8%, p < 0.001); and a higher prevalence of previous hospitalization for heart failure (64.5% vs. 23.3%, p < 0.001). The left ventricular ejection fraction was significantly lower in the group with LBBB (25.49% vs. 39.53%, p < 0.001). Age, cardiovascular risk factors, rhythmic and thromboembolic complications did not significantly differ. In patients with LBBB, 61.8% received cardiac resynchronization therapy performed both during the index hospital stay (50.9%) and previously (10.9%). Hospital outcome was marked by 20 in-hospital deaths in the group with LBBB and eight deaths in the group without LBBB (p = 0.008). CONCLUSION: Our analysis emphasizes increased in-hospital mortality and higher disease severity, over a short period of stay, in heart failure patients with left bundle branch block. PMID- 25544817 TI - The change in mitral regurgitation severity after trans-catheter aortic valve implantation. AB - BACKGROUND: Mitral regurgitation (MR) is a frequent finding in patients with aortic stenosis (AS). The objective of this study is to assess the change in MR severity following transcatheter aortic valve implantation (TAVI). METHODS: MR changes were assessed by comparing transthoracic echocardiography before and after the procedure. RESULTS: The prosthetic aortic valve was successfully implanted in 65 patients. The number of patients with pre-procedure MR was reduced from 58 (85.3%) to 43 (63.2%) (p < 0.001). Vena contracta width was decreased from 0.47 +/- 0.28 to 0.25 +/- 0.21, (p = 0.043). About 59.4% (19/32) of those who had moderate to severe MR and 85.7% (12/14) of those with severe MR experienced a significant improvement in MR after the procedure (p < 0.001). Improvement in MR was independent of prosthetic valve type with 54.2% in CoreValve and 43.9% in Edwards SAPIEN, p = 0.424; valve sizes were 25.8 +/- 1.9 in those who improved vs. 25.0 +/- 1.9 mm in those who did not improve, p = 0.105; femoral approach was 51.2% and apical approach was 41.7%, p = 0.457; MR etiology was 48.1% in organic and 48.6% in functional, p = 0.968; and operative risk was 50.0% in EuroScore >20 and 48.6% in EuroScore <20, p = 0.356. CONCLUSIONS: TAVI is associated with a significant improvement in MR, especially in severe types. The lack of influence of MR improvement by the etiology of MR, the type of valve implanted, and the operative risk need to be confirmed in a larger multi-center study. PMID- 25544818 TI - Single center experience on dosing and adverse events of recombinant factor seven use for bleeding after congenital heart surgery. AB - There are limited data on the relationship between the administered dose of recombinant factor seven (rFVIIa) and the development of adverse clinical outcomes after congenital heart surgery. This single institution case series reports on dosing, adverse events, and blood product usage after the administration of rFVIIa in the congenital heart surgery patient population. A retrospective review identified 16 consecutive pediatric patients at an academic, free-standing, children's hospital who received rFVIIa to curtail bleeding following congenital heart surgery between April 2004 and June 2012. Patients were assessed for survival to hospital discharge versus in-hospital mortality and the presence or absence of a major neurological event during inpatient hospitalization. The median age at surgery was 6.8 months (range: 3 days-42 years). Seven patients (44%) survived to hospital discharge and nine patients (56%) died. The cause of mortality included major neurological events (44%), uncontrolled bleeding (33%), and sepsis (23%). Eight patients (50%) required extracorporeal membrane oxygenation support following congenital heart surgery. The median cumulative rFVIIa dose administered was 97 mcg/kg, and the median cumulative amount of blood products administered was 452 ml/kg. In conclusion, this case series underscores the need to prospectively evaluate the effect that rFVIIa has on patient survival and the incidence of adverse events, including thrombotic and major neurological events, in congenital heart surgery patients. Ideally, a randomized, multicenter study would provide the sufficient numbers of patients and events to test these relationships. PMID- 25544819 TI - Association of aortic stiffness to brain natriuretic peptide in children before and after device closure of patent ductus arteriosus. AB - OBJECTIVES: We evaluated the influence of device closure for patent ductus arteriosus (PDA) on the aortic stiffness index (ASI) and brain natriuretic peptide (BNP) and their association with cardiac function. PATIENTS AND METHODS: ASI and echocardiography assessment before and after treatment (16 +/- 9 months) in 48 children with PDA (mean age 10 +/- 4.5) and 52 control children (mean age 9.7 +/- 4.6). BNP level was measured pre-closure for all children, and was measured six months after closure only for children with PDA. RESULTS: ASI was higher in PDA patients than in controls (P < 0.001). ASI correlated with age (P < 0.05), LVEF% (P < 0.01), E/E' (<0.03), pulmonary artery pressure (P < 0.001), and BNP (P < 0.001). ASI and BNP significantly decreased after closure (P < 0.001). ASI and BNP were independent predictors for post-closure systolic dysfunction (P < 0.001and <0.005, respectively). Receiver operating curve (ROC) analysis showed that ASI ? 13.5, BNP level ?75 pg/ml and basal mean pulmonary artery pressure (PAP) ? 23 were powerful predictors for post-closure systolic function. CONCLUSION: ASI is significantly associated with BNP and basal PAP in children with PDA. After device closure, aortic distensibility improved significantly and was associated with significant improvement in both systolic and diastolic functions. ASI can be used for monitoring the course of patients with PDA, and may give opportunities for early intervention. PMID- 25544821 TI - Hyperinsulinism in a child presenting with cardiac ischemia and bradycardia. AB - A 5-year-old boy referred to our service with suspected sinus node dysfunction. In addition to the arrhythmia, he had moderate mitral valve regurgitation and depressed ventricular function during a hypoglycemic episode. Cardiac abnormalities resolved with glucose infusion. We believe that hypoglycemia was responsible for the cardiac manifestations and it should be considered in unexplained rhythm disturbances or ischemia. PMID- 25544822 TI - Spontaneous resolution of plastic bronchitis in a patient post hemi Mustard/bidirectional Glenn atrial switch procedure in the double-switch operation for congenitally corrected transposition of great arteries after course of Augmentin. AB - We report the case of a five-year-old girl with plastic bronchitis after repaired complex congenital heart disease, who became asymptomatic after a short course of Augmentin. We report the disease regression as response either to antibiotic or as coincidental with spontaneous resolution. PMID- 25544820 TI - Untreated atrial fibrillation in the United Kingdom: Understanding the barriers and treatment options. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major preventable cause of stroke and hospitalization. Its prevalence is on the rise worldwide and experts believe it will continue to rise for the foreseeable future, due to the ageing population and increased survival from conditions associated with AF. Despite the fact that oral anticoagulation is effective in preventing strokes due to AF, there is extensive evidence suggesting this therapy remains underused. Barriers to the prescription of anticoagulation include patients' age per se, comorbidities, inadequate risk stratification, perceived risk of falls and bleeding, and the difficulty in achieving a stable international normalized ratio (INR) on warfarin. Also, asymptomatic patients with AF may not be identified and therefore not be candidates for anticoagulation. Physicians need continued better education on the identification of patients at risk of stroke and management of oral anticoagulation. This article reviews the barriers to anticoagulation in patients with AF in the United Kingdom and considers how those barriers may be overcome. PMID- 25544823 TI - Polycythemia vera presenting as acute myocardial infarction: An unusual presentation. AB - Acute myocardial infarction (AMI) is usually seen in the setting of atherosclerosis and its associated risk factors. Myocardial infarction in the young poses a particular challenge, as the disease is less likely, due to atherosclerosis. We report the case of a 37-year-old female patient who presented with ST segment elevation anterolateral AMI. The only abnormality on routine blood investigation was raised hemoglobin and hematocrit. After further testing, she was diagnosed according to the World Health Organization (WHO) criteria with polycythemia vera. This case illustrates the importance of recognizing polycythemia vera as an important cause of thrombosis, which can present initially as AMI, and to emphasize the early recognition of the disease in order to initiate appropriate management strategies. PMID- 25544824 TI - Congenital left ventricular diverticulum: Multimodality imaging evaluation and literature review. AB - Congenital ventricular diverticulum is a rare cardiac malformation. We present the case of a 57-year-old man who underwent cardiac catheterization for suspected unstable angina. No coronary artery disease was diagnosed and a left ventricular diverticulum was incidentally found. Coronary CT and cardiac MRI were performed in order to confirm the diagnosis of a muscular type diverticulum and to exclude a post-ischemic aneurysm. PMID- 25544825 TI - ST segment depression after Norwood/systemic-pulmonary artery shunt. PMID- 25544827 TI - The representation of the saccade target object depends on visual stability. PMID- 25544826 TI - Progress on Developing Adaptive Optics-Optical Coherence Tomography for In Vivo Retinal Imaging: Monitoring and Correction of Eye Motion Artifacts. AB - Recent progress in retinal image acquisition techniques, including optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO), combined with improved performance of adaptive optics (AO) instrumentation, has resulted in improvement in the quality of in vivo images of cellular structures in the human retina. Here, we present a short review of progress on developing AO-OCT instruments. Despite significant progress in imaging speed and resolution, eye movements present during acquisition of a retinal image with OCT introduce motion artifacts into the image, complicating analysis and registration. This effect is especially pronounced in high-resolution datasets acquired with AO-OCT instruments. Several retinal tracking systems have been introduced to correct retinal motion during data acquisition. We present a method for correcting motion artifacts in AO-OCT volume data after acquisition using simultaneously captured adaptive optics-scanning laser ophthalmoscope (AO-SLO) images. We extract transverse eye motion data from the AO-SLO images, assign a motion adjustment vector to each AO-OCT A-scan, and re-sample from the scattered data back onto a regular grid. The corrected volume data improve the accuracy of quantitative analyses of microscopic structures. PMID- 25544828 TI - The removal of uranium onto carbon-supported nanoscale zero-valent iron particles. AB - In the current work carbon-supported nanoscale zero-valent iron particles (CS nZVI), synthesised by the vacuum heat treatment of ferric citrate trihydrate absorbed onto carbon black, have been tested for the removal of uranium (U) from natural and synthetic waters. Two types of CS nZVI were tested, one vacuum annealed at 600 degrees C for 4 h and the other vacuum annealed at 700 degrees C for 4 h, with their U removal behaviour compared to nZVI synthesised via the reduction of ferrous iron using sodium borohydride. The batch systems were analysed over a 28-day reaction period during which the liquid and nanoparticulate solids were periodically analysed to determine chemical evolution of the solutions and particulates. Results demonstrate a well-defined difference between the two types of CS nZVI, with greater U removal exhibited by the nanomaterial synthesised at 700 degrees C. The mechanism has been attributed to the CS nZVI synthesised at 700 degrees C exhibiting (i) a greater proportion of surface oxide Fe2+ to Fe3+ (0.34 compared to 0.28); (ii) a greater conversion of ferric citrate trihydrate [2Fe(C6H5O7).H2O] to Fe0; and (iii) a larger surface area (108.67 compared to 88.61 m2 g-1). Lower maximum U uptake was recorded for both types of CS nZVI in comparison with the borohydride-reduced nZVI. A lower decrease in solution Eh and DO was also recorded, indicating that less chemical reduction of U was achieved by the CS nZVI. Despite this, lower U desorption in the latter stages of the experiment (>7 days) was recorded for the CS nZVI synthesised at 700 degrees C, indicating that carbon black in the CS nZVI is likely to have contributed towards U sorption and retention. Overall, it can be stated that the borohydride-reduced nZVI were significantly more effective than CS nZVI for U removal over relatively short timescales (e.g. <48 h), however, they were more susceptible to U desorption over extended time periods. PMID- 25544829 TI - Sex, desire and pleasure: considering the experiences of older Australian women. AB - Older age is often associated with asexuality. That is, older individuals are not viewed as desiring of sex, nor as sexually desirable to others. Broader social and cultural norms that downplay women's sexual desire and agency further compound these phenomena. Whether this popular image accurately reflects older women's sexual desires, behaviour and capacity to experience pleasure is unclear. Drawing on semi-structured interviews with 43 partnered Australian women aged 55 81, this article considers women's sexual experiences and desires in older age. The findings of our research confirm that older women's experiences of sex and sexual desire are diverse and fluid. Some of the factors that influenced participants' sexual behaviour and desire will be considered in this article, as will their understandings of what "counts" as sexual satisfaction and "successful sex". The factors affecting sexual behaviour and desire also influence the way in which women are able to negotiate sexual interaction with their partners. Participants expressed a need for education and resources in order to gain greater control and to make autonomous choices over their sexual experiences, desire and ability to give and receive pleasure. The implications of these findings for practitioners are also considered. PMID- 25544830 TI - Social connection, relationships and older lesbian and gay people1. AB - This paper presents data from a small study exploring the impacts of homophobia on the lives of older lesbian and gay Australians. Eleven in-depth interviews were conducted with older lesbians (6) and gay men (5) ranging in age from 65 to 79 years. The study found that participants' sense of self was shaped by the dominant medical, legal and religious institutions of their youth that defined them as sick, immoral or criminal. Participants described enforced "cure" therapies, being imprisoned, having employment terminated and being disowned and disinherited by family. In this context, intimate relationships and social networks provided refuge where trust was rebuilt and sexuality affirmed. Many created safe spaces for themselves. This equilibrium was threatened with increasing age, disability and the reliance on health and social services. Participants feared a return to institutional control and a need to "straighten up" or hide their sexuality. In response, partners stepped into the role of caregiver, at times beyond their capacity and at a cost to their relationship. The study describes the importance of understanding social connections in the lives of older lesbians and gay men. It highlights the need for inclusive services to ensure that social networks are supported and that health and well being are promoted. PMID- 25544831 TI - External validation of the Intensive Care National Audit & Research Centre (ICNARC) risk prediction model in critical care units in Scotland. AB - BACKGROUND: Risk prediction models are used in critical care for risk stratification, summarising and communicating risk, supporting clinical decision making and benchmarking performance. However, they require validation before they can be used with confidence, ideally using independently collected data from a different source to that used to develop the model. The aim of this study was to validate the Intensive Care National Audit & Research Centre (ICNARC) model using independently collected data from critical care units in Scotland. METHODS: Data were extracted from the Scottish Intensive Care Society Audit Group (SICSAG) database for the years 2007 to 2009. Recoding and mapping of variables was performed, as required, to apply the ICNARC model (2009 recalibration) to the SICSAG data using standard computer algorithms. The performance of the ICNARC model was assessed for discrimination, calibration and overall fit and compared with that of the Acute Physiology And Chronic Health Evaluation (APACHE) II model. RESULTS: There were 29,626 admissions to 24 adult, general critical care units in Scotland between 1 January 2007 and 31 December 2009. After exclusions, 23,269 admissions were included in the analysis. The ICNARC model outperformed APACHE II on measures of discrimination (c index 0.848 versus 0.806), calibration (Hosmer-Lemeshow chi-squared statistic 18.8 versus 214) and overall fit (Brier's score 0.140 versus 0.157; Shapiro's R 0.652 versus 0.621). Model performance was consistent across the three years studied. CONCLUSIONS: The ICNARC model performed well when validated in an external population to that in which it was developed, using independently collected data. PMID- 25544833 TI - Culturally Congruent End-of-Life Care for Rural Appalachian People and Their Families. PMID- 25544834 TI - Transcatheter Mitral Valve Repair. PMID- 25544832 TI - Anesthetic management of patients undergoing bariatric surgery: two year experience in a single institution in Switzerland. AB - BACKGROUND: In the field of anesthesia for bariatric surgery, a wide variety of recommendations exist, but a general consensus on the perioperative management of such patients is missing. We outline the perioperative experiences that we gained in the first two years after introducing a bariatric program. METHODS: The perioperative approach was established together with all relevant disciplines. Pertinent topics for the anesthesiologists were; successful airway management, indications for more invasive monitoring, and the planning of the postoperative period and deposition. This retrospective analysis was approved by the local ethics committee. Data are mean [SD]. RESULTS: 182 bariatric surgical procedures were performed (147 gastric bypass procedures (GBP; 146 (99.3%) performed laparascopically). GBP patients were 43 [10] years old, 78% female, BMI 45 [7] kg/m(2), 73% ASA physical status of 2. 42 patients (28.6%) presented with obstructive sleep apnea syndrome. 117 GBP (79.6%) patients were intubated conventionally by direct laryngoscopy (one converted to fiber-optic intubation, one aspiration of gastric contents). 32 patients (21.8%) required an arterial line, 10 patients (6.8%) a central venous line. Induction lasted 25 [16] min, the procedure itself 138 [42] min. No blood products were required. Two patients (1.4%) presented with hypothermia (<35 degrees C) at the end of their case. The emergence period lasted 17 [9] min. Postoperatively, 32 patients (21.8%) were transferred to the ICU (one ventilated). The other patients spent 4.1 [0.7] h in the post anesthesia care unit. 15 patients (10.2%) required take backs for surgical revision (two laparotomies). CONCLUSIONS: The physiology and anatomy of bariatric patients demand a tailored approach from both the anesthesiologist and the perioperative team. The interaction of a multi-disciplinary team is key to achieving good outcomes and a low rate of complications. TRIAL REGISTRATION: DRKS00005437 (date of registration 16(th) December 2013). PMID- 25544835 TI - DESIGN, SYNTHESIS, AND EVALUATION OF A FAMILY OF PROPARGYL PYRIDINYL ETHERS AS POTENTIAL CYTOCHROME P450 INHIBITORS. AB - Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism of endogenous and exogenous compounds including many drugs and environmental chemicals. In our previous research, we have determined that certain aryl and arylalkyl acetylenes act as inhibitors of these enzymes. Here we report a family of propargyl ethers containing a pyridine ring system. Five new compounds, 2,4-dimethyl-3-(prop-2-yn-1-yloxy)pyridine(I), 2,4-dimethyl-3-((prop-2 yn-1-yloxy) methyl)pyridine(II), 2,3-dimethyl-4-((prop-2-yn-1 yloxy)methyl)pyridine(III), 2-methyl-4-((prop-2-yn-1-yloxy)methyl)pyridine (IV), 2-methyl-4-(prop-2-yn-1-yloxy)pyridine (V) (Figure 1) have been synthesized and characterized. PMID- 25544836 TI - MYRIAD AFTER MYRIAD: THE PROPRIETARY DATA DILEMMA. AB - Myriad Genetics' long-time monopoly on BRCA gene testing was significantly narrowed by the Supreme Court's decision in AMP v. Myriad Genetics, Inc., and will be further narrowed in the next few years as many of its still-valid patents expire. But these developments have not caused the company to acquiesce in competition. Instead, it has launched a litigation offensive against a number of actual and potential competitors, suing them for infringement of numerous unexpired patents that survived the Supreme Court case. A parallel strategy may have even greater long-term significance, however. In announcing expanded operations in Europe, Myriad has emphasized that it will rely less on patents and more on its huge proprietary database of genetic mutations and associated health outcomes-a strategy that could be used in the United States as well. Myriad has built that database over its many years as a patent-based monopolist in the BRCA testing field, and has not shared it with the medical community for more than a decade. Consequently, Myriad has a unique ability to interpret the health significance of patients' genetic mutations, particularly in the case of rare "variants of unknown significance." This article reviews the current state of Myriad's patent portfolio, describes its ongoing litigation offensive, and then analyzes its proprietary database strategy. The article argues that Myriad's strategy, while legally feasible, undercuts important values and objectives in medical research and health policy. The article identifies several ways in which the research and health care communities might fight back, but acknowledges that it will be a difficult uphill fight. PMID- 25544838 TI - Forecasting the short-term passenger flow on high-speed railway with neural networks. AB - Short-term passenger flow forecasting is an important component of transportation systems. The forecasting result can be applied to support transportation system operation and management such as operation planning and revenue management. In this paper, a divide-and-conquer method based on neural network and origin destination (OD) matrix estimation is developed to forecast the short-term passenger flow in high-speed railway system. There are three steps in the forecasting method. Firstly, the numbers of passengers who arrive at each station or depart from each station are obtained from historical passenger flow data, which are OD matrices in this paper. Secondly, short-term passenger flow forecasting of the numbers of passengers who arrive at each station or depart from each station based on neural network is realized. At last, the OD matrices in short-term time are obtained with an OD matrix estimation method. The experimental results indicate that the proposed divide-and-conquer method performs well in forecasting the short-term passenger flow on high-speed railway. PMID- 25544837 TI - Functionalized fullerenes in photodynamic therapy. AB - Since the discovery of C60 fullerene in 1985, scientists have been searching for biomedical applications of this most fascinating of molecules. The unique photophysical and photochemical properties of C60 suggested that the molecule would function well as a photosensitizer in photodynamic therapy (PDT). PDT uses the combination of non-toxic dyes and harmless visible light to produce reactive oxygen species that kill unwanted cells. However the extreme insolubility and hydrophobicity of pristine CO60, mandated that the cage be functionalized with chemical groups that provided water solubility and biological targeting ability. It has been found that cationic quaternary ammonium groups provide both these features, and this review covers work on the use of cationic fullerenes to mediate destruction of cancer cells and pathogenic microorganisms in vitro and describes the treatment of tumors and microbial infections in mouse models. The design, synthesis, and use of simple pyrrolidinium salts, more complex decacationic chains, and light-harvesting antennae that can be attached to C60, C70 and C84 cages are covered. In the case of bacterial wound infections mice can be saved from certain death by fullerene-mediated PDT. PMID- 25544839 TI - Camel milk beneficial effects on treating gentamicin induced alterations in rats. AB - The potential effect of camel milk (CM) against gentamicin (GM) induced biochemical changes in the rat serum was evaluated. Four groups of six albino rats were used for control, CM fed, injected with GM(i.p.), and then fed and injected with GM. The results showed that the administration of GM significantly altered the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) activity in rat serum. CM restored these parameters to almost their normal range in group IV. Additionally, the present study showed that injection of rats with gentamicin caused an increase in malondialdehyde (MDA) and myeloperoxidase (MPO) activity while the antioxidant enzymes like superoxide dismutase (SOD) and glutathione s transferase (GST) activity decreased significantly (P <= 0.05). Administration of CM significantly (P <= 0.05) inhibited the formation of MDA and activity of MPO and upregulated the antioxidant enzymes (SOD and GST) activity. The overall findings of this study demonstrated that pretreatment with CM gave protection against GM induced hepatic damage possibly by inhibiting oxidative stress and inflammation, and hence camel milk can be identified as a new therapeutic agent. PMID- 25544840 TI - Diabetic women suffer more years of life lost than diabetic men. PMID- 25544841 TI - Cyclic Nanostructures of Tungsten Oxide (WO3) n (n = 2-6) as NO x Gas Sensor: A Theoretical Study. AB - Today's WO3-based gas sensors have received a lot of attention, because of important role as a sensitive layer for detection of the small quantities of NO x . In this research, a theoretical study has been done on the sensing properties of different cyclic nanoclusters of (WO3) n (n = 2-6) for NO x (x = 1,2) gases. Based on the calculated adsorption energies by B3LYP and X3LYP functionals, from the different orientations of NO x molecule on the tungsten oxide clusters, O-N?W was preferred. Different sizes of the mentioned clusters have been analyzed and W2O6 cluster was chosen as the best candidate for NO x detection from the energy viewpoint. Using the concepts of the chemical hardness and electronic charge transfer, some correlations between the energy of adsorption and interaction energy have been established. These analyses confirmed that the adsorption energy will be boosted with charge transfer enhancement. However, the chemical hardness relationship is reversed. Finally, obtained results from the natural bond orbital and electronic density of states analysis confirmed the electronic charge transfer from the adsorbates to WO3 clusters and Fermi level shifting after adsorption, respectively. The last parameter confirms that the cyclic clusters of tungsten oxide can be used as NO x gas sensors. PMID- 25544842 TI - Comparative evaluation of voids present in conventional and capsulated glass ionomer cements using two different conditioners: an in vitro study. AB - This in vitro study evaluated the presence of voids in powder-liquid and capsulated glass ionomer cement. 40 cavities were prepared on root surfaces of maxillary incisors and divided into four groups. Cavities were conditioned with glass ionomer cement liquid (GC Corporation, Tokyo, Japan) in Groups 1 and 3 and with dentin conditioner (GC Corporation, Tokyo, Japan) in Groups 2 and 4. Conventional powder-liquid glass ionomer cement (GC Fuji II, GC Corporation, Tokyo, Japan) was used as a restorative material in Groups 1 and 2. Capsulated glass ionomer cement (GC Fuji II, GC Corporation, Tokyo, Japan) was used in Groups 3 and 4. Samples were sectioned and viewed under stereomicroscope to check for the presence of voids within the cement and at the cement-tooth junction. Data was analyzed using one-way ANOVA and Tukey's post hoc tests. Group 4 showed statistically significant results (P < 0.05) when compared to Groups 1 and 2 for voids within the cement. However, for voids at the margins, the results were statistically insignificant. PMID- 25544843 TI - Candida glabrata Esophagitis: Are We Seeing the Emergence of a New Azole Resistant Pathogen? AB - Background. Candida glabrata (C. glabrata) has become a recognized pathogen in fungal esophagitis. A proportion of these isolates are azole-resistant which may have treatment implications. Variability in the prevalence of this organism exists in the limited data available. Objective. To determine the incidence of C. glabrata esophagitis in a North American hospital setting and to highlight factors that may predispose patients to this condition. Methods. Patient charts were collected from January 1, 2009 to July 30, 2011. Any charts of patients identified as having esophagitis with a positive fungal culture were reviewed for the species of Candida and the presence of factors that would predispose them to esophageal candidiasis. Results. The prevalence of Candida esophagitis based on culture was 2.2% (37 subjects). C. glabrata was the 2nd most prevalent pathogen identified (24.3% or 9 subjects). Of the C. glabrata cohort, all patients had at least one factor predisposing them to candidiasis. Conclusion. C. glabrata esophagitis makes up a large portion of the candidal esophagitis seen in hospital. C. glabrata infections were associated with at least one risk factor for candidal infection. Given its resistance to azole-based therapy, this may have treatment implications for how candidal esophagitis is approached by the clinician. PMID- 25544844 TI - Occult papillary thyroid carcinoma metastasis to the sacrum and the skull: an unusual presentation. AB - This case represents occult follicular variant of papillary thyroid carcinoma (FVPTC) with large metastasis to the sacrum. The patient, a 42-year-old female, presented after hemithyroidectomy for benign follicular adenoma with lower back pain associated with fever and sweating. A lytic lesion of the left sacral bone was found on the CT with biopsy showing metastatic carcinoma with morphology and immunophenotype of thyroid gland primary tumor proven to be FVPTC. The patient had completion thyroidectomy with benign pathology. PMID- 25544845 TI - Large Vessel Vasculitis Occurring in Rheumatoid Arthritis Patient under Anti-TNF Therapy. AB - Vasculitis is a heterogeneous group of disorders characterized by the presence of necrotic inflammatory phenomena and destruction of blood vessels. Vasculitis is classified as primary (idiopathic) or secondary to infections, connective tissue diseases and drugs but can also be considered as a paraneoplastic phenomenon. Evidence shows that the increasing use of biological agents results in a growing number of reports of autoimmune diseases induced by these therapies. An inflammatory articular chronic disease such as rheumatoid arthritis may be complicated by extra-articular manifestations, such as cutaneous or systemic vasculitis. Herewith, we describe the case of a great vessels arteritis in a patient affected by rheumatoid arthritis in therapy with an anti-TNF agent (etanercept). PMID- 25544846 TI - DNA Methylation Is Involved in the Expression of miR-142-3p in Fibroblasts and Induced Pluripotent Stem Cells. AB - MicroRNAs are differentially expressed in cells and regulate multiple biological processes. We have been analyzing comprehensive expression patterns of microRNA in human and mouse embryonic stem and induced pluripotent stem cells. We determined microRNAs specifically expressed in these pluripotent stem cells, and miR-142-3p is one of such microRNAs. miR-142-3p is expressed at higher levels in induced pluripotent stem cells relative to fibroblasts in mice. Level of expression of miR142-3p decreased during embryoid body formation from induced pluripotent stem cells. Loss-of-function analyses of miR-142-3p suggested that miR-142-3p plays roles in the proliferation and differentiation of induced pluripotent stem cells. CpG motifs were found in the 5' genomic region of the miR 142-3p; they were highly methylated in fibroblasts, but not in undifferentiated induced pluripotent stem cells. Treating fibroblasts with 5-aza-2'-deoxycytidine increased the expression of miR-142-3p significantly and reduced methylation at the CpG sites, suggesting that the expression of miR-142-3p is suppressed by DNA methylation in fibroblasts. Luciferase analysis using various lengths of the 5' genomic region of miR142-3p indicated that CpGs in the proximal enhancer region may play roles in suppressing the expression of miR-142-3p in fibroblasts. PMID- 25544847 TI - Fibroblast growth factor 18 increases the trophic effects of bone marrow mesenchymal stem cells on chondrocytes isolated from late stage osteoarthritic patients. AB - Coculture of mesenchymal stem cells with chondrocytes increases production of cartilaginous matrix. Chondrocytes isolated from late stage osteoarthritic patients usually lost their phenotype of producing cartilaginous matrix. Fibroblast growth factor 18 is believed to redifferentiate OA chondrocyte into functionally active chondrocytes. The aim of this study is to investigate the supportive effects of MSCs on OA chondrocytes and test if FGF18 could enhance the responsiveness of OA chondrocytes to the support of MSCs in a coculture system. Both pellet and transwell co-cultures were used. GAG quantification, hydroxyproline assay, and qPCR were performed. An ectopic models of cartilage formation was also applied. Our data indicated that, in pellets coculture of MSCs and OA chondrocytes, matrix production was increased in the presence of FGF18, comparing to the monoculture of chondrocytes. Results from transwell coculture study showed that expression of matrix producing genes in OA chondrocytes increased when cocultured with MSCs with FGF18 in culture medium, while hypertrophic genes were not changed by coculture. Finally, coimplantation of MSCs with OA chondrocytes produces more matrix than chondrocytes only. In conclusion, FGF18 can restore the responsiveness of OA chondrocytes to the trophic effects of MSCs. Coimplantation of MSCs and OA chondrocytes treated with FGF18 may be a good alternative cell source for regenerating cartilage tissue that is degraded during OA pathological changes. PMID- 25544848 TI - Transient Downregulation of Nanog and Oct4 Induced by DETA/NO Exposure in Mouse Embryonic Stem Cells Leads to Mesodermal/Endodermal Lineage Differentiation. AB - The function of pluripotency genes in differentiation is a matter of investigation. We report here that Nanog and Oct4 are reexpressed in two mouse embryonic stem cell (mESC) lines following exposure to the differentiating agent DETA/NO. Both cell lines express a battery of both endoderm and mesoderm markers following induction of differentiation with DETA/NO-based protocols. Confocal analysis of cells undergoing directed differentiation shows that the majority of cells expressing Nanog express also endoderm genes such as Gata4 and FoxA2 (75.4% and 96.2%, resp.). Simultaneously, mRNA of mesodermal markers Flk1 and Mef2c are also regulated by the treatment. Acetylated histone H3 occupancy at the promoter of Nanog is involved in the process of reexpression. Furthermore, Nanog binding to the promoter of Brachyury leads to repression of this gene, thus disrupting mesendoderm transition. PMID- 25544849 TI - Whole Genome Expression Profiling and Signal Pathway Screening of MSCs in Ankylosing Spondylitis. AB - The pathogenesis of dysfunctional immunoregulation of mesenchymal stem cells (MSCs) in ankylosing spondylitis (AS) is thought to be a complex process that involves multiple genetic alterations. In this study, MSCs derived from both healthy donors and AS patients were cultured in normal media or media mimicking an inflammatory environment. Whole genome expression profiling analysis of 33,351 genes was performed and differentially expressed genes related to AS were analyzed by GO term analysis and KEGG pathway analysis. Our results showed that in normal media 676 genes were differentially expressed in AS, 354 upregulated and 322 downregulated, while in an inflammatory environment 1767 genes were differentially expressed in AS, 1230 upregulated and 537 downregulated. GO analysis showed that these genes were mainly related to cellular processes, physiological processes, biological regulation, regulation of biological processes, and binding. In addition, by KEGG pathway analysis, 14 key genes from the MAPK signaling and 8 key genes from the TLR signaling pathway were identified as differentially regulated. The results of qRT-PCR verified the expression variation of the 9 genes mentioned above. Our study found that in an inflammatory environment ankylosing spondylitis pathogenesis may be related to activation of the MAPK and TLR signaling pathways. PMID- 25544850 TI - Considering race and the potential for ERG expression as a biomarker for prostate cancer. AB - Genomic rearrangement and overexpression of the ERG oncogene (also known as v-ets avian erythroblastosis virus E26 oncogene homolog) is estimated to occur at a rate of 40-50% in prostate cancer. Early evidence suggests that ERG overexpression may be associated with disease progression, and the utilization of ERG levels as a biomarker for prostate cancer is being strongly considered. However, the evidence is incomplete because it relies on studies that primarily focused on men of European ancestry, giving little consideration to African American men even though African-American men bear a greater disease burden in the form of significantly greater incidence and worse outcomes. In this perspective article we bring to light the issue that the potential use of ERG expression as a biomarker is yet to be solidly established and may have limited utility or varied applicably for African-American men as compared with European American men. PMID- 25544851 TI - A pilot study on effects of acupuncture and moxibustion by hyperspectral imaging technique. AB - This study was to observe the effects of acupuncture and moxibustion on spectrum features of acupoint using hyperspectral imaging (HSI) technique. HSI of the Neiguan (PC6) in the acupuncture groups, moxibustion groups, and control groups was scanned by the hyperspectral imager to analyze the spectrum features and the variations within the wavelength of 400-1000 nm and explore the relationship between the spectral characteristics and effects of acupuncture and moxibustion. The light absorption intensity was slightly reduced within the wave band of 540 590 nm after acupuncture. The absorption intensity of PC6 before moxibustion was significantly higher than that after moxibustion, and the maximum reduction was found at the wavelength of 580 nm with 20.5% reduction, P < 0.05. There was no significant change of the spectrum of palm and PC6 and the spectrum curves of the acupoint were basically identical in control group. The light absorption intensity of PC6 of human body was weakened after Acu-mox. Specific wavelengths were all exhibited at 580 nm and the effect of moxibustion was more significant. HSI technique can be used to measure the spectral characteristics of the acupoint areas. This first time research would be significant and beneficial for study on the effect of acupuncture and moxibustion. PMID- 25544852 TI - Specificity study on concentration of monoamine transmitters at acupoint and effect of acupuncture on its distribution. AB - To investigate the distribution of monoamine transmitters at acupoints and effect of acupuncture on it. Take this experiment by means of microdialysis. Twenty rabbits were randomly assigned to two groups (Group A: acupuncture Guanyuan (RN4), Group B: acupuncture nonacupoint which is besides Guanyuan (RN4) 1 cm). Before and after acupuncture was taken, tissue fluids both at Zhongwan (RN12) which is on the same meridian as Guanyuan and at a nonacupoint 1 cm away from Zhongwan were collected through microdialysis, respectively. The collected samples were analyzed to determine concentrations of monoamine transmitters. Epinephrine and 5-HT were detected. An unknown substance was found. Its concentration at acupoint was significantly higher than that at nonacupoint and decreased after acupuncture. Its significant specificity at acupoints suggests that it may play an important role in meridian's activity. PMID- 25544853 TI - Applications of data mining methods in the integrative medical studies of coronary heart disease: progress and prospect. AB - A large amount of studies show that real-world study has strong external validity than the traditional randomized controlled trials and can evaluate the effect of interventions in a real clinical setting, which open up a new path for researches of integrative medicine in coronary heart disease. However, clinical data of integrative medicine in coronary heart disease are large in amount and complex in data types, making exploring the appropriate methodology a hot topic. Data mining techniques are to analyze and dig out useful information and knowledge from the mass data to guide people's practices. The present review provides insights for the main features of data mining and their applications of integrative medical studies in coronary heart disease, aiming to analyze the progress and prospect in this field. PMID- 25544854 TI - Effects of acupuncture knife on inflammatory factors and pain in third lumbar vertebrae transverse process syndrome model rats. AB - The aim of this paper was to explore the long-term effects and pain relief mechanism of acupuncture knife on third lumbar vertebrae (L3) transverse process syndrome. Forty SD rats were randomized into control, model, electroacupuncture (EA), and acupuncture knife (AK) group. Except control rats, other rats were subjected to an operation to emulate L3 transverse process syndrome. Fourteen days after the operation, EA and AK rats were given electroacupuncture and acupuncture knife treatments, respectively. Fifty-six days after the operation, enzyme-linked immunosorbent assay was used to measure substance P (SP), 5 hydroxytryptamine (5-HT), interleukin-1beta (IL-1beta), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF beta) in peripheral blood. The tail flick test was used to observe pain threshold. We found that rats with the simulation operation had significantly higher levels of SP, 5-HT, IL-1, IL-10, TNF-alpha, and TGF-beta, while the AK rats had lower levels. In addition, the pain threshold of AK rats was similar to that of control rats. AK pretreatment could alleviate pain through modulating inflammatory response. PMID- 25544855 TI - In situ rheology of Staphylococcus epidermidis bacterial biofilms. AB - We developed a method to grow Staphylococcus epidermidis bacterial biofilms and characterize their rheological properties in situ in a continuously fed bioreactor incorporated into a parallel plate rheometer. The temperature and shear rates of growth modeled bloodstream conditions, a common site of S. epidermidis infection. We measured the linear elastic (G') and viscous moduli (G") of the material using small-amplitude oscillatory rheology and the yield stress using non-linear creep rheology. We found that the elastic and viscous moduli of the S. epidermidis biofilm were 11 +/- 3 Pa and 1.9 +/- 0.5 Pa at a frequency of 1 Hz (6.283 rad per s) and that the yield stress was approximately 20 Pa. We modeled the linear creep response of the biofilm using a Jeffreys model and found that S. epidermidis has a characteristic relaxation time of approximately 750 seconds and a linear creep viscosity of 3000 Pa s. The effects on the linear viscoelastic moduli of environmental stressors, such as NaCl concentration and extremes of temperature, were also studied. We found a non monotonic relationship between moduli and NaCl concentrations, with the stiffest material properties found at human physiological concentrations (135 mM). Temperature dependent rheology showed hysteresis in the moduli when heated and cooled between 5 degrees C and 60 degrees C. Through these experiments, we demonstrated that biofilms are rheologically complex materials that can be characterized by a combination of low modulus (~10 Pa), long relaxation time (~103 seconds), and a finite yield stress (20 Pa). This suggests that biofilms should be viewed as soft viscoelastic solids whose properties are determined in part by local environmental conditions. The in situ growth method introduced here can be adapted to a wide range of biofilm systems and applied over a broad spectrum of rheological and environmental conditions because the technique minimizes the risk of irreversible, non-linear deformation of the microbial specimen before analysis. PMID- 25544857 TI - FLAVIdB: A data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology. AB - BACKGROUND: The flavivirus genus is unusually large, comprising more than 70 species, of which more than half are known human pathogens. It includes a set of clinically relevant infectious agents such as dengue, West Nile, yellow fever, and Japanese encephalitis viruses. Although these pathogens have been studied extensively, safe and efficient vaccines lack for the majority of the flaviviruses. RESULTS: We have assembled a database that combines antigenic data of flaviviruses, specialized analysis tools, and workflows for automated complex analyses focusing on applications in immunology and vaccinology. FLAVIdB contains 12,858 entries of flavivirus antigen sequences, 184 verified T-cell epitopes, 201 verified B-cell epitopes, and 4 representative molecular structures of the dengue virus envelope protein. FLAVIdB was assembled by collection, annotation, and integration of data from GenBank, GenPept, UniProt, IEDB, and PDB. The data were subject to extensive quality control (redundancy elimination, error detection, and vocabulary consolidation). Further annotation of selected functionally relevant features was performed by organizing information extracted from the literature. The database was incorporated into a web-accessible data mining system, combining specialized data analysis tools for integrated analysis of relevant data categories (protein sequences, macromolecular structures, and immune epitopes). The data mining system includes tools for variability and conservation analysis, T-cell epitope prediction, and characterization of neutralizing components of B-cell epitopes. FLAVIdB is accessible at cvc.dfci.harvard.edu/flavi/ CONCLUSION: FLAVIdB represents a new generation of databases in which data and tools are integrated into a data mining infrastructures specifically designed to aid rational vaccine design by discovery of vaccine targets. PMID- 25544856 TI - Improving Outcome of Psychosocial Treatments by Enhancing Memory and Learning. AB - Mental disorders are prevalent and can lead to significant impairment. Some progress has been made toward establishing treatments; however, effect sizes are small to moderate, gains may not persist, and many patients derive no benefit. Our goal is to highlight the potential for empirically supported psychosocial treatments to be improved by incorporating insights from cognitive psychology and research on education. Our central question is: If it were possible to improve memory for the content of sessions of psychosocial treatments, would outcome substantially improve? We leverage insights from scientific knowledge on learning and memory to derive strategies for transdiagnostic and transtreatment cognitive support interventions. These strategies can be applied within and between sessions and to interventions delivered via computer, the Internet, and text message. Additional novel pathways to improving memory include improving sleep, engaging in exercise, and using imagery. Given that memory processes change across the lifespan, services to children and older adults may benefit from different types and amounts of cognitive support. PMID- 25544858 TI - Mass spectrometry-based proteomic approaches for discovery of HIV-host interactions. AB - A molecular understanding of viral infection requires a multi-disciplinary approach. Mass spectrometry has emerged as an indispensable tool to investigate the complex and dynamic interactions between HIV-1 and its host. It has been employed to study protein associations, changes in protein abundance and post translational modifications occurring after viral infection. Here, we review and provide examples of mass spectrometry-based proteomic approaches currently used to explore virus-host interaction. Efforts in this area are certain to accelerate the discovery of the unique molecular strategies utilized by the virus to commandeer the cell as well as mechanisms of host defense. PMID- 25544860 TI - Aesop: A framework for developing and researching arts in health programmes. AB - The field of arts in health is currently undergoing a burgeoning in activity. However, there remains a problem surrounding research into this field. Arts in health research can be confusing and is frequently misunderstood by those working in the arts and in health, artists, reviewers, researchers and funders. Aesop 1 is a framework specially devised to tackle these problems. It synthesises existing arts research methodologies, health research methodologies, health policy documents and reporting guidelines in order to guide projects right from the initial idea for an arts intervention, through the development and design of a research project, its delivery and its dissemination. This article outlines the rationale behind the framework and explains how it should be used, with the aim of facilitating the running of arts and health research projects and increasing their rigour and acceptance within both the arts and health communities. PMID- 25544859 TI - Cytokines are both villains and potential therapeutic targets in thyroid associated ophthalmopathy: From bench to bedside. AB - The pathophysiology underlying Graves' disease and its ocular manifestation, thyroid associated ophthalmopathy (TAO) is incompletely understood. Characterization of the mononuclear cells driving the disease and the cytokines they produce has led to significant advances in our understanding of TAO. This in turn has resulted in the identification of potentially attractive drug targets. For instance, development of inhibitors of specific cytokine pathways for use in other autoimmune diseases now presents an opportunity for their application in TAO. In this paper, we review the rationale for considering anti-cytokine therapy in TAO, evidence linking specific cytokines such as interleukin-6, tumor necrosis factor-alpha, and interleukin-17 pathways to TAO, and explore the potential for targeting of these pathways as therapy. PMID- 25544861 TI - The effects of arts-in-medicine programming on the medical-surgical work environment. AB - Background: Arts in medicine programs have significant impacts on patients and staff in long-term care environments, but the literature lacks evidence of effectiveness on hospital units with shorter average lengths of stay. Methods: The qualitative study used individual structured interviews to assess the impacts of arts programming on job satisfaction, stress, unit culture, support, quality of care, and patient outcomes on a short-term medical-surgical unit, and used a qualitative cross comparison grounded theory methodology to analyze data. Results: The study confirmed that arts programming can positively affect unit culture, nursing practice, and quality of care on short-stay medical-surgical units. Significant insights related to nursing practice and the art program were found, including that music can cause negative distraction for staff. Conclusions: While positive impacts of arts programming on the medical-surgical environment are clear, potential negative effects also need to be considered in the development of practice protocols for artists. PMID- 25544862 TI - Nuclear stiffening inhibits migration of invasive melanoma cells. AB - During metastasis, melanoma cells must be sufficiently deformable to squeeze through extracellular barriers with small pore sizes. We visualize and quantify deformability of single cells using micropipette aspiration and examine the migration potential of a population of melanoma cells using a flow migration apparatus. We artificially stiffen the nucleus with recombinant overexpression of Delta50 lamin A, which is found in patients with Hutchison Gilford progeria syndrome and in aged individuals. Melanoma cells, both WM35 and Lu1205, both show reduced nuclear deformability and reduced cell invasion with the expression of Delta50 lamin A. These studies suggest that cellular aging including expression of Delta50 lamin A and nuclear stiffening may reduce the potential for metastatic cancer migration. Thus, the pathway of cancer metastasis may be kept in check by mechanical factors in addition to known chemical pathway regulation. PMID- 25544863 TI - Angiogenesis in myeloproliferative neoplasms, new markers and future directions. AB - Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and antiangiogenic cytokines. This has been documented for solid tumors, and there is emerging evidence suggesting that tumor progression of hematological malignancies also depends on the induction of new blood vessel formation. Data on angiogenesis in the bone marrow of BCR-ABL1-negative myeloproliferative neoplasm patients suggest an increase of the microvessel density and vascular endothelial growth factor (VEGF) expression, and there is a relation to the JAK2-V617F status. The most important proangiogenic agent is VEGF, activating VEGF receptors 1 and 2. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities, and multiple new drugs are being tested in clinical trials. Most patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) that was not associated with a JAK2 or MPL alteration carried a somatic mutation in calreticulin (CALR). Thus, CALR mutations should be included in the next classification system for ET/PMF. This review summarizes recent advances in the basic understanding of the role of angiogenesis in myeloproliferative neoplasms and the translation of such basic findings into clinical studies. PMID- 25544864 TI - SU-8 microcantilever with an aperture, fluidic channel, and sensing mechanisms for biological and other applications. AB - We describe a method for fabricating an aperture on a fluidic cantilever device using SU-8 as a structural material. The device can ultimately be used for patch clamping, microinjections, fluidic delivery, fluidic deposition, and micromaterial removal. In the first generation of this device, the initial aperture diameter is 10 MUm and is fabricated on a silicon-on-insulator (SOI) wafer that is structurally used to define the aperture. The aperture can be reduced in size through mask design. This self-aligned process allows for patterning on the sharp tip projecting out of the fluidic plane on the cantilever and is batch fabricated, reducing the cost and time for manufacture. The initial mask, SOI device layer thickness, and the width of the base of the tip define the size of the aperture. The SU-8 micromachined cantilever includes an electrode and a force sensing mechanism. The cantilever can be easily integrated with an atomic force microscope or an optical microscope. PMID- 25544865 TI - LEVERAGING LOCAL IDENTITY-BY-DESCENT INCREASES THE POWER OF CASE/CONTROL GWAS WITH RELATED INDIVIDUALS. AB - Large case/control genome-wide association studies (GWAS) often include groups of related individuals with known relationships. When testing for associations at a given locus, current methods incorporate only the familial relationships between individuals. Here, we introduce the chromosome-based Quasi Likelihood Score (cQLS) statistic that incorporates local Identity-By-Descent (IBD) to increase the power to detect associations. In studies robust to population stratification, such as those with case/control sibling pairs, simulations show that the study power can be increased by over 50%. In our example, a GWAS examining late-onset Alzheimers disease, the p-values among the most strongly associated SNPs in the APOE gene tend to decrease, with the smallest p-value decreasing from 1.23 * 10-8 to 7.70 * 10-9. Furthermore, as a part of our simulations, we reevaluate our expectations about the use of families in GWAS. We show that, although adding only half as many unique chromosomes, genotyping affected siblings is more efficient than genotyping randomly ascertained cases. We also show that genotyping cases with a family history of disease will be less beneficial when searching for SNPs with smaller effect sizes. PMID- 25544866 TI - Hypertension Treatment for Patients with Advanced Chronic Kidney Disease. AB - Chronic kidney disease is common and frequently complicated with hypertension. As a major modifiable risk factor for cardiovascular disease in this high risk population, treatment of hypertension in chronic kidney disease is of paramount importance. We review the epidemiology and pathogenesis of hypertension in chronic kidney disease and then update the latest study results for treatment including salt restriction, invasive endovascular procedures, and pharmacologic therapy. Recent trials draw into question the efficacy of renal artery stenting or renal denervation for hypertension in chronic kidney disease, as well as renin angiotensin-aldosterone system blockade as first line therapy of hypertension in end stage renal disease. Positive trial results reemphasize salt restriction and challenge the prevailing prejudice against the use of thiazide-like diuretics in advanced chronic kidney disease. Lastly, clinical practice guidelines are trending away from recommending tight blood pressure control in chronic kidney disease. PMID- 25544868 TI - Trauma Exposure and Axis I Psychopathology: A Co-twin Control Analysis in Norwegian Young Adults. AB - Broad associations between trauma exposure (TE) and Axis I psychopathology have been noted in the literature. However, it is not clear if TE is directly associated with Axis I disorders or if the relationship is better accounted for by familial factors (i.e., early environment and/or genetic factors). The current investigation used the co-twin control method in a large sample of adult twin pairs from the Norwegian Twin Registry (N = 2,776), including 449 twin pairs discordant for DSM-IV Criterion A TE. History of TE and Axis I psychopathology was assessed using DSM-IV based clinical interview. Results suggested that TE was significantly associated with greater likelihood of meeting criteria for major depression, dysthymia, anxiety, substance abuse, eating disorders, and somatization disorder in the general population (odds ratios [OR] ranging from 1.33 to 2.21). Among twins discordant for TE, results suggested that TE may exert a direct influence on major depression, dysthymia, anxiety, substance abuse, eating disorders, and somatization disorder. Shared familial effects may also account for at least some of the relationship between TE and major depression. TE may play an important role in the development of a wide range of Axis I psychopathology above and beyond familial factors. Research and clinical implications are discussed. PMID- 25544867 TI - Dietary blueberry and bifidobacteria attenuate nonalcoholic fatty liver disease in rats by affecting SIRT1-mediated signaling pathway. AB - NAFLD model rats were established and divided into NAFLD model (MG group), SIRT1 RNAi (SI group), blueberry juice (BJ group), blueberry juice + bifidobacteria (BJB group), blueberry juice + SIRT1 RNAi (BJSI group), and blueberry juice + bifidobacteria + SIRT1 RNAi groups (BJBSI group). A group with normal rats was a control group (CG). BJB group ameliorated NAFLD, which was better than BJ group (P < 0.05). The lipid accumulation was lower in CG, BJ, and BJB groups than that in MG, SI, BJSI, and BJBSI groups (P < 0.05). The levels of SIRT1 and PPAR-alpha were higher in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P < 0.05). The levels of SREBP-1c were lower in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P < 0.05). The biochemical indexes SOD, GSH, and HDL-c were improved from CG to BJB group (P < 0.05). Inversely, the levels of AST and ALT, TG, TC, LDL-c, and MDA were decreased from CG to BJB group (P < 0.05). These changes enhance antioxidative capability and biochemical index of rats. Blueberry juice and bifidobacteria improve NAFLD by activating SIRTI mediating signaling pathway. PMID- 25544870 TI - Role of hepatectomy for recurrent or initially unresectable hepatocellular carcinoma. AB - As a result of donor shortage and high postoperative morbidity and mortality after liver transplantation, hepatectomy is the most widely applicable and reliable option for curative treatment of hepatocellular carcinoma (HCC). Because intrahepatic tumor recurrence is frequent after loco-regional therapy, repeated treatments are advocated provided background liver function is maintained. Among treatments including local ablation and transarterial chemoembolization, hepatectomy provides the best long-term outcomes, but studies comparing hepatectomy with other nonsurgical treatments require careful review for selection bias. In patients with initially unresectable HCC, transarterial chemo or radio-embolization, and/or systemic chemotherapy can down-stage the tumor and conversion to resectable HCC is achieved in approximately 20% of patients. However, complete response is rare, and salvage hepatectomy is essential to help prolong patients' survival. To counter the short recurrence-free survival, excellent overall survival is obtained by combining and repeating different treatments. It is important to recognize hepatectomy as a complement, rather than a contraindication, to other nonsurgical treatments in a multidisciplinary approach for patients with HCC, including recurrent or unresectable tumors. PMID- 25544869 TI - Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out. AB - As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies. PMID- 25544871 TI - Transarterial chemoembolization for hepatocellular carcinoma: A review of techniques. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide. While curative therapies, including resection, liver transplantation, and percutaneous ablation (percutaneous ethanol injection and radiofrequency ablation), are applicable for only a portion of the HCC population, transcatheter arterial chemoembolization (TACE) has been recognized as an effective palliative treatment option for patients with advanced HCC. TACE is also used even for single HCCs in which it is difficult to perform surgical resection or locoregional treatment due to systemic co-morbidities or anatomical problems. TACE has become widely adopted in the treatment of HCC. By using computed tomography-angiography, TACE is capable of performing diagnosis and treatment at the same time. Furthermore, TACE plays an important role in the multidisciplinary treatment for HCC when combined with other treatment. In this review, we first discuss the history of TACE, and then review the previous findings about techniques of achieving a locoregional treatment effect (liver infarction treatment, e.g., ultra-selective TACE, balloon-occluded TACE), and the use of TACE as a drug delivery system for anti-cancer agents (palliative, e.g., platinum complex agents, drug-eluting beads) for multiple lesions. PMID- 25544872 TI - How did hepatitis B virus effect the host genome in the last decade? AB - The principal reason of chronic liver disease, cirrhosis and hepatocellular carcinoma is chronic viral hepatitis all over the world. Hepatitis B virus (HBV) has some mutagenic effects on the host genome. HBV may be exhibiting these mutagenic effects through integrating into the host genome, through its viral proteins or through some epigenetic mechanisms related with HBV proteins. This review aims to summarize the molecular mechanisms used by HBV for effecting host genome determined in the last decade. The focus will be on the effects of integration, HBV proteins, especially HBV X protein and epigenetic mechanisms on the host genome. These interactions between HBV and the host genome also forms the underlying mechanisms of the evolution of hepatocellular carcinoma. PMID- 25544873 TI - Occult hepatitis B virus infection. AB - Occult hepatitis B virus (HBV) infection (OBI) refers to the presence of HBV DNA in the absence of detectable hepatitis B surface antigen. Since OBI was first described in the late 1970s, there has been increasing interest in this topic. The prevalence of OBI varies according to the different endemicity of HBV infection, cohort characteristics, and sensitivity and specificity of the methods used for detection. Although the exact mechanism of OBI has not been proved, intra-hepatic persistence of viral covalently closed circular DNA under the host's strong immune suppression of HBV replication and gene expression seems to be a cause. OBI has important clinical significance in several conditions. First, OBI can be transmitted through transfusion, organ transplantation including orthotopic liver transplantation, or hemodialysis. Donor screening before blood transfusion, prophylaxis for high-risk organ transplantation recipients, and dialysis-specific infection-control programs should be considered to reduce the risk of transmission. Second, OBI may reactivate and cause acute hepatitis in immunocompromised patients or those receiving chemotherapy. Close HBV DNA monitoring and timely antiviral treatment can prevent HBV reactivation and consequent clinical deterioration. Third, OBI may contribute to the progression of hepatic fibrosis in patients with chronic liver disease including hepatitis C. Finally, OBI seems to be a risk factor for hepatocellular carcinoma by its direct proto-oncogenic effect and by indirectly causing persistent hepatic inflammation and fibrosis. However, this needs further investigation. We review published reports in the literature to gain an overview of the status of OBI and emphasize the clinical importance of OBI. PMID- 25544874 TI - Functional foods effective for hepatitis C: Identification of oligomeric proanthocyanidin and its action mechanism. AB - Hepatitis C virus (HCV) is a major cause of viral hepatitis and currently infects approximately 170 million people worldwide. An infection by HCV causes high rates of chronic hepatitis (> 75%) and progresses to liver cirrhosis and hepatocellular carcinoma ultimately. HCV can be eliminated by a combination of pegylated alpha interferon and the broad-spectrum antiviral drug ribavirin; however, this treatment is still associated with poor efficacy and tolerability and is often accompanied by serious side-effects. While some novel direct-acting antivirals against HCV have been developed recently, high medical costs limit the access to the therapy in cost-sensitive countries. To search for new natural anti-HCV agents, we screened local agricultural products for their suppressive activities against HCV replication using the HCV replicon cell system in vitro. We found a potent inhibitor of HCV RNA expression in the extracts of blueberry leaves and then identified oligomeric proanthocyanidin as the active ingredient. Further investigations into the action mechanism of oligomeric proanthocyanidin suggested that it is an inhibitor of heterogeneous nuclear ribonucleoproteins (hnRNPs) such as hnRNP A2/B1. In this review, we presented an overview of functional foods and ingredients efficient for HCV infection, the chemical structural characteristics of oligomeric proanthocyanidin, and its action mechanism. PMID- 25544875 TI - Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies. AB - Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH. PMID- 25544876 TI - Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver disease during the last three decades. AB - Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and is the most common type of chronic liver diseases in the majority of developed countries. NAFLD shows a wide spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. While simple steatosis is recognized to be benign and stable, NASH is considered to be an aggressive form of the disease progressing to cirrhosis. Currently, differentiation between NASH and simple steatosis can be done only by liver biopsy. Despite many proposals and revisions, the histological criteria for the differentiation have not been perfected yet. In this review article, the changes in the histopathologic criteria of NAFLD during the last three decades are summarized, and perspectives of the future changes are demonstrated. The discussion focuses on how pathologists have been dealing with "hepatocellular ballooning". Loose criteria, in which hepatocellular ballooning was not required for the diagnosis of NASH, were applied in many clinical studies published in around 2000's, whereas a strict criterion based on the presence/absence of hepatocellular ballooning was approved recently. Hence, simple and reliable methods of identifying ballooned hepatocytes are being sought. Clinical and pathological predictors of NAFLD-related hepatocarcinogenesis will also be sought in the future. PMID- 25544878 TI - Recombinase polymerase amplification as a promising tool in hepatitis C virus diagnosis. AB - Hepatitis C virus (HCV) infection represents a significant health problem and represents a heavy load on some countries like Egypt in which about 20% of the total population are infected. Initial infection is usually asymptomatic and result in chronic hepatitis that give rise to complications including cirrhosis and hepatocellular carcinoma. The management of HCV infection should not only be focus on therapy, but also to screen carrier individuals in order to prevent transmission. In the present, molecular detection and quantification of HCV genome by real time polymerase chain reaction (PCR) represent the gold standard in HCV diagnosis and plays a crucial role in the management of therapeutic regimens. However, real time PCR is a complicated approach and of limited distribution. On the other hand, isothermal DNA amplification techniques have been developed and offer molecular diagnosis of infectious dieses at point-of care. In this review we discuss recombinase polymerase amplification technique and illustrate its diagnostic value over both PCR and other isothermal amplification techniques. PMID- 25544879 TI - Palliative external-beam radiotherapy for bone metastases from hepatocellular carcinoma. AB - The incidence of bone metastases (BMs) from hepatocellular carcinoma (HCC) is relatively low compared to those of other cancers, but it has increased recently, especially in Asian countries. Typically, BMs from HCC appear radiologically as osteolytic, destructive, and expansive components with large, bulky soft-tissue masses. These soft-tissue masses are unique to bone metastases from HCC and often replace the normal bone matrix and exhibit expansive growth. They often compress the peripheral nerves, spinal cord, or cranial nerves, causing not only bone pain but also neuropathic pain and neurological symptoms. In patients with spinal BMs, the consequent metastatic spinal cord compression (MSCC) causes paralysis. Skull base metastases (SBMs) with cranial nerve involvement can cause neurological symptoms. Therefore, patients with bony lesions often suffer from pain or neurological symptoms that have a severe, adverse effect on the quality of life. External-beam radiotherapy (EBRT) can effectively relieve bone pain and neurological symptoms caused by BMs. However, EBRT is not yet widely used for the palliative management of BMs from HCC because of the limited number of relevant studies. Furthermore, the optimal dosing schedule remains unclear, despite clinical evidence to support single-fraction radiation schedules for primary cancers. In this review, we outline data describing palliative EBRT for BMs from HCC in the context of (1) bone pain; (2) MSCC; and (3) SBMs. PMID- 25544881 TI - How Much Does Risk Tolerance Change? AB - Stability of preferences is central to how economists study behavior. This paper uses panel data on hypothetical gambles over lifetime income in the Health and Retirement Study to quantify changes in risk tolerance over time and differences across individuals. Maximum-likelihood estimation of a correlated random effects model utilizes information from 12,000 respondents in the 1992-2002 HRS. The results are consistent with constant relative risk aversion and career selection based on preferences. While risk tolerance changes with age and macroeconomic conditions, persistent differences across individuals account for over 70% of the systematic variation. PMID- 25544880 TI - Evaluation of hepatocellular carcinoma development in patients with chronic hepatitis C by EOB-MRI. AB - AIM: To evaluate the efficacy of ethoxibenzyl-magnetic resonance imaging (EOB MRI) as a predictor of hepatocellular carcinoma (HCC) development. METHODS: Between August 2008 and 2009, we studied 142 hepatitis C virus-infected patients (male 70, female 72), excluding those with HCC or a past history, who underwent EOB-MRI in our hospital. The EOB-MRI index [liver-intervertebral disc ratio (LI)] was calculated as: (post-liver intensity/post-intervertebral disc intensity)/(pre liver intensity/pre-intervertebral disc intensity). RESULTS: The median follow-up period was 3.1 years and the patients were observed until the end of the study period (31 December, 2012). In the follow-up period, HCC occurred in 21 patients. The cumulative occurrence rates were 2.1%, 9.1%, and 14.1% at 1, 2, and 3 years, respectively. Using the optimal cut-off value of LI 1.46, on univariate analysis, age, aspartate amino transferase (AST), alpha-fetoprotein (AFP) >= 10, albumin, total cholesterol, prothrombin time, platelets, and LI < 1.46 were identified as independent factors, but on multivariate analysis, LI < 1.46: risk ratio 6.05 (1.34-27.3, P = 0.019) and AFP >= 10: risk ratio 3.1 (1.03-9.35, P = 0.045) were identified as independent risk factors. LI and Fib-4 index have higher area under the receiver operating characteristic curves than other representative fibrosis evaluation methods, such as Forn's index and AST-to-platelet ratio index. CONCLUSION: LI is associated with the risk of HCC occurrence in hepatitis C patients. LI may be a substitute for liver biopsy when evaluating this risk and its combined use with Fib-4 is a better predictive method of HCC progression. PMID- 25544877 TI - Vitamin D deficiency in chronic liver disease. AB - Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomodulatory and anti inflammatory properties. Vitamin D deficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its importance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required. PMID- 25544882 TI - Carbon-Hydrogen (C-H) Bond Activation at PdIV: A Frontier in C-H Functionalization Catalysis. AB - The direct functionalization of carbon-hydrogen (C-H) bonds has emerged as a versatile strategy for the synthesis and derivatization of organic molecules. Among the methods for C-H bond activation, catalytic processes that utilize a PdII/PdIV redox cycle are increasingly common. The C-H activation step in most of these catalytic cycles is thought to occur at a PdII centre. However, a number of recent reports have suggested the feasibility of C-H cleavage occurring at PdIV complexes. Importantly, these latter processes often result in complementary reactivity and selectivity relative to analogous transformations at PdII. This Mini Review highlights proposed examples of C-H activation at PdIV centres. Applications of this transformation in catalysis as well as mechanistic details obtained from stoichiometric model studies are discussed. Furthermore, challenges and future perspectives for the field are reviewed. PMID- 25544883 TI - Diazo compounds for the bioreversible esterification of proteins. AB - A diazo compound is shown to convert carboxylic acids to esters efficiently in an aqueous environment. The basicity of the diazo compound is critical: low basicity does not lead to a reaction but high basicity leads to hydrolysis. This reactivity extends to carboxylic acid groups in a protein. The ensuing esters are hydrolyzed by human cellular esterases to regenerate protein carboxyl groups. This new mode of chemical modification could enable the key advantages of prodrugs to be translated from small-molecules to proteins. PMID- 25544884 TI - What Israeli policy can teach us about elective sex selection. AB - PIGD for gender selection for non medical reasons has been a subject of ethical, legal, and moral debate in many Western countries. This article discusses the background of elective sex selection, and highlights the impact of new technological developments on this dynamic discussion. The article published by Pessach et al., in this Journal, is an excellent study of Israeli health policy on non medically indicated preimplantation genetic screening for sex selection. In Israel, elective sex selection is prohibited, but exceptions can be made by application, for family balancing, and emotional and religious reasons. This review of a health policy over seven years is concordant with evolving views in many Western countries. The classic medical model for allowing sex selection for serious medical disorders may be too restrictive. There are different reasons that may be assessed in light of ethical criteria including a wider delineation of medical reasons, which may include emotional and psychological well being of the family, indirect medical reasons, as well as risk reduction for the following generations. The Israeli model may be a useful approach with wide application to reproductive health policies in many countries. PMID- 25544885 TI - Effects of recent Virginia AIDS Drug Assistance Program policy changes on diabetes and hyperlipidemia control in people living with HIV. AB - OBJECTIVES: To describe the impacts of Virginia AIDS Drug Assistance Program's elimination of diabetes and hyperlipidemia medication on disease outcomes in people living with HIV. METHODS: Data were collected on two groups of people living with HIV who were prescribed medications for diabetes and/or hyperlipidemia; one group received medications from AIDS Drug Assistance Program (ADAP) and the other group received medications from another source. Data were collected for 13 months before and after the policy change. Diabetes, hyperlipidemia, and HIV control were compared using standard laboratory measures. RESULTS: During the pre-policy-change time period, non-ADAP patients had better diabetes control than ADAP patients, but with multivariate analysis, ADAP status was no longer a statistically significant predictor. Otherwise, no significant differences between groups were identified. DISCUSSION: ADAP patients had worse diabetes control compared to the non-ADAP group before the policy change. It is possible that this is due to the AIDS Drug Assistance Program population's poor access to non-HIV primary care, including care for diabetes. It is reassuring that, even during a time of flux in AIDS Drug Assistance Program resources, the AIDS Drug Assistance Program patients' co-morbid and HIV outcomes were not negatively impacted. PMID- 25544886 TI - Phospholipase A2-responsive antibiotic delivery via nanoparticle-stabilized liposomes for the treatment of bacterial infection. AB - Adsorbing small charged nanoparticles onto liposome surfaces to stabilize them against fusion and payload leakage has resulted in a new class of liposomes capable of environment-responsive drug delivery. Herein, we engineered a liposome formulation with a lipid composition sensitive to bacterium-secreted phospholipase A2 (PLA2) and adsorbed chitosan-modified gold nanoparticles (AuChi) onto the liposome surface. The resulting AuChi-stabilized liposomes (AuChi liposomes) showed prohibited fusion activity and negligible drug leakage. However, upon exposure to either purified PLA2 enzyme or PLA2 secreted by Helicobacter pylori (H. pylori) bacteria in culture, AuChi-liposomes rapidly released the encapsulated payloads and such responsive release was retarded by adding quinacrine dihydrochloride, a PLA2 inhibitor. When loaded with doxycycline, AuChi-liposomes effectively inhibited H. pylori growth. Overall, the AuChi-liposomes allowed for smart "on-demand" antibitoic delivery: the more enzymes or bacteria present at the infection site, the more drug will be released to treat the infection. Given the strong association of PLA2 with a diverse range of diseases, the present liposomal delivery technique holds broad application potential for tissue microenvironment-responsive drug delivery. PMID- 25544887 TI - Is 6-month GRACE risk score a useful tool to predict stroke after an acute coronary syndrome? AB - OBJECTIVES: The risk of stroke after an acute coronary syndrome (ACS) has increased. The aim of this study was to do a comparative validation of the 6 month GRACE (Global Registry of Acute Coronary Events) risk score and CH2DS2VASc risk score to predict the risk of post-ACS ischaemic stroke. METHODS: This was a retrospective study carried out in a single centre with 4229 patients with ACS discharged between 2004 and 2010 (66.9+/-12.8 years, 27.9% women, 64.2% underwent percutaneous coronary intervention). The primary end point is the occurrence of an ischaemic stroke during follow-up (median 4.6 years, IQR 2.7-7.1 years). RESULTS: 184 (4.4%) patients developed an ischaemic stroke; 153 (83.2%) had sinus rhythm and 31 (16.9%) had atrial fibrillation. Patients with stroke were older, with higher rates of hypertension, diabetes, previous stroke and previous coronary artery disease. The HR for CHA2DS2VASc was 1.36 (95% CI, 1.27 to 1.48, p<0.001) and for GRACE, HR was 1.02(95% CI, 1.01 to 1.03, p<0.001). Both risk scores show adequate discriminative ability (c-index 0.63+/-0.02 and 0.60+/-0.02 for CHA2DS2VASc and GRACE, respectively). In the reclassification method there was no difference (Net Reclassification Improvement 1.98%, p=0.69). Comparing moderate-risk/high-risk patients with low-risk patients, both risk scores showed very high negative predictive value (98.5% for CHA2DS2VASc, 98.1% for GRACE). The sensitivity of CHA2DS2VASc score was higher than the GRACE risk score (95.1% vs 87.0%), whereas specificity was lower (14.4% vs 30.2%). CONCLUSIONS: The 6-month GRACE model is a clinical risk score that facilitates the identification of individual patients who are at high risk of ischaemic stroke after ACS discharge. PMID- 25544888 TI - Gender-related associations of genetic polymorphisms of alpha-adrenergic receptors, endothelial nitric oxide synthase and bradykinin B2 receptor with treadmill exercise test responses. AB - BACKGROUND: Treadmill exercise test responses have been associated with cardiovascular prognosis in individuals without overt heart disease. Neurohumoral and nitric oxide responses may influence cardiovascular performance during exercise testing. Therefore, we evaluated associations between functional genetic polymorphisms of alpha-adrenergic receptors, endothelial nitric oxide synthase, bradykinin receptor B2 and treadmill exercise test responses in men and women without overt heart disease. METHODS: We enrolled 766 (417 women; 349 men) individuals without established heart disease from a check-up programme at the Heart Institute, University of Sao Paulo Medical School. Exercise capacity, chronotropic reserve, maximum heart-rate achieved, heart-rate recovery, exercise systolic blood pressure (SBP), exercise diastolic blood pressure (DBP) and SBP recovery were assessed during exercise testing. Genotypes for the alpha adrenergic receptors ADRA1A Arg347Cys (rs1048101), ADRA2A 1780 C>T (rs553668), ADRA2B Del 301-303 (rs28365031), endothelial nitric synthase (eNOS) 786 T>C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by PCR and high-resolution melting analysis. RESULTS: Maximum SBP was associated with ADRA1A rs1048101 (p=0.008) and BK2R rs5810761 (p=0.008) polymorphisms in men and ADRA2A rs553668 (p=0.008) and ADRA2B rs28365031 (p=0.022) in women. Maximum DBP pressure was associated with ADRA2A rs553668 (p=0.002) and eNOS rs1799983 (p=0.015) polymorphisms in women. Exercise capacity was associated with eNOS rs2070744 polymorphisms in women (p=0.01) and with eNOS rs1799983 in men and women (p=0.038 and p=0.024). CONCLUSIONS: The findings suggest that genetic variants of alpha-adrenergic receptors and bradykinin B2 receptor may be involved with blood pressure responses during exercise tests. Genetic variants of endothelial nitric oxide synthase may be involved with exercise capacity and blood pressure responses during exercise tests. These responses may be gender-related. PMID- 25544889 TI - Diagnosis of pertussis using nasopharyngeal IgA and polymerase chain reaction in specimens from outpatients in Australia. AB - We assessed IgA antibodies and polymerase chain reaction (PCR) for diagnosis of pertussis in nasopharyngeal aspiration (NPA) samples from outpatients in Australia. A total of 1700 patients (849 adults, 851 children) from Western Australia and the Northern Territory fulfilled the laboratory case definition for pertussis between 2004 and 2013: 732 specimens were positive by NPA IgA alone, 559 by PCR alone, and 409 by both tests. Overall, 968 cases (56.8%) were positive by PCR and 1141 cases (67.2%) by IgA [p < 0.00025]. Among pediatric patients, PCR was positive in 524 (61.3%) and IgA in 569 (67%). In 849 adult cases, the respective proportions were 52.3% and 67.4% [p < 0.00025]. The duration of cough in 507 patients was shorter in 262 pediatric cases (mean, 2.51 weeks; standard deviation [SD], 2.25) than 245 adult patients (3.27 weeks; SD, 2.79) [p = 0.0009]. PCR positivity showed a season-dependent variance (range, 5.6 to 85.9%) and peaked in the second week (71.7%) of illness. IgA antibodies peaked in the fifth week (89.5%) postinfection, and the positivity rate for NPA IgA was less variable (range, 38.3-97.2%). Nasopharyngeal Bordetella pertussis-specific IgA antibodies are valuable in diagnosis of pertussis in Australia. Reliance on PCR alone misses a significant proportion of pertussis cases, especially those with a delayed presentation. PMID- 25544890 TI - Lack of association between Toxoplasma gondii infection and occupational exposure to animals. AB - The association of infection with Toxoplasma gondii and occupational exposure to animals has been scantly determined. We performed a case-control study with 200 subjects from Durango Province, Mexico, occupationally exposed to animals and 200 age- and gender-matched subjects without this occupation. Sera from all participants were analyzed for anti-T. gondii IgG and IgM antibodies using enzyme linked immunoassays. The association of seroprevalence with sociodemographic, work, clinical, and behavioral characteristics in cases was determined. Cases and controls had similar frequencies of anti-T. gondii IgG antibodies (12/200: 6.0% and 11/200: 5.5%, respectively) (OR = 3.0; 95% CI: 0.12-73.64; P = 1.0). The frequency of sera with high (>150 IU/ml) levels of anti-T. gondii IgG antibodies was comparable among cases and controls (P = 0.61). Seroprevalence of anti-T. gondii IgM antibodies was similar in cases (4, 2.0%) than in controls (4, 2.0%) (P = 1.0). Multivariate analysis showed that seropositivity was associated with eating while working (OR = 7.14; 95% CI: 1.91-26.72; P = 0.003) and consumption of duck meat (OR = 5.43; 95% CI: 1.43-20.54; P = 0.01). No association between seropositivity to T. gondii and occupational exposure to animals was found. However, risk factors for infection found should be taken into account to reduce the exposure to T. gondii. PMID- 25544891 TI - Prevalence of vulvovaginal candidiasis, trichomoniasis and bacterial vaginosis among pregnant women receiving antenatal care in Southwestern Nigeria. AB - Vaginal infections in pregnancy are associated with considerable discomfort and adverse pregnancy outcomes including preterm delivery, low birth weight and increased infant mortality and also predisposition to HIV/AIDS. This study evaluated the prevalence and factors associated with vulvovaginal candidiasis, trichomoniasis and bacterial vaginosis among women attending antenatal clinic at a hospital in Nigeria. A semi-structured questionnaire was administered and high vaginal swab samples were obtained from consenting pregnant women. The samples were processed following standard protocols. The prevalence of vulvovaginal candidiasis was 36%, while those of trichomoniasis and bacterial vaginosis were 2% and 38%, respectively. Infections were higher in the third trimester and many women admitted to practices that increase risk of these infections. Significant association was found between recent intake of antibiotics and vaginal candidiasis, same association was also found with bacterial vaginosis. Adequate investigation and prompt treatment will reduce the morbidity and attendant effects of these prevalent infections on mother and fetus. PMID- 25544892 TI - Pseudomonas infection in antibody deficient patients. AB - Pseudomonas aeruginosa (PA) is commonly isolated from the respiratory secretions of antibody deficiency patients, but the significance of this has not been well studied. We have reviewed our adult antibody deficiency cohort of 179 patients and assessed the prevalence and characteristics of PA infection and the effects of early antibiotic eradication treatments. Of the 34 patients with PA, 55.9% (19) underwent successful eradication and were infection-free, 38.2% (13) had intermittent infection, and 5.9% (2) had chronic PA. PA infection was significantly associated with bronchiectasis (p < 0.0001), with 36.1% (22 out of 61) of patients with bronchiectasis developing a PA infection. Infection status was also significantly associated with chronic sinusitis (p < 0.0001). Most treated PA exacerbations were symptomatic and with colony counts of >=1000 cfu/ml. Current eradication protocols used at our center involve early treatment at first positive isolate with ciprofloxacin for 3 weeks and nebulized colomycin for 3 months, and if eradication fails, intravenous ceftazidime and gentamycin or colomycin is administered for 2 weeks. Continued sputum surveillance and early eradication treatments upon positive PA culture may help to limit chronic PA infection in antibody deficiency patients. PMID- 25544893 TI - Saponins increase susceptibility of vancomycin-resistant enterococci to antibiotic compounds. AB - The resistance of commensal bacteria to first and second line antibiotics has reached an alarming level in many parts of the world and endangers the effective treatment of infectious diseases. In this study, the influence of the plant derived natural saponins glycyrrhizic acid, beta-aescin, alpha-hederin, hederacoside C, and primulic acid 1 on the susceptibility of vancomycin-resistant enterococci (VRE) against antibiotics of clinical relevance was investigated in 20 clinical isolates. Furthermore, the antibacterial properties of saponins under study against VRE were determined in vitro. Results reveal that the susceptibility of VRE against gentamicin, teicoplanin, and daptomycin was enhanced in the presence of the saponin glycyrrhizic acid. Most importantly, glycyrrhizic acid (1 mg/ml) diminished the minimal inhibitory concentration (MIC) of gentamicin in gentamicin low-level intrinsic resistant VRE from 2 - >8 mg/l to <= 0.125-1 mg/l. The adding of beta-aescin, alpha-hederin, hederacoside C, and primulic acid 1 to the antibiotics under study showed, compared to glycyrrhizic acid, less influence on the antibiotic potency. Only glycyrrhizic acid (1 mg/ml) and alpha-hederin (0.2 mg/ml) showed weak antibacterial properties against the clinical isolates. Our study points towards a therapeutic potential of saponins in the coapplication with antibiotics for bacterial infections. PMID- 25544894 TI - Selective gelatinase inhibition reduces apoptosis and pro-inflammatory immune cell responses in Campylobacter jejuni-infected gnotobiotic IL-10 deficient mice. AB - Increased levels of the matrix metalloproteinases-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in intestinal inflammation. We have recently shown that selective gelatinase blockage by the synthetic compound RO28-2653 ameliorates acute murine ileitis and colitis. We here investigated whether RO28-2653 exerts anti-inflammatory effects in acute Campylobacter jejuni induced enterocolitis of gnotobiotic IL-10(-/-) mice generated following antibiotic treatment. Mice were perorally infected with C. jejuni (day 0) and either treated with RO28-2653 (75 mg/kg body weight/day) or placebo from day 1 until day 6 post infection (p.i.) by gavage. Irrespective of the treatment, infected mice displayed comparable pathogen loads within the gastrointestinal tract. Following RO28-2653 administration, however, infected mice exhibited less severe symptoms such as bloody diarrhea as compared to placebo controls. Furthermore, less distinct apoptosis but higher numbers of proliferating cells could be detected in the colon of RO28-2653-treated as compared to placebo treated mice at day 7 p.i. Remarkably, gelatinase blockage resulted in lower numbers of T- and B-lymphocytes as well as macrophages and monocytes in the colonic mucosa of C. jejuni-infected gnotobiotic IL-10(-/-) mice. Taken together, synthetic gelatinase inhibition exerts anti-inflammatory effects in experimental campylobacteriosis. PMID- 25544896 TI - Bilateral obturator hernia diagnosed by computed tomography: a case report with review of the literature. AB - Obturator hernia is a rare form of abdominal hernia and a diagnostic challenge. It is commonly seen in elderly thin females. Its diagnosis is often delayed with resultant increased morbidity and mortality due to bowel ischemia/gangrene. It is mistakenly diagnosed as femoral or inguinal hernia on USG. Computed tomography is diagnostic and is a valuable tool for preoperative diagnosis. This report presents a case of 70-year-old thin female presenting with intestinal obstruction due to left sided obstructed obturator hernia. USG showed small bowel obstruction and an obstructed left sided femoral hernia. CT scan of abdomen and pelvis with inguinal and upper thigh region disclosed left sided obturator hernia. It also detected clinically occult right sided obturator hernia. Early diagnosis and surgical treatment contribute greatly in reducing the morbidity and mortality rate. PMID- 25544895 TI - Macular findings obtained by spectral domain optical coherence tomography in retinopathy of prematurity. AB - Purpose. To examine the macular findings obtained with spectral domain optical coherence tomography (SD OCT) in infants with retinopathy of prematurity (ROP). Materials and Methods. The macular SD OCT images of 190 premature infants were analyzed. Data regarding central foveal thickness (CFT), cystoid macular edema (CME), and cyst grading were compared. The relationships of CFT with gestational age and birth weight were investigated. Results. The results were obtained from 358 eyes of 179 infants (81 females and 98 males) of a mean gestational age of 30.9 +/- 2.7 weeks and a mean birth weight of 1609 +/- 477 g. ROP was diagnosed in 126 eyes and CME in 139 eyes. A significantly greater percentage of eyes with ROP were found to have CME (54%) compared to eyes without ROP (31%; P = 0.001). The incidence of CME was 46.3% for stage 1 ROP, 57.1% for stage 2, and 87.5% for stage 3. There was a weakly inverse correlation between CFT, gestational age, and birth weight (P = 0.025, r = -0.227; P = 0.002, r = -0.182, resp., Spearman correlation test). Conclusions. High-quality SD OCT images can be obtained from premature infants using the iVue system. Severity and frequency of CME in premature infants increase as stage of ROP increases. PMID- 25544897 TI - Antiatherosclerotic and Cardioprotective Potential of Acacia senegal Seeds in Diet-Induced Atherosclerosis in Rabbits. AB - Acacia senegal L. (Fabaceae) seeds are essential ingredient of "Pachkutta," a specific Rajasthani traditional food. The present study explored antiatherosclerotic and cardioprotective potential of Acacia senegal seed extract, if any, in hypercholesterolemic diet-induced atherosclerosis in rabbits. Atherosclerosis in rabbits was induced by feeding normal diet supplemented with oral administration of cholesterol (500 mg/kg body weight/day mixed with coconut oil) for 15 days. Circulating total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), triglycerides, and VLDL-cholesterol (VLDL-C) levels; atherogenic index (AI); cardiac lipid peroxidation (LPO); planimetric studies of aortal wall; and histopathological studies of heart, aorta, kidney, and liver were performed. Apart from reduced atherosclerotic plaques in aorta (6.34 +/- 0.72) and increased lumen volume (51.65 +/- 3.66), administration with ethanolic extract of Acacia senegal seeds (500 mg/kg/day, p.o.) for 45 days to atherosclerotic rabbits significantly lowered serum TC, LDL-C, triglyceride, and VLDL-C levels and atherogenic index as compared to control. Atherogenic diet induced cardiac LPO and histopathological abnormalities in aorta wall, heart, kidney, and liver were reverted to normalcy by Acacia senegal seed extract administration. The findings of the present study reveal that Acacia senegal seed extract ameliorated diet-induced atherosclerosis and could be considered as lead in the development of novel therapeutics. PMID- 25544898 TI - Utility of Intraoperative Neuromonitoring during Minimally Invasive Fusion of the Sacroiliac Joint. AB - Study Design. Retrospective case series. Objective. To document the clinical utility of intraoperative neuromonitoring during minimally invasive surgical sacroiliac joint fusion for patients diagnosed with sacroiliac joint dysfunction (as a direct result of sacroiliac joint disruptions or degenerative sacroiliitis) and determine stimulated electromyography thresholds reflective of favorable implant position. Summary of Background Data. Intraoperative neuromonitoring is a well-accepted adjunct to minimally invasive pedicle screw placement. The utility of intraoperative neuromonitoring during minimally invasive surgical sacroiliac joint fusion using a series of triangular, titanium porous plasma coated implants has not been evaluated. Methods. A medical chart review of consecutive patients treated with minimally invasive surgical sacroiliac joint fusion was undertaken at a single center. Baseline patient demographics and medical history, intraoperative electromyography thresholds, and perioperative adverse events were collected after obtaining IRB approval. Results. 111 implants were placed in 37 patients. Sensitivity of EMG was 80% and specificity was 97%. Intraoperative neuromonitoring potentially avoided neurologic sequelae as a result of improper positioning in 7% of implants. Conclusions. The results of this study suggest that intraoperative neuromonitoring may be a useful adjunct to minimally invasive surgical sacroiliac joint fusion in avoiding nerve injury during implant placement. PMID- 25544899 TI - Hindfoot Valgus following Interlocking Nail Treatment for Tibial Diaphysis Fractures: Can the Fibula Be Neglected? AB - Purpose. We evaluated whether intramedullary nail fixation for tibial diaphysis fractures with concomitant fibula fractures (except at the distal one-third level) managed conservatively with an associated fibula fracture resulted in ankle deformity and assessed the impact of the ankle deformity on lower extremity function. Methods. Sixty middle one-third tibial shaft fractures with associated fibular fractures, except the distal one-third level, were included in this study. All tibial shaft fractures were anatomically reduced and fixed with interlocking intramedullary nails. Fibular fractures were managed conservatively. Hindfoot alignment was assessed clinically. Tibia and fibular lengths were compared to contralateral measurements using radiographs. Functional results were evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Foot and Ankle Disability Index Score (FADI). Results. Anatomic union, defined as equal length in operative and contralateral tibias, was achieved in 60 fractures (100%). Fibular shortening was identified in 42 fractures (68%). Mean fibular shortening was 1.2 cm (range, 0.5-2 cm). Clinical exams showed increased hindfoot valgus in 42 fractures (68%). The mean KOOS was 88.4, and the mean FADI score was 90. Conclusion. Fibular fractures in the middle or proximal one-third may need to be stabilized at the time of tibial intramedullary nail fixation to prevent development of hindfoot valgus due to fibular shortening. PMID- 25544901 TI - Early Implementation of THAM for ICP Control: Therapeutic Hypothermia Avoidance and Reduction in Hypertonics/Hyperosmotics. AB - Background. Tromethamine (THAM) has been demonstrated to reduce intracranial pressure (ICP). Early consideration for THAM may reduce the need for other measures for ICP control. Objective. To describe 4 cases of early THAM therapy for ICP control and highlight the potential to avoid TH and paralytics and achieve reduction in sedation and hypertonic/hyperosmotic agent requirements. Methods. We reviewed the charts of 4 patients treated with early THAM for ICP control. Results. We identified 2 patients with aneurysmal subarachnoid hemorrhage (SAH) and 2 with traumatic brain injury (TBI) receiving early THAM for ICP control. The mean time to initiation of THAM therapy was 1.8 days, with a mean duration of 5.3 days. In all patients, after 6 to 12 hours of THAM administration, ICP stability was achieved, with reduction in requirements for hypertonic saline and hyperosmotic agents. There was a relative reduction in mean hourly hypertonic saline requirements of 89.1%, 96.1%, 82.4%, and 97.0% for cases 1, 2, 3, and 4, respectively, comparing pre- to post-THAM administration. Mannitol, therapeutic hypothermia, and paralytics were avoided in all patients. Conclusions. Early administration of THAM for ICP control could potentially lead to the avoidance of other ICP directed therapies. Prospective studies of early THAM administration are warranted. PMID- 25544900 TI - Recovery of olfactory function induces neuroplasticity effects in patients with smell loss. AB - The plasticity of brain function, especially reorganization after stroke or sensory loss, has been investigated extensively. Based upon its special characteristics, the olfactory system allows the investigation of functional networks in patients with smell loss, as it holds the unique ability to be activated by the sensorimotor act of sniffing, without the presentation of an odor. In the present study, subjects with chronic peripheral smell loss and healthy controls were investigated using functional magnetic resonance imaging (fMRI) to compare functional networks in one of the major olfactory areas before and after an olfactory training program. Data analysis revealed that olfactory training induced alterations in functional connectivity networks. Thus, olfactory training is capable of inducing neural reorganization processes. Furthermore, these findings provide evidence for the underlying neural mechanisms of olfactory training. PMID- 25544903 TI - Comprehensive orthodontic treatment of adult patient with cleft lip and palate. AB - The aim of the paper is to present full orthodontic treatment of an operated cleft lip adult patient. Case Report. An 18-year-old patient consulted for severe crowded teeth. He comes from a poor family. At that time he already had four operations (velum, palate, lip, and myringotomy). Treatment included maxillary expansion, tooth extraction, and fixed orthodontic, as well as kinesiology and speech therapy treatment. A multidisciplinary approach allowed us to achieve successfully an excellent result for this patient and gave him a harmonic smile and an optimal function without orthognathic surgery. Two years after treatment, occlusion remains stable. PMID- 25544902 TI - Systemic capillary leak syndrome: is methylene blue the silver bullet? AB - Background. Systemic capillary leak syndrome (SCLS) is a rare disorder characterized by unexplained, recurrent episodes of transient, abrupt increase in endothelial permeability, leading to severe hypotension, generalized edema, and hemoconcentration. Case Report. We report the case of a patient suffering from systemic capillary leak syndrome and present a possible interpretation of the pathophysiology of this condition. Besides the classical triad of hypotension, edema, and hemoconcentration, we recorded increased levels of methemoglobin, an index of NO overproduction. We present a possible interpretation of the pathophysiology of this condition based on the fast and complete reversal of symptoms after methylene blue administration (which opposes NO-induced effects) and speculate that increased NO levels could be implicated in the pathophysiology of the capillary leak phase. Why should an emergency physician be aware of this? The safety of this treatment and its fluid- and cathecolamine-sparing effect deserve consideration and further research. PMID- 25544904 TI - What Lies behind the Ischemic Stroke: Aortic Dissection? AB - Introduction. Some cases with aortic dissection (AD) could present with various complaints other than pain, especially neurological and cardiovascular manifestations. AD involving the carotid arteries could be associated with many clinical presentations, ranging from stroke to nonspecific headache. Case Report. A 71-year-old woman was admitted to emergency department with vertigo which started within the previous one hour and progressed with deterioration of consciousness following speech disorder. On arrival, she was disoriented and uncooperative. Diffusion magnetic resonance imaging (MRI) of brain was consistent with acute ischemia in the cerebral hemisphere. Fibrinolytic treatment has been planned since symptoms started within two hours. Echocardiography has shown the dilatation of ascending aorta with a suspicion of flap. Computed tomography (CT) angiography has been applied and intimal flap has been detected which was consistent with aortic dissection, intramural hematoma of which was reaching from aortic arch to bilateral common carotid artery. Thereafter, treatment strategy has completely changed and surgical invention has been done. Conclusion. In patients who are admitted to the emergency department with the loss of consciousness and stroke, inadequacy of anamnesis and carotid artery involvement of aortic dissection should be kept in mind. PMID- 25544905 TI - Histamine poisoning from ingestion of fish or scombroid syndrome. AB - The scombroid poisoning is due to the ingestion of poorly preserved fish (especially tuna, sardines, and mackerel) out of the cold chain. Under the influence of the proliferation of gram negative bacteria that occurs for heating, the histidine content in the muscle of the fish is converted into histamine, by the action of the enzyme histidine decarboxylase. If the histamine is ingested in large quantities, it causes an anaphylactoid reaction with a variety of symptoms from moderate to severe to life-threating. We will describe two cases that came under our observation after consuming a meal of bluefin tuna. The diagnosis of scombroid syndrome was made on the basis of the anamnestic data and the clinical one. The rapid resolution of the signs and symptoms after treatment with histamines H1-H2 receptor blockers confirmed the suspected diagnosis. PMID- 25544906 TI - A Pregnant Woman Who Underwent Laparoscopic Adrenalectomy due to Cushing's Syndrome. AB - Cushing's syndrome (CS) may lead to severe maternal and fetal morbidities and even mortalities in pregnancy. However, pregnancy complicates the diagnosis and treatment of CS. This study describes a 26-year-old pregnant woman admitted with hypertension-induced headache. Hormonal analyses performed due to her cushingoid phenotype revealed a diagnosis of adrenocorticotropic hormone- (ACTH-) independent CS. MRI showed a 3.5 cm adenoma in her right adrenal gland. After preoperative metyrapone therapy, she underwent a successful unilateral laparoscopic adrenalectomy at 14-week gestation. Although she had a temporary postoperative adrenal insufficiency, hormonal analyses showed that she has been in remission since delivery. Findings in this patient, as well as those in previous patients, indicate that pregnancy is not an absolute contraindication for laparoscopic adrenalectomy. Rather, such surgery should be considered a safe and efficient treatment method for pregnant women with cortisol-secreting adrenal adenomas. PMID- 25544907 TI - Epigenetic alterations in a gastric leiomyoma. AB - Leiomyomas constitute 2.5% of all resected neoplasms of the stomach. They are usually asymptomatic, but may present mucosal ulceration. Aberrant DNA methylation is a well-defined epigenetic change in human neoplasms; however, gene acquired methylation may not necessarily be related with a malignant phenotype. In this report we analyzed in a gastric leiomyoma, the methylation status of 84 CpGI in tumor suppressor and DNA repair genes. We analyzed the tumor center (TC) and tumor periphery (TP) separately. We found aberrant methylation in 2/84 CpGI in the TC portion, that is, MLH1 and MSH3, and 5/84 CpGI in the TP, that is, MLH1, MSH3, APC, MSH6, and MGMT. The gene with the highest methylation percentage in the TC and TP was MLH1. Given that MLH1 methylation has been associated with microsatellite instability, we analyzed the status of the microsatellite Bat-26. We found that neither the TC nor the TP presented instability. The methylation of MLH1, MGMT, and APC has been described in GISTs, but to the best of our knowledge this is the first time that the methylation of these genes has been associated with gastric leiomyoma. Further research should be conducted to identify reliable molecular markers that could differentiate between GISTs and gastric leiomyomas. PMID- 25544908 TI - Appendiceal diverticulitis clinically masquerading as an appendiceal carcinoma. AB - Appendiceal diverticulosis is a rare condition. Herein reported is a case of appendiceal diverticulosis and diverticulitis clinically masquerading as appendiceal carcinoma. A 62-year-old woman presented with abdominal pain. US and CT showed a tumor measuring 5 * 4 * 4 cm in vermiform appendix. Colon endoscopy showed mucosal elevation and irregularity in the orifice of vermiform appendix. A biopsy of the appendiceal mucosa showed no significant changes. Clinical diagnosis was appendiceal carcinoma and wide excision of terminal ileum, appendix, cecum, and ascending colon was performed. Grossly, the appendix showed a tumor measuring 5 * 3 * 4 cm. The appendiceal lumen was opened, and the appendiceal mucosa was elevated and irregular. The periappendiceal tissue showed thickening. Microscopically, the lesion was multiple appendiceal diverticula. The diverticula were penetrating the muscle layer. The mucosa showed erosions in places. Much fibrosis, abscess formations, and lymphocytic infiltration were seen in the subserosa. Abscesses were also seen in the diverticular lumens. Some diverticula penetrated into the subserosa. The pathologic diagnosis was appendiceal diverticulitis. When they encounter an appendiceal mass, clinicians should consider appendiceal diverticulitis as a differential diagnosis. PMID- 25544909 TI - Acquired Von Willebrand's Syndrome in Systemic Lupus Erythematosus. AB - Acquired von Willebrand syndrome (AVWS) is an uncommon, underdiagnosed, and heterogeneous disease which is increasingly recognized as a cause of bleeding diatheses. Systemic lupus erythematosus (SLE) is an infrequent cause of AVWS. Herein, we report a case of AVWS diagnosed during the initial presentation of SLE in a previously healthy young man with no family history of bleeding diathesis who presented with worsening epistaxis, gastrointestinal bleeding, and anasarca. He was found to have severe anemia and prolonged activated partial thromboplastin time (aPTT) with severely decreased levels of von Willebrand factor (VWF) measurements in addition to markedly decreased factor VIII levels. Further evaluation revealed nephrotic syndrome and interstitial lung disease due to SLE. He initially received combination therapy with intravenous immunoglobulin (IVIG) and von Willebrand factor/factor VIII concentrates without significant improvement. Treatment with steroids, cyclophosphamide, and rituximab was followed by clinical improvement evidenced by cessation of bleeding. The short follow-up did not allow us to definitely prove the therapeutic effect of immunosuppressive treatment on AVWS in SLE patients. This case adds to the literature supporting the relationship between AVWS and SLE and highlights the importance of combination therapy in the treatment of severe AVWS as well as the role of IVIG, cyclophosphamide, and rituximab in AVWS associated with SLE. PMID- 25544910 TI - Follicular lymphoma presenting with leptomeningeal disease. AB - Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Central nervous system metastasis is a very rare complication portending a very poor prognosis. We report a rare case of follicular lymphoma presenting with leptomeningeal involvement achieving a complete remission after initial therapy. PMID- 25544911 TI - Periodic Fever and Neutrophilic Dermatosis: Is It Sweet's Syndrome? AB - A 7-year-old boy with high grade fever (39 degrees C) and warm, erythematous, and indurated plaque above the left knee was referred. According to the previous records of this patient, these indurated plaques had been changed toward abscesses formation and then spontaneous drainage had occurred after about 6 to 7 days, and finally these lesions healed with scars. In multiple previous admissions, high grade fever, leukocytosis, and a noticeable increase in erythrocyte sedimentation rate and C-reactive protein were noted. After that, until 7th year of age, he had shoulder, gluteal, splenic, kidney, and left thigh lesions and pneumonia. The methylprednisolone pulse (30 mg/kg) was initiated with the diagnosis of Sweet's syndrome. After about 10-14 days, almost all of the laboratory data regressed to nearly normal limits. After about 5 months, he was admitted again with tachypnea and high grade fever and leukocytosis. After infusion of one methylprednisolone pulse, the fever and tachypnea resolved rapidly in about 24 hours. In this admission, colchicine (1 mg/kg) was added to the oral prednisolone after discharge. In the periodic fever and neutrophilic dermatosis, the rheumatologist should search for sterile abscesses in other organs. PMID- 25544912 TI - Cotreatment of congenital measles with vitamin a and intravenous immunoglobulin. AB - Although the measles vaccine has been part of routine national childhood vaccination programs throughout Europe, measles remains a public health concern. High numbers of cases and outbreaks have occurred throughout the European continent since 2011, and an increasing number of cases have been reported in Turkey since 2012. During a recent measles outbreak in Turkey, 2 pregnant women contracted measles prior to delivering preterm infants at Hacettepe University Hospital. Measles virus genomic RNA and IgM antibodies against measles were detected in the cord blood of infants and mothers in both cases. The infants were treated with intravenous immunoglobulin (IVIG) and vitamin A. Transient thrombocytopenia was present in 1 infant and treated with an additional dose of IVIG and vitamin A. The infants were discharged, without complications, within 10 days of birth. The successful treatment of these cases suggests that infants who have been exposed to, or infected with, measles may benefit from cotreatment of vitamin A and IVIG. PMID- 25544913 TI - Mycobacterium avium Complex Infection in a Patient with Sickle Cell Disease and Severe Iron Overload. AB - A 34-year-old female with sickle cell anemia (hemoglobin SS disease) and severe iron overload presented to our institution with the subacute presentation of recurrent pain crisis, fever of unknown origin, pancytopenia, and weight loss. A CT scan demonstrated both lung and liver nodules concerning for granulomatous disease. Subsequent biopsies of the liver and bone marrow confirmed the presence of noncaseating granulomas and blood cultures isolated Mycobacterium avium complex MAC. Disseminated MAC is considered an opportunistic infection typically diagnosed in the immunocompromised and rarely in immunocompetent patients. An appreciable number of mycobacterial infection cases have been reported in sickle cell disease patients without immune dysfunction. It has been reported that iron overload is known to increase the risk for mycobacterial infection in vitro and in vivo studies. While iron overload is primarily known to cause end organ dysfunction, the clinical relationship with sickle cell disease and disseminated MAC infection has not been reported. Clinical iron overload is a common condition diagnosed in the sub-Saharan African population. High dietary iron, genetic defects in iron trafficking, as well as hemoglobinopathy are believed to be the etiologies for iron overload in this region. Patients with iron overload in this region were 17-fold more likely to die from Mycobacterium tuberculosis. Both experimental and clinical evidence suggest a possible link to iron overload and mycobacterial infections; however larger observational studies are necessary to determine true causality. PMID- 25544914 TI - Gemella morbillorum Endocarditis. AB - Infective endocarditis caused by Gemella morbillorum is a rare disease. In this report 67-year-old male patient with G. morbillorum endocarditis was presented. The patient was hospitalized as he had a fever of unknown origin and in the two of the three sets of blood cultures taken at the first day of hospitalization G. morbillorum was identified. The transthoracic echogram revealed 14 * 10 mm vegetation on the aortic noncoronary cuspis. After 4 weeks of antibiotic therapy, the case was referred to the clinic of cardiovascular surgery for valve surgery. PMID- 25544915 TI - Ceftriaxone-induced acute encephalopathy in a peritoneal dialysis patient. AB - Encephalopathy is a rare side effect of third and fourth generation cephalosporins. Renal failure and preexisting neurological disease are notable risk factors. Recognition is important as discontinuing the offending agent usually resolves symptoms. We present a case of acute encephalopathy in a patient with end stage renal disease (ESRD) treated with peritoneal dialysis (PD) who received intravenous ceftriaxone for peritonitis. This case illustrates the potential severe neurologic effects of cephalosporins, which are recommended by international guidelines as first-line antimicrobial therapy for spontaneous bacterial peritonitis. PMID- 25544916 TI - Intraventricular hemorrhage after epidural blood patching: an unusual complication. AB - The authors present two cases of intraventricular hemorrhage (IVH) believed to be a result of epidural blood patching. The first was a 71-year-old woman who had new onset of nontraumatic IVH on computed tomography (CT) scan after undergoing an epidural blood patch (EBP). This amount of intraventricular blood was deemed an incidental finding since it was of very small volume to account for her overall symptoms. The second patient, a 29-year-old woman, was found to have nontraumatic IVH three days after undergoing an EBP. This was seen on CT scan of the head for workup of pressure-like headaches, nausea, vomiting, and absence seizures. Conservative management was followed in both instances. Serial CT scan of the head in our first patient displayed complete resolution of her IVH. The second patient did not have follow-up CT scans because her overall clinical picture had improved significantly. This highlights a potential sequel of EBP that may be observed on CT scan of the head. In the event that IVH is detected, signs and symptoms of hydrocephalus should be closely monitored with the consideration for a future workup if warranted by the clinical picture. PMID- 25544917 TI - Malouf syndrome with hypergonadotropic hypogonadism and cardiomyopathy: two-case report and literature review. AB - Malouf syndrome is a very rarely encountered syndrome which was first diagnosed in 1985 upon the examination of two sisters, with findings of hypergonadotropic hypogonadism, dilated cardiomyopathy, blepharoptosis, and broad nasal base. Later on, Narahara diagnosed another sporadic case with the same findings. A survey of relevant literature leads us to three women cases in total. Here we present two cases of Malouf syndrome and literature review. PMID- 25544918 TI - A case of placenta increta mimicking submucous leiomyoma. AB - In recent years with the increase in cesarean section rates, the frequency of placenta accreta cases rises. It causes 33-50% of all emergency peripartum hysterectomies. We present a 42-year-old case who was caught with early postpartum hemorrhage due to retained placental products. The ultrasonography showed a 65 * 84 mm mass in the uterine cavity after the delivery. Due to presence of early postpartum hemorrhage which needs transfusion, an intervention decision was made. The patient underwent curettage but the mass could not be removed so that placental retention was ruled out. Submucous leiomyoma was made as first-prediagnosis. Hysterectomy operation was performed as a curative treatment. Placenta increta diagnosis was made as a final diagnosis with pathological examination. As a result, placental attachment disorders may be overlooked if it is not a placenta previa case. PMID- 25544919 TI - A Case of Abruptio Placentae due to the Torsion of Gravid Uterus. AB - Torsion of a gravid uterus is a rare obstetric emergency potentially lethal for the fetus and the mother. Some of the cases described in literature are associated with preexisting gynecologic conditions related to pelvic and uterine anatomy, even if most of cases remain unexplained. We report a case of acute 180 degree torsion of uterus at 33 weeks of gestation associated with abruptio placentae in a young Asian woman without apparent risk factors. PMID- 25544920 TI - A case of multiple myeloma with metachronous chronic myeloid leukemia treated successfully with bortezomib, dexamethasone, and dasatinib. AB - The coexistence of multiple myeloma and chronic myeloid leukemia in a single patient is a very rare event that has been reported very infrequently in the literature. We report a case of a patient who developed chronic myeloid leukemia four years after his diagnosis with multiple myeloma. Historically, no link between the two malignancies has been identified. This synchronous existence complicates the treatment plan for these patients, and there is a lack of evidence on the best therapeutic approach. Our patient was successfully treated with a combination of bortezomib, dexamethasone, and dasatinib, which he tolerated well for eleven months until he eventually succumbed to cardiac complications and pulmonary hypertension leading to his death. PMID- 25544921 TI - Case report of optic disc drusen with simultaneous peripapillary subretinal hemorrhage and central retinal vein occlusion. AB - A 52-year-old Chinese gentleman presented with right eye floaters and photopsia over one week. His visual acuities were 20/20 bilaterally. Posterior segment examination showed a right eye swollen optic disc and central retinal vein occlusion (CRVO) associated with an area of subretinal hemorrhage adjacent to the optic disc. Fundus fluorescein (FA) and indocyanine green angiographies (ICGA) of the right eye did not demonstrate choroidal neovascularization (CNV), polypoidal choroidal vasculopathy (PCV), or retinal ischemia. Ultrasound B-scan revealed optic disc drusen (ODD). In view of good vision and absence of CNV, he was managed conservatively with spontaneous resolution after two months. Commonly, ODD may directly compress and mechanically rupture subretinal vessels at the optic disc, resulting in peripapillary subretinal hemorrhage, as was likely the case in our patient. Mechanical impairment of peripapillary circulation also results in retinal ischemia and may trigger the development of choroidal neovascularization (CNV) and/or polypoidal choroidal vasculopathy (PCV), leading to subretinal haemorrhage. Compromise in central venous outflow with increased retinal central venous pressure from the direct mechanical effects of enlarging ODD results in central retinal vein occlusion (CRVO). Patients with subretinal hemorrhage and CRVO from ODD should be monitored closely for the development of potentially sight-threatening complications. PMID- 25544922 TI - Vertebral Osteomyelitis Caused by Mycobacterium abscessus Surgically Treated Using Antibacterial Iodine-Supported Instrumentation. AB - Mycobacterium abscessus infections rarely develop in healthy individuals, and mostly they occur in immunocompromised hosts. Vertebral osteomyelitis due to Mycobacterium abscessus is very rare and only three previous cases of spinal infection caused by Mycobacterium abscessus have been reported. Mycobacterium abscessus isolates are uniformly resistant to antituberculous agents and can display a virulent biofilm-forming phenotype. The patient was a 67-year-old woman with vertebral osteomyelitis of the L1-2. She was healthy without immune suppressed condition, history of trauma, or intravenous drug use. The smear examination of the specimen harvested by CT-guided puncture of the paravertebral abscess revealed Mycobacterium abscessus. Her disease condition did not abate with conservative treatment using antimicrobial chemotherapy. Radical debridement of the vertebral osteomyelitis and anterior reconstruction from T12 to L2 using antibacterial iodine-supported instrumentation were performed. Chemotherapy using clarithromycin, amikacin, and imipenem was applied for 6 months after surgery as these antibiotics had been proven to be effective to Mycobacterium abscessus after surgery. Two years after surgery, the infected anterior site healed and bony fusion was successfully achieved without a recurrence of infection. PMID- 25544923 TI - Distal Clavicle Osteolysis after Modified Weaver-Dunn's Procedure for Chronic Acromioclavicular Dislocation: A Case Report and Review of Complications. AB - Distal clavicle osteolysis after acromioclavicular joint stabilization has only been described after the use of hardware for clavicle stabilization or synthetic graft causing a foreign body reaction. This paper reports a very rare case of distal clavicle osteolysis after modified Weaver-Dunn procedure for the treatment of chronic acromioclavicular joint dislocation. The paper also provides a comprehensive review of complications of this surgical technique and discusses a potential vascular etiology and preventive strategies aimed at avoiding clavicle osteolysis. PMID- 25544924 TI - A rare case of splenic marginal zone B-cell lymphoma mimicking relapsing polychondritis of the ear. AB - Relapsing polychondritis (RPC) is a poorly understood phenomenon associated with cartilaginous inflammation of the ear, nose, tracheobronchial tree, and peripheral joints. Many cases of RPC respond to anti-inflammatories and resolve with no further complications. However, RPC has also been linked to more insidious conditions such as malignancies, autoimmune disorders, vasculitis, or underlying infections. Given the spectrum of associated disorders, patients with RPC may need to be monitored for more insidious underlying conditions. In this case, we report a unique case of bilateral auricular inflammation and nasal inflammation mimicking RPC as the only presenting symptom of splenic marginal zone B-cell lymphoma and we survey related cases in the literature. PMID- 25544925 TI - Bilateral diffuse tumorous pseudoangiomatous stromal hyperplasia: a case of bilateral mastectomy in a 29-year-old woman. AB - Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast lesion commonly encountered as an incidental microscopic finding. However, it can also manifest as a mass-forming lesion (tumorous PASH) capable of recurrence after surgical excision. Most of the previously reported cases of tumorous PASH present as a single dominant mass. Here we reported a rare case of diffuse tumorous PASH involving bilateral breasts clinically mimicking malignancy. A 29-year-old African-American female presented with a one-year history of bilateral breast enlargement and asymmetry. Physical examination revealed multiple palpable nodules in bilateral breasts. Imaging studies demonstrated innumerable homogeneously enhancing masses throughout both breasts, greater on the left, with multiple cysts and edema. Biopsy of the breast nodules demonstrated histopathological changes consistent with PASH. Due to the extent of the lesions and progressive clinical symptoms, decision was made to perform bilateral mastectomy. Macroscopic examination of the bilateral mastectomy specimens revealed markedly enlarged breasts with marked edema and numerous well-defined firm nodules. Microscopic evaluation of the nodules confirmed the diagnosis of PASH. No evidence of malignancy was identified. Recognition of this rare form of PASH is essential for the proper clinical management. PMID- 25544926 TI - Myasthenia Gravis following Low-Osmolality Iodinated Contrast Media. AB - We describe the case of 79-year-old man admitted to our general hospital for a 6 week history of progressive dysphagia to solids and liquids associated with weight loss. To reach a diagnosis a total body CT scan with low-osmolality iodinate contrast agent was performed. Two hours later the patient developed an acute respiratory failure requiring orotracheal intubation and mechanical ventilation. The laboratory and neurological tests allow formulating the diagnosis of myasthenia gravis. In literature, other three case reports have associated myasthenic crisis with exposure to low-osmolality contrast media. This suggests being careful in administering low-osmolality contrast media in myasthenic patients. PMID- 25544927 TI - Sentinel bleeding as a sign of gastroaortic fistula formation after oesophageal surgery. AB - Gastroaortic fistula formation is a very rare complication following oesophageal resection and, in most cases, leads to sudden death. We report the case of a 65 year-old male with an adenocarcinoma of the oesophagus who underwent neoadjuvant chemoradiation followed by a minimally invasive transthoracic oesophagectomy with gastric tube reconstruction and intrathoracic anastomosis. After an uneventful postoperative course and hospital discharge, the patient reported blood regurgitation on postoperative day 23. Endoscopy revealed an adherent blood clot on the oesophageal wall, which after dislocation caused exsanguination. Autopsy determined the cause of death being massive haemorrhage due to a gastroaortic fistula. The sudden onset of haemorrhage makes this condition particularly difficult to treat. Recognition of warning signs such as thoracic or epigastric pain, regurgitation of blood, or the passing of bloody stools or melena is crucial in the early detection of fistula and may improve patient outcome. PMID- 25544928 TI - Kimura disease manifesting as synchronous bilateral parotid swelling in a young middle-eastern patient. AB - Kimura disease is a rare, benign, chronic inflammatory swelling of the subcutaneous tissue, lymph nodes, and glandular tissue. Characteristic features of the disease include, but not limited to, painless subcutaneous head and neck swelling, blood and tissue eosinophilia, and markedly elevated immunoglobulin E (IgE) levels. Herein, we report a rare case of Kimura disease manifesting as synchronous bilateral parotid swelling of 12 years duration in a 33-year-old Middle-Eastern man. To our knowledge only few cases have been reported in the literature involving bilateral parotid glands, and this is the first case to be reported in the Middle East. PMID- 25544929 TI - Renal Cell Carcinoma Metastasis from Biopsy Associated Hematoma Disruption during Robotic Partial Nephrectomy. AB - We describe a case in which a patient with a past medical history of ovarian cancer received a diagnostic renal biopsy for an incidentally discovered renal mass. During left robotic partial nephrectomy (RPN), a perinephric hematoma was encountered. The hematoma was not present on preoperative imaging and was likely a result of the renal biopsy. The renal cell carcinoma (RCC) and the associated hematoma were widely excised with negative surgical margins. On follow-up imaging at five months postoperatively, a recurrent renal mass at the surgical resection bed and several new nodules in the omentum were detected. During completion left robotic total nephrectomy and omental excision, intraoperative frozen sections confirmed metastatic RCC. We believe that a hematoma seeded with RCC formed as a result of the renal biopsy, and subsequent disruption of the hematoma during RPN caused contamination of RCC into the surrounding structures. PMID- 25544930 TI - Accidental Coverage of Both Renal Arteries during Infrarenal Aortic Stent-Graft Implantation: Cause and Treatment. AB - The purpose of this paper is to report a salvage maneuver for accidental coverage of both renal arteries during endovascular aneurysm repair (EVAR) of an infrarenal abdominal aortic aneurysm (AAA). A 72-year-old female with a 6 cm infrarenal abdominal aortic aneurysm was treated by endovascular means with a standard bifurcated graft. Upon completing an angiogram, both renal arteries were found to be accidentally occluded. Through a left percutaneous brachial approach, the right renal artery was catheterized and a chimney stent was deployed; however this was not possible for the left renal artery. A retroperitoneal surgical approach was therefore carried out with a retrograde chimney stent implanted to restore blood flow. After three months, both renal arteries were patent and renal function was not different from the baseline. Both endovascular with percutaneous access via the brachial artery and open retroperitoneal approaches with retrograde catheterization are feasible rescue techniques to recanalize the accidentally occluded renal arteries during EVAR. PMID- 25544931 TI - Exercise Hemodynamics and Quality of Life after Aortic Valve Replacement for Aortic Stenosis in the Elderly Using the Hancock II Bioprosthesis. AB - Background and Aim. While aortic valve replacement for aortic stenosis can be performed safely in elderly patients, there is a need for hemodynamic and quality of life evaluation to determine the value of aortic valve replacement in older patients who may have age-related activity limitation. Materials and Methods. We conducted a prospective evaluation of patients who underwent aortic valve replacement for aortic stenosis with the Hancock II porcine bioprosthesis. All patients underwent transthoracic echocardiography (TTE) and completed the RAND 36 Item Health Survey (SF-36) preoperatively and six months postoperatively. Results. From 2004 to 2007, 33 patients were enrolled with an average age of 75.3 +/- 5.3 years (24 men and 9 women). Preoperatively, 27/33 (82%) were New York Heart Association (NYHA) Functional Classification 3, and postoperatively 27/33 (82%) were NYHA Functional Classification 1. Patients had a mean predicted maximum V O2 (mL/kg/min) of 19.5 +/- 4.3 and an actual max V O2 of 15.5 +/- 3.9, which was 80% of the predicted V O2 . Patients were found to have significant improvements (P <= 0.01) in six of the nine SF-36 health parameters. Conclusions. In our sample of elderly patients with aortic stenosis, replacing the aortic valve with a Hancock II bioprosthesis resulted in improved hemodynamics and quality of life. PMID- 25544932 TI - Playing a Musical Instrument as a Protective Factor against Dementia and Cognitive Impairment: A Population-Based Twin Study. AB - Increasing evidence supports that playing a musical instrument may benefit cognitive development and health at young ages. Whether playing an instrument provides protection against dementia has not been established. In a population based cotwin control study, we examined the association between playing a musical instrument and whether or not the twins developed dementia or cognitive impairment. Participation in playing an instrument was taken from informant-based reports of twins' leisure activities. Dementia diagnoses were based on a complete clinical workup using standard diagnostic criteria. Among 157 twin pairs discordant for dementia and cognitive impairment, 27 pairs were discordant for playing an instrument. Controlling for sex, education, and physical activity, playing a musical instrument was significantly associated with less likelihood of dementia and cognitive impairment (odds ratio [OR] = 0.36 [95% confidence interval 0.13-0.99]). These findings support further consideration of music as a modifiable protective factor against dementia and cognitive impairment. PMID- 25544933 TI - Characteristic Fingerprint Based on Low Polar Constituents for Discrimination of Wolfiporia extensa according to Geographical Origin Using UV Spectroscopy and Chemometrics Methods. AB - The fungus species Wolfiporia extensa has a long history of medicinal usage and has also been commercially used to formulate nutraceuticals and functional foods in certain Asian countries. In the present study, a practical and promising method has been developed to discriminate the dried sclerotium of W. extensa collected from different geographical sites based on UV spectroscopy together with chemometrics methods. Characteristic fingerprint of low polar constituents of sample extracts that originated from chloroform has been obtained in the interval 250-400 nm. Chemometric pattern recognition methods such as partial least squares discriminant analysis (PLS-DA) and hierarchical cluster analysis (HCA) were applied to enhance the authenticity of discrimination of the specimens. The results showed that W. extensa samples were well classified according to their geographical origins. The proposed method can fully utilize diversified fingerprint characteristics of sclerotium of W. extensa and requires low-cost equipment and short-time analysis in comparison with other techniques. Meanwhile, this simple and efficient method may serve as a basis for the authentication of other medicinal fungi. PMID- 25544934 TI - Optimal conditions of mycelia growth of Laetiporus sulphureus sensu lato. AB - Laetiporus sulphureus is an edible wood-rotting basidiomycete, growing on decaying logs, stumps, and trunks of many deciduous and coniferous tree species. This fungus produces relatively large striking yellowish or orange-coloured bracket-like fruitbodies. L. sulphureus is widely consumed as a nutritional food because of its fragrance and texture. In this study, two L. sulphureus strains, MFLUCC 12-0546 and MFLUCC 12-0547, isolated from Chiang Rai, Thailand, were investigated for optimal conditions of mycelia growth. Potato dextrose agar and malt extract agar were observed as the favourable medium for mycelia growth. The optimum pH and temperature for the mushroom mycelia were 6-8 and 25-30 degrees C, respectively. PMID- 25544935 TI - Hymenoscyphus fraxineus vs. Hymenoscyphus albidus - A comparative light microscopic study on the causal agent of European ash dieback and related foliicolous, stroma-forming species. AB - Five species of Hymenoscyphus that fruit on black stromatized parts of dead leaves of deciduous trees are presented, giving details on their morphological and ecological characteristics. Several of these species have previously been misplaced in rutstroemiaceous genera because of the presence of a substratal stroma. However, the heteropolar, scutuloid ascospores with an often hook-like lateral protrusion at the rounded apex and the ascus apical ring of the Hymenoscyphus-type represent two reliable morphological characteristics that, together with molecular data, provide clear evidence for their placement in the genus Hymenoscyphus (Helotiaceae). Among the species treated is Hymenoscyphus fraxineus (=Hymenoscyphus pseudoalbidus), the causal agent of the European ash dieback disease. Since 1992 this species started within Europe to replace the rather uncommon Hymenoscyphus albidus, which is likewise confined to leaves of Fraxinus. Hy. fraxineus has been recorded already since 1990 in Eastern Asia (Japan, Korea, northeast of China), where it had been initially misidentified as Lambertella albida (=Hy. albidus). In these regions, it occurs as a harmless saprotroph on Fraxinus mandshurica and Fraxinus rhynchophylla, suggesting that those populations are native while the European ash dieback disease has a recent Eastern Asiatic origin. The distinctly higher genetic diversity found in Japanese Hy. fraxineus in contrast to European Hy. fraxineus supports this view. Genetic similarities between Japanese Hy. fraxineus and European Hy. albidus suggest that also Hy. albidus might be a descendant of Asian Hy. fraxineus, though having invaded Europe much earlier. However, consistent genetic deviation between European and Asian Hy. fraxineus at two nucleotide positions of the ITS region indicates that the European ash disease originates from a region different from the presently known areas in Eastern Asia. Our results underline the importance of detailed morphological studies in combination with molecular work. Hy. fraxineus was described from Europe as a cryptic species that differed from Hy. albidus by molecular data alone. However, the Hy. albidus/Hy. fraxineus species complex represents one of many examples within the ascomycetes in which subtle microscopic differences between closely related species, in this case the presence or absence of croziers at the ascus base, are strictly correlated with molecular characteristics. Two species that closely resemble Hy. albidus and Hy. fraxineus form pseudosclerotia in Aesculus leaves and again differ from each other mainly in the ascus base: Hymenoscyphus aesculi on Aesculus hippocastanum from Europe lacks croziers, whereas Hymenoscyphus honshuanus from Japan on Aesculus turbinata possesses croziers. Other taxa treated here include Hymenoscyphus vacini, a European species growing on stromatized net veins of skeletonized leaves of Acer, and Hymenoscyphus torquatus, a Chinese species on unidentified herbaceous stems. An equivalent stroma-forming North American species on leaves of Fraxinus, Rutstroemia longipes (Rutstroemiaceae), is discussed and compared. A key to the Hymenoscyphus species that form a dark stroma on leaves of Acer, Aesculus, Fraxinus, and Picrasma is provided. PMID- 25544936 TI - Parental Mindfulness and Dyadic Relationship Quality in Low-income Cohabiting Black Stepfamilies: Associations with Parenting Experienced by Adolescents. AB - Cohabitation is a family structure experienced by many Black children; yet, we have limited understanding of how personal and interpersonal processes operate within these families to influence the parenting provided to these children. Informed by both family systems theory and the spillover hypothesis and utilizing a model to account for the interdependence of the mother and her partner, the current study sought to understand the direct and indirect associations among parental mindfulness, the mother-partner relationship quality, and firm parenting practices in a sample of 121 Black cohabiting low-income stepfamilies. Assessment consisted of standardized measurements of maternal and male cohabiting partner reports on mindfulness (i.e., acting with awareness) and relationship quality (i.e., relationship satisfaction, ability to resolve conflict, and coparenting conflict) as well as adolescent report on parenting (i.e., parent's firm control). Mindfulness was directly related to each individual's own perceptions of relationship quality and some support emerged for a cross-informant link (e.g., mother's mindfulness related to partner report of relationship quality). Furthermore, maternal perceptions of relationship quality, as well as mindfulness operating through relationship quality, were related to youth reports of maternal firm parenting. The results suggest that both mindfulness and the relationship quality of adults are variables deserving attention when studying the parenting received by children in cohabiting stepfamilies. Clinical implications of the findings are considered. PMID- 25544938 TI - Taenia solium taeniasis and cysticercosis control and elimination through community-based interventions. AB - Taenia solium was declared potentially eradicable by the International Task Force for Disease Eradication in 1992. Yet, very few well-designed community-based randomized controlled trials have been conducted to measure the effectiveness of alternative control strategies. Most strategies have been tested in pre-post intervention designs in very few communities, often without a control group. The only two community-based randomized controlled trials suggest that an educational program alone or a combination of human and porcine mass treatment reduce porcine cysticercosis in the short term. A transmission dynamics model suggests that improved sanitation and pig management are more effective and sustainable than pig vaccination, human or porcine mass treatment. Current evidence does not support the eradication of Taenia solium in the foreseeable future. Investigators should follow international recommendations on the conduct of community-based randomized control trials to provide more valid estimates of the effect and cost effectiveness of alternative control strategies for cysticercosis. PMID- 25544939 TI - Fostering Resilience: Protective Agents, Resources, and Mechanisms for Adolescent Refugees' Psychosocial Well-Being. AB - BACKGROUND: Adolescent refugees face many challenges but also have the potential to become resilient. The purpose of this study was to identify and characterize the protective agents, resources, and mechanisms that promote their psychosocial well-being. METHODS: Participants included a purposively sampled group of 73 Burundian and Liberian refugee adolescents and their families who had recently resettled in Boston and Chicago. The adolescents, families, and their service providers participated in a two-year longitudinal study using ethnographic methods and grounded theory analysis with Atlas/ti software. A grounded theory model was developed which describes those persons or entities who act to protect adolescents (Protective Agents), their capacities for doing so (Protective Resources), and how they do it (Protective Mechanisms). Protective agents are the individuals, groups, organizations, and systems that can contribute either directly or indirectly to promoting adolescent refugees' psychosocial well-being. Protective resources are the family and community capacities that can promote psychosocial well-being in adolescent refugees. Protective mechanisms are the processes fostering adolescent refugees' competencies and behaviors that can promote their psychosocial well-being. RESULTS: Eight family and community capacities were identified that appeared to promote psychosocial well-being in the adolescent refugees. These included 1) finances for necessities; 2) English proficiency; 3) social support networks; 4) engaged parenting; 5) family cohesion; 6) cultural adherence and guidance; 7) educational support; and 8) faith and religious involvement. Nine protective mechanisms identified were identified and grouped into three categories: 1) Relational (supporting, connecting, belonging); 2) Informational (informing, preparing), and; 3) Developmental (defending, promoting, adapting). CONCLUSIONS: To further promote the psychosocial well-being of adolescent refugees, targeted prevention focused policies and programs are needed to enhance the identified protective agents, resources, and mechanisms. Because resilience works through protective mechanisms, greater attention should be paid to understanding how to enhance them through new programs and practices, especially informational and developmental protective mechanisms. PMID- 25544940 TI - Advanced extrauterine pregnancy at 33 weeks with a healthy newborn. AB - Abdominal pregnancy is a very rare form of ectopic pregnancy, associated with high morbidity and mortality for both fetus and mother. It is, and often, seen in poor resource nations, where early diagnosis is often a major challenge due to poor prenatal care and lack of medical resources. An advanced abdominal pregnancy with a good fetal and maternal outcome is therefore a more extraordinary occurrence in the modern developed world. We present a case of an abdominal pregnancy at 33.4 weeks in an individual with no documented prenatal care, who arrived in a hospital in the Bronx, in June 25th 2014, with symptoms of generalized, severe lower abdominal pain. Upon examination it was found that due to category III fetal tracing an emergent cesarean section was performed. At the time of laparotomy the fetus was located in the pelvis covered by the uterine serosa, with distortion of the entire right adnexa and invasion to the right parametrium. The placenta invaded the pouch of Douglas and the lower part of the sigmoid colon. A massive hemorrhage followed, followed by a supracervical hysterectomy. A viable infant was delivered and mother discharged on postoperative day 4. PMID- 25544941 TI - Ethnopharmacological assessment of medicinal plants used against livestock infections by the people living around Indus River. AB - The present study was aimed to document detailed ethnopharmacological knowledge of medicinal plants against livestock infections of an unexplored remote region of Pakistan. Semistructured questionnaires were used for data collection. Total 43 plants belonging to 26 families were found to be used in ethnoveterinary practices. Seeds (29%) were found to be the most frequent plant part used followed by leaves (22%). Ethnoveterinary recipes were mostly prepared in the form of decoction and powdering. Informant consensus factor (Fic) results revealed high consensus for gastrointestinal (0.81), mastitis (0.82), and dermatological infections (0.80). Curcuma longa ranked first with highest fidelity level (FL) value (66%) followed by Trachyspermum ammi that ranked second (58%). Preference ranking (PR) results showed that Zingiber officinale, Punica granatum, Triticum aestivum, Gossypium hirsutum, and Withania coagulans were the most preferred species for the treatment of diarrhea. Direct matrix ranking (DMR) results showed that Morus alba, Melia azedarach, Withania coagulans, Cassia fistula, Azadirachta indica, and Tamarix aphylla were the multipurpose species of the region. We invite the attention of pharmacologists and chemists for further exploration of plants having high Fic, FL, and PR values in the present study. Conservation strategies should be adopted for the protection of multipurpose plant species. PMID- 25544937 TI - Virulence Plasmids of Nonsporulating Gram-Positive Pathogens. AB - Gram-positive bacteria are leading causes of many types of human infection, including pneumonia, skin and nasopharyngeal infections, as well as urinary tract and surgical wound infections among hospitalized patients. These infections have become particularly problematic because many of the species causing them have become highly resistant to antibiotics. The role of mobile genetic elements, such as plasmids, in the dissemination of antibiotic resistance among Gram-positive bacteria has been well studied; less well understood is the role of mobile elements in the evolution and spread of virulence traits among these pathogens. While these organisms are leading agents of infection, they are also prominent members of the human commensal ecology. It appears that these bacteria are able to take advantage of the intimate association between host and commensal, via virulence traits that exacerbate infection and cause disease. However, evolution into an obligate pathogen has not occurred, presumably because it would lead to rejection of pathogenic organisms from the host ecology. Instead, in organisms that exist as both commensal and pathogen, selection has favored the development of mechanisms for variability. As a result, many virulence traits are localized on mobile genetic elements, such as virulence plasmids and pathogenicity islands. Virulence traits may occur within a minority of isolates of a given species, but these minority populations have nonetheless emerged as a leading problem in infectious disease. This chapter reviews virulence plasmids in nonsporulating Gram-positive bacteria, and examines their contribution to disease pathogenesis. PMID- 25544942 TI - Changing interdigestive migrating motor complex in rats under acute liver injury. AB - Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC) is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by d-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders. PMID- 25544944 TI - Final Gleason score prediction using discriminant analysis and support vector machine based on preoperative multiparametric MR imaging of prostate cancer at 3T. AB - OBJECTIVE: This study aimed at evaluating linear discriminant analysis (LDA) and support vector machine (SVM) classifiers for estimating final Gleason score preoperatively using multiparametric magnetic resonance imaging (mp-MRI) and clinical parameters. MATERIALS AND METHODS: Thirty-three patients who underwent mp-MRI on a 3T clinical MR scanner and radical prostatectomy were enrolled in this study. The input features for classifiers were age, the presence of a palpable prostate abnormality, prostate specific antigen (PSA) level, index lesion size, and Likert scales of T2 weighted MRI (T2w-MRI), diffusion weighted MRI (DW-MRI), and dynamic contrast enhanced MRI (DCE-MRI) estimated by an experienced radiologist. SVM based recursive feature elimination (SVM-RFE) was used for eliminating features. Principal component analysis (PCA) was applied for data uncorrelation. RESULTS: Using a standard PCA before final Gleason score classification resulted in mean sensitivities of 51.19% and 64.37% and mean specificities of 72.71% and 39.90% for LDA and SVM, respectively. Using a Gaussian kernel PCA resulted in mean sensitivities of 86.51% and 87.88% and mean specificities of 63.99% and 56.83% for LDA and SVM, respectively. CONCLUSION: SVM classifier resulted in a slightly higher sensitivity but a lower specificity than LDA method for final Gleason score prediction for prostate cancer for this limited patient population. PMID- 25544946 TI - Nonadherence and contributing factors among ambulatory patients with antidiabetic medications in Adama Referral Hospital. AB - The objective of this study was to determine the magnitude of nonadherence and its contributing factors among diabetic patients attending the diabetic clinic in Adama Hospital. METHODS: This descriptive cross-sectional study was carried out among patients with diabetes mellitus attending the diabetes mellitus clinic of Adama Referral Hospital. Every other patient was selected and data regarding their medication adherence was collected using a structured interview. Data analysis was carried out using SPSS-16. RESULT: The response rate from this study was 98.3%. A total of 270 patients were interviewed; 51.5% were males. A total of 68.1% of the patients included in the study were married. 14% were younger than 40 years, and 50% were between 40 and 60 years. 21.8% of the participants ascribed their nonadherence to forgetting to take their medications. Patients with duration of diabetes <=5 years (82.07%) were more compliant to their medication than those with >5 years (60.8%), which was found to be statistically significant (P = 0.003). Insulin, 47%, and glibenclamide plus metformin, 43.7%, were the most commonly prescribed mono- and combination therapies, respectively. Common comorbid conditions include hypertension, 148 (54.82%), and visual impairment, 89 (32.96%). The proportion of male patients adherent to their antidiabetic medications was found to be lower than 69.78% compared to the female patients (74.81%), but the difference was not statistically significant (P > 0.05). CONCLUSION: Most diabetic patients are currently being managed with the most effective available drugs. However the result from this study indicates that the desired blood sugar level could not be controlled and maintained adequately. This was because of poor adherence to the prescribed drug regimen and poor knowledge and practice of successful self-management. PMID- 25544947 TI - Working with LGBT Individuals: Incorporating Positive Psychology into Training and Practice. AB - This paper examines how positive psychology principles can be incorporated into clinical training and practice to work with lesbian, gay, bisexual and transgender (LGBT) clients. LGBT psychology literature has all too often relied on heterosexual and cisgender reference groups as the norm with respect to psychological health, primarily framing the experiences of LGBT individuals through the lens of psychopathology. As a result, strengths that could be ascribed to the LGBT experience have been overlooked within training and practice. While positive psychology is actively being incorporated into clinical and counseling psychology curricula, broadening the paradigm to include LGBT individuals has generally not been included in the discussion. Specific recommendations for training psychologists to incorporate and foster positive social institutions, positive subjective experiences and character strengths when working with LGBT clients and celebrating their unique experiences are provided. PMID- 25544945 TI - Development of a provisional model to improve transitional care for female adolescents with a rare genital malformation as an example for orphan diseases. AB - Deficits of care exist during the transitional period, when young people with ongoing needs of support to achieve their physical, social, and psychological potential are entering adulthood. This study aims to develop a patient oriented, structured provisional model to improve transitional care for adolescents with Mayer-Rokitansky-Kuester-Hauser-Syndrome as an example for orphan diseases, where problems of access and continuity are even more complex. The study is funded by the German Federal Ministry of Education and Research (BMBF-Funding Code 01GY1125). The target patient group are young females with this disorder, treated at the Centre for Rare Genital Malformations in Women (ZSGF), University Hospital of Tuebingen. The study comprises five phases: an appraisal of literature, assessment of patients (n = 25), parents', partners', and health and social care providers' (n = 24) needs and experienced deficits in care and support in a qualitative approach, construction of a provisional model via scenario technique, followed by communicative validation (including interested public, n = 100), preference finding, and identification of patient-oriented quality aims for follow-up. Quantitative data from questionnaires and chart review (as sociodemographic data, nonresponder analysis, and preference rating) are worked up for descriptive statistics. The results provide a platform for the development of future multidisciplinary transitional intervention programs in orphan diseases. PMID- 25544949 TI - Meet the new team! PMID- 25544948 TI - Calibration-free coronary artery measurements for interventional device sizing using inverse geometry x-ray fluoroscopy: in vivo validation. AB - Proper sizing of interventional devices to match coronary vessel dimensions improves procedural efficiency and therapeutic outcomes. We have developed a method that uses an inverse geometry x-ray fluoroscopy system [scanning beam digital x-ray (SBDX)] to automatically determine vessel dimensions from angiograms without the need for magnification calibration or optimal views. For each frame period (1/15th of a second), SBDX acquires a sequence of narrow beam projections and performs digital tomosynthesis at multiple plane positions. A three-dimensional model of the vessel is reconstructed by localizing the depth of the vessel edges from the tomosynthesis images, and the model is used to calculate the length and diameter in units of millimeters. The in vivo algorithm performance was evaluated in a healthy porcine model by comparing end-diastolic length and diameter measurements from SBDX to coronary computed tomography angiography (CCTA) and intravascular ultrasound (IVUS), respectively. The length error was -0.49 +/- 1.76 mm(SBDX- CCTA, mean +/- 1 SD). The diameter error was 0.07 +/- 0.27 mm (SBDX - minimum IVUS diameter, mean +/- 1 SD). The in vivo agreement between SBDX-based vessel sizing and gold standard techniques supports the feasibility of calibration-free coronary vessel sizing using inverse geometry x-ray fluoroscopy. PMID- 25544950 TI - Cytomictic anomalous male meiosis and 2n pollen grain formation in Mertensia echioides Benth. (Boraginaceae) from Kashmir Himalaya. AB - Presently Mertensia echioides Benth. (Boraginaceae) collected from Kashmir Himalaya, India, is cytologically analyzed for the first time revealing 2n = 2x = 24 (diploid). Interestingly we found 4.3-6.2% syncytic meiocytes/PMCs with 2n = 4x = 48 (tetraploid) in addition to normal meiocytes (2n = 24) during male meiosis. These comparatively larger PMCs (pollen mother cells) lead to the formation of fertile giant 2n pollen grains. A frequency of 6.4-13.3% PMCs shows transfer of chromatin material at prophase-I and, therefore, results in aneuploid meiocytes. Whole chromatin transfer by the process of cytomixis could also have led to the formation of tetraploid cells. Translocation heterozygosity is also evident in the form of multivalents in 12-17% diploid (2x) meiocytes at diakinesis and metaphase-I and is reported for the first time in this species. The syncytes formed depict open chain hexavalent and quadrivalent formation in the three populations with different frequencies. Moreover chromatin stickiness at metaphase-I is observed in 45% of PMCs in population-1 (P-1). Syncyte or unreduced PMC formation leading to unreduced fertile gametes is here speculated to act as a possible way out for infraspecific polyploidization in the species. PMID- 25544943 TI - Maternal obesity and occurrence of fetal macrosomia: a systematic review and meta analysis. AB - OBJECTIVE: To determine a precise estimate for the contribution of maternal obesity to macrosomia. DATA SOURCES: The search strategy included database searches in 2011 of PubMed, Medline (In-Process & Other Non-Indexed Citations and Ovid Medline, 1950-2011), and EMBASE Classic + EMBASE. Appropriate search terms were used for each database. Reference lists of retrieved articles and review articles were cross-referenced. METHODS OF STUDY SELECTION: All studies that examined the relationship between maternal obesity (BMI >=30 kg/m(2)) (pregravid or at 1st prenatal visit) and fetal macrosomia (birth weight >=4000 g, >=4500 g, or >=90th percentile) were considered for inclusion. TABULATION, INTEGRATION, AND RESULTS: Data regarding the outcomes of interest and study quality were independently extracted by two reviewers. Results from the meta-analysis showed that maternal obesity is associated with fetal overgrowth, defined as birth weight >= 4000 g (OR 2.17, 95% CI 1.92, 2.45), birth weight >=4500 g (OR 2.77,95% CI 2.22, 3.45), and birth weight >=90% ile for gestational age (OR 2.42, 95% CI 2.16, 2.72). CONCLUSION: Maternal obesity appears to play a significant role in the development of fetal overgrowth. There is a critical need for effective personal and public health initiatives designed to decrease prepregnancy weight and optimize gestational weight gain. PMID- 25544951 TI - Dynamical tangles in third-order oscillator with single jump function. AB - This contribution brings a deep and detailed study of the dynamical behavior associated with nonlinear oscillator described by a single third-order differential equation with scalar jump nonlinearity. The relative primitive geometry of the vector field allows making an exhaustive numerical analysis of its possible solutions, visualizations of the invariant manifolds, and basins of attraction as well as proving the existence of chaotic motion by using the concept of both Shilnikov theorems. The aim of this paper is also to complete, carry out and link the previous works on simple Newtonian dynamics, and answer the question how individual types of the phenomenon evolve with time via understandable notes. PMID- 25544952 TI - Low-energy plasma focus device as an electron beam source. AB - A low-energy plasma focus device was used as an electron beam source. A technique was developed to simultaneously measure the electron beam intensity and energy. The system was operated in Argon filling at an optimum pressure of 1.7 mbar. A Faraday cup was used together with an array of filtered PIN diodes. The beam target X-rays were registered through X-ray spectrometry. Copper and lead line radiations were registered upon usage as targets. The maximum electron beam charge and density were estimated to be 0.31 MUC and 13.5 * 10(16)/m(3), respectively. The average energy of the electron beam was 500 keV. The high flux of the electron beam can be potentially applicable in material sciences. PMID- 25544953 TI - Nasopupillary asymmetry. AB - PURPOSE: To establish the prevalence of nasopupillary asymmetry (difference in nasopupillary distances) in the population and its relation with the interpupillary distance. METHODS: A retrospective descriptive study was conducted by reviewing of 1262 medical records. The values of nasopupillary asymmetry and the interpupillary distance were obtained. A statistical analysis was made and the correlation between these variables was established. RESULTS: Seventy-nine percent of the population presented some degree of nasopupillary asymmetry. The interpupillary distance had a very low correlation with the nasopupillary asymmetry (r = 0.074, P = 0.0). CONCLUSION: It is advisable to use the nasopupillary distance of each eye as a standard measurement. PMID- 25544954 TI - Wind tunnel analysis of the aerodynamic loads on rolling stock over railway embankments: the effect of shelter windbreaks. AB - Wind-flow pattern over embankments involves an overexposure of the rolling stock travelling on them to wind loads. Windbreaks are a common solution for changing the flow characteristic in order to decrease unwanted effects induced by the presence of cross-wind. The shelter effectiveness of a set of windbreaks placed over a railway twin-track embankment is experimentally analysed. A set of two dimensional wind tunnel tests are undertaken and results corresponding to pressure tap measurements over a section of a typical high-speed train are herein presented. The results indicate that even small-height windbreaks provide sheltering effects to the vehicles. Also, eaves located at the windbreak tips seem to improve their sheltering effect. PMID- 25544955 TI - The effect of local injections of bupivacaine plus ketamine, bupivacaine alone, and placebo on reducing postoperative anal fistula pain: a randomized clinical trial. AB - BACKGROUND AND OBJECTIVE: This study aimed to compare the effects of different local anesthetic solutions on postoperative pain of anal surgery in adult patients. METHOD: In this randomized double-blind prospective clinical trial, 60 adult patients (18 to 60 years old) with physical status class I and class II that had been brought to a university hospital operating room for fistula anal surgery with spinal anesthesia were selected. Patients were randomly divided into 4 equal groups according to table of random numbers (created by Random Allocation Software 1). Group 1 received 3 mL of normal saline, group 2, 1 mL of normal saline plus 2 mL of bupivacaine 0.5%, group 3, 1 mL of ketamine plus 2 mL of bupivacaine 0.5%, and group 4, no infiltration. Intensity of pain in patients was measured using visual analogue scale (VAS) at 0 (transfer to ward), 2, 6, 12, and 24 hours after surgery. Time interval to administration of drugs and overall dose of drugs were measured in 4 groups. RESULTS: Mean level of pain was the lowest in group 3 at all occasions with a significant difference, followed by groups 2, 4, and lastly 1 (P < 0.001). Furthermore, groups 2 and 3 compared to groups 1 and 4 had the least overall dose of analgesics and requested them the latest, with a significant difference (P < 0.05). CONCLUSION: Local anesthesia (1 mL of ketamine plus 2 mL of bupivacaine 0.5% or 1 mL of normal saline plus 2 mL of bupivacaine 0.5%) combined with spinal anesthesia reduces postoperative pain and leads to greater comfort in recovering patients. PMID- 25544956 TI - Syntheses of isoxazoline-carbocyclic nucleosides and their antiviral evaluation: a standard protocol. AB - The current synthesis of racemic purine and pyrimidine isoxazoline-carbocyclic nucleosides is reported, detailing the key-steps for standard and reliable preparations. Improved yields were obtained by the proper tuning of the single synthetic steps, opening the way for the preparation of a variety of novel compounds. Some of the obtained compounds were also evaluated against a wide variety of DNA and RNA viruses including HIV. No specific antiviral activity was observed in the cases at hand. Novel compounds were prepared for future biological tests. PMID- 25544957 TI - Characterization of the algC gene expression pattern in the multidrug resistant Acinetobacter baumannii AIIMS 7 and correlation with biofilm development on abiotic surface. AB - Relative quantification of algC gene expression was evaluated in the multidrug resistant strain Acinetobacter baumannii AIIMS 7 biofilm (3 to 96 h, on polystyrene surface) compared to the planktonic counterparts. Comparison revealed differential algC expression pattern with maximum 81.59-fold increase in biofilm cells versus 3.24-fold in planktonic cells (P < 0.05). Expression levels strongly correlated with specific biofilm stages (scale of 3 to 96 h), coinciding maximum at initial surface attachment stage (9 h) and biofilm maturation stage (48 h). Cloning, heterologous expression, and bioinformatics analyses indicated algC gene product as the bifunctional enzyme phosphomannomutase/phosphoglucomutase (PMM/PGM) of ~ 53 kDa size, which augmented biofilms significantly in algC clones compared to controls (lacking algC gene), further localized by scanning electron microscopy. Moreover, molecular dynamics analysis on the three-dimensional structure of PMM/PGM (simulated up to 10 ns) revealed enzyme structure as stable and similar to that in P. aeruginosa (synthesis of alginate and lipopolysaccharide core) and involved in constitution of biofilm EPS (extracellular polymeric substances). Our observation on differential expression pattern of algC having strong correlation with important biofilm stages, scanning electron-microscopic evidence of biofilm augmentation taken together with predictive enzyme functions via molecular dynamic (MD) simulation, proposes a new basis of A. baumannii AIIMS 7 biofilm development on inanimate surfaces. PMID- 25544958 TI - Genetic diversity of freshwater leeches in Lake Gusinoe (eastern Siberia, Russia). AB - The study of leeches from Lake Gusinoe and its adjacent area offered us the possibility to determine species diversity. As a result, an updated species list of the Gusinoe Hirudinea fauna (Annelida, Clitellata) has been compiled. There are two orders and three families of leeches in the Gusinoe area: order Rhynchobdellida (families Glossiphoniidae and Piscicolidae) and order Arhynchobdellida (family Erpobdellidae). In total, 6 leech species belonging to 6 genera have been identified. Of these, 3 taxa belonging to the family Glossiphoniidae (Alboglossiphonia heteroclita f. papillosa, Hemiclepsis marginata, and Helobdella stagnalis) and representatives of 3 unidentified species (Glossiphonia sp., Piscicola sp., and Erpobdella sp.) have been recorded. The checklist gives a contemporary overview of the species composition of leeches and information on their hosts or substrates. The validity of morphological identification of each taxon has been verified by phylogenetic approach with a molecular marker adopted for a DNA barcoding of most invertebrates. PMID- 25544959 TI - Clinical response and transfusion reactions of sheep subjected to single homologous blood transfusion. AB - Studies in relation to blood conservation and responses to transfusion are scarce for ruminants. We evaluated the clinical manifestations of sheep that received a single homologous transfusion of whole blood, focusing on transfusion reactions. Eighteen adult sheep were subjected to a single phlebotomy to withdraw 40% of the total blood volume, which was placed into CPDA-1 bags and then divided into G0, animals that received fresh blood, and G15 and G35, animals that received blood stored for 15 or 35 days, respectively. Clinical observations were recorded throughout the transfusion, whereas heart rate, respiratory rate, and rectal temperature were assessed at the following times: 24 hours after phlebotomy and before transfusion; 30 minutes, six, twelve, 24, 48, 72, and 96 hours and eight and 16 days after transfusion. All groups presented transfusion reactions, among which hyperthermia was the most frequent (50% of animals). Tachycardia occurred most frequently in the G35 animals (50% of them). During transfusion G35 animals presented more clinical manifestation (P < 0.05). Transfusion of fresh or stored total blood improved the blood volume, but transfusion reactions occurred, demonstrating that a single transfusion of fresh or stored blood can cause inflammatory and febrile nonhemolytic transfusion reactions in sheep. PMID- 25544960 TI - Bell's palsy: symptoms preceding and accompanying the facial paresis. AB - This individual prospective cohort study aims to report and analyze the symptoms preceding and accompanying the facial paresis in Bell's palsy (BP). Two hundred sixty-nine patients affected by BP with a maximum delay of 48 hours from the onset were enrolled in the study. The evolution of the facial paresis expressed as House-Brackmann grade in the first 10 days and its correlation with symptoms were analyzed. At the onset, 136 patients presented postauricular pain, 114 were affected by dry eye, and 94 reported dysgeusia. Dry mouth was present in 54 patients (19.7%), facial pain, hyperlacrimation, aural fullness, and hyperacusis represented a smaller percentage of the reported symptoms. After 10 days, 39.9% of the group had a severe paresis while 10.2% reached a complete recovery. Dry mouth at the onset was correlated with severe grade of palsy and was prognostic for poor recovery in the early period. These outcomes lead to the deduction that the nervus intermedius plays an important role in the presentation of the BP and it might be responsible for most of the accompanying symptomatology of the paresis. Our findings could be of important interest to early address a BP patient to further examinations and subsequent therapy. PMID- 25544961 TI - Patients undergoing subacute physical rehabilitation following an acute hospital admission demonstrated improvement in cognitive functional task independence. AB - OBJECTIVE: This study investigated cognitive functioning among older adults with physical debility not attributable to an acute injury or neurological condition who were receiving subacute inpatient physical rehabilitation. DESIGN: A cohort investigation with assessments at admission and discharge. SETTING: Three geriatric rehabilitation hospital wards. PARTICIPANTS: Consecutive rehabilitation admissions (n = 814) following acute hospitalization (study criteria excluded orthopaedic, neurological, or amputation admissions). INTERVENTION: Usual rehabilitation care. MEASUREMENTS: The Functional Independence Measure (FIM) Cognitive and Motor items. RESULTS: A total of 704 (86.5%) participants (mean age = 76.5 years) completed both assessments. Significant improvement in FIM Cognitive items (Z-score range 3.93-8.74, all P < 0.001) and FIM Cognitive total score (Z-score = 9.12, P < 0.001) occurred, in addition to improvement in FIM Motor performance. A moderate positive correlation existed between change in Motor and Cognitive scores (Spearman's rho = 0.41). Generalized linear modelling indicated that better cognition at admission (coefficient = 0.398, P < 0.001) and younger age (coefficient = -0.280, P < 0.001) were predictive of improvement in Motor performance. Younger age (coefficient = -0.049, P < 0.001) was predictive of improvement in FIM Cognitive score. CONCLUSIONS: Improvement in cognitive functioning was observed in addition to motor function improvement among this population. Causal links cannot be drawn without further research. PMID- 25544962 TI - Sociodemographic correlates of unipolar major depression among the Chinese elderly in Klang Valley, Malaysia: an epidemiological study. AB - BACKGROUND: Depression, as one of the most disabling diseases around the world, had caught the global concern with its rising prevalence rate. There is a growing need of detecting depression, particularly in the old age population which is often left being overlooked. METHODS: We conducted a cross-sectional community based study which included 150 Chinese elderly aged 60 and above within Klang Valley area. We obtained the sociodemographic profiles and assessed the status of well-being, depression, and cognitive function of the participants with the help of instruments: WHO Five-Item Well-Being Index, Major (ICD-10) Depression Inventory, and 6-Item Cognitive Impairment Test. RESULTS: We found that the prevalence of depression among the Chinese elderly within Klang Valley region was 10.7%. With multiple logistic regression, decision to consult doctor on depressed mood or memory problem and presence of cognitive impairment were shown to be significantly associated with unipolar major depression, whereas wellbeing status was also found to be statistically correlated with depression in univariate analysis. CONCLUSION: The prevalence of unipolar depression among Chinese elderly within Klang Valley, Malaysia presented that there was an increased trend compared to the previous studies. PMID- 25544963 TI - Correlations of ezrin expression with pathological characteristics and prognosis of osteosarcoma: a meta-analysis. AB - We conducted a meta-analysis to comprehensively evaluate the correlations of ezrin expression with pathological characteristics and the prognosis of osteosarcoma. The MEDLINE (1966-2013), the Cochrane Library Database, EMBASE, CINAHL, Web of Science (1945-2013), and the Chinese Biomedical Database were searched without language restrictions. Meta-analyses conducted using STATA software were calculated. Ten studies met the inclusion criteria, including 459 patients with osteosarcoma. Meta-analysis results illustrated that ezrin expression may be closely associated with the recurrence of osteosarcoma or metastasis in osteosarcoma. Our findings also demonstrated that patients with grade III-IV osteosarcoma showed a higher frequency of ezrin expression than those with histological grade I-II osteosarcoma. Furthermore, we found that patients with positive expression of ezrin exhibited a shorter overall survival than those with negative ezrin expression. The results also indicated that positive ezrin expression was strongly correlated with poorer metastasis-free survival. Nevertheless, no significant relationships were observed between ezrin expression and clinical variables (age and gender). In the current meta-analysis, our results illustrated significant relationships of ezrin expression with pathological characteristics and prognosis of osteosarcoma. Thus, ezrin expression could be a promising marker in predicting the clinical outcome of patients with osteosarcoma. PMID- 25544964 TI - MobileRF: A Robust Device-Free Tracking System Based On a Hybrid Neural Network HMM Classifier. AB - We present a device-free indoor tracking system that uses received signal strength (RSS) from radio frequency (RF) transceivers to estimate the location of a person. While many RSS-based tracking systems use a body-worn device or tag, this approach requires no such tag. The approach is based on the key principle that RF signals between wall-mounted transceivers reflect and absorb differently depending on a person's movement within their home. A hierarchical neural network hidden Markov model (NN-HMM) classifier estimates both movement patterns and stand vs. walk conditions to perform tracking accurately. The algorithm and features used are specifically robust to changes in RSS mean shifts in the environment over time allowing for greater than 90% region level classification accuracy over an extended testing period. In addition to tracking, the system also estimates the number of people in different regions. It is currently being developed to support independent living and long-term monitoring of seniors. PMID- 25544965 TI - Motorized Force-Sensing Micro-Forceps with Tremor Cancelling and Controlled Micro Vibrations for Easier Membrane Peeling. AB - Retinal microsurgery requires the manipulation of extremely delicate tissues by various micron scale maneuvers and the application of very small forces. Among vitreoretinal procedures, membrane peeling is a standard procedure requiring the delamination of a very thin fibrous membrane on the retina surface. This study presents the development and evaluation of an integrated assistive system for membrane peeling. This system combines a force-sensing motorized micro-forceps with an active tremor-canceling handheld micromanipulator, Micron. The proposed system (1) attenuates hand-tremor when accurate positioning is needed, (2) provides auditory force feedback to keep the exerted forces at a safe level, and (3) pulsates the tool tip at high frequency to provide ease in delaminating membranes. Experiments on bandages and raw chicken eggs have revealed that controlled micro-vibrations provide significant ease in delaminating membranes. Applying similar amount of forces, much faster delamination was observed when the frequency of these vibrations were increased (up to 50 Hz). PMID- 25544966 TI - Development of A Miniaturized 3-DOF Force Sensing Instrument for Robotically Assisted Retinal Microsurgery and Preliminary Results. AB - Lack of force sensing is one of the most formidable technical challenges in retinal microsurgery. Incorporating high sensitivity force sensing into the ophthalmic tools has the potential to provide the surgeon useful force feedback and to enable safe robotic assistance. This paper presents a new design of a three degrees of freedom force sensing instrument based on fiber Bragg grating sensors. A new flexure is developed to achieve high axial force sensing sensitivity and low crosstalk noise. The force sensing segment of the tool, located directly proximal to the tool tip, is o0.9*8 mm. An extensive calibration shows that the force sensor can measure the transverse and axial force up to 21 mN with 0.5 mN and 3.3 mN accuracy, respectively. The new flexure design demonstrates the potential to improve axial force sensing. Analysis of the experiment results suggests improvements for the future iteration. PMID- 25544967 TI - Recurrent Salmonellosis in a Child with Complete IL-12Rbeta1 Deficiency. AB - A 3 year old boy presented with fever, abdominal pain and cervical lymphadenopathy. He had previously been treated empirically with anti-tuberculous therapy twice, at age 9 months and 27 months, for peripheral lymphadenopathy. An older sibling died of suspected tuberculous meningitis. Mantoux test was normal. Bone marrow and lymph node biopsy ruled out lymphoma and absolute neutrophil and lymphocyte counts were normal. Blood and lymph node cultures were positive for Salmonella typhi. The child's symptoms resolved with IV ceftriaxone and he was discharged. Over the next 2 years, the child was admitted every 2-3 months for culture positive S. typhi bacteremia with complaints of fever, abdominal distention and dysentery. HIV workup was negative. A prolonged course of probenicid and high dose amoxicillin increased interval between episodes to 4-5 months only. Cholecystectomy was debated and deferred due to suspicion of immunodeficiency. Blood samples from patient and parents were sent to France for workup and IL-12Rbeta1 deficiency was found. Parental counseling and subsequent patient management remained difficult in view of financial constraints and outstation residence of family. At age 7 years, the child presented with small bowel obstruction. He was managed conservatively with antibiotics, IV fluids and blood transfusions, but eventually succumbed to endotoxic shock. This case highlights the importance of considering IL-12Rbeta1 deficiency in children with repeated salmonellosis, a diagnosis which precludes intensive and aggressive monitoring and management of the patient in scenarios where bone marrow transplants are not feasible. PMID- 25544968 TI - Method for the determination of trajectory angles of directional secretory vesicles in cultured astrocytes. AB - Astrocytes provide a principal pathway for glutamate uptake in the mammalian brain, a task accomplished by the powerful action of excitatory amino acid transporters (EAAT) 1 and 2. These transporters are synthesized within the endoplasmic reticulum and are then trafficked to the plasma membrane. The characteristics of their intracellular traffic within astrocytes have not been investigated. We monitored the trafficking of secretory vesicles laden with the recombinant fluorescent protein chimera of EAAT2 in cultured astrocytes. Such vesicles appeared as fluorescent puncta, and their trafficking parameters were obtained using original algorithms, which we describe here in detail. We determined the maximal displacement, average instantaneous speed, and trajectory angle of individual puncta/vesicles, with angles near 0 degrees indicating radial movement directly away from or toward the nucleus and angles near 90 degrees indicating tangential movement. Analysis of these trafficking parameters demonstrated that trafficking of EAAT2-laden vesicles has typical characteristics expected of the trafficking of secretory vesicles in cultured astrocytes. The distribution of trajectory angles for directional vesicles, i.e. those with a maximal displacement greater than 1 MUm within the 40-s time-lapse imaging, was found to be unimodal, with angles near 0 degrees being the most prominent (mode 7 degrees ). These measurements are in good agreement with previous measurements of trajectory angles of similar trafficking vesicles carrying cannabinoid receptor 1, evidencing the validity and robustness of our analytical approach and algorithms. PMID- 25544969 TI - Transformation and stabilization of pyrogenic organic matter in a temperate forest field experiment. AB - Pyrogenic organic matter (PyOM) decomposes on centennial timescale in soils, but the processes regulating its decay are poorly understood. We conducted one of the first studies of PyOM and wood decomposition in a temperate forest using isotopically labeled organic substrate, and quantified microbial incorporation and physico-chemical transformations of PyOM in situ. Stable-isotope (13C and 15N) enriched PyOM and its precursor wood were added to the soil at 2 cm depth at ambient (N0) and increased (N+) levels of nitrogen fertilization. The carbon (C) and nitrogen (N) of added PyOM or wood were tracked through soil to 15 cm depth, in physically separated soil density fractions and in benzene polycarboxylic acids (BPCA) molecular markers. After 10 months in situ, more PyOM-derived C (>99% of initial 13C-PyOM) and N (90% of initial 15N-PyOM) was recovered than wood derived C (48% of 13C-wood) and N(89% under N0 and 48% under N+). PyOM-C and wood-C migrated at the rate of 126 mm yr -1 with 3-4% of PyOMC and 4-8% of wood-C recovered below the application depth. Most PyOM C was recovered in the free light fraction(fLF) (74%), with 20% in aggregate-occluded and 6% in mineral associated fractions - fractions that typically have much slower turnover times. In contrast, wood C was recovered mainly in occluded (33%) or dense fraction (27%).PyOM addition induced loss of native C from soil (priming effect), particularly in fLF (13%). The total BPCA-C content did not change but after 10 months the degree of aromatic condensation of PyOM decreased, as determined by relative contribution of benzene hexa-carboxylic acid (B6CA) to the total BPCA C. Soil microbial biomass assimilated 6-10% of C from the wood, while PyOM contributions was negligible (0.14-0.18%). The addition of N had no effect on the dynamics of PyOM while limited effect on wood. PMID- 25544970 TI - Dr Bashir Mamdani MD 1945-2014. PMID- 25544972 TI - Preface. PMID- 25544971 TI - Unusual abdominal radio-opaque densities in an ESRD patient. PMID- 25544973 TI - Heart disease and stroke decline in Europe. PMID- 25544974 TI - Estimating an individual person's course of coronary artery calcification. PMID- 25544975 TI - The CardioScape Project. PMID- 25544976 TI - Preface: two decades of InterDrought conferences: are we bridging the genotype-to phenotype gap? PMID- 25544977 TI - [In memory of Prof. Dr. med. Dr. med. h.c. Christian Herfarth]. PMID- 25544978 TI - [Rare tumor in the right lower abdomen]. PMID- 25544979 TI - Obituary: An appreciation of Gilbert G. Ashwell - A pioneer of glycobiology. PMID- 25544980 TI - Obituary: Dr. Yoshitaka Nagai (1931-2014). PMID- 25544981 TI - Author response. PMID- 25544982 TI - Author response. PMID- 25544983 TI - Cooperative catalysis with block copolymer micelles: a combinatorial approach. AB - A rapid approach to identifying complementary catalytic groups using combinations of functional polymers is presented. Amphiphilic polymers with "clickable" hydrophobic blocks were used to create a library of functional polymers, each bearing a single functionality. The polymers were combined in water, yielding mixed micelles. As the functional groups were colocalized in the hydrophobic microphase, they could act cooperatively, giving rise to new modes of catalysis. The multipolymer "clumps" were screened for catalytic activity, both in the presence and absence of metal ions. A number of catalyst candidates were identified across a wide range of model reaction types. One of the catalytic systems discovered was used to perform a number of preparative-scale syntheses. Our approach provides easy access to a range of enzyme-inspired cooperative catalysts. PMID- 25544984 TI - Periorbital lupus profundus successfully treated with oral tacrolimus plus low dose prednisolone. PMID- 25544985 TI - Disentangling the contributions of osmotic and ionic effects of salinity on stomatal, mesophyll, biochemical and light limitations to photosynthesis. AB - There are conflicting opinions on the relative importance of photosynthetic limitations under salinity. Quantitative limitation analysis of photosynthesis provides insight into the contributions of different photosynthetic limitations, but it has only been applied under saturating light conditions. Using experimental data and modelling approaches, we examined the influence of light intensity on photosynthetic limitations and quantified the osmotic and ionic effects of salinity on stomatal (LS ), mesophyll (LM ), biochemical (LB ) and light (LL ) limitations in cucumber (Cucumis sativus L.) under different light intensities. Non-linear dependencies of LS , LM and LL to light intensity were found. Osmotic effects on LS and LM increased with the salt concentration in the nutrient solution (Ss ) and the magnitude of LM depended on light intensity. LS increased with the Na(+) concentration in the leaf water (Sl ) and its magnitude depended on Ss . Biochemical capacity declined linearly with Sl but, surprisingly, the relationship between LB and Sl was influenced by Ss . Our results suggest that (1) improvement of stomatal regulation under ionic stress would be the most effective way to alleviate salinity stress in cucumber and (2) osmotic stress may alleviate the ionic effects on LB but aggravate the ionic effects on LS . PMID- 25544986 TI - Elevated plasma soluble CD14 and skewed CD16+ monocyte distribution persist despite normalisation of soluble CD163 and CXCL10 by effective HIV therapy: a changing paradigm for routine HIV laboratory monitoring? AB - OBJECTIVE: We investigated plasma and flow cytometric biomarkers of monocyte status that have been associated with prognostic utility in HIV infection and other chronic inflammatory diseases, comparing 81 HIV+ individuals with a range of treatment outcomes to a group of 21 healthy control blood donors. Our aim is to develop and optimise monocyte assays that combine biological relevance, clinical utility, and ease of adoption into routine HIV laboratory practice. DESIGN: Cross-sectional evaluation of concurrent plasma and whole blood samples. METHODS: A flow cytometry protocol was developed comprising single-tube CD45, CD14, CD16, CD64, CD163, CD143 analysis with appropriately matched isotype controls. Plasma levels of soluble CD14 (sCD14), soluble CD163 (sCD163) and CXCL10 were measured by ELISA. RESULTS: HIV status was associated with significantly increased expression of CD64, CD143 and CD163 on CD16+ monocytes, irrespective of the virological response to HIV therapy. Plasma levels of sCD14, sCD163 and CXCL10 were also significantly elevated in association with viremic HIV infection. Plasma sCD163 and CXCL10 levels were restored to healthy control levels by effective antiretroviral therapy while sCD14 levels remained elevated despite virological suppression (p<0.001). CONCLUSIONS: Flow cytometric and plasma biomarkers of monocyte activation indicate an ongoing systemic inflammatory response to HIV infection, characterised by persistent alterations of CD16+ monocyte expression profiles and elevated sCD14 levels, that are not corrected by antiretroviral therapy and likely to be prognostically significant. In contrast, sCD163 and CXCL10 levels declined on antiretroviral therapy, suggesting multiple activation pathways revealed by these biomarkers. Incorporation of these assays into routine clinical care is feasible and warrants further consideration, particularly in light of emerging therapeutic strategies that specifically target innate immune activation in HIV infection. PMID- 25544987 TI - Partial optimization of the 5-terminal codon increased a recombination porcine pancreatic lipase (opPPL) expression in Pichia pastoris. AB - Pancreatic lipase plays a key role in intestinal digestion of feed fat, and is often deficient in young animals such as weaning piglets. The objective of this study was to express and characterize a partial codon optimized porcine pancreatic lipase (opPPL). A 537 bp cDNA fragment encoding N-terminus amino acid residue of the mature porcine pancreatic lipase was synthesized according to the codon bias of Pichia pastoris and ligated to the full-length porcine pancreatic lipase cDNA fragment. The codon optimized PPL was cloned into the pPICZalphaA (Invitrogen, Beijing, China) vector. After the resultant opPPL/pPICZalphaAlpha plasmid was transformed into P. pastoris, the over-expressed extracellular opPPL containing a His-tag to the C terminus was purified using Ni Sepharose affinity column (GE Healthcare, Piscataway, NJ, USA), and was characterized against the native enzyme (commercial PPL from porcine pancreas, Sigma). The opPPL exhibited a molecular mass of approximately 52 kDa, and showed optimal temperature (40 degrees C), optimal pH (8.0), Km (0.041 mM), and Vmax (2.008 umol x mg protein( 1) x min(-1)) similar to those of the commercial enzyme with p-NPP as the substrate. The recombinant enzyme was stable at 60 degrees C, but lost 80% (P<0.05) of its activity after exposure to heat >=60 degrees C for 20 min. The codon optimization increased opPPL yield for ca 4 folds (146 mg x L(-1) vs 36 mg x L(-1)) and total enzyme activity increased about 5 folds (1900 IU x L(-1) vs 367 IU x L(-1)) compared with those native naPPL/pPICZalphaAlpha tranformant. Comparison of gene copies and mRNA profiles between the two strains indicated the increased rePPL yields may partly be ascribed to the increased protein translational efficiency after codon optimization. In conclusion, we successfully optimized 5-terminal of porcine pancreatic lipase encoding gene and over expressed the gene in P. pastoris as an extracellular, functional enzyme. The recombination enzyme demonstrates a potential for future use as an animal feed additive for animal improvement. PMID- 25544988 TI - Consumption of salted meat and its interactions with alcohol drinking and tobacco smoking on esophageal squamous-cell carcinoma. AB - Etiology of esophageal cancer has not yet been clearly documented, especially in high-risk regions. To evaluate the association between salted meat intake and esophageal squamous-cell carcinoma (ESCC) and to explore its joint effects with alcohol drinking and smoking, a population-based case-control study was conducted in a high ESCC risk area in China, including 942 incident ESCC cases and 942 age- and sex-matching controls. A validated food frequency questionnaire was used to collect information on dietary factors, alcohol drinking and tobacco smoking. Conditional logistic regressions were applied to estimate the association between salted meat intake and ESCC and its interactions with alcohol drinking and smoking, with adjustment for other confounders, including total energy intake. Salted meat intake was associated with an increased risk of ESCC, showing an exposure-response relationship (p for trend <0.001). Consumption of 50 g salted meat per week was related to an increased risk by 18% (odds ratio = 1.18, 95% confidence interval: 1.13-1.23). Salted meat in combination with either alcohol drinking or smoking had a greater risk than salted meat alone, which was more than additive. The strongest association was seen in the combination of all the three factors, particularly at the highest level of salted meat intake (odds ratio = 29.27, 95% confidence interval: 13.21-64.89). Salted meat intake is strongly associated with ESCC and its interactions with alcohol drinking and/or smoking highlights the significance of reducing salted meat intake among smokers and drinkers with respect to ESCC prevention. PMID- 25544989 TI - Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies. AB - This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program. PMID- 25544991 TI - The early history of the eosinophil. AB - In 1879 Paul Ehrlich published his technique for staining blood films and his method for differential blood cell counting using coal tar dyes and mentions the eosinophil for the first time. Eosin is a bright red synthetic dye produced by the action of bromine on fluorescein and stains basic proteins due to its acidic nature. It was discovered in 1874 by Heinrich Caro, Director of the German chemical company Badische Anilin- und Soda-Fabrik. Ehrlich introduced the term 'eosinophil' to describe cells with granules (which he called alpha-granules) having an affinity for eosin and other acid dyes. He also observed black staining, indulinophilic, beta-granules in bone marrow-derived eosinophils, which were probably immature crystalloid granules in eosinophil myelocytes. Ehrlich described the features of the alpha-granule and the cell's distribution in various species and tissues. He speculated correctly that the alpha-granule contents were secretory products and described several causes of eosinophilia including asthma, various skin diseases, helminths and reactions to medications. However, the cell was almost certainly observed by others before Ehrlich. In 1846 Thomas Wharton Jones (1808-1891) described 'granule blood cells' in the lamprey, frog, fowl, horse, elephant and man. He 'borrowed' the term granule cell from Julius Vogel (1814-1880) who had observed similar cells in inflammatory exudates. Vogel in turn was aware of the work of the Gottlieb (Theophile) Gluge (1812-1898) who used the term 'compound inflammatory globules' to describe cells in pus and serum. Almost 20 years before Ehrlich developed his staining methods, Max Johann Sigismund Schultze (1825-1874) performed functional experiments on coarse granular cells using a warm stage microscopic technique and showed they had amoeboid movement and phagocytic abilities. Although these early investigators recognised distinct granular cells Ehrlich's use of stains was a landmark contribution, which heralded modern studies on eosinophils and other blood leucocytes. PMID- 25544990 TI - Secular trends in prevalence of overweight and obesity among adults in rural Tianjin, China from 1991 to 2011: a population-based study. AB - OBJECTIVES: Obesity is associated with cardiovascular diseases and has become the main public health issue in western countries and urban China. However, the prevalence and secular trends of obesity in rural China are currently unknown. The aim of this study was to investigate secular trends in the prevalence of overweight and obesity among rural adults in northern China between 1991 and 2011. METHOD: The prevalence of overweight and obesity was assessed in adults aged 35-74 years living in a rural area in northern China by comparing two surveys that were conducted in 1991 and 2011, respectively. RESULT: The age adjusted prevalence of overweight increased from 24.5% in 1991 to 42.0% in 2011, and the prevalence of obesity increased from 5.7% in 1991 to 19.6% in 2011. Over the 21-year period, there were significant increases in the prevalence of overweight and obesity for both men and women in all age groups; however, the greatest increase was observed in men aged 35-44 years, with an 10.3-fold increase in obesity prevalence. The prevalence of obesity increased significantly in all risk factors categories, including education levels, blood pressure categories, diabetes previous history, current smoking situation and alcohol drinking situation over the past 21 years overall (p<0.05). The greatest increase in obesity prevalence appeared among those who consumed alcohol (increased by 8.0 fold). Next, there was a 5.3-fold increase in the prevalence of obesity in illiterate residents. CONCLUSION: The prevalence of overweight and obesity has increased rapidly among rural adults in Tianjin over the past 21 years, with the most dramatic increase observed in young men. Therefore, the burden of obesity should serve as a call for action. PMID- 25544992 TI - Caenorhabditis elegans: What We Can and Cannot Learn from Aging Worms. AB - SIGNIFICANCE: The nematode Caenorhabditis elegans is a widely used model organism for research into aging. However, nematodes diverged from other animals between 600 and 1300 million years ago. Beyond the intuitive impression that some aspects of aging appear to be universal, is there evidence that insights into the aging process of nematodes may be applicable to humans? RECENT ADVANCES: There have been a number of results in nematodes that appear to contradict long-held beliefs about mechanisms and causes of aging. For example, ablation of several key antioxidant systems has often failed to result in lifespan shortening in C. elegans. CRITICAL ISSUES: While it is clear that some central signaling pathways controlling lifespan are broadly conserved across large evolutionary distances, it is less clear to what extent downstream molecular mechanisms of aging are conserved. In this review we discuss the biology of C. elegans and mammals in the context of aging and age-dependent diseases. We consider evidence from studies that attempt to investigate basic, possibly conserved mechanisms of aging especially in the context of the free radical theory of aging. Practical points, such as the need for blinding of lifespan studies and for appropriate biomarkers, are also considered. FUTURE DIRECTIONS: As data on the aging process(es) in different organisms increase, it is becoming increasingly clear that there are both conserved (public) and private aspects to aging. It is important to explore the dividing lines between these two aspects and to be aware of the large gray areas in-between. PMID- 25544993 TI - Self-reported pain perception of patients after mucosal graft harvesting in the palatal area. AB - AIM: To evaluate the patient-reported pain perception after palatal graft harvesting during a 4 weeks healing period MATERIALS & METHODS: Ninety patients, scheduled for different periodontal and peri-implant plastic surgeries requiring palatal mucosal graft harvesting, were consecutively recruited. Mucosal thickness was measured at the donor sites with an ultrasonic device prior to the surgeries. Graft thickness, length, and width were assessed after harvesting, and the wound areas were calculated. Based on a Visual Analogue Scale (VAS), the patients were asked to report their perceived pain after the intervention and 1, 3, 7, 14, 21 and 28 days thereafter. RESULTS: Pain was most pronounced on the first postoperative day and decreased within the course of time. Graft thickness directly correlated with the amount of pain perceived while increased palatal mucosal thickness before and after graft harvesting decreased pain levels. The denuded wound surface area, however, did not influence the perceived pain level. CONCLUSIONS: The wound depth at the donor site (graft thickness) was positively correlated with the patient's perception for pain. The wound surface area, however, did not influence the perceived pain level. PMID- 25544996 TI - New conversations about health reform and academic health centers: introducing a new feature in Academic Medicine. PMID- 25544995 TI - Degradation of carbon tetrachloride in aqueous solution in the thermally activated persulfate system. AB - Thermal activation of persulfate (PS) has been identified to be effective in the destruction of organic pollutants. The feasibility of carbon tetrachloride (CT) degradation in the thermally activated PS system was evaluated. The experimental results showed that CT could be readily degraded at 50 degrees C with a PS concentration of 0.5M, and CT degradation and PS consumption followed the pseudo first order kinetic model. Superoxide radical anion (O2(*-)) was the predominant radical species responsible for CT degradation and the split of CCl was proposed as the possible reaction pathways for CT degradation. The process of CT degradation was accelerated by higher PS dose and lower initial CT concentration. No obvious effect of the initial pH on the degradation of CT was observed in the thermally activated PS system. Cl(*-), HCO3(*-), and humic acid (HA) had negative effects on CT degradation. In addition, the degradation of CT in the thermally activated PS system could be significantly promoted by the solvents addition to the solution. In conclusion, the thermally activated PS process is a promising option in in-situ chemical oxidation/reduction remediation for degrading highly oxidized organic contaminants such as CT that is widely detected in contaminated sites. PMID- 25544994 TI - Soluble macrophage biomarkers indicate inflammatory phenotypes in patients with knee osteoarthritis. AB - OBJECTIVE: To evaluate the ability of the macrophage markers CD163 and CD14 to predict different osteoarthritis (OA) phenotypes defined by severity of joint inflammation, radiographic features and progression, and joint pain. METHODS: We evaluated 2 different cohorts totaling 184 patients with radiographic knee OA. These included 25 patients from a cross-sectional imaging study for whom there were data on activated macrophages in the knee joint, and 159 patients (134 with 3-year longitudinal data) from the longitudinal Prediction of Osteoarthritis Progression study. Multivariable linear regression models with generalized estimating equations were used to assess the association of CD163 and CD14 in synovial fluid (SF) and blood with OA phenotypic outcomes. Models were adjusted for age, sex, and body mass index. P values less than or equal to 0.05 were considered significant. RESULTS: SF CD14, SF CD163, and serum CD163 were associated with the abundance of activated macrophages in the knee joint capsule and synovium. SF CD14 was positively associated with severity of joint space narrowing and osteophytes in both cohorts. SF and plasma CD14 were positively associated with self-reported knee pain severity in the imaging study. Both SF CD14 and SF CD163 were positively associated with osteophyte progression. CONCLUSION: Soluble macrophage biomarkers reflected the abundance of activated macrophages and appeared to mediate structural progression (CD163 and CD14) and pain (CD14) in OA knees. These data support the central role of inflammation as a determinant of OA severity, progression risk, and clinical symptoms, and they suggest a means of readily identifying a subset of patients with an active inflammatory state and worse prognosis. PMID- 25544997 TI - Youthful critics: the medical student voice in health reform. PMID- 25544998 TI - More on "fast" and "slow" thinking in diagnostic reasoning. PMID- 25544999 TI - In reply to Webster. PMID- 25545000 TI - Rethinking the role of conferences in academia. PMID- 25545001 TI - In reply to Walsh. PMID- 25545002 TI - Academic medicine in a transformational time. AB - Public policy and technology are having and will continue to have an extraordinary impact on virtually every aspect of academic medicine. The effects of this combination of policy and technology transformations can hardly be overstated. It is critical to recognize these transformative forces and work to accept and even embrace them enthusiastically. The author examines five major transformative forces affecting academic medicine today: big data, greater transparency, new payment models, emphasis on wellness, and scope of practice. He discusses each of these transformative forces within the context of the current U.S. health care environment and offers suggestions for academic medicine to leverage them. It will take resiliency, innovation, collaboration, engagement in public policy debates, and strong leadership for this country to make the U.S. health care system the success it should be. PMID- 25545003 TI - Contact/Isolation. PMID- 25545004 TI - Artists' statement: composition of character. PMID- 25545005 TI - Medicine and the arts. In Drear-Nighted December: by John Keats. Commentary. PMID- 25545007 TI - A mechanistic study of thioester hydrolysis with heavy atom kinetic isotope effects. AB - The carbonyl-C, carbonyl-O, and leaving-S kinetic isotope effects (KIEs) were determined for the hydrolysis of formylthiocholine. Under acidic conditions, (13)k(obs) = 1.0312, (18)k(obs) = 0.997, and (34)k(obs) = 0.995; for neutral conditions, (13)k(obs) = 1.022, (18)k(obs) = 1.010, and (34)k(obs) = 0.996; and for alkaline conditions, (13)k(obs) = 1.0263, (18)k(obs) = 0.992, and (34)k(obs) = 1.000. The observed KIEs provided helpful insights into a qualitative description of the bond orders in the transition state structure. PMID- 25545009 TI - Full-term newborn after repeated ovarian tissue transplants in a patient treated for Ewing sarcoma by sterilizing pelvic irradiation and chemotherapy. AB - We report the first successful transplantation of cryopreserved ovarian cortical tissue into heavily irradiated tissues in a patient who had received sterilizing pelvic radiotherapy (54 Gy) and 40 weeks of intensive high-dose chemotherapy for the treatment of Ewing's sarcoma 14 years earlier. Repeated transplantation procedures were required to obtain fully functional follicular development. Enlargement of the transplants over time and increase of the size of the uterus were demonstrated on sequential ultrasonographic examinations. Eggs of good quality that could be fertilized in vitro were obtained only after a substantial incremental increase of the amount of ovarian tissue transplanted. Single embryo replacement resulted in a normal pregnancy and the birth of a healthy child by cesarean section at full-term. No neonatal or maternal postoperative complications occurred. Women facing high-dose pelvic radiotherapy should not be systematically excluded from fertility preservation options, as is currently the trend. PMID- 25545008 TI - Differences between disease-associated endoplasmic reticulum aminopeptidase 1 (ERAP1) isoforms in cellular expression, interactions with tumour necrosis factor receptor 1 (TNF-R1) and regulation by cytokines. AB - Endoplasmic reticulum aminopeptidase 1 (ERAP1) processes peptides for major histocompatibility complex (MHC) class I presentation and promotes cytokine receptor ectodomain shedding. These known functions of ERAP1 may explain its genetic association with several autoimmune inflammatory diseases. In this study, we identified four novel alternatively spliced variants of ERAP1 mRNA, designated as DeltaExon-11, DeltaExon-13, DeltaExon-14 and DeltaExon-15. We also observed a rapid and differential modulation of ERAP1 mRNA levels and spliced variants in different cell types pretreated with lipopolysaccharide (LPS). We have studied three full-length allelic forms of ERAP1 (R127-K528, P127-K528, P127-R528) and one spliced variant (DeltaExon-11) and assessed their interactions with tumour necrosis factor receptor 1 (TNF-R1) in transfected cells. We observed variation in cellular expression of different ERAP1 isoforms, with R127-K528 being expressed at a much lower level. Furthermore, the cellular expression of full length P127-K528 and DeltaExon-11 spliced variant was enhanced significantly when co-transfected with TNF-R1. Isoforms P127-K528, P127-R528 and DeltaExon-11 spliced variant associated with TNF-R1, and this interaction occurred in a region within the first 10 exons of ERAP1. Supernatant-derived vesicles from transfected cells contained the full-length and ectodomain form of soluble TNF-R1, as well as carrying the full-length ERAP1 isoforms. We observed marginal differences between TNF-R1 ectodomain levels when co-expressed with individual ERAP1 isoforms, and treatment of transfected cells with tumour necrosis factor (TNF), interleukin (IL)-1beta and IL-10 exerted variable effects on TNF-R1 ectodomain cleavage. Our data suggest that ERAP1 isoforms may exhibit differential biological properties and inflammatory mediators could play critical roles in modulating ERAP1 expression, leading to altered functional activities of this enzyme. PMID- 25545011 TI - A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels. AB - BACKGROUND: In a cohort of well-characterized patients with different degrees of knee osteoarthritis (OA) and pain, the aims were to utilize mechanism-based quantitative sensory testing (QST) to (1) characterize subgroups of patients; (2) analyse the associations between clinical characteristics and QST; and (3) develop and apply a QST-based knee OA composite pain sensitivity index for patient classification. METHODS: Two hundred seventeen OA pain patients and 64 controls were included. Kellgren and Lawrence (KL) grading scores were obtained, and pressure pain thresholds (PPTs), temporal summation of pain to repeated painful pressure stimulation and conditioning pain modulation (CPM) were assessed. Associations between pain score/area/duration, radiological findings and QST-related parameters were analysed. A pain sensitivity index was developed and applied based on PPT, temporal summation and CPM. z-Score, as statistical tool, was calculated for statistically comparing the pain index of a single patient with a healthy control group. RESULTS: High knee pain associated with low KL grade showed particular signs of pain sensitization. Patients showed significant associations between clinical knee pain intensity/duration and lowering of knee PPTs (p < 0.01), facilitation of temporal summation (p < 0.01), reduction of CPM function (p < 0.01) and high pain sensitivity index (p < 0.01). The index classified 27-38% of the OA patients and 3% of the controls as highly sensitive with no association to KL. The index increased for high knee pain intensities and long pain duration. CONCLUSIONS: Radiological scores, contrary to clinical pain intensity/duration, were poorly associated with QST parameters. The pain sensitivity index could classify OA patients with different degrees of OA and pain. PMID- 25545010 TI - Differential binding of Lef1 and Msx1/2 transcription factors to Dkk1 CNEs correlates with reporter gene expression in vivo. AB - Besides the active Wnt signalling itself, the extracellular inhibition by Dkk1 is important for various embryonic developmental processes, such as optic vesicle differentiation and facial outgrowth. Although a feedback crosstalk of the active Wnt/beta-catenin signaling and Dkk1 regulation has been suggested, the control of Dkk1 transcription by the Tcf/Lef1 mediated Wnt signalling and its connection to additional signalling factors has not been elucidated in vivo. Here, we used a combination of transgenic mouse approaches and biochemical analyses to unravel the direct Dkk1 transcriptional regulation via Tcf/Lefs. By using site directed mutagenesis, we tested several conserved Tcf/Lef1 binding sites within Dkk1 conserved non-coding elements (CNEs) and found that these are required for tissue specific reporter expression. In addition a conserved Msx1/2 binding site is required for retinal reporter expression and Msx2 but not Msx1 binds its conserved binding site within CNE195 in the optic cups. Within craniofacial expression domains, Lef1 interferes with Dkk1 directly via two conserved Tcf/Lef1 binding sites in the craniofacial enhancer CNE114, both of which are required for the general craniofacial Dkk1 reporter activation. Furthermore, these Tcf/Lef1 sites are commonly bound in the whisker hair bud mesenchyme but specifically Tcf/Lef1 (no. 2) is required for mandibular activation and repression of maxillar Dkk1 activation. Lastly, we tested the Tcf/Lef1 binding capacities of the Dkk1 promoter and found that although Lef1 binds the Dkk1 promoter, these sites are not sufficient for tissue specific Dkk1 activation. Together, we here present the importance of conserved Tcf/Lef1 and Msx1/2 sites that are required for differential Dkk1 transcriptional reporter activation in vivo. This requirement directly correlates with Lef1 and Msx1/2 interaction with these genomic loci. PMID- 25545013 TI - Enrichment of denitrifying methane-oxidizing microorganisms using up-flow continuous reactors and batch cultures. AB - Denitrifying anaerobic methane oxidizing (DAMO) microorganisms were enriched from paddy field soils using continuous-flow and batch cultures fed with nitrate or nitrite as a sole electron acceptor. After several months of cultivation, the continuous-flow cultures using nitrite showed remarkable simultaneous methane oxidation and nitrite reduction and DAMO bacteria belonging to phylum NC10 were enriched. A maximum volumetric nitrite consumption rate of 70.4+/-3.4 mg-N.L( 1).day(-1) was achieved with very short hydraulic retention time of 2.1 hour. In the culture, about 68% of total microbial cells were bacteria and no archaeal cells were detected by fluorescence in situ hybridization. In the nitrate-fed continuous-flow cultures, 58% of total microbial cells were bacteria while archaeal cells accounted for 7% of total cell numbers. Phylogenetic analysis of pmoA gene sequence showed that enriched DAMO bacteria in the continuous-flow cultivation had over 98% sequence similarity to DAMO bacteria in the inoculum. In contrast, for batch culture, the enriched pmoA gene sequences had 89-91% sequence similarity to DAMO bacteria in the inoculum. These results indicate that electron acceptor and cultivation method strongly affect the microbial community structures of DAMO consortia. PMID- 25545012 TI - Citrate synthase expression affects tumor phenotype and drug resistance in human ovarian carcinoma. AB - Citrate synthase (CS), one of the key enzymes in the tricarboxylic acid (TCA) cycle, catalyzes the reaction between oxaloacetic acid and acetyl coenzyme A to generate citrate. Increased CS has been observed in pancreatic cancer. In this study, we found higher CS expression in malignant ovarian tumors and ovarian cancer cell lines compared to benign ovarian tumors and normal human ovarian surface epithelium, respectively. CS knockdown by RNAi could result in the reduction of cell proliferation, and inhibition of invasion and migration of ovarian cancer cells in vitro. The drug resistance was also inhibited possibly through an excision repair cross complementing 1 (ERCC1)-dependent mechanism. Finally, upon CS knockdown we observed significant increase expression of multiple genes, including ISG15, IRF7, CASP7, and DDX58 in SKOV3 and A2780 cells by microarray analysis and real-time PCR. Taken together, these results suggested that CS might represent a potential therapeutic target for ovarian carcinoma. PMID- 25545014 TI - Diadenosine polyphosphates in the tears of aniridia patients. AB - PURPOSE: To quantify diadenosine polyphosphate levels in tears of congenital aniridia patients to estimate the ocular surface changes associated with congenital aniridia compared to normal individuals. METHODS: Fifteen patients diagnosed with congenital aniridia and a control group of forty volunteers were studied. Tears were collected to quantify the levels of diadenosine polyphosphates Ap4 A and Ap5 A by high-performance liquid chromatography (H.P.L.C). Break-up time (BUT), corneal staining, McMonnies questionnaire and the Schirmer I test were applied to both groups. RESULTS: Dinucleotides in congenital aniridia patients were higher than in control subjects. For the congenital aniridia group, under 15 years old, the values were 0.77 +/- 0.01 MUm and 0.17 +/ 0.02 MUm for Ap4 A and Ap5 A, respectively. The group aged from 15 to 40 years old provided concentrations of 4.37 +/- 0.97 MUm and 0.46 +/- 0.05 MUm for Ap4 A and Ap5 A, the group over 40 gave concentrations of 11.17 +/- 5.53 MUm and 0.68 +/- 0.17 MUm for Ap4 A and Ap5 A. Dinucleotide concentrations increased with age, being statistically significant different among the three age groups (p < 0.05). Congenital aniridia patients showed a normal tear secretion and no dry eye McMonnies scores, except for the group over 40 years old. BUT values decreased and corneal staining increased with age and correlated with the levels of diadenosine polyphosphates (p < 0.05). CONCLUSIONS: The levels of dinucleotides in tears increase in aniridia patients compared with healthy subjects, and they seem to be related with the progression of corneal disorders in aniridia patients, both of which increase with ageing. PMID- 25545015 TI - Motivations for having children after cancer--a systematic review of the literature. AB - Over the last decade, fertility-related issues have come to the fore of clinical oncology. The majority of research though has focused on a medical perspective without considering reproductive motivations that influence decisions on fertility-preserving options. In order to identify specific parenthood motivations in young survivors of various types of cancer, a systematic review of the literature was conducted. Relevant literature was searched manually and using databases (Medline/PubMed, PsycInfo). Of 4848 articles retrieved, 20 studies met a priori defined inclusion criteria. Cancer was found to have a likely effect on reproductive intentions. All studies reported on specific reproductive concerns, mostly related to negative consequences for the patient or on the future child. Pregnancy concerns were overrepresented in breast cancer survivors. Practical barriers to post-cancer parenthood were financial or partner-referred. Overall, fewer incentives than disincentives for post-cancer parenthood were reported. They included the importance of parenthood, achieving normality and a desire to focus on the positive. As reproductive motivations and concerns affect the majority of cancer survivors of reproductive age, they should be assessed as early as possible post-diagnosis. While researchers should focus on the development of appropriate assessment methods, clinicians might address specific reproductive concerns. PMID- 25545016 TI - Acne conglobata and adalimumab: use of tumour necrosis factor-alpha antagonists in treatment-resistant acne conglobata, and review of the literature. AB - Acne conglobata (AC) is a chronic, severe, inflammatory variant of acne characterized by development of cystic nodules, abscesses and sinus tracts. AC may prove resistant to conventional acne therapy. The off-label use of adalimumab for the treatment of AC has been reported recently. We present a 26-year-old man with AC resistant to conventional treatment, who was treated with 40 mg adalimumab every other week, with significant clinical improvement. We review the evidence for the use of tumour necrosis factor antagonists in AC and related conditions. This case provides further evidence supporting the role of adalimumab in the treatment of AC. PMID- 25545017 TI - A rhodanine flanked nonfullerene acceptor for solution-processed organic photovoltaics. AB - A novel small molecule, FBR, bearing 3-ethylrhodanine flanking groups was synthesized as a nonfullerene electron acceptor for solution-processed bulk heterojunction organic photovoltaics (OPV). A straightforward synthesis route was employed, offering the potential for large scale preparation of this material. Inverted OPV devices employing poly(3-hexylthiophene) (P3HT) as the donor polymer and FBR as the acceptor gave power conversion efficiencies (PCE) up to 4.1%. Transient and steady state optical spectroscopies indicated efficient, ultrafast charge generation and efficient photocurrent generation from both donor and acceptor. Ultrafast transient absorption spectroscopy was used to investigate polaron generation efficiency as well as recombination dynamics. It was determined that the P3HT:FBR blend is highly intermixed, leading to increased charge generation relative to comparative devices with P3HT:PC60BM, but also faster recombination due to a nonideal morphology in which, in contrast to P3HT:PC60BM devices, the acceptor does not aggregate enough to create appropriate percolation pathways that prevent fast nongeminate recombination. Despite this nonoptimal morphology the P3HT:FBR devices exhibit better performance than P3HT:PC60BM devices, used as control, demonstrating that this acceptor shows great promise for further optimization. PMID- 25545018 TI - Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism. AB - OBJECTIVE: The treatment of schizophrenia is multifactorial, with antipsychotic medications comprising a major part of treatment. Paliperidone is a newly commercialized antipsychotic whose formulation includes the principal active metabolite risperidone, 9-hydroxyrisperidone. Ever since the relationship between schizophrenia and oxidative stress was first demonstrated, many studies have been conducted in order to probe the potential protective effects of antipsychotic drugs on the oxidant-antioxidant system and lipid peroxidation. The basic aim of this study is to determine the effects of the newly marketed drug paliperidone on the activities of the enzymes adenosine deaminase (ADA), xanthine oxidase (XO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) as well as on malondialdehyde (MDA) and nitric oxide (NO) levels in rat brain tissues. METHODS: Twenty male Sprague-Dawley rats were used for the study, which were divided into two equal groups. The first was the control group (n = 10) and the second was the paliperidone group (n = 10). Saline was administered once daily for 14 days in the control group. In the paliperidone group, paliperidone was administered once daily with a dose of 1 mg/kg for 14 days. All rats were sacrificed at the end of the fourteenth day. Brain samples were collected and then analyzed. RESULTS: Our results demonstrated that paliperidone significantly decreased the activities of ADA (P = 0.015), XO (P = 0.0001), and CAT (P = 0.004) while insignificantly increasing the activity of SOD (P = 0.49), MDA (P = 0.71), and NO (P = 0.26) levels in rat brain tissues. In addition, paliperidone insignificantly decreased the activity of GSH-Px (P = 0.30) compared to the control group in rat brain tissues. DISCUSSION: In conclusion, the data obtained in this study suggest that paliperidone can positively alter antioxidant status and, accordingly, can offer positive outcomes in the treatment of schizophrenia by reducing activity in the enzymes ADA and XO, which are associated with purine metabolism. We believe that such a comprehensive approach used with other antipsychotic drugs warrants further study. PMID- 25545019 TI - Plasmacytoid dendritic cells in alopecia areata: missing link? AB - BACKGROUND: Type I interferon (IFN) signature has been implicated in alopecia areata (AA). However, type I IFN source has never been documented. Plasmacytoid dendritic cells (PDCs) are generally known to be the main source and most potent producers of local type I IFNs. Their role in AA pathogenesis has never been investigated. OBJECTIVE: Investigate PDC role in AA. METHODS: Nineteen AA cases were retrieved from our database and were immunohistochemically tested for PDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies respectively. Comparison to 10 trichotillomania and 7 androgenetic alopecia (AGA) cases was also done. RESULTS: Plasmacytoid dendritic cells were present in all AA cases in a peri-bulbar location and, as indirectly assessed by MxA expression, were in an active state producing type I IFNs. All trichotillomania cases showed the presence of PDCs, though significantly less abundant and in a different distribution (mainly superficial perivascular) than that in AA. PDC presence and MxA expression were absent in AGA. CONCLUSIONS: Plasmacytoid dendritic cells constitute a central component of the peribulbar infiltrate in AA suggesting a significant role in AA pathogenesis. Additionally, PDC distribution could help in microscopically differentiating AA from trichotillomania or AGA. PMID- 25545020 TI - Low risk of liver decompensation among human immunodeficiency virus/hepatitis C virus-coinfected patients with mild fibrosis in the short term. AB - Liver fibrosis is used to make decisions about the timing of therapy against hepatitis C virus (HCV) in routine clinical practice, which should be based on the short-term likelihood of liver decompensations. Thus, we aimed at evaluating the risk of decompensations and death among human immunodeficiency virus (HIV)/HCV-coinfected individuals according to their baseline fibrosis classified by either liver biopsy or liver stiffness measurement (LSM). Patients coinfected with HIV/HCV, naive or without sustained virological response to HCV therapy, were included in this cohort. Fibrosis was classified by biopsy in 683 patients and by LSM in 1046 individuals. Reference categories were fibrosis stage 0 and LSM <6 kPa. For patients with biopsy, the adjusted subhazard ratio for decompensations and 95% confidence interval (95% CI) by fibrosis stage were as follows: stage 1, 2.3 (0.27-20.3), P = 0.443; stage 2, 2.8 (0.33-24), P = 0.345; stage 3, 4.91 (0.60-41), P = 0.137; stage 4, 9.89 (1.25-79.5), P = 0.030. For patients with LSM, the adjusted subhazard ratio and 95% CI by LSM category were as follows: 6-9.4 kPa, 1.89 (0.18-20.3), P = 0.599; 9.5-14.5 kPa, 6.59 (0.73 59.2), P = 0.092; >=14.6 kPa, 59.5 (8.3-427), P < 0.0001. Regarding the risk of death, the adjusted hazard ratio and 95% CI for death by fibrosis stage were as follows: stage 1, 1.3 (0.4-4.11), P = 0.677; stage 2, 2.68 (0.86-8.36), P = 0.090; stage 3, 2.58 (0.82-8.15), P = 0.106; stage 4, 4.35 (1.43-13.3), P = 0.010. For patients with LSM, the adjusted hazard ratio and 95% CI for death by LSM were as follows: 6-9.4 kPa, 1.7 (0.63-4.79), P = 0.288; 9.5-14.5 kPa, 3.38 (1.2-9.5), P = 0.021; >=14.6 kPa, 12.7 (4.9-33.6), P < 0.0001. CONCLUSION: Patients coinfected with HIV/HCV without advanced fibrosis are at very low risk of decompensations in the short term; deferral of HCV therapy for a few years and monitoring fibrosis progression is a safe option until cheaper, more effective, and more convenient HCV treatment becomes widely available. PMID- 25545021 TI - Functional role of the KCa3.1 potassium channel in synovial fibroblasts from rheumatoid arthritis patients. AB - Rheumatoid arthritis synovial fibroblasts (RA-SFs) show an aggressive phenotype and support joint inflammation and tissue destruction. New druggable targets in RA-SFs would therefore be of high therapeutic interest. The present study shows that the intermediate-conductance, calcium-activated potassium channel KCa3.1 (KCNN4) is expressed at the mRNA and protein level in RA-SFs, is functionally active, and has a regulatory impact on cell proliferation and secretion of pro inflammatory and pro-destructive mediators. Whole-cell patch-clamp recordings identified KCa3.1 as the dominant potassium channel in the physiologically relevant membrane voltage range below 0 mV. Stimulation with transforming growth factor beta1 (TGF-beta1) significantly increased transcription, translation, and channel function of KCa3.1. Inhibition of KCa3.1 by the selective, pore-blocking inhibitor TRAM-34, (and, in part, by siRNA) significantly reduced cell proliferation, as well as expression and secretion of pro-inflammatory factors (IL-6, IL-8, and MCP1) and the tissue-destructive protease MMP3. These effects were observed in non-stimulated and/or TGF-beta1-stimulated RA-SFs. Since small molecule-based interference with KCa3.1 is principally well tolerated in clinical settings, further evaluation of channel blockers in models of rheumatoid arthritis may be a promising approach to identify new pharmacological targets and develop new therapeutic strategies for this debilitating disease. PMID- 25545022 TI - Nature and origin of "squirting" in female sexuality. AB - INTRODUCTION: During sexual stimulation, some women report the discharge of a noticeable amount of fluid from the urethra, a phenomenon also called "squirting." To date, both the nature and the origin of squirting remain controversial. In this investigation, we not only analyzed the biochemical nature of the emitted fluid, but also explored the presence of any pelvic liquid collection that could result from sexual arousal and explain a massive fluid emission. METHODS: Seven women, without gynecologic abnormalities and who reported recurrent and massive fluid emission during sexual stimulation, underwent provoked sexual arousal. Pelvic ultrasound scans were performed after voluntary urination (US1), and during sexual stimulation just before (US2) and after (US3) squirting. Urea, creatinine, uric acid, and prostatic-specific antigen (PSA) concentrations were assessed in urinary samples before sexual stimulation (BSU) and after squirting (ASU), and squirting sample itself (S). RESULTS: In all participants, US1 confirmed thorough bladder emptiness. After a variable time of sexual excitation, US2 (just before squirting) showed noticeable bladder filling, and US3 (just after squirting) demonstrated that the bladder had been emptied again. Biochemical analysis of BSU, S, and ASU showed comparable urea, creatinine, and uric acid concentrations in all participants. Yet, whereas PSA was not detected in BSU in six out of seven participants, this antigen was present in S and ASU in five out of seven participants. CONCLUSIONS: The present data based on ultrasonographic bladder monitoring and biochemical analyses indicate that squirting is essentially the involuntary emission of urine during sexual activity, although a marginal contribution of prostatic secretions to the emitted fluid often exists. PMID- 25545023 TI - Impact of appropriate empirical antimicrobial therapy on outcome of dogs with septic peritonitis. AB - OBJECTIVE: To determine whether appropriate empirical antimicrobial therapy influenced survival in dogs with septic peritonitis. DESIGN: Retrospective case series (2003-2011). SETTING: University teaching hospital. ANIMALS: Eighty-six dogs with cytological confirmation or positive bacterial culture of abdominal sepsis and subsequent surgical intervention. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Forty-nine of 86 dogs (57%) survived to hospital discharge. Thirty seven of 86 dogs were classified as having ''abdominal infection,'' 31/86 as ''severe sepsis,'' and the remaining 18/86 as in ''septic shock.'' Mortality was greatest in the ''septic shock'' category (94%). Empirical antimicrobial treatments were appropriate in 41/78 dogs (52.6%). Appropriateness was not associated with treatment outcome overall or when compared between sepsis severity groups. Antimicrobials had been given in the 30 days before admission in 63/86 (73.3%) dogs. Prior therapy with antimicrobials showed no association with outcome (P = 0.512) but was associated with subsequent inappropriate empirical antimicrobial selection (P = 0.031). Recent abdominal surgery was associated with subsequent inappropriate empirical antimicrobial selection (P = 0.021). CONCLUSIONS: In this population, appropriateness of empirical antimicrobial choice was not associated with survival to discharge. Previous antimicrobial administration or abdominal surgery was associated with subsequent inappropriate empirical antimicrobial selection. PMID- 25545024 TI - A note on response-adaptive randomization. PMID- 25545025 TI - Dissemination of the Look AHEAD intensive lifestyle intervention in the United States Air Force: study rationale, design and methods. AB - BACKGROUND: Despite an increase in overweight and obesity similar to the civilian population, there have been few randomized controlled trials examining behavioral weight management interventions in the military settings. PURPOSE: This paper describes the design, intervention development and analysis plan of the Fit Blue study, a randomized controlled behavioral weight loss trial taking place in the United States Air Force. DESIGN: This study compares two adapted versions of the efficacious Look AHEAD Intensive Lifestyle Intervention (ILI), a counselor initiated condition and a self-paced condition. Also described are the unique steps required when conducting military-based health promotion research and adaptations made to the Look AHEAD intervention to accommodate the military environment. CONCLUSIONS: To our knowledge, this is the first translation of the Look AHEAD ILI in the military setting and one of the first translations of the ILI in general. If successful, this intervention could be disseminated to the entire U.S. Military as this project is designed to overcome the barriers and utilize the facilitators for weight loss that are unique to a military population. Programs validated in military populations can have a major public health impact given that with 1.4 million active duty personnel, the Department of Defense is the nation's largest employer. However, while this intervention is designed for a military population and there are unique aspects of the military that may enhance weight loss interventions, the diversity of the study population should help inform obesity efforts in both civilian and military settings. PMID- 25545026 TI - Effect of switching from intramuscular interferon beta-1a to oral fingolimod on time to relapse in patients with relapsing-remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS. AB - BACKGROUND: In the absence of controlled, parallel-group studies, statistical methods developed to estimate treatment effects in patients receiving alternative/rescue treatment in clinical trials may be used to estimate the effects of multiple sclerosis (MS) therapy switch using available clinical trial data. OBJECTIVE: To use TRANSFORMS data and parametric models to assess the time to first confirmed relapse in MS patients who switched from intramuscular interferon beta-1a (IFNbeta-1a IM) 30 MUg/mL once weekly to oral fingolimod 0.5 or 1.25mg once daily vs. remaining on IFNbeta-1a IM. METHODS: Post hoc analyses were conducted using data from the intent-to-treat population. The Branson and Whitehead switch model with iterative parameter estimation was used to estimate the ratio of the observed time to first confirmed relapse over the estimated time. RESULTS: Log-linear regression model results showed that fingolimod 0.5 and 1.25mg prolonged time to relapse, with an estimated median time to first relapse of 5.07 years (P=0.0026 vs. IFNbeta-1a IM) and 4.11 years (P=0.0113), respectively, versus 2.26 years with IFNbeta-1a IM. The estimated ratio of observed time to first confirmed relapse to the estimated time had the patient remained on IFNbeta-1a IM was 2.09 (95% CI, 1.45-3.04) for switching to fingolimod 0.5mg and 1.84 (95% CI, 1.30-2.65) for switching to fingolimod 1.25mg. CONCLUSION: During the extension, time to first confirmed relapse was approximately doubled in patients switching from IFNbeta-1a IM to fingolimod. These analytic methods may be useful in evaluating treatment switch effects in clinical trials with extension data. PMID- 25545028 TI - Synthetic polymers are more effective than natural flocculants for the clarification of tobacco leaf extracts. AB - The use of synthetic polymers as flocculants can increase filter capacity and thus reduce the costs of downstream processing during the production of plant derived biopharmaceutical proteins, but this may also attract regulatory scrutiny due to the potential toxicity of such compounds. Therefore, we investigated the efficacy of three non-toxic natural flocculants (chitosan, kaolin and polyphosphate) alone and in combination with each other or with a synthetic polymer (Polymin P) during the clarification of tobacco leaf extracts. We used a design-of-experiments approach to determine the impact of each combination on filter capacity. We found that Polymin P was most effective when used on its own but the natural flocculants were more effective when used in combination. The combination of chitosan and polyphosphate was the most effective natural flocculant, and this was identified as a potential replacement for Polymin P under neutral and acidic extraction conditions independent of the conductivity, even though the efficiency of flocculation was lower than for Polymin P. None of the tested flocculants reduced the concentration of total soluble protein in the feed stream or the recovery of the model fluorescent protein DsRed. PMID- 25545027 TI - Using registries to recruit subjects for clinical trials. AB - AIM: We studied the use of patient/disease registries to recruit potential subjects for prospective clinical trials - describing the number, types and major benefits of using this approach. METHODS: In December 2013, we conducted a focused database search in PubMed, EMBASE, and Web of Science for studies (English language only) that used registries to recruit subjects for clinical trials published in 2004-2013. Of the 233 unique citations identified, 21 used registries to recruit subjects - 10 papers and 11 abstracts. Pearling and search for subsequent full papers of the abstracts identified 4 more papers. RESULTS: Our analysis, based on these 25 citations, showed that 14 are related to cancer, 3 to diabetes mellitus, 1 each to stroke, asthma, and celiac disease and 5 are disease neutral. Many types of registries (population-based cancer, quality improvement, disease-specific, web-based disease-neutral registries, local general practice registers, and national health database) are used to recruit subjects for clinical trials and uncover new knowledge. Overall, 16 registries are in the US, 4 in UK, 1 each in Canada, Spain, and Australia and 1 involved in many countries. Registries can identify very large number of subjects for screening for eligibility for clinical trials, especially in very large trials, rare disease trials, and trials involving minority patients. CONCLUSIONS: Registries can retrospectively identify very large numbers of potential subjects for screening for eligibility and enrollment in prospective clinical trials. This matching can lead to more timely recruitment and help solve a major problem in conducting clinical trials. PMID- 25545029 TI - A novel in vitro permeability assay using three-dimensional cell culture system. AB - Three-dimensional (3D) cell culture systems are well-known to better represent the in vivo environment and they are applied to many areas of research. Spheroid model is one of the systems of 3D cell culture and here in our research, a permeability assay utilizing the spheroids was developed. Number of cells forming the spheroids, initial compound concentration, and incubation time were optimized to provide the best assay performance. After development of the assay, it was evaluated with 22 commercially available compounds. The developed Caco-2 3D spheroid permeability assay demonstrated a reasonable correlation with human absorption values. The parallel artificial membrane permeability assay (PAMPA) was also performed for the same set of compounds and the results were compared with those of the 3D permeability assay. The correlation with human absorption values was shown to be improved with the 3D permeability assay. The successful development of the Caco-2 3D spheroid permeability assay also suggests the potential application of the 3D cell culture systems to other areas of pharmacokinetic research. PMID- 25545031 TI - Microsurgery training using a smartphone. PMID- 25545030 TI - Altitude training causes haematological fluctuations with relevance for the Athlete Biological Passport. AB - The impact of altitude training on haematological parameters and the Athlete Biological Passport (ABP) was evaluated in international-level elite athletes. One group of swimmers lived high and trained high (LHTH, n = 10) for three to four weeks at 2130 m or higher whereas a control group (n = 10) completed a three week training camp at sea-level. Haematological parameters were determined weekly three times before and four times after the training camps. ABP thresholds for haemoglobin concentration ([Hb]), reticulocyte percentage (RET%), OFF score and the abnormal blood profile score (ABPS) were calculated using the Bayesian model. After altitude training, six swimmers exceeded the 99% ABP thresholds: two swimmers exceeded the OFF score thresholds at day +7; one swimmer exceeded the OFF score threshold at day +28; one swimmer exceeded the threshold for RET% at day +14; and one swimmer surpassed the ABPS threshold at day +14. In the control group, no values exceeded the individual ABP reference range. In conclusion, LHTH induces haematological changes in Olympic-level elite athletes which can exceed the individually generated references in the ABP. Training at altitude should be considered a confounding factor for ABP interpretation for up to four weeks after altitude exposure but does not consistently cause abnormal values in the ABP. PMID- 25545032 TI - Microbial dose response modeling: past, present, and future. AB - The understanding of the risk to humans from exposure to pathogens has been firmly put into a risk assessment framework. A key element of applying this approach is the understanding of the relationship between dose and response for particular pathogens. This understanding has progressed from early use of threshold concepts ("minimal infectious dose") thru multiple generations of models. Generation 1 models describe probability of response to exposed dose. Generation 2 models incorporate host factors (e.g., age) and/or pathogen factors (e.g., particle size of inhaled agents). Generation 3 models describe the rate at which effects develop, i.e. the epidemic curve. These (generation 1 through three models) have been developed and used in multiple contexts. Beyond Generation 3 lies an opportunity for the deep incorporation of in vivo physiological responses and the coupling of the individual host dynamics to the dynamics of spread of contagious diseases in the population. This would enable more direct extrapolation from controlled dosing studies to estimate population level effects. There remain also needs to understand broader categories of infectious agents, including pathogenic amoebae and fungi. More advanced models need to be validated against well-characterized human outbreak data. PMID- 25545033 TI - All-solid-state reduced graphene oxide supercapacitor with large volumetric capacitance and ultralong stability prepared by electrophoretic deposition method. AB - Portable energy storage devices have gained special attention due to the growing demand for portable electronics. Herein, an all-solid-state supercapacitor is successfully fabricated based on a poly(vinyl alcohol)-H3PO4 (PVA-H3PO4) polymer electrolyte and a reduced graphene oxide (RGO) membrane electrode prepared by electrophoretic deposition (EPD). The RGO electrode fabricated by EPD contains an in-plane layer-by-layer alignment and a moderate porosity that accommodate the electrolyte ions. The all-solid-state RGO supercapacitor is thoroughly tested to give high specific volumetric capacitance (108 F cm(-3)) and excellent energy and power densities (7.5 Wh cm(-3) and 2.9 W cm(-3), respectively). In addition, the all-solid-state RGO supercapacitor exhibits an ultralong lifetime for as long as 180 days (335 000 cycles), which is an ultrahigh cycling capability for a solid state supercapacitor. The RGO is also tested for being used as a transparent supercapacitor electrode demonstrating its possible use in various transparent optoelectronic devices. Due to the facile scale-up capability of the EPD process and RGO dispersion, the developed all-solid-state supercapacitor is highly applicable to large-area portable energy storage devices. PMID- 25545034 TI - Value of sonographic anterior-posterior renal pelvis measurements before and after voiding for predicting vesicoureteral reflux in children. AB - PURPOSE: Voiding cystourethrography (VCUG) is the gold standard for diagnosing vesicoureteral reflux (VUR), but it is important to minimize the use of VCUG because of the urinary catheterization and radiation exposure required. Ultrasound (US) observations suggest that pelvicalyceal dilatation varies according to the degree of bladder fullness in children with urinary tract infection. The aim of this study was to assess whether anterior-posterior (AP) measurements of the renal pelvis on US before and after voiding can be used as a screening tool while predicting the presence of VUR in children. METHODS: The subjects were toilet-trained children older than 4 years who required VCUG. Two groups were established based on the VCUG results: a VUR group of 40 kidney units (each unit defined as calyces and ureter) that exhibited different severities of reflux, and a control group of 68 kidney units unaffected by VUR. Prior to VCUG, US AP measurements of the renal pelvis of each kidney unit were recorded when the urinary bladder was full and again after bladder emptying. The change in AP measurement from before to after voiding was compared between the two groups. RESULTS: The mean change in AP measurements from before to after voiding in the VUR group was significantly greater than that in the control group (p = 0.003). CONCLUSIONS: Comparing US AP measurements of the renal pelvis before and after voiding is useful for identifying children who are suspected to have VUR and thus require immediate VCUG. PMID- 25545035 TI - Potential utility of melatonin as an antioxidant therapy in the management of sickle cell anemia. AB - This study aimed to assess antioxidant effects of melatonin treatment compared to N-acetylcysteine (NAC) and to their combination in a sickle cell suspension. Sickle erythrocytes were suspended in phosphate-buffered saline, pH 7.4, composing external control group. They were also suspended and incubated at 37 degrees C either in the absence (experimental control group) or in the presence of NAC, melatonin and their combination at concentrations of 100 pm, 100 nm and 100 MUm for 1 hr (treatment groups). The melatonin influences were evaluated by spectrophotometric [hemolysis degree, catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6 phosphate dehydrogenase (G6PDH), and superoxide dismutase (SOD) activities] and chromatographic methods [glutathione (GSH) and malondialdehyde (MDA) levels]. Incubation period was able to cause a rise about 64% on hemolysis degree as well as practically doubled the lipid peroxidation levels (P < 0.01). However, almost all antioxidants tested treatments neutralized this incubation effect observed in MDA levels. Among the antioxidant biomarkers evaluated, we observed a modulating effect of combined treatment on GPx and SOD activities (P < 0.01), which showed ~25% decrease in their activities. In addition, we found an antioxidant dose dependent effect for melatonin on lipid peroxidation (r = -0.29; P = 0.03) and for combined antioxidant treatments also on MDA levels (r = -0.37; P = 0.01) and on SOD activity (r = -0.54; P < 0.01). Hence, these findings contribute with important insight that melatonin individually or in combination with NAC may be useful for sickle cell anemia management. PMID- 25545037 TI - Absence of single pulmonary valve cusp. PMID- 25545036 TI - Emerging treatments in Neurogastroenterology: relamorelin: a novel gastrocolokinetic synthetic ghrelin agonist. AB - BACKGROUND: Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately sixfold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. PURPOSE: In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a prespecified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID- 25545038 TI - Pain beliefs and perceptions inventory: a cross-sectional study in chronic and episodic migraine. AB - OBJECTIVE/BACKGROUND: This study aims to compare differences in pain beliefs according to headache type, chronic vs episodic migraine, in a large cohort of patients, using the Pain Beliefs and Perceptions Inventory (PBPI), and to identify possible predictive factors of the same pain beliefs. METHODS: All patients referring for the first time at our center in 2011 were screened using PBPI and the Hamilton Anxiety and Depression Scale (a total of 1032 patients). PBPI is a 4-subscale questionnaire that explores a patient's personal beliefs on their subjective experience of pain. Headache patients also completed the Headache Impact Test (HIT-6) and a 30-day headache diary. For all participants, age, gender, duration of pain were collected. The sample was narrowed down to 899 as we experienced a nonresponse rate of 12.8%. For the purpose of this study, 2 groups were identified: chronic and episodic migraine, consisting of 116 and 126 patients, respectively, which were compared using Student's t-test; correlation analyses were conducted to investigate the relationship between variables before running a model selection based on Akaike's Information Criterion to identify possible predictive factors of different pain beliefs. Patients below 18 years of age and those diagnosed with other painful conditions were excluded from the analysis. RESULTS: Beliefs from chronic and episodic migraine patients were very similar, with only a difference in beliefs related to constancy of pain (Mean value +/- SD 0.5 +/- 1.1 vs -0.6 +/- 1.1, P<.001). Predictive factors were depression and HIT-6 scores for all PBPI subscales apart from Self-Blame, which showed a stronger relation to anxiety scores. Number of days with headache per month was correlated to higher constancy values. Diagnosis was a predictive factor for any particular belief. DISCUSSION: This is the first study, to our knowledge, that addresses differences and predictive factors in pain beliefs according to headache diagnosis. A deeper knowledge of beliefs pattern in patients could lead to better-tailored psychological management. PMID- 25545039 TI - The embryonic cell lineage of Caenorhabditis elegans: A modern hieroglyph: The best way to acquire knowledge in Developmental Biology is to learn how this knowledge was derived. AB - Nowadays, in the Internet databases era, certain knowledge is being progressively lost. This knowledge, which we feel is essential and should be acquired through education, is the understanding of how the pioneer researchers faced major questions in their field and made their discoveries. PMID- 25545040 TI - Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression. AB - WHAT IS KNOWN AND OBJECTIVE: The current pharmacotherapeutic treatment of major depressive disorder (MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment. COMMENT: Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose-response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine's antidepressant action. WHAT IS NEW AND CONCLUSION: It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders. PMID- 25545042 TI - Seeing is believing: Impact of social modeling on placebo and nocebo responding. AB - OBJECTIVE: This study investigated the impact of the social modeling of side effects following placebo medication ingestion on the nocebo and placebo effect. It also investigated whether medication branding (brand or generic labeling) moderated social modeling effects. METHOD: Eighty-two university students took part in the study which was purportedly investigating the impact of fast-acting beta-blocker medications (actually placebos) on preexamination anxiety. After taking the medication, participants were randomized to either witness a female confederate report experiencing side effects or no side effects after taking the same medication. Differences in symptom reporting, blood pressure, heart rate, and anxiety were assessed between the social modeling of side effects and no modeling groups. RESULTS: Seeing a female confederate report side effects reduced the placebo effect in systolic (p = .009) and diastolic blood pressure (p = .033). Seeing a female confederate report side effects also increased both total reported symptoms (mean [SE] 7.35 [.54] vs. 5.16 [0.53] p = .005) and symptoms attributed to the medication (5.27 [0.60] vs. 3.04 [0.59] p = .01), although the effect on symptoms was only seen in female participants. Females who saw the confederate report side effects reported approximately twice the number of symptoms as those in the no modeling group. Social modeling did not affect heart rate or anxiety. Medication branding did not influence placebo or nocebo outcomes. CONCLUSIONS: The social modeling of symptoms can substantially reduce or eliminate the placebo effect. Viewing a female confederate display symptoms after taking the same medication increases symptom reporting in females. PMID- 25545041 TI - Race-based differentials in the impact of mental health and stigma on HIV risk among young men who have sex with men. AB - OBJECTIVE: In the U.S., young men who have sex with men (YMSM) are disproportionately affected by HIV, with YMSM of color being the most impacted by the epidemic. METHOD: To advance prevention research, we examined race-based differences in gay-related stress in conjunction with the moderating role of mental health on substance use and sexual risk among 206 high-risk YMSM, recruited September, 2007-2010. RESULTS: Negative binomial regressions and 3-way interaction graphs indicated that psychological distress and acute gay-related stigma placed all participants at most risk for HIV acquisition. Low psychological distress appeared to "buffer" all YMSM against HIV risk, whereas the reverse was evidenced for those reporting low gay-related stigma and psychological distress. YMSM of color reported more risk behavior, and less decreases in risk with attenuated psychological distress, compared with White YMSM. We hypothesize these trends to be associated with experiencing multiple stigmatized identities, indicating points of intervention for YMSM of color to achieve positive identity integration. There were sharper increases in HIV risk behavior for White YMSM with increasing gay-related stigma than for YMSM of color, which could be attributed to the latter's prolonged exposure to discrimination necessitating building coping skills to manage the influx of adversity. CONCLUSIONS: Emphases on: (a) identity-based interventions for YMSM of color; and (b) skills-based interventions for White YMSM should supplement existing successful HIV risk-reduction programs. Lastly, mental health needs to be a target of intervention, as it constitutes a protective factor against HIV risk for all YMSM. PMID- 25545043 TI - Spirituality and the recovery of quality of life following hematopoietic stem cell transplantation. AB - OBJECTIVE: Spirituality has been linked to improved adjustment and functioning in individuals with cancer; however, its effect on quality of life following hematopoietic stem cell transplantation (HSCT) has not been well-studied. This study investigated changes in spirituality in hematologic cancer patients recovering from HSCT and relationships between spirituality and dimensions of quality of life following HSCT. METHODS: Participants (N = 220) completed measures of two dimensions of spirituality (meaning/peace and religious faith), depression, anxiety, fatigue, pain, and physical and functional well-being prior to transplant and at 1-, 3-, 6-, and 12-months posttransplant. RESULTS: Meaning/peace declined at 1-month posttransplant and returned to pretransplant levels by 6-months posttransplant, and faith increased from pretransplant to 6 months posttransplant. Mixed-effects linear regression models indicated that greater pretransplant meaning/peace, but not religious faith, predicted less depression, anxiety, and fatigue, and better physical and functional well-being during the 12-months following transplant. CONCLUSIONS: The capacity to find meaning and peace may facilitate recovery following HSCT. Results suggest that spirituality may be a resilience factor that could be targeted to improve quality of life for HSCT recipients. PMID- 25545045 TI - Neurodegeneration with Brain Iron Accumulation: Clinicoradiological Approach to Diagnosis. AB - Discovery of genetic abnormalities associated with neurodegeneration with brain iron accumulation (NBIA) has led to use of a genetic-based NBIA classification schema. Most NBIA subtypes demonstrate characteristic imaging abnormalities. While clinical diagnosis of NBIA is difficult, analysis of both clinical findings and characteristic imaging abnormalities allows accurate diagnosis of most of the NBIA subtypes. This article reviews recent updates in the genetic, clinical, and imaging findings of NBIA subtypes and provides a practical step-by-step clinicoradiological algorithm toward clinical diagnosis of different NBIA subtypes. PMID- 25545046 TI - Tunability of short-channel effects in MoS2 field-effect devices. AB - MoS2 transistors have been electrically characterized and analyzed in terms of their vulnerability to short channel effects and their response to various environments. We find that the electrical performance of MoS2 flakes is governed by an unexpected dependence on the effective body thickness of the devices that in turn depends on the amount of intercalated water molecules that exist in the layered structure. In particular, a decrease in effective body thickness is observed in air compared to the "water-free" scenario. Moreover, we find that the doping stage of a MoS2 field-effect transistor (FET) is p-type despite the appearance of electron conduction, and the amount of p-doping is higher in air than in vacuum. Most importantly, our results indicate that device characteristics of MoS2 can be substantially impacted by tuning the device electrostatics. This can be accomplished by controlling the effectively active body thickness of the MoS2 FET employing intercalation and engineering of the effective barrier between individual MoS2 layers. PMID- 25545048 TI - Selective changes of ocular vestibular myogenic potentials in Parkinson's disease. AB - BACKGROUND: Vestibular evoked myogenic potentials represent electrophysiological tools to measure vestibular reflex actions at different levels of the brainstem in Parkinson's disease. OBJECTIVE: To investigate cervical and ocular vestibular myogenic potentials in Parkinsonian patients with mild disability. METHODS: In 13 Parkinsonian patients and 13 age-matched healthy controls, cervical and ocular vestibular myogenic potentials were recorded after unilateral air-conducted tone bursts and bone-conducted stimuli delivered at the forehead or mastoids. RESULTS: In contrast to relatively preserved cervical vestibular evoked myogenic potentials, ocular vestibular evoked myogenic potentials were significantly delayed and of reduced amplitude, particularly after impulsive stimulation in Parkinsonian patients. Levodopa had no significant effect on either type of response. CONCLUSION: In mild to moderate Parkinson's disease, altered ocular vestibular myogenic potentials may indicate early functional involvement of the upper brainstem, in contrast to preserved lower brainstem function as reflected by normal cervical vestibular myogenic potentials. PMID- 25545049 TI - Using new tools to identify eggs of Engraulis anchoita (Clupeiformes, Engraulidae). AB - Efficiency of the identification of eggs of Engraulis anchoita can be greatly improved by a method developed from egg measurements, using photography and the ImageJ programme, analysed by discriminant analysis using R software. PMID- 25545047 TI - Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1. AB - Protective effects of prostacyclin (PC) or its stable analog beraprost against agonist-induced lung vascular inflammation have been associated with elevation of intracellular cAMP and Rac GTPase signaling which inhibited the RhoA GTPase dependent pathway of endothelial barrier dysfunction. This study investigated a distinct mechanism of PC-stimulated lung vascular endothelial (EC) barrier recovery and resolution of LPS-induced inflammation mediated by small GTPase Rap1. Efficient barrier recovery was observed in LPS-challenged pulmonary EC after prostacyclin administration even after 15 h of initial inflammatory insult and was accompanied by the significant attenuation of p38 MAP kinase and NFkappaB signaling and decreased production of IL-8 and soluble ICAM1. These effects were reproduced in cells post-treated with 8CPT, a small molecule activator of Rap1 specific nucleotide exchange factor Epac. By contrast, pharmacologic Epac inhibitor, Rap1 knockdown, or knockdown of cell junction-associated Rap1 effector afadin attenuated EC recovery caused by PC or 8CPT post-treatment. The key role of Rap1 in lung barrier restoration was further confirmed in the murine model of LPS-induced acute lung injury. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, and Evans blue extravasation and live imaging of vascular leak over 6 days using a fluorescent tracer. The data showed significant acceleration of lung recovery by PC and 8CPT post treatment, which was abrogated in Rap1a(-/-) mice. These results suggest that post-treatment with PC triggers the Epac/Rap1/afadin-dependent mechanism of endothelial barrier restoration and downregulation of p38MAPK and NFkappaB inflammatory cascades, altogether leading to accelerated lung recovery. PMID- 25545051 TI - Becoming a high-fidelity - super - imitator: what are the contributions of social and individual learning? AB - In contrast to other primates, human children's imitation performance goes from low to high fidelity soon after infancy. Are such changes associated with the development of other forms of learning? We addressed this question by testing 215 children (26-59 months) on two social conditions (imitation, emulation) - involving a demonstration - and two asocial conditions (trial-and-error, recall) involving individual learning - using two touchscreen tasks. The tasks required responding to either three different pictures in a specific picture order (Cognitive: Airplane->Ball->Cow) or three identical pictures in a specific spatial order (Motor-Spatial: Up->Down->Right). There were age-related improvements across all conditions and imitation, emulation and recall performance were significantly better than trial-and-error learning. Generalized linear models demonstrated that motor-spatial imitation fidelity was associated with age and motor-spatial emulation performance, but cognitive imitation fidelity was only associated with age. While this study provides evidence for multiple imitation mechanisms, the development of one of those mechanisms - motor spatial imitation - may be bootstrapped by the development of another social learning skill - motor-spatial emulation. Together, these findings provide important clues about the development of imitation, which is arguably a distinctive feature of the human species. PMID- 25545050 TI - HSPA12B inhibits lipopolysaccharide-induced inflammatory response in human umbilical vein endothelial cells. AB - Heat shock protein A12B (HSPA12B) is a newly discovered member of the HSP70 protein family. This study investigated the effects of HSPA12B on lipopolysaccharide (LPS)-induced inflammatory responses in human umbilical vein endothelial cells (HUVECs) and the possible mechanisms involved. A HUVECs inflammatory model was induced by LPS. Overexpression of HSPA12B in HUVECs was achieved by infection with recombinant adenoviruses encoding green fluorescence protein-HSPA12B. Knockdown of HSPA12B was achieved by siRNA technique. Twenty four hours after virus infection or siRNA transfection, HUVECs were stimulated with 1 MUg/ml LPS for 4 hrs. Endothelial cell permeability ability was determined by transwell permeability assay. The binding rate of human neutrophilic polymorphonuclear leucocytes (PMN) with HUVECs was examined using myeloperoxidase assay. Cell migrating ability was determined by the wound-healing assay. The mRNA and protein expression levels of interested genes were analyzed by RT-qPCR and Western blot, respectively. The release of cytokines interleukin-6 and tumour necrosis factor-alpha was measured by ELISA. HSPA12B suppressed LPS-induced HUVEC permeability and reduced PMN adhesion to HUVECs. HSPA12B also inhibited LPS induced up-regulation of adhesion molecules and inflammatory cytokine expression. By contrast, knockdown of HSPA12B enhanced LPS-induced increases in the expression of adhesion molecules and inflammatory cytokines. Moreover, HSPA12B activated PI3K/Akt signalling pathway and pharmacological inhibition of this pathway by Wortmannin completely abrogated the protection of HSPA12B against inflammatory response in HUVECs. Our results suggest that HSPA12B attenuates LPS induced inflammatory responses in HUVECs via activation of PI3K/Akt signalling pathway. PMID- 25545052 TI - Hydroxyurea-induced stomatocytes in a patient presenting with polycythemia vera. PMID- 25545053 TI - Simulated training in colonoscopic stenting of colonic strictures: validation of a cadaver model. AB - AIM: There are currently no available simulation models for training in colonoscopic stent deployment. The aim of this study was to validate a cadaver model for simulation training in colonoscopy with stent deployment for colonic strictures. METHOD: This was a prospective study enrolling surgeons at a single institution. Participants performed colonoscopic stenting on a cadaver model. Their performance was assessed by two independent observers. Measurements were performed for quantitative analysis (time to identify stenosis, time for deployment, accuracy) and a weighted score was devised for assessment. The Mann Whitney U-test and Student's t-test were used for nonparametric and parametric data, respectively. Cohen's kappa coefficient was used for reliability. RESULTS: Twenty participants performed a colonoscopy with deployment of a self-expandable metallic stent in two cadavers (groups A and B) with 20 strictures overall. The median time was 206 s. The model was able to differentiate between experts and novices (P = 0. 013). The results showed a good consensus estimate of reliability, with kappa = 0.571 (P < 0.0001). CONCLUSION: The cadaver model described in this study has content, construct and concurrent validity for simulation training in colonoscopic deployment of self-expandable stents for colonic strictures. Further studies are needed to evaluate the predictive validity of this model in terms of skill transfer to clinical practice. PMID- 25545054 TI - The implications of sarcopenia and sarcopenic obesity on cardiometabolic disease. AB - The important changes in body composition associated with aging are a decline in skeletal muscle mass and an increase in body fat. Body fat distribution also changes with age; subcutaneous fat decreases and visceral abdominal fat increase, which contributes to numerous cardiometabolic diseases (CMDs) such as type 2 diabetes, dyslipidemia, and cardiovascular disease (CVD). Sarcopenia often accompanied by an increase in body fat and vice versa, a scenario termed sarcopenic obesity (SO), which might lead to the cumulative risk of both sarcopenia and obesity. However, there is still no consensus regarding the definition and consequences of SO. The lack of a unified definition for SO might contribute to inconsistent findings about the association of SO with CMD. Complex etiologies are associated with development of SO. A vicious cycle between the loss of muscle and the accumulation of ectopic fat might be associated with CMD via an intricate interplay of factors including proinflammatory cytokines, oxidative stress, mitochondrial dysfunction, insulin resistance, dietary energy, physical activity, mitochondrial dysfunction, and other factors that have yet to be identified. Moreover, recent epidemiological studies suggest that SO is related to CVD and mortality. This review focuses on the current literature with regard to the association between sarcopenia, dynapenia, and obesity, as well as their implications for CMD. The ultimate goal of this Prospects is to encourage conduct of well-designed future studies that elucidate the relationship among sarcopenia, SO, and CMD. PMID- 25545056 TI - Gene therapy for the eye focus on mutation-independent approaches. AB - PURPOSE OF REVIEW: This review will discuss retinal gene therapy strategies with a focus on mutation-independent approaches to treat a large number of patients without knowledge of the mutant gene. These approaches rely on the secretion of neurotrophic factors to slow down retinal degeneration and the use of optogenetics to restore vision in late-stage disease. RECENT FINDINGS: Success in clinical application of adeno-associated virus (AAV)-mediated gene therapy for Leber's congenital amaurosis established the feasibility of retinal gene therapy. More clinical trials are currently on their way for recessive diseases with known mutations. However, the genetic and mechanistic diversity of the retinal diseases presents an enormous obstacle for the development of gene therapies tailored to each patient-specific mutation. To extend gene therapy's promise to a large number of patients, evidence suggests retina-specific trophic factors, such as rod-derived cone viability factor, can be used to slow down loss of cone cells responsible for our high acuity vision. In parallel, it has been shown that microbial opsins are able to restore light sensitivity when expressed in blind retinas. SUMMARY: Recent findings imply that using the viral technology that has been demonstrated as well tolerated in patients, there are opportunities to develop widely applicable gene therapeutic interventions in clinical ophthalmology. PMID- 25545055 TI - Color synesthesia. Insight into perception, emotion, and consciousness. AB - PURPOSE OF REVIEW: Synesthesia is an extraordinary perceptual phenomenon, in which individuals experience unusual percepts elicited by the activation of an unrelated sensory modality or by a cognitive process. Emotional reactions are commonly associated. The condition prompted philosophical debates on the nature of perception and impacted the course of art history. It recently generated a considerable interest among neuroscientists, but its clinical significance apparently remains underevaluated. This review focuses on the recent studies regarding variants of color synesthesia, the commonest form of the condition. RECENT FINDINGS: Synesthesia is commonly classified as developmental and acquired. Developmental forms predispose to changes in primary sensory processing and cognitive functions, usually with better performances in certain aspects and worse in others, and to heightened creativity. Acquired forms of synesthesia commonly arise from drug ingestion or neurological disorders, including thalamic lesions and sensory deprivation (e.g., blindness). Cerebral exploration using structural and functional imaging has demonstrated distinct patterns in cortical activation and brain connectivity for controls and synesthetes. Artworks of affected painters are most illustrative of the nature of synesthetic experiences. SUMMARY: Results of the recent investigations on synesthesia offered a remarkable insight into the mechanisms of perception, emotion and consciousness, and deserve attention both from neuroscientists and from clinicians. PMID- 25545057 TI - An ultra scale-down analysis of the recovery by dead-end centrifugation of human cells for therapy. AB - An ultra scale-down method is described to determine the response of cells to recovery by dead-end (batch) centrifugation under commercially defined manufacturing conditions. The key variables studied are the cell suspension hold time prior to centrifugation, the relative centrifugal force (RCF), time of centrifugation, cell pellet resuspension velocities, and number of resuspension passes. The cell critical quality attributes studied are the cell membrane integrity and the presence of selected surface markers. Greater hold times and higher RCF values for longer spin times all led to the increased loss of cell membrane integrity. However, this loss was found to occur during intense cell resuspension rather than the preceding centrifugation stage. Controlled resuspension at low stress conditions below a possible critical stress point led to essentially complete cell recovery even at conditions of extreme centrifugation (e.g., RCF of 10000 g for 30 mins) and long (~2 h) holding times before centrifugation. The susceptibility to cell loss during resuspension under conditions of high stress depended on cell type and the age of cells before centrifugation and the level of matrix crosslinking within the cell pellet as determined by the presence of detachment enzymes or possibly the nature of the resuspension medium. Changes in cell surface markers were significant in some cases but to a lower extent than loss of cell membrane integrity. PMID- 25545058 TI - Oridonin induces apoptosis in uveal melanoma cells by upregulation of Bim and downregulation of Fatty Acid Synthase. AB - Oridonin is an orally available drug isolated from Traditional Chinese Medicine. Previous studies with oridonin have demonstrated broad-spectrum anticancer activity in a variety of cancer types. However, the effect of oridonin in uveal melanoma has not been addressed. In this study, we aimed to investigate whether oridonin elicited anticancer activity and its underlying mechanism in human uveal melanoma cells. We demonstrated that oridonin potently reduced cell viability, induced apoptosis and inhibited clonogenic survival and growth with single digit micromolar concentrations in uveal melanoma OCM-1 and MUM2B cell lines. We found that oridonin markedly increased the expression of proapoptotic Bcl-2 family protein Bim in uveal melanoma cells, and knockdown Bim by small interfering RNA significantly attenuated oridonin-induced cell death, indicating an essential role of Bim in oridonin-mediated anticancer activity. Additionally, we observed that oridonin suppressed Fatty Acid Synthase (FAS) expression in uveal melanoma cells, and enforced FAS expression by insulin partially rescued the cells from oridonin-induced apoptosis, showing that inhibition of FAS also contributed to oridonin-mediated apoptosis. Taken together, we reported that oridonin displays potent anticancer effect against uveal melanoma cells through upregulation of Bim and inhibition of FAS. Since oridonin is a popular anticancer agent, our study therefore may have translational implication on the management of patients with uveal melanoma. PMID- 25545059 TI - Synthetic ceramide analogues increase amyloid-beta 42 production by modulating gamma-secretase activity. AB - gamma-Secretase cleaves amyloid beta-precursor protein (APP) to generate amyloid beta peptide (Abeta), which is a causative molecule of Alzheimer disease (AD). The C-terminal length of Abeta, which is determined by gamma-secretase activity, determines the aggregation and deposition profiles of Abeta, thereby affecting the onset of AD. In this study, we found that the synthetic ceramide analogues dl threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and (1S,2R-d erythro-2-N-myristoylamino)-1-phenyl-1-propanol (DMAPP) modulated gamma-secretase mediated cleavage to increase Abeta42 production. Unexpectedly, PDMP and DMAPP upregulated Abeta42 production independent of alteration of ceramide metabolism. Our results propose that synthetic ceramide analogues function as novel gamma secretase modulators that increase Abeta42, and this finding might lead to the understanding of the effect of the lipid environment on gamma-secretase activity. PMID- 25545060 TI - Evaluation of the reliability of the maximum entropy method for reconstructing 3D and 4D NOESY-type NMR spectra of proteins. AB - Despite their advantages in analysis, 4D NMR experiments are still infrequently used as a routine tool in protein NMR projects due to the long duration of the measurement and limited digital resolution. Recently, new acquisition techniques for speeding up multidimensional NMR experiments, such as nonlinear sampling, in combination with non-Fourier transform data processing methods have been proposed to be beneficial for 4D NMR experiments. Maximum entropy (MaxEnt) methods have been utilised for reconstructing nonlinearly sampled multi-dimensional NMR data. However, the artefacts arising from MaxEnt processing, particularly, in NOESY spectra have not yet been clearly assessed in comparison with other methods, such as quantitative maximum entropy, multidimensional decomposition, and compressed sensing. We compared MaxEnt with other methods in reconstructing 3D NOESY data acquired with variously reduced sparse sampling schedules and found that MaxEnt is robust, quick and competitive with other methods. Next, nonlinear sampling and MaxEnt processing were applied to 4D NOESY experiments, and the effect of the artefacts of MaxEnt was evaluated by calculating 3D structures from the NOE derived distance restraints. Our results demonstrated that sufficiently converged and accurate structures (RMSD of 0.91A to the mean and 1.36A to the reference structures) were obtained even with NOESY spectra reconstructed from 1.6% randomly selected sampling points for indirect dimensions. This suggests that 3D MaxEnt processing in combination with nonlinear sampling schedules is still a useful and advantageous option for rapid acquisition of high-resolution 4D NOESY spectra of proteins. PMID- 25545061 TI - Regulatory functions of evolutionarily conserved AN1/A20-like Zinc finger family proteins in Arabidopsis stress responses under high temperature. AB - AN1/A20-like Zinc finger family proteins are evolutionarily conserved regulatory components in eukaryotic signaling circuits. In Arabidopsis thaliana, the AN1/A20 Zinc finger family is encoded as 14 members in the genome and collectively referred to as stress-associated proteins (SAPs). Here we described AtSAP5 localized to the nucleus, and played a role in heat-responsive gene regulation together with MBF1c. Seedling survival assay of sap5 and mbf1c demonstrated consistent effects of AtSAP5 and MBF1C in response to two-step heat treatment, supporting their function in heat stress tolerance. Our findings yield an insight in A20/AN1-like Zinc finger protein AtSAP5 functions in plant adaptability under high temperature. PMID- 25545063 TI - High-frequency sarcomeric auto-oscillations induced by heating in living neonatal cardiomyocytes of the rat. AB - In the present study, we investigated the effects of infra-red laser irradiation on sarcomere dynamics in living neonatal cardiomyocytes of the rat. A rapid increase in temperature to >~38 degrees C induced [Ca(2+)]i-independent high frequency (~5-10 Hz) sarcomeric auto-oscillations (Hyperthermal Sarcomeric Oscillations; HSOs). In myocytes with the intact sarcoplasmic reticular functions, HSOs coexisted with [Ca(2+)]i-dependent spontaneous beating in the same sarcomeres, with markedly varying frequencies (~10 and ~1 Hz for the former and latter, respectively). HSOs likewise occurred following blockade of the sarcoplasmic reticular functions, with the amplitude becoming larger and the frequency lower in a time-dependent manner. The present findings suggest that in the mammalian heart, sarcomeres spontaneously oscillate at higher frequencies than the sinus rhythm at temperatures slightly above the physiologically relevant levels. PMID- 25545062 TI - Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis. AB - Omega-3 polyunsaturated fatty acid levels are reduced in the substantia nigra area in Parkinson's disease patients and animal models, implicating docosahexaenoic acid (DHA) as a potential treatment for preventing Parkinson's disease and suggesting the need for investigations into how DHA might protect against neurotoxin-induced dopaminergic neuron loss. The herbicide paraquat (PQ) induces dopaminergic neuron loss through the excessive production of reactive oxygen species (ROS). We found that treatment of dopaminergic SN4741 cells with PQ reduced cell viability in a dose-dependent manner, but pretreatment with DHA ameliorated the toxic effect of PQ. To determine the toxic mechanism of PQ, we measured intracellular ROS content in different organelles with specific dyes. As expected, all types of ROS were increased by PQ treatment, but DHA pretreatment selectively decreased cytosolic hydrogen peroxide content. Furthermore, DHA treatment-induced increases in glutathione reductase and glutamate cysteine ligase modifier subunit (GCLm) mRNA expression were positively correlated with glutathione (GSH) content. Consistent with this increase in GCLm mRNA levels, Western blot analysis revealed that DHA pretreatment increased nuclear factor erythroid 2 related factor 2 (Nrf2) protein levels. These findings indicate that DHA prevents PQ-induced neuronal cell loss by enhancing Nrf2-regulated GSH homeostasis. PMID- 25545064 TI - Reduced efficacy of transcatheter and surgical revascularization in Takayasu arteritis. AB - A 55-year-old woman with newly diagnosed Takayasu arteritis was followed for 7 years, during which time she underwent bare metal stenting, drug eluting stenting and coronary bypass grafting for critical coronary and renal artery stenoses. Interventions were initially successful but restenosis occurred within 24 months for all modalities. In contrast, native vessel disease was largely stable after the introduction of immunosuppressive therapy. We advocate a conservative revascularization approach in Takayasu arteritis in the absence of critical end organ ischemia and early optimization of medical therapy. PMID- 25545065 TI - Detection of Xeljanz enantiomers in diethyl amine active pharmaceutical ingredients and tablets. AB - A high-performance liquid chromatography (HPLC) method was established to detect Xeljanz enantiomers in active pharmaceutical ingredients (APIs) and tablets. The separation was achieved on a Chiralpak IC column using a mobile phase of hexane ethanol-diethylamine (65:35:0.1, v/v). The detection wavelength was 289 nm. The peak areas and the enantiomer concentrations in the range of 0.15-2.25 MUg*mL(-1) were in high linearity, with correlation coefficients higher than 0.999. The recoveries were 86.44% at the concentrations of 7.5, 18.75, and 37.5 MUg*mL(-1) . The limit of detection (LOD) and limit of quantification (LOQ) were 0.042 and 0.14 MUg*mL(-1) , respectively. This HPLC method is suitable for detecting the enantiomers of Xeljanz in its APIs and tablets. PMID- 25545066 TI - Large conductance Ca2+ -activated K+ channels (BK) promote secretagogue-induced transition from spiking to bursting in murine anterior pituitary corticotrophs. AB - Anterior pituitary corticotroph cells are a central component of the hypothalamic pituitary-adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophin hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modeling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium- and voltage-activated (BK) channels in spontaneous and secretagogue-induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non-selective conductances. Co-stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors. This article is protected by copyright. All rights reserved. PMID- 25545067 TI - Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-A syndrome-associated mutations. AB - Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression. PMID- 25545068 TI - Elective valve-in-valve implantation for migration of a Corevalve in a patient with bicuspid aortic valve stenosis. AB - Transcatheter aortic valve implantation for bicuspid aortic valve stenosis (BAVS) is controversial, as its unfavorable anatomy may lead to device dislocation or malfunctioning. If device failure occurs, the bailout intervention can be more complex and technically challenging. We here report a unique case of late migration of a CoreValve (Medtronic, MN) implanted in a patient with BAVS, who was successfully treated with elective valve-in-valve implantation using the first valve as a firm scaffold after waiting for it to adhere at the migrated position. This new strategy may represent a useful salvage option for some patients with prosthesis migration. PMID- 25545069 TI - Trends in childhood type 1 diabetes mellitus incidence in Beijing from 1995 to 2010: a retrospective multicenter study based on hospitalization data. AB - BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) is increasing rapidly worldwide for children of every age group. MATERIALS AND METHODS: A retrospective analysis of hospital registration data from five tertiary hospitals in Beijing, China, identified 485 patients (210 boys, 275 girls) younger than 15 years of age with newly diagnosed T1DM between 1995 and 2010. RESULTS: From 1995 to 2010, the incidence of T1DM in patients <15 years of age ranged from 0.935 3.26 per 100,000 per year. During this period, the average age-standardized incidence rate was 1.7 per 100,000 per year, and the average annual increase in T1DM incidence was 4.36%. The highest rate increases occurred in boys and in patients <5 years of age. For both genders and all age groups, T1DM incidence increased at an accelerated rate after 2006. By 2020, the incidence of T1DM among children in Beijing is projected to increase by a factor of 1.69. CONCLUSIONS: The incidence of T1DM among patients younger than 15 years of age in Beijing increased from 1995 to 2010, with rates growing at an accelerated pace since 2006. Based on recent trends, we project continued rapid growth in the number of new childhood T1DM cases in Beijing. PMID- 25545070 TI - Conserved amino acid residues of the NuoD segment important for structure and function of Escherichia coli NDH-1 (complex I). AB - The NuoD segment (homologue of mitochondrial 49 kDa subunit) of the proton translocating NADH:quinone oxidoreductase (complex I/NDH-1) from Escherichia coli is in the hydrophilic domain and bears many highly conserved amino acid residues. The three-dimensional structural model of NDH-1 suggests that the NuoD segment, together with the neighboring subunits, constitutes a putative quinone binding cavity. We used the homologous DNA recombination technique to clarify the role of selected key amino acid residues of the NuoD segment. Among them, residues Tyr273 and His224 were considered candidates for having important interactions with the quinone headgroup. Mutant Y273F retained partial activity but lost sensitivity to capsaicin-40. Mutant H224R scarcely affected the activity, suggesting that this residue may not be essential. His224 is located in a loop near the N-terminus of the NuoD segment (Gly217-Phe227) which is considered to form part of the quinone binding cavity. In contrast to the His224 mutation, mutants G217V, P218A, and G225V almost completely lost the activity. One region of this loop is positioned close to a cytosolic loop of the NuoA subunit in the membrane domain, and together they seem to be important in keeping the quinone binding cavity intact. The structural role of the longest helix in the NuoD segment located behind the quinone binding cavity was also investigated. Possible roles of other highly conserved residues of the NuoD segment are discussed. PMID- 25545072 TI - Yellow fever virus: genetic and phenotypic diversity and implications for detection, prevention and therapy. AB - Yellow fever virus (YFV) is the prototypical hemorrhagic fever virus, yet our understanding of its phenotypic diversity and any molecular basis for observed differences in disease severity and epidemiology is lacking, when compared to other arthropod-borne and haemorrhagic fever viruses. This is, in part, due to the availability of safe and effective vaccines resulting in basic YFV research taking a back seat to those viruses for which no effective vaccine occurs. However, regular outbreaks occur in endemic areas, and the spread of the virus to new, previously unaffected, areas is possible. Analysis of isolates from endemic areas reveals a strong geographic association for major genotypes, and recent epidemics have demonstrated the emergence of novel sequence variants. This review aims to outline the current understanding of YFV genetic and phenotypic diversity and its sources, as well as the available animal models for characterizing these differences in vivo. The consequences of genetic diversity for detection and diagnosis of yellow fever and development of new vaccines and therapeutics are discussed. PMID- 25545073 TI - Influence of body composition on survival in patients with head and neck cancer. AB - BACKGROUND: Recent evidence has suggested links between obesity and outcomes for various types of cancer. This study investigates the impact that body composition has on survival in patients with head and neck cancer. METHODS: Data prospectively collected from 578 patients were analyzed using Cox regression models to determine independent associations that pretreatment body mass index (BMI) and 3-month weight change have on observed survival. RESULTS: Higher BMIs were associated with better survival (p < .001). Five-year rates ranged from 33.8% for underweight to 75.3% for overweight/obese patients. Patients with stable weight had the highest 5-year rate (72.6%; p = .019), whereas patients who gained >=5% had worse survival (45.8%) than those who lost >=5% (65.8%). BMI independently predicted survival, whereas weight change was not an independent predictor. CONCLUSION: This demonstrated association between BMI and survival provides useful information when offering prognoses and investigating optimal treatments (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E261-E267, 2016. PMID- 25545071 TI - Surveying the global virome: identification and characterization of HCV-related animal hepaciviruses. AB - Recent advances in sequencing technologies have greatly enhanced our abilities to identify novel microbial sequences. Thus, our understanding of the global virome and the virome of specific host species in particular is rapidly expanding. Identification of animal viruses is important for understanding animal disease, the origin and evolution of human viruses, as well as zoonotic reservoirs for emerging infections. Although the human hepacivirus, hepatitis C virus (HCV), was identified 25years ago, its origin has remained elusive. In 2011, the first HCV homolog was reported in dogs but subsequent studies showed the virus to be widely distributed in horses. This indicated a wider hepacivirus host range and paved the way for identification of rodent, bat and non-human primate hepaciviruses. The equine non-primate hepacivirus (NPHV) remains the closest relative of HCV and is so far the best characterized. Identification and characterization of novel hepaciviruses may in addition lead to development of tractable animal models to study HCV persistence, immune responses and pathogenesis. This could be particular important, given the current shortage of immunocompetent models for robust HCV infection. Much remains to be learned on the novel hepaciviruses, including their association with disease, and thereby how relevant they will become as HCV model systems and for studies of animal disease. This review discusses how virome analysis led to identification of novel hepaci- and pegiviruses, their genetic relationship and characterization and the potential use of animal hepaciviruses as models to study hepaciviral infection, immunity and pathogenesis. This article forms part of a symposium in Antiviral Research on "Hepatitis C: Next steps toward global eradication." PMID- 25545074 TI - Expanding the scope of pressure-assisted electrokinetic injection for online concentration of positively charged analytes in capillary electrophoresis-mass spectrometry. AB - Sample injection is a crucial step in CE. In past, many efforts have been focused on concentrating the analytes into a sharp sample plug. In 2006, pressure assisted electrokinetic injection (PAEKI) was proposed as a new preconcentration technique for anions. In this study, we expanded the applicability of PAEKI to online preconcentrate positively charged analytes. L-Arginine, L-lysine, and imidazole were chosen as target analytes for method development. The enhancement factor of PAEKI was over 3000-fold. When CZE was coupled with a Q-TOF system, PAEKI delivers a detection limit of 18-28 pg/mL and a dynamic calibration range over four orders of magnitude. The RSD was less than 6.4% (n = 4) on both peak area and migration time, indicating a good repeatability. PMID- 25545075 TI - Sparse networks of directly coupled, polymorphic, and functional side chains in allosteric proteins. AB - Recent studies have highlighted the role of coupled side-chain fluctuations alone in the allosteric behavior of proteins. Moreover, examination of X-ray crystallography data has recently revealed new information about the prevalence of alternate side-chain conformations (conformational polymorphism), and attempts have been made to uncover the hidden alternate conformations from X-ray data. Hence, new computational approaches are required that consider the polymorphic nature of the side chains, and incorporate the effects of this phenomenon in the study of information transmission and functional interactions of residues in a molecule. These studies can provide a more accurate understanding of the allosteric behavior. In this article, we first present a novel approach to generate an ensemble of conformations and an efficient computational method to extract direct couplings of side chains in allosteric proteins, and provide sparse network representations of the couplings. We take the side-chain conformational polymorphism into account, and show that by studying the intrinsic dynamics of an inactive structure, we are able to construct a network of functionally crucial residues. Second, we show that the proposed method is capable of providing a magnified view of the coupled and conformationally polymorphic residues. This model reveals couplings between the alternate conformations of a coupled residue pair. To the best of our knowledge, this is the first computational method for extracting networks of side chains' alternate conformations. Such networks help in providing a detailed image of side-chain dynamics in functionally important and conformationally polymorphic sites, such as binding and/or allosteric sites. PMID- 25545076 TI - Prior antiplatelet agent use and outcomes after intravenous thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke: a meta analysis of cohort studies and randomized controlled trials. AB - BACKGROUND: There is uncertainty surrounding the influence of prior antiplatelet agent use on outcomes after intravenous thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke. AIM: We performed a systematic review with a final meta-analysis to evaluate the efficacy and safety of prior antiplatelet use before intravenous recombinant tissue plasminogen activator for acute ischemic stroke. SUMMARY OF REVIEW: We searched PubMed and Embase databases from 1997 to 2014. Primary outcome was functional outcome at the end of follow up; secondary outcomes were symptomatic intracranial hemorrhage and recanalization rate. The meta-analysis was performed with Review Manager 5.2 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Eleven studies with a total of 19,453 patients were included. A total of 6517 (33.5%) patients who had received intravenous recombinant tissue plasminogen activator were taking antiplatelet agent before stroke onset. Pooled analysis demonstrated a clear trend that previous antiplatelet users had a reduced probability of good outcome, although it was not conventionally statistically significant (OR 0.86; 95% CI 0.73-1.01; P = 0.06). There was no difference in recanalization rate between two groups (OR 1.23; 95% CI 0.30-4.99; P = 0.77). The risk of symptomatic intracranial hemorrhage was significantly increased in the antiplatelet group (OR 1.65; 95% CI 1.44-1.90; P < 0.01). CONCLUSIONS: In acute ischemic stroke patients receiving intravenous recombinant tissue plasminogen activator therapy, prior antiplatelet agent use did not lead to a significant difference in functional outcome, although it significantly increased the risk of symptomatic intracranial hemorrhage. Recanalization rate was not different between two groups. In the subgroup analysis, prior clopidogrel mono therapy may not increase the risk of symptomatic intracranial hemorrhage, which will need further studies to confirm. PMID- 25545077 TI - [Risk of bipolar disorder of universitary students with high depressive symptomatology]. AB - INTRODUCTION: This research aims to determine if there is a relation between high depressive symptoms and the risk of suffering from bipolar disorder in university students, as well as describing demographic variables and career preferences association with these variables. METHODS: A self-survey was carried out with 823 students who were asked to fill out the Beck Depression Inventory and the Bipolar Spectrum Disorder Scale. RESULTS: 12.7% of the population showed symptoms related to clinical depression while 1.9% presented either moderated or high bipolar disorder risk. The 22.4% of those who suffered from clinical depression showed high and moderated bipolar disorder risk. The 43.8% of those who showed high probability of suffering from bipolar disorder risk received psychopharmacological treatment and 87.5% received psychological treatment. The 12.5% of those who were detected as probable bipolar patients never received any treatment, 40% of them were studying an artistic career. CONCLUSION: The percentage of college students at high risk of bipolar disorder is similar to what have been found in the international literature. In people with high levels of depression symptomatology the risk increases being one in four of them at risk for bipolar disorder. PMID- 25545078 TI - [On the concept of lucidity]. AB - Kraepelin's concept of clarity of awareness (lucidity) had a stable signification during more than hundred years. It is the basis of most of current theories of disturbed consciousness. However, two alternative definitions that arise in Buenos Aires produce confusion due to their conceptual overlap. We discuss these definitions and propose a classification of disorders of consciousness that rely on traditional point of view. PMID- 25545079 TI - [The manic depressive disease: psychodinamic aspects and affective syntony]. AB - In a time when manic-depressive disease became bipolar disorder, and it is conceptualized and treated almost as a fully medical illness, such as epilepsy, we found worth returning to some psychodynamic aspects underlying this condition. Conventionally, we depart from the concept of melancholy, to introduce in a second time, the mania, as a liberating solution of the depression. To Abraham, mania is the liberation from suffering imposed by the reality principle For Freud, mania becomes a leak from the ego face a tyrannical superego (the encounter of ego and the ego ideal). Klein explains that the mania serves to counter the depressive position and thus avoid the guilt inside of ego. For Racamier, mania is clearly a frantic negation of the anguish and emotional suffering. Today, some authors as Chabot and Husain try to define the manic depression organization, with the help of projective tests. This personality structure would be between psychosis and borderline. An axial element of this structure is the research for an affective symbiosis with each other. These concept, strongly resemble the "syntony", from Bleuler. We trace the evolution of manic depression from a psychodynamic and structural point of view, with particular interesting in the concept of syntony. PMID- 25545080 TI - [Pregnancy and mental health]. PMID- 25545081 TI - [Postpartum psychiatric disorders]. AB - The postpartum period represents a very particular time in women's life, the beginning of a new bond, the maternity. As many times, beginnings are such turbulent, intense. In this period the women suffers deep changes in their hormonal status, with its body and changes and affective oscillations. Women are often so labile at this time, ranging from happiness to deep sadness. The vast majority suffers the blues, a benign form of mild depressive state. On the other hand, 20% may have a major depressive episode, and a much less percentage will suffer the most disruptive postpartum syndrome, the postpartum psychosis. In this paper it will be described the symptomatology of such cases, the most important treatment approaches and will focus on the clinical dilemma of using psychotropic medications during breastfeeding. PMID- 25545082 TI - [Pregnancy in bipolar disorders. Concepts for clinical and therapeutic management]. AB - Pregnancy in women affected with bipolar disorders supposes a complex clinical decision making process for those women affected and their clinicians. On one hand, a careful weighing of potential consequences of maintains pharmacologic treatment for obstetric health and embryo-fetal development is essential. On the other, a thorough consideration of risks of discontinuing treatment for pregnant women and fetal health is needed. In this paper, critical items to discuss with women that make informed decisions regarding their mood stabilizing treatment in these complex circumstances are described. Likewise, some clinical recommendations for psychiatric management of pregnancy in this population are presented. PMID- 25545083 TI - [Voluntary practice and subjective impact of abortion on women. Representations, meanings and social imaginary in clandestine scenario]. AB - The unplanned pregnancy is a common occurrence in women of reproductive age and at any social status since it is a critical and vital situation that forces women to make a decision. Despite being a public health issue, the act of voluntarily terminating a pregnancy is circumscribed to the clandestine, hidden, private sphere, due to the restrictive legal contexts that dominate the subject. The lack of professional assistance in these situations represents a risk to the health and lives of women. OBJECTIVE: In this article we propose to visualize the meanings and senses that each woman assigns to the process, the reflection about the subjective impact and the eventually psychological effects of the practice; we introduce the conclusions reached from the analysis of the stories of women who went through this process from the notification of an unplanned pregnancy, decision making and the practice of it, in a context of illegality; with the professional support that is provided from the Integrated Counseling in Sexual and Reproductive Health. This counseling is part of the public policies to reduce risk and damage from induced abortions. CONCLUSION: In this context and through the professional accompaniment the words appear in order to elaborate, psychically and symbolically, the effects that the voluntary pregnancy interruption in women produces. The meanings that each woman gives to abortion depends on the appeal from that experience, either as a drama that shocks and destabilizes the mental equilibrium, a critical event but surmountable, or an opportunity to reaffirm their autonomy. PMID- 25545084 TI - [Premenstrual syndrome and dysphoric premenstrual syndrome]. AB - Premenstrual syndrome is characterized by physical, cognitive, affective and behavioral symptoms that occur cyclically during the luteal phase of the menstrual cycle and resolved quickly at the beginning or within few days after menstruation started. The most severe form is represented by premenstrual dysphoric disorder included in the DSM 5. Over 40% of women experience emotional symptoms such as irritability, tension, emotional lability; and physical symptoms such as breast tenderness, fatigue, and abdominal distension. It has not yet been established the underlying pathophysiological mechanism, although hypotheses related to sex hormones and the GABAergic and serotonergic regulation have been postulated. Treatment includes nonpharmacologic and pharmacologic interventions, being serotonin reuptake inhibitors the first-line treatment. PMID- 25545085 TI - [Maternity during the climateric]. AB - The climacteric is the last stage of the evolving life of women between the fertile period and its completion. The climacteric process in every woman has different manifestations in relation to their own history, their health and culture to which they belong. Traditionally the menopause has been linked with depression; we today consider it as a vital crisis which brings new possibilities, including motherhood. The changes during the 20th century in the status of women, the increase in longevity and reproductive techniques suggest motherhood is possible beyond the limits imposed by biology. PMID- 25545086 TI - [The desire for a child in today parenthood: Infertility and reproductive techniques]. AB - The advances in reproductive medicine have unprecedentedly expanded the possibilities to form a family. Today we can speak of a diversity of ways to access to parenthood. The paradigm of family formations has also changed following the diversity of parenting projects: heterosexual couples, blended families (post-divorce), couples formed by lesbians and gays and single parenting. The vicissitudes of "desire for a child" under current parenthood lead us to think about their scope in clinical reproductive disorders or infertility and new family configurations. One of the destinies of the desire for a child in women is the "passion for a child", the child at any cost. Thinking of the changes in parenthood in this field involves not only the desire to have a child in a woman, a man or a couple, but also the history of the origins in children. Especially with some of the reproductive techniques used, such as surrogacy and the donation of gametes-eggs (ovum and sperm). In these cases we are dealing with new articulations of blood ties, kinship and parenthood. PMID- 25545087 TI - [Early life attachment: mother-baby relationship in Donald Winnicott's theory]. AB - The present article refers to the maternal function in the mother-infant early bond from Donald Winnicott's psychoanalitic point of view. This author, authorized since he was a pediatrician and a psychoanalitic doctor, was capable to see the prematurity of the human baby and the affective state of the mother function before the child's birth. The needs of the newborn and his mother far from being complementary have their specificity that make necessary to consider the holding function that is expected from the mother. This work addresses the dimension of the reality as a limit and an organizer of the psychism in the early mother-baby relationship. The author works this topic from the paradigm of the building of a space that takes place in the mutual dynamic. She analyzes the illusion and disillusion function to build a possible destiny for the maternity and in the transition of the baby to the autonomy of a new person. When it's said about "the primary", it is in the sense of the time of building the psychism. A relational time, as Winnicott says, in which when we find an infant, we will always find the maternal care. PMID- 25545088 TI - [Golden Age of Melancholy: Andre Du Laurens and his 'About melancholic diseases']. PMID- 25545089 TI - Xylan hydrolysis in Populus trichocarpa * P. deltoides and model substrates during hydrothermal pretreatment. AB - Previous studies defined easy and difficult to hydrolyze fractions of hemicellulose that may result from bonds among cellulose, hemicellulose, and lignin. To understand how such bonds affect hydrolysis, Populus trichocarpa * Populus deltoides, holocellulose isolated from P. trichocarpa * P. deltoides and birchwood xylan were subjected to hydrothermal flow-through pretreatment. Samples were characterized by glycome profiling, HPLC, and UPLC-MS. Glycome profiling revealed steady fragmentation and removal of glycans from solids during hydrolysis. The extent of polysaccharide fragmentation, hydrolysis rate, and total xylose yield were lowest for P. trichocarpa * P. deltoides and greatest for birchwood xylan. Comparison of results from P. trichocarpa * P. deltoides and holocellulose suggested that lignin-carbohydrate complexes reduce hydrolysis rates and limit release of large xylooligomers. Smaller differences between results with holocellulose and birchwood xylan suggest xylan-cellulose hydrogen bonds limited hydrolysis, but to a lesser extent. These findings imply cell wall structure strongly influences hydrolysis. PMID- 25545090 TI - Gaseous emissions during the solid state fermentation of different wastes for enzyme production at pilot scale. AB - The emissions of volatile organic compounds (VOC), CH4, N2O and NH3 during the solid state fermentation process of some selected wastes to obtain different enzymes have been determined at pilot scale. Orange peel+compost (OP), hair wastes+raw sludge (HW) and winterization residue+raw sludge (WR) have been processed in duplicate in 50 L reactors to provide emission factors and to identify the different VOC families present in exhaust gaseous emissions. Ammonia emission from HW fermentation (3.2+/-0.5 kg Mg(-1) dry matter) and VOC emission during OP processes (18+/-6 kg Mg(-1) dry matter) should be considered in an industrial application of these processes. Terpenes have been the most emitted VOC family during all the processes although the emission of sulphide molecules during HW SSF is notable. The most emitted compound was dimethyl disulfide in HW and WR processes, and limonene in the SSF of OP. PMID- 25545091 TI - Quantifying second generation ethanol inhibition: Design of Experiments approach and kinetic model development. AB - While softwoods represent a potential feedstock for second generation ethanol production, compounds present in their hydrolysates can inhibit fermentation. In this study, a novel Design of Experiments (DoE) approach was used to identify significant inhibitory effects on Saccharomyces cerevisiae D5A for the purpose of guiding kinetic model development. Although acetic acid, furfural and 5 hydroxymethyl furfural (HMF) were present at potentially inhibitory levels, initial factorial experiments only identified ethanol as a significant rate inhibitor. It was hypothesized that high ethanol levels masked the effects of other inhibitors, and a subsequent factorial design without ethanol found significant effects for all other compounds. When these non-ethanol effects were accounted for in the kinetic model, R-(2) was significantly improved over an ethanol-inhibition only model (R-(2)=0.80 vs. 0.76). In conclusion, when ethanol masking effects are removed, DoE is a valuable tool to identify significant non ethanol inhibitors and guide kinetic model development. PMID- 25545092 TI - Pyrolysis kinetics of raw and hydrothermally carbonized Karanj (Pongamia pinnata) fruit hulls via thermogravimetric analysis. AB - The pyrolysis of karanj fruit hulls (KFH) and karanj fruit hull hydrothermal carbonization (KFH-HTC) hydrochar was thermogravimetrically investigated under a nitrogen environment at 5 degrees C/min, 10 degrees C/min, and 20 degrees C/min. The pyrolysis decomposition of KFH biomass was faster than that of KFH-HTC hydrochar because of the high volatility and fixed carbon of KFH biomass. Weight loss percentage was also affected by the heating rates. The kinetic data were evaluated with the Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa methods. The activation energy values obtained with these two methods were 61.06 and 68.53 kJ/mol for KFH biomass and 130.49 and 135.87 kJ/mol for KFH-HTC hydrochar, respectively. The analysis of kinetic process mechanisms was verified with the Coats-Redfern method. KFH-HTC hydrochar may play a potential role in transforming biomass to energy-rich feedstock for thermochemical applications because of its high heating value, high fixed carbon, and low ash and sulfur contents. PMID- 25545093 TI - Cultivation of the benthic microalga Prorocentrum lima for the production of diarrhetic shellfish poisoning toxins in a vertical flat photobioreactor. AB - In this study, the cultivation conditions of Prorocentrum lima, including temperature, nutrient concentration, photoperiod, and salinity were observed, and then an effective method for the large-volume cultivation of P. lima using a vertical flat photobioreactor was developed for the first time. The maximum cell concentrations and toxin contents of P. lima cultured in the photobioreactor were reached after a 35 days cultivation. Moreover, a step-wise double-sedimentation centrifugation method was used to harvest the microalgae cells, with the harvest rate of 89%. Toxin analysis of dry microalgal powder indicated that OA and DTX1 contents were 15.2 and 21.6 mg g(-1), respectively. These results verify that the culture method using the proposed photobioreactor is effective to massively produce DSP toxin-containing P. lima. This study may serve as a guide for the large-scale production of toxin-producing red-tide benthic microalgae. PMID- 25545094 TI - Enhanced enzymatic hydrolysis and ethanol production from cashew apple bagasse pretreated with alkaline hydrogen peroxide. AB - The effect of combinations and ratios between different enzymes has been investigated in order to assess the optimal conditions for hydrolysis of cashew apple bagasse pretreated with alkaline hydrogen peroxide (the solids named CAB AHP). The separate hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) processes were evaluated in the ethanol production. The enzymatic hydrolysis conducted with cellulase complex and beta glucosidase in a ratio of 0.61:0.39, enzyme loading of 30FPU/g(CAB-AHP) and 66CBU/g(CAB-AHP), respectively, using 4% cellulose from CAB-AHP, turned out to be the most effective conditions, with glucose and xylose yields of 511.68 mg/g(CAB AHP) and 237.8 mg/g(CAB-AHP), respectively. Fermentation of the pure hydrolysate by Kluyveromyces marxianus ATCC 36907 led to an ethanol yield of 61.8kg/ton(CAB), corresponding to 15 g/L ethanol and productivity of 3.75 g/( Lh). The ethanol production obtained for SSF process using K. marxianus ATCC 36907 was 18 g/L corresponding to 80% yield and 74.2kg/ton(CAB). PMID- 25545095 TI - Effect of inulin on efficient production and regulatory biosynthesis of bacillomycin D in Bacillus subtilis fmbJ. AB - The effect of inulin on the production of bacillomycin D and the levels of mRNA of bacillomycin D synthetase genes: bmyA (BYA), bmyB (BYB), bmyC (BYC), the thioesterase gene (TE) and regulating genes: AbrB, ComA, DegU, PhrC, SigmaH and Spo0A in Bacillus subtilis fmbJ were investigated. The production of bacillomycin D was enhanced with the increase of biomass concentration. The maximum production and productivity of bacillomycin D were found to be 1227.49 mg/L and 10.23 mg/L h. Inulin significantly improved the expression of bacillomycin D synthetase genes: bmyA (BYA), bmyB (BYB), bmyC (BYC) and the thioesterase gene (TE). Also, inulin up-regulated ComA, DegU, SigmaH and Spo0A and therefore promoted the high production of bacillomycin D. Our results provided a practical approach for efficient production of bacillomycin D and a meaningful explanation for regulatory mechanism of bacillomycin D biosynthesis. PMID- 25545096 TI - Comparative analysis of microbial community of novel lactic acid fermentation inoculated with different undefined mixed cultures. AB - Three undefined mixed cultures (activated sludge) from different municipal wastewater treatment plants were used as seeds in a novel lactic acid fermentation process fed with potato peel waste (PPW). Anaerobic sequencing batch fermenters were run under identical conditions to produce predominantly lactic acid. Illumina sequencing was used to examine the 16S rRNA genes of bacteria in the three seeds and fermenters. Results showed that the structure of microbial communities of three seeds were different. All three fermentation products had unique community structures that were dominated (>96%) by species of the genus Lactobacillus, while members of this genus constituted <0.1% in seeds. The species of Lactobacillus sp. differed among the three fermentations. Results of this study suggest the structure of microbial communities in lactic acid fermentation of PPW with undefined mixed cultures were robust and resilient, which provided engineering prospects for the microbial utilization of carbohydrate wastes to produce lactic acid. PMID- 25545097 TI - A comparative study of soft sensor design for lipid estimation of microalgal photobioreactor system with experimental validation. AB - This study examines the applicability of various nonlinear estimators for online estimation of the lipid concentration in microalgae cultivation system. Lipid is a useful bio-product that has many applications including biofuels and bioactives. However, the improvement of lipid productivity using real-time monitoring and control with experimental validation is limited because measurement of lipid in microalgae is a difficult and time-consuming task. In this study, estimation of lipid concentration from other measurable sources such as biomass or glucose sensor was studied. Extended Kalman filter (EKF), unscented Kalman filter (UKF), and particle filter (PF) were compared in various cases for their applicability to photobioreactor systems. Furthermore, simulation studies to identify appropriate types of sensors for estimating lipid were also performed. Based on the case studies, the most effective case was validated with experimental data and found that UKF and PF with time-varying system noise covariance is effective for microalgal photobioreactor system. PMID- 25545098 TI - Variations of organic matters and microbial community in thermophilic anaerobic digestion of waste activated sludge with the addition of ferric salts. AB - Ferric salts will influence the thermophilic anaerobic digestion of waste activated sludge (WAS). FeCl3 was found to contribute to the anaerobic digestion process with a cumulative biogas production of 357 mL/gVS, 79.6% higher than that in the control group, and Fe2(SO4)3 had no distinct impact, while Fe(NO3)3 inhibited the methanogenesis process. A favorable balance between the release of organic matters from WAS and consumption rate was established after dosing FeCl3 from the perspective of variations of soluble COD, volatile fatty acids (VFAs) and the dissolved organic matters (DOM) assessed by EEM fluorescence spectroscopy and fluorescence regional integration (FRI) technique. Conversely, the system with Fe(NO3)3 achieved an unsuitable substrates environment. Pyrosequencing revealed that the anaerobic digestion system with FeCl3 enriched Coprothermobacter for proteins fermentation and Methanosarcina for methanogenesis with the values of 18.7% and 63.2%, respectively, while that with the supplementation of Fe(NO3)3 obtained the lowest relative abundance. PMID- 25545099 TI - Ethical guidance on the use of life-sustaining therapies for patients with Ebola in developed countries. PMID- 25545100 TI - Metazoan remaining genes for essential amino acid biosynthesis: sequence conservation and evolutionary analyses. AB - Essential amino acids (EAA) consist of a group of nine amino acids that animals are unable to synthesize via de novo pathways. Recently, it has been found that most metazoans lack the same set of enzymes responsible for the de novo EAA biosynthesis. Here we investigate the sequence conservation and evolution of all the metazoan remaining genes for EAA pathways. Initially, the set of all 49 enzymes responsible for the EAA de novo biosynthesis in yeast was retrieved. These enzymes were used as BLAST queries to search for similar sequences in a database containing 10 complete metazoan genomes. Eight enzymes typically attributed to EAA pathways were found to be ubiquitous in metazoan genomes, suggesting a conserved functional role. In this study, we address the question of how these genes evolved after losing their pathway partners. To do this, we compared metazoan genes with their fungal and plant orthologs. Using phylogenetic analysis with maximum likelihood, we found that acetolactate synthase (ALS) and betaine-homocysteine S-methyltransferase (BHMT) diverged from the expected Tree of Life (ToL) relationships. High sequence conservation in the paraphyletic group Plant-Fungi was identified for these two genes using a newly developed Python algorithm. Selective pressure analysis of ALS and BHMT protein sequences showed higher non-synonymous mutation ratios in comparisons between metazoans/fungi and metazoans/plants, supporting the hypothesis that these two genes have undergone non-ToL evolution in animals. PMID- 25545103 TI - Analysis of a new drug of abuse: cathinone derivative 1-(3,4-dimethoxyphenyl)-2 (ethylamino)pentan-1-one. AB - Recently, novel psychoactive drugs for human abuse such as amphetamines, phenethylamines, benzofuries, and tryptamines, cathinones have gained high popularity. These designer drugs are mainly sold via online stores as "bath salts" and are labeled "not for human consumption." Due to the novelty of the compounds, only a little information about pharmacology, toxicology, and the long term damage they may cause is available. Moreover, there are only few analytical methods for their identification and analysis. Among new cathinone derivatives, 1 (3,4-dimethoxyphenyl)-2-(ethylamino)pentan-1-one (DL-4662), became available via an internet shop. A sample of this compound was purchased and investigated. The first aim of our study was an identity check by NMR spectroscopy and gas chromatography with mass spectrometry. As many of the recreational drugs are chiral and are mainly sold as racemates, a further goal of our research was enantioseparation by gas chromatography with mass spectrometry and high performance liquid chromatography with UV detection, to prove whether DL-4662 was traded enantiomerically pure or as racemic mixture. Both chiral separation methods showed the presence of a racemate. PMID- 25545104 TI - Epoxycarotenoid-mediated synthesis of abscisic acid in Physcomitrella patens implicating conserved mechanisms for acclimation to hyperosmosis in embryophytes. AB - Plants acclimate to environmental stress signals such as cold, drought and hypersalinity, and provoke internal protective mechanisms. Abscisic acid (ABA), a carotenoid-derived phytohormone, which increases in response to the stress signals above, has been suggested to play a key role in the acclimation process in angiosperms, but the role of ABA in basal land plants such as mosses, including its biosynthetic pathways, has not been clarified. Targeted gene disruption of PpABA1, encoding zeaxanthin epoxidase in the moss Physcomitrella patens was conducted to determine the role of endogenous ABA in acclimation processes in mosses. The generated ppaba1 plants were found to accumulate only a small amount of endogenous ABA. The ppaba1 plants showed reduced osmotic acclimation capacity in correlation with reduced dehydration tolerance and accumulation of late embryogenesis abundant proteins. By contrast, cold-induced freezing tolerance was less affected in ppaba1, indicating that endogenous ABA does not play a major role in the regulation of cold acclimation in the moss. Our results suggest that the mechanisms for osmotic acclimation mediated by carotenoid-derived synthesis of ABA are conserved in embryophytes and that acquisition of the mechanisms played a crucial role in terrestrial adaptation and colonization by land plant ancestors. PMID- 25545101 TI - The impact of diet and lifestyle on gut microbiota and human health. AB - There is growing recognition of the role of diet and other environmental factors in modulating the composition and metabolic activity of the human gut microbiota, which in turn can impact health. This narrative review explores the relevant contemporary scientific literature to provide a general perspective of this broad area. Molecular technologies have greatly advanced our understanding of the complexity and diversity of the gut microbial communities within and between individuals. Diet, particularly macronutrients, has a major role in shaping the composition and activity of these complex populations. Despite the body of knowledge that exists on the effects of carbohydrates there are still many unanswered questions. The impacts of dietary fats and protein on the gut microbiota are less well defined. Both short- and long-term dietary change can influence the microbial profiles, and infant nutrition may have life-long consequences through microbial modulation of the immune system. The impact of environmental factors, including aspects of lifestyle, on the microbiota is particularly poorly understood but some of these factors are described. We also discuss the use and potential benefits of prebiotics and probiotics to modify microbial populations. A description of some areas that should be addressed in future research is also presented. PMID- 25545102 TI - Understanding how commensal obligate anaerobic bacteria regulate immune functions in the large intestine. AB - The human gastrointestinal tract is colonised by trillions of commensal bacteria, most of which are obligate anaerobes residing in the large intestine. Appropriate bacterial colonisation is generally known to be critical for human health. In particular, the development and function of the immune system depends on microbial colonisation, and a regulated cross-talk between commensal bacteria, intestinal epithelial cells and immune cells is required to maintain mucosal immune homeostasis. This homeostasis is disturbed in various inflammatory disorders, such as inflammatory bowel diseases. Several in vitro and in vivo studies indicate a role for Faecalibacterium prausnitzii, Bacteroides thetaiotaomicron, Bacteroides fragilis, Akkermansia muciniphila and segmented filamentous bacteria in maintaining intestinal immune homeostasis. These obligate anaerobes are abundant in the healthy intestine but reduced in several inflammatory diseases, suggesting an association with protective effects on human health. However, knowledge of the mechanisms underlying the effects of obligate anaerobic intestinal bacteria remains limited, in part due to the difficulty of co-culturing obligate anaerobes together with oxygen-requiring human epithelial cells. By using novel dual-environment co-culture models, it will be possible to investigate the effects of the unstudied majority of intestinal microorganisms on the human epithelia. This knowledge will provide opportunities for improving human health and reducing the risk of inflammatory diseases. PMID- 25545105 TI - Adolescent end of life preferences and congruence with their parents' preferences: results of a survey of adolescents with cancer. AB - BACKGROUND: Little is known about how well family members accurately represent adolescents when making EOL decisions on their behalf. This study reports on surveys given to adolescents with cancer and their parents as part of a larger study facilitating advanced care discussions, as well as the results of a survey for health care providers. PROCEDURE: Trained facilitators administered surveys orally to adolescents and families in the intervention arm of the FAmily CEntered Advance Care Planning (ACP) for Teens with Cancer (FACE-TC) study. In addition, a post-hoc survey was sent to oncology providers. RESULTS: Seventeen adolescent/family dyads completed this survey. Seventy five percent of adolescents believed it was appropriate to discuss EOL decisions early and only 12% were not comfortable discussing death. Most preferred to be at home if dying. There were substantial areas of congruence between adolescents and their surrogates, but lower agreement on the importance of dying a natural death, dying at home and "wanting to know if I were dying." Among providers, 83% felt their patients' participation in the study was helpful to the patients and 78% felt it was helpful to them as providers. CONCLUSIONS: Adolescents with cancer were comfortable discussing EOL, and the majority preferred to talk about EOL issues before they are facing EOL. There were substantive areas of agreement between adolescents and their surrogates, but important facets of adolescents' EOL wishes were not known by their families, reinforcing the importance of eliciting individual preferences and engaging dyads so parents can understand their children's wishes. PMID- 25545107 TI - ST Segment Depression in the Inferior Leads in Brugada Pattern: A New Sign. AB - BACKGROUND: Brugada pattern (BP) is characterized by J wave and elevated ST segment in the right precordial leads. At times the ECG signs are present only with the electrodes displaced 1 or 2 intercostal spaces above. METHODS: We analyzed the electrocardiograms of 87 subjects with type 1 BP looking for ST segment depression (>= 0.1 mV with duration >= 0.08 s) in the inferior leads. In 21 subjects, BP pattern was evident only with V1 -V2 electrodes at the 3rd or 2nd space. RESULTS: ST segment depression was present in 41 cases (47%). In the 21 patients with BP recognizable only at the 2nd or 3rd intercostal space, 10 (48%) presented a significant ST depression in the inferior leads. CONCLUSIONS: ST segment analysis in the inferior leads has never been considered for BP diagnosis. When accurately searched for, however, ST segment depression can be observed in those leads in BP, suggesting the need for further investigation. PMID- 25545108 TI - Carbon nanotube feedback-gate field-effect transistor: suppressing current leakage and increasing on/off ratio. AB - Field-effect transistors (FETs) based on moderate or large diameter carbon nanotubes (CNTs) usually suffer from ambipolar behavior, large off-state current and small current on/off ratio, which are highly undesirable for digital electronics. To overcome these problems, a feedback-gate (FBG) FET structure is designed and tested. This FBG FET differs from normal top-gate FET by an extra feedback-gate, which is connected directly to the drain electrode of the FET. It is demonstrated that a FBG FET based on a semiconducting CNT with a diameter of 1.5 nm may exhibit low off-state current of about 1 * 10(-13) A, high current on/off ratio of larger than 1 * 10(8), negligible drain-induced off-state leakage current, and good subthreshold swing of 75 mV/DEC even at large source-drain bias and room temperature. The FBG structure is promising for CNT FETs to meet the standard for low-static-power logic electronics applications, and could also be utilized for building FETs using other small band gap semiconductors to suppress leakage current. PMID- 25545109 TI - Au19 nanocluster featuring a V-shaped alkynyl-gold motif. AB - A novel Au19 nanocluster with a composition of [Au19(PhC=C)9(Hdppa)3](SbF6)2 was synthesized (Hdppa = N,N-bis(diphenylphosphino)amine). Single crystal X-ray structural analysis reveals that the cluster comprises a centered icosahedral Au13 core hugged by three V-shaped PhC=C-Au-C=C(Ph)-Au-C=CPh motifs. Such motif is observed for the first time in an alkynyl-protected gold nanocluster. The Au19 cluster shows two main optical-absorption bands at 1.25 and 2.25 eV, confirmed by time-dependent density functional theory. Orbital analysis indicates that PhC=C- groups can actively participate in the frontier orbitals of the whole cluster. The new Au19 cluster and the novel alkynyl-gold motif open the door to understanding the alkynyl-gold interface and discovering many potential members of this new class of gold clusters. PMID- 25545106 TI - Emerging proteomic technologies for elucidating context-dependent cellular signaling events: A big challenge of tiny proportions. AB - Aberrant cell signaling events either drive or compensate for nearly all pathologies. A thorough description and quantification of maladaptive signaling flux in disease is a critical step in drug development, and complex proteomic approaches can provide valuable mechanistic insights. Traditional proteomics based signaling analyses rely heavily on in vitro cellular monoculture. The characterization of these simplified systems generates a rich understanding of the basic components and complex interactions of many signaling networks, but they cannot capture the full complexity of the microenvironments in which pathologies are ultimately made manifest. Unfortunately, techniques that can directly interrogate signaling in situ often yield mass-limited starting materials that are incompatible with traditional proteomics workflows. This review provides an overview of established and emerging techniques that are applicable to context-dependent proteomics. Analytical approaches are illustrated through recent proteomics-based studies in which selective sample acquisition strategies preserve context-dependent information, and where the challenge of minimal starting material is met by optimized sensitivity and coverage. This review is organized into three major technological themes: (i) LC methods in line with MS; (ii) antibody-based approaches; (iii) MS imaging with a discussion of data integration and systems modeling. Finally, we conclude with future perspectives and implications of context-dependent proteomics. PMID- 25545111 TI - Why are organotin hydride reductions of organic halides so frequently retarded? Kinetic studies, analyses, and a few remedies. AB - Kinetic data for reduction of organic halides (RX) by tri-n-butylstannane (SnH) reveal a serious flaw in the current view of the kinetic radical chain: the tacit but unproven assumption that the speed of reaction is determined by the slowest propagation step. Our results show this is rarely true for reductive chains and that the observed rate is in fact controlled by unseen side-reactions of propagating R(*) and Sn(*) radicals with the solvent (notably, benzene!) or solvent impurities (e.g., trace benzophenone dryness indicator in THF) or, crucially, with allylic-CH and conjugated unsaturated groups in substrates and products. Most R(*) and/or Sn(*) radicals are therefore converted into relatively inert delocalized species A(*) and/or B(*) that inhibit the chain. Retardation in the degraded chain is given by a simple sum of terms, each being the ratio of the chain-transfer rate divided by the rate of chain-return. The model kinetic equation is linear and easy to ratify, interpret, and apply: to calculate retarding rate constants, optimize reaction conditions, and identify additives or "remedies" that repair the chain and accelerate reaction. The present work is thus expected to have a helpful impact on the practice and design of SnH radical chain based (and related) syntheses. PMID- 25545110 TI - Systemic delivery of stable siRNA-encapsulating lipid vesicles: optimization, biodistribution, and tumor suppression. AB - Lipid-based nanoparticles are considered as promising candidates for delivering siRNA into the cytoplasm of targeted cells. However, in vivo efficiency of these nanoparticles is critically dependent on formulation strategies of lipid-siRNA complexes. Adsorption of serum proteins to lipid-siRNA complexes and its charge determine siRNA degradation and serum half-life, thus significantly altering the bioavailability of siRNA. To address these challenges, we developed a formulation comprising dihydroxy cationic lipid, N,N-di-n-hexadecyl-N,N dihydroxyethylammonium chloride (DHDEAC), cholesterol, and varying concentrations of 1,2-distearoryl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol-2000)] (DSPE-PEG 2000). Using an ethanol dilution method, addition of these lipids to siRNA solution leads to formation of stable and homogeneous population of siRNA-encapsulated vesicles (SEVs). Biodistribution of these SEVs, containing 5 mol % of DSPE-PEG 2000 in xenograft mice, as monitored by live animal imaging and fluorescence microscopy, revealed selective accumulation in the tumor. Remarkably, four intravenous injections of the modified vesicles with equimolar amounts of siRNA targeting ErbB2 and AURKB genes led to significant gene silencing and concomitant tumor suppression in the SK-OV-3 xenograft mouse model. Safety parameters as evaluated by various markers of hepatocellular injury indicated the nontoxic nature of this formulation. These results highlight improved pharmacokinetics and effective in vivo delivery of siRNA by DHDEAC-based vesicles. PMID- 25545112 TI - Enhanced molecular level dispersion and interface bonding at low loading of modified graphene oxide to fabricate super nylon 12 composites. AB - Development of advanced graphene based polymer composites is still confronted with severe challenges due to its poor dispersion caused by restacking, weak interface bonding, and incompatibility with polymer matrices which suppress exertion of the actual potential of graphene sheets in composites. Here, we have demonstrated an efficient chemical modification process with polyethylenimine (PEI) to functionalize graphene oxide which can overcome the above-mentioned drawbacks and also can remarkably increase the overall strength of the nylon 12 composites even at very low graphene loading. Chemical modification was analyzed by various surface characterizations including X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. Addition of only 0.25 and 0.35 wt % modified GO showed 37% and 54% improvement in tensile strength and 65% and 74% in Young's modulus, respectively, compared with that of the neat polymer. The dynamic mechanical analysis showed ~39% and 63% increment in storage modulus of the nanocomposites. Moreover, the nanocomposites exhibited significantly high thermal stability (~15 degrees C increment by only 0.35 wt %) as compared to neat polymer. Furthermore, the composites rendered outstanding resistance against various chemicals. PMID- 25545113 TI - Incorporating expert judgments in utility evaluation of bacteroidales qPCR assays for microbial source tracking in a drinking water source. AB - Several assays for the detection of host-specific genetic markers of the order Bacteroidales have been developed and used for microbial source tracking (MST) in environmental waters. It is recognized that the source-sensitivity and source specificity are unknown and variable when introducing these assays in new geographic regions, which reduces their reliability and use. A Bayesian approach was developed to incorporate expert judgments with regional assay sensitivity and specificity assessments in a utility evaluation of a human and a ruminant specific qPCR assay for MST in a drinking water source. Water samples from Lake Radasjon were analyzed for E. coli, intestinal enterococci and somatic coliphages through cultivation and for human (BacH) and ruminant-specific (BacR) markers through qPCR assays. Expert judgments were collected regarding the probability of human and ruminant fecal contamination based on fecal indicator organism data and subjective information. Using Bayes formula, the conditional probability of a true human or ruminant fecal contamination given the presence of BacH or BacR was determined stochastically from expert judgments and regional qPCR assay performance, using Beta distributions to represent uncertainties. A web-based computational tool was developed for the procedure, which provides a measure of confidence to findings of host-specific markers and demonstrates the information value from these assays. PMID- 25545114 TI - Chinese experience in the treatment of alopecia areata with diphenylcyclopropenone. PMID- 25545116 TI - Tick saliva increases production of three chemokines including monocyte chemoattractant protein-1, a histamine-releasing cytokine. AB - The effect of Ixodes ricinus tick saliva on the production of various cytokines and chemokines by mouse splenocytes was tested by a cytokine array. We demonstrated a strong upregulation of three chemokines, monocyte chemoattractant protein-1 (MCP-1), thymus-derived chemotactic agent 3 (TCA-3) and macrophage inflammatory protein 2 (MIP-2). MCP-1 could be induced by tick saliva itself. While TCA-3 and MIP-2 are engaged in Th2 polarization of the host immune response associated with tick feeding, MCP-1 may act as a histamine release factor, increasing blood flow into the feeding lesion thus facilitating tick engorgement in the late, rapid feeding phase. PMID- 25545115 TI - Resistin-like molecule-beta (RELM-beta) targets airways fibroblasts to effect remodelling in asthma: from mouse to man. AB - BACKGROUND: RELM-beta has been implicated in airways inflammation and remodelling in murine models. Its possible functions in human airways are largely unknown. The aim was to address the hypothesis that RELM-beta plays a role in extracellular matrix deposition in asthmatic airways. METHODS: The effects of RELM-beta gene deficiency were studied in a model of allergen exposure in mice sensitised and challenged with Aspergillus fumigatus (Af). RELM-beta expression was investigated in bronchial biopsies from asthmatic patients. Direct regulatory effects of RELM-beta on human lung fibroblasts were examined using primary cultures and the MRC5 cell line in vitro. RESULTS: Sensitisation and challenge of wild-type mice with Af-induced release of RELM-beta with a time course coincident with that of procollagen in the airways. Af-induced expression of mRNA encoding some, but not all ECM in the lung parenchyma was attenuated in RELM-beta-/- mice. RELM-beta expression was significantly increased in the bronchial submucosa of human asthmatics compared with controls, and its expression correlated positively with that of fibronectin and alpha-smooth muscle actin. In addition to epithelial cells, macrophages, fibroblasts and vascular endothelial cells formed the majority of cells expressing RELM-beta in the submucosa. Exposure to RELM-beta increased TGF-beta1, TGF-beta2, collagen I, fibronectin, smooth muscle alpha actin, laminin alpha1, and hyaluronan and proteoglycan link protein 1 (Hapl1) production as well as proliferation by human lung fibroblasts in vitro. These changes were associated with activation of ERK1/2 in MRC5 cells. CONCLUSION: The data are consistent with the hypothesis that elevated RELM-beta expression in asthmatic airways contributes to airways remodelling at least partly by increasing fibroblast proliferation and differentiation with resulting deposition of extracellular matrix proteins. PMID- 25545118 TI - Erythema multiforme-like drug reaction with eosinophilia and systemic symptoms (DRESS). PMID- 25545117 TI - Contribution of income to self-management and health outcomes in pediatric type 1 diabetes. AB - Low income has been established as a risk factor for poorer outcomes in youth with type 1 diabetes; however, the effect of moderate income has not been studied. The purpose of this secondary analysis of baseline data from a multi site study was to compare glycemic control, self-management, and psychosocial outcomes [depression, stress, and quality of life (QOL)] at different income levels in adolescents with type 1 diabetes. Youth (n = 320, mean age = 12.3 + 1.1, 55% female, 64% white, mean A1C = 8.3 +/- 1.4) completed established self management and psychosocial measures. A1C levels were collected from medical records. Caregivers reported annual family income, categorized as high (>$80K), moderate ($40-80K), or low (<$40K). Youth from high-income families had significantly lower A1C (mean = 7.9 +/- 1.2) than those from the moderate-income group (8.6 +/- 1.7, p < 0.001) or the low-income group (mean A1C = 8.6 +/- 1.5, p = 0.003). Youth from the high-income group reported significantly better diabetes problem solving and more self-management goals than those from the moderate- or low-income groups (both p < 0.01). Youth from the high-income group also reported significantly fewer symptoms of depression, lower levels of perceived stress, and better QOL than those in the moderate or low-income groups (all p < 0.05). Multivariate linear regression models were used to test psychological and behavioral predictors of A1C and QOL. Parents' education status (p < 0.05) and self-management activities (p < 0.01) were significant predictors of hemoglobin A1c, while income (p < 0.01) and self-management activities (p < 0.05) were significant predictors of QOL. PMID- 25545119 TI - Can inter-professional simulation training influence the frequency of blood transfusions after birth? AB - OBJECTIVE: To investigate whether inter-professional simulation training influenced the rate of red blood cell (RBC) transfusions after birth. DESIGN: Two cohorts were compared retrospectively using a pre-post design. SETTING: Norwegian university hospital with 4800 deliveries annually. POPULATION: Women with estimated blood loss >500 mL within 24 h after birth in 2009 and 2011. METHODS: In 2010, all maternity staff attended a 6-h, scenario-based training on emergency obstetrics including postpartum hemorrhage, using a birthing simulator. The simulation focused on prevention, identification, and treatment of postpartum hemorrhage and on communication and leadership. Debrief immediately after the scenarios involved reflection and self-assessment. MAIN OUTCOME MEASURES: The frequency of women receiving RBC transfusions as a marker for blood loss. Secondary outcome was the frequency of surgical procedures in the management of postpartum hemorrhage. RESULTS: In 2009, 111/534 (20.8%) women with estimated blood loss >500 mL after birth received RBC transfusions vs. 67/546 (12.3%) in 2011 (p < 0.01). The adjusted odds ratio for women receiving RBC transfusions in 2011 vs. 2009 was 0.53 (95% CI 0.38-0.74). Parity, oxytocin augmentation, duration of second stage, episiotomy, operative vaginal delivery, and sphincter injury were included in the final model. The odds ratio was stable in all combinations of possible confounders. We observed a significant reduction in the frequencies of curettage (p < 0.01) and uterine artery embolizations (p = 0.01). CONCLUSION: We found a significant reduction in RBC transfusions after birth, which might be associated with mandatory simulation training. A causal link cannot be documented because of complex interactions of several variables. PMID- 25545120 TI - Adipokinetic hormone signalling system in the Chagas disease vector, Rhodnius prolixus. AB - Neuropeptides and their G protein-coupled receptors are widespread throughout Metazoa and in several cases, clear orthologues can be identified in both protostomes and deuterostomes. One such neuropeptide is the insect adipokinetic hormone (AKH), which is related to the mammalian gonadotropin-releasing hormone. AKH has been studied extensively and is known to mobilize lipid, carbohydrates and proline for energy-consuming activities such as flight. In order to determine the possible roles for this signalling system in Rhodnius prolixus, we isolated the cDNA sequences encoding R. prolixus AKH (Rhopr-AKH) and its receptor (Rhopr AKHR). We also examined their spatial expression pattern using quantitative PCR. Our expression analysis indicates that Rhopr-AKH is only expressed in the corpus cardiacum of fifth-instars and adults. Rhopr-AKHR, by contrast, is expressed in several peripheral tissues including the fat body. The expression of the receptor in the fat body suggests that AKH is involved in lipid mobilization, which was confirmed by knockdown of Rhopr-AKHR via RNA interference. Adult males that had been injected with double-stranded RNA (dsRNA) for Rhopr-AKHR exhibited increased lipid content in the fat body and decreased lipid levels in the haemolymph. Moreover, injection of Rhopr-AKH in Rhopr-AKHR dsRNA-treated males failed to elevate haemolymph lipid levels, confirming that this is indeed the receptor for Rhopr-AKH. PMID- 25545121 TI - Smoking during pregnancy and vision difficulties in children: a systematic review. AB - Cigarette smoking during pregnancy is a major public health concern. Intra uterine exposure to maternal cigarette smoking is associated with increased risks of growth and neurodevelopmental problems during childhood and later life. Few studies have focussed on visual difficulties in children in the context of maternal smoking during pregnancy. A systematic search of online databases was carried out between February and May 2013 to examine the trend in visual outcomes in children exposed to maternal cigarette smoking during intra-uterine life. Twenty-four non-randomized studies were identified. Each study was rated for quality using the Newcastle-Ottawa Scale. Most studies (n = 18) reported fetal exposure to active or passive maternal cigarette smoking to be associated with an increased risk of adverse visual outcomes in children. In particular, there were higher rates of strabismus, refractive errors and retinopathy among children of women who smoked during pregnancy. These findings suggest that fetal exposure to cigarette smoke is a significant risk factor for visual problems during later life and that certain visual faculties, such as the intraocular muscles and retinal neurons, are more affected than others. The findings provide evidence in support of public health policies aimed at reducing fetal exposure to smoking by advising both women and their partners to quit smoking during pregnancy. PMID- 25545122 TI - Autoimmune comorbid diseases associated with lichen planus: a nationwide case control study. AB - BACKGROUND: Lichen planus (LP) is a chronic inflammatory disorder with unknown aetiology. The association between LP and various autoimmune diseases has been reported, but nationwide study of the relationship of LP with associated diseases is quite limited. OBJECTIVE: Our study aims to clarify the association between LP and a variety of autoimmune diseases in Taiwanese. METHODS: Data were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan from 1997 to 2011. In total, 12,427 patients with LP and 49,708 age- and gender-matched controls were enrolled. RESULTS: Among patients with LP, there were significant associations with systemic lupus erythematosus (SLE) (multivariate odds ratio [mOR]: 2.87; 95% CI: 1.97-4.17), Sjogren's syndrome (mOR: 3.75; 95% CI: 2.66 5.28), dermatomyositis (mOR: 6.34; 95% CI: 1.82-22.16), vitiligo (mOR: 2.09; 95% CI: 1.31-3.32) and alopecia areata (mOR: 2.82; 95% CI: 2.20-3.62). On gender stratified analyses, SLE and alopecia areata were significantly associated with LP in both genders. The association with Sjogren's syndrome was significant only in female patients. The associations with dermatomyositis and vitiligo became insignificant in both genders. CONCLUSION: Lichen planus is associated with various autoimmune diseases. Further study is required to elucidate the possible underlying mechanisms and roles of autoimmunity in the aetiology of LP. PMID- 25545123 TI - Digital infarction in a hemodialysis patient due to embolism from a thrombosed brachial arteriovenous fistula. AB - Acute onset of digital ischemia and infarction is an unusual complication in patients undergoing hemodialysis. This is a report of a patient on regular hemodialysis who presented with acute distal extremity ischemia, progressing to digital infarction and on evaluation was found to have thrombosis of brachial arteriovenous fistula with embolization to the distal arteries causing digital artery occlusion. PMID- 25545124 TI - Asexuality: an extreme variant of sexual desire disorder? AB - INTRODUCTION: Human asexuality is defined as a lack of sexual attraction to anyone or anything. Various theories have been proposed to explain how asexuality should best be classified, and some have maintained that asexuality is an extreme variant of hypoactive sexual desire disorder (HSDD)-a sexual dysfunction characterized by a lack of interest in sex and significant distress. To date, this has never been empirically examined. AIM AND METHOD: Using measures of sexual desire and behavior, sex-related distress, personality, and psychopathology, the aim of the current study was to compare individuals scoring above the cutoff for asexuality identification (AIS >40) (n = 192) to sexual individuals (n = 231). The sexual group was further divided into a control group (n = 122), a HSDD group (n = 50), and a group with symptoms of low desire that were nondistressing (n = 59). RESULTS: Analyses were controlled for age. Individuals in the AIS >40 group had a greater likelihood of never previously engaging in sexual intercourse, fantasies, or kissing and petting than all other groups and a lower likelihood of experiencing sex-related distress than those with HSDD. For women, those in the HSDD and AIS >40 groups had significantly lower desire than the subclinical HSDD and control groups. Men in the AIS >40 group had significantly lower desire than the other three groups. Symptoms of depression were highest among those with subclinical HSDD and HSDD, whereas there were no group differences on alexithymia or desirable responding. A binary logistic regression indicated that relationship status (long-term dating/married), sexual desire, sex-related distress, and lower alexithymia scores were the best predictors of group membership (HSDD vs. AIS >40). CONCLUSION: Taken together, these results challenge the speculation that asexuality should be classified as a sexual dysfunction of low desire. PMID- 25545125 TI - Pharmacology of Src family kinases and therapeutic implications of their modulators. AB - Src family kinases (SFKs), the largest family of nonreceptor tyrosine kinases, include 10 members. Src was the first gene product discovered to have intrinsic protein tyrosine kinase activity. Src is widely expressed in many cell types and can have different locations within a cell; the subcellular location of Src can affect its function. Src can associate with cellular membranes, such as the plasma membrane, the perinuclear membrane, and the endosomal membrane. SFKs actions on mammalian cells are pleiotropic and include effect on cell morphology, adhesion, migration, invasion, proliferation, differentiation, and survival. SFKs at one end have been documented to play some important physiological functions; on the other end, they have been described in the pathophysiology of some disorders. In this review article, an exhaustive attempt has been made to unearth pharmacology of SFKs and therapeutic implications of SFKs modulators. PMID- 25545126 TI - Determinants of pressure drift in Manoscan(TM) esophageal high-resolution manometry system. AB - BACKGROUND: Manoscan(TM) is one of the commonly used high-resolution manometry (HRM) systems with declared measurement accuracy of 1-2 mmHg. However, the accuracy of pressure measurements is limited by development of pressure drift (PD) throughout recording. To date, there has been no systematic investigation to identify the factors contributing to PD. The aim of the present study was to characterize the frequency and magnitude of PD in Manoscan(TM) system and identify the factors contributing to PD. METHODS: Records of 560 consecutive clinical esophageal HRM studies recorded by six distinct HRM catheters were retrospectively reviewed. PD was defined as the residual pressure measurement by each sensor immediately after removal of the catheter. Non-parametric locally weighted regression analysis was performed to assess the effect of duration of study, number of prior uses of a catheter, peak and average pressure exposure during a study on the PD. KEY RESULTS: The majority (95%) of clinical manometry studies showed a non-negligible PD of more than 5 mmHg. The overall PD was 13 +/- 5 mmHg and the sensor with greatest amount of PD showed 23 +/- 12 mmHg of drift. The upper esophageal sphincter showed the highest PD. Average pressure exposure of a sensor throughout the recording was the most important predictor of PD. PD inversely correlated with number of prior uses of a catheter. CONCLUSIONS & INFERENCES: The PD preferentially affects esophageal high-pressure zones, and strongly correlates with 'average pressure exposure' of a sensor during manometry. Available algorithms of the analysis software do not adequately correct the PD. PMID- 25545127 TI - Paediatric and perinatal epidemiology: past accomplishments and looking to the future. PMID- 25545128 TI - Advancing Research through Replication. PMID- 25545129 TI - Paediatric and perinatal epidemiology: an appreciation to our impressive referees. PMID- 25545130 TI - Peripheral mycotic pulmonary artery aneurysms. AB - Mycotic pulmonary artery aneurysms are rare but potentially fatal complications of infective endocarditis. The literature on this rare condition was reviewed and its management is discussed. PMID- 25545131 TI - Basophils inhibit proliferation of CD4+ T cells in autologous and allogeneic mixed lymphocyte reactions and limit disease activity in a murine model of graft versus host disease. AB - Basophils are known to modulate the phenotype of CD4(+) T cells and to enhance T helper type 2 responses in vitro and in vivo. In this study, we demonstrate that murine basophils inhibit proliferation of CD4(+) T cells in autologous and allogeneic mixed lymphocyte reactions. The inhibition is independent of Fas and MHC class II, but dependent on activation of basophils with subsequent release of interleukin-4 (IL-4) and IL-6. The inhibitory effect of basophils on T-cell proliferation can be blocked with antibodies against IL-4 and IL-6 and is absent in IL-4/IL-6 double-deficient mice. In addition, we show that basophils and IL-4 have beneficial effects on disease activity in a murine model of acute graft versus-host disease (GvHD). When basophils were depleted with the antibody MAR-1 before induction of GvHD, weight loss, GvHD score, mortality and plasma tumour necrosis factor levels were increased while injection of IL-4 improved GvHD. Basophil-depleted mice with GvHD also have increased numbers of CD4(+) T cells in the mesenteric lymph nodes. Our data show for the first time that basophils suppress autologous and allogeneic CD4(+) T-cell proliferation in an IL-4 dependent manner. PMID- 25545132 TI - GROSS AND HISTOPATHOLOGIC CORRELATION OF LOW-FIELD MAGNETIC RESONANCE IMAGING FINDINGS IN THE STIFLE OF ASYMPTOMATIC HORSES. AB - With the recent introduction of a 0.25T rotating MRI system, clinical evaluation of the equine stifle joint is now possible in the average equine athlete. A recent publication described common abnormalities of horses with stifle lameness detected with a low-field MRI system; however, postmortem corroboration of the lesions detected was not possible. Therefore, our objective was to compare postmortem findings with low-field MRI findings in equine cadaver stifle joints. Ten fresh cadaver stifle joints from horses without clinical signs of stifle disease were evaluated using low-field MRI, gross dissection, and histopathology. In eight stifles, either the lateral or medial cranial meniscotibial ligament had an irregular shape, fiber separation, or moderate abnormal signal intensity (SI) on all sequences. In five stifles, the medial femoral condyle had articular cartilage fibrillation with or without an osteochondral defect over the weight bearing surface of the medial femoral condyle. All stifles had abnormal SI on all sequences within the patellar ligaments that corresponded with adipose tissue infiltrating between the collagen bundles. Other abnormalities identified included articular cartilage fibrillation of the tibial condyles in three stifles, and articular cartilage fibrillation with chondral defects in the patella in three stifles. All abnormalities detected with low-field MRI were corroborated by gross dissection. Findings from the current study supported the use of low-field MRI for detection of stifle joint lesions in horses and demonstrated that some stifle joint pathologies may be subclinical in horses. PMID- 25545133 TI - Synthesis of 2-spiropseudoindoxyls via an intramolecular nitroalkyne redox dipolar cycloaddition cascade. AB - Novel spiropseudoindoxyls were synthesized in high yields via a fully regioselective Au(III)-catalyzed cycloisomerization of easily obtainable o nitrophenylpropiolamides, followed by an intramolecular dipolar cycloaddition as key steps. This one-pot cascade reaction resulted in new tetracyclic pseudoindoxyls, which were hydrogenated toward the title compounds as single diastereomers via N-O cleavage. The mechanism of the gold catalyzed cycloisomerization was studied by DFT and suggests a reaction path without the intermediacy of gold carbenoid species in these cases. PMID- 25545134 TI - Age estimation of juvenile European hake Merluccius merluccius based on otolith microstructure analysis: a slow or fast growth pattern? AB - The main goal of this study was to examine otolith microstructure and to estimate the age and growth of European hake Merluccius merluccius from the eastern Mediterranean Sea. One hundred and twenty-nine specimens ranging from 102 to 438 mm in total length (LT ) were used. Age estimations were based on the study of the otolith microstructure, which was revealed after grinding both frontal sides of otoliths. The enumerations of the daily growth increments (DGI) as well as their width (WDGI ) measurements were made on calibrated digital images. The number of DGI in otoliths ranged between 163 and 717. Four phases in the WDGI evolution were distinguished: (1) larval-juvenile pelagic phase, with an increasing trend in WDGI up to the 60th DGI, (2) settlement phase, with a short term deceleration in WDGI between the 61st and 150th DGI, (3) juvenile demersal phase, characterized by a stabilization of WDGI from 151st to 400th DGI and (4) adult phase, with a decreasing trend in WDGI after the 400th DGI. Age, sex and month of formation were found to affect the WDGI in all phases, with the exception of age at the juvenile demersal phase. The power curve with intercept model described best the relationship of M. merluccius LT with age (TDGI ), according to Akaike criteria, revealing differences in growth between females [LT = 65 . 36(TDGI )(0 . 40) - 388 . 55] and males [LT = 69 . 32(TDGI )(0 . 37) - 352 . 88] for the sizes examined. The mean daily growth rates were 0.61 mm day(-1) for females and 0.52 mm day(-1) for males, resulting in an LT of 283 and 265 mm at the end of their first year of life. In comparison with previous studies on the Mediterranean Sea, the results of this study showed a greater growth rate, similar to results from tagging experiments and otolith microstructure analyses for M. merluccius in other geographic areas. PMID- 25545136 TI - From criminals to celebrities: perceptions of "the addict" in the print press from four European countries from nineties to today. AB - The article reviews portrayals of "the addict" in press items from Italy, Finland, Poland, and The Netherlands. The dataset consists of 1,327 items from four national newspapers published in 1991, 1998, 2011. The portrayals varied according to country, period, and type of addiction problem. Results can be read as four cases where different conceptualizations ("the sinner," "the sick," "the social problem," "the criminal," and "the famous") assume diverse importance. These conceptual frames-of-reference are clearly neither unambiguous nor fixed. They are constantly modified and part of different trends. PMID- 25545137 TI - Doing gender in a toxic world. Women and freebase cocaine in the city of Buenos Aires (Argentina). AB - Consumption of freebase cocaine in Argentina has been investigated among males but not females. This qualitative study focuses on the complexity of relationships between gender identity and the use of drugs, investigating freebase cocaine as an example in the Metropolitan Area of Buenos Aires, Argentina. In-depth interviews were conducted with female consumers in 2010. The results reveal the different ways in which female identity is constructed in the context of social vulnerability. We identify ways of doing gender and feeling like a woman in a man's world that are associated with a higher risk of violence and exclusion for being female. PMID- 25545138 TI - Are nondrinkers missing from the picture? AB - WHO statistics indicate that half the world's population does not drink alcohol. With a Western outlook this fact is often overlooked. FINDINGS: The article explores the global drinking patterns focusing on non-drinking and the global forces that contribute towards change. The large segment of non-drinking population is beneficial for public health but it is also seen as a great potential for the international alcoholic beverage industry. CONCLUSION: The forces of globalization towards conformity and a global mono-culture deprived of cultural diversity also affects non-drinking populations, to the detriment of public health. PMID- 25545139 TI - Drinking like everyone else: trait self-control moderates the association between peer and personal heavy episodic drinking. AB - BACKGROUND: Alcohol consumption often appears to be under social influence. However, we know relatively little about whether some people are particularly likely to exhibit similar drinking patterns to their peers. OBJECTIVES: Here we tested the extent to which trait social approval concerns and trait self-control are associated with the likelihood that individuals display similar heavy episodic drinking patterns to their peers. METHOD: One thousand and fifty-six young adults participated in an online study. We measured trait social approval concerns (the Need to Belong scale) and trait self-control (the Self-Control scale) alongside personal heavy episodic drinking and perceptions of peer heavy episodic drinking. RESULTS: Beliefs that one's peers (other students) drank heavily were associated with heavier personal episodic drinking. This relationship was moderated by trait self-control: The correlation between personal heavy episodic drinking and perceived peer drinking was much stronger in those with low self-control compared with those with high self-control. Contrary to hypotheses, trait social approval concerns did not moderate the relationship between perceived peer drinking and personal heavy episodic drinking. CONCLUSIONS: Social norms about drinking could act as a form of informational cue for one's own alcohol consumption, but the extent to which individuals follow or override this cue may depend on individual differences in self-control. PMID- 25545140 TI - "Vintage meds": a netnographic study of user decision-making, home preparation, and consumptive patterns of laudanum. AB - BACKGROUND: Reviews have commented on rising clandestine manufacture of opiate drug solutions for injecting, and to a lesser extent for oral use. Very little is known about user attempts to culture poppy seeds, widely available on the internet for manufacture of long acting medium-high potency oral solutions, both as poppy seed tea or as opium tincture (laudanum). OBJECTIVES: A netnographic research methodology aimed to provide online consumer insight into user sourcing and decision influences, experiences of home manufacture of laudanum, utilization of opium tincture recipes, and consumptive patterns. METHODS: A systematic internet search was conducted using the terms: "Laudanum," "Opium tincture," and "Tincture of Opium" in combination with "forum." Following screening of 810 forum threads with exclusion criteria and removal of duplicates, 75 fora threads on 6 online drug fora were analyzed using the empirical phenomenological psychological method. Four themes were generated. RESULTS: Findings illustrated the underpinning of user reminiscing about Victorian use of standardized laudanum, long duration shelf life, and medicinal use for opiate withdrawals with intentions to prepare. Preparation of famous recipes and use of authentic storage bottles boosted nostalgia. Participants appeared well versed in kitchen chemistry processes. Discussions centered on type and amount of alcohol used, use of additives to promote palatability and intoxication effect, homogenization of poppy seeds, and double extraction using opium tincture. Lack of detail available on intoxication experiences, with tentative dosage advised. CONCLUSIONS: Development of targeted and credible "counterpublic" harm reduction initiatives situated within online consumerism of communal drug knowledge is warranted. PMID- 25545135 TI - Mitochondrial sirtuins and their relationships with metabolic disease and cancer. AB - SIGNIFICANCE: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. RECENT ADVANCES: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyl-lysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. CRITICAL ISSUES: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. FUTURE DIRECTIONS: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. PMID- 25545141 TI - Estimating the need for hepato-pancreatico-biliary surgeons in the USA. AB - BACKGROUND: Hepato-pancreatico-biliary (HPB) fellowship training has risen in popularity in recent years and hence large numbers of graduating fellows enter the workforce each year. Studies have proposed that the increase in HPB-trained surgeons will outgrow demand in the USA. This study shows that the need for HPB trained surgeons refers not to the meeting of demand in terms of case volume, but to improving patient access to care. METHODS: The National Inpatient Sample (NIS) database for the years 2005-2011 was queried for CPT codes relating to pancreatic, liver and biliary surgical cases. These numbered 6627 in 2005 and increased to 8515 in 2011. Cases were then mapped to corresponding states. The number of procedures in an individual state was divided by the total number of procedures to give a ratio for each state. A similar ratio was calculated for the population of each state to the national population. These ratios were combined to give a ratio by state of observed to expected HPB surgical cases. RESULTS: Of the 46 states that participate in the NIS, only 18 achieved ratios of observed to expected cases of >1. In the remaining 28 states, the number of procedures was lower than that expected according to each state's population. CONCLUSIONS: The majority of the USA is underserved in terms of HPB surgery. Given the growing number of HPB-trained physicians entering the job market, this sector should focus on bringing understanding and management of complex disease to areas of the country that are currently in need. PMID- 25545143 TI - Patterns of communication in high-fidelity simulation. AB - High-fidelity simulation is commonplace in nursing education. However, critical thinking, decision making, and psychomotor skills scenarios are emphasized. Scenarios involving communication occur in interprofessional or intraprofessional settings. The importance of effective nurse-patient communication is reflected in statements from the American Nurses Association and Quality and Safety Education for Nurses, and in the graduate outcomes of most nursing programs. This qualitative study examined the patterns of communication observed in video recordings of a medical-surgical scenario with 71 senior students in a baccalaureate program. Thematic analysis revealed patterns of (a) focusing on tasks, (b) communicating-in-action, and (c) being therapeutic. Additional categories under the patterns included missing opportunities, viewing the "small picture," relying on informing, speaking in "medical tongues," offering choices...okay?, feeling uncomfortable, and using therapeutic techniques. The findings suggest the importance of using high-fidelity simulation to develop expertise in communication. In addition, the findings reinforce the recommendation to prioritize communication aspects of scenarios and debriefing for all simulations. PMID- 25545144 TI - The who, what, and how of evaluation within online nursing education: state of the science. AB - The resource capacity in nursing programs has a direct impact on student admissions and number of graduates who enter the nursing workforce. Online delivery of nursing education is identified as a solution to expand nursing program capacity. As nursing programs continue to address capacity with online course delivery, it is essential that nurse educators maintain consistent evaluation practices to ensure successful and positive outcomes, compared with traditional models. Evaluation is a central component to determine program quality and mastery of learning outcomes. This article examines the state of the science around the current evaluation of educational practices, instructional strategies, and outcomes within the context of online nursing education. Thirty six articles met the inclusion criteria. Despite substantive contributions to the state of the science, the findings reflect evaluation practices that are diffuse and superficial and serve as the basis for future recommendations and research opportunities. PMID- 25545145 TI - Nursing students' perceptions of their knowledge of lesbian, gay, bisexual, and transgender issues: effectiveness of a multi-purpose assignment in a public health nursing class. AB - Nurses work with diverse populations, but the nursing literature lacks research, theoretical frameworks, or practice guidelines regarding lesbian, gay, bisexual, and transgender (LGBT) health. Through diverse teaching strategies, students explored issues related to LGBT patients, families, and nurses using a cultural humility lens. Diverse teaching strategies included readings, a 2-hour presentation on LGBT health issues, and an assignment to conduct a scripted interview with two nurse key informants, based on the Health Care Equality Index (HEI). Students completed an online LGBT awareness preinterview survey, completed interviews, and completed a postinterview survey. Students showed a significant increase in knowledge about sexual orientation and gender identity and research and interview methods from pretest to posttest. The diverse teaching strategies involved in this assignment can enhance student knowledge, attitudes, and skills related to LGBT health care needs and increase appreciation of nursing research. PMID- 25545142 TI - Telocytes and putative stem cells in ageing human heart. AB - Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days-1 year), children (6-17 years) and adults (34-60 years). Morphometry was performed on low magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 +/- 4.9% in newborns to 41 +/- 5.2% in adults. Also, the number of blood capillaries (per mm(2) ) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52-62%; vascular smooth muscle cells and pericytes 22 28%, Schwann cells with nerve endings 6-7%, fibroblasts 3-10%, macrophages 1-8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults). PMID- 25545146 TI - Minimally invasive surgery for pediatric trauma-a multicenter review. AB - INTRODUCTION: The published experience with minimally invasive techniques to treat injured children is currently small. In this multicenter case series, we aimed to characterize the contemporary role of minimally invasive surgery (MIS) in pediatric trauma. MATERIALS AND METHODS: After obtaining Institutional Review Board approval at six pediatric regional trauma centers in the United States, a retrospective review was conducted on children who have undergone thoracoscopy or laparoscopy for the management of trauma over the past 13 years. RESULTS: There were 200 patients with a mean age of 9.6 +/- 4.2 years, and 73% were male. Laparoscopy was performed for 187 (94%) and thoracoscopy for 8 (4%), whereas 5 (2%) patients had both, for a total of 205 MIS procedures. Conversion to open surgery occurred in 36% (n=73). Median operative time was 77 (range, 16-369) minutes. Of the 132 procedures completed without conversion, 81 (61%) were diagnostic, whereas the remaining were therapeutic, including the repair of bowel injuries (n=20), distal pancreatectomy (n=5), splenectomy (n=2), repair of traumatic abdominal wall hernias (n=2), evacuation of hemothorax (n=3), and other thoracoscopic or laparoscopic interventions (n=19). Procedures that required conversion were most commonly for bowel injury (n=56). Patients with peritonitis were most likely to require conversion to an open procedure (77.4%). Mean time to a regular diet was 4.2 +/- 8.6 days, and mean hospital stay was 6.3 +/- 6.5 days. Postoperative complications occurred in 19 patients, long-term sequelae in 10 patients, and permanent disability in 2 patients. There were no deaths or missed injuries. CONCLUSIONS: In the stable pediatric trauma patient, laparoscopy and thoracoscopy can be performed safely and effectively for both diagnostic and therapeutic purposes. PMID- 25545147 TI - Human-Dromedary Camel Interactions and the Risk of Acquiring Zoonotic Middle East Respiratory Syndrome Coronavirus Infection. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) cases without documented contact with another human MERS-CoV case make up 61% (517/853) of all reported cases. These primary cases are of particular interest for understanding the source(s) and route(s) of transmission and for designing long-term disease control measures. Dromedary camels are the only animal species for which there is convincing evidence that it is a host species for MERS-CoV and hence a potential source of human infections. However, only a small proportion of the primary cases have reported contact with camels. Other possible sources and vehicles of infection include food-borne transmission through consumption of unpasteurized camel milk and raw meat, medicinal use of camel urine and zoonotic transmission from other species. There are critical knowledge gaps around this new disease which can only be closed through traditional field epidemiological investigations and studies designed to test hypothesis regarding sources of infection and risk factors for disease. Since the 1960s, there has been a radical change in dromedary camel farming practices in the Arabian Peninsula with an intensification of the production and a concentration of the production around cities. It is possible that the recent intensification of camel herding in the Arabian Peninsula has increased the virus' reproductive number and attack rate in camel herds while the 'urbanization' of camel herding increased the frequency of zoonotic 'spillover' infections from camels to humans. It is reasonable to assume, although difficult to measure, that the sensitivity of public health surveillance to detect previously unknown diseases is lower in East Africa than in Saudi Arabia and that sporadic human cases may have gone undetected there. PMID- 25545148 TI - Top-down but not bottom-up visual scanning is affected in hereditary pure cerebellar ataxia. AB - The aim of this study was to clarify the nature of visual processing deficits caused by cerebellar disorders. We studied the performance of two types of visual search (top-down visual scanning and bottom-up visual scanning) in 18 patients with pure cerebellar types of spinocerebellar degeneration (SCA6: 11; SCA31: 7). The gaze fixation position was recorded with an eye-tracking device while the subjects performed two visual search tasks in which they looked for a target Landolt figure among distractors. In the serial search task, the target was similar to the distractors and the subject had to search for the target by processing each item with top-down visual scanning. In the pop-out search task, the target and distractor were clearly discernible and the visual salience of the target allowed the subjects to detect it by bottom-up visual scanning. The saliency maps clearly showed that the serial search task required top-down visual attention and the pop-out search task required bottom-up visual attention. In the serial search task, the search time to detect the target was significantly longer in SCA patients than in normal subjects, whereas the search time in the pop-out search task was comparable between the two groups. These findings suggested that SCA patients cannot efficiently scan a target using a top-down attentional process, whereas scanning with a bottom-up attentional process is not affected. In the serial search task, the amplitude of saccades was significantly smaller in SCA patients than in normal subjects. The variability of saccade amplitude (saccadic dysmetria), number of re-fixations, and unstable fixation (nystagmus) were larger in SCA patients than in normal subjects, accounting for a substantial proportion of scattered fixations around the items. Saccadic dysmetria, re fixation, and nystagmus may play important roles in the impaired top-down visual scanning in SCA, hampering precise visual processing of individual items. PMID- 25545149 TI - The role of histamine in the retina: studies on the Hdc knockout mouse. AB - The role of histamine in the retina is not well understood, despite it regulating a number of functions within the brain, including sleep, feeding, energy balance, and anxiety. In this study we characterized the structure and function of the retina in mice that lacked expression of the rate limiting enzyme in the formation of histamine, histidine decarboxylase (Hdc-/- mouse). Using laser capture microdissection, Hdc mRNA expression was assessed in the inner and outer nuclear layers of adult C57Bl6J wildtype (WT) and Hdc(-/-)-retinae. In adult WT and Hdc(-/-)-mice, retinal fundi were imaged, retinal structure was assessed using immunocytochemistry and function was probed by electroretinography. Blood flow velocity was assessed by quantifying temporal changes in the dynamic fluorescein angiography in arterioles and venules. In WT retinae, Hdc gene expression was detected in the outer nuclear layer, but not the inner nuclear layer, while the lack of Hdc expression was confirmed in the Hdc-/- retina. Preliminary examination of the fundus and retinal structure of the widely used Hdc-/- mouse strain revealed discrete lesions across the retina that corresponded to areas of photoreceptor abnormality reminiscent of the rd8 (Crb1) mutation. This was confirmed after genotyping and the strain designated Hdcrd8/rd8. In order to determine the effect of the lack of Hdc-alone on the retina, Hdc-/- mice free of the Crb1 mutation were bred. Retinal fundi appeared normal in these animals and there was no difference in retinal structure, macrogliosis, nor any change in microglial characteristics in Hdc-/- compared to wildtype retinae. In addition, retinal function and retinal blood flow dynamics showed no alterations in the Hdc-/- retina. Overall, these results suggest that histamine plays little role in modulating retinal structure and function. PMID- 25545150 TI - Transpapillary drug delivery to the breast. AB - The study was aimed at investigating localized topical drug delivery to the breast via mammary papilla (nipple). 5-fluorouracil (5-FU) and estradiol (EST) were used as model hydrophilic and hydrophobic compounds respectively. Porcine and human nipple were used for in-vitro penetration studies. The removal of keratin plug enhanced the drug transport through the nipple. The drug penetration was significantly higher through the nipple compared to breast skin. The drug's lipophilicity had a significant influence on drug penetration through nipple. The ducts in the nipple served as a major transport pathway to the underlying breast tissue. Results showed that porcine nipple could be a potential model for human nipple. The topical application of 5-FU on the rat nipple resulted in high drug concentration in the breast and minimal drug levels in plasma and other organs. Overall, the findings from this study demonstrate the feasibility of localized drug delivery to the breast through nipple. PMID- 25545151 TI - Dealing with the complex drug-drug interactions: towards mechanistic models. AB - Unmanageable severe adverse events caused by drug-drug interactions (DDIs), leading to market withdrawals or restrictions in the clinical usage, are increasingly avoided with the improvement in our ability to predict such DDIs quantitatively early in drug development. However, significant challenges arise in the evaluation and/or prediction of complex DDIs caused by inhibitor drugs and/or metabolites that affect not one but multiple pathways of drug clearance. This review summarizes the discussion topics at the 2013 AAPS symposium on "Dealing with the complex drug-drug interactions: towards mechanistic models". Physiologically based pharmacokinetic (PBPK) models, in combination with the established in vitro-to-in vivo extrapolations of intestinal and hepatic disposition, have been successfully applied to predict clinical pharmacokinetics and DDIs, especially for drugs with CYP-mediated metabolism, and to explain transporter-mediated and complex DDIs. Although continuous developments are being made towards improved mechanistic prediction of the transporter-enzyme interplay in the hepatic and intestinal disposition and characterizing the metabolites contribution to DDIs, the prediction of DDIs involving them remains difficult. Regulatory guidelines also recommended use of PBPK modeling for the quantitative prediction and evaluation of DDIs involving multiple perpetrators and metabolites. Such mechanistic modeling approaches culminate to the consensus that modeling is helpful in predicting DDIs or quantitatively rationalizing the clinical findings in complex situations. Furthermore, they provide basis for the prediction and/or understanding the pharmacokinetics in populations like patients with renal impairment, pediatrics, or various ethnic groups where the conduct of clinical studies might not be feasible in early drug development stages and yet some guidance on management of dosage is necessary. PMID- 25545152 TI - Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in SKG mice. AB - OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that have the ability to suppress T cell responses. The aim of this study was to evaluate the effects of the JAK inhibitor tofacitinib on MDSCs in a mouse model of rheumatoid arthritis. METHODS: Arthritis was induced in SKG mice by zymosan A (ZyA) injection. MDSCs isolated from the bone marrow (BM) of donor SKG mice with arthritis were adoptively transferred to recipient mice with arthritis. In a separate experiment, tofacitinib was administered to arthritic SKG mice subcutaneously via osmotic pump, in some cases followed by injection of an anti-Gr-1 monoclonal antibody (mAb). BM cells from untreated mice were cultured for 5 days with granulocyte-macrophage colony-stimulating factor, with or without tofacitinib, and then analyzed by flow cytometry. RESULTS: The numbers of MDSCs and polymorphonuclear MDSCs (PMN-MDSCs) were significantly increased in the spleens of SKG mice following ZyA injection. Adoptive transfer of MDSCs to recipient arthritic mice reduced the severity of arthritis compared to that in untreated control mice. Treatment with tofacitinib also ameliorated the progression of arthritis in SKG mice and induced significantly higher numbers of MDSCs and PMN-MDSCs in the BM of these animals. Furthermore, administration of an anti-Gr-1 mAb reduced the antiarthritic effect of tofacitinib in SKG mice. In vitro, tofacitinib facilitated the differentiation of BM cells to MDSCs, and inhibited their differentiation to dendritic cells. CONCLUSION: Tofacitinib facilitates the expansion of MDSCs and ameliorates arthritis in SKG mice. PMID- 25545154 TI - Derelict fishing line provides a useful proxy for estimating levels of non compliance with no-take marine reserves. AB - No-take marine reserves (NTMRs) are increasingly being established to conserve or restore biodiversity and to enhance the sustainability of fisheries. Although effectively designed and protected NTMR networks can yield conservation and fishery benefits, reserve effects often fail to manifest in systems where there are high levels of non-compliance by fishers (poaching). Obtaining reliable estimates of NTMR non-compliance can be expensive and logistically challenging, particularly in areas with limited or non-existent resources for conducting surveillance and enforcement. Here we assess the utility of density estimates and re-accumulation rates of derelict (lost and abandoned) fishing line as a proxy for fishing effort and NTMR non-compliance on fringing coral reefs in three island groups of the Great Barrier Reef Marine Park (GBRMP), Australia. Densities of derelict fishing line were consistently lower on reefs within old (>20 year) NTMRs than on non-NTMR reefs (significantly in the Palm and Whitsunday Islands), whereas line densities did not differ significantly between reefs in new NTMRs (5 years of protection) and non-NTMR reefs. A manipulative experiment in which derelict fishing lines were removed from a subset of the monitoring sites demonstrated that lines re-accumulated on NTMR reefs at approximately one third (32.4%) of the rate observed on non-NTMR reefs over a thirty-two month period. Although these inshore NTMRs have long been considered some of the best protected within the GBRMP, evidence presented here suggests that the level of non compliance with NTMR regulations is higher than previously assumed. PMID- 25545153 TI - G-CSF priming, clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia, advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm. AB - Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony-stimulating factor (G-CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G-CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse-free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m(-2) day(-1) * 5 and cytarabine at 2 g m(-2) day(-1) * 5 after G-CSF priming in 50 newly-diagnosed patients ages 18-64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64-88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71-93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well-tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. PMID- 25545155 TI - Transcriptome analysis of Enterococcus faecalis during mammalian infection shows cells undergo adaptation and exist in a stringent response state. AB - As both a commensal and a major cause of healthcare-associated infections in humans, Enterococcus faecalis is a remarkably adaptable organism. We investigated how E. faecalis adapts in a mammalian host as a pathogen by characterizing changes in the transcriptome during infection in a rabbit model of subdermal abscess formation using transcriptional microarrays. The microarray experiments detected 222 and 291 differentially regulated genes in E. faecalis OG1RF at two and eight hours after subdermal chamber inoculation, respectively. The profile of significantly regulated genes at two hours post-inoculation included genes involved in stress response, metabolism, nutrient acquisition, and cell surface components, suggesting genome-wide adaptation to growth in an altered environment. At eight hours post-inoculation, 88% of the differentially expressed genes were down-regulated and matched a transcriptional profile consistent with a (p)ppGpp-mediated stringent response. Subsequent subdermal abscess infections with E. faecalis mutants lacking the (p)ppGpp synthetase/hydrolase RSH, the small synthetase RelQ, or both enzymes, suggest that intracellular (p)ppGpp levels, but not stringent response activation, influence persistence in the model. The ability of cells to synthesize (p)ppGpp was also found to be important for growth in human serum and whole blood. The data presented in this report provide the first genome-wide insights on E. faecalis in vivo gene expression and regulation measured by transcriptional profiling during infection in a mammalian host and show that (p)ppGpp levels affect viability of E. faecalis in multiple conditions relevant to mammalian infection. The subdermal abscess model can serve as a novel experimental system for studying the E. faecalis stringent response in the context of the mammalian immune system. PMID- 25545157 TI - Ezrin finds its groove in cholangiocytes. PMID- 25545156 TI - Attentional control and subjective executive function in treatment-naive adults with Attention Deficit Hyperactivity Disorder. AB - We investigated performance-derived measures of executive control, and their relationship with self- and informant reported executive functions in everyday life, in treatment-naive adults with newly diagnosed Attention Deficit Hyperactivity Disorder (ADHD; n = 36) and in healthy controls (n = 35). Sustained attentional control and response inhibition were examined with the Test of Variables of Attention (T.O.V.A.). Delayed responses, increased reaction time variability, and higher omission error rate to Go signals in ADHD patients relative to controls indicated fluctuating levels of attention in the patients. Furthermore, an increment in NoGo commission errors when Go stimuli increased relative to NoGo stimuli suggests reduced inhibition of task-irrelevant stimuli in conditions demanding frequent responding. The ADHD group reported significantly more cognitive and behavioral executive problems than the control group on the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF A). There were overall not strong associations between task performance and ratings of everyday executive function. However, for the ADHD group, T.O.V.A. omission errors predicted self-reported difficulties on the Organization of Materials scale, and commission errors predicted informant reported difficulties on the same scale. Although ADHD patients endorsed more symptoms of depression and anxiety on the Achenbach System of Empirically Based Assessment (ASEBA) than controls, ASEBA scores were not significantly associated with T.O.V.A. performance scores. Altogether, the results indicate multifaceted alteration of attentional control in adult ADHD, and accompanying subjective difficulties with several aspects of executive function in everyday living. The relationships between the two sets of data were modest, indicating that the measures represent non-redundant features of adult ADHD. PMID- 25545158 TI - Carbonyl traps as potential protective agents against methimazole-induced liver injury. AB - Liver injury is a deleterious adverse effect associated with methimazole administration, and reactive intermediates are suspected to be involved in this complication. Glyoxal is an expected reactive intermediate produced during methimazole metabolism. Current investigation was undertaken to evaluate the role of carnosine, metformin, and N-acetyl cysteine as putative glyoxal (carbonyl) traps, against methimazole-induced hepatotoxicity. Methimazole (100 mg/kg, intraperitoneally) was administered to intact and/or glutathione (GSH)-depleted mice and the role of glyoxal trapping agents was investigated. Methimazole caused liver injury as revealed by an increase in serum alanine aminotransferase and aspartate aminotransferase. Moreover, lipid peroxidation and protein carbonylation occurred significantly in methimazole-treated animals' liver. Hepatic GSH reservoirs were decreased, and inflammatory cells infiltration was observed in liver histopathology. Methimazole-induced hepatotoxicity was severe in GSH-depleted mice and accompanied with interstitial hemorrhage and necrosis of the liver. Glyoxal trapping agents effectively diminished methimazole-induced liver injury both in intact and/or GSH-depleted animals. PMID- 25545159 TI - A convenient method for the synthesis of (prop-2-ynyloxy)benzene derivatives via reaction with propargyl bromide, their optimization, scope and biological evaluation. AB - A highly convenient method has been developed for the synthesis of (prop-2 ynyloxy) benzene and its derivatives. Differently substituted phenol and aniline derivatives were allowed to react with propargyl bromide in the presence of K2CO3 base and acetone as solvent. The compounds were synthesized in good yields (53 85%). Low cost, high yields and easy availability of compounds helped in the synthesis. Electron withdrawing groups favor the formation of stable phenoxide ion thus in turn favors the formation of product while electron donating groups do not favor the reaction. Phenol derivatives gave good yields as compared to that of aniline. As aprotic polar solvents favor SN2 type reactions so acetone provided best solvation for the reactions. K2CO3 was proved to be good for the synthesis. Antibacterial, Antiurease and NO scavenging activity of synthesized compounds were also examined. 4-bromo-2-chloro-1-(prop-2-ynyloxy)benzene 2a was found most active compound against urease enzyme with a percentage inhibition of 82.00+/-0.09 at 100 ug/mL with IC50 value of 60.2. 2-bromo-4-methyl-1-(prop-2 ynyloxy)benzene 2d was found potent antibacterial against Bacillus subtillus showing excellent inhibitory action with percentage inhibition of 55.67+/-0.26 at 100 ug/ml wih IC50 value of 79.9. Based on results, it can be concluded that some of the synthesized compounds may have potential antiurease and antibacterial effects against several harmful substances. PMID- 25545160 TI - Characterization of the in vivo host response to a bi-labeled chitosan-dextran based hydrogel for postsurgical adhesion prevention. AB - In developing a chitosan/dextran-based (CD) hydrogel as an adhesion prevention postsurgical aid, the in vivo biodegradation rate, biodistribution, and inflammatory response are important parameters to the biomedical device design. Herein, for the first time, a CD hydrogel was prepared by mixing aqueous solutions of a near infrared (NIR) labeled succinylated chitosan (SC) and tritiated [(3) H] oxidized dextran (DA). The biodegradation and biodistribution of the NIR/[(3) H]-CD hydrogel was tracked noninvasively using NIR fluorescence imaging, and by liquid scintillation counting (LSC) of organs/tissues after subcutaneous injection in BALB/c mice. The inflammatory response was assessed by measuring serum cytokine levels using a Bio-plex assay and by histological examination of injection site tissue. Fluorescence imaging showed the hydrogel to degrade in under a week. LSC revealed the hydrogel to reside mainly at the injection site, and excreted primarily via the urine within the first 48 h. The CD hydrogel showed a mild inflammatory response as cytokine levels were comparable to saline injected controls. Histological examination of injection site tissue confirmed the cytokine results. In summary, the CD hydrogel's in vivo biodegradation rate, biodistribution, and inflammatory response was determined. Our results indicate that the CD hydrogel has an appropriate biocompatibility after s.c. administration. PMID- 25545161 TI - The effect of low-frequency sound stimulation on patients with fibromyalgia: a clinical study. AB - BACKGROUND: The search for effective treatments for fibromyalgia (FM) has continued for years. The present study premises that thalamocortical dysrhythmia is implicated in fibromyalgia and that low-frequency sound stimulation (LFSS) can play a regulatory function by driving neural rhythmic oscillatory activity. OBJECTIVE: To assess the effect of LFSS on FM. METHOD: The present open-label study with no control group used a repeated-measures design with no noncompleters. Nineteen female volunteers (median age 51 years; median duration of FM 5.76 years) were administered 10 treatments (twice per week for five weeks). Treatments involved 23 min of LFSS at 40 Hz, delivered using transducers in a supine position. Measures (repeated before and after treatment) included the Fibromyalgia Impact Questionnaire, Jenkins Sleep Scale, Pain Disability Index, sitting and standing without pain (in minutes), cervical muscle range of motion and muscle tone. Mean percentages were calculated on end of treatment self reports of improvement on pain, mood, insomnia and activities of daily living. RESULTS: Significant improvements were observed with median scores: Fibromyalgia Impact Questionnaire, 81% (P<0.0001); Jenkins Sleep Scale, 90% (P<0.0001); and Pain Disability Index, 49.1% (P<0.0001). Medication dose was reduced in 73.68% of patients and completely discontinued in 26.32%. Time sitting and standing without pain increased significantly (P<0.0001). Cervical muscle range of motion increased from 25% to 75% (P=0.001), while muscle tone changed from hypertonic to normal (P=0.0002). CONCLUSION: In the present study, the LFSS treatment showed no adverse effects and patients receiving the LFSS treatment showed statistically and clinically relevant improvement. Further phase 2 and 3 trials are warranted. PMID- 25545162 TI - Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations. AB - Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in which the productive binding orientation was expected to be stabilized, thus leading to increased turnover of CBZ to the 10,11-epoxide product. In addition, we generated CYP3A4 mutant S119A as a control construct with putative destabilization of the productive binding pose. Evaluation of the kinetics profiles of CBZ epoxidation demonstrate that CYP3A4-containing bacterial membranes (bactosomes) as well as purified CYP3A4 (wild-type and mutants I369L/F) exhibit substrate inhibition in reconstituted systems. In contrast, mutants S119A and A370V/L exhibit S-shaped profiles that are indicative of homotropic cooperativity. MD simulations with two to four CBZ molecules provide evidence that the substrate-binding pocket of CYP3A4 can accommodate more than one molecule of CBZ. Analysis of the kinetics profiles of CBZ metabolism with a model that combines the formalism of the Hill equation with an allowance for substrate inhibition demonstrates that the mechanism of interactions of CBZ with CYP3A4 involves multiple substrate-binding events (most likely three). Despite the retention of the multisite binding mechanism in the mutants, functional manifestations reveal an exquisite sensitivity to even minor structural changes in the binding pocket that are introduced by conservative substitutions such as I369F, I369L, and A370V. PMID- 25545163 TI - A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia. AB - IMPORTANCE: Apart from Huntington's disease, little is known of the genetics of autosomal dominant chorea associated with dystonia. Here we identify adenylate cyclase 5 (ADCY5) as a likely new causal gene for early-onset chorea and dystonia. OBSERVATIONS: Whole exome sequencing in a three-generation family affected with autosomal dominant chorea associated with dystonia identified a single de novo mutation-c.2088+1G>A in a 5' donor splice-site of ADCY5 segregating with the disease. This mutation seeming leads to RNA instability and therefore ADCY5 haploinsufficiency. CONCLUSIONS AND RELEVANCE: Our finding confirms the genetic/clinical heterogeneity of the disorder; corroborated by previous identification of ADCY5 mutations in one family with dyskinesia-facial myokymia and in two unrelated sporadic cases of paxoysmal choreic/dystonia-facial myokymia; ADCY5's high expression in the striatum and movement disorders in ADCY5 deficient mice. Hence ADCY5 genetic analyses may be relevant in the diagnostic workup of unexplained early-onset hyperkinetic movement disorders. PMID- 25545164 TI - Clinical use of proteasome inhibitors in the treatment of multiple myeloma. AB - Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib), as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents. PMID- 25545166 TI - HIF-1 Alpha and Placental Growth Factor in Pregnancies Complicated With Preeclampsia: A Qualitative and Quantitative Analysis. AB - BACKGROUND: The pathophysiology of preeclampsia is not clearly understood worldwide. Hypoxia inducible factor 1alpha (HIF-1alpha) is thought to be the preliminary factor for the hypoxic conditions prevailing in preeclampsia, which causes imbalance in the expression of angiogenic proteins. A proangiogenic protein, placental growth factor (PIGF), is reported to be dysregulated in preeclampsia. Therefore, this study focuses on the investigation of HIF-1alpha and PIGF in preeclamptic conditions and a possible molecular association between them. METHODS: Placental tissue (n = 45 + 45) and serum samples (n = 80 + 80) of preeclamptic patients and healthy control were collected and processed for the analysis of HIF-1alpha and PIGF by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). RESULTS: In preeclamptic group, the significant nuclear and cytoplasmic expression of HIF-1alpha was noticed in syncytiotrophoblast (P = 0.0001) but in control placenta, it was localized to cytoplasm (P = 0.0001). The intensity of PIGF expression was lower in syncytiotrophoblast cytoplasm (P = 0.0001) in preeclamptic cases as compared with control. Also, the significant upregulated concentration of HIF-1alpha and downregulated PIGF was observed in serum samples of preeclamptic woman (P = 0.0001). Thus, there was a significant direct negative correlation between HIF 1alpha and PIGF both at tissue and serum level (P < 0.01). CONCLUSION: The direct inverse association between HIF-1alpha and PIGF in serum and placental tissues may be responsible for the low oxidative stress and endothelial dysfunction, leading to the pathogenesis of preeclampsia. PMID- 25545167 TI - Monitoring of drug intake during pregnancy by questionnaires and LC-MS/MS drug urine screening: evaluation of both monitoring methods. AB - Various studies pointed towards a relationship between chronic diseases such as asthma and allergy and environmental risk factors, which are one aspect of the so called Exposome. These environmental risk factors include also the intake of drugs. One critical step in human development is the prenatal period, in which exposures might have critical impact on the child's health outcome. Thereby, the health effects of drugs taken during gestation are discussed controversially with regard to newborns' disease risk. Due to this, the drug intake of pregnant women in the third trimester was monitored by questionnaire, in addition to biomonitoring using a local birth cohort study, allowing correlations of drug exposure with disease risk. Therefore, 622 urine samples were analyzed by an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) urine screening and the results were compared to self-administered questionnaires. In total, 48% (n = 296) reported an intake of pharmaceuticals, with analgesics as the most frequent reported drug class in addition to dietary supplements. 182 times compounds were detected by urine screening, with analgesics (42%; n = 66) as the predominantly drug class. A comparison of reported and detected drug intake was performed for three different time spans between completion of the questionnaires and urine sampling. Even if the level of accordance was low in general, similar percentages (~25%, ~19%, and ~ 20%) were found for all groups. This study illustrates that a comprehensive evaluation of drug intake is neither achieved by questionnaires nor by biomonitoring alone. Instead, a combination of both monitoring methods, providing complementary information, should be considered. PMID- 25545165 TI - The rarity of ALDH(+) cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients. AB - To understand the precise disease driving mechanisms in acute myeloid leukemia (AML), comparison of patient matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. In this analysis, we have examined the value of aldehyde dehydrogenase (ALDH) activity in combination with CD34 expression for the separation of HSC from LSC in 104 patients with de novo AML. The majority of AML patients (80 out of 104) had low percentages of cells with high ALDH activity (ALDH(+) cells; <1.9%; ALDH-rare AML), whereas 24 patients had relatively numerous ALDH(+) cells (>=1.9%; ALDH-numerous AML). In patients with ALDH-rare AML, normal HSC could be separated by their CD34(+) ALDH(+) phenotype, whereas LSC were exclusively detected among CD34(+) ALDH(-) cells. For patients with ALDH numerous AML, the CD34(+) ALDH(+) subset consisted mainly of LSC and separation from HSC was not feasible. Functional analyses further showed that ALDH(+) cells from ALDH-numerous AML were quiescent, refractory to ARA-C treatment and capable of leukemic engraftment in a xenogenic mouse transplantation model. Clinically, resistance to chemotherapy and poor long-term outcome were also characteristic for patients with ALDH-numerous AML providing an additional risk-stratification tool. The difference in spectrum and relevance of ALDH activity in the putative LSC populations demonstrates, in addition to phenotypic and genetic, also functional heterogeneity of leukemic cells and suggests divergent roles for ALDH activity in normal HSC versus LSC. By acknowledging these differences our study provides a new and useful tool for prospective identification of AML cases in which separation of HSC from LSC is possible. PMID- 25545168 TI - Isolation of a hydrogen-bridged bis(silylene) tungsten complex: a snapshot of a transition state for 1,3-hydrogen migration. AB - A hydrogen-bridged bis(silylene) complex, which can be viewed as a snapshot of a transition state for 1,3-hydrogen migration, was isolated, and its unprecedented WSi2H four-membered-ring structure with a short diagonal Si-Si distance was revealed by X-ray crystallography. NMR studies including determination of the W Si, Si-Si, and Si-H coupling constants and theoretical calculations suggest that a novel multicenter bond is formed in the WSi2H system, in which the bridging hydrogen takes on a hydridic nature. PMID- 25545169 TI - HMGB1 induces angiogenesis in rheumatoid arthritis via HIF-1alpha activation. AB - High-mobility group box protein 1 (HMGB1), a nonhistone nuclear protein and a cytokine mediator, is implicated in the pathogenesis of rheumatoid arthritis (RA). Extracellular HMGB1 binds to its receptors and triggers downstream signal cascade leading to the perpetuation of synovitis and local tissue invasion. Here, we investigated a novel role of HMGB1 in regulating hypoxia-inducible factor (HIF)-1alpha to mediate angiogenesis in RA synovium. HIF-1alpha mRNA levels and activities in synovial fibroblasts from RA patients were enhanced by HMGB1. Pharmacological inhibition of TLR4 and NF-kappaB activation blocked the HMGB1 dependent upregulation of HIF-1alpha mRNA expression and its activity, suggesting the involvement of transcriptional regulation. HMGB1 stimulated expression of vascular endothelial growth factor (VEGF), and inhibition of HIF-1alpha attenuated HMGB1-induced VEGF. Conditioned media derived from HMGB1-stimulated synovial fibroblasts enhanced tube formation in human microvascular endothelial cells by upregulating HIF-1alpha. In the joint tissues of mice with collagen induced arthritis, treatment with anti-HMGB1 neutralizing antibody prevented blood vessel formation in association with decreased expression of HIF-1alpha. These observations support the idea that increased HMGB1 induces an extension of inflamed synovium by accelerating angiogenesis in RA through enhancement of HIF 1alpha activation. Therefore, inhibition of HMGB1 could prove beneficial for the treatment of angiogenesis in RA. PMID- 25545170 TI - Midcheek endoscopic anatomy. AB - BACKGROUND: Surgical approaches to the midcheek area are challenging. Recent clinical reports have proposed minimally endoscopic approach again, in order to obtain to obtain a correct balance between the operation's safety and the cosmetic and minimally invasive outcome, but none of them provides a careful anatomic description of the midcheek area. The purpose of this study was to provide a new anatomic perception of the midcheek area through a detailed anatomic endoscopic-assisted dissection. METHODS: Four freshly injected cadaver heads were dissected to illustrate the endoscopic anatomy of the midcheek region. RESULTS: An endoscope provided an excellent surgical window that achieved greater exposure for dissection and at the same time improved magnification of the noble key anatomic elements. CONCLUSION: This study emphasizes the critical role of the transverse facial artery and the facial retaining ligaments as a fundamental endoscopic landmark that allows the identification of key anatomic structures and the creation of safe surgical corridors. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E268-E273, 2016. PMID- 25545171 TI - A framework for real-time glycosylation monitoring (RT-GM) in mammalian cell culture. AB - Glycosylation is a critical characteristic of biotherapeutics because of its central role in in vivo efficacy. Multiple factors including medium composition and process conditions impact protein glycosylation and characterizing cellular response to these changes is essential to understand the underlying relationships. Current practice typically involves glycosylation characterization at the end of a fed-batch culture, which in addition to being an aggregate of the process, reflects a bias towards the end of the culture where a majority of the product is made. In an attempt to rigorously characterize the entire time-course of a fed-batch culture, a real-time glycosylation monitoring (RT-GM) framework was developed. It involves using the micro sequential injection (MUSI) system as a sample preparation platform coupled with an ultra-performance liquid chromatography (UPLC) system for real-time monitoring of the antibody glycan profile. Automated sampling and sample preparations were performed using the MUSI system and this framework was used to study manganese (Mn)-induced glycosylation changes over the course of a fed-batch culture. As expected, Mn-supplemented cultures exhibited higher galactosylation levels compared to control while the fucosylation and mannosylation were consistent for both supplemented and control cultures. Overall, the approach presented in the study allows real time monitoring of glycosylation changes and this information can be rapidly translated into process control and/or process optimization decisions to accelerate process development. PMID- 25545173 TI - Significant transaortic gradient after direct flow aortic valve implantation. AB - A patient with severe aortic valve disease and high surgical risk underwent Direct Flow (DF) valve implantation. Anatomical assessment (Trans-esophageal echocardiography (TEE) and CT scan) revealed a 3-leaflet aortic valve (annulus diameter 23.4 mm) that was functionally bicuspid because of complete and linearly calcified fusion of noncoronary and right cusps. The valve had severe stenosis (peak/mean gradients of 70/45 mm Hg) and moderate to severe regurgitation. A balloon valvuloplasty (semicompliant 23 mm * 45 mm balloon, 2 inflations) was performed with persistence of balloon waist. A 25 DF valve was positioned in the aortic annulus, with both rings well expanded. A mild deformity in the vertical supporting tubes was observed but considered nonrelevant because valve function (peak/mean gradients of 25/12 mm Hg respectively and no aortic regurgitation) was acceptable. Then the polymer was injected and the valve released from its attachments. Postoperative course was uneventful without clinical complications; nevertheless 3 days later Doppler peak/mean transaortic gradients were 80/45 mm Hg. These high gradients were confirmed by direct invasive measurements while CT scan documented a severe geometrical deformation of the valve cuff. Since patient was in good clinical condition, a conservative strategy was adopted. Eight months later, patient functional status had improved (NYHA class II), left ventricular dimensions decreased, left ventricular ejection fraction (LVEF) increased, and valve gradients remained unchanged; therefore surgical aortic valve replacement has been deferred until clinical indication. Such a favorable course can be explained by disappearance of aortic regurgitation. Patient anatomical and procedural features that conditioned this very rare phenomenon are discussed as well as clues to prevent it. PMID- 25545172 TI - A computational modelling approach combined with cellular electrophysiology data provides insights into the therapeutic benefit of targeting the late Na+ current. AB - KEY POINTS: The ventricular action potential plateau is a phase of high resistance, which makes ventricular myocytes vulnerable to small electrical perturbations. We developed a computationally based model of GS-458967 interaction with the cardiac Na+ channel, informed by experimental data recorded from guinea pig isolated single ventricular myocytes. The model predicts that the therapeutic potential of GS-458967 derives largely from the designed property of significant potent selectivity for INaL. ABSTRACT: Selective inhibition of the slowly inactivating or late Na(+) current (INaL) in patients with inherited or acquired arrhythmia syndrome may confer therapeutic benefit by reducing the incidence of triggers for arrhythmia and suppressing one component of arrhythmia promoting cardiac substrates (e.g. prolonged refractoriness and spatiotemporal dispersion of action potential duration). Recently, a novel compound that preferentially and potently reduces INaL, GS-458967 (IC50 for block of INaL = 130 nM) has been studied. Experimental measurements of the effects of GS-458967 on endogenous INaL in guinea pig ventricular myocytes demonstrate a robust concentration-dependent reduction in action potential duration (APD). Using experimental data to calibrate INaL and the rapidly activating delayed rectifier K(+) current, IKr, in the Faber-Rudy computationally based model of the guinea pig ventricular action potential, we simulated effects of GS-458967 on guinea pig ventricular APD. GS-458967 (0.1 MUM) caused a 28.67% block of INaL and 12.57% APD shortening in experiments, while the model predicted 10.06% APD shortening with 29.33% block of INaL. An additional effect of INaL block is to reduce the time during which the membrane potential is in a high resistance state (i.e. the action potential plateau). To test the hypothesis that targeted block of INaL would make ventricular myocytes less susceptible to small electrical perturbations, we used the computational model to test the degree of APD prolongation induced by small electrical perturbations in normal cells and in cells with simulated long QT syndrome. The model predicted a substantial dose dependent reduction in sensitivity to small electrical perturbations as evidenced by action potential duration at 90% repolarization variability in the presence of GS-458967-induced INaL block. This effect was especially potent in the 'disease setting' of inherited long QT syndrome. Using a combined experimental and theoretical approach, our results suggest that INaL block is a potent therapeutic strategy. This is because reduction of INaL stabilizes the action potential waveform by reducing depolarizing current during the plateau phase of the action potential. This reduces the most vulnerable phase of the action potential with high membrane resistance. In summary, by reducing the sensitivity of the myocardial substrate to small electrical perturbations that promote arrhythmia triggers, agents such as GS-458967 may constitute an effective antiarrhythmic pharmacological strategy. PMID- 25545174 TI - Simultaneous determination of ten flavonoids of crude and wine-processed Radix Scutellariae aqueous extracts in rat plasma by UPLC-ESI-MS/MS and its application to a comparative pharmacokinetic study. AB - Radix Scutellariae (RS) is a herbal medicine with various pharmacological activities to treat inflammation, respiratory and gastrointestinal infections, etc. In this study, a rapid, sensitive and selective UPLC-ESI-MS/MS method was developed for simultaneous determination of 10 flavonoids - scutellarin, scutellarein, chrysin, wogonin, baicalein, apigenin, wogonoside, oroxylin A-7-O glucuronide, oroxylin A and baicalin - from RS aqueous extracts in rat plasma with propyl paraben as internal standard (IS). Chromatographic separation was achieved on a C18 column using gradient elution with the mobile phase consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The detection was performed in multiple reaction monitoring mode using electrospray ionization in negative mode. The validated method showed good linearity over a wide concentration range (r >0.9935). The intra- and interday assay variabilities were <9.5% and <12.4% for all analytes, respectively. The extraction recovery ranged from 71.2 to 89.7% for each analyte and IS. This method was successfully applied to pharmacokinetic comparision after oral administration of crude and wine-processed RS aqueous extracts. There were significant differences in some pharmacokinetic parameters of most analytes between crude and wine-processed RS. This suggested that wine-processing exerted effects absorption of most flavonoids. PMID- 25545175 TI - In memoriam: the life and works of Itai Bab (1945-2014). PMID- 25545177 TI - Freely tunable broadband polarization rotator for terahertz waves. AB - A freely tunable polarization rotator for broadband terahertz waves is demonstrated using a three-rotating-layer metallic grating structure, which can conveniently rotate the polarization of a linearly polarized terahertz wave to any desired direction with nearly perfect conversion efficiency. This low-cost, high-efficiency, and freely tunable device has potential applications as material analysis, wireless communication, and THz imaging. PMID- 25545178 TI - Comparison of full-thickness skin grafts versus second-intention healing for Mohs defects of the helix. AB - BACKGROUND: Two repair options for Mohs defects of the helix include full thickness skin grafting and second-intention healing. Limited long-term data exist comparing these 2 repair options. OBJECTIVE: To compare outcomes of full thickness skin grafts (FTSG) versus second-intention wound healing for Mohs defects on the helix. METHODS: In this study, 29 second-intention and 18 FTSG repairs were evaluated using a visual analog scale (VAS). Patient questionnaires and retrospective chart analysis were used to assess secondary outcomes. RESULTS: The average second-intention VAS score was 82.1 (standard deviation [SD] = 7.6), and the average FTSG VAS score was 75.2 (SD = 16.7) (difference of 6.9, 95% confidence interval: -1.3 to 15.1, p = .061). A subsequent noninferiority test indicated that cosmetic outcome of second-intention healing was at least as good as that of FTSG in the authors' study (p < .001). Retrospective chart analysis revealed no significant difference in complications. Patient-reported outcomes were not significantly different. CONCLUSION: Mohs surgical defects of the helix left to heal by second-intention have comparable long-term cosmetic outcomes to those repaired by FTSG. There was no significant difference in complications, and patients were highly satisfied with both repair options. PMID- 25545179 TI - Postauricular skin: an excellent donor site for split-thickness skin grafts for the head, neck, and upper chest. AB - BACKGROUND: Postauricular skin is one of the potential donor sites for split thickness skin grafts (STSGs). OBJECTIVE: To objectively quantify how postauricular donor sites heal after STSG harvesting. MATERIALS AND METHODS: A cohort of 39 Mohs micrographic surgery patients repaired with STSGs (total 41 surgical defects) was established. Scars resulting from postauricular donor site harvesting were objectively quantified by applying the Vancouver Scar Scale (VSS), in which healing of scars is ranked from 0 (best possible outcome) to 13 (worst possible outcome). RESULTS: Vancouver Scar Scale scores were 1.87 for sites followed for >=6 months (n = 16), 3 for sites followed for 3 to 6 months (n = 7), and 1.61 for sites followed for 6 to 11 weeks (n = 18). Four patients developed mild hypertrophic scarring that resolved spontaneously or with intralesional triamcinolone injections at a concentration of 10 mg/mL. CONCLUSION: The postauricular skin is an excellent donor site for small-to moderate sized STSGs (<10 cm). The donor sites healed well, as noted by the low scores on the VSS consistent with mild changes in erythema, pigmentation, and texture. The incidence of hypertrophic scarring was low and resolved with observation or treatment. PMID- 25545180 TI - Commentary on sebaceous carcinoma. PMID- 25545181 TI - Probing the mechanism of the interaction between l-cysteine-capped-CdTe quantum dots and Hg(2+) using capillary electrophoresis with ensemble techniques. AB - A good understanding of the mechanism of interaction between quantum dots (QDs) and heavy metal ions is essential for the design of more effective sensor systems. In this work, CE was introduced to explore how l-cysteine-capped-CdTe QDs (l-cys-CdTe QDs) interacts with Hg(2+) . The change in electrophoretic mobility can synchronously reflect the change in the composition and property of QDs. The effects of the free and capping ligands on the system are discussed in detail. ESI-MS, dynamic light scattering (DLS), zeta potential, and fluorescence (FL) were also applied as cooperative tools to study the interaction mechanism. Furthermore, the interaction mechanism, which principally depended on the concentration of Hg(2+) , was proposed reasonably. At the low concentration of Hg(2+) , the formation of a static complex between Hg(2+) and the carboxyl and amino groups of l-cys-CdTe QDs surface was responsible for the FL quenching. With the increase of Hg(2+) concentration, the capping l-cys was stripped from the surface of l-cys-CdTe QDs due to the high affinity of Hg(2+) to the thiol group of l-cys. Our study demonstrates that CE can reveal the mechanism of the interaction between QDs and heavy metal ions, such as FL quenching. PMID- 25545182 TI - Neuropsychological late effects of treatment for acute leukemia in children with Down syndrome. AB - BACKGROUND: Children with Down syndrome (DS) have an elevated risk of developing acute leukemia, but little is known about treatment-related neuropsychological morbidity because they are systematically excluded from research in this area. The current study investigated neuropsychological outcomes in children with DS treated for acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) compared to children with DS with no history of cancer. PROCEDURE: Participants were 4 to 17 years of age at testing and were administered measures of intelligence, academic achievement, language, visual-motor and fine-motor skills, and adaptive function. Patients had been off treatment for at least 2 years. RESULTS: The AML group (N = 12) had significantly lower verbal intelligence and receptive vocabulary compared to controls (N = 21). By contrast, the ALL group (N = 14) performed significantly worse than controls on measures of verbal intelligence, spelling, receptive and expressive vocabulary, visual-motor skills, and adaptive function. CONCLUSIONS: Patients with DS treated for AML may have specific post-treatment morbidity in verbal function, whereas those treated for ALL have broader morbidity affecting multiple neuropsychological domains and overall adaptive function. We hypothesize that the broader impairment profile of ALL survivors may be related to a combination of the longer duration of central nervous system-directed treatment for ALL compared to AML and the concomitant limited access to intervention opportunities during active treatment. PMID- 25545183 TI - Relevance of age at diagnosis to prevention of late-onset group B streptococcal disease by maternal immunization. AB - Among 248 infants with late-onset group B streptococcal (GBS) disease from 1993 to 2012, approximately two thirds (63%) had a gestation of at least 35 weeks and 72% of these became ill within 6 weeks of life (median 27 days), suggesting that third trimester maternal GBS immunization could substantially reduce the late onset GBS disease burden in the United States. PMID- 25545184 TI - Low Prevalence of Parvovirus 4 in HIV-infected Children in Denmark. AB - Parvovirus 4 (PARV4) has been associated with HIV infection in adults. We examined plasma samples from 46 HIV-infected 0-year-old to 16-year-old children for the presence of PARV4. Four children (8.7%) had detectable PARV4 IgG and 1 had IgM. The result of PARV4 polymerase chain reaction was found to be negative in all patients. PARV4 seropositivity was associated with low CD4 count but not with HIV viral load. PMID- 25545185 TI - Vesicular Mycosis Fungoides. AB - Mycosis fungoides (MF), the most common form of cutaneous lymphoma is derived from postthymic T cells that migrate to the skin likely under the influence of chronic antigen stimulation. Less common histomorphologic variants are diagnostically challenging because of their resemblance to reactive conditions. Three men aged 46, 73, and 74 years and one 83-year-old woman were encountered in the files of one of the authors and represented the patients. The patients had a longstanding eruption for several years. In 2 cases, the clinical course was aggressive with extracutaneous lymph node and/or peripheral blood dissemination. One patient had vesicles noted clinically. In all cases, vesiculation was a prominent feature histologically, which lead to an erroneous categorization initially as a reactive process. Basilar colonization by cerebriform lymphocytes along with the mucinous quality of the vesicle was diagnostic clue histologically, whereas the phenotypic and molecular profile was typical for MF. Strong expression of interleukin 5 and interleukin 10 in atypical lymphocytes in comparison with interferon gamma suggested a T-helper type 2-dominant cytokine microenvironment. In reviewing the literature of the 6 previously reported cases, 3 patients died of the disease; all these patients had vesicular lesions both clinically and histologically. We concluded that vesicular MF is a distinct histological and in some instances clinical variant of MF. The correlation of the vesicular eczematous quality of the eruption and a more aggressive clinical course may reflect the skewing toward a T-helper type 2-dominant cytokine milieu typical of advanced disease. PMID- 25545186 TI - Exenatide-Induced Eosinophil-Rich Granulomatous Panniculitis: A Novel Case Showing Injected Microspheres. PMID- 25545187 TI - Ionic-liquid-based surfactant-emulsified microextraction procedure accelerated by ultrasound radiation followed by high-performance liquid chromatography for the simultaneous determination of antidepressant and antipsychotic drugs. AB - In the present work, an efficient and environmental friendly method of ionic liquid-based emulsified microextraction procedure accelerated by ultrasound radiation has been developed. Subsequently, its performance was compared with dispersive liquid-liquid microextraction and ultrasound-assisted surfactant-based emulsification microextraction methods. The optimization of experimental conditions was carried out by combination of central composite design and response surface methodology. The optimum conditions of variables were set as follows: 50 MUL of 1-hexyl-3-methylimidazolium hexafluorophosphate (extracting solvent), 10 min ultrasound time, and 10 min vortex time for agitating 6 mL sample solution in pH 3 in the presence of 4 mg sodium dodecyl sulfate without addition of salt and 200 MUL of methanol as diluent solvent. Under these conditions, the responses are linear for doxepin and perphenazine in the range of 0.3-1000 and 5-1000 MUg/L, respectively. The limits of detection were 0.1 MUg/L for doxepin and 1 MUg/L for perphenazine. Relative standard deviations were lower than 3.5 for the determination of both species. Finally, the method was used for the preconcentration and determination of doxepin and perphenazine in urine sample with relative recoveries in the range of 89-98%. PMID- 25545188 TI - Biochemical investigations of human papillomavirus-infected cervical fluids. AB - PURPOSE: Cervical cancer is caused by persistent infection with high-risk types of human papillomavirus (HPV). The aim of this study was to investigate the potential of Raman spectroscopy as a stand-alone analytical tool for clinical diagnosis of HPV infection using human cervical fluids. METHOD: A drop-coating deposition surface-enhanced Raman scattering (DCD-SERS) method was identified as the most effective method of biochemical analysis in cervical biofluids. RESULTS: Using a 2-uL sample, the proposed DCD-SERS method yielded Raman spectra with high reproducibility, noise-independence, and uniformity. Additionally, the produced spectra were independent of the volume of fluid used and detection zone analyzed within the central and the ring zones. The optical detection of HPV infection in cervical fluids could be detected accurately in the central zone. Different Raman spectra were obtained according to HPV type. In particular, HPV-16 and HPV-18, which are the major risk factors for cervical cancer, showed a distinct spectral difference in cervical fluids, with a similar pattern for high Raman bands at >1,000 cm(-1) but a different pattern for low Raman bands at <1,000 cm(-1) . Therefore, all ranges of HPV-gated DCD-SERS could be used to detect the presence of HPV infection. CONCLUSIONS: Raman spectroscopy provides a good alternative method for early clinical diagnosis of HPV infection, and we are hopeful that this proposed method of HPV assessment will be approved for use in obstetrics and gynecology clinics. PMID- 25545189 TI - Circadian sleep/wake rhythm abnormalities as a risk factor of a poststroke apathy. AB - BACKGROUND: Poststroke apathy affects 19-55% of patients following stroke and has a negative impact on functional recovery, general health, and quality of life, as well as being a source of significant burden for caregivers. AIMS: A major clinical issue is the delayed diagnosis of poststroke apathy, and so the aim of our study is to evaluate the relationship between early poststroke alterations of circadian rhythms of sleep/wake cycles and the occurrence of poststroke apathy. METHODS: Forty-six patients with a recent magnetic resonance imaging confirmed stroke were included. Main exclusion criteria were a mild to severe disability impeding home discharge from the hospital and the presence of apathy or dementia before stroke. Cerebrovascular lesions were evaluated by magnetic resonance imaging. At hospital discharge, an actigraph was used to measure patient's global activity as well as parameters of circadian rhythmicity (relative amplitude, interdaily stability, intradaily variability) and sleep (sleep duration, sleep efficiency, fragmentation index) over seven-days. Apathy was assessed at hospital discharge as well as at three-months using the Apathy Inventory and the Lille Apathy Rating Scale. RESULTS: Of the 46 patients evaluated, 10 (22%) showed apathy three-months after stroke (median Apathy Inventory = 4.5). Before inclusion, these 10 subjects did not differ significantly from other patients concerning their sleep and, at inclusion, they did not differ concerning apathy, anxiety, depression, or cognitive and functional abilities. However, actigraphy measured at discharged identified significant alterations of sleep (P < 0.005). Future poststroke apathy patients exhibited a decrease in sleep efficiency (actual sleep time expressed as a percentage of time in bed) and an increase in the fragmentation index (degree of fragmentation during the sleep period) at three-months. No association was observed between poststroke apathy and the characteristics of cerebrovascular lesions (stroke location, extent of leucoencephalopathy, number of lacunes and microbleeds). CONCLUSION: These results indicate that early poststroke alterations of sleep/wake circadian rhythms--easily evaluated by actigraphy--are associated with a higher risk of poststroke apathy at three-months. In terms of clinical outcomes, our results provide targets for very early identification of patients at risk to develop apathy after stroke and for assessing when to start specific therapy to optimize rehabilitation efficiency. PMID- 25545190 TI - Effects of pulsed magnetic stimulation on isolated crayfish heart. AB - Cardiac muscular contraction of the neurogenic heart that could be excited by pulsed magnetic stimulation (PMS) was investigated using preparation of the isolated crayfish heart. When a figure-eight magnetic coil was set over the isolated heart, cardiac contraction induced by a single PMS was not observed. Cardiac arrest occurred immediately after repetitive PMS and persisted for dozens of seconds depending on the number of stimuli. We concluded that PMS caused neuronal modulation in the neuronal network in the cardiac ganglion. PMID- 25545191 TI - Subsurface imaging of coupled carrier transport in GaAs/AlGaAs core-shell nanowires. AB - We demonstrate spatial probing of carrier transport within GaAs/AlGaAs core-shell nanowires with nanometer lateral resolution and subsurface sensitivity by energy variable electron beam induced current imaging. Carrier drift that evolves with applied electric field is distinguished from a coupled drift-diffusion length. Along with simulation of injected electron trajectories, combining beam energy tuning with precise positioning for selective probing of core and shell reveals axial position- and bias-dependent differences in carrier type and transport along parallel conduction channels. These results indicate how analysis of transport within heterostructured nanomaterials is no longer limited to nonlocal or surface measurements. PMID- 25545192 TI - Treatment of elderly patients with acute myeloid leukemia with azacitidine results in fewer hospitalization days and infective complications but similar survival compared with intensive chemotherapy. AB - AIMS: Azacitidine has been shown to prolong overall survival (OS) compared with best supportive care in elderly patients with acute myeloid leukemia (AML) with low blast counts but it is unknown if azacitidine has a similar efficacy in patients with blast counts of >30%. It is also unknown if azacitidine is comparable to intensive chemotherapy in terms of survival and morbidity. METHODS: Differences between the outcomes of elderly AML patients who received intensive chemotherapy, azacitidine-based therapy or best supportive care are studied in this retrospective review. Patients 60 years or older diagnosed with AML between January 2009 and June 2011 were included. Those who passed away within less than 2 weeks of diagnosis were excluded. RESULTS: At a median follow-up of 7.2 months (range: 0.5-26.4 months), estimated median OS for patients who received azacitidine-based therapy was 9.8 months (range: 2.4-22.5 months) compared with 8.9 months (range: 0.9-26.4 months) for patients who received intensive chemotherapy (P=0.89). Compared with azacitidine-based therapy, intensive chemotherapy is associated with more inpatient days and episodes of febrile illness requiring inpatient stay or intravenous antibiotics. CONCLUSIONS: Compared with intensive chemotherapy in elderly patients with AML, azacitidine based therapy is associated with similar median survival but lower number of hospitalization days and infective episodes. PMID- 25545193 TI - Land-use intensity and host plant identity interactively shape communities of arbuscular mycorrhizal fungi in roots of grassland plants. AB - We studied the effect of host plant identity and land-use intensity (LUI) on arbuscular mycorrhizal fungi (AMF, Glomeromycota) communities in roots of grassland plants. These are relevant factors for intraradical AMF communities in temperate grasslands, which are habitats where AMF are present in high abundance and diversity. In order to focus on fungi that directly interact with the plant at the time, we investigated root-colonizing communities. Our study sites represent an LUI gradient with different combinations of grazing, mowing, and fertilization. We used massively parallel multitag pyrosequencing to investigate AMF communities in a large number of root samples, while being able to track the identity of the host. We showed that host plants significantly differed in AMF community composition, while land use modified this effect in a plant species specific manner. Communities in medium and low land-use sites were subsets of high land-use communities, suggesting a differential effect of land use on the dispersal of AMF species with different abundances and competitive abilities. We demonstrate that in these grasslands, there is a small group of highly abundant, generalist fungi which represent the dominating species in the AMF community. PMID- 25545194 TI - Secondary successional trajectories of structural and catabolic bacterial communities in oil-polluted soil planted with hybrid poplar. AB - Poplars have widely been used for rhizoremediation of a broad range of organic contaminants for the past two decades. Still, there is a knowledge gap regarding the rhizosphere-associated bacterial communities of poplars and their dynamics during the remediation process. It is envisaged that a detailed understanding of rhizosphere-associated microbial populations will greatly contribute to a better design and implementation of rhizoremediation. To investigate the long-term succession of structural and catabolic bacterial communities in oil-polluted soil planted with hybrid poplar, we carried out a 2-year field study. Hybrid aspen (Populus tremula * Populus tremuloides) seedlings were planted in polluted soil excavated from an accidental oil-spill site. Vegetated and un-vegetated soil samples were collected for microbial community analyses at seven different time points during the course of 2 years and sampling time points were chosen to cover the seasonal variation in the boreal climate zone. Bacterial community structure was accessed by means of 16S rRNA gene amplicon pyrosequencing, whereas catabolic diversity was monitored by pyrosequencing of alkane hydroxylase and extradiol dioxygenase genes. We observed a clear succession of bacterial communities on both structural and functional levels from early to late-phase communities. Sphingomonas type extradiol dioxygenases and alkane hydroxylase homologs of Rhodococcus clearly dominated the early-phase communities. The high-dominance/low diversity functional gene communities underwent a transition to low dominance/high-diversity communities in the late phase. These results pointed towards increased catabolic capacities and a change from specialist to generalist strategy of bacterial communities during the course of secondary succession. PMID- 25545195 TI - P-wave changes in hemodialysis patients: reply to Marano et al. PMID- 25545196 TI - A two-year follow-up of oral antioxidant supplementation in primary open-angle glaucoma: an open-label, randomized, controlled trial. AB - PURPOSE: To evaluate the effect of oral antioxidant supplementation (OAS) on primary open-angle glaucoma (POAG) over a 2-year follow-up period. PATIENTS AND METHODS: In this open-label, randomized controlled trial, 117 eyes of 117 patients with mild or moderate POAG and intraocular pressure under control with topical antiglaucoma medications were recruited and randomly divided into three groups according to supplementation: (1) OAS with (ICAPS R((r)) - Alcon Laboratories, n = 26); (2) OAS without omega-3 fatty acids (OFTAN MACULA((r)) - Laboratorios Esteve, n = 28); and (3) a control group without OAS (n = 63). They all underwent visual field (VF) tests (Humphrey 24-2) and scans using a Fourier domain optical coherence tomography (FD-OCT) device (RTVue-100) at the beginning of the study and 2 years later. Mean deviation (MD), standard pattern deviation (PSD), peripapillary retinal nerve fibre layer (RNFL) and macular ganglion cell complex (GCC) parameters were considered for the analysis. Patients were also classified according to MD deterioration (fast deterioration vs. slow deterioration). RESULTS: Visual field global indices, peripapillary RNFL thickness and macular GCC thickness showed no differences among the groups at the beginning and end of the follow-up. Besides all the comparisons among groups for differences before and after the follow-up of the MD, PSD, RNFL and GCC parameters were also non-significant. The proportions of patients according to MD deterioration were similar among the groups and subgroups (p > 0.05 for all the comparisons). CONCLUSION: Oral antioxidant supplementation with or without omega 3 fatty acids does not appear useful as an adjuvant treatment of mild/moderate POAG in the short term. PMID- 25545197 TI - The potential of liquid-based cytology in lymph node cytological evaluation: the role of morphology and the aid of ancillary techniques. AB - OBJECTIVES: Our aim was to evaluate the feasibility and diagnostic accuracy of liquid-based cytology (LBC) on lymph node fine needle aspiration (FNA). FNA may fulfil a challenging role in the evaluation of the majority of primary (benign and malignant) diagnoses as well as metastatic lymph node lesions. Although the morphological features may be quite easily recognized, cytological samples with a scant cellular component may raise some issues. METHODS: We appraised 263 cytological lymph nodes from different body regions analysed between January and December 2013, including 137 male and 126 female patients, and processed with LBC. RESULTS: The cytological diagnoses included 160 benign and 103 malignant lesions. We reported 35 benign and 73 malignant lesions from 108 with surgical follow-up. The latter malignant series included 68 metastatic lesions, four suspicious for malignancy and one inadequate sample. The cytological diagnoses were supported by 62 conclusive immunocytochemical and 28 molecular analyses. Of the 108 cases, we documented 35 true negatives, 72 true positives, one false negative and no false positives, resulting in 98.6% sensitivity, 100% specificity, 99% diagnostic accuracy, 97.2% negative predictive value and 100% positive predictive value. CONCLUSIONS: FNA represents the first diagnostic tool in lymph node management and a reliable approach in order to avoid an excision biopsy. Furthermore, LBC is a feasible method for ancillary tests for which methanol-fixed samples are suitable, such as immunocytochemistry and molecular analysis. PMID- 25545198 TI - Kinetic solvent effects on the reactions of the cumyloxyl radical with tertiary amides. Control over the hydrogen atom transfer reactivity and selectivity through solvent polarity and hydrogen bonding. AB - A laser flash photolysis study on the role of solvent effects on hydrogen atom transfer (HAT) from the C-H bonds of N,N-dimethylformamide (DMF), N,N dimethylacetamide (DMA), N-formylpyrrolidine (FPRD), and N-acetylpyrrolidine (APRD) to the cumyloxyl radical (CumO(*)) was carried out. From large to very large increases in the HAT rate constant (kH) were measured on going from MeOH and TFE to isooctane (kH(isooctane)/kH(MeOH) = 5-12; kH(isooctane)/kH(TFE) > 80). This behavior was explained in terms of the increase in the extent of charge separation in the amides determined by polar solvents through solvent-amide dipole-dipole interactions and hydrogen bonding, where the latter interactions appear to play a major role with strong HBD solvents such as TFE. These interactions increase the electron deficiency of the amide C-H bonds, deactivating these bonds toward HAT to an electrophilic radical such as CumO(*), indicating that changes in solvent polarity and hydrogen bonding can provide a convenient method for deactivation of the C-H bond of amides toward HAT. With DMF, a solvent-induced change in HAT selectivity was observed, suggesting that solvent effects can be successfully employed to control the reaction selectivity in HAT-based procedures for the functionalization of C-H bonds. PMID- 25545199 TI - Flat-lying semiconductor-insulator interfacial layer in DNTT thin films. AB - The molecular order of organic semiconductors at the gate dielectric is the most critical factor determining carrier mobility in thin film transistors since the conducting channel forms at the dielectric interface. Despite its fundamental importance, this semiconductor-insulator interface is not well understood, primarily because it is buried within the device. We fabricated dinaphtho[2,3 b:2',3'-f]thieno[3,2-b]thiophene (DNTT) thin film transistors by thermal evaporation in vacuum onto substrates held at different temperatures and systematically correlated the extracted charge mobility to the crystal grain size and crystal orientation. As a result, we identify a molecular layer of flat-lying DNTT molecules at the semiconductor-insulator interface. It is likely that such a layer might form in other material systems as well, and could be one of the factors reducing charge transport. Controlling this interfacial flat-lying layer may raise the ultimate possible device performance for thin film devices. PMID- 25545200 TI - Pemphigus herpetiformis: six additional cases with an emphasis on eczema-like features and the diagnostic utility of Tzanck smears. PMID- 25545201 TI - Normative values in esophageal high-resolution manometry. AB - BACKGROUND: Esophageal high-resolution manometry (HRM) has rapidly gained much popularity worldwide. The Chicago Classification for esophageal motility disorders is based on a set of normative values for key metrics that was obtained using one of the commercially available HRM systems. Thus, it is of great importance to evaluate whether these normative values can be used for other HRM systems as well. PURPOSE: In this review, we describe the presently available HRM systems, the currently known normative thresholds and the factors that influence them, and assess the use of these thresholds. Numerous factors including the type of HRM system, demographic factors, catheter diameter, body position during testing, consistency of bolus swallows, and esophageal length have an influence on the normative data. It would thus be ideal to have different sets of normal values for each of these factors, yet at the moment the amount of normative data is limited. We suggest broadening the normal range for parameters, as this would allow abnormal values to be of more significance. In addition, we suggest conducting studies to assess the physiological relevance of abnormal values and stress that for each system different normative thresholds may apply. PMID- 25545202 TI - Measurements of the pulmonary vasculature on thoracic radiographs in healthy dogs compared to dogs with mitral regurgitation. AB - This study reassessed the previously reported radiographic method of comparing pulmonary vessels versus rib diameter for differentiating healthy dogs and dogs with mitral regurgitation. The width of the right cranial pulmonary artery and vein at the fourth rib level, right caudal pulmonary artery and vein at the ninth rib level, and the diameters of the fourth rib and ninth rib were measured in prospectively recruited healthy dogs (n = 40) and retrospectively recruited dogs with mitral regurgitation (n = 58). In healthy dogs, the pulmonary arteries and accompanying veins were similar in size. The cranial lobar vessels were smaller than the fourth rib. However, 67.5% of right caudal pulmonary artery diameters and 65% of vein diameters were larger than the ninth rib in healthy dogs. The right caudal pulmonary vein diameter in dogs with mitral regurgitation, particularly those within moderate and severe grades, was significantly larger than that in healthy dogs (P < 0.001). The comparative method used to detect enlargement of the right caudal pulmonary vein relative to the accompanying pulmonary artery had the highest sensitivity (80.2%) and specificity (82.5%) for predicting mitral regurgitation. A cut-off of 1.22 when applying the ninth rib criterion had better specificity (73%) than the most used value <= 1 (89.7% sensitivity and 63.8% specificity), although it has less sensitivity (73%). We recommend using the accompanying pulmonary artery and 1.22 * the diameter of the ninth rib as a radiographic criterion for assessing the size of the right caudal pulmonary vein and differentiating healthy dogs from those with mitral regurgitation. PMID- 25545203 TI - Contrast-enhanced MRI in preoperative assessment of myometrial and cervical invasion, and lymph node metastasis: diagnostic value and error analysis in endometrial carcinoma. AB - OBJECTIVE: To determine the ability of contrast-enhanced magnetic resonance imaging to predict myometrial invasion, cervical invasion, and pelvic lymph node metastasis in endometrial carcinoma and to analyze factors that lead to errors in this identification. DESIGN: A retrospective study. SETTING: University general hospital. POPULATION: A total of 167 women diagnosed with endometrial carcinoma. METHODS: All patients received a preoperative contrast-enhanced magnetic resonance imaging scan. Histopathological findings were used as the definitive diagnosis. MAIN OUTCOME MEASURES: The results were compared with histopathological findings, factors that make accurate assessment of myometrial invasion, cervical invasion, and pelvic lymph node metastasis difficult by contrast-enhanced magnetic resonance imaging were analyzed. RESULTS: The sensitivity, specificity, diagnostic accuracy, positive predictive values, and negative predictive values of contrast-enhanced magnetic resonance imaging were 90.9, 91.8, 91.6, 73.2 and 97.6%, respectively, for identifying deep myometrial invasion; 84.2, 96.0, 94.6, 72.7 and 97.9%, respectively, for identifying cervical invasion; and 45.0, 91.2, 85.6, 40.9 and 92.4%, respectively, for identifying pelvic lymph node metastasis. The main causes of error in contrast enhanced magnetic resonance imaging were myomas, cornual lesions, deep myometrial invasion, large tumor size, non-endometrioid tumor type, and lower tumor grade. CONCLUSION: Contrast-enhanced magnetic resonance imaging has a high accuracy and a low tendency to produce false-negative predictive values. Gynecological oncologists should combine the imaging data and clinical information to make therapeutic decisions and avoid diagnostic errors. PMID- 25545204 TI - Long-term (~57 ka) controls on mercury accumulation in the Southern Hemisphere reconstructed using a peat record from Pinheiro mire (Minas Gerais, Brazil). AB - Natural archives have been used to reconstruct mercury atmospheric deposition at different spatial and temporal scales during the Holocene in the Northern Hemisphere. In this study, we present the results from a Brazilian mountain mire (Pinheiro mire, Minas Gerais, SE Brazil), extending back to ~57 ka. The core was analyzed for mercury concentration, organic matter content, organic carbon isotopic composition, and tracers of mineral matter flux. Principal components analysis followed by principal components regression enabled us to determine the evolution of the weight of the latent processes governing the accumulation of mercury through time. We show that climate change was the main driver for the variations of mercury concentrations, either indirectly by (i) enhancing soil erosion in the mire's catchment, which led to a decrease in mercury concentration due to dilution by low mercury-containing mineral matter, (ii) increasing regional dust deposition, which resulted in increased concentrations, or directly, by long-term changes in atmospheric wet deposition (arid vs humid periods). Internal peat processes (i.e., decomposition and mass loss) had a minor influence at the time scale represented by the core. PMID- 25545205 TI - Cloning murine antibody V-genes with non-degenerate primers and conversion to a recombinant antibody format. AB - Monoclonal antibodies are produced in cultured hybridoma cell lines, but these cells tend to be unstable; it is therefore necessary to rescue the corresponding genetic information. Here we describe an improved method for the amplification of antibody variable gene (V-gene) information from murine hybridoma cells using a panel of specific, non-degenerate primers. This primer set allows sequences to be rescued from all murine V-genes, except the lambda light chain genes, which rarely contribute to murine immune diversity. We tested the primers against a range of antibodies and recovered specific amplification products in all cases. The heavy and light chain variable regions were subsequently joined by a two-step cloning strategy or by splice overlap extension PCR. PMID- 25545206 TI - Proteoliposome-based selection of a recombinant antibody fragment against the human M2 muscarinic acetylcholine receptor. AB - The development of antibodies against human G-protein-coupled receptors (GPCRs) has achieved limited success, which has mainly been attributed to their low stability in a detergent-solubilized state. We herein describe a method that can generally be applied to the selection of phage display libraries with human GPCRs reconstituted in liposomes. A key feature of this approach is the production of biotinylated proteoliposomes that can be immobilized on the surface of streptavidin-coupled microplates or paramagnetic beads and used as a binding target for antibodies. As an example, we isolated a single chain Fv fragment from an immune phage library that specifically binds to the human M2 muscarinic acetylcholine receptor with nanomolar affinity. The selected antibody fragment recognized the GPCR in both detergent-solubilized and membrane-embedded forms, which suggests that it may be a potentially valuable tool for structural and functional studies of the GPCR. The use of proteoliposomes as immunogens and screening bait will facilitate the application of phage display to this difficult class of membrane proteins. PMID- 25545207 TI - Detection of constant domain of human T cell antigen receptor alpha-chain via novel monoclonal antibody 7F18. AB - The alphabeta T cell antigen receptor (TCR) endows T lymphocytes with immune specificity and controls their effector functions. Each person possesses a vast repertoire of TCRs that is generated by the well-studied processes of somatic recombination and thymic selection. While many antibodies specific for TCRbeta variable domains are available, antibodies specific for human TCRalpha are rare. We now report a novel monoclonal antibody, 7F18, which binds to human TCRalpha constant region, with specificity for a denatured epitope that can be visualized by SDS-PAGE followed by Western blot. Both immature and mature TCR alpha-chain products can be visualized, making 7F18 potentially applicable to various biochemical assays of multiprotein complex assembly and maturation. This new monoclonal antibody provides a tool that can potentially facilitate the biochemical analysis of comprehensive populations of human alphabeta TCR complexes that need not be limited to small subsets of the repertoire. PMID- 25545208 TI - Monoclonal antibodies specific for human IgM Fc receptor inhibit ligand-binding activity. AB - A panel of six different murine hybridoma clones secreting IgG monoclonal antibodies (MAbs) specific for the human IgM Fc receptor (FcMUR) was generated. All MAbs specifically precipitated a major protein of ~60 kDa from membrane lysates of FcMUR-bearing, but not FcMUR-negative, cells as did IgM-ligands. Pre incubation of membrane lysate of FcMUR-bearing cells with these MAbs completely removed the ~60 kDa IgM-reactive protein. By using recombinant human/mouse chimeric FcMUR proteins, the epitope recognized by HM7 and HM10 MAbs was mapped to the Ig-like domain of human FcMUR, whereas the other MAbs recognized the stalk region. Pre-incubation of FcMUR(+) cells with the Ig-like domain-specific MAbs, but not with others, markedly inhibited subsequent IgM-ligand binding. A similar, but much weaker, inhibition was also observed when the incubation order was reversed. When FcMUR(+) cells were simultaneously incubated with both IgM-ligands and MAbs, HM7 MAb efficiently competed with IgM for FcMUR binding. Unlike control Jurkat cells, FcMUR-bearing cells were resistant to apoptosis induced by agonistic IgM anti-Fas MAb (CH11); however, addition of the HM7 MAb inhibited the interaction of the Fc portion of CH11 MAb with FcMUR, thereby promoting apoptosis of FcMUR-bearing Jurkat cells. The variable regions of the HM7 MAb were composed of Ighv14-3, Ighd1-2, and Ighj2 for the gamma2b heavy chain and Igk3-4 and Igkj2 for the kappa light chain. These findings suggest that HM7 MAb efficiently blocks the ligand-binding activity of FcMUR. PMID- 25545209 TI - Characterization of a monoclonal antibody against CREPT, a novel protein highly expressed in tumors. AB - CREPT (cell-cycle related and expression-elevated protein in tumor), a novel gene also called RPRD1B and C20ORF77, was recently identified to promote tumorigenesis through up-regulation of the expression of genes related to cell cycle. The previous study demonstrated that CREPT is highly expressed in a variety of tumors and enhances the expression of Cyclin D1 by promoting the formation of a chromatin loop. To study the correlation of CREPT expression with clinical factors in different tumors, we generated a monoclonal antibody (3E10) using purified recombinant human GST-CREPT protein as an antigen. In this study, we characterized the specificity of the monoclonal antibody and cloned the gene encoding the antibody for preparation of industrial production. Our results showed that the monoclonal antibody 3E10 was sensitive and specific to recognize human endogenous CREPT protein. We have mapped the epitope of the antibody and cloned the variable region sequence of the gene encoding the antibody. We confirmed that the cloned gene produced an equivalent antibody as that produced by the original hybridoma. This study provided a basis for large-scale production of the CREPT antibody, which will be useful for the study of the role of CREPT in different tumors. PMID- 25545210 TI - Production of monoclonal antibody against EP0 protein of pseudorabies virus and determination of its recognized epitope. AB - Early protein 0 (EP0) is especially important for modulating PRV gene expression and reactivation from the latent state, but the mechanisms have not been elucidated. In this study, six monoclonal antibodies (MAbs) against EP0 protein of PRV were generated and their characterizations were investigated. Western blot analysis showed all six MAbs could react with immunizing antigen, but only 2B12 and 2C6 could react with native EP0 protein from PRV-infected cells. ELISA additivity tests revealed that at least three epitopes in EP0 were defined by six MAbs. The epitope recognized by MAb 2B12 was further identified in 287-292 aa of EP0 protein using a series of expressed overlapping peptides. These MAbs may provide valuable tools for further research of the functions of EP0 in PRV infection. PMID- 25545211 TI - Production and characterization of highly specific monoclonal antibodies to D glutamic acid. AB - Most of the functions of D-amino acids (D-AA) remain unclear because of little analytic methods for specific detection/determination. In this study, a highly specific monoclonal antibody to D-glutamic acid (D-Glu-MAb) was produced using a hybridoma method. Characterization of D-Glu-MAb by indirect enzyme-linked immunosorbent assay (ELISA) revealed that it has high selectivity against D-Glu glutaraldehyde (GA) conjugates, while no cross-reaction was observed when 38 other kinds of AA-GA conjugates were used. Moreover, subsequent indirect competitive ELISA disclosed that an epitope of D-Glu-MAb is a D-Glu-GA molecule in the conjugates, suggesting that D-Glu-MAb could be a useful tool to investigate the functional analysis of D-Glu in immunostaining. PMID- 25545212 TI - Preparation of monoclonal antibodies against Mycobacterium tuberculosis TB10.4 antigen. AB - TB10.4 protein is a member of the ESX family that is necessary for Mycobacterium tuberculosis survival and plays a vital role in mycobacterial pathogenesis. In this study, the gene encoding TB10.4 was cloned into prokaryotic expression vecters pET-30(a) and pGEX-6p-1. The two recombinant proteins His-TB10.4 and GST TB10.4 were then expressed in vitro in prokaryotic expression systems to develop monoclonal antibodies (MAbs) against TB10.4 protein. The purified rHis-TB10.4 protein was used to immunize BALB/c mice, and eight MAbs were produced. An immunoblotting analysis indicated that all these MAbs specifically recognize the TB10.4 protein. These new MAbs provide powerful reagents for further functional research into TB10.4 protein. PMID- 25545215 TI - Fibroblastic rheumatism: the first case with infiltration of multinuclear giant cells and raised blood lead level. AB - Fibroblastic rheumatism (FR) is a rare condition characterized by symmetrical polyarthritis and multiple cutaneous nodules. Approximately 30 cases have been reported worldwide to date. Laboratory tests are not particular useful to confirm the disease. Diagnosis is mainly dependent on the characteristic histopathological features: thickened collagen fibres with spindle-shaped cell proliferation in the skin lesion. We report a case of a 48-year-old Chinese man with typical clinical features of FR. In addition to the characteristic histopathological findings, multinuclear giant cell infiltration in skin lesions was detected, in this case. The evaluation of microelements revealed a raised blood lead level) of 129 MUg/L (normal range 0-99 MUg/L) These two features have never been described in the previous medical literature on FR. Thus, we propose that examining the infiltrated cells in detail in histopathological studies and inspecting the levels of lead and other microelements in the blood may increase our understanding of the pathogenesis of FR. PMID- 25545216 TI - Bowen's disease on the palm presents refractory skin erosion without erythematous plaque. PMID- 25545217 TI - Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. AB - Cancer is a leading cause of death worldwide. Currently available therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology towards the development of nanomedicine products holds great promise to improve therapeutic strategies against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multi functionality. They can improve the pharmacokinetic and pharmacodynamic profiles of conventional therapeutics and may thus optimize the efficacy of existing anti cancer compounds. In this review, we discuss state-of-the-art nanoparticles and targeted systems that have been investigated in clinical studies. We emphasize the challenges faced in using nanomedicine products and translating them from a preclinical level to the clinical setting. Additionally, we cover aspects of nanocarrier engineering that may open up new opportunities for nanomedicine products in the clinic. PMID- 25545218 TI - Brugia malayi infective larvae fail to activate Langerhans cells and dermal dendritic cells in human skin. AB - Filarial infection in humans is initiated when a mosquito deposits third-stage parasite larvae (L3) in the skin. Langerhans cells (LCs) and dermal dendritic cells (DDCs) are the first cells that the parasite encounters, and L3s must evade these highly effective antigen-presenting cells to establish infection. To assess LC and DDC responses to L3 in human skin, we employed three models of increasing physiologic relevance: in vitro-generated LCs, epidermal blister explants and full-thickness human skin sections. In vitro-generated LCs expressed TLR1-10 and robustly produced IL-6 and TNF-alpha in response to PolyI:C, but pre-exposure to L3s did not alter inflammatory cytokine production or TLR expression. L3s did not modulate expression of LC markers CDH1, CD207, or CD1a, or the regulatory products TSLP or IDO in epidermal explants or in vitro-generated LC. LC, CD14+ DDC, CD1c+ DC and CD141+ DC from human skin sections were analysed by flow cytometry. While PolyI:C potently induced CCL22 production in LC, CD1c+ DC, and CD141+ DC, and IL-10 production in LC, L3s did not modulate the numbers of or cytokine production by any skin DC subset. L3s broadly failed to activate or modulate LCs or DDCs, suggesting filarial larvae expertly evade APC detection in human skin. PMID- 25545219 TI - A qualitative study of patient and clinician attitudes regarding surveillance after a resection of pancreatic and peri-ampullary cancer. AB - BACKGROUND: After surgical resection of pancreatic adenocarcinoma, most patients will develop recurrence within 2 years. Intense follow-up is often recommended; however, its impact on survival is unknown. Patient and clinician attitudes towards follow-up were qualitatively assessed along with the perceived benefits and challenges. METHODS: A semi-structured interview guide was developed. Purposive sampling identified patients who were in active surveillance or had developed recurrence. Clinicians involved in patient care were also interviewed. Interviews were conducted until saturation was reached and themes were derived using standard qualitative methods. RESULTS: A total of 15 patients and seven clinicians were interviewed. Patient themes included a limited understanding of disease prognosis, a desire for reassurance, a desire to know if and when recurrence occurred and minimal difficulties with follow-up. Clinician themes included expectation that patients are aware of the recurrence risk, a desire to provide reassurance, support for intense follow-up and perceived patient challenges in follow-up. Overall, the dominant theme was one of disconnect between patients and clinicians in the understanding of the disease and its prognosis. DISCUSSION: Patients have an intense need for reassurance and obtain this through follow-up appointments with their oncologists. Consequently, they express few difficulties with the process. Clinicians recognize this desire for reassurance. Patients' understanding and expectations contrast starkly with clinicians' perspectives regarding prognosis. PMID- 25545220 TI - A cross-sectional descriptive analysis of authorship trends in China-based dermatology literature in international journals, 2000-2010. PMID- 25545223 TI - The health and well-being of indigenous youth. PMID- 25545221 TI - Laboratory and clinical features of abnormal macroenzymes found in human sera. AB - We report the analysis of unusual macroenzymes, performed in our laboratory, and review the relevant literature. In particular, we focused on macro AST, macroamylase, macro LD and macro CK. Macroenzymes are seen in healthy subjects, but can also be related to disease; thus, accurate detection is useful in day-to day clinical practice. The macroenzyme is thought to be a specific antigen antibody complex from the following findings: (1) the complex could be dissociated under acidic pH levels; (2) binding specificity of immunoglobulin in the complex was observed; (3) the binding site of immunoglobulin in the complex was Fab portion; and (4) the maternal IgG involved with macroenzyme was transferred to her children. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25545224 TI - Gestational age, birthweight, and their influence on neonatal outcome. PMID- 25545228 TI - Foundational issues: is risk analysis advice trustworthy enough to help resolve conflicts? PMID- 25545230 TI - Serum gamma-glutamyl transferase is associated with the elevated uric acid levels in normotensive Chinese adults. AB - BACKGROUND: Although both serum gamma-glutamyltransferase (GGT) and uric acid are correlated with hypertension, studies on the association between serum GGT and uric acid in normotensive individuals are rare. In this study, we tried to reveal this relationship in normotensive Chinese adults. METHODS: Four hundred seven normotensive adults were recruited. The subjects were divided into 3 subgroups according to serum GGT tertiles. Anthropometric parameters as well as systolic blood pressure (SBP), diastolic blood pressure (DBP), uric acid, GGT, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood glucose, blood lipids, and fasting insulin were measured. Insulin resistance was assessed using HOMA-IR index. RESULTS: Uric acid was increased in parallel with increasing serum GGT (P<0.001). After correction for age, sex, smoking and alcohol consumption, serum GGT was positively associated with uric acid (r=0.42, P<0.001), SBP (r=0.22, P<0.001), and DBP (r=0.19, P<0.001). When compared with lowest GGT tertile, the odds ratio of the middle tertile for the increased serum uric acid was 3.43 (95% CI, 1.39-8.47) and 7.29 (95% CI, 1.57-33.82) for the highest tertile after adjustment for age, sex, BMI, smoking, alcohol consumption, SBP, DBP, creatinine and HOMA-IR. CONCLUSIONS: Serum GGT is strongly associated with the increased uric acid concentrations in normotensive Chinese adults. PMID- 25545227 TI - Metabolic requirements for neutrophil extracellular traps formation. AB - As part of the innate immune response, neutrophils are at the forefront of defence against infection, resolution of inflammation and wound healing. They are the most abundant leucocytes in the peripheral blood, have a short lifespan and an estimated turnover of 10(10) to 10(11) cells per day. Neutrophils efficiently clear microbial infections by phagocytosis and by oxygen-dependent and oxygen independent mechanisms. In 2004, a new neutrophil anti-microbial mechanism was described, the release of neutrophil extracellular traps (NETs) composed of DNA, histones and anti-microbial peptides. Several microorganisms, bacterial products, as well as pharmacological stimuli such as PMA, were shown to induce NETs. Neutrophils contain relatively few mitochondria, and derive most of their energy from glycolysis. In this scenario we aimed to analyse some of the metabolic requirements for NET formation. Here it is shown that NETs formation is strictly dependent on glucose and to a lesser extent on glutamine, that Glut-1, glucose uptake, and glycolysis rate increase upon PMA stimulation, and that NET formation is inhibited by the glycolysis inhibitor, 2-deoxy-glucose, and to a lesser extent by the ATP synthase inhibitor oligomycin. Moreover, when neutrophils were exposed to PMA in glucose-free medium for 3 hr, they lost their characteristic polymorphic nuclei but did not release NETs. However, if glucose (but not pyruvate) was added at this time, NET release took place within minutes, suggesting that NET formation could be metabolically divided into two phases; the first, independent from exogenous glucose (chromatin decondensation) and, the second (NET release), strictly dependent on exogenous glucose and glycolysis. PMID- 25545229 TI - Cardiac troponin assays in the management of heart failure. AB - Cardiac troponins I and T are established biomarkers of cardiac injury. Testing for either of these two cardiac troponins has long been an essential component of the diagnosis of acute myocardial infarction. In addition, cardiac troponin concentrations after acute myocardial infarction predict future adverse events including development of ischemic heart failure and chronic elevations of cardiac troponin correlate with heart failure severity. These predictions and correlations are particularly obvious when cardiac troponin concentrations are measured using the new high sensitivity cardiac troponin assays. Thus, a growing body of literature suggests that cardiac troponin testing may have important clinical implications for heart failure patients with reduced or preserved ejection fraction. In this review, we explore the prognostic utility of measuring cardiac troponin concentrations in patients with acute or chronic heart failure and in populations at risk of developing heart failure and the relationship between cardiac troponin levels and disease severity. We also summarize the ongoing debates and research on whether serial monitoring of cardiac troponin levels may become a useful tool for guiding therapeutic interventions in patients with heart failure. PMID- 25545231 TI - The efficacy of powered toothbrushes following a brushing exercise: a systematic review. AB - AIM: The primary objective was to determine, based on the available published evidence, the efficacy of powered toothbrushing following a brushing exercise and secondary to what magnitude this effect is dependent on the plaque index score, power supply and mode of action. MATERIAL AND METHODS: The PubMed-MEDLINE and Cochrane CENTRAL databases were searched through and up to August 2014 to identify appropriate studies. The outcome measurement was the weighted mean (WM) percentage plaque score reduction of a full-mouth assessment following subject brushing. RESULTS: The search yielded 2420 titles and abstracts. Ultimately, 58 articles with 146 brushing exercises as separate legs were selected. The overall effect of a powered brushing exercise provides a 46% WM plaque score reduction. One hundred and six experiments provided data as assessed according to the Quigley and Hein plaque index. The WM reduction from baseline in plaque scores was 36%. A WM plaque score reduction of 65% was observed in 39 experiments using the Navy plaque index. Subanalysis on power supply and mode of action showed WM plaque score reductions ranging from 33% up to 71% depending on plaque index score. CONCLUSION: The efficacy in plaque removal following a brushing exercise using a powered toothbrush provides a WM plaque score reduction of 46% on average, with a range of 36-65% dependent on the index scale to score plaque. The available evidence indicates that the power supply (rechargeable or replaceable battery), mode of action, as well as brushing duration and type of instructions are factors which contribute to the variation in the observed efficacy. PMID- 25545232 TI - Donors with HLA-B*58:01/TNFalpha - 308A haplotype are unfavorable to haploidentical hematopoietic stem cell transplantation in acute lymphoblastic leukemia. AB - We investigated the clinical characteristics of acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) using haploidentical donors carrying HLA-B*58:01/TNFalpha - 308A (B*58:01-TNF2) haplotype. A total of 136 B-ALL and 29T/NK-ALL cases were recruited. DNA samples from the patients and their family members were assayed for HLA typing and genotyping of TNFalpha -308 (rs1800629). The B*58:01-TNF2 haplotype in related donors was determined by their family relationships. Outcomes within 2 years, disease course, and complications within 100 days were compared among patients using haploidentical donors carrying B*58:01-TNF2 haplotype (21 cases), those using haploidentical donors without B*58:01-TNF2 haplotype (100 cases), and those using HLA-identical sibling donors with or without B*58:01-TNF2 haplotype (44 cases). Compared with the other two groups, patients using haploidentical donors carrying B*58:01-TNF2 haplotype had higher overall mortality (adjusted P = 0.039) and non-relapse mortality (adjusted P = 0.001) within 2 years, delayed platelet engraftment (adjusted P < 0.0001), higher incidences of severe acute graft-versus-host disease (aGVHD) (P = 0.007), severe late-onset hemorrhagic cystitis (P = 0.002), blood stream infection (P = 0.017), and invasive fungal disease (P = 0.004) within 100 days. Therefore, donors carrying the B*58:01-TNF2 haplotype may cause more serious complications and poorer outcomes to ALL recipients. PMID- 25545234 TI - Thoracic endovascular aortic repair for ruptured descending thoracic aortic aneurysm. AB - BACKGROUND: We evaluated clinical outcomes of thoracic endovascular aortic repair (TEVAR) for ruptured descending thoracic aortic aneurysm (rDTAA). METHODS: Twenty three patients with rDTAA (mean age, 76.8 +/- 8.8 years) underwent TEVAR at our center between January 2008 and April 2013. RESULTS: In twenty-three patients, five patients (21.7%) were in shock before surgery. Technical success was achieved in 21 patients. After TEVAR, retrograde Type A aortic dissection occurred in one patient, Type I endoleak in one patient, and Type II endoleak in three patients. The 30-day mortality rate was 4.3% (n = 1), and there were five in-hospital deaths (21.7%). Six patients (26.1%) developed cerebral complications and two patients suffered from paraplegia. In the late phase, four patients died because of the following aortic events: re-rupture in one patient, rupture of another untreated aneurysm in two patients, and esophageal perforation in one patient. CONCLUSIONS: TEVAR is associated with relatively low early morbidity and mortality and can be performed in older and high-risk patients. However, because aortic events during follow-up after TEVAR are not rare, we recommend close follow-up and application of early and aggressive reintervention. PMID- 25545233 TI - Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia: A systematic review. AB - BACKGROUND: Over half of the people with diabetes in the world live in Asia. Emerging scientific evidence suggests that diabetes is associated with environmental pollutants, exposures that are also abundant in Asia. OBJECTIVE: To systematically review the literature concerning the association of persistent organic pollutants (POPs) and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia. METHODS: PubMed and Embase were searched to identify studies published up to November 2014. A secondary reference review of all extracted articles and the National Toxicology Program Workshop on the association of POPs with diabetes was also conducted. A total of 19 articles met the inclusion criteria and were evaluated in this review. RESULTS: To date, the evidence relating POPs and non-persistent pesticides with diabetes in Asian populations is equivocal. Positive associations were reported between serum concentrations of polychlorinated dibenzodioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and several organochlorine pesticides (DDT, DDE, oxychlordane, trans-nonachlor, hexachlorobenzene, hexachlorocyclohexane) with diabetes. PCDD/Fs were also associated with blood glucose and insulin resistance, but not beta-cell function. There were substantial limitations of the literature including: most studies were cross-sectional, few studies addressed selection bias and confounding, and most effect estimates had exceptionally wide confidence intervals. Few studies evaluated the effects of organophosphates. CONCLUSIONS: Well-conducted research is urgently needed on these pervasive exposures to inform policies to mitigate the diabetes epidemic in Asia. PMID- 25545235 TI - The BCoS cognitive profile screen: Utility and predictive value for stroke. AB - OBJECTIVE: We examined the utility of the Birmingham Cognitive Screen (BCoS) in discriminating cognitive profiles and recovery of function across stroke survivors. BCoS was designed for stroke-specific problems across 5 cognitive domains: (a) controlled and spatial attention, (b) language, (c) memory, (d) number processing, and (e) praxis. METHOD: On the basis of specific inclusion criteria, this cross-section observational study analyzed cognitive profiles of 657 subacute stroke patients, 331 of them reassessed at 9 months. Impairments on 32 measures were evaluated by comparison with 100 matched healthy controls. Measures of affect, apathy, and activities of daily living were also taken. Between-subjects group comparisons of mean performance scores and impairment rates and within-subject examination of impairment rates over time were conducted. Logistic regressions and general linear modeling were used for multivariate analysis of domain-level effects on outcomes. RESULTS: Individuals with repeated stroke experienced significantly less cognitive recovery at 9 months than those with a first stroke despite similar initial level of cognitive performance. Individuals with left hemisphere lesions performed more poorly than those with right hemisphere lesions, but both groups showed similar extent of recovery at 9 months. BCoS also revealed lesion-side-specific deficits and common areas of persistent problems. Functional outcome at 9 months correlated with domain-level deficits in controlled attention, spatial attention, and praxis over and above initial dependency and concurrent levels of affect and apathy. CONCLUSION: The study demonstrates how BCoS can identify differential cognitive profiles across patient groups. This can potentially help predict outcomes and inform rehabilitation. PMID- 25545237 TI - An assessment of morphometric indices, blood chemistry variables and an energy meter as indicators of the whole body lipid content in Micropterus dolomieu, Sander vitreus and Ictalurus punctatus. AB - The effectiveness of several non-lethal techniques as indicators of total lipid content in smallmouth bass Micropterus dolomieu, walleye Sander vitreus and channel catfish Ictalurus punctatus was investigated. The techniques included (1) the Fulton and relative condition factors, (2) relative mass, (3) plasma indicators of nutritional status (alkaline phosphatase, calcium, cholesterol, protein, triglycerides and glucose) and (4) readings from a hand-held, microwave energy meter. Although simple linear regression analysis showed that lipid content was significantly correlated with several predictor variables in each species, the r2 values for the relations ranged from 0.17 to 0.50 and no single approach was consistent for all species. Only one model, between energy-meter readings and lipid content in I. punctatus, had an r2 value (0.83) high enough to justify using it as a predictive tool. Results indicate that no single variable was an accurate and reliable indicator of whole body lipid content in these fishes, except the energy meter for I. punctatus. PMID- 25545238 TI - Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects. AB - PURPOSE: To investigate the pharmacokinetic/pharmacodynamic (PK/PD) interaction between irbesartan (IRB) and hydrochlorothiazide (HCT) in normotensive subjects. METHODS: A three-way crossover study was used. Serial drug concentrations and drug effects, including systolic and diastolic blood pressure and heart rate were monitored after administration of irbesartan and hydrochlorothiazide alone and in combination. The data were fitted to a PK/PD model and the parameters for irbesartan and hydrochlorothiazide when administered alone and in combination were compared. RESULTS: The plasma profiles for irbesartan and hydrochlorothiazide followed the two-compartment model after a single dose. The PK parameters of irbesartan were not affected by hydrochlorothiazide; however irbesartan decreased the hydrochlorothiazide AUC by 25% and increased its clearance by 25%. There were no significant changes in heart rate after each drug alone or in combination. Irbesartan plus hydrochlorothiazide had a greater blood pressure lowering effect compared with irbesartan alone, despite the unchanged irbesartan PK. The relationship between irbesartan plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of irbesartan on systolic blood pressure, when administered with hydrochlorothiazide were significantly different from those when irbesartan was administered alone. This was manifested by a 25% increase in Emax , and a 40% decrease in EC50 , suggesting a synergistic blood pressure lowering effect for the combination. While parameter estimates for the effect of irbesartan on diastolic blood pressure were changed by hydrochlorothiazide, the differences were only significant for EC50 . CONCLUSION: A limited potential for clinically significant interactions between irbesartan and hydrochlorothiazide at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. (ClinicalTrials.gov Identifier NCT01858610) PMID- 25545239 TI - The past and future Office of the Surgeon General. PMID- 25545236 TI - Hypoxia-dependent reactive oxygen species signaling in the pulmonary circulation: focus on ion channels. AB - SIGNIFICANCE: An acute lack of oxygen in the lung causes hypoxic pulmonary vasoconstriction, which optimizes gas exchange. In contrast, chronic hypoxia triggers a pathological vascular remodeling causing pulmonary hypertension, and ischemia can cause vascular damage culminating in lung edema. RECENT ADVANCES: Regulation of ion channel expression and gating by cellular redox state is a widely accepted mechanism; however, it remains a matter of debate whether an increase or a decrease in reactive oxygen species (ROS) occurs under hypoxic conditions. Ion channel redox regulation has been described in detail for some ion channels, such as Kv channels or TRPC6. However, in general, information on ion channel redox regulation remains scant. CRITICAL ISSUES AND FUTURE DIRECTIONS: In addition to the debate of increased versus decreased ROS production during hypoxia, we aim here at describing and deciphering why different oxidants, under different conditions, can cause both activation and inhibition of channel activity. While the upstream pathways affecting channel gating are often well described, we need a better understanding of redox protein modifications to be able to determine the complexity of ion channel redox regulation. Against this background, we summarize the current knowledge on hypoxia-induced ROS-mediated ion channel signaling in the pulmonary circulation. PMID- 25545240 TI - Randomized controlled trial of adalimumab in patients with nonpsoriatic peripheral spondyloarthritis. AB - OBJECTIVE: To evaluate the efficacy and safety of adalimumab in patients with active nonpsoriatic peripheral spondyloarthritis (SpA). METHODS: ABILITY-2 is an ongoing phase III, multicenter study of adalimumab treatment. Eligible patients age >=18 years fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for peripheral SpA, did not have a prior diagnosis of psoriasis, psoriatic arthritis (PsA), or ankylosing spondylitis (AS), and had an inadequate response or intolerance to nonsteroidal antiinflammatory drugs (NSAIDs). Patients were randomized 1:1 to receive adalimumab 40 mg every other week or matching placebo for 12 weeks, followed by a 144-week open-label period. The primary end point was the proportion of patients achieving 40% improvement in disease activity according to the Peripheral SpA Response Criteria (PSpARC40) at week 12. This was defined as >=40% improvement from baseline (>=20-mm absolute improvement on a visual analog scale) in patient's global assessments of disease activity and pain, and >=40% improvement in at least one of the following features: swollen joint and tender joint counts, total enthesitis count, or dactylitis count. Adverse events were recorded throughout the study. RESULTS: In total, 165 patients were randomized to a treatment group, of whom 81 were randomized to receive placebo and 84 to receive adalimumab. Baseline demographics and disease characteristics were generally similar between the 2 groups. At week 12, a greater proportion of patients receiving adalimumab achieved a PSpARC40 response compared to patients receiving placebo (39% versus 20%; P = 0.006). Overall, improvement in other outcomes was greater in the adalimumab group compared to the placebo group. The rates of adverse events were similar in both treatment groups. CONCLUSION: Treatment with adalimumab ameliorated the signs and symptoms of disease and improved physical function in patients with active nonpsoriatic peripheral SpA who exhibited an inadequate response or intolerance to NSAIDs, with a safety profile consistent with that observed in patients with AS, PsA, or other immune-mediated diseases. PMID- 25545241 TI - Adjuvant effects elicited by novel oligosaccharide variants of detoxified meningococcal lipopolysaccharides on Neisseria meningitidis recombinant PorA protein: a comparison in mice. AB - Neisseria meningitidis lipopolysaccharide (LPS) has adjuvant properties that can be exploited to assist vaccine immunogenicity. The modified penta-acylated LPS retains the adjuvant properties of hexa-acylated LPS but has a reduced toxicity profile. In this study we investigated whether two modified glycoform structures (LgtE and IcsB) of detoxified penta-acylated LPS exhibited differential adjuvant properties when formulated as native outer membrane vesicles (nOMVs) as compared to the previously described LgtB variant. Detoxified penta-acylated LPS was obtained by disruption of the lpxL1 gene (LpxL1 LPS), and three different glycoforms were obtained by disruption of the lgtB, lgtE or icsB genes respectively. Mice (mus musculus) were immunized with a recombinant PorA P1.7-2,4 (rPorA) protein co-administered with different nOMVs (containing a different PorA serosubtype P1.7,16), each of which expressed one of the three penta-acylated LPS glycoforms. All nOMVs induced IgG responses against the rPorA, but the nOMVs containing the penta-acylated LgtB-LpxL1 LPS glycoform induced significantly greater bactericidal activity compared to the other nOMVs or when the adjuvant was Alhydrogel. Compared to LgtE or IcsB LPS glycoforms, these data support the use of nOMVs containing detoxified, modified LgtB-LpxL1 LPS as a potential adjuvant for future meningococcal protein vaccines. PMID- 25545242 TI - A novel cryptic binding motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP 3/7-cleaved osteopontin as a novel ligand for alpha9beta1 integrin is involved in the anti-type II collagen antibody-induced arthritis. AB - Osteopontin (OPN) is a multifunctional protein that has been linked to various intractable inflammatory diseases. One way by which OPN induces inflammation is the production of various functional fragments by enzyme cleavage. It has been well appreciated that OPN is cleaved by thrombin, and/or matrix metalloproteinase 3 and -7 (MMP-3/7). Although the function of thrombin-cleaved OPN is well characterized, little is known about the function of MMP-3/7-cleaved OPN. In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP 3/7-cleaved mouse OPN binds to alpha9beta1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA. PMID- 25545243 TI - Oxidative stress-related genetic polymorphisms are associated with the prognosis of metastatic gastric cancer patients treated with epirubicin, oxaliplatin and 5 fluorouracil combination chemotherapy. AB - BACKGROUND: Oxidative stress genes are related to cancer development and treatment response. In this study, we aimed to determine the predictive and prognostic roles of oxidative stress-related genetic polymorphisms in metastatic gastric cancer (MGC) patients treated with chemotherapy. METHODS: In this retrospective study, we genotyped nine oxidative stress-related single nucleotide polymorphisms (SNPs) in NQO1, SOD2, SOD3, PON1, GSTP1, GSTT1, and NOS3 (rs1800566, rs10517, rs4880, rs1799895, rs662, rs854560, rs1695, rs2266637, rs1799983, respectively) in 108 consecutive MGC patients treated with epirubicin, oxaliplatin, and 5-fluorouracil (EOF) regimen as the first-line chemotherapy and analyzed the association between the genotypes and the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: We found that, in addition to a lower pathological grade (p = 0.017), NQO1 rs1800566 CT/TT genotype was an independent predictive factor of poor PFS (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.23-3.16; p = 0.005). PON1 rs662 AA/AG genotype was significantly associated with poor OS (HR = 1.95, 95% CI = 1.07-3.54; p = 0.029). No associations were detected between the nine SNPs and DCR. CONCLUSIONS: NQO1 rs1800566 is an independent predictive factor of PFS for MGC patients treated with EOF chemotherapy, and PON1 rs662 is a noteworthy prognostic factor of OS. Information on oxidative stress-related genetic variants may facilitate optimization of individualized chemotherapy in clinical practice. PMID- 25545244 TI - Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b. AB - Fifty-one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg-proline-IFNalpha-2b, AOP2014/P1101). Peg-proline-IFNalpha-2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFNalpha) is known to be an effective antineoplastic therapy for a long time, it is currently not well understood which genetic alterations influence therapeutic outcomes. Apart from somatic changes in specific genes, large chromosomal aberrations could impact responses to IFNalpha. Therefore, we evaluated the interplay of cytogenetic changes and IFNalpha responses in the PEGINVERA cohort. We performed high resolution SNP microarrays to analyze chromosomal aberrations prior and during peg-proline-IFNalpha-2b therapy. Similar numbers and types of chromosomal aberrations in responding and non-responding patients were observed, suggesting that peg-proline-IFNalpha-2b responses are achieved independently of chromosomal aberrations. Furthermore, complete cytogenetic remissions were accomplished in three patients, of which two showed more than one chromosomal aberration. These results imply that peg-proline-IFNalpha-2b therapy is an effective drug for PV patients, possibly including patients with complex cytogenetic changes. PMID- 25545247 TI - Confronting bias. PMID- 25545245 TI - Identification of neutrophil activation markers as novel surrogate markers of CF lung disease. AB - BACKGROUND AND AIMS: Cystic Fibrosis (CF) lung disease is characterized by progressively declining lung function and represents a major factor contributing to the high morbidity and mortality associated with CF. However, apart from spirometry, respiratory disease surrogate markers reliably indicating CF lung disease and the occurrence of pulmonary exacerbations (PEx) are still lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CF lung disease. METHODS: 54 adult and 26 pediatric CF patients were included in the study and serum concentrations of MMP-1, -2, -8, -9, -13, TIMP-1, TIMP-2, YKL-40, hyaluronic acid, procollagen III peptide were quantified by ELISA. CF lung disease was diagnosed by lung function test, PEx was defined based on a clinical scoring established by Rosenfeld in 2001. RESULTS: Adults and children with moderate to severe CF lung disease exhibited significantly increased serum expression of MMP-8, MMP-9, YKL-40 and TIMP-1. Further, MMP-8, MMP-9 and YKL-40 were significantly increased in adult CF patients suffering from PEx compared to those without clinical signs of respiratory exacerbation. MMP-8, MMP-9, YKL-40, and TIMP-1 serum levels were unaffected by the presence or absence of CF liver disease or pancreatic insufficiency. CONCLUSIONS: MMP-8, MMP-9, and YKL-40 might serve as novel non-invasive biomarkers of CF lung disease and PEx. PMID- 25545246 TI - Synphilin-1 binds ATP and regulates intracellular energy status. AB - Recent studies have suggested that synphilin-1, a cytoplasmic protein, is involved in energy homeostasis. Overexpression of synphilin-1 in neurons results in hyperphagia and obesity in animal models. However, the mechanism by which synphilin-1 alters energy homeostasis is unknown. Here, we used cell models and biochemical approaches to investigate the cellular functions of synphilin-1 that may affect energy balance. Synphilin-1 was pulled down by ATP-agarose beads, and the addition of ATP and ADP reduced this binding, indicating that synphilin-1 bound ADP and ATP. Synphilin-1 also bound GMP, GDP, and GTP but with a lower affinity than it bound ATP. In contrast, synphilin-1 did not bind with CTP. Overexpression of synphilin-1 in HEK293T cells significantly increased cellular ATP levels. Genetic alteration to abolish predicted ATP binding motifs of synphilin-1 or knockdown of synphilin-1 by siRNA reduced cellular ATP levels. Together, these data demonstrate that synphilin-1 binds and regulates the cellular energy molecule, ATP. These findings provide a molecular basis for understanding the actions of synphilin-1 in energy homeostasis. PMID- 25545248 TI - Annual banned-substance review: analytical approaches in human sports drug testing. AB - Within the mosaic display of international anti-doping efforts, analytical strategies based on up-to-date instrumentation as well as most recent information about physiology, pharmacology, metabolism, etc., of prohibited substances and methods of doping are indispensable. The continuous emergence of new chemical entities and the identification of arguably beneficial effects of established or even obsolete drugs on endurance, strength, and regeneration, necessitate frequent and adequate adaptations of sports drug testing procedures. These largely rely on exploiting new technologies, extending the substance coverage of existing test protocols, and generating new insights into metabolism, distribution, and elimination of compounds prohibited by the World Anti-Doping Agency (WADA). In reference of the content of the 2014 Prohibited List, literature concerning human sports drug testing that was published between October 2013 and September 2014 is summarized and reviewed in this annual banned substance review, with particular emphasis on analytical approaches and their contribution to enhanced doping controls. PMID- 25545249 TI - Resilience and tipping points of an exploited fish population over six decades. AB - Complex natural systems with eroded resilience, such as populations, ecosystems and socio-ecological systems, respond to small perturbations with abrupt, discontinuous state shifts, or critical transitions. Theory of critical transitions suggests that such systems exhibit fold bifurcations featuring folded response curves, tipping points and alternate attractors. However, there is little empirical evidence of fold bifurcations occurring in actual complex natural systems impacted by multiple stressors. Moreover, resilience of complex systems to change currently lacks clear operational measures with generic application. Here, we provide empirical evidence for the occurrence of a fold bifurcation in an exploited fish population and introduce a generic measure of ecological resilience based on the observed fold bifurcation attributes. We analyse the multivariate development of Barents Sea cod (Gadus morhua), which is currently the world's largest cod stock, over six decades (1949-2009), and identify a population state shift in 1981. By plotting a multivariate population index against a multivariate stressor index, the shift mechanism was revealed suggesting that the observed population shift was a nonlinear response to the combined effects of overfishing and climate change. Annual resilience values were estimated based on the position of each year in relation to the fitted attractors and assumed tipping points of the fold bifurcation. By interpolating the annual resilience values, a folded stability landscape was fit, which was shaped as predicted by theory. The resilience assessment suggested that the population may be close to another tipping point. This study illustrates how a multivariate analysis, supported by theory of critical transitions and accompanied by a quantitative resilience assessment, can clarify shift mechanisms in data-rich complex natural systems. PMID- 25545250 TI - Prometheus and progenitors. PMID- 25545251 TI - Size-exclusion chromatography for the determination of the boiling point distribution of high-boiling petroleum fractions. AB - The paper describes a new procedure for the determination of boiling point distribution of high-boiling petroleum fractions using size-exclusion chromatography with refractive index detection. Thus far, the determination of boiling range distribution by chromatography has been accomplished using simulated distillation with gas chromatography with flame ionization detection. This study revealed that in spite of substantial differences in the separation mechanism and the detection mode, the size-exclusion chromatography technique yields similar results for the determination of boiling point distribution compared with simulated distillation and novel empty column gas chromatography. The developed procedure using size-exclusion chromatography has a substantial applicability, especially for the determination of exact final boiling point values for high-boiling mixtures, for which a standard high-temperature simulated distillation would have to be used. In this case, the precision of final boiling point determination is low due to the high final temperatures of the gas chromatograph oven and an insufficient thermal stability of both the gas chromatography stationary phase and the sample. Additionally, the use of high performance liquid chromatography detectors more sensitive than refractive index detection allows a lower detection limit for high-molar-mass aromatic compounds, and thus increases the sensitivity of final boiling point determination. PMID- 25545252 TI - Coal ash ecological risk assessment in context: Lessons learned from the Kingston Fossil Plant ash spill. PMID- 25545254 TI - Too little water in too many cities. PMID- 25545255 TI - Effective environmental risk communication-Success stories or urban legends? PMID- 25545256 TI - Three propositions for improved science communication from environmental research. PMID- 25545257 TI - Overview of scientific evidence for chocolate health benefits. PMID- 25545258 TI - Multimedia mass-balance models for chemicals in the environment: Reliable tools or bold oversimplifications? PMID- 25545260 TI - Trends in human papillomavirus-related oropharyngeal cancer in Israel. AB - BACKGROUND: The role of human papillomavirus (HPV) infection in oropharyngeal cancer (SCC) is well established. The annual incidence of oropharyngeal SCC in Israel is considerably lower than that in the United States. The purpose of this study was to assess the rate of HPV-related oropharyngeal SCC in Israel. METHODS: The cohort included patients with oropharyngeal SCC who were treated during 1999 to 2011 in Israel. HPV typing was carried out using reverse hybridization and immunohistochemistry. RESULTS: Of the 74 patients analyzed, 25 (33.7%) had detectable HPV DNA. Patients in the HPV-positive group tended to be younger, with a higher rate of nodal metastases, and no history of smoking (p < .02). CONCLUSION: This study demonstrated a rate of HPV-related oropharyngeal SCC in Israel as approximately 3-fold lower than in Western countries. Low exposure to HPV-16, a lower rate of transformation, to cancer or protective genetic factors may contribute to the lower rate of oropharyngeal SCC in Israel. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E274-E278, 2016. PMID- 25545261 TI - Development of Pyrosequencing Method for Detection of UGT1A1 Polymorphisms in Thai Colorectal Cancers. AB - BACKGROUND: UGT1A1 is a polymorphic enzyme that has been associated with irinotecan drug metabolisms. We developed a pyrosequencing method to detect allele frequency and genotype of UGT1A1 polymorphisms (UGT1A1*28 and UGT1A1*6) in Thai colorectal cancer patients. METHOD: A pyrosequencing method was designed to determine UGT1A1 genetic polymorphisms including UGT1A1*28 (A[TA]7TAA) and UGT1A1*6 (211G>A) in 91 Thai colorectal cancers. RESULT: Genotyping by the pyrosequencing technique was 100% concordant with capillary electrophoresis sequencing. The allele frequencies for UGT1A1 genetic polymorphisms were *1/*1 (54.95%), *1/*6 (13.19%), *1/*28 (25.27%), *28/*6 (4.40%), and *28/*28 (2.20%). No homozygous mutation UGT1A1*6 was found in our population. CONCLUSIONS: We developed a rapid, reliable, more cost-effective, and simple assay to detect UGT1A1 genetic polymorphisms in routine practice before initiating irinotecan therapy. The UGT1A1*28 and UGT1A1*6 alleles were found to be similar in the Asian populations. PMID- 25545262 TI - The power in numbers: gut microbiota in Parkinson's disease. PMID- 25545263 TI - Application of gas sensor arrays in assessment of wastewater purification effects. AB - A gas sensor array consisting of eight metal oxide semiconductor (MOS) type gas sensors was evaluated for its ability for assessment of the selected wastewater parameters. Municipal wastewater was collected in a wastewater treatment plant (WWTP) in a primary sedimentation tank and was treated in a laboratory-scale sequential batch reactor (SBR). A comparison of the gas sensor array (electronic nose) response to the standard physical-chemical parameters of treated wastewater was performed. To analyze the measurement results, artificial neural networks were used. E-nose-gas sensors array and artificial neural networks proved to be a suitable method for the monitoring of treated wastewater quality. Neural networks used for data validation showed high correlation between the electronic nose readouts and: (I) chemical oxygen demand (COD) (r = 0.988); (II) total suspended solids (TSS) (r = 0.938); (III) turbidity (r = 0.940); (IV) pH (r = 0.554); (V) nitrogen compounds: N-NO3 (r = 0.958), N-NO2 (r = 0.869) and N-NH3 (r = 0.978); (VI) and volatile organic compounds (VOC) (r = 0.987). Good correlation of the abovementioned parameters are observed under stable treatment conditions in a laboratory batch reactor. PMID- 25545264 TI - Memory and energy optimization strategies for multithreaded operating system on the resource-constrained wireless sensor node. AB - Memory and energy optimization strategies are essential for the resource constrained wireless sensor network (WSN) nodes. In this article, a new memory optimized and energy-optimized multithreaded WSN operating system (OS) LiveOS is designed and implemented. Memory cost of LiveOS is optimized by using the stack shifting hybrid scheduling approach. Different from the traditional multithreaded OS in which thread stacks are allocated statically by the pre-reservation, thread stacks in LiveOS are allocated dynamically by using the stack-shifting technique. As a result, memory waste problems caused by the static pre-reservation can be avoided. In addition to the stack-shifting dynamic allocation approach, the hybrid scheduling mechanism which can decrease both the thread scheduling overhead and the thread stack number is also implemented in LiveOS. With these mechanisms, the stack memory cost of LiveOS can be reduced more than 50% if compared to that of a traditional multithreaded OS. Not is memory cost optimized, but also the energy cost is optimized in LiveOS, and this is achieved by using the multi-core "context aware" and multi-core "power-off/wakeup" energy conservation approaches. By using these approaches, energy cost of LiveOS can be reduced more than 30% when compared to the single-core WSN system. Memory and energy optimization strategies in LiveOS not only prolong the lifetime of WSN nodes, but also make the multithreaded OS feasible to run on the memory constrained WSN nodes. PMID- 25545265 TI - One single molecule as a multifunctional fluorescent probe for ratiometric sensing of Fe3+, Cr3+ and colorimetric sensing of Cu2+. AB - The reagent Rh-C, incorporating a rhodamine moiety and a coumarin backbone and prepared via click chemistry, was developed as the first single molecule for detecting Cu2+, Fe3+ and Cr3+. Its response to Cu2+ in different solutions is visible to the naked eye and it exhibits a ratiometric fluorescence response to Fe3+ in methanol and Cr3+ in acetonitrile. PMID- 25545266 TI - Analysis of latency performance of bluetooth low energy (BLE) networks. AB - Bluetooth Low Energy (BLE) is a short-range wireless communication technology aiming at low-cost and low-power communication. The performance evaluation of classical Bluetooth device discovery have been intensively studied using analytical modeling and simulative methods, but these techniques are not applicable to BLE, since BLE has a fundamental change in the design of the discovery mechanism, including the usage of three advertising channels. Recently, there several works have analyzed the topic of BLE device discovery, but these studies are still far from thorough. It is thus necessary to develop a new, accurate model for the BLE discovery process. In particular, the wide range settings of the parameters introduce lots of potential for BLE devices to customize their discovery performance. This motivates our study of modeling the BLE discovery process and performing intensive simulation. This paper is focused on building an analytical model to investigate the discovery probability, as well as the expected discovery latency, which are then validated via extensive experiments. Our analysis considers both continuous and discontinuous scanning modes. We analyze the sensitivity of these performance metrics to parameter settings to quantitatively examine to what extent parameters influence the performance metric of the discovery processes. PMID- 25545267 TI - Rapid detection of microorganisms based on active and passive modes of QCM. AB - Label-free immunosensors are well suited for detection of microorganisms because of their fast response and reasonable sensitivity comparable to infection doses of common pathogens. Active (lever oscillator and frequency counter) and passive (impedance analyzer) modes of quartz crystal microbalance (QCM) were used and compared for rapid detection of three strains of E. coli. Different approaches for antibody immobilization were compared, the immobilization of reduced antibody using Sulfo-SMCC was most effective achieving the limit of detection (LOD) 8 * 104 CFU.mL-1 in 10 min. For the passive mode, software evaluating impedance characteristics in real-time was developed and used. Almost the same results were achieved using both active and passive modes confirming that the sensor properties are not limited by the frequency evaluation method but mainly by affinity of the antibody. Furthermore, reference measurements were done using surface plasmon resonance. Effect of condition of cells on signal was observed showing that cells ruptured by ultrasonication provided slightly higher signal changes than intact microbes. PMID- 25545268 TI - Biosignal PI, an affordable open-source ECG and respiration measurement system. AB - Bioimedical pilot projects e.g., telemedicine, homecare, animal and human trials usually involve several physiological measurements. Technical development of these projects is time consuming and in particular costly. A versatile but affordable biosignal measurement platform can help to reduce time and risk while keeping the focus on the important goal and making an efficient use of resources. In this work, an affordable and open source platform for development of physiological signals is proposed. As a first step an 8-12 leads electrocardiogram (ECG) and respiration monitoring system is developed. Chips based on iCoupler technology have been used to achieve electrical isolation as required by IEC 60601 for patient safety. The result shows the potential of this platform as a base for prototyping compact, affordable, and medically safe measurement systems. Further work involves both hardware and software development to develop modules. These modules may require development of front-ends for other biosignals or just collect data wirelessly from different devices e.g., blood pressure, weight, bioimpedance spectrum, blood glucose, e.g., through Bluetooth. All design and development documents, files and source codes will be available for non-commercial use through project website, BiosignalPI.org. PMID- 25545269 TI - Comparison of treatment outcomes of transnasal vocal fold polypectomy versus microlaryngoscopic surgery. AB - OBJECTIVES/HYPOTHESIS: Office-based procedures have been proposed for the treatment of vocal polyps, including indirect laryngoscopic surgery and angiolytic laser photocoagulation. Our previous report documented good treatment outcomes by combining the two aforementioned procedures. This study was intended to further compare the treatment outcomes of office transnasal vocal fold polypectomy (VFP) with those of microlaryngoscopic surgery (MLS). STUDY DESIGN: A matched cohort study. METHODS: This study retrospectively enrolled 50 age-, gender-, and size-matched patients with vocal polyps treated by VFP or MLS at a tertiary teaching hospital from January 2012 to October 2013. Treatment outcomes were evaluated before, 2 weeks, and 6 weeks after the procedures via perceptual rating of voice quality, acoustic measurement of the speech signal, 10-item voice handicap index, maximal phonation time, subjective rating of voice quality, and videolaryngostroboscopic evaluation. RESULTS: Both VFP and MLS resulted in significant clinical improvements 2 and 6 weeks postoperatively. Study results exhibited similar objective outcomes between VFP and MLS, whereas patients who received VFP reported higher subjective voice quality than those receiving MLS 2 weeks postoperatively. Six weeks after the procedures, the objective and subjective treatment outcomes were not significantly different between the two treatment groups. CONCLUSION: This study shows that transnasal VFP may be used as an effective alternative treatment for small vocal polyps. Patients who received office VFP experienced rapid symptomatic relief with a higher degree of subjective effectiveness than MLS 2 weeks postoperatively, whereas the overall treatment outcomes showed a comparable level of effectiveness for both modalities. LEVEL OF EVIDENCE: 3B. PMID- 25545270 TI - OX40 blockade inhibits house dust mite driven allergic lung inflammation in mice and in vitro allergic responses in humans. AB - The costimulatory receptor OX40 is expressed on activated T cells and regulates T cell responses. Here, we show the efficacy and mechanism of action of an OX40 blocking antibody using the chronic house dust mite (HDM) mouse model of lung inflammation and in vitro HDM stimulation of cells from HDM allergic human donors. We have demonstrated that OX40 blockade leads to a reduction in the number of eosinophils and neutrophils in the lavage fluid and lung tissue of HDM sensitized mice. This was accompanied by a decrease in activated and memory CD4(+) T cells in the lungs and further analysis revealed that both the Th2 and Th17 populations were inhibited. Improved lung function and decreased HDM specific antibody responses were also noted. Significantly, efficacy was observed even when anti-OX40 treatment was delayed until after inflammation was established. OX40 blockade also inhibited the release of the Th2 cytokines IL-5 and IL-13 from cells isolated from HDM allergic human donors. Altogether, our data provide evidence of a role of the OX40/OX40L pathway in ongoing allergic lung inflammation and support clinical studies of a blocking OX40 antibody in Th2 high severe asthma patients. PMID- 25545272 TI - Experimental and theoretical mechanistic investigation of the iridium-catalyzed dehydrogenative decarbonylation of primary alcohols. AB - The mechanism for the iridium-BINAP catalyzed dehydrogenative decarbonylation of primary alcohols with the liberation of molecular hydrogen and carbon monoxide was studied experimentally and computationally. The reaction takes place by tandem catalysis through two catalytic cycles involving dehydrogenation of the alcohol and decarbonylation of the resulting aldehyde. The square planar complex IrCl(CO)(rac-BINAP) was isolated from the reaction between [Ir(cod)Cl]2, rac BINAP, and benzyl alcohol. The complex was catalytically active and applied in the study of the individual steps in the catalytic cycles. One carbon monoxide ligand was shown to remain coordinated to iridium throughout the reaction, and release of carbon monoxide was suggested to occur from a dicarbonyl complex. IrH2Cl(CO)(rac-BINAP) was also synthesized and detected in the dehydrogenation of benzyl alcohol. In the same experiment, IrHCl2(CO)(rac-BINAP) was detected from the release of HCl in the dehydrogenation and subsequent reaction with IrCl(CO)(rac-BINAP). This indicated a substitution of chloride with the alcohol to form a square planar iridium alkoxo complex that could undergo a beta-hydride elimination. A KIE of 1.0 was determined for the decarbonylation and 1.42 for the overall reaction. Electron rich benzyl alcohols were converted faster than electron poor alcohols, but no electronic effect was found when comparing aldehydes of different electronic character. The lack of electronic and kinetic isotope effects implies a rate-determining phosphine dissociation for the decarbonylation of aldehydes. PMID- 25545271 TI - Magic angle spinning nuclear magnetic resonance characterization of voltage dependent anion channel gating in two-dimensional lipid crystalline bilayers. AB - The N-terminus of the voltage-dependent anion channel (VDAC) has been proposed to contain the mechanistically important gating helices that modulate channel opening and closing. In this study, we utilize magic angle spinning nuclear magnetic resonance (MAS NMR) to determine the location and structure of the N terminus for functional channels in lipid bilayers by measuring long-range (13)C (13)C distances between residues in the N-terminus and other domains of VDAC reconstituted into DMPC lipid bilayers. Our structural studies show that the distance between A14 Cbeta in the N-terminal helix and S193 Cbeta is ~4-6 A. Furthermore, VDAC phosphorylation by a mitochondrial kinase at residue S193 has been claimed to delay mitochondrial cell death by causing a conformational change that closes the channel, and a VDAC-Ser193Glu mutant has been reported to show properties very similar to those of phosphorylated VDAC in a cellular context. We expressed VDAC-S193E and reconstituted it into DMPC lipid bilayers. Two dimensional (13)C-(13)C correlation experiments showed chemical shift perturbations for residues located in the N-terminus, indicating possible structural perturbations to that region. However, electrophysiological data recorded on VDAC-S193E showed that channel characteristics were identical to those of wild type samples, indicating that phosphorylation of S193 does not directly affect channel gating. The combination of NMR and electrophysiological results allows us to discuss the validity of proposed gating models. PMID- 25545273 TI - Expression levels of chaperones influence biotransformation activity of recombinant Escherichia coli expressing Micrococcus luteus alcohol dehydrogenase and Pseudomonas putida Baeyer-Villiger monooxygenase. AB - We demonstrated for the first time that the archaeal chaperones (i.e., gamma prefoldin and thermosome) can stabilize enzyme activity in vivo. Ricinoleic acid biotransformation activity of recombinant Escherichia coli expressing Micrococcus luteus alcohol dehydrogenase and the Pseudomonas putida KT2440 Baeyer-Villiger monooxygenase improved significantly with co-expression of gamma-prefoldin or recombinant themosome originating from the deep-sea hyperthermophile archaea Methanocaldococcus jannaschii. Furthermore, the degree of enhanced activity was dependent on the expression levels of the chaperones. For example, whole-cell biotransformation activity was highest at 12 umol/g dry cells/min when gamma prefoldin expression level was approximately 46% of the theoretical maximum. This value was approximately two-fold greater than that in E. coli, where the gamma prefoldin expression level was zero or set to the theoretical maximum. Therefore, it was assumed that the expression levels of chaperones must be optimized to achieve maximum biotransformation activity in whole-cell biocatalysts. PMID- 25545278 TI - Inward rectifier potassium currents in mammalian skeletal muscle fibres. AB - Inward rectifying potassium (Kir) channels play a central role in maintaining the resting membrane potential of skeletal muscle fibres. Nevertheless their role has been poorly studied in mammalian muscles. Immunohistochemical and transgenic expression were used to assess the molecular identity and subcellular localization of Kir channel isoforms. We found that Kir2.1 and Kir2.2 channels were targeted to both the surface and the transverse tubular system membrane (TTS) compartments and that both isoforms can be overexpressed up to 3-fold 2 weeks after transfection. Inward rectifying currents (IKir) had the canonical features of quasi-instantaneous activation, strong inward rectification, depended on the external [K(+)], and could be blocked by Ba(2+) or Rb(+). In addition, IKir records show notable decays during large 100 ms hyperpolarizing pulses. Most of these properties were recapitulated by model simulations of the electrical properties of the muscle fibre as long as Kir channels were assumed to be present in the TTS. The model also simultaneously predicted the characteristics of membrane potential changes of the TTS, as reported optically by a fluorescent potentiometric dye. The activation of IKir by large hyperpolarizations resulted in significant attenuation of the optical signals with respect to the expectation for equal magnitude depolarizations; blocking IKir with Ba(2+) (or Rb(+)) eliminated this attenuation. The experimental data, including the kinetic properties of IKir and TTS voltage records, and the voltage dependence of peak IKir, while measured at widely dissimilar bulk [K(+)] (96 and 24 mm), were closely predicted by assuming Kir permeability (PKir) values of ~5.5 * 10(-6 ) cm s(-1) and equal distribution of Kir channels at the surface and TTS membranes. The decay of IKir records and the simultaneous increase in TTS voltage changes were mostly explained by K(+) depletion from the TTS lumen. Most importantly, aside from allowing an accurate estimation of most of the properties of IKir in skeletal muscle fibres, the model demonstrates that a substantial proportion of IKir (>70%) arises from the TTS. Overall, our work emphasizes that measured intrinsic properties (inward rectification and external [K] dependence) and localization of Kir channels in the TTS membranes are ideally suited for re capturing potassium ions from the TTS lumen during, and immediately after, repetitive stimulation under physiological conditions. PMID- 25545279 TI - Expression and function of Ccbe1 in the chick early cardiogenic regions are required for correct heart development. AB - During the course of a differential screen to identify transcripts specific for chick heart/hemangioblast precursor cells, we have identified Ccbe1 (Collagen and calcium-binding EGF-like domain 1). While the importance of Ccbe1 for the development of the lymphatic system is now well demonstrated, its role in cardiac formation remained unknown. Here we show by whole-mount in situ hybridization analysis that cCcbe1 mRNA is initially detected in early cardiac progenitors of the two bilateral cardiogenic fields (HH4), and at later stages on the second heart field (HH9-18). Furthermore, cCcbe1 is expressed in multipotent and highly proliferative cardiac progenitors. We characterized the role of cCcbe1 during early cardiogenesis by performing functional studies. Upon morpholino-induced cCcbe1 knockdown, the chick embryos displayed heart malformations, which include aberrant fusion of the heart fields, leading to incomplete terminal differentiation of the cardiomyocytes. cCcbe1 overexpression also resulted in severe heart defects, including cardia bifida. Altogether, our data demonstrate that although cardiac progenitors cells are specified in cCcbe1 morphants, the migration and proliferation of cardiac precursors cells are impaired, suggesting that cCcbe1 is a key gene during early heart development. PMID- 25545280 TI - Edge effects are important in supporting beetle biodiversity in a gravel-bed river floodplain. AB - Understanding complex, dynamic, and diverse ecosystems is essential for developing sound management and conservation strategies. Gravel-bed river floodplains are composed of an interlinked mosaic of aquatic and terrestrial habitats hosting a diverse, specialized, and endangered fauna. Therefore, they serve as excellent models to investigate the biodiversity of multiple ecotones and related edge effects. In this study, we investigated the abundance, composition, richness, and conservation status of beetle assemblages at varying sediment depth (0, 0.1, 0.6 and 1.1 m), distance from the channel (1, 5, 20, and 60-100 m, and 5 m within the riparian forest), and time of the year (February November) across a 200 m-wide gravel bar at the near-natural Tagliamento River (Italy), to detect edge effects in four floodplain ecotones: aquatic-terrestrial, forest-active floodplain, sediment-air, and sediment-groundwater. We used conventional pitfall traps and novel tube traps to sample beetles comparably on the sediment surface and within the unsaturated sediments. We found a total of 308 beetle species (including 87 of conservation concern) that showed multiple, significant positive edge effects across the floodplain ecotones, mainly driven by spatial heterogeneity: Total and red list beetle abundance and richness peaked on the sediment surface, at channel margins, and at the edge of the riparian forest. All ecotones possessed edge/habitat specialists. Most red list species occurred on the sediment surface, including five species previously considered extinct--yet two of these species occurred in higher densities in the unsaturated sediments. Conservation and management efforts along gravel-bed rivers must therefore promote a dynamic flow and sediment regime to create and maintain habitat heterogeneity and ecotone diversity, which support a unique and high biodiversity. PMID- 25545281 TI - Transcatheter aortic-valve implantation with one single minimal contrast media injection. AB - OBJECTIVES: Performing transcatheter aortic valve implantation (TAVI) with the use of minimal contrast in patients at high-risk for acute kidney injury (AKI). BACKGROUND: Contrast-induced nephropathy (CIN) is a major cause of AKI following TAVI and is associated with increased morbidity and mortality. The amount of contrast media used increases the risk for CIN. METHODS: Computed tomography was omitted during the screening process. For the procedure transfemoral access was default. The self-expanding CoreValve prosthesis was chosen in all patients to minimize the risk of annular rupture in case of oversizing. Valve sizing was based on echocardiography, aortography, calcification on fluoroscopy, as well as weight and height of the patient. A single contrast injection was performed to confirm correct position of the pigtail catheter at the level of the annulus. The pigtail then served as the marker for the device landing zone. Intraprocedural assessment of the implantation result relied on echocardiography and hemodynamics. RESULTS: Five patients with severe aortic stenosis and at high risk for developing CIN were included. Device success was achieved in all patients and no major complications occurred. The median dose of injected contrast media was 8 ml (4-9). All but one patient had improved renal function after the intervention compared to baseline. CONCLUSIONS: Our study shows feasibility of performing TAVI with a single minimal contrast media injection, using a self-expandable valve. This technique has the potential to reduce the incidence of CIN. PMID- 25545282 TI - Study on the interaction of plasma protein binding rate between edaravone and taurine in human plasma based on HPLC analysis coupled with ultrafiltration technique. AB - In this work, two high-performance liquid chromatography (HPLC) assays were developed and validated for the independent determination of edaravone and taurine using 3-methyl-1-p-tolyl-5-pyrazolone and L-glutamine as internal standards. In in vitro experiments, human plasma was separately spiked with a mixture of edaravone and taurine, edaravone or taurine alone. Plasma was precipitated with acetonitrile containing 0.1% formic acid. Ultrafiltration was employed to obtain the unbound ingredients of the two drugs. The factors that might influence the ultrafiltration effiency were elaborately optimized. Plasma supernatant and ultrafiltrate containing taurine were derivated with o phthalaldehyde and ethanethiol in the presence of 40 mmol/L sodium borate buffer (pH 10.2) at room temperature within 1 min. Chromatographic separations were achieved on an InertSustain C18 column (250 * 4.6 mm, 5 um). Isocratic 50 mmol/L ammonium acetate-acetonitrile and gradient 50 mmol/L sodium acetate (pH 5.3) methanol were respectively selected as the mobile phase for the determination of edaravone and taurine. All of the validation data including linearity, extraction recovery, precision, accuracy and stability conformed to the requirements. Results showed that there were no significant alterations in the plasma protein binding rate of taurine and edaravone, implying that the proposed combination therapy was pharmacologically feasible. PMID- 25545285 TI - Ultrathin pancharatnam-berry metasurface with maximal cross-polarization efficiency. AB - Novel ultrathin dual-functional metalenses are proposed, fabricated, tested, and verified in the microwave regime for the first time. The significance is that their anomalous transmission efficiency almost reaches the theoretical limit of 25%, showing a remarkable improvement compared with earlier ultrathin metasurface designs with less than 5% coupling efficiency. The planar metalens proposed empowers significant reduction in thickness, versatile focusing behavior, and high transmission efficiency simultaneously. PMID- 25545287 TI - Laparoscopic non-microsurgical tubal reanastomosis: A retrospective cohort study. AB - OBJECTIVE: To determine the pregnancy rate achieved through laparoscopic tubal reanastomosis using only standard 5 mm laparoscopic instruments and standard suturing material. METHODS: Data from 100 consecutive laparoscopic tubal reanastomosis procedures done between September 2002 and September 2010 were retrospectively analysed. All procedures were performed by the same surgeon using standard 5 mm laparoscopic instruments and with the placing of three or four sutures of standard polyglycan 4/0 suturing material. The main outcome measures were: (intrauterine) pregnancy rate and live birth rate before and after 40 years of age, and tubal patency rate. RESULTS: Six patients had no active child wish and six others were lost to follow-up, thus leaving 88 of 100 patients for evaluation. Fifty-eight of these conceived, giving a total pregnancy rate (PR) of 66%. The PR in women younger than 40 years was significantly greater than that achieved by those aged 40 or more (73% vs. 29%, p = 0.001). CONCLUSIONS: Laparoscopic tubal reanastomosis with standard 5 mm laparoscopic instruments results in a satisfactory pregnancy rate. PMID- 25545286 TI - Airway reactions and emergence times in general laryngeal mask airway anaesthesia: a meta-analysis. AB - BACKGROUND: Desflurane's short emergence time supports fast track anaesthesia. Data on the rate of upper airway complications and emergence time when desflurane is used with laryngeal mask airway (LMA) are controversial and limited. OBJECTIVES: To compare recovery time variables and the rates of upper airway adverse events in patients with an LMA undergoing general surgery with desflurane, sevoflurane, isoflurane or propofol anaesthesia. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: A systematic search for eligible RCTs in Embase (Elsevier) and in PubMed (National Library of Medicine) databases up to September 2013. ELIGIBILITY CRITERIA: RCTs investigating the rates of cough overall, cough at emergence, laryngospasm, time to eye opening, time to removal of the LMA, time to respond to command and time to state date of birth in patients with an LMA, during emergence from desflurane, sevoflurane, isoflurane or propofol anaesthesia. RESULTS: Thirteen RCTs were included and analysed. We found a strong interstudy variability. There was no difference in the rates of upper airway events between desflurane and sevoflurane or between desflurane and a control group consisting of all the other anaesthetics combined. Comparing desflurane (n = 284) with all other anaesthetic groups (n = 313), the risk ratio [95% confidence interval (95% CI)] was 1.12 (0.63 to 2.02, P = 0.70). Cough at emergence was only measured in patients receiving desflurane (n = 148) and sevoflurane (n = 146): the risk ratio (95% CI) was 1.49 (0.55 to 4.02, P = 0.43). Laryngospasm was rare and there was no significant difference in its incidence when desflurane (n = 262) was compared with all other anaesthetics combined (n = 289; risk ratio 1.03; 95% CI 0.33 to 3.20, P = 0.96). The times of all emergence variables were significantly faster in the desflurane group than in all other groups. CONCLUSION: When using an LMA, upper airway adverse reactions in association with desflurane anaesthesia were no different from those noted with sevoflurane, isoflurane or propofol anaesthesia. Emergence from general anaesthesia with desflurane is significantly faster than all the other anaesthetics. Due to interstudy variations and the small size of the trials, further large-scale, multicentre studies are required to confirm or refute the results of this meta-analysis. PMID- 25545288 TI - A mapping of the positions of adults in Toulouse, France, regarding induced abortion. AB - BACKGROUND: Are people's views on abortion as polarised as is suggested by the 'marches for life' that regularly take place in Paris and other capitals? Objective To map French people's positions regarding the acceptability of induced abortion. METHODS: One hundred and fifty-nine participants were presented with stories composed according to a three within-subject design: Reason for abortion (e.g., the woman's life is endangered) * Gestational age * Woman's age. They assessed the extent to which abortion would be, in each case, an acceptable medical/surgical procedure. RESULTS: Five qualitatively different positions were identified: (i) always acceptable, irrespective of circumstances (31% of the sample), (ii) strictly depends on the reason for abortion (27%), (iii) legalist (23%), (iv) depends on the reason and on the gestational age (18%), and (v) always unacceptable (1%). CONCLUSIONS: Only one-fifth of the participants agreed with the part of the French law that permits abortion on request when gestational age does not exceed ten weeks. The others disagreed either because they thought that abortion on demand should never be permitted or because they thought that the age limit should be extended. This divide in people's opinions guarantees that the debate over induced abortions will continue. PMID- 25545289 TI - Detection of central nervous system involvement in childhood acute lymphoblastic leukemia by cytomorphology and flow cytometry of the cerebrospinal fluid. AB - BACKGROUND: Therapy directed at the central nervous system (CNS) is an essential part of the treatment for childhood acute lymphoblastic leukemia (ALL). The current evaluation of CNS involvement based on cytomorphological examination of the cerebrospinal fluid (CSF) alone is not as sensitive with low cell counts as flow cytometric immunophenotyping (FCI) of the CSF. However, the importance of low CSF blasts counts at diagnosis is uncertain. We sought to determine the significance of FCI in relation to conventional morphological examination. PROCEDURE: We retrospectively compared FCI of the CSF with cytomorphology at diagnosis or relapse of childhood ALL. All patients were diagnosed 2000-2012 in Stockholm or Umea, Sweden. Clinical data were collected from medical records and the Nordic leukemia registry. Treatment assignment was based on morphological examination only. RESULTS: The cohort was comprised of 214 patients with ALL. CSF involvement was detected by both methods in 20 patients, in 17 by FCI alone, and in one patient by cytomorphology alone. The relapse rate was higher for patients with negative cytology but positive FCI compared to those without CNS involvement using both methods. The difference was especially marked in the current protocol. However, none of the patients with negative CSF cytology but positive FCI had a CNS relapse. CONCLUSIONS: FCI of the CSF increased the detection rate of CNS involvement of ALL approximately two times compared to cytomorphology. Patients with low-level CNS involvement may benefit from additional intensified systemic or CNS-directed therapy, but larger studies are needed. PMID- 25545290 TI - Topics in Cognitive Science. Introduction to volume 7, issue 1 of topiCS. PMID- 25545292 TI - Probing complex reflection coefficients in one-dimensional surface plasmon polariton waveguides and cavities using STEM EELS. AB - The resonant properties of a plasmonic cavity are determined by the size of the cavity, the surface plasmon polariton (SPP) dispersion relationship, and the complex reflection coefficients of the cavity boundaries. In small wavelength scale cavities, the phase propagation due to reflections from the cavity walls is of a similar magnitude to propagation due to traversing the cavity. Until now, this reflection phase has been inferred from measurements of the resonant frequencies of a cavity of known dispersion and length. In this work, we present a method for measuring the complex reflection coefficients of a truncation in a 1D surface plasmon waveguide using electron energy loss spectroscopy in the scanning transmission electron microscope (STEM EELS) and show that this insight can be used to engineer custom cavities with engineered reflecting boundaries, whose resonant wavelengths and internal mode density profiles can be analytically predicted given knowledge of the cavity dimensions and complex reflection coefficients of the boundaries. PMID- 25545291 TI - Imaging of occlusive thrombi in acute ischemic stroke. AB - Thrombi, or clots, often occlude proximal segments of the cerebral arterial circulation in acute ischemic stroke. Thromboembolic occlusion or thrombi superimposed on atherosclerotic plaque are the principal focus of acute stroke therapies such as thrombolysis or thrombectomy. We review the imaging characteristics of thrombi on multimodal computed tomography and magnetic resonance imaging, angiography, and ultrasonography, summarizing recent studies that facilitate therapeutic decision-making from these noninvasive studies. Information about the location, size, and imaging characteristics can be ascertained using these techniques. Imaging findings in relation to occlusive thrombus have been correlated with clot pathology, response to therapeutic interventions, and clinical outcome. Diagnostic evaluation of occlusive thrombi on noninvasive studies now constitutes an integral component of acute stroke management. PMID- 25545293 TI - Increased expression of human leucocyte antigen class I free heavy chains on monocytes of patients with spondyloarthritis and cells transfected with HLA-B27. AB - Human leucocyte antigen (HLA)-B27 expression is correlated with spondyloarthritis (SpA), but its role in disease pathogenesis remains unclear. The aim of the study was to determine whether HLA-B27 free heavy chain (FHC) contributes to SpA pathogenesis. Flow cytometry was used to analyse the FHC expression on CD3+ and CD14+ cells in the peripheral blood (PB) and synovial fluid (SF) from SpA patients, healthy controls, and rheumatoid arthritis (RA) patients. Human monocytic U937 cell lines stably expressing enhanced green fluorescence protein (EGFP)/HLA-B27, EGFP/HLA-A2 or EGFP alone were created to further investigate the relation between HLA-B27 and FHC expression. The relative FHC level on CD14+ PB cells was significantly higher in SpA patients than in controls, but lower than on the SF cells of SpA patients. No significant correlation was found for relative FHC expression with HLA-B27 or beta2-microglobulin expression. HLA-B27 transfected U937 cells expressed higher FHC levels than either EGFP/HLA-A2- or EGFP-transfected cells. HLA class I FHC expression was significantly increased on monocytes of SpA patients and HLA-B27-transfected cells, implying that FHC, perhaps mostly derived from HLA-B27, plays an important role in SpA pathogenesis. PMID- 25545294 TI - Two Cases of Ventricular Proarrhythmia from Automatic Threshold Measurement Features in a CRTD and an ICD. AB - The present case report presents two cases in which automatic threshold measurement features in an implantable cardiac defibrillator and in a CRTD act proarrhythmic by inducing polymorphic ventricular arrhythmia. By programming these features off the problem was solved. The mechanisms seem to be different from previously reported proarrhythmic interactions from such device features. PMID- 25545296 TI - Contrasting effects of nicotianamine synthase knockdown on zinc and nickel tolerance and accumulation in the zinc/cadmium hyperaccumulator Arabidopsis halleri. AB - Elevated nicotianamine synthesis in roots of Arabidopsis halleri has been established as a zinc (Zn) hyperaccumulation factor. The main objective of this study was to elucidate the mechanism of nicotianamine-dependent root-to-shoot translocation of metals. Metal tolerance and accumulation in wild-type (WT) and AhNAS2-RNA interference (RNAi) plants were analysed. Xylem exudates were subjected to speciation analysis and metabolite profiling. Suppression of root nicotianamine synthesis had no effect on Zn and cadmium (Cd) tolerance but rendered plants nickel (Ni)-hypersensitive. It also led to a reduction of Zn root to-shoot translocation, yet had the opposite effect on Ni mobility, even though both metals form coordination complexes of similar stability with nicotianamine. Xylem Zn concentrations were positively, yet nonstoichiometrically, correlated with nicotianamine concentrations. Two fractions containing Zn coordination complexes were detected in WT xylem. One of them was strongly reduced in AhNAS2 suppressed plants and coeluted with (67) Zn-labelled organic acid complexes. Organic acid concentrations were not responsive to nicotianamine concentrations and sufficiently high to account for complexing the coordinated Zn. We propose a key role for nicotianamine in controlling the efficiency of Zn xylem loading and thereby the formation of Zn coordination complexes with organic acids, which are the main Zn ligands in the xylem but are not rate-limiting for Zn translocation. PMID- 25545295 TI - Stability of the gorilla microbiome despite simian immunodeficiency virus infection. AB - Simian immunodeficiency viruses (SIVs) have been discovered in over 45 primate species; however, the pathogenic potential of most SIV strains remains unknown due to difficulties inherent in observing wild populations. Because those SIV infections that are pathogenic have been shown to induce changes in the host's gut microbiome, monitoring the microbiota present in faecal samples can provide a noninvasive means for studying the effects of SIV infection on the health of wild living primates. Here, we examine the effects of SIVgor, a close relative of SIVcpz of chimpanzees and HIV-1 of humans, on the gut bacterial communities residing within wild gorillas, revealing that gorilla gut microbiomes are exceptionally robust to SIV infection. In contrast to the microbiomes of HIV-1 infected humans and SIVcpz-infected chimpanzees, SIVgor-infected gorilla microbiomes exhibit neither rises in the frequencies of opportunistic pathogens nor elevated rates of microbial turnover within individual hosts. Regardless of SIV infection status, gorilla microbiomes assort into enterotypes, one of which is compositionally analogous to those identified in humans and chimpanzees. The other gorilla enterotype appears specialized for a leaf-based diet and is enriched in environmentally derived bacterial genera. We hypothesize that the acquisition of this gorilla-specific enterotype was enabled by lowered immune system control over the composition of the microbiome. Our results indicate differences between the pathology of SIVgor and SIVcpz/HIV-1 infections, demonstrating the utility of investigating host microbial ecology as a means for studying disease in wild primates of high conservation priority. PMID- 25545297 TI - Distal renal artery stenosis after percutaneous renal denervation leading to renal impairment but normotension. PMID- 25545298 TI - Comparative assessment of a canine-specific medium to support colony formation from canine hair follicular keratinocytes. AB - BACKGROUND: Follicular stem cells and their progeny are responsible for the cyclical renewal of hair follicles and maintenance of the hair coat. The understanding of pathways involved in this process is essential to elucidate the pathogenetic mechanisms of primary alopecia. Stem cells and their direct descendants are located in the bulge region of the isthmus of hair follicles. Although these cells have been studied extensively in mice and humans, data for canine isthmic keratinocyte activation and proliferation are not available. HYPOTHESIS/OBJECTIVES: The aim was to establish an accurate and reliable in vitro system to study the growth potential of canine isthmic keratinocytes. We assessed the colony-promoting capability of a commercially available canine-specific medium, CELLnTEC (CnT-09), compared with a well-established home-made medium, complete FAD (cFAD). The CnT-09 medium is specific for the growth of canine keratinocytes, while the cFAD medium can support growth and colony formation of keratinocytes from several species. ANIMALS: Skin biopsies were obtained from 15 recently euthanized dogs of various breeds with no skin abnormalities. METHODS: The isthmic region of compound hair follicles was isolated by microdissection and cell growth monitored using several parameters with colony-forming assays. RESULTS: The CnT-09 and cFAD media provided similar growth as measured by the total number and size of colonies, as well as rate of cell differentiation. CONCLUSIONS: The commercial canine-specific CnT-09 medium was comparable to the home-made cFAD medium in supporting the growth and proliferation of canine follicular keratinocytes in vitro. The CnT-09 medium should be a viable alternative growth medium for molecular studies of alopecic disorders in dogs. PMID- 25545299 TI - Danish Rural Eye Study: the association of preschool vision screening with the prevalence of amblyopia. AB - PURPOSE: To determine the prevalence of amblyopia in Denmark before and after the initiation of the Danish national preschool vision screening programme. METHODS: In a population-based cross-sectional study, 3826 participants of the Danish General Suburban Population Study (GESUS) aged 20 years and older from a Danish rural municipality received a complete general health examination and an ophthalmological interview and examination. This study included a comprehensive ophthalmologic interview, measurement of best corrected visual acuity (BCVA) in each eye, Hirschberg's test for strabismus and two 45-degree retinal fundus photographs of each eye. A complete ophthalmologic examination was performed when indicated. RESULTS: The prevalence of monocular visual impairment (MVI) was 4.26% (95% CI, 3.66-4.95, n = 163). Amblyopia was the most common cause, accounting for 33%. The prevalence of amblyopia was 1.44% (95% CI, 1.01-1.81, n = 55), being higher among non-preschool vision screened persons compared to those who were offered (estimated 95% attendance) preschool vision screening (1.78%, n = 41, 95% CI 1.24-2.33 versus 0.44%, n = 2, 95% CI, 0.12-1.60, p = 0.024). The leading cause of amblyopia was anisometropia (45.5%, 25/55). CONCLUSIONS: Amblyopia was the most common cause of MVI. Following the initiation of the Danish national preschool vision screening programme, which has an approximate attendance rate of 95%, the prevalence of amblyopia decreased by fourfold. PMID- 25545300 TI - Batch recall of French plasma-derived products due to variant Creutzfeldt-Jakob disease risk: the psychological impact on haemophilic patients, changes in their therapeutic demands and behaviour and ethical considerations. AB - The choice of plasma-derived products (PdP) vs. recombinant products (RP) for treating haemophilia is influenced by the infectious and perceived safety of the products. Batch recall of PdP due to the risk of variant Creutzfeldt-Jakob disease (vCJD) may have unfavourable psychological impacts on haemophilia patients and influence their product preferences. This study aimed to assess the psychological impact of batch recalls of PdP in six haemophilia patients and their therapeutic demands, and to discuss the ethical problems in physicians' management of this event. A survey was conducted using a new interview form and an existing anxiety and depression questionnaire. Batch recalls produce recurrent negative emotional outcomes in haemophiliacs and their families. The quality, understanding and efficiency of the batch recall announcements were unsatisfactory in some respects. Only one patient still had some of the vials in question, and only three patients understood the real reason for the batch recall. Four patients asked to change their PdP for RP; a fifth patient was considering doing so. Here, topics for discussion include the delivery of an unclear message to patients about a very uncertain risk of a frightening disease, the reasons to maintain PdP when RP are largely available, except in specific cases, and the related discomfort for caregivers. The ethical questions revealed by batch recalls and the high psychological impact of vCJD risk on patients can no longer be ignored, and require surveys assessing the rationales and choices of the healthcare authorities, manufacturers, prescribers and users. PMID- 25545301 TI - Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system. AB - The diagnosis of von Willebrand disease (VWD) is difficult due to the wide spectrum of clinical phenotypes associated with this disorder. We have analysed and characterized haemostatic function in VWD patients using a microchip-based flow chamber system. Microchips coated with either collagen [platelet (PL)-chip] or collagen/thromboplastin [atherome (AR)-chip] were used to evaluate platelet thrombus formation at 1000 s(-1) and fibrin-rich platelet thrombus formation at 240 s(-1) respectively. Blood samples from an asymptomatic patient with VWD type 1 [von Willebrand factor (VWF): RCo 3.2%; bleeding score (BS 2] displayed normal thrombus formation in both PL- and AR-chips, whereas blood from a symptomatic type 1 patient (VWF: RCo 14%, BS 9) had significantly delayed capillary occlusion. Nearly complete suppression of the flow pressure increase was observed in symptomatic patients with VWD type 2A (BS 13) and 2N (BS 27), whereas no flow pressure was found for the type 3 patient (BS 6). Fibrin-rich platelet thrombus formation was only weakly increased by the in vitro addition of factor VIII (FVIII) to blood samples from the type 3 patient, but was normalized by the addition of VWF/FVIII. The in vivo effects of treatment with desmopressin or VWF/FVIII for the symptomatic patients were analysed using two types of microchips. The PL-chip was highly sensitive for patients' VWF-mediated platelet functions, whereas the AR-chip allowed assessment of overall haemostatic ability, including sensitivity to both VWF and FVIII. The combined analysis with PL- and AR-chips may be potentially useful for the diagnosis of VWD based on clinical phenotypes, and for monitoring drug effects. PMID- 25545302 TI - Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype. AB - Rare bleeding disorders (RBDs) comprise 3-5% of all congenital bleeding disorders. They can evade typical coagulation screening tests and there is a poor correlation between laboratory results and bleeding phenotype. Thromboelastography (TEG) measures coagulation globally in whole blood samples. The aims of this study were to evaluate the utility of TEG as an adjunct to the routine screening tests employed for the diagnosis of RBDs and to correlate TEG results with the bleeding phenotype in RBDs. TEG parameters and clot kinetics were compared to bleeding phenotypes (asymptomatic, mild, moderate and severe) in 26 RBD patients and 30 normal controls. Clot kinetics correlated strongly with RBDs and with the severity of bleeding phenotype with mean maximum rate of thrombus generation (MRTG) 15.4 mm min(-1) in controls vs. 6.0 in RBDs (P < 0.0001, Wilcoxin). The mean MRTG was 7.7 in mildly symptomatic, 5.5 in moderately symptomatic and 4.1 in severely symptomatic patients (P < 0.0001, Kruskal Wallis). Disorders that are often missed by conventional screening tests, dysfibrinogenaemia and platelet disorders displayed a distinctive TEG curve with markedly decreased maximum amplitude (MA) and low MRTG values. Factor XIII and PAI deficient patients displayed increased fibrinolysis in addition to low MRTGs. All patients with RBDs, but none of the normal controls, had abnormal clot kinetics suggesting that TEG may be an effective screening test for RBDs. PMID- 25545304 TI - External fixators for open fractures of tibia and fibula in patients with haemophilia A. AB - To evaluate the efficacy of external fixators(EFs) for management of open fractures of tibia and fibula in patients with haemophilia A. EFs are commonly used in the clinical management of infected or open fractures when internal fixation is contraindicated and plaster immobilization is inadequate. However, EFs have not been frequently used for these indications in haemophilic patients for fear of pin tract infection and bleeding. This is a retrospective therapeutic study. We describe the use of EF (Orthofix uniplanar fixators) in five patients (mean age: 31.4 years; range: 10-52) with haemophilia A suffering from open fracture of tibia and fibula (Gustilo classification ranging from II to IIIA). The average time to union was 23 weeks (range: 18-30 weeks). Much lower levels were subsequently maintained till wound healing. The average total factor consumption was 358.30 IU kg(-1) (range: 272-421 IU kg(-1) ), administered over a period of 14.2 days (range 9-21). There were no major complications related to EF. In summary, EFs can be used safely and effectively in management of open fractures of tibia and fibula in patients with haemophilia A. PMID- 25545303 TI - Long-term follow up of HIV-1-infected Korean haemophiliacs, after infection from a common source of virus. AB - In the early 1990s, 20 haemophiliacs (HPs) were infected with a common source of HIV-1 viruses through the contaminated clotting factor IX. The aim of this study is to review 20 HPs infected with a common source of virus. The enrolled patients have been consecutively treated with Korean red ginseng (KRG), zidovudine (ZDV) or two-drug therapy and highly active antiretroviral therapy (HAART). We determined full-length pol gene over 20 years and human leukocyte antigen (HLA) class I with peripheral blood mononuclear cells and reviewed medical records. Eighteen HPs experienced various opportunistic infections or clinical manifestations. There were significant inverse correlations between the HLA prognostic score and the annual decrease in CD4+ T-cell counts prior to HAART (AD) (P < 0.05) and the amount of KRG and the AD (P < 0.01). From 1998, the HPs had been treated with HAART. Each of the two patients died without and with HAART regimen respectively. At present, 16 HPs have been alive with HAART. Among the 16 HPs, 12 and 4 are on HAART-plus-KRG and HAART only respectively. Eleven HPs including 2 HPs with G-to-A hypermutations had revealed resistance mutations. Ten and two HPs have shown poor adherence and incomplete viral suppres-sion on HAART respectively. Virological failure based on WHO guidelines was not observed on KRG plus-HAART. Two HPs revealed additional resistance mutations against two classes on KRG-plus-HAART. As a nationwide study, we first report overall features on clinical course of Korean haemophiliacs. Further education on the importance of drug adherence is needed. PMID- 25545305 TI - USPIO-related T1 and T2 mapping MRI of cartilage in a rabbit model of blood induced arthritis: a pilot study. AB - Ultrasmall paramagnetic iron oxide (USPIO)-enhanced MRI is promising for evaluating inflammation. The aims of this study were to investigate the effect of USPIO on cartilage T1 and T2 mapping, and to evaluate a proposed rapid vs. conventional T2 map method for imaging cartilage in a blood-induced arthritis model. Knees of nine arthritic (induction by intra-articular autologous blood injection) and six control rabbits were imaged over time (baseline, weeks 1, 5, 10) by 1.5 T MRI. All rabbits had USPIO (35-75 MUmol Fe/kg)-enhanced MRI at each time point. T1 and T2 (conventional and rapid) maps and signal-to-noise ratios (SNR) were obtained pre- and post-USPIO administration. Cartilage biochemistry and histology were compared with MRI. Excellent correlations were noted between T1 map values and histologic scores at week 10 pre-USPIO (medial, r = 0.93, P = 0.0007; lateral, r = 0.87, P = 0.005) in the arthritic group, but not between T2 map and histology. Marginally and significant differences were observed between pre- and post-USPIO T2 values at weeks 5 (P = 0.06) and 10 (P = 0.02), but only with the administration of high USPIO doses in the arthritic group using the conventional method. No significant differences were noted between pre- and post USPIO T1 values at any imaging time points. Cartilage T2 maps with short-TR and conventional protocols provided similar T2 values [(decreased trend)] (P > 0.05). Concomitant use of USPIO to T1 and T2 mapping of cartilage would not impair the identification of interval changes of T1 and T2 maps. Rapid T2 map provides similar results compared to conventional method, but its validation warrants further investigation. PMID- 25545306 TI - Nitrogen-doped graphene aerogels as efficient supercapacitor electrodes and gas adsorbents. AB - Nitrogen-doped graphene has been demonstrated to be an excellent multifunctional material due to its intriguing features such as outstanding electrocatalytic activity, high electrical conductivity, and good chemical stability as well as wettability. However, synthesizing the nitrogen-doped graphene with a high nitrogen content and large specific surface area is still a challenge. In this study, we prepared a nitrogen-doped graphene aerogel (NGA) with high porosity by means of a simple hydrothermal reaction, in which graphene oxide and ammonia are adopted as carbon and nitrogen source, respectively. The microstructure, morphology, porous properties, and chemical composition of NGA were well disclosed by a variety of characterization methods, such as scanning electron microscopy, nitrogen adsorption-desorption measurements, X-ray photoelectron spectroscopy, and Raman spectroscopy. The as-made NGA displays a large Brunauer Emmett-Teller specific surface area (830 m(2) g(-1)), high nitrogen content (8.4 atom %), and excellent electrical conductivity and wettability. On the basis of these features, the as-made NGA shows superior capacitive behavior (223 F g(-1) at 0.2 A g(-1)) and long-term cycling performance in 1.0 mol L(-1) H2SO4 electrolyte. Furthermore, the NGA also possesses a high carbon dioxide uptake capacity at 1.0 bar and 273 K (11.3 wt %). PMID- 25545307 TI - Vaccine-induced pityriasis rosea and pityriasis rosea-like eruptions: a review of the literature. PMID- 25545308 TI - Computed tomographic pneumocolonography in normal dogs. AB - Objectives of this prospective study were to describe effects of varying technical components that may contribute to an optimal protocol for computed tomographic pneumocolonography (CTP) in dogs, and to develop a standardized methodology for CTP as a future potential diagnostic tool in canine clinical patients with large bowel disease. Eight purpose-bred intact male hound cross research dogs were enrolled and randomized to groups based on variables of pressure/body position (n = 4) and insufflation time (n = 4). For each segment of large bowel (rectum, colorectal junction, descending colon, transverse colon, ascending colon), the adequacy of bowel preparation, % of bowel lumen filled with fecal material, and bowel tortuosity or folding were assessed. Measurements of bowel wall thickness (cm), cross-sectional bowel lumen diameter (cm), and cross sectional bowel luminal area (cm(2) ) were obtained at standardized locations within the large bowel. False discovery rates (FDR) were calculated to adjust for multiple testing. Values of FDR < 0.05 were considered significant. Differences in mean cross-sectional area and diameter and bowel wall thickness under increasing pressure were not significant after adjusting for multiple testing; some had raw p values <0.05. Ascending colon diameter and ascending colon area significantly increased with insufflation time (FDR < 0.05). No other response variables showed a significant change with insufflation time. The optimal insufflation pressure for maintaining pneumocolon in this study was determined to be 20 mmHg. CTP is a feasible technique to provide consistent distension for imaging of the large bowel and further study on application of CTP in clinical patients is warranted. PMID- 25545309 TI - Serum anti-Mullerian hormone and ovarian morphology assessed by magnetic resonance imaging in response to acupuncture and exercise in women with polycystic ovary syndrome: secondary analyses of a randomized controlled trial. AB - OBJECTIVE: To investigate whether electro-acupuncture or physical exercise influence serum anti-Mullerian hormone (AMH), antral follicle count (AFC) or ovarian volume in women with polycystic ovary syndrome (PCOS). DESIGN: Secondary analyses of a prospective, randomized controlled clinical trial. SETTING: University Hospital, Sweden. PATIENTS: Seventy-four women with PCOS recruited from the general population. INTERVENTIONS: Women with PCOS were randomized to 16 weeks of electro-acupuncture (14 treatments), exercise (at least three times/week), or no intervention. MAIN OUTCOME MEASURES: Serum AMH recorded at baseline, after 16 weeks of intervention, and at follow up at 32 weeks. AFC, and ovarian volume assessed by magnetic resonance imaging at baseline and at follow up at 32 weeks. RESULTS: After 16 weeks of intervention, serum levels of AMH were significantly decreased in the electro-acupuncture group by 17.5% (p < 0.001), and differed from the change in the exercise group. AMH remained decreased by 15% (p = 0.004) also at follow up at 32 weeks, but did not differ from the exercise or the no intervention groups. There was a decrease by 8.5% (p = 0.015) in ovarian volume between baseline and follow up in the electro-acupuncture group, and by 11.7% (p = 0.01) in AFC in the physical exercise group. No other variables were affected. CONCLUSIONS: This study is the first to demonstrate that acupuncture reduces serum AMH levels and ovarian volume. Physical exercise did not influence circulating AMH or ovarian volume. Despite a within-group decrease in AFC, exercise did not lead to a between-group difference. PMID- 25545310 TI - A new class of cuprous bromide cluster-based hybrid materials: direct observation of the stepwise replacement of hydrogen bonds by coordination bonds. AB - Although a variety of functional metal-organic frameworks (MOFs) have been synthesized, post-modified, and applied in various areas, there is little knowledge about how molecular cluster building units are stepwise evolved into MOFs via intermediates. Coordination bonds are generally stronger than hydrogen bonds, and thus equivalent replacement of X-H...Y hydrogen bonds by X-M-Y coordination bonds can transform hydrogen bond networks into MOFs. In this work, solvothermal in situ reduction reactions of CuBr2 and 1,4 diazoniabicyclo[2,2,2]octane (DABCO) generated a myriad of tunable photoluminescent cuprous body-centered cubic bromide cluster-based networks with the general formula [Cu4+xH4-xBr6(DABCO)4](HCO2)2.S (x = 0, 0.56, 0.81, 1.27, 1.39, 2.56, 2.78, and 4 for compounds 1-8, respectively). All of these compounds crystallize in the cubic space group with the largest volume difference being only 5.2%, but they belong to three remarkably different kinds of crystals. Complex 1 is a molecular crystal and consists of tetrahedral [Cu4Br6(HDABCO)4](2+) clusters with monodentate HDABCO groups that are supported via N-H...Br synthons in the hydrogen bond network. Compound 8 is a [Cu8Br6](2+) cube cluster-based MOF with bridged DABCO ligands. Complexes 2-7 are seemingly impossible Cu/H-substituted solid solutions of 1 and 8. The CuBr framework components in 1-8 are Cu4Br6, Cu4.56Br6, Cu4.81Br6, Cu5.27Br6, Cu5.39Br6, Cu6.56Br6, Cu6.78Br6, and Cu8Br6, respectively. Crystallization kinetics studies revealed that the [Cu4Br6(HDABCO)4](2+) cluster-based hydrogen bond network (1) was initially formed such that N-H...Br hydrogen bonds could be stepwise replaced by N-Cu-Br coordination bonds to form the [Cu8Br6](2+) cube cluster-based MOF (8) via solid solutions. These observations directly reveal the equivalence and transformation between the N-H...Br hydrogen bond and the N-Cu-Br coordination bond and the evolutionary mechanism of a molecular crystal to a MOF via solid solutions, which is of fundamental importance in materials but has never before been revealed. DFT calculations suggest that equivalent replacement of a N-H...Br hydrogen bond by a N-Cu-Br coordination bond is exothermic and exergonic, which also supports the transformation from molecule 1 to MOF 8. PMID- 25545312 TI - First identification of the herpes simplex virus by skin-dedicated ex vivo fluorescence confocal microscopy during herpetic skin infections. AB - BACKGROUND: Skin-dedicated ex vivo fluorescence confocal microscopy (FCM) has so far been used to identify cutaneous tumours on freshly excised samples using acridine orange as fluorochrome. AIM: To use FCM for a new indication, namely, the identification of the herpes simplex virus (HSV) in skin lesions, using fluorescent antibodies. METHODS: Six roof samples from skin vesicles suspicious for HSV lesions were incubated with anti-HSV-1 and anti-HSV-2 antibodies coupled with fluorescein isothiocyanate, and examined under skin-dedicated ex vivo FCM. The positive controls were swabs taken from the floor of each vesicle and observed under conventional direct fluorescence assay (DFA) and by viral cultures. Roof samples from three bullae of bullous pemphigoid were the negative controls. RESULTS: Using ex vivo FCM, the samples from the lesions clinically suspicious for HSV infection were seen to be fluorescent after incubation with anti-HSV-1, and were negative after incubation with anti-HSV-2 antibodies. Conventional DFA with an optical microscope and cultures confirmed the presence of HSV-1 infection. CONCLUSIONS: By using fluorescent antibodies to identify precise structures, ex vivo FCM can be used for indications other than tumour identification. More specifically, it can be an additional diagnostic tool for HSV infection. PMID- 25545311 TI - Complete Sequence of Four Multidrug-Resistant MOBQ1 Plasmids Harboring blaGES-5 Isolated from Escherichia coli and Serratia marcescens Persisting in a Hospital in Canada. AB - The usefulness of carbapenems for gram-negative infections is becoming compromised by organisms harboring carbapenemases, enzymes which can hydrolyze the drug. Currently KPC (class A), NDM (class B), and OXA-48 types (class D) are the most globally widespread carbapenemases. However, among the GES-type class A extended-spectrum beta-lactamases (ESBLs) there are variants that hydrolyze carbapenems, with blaGES-5 being the most common. Two Escherichia coli and two Serratia marcescens harboring blaGES-5 on plasmids were isolated by the Canadian Nosocomial Infection Surveillance Program (CNISP) from four different patients in a single hospital over a 2-year period. Complete sequencing of the blaGES-5 plasmids indicated that all four had nearly identical backbones consisting of genes for replication, partitioning, and stability, but contained variant accessory regions consisting of mobile elements and antimicrobial resistance genes. The plasmids were of a novel replicon type, but belonged to the MOBQ1 group based on relaxase sequences, and appeared to be mobilizable, but not self transmissible. Considering the time periods of bacterial isolation, it would appear the blaGES-5 plasmid has persisted in an environmental niche for at least 2 years in the hospital. This has implications for infection control and clinical care when it is transferred to clinically relevant gram-negative organisms. PMID- 25545313 TI - Deproteinized bovine bone remodeling pattern in alveolar socket: a clinical immunohistological evaluation. AB - OBJECTIVES: Considering the low rate of deproteinized bovine bone (DBB) graft resorption in vivo and vitro, the aim of this study was to investigate, through an immunohistochemical method, DBB remodeling patterns in human. MATERIAL AND METHODS: Socket preservation, a highly documented and affirmed technique, was selected as the best in vitro model to analyze DBB effect on bone remodeling. Following premolar extraction (T0), 20 patients were randomized into two treatment groups. In the test group (t), the alveolar sockets were grafted with DBB, while in the control group (c) no bone graft was applied and the alveolar sockets were left to heal spontaneously. After 5 months, a re-entry procedure was performed, and one implant was placed according to manufacturer's protocols (T1). Bone biopsies were harvested for each patient both at T0 and at T1. On the bone samples, immunohistochemical investigations were performed to analyze BMP-2, BMP 7, ALP, IL-6, TNF-alpha expression. RESULTS: Bone morphogenetic proteins were more expressed in the control group than in the test group (BMP-2: P < 0.001; BMP 7: P = 0.017), while TNF-alpha value was larger in the test group (P < 0.001); no statistically significant differences were observed for the other markers. When considering time as the main variable, statistically significant differences were found for BMP-2 (P < 0.001), BMP-7 (P < 0.001), IL-6 (P < 0.001), ALP (P < 0.05), and TNF-alpha (P < 0.001). Significant interaction between groups and time was found for BMP-2 (P < 0.001), BMP-7 (P < 0.001), TNF-alpha (P < 0.001). CONCLUSIONS: Deproteinized bovine bone guarantees the activity of bone remodeling processes in human extraction socket at 5 months of healing, bringing to a higher expression of anabolic and catabolic bone markers. PMID- 25545314 TI - Local tolerance and systemic toxicity of single and repeated intramuscular administrations of two different formulations of the RTS,S malaria candidate vaccine in rabbits. AB - RTS,S malaria antigen is weakly immunogenic as such and needs to be formulated with an adjuvant to improve the magnitude and duration of the immune responses to RTS,S. Two Adjuvant Systems, AS01 and AS02 were evaluated during the development of the RTS,S vaccine. The evaluation included non-clinical studies in rabbits to evaluate the local intramuscular tolerance following administration on a single occasion, and the local and systemic effects following repeated administrations of RTS,S/AS01 or RTS,S/AS02 formulations. In the first study, rabbits were injected on one occasion with RTS,S/AS01, RTS,S/AS02 or controls, and the local intramuscular tolerance was evaluated up to 3 days after injection. In the second study, the different formulations were injected on Days 0, 14, 28 and 42. General health status, haematology and blood chemistry parameters were monitored on a regular basis. Macroscopic and microscopic evaluations were made after termination of the study. No sign of toxicity was detected following single or repeated administrations of the adjuvanted RTS,S formulations. Changes in haematology or clinical chemistry parameters were indicative of a developing immune response in the groups receiving either RTS,S formulation. All examined parameters returned to normal within 28 days after the last injection. The absence of toxicological effects following the injection of RTS,S/AS01 or RTS,S/AS02 in rabbits was supportive of further clinical evaluation of these two formulations. PMID- 25545315 TI - (Q)SAR assessments of potentially mutagenic impurities: a regulatory perspective on the utility of expert knowledge and data submission. AB - (Quantitative) structure activity relationship [(Q)SAR] modeling is the primary tool used to evaluate the mutagenic potential associated with drug impurities. General recommendations regarding the use of (Q)SAR in regulatory decision making have recently been provided in the ICH M7 guideline. Although (Q)SAR alone is capable of achieving reasonable sensitivity and specificity, reliance on a simple positive or negative prediction can be problematic. The key to improving (Q)SAR performance is to integrate supporting information, also referred to as expert knowledge, into the final conclusion. In the regulatory context, expert knowledge is intended to (1) maximize confidence in a (Q)SAR prediction, (2) provide rationale to supersede a positive or negative (Q)SAR prediction, or (3) provide a basis for assessing mutagenicity in absence of a (Q)SAR prediction. Expert knowledge is subjective and is associated with great variability in regards to content and quality. However, it is still a critical component of impurity evaluations and its utility is acknowledged in the ICH M7 guideline. The current paper discusses the use of expert knowledge to support regulatory decision making, describes case studies, and provides recommendations for reporting data from (Q)SAR evaluations. PMID- 25545316 TI - Lead isotope profiling in dairy calves. AB - Lead (Pb) is a common cause of heavy metal poisonings in cattle. Sources of Pb on farms include crankcase oil, machinery grease, batteries, plumbing, and paint chips. Consequently, consumption of Pb from these sources may negatively impact animal health and Pb may be inadvertently introduced into the food supply. Therefore, the scope of poisoning incidents must be clearly assessed and sources of intoxication identified and strategies to mitigate exposure evaluated and implemented to prevent future exposures. Stable isotope analysis by inductively coupled plasma mass spectrometry (ICP-MS) has proven itself of value in forensic investigations. We report on the extension of Pb stable isotope analysis to bovine tissues and profile comparisons with paint chips and soils collected from an affected dairy farm to elucidate the primary source. Pb occurs naturally as four stable isotopes: (204)Pb, (206)Pb, (207)Pb, and (208)Pb. Herein a case is reported to illustrate the use of (207)Pb/(206)Pb and (208)Pb/(206)Pb ratios to link environmental sources of exposure with tissues from a poisoned animal. Chemical Pb profiling provides a valuable tool for field investigative approaches to Pb poisoning in production agriculture and is applicable to subclinical exposures. PMID- 25545317 TI - Purification, characterization and safety assessment of the introduced cold shock protein B in DroughtGard maize. AB - DroughtGard maize was developed through constitutive expression of cold shock protein B (CSPB) from Bacillus subtilis to improve performance of maize (Zea mays) under water-limited conditions. B. subtilis commonly occurs in fermented foods and CSPB has a history of safe use. Safety studies were performed to further evaluate safety of CSPB introduced into maize. CSPB was compared to proteins found in current allergen and protein toxin databases and there are no sequence similarities between CSPB and known allergens or toxins. In order to validate the use of Escherichia coli-derived CSPB in other safety studies, physicochemical and functional characterization confirmed that the CSPB produced by DroughtGard possesses comparable molecular weight, immunoreactivity, and functional activity to CSPB produced from E. coli and that neither is glycosylated. CSPB was completely digested with sequential exposure to pepsin and pancreatin for 2 min and 30 s, respectively, suggesting that CSPB will be degraded in the mammalian digestive tract and would not be expected to be allergenic. Mice orally dosed with CSPB at 2160 mg/kg, followed by analysis of body weight gains, food consumption and clinical observations, showed no discernible adverse effects. This comprehensive safety assessment indicated that the CSPB protein from DroughtGard is safe for food and feed consumption. PMID- 25545318 TI - Impairment of host resistance to helminthes with age in murine small intestine. AB - Age-associated alterations of Th2 immune responses against nematode parasites are largely unknown. We investigated primary and memory responses against two types of gastrointestinal nematode parasites, Heligmosomoides polygyrus (Hp) and Nippostrongylus brasiliensis (Nb), in aged mice. The small intestinal gene expression of Th2 cytokines was almost unchanged after primary (Nb and Hp) and secondary infection (Hp) in aged mice in contrast to strongly increased small intestinal gene expression of Th2 cytokines in young (3-month-old) mice. Mucus production decreased (Nb), and worm expulsion was impaired (Nb and Hp) compared with the young mice. Immunofluorescent staining revealed that after Hp infection, the number of alternatively activated macrophages, which are induced by Th2 cytokines, was lower in the aged mice. On the other hand, the number of CD4(+) T cells recruited to the worm cysts was normal compared with the young mice. These results suggest that migration of CD4(+) T cells to the host-parasite interface is not affected by ageing. Alterations in Th2 immune responses in aged mice might be due to inappropriate or insufficient activation of CD4(+) T cells in the submucosa. PMID- 25545319 TI - Results of laparoscopic radiofrequency ablation for HCC. Could the location of the tumour influence a complete response to treatment? A single European centre experience. AB - INTRODUCTION: In selected patients, radiofrequency ablation (RFA) is a well established treatment for hepatocellular carcinoma (HCC). However, subcapsular or lesions close to adjacent viscera preclude a percutaneous approach. In this setting laparoscopic-RFA (LRFA) is a potential alternative. The aim of this study was to analyse the safety and feasibility of LRFA in patients with HCC. PATIENTS AND METHODS: Retrospective study of patients with HCC meeting strict inclusion criteria who underwent LRFA at a single Institution from December 2000 to March 2013. RESULTS: Forty-one patients underwent 42 LRFA of 51 nodules. The median size of the nodule was 2.5 (range 1.2-4.7) cm. Thirty-one tumours were subcapsular and 17 located near the gallbladder. Major complications occurred in 17 patients. The initial complete response (ICR) rate was 94% and was lower among tumours located adjacent to the gallbladder. At the end of the follow-up period, the sustained complete response (SCR) rate was 70% and was lower in tumours adjacent to the gallbladder while increased for subcapsular tumours. The 1-, 3- and 5-year overall survival rate was 92.6%, 64.5% and 43%, respectively. CONCLUSION: LRFA of HCC is safe, feasible and achieves excellent results in selected patients. LRFA should be the first-line technique for subcapsular lesions as it minimizes the risk of tumoural seeding and improves ICR. Proximity to gallbladder interferes in treatment efficacy (lower rate of ICR and lower rate of SCR). PMID- 25545320 TI - Leukoderma in patients with atopic dermatitis. AB - Atopic dermatitis (AD) is occasionally associated with vitiligo, however, the incidence and conditions of vitiligo or leukoderma, and the characteristics of concurrent AD, remain unclear. We conducted a prospective observational study to investigate the leukoderma-related clinical manifestations and bioparameters of AD. Because vitiligo in AD lesions is occasionally associated with inflammation, we used leukoderma in this study. Enrolled were all AD patients who had been followed up in our AD outpatient clinic and visited within the previous 4 months. During this period, we carefully inspected whether the patients had leukoderma. Eight of 52 patients had leukoderma (15.4%) and were designated as the leukoderma group, and the remaining 44 patients comprised the non-leukoderma group. While the ages were statistically not different between the two groups, female preponderance was significantly observed in the leukoderma group. The leukoderma patients tended to have higher values of SCORAD, CCL17/thymus and activation regulated chemokine and lactate dehydrogenase than the non-leukoderma patients. The leukoderma group was also characterized by a lower frequency of allergic rhinitis and a higher frequency of prurigo lesions. Thus, despite the possession of high AD severity, the leukoderma patients may possibly retain a relatively T helper 1-skewing state in relation to the development of leukoderma and less association with rhinitis. PMID- 25545321 TI - The effect of latanoprost on vitiligo: a preliminary comparative study. AB - Latanoprost (LT), a prostaglandin F 2alpha (PGF2a ) analogue used in the treatment of glaucoma, was found to induce skin pigmentation in guinea pigs in addition to its known periocular and iridal pigmentation side effects. This study aims to evaluate the efficacy of topical LT in the induction of skin repigmentation in patients with vitiligo and to compare its potency with narrow band ultraviolet (UV) B (NB-UVB). The result of their combination was also assessed. This study involved 22 patients with bilateral and symmetrical vitiligo lesions, stable for the last three months, divided into three groups: group I, to evaluate LT vs. placebo; group II, to evaluate LT vs. NB-UVB; and group III, to evaluate the effect of their combination. The response to treatment was evaluated by taking photographic records of the treated lesions with follow-up photography every two weeks. After three months, assessment of the degree and extent of repigmentation was performed. Follow-up assessment was done six months after termination of the trial for the persistence of pigmentation, recurrence, or development of any side effects. LT was found to be better than placebo and comparable with the NB-UVB in inducing skin repigmentation. This effect was enhanced by the addition of NB-UVB. LT could be a promising treatment for vitiligo, especially the periocular variant. Its effect on skin repigmentation could be enhanced by NB-UVB exposure. PMID- 25545322 TI - Folate-decorated hydrophilic three-arm star-block terpolymer as a novel nanovehicle for targeted co-delivery of doxorubicin and Bcl-2 siRNA in breast cancer therapy. AB - To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer, [poly(l-glutamic acid gamma-hydrazide)-b-poly(N,N-dimethylaminopropyl methacrylamide)]3-g poly(ethylene glycol) ((PGAH-b-PDMAPMA)3-g-PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition-fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by (1)H NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ?4:1 to form "two-in-one" nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3 nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione: 10mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co delivery of doxorubicin and therapeutic siRNA in cancer therapy. PMID- 25545323 TI - Injectable biodegradable hybrid hydrogels based on thiolated collagen and oligo(acryloyl carbonate)-poly(ethylene glycol)-oligo(acryloyl carbonate) copolymer for functional cardiac regeneration. AB - Injectable biodegradable hybrid hydrogels were designed and developed based on thiolated collagen (Col-SH) and multiple acrylate containing oligo(acryloyl carbonate)-b-poly(ethylene glycol)-b-oligo(acryloyl carbonate) (OAC-PEG-OAC) copolymers for functional cardiac regeneration. Hydrogels were readily formed under physiological conditions (37 degrees C and pH 7.4) from Col-SH and OAC-PEG OAC via a Michael-type addition reaction, with gelation times ranging from 0.4 to 8.1 min and storage moduli from 11.4 to 55.6 kPa, depending on the polymer concentrations, solution pH and degrees of substitution of Col-SH. The collagen component in the hybrid hydrogels retained its enzymatic degradability against collagenase, and the degradation time of the hydrogels increased with increasing polymer concentration. In vitro studies showed that bone marrow mesenchymal stem cells (BMSCs) exhibited rapid cell spreading and extensive cellular network formation on these hybrid hydrogels. In a rat infarction model, the infarcted left ventricle was injected with PBS, hybrid hydrogels, BMSCs or BMSC encapsulating hybrid hydrogels. Echocardiography demonstrated that the hybrid hydrogels and BMSC-encapsulating hydrogels could increase the ejection fraction at 28 days compared to the PBS control group, resulting in improved cardiac function. Histology revealed that the injected hybrid hydrogels significantly reduced the infarct size and increased the wall thickness, and these were further improved with the BMSC-encapsulating hybrid hydrogel treatment, probably related to the enhanced engraftment and persistence of the BMSCs when delivered within the hybrid hydrogel. Thus, these injectable hybrid hydrogels combining intrinsic bioactivity of collagen, controlled mechanical properties and enhanced stability provide a versatile platform for functional cardiac regeneration. PMID- 25545324 TI - A novel automated detection system for swallowing sounds during eating and speech under everyday conditions. AB - The wave analysis of swallowing sounds has been receiving attention because the recording process is easy and non-invasive. However, up until now, an expert has been needed to visually examine the entire recorded wave to distinguish swallowing from other sounds. The purpose of this study was to establish a methodology to automatically distinguish the sound of swallowing from sound data recorded during a meal in the presence of everyday ambient sound. Seven healthy participants (mean age: 26.7 +/- 1.3 years) participated in this study. A laryngeal microphone and a condenser microphone attached to the nostril were used for simultaneous recording. Recoding took place while participants were taking a meal and talking with a conversational partner. Participants were instructed to step on a foot pedal trigger switch when they swallowed, representing self enumeration of swallowing, and also to achieve six additional noise-making tasks during the meal in a randomised manner. The automated analysis system correctly detected 342 out of the 352 self-enumerated swallowing events (sensitivity: 97.2%) and 479 out of the 503 semblable wave periods of swallowing (specificity: 95.2%). In this study, the automated detection system for swallowing sounds using a nostril microphone was able to detect the swallowing event with high sensitivity and specificity even under the conditions of daily life, thus showing potential utility in the diagnosis or screening of dysphagic patients in future studies. PMID- 25545325 TI - Signal transducer and activator of transcription 1 (STAT-1) plays a critical role in control of Trypanosoma cruzi infection. AB - The control of Trypanosoma cruzi infection is related to interferon-gamma (IFN gamma) activation leading to intracellular clearance of parasites. The transcription factor signal transducer and activator of transcription 1 (STAT-1) is a key mediator of IFN-gamma intracellular signalling and knockout of this protein leads to susceptibility to several intracellular microbes. To determine the role of STAT-1 in host susceptibility to T. cruzi infection we compared the survival, parasite loads and balance of IFN-gamma and interleukin-10 (IL-10) responses between wild-type and STAT-1 knockout mice. We found that the lack of STAT-1 resulted in a more robust infection, leading to higher levels of blood and tissue parasites and markedly reduced survival. In addition, infected STAT-1 knockout mice had higher systemic levels of both IFN-gamma and IL-10, suggesting that the absence of STAT-1 leads to a disequilibrium of pro-inflammatory and anti inflammatory cytokines. Analysis of spleen cells indicates that CD4, CD8 cells generate IFN-gamma and natural killer cells express IL-13 in STAT-1 knockout animals. The production of IL-17 is particularly enhanced in the absence STAT-1 expression but did not reduce mortality. Overall these results indicate that STAT 1 is important for the control of T. cruzi infection in mice. PMID- 25545327 TI - Design and synthesis of novel 19F-amino acid: a promising 19F NMR label for peptide studies. AB - Novel aliphatic (19)F-substituted amino acid was designed as a (19)F NMR label for peptide studies. The synthesis was performed in 11 steps and 9% overall yield from a commercially available starting material. The key transformation was a decarboxylative fluorination of an aliphatic carboxylic acid with XeF2 in C6F6. PMID- 25545326 TI - Overexpression of a NAC transcription factor delays leaf senescence and increases grain nitrogen concentration in wheat. AB - Increasing the duration of leaf photosynthesis during grain filling using slow senescing functional stay-green phenotypes is a possible route for increasing grain yields in wheat (Triticum aestivum L.). However, delayed senescence may negatively affect nutrient remobilisation and hence reduce grain protein concentrations and grain quality. A novel NAC1-type transcription factor (hereafter TaNAC-S) was identified in wheat, with gene expression located primarily in leaf/sheath tissues, which decreased during post-anthesis leaf senescence. Expression of TaNAC-S in the second leaf correlated with delayed senescence in two doubled-haploid lines of an Avalon * Cadenza population (lines 112 and 181), which were distinct for leaf senescence. Transgenic wheat plants overexpressing TaNAC-S resulted in delayed leaf senescence (stay-green phenotype). Grain yield, aboveground biomass, harvest index and total grain N content were unaffected, but NAC over-expressing lines had higher grain N concentrations at similar grain yields compared to non-transgenic controls. These results indicate that TaNAC-S is a negative regulator of leaf senescence, and that delayed leaf senescence may lead not only to increased grain yields but also to increased grain protein concentrations. PMID- 25545328 TI - Concordance of Noncarcinogenic Endpoints in Rodent Chemical Bioassays. AB - Prediction of noncancer toxicologic outcomes in rodent bioassays of 37 chemicals from the National Toxicology Program was evaluated. Using the nonneoplastic lesions noted by NTP pathologists, we evaluate both agreement in toxic lesions across experiments and the predictive value of the presence (or absence) of a lesion in one group for other groups. We compare lesions between mice and rats, male mice and male rats, and female mice and female rats in both short-term and long-term bioassays. We also examine whether lesions found in a specific organ in a short-term test are also found in the long-term test of the same chemical. We find agreement (concordance) across species for specific lesions, as evaluated by the Kappa statistic, ranging from 0.58 (for concordance of nasal lesions between female mice and rats in long-term studies) to -0.14 (lung lesions between mice and rats in long-term studies). Predictive values are limited by the relatively small numbers of observations of each type of lesion. Positive predictive values range from 100% to 0%. Comparing the lesions found in short-term tests to those found in long-term tests resulted in Kappa statistic values from 0.76 (spleen lesions in male rats) to -0.61 (lung lesions in female mice). Positive predictive values of short-term tests for long-term tests range from 70% to 0%. Overall, there is considerable uncertainty in predicting the site of toxic lesions in different species exposed to the same chemical and from short-term to long-term tests of the same chemical. PMID- 25545329 TI - Activity-associated effect of LDL receptor missense variants located in the cysteine-rich repeats. AB - BACKGROUND: The LDL receptor (LDLR) is a Class I transmembrane protein critical for the clearance of cholesterol-containing lipoprotein particles. The N-terminal domain of the LDLR harbours the ligand-binding domain consisting of seven cysteine-rich repeats of approximately 40 amino acids each. Mutations in the LDLR binding domain may result in loss of receptor activity leading to familial hypercholesterolemia (FH). In this study the activity of six mutations located in the cysteine-rich repeats of the LDLR has been investigated. METHODS: CHO-ldlA7 transfected cells with six different LDLR mutations have been used to analyse in vitro LDLR expression, lipoprotein binding and uptake. Immunoblotting of cell extracts, flow cytometry and confocal microscopy have been performed to determine the effects of these mutations. In silico analysis was also performed to predict the mutation effect. RESULTS AND CONCLUSION: From the six mutations, p.Arg257Trp turned out to be a non-pathogenic LDLR variant whereas p.Cys116Arg, p.Asp168Asn, p.Asp172Asn, p.Arg300Gly and p.Asp301Gly were classified as binding-defective LDLR variants whose effect is not as severe as null allele mutations. PMID- 25545330 TI - Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis. AB - OBJECTIVE: Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. METHODS: High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F):Stat3(-/+):ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F):ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed. RESULTS: Aortic plaque development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) mice were significantly reduced (3 fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F):ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/ ) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) and gp130(F/F):Stat3(-/+):ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F):Stat3(-/+):ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F):ApoE(-/-) (ApoE(F/F:ApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells. CONCLUSIONS: Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques. PMID- 25545332 TI - Photocatalytic antibacterial activity of nano-TiO2 (anatase)-based thin films: effects on Escherichia coli cells and fatty acids. AB - Titanium dioxide is a photocatalyst with well-known ability to oxidise a wide range of organic contaminants as well as to destroy microbial cells. In the present work TiO2 nanoparticles with high specific surface area (150m(2)/g) were used to prepare nanostructured films. The TiO2 nanoparticle-based film in combination with UV-A illumination with intensity (22W/m(2)) comparable to that of the sunlight in the UV-A region was used to demonstrate light-induced antibacterial effects. Fast and effective inactivation of Escherichia coli cells on the prepared thin films was observed. Visualization of bacterial cells under scanning electron microscopy (SEM) showed enlargement of the cells, distortion of cellular membrane and possible leakage of cytoplasm after 10min of exposure to photoactivated TiO2. According to the plate counts there were no viable cells as early as after 20min of exposure to UV-A activated TiO2. In parallel to effects on bacterial cell viability and morphology, changes in saturated and unsaturated fatty acids - important components of bacterial cell membrane-were studied. Fast decomposition of saturated fatty acids and changes in chemical structure of unsaturated fatty acids were detected. Thus, we suggest that peroxidation and decomposition of membrane fatty acids could be one of the factors contributing to the morphological changes of bacteria observed under SEM, and ultimately, cell death. PMID- 25545331 TI - A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. AB - BACKGROUND: Coenzyme Q10 (CoQ10) supplementation is the most popular therapy for statin myalgia among both physicians and patients despite limited and conflicting evidence of its efficacy. OBJECTIVE: This study examined the effect of coenzyme Q10 (CoQ10) supplementation on simvastatin-associated muscle pain, muscle strength and aerobic performance in patients with confirmed statin myalgia. METHODS: Statin myalgia was confirmed in 120 patients with prior symptoms of statin myalgia using an 8-week randomized, double-blind crossover trial of simvastatin 20 mg/d and placebo. Forty-one subjects developed muscle pain with simvastatin but not with placebo and were randomized to simvastatin 20 mg/d combined with CoQ10 (600 mg/d ubiquinol) or placebo for 8 weeks. Muscle pain (Brief Pain Inventory [BPI]), time to pain onset, arm and leg muscle strength, and maximal oxygen uptake (VO2max) were measured before and after each treatment. RESULTS: Serum CoQ10 increased from 1.3 +/- 0.4 to 5.2 +/- 2.3 mcg/mL with simvastatin and CoQ10, but did not increase with simvastatin and placebo (1.3 +/- 0.3 to 0.8 +/- 0.2) (p < 0.05). BPI pain severity and interference scores increased with simvastatin therapy (both p < 0.01), irrespective of CoQ10 assignment (p = 0.53 and 0.56). There were no changes in muscle strength or VO2max with simvastatin with or without CoQ10 (all p > 0.10). Marginally more subjects reported pain with CoQ10 (14 of 20 vs 7 of 18; p = 0.05). There was no difference in time to pain onset in the CoQ10 (3.0 +/- 2.0 weeks) vs. placebo (2.4 +/- 2.1 wks) groups (p = 0.55). A similar lack of CoQ10 effect was observed in 24 subjects who were then crossed over to the alternative treatment. CONCLUSIONS: Only 36% of patients complaining of statin myalgia develop symptoms during a randomized, double-blind crossover of statin vs placebo. CoQ10 supplementation does not reduce muscle pain in patients with statin myalgia. Trial RegistrationNCT01140308; www.clinicaltrials.gov. PMID- 25545333 TI - C-MYC and C-FOS expression changes and cellular aspects of the photodynamic reaction with photosensitizers TMPyP and ClAlPcS2. AB - Photodynamic therapy (PDT) is based on the tumor-selective accumulation of photosensitizer followed by irradiation with light of an appropriate wavelength. After irradiation and in the presence of oxygen, photosensitizer induces cellular damage. The aim of this study was to evaluate effects of two photosensitizers TMPyP and ClAlPcS2 on cell lines to obtain better insight into their mechanisms of action. We determined cell viability, reactive oxygen species (ROS) generation and changes in expression levels of two important early response genes, C-MYC and C-FOS, on tumor MCF7 (human breast adenocarcinoma) and G361 (human melanoma) cell lines and non-tumor BJ cell line (human fibroblast) after photodynamic reaction with TMPyP and ClAlPcS2 as photosensitizers. In addition TMPyP and ClAlPcS2 cellular uptake and clearance and antioxidant capacity of the mentioned cell lines were investigated. We found appropriate therapeutic doses and confirmed that both tested photosensitizers are photodynamically efficient in treatment used cells in vitro. TMPyP is more efficient; it had higher ROS production and toxicity after irradiation by intermediate therapeutic doses than ClAlPcS2. We revealed that both TMPyP and ClAlPcS2-PDT increased C-FOS expression on tumor cell lines (G361 and MCF7), but not on non-tumor BJ cell line. Conversely, both TMPyP and ClAlPcS2-PDT decreased C-MYC expression on non-tumor BJ cell line but not on tumor cell lines. As first we tested these photosensitizers in such extent and we believe that it can help to better understand mechanisms of PDT and increase its efficiency and applicability. PMID- 25545334 TI - Examining quality of contraceptive services for adolescents in Oregon's family planning program. AB - OBJECTIVE: To assess the quality of care provided to adolescents (10-19 years old) compared to women (aged 20-25 years) who accessed services in Oregon's Contraceptive Care (CCare) program. STUDY DESIGN: We analyzed data routinely collected using the Clinic Visit Record form from women aged 25 years and younger who visited CCare clinics between January 1, 2004, and October 31, 2010. Modern methods were characterized into three tiers: Tier 1 is the intrauterine device, implant and sterilization; Tier 2, hormonal methods; and Tier 3, all barrier methods. Nonmodern methods included no method, withdrawal and natural family planning. We used multivariable logistic regression models to examine the effect of age on three indicators of quality of contraceptive care: transitioning from a nonmodern to a modern method, transitioning from Tier 3 methods to Tier 1 or Tier 2 methods, and initiation of long-acting reversible contraception (LARC). We then produced predicted probabilities to facilitate data interpretation. RESULTS: Adolescents accounted for 344,856 (41%) of the 848,221 clinic visits occurring in CCare among women under age 25. Compared with women (ages 20-25 years), young and older adolescents had decreased odds of LARC initiation [odds ratio (OR) 0.24 (95% confidence interval [CI] 0.16-0.35) and OR 0.44 (95% CI 0.38-0.52), respectively]. However, compared with women, both young and older adolescents had increased odds of leaving with any contraceptive method [OR 1.8 95% (CI 1.26 2.59) and OR 1.42 (95% CI 1.21-1.66)]. Among clients presenting with no method of contraception at the beginning of the visit, 78.7% of young adolescents (95% CI 73.84-83.03) compared with 81.44% (95% CI 77.02-85.52) of older adolescents, and 76.63% (95% CI 69.90-80.75) of young women left with a modern method, controlling for other covariates. CONCLUSION: Although adolescents served by CCare are more likely to initiate contraception, they are less likely to receive LARC than women aged 20-25 years. IMPLICATION: Efforts are needed to ensure that adolescents have access to highly effective reversible contraception. PMID- 25545335 TI - Treating Class II malocclusion in children. Vertical skeletal effects of high pull or low-pull headgear during comprehensive orthodontic treatment and retention. AB - OBJECTIVES: To evaluate, in Class II malocclusion children, vertical skeletal changes occurring with high- and low-pull headgear during non-extraction comprehensive orthodontic treatment, and retention. SETTING AND SAMPLE POPULATION: Two groups of thirty Class II malocclusion children (mean age 10.8 years) who had undergone non-extraction comprehensive orthodontic treatment with either high- or low-pull headgear and fixed appliances. MATERIAL AND METHODS: Retrospective longitudinal study, where pre-treatment, post-treatment and at least 2 year post-retention lateral cephalometric radiographs were analyzed. Comparisons were made concerning changes during treatment and retention in high- or low-pull headgear-treated children. Correlation analyses were carried out investigating changes in vertical cephalometric parameters and pre-treatment vertical facial pattern or type of headgear used. RESULTS: During treatment, sagittal relationships improved in all children and remained stable during retention. Vertically, in both high- and low-pull headgear groups, the intermaxillary angle as well as the maxillary and mandibular plane angles did not show statistically significant changes during treatment or retention, and large variation was seen between patients. When pooling the whole patient sample, change in the vertical facial pattern was independent of the pre-treatment vertical facial pattern or type of headgear used. CONCLUSION: When treating Class II malocclusion children non-extraction with high- or low-pull headgear and fixed appliances, changes in vertical skeletal relationships demonstrate wide variation, both during treatment and retention. Dentoalveolar changes brought about by these appliances may not be able to make a predictable difference in vertical skeletal patterns of growing patients. PMID- 25545336 TI - Development and pharmacological validation of novel methods of B cell activation in rat whole blood. AB - INTRODUCTION: Whole blood functional assays are pharmacologically relevant in the drug discovery process to evaluate potency in a relevant biological matrix, to support establishment of PK/PD relationships and to aid in human dose predictions. However development of B cell activation assays by BCR ligation in rat whole blood has not been previously described. The aim of the present study was to develop novel methods of B cell activation in rat whole blood. METHODS: B cell activation in rat whole blood was evaluated by measuring CD86 up-regulation via flow cytometry. Rat B cells in whole blood were stimulated with dextran coupled anti-IgD or a combination of anti-IgD and TLR9 agonist. BTK, SYK, and PI3Kdelta inhibitors were added to rat whole blood prior to activation with dextran-coupled anti-IgD or anti-IgD and TLR9 agonist combination for pharmacological validation of the assay. RESULTS: Both methods of stimulation in rat whole blood evoked robust B cell activation in a uni-modal fashion. Highly selective inhibitors of BTK, SYK, and PI3Kdelta dose-dependently attenuated B cell activity evoked by both dextran-coupled anti-IgD and combined anti-IgD and TLR9 agonist. Compound potencies and rank order determined by the two assays were comparable. DISCUSSION: Two novel methods were developed to stimulate B cells in rat whole blood, that have the potential to be used to support drug discovery efforts in the therapeutic targeting of B cells. Furthermore, we pharmacologically validated these whole blood assays using highly selective inhibitors of BTK, SYK, and PI3Kdelta, signaling kinases which are downstream of the B cell receptor. PMID- 25545337 TI - Comparison of minipig, dog, monkey and human drug metabolism and disposition. AB - INTRODUCTION: This article gives an overview of the drug metabolism and disposition (ADME) characteristics of the most common non-rodent species used in toxicity testing of drugs (minipigs, dogs, and monkeys) and compares these to human characteristics with regard to enzymes mediating the metabolism of drugs and the transport proteins which contribute to the absorption, distribution and excretion of drugs. METHODS: Literature on ADME and regulatory guidelines of relevance in drug development of small molecules has been gathered. RESULTS: Non human primates (monkeys) are the species that is closest to humans in terms of genetic homology. Dogs have an advantage due to the ready availability of comprehensive background data for toxicological safety assessment and dogs are easy to handle. Pigs have been used less than dogs and monkeys as a model in safety assessment of drug candidates. However, when a drug candidate is metabolised by aldehyde oxidase (AOX1), N-acetyltransferases (NAT1 and NAT2) or cytochrome (CYP2C9-like) enzymes which are not expressed in dogs, but are present in pigs, this species may be a better choice than dogs, provided that adequate exposure can be obtained in pigs. Conversely, pigs might not be the right choice if sulfation, involving 3-phospho-adenosyl-5-phosphosulphate sulphotransferase (PAPS) is an important pathway in the human metabolism of a drug candidate. DISCUSSION: In general, the species selection should be based on comparison between in vitro studies with human cell-based systems and animal-cell-based systems. Results from pharmacokinetic studies are also important for decision making by establishing the obtainable exposure level in the species. Access to genetically humanized mouse models and highly sensitive analytical methods (accelerator mass spectrometry) makes it possible to improve the chance of finding all metabolites relevant for humans before clinical trials have been initiated and, if necessary, to include another animal species before long term toxicity studies are initiated. In conclusion, safety testing can be optimized by applying knowledge about species ADME differences and utilising advanced analytical techniques. PMID- 25545338 TI - Supra-annular mitral valve implantation in very small children. AB - OBJECTIVE: Mitral valve replacement (MVR) is a surgical option when mitral valvuloplasty is not feasible/successful. This study reviews our experience with MVR in very young children. METHODS: From July 2004 to January 2014, seven children (mean age 13.3 +/- 11.2 months; range 4 months to 35 months; mean body weight 6.0 +/- 2.2 kg) underwent MVR with a mechanical prosthesis in the supra annular position. To provide better exposure in the left atrium, we performed in all but one case a biatrial transeptal incision according to Guiraudon. Six patients had congenital defects of the mitral valve and one had rheumatic. Six patients had undergone previous cardiosurgical procedures. RESULTS: All patients were implanted with a CarboMedics (CarboMedics, Austin, TX, USA) mechanical prosthesis. Mean prosthesis size was 19.0 +/- 3.1 mm (range 16 to 25). There were no cases of operative or late mortality. At follow-up (mean 67.1 +/- 34.8 months; range 25 to 108 months) two patients (28.6%) required reoperation both for thrombotic pannus formation over the disc at two and three months from first operation, respectively; only in one case was replacement necessary. CONCLUSION: Supra-annular MVR may be considered a feasible secondary surgical option in children with a small annulus when mitral valvuloplasty is unsuccessful or unsuitable. Early and mid-term outcomes are acceptable but complications are not uncommon, especially related to thrombotic events. PMID- 25545339 TI - Arterial-atrial coupling in untreated hypertension. AB - Recently, there has been growing interest in an interplay of vascular mechanics and heart function (arterial-ventricular-atrial coupling). The contribution of arterial stiffness (AS) to left atrial (LA) enlargement is unclear. The aim of this study was to verify whether the association between carotid AS and LA volume in untreated arterial hypertension is independent of such confounders as age, sex, body mass index (BMI), blood pressure, left ventricular hypertrophy (LVH), left ventricular (LV) diastolic and systolic function. The study included 133 patients, among them 107 individuals with hypertension (51 men and 56 women, mean age 56.8 +/- 10.3 years) and 26 matched controls. Each patient was subjected to echocardiography, ultrasonographic measurement of mean carotid intima-media thickness (IMT) and echo-tracking assessment of AS and wave reflection. LA volume was calculated by ellipsoid method. The indexed LA volume showed significant linear correlations with age (r = 0.32; p < 0.05), BMI (r = 0.21; p < 0.05), pulse pressure (r = 0.26; p < 0.05), B-type natriuretic peptide (r = 0.64; p < 0.05), LV end-diastolic volume (r = 0.42; p < 0.05), LV mass index (LVMI; r = 0.58; p < 0.05), septum thickness (r = 0.40; p < 0.05), posterior wall thickness (r = 0.34; p < 0.05), early filling wave of mitral inflow (E; r = 0.30; p < 0.05), early diastolic myocardial velocity of mitral annulus (e'; r = - 0.22; p < 0.05), E/e' ratio (r = 0.45; p < 0.05), IMT (r = 0.26; p < 0.05) and augmentation index (AI; r = 0.27; p < 0.05). Progressive multivariate analysis identified LVMI, age, AI and BMI as independent determinants of indexed LA volume in patients with arterial hypertension. The study showed the significant relationship between wave reflection expressed by AI and LA structural remodeling, which supports the hypothesis of arterial-atrial coupling in hypertension. PMID- 25545340 TI - Sympatric populations of sister species of Brachyrhaphis. AB - The first records of sympatric populations of the poorly studied sister species Brachyrhaphis roseni and Brachyrhaphis terrabensis are presented. Sympatric populations were found in a total of 14 localities in four river drainages throughout the Pacific slopes of western Panama, and they occurred in a wide range of elevations, from 90 to 651 m. These data expand the elevation range of each species, and provide the first case of sympatric sister species within the genus. PMID- 25545341 TI - Intravascular optical coherence tomography light scattering artifacts: merry-go rounding, blooming, and ghost struts. AB - We sought to elucidate the mechanisms underlying two common intravascular optical coherence tomography (IV-OCT) artifacts that occur when imaging metallic stents: "merry-go-rounding" (MGR), which is an increase in strut arc length (SAL), and "blooming," which is an increase in the strut reflection thickness (blooming thickness). Due to uncontrollable variables that occur in vivo, we performed an in vitro assessment of MGR and blooming in stented vessel phantoms. Using Xience V and Driver stents, we examined the effects of catheter offset, intimal strut coverage, and residual blood on SAL and blooming thickness in IV-OCT images. Catheter offset and strut coverage both caused minor MGR, while the greatest MGR effect resulted from light scattering by residual blood in the vessel lumen, with 1% hematocrit (Hct) causing a more than fourfold increase in SAL compared with saline (p<0.001 ). Residual blood also resulted in blooming, with blooming thickness more than doubling when imaged in 0.5% Hct compared with saline (p<0.001 ). We demonstrate that a previously undescribed mechanism, light scattering by residual blood in the imaging field, is the predominant cause of MGR. Light scattering also results in blooming, and a newly described artifact, three-dimensional-MGR, which results in "ghost struts" in B-scans. PMID- 25545342 TI - Fluorescent probes concentration estimation in vitro and ex vivo as a model for early detection of Alzheimer's disease. AB - The pathogenic process of Alzheimer's disease (AD) begins years before clinical diagnosis. Here, we suggest a method that may detect AD several years earlier than current exams. The method is based on previous reports that relate the concentration ratio of biomarkers (amyloid-beta and tau) in the cerebrospinal fluid (CSF) to the development of AD. Our method replaces the lumbar puncture process required for CSF drawing by using fluorescence measurements. The system uses an optical fiber coupled to a laser source and a detector. The laser radiation excites two fluorescent probes which may bond to the CSF biomarkers. Their concentration ratio is extracted from the fluorescence intensities and can be used for future AD detection. First, we present a theoretical model for fluorescence concentration ratio estimation. The method's feasibility was validated using Monte Carlo simulations. Its accuracy was then tested using multilayered tissue phantoms simulating the epidural fat, CSF, and bone. These phantoms have various optical properties, thicknesses, and fluorescence concentrations in order to simulate human anatomy variations and different fiber locations. The method was further tested using ex vivo chicken tissue. The average errors of the estimated concentration ratios were low both in vitro (4.4%) and ex vivo (10.9%), demonstrating high accuracy. PMID- 25545343 TI - Predatory publishing: what authors need to know. PMID- 25545345 TI - Articular soft tissue anatomy of the archosaur hip joint: Structural homology and functional implications. AB - Archosaurs evolved a wide diversity of locomotor postures, body sizes, and hip joint morphologies. The two extant archosaurs clades (birds and crocodylians) possess highly divergent hip joint morphologies, and the homologies and functions of their articular soft tissues, such as ligaments, cartilage, and tendons, are poorly understood. Reconstructing joint anatomy and function of extinct vertebrates is critical to understanding their posture, locomotor behavior, ecology, and evolution. However, the lack of soft tissues in fossil taxa makes accurate inferences of joint function difficult. Here, we describe the soft tissue anatomies and their osteological correlates in the hip joint of archosaurs and their sauropsid outgroups, and infer structural homology across the extant taxa. A comparative sample of 35 species of birds, crocodylians, lepidosaurs, and turtles ranging from hatchling to skeletally mature adult were studied using dissection, imaging, and histology. Birds and crocodylians possess topologically and histologically consistent articular soft tissues in their hip joints. Epiphyseal cartilages, fibrocartilages, and ligaments leave consistent osteological correlates. The archosaur acetabulum possesses distinct labrum and antitrochanter structures on the supraacetabulum. The ligamentum capitis femoris consists of distinct pubic- and ischial attachments, and is homologous with the ventral capsular ligament of lepidosaurs. The proximal femur has a hyaline cartilage core attached to the metaphysis via a fibrocartilaginous sleeve. This study provides new insight into soft tissue structures and their osteological correlates (e.g., the antitrochanter, the fovea capitis, and the metaphyseal collar) in the archosaur hip joint. The topological arrangement of fibro- and hyaline cartilage may provide mechanical support for the chondroepiphysis. The osteological correlates identified here will inform systematic and functional analyses of archosaur hindlimb evolution and provide the anatomical foundation for biomechanical investigations of joint tissues. PMID- 25545344 TI - Direct infection of primary salivary gland epithelial cells by human T lymphotropic virus type I in patients with Sjogren's syndrome. AB - OBJECTIVE: To investigate whether human T lymphotropic virus type I (HTLV-I) directly infects salivary gland epithelial cells (SGECs) and induces the niche of the salivary glands in patients with Sjogren's syndrome (SS). METHODS: SGECs were cultured with the HTLV-I-producing CD4+ T cell line HCT-5 or with Jurkat cells. Antibody arrays, immunofluorescence analysis, and enzyme-linked immunosorbent assay (ELISA) were used to determine the profiles of inflammation-related molecules, and the profiles of apoptosis-related molecules were determined by antibody array and immunofluorescence analysis. The presence of HTLV-I-related molecules was assessed by immunofluorescence analysis and in situ polymerase chain reaction. Apoptosis of SGECs was evaluated by TUNEL staining. RESULTS: Among the SGECs, 7.8 +/- 1.3% (mean +/- SD) were positive for HTLV-I-related proteins after 96-hour coculture with HCT-5 cells. Nuclear NF-kappaB p65 was also detected in 10% of the SGECs. The presence of HTLV-I proviral DNA in SGECs after coculture with HCT-5 cells was detected by in situ polymerase chain reaction. After coculture of SGECs with HCT-5, the expression of cytokines and chemokines, including soluble intercellular adhesion molecule 1, RANTES, and interferon gamma induced protein 10 kd (IP-10/CXCL10) was increased in a time-dependent manner. The expression of proapoptotic molecules (e.g., cytochrome c and Fas) and antiapoptotic molecules (e.g., Bcl-2, Heme oxygenase 2, and Hsp27) was increased in the SGECs cocultured with HCT-5, showing that apoptosis of SGECs was not detected after coculture with HCT-5 or Jurkat cells. CONCLUSION: HTLV-I is thought to infect SGECs and alter their cellular functions. These changes may induce the niche of SS and contribute to the development of SS in anti-HTLV-I antibody-positive individuals. PMID- 25545346 TI - The genomic landscape of phaeochromocytoma. AB - Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare neural crest-derived tumours originating from adrenal chromaffin cells or extra-adrenal sympathetic and parasympathetic tissues. More than a third of PCC/PGL cases are associated with heritable syndromes involving 13 or more known genes. These genes have been broadly partitioned into two groups based on pseudo-hypoxic and receptor tyrosine kinase (RTK) signalling pathways. Many of these genes can also become somatically mutated, although up to one third of sporadic cases have no known genetic driver. Furthermore, little is known of the genes that co-operate with known driver genes to initiate and drive tumourigenesis. To explore the genomic landscape of PCC/PGL, we applied exome sequencing, high-density SNP-array analysis, and RNA sequencing to 36 PCCs and four functional PGL tumours. All tumours displayed low mutation frequency, in contrast to frequent large segmental copy-number alterations, aneuploidy, and evidence for chromothripsis in one case. Multi region sampling of one benign familial PCC tumour provided evidence for the timing of mutations during tumourigenesis and ongoing clonal evolution. Thirty one of 40 (77.5%) cases could be explained by germline or somatic mutations or structural alterations affecting known PCC/PGL genes. Deleterious somatic mutations were also identified in known tumour-suppressor genes associated with genome maintenance and epigenetic modulation. A multitude of other genes were also found mutated that are likely important for normal neuroendocrine cell function. We revisited the gene-expression subtyping of PCC/PGL by integrating published microarray data with our RNA-seq data, enabling the identification of six robust gene-expression subtypes. The majority of cases in our cohort with no identifiable driver mutation were classified into a gene-expression subtype bearing similarity to MAX mutant PCC/PGL. Our data suggest there are yet unknown PCC/PGL cancer genes that can phenocopy MAX mutant PCC/PGL tumours. This study provides new insight into the molecular diversity and genetic origins of PCC/PGL tumours. PMID- 25545347 TI - Improving the success of treating tobacco smokers. PMID- 25545348 TI - Detection and characterization of betamethasone metabolites in human urine by LC MS/MS. AB - Glucocorticosteroids are prohibited in sports when administered by systemic routes and allowed using other administrations for therapeutic reasons. Therefore, markers to distinguish between routes of administration through the analysis of urine samples are needed in anti-doping control. As a first step to achieve that goal, the metabolism of betamethasone (BET) was investigated in the present work. Urine samples obtained after BET intramuscular injection were hydrolyzed with beta-glucuronidase and subjected to liquid-liquid extraction with ethyl acetate in alkaline conditions. The extracts were analyzed by liquid chromatography coupled to tandem mass spectrometry. Common open screening methods for fluorine containing corticosteroids (precursor ion scan method of m/z 121, 147, 171, and neutral loss (NL) scan methods of 20 and 38 Da in positive ionization, and 46 and 76 Da in negative ionization) were applied to detect BET metabolites. Moreover, an NL method was applied to detect A-ring reduced metabolites of BET, which are ionized as [M+NH4 ](+) (NL of 55, 73, and 91 Da, corresponding to the consecutive losses of NH3 , HF and one, two and three water molecules, respectively). BET and 24 metabolites were detected. Six metabolites were identified by comparison with standards, and for ten, feasible structures were proposed based on mass spectrometric data. Eleven of the characterized metabolites had not been previously reported. Metabolites resulting from 11 oxidation, 6-hydroxylation, C20 or 4-ene-3-one reduction and combination of some of them were detected. Moreover one metabolite resulting from cleavage of the side chain with subsequent oxidation of carbon at C17 was also detected. PMID- 25545349 TI - Moss delta(13) C: an accurate proxy for past water environments in polar regions. AB - Increased aridity is of global concern. Polar regions provide an opportunity to monitor changes in bioavailable water free of local anthropogenic influences. However, sophisticated proxy measures are needed. We explored the possibility of using stable carbon isotopes in segments of moss as a fine-scale proxy for past bioavailable water. Variation in delta(13) C with water availability was measured in three species across three peninsulas in the Windmill Islands, East Antarctica and verified using controlled chamber experiments. The delta(13) C from Antarctic mosses accurately recorded long-term variations in water availability in the field, regardless of location, but significant disparities in delta(13) C between species indicated some make more sensitive proxies. delta(13) CSUGAR derived from living tissues can change significantly within the span of an Antarctic season (5 weeks) in chambers, but under field conditions, slow growth means that this technique likely represents multiple seasons. delta(13) CCELLULOSE provides a precise and direct proxy for bioavailable water, allowing reconstructions for coastal Antarctica and potentially other cold regions over past centuries. PMID- 25545351 TI - Validated green high-performance liquid chromatographic methods for the determination of coformulated pharmaceuticals: a comparison with reported conventional methods. AB - The introduction of sustainable development concepts to analytical laboratories has recently gained interest, however, most conventional high-performance liquid chromatography methods do not consider either the effect of the used chemicals or the amount of produced waste on the environment. The aim of this work was to prove that conventional methods can be replaced by greener ones with the same analytical parameters. The suggested methods were designed so that they neither use nor produce harmful chemicals and produce minimum waste to be used in routine analysis without harming the environment. This was achieved by using green mobile phases and short run times. Four mixtures were chosen as models for this study; clidinium bromide/chlordiazepoxide hydrochloride, phenobarbitone/pipenzolate bromide, mebeverine hydrochloride/sulpiride, and chlorphenoxamine hydrochloride/caffeine/8-chlorotheophylline either in their bulk powder or in their dosage forms. The methods were validated with respect to linearity, precision, accuracy, system suitability, and robustness. The developed methods were compared to the reported conventional high-performance liquid chromatography methods regarding their greenness profile. The suggested methods were found to be greener and more time- and solvent-saving than the reported ones; hence they can be used for routine analysis of the studied mixtures without harming the environment. PMID- 25545350 TI - Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity. AB - Bile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed-state metabolism. Since the detergent-like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. Bile acid homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary BA receptor, farnesoid X receptor, and small heterodimer partner, which inhibits BA synthesis by recruiting repressive histone modifying enzymes. Although histone modifiers have been shown to regulate BA responsive genes, their in vivo functions remain unclear. Here, we show that lysine-specific histone demethylase1 (LSD1) is directly induced by BA-activated farnesoid X receptor, is recruited to the BA synthetic genes Cyp7a1 and Cyp8b1 and the BA uptake transporter gene Ntcp, and removes a gene-activation marker, trimethylated histone H3 lysine-4, leading to gene repression. Recruitment of LSD1 was dependent on small heterodimer partner, and LSD1-mediated demethylation of trimethylated histone H3 lysine-4 was required for additional repressive histone modifications, acetylated histone 3 on lysine 9 and 14 deacetylation, and acetylated histone 3 on lysine 9 methylation. A BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenovirus-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum alanine aminotransferase and aspartate aminotransferase levels, and hepatic inflammation. CONCLUSION: This study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the farnesoid X receptor and small heterodimer partner that reduces hepatic BA levels and protects the liver against BA toxicity. PMID- 25545352 TI - Intracellular ESAT-6: A new biomarker for Mycobacterium tuberculosis infection. AB - BACKGROUND: Early secreted antigenic target 6 (ESAT-6) is a virulent factor of Mycobacterium tuberculosis (MTB). The identification of intracellular (i/c) ESAT 6 in host cells would be a direct marker of MTB infection. We developed a method to detect i/cESAT-6 by flow cytometry. The aim of this study is to investigate the expression of i/cESAT-6 in the host cells of individuals with MTB infection. METHODS: The expression of i/cESAT-6 was examined in the blood of 58 active TB patients, in 10 naive to TB infection controls, in 17 patients who completed anti TB treatment, and in 56 close contacts with an index TB case. Additionally, it was examined in the sputum of 12 active TB patients. RESULTS: The i/cESAT-6 was positively detected in the blood of 52 out of 58 (90%) active TB patients. All naive to TB infection controls were negative. Three out of 17 (18%) patients at the end of anti-TB treatment were positive. Twenty-six out of 56 (46%) close contacts tested positive. The i/cESAT-6 was detected in all culture positive TB sputum specimens. CONCLUSIONS: The i/cESAT-6 is a promising biomarker of MTB infection that could be used in the evaluation of active TB patients and in the diagnosis of latent TB infection. Further studies are needed to validate its potential diagnostic role. (c) 2014 International Clinical Cytometry Society. PMID- 25545353 TI - Effects of fibroblasts on the function of acinar cells from the same human parotid gland. AB - BACKGROUND: Artificial salivary gland replacement would be an ideal treatment for xerostomia. In vivo, salivary gland cells are surrounded by a complex stromal environment in which fibroblasts are the main cell type in proximity to the gland cells. However, very little is known about the relationship between these fibroblasts and the gland cells. METHODS: Parotid gland acinar cells (PGACs) and fibroblasts from the same human gland were cocultured. PGAC function-related protein expression was investigated. RESULTS: The expression of alpha-amylase in PGACs was increased in a fibroblast ratio-dependent manner. Both fibroblast conditioned medium and direct coculture also significantly enhanced the PGAC expression of alpha-amylase. Basic fibroblast growth factor (bFGF) seems to be a regulator of alpha-amylase expression in PGACs. CONCLUSION: An appropriate number of fibroblasts in contact with the PGACs is necessary to promote PGAC function. Fibroblast-secreted bFGF may play a paracrine signaling role in the regulation of alpha-amylase expression in PGACs. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E279-E286, 2016. PMID- 25545354 TI - Correlation Between Abnormal Platelet Count and Respiratory Viral Infection in Patients From Cheonan, Korea. AB - BACKGROUND: In this study, the effects of viral infections on platelet (PLT) count have been reported. This study examined the correlation between PLT count and respiratory virus (RV) infections. METHODS: Patients who visited Dankook University Hospital between December 2006 and February 2014 with symptoms of suspected RV infection were recruited. Multiplex reverse transcriptase polymerase chain reactions identified the causative virus(es). PLT counts were analyzed with respect to virus, age and sex of the patient, and length of hospital stay. RESULTS: Of the 8,147 patients, 62.8% were RV-positive, and 18.6% of RV-positive patients had abnormal PLT counts. There were no differences in the rates of abnormal PLT counts between single-infection and virus co-infection cases. In RV infection patients, the incidence of abnormal PLT count increased with age and varied depending on the RV infection type. Patients with abnormal PLT count stayed in hospital longer than those with normal PLT count. CONCLUSIONS: The incidence of thrombocytopenia was higher among the elderly; in younger patients, thrombocytosis was more prevalent than thrombocytopenia. Respiratory tract infections caused by different viruses resulted in varied PLT count changes. Further systematic research of PLT count changes related to viral infections is required. PMID- 25545355 TI - Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents. AB - BACKGROUND: While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. METHODS: In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). RESULTS: The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076. CONCLUSIONS: Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). IMPACT: Dopaminergic pathways may be salient during early smoking and the development of ND. PMID- 25545356 TI - Vitamin D from different sources is inversely associated with Parkinson disease. AB - An inverse association between Parkinson disease (PD) and total vitamin D levels has been reported, but whether vitamin D from different sources, that is, 25(OH)D2 (from diet and supplements) and 25(OH)D3 (mainly from sunlight exposure), all contribute to the association is unknown. Plasma total 25(OH)D, 25(OH)D2, and 25(OH)D3 levels were measured by liquid chromatography-tandem mass spectrometry in PD patients (n = 478) and controls (n = 431). Total 25(OH)D was categorized by clinical insufficiency or deficiency; 25(OH)D2 and 25(OH)D3 were analyzed in quartiles. Vitamin D deficiency (total 25[OH]D < 20 ng/mL) and vitamin D insufficiency (total 25[OH]D < 30 ng/mL) are associated with PD risk (odds ratio [OR] = 2.6 [deficiency] and 2.1 [insufficiency]; P < 0.0001), adjusting for age, sex, and sampling season. Both 25(OH)D2 and 25(OH)D3 levels are inversely associated with PD (P(trend) < 0.0001). The association between 25(OH)D2 and PD risk is largely confined to individuals with low 25(OH)D3 levels (P(trend) = 0.0008 and 0.12 in individuals with 25[OH]D3 < 20 ng/mL and 25[OH]D3 >= 20 ng/mL, respectively). Our data confirm the association between vitamin D deficiency and PD, and for the first time demonstrate an inverse association of 25(OH)D2 with PD. Given that 25(OH)D2 concentration is independent of sunlight exposure, this new finding suggests that the inverse association between vitamin D levels and PD is not simply attributable to lack of sunlight exposure in PD patients with impaired mobility. The current study, however, cannot exclude the possibility that gastrointestinal dysfunction, a non-motor PD symptom, contributes to the lower vitamin D2 levels in PD patients. PMID- 25545357 TI - IL-34- and M-CSF-induced macrophages switch memory T cells into Th17 cells via membrane IL-1alpha. AB - Macrophages orchestrate the immune response via the polarization of CD4(+) T helper (Th) cells. Different subsets of macrophages with distinct phenotypes, and sometimes opposite functions, have been described. M-CSF and IL-34 induce the differentiation of monocytes into IL-10(high) IL-12(low) immunoregulatory macrophages, which are similar to tumor-associated macrophages (TAMs) in ovarian cancer. In this study, we evaluated the capacity of human macrophages induced in the presence of M-CSF (M-CSF macrophages) or IL-34 (IL-34 macrophages) and ovarian cancer TAMs to modulate the phenotype of human CD4(+) T cells. Taken together, our results show that M-CSF-, IL-34 macrophages, and TAMs switch non Th17 committed memory CD4(+) T cells into conventional CCR4(+) CCR6(+) CD161(+) Th17 cells, expressing or not IFN-gamma. Contrary, the pro-inflammatory GM-CSF macrophages promote Th1 cells. The polarization of memory T cells into Th17 cells is mediated via membrane IL-1alpha (mIL-1alpha), which is constitutively expressed by M-CSF-, IL-34 macrophages, and TAMs. This study elucidates a new mechanism that allows macrophages to maintain locally restrained and smoldering inflammation, which is required in angiogenesis and metastasis. PMID- 25545358 TI - Effects of tau domain-specific antibodies and intravenous immunoglobulin on tau aggregation and aggregate degradation. AB - Tau pathology, including neurofibrillary tangles, develops in Alzheimer's disease (AD). The aggregation and hyperphosphorylation of tau are potential therapeutic targets for AD. Administration of anti-tau antibodies reduces tau pathology in transgenic "tauopathy" mice; however, the optimal tau epitopes and conformations to target are unclear. Also unknown is whether intravenous immunoglobulin (IVIG) products, currently being evaluated in AD trials, exert effects on pathological tau. This study examined the effects of anti-tau antibodies targeting different tau epitopes and the IVIG Gammagard on tau aggregation and preformed tau aggregates. Tau aggregation was assessed by transmission electron microscopy and fluorescence spectroscopy, and the binding affinity of the anti-tau antibodies for tau was evaluated by enzyme-linked immunosorbent assays. Antibodies used were anti-tau 1-150 ("D-8"), anti-tau 259-266 ("Paired-262"), anti-tau 341-360 ("A 10"), and anti-tau 404-441 ("Tau-46"), which bind to tau's N-terminus, microtubule binding domain (MBD) repeat sequences R1 and R4, and the C-terminus, respectively. The antibodies Paired-262 and A-10, but not D-8 and Tau-46, reduced tau fibrillization and degraded preformed tau aggregates, whereas the IVIG reduced tau aggregation but did not alter preformed aggregates. The binding affinities of the antibodies for the epitope for which they were specific did not appear to be related to their effects on tau aggregation. These results confirm that antibody binding to tau's MBD repeat sequences may inhibit tau aggregation and indicate that such antibodies may also degrade preformed tau aggregates. In the presence of anti-tau antibodies, the resulting tau morphologies were antigen dependent. The results also suggested the possibility of different pathways regulating antibody-mediated inhibition of tau aggregation and antibody-mediated degradation of preformed tau aggregates. PMID- 25545359 TI - VOCALSS: Versatile optimally constructed aid for laryngeal surgery simulation. PMID- 25545361 TI - Pd-catalyzed intramolecular C-N bond cleavage, 1,4-migration, sp3 C-H activation, and Heck reaction: four controllable diverse pathways depending on the judicious choice of the base and ligand. AB - Diverse and controllable pathways induced by palladium-catalyzed intramolecular Heck reaction of N-vinylacetamides for the synthesis of nitrogen-containing products in reasonable to high yields via tuning the phosphine ligands and bases are reported. Domino reactions including unique beta-N-Pd elimination, 1,4-Pd migration, or direct acyl C-H bond functionalization were found to be involved forming different products, respectively. Given the ability of using the same starting material to generate diverse products via completely different chemoselective processes, these current methodologies offer straightforward access to valuable nitrogen-containing products under mild reaction conditions as well as inspire the discovery of novel reactions. PMID- 25545360 TI - C-terminal juxtamembrane region of full-length M2 protein forms a membrane surface associated amphipathic helix. AB - The influenza A M2 protein is a 97-residue integral membrane protein involved in viral budding and proton conductance. Although crystal and NMR structures exist of truncated constructs of the protein, there is disagreement between models and only limited structural data are available for the full-length protein. Here, the structure of the C-terminal juxtamembrane region (sites 50-60) is investigated in the full-length M2 protein using site-directed spin-labeling electron paramagnetic resonance (EPR) spectroscopy in lipid bilayers. Sites 50-60 were chosen for study because this region has been shown to be critical to the role the M2 protein plays in viral budding. Continuous wave EPR spectra and power saturation data in the presence of paramagnetic membrane soluble oxygen are consistent with a membrane surface associated amphipathic helix. Comparison between data from the C-terminal juxtamembrane region in full-length M2 protein with data from a truncated M2 construct demonstrates that the line shapes and oxygen accessibilities are remarkably similar between the full-length and truncated form of the protein. PMID- 25545362 TI - Long-chain alkane production by the yeast Saccharomyces cerevisiae. AB - In the past decade industrial-scale production of renewable transportation biofuels has been developed as an alternative to fossil fuels, with ethanol as the most prominent biofuel and yeast as the production organism of choice. However, ethanol is a less efficient substitute fuel for heavy-duty and maritime transportation as well as aviation due to its low energy density. Therefore, new types of biofuels, such as alkanes, are being developed that can be used as drop in fuels and can substitute gasoline, diesel, and kerosene. Here, we describe for the first time the heterologous biosynthesis of long-chain alkanes by the yeast Saccharomyces cerevisiae. We show that elimination of the hexadecenal dehydrogenase Hfd1 and expression of a redox system are essential for alkane biosynthesis in yeast. Deletion of HFD1 together with expression of an alkane biosynthesis pathway resulted in the production of the alkanes tridecane, pentadecane, and heptadecane. Our study provides a proof of principle for producing long-chain alkanes in the industrial workhorse S. cerevisiae, which was so far limited to bacteria. We anticipate that these findings will be a key factor for further yeast engineering to enable industrial production of alkane based drop-in biofuels, which can allow the biofuel industry to diversify beyond bioethanol. PMID- 25545364 TI - Gene electro transfer of plasmid encoding vascular endothelial growth factor for enhanced expression and perfusion in the ischemic swine heart. AB - Myocardial ischemia can damage heart muscle and reduce the heart's pumping efficiency. This study used an ischemic swine heart model to investigate the potential for gene electro transfer of a plasmid encoding vascular endothelial growth factor for improving perfusion and, thus, for reducing cardiomyopathy following acute coronary syndrome. Plasmid expression was significantly greater in gene electro transfer treated tissue compared to injection of plasmid encoding vascular endothelial growth factor alone. Higher gene expression was also seen in ischemic versus non-ischemic groups with parameters 20 Volts (p<0.03), 40 Volts (p<0.05), and 90 Volts (p<0.05), but not with 60 Volts (p<0.09) while maintaining a pulse width of 20 milliseconds. The group with gene electro transfer of plasmid encoding vascular endothelial growth factor had increased perfusion in the area at risk compared to control groups. Troponin and creatine kinase increased across all groups, suggesting equivalent ischemia in all groups prior to treatment. Echocardiography was used to assess ejection fraction, cardiac output, stroke volume, left ventricular end diastolic volume, and left ventricular end systolic volume. No statistically significant differences in these parameters were detected during a 2-week time period. However, directional trends of these variables were interesting and offer valuable information about the feasibility of gene electro transfer of vascular endothelial growth factor in the ischemic heart. The results demonstrate that gene electro transfer can be applied safely and can increase perfusion in an ischemic area. Additional study is needed to evaluate potential efficacy. PMID- 25545363 TI - PCR primers to study the diversity of expressed fungal genes encoding lignocellulolytic enzymes in soils using high-throughput sequencing. AB - Plant biomass degradation in soil is one of the key steps of carbon cycling in terrestrial ecosystems. Fungal saprotrophic communities play an essential role in this process by producing hydrolytic enzymes active on the main components of plant organic matter. Open questions in this field regard the diversity of the species involved, the major biochemical pathways implicated and how these are affected by external factors such as litter quality or climate changes. This can be tackled by environmental genomic approaches involving the systematic sequencing of key enzyme-coding gene families using soil-extracted RNA as material. Such an approach necessitates the design and evaluation of gene family specific PCR primers producing sequence fragments compatible with high-throughput sequencing approaches. In the present study, we developed and evaluated PCR primers for the specific amplification of fungal CAZy Glycoside Hydrolase gene families GH5 (subfamily 5) and GH11 encoding endo-beta-1,4-glucanases and endo beta-1,4-xylanases respectively as well as Basidiomycota class II peroxidases, corresponding to the CAZy Auxiliary Activity family 2 (AA2), active on lignin. These primers were experimentally validated using DNA extracted from a wide range of Ascomycota and Basidiomycota species including 27 with sequenced genomes. Along with the published primers for Glycoside Hydrolase GH7 encoding enzymes active on cellulose, the newly design primers were shown to be compatible with the Illumina MiSeq sequencing technology. Sequences obtained from RNA extracted from beech or spruce forest soils showed a high diversity and were uniformly distributed in gene trees featuring the global diversity of these gene families. This high-throughput sequencing approach using several degenerate primers constitutes a robust method, which allows the simultaneous characterization of the diversity of different fungal transcripts involved in plant organic matter degradation and may lead to the discovery of complex patterns in gene expression of soil fungal communities. PMID- 25545365 TI - Wnt signalling suppresses voltage-dependent Na+ channel expression in postnatal rat cardiomyocytes. AB - Wnt signalling plays crucial roles in heart development, but is normally suppressed postnatally. In arrhythmogenic conditions, such as cardiac hypertrophy and heart failure, Wnt signalling is reactivated. To explore the potential role of Wnt signalling in arrhythmogenic electrical remodelling, we examined voltage dependent ion channels in cardiomyocytes. Treatment of neonatal rat ventricular myocytes with either recombinant Wnt3a protein or CHIR-99021 (CHIR, a glycogen synthase kinase-3beta inhibitor) caused a dose-dependent increase in Wnt target gene expression (Axin2 and Lef1), indicating activation of the Wnt/beta-catenin pathway. Cardiac Na(+) current (INa) density was reduced by Wnt3a (-20 +/- 4 vs. control -59 +/- 7 pA pF(-1) , at -30 mV) or CHIR (-22 +/- 5 pA pF(-1) ), without changes in steady-state activation, inactivation or repriming kinetics. Wnt3a and CHIR also produced dose-dependent reductions in the mRNA level of Scn5a (the cardiac Na(+) channel alpha subunit gene), as well as a 56% reduction (by Wnt3a) in the Nav 1.5 protein level. Consistent with INa reduction, action potentials in Wnt3a-treated neonatal rat ventricular myocytes had a lower upstroke amplitude (91 +/- 3 vs. control 137 +/- 2 mV) and decreased maximum upstroke velocity (70 +/- 10 vs. control 163 +/- 15 V s(-1)). In contrast, inward rectifier K(+) current and L-type Ca(2+) channels were not affected by Wnt3a treatment. Taken together, our data indicate that the Wnt/beta-catenin pathway suppresses INa in postnatal cardiomyocytes and may contribute to ion channel remodelling in heart disease. PMID- 25545366 TI - miR-1470 mediates lapatinib induced p27 upregulation by targeting c-jun. AB - Our previous study indicated that lapatinib induces p27-dependent G(1) arrest through both transcriptional and post-translational mechanisms. Using miRNA microarray technology and quantitative RT-PCR, we further investigated the potential miRNAs that involved in p27 upregulation and Her-2 signaling pathway alteration with lapatinib treatment. A subset of 7 miRNAs was significantly affected in both 0.5 uM and 2.0 uM and 24 h and 48 h lapatinib treatment. Among them, only miR-1470, miR-126, and miR-1208 were identified in the Her-2 pathway after KEGG pathway analysis. However, luciferase reporter assay confirmed that miR-1470 directly recognized the 3'-untranslated region of c-jun transcripts, which was consistent with TargetScan analysis. miR-1470 significantly decreased c jun expression, thus miR-1470 may repressc-jun activation of cyclinD1 expression, and consequently promoted the upregulation of p27, a key molecule in the cell cycle arrest. Taken together, the present study provided the first evidences that miR-1470 mediated lapatinib induced p27 upregulation by targeting c-jun. PMID- 25545369 TI - Transarterial chemoembolization does not harm the hepatic artery at transplantation. PMID- 25545367 TI - Cdk1-mediated phosphorylation of human ATF7 at Thr-51 and Thr-53 promotes cell cycle progression into M phase. AB - Activating transcription factor 2 (ATF2) and its homolog ATF7 are phosphorylated at Thr-69/Thr-71 and at Thr-51/Thr-53, respectively, by stress-activated MAPKs regulating their transcriptional functions in G1 and S phases. However, little is known about the role of ATF2 and ATF7 in G2/M phase. Here, we show that Cdk1 cyclin B1 phosphorylates ATF2 at Thr-69/Thr-71 and ATF7 at Thr-51/Thr-53 from early prophase to anaphase in the absence of any stress stimulation. Knockdown of ATF2 or ATF7 decreases the rate of cell proliferation and the number of cells in M-phase. In particular, the knockdown of ATF7 severely inhibits cell proliferation and G2/M progression. The inducible expression of a mitotically nonphosphorylatable version of ATF7 inhibits G2/M progression despite the presence of endogenous ATF7. We also show that mitotic phosphorylation of ATF7 promotes the activation of Aurora kinases, which are key enzymes for early mitotic events. These results suggest that the Cdk1-mediated phosphorylation of ATF7 facilitates G2/M progression, at least in part, by enabling Aurora signaling. PMID- 25545370 TI - Separation and identification of multiple constituents in Xiao Chai Hu Decoction (Sho-saiko-to) by bioactivity-guided fractionation combined with LC-ESI QTOFMS/MS. AB - Xiao Chai Hu Decoction (XCHD), named Sho-saiko-to in Japanese, is a well-known traditional Chinese medicine formula used in Asia. However, the characterization methods used in the past have lacked sensitivity and the nature of the active constituents of XCHD remains unclear. This study was carried out to establish the hyphenated method of bioactivity-guided fractionation and liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOFMS/MS) in order to identify the major bioactive constituents of XCHD. D101 macroporous resin was used to separate and enrich the material base into four fractions, XCHD-1, XCHD-2, XCHD-3 and XCHD-4. Each fraction was then evaluated for its antidepressant effect using depression-related parameters. An LC-ESI-QTOFMS/MS method in both positive and negative ion mode was also applied for separation and identification of the biological active fractions of XCHD. As a result, 79 compounds including polysaccharides, flavonoids, saikosaponins, ginsenosides, licoricesaponins and gingerols were detected, 69 of them were identified or tentatively characterized. Based on our preliminary characterization investigations, polysaccharides, gingerols and flavonoids in XCHD may contribute to the antidepressant effect of XCHD. In conclusion, the hyphenated method of bioactivity-guided fractionation and LC-ESI-QTOFMS/MS was meaningful for the isolation and preliminary identification of the biological active components in complex matrices of traditional Chinese medicine. PMID- 25545371 TI - Quantum-chemistry based calibration of the alkali metal cation series (Li(+) Cs(+)) for large-scale polarizable molecular mechanics/dynamics simulations. AB - The alkali metal cations in the series Li(+)-Cs(+) act as major partners in a diversity of biological processes and in bioinorganic chemistry. In this article, we present the results of their calibration in the context of the SIBFA polarizable molecular mechanics/dynamics procedure. It relies on quantum chemistry (QC) energy-decomposition analyses of their monoligated complexes with representative O-, N-, S-, and Se- ligands, performed with the aug-cc-pVTZ(-f) basis set at the Hartree-Fock level. Close agreement with QC is obtained for each individual contribution, even though the calibration involves only a limited set of cation-specific parameters. This agreement is preserved in tests on polyligated complexes with four and six O- ligands, water and formamide, indicating the transferability of the procedure. Preliminary extensions to density functional theory calculations are reported. PMID- 25545368 TI - Recombinant neuregulin 1 does not activate cardiomyocyte DNA synthesis in normal or infarcted adult mice. AB - OBJECTIVES: Neuregulin 1 signaling plays an important role in cardiac trabecular development, and in sustaining functional integrity in adult hearts. Treatment with neuregulin 1 enhances adult cardiomyocyte differentiation, survival and/or function in vitro and in vivo. It has also been suggested that recombinant neuregulin 1beta1 (NRG1beta1) induces cardiomyocyte proliferation in normal and injured adult hearts. Here we further explore the impact of neuregulin 1 signaling on adult cardiomyocyte cell cycle activity. METHODS AND RESULTS: Adult mice were subjected to 9 consecutive daily injections of recombinant NRG1beta1 or vehicle, and cardiomyocyte DNA synthesis was quantitated via bromodeoxyuridine (BrdU) incorporation, which was delivered using mini-osmotic pumps over the entire duration of NRG1beta1 treatment. NRG1beta1 treatment inhibited baseline rates of cardiomyocyte DNA synthesis in normal mice (cardiomyocyte labelling index: 0.019+/-0.005% vs. 0.003+/-0.001%, saline vs. NRG1beta1, P<0.05). Acute NRG1beta1 treatment did result in activation of Erk1/2 and cardiac myosin regulatory light chain (down-stream mediators of neuregulin signalling), as well as activation of DNA synthesis in non-cardiomyocytes, validating the biological activity of the recombinant protein. In other studies, mice were subjected to permanent coronary artery occlusion, and cardiomyocyte DNA synthesis was monitored via tritiated thymidine incorporation which was delivered as a single injection 7 days post-infarction. Daily NRG1beta1 treatment had no impact on cardiomyocyte DNA synthesis in the infarcted myocardium (cardiomyocyte labelling index: 0.039+/-0.011% vs. 0.027+/-0.021%, saline vs. NRG1beta1, P>0.05). SUMMARY: These data indicate that NRG1beta1 treatment does not increase cardiomyocyte DNA synthesis (and consequently does not increase the rate of cardiomyocyte renewal) in normal or infarcted adult mouse hearts. Thus, any improvement in cardiac structure and function observed following neuregulin treatment of injured hearts likely occurs independently of overt myocardial regeneration. PMID- 25545373 TI - An experimental treatment of ocular quinine toxicity with high-dose 9-cis Beta carotene. AB - PURPOSE: To report a case of severe ocular quinine toxicity after a suicide attempt and an experimental treatment with high-dose 9-cis beta-carotene. METHODS: Interventional case report. RESULTS: A 59-year-old woman presented with acute bilateral blindness after ingesting high dose (12 g) of quinine sulphate. Her vision was no light perception in either eye, and her pupils were fixed and middilated. Because of limited vision and poor prognosis, she was treated with an experimental rescue therapy of high-dose 9-cis beta-carotene Dunaliella bardawil powder for 3 months, starting 10 days postingestion. Electroretinography measurements showed transient improvement in a-wave amplitudes. The electroretinography b-wave showed only partial transient improvement in the left eye. Overall, the patient's visual acuity improved to 20/33 in the right eye and 20/40 in the left eye, but with extremely constricted visual fields. CONCLUSION: Transient improvement in electroretinography measurements was observed under treatment with high-dose 9-cis beta-carotene in ocular quinine toxicity, although no clinical benefit was documented. More research is needed to determine its effect in patients with toxic retinal damage. PMID- 25545372 TI - Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway. AB - Colorectal cancer (CRC) is the third most common malignancy in males and the second most common cancer worldwide. Chronic colonic inflammation is a known risk factor for CRC. Cocoa contains many polyphenolic compounds that have beneficial effects in humans. The objective of this study is to explore the antioxidant properties of cocoa in the mouse model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer, focusing on the activation of Nrf2 signaling. Mice were treated with AOM/DSS and randomized to receive either a control diet or a 5 and 10% cocoa diet during the study period. On day 62 of the experiment, the entire colon was processed for biochemical and histopathological examination and further evaluations. Increased levels of malondialdehyde (MDA) were observed in AOM/DSS-induced mice; however, subsequent administration of cocoa decreased the MDA. Enzymatic and nonenzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, were decreased in the AOM/DSS mice. Cocoa treatment increases the activities/levels of enzymatic and nonenzymatic antioxidants. Inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were elevated during AOM/DSS-induction, and treatment with 5 and 10% cocoa effectively decreases the expression of iNOS and COX-2. The NF-E2-related factor 2 and its downstream targets, such as NQO1 and UDP-GT, were increased by cocoa treatment. The results of our study suggest that cocoa may merit further clinical investigation as a chemopreventive agent that helps prevent CAC. PMID- 25545374 TI - High suppressor of cytokine signaling-3 expression impairs STAT3-dependent protective effects of interleukin-22 in ulcerative colitis in remission. AB - BACKGROUND: High SOCS3 expression in intestinal epithelial cells (IECs) of patients with ulcerative colitis (UC) in remission reflects the shorter time to relapse. We investigated whether high SOCS3 increased risk for relapse through violating STAT3-dependent protective effects of interleukin (IL)-22 during UC remission. METHODS: Expression of IL-22 and c-Myc in UC remission mucosa was analyzed by immunohistochemistry. Effects of IL-22 on migration and proliferation of IEC cell lines with enforced SOCS3 expression were assessed with wounding assay and CCK-8 assay, respectively. Influence of STAT3 interference and SOCS3 overexpression on IL-22-regulated expression of antimicrobial peptide and proliferation-related molecules, including DMBT1, c-Myc, Survivin, Bcl-2, and Bcl xL, were performed with quantitative real-time polymerase chain reaction or Western blot. RESULTS: Patients with UC in remission showed significantly more IL 22-positive immune cells, but no difference of epithelial c-Myc levels, in mucosa compared with healthy controls. Overexpression of SOCS3 nearly abolished IL-22 induced activation of STAT3. By inhibiting STAT3 signaling, SOCS3 influenced IL 22-induced expression of DMBT1, c-Myc, Survivin, and Bcl-2 as well as proliferation and migration processes in cultured IEC cell line. CONCLUSIONS: SOCS3 overexpression impairs IL-22-mediated epithelial homeostasis and mucosal wound healing, which could be the mechanism for high SOCS3 IEC expression contributed early relapse of mucosal inflammation. Prevention of SOCS3 expression or enhancement of IL-22/STAT3 signaling in IEC seems to be rational therapeutic strategies for UC remission maintenance. PMID- 25545375 TI - Cancer and immunomodulators in inflammatory bowel diseases. AB - The widespread use of thiopurines and anti-tumor necrosis factors (TNFs) in inflammatory bowel disease (IBD) is a rising concern regarding their potential cancer risk. MEDLINE, EMBASE, and the Cochrane Library database were searched for articles regarding immunomodulators anti-TNF agents in IBD, hematologic malignancies, and solid tumors. Current evidences support that thiopurines and anti-TNFs used alone or in combination do not increase the overall cancer risk in IBD. Thiopurines use, with or without anti-TNFs, is associated with an increased risk of lymphoma, particularly non-Hodgkin lymphoma, in Crohn's disease. Combined treatment significantly increases the risk of a rare hepatosplenic T-cell lymphoma, particularly in young male patients with Crohn's disease. An increased risk of nonmelanotic skin cancer is also observed when using thiopurines in IBD, whereas a slightly increased risk of melanoma is observed when using anti-TNFs. The role played by immunomodulators in the development of other cancer types (i.e., urinary) as also by the severity of IBD is under investigation. Although the incidence of specific malignancies (lymphoma, skin cancers) seems to be increased by immunomodulators, their absolute number is low. As thiopurines and anti-TNFs are highly effective in IBD, current evidences support that in appropriate hands, their benefits overwhelm the cancer risk. However, a careful selection of both patients and timing of treatment is mandatory, particularly in young male patients with Crohn's disease. Immunomodulators should therefore be handled by experienced and dedicated gastroenterologists who aware of the potential, although low, cancer risk associated with their use in patients with IBD. PMID- 25545377 TI - Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis. AB - BACKGROUND: Pharmacological induction of hypoxia-inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of colitis, and epithelial cells are critical for the observed therapeutic efficacy. Because systemic HIF activation may lead to potentially negative off-target effects, we hypothesized that targeting epithelial HIF through oral delivery of PHDi would be sufficient to protect against colitis in a mouse model. METHODS: Using a chemically induced trinitrobenzene sulfonic acid murine model of colitis, we compared the efficacy of oral and intraperitoneal (i.p.) delivery of the PHDi; AKB-4924 in preventing colitis, as measured by endoscopy, histology, barrier integrity, and immune profiling. Furthermore, we measured potential off-target effects, examining HIF and HIF target genes in the heart and kidney, as well as erythropoietin and hematocrit levels. RESULTS: Oral administration of AKB-4924 exhibited mucosal protection comparable i.p. dosing. Oral delivery of PHDi led to reduced colonic epithelial HIF stabilization compared with i.p. delivery, but this was still sufficient to induce transcription of downstream HIF targets. Furthermore, oral delivery of PHDi led to reduced stabilization of HIF and activation of HIF targets in extraintestinal organs. CONCLUSIONS: Oral delivery of PHDi therapies to this intestinal mucosa protects against colitis in animal models and represents a potential therapeutic strategy for inflammatory bowel disease, which also precludes unwanted extraintestinal effects. PMID- 25545376 TI - Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program. AB - BACKGROUND: Iron deficiency anemia (IDA) is frequently seen in inflammatory bowel disease. Traditionally, oral iron supplementation is linked to extensive gastrointestinal side effects and possible disease exacerbation. This multicenter phase-3 study tested the efficacy and safety of ferric maltol, a complex of ferric (Fe) iron with maltol (3-hydroxy-2-methyl-4-pyrone), as a novel oral iron therapy for IDA. METHODS: Adult patients with quiescent or mild-to-moderate ulcerative colitis or Crohn's disease, mild-to-moderate IDA (9.5-12.0 g/dL and 9.5-13.0 g/dL in females and males, respectively), and documented failure on previous oral ferrous products received oral ferric maltol capsules (30 mg twice a day) or identical placebo for 12 weeks according to a randomized, double-blind, placebo-controlled study design. The primary efficacy endpoint was change in hemoglobin (Hb) from baseline to week 12. Safety and tolerability were assessed. RESULTS: Of 329 patients screened, 128 received randomized therapy (64 ferric maltol-treated and 64 placebo-treated patients) and comprised the intent-to-treat efficacy analysis: 55 ferric maltol patients (86%) and 53 placebo patients (83%) completed the trial. Significant improvements in Hb were observed with ferric maltol versus placebo at weeks 4, 8, and 12: mean (SE) 1.04 (0.11) g/dL, 1.76 (0.15) g/dL, and 2.25 (0.19) g/dL, respectively (P < 0.0001 at all time-points; analysis of covariance). Hb was normalized in two-thirds of patients by week 12. The safety profile of ferric maltol was comparable with placebo, with no impact on inflammatory bowel disease severity. CONCLUSIONS: Ferric maltol provided rapid clinically meaningful improvements in Hb and showed a favorable safety profile, suggesting its possible use as an alternative to intravenous iron in IDA inflammatory bowel disease. PMID- 25545379 TI - Gut fungal microbiota: the Yin and Yang of inflammatory bowel disease. AB - The prevalence of inflammatory bowel diseases (IBD) has been steadily increasing since 1960. They are widespread throughout Europe, North America, China, and Japan and are emerging as a global disease. The equilibrium among epithelial cells, the immune system, and the related microbiota seems to be paramount in ensuring the absence of these IBD. The role of bacteria in the setting of the gut microbiota has been thoroughly documented, but the role of fungi, which are less abundant, needs to be investigated. Our understanding of the fungal microbiota composition and its impact on IBD has greatly increased in the past 8 years. In this review, we compiled data obtained for the composition of fungal gut microbiota. Special attention was paid to the various effects of this microbial community on the IBD, i.e., the mechanisms and immune pathways involved in these interactions. PMID- 25545378 TI - Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn's disease. AB - BACKGROUND: The ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in inflammatory gene expression. METHODS: To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segments from 6 healthy controls, 6 patients with active Crohn's disease, and 6 patients with inactive Crohn's disease. Disease activity was based on the simple endoscopic score for Crohn's disease. Expression of 7 proinflammatory genes was measured from each biopsy using quantitative polymerase chain reaction. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn's disease was calculated. RESULTS: Total simple endoscopic score for Crohn's disease score corresponds with expression of most inflammatory biomarkers. For most genes, 2 to 5 biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn's disease, 1 to 2 intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%. CONCLUSIONS: Measuring proinflammatory gene expression from mucosal biopsies from patients with Crohn's disease is practicable and provides objective biomarkers that can be used in proof-of concept and mechanism-of-action trials to assess response to therapy. PMID- 25545380 TI - The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). AB - While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. PMID- 25545381 TI - Using mass spectrometry to detect, differentiate, and semiquantitate closely related peptide hormones in complex milieu: measurement of IGF-II and vesiculin. AB - The search for an islet beta-cell growth factor has been a key objective in recent diabetes research, because the ability to regenerate and/or protect the functioning beta-cell population in patients could result in a great advancement for diabetes treatment. IGF-I and IGF-II are known to play crucial roles in fetal growth and prenatal development, and there is growing evidence that IGF-II increases beta-cell proliferation and survival in vitro and in vivo. A search for the source of IGF-II-like immunoreactivity in isolated beta-cell secretory granules from the murine cell line betaTC6-F7 revealed a novel 2-chain IGF-II derived peptide, which we named vesiculin and which has been shown to be a full insulin agonist. Here, we present a liquid chromatography-tandem mass spectrometry method that enables selective detection and semiquantitation of the highly related IGF-II and vesiculin molecules. We have used this method to measure these 2 peptides in conditioned media from 2 beta-cell lines, produced under increasing glucose concentrations. This technique detected both IGF-II and vesiculin in media conditioned by MIN6 and betaTC6-F7 cells at levels in the range of 0 to 6 MUM (total insulin, 80-450 MUM) and revealed a glucose-stimulated increase in insulin, IGF-II, and vesiculin. IGF-II was detected in adult human and neonatal mouse serum in high levels, but vesiculin was not present. The methodology we present herein has utility for detecting and differentiating active peptides that are highly related and of low abundance. PMID- 25545382 TI - Exposure of female macaques to Western-style diet with or without chronic T in vivo alters secondary follicle function during encapsulated 3-dimensional culture. AB - Increased adiposity and hyperandrogenemia alter reproductive parameters in both animal models and women, but their effects on preantral follicles in the ovary remain unknown. We recently reported that Western-style diet (WSD) consumption over 1 year, with or without chronic exposure to elevated circulating T, increased the body fat percentage, elicited insulin resistance, suppressed estradiol and progesterone production, as well as altered the numbers, size, and dynamics of antral follicles in the ovary during the menstrual cycle in female macaques. Therefore, experiments were designed to compare the WSD and WSD+T effects to age-matched controls on the survival, growth, and function of isolated secondary follicles during 5 weeks of encapsulated 3-dimensional culture. Follicle survival significantly declined in the WSD and WSD+T groups compared with the control (CTRL) group. Although media progesterone levels were comparable among groups, androstenedione and estradiol levels were markedly reduced in the WSD and WSD+T groups compared with the CTRL group at week 5. Anti-Mullerian hormone levels peaked at week 3 and were lower in the WSD+T group compared with the WSD or CTRL group. Vascular endothelial growth factor levels also decreased at week 5 in the WSD+T group compared with the WSD or CTRL group. After human chorionic gonadotropin exposure, only antral follicles developed from the CTRL group yielded metaphase II oocytes. Thus, WSD with or without T exposure affects the cohort of secondary follicles in vivo, suppressing their subsequent survival, production of steroid hormones and local factors, as well as oocyte maturation in vitro. PMID- 25545383 TI - Pituitary and brain dopamine D2 receptors regulate liver gene sexual dimorphism. AB - Liver sexual gene dimorphism, which depends mainly on specific patterns of GH secretion, may underlie differential susceptibility to some liver diseases. Because GH and prolactin secretion are regulated by dopaminergic pathways, we studied the participation of brain and lactotrope dopamine 2 receptors (D2Rs) on liver gene sexual dimorphism, to explore a link between the brain and liver gene expression. We used global D2R knockout mice (Drd2(-/-)) and conducted a functional dissection strategy based on cell-specific Drd2 inactivation in neurons (neuroDrd2KO) or pituitary lactotropes. Disruption of neuronal D2Rs (which impaired the GH axis) decreased most of male or female-predominant class I liver genes and increased female-predominant class II genes in males, consistent with the positive (class I) or negative (class II) regulation of these genes by GH. Notably, sexual dimorphism was lost for class I and II genes in neuroDrd2KO mice. Disruption of lactotrope D2Rs did not modify class I or II genes in either sex, because GH axis was preserved. But surprisingly, 1 class II gene (Prlr) and female-predominant class I genes were markedly up-regulated in lacDrd2KO females, pointing to direct or indirect effects of prolactin in the regulation of selected female-predominant liver genes. This suggestion was strengthened in the hyperprolactinemic Drd2(-/-) female mouse, in which increased expression of the same 4 liver genes was observed, despite a decreased GH axis. We hereby demonstrate endocrine-mediated D2R actions on sexual dimorphic liver gene expression, which may be relevant during chronic dopaminergic medications in psychiatric disease. PMID- 25545384 TI - Absence of intracellular ion channels TPC1 and TPC2 leads to mature-onset obesity in male mice, due to impaired lipid availability for thermogenesis in brown adipose tissue. AB - Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 and transient receptor potential vanilloid-4. Because the endo-lysosomal two-pore channels (TPCs) have also been ascribed with metabolic functionality, we studied the effect of simultaneously knocking out TPC1 and TPC2 on body composition and energy balance in male mice fed a chow diet. Compared with wild-type mice, TPC1 and TPC2 double knockout (Tpcn1/2(-/-)) animals had a higher respiratory quotient and became obese between 6 and 9 months of age. Although food intake was unaltered, interscapular brown adipose tissue (BAT) maximal temperature and lean-mass adjusted oxygen consumption were lower in Tpcn1/2(-/-) than in wild type mice. Phosphorylated hormone-sensitive lipase expression, lipid density and expression of beta-adrenergic receptors were also lower in Tpcn1/2(-/-) BAT, whereas mitochondrial respiratory chain function and uncoupling protein-1 expression remained intact. We conclude that Tpcn1/2(-/-) mice show mature-onset obesity due to reduced lipid availability and use, and a defect in beta-adrenergic receptor signaling, leading to impaired thermogenic activity, in BAT. PMID- 25545387 TI - The management of children and adolescents with medulloblastoma in low and middle income countries. PMID- 25545385 TI - Melatonin regulates somatotrope and lactotrope function through common and distinct signaling pathways in cultured primary pituitary cells from female primates. AB - Melatonin (MT) is secreted by the pineal gland and exhibits a striking circadian rhythm in its release. Depending on the species studied, some pituitary hormones also display marked circadian/seasonal patterns and rhythms of secretion. However, the precise relationship between MT and pituitary function remains controversial, and studies focusing on the direct role of MT in normal pituitary cells are limited to nonprimate species. Here, adult normal primate (baboons) primary pituitary cell cultures were used to determine the direct impact of MT on the functioning of all pituitary cell types from the pars distalis. MT increased GH and prolactin (PRL) expression/release in a dose- and time-dependent fashion, a response that was blocked by somatostatin. However, MT did not significantly affect ACTH, FSH, LH, or TSH expression/release. MT did not alter GHRH- or ghrelin-induced GH and/or PRL secretions, suggesting that MT may activate similar signaling pathways as ghrelin/GHRH. The effects of MT on GH/PRL release, which are likely mediated through MT1 receptor, involve both common (adenylyl cyclase/protein kinase A/extracellular calcium-channels) and distinct (phospholipase C/intracellular calcium-channels) signaling pathways. Actions of MT on pituitary cells also included regulation of the expression of other key components for the control of somatotrope/lactotrope function (GHRH, ghrelin, and somatostatin receptors). These results show, for the first time in a primate model, that MT directly regulates somatotrope/lactotrope function, thereby lending support to the notion that the actions of MT on these cells might substantially contribute to the define daily patterns of GH and PRL observed in primates and perhaps in humans. PMID- 25545386 TI - Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor alpha in kisspeptin neurons. AB - Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor alpha (ERalpha) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERalpha in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERalpha in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell specific deletion of ERalpha (KERalphaKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERalphaKO mice, E2 also effectively decreased LH levels in OVX KERalphaKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERalphaKO mice. These experiments clearly demonstrate that ERalpha in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERalphaKO mice to exhibit GnRH/LH surges reflects the role of ERalpha in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both. PMID- 25545388 TI - Discovery and microbial content of the driest site of the hyperarid Atacama Desert, Chile. AB - The Atacama Desert is the driest and oldest desert on Earth. Eleven years ago, the Yungay region was established as the driest site of this hyperarid desert and also close to the dry limit for life on Earth. Since then, much has been published about the extraordinary characteristics of this site and its pertinence as a Mars analogue model. However, as a result of a more systematic search in the Atacama here, we describe a new site, Maria Elena South (MES), which is much drier than Yungay. The mean atmospheric relative humidity (RH) at MES was 17.3%, with the RH of its soils remaining at a constant 14% at the depth of 1 m, a value that matches the lowest RH measurements taken by the Mars Science Laboratory at Gale Crater. Remarkably, we found a number of viable bacterial species in the soil profile at MES using a combination of molecular dependent and independent methods, unveiling the presence of life in the driest place on the Atacama Desert reported to date. PMID- 25545389 TI - Use of an exposure chamber to maintain aqueous phase nanoparticle dispersions for improved toxicity testing in fish. AB - A novel chamber for maintaining aqueous phase dispersions of nanoparticles (NPs) to enable improved toxicity testing in larval zebrafish was developed. Aqueous concentrations were within 80% of initial NP concentrations, and the 96-h median lethal concentration (LC50) values were highly reproducible (coefficient of variation <0.16, n = 3 tests). Significantly lower toxicity for each NP tested (Ag, Cu, and TiO2 NPs) in static beakers suggested that traditional acute toxicity tests may underestimate aqueous phase toxicity of NPs. PMID- 25545390 TI - Hypertriglyceridemia-induced pancreatitis and risk of persistent systemic inflammatory response syndrome. AB - BACKGROUND: The mechanisms responsible for the development of acute pancreatitis (AP) and its complications are not fully understood. AIM: To assess the role of clinical and host molecular factors for the development and outcome of persistent systemic inflammatory response syndrome (SIRS) in patients with AP. METHODS: We included 191 patients with AP in the study. The considered variables were demographic characteristics, prognosis and outcome, etiology, laboratory findings and complications. Interleukin (IL) 10 (-1082 G/A, -592 C/A), TNFA-308 (G/A) and ILB-31 (C/T) polymorphisms were determined by pyrosequencing. An amplification refractory mutation system-polymerase chain reaction method was used to genotype the IL8-251 (A/T) polymorphism. RESULTS: Demographic characteristics were not statistically significant risk factors for the acquisition of persistent SIRS in patients with AP. Patients with hypertriglyceridemia were more likely to develop persistent SIRS (P < 0.05). No association with the TNFA, ILB, IL8-251 (A/T) and IL10 single-nucleotide polymorphisms was detected from the allele, genotype or haplotype frequencies. CONCLUSIONS: Patients with hypertriglyceridemia-induced AP were more likely to develop persistent SIRS. PMID- 25545392 TI - A group-specific sequence-based typing approach for HLA-DQA1. AB - An HLA-DQA1 sequence-based typing method reliant upon group-specific amplification to achieve an unambiguous second-field DQA1 typing assignment is presented. Method validation, using 51 reference DNA samples covering 21 different DQA1 alleles, showed 100% concordance with the reference types. This typing strategy has several important uses including identifying DQA1 mismatches in kidney donor/recipient pairs to inform patient DQ antibody assignments. PMID- 25545394 TI - The effects of gender and self-insight on early semantic processing. AB - This event-related potential (ERP) study explored individual differences associated with gender and level of self-insight in early semantic processing. Forty-eight Chinese native speakers completed a semantic judgment task with three different categories of words: abstract neutral words (e.g., logic, effect), concrete neutral words (e.g., teapot, table), and emotion words (e.g., despair, guilt). They then assessed their levels of self-insight. Results showed that women engaged in greater processing than did men. Gender differences also manifested in the relationship between level of self-insight and word processing. For women, level of self-insight was associated with level of semantic activation for emotion words and abstract neutral words, but not for concrete neutral words. For men, level of self-insight was related to processing speed, particularly in response to abstract and concrete neutral words. These findings provide electrophysiological evidence for the effects of gender and self-insight on semantic processing and highlight the need to take into consideration subject variables in related research. PMID- 25545395 TI - Hemodialysis affects interatrial conduction. PMID- 25545393 TI - Borrelia burgdorferi promotes the establishment of Babesia microti in the northeastern United States. AB - Babesia microti and Borrelia burgdorferi, the respective causative agents of human babesiosis and Lyme disease, are maintained in their enzootic cycles by the blacklegged tick (Ixodes scapularis) and use the white-footed mouse (Peromyscus leucopus) as primary reservoir host. The geographic range of both pathogens has expanded in the United States, but the spread of babesiosis has lagged behind that of Lyme disease. Several studies have estimated the basic reproduction number (R0) for B. microti to be below the threshold for persistence (<1), a finding that is inconsistent with the persistence and geographic expansion of this pathogen. We tested the hypothesis that host coinfection with B. burgdorferi increases the likelihood of B. microti transmission and establishment in new areas. We fed I. scapularis larva on P. leucopus mice that had been infected in the laboratory with B. microti and/or B. burgdorferi. We observed that coinfection in mice increases the frequency of B. microti infected ticks. To identify the ecological variables that would increase the probability of B. microti establishment in the field, we integrated our laboratory data with field data on tick burden and feeding activity in an R0 model. Our model predicts that high prevalence of B. burgdorferi infected mice lowers the ecological threshold for B. microti establishment, especially at sites where larval burden on P. leucopus is lower and where larvae feed simultaneously or soon after nymphs infect mice, when most of the transmission enhancement due to coinfection occurs. Our studies suggest that B. burgdorferi contributes to the emergence and expansion of B. microti and provides a model to predict the ecological factors that are sufficient for emergence of B. microti in the wild. PMID- 25545396 TI - Opening Enediyne Scissors Wider: pH-Dependent DNA Photocleavage by meta-Diyne Lysine Conjugates. AB - Photochemical activation of meta-diynes incapable of Bergman and C1-C5 cyclizations still leads to efficient double-strand DNA cleavage. Spatial proximity of the two arylethynyl groups is not required for efficient DNA photocleavage by the enediyne-lysine conjugates. Efficiency of the cleavage is a function of the external pH and DNA damage is strongly enhanced at pH < 7. The pH dependence of the DNA photocleavage activity stems from the protonation states of lysine amino groups, the internal electron donors responsible for intramolecular PET quenching and deactivation of the photoreactive excited states. DNA-binding analysis suggests intercalative DNA binding for phenyl substituted conjugate and groove binding for TFP-substituted conjugate. Additional insights in the possible mechanism for DNA damage from the ROS (Reactive Oxygen Species) scavenger experiments found that generation of singlet oxygen is partially involved in the DNA damage. PMID- 25545397 TI - Length polymorphism in the Period 3 gene is associated with sleepiness and maladaptive circadian phase in night-shift workers. AB - The objective of the current study was to determine if night-shift workers carrying the five-repeat variant of the Period 3 gene show elevated levels of nocturnal sleepiness and earlier circadian phase compared with homozygotes for the four-repeat allele. Twenty-four permanent night-shift workers were randomly selected from a larger study. Participants took part in an observational laboratory protocol including an overnight multiple sleep latency test and half hourly saliva collection for calculation of dim-light melatonin onset. Period 3( /5) shift workers had significantly lower multiple sleep latency test during overnight work hours compared with Period 3(4/4) workers (3.52 +/- 23.44 min versus 10.39 +/- 6.41 min, P = 0.003). We observed no significant difference in sleepiness during early morning hours following acute sleep deprivation. Long allele carriers indicated significantly higher sleepiness on the Epworth Sleepiness Scale administered at 17:00 hours (12.08 +/- 2.55 versus 8.00 +/- 1.94, P < 0.001). We observed a significantly earlier melatonin onset in Period 3(-/5) individuals compared with Period 3(4/4) shift workers (20:44 +/- 6:37 versus 02:46 +/- 4:58, P = 0.021). Regression analysis suggests that Period 3 genotype independently predicts sleepiness even after controlling for variations in circadian phase, but we were unable to link Period 3 to circadian phase when controlling for sleepiness. Period 3(-/5) shift workers showed both subjective and objective sleepiness in the pathological range, while their Period 3(4/4) counterparts showed sleepiness within normal limits. Period 3(-/5) night workers also show a mean circadian phase 6 h earlier (i.e. less adapted) than Period 3(4/4) workers. Because Period 3(-/5) workers have maladaptive circadian phase as well as pathological levels of sleepiness, they may be at greater risk for occupational and automotive accidents. We interpret these findings as a call for future research on the role of Period 3 in sleepiness and circadian phase, especially as they relate to night work. PMID- 25545399 TI - Reliability and agreement in the use of four- and six-point ordinal scales for the assessment of erythema in digital images of canine skin. AB - BACKGROUND: Grading of erythema in clinical practice is a subjective assessment that cannot be confirmed using a definitive test; nevertheless, erythema scores are typically measured in clinical trials assessing the response to treatment interventions. Most commonly, ordinal scales are used for this purpose, but the optimal number of categories in such scales has not been determined. HYPOTHESIS/OBJECTIVES: This study aimed to compare the reliability and agreement of a four-point and a six-point ordinal scale for the assessment of erythema in digital images of canine skin. METHODS: Fifteen digital images showing varying degrees of erythema were assessed by specialist dermatologists and laypeople, using either the four-point or the six-point scale. Reliability between the raters was assessed using intraclass correlation coefficients and Cronbach's alpha. Agreement was assessed using the variation ratio (the percentage of respondents who chose the mode, the most common answer). Intraobserver variability was assessed by comparing the results of two grading sessions, at least 6 weeks apart. RESULTS: Both scales demonstrated high reliability, with intraclass correlation coefficient values and Cronbach's alpha above 0.99. However, the four-point scale demonstrated significantly superior agreement, with variation ratios for the four-point scale averaging 74.8%, compared with 56.2% for the six-point scale. Intraobserver consistency for the four-point scale was very high. CONCLUSIONS AND CLINICAL IMPORTANCE: Although both scales demonstrated high reliability, the four-point scale was superior in terms of agreement. For the assessment of erythema in clinical trials, a four-point ordinal scale is recommended. PMID- 25545398 TI - Short-term variability in outpatient pain intensity scores in a national sample of older veterans with chronic pain. AB - OBJECTIVE: The Department of Veterans Affairs (VA) uses the 11-point pain numeric rating scale (NRS) to gather pain intensity information from veterans at outpatient appointments. Yet, little is known about how NRS scores may vary over time within individuals; NRS variability may have important ramifications for treatment planning. Our main objective was to describe variability in NRS scores within a 1-month timeframe, as obtained during routine outpatient care in older patients with chronic pain treated in VA hospitals. A secondary objective was to explore for patient characteristics associated with within-month NRS score variability. DESIGN: Retrospective cohort study. SUBJECTS: National sample of veterans 65 years or older seen in VA in 2010 who had multiple elevated NRS scores indicating chronic pain. METHODS: VA datasets were used to identify the sample and demographic and clinical variables including NRS scores. For the main analysis, we identified subjects with two or more NRS scores obtained in each of two or more months in a 12-month period; we examined ranges in NRS scores across the first two qualifying months. RESULTS: Among 4,336 individuals in the main analysis cohort, the mean and median of the average NRS score range across the 2 months were 2.7 and 2.5, respectively. In multivariable models, main significant predictors of within-month NRS score variability were baseline pain intensity, overall medical comorbidity, and being divorced/separated. CONCLUSIONS: The majority of patients in the sample had clinically meaningful variation in pain scores within a given month. This finding highlights the need for clinicians and their patients to consider multiple NRS scores when making chronic pain treatment decisions. PMID- 25545400 TI - Metformin and its effects on myocardial dimension and left ventricular hypertrophy in normotensive patients with coronary heart disease (the MET-REMODEL study): rationale and design of the MET-REMODEL study. AB - Left ventricular hypertrophy (LVH) is a common and independent risk factor for cardiovascular events in patients with coronary artery disease (CAD). Controlling blood pressure is the standard approach to the management of LVH, but this is only partially effective as LVH also persists in normotensive patients. Apart from blood pressure (BP), other main risk factors associated with LVH are insulin resistance (IR) and central obesity. The diabetic medication, Metformin, reduces IR and aids weight loss and may therefore regress LVH. The MET REMODEL study will investigate the ability of Metformin to regress LVH in 64 patients with CAD. The MET-REMODEL trial is a single-center, phase IV, double blind, randomized, placebo controlled trial to investigate the efficacy of Metformin in regression of the independent cardiac risk factor of LVH in patients with CAD who are insulin resistant. A minimum of 64 adults with a history of CAD with LVH and IR will be randomized into two groups to receive, either Metformin XL or placebo. The primary endpoint of this trial is to investigate any change in left ventricular mass index. Secondary endpoints include changes to insulin resistance measured using fasting insulin resistance index (FIRI), obesity, LV size, and function and improvement in endothelial function. A positive result will assist clinicians to identify a new mechanism for LVH regression by administering Metformin XL. This may also lead to investigating the mortality benefit of Metformin in patients with CAD and LVH. PMID- 25545401 TI - Correlation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol. AB - Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol-evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol sensitized mice. Finally, ethanol superfusion (10-100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol. PMID- 25545402 TI - Single-step preparation of TiO2/MWCNT Nanohybrid materials by laser pyrolysis and application to efficient photovoltaic energy conversion. AB - This paper presents the continuous-flowand single-step synthesis of a TiO2/MWCNT (multiwall carbon nanotubes) nanohybrid material. The synthesis method allows achieving high coverage and intimate interface between the TiO2particles and MWCNTs, together with a highly homogeneous distribution of nanotubes within the oxide. Such materials used as active layer in theporous photoelectrode of solid state dye-sensitized solar cells leads to a substantial performance improvement (20%) as compared to reference devices. PMID- 25545403 TI - Associations between meal size, gastric emptying and post-prandial plasma glucose, insulin and lactate concentrations in meal-fed cats. AB - Plasma glucose and insulin concentrations are increased for 12-24 h in healthy cats following moderate- to high-carbohydrate meals. This study investigated associations between gastric emptying time and post-prandial plasma glucose, insulin and lactate concentrations in cats fed an extruded dry, high carbohydrate, moderate-fat, low-protein diet (51, 28, 21% metabolizable energy, respectively) once daily by varying meal volume. Eleven healthy, non-obese, neutered adult cats were enrolled in a prospective study and fed to maintain body weight. Ultrasound examinations were performed for up to 26 h, and blood collections over 24 h after eating meals containing approximately 100% and 50% of the cats' daily caloric intake (209 and 105 kJ/kg BW, respectively). Gastric emptying time was increased after a meal of 209 kJ/kg BW compared with 105 kJ/kg BW (median gastric emptying times 24 and 14 h, respectively; p = 0.03). Time for glucose to return to fasting was longer after the 209 kJ/kg BW meal (median 20 h; 25th and 75th percentiles 15 and 23 h, respectively) than the 105 kJ/kg BW meal (13, 12 and 14 h; p < 0.01); however, peak glucose was not higher after the 209 kJ/kg BW meal compared with the 105 kJ/kg BW meal [(mean +/- SD) 6.6 +/- 0.6 and 7.8 +/- 1.2 mmol/l, respectively, p = 0.07]. Times for insulin to return to fasting were not significantly longer after the 209 kJ/kg BW meal than the 105 kJ/kg BW meal (p = 0.29). d- and l-lactate concentrations were not associated with gastric emptying time or post-prandial blood glucose and insulin. Based on results obtained, prolonged gastric emptying contributes to prolonged post prandial hyperglycemia in cats meal fed a high-carbohydrate, low-protein, dry diet and fasting times for cats' meal-fed diets of similar composition should be 14-26 h, depending on meal size. PMID- 25545404 TI - Emergency department visits related to Clostridium difficile infection: results from the nationwide emergency department sample, 2006 through 2010. AB - OBJECTIVES: The objective was to estimate emergency department (ED) visits for Clostridium difficile infection in the United States for the years 2006 through 2010. METHODS: Estimates of ED visits for C. difficile infection were calculated in patients 18 years and older using the Nationwide Emergency Department Sample. RESULTS: During the calendar years 2006 through 2010, there were an estimated total of 491,406,018 ED visits. Of these, 462,160 ED visits were associated with a primary International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis of C. difficile. The C. difficile infection ED visit rate (visits/100,000 census population) increased from 34.1 in 2006 to 42.3 in 2010, an increase of 24% (p < 0.01). There was also a significant overall increased trend in the number of ED visits for C. difficile from 2006 through 2010 (p < 0.01). The highest ED visit rate for C. difficile was observed for patients 65 years and older (163.18 per 100,000), while the lowest visit rate was for patients aged 18 to 24 years (5.10 per 100,000). The greatest increase in C. difficile infection visits occurred in the age group 18 to 24 years. CONCLUSIONS: These results indicate an increased trend of ED visits for C. difficile in the period 2006 through 2010 with an overall population-adjusted increase of 24%. This represents important complementary data to previous studies reporting an increase in the rate of C. difficile infections in the U.S. hospitalized population. PMID- 25545405 TI - Screening for congenital heart defects by transabdominal ultrasound - role of early gestational screening and importance of operator training. AB - The majority of congenital heart defects occur without identifiable risk factors. Detection rates are therefore highly dependent on the experience and expertise of the obstetrical screening operator. In the first trimester, the risk of congenital heart defects increases with increasing nuchal thickness (>=2.5 mm detects 44% of major congenital heart defects), but because of the number of false positives, the positive predictive value is only a few percent. The anatomy of major congenital heart defects may be delineated in less than half of the fetuses during early second trimester. The reported yield of congenital heart defects detection during the mid-gestational routine obstetrical screening has improved over time and detection rates up to 85% of major congenital heart defects have been reported when outflow tract and three-vessel views are included in conjunction with the four-chamber view. Improved detection rates have been achieved following screening operator training interventions combined with a low referral threshold to obtain a detailed fetal echocardiographic study. PMID- 25545406 TI - Oxo-bridge scenario behind single-site water-oxidation catalysts. AB - High-oxidation-state decay of mononuclear complexes [RuTB(H2O)](2+) (X(2+), where B = 2,2'-bpy or bpy for X = 1; B = 5,5'-F2-bpy for X = 2; B = 6,6'-F2-bpy for X = 3; T = 2,2':6',2"-terpyridine) oxidized with a large excess of Ce(IV) generates a manifold of polynuclear oxo-bridged complexes. These include the following complexes: (a) dinuclear [TB-Ru(IV)-O-Ru(IV)-(T)(O)OH2](2+) (1-dn(4+)), [TB Ru(III)-O-Ru(III)-T(MeCN)2](4+) (1-dn-N(4+)), and {[Ru(III)(trpy)(bpy)]2(MU O)}(4+) (1-dm(4+)); (b) trinuclear {[Ru(III)(trpy)(bpy)(MU O)]2Ru(IV)(trpy)(H2O)}(ClO4)5(6+) (1-tr(6+)) and {[Ru(III)(trpy)(bpy)(MU O)]2Ru(IV)(pic)2}(ClO4)4 (1-tr-P(4+), where P is the 2-pyridinecarboxylate anion); and (c) tetranuclear [TB-Ru(III)-O-TRu(IV)(H2O)-O-TRu(IV)(H2O)-O-Ru(III) TB](8+) (1-tn(8+)), [TB-Ru(III)-O-TRu(IV)(AcO)-O-TRu(IV)(AcO)-O-Ru(III)-TB](6+) (1-tn-Ac(6+)), and [TB-Ru(II)-O-TRu(IV)(MeCN)-O-TRu(IV)(MeCN)-O-Ru(II)-TB](6+) (1 tn-N(6+)). These complexes have been characterized structurally by single-crystal X-ray diffraction analysis, and their structural properties were correlated with their electronic structures. Dinuclear complex 1-dm(4+) has been further characterized by spectroscopic and electrochemical techniques. Addition of excess Ce(IV) to 1-dm(4+) generates dioxygen in a catalytic manner. However, resonance Raman spectroscopy points to the in situ formation of 1-dn(4+) as the active species. PMID- 25545408 TI - Investigation of Werner protein as an early DNA damage response in actinic keratosis, Bowen disease and squamous cell carcinoma. AB - BACKGROUND: Werner protein (WRN) has DNA helicase activity and participates in recombination, replication and repair of DNA. Loss-of-function mutations in WRN gives rise to genetic instability and diseases such as premature ageing and cancer. Upregulation of WRN promotes proliferation and survival of cancer cells. AIM: To evaluate the expression pattern of WRN in closely related skin cancers and their correlation with age, sex and UV exposure. METHODS: Immunohistochemistry was used to investigate expression of WRN in formalin-fixed, paraffin wax-embedded tissue specimens of 9 squamous cell carcinoma (SCC), 15 actinic keratosis (AK), 11 Bowen disease (BD) and 11 normal-appearing peripheral tissue samples, obtained from patients during surgical resections. RESULTS: WRN expression was significantly increased in BD, AK and SCC compared with normal controls, with the mean WRN staining score being highest in BD, followed by AK and SCC. However, age, sex and sun exposure were not associated with WRN expression. CONCLUSIONS: To our knowledge, this is the first report to date investigating the expression of WRN in skin cancers. The overtly high expression of WRN in premalignant lesions and in in situ cancer, with relatively low WRN expression in SCC, may indicate that WRN contributes as a checkpoint for early DNA damage response in skin tumorigenesis. PMID- 25545407 TI - Sirt1-deficient mice have hypogonadotropic hypogonadism due to defective GnRH neuronal migration. AB - Hypogonadatropic hypogonadism (HH) can be acquired through energy restriction or may be inherited as congenital hypogonadotropic hypogonadism and its anosmia associated form, Kallmann's syndrome. Congenital hypogonadotropic hypogonadism is associated with mutations in a group of genes that impact fibroblast growth factor 8 (FGF8) function. The Sirt1 gene encodes a nicotinamide adenine dinucleotide-dependent histone deacetylase that links intracellular metabolic stress to gene expression. Herein Sirt1(-/-) mice are shown to have HH due to failed GnRH neuronal migration. Sirtuin-1 (Sirt1) catalytic function induces GnRH neuronal migration via binding and deacetylating cortactin. Sirt1 colocalized with cortactin in GnRH neurons in vitro. Sirt1 colocalization with cortactin was regulated in an FGF8/fibroblast growth factor receptor-1 dependent manner. The profound effect of Sirt1 on the hormonal status of Sirt1(-/-) mice, mediated via defective GnRH neuronal migration, links energy metabolism directly to the hypogonadal state. Sirt1-cortactin may serve as the distal transducer of neuronal migration mediated by the FGF8 synexpression group of genes that govern HH. PMID- 25545409 TI - Single-leg drop landing movement strategies 6 months following first-time acute lateral ankle sprain injury. AB - No research exists predicating a link between acute ankle sprain injury affiliated movement patterns and those of chronic ankle instability (CAI) populations. The aim of the current study was to perform a biomechanical analysis of participants, 6 months after they sustained a first-time acute lateral ankle sprain (LAS) injury to establish this link. Fifty-seven participants with a 6 month history of first-time LAS and 20 noninjured participants completed a single leg drop landing task on both limbs. Three-dimensional kinematic (angular displacement) and sagittal plane kinetic (moment of force) data were acquired for the joints of the lower extremity, from 200 ms pre-initial contact (IC) to 200 ms post-IC. Individual joint stiffnesses and the peak magnitude of the vertical component of the ground reaction force (GRF) were also computed. LAS participants displayed increases in hip flexion and ankle inversion on their injured limb (P < 0.05); this coincided with a reduction in the net flexion-extension moment at the hip joint, with an increase in its stiffness (P < 0.05). There was no difference in the magnitude of the peak vertical GRF for either limb compared with controls. These results demonstrate that altered movement strategies persist in participants, 6 months following acute LAS, which may precipitate the onset of CAI. PMID- 25545410 TI - Involvement of the dorsolateral prefrontal cortex and superior temporal sulcus in impaired social perception in schizophrenia. AB - BACKGROUND: Schizophrenia is a mental disorder characterized by impairments in diverse thinking and emotional responses, which are related to social perception dysfunction. This fMRI study was designed to investigate a neurobiological basis of social perception deficits of patients with schizophrenia in various social situations of daily life and their relationship with clinical symptoms and social dysfunction. METHODS: Seventeen patients and 19 controls underwent functional magnetic resonance imaging, during which participants performed a virtual social perception task, containing an avatar's speech with positive, negative or neutral emotion in a virtual reality space. Participants were asked to determine whether or not the avatar's speech was appropriate to each situation. RESULTS: The significant group*appropriateness interaction was seen in the left dorsolateral prefrontal cortex (DLPFC), resulting from lower activity in patients in the inappropriate condition, and left DLPFC activity was negatively correlated with the severity of negative symptoms and positively correlated with the level of social functioning. The significant appropriateness*emotion interaction observed in the left superior temporal sulcus (STS) was present in controls, but absent in patients, resulting from the existence and absence of a difference between the inappropriate positive and negative conditions, respectively. CONCLUSIONS: These findings indicate that dysfunction of the DLPFC-STS network may underlie patients' abnormal social perception in various social situations of daily life. Abnormal functioning of this network may contribute to increases of negative symptoms and decreases of social functioning. PMID- 25545412 TI - Immunoglobulin A vasculitis in the oldest old. PMID- 25545411 TI - Is self-management feasible and acceptable for addressing nutrition and physical activity needs of cancer survivors? AB - BACKGROUND: Self-management is recommended for patients with chronic conditions, but its use with cancer survivors is underexplored. Optimal strategies for achieving lifestyle changes in cancer survivors are not known. OBJECTIVE: We aimed to determine feasibility, acceptability and preliminary efficacy of self management-based nutrition and physical activity interventions for cancer survivors. DESIGN, SETTING AND PARTICIPANTS: Adult survivors (n = 25) during (Group 1 , n = 11) or post (Group 2, n = 14)-curative chemotherapy for solid tumours, most (n = 20, 80%) with breast cancer, were recruited prospectively from a single clinical centre. INTERVENTION: The Flinders Living Well Self-Management Program, a generic self-management care planning programme, was utilized to establish patient-led nutrition and exercise goals within a tailored 12-week intervention. Fortnightly progress reviews occurred with assessments at baseline, 6 and 12 weeks. RESULTS: Most participants (84%) found the intervention acceptable/very acceptable. Both groups showed a trend towards significant improvement in the self-management capability 'knowledge about changing risk factors' (P = 0.047); Group 2 showed a trend towards significantly improved 'psychological impacts' (P = 0.007). Goal ratings improved for both groups (P = 0.001). Quality of life improved for both groups for emotional functioning (P = 0.03). Physical functioning improved for Group 2 (P = 0.05); however, most symptom domains worsened for Group 1, as expected given their treatment stage. DISCUSSION AND CONCLUSIONS: Self-management interventions are feasible for this population. In particular, building self-management capacity during the active phase of patients' cancer treatment provides health and psychosocial benefits. Larger randomized controlled trials are required to further determine efficacy. Further translational research is also needed to determine acceptability,feasibility, enablers and barriers for clinicians embedding this approach into routine cancer survivorship care. PMID- 25545413 TI - Dual labeling with 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine for estimation of cell migration rate in the small intestinal epithelium. AB - Small intestinal epithelium is a self-renewing system in which the entire sequence of cell proliferation, differentiation, and removal is coupled to cell migration along the crypt-villus axis. We examined whether dual labeling with different thymidine analogues, 5-bromo-2'-deoxyuridine (BrdU) and 5-ethynyl-2' deoxyuridine (EdU), can be used to estimate cell migration rates on the villi of small intestines in rats. Rats received a single intraperitoneal injection of BrdU and EdU within a time interval, and signals in tissue sections were examined by immunohistochemistry and the "click" reaction, respectively. We successfully observed BrdU- and EdU-positive cells on the epithelium with no cross-reaction. In addition, we observed an almost complete overlapping of BrdU- and EdU-positive cells in rats administered simultaneously with BrdU and EdU. By calculating the cell migration rate by dividing the distance between the median cell positions of the distribution of BrdU- and EdU-positive cells by the time between the injection of BrdU and EdU, we estimated approximately 9 and 5 MUm/h for the cell migration rates on the villi in the jejunum and ileum, respectively. We propose that dual labeling with BrdU and EdU within a time interval, followed by detecting with immunohistochemistry and the click reaction, respectively, is useful to estimate accurately the cell migration rate in the intestinal epithelium in a single animal. PMID- 25545415 TI - Histamine and substance P in synovial fluid of patients with temporomandibular disorders. AB - Although psychosocial factors and malocclusion are regarded as potential causes of temporomandibular disorders (TMD), the underlying pathogenesis is poorly understood. Recent studies suggest that substance P (SP), which has been associated with both psychosocial factors and malocclusion, and histamine, whose release can be induced by SP, may be implicated in the pathogenetic process. This study was designed to measure the concentration of histamine and SP in synovial fluid (SF) of both 38 patients with TMD and 11 healthy controls, and analyse the correlation between histamine and SP. Patients with TMD were divided into three subgroups: displaced disc with reduction (DDR), displaced disc without reduction (DDNR) and osteoarthritis (OA), with 10, 13, 15 subjects in every subgroup, respectively. After collecting SF samples, histamine and SP levels were measured by enzyme-linked immunosorbent assay analysis (ELISA) and calibrated by bicinchoninic acid (BCA)-quantified protein level in the samples. The results suggest that OA group presented a significantly higher level of both histamine and SP than DDNR, DDR and healthy control groups. Histamine or SP in DDR and DDNR groups tend to be higher than control group, but no significance was found. Painful TMJs show higher histamine and SP than painless TMJs. Correlation analysis reveals a significant correlation between histamine and SP concentrations. Collectively, this study showed the changes of histamine and SP in the SF from different stages of TMD and found a significant correlation between the two substances, suggesting their potential implication in the pathogenesis of TMD. PMID- 25545416 TI - Live music reduces stress levels in very low-birthweight infants. AB - AIM: Music might benefit preterm infants in stressful, intensive care environments. However, data on stress level indicators, determined by salivary cortisol levels, are scarce. We evaluated the effect of live harp music on the stress level indicators of preterm infants in a neonatal intensive care unit (NICU). METHODS: We exposed 20 stable preterm infants to music for 15 min on three consecutive days. Saliva was collected before the music was played and 25 min and 4 h after it ended. Salivary cortisol levels were measured by liquid chromatography-tandem mass spectrometry and vital signs, oxygen saturation, bradycardia, apnoeas and oxygen desaturations were recorded. Pain levels were assessed by the Bernese Pain Scale for Neonates. RESULTS: Salivary cortisol was significantly lower 25 min (18.9 nmol/L [3.9-35.6] p = 0.001) and 4 h after music (17.4 nmol/L [3.9-35.3] p = 0.003) than at baseline 4 h before exposure (19.5 nmol/L [7.2-51.1]). After music, the number of apnoeas and oxygen desaturations was significantly reduced on all three, days and the number of bradycardia episodes on day one. Pain scores significantly improved after music on all 3 days. CONCLUSION: Exposure to live music reduced salivary cortisol and had beneficial effects on the physiologic parameters of stable preterm infants in a NICU. PMID- 25545414 TI - Plasmodium vivax trophozoite-stage proteomes. AB - Plasmodium vivax is the causative infectious agent of 80-300 million annual cases of malaria. Many aspects of this parasite's biology remain unknown. To further elucidate the interaction of P. vivax with its Saimiri boliviensis host, we obtained detailed proteomes of infected red blood cells, representing the trophozoite-enriched stage of development. Data from two of three biological replicate proteomes, emphasized here, were analyzed using five search engines, which enhanced identifications and resulted in the most comprehensive P. vivax proteomes to date, with 1375 P. vivax and 3209 S. boliviensis identified proteins. Ribosome subunit proteins were noted for both P. vivax and S. boliviensis, consistent with P. vivax's known reticulocyte host-cell specificity. A majority of the host and pathogen proteins identified belong to specific functional categories, and several parasite gene families, while 33% of the P. vivax proteins have no reported function. Hemoglobin was significantly oxidized in both proteomes, and additional protein oxidation and nitration was detected in one of the two proteomes. Detailed analyses of these post-translational modifications are presented. The proteins identified here significantly expand the known P. vivax proteome and complexity of available host protein functionality underlying the host-parasite interactive biology, and reveal unsuspected oxidative modifications that may impact protein function. BIOLOGICAL SIGNIFICANCE: Plasmodium vivax malaria is a serious neglected disease, causing an estimated 80 to 300 million cases annually in 95 countries. Infection can result in significant morbidity and possible death. P. vivax, unlike the much better studied Plasmodium falciparum species, cannot be grown in long-term culture, has a dormant form in the liver called the hypnozoite stage, has a reticulocyte host cell preference in the blood, and creates caveolae vesicle complexes at the surface of the infected reticulocyte membranes. Studies of stage-specific P. vivax expressed proteomes have been limited in scope and focused mainly on pathogen proteins, thus limiting understanding of the biology of this pathogen and its host interactions. Here three P. vivax proteomes are reported from biological replicates based on purified trophozoite-infected reticulocytes from different Saimiri boliviensis infections (the main non-human primate experimental model for P. vivax biology and pathogenesis). An in-depth analysis of two of the proteomes using 2D LC/MS/MS and multiple search engines identified 1375 pathogen proteins and 3209 host proteins. Numerous functional categories of both host and pathogen proteins were identified, including several known P. vivax protein family members (e.g., PHIST, eTRAMP and VIR), and 33% of protein identifications were classified as hypothetical. Ribosome subunit proteins were noted for both P. vivax and S. boliviensis, consistent with this parasite species' known reticulocyte host-cell specificity. In two biological replicates analyzed for post-translational modifications, hemoglobin was extensively oxidized, and various other proteins were also oxidized or nitrated in one of the two replicates. The cause of such protein modification remains to be determined but could include oxidized heme and oxygen radicals released from the infected red blood cell's parasite-induced acidic digestive vacuoles. In any case, the data suggests the presence of distinct infection-specific conditions whereby both the pathogen and host infected red blood cell proteins may be subject to significant oxidative stress. PMID- 25545417 TI - Detection and decay rates of prey and prey symbionts in the gut of a predator through metagenomics. AB - DNA methods are useful to identify ingested prey items from the gut of predators, but reliable detection is hampered by low amounts of degraded DNA. PCR-based methods can retrieve minute amounts of starting material but suffer from amplification biases and cross-reactions with the predator and related species genomes. Here, we use PCR-free direct shotgun sequencing of total DNA isolated from the gut of the harlequin ladybird Harmonia axyridis at five time points after feeding on a single pea aphid Acyrthosiphon pisum. Sequence reads were matched to three reference databases: Insecta mitogenomes of 587 species, including H. axyridis sequenced here; A. pisum nuclear genome scaffolds; and scaffolds and complete genomes of 13 potential bacterial symbionts. Immediately after feeding, multicopy mtDNA of A. pisum was detected in tens of reads, while hundreds of matches to nuclear scaffolds were detected. Aphid nuclear DNA and mtDNA decayed at similar rates (0.281 and 0.11 h(-1) respectively), and the detectability periods were 32.7 and 23.1 h. Metagenomic sequencing also revealed thousands of reads of the obligate Buchnera aphidicola and facultative Regiella insecticola aphid symbionts, which showed exponential decay rates significantly faster than aphid DNA (0.694 and 0.80 h(-1) , respectively). However, the facultative aphid symbionts Hamiltonella defensa, Arsenophonus spp. and Serratia symbiotica showed an unexpected temporary increase in population size by 1-2 orders of magnitude in the predator guts before declining. Metagenomics is a powerful tool that can reveal complex relationships and the dynamics of interactions among predators, prey and their symbionts. PMID- 25545418 TI - How specialised is bird pollination in the Cactaceae? AB - Many cactus species produce 'bird' flowers; however, the reproductive biology of the majority of these species has not been studied. Here, we report on a study of the pollination of two species from the Cleistocactus genus, cited as an ornithophilous genus, in the context of the different ways in which they are specialised to bird pollination. In addition, we re-evaluate the level of specialisation of previous studies of cacti with bird pollination and evaluate how common phenotypic specialisation to birds is in this family. Both Cleistocactus species exhibited ornithophilous floral traits. Cleistocactus baumannii was pollinated by hummingbirds, whereas Cleistocactus smaragdiflorus was pollinated by hummingbirds and bees. Pollination by birds has been recorded in 27 cactus species, many of which exhibit ornithophilous traits; however, they show generalised pollination systems with bees, bats or moths in addition to birds being their floral visitors. Of all cactus species, 27% have reddish flowers. This trait is associated with diurnal anthesis and a tubular shape. Phenotypic specialisation to bird pollination is recognised in many cactus species; however, it is not predictive of functional and ecological specialisation in this family. PMID- 25545419 TI - Betty Joseph 1917-2013. PMID- 25545420 TI - Partitioning of Dietary Metal Intake--A Metal Dietary Exposure Screening Tool. AB - Detection of heavy metals at trace or higher levels in foods and food ingredients is not unexpected given the widespread unavoidable presence of several metals in nature, coupled with advancement in analytical methods and lowering limits of detection. To assist risk managers with a rapid risk assessment when facing these situations, a metal dietary exposure screening tool (MDEST) was developed. The tool uses food intake rates based on the National Health and Nutrition Examination Survey 2005-2010 consumption data for the U.S. population two+ years and up and for infants age six months to 95th percentile for gestational age [GA]). The term protocol (March 2010-July 2012) specified delivery at 39(0/7) weeks with normal S:D ratios and 37(0/7) weeks with elevated S:D ratios when antenatal testing was reassuring. RESULTS: There were 228 and 312 women in the early term and term protocol, respectively, who met inclusion criteria. Compared with the early term group, the term group had an increased median GA at delivery (37.1 vs. 38.6%, p < 0.001), decreased deliveries less than 37(0/7) weeks (37 vs. 24%, p = 0.01) and decreased neonatal intensive care unit (NICU) admissions (38 vs. 28%, p = 0.02). CONCLUSION: A protocol specifying delivery at 39(0/7) weeks when UA S:D ratios are normal and delivery at 37(0/7) weeks when UA S:D ratios are elevated when other antenatal testing is reassuring in FGR: (1) prolonged gestation, (2) decreased preterm births, and (3) decreased NICU admissions. PMID- 25545441 TI - Antenatal corticosteroids for preterm premature rupture of membranes: single or repeat course? AB - OBJECTIVE: The aim of this article is to determine the risk of maternal chorioamnionitis and neonatal morbidity in women with preterm premature rupture of membranes (PPROM) exposed to one corticosteroid course versus a single repeat corticosteroid steroid course. STUDY DESIGN: Secondary analysis of a cohort of women with singleton pregnancies and PPROM. The primary outcome was a clinical diagnosis of maternal chorioamnionitis. Using multivariate logistic regression, we controlled for maternal age, race, body mass index, diabetes, gestational age at membrane rupture, preterm labor, and antibiotic administration. Neonatal morbidities were compared between groups controlling for gestational age at delivery. RESULTS: Of 1,652 women with PPROM, 1,507 women received one corticosteroid course and 145 women received a repeat corticosteroid course. The incidence of chorioamnionitis was similar between groups (single course = 12.3% vs. repeat course = 11.0%; p = 0.8). Women receiving a repeat corticosteroid course were not at increased risk of chorioamnionitis (adjusted odds ratio, 1.28; 95% confidence interval, 0.69-2.14). A repeat course of steroids was not associated with an increased risk of any neonatal morbidity. CONCLUSION: Compared with a single steroid course, our findings suggest that the risk of maternal chorioamnionitis or neonatal morbidity may not be increased for women with PPROM receiving a repeat corticosteroid course. PMID- 25545443 TI - Assessment of association between rapid fluctuations in serum sodium and intraventricular hemorrhage in hypernatremic preterm infants. AB - AIM: This study aims to determine the association between the rapid fluctuations in serum sodium and intraventricular hemorrhage (IVH) or death in hypernatremic preterm infants. STUDY DESIGN: Single center observational study including 216 infants < 1,000 g birth weight and <29 weeks gestational age, who had serum sodium levels monitored at least every 12 hours. Logistic regression analyses were used to identify which of the commonly cited risk factors for IVH, including the rapid (to the extent of >=10 and >=15 mmol/L/d) rise or fall in serum sodium, was associated with the primary outcome of any IVH, or the secondary composite outcome of severe IVH or death during the first 10 days of life in hypernatremic infants. RESULTS: Of 216 infants, 126 (58%) studied developed hypernatremia (serum sodium >= 150 mmol/L). IVH was more frequent in hypernatremic infants (p = 0.01). Presence of hypernatremia was an independent risk factor for IVH on logistic regression analysis (p = 0.022, odds ratio 2.0, 95% confidence interval: 1.1-3.8). Rapid (>= 10 and >= 15 mmol/L/d) rise or fall in serum sodium in hypernatremic infants was not associated with the outcomes. CONCLUSION: Hypernatremia per se, but not the rapid fluctuations (not exceeding 10-15 mmol/L/d) in serum sodium was independently associated with IVH. PMID- 25545444 TI - Impact of routine methicillin-resistant Staphylococcus aureus (MRSA) surveillance and cohorting on MRSA-related bloodstream infection in neonatal intensive care unit. AB - OBJECTIVE: To study the impact of methicillin-resistant Staphylococcus aureus (MRSA) surveillance on the incidence of MRSA-related bloodstream infection (BSI) in neonatal intensive care unit (NICU) and to evaluate cost-effectiveness of MRSA surveillance. STUDY DESIGN: MRSA surveillance policy was introduced in our NICU in April 2008. Pre-MRSA surveillance period (P1, April 2006-March 2008) was compared with the surveillance period (P2, April 2008-April 2010) for MRSA related BSI (MRSA BSI). RESULTS: During P1 and P2, 1,576 and 1,512 neonates were enrolled. Of these, 3.8/1,000 and 5.3/1,000 developed MRSA BSI, respectively. During P2, 100% MRSA-related BSI occurred in MRSA-colonized neonates, as compared with zero in noncolonized group (p < 0.0001). Overall, 7 (30%) of the 23 neonates colonized during hospitalization developed MRSA BSI as compared with 1 of the 31 (3%) neonates colonized at admission (p = 0.007). Direct screening cost was $208 per patient. Since 28 neonates had to be screened to detect one colonization, $5,824 estimated per detection, excluding indirect costs. CONCLUSIONS: MRSA surveillance may protect non-MRSA colonized neonates from becoming colonized. This is of considerable importance because the acquisition of colonization during hospitalization was associated with a 10-fold increase in risk of developing MRSA BSI. Cost-effectiveness of MRSA surveillance remains debatable and further studies are needed to delineate cost-benefit ratio. PMID- 25545445 TI - Nil-per-os days and necrotizing enterocolitis in extremely preterm infants. AB - OBJECTIVE: This study aims to evaluate the association between nil-per-os (NPO) days and development of necrotizing enterocolitis (NEC) in extremely preterm neonates (<29 weeks gestational age). STUDY DESIGN: A case-control study of 234 extremely preterm neonates who developed stage II or III NEC and 467 matched control infants admitted to participating sites in the Canadian Neonatal Network between 2010 and 2011 was conducted. The number and percentage of NPO days before the development of NEC was compared with the equivalent period in control infants using logistic regression. RESULTS: Infants with NEC were NPO on average 5.6 days (28% of days before NEC) versus 3.7 days (19% of equivalent days; p < 0.01) among controls. NEC cases required more days of inotropic support, antibiotic use, and had higher rates of patent ductus arteriosus (PDA). After adjusting for inotrope use, PDA, antibiotics, and severity of illness, for each additional NPO day the adjusted odds for NEC increased by 1.08 (95% confidence interval: 1.04-1.12). CONCLUSION: Among extremely preterm neonates, those who developed NEC were NPO for a longer period of time than control infants who were NEC-free. We speculate that delayed initiation or interruption of feeding may be a potent risk factor for NEC. PMID- 25545446 TI - Broad-spectrum light versus blue light for phototherapy in neonatal hyperbilirubinemia: a randomized controlled trial. AB - Phototherapy is standard care for treatment of neonatal hyperbilirubinemia. Our aim was to compare the effectiveness of broad-spectrum light (BSL) to that of blue light emitting diodes (LED) phototherapy for the treatment of jaundiced late preterm and term infants. Infants with gestational age from 35(+0) to 41(+6) weeks of gestation and nonhemolytic hyperbilirubinemia were randomized to treatment with BSL phototherapy or blue LED phototherapy. A total of 20 infants were included in the blue LED phototherapy group and 20 in the BSL phototherapy group. The duration of phototherapy was lower in the BSL than in the blue LED phototherapy group (15.8 +/- 4.9 vs. 20.6 +/- 6.0 hours; p = 0.009), and infants in the former group had a lower probability (p = 0.015) of remaining in phototherapy than infants in the latter. We concluded that BSL phototherapy is more effective than blue LED phototherapy for the treatment of hyperbilirubinemia in late preterm and term infants. Our data suggest that these results are not due to the different irradiance of the two phototherapy systems, but probably depend on their different peak light emissions. PMID- 25545447 TI - Differing effects of resibufagenin on cinobufatalin- versus marinobufagenin induced preeclampsia in a rodent model. AB - OBJECTIVE: Previous studies from this laboratory have demonstrated that the bufodienolide, marinobufagenin, causes a syndrome in the pregnant rat that resembles human preeclampsia. Furthermore, marinobufagenin urinary excretion is elevated in approximately 85% of preeclamptic patients. Resibufagenin, an antagonist to marinobufagenin, completely prevents the syndrome (hypertension, proteinuria, and intrauterine growth restriction) if given from early pregnancy. STUDY DESIGN: We investigated the effects of another bufodienolide, cinobufatalin, to determine if it, likewise, could induce the rat "preeclamptic" syndrome, which it did. We then examined whether resibufagenin could prevent the syndrome due to cinobufatalin. RESULTS: Resibufagenin improved hypertension but not proteinuria, and did not prevent uterine growth restriction. CONCLUSION: We conclude that more than one bufodienolide may induce the preeclamptic syndrome and that each may require a specific antagonist to prevent (or treat) the syndrome. PMID- 25545448 TI - Interaction between maternal obesity and 1-hour glucose challenge test results on maternal and perinatal outcomes. AB - OBJECTIVE: The objective of this study was to examine the relationship between positive glucose challenge test (GCT) values and perinatal outcomes stratified by maternal body mass index (BMI). STUDY DESIGN: Retrospective cohort of singleton gestations with a GCT performed at >20 weeks and documented BMI at entry to care. Subjects were classified by GCT level and BMI. Primary outcomes included large for gestational age (LGA), macrosomia, shoulder dystocia, and pregnancy-induced hypertension. Cochran-Armitage tests for trend and logistic regression were used to compare the GCT categories. RESULTS: A total of 14,525 women met enrollment criteria-8,521 with a GCT < 120 mg/dL and 6,004 with a GCT >= 120 mg/dL. When BMI < 25 kg/m(2) was considered, the risks were not increased at any level of GCT for any outcome. However, for subjects with BMI >= 25 kg/m(2), the risk of LGA for a GCT 130 to 134 mg/dL was increased, but not at GCT of 135 to 139 mg/dL (p < 0.001). Similar, but nonsignificant, trends were observed for macrosomia and shoulder dystocia. CONCLUSION: Increasing GCT is associated with adverse outcomes primarily in women with a BMI >= 25 kg/m(2). Women with a BMI >= 25 kg/m(2) and a GCT 135 to 140 mg/dL appear to have less risk of LGA than women with GCT 130 to 134 mg/dL, suggesting a possible effect of diagnosing and treating gestational diabetes mellitus in this group. PMID- 25545449 TI - Optimal timing for term delivery of twin pregnancies: a population-based study. AB - OBJECTIVE: The objective of this study was to examine the risk of adverse neonatal outcomes after twin delivery according to gestational age. MATERIALS AND METHODS: The U.S. Natality Database from 2007 to 2010 was reviewed. Inclusion criteria were twin deliveries and gestational age of 37 to 42 weeks. Exclusion criteria were congenital anomalies and missing/incomplete data. Cases were subdivided by gestational age into early term, term, and late term. Singleton pregnancies matched by delivery time and location were selected as controls. Outcome variables included were low Apgar score, assisted ventilation, neonatal intensive care unit admission, surfactant/antibiotic use, seizures, and birth injury. Logistic regression analysis was used to calculate adjusted odds ratios according to gestational age and plurality, using singleton term as reference. RESULTS: A total of 220,169 twin and 270,540 singleton deliveries were identified. The risk of adverse neonatal outcomes for twins was higher than for singletons. For twins, the distribution of the risks of the composite of adverse neonatal outcomes was linear, being the lowest at early term and the highest at late term, whereas the distribution for singletons was u-shaped being lowest at term compared with early and late term. CONCLUSIONS: Twins are at higher risk of suboptimal neonatal outcomes than singletons, but do better when delivered at early term rather than term or late term. PMID- 25545450 TI - Obstetric Recommendations in American Congress of Obstetricians and Gynecologists Practice Bulletins versus UpToDate: a comparison. AB - OBJECTIVE: To compare the obstetric recommendations in American Congress of Obstetricians and Gynecologists (ACOG) practice bulletins (PB) with similar topics in UpToDate (UTD). STUDY DESIGN: We accessed all obstetric PB and cross searched UTD (May 1999-May 2013). We analyzed only the PB which had corresponding UTD chapter with graded recommendations (level A-C). To assess comparability of recommendations for each obstetric topic, two maternal-fetal medicine (MFM) subspecialists categorized the statement as similar, dissimilar, or incomparable. Simple and weighted kappa statistics were calculated to assess agreement between the two raters. RESULTS: We identified 46 ACOG obstetric PB and 86 UTD chapters. There were 50% fewer recommendations in UTD than in PB (181 vs. 365). The recommendations being categorized as level A, B, or C was significantly different (p < 0.001) for the two guidelines. While the overall concordance rate between the two MFM subspecialists was 83% regarding the recommendations for the same topic as similar, dissimilar, or incomparable, the agreement was moderate (kappa, 0.56; 95% confidence intervals, 0.48-0.65). CONCLUSION: Though obstetricians have two sources for graded recommendations, incongruity among them may be a source of consternation. Congruent recommendations from ACOG and UTD could enhance compliance and potentially optimize outcomes. PMID- 25545451 TI - Prospective effects of possible selves on alcohol consumption in adolescents. AB - Possible selves, cognitions about the self that reflect hopes, fears, and expectations for the future, are reliable predictors of health risk behaviors but have not been explored as predictors of adolescents' alcohol use. In a secondary analysis of data from 137 adolescents, we examined the influence of possible selves assessed in eighth grade on alcohol consumption (yes/no and level of use) in ninth grade. Having a most important feared possible self related to academics in eighth grade predicted alcohol abstinence in ninth grade. Among those who reported alcohol use, having many hoped-for possible selves and a most important hoped-for possible self related to academics in eighth grade predicted lower level of alcohol consumption in ninth grade. Interventions that foster the personal relevance and importance of academics and lead to the development of hoped-for possible selves may reduce adolescents' alcohol consumption. PMID- 25545452 TI - Synthesis and in vivo evaluation of gallium-68-labeled glycine and hippurate conjugates for positron emission tomography renography. AB - The objective of this study was to evaluate four new (68) Ga-labeled 1,4,7,10 cyclododeca-1,4,7,10-tetraacetic acid (DOTA)/1,4,7-triazacyclononane-1,4,7 triacetic acid derived (NODAGA)-glycine/hippurate conjugates and select a lead candidate for potential application in positron emission tomography (PET) renography. The non-metallated conjugates were synthesized by a solid phase peptide synthesis method. The (68) Ga labeling was achieved by reacting an excess of the non-metallated conjugate with (68) GaCl4 (-) at pH -4.5 and 10-min incubation either at room temperature for NODAGA or 90 degrees C for DOTA. Radiochemical purity of all (68) Ga conjugates was found to be >98%. (68) Ga NODAGA-glycine displayed the lowest serum protein binding (0.4%) in vitro among the four (68) Ga conjugates. Biodistribution of (68) Ga conjugates in healthy Sprague Dawley rats at 1-h post-injection revealed an efficient clearance from circulation primarily through the renal-urinary pathway with <0.2% of injected dose per gram remaining in the blood. The kidney/blood and kidney/muscle ratios of (68) Ga-NODAGA-glycine were significantly higher than other (68) Ga conjugates. On the basis of these results, (68) Ga-NODAGA-glycine was selected as the lead candidate. (68) Ga-NODAGA-glycine PET renograms obtained in healthy rats suggest (68) Ga-NODAGA-glycine as a PET alternate of (99m) Tc Diethylenetriaminepentaacetic acid (DTPA). PMID- 25545453 TI - A randomised trial of continuous skin-to-skin contact after preterm birth and the effects on salivary cortisol, parental stress, depression, and breastfeeding. AB - AIM: To evaluate the effects of almost continuous skin-to-skin contact (SSC) on salivary cortisol, parental stress, parental depression, and breastfeeding. STUDY DESIGN: This is a randomised study engaging families of late preterm infants (32 35 weeks gestation). Salivary cortisol reactivity was measured in infants during a nappy change at one month corrected age, and in infants and mothers during still-face at four month corrected age. Both parents completed the Swedish Parenthood Stress Questionnaire (SPSQ) at one month and the Edinburgh Postnatal Depression Scale (EPDS) at one and four months. Ainsworth's sensitivity scale was used to control for parental sensitivity. SUBJECTS: Thirty-seven families from two different neonatal care units in Sweden, randomised to either almost continuous SSC or standard care (SC). RESULTS: Infants randomised to SSC had a lower salivary cortisol reactivity at one month (p=0.01). There was a correlation between the mothers' and the preterm infants' salivary cortisol levels at four months in the SSC group (rho=0.65, p=0.005), but not in the SC group (rho=0.14, p=0.63). Fathers in SSC scored lower on the SPSQ sub-scale spouse relationship problems compared to fathers in SC (p<0.05). CONCLUSIONS: Almost continuous SSC decreases infants' cortisol reactivity in response to handling, improves the concordance between mothers' and infants' salivary cortisol levels, and decreases fathers' experiences of spouse relationship problems. PMID- 25545454 TI - A simple intervention to improve hospital flow from emergency department to inpatient units. PMID- 25545456 TI - Effect of leptin on the relationship between body weight and knee osteoarthritis- a methodologic approach: comment on the article by Fowler-Brown et al. PMID- 25545457 TI - Tropomyosin isoforms support actomyosin biogenesis to generate contractile tension at the epithelial zonula adherens. AB - Epithelial cells generate contractile forces at their cell-cell contacts. These are concentrated at the specialized apical junction of the zonula adherens (ZA), where a ring of stabilized E-cadherin lies adjacent to prominent actomyosin bundles. Coupling of adhesion and actomyosin contractility yields tension in the junction. The biogenesis of junctional contractility requires actin assembly at the ZA as well as the recruitment of nonmuscle myosin II, but the molecular regulators of these processes are not yet fully understood. We now report a role for tropomyosins 5NM1 (Tm5NM1) and 5NM2 (Tm5NM2) in their generation. Both these tropomyosin isoforms were found at the ZA and their depletion by RNAi or pharmacological inhibition reduced both F-actin and myosin II content at the junction. Photoactivation analysis revealed that the loss of F-actin was attributable to a decrease in filament stability. These changes were accompanied by a decrease in E-cadherin content at junctions. Ultimately, both long-term depletion of Tm5NM1/2 and acute inhibition with drugs caused junctional tension to be reduced. Thus these tropomyosin isoforms are novel contributors to junctional contractility and integrity. PMID- 25545458 TI - The Questionnaire on Eating and Weight Patterns-5: an updated screening instrument for binge eating disorder. PMID- 25545459 TI - Significant nonsymbiotic nitrogen fixation in Patagonian ombrotrophic bogs. AB - Nitrogen (N) nutrition in pristine peatlands relies on the natural input of inorganic N through atmospheric deposition or biological dinitrogen (N2 ) fixation. However, N2 fixation and its significance for N cycling, plant productivity, and peat buildup are mostly associated with the presence of Sphagnum mosses. Here, we report high nonsymbiotic N2 -fixation rates in two pristine Patagonian bogs with diversified vegetation and natural N deposition. Nonsymbiotic N2 fixation was measured in samples from 0 to 10, 10 to 20, and 40 to 50 cm depth using the (15) N2 assay as well as the acetylene reduction assay (ARA). The ARA considerably underestimated N2 fixation and can thus not be recommended for peatland studies. Based on the (15) N2 assay, high nonsymbiotic N2 -fixation rates of 0.3-1.4 MUmol N2 g(-1) day(-1) were found down to 50 cm under micro-oxic conditions (2 vol.%) in samples from plots covered by Sphagnum magellanicum or by vascular cushion plants, latter characterized by dense and deep aerenchyma roots. Peat N concentrations point to greater potential of nonsymbiotic N2 fixation under cushion plants, likely because of the availability of easily decomposable organic compounds and oxic conditions in the rhizosphere. In the Sphagnum plots, high N2 fixation below 10 cm depth rather reflects the potential during dry periods or low water level when oxygen penetrates the top peat layer and triggers peat mineralization. Natural abundance of the (15) N isotope of live Sphagnum (5.6 delta0/00) from 0 to 10 cm points to solely N uptake from atmospheric deposition and nonsymbiotic N2 fixation. A mean (15) N signature of -0.7 delta0/00 of peat from the cushion plant plots indicates additional N supply from N mineralization. Our findings suggest that nonsymbiotic N2 fixation overcomes N deficiency in different vegetation communities and has great significance for N cycling and peat accumulation in pristine peatlands. PMID- 25545460 TI - Simultaneous determination of amino acids and neurotransmitters in plasma samples from schizophrenic patients by hydrophilic interaction liquid chromatography with tandem mass spectrometry. AB - A sensitive, reproducible, and rapid method was developed for the simultaneous determination of underivatized amino acids (aspartate, serine, glycine, alanine, methionine, leucine, tyrosine, and tryptophan) and neurotransmitters (glutamate and gamma-aminobutyric acid) in plasma samples using hydrophilic interaction liquid chromatography coupled to triple quadrupole tandem mass spectrometry. The plasma concentrations of amino acids and neurotransmitters obtained from 35 schizophrenic patients in treatment with clozapine (27 patients) and olanzapine (eight patients) were compared with those obtained from 38 healthy volunteers to monitor the effectiveness of treatment. The chromatographic conditions separated ten target compounds within 3 min. This method presented linear ranges that varied from (lower limit of quantification: 9.7-13.3 nmol/mL) to (upper limit of quantification: 19.4-800 nmol/mL), intra- and interassay precision with coefficients of variation lower than 10%, and relative standard error values of the accuracy ranged from -2.1 to 9.9%. The proposed method appropriately determines amino acids and neurotransmitters in plasma from schizophrenic patients. Compared with the control group (healthy volunteers), the plasma levels of methionine in schizophrenic patients treated with olanzapine are statistically significantly higher. Moreover, schizophrenic patients treated with clozapine tend to have increased plasma levels of glutamate. PMID- 25545461 TI - drd2-cre:ribotag mouse line unravels the possible diversity of dopamine d2 receptor-expressing cells of the dorsal mouse hippocampus. AB - Increasing evidences suggest that dopamine facilitates the encoding of novel memories by the hippocampus. However, the role of dopamine D2 receptors (D2R) in such regulations remains elusive due to the lack of the precise identification of hippocampal D2R-expressing cells. To address this issue, mice expressing the ribosomal protein Rpl22 tagged with the hemagglutinin (HA) epitope were crossed with Drd2-Cre mice allowing the selective expression of HA in D2R-containing cells (Drd2-Cre:RiboTag mice). This new transgenic model revealed a more widespread pattern of D2R-expressing cells identified by HA immunoreactivity than the one initially reported in Drd2-EGFP mice, in which the hilar mossy cells were the main neuronal population detectable. In Drd2-Cre:RiboTag mice, scattered HA/GAD67-positive neurons were detected throughout the CA1/CA3 subfields, being preferentially localized in stratum oriens and stratum lacunosum-moleculare. At the cellular level, HA-labeled cells located in CA1/CA3 subfields co-localized with calcium-binding proteins (parvalbumin, calbindin, and calretinin), neuropeptides (neuropeptide Y, somatostatin), and other markers (neuronal nitric oxide synthase, mGluR1alpha, reelin, coupTFII, and potassium channel-interacting protein 1). These results suggest that in addition to the glutamatergic hilar mossy cells, D2R-expressing cells constitute a subpopulation of GABAergic hippocampal interneurons. PMID- 25545462 TI - Electrodeposited silk coatings for bone implants. AB - The aim of this study was to characterize the mechanical properties and drug elution features of silk protein-based electrodeposited dental implant coatings. Silk processing conditions were modified to obtain coatings with a range of mechanical properties on titanium studs. These coatings were assessed for adhesive strength and dissolution, with properties tuned using water vapor annealing or glycerol incorporation to modulate crystalline content. Coating reproducibility was demonstrated over a range of silk concentrations from 1% to 10%. Surface roughness of titanium substrates was altered using industry relevant acid etching and grit blasting, and the effect of surface topography on silk coating adhesion was assessed. Florescent compounds were incorporated into the silk coatings, which were modulated for crystalline content, to achieve four days of sustained release of the compounds. This silk electrogelation technique offers a safe and relatively simple approach to generate mechanically robust, biocompatible, and degradable implant coatings that can also be functionalized with bioactive compounds to modulate the local regenerative tissue environment. PMID- 25545463 TI - Clinical outcome analysis of 47 patients with advanced head and neck cancer with preoperative suspicion of carotid artery invasion. AB - BACKGROUND: The purpose of this study was to retrospectively analyze the feasibility of the surgical management of the carotid artery in advanced head and neck cancer with preoperative suspicion of carotid artery invasion. METHODS: A total of 47 patients were retrospectively analyzed. Twenty-one patients (44.7%) received surgery as initial treatment, and 26 patients (55.3%) had salvage surgical treatment for recurrences. Intraoperative dissection and preservation of the carotid artery was achieved in 39 patients (83%). Eight patients underwent carotid resection with/without reconstruction (17%). RESULTS: The cumulative 2 year and 5-year overall survival rates were 40.4% and 34%, and the disease specific survival rates were 59.5% and 55.3%, respectively. The overall perioperative mortality rate was 6.4%. Carotid blowout developed in 6 patients. CONCLUSION: Surgical treatment of the carotid artery in selected patients can provide locoregional control and the possibility of prolonged disease-free survival with acceptable morbidity. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E287-E292, 2016. PMID- 25545464 TI - Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum. AB - BACKGROUND: Selenoprotein P (SeP), a selenium-rich extracellular glycoprotein, is the primary selenoprotein in the plasma. SeP plays an important role in the maintenance of selenium levels in the peripheral tissues. We developed a new sol particle homogeneous immunoassay (SPIA) for measuring full-length SeP (FL-SeP) levels in the human serum. METHODS: We used colloidal gold particles coated with two types of anti-SeP monoclonal antibodies, one recognizing the N-terminal side domain of SeP and the other recognizing the C-terminal side domain. RESULTS: The assay range was 0.2-9 mg/l, and the linearity was excellent. The within-day and between-day coefficients of variation ranged from 0.73% to 2.24% and 0.45% to 1.11%, respectively. Serum samples (n = 200) were examined using the newly developed assay system (employing a Model 7070 Hitachi automatic clinical analyzer) and the conventional enzyme-linked immunosorbent assay. These two methods were compared using the Passing-Bablok regression analysis; the resulting regression equation and correlation coefficient were y = 0.940x + 0.165 and r = 0.954, respectively. CONCLUSIONS: Our new SPIA assay is a fully automated homogeneous immunoassay that can be used in conjunction with various commercial analyzers. The assay was sensitive, precise, and suitable for clinical measurement of the FL-SeP in the human serum. PMID- 25545466 TI - Monocyte-derived dendritic cells can induce autoreactive CD4(+) T cells showing myeloid lineage directed reactivity in healthy individuals. AB - T cells against self-antigens can be detected in peripheral blood of healthy individuals, although intrathymic negative selection removes most high-avidity T cells specific for self-antigens from the peripheral repertoire. Moreover, spontaneous T-cell proliferation following stimulation with autologous monocyte derived dendritic cells (autoDCs) has been observed in vitro. In this study, we characterized the nature and immunological basis of the autoDC reactivity in the T-cell repertoire of healthy donors. We show that a minority of naive and memory CD4(+) T cells within the healthy human T-cell repertoire mediates HLA-restricted reactivity against autoDCs, which behave like a normal antigen-specific immune response. This reactivity appeared to be primarily directed against myeloid lineage cells. Although cytokine production by the reactive T cells was observed, this did not coincide with overt cytotoxic activity against autoDCs. AutoDC reactivity was also observed in the CD8(+) T-cell compartment, but this appeared to be mainly cytokine-induced rather than antigen-driven. In conclusion, we show that the presence of autoreactive T cells harboring the potential to react against autologous and HLA-matched allogeneic myeloid cells is a common phenomenon in healthy individuals. These autoDC-reactive T cells may help the induction of primary T-cell responses at the DC priming site. PMID- 25545467 TI - Conservation and diversity in the primary forward photodynamics of red/green cyanobacteriochromes. AB - Phytochromes are red/far-red photosensory proteins that detect the ratio of red to far-red light. Crucial to light regulation of plant developmental biology, phytochromes are also found in fungi, bacteria, and eukaryotic algae. In addition to phytochromes, cyanobacteria also can contain distantly related cyanobacteriochromes (CBCRs) that, like phytochromes, utilize the photoisomerization of a linear tetrapyrrole (bilin) chromophore to convert between two photostates with distinct spectral properties. CBCRs exhibit a wide range of photostates spanning the visible and even near-ultraviolet spectrum. In both phytochromes and CBCRs, biosynthesis initially yields a holoprotein with bilin in the 15Z configuration, and the 15E photoproduct can often revert to the 15Z photostate in the absence of light (dark reversion). One CBCR subfamily, red/green CBCRs, typically exhibits red-absorbing dark states and green-absorbing photoproducts. Dark reversion is extremely variable in red/green CBCRs with known examples ranging from seconds to days. One red/green CBCR, NpR6012g4 from Nostoc punctiforme, is also known to exhibit forward photoconversion that has an unusually high quantum yield at ~40% compared to 10-20% for phytochromes and CBCRs from other subfamilies. In the current study, we use time-resolved pump probe absorption spectroscopy with broadband detection and multicomponent global analysis to characterize forward photoconversion of seven additional red/green CBCRs from N. punctiforme on an ultrafast time scale. Our results reveal that red/green CBCRs exhibit a conserved pathway for primary forward photoconversion but that considerable diversity exists in their excited-state lifetimes, photochemical quantum yields, and primary photoproduct stabilities. PMID- 25545465 TI - Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12 month, open-label results. AB - Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. PMID- 25545468 TI - Is the OSA-18 predictive of obstructive sleep apnea: comparison to polysomnography. AB - OBJECTIVES/HYPOTHESIS: To examine the ability of the OSA-18 to predict Obstructive Sleep Apnea (OSA) in a racially diverse population when compared to overnight polysomnography (PSG). STUDY DESIGN: Cross-sectional retrospective. METHODS: Children 2 to 12 years of age diagnosed with OSA who were treated at a tertiary care institution between 2008 and 2013 and had complete PSG and OSA-18 data were included. We performed logistic regression with OSA as the dependent variable and the OSA-18 total symptom score (TSS), age, gender, race, asthma, and body mass index (BMI) as independent variables. RESULTS: Seventy-nine children (32 females) were included (mean age 5.2 +/- 2.4 years). The positive predictive value (PPV) was greater than 90 for an obstructive apnea-hypopnea index (oAHI) >= 1. The PPV and specificity were higher for white than for nonwhite children; however, sensitivity and negative predictive value (NPV) of OSA-18 TSS were low for mild, moderate, and severe OSA regardless of race. Age, race, and BMI were not significantly associated with oAHI. CONCLUSIONS: This study, conducted in a racially diverse cohort, examined the ability of the OSA-18 to predict OSA when compared to PSG-the gold standard-and found that sensitivity and NPV were extremely low for both white and nonwhite children. This suggests that the OSA-18 is not sufficiently sensitive to detect OSA nor sufficiently specific to determine the absence of OSA. The OSA-18 should be used as a quality-of-life indicator and is not a reliable substitute for PSG. LEVEL OF EVIDENCE: 4. PMID- 25545469 TI - Structure, activity, and stability of metagenome-derived glycoside hydrolase family 9 endoglucanase with an N-terminal Ig-like domain. AB - A metagenome-derived glycoside hydrolase family 9 enzyme with an N-terminal immunoglobulin-like (Ig-like) domain, leaf-branch compost (LC)-CelG, was characterized and its crystal structure was determined. LC-CelG did not hydrolyze p-nitrophenyl cellobioside but hydrolyzed CM-cellulose, indicating that it is endoglucanase. LC-CelG exhibited the highest activity at 70 degrees C and >80% of the maximal activity at a broad pH range of 5-9. Its denaturation temperature was 81.4 degrees C, indicating that LC-CelG is a thermostable enzyme. The structure of LC-CelG resembles those of CelD from Clostridium thermocellum (CtCelD), Cel9A from Alicyclobacillus acidocaldarius (AaCel9A), and cellobiohydrolase CbhA from C. thermocellum (CtCbhA), which show relatively low (29-31%) amino acid sequence identities to LC-CelG. Three acidic active site residues are conserved as Asp194, Asp197, and Glu558 in LC-CelG. Ten of the thirteen residues that form the substrate binding pocket of AaCel9A are conserved in LC-CelG. Removal of the Ig like domain reduced the activity and stability of LC-CelG by 100-fold and 6.3 degrees C, respectively. Removal of the Gln40- and Asp99-mediated interactions between the Ig-like and catalytic domains destabilized LC-CelG by 5.0 degrees C without significantly affecting its activity. These results suggest that the Ig like domain contributes to the stabilization of LC-CelG mainly due to the Gln40- and Asp99-mediated interactions. Because the LC-CelG derivative lacking the Ig like domain accumulated in Escherichia coli cells mostly in an insoluble form and this derivative accumulated in a soluble form exhibited very weak activity, the Ig-like domain may be required to make the conformation of the active site functional and prevent aggregation of the catalytic domain. PMID- 25545470 TI - Role of water in ligand binding to maltose-binding protein: insight from a new docking protocol based on the 3D-RISM-KH molecular theory of solvation. AB - Maltose-binding protein is a periplasmic binding protein responsible for transport of maltooligosaccarides through the periplasmic space of Gram-negative bacteria, as a part of the ABC transport system. The molecular mechanisms of the initial ligand binding and induced large scale motion of the protein's domains still remain elusive. In this study, we use a new docking protocol that combines a recently proposed explicit water placement algorithm based on the 3D-RISM-KH molecular theory of solvation and conventional docking software (AutoDock Vina) to explain the mechanisms of maltotriose binding to the apo-open state of a maltose-binding protein. We confirm the predictions of previous NMR spectroscopic experiments on binding modes of the ligand. We provide the molecular details on the binding mode that was not previously observed in the X-ray experiments. We show that this mode, which is defined by the fine balance between the protein ligand direct interactions and solvation effects, can trigger the protein's domain motion resulting in the holo-closed structure of the maltose-binding protein with the maltotriose ligand in excellent agreement with the experimental data. We also discuss the role of water in blocking unfavorable binding sites and water-mediated interactions contributing to the stability of observable binding modes of maltotriose. PMID- 25545471 TI - Evaluation of a new mist-chamber bioreactor for biotechnological applications. AB - In this article we describe the development, the characterization and the evaluation of a novel bioreactor type for the cultivation of different pro- and eukaryotic cell-systems: the mist-chamber bioreactor. This innovative bioreactor meets the demand of cultivation systems for shear stress sensitive cells with high requirements for gas supply. Within the mist-chamber bioreactor the cells are cultivated inside an aerosol of vaporized medium generated by ultrasonic vaporization. In contrast to many established bioreactor systems the mist-chamber bioreactor offers an environment with an excellent gas supply without any impeller or gas bubble induced shear stress. A mist-chamber bioreactor prototype has been manufactured and characterized during this work. In the technical and chemical characterization we evaluated the vaporization process, resulting in a vaporization performance of 32 mL/h at working conditions. On this basis we calculated a biomass of 1.4 g (S. cerevisiae, qs = 3.45 * 10-3 mol/g/h) and 3.4 g (Aspergillus niger, qs = 1.33 * 10-3 mol/g/h) where the growth rate becomes limited by transport processes. Additionally, we determined a homogenous cultivation area to a height of 3 cm giving a total volume of 0.45 L for the cultivation. Medium components were examined according to their stability during vaporization with the result that all components are stable for at least 5 days. After the technical characterization we demonstrated the feasibility to cultivate S. cerevisiae and F. velupites in the mist-chamber bioreactor. The results demonstrated that the mist-chamber bioreactor is able to transport a sufficient amount of nutrients consistently to the cell samples and offers an excellent oxygen supply without any shear stress inducing aeration. Furthermore we successfully cultivated F. velupites in a solid state cultivation in a long term experiment. The data indicate that the new bioreactor concept can contribute to improve various fermentations and cell culture processes depending on the cultured cell types. PMID- 25545472 TI - Asian women have attenuated sympathetic activation but enhanced renal-adrenal responses during pregnancy compared to Caucasian women. AB - Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal-adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 +/- 1 years (mean +/- SEM)) and 12 Caucasians (29 +/- 1 years) during pre-, early (<=8 weeks of gestation) and late (32-36 weeks) pregnancy, and post-partum (6-10 weeks after delivery). Supine MSNA increased with pregnancy in both groups (P < 0.001); it was significantly lower in Asians than Caucasians (14 +/- 3 vs. 23 +/- 3 bursts min(-1) and 16 +/- 5 vs. 30 +/- 3 bursts min(-1) in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy (P < 0.001), but was restored during late pregnancy. HR increased during pregnancy (P < 0.001) with no racial difference (P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 +/- 6 vs. 49 +/- 3 bursts min(-1) at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy (P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians (P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal-adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy. PMID- 25545473 TI - Cannabinoid receptor 1 but not 2 mediates macrophage phagocytosis by G(alpha)i/o /RhoA/ROCK signaling pathway. AB - Phagocytosis is critical to macrophages linking innate and adaptive immune reaction. Cannabinoid receptor 1 (CB1) and 2 (CB2) mediate immune modulation. However, the role of cannabinoid receptors in macrophage phagocytosis is undefined. In this study, we found that two murine macrophage lines (J774A.1 and RAW264.7) and peripheral blood macrophages all expressed CB1 and CB2 by immunofluorescence-staining, real time RT-PCR and Western blot. Macrophage phagocytic activity was determined by quantifying fluorescent intensity of the engulfed BioParticles or fluorescence-activated cell sorting. mAEA (CB1 agonist) enhanced phagocytosis of macrophages, but JWH133 (CB2 agonist) had no influence. Pharmacological or genetic ablation of CB1 inhibited mAEA-enhanced phagocytosis, while CB2 had no such effects. Meanwhile, activation of CB1 increased GTP bounding active form of small GTPase RhoA, but not Rac1 or Cdc42. AM281 (CB1 antagonist) and pertussis toxin (PTX, G((alpha)i/o) protein inhibitor) decreased GTP-bound RhoA protein level with mAEA. In addition, PTX, C3 Transferase (RhoA inhibitor) or Y27632 (Rho-associated kinase ROCK inhibitor) attenuated CB1 mediated phagocytosis. These results confirm that activation of CB1 regulates macrophage phagocytosis through G((alpha)i/o)/RhoA/ROCK signaling pathway. Moreover, activation of CB1 induced significant up-regulation of CB1 expression by real time RT-PCR and Western blot analysis, but not CB2. It indicated the existence of a positive feedback between CB1 activation and CB1 expression. The up-regulation of CB1 was RhoA-independent but it may contribute to maintaining high phagocytic activity of macrophages for a longer time. In conclusion, CB1 mediates macrophage phagocytosis by G((alpha)i/o)/RhoA/ROCK signal axis. These data further underline the role of CB1 in macrophage phagocytic process. PMID- 25545475 TI - Pure laparoscopic management of early biliary leakage after liver transplantation: abdominal lavage and T-tube placement. PMID- 25545474 TI - Melanocytes in the skin--comparative whole transcriptome analysis of main skin cell types. AB - Melanocytes possess several functions besides a role in pigment synthesis, but detailed characteristics of the cells are still unclear. We used whole transcriptome sequencing (RNA-Seq) to assess differential gene expression of cultivated normal human melanocytes with respect to keratinocytes, fibroblasts and whole skin. The present results reveal cultivated melanocytes as highly proliferative cells with possible stem cell-like properties. The enhanced readiness to regenerate makes melanocytes the most vulnerable cells in the skin and explains their high risk of developing into malignant melanoma. PMID- 25545476 TI - Shotgun metabolomic profiles in maternal urine identify potential mass spectral markers of abnormal fetal biochemistry - dihydrouracil and progesterone in the metabolism of Down syndrome. AB - In Down syndrome (DS) in particular, the precise cellular mechanisms linking genotype to phenotype is not straightforward despite a clear mapping of the genetic cause. Metabolomic profiling might be more revealing in understanding molecular-cellular mechanisms of inborn errors of metabolism/syndromes than genomics alone and also result in new prenatal screening approaches. The urinary metabolome of 122 maternal urine from women with and without an aneuploid pregnancy (predominantly Down syndrome) were compared by both zwitterionic hydrophilic interaction chromatography (ZIC-HILIC) and reversed-phase liquid chromatography (RPLC) coupled to hybrid ion trap time of flight mass spectral analysis. ZIC-HILIC mass spectrometry resolved 10-fold more unique molecular ions than RPLC mass spectrometry, of which molecules corresponding to ions of m/z 114.07 and m/z 314.20 showed maternal urinary level changes that significantly coincided with the presence of a DS fetus. The ion of m/z 314.20 was identified as progesterone and m/z 114.07 as dihydrouracil. A metabolomics profiling-based maternal urinary screening test modelled from this separation data would detect approximately 87 and 60.87% (using HILIC-MS and RPLC-MS, respectively) of all DS pregnancies between 9 and 23 weeks of gestation with no false positives. PMID- 25545479 TI - Effect of internal limiting membrane peeling on the development of epiretinal membrane after pars plana vitrectomy for primary rhegmatogenous retinal detachment. AB - PURPOSE: To investigate the difference in the occurrence of postoperative epiretinal membranes (ERMs) in vitrectomy for rhegmatogenous retinal detachment with and without peeling of the internal limiting membrane (ILM). METHODS: The medical records of the 135 patients, who underwent vitrectomy for primary rhegmatogenous retinal detachment from November 2007 to August 2011, were analyzed retrospectively. Of the subjects, 70 patients underwent ILM peeling during the surgery and 65 did not. The best-corrected visual acuity, fundus photograph, and optical coherence tomography were collected 3, 6, and 12 months postoperatively. The relationship between ILM peeling and the preoperative findings of rhegmatogenous retinal detachment and development of a postoperative ERM was analyzed. RESULTS: No ERM occurred in the ILM peeling group, whereas an ERM occurred in 14 of 65 patients who underwent vitrectomy without ILM peeling (21.5%). This difference was significant (P < 0.001). The occurrence of a postoperative ERM was not significantly correlated with other preoperative factors. In the macular-on group, the overall mean best-corrected visual acuity was better in the ILM peeling group and was significantly higher 12 months postoperatively (P = 0.03). CONCLUSION: Internal limiting membrane peeling seems to prevent the occurrence of a postoperative ERM in patients with primary rhegmatogenous retinal detachment. PMID- 25545477 TI - Extracellular deposition of mouse senile AApoAII amyloid fibrils induced different unfolded protein responses in the liver, kidney, and heart. AB - Mouse senile amyloidosis is a disorder in which apolipoprotein A-II deposits extracellularly in many organs as amyloid fibrils (AApoAII). In this study, we intravenously injected 1 MUg of isolated AApoAII fibrils into R1.P1-Apoa2(c) mice, to induce AApoAII amyloidosis. We observed that the unfolded protein response was induced by deposition of AApoAII amyloid. We found that the mRNA and the protein expression levels of heat shock protein A5 (HSPA5; also known as glucose-regulated protein 78) were increased in the liver with AApoAII amyloid deposits. Immunohistochemistry showed that HSPA5 was only detected in hepatocytes close to AApoAII amyloid deposits. Furthermore, gene transcription of several endoplasmic reticulum (ER) stress-related proteins increased, including eukaryotic translation initiation factor 2 alpha kinase 3 (Eif2ak3), activating transcription factor 6 (Atf6), activating transcription factor 4 (Atf4), X-box binding protein 1 splicing (Xbp1s), DNA-damage inducible transcript 3 (Ddit3), and autophagy protein 5 (Atg5). Moreover, apoptosis-positive cells were increased in the liver. Similar results were seen in the kidney but not in the heart. Our study indicates that ER stress responses differed among tissues with extracellular AApoAII amyloid fibril deposition. Although upregulated HSPA5 and the activated unfolded protein response might have roles in protecting tissues against aggregated extracellular AApoAII amyloid deposition, prolonged ER stress induced apoptosis in the liver and the kidney. PMID- 25545480 TI - Long-term risk of glaucoma after encircling scleral buckle. AB - PURPOSE: To determine the long-term risk of developing glaucoma after an encircling scleral buckle procedure. METHODS: Retrospective case series of patients with at least 10 years of follow-up who underwent successful, unilateral retinal detachment repair by encircling scleral buckle. The main outcome measure was the proportion of eyes that developed perimetric glaucoma of buckled compared with fellow eyes. RESULTS: Sixty-eight patients with an average postoperative follow-up of 21 years were included. Perimetric glaucoma developed in 13% (9 patients), and an additional 22% (15 patients) had preperimetric glaucoma or were glaucoma suspects. Perimetric glaucoma was present in 2.9% of patients in the buckled eye only, 8.8% in the fellow eye only (P = 0.27), and 1.3% in both eyes. There was no increased prevalence of ocular antihypertensive use in buckled (5.9%) compared with fellow eyes (11.8%, P = 0.36). CONCLUSION: Our study showed no evidence of increased risk for developing glaucoma after repair of retinal detachment in eyes that underwent an encircling scleral buckling technique compared with fellow eyes with follow-up of at least 10 years. PMID- 25545478 TI - Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression. AB - Intestinal dysbiosis has been reported in patients with colorectal cancer, and there is a high prevalence of Escherichia coli belonging to B2 phylogroup and producing a genotoxin, termed colibactin. Macrophages are one of the predominant tumor-infiltrating immune cells supporting key processes in tumor progression by producing protumoral factors such as cyclooxygenase-2 (COX-2). Here, we investigated whether B2 E. coli colonizing colon tumors could influence protumoral activities of macrophages. In contrast to commensal or nonpathogenic E. coli strains that were efficiently and rapidly degraded by macrophages at 24 h after infection, colon cancer-associated E. coli were able to resist killing by human THP-1 macrophages, to replicate intracellularly, and to persist inside host cells until at least 72 h after infection. Significant increases in COX-2 expression were observed in macrophages infected with colon cancer E. coli compared with macrophages infected with commensal and nonpathogenic E. coli strains or uninfected cells at 72 h after infection. Induction of COX-2 expression required live bacteria and was not due to colibactin production, as similar COX-2 levels were observed in macrophages infected with the wild-type colon cancer-associated E. coli 11G5 strain or a clbQ mutant unable to produce colibactin. Treatment of macrophages with ofloxacin, an antibiotic with intracellular tropism, efficiently decreased the number of intracellular bacteria and suppressed bacteria-induced COX-2 expression. This study provides new insights into the understanding of how tumor- infiltrating bacteria could influence cancer progression through their interaction with immune cells. Manipulation of microbes associated with tumors could have a deep influence on the secretion of protumoral molecules by infiltrating macrophages. PMID- 25545481 TI - Peripheral retinal vasculopathy in childhood glaucoma. AB - PURPOSE: To report wide-field fluorescein angiography findings in the peripheral retina of eyes with childhood glaucoma. METHODS: Fluorescein angiograms were examined retrospectively in 12 patients with childhood glaucoma who underwent wide-field fluorescein angiography after surgical or medical treatment of glaucoma. This series included 12 eyes of 6 patients with primary congenital glaucoma, 5 eyes of 3 patients with glaucoma associated with congenital cataract surgery, 4 eyes of 2 patients with glaucoma associated with a systemic condition, and 1 eye of 1 patient with phakomatosis pigmentovascularis Type II. RetCam fundus photography images and digital fluorescein angiography were performed under general anesthesia. RESULTS: The most common finding observed in our series was peripheral retinal nonperfusion, which affected 20 eyes (91%). Other notable features seen were circumferential branching of the retinal vessels parallel to the ora serrata (77%), venous shunts (50%), and abnormal capillary branching patterns, including capillary dilatation (41%) and tortuous capillary tangles (18%). Leakage at the junction of vascular and avascular retina was not commonly seen (13.6%). None of the eyes had evidence of retinal neovascularization or fibrovascular proliferation. CONCLUSION: Retinal vascular abnormalities and peripheral nonperfusion are novel findings in childhood glaucoma. Further studies are needed to understand the significance and possible long-term consequences of these findings. PMID- 25545483 TI - Peripapillary serous detachment in multiple evanescent white dot syndrome. AB - BACKGROUND: To report the presence of transient peripapillary serous detachments in multiple evanescent white dot syndrome. METHODS: Retrospective case series. RESULTS: Four eyes of four patients diagnosed with multiple evanescent white dot syndrome presented with peripapillary serous detachments. Diagnosis was based on clinical presentation, fundus findings, and angiographic findings. All 4 were female with age ranges between 24 and 40 years and presented with photopsias, an enlarged scotoma contiguous with the blind spot, and chorioretinal white dots in the posterior pole with characteristic angiographic features. All of the serous detachments resolved or were greatly reduced concomitantly with the resolution of the patient's other clinical symptoms and fundus findings. CONCLUSION: The authors report peripapillary serous detachments as a previously unreported manifestation of multiple evanescent white dot syndrome. These seem to be self limited with concurrent resolution with the rest of the patient's symptoms. PMID- 25545482 TI - New best1 mutations in autosomal recessive bestrophinopathy. AB - PURPOSE: To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. METHODS: Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. RESULTS: Five affected patients from four families were identified. Mean age was 16 years (range, 6-42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. CONCLUSION: Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy-associated dominant mutations. PMID- 25545484 TI - TUMORS OF THE NONPIGMENTED EPITHELIUM OF THE CILIARY BODY: The Lorenz E. Zimmerman Tribute Lecture. AB - BACKGROUND: In 1970, Dr. Lorenz Zimmerman delivered the Norman McAlister Gregg Lecture entitled "The remarkable polymorphism of tumors of the ciliary epithelium." Therein, he proposed a classification of these tumors that included congenital lesions (mainly medulloepithelioma) and acquired lesions (mainly adenoma and adenocarcinoma). The classification was based on histopathologic observations without detailed clinical information. METHODS: Review of the published literature and personal experience with tumors of the nonpigmented ciliary body epithelium. RESULTS: Since 1970, further observations through clinical examination and advanced testing with ultrasound biomicroscopy, anterior segment optical coherence tomography, and magnetic resonance imaging have expanded our knowledge regarding tumors of the nonpigmented ciliary body epithelium. Regarding medulloepithelioma, we have learned of the common associated features of neovascular glaucoma, retrolenticular neoplastic or vascular cyclitic membrane, intralesional cysts, response to radiotherapy, and association with Dicer-1 mutation. Regarding adenoma/adenocarcinoma, improved management with surgical resection (sparing globe) can be achieved. Fuchs adenoma, also termed coronal adenoma, is commonly found histopathologically, despite its rare clinical visualization, and should be added to the Zimmerman classification. CONCLUSION: Since Zimmerman's report on histopathologic features of tumors of the nonpigmented ciliary body epithelium, there have been numerous publications and further observations on the clinical features and management of these intriguing neoplasms. PMID- 25545485 TI - Agreement and reproducibility of retinal pigment epithelial detachment volumetric measurements through optical coherence tomography. AB - PURPOSE: To assess the agreement and reproducibility of retinal pigment epithelial detachment (RPED) volumetric measurements using a commercially available optical coherence tomography software available for the Zeiss Cirrus HD OCT. METHODS: Twelve eyes of 10 patients with a diagnosis of neovascular age related macular degeneration with RPED, seen at the New England Eye Center between October 2012 and December 2012, were enrolled in the study. Three separate scans per affected eye were obtained using the "Macular Cube 512 * 128" protocol. "Retinal pigment epithelial (RPE) elevation analysis" software was used to measure RPED volumes in the central 3-mm and 5-mm circles by calculating the volume between the "RPE fit" and "true RPE" lines. All 128 raster scans for each eye were exported into the AMIRA software for manual segmentation of RPED volumes in the central 3-mm and 5-mm circles. Interscan reproducibility and manual-to automated agreement were assessed by intraclass correlation coefficient. Incidence of automated segmentation line error for both RPE fit and true RPE lines in the central 1 mm region was calculated. RESULTS: Average RPED volumes through automated segmentation software were 0.14 mm3 and 0.21 mm3 in the central 3-mm and 5-mm circles, respectively. Manual segmentation yielded average RPED volumes of 0.50 mm3 in the 3-mm circles and 0.92 mm3 in the 5-mm circles. Manual segmentation yielded significantly greater RPED volumes compared with automated measurements (P < 0.05). Intraclass correlation coefficients across the 3 automated measurements were 0.954 and 0.983 for volume in the 3-mm and 5-mm circles, respectively. Intraclass correlation coefficients between the manual and automatic volumes were 0.296 and 0.337 for the 3-mm and 5-mm circles, respectively. In the central 1 mm region, 11 of the 12 scans had breakdown in RPE fit line, whereas 8 of the 12 scans showed true RPE line breakdown. CONCLUSION: Automated "RPED elevation" software demonstrated high interscan reproducibility. However, it showed low agreement with manual measurements from high rates of segmentation line breakdown, especially at the level of the RPE fit line (91.7%). Manual measurements resulted in greater volumes compared with automated measurements. PMID- 25545486 TI - VITRECTOMY WITH INTERNAL LIMITING MEMBRANE PEELING FOR TRACTIONAL AND NONTRACTIONAL DIABETIC MACULAR EDEMA: Long-term Results of a Comparative Study. AB - PURPOSE: To compare the long-term outcomes of vitreomacular surgery in eyes with nontractional diabetic macular edema (DME) with those from eyes with tractional DME. METHODS: Retrospective comparative study from 55 consecutive patients (73 eyes). Twenty eyes were operated on for tractional DME and 53 eyes for nontractional DME unresponsive to laser photocoagulation or triamcinolone intravitreal injections. The best-corrected visual acuity, the central macular thickness, and the surgical complications were analyzed. RESULTS: The mean follow up duration was 5.3 +/- 2.4 years for the group with traction and 4.4 +/- 1.7 years for the group without traction (P = 0.13). At 3 years, the mean logarithm of the minimum angle of resolution best-corrected visual acuity had improved significantly from 0.78 to 0.58 for the group without traction and from 0.75 to 0.45 for the group with traction (P < 0.001). At the final visit, there was no significant difference between the 2 groups in regard to visual or central macular thickness improvement (P = 0.447 and P = 0.742, respectively). The incidence of surgical complications was not significant between the two groups. The preoperative best-corrected visual acuity was the only predictive factor for the final best-corrected visual acuity. CONCLUSION: The results of vitrectomy were not different in terms of anatomical and visual outcomes and surgical complications between eyes without tractional DME and eyes with tractional DME. PMID- 25545487 TI - Evaluating the New York State 2010 HIV testing law amendments: context, challenges, and conclusions. PMID- 25545488 TI - New York State 2010 HIV testing law: an evaluation of testing rates using laboratory data. AB - As of September 2010, New York State (NYS) Public Health Law mandates the offer of HIV testing to all persons aged 13-64 years receiving hospital or primary care services. Changes in the number of HIV tests 13 months before and after law enactment were assessed using HIV test volume data from 166 laboratories holding NYS permits to conduct HIV testing on specimens originating in NYS. Compared with the pre-enactment baseline, overall HIV testing volume increased by 13% following enactment, with the volume of conventional and rapid HIV screening tests increasing by 12.0% and 13.7%, respectively. These data suggest that testing law is having an impact consistent with the legislative intent to increase HIV testing in NYS. Monitoring should be continued to assess testing trends across a variety of health care venues to identify and address additional barriers to HIV testing access. PMID- 25545489 TI - Evaluating the 2010 New York State HIV testing law in NYC ambulatory practices using electronic health records. AB - INTRODUCTION: In 2010, the New York State Legislature made it mandatory to offer an HIV test to people aged 13-64 years receiving hospital or primary care services, with limited exceptions. In this study, we used data from New York City practices to evaluate the impact of the law on HIV testing rates in ambulatory care. METHODS: We collected quarterly testing data from the electronic health records of 218 practices. We calculated overall and stratified crude testing rates. Using univariate and multivariate generalized estimating equation models, we assessed the odds of testing in the year before the law (baseline) versus the first and second year after the law's implementation (year 1 and year 2). RESULTS: During baseline, the odds of testing did not increase significantly. During year 1, the odds of testing significantly increased by 50% in the univariate model and 200% after adjusting for confounders. During year 2, the odds of testing increased 10%. This was only significant in the univariate model. The crude quarterly testing rate increased from 2.8% to 5.7% from baseline to year 2. CONCLUSIONS: Our evaluation showed that after the implementation of the HIV testing law, there was an increase in HIV testing among NYC ambulatory practices. Testing rates remained modest, but considerable improvement was seen in community health centers, in age ranges targeted by the law and in practices that were screening for HIV at baseline. This study suggests that legislation may be effective when used in a comprehensive prevention strategy. PMID- 25545490 TI - Correlates of routine HIV testing practices: a survey of New York State primary care physicians, 2011. AB - BACKGROUND: The New York State (NYS) HIV Testing Law of 2010 mandates that medical providers offer HIV testing to patients aged between 13 and 64 years during primary care, to increase the number of people aware of their infection status, and to ensure linkage to medical treatment. To assess physician practices related to this legislation, we conducted a study to identify the frequency and correlates of routine HIV testing behavior among primary care physicians approximately 15 months after the new law went into effect. METHODS: During September 2011 to January 2012, we mailed self-administered surveys to a representative sample of NYS primary care physicians drawn from the AMA Masterfile of Physicians. Questions included physician practices, knowledge, attitudes, and beliefs related to routine HIV testing. Bivariate and multivariate analyses with a sample of 973 physicians were conducted to identify the most influential predictors of routine HIV testing behaviors. RESULTS: A minority of physicians reported "always" or "frequently" practicing behaviors consistent with routine HIV testing, with 41.7% [95% confidence interval (CI): 37.4 to 46.2] routinely offering tests to patients aged 13-64 years, 40.5% (95% CI: 36.3 to 44.8) to new patients, and 33.3% (95% CI: 29.4 to 37.6) to patients during routine physicals. Only 61.4% (95% CI: 57.4 to 65.6) said they had heard of the new law. In multivariate analyses, specialty, perceived barriers, familiarity with the law, and interaction terms representing familiarity by region and self efficacy by region were significant predictors across the 3 scenarios of routine HIV testing behavior. CONCLUSIONS: Additional technical assistance and training is needed for physicians on adopting routine testing behaviors, minimizing barriers and enhancing skills. PMID- 25545491 TI - Routine HIV testing capacity, practices, and perceptions among school-based health center providers in New York State after enactment of the 2010 amended HIV testing law. AB - BACKGROUND: The 2010 New York State (NYS) HIV Testing Law requires that primary care providers routinely offer HIV testing to patients aged 13-64 years, regardless of risk, and link individuals with HIV to medical care. School-based health centers (SBHCs) are in a position to offer HIV screening to a significant proportion of youth. One year after the law went into effect, we conducted a study to assess whether NYS SBHCs implemented these provisions. METHODS: Medical providers from 83 NYS SBHCs, serving students age 13 and older, participated in a Web-based survey regarding school-based health center capacity for and implementation of routine HIV testing, linkage to care, attitudes, and barriers. RESULTS: On-site HIV testing was reported to be available at 71% of SBHCs. Linkages to age-appropriate HIV care were reported to be available at 85% of SBHCs. The routine offer of HIV testing for eligible students was reported to be implemented at 55% of SBHCs. Forty-one percent reported that HIV testing was offered to at least half of eligible students during the 2010-2011 school year. New York City and high school providers were more likely to report the routine offer of HIV testing, on-site testing, linkages to care, perceive students as willing to test, indicate fewer barriers, and report having offered testing to a majority of eligible students in the previous year. CONCLUSIONS: Many SBHCs have adopted key provisions of the amended NYS HIV Testing Law. Additional assistance may be needed to achieve full implementation; however, especially among SBHCs serving younger populations and those located outside New York City. PMID- 25545492 TI - HIV test offers and acceptance: New York State findings from the behavioral risk factor surveillance system and the National HIV behavioral surveillance, 2011 2012. AB - BACKGROUND: The New York State HIV testing law requires that patients aged 13-64 years be offered HIV testing in health care settings. We investigated the extent to which HIV testing was offered and accepted during the 24 months after law enactment. METHODS: We added local questions to the Behavioral Risk Factor Surveillance System (BRFSS) and the National HIV Behavioral Surveillance (NHBS) surveys asking respondents aged 18-64 years whether they were offered an HIV test in health care settings, and whether they had accepted testing. Statewide prevalence estimates of test offers and acceptance were obtained from a combined 2011-2012 BRFSS sample (N = 6,223). Local estimates for 2 high-risk populations were obtained from NHBS 2011 men who have sex with men (N = 329) and 2012 injection drug users (N = 188) samples. RESULTS: BRFSS data showed that 73% of New Yorkers received care in any health care setting in the past 12 months, of whom 25% were offered an HIV test. Sixty percent accepted the test when offered. The levels of test offer increased from 20% to 29% over time, whereas acceptance levels decreased from 68% to 53%. NHBS data showed that 81% of men who have sex with men received care, of whom 43% were offered an HIV test. Eighty-eight percent accepted the test when offered. Eighty-five percent of injection drug users received care, of whom 63% were offered an HIV test, and 63% accepted the test when offered. CONCLUSIONS: We found evidence of partial and increasing implementation of the HIV testing law. Importantly, these studies demonstrated New Yorkers' willingness to accept an offered HIV test as part of routine care in health care settings. PMID- 25545493 TI - HIV testing experience in New York City: offer of and willingness to test in the context of new legal support of routine testing. AB - BACKGROUND: In the United States, routine HIV testing is recommended for persons aged 13-64 years. In 2010, New York State passed a law mandating offer of testing in most health-care settings. We report on the consumer perspective in New York City (NYC) shortly after the law's enactment. METHODS: We analyzed data from a 2011 telephone survey representative of NYC adults aged 18-64 years (n = 1,846). This analysis focused on respondents' report of HIV test offer at last clinical visit and of willingness to test if recommended by their doctor. Offer and willingness were estimated by age, gender, race/ethnicity, education, income, marital status, sexual identity, partner number, and HIV testing history; associations were examined using multivariable regression. RESULTS: Among NYC adults, 35.7% reported an HIV test in the past year and 31.8% had never tested. Among 86.7% with a clinical visit in the past year, 31.4% reported being offered a test at last visit. Offer was associated with younger age, race/ethnicity other than white, non-Hispanic, lower income, and previous testing. Only 6.7% of never testers were offered a test at last clinical visit. Willingness to test if recommended was high overall (90.2%) and across factors examined. CONCLUSIONS: After a new law was enacted in support of routine HIV testing, approximately 1 in 3 New Yorkers aged 18-64 years were offered a test at last clinical visit; 9 in 10 were willing to test if recommended by their doctor. This suggests that patient attitudes will not be a barrier to complete implementation of the law. PMID- 25545494 TI - The evolution of HIV testing requirements in New York State, 1989-2013. AB - In 2010, New York State (NYS) made major changes to its HIV testing law to come more closely into compliance with 2006 recommendations of the Centers for Disease Control and Prevention. Because of the size and severity of the epidemic in NYS, the strong public health response, and powerful advocacy community, the state had early on enacted strict rules around all aspects of HIV testing. Between 2006 and 2010, 12 distinct legislative proposals were advanced to modernize NYS's approach, leading ultimately to the bill that became law and went into effect on September 10, 2010. The approved changes included oral consent for rapid HIV tests, streamlined provision of pretest information, and most notably a mandated offer of HIV testing to all persons between 13 and 64 years of age. In 2014, NYS finally removed the requirement for written informed consent (except in criminal justice settings). In a separate legislative action and in tacit acknowledgment to the success of the 2010 HIV testing law, a mandate for hepatitis C testing for persons born between 1945 and 1965 was adopted. For a variety of reasons, HIV related statutes have sometimes been difficult to change, but once the initial inertia is overcome, additional changes may come more quickly. PMID- 25545495 TI - Timing of entry to care by newly diagnosed HIV cases before and after the 2010 New York State HIV testing law. AB - Prompt entry to care after HIV diagnosis benefits the infected individual and reduces the likelihood of further transmission of the virus. The New York State HIV Testing Law of 2010 requires diagnosing providers to refer persons newly diagnosed with HIV to follow-up medical care. This study used routinely collected HIV-related laboratory data from the New York State HIV surveillance system to assess whether the fraction of newly diagnosed cases entering care within 90 days of diagnosis increased after the implementation of the law. Laboratory data on 23,302 newly diagnosed cases showed that entry to care within 90 days rose steadily from 72.0% in 2007 to 85.4% in 2012. The rise was observed across all race/ethnic groups, ages, transmission risk groups, sexes, and regions of residence. Logistic regression analyses of entry to care pre-law and post-law, controlling for demographic characteristics, transmission risk, and geographic area, indicate that percentage of newly diagnosed cases entering care within 90 days grew more rapidly in the post-law period. This is consistent with a positive effect of the law on entry to care. PMID- 25545496 TI - Mandating the offer of HIV testing in New York: simulating the epidemic impact and resource needs. AB - BACKGROUND: A 2010 New York law requires that patients aged 13-64 years be offered HIV testing in routine medical care settings. Past studies report the clinical outcomes, cost-effectiveness, and budget impact of expanded HIV testing nationally and within clinics but have not examined how state policies affect resource needs and epidemic outcomes. METHODS: A system dynamics model of HIV testing and care was developed, where disease progression and transmission differ by awareness of HIV status, engagement in care, and disease stage. Data sources include HIV surveillance, Medicaid claims, and literature. The model projected how alternate implementation scenarios would change new infections, diagnoses, linkage to care, and living HIV cases over 10 years. RESULTS: Without the law, the model projects declining new infections, newly diagnosed cases, individuals newly linked to care, and fraction of undiagnosed cases (reductions of 62.8%, 59.7%, 54.1%, and 57.8%) and a slight increase in living diagnosed cases and individuals in care (2.2% and 6.1%). The law will further reduce new infections, diagnosed AIDS cases, and the fraction undiagnosed and initially increase and then decrease newly diagnosed cases. Outcomes were consistent across scenarios with different testing offer frequencies and implementation times but differed according to the level of implementation. CONCLUSIONS: A mandatory offer of HIV testing may increase diagnoses and avert infections but will not eliminate the epidemic. Despite declines in new infections, previously diagnosed cases will continue to need access to antiretroviral therapy, highlighting the importance of continued funding for HIV care. PMID- 25545497 TI - Association of QCT Bone Mineral Density and Bone Structure With Vertebral Fractures in Patients With Multiple Myeloma. AB - Computed tomography (CT) is used for staging osteolytic lesions and detecting fractures in patients with multiple myeloma (MM). In the OsteoLysis of Metastases and Plasmacell-infiltration Computed Tomography 2 study (OLyMP-CT) study we investigated whether patients with and without vertebral fractures show differences in bone mineral density (BMD) or microstructure that could be used to identify patients at risk for fracture. We evaluated whole-body CT scans in a group of 104 MM patients without visible osteolytic lesions using an underlying lightweight calibration phantom (Image Analysis Inc., Columbia, KY, USA). QCT software (StructuralInsight) was used for the assessment of BMD and bone structure of the T11 or T12 vertebral body. Age-adjusted standardized odds ratios (sORs) per SD change were derived from logistic regression analyses, and areas under the receiver operating characteristics (ROC) curve (AUCs) analyses were calculated. Forty-six of the 104 patients had prevalent vertebral fractures (24/60 men, 22/44 women). Patients with fractures were not significantly older than patients without fractures (mean +/- SD, 64 +/- 9.2 versus 62 +/- 12.3 years; p = 0.4). Trabecular BMD in patients with fractures versus without fractures was 169 +/- 41 versus 192 +/- 51 mg/cc (AUC = 0.62 +/- 0.06, sOR = 1.6 [1.1 to 2.5], p = 0.02). Microstructural variables achieved optimal discriminatory power at bone thresholds of 150 mg/cc. Best fracture discrimination for single microstructural variables was observed for trabecular separation (Tb.Sp) (AUC = 0.72 +/- 0.05, sOR = 2.4 (1.5 to 3.9), p < 0.0001). In multivariate models AUCs improved to 0.77 +/- 0.05 for BMD and Tb.Sp, and 0.79 +/ 0.05 for Tb.Sp and trabecular thickness (Tb.Th). Compared to BMD values, these improvements of AUC values were statistically significant (p < 0.0001). In MM patients, QCT-based analyses of bone structure derived from routine CT scans permit discrimination of patients with and without vertebral fractures. Rarefaction of the trabecular network due to plasma cell infiltration and osteoporosis can be measured. Deterioration of microstructural measures appear to be of value for vertebral fracture risk assessment and may indicate early stages of osteolytic processes not yet visible. PMID- 25545498 TI - Magnesium modifies the cardiovascular mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis: a cohort study. AB - BACKGROUND: In vitro studies have shown inhibitory effects of magnesium (Mg) on phosphate-induced calcification of vascular smooth muscle cells, raising the possibility that maintaining a high Mg level may be useful for reducing cardiovascular risks of patients with hyperphosphatemia. We examined how serum Mg levels affect the association between serum phosphate levels and the risk of cardiovascular mortality in patients undergoing hemodialysis. METHODS: A nationwide register-based cohort study was conducted using database of the Renal Data Registry of the Japanese Society for Dialysis Therapy in 2009. We identified 142,069 patients receiving in-center hemodialysis whose baseline serum Mg and phosphate levels were available. Study outcomes were one-year cardiovascular and all-cause mortality. Serum Mg levels were categorized into three groups (lower, <2.7 mg/dL; intermediate, >=2.7, <3.1 mg/dL; and higher, >=3.1 mg/dL). RESULTS: During follow-up, 11,401 deaths occurred, out of which 4,751 (41.7%) were ascribed to cardiovascular disease. In multivariable analyses, an increase in serum phosphate levels elevated the risk of cardiovascular mortality in the lower and intermediate-Mg groups, whereas no significant risk increment was observed in the higher-Mg group. Moreover, among patients with serum phosphate levels of >=6.0 mg/dL, the cardiovascular mortality risk significantly decreased with increasing serum Mg levels (adjusted odds ratios [95% confidence intervals] of the lower-, intermediate-, and higher-Mg groups were 1.00 (reference), 0.81 [0.66 0.99], and 0.74 [0.56-0.97], respectively.). An interaction between Mg and phosphate on the risk of cardiovascular mortality was statistically significant (P = 0.03). CONCLUSION: Serum Mg levels significantly modified the mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis. PMID- 25545499 TI - High yields of active Thermus thermophilus proline dehydrogenase are obtained using maltose-binding protein as a solubility tag. AB - Proline dehydrogenase (ProDH) catalyzes the FAD-dependent oxidation of proline to Delta(1) -pyrroline-5-carboxylate, the first step of proline catabolism in many organisms. Next to being involved in a number of physiological processes, ProDH is of interest for practical applications because the proline imino acid can serve as a building block for a wide range of peptides and antibiotics. ProDH is a membrane-associated protein and recombinant soluble forms of the enzyme have only been obtained in limited amounts. We here report on the heterologous production of ProDH from Thermus thermophilus (TtProDH) in Escherichia coli. Using maltose-binding protein as solubility tag, high yields of active holoenzyme are obtained. Native TtProDH can be produced from cleaving the purified fusion protein with trypsin. Size-exclusion chromatography shows that fused and clipped TtProDH form oligomers. Thermal stability and co-solvent tolerance indicate the conformational robustness of TtProDH. These properties together with the high yield make TtProDH attractive for industrial applications. PMID- 25545501 TI - Reassessing dose constraints of organs at risk in children with abdominal neuroblastoma treated with definitive radiation therapy: a correlation with late toxicity. AB - BACKGROUND: In children treated with definitive radiation therapy (RT) for abdominal neuroblastoma, normal tissue constraints for organs at risk (OARs) are not well-standardized or evidence-based. In this study, we analyze dosimetric data of principal abdominal OARs, reassess existing RT planning constraints, and examine corresponding acute and late toxicity to OARs. PROCEDURE: The treatment plans of 30 consecutive children who underwent definitive RT for high-risk abdominal neuroblastoma were reviewed. Dose-volume histogram (DVH) statistics were recorded for the ipsilateral kidney (if unresected), contralateral kidney, and liver. DVH data were analyzed to determine if OAR constraints from recent protocols were met and correlated with the development of toxicity. RESULTS: The median follow-up period was 53.0 months. Ten, thirteen, and ten percent of patients' RT plans did not meet OAR DVH constraints for the liver, ipsilateral kidney, and contralateral kidney, respectively. Of the three patients whose plans did not achieve ipsilateral kidney DVH constraint(s), two developed evidence of late ipsilateral kidney hypoplasia, but maintained normal laboratory kidney function. No patient experienced late toxicity of the contralateral kidney nor developed RT-related late hepatic complications. CONCLUSIONS: In children treated for abdominal neuroblastoma, the risk of developing clinically significant RT related late toxicity of the kidney and liver is not appreciable, even when current DVH parameters for OARs are not achieved in planning. Toxicity outcomes did not necessarily correlate with present-day OAR dose constraints. Currently utilized DVH constraints are highly variable, and must be further studied and supported by toxicity outcomes to more accurately characterize risk of complications. PMID- 25545500 TI - Coarse electrocorticographic decoding of ipsilateral reach in patients with brain lesions. AB - In patients with unilateral upper limb paralysis from strokes and other brain lesions, strategies for functional recovery may eventually include brain-machine interfaces (BMIs) using control signals from residual sensorimotor systems in the damaged hemisphere. When voluntary movements of the contralateral limb are not possible due to brain pathology, initial training of such a BMI may require use of the unaffected ipsilateral limb. We conducted an offline investigation of the feasibility of decoding ipsilateral upper limb movements from electrocorticographic (ECoG) recordings in three patients with different lesions of sensorimotor systems associated with upper limb control. We found that the first principal component (PC) of unconstrained, naturalistic reaching movements of the upper limb could be decoded from ipsilateral ECoG using a linear model. ECoG signal features yielding the best decoding accuracy were different across subjects. Performance saturated with very few input features. Decoding performances of 0.77, 0.73, and 0.66 (median Pearson's r between the predicted and actual first PC of movement using nine signal features) were achieved in the three subjects. The performance achieved here with small numbers of electrodes and computationally simple decoding algorithms suggests that it may be possible to control a BMI using ECoG recorded from damaged sensorimotor brain systems. PMID- 25545502 TI - Galanin modulates human and murine neutrophil activation in vitro. AB - AIMS: Polymorphonuclear neutrophils are key players in innate immunity. The innate immune system needs to be tightly controlled to ensure proper activation but also no overactivation. Galanin has been shown to regulate inflammatory reactions, and therefore, we aimed to elucidate the expression of galanin and its three receptors (GAL1 -GAL3 ) in polymorphonuclear neutrophils and to evaluate whether galanin exerts direct or indirect effects on human and murine polymorphonuclear neutrophils. METHODS: Human peripheral polymorphonuclear neutrophils were isolated from fresh blood of healthy donors, and murine polymorphonuclear neutrophils were isolated from bone marrow of C57BL/6N mice. Gene expression was evaluated by qRT-PCR. As a marker for polymorphonuclear neutrophil activation, CD11b integrin surface expression was measured by FACS analysis. Furthermore, a label-free technology measuring ligand-induced dynamic mass redistribution was used to evaluate the response of polymorphonuclear neutrophils to galanin. RESULTS: GAL2 receptor expression was found in both human and murine polymorphonuclear neutrophils, galanin and GAL3 receptor were exclusively expressed in murine bone marrow polymorphonuclear neutrophils, and GAL1 receptor was not detectable in polymorphonuclear neutrophils of either species. Galanin treatment was not able to induce CD11b integrin surface expression or dynamic mass redistribution in human polymorphonuclear neutrophils and murine bone marrow polymorphonuclear neutrophils. However, galanin treatment significantly enhanced the response of polymorphonuclear neutrophils of both species to interleukin-8. CONCLUSION: Galanin can be regarded as an immunomodulatory peptide as it can sensitize polymorphonuclear neutrophils towards pro-inflammatory cytokines in humans and mice. PMID- 25545503 TI - Fast and highly sensitive fiber-enhanced Raman spectroscopic monitoring of molecular H2 and CH4 for point-of-care diagnosis of malabsorption disorders in exhaled human breath. AB - Breath gas analysis is a novel powerful technique for noninvasive, early-stage diagnosis of metabolic disorders or diseases. Molecular hydrogen and methane are biomarkers for colonic fermentation, because of malabsorption of oligosaccharides (e.g., lactose or fructose) and for small intestinal bacterial overgrowth. Recently, the presence of these gases in exhaled breath was also correlated with obesity. Here, we report on the highly selective and sensitive detection of molecular hydrogen and methane within a complex gas mixture (consisting of H2, CH4, N2, O2, and CO2) by means of fiber-enhanced Raman spectroscopy (FERS). An elaborate FERS setup with a microstructured hollow core photonic crystal fiber (HCPCF) provided a highly improved analytical sensitivity. The simultaneous monitoring of H2 with all other gases was achieved by a combination of rotational (H2) and vibrational (other gases) Raman spectroscopy within the limited spectral transmission range of the HCPCF. The HCPCF was combined with an adjustable image plane aperture pinhole, in order to separate the H2 rotational Raman bands from the silica background signal and improve the sensitivity down to a limit of detection (LOD) of 4.7 ppm (for only 26 fmol H2). The ability to monitor the levels of H2 and CH4 in a positive hydrogen breath test (HBT) was demonstrated. The FERS sensor possesses a high dynamic range (~5 orders of magnitude) with a fast response time of few seconds and provides great potential for miniaturization. We foresee that this technique will pave the way for fast, noninvasive, and painless point-of-care diagnosis of metabolic diseases in exhaled human breath. PMID- 25545506 TI - Marking time. PMID- 25545504 TI - A mathematical model of bimodal epigenetic control of miR-193a in ovarian cancer stem cells. AB - Accumulating data indicate that cancer stem cells contribute to tumor chemoresistance and their persistence alters clinical outcome. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by surface antigen CD44 and c-KIT (CD117). It has been experimentally demonstrated that a microRNA, namely miR-193a, targets c-KIT mRNA for degradation and could play a crucial role in ovarian cancer development. How miR-193a is regulated is poorly understood and the emerging picture is complex. To unravel this complexity, we propose a mathematical model to explore how estrogen-mediated up-regulation of another target of miR-193a, namely E2F6, can attenuate the function of miR-193a in two ways, one through a competition of E2F6 and c-KIT transcripts for miR-193a, and second by binding of E2F6 protein, in association with a polycomb complex, to the promoter of miR-193a to down-regulate its transcription. Our model predicts that this bimodal control increases the expression of c-KIT and that the second mode of epigenetic regulation is required to generate a switching behavior in c-KIT and E2F6 expressions. Additional analysis of the TCGA ovarian cancer dataset demonstrates that ovarian cancer patients with low expression of EZH2, a polycomb-group family protein, show positive correlation between E2F6 and c-KIT. We conjecture that a simultaneous EZH2 inhibition and anti-estrogen therapy can constitute an effective combined therapeutic strategy against ovarian cancer. PMID- 25545507 TI - Direct-to-consumer drug advertising. PMID- 25545505 TI - A cyclic peptidic serine protease inhibitor: increasing affinity by increasing peptide flexibility. AB - Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase-type plasminogen activator (uPA). We used X-ray crystal structure analysis, site-directed mutagenesis, liquid state NMR, surface plasmon resonance analysis, and isothermal titration calorimetry and wild type and engineered variants of murine and human uPA. We demonstrate that Arg6 inserts into the S1 specificity pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending on changes in both P1 - S1 and exosite interactions. Site-directed mutagenesis showed that exosite interactions, while still supporting high affinity binding, differed substantially between different uPA variants. Surprisingly, high affinity binding was facilitated by Ala substitution of Asp9 of the peptide, in spite of a less favorable binding entropy and loss of a polar interaction. We conclude that increased flexibility of the peptide allows more favorable exosite interactions, which, in combination with the use of novel Arg analogues as P1 residues, can be used to manipulate the affinity and specificity of this peptidic inhibitor, a concept different from conventional attempts at improving inhibitor affinity by reducing the entropic burden. PMID- 25545508 TI - Just write. PMID- 25545509 TI - Just write. PMID- 25545510 TI - Just write. PMID- 25545511 TI - Overdose reversal. PMID- 25545513 TI - Real case studies. PMID- 25545512 TI - Central line care. PMID- 25545517 TI - The ACA continues to run the gauntlet. PMID- 25545514 TI - The top health care story of 2014: a year of infectious diseases. PMID- 25545520 TI - Controversy over pelvic examinations. PMID- 25545528 TI - Preparing for retirement in uncertain times. PMID- 25545533 TI - Fostering clinical reasoning in nursing students. AB - This article is one in a series on the roles of adjunct clinical faculty and preceptors, who teach nursing students to apply knowledge in clinical settings. This article describes why it's important that nursing students develop clinical reasoning skills and how clinical nursing instructors can help them learn these skills. PMID- 25545534 TI - Reducing hospital readmissions. AB - This column is designed to provide a nursing perspective on new hospital quality measurements. Future articles will cover the various quality indicators hospitals face and the role of the nurse in meeting mandated benchmarks. Reader responses to this column are welcome and will help to make it more useful to nurses in meeting the challenges posed by health care reform and changing Medicare reimbursement programs. PMID- 25545536 TI - Mannitol vs. hypertonic saline for brain relaxation in patients undergoing craniotomy. PMID- 25545537 TI - The tables turned. PMID- 25545538 TI - Sublethal effects of aged oil sands-affected water on white sucker (Catostomus commersonii). AB - To investigate impacts of proposed oil sands aquatic reclamation techniques on benthic fish, white sucker (Catostomus commersonii Lacepede, 1803) were stocked in 2 experimental ponds-Demonstration Pond, containing aged fine tailings capped with fresh water, consistent with proposed end-pit lake designs, and South Bison Pond, containing aged unextracted oil sands material-to examine the effects of unmodified hydrocarbons. White sucker were stocked from a nearby reservoir at both sites in May 2010 and sampled 4 mo later to measure indicators of energy storage and utilization. Comparisons were then made with the source population and 2 reference lakes in the region. After exposure to aged tailings, white sucker had smaller testes and ovaries and reduced growth compared with the source population. Fish introduced to aged unextracted oil sands material showed an increase in growth over the same period. Limited available energy, endocrine disruption, and chronic stress likely contributed to the effects observed, corresponding to elevated concentrations of naphthenic acids, aromatic compounds in bile, and increased CYP1A activity. Because of the chemical and biological complexity of these systems, direct cause-effect relationships could not be identified; however, effects were associated with naphthenic acids, polycyclic aromatic hydrocarbons, ammonia, and high pH. Impacts on growth have not been previously observed in pelagic fishes examined in these systems, and may be related to differences in sediment interaction. PMID- 25545539 TI - Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients. AB - Accelerated formation and tissue accumulation of advanced glycation end products (AGEs), reflecting cumulative glycemic and oxidative stress, occurs in age related and chronic diseases like diabetes mellitus (DM) and renal failure, and contributes to vascular damage. Skin autofluorescence (AFR), a noninvasive measurement method, reflects tissue accumulation of AGEs. AFR has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. We assessed the relationship between levels of AFR and the prevalence of cardiovascular disease (CVD), and clarified the prognostic usefulness of skin AFR levels in Asian (non-Caucasian) hemodialysis (HD) patients. AFR was measured with an autofluorescence reader in 64 HD patients. Overall and cardiovascular mortality was monitored prospectively during the 3-year follow-up. During follow up, CVD events occurred in 21 patients. The deaths of 10 HD patients were associated with CVD. Multivariate logistic regression analyses showed that initial AFR was an independent risk factor for de novo CVD in HD patients with or without diabetes. When patients were classified on the basis of AFR tertiles, Cochran-Armitage analysis demonstrated that the highest tertile of AFR level showed an increased odds ratio for the prevalence of CVD. These findings suggest that AFR levels can be used to detect the prevalence of CVD in HD patients with or without diabetes. PMID- 25545540 TI - Noninvasive Assessment of Atrioventricular Nodal Function: Effect of Rate-Control Drugs during Atrial Fibrillation. AB - BACKGROUND: During atrial fibrillation (AF), conventional electrophysiological techniques for assessment of refractory period or conduction velocity of the atrioventricular (AV) node cannot be used. We aimed at evaluating changes in AV nodal properties during administration of tecadenoson and esmolol using a novel ECG-based method. METHODS: Fourteen patients (age 58 +/- 8 years, 10 men) with AF were randomly assigned to either 75 or 300 MUg intravenous tecadenoson. After tecadenoson wash-out, patients received esmolol continuously (100 MUg/kg per min for 10 mins, then 50 MUg/kg per min for 50 mins). Atrial fibrillatory rate (AFR) and heart rate (HR) were assessed in 15-min segments. Using the novel method, we assessed the absolute refractory periods of the slow and fast pathways (aRPs and aRPf) of the AV node to produce an estimate of the functional refractory period. RESULTS: During esmolol infusion, AFR and HR were significantly decreased and the absolute refractory period was significantly prolonged in both pathways (aRPs: 387 +/- 73 vs 409 +/- 62 ms, P < 0.05; aRPf: 490 +/- 80 vs 529 +/- 58 ms, P < 0.05). During both tecadenoson doses, HR decreased significantly and AFR was unchanged. Both aRPs and aRPf were prolonged for a 75 MUg dose (aRPs: 322 +/- 97 vs 476 +/- 75 ms, P < 0.05; aRPf: 456 +/- 102 vs 512 +/- 55 ms, P < 0.05) whereas a trend toward prolongation was observed for a 300 MUg dose. CONCLUSIONS: The estimated parameters reflect expected changes in AV nodal properties, i.e., slower conduction through the AV node for tecadenoson and prolongation of the AV node refractory period for esmolol. Thus, the proposed approach may be used to assess drug effects on the AV node in AF patients. PMID- 25545541 TI - Comparing treatment-seeking codeine users and strong opioid users: Findings from a novel case series. AB - INTRODUCTION AND AIMS: Few studies have described those seeking treatment for codeine dependence. This study aimed to compare patients presenting for treatment where either codeine or a strong pharmaceutical opioid (oxycodone or morphine) was the principal drug of concern to understand if codeine users may have unique treatment needs. DESIGN AND METHODS: Retrospective case review of 135 patients from three geographical areas in New South Wales, Australia. Cases where the principal drug of concern was codeine (n = 53) or a strong pharmaceutical opioid (oxycodone or morphine, n = 82) were compared. Differences in demographic characteristics, pain history, mental health, substance use history and, subsequently, the treatment that was received were examined. RESULTS: People whose principal drug of concern was codeine were more likely to be female (66% vs. 37%, P < 0.001), employed (43% vs. 22%, P < 0.01) and use only one pharmaceutical opioid (91% vs. 49%, P < 0.001). There was no difference in age between the codeine group (mean 38.6 years) and the strong opioid group (39.3 years). Opioid substitution therapy was the most common treatment received by both groups although codeine patients were more likely to be treated with buprenorphine than methadone (odds ratio = 7.7, 95% confidence interval 2.2-27.2, P < 0.001) and more likely to attempt withdrawal (odds ratio = 2.6, 95% confidence interval 1.2-5.3, P = 0.010). DISCUSSION AND CONCLUSIONS: There are important differences between codeine-dependent patients and strong prescription opioid-dependent patients. Further work should explore the outcomes of withdrawal versus maintenance treatment for codeine users. PMID- 25545542 TI - MnTM-4-PyP modulates endogenous antioxidant responses and protects primary cortical neurons against oxidative stress. AB - AIMS: Oxidative stress is a direct cause of injury in various neural diseases. Manganese porphyrins (MnPs), a large category of superoxide dismutase (SOD) mimics, shown universally to have effects in numerous neural disease models in vivo. Given their complex intracellular redox activities, detailed mechanisms underlying the biomedical efficacies are not fully elucidated. This study sought to investigate the regulation of endogenous antioxidant systems by a MnP (MnTM-4 PyP) and its role in the protection against neural oxidative stress. METHODS: Primary cortical neurons were treated with MnTM-4-PyP prior to hydrogen peroxide induced oxidative stress. RESULTS: MnTM-4-PyP increased cell viability, reduced intracellular level of reactive oxygen species, inhibited mitochondrial apoptotic pathway, and ameliorated endoplasmic reticulum function. The protein levels and activities of endogenous SODs were elevated, but not those of catalase. SOD2 transcription was promoted in a transcription factor-specific manner. Additionally, we found FOXO3A and Sirt3 levels also increased. These effects were not observed with MnTM-4-PyP alone. CONCLUSION: Induction of various levels of endogenous antioxidant responses by MnTM-4-PyP has indispensable functions in its protection for cortical neurons against hydrogen peroxide-induced oxidative stress. PMID- 25545543 TI - Assessment of body composition in subjects with metabolic syndrome comparing single-frequency bioelectrical impedance analysis and bioelectrical spectroscopy. AB - BACKGROUND: The aim of this study was to investigate the agreement between body composition measurements made with two methods-single-frequency bioelectrical impedance analysis (SF-BIA) and bioelectrical impedance spectroscopy (BIS). METHODS: The body composition measurements using SF-BIA and BIS were performed seven times during 6 months on 41 patients (13 men and 28 women) with metabolic syndrome who were taking part in a dietary intervention study. RESULTS: The mean [standard deviation (SD)] fat mass (FM) and median [interquartile range (IQR)] FM% measured with SF-BIA were 32.7 (6.7) kg and 36.3 (30.3-39.3)%, respectively, compared with 38.2 (8.7) kg and 40.9 (35.5-45.6)%, respectively, using BIS. The median (IQR) fat-free mass (FFM) was 60.0 (53.3-73.5) kg according to SF-BIA and 55.4 (48.8-66.5) kg according to BIS. These results obtained with the two methods were significantly different (P<0.001). Still highly significant correlations were found between the results obtained with SF-BIA and BIS for FM and FFM (all r>=0.89, P<0.001). Using Bland-Altman analysis, the bias was found to be -5.4 (4.1) kg for FM, -5.5 (3.7)% for FM%, and 5.4 (4.1) kg for FFM. Rather wide limits of agreement were found for FM, FM%, and FFM. CONCLUSION: Body composition data obtained using SF-BIA and BIS in subjects with metabolic syndrome were highly correlated but not interchangeable. FM was systematically lower when using SF-BIA than when using BIS. PMID- 25545544 TI - The effects of exposure duration to optimal concentration of 2-phenoxyethanol on primary and secondary stress responses in kutum (Rutilus frisii kutum). AB - The goal of this study was to assess the anaesthetic induction and recovery time in kutum (Rutilus frisii kutum) after exposure to various concentrations (0.1, 0.3, 0.5, 0.7 and 0.9 ml/l) of 2-PE as an anaesthetic, as well as the effects of optimal concentration (0.7 ml/l) of 2-PE in relation to different exposure time (3, 10, 15 min) on some haematological and serum biochemical indices in this species. Moreover, the effects of 0.7 ml/l on blood parameters were assessed 24 h after the longest exposure. Significant increase was determined in Hb, MCH and MCHC after 10-min exposure to 2-PE (p < 0.05). Moreover, Hct, Hb and RBC levels increased significantly after 15 min-exposure to 2-PE (p < 0.05). There were no prominent changes in WBC and MCV. The plasma concentrations of glucose, cholesterol and cortisol increased significantly after 10- and 15-min exposure to 2-PE (p < 0.05) compared with the control group and all other exposure times. The activity of ALT and AST were significantly increased after 10- and 15-min exposure respectively (p < 0.05). In this study, it appears that anaesthetizing kutum with 2-PE at 0.7 ml/l for 3 min had no effect on the stress markers. PMID- 25545546 TI - Polyoxotungstate incorporating organotriphosphonate ligands: synthesis, characterization, and catalytic for alkene epoxidation. AB - A S-shaped organotriphosphonate polyoxotungstate, K4H6[H4{(AsW9O33)Zn(H2O)W5O11(N(CH2PO3)3)}2(MU2-O)2].27H2O (1), has been synthesized and characterized. Compound 1 contains a different geometry of [{Zn(H2O)W5O19(N(CH2PO3)3)}](12-) clusters, which forms a chiral conformation. The catalysis of 1 for alkene epoxidation was investigated with a hydrogen peroxide (H2O2) oxidant. PMID- 25545545 TI - Circadian variation of the human metabolome captured by real-time breath analysis. AB - Circadian clocks play a significant role in the correct timing of physiological metabolism, and clock disruption might lead to pathological changes of metabolism. One interesting method to assess the current state of metabolism is metabolomics. Metabolomics tries to capture the entirety of small molecules, i.e. the building blocks of metabolism, in a given matrix, such as blood, saliva or urine. Using mass spectrometric approaches we and others have shown that a significant portion of the human metabolome in saliva and blood exhibits circadian modulation; independent of food intake or sleep/wake rhythms. Recent advances in mass spectrometry techniques have introduced completely non-invasive breathprinting; a method to instantaneously assess small metabolites in human breath. In this proof-of-principle study, we extend these findings about the impact of circadian clocks on metabolomics to exhaled breath. As previously established, our method allows for real-time analysis of a rich matrix during frequent non-invasive sampling. We sampled the breath of three healthy, non smoking human volunteers in hourly intervals for 24 hours during total sleep deprivation, and found 111 features in the breath of all individuals, 36-49% of which showed significant circadian variation in at least one individual. Our data suggest that real-time mass spectrometric "breathprinting" has high potential to become a useful tool to understand circadian metabolism, and develop new biomarkers to easily and in real-time assess circadian clock phase and function in experimental and clinical settings. PMID- 25545547 TI - Effect of changes in end-tidal carbon dioxide tension on oral tissue blood flow during dexmedetomidine infusion in rabbits. AB - A decrease in arterial carbon dioxide tension induces an increase in masseter muscle blood flow and a decrease in mandibular bone marrow blood flow during general anesthesia. In addition, dexmedetomidine infusion reduces oral tissue blood flow. In this study we investigated how end-tidal carbon dioxide tension (ET-CO2 ) changes influence on oral tissue blood flow during continuous dexmedetomidine infusion in rabbits. Eleven male Japan White rabbits were anesthetized with sevoflurane. Then, ET-CO2 was set at 30 mmHg and adjusted to 40 and 60 mmHg, and heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, common carotid artery blood flow, mandibular bone marrow blood flow, masseter muscle blood flow, and blood flow in other oral tissues were measured. Following this, the ET-CO2 was returned to 30 mmHg and dexmedetomidine was infused over 60 min. The measurements were repeated. Most parameters increased, regardless of whether or not dexmedetomidine was present, and heart rate and masseter muscle blood flow decreased in an ET-CO2 -dependent manner. Dexmedetomidine infusion suppressed ET-CO2 -dependent masseter muscle blood flow change. Masseter muscle blood flow during ET-CO2 at 30 mmHg with dexmedetomidine was the same as that during ET-CO2 at 40 mmHg without dexmedetomidine. Our findings suggest that dexmedetomidine infusion and slight hypocapnia under general anesthesia suppress an increase in masseter muscle blood flow as well as reducing mandibular bone marrow blood flow. These results may be of significance for decreasing bleeding during oral and maxillofacial surgery. PMID- 25545548 TI - A microfluidic platform for correlative live-cell and super-resolution microscopy. AB - Recently, super-resolution microscopy methods such as stochastic optical reconstruction microscopy (STORM) have enabled visualization of subcellular structures below the optical resolution limit. Due to the poor temporal resolution, however, these methods have mostly been used to image fixed cells or dynamic processes that evolve on slow time-scales. In particular, fast dynamic processes and their relationship to the underlying ultrastructure or nanoscale protein organization cannot be discerned. To overcome this limitation, we have recently developed a correlative and sequential imaging method that combines live cell and super-resolution microscopy. This approach adds dynamic background to ultrastructural images providing a new dimension to the interpretation of super resolution data. However, currently, it suffers from the need to carry out tedious steps of sample preparation manually. To alleviate this problem, we implemented a simple and versatile microfluidic platform that streamlines the sample preparation steps in between live-cell and super-resolution imaging. The platform is based on a microfluidic chip with parallel, miniaturized imaging chambers and an automated fluid-injection device, which delivers a precise amount of a specified reagent to the selected imaging chamber at a specific time within the experiment. We demonstrate that this system can be used for live-cell imaging, automated fixation, and immunostaining of adherent mammalian cells in situ followed by STORM imaging. We further demonstrate an application by correlating mitochondrial dynamics, morphology, and nanoscale mitochondrial protein distribution in live and super-resolution images. PMID- 25545549 TI - Bioequivalence of 0.1% mometasone furoate lotion to 0.1% mometasone furoate hydrogel. AB - BACKGROUND/OBJECTIVES: Vehicles used for topical therapy can affect drug delivery and patient adherence. This study compared the bioequivalence of 0.1% mometasone furoate lotion (reference) and 0.1% mometasone furoate hydrogel (test). Moisturising capacity and sensitivity/irritancy potential were also determined. METHODS: Bioequivalence was assessed by vasoconstriction assay and analysis of area under the effect curve (AUEC0-24 ) according to the Food and Drug Administration (FDA) guidance. In total, 131 individuals were screened in a pilot dose duration-response study, and 90 responders enrolled. For the pivotal study, lotion and hydrogel (5 mg/cm(2) ) were applied in a double-blind manner. Vasoconstriction was evaluated by chromameter at 0, 2, 4, 6, 19 and 24 h following lotion and hydrogel removal. Barrier function was measured by assessment of transepidermal water loss (TEWL) and skin hydration. Sensitivity/irritancy potential was assessed by repeat insult patch tests. RESULTS: The mean AUEC0-24 of the test hydrogel and reference lotion were -18.200 and -18.953, respectively, with test/reference = 96%, with 90% confidence interval (0.81, 1.12), which was within FDA guidance limits. TEWL was found to significantly decrease by 43 and 29% after 2 and 24 h, respectively, while skin hydration significantly increased by 38% after 24 h following a single application of hydrogel. The hydrogel was also found to be non-irritating and non sensitising. No adverse events were observed. CONCLUSIONS: Mometasone furoate hydrogel is bioequivalent to mometasone furoate lotion. This novel hydrogel formulation provides effective drug delivery, increases moisturisation and affords greater ease and tolerability of application, improving patients' adherence to therapy. PMID- 25545550 TI - Robust biomimetic-structural superhydrophobic surface on aluminum alloy. AB - The following facile approach has been developed to prepare a biomimetic structural superhydrophobic surface with high stabilities and strong resistances on 2024 Al alloy that are robust to harsh environments. First, a simple hydrothermal treatment in a La(NO3)3 aqueous solution was used to fabricate ginkgo-leaf like nanostructures, resulting in a superhydrophilic surface on 2024 Al. Then a low-surface-energy compound, dodecafluoroheptyl-propyl trimethoxylsilane (Actyflon-G502), was used to modify the superhydrophilic 2024 Al, changing the surface character from superhydrophilicity to superhydrophobicity. The water contact angle (WCA) of such a superhydrophobic surface reaches up to 160 degrees , demonstrating excellent superhydrophobicity. Moreover, the as-prepared superhydrophobic surface shows high stabilities in air storage, chemical and thermal environments, and has strong resistances to UV irradiation, corrosion, and abrasion. The WCAs of such a surface almost remain unchanged (160 degrees ) after storage in air for 80 days, exposure in 250 degrees C atmosphere for 24 h, and being exposed under UV irradiation for 24 h, are more than 144 degrees whether in acidic or alkali medium, and are more than 150 degrees after 48 h corrosion and after abrasion under 0.98 kPa for 1000 mm length. The remarkable durability of the as-prepared superhydrophobic surface can be attributed to its stable structure and composition, which are due to the existence of lanthanum (hydr)oxides in surface layer. The robustness of the as prepared superhydrophobic surface to harsh environments will open their much wider applications. The fabricating approach for such robust superhydrophobic surface can be easily extended to other metals and alloys. PMID- 25545551 TI - Diagnostic accuracy of tinea unguium based on clinical observation. PMID- 25545553 TI - Antidepressant-like effect of evodiamine on chronic unpredictable mild stress rats. AB - Evodiamine is a major alkaloid compound extracted from the dry unripened fruit Evodia fructus (Evodia rutaecarpa Benth., Rutaceae), which has a variety of pharmacological activities. The present study aims to determine the antidepressant-like effect of evodiamine in a rat model of chronic unpredictable mild stress (CUMS). We identified that evodiamine could reverse the following CUMS-induced behavioural deficits and biochemical changes in rats: the decreases of sucrose preference, number of crossings, 5-HT and NA levels, as well as the increase of immobility time. Evodiamine treatments also ameliorated the corticosterone hypersecretion induced by CUMS. Furthermore, we found that evodiamine was able to up-regulate the expression of brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase B (pTrkB) without altering TrkB. This study suggests potential antidepressant-like effect of evodiamine on CUMS rats, and its underlying mechanisms can be potentially linked to their modulating effects on the monoamine transmitters and BDNF-TrkB signaling in the hippocampus. PMID- 25545554 TI - Social interaction with rat exposed to constant light during lactation prevents depressive-like behavior induced by constant light in adulthood. AB - Circadian rhythm disruptions are often observed in depressed patients, and changes in the light/dark cycle promote depressive-like behavior in animal models. Prolonged exposure to constant light (LL) is known to lead to arrhythmicity of circadian locomotor activity and depressive-like behavior in rats. Interestingly, neonatal exposure to LL prevents both arrhythmicity and depressive behavior in adulthood. Arrhythmic rats under LL conditions that cohabitate with a rhythmic rat exhibit improvement in circadian rhythms. We tested whether such cohabitation also protects against LL-induced depressive-like behavior. Wistar rats were assigned to conditions of either neonatal constant light (neonatal-LL) on postnatal days 10-22 or a regular light/dark cycle (neonatal-LD). On day 45, the animals were assigned to three possible pair combinations. After a baseline sucrose preference test, half of the pairs were placed under LL conditions. Weekly sucrose preference tests were conducted to evaluate depressive-like behavior. The animals were isolated by an aluminum wall on the test day. At week 2 of LL, sucrose preference was reduced in neonatal LD/neonatal-LD pairs of animals. At week 5, neonatal-LD/neonatal-LD pairs exhibited anhedonic-like behavior, but the pairs with at least one neonatal-LL rat did not. The LL cycle was returned to an LD cycle, and the neonatal LD/neonatal-LD pairs exhibited a restoration of sucrose preference 2 weeks later. We conclude that social interaction can prevent depressive-like behavior induced by circadian rhythm disruption as long as one of the animals is more prone to present a strong rhythm. PMID- 25545552 TI - In-hospital neurologic deterioration following fractures of the ankylosed spine: a single-institution experience. AB - OBJECTIVE: To determine the rate and severity of in-hospital neurologic deterioration following vertebral fractures of spinal hyperostosis. METHODS: A retrospective review of 92 fractures in 81 patients with diffuse idiopathic skeletal hyperostosis (42%) or ankylosing spondylitis (58%) was performed. Data on demographics, comorbidities, and fracture and treatment characteristics were recorded. Neurologic presentation and outcomes were categorized using American Spinal Injury Association grades and the modified Rankin Scale. Univariate and multivariate analyses were used to identify risk factors for neurologic deterioration or poor outcome (modified Rankin Scale 4-6). RESULTS: Most fractures (66%) occurred after falls of standing height or less. Presentation was delayed in 41% of patients (median 7 days), and diagnosis was delayed in 21% (median 8 days). Most fractures were extension (60%) or distraction (78%) injuries involving all 3 spinal columns. Median Subaxial Cervical Spine Injury Classification and Thoracolumbar Injury Severity Scale scores were 6 (interquartile range 5-7) and 7 (interquartile range 6-8), respectively. Of patients, 62% underwent open operative fusion either as initial therapy or after failed conservative treatment, 20% had percutaneous instrumentation, and 27% were treated in an external orthosis (52% required open fusion). Neurologic deterioration after presentation occurred in 7 patients (8.6%); 5 of these patients deteriorated after surgical treatment, constituting a 7.6% surgical risk. The presenting American Spinal Injury Association grade and patient age predicted poor outcome at 1-year outcome (P < 0.001). Death occurred in 17 patients within 1 year of injury (23%). CONCLUSIONS: Neurologic deterioration during the initial hospitalization after spinal fractures in the setting of diffuse idiopathic skeletal hyperostosis or ankylosing spondylitis is common, and 1-year mortality is high. PMID- 25545555 TI - Effects of tityustoxin on cerebral inflammatory response in young rats. AB - Accidents caused by scorpion stings, mainly affecting children, are considered an important cause of morbidity and mortality in tropical countries. Clinical studies demonstrate the relevant role of systemic inflammatory events in scorpion envenoming. However, remains poorly understood whether the major lethal component in Tityus serrulatus venom, tityustoxin (TsTX), is able to induce inflammatory responses in the cerebral microcirculation. In this study, we systematically examined leukocyte recruitment into the CNS in response to TsTX injection. Accordingly, developing rats were subjected to a subcutaneous (s.c.) injection of TsTX (0.75mg/kg), and leukocyte recruitment (i.e., 4, 8 and 12h after injection) and TNF-alpha levels were evaluated. Rats injected with TsTX presented a significant increase in leukocyte rolling and adhesion and higher levels of TNF alpha at all time points studied, compared to the control group. Altogether, this work demonstrates the triggering of neuroimmunological mechanisms induced by TsTX injection in young rats. PMID- 25545556 TI - Interaction between 5-HT1B receptors and nitric oxide in zebrafish responses to novelty. AB - Nitric oxide (NO) and serotonin (5-HT) interact at the molecular and systems levels to control behavioral variables, including agression, fear, and reactions to novelty. In zebrafish, the 5-HT1B receptor has been implicated in anxiety and reactions to novelty, while the 5-HT1A receptor is associated with anxiety-like behavior; this role of the 5-HT1A receptor is mediated by NO. This work investigated whether NO also participates in the mediation of novelty responses by the 5-HT1B receptor. The 5-HT1B receptor inverse agonist SB 224,289 decreased bottom-dwelling and erratic swimming in zebrafish; the effects on bottom dwelling, but not on erratic swimming, were blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME. These effects underline a novel mechanism by which 5-HT controls zebrafish reactivity to novel environments, with implications for the study of neotic reactions, exploratory behavior, and anxiety like states. PMID- 25545557 TI - Measurement of cerebral blood volume dynamics during volitional swallowing using functional near-infrared spectroscopy: an exploratory study. AB - The aim of this study was to examine cerebral blood volume dynamics during volitional swallowing using multi-channel functional near-infrared spectroscopy (fNIRS) to understand the basic cortical activation patterns. Fifteen volunteers (age, 26.5+/-1.3 years, mean+/-SD) performed volitional swallowing of a 5-ml bolus of water as a task. A 52-channel fNIRS system was used for measuring oxy-Hb levels. We determined the oxy-Hb concentration changes in each channel by calculating the differences between rest and task oxy-Hb levels. Differences in rest and task data were assessed using a paired-t test (p<0.05). A significant increase in oxy-Hb was found in 21 channels. The cortical regions that exhibited increased oxy-Hb concentration included the bilateral precentral gyrus, postcentral gyrus, inferior frontal gyrus, superior temporal gyrus, middle temporal gyrus, and supramarginal gyrus. These data provide a description of cortical activation patterns during volitional swallowing using fNIRS, which will be useful for the evaluation of dysphasia and the effects of the rehabilitation [Corrected]. PMID- 25545558 TI - Loss of AQP4 polarized localization with loss of beta-dystroglycan immunoreactivity may induce brain edema following intracerebral hemorrhage. AB - The aquaporin-4 (AQP4) water channel contributes to brain water homeostasis in perivascular and subpial membrane domains of astrocytes where it is concentrated. These membranes form the interface between the neuropil and the extracellular liquid spaces. The brain-selective deletion of the dystroglycan (DG) gene causes a disorganization of AQP4 on the astroglial endfeet. First, we analyzed the expression of AQP4, beta-DG in the brain following intracerebral hemorrhage (ICH) and correlated AQP4 expression with the expression pattern of the beta-DG, which is a component of dystrophin-dystroglycan complex (DDC). Besides, the vessels ultrastructure and brain water content were investigated at different time points post-ICH (day 1, day 3, day 7). We found that AQP4 polarity was disturbed in parallel with the loss of beta-DG in the perihematomal area post-ICH. At day 1 post-ICH, brain edema was obvious and the damage of vascular ultrastructure was the most severe. These results suggest a role for beta-DG in targeting and stabilizing AQP4 channel in astrocytic cells, which may be critical for water homeostasis in brain. PMID- 25545559 TI - White matter abnormalities associate with type and localization of focal epileptogenic lesions. AB - OBJECTIVE: To evaluate white matter (WM) integrity of distinct groups of patients with antiepileptic drug (AED)-resistant localization-related epilepsies. METHODS: We used diffusion tensor imaging (DTI) fiber-tractography and voxel-based morphometry (VBM) to investigate differences of WM micro- and macrostructural integrity in patients with different drug-resistant localization-related epilepsies: 17 with temporal lobe epilepsy with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 17 with TLE and normal MRI (TLE-NL), 14 with frontal lobe epilepsy and subtle MRI signs of focal cortical dysplasia (FLE FCD), and 112 healthy controls. We performed fiber-tractography using a semiautomatic deterministic method to yield average fractional anisotropy (FA), axial (AD), and radial (RD) diffusivity ipsilateral and contralateral to the epileptogenic zone of the following tracts based on their functional and anatomic relevance: body of fornix (BoF), body of cingulum (BoC), inferior frontal occipital (IFO), and uncinate fasciculi (UF). In addition, we performed VBM of the WM maps to assess macrostructural integrity differences among groups. RESULTS: TLE-HS had ipsilateral and contralateral decreased FA and increased RD for all tracts. VBM showed WM alterations mainly in the ipsilateral parahippocampal region and contralateral superior temporal gyrus. FLE-FCD showed bilateral FA decreases only in the BoC and ipsilateral RD increases also in the BoC. VBM showed WM reduction mainly in the ipsilateral precuneus and posterior and anterior cingulum. No significant WM alterations were found in the TLE-NL in DTI or VBM analysis. SIGNIFICANCE: WM abnormalities differ in distinct AED resistant localization-related epilepsies. The diverse distribution of the WM damage in these patients suggests that the localization of the epileptic networks may play a role in the WM burden. However, the distinct degree of this damage, more accentuated in TLE-HS, also suggests that the underlying cause of the epilepsy is probably an additional factor to explain this WM damage. PMID- 25545560 TI - Pain medicine--a new credential in Canada. AB - OBJECTIVE: In 2010, Pain Medicine was formally recognized as a subspecialty in Canada by the Royal College of Physicians and Surgeons of Canada, a national organization with oversight of the medical education of specialists in Canada. The first trainees began their training at the Western University, London, Canada in July, 2014. This article traces the process of Pain Medicine's development as a discipline in Canada and outlines its multiple entry routes, 2-year curriculum, and assessment procedures. DESIGN: The application for specialty status was initiated in 2007 with the understanding that while Anesthesiology would be the parent specialty, the curriculum would train clinicians in a multidisciplinary setting. To receive recognition as a Royal College subspecialty, Pain Medicine had to successfully pass through three phases, each stage requiring formal approval by the Committee on Specialties. The multiple entry routes to this 2 year subspecialty program are described in this article as are the objectives of training, the curriculum, assessment of competency and the practice-eligibility route to certification. The process of accreditation of new training programs across Canada is also discussed. CONCLUSIONS: The new Pain Medicine training program in Canada will train experts in the prevention, diagnosis, treatment and rehabilitation of the spectrum of acute pain, cancer pain and non-cancer pain problems. These physicians will become leaders in education, research, advocacy and administration of this emerging field. PMID- 25545561 TI - Moving beyond childish notions of fair and equitable. PMID- 25545562 TI - Equality, diversity and fairness in medical education: international perspectives. PMID- 25545563 TI - Policy matters: medical education for whom? Are locally or globally trained doctors best? PMID- 25545564 TI - Our social accountability: when will we walk the talk? PMID- 25545565 TI - Diversity in medical school admission: insights from personnel recruitment and selection. PMID- 25545566 TI - Widening participation in medicine: moving beyond the numbers. PMID- 25545567 TI - Social networks (and more) are necessary for student and faculty resilience. PMID- 25545568 TI - Ethnic and social disparities in medical education. PMID- 25545569 TI - When I say... intersectionality in medical education research. PMID- 25545570 TI - When I say... social accountability in medical education. PMID- 25545571 TI - Taking context seriously: explaining widening access policy enactments in UK medical schools. AB - CONTEXT: Since the 1970s, the UK medical student body has become increasingly diverse in terms of gender, ethnicity and age, but not in socio-economic background. This variance may be linked to large differences in how individual medical schools interpret and put into practice widening participation (WP) policy. However, attempts to theorise what happens when policy enters practice are neglected in medical education. We aimed to explore the dynamics of policy enactment to give a novel perspective on WP practices across UK medical schools. METHODS: We used a qualitative design employing individual telephone interviews to elicit views and concerns around WP from admissions deans and admissions staff within UK medical schools. We carried out interviews with representatives from 24 of 32 UK medical schools. Data coding and analysis were initially inductive, using framework analysis. After the themes emerged, we applied a deductive framework to group themes into four contextual dimensions of 'situation', 'professional', 'material' and 'external'. RESULTS: Our participants held different positions in relation to the interpreting and translating of WP policy, which were influenced by a number of contextual factors including: geographical locality and positioning of the medical school; the expectations of the university and other key stakeholders, and resources. The latter were subtle and referred to resources for medical selection processes rather than for WP per se. The data hinted that the political goal of WP and medical education's goal of producing the best doctors may conflict. CONCLUSIONS: This is the first study to explicitly explore WP policy enactment in medical education. Our analysis is useful for understanding differences in how WP policy is played out in local contexts, and for planning for future policy enactment and research. The messages identified will resonate internationally with all those engaged in efforts to widen participation in medical education. PMID- 25545572 TI - Seeking inclusion in an exclusive process: discourses of medical school student selection. AB - CONTEXT: Calls to increase medical class representativeness to better reflect the diversity of society represent a growing international trend. There is an inherent tension between these calls and competitive student selection processes driven by academic achievement. How is this tension manifested? METHODS: Our three-phase interdisciplinary research programme focused on the discourses of excellence, equity and diversity in the medical school selection process, as conveyed by key stakeholders: (i) institutions and regulatory bodies (the websites of 17 medical schools and 15 policy documents from national regulatory bodies); (ii) admissions committee members (ACMs) (according to semi-structured interviews [n = 9]), and (iii) successful applicants (according to semi structured interviews [n = 14]). The work is theoretically situated within the works of Foucault, Bourdieu and Bakhtin. The conceptual framework is supplemented by critical hermeneutics and the performance theories of Goffman. RESULTS: Academic excellence discourses consistently predominate over discourses calling for greater representativeness in medical classes. Policy addressing demographic representativeness in medicine may unwittingly contribute to the reproduction of historical patterns of exclusion of under-represented groups. In ACM selection practices, another discursive tension is exposed as the inherent privilege in the process is marked, challenging the ideal of medicine as a meritocracy. Applicants' representations of self in the 'performance' of interviewing demonstrate implicit recognition of the power inherent in the act of selection and are manifested in the use of explicit strategies to 'fit in'. CONCLUSIONS: How can this critical discourse analysis inform improved inclusiveness in student selection? Policymakers addressing diversity and equity issues in medical school admissions should explicitly recognise the power dynamics at play between the profession and marginalised groups. For greater inclusion and to avoid one authoritative definition of excellence, we suggest a transformative model of faculty development aimed at promoting multiple kinds of excellence. Through this multi-pronged approach, we call for the profession to courageously confront the cherished notion of the medical meritocracy in order to avoid unwanted aspects of elitism. PMID- 25545573 TI - Equal, global, local: discourses in Taiwan's international medical graduate debate. AB - CONTEXT: With the globalisation of medicine, the role of international medical graduates (IMGs) has expanded. Nonetheless, the experiences of native-born IMGs remain under-researched. In Taiwan, public controversy has unfolded around IMGs educated in Poland, calling into question the meaning(s) of equality in policy and medicine. In focusing on the return of IMGs to their countries of origin, this study adds to the growing literature concerning equality and globalisation in medical education. OBJECTIVES: The primary research aim was to analyse how stakeholders in the IMG debate use equality in their arguments. The authors set out to frame the dispute within the recent history of Taiwanese medical governance. An overarching objective was to contribute a critical, historical view of how discourses of globalisation and equality construct different policy approaches to international medical education. METHODS: The authors performed a critical discourse analysis of a public policy dispute in Taiwan, assembling an archive from online interactions, government reports and news articles. Coding focused on stakeholders' uses of equality to generate broader discourses. RESULTS: International and domestic Taiwanese students conceived of equality differently, referencing both 'equality of opportunity' and 'equality of outcome' within localisation and globalisation frameworks, respectively. The dominance of localisation discourse is reflected in hostile online rhetoric towards Poland educated IMGs. CONCLUSIONS: Rhetorical disagreements over equality in medical education trace shifting state policies, from earlier attempts to remove barriers for IMGs to the present-day push to regulate IMGs for acculturation and quality assurance. The global Internet had a double-sided influence, facilitating both democratic political mobilization and the spread of hate speech. The policy debate in Taiwan mirrors discourses in Canada, where IMGs are likewise conceived either as globally competent physicians or as lacking in merit and technical competence. Future research could investigate the discursive formation and evidential basis of policies regulating international medical education. PMID- 25545574 TI - Impact of selection strategies on representation of underserved populations and intention to practise: international findings. AB - CONTEXT: Socially accountable medical schools aim to reduce health inequalities by training workforces responsive to the priority health needs of underserved communities. One key strategy involves recruiting students from underserved and unequally represented communities on the basis that they may be more likely to return and address local health priorities. This study describes the impacts of different selection strategies of medical schools that aspire to social accountability on the presence of students from underserved communities in their medical education programmes and on student practice intentions. METHODS: A cross sectional questionnaire was administered to students starting medical education in five institutions with a social accountability mandate in five different countries. The questionnaire assessed students' background characteristics, rurality of background, and practice intentions (location, discipline of practice and population to be served). The results were compared with the characteristics of students entering medical education in schools with standard selection procedures, and with publicly available socio-economic data. RESULTS: The selection processes of all five schools included strategies that extended beyond the assessment of academic achievement. Four distinct strategies were identified: the quota system; selection based on personal attributes; community involvement, and school marketing strategies. Questionnaire data from 944 students showed that students at the five schools were more likely to be of non-urban origin, of lower socio-economic status and to come from underserved groups. A total of 407 of 810 (50.2%) students indicated an intention to practise in a non-urban area after graduation and the likelihood of this increased with increasing rurality of primary schooling (p = 0.000). Those of rural origin were statistically less likely to express an intention to work abroad (p = 0.003). CONCLUSIONS: Selection strategies to ensure that members of underserved communities can pursue medical careers can be effective in achieving a fair and equitable representation of underserved communities within the student body. Such strategies may contribute to a diverse medical student body with strong intentions to work with underserved populations. PMID- 25545575 TI - Disadvantage and the 'capacity to aspire' to medical school. AB - OBJECTIVES: This study was designed to elucidate why students from backgrounds of lower socio-economic status (SES) and who may be first in their family (FIF) to enter university continue to be under-represented in medical schools. METHODS: Academically able high school students (n = 33) from a range of socio-economic backgrounds participated in focus groups. School careers advisors (n = 5) were interviewed. Students discussed their career and education plans and ideas about a medical career. Careers advisors discussed enablers and barriers to a medical career for their students. RESULTS: Students of lower SES and of FIF status attending schools situated in poorer geographic locations had limited access to suitable work experience and, despite their participation in gifted and talented classes, were considered to be at greater risk of not achieving the high level of academic achievement required for admission to medical school. CONCLUSIONS: There is utility in exploring intersecting differences and Appardurai's theory of the 'capacity to aspire' for the purpose of understanding the causes of the under representation of disadvantaged students in medical schools. A focused materialist approach to building the aspirations of disadvantaged students, particularly those attending schools located in poorer areas, is required if effective pre-entry equity programmes are to be developed and evaluated. Alternatively, medical schools might rethink their reliance on very high academic attainment in the admission process. PMID- 25545576 TI - Ensuring a fair and equitable selection of students to serve society's health care needs. AB - OBJECTIVES: This study aimed to evaluate a selection and programmatic intervention designated 'Conditional Admissions' (CA), which is intended to expand access to medical education for individuals from under-represented ethnic, racial and rural groups. Further aims were to establish principles of practice designed to increase access for under-represented groups based on an empirical comparison of programmatic changes made to CA in 2005, and to quantify the costs associated with its implementation. METHODS: Data for all students admitted between 1999 and 2009 (n = 3227) were compiled; these included demographic data, undergraduate college performance grades, medical school performance indicators, and information on honours, residency placement and md degree completion. To examine the outcomes of the CA intervention, students were divided into two cohorts of those admitted through the CA initiative during 1999-2004 and 2005 2009, respectively, and analysed for differences. Costs associated with CA were also calculated. RESULTS: There were 274 students admitted through CA (8.5% of all admittances) during 1999-2009; of these, 81.4% were from under-represented ethnic or racial backgrounds and 18.6% were from rural backgrounds. These students had more hours of science coursework, lower science and cumulative grade point averages (GPAs), and lower mean Medical College Admission Test (MCAT) scores than non-CA students. However, first-time pass rates and mean scores on the US Medical Licensing Examination (USMLE) Step 1 and USMLE Step 2 Clinical Knowledge increased significantly in the CA cohort during 2005-2009. Additional costs incurred per student ranged between US$849 and US$3801. CONCLUSIONS: Interventions such as CA can significantly increase diversity in the physician workforce. Interventions must be based on careful assessment of academic preparedness, as well as on non-academic factors that contribute to ability to successfully manage the rigors of medical education. Furthermore, the selection and subsequent professional development of students must nurture commitment to addressing the health care needs of diverse communities. Equity must be viewed as a means of increasing fairness for both prospective medical students and the residents of communities that may benefit from the eventual service. PMID- 25545577 TI - Textual analysis of internal medicine residency personal statements: themes and gender differences. AB - CONTEXT: Applicants to US residency training programmes are required to submit a personal statement, the content of which is flexible but often requires them to describe their career goals and aspirations. Despite their importance, no systematic research has explored common themes and gender differences inherent to these statements. OBJECTIVES: This study was conducted to analyse US applicants' Electronic Residency Application Service (ERAS) personal statements using two automated textual analysis programs, and to assess for common themes and gender associated differences. METHODS: A retrospective cohort study of 2138 personal statements (containing 1,485,255 words) from candidates from 377 national and international medical schools applying to US internal medicine (IM) residency programmes through ERAS was conducted. A mathematical analysis of text segments using a recursive algorithm was performed; two different specifications of the text segments were used to conduct an internal validation. RESULTS: Five statistically significant thematic classes were identified through independent review by the researchers. These were best defined as referring to: the appeal of the residency programme; memorable patients; health care as public policy; research and academia, and family inspiration. Some themes were common to all applications. However, important gender-specific differences were identified. Notably, men were more likely to describe personal attributes and to self promote, whereas women more frequently expressed the communicative and team-based aspects of doctoring. The results were externally validated using a second software program. Although these data comprise part of the national pool, they represent applicants to a single specialty at a single institution. CONCLUSIONS: By applying textual analysis to material derived from a national cohort, we identified common narrative themes in the personal statements of future US physicians, noting differences between men and women. Together, these data provide novel insight into the dominant discourse of doctoring in this generation of students applying for further training in US IM residency programmes, and depict a diverse group of applicants with multiple motivations, desires and goals. Furthermore, differences seen between men and women add to the growing understanding of bias in medical education. Training programmes may benefit by adapting curricula to foster such diverse interests. PMID- 25545578 TI - The interaction of socio-economic status and gender in widening participation in medicine. AB - CONTEXT: The lack of representation of people from low socio-economic and socio educational backgrounds in the medical profession is of growing concern and yet research investigating the problem typically studies recruitment and selection in isolation. This study examines the impacts of home and school socio-economic status (SES) from application to selection in an undergraduate medical degree. Socio-cognitive career theory and stereotype bias are used to explain why those from backgrounds of low SES may be disadvantaged, especially if they are female. METHODS: Home and high school SES information for 2955 applicants and 202 medical students at one Australian medical school was related to application rates and performance on three selection tests (high school matriculation, the Undergraduate Medical and Health Sciences Admissions Test [UMAT] cognitive ability test, a multiple mini-interview) and academic performance in medical school. Interactions between gender and SES were assessed using moderated regression analyses. RESULTS: Applicants from backgrounds of low SES were under represented. They were further disadvantaged at selection by the use of high school matriculation and cognitive ability tests, but not by the interview. They did not perform more poorly in medical school. Although females applied in greater numbers, a significant interaction between SES and gender indicated that female applicants of low SES were the most disadvantaged by the use of cognitive ability testing at selection. A targeted allowance of applicants from regions of low SES overcame this adverse impact to some extent. CONCLUSIONS: Efforts to widen participation that focus on recruitment are insufficient when selection tests have adverse impacts on people from backgrounds of low SES. The addressing of low self-efficacy that arises from socio-cultural factors, together with reductions in stereotype threat, may reduce the current disadvantages imposed by SES in the medical profession. PMID- 25545579 TI - Bridging the gap: the roles of social capital and ethnicity in medical student achievement. AB - OBJECTIVES: Within medical education, there is a discrepancy between the achievement level of White students and that of their ethnic minority peers. The processes underlying this disparity have not been adequately investigated or explained. This study utilises social network analysis to investigate the impact of relationships on medical student achievement by ethnicity, specifically by examining homophily (the tendency to interact with others in the same group) by ethnicity, age and role. METHODS: Data from a cross-sectional social network study conducted in one UK medical school are presented and are analysed alongside examination records obtained from the medical school. Participants were sampled across the four hospital placement sites; a total of 158 medical students in their clinical phase (Years 3 and 4) completed the survey. The research was designed and analysed using social capital theory. RESULTS: Although significant patterns of ethnic and religious homophily emerged, no link was found between these factors and achievement. Interacting with problem-based learning (PBL) group peers in study-related activities, and having seniors in a wider academic support network were directly linked to better achievement. Students in higher academic quartiles were more likely to be named by members of their PBL group in study activities and to name at least one tutor or clinician in their network. Students from lower-achieving groups were least likely to have the social capital enabling, and resulting from, interactions with members of more expert social groups. CONCLUSIONS: Lower levels of the social capital that mediates interaction with peers, tutors and clinicians may be the cause of underperformance by ethnic minority students. Because of ethnic homophily, minority students may be cut off from potential and actual resources that facilitate learning and achievement. PMID- 25545580 TI - Ethnic and social disparities in performance on medical school selection criteria. AB - CONTEXT: Medical schools in Western societies seek measures to increase the diversity of their student bodies with respect to ethnicity and social background. Currently, little is known about the effects of different selection procedures on student diversity. OBJECTIVES: This prospective cohort study aimed to determine performance differences between traditional and non-traditional (i.e. ethnic minority and first-generation university candidates) medical school applicants in academic and non-academic selection criteria. METHODS: Applicants in 2013 (n = 703) were assessed on academic and non-academic selection criteria. They also completed a questionnaire on ethnicity and social background. Main outcome measures were 'not selected' (i.e. failure on any criteria), 'failure on academic criteria' and 'failure on non-academic criteria'. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression analysis for ethnic subgroups (Surinamese/Antillean, Turkish/Moroccan/African, Asian, Western) compared with Dutch applicants, adjusted for age, gender, additional socio demographic variables (first-generation immigrant, first-generation university applicant, first language, medical doctor as parent) and pre-university grade point average (pu-GPA). Similar analyses were performed for first-generation university applicants. RESULTS: Compared with Dutch applicants, Surinamese/Antillean applicants underperformed in the selection procedure (failure rate: 78% versus 57%; adjusted OR 2.52, 95% CI 1.07-5.94), in particular on academic criteria (failure rate: 66% versus 34%; adjusted OR 3.00, 95% CI 1.41 6.41). The higher failure rate of first-generation university applicants on academic criteria (50% versus 37%; unadjusted OR 1.66, 95% CI 1.18-2.33) was partly explained by additional socio-demographic variables and pu-GPA. The outcome measure 'failure on non-academic criteria' showed no significant differences among the ethnic or social subgroups. CONCLUSIONS: The absence of differences on non-academic criteria was promising with reference to increasing social and ethnic diversity; however, the possibility that self-selection instigated by the selection procedure is stronger in applicants from non traditional backgrounds cannot be ruled out. Further research should also focus on why cognitive tests might favour traditional applicants. PMID- 25545581 TI - Changes in insurance status and emergency department visits after the 2008 economic downturn. AB - OBJECTIVES: As the U.S. economy began its downward trend in 2008, many citizens lost their jobs and, ultimately, their employer-sponsored health care insurance. The expectation was that many of the newly uninsured would turn to emergency departments (EDs) for their health care. This study was undertaken to determine, first, if changes in the insurance status of the general population were reflected in the ED insurance payer mix and, second, whether there was evidence of an increased reliance on the ED as a continuing source of health care for any payer group(s). METHODS: This was a retrospective observational study using public data files from the National Hospital Ambulatory Medical Care Survey for Emergency Departments for years 2006 through 2010 (2008 +/- 2 years). Changes in the relative proportions of ED visits funded annually by private insurance, Medicaid, Medicare, and self-pay (uninsured) were analyzed using a logistic model. Poisson regression was used to compare trends in the rates of ED visits for each payer type (i.e., number of ED visits per 100 persons with each insurance type). A linear spline term was used to determine if there was a change in each risk estimate after 2008 compared to the risk estimate before 2008. RESULTS: Before 2008, the odds of an ED visit being funded by private insurance increased by 4% per year (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 0.98 to 1.10; p = 0.15), but after 2008 the odds reversed, decreasing by nearly 10% per year (OR = 0.91, 95% CI = 0.85 to 0.97; p = 0.02). Medicaid-funded visits demonstrated opposite trends with a small decreasing trend of 2% per year before 2008 (OR = 0.98, 95% CI = 0.92 to 1.04; p = 0.52), followed by a significantly increasing trend of 20% per year after 2008 (OR = 1.20, 95% CI = 1.12 to 1.27; p = 0.001). The growth in Medicaid-funded ED visits was attributable to increased numbers of visits by both pediatric (<18 years old) and non-elderly adult (19 to 64 years old) patients. For both Medicaid and private insurance visits, the change in trend in 2008 was statistically significant (p < 0.001 and p = 0.004, respectively). Self-pay visits were fairly steady before 2008 and then increased by about 5% per year after 2008, but this was not statistically significant (OR = 1.05, 95% CI = 0.96 to 1.14; p = 0.46), nor was the change in trend (p = 0.29). The results for Medicare-funded visits were also small and not statistically significant. There was also evidence of increased reliance on the ED by Medicaid funded patients based on the comparison of ED visit rates. After 2008, the incidence rate ratio (IRR) for Medicaid-funded visits increased by 10% per year (IRR = 1.10, 95% CI = 1.10 to 1.10; p < 0.001) while the IRR for the other three payer groups changed about 1% per year (IRR = 0.99, 95% CI = 0.99 to 0.099; p < 0.001), indicating an increasing utilization of the ED by patients with Medicaid funded care. CONCLUSIONS: After 2008, Medicaid patients were more dependent on ED services than uninsured, Medicare, or privately insured patients. Medicaid patients made up an increasing proportion of ED patients, and the rate of usage of ED services by all ages of Medicaid patients was significantly greater than that of the other three payer groups. PMID- 25545582 TI - Temporomandibular joint articulations on working side during chewing in adult females with cross-bite and mandibular asymmetry. AB - Influence of mandibular asymmetry and cross-bite on temporomandibular joint (TMJ) articulation remained unknown. This study aimed to investigate whether/how the working-side condylar movement irregularity and articular spaces during chewing differ between patients with mandibular asymmetry/cross-bite and control subjects. The cross-bite group and the control group consisted of 10 adult female patients and 10 adult female subjects, respectively. They performed unilateral gum-chewing. The mandibular movements were recorded using a video-based opto electronic system. The 3D articular surface of the TMJ for each individual was reconstructed using CT/MRI data. For local condylar points, the normalised jerk cost (NJC) towards normal direction to the condylar surface, the angle between tangential velocity vector and condylar long axis and intra-articular space were measured. Three rotatory angles at centre of the condyle were also measured. During closing and intercuspation, (i) movements of posterior portion of the deviated side condyle showed significantly less smoothness as compared with those for the non-deviated side and control subjects, (ii) the rotations of the condyle on the deviated side induced greater intra-articular space at posterior and lateral portions. These findings suggest that chewing on the side of mandibular deviation/cross-bite may cause irregular movement and enlarged intra-articular space at posterior portion of the deviated side condyle. PMID- 25545583 TI - Assessing the tongue colour of newly born infants may help to predict the need for supplemental oxygen in the delivery room. AB - AIM: It takes several minutes for infants to become pink after birth. Preductal oxygen saturation (SpO2) measurements are used to guide the delivery of supplemental oxygen to newly born infants, but pulse oximetry is not available in many parts of the world. We explored whether the pinkness of an infant's tongue provided a useful indication that supplemental oxygen was required. METHODS: This was a prospective observational study of infants delivered by Caesarean section. Simultaneous recording of SpO2 and visual assessment of whether the tongue was pink or not was made at 1-7 and 10 min after birth. RESULTS: The 38 midwives and seven paediatric trainees carried out 271 paired assessments on 68 infants with a mean (SD) birthweight of 3214 (545) grams and gestational age of 38 (2) weeks. When the infant did not have a pink tongue, this predicted SpO2 of <70% with a sensitivity of 26% and a specificity of 96%. CONCLUSION: Tongue colour was a specific but insensitive sign that indicated when SpO2 was <70%. When the tongue is pink, it is likely that an infant has an SpO2 of more than 70% and does not require supplemental oxygen. PMID- 25545584 TI - Next-generation sequencing workflow for assembly of nonmodel mitogenomes exemplified with North Pacific albatrosses (Phoebastria spp.). AB - Use of complete mitochondrial genomes (mitogenomes) can greatly increase the resolution achievable in phylogeographic and historical demographic studies. Using next-generation sequencing methods, it is now feasible to efficiently sequence mitogenomes of large numbers of individuals once a reference mitogenome is available. However, assembling the initial mitogenomes of nonmodel organisms can present challenges, for example, in birds, where mtDNA is often subject to gene rearrangements and duplications. We developed a workflow based on Illumina paired-end, whole-genome shotgun sequencing, which we used to generate complete 19-kilobase mitogenomes for each of three species of North Pacific albatross, a group of birds known to carry a tandem duplication. Although this duplication had been described previously, our procedure did not depend on this prior knowledge, nor did it require a closely related reference mitogenome (e.g. a mammalian mitogenome was sufficient). We employed an iterative process including de novo assembly, reference-guided assembly and gap closing, which enabled us to detect duplications, determine gene order and identify sequence for primer positioning to resolve any mitogenome ambiguity (via minimal targeted Sanger sequencing). We present full mtDNA annotations, including 22 tRNAs, 2 rRNAs, 13 protein-coding genes, a control region and a duplicated feature for all three species. Pairwise comparisons supported previous hypotheses regarding the phylogenetic relationships within this group and occurrence of a shared tandem duplication. The resulting mitogenome sequences will enable rapid, high-throughput NGS mitogenome sequencing of North Pacific albatrosses via direct reference-guided assembly. Moreover, our approach to assembling mitogenomes should be applicable to any taxon. PMID- 25545585 TI - Control of resin production in Araucaria angustifolia, an ancient South American conifer. AB - Araucaria angustifolia is an ancient slow-growing conifer that characterises parts of the Southern Atlantic Forest biome, currently listed as a critically endangered species. The species also produces bark resin, although the factors controlling its resinosis are largely unknown. To better understand this defence related process, we examined the resin exudation response of A. angustifolia upon treatment with well-known chemical stimulators used in fast-growing conifers producing both bark and wood resin, such as Pinus elliottii. The initial hypothesis was that A. angustifolia would display significant differences in the regulation of resinosis. The effect of Ethrel((r)) (ET - ethylene precursor), salicylic acid (SA), jasmonic acid (JA), sulphuric acid (SuA) and sodium nitroprusside (SNP - nitric oxide donor) on resin yield and composition in young plants of A. angustifolia was examined. In at least one of the concentrations tested, and frequently in more than one, an aqueous glycerol solution applied on fresh wound sites of the stem with one or more of the adjuvants examined promoted an increase in resin yield, as well as monoterpene concentration (alpha-pinene, beta-pinene, camphene and limonene). Higher yields and longer exudation periods were observed with JA and ET, another feature shared with Pinus resinosis. The results suggest that resinosis control is similar in Araucaria and Pinus. In addition, A. angustifolia resin may be a relevant source of valuable terpene chemicals, whose production may be increased by using stimulating pastes containing the identified adjuvants. PMID- 25545586 TI - The experiences of HIV-serodiscordant couples in Soweto, South Africa. AB - INTRODUCTION: The study was carried out in a single township in South Africa with a sample size of seven human immunodeficiency virus (HIV)-serodiscordant couples. BACKGROUND: South Africa has the highest number of HIV cases in the world, with an estimated 6.4 million of its inhabitants living with this infection. Most people in stable relationships are unaware of the HIV serostatuses of their partners. Many people with an HIV partner are also generally unaware of their own HIV serostatuses. There is a high risk of acquisition of the HIV among couples in HIV-serodiscordant relationships. Yet, there is a dearth of research on HIV serodiscordant couples. AIM: To explore the experiences and knowledge of HIV serodiscordant couples on HIV serodiscordance. METHODS: A qualitative design of interpretative phenomenological analysis was used. Data were collected from seven HIV-serodiscordant couples using a semi-structured interview format. Data were analysed thematically using the principles of interpretative phenomenological analysis. RESULTS: Three superordinate themes emerged from data analysis: experiences of stress, effects of HIV serodiscordance on couples and knowledge of HIV serodiscordance. The study outcomes were based on retrospective accounts of couples' experiences of HIV serodiscordance. Such accounts are subject to memory bias. CONCLUSION: HIV-serodiscordant relationships are riddled with stress. Couples and nurses' knowledge and understanding of the concept of HIV serodiscordance is limited. Such limitation may negatively influence the quality of care and support offered to couples in these relationships. IMPLICATIONS FOR NURSING AND HEALTH POLICY: HIV-serodiscordant couples need to be educated on this phenomenon. Nurses also need to be offered training on how to support and care for couples in these relationships. Such training should be shaped by couples' health-seeking behaviours and cultural norms. Specific guidelines and policy on HIV serodiscordance should be developed to ensure consistency in care provision and enhance uptake of support services. PMID- 25545587 TI - Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose-Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig. AB - The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species. PMID- 25545588 TI - Copper(I)-catalyzed cycloaddition of 4-bromosydnones and alkynes for the regioselective synthesis of 1,4,5-trisubstituted pyrazoles. AB - Copper-catalyzed cycloaddition of alkynes with 4-bromosydnones provides a convenient, mild, and regioselective method for the synthesis of a wide range of bromopyrazoles. The broad functional group tolerance of the cycloaddition reaction and further palladium-catalyzed cross-coupling reactions allowed the preparation of polyfunctionalized 1,4,5-pyrazoles that are otherwise difficult to obtain by conventional methods. PMID- 25545589 TI - Development, identification and utilization of introgression lines using Chinese endemic and synthetic wheat as donors. AB - Chromosome segmental introgression lines (ILs) are an effective way to utilize germplasm resources in crops. To improve agronomic traits of wheat cultivar (Triticum aestivum) Shi 4185, four sets of ILs were developed. The donors were Chinese endemic subspecies accessions Yunnan wheat (T. aestivum ssp. yunnanense) YN3, Tibetan semi-wild wheat (T. aestivum ssp. tibetanum) XZ-ZM19450, and Xinjiang wheat (T. aestivum ssp. petropavlovskyi) XJ5, and synthetic wheat HC XM1620 derived from a cross between T. durum acc. D67.2/P66.270 with Aegilops tauschii acc. 218. Totals of 356, 366, 445 and 457 simple sequence repeat (SSR) markers were polymorphic between Shi 4185 and YN3, XZ-ZM19450, XJ5 and HC-XM1620, respectively. In total, 991 ILs were identified, including 300 derived from YN3, covering 95% of the genome of Shi 4185, 218 from XZ-ZM19450 (79%), 279 from XJ5 (97%), and 194 from HC-ZX1620 (84%). The sizes and locations of each introgression were determined from a consensus SSR linkage map. Using the ILs, 11 putative quantitative trait loci (QTLs) were identified for plant height (PH), spike length (SL) and grain number per spike (GNS). Comparative analyses of 24 elite ILs with the parents revealed that the four donor parents could be important resources to improve wheat SL and GNS. Our work offers a case for utilizing endemic landraces for QTL mapping and improvement of wheat cultivars using introgression lines. PMID- 25545590 TI - The cobalamin-independent methionine synthase enzyme captured in a substrate induced closed conformation. AB - The cobalamin-independent methionine synthase enzyme catalyzes a challenging reaction: the direct transfer of a methyl from 5-methyl-tetrahydrofolate glutamate3 to the l-homocysteine thiol. The enzyme has a dual (betaalpha)8 TIM barrel structure that binds, activates and brings the reactants into reaction proximity by conformational movements. In the previously observed open structures, the substrates bind too far apart to react, but we have captured a ternary complex with both substrates bound in a closed form of the enzyme. The closing is described in terms of a hinge between the N- and C-terminal TIM barrels and a rearrangement of key loops within the C domain. The substrate specificity can now be rationalized and the structure reveals His707 as the acid that protonates the THF leaving group through a water molecule trapped in the closed active site. The substrates are correctly oriented for an in-line attack by l-homocysteine on the N(5)-methyl. PMID- 25545592 TI - Novel essential gene Involved in 16S rRNA processing in Escherichia coli. AB - Biogenesis of ribosomes is a complex process mediated by many factors. While its transcription proceeds, ribosomal RNA (rRNA) folds itself into a characteristic three-dimensional structure through interaction with ribosomal proteins, during which its ends are processed. Here, we show that the essential protein YqgF, a RuvC family protein with an RNase-H-like motif, is involved in the processing of pre-16S rRNA during ribosome maturation. Indeed, pre-16S rRNA accumulated in cells of a temperature-sensitive yqgF mutant (yqgF(ts)) cultured at a non permissive temperature. In addition, purified YqgF was shown to process the 5' end of pre-16S rRNA within 70S ribosomes in vitro. Mass spectrometry analysis of the total proteins in the yqgF(ts) mutant cells showed that the expression of genes containing multiple Shine-Dalgarno-like sequences was observed to be lower than in wild type. These results are interpreted to indicate that YqgF is involved in a novel enzymic activity necessary for the processing of pre-16S rRNA, thereby affecting elongation of translation. PMID- 25545591 TI - Structure of Salmonella FlhE, conserved member of a flagellar type III secretion operon. AB - The bacterial flagellum is assembled by a multicomponent transport apparatus categorized as a type III secretion system. The secretion of proteins that assemble into the flagellum is driven by the proton motive force. The periplasmic protein FlhE is a member of the flhBAE operon in the majority of bacteria where FlhE is found. FlhA and FlhB are established components of the flagellar type III secretion system. The absence of FlhE results in a proton leak through the flagellar system, inappropriate secretion patterns, and cell death, indicating that FlhE regulates an important aspect of proper flagellar biosynthesis. We isolated FlhE from the periplasm of Salmonella and solved its structure to 1.5A resolution. The structure reveals a beta-sandwich fold, with no close structural homologs. Possible roles of FlhE, including that of a chaperone, are discussed. PMID- 25545593 TI - A bivalent conjugate vaccine containing PspA families 1 and 2 has the potential to protect against a wide range of Streptococcus pneumoniae strains and Salmonella Typhi. AB - Previously we showed that conjugation of pneumococcal surface protein A (PspA) to Vi capsular polysaccharide from Salmonella Typhi enhanced the anti-PspA response without the need to add adjuvant. In the current study conjugates consisting of the alpha helical regions of PspA families 1 or 2 bound to Vi were used to vaccinate mice to test their ability to protect against a lethal intravenous challenge of a range of various strains of Streptococcus pneumoniae. Conjugate vaccine containing PspA family 1 provided good protection from PspA family 1 challenge strains but offered very little protection against PspA family 2 challenge strains. Similarly, PspA family 2 conjugates provided good protection from PspA family 2 challenge strains and poor protection against PspA family 1 challenge strains. This observation was supported by the low levels of cross reactivity of PspA antibodies seen in ELISA plates coated with the heterologous PspA family. Cytokine profiles showed a mixed Th1/Th2 response to Vi and the Vi PspA conjugates. IgG subclass analysis of the anti-Vi response showed a shift from predominantly IgG2a/3 to IgG1 after conjugation to PspA was consistent with other polysaccharide conjugate vaccines. The results demonstrate that conjugation of the alpha helical region of PspA to Vi enhances its capacity to induce a protective immune response and that a vaccine based on the alpha helical region of PspA should contain PspA from both families 1 and 2 to achieve broad cross protection. PMID- 25545594 TI - Comparison of severely ill patients with influenza A(H1N1)pdm09 infection during the pandemic and post-pandemic periods in Singapore. AB - BACKGROUND/OBJECTIVES: Singapore is a tropical country with influenza seasons occurring bi-annually. We compared the profile of severely ill patients with laboratory confirmed influenza A(H1N1)pdm09 infection in Singapore during the pandemic and post-pandemic periods, and studied their risk factors associated with mortality. PATIENTS/METHODS: Three periods were defined for this study; pandemic period from 18 June to 29 August 2009, early post-pandemic period from 30 August 2009 to 12 February 2010, and late post-pandemic period from 13 February to 10 August 2010. RESULTS: A total of 172 severely ill patients were admitted to hospitals from 18 June 2009 to 10 August 2010, of whom 23.8% died. The median age in the late post-pandemic period was significantly older than that in the early post-pandemic period (52 years versus 35 years, P=0.02). The median age of patients who died was significantly older than those who survived (52 years versus 44 years, P<0.01). The median length of stay under intensive care in the late post-pandemic period was twice that in the early post-pandemic (6 days versus 3 days, P=0.045). The proportion who died in the late post-pandemic period was more than 2.5 times that in the early post-pandemic period (29.8% versus 11.1%, P=0.043). CONCLUSIONS: Severely ill patients were of older age in the late post-pandemic period. Older age was also significantly associated with mortality. It is important to maintain heightened vigilance and continue the surveillance of severely ill patients with influenza post-pandemic, so that patients with suspected infections could be promptly identified for early diagnosis and treatment. PMID- 25545595 TI - Development of high yield reassortants for influenza type B viruses and analysis of their gene compositions. AB - A critical step in producing the annual inactivated influenza vaccine is the development of high yield (hy) seed viruses by reassortment for improved growth in ovo. Although hy reassortants for type A influenza viruses have been developed for many years, hy B influenza reassortant virus development for vaccine production has proven difficult. In this study, we have developed fourteen hy influenza type B reassortants as vaccine candidate strains with B/Lee/40 as the donor virus. Upon characterization by the Influenza Division at the Centers for Disease Control and Prevention (CDC) and the verification of HA by sequencing, all B reassortants were found to be antigenically indistinguishable from the wild type (wt) parents and suitable for vaccine production. However, only one hy reassortant seed virus from this group was used by a manufacturer for vaccine production. In general, hy reassortants showed an increase in hemagglutination (HA) titers over their wt parents by approximately 8 fold (range 1-32 fold). Gene compositions of the hy B reassortants were analyzed by restriction fragment length polymorphism (RFLP) and the wt origin of the HA and neuraminidase (NA) were confirmed. However, in contrast to hy A reassortants which require the M gene (hy donor A/PR/8/34) for high yield, all fourteen hy B reassortants obtained the NP gene from the hy donor strain (B/Lee/40). The parental source for the remaining genes varied among the hy B reassortants. The results indicate that the B/Lee/40 NP and PB1 gene segments are important contributors to high yield growth in influenza B reassortant viruses for both Yamagata and Victoria lineages. The B/Lee/40 PB2 gene along with wt NS gene also contributed to the improved growth for hy reassortants of Yamagata lineage. PMID- 25545596 TI - Cross-sectional survey: risk-averse French general practitioners are more favorable toward influenza vaccination. AB - OBJECTIVES: We tested the following hypotheses: (i) risk-averse general practitioners (GPs) are more likely to be vaccinated against influenza; (ii) and risk-averse GPs recommend influenza vaccination more often to their patients. In risk-averse GPs, the perceived benefits of the vaccine and/or the perceived risks of the infectious disease might indeed outweigh the perceived risks of the vaccine. PATIENTS/METHODS: In 2010-2012, we conducted a cross-sectional survey of a nationwide French representative sample of 1136 GPs. Multivariate analyses adjusted for four stratification variables (age, gender, urban/suburban/rural practice location and annual patient consultations) and for GPs' characteristics (group/solo practice, and occasional practice of alternative medicine, e.g., homeopathy) looked for associations between their risk attitudes and self reported vaccination behavior. Individual risk attitudes were expressed as a continuous variable, from 0 (risk-tolerant) to 10 (risk-averse). RESULTS: Overall, 69% of GPs reported that they were very favorable toward vaccination in general. Self-reported vaccination coverage was 78% for 2009/2010 seasonal influenza and 62% for A/H1N1 pandemic influenza. Most GPs (72%) reported recommending the pandemic influenza vaccination to at-risk young adults in 2009, but few than half (42%) to young adults not at risk. In multivariate analyses, risk-averse GPs were more often vaccinated against seasonal (marginal effect=1.3%, P=0.02) and pandemic influenza (marginal effect=1.5%, P=0.02). Risk averse GPs recommended the pandemic influenza vaccination more often than their more risk-tolerant colleagues to patients without risk factors (marginal effect=1.7%, P=0.01), but not to their at-risk patients and were more favorable toward vaccination in general (marginal effect=1.5%, P=0.04). CONCLUSION: Individual risk attitudes may influence GPs' practices regarding influenza vaccination, both for themselves and their patients. Our results suggest that risk-averse GPs may perceive the risks of influenza to outweigh the potential risks related to the vaccine. PMID- 25545597 TI - Supporting countries in establishing and strengthening NITAGs: lessons learned from 5 years of the SIVAC initiative. AB - To empower governments to formulate rational policies without pressure from any group, and to increase the use of evidence-based decision-making to adapt global recommendations on immunization to their local context, the WHO has recommended on multiple occasions that countries should establish National Immunization Technical Advisory Groups (NITAGs). The World Health Assembly (WHA) reinforced those recommendations in 2012 when Member States endorsed the Decade of Vaccines Global Vaccine Action Plan (GVAP). NITAGs are multidisciplinary groups of national experts responsible for providing independent, evidence-informed advice to health authorities on all policy-related issues for all vaccines across all populations. In 2012, according to the WHO-UNICEF Joint Reporting Form, among 57 countries eligible for immunization program financial support from the GAVI Alliance, only 9 reported having a functional NITAG. Since 2008, the Supporting Independent Immunization and Vaccine Advisory Committees (SIVAC) Initiative (at the Agence de Medecine Preventive or AMP) in close collaboration with the WHO and other partners has been working to accelerate and systematize the establishment of NITAGs in low- and middle-income countries. In addition to providing direct support to countries to establish advisory groups, the initiative also supports existing NITAGs to strengthen their capacity in the use of evidence-based processes for decision-making aligned with international standards. After 5 years of implementation and based on lessons learned, we recommend that future efforts should target both expanding new NITAGs and strengthening existing NITAGs in individual countries, along three strategic lines: (i) reinforce NITAG institutional integration to promote sustainability and credibility, (ii) build technical capacity within NITAG secretariats and evaluate NITAG performance, and (iii) increase networking and regional collaborations. These should be done through the development and dissemination of tools and guidelines, and information through a variety of adapted mechanisms. PMID- 25545598 TI - Telemedicine for children with developmental disabilities: a more effective clinical process than office-based care. AB - BACKGROUND: The literature on the use of telemedicine for children with developmental disabilities (DD) is limited and mostly describes telemedicine being used to link patients with distant subspecialty multidisciplinary care. Parents generally have reported satisfaction with such care and have perceived it to be equally effective as in-person care. Here we report on the use of school based asynchronous telemedicine to connect children with DD with primary care providers. MATERIALS AND METHODS: We developed Tele-Health-Kids, a school-based program using asynchronous telemedicine to connect children with DD with their primary care physician for the care of minor illnesses. We surveyed parents at enrollment and after the child's first telemedicine visit to assess satisfaction. We describe 4 cases that illustrate benefits, particularly for children with DD and challenging behaviors, suggesting that asynchronous telemedicine may actually be superior to traditional in-office visits in some circumstances. RESULTS: Most parents expressed a high level of satisfaction with the program. Benefits identified include decreased stress to the child and the parents as well as increasing the likelihood of a successful medical examination due to greater cooperation by the child. Visits using asynchronous or "store and forward" telemedicine technology may be superior in some situations by allowing the visit to be performed at a pace that can be adjusted to the needs of the child with DD. CONCLUSIONS: More research in the use of asynchronous telemedicine for children and youth with DD, particularly for children with DD and challenging behaviors, is needed. PMID- 25545600 TI - Amphetamine abuse as a rare cause of recurrent LVAD pump thrombosis. AB - We report a patient with recurrent left ventricular assist device (LVAD) thrombosis due to amphetamine addiction. The management of this complication is reviewed. PMID- 25545601 TI - The impact of cognitive impairment, neurological soft signs and subdepressive symptoms on functional outcome in bipolar disorder. AB - BACKGROUND: Cognitive impairments and subsyndromal depressive symptoms are present during euthymic periods of bipolar disorder (BD). Most studies have determined that cognitive impairments and residual depressive symptoms have major impacts on psychosocial functioning. The aim of the present study was to identify the major factor responsible for low psychosocial functioning in a subgroup of patients with BD despite clinical recovery. METHODS: Sixty patients with bipolar I disorder and 41 healthy subjects were enrolled in this study. Cognitive performance, neurological soft signs (NSSs), psychosocial functioning, residual mood symptoms and illness characteristics were assessed. Using the median value of the Functioning Assessment Short Test (FAST) as the cut-off point, the patients were divided into two groups, high- (n=29) or low-functioning (n=31), and they were compared based on total NSS, residual depressive symptoms, cognitive performance and clinical variables. RESULTS: Performances on the verbal memory tests and social functioning were significantly worse in the euthymic patients with BD. Increased rates of NSS were identified in the patients compared with the normal controls. The low-functioning patients performed significantly worse on verbal memory, and their NSS and residual depressive symptoms were significantly higher compared to high-functioning patients. In the regression analysis, subsyndromal depressive symptoms and verbal learning measures were identified as the best predictors of psychosocial functioning. LIMITATIONS: The patients were artificially separated into two groups based on a FAST score cut off. CONCLUSIONS: In this study, residual depressive symptoms and verbal memory impairments were the most prominent factors associated with the level of functioning. PMID- 25545602 TI - IL-23 and TGF-beta1 levels as potential predictive biomarkers in treatment of bipolar I disorder with acute manic episode. AB - BACKGROUND: Growing evidence suggests that immune dysfunction may be involved in the physiopathology of bipolar disorders, with typical first-line treatment using lithium and quetiapine serving to restore pro-inflammation status. This study aimed to explore the relationship between inflammatory cytokines-especially regulatory factors and the effect of combination treatment-with quetiapine and lithium in manic patients. METHODS: 41 patients of bipolar I disorder with manic episode were enrolled and received combination treatment with quetiapine and lithium. Blood sampling and assessments were performed at baseline and after 8 week treatment. YMRS was used to evaluate the severity of manic symptoms at the same time of detecting plasma levels. A control group comprised of 36 age and gender matched healthy volunteers were enrolled, and their blood samples were assessed at the time of enrollment. RESULTS: TGF-beta1 and IL-23 plasma levels in patients were significantly higher than healthy controls at baseline (P<0.05). When comparing remitted patients with non-remitted patients, initial plasma level TGF-beta1 was higher (P=0.029) while IL-23 was lower (P=0.035). The plasma levels of TNF-alpha, TGF-beta1, IL-23 and IL-17 significantly decreased after treatment among the patients who achieved response (P<0.05). LIMITATIONS: The relatively small sample size in patients and control groups should be considered as a limitation of the study. CONCLUSIONS: The high initial plasma level of TGF-beta1 and low initial plasma level of IL-23 indicated better prognosis during combination treatment with quetiapine and lithium in manic patients. The trend of decreasing plasma levels of TNF-alpha, TGF-beta1, IL-23 and IL-17 indicated therapeutic effect. PMID- 25545603 TI - Comorbid obsessive compulsive disorder in patients with bipolar-I disorder. AB - BACKGROUND: Limited numbers of studies have examined the prevalence of OCD systematically in consecutively sampled adult bipolar disorder type I (BD-I) patients. We examined the frequency of OCD in a large number (n=396) of consecutively hospitalized patients with BD-I and identified socio-demographic and clinical correlates of BD-I with and without OCD. METHOD: BD-I patients (n=396) were assessed using the Mini International Neuropsychiatric Interview for Bipolar Disorder Studies, the Structured clinical interview for (Axis II) DSM-IV, the Family interview for genetic studies, the Yale-Brown Obsessive-Compulsive Scale, the Young Mania Rating Scale, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning (GAF) and the Clinical Global Impression scale. Patients with and without OCD were compared in terms of various socio demographic and clinical variables. RESULTS: Thirty (7.6%) of the 396 inpatients studied had OCD and 15 (3.8%) had subclinical OCD. BD-OCD group had significantly lower GAF scores, higher rates of unemployment, and lower incidence of psychotic symptoms. In addition, BD-OCD group had higher rates of comorbid social anxiety and anxious avoidant personality disorder (AAPD) and OCD in first-degree relatives. Those with clinical and subclinical OCD did not differ on functioning and severity measures. LIMITATIONS: Retrospective design and recruitment of patients from inpatient services of a tertiary psychiatric hospital. CONCLUSION: OCD is not an uncommon comorbid disorder in BD-I and appears to be associated with greater functional disability. BD-I with comorbid OCD is associated with greater family history of OCD, comorbidities of social phobia and AAPD and less of psychotic symptoms. PMID- 25545599 TI - Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. AB - Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity. PMID- 25545604 TI - What is important in being cured from: does discordance between physicians and patients matter? (2). AB - AIMS: The influence of discordance in what is important in being cured from depression on clinical outcome at 6 months, assessed with a divergence index. METHODS: 304 outpatients treated for depression by general practitioners or by psychiatrists and completing a 6-month treatment period: a divergence index (divergence between physician and patient view on what is important in being cured from depression) was calculated for each physician-patient pair. The relation between this index and outcome at 6 months was analyzed (including depressive, anxious and somatic symptom severity, positive effect, functional impairment and quality of life (psychological and social relations). RESULTS: Response rates (50% improvement) were 65.9% for depressive symptomatology and 46.2% for anxious symptomatology. The subgroup with a poor physician-patient agreement (highest quartile) on expectations had a worse clinical outcome than the subgroup with an excellent physician-patient agreement (lowest quartile): differences in response rate between these groups ranged from 9% to 27%; this difference reached statistical significance for 3 outcome variables (anxiety, positive effect and social relationships). CONCLUSIONS: The study shows that outcomes with standard antidepressant drugs are still suboptimal and that discordance between what patients' and physicians' consider important in the definition of cure from depression significantly influences clinical outcomes at 6 months. PMID- 25545605 TI - Comorbidity in pediatric bipolar disorder: prevalence, clinical impact, etiology and treatment. AB - BACKGROUND: Research on pediatric bipolar disorder (PBD) is providing a plethora of empirical findings regarding its comorbidity. We addressed this question through a systematic review concerning the prevalence, clinical impact, etiology and treatment of main comorbid disorders involved. METHOD: A comprehensive database search was performed from 1990 to August 2014. Overall, 167 studies fulfilled the inclusion criteria. RESULTS: Bipolar youth tend to suffer from comorbid disorders, with highest weighted mean prevalence rate arising from anxiety disorders (54%), followed by attention deficit hyperactivity disorder (ADHD) (48%), disruptive behavior disorders (31%), and substance use disorders (SUD) (31%). Furthermore, evidence indicates that ADHD and anxiety disorders negatively affect the symptomatology, neurocognitive profile, clinical course and the global functioning of PBD. Likewise, several theories have been posited to explain comorbidity rates in PBD, specifically common risk factors, one disorder being a risk factor for the other and nosological artefacts. Lastly, randomized controlled trials highlight a stronger therapeutic response to stimulants and atomoxetine (vs. placebo) as adjunctive interventions for comorbid ADHD symptoms. In addition, research focused on the treatment of other comorbid disorders postulates some benefits from mood stabilizers and/or SGA. LIMITATIONS: Epidemiologic follow-up studies are needed to avoid the risk of nosological artefacts. Likewise, more research is needed on pervasive developmental disorders and anxiety disorders, especially regarding their etiology and treatment. CONCLUSIONS: Psychiatric comorbidity is highly prevalent and is associated with a deleterious clinical effect on pediatric bipolarity. Different etiological pathways may explain the presence of these comorbid disorders among bipolar youth. Standardized treatments are providing ongoing data regarding their effectiveness for these comorbidities among bipolar youth. PMID- 25545606 TI - What is important in being cured from depression? Discordance between physicians and patients (1). AB - AIMS: The comparison of what physicians and patients consider important in being cured from depression. METHODS: 426 outpatients (in primary care and in psychiatric care) with a clinical diagnosis of major depression were included: at the start of antidepressant treatment, the importance of a range of items for being cured from depression (depressive, anxious and somatic symptoms, positive affect, functional impairment, quality of life) was assessed in physicians and patients separately and a ranking was made; after 3 months of treatment, the importance of these items for being cured from depression was re-assessed in the patients. RESULTS: The items ranked top 10 by physicians mainly contain depressive symptoms while those ranked top 10 by patients mainly contain positive affect items and this attention to positive affect even increases at 3 months follow-up and is higher in patients with recurrent depression than in patients with a first episode of depression. Somatic symptoms consistently get the lowest ranking, as well in physicians as in patients. CONCLUSIONS: Physicians differ significantly from patients in what they consider important for 'being cured from depression': physicians mainly focus on alleviation of depressive symptoms while patients mainly focus on the restoration of positive affect. PMID- 25545607 TI - Haematological effects of 2-phenoxyethanol and etomidate in carp (Cyprinus carpio L.). AB - OBJECTIVE: To evaluate the effects of handling alone versus handling under anaesthesia with 2-phenoxyethanol or etomidate on haematological parameters in carp. STUDY DESIGN: Prospective, randomized, laboratory experiment. ANIMALS: Seventy-two juvenile carp (Cyprinus carpio) weighing 35.9 +/- 10.4 g were divided into six groups of 12 fish. METHODS: Either 2-phenoxyethanol or 2% etomidate were administered to induce deep anaesthesia (0.3 mL L(-1) and 0.6 mL L(-1) , respectively) or deep sedation (0.15 mL L(-1) and 0.3 mL L(-1) , respectively). Fish were handled with and without sedation. Blood was sampled at 1 hour and 1 week post-treatment. Phagocyte oxidative activity [nitrotetrazolium blue reduction test (NBT)] and differential erythrocyte [red blood cell (RBC)] and leukocyte (white blood cell) counts were evaluated. RESULTS: At 1 hour after the induction of anaesthesia, haematocrit (Ht) and haemoglobin (Hb) were increased in fish anaesthetized with 2-phenoxyethanol, and mean corpuscular haemoglobin (MCH) was increased in fish anaesthetized with etomidate. At 1 week, an increase in RBC, erythroblastosis, erythrocyte damage, lymphopenia, neutrophilia, monocytosis and thrombocytosis occurred in both groups. Red blood parameters did not change 1 hour after handling alone, but after 1 week Ht, Hb and mean cell volume decreased, whereas MCH concentration (MCHC) and abnormal erythrocytes increased. Lymphopenia, neutrophilia, monocytosis, thrombocytosis and a decrease in NBT occurred. Fish handled under sedation showed an increase in Hb and MCHC followed by a decrease at 1 week in Ht, Hb and MCH, erythroblastosis and increased abnormal erythrocytes. Lymphopenia and neutrophilia were less pronounced than in fish handled without sedation, but a decrease in NBT was noted at 1 week post treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Deep anaesthesia with 2 phenoxyethanol or etomidate induced significant haematological alterations in juvenile carp. Deep sedation reduced the immediate immunosuppressive effects of handling but did not eliminate longterm effects. These anaesthetics should be avoided during experimental procedures involving haematological measurements. In contexts that require the short-term handling of carp, these drugs should be used with caution in view of their possible side effects. PMID- 25545608 TI - Target-enriched next-generation sequencing reveals differences between primary and secondary ovarian tumors in formalin-fixed, paraffin-embedded tissue. AB - Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can be challenging. We compared somatic mutation profiles of primary and secondary ovarian cancers to investigate if these profiles can help diagnose ovarian tumors. Cancer-related genes (n = 115) were screened by target enriched next-generation sequencing in formalin-fixed, paraffin-embedded tumor tissue from 43 primary endometrioid and mucinous ovarian carcinomas and 28 proven colorectal cancer metastases to the ovary. Results were validated by high resolution melting curve analysis and Sanger sequencing. TP53, NOTCH1, PIK3CA, and FAT4 versus APC, TP53, KRAS, and FAT4 mutations were the most common in the primary ovarian tumors and ovarian colorectal cancer metastases, respectively. An inactivating APC mutation was found in 4.7% of primary ovarian tumors (2 of 43; 95% CI, 1.6%-10.9%). In contrast, inactivating APC mutations were identified in 71% of colorectal cancer metastases (20 of 28; 95% CI, 55%-88%) (P < 0.001; sensitivity: 71.4%, 95% CI, 51.1%-86.0%; specificity: 95.4%, 95% CI, 82.9% 99.1%). Loss of heterozygosity and APC promoter hypermethylation did not differ significantly between the primary and secondary ovarian tumors. NOTCH1 mutations were observed specifically in primary ovarian tumors, although at a low frequency, but not in metastases (6 of 41; 14.6%; 95% CI, 3.8%-25.4%). APC mutation analysis can be used to differentiate primary endometrioid and mucinous ovarian tumors from colorectal cancer metastases to the ovary. PMID- 25545609 TI - In situ assessment of the renal microcirculation in mechanically ventilated rats using sidestream dark-field imaging. AB - For microcirculation research there is a need for baseline data and feasibility protocols describing microcirculation of various organs. The aim of our study was to examine the reliability and reproducibility of sidestream dark-field (SDF) imaging within the renal cortical microcirculation in rats. Renal microcirculation was observed using SDF probe placed on the exposed renal surface via the upper midline laparotomy. Video sequences recorded intermittently in short apneic pauses were analyzed off-line by using AVA 3.0 software (MicroVision Medical, Amsterdam, the Netherlands). Results are expressed as mean (SD) or median (25-75% percentiles). We obtained 60 clear sequences from all recorded analyzable videos from all the animals. The total small vessel and all vessel density (in mm.mm(-2) ) were (28.79 +/- 0.40) and (28.95 +/- 0.40), respectively. The perfused small and all vessel density were (28.79 +/- 0.40) and (28.95 +/- 0.40), respectively. The DeBacker Score was (19.14 +/- 0.43), the proportion of perfused vessels was 100% (100-100%) and the microvascular flow index was 3.49 (3 3.75). We conclude SDF imaging provides a reliable method to examine the renal microvascular bed in vivo and thus can be used for the study of the renal cortical vascular network in various experimental diseases models and clinical settings. PMID- 25545610 TI - Outcomes associated with preoperative use of extracorporeal membrane oxygenation in children undergoing heart operation for congenital heart disease: a multi institutional analysis. AB - BACKGROUND: There are very sparse data on patient outcomes related to the use of extracorporeal membrane oxygenation (ECMO) prior to heart operation in children with congenital heart disease. This study was designed to evaluate this association using the Pediatric Health Information System (PHIS) database. HYPOTHESIS: We hypothesize that patients receiving ECMO prior to heart operation will have worse outcomes, including mortality, compared with patients receiving ECMO after heart operation. METHODS: Patients age <=18 years receiving ECMO before or after pediatric heart operation (with or without cardiopulmonary bypass) at a PHIS-participating hospital from 2004 to 2013 were included. Multivariable logistic regression or Cox proportional-hazards models were fitted to study the effect of timing of ECMO initiation in relation to cardiac surgery on study outcomes. RESULTS: A total of 3498 patients from 42 hospitals qualified for inclusion. Of these, 494 (14%) received ECMO prior to heart operation (presurgery ECMO) and 3004 (86%) received ECMO after heart operation (postsurgery ECMO). Unadjusted mortality was significantly lower in the presurgery ECMO group compared with the postsurgery ECMO group (30% vs 45%; P < 0.0001). After adjusting for patient and center characteristics, odds of mortality were significantly lower in the presurgery ECMO group (odds ratio: 0.46, 95% confidence interval: 0.36-0.59, P < 0.0001). There were no significant differences in ECMO duration, length of hospital stay, and hospital charges between the 2 groups in adjusted models. CONCLUSIONS: This study suggests that ECMO can be used with satisfactory outcomes prior to heart operation in children with congenital heart disease. PMID- 25545611 TI - Association of cardiovascular trial registration with positive study findings: Epidemiological Study of Randomized Trials (ESORT). PMID- 25545612 TI - Multiple Linear Regression Analysis Indicates Association of P-Glycoprotein Substrate or Inhibitor Character with Bitterness Intensity, Measured with a Sensor. AB - P-glycoprotein (P-gp) regulates absorption of many drugs in the gastrointestinal tract and their accumulation in tumor tissues, but the basis of substrate recognition by P-gp remains unclear. Bitter-tasting phenylthiocarbamide, which stimulates taste receptor 2 member 38 (T2R38), increases P-gp activity and is a substrate of P-gp. This led us to hypothesize that bitterness intensity might be a predictor of P-gp-inhibitor/substrate status. Here, we measured the bitterness intensity of a panel of P-gp substrates and nonsubstrates with various taste sensors, and used multiple linear regression analysis to examine the relationship between P-gp-inhibitor/substrate status and various physical properties, including intensity of bitter taste measured with the taste sensor. We calculated the first principal component analysis score (PC1) as the representative value of bitterness, as all taste sensor's outputs shared significant correlation. The P gp substrates showed remarkably greater mean bitterness intensity than non-P-gp substrates. We found that Km value of P-gp substrates were correlated with molecular weight, log P, and PC1 value, and the coefficient of determination (R(2) ) of the linear regression equation was 0.63. This relationship might be useful as an aid to predict P-gp substrate status at an early stage of drug discovery. PMID- 25545613 TI - Lung ultrasound for critical care physiotherapists: a narrative review. AB - BACKGROUND: In critical care, part of the physiotherapist's respiratory assessment aims to identify parenchymal pulmonary pathology, which may be amenable to respiratory physiotherapy. In addition to clinical assessment, the tools that are most readily available to the respiratory physiotherapist to distinguish between acute pulmonary pathologies include auscultation and chest Xray. The limited diagnostic accuracy of these tools may not allow for the accurate differentiation between conditions such as lung collapse, consolidation and pleural effusion. Although computed tomography allows for this differentiation, it requires patient transport and exposes the patient to increased risk and high levels of radiation. Diagnostic lung ultrasound (LUS) has emerged as a highly sensitive bedside diagnostic tool with high level evidence to support its use for the differentiation of various common acute pulmonary pathologies. In this review, the diagnostic performances of auscultation, chest Xray and LUS are reviewed, and the usefulness of LUS as an adjunct to respiratory physiotherapy assessment is discussed. The issues surrounding training physiotherapists and the implementation of LUS are also explored. METHODS: The method used is a narrative review of the literature. CONCLUSION: To our knowledge, LUS is not routinely utilized by critical care physiotherapists. However, its superior sensitivity and specificity would enable the physiotherapist to make an accurate, timely and point of care diagnosis of lung pathology and determine whether the pathology is amenable to respiratory physiotherapy. PMID- 25545614 TI - Determination of neuroprotective oxysterols in Calculus bovis, human gallstones, and traditional Chinese medicine preparations by liquid chromatography with mass spectrometry. AB - So far, the components responsible for the neuroprotective effects of Calculus bovis are unclear. Cholesterol, one of the major components in Calculus bovis, is easily oxidized into oxysterols, which possess direct or indirect neuroprotective effects proved by our and others' previous studies. Therefore, a liquid chromatography with mass spectrometry method coupled with ultrasonic extraction and solid-phase extraction was developed for the determination of neuroprotective oxysterols in Calculus bovis, human gallstones, and traditional Chinese medicine preparations. Chromatographic separation was achieved on a C18 column with isocratic elution at a flow rate of 1 mL/min. The established method showed good linearity (R(2) > 0.998), sensitivity with low limits of detection (0.06-0.39 MUg/g), acceptable precisions (relative standard deviations <= 7.4%), stability (relative standard deviations <= 5.9%), and satisfactory accuracy (92.4-102.9%) for all analytes identified by different retention times, which could be applied for the determination of oxysterols. Five kinds of oxysterols proved to function as neuroprotectants were detected at different concentrations. Among them, 7beta hydroxycholesterol and cholestane-3beta,5alpha,6beta-triol were rather abundant in the samples. It could be concluded that the potential neuroprotective components in Calculus bovis may be these oxysterols. PMID- 25545615 TI - Fate of patients with nasopharyngeal cancer who developed distant metastasis as first failure after definitive radiation therapy. AB - BACKGROUND: No consensus has been reached on the optimal treatment for patients with nasopharyngeal cancer (NPC) who develop distant metastasis after initial radiation therapy (RT). METHODS: Two hundred eighty-two patients with NPC received curative RT (+/- chemotherapy). Forty-six patients (16.3%) who developed distant metastasis as first failure formed the study group for the current analysis. RESULTS: The median interval from initial RT until distant metastasis was 11.6 months. With a median follow-up of 30 months among survivors, overall survival (OS) rates at 2 and 5 years were 53.7% and 30.5%, respectively. On multivariate analyses, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT for initial staging, RT plus chemotherapy as initial treatment, metastatic lesion number <6, disease-free interval >9 months, distant metastasis only to lungs, and treatment with curative intent after distant metastasis were predictive of significantly better OS. CONCLUSION: Combined with FDG-PET/CT, an aggressive treatment approach using locoregional modalities might be beneficial to patients with NPC with favorable prognostic factors, even after distant metastasis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E293-E299, 2016. PMID- 25545616 TI - Reply: To PMID 25302634. PMID- 25545617 TI - Reproducibility measurements of three methods for calculating in vivo MR-based knee kinematics. AB - PURPOSE: To describe three quantification methods for magnetic resonance imaging (MRI)-based knee kinematic evaluation and to report on the reproducibility of these algorithms. MATERIALS AND METHODS: T2 -weighted, fast-spin echo images were obtained of the bilateral knees in six healthy volunteers. Scans were repeated for each knee after repositioning to evaluate protocol reproducibility. Semiautomatic segmentation defined regions of interest for the tibia and femur. The posterior femoral condyles and diaphyseal axes were defined using the previously defined tibia and femur. All segmentation was performed twice to evaluate segmentation reliability. Anterior tibial translation (ATT) and internal tibial rotation (ITR) were calculated using three methods: a tibial-based registration system, a combined tibiofemoral-based registration method with all manual segmentation, and a combined tibiofemoral-based registration method with automatic definition of condyles and axes. Intraclass correlation coefficients and standard deviations across multiple measures were determined. RESULTS: Reproducibility of segmentation was excellent (ATT = 0.98; ITR = 0.99) for both combined methods. ATT and ITR measurements were also reproducible across multiple scans in the combined registration measurements with manual (ATT = 0.94; ITR = 0.94) or automatic (ATT = 0.95; ITR = 0.94) condyles and axes. CONCLUSION: The combined tibiofemoral registration with automatic definition of the posterior femoral condyle and diaphyseal axes allows for improved knee kinematics quantification with excellent in vivo reproducibility. PMID- 25545619 TI - Follow-up mortality study of compulsorily treated patients with anorexia nervosa. AB - OBJECTIVE: In a previous study we found that compulsory inpatient treatment was associated with an increase in the number of deaths over the following 5 years when compared to non-compulsory admission. This study aimed to examine the longer term mortality of patients admitted compulsorily. METHOD: The mortality outcome of patients with a compulsory admission (n = 81) and a comparison group (n = 81) of patients admitted to the specialized eating disorder unit at the Maudsley Hospital in the period 1983-95 was traced over two decades through the National Register held by the National Health Service (NHS) Central Register. RESULTS: Approximately 20 years following admission there were 27 deaths in the series. The standardized mortality rate in the compulsory treatment group no longer differed significantly from that of the non-compulsory group. The suicides were not particularly linked with compulsory admission. DISCUSSION: Although the mortality in the 5 years following a compulsory admission is higher than that seen in the non-compulsory patients, this difference is attenuated over time. The overall standardized mortality rate remains elevated. PMID- 25545618 TI - Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. AB - We have previously reported that adoptive transfer of tumor-draining lymph node (TDLN) B cells confers tumor regression in a spontaneous pulmonary metastasis mouse model of breast cancer. In this study, we identified IL-10-producing cells within these B cells, and found that IL-10 removal, either by using IL-10(-/-) TDLN B cells or by systemic neutralization of IL-10, significantly augmented the therapeutic efficacy of adoptively transferred TDLN B cells. Depletion of IL-10 in B-cell adoptive transfers significantly increased CTLs and B-cell activity of PBMCs and splenic cells in the recipient. Activated TDLN B cells express Fas ligand, which was further enhanced by coculture of these TDLN B cells with 4T1 tumor cells. Effector B cells killed tumor cells directly in vitro in an antigen specific and Fas ligand-dependent manner. Trafficking of TDLN B cells in vivo suggested that they were recruited to the tumor and lung as well as secondary lymphoid organs. These findings further define the biological function of antitumor effector B cells, which may offer alternative cellular therapies to cancer. PMID- 25545621 TI - When an Analytical Interference Is a Useful Diagnostic Tool: Finding Monoclonal Gammopathies in Routine Analysis. AB - BACKGROUND: The daily productivity of a clinical laboratory depends on the large number of interferences that affect analytical accuracy. Obviously, they have always been considered as a very important aspect to keep accuracy under control. Nevertheless, we wondered if this aspect would be beneficial. In this article, we propose a method for finding monoclonal gammopathies that are based on the fact that the presence of paraprotein in the sample may interfere with routine laboratory assays, specifically, with the quantification of uric acid and conjugated bilirubin. METHODS: Over a 5-month period, we evaluated 18,278 sera samples of patients from primary care. None of them were suspected of having plasma cell dyscrasias (not observed hypercalcemia, renal failure, anemia, and/or lytic bone lesions). Although biochemical findings suggested paraprotein interference, we carried out serum capillary electrophoresis (CE) and quantification of immunoglobulins and serum-free light chains (SFLCs). We also confirmed the results obtained by performing the corresponding immunofixation electrophoresis (IFE). Flow cytometry analyses were conducted for immunophenotypic characterization of plasma cells from these patients. RESULTS: The proposed detection method allowed us to identify eight patients with previously undiagnosed monoclonal gammopathy. CONCLUSIONS: The results show that it is possible to use analytical interference for diagnostic purposes, and most importantly, almost all cases were identified at an early stage of the disease, when associated clinical manifestations were not yet observed. PMID- 25545620 TI - Contrasting biofunctionalization strategies for the enhanced endothelialization of biodegradable vascular grafts. AB - Surface modification of biodegradable vascular grafts is an important strategy to improve the in situ endothelialization of tissue engineered vascular grafts (TEVGs) and prevent major complications associated with current synthetic grafts. Important strategies for improving endothelialization include increasing endothelial cell mobilization and increased endothelial cell capture through biofunctionalization of TEVGs. The objective of this study was to assess two biofunctionalization strategies for improving endothelialization of biodegradable polyester vascular grafts. These techniques consisted of cross-linking heparin to graft surfaces to immobilize vascular endothelial growth factor (VEGF) or antibodies against CD34 (anti-CD34Ab). To this end, heparin, VEGF, and anti CD34Ab attachment and quantification assays confirmed the efficacy of the modification strategy. Cell attachment and proliferation on these groups were compared to unmodified grafts in vitro and in vivo. To assess in vivo graft functionality, the grafts were implanted as inferior vena cava interpositional conduits in mice. Modified vascular grafts displayed increased endothelial cell attachment and activity in vivo, according to microscopy techniques, histological results, and eNOS expression. Inner lumen diameter of the modified grafts was also better maintained than controls. Overall, while both functionalized grafts outperformed the unmodified control, grafts modified with anti-CD34Ab appeared to yield the most improved results compared to VEGF-loaded grafts. PMID- 25545623 TI - On the relationship between tumor structure and complexity of the spatial distribution of cancer cell nuclei: a fractal geometrical model of prostate carcinoma. AB - BACKGROUND: A risk of the prostate cancer patient is defined by both the objective and subjective criteria, that is, PSA concentration, Gleason score, and pTNM-stage. The subjectivity of tumor grading influences the risk assessment owing to a large inter- and intra-observer variability. Pathologists propose a central prostate pathology review as a remedy for this problem; yet, the review cannot eliminate the subjectivity from the diagnostic algorithm. The spatial distribution of cancer cell nuclei changes during tumor progression. It implies changes in complexity measured by the capacity dimension D0, the information dimension D1, and the correlation dimension D2. METHODS: The cornerstone of the approach is a model of prostate carcinomas composed of the circular fractals CF(4), CF(6 + 0), and CF(6 + 1). This model is both geometrical and analytical, that is, its structure is well-defined, the capacity fractal dimension D0 can be calculated for the infinite circular fractals, and the dimensions D0, D1, D2 can be computed for their finite counterparts representing distribution of cell nuclei. The model enabled both the calibration of the software and the validation of the measurements in 124 prostate carcinomas. The ROC analysis defined the cut off D0 values for seven classes of complexity. RESULTS: The Gleason classification matched in part with the classification based on the D0 values. The mean ROC sensitivity was 81.3% and the mean ROC specificity 75.2%. Prostate carcinomas were re-stratified into seven classes of complexity according to their D0 values. This increased both the mean ROC sensitivity and the mean ROC specificity to 100%. All homogeneous Gleason patterns were subordinated to the class C1, C4, or C7. D0 = 1.5820 was the cut-off D0 value between the complexity class C2 and C3 representing low-risk cancers and intermediate-risk cancers, respectively. CONCLUSIONS: The global fractal dimensions eliminate the subjectivity in the diagnostic algorithm of prostate cancer. Those complexity measures enable the objective subordination of carcinomas to the well-defined complexity classes, and define subgroups of carcinomas with very low malignant potential (complexity class C1) or at a large risk of progression (complexity ass C7). PMID- 25545622 TI - Endothelial monolayers and transendothelial migration depend on mechanical properties of the substrate. AB - Endothelial cells (ECs) line the microvasculature and constitute a barrier between the vessel lumen and surrounding tissues. ECs inform circulating immune cells of the health and integrity of surrounding tissues, recruiting them in response to pathogens and tissue damage. ECs play an active role in the transmigration of immune cells across the vessel wall. We have discovered important differences in the properties of ECs on soft hydrogel substrates of varying stiffness, in comparison to glass. Primary ECs from several human sources were tested; all formed monolayers normally on soft substrates. EC monolayers formed more mature cell-cell junctions on soft substrates, relative to glass, based on increased recruitment of vinculin and F-actin. EC monolayers supported transendothelial migration (TEM) on soft substrates. Immune cells, including peripheral blood lymphocytes (PBLs) and natural killer cells, showed decreasing numbers of paracellular (between-cell) transmigration events with decreasing substrate stiffness, while the number of transcellular (through-cell) events increased for PBLs. Melanoma cancer cells showed increased transmigration with decreased stiffness. Our findings demonstrate that endothelial monolayers respond to the mechanical properties of their surroundings, which can regulate the integrity and function of the monolayer independently from inflammatory signals. Soft hydrogel substrates are a more appropriate and physiological model for tissue environments than hard substrates, with important implications for the experimental analysis of TEM. PMID- 25545624 TI - New postcranial material of the early caseid Casea broilii Williston, 1910 (Synapsida: Caseidae) with a review of the evolution of the sacrum in Paleozoic non-mammalian synapsids. AB - Here we use the description of a new specimen of the small caseid synapsid Casea broilii that preserves the sacral, pelvic and hind limb regions in great detail and in three dimensions, as a unique opportunity to reevaluate the early stages in the evolution of the sacrum in the lineage that led to mammals. We place this new material in the context of sacral evolution in early caseid synapsids and conclude that the transition from two to three sacral vertebrae occurred in small bodied species, suggesting that it was not an adaptation to heavy weight bearing. Furthermore, we compare descriptions of sacral anatomy among known early synapsids, including caseids, ophiacodontids, edaphosaurids, varanopids, and sphenacodontians and review sacral evolution in early synapsids. Based on the descriptions of new species of caseids, edaphosaurids, and varanopids over the past several decades, it is clear that a sacrum consisting of three vertebrae evolved independently at least four times in synapsids during the Late Carboniferous and Early Permian. Furthermore, similarities in the morphologies of the sacral vertebrae and ribs of these early synapsids lead us to conclude that an anterior caudal vertebra had been incorporated into the sacral series convergently in these groups. Given the repeated acquisition of a three-vertebra sacrum in early synapsids and no apparent link to body size, we argue that this sacral anatomy was related to more efficient terrestrial locomotion than to increased weight bearing. PMID- 25545625 TI - Establishing principles of macromolecular crowding for in vitro fibrosis research of the vocal fold lamina propria. AB - OBJECTIVES/HYPOTHESIS: Vocal fold fibrosis represents a major disease burden. Screening of antifibrotic compounds could be facilitated by an in vitro fibrogenesis system. Limitations of existing models might be overcome by implication of the excluded volume effect. STUDY DESIGN: In-vitro study. METHODS: Vocal fold fibroblasts obtained from rats' lamina propria were cultured in four different settings: in standard medium, under "crowded" conditions by adding inert macromolecules, under external administration of transforming growth factor (TGF)beta-1, and under a combination of both. After 5 days, supernatant and cell layer were collected and analyzed by enzyme-linked immunosorbent assay. Immunofluorescence was additionally performed. RESULTS: Collagen-alpha1(I) deposition increased significantly under crowded conditions and after administration of TGFbeta-1. Amounts of collagen in the cell layer were significantly higher under crowding conditions with TGFbeta-1 compared to administration of TGFbeta-1 alone. CONCLUSION: Crowding enhanced collagen deposition, resulting in more favorable conditions for studying fibrogenesis. This can be the first step toward developing a robust in vitro model for testing antifibrotic compounds. LEVEL OF EVIDENCE: NA. PMID- 25545626 TI - Voluntary organ donation system adapted to Chinese cultural values and social reality. AB - Organ donation and transplant systems have unique characteristics based on the local culture and socioeconomic context. China's transplant and organ donation systems developed without regulatory oversight until 2006 when regulation and policy were developed and then implemented over the next several years. Most recently, the pilot project of establishing a voluntary citizen-based deceased donor program was established. The pilot program addressed the legal, financial, and cultural barriers to organ donation in China. The pilot program has evolved into a national program. Significantly, it established a uniquely Chinese donor classification system. The Chinese donor classification system recognizes donation after brain death (category I), donation after circulatory death (category II), and donation after brain death followed by circulatory death (category III). Through August 2014, the system has identified 2326 donors and provided 6416 organs that have been allocated though a transparent organ allocation system. The estimated number of donors in 2014 is 1147. As China's attitudes toward organ donation have matured and evolved and as China, as a nation, is taking its place on the world stage, it is recognizing that its past practice of using organs from executed prisoners is not sustainable. It is time to recognize that the efforts to regulate transplantation and provide voluntary citizen-based deceased organ donation have been successful and that China should use this system to provide organs for all transplants in every province and hospital in China. At the national organ transplant congress on October 30, 2014, the Chairman of the China's national organ donation and transplantation committee, Jeifu Huang required all hospitals to stop using organs from executed prisoners immediately and the civilian organ donation will be sole source for organ transplant in China starting January 2015. PMID- 25545627 TI - In-depth evaluation of software tools for data-independent acquisition based label-free quantification. AB - Label-free quantification (LFQ) based on data-independent acquisition workflows currently experiences increasing popularity. Several software tools have been recently published or are commercially available. The present study focuses on the evaluation of three different software packages (Progenesis, synapter, and ISOQuant) supporting ion mobility enhanced data-independent acquisition data. In order to benchmark the LFQ performance of the different tools, we generated two hybrid proteome samples of defined quantitative composition containing tryptically digested proteomes of three different species (mouse, yeast, Escherichia coli). This model dataset simulates complex biological samples containing large numbers of both unregulated (background) proteins as well as up- and downregulated proteins with exactly known ratios between samples. We determined the number and dynamic range of quantifiable proteins and analyzed the influence of applied algorithms (retention time alignment, clustering, normalization, etc.) on quantification results. Analysis of technical reproducibility revealed median coefficients of variation of reported protein abundances below 5% for MS(E) data for Progenesis and ISOQuant. Regarding accuracy of LFQ, evaluation with synapter and ISOQuant yielded superior results compared to Progenesis. In addition, we discuss reporting formats and user friendliness of the software packages. The data generated in this study have been deposited to the ProteomeXchange Consortium with identifier PXD001240 (http://proteomecentral.proteomexchange.org/dataset/PXD001240). PMID- 25545628 TI - New insights into Capsicum spp relatedness and the diversification process of Capsicum annuum in Spain. AB - The successful exploitation of germplasm banks, harbouring plant genetic resources indispensable for plant breeding, will depend on our ability to characterize their genetic diversity. The Vegetable Germplasm Bank of Zaragoza (BGHZ) (Spain) holds an important Capsicum annuum collection, where most of the Spanish pepper variability is represented, as well as several accessions of other domesticated and non-domesticated Capsicum spp from all over the five continents. In the present work, a total of 51 C. annuum landraces (mainly from Spain) and 51 accessions from nine Capsicum species maintained at the BGHZ were evaluated using 39 microsatellite (SSR) markers spanning the whole genome. The 39 polymorphic markers allowed the detection of 381 alleles, with an average of 9.8 alleles per locus. A sizeable proportion of alleles (41.2%) were recorded as specific alleles and the majority of these were present at very low frequencies (rare alleles). Multivariate and model-based analyses partitioned the collection in seven clusters comprising the ten different Capsicum spp analysed: C. annuum, C. chinense, C. frutescens, C. pubescens, C. bacatum, C. chacoense and C. eximium. The data clearly showed the close relationships between C. chinense and C. frutescens. C. cardenasii and C. eximium were indistinguishable as a single, morphologically variable species. Moreover, C. chacoense was placed between C. baccatum and C. pubescens complexes. The C. annuum group was structured into three main clusters, mostly according to the pepper fruit shape, size and potential pungency. Results suggest that the diversification of C. annuum in Spain may occur from a rather limited gene pool, still represented by few landraces with ancestral traits. This ancient population would suffer from local selection at the distinct geographical regions of Spain, giving way to pungent and elongated fruited peppers in the South and Center, while sweet blocky and triangular types in Northern Spain. PMID- 25545629 TI - Effects of rasagiline on the progression of nonmotor scores of the MDS-UPDRS. AB - BACKGROUND: A draft version of part 1 (Non-Motor Aspects of Experiences of Daily Living; nM-EDL) of the MDS-UPDRS scale was employed as a secondary outcome in the ADAGIO study, which assessed the effect of rasagiline in early Parkinson's disease (PD) patients. METHODS: This analysis includes 1,150 untreated PD patients randomized to placebo or rasagiline 1 or 2 mg/day for 36 weeks in the placebo-controlled phase of ADAGIO who had draft-nM-EDL assessments at baseline and week 36. RESULTS: Over the 9-month placebo-controlled phase of the study, nM EDL scores significantly deteriorated from baseline in the placebo group only (0.34 +/- 0.10 units; P < 0.001). Compared to the placebo group (n = 583), there was significantly less deterioration in the 1-mg/day rasagiline group (n = 280; treatment effect: -0.33 units; P < 0.05), whereas the treatment effect in the 2 mg/day rasagiline group (n = 287) was not statistically significant (-0.25 +/- 0.17 units; P = 0.131). CONCLUSIONS: The nM-EDL subscale appears sensitive to change in very early PD, and treatment with rasagiline 1 mg/day was associated with significantly less decline in nonmotor experiences of daily living versus placebo. Given that score changes were numerically small, the clinical implications of this effect remain unclear. PMID- 25545630 TI - UV-absorbent lignin-based multi-arm star thermoplastic elastomers. AB - Lignin-grafted copolymers, namely lignin-graft-poly(methyl methacrylate-co-butyl acrylate) (lignin-g-P(MMA-co-BA)), are synthesized via "grafting from" atom transfer radical polymerization (ATRP) with the aid of lignin-based macroinitiators. By manipulating the monomer feed ratios of MMA/BA, grafted copolymers with tunable glass transition temperatures (-10-40 degrees C) are obtained. These copolymers are evaluated as sustainable thermoplastic elastomers (TPEs). The results suggest that the mechanical properties of these TPEs lignin-g P(MMA-co-BA) copolymers are improved significantly by comparing with those of linear P(MMA-co-BA) copolymer counterparts, and the elastic strain recovery is nearly 70%. Lignin-g-P(MMA-co-BA) copolymers exhibit high absorption in the range of the UV spectrum, which might allow for applications in UV-blocking coatings. PMID- 25545631 TI - How does mild hypothermia affect monoclonal antibody glycosylation? AB - The application of mild hypothermic conditions to cell culture is a routine industrial practice used to improve recombinant protein production. However, a thorough understanding of the regulation of dynamic cellular processes at lower temperatures is necessary to enhance bioprocess design and optimization. In this study, we investigated the impact of mild hypothermia on protein glycosylation. Chinese hamster ovary (CHO) cells expressing a monoclonal antibody (mAb) were cultured at 36.5 degrees C and with a temperature shift to 32 degrees C during late exponential/early stationary phase. Experimental results showed higher cell viability with decreased metabolic rates. The specific antibody productivity increased by 25% at 32 degrees C and was accompanied by a reduction in intracellular nucleotide sugar donor (NSD) concentrations and a decreased proportion of the more processed glycan structures on the mAb constant region. To better understand CHO cell metabolism at 32 degrees C, flux balance analysis (FBA) was carried out and constrained with exometabolite data from stationary phase of cultures with or without a temperature shift. Estimated fluxomes suggested reduced fluxes of carbon species towards nucleotide and NSD synthesis and more energy was used for product formation. Expression of the glycosyltransferases that are responsible for N-linked glycan branching and elongation were significantly lower at 32 degrees C. As a result of mild hypothermia, mAb glycosylation was shown to be affected by both NSD availability and glycosyltransferase expression. The combined experimental/FBA approach generated insight as to how product glycosylation can be impacted by changes in culture temperature. Better feeding strategies can be developed based on the understanding of the metabolic flux distribution. PMID- 25545632 TI - Toxicity of sediments from lead-zinc mining areas to juvenile freshwater mussels (Lampsilis siliquoidea) compared to standard test organisms. AB - Sediment toxicity tests compared chronic effects on survival, growth, and biomass of juvenile freshwater mussels (28-d exposures with Lampsilis siliquoidea) to the responses of standard test organisms-amphipods (28-d exposures with Hyalella azteca) and midges (10-d exposures with Chironomus dilutus)-in sediments from 2 lead-zinc mining areas: the Tri-State Mining District and Southeast Missouri Mining District. Mussel tests were conducted in sediments sieved to <0.25 mm to facilitate recovery of juvenile mussels (2-4 mo old). Sediments were contaminated primarily with lead, zinc, and cadmium, with greater zinc and cadmium concentrations in Tri-State sediments and greater lead concentrations in southeast Missouri sediments. The frequency of highly toxic responses (reduced 10% or more relative to reference sites) in Tri-State sediments was greatest for amphipod survival (25% of samples), midge biomass (20%), and mussel survival (14%). In southeast Missouri sediments, the frequency of highly toxic samples was greatest for mussel biomass (25%) and amphipod biomass (13%). Thresholds for metal toxicity to mussels, expressed as hazard quotients based on probable effect concentrations, were lower for southeast Missouri sediments than for Tri-State sediments. Southeast Missouri sites with toxic sediments had 2 or fewer live mussel taxa in a concurrent mussel population survey, compared with 7 to 26 taxa at reference sites. These results demonstrate that sediment toxicity tests with juvenile mussels can be conducted reliably by modifying existing standard methods; that the sensitivity of mussels to metals can be similar to or greater than standard test organisms; and that responses of mussels in laboratory toxicity tests are consistent with effects on wild mussel populations. PMID- 25545633 TI - Personal experience with narrated events modulates functional connectivity within visual and motor systems during story comprehension. AB - Past experience of everyday life activities, which forms the basis of our knowledge about the world, greatly affects how we understand stories. Yet, little is known about how this influence is instantiated in the human brain. Here, we used functional magnetic resonance imaging to investigate how past experience facilitates functional connectivity during the comprehension of stories rich in perceptual and motor details. We found that comprehenders' past experience with the scenes and actions described in the narratives selectively modulated functional connectivity between lower- and higher-level areas within the neural systems for visual and motor processing, respectively. These intramodal interactions may play an important role in integrating personal knowledge about a narrated situation with an evolving discourse representation. This study provides empirical evidence consistent with the idea that regions related to visual and motor processing are involved in the reenactment of experience as proposed by theories of embodied cognition. PMID- 25545634 TI - Hepatic regenerative potential of mouse bone marrow very small embryonic-like stem cells. AB - Very small embryonic-like stem cells (VSELs) are a Sca-1 (+) Lin(-) CD45(-) cell population that has been isolated from the bone marrow of mice. The similarities and differences between the mRNA profiles of VSELs and embryonic stem (ES) cells have not yet been defined. Here, we report the whole genome gene expression profile of VSELs and ES cells. We analyzed the global gene expression of VSELs and compared it with ES cells by microarray analysis. We observed that 9,521 genes are expressed in both VSELs and ES cells, 1,159 genes are expressed uniquely in VSELs, and 420 genes are expressed uniquely in ES cells. We found that although VSELs are similar to ES cells in their expression of genes associated with stem cell behavior and pluripotency, there are also differences in their mRNA expression. We further analyzed the expression of stem cell associated genes in VSELs and ES cells, and found that there were differences in these genes. For instance, the Pkd2 and Yap1 gene were reduced in their expression in VSELs when compared with ES cells. But we also found Zfp54 gene expression was higher in VSELs compared with ES cells. More interestingly, we demonstrated that VSELs express c-kit, the stem cell factor (SCF) receptor. In vitro, SCF promoted VSEL differentiation into hepatic colonies in the presence of hepatocyte growth factor. In vivo, transplantation of VSELs directly into CCl4 induced injured livers significantly reduced serum ALT and AST levels. Therefore, these data suggest that VSELs play a role in the repair of injured livers. PMID- 25545635 TI - Is it patience or motivation? On motivational confounds in intertemporal choice tasks. AB - Intertemporal choices create a tension between amount maximization, which would favor the larger and later option (LL), and delay minimization, which would promote the smaller and sooner reward (SS). Two common interpretations of intertemporal choice behavior are discussed: looking at LL responses as indicative of self-control, and using intertemporal choices to assess delay aversion. We argue that both interpretations need to take into account motivational confounds, in order to be warranted by data. In intertemporal choices with prepotent, salient stimuli (e.g., food amounts, typically used with nonhuman primates), LL responses could also be indicative of failed inhibition of a "go for more" impulsive response-the opposite of self-control. Similarly, intertemporal choices can be used to measure delay aversion only with respect to the subject's baseline motivation to maximize the reinforcer in question, and this baseline is not always assessed in current experimental protocols. This concern is especially crucial in comparing intertemporal choices across different groups or manipulation. We focus in particular on the effects of reward types on intertemporal choices, presenting two experimental studies where the difference in behavior with monetary versus food rewards is the product of different baseline motivation, rather than variations in delay aversion. We conclude discussing the implications of these and other similar recent findings, which are far-reaching. PMID- 25545636 TI - Determinants of initial utilization of community healthcare services among patients with major non-communicable chronic diseases in South China. AB - BACKGROUND: Although expected to act as gate-keeping primary care providers, as community health service (CHS) facilities are severely under-utilized; Chinese people in both rural and urban areas used predominantly higher-tier facilities for primary care purpose, with significant financial and outcome consequences. This study intends to explore the determinants of initial utilization of CHS among patients with major non-communicable chronic diseases (NCDs) in order to understand the care-seeking behavior among urban and rural residents in South China. METHODS: A multi-stage cluster random sampling methodology was adopted to create a sample of 19,466 adults with NCDs from 7,970 urban households and 32,035 adults with NCDs from 3,860 rural households in Guangdong, China. Interviews and physical examinations were conducted in 2010 to collect data on patient characteristics, medical conditions, and awareness and utilization of healthcare. Descriptive analysis and logistic regression analysis were performed to study utilization patterns and the factors associated with the patterns. RESULTS: Prevalence of major NCDs in urban areas was significantly higher than that in rural areas (12.55% vs. 8.70%; p<0.001). Second-tier district hospitals were most preferred for initial consultation (46.05% in rural areas vs. 45.32% in urban areas; p<0.001), followed by tertiary general or specialized hospitals (28.39% in rural areas vs. 33.89% in urban areas; p<0.001). The proportion of patients who had initial use of CHS was relatively low (25.56% in rural areas vs. 20.79% in urban areas; p<0.001). Awareness of self-care and the presence of medical insurance were leading factors associated with first contact of CHS facilities in both urban and rural areas. CONCLUSION: The study suggests that CHS facilities are not often used as the first contact for patients in both rural and urban areas in south China. Much effect must be made to enhance the gatekeeper system and improve medical insurance coverage in future healthcare reforms. PMID- 25545638 TI - Ca2+ and Mg2+ binding site engineering increases the degradation of polyethylene terephthalate films by polyester hydrolases from Thermobifida fusca. AB - Several bacterial polyester hydrolases are able to hydrolyze the synthetic polyester polyethylene terephthalate (PET). For an efficient enzymatic degradation of PET, reaction temperatures close to the glass transition temperature of the polymer need to be applied. The esterases TfH, BTA2, Tfu_0882, TfCut1, and TfCut2 produced by the thermophilic actinomycete Thermobifida fusca exhibit PET-hydrolyzing activity. However, these enzymes are not sufficiently stable in this temperature range for an efficient degradation of post-consumer PET materials. The addition of Ca2+ or Mg2+ cations to the enzymes resulted in an increase of their melting points between 10.8 and 14.1 degrees C determined by circular dichroism spectroscopy. The thermostability of the polyester hydrolases was sufficient to degrade semi-crystalline PET films at 65 degrees C in the presence of 10 mM Ca2+ and 10 mM Mg2+ resulting in weight losses of up to 12.9% after a reaction time of 48 h. The residues Asp174, Asp204, and Glu253 were identified by molecular dynamics simulations as potential binding residues for the two cations in TfCut2. This was confirmed by their substitution with arginine, resulting in a higher thermal stability of the corresponding enzyme variants. The generated variants of TfCut2 represent stabilized catalysts suitable for PET hydrolysis reactions performed in the absence of Ca2+ or Mg2+. PMID- 25545637 TI - Cardiac mechanics and ventricular twist by three-dimensional strain analysis in relation to B-type natriuretic peptide as a clinical prognosticator for heart failure patients. AB - BACKGROUND: Three dimensional (3D) echocardiography-derived measurements of myocardial deformation and twist have recently advanced as novel clinical tools. However, with the exception of left ventricular ejection fraction and mass quantifications in hypertension and heart failure populations, the prognostic value of such imaging techniques remains largely unexplored. METHODS: We studied 200 subjects (mean age: 60.2+/-16 years, 54% female, female n = 107) with known hypertension (n = 51), diastolic heart failure (n = 61), or systolic heart failure (n = 30), recruited from heart failure outpatient clinics. Fifty-eight healthy volunteers were used as a control group. All participants underwent 3D based myocardial deformation and twist analysis (Artida, Toshiba Medical Systems, Tokyo, Japan). We further investigated associations between these measures and brain natriuretic peptide levels and clinical outcomes. RESULTS: The global 3D strain measurements of the healthy, hypertension, diastolic heart failure, and systolic heart failure groups were 28.03%, 24.43%, 19.70%, and 11.95%, respectively (all p<0.001). Global twist measurements were estimated to be 9.49 degrees , 9.77 degrees , 8.32 degrees , and 4.56 degrees , respectively. We observed significant differences regarding 3D-derived longitudinal, radial, and global 3D strains between the different disease categories (p<0.05), even when age, gender, BMI and heart rate were matched. In addition, 3D-derived longitudinal, circumferential, and 3D strains were all highly correlated with brain natriuretic peptide levels (p<0.001). At a mean 567.7 days follow-up (25th 75th IQR: 197-909 days), poorer 3D-derived longitudinal, radial, and global 3D strain measurements remained independently associated with a higher risk of cardiovascular related death or hospitalization due to heart failure, after adjusting for age, gender, and left ventricular ejection fraction (all p<0.05). CONCLUSIONS: 3D-based strain analysis may be a feasible and useful diagnostic tool for discriminating the extent of myocardial dysfunction. Furthermore, it is able to provide a prognostic value beyond traditional echocardiographic parameters in terms of ejection fraction. PMID- 25545639 TI - The power of disruptive technological innovation: Transcatheter aortic valve implantation. AB - We sought to evaluate the principles of disruptive innovation, defined as technology innovation that fundamentally shifts performance and utility metrics, as applied to transcatheter aortic valve implantation (TAVI). In particular, we considered implantation procedure, device design, cost, and patient population. Generally cheaper and lower performing, classical disruptive innovations are first commercialized in insignificant markets, promise lower margins, and often parasitize existing usage, representing unattractive investments for established market participants. However, despite presently high unit cost, TAVI is less invasive, treats a "new," generally high risk, patient population, and is generally done by a multidisciplinary integrated heart team. Moreover, at least in the short-term TAVI has not been lower-performing than open surgical aortic valve replacement in high-risk patients. We conclude that TAVI extends the paradigm of disruptive innovation and represents an attractive commercial opportunity space. Moreover, should the long-term performance and durability of TAVI approach that of conventional prostheses, TAVI will be an increasingly attractive commercial opportunity. PMID- 25545640 TI - Influence of hepatitis C virus and IL28B genotypes on liver stiffness. AB - OBJECTIVE: Liver fibrosis has been associated with hepatitis C virus (HCV) genotype and genetic variation near the interleukin 28B (IL28B) gene, but the relative contribution is unknown. We aimed to investigate the relation between HCV genotypes, IL28B and development of liver stiffness. PATIENTS AND METHODS: This cross-sectional study consists of 369 patients with chronic hepatitis C (CHC). Liver stiffness was evaluated using transient elastograhy (TE). Factors associated with development of liver fibrosis were identified by logistic regression analysis. RESULTS: We identified 369 patients with CHC. 235 were male, 297 Caucasians, and 223 had been exposed to HCV through intravenous drug use. The overall median TE value was 7.4 kPa (interquartile range (IQR) 5.7-12.1). HCV replication was enhanced in patients carrying the IL28B CC genotype compared to TT and TC (5.8 vs. 5.4 log10 IU/mL, p = 0.03). Patients infected with HCV genotype 3 had significantly higher TE values (8.2 kPa; IQR, 5.9-14.5) compared to genotype 1 (6.9 kPa; IQR, 5.4-10.9) and 2 (6.7 kPa; IQR, 4.9-8.8) (p = 0.02). Within patients with genotype 3, IL28B CC genotype had the highest TE values (p = 0.04). However, in multivariate logistic regression, using various cut-off values for fibrosis and cirrhosis, only increasing age (odds ratio (OR) 1.09 (95% confidence interval (CI), 1.05-1.14 per year increment)), ALT (OR 1.01 (95% CI, 1.002-1.011), per unit increment) and HCV genotype 3 compared to genotype 1 (OR 2.40 (95% CI, 1.19-4.81), were consistently associated with cirrhosis (TE>17.1 kPa). CONCLUSIONS: Age, ALT and infection with HCV genotype 3 were associated with cirrhosis assessed by TE. However, IL28B genotype was not an independent predictor of fibrosis in our study. PMID- 25545641 TI - A 7.5-Mb duplication at chromosome 11q21-11q22.3 is associated with a novel spastic ataxia syndrome. AB - BACKGROUND: The autosomal dominant spinocerebellar ataxias are most commonly caused by nucleotide repeat expansions followed by base-pair changes in functionally important genes. Structural variation has recently been shown to underlie spinocerebellar ataxia types 15 and 20. METHODS: We applied single nucleotide polymorphism (SNP) genotyping to determine whether structural variation causes spinocerebellar ataxia in a family from France. RESULTS: We identified an approximately 7.5-megabasepair duplication on chromosome 11q21 11q22.3 that segregates with disease. This duplication contains an estimated 44 genes. Duplications at this locus were not found in control individuals. CONCLUSIONS: We have identified a new spastic ataxia syndrome caused by a genomic duplication, which we have denoted as spinocerebellar ataxia type 39. Finding additional families with this phenotype will be important to identify the genetic lesion underlying disease. PMID- 25545643 TI - Evaluation and treatment of posterolateral instability of the knee. PMID- 25545644 TI - Anatomy and biomechanics of the lateral side of the knee and surgical implications. AB - A detailed understanding of the anatomy and biomechanics of the lateral knee is essential for the clinical diagnosis and surgical treatment of lateral-sided knee injuries. In the past, the structure and function of the lateral and posterolateral knee was poorly understood and was dubbed by some as "the dark side of the knee." However, recent advances in quantitative anatomy and biomechanics of this region have led to the development of anatomic-based reconstruction techniques and improved objective and subjective patient-based outcomes. Although the lateral knee consists of 28 unique structures, the primary lateral knee stabilizers include the fibular collateral ligament, popliteus tendon, and popliteofibular ligament. Together, these structures function to resist lateral compartment varus gapping and rotatory knee instability. This work will summarize the current state of knowledge regarding the anatomy and biomechanics of the lateral knee structures, while emphasizing implications for surgical treatment. PMID- 25545645 TI - Physical examination and imaging of the lateral collateral ligament and posterolateral corner of the knee. AB - The initial assessment of injury to the lateral collateral ligament and posterolateral corner is often challenging, particularly in the context of a multiligamentous injury. Although advanced imaging techniques have enhanced the evaluation of knee injuries, the significant, and often unique, contribution of clinical examination should not be overlooked. Clinical examination starts with a thorough history, which is instrumental in elucidating not only the patient's symptomatology but also the mechanism of injury. Differentiating between acute and chronic injury and teasing out the patient's functional limitations are instructive in defining the appropriate treatment plan. The treating physician needs patience, vigilance, and a variety of diagnostic tools to reach a precise diagnosis. Each injury should be approached in a methodical and systematic manner to ensure an accurate initial assessment. This review provides a step-wise approach to the clinical assessment of the lateral collateral ligament and posterolateral corner injured knee. Adjunctive imaging modalities and investigations are also discussed. PMID- 25545646 TI - Isolated fibular collateral ligament injuries in athletes. AB - Isolated injuries to the fibular collateral ligament (FCL) are rare. Although recent data suggest that operative and nonoperative treatment can both result in good functional outcomes, limited data exist on return to play for nonoperative treatment of FCL injuries and the value of magnetic resonance imaging in predicting prognosis. In this article, we present a review of the current literature and present a focused review regarding the diagnosis, treatment, and prognosis of FCL injuries, as well as the senior authors experience and a cohort of National Football League players. Magnetic resonance imaging can be useful to predict the length of disability in isolated FCL injuries, and both operative and nonoperative management of isolated FCL injuries successfully resulted in return to play in all players in several series of elite athletes; however, nonoperative management may result in faster return to play. Evaluation of potential concomitant injury is imperative in treatment of FCL injuries. PMID- 25545647 TI - Repair versus reconstruction in acute posterolateral instability of the knee. AB - Acute posterolateral corner injuries of the knee are rare and, when present, are frequently associated with concurrent ligament injury, neurovascular damage, or fractures of the femur or tibia. Early surgical treatment has been shown to be superior to delayed and nonoperative treatment of multiligamentous knee injuries. Historically, repair has been advocated. High-quality studies comparing repair versus reconstruction have shown that reconstruction yields superior results with respect to failure of the construct and similar outcomes with respect to patient satisfaction. Our preferred technique for reconstruction of the acute posterolateral corner with reinforcement is described. PMID- 25545648 TI - Posterolateral reconstruction of the knee using capsular procedures for evaluation and treatment of posterolateral instability of the knee. AB - Posterolateral rotatory instability of the knee causes significant morbidity if unrecognized and left untreated. With both acute and chronic injuries, restoration of the normal anatomy is crucial for a good outcome. During capsular repairs, detailed knowledge of the anatomy will help the surgeon repair the pathoanatomy. To complement the direct approach, an osteotomy of the lateral femoral condyle that includes the attachments of the fibular collateral ligament and popliteal tendon allows superior visualization of the lateral meniscus and its attachments, as well as the associated deep structures. The osteotomy also permits placement of posterior capsular sutures that allow the capsular shift to tighten the injured structures. Fine-tuning the tension of these structures may be accomplished by slightly adjusting the position of the bone block as it is reattached without significantly affecting isometry. The osteotomy is not required for all reconstructions; however, it provides excellent access to the deep structures of the posterolateral corner. The capsular shift can complement the direct repair of structures and may be done as an isolated or staged procedure or in combination with other reconstructive treatment options. PMID- 25545649 TI - Fibular head-based posterolateral reconstruction of the knee combined with capsular shift procedure. AB - Posterolateral instability (PLI) is common with posterior cruciate ligament tears, is less common with anterior cruciate ligament tears, and isolated PLI is rare. There are varying degrees of PLI with respect to pathologic external tibial rotation and varus laxity. Surgical treatment of PLI must address all components of the PLI (popliteus tendon, popliteofibular ligament, lateral collateral ligament, and the lateral-posterolateral capsule), the abnormal planes of motion, as well as other structural injuries. Successful posterior cruciate ligament and anterior cruciate ligament surgery depends upon recognition and treatment of posterolateral corner injuries. PMID- 25545642 TI - The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour. AB - Neuropeptide Y (NPY), one of the most abundant peptides in the nervous system, exerts its effects via five receptor types, termed Y1, Y2, Y4, Y5 and Y6. NPY's pleiotropic functions comprise the regulation of brain activity, mood, stress coping, ingestion, digestion, metabolism, vascular and immune function. Nerve derived NPY directly affects immune cells while NPY also acts as a paracrine and autocrine immune mediator, because immune cells themselves are capable of producing and releasing NPY. NPY is able to induce immune activation or suppression, depending on a myriad of factors such as the Y receptors activated and cell types involved. There is an intricate relationship between psychological stress, mood disorders and the immune system. While stress represents a risk factor for the development of mood disorders, it exhibits diverse actions on the immune system as well. Conversely, inflammation is regarded as an internal stressor and is increasingly recognized to contribute to the pathogenesis of mood and metabolic disorders. Intriguingly, the cerebral NPY system has been found to protect against distinct disturbances in response to immune challenge, attenuating the sickness response and preventing the development of depression. Thus, NPY plays an important homeostatic role in balancing disturbances of physiological systems caused by peripheral immune challenge. This implication is particularly evident in the brain in which NPY counteracts the negative impact of immune challenge on mood, emotional processing and stress resilience. NPY thus acts as a unique signalling molecule in the interaction of the immune system with the brain in health and disease. PMID- 25545650 TI - Fibular head and tibial-based (2-Tailed) posterolateral corner reconstruction. AB - Two-tailed techniques for reconstruction of the posterolateral corner use grafts that originate on the femur and insert onto both the proximal tibia and the fibular head. Two-tailed reconstruction aims to reconstruct the fibular collateral ligament, popliteus tendon, and popliteofibular ligament with anatomically placed grafts. This article will review the history, indications, and authors' preferred technique for 2-tailed posterolateral corner reconstruction, as well as biomechanical and clinical outcomes of this technique. PMID- 25545651 TI - Complications of posterolateral corner injuries of the knee and how to avoid them. AB - Knee dislocations and in particular posterolateral corner injuries to the knee are severe injuries demanding an organized approach and technically challenging surgery. Complications include unrecognized vascular or neurological injury and failure to reconstruct appropriately. During reconstruction, performing an inappropriate operation (failure to recognize malalignment) or technical error with tunnel or hardware placement can lead to delayed problems. Wound infection and wound breakdown is common as in arthrofibrosis often from overconstraint of the knee. Attention to principles and expertise in technique can minimize these complications. PMID- 25545652 TI - Outcomes for surgical treatment of posterolateral instability of the knee. AB - Injuries to the posterolateral corner (PLC) of the knee can be associated with a variety of additional ligamentous and soft-tissue injuries. The clinical outcome of a PLC injury is dependent on associated injuries, the chronicity of injury, and the method of reconstruction. This chapter discusses the current literature regarding outcomes of surgical treatment of acute and chronic injuries. The majority of the current literature includes level IV case series evidence. Anatomic reconstruction of the PLC with concomitant treatment of associated knee ligament injuries in acute and chronic cases is the preferred treatment. There are mixed outcomes with acute repair of injured tissues as well as advancement procedures. The surgical treatment must be tailored to the specific needs of the patient and the ligament injury pattern. PMID- 25545653 TI - Effects of acute respiratory and metabolic acidosis on diaphragm muscle obtained from rats. AB - BACKGROUND: Acute respiratory acidosis is associated with alterations in diaphragm performance. The authors compared the effects of respiratory acidosis and metabolic acidosis in the rat diaphragm in vitro. METHODS: Diaphragmatic strips were stimulated in vitro, and mechanical and energetic variables were measured, cross-bridge kinetics calculated, and the effects of fatigue evaluated. An extracellular pH of 7.00 was obtained by increasing carbon dioxide tension (from 25 to 104 mmHg) in the respiratory acidosis group (n = 12) or lowering bicarbonate concentration (from 24.5 to 5.5 mM) in the metabolic acidosis group (n = 12) and the results compared with a control group (n = 12, pH = 7.40) after 20-min exposure. RESULTS: Respiratory acidosis induced a significant decrease in maximum shortening velocity (-33%, P < 0.001), active isometric force (-36%, P < 0.001), and peak power output (-59%, P < 0.001), slowed relaxation, and decreased the number of cross-bridges (-35%, P < 0.001) but not the force per cross-bridge, and impaired recovery from fatigue. Respiratory acidosis impaired more relaxation than contraction, as shown by impairment in contraction-relaxation coupling under isotonic (-26%, P < 0.001) or isometric (-44%, P < 0.001) conditions. In contrast, no significant differences in diaphragmatic contraction, relaxation, or contraction-relaxation coupling were observed in the metabolic acidosis group. CONCLUSIONS: In rat diaphragm, acute (20 min) respiratory acidosis induced a marked decrease in the diaphragm contractility, which was not observed in metabolic acidosis. PMID- 25545654 TI - Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. PMID- 25545655 TI - Feasibility of closed-loop titration of propofol and remifentanil guided by the bispectral monitor in pediatric and adolescent patients: a prospective randomized study. AB - BACKGROUND: This study was designed to assess the feasibility of dual closed-loop titration of propofol and remifentanil guided solely by the Bispectral Index (BIS) monitor in pediatric and adolescent patients during anesthesia. METHODS: Children undergoing elective surgery in this single-blind randomized study were allocated into the closed-loop (auto) or manual (manual) group. Primary outcome was the percentage of time with the BIS in the range 40 to 60 (BIS40-60). Secondary outcomes were the percentage of deep (BIS<40) anesthesia and drug consumption. Data are presented as median (interquartile range) or number (%). RESULTS: Twenty-three patients (12 [10 to 14] yr) were assigned to the auto group and 19 (14 [7 to 14] yr) to the manual group. The closed-loop controller was able to provide induction and maintenance for all patients. The percentage of time with BIS40-60 was greater in the auto group (87% [75 to 96] vs. 72% [48 to 79]; P = 0.002), with a decrease in the percentage of BIS<40 (7% [2 to 17] vs. 21% [11 to 38]; P = 0.002). Propofol (2.4 [1.9 to 3.3] vs. 1.7 [1.2 to 2.8] mg/kg) and remifentanil (2.3 [2.0 to 3.0] vs. 2.5 [1.2 to 4.3] MUg/kg) consumptions were similar in auto versus manual groups during induction, respectively. During maintenance, propofol consumption (8.2 [6.0 to 10.2] vs. 7.9 [7.2 to 9.1] mg kg h; P = 0.89) was similar between the two groups, but remifentanil consumption was greater in the auto group (0.39 [0.22 to 0.60] vs. 0.22 [0.17 to 0.32] MUg kg min; P = 0.003). Perioperative adverse events and length of stay in the postanesthesia care unit were similar. CONCLUSION: Intraoperative automated control of hypnosis and analgesia guided by the BIS is clinically feasible in pediatric and adolescent patients and outperformed skilled manual control. PMID- 25545656 TI - Relationship of fragmented QRS with prognostic markers and long-term major adverse cardiac events in patients undergoing coronary artery bypass graft surgery. AB - BACKGROUND: Fragmented QRS (fQRS) complex is associated with increased sudden cardiac death, recurrent cardiovascular events, morbidity and mortality. However, the prognostic role of fQRS has not been comprehensively studied in patients undergoing coronary artery bypass graft (CABG) surgery. In this study, we planned to investigate the relationship of fQRS with prognostic markers and long-term major adverse cardiovascular events (MACEs) following isolated CABG surgery. METHODS: Two hundred and thirteen patients who underwent CABG surgery at our institution were enrolled consecutively. MACE was defined as cardiac death, recurrent myocardial infarction, decompensated heart failure and re hospitalization. The patients were followed up for a mean duration of 26 +/- 10 months for MACE. RESULTS: Patients with fQRS had a higher rate of Q wave on ECG (30 vs. 10%, P < 0.001), more prolonged QRS time (99 +/- 11 vs. 88 +/- 13 ms, P < 0.001), higher EUROSCORE (4.0 +/- 1.9 vs. 2.7 +/- 1.5, P < 0.001) and lower left ventricular ejection fraction (44 +/- 12 vs. 56 +/- 12, P < 0.001) in comparison with patients with non-fQRS. In addition, patients with fQRS had increased short term and long-term MACE (17 vs. 4%, P = 0.002; 23 vs. 6%, P < 0.001, respectively) after discharge. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of fQRS for predicting MACE were 67, 71, 23, 94 and 70%, respectively. fQRS [odds ratio (OR) 3.110, 95% confidence interval (CI) 1.157-8.362, P = 0.025] and prolonged QRS duration (>100 ms) (OR 3.898, 95% CI 1.463-10.39, P = 0.007) were the only independent predictors of long-term MACE in multivariate logistic regression analysis. However, QRS duration had a better association with MACE than the presence of fQRS. CONCLUSION: fQRS and prolonged QRS duration may have an additional value in predicting cardiac status and long-term prognosis. Fragmentations on admission ECG and prolonged QRS duration may be useful for identifying patients with higher long-term risk who will need more intense treatment and close follow-up after CABG surgery. PMID- 25545657 TI - Nitinol flexigrip sternal closure system and standard sternal steel wiring: insight from a matched comparative analysis. AB - OBJECTIVE: We sought to assess the efficiency of two different sternal closure techniques in preventing sternal wound instability in high-risk patients. MATERIALS AND METHODS: Between January 2009 and February 2012, 2068 consecutive cardiac patients were prospectively collected in our database. The 561 patients in whom the thermoreactive nitilium clips (Flexigrip) have been used (group A) were matched 1 : 1 with 561 patients who received a standard parasternal wiring technique (group B) on 10 available risk factors known to affect sternal wound healing (age, age >75 years, sex, diabetes mellitus, cardiac procedure, obesity, re-intervention, cross-clamp, and total operative times). The study was completed with a cost analysis. RESULTS: The two groups were well matched, although different for bilateral internal thoracic harvesting, chronic obstructive pulmonary disease, renal insufficiency, and congestive heart failure, which were significantly more frequent in group A. At 30 days of follow-up, the association of wound complication and sternal instability was significantly less frequent in group A versus group B (0.2 versus 1.6%) (P = 0.04). Overall incidence of sternal wound complication was lower in group A (2 versus 3.5%) (P = 0.28). In the presence of wound infection, a sternal wound instability was never observed in group A (P = 0.06). Overall costs were ?8,701,854 and ?9,243,702 in groups A and B, respectively; thus the Flexigrip closure technique offered a ?541,848 cost saving. CONCLUSIONS: Flexigrip use in high-risk patients showed a lower incidence of sternal wound instability with no need for sternal re-wiring in any case, even in the presence of wound infection. PMID- 25545658 TI - Prevention of pericarditis with colchicine: an updated meta-analysis. PMID- 25545659 TI - Cytoplasmic translocation of polypyrimidine tract-binding protein and its binding to viral RNA during Japanese encephalitis virus infection inhibits virus replication. AB - Japanese encephalitis virus (JEV) has a single-stranded, positive-sense RNA genome containing a single open reading frame flanked by the 5'- and 3'-non coding regions (NCRs). The virus genome replicates via a negative-sense RNA intermediate. The NCRs and their complementary sequences in the negative-sense RNA are the sites for assembly of the RNA replicase complex thereby regulating the RNA synthesis and virus replication. In this study, we show that the 55-kDa polypyrimidine tract-binding protein (PTB) interacts in vitro with both the 5' NCR of the positive-sense genomic RNA--5NCR(+), and its complementary sequence in the negative-sense replication intermediate RNA--3NCR(-). The interaction of viral RNA with PTB was validated in infected cells by JEV RNA co immunoprecipitation and JEV RNA-PTB colocalization experiments. Interestingly, we observed phosphorylation-coupled translocation of nuclear PTB to cytoplasmic foci that co-localized with JEV RNA early during JEV infection. Our studies employing the PTB silencing and over-expression in cultured cells established an inhibitory role of PTB in JEV replication. Using RNA-protein binding assay we show that PTB competitively inhibits association of JEV 3NCR(-) RNA with viral RNA-dependent RNA polymerase (NS5 protein), an event required for the synthesis of the plus sense genomic RNA. cAMP is known to promote the Protein kinase A (PKA)-mediated PTB phosphorylation. We show that cells treated with a cAMP analogue had an enhanced level of phosphorylated PTB in the cytoplasm and a significantly suppressed JEV replication. Data presented here show a novel, cAMP-induced, PTB mediated, innate host response that could effectively suppress JEV replication in mammalian cells. PMID- 25545660 TI - The relationship between central visual field damage and motor vehicle collisions in primary open-angle glaucoma patients. AB - PURPOSE: To investigate the relationship between visual field (VF) damage and history of motor vehicle collisions (MVCs) in subjects with primary open-angle glaucoma (POAG). METHODS: MVC history and driving habits were recorded using patient questionnaires in 247 POAG patients. Patients' driving attitudes (carefulness) were estimated using Rasch analysis. The relationship between MVC outcomes and 52 total deviation (TD) values of integrated binocular VF (IVF), better and worse visual acuities (VAs), age and gender was analyzed using principal component analysis and logistic regression. RESULTS: 51 patients had the history of MVCs. Significant difference was observed between patients with and without history of MVCs only for: better VA, a single TD value in the superior-right VF, and the typical distance driven in a week (unpaired t-test, p = 0.002, 0.015 and 0.006, respectively). There was not a significant relationship between MVCs and mean deviation (MD) of IVF (p = 0.41, logistic regression). None of the principal components were significantly correlated with MVC outcome (p>0.05, polynomial logistic regression analysis). There was a significant relationship between IVF MD and Rasch derived Person parameter (R2 = 0.023, p = 0.0095). There was also a significant positive relationship between MVCs and the distance driven in a week (p = 0.005, logistic regression). CONCLUSIONS: In this study of POAG patients, MVCs were not related to central binocular VF damage. These results suggest the relationship between visual function and driving is not straightforward, and careful consideration should be given when predicting patients' driving ability using their VF. PMID- 25545661 TI - Quality of life, age of onset of alcohol use and alcohol use disorders in adolescence and young adulthood: Findings from an Australian birth cohort. AB - INTRODUCTION AND AIMS: Alcohol consumption among adolescents and young adults is a persistent community concern. Little is known about the short-term effects on the young adult drinker's quality of life (QOL), particularly prior to the first use of alcohol and the effect of alcohol consumption on subsequent QOL assessments. There is a need to know more about the QOL of those who decide to use alcohol in adolescence and the effect of alcohol consumption on young adult QOL. DESIGN AND METHODS: This is a prospective longitudinal study of a birth cohort. Data were taken from the 14- and 21-year follow ups. At both time points, QOL was indicated by a measure of happiness and satisfaction. Alcohol use was also measured at 14- and 21-year follow ups. At the 21-year follow up, alcohol use disorder (AUD) was assessed using the Composite International Diagnostic Interview. RESULTS: At the 14-year follow up, there was a strong association between QOL and quantity of alcohol consumed. QOL at 14 years also predicted more frequent alcohol use at 21 years of age. Poor QOL at 14 years was a strong predictor of earlier age of onset of an AUD. However, when age of onset of AUD was used to predict subsequent QOL, the associations were weak and inconsistent. DISCUSSION AND CONCLUSION: Poor QOL was associated with the early age of onset of alcohol use and AUDs. Addressing adolescent and young adult QOL may reduce the early onset of alcohol use and its potential for harm. PMID- 25545662 TI - Incidence of Positive Ventricular Late Potentials Differs in Postural Changes among Supine, Left, and Right Lateral Decubitus, and Prone and Sitting Positions in Brugada Syndrome. AB - BACKGROUND: High-risk patients with Brugada syndrome (BrS) have inherent late potential (LP) fluctuations that might be explained by autonomic activity, electrolyte abnormality, and body temperature changes. However, the correlation between postural changes and LP determinates remains unknown. METHODS: Forty patients with BrS (38 men, 43.9 +/- 13.5 years) and 15 controls (15 men, 42.4 +/- 11.2 years) were enrolled. LP variations were investigated at five body positions using high-resolution ambulatory monitoring electrocardiography (HR-ambulatory ECG). The HR-ambulatory ECG was recorded for 3 hours and LP parameters (fQRSd, LAS40, and RMS40) were obtained for at least 15 minutes in each at the supine, left and right lateral decubitus, and prone and sitting positions. RESULTS: Determinate LP in the BrS group was significantly abnormal in all positions. Among the five body positions, positive LP were much more frequent in the supine and left and right lateral decubitus positions than in the prone and sitting positions and normalized in the last two positions in patients with BrS. RMS40 variance by postural change was significantly larger in the coved group than in the saddle back group. Determinate LP improved in the sitting position compared to the supine position in the coved group. CONCLUSIONS: Positive LP findings normalized in the sitting position in patients in the coved BrS group with a resuscitation history, suggesting that depolarization instability might be related to the risk of fatal ventricular arrhythmia. Posture-induced LP variance should be examined using HR-ambulatory ECG analysis in patients with BrS. PMID- 25545663 TI - Influence of methyl mercaptan on the repair bond strength of composites fabricated using self-etch adhesives. AB - The influence of methyl mercaptan on the repair bond strength of composites fabricated using self-etch adhesives was investigated. The surface free-energies were determined by measuring the contact angles of test liquids placed on composites that had been immersed in different concentrations of methyl mercaptan (0.01, 0.1, and 1.0 M). To determine the repair bond strength, self-etch adhesives were applied to the aged composite, and then newly added composites were condensed. Ten samples of each specimen were subjected to shear testing at a crosshead speed of 1.0 mm min(-1). Samples were analyzed using two-way ANOVA followed by Tukey's honestly significant difference (HSD) test. Although the dispersion force of the composites remained relatively constant, their polar force increased slightly as the concentration of methyl mercaptan increased. The hydrogen-bonding forces were significantly higher after immersion in 1.0 M methyl mercaptan, leading to higher surface-free energies. However, the repair bond strengths for the repair restorations prepared from composites immersed in 1.0 M methyl mercaptan were significantly lower than for those immersed in 0.01 and 0.10 M methyl mercaptan. Considering the results of this study, it can be concluded that the repair bond strengths of both the aged and newly added composites were affected by immersion in methyl mercaptan solutions. PMID- 25545664 TI - Chemical composition of yak colostrum and transient milk. AB - The objective of this study was to assess the changes in the chemical composition of yak colostrum and transient milk. Samples were collected from 12 yaks on days 1, 2, 3, 4, 5, 6 and 7 post-partum (PP). The gross composition, nitrogen fraction distribution, amino acid (AA) profile and fatty acid (FA) profile were analysed. All the components decreased rapidly during the first 3 days except lactose which increased. The ratio of whey protein to casein protein decreased from 46:54 to 17:83 during the first 7 days PP. The content of all the AAs decreased, while the percentages of eight essential AAs in protein of samples increased during the study period. Monounsaturated FAs and polyunsaturated FAs decreased in the first 7 days PP, whereas saturated FAs increased. In conclusion, the changes in chemical composition were remarkable during the first 3 days. The slight variations, happened during the transient period, are not negligible, which also should be taken into account in the development of yak colostrum supplements. PMID- 25545665 TI - Management and follow-up of urothelial neoplasms of the bladder in children: a report from the TREP project. AB - BACKGROUND: Urothelial neoplasms of the bladder (UNB) are rare in patients under 20 years of age, and even rarer in the first decade of life. The present series was investigated to provide recommendations on patient management in terms of therapeutic strategy and follow-up. PROCEDURE: This is a retrospective analysis on 12 patients with UNB under 18 years of age. Data were extracted from the national database of the TREP (Tumori Rari in Eta Pediatrica) Project. RESULTS: Ten of the 12 patients presented with a single episode of hematuria, while the discovery of the lesion was incidental in two. Eleven of the 12 lesions were G1 and one was G2/G3; none of the lesions invaded the lamina propria. All lesions were removed completely by transurethral resection. No further treatment was administered in nine children but three received a single dose of intravesical chemotherapy (epirubicin in 2, mitomycin in 1). Only one patient experienced a recurrence and all patients are alive in complete remission with a median follow up of 30 months (range 4-112). Follow-up investigations varied at the different centers and included abdominal ultrasound in nine patients, cystoscopy in seven, and additional radiological investigations in a few cases. CONCLUSIONS: UNB in children seems to be a low-grade, scarcely aggressive disease with an excellent prognosis. The role of intravesical chemotherapy is debatable. Follow-up can be based on ultrasound. The adoption of shared recommendations should enable unnecessary treatment and invasive investigations to be avoided. PMID- 25545666 TI - Quantitative shearing linear amplification polymerase chain reaction: an improved method for quantifying lentiviral vector insertion sites in transplanted hematopoietic cell systems. AB - In gene therapy trials targeting blood disorders, it is important to detect dominance of transduced hematopoietic stem cell (HSC) clones arising from vector insertion site (VIS) effects. Current methods for VIS analysis often do not have defined levels of quantitative accuracy and therefore can fail to detect early clonal dominance. We have developed a rapid and inexpensive method for measuring clone size based on random shearing of genomic DNA, minimal exponential PCR amplification, and shear site counts as a quantitative endpoint. This quantitative shearing linear amplification PCR (qsLAM PCR) assay utilizes an internal control sample containing 19 lentiviral insertion sites per cell that is mixed with polyclonal samples derived from transduced human CD34+ cells. Samples were analyzed from transplanted pigtail macaques and from a participant in our X linked severe combined immunodeficiency (XSCID) lentiviral vector trial and yielded controlled and quantitative results in all cases. One case of early clonal dominance was detected in a monkey transplanted with limiting numbers of transduced HSCs, while the clinical samples from the XSCID trial participant showed highly diverse clonal representation. These studies demonstrate that qsLAM PCR is a facile and quantitative assay for measuring clonal repertoires in subjects enrolled in human gene therapy trials using lentiviral-transduced HSCs. PMID- 25545667 TI - Nonadiabatic dynamics of photoinduced proton-coupled electron transfer in a solvated phenol-amine complex. AB - Photoinduced concerted electron-proton transfer (EPT), denoted photo-EPT, is important for a wide range of energy conversion processes. Transient absorption and Raman spectroscopy experiments on the hydrogen-bonded p-nitrophenylphenol-t butylamine complex, solvated in 1,2-dichloroethane, suggested that this complex may undergo photo-EPT. The experiments probed two excited electronic states that were interpreted as an intramolecular charge transfer (ICT) state and an EPT state. Herein mixed quantum mechanical/molecular mechanical nonadiabatic surface hopping dynamics is used to investigate the relaxation pathways following photoexcitation. The potential energy surface is generated on the fly with a semiempirical floating occupation molecular orbital complete active space configuration interaction method for the solute molecule and a molecular mechanical force field for the explicit solvent molecules. The free energy curves along the proton transfer coordinate illustrate that proton transfer is thermodynamically and kinetically favorable on the lower-energy excited state but not on the higher-energy excited state, supporting the characterization of these states as EPT and ICT, respectively. The nonadiabatic dynamics simulations indicate that the population decays from the ICT state to the EPT state in ~100 fs and from the EPT state to the ground state on the slower time scale of ~1 ps, qualitatively consistent with the experimental measurements. For ~54% of the trajectories, the proton transfers from the phenol to the amine in ~400 fs on the EPT state and then transfers back to the phenol rapidly upon decay to the ground state. Thus, these calculations augment the original interpretation of the experimental data by providing evidence of proton transfer on the EPT state prior to decay to the ground state. The fundamental insights obtained from these simulations are also relevant to other photo-EPT processes. PMID- 25545668 TI - Entropy-based financial asset pricing. AB - We investigate entropy as a financial risk measure. Entropy explains the equity premium of securities and portfolios in a simpler way and, at the same time, with higher explanatory power than the beta parameter of the capital asset pricing model. For asset pricing we define the continuous entropy as an alternative measure of risk. Our results show that entropy decreases in the function of the number of securities involved in a portfolio in a similar way to the standard deviation, and that efficient portfolios are situated on a hyperbola in the expected return-entropy system. For empirical investigation we use daily returns of 150 randomly selected securities for a period of 27 years. Our regression results show that entropy has a higher explanatory power for the expected return than the capital asset pricing model beta. Furthermore we show the time varying behavior of the beta along with entropy. PMID- 25545669 TI - How nurse managers in Japanese hospital wards manage patient violence toward their staff. AB - AIM: This study explores nurse managers' experiences in dealing with patient/family violence toward their staff. BACKGROUND: Studies and guidelines have emphasised the responsibility of nurse managers to manage violence directed at their staff. Although studies on nursing staff have highlighted the ineffectiveness of strategies used by nurse managers, few have explored their perspectives on dealing with violence. METHODS: This qualitative study adopted a grounded theory approach to explore the experiences of 26 Japanese nurse managers. RESULTS: The nurse managers made decisions using internalised ethical values, which included maintaining organisational functioning, keeping staff safe, advocating for the patient/family and avoiding moral transgressions. They resolved internal conflicts among their ethical values by repeating a holistic assessment and simultaneous approach consisting of damage control and dialogue. They facilitated the involved persons' understanding, acceptance and sensemaking of the incident, which contributed to a resolution of the internal conflicts among their ethical values. CONCLUSIONS: Nurse managers adhere to their ethical values when dealing with patient violence toward nurses. Their ethical decision making process should be acknowledged as an effective strategy to manage violence. IMPLICATIONS FOR NURSING MANAGEMENT: Organisational strategies that support and incorporate managers' ethical decision-making are needed to prevent and manage violence toward nurses. PMID- 25545670 TI - Photoinduced smart, self-healing polymer sealant for photovoltaics. AB - Polyisobutylene (PIB)-based polymer networks potentially useful as smart coatings for photovoltaic devices have been developed. Low molecular weight coumarin functional triarm star PIB was synthesized via a single step SN2 reaction of bromoallyl functional triarm star PIB with 4-methylumbelliferone or umbelliferone in the presence of sodium hydride. Quantitative end functionality was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. UVA (lambdamax = 365 nm) induced reversible photodimerization of the coumarin moieties resulted in cross-linked elastomeric films exhibiting self-healing behavior. The extent of photodimerization/photoscission was monitored by UV-vis spectroscopy. The low oxygen (1.9 * 10(-16) mol m m(-2) s(-1) Pa(-1)) and moisture (46 * 10(-16) mol m m(-2) s(-1) Pa(-1)) permeability of the cross-linked polymer films suggest excellent barrier properties of the cross-linked polymer films. The self-healing process was studied by atomic force microscopy (AFM). For this, mechanical cuts were introduced in the cross-linked PIB films through micromachining with an AFM tip and the rate of healing induced by UV, sunlight, or both was followed by taking AFM images of the film at different time intervals during the repair process. PMID- 25545671 TI - Juvenile slow progressive antineutrophil cytoplasmic antibody-associated vasculitis diagnosed after kidney transplantation: a case report. PMID- 25545672 TI - Apolipoprotein E gene polymorphisms in relation to chronic periodontitis, periodontopathic bacteria, and lipid levels. AB - OBJECTIVE: Inflammatory periodontal diseases may be associated with common systemic conditions and, as recently described, alterations in lipid levels in the blood. The aim of this study was to determine the possible effects of apolipoprotein E (ApoE) genotypes on the lipid levels in healthy people and patients with chronic periodontitis (CP) in relation to periodontopathic bacteria. DESIGN: This case-control study comprised 469 unrelated subjects. The genomic DNA of 294 patients with CP and 175 healthy/non-periodontitis controls were genotyped, using the real-time polymerase chain reaction (RT-PCR) method, for ApoE (rs429358 and rs7412) gene polymorphisms. Subgingival bacterial colonization was investigated by the DNA microarray using a periodontal pathogen detection kit and lipid levels were measured in a subgroup of subjects (N = 275). RESULTS: There was no evidence for a significant association between ApoE gene polymorphisms and CP (P > 0.05). Patients with CP had increased levels of total cholesterol and low-density lipoprotein (LDL) compared to controls (P< 0.05); however, no significant difference was found for triglyceride and high-density lipoprotein (HDL) levels. ApoE gene variability influenced LDL levels marginally (P = 0.08) but it did not modify total cholesterol, triglyceride, and HDL levels or the occurrence of periodontal pathogens in subgingival pockets.(23) CONCLUSIONS: In the Czech population studied, ApoE genetic variations were not associated with susceptibility to CP or the presence of periodontopathic bacteria. PMID- 25545673 TI - The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial. AB - The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts <350 cells/mm3 and plasma HIV RNA levels <40 copies/ml on antiretroviral therapy (ART) to add mesalamine vs. placebo to their existing regimen for 12 weeks followed by a 12 week crossover to the other arm. Compared to placebo-treated subjects, mesalamine treated subjects did not experience any significant change in the percent CD38+HLA-DR+ peripheral blood CD4+ and CD8+ T cells at week 12 (P = 0.38 and P = 0.63, respectively), or in the CD4+ T cell count at week 12 (P = 0.83). The percent CD38+HLA-DR+ CD4+ and CD8+ T cells also did not change significantly in rectal tissue (P = 0.86, P = 0.84, respectively). During the period of mesalamine administration, plasma sCD14, IL-6, D-dimer, and kynurenine to tryptophan ratio were not changed significantly at week 12 and were similarly unchanged at week 24. This study suggests that, at least under the conditions studied, the persistent immune activation associated with HIV infection is not impacted by the anti-inflammatory effects of mesalamine. TRIAL REGISTRATION: ClinicalTrials.gov NCT01090102. PMID- 25545675 TI - Molecular detection of invertebrate prey in vertebrate diets: trophic ecology of Caribbean island lizards. AB - Understanding community assembly and population dynamics frequently requires detailed knowledge of food web structure. For many consumers, obtaining precise information about diet composition has traditionally required sacrificing animals or other highly invasive procedures, generating tension between maintaining intact study populations and knowing what they eat. We developed 16S mitochondrial DNA sequencing methods to identify arthropods in the diets of generalist vertebrate predators without requiring a blocking primer. We demonstrate the utility of these methods for a common Caribbean lizard that has been intensively studied in the context of small island food webs: Anolis sagrei (a semi-arboreal 'trunk-ground' anole ecomorph). Novel PCR primers were identified in silico and tested in vitro. Illumina sequencing successfully characterized the arthropod component of 168 faecal DNA samples collected during three field trips spanning 12 months, revealing 217 molecular operational taxonomic units (mOTUs) from at least nine arthropod orders (including Araneae, Blattodea, Coleoptera, Hemiptera, Hymenoptera, Isoptera, Lepidoptera and Orthoptera). Three mOTUs (one beetle, one cockroach and one ant) were particularly frequent, occurring in >=50% of samples, but the majority of mOTUs were infrequent (180, or 83%, occurred in <=5% of samples). Species accumulation curves showed that dietary richness and composition were similar between size dimorphic sexes; however, female lizards had greater per-sample dietary richness than males. Overall diet composition (but not richness) was significantly different across seasons, and we found more pronounced interindividual variation in December than in May. These methods will be generally useful in characterizing the diets of diverse insectivorous vertebrates. PMID- 25545674 TI - DNA methylation analysis of the macrosatellite repeat associated with FSHD muscular dystrophy at single nucleotide level. AB - Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited diseases of the skeletal muscle. It is characterized by asymmetric muscle weakness and variable penetrance. FSHD is linked to a reduction in copy number of the D4Z4 3.3 kb macrosatellite repeat, located in 4q35. This causes the epigenetic de-repression of FSHD candidate genes leading to disease. Nevertheless, the molecular mechanism responsible for silencing of FSHD candidate genes in healthy subjects is not fully understood. While a role for DNA methylation has been suggested, so far there is limited information regarding the methylation status of the 325 CpGs contained in each D4Z4 unit. Using a human/rodent monochromosomal hybrid cell line containing a single human chromosome 4, we performed an in depth analysis of DNA methylation for the majority of the CpGs inside D4Z4 at single nucleotide level. We found that D4Z4 is not uniformly methylated and that the level of DNA methylation does not correlate with the density of CpG dinucleotides. Moreover, in several D4Z4 regions characterized by near complete methylation, we found specific unmethylated CpGs. These elements are enriched in transcription factor binding sites that could be involved in muscle-specific D4Z4 activity. Our approach also detected differential methylation among different D4Z4 units, suggesting that the D4Z4 array is a mosaic of euchromatic and heterochromatic domains. Finally, we found that DNA methylation and histone de-acetylation are required to maintain FSHD candidate genes repressed. Taken together, our data underscore new players involved in the epigenetic regulation of the FSHD locus that could be targeted for therapeutic purposes. PMID- 25545676 TI - Central line bloodstream infections can be reduced in newborn infants using the modified Seldinger technique and care bundles of preventative measures. AB - AIM: There has been no evidence to show whether care bundles of preventive measures reduce central line-associated bloodstream infection (CLABSI) in peripherally inserted central catheters using the modified Seldinger technique, which requires more specific skills than the traditional technique. The aim of this study was to address that gap in our knowledge and to determine whether other variables influenced the outcome. METHODS: This prospective observational study was conducted on a neonatal intensive care unit. We observed the incidence of CLABSI in 45 newborn infants with peripheral catheters before the introduction of bundles of preventative measures and 88 infants after the introduction. RESULTS: Laboratory-confirmed CLABSI decreased after the introduction of the bundles, from 12.9 per 1000 days to 4.7/1000 days (p = 0.09). When we combined the rates for laboratory-confirmed CLABSI and clinical CLABSI in a survival analysis, the incidence reduced significantly after introduction of the bundles (p = 0.02). There were no other variables that affected the outcome. CONCLUSION: Cost-effective care bundles reduced CLABSI in peripherally inserted central catheters using the modified Seldinger technique, despite the specific insertion skills that were required. The bundles of preventative measures may increase healthcare professionals' awareness of the need to care for central catheters and reduce CLABSI infections. PMID- 25545678 TI - A DFT study of the unusual substrate-assisted mechanism of Serratia marcescens chitinase B reveals the role of solvent and mutational effect on catalysis. AB - Serratia marcescens chitinase B (SmChiB) catalyzes the hydrolysis of beta-1,4 glycosidic bond, via an unusual substrate-assisted mechanism, in which the substrate itself acts as an intramolecular nucleophile. In this paper, the catalytic mechanism of SmChiB has been investigated by using density functional theory. The details of two consecutive steps (glycosylation and deglycosylation), the structures and energetics along the whole catalytic reaction, and the roles of solvent molecules as well as some conserved SmChiB residues (Asp142, Tyr214, Asp215, and Arg294) during catalysis are highlighted. Our calculations show that the formation of the oxazolinium cation intermediate in the glycosylation step was found to be a rate-determining step (with a barrier of 23 kcal/mol), in line with our previous computational studies (Jitonnom et al., 2011, 2014). The solvent water molecules have a significant effect on a catalytic efficiency in the degycosylation step: the catalytic water is essentially placed in a perfect position for nucleophic attack by hydrogen bond network, lowering the barrier height of this step from 11.3 kcal/mol to 2.9 kcal/mol when more water molecules were introduced. Upon the in silico mutations of the four conserved residues, their mutational effects on the relative stability of the reaction intermediates and the computed energetics can be obtained by comparing with the wild-type results. Mutations of Tyr214 to Phe or Ala have shown a profound effect on the relative stability of the oxazolinium intermediate, emphasizing a direct role of this residue in destabilizing the intermediate. In line with the experiment that the D142A mutation leads to almost complete loss of SmChiB activity, this mutation greatly decreases the stability of the intermediate, resulting in a very large increase in the activation barrier up to 50 kcal/mol. The salt-bridges residues (Asp215 and Arg294) were also found to play a role in stabilizing the oxazolinium intermediate. PMID- 25545677 TI - Elimination of African onchocerciasis: modeling the impact of increasing the frequency of ivermectin mass treatment. AB - The African Programme for Onchocerciasis Control (APOC) is currently shifting its focus from morbidity control to elimination of infection. To enhance the likelihood of elimination and speed up its achievement, programs may consider to increase the frequency of ivermectin mass treatment from annual to 6-monthly or even higher. In a computer simulation study, we examined the potential impact of increasing the mass treatment frequency for different settings. With the ONCHOSIM model, we simulated 92,610 scenarios pertaining to different assumptions about transmission conditions, history of mass treatment, the future mass treatment strategy, and ivermectin efficacy. Simulation results were used to determine the minimum remaining program duration and number of treatment rounds required to achieve 99% probability of elimination. Doubling the frequency of treatment from yearly to 6-monthly or 3-monthly was predicted to reduce remaining program duration by about 40% or 60%, respectively. These reductions come at a cost of additional treatment rounds, especially in case of 3-monthly mass treatment. Also, aforementioned reductions are highly dependent on maintained coverage, and could be completely nullified if coverage of mass treatment were to fall in the future. In low coverage settings, increasing treatment coverage is almost just as effective as increasing treatment frequency. We conclude that 6-monthly mass treatment may only be worth the effort in situations where annual treatment is expected to take a long time to achieve elimination in spite of good treatment coverage, e.g. because of unfavorable transmission conditions or because mass treatment started recently. PMID- 25545679 TI - A simple, sensitive and safe method to determine the human alpha/beta-tryptase genotype. AB - The human tryptase locus on chromosome 16 contains one gene encoding only beta tryptase and another encoding either beta-tryptase or the homologous alpha tryptase, providing alpha:beta gene ratios of 0:4, 1:3 or 2:2 in the diploid genome, these genotypes being of potential clinical relevance in severe atopy. Using an EcoRV restriction site in alpha- but not beta-tryptase, PCR products, spanning intron 1 to exon 5, were used to determine alpha/beta-tryptase gene ratios using non-radioactive labels, including ethidium bromide labeling of all PCR products, and either digoxigenin-primer or DY682-primer labeling of only the final PCR cycle products. Sensitivity increased ~60-fold with each final PCR cycle labeling technique. Ethidium bromide labeling underestimated amounts of alpha-tryptase, presumably because heteroduplexes of alpha/beta-tryptase amplimers, formed during annealing, were EcoRV resistant. In contrast, both final PCR cycle labeling techniques precisely quantified these gene ratios, because only homoduplexes were labeled. Using the DY682-primer was most efficient, because PCR/EcoRV products could be analyzed directly in the gel; while digoxigenin-labeled products required transfer to a nitrocellulose membrane followed by immunoblotting. This technique for determining the alpha/beta tryptase genotype is sensitive, accurate, simple and safe, and should permit high throughput screening to detect potential phenotype-genotype relations for alpha/beta-tryptases, and for other closely related alleles. PMID- 25545680 TI - Elevated frequencies of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells, and increased levels of IL-21 in bleomycin-induced mice may be associated with dermal and pulmonary inflammation and fibrosis. AB - AIM: Systemic sclerosis (SSc) is characterized by immune abnormalities, progressive fibrosis of the skin and internal organs, and microvascular injury and damage. Interleukin-21 receptor (IL-21R) is expressed in the epidermis from patients with SSc. However, information describing the role of IL-21 in SSc is limited. METHODS: We established a mouse model of bleomycin (BLM)-induced fibrosis. The frequency of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells in peripheral blood, skin and lungs of BLM-induced mice were detected by flow cytometry; IL-21 levels in the peripheral blood were evaluated by enzyme linked immunosorbent assay (ELISA). CD4(+) T cells were isolated from the spleen of BLM-induced and control mice and cultured in vitro alone or in the presence of mrIL-21 or mrIL-21 plus transforming growth factor (TGF)-beta1. The frequency of Th17 cells was detected by flow cytometry; levels of IL-17 were evaluated by ELISA, and the expression of IL-17A and retinoic-acid-receptor-related orphan receptors gamma t (RORgammat) messenger RNA were analyzed by real-time polymerase chain reaction. RESULTS: Compared to control mice, the frequency of CD4(+) IL 21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were significantly increased in BLM-induced mice. The frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were correlated with dermal and pulmonary inflammation and fibrosis. In vitro analyses indicate that IL-21 promoted the differentiation of Th17 cells from CD4(+) cells isolated from the spleen of BLM-induced mice. CONCLUSION: IL-21 may play an important role in the pathogenesis of SSc as a Th17 effector cytokine, and IL-21 may induce the differentiation of Th17 cells in the BLM-induced SSc mouse model. PMID- 25545681 TI - Characterization of the fast GABAergic inhibitory action of etifoxine during spinal nociceptive processing in male rats. AB - Etifoxine (EFX) is a non-benzodiazepine anxiolytic which potentiate GABAA receptor (GABAAR) function directly or indirectly via the production of 3alpha reduced neurosteroids. The later effect is now recognized to account for the long term reduction of pain symptoms in various neuropathic and inflammatory pain models. In the present study, we characterized the acute antinociceptive properties of EFX during spinal pain processing in naive and monoarthritic rats using in vivo electrophysiology. The topical application of EFX on lumbar spinal cord segment, at concentrations higher than 30 MUM, reduced the excitability of wide dynamic range neurons receiving non-nociceptive and nociceptive inputs. Windup discharge resulting from the repetitive stimulation of the peripheral receptive field, and recognized as a short-term plastic process seen in central nociceptive sensitization, was significantly inhibited by EFX at these concentrations. In good agreement, mechanical nociceptive thresholds were also significantly increased following an acute intrathecal injection of EFX. The acute modulatory properties of EFX on spinal pain processing were never seen in the simultaneous presence of bicuculline. This result further confirmed EFX antinociception to result from the potentiation of spinal GABAA receptor function. PMID- 25545683 TI - The role of emotion regulation and cognitive control in the association between mindfulness disposition and stress. AB - Dispositional mindfulness is associated with lower levels of perceived stress, with increased emotional regulation and cognitive control proposed as mechanisms underlying these stress-buffering effects of mindfulness. Within aging, these controlled processes represent paradoxically divergent trajectories such that older adults exhibit reduced cognitive control capacities, while emotional regulation abilities are well maintained, and at times enhanced. Our study seeks to examine the role of emotional regulation and cognitive control as possible mediators of the association between mindfulness and perceived stress. In addition, we examined age-related differences in the observed associations among mindfulness, stress, and controlled regulatory behavior. Fifty older adults and fifty young adults were recruited for the study and completed self-report measures assessing mindfulness disposition, perceived stress, and emotional regulation. In addition, computerized measures of cognitive control assessing working memory, inhibitory control, and set-shifting were also administered. We hypothesized a negative correlation between mindfulness disposition and perceived stress such that participants reporting higher levels of dispositional mindfulness would report lower stress. In addition, we hypothesized increased difficulties in emotion regulation and lower cognitive control to mediate this relationship. Corroborating previous literature, results revealed that mindfulness disposition and perceived stress were negatively correlated in both groups. However, emotion regulation, but not cognitive control, was found to mediate the relationship between mindfulness and perceived stress in both groups. Age group was not found to moderate the observed effects. Our findings reveal the role of enhanced emotional regulation abilities as a potential factor associated with the stress-reducing capacity of dispositional mindfulness. PMID- 25545682 TI - Mycobacterium marinum MgtC plays a role in phagocytosis but is dispensable for intracellular multiplication. AB - MgtC is a virulence factor involved in intramacrophage growth that has been reported in several intracellular pathogens, including Mycobacterium tuberculosis and Salmonella enterica serovar Typhimurium. MgtC participates also in adaptation to Mg2+ deprivation. Herein, we have constructed a mgtC mutant in Mycobacterium marinum to further investigate the role of MgtC in mycobacteria. We show that the M. marinum mgtC gene (Mma mgtC) is strongly induced upon Mg2+ deprivation and is required for optimal growth in Mg2+-deprived medium. The behaviour of the Mma mgtC mutant has been investigated in the Danio rerio infection model using a transgenic reporter zebrafish line that specifically labels neutrophils. Although the mgtC mutant is not attenuated in the zebrafish embryo model based on survival curves, our results indicate that phagocytosis by neutrophils is enhanced with the mgtC mutant compared to the wild-type strain following subcutaneous injection. Increased phagocytosis of the mutant strain is also observed ex vivo with the murine J774 macrophage cell line. On the other hand, no difference was found between the mgtC mutant and the wild-type strain in bacterial adhesion to macrophages and in the internalization into epithelial cells. Unlike the role reported for MgtC in other intracellular pathogens, Mma MgtC does not contribute significantly to intramacrophage replication. Taken together, these results indicate an unanticipated function of Mma MgtC at early step of infection within phagocytic cells. Hence, our results indicate that although the MgtC function is conserved among pathogens regarding adaptation to Mg2+ deprivation, its role towards phagocytic cells can differ, possibly in relation with the specific pathogen's lifestyles. PMID- 25545684 TI - Cardiovascular perforation during placement of an Avalon Elite(r) Bicaval dual lumen ECMO cannula in a newborn. AB - Proper functioning of the Avalon Elite(r) bicaval dual lumen ECMO cannula (Maquet Cardiovascular, Wayne, NJ, USA) requires precise placement of the distal draining port within the lumen of the inferior vena cava (IVC). In order to advance the cannula to the correct position, a 0.038" guidewire is placed into the IVC under echocardiographic or fluoroscopic guidance. We report a case of perforation of the intrapericardiac section of the IVC by the guidewire in a neonate, not detected at the time of placement, resulting in cardiac tamponade and death. We recommend routine echocardiographic surveillance after placement of Avalon Elite(r) cannulas to rule out hemopericardium. PMID- 25545685 TI - Lewis Sheiner ISoP/UCSF Lecturer Award: From Drug Use to Statistical Models and Vice Versa. AB - I was very honored to receive the University of California, San Francisco, and the International Society of Pharmacometrics Lewis Sheiner lecturer award in May 2013. In the present perspective, I outline the main points of my lecture at the American Conference of Pharmacometrics (slides in Supplementary Material 1). I first emphasize the scientific contributions of Lewis Sheiner as a quantitative pharmacologist toward the better use of drugs. I then focus on three statistical topics in pharmacometrics, describing Lewis Sheiner's impact and my own contributions and interactions with him. PMID- 25545686 TI - The variation of root exudates from the hyperaccumulator Sedum alfredii under cadmium stress: metabonomics analysis. AB - Hydroponic experiments were conducted to investigate the variation of root exudates from the hyperaccumulator Sedum alfredii under the stress of cadmium (Cd). S. alfredii was cultured for 4 days in the nutrient solution spiked with CdCl2 at concentrations of 0, 5, 10, 40, and 400 uM Cd after the pre-culture. The root exudates were collected and analyzed by GC-MS, and 62 compounds were identified. Of these compounds, the orthogonal partial least-squares discrimination analysis (OPLS-DA) showed that there were a distinct difference among the root exudates with different Cd treatments and 20 compounds resulting in this difference were found out. Changing tendencies in the relative content of these 20 compounds under the different Cd treatments were analyzed. These results indicated that trehalose, erythritol, naphthalene, d-pinitol and n-octacosane might be closely related to the Cd stabilization, phosphoric acid, tetradecanoic acid, oxalic acid, threonic acid and glycine could be attributed to the Cd mobilization, and mannitol, oleic acid, 3-hydroxybutanoic acid, fructose, octacosanol and ribitol could copy well with the Cd stress. PMID- 25545687 TI - Recruitment of activating NK-cell receptors 2B4 and NKG2D to membrane microdomains in mammalian cells is dependent on their transmembrane regions. AB - Membrane microdomains play an important role in the regulation of natural killer (NK) cell activities. These cholesterol-rich membrane domains are enriched at the activating immunological synapse and several activating NK-cell receptors are known to localize to membrane microdomains upon receptor engagement. In contrast, inhibitory receptors do not localize in these specialized membrane domains. In addition, the functional competence of educated NK cells correlates with a confinement of activating receptors in membrane microdomains. However, the molecular basis for this confinement is unknown. Here, we investigate the structural requirements for the recruitment of the human-activating NK-cell receptors NKG2D and 2B4 to detergent-resistant membrane fractions in the murine BA/F3 cell line and in the human NK-cell line NKL. This stimulation-dependent recruitment occurred independently of the intracellular domains of the receptors. However, either interfering with the association between NKG2D and DAP10, or mutating the transmembrane region of 2B4 impacted the recruitment of the receptors to detergent-resistant membrane fractions and modulated the function of 2B4 in NK cells. Our data suggest a potential interaction between the transmembrane region of NK-cell receptors and membrane lipids as a molecular mechanism involved in determining the membrane confinement of activating NK-cell receptors. PMID- 25545688 TI - An uncommon primary lung tumour: hyalinizing clear cell carcinoma, salivary gland type. PMID- 25545689 TI - VennDIS: a JavaFX-based Venn and Euler diagram software to generate publication quality figures. AB - Venn diagrams are graphical representations of the relationships among multiple sets of objects and are often used to illustrate similarities and differences among genomic and proteomic datasets. All currently existing tools for producing Venn diagrams evince one of two traits; they require expertise in specific statistical software packages (such as R), or lack the flexibility required to produce publication-quality figures. We describe a simple tool that addresses both shortcomings, Venn Diagram Interactive Software (VennDIS), a JavaFX-based solution for producing highly customizable, publication-quality Venn, and Euler diagrams of up to five sets. The strengths of VennDIS are its simple graphical user interface and its large array of customization options, including the ability to modify attributes such as font, style and position of the labels, background color, size of the circle/ellipse, and outline color. It is platform independent and provides real-time visualization of figure modifications. The created figures can be saved as XML files for future modification or exported as high-resolution images for direct use in publications. PMID- 25545690 TI - Use of provider-level dashboards and pay-for-performance in venous thromboembolism prophylaxis. AB - BACKGROUND: Despite safe and cost-effective venous thromboembolism (VTE) prevention measures, VTE prophylaxis rates are often suboptimal. Healthcare reform efforts emphasize transparency through programs to report performance and payment incentives through pay-for-performance programs. OBJECTIVE: To sequentially examine an individualized physician dashboard and pay-for performance program to improve VTE prophylaxis rates among hospitalists. DESIGN: Retrospective analysis of 3144 inpatient admissions. After a baseline observation period, VTE prophylaxis compliance was compared during both interventions. SETTING: A 1060-bed tertiary care medical center. PARTICIPANTS: Thirty-eight part time and full-time academic hospitalists. INTERVENTIONS: A Web-based hospitalist dashboard provided VTE prophylaxis feedback. After 6 months of feedback only, a pay-for-performance program was incorporated, with graduated payouts for compliance rates of 80% to 100%. MEASUREMENTS: Prescription of American College of Chest Physicians' guideline-compliant VTE prophylaxis and subsequent pay-for performance payments. RESULTS: Monthly VTE prophylaxis compliance rates were 86% (95% confidence interval [CI]: 85-88), 90% (95% CI: 88-93), and 94% (95% CI: 93 96) during the baseline, dashboard, and combined dashboard/pay-for-performance periods, respectively. Compliance significantly improved with the use of the dashboard (P = 0.01) and addition of the pay-for-performance program (P = 0.01). The highest rate of improvement occurred with the dashboard (1.58%/month; P = 0.01). Annual individual physician performance payments ranged from $53 to $1244 (mean $633; standard deviation +/-$350). CONCLUSIONS: Direct feedback using dashboards was associated with significantly improved compliance, with further improvement after incorporating an individual physician pay-for-performance program. Real-time dashboards and physician-level incentives may assist hospitals in achieving higher safety and quality benchmarks. PMID- 25545692 TI - Changes in glucose fermentation pathways by an enriched bacterial culture in response to regulated dissolved H2 concentrations. AB - It is well established that metabolic pathways in the fermentation of organic waste are primarily controlled by dissolved H2 concentrations, but there is no reported study that compares observed and predicted shifts in fermentation pathways induced by manipulating the dissolved H2 concentration. A perfusion system is presented that was developed to control dissolved H2 concentrations in the continuous fermentation of glucose by a culture highly enriched towards Thermoanaerobacterium thermosaccharolyticum (86 +/- 9% relative abundance) from an originally diverse consortia in the leachate of a laboratory digester fed with municipal solid waste. Media from a 2.5 L CSTR was drawn through sintered steel membrane filters to retain biomass, allowing vigorous sparging in a separate chamber without cellular disruption. Through a combination of sparging and variations in glucose feeding rate from 0.8 to 0.2 g/L/d, a range of steady state fermentations were performed with dissolved H2 concentrations as low as an equivalent equilibrated H2 partial pressure of 3 kPa. Trends in product formation rates were simulated using a H2 regulation partitioning model. The model correctly predicted the direction of products redistribution in response to H2 concentration changes and the acetate and butyrate formation rates when H2 concentrations were less than 6 kPa. However, the model over-estimated acetate, ethanol and butanol productions at the expense of butyrate production at higher H2 concentrations. The H2 yield at the lowest dissolved H2 concentration was 2.67 +/- 0.08 mol H2 /mol glucose, over 300% higher than the yield achieved in a CSTR operated without sparging. PMID- 25545693 TI - The Thin Reed: Accommodating Weak Evidence for Critical Parameters in Cost Benefit Analysis. AB - Policy analysis often demands quantitative prediction-especially cost-benefit analysis, which requires the comprehensive quantification and monetization of all valued impacts. Using parameter estimates and their precisions, analysts can apply Monte Carlo simulation to create distributions of net benefits that convey the levels of certainty about the fundamental question of interest: Will net benefits be positive if the policy is adopted? An inappropriate focus on hypothesis testing of parameters rather than prediction sometimes leads analysts to treat statistically insignificant coefficients as if they, and their standard errors, are zero. One alternative method is to use all estimates and their standard errors whether or not the estimates are statistically significant. Another alternative is to use all estimates but to shrink them toward zero and adjust their standard errors in an effort to guard against regression to the mean. Comparing the three methods (only use statistically significant estimates and their standard errors, use all estimates and their standard errors, use shrunk estimates and adjusted standard errors) in Monte Carlo simulation suggests that treating statistically insignificant coefficients as zero rarely minimizes the mean squared error of prediction. Using shrunk estimates appears to provide a more robust minimization of the mean squared error of prediction. The simulations presented here suggest that routinely shrinking estimates is a robust approach if one believes that there is a substantial probability that the true value of the parameter is near zero. PMID- 25545691 TI - Enhancing in silico protein-based vaccine discovery for eukaryotic pathogens using predicted peptide-MHC binding and peptide conservation scores. AB - Given thousands of proteins constituting a eukaryotic pathogen, the principal objective for a high-throughput in silico vaccine discovery pipeline is to select those proteins worthy of laboratory validation. Accurate prediction of T-cell epitopes on protein antigens is one crucial piece of evidence that would aid in this selection. Prediction of peptides recognised by T-cell receptors have to date proved to be of insufficient accuracy. The in silico approach is consequently reliant on an indirect method, which involves the prediction of peptides binding to major histocompatibility complex (MHC) molecules. There is no guarantee nevertheless that predicted peptide-MHC complexes will be presented by antigen-presenting cells and/or recognised by cognate T-cell receptors. The aim of this study was to determine if predicted peptide-MHC binding scores could provide contributing evidence to establish a protein's potential as a vaccine. Using T-Cell MHC class I binding prediction tools provided by the Immune Epitope Database and Analysis Resource, peptide binding affinity to 76 common MHC I alleles were predicted for 160 Toxoplasma gondii proteins: 75 taken from published studies represented proteins known or expected to induce T-cell immune responses and 85 considered less likely vaccine candidates. The results show there is no universal set of rules that can be applied directly to binding scores to distinguish a vaccine from a non-vaccine candidate. We present, however, two proposed strategies exploiting binding scores that provide supporting evidence that a protein is likely to induce a T-cell immune response-one using random forest (a machine learning algorithm) with a 72% sensitivity and 82.4% specificity and the other, using amino acid conservation scores with a 74.6% sensitivity and 70.5% specificity when applied to the 160 benchmark proteins. More importantly, the binding score strategies are valuable evidence contributors to the overall in silico vaccine discovery pool of evidence. PMID- 25545694 TI - Variability in early do not attempt resuscitation orders among patients with serious traumatic brain injury. AB - OBJECTIVES: The objective was describe the use of early do not attempt resuscitation (DNAR) orders in patients with serious traumatic brain injury (TBI) and its association with outcomes. METHODS: This was a retrospective cohort study of all serious TBI patients admitted through the emergency department (ED) to acute care hospitals in California between 2002 and 2010 using ED International Classification of Diseases, 9th revision (ICD-9), admitting diagnosis codes specifying intracranial hemorrhage. DNAR placement within 24 hours of admission was the primary variable of interest. Outcomes included neurosurgical procedures and in-hospital mortality. Hospital and patient characteristics were analyzed using descriptive statistics and multivariable generalized estimation equation regression models to account for hospital-level clustering. RESULTS: Of all 76,962 patients with serious TBI, 71,275 were admitted at 141 hospitals that each cared for at least 10 serious TBI patients annually and formed the primary sample. Early DNAR orders were placed in 7.5% of patients (range = 0 to 36.1% by hospital). Early DNAR use varied by trauma designation: Level I, 4.0% (95% confidence interval [CI] = 3.8% to 4.4%); Level II, 6.7% (95% CI = 6.5% to 7.1%); Level III, 9.7% (95% CI = 8.4% to 11.3%); and nontrauma hospitals, 10.8% (95% CI = 10.6% to 11.3%). Early DNAR was also less likely in teaching hospitals (9.3% vs. 4.3%). These results persisted after accounting for age, year, and hospital level clustering. In-hospital mortality (39.4% vs. 8.7%) and neurosurgical interventions (14.5% vs. 19.7%) also differed for patients with versus without early DNAR orders. Patients 65 years of age and older constituted 87.7% of those with early DNAR orders; our findings remained qualitatively unchanged when restricted to older adults. CONCLUSIONS: Use of early DNAR orders among patients with serious TBI is highly variable by individual hospital and hospital type, suggesting substantial practice variation. Associations with fewer surgical intervention and higher mortality suggest that such practice variation may be contributing to differences in TBI outcomes, particularly among older adults. PMID- 25545695 TI - Perioperative factors associated with HCAHPS responses of 2,758 surgical patients. AB - OBJECTIVE: To determine perioperative treatments and events associated with Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey responses. DESIGN: Retrospective analysis. SETTING: Single tertiary care, academic, urban, level-1 trauma center. PARTICIPANTS: Final cohort represents 2,758 consecutive surgical inpatients meeting criteria for evaluation by HCAHPS. EXPOSURES: Responses to four HCAHPS questions were compared against 19 perioperative treatments and events. MEASURES: Positive and negative responses to HCAHPS questions. RESULTS: Patients responding affirmatively with a "9" or "10" to "what number would you use to rate this hospital" were associated with decreased lengths of hospitalization, greater lengths of surgery, decreased intraoperative opioid equianalgesic doses, greater preoperative midazolam doses, shorter post anesthesia care unit (PACU) lengths of stay and decreased last PACU numerical rating scale (NRS) pain scores. Patients responding affirmatively with "yes, definitely" to "would you recommend this hospital to your family" were associated with decreased last PACU NRS pain scores. Patients responding affirmatively with "yes, always" to "How often did the hospital staff do everything to help with your pain" were associated with decreased hospital lengths of stay, decreased chronic benzodiazepine use, greater chronic NSAID use, and decreased PACU lengths of stay. Patients responding affirmatively with "yes, always" to "how often was your pain well controlled" were associated with decreased chronic opioid use, decreased chronic benzodiazepine use, greater chronic NSAID use, increased length of surgery, decreased last PACU NRS pain score, and decreased first PACU NRS pain scores. Subgroup analysis of patients undergoing different types of surgery further characterized factors associated with HCAHPS responses among different surgical populations. CONCLUSIONS: These data suggest that demographic factors, preadmission medications, and PACU pain scores but not analgesic medications are associated with patient satisfaction with regards to both pain management and overall satisfaction. PMID- 25545696 TI - Association of radiation dose with prevalence of thyroid nodules among atomic bomb survivors exposed in childhood (2007-2011). AB - IMPORTANCE: Few studies have evaluated the association of radiation dose with thyroid nodules among adults exposed to radiation in childhood. OBJECTIVE: To evaluate radiation dose responses on the prevalence of thyroid nodules in atomic bomb survivors exposed in childhood. DESIGN, SETTING, AND PARTICIPANTS: This survey study investigated 3087 Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years at exposure and participated in the thyroid study of the Adult Health Study at the Radiation Effects Research Foundation. Thyroid examinations including thyroid ultrasonography were conducted between October 2007 and October 2011, and solid nodules underwent fine-needle aspiration biopsy. Data from 2668 participants (86.4% of the total participants; mean age, 68.2 years; 1213 men; and 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; median dose, 0.018 Gy; dose range, 0-4.040 Gy) were analyzed. MAIN OUTCOMES AND MEASURES: The prevalence of all thyroid nodules having a diameter of 10 mm or more (consisting of solid nodules [malignant and benign] and cysts), prevalence of small thyroid nodules that were less than 10 mm in diameter detected by ultrasonography, and atomic bomb radiation dose responses. RESULTS: Thyroid nodules with a diameter of 10 mm or more were identified in 470 participants (17.6%): solid nodules (427 cases [16.0%]), malignant tumors (47 cases [1.8%]), benign nodules (186 cases [7.0%]), and cysts (49 cases [1.8%]), and all were significantly associated with thyroid radiation dose. Excess odds ratios per gray unit were 1.65 (95% CI, 0.89-2.64) for all nodules, 1.72 (95% CI, 0.93-2.75) for solid nodules, 4.40 (95% CI, 1.75-9.97) for malignant tumors, 2.07 (95% CI, 1.16-3.39) for benign nodules, and 1.11 (95% CI, 0.15-3.12) for cysts. The interaction between age at exposure and the dose was significant for the prevalence of all nodules (P = .003) and solid nodules (P < .001), indicating that dose effects were significantly higher with earlier childhood exposure. No interactions were seen for sex, family history of thyroid disease, antithyroid antibodies, or seaweed intake. No dose-response relationships were observed for small (<10-mm diameter) thyroid nodules. CONCLUSIONS AND RELEVANCE: Radiation effects on thyroid nodules exist in atomic bomb survivors 62 to 66 years after their exposure in childhood. However, radiation exposure is not associated with small thyroid nodules. PMID- 25545698 TI - Is prosthodontic treatment age-dependent in patients 60 years and older in Public Dental Services? AB - Prosthodontic treatment is a common procedure for the elderly as tooth loss is a reality in old age. Dentists take care of increasingly older patients with physiological age manifesting as cognitive impairment, frailty or multiple chronic diseases or who have side effects of medicines. We evaluated how patients' age affects prosthodontic treatment choice and whether we could identify the age when a change in practice occurs. In addition, we determined how common the treatment method of fixed prostheses is among patients aged 60 years or over in Public Dental Services (PDS) and how common rehabilitation of dentition with new dentures is compared with repair of existing dentures. Our data cover all patients aged 60 years and older (n = 130,060) treated in Helsinki PDS in 2007-2012. Data were aggregated into seven groups: 60-64, 65-69, 70-74, 75 79, 80-84, 85-89, and 90 years and over. During the 6-year period, the mean annual number of the population was about 114,000 and the mean annual number of patients treated with prosthodontics 1700. Prosthodontic treatment choices (repair, removable prosthodontics, fixed prostheses, fibre-reinforced composite fixed prostheses) vary by age; the older the patient, the rarer fixed or fibre reinforced composite fixed prostheses and removable prostheses and the more frequent repairs (P < 0.001). Denture repair was virtually the only treatment that patients over 90 years received. Based on our results, the age at which prosthodontic treatment practices in PDS change is around 70 years. Beyond this age, fixed prosthodontic treatment modalities are very rare and repairs are more common. PMID- 25545697 TI - A versatile electrophoresis-based self-test platform. AB - This paper reports on recent research creating a family of electrophoresis-based point of care devices for the determination of a wide range of ionic analytes in various sample matrices. These devices are based on a first version for the point of-care measurement of Li(+), reported in 2010 by Floris et al. (Lab Chip 2010, 10, 1799-1806). With respect to this device, significant improvements in accuracy, precision, detection limit, and reliability have been obtained especially by the use of multiple injections of one sample on a single chip and integrated data analysis. Internal and external validation by clinical laboratories for the determination of analytes in real patients by a self-test is reported. For Li(+) in blood better precision than the standard clinical determination for Li(+) was achieved. For Na(+) in human urine the method was found to be within the clinical acceptability limits. In a veterinary application, Ca(2+) and Mg(2+) were determined in bovine blood by means of the same chip, but using a different platform. Finally, promising preliminary results are reported with the Medimate platform for the determination of creatinine in whole blood and quantification of both cations and anions through replicate measurements on the same sample with the same chip. PMID- 25545699 TI - Superadditive opercular activation to food flavor is mediated by enhanced temporal and limbic coupling. AB - Food perception is characterized by a transition from initially separate sensations of the olfactory and gustatory properties of the object toward their combined sensory experience during consumption. The holistic flavor experience, which occurs as the smell and taste merge, extends beyond the mere addition of the two chemosensory modalities, being usually perceived as more object-like, intense and rewarding. To explore the cortical mechanisms which give rise to olfactory-gustatory binding during natural food consumption, brain activation during consumption of a pleasant familiar beverage was contrasted with presentation of its taste and orthonasal smell alone. Convergent activation to all presentation modes was observed in executive and chemosensory association areas. Flavor, but not orthonasal smell or taste alone, stimulated the frontal operculum, supporting previous accounts of its central role in the formation of the flavor percept. A functional dissociation was observed in the insula: the anterior portion was characterized by sensory convergence, while mid-dorsal sections activated exclusively to the combined flavor stimulus. psycho physiological interaction analyses demonstrated increased neural coupling between the frontal operculum and the anterior insula during flavor presentation. Connectivity was also increased with the lateral entorhinal cortex, a relay to memory networks and central node for contextual modulation of olfactory processing. These findings suggest a central role of the insular cortex in the transition from mere detection of chemosensory convergence to a superadditive flavor representation. The increased connections between the frontal operculum and medial temporal memory structures during combined olfactory-gustatory stimulation point to a potential mechanism underlying the acquisition and modification of flavor preferences. PMID- 25545700 TI - Fifteen years and 382 extended right grafts from in situ split livers in a multicenter study: Are these still extended criteria liver grafts? AB - In situ split liver extended right grafts (SL-ERGs) are still considered marginal grafts. Our aim was to verify this statement at the present time. From 1997 to 2011, a multicenter, retrospective study based on a prospective database was performed at 9 liver transplantation (LT) centers in northern Italy; it included 382 in situ SL-ERG transplants in adults. There were 358 primary LTs and 24 retransplantations (RETXs). The 1-, 3-, and 5-year overall graft survival rate for LT with in situ SL-ERGs were 73.5%, 63.3%, and 60.7%, respectively, from 1997 to 2004 and 83.5%, 80.3%, and 80.3%, respectively, thereafter (P=0.0001). A shorter total ischemia time and fewer RETX grafts were the main differences between the characteristics of the 2 periods. From 1997 to 2011, the 1-, 3-, and 5-year graft survival rates showed a significant difference between the 358 primary LT in situ SL-ERGs and the 24 RETX in situ SL-ERGs (P<0.001). In a multivariate analysis, the main prognostic factor for 60-day graft survival was a total ischemia time<8 hours for the 358 primary in situ SL-ERGs. From 2005 to 2011, in 2473 LTs, the 5-year graft survival for 184 in situ SL-ERGs and 2289 whole grafts was 75% and 80% (P=0.3), respectively. Univariate and multivariate studies alike failed to indicate that the type of graft was a prognostic factor for graft survival. A donor age>60 years, RETX grafts, and urgency were the main prognostic factors for failure for all of the grafts. Although caution should be taken regarding the choice of appropriate donors, in situ SL-ERGs should no longer be considered marginal grafts for experienced LT centers. SL-ERGs should not be used in RETX settings, and when SL-ERGs are used as primary grafts, the total ischemia time should be less than 8 hours. PMID- 25545702 TI - Short-term chilled storage of zebrafish (Danio rerio) embryos in cryoprotectant as an alternative to cryopreservation. AB - As zebrafish embryos have never been cryopreserved, we developed a protocol to store zebrafish embryos (50% epiboly-5.3 hour post fertilization) for up to 18 h at 0 degrees C. Initial experiments to optimize the cryoprotectant (CPA) solution demonstrated improved embryo hatching rate following chilling at 0 degrees C for 18 h with 1 M MeOH+0.1 M sucrose (56 +/- 5%) compared with other combinations of methanol (0.2-0.5 M) and sucrose (0.05-0.1 M). This combination of CPAs that protects against chilling injury was further tested to assess its impact on sox gene and protein expression. Significant decreases in sox3 gene expression were observed in hatched embryos that had been chilled for 18 h in 1 M MeOH+0.1 sucrose compared with non-chilled controls, however the expression of both sox2 and sox3 proteins was unaffected. Significant decreases in sox2 protein expression were, however, observed in embryos that had been chilled without CPAs and these embryos also had lower hatching rates than those chilled with the optimal CPA solution. We, therefore, conclude that the CPA combination of 1 M MeOH+0.1 M sucrose facilitates chilled storage of early stage (50% epiboly) zebrafish embryos for up to 18 h without compromising transcriptional response. PMID- 25545701 TI - Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. AB - BACKGROUND: Laboratory studies have shown the anti-tumor effect of metformin on prostate cancer. However, recent epidemiological studies have yielded inconclusive results. METHODS: We searched PubMed database from the inception to May 30 2014 for studies which assessed the effect of metformin use on cancer risk of prostate cancer, biochemical recurrence (BCR) and all-cause mortality of patients with prostate cancer. The pooled results and 95% confidence intervals (CIs) were estimated by random-effect model. RESULTS: Twenty-one studies were eligible according to the inclusion criteria. Based on the pooled results of available observational studies, metformin use was significantly associated with a decreased cancer risk (14 datasets, 963991 male subjects, odds ratio: 0.91, 95% CI: 0.85-0.97) and BCR (6 datasets, 2953 patients, hazard ratio: 0.81, 95% CI: 0.68-0.98) of prostate cancer. However, the association of metformin use with all cause mortality of patients with prostate cancer was not significant (5 datasets, 9241 patients, hazard ratio: 0.86, 95% CI: 0.64-1.14). CONCLUSION: Results suggest that metformin use appears to be associated with a significant reduction in the cancer risk and BCR of prostate cancer, but not in all-cause mortality of patients with prostate cancer. PMID- 25545703 TI - Improved surgical margin definition by narrow band imaging for resection of oral squamous cell carcinoma: A prospective gene expression profiling study. AB - BACKGROUND: Incomplete primary tumor excision contributes to localized postsurgical recurrence of oral squamous cell carcinoma (OSCC). The purpose of this study was to provide molecular evidence that surgical margin definition using narrow band imaging (NBI) resulted in more complete OSCC excision than conventional white light (WL) panendoscopy. METHODS: Molecular divergence among tumor, WL, and NBI-defined surgical margins was compared in 18 patients through microarray analysis (GeneChip U133-plus-2.0). RESULTS: The numbers of differentially expressed genes (NBI = 4387; WL = 3266; vs tumor) signified that NBI placed margins into less involved tissue than WL examination. Principal component analysis segregated tumor, WL, and NBI tissues appropriately based solely on mRNA profiles, and unsupervised hierarchical clustering identified 4 patients (22%) who benefited directly from NBI surgical margin definition. Gene ontology enrichment indicated increasing cell phenotypic diversity: tumor= 8 times per month before day hospital (DH), and had <= 2 episodes per month in the last month of DH and the first month after DH. Rapid relapse was defined as >= 8 episodes per month for 3 months starting within 6 months. RESULTS: The rate of rapid relapse was 27.6%. Patients who relapsed soon after DH had higher frequencies of bingeing and vomiting before treatment, engaged in less body avoidance before treatment and were more likely to be slow responders to treatment. Weight and shape concerns and body checking were not significant predictors. DISCUSSION: More frequent bulimic symptoms accompanied by less body avoidance may indicate an entrenchment in the illness which in turn augurs a labored and transient response to DH treatment that is difficult to sustain after intensive treatment ends. PMID- 25545722 TI - Editorial. PMID- 25545721 TI - Targeted excision of VCP R155H mutation by Cre-LoxP technology as a promising therapeutic strategy for valosin-containing protein disease. AB - Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is attributed to mutations in the valosin-containing protein (VCP) gene, mapped to chromosomal region 9p13.3-12. Affected individuals exhibit scapular winging and die from progressive muscle weakness and cardiac and respiratory failure in their 40s to 50s. Mutations in the VCP gene have also been associated with amyotrophic lateral sclerosis in 10-15% of individuals with hereditary inclusion body myopathy and 2-3% of isolated familial amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP-related myopathy or dementia. To determine the effects of targeted excision of the most common R155H mutation in VCP disease, we generated the Cre-ERTM-VCPR155H/+ tamoxifen-inducible model. We administered tamoxifen (0.12 mg/g body weight) or corn oil (vehicle) to the pregnant dams by oral gavage and monitored survival and muscle strength measurements of the pups until 18 months of age. We confirmed efficient removal of exons 4 and 5 and recombination of the mutant/floxed VCP copies by Q-PCR analyses. The activity and specificity of Cre recombinase was confirmed by immunostaining. Herein, we report that Cre-ERTM-VCPR155H/+ mice demonstrated improved muscle strength and quadriceps fibers architecture, autophagy signaling pathway, reduced brain neuropathology, decreased apoptosis, and less severe Paget-like bone changes. The Cre-ERTM-VCPR155H/+ mouse model provides proof of principle by demonstrating that removal of the mutated exons could be beneficial to patients with VCP-related neurodegenerative diseases, and serves as an excellent platform in understanding the underlying pathophysiological mechanism(s) in the hopes of a promising therapeutic approach. PMID- 25545723 TI - Comparison of voice outcome after vocal fold augmentation with fat or calcium hydroxylapatite. AB - OBJECTIVES/HYPOTHESIS: To evaluate the short-term voice outcomes of vocal fold augmentation using fat compared to calcium hydroxylapatite product Radiesse Voice (Merz Aesthetics). STUDY DESIGN: Retrospective study design. METHODS: Sixty-six consecutive patients with vocal fold insufficiency were recruited, including the final 33 patients treated with fat and all 33 patients treated with calcium hydroxylapatite product. Before April 2011, fat augmentation was the standard treatment; from April 2011, only calcium hydroxylapatite product was used. For all subjects, videolaryngostroboscopic evaluation, s/z ratios, and voice handicap index (VHI) were analyzed. METHODS: Treatment outcomes were evaluated 3 months after the augmentation. Two patients augmented with fat (both after 6 months), versus four augmented with calcium hydroxylapatite product (mean after 7 months), needed reintervention. Mean VHI decreased from 18 points in the fat augmentation group compared to 17 points in the calcium hydroxylapatite group. Mean s/z ratio changed -0.33 in the fat augmentation group compared to -0.46 in the calcium hydroxylapatite group. CONCLUSION: This retrospective cohort demonstrates that there are no short-term differences in VHI outcome or number of reinterventions for augmentation with fat compared to calcium hydroxylapatite product Radiesse Voice (Merz Aesthetics). LEVEL OF EVIDENCE: Level 4. PMID- 25545724 TI - Febrile and postinfectious myoclonus: case reports and review of the literature. AB - PURPOSE: Myoclonus associated with fever or following an infectious event (parainfectious myoclonic jerks) is a transient event with an abrupt onset. It is not common and often not recognized. In these reports, its clinical features and its favorable outcome are described. PATIENTS AND METHODS: We identified three pediatric patients with parainfectious myoclonic jerks who were treated at Children's Neuropsychiatry Unit at the University-Hospital of Parma (Italy). RESULTS: The myoclonic jerks presented an abrupt onset and were characterized by brief involuntary muscle contractions temporally related to febrile episodes or following infectious illnesses. The outcome was positive as they resolve spontaneously with cessation of febrile/infective events. CONCLUSION: Parainfectious myoclonic jerks are temporary benign phenomena that could occur in association with the fever or following an infectious event. It is quite important to make a correct diagnosis as early as possible to avoid unnecessary hospitalizations or investigations. PMID- 25545726 TI - Central nervous system involvement in acute myeloid leukemia patients undergoing hematopoietic cell transplantation. AB - Knowledge regarding the rate of central nervous system (CNS) involvement and risk factors for its development in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (HCT) are limited. In this study we retrospectively evaluated CNS involvement in 327 patients who underwent myeloablative HCT at our institute in which all patients have cerebrospinal fluid examined by morphology or flow cytometry before HCT. Twenty-two patients (7%) had CNS AML involvement at pre-HCT evaluation. Covariates associated with such involvement were higher WBC at diagnosis, prior CNS or other extramedullary disease, and evidence of systemic disease at pre-HCT evaluation. History of prior CNS disease and disease status at pre-HCT evaluation allowed stratification of patients into 3 risk groups: 35% (20 patients), 16% (51 patients), and 3% (256 patients) rates of pre-HCT CNS involvement. Treatment of pre-HCT CNS disease was uniformly successful regardless of whether cranial irradiation therapy was used. Perhaps as a result, presence of CNS pre-HCT had no independent influence on post HCT outcome, which was primarily influenced by status of systemic disease at time of HCT. PMID- 25545727 TI - Few and nonsevere adverse infusion events using an automated method for diluting and washing before unrelated single cord blood transplantation. AB - Graft dilution and DMSO washing before cord blood (CB) administration using an automated system may offer low incidence of adverse infusion events (AIE), ensuring reproducible cell yields. Hence, we analyzed the incidences and significance of immediate AIE, cellular yield, and engraftment after single CB infusion. One hundred and fifty-seven patients (median age, 20 years; range, 1 to 60) received a single CB unit for treatment of hematologic and nonhematologic malignancies with myeloablative conditioning after graft dilution and washing. The median total nucleated cell (TNC) doses was 3.4 * 10(7)/kg (range, 2 to 26) and the median post-thaw recovery was 84% (range, 45 to 178). The cumulative incidence of neutrophil engraftment at 50 days was 84% (95% confidence interval [CI], 83 to 93). A total of 118 immediate AIE were observed in fifty-two (33%) patients. All reported AIE were transient, graded from 1 to 2 by Common Terminology Adverse Events version 4. The most frequent toxicity was cardiovascular but without any life-threatening reaction. Infused TNC, recipient's weight, and rate of infusion per kilogram were risk factors associated with cardiovascular AIE in multivariate analysis (odds ratio [OR], 1.2 (95% CI, 1.1 to 1.4); P < .001; OR, .94 (95% CI, .9 to .97); P < .001; and OR, 1.5 (95% CI, 1.2 to 1.8); P < .001; respectively). In summary, use of an automated method for graft washing before CB administration showed low incidence of AIE without compromising cell yields and engraftment. Infused TNC dose, recipient's weight, and rate of infusion per kilogram were risk factors associated with infusion reactions. PMID- 25545725 TI - Delay discounting and the use of mindful attention versus distraction in the treatment of drug addiction: a conceptual review. AB - In recent decades, researchers have integrated measurements of delay discounting, how the subjective valuation of a reward changes as a function of time, into their study of addiction. Research has begun to explore the idea that delay discounting may serve as both a marker for the effectiveness of existing treatments for addiction and a potential target for novel intervention strategies. As this work is in its infancy, many potentially significant connections between the construct of delay discounting and the treatment of addiction have yet to be explored. Here, we present a conceptual review highlighting novel points of intersection between delay discounting and two approaches to treating addiction that have become increasingly popular in recent years: those that focus on the development of mindfulness skills and those that emphasize the use of distraction techniques. Viewing these two techniques through the lens of delay discounting is particularly intriguing because of the very different way that they address the experience of drug cravings in the present moment (nonjudgmentally attending to vs. shifting attention away from subjective cravings, respectively). We propose that these opposing strategies for dealing with cravings may interact with delay discounting in ways that have important implications for treatment effectiveness. PMID- 25545728 TI - Antibacterial properties of hLf1-11 peptide onto titanium surfaces: a comparison study between silanization and surface initiated polymerization. AB - Dental implant failure can be associated with infections that develop into peri implantitis. In order to reduce biofilm formation, several strategies focusing on the use of antimicrobial peptides (AMPs) have been studied. To covalently immobilize these molecules onto metallic substrates, several techniques have been developed, including silanization and polymer brush prepared by surface-initiated atom transfer radical polymerization (ATRP), with varied peptide binding yield and antibacterial performance. The aim of the present study was to compare the efficiency of these methods to immobilize the lactoferrin-derived hLf1-11 antibacterial peptide onto titanium, and evaluate their antibacterial activity in vitro. Smooth titanium samples were coated with hLf1-11 peptide under three different conditions: silanization with 3-aminopropyltriethoxysilane (APTES), and polymer brush based coatings with two different silanes. Peptide presence was determined by X-ray photoelectron spectroscopy, and the mechanical stability of the coatings was studied under ultrasonication. The LDH assays confirmed that HFFs viability and proliferation were no affected by the treatments. The in vitro antibacterial properties of the modified surfaces were tested with two oral strains (Streptococcus sanguinis and Lactobacillus salivarius) showing an outstanding reduction. A higher decrease in bacterial attachment was noticed when samples were modified by ATRP methods compared to silanization. This effect is likely due to the capacity to immobilize more peptide on the surfaces using polymer brushes and the nonfouling nature of polymer PDMA segment. PMID- 25545729 TI - Olfactory dysfunction in Parkinson's disease: Positive effect of cigarette smoking. AB - BACKGROUND: There is compelling evidence from over 60 epidemiological studies that smoking significantly reduces the risk of Parkinson's disease (PD). In general, those who currently smoke cigarettes, as well as those with a past history of such smoking, have a reduced risk of PD compared to those who have never smoked. Recently it has been suggested that a cardinal nonmotor sensory symptom of PD, olfactory dysfunction, may be less severe in PD patients who smoke than in PD patients who do not, in contrast to the negative effect of smoking on olfaction described in the general population. METHODS: We evaluated University of Pennsylvania Smell Identification Test (UPSIT) scores from 323 PD patients and 323 controls closely matched individually on age, sex, and smoking history (never, past, or current). RESULTS: Patients exhibited much lower UPSIT scores than did the controls (P < 0.0001). The relative decline in dysfunction of the current PD smokers was less than that of the never- and past-PD smokers (respective Ps = 0.0005 and 0.0019). Female PD patients outperformed their male counterparts by a larger margin than did the female controls (3.66 vs. 1.07 UPSIT points; respective Ps < 0.0001 and 0.06). Age-related declines in UPSIT scores were generally present (P < 0.0001). No association between the olfactory measure and smoking dose, as indexed by pack-years, was evident. CONCLUSIONS: PD patients who currently smoke do not exhibit the smoking-related decline in olfaction observed in non-PD control subjects who currently smoke. The physiological basis of this phenomenon is yet to be defined. PMID- 25545730 TI - Graphene-coated cotton fibers as a sorbent for the extraction of multiclass pesticide residues from water and their determination by gas chromatography with mass spectrometry. AB - A straightforward functionalization procedure is proposed for synthesizing a cotton-supported graphene as an extraction material, which is effectively employed for the extraction of multiclass pesticides from environmental waters prior to their determination by gas chromatography with mass spectrometry. Different experimental parameters that affect the extraction efficiency, including pH of the extraction, stirring rate, extraction time, ionic strength, presence of humic acid, sample volume, amount of sorbent, and elution conditions, were investigated and properly established. The advantages of the present extraction method are the simplicity of implementation, rapidity, and low consumption of sorbent per extraction. Moreover, the pesticides on the adsorbent are stable, under certain storage conditions, rendering the cotton-supported graphene suitable for environmental field studies. The applicability of the cotton-graphene-based procedure for routine analysis was demonstrated by the determination of pesticides in a lake water sample. The recoveries ranged from 83 to 107%, the limits of quantitation were in the range of 0.02-0.09 MUg/L, and the calculated relative standard deviations varied from 3 to 8% (data obtained with the same batch of sorbent). Because of the acceptable analytical characteristics, the developed method shows great prospects in determining certain classes of pesticides in water. PMID- 25545733 TI - AMPK-dependent signaling modulates the suppression of invasion and migration by fenofibrate in CAL 27 oral cancer cells through NF-kappaB pathway. AB - Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist and lipid-lowering agent, has been used worldwide for treatment of hyperlipidemia. The clinical trials demonstrate that fenofibrate possesses multiple pharmacological activities, including antitumor effects. However, the precise mechanisms in oral squamous cell carcinoma (OSCC) remain unclear. In this study, we investigated the anticancer effects of fenofibrate on the migration and invasion of human oral cancer CAL 27 cells. Fenofibrate inhibited the cell migration and invasion of CAL 27 cells by the wound healing and Boyden chamber transwell assays, respectively. In addition, fenofibrate reduced the protein expressions of MMP-1, MMP-2, MMP-7, and MMP-9 by Western blotting and inhibited enzyme activities of MMP-2/-9 using gelatin zymography assay. Results from immunoblotting analysis showed that the proteins of p-LKB1 (Ser428), LKB1, p AMPKalpha (Thr172), p-AMPKalpha1/alpha2 (Ser425/Ser491), p-AMPKbeta1 (Ser108), and AMPKgamma1 were upregulated by fenofibrate; the levels of p-IKKalpha/beta (Ser176) and p-IkappaBalpha were reduced in fenofibrate-treated cells. Also, fenofibrate suppressed the expressions of nuclear NF-kappaB p65 and p50 by immunoblotting and NF-kappaB DNA binding activity by EMSA assay. The anti invasive effect of fenofibrate was attenuated by compound C [an adenosine 5' monophosphate-activated protein kinase (AMPK) inhibitor] or dominant negative form of AMPK (DN-AMPKalpha1). Thus, fenofibrate considerably inhibited metastatic behaviors of CAL 27 cells might be mediated through blocking NF-kappaB signaling, resulting in the inhibition of MMPs; these effects were AMPK-dependent rather than PPARalpha signaling. Our findings provide a molecular rationale, whereby fenofibrate exerts anticancer effects and additional beneficial effects for the treatment of cancer patients. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 866-876, 2016. PMID- 25545734 TI - Correlations Between Serum IL-6 Levels and Radiation Pneumonitis in Lung Cancer Patients: A Meta-Analysis. AB - OBJECTIVE: Diagnostic significance of interleukin 6 (IL-6) for lung cancer patients with radiation pneumonitis (RP) was examined within various studies, but yielded conflicting results. Thus, this meta-analysis was performed to demonstrate correlations between serum IL-6 levels and RP in lung cancer patients. METHOD: Electronic databases updated to March 2014 were searched to find relevant studies. Relevant literatures were searched under the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM and CNKI databases. STATA statistical software (Version 12.0, Stata Corporation, and College Station, TX) Standardized mean difference (SMD), and its corresponding 95% confidence intervals (CIs) were used for this meta-analysis. In addition, nine cohort studies met the inclusion criteria and involved a total of 137 RP patients and 295 non-RP patients. RESULTS: The results of combined SMD suggested that serum IL-6 levels in RP patients was significantly higher than in non-RP patients before radiotherapy. While, there was a significant difference in serum IL-6 levels of RP patients between before and after radiotherapy, we observed no difference in serum IL-6 levels between RP patients and non-RP patients after radiotherapy. Ethnicity-stratified analyses indicated that increased serum IL-6 levels were related to the risk of RP in lung cancer patients among Caucasians, but not detected among Asians (all P > 0.05). CONCLUSION: The main finding of our meta-analysis reveals that increased serum IL-6 levels may contribute to the incidence of RP in lung cancer patients, especially among Caucasians. PMID- 25545735 TI - Evolving epidemiology of injecting drug use-associated infective endocarditis: A regional centre experience. AB - INTRODUCTION AND AIMS: Injecting drug use (IDU) is a major risk factor for infective endocarditis (IE). An understanding of the epidemiology of IE and IDU is vital for delivery of health care for this disease. Our aim was to examine the rates of IDU-associated IE (IDU-IE) in a single centre over the last 12 years. DESIGN AND METHODS: Retrospective analysis of two cohorts of consecutive patients (n = 226) admitted with IE from 2002 to 2013. Numbers of cases and rates of IE were compared between two cohorts (2002-2006 and 2009-2013). Rate ratios were calculated using Poisson distributions. Poisson regression was used to examine relationship over time. RESULTS: One hundred thirty cases of endocarditis were seen in the first observation period (6 IDU-IE) and 96 in the second observation period (15 IDU-IE). The estimated incidence rate of IE had fallen from 10.1 to 6.45 per 100, 000 person-years [rate ratio 0.64, 95% confidence interval (CI) 0.48, 0.85]. In contrast, the estimated incidence rate of IDU-E has risen from 0.48 to 0.79 per 100, 000 person-years (rate ratio 1.65, 95% CI 0.59, 4.57). Incidence rate regression suggests that the number of IDU-IE cases is expected to increase by a factor of 1.25 (95%CI 1.09-1.44) for each increase of 1 year. DISCUSSION AND CONCLUSIONS: Over the last decade, there has been a decrease in incidence rate and total number of cases of IE but a rise in rate and number of cases of IDU-IE. This may indicate increasing IDU or increased rates of endocarditis in intravenous drug users in this region. This finding may inform health-care planning in the area. PMID- 25545737 TI - Anticipated increase in the number of patients who require dialysis treatment among the aging population of Japan. AB - The aging population is anticipated to have a large impact on the number of incident dialysis patients, as the risk of end-stage kidney disease increases with age. This study aimed to examine trends in the sex- and age-specific incidence rates of dialysis between 2008 and 2012, and to assess the impact of population aging on the number of incident dialysis patients over the next decade in Japan. Incidence was calculated using published data and Japan's population statistics. The 2012 incidence was extrapolated, and projected future demographic changes within the Japanese population were used to estimate the number of incident dialysis patients in 2020 and 2025. As a general trend, the sex- and age specific incidence rates of dialysis decreased gradually between 2008 and 2012, except among men aged >=80 years. The total number of incident dialysis patients was projected to increase by 12.8% from 36 590 in 2012 to 41 270 in 2025. Greater increases were observed in the oldest age group (>=85 years). In 2025, the number of incident dialysis patients in this group was projected to increase by 92.6% in men and 62.2% in women. This study shows the number of patients who initiate dialysis treatment is projected to increase over the next decade in Japan due to aging of the population. Effective strategies are needed to offset the challenges faced by the aging population, with a particular focus on octogenarians and older, given the notable proportion of patients requiring dialysis treatment in the future. PMID- 25545738 TI - 'We don't have recipes; we just have loads of ingredients': explanations of evidence and clinical decision making by speech and language therapists. AB - RATIONALE, AIMS AND OBJECTIVES: Research findings consistently suggest that speech and language therapists (SLTs) are failing to draw effectively on research based evidence to guide clinical practice. This study aimed to examine what constitutes the reasoning provided by SLTs for treatment choices and whether science plays a part in those decisions. METHOD: This study, based in Ireland, reports on the qualitative phase of a mixed-methods study, which examined attitudes underpinning treatment choices and the therapy process. SLTs were recruited from community, hospital and disability work settings via SLT managers who acted as gatekeepers. A total of three focus groups were run. Data were transcribed, anonymized and analysed using thematic analysis. RESULTS: In total, 48 participants took part in the focus groups. The majority of participants were female, represented senior grades and had basic professional qualifications. Three key themes were identified: practice imperfect; practice as grounded and growing; and critical practice. Findings show that treatment decisions are scaffolded primarily on practice evidence. The uniqueness of each patient results in dynamic and pragmatic practice, constraining the application of unmodified therapies. CONCLUSION: The findings emerging from the data reflect the complexities and paradoxes of clinical practice as described by SLTs. Practice is pivoted on both the patient and clinician, through their membership of groups and as individuals. Scientific thinking is a component of decision making; a tool with which to approach the various ingredients and the dynamic nature of clinical practice. However, these scientific elements do not necessarily reflect evidence based practice as typically constructed. PMID- 25545739 TI - Evaluation of the effective cross-sections for recombination and trapping in the case of pure spinel. AB - In this paper, we have investigated the evolution of the secondary electron emission in the case of pure spinel during electron irradiation, achieved in a scanning electron microscope at room temperature, which is derived from the measurement of the induced and the secondary electron currents. It was observed from the experimental results, that there are two regimes during the charging process: a plateau followed by a linear variation, which are better identified by plotting the logarithm of the secondary electron emission yield lnsigma as function of the total surface density of trapped charges in the material QT . For positive charging, E0 = 1.1 and 5 keV, the slope of the linear part, whose value is of about 10(-10) cm(2) charge(-1), is independent of the primary electron energy. It is interpreted as a microscopic cross section for electron-hole recombination. For negative charging of pure spinel, E0 = 15 and 30 keV, the slope is associated with an electron trapping cross section close to 10(-14) cm(2) charge(-1), which can be assigned to the microscopic cross section for electron trapping. This trapping cross section is four orders of magnitude lower than the recombination one. PMID- 25545736 TI - P2Y2 receptor activation decreases blood pressure via intermediate conductance potassium channels and connexin 37. AB - AIMS: Nucleotides are important paracrine regulators of vascular tone. We previously demonstrated that activation of P2Y2 receptors causes an acute, NO independent decrease in blood pressure, indicating this signalling pathway requires an endothelial-derived hyperpolarization (EDH) response. To define the mechanisms by which activation of P2Y2 receptors initiates EDH and vasodilation, we studied intermediate-conductance (KCa3.1, expressed in endothelial cells) and big-conductance potassium channels (KCa1.1, expressed in smooth muscle cells) as well as components of the myoendothelial gap junction, connexins 37 and 40 (Cx37, Cx40), all hypothesized to be part of the EDH response. METHODS: We compared the effects of a P2Y2/4 receptor agonist in wild-type (WT) mice and in mice lacking KCa3.1, KCa1.1, Cx37 or Cx40 under anaesthesia, while monitoring intra-arterial blood pressure and heart rate. RESULTS: Acute activation of P2Y2/4 receptors (0.01-3 mg kg(-1) body weight i.v.) caused a biphasic blood pressure response characterized by a dose-dependent and rapid decrease in blood pressure in WT (maximal response % of baseline at 3 mg kg(-1) : -38 +/- 1%) followed by a consecutive increase in blood pressure (+44 +/- 11%). The maximal responses in KCa3.1(-/-) and Cx37(-/-) were impaired (-13 +/- 5, +17 +/- 7 and -27 +/- 1, +13 +/- 3% respectively), whereas the maximal blood pressure decrease in response to acetylcholine at 3 MUg kg(-1) was not significantly different (WT: -53 +/- 3%; KCa3.1(-/-) : -52 +/- 3; Cx37(-/-) : -53 +/- 3%). KCa1.1(-/-) and Cx40(-/-) showed an identical biphasic response to P2Y2/4 receptor activation compared to WT. CONCLUSIONS: The data suggest that the P2Y2/4 receptor activation elicits blood pressure responses via distinct mechanisms involving KCa3.1 and Cx37. PMID- 25545740 TI - Similar outcome after transplantation of moderate macrovesicular steatotic and nonsteatotic livers when the cold ischemia time is kept very short. AB - BACKGROUND: Livers with moderate (30-60%) macrovesicular steatosis have been associated with poor outcome after transplantation. Aim of this study was to examine the outcome after transplantation of livers with moderate macrovesicular steatosis when the cold ischemia time (CIT) is kept very short. METHODS: Postoperative outcome of 19 recipients of a moderate steatotic liver were compared with a matched control group of 95 recipients of a nonsteatotic liver graft (1:5 ratio). We studied graft/patient survival rates, incidences of primary nonfunction, postoperative complications (classified according to the Clavien Dindo classification), first-week postoperative hepatic injury serum markers (AST/ALT), and liver function tests (PT time/bilirubin/lactate). In addition, we studied reversal of graft steatosis in follow-up biopsies. RESULTS: Median CIT in livers with moderate steatosis and in controls was below 8 h in both groups. Although short- and long-term patient/graft survival rates and results of liver function tests were similar, serum markers of hepatic injury and postoperative complications (especially grade IVa) were significantly higher in recipients of a moderate steatotic liver. Reversal of steatosis was seen in 9 of the 11 (82%) recipients with follow-up liver biopsies. CONCLUSION: Despite the association with severe postoperative complications, moderate macrovesicular steatotic livers can be used successfully for transplantation if the CIT is kept very short. PMID- 25545741 TI - Individual maternal and child exposure to antibiotics in hospital - a national population-based validation study. AB - AIM: Exposure to antibiotics in early life may affect future health. Most antibiotics are prescribed in outpatient care, but inpatient exposure is also important. We estimated how specific diagnoses in hospitals corresponded to individual antibiotic exposure. METHODS: All pregnant women and children from birth to 5 years of age with infectious diseases and common inpatient diagnoses between July 2005 and November 2011 were identified from the Swedish National Patient Register. Random samples of individuals from predefined groups were drawn, and medical records received from the clinics were manually reviewed for antibiotics. RESULTS: Medical records for 4319 hospital visits were requested and 3797 (88%) were received. A quarter (25%) of children diagnosed as premature had received antibiotics, and in children from one to 5 years of age, diagnoses associated with bacterial infections were more commonly treated with antibiotics (62.4-90.6%) than those associated with viruses (6.3-22.2%). Pregnant women who had undergone a Caesarean section were more likely to be treated with antibiotics than those who had had a vaginal delivery (40.1% versus 11.1%). CONCLUSION: This study defines the proportion of new mothers and young children who received individual antibiotic treatment for specific inpatient diagnoses in Sweden and provides a useful basis for future studies focusing on antibiotic use. PMID- 25545742 TI - WNT10A coding variants and maxillary lateral incisor agenesis with associated dental anomalies. AB - Congenital maxillary lateral incisor agenesis (MLIA) is one of the most common subtypes of dental agenesis. Because little is known with regard to the aetiology of this anomaly, the aim of the study was to determine the contribution of nucleotide variants in wingless-type MMTV integration site family, member 10A (WNT10A), msh homeobox 1 (MSX1), and paired box 9 (PAX9) to the risk of MLIA in a Polish population. Coding regions of the selected genes were analysed by direct sequencing in a group of 20 individuals with unilateral and bilateral MLIA, associated or not with other dental anomalies. The frequencies of the identified nucleotide variants were assessed in an additional cohort of patients with isolated dental agenesis (n = 147) and in 178 controls. Mutation screening showed four non-synonymous substitutions located in the highly conserved coding sequence of WNT10A in five (25%) of the 20 patients. Analysis of genotyping results revealed that three of these variants--p.Arg113Cys, p.Phe228Ile, and the newly identified p.Arg171Leu--may represent aetiological mutations underlying MLIA with associated dental anomalies. No mutations that were potentially aetiologic were identified in MSX1 and PAX9. In conclusion, this is the first report implicating coding variants in the WNT10A gene in the aetiology of MLIA. These results will require further confirmation using larger-scale studies. PMID- 25545743 TI - Motivational needs on team performance of Korean nursing students. AB - AIM: The purpose of this study was to examine the effects of an individual's motivational needs on team performance, centering on the needs for affiliation, power and achievement, following the McClelland's Achievement Motivation Theory. BACKGROUND: Most previous studies related to McClelland's Achievement Motivation Theory have focused on achievement motivation as a predictor of team performance. In contrast, affiliation and power motivations were relatively little known in connection with team performance. METHODS: This was a descriptive, cross sectional study using data from 181 junior nursing students in Korea. Data were collected from a questionnaire when the subjects' teamwork task was completed in November 2013. Multiple regression analysis was used to examine the influence of motivational needs on team performance. FINDING: Each group having high levels of the need for affiliation, or the need for power and/or the need for achievement showed a significantly high level of teamwork skills and team effectiveness. The factors influencing teamwork skills were the need for affiliation and the need for achievement. Additionally, the factors influencing team effectiveness were also the need for affiliation and the need for achievement. CONCLUSION: The study reconfirmed the positive influence of the need for achievement, which was the focus of most previous research, in regard to personal and organizational growth. Furthermore, it identified that the need for affiliation, another type of internal motive, positively affected team performance as well. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nursing schools and nursing organizations should pay attention to their members' affiliation and achievement needs to enhance organizational efficiencies. Through efforts such as developing diverse continuing education programmes for need training, they could enhance their members' needs for affiliation or achievement and consequently increase nursing team performance. PMID- 25545746 TI - Long live reproductive diversity... and the marvelous monotremes. PMID- 25545748 TI - Reproductive isolation between sympatric sister species, Mussaenda kwangtungensis and M. pubescens var. alba. AB - Reproductive isolation defines the biological species concept and plays a key role in the formation and maintenance of species. The relative contributions of different isolating stages has been suggested to be closely associated with phylogenetic relatedness. Few studies have focused on the relative contributions of pre- versus post-zygotic mechanisms, and even fewer have been conducted under strict phylogenetic frameworks. Pre- and post-zygotic reproductive isolation stages have been investigated in the sister species Mussaenda kwangtungensis and M. pubescens var. alba. The two species have partly overlapping distribution ranges and flowering times, while the principal pollinators differed strikingly for them, demonstrating strong pre-zygotic isolations. Natural hybrids were detected by simple sequence repeat markers and their maternal parents were identified based on chloroplast gene sequences. Five out of 81 individuals were suggested to be hybrids that fall into the categories F2, BC1, and BC2 by the NewHybrids analysis. Interspecific crossings resulted in significantly reduced fruit set and seed germination rates. Phylogenetic analysis revealed short Kimura 2-parameter distance between M. kwangtungensis and M. pubescens var. alba. These findings strongly supported the hypothesis that for species with a closer phylogenetic relationship, pre-zygotic isolation plays an important part in limiting gene exchange in sympatric areas. PMID- 25545744 TI - Randomized clinical trial of brewed green and black tea in men with prostate cancer prior to prostatectomy. AB - BACKGROUND: Preclinical and epidemiologic studies suggest chemopreventive effects of green tea (GT) and black tea (BT) in prostate cancer. In the current study we determined the effect of GT and BT consumption on biomarkers related to prostate cancer development and progression. METHODS: In this exploratory, open label, phase II trial 113 men diagnosed with prostate cancer were randomized to consume six cups daily of brewed GT, BT or water (control) prior to radical prostatectomy (RP). The primary endpoint was prostate tumor markers of cancer development and progression determined by tissue immunostaining of proliferation (Ki67), apoptosis (Bcl-2, Bax, Tunel), inflammation (nuclear and cytoplasmic nuclear factor kappa B [NFkappaB]) and oxidation (8-hydroxydeoxy-guanosine [8OHdG]). Secondary endpoints of urinary oxidation, tea polyphenol uptake in prostate tissue, and serum prostate specific antigen (PSA) were evaluated by high performance liquid chromatography and ELISA analysis. RESULTS: Ninety three patients completed the intervention. There was no significant difference in markers of proliferation, apoptosis and oxidation in RP tissue comparing GT and BT to water control. Nuclear staining of NFkappaB was significantly decreased in RP tissue of men consuming GT (P = 0.013) but not BT (P = 0.931) compared to water control. Tea polyphenols were detected in prostate tissue from 32 of 34 men consuming GT but not in the other groups. Evidence of a systemic antioxidant effect was observed (reduced urinary 8OHdG) only with GT consumption (P = 0.03). GT, but not BT or water, also led to a small but statistically significant decrease in serum prostate-specific antigen (PSA) levels (P = 0.04). CONCLUSION: Given the GT-induced changes in NFkappaB and systemic oxidation, and uptake of GT polyphenols in prostate tissue, future longer-term studies are warranted to further examine the role of GT for prostate cancer prevention and treatment, and possibly for other prostate conditions such as prostatitis. PMID- 25545749 TI - Evidence for thiol/disulfide exchange reactions between tubulin and glyceraldehyde-3-phosphate dehydrogenase. AB - While thiol redox reactions are a common mechanism to regulate protein structure and function, protein disulfide bond formation is a marker of oxidative stress that has been linked to neurodegeneration. Both tubulin and glyceraldehyde-3 phosphate dehydrogenase (GAPDH) contain multiple cysteines that have been identified as targets for oxidation to disulfides, S-nitrosation and S glutathionylation. We show that GAPDH is one of three prominent brain microtubule associated proteins (MAPs), in addition to MAP-2 and tau, with reactive cysteines. We detected a threefold to fourfold increase in tubulin cysteine oxidation by hydrogen peroxide in the presence of rabbit muscle GAPDH by 5 iodoacetamidofluorescein labeling and by Western blot detection of higher molecular weight inter-chain tubulin disulfides. In thiol/disulfide exchange experiments, tubulin restored ~50% of oxidized GAPDH cysteines and the equilibrium favored reduced GAPDH. Further, we report that oxidized GAPDH is repaired by the thioredoxin reductase system (TRS). Restoration of GAPDH activity after reduction by both tubulin and the TRS was time-dependent suggesting conformational changes near the active site cysteine149. The addition of brain MAPs to oxidized tubulin reduced tubulin disulfides and labeling of MAP-2 and of GAPDH decreased. Because the extent of tubulin repair of oxidized GAPDH was dependent on buffer strength, we conclude that electrostatics influence thiol/disulfide exchange between the two proteins. The novel interactions presented herein may protect GAPDH from inhibition under oxidative stress conditions. PMID- 25545750 TI - An ultrasound evaluation of laryngeal mask airway position in pediatric patients: an observational study. AB - BACKGROUND: In children, the laryngeal mask airway (LMA) is frequently displaced within the hypopharynx, resulting in repositioning of the device. When the tip of the LMA is placed in the esophageal inlet, the arytenoids are moved ventrally. When the LMA is rotated or deviated, the ventral movement of the arytenoids may result in asymmetric elevation of an arytenoid cartilage, which can be detected with ultrasound (US). In this study, we sought to estimate the incidence of LMA malposition detected with US in pediatric patients. The primary end point was to compare the incidence of LMA malposition between US and fiber optic bronchoscopy (FOB). The secondary end points were to find the interrelationship between US detected and FOB-detected malposition of the LMA and to locate the diagnostic performance of US in detecting LMA malposition. METHODS: In this observational study, 100 consecutive children were included. After anesthetic induction, US evaluation was performed before and after LMA insertion to obtain the glottic image on the anterior neck. FOB was performed to assess LMA position (FOB LMA grade and LMA rotation grade). With a post-LMA US image, the symmetry of the arytenoid cartilages was evaluated. Asymmetrical elevation of an arytenoid cartilage in reference to the glottic midline and the opposite arytenoid cartilage was graded as 0 to 3 (US arytenoid grade). The interrelationships between US arytenoid grade and FOB LMA grade or LMA rotation grade were assessed. RESULTS: The incidence of asymmetrical elevation of an arytenoid was 50% (95% confidence interval [CI], 40%-60%). On FOB, the incidence of LMA malposition was 78% (95% CI, 69%-86%), and that of LMA rotation was 43% (95% CI, 33%-53%). The incidence of LMA malposition was higher with FOB (P < 0.0001), but the incidence of rotation was similar (P = 0.395). US arytenoid grade did not correlate with FOB LMA grade (P = 0.611) but showed a significant correlation with LMA rotation grade (P < 0.0001; 95% CI, 60%-83%). To detect a rotated LMA, US had a sensitivity of 93% (95% CI, 81%-98%) and a specificity of 82% (95% CI, 70%-91%). The positive and negative predictive values were 80% (95% CI, 66%-90%) and 94% (95% CI, 83%-99%), respectively. The accuracy was 87% (95% CI, 79%-93%). CONCLUSIONS: Although US could not detect the suboptimal depth of an LMA, US has promise of being an accurate tool in detecting a rotated LMA. PMID- 25545751 TI - Changes in coagulation in standard laboratory tests and ROTEM in trauma patients between on-scene and arrival in the emergency department. AB - BACKGROUND: When trauma patients arrive in the emergency department (ED), coagulopathy frequently is present. The time course, however, in which this coagulopathy develops is poorly understood. No study has fully evaluated the coagulation status, including thromboelastometry on-scene and at hospital arrival. We hypothesized that measured coagulation variables might change when measured at the scene of injury and upon arrival to the ED. METHODS: We performed a prospective, single-center, observational study investigating coagulation status in 50 trauma patients on-scene and at arrival in the ED. Measurements included arterial blood gases, ROTEM(r), protein S100, protein C activity, protein S, Quick value, international normalized ratio, activated partial thromboplastin time, D-dimer, coagulation factor V (FV), coagulation factor XIII (FXIII), fibrinogen, hemoglobin, hematocrit, platelets, and volume and blood products being administered during the first 24 hours. RESULTS: Significant changes between on-scene and the ED were observed for the following values: partial venous oxygen pressure increased and sodium, glucose, and lactate decreased. For EXTEM, INTEM, and APTEM, clotting time and clot formation time increased significantly, whereas maximal clot firmness and angle alpha decreased significantly (all P <= 0.004). For FIBTEM, clotting time increased significantly and maximal clot firmness decreased significantly. In the laboratory, significant reductions in hemoglobin, hematocrit, platelets, activated partial thromboplastin time, fibrinogen, FV, FXIII, protein C activity, protein S, and protein S100 were observed (all P <= 0.001). CONCLUSIONS: Although most all laboratory and rotational thromboelastometry coagulation tests worsened over time when measured on-scene and in the ED, monitoring coagulation at the scene of trauma does not provide clinically important information in a majority of trauma patients. One hour after injury, significant activation and consumption of fibrinogen, FV, FXIII, protein C activity, and protein S were observed. PMID- 25545752 TI - Investigation of the pruritus-induced functional activity in the rat brain using manganese-enhanced MRI. AB - PURPOSE: To provide clear information on the activation regions of itching, we investigated the functional activity of cerebral regions in the pruritus-induced rat model using manganese-enhanced magnetic resonance imaging (MEMRI). MATERIALS AND METHODS: Itching was induced via neonatal capsaicin treatment in Sprague Dawley rats (itching rats), and scratching behavior of the control, itching, and gabapentin (GBP)-treated itching rats was compared. Then the activated or deactivated brain regions were investigated in the control, itching, and GBP treated itching rats using a 4.7T MRI system. RESULTS: While the itching rats engaged in vigorous scratching (121.2 +/- 22.4 times), the scratching behavior was decreased in the GBP-treated itching rats (30.6 +/- 8.8 times). GBP induced the attenuation of functional activity in two regions -7.10 mm from bregma, in one region -6.65 mm from bregma, and in one region -6.06 mm from bregma. The brain regions related to itching were as follows: parafascicular nucleus, thalamus, superior/inferior colliculus, periaqueductal gray, cingulate cortex, amygdala, midbrain regions, lateral habenula, and hypothalamic areas. CONCLUSION: Our MEMRI investigation indicates new functional activity of cerebral regions in rats due to the effect of itching or GBP. This information could be used to monitor the therapeutic effects of novel agents or for clinical strategies to treat pathological itch. PMID- 25545753 TI - A Ca(2+) concentration of 1.5 mM, as present in IMDM but not in RPMI, is critical for maximal response of Th cells to PMA/ionomycin. PMID- 25545754 TI - Detection of Norovirus and Sapovirus from diarrheic dogs and cats in Japan. AB - Norovirus (NoV) and sapovirus (SaV) are important causes of human diarrhea. In this study, between 2007 and 2014 fecal samples were collected from 97 dogs and 83 cats with diarrhea and examined to determine the prevalence of NoV and SaV infections in Japan. To detect caliciviruses, approximately 300 bases targeting the polymerase gene were amplified using RT-PCR and subjected to phylogenetic and homology analyses. Specific PCR products were obtained from four canine and nine feline samples: two canine and one feline isolate were classified as NoV, two canine isolates as SaV and the remaining eight feline isolates as vesivirus (VeV). The three NoV isolates were classified into the same clade as that of known canine and feline NoVs; their homologies (75.9-92.3%) were higher than those with human genogroup IV (GIV) NoVs (59.1-65.9%). The homology of the feline NoV isolate with previously reported feline NoV isolates was particularly high (91.7-92.3%). Regarding SaV, the two canine isolates were classified into the same clade as known canine SaVs and their homologies (72.5-86.5%) were higher than those with other mammal SaVs (20.7-58.0%). The eight feline VeV isolates were assumed to be feline calicivirus. The present study is the first report of the presence of NoV- and SaV-infected dogs and cats in Japan. The findings suggest there are species-specific circulations of NoV and SaV among dogs and cats, in Japan. PMID- 25545755 TI - Statistics commentary series: commentary #6--are trial participants representative of "real" patients? PMID- 25545756 TI - Dual-Functions of miR-373 and miR-520c by Differently Regulating the Activities of MMP2 and MMP9. AB - MicroRNA-520c (miR-520c) and microRNA-373 (miR-373) are originally characterized as both oncogenes and tumor suppressors in different types of human cancers. In this study, we found that translation of mRNA of MT1-MMP, an oncogene related to tumor metastasis, was well inhibited by miR-520c and miR-373 in several types of human cancer cells. Our experimental data demonstrated that these two microRNAs inhibited the translation of mRNA of MT1-MMP and down-regulated its proteolytic enzyme activities via targeting 3'UTR of mRNA of MT1-MMP, further decreased activating proMMP2 into active MMP2 in fibrosarcoma HT1080, benign prostatic hyperplasia epithelial cell BPH-1 and glioblastoma U87GM. More interestingly, from the effects of microRNAs on cell functions, we found that cell growth were all blocked on fibronectin and type IV collagen coated plates and also in three dimension type I collagen lattice but enhanced only in HT1080 cells on type IV collagen coated plates and in three-dimension type I collagen lattice; cell migration results showed the same effect as that of cell growth. The difference was due to up-regulating the expression of MMP9 gene by miR-520c and miR-373 in HT1080 cells but not in BPH-1 and U87GM cells. Our findings suggest that miR-520c and miR-373, which have different roles in different type of cancer via regulating the translation of mRNA of MT1-MMP and the expression of MMP9 gene, might have an important clue on clinic when selecting the therapeutic regimen and finding new drugs for intervention in different kinds of cancer. PMID- 25545757 TI - Glutamic acid not beneficial for the prevention of vincristine neurotoxicity in children with cancer. AB - BACKGROUND: Vincristine causes known side effects of peripheral sensory, motor, autonomic and cranial neuropathies. No preventive interventions are known. PROCEDURE: We performed a randomized, placebo-controlled, double-blind trial of oral glutamic acid as a preventive agent in pediatric patients with cancer who would be receiving vincristine therapy for at least 9 consecutive weeks (Stratum 1 = Wilms tumor and rhabdomyosarcoma) or 4 consecutive weeks in conjunction with steroids (Stratum 2 = Acute lymphoblastic leukemia and non-Hodgkin lymphoma). At designated time points, a scored neurologic exam using the Modified Balis Pediatric Scale of Peripheral Neuropathies was performed to document neurologic toxicity. RESULTS: Between 2007 and 2012, 250 patients were enrolled (Stratum 1 = 50, Stratum 2 = 200). The glutamic acid treated group did not have a significantly lower percentage of neurotoxicity compared to placebo treated group either overall or within stratum or age subgroups. The only subgroup which was suggestive of treatment effect was for age. Patients 13 years or older showed a larger benefit in favor of glutamic acid (P = 0.055) compared to patients less than 13 years (P = 1.00). Constipation was the most frequently reported (14%) Grade II or higher neurotoxicity. CONCLUSION: Vincristine-associated neurotoxicity in pediatric oncology remains a frequent complication of chemotherapy for multiple diagnoses with an approximate 30% of patients affected. Glutamic acid is not effective for prevention in pre-adolescents. There is a suggestion of benefit in patients 13 years or older, but the study was not designed to provide adequate power to test the treatment effect within this age group alone. PMID- 25545758 TI - Spinal cord injury is related to an increased risk of multiple sclerosis: a population-based, propensity score-matched, longitudinal follow-up study. AB - Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). Trauma to the CNS has been postulated to play a role in triggering CNS autoimmune disease. Although the association between traumatic brain injury and MS has been suggested in previous studies, epidemiological data on the association between spinal cord injury (SCI) and MS is still lacking. The aim of the present population-based, propensity score-matched, longitudinal follow-up study was therefore to investigate whether patients with SCI were at a higher risk of developing MS. A total of 11,913 subjects ages between 20 and 90 years with at least two ambulatory visits with the principal diagnosis of SCI in 2001 were enrolled in the SCI group. We used a logistic regression model that included age, sex, pre-existing comorbidities, and socioeconomic status as covariates to compute the propensity score. The non-SCI group consisted of 59,565 propensity score-matched, randomly sampled subjects without SCI. Stratified Cox proportional hazard regression with patients matched by propensity score was used to estimate the effect of SCI on the risk of developing subsequent MS. During follow-up, five subjects in the SCI group and four in the non-SCI group developed MS. The incidence rates of MS were 17.60 (95% confidence interval [CI], 5.71 41.0) per 100,000 person-years in the SCI group and 2.82 (95% CI, 0.77-7.22) per 100,000 person-years in the non-SCI group. Compared with the non-SCI group, the hazard ratio of MS for the SCI group was 8.33 (95% CI, 1.99-34.87, p=0.0037). Our study therefore shows that patients with SCI have an increased risk of developing MS. PMID- 25545759 TI - Parkinson's disease correlates with promoter methylation in the alpha-synuclein gene. AB - BACKGROUND: Genome-wide association studies have demonstrated association between SNCA variability and susceptibility to Parkinson's disease, but causal mechanisms are unclear. We hypothesized that risk variants affect methylation of a putative promoter in SNCA intron 1, previously highlighted in epigenetic studies of Parkinson's disease. METHODS: We analyzed sample sets from blood (n = 72) and cerebral cortex (n = 24) in Parkinson's disease patients and healthy controls. We genotyped SNCA single-nucleotide polymorphisms, examined messenger RNA (mRNA) expression and assessed intron 1 methylation levels by methylation-sensitive restriction enzyme digestion and quantitative polymerase chain reaction (PCR). RESULTS: Patients showed significant hypomethylation as compared with controls in the blood sample set. In addition, rs3756063 was associated with SNCA methylation level in both blood (P = 5.9 * 10(-5)) and brain (P = 0.023). CONCLUSIONS: Our findings support a link between SNCA variability, promoter methylation, and Parkinson's disease risk and indicate that methylation patterns in brain are mirrored in the blood. SNCA methylation warrants further investigation as a potential biomarker. PMID- 25545760 TI - Technical decision-making with higher order structure data: specific binding of a nonionic detergent perturbs higher order structure of a therapeutic monoclonal antibody. AB - Robust higher order structure (HOS) characterization capability and strategy are critical throughout biopharmaceutical development from initial candidate selection and formulation screening to process optimization and manufacturing. This case study describes the utility of several orthogonal HOS methods as investigational tools during purification process development. An atypically high level of residual detergent in a development drug substance batch of a therapeutic monoclonal antibody triggered a root cause investigation. Several orthogonal biophysical techniques were used to uncover and characterize a specific interaction between the detergent and the antibody. Isothermal titration calorimetry (ITC) was used to quantify the molar ratio and affinity of the binding event, and circular dichroism (CD) spectroscopy and differential scanning calorimetry (DSC) were used to evaluate corresponding impacts on secondary/tertiary structure and thermal stability, respectively. As detergents are used routinely in biopharmaceutical processing, this case study highlights the value and power of HOS data in informing technical investigations and underlines the importance of HOS characterization as a component of overall biopharmaceutical analytical control strategy. PMID- 25545761 TI - A large national cohort of French patients with chronic recurrent multifocal osteitis. AB - OBJECTIVE: To document more fully the characteristics of chronic recurrent multifocal osteomyelitis (CRMO) in pediatric patients, to collect data on the outcomes and management of the disease, and to define prognostic factors. METHODS: One hundred seventy-eight patients were included (123 female patients and 55 male patients), with a mean +/- SD age at diagnosis of 10.9 +/- 2.9 years. Inclusion criteria were a diagnosis of CRMO, evidence of at least one lesion of osteitis confirmed by imaging, and development of the syndrome before age 18 years. RESULTS: Longitudinal clinical and imaging studies revealed that only 12 of 178 CRMO patients (7%) had unifocal lesions at the last medical visit. We were able to apply the clinical chronic nonbacterial osteomyelitis score to 110 of 178 patients (62%), which indicated that bone biopsy could have been avoided in 27 cases (25%). At the last medical visit, disease was in remission in only 73 of 171 patients (43%) (41% receiving therapy) after a mean +/- SD of 47.9 +/- 38.9 months; 44 of 171 patients (26%) experienced sequelae. Using cluster analysis, the CRMO cohort was separated into 3 homogeneous phenotypes (severe, mild, and intermediate). Patients with the severe phenotype had the worst prognosis. This group was entirely composed of male patients, most of whom had the multifocal form of CRMO and inflammatory syndrome. Patients with the mild phenotype had the best prognosis. This group was primarily composed of female patients with a unifocal form of CRMO and infrequent clavicle involvement and inflammatory syndrome. Patients with the intermediate phenotype had a good prognosis but greater reliance on treatment. This group primarily included female patients with multifocal lesions and inflammatory syndrome. CONCLUSION: This is the largest CRMO cohort described in the literature to date. Clinical evolution and imaging investigations confirmed the multifocal pattern of the disease. Three distinct subgroups of CRMO patients were distinguished, with very different prognoses. PMID- 25545762 TI - Ingenol mebutate gel treatment for actinic cheilitis: report of four cases. AB - Actinic cheilitis (AC) are premalignant lesions that have an increased risk of malignant transformation. Their treatment, therefore, is essential to prevent carcinogenesis. However, optimal therapy is not well established and different modalities yield variable results. Ingenol mebutate gel has recently been approved by the US Food and Drug Administration for topical treatment of actinic keratosis, with high clearance rates. On the basis of these findings, we report our experience with this drug for the treatment of AC. PMID- 25545763 TI - Organizing pneumonia with atypical computed tomography findings in Sjogren's syndrome. PMID- 25545764 TI - Sexual discounting among high-risk youth ages 18-24: implications for sexual and substance use risk behaviors. AB - Youth under 25 show substantial sexual and substance use risk behaviors. One factor associated with risk behaviors is delay discounting, the devaluation of delayed outcomes. This study determined if delay discounting for sexual outcomes is related to sexual risk and substance use among 18-24 year olds. Females (70) and males (56) completed the Sexual Discounting Task, which assessed their likelihood of having unprotected immediate sex versus waiting for sex with a condom, at various delays, with 4 hypothetical sexual partners selected from photographs: the person they most wanted to have sex with, least wanted to have sex with, judged most likely to have a sexually transmitted infection (STI), and judged least likely to have an STI. They also completed instruments assessing HIV knowledge, sexual behaviors, substance use, risk attitudes, inhibition, impulsivity, and sensation-seeking. Condom use likelihood generally decreased with increasing delay. Preference for immediate, unprotected sex was greater for partners whom participants most (vs. least) wanted to have sex with and judged least (vs. most) likely to have an STI. Preference for immediate, unprotected sex in the "most want to have sex with" and "least likely to have an STI" conditions was related to greater lifetime risky sexual partners, lifetime number of unique substances used, disregard of social approval/danger, disinhibition, and sensation/excitement-seeking. Males showed greater likelihood of unprotected sex than females when condom use was undelayed, but delay similarly affected condom use between sexes. Delay discounting should be considered in strategies to minimize youth risk behavior. PMID- 25545765 TI - Paced mating behavior is affected by clitoral-vaginocervical lidocaine application in combination with sexual experience. AB - The present study tested the effects of lidocaine anesthetic ointment applied to the vaginocervical (Experiment 1) or clitoral-vaginocervical (Experiment 2) areas on the display of paced mating behavior over the course of five weekly tests in ovariectomized, hormone-primed, Long-Evans rats. Experiment 3 tested whether rats that acquired sexual experience without ointment application would exhibit altered paced mating behavior on a fifth test under clitoral-vaginocervical lidocaine or vehicle application. Although rats in Experiment 1 and Experiment 2 exhibited shorter contact-return latencies after intromission and reduced likelihood of leaving the male compartment following mounts and intromissions after gaining sexual experience, only rats that received clitoral-vaginocervical lidocaine exhibited altered paced mating behavior relative to vehicle. Specifically, clitoral-vaginocervical lidocaine resulted in shorter contact return latency to ejaculation and greater percentage of time with the male. Paced mating behavior of sexually experienced rats in Experiment 3 was not disrupted when tested after clitoral-vaginocervical lidocaine treatment. Together, these studies suggest that the sensory input during repeated mating encounters affects the pattern of paced mating behavior that develops with sexual experience. PMID- 25545766 TI - Investigating the long-term effect of subchronic phencyclidine-treatment on novel object recognition and the association between the gut microbiota and behavior in the animal model of schizophrenia. AB - Subchronic phencyclidine (subPCP) treatment induces schizophrenic-like behavior in rodents, including cognitive deficits and increased locomotor sensitivity towards acute administration of PCP. Evidence is accumulating that the gut microbiota (GM) influences behavior through modulation of the microbiota-gut brain axis, and hence, part of the variation within this animal model may derive from variation in the GM. The aims of this study was to investigate first, the duration of subPCP-induced cognitive impairment in the novel object recognition test, and second, the possible effect of subchronic PCP-treatment on the GM, and the association between the GM and the behavioral parameters. The association was further investigated by antibiotic reduction of the GM. Male Lister Hooded rats were dosed twice daily i.p. with either 5mg/kg PCP or sterile isotonic saline for seven days followed by a seven-day washout period. Rats were tested in the novel object recognition and the locomotor activity assays immediately after, three weeks after, or six weeks after washout, and the fecal GM was analyzed by high throughput sequencing. Antibiotic- and control-treated rats were tested in the same manner following washout. In conclusion, subPCP-treatment impaired novel object recognition up to three weeks after washout, whereas locomotor sensitivity was increased for at least six weeks after washout. Differences in the core gut microbiome immediately after washout suggested subPCP treatment to alter the GM. GM profiles correlated to memory performance. Administration of ampicillin abolished the subPCP-induced memory deficit. It thus seems reasonable to speculate that the GM influences memory performance, contributing to variation within the model. PMID- 25545768 TI - Evidence-based conservation: reply to Tepedino et al. PMID- 25545767 TI - Female breakfast skippers display a disrupted cortisol rhythm and elevated blood pressure. AB - Chronic stress and over-activity in the hypothalamic-pituitary-adrenal (HPA) axis may link breakfast skipping and poor cardiometabolic health. Missing the first major meal of the day in rodents prolongs elevated circulating corticosterone at a time when it's normally decreasing. To extend these findings to humans, we hypothesized that habitual breakfast skippers would display a similar pattern of circulating cortisol and alterations in meal and stress-induced cortisol reactions. Normal weight to obese women aged 18-45 years old who were strictly defined as either breakfast skippers (n=30) or breakfast eaters (n=35) were invited to participate in our study. Normal breakfast habits were maintained for the entire study period and each participant attended 4 lab visits. Over the first 2 lab visits, body composition, fasting clinical chemistries, and self reports of chronic stress were assessed. On each of 2 additional days (lab visits 3 and 4), salivary free cortisol was measured at home upon waking and at bedtime, and in the lab in response to a standard lunch, ad libitum afternoon snack buffet, and stress and control (relaxation) tasks. The order of the control and stress test visits was randomized. While body weight, body composition, HOMA-IR, total and HDL cholesterol did not statistically differ (p>0.05), both diastolic and systolic blood pressure was elevated (p<0.01) and LDL cholesterol was lower (p=0.04) in the breakfast skipper group. Compared to the breakfast eaters and on the control task visit only, breakfast skippers had higher circulating cortisol from arrival to midafternoon (p<0.01) and during the snack buffet (p<0.05). Furthermore, the lunch-induced cortisol reaction was larger in the 'skippers' (p=0.03). On both stress and control visit days, the diurnal cortisol amplitude was significantly (p=0.02) blunted in breakfast skippers. Self-reports of chronic stress did not differ between the groups. These data indicate that habitually skipping breakfast is associated with stress-independent over-activity in the HPA axis which, if prolonged, may increase risk (e.g., hypertension) for cardiometabolic disease in some people. PMID- 25545769 TI - Development and deployment of the Computer Assisted Neighborhood Visual Assessment System (CANVAS) to measure health-related neighborhood conditions. AB - Public health research has shown that neighborhood conditions are associated with health behaviors and outcomes. Systematic neighborhood audits have helped researchers measure neighborhood conditions that they deem theoretically relevant but not available in existing administrative data. Systematic audits, however, are expensive to conduct and rarely comparable across geographic regions. We describe the development of an online application, the Computer Assisted Neighborhood Visual Assessment System (CANVAS), that uses Google Street View to conduct virtual audits of neighborhood environments. We use this system to assess the inter-rater reliability of 187 items related to walkability and physical disorder on a national sample of 150 street segments in the United States. We find that many items are reliably measured across auditors using CANVAS and that agreement between auditors appears to be uncorrelated with neighborhood demographic characteristics. Based on our results we conclude that Google Street View and CANVAS offer opportunities to develop greater comparability across neighborhood audit studies. PMID- 25545770 TI - Social class inequalities in health among occupational cohorts from Finland, Britain and Japan: a follow up study. AB - We examined whether relative occupational social class inequalities in physical health functioning widen, narrow or remain stable among white collar employees from three affluent countries. Health functioning was assessed twice in occupational cohorts from Britain (1997-1999 and 2003-2004), Finland (2000-2002 and 2007) and Japan (1998-1999 and 2003). Widening inequalities were seen for British and Finnish men, whereas inequalities among British and Finnish women remained relatively stable. Japanese women showed reverse inequalities at follow up, but no health inequalities were seen among Japanese men. Health behaviours and social relations explained 4-37% of the magnitude in health inequalities, but not their widening. PMID- 25545772 TI - Care as a continuum: will hospital outcomes be influenced by outpatient care? PMID- 25545771 TI - Abnormal nuclear expression of Pygopus-2 in human primary hepatocellular carcinoma correlates with a poor prognosis. AB - AIMS: Pygopus-2 (Pygo2) is a critical element of the canonical Wnt/beta-catenin transcriptional complex. The aim of the present study was to investigate the expression patterns and clinicopathological significance of Pygo2 in human primary hepatocellular carcinoma (HCC). METHODS AND RESULTS: Real-time polymerase chain reaction (PCR) analysis of the mRNA levels of Pygo2 in 50 paired HCC cancer/adjacent non-cancerous tissues showed that Pygo2 mRNA expression was significantly higher in cancerous tissues (P = 0.009). Immunohistochemical analysis showed that abnormal Pygo2 protein expression in HCC patients was associated with age (P = 0.025), tumour size (P = 0.005), intra- or extra-hepatic metastasis (P = 0.029), vascular invasion (P = 0.026) and tumour differentiation (P = 0.004). Patients with normal Pygo2 protein expression showed a longer survival time (P = 0.031) and a higher 1-year survival rate (P = 0.032) than those with abnormal Pygo2 expression. Cox's proportional hazard regression model showed that abnormal Pygo2 protein expression was a risk factor associated with the prognosis of HCC patients (P = 0.043). CONCLUSION: To the best of our knowledge, this is the first report investigating Pygo2 expression patterns and their clinicopathological significance in HCC. Our findings suggest that Pygo2 may be an important predictor of poor outcome in HCC patients, and could serve as a novel biomarker for HCC. PMID- 25545773 TI - Pseudomonas putida Fis binds to the lapF promoter in vitro and represses the expression of LapF. AB - The biofilm matrix of the rhizospheric bacterium Pseudomonas putida consists mainly of a proteinaceous component. The two largest P. putida proteins, adhesins LapA and LapF, are involved in biofilm development but prevail in different developmental stages of the biofilm matrix. LapA is abundant in the initial stage of biofilm formation whereas LapF is found in the mature biofilm. Although the transcriptional regulation of the adhesins is not exhaustively studied, some factors that can be involved in their regulation have been described. For example, RpoS, the major stress response sigma factor, activates, and Fis represses LapF expression. This study focused on the LapF expression control by Fis. Indeed, using DNase I footprint analysis a Fis binding site Fis-F2 was located 150 bp upstream of the lapF gene coding sequence. The mapped 5' end of the lapF mRNA localized the promoter to the same region, overlapping with the Fis binding site Fis-F2. Monitoring the lapF promoter activity by a beta galactosidase assay revealed that Fis overexpression causes a 4-fold decrease in the transcriptional activity. Furthermore, mutations that diminished Fis binding to the Fis-F2 site abolished the repression of the lapF promoter. Thus, these data suggest that Fis is involved in the biofilm regulation via repression of LapF expression. PMID- 25545774 TI - Comparative analysis of macaque and human sperm proteomes: Insights into sperm competition. AB - Male macaques produce faster sperm than male humans due to a higher pressure of sperm competition in macaques. To explore the molecular basis of this biological difference, we firstly constructed macaque and human sperm proteomes using LC MS/MS. We then detected the positively selected genes specifically on the branch of macaque based on branch-site likelihood method. We identified 197 positively selected genes specifically on the branch of macaque that are unselected in corresponding human orthologs. These genes are highly associated with mitochondria and axoneme that directly drive sperm motility. We further compared the ultrastructural differences of the midpiece between macaque and human sperms to provide evidence for our findings using transmission electron microscopy. In conclusion, our results provide potential molecular targets for explaining the different phenotypes under sperm competition between macaques and humans, and also provide resources for the analysis of male fertility. PMID- 25545775 TI - Evaluation of a murine single-blood-injection SAH model. AB - The molecular pathways underlying the pathogenesis after subarachnoid haemorrhage (SAH) are poorly understood and continue to be a matter of debate. A valid murine SAH injection model is not yet available but would be the prerequisite for further transgenic studies assessing the mechanisms following SAH. Using the murine single injection model, we examined the effects of SAH on regional cerebral blood flow (rCBF) in the somatosensory (S1) and cerebellar cortex, neuro behavioural and morphological integrity and changes in quantitative electrocorticographic and electrocardiographic parameters. Micro CT imaging verified successful blood delivery into the cisterna magna. An acute impairment of rCBF was observed immediately after injection in the SAH and after 6, 12 and 24 hours in the S1 and 6 and 12 hours after SAH in the cerebellum. Injection of blood into the foramen magnum reduced telemetric recorded total ECoG power by an average of 65%. Spectral analysis of ECoGs revealed significantly increased absolute delta power, i.e., slowing, cortical depolarisations and changes in ripples and fast ripple oscillations 12 hours and 24 hours after SAH. Therefore, murine single-blood-injection SAH model is suitable for pathophysiological and further molecular analysis following SAH. PMID- 25545776 TI - Kinetic parameter estimation in N. europaea biofilms using a 2-D reactive transport model. AB - Biofilms of the ammonia oxidizing bacterium Nitrosomonas europaea were cultivated to study microbial processes associated with ammonia oxidation in pure culture. We explored the hypothesis that the kinetic parameters of ammonia oxidation in N. europaea biofilms were in the range of those determined with batch suspended cells. Oxygen and pH microelectrodes were used to measure dissolved oxygen (DO) concentrations and pH above and inside biofilms and reactive transport modeling was performed to simulate the measured DO and pH profiles. A two dimensional (2 D) model was used to simulate advection parallel to the biofilm surface and diffusion through the overlying fluid while reaction and diffusion were simulated in the biofilm. Three experimental studies of microsensor measurements were performed with biofilms: i) NH3 concentrations near the Ksn value of 40 MUM determined in suspended cell tests ii) Limited buffering capacity which resulted in a pH gradient within the biofilms and iii) NH3 concentrations well below the Ksn value. Very good fits to the DO concentration profiles both in the fluid above and in the biofilms were achieved using the 2-D model. The modeling study revealed that the half-saturation coefficient for NH3 in N. europaea biofilms was close to the value measured in suspended cells. However, the third study of biofilms with low availability of NH3 deviated from the model prediction. The model also predicted shifts in the DO profiles and the gradient in pH that resulted for the case of limited buffering capacity. The results illustrate the importance of incorporating both key transport and chemical processes in a biofilm reactive transport model. PMID- 25545778 TI - Systematic Review of Health Economic Analyses of Measles and Rubella Immunization Interventions. AB - Economic analyses for vaccine-preventable diseases provide important insights about the value of prevention. We reviewed the literature to identify all of the peer-reviewed, published economic analyses of interventions related to measles and rubella immunization options to assess the different types of analyses performed and characterize key insights. We searched PubMed, the Science Citation Index, and references from relevant articles for studies in English and found 67 analyses that reported primary data and quantitative estimates of benefit-cost or cost-effectiveness analyses for measles and/or rubella immunization interventions. We removed studies that we characterized as cost-minimization analyses from this sample because they generally provide insights that focused on more optimal strategies to achieve the same health outcome. The 67 analyses we included demonstrate the large economic benefits associated with preventing measles and rubella infections using vaccines and the benefit of combining measles and rubella antigens into a formulation that saves the costs associated with injecting the vaccines separately. Despite the importance of population immunity and dynamic viral transmission, most of the analyses used static models to estimate cases prevented and characterize benefits, although the use of dynamic models continues to increase. Many of the analyses focused on characterizing the most significant adverse outcomes (e.g., mortality for measles, congenital rubella syndrome for rubella) and/or only direct costs, and the most complete analyses present data from high-income countries. PMID- 25545777 TI - Demineralized bone matrix combined bone marrow mesenchymal stem cells, bone morphogenetic protein-2 and transforming growth factor-beta3 gene promoted pig cartilage defect repair. AB - OBJECTIVES: To investigate whether a combination of demineralized bone matrix (DBM) and bone marrow mesenchymal stem cells (BMSCs) infected with adenovirus mediated- bone morphogenetic protein (Ad-BMP-2) and transforming growth factor beta3 (Ad-TGF-beta3) promotes the repair of the full-thickness cartilage lesions in pig model. METHODS: BMSCs isolated from pig were cultured and infected with Ad BMP-2(B group), Ad-TGF-beta3 (T group), Ad-BMP-2 + Ad-TGF-beta3(BT group), cells infected with empty Ad served as a negative group(N group), the expression of the BMP-2 and TGF-beta3 were confirmed by immunofluorescence, PCR, and ELISA, the expression of SOX-9, type II collagen(COL-2A), aggrecan (ACAN) in each group were evaluated by real-time PCR at 1w, 2w, 3w, respectively. The chondrogenic differentiation of BMSCs was evaluated by type II collagen at 21d with immunohistochemical staining. The third-passage BMSCs infected with Ad-BMP-2 and Ad-TGF-beta3 were suspended and cultured with DBM for 6 days to construct a new type of tissue engineering scaffold to repair full-thickness cartilage lesions in the femur condyles of pig knee, the regenerated tissue was evaluated at 1,2 and 3 months after surgery by gross appearance, H&E, safranin O staining and O'driscoll score. RESULTS: Ad-BMP-2 and Ad-TGF-beta3 (BT group) infected cells acquired strong type II collagen staining compared with Ad-BMP-2 (B group) and Ad-TGF beta3 (T group) along. The Ad-BMP-2 and Ad-TGF-beta3 infected BMSCs adhered and propagated well in DBM and the new type of tissue engineering scaffold produced hyaline cartilage morphology containing a stronger type II collagen and safranin O staining, the O'driscoll score was higher than other groups. CONCLUSIONS: The DBM compound with Ad-BMP-2 and Ad-TGF-beta3 infected BMSCs scaffold has a good biocompatibility and could well induce cartilage regeneration to repair the defects of joint cartilage. This technology may be efficiently employed for cartilage lesions repair in vivo. PMID- 25545780 TI - Material need insecurities, control of diabetes mellitus, and use of health care resources: results of the Measuring Economic Insecurity in Diabetes study. AB - IMPORTANCE: Increasing access to care may be insufficient to improve the health of patients with diabetes mellitus and unmet basic needs (hereinafter referred to as material need insecurities). How specific material need insecurities relate to clinical outcomes and the use of health care resources in a setting of near universal access to health care is unclear. OBJECTIVE: To determine the association of food insecurity, cost-related medication underuse, housing instability, and energy insecurity with control of diabetes mellitus and the use of health care resources. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional data were collected from June 1, 2012, through October 31, 2013, at 1 academic primary care clinic, 2 community health centers, and 1 specialty center for the treatment of diabetes mellitus in Massachusetts. A random sample of 411 patients, stratified by clinic, consisted of adults (aged >=21 years) with diabetes mellitus (response rate, 62.3%). MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was a composite indicator of poor diabetes control (hemoglobin A1c level, >9.0%; low-density lipoprotein cholesterol level, >100 mg/dL; or blood pressure, >140/90 mm Hg). Prespecified secondary outcomes included outpatient visits and a composite of emergency department (ED) visits and acute care hospitalizations (ED/inpatient visits). RESULTS: Overall, 19.1% of respondents reported food insecurity; 27.6%, cost-related medication underuse; 10.7%, housing instability; 14.1%, energy insecurity; and 39.1%, at least 1 material need insecurity. Poor diabetes control was observed in 46.0% of respondents. In multivariable models, food insecurity was associated with a greater odds of poor diabetes control (adjusted odds ratio [OR], 1.97 [95% CI, 1.58-2.47]) and increased outpatient visits (adjusted incident rate ratio [IRR], 1.19 [95% CI, 1.05-1.36]) but not increased ED/inpatient visits (IRR, 1.00 [95% CI, 0.51 1.97]). Cost-related medication underuse was associated with poor diabetes control (OR, 1.91 [95% CI, 1.35-2.70]) and increased ED/inpatient visits (IRR, 1.68 [95% CI, 1.21-2.34]) but not outpatient visits (IRR, 1.07 [95% CI, 0.95 1.21]). Housing instability (IRR, 1.31 [95% CI, 1.14-1.51]) and energy insecurity (IRR, 1.12 [95% CI, 1.00-1.25]) were associated with increased outpatient visits but not with diabetes control (OR, 1.10 [95% CI, 0.60-2.02] and OR, 1.27 [95% CI, 0.96-1.69], respectively) or with ED/inpatient visits (IRR, 1.49 [95% CI, 0.81 2.73] and IRR, 1.31 [95% CI, 0.80-2.13], respectively). An increasing number of insecurities was associated with poor diabetes control (OR for each additional need, 1.39 [95% CI, 1.18-1.63]) and increased use of health care resources (IRR for outpatient visits, 1.09 [95% CI, 1.03-1.15]; IRR for ED/inpatient visits, 1.22 [95% CI, 0.99-1.51]). CONCLUSIONS AND RELEVANCE: Material need insecurities were common among patients with diabetes mellitus and had varying but generally adverse associations with diabetes control and the use of health care resources. Material need insecurities may be important targets for improving care of diabetes mellitus. PMID- 25545782 TI - Anticancer activity using positron emission tomography-computed tomography and pharmacokinetics of beta-eudesmol in human cholangiocarcinoma xenografted nude mouse model. AB - Cholangiocarcinoma (CCA) is an important public health problem in several parts of South East Asia, particularly in Thailand. The limited availability of effective diagnostic tools for early stage CCA, including chemotherapeutic options, constitutes a major problem for treatment and control of CCA. The aim of the present study was to assess the anti-CCA activity and pharmacokinetics of beta-eudesmol in CCA-xenografted nude mouse model and healthy mice. Positron emission tomography-computed tomography (PET-CT) with (18)F-fluorodeoxyglucose was used for detecting and monitoring tumour development, and PET-CT with technetium-99m was used to investigate its pharmacokinetics property. Results support the role of PET-CT as a potential tool for detecting and monitoring the progress of lung metastasis. Tumour size and lung metastasis were significantly inhibited by 91.6% (of baseline) and 95% (of total lung mass), respectively, following treatment with high-dose beta-eudesmol (100 mg/kg body weight for 30 days). Survival time was prolonged by 64.4% compared with untreated controls. Systemic clearance of the compound was rapid, particularly during the first 60 min. The compound was distributed to the vital organs at maximum levels 2 h after oral administration and 15 min after intravenous injection. Results from the present study suggest the potential of beta-eudesmol as a promising candidate for further development as an anti-CCA drug with respect to its pharmacodynamics and pharmacokinetic properties. PET-CT, with radiotracers (18)F-fluorodeoxyglucose and technetium-99m, was shown to be a reliable tool in the investigation of anti CCA and pharmacokinetic properties of beta-eudesmol in CCA-xenografted and healthy mice. PMID- 25545781 TI - Impact of peripheral nerve block with low dose local anesthetics on analgesia and functional outcomes following total knee arthroplasty: a retrospective study. AB - OBJECTIVE: While the safety and efficacy of peripheral nerve blocks for postoperative pain management has been established in several well controlled prospective trials, the local anesthetic (LA) concentration and volume used in these studies was associated with a significant increase muscle weakness due to motor nerve block. The purpose of the present retrospective study of patients undergoing total knee arthroplasty was to assess the relative analgesic efficacy and functional outcomes of the low concentration, low volume of LA used in peripheral nerve blocks for postoperative pain management. METHODS: Twenty-four months of deidentified patient data were extracted from an electronic medical record system. All patients received opioids with or without continuous femoral and sciatic nerve block infusions for postoperative analgesia. Pain (resting and with activity), cumulative opioid and LA use were primary endpoints, participation in physical therapy (PT), muscle strength deficits and length of hospital stay (LOS) were secondary endpoints. RESULTS: Postoperative pain and opioid use were significantly lower in patients with peripheral nerve blocks (n = 1,329) than those with opioids alone (n = 439). There was no detectable decrease in strength associated with nerve blocks, while a significantly greater proportion of patients with nerve blocks were able to participate in PT on postoperative day 1 (96.4% vs 57.1%). These differences were not due to the impact of the surgeon per se, but whether or not the surgeon used nerve blocks for pain management. There was a small but statistically significant decrease in the average LOS in patients with blocks. CONCLUSION: This analysis supports the use of low concentration, low volume of LA based peripheral nerve blocks for postoperative pain management. PMID- 25545783 TI - Development of a microfluidic-based assay on a novel nitrocellulose platform. AB - A novel microfluidic paper-based analytical device (MUPAD) utilizing a nitrocellulose (NC) membrane to detect IgG antibodies through a colorimetric analysis is described. The MUPAD was constructed using layered polyethylene terephthalate (PET) and pressure-sensitive adhesives (PSA). The biotin labeled Goat Anti-Mouse IgG antibody was spotted and dried on the NC channel prior to subjecting it to a series of wash solutions (Tris-tween), increasing concentrations of alkaline phosphatase conjugated to streptavidin (Strep-ALP), and para-nitrophenyl phosphate (p-NPP) realizing a vibrant yellow color. The reaction proceeds for 10 min before applying the p-NPP stop solution. The device was then dried, scanned, and analyzed yielding a linear range of inverse yellow color intensities versus Strep-ALP concentrations. The development of this simple MUPAD should further facilitate the use of NC in colorimetric assays to detect and quantitate antibodies. PMID- 25545784 TI - Abnormal hippocampal morphology in dissociative identity disorder and post traumatic stress disorder correlates with childhood trauma and dissociative symptoms. AB - Smaller hippocampal volume has been reported in individuals with post-traumatic stress disorder (PTSD) and dissociative identity disorder (DID), but the regional specificity of hippocampal volume reductions and the association with severity of dissociative symptoms and/or childhood traumatization are still unclear. Brain structural magnetic resonance imaging scans were analyzed for 33 outpatients (17 with DID and 16 with PTSD only) and 28 healthy controls (HC), all matched for age, sex, and education. DID patients met criteria for PTSD (PTSD-DID). Hippocampal global and subfield volumes and shape measurements were extracted. We found that global hippocampal volume was significantly smaller in all 33 patients (left: 6.75%; right: 8.33%) compared with HC. PTSD-DID (left: 10.19%; right: 11.37%) and PTSD-only with a history of childhood traumatization (left: 7.11%; right: 7.31%) had significantly smaller global hippocampal volume relative to HC. PTSD-DID had abnormal shape and significantly smaller volume in the CA2-3, CA4-DG and (pre)subiculum compared with HC. In the patient groups, smaller global and subfield hippocampal volumes significantly correlated with higher severity of childhood traumatization and dissociative symptoms. These findings support a childhood trauma-related etiology for abnormal hippocampal morphology in both PTSD and DID and can further the understanding of neurobiological mechanisms involved in these disorders. PMID- 25545785 TI - The effect of inversion at 8p23 on BLK association with lupus in Caucasian population. AB - To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population. METHODS: Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed. RESULTS: Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18*10(-7), OR = 1.18, 95%CI = 1.10-1.26). CONCLUSION: Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus. PMID- 25545786 TI - Heterologous expression of the AtDREB1A gene in transgenic peanut-conferred tolerance to drought and salinity stresses. AB - Research on genetic transformation in various crop plants using the DREB1A transcription factor has shown better abiotic stress tolerance in transgenic crops. The AtDREB1A transgenic peanut (Arachis hypogaea L. cv. GG 20), which was previously developed, was characterized in terms of its physio-biochemical, molecular and growth parameters. The tolerance of this transgenic peanut to drought and salinity stresses was evaluated at the seedling (18 days old) and maturity stages. Transgenic peanut lines showed improved tolerance to both stresses over wild-type, as observed by delayed and less severe wilting of leaves and by improved growth parameters that were correlated with physio-biochemical parameters such as proline content, total chlorophyll content, osmotic potential, electrolytic leakage and relative water content. The expression pattern of the AtDREB1A gene evaluated using qPCR at different time points demonstrated that transgene expression was induced within two hours of stress imposition. The better performance of transgenic AtDREB1A peanut at the seedling stage and the improved growth parameters were due to the expression of the transgene, which is a transcription factor, and the possible up-regulation of various stress inducible, downstream genes in the signal transduction pathway under abiotic stress. PMID- 25545787 TI - Thrombolytic protocol minimizes ischemic-type biliary complications in liver transplantation from donation after circulatory death donors. AB - Liver transplantation (LT) with donation after circulatory death (DCD) donors has been associated with a high rate of ischemic-type biliary strictures (ITBSs) and inferior graft survival. To investigate the impact of an intraoperative tissue plasminogen activator (tPA) on outcomes following DCD LT, we conducted a retrospective analysis of DCD LT at the Toronto General Hospital (TGH) and the Ochsner Medical Center (OMC). Between 2009 and 2013, 85 DCD LTs were performed with an intraoperative tPA injection (n = 30 at TGH, n = 55 at OMC), and they were compared with 33 DCD LTs without a tPA. Donor and recipient characteristics were similar in the 2 groups. There was no significant difference in the intraoperative packed red blood cell transfusion requirement (3.2 +/- 3.4 versus 3.1 +/- 2.3 U, P = 0.74). Overall, biliary strictures occurred less commonly in the tPA-treated group (16.5% versus 33.3%, P = 0.07) with a much lower rate of diffuse intrahepatic strictures (3.5% versus 21.2%, P = 0.005). After 1 and 3 years, the tPA group versus the non-tPA group had superior patient survival (97.6% versus 87.0% and 92.7% versus 79.7%, P = 0.016) and graft survival (96.4% versus 69.7% and 90.2% versus 63.6%, P < 0.001). In conclusion, a tPA injection into the hepatic artery during DCD LT reduces ITBSs and improves graft and patient survival without increasing the risk for bleeding. PMID- 25545788 TI - The genetic structure of an invasive pest, the Asian citrus psyllid Diaphorina citri (Hemiptera: Liviidae). AB - The Asian citrus psyllid Diaphorina citri is currently the major threat to the citrus industry as it is the vector of Candidatus Liberibacter, the causal agent of huanglongbing disease (HLB). D. citri is native to Asia and now colonizes the Americas. Although it has been known in some countries for a long time, invasion routes remain undetermined. There are no efficient control methods for the HLB despite the intensive management tools currently in use. We investigated the genetic variability and structure of populations of D. citri to aid in the decision making processes toward sustainable management of this species/disease. We employed different methods to quantify and compare the genetic diversity and structure of D. citri populations among 36 localities in Brazil, using an almost complete sequence of the cytochrome oxidase I (COI) gene. Our analyses led to the identification of two geographically and genetically structured groups. The indices of molecular diversity pointed to a recent population expansion, and we discuss the role of multiple invasion events in this scenario. We also argue that such genetic diversity and population structure may have implications for the best management strategies to be adopted for controlling this psyllid and/or the disease it vectors in Brazil. PMID- 25545789 TI - Strong premating reproductive isolation drives incipient speciation in Mimulus aurantiacus. AB - Determining which forms of reproductive isolation have the biggest impact on the process of divergence is a major goal of speciation research. These barriers are often divided into those that affect the potential for hybridization (premating isolation), and those that occur after mating (postmating isolation), and much debate has surrounded the relative importance of these categories. Within the species Mimulus aurantiacus, red- and yellow-flowered ecotypes occur in the southwest corner of California, and a hybrid zone occurs where their ranges overlap. We show that premating barriers are exclusively responsible for isolation in this system, with both ecogeographic and pollinator isolation contributing significantly to total isolation. Postmating forms of reproductive isolation have little or no impact on gene flow, indicating that hybrids likely contribute to introgression at neutral loci. Analysis of molecular variation across thousands of restriction-site associated DNA sequencing (RAD-seq) markers reveals that the genomes of these taxa are largely undifferentiated. However, structure analysis shows that these taxa are distinguishable genetically, likely due to the impact of loci underlying differentiated adaptive phenotypes. These data exhibit the power of divergent natural selection to maintain highly differentiated phenotypes in the face of gene flow during the early stages of speciation. PMID- 25545791 TI - Effect of smoke derivatives on in vitro pollen germination and pollen tube elongation of species from different plant families. AB - Plant-derived smoke stimulates seed germination in numerous plant species. Smoke also has a positive stimulatory effect on pollen germination and pollen tube growth. The range of plant families affected my smoke still needs to be established since the initial study was restricted to only three species from the Amaryllidaceae. The effects of smoke-water (SW) and the smoke-derived compounds, karrikinolide (KAR1 ) and trimethylbutenolide (TMB) on pollen growth characteristics were evaluated in seven different plant families. Smoke-water (1:1000 and 1:2000 v:v) combined with either Brewbaker and Kwack's (BWK) medium or sucrose and boric acid (SB) medium significantly improved pollen germination and pollen tube growth in Aloe maculata All., Kniphofia uvaria Oken, Lachenalia aloides (L.f.) Engl. var. aloides and Tulbaghia simmleri P. Beauv. Karrikinolide (10(-6) and 10(-7) m) treatment significantly improved pollen tube growth in A. maculata, K. uvaria, L. aloides and Nematanthus crassifolius (Schott) Wiehle compared to the controls. BWK or SB medium containing TMB (10(-3) m) produced significantly longer pollen tubes in A. maculata, K. uvaria and N. crassifolius. These results indicate that plant-derived smoke and the smoke-isolated compounds may stimulate pollen growth in a wide range of plant species. PMID- 25545790 TI - Hydrogen sulfide inhibits amyloid formation. AB - Amyloid fibrils are large aggregates of misfolded proteins, which are often associated with various neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and vascular dementia. The amount of hydrogen sulfide (H2S) is known to be significantly reduced in the brain tissue of people diagnosed with Alzheimer's disease relative to that of healthy individuals. These findings prompted us to investigate the effects of H2S on the formation of amyloids in vitro using a model fibrillogenic protein hen egg white lysozyme (HEWL). HEWL forms typical beta-sheet rich fibrils during the course of 70 min at low pH and high temperatures. The addition of H2S completely inhibits the formation of beta-sheet and amyloid fibrils, as revealed by deep UV resonance Raman (DUVRR) spectroscopy and ThT fluorescence. Nonresonance Raman spectroscopy shows that disulfide bonds undergo significant rearrangements in the presence of H2S. Raman bands corresponding to disulfide (RSSR) vibrational modes in the 550 500 cm(-1) spectral range decrease in intensity and are accompanied by the appearance of a new 490 cm(-1) band assigned to the trisulfide group (RSSSR) based on the comparison with model compounds. The formation of RSSSR was proven further using a reaction with TCEP reduction agent and LC-MS analysis of the products. Intrinsic tryptophan fluorescence study shows a strong denaturation of HEWL containing trisulfide bonds. The presented evidence indicates that H2S causes the formation of trisulfide bridges, which destabilizes HEWL structure, preventing protein fibrillation. As a result, small spherical aggregates of unordered protein form, which exhibit no cytotoxicity by contrast with HEWL fibrils. PMID- 25545792 TI - Long-term prospective evaluation comparing robotic parathyroidectomy with minimally invasive open parathyroidectomy for primary hyperparathyroidism. AB - BACKGROUND: Targeted parathyroidectomy is a popular technique for localized pathology. No single technique is established as superior. The purpose of this study was to compare robotic-assisted parathyroidectomy (RAP) with the most common approach. METHODS: This was a prospective, nonrandomized study. Fifteen consecutive patients who underwent RAP were compared to 15 matched controls undergoing focused lateral parathyroidectomy (FLP). RESULTS: Biochemical cure occurred in 29 of 30 patients (97%). No major complications occurred, although there was 1 robotic conversion. RAP demonstrated a significant time reduction (R(2) = 0.436; p = .01) but took much longer to perform than FLP (119 minutes vs 34 minutes; p = .001). RAP was associated with less initial postoperative pain (p = .036) and higher satisfaction with scar cosmesis (p = .002) until 6 months. Quality of life (QOL) improved in both groups (p = .007). CONCLUSION: RAP provides superior early cosmesis with equivalent global health improvement compared to FLP. The high cost and learning curve may preclude widespread adoption. Further evaluation is necessary to establish its clinical efficacy regarding scar cosmesis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E300-E7, 2016. PMID- 25545793 TI - Interacting memory systems-does EEG alpha activity respond to semantic long-term memory access in a working memory task? AB - Memory consists of various individual processes which form a dynamic system co ordinated by central (executive) functions. The episodic buffer as direct interface between episodic long-term memory (LTM) and working memory (WM) is fairly well studied but such direct interaction is less clear in semantic LTM. Here, we designed a verbal delayed-match-to-sample task specifically to differentiate between pure information maintenance and mental manipulation of memory traces with and without involvement of access to semantic LTM. Task related amplitude differences of electroencephalographic (EEG) oscillatory brain activity showed a linear increase in frontal-midline theta and linear suppression of parietal beta amplitudes relative to memory operation complexity. Amplitude suppression at upper alpha frequency, which was previously found to indicate access to semantic LTM, was only sensitive to mental manipulation in general, irrespective of LTM involvement. This suggests that suppression of upper EEG alpha activity might rather reflect unspecific distributed cortical activation during complex mental processes than accessing semantic LTM. PMID- 25545794 TI - Redox regulated peroxisome homeostasis. AB - Peroxisomes are ubiquitous organelles present in nearly all eukaryotic cells. Conserved functions of peroxisomes encompass beta-oxidation of fatty acids and scavenging of reactive oxygen species generated from diverse peroxisomal metabolic pathways. Peroxisome content, number, and size can change quickly in response to environmental and/or developmental cues. To achieve efficient peroxisome homeostasis, peroxisome biogenesis and degradation must be orchestrated. We review the current knowledge on redox regulated peroxisome biogenesis and degradation with an emphasis on yeasts and plants. PMID- 25545795 TI - Cellular interactions and photoprotective effects of idebenone-loaded nanostructured lipid carriers stabilized using PEG-free surfactant. AB - In past years, nanostructured lipid carriers (NLCs) have emerged as novel topical antioxidant delivery systems because of combined positive features of liposomes and polymeric nanoparticles. Here, we seek to unlock the possibility of idebenone (IDB; an antioxidant)-loaded NLCs (IDB-NLCs) cellular interactions such as, viability and uptake, and its photoprotective effects against Ultraviolet-B (UVB) mediated oxidative stress in immortal human keratinocyte cell line (HaCaT). The two-step preformulation strategy followed by three-level, three-variable, L9 (3(3)) Taguchi robust orthogonal design employed was important in improving IDB NLCs key physicochemical aspects such as, entrapment efficiency, drug release (sustained), occlusion, skin deposition and physical stability. UV crosslinker, confocal microscopy and flow cytometry techniques were used to (1) mediate oxidative stress in HaCaT cells, (2) study a qualitative cellular uptake, (3) measure intracellular reactive oxygen species (ROS), and mitochondrial membrane potential, respectively. NLCs markedly improved biocompatibility of IDB under normal as well as stress conditions. Quantitative and qualitative cell uptake studies demonstrated a significant uptake of IDB-NLCs (3-fold increase) and nile red-labeled IDB-NLCs (NR-IDB-NLCs) at 2 h, respectively, hence exerted improved photoprotective effects. PMID- 25545796 TI - Transport properties in aqueous ethambutol dihydrochloride. AB - Mutual diffusion coefficients, densities and viscosities are reported for aqueous solutions of ethambutol as its dihydrochloride (EMBDHC) at finite concentrations and at 298.15K. From these experimental results and by using the appropriate models (Stokes-Einstein and Hartley), the hydrodynamic radii Rh, the diffusion coefficient at infinitesimal concentration D(0) and the thermodynamic factors, FT, have been estimated, permitting us to have a better understanding of the transport behavior of ethambutol dihydrochloride in solution. Elucidation of lack of any possible drug-drug interactions in these systems was obtained by complementary (1)H nuclear magnetic resonance (NMR) spectroscopy data. PMID- 25545798 TI - Direct-write deposition and focused-electron-beam-induced purification of gold nanostructures. AB - Three-dimensional gold (Au) nanostructures offer promise in nanoplasmonics, biomedical applications, electrochemical sensing and as contacts for carbon-based electronics. Direct-write techniques such as focused-electron-beam-induced deposition (FEBID) can provide such precisely patterned nanostructures. Unfortunately, FEBID Au traditionally suffers from a high nonmetallic content and cannot meet the purity requirements for these applications. Here we report exceptionally pure pristine FEBID Au nanostructures comprising submicrometer large monocrystalline Au sections. On the basis of high-resolution transmission electron microscopy results and Monte Carlo simulations of electron trajectories in the deposited nanostructures, we propose a curing mechanism that elucidates the observed phenomena. The in situ focused-electron-beam-induced curing mechanism was supported by postdeposition ex situ curing and, in combination with oxygen plasma cleaning, is utilized as a straightforward purification method for planar FEBID structures. This work paves the way for the application of FEBID Au nanostructures in a new generation of biosensors and plasmonic nanodevices. PMID- 25545797 TI - A bufadienolide-loaded submicron emulsion for oral administration: stability, antitumor efficacy and toxicity. AB - The purpose of this study was to develop an alternative submicron emulsion containing three bufadienolides for oral administration and evaluate its preclinical stability, efficacy, and toxicity. The bufadienolide-loaded oral submicron emulsion (BU-OE) was prepared by high-pressure homogenization. The storage stability, in vitro cytotoxicity, in vivo antitumor efficacy, acute toxicity, and long-term toxicity of BU-OE were investigated in detail to evaluate the formulation. The stability study suggested that BU-OE was stable at room temperature and could be stored for at least 18 months at 6+/-2 degrees C. The cytotoxicity test revealed that BU-OE had marked cytotoxic activities against cancer cells, but no evident inhibitory effects on normal cells. Likewise, BU-OE exhibited significant antitumor efficacy against Hep G2, HCT-8, and EC9706 cell lines and a slight inhibitory effect on BGC 803 cell line in nude mice, while comparable antitumor activity with fluorouracil injection. The LD50 of BU-OE in mice was 29.4 mg/kg (male) and 22.8 mg/kg (female), respectively. As for the long term toxicity, BU-OE showed no apparent toxic effects except minor cardiotoxic effects which were reversible. In conclusion, submicron emulsion is a suitable delivery system for oral administration of bufadienolides, with satisfactory stability, superior antitumor efficacy and low toxicity. PMID- 25545799 TI - Practical route to 2-quinolinones via a Pd-catalyzed C-H bond activation/C-C bond formation/cyclization cascade reaction. AB - Quinolinone derivatives were constructed via a Pd-catalyzed C-H bond activation/C C bond formation/cyclization cascade process with simple anilines as the substrates. This finding provides a practical procedure for the synthesis of quinolinone-containing alkaloids and drug molecules. The utility of this method was demonstrated by a formal synthesis of Tipifarnib. PMID- 25545801 TI - Application of species sensitivity distribution in aquatic probabilistic ecological risk assessment of cypermethrin: a case study in an urban stream in South China. AB - A tiered ecological risk assessment was applied to quantitatively refine the overall probabilistic risk of cypermethrin, a pyrethroid insecticide, to aquatic organisms. These results were then validated through the bioassays using field water from an urban stream, Chebei Creek in Guangzhou, South China. Seventeen water samples were collected along Chebei Creek for evaluation. In total, 71% of the field waters were acutely toxic to Hyallela azteca and 24% of the waters caused 100% mortality. Toxic unit evaluation suggested that cypermethrin was one of the main contributors to toxicity. The tiered ecological risk assessment approach (deterministic quotient method and probabilistic methods, including joint probability curve and Monte Carlo Simulation) suggested that cypermethrin posed significant threats to aquatic ecology in this stream. The overall probabilistic risk of cypermethrin to aquatic species in Chebei Creek reached 66% when acute-to-chronic ratios were set at 125. An exceedance probability of cypermethrin in Chebei Creek that affected H. azteca as modeled using the joint probability curve method was 88%, suggesting that most sites were at risk due to cypermethrin exposure. This value was similar to the results obtained from acute toxicity tests (71% of field water samples were acutely toxic to H. azteca), indicating the effectiveness of the tiered approach to assess risk of cypermethrin in urban waterways. To the authors' knowledge, the present study is the first to provide a focused probabilistic evaluation of ecological risk for cypermethrin in a complex urban waterway environment. Despite uncertainties existing in the ecological risk assessment procedure, this approach provides a comprehensive assessment of ecological risk of cypermethrin, and subsequently, a foundation for further risk diagnosis and management in urban waterways. PMID- 25545800 TI - Unilateral muscle overuse causes bilateral changes in muscle fiber composition and vascular supply. AB - Unilateral strength training can cause cross-transfer strength effects to the homologous contralateral muscles. However, the impact of the cross-over effects on the muscle tissue is unclear. To test the hypothesis that unilateral muscle overuse causes bilateral alterations in muscle fiber composition and vascular supply, we have used an experimental rabbit model with unilateral unloaded overstrain exercise via electrical muscle stimulation (E/EMS). The soleus (SOL) and gastrocnemius (GA) muscles of both exercised (E) and contralateral non exercised (NE) legs (n = 24) were morphologically analyzed after 1 w, 3 w and 6 w of EMS. Non-exercised rabbits served as controls (n = 6). After unilateral intervention the muscles of both E and NE legs showed myositis and structural and molecular tissue changes that to various degrees mirrored each other. The fiber area was bilaterally smaller than in controls after 3 w of E/EMS in both SOL (E 4420 and NE 4333 um2 vs. 5183 um2, p<0.05) and GA (E 3572 and NE 2983 um2 vs. 4697 um2, p<0.02) muscles. After 6 w of E/EMS, the percentage of slow MyHCI fibers was lower than in controls in the NE legs of SOL (88.1% vs. 98.1%, p<0.009), while the percentage of fast MyHCIIa fibers was higher in the NE legs of GA (25.7% vs. 15.8%, p = 0.02). The number of capillaries around fibers in the E and NE legs was lower (SOL 13% and 15%, respectively, GA 25% and 23%, respectively, p<0.05) than in controls. The overall alterations were more marked in the fast GA muscle than in the slow SOL muscle, which on the other hand showed more histopathological muscle changes. We conclude that unilateral repetitive unloaded overuse exercise via EMS causes myositis and muscle changes in fiber type proportions, fiber area and fiber capillarization not only in the exercised leg, but also in the homologous muscles in the non-exercised leg. PMID- 25545802 TI - Giant pulmonary artery aneurysm secondary to patent ductus arteriosus: a case report. AB - Aneurysms involving the main pulmonary artery and its branches are rare. Clinical experience is limited, and their management is not well established. We present the case of a 35-year-old male patient with dyspnea and hemoptysis in whom subsequent imaging studies revealed a giant pulmonary artery aneurysm associated with an uncorrected patent ductus arteriosus and Eisenmenger's syndrome. We chose to treat the patient conservatively with medical management due to the development of Eisenmenger's physiology while waiting for heart-lung transplantation. PMID- 25545803 TI - Total and domain-specific sitting time among employees in desk-based work settings in Australia. AB - OBJECTIVE: To describe the total and domain-specific daily sitting time among a sample of Australian office-based employees. METHODS: In April 2010, paper-based surveys were provided to desk-based employees (n=801) in Victoria, Australia. Total daily and domain-specific (work, leisure-time and transport-related) sitting time (minutes/day) were assessed by validated questionnaires. Differences in sitting time were examined across socio-demographic (age, sex, occupational status) and lifestyle characteristics (physical activity levels, body mass index [BMI]) using multiple linear regression analyses. RESULTS: The median (95% confidence interval [CI]) of total daily sitting time was 540 (531-557) minutes/day. Insufficiently active adults (median=578 minutes/day, [95%CI: 564 602]), younger adults aged 18-29 years (median=561 minutes/day, [95%CI: 540-577]) reported the highest total daily sitting times. Occupational sitting time accounted for almost 60% of total daily sitting time. In multivariate analyses, total daily sitting time was negatively associated with age (unstandardised regression coefficient [B]=-1.58, p<0.001) and overall physical activity (minutes/week) (B=-0.03, p<0.001) and positively associated with BMI (B=1.53, p=0.038). CONCLUSIONS: Desk-based employees reported that more than half of their total daily sitting time was accrued in the work setting. IMPLICATIONS: Given the high contribution of occupational sitting to total daily sitting time among desk based employees, interventions should focus on the work setting. PMID- 25545804 TI - Evaporation of a non-ideal solution and its application to writing ink aging. AB - The evaporation of a solution consisting of a non-volatile solute dissolved in a volatile solvent has been previously treated using a simple model called the beaker model. This model considers the solution to be in a non-porous container that has vertical walls like a glass beaker and assumes the solution is an ideal solution so that Raoult's law is obeyed. A particular novel finding was that under a certain condition, the evaporation or aging curve of the solution has a point of maximum acceleration. Prior to this point, the solution is in its fast drying mode and after this point, it is in its slow drying mode. This phenomenon is observed in the drying of many writing inks. In this work this model is modified to consider the evaporation of (a) a non-ideal solution, (b) a solution that become saturated, (c) a solution on a glass slide, and (d) a solution on a porous substrate. In each of these cases, the existence and location of the point of maximum acceleration of the drying process are examined. These modifications lead to a description of the dying process of a solution that is remarkably similar to that of writing inks but obtained via an entirely different physical model. PMID- 25545805 TI - A randomized two-stage design for phase II clinical trials based on a Bayesian predictive approach. AB - The rate of failure in phase III oncology trials is surprisingly high, partly owing to inadequate phase II studies. Recently, the use of randomized designs in phase II is being increasingly recommended, to avoid the limits of studies that use a historical control. We propose a two-arm two-stage design based on a Bayesian predictive approach. The idea is to ensure a large probability, expressed in terms of the prior predictive probability of the data, of obtaining a substantial posterior evidence in favour of the experimental treatment, under the assumption that it is actually more effective than the standard agent. This design is a randomized version of the two-stage design that has been proposed for single-arm phase II trials by Sambucini. We examine the main features of our novel design as all the parameters involved vary and compare our approach with Jung's minimax and optimal designs. An illustrative example is also provided online as a supplementary material to this article. PMID- 25545806 TI - A study of aneuploidy and DNA fragmentation in spermatozoa of three men with sex chromosome mosaicism including a 45,X cell line. AB - Meiotic segregation of mosaic males with a 45,X cell line has been little examined. In this study, we evaluated the risk of aneuploid gametes using fluorescence in situ hybridization (FISH) and DNA fragmentation in ejaculated spermatozoa of three men with sex chromosome mosaicism including a 45,X cell line. Triple- and dual-color FISH were performed. Sperm DNA fragmentation was detected using the TUNEL assay. A significantly increased frequency of XY disomic spermatozoa was observed for patients (P)1 and P2. A significant increase in diploidy and autosomal aneuploidy was found in P2 and P3, respectively. The rate of DNA fragmentation was not different from that observed in a control group. Data from the literature are scarce (only 3 cases reported), making comparison of the present data difficult, especially as the frequencies of the cell lines comprising the mosaicism differed between patients. Furthermore, the proportion of the different cell lines can differ from one tissue to another in the same patient. Whether the relative levels of the several cell lines present in the mosaicism can influence the rate of aneuploid spermatozoa remains unknown. PMID- 25545808 TI - Controlled motion with the XL-TDR lateral-approach lumbar total disk replacement: in vitro kinematic investigation. AB - OBJECTIVE: Anterior-approach total disk replacement (TDR) devices are thought to retain close to so-called normal range of motion (ROM); however, they are also inherently unstable due to resection of the anterior longitudinal ligament and annulus. This instability/laxity is manifested as increased neutral zone (NZ) motion. The XL-TDR device (NuVasive, Inc., San Diego, California, United States) is implanted through a lateral approach that preserves the anterior ligamentous and annular structures. This potentially makes the XL-TDR device more stable than those delivered anteriorly. This study investigates XL-TDR biomechanical features in a cadaveric model. METHODS: Biomechanical evaluation consisting of nondestructive multidirectional testing was performed with the hybrid protocol on six fresh-frozen cadaveric specimens (L2-S1). Motion segment kinematics were obtained using an optoelectronic system. Test conditions were (1) intact spine, (2) XL-TDR at L4-L5, and (3) XL-TDR at L4-L5 with anterior annulus/ligament resected. ROM and NZ were calculated for each condition in each loading direction (flexion-extension total, flexion alone, extension alone, lateral bending, and axial rotation). RESULTS: Insertion of the XL-TDR device decreased ROM with respect to intact in all directions. NZ in all directions was not statistically different from intact (p < 0.05), although there was a trend toward decreased NZ in flexion (p = 0.078). Removing the anterior ligament/annulus increased ROM significantly with respect to the XL-TDR condition in all directions (p < 0.003). NZ also increased, with the most significant changes in extension, lateral bending, and axial rotation (p < 0.002). CONCLUSIONS: The kinematics of XL-TDR have demonstrated that the retention of the anterior ligament/annulus has a significant stabilizing effect, diminishing ROM to less than intact, with a more controlled motion (more natural NZ). Removing the anterior ligament/annulus illustrated its stabilizing role, with ROM and NZ increasing significantly. Future studies will investigate the potential benefit of controlled XL-TDR motion on facet kinematics that may have clinical implications related to limiting facet degeneration. PMID- 25545809 TI - Intraventricular hemorrhage is associated with early hydrocephalus, symptomatic vasospasm, and poor outcome in aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: We hypothesized that the subset of patients with early hydrocephalus following aneurysmal subarachnoid hemorrhage may represent a subset of patients with a more vehement inflammatory reaction to blood products in the subarachnoid space. We thus examined risk factors for early hydrocephalus and examined the relationship between early hydrocephalus and symptomatic vasospasm as well as clinical outcome. METHODS: We retrospectively analyzed all patients presenting to our institution with subarachnoid hemorrhage over a 7-year period. We examined for risk factors, including early hydrocephalus, for poor clinical outcome and symptomatic vasospasm. RESULTS: We found intraventricular hemorrhage to be strongly associated with the development of early hydrocephalus. In univariate analysis, early hydrocephalus was strongly associated with both poor functional outcome and symptomatic vasospasm. In multivariate analysis, intraventricular hemorrhage and tobacco use were associated with symptomatic vasospasm; intraventricular hemorrhage, intraparenchymal hemorrhage, and symptomatic vasospasm were associated with poor functional outcome. CONCLUSIONS: We found that intraventricular hemorrhage was strongly associated with early hydrocephalus. Further exploration of the mechanistic explanation is needed, but we suggest this may be from a combination of obstruction of cerebrospinal fluid pathways by blood products and inflammation in the choroid plexus resulting in increased cerebrospinal fluid production. Further, we suggest that both early hydrocephalus and cerebral vasospasm may be parts of the overall inflammatory cascade that occurs with intraventricular hemorrhage and ultimately results in a poorer clinical outcome. PMID- 25545807 TI - A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology. AB - OBJECTIVE: Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD. METHODS: Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes. RESULTS: We provide evidence that an intronic variant, rs6910730(G) , in TREM1, is associated with an increased burden of neuritic plaques (p = 3.7 * 10(-4) ), diffuse plaques (p = 4.1 * 10(-3) ), and Abeta density (p = 2.6 * 10( 3) ) as well as an increased rate of cognitive decline (p = 5.3 * 10(-3) ). A variant upstream of TREM2, rs7759295(C) , is independently associated with an increased tau tangle density (p = 4.9 * 10(-4) ), an increased burden of neurofibrillary tangles (p = 9.1 * 10(-3) ), and an increased rate of cognitive decline (p = 2.3 * 10(-3) ). Finally, a cytometric analysis shows that the TREM1 rs6910730(G) allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 * 10(-3) ). INTERPRETATION: We provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function. PMID- 25545810 TI - Comparison of three different polyvinyl alcohol packs following functional endoscopic Nasal surgery. AB - OBJECTIVES/HYPOTHESIS: To compare the extent of bleeding and patient discomfort during packing removal of three different polyvinyl alcohol (PVA) packs: 1) a standard PVA sponge (s-PVA) (Mondocel Standard 10 cm; Mondomed NV, Hamont-Achel, Belgium); 2) a PVA sponge with oxidized cellulose (oc-PVA) (Merocel Hemox 10 cm; Medtronic Xomed Surgical Products, Jacksonville, FL); and 3) a PVA sponge with polyethylene film (pf-PVA) (Merocel 2000 8 cm; Medtronic Xomed Surgical Products, Jacksonville, FL), after functional endoscopic sinus surgery and inferior turbinoplasty. STUDY DESIGN: A prospective, randomized, blinded, controlled trial. METHODS: Ninety consecutive patients were enrolled and randomized to receive in each side one pack in the middle meatus and another pack of the same material in the nasal fossa. The patients were equally divided in three groups of 30 patients each. Group A received the pf-PVA; group B received oc-PVA; and group C received s-PVA. Postoperatively, bleeding after removal of the entire nasal packing was evaluated by an observer, whereas the severity of pain was rated by patients with visual analog scales. RESULTS: Our study evaluated three nasal packing materials, demonstrating that the pf-PVA is less painful than the others but with intermediate bleeding ratio. However, the oc-PVA has an intermediate pain score but minimum bleeding. The s-PVA showed the worst pain and bleeding results. CONCLUSIONS: Considering that removal of the second pack (middle meatus) is more painful than the first (nasal fossa), our results suggest that a pf-PVA can be placed in the middle meatus and a oc-PVA in the nasal fossa in order to reduce patient's discomfort in terms of pain and bleeding. LEVEL OF EVIDENCE: 1b. PMID- 25545811 TI - Antisense suppression of LOX3 gene expression in rice endosperm enhances seed longevity. AB - Lipid peroxidation plays a major role in seed longevity and viability. In rice grains, lipid peroxidation is catalyzed by the enzyme lipoxygenase 3 (LOX3). Previous reports showed that grain from the rice variety DawDam in which the LOX3 gene was deleted had less stale flavour after grain storage than normal rice. The molecular mechanism by which LOX3 expression is regulated during endosperm development remains unclear. In this study, we expressed a LOX3 antisense construct in transgenic rice (Oryza sativa L.) plants to down-regulate LOX3 expression in rice endosperm. The transgenic plants exhibited a marked decrease in LOX mRNA levels, normal phenotypes and a normal life cycle. We showed that LOX3 activity and its ability to produce 9-hydroperoxyoctadecadienoic acid (9 HPOD) from linoleic acid were significantly lower in transgenic seeds than in wild-type seeds by measuring the ultraviolet absorption of 9-HPOD at 234 nm and by high-performance liquid chromatography. The suppression of LOX3 expression in rice endosperm increased grain storability. The germination rate of TS-91 (antisense LOX3 transgenic line) was much higher than the WT (29% higher after artificial ageing for 21 days, and 40% higher after natural ageing for 12 months). To our knowledge, this is the first report to demonstrate that decreased LOX3 expression can preserve rice grain quality during storage with no impact on grain yield, suggesting potential applications in agricultural production. PMID- 25545812 TI - The arithmetic of discounting. AB - Most current models of delay discounting multiply the nominal value of a good whose receipt is delayed, by a discount factor that is some function of that delay. This article reviews the logic of a theory that discounts the utility of delayed goods by adding the utility of the good to the disutility of the delay. In limiting cases it approaches other familiar models, such as hyperbolic discounting. In nonlimit cases it makes different predictions, generally requiring, inter alia, a magnitude effect when the value of goods is varied. A different theory is proposed for conditioning experiments. In it utility is computed as the average reinforcing strength of the stimuli that signal the delay. Both theories are extended to experiments in which degree of preference is measured, rather than adjustment to iso-utility values. PMID- 25545814 TI - IAP gene deletion and conditional knockout models. AB - Gene deletion studies have helped reveal the unique and overlapping roles played by IAP proteins. Crossing IAP mutant mice has helped unravel the complex feed back regulatory circuits in which cIAP1, cIAP2 and XIAP allow innate defensive responses to microbial pathogens, without the development of auto-inflammatory syndromes. Deletion of genes for Survivin and its homologs in yeasts, invertebrates and mammals has shown that it functions differently, as it is not a regulator of innate immunity or apoptosis, but acts together with INCENP, aurora kinase B and Borealin to allow chromosome segregation during mitosis. PMID- 25545815 TI - Multimetallic catalysis based on heterometallic complexes and clusters. PMID- 25545813 TI - Bridging the divide between pathogenesis and detection in lymphedema. AB - While our understanding of the lymphatic system has improved substantially in the past few decades, the translation of this knowledge into improved healthcare solutions for patients suffering from secondary lymphedema has been severely limited. The challenge facing clinicians is two-fold. First, there is no reliable, affordable, diagnostic capable of detecting the disease before symptoms of the lymphedema develop and the efficacy of treatment options becomes limited. Second, our understanding of the disease pathogenesis, its risk factors, and the underlying physiologic mechanisms is still in its infancy. These two challenges go hand in hand as limited diagnostic options have hindered our ability to understand lymphedema progression, and the lack of known underlying mechanisms involved in the disease prohibits the development of new diagnostic targets. This review serves to discuss the recent developments in clinical and lab research settings of both lymphedema diagnostic technologies and our understanding of the mechanisms driving disease risk and progression. We will show how these two lines of research are synergistically working with the ultimate goal of improving patient outcomes for those suffering from this horrible disease, identifying key areas of further research that are warranted to move the field forward and provide clinical relief for this neglected patient population. PMID- 25545816 TI - Ultrasound-based motion analysis demonstrates bilateral arm hypokinesia during gait in heterozygous PINK1 mutation carriers. AB - Carriers of a single heterozygous PINK1 (PTEN-induced putative kinase 1) gene mutation provide an ideal opportunity to study the development of parkinsonian motor signs from the very beginning. Measuring tools that reliably represent mild motor symptoms could also facilitate the assessment of future neuroprotective therapies and early diagnosis of Parkinson's disease (PD). We investigated nine family members carrying a heterozygous PINK1 mutation in comparison with 25 age matched healthy controls. Arm kinematics were quantified during treadmill walking at four different speeds using ultrasound-based motion analysis. Heterozygous PINK1 mutation carriers showed a bilateral reduction of arm swing amplitudes (P = 0.003) and arm anteversion (P = 0.001), which was more pronounced on the predominantly affected body side but also was present, albeit to a lesser degree, contralaterally (amplitude P = 0.01, anteversion P = 0.002, repeated measures analysis of covariance [rmANCOVA]). Single post-hoc comparisons revealed similar results for all speeds on both body sides (P < 0.05) except for 2.0 km/h on the less affected side. A single heterozygous mutation in the PINK1 gene is associated with a bilateral dopaminergic dysfunction in this family. Ultrasound based three-dimensional motion analysis of arm swing during gait is a suitable tool to quantify even subtle hypokinesia in mildly affected PINK1 mutation carriers, which tends to be easily overlooked on the less affected body side during clinical examination. Therefore, this technique is a promising application in early stage PD and in at-risk populations for the disease. PMID- 25545817 TI - On-line determination of sarcosine in biological fluids utilizing dummy molecularly imprinted polymers in microextraction by packed sorbent. AB - Several years ago, sarcosine received attention as a prostate-cancer marker. Prostate cancer is one of the most widespread types of tumor diseases in men. The prostate-specific antigen is normally used as a marker, and it can only be detected in blood with a sensitivity of approximately 80%. In the present study, dummy molecularly imprinted polymers in microextraction by packed sorbent with on line liquid chromatography coupled to tandem mass spectrometry was used for the determination of sarcosine in human plasma and urine samples. The polymer network glycine was used for the dummy molecularly imprinted polymers. The selectivity of the method was evaluated using similar prostate-cancer biomarkers. In addition, various parameters affecting the extraction performance were investigated. The method limits of detection and quantification in the plasma and urine were 1.0 and 3.0 ng/mL, respectively. The values of the coefficient of determination were over 0.99 for all runs in the studied concentration range (3.0-10 000 ng/mL). The method recovery was 87 and 89% in plasma and urine, respectively. The intraday and interday precisions of sarcosine in the plasma and urine samples were in the ranges of 4.0-7.1, 3.0-6.3, 2.9-4.7, and 5.0-6.7, respectively. PMID- 25545819 TI - Diagnostic Algorithm for the Diagnosis of Pediatric Parasitic Gastroenteritis. AB - BACKGROUND: Current practices for ordering stool studies in patients with abdominal and gastrointestinal symptoms are not standardized. We hypothesized that an algorithm involving first-line use of a Cryptosporidium/Giardia combination antigen test and stricter use of ova and parasite (O&P) examinations would be clinically and cost effective. METHODS: In this study, stool O&P test results for pediatric patients in Dallas, Texas, were reviewed. All results obtained between 2009 and 2012 were included. Patient charts were reviewed to determine test results, symptoms, treatment, travel, and past medical history. Using these data, a retrospective modeling study was done to evaluate the utility of a diagnostic algorithm that limits O&P testing to those patients who are immunocompromised or have travelled outside the United States. RESULTS: Over the 3-year period of this study, we found that the prevalence of gastrointestinal parasitic disease in children was 1.9%. Analysis of the diagnostic algorithm for the judicious use of stool O&P showed that as much as 65% of testing may be unnecessary and could be eliminated. CONCLUSIONS: Our findings show that the prevalence of pediatric gastrointestinal parasitic disease in Texas may be lower than expected. In addition, these data show that a diagnostic algorithm limiting O&P testing may be both clinically and cost effective in low-prevalence settings. However, such an algorithm would miss a significant number of infections due to Dientamoeba fragilis and Blastocystis hominis. PMID- 25545820 TI - 21st century agriculture: integration of plant microbiomes for improved crop production and food security. PMID- 25545821 TI - Acute intradialytic cardiac function and inflammatory cytokine changes during high-efficiency online hemodiafiltration with acetate-free and standard dialysis solutions. AB - Acetate in standard acetate-containing bicarbonate (AC) dialysis fluid could induce peripheral vasodilatation, suppression of myocardial function, and inflammatory cytokine production, resulting in intradialytic hypotension in conventional hemodialysis (HD) patients. Online hemodiafiltration (HDF) provides superior hemodynamic stability over HD. The potentially additive hemodynamic benefits of the novel acetate-free bicarbonate (AF) dialysis fluid in online HDF have never been explored before. The present randomized, double-blind, crossover study was conducted in 22 online HDF patients to investigate the impact of AF dialysis fluid on hemodynamic and cytokine changes compared with AC dialysis fluid in online HDF. The results demonstrated the comparable changes of arterial pressure between AF and AC online HDF. During the study periods, the incidences of composite intradialytic hypotension and other adverse events were not different. The baseline and hourly changes of cardiac index, cardiac output, and peripheral vascular resistance during dialysis were comparable (P=0.534, 0.199, and 0.641, respectively). The percent reductions of NT-proBNP and cTnT were not significantly different (72.6 +/- 12.3 vs. 72.6 +/- 12.8%, P=0.99 and 35.2 +/- 12.8 vs. 36.7 +/- 12.0%, P=0.51). The changes of all pro-inflammatory cytokines (IL-2beta, IL-6, IL-8, and TNF-alpha) and anti-inflammatory cytokine (IL-10) during dialysis were comparable between both groups. In conclusion, AF dialysis solution does not offer additional hemodynamic benefit for stable online HDF patients. The hemodynamic stability provided by online HDF might protect the adverse effects of acetate. PMID- 25545822 TI - Parents' level of support for adults' purchase and consumption of alcohol at primary school events when children are present. AB - INTRODUCTION: Environmental and societal factors are significant determinants of children's initiation to and use of alcohol. Schools are important settings for promoting well-being and substantial resources have been devoted to curriculum based alcohol programs, but the effects of these in reducing the misuse of alcohol have been modest. Adults can and do consume alcohol at school events when students are present, but there is a dearth of evidence about parents' level of support for the practice. The aim of this study was to examine parents' level of support for the purchase and consumption of alcohol at primary school fundraising events when children are present. METHODS: Four hundred seventy-nine Australian parents of children aged 0-12 years participated in an online survey. Logistic regression was used to assess the impact of parent characteristics on the level of agreement with parental purchase and consumption of alcohol at school fundraising events when children are present. RESULTS: The majority of parents (60%) disagreed/strongly disagreed with the practice of adults being able to purchase and consume alcohol at school fundraising events when children were present. The 21% of parents who supported the practice were more likely to be daily smokers and/or have higher (>6) Alcohol Use Disorders Identification Test alcohol consumption scores. CONCLUSIONS: Despite the fact that the majority of parents disagree with this practice, published reports suggest that adults' use of alcohol at primary school events is an emerging issue. It is important that school decision-makers are mindful of the financial and educational value of fundraising activities. PMID- 25545818 TI - Fear extinction as a model for synaptic plasticity in major depressive disorder. AB - BACKGROUND: The neuroplasticity hypothesis of major depressive disorder proposes that a dysfunction of synaptic plasticity represents a basic pathomechanism of the disorder. Animal models of depression indicate enhanced plasticity in a ventral emotional network, comprising the amygdala. Here, we investigated fear extinction learning as a non-invasive probe for amygdala-dependent synaptic plasticity in patients with major depressive disorder and healthy controls. METHODS: Differential fear conditioning was measured in 37 inpatients with severe unipolar depression (International Classification of Diseases, 10th revision, criteria) and 40 healthy controls. The eye-blink startle response, a subcortical output signal that is modulated by local synaptic plasticity in the amygdala in fear acquisition and extinction learning, was recorded as the primary outcome parameter. RESULTS: After robust and similar fear acquisition in both groups, patients with major depressive disorder showed significantly enhanced fear extinction learning in comparison to healthy controls, as indicated by startle responses to conditioned stimuli. The strength of extinction learning was positively correlated with the total illness duration. CONCLUSIONS: The finding of enhanced fear extinction learning in major depressive disorder is consistent with the concept that the disorder is characterized by enhanced synaptic plasticity in the amygdala and the ventral emotional network. Clinically, the observation emphasizes the potential of successful extinction learning, the basis of exposure therapy, in anxiety-related disorders despite the frequent comorbidity of major depressive disorder. PMID- 25545823 TI - The extracellular fragment of GPNMB (Glycoprotein nonmelanosoma protein B, osteoactivin) improves memory and increases hippocampal GluA1 levels in mice. AB - Glycoprotein nonmelanoma protein B (GPNMB, alias osteoactivin), a type I transmembrane glycoprotein, is cleaved by extracellular proteases, resulting in release of an extracellular fragment (ECF). GPNMB is widely expressed by neurons within the CNS, including the hippocampus; however, its function in the brain remains unknown. Here, we investigated the role of GPNMB in memory and learning by using transgenic (Tg) mice over-expressing GPNMB (Tg mice on a BDF-1 background) and ECF-treated mice. In the hippocampus of both wild-type and Tg mice, GPNMB was highly expressed in neurons and astrocytes. Tg mice exhibited memory improvements in two types of learning tasks but were impaired in a passive avoidance test. In Tg mice, the hippocampus displayed increased levels of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunit GluA1. Intracerebroventricular administration of ECF (50 ng) to Institute of Cancer Research (ICR) mice also improved memory in a passive-avoidance test and increased hippocampal GluA1 levels 24 h after treatment. In Tg mice and ECF (0.25 MUg/mL)-treated hippocampal slices, long-term potentiation was promoted. These findings suggest that GPNMB may be a novel target for research on higher order brain functions. PMID- 25545824 TI - Age and weight at final discharge from an early discharge programme for stable but tube-fed preterm infants. AB - AIM: Preterm birth is often associated with prolonged hospitalisation, complicating the parent-child relationship and breastfeeding rates. As a result, an early discharge programme was implemented in the department of neonatology at Rigshospitalet. The infants were stable, but required tube feeding, and during the programme, they received home visits by neonatal nurses. We evaluated the programme, focusing on the infants' well-being, using weight gain, breastfeeding rates and total duration of hospitalisation as outcomes. METHODS: Over an 11-year period, 500 infants participated in the programme and they constituted the early discharge group. They were compared with 400 infants discharged from the Naestved and Nykoebing Falster hospitals. RESULTS: The early discharge group's length of hospitalisation was only three days shorter than the comparison group, but they were eight days younger when they joined the programme (p < 0.0001). Total admission was 21 days longer (p < 0.0001). There was no difference in weight-for age at discharge (p = 0.15), but infants in the early discharge group were more frequently fully or partly breastfed (88% versus 80%, p < 0.005). CONCLUSION: While recognising the limited comparability of the two groups, weight-for-age at discharge was similar, but the programme appeared to allow better breastfeeding success at the expense of a later final discharge. PMID- 25545825 TI - Titer rebound after ABO-incompatible kidney transplantation--is all accommodated for? PMID- 25545826 TI - Endoscopic treatment of pediatric post-transplant biliary complications is safe and effective. AB - BACKGROUND AND AIM: Biliary complications (BC) after liver transplantation (LT) are associated with significant morbidity and mortality. Incidence of BC after pediatric LT is more than 10%. In adults, treatment by endoscopic retrograde cholangiopancreaticography (ERCP) is successful. As data in pediatric patients are limited, endoscopic treatment of BC in a pediatric cohort in a German transplant center was analyzed. METHODS: LT recipients <18 years of age who were endoscopically treated for BC at University Hospital Essen were retrospectively analyzed. Characteristics of LT, endoscopic treatment measures, clinical and endoscopic presentation of BC, and outcomes after endoscopic treatment were evaluated. RESULTS: Seventeen patients (median age 12 years) with clinical signs of BC were treated endoscopically using ERCP. Eleven patients had received a full size liver, and six a left-sided living-donor transplant graft. In 12 patients, the bile ducts were accessible via Vater's papilla and five patients had a bilioenteric anastomosis. Biliary sphincterotomy was done in 13 patients. Eleven patients presented with stricture of the biliary anastomosis (AST), either isolated (nine) or in combination with biliary cast syndrome (BCS) or biliary leakage (one patient each). Ischemia-type biliary lesions (ITBL) were found in two patients. Five patients suffered from BCS, either as isolated pathology (two) or in combination with AST, bile leak or ITBL. In one patient, biliary access via the major papilla was not obtainable. CONCLUSIONS: BC in pediatric LT were treated safely and successfully in pediatric patients when the biliary tract was accessible. The most common complications were AST, BCS and ITBL. PMID- 25545827 TI - Reconstruction of expanding tracheoesophageal fistulae in post-radiation therapy patients who undergo total laryngectomy with a bipaddled radial forearm free flap: Report of 8 cases. AB - BACKGROUND: Our surgical approach describes a bipaddled radial forearm free flap (RFFF) for closure of chronic tracheoesophageal fistulae (TEF) in patients who underwent total laryngectomy. The desired functional results were achieved. METHODS: Eight patients underwent the procedure. The surgical approach includes exposure and resection of the fistula tract, and a bipaddled RFFF transfer. Key surgical maneuvers include: circumferential dissection and mobilization of the trachea; partial sternal resection in select cases; inset of flap's distal paddle into the anterior esophageal wall; and inset of the proximal skin paddle to the posterior tracheal wall and cervical skin. RESULTS: Successful reconstruction of all 8 cases was done to restore a normal diet and a widely patent tracheal opening. One patient developed a delayed esophageal stricture, which was successfully managed with home dilation. CONCLUSION: Several TEF treatment approaches have been reported. Our 87.5% esophageal lumen preservation success rate, reestablishment of adequate airway, and uncomplicated postoperative courses demonstrates the reliability of this surgical approach. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E172-E178, 2016. PMID- 25545829 TI - Trends of ambulatory sinus surgery for chronic rhinosinusitis. AB - BACKGROUND: We sought to examine the trends in rates and demographics of ambulatory endoscopic and open sinus surgery for chronic sinusitis over a 7-year period in the state of California. METHODS: Patient records with Current Procedural Terminology (CPT) codes for endoscopic or open sinus surgery, and diagnosis codes for chronic rhinosinusitis were extracted from the California Ambulatory Surgery Datasets from 2005 to 2011. Population-adjusted surgery rates were calculated as the number of surgeries per 100,000 California residents. Location of surgery was analyzed in 2 contexts: freestanding ambulatory surgery centers (ASCs) vs any hospital setting, and academic (university medical centers) vs nonacademic centers (ASCs and non-university hospitals combined). Patients' demographics were also examined. RESULTS: A total of 91,984 sinus surgeries were performed during 2005 to 2011. The overall population-adjusted surgery rate declined 24%, from 38.9 to 29.6 (p = 0.004). Although the rates for both endoscopic and open surgeries declined, the percentage of endoscopic procedures increased from 87.3% to 92.5% of all surgeries (p = 0.002). Over the studied period, there was an increase in the proportion of sinus surgeries performed in hospitals (73.2% to 91.3%; p = 0.01), in academic centers (5.9% to 10.1%; p = <0.001), on patients >65 years (14.7% to 17.8%; p = 0.003), and on non-Caucasians (10.3% to 16.9%; p < 0.001). Gender distribution remained unchanged (51% male; p = 0.25). CONCLUSION: The overall rate of ambulatory sinus surgery in California declined over the study period. A shift from open to endoscopic procedures, from ASCs to hospitals, and from nonacademic to academic centers was observed. Further investigation of the observed trends may be warranted. PMID- 25545830 TI - Occupational contact allergy in nurses: results from the Information Network of Departments of Dermatology 2003-2012. AB - BACKGROUND: Healthcare workers are occupationally exposed to various allergens in protective gloves, surface or instrument disinfectants, drugs, and skin care products. An increased prevalence of sensitization to thiurams, glutaraldehyde, formaldehyde and glyoxal in nurses with occupational contact dermatitis (OCD) has been known since the 1990s. OBJECTIVES: To update the range of occupational allergens in healthcare professionals. METHODS: We retrospectively analysed patch test data from the Information Network of Departments of Dermatology (IVDK), 2003 2012. Patch test results from 2248 nurses with OCD were compared with those of 2138 nurses without OCD. RESULTS: Significantly increased sensitization rates were found for thiuram mix (6.7%), potassium dichromate (5.7%), methylchloroisothiazolinone/methylisothiazolinone (4.4%), colophonium (3.4%), 2 bromo-2-nitropropane-1,3-diol (1.7%), and zinc diethyldithiocarbamate (1.7%). Patch testing with products from the patients' workplaces gave additional clues to further allergens, for example tetrazepam. CONCLUSIONS: The known range of contact sensitization in nurses with OCD has been confirmed. Formaldehyde allergy seems to be less important today. Drugs such as tetrazepam are occupational sensitizers in nurses. The increase in chromium sensitization remains unexplained. PMID- 25545832 TI - Dr. Robert Bartlett and his lifelong accomplishments in the field of extracorporeal membrane oxygenation. PMID- 25545831 TI - Bmp2 deletion causes an amelogenesis imperfecta phenotype via regulating enamel gene expression. AB - Although Bmp2 is essential for tooth formation, the role of Bmp2 during enamel formation remains unknown in vivo. In this study, the role of Bmp2 in regulation of enamel formation was investigated by the Bmp2 conditional knock out (Bmp2 cKO) mice. Teeth of Bmp2 cKO mice displayed severe and profound phenotypes with asymmetric and misshaped incisors as well as abrasion of incisors and molars. Scanning electron microscopy analysis showed that the enamel layer was hypoplastic and enamel lacked a typical prismatic pattern. Teeth from null mice were much more brittle as tested by shear and compressive moduli. Expression of enamel matrix protein genes, amelogenin, enamelin, and enamel-processing proteases, Mmp-20 and Klk4 was reduced in the Bmp2 cKO teeth as reflected in a reduced enamel formation. Exogenous Bmp2 up-regulated those gene expressions in mouse enamel organ epithelial cells. This result for the first time indicates Bmp2 signaling is essential for proper enamel development and mineralization in vivo. PMID- 25545833 TI - A New Variant of Connective Tissue Nevus with Elastorrhexis and Predilection for the Upper Chest. AB - Localized changes in cutaneous elastic tissue often manifest with flesh-colored, hypopigmented, or yellow papules, plaques, and nodules. We present five children with clinically similar cobblestone plaques composed of multiple hypopigmented, nonfollicular, pinpoint papules located unilaterally over the upper chest. All lesions first appeared at birth or during early infancy. No associated extracutaneous abnormalities have been identified. Histopathology was remarkable for many, thick elastic fibers with elastorrhexis. We believe that these cases represent a distinct and unique variant of connective tissue nevi. PMID- 25545835 TI - Ultrafast 3D balanced steady-state free precession MRI of the lung: Assessment of anatomic details in comparison to low-dose CT. AB - PURPOSE: To evaluate the anatomical details offered by a new single breath-hold ultrafast 3D balanced steady-state free precession (uf-bSSFP) sequence in comparison to low-dose chest computed tomography (CT). MATERIALS AND METHODS: This was an Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant prospective study. A total of 20 consecutive patients enrolled in a lung cancer screening trial underwent same-day low-dose chest CT and 1.5T MRI. The presence of pulmonary nodules and anatomical details on 1.9 mm isotropic uf-bSSFP images was compared to 2 mm lung window reconstructions by two readers. The number of branching points on six predefined pulmonary arteries and the distance between the most peripheral visible vessel segment to the pleural surface on thin slices and 50 mm maximum intensity projections (MIP) were assessed. Image quality and sharpness of the pulmonary vasculature were rated on a 5-point scale. RESULTS: The uf-bSSFP detection rate of pulmonary nodules (32 nodules visible on CT and MRI, median diameter 3.9 mm) was 45.5% with 21 false-positive findings (pooled data of both readers). Uf-bSSFP detected 71.2% of branching points visible on CT data. The mean distance between peripheral vasculature and pleural surface was 13.0 +/- 4.2 mm (MRI) versus 8.5 +/- 3.3 mm (CT) on thin slices and 8.6 +/- 3.9 mm (MRI) versus 4.6 +/- 2.5 mm (CT) on MIPs. Median image quality and sharpness were rated 4 each. CONCLUSION: Although CT is superior to MRI, uf-bSSFP imaging provides good anatomical details with sufficient image quality and sharpness obtainable in a single breath-hold covering the entire chest. PMID- 25545834 TI - Rh(I)-bisphosphine-catalyzed asymmetric, intermolecular hydroheteroarylation of alpha-substituted acrylate derivatives. AB - Asymmetric hydroheteroarylation of alkenes represents a convenient entry to elaborated heterocyclic motifs. While chiral acids are known to mediate asymmetric addition of electron-rich heteroarenes to Michael acceptors, very few methods exploit transition metals to catalyze alkylation of heterocycles with olefins via a C-H activation, migratory insertion sequence. Herein, we describe the development of an asymmetric, intermolecular hydroheteroarylation reaction of alpha-substituted acrylates with benzoxazoles. The reaction provides 2-substitued benzoxazoles in moderate to excellent yields and good to excellent enantioselectivities. Notably, a series of mechanistic studies appears to contradict a pathway involving enantioselective protonation of a Rh(I)-enolate, despite the fact that such a mechanism is invoked almost unanimously in the related addition of aryl boronic acids to methacrylate derivatives. Evidence suggests instead that migratory insertion or beta-hydride elimination is enantiodetermining and that isomerization of a Rh(I)-enolate to a Rh(I) heterobenzyl species insulates the resultant alpha-stereocenter from epimerization. A bulky ligand, CTH-(R)-Xylyl-P-Phos, is crucial for reactivity and enantioselectivity, as it likely discourages undesired ligation of benzoxazole substrates or intermediates to on- or off-cycle rhodium complexes and attenuates coordination-promoted product epimerization. PMID- 25545836 TI - Comparison of a fludarabine and melphalan combination-based reduced toxicity conditioning with myeloablative conditioning by radiation and/or busulfan in acute myeloid leukemia in Japanese children and adolescents. AB - BACKGROUND: The relative efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) after reduced toxicity conditioning (RTC) compared with standard myeloablative conditioning (MAC) in pediatric patients with acute myeloid leukemia (AML) has not been studied extensively. To address whether RTC is a feasible approach for pediatric patients with AML in remission, we performed a retrospective investigation of the outcomes of the first transplant in patients who had received an allo-HCT after RTC or standard MAC, using nationwide registration data collected between 2000 and 2011 in Japan. PROCEDURE: We compared a fludarabine (Flu) and melphalan (Mel)-based regimen (RTC; n = 34) with total body irradiation (TBI) and/or busulfan (Bu)-based conditioning (MAC; n = 102) in demographic- and disease-criteria-matched childhood and adolescent patients with AML in first or second complete remission (CR1/CR2). RESULTS: The incidence of engraftment, early complications, grade II-IV acute graft-versus host disease (GVHD), and chronic GVHD were similar in each conditioning group. The risk of relapse (25% vs. 26%) and non-relapse mortality (13% vs. 11%) after 3 years did not differ between these groups, and univariate and multivariate analyses demonstrated that the 3-year overall survival (OS) rates after Flu/Mel RTC and MAC were comparable (mean, 72% [range, 51-85%] and 68% [range, 58-77%], respectively). CONCLUSIONS: The results suggest that the Flu/Mel-RTC regimen is a clinically acceptable conditioning strategy for childhood and adolescent patients with AML in remission. Although this retrospective, registry-based analysis has several limitations, RTC deserves to be further investigated in prospective trials. PMID- 25545837 TI - Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier. AB - The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) TEM -cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM-1, promoted rapid initiation of transcellular diapedesis of CD4(+) T cells across the BBB, while intermediate levels of endothelial ICAM-1 favored paracellular CD4(+) T-cell diapedesis. Importantly, the route of T-cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4(+) TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM-1 and ICAM-2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM-1(null) //ICAM-2(-/-) C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM-1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T cell diapedesis across the BBB. PMID- 25545838 TI - Neck circumference and prehypertension: the cardiometabolic risk in Chinese study. AB - BACKGROUND: We have previously found that neck circumference was related to insulin resistance, a risk factor for hypertension in Chinese. Little is known about whether high neck circumference is associated with elevated blood pressure. METHOD: The study samples were from a community-based health examination survey in central China. In total, 1709 men and women with neck circumference measurement were included. We analysed the associations between neck circumference and the risk of prehypertension. RESULTS: Although neck circumference was strongly associated with SBP/DBP in a univariate analysis, it was no longer associated with SBP and the association was much weaker with DBP when the association was adjusted for BMI or waist circumference. Similarly, high neck circumference was significantly related to an increased risk of prehypertension [odds ratio 1.254; 95% confidence interval (95% CI) 1.171-1.343] in a univariate analysis, and the association became marginal in models further adjusting for BMI or waist. CONCLUSION: Our data suggest that neck circumference as predictor for prehypertension is not obvious given the moderate improvement of disease prediction. PMID- 25545839 TI - Modulating the dehydration conditions of adefovir dipivoxil dihydrate to obtain different physical forms of anhydrate. AB - The physical form of anhydrous adefovir dipivoxil (AD), obtained following the dehydration of AD dihydrate, was governed by the kinetics of water removal. The rate and extent of water removal following the dehydration of AD dihydrate was manipulated by altering the sample size, pan configuration, and heating rate in a differential scanning calorimeter. Interestingly, when there was moderate resistance to water removal, a new anhydrous polymorph (melting point 80 degrees C) was obtained. High resistance to water removal resulted in amorphous AD. Variable temperature XRD of AD provided direct and unambiguous evidence of this new polymorph. We have prepared and characterized this new anhydrous polymorph as well as amorphous AD. Based on HPLC, AD dihydrate heated under different conditions in the DSC was observed to be chemically stable. When exposed to water vapor (RH >= 80%; 25 degrees C), the new polymorph had a stronger propensity to convert to AD dihydrate than the amorphous anhydrate or AD form I. PMID- 25545840 TI - Narcissistic rage revisited. AB - Narcissists are thought to exhibit "narcissistic rage," an explosive mix of anger and hostility arising from threats to narcissists' fractured sense of self. Building on clinical views of narcissism, we present empirical evidence on the nature and sources of narcissistic rage. Findings from 4 studies reveal narcissistic vulnerability (but not grandiosity) as a powerful driver of rage, hostility, and aggressive behavior, fueled by suspiciousness, dejection, and angry rumination. Consistent with theorizing about narcissistic rage, Study 1 showed that vulnerable (but not grandiose) narcissism predicted more anger internalization and externalization, as well as poorer anger control. Study 2 revealed vulnerable narcissism as a stronger indicator of shame and aggressiveness, especially hostility and anger. Study 3 identified distrust of others and angry rumination as key factors accounting for vulnerable narcissists' reactive and displaced aggression. Study 4 provided behavioral evidence that vulnerable (but not grandiose) narcissism amplifies reactive and displaced aggression in the face of provocation. Taken together, the findings not only establish narcissistic vulnerability as a key source of narcissistic rage but also reveal an important pathway to narcissistic aggression that does not involve competitiveness or exploitativeness. In addition, the results support clinical views of narcissistic aggression and implicate deficient self-esteem as an important driver of aggressive behavior. PMID- 25545842 TI - Patterns and sources of personality development in old age. AB - Despite abundant evidence that personality development continues in adulthood, little is known about the patterns and sources of personality development in old age. We thus investigated mean-level trends and individual differences in change as well as the genetic and environmental sources of rank-order continuity and change in several personality traits (neuroticism, extraversion, openness, agreeableness, conscientiousness, perceived control, and affect intensity) and well-being. In addition, we analyzed the interrelation between perceived control and change in other personality traits as well as between change in personality traits and change in well-being. We analyzed data from older adult twins, aged 64 85 years at Time 1 (N = 410; 135 males and 275 females; 134 monozygotic and 63 dizygotic twin pairs), collected at 2 different time points about 5 years apart. On average, neuroticism increased, whereas extraversion, conscientiousness, and perceived control significantly decreased over time. Change in perceived control was associated with change in neuroticism and conscientiousness, pointing to particular adaptation mechanisms specific to old age. Whereas individual differences in personality traits were fairly stable due to both genetic and environmental sources, individual differences in change were primarily due to environmental sources (beyond random error) indicating plasticity in old age. Even though the average level of well-being did not significantly change over time, individual well-being tended to decrease with strongly increasing levels of neuroticism as well as decreasing extraversion, conscientiousness, and perceived control, indicating that personality traits predict well-being but not vice versa. We discuss implications for theory on personality development across the lifespan. PMID- 25545841 TI - Vagal flexibility: A physiological predictor of social sensitivity. AB - This research explores vagal flexibility--dynamic modulation of cardiac vagal control--as an individual-level physiological index of social sensitivity. In 4 studies, we test the hypothesis that individuals with greater cardiac vagal flexibility, operationalized as higher cardiac vagal tone at rest and greater cardiac vagal withdrawal (indexed by a decrease in respiratory sinus arrhythmia) during cognitive or attentional demand, perceive social-emotional information more accurately and show greater sensitivity to their social context. Study 1 sets the foundation for this investigation by establishing that vagal flexibility can be elicited consistently in the laboratory and reliably over time. Study 2 demonstrates that vagal flexibility has different associations with psychological characteristics than does vagal tone, and that these characteristics are primarily social in nature. Study 3 links individual differences in vagal flexibility with accurate detection of social and emotional cues depicted in still facial images. Study 4 demonstrates that individuals with greater vagal flexibility respond to dynamic social feedback in a more context-sensitive manner than do individuals with less vagal flexibility. Specifically, compared with their less flexible counterparts, individuals with greater vagal flexibility, when assigned to receive negative social feedback, report more shame, show more pronounced blood pressure responses, and display less sociable behavior, but when receiving positive social feedback display more sociable behavior. Taken together, these findings suggest that vagal flexibility is a useful individual difference physiological predictor of social sensitivity, which may have implications for clinical, developmental, and health psychologists. PMID- 25545843 TI - Likelihood-based tree reconstruction on a concatenation of aligned sequence data sets can be statistically inconsistent. AB - The reconstruction of a species tree from genomic data faces a double hurdle. First, the (gene) tree describing the evolution of each gene may differ from the species tree, for instance, due to incomplete lineage sorting. Second, the aligned genetic sequences at the leaves of each gene tree provide merely an imperfect estimate of the topology of the gene tree. In this note, we demonstrate formally that a basic statistical problem arises if one tries to avoid accounting for these two processes and analyses the genetic data directly via a concatenation approach. More precisely, we show that, under the multispecies coalescent with a standard site substitution model, maximum likelihood estimation on sequence data that has been concatenated across genes and performed under the incorrect assumption that all sites have evolved independently and identically on a fixed tree is a statistically inconsistent estimator of the species tree. Our results provide a formal justification of simulation results described of Kubatko and Degnan (2007) and others, and complements recent theoretical results by DeGIorgio and Degnan (2010) and Chifman and Kubtako (2014). PMID- 25545844 TI - Pregnancy-related issues in women with systemic lupus erythematosus. AB - While fertility is preserved in females with systemic lupus erythematosus (SLE), it is well established that pregnancy in these patients is associated with adverse maternal and fetal outcomes, including pregnancy loss, pre-eclampsia, preterm delivery and intrauterine growth retardation, as well as neonatal mortality. Mechanisms underlying these adverse outcomes are poorly understood, and better understanding of these would allow development of targeted and personalized treatment strategies. Established risk factors for adverse pregnancy outcomes include active disease within 6 months prior to conception and during pregnancy, active nephritis, maternal hypertension, antiphospholipid antibodies and hypocomplementemia. While intensive monitoring is recommended, the comparative effectiveness of appropriate management strategies is unclear. While current strategies are able to achieve live births in 85-90% of pregnancies, certain aspects such as prevention of preterm birth, treatment of congenital heart block due to neonatal lupus and recurrent pregnancy loss despite best management, remains challenging. Pregnancy is also associated with an increased risk of flare of lupus, particularly in patients with active disease at time of conception or within 6 months prior to conception. Pregnant patients with SLE should be followed in a high-risk obstetric clinic, and care should be closely coordinated between the obstetrician and rheumatologist. PMID- 25545846 TI - Editorial: What is peripheral spondyloarthritis? PMID- 25545845 TI - An infant with a long-standing ulcer successfully treated with a novel treatment combination. PMID- 25545847 TI - Documenting bee decline or squandering scarce resources. PMID- 25545848 TI - Metallopeptide catalysts and artificial metalloenzymes containing unnatural amino acids. AB - Metallopeptide catalysts and artificial metalloenzymes built from peptide scaffolds and catalytically active metal centers possess a number of exciting properties that could be exploited for selective catalysis. Control over metal catalyst secondary coordination spheres, compatibility with library based methods for optimization and evolution, and biocompatibility stand out in this regard. A wide range of unnatural amino acids (UAAs) have been incorporated into peptide and protein scaffolds using several distinct methods, and the resulting UAAs containing scaffolds can be used to create novel hybrid metal-peptide catalysts. Promising levels of selectivity have been demonstrated for several hybrid catalysts, and these provide a strong impetus and important lessons for the design of and optimization of hybrid catalysts. PMID- 25545849 TI - Morphological and genetic classification of lung cancer: variation in practice and implications for tailored treatment. AB - AIMS: Tailored therapy of lung cancer requires high-quality pathology. Tumours must be subtyped accurately and material preserved for genetic analysis upon which treatment is increasingly based. There is a presumption that pathologists have risen to this challenge, but the nature and degree of variation in practice and quality are unknown. METHODS AND RESULTS: We collected detailed information on 1507 consecutive, newly diagnosed patients referred to 19 UK lung cancer units, ranging from district general hospitals to specialist cardiothoracic units. In only four centres were pathologists handling thoracic biopsies enrolled in the thoracic external quality assessment (EQA) scheme. Achievement of a positive diagnosis of malignancy ranged from 53 to 88%. Variation in tumour subtypes was wide, and the proportion of biopsies classified as merely 'non-small cell lung cancer, not otherwise specified' varied from 3 to 20%, despite almost universal use of immunochemistry. The proportion of tumours tested for epidermal growth factor receptor (EGFR) gene mutation ranged from 12 to 92%. CONCLUSIONS: There is considerable variation in practice among UK pathologists and arguably in the quality of pathology, raising questions about expertise, adherence to guidelines, rigour of EQA and, ultimately, the reliability of the pathology that underpins the management of lung cancer. PMID- 25545850 TI - Comparative investigation of seed coats of brown- versus yellow-colored soybean seeds using an integrated proteomics and metabolomics approach. AB - Seed coat color is an important attribute determining consumption of soybean seeds. Soybean cultivar Mallikong (M) has yellow seed coat while its naturally mutated cultivar Mallikong mutant (MM), has brown colored seed coat. We used integrated proteomics and metabolomics approach to investigate the differences between seed coats of M and MM during different stages of seed development (4, 5, and 6 weeks after flowering). 2DE profiling of total seed coat proteins from three stages showed 178 differentially expressed spots between M and MM of which 172 were identified by MALDI-TOF/TOF. Of these, 62 were upregulated and 105 were downregulated in MM compared with M, while five spots were detected only in MM. Proteins involved in primary metabolism showed downregulation in MM suggesting energy in MM might be utilized for proanthocyanidin biosynthesis via secondary metabolic pathways that leads to the development of brown seed coat color. Besides, downregulation of two isoforms of isoflavone reductase indicated reduced isoflavones in seed coat of MM that was confirmed by quantitative estimation of total and individual isoflavones using HPLC. We propose that low isoflavones level in MM may offer a high substrate for proanthocyanidin production that results in the development of brown seed coat in MM. PMID- 25545851 TI - Molecular polygamy: The promiscuity of l-phenylalanyl-tRNA-synthetase triggers misincorporation of meta- and ortho-tyrosine in monoclonal antibodies expressed by Chinese hamster ovary cells. AB - In-depth analytical characterization of biotherapeutics originating from different production batches is mandatory to ensure product safety and consistent molecule efficacy. Previously, we have shown unintended incorporation of tyrosine (Tyr) and leucine/isoleucine (Leu/Ile) at phenylalanine (Phe) positions in a recombinant produced monoclonal antibody (mAb) using an orthogonal MASCOT/SIEVE based approach for mass spectrometry data analysis. The misincorporation could be avoided by sufficient supply of phenylalanine throughout the process. Several non annotated signals in the primarily chromatographic peptide separation step for apparently single Phe->Tyr sequence variants (SVs) suggest a role for isobar tyrosine isoforms. Meta- and ortho-Tyr are spontaneously generated during aerobic fed-batch production processes using Chinese hamster ovary (CHO) cell lines. Process induced meta- and ortho-Tyr but not proteinogenic para-Tyr are incorporated at Phe locations in Phe-starved CHO cultures expressing a recombinant mAb. Furthermore, meta- and ortho-Tyr are preferably misincorporated over Leu. Structural modeling of the l-phenylalanyl-tRNA-synthetase (PheRS) substrate activation site indicates a possible fit of non-cognate ortho-Tyr and meta-Tyr substrates. Dose-dependent misincorporations of Tyr isoforms support the hypothesis that meta- and ortho-Tyr are competing, alternative substrates for PheRS in CHO processes. Finally, easily accessible at-line surrogate markers for Phe->Tyr SV formation in biotherapeutic production were defined by the calculation of critical ratios for meta-Tyr/Phe and ortho-Tyr/Phe to support early prediction of SV probability, and finally, to allow for immediate process controlled Phe->Tyr SV prevention. PMID- 25545852 TI - Disease severity in newly diagnosed glaucoma patients with visual field loss: trends from more than a decade of data. AB - PURPOSE: Large archives of visual field (VF) records from automated perimetry are used to examine severity of vision loss at diagnosis in glaucoma patients over a 13 year period in England. METHODS: A total of 473 252 Humphrey VFs recorded at four regionally different glaucoma clinics in England were retrospectively examined. Patients were required to have a Humphrey mean deviation (MD) outside 95% normative limits in at least one eye and had at least two visits to the glaucoma clinic in a study period between the start of 1999 and the end of 2011. No other clinical data was considered. MD of the worse eye at the first hospital visit was used as an estimate of vision loss for a patient at diagnosis; proportion of patients categorised as having 'early' (better than -6 dB) or 'advanced' (worse than -12 dB) VF loss were also calculated. Simple linear regression of MD against the date of first visit was used to estimate changes in vision loss at diagnosis over time. RESULTS: Median age, at the time of diagnosis, of the 25 521 patients included in the analysis was 67 (interquartile range 55-76) years. Average level of glaucoma vision loss at diagnosis, in those patients presenting to secondary care with a VF defect, improved by an average 0.11 dB per year over the study period (95% confidence interval: 0.08-0.13 dB per year; p < 0.0001). Percentage of patients with 'advanced' VF loss in at least one eye at diagnosis changed from 30% (1999-2001) to 21% in (2009-2011) (p < 0.0001). CONCLUSIONS: Severity of vision loss at the point of glaucoma detection, in those patients diagnosed with a VF defect, is improving over time in England. Nevertheless, the improvement is modest and large numbers of patients still present at glaucoma clinics with significant vision loss in at least one eye. Large scale digital VF data can be used to help monitor and audit health service delivery of glaucoma. PMID- 25545853 TI - Assessment of alpha-fetoprotein targeted HSV1-tk expression in hepatocellular carcinoma with in vivo imaging. AB - Tumor-specific enhancer/promoter is applicable for targeting gene expression in tumors and helpful for tumor-targeting imaging and therapy. We aimed to acquire alpha-fetoprotein (AFP)-producing hepatocellular carcinoma (HCC) specific images using adenovirus containing HSV1-tk gene controlled by AFP enhancer/promoter and evaluate in vivo ganciclovir (GCV)-medicated therapeutic effects on AFP-targeted HSV1-tk expression with (18)F-FDG positron emission tomography (PET). Recombinant adenovirus expressing HSV1-tk under AFP enhancer/promoter was produced (AdAFP-TK) and the expression levels were evaluated by RT-PCR and (125)I-IVDU uptake. GCV mediated HSV1-tk cytotoxicity was determined by MTT assay. After the mixture of AdAFP-fLuc and AdAFP-TK was administrated, bioluminescent images (BLIs) and (18)F FHBG PET images were obtained in tumor-bearing mice. In vivo therapeutic effects of AdAFP-TK and GCV in the HuH-7 xenograft model were monitored by (18)F-FDG PET. When infected with AdAFP-TK, cell viability in HuH-7 was reduced, but those in HT 29 and SK-Hep-1 were not significantly decreased at any GCV concentration less than 100 MUM. AFP-targeted fLuc and HSV1-tk expression were clearly visualized by BLI and (18)F-FHBG PET images in AFP-producing HCC, respectively. In vivo GCV mediated tumor growth inhibition by AFP-targeted HSV1-tk expression was monitored by (18)F-FDG PET. Recombinant AdAFP-TK could be applied for AFP-targeted HCC gene therapy and imaging in AFP-producing HCC. PMID- 25545854 TI - Anti-HIV drugs, lopinavir/ritonavir and atazanavir, modulate innate immune response triggered by Leishmania in macrophages: the role of NF-kappaB and PPAR gamma. AB - This study evaluated the influence of HIV protease inhibitors lopinavir/ritonavir (LPV/RTV) and atazanavir (ATV) on macrophage functions during their first interaction with Leishmania. Macrophages from BALB/c mice treated for 10days with LPV/RTV and ATV, infected or not in vitro with L. (L.) amazonensis, were used to investigate the effects of these drugs on infection index, leishmanicidal capacity, cytokine production and PPAR-gamma and RelB expression. LPV/RTV and ATV treatments significantly increased the infection index and the percentage of Leishmania-infected macrophages compared to untreated infected macrophages. There was no correlated increase in the production of NO and H2O2 leishmanicidal molecules. Promastigotes derived from Leishmania-infected macrophages from LPV/RTV and ATV-treated BALB/c mice had an in vitro growth 45.1% and 56.4% higher in groups treated with LPV/RTV and ATV than with PBS in culture. ATV treatment reduced IL-12p70 and IL-10 secretion in Leishmania-infected macrophages, but had no effect on IL-23 and TNF production. LPV reduced IL-10 and had no effect on IL 12p70, TNF and IL-23 secretion. ATV treatment decreased PPAR-gamma expression in Leishmania-infected macrophages compared to untreated infected macrophages. In addition, LPV/RTV, but not ATV, reduced RelB cytoplasm-to-nucleus translocation in Leishmania-infected macrophages. Results showed that LPV/RTV and ATV HIV protease inhibitors were able to modulate innate defense mechanisms against Leishmania via different intracellular pathways. Although HIV protease inhibitors are highly efficient to control the Human Immunodeficiency Virus, these drugs might also influence the course of leishmaniasis in HIV-Leishmania-co-infected individuals. PMID- 25545856 TI - Pain perception in healthy young men is modified by time-of-day and is modality dependent. AB - OBJECTIVE: Several physiological processes exhibit 24-hour oscillations termed circadian rhythms. Despite numerous investigations on the circadian dynamics of pain perception, findings related to this issue remain inconsistent. This study aimed to assess the effect of time-of-day on multimodal experimental pain perception in healthy males, including "static" and "dynamic" quantitative sensory tests. DESIGN: A random order tests were performed in the morning, afternoon and evening. SUBJECTS: Forty-eight healthy males (25.9 +/- 4.7 years old). METHODS: Three different pain modalities i) mechanical (pain threshold, tolerance, and intensity), ii) heat (pain threshold and intensity), iii) cold (pain threshold measured in degrees C and in seconds and cold pain tolerance and intensity) utilizing nine "static" pain parameters, and two "dynamic" pain paradigms i) temporal summation and ii) conditioned pain modulation were assessed in each session. RESULTS: Pain scores varied significantly in six pain parameters during the day. Specifically, lower pain scores were found in the morning for cold pain threshold (in seconds and in degrees C), cold pain intensity, cold pain tolerance, heat pain threshold and intensity. There were no significant diurnal differences in the mechanical evoked pain parameters or in either of the "dynamic" pain paradigms. CONCLUSIONS: Thermal pain scores varies during the day and morning seems to be the time-of-day most insensitive to pain. Also, dynamic tests and the mechanical pain model are not appropriate for detecting diurnal variability in pain. The results of this study may be partially explained by a potential analgesic effect of some hormones known to have diurnal variation (e.g., melatonin and cortisol). PMID- 25545855 TI - Adolescent patient preferences surrounding partner notification and treatment for sexually transmitted infections. AB - OBJECTIVES: Important barriers to addressing the sexually transmitted infection (STI) epidemic among adolescents are the inadequate partner notification of positive STI results and insufficient rates of partner testing and treatment. However, adolescent attitudes regarding partner notification and treatment are not well understood. The aim was to qualitatively explore the barriers to and preferences for partner notification and treatment among adolescent males and females tested for STIs in an emergency department (ED) setting and to explore the acceptability of ED personnel notifying their sexual partners. METHODS: This was a descriptive, qualitative study in which a convenience sample of 40 adolescents (18 females, 22 males) 14 to 21 years of age who presented to either adult or pediatric EDs with STI-related complaints participated. Individualized, semistructured, confidential interviews were administered to each participant. Interviews were audiotaped and transcribed verbatim by an independent transcriptionist. Data were analyzed using framework analysis. RESULTS: Barriers to partner notification included fear of retaliation or loss of the relationship, lack of understanding of or concern for the consequences associated with an STI, and social stigma and embarrassment. Participants reported two primary barriers to their partners obtaining STI testing and treatment: lack of transportation to the health care site and the partner's fear of STI positive test results. Most participants preferred to notify their main sexual partners of an STI exposure via a face-to-face interaction or a phone call. Most participants were agreeable with a health care provider (HCP) notifying their main sexual partners of STI exposure and preferred that the HCP notify the partner by phone call. CONCLUSIONS: There are several adolescent preferences and barriers for partner notification and treatment. To be most effective, future interventions to prevent adolescent STIs should incorporate these preferences and address the barriers to partner notification. In an ED setting, using HCPs to provide partner notification of STI exposures is acceptable to adolescent patients; however, the feasibility of this type of program needs further exploration. PMID- 25545857 TI - Elevated cannabinoid receptor 1 and G protein-coupled receptor 55 expression in proximal tubule cells and whole kidney exposed to diabetic conditions. AB - Hyperglycaemia increases the risk of developing diabetic nephropathy, with primary targets in the glomerulus and proximal tubule. Importantly, glomerular damage in the kidney leads to elevated albumin levels in the filtrate, which contributes to tubular structural modifications that lead to dysfunction. Diabetes alters the endocannabinoid system in a number of target organs, with previous research characterizing tissue-specific changes in the expression of the cannabinoid receptor 1 (CB1 ) and G protein-coupled receptor 55 (GPR55), a putative cannabinoid receptor, in diabetes. Although these receptors have a functional role in the cannabinoid system in the kidney, there has been little investigation into changes in the expression of CB1 and GPR55 in the proximal tubule under diabetic conditions. In this study, CB1 and GPR55 messenger RNA and protein levels were quantified in cultured human kidney cells and then treated with either elevated glucose, elevated albumin, or a combination of glucose and albumin for 4, 6, 18, or 24 h. In addition, CB1 and GPR55 protein expression was characterized in whole-kidney lysate from streptozotocin-induced diabetic Sprague Dawley rats. In vitro exposure to elevated glucose and albumin increased CB1 and GPR55 messenger RNA and protein expression in proximal tubule cells in a time dependant manner. In whole kidney of streptozotocin-induced diabetic rats, CB1 protein was upregulated, whereas GPR55 protein concentration was not altered. Thus, expression of CB1 and GPR55 in proximal tubules is altered in response to elevated levels of glucose and albumin. Further investigations should determine if these receptors are effective physiological targets for the treatment and prevention of diabetic nephropathy. PMID- 25545858 TI - Increasing varenicline dose in smokers who do not respond to the standard dosage: a randomized clinical trial. AB - IMPORTANCE: Standard varenicline tartrate dosing was formulated to avoid adverse effects (primarily nausea), but some patients may be underdosed. To our knowledge, no evidence-based guidance exists for physicians considering increasing varenicline dose if there is no response to the standard dosage. OBJECTIVE: To determine whether increasing varenicline dose in patients showing no response to the standard dosage improves treatment efficacy. DESIGN, SETTING, AND PARTICIPANTS: In a double-blind randomized placebo-controlled trial, 503 smokers attending a stop smoking clinic commenced varenicline use 3 weeks before their target quit date (TQD). Two hundred participants reporting no strong nausea, no clear reduction in smoking enjoyment, and less than 50% reduction in their baseline smoking on day 12 received additional tablets of varenicline or placebo. INTERVENTIONS: All participants began standard varenicline tartrate dosing, gradually increasing to 2 mg/d. Dose increases of twice-daily varenicline (0.5 mg) or placebo took place on days 12, 15, and 18 (up to a maximum of 5 mg/d). MAIN OUTCOMES AND MEASURES: Participants rated their smoking enjoyment during the prequit period and withdrawal symptoms weekly for the first 4 weeks after the TQD. Continuous validated abstinence rates were assessed at 1, 4, and 12 weeks after the TQD. RESULTS: The dose increase reduced smoking enjoyment during the prequit period, with mean (SD) ratings of 1.7 (0.8) for varenicline vs 2.1 (0.7) for placebo (P = .001). It had no effect on the mean (SD) frequency of urges to smoke at 1 week after the TQD, their strength, or the severity of withdrawal symptoms: these ratings for varenicline vs placebo were 2.7 (1.1) vs 2.6 (0.9) (P = .90), 2.6 (1.1) vs 2.8 (1.0) (P = .36), and 1.5 (0.4) vs 1.6 (0.5) (P = .30), respectively. The dose increase also had no effect on smoking cessation rates for varenicline vs placebo at 1 week (37 [37.0%] vs 48 [48.0%], P = .14), 4 weeks (51 [51.0%] vs 59 [59.0%], P = .32), and 12 weeks (26 [26.0%] vs 23 [23.0%], P = .61) after the TQD. There was significantly more nausea (P < .001) and vomiting (P < .001) reported in the varenicline arm than in the placebo arm. CONCLUSIONS AND RELEVANCE: Increasing varenicline dose in smokers with low response to the drug had no significant effect on tobacco withdrawal symptoms or smoking cessation. Physicians often consider increasing the medication dose if there is no response to the standard dosage. This approach may not work with varenicline. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01206010. PMID- 25545859 TI - Retinal proteins associated with redox regulation and protein folding play central roles in response to high glucose conditions. AB - Diabetic retinopathy typically causes poor vision and blindness. A previous study revealed that a high blood glucose concentration induces glycoxidation and weakens the retinal capillaries. Nevertheless, the molecular mechanisms underlying the effects of high blood glucose induced diabetic retinopathy remain to be elucidated. In the present study, we cultured the retinal pigmented epithelial cell line ARPE-19 in mannitol-balanced 5.5, 25, and 100 mM glucose media and investigated protein level alterations. Proteomic analysis revealed significant changes in 137 protein features, of which 124 demonstrated changes in a glucose concentration dependent manner. Several proteins functionally associated with redox regulation, protein folding, or the cytoskeleton are affected by increased glucose concentrations. Additional analyses also revealed that cellular oxidative stress, including endoplasmic reticulum stress, was significantly increased after treatment with high glucose concentrations. However, the mitochondrial membrane potential and cell survival remained unchanged during treatment with high glucose concentrations. To summarize, in this study, we used a comprehensive retinal pigmented epithelial cell based proteomic approach for identifying changes in protein expression associated retinal markers induced by high glucose concentrations. Our results revealed that a high glucose condition can induce cellular oxidative stress and modulate the levels of proteins with functions in redox regulation, protein folding, and cytoskeleton regulation; however, cell viability and mitochondrial integrity are not significantly disturbed under these high glucose conditions. PMID- 25545860 TI - Woody species diversity in forest plantations in a mountainous region of Beijing, China: effects of sampling scale and species selection. AB - The role of forest plantations in biodiversity conservation has gained more attention in recent years. However, most work on evaluating the diversity of forest plantations focuses only on one spatial scale; thus, we examined the effects of sampling scale on diversity in forest plantations. We designed a hierarchical sampling strategy to collect data on woody species diversity in planted pine (Pinus tabuliformis Carr.), planted larch (Larix principis rupprechtii Mayr.), and natural secondary deciduous broadleaf forests in a mountainous region of Beijing, China. Additive diversity partition analysis showed that, compared to natural forests, the planted pine forests had a different woody species diversity partitioning pattern at multi-scales (except the Simpson diversity in the regeneration layer), while the larch plantations did not show multi-scale diversity partitioning patterns that were obviously different from those in the natural secondary broadleaf forest. Compare to the natural secondary broadleaf forests, the effects of planted pine forests on woody species diversity are dependent on the sampling scale and layers selected for analysis. Diversity in the planted larch forest, however, was not significantly different from that in the natural forest for all diversity components at all sampling levels. Our work demonstrated that the species selected for afforestation and the sampling scales selected for data analysis alter the conclusions on the levels of diversity supported by plantations. We suggest that a wide range of scales should be considered in the evaluation of the role of forest plantations on biodiversity conservation. PMID- 25545861 TI - Shape up or ship out: can we enhance productivity in coastal aquaculture to compete with other uses? AB - Coastal resources are coming under increasing pressure from competition between recreational, commercial and conservation uses. This is particularly so in coastal areas adjacent to major population centres. Given high recreational and conservation values in such areas, economic activities need to be highly efficient in order to persist. Management of these industries must therefore also encourage efficient production and full utilisation of the areas available. In order to achieve this, managers must first understand the level and drivers of productivity, and how these can be influenced. In this study, by way of illustration, the focus was on the Sydney rock oyster industry within Queensland's Moreton Bay, a multiple use marine park with high recreational and conservation value adjacent to Australia's third largest city. Productivity of the oyster industry in Moreton Bay is currently low compared to historic levels, and management has an objective of reversing this trend. It is unclear whether this difference is due to oyster farmers' business choices and personal characteristics or whether varying environmental conditions in the Moreton Bay limit the capacity of the oyster industry. These require different management responses in order to enhance productivity. The study examined different productivity measures of the oyster industry using data envelopment analysis (DEA) to determine where productivity gains can be made and by how much. The findings suggest that the industry is operating at a high level of capacity utilisation, but a low level of efficiency. The results also suggest that both demographic and environmental conditions affect technical efficiency in the Bay, with water characteristics improvements and appropriate training potentially providing the greatest benefits to the industry. Methods used in this study are transferable to other industries and provide a means by which coastal aquaculture may be managed to ensure it remains competitive with other uses of coastal resources. PMID- 25545862 TI - Reorganization of functional brain networks mediates the improvement of cognitive performance following real-time neurofeedback training of working memory. AB - Working memory (WM) is essential for individuals' cognitive functions. Neuroimaging studies indicated that WM fundamentally relied on a frontoparietal working memory network (WMN) and a cinguloparietal default mode network (DMN). Behavioral training studies demonstrated that the two networks can be modulated by WM training. Different from the behavioral training, our recent study used a real-time functional MRI (rtfMRI)-based neurofeedback method to conduct WM training, demonstrating that WM performance can be significantly improved after successfully upregulating the activity of the target region of interest (ROI) in the left dorsolateral prefrontal cortex (Zhang et al., [2013]: PloS One 8:e73735); however, the neural substrate of rtfMRI-based WM training remains unclear. In this work, we assessed the intranetwork and internetwork connectivity changes of WMN and DMN during the training, and their correlations with the change of brain activity in the target ROI as well as with the improvement of post-training behavior. Our analysis revealed an "ROI-network-behavior" correlation relationship underlying the rtfMRI training. Further mediation analysis indicated that the reorganization of functional brain networks mediated the effect of self-regulation of the target brain activity on the improvement of cognitive performance following the neurofeedback training. The results of this study enhance our understanding of the neural basis of real-time neurofeedback and suggest a new direction to improve WM performance by regulating the functional connectivity in the WM related networks. PMID- 25545864 TI - A comparative study of egg recognition signature mixtures in Formica ants. AB - Processing of information from the environment, such as assessing group membership in social contexts, is a major determinant of inclusive fitness. For social insects, recognizing brood origin is crucial for inclusive fitness in many contexts, such as social parasitism and kin conflicts within colonies. Whether a recognition signature is informative in kin conflicts depends on the extent of a genetic contribution into the cues. We investigated colony- and matriline specific variation in egg surface hydrocarbons in seven species of Formica ants. We show that chemical variance is distributed similarly to genetic variation, suggesting a significant genetic contribution to eggs odors in the genus. Significant among matriline components, and significant correlations between chemical and genetic similarity among individuals also indicate kin informative egg odors in several species. We suggest that egg odor surface variation could play a large role in within colony conflicts, and that a comparative method can reveal novel insight into communication of identity. PMID- 25545863 TI - Implementation of a phase detection algorithm for dynamic cardiac computed tomography analysis based on time dependent contrast agent distribution. AB - This paper presents a phase detection algorithm for four-dimensional (4D) cardiac computed tomography (CT) analysis. The algorithm detects a phase, i.e. a specific three-dimensional (3D) image out of several time-distributed 3D images, with high contrast in the left ventricle and low contrast in the right ventricle. The purpose is to use the automatically detected phase in an existing algorithm that automatically aligns the images along the heart axis. Decision making is based on the contrast agent distribution over time. It was implemented in KardioPerfusion- a software framework currently being developed for 4D CT myocardial perfusion analysis. Agreement of the phase detection algorithm with two reference readers was 97% (95% CI: 82-100%). Mean duration for detection was 0.020 s (95% CI: 0.018 0.022 s), which was 800 times less than the readers needed (16+/-7 s, p<03001). Thus, this algorithm is an accurate and fast tool that can improve work flow of clinical examinations. PMID- 25545865 TI - Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes. AB - Ischemia/reperfusion injury (IRI) that develops after liver implantation may prejudice long-term graft survival, but it remains poorly understood. Here we correlate the severity of IRIs that were determined by histological grading of time-zero biopsies sampled after graft revascularization with patient and graft outcomes. Time-zero biopsies of 476 liver transplants performed at our center between 2000 and 2010 were graded as follows: nil (10.5%), mild (58.8%), moderate (26.1%), and severe (4.6%). Severe IRI was associated with donor age, donation after circulatory death, prolonged cold ischemia time, and liver steatosis, but it was also associated with increased rates of primary nonfunction (9.1%) and retransplantation within 90 days (22.7%). Longer term outcomes in the severe IRI group were also poor, with 1-year graft and patient survival rates of only 55% and 68%, respectively (cf. 90% and 93% for the remainder). Severe IRI on the time zero biopsy was, in a multivariate analysis, an independent determinant of 1-year graft survival and was a better predictor of 1-year graft loss than liver steatosis, early graft dysfunction syndrome, and high first-week alanine aminotransferase with a positive predictive value of 45%. Time-zero biopsies predict adverse clinical outcomes after liver transplantation, and severe IRI upon biopsy signals the likely need for early retransplantation. PMID- 25545866 TI - Effect of adhesive properties of buffy coat on the quality of blood components produced with Top & Top and Top & Bottom bags. AB - BACKGROUND: The Transfusion Medicine Unit of Reggio Emilia currently collects whole blood using conventional quadruple Fresenius Top & Top bags. In this study, new Fresenius Top & Bottom bags were assessed and compared to the routine method with regards to product quality and operational requirements. MATERIAL AND METHODS: Twenty-one whole blood units were collected with both the new and the traditional bags, and then separated. Quality control data were evaluated and compared in order to estimate yield and quality of final blood components obtained with the two systems. We collected other bags, not included in the ordinary quality control programme, for comparison of platelet concentrates produced by pools of buffy coat. RESULTS: Compared to the traditional system, the whole blood units processed with Top & Bottom bags yielded larger plasma volumes (+5.7%) and a similar amount of concentrated red blood cells, but with a much lower contamination of lymphocytes (-61.5%) and platelets (-86.6%). Consequently, the pooled platelets contained less plasma (-26.3%) and were significantly richer in platelets (+17.9%). DISCUSSION: This study investigated the effect of centrifugation on the adhesiveness of the buffy coat to the bag used for whole blood collection. We analysed the mechanism by which this undesirable phenomenon affects the quality of packed red blood cells in two types of bags. We also documented the incomparability of measurements on platelet concentrates performed with different principles of cell counting: this vexing problem has important implications for biomedical research and for the establishment of universal product standards. Our results support the conclusion that the Top & Bottom bags produce components of higher quality than our usual system, while having equal operational efficiency. Use of the new bags could result in an important quality improvement in blood components manufacturing. PMID- 25545867 TI - Role of rituximab in the treatment of postpartum acquired haemophilia A: a systematic review of the literature. PMID- 25545868 TI - Free-flow electrophoresis to clean donated blood before transfusion at the point of care: a proof-of-concept study. PMID- 25545869 TI - Human Parvovirus B19 and blood product safety: a tale of twenty years of improvements. PMID- 25545870 TI - The high oxygen affinity haemoglobin Nantes: a family case description. PMID- 25545871 TI - More or less living according to your blood type. PMID- 25545873 TI - Blood collection staff education in the prevention of venepuncture failures and donor adverse reactions: from inexperienced to skilful staff. PMID- 25545872 TI - Haemostatic and fibrinolytic changes in obese subjects undergoing bariatric surgery: the effect of different surgical procedures. AB - BACKGROUND: Little is known about effects of different bariatric surgery procedures on haemostatic and fibrinolytic parameters. MATERIAL AND METHODS: Consecutive obese subjects undergoing gastric bypass (GBP) or sleeve gastrectomy (SG) were enrolled. In all patients, levels of haemostatic factors (FII, FVII, FVIII, FIX, FX, vWF, fibrinogen), fibrinolytic variables (PAI-1, t-PA and D dimer) and natural anticoagulants (AT, protein C and protein S) were evaluated before and 2 months after surgery. RESULTS: A total of 77 GBP and 79 SG subjects completed the study. At baseline no difference in coagulation parameters was found between the two groups. After both GBP and SG, subjects showed significant changes in haemostatic and fibrinolytic variables and in natural anticoagulant levels. The Delta% changes in FVII, FVIII, FIX, vWF, fibrinogen, D-dimer, protein C and protein S levels were significantly higher in subjects who underwent GBP than in those who underwent SG. Multivariate analysis confirmed that GBP was a predictor of higher Delta% changes in FVII (beta=0.268, p=0.010), protein C (beta=0.274, p=0.003) and protein S (beta=0.297, p<0.001), but not in all the other variables. Following coagulation factor reduction, 31 subjects (25.9% of GBP and 13.9% of SG; p=0.044) showed overt FVII deficiency; protein C deficiency was reported by 34 subjects (32.5% of GBP vs 11.4% of SG, p=0.033) and protein S deficiency by 39 (37.6% of GBP vs 12.6% of SG, p=0.009). Multivariate analyses showed that GBP was associated with an increased risk of deficiency of FVII (OR: 3.64; 95% CI: 1.73-7.64, p=0.001), protein C (OR: 4.319; 95% CI: 1.33-13.9, p=0.015) and protein S (OR: 5.50; 95% CI: 1.71-17.7, p=0.004). DISCUSSION: GBP is associated with an increased risk of post-operative deficiency in some vitamin K dependent coagulation factors. Whereas such deficiency is too weak to cause bleeding, it is significant enough to increase the risk of thrombosis. PMID- 25545874 TI - Molecular immunohaematology round table discussions at the AABB Annual Meeting, Denver 2013. PMID- 25545875 TI - Direct oral anticoagulants for the treatment of unprovoked venous thromboembolism: a meta-analysis of randomised controlled trials. PMID- 25545876 TI - Syphilis testing in blood donors: an update. PMID- 25545877 TI - Association of haematocrit and red blood cell transfusion with outcomes in infants with shunt-dependent pulmonary blood flow and univentricular physiology. AB - BACKGROUND: The aim of this study was to investigate the association between red blood cell (RBC) transfusion and haematocrit values with outcomes in infants with univentricular physiology undergoing surgery for a modified Blalock-Taussig shunt. MATERIAL AND METHODS: This study included infants <= 2 months of age who underwent modified Blalock-Taussig shunt surgery at the Arkansas Children's Hospital (2006-2012). Infants undergoing a Norwood operation or Damus-Kaye Stansel operation with modified Blalock-Taussig shunt were excluded. Demographics, pre-operative, operative, daily laboratory data, and post-operative variables were collected. We studied the association between haematocrit and blood transfusion with a composite clinical outcome. Multivariable logistic regression models were fitted to study the probability of study outcomes as a function of haematocrit values and RBC transfusions after operation. RESULTS: Seventy-three patients qualified for inclusion. All study patients received blood transfusion within the first 48 hours after heart surgery. The median haematocrit was 44.3 (interquartile range [IQR] 42.5-46.2), and the median volume of RBC transfused was 28 mL/kg (IQR, 10-125) in the first 14 days after surgery. The overall in-hospital mortality rate was 13.6% (10 patients). A multivariable analysis adjusted for risk factors, including weight, prematurity, cardiopulmonary bypass and postoperative need for nitric oxide and dialysis, revealed no association between haematocrit values and RBC transfusion with the composite clinical outcome. DISCUSSION: We did not find an association between higher haematocrit values and increasing RBC transfusions with improved outcomes in infants with shunt-dependent pulmonary blood flow and univentricular physiology. The power of our study was small, which prevents any strong statement on this lack of association. Future multi-centre, randomised controlled trials are needed to investigate this topic in further detail. PMID- 25545878 TI - Risk of bleeding in oral surgery in patients with disorders of haemostasis. PMID- 25545879 TI - The importance of studying red blood cells microparticles. PMID- 25545880 TI - Transient inhibition of neutrophil migration following plasma or plasma-platelet apheresis donation procedures. PMID- 25545881 TI - Polymorphism in self-assembly of peptide-based beta-hairpin contributes to network morphology and hydrogel mechanical rigidity. AB - Hydrogels are proving to be an excellent class of materials for biomedical applications. The molecular self-assembly of designed MAX1 beta-hairpin peptides into fibrillar networks has emerged as a novel route to form responsive hydrogels. Herein, computational modeling techniques are used to investigate the relative arrangements of individual hairpins within the fibrils that constitute the gel. The modeling provides insight into the morphology of the fibril network, which defines the gel's mechanical properties. Our study suggests polymorphic arrangements of the hairpins within the fibrils; however, the relative populations and the relative conformational energies of the polymorphic arrangements show a preference toward an arrangement of hairpins where their turn regions are not capable of forming intermolecular interaction. Repulsive intramolecular electrostatic interactions appear to dictate the formation of fibrils with shorter, rather than longer, persistent lengths. These repulsive intramolecular interactions also disfavor the formation of fibril entanglements. Taken together, the modeling predicts that MAX1 forms a network containing a large number of branch points, a network morphology supported by the formation of short fibril segments. We posit that, under static conditions, the preferred branched structures of the MAX1 peptide assembly result in a cross-linked hydrogel organization. At the same time, the shear stress leads to short fibrillar structures, thus fluidic hydrogel states. PMID- 25545882 TI - Safety, sterility and stability of direct-from-vial multiple dosing intravitreal injection of bevacizumab. AB - BACKGROUND: This study aims to determine the stability, sterility and safety of bevacizumab multiple dosing from a single vial without prior aliquoting. METHODS: In-vitro and human study. Six bevacizumab vials, used in multiple patients on a single day by direct withdrawal from the vial, and stored in 4 degrees C up to a variable period, were tested for stability (high-performance liquid chromatography; [HPLC]), sterility (culture), conformational stability by circular dichroism and fluorescence spectroscopy and the rubber cork structural integrity (electron microscopy [EM]). RESULTS: HPLC of all six samples of used bevacizumab and the control bevacizumab sample were similar; culture was negative; and the EM of rubber corks did not show an open communication. Spectroscopic studies indicated drug conformational stability. Further, there was no infection or inflammation in 221 consecutive patients (973 injections) when bevacizumab was stored at 4 degrees C and used for one week. CONCLUSION: Bevacizumab does not lose stability when stored at 4 degrees C. It may be used for a week by direct withdrawal from the vial without fear of infection or inflammation if all standard precautions related to intravitreal injection are adhered to. PMID- 25545883 TI - Long-term swallowing after chemoradiotherapy: Prospective study of functional and patient-reported changes over time. AB - BACKGROUND: This prospective study evaluated long-term swallowing outcomes and associated risk factors 5 years postchemoradiotherapy for head and neck cancer. METHODS: Following an earlier study of 69 patients, 39 patients had patient reported activity and quality of life (QOL) data collected. Twenty-one patients also underwent a videofluoroscopy swallowing study (VFSS). RESULTS: Between 6 months and 5 years posttreatment, patient-reported activity for solid foods significantly improved (p < .001), returning to pretreatment levels for 74% of patients. On VFSS, swallowing function for semisolids declined, with 5 patients demonstrating a clinically significant deterioration. Factors that predicted poorer long-term swallowing were the same as at 6 months, with the addition of older age and disease stage. CONCLUSION: Although long-term patient-reported activity improves and swallowing-related QOL is high, up to 24% of patients may demonstrate a clinically significant deterioration in swallowing function at 5 years posttreatment. This divergence suggests a degree of adaptation that patients develop, which warrants further investigation. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E307-E315, 2016. PMID- 25545886 TI - Laccase engineering: from rational design to directed evolution. AB - Laccases are multicopper oxidoreductases considered by many in the biotechonology field as the ultimate "green catalysts". This is mainly due to their broad substrate specificity and relative autonomy (they use molecular oxygen from air as an electron acceptor and they only produce water as by-product), making them suitable for a wide array of applications: biofuel production, bioremediation, organic synthesis, pulp biobleaching, textiles, the beverage and food industries, biosensor and biofuel cell development. Since the beginning of the 21st century, specific features of bacterial and fungal laccases have been exhaustively adapted in order to reach the industrial demands for high catalytic activity and stability in conjunction with reduced production cost. Among the goals established for laccase engineering, heterologous functional expression, improved activity and thermostability, tolerance to non-natural media (organic solvents, ionic liquids, physiological fluids) and resistance to different types of inhibitors are all challenges that have been met, while obtaining a more comprehensive understanding of laccase structure-function relationships. In this review we examine the most significant advances in this exciting research area in which rational, semi-rational and directed evolution approaches have been employed to ultimately convert laccases into high value-added biocatalysts. PMID- 25545887 TI - Organic nanowire/crystalline silicon p-n heterojunctions for high-sensitivity, broadband photodetectors. AB - Organic/inorganic hybrid devices are promising candidates for high-performance, low-cost optoelectronic devices, by virtue of their unique properties. Polycrystalline/amorphous organic films are widely used in hybrid devices, because defects in the films hamper the improvement of device performance. Here, we report the construction of 2,4-bis[4-(N,N-dimethylamino)phenyl]squaraine (SQ) nanowire (NW)/crystalline Si (c-Si) p-n heterojunctions. Thanks to the high crystal quality of the SQ NWs, the heterojunctions exhibit excellent diode characteristics in darkness. It is significant that the heterojunctions have been found to be capable of detecting broadband light with wavelengths spanning from ultraviolet (UV) light, to visible (Vis) light, to near-infrared (NIR) light, because of the complementary spectrum absorption of SQ NWs with Si. The junction is demonstrated to play a core role in enhancing the device performance, in terms of ultrahigh sensitivity, excellent stability, and fast response. The photovoltaic characteristics of the heterojunctions are further investigated, revealing a power conversion efficiency (PCE) of up to 1.17%. This result also proves the potential of the device as self-powered photodetectors operating at zero external bias voltage. This work presents an important advance in constructing single-crystal organic nanostructure/inorganic heterojunctions and will enable future exploration of their applications in broadband photodetectors and solar cells. PMID- 25545884 TI - Regulation of the Tumor-Suppressor Function of the Class III Phosphatidylinositol 3-Kinase Complex by Ubiquitin and SUMO. AB - The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes-autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3 phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1. Furthermore, a growing list of regulatory proteins associates with VPS34 via Beclin 1. These accessory factors define distinct subunit compositions and thereby guide the PI3K-III complex to its different cellular and physiological roles. Here we discuss the regulation of the PI3K-III complex components by ubiquitination and SUMOylation. Especially Beclin 1 has emerged as a highly regulated protein, which can be modified with Lys11-, Lys48- or Lys63-linked polyubiquitin chains catalyzed by distinct E3 ligases from the RING-, HECT-, RBR- or Cullin-type. We also point out other cross-links of these ligases with autophagy in order to discuss how these data might be merged into a general concept. PMID- 25545888 TI - New organocatalyst scaffolds with high activity in promoting hydrazone and oxime formation at neutral pH. AB - The discovery of two new classes of catalysts for hydrazone and oxime formation in water at neutral pH, namely 2-aminophenols and 2-(aminomethyl)benzimidazoles, is reported. Kinetics studies in aqueous solutions at pH 7.4 revealed rate enhancements up to 7-fold greater than with classic aniline catalysis. 2 (Aminomethyl)benzimidazoles were found to be effective catalysts with otherwise challenging aryl ketone substrates. PMID- 25545889 TI - Influence of carbon nanotubes on the bioavailability of fluoranthene. AB - Concurrent with the increase in the use of carbon nanotubes (CNTs) in society is the rise of their introduction into the environment. Carbon nanotubes cause adverse effects themselves, and they have the potential to adsorb contaminants such as polycyclic aromatic hydrocarbons (PAHs). Although CNTs have a high adsorption capacity for PAHs and these contaminants can co-occur in the environment, few studies have characterized the bioavailability of CNT-adsorbed PAHs to fish. The goal of the present study was to characterize the bioavailability of fluoranthene adsorbed to suspended multiwalled-carbon nanotubes (MWNTs) in freshwater containing natural organic matter (NOM). Adsorption isotherms indicated that NOM influenced the adsorption of fluoranthene to MWNTs, although in the absence of MWNTs it did not influence the bioavailability of fluoranthene to Pimephales promelas. Pimephales promelas were exposed for 16 h in synthetic moderately hard water containing fluoranthene in the presence of different concentrations of NOM, and fluoranthene adsorbed to MWNTs in the presence of NOM. Bioavailable fluoranthene was quantified in each exposure through bile analysis using fluorescence spectrophotometry. By comparing the concentration of fluoranthene metabolites in the bile with the concentration of fluoranthene added to MWNT and NOM solutions, the relative bioavailability of fluoranthene adsorbed to MWNTs was quantified. Results indicate that approximately 60% to 90% of the fluoranthene was adsorbed to the MWNTs and that adsorbed fluoranthene was not bioavailable to P. promelas. The results also suggest that fluoranthene is not desorbed from ingested MWNT, and the bioavailable fraction is only the freely dissolved fluoranthene in the aqueous phase. PMID- 25545885 TI - p53 Acetylation: Regulation and Consequences. AB - Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 transcriptional activity, selection of growth inhibitory vs. apoptotic gene targets, and biological outcomes in response to diverse cellular insults. Yet recent in vivo evidence from mouse models questions the importance of p53 acetylation (at least at certain sites) as well as canonical p53 functions (cell cycle arrest, senescence and apoptosis) to tumor suppression. This review discusses the cumulative findings regarding p53 acetylation, with a focus on the acetyltransferases that modify p53 and the mechanisms regulating their activity. We also evaluate what is known regarding the influence of other post translational modifications of p53 on its acetylation, and conclude with the current outlook on how p53 acetylation affects tumor suppression. Due to redundancies in p53 control and growing understanding that individual modifications largely fine-tune p53 activity rather than switch it on or off, many questions still remain about the physiological importance of p53 acetylation to its role in preventing cancer. PMID- 25545891 TI - Incidence of otitis media in a contemporary Danish National Birth Cohort. AB - OBJECTIVES: In recent years welfare in Denmark has increased which might be expected to reduce otitis media (OM) incidence. We examined the age-specific incidence of OM in a nation-wide cohort of children aged 0-7 years born in 1996 2003 (Danish National Birth Cohort, DNBC). Only selection was ability to understand and speak Danish. METHODS: Information of OM and ventilation tubes (VT) was collected through three maternal interviews at 6-month, 18-month and 7 years of age and based on this age-specific and cumulative incidence of OM was calculated. As different numbers of the total population answered the different interviews, the calculations are done with different denominators. The information in DNBC was validated against two population based registries containing information of VT insertions. RESULTS: Cumulative incidence of OM at 7 years was 60.6% (31,982/52,755). For children with OM, 16.2% (7143/44194) had their first OM episodes between 0-6 months of age, 44.3% (19579/44194) between 7 18 months, and 39.5% (17472/44194) between 19 months and 7 years. Four or more OM episodes before 7 years were reported by 39.5% (12620/31982) and by 64.0% (2482/3881) of those who had their OM debut between 0-6 months; by 48.2% (4998/10378) with debut between 7-18 months; and by 28.7% (4996/17344) with debut between 19 months and 7 years. These figures are essentially unchanged from earlier figures from Denmark. VT insertion at least once was reported by 26,1% in the 7-year interview. Assuming recordings in the Danish National Patient Registry to be gold standard, maternal self-reportings in DNBC of insertion of VT showed high sensitivity (96.4%), specificity (98.2%), and positive (94.8%) and negative predictive values (98.8%). CONCLUSION: OM affects nearly 2/3 of preschool children in Denmark despite reduction in known OM risk factors. PMID- 25545890 TI - Ecstasy exposure & gender: examining components of verbal memory functioning. AB - OBJECTIVE: Studies have demonstrated verbal memory deficits associated with past year ecstasy use, although specific underlying components of these deficits are less understood. Further, prior research suggests potential gender differences in ecstasy-induced serotonergic changes. Therefore, the current study investigated whether gender moderated the relationship between ecstasy exposure and components of verbal memory after controlling for polydrug use and confounding variables. METHOD: Data were collected from 65 polydrug users with a wide range of ecstasy exposure (ages 18-35; 48 ecstasy and 17 marijuana users; 0-2310 ecstasy tablets). Participants completed a verbal learning and memory task, psychological questionnaires, and a drug use interview. RESULTS: Increased past year ecstasy exposure predicted poorer short and long delayed free and cued recalls, retention, and recall discrimination. Male ecstasy users were more susceptible to dose-dependent deficits in retention than female users. CONCLUSION: Past year ecstasy consumption was associated with verbal memory retrieval, retention, and discrimination deficits in a dose-dependent manner in a sample of healthy young adult polydrug users. Male ecstasy users were at particular risk for deficits in retention following a long delay. Gender difference may be reflective of different patterns of polydrug use as well as increased hippocampal sensitivity. Future research examining neuronal correlates of verbal memory deficits in ecstasy users are needed. PMID- 25545892 TI - Hand function is altered in individuals with a history of illicit stimulant use. AB - Use of illicit stimulant drugs such as methamphetamine, cocaine, and ecstasy are a significant worldwide problem. However, little is known about the effect of these drugs on movement. The aim of the current study was to investigate hand function in adults with a history of illicit stimulant use. We hypothesized that prior use of illicit stimulant drugs is associated with abnormal manipulation of objects. The study involved 22 subjects with a history of illicit stimulant use (aged 29+/-8 yrs; time since last use: 1.8+/-4.0 yrs) and two control groups comprising 27 non-drug users (aged 25+/-8 yrs) and 17 cannabis users with no history of stimulant use (aged 22+/-5 yrs). Each subject completed screening tests (neuropsychological assessment, medical history questionnaire, lifetime drug history questionnaire, and urine drug screen) prior to gripping and lifting a light-weight object with the dominant right hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus electromyographic (EMG) activity were recorded during three trials. In trial one, peak grip force was significantly greater in the stimulant group (12.8+/-3.9 N) than in the control groups (non-drug: 10.3+/-4.6 N; cannabis: 9.4+/-2.9 N, P<0.022). However, peak grip force did not differ between groups in trials two and three. The results suggest that individuals with a history of stimulant use overestimate the grip force required to manipulate a novel object but, are able to adapt grip force in subsequent lifts. The results suggest that movement dysfunction may be an unrecognized consequence of illicit stimulant use. PMID- 25545893 TI - Obstetrics anal sphincter injury and repair technique: a review. AB - The Urogynecology Committee of the Asia and Oceania Federation of Obstetrics and Gynaecology (AOFOG) has held seminars and workshops on various urogynecological problems in each country in the Asia-Oceania area in order to encourage young obstetricians and gynecologists. In 2013, we organized the operative seminar for obstetrical anal sphincter injuries (OASIS) in which we prepared porcine models to educate young physicians in a hands-on workshop at the 23rd Asian and Oceanic Congress of Obstetrics and Gynaecology in Bangkok, Thailand. Laceration of the anal sphincter mostly occurs during vaginal delivery and it can develop into anal sphincter deficiency, which causes fecal incontinence, if an appropriate suture is not performed. OASIS has become an important issue, especially in developing countries. The prevalence of OASIS of more than the third degree is around 5% in primary parous women and the frequency is higher when detected by ultrasonographic evaluation. Several risk factors, such as macrosomia, instrumental labor, perineal episiotomy and high maternal age, have been recognized. In a society where pregnant women are getting older, OASIS is becoming a more serious issue. An intrapartum primary appropriate stitch is important, but the 1-year outcome of a delayed operation after 2 weeks postpartum is similar. A randomized controlled study showed that overlapping suture of the external sphincter is better than that of end-to-end surgical repair. The Urogynecology Committee of the AOFOG would like to continue with educative programs about the appropriate therapy for OASIS. PMID- 25545895 TI - Automated differentiation between epileptic and nonepileptic convulsive seizures. AB - Our objective was the clinical validation of an automated algorithm based on surface electromyography (EMG) for differentiation between convulsive epileptic and psychogenic nonepileptic seizures (PNESs). Forty-four consecutive episodes with convulsive events were automatically analyzed with the algorithm: 25 generalized tonic-clonic seizures (GTCSs) from 11 patients, and 19 episodes of convulsive PNES from 13 patients. The gold standard was the interpretation of the video-electroencephalographic recordings by experts blinded to the EMG results. The algorithm correctly classified 24 GTCSs (96%) and 18 PNESs (95%). The overall diagnostic accuracy was 95%. This algorithm is useful for distinguishing between epileptic and psychogenic convulsive seizures. PMID- 25545894 TI - Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures. AB - Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G * E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G * E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association. PMID- 25545899 TI - An investigator's odyssey into preterm birth prevention. PMID- 25545900 TI - 'Your English is better than my Dutch'. PMID- 25545903 TI - Parallels and divergence in head and neck and cervical cancer. PMID- 25545904 TI - The Veress needle causes most laparoscopic injuries and should be abandoned: FOR: the open technique is safer and saves time. PMID- 25545896 TI - Fanconi anemia gene editing by the CRISPR/Cas9 system. AB - Genome engineering with designer nucleases is a rapidly progressing field, and the ability to correct human gene mutations in situ is highly desirable. We employed fibroblasts derived from a patient with Fanconi anemia as a model to test the ability of the clustered regularly interspaced short palindromic repeats/Cas9 nuclease system to mediate gene correction. We show that the Cas9 nuclease and nickase each resulted in gene correction, but the nickase, because of its ability to preferentially mediate homology-directed repair, resulted in a higher frequency of corrected clonal isolates. To assess the off-target effects, we used both a predictive software platform to identify intragenic sequences of homology as well as a genome-wide screen utilizing linear amplification-mediated PCR. We observed no off-target activity and show RNA-guided endonuclease candidate sites that do not possess low sequence complexity function in a highly specific manner. Collectively, we provide proof of principle for precision genome editing in Fanconi anemia, a DNA repair-deficient human disorder. PMID- 25545905 TI - AGAINST: Evidence indicates that the primary trocar, not the Veress, causes most serious complications. PMID- 25545906 TI - Surgical techniques at caesarean might modify placenta accreta risk. PMID- 25545907 TI - Mini commentary author's reply. PMID- 25545908 TI - Author's reply: To PMID 24666658. PMID- 25545909 TI - Economic evaluation of robot-assisted hysterectomy: a cost-minimisation analysis. PMID- 25545910 TI - Authors' reply: Economic evaluation of robot-assisted hysterectomy: a cost minimisation analysis. PMID- 25545911 TI - A report from #BlueJC: Should we use oral or parenteral medications for severe hypertension in pregnancy? PMID- 25545912 TI - H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations? AB - Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations. PMID- 25545913 TI - Effect of central inset pharyngeal flap for velopharyngeal insufficiency on eustachian tube function. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to assess the effect of the central inset pharyngeal flap, used for correcting persistent velopharyngeal incompetence after cleft palate repair, on Eustachian tube (ET) function. METHODS: This study included 28 patients who were diagnosed with persistent velopharyngeal insufficiency following primary cleft palate repair, together with otitis media with effusion (OME) and/or ET dysfunction that failed to improve after the primary palatoplasty and extensive medical treatment. Diagnosis of velopharyngeal insufficiency (VPI) in these cases was performed by video nasoendoscopy and speech assessment. Prior to and after surgery, patients were assessed through otoscopic, tympanometric, and audiometric evaluation. RESULTS: All postoperative otoscopic findings were significantly better than preoperative (P < 0.05) finding, except for tympanic membrane (TM) calcification (P > 0.05). Postoperative tympanometry revealed type A curve (normal) in 30 ears (53.6%), with significant improvement in ET function after this type of flap (P < 0.001). CONCLUSION: ET can be improved after performing the superiorly based flap with new central inset in patients with persistent VPI following palatoplasty. Thus, there is no need for surgical interference to manage OME in these cases, except after trying this technique. PMID- 25545914 TI - Intestinal ammonia transport in freshwater and seawater acclimated rainbow trout (Oncorhynchus mykiss): evidence for a Na+ coupled uptake mechanism. AB - In vitro gut sac experiments were performed on freshwater and 60% seawater acclimated trout (Oncorhynchus mykiss) under treatments designed to discern possible mechanisms of intestinal ammonia transport. Seawater acclimation increased ammonia flux rate into the serosal saline (Jsamm) in the anterior intestine, however it did not alter Jsamm in the mid- or posterior intestine suggesting similar mechanisms of ammonia handling in freshwater and seawater fish. Both fluid transport rate (FTR) and Jsamm were inhibited in response to basolateral ouabain treatment, suggesting a linkage of ammonia uptake to active transport, possibly coupled to fluid transport processes via solvent drag. Furthermore, decreases in FTR and Jsamm caused by low Na(+) treatment indicated a Na(+) linked transport mechanism. Mucosal bumetanide (10(-4) M) had no impact on FTR, yet decreased Jsamm in the anterior and mid-intestine, suggesting NH4(+) substitution for K(+) on an apical NKCC, and at least a partial uncoupling of ammonia transport from fluid transport. Additional treatments (amiloride, 5-(N ethyl-N-isopropyl)amiloride (EIPA), phenamil, bafilomycin, 4',6-diamidino-2 phenylindole (DAPI), high sodium) intended to disrupt alternative routes of Na(+) uptake yielded no change in FTR or Jsamm, suggesting the absence of direct competition between Na(+) and ammonia for transport. Finally, [(14)C]methylamine permeability (PMA) measurements indicated the likely presence of an intestinal Rh mediated ammonia transport system, as increasing NH4Cl (0, 1, 5 mmol l(-1)) concentrations reduced PMA, suggesting competition for transport through Rh proteins. Overall, the data presented in this paper provide some of the first insights into mechanisms of teleost intestinal ammonia transport. PMID- 25545915 TI - Bornyl acetate has an anti-inflammatory effect in human chondrocytes via induction of IL-11. AB - Both pro-inflammatory cytokines and anti-inflammatory cytokines generated by chondrocytes play essential roles in the process of Rheumatoid arthritis and osteoarthritis (OA). Bornyl acetate is the main volatile constituent in numerous conifer oils and some Chinese traditional herbs, which has displayed an anti inflammatory effect before. In this study, we found that bornyl acetate elevates the expression of IL-11 at both the mRNA and protein levels. Interestingly, our results indicated that IL-1beta-mediated up-regulation of IL-6, IL-8, MMP-1, and MMP-13 was significantly compromised by IL-11 co-treatment on mRNA levels and protein levels. The antagonistic effects of bornyl acetate on IL-1beta induced targets MMP-1 and MMP-13 were diminished by IL-11 knockdown. Mechanistically, our results indicated that bornyl acetate significantly elevates the expression of AP 1 component c-fos, which may influence gross AP-1 activity and initial the transcription of IL-11. Indeed, expression of IL-11 was reversed upon c-fos knockdown. Our results suggest the therapeutic potentials of bornyl acetate in patients with OA. PMID- 25545916 TI - Preparation of a weak anion exchange/hydrophobic interaction dual-function mixed mode chromatography stationary phase for protein separation using click chemistry. AB - In this study, 3-diethylamino-1-propyne was covalently bonded to the azide-silica by a click reaction to obtain a novel dual-function mixed-mode chromatography stationary phase for protein separation with a ligand containing tertiary amine and two ethyl groups capable of electrostatic and hydrophobic interaction functionalities, which can display hydrophobic interaction chromatography character in a high-salt-concentration mobile phase and weak anion exchange character in a low-salt-concentration mobile phase employed for protein separation. As a result, it can be employed to separate proteins with weak anion exchange and hydrophobic interaction modes, respectively. The resolution and selectivity of the stationary phase were evaluated in both hydrophobic interaction and ion exchange modes with standard proteins, respectively, which can be comparable to that of conventional weak anion exchange and hydrophobic interaction chromatography columns. Therefore, the synthesized weak anion exchange/hydrophobic interaction dual-function mixed-mode chromatography column can be used to replace two corresponding conventional weak anion exchange and hydrophobic interaction chromatography columns to separate proteins. Based on this mixed-mode chromatography stationary phase, a new off-line two-dimensional liquid chromatography technology using only a single dual-function mixed-mode chromatography column was developed. Nine kinds of tested proteins can be separated completely using the developed method within 2.0 h. PMID- 25545917 TI - Serum Preptin and Amylin Values in Psoriasis Vulgaris and Behcet's Patients. AB - BACKGROUND: Insulin resistance is found in both psoriasis and Behcet's disease. No study has yet explored whether preptin and amylin, two hormones associated with insulin resistance, are involved in the insulin resistance observed in patients with psoriasis and Behcet's disease. OBJECTIVES: We aimed to explore how the amounts of preptin and amylin change in psoriasis and Behcet's disease and whether they are involved in the etiopathology of these two diseases, by comparing hormone levels in patients and healthy controls. METHODS: The study registered 30 patients with psoriasis, 30 patients with Behcet's disease, and 30 healthy volunteers (as a control group). Fasting blood sugar, triglyceride, LDL, VLDL, HDL, total cholesterol, HbA1c, C-peptide, insulin, and serum preptin and amylin levels were measured in all subjects. RESULTS: Serum preptin and amylin levels were significantly lower in the patients with psoriasis and Behcet's disease than in the control group (P < 0.001, P = 0.004, and P = 0.008, respectively). A comparison of the serum preptin and amylin levels between the patients with psoriasis and Behcet's disease did not reveal a statistically significant difference. Serum insulin level and The homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly lower in the psoriasis patient group relative to the control group (P = 0.02 and P = 0.03, respectively), while the values for the Behcet's disease group did not differ significantly from those for the control group CONCLUSIONS: Serum levels of preptin and amylin were significantly lower in patients with psoriasis and Behcet's disease, indicating that these hormones may be a factor for development of metabolic syndrome in these two diseases. PMID- 25545918 TI - Silent clusters - speak up! PMID- 25545920 TI - Microfluidic methods for non-viral gene delivery. AB - Microfluidics is a compelling technology that shows considerable promise in applications ranging from gene expression profiling to cell-based assays. Owing to its capacity to enable generation of single droplets and multiple droplet arrays with precisely controlled composition and a narrow size distribution, recently microfluidics has been exploited for delivery of genes. This article provides an overview of recent advances in microfluidic gene delivery, and speculates the prospects for further research. The objectives of this article are to illustrate the potential roles played by microfluidics in gene delivery research, and to shed new light on strategies to enhance the efficiency of gene therapy. PMID- 25545921 TI - Making regional facility location decisions: the example of Hospital do Oeste Norte, Portugal. AB - This paper seeks to contribute to the debate on the decision-making process for the location of large public facilities, responding to the growing demand for greater rationality in public investment whilst still offering services of quality and addressing the problem of spatial friction. The specific problem analysed in this paper is the need to define the best location for a public hospital in a particular region of Portugal. The singularity of the approach adopted lies above all in the segmentation into macro-location and micro location. PMID- 25545919 TI - Effects of APC De-targeting and GAr modification on the duration of luciferase expression from plasmid DNA delivered to skeletal muscle. AB - Immune responses to expressed foreign transgenes continue to hamper progress of gene therapy development. Translated foreign proteins with intracellular location are generally less accessible to the immune system, nevertheless they can be presented to the immune system through both MHC Class I and Class II pathways. When the foreign protein luciferase was expressed following intramuscular delivery of plasmid DNA in outbred mice, expression rapidly declined over 4 weeks. Through modifications to the expression plasmid and the luciferase transgene we examined the effect of detargeting expression away from antigen presenting cells (APCs), targeting expression to skeletal muscle and fusion with glycine-alanine repeats (GAr) that block MHC-Class I presentation on the duration of luciferase expression. De-targeting expression from APCs with miR142-3p target sequences incorporated into the luciferase 3'UTR reduced the humoral immune response to both native and luciferase modified with a short GAr sequence but did not prolong the duration of expression. When a skeletal muscle specific promoter was combined with the miR target sequences the humoral immune response was dampened and luciferase expression persisted at higher levels for longer. Interestingly, fusion of luciferase with a longer GAr sequence promoted the decline in luciferase expression and increased the humoral immune response to luciferase. These studies demonstrate that expression elements and transgene modifications can alter the duration of transgene expression but other factors will need to overcome before foreign transgenes expressed in skeletal muscle are immunologically silent. PMID- 25545922 TI - A new multidimensional population health indicator for policy makers: absolute level, inequality and spatial clustering - an empirical application using global sub-national infant mortality data. AB - The need for a multidimensional measure of population health that accounts for its distribution remains a central problem to guide the allocation of limited resources. Absolute proxy measures, like the infant mortality rate (IMR), are limited because they ignore inequality and spatial clustering. We propose a novel, three-part, multidimensional mortality indicator that can be used as the first step to differentiate interventions in a region or country. The three-part indicator (MortalityABC index) combines absolute mortality rate, the Theil Index to calculate mortality inequality and the Getis-Ord G statistic to determine the degree of spatial clustering. The analysis utilises global sub-national IMR data to empirically illustrate the proposed indicator. The three-part indicator is mapped globally to display regional/country variation and further highlight its potential application. Developing countries (e.g. in sub-Saharan Africa) display high levels of absolute mortality as well as variable mortality inequality with evidence of spatial clustering within certain sub-national units ("hotspots"). Although greater inequality is observed outside developed regions, high mortality inequality and spatial clustering are common in both developed and developing countries. Significant positive correlation was observed between the degree of spatial clustering and absolute mortality. The proposed multidimensional indicator should prove useful for spatial allocation of healthcare resources within a country, because it can prompt a wide range of policy options and prioritise high-risk areas. The new indicator demonstrates the inadequacy of IMR as a single measure of population health, and it can also be adapted to lower administrative levels within a country and other population health measures. PMID- 25545923 TI - Disease mapping and spatio-temporal analysis: importance of expected-case computation criteria. AB - The municipal, spatial pattern of male stomach cancer mortality in Spain, spanning the period 1989-2008, was studied, comparing the results of depicting mortality using different expected-case computation methods in a spatial and spatio- temporal modelling context. Expected cases for each municipality were first calculated by two methods: (i) using reference rates for each 5-year period; and (ii) using average reference rates for the overall period. This was visualised by two types of models: (i) independent maps for each period based on the model proposed by Besag, York and Mollie; and (ii) a series of maps over time based on a model with spatio-temporal interaction terms. An additional model, based on mortality rate ratios as an alternative to the traditional use of standardised mortality ratios, was also fitted. Integrated nested Laplace approximations were used as the Bayesian inference tool. The results show that, in general, the geographical pattern was maintained across the study period, and that the maps differed appreciably according to the method used to obtain the expected number of cases. While the use of average reference rates appears to be the most suitable choice where the aim is to study time trends by area, it may nevertheless mask the spatial pattern in situations where the time trend is very marked and the study period is long. When it comes to studying changes in the spatial pattern of stomach cancer mortality, we feel that it is most useful to plot independent maps by period and use the "local" rates for each period as reference in the computation of expected cases. PMID- 25545924 TI - The influence of the built environment on outcomes from a "walking school bus study": a cross-sectional analysis using geographical information systems. AB - Active commuting to school increases children's daily physical activity. The built environment is associated with children's physical activity levels in cross sectional studies. This study examined the role of the built environment on the outcomes of a "walking school bus" study. Geographical information systems was used to map out and compare the built environments around schools participating in a pilot walking school bus randomised controlled trial, as well as along school routes. Multi-level modelling was used to determine the built environment attributes associated with the outcomes of active commuting to school and accelerometer-determined moderate-to-vigorous physical activity (MPVA). There were no differences in the surrounding built environments of control (n = 4) and intervention (n = 4) schools participating in the walking school bus study. Among school walking routes, park space was inversely associated with active commuting to school (beta = -0.008, SE = 0.004, P = 0.03), while mixed-land use was positively associated with daily MPVA (beta = 60.0, SE = 24.3, P = 0.02). There was effect modification such that high traffic volume and high street connectivity were associated with greater moderate-to-vigorous physical activity. The results of this study suggest that the built environment may play a role in active school commuting outcomes and daily physical activity. PMID- 25545925 TI - Building obesity in Canada: understanding the individual- and neighbourhood-level determinants using a multi-level approach. AB - The objective of this paper was to identify heterogeneities associated with the relationships between the body mass index (BMI) and individual as well as socio environmental correlates at the individual- and area-levels. The data sources used were: (i) the 2003 Canadian Community Health Survey; (ii) the 2001 Canadian Census; and (iii) the Enhanced Points of Interest (EPOI) database from the Desktop Mapping Technologies Inc. Participants were adults (>= 20 years; n = 12,836; based on a survey weight scheme N(weighted) = 5,418,218) from Toronto and Vancouver census metropolitan areas with no missing BMI records. In addition to conventional 1 km-buffers, we constructed activity-space-buffers to better assess the walkability and potentially increased BMI of individuals. Multi-level analysis was then applied to estimate the relative effects of both individual- and area-level risk-factors for increased BMI. The findings demonstrate a negative association between BMI and energy expenditure, mixed land uses, residential density and average value of dwellings, while a positive association was found with low educational attainment. Relationships were independent of individual characteristics such as age and ethnicity. Although the majority of the variation in these outcomes was found to be due to individual-level differences, this study did show significant differences at the area-level as well. The activity-space-buffers presented a vast improvement compared to the conventional 1 km-buffers. The results presented support the rationale that targeting high-risk individuals will only address a portion of the increasing BMI problem; it is essential to also address the characteristics of places that compel individuals to make unhealthy choices. PMID- 25545927 TI - A methodology for combining multiple commercial data sources to improve measurement of the food and alcohol environment: applications of geographical information systems. AB - Commercial data sources have been increasingly used to measure and locate community resources. We describe a methodology for combining and comparing the differences in commercial data of the food and alcohol environment. We used commercial data from two commercial databases (InfoUSA and Dun&Bradstreet) for 2003 and 2009 to obtain information on food and alcohol establishments and developed a matching process using computer algorithms and manual review by applying ArcGIS to geocode addresses, standard industrial classification and North American industry classification taxonomy for type of establishment and establishment name. We constructed population and area-based density measures (e.g. grocery stores) and assessed differences across data sources and used ArcGIS to map the densities. The matching process resulted in 8,705 and 7,078 unique establishments for 2003 and 2009, respectively. There were more establishments captured in the combined dataset than relying on one data source alone, and the additional establishments captured ranged from 1,255 to 2,752 in 2009. The correlations for the density measures between the two data sources was highest for alcohol outlets (r = 0.75 and 0.79 for per capita and area, respectively) and lowest for grocery stores/supermarkets (r = 0.32 for both). This process for applying geographical information systems to combine multiple commercial data sources and develop measures of the food and alcohol environment captured more establishments than relying on one data source alone. This replicable methodology was found to be useful for understanding the food and alcohol environment when local or public data are limited. PMID- 25545926 TI - Application of global positioning system methods for the study of obesity and hypertension risk among low-income housing residents in New York City: a spatial feasibility study. AB - The purpose of this study was to evaluate the feasibility of using global positioning system (GPS) methods to understand the spatial context of obesity and hypertension risk among a sample of low-income housing residents in New York City (n = 120). GPS feasibility among participants was measured with a pre- and post survey as well as adherence to a protocol which included returning the GPS device as well as objective data analysed from the GPS devices. We also conducted qualitative interviews with 21 of the participants. Most of the sample was overweight (26.7%) or obese (40.0%). Almost one-third (30.8%) was pre hypertensive and 39.2% was hypertensive. Participants reported high ratings of GPS acceptability, ease of use and low levels of wear-related concerns in addition to few concerns related to safety, loss or appearance, which were maintained after the baseline GPS feasibility data collection. Results show that GPS feasibility increased over time. The overall GPS return rate was 95.6%. Out of the total of 114 participants with GPS, 112 (98.2%) delivered at least one hour of GPS data for one day and 84 (73.7%) delivered at least one hour on 7 or more days. The qualitative interviews indicated that overall, participants enjoyed wearing the GPS devices, that they were easy to use and charge and that they generally forgot about the GPS device when wearing it daily. Findings demonstrate that GPS devices may be used in spatial epidemiology research in low income and potentially other key vulnerable populations to understand geospatial determinants of obesity, hypertension and other diseases that these populations disproportionately experience. PMID- 25545928 TI - Geographic disparities of asthma prevalence in south-western United States of America. AB - Asthma is one of the most prevalent chronic diseases in the United States of America (USA), and many of its risk factors have so far been investigated and identified; however, evidence is limited on how spatial disparities impact the disease. The purpose of this study was to provide scientific evidence on the location influence on asthma in the four states of southwestern USA (California, Arizona, New Mexico and Texas) which, together, include 360 counties. The Behavioral Risk Factor Surveillance System database for these four states covering the period of 2000 to 2011 was used in this analysis, and a Bayesian structured additive regression model was applied to analyse by a geographical information system. After adjusting for individual characteristics, socioeconomic status and health behaviour, this study found higher odds associated with asthma and a likely cluster around the Bay Area in California, while lower odds appeared in several counties around the larger cities of Texas, such as Dallas, Houston and San Antonio. The significance map shows 43 of 360 counties (11.9%) to be high risk areas for asthma. The level of geographical disparities demonstrates that the county risk of asthma prevalence varies significantly and can be about 19.9% (95% confidence interval: 15.3-25.8) higher or lower than the overall asthma prevalence. We provide an efficient method to utilise and interpret the existing surveillance data on asthma. Visualisation by maps may help deliver future interventions on targeted areas and vulnerable populations to reduce geographical disparities in the burden of asthma. PMID- 25545929 TI - The spatial and seasonal distribution of Bulinus truncatus, Bulinus forskalii and Biomphalaria pfeifferi, the intermediate host snails of schistosomiasis, in N'Djamena, Chad. AB - There is a paucity of epidemiological and malacological data pertaining to schistosomiasis in Chad. In view of a recently articulated elimination agenda, a deeper understanding of the spatio-temporal distribution of schistosomiasis intermediate host snails is pivotal. We conducted cross-sectional malacological surveys during the dry season (April/May 2013) and after the short rainy season (October 2013) in N'Djamena, the capital of Chad. Snails were identified at the genus and species level using morphological keys and molecular DNA barcoding approaches. Those belonging to Bulinus and Biomphalaria were examined for cercarial shedding. Snail habitats were characterised and their predictive potential for the presence of schistosomiasis intermediate host snails explored. Seasonal patterns were studied using geographical information system and kriging in order to interpolate snail abundance data to make predictions at non-sampled locations across N'Djamena. Overall, 413 Bulinus truncatus, 369 Bulinus forskalii and 108 Biomphalaria pfeifferi snails were collected and subjected to cercarial shedding. During the dry season, one Bu. truncatus of 119 snails collected shed Schistosoma spp. cercariae (0.84%), while S. mansoni was shed by one of 108 Bi. pfeifferi snails (0.93%). None of the snails collected after the rainy season shed Schistosoma spp. cercariae. The abundance of Bu. truncatus and Bu. forskalii showed an inverse U-shape relationship with the square term of conductivity, i.e. low abundance at the lowest and highest levels of conductivity and high abundance at intermediate levels. Bi. pfeifferi showed a negative, linear association with pH in the dry seasons. It is planned to link these intermediate host snail data to infection data in human populations with the goal to draw a predictive risk map that can be utilised for control and elimination of schistosomiasis in N'Djamena. PMID- 25545930 TI - Mosquito habitat and dengue risk potential in Kenya: alternative methods to traditional risk mapping techniques. AB - Outbreaks, epidemics and endemic conditions make dengue a disease that has emerged as a major threat in tropical and sub-tropical countries over the past 30 years. Dengue fever creates a growing burden for public health systems and has the potential to affect over 40% of the world population. The problem being investigated is to identify the highest and lowest areas of dengue risk. This paper presents "Similarity Search", a geospatial analysis aimed at identifying these locations within Kenya. Similarity Search develops a risk map by combining environmental susceptibility analysis and geographical information systems, and then compares areas with dengue prevalence to all other locations. Kenya has had outbreaks of dengue during the past 3 years, and we identified areas with the highest susceptibility to dengue infection using bioclimatic variables, elevation and mosquito habitat as input to the model. Comparison of the modelled risk map with the reported dengue epidemic cases obtained from the open source reporting ProMED and Government news reports from 1982-2013 confirmed the high-risk locations that were used as the Similarity Search presence cells. Developing the risk model based upon the bioclimatic variables, elevation and mosquito habitat increased the efficiency and effectiveness of the dengue fever risk mapping process. PMID- 25545931 TI - Spatio-temporal patterns of dengue in Malaysia: combining address and sub district level. AB - Spatio-temporal patterns of dengue risk in Malaysia were studied both at the address and the sub-district level in the province of Selangor and the Federal Territory of Kuala Lumpur. We geocoded laboratory-confirmed dengue cases from the years 2008 to 2010 at the address level and further aggregated the cases in proportion to the population at risk at the sub-district level. Kulldorff's spatial scan statistic was applied for the investigation that identified changing spatial patterns of dengue cases at both levels. At the address level, spatio temporal clusters of dengue cases were concentrated at the central and south eastern part of the study area in the early part of the years studied. Analyses at the sub-district level revealed a consistent spatial clustering of a high number of cases proportional to the population at risk. Linking both levels assisted in the identification of differences and confirmed the presence of areas at high risk for dengue infection. Our results suggest that the observed dengue cases had both a spatial and a temporal epidemiological component, which needs to be acknowledged and addressed to develop efficient control measures, including spatially explicit vector control. Our findings highlight the importance of detailed geographical analysis of disease cases in heterogeneous environments with a focus on clustered populations at different spatial and temporal scales. We conclude that bringing together information on the spatio-temporal distribution of dengue cases with a deeper insight of linkages between dengue risk, climate factors and land use constitutes an important step towards the development of an effective risk management strategy. PMID- 25545932 TI - Geographical distribution of the association between El Nino South Oscillation and dengue fever in the Americas: a continental analysis using geographical information system-based techniques. AB - El Nino South Oscillation (ENSO) is one climatic phenomenon related to the inter annual variability of global meteorological patterns influencing sea surface temperature and rainfall variability. It influences human health indirectly through extreme temperature and moisture conditions that may accelerate the spread of some vector-borne viral diseases, like dengue fever (DF). This work examines the spatial distribution of association between ENSO and DF in the countries of the Americas during 1995-2004, which includes the 1997-1998 El Nino, one of the most important climatic events of 20(th) century. Data regarding the South Oscillation index (SOI), indicating El Nino-La Nina activity, were obtained from Australian Bureau of Meteorology. The annual DF incidence (AIy) by country was computed using Pan-American Health Association data. SOI and AIy values were standardised as deviations from the mean and plotted in bars-line graphics. The regression coefficient values between SOI and AIy (rSOI,AI) were calculated and spatially interpolated by an inverse distance weighted algorithm. The results indicate that among the five years registering high number of cases (1998, 2002, 2001, 2003 and 1997), four had El Nino activity. In the southern hemisphere, the annual spatial weighted mean centre of epidemics moved southward, from 6 degrees 31' S in 1995 to 21 degrees 12' S in 1999 and the rSOI,AI values were negative in Cuba, Belize, Guyana and Costa Rica, indicating a synchrony between higher DF incidence rates and a higher El Nino activity. The rSOI,AI map allows visualisation of a graded surface with higher values of ENSO-DF associations for Mexico, Central America, northern Caribbean islands and the extreme north northwest of South America. PMID- 25545933 TI - Landscape, demographic and climatic associations with human West Nile virus occurrence regionally in 2012 in the United States of America. AB - After several years of low West Nile virus (WNV) occurrence in the United States of America (USA), 2012 witnessed large outbreaks in several parts of the country. In order to understand the outbreak dynamics, spatial clustering and landscape, demographic and climatic associations with WNV occurrence were investigated at a regional level in the USA. Previous research has demonstrated that there are a handful of prominent WNV mosquito vectors with varying ecological requirements responsible for WNV transmission in the USA. Published range maps of these important vectors were georeferenced and used to define eight functional ecological regions in the coterminous USA. The number of human WNV cases and human populations by county were attained in order to calculate a WNV rate for each county in 2012. Additionally, a binary value (high/low) was calculated for each county based on whether the county WNV rate was above or below the rate for the region it fell in. Global Moran's I and Anselin Local Moran's I statistics of spatial association were used per region to examine and visualize clustering of the WNV rate and the high/low rating. Spatial data on landscape, demographic and climatic variables were compiled and derived from a variety of sources and then investigated in relation to human WNV using both Spearman rho correlation coefficients and Poisson regression models. Findings demonstrated significant spatial clustering of WNV and substantial inter-regional differences in relationships between WNV occurrence and landscape, demographic and climatically related variables. The regional associations were consistent with the ecologies of the dominant vectors for those regions. The large outbreak in the Southeast region was preceded by higher than normal winter and spring precipitation followed by dry and hot conditions in the summer. PMID- 25545934 TI - Elimination of malaria due to Plasmodium vivax in central part of the People's Republic of China: analysis and prediction based on modelling. AB - Five provinces in central People's Republic of China (P.R. China) have successfully reduced the burden of malaria due to Plasmodium vivax in the last 7 years. The results of the Action Plan of China Malaria Elimination (APCME) that commenced in 2010 are analysed against the background of the progress reached by the national malaria control programme (NMEP) that was launched in 2006. We examined the epidemiological changes in the number of autochthonous cases over time and discuss the feasibility of achieving the goal of malaria elimination by 2020. There was a total decline of 34,320 malaria cases between 2006 and 2012 arriving at an average annual incidence of 0.04 per 10,000 people by 2012. At the same time, the number of counties reporting autochthonous cases declined from 290 to 19. Spatial autocorrelation and Bayesian modelling were used to evaluate the datasets and predict the spatio-temporal pattern in the near future. The former approach showed that spatial clusters of P. vivax malaria existed in the study region during the study period, while the risk prediction map generated by the Bayesian model indicates that only sporadic malaria cases will appear during in the future. The results suggest that the initial NMEP approach and the follow-up APCME strategy have played a key role in reducing the threat of malaria in central P.R. China. However, to achieve the goal of malaria elimination by the end of the current decade, intervention plans must be adjusted with attention paid to those endemic counties still at risk according to the prediction map. PMID- 25545935 TI - Environmental modelling of visceral leishmaniasis by susceptibility-mapping using neural networks: a case study in north-western Iran. AB - Visceral leishmaniasis (VL) is a potentially fatal vector-borne zoonotic disease, which has become an increasing public health problem in the north-western part of Iran. This work presents an environmental health modelling approach to map the potential of VL outbreaks in this part of the country. Radial basis functional link networks is used as a data-driven method for predictive mapping of VL in the study area. The high susceptibility areas for VL outbreaks account for 36.3% of the study area and occur mainly in the north (which may affect the neighbouring countries) and South (which is a warning for other provinces in Iran). These parts of the study area have many nomadic, riverside villages. The overall accuracy of the resultant map was 92% in endemic villages. Such susceptibility maps can be used as reconnaissance guides for planning of effective control strategies and identification of possible new VL endemic areas. PMID- 25545936 TI - Ecological niche model of Phlebotomus perniciosus, the main vector of canine leishmaniasis in north-eastern Italy. AB - With respect to the epidemiology of leishmaniasis, it is crucial to take into account the ecoclimatic and environmental characteristics that influence the distribution patterns of the vector sand fly species. It is also important to consider the possible impact of on-going climate changes on the emergence of this disease. In order to map the potential distribution of Phlebotomus perniciosus, the main vector species of canine leishmaniasis in north-eastern Italy, geographical information systems tools, ecological niche models (ENM) and remotely sensed environmental data were applied for a retrospective analysis of an entomological survey conducted in north-eastern Italy over 12 years. Sand fly trapping was conducted from 2001 to 2012 in 175 sites in the provinces of Veneto, Friuli-Venezia Giulia and Trentino-Alto Adige. We developed a predictive model of potential distribution of P. perniciosus using the maximum entropy algorithm software, based on seasonal normalized difference vegetation index, day and night land surface temperature, the Corine land cover 2006, a digital elevation model (GTOPO30) and climate layers obtained from the WorldClim database. The MaxEnt prediction found the more suitable habitat for P. perniciosus to be hilly areas (100-300 m above the mean sea level) characterised by temperate climate during the winter and summer seasons, high winter vegetation cover and moderate rainfall during the activity season of vector sand fly. ENM provided a greater understanding of the geographical distribution and ecological requirements of P. perniciosus in the study area, which can be applied for the development of future surveillance strategies. PMID- 25545937 TI - A determination of the spatial concordance between Lyme disease incidence and habitat probability of its primary vector Ixodes scapularis (black-legged tick). AB - The spatial distribution of Ixodes scapularis, the most common tick vector of the bacterium Borrelia burgdorferi, the cause of Lyme disease in humans, has not been studied previously in Texas, United States of America. It has only rarely been reported in this state, so its local, spatial relationship to the distribution of this disease is unknown. From an epidemiological perspective, one would tend to hypothesise that there should be a high degree of spatial concordance between habitat suitability for the tick and incidence of the disease. Both maximum entropy modelling of the tick's habitat probability and modelling of human incidence of Lyme disease using spatially adaptive filters provide reliable portrayals of the spatial distributions of these phenomena. Even though rates of human cases of Lyme disease as well as rates of Ixodes ticks infected with Borrelia bacteria are both relatively low in Texas, the best data currently available indicate that the assumption of high levels of spatial concordance would not be correct in Texas (Kappa coefficient of agreement = 0.039). It will take substantially more data to provide conclusive findings and to understand the results reported here, but this study provides an approach to begin understanding the discrepancy. PMID- 25545938 TI - Using geographical information system for spatial evaluation of canine extruded disc herniation. AB - Disc herniation is one of the most common pathologies of the vertebral column in dogs. The aim of this study was to develop a geographical information system (GIS)-based vertebral canal (VC) map useful for spatial evaluation of extruded disc herniation (EDH) in dogs. ArcGIS(r) was used to create two-dimensional and three-dimensional maps, in which the VC surface is divided into polygons by lines representing latitude and longitude. Actual locations and directions of the herniated disc material were assessed by a series of 142 computer tomographies of dogs collected between 2005 and 2013. Most EDHs were located on the cervical and transitional regions (thoraco-lumbar and lumbo-sacral) and shown at the level of the ventro- cranial and ventro-central polygons created. Choropleth maps, highlighting the distribution and the location/direction patterns of the EDHs throughout the VC, were produced based on the frequency of the ailment. GIS proved to be a valuable tool in analysing EDH in dogs. Further studies are required for biomechanical analysis of EDH patterns. PMID- 25545939 TI - Potential for spread of the white-nose fungus (Pseudogymnoascus destructans) in the Americas: use of Maxent and NicheA to assure strict model transference. AB - Emerging infectious diseases can present serious threats to wildlife, even to the point of causing extinction. Whitenose fungus (Pseudogymnoascus destructans) is causing an epizootic in bats that is expanding rapidly, both geographically and taxonomically. Little is known of the ecology and distributional potential of this intercontinental pathogen. We address this gap via ecological niche models that characterise coarse resolution niche differences between fungus populations on different continents, identifying areas potentially vulnerable to infection in South America. Here we explore a novel approach to identifying areas of potential distribution across novel geographic regions that avoids perilious extrapolation into novel environments. European and North American fungus populations show differential use of environmental space, but rather than niche differentiation, we find that changes are best attributed to climatic differences between the two continents. Suitable areas for spread of the pathogen were identified across southern South America; however caution should be taken to avoid underestimating the potential for spread of this pathogen in South America. PMID- 25545940 TI - Relationship between altitude and lithium in groundwater in the United States of America: results of a 1992-2003 study. AB - Therapeutic dosages of lithium are known to reduce suicide rates, which has led to investigations of confounding environmental risk factors for suicide such as lithium in groundwater. It has been speculated that this might play a role in the potential relationship between suicide and altitude. A recent study in Austria involving geospatial analysis of lithium in groundwater and suicide found lower levels of lithium at higher altitudes. Since there is no reason to suspect this correlation is universal given variation in geology, the current study set out to investigate the relationship between altitude and lithium in groundwater in the United States of America (USA). The study utilised data extracted from the National Water-Quality Assessment programme implemented by the United States Geological Survey that has collected 5,183 samples from 48 study areas in USA for the period of 1992 to 2003. Lithium was the trace-element of interest and 518 samples were used in the current analyses. Due to uneven lithium sampling within the country, only the states (n=15) with the highest number of lithium samples were included. Federal information processing standard codes were used to match data by county with the mean county altitude calculated using altitude data from the Shuttle Radar Topography Mission. The study was controlled for potential confounding factors known to affect levels of lithium in groundwater including aquifer, aquifer type, lithology, water level and the depths of wells. The levels of lithium in groundwater, increased with altitude (R(2) = 0.226, P <0.001) during the study period. These findings differ from the Austrian study and suggest a need for further research accounting also for the impact of geographical variation. PMID- 25545941 TI - Interpreting predictive maps of disease: highlighting the pitfalls of distribution models in epidemiology. AB - The application of spatial modelling to epidemiology has increased significantly over the past decade, delivering enhanced understanding of the environmental and climatic factors affecting disease distributions and providing spatially continuous representations of disease risk (predictive maps). These outputs provide significant information for disease control programmes, allowing spatial targeting and tailored interventions. However, several factors (e.g. sampling protocols or temporal disease spread) can influence predictive mapping outputs. This paper proposes a conceptual framework which defines several scenarios and their potential impact on resulting predictive outputs, using simulated data to provide an exemplar. It is vital that researchers recognise these scenarios and their influence on predictive models and their outputs, as a failure to do so may lead to inaccurate interpretation of predictive maps. As long as these considerations are kept in mind, predictive mapping will continue to contribute significantly to epidemiological research and disease control planning. PMID- 25545942 TI - Health risk assessment along the wastewater and faecal sludge management and reuse chain of Kampala, Uganda: a visualization. AB - Reuse of wastewater in agriculture is a common feature in the developing world. While this strategy might contribute to the livelihood of farming communities, there are health risks associated with the management and reuse of wastewater and faecal sludge. We visualise here an assessment of health risks along the major wastewater channel in Kampala, Uganda. The visualization brings to bear the context of wastewater reuse activities in the Nakivubo wetlands and emphasises interconnections to disease transmission pathways. The contextual features are complemented with findings from environmental sampling and a cross-sectional epidemiological survey in selected exposure groups. Our documentation can serve as a case study for a step-by-step implementation of risk assessment and management as described in the World Health Organization's 2006 guidelines for the safe use of wastewater, greywater and excreta in light of the forthcoming sanitation safety planning approach. PMID- 25545943 TI - Illicit drug consumption estimated by wastewater analysis in different districts of Milan: A case study. AB - INTRODUCTION AND AIMS: Wastewater analysis is a new approach developed to estimate illicit drug (ID) consumption in large communities, such as a city. We tested the ability of this approach to detect differences in consumption in different districts of a city. DESIGN AND METHODS: Consumption of cocaine, heroin, tetrahydrocannabinol (THC) (cannabis active principle), amphetamine, methamphetamine and ecstasy was estimated by analysis of selected drug excretion residues in composite 24 h samples of untreated urban wastewater by liquid chromatography-tandem mass spectrometry. Samples were collected from the inlet of the three main Milan wastewater treatment plants (WWTP), each serving a district of the city (west, center and east). In each WWTP, samples were taken daily for seven consecutive days in November 2010 and March 2011. RESULTS: We observed significant differences of ID consumption (expressed as mg/day/1000 inhabitants) among districts: consumption of some ID was significantly higher in the eastern district (P < 0.01 for THC, P < 0.001 for cocaine and P < 0.0001 for heroin by one-way analysis of variance), while consumption of methamphetamine and amphetamine was higher in the central area (P < 0.0001). Overall, from 2010 to 2011, ID consumption decreased in all the districts, in line with a recent population survey showing decreases from 25 to 55% in the annual prevalence of ID users in Italy. DISCUSSION AND CONCLUSIONS: This approach may help to detect ID consumption in different districts of a city and may be useful for planning interventions aimed at specific city areas and substances. PMID- 25545944 TI - Graphical displays for assessing covariate balance in matching studies. AB - RATIONALE, AIMS AND OBJECTIVES: An essential requirement for ensuring the validity of outcomes in matching studies is that study groups are comparable on observed pre-intervention characteristics. Investigators typically use numerical diagnostics, such as t-tests, to assess comparability (referred to as 'balance'). However, such diagnostics only test equality along one dimension (e.g. means in the case of t-tests), and therefore do not adequately capture imbalances that may exist elsewhere in the distribution. Furthermore, these tests are generally sensitive to sample size, raising the concern that a reduction in power may be mistaken for an improvement in covariate balance. In this paper, we demonstrate the shortcomings of numerical diagnostics and demonstrate how visual displays provide a complete representation of the data to more robustly assess balance. METHODS: We generate artificial datasets specifically designed to demonstrate how widely used equality tests capture only a single-dimension of the data and are sensitive to sample size. We then plot the covariate distributions using several graphical displays. RESULTS: As expected, tests showing perfect covariate balance in means failed to reflect imbalances at higher moments (variances). However, these discrepancies were easily detected upon inspection of the graphic displays. Additionally, smaller sample sizes led to the appearance of covariate balance, when in fact it was a result of lower statistical power. CONCLUSIONS: Given the limitations of numerical diagnostics, we advocate using graphical displays for assessing covariate balance and encourage investigators to provide such graphs when reporting balance statistics in their matching studies. PMID- 25545945 TI - MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose deprived microglia by targeting Toll-like receptor 4. AB - Cerebral hypoxia/ischemia rapidly induces inflammation in the brain, which is characterized by microglial activation and the release of inflammatory cytokines. We have previously demonstrated that miR-181c can directly regulate tumor necrosis factor (TNF)-alpha production post-transcriptionally. Here, we determined that hypoxia up-regulated TLR4 expression but down-regulated miR-181c expression in primary microglia. We also demonstrated that miR-181c suppresses TLR4 by directly binding its 3'-untranslated region. In addition, miR-181c inhibited NF-kappaB activation and the downstream production of proinflammatory mediators, such as TNF-alpha, IL-1beta, and iNOS. Knocking down TLR4 in microglia significantly decreased TLR4 expression and inhibited NF-kappaB activation and the downstream production of proinflammatory mediators, whereas ectopic TLR4 expression significantly abrogated the suppressed inflammatory response induced by miR-181c. Therefore, our study identified an important role for the miR-181c TLR4 pathway in hypoxic microglial activation and neuroinflammation. This pathway could represent a potential therapeutic target for cerebral hypoxic diseases associated with microglial activation and the inflammatory response. Cerebral hypoxia/ischemia induces microglial activation and the release of inflammatory cytokines. We found that hypoxia down-regulated miR-181c in primary microglia. In addition, miR-181c inhibited TLR4 expression through binding to its 3'UTR, thus inhibiting NF-kB activation and the production of downstream proinflammatory mediators. Therefore, the miR-181c-TLR4 pathway may be a potential therapeutic target for the treatment of cerebral hypoxic diseases. PMID- 25545946 TI - Australian competencies: twenty-one years on and still at the heart of our profession. PMID- 25545947 TI - Biomechanical properties of the keratoconic cornea: a review. AB - There has been a recent surge of interest in assessing corneal biomechanical properties due to potential clinical applications, particularly in the early detection of keratoconus (KC). This review discusses the effects of keratoconus on the biomechanical properties of the cornea and the current techniques used to detect these changes both in the laboratory and clinical setting. Specific structural changes occurring in the corneal stroma as part of the disease process can be linked to alterations in the viscous and elastic properties of the cornea in keratoconus. Although there are extensive ex vivo studies using techniques such as extensometry and inflation testing to analyse the biomechanical properties of the normal cornea, few have investigated the keratoconic cornea using the same methods. There are a number of ex vivo studies that confirm the effectiveness of collagen cross-linking in increasing Young's modulus in healthy corneas. Recently, research has focussed on measuring corneal biomechanical parameters in vivo using two commercially available instruments: the Ocular Response Analyser (ORA) and the CorVis ST (CST). Both instruments analyse the dynamic behaviour of the cornea, when temporarily deformed by an air puff; however, the outputs of these instruments are not directly comparable due to differences in the characteristics of the air puff and output parameters. Studies using these instruments have reported significant differences between keratoconic and healthy corneas; however, neither instrument can currently be used in isolation to reliably diagnose keratoconus. Further research analysing the outputs of these instruments may enhance their diagnostic capabilities. PMID- 25545948 TI - Normal corneal sensitivity and its changes with age in Tehran, Iran. AB - BACKGROUND: The present study sets out to determine normal corneal sensitivity in five corneal regions and its changes with age in an Iranian population. METHODS: The corneal sensitivity of the centre of the cornea and at four corneal regions, namely, nasal, inferior, temporal and superior at 2.0 mm from the limbus of the right eye of 596 subjects aged 15 to 81 were measured using a Cochet-Bonnet aesthesiometer. All measurements were performed by the same examiner at 18 degrees centigrade and 35 per cent humidity between 2:00 and 5:00 pm. The subjects were divided into six age groups of 15 to 25 years, 26 to 35, 36 to 45, 46 to 55, 56 to 65 and over 65 years, respectively. Since the measurement outcomes were not continuous, the data was analysed using non-parametric statistics. RESULTS: The frequency of corneal sensitivity of 60 mm in all corneal regions was decreased with advancing age after 35 years (chi(2) p < 0.001). The strongest correlation between age and corneal sensitivity was for the centre of the cornea (-0.52), followed by nasal (-0.49), temporal (-0.48), inferior (-0.47) and superior (-0.46) regions of the cornea, which had significant negative correlations (p < 0.001). The five different corneal regions showed significant differences of corneal sensitivity (p < 0.001). In different age groups, the difference was seen in the three lower age groups of 1, 2 and 3, while in the three older age groups of 4, 5 and 6, there were no differences in corneal sensitivity among five corneal regions (p > 0.05). CONCLUSION: Based on the findings of the current study, all regions of the cornea showed a faster reduction in sensitivity with age in this sunny environment compared to the results of previous studies. PMID- 25545949 TI - Optometry Australia Entry-level Competency Standards for Optometry 2014. AB - BACKGROUND: Competency standards for entry-level to the profession of optometry in Australia were first developed in 1993, revised in 1997 and 2000, and again in 2008, when therapeutic competency standards were introduced but differentiated from the entry-level competencies. Therapeutic competencies were an additional requirement for the purpose of endorsing optometric registration to allow prescription of medicines for conditions of the eye. Recent changes to educational and registration requirements mean that therapeutic competencies are now required at entry-level. To address this and to ensure the standards reflect current best practice, a full revision of the standards was undertaken. METHODS: A steering committee oversaw the review of the standards, which involved a literature review, workshops with optometrists and broad consultation with stakeholders, including the Optometry Board of Australia, individual optometrists and employers of optometrists, to identify changes needed. Representatives of the profession from Australia and New Zealand and from academia in Australia were involved. A modified document based on the feedback received was circulated to the State Divisions and the National Board of the then Optometrists Association Australia. RESULTS: The updated standards reflect the state of entry to the optometric profession in 2014; competencies for prescribing of scheduled medicines are included, new material has been added, other areas have been modified. The updated entry-level competency standards were adopted on behalf of the profession by the National Board of the then Optometrists Association Australia in March 2014. DISCUSSION: Competency standards have been updated so that they continue to be current and useful for the profession, individual optometrists and Australian and New Zealand registration authorities for the purposes of accreditation of optometric programs and assessment of overseas trained optometrists. This paper details the revision process and presents the 2014 version of competency standards for entry-level to the profession of optometry in Australia. PMID- 25545950 TI - A rare occurrence of epithelial inclusion iris cyst after phacoemulsification. PMID- 25545951 TI - Re.: 'A pilot study of an acupuncture protocol to improve visual function in retinitis pigmentosa patients' by Bittner and colleagues. PMID- 25545952 TI - Response to Re: A pilot study of an acupuncture protocol to improve visual function in retinitis pigmentosa patients. PMID- 25545955 TI - Effect of partial H2O-D2O replacement on the anisotropy of transverse proton spin relaxation in bovine articular cartilage. AB - Anisotropy of transverse proton spin relaxation in collagen-rich tissues like cartilage and tendon is a well-known phenomenon that manifests itself as the "magic-angle" effect in magnetic resonance images of these tissues. It is usually attributed to the non-zero averaging of intra-molecular dipolar interactions in water molecules bound to oriented collagen fibers. One way to manipulate the contributions of these interactions to spin relaxation is by partially replacing the water in the cartilage sample with deuterium oxide. It is known that dipolar interactions in deuterated solutions are weaker, resulting in a decrease in proton relaxation rates. In this work, we investigate the effects of deuteration on the longitudinal and the isotropic and anisotropic contributions to transverse relaxation of water protons in bovine articular cartilage. We demonstrate that the anisotropy of transverse proton spin relaxation in articular cartilage is independent of the degree of deuteration, bringing into question some of the assumptions currently held over the origins of relaxation anisotropy in oriented tissues. PMID- 25545956 TI - Two methods of vitrification followed by in vitro culture of the ovine ovary: evaluation of the follicular development and ovarian extracellular matrix. AB - The aim of this study was to evaluate the influence of two vitrification techniques on the extra cellular matrix (ECM) and ovarian follicular development. The ovarian cortex was fragmented (9 mm(3)) and divided into six groups, viz. fresh control, cultured control, vitrified by the Ovarian Tissue Cryosystem (OTC) method, conventional solid surface vitrification (SSV) method, OTC/cultured and SSV/cultured. Follicles from all the fragments were analysed for morphology, development and viability. The ECM was evaluated based on the condition of collagen and reticular fibres and the immunolocalization of type I collagen and fibronectin. After 7 days of culture, the tissue vitrified by OTC revealed a higher percentage (p < 0.05) of morphologically normal (30.66%) and viable (60.00%) follicles when compared with those vitrified using the SSV technique (21.33% and 23.00%). In all the fragments cultured, regardless of the vitrification method, a significantly higher percentage of developing follicles was observed when compared with the non-cultured tissue. Analysis of the type I collagen showed increased immunostaining after the in vitro culture in the vitrified fragments. In conclusion, the OTC is better for preserving the follicular viability and morphology and maintaining the integrity of the extracellular matrix components of the ovine ovary. PMID- 25545957 TI - New fully covered large-bore wide-flare removable metal stent for drainage of pancreatic fluid collections: results of a multicenter study. AB - BACKGROUND AND AIM: Endoscopic transmural drainage (ETMD) of peripancreatic fluid collections (PFC) is an effective alternative to surgical drainage. Conventional drainage using plastic stents has its limitations. A wide-bore short-length wide flange fully covered self-expandable metallic stent (FCSEMS) has recently been developed. The present study evaluates the efficacy of this new FCSEMS for ETMD of PFC. METHODS: This was a retrospective, multicenter study. Patients with PFC undergoing endoscopic ultrasound (EUS)-guided drainage of PFC using specially designed FCSEMS were included. Parameters evaluated were technical success of stent placement, clinical success as defined by resolution of PFC without any further surgical intervention, ability to carry out endoscopic necrosectomy, complications and feasibility of endoscopic stent removal. RESULTS: Twenty-one PFC in 19 patients were drained using FCSEMS. Technical and clinical success for drainage was seen in all patients (100%). Endoscopic necrosectomy was carried out in seven (33%) PFC. Complications occurred in two patients (10.5%). Stents could be endoscopically removed in all patients (100%). CONCLUSIONS: The new specially designed FCSEMS is safe and effective for drainage of PFC. Necrosectomy can be carried out through the stent. Stent can be removed endoscopically at the end of the treatment period. PMID- 25545958 TI - The total number of Leydig and Sertoli cells in the testes of men across various age groups - a stereological study. AB - The aim of this study was to estimate the total number of Sertoli and Leydig cells in testes from male subjects across the human lifespan, using an optimized stereological method for cell-counting. In comparison with many other organs, estimation of the total cell numbers in the testes is particularly sensitive to methodological problems. Therefore, using the optical fractionator technique and a sampling design specifically optimized for human testes, we estimated the total number of Sertoli and Leydig cells in the testes from 26 post mortem male subjects ranging in age from 16 to 80 years. The mean unilateral total number of Sertoli cells was 407 * 10(6) [range: 86 * 10(6) to 665 * 10(6) , coefficient of variation (CV) = 0.33], and the mean unilateral total number of Leydig cells was 99 * 10(6) (range: 47 * 10(6) to 245 * 10(6) , CV = 0.48). There was a significant decline in the number of Sertoli cells with age; no such decline was found for Leydig cells. Quantitative stereological analysis of post mortem tissue may help understand the influence of age or disease on the number of human testicular cells. PMID- 25545959 TI - Targeting CD133 in the enhancement of chemosensitivity in oral squamous cell carcinoma-derived side population cancer stem cells. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world. Previously, we enriched a subpopulation of OSCC-derived cancer stem cells (OSCC-CSCs), and identified CD133 as an OSCC-CSC marker. METHOD: We determined the function of CD133 on chemosensitivity of oral cancer CSCs by silencing CD133. RESULTS: Initially, we observed that the expression profile of CD133 in OSCC-side population (OSCC-SPs) cells, which exerted properties of CSCs, was significantly upregulated than that of major population (MPs) cells of OSCCs. The cell viability experiments showed that SPs were more chemoresistant compared with major populations. Importantly, targeting CD133 ameliorated the drug resistance of OSCC-SPs to cisplatin treatment. Targeting CD133 and cisplatin co treatment led to the maximal inhibition on tumor initiating properties in OSCC SPs. CONCLUSION: Side population cells with CSCs properties existed in OSCCs, and silencing CD133 exhibited a prominent therapeutic effect in enhancing the sensitivity of chemotherapy in OSCC through elimination of CSCs. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E231-E238, 2016. PMID- 25545961 TI - The dorsal striatum and ventral striatum play different roles in the programming of social behaviour: a tribute to Lex Cools. AB - Early work by Lex Cools suggested that the caudate nucleus (dorsal striatum) plays a role in programming social behaviour: enhanced activity in the caudate nucleus increased the extent to which ongoing behaviour is controlled by the individual's own behaviour (internal control) rather than by that of its partners (external control). Interestingly, later studies by others have indicated that the ventral striatum plays a role in external rather than internal control. Here, I discuss the role of these different striatal areas - and the emotional (ventral striatum) and cognitive control (dorsal striatum) system in which they are embedded - in the organization of social behaviour in the context of locus of control. Following on from this discussion, I will pay particular attention to individual differences in social behaviour (individuals with more internal or external control), focusing on the role of dopamine, serotonin and the effects of stress-related challenges in relation to their different position in a dominance hierarchy. I will subsequently allude to potential psychological and behavioural problems in the social domain following on from these differences in locus of control ['social obliviousness' (dorsal stratum) and 'social impulsivity' (ventral striatum)]. In doing so, I provide as a tribute a historical account of the early research by Lex Cools. PMID- 25545962 TI - An order of magnitude increase in the quantum efficiency of (Al)GaAs nanowires using hybrid photonic-plasmonic modes. AB - We demonstrate 900% relative enhancement in the quantum efficiency (QE) of surface passivated GaAs nanowires by coupling them to resonant nanocavities that support hybrid photonic-plasmonic modes. This nonconventional approach to increase the QE of GaAs nanowires results in QE enhancement over the entire nanowire volume and is not limited to the near-field of the plasmonic structure. Our cavity design enables spatially and spectrally tunable resonant modes and efficient in- and out-coupling of light from the nanowires. Furthermore, this approach is not fabrication intensive; it is scalable and can be adapted to enhance the QE of a wide range of low QE semiconductor nanostructures. PMID- 25545960 TI - CopM is a novel copper-binding protein involved in copper resistance in Synechocystis sp. PCC 6803. AB - Copper resistance system in the cyanobacterium Synechocystis sp. PCC 6803 comprises two operons, copMRS and copBAC, which are expressed in response to copper in the media. copBAC codes for a heavy-metal efflux-resistance nodulation and division (HME-RND) system, while copMRS codes for a protein of unknown function, CopM, and a two-component system CopRS, which controls the expression of these two operons. Here, we report that CopM is a periplasmic protein able to bind Cu(I) with high affinity (KD ~3 * 10(-16) ). Mutants lacking copM showed a sensitive copper phenotype similar to mutants affected in copB, but lower than mutants of the two-component system CopRS, suggesting that CopBAC and CopM constitute two independent resistance mechanisms. Moreover, constitutive expression of copM is able to partially suppress the copper sensitivity of the copR mutant strain, pointing out that CopM per se is able to confer copper resistance. Furthermore, constitutive expression of copM was able to reduce total cellular copper content of the copR mutant to the levels determined in the wild type (WT) strain. Finally, CopM was localized not only in the periplasm but also in the extracellular space, suggesting that CopM can also prevent copper accumulation probably by direct copper binding outside the cell. PMID- 25545963 TI - Miniaturized Cultivation of Microbiota for Antimalarial Drug Discovery. AB - The ongoing search for effective antiplasmodial agents remains essential in the fight against malaria worldwide. Emerging parasitic drug resistance places an urgent need to explore chemotherapies with novel structures and mechanisms of action. Natural products have historically provided effective antimalarial drug scaffolds. In an effort to search nature's chemical potential for antiplasmodial agents, unconventionally sourced organisms coupled with innovative cultivation techniques were utilized. Approximately 60,000 niche microbes from various habitats (slow-growing terrestrial fungi, Antarctic microbes, and mangrove endophytes) were cultivated on a small-scale, extracted, and used in high throughput screening to determine antimalarial activity. About 1% of crude extracts were considered active and 6% partially active (>= 67% inhibition at 5 and 50 MUg/mL, respectively). Active extracts (685) were cultivated on a large scale, fractionated, and screened for both antimalarial activity and cytotoxicity. High interest fractions (397) with an IC50 < 1.11 MUg/mL were identified and subjected to chromatographic separation for compound characterization and dereplication. Identifying active compounds with nanomolar antimalarial activity coupled with a selectivity index tenfold higher was accomplished with two of the 52 compounds isolated. This microscale, high throughput screening project for antiplasmodial agents is discussed in the context of current natural product drug discovery efforts. PMID- 25545964 TI - Dual Effect of Cyanidin on RANKL-Induced Differentiation and Fusion of Osteoclasts. AB - Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts are multinucleated cells derived from hematopoietic stem cells (HSCs) or monocyte/macrophage progenitor cells and formed by osteoclasts precursors (OCPs) fusion. Cyanidin is an anthocyanin widely distributed in food diet with novel antioxidant activity. However, the effect of cyanidin on osteoclasts is still unknown. We investigated the effect of cyanidin on RANKL-induced osteoclasts differentiation and cell fusion. The results showed that cyanidin had a dual effect on RANKL-induced osteoclastogenesis. Lower dosage of cyanidin (< 1 ug/ml) has a promoting effect on osteoclastogenesis while higher dosage of cyanidin (> 10 ug/ml) has an inhibitory effect. Fusogenic genes like CD9, ATP6v0d2, DC-STAMP, OC-STAMP, and osteoclasts related genes like NFATc1, mitf, and c-fos were all regulated by cyanidin consistent to its dual effect. Further exploration showed that low concentration of cyanidin could increase osteoclasts fusion whereas higher dosage of cyanidin lead to the increase of LXR beta expression and activation which is suppressive to osteoclasts differentiaton. All these results showed that cyanidin exhibits therapeutic potential in prevention of osteoclasts related bone disorders. PMID- 25545965 TI - Crystal Clear? The Relationship Between Methamphetamine Use and Sexually Transmitted Infections. AB - Public health officials have cited methamphetamine control as a tool with which to decrease HIV and other sexually transmitted infections, based on previous research that finds a strong positive correlation between methamphetamine use and risky sexual behavior. However, the observed correlation may not be causal, as both methamphetamine use and risky sexual behavior could be driven by a third factor, such as a preference for risky behavior. We estimate the effect of methamphetamine use on risky sexual behavior using monthly data on syphilis diagnoses in California and quarterly data on syphilis, gonorrhea, and chlamydia diagnoses across all states. To circumvent possible endogeneity, we use a large exogenous supply shock in the US methamphetamine market that occurred in May 1995 and a later shock stemming from the Methamphetamine Control Act, which went into effect in October 1997. While the supply shocks had large negative effects on methamphetamine use, we find no evidence that they decreased syphilis, gonorrhea, or chlamydia rates. Our results have broad implications for public policies designed to decrease sexually transmitted infection rates. PMID- 25545966 TI - Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease. AB - Monoclonal antibodies (mAbs) inhibiting cytokines have recently emerged as new drug modalities for the treatment of chronic inflammatory diseases. Interleukin 17 (IL-17) is a T-cell-derived central mediator of autoimmunity. Immunization with Qbeta-IL-17, a virus-like particle based vaccine, has been shown to produce autoantibodies in mice and was effective in ameliorating disease symptoms in animal models of autoimmunity. To characterize autoantibodies induced by vaccination at the molecular level, we generated mouse mAbs specific for IL-17 and compared them to germline Ig sequences. The variable regions of a selected hypermutated high-affinity anti-IL-17 antibody differed in only three amino acid residues compared to the likely germline progenitor. An antibody, which was backmutated to germline, maintained a surprisingly high affinity (0.5 nM). The ability of the parental hypermutated antibody and the derived germline antibody to block inflammation was subsequently tested in murine models of multiple sclerosis (experimental autoimmune encephalomyelitis), arthritis (collagen induced arthritis), and psoriasis (imiquimod-induced skin inflammation). Both antibodies were able to delay disease onset and significantly reduced disease severity. Thus, the mouse genome unexpectedly encodes for antibodies with the ability to functionally neutralize IL-17 in vivo. PMID- 25545968 TI - Gingival Embrasure Fill In Fixed Implant-Supported Prosthetics: A Review. AB - After provisional or definitive cementation of fixed implant-supported prostheses, spontaneous gingival proliferation may occur to fill the cervical embrasure areas of the prosthesis. Adequate oral hygiene, osseous spacing between the supporting implants and attached or immovable soft tissue may be the conditions that allow this phenomenon. This proliferation embrasure fill eliminates interproximal gingival voids, that is, black triangles, and makes the outcome more esthetically acceptable. Since interproximal prosthetic deign and implant positioning may be the primary factors for the fill, the gingival fill may be, in fact, an epulis. PMID- 25545967 TI - Improvement in influenza vaccination rates in a pediatric sickle cell disease clinic. AB - BACKGROUND: Children with sickle cell disease (SCD) are at increased risk of complications from influenza. However, despite widespread recommendations that these patients receive an annual influenza immunization, reported vaccination rates remain very low at under 50%. PROCEDURE: Our aim was to increase the influenza vaccination rate among our pediatric patients with SCD aged 6 months to 21 years over two influenza seasons, 2012-2013 and 2013-2014, to 80%, consistent with the Health People 2020 goal. We used multiple quality improvement methods, based on the literature and our previous experience in other aspects of SCD care, including parent and provider education, enhancement of our EHR, use of a SCD patient registry and reminder and recall done by a patient navigator. RESULTS: We vaccinated 80% of our pediatric patients with SCD for influenza during the 2012 2013 season and 90% of patients in 2013-2014. Our early season vaccination rates were nearly double that of those for the general population. CONCLUSIONS: Use of quality improvement methods can increase rates of influenza vaccination for this high-risk population, suggesting that less health care utilization and lower cost might result. PMID- 25545970 TI - "The world is flat". PMID- 25545969 TI - Abnormal functional connectivity of the amygdala is associated with depression in Parkinson's disease. AB - Depressive symptoms are common in Parkinson's disease (PD), but the pathophysiology and neural basis underlying depression in PD is not well understood. Abnormal functional connectivity of the amygdala with various cortical and subcortical areas has been observed in major depressive disorder, indicating that dysfunction of the corticolimbic network may be involved in the pathogenesis of major depressive disorder. However, little is known about alterations of amygdala functional connectivity in depressed PD patients. In the present study, 20 depressed PD patients, 40 nondepressed PD patients, and 43 matched healthy controls underwent neuropsychological tests and resting-state functional MRI scanning. Between-group differences in amygdala functional connectivity network were examined using t tests. Compared to the nondepressed PD patients, depressed PD patients showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, right amygdala functional connectivity with the left superior temporal gyrus, and left calcarine gyrus. Compared to the healthy controls, the depressed PD group also showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, but decreased left amygdala functional connectivity with the left putamen, left inferior frontal gyrus, and the right cerebellum, as well as decreased right amygdala functional connectivity with the left inferior orbitofrontal gyrus, the left gyrus rectus, and the right putamen. The increased connectivity between limbic regions and decreased connectivity between the corticolimbic networks may reflect impaired high-order cortical regulatory effects on the emotion-related limbic areas, which may lead to mood dysregulation. Our study should advance the understanding of neural mechanisms underlying depression in PD. PMID- 25545971 TI - An in vitro comparison of microbial ingress into 8 different needleless IV access devices. AB - There are conflicting reports of the effect needleless intravenous access devices have on rates of catheter-related bloodstream infection. The aim of this study was to identify any differences between the rates of microbial ingress into 8 different devices following contamination. Each type of device was subjected to a 7-day clinical simulation that involved repeated microbial contamination of the injection site and decontamination followed by saline flushes. Significant differences in the number of microorganisms associated with each device were detected in the saline eluates. Three positive-displacement mechanical valves were associated with the ingress of significantly fewer microorganisms compared with other devices. PMID- 25545972 TI - Intermittently delivered IV medication and pH: reevaluating the evidence. AB - The Infusion Nurses Society's Infusion Nursing Standards of Practice has treated pH as a critical factor in the decision-making process for vascular access device selection, stating that an infusate with a pH less than 5 or greater than 9 is not appropriate for short peripheral or midline catheters. Because of the Standards, drug pH is not an uncommon factor driving the decision for central vascular access. In this era of commitment to evidence-based practice, the pH recommendation requires reevaluation and a critical review of the research leading to infusate pH as a decisional factor. In this narrative literature review, historical and current research was appraised and synthesized for pH of intermittently delivered intravenous medications and the development of infusion thrombophlebitis. On the basis of this review, the authors conclude and assert that pH alone is not an evidence-based indication for central line placement. PMID- 25545973 TI - Postinsertion central line site care: quality improvement in a medical cardiac ICU. AB - Using the Six Sigma quality improvement framework of Define, Measure, Analyze, Improve, and Control, nurses in the medical cardiac intensive care unit at a large academic medical center in the Midwest identified a gap in the quality of central line site care, evaluated the current state of site care, implemented an intervention to create an improvement in nursing performance of site care, quantified this improvement, and created a model for sustained quality control. Reasons for nonocclusive dressings were revealed and addressed. An unexpected benefit was found in a unifying sense of pride in improving patient care. PMID- 25545974 TI - Teaching new graduate nurses about infusion therapy in a nurse residency program. AB - The purpose of this article is to describe how the concept of infusion nursing was incorporated into orientation for new graduate nurses at an academic medical center in the Midwest. Strategies were identified based on their unique learning needs and a desire to instill safe infusion practices early in their nursing careers. (A Supplemental Video Abstract for this article is available at http://links.lww.com/JIN/A64.). PMID- 25545975 TI - Use of a policy-driven education program to reduce central line-associated bloodstream infection rates. AB - Central line-associated bloodstream infections (CLABSIs) account for a significant portion of hospital-acquired infections. Current research supports the use of chlorhexidine for site cleansing and staff education programs on infection-control practices to reduce CLABSI rates. This project evaluates the efficacy of implementing site cleaning policies and protocols and formal staff education in reducing CLABSI rates in a critical access hospital. Efficacy was measured by infection rates per 1000 catheter days through a retrospective chart review before and after implementation of a policy and protocol bundle and staff education. PMID- 25545976 TI - Subcutaneous immunoglobulin replacement therapy: ensuring success. AB - Subcutaneous immunoglobulin (SCIg) infusions are an option for patients requiring immunoglobulin therapy. Nurses are uniquely positioned to advocate for patients and to teach them how to successfully manage their infusions. The purpose of this review is to describe SCIg therapy and to provide teaching instructions as well as creative tips to ensure treatment success. PMID- 25545977 TI - Hot-hand bias in rhesus monkeys. AB - Human decision-makers often exhibit the hot-hand phenomenon, a tendency to perceive positive serial autocorrelations in independent sequential events. The term is named after the observation that basketball fans and players tend to perceive streaks of high accuracy shooting when they are demonstrably absent. That is, both observing fans and participating players tend to hold the belief that a player's chance of hitting a shot are greater following a hit than following a miss. We hypothesize that this bias reflects a strong and stable tendency among primates (including humans) to perceive positive autocorrelations in temporal sequences, that this bias is an adaptation to clumpy foraging environments, and that it may even be ecologically rational. Several studies support this idea in humans, but a stronger test would be to determine whether nonhuman primates also exhibit a hot-hand bias. Here we report behavior of 3 monkeys performing a novel gambling task in which correlation between sequential gambles (i.e., temporal clumpiness) is systematically manipulated. We find that monkeys have better performance (meaning, more optimal behavior) for clumped (positively correlated) than for dispersed (negatively correlated) distributions. These results identify and quantify a new bias in monkeys' risky decisions, support accounts that specifically incorporate cognitive biases into risky choice, and support the suggestion that the hot-hand phenomenon is an evolutionary ancient bias. PMID- 25545978 TI - The cognitive underpinnings of flexible tool use in great apes. AB - Nonhuman primates perform poorly in trap tasks, a benchmark test of causal knowledge in nonhuman animals. However, recent evidence suggests that when the confound of tool use is avoided, great apes' performance improves dramatically. In the present study, we examined the cognitive underpinnings of tool use that contribute to apes' poor performance in trap tasks. We presented chimpanzees (Pan troglodytes), bonobos (Pan paniscus), and orangutans (Pongo abelii) with different versions of a maze-like multilevel trap task. We manipulated whether the apes had to use their fingers or a stick to negotiate a reward through the maze. Furthermore, we varied whether the apes obtained visual information about the functionality of the traps (i.e., blockage of free passage) or only arbitrary color stimuli indicating the location of the traps. We found that (a) apes in the finger-maze task outperformed apes in the tool-use-maze task (and partially planned their moves multiple steps ahead), and (b) tool-using apes failed to learn to avoid the traps and performed similar to apes that did not obtain functional information about the traps. Follow-up experiments with apes that already learned to avoid the traps showed that tool use or the color cues per se did not pose a problem for experienced apes. These results suggest that simultaneously monitoring 2 spatial relations (the tool-reward and reward-surface relation) might overstrain apes' cognitive system. Thus, trap tasks involving tool use might constitute a dual task loading on the same cognitive resources; a candidate for these shared resources is the attentional system. PMID- 25545979 TI - Transposition and its generalization in common marmosets. AB - Whether animals use relational cues in transposition tests has long been considered a controversial issue. In the present study, we examined whether common marmosets could generalize relational responses to untrained stimulus pairs and further apply these generalizations to unknown shapes. The subjects were trained to perform simple discrimination tasks using a pair of stimuli. The stimuli differed in size, and the subjects were required to select the larger or smaller of the 2 sizes, depending on the given contingencies. After experiencing several reversals, the subjects were examined using 2 different tests: transposition and shape generalization. In the transposition test trials, in which squares of different sizes than those used in the training trials were presented, the subjects selected the stimulus based on the relative size of the stimulus. In the shape generalization tests, sets of 5 novel shapes with the same relative sizes were presented with the training stimuli. The subjects' performance indicated successful transposition to the novel stimulus pairs, and further analysis showed that transposition was more likely to occur when the test stimuli shared physical features, such as the outer length and the number of line segments, with the trained stimuli. Thus, the present study demonstrated the robust ability of transposition in common marmosets based on relative size, both with and without common shape features, and offered a possible method for specifying the critical stimulus features through which transposition can be more readily observed. PMID- 25545980 TI - Differential effect of the intermixed and blocked preexposure schedules on the strength of within-compound associations. AB - In Experiment 1, we demonstrated an intermixed-blocked effect where intermixed preexposure to a flavor compound and to an element of that compound (AX, X, AX, X . . .) reduced generalization between them more than equivalent blocked preexposure (AX, AX . . . X, X . . . , or X, X, AX, AX). Then we used sensory preconditioning (Experiment 2) and conditioned flavor preference (Experiment 3) procedures to assess the strength of the X-A within-compound association resulting from those preexposure schedules. In both experiments, we observed that the within-compound association was stronger after blocked than intermixed preexposure. We suggest that these differences in strength produce more mediated generalization in the blocked than intermixed preexposure. PMID- 25545981 TI - Conditioned inhibition and reinforcement rate. AB - We investigated conditioned inhibition in a magazine approach paradigm. Rats were trained on a feature negative discrimination between an auditory conditioned stimulus (CS) reinforced at one rate versus a compound of that CS and a visual stimulus (L) reinforced at a lower rate. This training established L as a conditioned inhibitor. We then tested the inhibitory strength of L by presenting it in compound with other auditory CSs. L reduced responding when tested with a CS that had been reinforced at a high rate, but had less or even no inhibitory effect when tested with a CS that had been reinforced at a low rate. The inhibitory strength of L was greater if it signaled a decrease in reinforcement from an already low rate than if it signaled an equivalent decrease in reinforcement from a high rate. We conclude that the strength of inhibition is not a linear function of the change in reinforcement that it signals. We discuss the implications of this finding for models of learning (e.g., Rescorla & Wagner, 1972) that identify inhibition with a difference (subtraction) rule. PMID- 25545983 TI - ABA renewal is greater when extinction occurs in the same context as cue pre exposure. AB - Renewal has been observed in several protocols. One, termed ABA, trains a conditioned stimulus (CS) in one context, A, extinguishes the CS in a second context, B, and tests either in A or B. We used between- and within-subjects designs in three experiments with rats to study how a history of cue pre-exposure affects extinction and renewal of conditioned fear responses (freezing). In each experiment, a stimulus was pre-exposed in either context B or context C, paired with an aversive unconditioned stimulus (US) in a third context, A, extinguished in B, and finally tested in A. Freezing declined at the same rate when extinction occurred in the same or a different context as pre-exposure in between-subjects designs (Experiments 1 and 2), but declined faster when extinction and pre exposure occurred in the same than in a different context in a within-subjects design (Experiment 3). In each experiment, renewal of freezing responses in the conditioning context, A, was greater when subjects were tested with the CS extinguished in its pre-exposure context than with the CS extinguished outside its pre-exposure context. The results were interpreted to mean that what was learned about the context-stimulus relation in pre-exposure enhanced control by that context over what was learned in extinction, thereby enhancing renewal when the rats were returned to the conditioning context for testing. PMID- 25545982 TI - Mechanisms of renewal after the extinction of discriminated operant behavior. AB - Three experiments demonstrated, and examined the mechanisms that underlie, the renewal of extinguished discriminated operant behavior. In Experiment 1, rats were trained to perform 1 response (lever press or chain pull) in the presence of one discriminative stimulus (S; light or tone) in Context A, and to perform the other response in the presence of the other S in Context B. Next, each of the original S/response combinations was extinguished in the alternate context. When the S/response combinations were tested back in the context in which they had been trained, responding in the presence of S returned (an ABA renewal effect was observed). This renewal could not be due to differential context-reinforcer associations, suggesting instead that the extinction context inhibits either the response and/or the effectiveness of the S. Consistent with the latter mechanism, in Experiment 2, ABA renewal was still observed when both the extinction and renewal contexts inhibited the same response. However, in Experiment 3, previous extinction of the response in the renewing context (occasioned by a different S) reduced AAB renewal more than did extinction of the different response. Taken together, the results suggest at least 2 mechanisms of renewal after instrumental extinction. First, extinction performance is at least partly controlled by a direct inhibitory association that is formed between the context and the response. Second, in the discriminated operant procedure, extinction performance can sometimes be partly controlled by a reduction in the effectiveness of the S in the extinction context. Renewal of discriminated operant behavior can be produced by a release from either of these forms of inhibition. PMID- 25545984 TI - Methylmercury causes neuronal cell death through the suppression of the TrkA pathway: in vitro and in vivo effects of TrkA pathway activators. AB - Methylmercury (MeHg) is an environmental toxin which induces cell death specific for the nervous systems. Here we show that MeHg causes neuronal cell death through the suppression of the tropomyosin receptor kinase A (TrkA) pathway, and that compounds activating the TrkA pathway prevent MeHg-induced nerve damage in vitro and in vivo. We first investigated the mechanism of MeHg-induced neurotoxicity in differentiating neurons using PC12 cells. Exposure to 100nM MeHg for 1day induced apoptosis in differentiating PC12 cells. Further, MeHg-induced apoptosis was preceded by inhibition of neurite extension, as determined by ELISA analyses of the neurite-specific protein neurofilament triplet H protein (NF-H). To determine the mechanism of MeHg-induced apoptosis, we evaluated the effects of MeHg on the TrkA pathway, which is known to regulate neuronal differentiation and viability. Western blot analysis demonstrated that, like the TrkA phosphorylation inhibitor K252a, MeHg inhibited phosphorylation of TrkA and its downstream effectors. Furthermore, GM1 ganglioside and its analog MCC-257, which enhance TrkA phosphorylation, overcame the effect of MeHg in neurons, supporting the involvement of the TrkA pathway in MeHg-induced nerve damage. Finally, we demonstrated that MCC-257 rescued the clinical sign and pathological changes in MeHg-exposed rats. These findings indicate that MeHg-induced apoptosis in neuron is triggered by inhibition of the TrkA pathway, and that GM1 ganglioside and MCC 257 effectively prevent MeHg-induced nerve damage. PMID- 25545986 TI - Mitochondrial iron accumulation exacerbates hepatic toxicity caused by hepatitis C virus core protein. AB - Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS). The overproduction of ROS in the liver is the net result of HCV core protein-induced dysfunction of the mitochondrial respiratory chain. This study examined the impact of ferric nitrilacetic acid (Fe-NTA)-mediated iron overload on mitochondrial damage and ROS production in HCV core protein-expressing HepG2 (human HCC) cells (Hep39b cells). A decrease in mitochondrial membrane potential and ROS production were observed following Fe-NTA treatment. After continuous exposure to Fe-NTA for six days, cell toxicity was observed in Hep39b cells, but not in mock (vector-transfected) HepG2 cells. Moreover, mitochondrial iron ((59)Fe) uptake was increased in the livers of HCV core protein-expressing transgenic mice. This increase in mitochondrial iron uptake was inhibited by Ru360, a mitochondrial Ca(2+) uniporter inhibitor. Furthermore, the Fe-NTA-induced augmentation of mitochondrial dysfunction, ROS production, and cell toxicity were also inhibited by Ru360 in Hep39b cells. Taken together, these results indicate that Ca(2+) uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein. PMID- 25545985 TI - Diethylene glycol-induced toxicities show marked threshold dose response in rats. AB - Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10g/kg DEG and blood, kidney and liver tissues were collected at 48h. Both rat strains treated with 10g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10g/kg DEG, but no DGA was present at 2 or 5g/kg, asserting its necessary role in DEG induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. PMID- 25545988 TI - Development of aseptic subcutaneous abscess after tocilizumab therapy in a patient with SAPHO syndrome complicated by amyloid A amyloidosis. PMID- 25545987 TI - Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs. AB - In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6 months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30 days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O3) or HDMA/ozone (HDMA+O3) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30 months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA+O3 alters the development process in the lung alveoli. PMID- 25545989 TI - Porokeratosis on the scrotum: two cases. AB - Porokeratosis is a group of hereditary or acquired disorders of epidermal keratinization, characterized by keratotic lesions with an atrophic center and a prominent peripheral ridge. At least seven clinical variants have been identified: the plaque type, disseminated superficial porokeratosis, disseminated superficial actinic porokeratosis, linear porokeratosis, giant porokeratosis, porokeratosis plantaris palmaris et disseminate, and punctuate porokeratosis. Genital porokeratosis is a rare condition even in disseminated forms. We described two male patients who had porokeratosis only affecting the scrotum. The patients were treated by surgical excision under local anesthesia. One-year follow-up revealed no sign of recurrences and malignant changes. PMID- 25545990 TI - High fidelity between saliva proteomics and the biologic state of salivary glands defines biomarker signatures for primary Sjogren's syndrome. AB - OBJECTIVE: Dependence on invasive procedures for classification of patients with Sjogren's syndrome (SS) hampers timely diagnosis and suitable patient followup. The aim of this study was to recapitulate the diagnosis of SS through noninvasive means and to define the biologic state of SS patients' salivary glands. METHODS: Using a 187-plex capture antibody-based assay, salivary proteomic biomarker profiles were generated from patients with primary SS, patients with rheumatoid arthritis, and asymptomatic controls. Discriminant function analyses and Gene Ontology-based network analyses allowed data analyses with a reductionist approach and with a focus on systems biology. RESULTS: Characterized by significant changes in 61 and 55 proteins, respectively, the salivary proteome of SS patients appeared profoundly altered compared to that of individuals without SS. On this basis, 4-plex and 6-plex biomarker signatures, both including interleukin-4 (IL-4), IL-5, and clusterin, achieved accurate prediction of an individual's group membership for at least 94% of cases. Of note, all misclassified SS patients presented with ectopic germinal center-like structures. Systematic inference of biologic meaning identified SS-related protein patterns delineating B cell-dominated immune responses, macrophage differentiation, and signs of T cell chemotaxis. In addition, proteomic Multi-Analyte Profiles provided insight about proteins related to collagen, cytokine, and growth factor synthesis as well as lipid transport. CONCLUSION: The SS-related molecular landscape conveyed by saliva showed great congruence with histopathologic features found in SS and advances understanding of this disease at a molecular level. Such salivary biomarker signatures harbor great potential for improving timeliness of SS diagnosis and enabling suitable patient followup. PMID- 25545991 TI - The case for policy-relevant conservation science. AB - Drawing on the "evidence-based" (Sutherland et al. 2013) versus "evidence informed" debate (Adams & Sandbrook 2013), which has become prominent in conservation science, I argue that science can be influential if it holds a dual reference (Lentsch & Weingart 2011) that contributes to the needs of policy makers whilst maintaining technical rigor. In line with such a strategy, conservation scientists are increasingly recognizing the usefulness of constructing narratives through which to enhance the influence of their evidence (Leslie et al. 2013; Lawton & Rudd 2014). Yet telling stories alone is rarely enough to influence policy; instead, these narratives must be policy relevant. To ensure that evidence is persuasive alongside other factors in a complex policy making process, conservation scientists could follow 2 steps: reframe within salient political contexts and engage more productively in boundary work, which is defined as the ways in which scientists "construct, negotiate, and defend the boundary between science and policy" (Owens et al. 2006:640). These will both improve the chances of evidence-informed conservation policy. PMID- 25545992 TI - How many papers can be published from one study? PMID- 25545993 TI - Cellular interactions during tracheary elements formation and function. AB - The survival of higher plant species on land depends on the development and function of an efficient vascular system distributing water and minerals absorbed by roots to all aerial organs. This conduction and distribution of plant sap relies on specialized cells named tracheary elements (TEs). In contrast to many other cell types in plants, TEs are functionalized by cell death that hollows the cell protoplast to make way for the sap. To maintain a stable conducting function during plant development, recovery from vascular damages as well as to adapt to environmental changes, TEs are completely dependent on direct cellular interactions with neighboring xylem parenchyma cells (XPs). PMID- 25545994 TI - In vitro colonic catabolism of orange juice (poly)phenols. AB - SCOPE: The role of colonic microbiota in the breakdown of hesperetin, naringenin, and ferulic acid, compounds found as glycosides in orange juice, was investigated using an in vitro fermentation model. METHODS AND RESULTS: Test compounds were incubated with human fecal slurries cultured under anaerobic conditions, and the production of phenolic acid catabolites were monitored by GC-MS and HPLC-MS(2) . Hesperetin was converted to 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid, 3 (3',4'-dihydroxyphenyl)propionic acid, and 3-(3'-hydroxyphenyl)propionic acid while 3-(phenyl)propionic acid was the major end product derived from naringenin. The data obtained are compared to our previously published data on urinary excretion of phenolic and aromatic acids after acute orange juice consumption (Pereira-Caro et al. Am. J. Clin. Nutr. 2014, 100, 1385-1391). Catabolism pathways are proposed for events occurring in the colon and those taking place postabsorption into the circulatory system with particular reference to the excretion of 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic acid, which is not formed in fecal incubations. Ferulic acid was also degraded by the colonic microflora being converted principally to 3-(3'-methoxy-4'-hydroxyphenyl)propionic acid, a phenolic acid that appears in urine after orange juice consumption. CONCLUSION: The study provides novel information on the potential involvement of the colonic microbiota in the overall bioavailability of orange juice (poly)phenols through the production of phenylpropionic acids and subsequent hepatic conversions that lead to hippuric acid and its hydroxylated analogues. PMID- 25545995 TI - Unraveling the seed endosperm proteome of the lotus (Nelumbo nucifera Gaertn.) utilizing 1DE and 2DE separation in conjunction with tandem mass spectrometry. AB - Nelumbo nucifera (Gaertn.) or lotus, is an aquatic plant native to India, and presently consumed as food mainly in China and Japan. Lotus is also widely used in Indian and Chinese traditional medicine. Extracts from different parts of the lotus plant have been reported to show diverse biological activities-antioxidant, free radical scavenging, anti-inflammatory, and immunomodulatory. Despite this, little work has been done in isolating and identifying proteins responsible for these activities, or yet importantly to establish a lotus proteome. The aim of our group is to develop a proteome catalog of the lotus plant, starting with its seed, the nutrient rich food source. In this present study, the seed endosperm most abundant in proteins, and main nutrient storage tissue-was targeted for protein extraction by testing five different extraction protocols, followed by their proteomic analyses using complementary 1DE and 2DE approaches in conjunction with MS/MS. The inventory of 66 nonredundant proteins obtained by 1DE MS and the 30 obtained by 2DE-MS provides the first catalog of the lotus seed endosperm, where the most abundant protein functions were in categories of metabolic activities related to carbohydrate metabolism and nutrient storage. PMID- 25545996 TI - Quantitative corneal anatomy: evaluation of the effect of diabetes duration on the endothelial cell density and corneal thickness. AB - PURPOSE: To evaluate the differences in endothelial cell density (ECD) and central corneal thickness (CCT) between type II diabetic patients and age-matched healthy controls, and determine the impact of time from diagnosis. METHODS: This is a comparative study of 77 eyes of type II diabetic patients (33 males, 44 females) and 80 eyes of healthy subjects (42 males, and 38 females) whose ages ranged from 38 to 56 years. CCT, ECD, HbA(1c) levels, and Goldmann tonometry were measured. RESULTS: The CCT was significantly higher and the ECD significantly lower in long-term diabetic patients (10 years + since diagnosis) when compared with short-term diabetic patients (<1 year since diagnosis) and controls (both p < 0.001). No significant differences in CCT (p = 0.30) and ECD (p = 0.31) were found between control groups. Multivariate analysis of variance indicated that there was a significant effect of the diabetes duration in CCT and ECD. In diabetic patients, a two-way analysis of variance showed that CCT was significantly different for a 7.5% HbA(1c) cut-off value, and ECD for both 7.0% and 7.5% HbA(1c) cut-off values. CONCLUSION: Type II diabetes causes a significant alteration in corneal structure and function in the long term. Our study seems to confirm the effect of diabetes duration and poor glycaemic control on CCT and ECD changes. PMID- 25545997 TI - Effects of social conditions during adolescence on courtship and aggressive behavior are not abolished by adult social experience. AB - Social experience during adolescence has long-lasting consequences for adult social behavior in many species. In zebra finches, individuals reared in pairs during adolescence start to court females faster, sing more courtship motifs to females and are more aggressive compared with group-reared males. We investigated whether such differences are stable during adulthood or can be abolished by novel social experience after adolescence by giving all birds extensive experience with group life during adulthood. Courtship and aggressiveness increased in all males, but pair-reared males still had a higher motif rate and were more aggressive than group-reared males. Males no longer differed in courtship latency. In addition to the stable treatment differences, individual differences in behavior remained stable over time. Our results show that differences in behavior acquired during adolescence are preserved into adulthood, although adults still change their social behavior. Adolescence can thus be seen as a sensitive period during which social conditions have a lasting effect on adult behavior. PMID- 25545999 TI - Male-female differences in diabetic retinopathy? AB - The purpose of this paper is to review male-female differences in the incidence and prevalence of diabetes and diabetic retinopathy. These differences will be established primarily through results from our present research and a review of related literature. Previously, we have demonstrated that neuroretinal dysfunction can be used to predict the location of future retinopathy up to three years before it is manifest. Our current research suggests that, for type 2 diabetes, the normal differences in neuroretinal function between nondiabetic males and females under 50 years of age are altered in patients with type 2 diabetes. Furthermore, local neuroretinal function in type 2 diabetes is more abnormal in adult males compared with adult females. The literature also suggests that there are male-female differences in the occurrence of diabetes. In adolescence, the incidence of type 1 diabetes is greater in males, whereas in type 2 diabetes, the incidence is greater in females. This excess of females in type 2 diabetes shifts to a more equal incidence between the two sexes in adults. In addition, advanced retinopathy in type 1 diabetes appears to be more common in males, and the presence and severity of diabetic retinopathy at the time of diagnosis in type 2 diabetes appears to be more associated with male sex. Although the reasons for male-female differences identified in this review are unknown, sex appears to be a significant factor in certain aspects of diabetes incidence and diabetic retinopathy. PMID- 25546000 TI - Pulmonary embolus in transit. PMID- 25546002 TI - Screening and surveillance for Barrett esophagus. PMID- 25546001 TI - The effect of tafamidis on the QTc interval in healthy subjects. AB - AIMS: The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day(-1) ). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QTc interval in healthy subjects. METHODS: This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra therapeutic Cmax of ~20 ug ml(-1) ) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of >= 14 days. Serial triplicate 12-lead electrocardiograms were performed. QTc intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs). RESULTS: A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QTc F between tafamidis 400 mg and placebo was <10 ms (non inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin tmax of 3 h post-dose, confirming assay sensitivity. Cmax and AUC(0,24 h) for tafamidis were 20.36 ug ml(-1) and 305.4 ug ml(-1) h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs. CONCLUSIONS: This thorough QTc study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QTc interval and is well-tolerated in healthy volunteers. PMID- 25546003 TI - Pain management in the emergency chain: the use and effectiveness of pain management in patients with acute musculoskeletal pain. AB - OBJECTIVE: While acute musculoskeletal pain is a frequent complaint in emergency care, its management is often neglected, placing patients at risk for insufficient pain relief. Our aim is to investigate how often pain management is provided in the prehospital phase and emergency department (ED) and how this affects pain relief. A secondary goal is to identify prognostic factors for clinically relevant pain relief. DESIGN: This prospective study (PROTACT) includes 697 patients admitted to ED with musculoskeletal extremity injury. Data regarding pain, injury, and pain management were collected using questionnaires and registries. RESULTS: Although 39.9% of the patients used analgesics in the prehospital phase, most patients arrived at the ED with severe pain. Despite the high pain prevalence in the ED, only 35.7% of the patients received analgesics and 12.5% received adequate analgesic pain management. More than two-third of the patients still had moderate to severe pain at discharge. Clinically relevant pain relief was achieved in only 19.7% of the patients. Pain relief in the ED was higher in patients who received analgesics compared with those who did not. Besides analgesics, the type of injury and pain intensity on admission were associated with pain relief. CONCLUSIONS: There is still room for improvement of musculoskeletal pain management in the chain of emergency care. A high percentage of patients were discharged with unacceptable pain levels. The use of multimodal pain management or the implementation of a pain management protocol might be useful methods to optimize pain relief. Additional research in these areas is needed. PMID- 25546004 TI - High-resolution quantification by charge-dominant electrophoretic mobility shift of quantum dots. AB - Conjugation of biomolecules to colloidal nanoparticles, such as quantum dots (QDs), often leads to change in mobility. We discover that linking DNA molecules to quantum dots alters their surface charge density without significantly increasing the hydrodynamic radius, causing a prominent shift in electrophoretic mobility. In this study, a high-resolution molecular quantification method named quantification by QDs electrophoretic mobility shift (qQEMS) is developed based on the charge-dominant transformation that closely associates DNA quantity to QDs electrophoretic mobility. The versatility of qQEMS is demonstrated by a number of quantification assays in which DNA molecules functioned as enzyme substrates, target-specific probes, and competitive charge carriers. qQEMS shows a great potential as a generic and versatile quantification platform for a wide range of applications. PMID- 25546007 TI - Response differences between Ectocarpus siliculosus populations to copper stress involve cellular exclusion and induction of the phytochelatin biosynthetic pathway. AB - Some populations of brown seaweed species inhabit metal-polluted environments and can develop tolerance to metal stress, but the mechanisms by which this is accomplished are still to be elucidated. To address this, the responses of two strains of the model brown alga Ectocarpus siliculosus isolated from sites with different histories of metal contamination exposed to total copper (CuT) concentrations ranging between 0 and 2.4 MUM for 10 days were investigated. The synthesis of the metal-chelator phytochelatin (PCs) and relative levels of transcripts encoding the enzymes gamma-glutamylcysteine synthetase (gamma-GCS), glutathione synthase (GS) and phytochelatin synthase (PCS) that participate in the PC biosynthetic pathway were measured, along with the effects on growth, and adsorption and uptake of Cu. Growth of strain LIA, from a pristine site in Scotland, was inhibited to a greater extent, and at lower concentrations, than that of Es524, isolated from a Cu-contaminated site in Chile. Concentrations of intra-cellular Cu were higher and the exchangeable fraction was lower in LIA than Es524, especially at the highest exposure levels. Total glutathione concentrations increased in both strains with Cu exposure, whereas total PCs levels were higher in Es524 than LIA; PC2 and PC3 were detected in Es524 but PC2 only was found in LIA. The greater production and levels of polymerisation of PCs in Es524 can be explained by the up-regulation of genes encoding for key enzymes involved in the synthesis of PCs. In Es524 there was an increase in the transcripts of gamma-GCS, GS and PCS, particularly under high Cu exposure, whereas in LIA4 transcripts of gamma-GCS1 increased only slightly, gamma-GCS2 and GS decreased and PCS did not change. The consequences of higher intra-cellular concentrations of Cu, lower production of PCs, and lower expression of enzymes involved in GSH-PCs synthesis may be contributing to an induced oxidative stress condition in LIA, which explains, at least in part, the observed sensitivity of LIA to Cu. Therefore, responses to Cu exposure in E. siliculosus relate to the contamination histories of the locations from where the strains were isolated and differences in Cu exclusion and PCs production are in part responsible for the development of intra-specific resistance. PMID- 25546005 TI - The cytotoxic mechanism of karlotoxin 2 (KmTx 2) from Karlodinium veneficum (Dinophyceae). AB - This study demonstrates that the polyketide toxin karlotoxin 2 (KmTx 2) produced by Karlodinium veneficum, a dinoflagellate associated with fish kills in temperate estuaries world-wide, alters vertebrate cell membrane permeability. Microfluorimetric and electrophysiological measurements were used to determine that vertebrate cellular toxicity occurs through non-selective permeabilization of plasma membranes, leading to osmotic cell lysis. Previous studies showed that KmTx 2 is lethal to fish at naturally-occurring concentrations measured during fish kills, while sub-lethal doses severely damage gill epithelia. This study provides a mechanistic explanation for the association between K. veneficum blooms and fish kills that has long been observed in temperate estuaries worldwide. PMID- 25546006 TI - Expression and function of ryanodine receptor related pathways in PCB tolerant Atlantic killifish (Fundulus heteroclitus) from New Bedford Harbor, MA, USA. AB - Atlantic killifish (Fundulus heteroclitus) thrive in New Bedford Harbor (NBH), MA, highly contaminated with polychlorinated biphenyls (PCBs). Resident killifish have evolved tolerance to dioxin-like (DL) PCBs, whose toxic effects through the aryl hydrocarbon receptor (AhR) are well studied. In NBH, non-dioxin like PCBs (NDL PCBs), which lack activity toward the AhR, vastly exceed levels of DL congeners yet how killifish counter NDL toxic effects has not been explored. In mammals and fish, NDL PCBs are potent activators of ryanodine receptors (RyR), Ca(2+) release channels necessary for a vast array of physiological processes. In the current study we compared the expression and function of RyR related pathways in NBH killifish with killifish from the reference site at Scorton Creek (SC, MA). Relative to the SC fish, adults from NBH displayed increased levels of skeletal muscle RyR1 protein, and increased levels of FK506-binding protein 12 kDa (FKBP12) an accessory protein essential for NDL PCB-triggered changes in RyR channel function. In accordance with increased RyR1 levels, NBH killifish displayed increased maximal ligand binding, increased maximal response to Ca(2+) activation and increased maximal response to activation by the NDL PCB congener PCB 95. Compared to SC, NBH embryos and larvae had increased levels of mtor and ryr2 transcripts at multiple stages of development, and generations, while levels of serca2 were decreased at 9 days post-fertilization in the F1 and F2 generations. These findings suggest that there are compensatory and heritable changes in RyR mediated Ca(2+) signaling proteins or potential signaling partners in NBH killifish. PMID- 25546008 TI - Timing matters: sensitivity of Daphnia magna dormant eggs to fenoxycarb exposure depends on embryonic developmental stage. AB - Although Daphnia magna is a key species in many lentic freshwater ecosystems and is commonly used as model organism in ecology and ecotoxicology, very little is known about the effects of chemicals on their dormant life stages. Dormant eggs (ephippia) are produced when environmental conditions deteriorate, and Daphnia switch from clonal to sexual reproduction. Ephippia produced over different growing seasons can accumulate in the sediment of ponds and lakes, where they can be exposed to pesticides and other (anthropogenic) stressors. In the present study, we have investigated the effects of pesticide exposure on dormant eggs at different embryonic developmental stages and evaluated the degree of protection against pollution provided by the ephippial case. We therefore conducted a hatching experiment in which decapsulated and encapsulated dormant eggs were exposed to an insect growth regulator (fenoxycarb) at different stages during their development, both before and after activation of the eggs. In addition, we developed an analytical method to measure fenoxycarb concentrations in the dormant eggs. Fenoxycarb negatively affected development and hatching success and changed the timing of hatching in activated and in dormant eggs. Hatching characteristics as well as fenoxycarb concentrations inside the eggs differed significantly between exposure treatments. Final stages of embryonic development were most sensitive to pesticide exposure and had the highest tissue concentrations of fenoxycarb. Tissue concentrations did not differ significantly between decapsulated and encapsulated eggs, suggesting that the ephippial case offers limited or no direct protection against pesticide exposure. With this study we provide new evidence showing that pesticides can bioconcentrate in and affect D. magna dormant eggs. The severity of the effects on developing embryos depends on the timing of pesticide exposure. Our results stress the importance of considering the full life-cycle of model organisms used in ecotoxicological studies, since these are ultimately aimed at assessing risks of chemical exposure on natural aquatic ecosystems. PMID- 25546010 TI - Evolution of risk-taking during conspicuous mating displays. AB - In many species, males possess conspicuous characteristics to attract females. These traits often attract predators as well, and males thus may have to balance the conspicuousness of their signals in relation to the prevailing predation risk. Here we develop a theoretical model of optimal signaling and risk-taking behavior for males differing in the attractiveness of their signals. All else being equal, more attractive males should behave more cautiously. Yet this prediction may drastically change if males differ in any additional characteristic, especially if basal mortality rate or signaling costs are higher or if the vulnerability to predators is lower for attractive males. A key insight from our model is that male competition will create a positive feedback so that selection on male risk-taking strategies is acting in opposite directions. If selection acts on one male type to behave more cautiously, this will strengthen selection on males of the other types to take higher risks and vice versa. Our results further demonstrate that the asset-protection principle, which states that individuals with higher future expectations should behave more cautiously, may often be violated. We also offer an alternative to the handicap principle explaining the often found positive association between male ornamentation and viability: attractive males may simply behave more cautiously. PMID- 25546009 TI - Signalling Through Retinoic Acid Receptors is Required for Reprogramming of Both Mouse Embryonic Fibroblast Cells and Epiblast Stem Cells to Induced Pluripotent Stem Cells. AB - We previously demonstrated that coexpressing retinoic acid (RA) receptor gamma and liver receptor homolog-1 (LRH1 or NR5A2) with OCT4, MYC, KLF4, and SOX2 (4F) rapidly reprograms mouse embryonic fibroblast cells (MEFs) into induced pluripotent stem cells (iPSCs). Here, we further explore the role of RA in reprogramming and report that the six factors (6F) efficiently and directly reprogram MEFs into integration-free iPSCs in defined medium (N2B27) in the absence of feeder cells. Through genetic and chemical approaches, we find that RA signalling is essential, in a highly dose-sensitive manner, for MEF reprogramming. The removal of exogenous RA from N2B27, the inhibition of endogenous RA synthesis or the expression of a dominant-negative form of RARA severely impedes reprogramming. By contrast, supplementing N2B27 with various retinoids substantially boosts reprogramming. In addition, when coexpressed with LRH1, RA receptors (RARs) can promote reprogramming in the absence of both exogenous and endogenously synthesized RA. Remarkably, the reprogramming of epiblast stem cells into embryonic stem cell-like cells also requires low levels of RA, which can modulate Wnt signalling through physical interactions of RARs with beta-catenin. These results highlight the important functions of RA signalling in reprogramming somatic cells and primed stem cells to naive pluripotency. Stem Cells 2015;33:1390-1404. PMID- 25546011 TI - Surgically placed abdominal wall catheters on postoperative analgesia and outcomes after living liver donation. AB - Living donor liver resections are associated with significant postoperative pain. Epidural analgesia is the gold standard for postoperative pain management, although it is often refused or contraindicated. Surgically placed abdominal wall catheters (AWCs) are a novel pain modality that can potentially provide pain relief for those patients who are unable to receive an epidural. A retrospective review was performed at a single center. Patients were categorized according to their postoperative pain modality: intravenous (IV) patient-controlled analgesia (PCA), AWCs with IV PCA, or patient-controlled epidural analgesia (PCEA). Pain scores, opioid consumption, and outcomes were compared for the first 3 postoperative days. Propensity score matches (PSMs) were performed to adjust for covariates and to confirm the primary analysis. The AWC group had significantly lower mean morphine-equivalent consumption on postoperative day 3 [18.1 mg, standard error (SE)=3.1 versus 28.2 mg, SE=3.0; P=0.02] and mean cumulative morphine-equivalent consumption (97.2 mg, SE=7.2 versus 121.0 mg, SE=9.1; P=0.04) in comparison with the IV PCA group; the difference in cumulative-morphine equivalent remained significant in the PSMs. AWC pain scores were higher than those in the PCEA group and were similar to the those in the IV PCA group. The AWC group had a lower incidence of pruritus and a shorter hospital stay in comparison with the PCEA group and had a lower incidence of sedation in comparison with both groups. Time to ambulation, nausea, and vomiting were comparable among all 3 groups. The PSMs confirmed all results except for a decrease in the length of stay in comparison with PCEA. AWCs may be an alternative to epidural analgesia after living donor liver resections. Randomized trials are needed to verify the benefits of AWCs, including the safety and adverse effects. PMID- 25546012 TI - Thermodynamics of ice nucleation in liquid water. AB - We present a density functional theory approach to investigate the thermodynamics of ice nucleation in supercooled water. Within the theoretical framework, the free-energy functional is constructed by the direct correlation function of oxygen-oxygen of the equilibrium water, and the function is derived from the reference interaction site model in consideration of the interactions of hydrogen hydrogen, hydrogen-oxygen, and oxygen-oxygen. The equilibrium properties, including vapor-liquid and liquid-solid phase equilibria, local structure of hexagonal ice crystal, and interfacial structure and tension of water-ice are calculated in advance to examine the basis for the theory. The predicted phase equilibria and the water-ice surface tension are in good agreement with the experimental data. In particular, the critical nucleus radius and free-energy barrier during ice nucleation are predicted. The critical radius is similar to the simulation value, suggesting that the current theoretical approach is suitable in describing the thermodynamic properties of ice crystallization. PMID- 25546014 TI - Necrotizing dacryometaplasia: a rare lacrimal lesion mimicking malignancy. PMID- 25546013 TI - An HIV-1 envelope immunogen with W427S mutation in CD4 binding site induced more T follicular helper memory cells and reduced non-specific antibody responses. AB - The CD4 binding site (CD4BS) of the HIV-1 envelope glycoprotein (Env) contains epitopes for broadly neutralizing antibody (nAb) and is the target for the vaccine development. However, the CD4BS core including residues 425-430 overlaps the B cell superantigen site and may be related to B cell exhaustion in HIV-1 infection. Furthermore, production of nAb and high-affinity plasma cells needs germinal center reaction and the help of T follicular helper (Tfh) cells. We believe that strengthening the ability of Env CD4BS in inducing Tfh response and decreasing the effects of the superantigen are the strategies for eliciting nAb and development of HIV-1 vaccine. We constructed a gp120 mutant W427S of an HIV-1 primary R5 strain and examined its ability in the elicitation of Ab and the production of Tfh by immunization of BALB/c mice. We found that the trimeric wild type gp120 can induce more non-specific antibody-secreting plasma cells, higher serum IgG secretion, and more Tfh cells by splenocyte. The modified W427S gp120 elicits higher levels of specific binding antibodies as well as nAbs though it produces less Tfh cells. Furthermore, higher Tfh cell frequency does not correlate to the specific binding Abs or nAbs indicating that the wild-type gp120 induced some non-specific Tfh that did not contribute to the production of specific Abs. This gp120 mutant led to more memory Tfh production, especially, the effector memory Tfh cells. Taken together, W427S gp120 could induce higher level of specific binding and neutralizing Ab production that may be associated with the reduction of non-specific Tfh but strengthening of the memory Tfh. PMID- 25546015 TI - Differences in human cortical gene expression match the temporal properties of large-scale functional networks. AB - We explore the relationships between the cortex functional organization and genetic expression (as provided by the Allen Human Brain Atlas). Previous work suggests that functional cortical networks (resting state and task based) are organized as two large networks (differentiated by their preferred information processing mode) shaped like two rings. The first ring--Visual-Sensorimotor Auditory (VSA)--comprises visual, auditory, somatosensory, and motor cortices that process real time world interactions. The second ring--Parieto-Temporo Frontal (PTF)--comprises parietal, temporal, and frontal regions with networks dedicated to cognitive functions, emotions, biological needs, and internally driven rhythms. We found--with correspondence analysis--that the patterns of expression of the 938 genes most differentially expressed across the cortex organized the cortex into two sets of regions that match the two rings. We confirmed this result using discriminant correspondence analysis by showing that the genetic profiles of cortical regions can reliably predict to what ring these regions belong. We found that several of the proteins--coded by genes that most differentiate the rings--were involved in neuronal information processing such as ionic channels and neurotransmitter release. The systematic study of families of genes revealed specific proteins within families preferentially expressed in each ring. The results showed strong congruence between the preferential expression of subsets of genes, temporal properties of the proteins they code, and the preferred processing modes of the rings. Ionic channels and release-related proteins more expressed in the VSA ring favor temporal precision of fast evoked neural transmission (Sodium channels SCNA1, SCNB1 potassium channel KCNA1, calcium channel CACNA2D2, Synaptotagmin SYT2, Complexin CPLX1, Synaptobrevin VAMP1). Conversely, genes expressed in the PTF ring favor slower, sustained, or rhythmic activation (Sodium channels SCNA3, SCNB3, SCN9A potassium channels KCNF1, KCNG1) and facilitate spontaneous transmitter release (calcium channel CACNA1H, Synaptotagmins SYT5, Complexin CPLX3, and synaptobrevin VAMP2). PMID- 25546016 TI - Improvement of IFNg ELISPOT Performance Following Overnight Resting of Frozen PBMC Samples Confirmed Through Rigorous Statistical Analysis. AB - Immune monitoring of functional responses is a fundamental parameter to establish correlates of protection in clinical trials evaluating vaccines and therapies to boost antigen-specific responses. The IFNg ELISPOT assay is a well-standardized and validated method for the determination of functional IFNg-producing T-cells in peripheral blood mononuclear cells (PBMC); however, its performance greatly depends on the quality and integrity of the cryopreserved PBMC. Here, we investigate the effect of overnight (ON) resting of the PBMC on the detection of CD8-restricted peptide-specific responses by IFNg ELISPOT. The study used PBMC from healthy donors to evaluate the CD8 T-cell response to five pooled or individual HLA-A2 viral peptides. The results were analyzed using a modification of the existing distribution free resampling (DFR) recommended for the analysis of ELISPOT data to ensure the most rigorous possible standard of significance. The results of the study demonstrate that ON resting of PBMC samples prior to IFNg ELISPOT increases both the magnitude and the statistical significance of the responses. In addition, a comparison of the results with a 13-day preculture of PBMC with the peptides before testing demonstrates that ON resting is sufficient for the efficient evaluation of immune functioning. PMID- 25546017 TI - Glottic cancer in patients without complaints of hoarseness. AB - BACKGROUND: Few studies have investigated the clinical characteristics of patients with glottic cancer without hoarseness. METHODS: This retrospective clinical study investigated 371 patients with glottic cancer. RESULTS: Thirty-two of the 371 patients (8.6%) with glottic cancer first presented to hospitals with complaints other than hoarseness. Although proportions of stage I and T1 disease were significantly higher among patients without hoarseness than among those with hoarseness (p = .0036 and p = .0004, respectively), survival curves showed no significant differences between groups (p = .1334). CONCLUSION: Patients with glottic cancer without complaints of hoarseness were diagnosed at an earlier stage than those with hoarseness. Accumulation of more cases may lead to better survival of patients with glottic cancer without hoarseness compared to those with hoarseness. Checking the larynx of patients without hoarseness or encouraging internists to check the larynx when performing gastroscopic or respiratory examinations may lead to improvement of glottic cancer prognosis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E316-E320, 2016. PMID- 25546018 TI - Live cell imaging of the nascent inactive X chromosome during the early differentiation process of naive ES cells towards epiblast stem cells. AB - Random X-chromosome inactivation ensures dosage compensation in mammals through the transcriptional silencing of one of the two X chromosomes present in each female cell. Silencing is initiated in the differentiating epiblast of the mouse female embryos through coating of the nascent inactive X chromosome by the non coding RNA Xist, which subsequently recruits the Polycomb Complex PRC2 leading to histone H3-K27 methylation. Here we examined in mouse ES cells the early steps of the transition from naive ES cells towards epiblast stem cells as a model for inducing X chromosome inactivation in vitro. We show that these conditions efficiently induce random XCI. Importantly, in a transient phase of this differentiation pathway, both X chromosomes are coated with Xist RNA in up to 15% of the XX cells. In an attempt to determine the dynamics of this process, we designed a strategy aimed at visualizing the nascent inactive X-chromosome in live cells. We generated transgenic female XX ES cells expressing the PRC2 component Ezh2 fused to the fluorescent protein Venus. The fluorescent fusion protein was expressed at sub-physiological levels and located in nuclei of ES cells. Upon differentiation of ES cell towards epiblast stem cell fate, Venus fluorescent territories appearing in interphase nuclei were identified as nascent inactive X chromosomes by their association with Xist RNA. Imaging of Ezh2-Venus for up to 24 hours during the differentiation process showed survival of some cells with two fluorescent domains and a surprising dynamics of the fluorescent territories across cell division and in the course of the differentiation process. Our data reveal a strategy for visualizing the nascent inactive X chromosome and suggests the possibility for a large plasticity of the nascent inactive X chromosome. PMID- 25546019 TI - Battle of the hemichannels--Connexins and Pannexins in ischemic brain injury. AB - Perinatal ischemic brain injury can occur as a result of a global ischemic insult or focal ischemic stroke in the preterm or full-term neonate. One of the most striking features of HI injury is that, after initial recovery of cellular oxidative metabolism, there is a delayed, 'secondary' mitochondrial failure that spreads over time from the most severely damaged areas outwards, into previously undamaged regions. This secondary failure is accompanied by transient seizure activity and cytotoxic edema. The specific mechanisms of this spread are poorly understood, but it is at least partly associated with spreading waves of depression that can trigger cell death in neighboring uninjured tissues. Both Connexin and Pannexin hemichannels may mediate release of paracrine molecules that in turn propagate cell death messages by releasing intracellular mediators, such as ATP, NAD(+), or glutamate or by abnormally prolonged opening to allow cell edema. This review will discuss the controversy around the relative contribution of both Connexin and Pannexin hemichannels and mechanisms by which they may contribute to the spread of ischemic brain injury. PMID- 25546020 TI - Ruthenium polypyridyl TG6 dye for the sensitization of nanoparticle and nanocrystallite spherical aggregate photoelectrodes. AB - A ruthenium polypyridyl dye containing a hexasulfanyl-styryl modified bipyridyl group as ancillary ligand, coded TG6, is investigated as a sensitizer for ZnO based dye-sensitized solar cells (DSSCs). The advantages of this dye are a broad wavelength absorption spectrum, a large loading in ZnO photoelectrodes, a significantly larger extinction coefficient compared to more classical Ru polypyridyl dyes, and the formation of less agglomerate in the pores of the ZnO layers. TG6 has been used to sensitize ZnO nanorod particle layers of high structural quality and ZnO layers made of submicrometer spheres composed of aggregated nanocrystallites and that develop an internal surface area. The latter are highly light-scattering in the visible wavelength region but more difficult to sensitize correctly. The TG6 dye has been compared with the metal-free D149 dye and has been shown more efficient for photoconversion. The best performances have been obtained by combining TG6 with the nanorod layer, the optimal power conversion efficiency being measured at 5.30% in that case. The cells have been investigated by impedance spectroscopy over a large applied voltage range. We especially show that the submicrometer sphere layers exhibit lower conductivity and lower charge collection efficiency as compared to the nanorod particle ones. PMID- 25546021 TI - Spatial attentional control is not impaired in schizophrenia: Dissociating specific deficits from generalized impairments. AB - A large literature has established that people with schizophrenia are impaired on tasks that require attentional control. However, evidence is mixed as to whether these impairments are specific deficits (Oltmanns & Neale, 1975) or merely reflect a generalized impairment (Dickinson & Harvey, 2009). Recent evidence also suggests visual attentional control for encoding into working memory may be selectively spared in people with schizophrenia (Gold et al., 2006). The current study used a cued backward masking task to investigate 23 people with schizophrenia and 27 healthy controls. People with schizophrenia were hypothesized to perform better on invalidly cued trials when making a simple identification or location judgment. However, we found schizophrenia impaired performance on both valid and invalid cues to the same degree whether the cue was a stored representation (top-down) or presented at the location of the stimulus (bottom-up). In contrast to a large neuropsychological literature, these findings suggest that people with schizophrenia show no specific spatial attentional control deficit. The errors that they make on such task may be consistent with a generalized impairment. PMID- 25546022 TI - Fate of flame retardants and the antimicrobial agent triclosan in planted and unplanted biosolid-amended soils. AB - A comprehensive understanding of the fate of contaminant-laden biosolids is needed to fully evaluate the environmental impacts of biosolid land application. The present study examined the fate of several flame retardants and triclosan in biosolid-amended soil in a 90-d greenhouse experiment. Objectives included evaluating the persistence of these compounds in soil, their phytoaccumulation potential by alfalfa (Medicago sativa), and potential degradation reactions. Concentrations of the polybrominated diphenyl ether (PBDE) congeners BDE-47 and BDE-209 and the antimicrobial triclosan declined significantly over time in biosolid-amended soil planted with alfalfa and then reached a steady state by day 28. In contrast, no significant losses of those analytes were observed from soil in nonvegetated pots. The amount of an analyte lost from vegetated soil ranged from 43% for the flame retardant di(2-ethylhexyl)-2,3,4,5-tetrabromophthalate to 61% for triclosan and was significantly and negatively related to the log octanol water partition coefficient. Alfalfa roots and shoots were monitored for the compounds, but no clear evidence of phytoaccumulation was observed. Methyl triclosan formation was observed in the biosolid-amended soils during the study period, indicating in situ biotransformation of triclosan. The present study demonstrates that, although they are highly recalcitrant, PBDEs, selected alternate brominated flame retardants, and triclosan are capable of undergoing dissipation from biosolid-amended soils in the presence of plants. PMID- 25546023 TI - Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors. AB - Angiotensin converting enzyme (ACE) inhibitors are the mainstay of treatment for diabetic nephropathy to slow progression of disease. Diabetic women of childbearing age with nephropathy should be treated with ACE inhibitors as per guidelines in the pre-pregnancy period. ACE inhibitor use and exposure in the first trimester is controversial and requires counselling pre-pregnancy regarding the risks and benefits of use up to the first trimester, as well as the need to stop ACE inhibitors prior to the second trimester. Current evidence does not suggest that ACE inhibitors in the first trimester are associated with a greater risk of fetal malformations when compared to other antihypertensives. This topic is reviewed in depth, along with blood pressure targets in pregnant women with diabetic proteinuric disease, evidence for prevention of pre-eclampsia, self monitoring of blood pressures at home in the latter half of pregnancy and the signs and symptoms of pre-eclampsia, proteinuria evolution in pregnancy, renal function prognosis, and restarting ACE inhibitors when breast feeding in the post partum period. PMID- 25546024 TI - Risk of microalbuminuria in relatives of subjects with diabetic nephropathy: a predictive model based on multivariable dimensionality reduction approach. AB - AIM: To evaluate a predictive model of microalbuminuria by using anthropometric, clinical and genetic variables in relatives of subjects with diabetic nephropathy. METHODS: Eligible subjects, aged 18-63 years with body mass index<35 kg/m2, and first degree relatives of patients with type 2 diabetes and diabetic nephropathy were enrolled in a cross-sectional study. A total of 70 individuals with microalbuminuria were compared with 60 individuals without microalbuminuria. Based on a morning urinary sample, microalbuminuria was defined as albumin>=30<300 mg/dL. Genotyping of single nucleotide polymorphisms (SNPs) G 174C of IL6 (rs1800795), G-308A of TNF (rs1800629), and Pro12Ala of PPARI32 (rs1801282) genes were determined. The multivariable dimensionality reduction analysis was performed using the software multifactor dimensionality reduction package. RESULTS: The multivariable dimensionality reduction analysis showed that obesity and SNP G-308A of TNF gene exhibited main effects with 1.10 and 1.98% of information gain (IG), respectively. The IL6 showed synergy (interaction) with HDL-c (IG 1.27%) and sex (IG 1.02%); also high-sensitivity C-reactive protein and triglycerides levels showed synergy (IG 1.08%). The consistency of the cross validation for this model was 0.6836, with sensitivity and specificity of 0.58 and 0.76 (odds ratio 4.64; 95% CI 4.0-10.0, p<0.0001). CONCLUSION: Our results indicate that obesity and/or high blood pressure, in synergism with high sensitivity C-reactive protein and high-density lipoprotein cholesterol levels, is the main predictive risk factor of diabetic nephropathy in healthy subjects, relatives of patients with type 2 diabetes and diabetic nephropathy. PMID- 25546025 TI - Impact of overnight oximetry findings on cardiac autonomic modulation in women during second trimester of uncomplicated pregnancy. AB - AIM: Although sleep-disordered breathing (SDB) might impose an underlying health threat upon some pregnant women, the influence of SDB on the health status of most pregnant women is not discernible. In order to find out which pregnant women should be evaluated for clinically meaningful SDB during the second trimester, the present study aimed to determine which overnight oximetry findings significantly affect maternal resting cardiac autonomic modulations. MATERIAL AND METHODS: Overnight arterial oxygen saturation (SaO2 ) was monitored at home using pulse oximetry by 64 women with uncomplicated pregnancy between 24 and 28 weeks of gestation. We then determined the impact of the findings on maternal resting heart rate variability (HRV) using 5-min photoplethysmography. RESULTS: A relatively increased oxygen desaturation index (number of oxygen desaturation events where SaO2 fell >3% below the baseline saturation/h) of >=3.0 in five women did not significantly impact HRV. On the other hand, events associated with profound oxygen desaturation (minimum SaO2 <= 90%) in three women were associated with decreased HRV, including high- and low-frequency powers. CONCLUSION: Parasympathetic activities of cardiac autonomic modulations might be attenuated in women who experience profound night-time oxygen desaturation, even if the incidence of significant events is quite low. The oximetry finding of minimum SaO2 <= 90% might be a valuable criterion for clinically meaningful sleep-disordered breathing among women with early uncomplicated pregnancy. PMID- 25546026 TI - Laparoscopic pancreatic reconstruction technique following laparoscopic pancreaticoduodenectomy. AB - With the advance of laparoscopic experiences and techniques, it is carefully regarded that laparoscopic pancreaticoduodenectomy (lap-PD) is feasible and safe in managing perimapullary pancreatic pathology. Especially, laparoscopic management of remnant pancreas can be a critical step toward completeness of minimally invasive PD. According to available published reports, there is a wide range of technical differences in choosing surgical options in managing remnant pancreas after lap-PD. For the evidence-based surgical approach, it would be ideal to test potential techniques by randomized controlled trials, but, currently, it is thought to be very difficult to expect those clinical trials to be successful because there are still a lack of expert surgeons with sound surgical techniques and experience. In addition, lap-PD is so complicated and technically demanding that many surgeons are still questioning whether this surgical approach could be standardized and popular like laparoscopic cholecystectomy. In general, surgical options are usually chosen based on following question: (1) Is it simple? (2) Is it easy and feasible? (3) Is it secure and safe? (4) Is there any supporting scientific evidence? It would be interesting to estimate which surgical technique would be appropriate in managing remnant pancreas under these considerations. It is hoped that a well standardized multicenter-based randomized control study would be successful to test this fundamental issues based on sound surgical techniques and scientific background. PMID- 25546027 TI - Bio-analytical method based on MALDI-MS analysis for the quantification of CIGB 300 anti-tumor peptide in human plasma. AB - A fully validated bio-analytical method based on Matrix-Assisted-Laser Desorption/Ionization-Time of Flight Mass Spectrometry was developed for quantitation in human plasma of the anti-tumor peptide CIGB-300. An analog of this peptide acetylated at the N-terminal, was used as internal standard for absolute quantitation. Acid treatment allowed efficient precipitation of plasma proteins as well as high recovery (approximately 80%) of the intact peptide. No other chromatographic step was required for sample processing before MALDI-MS analysis. Spectra were acquired in linear positive ion mode to ensure maximum sensitivity. The lower limit of quantitation was established at 0.5 MUg/mL, which is equivalent to 160 fmol peptide. The calibration curve was linear from 0.5 to 7.5 MUg/mL, with R(2)>0.98, and permitted quantitation of highly concentrated samples evaluated by dilution integrity testing. All parameters assessed for five validation batches met the FDA guidelines for industry. The method was successfully applied to analysis of clinical samples obtained in a phase I clinical trial following intravenous administration of CIGB-300 at a dose of 1.6 mg/kg body weight. With the exception of Cmax and AUC, pharmacokinetic parameters were similar for ELISA and MALDI-MS methods. PMID- 25546028 TI - Isolation and characterization of the alkaloid Nitidine responsible for the traditional use of Phyllanthus muellerianus (Kuntze) Excell stem bark against bacterial infections. AB - Phyllanthus muellerianus (Kuntze) Excell (family Euphorbiaceae) stem bark methanol extract inhibited the growth of Clostridium sporogenes and Streptococcus pyogenes, responsible for gas gangrene and suppurative and non suppurative diseases, respectively. After the HPLC fingerprint acquisition a bioguided fractionation of the defatted methanol extract allowed the isolation of six fractions whose activity was evaluated against the two pathogen bacteria. A further purification of the most active fraction afforded a pure compound responsible for the very interesting inhibitory activity against C. sporogenes and S. pyogenes (MIC 0.91 MUM, MIC 3.64 MUM). (1)H NMR and MS analytical techniques allowed the identification of the bioactive as Nitidine; this quaternary ammonium alkaloid was observed in the genus Phyllanthus for the first time. A study on Nitidine counter ion, performed using energy dispersive spectroscopy (EDS) coupled with scanning electron microscopy (SEM) was also carried out. PMID- 25546029 TI - Adjusting for time-dependent sensitivity in an illness-death model, with application to mother-to-child transmission of HIV. AB - In mother-to-child transmission of HIV, identifying infected infants relies on a diagnostic test with imperfect sensitivity that is administered at scheduled visits. Under this scenario, a participant's true state may be unknown at the start and end times of the study, and the detection of transitions into illness may be delayed or missed altogether. This could lead to biased estimates of the risk of transmission and covariate associations. When a test has imperfect sensitivity, but perfect specificity, the additional uncertainty can be captured as a random variable measuring delay in detection. The cumulative distribution then defines a time-dependent sensitivity function that increases over time. We present a maximum likelihood based illness-death model that accounts for imperfect sensitivity by including the delay as an exponential distribution. We specify transition rates as penalized B-splines to allow for nonhomogeneity of risk and discuss the model under Markov and semi-Markov assumptions. We apply this method to our motivating data set, a study of 1499 mother and infant pairs at three sites in Africa. PMID- 25546030 TI - Effect of input compression and input frequency response on music perception in cochlear implant users. AB - OBJECTIVE: A study was conducted to determine whether modifications to input compression and input frequency response characteristics can improve music listening satisfaction in cochlear implant users. DESIGN: Experiment 1 compared three pre-processed versions of music and speech stimuli in a laboratory setting: original, compressed, and flattened frequency response. Music excerpts comprised three music genres (classical, country, and jazz), and a running speech excerpt was compared. Experiment 2 implemented a flattened input frequency response in the speech processor program. In a take-home trial, participants compared unaltered and flattened frequency responses. STUDY SAMPLE: Ten and twelve adult Nucleus Freedom cochlear implant users participated in Experiments 1 and 2, respectively. RESULTS: Experiment 1 revealed a significant preference for music stimuli with a flattened frequency response compared to both original and compressed stimuli, whereas there was a significant preference for the original (rising) frequency response for speech stimuli. Experiment 2 revealed no significant mean preference for the flattened frequency response, with 9 of 11 subjects preferring the rising frequency response. CONCLUSIONS: Input compression did not alter music enjoyment. Comparison of the two experiments indicated that individual frequency response preferences may depend on the genre or familiarity, and particularly whether the music contained lyrics. PMID- 25546031 TI - Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. AB - OBJECTIVE: In patients suffering multiple sclerosis activity despite treatment with interferon beta or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents. METHODS: Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. RESULTS: Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p < 0.001). INTERPRETATION: This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden. PMID- 25546033 TI - Surgical task shifting in Sierra Leone: a controversial attempt to reduce maternal mortality. PMID- 25546034 TI - Childbed fever: history repeats itself? PMID- 25546035 TI - Anaemia, pregnancy, and maternal mortality: the problem with globally standardised haemoglobin cutoffs. PMID- 25546036 TI - Anaemia in pregnancy--a renewed focus needed. PMID- 25546037 TI - A systematic review of essential obstetric and newborn care capacity building in rural sub-Saharan Africa. AB - BACKGROUND: Progress in maternal survival in sub-Saharan Africa has been poor since the Millennium Declaration. OBJECTIVES: This systematic review aims to investigate the presence and rigour of evidence for effective capacity building for Essential Obstetric and Newborn Care (EONC) to reduce maternal mortality in rural, sub-Saharan Africa, where maternal mortality ratios are highest globally. SEARCH STRATEGY: MEDLINE (1990-January 2014), EMBASE (1990-January 2014), and the Cochrane Library were included in our search. Key developing world issues of The Lancet and the British Journal of Obstetrics and Gynaecology, African Ministry of Health websites, and the WHO reproductive health library were searched by hand. SELECTION CRITERIA: Studies investigating essential obstetric and newborn care packages in basic and comprehensive care facilities, at community and institutional level, in rural sub-Saharan Africa were included. Studies were included if they reported on healthcare worker performance, access to care, community behavioural change, and emergency obstetric and newborn care. DATA COLLECTION AND ANALYSIS: Data were extracted and all relevant studies independently appraised using structured abstraction and appraisal tools. MAIN RESULTS: There is moderate evidence to support the training of healthcare workers of differing cadres in the provision of emergency obstetric and newborn services to reduce institutional maternal mortality and case-fatality rates in rural sub Saharan Africa. Community schemes that sensitise and enable access to maternal health services result in a modest rise in facility birth and skilled birth attendance in this rural setting. AUTHORS' CONCLUSION: Essential Obstetric and Newborn Care has merit as an intervention package to reduce maternal mortality in rural sub-Saharan Africa. PMID- 25546038 TI - She did the right thing: the high price of poor access to obstetric care. PMID- 25546032 TI - Ankle-brachial index and inter-artery blood pressure differences as predictors of cognitive function in overweight and obese older adults with diabetes: results from the Action for Health in Diabetes movement and memory study. AB - OBJECTIVE: Ankle-brachial index (ABI) and interartery systolic blood pressure differences, as markers of vascular disease, are plausible risk factors for deficits in cognitive function among overweight and obese adults with type 2 diabetes. METHODS: The ABI and maximum interartery differences (MIAD) in systolic blood pressures were assessed annually for five years among 479 participants assigned to the control condition in a randomized clinical trial of a behavioral weight loss intervention. A battery of standardized cognitive function tests was administered 4 to 5 years later. Analyses of covariance were used to assess relationships that ABI, MIAD, and progression of ABI and MIAD had with cognitive function. RESULTS: There was a curvilinear relationship between ABI and a composite index of cognitive function (p = 0.03), with lower ABI being associated with poorer function. In graded fashions, both greater MIAD and increases in MIAD over time also had modest relationships with poorer verbal memory (both p <= 0.05), processing speed (both p <= 0.05), and composite cognitive function (both p < 0.04). These relationships were independent of each other and remained evident after extensive covariate adjustment. CONCLUSIONS: In overweight and obese adults with type 2 diabetes, lower ABI and larger interartery systolic blood pressure differences have modest, independent, graded relationships with poorer cognitive function 4-5 years later. PMID- 25546039 TI - The global met need for emergency obstetric care: a systematic review. AB - BACKGROUND: Of the 287,000 maternal deaths every year, 99% happen in low- and middle-income countries. The vast majority could be averted with timely access to appropriate emergency obstetric care (EmOC). The proportion of women with complications of pregnancy or childbirth who actually receive treatment is reported as 'Met need for EmOC'. OBJECTIVE: To estimate the global met need for EmOC and to examine the correlation between met need, maternal mortality ratio and other indicators. SEARCH STRATEGY: A systematic review was performed according to the PRISMA guidelines. Searches were made in PubMed, EMBASE and Google Scholar. SELECTION CRITERIA: Studies containing data on met need in EmOC were selected. DATA COLLECTION AND ANALYSIS: Analysis was performed with data extracted from 62 studies representing 51 countries. World Bank data were used for univariate and multiple linear regression. MAIN RESULTS: Global met need for EmOC was 45% (IQR: 28-57%), with significant disparity between low- (21% [12 31%]), middle- (32% [15-56%]), and high-income countries (99% [99-99%]), (P = 0.041). This corresponds to 11.4 million (8.8-14.8) untreated complications yearly and 951 million (645-1174 million) women without access to EmOC. We found an inverse correlation between met need and maternal mortality ratio (r = -0.42, P < 0.001). Met need was significantly correlated with the proportion of births attended by skilled birth attendants (beta = 0.53 [95% CI 0.41-0.65], P < 0.001). AUTHORS' CONCLUSIONS: The results suggest a considerable inadequacy in global met need for EmOC, with vast disparities between countries of different income levels. Met need is a powerful indicator of the response to maternal mortality and strategies to improve EmOC act in synergy with the expansion of skilled birth attendance. PMID- 25546040 TI - Global women's health: current clinical trials in low- and middle-income countries. AB - BACKGROUND: Clinical trials in low- and middle-income countries (LMICs) are necessary to develop evidence-based approaches to improve women's health. Understanding what research is currently being conducted will allow the identification of research gaps, avoidance of duplication, planning of future studies, collaboration amongst research groups, and geographical targeting for research investments. OBJECTIVES: To provide an overview of active women's health trials in LMICs. SEARCH STRATEGY: The World Health Organization's International Clinical Trials Registry Platform was searched for trials registered between 1 April 2012 and 31 March 2014. SELECTION CRITERIA: Selected trials were randomised, conducted in LMICs, active, and with a women's health intervention or a significant outcome for the woman. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data. Analysis included geographical spread, speciality areas, pre enrolment registration, study size, and funders. MAIN RESULTS: Of the 8966 records, 509 were eligible for inclusion. Gynaecology trials made up 57% of the research, whereas the remaining 43% of trials were in obstetrics. Research activity focused on fertility (17%), the antenatal period (15%), benign gynaecology (14%), intrapartum care (9%), and pre-invasive disease and cancers (8%). The majority of trials (84%) took place in middle-income countries (MICs). In low-income countries (LICs) 83% of research investigated obstetrics, and in MICs 60% of research investigated gynaecology. Most trials (80%) had a sample size of 500 or fewer participants. The median size of trials in LICs was 815 compared with 128 in MICs. Pre-enrolment registration occurred in 54% of trials. The majority (62%) of trials were funded locally. AUTHORS' CONCLUSIONS: Many LMICs are active in women's health research. The majority of registered trials are located in MICs; however, the trials in LICs are often larger. The focus of research in MICs may be driven by local priorities and funding, with fertility being highly researched. In LICs, pregnancy is the focus, perhaps reflecting the international prioritisation of maternal health. PMID- 25546041 TI - Women's health trials in developing countries: under-registration is the keyword? PMID- 25546042 TI - Reviewing current clinical trials in women's health raises questions about research priority-setting in low-income countries. PMID- 25546044 TI - Translating clinical management into an effective public health response for postpartum haemorrhage. PMID- 25546045 TI - Women's rights are integral to prevention and treatment of PPH. PMID- 25546046 TI - Reducing infection-related preterm birth. PMID- 25546047 TI - Surgically avertable burden of obstetric conditions in low- and middle-income regions: a modelled analysis. AB - OBJECTIVE: To quantify the burden of maternal and neonatal conditions in low- and middle-income countries (LMICs) that could be averted by full access to quality first-level obstetric surgical procedures. DESIGN: Burden of disease and epidemiological modelling. SETTING: LMICs from all global regions. POPULATION: The entire population in 2010. METHODS: We included five conditions in our analysis: maternal haemorrhage; obstructed labour; obstetric fistula; abortion(1) ; and neonatal encephalopathy. Demographic and epidemiological data were obtained from the Global Burden of Disease 2010 study. We split the disability-adjusted life years (DALYs) of these conditions into surgically 'avertable' and 'non avertable' burdens. We applied the lowest age-specific fatality rates from all global regions to each LMIC region to estimate the avertable deaths, assuming that the differences of death rates between each region and the lowest rates reflect the gap in surgical care. MAIN OUTCOME MEASURES: Deaths and DALYs avertable. RESULTS: Of the estimated 56.6 million DALYs (i.e. 56.6 million years of healthy life lost) of the selected five conditions, 21.1 million DALYs (37%) are avertable by full coverage of quality obstetric surgery in LMICs. The avertable burden in absolute term is substantial given the size of burden of these conditions in LMICs. Neonatal encephalopathy constitutes the largest portion of avertable burden (16.2 million DALYs) among the five conditions, followed by abortion (2.1 million DALYs). CONCLUSIONS: Improving access to quality surgical care at first-level hospitals could reduce a tremendous burden of maternal and neonatal conditions in LMICs. PMID- 25546048 TI - Is the enabling environment ready to address the surgically avertable burden of obstetric conditions in low- and middle-income regions? PMID- 25546049 TI - Global maternal health: from women's survival to respectful care. PMID- 25546050 TI - Shock index: an effective predictor of outcome in postpartum haemorrhage? AB - OBJECTIVES: To compare the predictive value of the shock index (SI) with conventional vital signs in postpartum haemorrhage (PPH), and to establish 'alert' thresholds for use in low-resource settings. DESIGN: Retrospective cohort study. SETTING: UK tertiary centre. POPULATION: Women with PPH >= 1500 ml (n = 233). METHODS: Systolic blood pressure (BP), diastolic BP, mean arterial pressure, pulse pressure, heart rate (HR) and SI (HR/systolic BP) were measured within the first hour following PPH. Values measured at the time of highest SI were selected for analysis. The area under the receiver operating characteristic curve (AUROC) for each parameter, used to predict admission to an intensive care unit and other adverse outcomes, was calculated. Sensitivity, specificity and negative/positive predictive values determined thresholds of the best predictor. MAIN OUTCOME MEASURES: Intensive care unit (ICU) admission, blood transfusion >= 4 iu, haemoglobin level <7 g/dl, and invasive surgical procedures. RESULTS: Shock index has the highest AUROC to predict ICU admissions (0.75 for SI [95% CI 0.63 0.87] compared with 0.64 [95% CI 0.44-0.83] for systolic BP). SI compared favourably for other outcomes: SI >= 0.9 had 100% sensitivity (95% CI 73.5-100) and 43.4% specificity (95% CI 36.8-50.3), and SI >= 1.7 had 25.0% sensitivity (95% CI 5.5-57.2) and 97.7% specificity (CI 94.8-99.3), for predicting ICU admission. CONCLUSIONS: Shock index compared favourably with conventional vital signs in predicting ICU admission and other outcomes in PPH, even after adjusting for confounding; SI <0.9 provides reassurance, whereas SI >= 1.7 indicates a need for urgent attention. In low-resource settings this simple parameter could improve outcomes. It was not possible to adjust for resuscitative measures administered following vital sign measurement that may have influenced the outcome. PMID- 25546052 TI - Effects of oxymetazoline on nasal flow and maximum aerobic exercise performance in patients with inferior turbinate hypertrophy. AB - OBJECTIVES/HYPOTHESIS: To determine the effect of topical intranasal oxymetazoline on nasal resistance and aerobic exercise performance in patients with nasal congestion caused by inferior turbinate hypertrophy. STUDY DESIGN: Individual randomized controlled trial. METHODS: Eight patients with inferior turbinate hypertrophy performed a set of exercise tests to exhaustion 1 week apart. They were given oxymetazoline or a placebo before each of the two test sessions according to a random pattern. Changes in nasal airflow were measured as peak nasal flow and ventilatory efficiency parameters, ventilatory equivalents, end-expiratory pressure, oxygen consumption, cardiac efficiency, rate of perceived exertion, and maximal and submaximal mechanical power. RESULTS: Ten minutes after use of the drug or placebo, improvements in maximum nasal airflow were seen in the oxymetazoline group (P < 0.05). However, exercise tests showed improvements in both groups (P < 0.05). After exertion, there was no difference between the two groups in maximum nasal airflow (P > 0.05). There were no differences between groups in oxygen consumption, rate of perceived exertion, respiratory exchange ratio, ventilation, or ventilatory equivalents for oxygen. CONCLUSION: Oxymetazoline increased nasal airflow in patients with turbinate hypertrophy, but this change did not translate into gains in physical exercise parameters or perceived exertion. LEVEL OF EVIDENCE: 1b. PMID- 25546053 TI - Discovery of kokumi peptide from yeast extract by LC-Q-TOF-MS/MS and sensomics approach. AB - BACKGROUND: Yeast extract can impart thickness, complexity and long-lasting taste impression, coined kokumi taste, to blank chicken broth. In this research, the kokumi-active peptide in yeast extract was discovered by ultrafiltration, liquid chromatographic and quadrupole-time-of-flight-tandem mass spectrometric technologies. Furthermore, the sensory characters of these peptides were evaluated by a sensomics approach. RESULTS: A total of 10 kokumi peptides were identified from yeast extract. They were gamma-Glu-Cys-Gly, gamma-Glu-Leu, gamma Glu-Val, gamma-Glu-Tyr, Leu-Lys, Leu-Gln, Leu-Ala, Leu-Glu, Leu-Thr and Ala-Leu. Apart from the well-known kokumi-active glutathione and gamma-glutamyl dipeptides, five leucyl dipeptides were first proposed having kokumi activity. Among them, Ala-Leu was found to have the highest kokumi threshold concentration (1.5 mmol L(-1) ) in the blank chicken broth, while Leu-Glu was the lowest (0.3 mmol L(-1) ). A subsequent dose-response experiment indicated that the bitter tasting leucyl dipeptides could impart kokumi taste to chicken broth at low concentrations (less than bitter threshold concentrations). Interestingly, the kokumi sensation began to decrease when such peptides exceeded the threshold concentration by approximately 16-fold in the blank chicken broth. CONCLUSION: Key kokumi-active fractions were purified from yeast extract. Among them, ten important kokumi peptides from yeast extract were identified. PMID- 25546054 TI - Application of a novel grey self-memory coupling model to forecast the incidence rates of two notifiable diseases in China: dysentery and gonorrhea. AB - OBJECTIVE: In this study, a novel grey self-memory coupling model was developed to forecast the incidence rates of two notifiable infectious diseases (dysentery and gonorrhea); the effectiveness and applicability of this model was assessed based on its ability to predict the epidemiological trend of infectious diseases in China. METHODS: The linear model, the conventional GM(1,1) model and the GM(1,1) model with self-memory principle (SMGM(1,1) model) were used to predict the incidence rates of the two notifiable infectious diseases based on statistical incidence data. Both simulation accuracy and prediction accuracy were assessed to compare the predictive performances of the three models. The best-fit model was applied to predict future incidence rates. RESULTS: Simulation results show that the SMGM(1,1) model can take full advantage of the systematic multi time historical data and possesses superior predictive performance compared with the linear model and the conventional GM(1,1) model. By applying the novel SMGM(1,1) model, we obtained the possible incidence rates of the two representative notifiable infectious diseases in China. CONCLUSION: The disadvantages of the conventional grey prediction model, such as sensitivity to initial value, can be overcome by the self-memory principle. The novel grey self memory coupling model can predict the incidence rates of infectious diseases more accurately than the conventional model, and may provide useful references for making decisions involving infectious disease prevention and control. PMID- 25546055 TI - Transcripts involved in steroid biosynthesis and steroid receptor signaling are expressed early in development in the fathead minnow (Pimephales promelas). AB - Sex differentiation in organisms is correlated to sex steroid production and receptor signaling pathways involving androgens and estrogens. Timing of expression is critical, and characterization of sensitive windows is needed to determine how environmental stressors may perturb sex differentiation. The objectives of this study were to determine whether genes related to steroid biosynthesis, steroid receptor signaling, and those related to sex differentiation were expressed in pre-differentiated fathead minnow (FHM) embryos, an ecotoxicological model. Transcripts were measured over two weeks (1 day post fertilization (dpf) to 14 days), prior to sex differentiation. The first three time points investigated (1, 3, and 5 dpf) corresponded to the neurula stage, dorsal swim bladder pigmentation, and pre-hatch. The fourth time point (6 dpf) was collected immediately post-hatch and the fifth time point investigated was after 8 days of larval growth (14 dpf). The majority of transcripts investigated, for example estrogen, androgen, and thyroid receptors as well as steroid biosynthesis transcripts, were expressed within the first 72 hours of development; exceptions were star (steroidogenic acute regulatory protein) and cyp19a, which did not have detectable expression until 5 dpf (pre-hatch). Transcripts that increased in relative mRNA abundance over the first two weeks of development included ar, dax1, hsd11b2, hsd17b, cyp19a and thra. This study demonstrates that there is early expression of transcripts related to steroid biosynthesis, steroid receptor signaling, and sex differentiation in pre-hatch FHM embryos. Additional studies are required to determine their relative roles in male and female differentiation during these early developmental periods. PMID- 25546056 TI - Micronutrient deficiencies and related factors in school-aged children in Ethiopia: a cross-sectional study in Libo Kemkem and Fogera districts, Amhara Regional State. AB - INTRODUCTION: The present study describes the distribution of selected micronutrients and anaemia among school-aged children living in Libo Kemkem and Fogera (Amhara State, Ethiopia), assessing differences by socio-demographic characteristics, health status and dietary habits. METHODS: A cross-sectional survey was carried out during May-December 2009. Socio-demographic characteristics, health status and dietary habits were collected. Biomarkers were determined for 764 children. Bivariate and multivariable statistical methods were employed to assess micronutrient deficiencies (MD), anaemia, and their association with different factors. RESULTS: More than two thirds of the school aged children (79.5%) had at least one MD and 40.5% had two or more coexisting micronutrient deficiencies. The most prevalent deficiencies were of zinc (12.5%), folate (13.9%), vit A (29.3%) and vit D (49%). Anaemia occurred in 30.9% of the children. Children living in rural areas were more likely to have vit D insufficiency [OR: 5.9 (3.7-9.5)] but less likely to have folate deficiency [OR: 0.2 (0.1-0.4)] and anaemia [OR: 0.58 (0.35-0.97)]. Splenomegaly was positively associated with folate deficiency and anaemia [OR: 2.77 (1.19-6.48) and 4.91 (2.47-9.75)]. Meat and fish consumption were inversely correlated with zinc and ferritin deficiencies [OR: 0.2 (0.1-0.8) and 0.2 (0.1-0.9)], while oil consumption showed a negative association with anaemia and deficiencies of folate and vitamin A [0.58 (0.3-0.9), OR: 0.5 (0.3-0.9) and 0.6 (0.4-0.9)]. Serum ferritin levels were inversely correlated to the presence of anaemia (p<0.005). CONCLUSION: There is a high prevalence of vitamin A deficiency and vitamin D insufficiency and a moderate prevalence of zinc and folate deficiencies in school aged children in this area. The inverse association of anaemia and serum ferritin levels may be due to the presence of infectious diseases in the area. To effectively tackle malnutrition, strategies should target not only isolated micronutrient supplementation but also diet diversification. PMID- 25546058 TI - Quorum sensing and biofilm formation in mycobacteria: role of c-di-GMP and methods to study this second messenger. AB - Bacteria have evolved to survive the ever-changing environment using intriguing mechanisms of quorum sensing (QS). Very often, QS facilitates formation of biofilm to help bacteria to persist longer and the formation of such biofilms is regulated by c-di-GMP. It is a well-known second messenger also found in mycobacteria. Several methods have been developed to study c-di-GMP signaling pathways in a variety of bacteria. In this review, we have attempted to highlight a connection between c-di-GMP and biofilm formation and QS in mycobacteria and several methods that have helped in better understanding of c-di-GMP signaling. PMID- 25546057 TI - Integration of developmental and environmental signals via a polyadenylation factor in Arabidopsis. AB - The ability to integrate environmental and developmental signals with physiological responses is critical for plant survival. How this integration is done, particularly through posttranscriptional control of gene expression, is poorly understood. Previously, it was found that the 30 kD subunit of Arabidopsis cleavage and polyadenylation specificity factor (AtCPSF30) is a calmodulin regulated RNA-binding protein. Here we demonstrated that mutant plants (oxt6) deficient in AtCPSF30 possess a novel range of phenotypes--reduced fertility, reduced lateral root formation, and altered sensitivities to oxidative stress and a number of plant hormones (auxin, cytokinin, gibberellic acid, and ACC). While the wild-type AtCPSF30 (C30G) was able to restore normal growth and responses, a mutant AtCPSF30 protein incapable of interacting with calmodulin (C30GM) could only restore wild-type fertility and responses to oxidative stress and ACC. Thus, the interaction with calmodulin is important for part of AtCPSF30 functions in the plant. Global poly(A) site analysis showed that the C30G and C30GM proteins can restore wild-type poly(A) site choice to the oxt6 mutant. Genes associated with hormone metabolism and auxin responses are also affected by the oxt6 mutation. Moreover, 19 genes that are linked with calmodulin-dependent CPSF30 functions, were identified through genome-wide expression analysis. These data, in conjunction with previous results from the analysis of the oxt6 mutant, indicate that the polyadenylation factor AtCPSF30 is a regulatory hub where different signaling cues are transduced, presumably via differential mRNA 3' end formation or alternative polyadenylation, into specified phenotypic outcomes. Our results suggest a novel function of a polyadenylation factor in environmental and developmental signal integration. PMID- 25546059 TI - Application of packed porous nanofibers-solid-phase extraction for the detection of sulfonamide residues from environmental water samples by ultra high performance liquid chromatography with mass spectrometry. AB - Porous electrospun nanofibers, as new materials for solid-phase extraction, were synthesized by electrospinning and coupled with ultra high performance liquid chromatography and mass spectrometry to determine sulfonamide residues in environmental water. Aligned porous polystyrene electrospun nanofibers were fabricated under the mechanism of phase separation. The high-specific surface of these nanofibers (70 m(2)/g) could improve recoveries of the target sulfonamides 4-10 times compared with that of polystyrene nonporous material (3.8 m(2)/g). Under the optimized conditions, 13 sulfonamide residues showed an excellent linear relationship in the range of 0.125-12.5 ng/mL with a linear correlation coefficient (r(2)) greater than 0.99, and the detection limits of sulfonamides were as low as 0.80-5.0 ng/L. Compared to the commercial C18 and HLB columns, the homemade porous nanofibers columns had some merits including simple fabrication and extraction process, short process time and environmental friendliness. The optimized method was applied to eight water samples collected from different livestock farms (Xuzhou, China). The results showed that polystyrene porous nanofibers were promising to preconcentrate sulfonamides of different polarities in the waste water. PMID- 25546060 TI - A Mutagenic Primer Assay for Genotyping of the CRHR1 Gene Rare Variant rs1876828 (A/G) in Asians: A Cost-Effective SNP Typing. AB - BACKGROUND: Today, the genetic and genomic research entered in a new era of high throughput genotyping technology. However, mutagenic polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) is still a choice of genotyping method in molecular epidemiological research. It has been extensively used for the detection of risk alleles, if the target SNP has no natural discriminating restriction site. We undertook this study to develop a mutagenic primer assay for a CRHR1 rare gene variant: rs1876828 (A/G) and to determine their allele frequency in north Indian children. METHODS: The mutagenic primers were designed and assay conditions were optimized to perform mutagenic PCR-RFLP in 550 subjects. The efficiency of assay and results were validated by sequencing. RESULTS: This study demonstrated that the mutagenic primer assay is feasible and applicable to discriminate CRHR1 gene rare variant rs1876828 (A/G) and the "frequency of allele "G" was 100% in north Indian asthmatics as well as normal subjects. CONCLUSION: This method can be used for both large- and small scale study of complex genetic, where CRHR1 gene plays the pivotal roles. PMID- 25546061 TI - The manufacturing microbe. PMID- 25546062 TI - Effect of electric current stimulation in combination with external fixator on bone healing in a sheep fracture model. AB - Biophysical stimulations with electric and electromagnetic fields have been demonstrated to accelerate the bone-healing rate. This study has been designed to investigate the effects of electricity directly connected with the central pins of an external fixator in an experimental osteotomy model in sheep. Thirty mg/kg of tetracycline chloride were administered on the 30th and on the 45th day after surgery for histomorphometric studies. Plain radiographs were obtained in standard projections every 15 days after surgery and were analyzed with a software program (Corel Photo-Paint Pro X2, Corel Corporation, Ottawa, Canada). The specimens obtained after 60 days were examined with histological analysis. The results show that biophysical treatment with alternating electricity in combination with external fixator enhances new-bone formation. The translational value of this study, due to the similarities between ovine and human species, suggests that this treatment could be useful in speeding the bone-healing rate both in animals and humans. PMID- 25546063 TI - First evidence of Brucella ovis infection in rams in the Pirot Municipality, Serbia. AB - This paper describes a research on Brucella ovis infection in rams in the Pirot Municipality of South Serbia. A positive result with indirect immunoenzyme test (i-ELISA) was confirmed in 67 (29.8%) and suspicious in 31 (13.8%) out of 225 tested rams. Complement fixation test (CFT) was used as a confirmation test on 67 ELISA positive sera and gave positive reaction in 41 (61.2%) ram serum samples. Rams originated from 113 flocks with 4751 sheep, from 28 villages in the Pirot Municipality of southern Serbia. Clinical examination was performed on epididymis and testes of 12 rams from 7 seropositive flocks by inspection and palpation. The examination showed scrotum asymmetry and unilateral increase of the epididymistail in 5 (41.7%) out of 12 seropositive rams. Pathomorphological examination of testes and epididymis confirmed pathological changes in 7 (58.3%) of the 12 examined rams. Onesided epididymitis with pronounced hypertrophy of the epididymitis was also confirmed. Twelve rams were tested for the presence of bacteria, i.e. 21 epididymis, testes and lymph nodes samples. We isolated 20 Brucella strains from 11 (91.7%) of the 12 examined animals. All isolates were identified with bacteriological and molecular techniques as B. ovis. This is the first evidence of ovine epididymitis (B. ovis) in Republic of Serbia. PMID- 25546064 TI - Development of multiplex real-time PCR assay for the detection of Brucella spp., Leptospira spp. and Campylobacter foetus. AB - Abortion among dairy cattle is one of the major causes of economic losses in the livestock industry. This study describes a 1-step multiplex real-time polymerase chain reaction (PCR) to detect Brucella spp., Leptospira spp. and Campylobacter foetus, these are significant bacteria commonly implicated in bovine abortion. beta-actin was added to the same PCR reaction as an internal control to detect any extraction failure or PCR inhibition. The detection limit of multiplex real time PCR using purified DNA from cultured organisms was set to 5 fg for Leptospira spp. and C. foetus and to 50 fg for Brucella spp. The multiplex real time PCR did not produce any non-specific amplification when tested with different strains of the 3 pathogens. This multiplex real-time PCR provides a valuable tool for diagnosis, simultaneous and rapid detection for the 3 pathogens causing abortion in bovine. PMID- 25546065 TI - Seasonality and antibiotic resistance of Campylobacter in Turkish chicken meat. AB - This study investigated the seasonal prevalence and the antimicrobial susceptibility of Campylobacter jejuni and Campylobacter coli in 264 samples of chicken meat. The samples encompassed wings (n=88), breasts (n=79) and thighs (n=97) and were purchased from different butcheries and markets in Elazig province, in Eastern Turkey, between December 2009 and November 2010. The meat samples were tested for Campylobacter presence and the collected isolates were identified as Campylobacter jejuni and Campylobacter coli using polymerase chain reaction (PCR). Resistance rates to 7 antimicrobials were investigated by the disk diffusion method. Campylobacter jejuni was found at a higher prevalence (41.7%) than C. coli (14.4%); C. jejuni was isolated most frequently from breast samples (53.2%) than from thighs (40.2%) and wings (32.9%) samples. The prevalence of C. jejuni and C. coli peaked during the Summer (June-August), with the highest peak occurring in July (77.3%). The lowest prevalence (30%) was detected in February. The prevalence in the Summer (June-August) was significantly higher (71.2%) than the one reported during the Winter (December February) (39.4%, P< 0.05). The highest resistance rate among C. jejuni isolates was observed to tetracycline (38.2%), nalidixic acid (29.1%), and ciprofloxacin (24.5%). Campylobacter coli also showed a high resistance to these antibiotics, although in slightly different proportions: tetracycline (42.1%), ciprofloxacin (31.6%), and nalidixic acid (26.3%). None of the C. jejuni or C. coli isolates was resistant to gentamicin. PMID- 25546066 TI - Leptospira spp. infection in wild ruminants: a survey in Central Italian Alps. AB - Leptospirosis is an important zoonotic disease diffused worldwide, and wildlife species are commonly considered to be important epidemiological carriers. Four hundred and forty-one serological and 198 renal samples from red deer, roe deer and chamois collected in the Province of Sondrio were analysed using the microscopic agglutination test and histopathologic examination. Positive serological findings were found only in 15 red deer and 19 positive serologic reactions were recorded. The most frequent serovars were Bratislava and Grippotyphosa, followed by Pomona, Hardjo and Copenhagheni. Twenty-two per cent of renal samples from seropositive red deer were affected by mild to moderate multifocal chronic lymphoplasmacytic and fibrosing tubulo-interstitial nephritis, mainly involving the cortical parenchyma. In this study, antibodies to Leptospira spp. were infrequent in wild ruminants, and only red deer seemed to be sensitive to the infection. Given the low presence and the fact that there was no record of Leptospira spp. infections in cattle, sheep, goats and also hunters in area during the study period, wild ruminants in Alpine environments cannot be considered as reservoirs or important sources of Leptospira spp. infection for humans or domestic animals. PMID- 25546067 TI - A survey on bacterial involvement in neonatal mortality in dogs. AB - Bacterial infections represent the second cause of neonatal morbidity and mortality in dogs, so the present study aimed to investigate the bacterial involvement in canine neonatal mortality and to evaluate the antibiotic susceptibility of the isolated bacteria. Fifty-one newborn purebred puppies, born dead or dead within 28 days of age, belonging to 36 different litters, were enrolled and the following procedures were performed on their fresh dead bodies: necropsy, collection of swabs by liver, kidney, lung, small bowel, and possible thoracic and/ or abdominal effusion, for both bacteriological examination and antimicrobial susceptibility testing, and collection of samples by the same organs for histology. About 47% of total swabs were positive at bacteriology (pure bacterial culture or bacterial association). In 65% of the newborn puppies the mortality could be attributed to a bacterial infection. Although the high multidrug resistance, the most effective antimicrobials were third generation cephalosporins and fluorquinolones. In case of neonatal mortality, bacterial culture and antimicrobial susceptibility testing become essential for a targeted therapy in surviving littermates and for the management of following pregnancies in bitches with recurrent neonatal loss. PMID- 25546068 TI - Sclerosing peritoneal mesothelioma in a dog: histopathological, histochemical and immunohistochemical investigations. AB - Mesotheliomas are rare neoplasm affecting on rare occasions both animals and humans and which arise from the mesothelial cells lining the coelomic cavities. We report herein the histopathological, histochemical and immunohistochemical findings in a dog affected by sclerosing peritoneal mesothelioma, a rare variant of canine mesothelioma, and submitted to laparotomy in December 2012 (Teramo, Italy). Our data confirm that mesothelioma still represents a diagnostic challenge and that immunohistochemistry can be extremely useful as supportive diagnostic technique. PMID- 25546069 TI - Molecular evidence of Leishmania infantum in Ixodes ricinus ticks from dogs and cats, in Italy. AB - Leishmaniosis, caused by Leishmania infantum, is an endemic zoonosis in the Mediterranean basin. To date, phlebotomine sand flies are the only accepted biological vectors of Leishmania parasites to dogs and humans. The absence of the primary vector in autochthonous Leishmania outbreaks suggests a possible role of fleas or ticks as alternative vectors. In this study, 119 ticks were collected between August 2007-June 2008 and between March 2010-October 2010 from various animal species and humans living in Italian areas where canine leishmaniosis is endemic (i.e. rural areas of the North) and were tested for the presence of L. infantum DNA. Nine (7.5%) out of 119 ticks resulted PCR positive. All ticks were morphologically identified as Ixodes ricinus ticks, 3 from 1 cat, 6 from 4 dogs. To our knowledge, this is the first evidence of L. infantum DNA in ticks from cat, suggesting that the debate about the epidemiological role of ticks in canine leishmaniosis might be extended to feline leishmaniosis. PMID- 25546070 TI - First detection of Arcobacter sp. in Eurasian collared doves (Streptopelia decaocto). AB - Data about the presence of Arcobacter in wild birds are currently lacking. In this study cloacal swabs from 95 collared doves (Streptopelia decaocto), submitted to the Department of Veterinary Medical Sciences (Bologna, Italy) between 2011 and 2013 from various urban and suburban areas of the Emilia-Romagna region (Northern Italy), were tested for the presence of Arcobacter sp. by a rRNA 23S nested Polymerase Chain Reaction (PCR). Eighteen out of 95 (19%) samples showed the expected PCR product. Further cultural and molecular studies are needed to assess the Arcobacter prevalence in wild birds and elucidate their potential epidemiological role as source of animal and human infections. PMID- 25546071 TI - Alcohol use among a community-based sample of gay men: Correlates of high-risk use and implications for service provision. AB - INTRODUCTION AND AIMS: International research has shown that gay, bisexual and other homosexually active men (hereafter 'gay men') report disproportionately higher rates of risky alcohol use and associated problems compared with heterosexual men. However, little is known about alcohol use among this population in Australia. This study aimed to examine rates of risky alcohol use among a community-based sample of gay men in Sydney and characteristics of men reporting high-risk alcohol use and adverse consequences. DESIGN AND METHODS: A cross-sectional survey of gay men was conducted in Sydney in August 2013 as part of the ongoing Gay Community Periodic Surveys (n = 1546 eligible respondents). The Alcohol Use Disorders Identification Test-Consumption questions were used to assess alcohol use in the previous 12 months. RESULTS: Nine percent of respondents were categorised as abstinent from alcohol, 33% as low-risk drinkers, 42% as moderate-risk drinkers and 16% as high-risk drinkers. In separate multivariate logistic regression analyses, high-risk drinking and reporting >=4 adverse alcohol consequences were associated with younger age, being Australian born, recruitment from licensed premises and having met men for sex at gay bars and dance parties. Fifty-eight percent of high-risk drinkers reported a desire to reduce their alcohol use. DISCUSSION AND CONCLUSIONS: In this community-based sample of gay men, we found high levels of moderate- to high-risk alcohol use. The results suggest that gay men should be a priority population for health promotion campaigns and treatment services. PMID- 25546074 TI - Living with chronicity and complexity: Lessons for redesigning case management from patients' life stories - A qualitative study. AB - RATIONALE, AIMS AND OBJECTIVES: Case management is commonly used to provide health care for patients with multiple chronic conditions. However, the most effective form of team organization and the necessary support structures need to be identified. In this respect, patients' views could provide a valuable contribution to improving the design of these services. To analyse the experiences of patients with chronic diseases and of caregivers, in relation to health care services and mechanisms, and to identify means of modelling case management services. METHODS: The method used was a qualitative study based on life stories, and semi-structured interviews with 18 patients with complex chronic diseases and with their family caregivers, selected by purposeful sampling in primary health care centres in Andalusia (southern Spain) from 2009 to 2011. RESULTS: Three transition points were clearly identified: the onset and initial adaptation, the beginning of quality-of-life changes, and the final stage, in which the patients' lives are governed by the complexity of their condition. Health care providers have a low level of proactivity with respect to undertaking early measures for health promotion and self-care education. Care is fragmented into a multitude of providers and services, with treatments aimed at specific problems. CONCLUSIONS: Many potentially valuable interventions in case management, such as information provision, self-care education and coordination between services and providers, are still not provided. PMID- 25546073 TI - Porphyromonas gingivalis and related bacteria: from colonial pigmentation to the type IX secretion system and gliding motility. AB - Porphyromonas gingivalis is a gram-negative, non-motile, anaerobic bacterium implicated as a major pathogen in periodontal disease. P. gingivalis grows as black-pigmented colonies on blood agar, and many bacteriologists have shown interest in this property. Studies of colonial pigmentation have revealed a number of important findings, including an association with the highly active extracellular and surface proteinases called gingipains that are found in P. gingivalis. The Por secretion system, a novel type IX secretion system (T9SS), has been implicated in gingipain secretion in studies using non-pigmented mutants. In addition, many potent virulence proteins, including the metallocarboxypeptidase CPG70, 35 kDa hemin-binding protein HBP35, peptidylarginine deiminase PAD and Lys-specific serine endopeptidase PepK, are secreted through the T9SS. These findings have not been limited to P. gingivalis but have been extended to other bacteria belonging to the phylum Bacteroidetes. Many Bacteroidetes species possess the T9SS, which is associated with gliding motility for some of these bacteria. PMID- 25546072 TI - Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in the ventral striatum. AB - Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug-related reward. Indeed, in alcohol-dependent patients, reactivity in dopaminergic target areas is shifted from non-drug-related stimuli towards drug related stimuli. Such 'hijacked' dopamine signals may impair flexible learning from non-drug-related rewards, and thus promote craving for the drug of abuse. Here, we used functional magnetic resonance imaging to measure ventral striatal activation by reward prediction errors (RPEs) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N = 27). All participants also underwent 6-[(18) F]fluoro-DOPA positron emission tomography to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation by RPEs nor striatal dopamine synthesis capacity differed between groups. However, ventral striatal coding of RPEs correlated inversely with craving in patients. Furthermore, we found a negative correlation between ventral striatal coding of RPEs and dopamine synthesis capacity in healthy controls, but not in alcohol-dependent patients. Moderator analyses showed that the magnitude of the association between dopamine synthesis capacity and RPE coding depended on the amount of chronic, habitual alcohol intake. Despite the relatively small sample size, a power analysis supports the reported results. Using a multimodal imaging approach, this study suggests that dopaminergic modulation of neural learning signals is disrupted in alcohol dependence in proportion to long-term alcohol intake of patients. Alcohol intake may perpetuate itself by interfering with dopaminergic modulation of neural learning signals in the ventral striatum, thus increasing craving for habitual drug intake. PMID- 25546076 TI - Revisiting the argument for 1- versus 2-vein outflow in head and neck free tissue transfers: A review of 317 microvascular reconstructions. AB - BACKGROUND: The purpose of this study was to determine the benefit of 1-vein versus 2-vein outflow in microvascular free tissue transfers. METHODS: A retrospective review reflects the experience of 6 surgeons. Analysis included all patients who underwent reconstruction at a single institution between January 2004 and December 2012. RESULTS: Three hundred nine patients underwent a total of 317 microvascular free flap reconstructions for head and neck defects. Two hundred thirteen of 317 flaps (67.2%) used 1 venous anastomosis and 104 (32.8%) used 2 venous anastomoses. Venous congestion necessitated urgent take back in 37 of 57 patients (64.9%) requiring exploration for perioperative complications. Thirty of 37 flaps (81.1%) with venous congestion had 1 vein anastomosis, whereas 7 (18.9%) had dual vein outflow (p = .03). Overall flap success was 303 of 317 (95.6%), despite an 18.0% (57 of 317) perioperative take back rate. CONCLUSION: Coapting 2 veins was shown to minimize venous congestion. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 820-823, 2016. PMID- 25546075 TI - Cellular and molecular maturation in fetal and adult ovine calcaneal tendons. AB - Processes of development during fetal life profoundly transform tendons from a plastic tissue into a highly differentiated structure, characterised by a very low ability to regenerate after injury in adulthood. Sheep tendon is frequently used as a translational model to investigate cell-based regenerative approaches. However, in contrast to other species, analytical and comparative baseline studies on the normal developmental maturation of sheep tendons from fetal through to adult life are not currently available. Thus, a detailed morphological and biochemical study was designed to characterise tissue maturation during mid- (2 months of pregnancy: 14 cm of length) and late fetal (4 months: 40 cm of length) life, through to adulthood. The results confirm that ovine tendon morphology undergoes profound transformations during this period. Endotenon was more developed in fetal tendons than in adult tissues, and its cell phenotype changed through tendon maturation. Indeed, groups of large rounded cells laying on smaller and more compacted ones expressing osteocalcin, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were identified exclusively in fetal mid-stage tissues, and not in late fetal or adult tendons. VEGF, NGF as well as blood vessels and nerve fibers showed decreased expression during tendon development. Moreover, the endotenon of mid- and late fetuses contained identifiable cells that expressed several pluripotent stem cell markers [Telomerase Reverse Transcriptase (TERT), SRY Determining Region Y Box-2 (SOX2), Nanog Homeobox (NANOG) and Octamer Binding Transcription Factor-4A (OCT-4A)]. These cells were not identifiable in adult specimens. Ovine tendon development was also accompanied by morphological modifications to cell nuclei, and a progressive decrease in cellularity, proliferation index and expression of connexins 43 and 32. Tendon maturation was similarly characterised by modulation of several other gene expression profiles, including Collagen type I, Collagen type III, Scleraxis B, Tenomodulin, Trombospondin 4 and Osteocalcin. These gene profiles underwent a dramatic reduction in adult tissues. Transforming growth factor-beta~1 expression (involved in collagen synthesis) underwent a similar decrease. In conclusion, these morphological studies carried out on sheep tendons at different stages of development and aging offer normal structural and molecular baseline data to allow accurate evaluation of data from subsequent interventional studies investigating tendon healing and regeneration in ovine experimental models. PMID- 25546083 TI - Cisplatin resistance in germ cell tumours: models and mechanisms. AB - Recent years have led to a better understanding of the mechanisms underlying cisplatin response and resistance in germ cell tumours (GCT), and several promising targets have been identified. Two main mechanisms of the responsiveness to DNA damaging agents have been postulated. Firstly, GCT readily activate a DNA damage response, but show deficits in several damage repair pathways. In particular, they have been found to have defects in interstrand crosslink repair and in homologous recombination (HR). Secondly, GCT, especially embryonal carcinoma (EC) cells, show a hypersensitive apoptotic response to DNA damage, which activates p53, and leads to up-regulation of the pro-apoptotic factors Noxa, Puma and Fas in non-resistant EC. These cells fail to activate p21 which induces a G1/S arrest, but accumulate in G2/M phase. In the absence of functional p53, family members like p73 and GTAp63 might be important in initiating this response. Mechanisms involved in cisplatin resistance are as follows: down regulation of Oct4 (e.g. as a result of hypoxia, treatment with retinoic acid or exposure to cisplatin) and failure to induce Puma and Noxa; changes in the expression levels of micro-RNAs such as miR-17/-106b, miR-302a, or miR-371 to 373; elevated levels of MDM2 and cytoplasmic translocation of p21 by phosphorylation; and activation of the PDGFRbeta/PI3K/pAKT pathway. Several approaches to overcome resistance have been successfully examined in vitro and in vivo, including PARP inhibitors, especially in cells showing deficient HR-repair; stabilization of p53 using nutlin-3; inhibition of several components of the PI3K/pAKT pathway using small molecules; and DNA demethylation by 5-azacytidine or 5-aza-deoxy-cytidine, among others. Many of these substances deserve further exploration, alone or in combination with DNA damaging agents, and the most promising approaches should be taken forward to clinical testing. Targeted therapy based on mechanistic insights holds the promise to turn cisplatin resistant GCT into a curable disease. PMID- 25546077 TI - Ganglion cell and displaced amacrine cell density distribution in the retina of the howler monkey (Alouatta caraya). AB - Unlike all other New World (platyrrine) monkeys, both male and female howler monkeys (Alouatta sp.) are obligatory trichromats. In all other platyrrines, only females can be trichromats, while males are always dichromats, as determined by multiple behavioral, electrophysiological, and genetic studies. In addition to obligatory trichromacy, Alouatta has an unusual fovea, with substantially higher peak cone density in the foveal pit than every other diurnal anthropoid monkey (both platyrrhines and catarrhines) and great ape yet examined, including humans. In addition to documenting the general organization of the retinal ganglion cell layer in Alouatta, the distribution of cones is compared to retinal ganglion cells, to explore possible relationships between their atypical trichromacy and foveal specialization. The number and distribution of retinal ganglion cells and displaced amacrine cells were determined in six flat-mounted retinas from five Alouatta caraya. Ganglion cell density peaked at 0.5 mm between the fovea and optic nerve head, reaching 40,700-45,200 cells/mm2. Displaced amacrine cell density distribution peaked between 0.5-1.75 mm from the fovea, reaching mean values between 2,050-3,100 cells/mm2. The mean number of ganglion cells was 1,133,000+/-79,000 cells and the mean number of displaced amacrine cells was 537,000+/-61,800 cells, in retinas of mean area 641+/-62 mm2. Ganglion cell and displaced amacrine cell density distribution in the Alouatta retina was consistent with that observed among several species of diurnal Anthropoidea, both platyrrhines and catarrhines. The principal alteration in the Alouatta retina appears not to be in the number of any retinal cell class, but rather a marked gradient in cone density within the fovea, which could potentially support high chromatic acuity in a restricted central region. PMID- 25546085 TI - Foreword. The 20th year of Blood Pressure Monitoring. PMID- 25546086 TI - Ubiquitin-specific protease 22 (USP22) positively regulates RCAN1 protein levels through RCAN1 de-ubiquitination. AB - Protein ubiquitination can be reversed by de-ubiquitinating enzymes (DUBs), which are classified into two main classes, cysteine proteases and metalloproteases. Cysteine proteases include ubiquitin-specific proteases (USPs) and ubiquitin C terminal hydrolases. USP22 is a USP family member and a component of the mammalian Spt-Ada-Gcn5 acetyltransferase transcriptional coactivating complex. Regulator of calcineurin 1 (RCAN1; also known as DSCR1 or MCIP1) functions as an endogenous inhibitor of calcineurin signaling. In the present study, we have identified a novel interaction between USP22 and RCAN1 (RCAN1-1S) in the mammalian cells. In addition, the overexpression of USP22 caused the increase of RCAN1 protein stability. USP22 antagonized the actions of FBW7, NEDD4-2, and beta TrCP E3 ligase on RCAN1 and promoted RCAN1 de-ubiquitination. Moreover, we found that RCAN1 was bound to USP22 in basal conditions, and interferon-alpha (IFN alpha) treatment caused the dissociation of RCAN1 from USP22, which subsequently triggered RCAN1 ubiquitination and proteasome degradation. Taken together, these results suggest that USP22 positively regulates RCAN1 levels, which would consequently affect diverse RCAN1-linked cellular processes, such as the inflammatory process involving the release of IFN-alpha. PMID- 25546084 TI - Bioactive DNA-peptide nanotubes enhance the differentiation of neural stem cells into neurons. AB - We report the construction of DNA nanotubes covalently functionalized with the cell adhesion peptide RGDS as a bioactive substrate for neural stem cell differentiation. Alteration of the Watson-Crick base pairing program that builds the nanostructures allowed us to probe independently the effect of nanotube architecture and peptide bioactivity on stem cell differentiation. We found that both factors instruct synergistically the preferential differentiation of the cells into neurons rather than astrocytes. PMID- 25546087 TI - Alpha-adrenoceptor modulation in central nervous system trauma: pain, spasms, and paralysis--an unlucky triad. AB - Many researchers have attempted to pharmacologically modulate the adrenergic system to control locomotion, pain, and spasms after central nervous system (CNS) trauma, although such efforts have led to conflicting results. Despite this, multiple studies highlight that alpha-adrenoceptors (alpha-ARs) are promising therapeutic targets because in the CNS, they are involved in reactivity to stressors and regulation of locomotion, pain, and spasms. These functions can be activated by direct modulation of these receptors on neuronal networks in the brain and the spinal cord. In addition, these multifunctional receptors are also broadly expressed on immune cells. This suggests that they might play a key role in modulating immunological responses, which may be crucial in treating spinal cord injury and traumatic brain injury as both diseases are characterized by a strong inflammatory component. Reducing the proinflammatory response will create a more permissive environment for axon regeneration and may support neuromodulation in combination therapies. However, pharmacological interventions are hindered by adrenergic system complexity and the even more complicated anatomical and physiological changes in the CNS after trauma. This review is the first concise overview of the pros and cons of alpha-AR modulation in the context of CNS trauma. PMID- 25546088 TI - Multiscattering-enhanced absorption spectroscopy. AB - An original scheme for sensitive absorption measurements, particularly well suited for low analyte concentrations, is presented. The technique is based on multiscattering-enhanced absorption spectroscopy (MEAS) and benefits from the advantages of conventional absorption spectroscopy: simplicity, rapidity, and low costs. The technique relies on extending the optical path through the sensing volume by suspending dielectric beads in the solution containing the analytes of interest, resulting in multiple scattering of light, which increases the optical path length through the sample. This way, a higher sensitivity and lower limit of detection, compared to those of conventional absorption spectroscopy, can be achieved. The approach is versatile and can be used for a broad variety of analytes. Here, it is applied to the detection of phenol red, 10 nm gold nanoparticles, and envy green fluorescence dye; the limit of detection is decreased by a factor of 7.2 for phenol red and a factor of 3.3 for nanoparticles and dye. The versatility of this approach is illustrated by its application in increasing the sensitivity of colorimetric detection with gold nanoparticle probes and a commercially available hydrogen peroxide bioassay. The influence of different parameters describing the scattering medium is investigated in detail experimentally and numerically, with very good agreement between the two. Those parameters can be effectively used to tailor the enhancement for specific applications and analytes. PMID- 25546091 TI - Low and fixed dose of hydroxyurea is effective and safe in patients with HbSbeta(+) thalassemia with IVS1-5(G->C) mutation. AB - BACKGROUND: Despite compelling evidence that hydroxyurea is safe and effective in sickle cell disease, it is prescribed sparingly due to several barriers like knowledge gaps in certain genotypes, apprehension about its safety and toxicity, and limited resources. We undertook this study to find out the efficacy and safety of HU in patients with HbSbeta(+) -thalassemia with IVS1-5(G->C) mutation. PROCEDURE: We registered 318 patients with HbSbeta(+) -thalassemia with IVS1-5(G >C) mutation. Of these, 203 were enrolled for hydroxyurea treatment at a low and fixed dose of 10 mg/kg/day. One hundred four patients (Group-I: 37 children and Group-II: 67 adults) with >=2 years of hydroxyurea treatment were studied. RESULTS: The rate of vaso-occlusive crises, requirement of blood transfusion and rate of hospitalization reduced from 3 to 0.5, 1 to 0 and 1 to 0 in Group-I and 3 to 0, 1 to 0 and 0.5 to 0 in Group-II respectively after HU therapy (P < 0.0001). %HbF level, hemoglobin, MCV and MCH increased significantly, whereas HbS, WBC, platelet count, serum-bilirubin and LDH levels decreased significantly after HU therapy. It has been observed that along with fairly subtle hematological changes following HU therapy, there was a substantial clinical improvement occurred in these patients. Transient myelotoxicity was observed in 4.8%. There was minimal gonadal toxicity without affecting reproductive function. CONCLUSION: In view of easy affordability, better acceptability, minimal toxicity, the need of infrequent monitoring and its potential effectiveness, low and fixed dose of hydroxyurea is suitable for treatment of patients with HbSbeta(+) -thalassemia in resource poor setting. PMID- 25546089 TI - Using optical coherence tomography to rapidly phenotype and quantify congenital heart defects associated with prenatal alcohol exposure. AB - BACKGROUND: The most commonly used method to analyze congenital heart defects involves serial sectioning and histology. However, this is often a time-consuming process where the quantification of cardiac defects can be difficult due to problems with accurate section registration. Here we demonstrate the advantages of using optical coherence tomography, a comparatively new and rising technology, to phenotype avian embryo hearts in a model of fetal alcohol syndrome where a binge-like quantity of alcohol/ethanol was introduced at gastrulation. RESULTS: The rapid, consistent imaging protocols allowed for the immediate identification of cardiac anomalies, including ventricular septal defects and misaligned/missing vessels. Interventricular septum thicknesses and vessel diameters for three of the five outflow arteries were also significantly reduced. Outflow and atrioventricular valves were segmented using image processing software and had significantly reduced volumes compared to controls. This is the first study to our knowledge that has 3D reconstructed the late-stage cardiac valves in precise detail to examine their morphology and dimensions. CONCLUSIONS: We believe, therefore, that optical coherence tomography, with its ability to rapidly image and quantify tiny embryonic structures in high resolution, will serve as an excellent and cost-effective preliminary screening tool for developmental biologists working with a variety of experimental/disease models. PMID- 25546092 TI - Sex allocation, juvenile mortality and the costs imposed by offspring on parents and siblings. AB - Generally, sex-specific mortality is not expected to affect optimal patterns of sex allocation. Several authors have, however, made verbal arguments that this is not true if juvenile mortality is sex specific during the period of parental care. Here, we provide formal mathematical models exploring the effect of such mortality on optimal sex allocation. We confirm the prediction that biased production of the sex with higher mortality during care is favoured. Crucially, however, this is only true when juvenile mortality in the period of parental care frees up resources for their current/future siblings (i.e. the saved investment is transferable). Furthermore, we show that although optimal sex allocation is consistent with the theory of equal investment (as asserted by previous authors), thinking in terms of equal investment is not readily feasible in some scenarios. We also show that differences in early mortality overcome biased sex allocation such that the sex ratio at independence is generally, but not always, biased in the opposite direction from that at birth. Our models should prove useful to empiricists investigating the effect of sex-specific juvenile mortality and antagonistic sibling interactions on sex allocation. PMID- 25546090 TI - Regulation of natural cytotoxicity receptors by heparan sulfate proteoglycans in cis: A lesson from NKp44. AB - NKp44 (NCR2) is a distinct member of natural cytotoxicity receptors (NCRs) family that can induce cytokine production and cytolytic activity in human NK cells. Heparan sulfate proteoglycans (HSPGs) are differentially expressed in various normal and cancerous tissues. HSPGs were reported to serve as ligands/co-ligands for NKp44 and other NCRs. However, HSPG expression is not restricted to either group and can be found also in NK cells. Our current study reveals that NKp44 function can be modulated through interactions with HSPGs on NK cells themselves in -cis rather than on target cells in -trans. The intimate interaction of NKp44 and the NK cell-associated HSPG syndecan-4 (SDC4) in -cis can directly regulate membrane distribution of NKp44 and constitutively dampens the triggering of the receptor. We further demonstrate, that the disruption of NKp44 and SDC4 interaction releases the receptor to engage with its ligands in -trans and therefore enhances NKp44 activation potential and NK cell functional response. PMID- 25546093 TI - Quality of hospice care: comparison between rural and urban residents. AB - Discrepancies between needed and received hospice care exist, especially in rural areas. Hospice care quality ratings for 743 rural and urban patients and their families were compared. Rural participants reported higher overall satisfaction and with pain/symptom management. Regardless of geographic location, satisfaction was higher when patients were informed and emotionally supported. Patients and family ratings did not differ. Findings support prior reports using retrospective rather than our study's point-of-care surveys. PMID- 25546095 TI - Rehabilitation of a Severely Atrophic Mandible Using Soft Tissue Matrix Expansion (Tent-Pole). PMID- 25546094 TI - A population-based study on combined markers for early Parkinson's disease. AB - The prerequisite for an earlier diagnosis of Parkinson's disease (PD) are markers that are both sensitive and specific for clinically definite PD and its prediagnosic phases. Promising candidates include enlarged hyperechogenicity of the substantia nigra (SN+) on transcranial sonography (TCS) and hyposmia. However, despite good sensitivity and specificity, both markers have yet failed to yield reliable predictions. We pursue the possibility of combined use in an ongoing population-based cohort. Subjects were recruited from 10,000 inhabitants of Luebeck/Germany aged 50 to 79 years and additional PD patients from our outpatient clinic. After neurological examination, 715 subjects were grouped into clinically definite PD (n = 106), possible prediagnostic PD (ppPD; n = 73), and a control group subdivided into healthy individuals (n = 283) and controls with diseases other than PD (n = 253). Subjects underwent TCS and smell testing. Sensitivity and specificity of SN+ and hyposmia were good for PD; however, positive predictive values (PPV) of both SN+ (5.2%) and olfaction (2.5%) were low. At least one positive/both positive markers were present in 33%/1% of healthy controls, 33%/2% of diseased controls, 62%/7% of ppPD, and 94%/51% of PD. When combining SN+ and hyposmia, PPV increased to 17.6%, with a sensitivity of 51% and a specificity of 98%. Both SN+ and hyposmia offer good enrichment towards PD and ppPD, are stable against other diseases, and the combination of markers highly increases specificity. However, if the combination of SN+ and hyposmia were used as criterion for PD diagnosis, almost half of clinically definite PD and more than 90% of ppPD would have been missed. PMID- 25546096 TI - Temporal contiguity in associative learning: Interference and decay from an historical perspective. AB - The greater the separation in time between 2 events, A followed by B, the less likely they are to become associated. The dominant explanation of this temporal contiguity effect has been trace decay: During the interval between A and B, the trace left by A becomes too weak by the time B occurs for an association to be formed between them. Pavlov adopted this idea in the context of classical conditioning and Hull used it to account for the deleterious effect of delaying reinforcement on the acquisition of instrumental responses. By 1960 various studies supported the conclusion that animals could not learn to associate 2 events separated by more than around 45 s. Research on human skill acquisition with delayed feedback and later studies using causal or predictive judgment tasks indicated that explicit cognitive processing is generally involved when humans associate events separated by more than a few seconds. The discovery of long delay taste aversion learning prompted Revusky's (1971) alternative analysis of contiguity effects in terms of interference: The greater the separation between A and B, the more likely that extraneous events compete for association with A and B. Although the analysis of overshadowing provided by associative learning theories provides a context for this account, none of these theories provide a satisfactory account of evidence on temporal contiguity from a wide range of animal studies. Alternative timing theories are arguably also unsatisfactory. PMID- 25546099 TI - Perceptual learning transfer: Salience of the common element as a factor contributing to the intermixed/blocked effect. AB - Rats received intermixed or blocked preexposure to 2 similar flavor compounds, AX and BX. Following preexposure, conditioning trials took place in which a novel compound stimulus NX was paired with an illness-induced unconditioned stimulus. Animals that were given intermixed preexposure to AX and BX showed lower generalization of the aversive response conditioned to NX to a new compound, ZX, than animals that were given blocked preexposure. The results support the proposal that intermixed preexposure reduces the salience of the common element X to a greater extent than blocked preexposure. The way in which current theories of perceptual learning can predict a differential salience of X after intermixed and blocked preexposure is discussed. PMID- 25546098 TI - Scene-based contextual cueing in pigeons. AB - Repeated pairings of a particular visual context with a specific location of a target stimulus facilitate target search in humans. We explored an animal model of such contextual cueing. Pigeons had to peck a target, which could appear in 1 of 4 locations on color photographs of real-world scenes. On half of the trials, each of 4 scenes was consistently paired with 1 of 4 possible target locations; on the other half of the trials, each of 4 different scenes was randomly paired with the same 4 possible target locations. In Experiments 1 and 2, pigeons exhibited robust contextual cueing when the context preceded the target by 1 s to 8 s, with reaction times to the target being shorter on predictive-scene trials than on random-scene trials. Pigeons also responded more frequently during the delay on predictive-scene trials than on random-scene trials; indeed, during the delay on predictive-scene trials, pigeons predominately pecked toward the location of the upcoming target, suggesting that attentional guidance contributes to contextual cueing. In Experiment 3, involving left-right and top-bottom scene reversals, pigeons exhibited stronger control by global than by local scene cues. These results attest to the robustness and associative basis of contextual cueing in pigeons. PMID- 25546100 TI - The Hall-Rodriguez theory of latent inhibition: Further assessment of compound stimulus preexposure effects. AB - According to a recent theory (Hall & Rodriguez, 2010), the latent inhibition produced by nonreinforced exposure to a target stimulus (B) will be deepened by subsequent exposure of that stimulus in compound with another (AB). This effect of compound exposure is taken to depend on the addition of a novel A to the familiar B and is not predicted for equivalent preexposure on which AB trials precede the A trials. This prediction was tested in 2 experiments using rats. Experiment 1 used an aversive procedure with flavors as the stimuli; Experiment 2 used an appetitive procedure with visual and auditory stimuli. In both, we found that conditioning with B as the conditioned stimulus proceeded more slowly (i.e., latent inhibition was greater) in subjects given the B-AB sequence in preexposure than in subjects given the AB-B sequence. PMID- 25546101 TI - Integrating timing and conditioning approaches to study behavior. AB - Skinner and Pavlov had innovative ways to measure both the times of their subject's responses, as well as the rate of their responses. Since then, different subfields within the study of animal behavior have prioritized either the rate or timing of responses, creating a divide in data and theory. Both timing and conditioning fields have proven fruitful, producing large bodies of empirical data and developing sophisticated models. Despite their individual successes, a unified view of simple behavior is still lacking. This may be caused, at least in part, by the differential emphasis on data collection and analysis techniques. The result is that these subfields produce models that fit their data well, but fail to translate to the other domain. This is startling given the fact that both subfields use nearly identical experimental procedures. To highlight similarities within the subfields, and provide empirical data in support of this integration, 18 Sprague-Dawley rats were trained on trace, delay, and backward conditioning procedures. Using these empirical data we discuss how traditional summary measures used by these subfields can be limiting, and suggest methods that may aid in the integration of these subfields toward common goals. PMID- 25546102 TI - Extinguished second-order conditioned fear responses are renewed but not reinstated. AB - A series of experiments used rats to examine renewal and reinstatement of extinguished second-order conditioned fear (freezing) responses. The initial experiment demonstrated that freezing responses to a stimulus (S2) were contingent on its pairings with a second stimulus (S1) and on the prior pairings of S1 and an aversive unconditioned stimulus (US). Subsequent experiments showed that these freezing responses extinguished across S2 alone presentations, but were renewed when: S2-S1 pairings and S2 alone presentations occurred in the same context and testing of S2 occurred elsewhere; S2-S1 pairings and testing were in the same context and S2 alone presentations were elsewhere; and when S2-S1 pairings, S2 alone presentations and testing occurred in different contexts. Freezing responses to an extinguished S1 were reinstated by US alone presentations. However, these responses were not reinstated to an extinguished S2 by US or S1 alone presentations, and, conversely, freezing to a nonextinguished S2 was unaffected by extinction of S1. The results were interpreted to mean that S2-S1 pairings produced an association between S2 and the fear responses elicited by S1 and that extinction of this association is controlled by context. The failure to reinstate fear responses to S2 is discussed in terms of theories developed to explain reinstatement of S1. PMID- 25546103 TI - Temporal analysis of free exploration of an elevated plus-maze in mice. AB - The elevated plus-maze (EPM) is a very common rodent test of anxiety. It is based on an approach-avoidance conflict between secure closed arms and aversive open arms. However, discrepancies remain on the interpretation of animals' behavior in this assay. The purpose of our study was to get a better understanding of the mouse behavior in the EPM. We applied a minute-by-minute analysis to compare the behavior of mice forcibly exposed to the maze or set free to explore the maze from a familiar box. Three strains of mice (CD1, BALB/c, and C57Bl/6) were tested. The combination of our different conditions of the test with the minute by-minute analysis showed that mice did not avoid open arms during the first 2 min of the test when they were forcibly exposed to the EPM. Conversely, free exploration of the EPM resulted in a pattern of behavior characterized by open arm avoidance from the outset, demonstrating that open arm avoidance in mice is unconditioned. These findings generalize across the 3 mouse strains. These data suggest that rodents enter the open arms to complete spatial information about the apparatus as a whole before their natural tendency to avoid them is expressed. Our data also indicate that a detailed behavioral analysis is needed whenever BALB/c mice are to be exposed by force to the EPM. Further studies are required to fully understand the behavior of rodents in the EPM and to avoid false interpretations in the fields of psychopharmacology and behavioral neuroscience. PMID- 25546104 TI - Control of working memory in rhesus monkeys (Macaca mulatta). AB - Cognitive control is critical for efficiently using the limited resources in working memory. It is well established that humans use rehearsal to increase the probability of remembering needed information, but little is known in nonhumans, with some studies reporting the absence of active control and others subject to alternative explanations. We trained monkeys in a visual matching-to-sample paradigm with a post-sample memory cue. Monkeys either saw a remember cue that predicted the occurrence of a matching test that required memory for the sample, or a forget cue that predicted a discrimination test that did not require memory of the sample. Infrequent probe trials on which monkeys were given tests of the type not cued on that trial were used to assess whether memory was under cognitive control. Our procedures controlled for reward expectation and for the surprising nature of the probes. Monkeys matched less accurately after forget cues, whereas discrimination accuracy was equivalent in the 2 cue conditions. We also tested monkeys with lists of 2 consecutive sample images that shared the same cue. Again, memory for expected memory tests was superior to that on unexpected tests. Together these results show that monkeys cognitively control their working memory. PMID- 25546105 TI - Effects of spatial training on transitive inference performance in humans and rhesus monkeys. AB - It is often suggested that transitive inference (TI; if A > B and B > C, then A > C) involves mentally representing overlapping pairs of stimuli in a spatial series. However, there is little direct evidence to unequivocally determine the role of spatial representation in TI. We tested whether humans and rhesus monkeys use spatial representations in TI by training them to organize 7 images in a vertical spatial array. Then, we presented subjects with a TI task using these same images. The implied TI order was either congruent or incongruent with the order of the trained spatial array. Humans in the congruent condition learned premise pairs more quickly, and were faster and more accurate in critical probe tests, suggesting that the spatial arrangement of images learned during spatial training influenced subsequent TI performance. Monkeys first trained in the congruent condition also showed higher test trial accuracy when the spatial and inferred orders were congruent. These results directly support the hypothesis that humans solve TI problems by spatial organization, and suggest that this cognitive mechanism for inference may have ancient evolutionary roots. PMID- 25546107 TI - Chimpanzees prefer African and Indian music over silence. AB - [Correction Notice: An Erratum for this article was reported in Vol 40(4) of Journal of Experimental Psychology: Animal Learning and Cognition (see record 2014-35305-001). For the article, the below files were used to create the audio used in this study. The original West African akan and North Indian raga pieces were used in their entirety and the Japanese taiko piece was used from the 0:19 second mark through the end. The tempo of each piece was adjusted so that they maintained an identical base tempo of 90 beats per minute, then looped to create 40 minutes of continuous music. Additionally, the volume of the music was standardized at 50 dB so that the all music maintained the same average amplitude. All audio manipulations were completed using GarageBand (c) (Apple Inc.).] All primates have an ability to distinguish between temporal and melodic features of music, but unlike humans, in previous studies, nonhuman primates have not demonstrated a preference for music. However, previous research has not tested the wide range of acoustic parameters present in many different types of world music. The purpose of the present study is to determine the spontaneous preference of common chimpanzees (Pan troglodytes) for 3 acoustically contrasting types of world music: West African akan, North Indian raga, and Japanese taiko. Sixteen chimpanzees housed in 2 groups were exposed to 40 min of music from a speaker placed 1.5 m outside the fence of their outdoor enclosure; the proximity of each subject to the acoustic stimulus was recorded every 2 min. When compared with controls, subjects spent significantly more time in areas where the acoustic stimulus was loudest in African and Indian music conditions. This preference for African and Indian music could indicate homologies in acoustic preferences between nonhuman and human primates. . PMID- 25546108 TI - Nanoengineered drug delivery systems for enhancing antibiotic therapy. AB - Formulation scientists are recognizing nanoengineered drug delivery systems as an effective strategy to overcome limitations associated with antibiotic drug therapy. Antibiotics encapsulated into nanodelivery systems will contribute to improved management of patients with various infectious diseases and to overcoming the serious global burden of antibiotic resistance. An extensive review of several antibiotic-loaded nanocarriers that have been formulated to target drugs to infectious sites, achieve controlled drug release profiles, and address formulation challenges, such as low-drug entrapment efficiencies, poor solubility and stability is presented in this paper. The physicochemical properties and the in vitro/in vivo performances of various antibiotic-loaded delivery systems, such as polymeric nanoparticles, micelles, dendrimers, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanohybirds, nanofibers/scaffolds, nanosheets, nanoplexes, and nanotubes/horn/rods and nanoemulsions, are highlighted and evaluated. Future studies that will be essential to optimize formulation and commercialization of these antibiotic-loaded nanosystems are also identified. The review presented emphasizes the significant formulation progress achieved and potential that novel nanoengineered antibiotic drug delivery systems have for enhancing the treatment of patients with a range of infections. PMID- 25546106 TI - Cashing out: The decisional flexibility of uncertainty responses in rhesus macaques (Macaca mulatta) and humans (Homo sapiens). AB - Researchers are exploring whether animals share with humans something like a metacognitive capacity. Though some results point to human-animal continuities in this domain, they face the dominant criticism that animals' performances might be associative. A persistent problem is that animal-metacognition paradigms present static environments of risk and reward that may foster inflexible and conditioned responding. Those environments do not challenge animals to show the flexibility in their decision strategies that could indicate an antecedent capacity to metacognition. Accordingly, we tested macaques and humans on an uncertainty monitoring paradigm in which risk changed dynamically. Participants classified stimuli of different difficulties while also choosing when to use a cashout response to collect the accumulated rewards that would be forfeit on a discrimination error. Macaques (Macaca mulatta) and humans flexibly adjusted their decision criteria to achieve appropriate protection against the cost of error that could differ depending on trial difficulty and the number of rewards at risk. In particular, monkeys widened their cashout-response region as their accumulated rewards increased, providing more protection against a more costly error. These findings demonstrate a new continuity between humans' and animals' uncertainty systems. They reveal a calibration by macaques of present risk to trial difficulty tolerated. They show that animals' uncertainty-monitoring and risk-management systems have substantial trial-by-trial flexibility. PMID- 25546109 TI - Plasma homocysteine level in patients with Behcet's disease. PMID- 25546110 TI - A case of refractory chronic neutrophilic pustular folliculitis treated with adalimumab. AB - Neutrophilic folliculitis is an often overlooked chronic condition characterized by a monomorphic eruption of "sterile" papulopustules. Neutrophilic folliculitis is often refractory to conventional treatment with topical and systemic antibiotics or isotretinoin. We report a case of severe pustular neutrophilic folliculitis successfully treated with the tumor necrosis factor-alpha inhibitor adalimumab. PMID- 25546111 TI - Survival advantage of marriage in uterine cancer patients contrasts poor outcome for widows: a Surveillance, Epidemiology and End Results study. AB - BACKGROUND: Marriage confers a survival advantage for many cancers but has yet to be evaluated in uterine cancer patients. We sought to determine whether uterine cancer survival varied by self-reported relationship status. METHODS: Data were downloaded from the Surveillance, Epidemiology, and End Results program for women diagnosed with uterine cancer (between 1991 and 2010 in nine geographic regions). Patients with complete clinical data for analysis were categorized as married, single, widowed or other (divorced or separated). Differences in distributions were evaluated using Chi-square, exact and/or Mantel-Haenszel test. Uterine cancer survival was analyzed by Kaplan-Meier method with log-rank test and multivariate Cox regression analysis. RESULTS: Of 47,420 eligible patients, 56% were married, 15% were single and 19% were widows. Married vs. non-married women had a higher likelihood of having low risk (grade 1/2 endometrioid) endometrial cancer and local disease (p<0.0001), and a reduced risk of cancer death (HR=0.8, 95% CI=0.77-0.84). Multivariate evaluation of uterine cancer survival by relationship type indicated that widows consistently had significantly worse uterine cancer survival than single, married and other women in all patients and subset analyses (p<0.0001). CONCLUSION: While marital status is associated with differential uterine cancer survival, evaluation of self-reported relationship by type indicated that the poor outcome observed in widows explained most of the benefit attributed to marriage. This report identifies widows as a new high-risk subpopulation with significantly inferior outcomes potentially benefiting from personalized care and social support. PMID- 25546112 TI - Improvement in symptom burden within one day after palliative care consultation in a cohort of gynecologic oncology inpatients. AB - OBJECTIVE: The aim of this study is to evaluate the magnitude and time course of change in symptom burden after palliative care (PC) consultation in a cohort of gynecologic oncology inpatients. METHODS: Women with a gynecologic malignancy and PC consultation for symptom management between 3/1/12 and 2/28/13 were identified. Charts were reviewed for demographic and disease characteristics. Symptom scores on a modified Edmonton Symptom Assessment System (ESAS) scale were abstracted for pain, anorexia, fatigue, depression, anxiety, nausea and dyspnea. Prevalence of moderate-to-severe symptom intensity was compared between the day of PC consultation (D1), the day after PC consultation (D2) and the last recorded symptoms before discharge (DLast). RESULTS: PC was consulted for symptom management during 129 admissions of 95 unique patients. Median age was 59, 84% were white and 67% had stage III/IV disease, with ovarian the most common site (52%). Symptom prevalence on D1 for at least mild intensity ranged 14% (dyspnea) to 80% (pain) and for at least moderate intensity from 3% (dyspnea) to 50% (pain). Statistically significant decreases in prevalence of moderate to severe symptom intensity between D1 and DLast occurred for pain, anorexia, fatigue and nausea (magnitude 58-66%) and between D1 and D2 for pain, fatigue and nausea (magnitude 50-55%). The majority of the improvement that occurred between D1 and DLast happened by D2. CONCLUSIONS: PC consultation is associated with improvement in symptom burden, the majority of which occurs within one day of consultation. PC may be an effective tool for symptom management in patients with moderate to severe symptom intensity even during short hospitalizations and should be considered early in the hospitalization to effect timely symptom relief. PMID- 25546113 TI - The prognostic value of dividing epithelial ovarian cancer into type I and type II tumors based on pathologic characteristics. AB - OBJECTIVE: To investigate the prognostic significance of dividing epithelial ovarian cancer (EOC) in type I and type II tumors based on pathologic variables. METHODS: We used the Danish Gynecologic Cancer Database to identify all patients diagnosed with EOC from 2005 to 2012. Information on histologic type and grade were used to classify tumors as either type I or type II. Death, and several prognostic factors were used in the multivariate Cox regression, and Landmark analysis was used to estimate hazard ratios of all-cause mortality. RESULTS: Among 2660 patients diagnosed with EOC, 735 were categorized as type I tumors, and 1925 as type II tumors. Patients with type II EOC were more frequently diagnosed in late FIGO stages (stages III-IV) than patients with type I EOC (78.1% vs. 32.1% respectively; P<0.001). Time dependent multivariate Cox analysis, adjusted for known prognostic variables, showed no significant difference in survival within the first two years after diagnosis, however, after 730days of follow-up a significantly increased overall survival for type I tumors was observed (hazard ratio 1.72, 95% confidence interval: 1.28-2.31, P<0.001). Similarly the Landmark analysis for survival confirmed the increased overall survival for type I tumors after two years of follow-up (hazard ratio: 1.85, 95% confidence interval: 1.35-2.54, P<0.001). CONCLUSION: Classification of EOC in type I and type II tumors based on pathologic variables was associated with an increased risk of death for type II tumors after two years of follow-up, while no increased risk was seen during the first two years of follow-up. PMID- 25546115 TI - Robotic transperitoneal infra-renal aortic lymphadenectomy in early-stage endometrial cancer. AB - OBJECTIVES: To assess the clinical performance of robotic-assisted infra-renal aortic lymphadenectomy (IRL) using a single center-docked approach for patients with endometrial cancer. METHODS: Robotic-assisted hysterectomy with pelvic and aortic lymphadenectomy was performed in 97 clinical stage I endometrial cancer (EC) patients with the intent to remove infra-renal aortic lymph nodes. Peri operative data was contemporaneously accessioned and a retrospective database analysis was performed to examine clinical outcomes. RESULTS: IRL versus infra mesenteric artery (IMA) dissections were accomplished in 88 (90.7%) and nine (9.3%) cases, respectively. There were no laparotomy conversions. Histology included 20.6% G1, 41.2% G2, and 38.1% G3 (endometrioid and Type II histologies). Forty-four (45.4%) cases had >50% depth-of-invasion and 43 (44.3%) cases had lymphovascular space invasion. Lymph node metastases were detected in 39 (40.2%) cases [37 (38.1%) pelvic, 16 (16.5%) pelvic+aortic, two (2.1%) isolated aortic lymph nodes]. Aortic metastasis was identified in 16/37 (43.2%) pelvic node positive cases, and 6/34 (17.7%) IRL cases with positive pelvic nodes had infra renal metastasis, yet normal aortic nodes below the IMA. Harvested aortic lymph nodes for IRL exceeded IMA cases (15.9+/-6.3 vs. 8.9+/-4.6; p<0.01). Mean BMI for IMA cases exceeded IRL cases (37.4+/-3.3 vs. 31.4+/-7.1kg/m(2); p<0.001). Twenty five (81%) patients with BMI >35kg/m(2) underwent successful IRL (range 36 47kg/m(2)) compared to 95% of cases <35kg/m(2) (p=0.03). CONCLUSIONS: IRL was accomplished in 95% of EC patients with BMI <35kg/m(2) and 81% with BMI >35kg/m(2) using a single center-docked approach. A strict 35kg/m(2) BMI cut-off for avoiding IRL is therefore not advised. PMID- 25546114 TI - The role of systemic chemotherapy in the management of granulosa cell tumors. AB - OBJECTIVE: Granulosa cell tumors (GCTs) are rare, and the role of chemotherapy in their management is not clearly defined. METHODS: We performed a retrospective cohort study of GCT patients diagnosed from January 1996 through June 2013 at the Memorial Sloan Kettering Cancer Center, comparing those who received adjuvant chemotherapy to those who did not. Differences between groups were assessed using the log-rank test. Statistical significance was set at p<0.05. RESULTS: Of 118 patients, 10 (8%) received adjuvant chemotherapy (1 [1%] of 103 stage I and 9 [60%] of 15 stage II-IV patients). Thirty-two patients (27%) experienced disease recurrence. Four patients had residual disease after initial surgery, and all received adjuvant chemotherapy; each recurred within 24.3 months (median PFS, 8.2 months). The time to first recurrence was longer in patients who did not receive adjuvant chemotherapy. For patients with recurrent disease, receiving chemotherapy after surgery for first recurrence did not seem to improve time to second recurrence versus surgery alone (HR 0.98; p=0.965). Additionally, 12 patients (10%) had a previous diagnosis of breast cancer-an incidence rate 3.22 times higher than Surveillance, Epidemiology, and End Results (SEER) data predicts (p<0.001). CONCLUSIONS: Although the numbers were small, in this analysis chemotherapy was not found to improve the recurrence-free interval of patients with GCTs, a finding that requires prospective validation. Residual disease after surgery was associated with poor prognosis. Finally, there was a significantly higher than expected incidence of antecedent breast cancer in this population, an association that deserves further exploration. PMID- 25546117 TI - Nurse practitioner continuing education: exploring influences. AB - PURPOSE: This article introduces the interrelated concepts of nurse practitioner (NP) continuing education (CE) funding patterns, regulatory guidance surrounding NP CE, and its effect on patient outcomes in the United States. DATA SOURCES: A literature review was done by searching online databases: MEDLINE and CINAHL. Searches included review of NP certifying body websites, Institute of Medicine, Josiah Macy Foundation, and the National Council of State Boards of Nursing websites. CONCLUSIONS: The nursing literature supports no connection between required CE and improvement in provision of care to patients, nor does it support improvement in individual provider competence. The funding patterns for nursing and medicine indicate a bias toward biomedical and pharmacological interventions. This type of funding stream may contribute to practice gaps rather than improve them. IMPLICATIONS FOR PRACTICE: Understanding factors that influence CE program availability, plus the choices NPs make regarding mandatory CE, can provide planning guidance. This guidance can help reach the goal of improved patient outcomes and decreased healthcare disparities as a result of CE interventions. NP specific findings may potentially influence regulatory reform relevant to mandatory CE and maintenance of certification. It is important that NPs recognize existing conflicts of interest in order to make informed program choices. PMID- 25546116 TI - Measuring coping style following acquired brain injury: a modification of the Coping Inventory for Stressful Situations Using Rasch analysis. AB - OBJECTIVE: The importance of coping style factors in the process of emotional adjustment following acquired brain injury (ABI) has been gaining increased attention. To assess ways of coping with distress accurately, clear conceptual definitions and measurement precision is vital. The purpose of this study was to investigate the psychometric properties of a well-known measure of coping, the Coping Inventory for Stressful Situations (CISS), for people who have experienced an ABI; and to modify the CISS, where necessary, to create a more reliable and valid measurement tool for this clinical group. METHODS: Psychometric properties were investigated using Rasch analysis of responses from a sample of adults with ABI (n = 207). The internal consistency reliability and construct validity of the scale were examined. RESULTS: All originally proposed subscales were not valid or reliable and, as such, were incapable of interval-level measurement within this sample - Task: chi(2) (32, N = 207) = 105.1, p < .001; Emotion: chi(2) (32, N = 204) = 121.9, p < .001; Avoidance: chi(2) (32, N = 207) = 66.7, p < .001. Three valid and reliable subscales were derived measuring emotion-, task-, and avoidance-oriented coping styles by removing items that provided the most unreliable information and exploring fit to the Rasch model. CONCLUSIONS: The original version of the CISS may not be a valid and reliable measure of coping style following ABI. Modified subscales of the three distinct coping domains have been proposed that would help to improve measurement of coping style following ABI in future research and clinical practice. PRACTITIONER POINTS: How people cope with difficulties following an ABI has been shown to impact upon emotional outcomes and functional recovery. The original version of the CISS was found to be an imprecise measure of coping following ABI. A modified version of the CISS was found to be a valid and reliable measure of three styles of coping (task focused, emotion-focused, and avoidance-focused) that conforms to the properties of interval-level measurement as represented by the Rasch model. This structure is in keeping with previous theoretical models of coping. We advise caution about including items (1, 6, 7, 22, 24, 28, 29, 33, 34, and 46) that were found to diverge from the expectations of the Rasch measurement model in total subscale scores for measuring change in coping style. A conversion table for the three modified subscales is included in this paper to convert total raw scores into Rasch transformed logit values. Identifying strengths and weaknesses in coping style could be a means of guiding psychological intervention to promote good recovery following ABI. The sample included mainly people who had experienced non traumatic brain injuries (e.g., a stroke). This research could be extended to include broader sample of people with differing brain injury aetiologies and neurological disorders. PMID- 25546118 TI - A cross-sectional survey of factors related to inpatient assault of staff in a forensic psychiatric hospital. AB - AIM: To understand staff factors associated with patient aggression towards the staff of an inpatient forensic psychiatric hospital. BACKGROUND: Violence by patients is a serious concern in psychiatric hospitals and staff are the most frequent targets of physical and verbal assault. Assault and its consequences can severely disrupt the hospital environment and impair the functioning of staff members and patients. This study examined the interplay of staff dispositional and interpersonal factors associated with patient violence. DESIGN: This cross sectional study surveyed the staff of a large public forensic hospital. METHODS: A sample of 348 psychiatric staff participated in an online survey about their workplace experiences, psychosocial characteristics and well-being. Data were collected from November - December 2011. FINDINGS: Nearly all staff reported verbal conflict with patients (99%) and 70% reported being assaulted during the previous 12 months. Verbal conflict with other staff (92%) was also high. Multiple regression analyses indicated that in addition to static risk factors (i.e. staff position, years of experience and gender), the risk of assault was associated with the frequency of conflicts with staff and patients, which in turn was moderated by personal stress reactivity. CONCLUSION: Physical violence by patients was a pervasive threat for a high proportion of staff. Frequent conflict interactions with volatile patients contributed the most risk, but reactivity to conflict was a dynamic risk factor. The strain associated with assault risk and stress reactivity could be prospectively mitigated by resilience enhancement programming for staff. PMID- 25546119 TI - Growth inhibition and apoptosis induction by Scutellaria pinnatifida A. Ham. on HL-60 and K562 leukemic cell lines. AB - A rich flavonoid plant extensively used in traditional medicine is Scutellaria (Lamiaceae). In this study the cytotoxic effects of different extracts of Scutellaria pinnatifida were explored on two different cancer cell lines including K562 and HL-60 and a normal cell line. Also, the role of apoptosis on this toxicity was explored. The cell viability was quantitated by alamarBlue((r)) assay. S. pinnatifida could effectively decrease the viability of malignant cells and the CH2Cl2 extract of S. pinnatifida had showed the most cytotoxic effects among other extracts. Apoptosis was confirmed after propidium iodide staining of DNA fragments and detection of the sub-G1 peak in the related flow cytometry histogram of cells. The results of western blot assay showed that CH2Cl2 extract has been able to increase the amount of Bax and cleavage of PARP protein after a 48h contact with cells. Neobaicalein (skullcapflavone II) and wogonin were identified in the extract of S. pinnatifida as the active components. The result of the present study confirmed the putative role of neobaicalein (skullcapflavone II) and wogonin as cytotoxic components in the CH2Cl2 extract of S. pinnatifida. PMID- 25546120 TI - Pharmacokinetic profile of cefquinome after oral subchronic flubendiamide exposure and in vitro plasma protein binding in buffalo calves. AB - The disposition kinetics study of cefquinome was conducted following single intravenous (IV) administration of 2mg/kg bodyweight in buffalo calves after oral subchronic exposure to flubendiamide and to determine the in vitro plasma protein binding of cefquinome. Plasma concentrations of cefquinome were analyzed using reverse-phase high performance liquid chromatography (HPLC). The results were compared with our earlier study on the pharmacokinetics of cefquinome in untreated buffalo calves. Plasma concentration-time data for cefquinome following IV injection were best fit into a two-compartmental open model in flubendiamide exposed buffalo calves. Following flubendiamide exposure, most of the pharmacokinetic parameters of cefquinome were significantly altered in buffalo calves. Cefquinome was bound to plasma proteins of buffalo calves to the extent of 11.4+/-0.66%. In flubendiamide-exposed animals an intravenous dose of 2mg/kg body weight would maintain the therapeutic plasma levels required to be effective against the bacterial pathogens with MIC values <=0.39MUg/mL for only 12h, whereas in untreated buffalo calves the same dose of 2mg/kg body weight would maintain the plasma levels up to 24h, The study revealed that subchronic flubendiamide exposure significantly alters the disposition of cefquinome in buffalo calves. PMID- 25546121 TI - Establishment of a rapid drug screening system based on embryonic stem cells. AB - Embryonic stem (ES) cells have the capacity for self-renewal and differentiation into three germ layers following formation of embryonic bodies (EB). To investigate toxicity of pharmaceutical compounds, five toxic chemicals, indomethacin, dexamethasone, hydroxyurea, 5-fluorouracil, and cytosine arabinoside were applied in mouse ES cells during formation of EBs. Using microscopic evaluation, the size of EBs was reduced in a dose-dependent manner by treatment with pharmaceutical chemicals. While apoptosis-related proteins, cleaved caspase-3 and PARP, were decreased in compound-exposed EBs, necrosis related protein (Hmgb1) was present in culture media of EBs, indicating that detection of Hmgb1 can result in activation of necrosis by pharmaceutical compounds. While pharmaceutical compounds impaired the differentiation of mES cells linked with spontaneous apoptotic cell death, it was determined that cytotoxic cell damage is necrosis-dependent in mES cells. In addition, an apoptotic transcript (Noxa mRNA) in toxicant-exposed EBs was decreased in parallel with apoptosis-related proteins. Following impairment of apoptosis, differentiation-related markers including un-differentiation (Sox2), endoderm (Hnf4), mesoderm (Bmp4), and ectoderm (Pax6) also fluctuated by treatment with pharmaceutical compounds. Taken together, the data imply that exposure to pharmaceutical compounds results in increased cell death hindering the spontaneous apoptosis of cells to undergo differentiation. Using both characteristics of ES cells like self-renewal or cellular pluripotency and potentials of ES cells for evaluation in toxicity of various compounds, the current study was conducted for establishment of a novel drug screening system beyond hidden virtues of the well-known chemicals. PMID- 25546122 TI - Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress. AB - The average length of human life is increasing, but so does the incidence of age- and lifestyle-related diseases. Improving diet and lifestyle is a key strategy for lifelong health and underlying mechanisms may well include increasing resilience pathways. The purpose of this review is to highlight and evaluate novel mechanisms by which dietary pro-oxidants, including bioactive phytochemicals and fatty acids, increase reactive oxygen species (ROS) concentrations just enough to activate transcription factor activation of nuclear factor erythroid 2 related factor 2 (Nrf-2) and heat shock factor (HSF), leading to an increase in levels of antioxidant enzymes and heat shock proteins that protect against the damaging effects of ROS. An increasing number of in vivo studies have now shown that dietary pro-oxidant compounds can increase the production of such resilience products. In most studies, dietary pro-oxidants normalized levels of antioxidant enzymes that were decreased by a range of different challenges, rather than raising levels of resilience products per se. Also, it is important to consider that the antioxidant response can be different for different organs. For future studies, however, the measurement of resilience markers may significantly improve our ability to prove the efficacy by which dietary bioactives with pro-oxidant capacities improve lifelong health. PMID- 25546123 TI - Proteomics analysis of rough endoplasmic reticulum in pancreatic beta cells. AB - Pancreatic beta cells have well-developed ER to accommodate for the massive production and secretion of insulin. ER homeostasis is vital for normal beta cell function. Perturbation of ER homeostasis contributes to beta cell dysfunction in both type 1 and type 2 diabetes. To systematically identify the molecular machinery responsible for proinsulin biogenesis and maintenance of beta cell ER homeostasis, a widely used mouse pancreatic beta cell line, MIN6 cell was used to purify rough ER. Two different purification schemes were utilized. In each experiment, the ER pellets were solubilized and analyzed by 1D SDS-PAGE coupled with HPLC-MS/MS. A total of 1467 proteins were identified in three experiments with >=95% confidence, among which 1117 proteins were found in at least two separate experiments and 737 proteins found in all three experiments. GO analysis revealed a comprehensive profile of known and novel players responsible for proinsulin biogenesis and ER homeostasis. Further bioinformatics analysis also identified potential beta cell specific ER proteins as well as ER proteins present in the risk genetic loci of type 2 diabetes. This dataset defines a molecular environment in the ER for proinsulin synthesis, folding and export and laid a solid foundation for further characterizations of altered ER homeostasis under diabetes-causing conditions. All MS data have been deposited in the ProteomeXchange with identifier PXD001081 (http://proteomecentral.proteomexchange.org/dataset/PXD001081). PMID- 25546124 TI - Alkaline phosphatase is a useful cytochemical marker for the diagnosis of acute myelomonocytic and monocytic leukemia in the dog. AB - BACKGROUND: Immunophenotyping has replaced cytochemical staining as the preferred technique for classifying acute leukemia. However, some acute myeloid leukemias (AML) lack lineage-associated markers. In our experience, alkaline phosphatase (ALP) is expressed in immature canine monocytes. We hypothesized that ALP is a useful marker for monocytic AML. OBJECTIVES: The objective was to compare ALP expression in neoplastic cells from dogs with lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoid leukemia (ALL), and AML. METHODS: Alkaline phosphatase results were retrieved from medical records of dogs with acute leukemia. Smears from dogs with lymphoma or leukemia were also prospectively stained for ALP activity. CLL was based on persistent lymphocytosis (10 * 10(9) /L) and acute leukemia on >= 20% blasts in blood or bone marrow. ALL was classified based on positive phenotyping for T- or B-lymphocyte antigens, and AML on positive phenotyping for CD11b, CD11c or CD14, or cytochemical staining for chloroacetate esterase, Sudan Black B, or myeloperoxidase. RESULTS: There was no ALP activity in all 49 lymphomas and 7 CLLs. Weak ALP activity was seen in 31% of 14 ALL (all T-ALL). ALP activity was seen in all 20 AML (P < .001 vs ALL) with strong activity in 64% (vs 25% ALL) in most neoplastic cells (median 75% vs 9% ALL, P = .020). Of AML, 80% were CD34+ (vs 39% ALL, P = .027) and 100% were MHCII (vs 43% ALL, P = .002). CONCLUSIONS: ALP activity may be useful for AML confirmation in dogs, particularly if neoplastic cells only express CD34+ on immunophenotyping. PMID- 25546126 TI - Abstracts of the 2014 International Society Developmental Psychobiology Meeting, November 12-14, 2014, Washington, DC, USA. PMID- 25546128 TI - Ebola, physicians in training, and the duty to treat. PMID- 25546127 TI - Endothelin2 Induces Expression of Genes Associated with Reactive Gliosis in Retinal Muller Cells. AB - PURPOSE/AIM OF THE STUDY: Photoreceptor degeneration is normally accompanied by reactive gliosis and gene expression changes in Muller (glial) cells. The signaling pathway involved inducing these changes in Muller cells is not known. It has been proposed that endothelin2 (EDN2) released by degenerating photoreceptors might induce gliotic changes in Muller cells. In the present study, we directly tested the hypothesis by determining whether treatment of Muller cell cultures with EDN2 results in upregulation of genes known to be expressed in activated Muller cells in vivo. MATERIALS AND METHODS: Experiments were carried using an established rat Muller cell line (rMC-1), and gene expression was assessed by qRT-PCR. RESULTS: We observed that EDN2 treatment upregulated transcripts for glial fibrillary acidic protein (Gfap), Serpina3n and endothelin receptor B (EdnrB), three genes associated with reactive gliosis in Muller cells. Ciliary neurotrophic factor (CNTF) treatment similarly led to induction of Gfap, Serpina3n and EdnrB transcripts, whereas glutamate treatment had no significant effect. CONCLUSIONS: The finding supports a role for EDN2 as a signaling agent between photoreceptors and Muller cells. PMID- 25546129 TI - Anogenital granulomatosis: report of two cases. AB - Anogenital granulomatosis (AGG) is a rare chronic inflammatory disorder of unknown aetiology. It presents clinically with swelling of the genital or anoperineal area, with histopathological findings of noncaseating giant cell granulomas. Some cases of AGG are associated with underlying systemic disease, mainly Crohn disease. We report two patients with AGG. The first was a young man with ulcerative colitiis treated with infliximab, which also alleviated the developing symptoms of AGG. The second was a young woman who was otherwise healthy. After the introduction of complex decongestive therapy, the oedema was considerably reduced in both patients. PMID- 25546130 TI - Posterior cortical atrophy as an extreme phenotype of GRN mutations. AB - IMPORTANCE: Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described. OBSERVATIONS: We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient. CONCLUSIONS AND RELEVANCE: This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present. PMID- 25546131 TI - Determination of beta-agonists in swine hair by MUFIA and chemiluminescence. AB - beta-Agonists are a group of illegal feed additives. In this paper, it was found that the light emission produced by the oxidation of luminol by potassium ferricyanide was enhanced by the beta-agonists (ractopamine, salbutamol, and terbutaline). Based on chemiluminescence phenomenon, a novel, rapid, and sensitive microflow injection analysis system on a microfluidic glass chip was established for determination of the beta-agonists. The chip was fabricated from two glass plates (64 mm * 32 mm) with microchannels of 200 MUm width and 100 MUm depth. The detection limits were achieved at 2.0 * 10(-8) mol/L of ractopamine, 1.0 * 10(-8) mol/L of terbutaline and 5.0 * 10(-7) mol/L of salbutamol. In this report, our method was applied for determination of the beta-agonists in swine hair from three different sources with satisfactory results. PMID- 25546132 TI - Extradural thoracic spinal lesion presenting as low back and leg pain. PMID- 25546134 TI - Noise affects the shape of female preference functions for acoustic signals. AB - The shape of female mate preference functions influences the speed and direction of sexual signal evolution. However, the expression of female preferences is modulated by interactions between environmental conditions and the female's sensory processing system. Noise is an especially relevant environmental condition because it interferes directly with the neural processing of signals. Although noise is therefore likely a significant force in the evolution of communication systems, little is known about its effects on preference function shape. In the grasshopper Chorthippus biguttulus, female preferences for male calling song characteristics are likely to be affected by noise because its auditory system is sensitive to fine temporal details of songs. We measured female preference functions for variation in male song characteristics in several levels of masking noise and found strong effects of noise on preference function shape. The overall responsiveness to signals in noise generally decreased. Preference strength increased for some signal characteristics and decreased for others, largely corresponding to expectations based on neurophysiological studies of acoustic signal processing. These results suggest that different signal characteristics will be favored under different noise conditions, and thus that signal evolution may proceed differently depending on the extent and temporal patterning of environmental noise. PMID- 25546135 TI - A quantitative proteomics tool to identify DNA-protein interactions in primary cells or blood. AB - Interactions between transcription factors and genomic DNA, and in particular their impact on disease and cell fate, have been extensively studied on a global level using techniques based on next-generation sequencing. These approaches, however, do not allow an unbiased study of protein complexes that bind to certain DNA sequences. DNA pulldowns from crude lysates combined with quantitative mass spectrometry were recently introduced to close this gap. Established protocols, however, are restricted to cell lines because they are based on metabolic labeling or require large amounts of material. We introduce a high-throughput compatible DNA pulldown that combines on-bead digestion with direct dimethyl labeling or label-free protein quantification. We demonstrate that our method can efficiently identify transcription factors binding to their consensus DNA motifs in extracts from primary foreskin fibroblasts and peripheral blood mononuclear cells (PBMCs) freshly isolated from human donors. Nuclear proteomes with absolute quantification of nearly 7000 proteins in K562 cells and PBMCs clearly link differential interactions to differences in protein abundance, hence stressing the importance of selecting relevant cell extracts for any interaction in question. As shown for rs6904029, a SNP highly associated with chronic lymphocytic leukemia, our approach can provide invaluable functional data, for example, through integration with GWAS. PMID- 25546133 TI - Contrasting roles for C/EBPalpha and Notch in irradiation-induced multipotent hematopoietic progenitor cell defects. AB - Ionizing radiation (IR) is associated with reduced hematopoietic function and increased risk of hematopoietic malignancies, although the mechanisms behind these relationships remain poorly understood. Both effects of IR have been commonly attributed to the direct induction of DNA mutations, but evidence supporting these hypotheses is largely lacking. Here we demonstrate that IR causes long-term, somatically heritable, cell-intrinsic reductions in hematopoietic stem cell (HSC) and multipotent hematopoietic progenitor cell (mHPC) self-renewal that are mediated by C/EBPalpha and reversed by Notch. mHPC from previously irradiated (>9 weeks prior), homeostatically restored mice exhibit gene expression profiles consistent with their precocious differentiation phenotype, including decreased expression of HSC-specific genes and increased expression of myeloid program genes (including C/EBPalpha). These gene expression changes are reversed by ligand-mediated activation of Notch. Loss of C/EBPalpha expression is selected for within previously irradiated HSC and mHPC pools and is associated with reversal of IR-dependent precocious differentiation and restoration of self-renewal. Remarkably, restoration of mHPC self-renewal by ligand-mediated activation of Notch prevents selection for C/EBPalpha loss of function in previously irradiated mHPC pools. We propose that environmental insults prompt HSC to initiate a program limiting their self-renewal, leading to loss of the damaged HSC from the pool while allowing this HSC to temporarily contribute to differentiated cell pools. This "programmed mediocrity" is advantageous for the sporadic genotoxic insults animals have evolved to deal with but becomes tumor promoting when the entire HSC compartment is damaged, such as during total body irradiation, by increasing selective pressure for adaptive oncogenic mutations. PMID- 25546137 TI - Transcorneal oxygen therapy in two patients with traumatic hyphema and sickle cell trait. PMID- 25546139 TI - Osseointegrated implant-based dental rehabilitation in head and neck reconstruction patients. AB - BACKGROUND: Dental restoration is an integral part of head and neck cancer reconstruction. METHODS: We evaluated the success rate of osseointegrated implants in patients with head and neck cancer, comparing outcomes between implants placed in fibula free flaps to those placed in native mandibular and maxillary bone. RESULTS: A total of 1132 implants were placed in 246 patients. The overall implant loss rate was 3.7% and was higher in fibula flaps (8.2%) compared to the native mandible (2.6%) and maxilla (2.2%), although these differences did not reach statistical significance (p = .059 and p = .053, respectively). The failure rate was 8.0% for implants placed after radiation and 3.6% in patients who did not undergo radiation (p = .097). Osteoradionecrosis (ORN) occurred in 19 patients (7.7%) after implant placement, and tobacco use was found to be a risk factor (p = .027). CONCLUSION: Osseointegrated implants are reliable in patients with head and neck cancer, including those undergoing bony free flap reconstruction. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E321 E327, 2016. PMID- 25546138 TI - Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1. AB - Expression of miRNAs in Neuroendocrine Neoplasms (NEN) is poorly characterized. We therefore wanted to examine the miRNA expression in Neuroendocrine Tumors (NETs), and identify their targets and importance in NET carcinogenesis. miRNA expression in six NEN primary tumors, six NEN metastases and four normal intestinal tissues was characterized using miRNA arrays, and validated by in-situ hybridization and qPCR. Among the down-regulated miRNAs miR-129-5p and the let 7f/let-7 family, were selected for further characterization. Transfection of miR 129-5p inhibited growth of a pulmonary and an intestinal carcinoid cell line. Analysis of mRNA expression changes identified EGR1 and G3BP1 as miR-129-5p targets. They were validated by luciferase assay and western blotting, and found robustly expressed in NETs by immunohistochemistry. Knockdown of EGR1 and G3BP1 mimicked the growth inhibition induced by miR-129-5p. let-7 overexpression inhibited growth of carcinoid cell lines, and let-7 inhibition increased protein content of the transcription factor BACH1 and its targets MMP1 and HMGA2, all known to promote bone metastases. Immunohistochemistry analysis revealed that let 7 targets are highly expressed in NETs and metastases. We found down-regulation of miR-129-5p and the let-7 family, and identified new neuroendocrine specific targets for these miRNAs, which contributes to the growth and metastatic potential of these tumors. PMID- 25546140 TI - Mutation of purD and purF genes further attenuates Brucella abortus strain RB51. AB - In the present study, transposon mutagenesis was used to further attenuate Brucella abortus RB51 vaccine strain. Two purD and purF mutants were constructed, characterized and evaluated for attenuation via intracellular survival in murine macrophage-like RAW264.7 and HeLa cells, and by clearance in BALB/c mice. The purD and purF mutants showed significantly decreased intracellular survival, and complementation of these mutants with intact copies of purD or purF genes of RB51 strain was able to restore these defects. In addition, the pur mutants presented significantly lowered persistence in mice. Immunization with purD and purF mutants protected mice against a challenge with the virulent B. abortus strain 544 at a level similar to that of the parent RB51. These data suggest that genes encoding the early stages of purine biosynthesis (purD and purF) are required for intracellular survival and virulence of B. abortus. PMID- 25546141 TI - Computational design of a time-dependent histone deacetylase 2 selective inhibitor. AB - Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2 selective inhibitor, beta-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the beta-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2. PMID- 25546142 TI - Drinking motives mediate the negative associations between mindfulness facets and alcohol outcomes among college students. AB - Mindfulness and drinking motives have both been linked to affect regulation, yet the relationship between mindfulness and drinking motives is poorly understood. The present study examined whether drinking motives, particularly mood regulatory motives, mediated the associations between facets of mindfulness and alcohol related outcomes among college students (N = 297). We found 3 specific facets of mindfulness (describing, nonjudging of inner experience, and acting with awareness) to have negative associations with alcohol outcomes. Importantly, specific drinking motives mediated these associations such that lower levels of mindfulness were associated with drinking for distinct reasons (enhancement, coping, conformity), which in turn predicted alcohol use and/or alcohol problems. Our findings suggest that drinking motives, especially mood regulatory and negative reinforcement motives, are important to examine when studying the role of mindfulness in college student drinking behavior. (PsycINFO Database Record PMID- 25546143 TI - College students' drinking motives and social-contextual factors: Comparing associations across levels of analysis. AB - Prior investigations have established between-person associations between drinking motives and both levels of alcohol use and social-contextual factors surrounding that use, but these relations have yet to be examined at the within person level of analysis. Moreover, exploring previously posited subtypes of coping motives (i.e., coping with depression, anxiety, and anger) may shed light on the within-person processes underlying drinking to cope. In this daily diary study of college student drinking (N = 722; 54% female), students reported each day how many drinks they consumed the previous evening in both social and nonsocial settings along with their motives for each drinking episode. Additionally, they reported whether they attended a party the evening before, the number of people they were with, the gender makeup of that group, and their perceptions of their companions' drinking prevalence and quantity. External reasons for drinking-social and conformity motives-showed patterns largely consistent across levels of analysis and in agreement with motivational models. However, internal reasons for drinking-enhancement and coping motives demonstrated divergent associations that suggest different processes across levels of analysis. Finally, coping subtypes showed differing associations with drinking levels and social-contextual factors dependent on the predisposing emotion and the level of analysis. These results suggest that internal drinking motives have unique state and trait components, which could have important implications for the application of motivational models to prevention and treatment efforts. We recommend including drinking motives (including coping subtypes) as within-person measures in future microlongitudinal studies. (PsycINFO Database Record PMID- 25546145 TI - The influence of natural organic matter and aging on suspension stability in guideline toxicity testing of silver, zinc oxide, and titanium dioxide nanoparticles with Daphnia magna. AB - The present study investigated changes in suspension stability and ecotoxicity of engineered nanoparticles (ENPs) by addition of Suwannee River natural organic matter and aging of stock and test suspensions prior to testing. Acute toxicity tests of silver (Ag), zinc oxide (ZnO), and titanium dioxide (TiO2 ) ENPs with Daphnia magna were carried out following Organisation for Economic Co-operation and Development test guidelines. Daphnia magna was found to be very sensitive to Ag ENPs (48-h 50% effective concentration 33 MUg L(-1) ), and aging of the test suspensions in M7 medium (up to 48 h) did not decrease toxicity significantly. Conversely, the presence of Suwannee River natural organic matter (NOM; 20 mg L( 1) ) completely alleviated Ag ENP toxicity in all testing scenarios and did not aid in stabilizing suspensions. In contrast, addition of Suwannee River NOM stabilized ZnO ENP suspensions and did not decrease toxicity. Aging for 48 h generated monotonous concentration-response curves in the presence and absence of Suwannee River NOM. At concentrations up to 100 mg L(-1) TiO2 ENPs did not cause immobilization of D. magna under any of the tested conditions. Presence of Suwannee River NOM caused agglomeration in stock suspensions. The authors' results suggest that aging and presence of Suwannee River NOM are important parameters in standard toxicity testing of ENPs, which in some cases may aid in gaining better control over the exposure conditions but in other cases might contribute to agglomeration or elimination of ENP toxicity. Therefore, modifications to the current guidelines for testing ENPs should be evaluated on a case-by-case basis. Environ Toxicol Chem 2015;34:497-506. (c) 2014 SETAC. PMID- 25546144 TI - Project INTEGRATE: An integrative study of brief alcohol interventions for college students. AB - This article provides an overview of a study that synthesizes multiple, independently collected alcohol intervention studies for college students into a single, multisite longitudinal data set. This research embraced innovative analytic strategies (i.e., integrative data analysis or meta-analysis using individual participant-level data), with the overall goal of answering research questions that are difficult to address in individual studies such as moderation analysis, while providing a built-in replication for the reported efficacy of brief motivational interventions for college students. Data were pooled across 24 intervention studies, of which 21 included a comparison or control condition and all included one or more treatment conditions. This yielded a sample of 12,630 participants (42% men; 58% first-year or incoming students). The majority of the sample identified as White (74%), with 12% Asian, 7% Hispanic, 2% Black, and 5% other/mixed ethnic groups. Participants were assessed 2 or more times from baseline up to 12 months, with varying assessment schedules across studies. This article describes how we combined individual participant-level data from multiple studies, and discusses the steps taken to develop commensurate measures across studies via harmonization and newly developed Markov chain Monte Carlo (MCMC) algorithms for 2-parameter logistic item response theory models and a generalized partial credit model. This innovative approach has intriguing promises, but significant barriers exist. To lower the barriers, there is a need to increase overlap in measures and timing of follow-up assessments across studies, better define treatment and control groups, and improve transparency and documentation in future single intervention studies. PMID- 25546147 TI - Pax7 is back. AB - Two recent studies have reinvigorated the conversation regarding the role of Pax7 in adult satellite. Studies by Gunther et al (Cell Stem Cell 13:590-601, 2013) and Von Maltzhen et al (Proc Natl Acad Sci U S A 110:16474-16479) show that Pax7 is critical for adult satellite cell function and their contribution to muscle repair. Previously, Lepper et al (Nature 460:627-631, 2009) demonstrated that Pax7 was dispensable for adult muscle repair. In this commentary I have summarized the results from these studies, focusing on the differences in experimental paradigms that led the authors to different conclusions. I also take this opportunity to discuss the potential limitations and hurdles of Cre-lox technology that are responsible for the discrepant results. PMID- 25546146 TI - Parallel force assay for protein-protein interactions. AB - Quantitative proteome research is greatly promoted by high-resolution parallel format assays. A characterization of protein complexes based on binding forces offers an unparalleled dynamic range and allows for the effective discrimination of non-specific interactions. Here we present a DNA-based Molecular Force Assay to quantify protein-protein interactions, namely the bond between different variants of GFP and GFP-binding nanobodies. We present different strategies to adjust the maximum sensitivity window of the assay by influencing the binding strength of the DNA reference duplexes. The binding of the nanobody Enhancer to the different GFP constructs is compared at high sensitivity of the assay. Whereas the binding strength to wild type and enhanced GFP are equal within experimental error, stronger binding to superfolder GFP is observed. This difference in binding strength is attributed to alterations in the amino acids that form contacts according to the crystal structure of the initial wild type GFP-Enhancer complex. Moreover, we outline the potential for large-scale parallelization of the assay. PMID- 25546148 TI - Evaluation of portal vein invasion of distal cholangiocarcinoma as borderline resectability. AB - BACKGROUND: The concept of borderline resectability has not yet been introduced for extrahepatic cholangiocarcinoma (ECC). In this study, the surgical results of ECC patients were analyzed to clarify the implications of surgery for distal ECC with portal vein (PV) invasion as a preliminary step for the introduction of the concept of borderline resectability. METHODS: The clinicopathological data of 129 patients who had undergone pancreatoduodenectomy of distal ECC were reviewed retrospectively. Combined PV resection was performed in 10 patients. The clinicopathological variables were evaluated using univariate and multivariate analyses. RESULTS: Pathological PV invasion was observed in eight of the 129 patients. The survival rates of patients with PV invasion were significantly poorer than those of patients without PV invasion: 3 and 5 years after surgery, 17% and 0% versus 50% and 39% (P < 0.001), respectively. Presence of pancreatic or PV invasion, tumor progression, nodal status, and residual tumor were significant prognostic factors on univariate analysis. On multivariate analysis, PV invasion was the only significant independent predictive factor of a poor prognosis. CONCLUSIONS: PV invasion of distal ECC should be regarded as indicating borderline resectability. PMID- 25546149 TI - Altered autonomic nervous system activity in women with unexplained recurrent pregnancy loss. AB - AIM: Autonomic nervous system activity was studied to evaluate the physical and mental state of women with unexplained recurrent pregnancy loss (RPL). METHODS: Heart rate variability (HRV) is a measure of beat-to-beat temporal changes in heart rate and provides indirect insight into autonomic nervous system tone and can be used to assess sympathetic and parasympathetic tone. We studied autonomic nervous system activity by measuring HRV in 100 women with unexplained RPL and 61 healthy female volunteers as controls. The degree of mental distress was assessed using the Kessler 6 (K6) scale. RESULTS: The K6 score in women with unexplained RPL was significantly higher than in control women. HRV evaluated on standard deviation of the normal-to-normal interval (SDNN) and total power was significantly lower in women with unexplained RPL compared with control women. These indices were further lower in women with unexplained RPL >=4. On spectral analysis, high-frequency (HF) power, an index of parasympathetic nervous system activity, was significantly lower in women with unexplained RPL compared with control women, but there was no significant difference in the ratio of low frequency (LF) power to HF power (LF/HF), an index of sympathetic nervous system activity, between the groups. CONCLUSIONS: The physical and mental state of women with unexplained RPL should be evaluated using HRV to offer mental support. Furthermore, study of HRV may elucidate the risk of cardiovascular diseases and the mechanisms underlying unexplained RPL. PMID- 25546152 TI - On a preference-based instrumental variable approach in reducing unmeasured confounding-by-indication. AB - Treatment preferences of groups (e.g., clinical centers) have often been proposed as instruments to control for unmeasured confounding-by-indication in instrumental variable (IV) analyses. However, formal evaluations of these group preference-based instruments are lacking. Unique challenges include the following: (i) correlations between outcomes within groups; (ii) the multi-value nature of the instruments; (iii) unmeasured confounding occurring between and within groups. We introduce the framework of between-group and within-group confounding to assess assumptions required for the group-preference-based IV analyses. Our work illustrates that, when unmeasured confounding effects exist only within groups but not between groups, preference-based IVs can satisfy assumptions required for valid instruments. We then derive a closed-form expression of asymptotic bias of the two-stage generalized ordinary least squares estimator when the IVs are valid. Simulations demonstrate that the asymptotic bias formula approximates bias in finite samples quite well, particularly when the number of groups is moderate to large. The bias formula shows that when the cluster size is finite, the IV estimator is asymptotically biased; only when both the number of groups and cluster size go to infinity, the bias disappears. However, the IV estimator remains advantageous in reducing bias from confounding by-indication. The bias assessment provides practical guidance for preference based IV analyses. To increase their performance, one should adjust for as many measured confounders as possible, consider groups that have the most random variation in treatment assignment and increase cluster size. To minimize the likelihood for these IVs to be invalid, one should minimize unmeasured between group confounding. PMID- 25546150 TI - Human papillomavirus prevalence in invasive laryngeal cancer in the United States. AB - PURPOSE: Human papillomavirus (HPV) is a major risk factor for specific cancers of the head and neck, particularly malignancies of the tonsil and base of the tongue. However, the role of HPV in the development of laryngeal cancer has not been definitively established. We conducted a population-based, cancer registry study to evaluate and characterize the genotype-specific prevalence of HPV in invasive laryngeal cancer cases diagnosed in the U.S. METHODS: The presence of genotype-specific HPV DNA was evaluated using the Linear Array HPV Genotyping Test and the INNO-LiPA HPV Genotyping Assay in formalin-fixed paraffin embedded tissue from 148 invasive laryngeal cancer cases diagnosed in 1993-2004 within the catchment area of three U.S. SEER cancer registries. RESULTS: HPV DNA was detected in 31 of 148 (21%) invasive laryngeal cancers. Thirteen different genotypes were detected. Overall, HPV 16 and HPV 33 were the most commonly detected types. HPV was detected in 33% (9/27) of women compared with 18% (22/121) of men (p = 0.08). After adjustment for age and year of diagnosis, female patients were more likely to have HPV-positive laryngeal tumors compared to males (adjusted OR 2.84, 95% CI 1.07-7.51). Viral genotype differences were also observed between the sexes. While HPV 16 and 18 constituted half of HPV positive cases occurring in men, among women, only 1 was HPV 16 positive and none were positive for HPV 18. Overall 5-year survival did not vary by HPV status. CONCLUSIONS: HPV may be involved in the development of a subset of laryngeal cancers and its role may be more predominant in women compared to men. PMID- 25546153 TI - Magnetic resonance imaging pattern learning in temporal lobe epilepsy: classification and prognostics. AB - OBJECTIVE: In temporal lobe epilepsy (TLE), although hippocampal atrophy lateralizes the focus, the value of magnetic resonance imaging (MRI) to predict postsurgical outcome is rather modest. Prediction solely based on the hippocampus may be hampered by widespread mesiotemporal structural damage shown by advanced imaging. Increasingly complex and high-dimensional representation of MRI metrics motivates a shift to machine learning to establish objective, data-driven criteria for pathogenic processes and prognosis. METHODS: We applied clustering to 114 consecutive unilateral TLE patients using 1.5T MRI profiles derived from surface morphology of hippocampus, amygdala, and entorhinal cortex. To evaluate the diagnostic validity of the classification, we assessed its yield to predict outcome in 79 surgically treated patients. Reproducibility of outcome prediction was assessed in an independent cohort of 27 patients evaluated on 3.0T MRI. RESULTS: Four similarly sized classes partitioned our cohort; in all, alterations spanned over the 3 mesiotemporal structures. Compared to 46 controls, TLE-I showed marked bilateral atrophy; in TLE-II atrophy was ipsilateral; TLE-III showed mild bilateral atrophy; whereas TLE-IV showed hypertrophy. Classes differed with regard to histopathology and freedom from seizures. Classwise surface-based classifiers accurately predicted outcome in 92 +/- 1% of patients, outperforming conventional volumetry. Predictors of relapse were distributed bilaterally across structures. Prediction accuracy was similarly high in the independent cohort (96%), supporting generalizability. INTERPRETATION: We provide a novel description of individual variability across the TLE spectrum. Class membership was associated with distinct patterns of damage and outcome predictors that did not spatially overlap, emphasizing the ability of machine learning to disentangle the differential contribution of morphology to patient phenotypes, ultimately refining the prognosis of epilepsy surgery. PMID- 25546151 TI - Integrated miRNA and mRNA expression profiling in inflamed colon of patients with ulcerative colitis. AB - BACKGROUND: Ulcerative colitis (UC) is associated with differential colonic expression of genes involved in immune response (e.g. IL8) and barrier integrity (e.g. cadherins). MicroRNAs (miRNAs) are regulators of gene expression and are involved in various immune-related diseases. In this study, we investigated (1) if miRNA expression in UC mucosa is altered and (2) if any of these changes correlate with mucosal mRNA expression. Integration of mRNA and miRNA expression profiling may allow the identification of functional links between dysregulated miRNAs and their target mRNA. METHODOLOGY: Colonic mucosal biopsies were obtained from 17 UC (10 active and 7 inactive) patients and 10 normal controls. Total RNA was used to analyze miRNA and mRNA expression via Affymetrix miRNA 2.0 and Affymetrix Human Gene 1.0ST arrays, respectively. Both miRNA and gene expression profiles were integrated by correlation analysis to identify dysregulated miRNAs with their corresponding predicted target mRNA. Microarray data were validated with qRT-PCR. Regulation of IL8 and CDH11 expression by hsa-miR-200c-3p was determined by luciferase reporter assays. RESULTS: When comparing active UC patients vs. controls, 51 miRNAs and 1543 gene probe sets gave significantly different signals. In contrast, in inactive UC vs. controls, no significant miRNA expression differences were found while 155 gene probe sets had significantly different signals. We then identified potential target genes of the significantly dysregulated miRNAs and genes in active UC vs. controls and found a highly significant inverse correlation between hsa-miR-200c-3p and IL8, an inflammatory marker, and between hsa-miR-200c-3p and CDH11, a gene related to intestinal epithelial barrier function. We could demonstrate that hsa-miR-200c-3p directly regulates IL8 and CDH11 expression. CONCLUSION: Differential expression of immune and barrier-related genes in inflamed UC mucosa may be influenced by altered expression of miRNAs. Integrated analysis of miRNA and mRNA expression profiles revealed hsa-miR-200c-3p for use of miRNA mimics as therapeutics. PMID- 25546154 TI - Changes in serum iodine concentration, urinary iodine excretion and thyroid function after hysterosalpingography using an oil-soluble iodinated contrast medium (lipiodol). AB - OBJECTIVE: Reports of hypothyroidism after hysterosalpingography (HSG) using lipiodol are emerging. The present study was designed to investigate the changes in serum iodine concentration (SIC), urinary iodine concentration/creatinine excretion (UI/Cr), and thyroid function before and after HSG using lipiodol. METHODS: The prospective observation study included 22 infertile euthyroid women with no previous history of thyroid disease. All underwent HSG between April 2007 and August 2008 at our institution. We examined SIC, UI/Cr, and thyroid function before HSG, and at 4, 8, 12, and 24 weeks, and 9-12 months after HSG. RESULTS: The median value of SIC and UI/Cr peaked at 4 weeks after HSG and remained at significantly high levels at 8, 12, and 24 weeks post-HSG compared with pre-HSG. In sync with the increase of iodine, the mean level of TSH significantly increased at 4, 8, 12, and 24 weeks post-HSG compared with pre-HSG. After 24 weeks, differences in SIC, UI/Cr, and TSH levels before and after HSG became nonsignificant. The mean value of free triiodothyronine and free thyroxine showed no significant difference at any of the time points compared with pre-HSG. Three cases (13.6%) showed transient high TSH (>5 MUIU/L) with normal thyroid hormones at 4 or 8 weeks after HSG. CONCLUSION: Thyroid monitoring should be conducted in the first 4-8 weeks after HSG using lipiodol and attention to thyroid dysfunction should be paid for up to 6 months after the procedure due to the possibility of excess iodine. PMID- 25546155 TI - Time to recovery of adrenal function after curative surgery for Cushing's syndrome depends on etiology. AB - CONTEXT: Successful tumor resection in endogenous Cushing's syndrome (CS) results in tertiary adrenal insufficiency requiring hydrocortisone replacement therapy. OBJECTIVE: The aim was to analyze the postsurgical duration of adrenal insufficiency of patients with Cushing's disease (CD), adrenal CS, and ectopic CS. DESIGN: We performed a retrospective analysis based on the case records of 230 patients with CS in our tertiary referral center treated from 1983-2014. The mean follow-up time was 8 years. PATIENTS: We included 91 patients of the three subtypes of CS undergoing curative intended surgery and documented followup after excluding cases with persistent disease, pituitary radiation, concurrent adrenostatic or somatostatin analog treatment, and malignant adrenal disease. RESULTS: The probability of recovering adrenal function within a 5 years followup differed significantly between subtypes (P = .001). It was 82% in ectopic CS, 58% in CD and 38% in adrenal CS. In the total cohort with restored adrenal function (n = 52) the median time to recovery differed between subtypes: 0.6 years (interquartile range [IQR], 0.03-1.1 y) in ectopic CS, 1.4 years (IQR, 0.9-3.4 y) in CD, and 2.5 years (IQR, 1.6-5.4 y) in adrenal CS (P = .002). In CD the Cox proportional-hazards model showed that the probability of recovery was associated with younger age (hazard ratio, 0.896; 95% confidence interval, 0.822-0.976; P = .012), independently of sex, body mass index, duration of symptoms, and basal ACTH and cortisol levels. There was no correlation with length and extend of hypercortisolism or postoperative glucocorticoid replacement doses. CONCLUSIONS: Time to recovery of adrenal function is dependent on the underlying etiology of CS. PMID- 25546156 TI - Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization. AB - CONTEXT: Endometriosis is a common gynecological disease affecting one in 10 women of reproductive age and is a major cause of pelvic pain and impaired fertility. Endometrial stromal cells of women with endometriosis exhibit a reduced response to in vitro decidualization. NOTCH1 is critical for decidualization of both mouse and human uterine stromal cells. OBJECTIVE: This study aimed to determine whether decidualization failure in women with endometriosis is a consequence of impaired Notch signaling. SETTING AND DESIGN: We investigated expression levels of Notch signaling components in the endometrium of women and baboons with or without endometriosis. We identified NOTCH1-regulated genes during decidualization of human uterine fibroblast (HuF) cells by microarray and quantified their expression levels in in vitro decidualized endometrial stromal cells isolated from women with or without endometriosis. RESULTS: Notch signaling receptors NOTCH1 and NOTCH4, ligands JAGGED2 and DLL4, as well as direct target genes HES5 and HEY1 were decreased in the eutopic endometrium of women and baboons with endometriosis. Notch signaling was decreased in stromal cells isolated from women with endometriosis, which was associated with impaired in vitro decidualization. Genes that were down-regulated by NOTCH1 silencing in decidualized HuF cells were also decreased in decidualized endometrial stromal cells of women with endometriosis. FOXO1 acts as a downstream target of Notch signaling and endometriosis is associated with decreased expression of NOTCH1-regulated, FOXO1-responsive genes during decidualization. CONCLUSIONS: Decreased Notch signaling is associated with endometriosis and contributes to impaired decidualization through the down-regulation of FOXO1. PMID- 25546157 TI - RET fusion as a novel driver of medullary thyroid carcinoma. AB - INTRODUCTION: Oncogenic RET tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. Although RET point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma (MTC), no fusions have been described to date. OBJECTIVE: We evaluated the role of RET fusion as an oncogenic driver in MTC. METHODS: We describe a patient who died from aggressive sporadic MTC < 10 months after diagnosis. Her tumor was evaluated by means of next-generation sequencing, including an intronic capture strategy. RESULTS: A reciprocal translocation involving RET intron 12 was identified. The fusion was validated using a targeted break apart fluorescence in situ hybridization probe, and RNA sequencing confirmed the existence of an in-frame fusion transcript joining MYH13 exon 35 with RET exon 12. Ectopic expression of fusion product in a murine Ba/F3 cell reporter model established strong oncogenicity. Three tyrosine kinase inhibitors currently used to treat MTC in clinical practice blocked tumorigenic cell growth. CONCLUSION: This finding represents the report of a novel RET fusion, the first of its kind described in MTC. The finding of this potential novel oncogenic mechanism has clear implications for sporadic MTC, which in the majority of cases has no driver mutation identified. The presence of a RET fusion also provides a plausible target for RET tyrosine kinase inhibitor therapies. PMID- 25546158 TI - Refinement by shifting secondary structure elements improves sequence alignments. AB - Constructing a model of a query protein based on its alignment to a homolog with experimentally determined spatial structure (the template) is still the most reliable approach to structure prediction. Alignment errors are the main bottleneck for homology modeling when the query is distantly related to the template. Alignment methods often misalign secondary structural elements by a few residues. Therefore, better alignment solutions can be found within a limited set of local shifts of secondary structures. We present a refinement method to improve pairwise sequence alignments by evaluating alignment variants generated by local shifts of template-defined secondary structures. Our method SFESA is based on a novel scoring function that combines the profile-based sequence score and the structure score derived from residue contacts in a template. Such a combined score frequently selects a better alignment variant among a set of candidate alignments generated by local shifts and leads to overall increase in alignment accuracy. Evaluation of several benchmarks shows that our refinement method significantly improves alignments made by automatic methods such as PROMALS, HHpred and CNFpred. The web server is available at http://prodata.swmed.edu/sfesa. PMID- 25546160 TI - Association of time-to-levodopa with initial Parkinsonian medication: a retrospective cohort study. AB - OBJECTIVES: To determine the initial distribution of medication in patients with de novo Parkinson's disease (PD), to estimate the share of patients who not receive a recommended initial therapy according to current German guidelines, and to compare the time-to-levodopa. METHODS: We used the Disease Analyzer database (IMS HEALTH), containing basic medical data from ~20 million patients in Germany. The primary outcome was the therapy change rate from initial treatment to levodopa estimated by Kaplan-Meier analyses. A Cox proportional hazards model was used to estimate the relationship between time-to-levodopa and confounders for a maximum follow-up of 10 years (between January 2002 and December 2011). Adjusted hazard ratios (HR) and 95% confidence intervals (CI) are presented for change-to levodopa rate. RESULTS: A representative sample of de-novo patients diagnosed with PD was drawn (n=108,885). 71.8% of patients received levodopa as a first line treatment. 29,708 patients started with other anti-PD substances: 13.3% with dopamine agonists (DA), 3.6% with amantadine, 5.9% with anticholinergics, and 0.8% with monoamine oxidase B (MAO-B) inhibitors. Therefore, the proportion of patients who not receive a recommended initial therapy according to current German guidelines was ~10%. 29.0% of patients not starting with levodopa switched to levodopa within 5 years. After 5 years, more than 80% of PD patients using anticholinergics as their initial treatment remained levodopa-free. MAOB- inhibitors and DAs showed significantly lower proportions of levodopa-free patients after 5 years (35% and 55%, respectively). Compared to MAO-B inhibitors, the HR for switching to levodopa was 0.38 (CI 0.34-0.43; p<0.001) for anticholinergics and 0.85 (CI 0.75-0.97; p=0.017) for nonergot DA. CONCLUSIONS: Surprisingly, initial treatment with anticholinergics is correlated with the longest delay of levodopa treatment among all monotherapies. Our results suggest re-evaluating the comparative effectiveness of all initial PD treatments in head tohead comparisons. PMID- 25546159 TI - Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age associated changes in sleep quality and adiposity. AB - The dorsomedial hypothalamus (DMH) controls a number of essential physiological responses. We have demonstrated that the DMH plays an important role in the regulation of mammalian aging and longevity. To further dissect the molecular basis of the DMH function, we conducted microarray-based gene expression profiling with total RNA from laser-microdissected hypothalamic nuclei and tried to find the genes highly and selectively expressed in the DMH. We found neuropeptide VF precursor (Npvf), PR domain containing 13 (Prdm13), and SK1 family transcriptional corepressor (Skor1) as DMH-enriched genes. Particularly, Prdm13, a member of the Prdm family of transcription regulators, was specifically expressed in the compact region of the DMH (DMC), where Nk2 homeobox 1 (Nkx2-1) is predominantly expressed. The expression of Prdm13 in the hypothalamus increased under diet restriction, whereas it decreased during aging. Prdm13 expression also showed diurnal oscillation and was significantly upregulated in the DMH of long-lived BRASTO mice. The transcriptional activity of the Prdm13 promoter was upregulated by Nkx2-1, and knockdown of Nkx2-1 suppressed Prdm13 expression in primary hypothalamic neurons. Interestingly, DMH-specific Prdm13 knockdown mice showed significantly reduced wake time during the dark period and decreased sleep quality, which was defined by the quantity of electroencephalogram delta activity during NREM sleep. DMH-specific Prdm13 knockdown mice also exhibited progressive increases in body weight and adiposity. Our findings indicate that Prdm13/Nkx2-1-mediated signaling in the DMC declines with advanced age, leading to decreased sleep quality and increased adiposity, which mimic age-associated pathophysiology, and provides a potential link to DMH mediated aging and longevity control in mammals. PMID- 25546161 TI - Estimation of the inter- and intrasubject variability of the diurnal serum cortisol rhythm in healthy male subjects to evaluate the biomarker potential for drug target engagement. AB - OBJECTIVE: Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy males, through determination of the inter- and intrasubject variability, to facilitate evaluation of this biomarker for drug target engagement. MATERIALS AND METHODS: This open-label, 2-period study design evaluated serum cortisol release over a 24-hour period in 18 healthy males. A cosinor model was used to model the cortisol diurnal rhythm, and the inter- and intrasubject coefficients of variation (CVs) were calculated across the 2 periods. RESULTS: Three significant cortisol concentration peaks were observed at ~7 AM, 1 PM, and 7 PM. The intersubject CVs (%) for the amplitude, acrophase, and midline estimating statistic of rhythm (MESOR) were 18.2, 19.3, and 16.8, respectively. The intrasubject CVs (%) were 11.2, 7.6, and 6.9, respectively. The inter- and intrasubject CVs (%) for the lunch-induced 1 PM peak and the >dinner induced 7 PM peak were 22.1, 17.3, 44.7, and 22.1 respectively. CONCLUSIONS: Assessment of serum cortisol diurnal rhythm suggests that the amplitude, acrophase, and MESOR, but not the meal-induced peaks, have the potential to be a reliable biomarker in drug development targeting the hypothalamic-pituitary adrenocortical (HPA) axis. PMID- 25546162 TI - Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects. AB - OBJECTIVE: To evaluate the effect of ethnicity on the pharmacokinetics (PK) of tildrakizumab, a novel anti-IL-23 monoclonal antibody for the treatment of psoriasis. MATERIALS AND METHODS: This was an open-label, 2-part study in healthy adult subjects. In part 1, Japanese subjects and matched Caucasian and Chinese subjects (to Japanese) were assigned to 1 of 3 cohorts and administered tildrakizumab 50, 200, or 400 mg subcutaneously (SC). In part 2, Japanese subjects received tildrakizumab 10 mg/kg IV. Pre- and post-treatment antidrug antibodies were assessed. Safety and tolerability were assessed throughout the study. RESULTS: 59 subjects were enrolled; 53 in part 1 and 6 in part 2. Overall geometric mean AUCinfinity was 6.15, 6.05, and 6.32 day*MUg/mL/mg in Japanese, Caucasian, and Chinese subjects, respectively, after administration of a single SC dose. Bioavailability was ~92%. Six out of 58 evaluable subjects were positive for post-treatment ADA; 2 of these positive subjects had reduced tildrakizumab exposure. Most AEs were mild in intensity and the most frequent treatment-related AEs were injection site hematoma (15%), injection site pain (10%), and injection site erythema (8%). CONCLUSIONS: The pharmacokinetics of tildrakizumab were similar in Japanese, Caucasian, and Chinese subjects. Tildrakizumab exposure increased proportionally with dose in the range of 50-400 mg. A single SC dose of 50, 200, and 400 mg or a single IV dose of 10 mg/kg was generally well tolerated. PMID- 25546163 TI - The role of the clinical pharmacist in reducing mortality in hospitalized cardiac patients: A prospective, nonrandomized controlled trial using propensity score methods. AB - BACKGROUND: Meta-analyses have suggested that pharmacist-led medication reviews have no discernable effect on patient mortality. These analyses may not have found a statistically significant effect because they did not adequately control for the patient selection parameters. Therefore, a more precise approach to evaluating the effect of clinical pharmacist interventions on the mortality rates of hospitalized cardiac patients is required. OBJECTIVE: To evaluate the impact of the clinical pharmacist as a direct patient-care team member on the mortality of all patients admitted to cardiology units. METHODS: A prospective, nonrandomized observational study compared patients who received standard care with patients admitted to a service that included clinical pharmacists. Propensity score matching was applied to enhance the comparability. The primary endpoint of the study was the composite of all-cause mortality in the study group and the control group. RESULTS: Pharmacists were consulted by physicians to correct any drug-related issues that they suspected may cause or contribute to a fatal outcome in the cardiology ward. A total of 428 interventions were suggested by the clinical pharmacist in the study group; 375 (87.6%) of them were accepted by the cardiology team. All-cause mortality was 1.8% during phase 1 treatment (preintervention) and was reduced to 1.1% during phase 2 treatment (postintervention); the difference was statistically significant. There was no statistical difference in all-cause mortality in the control unit between phase 1 and phase 2. Results were similar in the propensity score-matched subcohort. CONCLUSIONS: Drug-related problems that were suspected to cause or contribute to a possibly fatal outcome were determined by the clinical pharmacist service in patients hospitalized in a cardiology ward. Correction of these drug-related problems by physicians after the pharmacist's advice caused a significant decrease in mortality as analyzed by propensity score matching. The significant reduction in the mortality rate in this patient population observed in this study is "hypothesis generating" for future randomized studies. PMID- 25546164 TI - Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin. AB - The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5-111.0) and 107.1 (100.1-114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments. PMID- 25546165 TI - Effect of food on the pharmacokinetics of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid, in healthy subjects. AB - OBJECTIVE: The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4 trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions. METHODS: The study participants (n=12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. RESULTS: The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 hxMUg/mL for the fasting state and 22.20, 5,038 hxMUg/mL for the fed state, the AUC0-infinity of triflusal and HTB were 19.79, 6,333 hxMUg/mL for the fasting state and 22.44, 5,632 hxMUg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB. CONCLUSION: High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects. PMID- 25546166 TI - Effect of food on the pharmacokinetics of canagliflozin/metformin (150/1,000 mg) immediate-release fixed-dose combination tablet in healthy participants. AB - OBJECTIVE: To assess the effect of food on the pharmacokinetics (PK) of canagliflozin and metformin following administration of a canagliflozin/metformin (150/1,000 mg) immediate-release (IR) fixed-dose combination (FDC) tablet. METHODS: A randomized, open-label, singlecenter, single-dose, 2-period, 2 sequence crossover study was conducted in healthy participants. Participants were randomized to 2 sequences of fasted and fed (or vice versa) administration of one 150/1,000 mg canagliflozin/metformin IR FDC, with 10-14 day washout between treatments PK parameters (AUC, Cmax, tmax, t1/2) were assessed for canagliflozin and metformin. Safety was evaluated. RESULTS: When comparing the IR FDC tablet administered with and without food, PK parameters of canagliflozin were bioequivalent as the 90% confidence intervals (CIs) for log-transformed AUClast, AUCa??, and Cmax were within the bioequivalence limits of 80-125%. For metformin, overall exposure was similar under fed and fasted conditions as geometric mean ratios for AUC and associated 90% CI were contained within the bioequivalence limits, but geometric mean Cmax decreased by 16% in the fed compared to fasted state. Both treatments were well tolerated with similar adverse events and most common were gastrointestinal events, generally attributed to metformin. CONCLUSIONS: Food did not affect canagliflozin bioavailability parameters (Cmax and AUCs) or AUCs of metformin. The Cmax of metformin was decreased by 16%, which is not considered clinically meaningful. The canagliflozin/metformin FDC tablet is recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin. PMID- 25546167 TI - Effect of drying and frying conditions on physical and chemical characteristics of fish maw from swim bladder of seabass (Lates calcarifer). AB - BACKGROUND: Swim bladder is generated as a by-product during evisceration. It has been used for the production of fish maw, in which several processing parameters determine the characteristics or quality of the resulting fish maw. The present study aimed to investigate the characteristics of fish maws from seabass swim bladder as influenced by drying and frying conditions. RESULTS: The expansion ratio and oil uptake content of fish maw increased as the moisture content of swim bladder increased (P < 0.05). Nevertheless, the expansion ratio of fish maw decreased when the moisture content was higher than 150 g kg(-1) . The L*-value decreased, whilst the a*- and b*-values of fish maw increased with increasing moisture content. When pre-frying and frying temperatures increased, the expansion ratio of fish maw increased (P < 0.05). However, the expansion ratio decreased when the frying was performed at a temperature higher than 200 degrees C. The oil uptake contents of fish maw with frying temperatures of 180 and 200 degrees C were in the range of 451.06-578.06 g kg(-1) , whereas the lower contents (378.60-417.17 g kg(-1) ) were found in those having frying temperatures of 220-240 degrees C. Hardness of fish maw decreased but no changes in fracturability were observed with increasing pre-frying temperature when subsequent frying was carried out 200 degrees C. CONCLUSION: Drying temperatures, moisture content, pre-frying and frying temperatures were the factors influencing the characteristics and properties of fish maws from seabass swim bladder. Fish maw could be prepared by pre-frying swim bladder, dried at 60 degrees C to obtain 150 g kg(-1) moisture content, at 110 degrees C for 5 min, followed by frying at 200 degrees C for 20 s. PMID- 25546168 TI - Using preoperative SNOT-22 score to inform patient decision for Endoscopic sinus surgery. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study is to improve patient understanding of surgical outcomes while they make a preference-sensitive decision regarding electing endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective observational cohort study. METHODS: Patients with CRS who elected ESS were prospectively enrolled into a multi-institutional, observational cohort study. Patients' were categorized into 10 preoperative Sino-Nasal Outcome Test (SNOT-22) groups based on 10-point increments beginning with a score of 10 and ending at 110. The proportion of patients achieving a SNOT-22 minimal clinically important difference (MCID) (9 points) and the percentage of relative improvement (%) for each preoperative SNOT 22 group were calculated. A subgroup analysis based on polyp status was performed. RESULTS: A total of 327 patients were included in this study. Patients with a SNOT-22 score between 10 and 19 had the lowest chance of achieving an MCID (37.5%) and received a relative mean worsening of their quality of life (QoL) after ESS (+18.8%). Patients with a SNOT-22 score greater than 30 obtained a greater than 75% chance of achieving an MCID, and there was a relative improvement of 45% in QoL (all < -44.9%) after ESS. Outcomes from the polyp status subgroup analysis were similar to the findings from the overall cohort. CONCLUSION: Outcomes from this study suggest that patients with a preoperative SNOT-22 score higher than 30 points receive a greater than 75% chance of achieving an MCID and on average obtain a 45% relative improvement in their QoL after ESS. Patients with SNOT-22 score of less than 20 did not experience improved QoL from ESS. PMID- 25546169 TI - Directed shift of vaginal microbiota induced by vaginal application of sucrose gel in rhesus macaques. AB - OBJECTIVES: Sucrose gel was used to treat bacterial vaginosis in a phase III clinical trial. However, the changes of vaginal flora after treatment were only examined by Nugent score in that clinical trial, While the vaginal microbiota of rhesus macaques is characterized by anaerobic, Gram-negative bacteria, few lactobacilli, and pH levels above 4.6, similar to the microbiota of patients with bacterial vaginosis. This study is aimed to investigate the change of the vaginal microbiota of rehsus macaques after topical use of sucrose gel to reveal more precisely the bacterial population shift after the topical application of sucrose gel. METHODS: Sixteen rhesus macaques were treated with 0.5 g sucrose gel vaginally and three with 0.5 g of placebo gel. Vaginal swabs were collected daily following treatment. Vaginal pH levels and Nugent scores were recorded. The composition of the vaginal micotbiota was tested by V3~V4 16S rDNA metagenomic sequencing. Dynamic changes in the Lactobacillus genus were analyzed by qPCR. RESULTS: The vaginal microbiota of rhesus macaques are dominated by anaerobic Gram-negative bacteria, with few lactobacilli and high pH levels above 4.6. After five days' treatment with topical sucrose gel, the component percentage of Lactobacillus in vaginal microbiota increased from 1.31% to 81.59%, while the component percentage of Porphyromonas decreased from 18.60% to 0.43%, Sneathia decreased from 15.09% to 0.89%, Mobiluncus decreased from 8.23% to 0.12%, etc.. The average vaginal pH values of 16 rhesus macaques of the sucrose gel group decreased from 5.4 to 3.89. There were no significant changes in microbiota and vaginal pH observed in the placebo group. CONCLUSIONS: Rhesus macaques can be used as animal models of bacterial vaginosis to develop drugs and test treatment efficacy. Furthermore, the topical application of sucrose gel induced the shifting of vaginal flora of rhesus macaques from a BV kind of flora to a lactobacilli-dominating flora. PMID- 25546170 TI - Rapid and sensitive analysis of multiple bioactive constituents in tripterygium glycosides tablets using liquid chromatography coupled with time-of-flight mass spectrometry. AB - A simultaneous determination method based on liquid chromatography coupled with time-of-flight mass spectrometry was developed for the analysis of 11 bioactive constituents in tripterygium glycosides tablets, an immune and inflammatory prescription used in China. The analysis was fully optimized on a 1.8 MUm particle size C18 column with linear gradient elution, permitting good separation of the 11 analytes and two internal standards in 21 min. The quantitation of each target constituent was carried out using the narrow window extracted ion chromatograms with a +/-l0 ppm extraction window, yielding good linearity (r(2) > 0.996) with a linear range of 10-1000 ng/mL. The limits of quantitation were low ranging from 0.25 to 5.02 ng/mL for the 11 analytes, and the precisions and repeatability were better than 1.6 and 5.3%, respectively. The acceptable recoveries obtained were in the range of 93.4-107.4%. This proposed method was successfully applied to quantify the 11 bioactive constituents in commercial samples produced by nine pharmaceutical manufacturers to profile the quality of these preparations. The overall results demonstrate that the contents of the 11 bioactive constituents in different samples were in great diversity, therefore, the quality, clinical safety, and efficacy of this drug needs further research and evaluation. PMID- 25546171 TI - Expression of Phosphodiesterase 4B cAMP-Specific Gene in Subjects With Cryptorchidism and Down's Syndrome. AB - Cryptorchidism represents a risk factor for infertility and germ cell testicular neoplasia. An increased rate of cryptorchidism has been reported in subjects with Down's syndrome. Cyclic nucleotide phosphodiesterases (PDEs) are important messengers that regulate and mediate a number of cellular responses to extracellular signals, such as neurotransmitters and hormones. PDE4B, cAMP specific (PDE4B) gene which maps to chromosome 1p31.3 appears to be involved in schizophrenia, chronic psychiatric illness, learning, memory, and mood disturbances. Expression of PDE4 enzymes have been studied in testes of cryptorchid rats. Expression of PDE4B protein examination showed marked degenerative changes in the epithelial lining of the seminiferous tubules. These findings led us to evaluate PDE4 mRNA expression in leukocytes of peripheral blood of five men with DS and cryptorchidism and eleven subjects with DS without cryptorchidism compared with healthy men (controls) by quantitative Real Time PCR (qRT-PCR). This study showed that the PDE4B gene was downexpressed in men with DS and cryptorchidism compared to normal controls and DS without cryptorchidism. A lower expression of the PDE4B gene may be involved in the neurological abnormalities in subjects with Down's syndrome. Moreover, PDE4B gene may be involved in the testicular abnormalities of men with DS and cryptorchidism. PMID- 25546172 TI - NextGen microbial natural products discovery. PMID- 25546173 TI - Ontogeny of the spheno-occipital synchondrosis in a modern Queensland, Australian population using computed tomography. AB - Due to disparity regarding the age at which skeletal maturation of the spheno occipital synchondrosis occurs in forensic and biological literature, this study provides recalibrated multislice computed tomography (MSCT) age standards for the Australian (Queensland) population, using a Bayesian statistical approach. The sample comprises retrospective cranial/cervical MSCT scans obtained from 448 males and 416 females aged birth to 20 years from the Skeletal Biology and Forensic Anthropology Research Osteological Database. Fusion status of the synchondrosis was scored using a modified six-stage scoring tier on an MSCT platform, with negligible observer error (kappa = 0.911 +/- 0.04, intraclass correlation coefficient = 0.994). Bayesian transition analysis indicates that females are most likely to transition to complete fusion at 13.1 years and males at 15.6 years. Posterior densities were derived for each morphological stage, with complete fusion of the synchondrosis attained in all Queensland males over 16.3 years of age and females aged 13.8 years and older. The results demonstrate significant sexual dimorphism in synchondrosis fusion and are suggestive of intrapopulation variation between major geographic regions in Australia. This study contributes to the growing repository of contemporary anthropological standards calibrated for the Queensland milieu to improve the efficacy of the coronial process for medicolegal death investigation. As a stand-alone age indicator, the basicranial synchondrosis may be consulted as an exclusion criterion when determining the age of majority that constitutes 17 years in Queensland forensic practice. PMID- 25546175 TI - Passion for a Cause: How It Affects Health and Subjective Well-Being. AB - Using the dualistic model of passion (Vallerand et al., 2003), this research investigated how harmonious passion (HP) or obsessive passion (OP) for a cause can affect volunteers' health and subjective well-being. Three studies with volunteers for local (local emergency crises and community help) and international (humanitarian missions) causes assessed physical and psychological health using cross-sectional and longitudinal designs. Study 1 (N = 108) showed that HP was positively related to satisfaction with one's involvement in the cause and unrelated to physical injuries due to cause involvement. OP was unrelated to satisfaction but positively associated with injuries. Findings were replicated in Study 2 (N = 83). Moreover, self-neglect mediated the positive and negative effects of HP and OP, respectively, on injuries. Study 3 (N = 77) revealed that HP predicted an increase in satisfaction and health over a 3-month mission. OP predicted an increase in physical symptoms and a decrease in health. Furthermore, OP before a mission was positively related to self-neglect that was positively associated with physical symptoms after a mission. OP also positively predicted rumination that was conducive to posttraumatic stress disorder. HP was unrelated to these variables. Findings underscore the role of passion for a cause in predicting intrapersonal outcomes of volunteers. PMID- 25546174 TI - Stimulus intensity determines experience-dependent modifications in neocortical neuron firing rates. AB - Although subthreshold inputs of neocortical sensory neurons are broadly tuned, the spiking output is more restricted. These subthreshold inputs provide a substrate for stimulus intensity-dependent changes their spiking output, as well as for experience-dependent plasticity to alter firing properties. Here we investigated how different stimulus intensities modified the firing output of individual neurons in layer 2/3 of the mouse barrel cortex. Decreasing stimulus intensity over a 30-fold range lowered the firing rates evoked by principal whisker stimulation and reduced the overall size of the responding ensemble in whisker-undeprived animals. We then examined how these responses were changed after single-whisker experience (SWE). After 7 days of SWE, the mean magnitude of response to spared whisker stimulation at the highest stimulus intensity was not altered. However, lower-intensity whisker stimulation revealed a more than 10 fold increase in mean firing output compared with control animals. Also, under control conditions, only ~15% of neurons showed any firing at low stimulus intensity, compared with more than 70% of neurons after SWE. However, response changes measured in the immediately surrounding representations were detected only for the highest stimulus intensity. Overall, these data showed that the measurement of experience-dependent changes in the spike output of neocortical neurons was highly dependent upon stimulus intensity. PMID- 25546176 TI - DCE-MRI of the liver: reconstruction of the arterial input function using a low dose pre-bolus contrast injection. AB - PURPOSE: To assess the quality of the arterial input function (AIF) reconstructed using a dedicated pre-bolus low-dose contrast material injection imaged with a high temporal resolution and the resulting estimated liver perfusion parameters. MATERIALS AND METHODS: In this IRB-approved prospective study, 24 DCE-MRI examinations were performed in 21 patients with liver disease (M/F 17/4, mean age 56 y). The examination consisted of 1.3 mL and 0.05 mmol/kg of gadobenate dimeglumine for pre-bolus and main bolus acquisitions, respectively. The concentration-curve of the abdominal aorta in the pre-bolus acquisition was used to reconstruct the AIF. AIF quality and shape parameters obtained with pre-bolus and main bolus acquisitions and the resulting estimated hepatic perfusion parameters obtained with a dual-input single compartment model were compared between the 2 methods. Test-retest reproducibility of perfusion parameters were assessed in three patients. RESULTS: The quality of the pre-bolus AIF curve was significantly better than that of main bolus AIF. Shape parameters peak concentration, area under the time activity curve of gadolinium contrast at 60 s and upslope of pre-bolus AIF were all significantly higher, while full width at half maximum was significantly lower than shape parameters of main bolus AIF. Improved liver perfusion parameter reproducibility was observed using pre-bolus acquisition [coefficient of variation (CV) of 4.2%-38.7% for pre-bolus vs. 12.1 71.4% for main bolus] with the exception of distribution volume (CV of 23.6% for pre-bolus vs. 15.8% for main bolus). The CVs between pre-bolus and main bolus for the perfusion parameters were lower than 14%. CONCLUSION: The AIF reconstructed with pre-bolus low dose contrast injection displays better quality and shape parameters and enables improved liver perfusion parameter reproducibility, although the resulting liver perfusion parameters demonstrated no clinically significant differences between pre-bolus and main bolus acquisitions. PMID- 25546177 TI - Sono-electro-magnetic therapy for treating chronic pelvic pain syndrome in men: a randomized, placebo-controlled, double-blind trial. AB - OBJECTIVE: To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. RESULTS: The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI 14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). CONCLUSIONS: Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00688506. PMID- 25546179 TI - Local reaction after subcutaneous injection of methotrexate: uncommon side effect. PMID- 25546178 TI - Application of prospective ECG-gated high-pitch 128-slice dual-source CT angiography in the diagnosis of congenital extracardiac vascular anomalies in infants and children. AB - PURPOSE: To investigate the value of prospective ECG-gated high-pitch 128-slice dual-source CT (DSCT) angiography in the diagnosis of congenital extracardiac vascular anomalies in infants and children in comparison with transthoracic echocardiography (TTE). METHODS: Eighty consecutive infants or children clinically diagnosed of congenital heart disease and suspected with extracardiac vascular anomaly were enrolled, and 75 patients were finally included in this prospective study. All patients underwent prospective ECG-gated high-pitch DSCT angiography after TTE with an interval of 1-7 days. The diagnostic accuracy and sensitivity of high-pitch DSCT angiography and TTE were compared according to the surgical/CCA findings. The image quality of DSCT was assessed using a five-point scale. The effective radiation dose (ED) was calculated. RESULTS: A total of 17 congenital heart diseases and 162 separate extracardiac vascular anomalies were confirmed by surgical/CCA findings in 75 patients. The diagnostic accuracy of high-pitch DSCT angiography and TTE was 99.67% and 97.89%, respectively. The sensitivity of high-pitch DSCT angiography and TTE was 97.53% and 79.62%, respectively. There was significant difference regarding to the diagnostic accuracy and the sensitivity between high-pitch DSCT angiography and TTE (chi2 = 23.561 and 28.013, P<0.05). The agreement on the image quality scoring of DSCT between the two observers was excellent (kappa = 0.81), and the mean score of image quality was 4.1+/-0.7. The mean ED of DSCT was 0.29+/-0.08 mSv. CONCLUSIONS: Prospective ECG-gated high-pitch 128-slice DSCT angiography with low radiation dose and high diagnostic accuracy has higher sensitivity compared to TTE in the detection of congenital extracardiac vascular anomalies in infants and children. PMID- 25546180 TI - Central obesity induces a greater risk of hepatocellular carcinoma than general obesity. PMID- 25546181 TI - Evidence on effectiveness of intensity-modulated radiotherapy versus 2 dimensional radiotherapy in the treatment of nasopharyngeal carcinoma: Meta analysis and a systematic review of the literature. AB - BACKGROUND: Current management of nasopharyngeal carcinoma (NPC) uses radiotherapy (RT) as the curative treatment modality. Radiation delivery techniques for NPC can be achieved using 2D conventional RT or intensity modulated radiotherapy (IMRT). METHODS: A systematic review and meta-analysis of the literature was undertaken to assess the effectiveness of IMRT versus 2D conventional RT in primary treatment of NPC. RESULTS: IMRT showed better results than 2D conventional RT in terms of local control, regional control, and overall survival, but when stratified, only in T4, N2, and stage III were the differences that were seen. Objective saliva measurements and physician-graded xerostomia were better in IMRT. However, patient-reported xerostomia showed minimal improvement only in IMRT. The evidence of superiority of IMRT over 2D conventional RT is not clear. CONCLUSION: In the absence of more clinical data demonstrating the superiority of IMRT in the treatment of nasopharyngeal carcinoma, 2D conventional RT seems to be a reasonable treatment option, especially in limited resource settings. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2130-E2142, 2016. PMID- 25546182 TI - Introduction to special theme section: mobility and the rheumatic diseases. PMID- 25546184 TI - The locus C11orf30 increases susceptibility to poly-sensitization. AB - A number of genetic variants have been associated with allergic sensitization, but whether these are allergen specific or increase susceptibility to poly sensitization is unknown. Using data from the large multicentre population-based European Community Respiratory Health Survey, we assessed the association between 10 loci and specific IgE and skin prick tests to individual allergens and poly sensitization. We found that the 10 loci associate with sensitization to different allergens in a nonspecific manner and that one in particular, C11orf30 rs2155219, doubles the risk of poly-sensitization (specific IgE/4 allergens: OR = 1.81, 95% CI 0.80-4.24; skin prick test/4+ allergens: OR = 2.27, 95% CI 1.34 3.95). The association of rs2155219 with higher levels of expression of C11orf30, which may be involved in transcription repression of interferon-stimulated genes, and its association with sensitization to multiple allergens suggest that this locus is highly relevant for atopy. PMID- 25546185 TI - Dominant negative inhibition data should be analyzed using mathematical modeling- re-interpreting data from insulin signaling. AB - As our ability to measure the complexity of intracellular networks has evolved, it has become increasingly clear that we need new methods for data analysis: methods involving mathematical modeling. Nevertheless, it is still uncontroversial to publish and interpret experimental results without a model based proof that the reasoning is correct. In the present study, we argue that this attitude probably needs to change in the future. We illustrate this need for modeling by considering the common experimental technique of using dominant negative constructs. More specifically, we consider published time-series and dose-response data which previously have been used to argue that the protein S6 kinase does not phosphorylate insulin receptor substrate-1 at a specific serine residue. Using a presented general approach to interpret such data, we now demonstrate that the given dominant-negative data are not conclusive (i.e. that in the absence of other proofs, S6 kinase still may be the kinase). Using simulations with uncertainty analysis and analytical solutions, we show that an alternative explanation is centered around depletion of substrate, which can be tested experimentally. This analysis thus illustrates both the necessity and the benefits of using mathematical modeling to fully understand the implications of biological data, even for a small system and relatively simple data. PMID- 25546186 TI - Intrathoracic splenosis: a rare false-positive cause of somatostatin imaging in characterization of solitary pulmonary nodule. AB - Scanning using a somatostatin receptor analog such as Tc-EDDA/HYNIC-TOC has sensitivity and specificity similar to those of FDG-PET, which has high accuracy in the characterization of a solitary pulmonary nodule (SPN). We describe a 63 year-old man with well-defined SPN in the left lung on chest x-ray and CT scan. Whole-body scanning and chest SPECT were performed with Tc-EDDA/HYNIC-TOC for the characterization of SPN. Abnormal focal increased radiotracer uptake in the left hemithorax was detected. In addition, no spleen activity was observed in the anatomical location. Cytopathologic evaluation of SPN revealed splenosis. PMID- 25546187 TI - The performance of contrast-enhanced FDG PET/CT for the differential diagnosis of unexpected ovarian mass lesions in patients with nongynecologic cancer. AB - PURPOSE: This study aimed to evaluate the diagnostic accuracy of contrast enhanced FDG PET/CT for unexpected ovarian lesions in patients with nongynecologic cancers. PATIENTS AND METHODS: The present retrospective study was approved by the hospital institutional review board. We enrolled 72 nongynecologic cancer patients (33 colorectal cancer, 20 breast cancer, and 19 gastric cancer) who showed unexpected ovarian lesions on contrast-enhanced FDG PET/CT and subsequently underwent surgical resection of the ovarian lesions. The SUVmax values of the ovarian lesions were compared according to the histopathological results, and the accuracy of PET/CT was evaluated. RESULTS: A total of 103 ovarian lesions were surgically resected from 72 patients (64 ovarian lesions were metastases, 21 were benign, and 18 were malignant primary ovarian cancer). SUVmax among the 3 groups were different (P < 0.0001). Using a cutoff SUVmax of 2.5, the sensitivity, specificity, and accuracy of PET/CT for detecting malignant ovarian lesions were 80.5%, 81.0%, and 80.6%, respectively. Detection rates of PET/CT for colorectal, breast, and gastric cancer metastases, as well as primary ovarian cancers were 91.4%, 83.3%, 47.8%, and 100.0%, respectively. Using contrast-enhanced CT findings with SUVmax, the sensitivity, specificity, and accuracy of contrast-enhanced FDG PET/CT were improved to 95.1%, 76.2%, and 91.3%, respectively (P = 0.003). CONCLUSIONS: Conventional FDG PET/CT showed moderate diagnostic accuracy for the detection of malignant ovarian lesions mainly due to low detection rate in gastric cancer metastases. The PET/CT detection rate of malignant ovarian lesions can be improved using contrast enhanced CT findings with FDG uptake measurement. PMID- 25546188 TI - Penile metastasis from rectal cancer by PET/CT. AB - It is extremely rare for rectal tumors to metastasize to the penis, and when it occurs, it is associated with poor prognosis. The appearance of penile metastasis from rectal primary tumor on PET imaging has not been widely reported. We report a case of a 70-year-old man with previous history of treated stage III adenocarcinoma of the rectum 26 months ago. The restaging 18F-FDG PET/CT scan demonstrated a hypermetabolic mass at the base of his penile shaft. This lesion was confirmed on core biopsy to be a metastatic adenocarcinoma of colorectal origin consistent with the known primary rectal tumor. PMID- 25546189 TI - Metastatic melanoma to the thyroid gland expressing somatostatin receptors imaging with 68Ga-DOTANOC PET/CT. AB - Malignant melanoma is an aggressive tumor with poor prognosis that can have widespread metastases at presentation. Melanoma is known to undergo neuroendocrine differentiation. We report a case of a 60-year-old woman with malignant melanoma showing a metastatic lesion in the thyroid expressing somatostatin receptors as evident by Ga-DOTANOC PET/CT and metabolically active widespread subcutaneous metastases on F-FDG PET/CT imaging. PMID- 25546190 TI - Bilateral alien hand syndrome in cerebrovascular disease: CT, MR, CT angiography, and 99mTc-HMPAO-SPECT findings. AB - We report a 65-year-old man with a right cerebral infarction that occurred 15 years ago and a residual left hemiparesis that began with progressive contralateral hemiparesis. During the hospitalization, the patient developed a bilateral alien hand syndrome. Urgent CT, MR, CT angiography, and brain perfusion SPECT were performed that revealed an old right cerebral infarction and a new ischemic lesion in left parietal lobe and adjacent brain territories. PMID- 25546191 TI - Differential alterations of dopamine transporter in the striatum and midbrain in patients with parkinsonian syndrome. AB - OBJECTIVES: Differential vulnerabilities of subregional dopamine neurons have been suggested in movement disorders such as idiopathic Parkinson disease. In this study, we examined dopamine transporter (DaT) density in the striatum versus midbrain (MB) in patients with nigrostriatal denervation. METHODS: Brain SPECT was performed in 39 patients with parkinsonian syndrome (age 61 +/- 15 years, 18 male patients) 4 hours after IV injection of 3 to 5 mCi 123I ioflupane using SPECT-CT acquisition. Images were reconstructed using OSEM with resolution recovery and correction for scatter and attenuation based on a low-dose CT. Peak pixel counts within the caudate head (CA), mid putamen (PT), and MB localized by sagittal CT, as well as averaged counts around the calcarine fissure as reference, were determined by region-of-interest analysis. Semiquantitative DaT values were expressed as CA, PT, or MB uptake relative to the reference. We then assessed the relationship between the MB measurements and independent clinical evaluation of motor symptoms in these patients. RESULTS: Averaged striatal DaT values for both hemispheres ranged from 1.67 to 6.59 for CA, 1.50 to 5.33 for PT, and 1.08 to 2.24 for MB. Within the high striatal DaT group (mean, 4.76 [SD, 0.55]) and low DaT group (mean, 2.71 [SD, 0.58]; dichotomy defined as a threshold of 4), mean DaT values in MB were 1.68 (SD, 0.32) and 1.53 (SD, 0.29), respectively, indicating nonsignificant 9% decrease (P > 0.15) in comparison to 43% decrease in the averaged striatal uptake. Within the high striatal DaT group, Pearson correlations between DaT values of CA and PT versus MB were highly significant at 0.81 and 0.82 (P <= 0.001), respectively, but those correlations were not significant, 0.35 (P > 0.05) and 0.06 (P > 0.75), in the low striatal DaT group. Midbrain uptake measurements did not correlate with motor symptoms (bradykinesia, tremor, rigidity, and postural instability). CONCLUSIONS: These findings indicate that reductions in DaT values in the striatum and MB are not necessarily simultaneous with the process of nigrostriatal denervation, and correlation of DaT values among CA/PT and MB becomes weaker as the denervation becomes more severe. Differential regional DaT loss may indicate differential vulnerability of DaT-containing neurons in these structures or could be in part related to tracer binding to non-DaT targets. PMID- 25546192 TI - Resolution of Malignant Ascites and Stabilization of Metastases in a Patient With Small Bowel Neuroendocrine Tumor With 177Lu-DOTATATE Following Progression After 17 131I-MIBG Treatments and Chemotherapy. AB - A 39-year-old man diagnosed with a small bowel neuroendocrine tumor metastatic to the liver, lymph nodes, and bones achieved stable disease with 131I-MIBG therapy totalling 17 treatments over 9 years (cumulative dose of 1.9 Ci). His disease progressed after the 17th 131I-MIBG treatment, and he went on to fail chemotherapy, developing severe ascites requiring up to 8 L of weekly paracentesis. He was referred for 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE) therapy, and after 4 induction cycles, his ascites resolved completely, and his metastatic disease stabilized. 177Lu-DOTATATE may be useful in patients with an extensive history of radioisotope therapy with 131I-MIBG. PMID- 25546193 TI - Thyroglobulin flare response after radioiodine ablation in 2 patients with differentiated thyroid cancer. AB - Serum thyroglobulin (Tg) measurement facilitates monitoring differentiated thyroid cancer. We describe 2 patients with papillary thyroid cancer who developed dramatic transient serum Tg level elevations within 1 week of I radioiodine (RAI) ablation without cancer recurrence on follow-up. The first patient received recombinant human thyroid-stimulating hormone injections. The pre-injection Tg level was 3.8 MUg/L and increased to 3060 MUg/L 3 days post-RAI. In the second patient, the serum Tg level increased from 1.3 MUg/L to 209.9 MUg/L 7 days after RAI. This transient early serum Tg "flare response" could be misleading if interpreted as suggesting more extensive high-risk thyroid cancer. PMID- 25546194 TI - 13N-ammonia combined with 18F-FDG could discriminate between necrotic high-grade gliomas and brain abscess. AB - PURPOSE: Accurate prediction of brain abscess is beneficial for timely management. In this study, we investigated the utility of 13N-ammonia and its combination with 18F-FDG in differentiating brain abscess from necrotic high grade gliomas. PATIENTS AND METHODS: Thirteen patients with ring-like enhancement high-grade gliomas and 11 patients with brain abscess were recruited in our study. All of them underwent both 18F-FDG and 13N-ammonia PET imaging. Lesion uptake was evaluated by lesion to normal gray matter ratio (L/N). Histopathology diagnosis was obtained for all the patients after PET imaging. RESULTS: The L/N values of 18F-FDG were not significantly different between brain abscess and necrotic high-grade gliomas (P = 0.35). The uptake of 13N-ammonia in gliomas was higher than that in abscess lesions (L/N: 1.38 +/- 0.31 vs 0.84 +/- 0.18, P < 0.001). The receiver operating characteristic curve analysis determined the optimal L/N cutoff value (13N-ammonia) of 1.0 with the area under the curve of 0.94 and the overall accuracy of 87.5%. Discriminant analysis demonstrated that the combination of 18F-FDG and 13N-ammonia could distinguish the 2 clinical entities with higher accuracy of 95%, and only 1 necrotic glioma lesion was misclassified into the abscess group. CONCLUSIONS: 13N-ammonia is effective in distinguishing brain abscess from necrotic high-grade gliomas, and its combination with 18F-FDG could further elevate the diagnostic accuracy. PMID- 25546195 TI - A case of secondary syphilis involving tonsil, pulmonary, and multiple lymph nodes: 18F-FDG PET/CT findings. AB - A 50-year-old man with general fatigue and weight loss underwent FDG PET/CT scan to detect possible occult malignancy. The images revealed abnormal FDG activity in the tonsils, right lung, and in the cervical, axillary, and inguinal lymph nodes. Lymphoma was initially suspected. However, pathologic examination after cervical lymph node biopsy revealed only reactive hyperplasia. Further examinations including serologic tests led to a diagnosis of secondary syphilis. A follow-up PET/CT scan after a 6-month benzylpenicillin therapy showed significant interval improvement. PMID- 25546196 TI - FDG PET/CT of neuroendocrine carcinoma of the thyroid gland. AB - Neuroendocrine carcinoma of the thyroid gland is very rare and difficult to diagnose preoperatively. Hereby we describe a case of neuroendocrine carcinoma of the thyroid that showed intense FDG activity on PET/CT in a 61-year-old woman who had partial thyroidectomy 5 years ago for a suspicious thyroid nodule that was diagnosed as neurofibroma pathologically. PMID- 25546197 TI - Increased 18F-FDG uptake of widespread endometriosis mimicking ovarian malignancy. AB - Endometriosis is a benign disease characterized by the implantation of functional endometrial tissue in ectopic locations. We present a case of a 42-year-old woman with widespread endometriosis that mimicked ovarian malignancy on FDG PET/CT. Increased FDG uptake was observed not only in the right ovary, but also in the liver capsule, perihepatic nodules, greater omentum, and the mesentery. This case indicates that widespread endometriosis may be a cause of multiple FDG uptakes in women of reproductive age and should always be kept in mind in the differential diagnoses of suspicious malignancy. PMID- 25546198 TI - 18F-FLT PET imaging in a patient with sarcoidosis with cardiac involvement. AB - FDG PET has been proposed to play a role in the diagnosis and therapy monitoring of sarcoidosis including cardiac involvement. However, assessing inflammatory lesions in cardiac sarcoidosis using FDG can be challenging because the FDG accumulates in normal myocardium. We report a case of sarcoidosis with cardiac involvement that underwent 3'-deoxy-3'-F-fluorothymidine (FLT) PET. FLT PET images demonstrated increased uptake in the lymph nodes and left ventricle. After immunosuppressive therapy, a follow-up PET scan showed disappearance of FLT uptake in the lymph nodes and left ventricle. PMID- 25546199 TI - Importance of SPECT/CT in detecting multiple hemangiomas on 99mTc-labeled RBC blood pool scintigraphy. AB - Vascular malformations and hemangiomas are common in children, but gastric hemangioma is extremely rare with less than 15 reported cases in the pediatric age group. Gastric hemangioma accounts for only 0.05% of all gastrointestinal neoplasms, and intra-abdominal hemangiomas are rarely found outside of the liver. We present a unique case of gastric hemangioma, and multiple hemangiomas were detected in a single scan by 99mTc-labeled RBC blood pool imaging. This case also depicts the incremental role of SPECT/CT over planar acquisition for detecting multiple hemangiomas, especially for those lesions located adjacent to physiological blood pool activity. PMID- 25546200 TI - Somatostatin receptor expressing bilateral ovarian metastases detected by (68)Ga DOTANOC PET/CT. AB - Bilateral ovarian metastasis from neuroendocrine tumor (NET) is uncommon. Ovarian NET could be primary or metastatic, and if it is bilateral, then the chances of metastatic disease are from 88% to 94%. Proper identification and appropriate management become necessary in such patients. Somatostatin receptor imaging by Ga labeled DOTANOC ([1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1 NaI3-Octreotide) PET/CT can be used for localization, staging, and restaging of NET, and it also has an impact on appropriate clinical management of patients with NET. We present here a case of somatostatin receptor expressing bilateral ovarian metastases from NET demonstrated by Ga DOTANOC PET/CT imaging. PMID- 25546201 TI - Unusual uptake of radioiodine in a retroperitoneal bronchogenic cyst in a patient with thyroid carcinoma. AB - The incidence of retroperitoneal bronchial cyst is rare and is unusual to be visualized on I scan. We report a 52-year-old man who received I therapy for papillary thyroid cancer. The postablation whole-body scan revealed increased radioiodine activity in the left abdomen. SPECT/CT localized this activity from a soft tissue mass in the retroperitoneal space. A retroperitoneal tumor was considered, and retroperitoneal laparoscopic tumor resection was performed. Pathologic examination confirmed a retroperitoneal bronchogenic cyst. PMID- 25546202 TI - Solitary choroidal metastasis from atypical carcinoid of the lung detected by (68)Ga DOTATATE PET/CT. AB - A 71-year-old woman with a history of surgically treated bronchial atypical carcinoid underwent Ga DOTATATE PET/CT for restaging. Somatostatin receptor PET/CT revealed a focal area of mild radiopharmaceutical uptake corresponding to a thickening of the right choroid. No other areas of abnormal tracer uptake were detected in the rest of the body. Based on these PET/CT findings, the patient underwent examination of fundus oculi, MRI, and fluoroangiography, which confirmed the presence of a choroidal lesion interpreted as solitary choroidal metastasis of neuroendocrine tumor. Subsequently, the patient was referred for brachytherapy with radical intent. PMID- 25546203 TI - Constipation causing elevated iodine activity in the rectum mimicking thyroid cancer metastases. AB - Iodine activity in the gastrointestinal tract on I or I imaging is usually diffuse and easy to recognize. Hereby we describe 2 cases of intense focal iodine activity in the rectum mimicking sacral metastases that were caused by constipation. Careful history taking and SPECT/CT imaging can be helpful in distinguishing rectal activity from metastatic lesions in such situations. PMID- 25546204 TI - Prognostic value comparison between (18)F-FLT PET/CT and (18)F-FDG PET/CT volume based metabolic parameters in patients with head and neck cancer. AB - PURPOSE: The present study compared the potential of pretreatment 3'-deoxy-3'-[F] fluorothymidine (F-FLT) uptake parameters and those of F-FDG to predict the clinical outcome of head and neck squamous cell carcinoma treated with chemoradiotherapy. METHODS: A total 53 patients undergoing pretreatment F-FLT PET/CT and F-FDG PET/CT from May 2006 to April 2013 were evaluated. The SUVmax, metabolic tumor volume (MTV), total lesion glycolysis, and total lesion proliferation (TLP) were determined semiquantitatively. Associations between clinical factors and PET/CT parameters and prognostic value were analyzed. RESULTS: In univariate analyses, F-FLT SUVmax, MTV, TLP, F-FDG MTV, and total lesion glycolysis correlated with locoregional control (P = 0.02, P = 0.0007, P = 0.0001, P = 0.007, and P = 0.013, respectively). Clinical T stage, F-FLT SUVmax, MTV, TLP, and F-FDG SUVmax correlated with overall survival (P = 0.012, P = 0.0057, P = 0.0018, P = 0.0012, and P = 0.047, respectively). On multivariate analyses, F-FLT TLP was an independent factor for locoregional control (P = 0.002; hazards ratio [HR], 5.13; 95% confidence interval [CI], 1.81-14.54), as were F-FLT SUVmax and MTV for overall survival (P = 0.021; HR, 3.47; 95% CI, 1.2 10.01 and P = 0.029; HR, 3.17; 95% CI, 1.12-8.95). CONCLUSIONS: Pretreatment F FLT PET/CT volume-based metabolic parameters are superior prognostic predictors to those of F-FDG PET/CT. F-FLT SUVmax and MTV can provide important prognostic information for patients with head and neck squamous cell carcinomas administered with chemoradiotherapy. PMID- 25546205 TI - Solitary splenic metastasis from hepatocellular carcinoma detected on (18)F-FDG PET/CT. AB - We report a case of solitary splenic metastasis from hepatocellular carcinoma detected on F-FDG PET/CT. A 67-year-old man with hepatocellular carcinoma was referred for F-FDG PET/CT to determine the cause of his elevated serum alpha fetoprotein levels after liver segmentectomy and radio-frequency ablation. F-FDG PET/CT imaging showed focal FDG uptake in the spleen, with no other abnormal findings. A splenectomy was performed, and histopathologic examination confirmed the lesion as a metastasis from the hepatocellular carcinoma. PMID- 25546206 TI - Tips for a physician in getting the right job, Part XX: more comments on employment contracts. AB - This article discusses a variety of important employment contract issues. This includes remuneration, fringe benefits, and time off. It also includes dispute resolution and the protection of assets and information. Several types of restrictive covenants are also discussed. This information should be useful to job seekers attempting to understand contracts. However, all employment contracts should be discussed with the job seeker's attorney before signing it. PMID- 25546207 TI - Is there a role for PET/CT with esophagogastric junction adenocarcinoma? AB - The value of 18F-FDG PET/CT in the initial diagnosis and in the locoregional staging of esophagogastric junction adenocarcinoma is not fully established. However, 18F-FDG PET/CT is widely accepted as the best modality for identification of suspected metastases in staging of the disease. Results published in the literature suggest that 18F-FDG PET/CT may provide useful information for response assessment to neoadjuvancy and to differentiate responding and nonresponding tumors. We review the potential role of 18F-FDG PET/CT imaging in staging, restaging, and prognostic value after chemoradiation therapy in esophagogastric junction adenocarcinoma. PMID- 25546208 TI - Pituitary involvement of langerhans cell histiocytosis in an adult unveiled by FDG PET/CT. AB - A 39-year-old woman with complains of polydipsia and dieresis was admitted to endocrinology service for evaluation and potential treatment of diabetes insipidus. During the hospitalization, the patient was found to have unexplained fever, for which an FDG PET/CT was performed to explore the source. The images revealed multiple regions of abnormal hypermetabolism throughout the body. Notably, there was an intense activity in the region of pituitary stalk. Pathological results after biopsy showed pituitary involvement of Langerhans cell histiocytosis. PMID- 25546209 TI - FDG PET/CT appearance of tumor thrombus of ovarian vessels masquerading as retroperitoneal fibrosis. AB - A 23-year-old woman with recurrent uterine endometrial stromal sarcoma underwent FDG PET/CT, which showed pelvic recurrence and multiple pulmonary metastases. In addition, increased activity in a vertical soft tissue mass along the left ureter was noted, which appears similar to retroperitoneal fibrosis on PET/CT images. However, pathological examination demonstrated that the elevated FDG activity in this mass was a result of tumor thrombus from endometrial stromal sarcoma in the left ovarian arteries and veins. PMID- 25546210 TI - Nasopharyngeal tuberculosis mimicking nasopharyngeal carcinoma on (18)F-FDG PET/CT in a young patient. AB - A 30-year-old woman presented with a painless left upper neck swelling for more than a week. Fibrolaryngoscope examination suggested nasopharyngeal carcinoma. FDG PET/CT was performed for an initial staging, which revealed intense activity in the soft tissue mass in the nasopharynx and cervical lymph nodes. However, biopsy from the nasopharyngeal lesion demonstrated tuberculosis. PMID- 25546211 TI - Early assessment of metabolic response by 18F-FDG PET during concomitant radiochemotherapy of non-small cell lung carcinoma is associated with survival: a retrospective single-center study. AB - BACKGROUND AND PURPOSE: We performed a retrospective single-center study to assess if midtreatment 18F-FDG PET/CT could predict local control and survival in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy. METHODS: Thirty-one consecutive patients with unresectable or locally advanced lung cancer (T2-4 N0-3 M0) were treated with concurrent chemoradiotherapy in our center. Each patient received 18F-FDG PET/CT before treatment and at midtreatment time when a radiation therapy dose of 30 Gy was delivered. We assessed several PET/CT parameters as follows: SUV max, DeltaSUV mean, DeltaSUV max, variation of hypermetabolic tumor volume, and the variation of tumor total lesion glycolysis (DeltaTLG). Univariate analysis was performed, and a stepwise procedure was used to define final multivariate model. RESULTS: The DeltaTLG was statistically correlated to overall survival (OS) (P = 0.035), progression-free survival (P = 0.023), and local control (P = 0.043) in univariate analysis. A decrease in TLG over 15% was statistically correlated to a better OS (P = 0.007; hazards ratio [HR], 7.439; 95% confidence interval [CI], 1.168-28.897) and progression-free survival (P = 0.010; HR, 5.695; 95% CI, 1.506 21.537) in univariate analysis. In multivariate analysis, DeltaTLG superior to 15% was significantly correlated to a worse OS (P = 0.020; HR, 5.973; 95% CI, 1.324-26.953). CONCLUSIONS: Early assessment of TLG response by 18F-FDG PET/CT during concomitant radiochemotherapy of non-small cell lung cancer might be associated with survival. PMID- 25546212 TI - Atypical Parkinsonian syndromes with very poor striatal uptake on 123I-ioflupane SPECT imaging. AB - We report a case series of unusual I-ioflupane SPECT imaging findings. Three patients with atypical parkinsonian symptoms underwent I-ioflupane imaging to assist in diagnosis. The patients had complete or near-complete absence of striatal activity. The imaging deficit severity did not consistently correlate with the clinical deficit severity. These cases suggest that markedly abnormal uptake patterns may be seen with atypical parkinsonian syndromes. Further research is warranted to evaluate differences in I-ioflupane uptake patterns among the various parkinsonian syndromes. PMID- 25546213 TI - 67Ga SPECT/CT of infected bladder stones and pyelitis. AB - A 64-year-old male patient diagnosed with amyotrophic lateral sclerosis 2 years ago was admitted with fever and chills. The patient had complex medical history and several indwelling catheters/tubes in his body. To identify the infection focus, 67Ga whole-body scintigraphy and SPECT/CT were obtained. 67Ga whole-body scintigraphy demonstrated focal 67Ga uptake in the lower pelvic cavity and the right kidney. Additional Ga SPECT/CT images were obtained, and it enabled characterization of these uptakes as infection of bladder stones that result in pyelitis. PMID- 25546214 TI - Rheumatic fever: a forgotten but still existing cause of fever of unknown origin detected on FDG PET/CT. AB - We present a case of heterogeneous and strongly increased myocardial and valvular 18F-FDG uptake on 18F-FDG PET/CT in an HIV-positive patient with productive cough, fever, weight loss, and progressive dyspnea for 6 months. Contrast enhanced CT did not reveal the cause of fever, but hyperechogenic valvular lesions on echocardiography in combination with PET/CT findings are suggestive of endocarditis/myocarditis. Postmortem histology 3 weeks after PET/CT showed Aschoff bodies with Anitschkow cells, pathognomonic for rheumatic carditis. This case illustrates that rheumatic heart disease can be detected on 18F-FDG PET/CT and demonstrates the value of 18F-FDG PET/CT in patients with fever of unknown origin. PMID- 25546215 TI - Prognostic role of 18F-FDG PET/CT in the postoperative evaluation of differentiated thyroid cancer patients. AB - PURPOSE: The aim of this study was to evaluate the role of F-FDG PET/CT performed after surgery but before radioiodine therapy in patients with differentiated thyroid cancer. PROCEDURES: FDG PET/CT was performed off l-thyroxine in 60 newly diagnosed differentiated thyroid cancer patients. Clinical and hematological evaluation as well as high-resolution neck ultrasound were performed. All patients underwent a complete follow-up (range, 6-67 months; mean [SD], 31.7 [20.6] months). The date of recurrence or the most recent office visit was recorded. Progression-free survival (PFS) is the primary end point of this study. Analysis was performed by Cox proportional hazards model. Survival curves were generated using Kaplan-Meier estimates, and the log-rank test was used to assess significance. RESULTS: FDG PET/CT was negative in 63% of patients, 20% had FDG thyroid bed uptake, 5% distant metastases, and 12% lymph node FDG uptake. In patients with positive FDG PET/CT scan (ie, those with distant metastases or lymph node uptake), a higher rate of recurrence was observed (50% vs 6%, P < 0.05). Thyroglobulin, neck ultrasound, stage, and FDG PET/CT correlated with PFS at univariate analysis. At multivariate analysis, only thyroglobulin and FDG PET/CT continued to be predictors of PFS. Patients with a negative FDG PET/CT scan have a better PFS either in the whole group or in those with elevated thyroglobulin level (both >2 ng/mL and >10 ng/mL). CONCLUSIONS: FDG PET/CT was abnormal in 17% of patients. Moreover, FDG PET/CT has an independent prognostic role, with a better PFS in patients with a negative scan. PMID- 25546216 TI - Paraganglioma and pancreatic neuroendocrine tumor with rare metastatic sites detected on 68Ga-DOTATATE PET/CT imaging. AB - Pancreatic neuroendocrine tumors (PNETs) represent a small percentage of all pancreatic malignancies, and most of these present as metastatic disease. Somatostatin receptor scintigraphy had been used successfully for the assessment of patients with NET. Somatostatin receptor scintigraphy is indispensable for localization of ectopic NET and the distribution of NET throughout the body. PMID- 25546217 TI - Paralytic subileus as an adverse effect of amino acid-based nephroprotection in a patient undergoing peptide receptor radionuclide therapy. AB - Peptide receptor radionuclide therapy is routinely used for neuroendocrine tumors. To prevent radiopeptide retention at the proximal tubule of the kidney, positively charged amino are coinfused. However, hyperkalemia (>5.0 mmol/L) in more than three fourth of patients has been reported. In our case, the patient experienced acute hyperkalemia with blood values greater than 7.0 mmol/L with gastroparesis and subileus. PMID- 25546218 TI - Subcutaneously obstructed ventriculoperitoneal shuntogram. AB - A 65-year-old man presented with headache, altered mental status, and somnolence. The patient had a ventriculoperitoneal (VP) shunt revised a month earlier. A CT of the head was performed, which demonstrated interval development of hydrocephalus compared with the prior examination done at the time of the shunt revision. Further evaluation of the VP shunt dynamics was obtained through a radionuclide shuntogram using 99mTcO4. The shuntogram demonstrated passage of the radiotracer down the VP shunt tubing. This case illustrates the utility of radionuclide shuntogram in demonstrating an unusual cause of hydrocephalus after VP shunt placement. PMID- 25546219 TI - Complete Resolution of Neuroendocrine Tumor Soft Tissue Metastases After 177Lu DOTATATE PRRT Induction and Maintenance Therapy. AB - A 60-year-old woman diagnosed with a well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes was treated with 4 induction cycles and 2 maintenance cycles of (177)Lu [DOTA,(0)Tyr(3)]octreotate (DOTATATE) peptide receptor radionuclide therapy. Her posttreatment imaging showed partial response after 4 induction cycles and complete response after 2 additional maintenance cycles. This case highlights the need for further research into maintenance (177)Lu DOTATATE therapy to improve outcomes in neuroendocrine tumor patients. PMID- 25546220 TI - Is there a role for peptide receptor radionuclide therapy in medullary thyroid cancer? AB - BACKGROUND: Medullary thyroid cancer (MTC) is a rare but potentially life threatening disease with limited therapeutic options. As a neuroendocrine tumor, MTC expresses somatostatin receptors, and therefore, somatostatin-labeled radiopharmaceuticals could be used to treat patients with MTC. OBJECTIVE: The aims of this study were to evaluate tumor shrinkage after Lu-DOTATATE treatment, to analyze the impact on quality of life as accessed by the SF-36 questionnaire, and to demonstrate a possible prognostic role for In-DTPA-octreotide uptake in patients with MTC. PATIENTS AND METHODS: Patients with progressive MTC underwent evaluation using In-DTPA-octreotide. Patients who demonstrated In-DTPA-octreotide uptake were treated with 4 cycles of 200 mCi of Lu-DOTATATE and were evaluated using CT scans over 8 to 12 months of treatment. RESULTS: Of the 16 patients initially enrolled, 9 (56.25%) had lesions that were observed in the In-DTPA octreotide scans and were eligible for therapy with Lu-DOTATATE. Three patients had a partial response, 3 patients were classified as having stable disease and, 1 patient had a progressive disease. All responders indicated improvement in quality of life 6 to 12 months after therapy. CONCLUSIONS: Treatment with Lu DOTATATE seems to be an alternative therapy for somatostatin receptor-positive tumors, with very mild adverse effects and quality-of-life improvement, at least during a short-term period. Further studies are needed to determine long-term benefits and to identify which patients are more likely to respond to this modality of therapy. PMID- 25546221 TI - Fluorothymidine PET/CT in neurolymphomatosis. AB - Neurolymphomatosis, a rare extranodal lymphoma, may involve the cranial nerves, peripheral nerves, spinal nerve roots, or nerve plexus. F-FDG PET/CT however shows increased FDG uptake in the nerves but is not specific for malignancy. We report a patient with neurolymphomatosis who underwent F-FDG PET/CT and F fluorothymidine PET/CT where both the scans showed increased tracer uptake in the right sciatic nerve, proven later as neurolymphomatosis on nerve biopsy. Furthermore, the F-FDG avid mediastinal lymph nodes did not show F fluorothymidine avidity, suggesting an inflammatory etiology. PMID- 25546222 TI - 18F-FDG PET/CT findings of a recurrent adenocarcinoma arising from malignant transformation of abdominal wall endometriosis. AB - Abdominal wall endometriosis (AWE) is defined as endometrial tissue located superficial to the peritoneum, which usually develops in a surgical scar of cesarean delivery. Malignant transformation of AWE is a very rare disease. The most frequent histotype of malignancy developing from AWE is endometrioid adenocarcinoma. We present F-FDG PET/CT findings in a 37-year-old woman with a recurrent adenocarcinoma arising from malignant transformation of AWE, who underwent a repeat PET/CT scan because of a recurrent mass at the upper right side of the surgical incision after a previous cesarean delivery. PMID- 25546223 TI - 18F-FDG PET increases visibility of bone lesions in relapsed multiple myeloma: is this hypoxia-driven? AB - INTRODUCTION: Whole-body x-ray (WBX) is used for detecting skeleton abnormalities in patients with multiple myeloma (MM). An alternative might be 18F-FDG PET, which makes use of metabolic changes of malignant cells. The aims of this study were to evaluate whether 18F-FDG PET detects more lesions compared with WBX in patients with relapsing MM and to define its prognostic value. In addition 1 alpha-D-(5-deoxy-5-[F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA) scan and immunohistochemical staining on bone marrow were performed to define whether FDG uptake coincides with angiogenesis-related tumor hypoxia. PATIENTS AND METHODS: 18F-FDG PET (n = 44) and 18F-FAZA-PET (n = 5) were performed in patients with relapsed MM. Bone marrow biopsies (n = 20) were evaluated for hypoxia inducible factors (HIF) 1alpha and 2alpha, vascular endothelial growth factor, glucose transport proteins 1 and 3, and the microvessel density. RESULTS: New lesions were more frequently demonstrated on 18F-FDG PET than on WBX (P = 0.000001). 18F-FDG PET was not predictive for progression-free survival and overall survival. Immunohistochemical staining on bone marrow biopsies demonstrated a significant increase in microvessel density and elevated expression of vascular endothelial growth factor, HIF-2alpha, and glucose transport protein 3 by the malignant plasma cells. However, HIF-1alpha expression and 18F-FAZA scan results were negative. CONCLUSIONS: Our results demonstrate that 18F-FDG PET is relevant for diagnostic purposes compared with WBX in relapsing MM. The enhanced uptake of 18F-FDG PET is likely related to the activation of the HIF-2alpha signaling pathway but probably independent of hypoxia-induced signaling in view of the negative findings on both 18F-FAZA-PET and HIF-1alpha expression. PMID- 25546224 TI - Incidental mammary fibromyoblastoma on 82Rb myocardial perfusion imaging. AB - 82Rb is frequently used in PET myocardial perfusion imaging to detect ischemia. We present the case of a 64-year-old man referred for PET myocardial perfusion imaging to rule out ischemia. On PET images, an abnormal focus of uptake was present in the subcutaneous soft tissue overlying the right chest, which corresponded to a soft-tissue nodule on CT. This lesion was biopsied and proved to be a mammary fibromyoblastoma, an extremely rare and benign lesion. This case is presented to emphasize the importance of reviewing extracardiac structures on PET/CT myocardial perfusion studies. PMID- 25546225 TI - 18F-sodium fluoride PET/CT in oncology: an atlas of SUVs. AB - PURPOSE: The purpose of this study was to analyze the distribution of 18F Sodium Fluoride (18F-NaF) uptake in the normal skeleton, benign and malignant bone lesions, and extraskeletal tissues, using semiquantitative SUV measurements. PATIENTS AND METHODS: We retrospectively analyzed data from 129 patients who had 18F-NaF PET/CT at our institution for an oncological diagnosis between 2007 and 2014. There were 99 men and 30 women, 19 to 90 years old (mean [SD], 61.5 [15.5]). The range, average, and SD of SUV were measured for normal bone and extraskeletal tissues uptake for the entire patient population. A separate statistical analysis was performed to compare group A, which corresponds to the population of patient with no 18F-NaF-avid metastatic lesions, and group B, which corresponds to the population of patient with 18F-NaF-avid metastatic lesions. We also measured SUV max and SUV mean for bony metastases and degenerative changes RESULTS: The PET/CT images were acquired at 30 to 169 minutes (mean [SD], 76.5 [22.8]) after injection of 3.9 to 13.6 mCi (mean [SD], 7.3 [2.4]) of 18F-NaF. The range and mean (SD) of SUV max for 18F-NaF-avid metastasis were 4.5 to 103.3 and 25.9 (16.6) and for 18F-NaF-avid degenerative changes were 3.3 to 52.1 and 16.5 (7.9), respectively. CONCLUSIONS: Various skeletal sites have different normal SUVs. Skeletal metastases have different SUVs when compared with benign findings such as degenerative changes. PMID- 25546226 TI - Focal hepatic 11C-acetate activity on PET/CT scan due to lymphoid hyperplasia. AB - A 69-year-old woman complaining of abdominal bloating underwent ultrasonography, which revealed a small lesion in the left lobe of the liver. The lesion had elevated activity of both 18F-FDG and 11C-acetate on PET/CT scan and was suspected of being malignant. Postresection pathological examination demonstrated that this lesion was a focal intrahepatic lymphoid hyperplasia. PMID- 25546227 TI - Monodispersed sulfur nanoparticles for lithium-sulfur batteries with theoretical performance. AB - While Li-S batteries are poised to be the next generation high-density energy storage devices, low sulfur utilization and slow rate performance have limited their practical applications. Here, we report the synthesis of monodispersed S8 nanoparticles (NPs) with different diameter and the nanosize dependent kinetic characteristics of the corresponding Li-S batteries. Most remarkably, 5 nm S NPs display the theoretical discharging/charging capacity of 1672 mAh g(-1) at 0.1 C rate and a discharge capacity of 1089 mAh g(-1) at 4 C. PMID- 25546228 TI - Growth capacity and biochemical mechanisms involved in rhizobia tolerance to salinity and water deficit. AB - The aim of the present study was to evaluate abiotic stress tolerance of rhizobial strains belonging to Mesorhizobium, Sinorhizobium, and Rhizobium genera, as well as to investigate specie specific stress response mechanisms. Effect of NaCl and PEG on growth capacity, protein, lipid peroxydation (MDA), membrane fatty acid composition and antioxidant enzymes were investigated. Growth capacity and viability of overall rhizobia strains decreased proportionally to the increase of NaCl and PEG levels in the medium. Sinorhizobium strains appeared the most tolerant, where 4H41strain was able to grow at 800 mM NaCl and 40% PEG. On the other hand, growth of R. gallicum and M. mediterraneum was inhibited by 200 mM NaCl. The content of MDA was unchanged in Sinorhizobium strains under both stresses. For Mesorhizobium, only PEG treatment increased the content of MDA. Amount of the C19:0 cyclo fatty-acid was increased in both Sinorhizobium and Mesorhizobium tolerant strains. NaCl stress increased Superoxide dismutase (SOD) activity of overall species; especially the most tolerant strain 4H41. Both treatments increased catalase (CAT) activity in 4H41, TII7, and 835 strains. Obtained results suggest that major response of tolerant Sinorhizobium and Mesorhizobium strains to NaCl and PEG stresses is a preferential accumulation of the C19:0 cyclo fatty acid within bacterial membrane as mechanism to reduce fluidity and maintain integrity. Cell integrity and functioning is also assured by maintaining and/or increasing activity of SOD and CAT antioxidant enzymes for tolerant strains to omit structural and functional damages related to reactive oxygen species overproduced under stressful conditions. PMID- 25546229 TI - Chemokine (C-C Motif) Ligand 5 is Involved in Tumor-Associated Dendritic Cell Mediated Colon Cancer Progression Through Non-Coding RNA MALAT-1. AB - Tumor micro-environment is a critical factor in the development of cancer. The aim of this study was to investigate the inflammatory cytokines secreted by tumor associated dendritic cells (TADCs) that contribute to enhanced migration, invasion, and epithelial-to-mesenchymal transition (EMT) in colon cancer. The administration of recombinant human chemokine (C-C motif) ligand 5 (CCL5), which is largely expressed by colon cancer surrounding TADCs, mimicked the stimulation of TADC-conditioned medium on migration, invasion, and EMT in colon cancer cells. Blocking CCL5 by neutralizing antibodies or siRNA transfection diminished the promotion of cancer progression by TADCs. Tumor-infiltrating CD11c(+) DCs in human colon cancer specimens were shown to produce CCL5. The stimulation of colon cancer progression by TADC-derived CCL5 was associated with the up-regulation of non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), which subsequently increased the expression of Snail. Blocking MALAT-1 significantly decreased the TADC-conditioned medium and CCL5-mediated migration and invasion by decreasing the enhancement of Snail, suggesting that the MALAT 1/Snail pathway plays a critical role in TADC-mediated cancer progression. In conclusion, the inhibition of CCL5 or CCL5-related signaling may be an attractive therapeutic target in colon cancer patients. PMID- 25546230 TI - High-sensitivity immunoassay with surface plasmon field-enhanced fluorescence spectroscopy using a plastic sensor chip: application to quantitative analysis of total prostate-specific antigen and GalNAcbeta1-4GlcNAc-linked prostate-specific antigen for prostate cancer diagnosis. AB - A high-sensitivity immunoassay system with surface plasmon field-enhanced fluorescence spectrometry (SPFS) was constructed using a plastic sensor chip and then applied to the detection of total prostate-specific antigen (total PSA) and GalNAcbeta1-4GlcNAc-linked prostate-specific antigen (LacdiNAc-PSA) in serum, to discriminate between prostate cancer (PC) and benign prostate hyperplasia (BPH). By using this automated SPFS immunoassay, the detection limit for total PSA in serum was as low as 0.04 pg/mL, and the dynamic range was estimated to be at least five digits. A two-step sandwich SPFS immunoassay for LacdiNAc-PSA was constructed using both the anti-PSA IgG antibody to capture PSA and Wisteria floribunda agglutinin (WFA) for the detection of LacdiNAc. The results of the LacdiNAc-PSA immunoassay with SPFS showed that the assay had a sensitivity of 20.0 pg/mL and permitted the specific distinction between PC and BPH within the PSA gray zone. These results suggested that high-sensitivity automated SPFS immunoassay systems might become a powerful tool for the diagnosis of PC and other diseases. PMID- 25546232 TI - Clinical relevance and cost-effectiveness of HLA genotyping in children with Type 1 diabetes mellitus in screening for coeliac disease in the Netherlands. AB - AIMS: To investigate the clinical relevance and cost-effectiveness of human leukocyte antigen (HLA)-genotyping in the Netherlands as a screening tool for the development of coeliac disease in children with Type 1 diabetes mellitus. METHODS: A retrospective analysis was performed in 110 children with Type 1 diabetes mellitus diagnosed between January 1996 and January 2013. All children were screened for coeliac disease using coeliac disease-specific antibodies and HLA genotyping was performed in all children. RESULTS: One hundred and ten children were screened for coeliac disease, and coeliac disease could be confirmed in seven. Eighty-six per cent of the children with Type 1 diabetes mellitus had one of the variants of HLA-DQ2.5 and DQ8. HLA genotypes observed in children with Type 1 diabetes mellitus children and coeliac disease were heterozygote DQ2.5, homozygote DQ2.5 and heterozygote DQ2.5/DQ8. HLA genotyping in coeliac disease screening in children with Type 1 diabetes mellitus is more expensive than screening for coeliac disease with antibodies alone (?326 vs. ?182 per child). CONCLUSIONS: The risk of coeliac disease development in children with Type 1 diabetes mellitus is increased when they are heterozygote DQ2.5/DQ8, homozygote or heterozygote DQ2.5. The implementation of HLA genotyping as a first line screening tool has to be reconsidered because it is not distinctive or cost effective. PMID- 25546231 TI - Heterogeneity in vascular smooth muscle cell embryonic origin in relation to adult structure, physiology, and disease. AB - Regional differences in vascular physiology and disease response exist throughout the vascular tree. While these differences in physiology and disease correspond to regional vascular environmental conditions, there is also compelling evidence that the embryonic origins of the smooth muscle inherent to the vessels may play a role. Here, we review what is known regarding the role of embryonic origin of vascular smooth muscle cells during vascular development. The focus of this review is to highlight the heterogeneity in the origins of vascular smooth muscle cells and the resulting regional physiologies of the vessels. Our goal is to stimulate future investigation into this area and provide a better understanding of vascular organogenesis and disease. . PMID- 25546233 TI - Surrogate light chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by marginal zone B cells. AB - Selection of the primary antibody repertoire takes place in pro-/pre-B cells, and subsequently in immature and transitional B cells. At the first checkpoint, MU heavy (MUH) chains assemble with surrogate light (SL) chain into a precursor B cell receptor. In mice lacking SL chain, MUH chain selection is impaired, and serum autoantibody levels are elevated. However, whether the development of autoantibody-producing cells is due to an inability of the resultant B-cell receptors to induce central and/or peripheral B-cell tolerance or other factors is unknown. Here, we show that receptor editing is defective, and that a higher proportion of BM immature B cells are prone to undergoing apoptosis. Furthermore, transitional B cells are also more prone to undergoing apoptosis, with a stronger selection pressure to enter the follicular B-cell pool. Those that enter the marginal zone (MZ) B-cell pool escape selection and survive, possibly due to the B-lymphopenia and elevated levels of B-cell activating factor. Moreover, the MZ B cells are responsible for the elevated IgM anti-dsDNA antibody levels detected in these mice. Thus, the SL chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by MZ B cells. PMID- 25546234 TI - MicroRNA-33b suppresses migration and invasion by targeting c-Myc in osteosarcoma cells. AB - MicroRNAs have emerged as fundamental regulators in gene expression through silencing gene expression at the post-transcriptional and translational levels. Osteosarcoma is the most common type of primary malignant bone tumor and is characterized by complex genetic changes and resistance to conventional treatments. In our study, the role of miR-33b in the progression and metastasis of osteosarcoma was investigated. Our results showed that miR-33b was significantly downregulated in osteosarcoma tissue and cell lines. Overexpression of miR-33b significantly inhibited cell proliferation, migration, and invasion in the MG-63 osteosarcoma cell line. Moreover, we also showed that c-Myc was negatively regulated by miR-33b at the posttranscriptional level, via a specific target site within the 3'UTR. Overexpression of c-Myc impaired miR-33b-induced inhibition of proliferation and invasion in osteosarcoma cells. The expression of c-Myc was frequently downregulated in osteosarcoma tumors and cell lines and was inversely correlated with miR-33b expression. Thus, our findings suggest that miR 33b inhibits osteosarcoma cells migration and invasion by targeting the c-Myc gene, acting as tumor suppressor. The findings of this study contribute to current understanding of the functions of miR-33b in osteosarcoma. PMID- 25546236 TI - Fifty years of paediatric clinical pharmacology. PMID- 25546237 TI - Fellowship training in neuro-ophthalmology in the United States. PMID- 25546235 TI - The effects of the covalent attachment of 3-(4-hydroxy-3,5-di-tert-butylphenyl) propyl amine to glutaraldehyde pretreated bovine pericardium on structural degeneration, oxidative modification, and calcification of rat subdermal implants. AB - Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials, porcine aortic valves or bovine pericardium (BP), are widely used in cardiac surgery. BHV progressively fail in clinical use due to structural degeneration. Previously we reported that dityrosine, an oxidized amino acid, was present in failed clinical BP-BHV explants; unimplanted BP had no detectable dityrosine. In the same studies BP were demonstrated in vitro to be susceptible to oxidative damage, that could be mitigated with BP covalently modified with the antioxidant, 3-(4-hydroxy-3,5-di-tert-butylphenyl)propyl amine (DBP). The present studies compared in rat subdermal implants glutaraldehyde pretreated BP to BP modified with either DBP or the chemical reactions used to link DBP. All BP explants regardless of DBP demonstrated reduced hydroxyproline and increased digestibility by collagenase. However, the DBP-BP explants showed significant inhibition of reduced explant shrink temperatures (an index of crosslinking) as compared with control BP. Significant mitigation of calcification was observed in both the BP-DBP and chemically modified explants as compared with BP. Dityrosine was not detectable in the 90 day explants. It is concluded that rat subdermal BP implants undergo both calcific and noncalcific structural degeneration, but without the formation of dityrosine, unlike clinical BP explants. PMID- 25546238 TI - 'We're all carrying a burden that we're not sharing': a qualitative study of the impact of cutaneous T-cell lymphoma on the family. AB - BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare, progressive cancer that can be life limiting and highly disfiguring. Patients with CTCL experience poor quality of life; however, there is little published about the experiences of their families. OBJECTIVES: To describe the impact of CTCL on family members and how they cope and adjust, to inform support services. METHODS: Semistructured qualitative interviews were conducted with adult informal caregivers of patients with CTCL recruited via a supraregional CTCL clinic. Interviews explored the history of each patient's illness, the impact of CTCL on the patient and the family, and views about family support. Data were analysed thematically using the Family Adjustment and Adaptation Response model as an interpretative framework. RESULTS: Fourteen caregivers were interviewed (11 spouses, one friend, two daughters; 10 women, four men; all white British; aged 39-85 years). Three key themes emerged: (i) demands of CTCL (the disease, caregiving, financial impact, physical and emotional intimacy); (ii) family capabilities (family support, information, healthcare provider support, other coping strategies); and (iii) adjustment and adaptation (acceptance, changes in patient-caregiver relationship and family dynamics). CTCL was central in many aspects of caregivers' lives, particularly relationships, communication and intimacy. CONCLUSIONS: Our findings demonstrate the multiple demands that CTCL places on caregivers, the capabilities and resources they draw upon to cope, and the significant impact of CTCL on the family. To support families and patients, easily accessible services are needed that include the family in the unit of care, provide support and information, and understand the process of family adjustment and adaptation. PMID- 25546239 TI - The significance of motor (a)symmetry in Parkinson's disease. AB - This study was undertaken to evaluate whether the predominant motor distribution pattern (ie, symmetric or asymmetric) observed in patients with Parkinson's disease (PD) contributes independently to disease severity and progression. We further examine whether this pattern is stable over time, and whether a potential change in pattern affects the course of the disease. We used data from the longitudinal PROPARK study (N > 400) to examine the association of the predominant motor distribution pattern with motor, cognitive, depressive, psychotic, and autonomic symptoms, and with excessive daytime sleepiness. We found that a symmetrical distribution of motor features was associated with poorer performance on nearly all domains, but that this was entirely explained by confounding, in particular by higher age and longer disease duration. We also found that greater asymmetry was associated with younger age, younger age at onset, and shorter disease duration. We further observed a clear tendency to develop a more symmetric distribution pattern as the disease advanced. Conversion to a symmetric pattern was associated with more severe disease, but this conversion did not contribute independently to the less favorable disease course. With increasing age and disease duration comes a clear tendency to develop a more symmetric distribution of motor features in PD. Although this change in distribution pattern is associated with more severe disease as compared with nonconvertors, this pattern change did not contribute independently to the less favorable course. We discuss these findings in light of the evidence from the literature. PMID- 25546240 TI - Porcine Dermis-Derived Collagen Membranes Induce Implantation Bed Vascularization Via Multinucleated Giant Cells: A Physiological Reaction? AB - In this study, the tissue reactions to 2 new porcine dermis-derived collagen membranes of different thickness were analyzed. The thicker material (Mucoderm) contained sporadically preexisting vessel skeletons and fatty islands. The thinner membrane (Collprotect) had a bilayered structure (porous and occlusive side) without any preexisting structures. These materials were implanted subcutaneously in mice to analyze the tissue reactions and potential transmembranous vascularization. Histological and histomorphometrical methodologies were performed at 4 time points (3, 10, 15, and 30 days). Both materials permitted stepwise connective tissue ingrowth into their central regions. In the Mucoderm matrix, newly built microvessels were found within the preexisting vessel and fatty island skeletons after 30 days. This vascularization was independent of the inflammation-related vascularization on both material surfaces. The Collprotect membrane underwent material disintegration by connective tissue strands in combination with vessels and multinucleated giant cells. The histomorphometric analyses revealed that the thickness of Mucoderm did not decrease significantly, while an initial significant decrease of membrane thickness in the case of Collprotect was found at day 15. The present results demonstrate that the 2 analyzed collagen membranes underwent a multinucleated giant cell-associated vascularization. Neither of the materials underwent transmembraneous vascularization. The microvessels were found within the preexisting vessel and fatty island skeletons. Additional long-term studies and clinical studies are necessary to determine how the observed foreign body giant cells affect tissue regeneration. PMID- 25546241 TI - Engineering of recombinant spider silk proteins allows defined uptake and release of substances. AB - Drug delivery carriers stabilize drugs and control their release, expanding the therapeutic window, and avoiding side effects of otherwise freely diffusing drugs in the human body. Materials used as carrier vehicles have to be biocompatible, biodegradable, nontoxic, and nonimmunogenic. Previously, particles made of the recombinant spider silk protein eADF4(C16) could be effectively loaded with positively and neutrally charged model substances. Here, a new positively charged variant thereof, named eADF4(kappa16), has been engineered. Its particle formation is indistinguishable to that of polyanionic eADF4(C16), but in contrast polycationic eADF4(kappa16) allows incorporation of negatively charged substances. Both high-molecular-weight substances, such as nucleic acids, and low molecular-weight substances could be efficiently loaded onto eADF4(kappa16) particles, and release of nucleic acids was shown to be well controlled. PMID- 25546242 TI - Value of HLA-DR genotype in systemic lupus erythematosus and lupus nephritis: a meta-analysis. AB - AIM: Human leukocyte antigen (HLA)-DRB1 allele polymorphisms have been reported to be associated with systemic lupus erythematosus (SLE) susceptibility, but the results of these previous studies have been inconsistent. The purpose of the present study was to systematically summarize and explore whether specific HLA DRB1 alleles confer susceptibility or resistance to SLE and lupus nephritis. METHODS: This review was guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) approach. A comprehensive search was made for articles from PubMed, Medline, Elsevier Science, Springer Link and Cochrane Library database. A total of 25 case-control studies on the relationship between gene polymorphism of HLA-DRB l and SLE were performed and data were analyzed and processed using Review Manager 5.2 and Stata 11.0. RESULTS: At the allelic level, HLA-DR4, DR11 and DR14 were identified as protective factors for SLE (0.79 [0.69,0.91], P < 0.001; 0.72 [0.60, 0.85], P < 0.0001; 0.47 [0.59, 0.95], P < 0.05, respectively). HLA-DR3, DR9, DR15 were potent risk factors for SLE (1.88 [1.58, 2.23], P < 0.001; 1.24 [1.07, 1.45], P < 0.05; 1.25 [1.10, 1.43], P < 0.001, respectively). However, HLA-DR8 was not statistically significant between the SLE group and control group (OR, 1.11 [0.96, 1.30], P > 0.05). DR4 and 11 (OR, 0.55 [0.39, 0.79], P < 0.01; 0.60 [0.37, 0.96], P < 0.05, respectively) conferred a significant protective effect for lupus nephritis. DR3 and DR15 (OR, 2.00 [1.49, 2.70], P < 0.05; 1.60 [1.21, 2.12], P < 0.001, respectively) were at a high risk of developing lupus nephritis. HLA-DR8, DR9 and DR14 (OR, 1.47 [0.9, 2.33], P > 0.05; 0.90 [0.64, 1.27], P > 0.05; 0.61 [0.36, 1.03], P > 0.05, respectively) were not statistically significant between the lupus nephritis and control groups. CONCLUSIONS: The HLA-DR4, DR11, DR14 alleles might be protective factors for SLE and HLA-DR3, DR9, DR15 were potent risk factors. In addition, HLA DR4 and DR11 alleles might be protective factors for lupus nephritis and DR3 and DR15 suggest a risk role. These results proved that HLA-DR3, DR15, DR4 and DR11 might be identified as predictors for lupus nephritis and SLE. PMID- 25546243 TI - Inflammatory IL-1beta-driven JNK activation in stage III melanoma. PMID- 25546244 TI - Meta-analysis of continuous oral anticoagulants versus heparin bridging in patients undergoing CIED surgery: reappraisal after the BRUISE study. AB - BACKGROUND: Management of patients treated with oral anticoagulation (OAC) requiring a cardiovascular implantable electronic device (CIED) surgery is a challenge that requires balancing the risk of bleeding complications with the risk of thromboembolic events. Recently the approach of performing these procedures while the patient remains with a therapeutic international normalized ratio has gained interest due to several publications showing its relative safety. OBJECTIVES: To evaluate the safety and effectiveness of continuous use of OAC compared with heparin bridging in the perioperative setting of CIED surgery using a meta-analysis. METHODS: A systematic review of PubMed/MEDLINE, Ovid, and Elsevier databases was performed. Eligible randomized controlled trials and cohort studies were included. The outcomes studied were risk of clinically significant bleeding and of thromboembolic events. Our analysis was restricted to OAC with vitamin K antagonists. RESULTS: Of 560 manuscripts initially considered relevant, seven were included in the meta-analysis, totaling 2,191 patients. Data are reported as odds ratios (ORs) with confidence interval (CI) of 95%. Maintenance of OAC was associated with a significantly lower risk of postoperative bleeding compared with heparin bridge (OR = 0.25, 95% CI 0.17-0.36, P < 0.00001). There was no difference noted in the risk of thromboembolic events between the two strategies (OR = 1.86, 95% CI 0.29-12.17, P = 0.57). CONCLUSIONS: Uninterrupted use of OAC in the perioperative of CIED surgery was associated with a reduced risk of bleeding. This strategy should be considered the preferred one in patients at moderate-to-high risk of thromboembolic events. PMID- 25546245 TI - Denaturant effects on HbGp hemoglobin as monitored by 8-anilino-1-naphtalene sulfonic acid (ANS) probe. AB - Glossoscolex paulistus extracellular hemoglobin (HbGp) stability has been monitored in the presence of denaturant agents. 8-Anilino-1-naphtalene-sulfonic acid (ANS) was used, and spectroscopic and hydrodynamic studies were developed. Dodecyltrimethylammonium bromide (DTAB) induces an increase in ANS fluorescence emission intensity, with maximum emission wavelength blue-shifted from 517 to 493 nm. Two transitions are noticed, at 2.50 and 9.50 mmol/L of DTAB, assigned to ANS interaction with pre-micellar aggregates and micelles, respectively. In oxy-HbGp, ANS binds to protein sites less exposed to solvent, as compared to DTAB micelles. In DTAB-HbGp-ANS ternary system, at pH 7.0, protein aggregation, oligomeric dissociation and unfolding were observed, while, at pH 5.0, aggregation is absent. DTAB induced unfolding process displays two transitions, one due to oligomeric dissociation and the second one, probably, to the denaturation of dissociated subunits. Moreover, guanidine hydrochloride and urea concentrations above 1.5 and 4.0 mol/L, respectively, induce the full HbGp denaturation, with reduction of ANS-bound oxy-HbGp hydrophobic patches, as noticed by fluorescence quenching up to 1.0 and 5.0 mol/L of denaturants. Our results show clearly the differences in probe sensitivity to the surfactant, in the presence and absence of protein, and new insights into the denaturant effects on HbGp unfolding. PMID- 25546246 TI - Treatment of keratitis-ichthyosis- deafness (KID) syndrome in children: a case report and review of the literature. AB - Keratitis-ichthyosis-deafness (KID) syndrome is a rare hereditary cornification disorder resulting from mutations in connexin 26, a protein important for intercellular communication. In addition to the characteristic clinical triad of congenital bilateral sensorineural hearing loss, keratitis, and erythrokeratoderma, affected individuals also suffer from chronic bacterial and fungal infections and have an increased risk of benign and malignant cutaneous tumors. Treatments with antibiotics, antifungals, and systemic retinoids have been reported with variable response. Ocular and skeletal toxicity from prolonged exposure to systemic retinoids is a major concern especially in children. We report a case of a 7-year-old boy with KID syndrome complicated by frequent infections who responded well to acitretin 0.5-1.0 mg/kg/day. The patient had significant improvement of the hyperkeratosis on the scalp, trunk, and extremities within 4 weeks after initiating treatment. The patient has been on treatment for over a year without notable ocular, skeletal, or laboratory side effects. A review of the literature focusing on therapeutic options for KID syndrome and concerns about safety and tolerability is presented. PMID- 25546247 TI - APRN prescribing in Georgia: An evolving environment. AB - PURPOSE: While it took over 20 years to achieve legal authority to write prescriptions in Georgia, effective July 1, 2006, nearly 40% of Georgia advanced practice registered nurses (APRNs) are still not using this method of prescribing. An investigation was conducted to identify the current practice environment and barriers to practice in order to identify causes for this lack of participation and implications for advanced practice nursing and the provision of health care. DATA SOURCES: A survey of APRNs in Georgia in 2011 describes demographics, practice environment, APRN education, barriers to practice, and prescribing activity. CONCLUSIONS: Georgia is one of the most restrictive states in terms of APRN scope of practice, and has an anticipated escalation of underserved population with health disparities demanding attention. IMPLICATIONS FOR PRACTICE: Many of the identified barriers are common to APRNs nationwide, but specific barriers to Georgia APRNs are being strategically addressed. Policy changes are recommended to enhance the practice environment of APRNs to support the delivery of quality care. PMID- 25546248 TI - Potent inhibition of VEGFR-2 activation by tight binding of green tea epigallocatechin gallate and apple procyanidins to VEGF: relevance to angiogenesis. AB - SCOPE: Excessive concentrations of vascular endothelial growth factor (VEGF) drive angiogenesis and cause complications such as increased growth of tumours and atherosclerotic plaques. The aim of this study was to determine the molecular mechanism underlying the potent inhibition of VEGF signalling by polyphenols. METHODS AND RESULTS: We show that the polyphenols epigallocatechin gallate from green tea and procyanidin oligomers from apples potently inhibit VEGF-induced VEGF receptor-2 (VEGFR-2) signalling in human umbilical vein endothelial cells by directly interacting with VEGF. The polyphenol-induced inhibition of VEGF-induced VEGFR-2 activation occurred at nanomolar polyphenol concentrations and followed bi-phasic inhibition kinetics. VEGF activity could not be recovered by dialysing VEGF-polyphenol complexes. Exposure of VEGF to epigallocatechin gallate or procyanidin oligomers strongly inhibited subsequent binding of VEGF to human umbilical vein endothelial cells expressing VEGFR-2. Remarkably, even though VEGFR-2 signalling was completely inhibited at 1 MUM concentrations of polyphenols, endothelial nitric oxide synthase was shown to still be activated via the PI3K/Akt signalling pathway which is downstream of VEGFR-2. CONCLUSION: These data demonstrate for the first time that VEGF is a key molecular target for specific polyphenols found in tea, apples and cocoa which potently inhibit VEGF signalling and angiogenesis at physiological concentrations. These data provide a plausible mechanism which links bioactive compounds in food with their beneficial effects. PMID- 25546249 TI - Exploring diversity in socioeconomic inequalities in health among rural dwelling Canadians. AB - PURPOSE: To describe the patterning of socioeconomic inequalities in health among rural dwelling women and men in a Canadian province, exploring diversity in associations by measure of socioeconomic position, health outcome, and demographic characteristics. METHODS: Baseline data from the Saskatchewan Rural Health Study was used, an ongoing prospective cohort study examining the health of rural people in Saskatchewan, Canada. Of the 11,004 eligible addresses, responses to mailed questionnaires were obtained from 4,624 (42%) households, representing 8,261 women and men. Multiple logistic regression was the primary method of analysis; generalized estimating equations were utilized to account for household clustering. Associations between 5 health outcomes (self-rated health, chronic obstructive lung disease, diabetes, heart attack, high blood pressure) and 4 indicators of socioeconomic position (income, education, financial strain, occupational skill level) were assessed, with age and gender as potential effect modifiers. FINDINGS: With the exception of occupational skill level, socioeconomic position (SEP) indicators were strongly and inversely related to most health outcomes, often in a graded manner. Associations between SEP and several health outcomes were weaker for older than younger participants (heart attack, high blood pressure, lung disease) and stronger among women compared to men (high blood pressure, lung disease). CONCLUSIONS: The patterning of SEP health associations observed in this rural Canadian sample suggests the need for health promotion strategies and policy initiatives to be broadly targeted at individuals and families occupying a wide range of socioeconomic circumstances. PMID- 25546250 TI - Post-tsunami relocation of fisher settlements in South Asia: evidence from the Coromandel Coast, India. AB - The tsunami that struck the coasts of India on 26 December 2004 resulted in the large-scale destruction of fisher habitations. The post-tsunami rehabilitation effort in Tamil Nadu was directed towards relocating fisher settlements in the interior. This paper discusses the outcomes of a study on the social effects of relocation in a sample of nine communities along the Coromandel Coast. It concludes that, although the participation of fishing communities in house design and in allocation procedures has been limited, many fisher households are satisfied with the quality of the facilities. The distance of the new settlements to the shore, however, is regarded as an impediment to engaging in the fishing profession, and many fishers are actually moving back to their old locations. This raises questions as to the direction of coastal zone policy in India, as well as to the weight accorded to safety (and other coastal development interests) vis-a-vis the livelihood needs of fishers. PMID- 25546251 TI - Detection of influenza antigenic variants directly from clinical samples using polyclonal antibody based proximity ligation assays. AB - Identification of antigenic variants is the key to a successful influenza vaccination program. The empirical serological methods to determine influenza antigenic properties require viral propagation. Here a novel quantitative PCR based antigenic characterization method using polyclonal antibody and proximity ligation assays, or so-called polyPLA, was developed and validated. This method can detect a viral titer that is less than 1000 TCID50/mL. Not only can this method differentiate between different HA subtypes of influenza viruses but also effectively identify antigenic drift events within the same HA subtype of influenza viruses. Applications in H3N2 seasonal influenza data showed that the results from this novel method are consistent with those from the conventional serological assays. This method is not limited to the detection of antigenic variants in influenza but also other pathogens. It has the potential to be applied through a large-scale platform in disease surveillance requiring minimal biosafety and directly using clinical samples. PMID- 25546253 TI - Characterisation of three novel giant viruses reveals huge diversity among viruses infecting Prymnesiales (Haptophyta). AB - We have isolated three novel lytic dsDNA-viruses from Raunefjorden (Norway) that are putative members of the Mimiviridae family, namely Haptolina ericina virus RF02 (HeV RF02), Prymnesium kappa virus RF01 (PkV RF01), and Prymnesium kappa virus RF02 (PkV RF02). Each of the novel haptophyte viruses challenges the common conceptions of algal viruses with respect to host range, phylogenetic affiliation and size. PkV RF01 has a capsid of ~310 nm and is the largest algal virus particle ever reported while PkV RF01 and HeV RF02 were able to infect different species, even belonging to different genera. Moreover, PkV RF01 and HeV RF02 infected the same hosts, but phylogenetic analysis placed them in different groups. Our results reveal large variation among viruses infecting closely related microalgae, and challenge the common conception that algal viruses have narrow host range, and phylogeny reflecting their host affiliation. PMID- 25546252 TI - Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides. AB - Combinations of direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) have the potential to revolutionize the HCV therapeutic regime. An integral component of DAA combination therapies is HCV NS5A inhibitors. It has previously been proposed that NS5A DAAs inhibit two functions of NS5A: RNA replication and virion assembly. In this study, we characterize the impact of a prototype NS5A DAA, daclatasvir (DCV), on HCV replication compartment formation. DCV impaired HCV replicase localization and NS5A motility. In order to characterize the mechanism behind altered HCV replicase localization, we examined the impact of DCV on the interaction of NS5A with its essential cellular cofactor, phosphatidylinositol-4-kinase III alpha (PI4KA). We observed that DCV does not inhibit PI4KA directly, nor does it impair early events of the NS5A-PI4KA interaction that can occur when NS5A is expressed alone. NS5A functions that are unaffected by DCV include PI4KA binding, as determined by co-immunoprecipitation, and a basal accumulation of the PI4KA product, PI4P. However, DCV impairs late steps in PI4KA activation that requires NS5A expressed in the context of the HCV polyprotein. These NS5A functions include hyper-stimulation of PI4P levels and appropriate replication compartment formation. The data are most consistent with a model wherein DCV inhibits conformational changes in the NS5A protein or protein complex formations that occur in the context of HCV polyprotein expression and stimulate PI4P hyper-accumulation and replication compartment formation. PMID- 25546254 TI - Lactococcus lactis displayed neuraminidase confers cross protective immunity against influenza A viruses in mice. AB - Influenza A viruses pose a serious threat to public health. Current influenza A vaccines predominantly focus on hemagglutinin (HA) and show strain-specific protection. Neuraminidase (NA) is much less studied in the context of humoral immunity against influenza A viruses. The purpose of this study is to evaluate the cross protective immunity of NA presented on Lactococcus lactis (L.lactis) surface against homologous and heterologous influenza A viruses in the mouse model. L.lactis/pNZ8110-pgsA-NA was constructed in which pgsA was used as an anchor protein. Mice vaccinated orally with L.lactis/pNZ8110-pgsA-NA could elicit significant NA-specific serum IgG and mucosa IgA antibodies, as well as neuraminidase inhibition (NI) titers. Importantly, L.lactis/pNZ8110-pgsA-NA provided 80% protection against H5N1, 60% protection against H3N2 and H1N1, respectively. These findings suggest that recombinant L.lactis/pNZ110-pgsA-NA in the absence of adjuvant via oral administration can be served as an effective vaccine candidate against diverse strains of influenza A viruses. PMID- 25546255 TI - You've got mail ... and need follow-up: the effect and patient perception of e mail follow-up reminders after emergency department discharge. AB - OBJECTIVES: The hypothesis was that a reminder about recommended primary care physician (PCP) follow-up, sent via e-mail to patients discharged from the emergency department (ED), would increase the proportion of patients who followed up with their PCPs within the recommended time frame. Patient receptiveness to e mail follow-up reminders was also assessed. METHODS: This was a mixed methods clinical intervention study with subjects randomized either to receive the usual care discharge instructions only or to also receive a reminder e-mail message the day after the ED visit. The reminder e-mail contained the subject's PCP's name and address and the recommended PCP follow-up time interval. A blinded review of outpatient PCP medical records was conducted to determine whether and when follow up occurred. Researchers attempted to contact patients with a telephone survey 2 weeks after their ED visits. The primary outcomes between groups were compared using chi-square tests and relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Thirty-three percent of the intervention group and 32% of the control group followed-up as recommended (RR = 1.04, 95% CI = 0.81 to 1.33); 52% of the intervention group and 48% of the control group followed-up within 10 days of the recommended time (RR = 1.08, 95% CI = 0.91 to 1.29). The 334 patients (57%) successfully contacted via telephone demonstrated a high interest in receiving future e-mail reminders (75%), with the group that received e-mail reminders more likely to want one in the future than those who did not receive e mail reminders (82.5% vs. 69.76%; p = 0.04). CONCLUSIONS: E-mail reminders sent after ED visits did not improve patients' adherence to the recommended timing of primary care follow-up contained in discharge instructions. Subjects in both the control and the intervention groups favorably viewed the concept of e-mail reminders, suggesting that the value of e-mail reminders after ED discharge may be in areas such as patient satisfaction that were not specifically targeted for measurement in this study. PMID- 25546257 TI - Moving targets for hematopoietic stem cell transplantation for multiple sclerosis. PMID- 25546256 TI - Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism. AB - Mitochondria are the main cellular source of reactive oxygen species and are recognized as key players in several age-associated disorders and neurodegeneration. Their dysfunction has also been linked to cellular aging. Additionally, mechanisms leading to the preservation of mitochondrial function promote longevity. In this study we investigated the proteomic and functional alterations in brain mitochondria isolated from mature (5 months old), old (12 months old), and aged (24 months old) mice as determinants of normal "healthy" aging. Here the global changes concomitant with aging in the mitochondrial proteome of mouse brain analyzed by quantitative mass-spectrometry based super SILAC identified differentially expressed proteins involved in several metabolic pathways including glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Despite these changes, the bioenergetic function of these mitochondria was preserved. Overall, this data indicates that proteomic changes during aging may compensate for functional defects aiding in preservation of mitochondrial function. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD001370 (http://proteomecentral.proteomexchange.org/dataset/PXD001370). PMID- 25546258 TI - A 10-year survey: prevalence of ocular surface squamous neoplasia in clinically benign pterygium specimens. AB - PURPOSE: It is essential to assess the yield of routine histopathological examination of pterygium specimens excised from clinically benign pterygium. The purpose of this study was to determine the rate of histopathologically identified ocular surface squamous neoplasia (OSSN) in clinically benign pterygium specimens. MATERIALS AND METHODS: This retrospective consecutive study consisted of patients from the cornea services of the ophthalmology departments of Meir Medical Center, Kfar Sava, and Rabin Medical Center, Petah Tikva, Israel. Included patients were those with clinically benign pterygium who underwent pterygium excision between January 2002 and December 2011. The pterygium specimens were sent for histopathological examination and the pathology reports were reviewed for evidence of OSSN. RESULTS: Overall, pathology reports of 682 eyes of 585 sequential patients were included in the study. There was a male predominance of cases (59%). Patients' age ranged from 16 to 87 years with an average age of 56 years. Six hundred and forty-three cases were primary (94%) and 39 cases were recurrent (6%). CONCLUSIONS: Cases of clinically benign pterygium diagnosed and excised by an experienced corneal expert are less likely to harbor OSSN. The yield of routine histopathological examination of such specimens may be low. PMID- 25546259 TI - A new fluorescent quenching method for the determination of phosphoproteins by using calconcarboxylic acid. AB - A fluorescent quenching detection method for phosphoproteins in SDS-PAGE by using calconcarboxylic acid (CCA) was described. In this method, the fluorescence intensity of CCA was greatly increased with the presence of Al(3+) in the gel background, while in zones where phosphoproteins are located this intensity was absent because of fluorescence quenching phenomenon through the formation of CCA Al(3+) -phosphoprotein appended complex. Approximately 4-8 ng of phosphoproteins can be selectively detected within 1 h (1D SDS-PAGE), which is similar to that of the most commonly used Pro-Q Diamond stain. The specificity of this novel technique for phosphoproteins was confirmed by dephosphorylation, Western blot, and LC-MS/MS analysis, respectively. Furthermore, to better understand the newly developed method, the detection mechanism of CCA stain was explored by fluorescent spectrometry. According to the results, it is believed that CCA stain may provide a new choice for selective, economical, MS compatible, and convenient visualization of gel-separated phosphoproteins. PMID- 25546261 TI - Hypohidrosis: an early clue in the diagnosis of Fabry disease. PMID- 25546260 TI - Hematopoietic stem/progenitor cells directly contribute to arteriosclerotic progression via integrin beta2. AB - Recent studies described the association between hematopoietic stem/progenitor cell (HSPC) expansion in the bone marrow (BM), leukocytosis in the peripheral blood, and accelerated atherosclerosis. We hypothesized that circulating HSPC may home to inflamed vessels, where they might contribute to inflammation and neointima formation. We demonstrated that Lin(-) Sca-1(+) cKit(+) (LSK cells) in BM and peripheral blood of LDLr(-/-) mice on high fat diet expressed significantly more integrin beta2 , which was responsible for LSK cell adhesion and migration toward ICAM-1 in vitro, and homing to injured arteries in vivo, all of which were blocked with an anti-CD18 blocking antibody. When homed LSK cells were isolated from ligated artery and injected to irradiated recipients, they resulted in BM reconstitution. Injection of CD18(+/+) LSK cells to immunodeficient Balb/C Rag2(-) gammaC(-/-) recipients resulted in more severe inflammation and reinforced neointima formation in the ligated carotid artery, compared to mice injected with PBS and CD18(-/-) LSK cells. Hypercholesterolemia stimulated ERK phosphorylation (pERK) in LSK cells of LDLr(-/-) mice in vivo. Blockade of pERK reduced ARF1 expression, leading to decreased integrin beta2 function on HSPC. In addition, integrin beta2 function could be regulated via ERK independent LRP1 pathway. Integrin beta2 expression on HSPC is regulated by hypercholesterolemia, specifically LDL, in pERK-dependent and -independent manners, leading to increased homing and localization of HSPC to injured arteries, which is highly correlated with arteriosclerosis. PMID- 25546262 TI - The Impact of a National Guideline on the Management of Cancer Pain on the Practice of Pain Assessment and Registration. AB - The Dutch clinical practice guideline on the diagnosis and management of pain in patients with cancer was published in 2008 and intensively promoted to healthcare professionals who see patients with cancer. One of the most important recommendations is the systematic registering of the pain and its intensity. To evaluate in which degree this part of the practice guideline is implemented, we analyzed the medical records of patients attending the outpatient oncological clinic in an academic hospital, a large teaching hospital, and 4 smaller peripheral hospitals. None of the participating hospitals assessed pain by a standardized scale. Reference to pain in the medical record happened more frequently in the academic hospital than in the other hospitals. The frequency of recording pain in the medical record in the academic hospital was much higher in this study than the one previously reported, whereas the findings in the other hospitals were comparable. There may be several reasons for the difference in reporting rate of pain in patients with cancer. Our findings indicate that the clinical practice guideline with regard to pain registration is poorly implemented in oncology outpatient clinics. More efforts should be made to generate the awareness for the need of pain registration. PMID- 25546263 TI - Team performance and collective efficacy in the dynamic psychology of competitive team: a Bayesian network analysis. AB - The purpose of this paper was to discover the relationships among 22 relevant psychological features in semi-professional football players in order to study team's performance and collective efficacy via a Bayesian network (BN). The paper includes optimization of team's performance and collective efficacy using intercausal reasoning pattern which constitutes a very common pattern in human reasoning. The BN is used to make inferences regarding our problem, and therefore we obtain some conclusions; among them: maximizing the team's performance causes a decrease in collective efficacy and when team's performance achieves the minimum value it causes an increase in moderate/high values of collective efficacy. Similarly, we may reason optimizing team collective efficacy instead. It also allows us to determine the features that have the strongest influence on performance and which on collective efficacy. From the BN two different coaching styles were differentiated taking into account the local Markov property: training leadership and autocratic leadership. PMID- 25546264 TI - A taxonomy of endogenous and exogenous uncertainty in high-risk, high-impact contexts. AB - By reference to a live hostage negotiation exercise, this study presents a taxonomy of uncertainty that can be usefully applied to assist in the categorization and application of findings from decision-making research conducted in naturalistic (specifically critical incident) settings. Uncertainty was measured via observational methods (during the exercise and by reference to video footage), decision logs, and postincident simulated recall interviews with trainee police officers. Transcripts were coded and analyzed thematically. Uncertainty was dichotomized as deriving from either endogenous sources (about the problem situation itself) or exogenous sources (about the operating system that is dealing with the incident). Overall, exogenous uncertainty (75%) was more prevalent than endogenous uncertainty (25%), specifically during discussions on plan formulation and execution. It was also qualitatively associated with poor role understanding and trust. Endogenous uncertainty was more prevalent during discussions on situation assessment and plan formulation. The taxonomy provides a useful way for organizational researchers to categorize uncertainty during the naturalistic observations of workplace interactions and decision making. It reduces the complexity associated with observational research to allow organizational psychologists to better tailor their recommendations for reducing uncertainty. Dealing with endogenous uncertainties would entail targeting decision making specific to the problem incident (e.g., introduce training or policy to reduce redundant fixation on rote-repetitive superordinate goals and focus on more short-term actionable goals during situation assessments). Dealing with exogenous uncertainties would entail improving decision making relating to management and team processes across critical incidents (e.g., training to clarify distributed roles in critical incident teams to aid plan formulation and execution). Organizational researchers interested in uncertainty management in the workplace should utilize this taxonomy as a guide to (a) categorize uncertainty and (b) generate applicable recommendations from their findings. PMID- 25546265 TI - Age differences in feedback reactions: The roles of employee feedback orientation on social awareness and utility. AB - Organizations worldwide are currently experiencing shifts in the age composition of their workforces. The workforce is aging and becoming increasingly age diverse, suggesting that organizational researchers and practitioners need to better understand how age differences may manifest in the workplace and the implications for human resource practice. Integrating socioemotional selectivity theory with the performance feedback literature and using a time-lagged design, the current study examined age differences in moderating the relationships between the characteristics of performance feedback and employee reactions to the feedback event. The results suggest that older workers had higher levels of feedback orientation on social awareness, but lower levels of feedback orientation on utility than younger workers. Furthermore, the positive associations between favorability of feedback and feedback delivery and feedback reactions were stronger for older workers than for younger workers, whereas the positive association between feedback quality and feedback reactions was stronger for younger workers than for older workers. Finally, the current study revealed that age-related differences in employee feedback orientation could explain the different patterns of relationships between feedback characteristics and feedback reactions across older and younger workers. These findings have both theoretical and practical implications for building theory about workplace aging and improving ways that performance feedback is managed across employees from diverse age groups. PMID- 25546266 TI - There are lots of big fish in this pond: The role of peer overqualification on task significance, perceived fit, and performance for overqualified employees. AB - Research has uncovered mixed results regarding the influence of overqualification on employee performance outcomes, suggesting the existence of boundary conditions for such an influence. Using relative deprivation theory (Crosby, 1976) as the primary theoretical basis, in the current research, we examine the moderating role of peer overqualification and provide insights to the questions regarding whether, when, and how overqualification relates to employee performance. We tested the theoretical model with data gathered across three phases over 6 months from 351 individuals and their supervisors in 72 groups. Results showed that when working with peers whose average overqualification level was high, as opposed to low, employees who felt overqualified for their jobs perceived greater task significance and person-group fit, and demonstrated higher levels of in-role and extra-role performance. We discuss theoretical and managerial implications for overqualification at the individual level and within the larger group context. PMID- 25546267 TI - Thromboprophylaxis in patients undergoing total hip and knee arthroplasty: a review of current practices in an Australian teaching hospital. AB - BACKGROUND: Venous thromboembolism (VTE) remains a cause of significant morbidity and mortality following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Prophylaxis significantly reduces the rate of VTE following these procedures. Previous studies report suboptimal uptake of guideline recommended thromboprophylaxis. AIMS: To describe VTE prophylaxis prescribing practices in a major hospital for joint replacement surgery. To determine the proportion of patients receiving guideline recommended thromboprophylaxis. To define the incidence of in-hospital VTE following THA and TKA. METHODS: A retrospective chart review of 402 consecutive patients undergoing THA or TKA from June to October 2013. Patient characteristics, operative and anaesthetic factors, details of thromboprophylaxis and the incidence of in-hospital VTE are reported. Comparison is made with recent guidelines. RESULTS: Four hundred and two patients underwent THA (n = 202) or TKA (n = 200). Ninety-nine per cent of patients received mechanical prophylaxis. One hundred percent of patients received chemoprophylaxis in hospital. Enoxaparin was most commonly prescribed followed by aspirin. Patients undergoing TKA were more likely to receive an anticoagulant (89.9% vs 47.8% for THA, P < 0.05). 74.5% received chemoprophylaxis on discharge (mean duration 22.1 days). The incidence of in-hospital VTE was 4.7%. CONCLUSIONS: The proportion of study patients receiving thromboprophylaxis compares favourably with prior research. The overall incidence of VTE is higher than that demonstrated in major orthopaedic trials. Inadequate duration of chemoprophylaxis remains a potential area of improvement. Extended prophylaxis should be prescribed as per current guidelines. Comparison between efficacy and safety of various agents is the subject of future research. PMID- 25546268 TI - Patterns of host plant utilization and diversification in the brush-footed butterflies. AB - Herbivorous insects represent one of the most successful animal radiations known. They occupy a wide range of niches, feed on a great variety of plants, and are species rich; yet the factors that influence their diversification are poorly understood. Host breadth is often cited as a major factor influencing diversification, and, according to the Oscillation Hypothesis, shifts from generalist to specialist feeding states increase the diversification rate for a clade. We explored the relationship between host breadth and diversification within the Nymphalidae (Lepidoptera) and explicitly tested predictions of the Oscillation Hypothesis. We found strong evidence of diversification rate heterogeneity, but no difference in host breadth between clades with a higher diversification rate compared to their sisters. We also found some clades exhibited phylogenetic nonindependence in host breadth and these clades had lower host plant turnover than expected by chance, suggesting host breadth is evolutionarily constrained. Finally, we found that transitions among host breadth categories varied, but the likelihood of reductions in host breadth was greater than that of increases. Our results indicate host breadth is decoupled from diversification rate within the Nymphalidae, and that constraints on diet breadth might play an important role in the evolution of herbivorous insects. PMID- 25546269 TI - Qualis-SIS: automated standard curve generation and quality assessment for multiplexed targeted quantitative proteomic experiments with labeled standards. AB - Multiplexed targeted quantitative proteomics typically utilizes multiple reaction monitoring and allows the optimized quantification of a large number of proteins. One challenge, however, is the large amount of data that needs to be reviewed, analyzed, and interpreted. Different vendors provide software for their instruments, which determine the recorded responses of the heavy and endogenous peptides and perform the response-curve integration. Bringing multiplexed data together and generating standard curves is often an off-line step accomplished, for example, with spreadsheet software. This can be laborious, as it requires determining the concentration levels that meet the required accuracy and precision criteria in an iterative process. We present here a computer program, Qualis-SIS, that generates standard curves from multiplexed MRM experiments and determines analyte concentrations in biological samples. Multiple level-removal algorithms and acceptance criteria for concentration levels are implemented. When used to apply the standard curve to new samples, the software flags each measurement according to its quality. From the user's perspective, the data processing is instantaneous due to the reactivity paradigm used, and the user can download the results of the stepwise calculations for further processing, if necessary. This allows for more consistent data analysis and can dramatically accelerate the downstream data analysis. PMID- 25546271 TI - Applying an Ecohealth perspective in a state of the environment report: experiences of a local public health unit in Canada. AB - We applied an Ecohealth perspective into a State of the Environment report for Grey Bruce Health Unit and summarized environmental and health data relevant for public health practice. We aimed for comprehensiveness in our data compilation, including: standard media categories (e.g., air, water, land); and ecological indicators (e.g., vectors, forests, wetlands). Data sources included both primary (collected by an organization) and secondary (assembled by others). We organized indicators with the Driving forces-Pressure-State-Exposure-Effect-Action (DPSEEA) framework created by the World Health Organization. Indicators of air, water and land quality generally appeared to point towards a healthy state. Vector-borne diseases remained low. Forests and wetlands appeared to be in good condition, however more monitoring data was needed to determine trends in their ecological indicators. Data were not available on biodiversity and fish conditions. The results of our application of the DPSEEA framework suggest that routinely collected environmental and health data can be structured into the framework, though challenges arose due to gaps in data availability, particularly for social and gender analyses. Ecohealth approaches had legitimacy with broader healthy community partners but applying such approaches was a complex undertaking. PMID- 25546270 TI - A systematic review and meta-analysis of dengue risk with temperature change. AB - Dengue fever (DF) is the most serious mosquito-borne viral disease in the world and is significantly affected by temperature. Although associations between DF and temperatures have been reported repeatedly, conclusions have been inconsistent. Six databases were searched up to 23 March 2014, without language and geographical restrictions. The articles that studied the correlations between temperatures and dengue were selected, and a random-effects model was used to calculate the pooled odds ratio and 95% confidence intervals. Of 1589 identified articles, 137 were reviewed further, with 33 satisfying inclusion criteria. The closest associations were observed between mean temperature from the included studies (23.2-27.7 degrees C) and DF (OR 35.0% per 1 degrees C; 95% CI 18.3% 51.6%) positively. Additionally, minimum (18.1-24.2 degrees C) (29.5% per 1 degrees C; 20.9%-38.1%) and maximum temperature (28.0-34.5 degrees C) (28.9%; 10.3%-47.5%) were also associated with increased dengue transmission. The OR of DF incidence increased steeply from 22 degrees C to 29 degrees C, suggesting an inflexion of DF risk between these lower and upper limits of DF risk. This discovery is helpful for government decision-makers focused on preventing and controlling dengue in areas with temperatures within this range. PMID- 25546272 TI - Agricultural and management practices and bacterial contamination in greenhouse versus open field lettuce production. AB - The aim of this study was to gain insight into potential differences in risk factors for microbial contamination in greenhouse versus open field lettuce production. Information was collected on sources, testing, and monitoring and if applicable, treatment of irrigation and harvest rinsing water. These data were combined with results of analysis on the levels of Escherichia coli as a fecal indicator organism and the presence of enteric bacterial pathogens on both lettuce crops and environmental samples. Enterohemorragic Escherichia coli (EHEC) PCR signals (vt1 or vt2 positive and eae positive), Campylobacter spp., and Salmonella spp. isolates were more often obtained from irrigation water sampled from open field farms (21/45, 46.7%) versus from greenhouse production (9/75, 12.0%). The open field production was shown to be more prone to fecal contamination as the number of lettuce samples and irrigation water with elevated E. coli was significantly higher. Farmers comply with generic guidelines on good agricultural practices available at the national level, but monitoring of microbial quality, and if applicable appropriateness of water treatment, or water used for irrigation or at harvest is restricted. These results indicate the need for further elaboration of specific guidelines and control measures for leafy greens with regard to microbial hazards. PMID- 25546273 TI - NNK, a tobacco-specific carcinogen, inhibits the expression of lysyl oxidase, a tumor suppressor. AB - A tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is believed to contribute to the cancer burden in cigarette smokers. To evaluate NNK effects on the expression of lysyl oxidase (LOX), a tumor suppressor, we examined this enzyme at various levels in NNK-treated rat fetal lung fibroblasts (RFL6). Exposure of cells to NNK reduced levels of steady-states LOX mRNA and new transcript synthesis. NNK inhibited all LOX protein species in a dose-dependent manner. Although 300 uM NNK markedly decreased the level in the 46 kDa preproenzyme, under same conditions, there was no detectable amounts of the 50 kDa proenzyme and the 32 kDa mature enzyme suggesting NNK perturbing the LOX protein processing to its mature form. Moreover, NNK also suppressed LOX activities in conditioned media of treated cells. At the promoter level, NNK enhanced methylation of CpG, but decreased acetylation of histone H3 at the core promoter region of the LOX gene. These results indicated that transcriptional and translational processes of LOX are major targets for NNK. Thus, inactivation of tumor suppressor gene LOX may play a critical role in NNK carcinogenesis. PMID- 25546275 TI - Moving beyond green: exploring the relationship of environment type and indicators of perceived environmental quality on emotional well-being following group walks. AB - Against the backdrop of increasing interest in the relationship between Nature and health, this study examined the effect of perceived environment type and indicators of perceived environmental quality on short-term emotional well-being following outdoor group walks. Participants (n = 127) of a national group walk program completed pre- and post-walk questionnaires for each walk attended (n = 1009) within a 13-week study period. Multilevel linear modelling was used to examine the main and moderation effects. To isolate the environmental from the physical activity elements, analyses controlled for walk duration and perceived intensity. Analyses revealed that perceived restorativeness and perceived walk intensity predicted greater positive affect and happiness following an outdoor group walk. Perceived restorativeness and perceived bird biodiversity predicted post-walk negative affect. Perceived restorativeness moderated the relationship between perceived naturalness and positive affect. Results suggest that restorative quality of an environment may be an important element for enhancing well-being, and that perceived restorativeness and naturalness of an environment may interact to amplify positive affect. These findings highlight the importance of further research on the contribution of environment type and quality on well being, and the need to control for effects of physical activity in green exercise research. PMID- 25546274 TI - Blood lead concentrations in Jamaican children with and without autism spectrum disorder. AB - Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting by early childhood. Lead is a toxic metal shown to cause neurodevelopmental disorders in children. Several studies have investigated the possible association between exposure to lead and ASD, but their findings are conflicting. Using data from 100 ASD cases (2-8 years of age) and their age- and sex-matched typically developing controls, we investigated the association between blood lead concentrations (BLC) and ASD in Jamaican children. We administered a questionnaire to assess demographic and socioeconomic information as well as exposure to potential lead sources. We used General Linear Models (GLM) to assess the association of BLC with ASD status as well as with sources of exposure to lead. In univariable GLM, we found a significant difference between geometric mean blood lead concentrations of ASD cases and controls (2.25 MUg/dL cases vs. 2.73 MUg/dL controls, p < 0.05). However, after controlling for potential confounders, there were no significant differences between adjusted geometric mean blood lead concentrations of ASD cases and controls (2.55 MUg/dL vs. 2.72 MUg/dL, p = 0.64). Our results do not support an association between BLC and ASD in Jamaican children. We have identified significant confounders when assessing an association between ASD and BLC. PMID- 25546276 TI - Suicide risks among adolescents and young adults in rural China. AB - BACKGROUND: In China, suicide is one of the major causes of death among adolescents and young adults aged 15 to 34 years. AIM: The current study examines how risk factors vary by age groups in rural China, referring to those aged 15 to 24 years and those aged 25 to 34 years. METHOD: A case-control psychological autopsy (PA) study is conducted in sixteen counties from three Chinese provinces, including 392 suicide cases and 416 community living controls in the sample. RESULTS: In China, young adults aged 25 to 34 years have a higher risk for suicide than adolescents aged 15 to 24 years, and it holds true even controlling for relevant social factors. In addition, age-related factors such as education, marital status, whether having children, status in the family, physical health, and personal income all have varying degrees of impact on suicide risks for rural youth. CONCLUSIONS: This study shows that there are some age-related risk factors for suicide at certain life stages and emphasizes that young adults in rural China aged 25 to 34 years have an increased risk of suicide as a result of experiencing more psychological strains with age. PMID- 25546277 TI - Daily physical activity and screen time, but not other sedentary activities, are associated with measures of obesity during childhood. AB - Childhood obesity is related to low physical activity level and a sedentary lifestyle. The aim of this study was to assess the physical activity level and sedentary behaviour of Malaysian children aged 7 to 12 years and to examine their association with body mass index (BMI), BMI-for-age Z-score (BAZ), body fatness (%BF) and waist circumference (WC). A total of 1736 children, representing all ethnic groups were recruited from six regions of Malaysia. Anthropometric measurements included body weight, height and waist circumference. Body fat percentage (%BF) was assessed using bioelectrical impedance. Physical activity was assessed by a physical activity questionnaire (PAQ) in all children and by pedometers in a subsample (n = 514). PAQ score and pedometer step counts were negatively associated with BMI, BAZ, %BF and WC after adjusting for covariates. Screen time was positively associated with BAZ and WC. However, other sedentary activities were not significantly related with any anthropometric indicators. Strategies to promote active living among children in Malaysia should focus not only on increasing physical activity but also emphasise reduction in sedentary behaviours. PMID- 25546279 TI - Residents' preferences for household kitchen waste source separation services in Beijing: a choice experiment approach. AB - A source separation program for household kitchen waste has been in place in Beijing since 2010. However, the participation rate of residents is far from satisfactory. This study was carried out to identify residents' preferences based on an improved management strategy for household kitchen waste source separation. We determine the preferences of residents in an ad hoc sample, according to their age level, for source separation services and their marginal willingness to accept compensation for the service attributes. We used a multinomial logit model to analyze the data, collected from 394 residents in Haidian and Dongcheng districts of Beijing City through a choice experiment. The results show there are differences of preferences on the services attributes between young, middle, and old age residents. Low compensation is not a major factor to promote young and middle age residents accept the proposed separation services. However, on average, most of them prefer services with frequent, evening, plastic bag attributes and without instructor. This study indicates that there is a potential for local government to improve the current separation services accordingly. PMID- 25546278 TI - Childhood obesity: a role for gut microbiota? AB - Obesity is a serious public health issue affecting both children and adults. Prevention and management of obesity is proposed to begin in childhood when environmental factors exert a long-term effect on the risk for obesity in adulthood. Thus, identifying modifiable factors may help to reduce this risk. Recent evidence suggests that gut microbiota is involved in the control of body weight, energy homeostasis and inflammation and thus, plays a role in the pathophysiology of obesity. Prebiotics and probiotics are of interest because they have been shown to alter the composition of gut microbiota and to affect food intake and appetite, body weight and composition and metabolic functions through gastrointestinal pathways and modulation of the gut bacterial community. As shown in this review, prebiotics and probiotics have physiologic functions that contribute to changes in the composition of gut microbiota, maintenance of a healthy body weight and control of factors associated with childhood obesity through their effects on mechanisms controlling food intake, fat storage and alterations in gut microbiota. PMID- 25546280 TI - Water-borne diseases and extreme weather events in Cambodia: review of impacts and implications of climate change. AB - Cambodia is prone to extreme weather events, especially floods, droughts and typhoons. Climate change is predicted to increase the frequency and intensity of such events. The Cambodian population is highly vulnerable to the impacts of these events due to poverty; malnutrition; agricultural dependence; settlements in flood-prone areas, and public health, governance and technological limitations. Yet little is known about the health impacts of extreme weather events in Cambodia. Given the extremely low adaptive capacity of the population, this is a crucial knowledge gap. A literature review of the health impacts of floods, droughts and typhoons in Cambodia was conducted, with regional and global information reviewed where Cambodia-specific literature was lacking. Water-borne diseases are of particular concern in Cambodia, in the face of extreme weather events and climate change, due to, inter alia, a high pre-existing burden of diseases such as diarrhoeal illness and a lack of improved sanitation infrastructure in rural areas. A time-series analysis under quasi-Poisson distribution was used to evaluate the association between floods and diarrhoeal disease incidence in Cambodian children between 2001 and 2012 in 16 Cambodian provinces. Floods were significantly associated with increased diarrhoeal disease in two provinces, while the analysis conducted suggested a possible protective effect from toilets and piped water. Addressing the specific, local pre-existing vulnerabilities is vital to promoting population health resilience and strengthening adaptive capacity to extreme weather events and climate change in Cambodia. PMID- 25546281 TI - Association between changing mortality of digestive tract cancers and water pollution: a case study in the Huai River Basin, China. AB - The relationship between the ever-increasing cancer mortality and water pollution is an important public concern in China. This study aimed to explore the association between serious water pollution and increasing digestive cancer mortality in the Huai River Basin (HRB) in China. A series of frequency of serious pollution (FSP) indices including water quality grade (FSPWQG), biochemical oxygen demand (FSPBOD), chemical oxygen demand (FSPCOD), and ammonia nitrogen (FSPAN) were used to characterize the surface water quality between 1997 and 2006. Data on the county-level changing mortality (CM) due to digestive tract cancers between 1975 and 2006 were collected for 14 counties in the study area. Most of investigated counties (eight) with high FSPWQG (>50%) distributed in the northern region of the HRB and had larger CMs of digestive tract cancers. In addition to their similar spatial distribution, significant correlations between FSP indices and CMs were observed by controlling for drinking water safety (DWS), gross domestic product (GDP), and population (POP). Furthermore, the above mentioned partial correlations were clearly increased when only controlling for GDP and POP. Our study indicated that county-level variations of digestive cancer mortality are remarkably associated with water pollution, and suggested that continuous measures for improving surface water quality and DWS and hygienic interventions should be effectively implemented by local governments. PMID- 25546282 TI - The excess heat factor: a metric for heatwave intensity and its use in classifying heatwave severity. AB - Heatwaves represent a significant natural hazard in Australia, arguably more hazardous to human life than bushfires, tropical cyclones and floods. In the 2008/2009 summer, for example, many more lives were lost to heatwaves than to that summer's bushfires which were among the worst in the history of the Australian nation. For many years, these other forms of natural disaster have received much greater public attention than heatwaves, although there are some signs of change. We propose a new index, called the excess heat factor (EHF) for use in Australian heatwave monitoring and forecasting. The index is based on a three-day-averaged daily mean temperature (DMT), and is intended to capture heatwave intensity as it applies to human health outcomes, although its usefulness is likely to be much broader and with potential for international applicability. The index is described and placed in a climatological context in order to derive heatwave severity. Heatwave severity, as characterised by the climatological distribution of heatwave intensity, has been used to normalise the climatological variation in heatwave intensity range across Australia. This methodology was used to introduce a pilot national heatwave forecasting service for Australia during the 2013/2014 summer. Some results on the performance of the service are presented. PMID- 25546283 TI - Developing a heatwave early warning system for Sweden: evaluating sensitivity of different epidemiological modelling approaches to forecast temperatures. AB - Over the last two decades a number of heatwaves have brought the need for heatwave early warning systems (HEWS) to the attention of many European governments. The HEWS in Europe are operating under the assumption that there is a high correlation between observed and forecasted temperatures. We investigated the sensitivity of different temperature mortality relationships when using forecast temperatures. We modelled mortality in Stockholm using observed temperatures and made predictions using forecast temperatures from the European Centre for Medium-range Weather Forecasts to assess the sensitivity. We found that the forecast will alter the expected future risk differently for different temperature mortality relationships. The more complex models seemed more sensitive to inaccurate forecasts. Despite the difference between models, there was a high agreement between models when identifying risk-days. We find that considerations of the accuracy in temperature forecasts should be part of the design of a HEWS. Currently operating HEWS do evaluate their predictive performance; this information should also be part of the evaluation of the epidemiological models that are the foundation in the HEWS. The most accurate description of the relationship between high temperature and mortality might not be the most suitable or practical when incorporated into a HEWS. PMID- 25546284 TI - Correspondence surveillance of gastroschisis and omphalocele: ICD-9 and ICD-10 codes! PMID- 25546285 TI - A population-based cross-sectional study that defined normative population data for the Life-Space Mobility Assessment-composite score. AB - CONTEXT: Mobility is linked to health status and quality of life. Life-Space Mobility Assessment (LSMA; range 0-120) measures the spatial extent of people's excursion and physical support needs over the preceding month. OBJECTIVES: The aim of this study was to generate normative population data for an LSMA-Composite (LSMA-C) score, irrespective of age or health service contact and explore the LSM of people with diabetes, current asthma, arthritis, and osteoporosis. METHODS: LSMA questions were included in the 2011 South Australian Health Omnibus Survey, a multistage, systematic, and clustered sample of household face-to-face interviews. Sociodemographic and clinical variables were explored in relation to LSMA scores using descriptive, univariable, and multivariable analyses and receiver operator curves. RESULTS: For the 3032 respondents, the mean LSMA score was 98.3 (SD 20.3; median 100; interquartile range 34 [86-120]; range 6-120). Five percent of respondents scored <60, 11% scored between >= 60 and 79, 27% scored between >= 80 and 99, and the remainder scored between 100 and 120. After 55 years of age, LSMA-C scores declined, more so in females. In multivariable analysis, declining scores were associated with being female, being older, living in rural areas, lower educational attainment, not working, lower household income, and higher numbers of chronic conditions (R(2) = 0.35, P < 0.001). The receiver operator curve demonstrated a highly specific but relatively insensitive measure. CONCLUSION: Having controlled for known confounders, the male/female difference cannot be easily explained. These data will help to contextualize studies in the future that use the LSMA-C score. PMID- 25546286 TI - A systematic review of strategies used to increase recruitment of people with cancer or organ failure into clinical trials: implications for palliative care research. AB - CONTEXT: The challenges of palliative care clinical trial recruitment are well documented. OBJECTIVES: The aim of the study was to review tested strategies to improve recruitment to trials of people with a range of conditions who may access palliative care services but are not explicitly stated to be "palliative." METHODS: This was a systematic review with narrative description. The Cochrane, Embase, PubMed, PsycINFO, and CINAHL electronic databases were searched (English; January 2002 to February 2014) for quasi-experimental and randomized controlled trials (RCTs) testing the effect of recruitment strategies on accrual to clinical trials of people with organ failure and cancer. Titles, abstracts, and retrieved articles were screened by two researchers and categorized by recruitment challenge: 1) patients with reduced cognition, 2) those requiring emergency treatment, and 3) willingness of patients and clinical staff to contribute to trials. RESULTS: Of 549 articles identified, 15 were included. Thirteen reported RCTs and two papers reported three quasi-experimental studies. Five were cluster RCTs of recruiting sites/institutions. One was a randomized cluster, crossover, feasibility study. Seven studies recruited patients with cancer. Others included patients with dementia, stroke, cardiovascular disease, diabetes, frail elderly, and bereaved carers. Some interventions improved recruitment: memory aid, contact before arrival, cluster consent, "opt out" consent. Others either reduced recruitment (formal mental capacity assessment) or made no difference (advance research directive; a variety of educational, supportive, and advertising interventions). CONCLUSION: Successful strategies from other disciplines could be considered by palliative care researchers. Tailored, efficient, evidence-based strategies must be developed, acknowledging that strategies with face validity are not necessarily the most effective. PMID- 25546288 TI - Patient-controlled analgesia for children at home. AB - CONTEXT: Pain is a common and significant symptom experienced by children with advanced malignant disease. There is limited research on pain management of these children at home. OBJECTIVES: To describe and review the indications for using patient-controlled analgesia (PCA) in the form of a Computerized Ambulatory Drug Delivery device (CADD((r))) in the home setting. METHODS: A retrospective chart review was conducted in children discharged home with opioid infusions using a CADD. Charts from January 2008 to February 2012 were surveyed. RESULTS: Thirty seven CADDs were dispensed during the study period, and of these, 33 were prescribed for patients with cancer-related pain. A third of the CADDs were commenced at home and almost all PCA CADDs were used for end-of-life care. Hydromorphone was the most commonly prescribed opioid. Patients remained at home and pain control was achieved by either increasing the opioid dose or switching the opioid and using adjuvant therapy. Sixteen patients were readmitted to hospital from home and three admissions were related to pain. The median duration on a PCA CADD at home was 33.7 days (range, 1-150 days), and the mean morphine equivalent dose was 2.13 mg/kg/day. CONCLUSION: PCA with a CADD can be used to manage pain in the home setting. Dose adjustments and opioid switches were performed with no adverse incidents. PMID- 25546287 TI - Use of an Item Bank to Develop Two Short-Form FAMCARE Scales to Measure Family Satisfaction With Care in the Setting of Serious Illness. AB - CONTEXT: Family satisfaction is an important and commonly used research measure. Yet current measures of family satisfaction are lengthy and may be unnecessarily burdensome--particularly in the setting of serious illness. OBJECTIVES: To use an item bank to develop short forms of the Family Satisfaction with End-of-Life Care (FAMCARE) scale, which measures family satisfaction with care. METHODS: To shorten the existing 20-item FAMCARE measure, item response theory parameters from an item bank were used to select the most informative items. The psychometric properties of the new short-form scales were examined. The item bank was based on data from family members from an ethnically diverse sample of 1983 patients with advanced cancer. RESULTS: Evidence for the new short-form scales supported essential unidimensionality. Reliability estimates from several methods were relatively high, ranging from 0.84 for the five-item scale to 0.94 for the 10-item scale across different age, gender, education, ethnic, and relationship groups. CONCLUSION: The FAMCARE-10 and FAMCARE-5 short-form scales evidenced high reliability across sociodemographic subgroups and are potentially less burdensome and time-consuming scales for monitoring family satisfaction among seriously ill patients. PMID- 25546289 TI - Extracorporeal photopheresis as a therapy for autoimmune diseases. AB - Systemic autoimmune diseases (AID) have multiorgan, heterogeneous clinical presentations and are characterized by dysregulation of the immune system, immunodeficiency, irreversible organ damage and increased morbidity and mortality. Preventing or decreasing flares of AID correlate with durable disease control, significant reduction of inflammation and prevention of disability or therapy-related toxicity. There is an urgent need for better treatment of severe, therapy-refractory AID. Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory treatment which has been extensively used in variety of autoimmune disorders for the last two decades. ECP treatment is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL) with particularly promising results seen in graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Prolonged therapy is safe, well tolerated and allows reduction of systemic immunosuppression in therapy-refractory patients. Both clinical and experimental evidence suggest that ECP mechanism of action is characterized by apoptosis and phagocytosis of activated cells by antigen presenting cells (APC), secretion of anti-inflammatory cytokines and stimulation of regulatory T cells (Tregs). The focus of this paper is to review the current evidence of ECP use in the treatment of AID. Here, we summarize the experience of nine major AID from 65 published reports. The key findings demonstrate substantial evidence of ECP feasibility, safety and in some AID also promising efficacy. However, the role of ECP in AID therapy is not established as most published studies are retrospective with limited number of patients and the trials are small or poorly standardized. The available data support future investigations of ECP as a therapeutic modality for the treatment of AID in well designed prospective clinical studies. J PMID- 25546290 TI - Estimation of ROC curve with complex survey data. AB - The receiver operating characteristic (ROC) curve can be utilized to evaluate the performance of diagnostic tests. The area under the ROC curve (AUC) is a widely used summary index for comparing multiple ROC curves. Both parametric and nonparametric methods have been developed to estimate and compare the AUCs. However, these methods are usually only applicable to data collected from simple random samples and not surveys and epidemiologic studies that use complex sample designs such as stratified and/or multistage cluster sampling with sample weighting. Such complex samples can inflate variances from intra-cluster correlation and alter the expectations of test statistics because of the use of sample weights that account for differential sampling rates. In this paper, we modify the nonparametric method to incorporate sampling weights to estimate the AUC and employ leaving-one-out jackknife methods along with the balanced repeated replication method to account for the effects of the complex sampling in the variance estimation of our proposed estimators of the AUC. The finite sample properties of our methods are evaluated using simulations, and our methods are illustrated by comparing the estimated AUC for predicting overweight/obesity using different measures of body weight and adiposity among sampled children and adults in the US Hispanic Health and Nutrition Examination Survey. PMID- 25546291 TI - Oral squamous cell carcinoma of the tongue: Prospective and objective speech evaluation of patients undergoing surgical therapy. AB - BACKGROUND: Prospective speech intelligibility assessments lack objectivity in patients undergoing surgery for oral squamous cell carcinoma (OSCC) of the tongue. METHODS: Speech intelligibility was measured based on word recognition by means of an automatic and objective speech recognition system preoperatively, and 14 to 20 days, and 3 months, 6 months, and 12 months postoperatively. The study comprised 25 patients with OSCC of the tongue and a healthy control group (n = 40). RESULTS: Patients yielded significant speech impairments compared to the healthy control group both before surgery and after 12 months (p <= .002). The speech intelligibility of the patients decreased significantly 14 to 20 days after surgery (p < .001) but realigned to preoperative values after 12 months (p = .159). Preservation of the tip of the tongue resulted in significantly higher word recognition after 12 months (p = .007; Deltaword recognition = 16.29). CONCLUSION: Having OSSC of the tongue results in a significant impairment of speech intelligibility. The preservation of the tip of the tongue seems to be a central factor concerning the recovery of speech. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 993-1001, 2016. PMID- 25546292 TI - Assessment of percutaneous transhepatic portal vein embolization with portal vein stenting for perihilar cholangiocarcinoma with severe portal vein stenosis. AB - BACKGROUND: The aim of the present study was to assess the clinical efficiency of portal vein (PV) stenting when performed with preoperative percutaneous transhepatic portal vein embolization (PTPVE) in patients with severe PV stenosis due to tumor invasion. METHODS: Between 2007 and 2013, four consecutive patients (one male, three females; mean age, 52 years; age range, 25-73 years) with perihilar cholangiocarcinoma and PV stenosis underwent PTPVE and PV stenting. Patients were analyzed with regard to the procedure, hypertrophy of the future remnant liver (FRL), and plasma clearance rate of indocyanine green by the FRL (ICGK-F). Further, the %FRL volume increase in PTPVE was compared between the stenting group and the usual PTPVE group who have perihilar cholangiocarcinomas without PV stenosis. RESULTS: Preoperative PTPVE with PV stenting was successfully performed and portal flow to the FRL improved after stenting in all four patients. The %FRL volume increase was 18-60% (mean, 34%) in the stenting group and was 12-51% (mean, 21%) in the usual PTPVE group. The ICGK-F value after PTPVE exceeded 0.05 in all four patients. All patients achieved R0 resection. CONCLUSIONS: Preoperative PTPVE with PV stenting appears to be feasible in cases of severe PV tumor invasion and stenosis. This procedure may allow a broader indication for surgery. PMID- 25546294 TI - Mirror syndrome associated with fetal leukemia. AB - Mirror syndrome describes the association of fetal and placental hydrops with maternal edema. This case is the first reported case of mirror syndrome relative to fetal leukemia. We suggest that fetal leukemia can have a major impact on mirror syndrome, and provide a brief review of the literature related to this syndrome. PMID- 25546295 TI - Play or hard work: unpacking well-being at preschool. AB - Well-being or quality of life is thought to give a more accurate picture of the impact a condition has on day-to-day functioning than traditional outcome measures. This study sought to examine the relationship between engagement in play and well-being for preschool children with and without developmental coordination disorder (DCD). A quasi-experimental design was used with two independent groups of preschool children aged 4-6 years with (n=32) and without (n=31) probable DCD. Play skills were assessed using the Play Observation Scale based on 30min of videotape of free-play at preschool. Well-being was assessed using a parent-proxy version of the Revised Children Quality of Life Questionnaire (KINDL(R)). Spearman rho correlations were performed to examine the relationship between play and well-being. Well-being at preschool was significantly lower for the children in the DCD group however overall well-being was not significantly different. Engagement in type of social play (solitary, parallel or group) was found to predict well-being for the typically developing children. For the children with DCD, engagement in group play was not associated with well-being. An explanation for this difference may be that children with DCD may not experience free-play at preschool as "play" but rather as hard work. Further research is needed to determine why children with DCD experience lower well-being at preschool than their peers and to investigate children's perceptions of free-play. This may enable teachers and therapists to better support children with DCD in the preschool environment. PMID- 25546293 TI - HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of beta catenin in human iPSC-derived neuronal cells. AB - We examined the effects of isoform-specific histone deacetylase (HDAC) inhibitors on beta-catenin posttranslational modifications in neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs). beta-catenin is a multifunctional protein with important roles in the developing and adult central nervous system. Activation of the Wnt pathway results in stabilization and nuclear translocation of beta-catenin, resulting in activation of multiple target genes. In addition, beta-catenin forms a complex with cadherins at the plasma membrane as part of the adherens junctions. The N-terminus of beta-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3beta (GSK3beta). beta-Catenin phosphorylated at these sites is recognized by beta-transducin repeat-containing protein (betaTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of beta-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1alpha (CK1alpha) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of beta-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of beta-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of beta-catenin, it results in increased membrane localization of beta catenin. PMID- 25546296 TI - The Chinese version of the Child and Adolescent Scale of Environment (CASE-C): validity and reliability for children with disabilities in Taiwan. AB - Measurement of children's participation and environmental factors is a key component of the assessment in the new Disability Evaluation System (DES) in Taiwan. The Child and Adolescent Scale of Environment (CASE) was translated into Traditional Chinese (CASE-C) and used for assessing environmental factors affecting the participation of children and youth with disabilities in the DES. The aim of this study was to validate the CASE-C. Participants were 614 children and youth aged 6.0-17.9 years with disabilities, with the largest condition group comprised of children with intellectual disability (61%). Internal structure, internal consistency, test-retest reliability, convergent validity, and discriminant (known group) validity were examined using exploratory factor analyses, Cronbach's alpha coefficient, intra-class correlation coefficients (ICC), correlation analyses, and univariate ANOVAs. A three-factor structure (Family/Community Resources, Assistance/Attitude Supports, and Physical Design Access) of the CASE-C was produced with 38% variance explained. The CASE-C had adequate internal consistency (Cronbach's alpha=.74-.86) and test-retest reliability (ICCs=.73-.90). Children and youth with disabilities who had higher levels of severity of impairment encountered more environmental barriers and those experiencing more environmental problems also had greater restrictions in participation. The CASE-C scores were found to distinguish children on the basis of disability condition and impairment severity, but not on the basis of age or sex. The CASE-C is valid for assessing environmental problems experienced by children and youth with disabilities in Taiwan. PMID- 25546297 TI - Supporting self-managed leisure engagement and communication in post-coma persons with multiple disabilities. AB - Post-coma persons affected by extensive motor impairment and lack of speech, with or without disorders of consciousness, need special support to manage leisure engagement and communication. These two studies extended research efforts aimed at assessing basic technology-aided programs to provide such support. Specifically, Study I assessed a program for promoting independent stimulation choice in four post-coma persons who combined motor and speech disabilities with disorders of consciousness (i.e., were rated between the minimally conscious state and the emergence from such state). Study II assessed a program for promoting independent television operation and basic communication in three post coma participants who, contrary to those involved in Study I, did not have disorders of consciousness (i.e., had emerged from a minimally conscious state). The results of the studies were largely positive with substantial levels of independent stimulation choice and access for the participants of Study I and independent television operation and communication for the participants of Study II. The results were analyzed in relation to previous data in the area and in terms of their implications for daily contexts dealing with these persons. PMID- 25546298 TI - Histone deacetylase 6 activity is critical for the metastasis of Burkitt's lymphoma cells. AB - BACKGROUND: Burkitt's lymphoma is an aggressive malignancy with high risk of metastasis to extranodal sites, such as bone marrow and central nervous system. The prognosis of metastatic Burkitt's lymphoma is poor. Here we sought to identify a role of histone deacetylase 6 (HDAC6) in the metastasis of Burkitt's lymphoma cells. METHODS: Burkitt's lymphoma cells were pharmacologically treated with niltubacin, tubacin or sodium butyrate (NaB) or transfected with siRNAs to knock down the expression of HDAC6. Cell migration and invasion ability were measured by transwell assay, and cell cycle progression was analyzed by flow cytometry. Cell adhesion and proliferation was determined by CellTiter-Glo luminescent cell viability assay kit. Cell morphological alteration and microtubule stability were analyzed by immunofluorescence staining. Effect of niltubacin, tubacin and NaB on acetylated tubulin and siRNA efficacy were measured by western blotting. RESULTS: Suppression of histone deacetylase 6 activity significantly compromised the migration and invasion of Burkitt's lymphoma cells, without affecting cell proliferation and cell cycle progression. Mechanistic study revealed that HDAC6 modulated chemokine induced cell shape elongation and cell adhesion probably through its action on microtubule dynamics. CONCLUSIONS: We identified a critical role of HDAC6 in the metastasis of Burkitt's lymphoma cells, suggesting that pharmacological inhibition of HDAC6 could be a promising strategy for the management of metastatic Burkitt's lymphoma. PMID- 25546299 TI - Deer bone extract prevents against scopolamine-induced memory impairment in mice. AB - Deer bone has been used as a health-enhancing food as well as an antiaging agent in traditional Oriental medicine. Recently, the water extract of deer bone (DBE) showed a neuroprotective action against glutamate or Abeta1-42-induced cell death of mouse hippocampal cells by exerting antioxidant activity through the suppression of MAP kinases. The present study is to examine whether DBE improves memory impairment induced by scopolamine. DBE (50, 100 or 200 mg/kg) was administered orally to mice for 14 days, and then scopolamine (2 mg/kg, i.p.) was administered together with DBE for another 7 days. Memory performance was evaluated in the Morris water maze (MWM) test and passive avoidance test. Also, brain acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activity, biomarkers of oxidative stress and the loss of neuronal cells in the hippocampus, was evaluated by histological examinations. Administration of DBE significantly restored memory impairments induced by scopolamine in the MWM test (escape latency and number of crossing platform area), and in the passive avoidance test. Treatment with DBE inhibited the AChE activity and increased the ChAT activity in the brain of memory-impaired mice induced by scopolamine. Additionally, the administration of DBE significantly prevented the increase of lipid peroxidation and the decrease of glutathione level in the brain of mice treated with scopolamine. Also, the DBE treatment restored the activities of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and glutathione reductase to control the level. Furthermore, scopolamine-induced oxidative damage of neurons in hippocampal CA1 and CA3 regions were prevented by DBE treatment. It is suggested that DBE may be useful for memory improvement through the regulation of cholinergic marker enzyme activities and the suppression of oxidative damage of neurons in the brain of mice treated with scopolamine. PMID- 25546300 TI - Interneuron activity leads to initiation of low-voltage fast-onset seizures. AB - Seizures in temporal lobe epilepsy can be classified as hypersynchronous and low voltage fast according to their onset patterns. Experimental evidence suggests that low-voltage fast-onset seizures mainly result from the synchronous activity of gamma-aminobutyric acid-releasing cells. In this study, we tested this hypothesis using the optogenetic control of parvalbumin-positive interneurons in the entorhinal cortex, in the in vitro 4-aminopyridine model. We found that both spontaneous and optogenetically induced seizures had similar low-voltage fast onset patterns. In addition, both types of seizures presented with higher ripple than fast ripple rates. Our data demonstrate the involvement of interneuronal networks in the initiation of low-voltage fast-onset seizures. PMID- 25546302 TI - Individual differences in the exercise-mediated blood pressure response: regression to the mean in disguise? PMID- 25546301 TI - Crystal structure of a fully glycosylated HIV-1 gp120 core reveals a stabilizing role for the glycan at Asn262. AB - The crystal structure of a fully glycosylated HIV-1 gp120 core in complex with CD4 receptor and Fab 17b at 4.5-A resolution reveals 9 of the 15 N-linked glycans of core gp120 to be partially ordered. The glycan at position Asn262 had the most extensive and well-ordered electron density, and a GlcNAc(2)Man(7) was modeled. The GlcNAc stem of this glycan is largely buried in a cleft in gp120, suggesting a role in gp120 folding and stability. Its arms interact with the stems of neighboring glycans from the oligomannose patch, which is a major target for broadly neutralizing antibodies. PMID- 25546303 TI - Random networks of single-walled carbon nanotubes promote mesenchymal stem cell's proliferation and differentiation. AB - Studies on the interaction of cells with single-walled carbon nanotubes (SWCNTs) have been receiving increasing attention owing to their potential for various cellular applications. In this report, we investigated the interactions between biological cells and nanostructured SWCNTs films and focused on how morphological structures of SWCNT films affected cellular behavior such as cell proliferation and differentiation. One directionally aligned SWCNT Langmuir-Blodgett (LB) film and random network SWCNT film were fabricated by LB and vacuum filteration methods, respectively. We demonstrate that our SWCNT LB and network film based scaffolds do not show any cytotoxicity, while on the other hand, these scaffolds promote differentiation property of rat mesenchymal stem cells (rMSCs) when compared with that on conventional tissue culture polystyrene substrates. Especially, the SWCNT network film with average thickness and roughness values of 95 +/- 5 and 9.81 nm, respectively, demonstrated faster growth rate and higher cell thickness for rMSCs. These results suggest that systematic manipulation of the thickness, roughness, and directional alignment of SWCNT films would provide the convenient strategy for controlling the growth and maintenance of the differentiation property of stem cells. The SWCNT film could be an alternative culture substrate for various stem cells, which often require close control of the growth and differentiation properties. PMID- 25546304 TI - Acoustic radiation force impulse imaging for non-invasive assessment of renal histopathology in chronic kidney disease. AB - OBJECTIVE: To investigate the stiffness values obtained by acoustic radiation force impulse (ARFI) quantification in assessing renal histological fibrosis of chronic kidney disease (CKD). METHODS: 163 patients with CKD and 32 healthy volunteers were enrolled between June 2013 and April 2014. ARFI quantification, given as shear wave velocity (SWV), was performed to measure renal parenchyma stiffness. Diagnostic performance of ARFI imaging and conventional ultrasound (US) were compared with histologic scores at renal biopsy. Intra- and inter observer reliability of SWV measurement was analyzed. RESULTS: In CKD patients, SWV measurements correlated significantly with pathological parameters (r = 0.422--0.511, P<0.001), serum creatinine (r = -0.503, P<0.001), and glomerular filtration rate (r = 0.587, P<0.001). The mean SWV in kidneys with severely impaired (histologic score: >=19 points) was significant lower than that mildly impaired (histologic score: <=9 points), moderately impaired (histologic score: 10-18 points), and control groups (all P<0.001). Receiver operating characteristic (ROC) curves analyses indicated that the area under the ROC curve for the diagnosis of renal histological fibrosis using ARFI imaging was superior to these conventional US parameters. Using the optimal cut-off value of 2.65 m/s for the diagnosis of mildly impaired kidneys, 2.50 m/s for moderately impaired kidneys, and 2.33 m/s for severely impaired kidneys, the corresponding area under the ROC curves were 0.735, 0.744, and 0.895, respectively. Intra- and intre observer agreement of SWV measurements were 0.709 (95% CI: 0.390-0.859, P<0.001) and 0.627 (95% CI: 0.233-0.818, P = 0.004), respectively. CONCLUSIONS: ARFI may be an effective tool for evaluating renal histological fibrosis in CKD patients. PMID- 25546305 TI - A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal. AB - Ultradian (~4 hr) rhythms in locomotor activity that do not depend on the master circadian pacemaker in the suprachiasmatic nucleus have been observed across mammalian species, however, the underlying mechanisms driving these rhythms are unknown. We show that disruption of the dopamine transporter gene lengthens the period of ultradian locomotor rhythms in mice. Period lengthening also results from chemogenetic activation of midbrain dopamine neurons and psychostimulant treatment, while the antipsychotic haloperidol has the opposite effect. We further reveal that striatal dopamine levels fluctuate in synchrony with ultradian activity cycles and that dopaminergic tone strongly predicts ultradian period. Our data indicate that an arousal regulating, dopaminergic ultradian oscillator (DUO) operates in the mammalian brain, which normally cycles in harmony with the circadian clock, but can desynchronize when dopamine tone is elevated, thereby producing aberrant patterns of arousal which are strikingly similar to perturbed sleep-wake cycles comorbid with psychopathology. PMID- 25546306 TI - Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy. AB - Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4(+) autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD-1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation. PMID- 25546307 TI - Genetic transformation of structural and functional circuitry rewires the Drosophila brain. AB - Acquisition of distinct neuronal identities during development is critical for the assembly of diverse functional neural circuits in the brain. In both vertebrates and invertebrates, intrinsic determinants are thought to act in neural progenitors to specify their identity and the identity of their neuronal progeny. However, the extent to which individual factors can contribute to this is poorly understood. We investigate the role of orthodenticle in the specification of an identified neuroblast (neuronal progenitor) lineage in the Drosophila brain. Loss of orthodenticle from this neuroblast affects molecular properties, neuroanatomical features, and functional inputs of progeny neurons, such that an entire central complex lineage transforms into a functional olfactory projection neuron lineage. This ability to change functional macrocircuitry of the brain through changes in gene expression in a single neuroblast reveals a surprising capacity for novel circuit formation in the brain and provides a paradigm for large-scale evolutionary modification of circuitry. PMID- 25546308 TI - Abnormal pulmonary function and respiratory muscle strength findings in Chinese patients with Parkinson's disease and multiple system atrophy--comparison with normal elderly. AB - BACKGROUND: There have been limited comparative data regarding the investigations on pulmonary and respiratory muscle function in the patients with different parkinsonism disorders such as Parkinson's disease (PD) and multiple system atrophy (MSA) versus normal elderly. The present study is aiming to characterize the performance of pulmonary function and respiratory muscle strength in PD and MSA, and to investigate the association with severity of motor symptoms and disease duration. METHODS: Pulmonary function and respiratory muscle strength tests were performed in 30 patients with PD, 27 with MSA as well as in 20 age-, sex-, height-, weight-matched normal elderly controls. All the patients underwent United Parkinson's disease rating scale (UPDRS) or united multiple system atrophy rating scale (UMSARS) separately as diagnosed. RESULTS: Vital capacity, forced expiratory volume in 1 second and forced vital capacity decreased, residual volume and ratio of residual volume to total lung capacity increased in both PD and MSA groups compared to controls (p<0.05). Diffusing capacity was decreased in the MSA group, compared with PD and normal elderly control groups (p<0.05). Respiratory muscle strength was lower in both PD and MSA groups than in controls (p<0.05). The values representing spirometry function and respiratory muscle strength were found to have a negative linear correlation with mean score of UPDRS-III in PD and mean score of UMSARS-I in MSA. Respiratory muscle strength showed a negative linear correlation with the mean score of UMSARS-II and disease duration in MSA patients. CONCLUSIONS: These findings suggest that respiratory dysfunction is involved in PD and MSA. Respiratory muscle strength is remarkably reduced, and some of the parameters correlate with disease duration and illness severity. The compromised respiratory function in neurodegenerative disorders should be the focus of further researches. PMID- 25546309 TI - Huanglongbing modifies quality components and flavonoid content of 'Valencia' oranges. AB - BACKGROUND: In order to evaluate the effect of citrus greening disease, or Huanglongbing (HLB), on quality components and flavonoid contents of 'Valencia' oranges, fruit from non-infected trees (control), from infected trees but symptom less (asymptomatic) and from infected trees and showing clear HLB symptoms (symptomatic) were harvested in March and in May, 2013. Fruit peel, pulp and juice were separated, the main quality components were determined, and hesperidin, nobiletin, tangeretin, narirutin and didymin were quantified using liquid chromatography. RESULTS: Peel colour, total soluble solids and citric acid were similar in control and asymptomatic fruits. Symptomatic fruits were smaller, yielded less juice, had higher acidity and lower sugar and peel colour than control fruits. In the peel, hesperidin, nobiletin, tangeretin, narirutin and didymin were higher in symptomatic than in asymptomatic and control fruits. Peel flavonoids decreased with fruit maturation. Also, in pulp and juice, flavonoid content was higher in symptomatic than in asymptomatic and control fruits. CONCLUSIONS: These results show that asymptomatic fruits are similar to control fruits more than to symptomatic fruits, suggesting that secondary metabolism and physical properties of fruits are only affected at a later and more advanced stage of HLB infection. Despite the significant loss of quality, fruit with clear HLB symptoms accumulate high quantities of flavonoids in peel and pulp. PMID- 25546311 TI - Changes in the midgut diverticula in the harvestmen Amilenus aurantiacus (Phalangiidae, Opiliones) during winter diapause. AB - The harvestmen Amilenus aurantiacus overwinter in diapause in hypogean habitats. The midgut diverticula have been studied microscopically (light microscopy, TEM) and biochemically (energy-storing compounds: lipids and glycogen) to analyze changes during this programmed starvation period. Throughout the investigated period, the epithelium of the midgut diverticula is composed of secretory cells, digestive cells and adipocytes. Additionally, after the middle of overwintering, the excretory cells appear, and two assemblages of secretory cells are present: the SC1 secretory cells are characterized by electron-dense cytoplasm with numerous protein granules, and the SC2 cells by an electron-lucent cytoplasm with fewer protein granules. The autophagic activity is observed from the middle of overwintering, indicating its vital role in providing nutrients during this non feeding period. Lipids and glycogen are present in the midgut diverticula cells, except in the excretory cells. Measurements of the lipid droplet diameters and the lipid quantities yielded quite comparable information on their consumption. Lipids are gradually spent in both sexes, more rapidly in females, owing to ripening of the ovaries. Glycogen rates decrease towards the middle, and increase just before the end of overwintering, indicating that individuals are preparing for the epigean active ecophase. PMID- 25546310 TI - Non-enzymatic depurination of nucleic acids: factors and mechanisms. AB - Depurination has attracted considerable attention since a long time for it is closely related to the damage and repair of nucleic acids. In the present study, depurination using a pool of 30-nt short DNA pieces with various sequences at diverse pH values was analyzed by High Performance Liquid Chromatography (HPLC). Kinetic analysis results showed that non-enzymatic depurination of oligodeoxynucleotides exhibited typical first-order kinetics, and its temperature dependence obeyed Arrhenius' law very well. Our results also clearly showed that the linear relationship between the logarithms of rate constants and pH values had a salient point around pH 2.5. Interestingly and unexpectedly, depurination depended greatly on the DNA sequences. The depurination of poly (dA) was found to be extremely slow, and thymine rich sequences depurinated faster than other sequences. These results could be explained to some extent by the protonation of nucleotide bases. Moreover, two equations were obtained based on our data for predicting the rate of depurination under various conditions. These results provide basic data for gene mutagenesis and nucleic acids metabolism in acidic gastric juice and some acidic organelles, and may also help to rectify some misconceptions about depurination. PMID- 25546312 TI - What else can we do to mitigate contamination of fresh produce by foodborne pathogens? PMID- 25546313 TI - Effects of a continuous electromagnetic field on wound healing in human airway. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the effect of a 1.8-GHz continuous electromagnetic field (EMF) on wound healing in a human airway cell-culture system. STUDY DESIGN: In vitro study using a cell line. METHODS: Immortalized human bronchial epithelial cells (a BEAS-2B cell line) were exposed to a 1.8-GHz EMF (specific absorption rate = 1.0 W/kg). We evaluated the effect of EMF on the cells using an 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay, by cell counting, and by using fluorescence activated cell sorting (FACS) analysis of cell cycle dynamics and apoptosis. Inhibition of migration was tested by a wound-healing assay on scratched cell cultures. RESULTS: Cell migration in the wound-healing assay was decreased by the EMF treatment compared with controls. The MTT assay and cell counting consistently showed that the EMF used was not cytotoxic and did not inhibit cell proliferation. FACS analysis showed no alterations in the cell-cycle phase distribution or in apoptosis after EMF exposure. CONCLUSION: EMF can inhibit wound healing in vitro by inhibiting cell migration. PMID- 25546314 TI - New findings on the three-dimensional anatomical relations between the bronchi and pulmonary blood vessels at the pulmonary hilum. AB - During the 1940s, considerable knowledge was acquired about the anatomy of pulmonary segments, and anatomical terms were proposed and have been widely accepted. In recent years, minimally invasive and thoracoscopic segmentectomy has been performed with a versatile sublobar resection approach on patients with early peripheral lung cancer, metastatic lung tumors, and undiagnosed nodules. The three-dimensional (3D) anatomy of the bronchi and the pulmonary vessels has also been studied in individual patients. Three-dimensional models of the bronchi and pulmonary vessels were prepared using homemade software from computed tomograms (CT) of the chests of patients scheduled to undergo surgical procedures. Using these models, the authors examined the 3D positional relationships of the segmental broncho-arterial triangle (SBAT) created by three points defined by the origins and courses of the bronchi and the pulmonary arteries, which are located apart from each other at the pulmonary hilum, and the segmental pulmonary veins (SPV), which run near the SBAT. In the left and right upper lobes, many branches of the pulmonary arteries and parallel bronchi in subsegments were widely separated at the origin of the pulmonary hilum, creating a relatively large SBAT. However, as an exceptional case, an SPV passed through an SBAT in only one of 158 patients. To our knowledge, no similar findings have been documented previously. Our findings could help to determine resection surfaces for thoracoscopic segmentectomy in the future, and provide new insights into the 3D anatomy and development of the lung. PMID- 25546315 TI - Determination of tetrakis(hydroxymethyl)phosphonium sulfate in commercial formulations and cooling water by capillary electrophoresis with contactless conductivity detection. AB - A novel capillary electrophoresis method using capacitively coupled contactless conductivity detection is proposed for the determination of the biocide tetrakis(hydroxymethyl)phosphonium sulfate. The feasibility of the electrophoretic separation of this biocide was attributed to the formation of an anionic complex between the biocide and borate ions in the background electrolyte. Evidence of this complex formation was provided by (11) B NMR spectroscopy. A linear relationship (R(2) = 0.9990) between the peak area of the complex and the biocide concentration (50-900 MUmol/L) was found. The limit of detection and limit of quantification were 15.0 and 50.1 MUmol/L, respectively. The proposed method was applied to the determination of tetrakis(hydroxymethyl)phosphonium sulfate in commercial formulations, and the results were in good agreement with those obtained by the standard iodometric titration method. The method was also evaluated for the analysis of tap water and cooling water samples treated with the biocide. The results of the recovery tests at three concentration levels (300, 400, and 600 MUmol/L) varied from 75 to 99%, with a relative standard deviation no higher than 9%. PMID- 25546316 TI - Novel Glycoconjugate of 8-Fluoro Norfloxacin Derivatives as Gentamicin-resistant Staphylococcus aureus Inhibitors: Synthesis and Molecular Modelling Studies. AB - Antibiotic resistance has been the subject of interest in clinical practice due to high prevalence of antibiotic-resistant pathogenic organisms. In view of the prevalence of lesser resistance in antibiotics belonging to aminoglycoside class of compounds viz. Food and Drug Administration-approved gentamicin for the treatment of Staphylococcus infections, which also has instances of resistance in the clinical isolates of Staphylococcus aureus, a series of novel glycoconjugates of 8-fluoro norfloxacin analogues with high regio-selectivity by employing copper (I)-catalyzed 1, 3-dipolar cycloaddition of 1-O-propargyl monosaccharides has been synthesized and evaluated for the antibacterial activity against gentamicin resistance Staphylococcus aureus. Among these compounds, the compound 10g showed better antibacterial activity (MIC = 3.12 MUg/ml) than gentamicin (Escherichia coli (12.5 MUg/ml), Staphylococcus aureus (6.25 MUg/ml) and Klebsiella pneumonia (6.25 MUg/ml), including gentamicin resistant (>50 MUg/ml) strain in vitro). The docking studies suggest DNA gyrase of Staphylococcus aureus as a probable target for the antibacterial action of compound 10g. PMID- 25546318 TI - Interests shape how adolescents pay attention: the interaction of motivation and top-down attentional processes in biasing sensory activations to anticipated events. AB - The voluntary allocation of attention to environmental inputs is a crucial mechanism of healthy cognitive functioning, and is probably influenced by an observer's level of interest in a stimulus. For example, an individual who is passionate about soccer but bored by botany will obviously be more attentive at a soccer match than an orchid show. The influence of monetary rewards on attention has been examined, but the impact of more common motivating factors (i.e. the level of interest in the materials under observation) remains unclear, especially during development. Here, stimulus sets were designed based on survey measures of the level of interest of adolescent participants in several item classes. High density electroencephalography was recorded during a cued spatial attention task in which stimuli of high or low interest were presented in separate blocks. The motivational impact on performance of a spatial attention task was assessed, along with event-related potential measures of anticipatory top-down attention. As predicted, performance was improved for the spatial target detection of high interest items. Further, the impact of motivation was observed in parieto occipital processes associated with anticipatory top-down spatial attention. The anticipatory activity over these regions was also increased for high vs. low interest stimuli, irrespective of the direction of spatial attention. The results also showed stronger anticipatory attentional and motivational modulations over the right vs. left parieto-occipital cortex. These data suggest that motivation enhances top-down attentional processes, and can independently shape activations in sensory regions in anticipation of events. They also suggest that attentional functions across hemispheres may not fully mature until late adolescence. PMID- 25546319 TI - Ancient DNA reveals a migration of the ancient Di-qiang populations into Xinjiang as early as the early Bronze Age. AB - Xinjiang is at the crossroads between East and West Eurasia, and it harbors a relatively complex genetic history. In order to better understand the population movements and interactions in this region, mitochondrial and Y chromosome analyses on 40 ancient human remains from the Tianshanbeilu site in eastern Xinjiang were performed. Twenty-nine samples were successfully assigned to specific mtDNA haplogroups, including the west Eurasian maternal lineages of U and W and the east Eurasian maternal lineages of A, C, D, F, G, Z, M7, and M10. In the male samples, two Y chromosome haplogroups, C* and N1 (xN1a, N1c), were successfully assigned. Our mitochondrial and Y-chromosomal DNA analyses combined with the archaeological studies revealed that the Di-qiang populations from the Hexi Corridor had migrated to eastern Xinjiang and admixed with the Eurasian steppe populations in the early Bronze Age. PMID- 25546320 TI - Regulatory Focus and the Interpersonal Dynamics of Romantic Partners' Personal Goal Discussions. AB - Guided by regulatory focus theory, we examined how romantic partners' chronic concerns with promotion (advancement) and prevention (security) shape the interpersonal dynamics of couples' conversations about different types of personal goals. Members of 95 couples (N = 190) first completed chronic regulatory focus measures and then engaged in videotaped discussions of two types of goals that were differentially relevant to promotion and prevention concerns. Participants also completed measures of goal- and partner-relevant perceptions. Independent observers rated the discussions for support-related behaviors. Highly promotion-focused people approached their partners more, perceived greater partner responsiveness, and received more support when discussing goals that were promotion-relevant and that they perceived as less attainable. When partners' responsiveness to promotion-relevant goals was low, highly promotion-focused people reported greater self-efficacy regarding these goals. Highly prevention focused people perceived more responsiveness when partners were less distancing during discussions of their prevention-relevant goals, and greater responsiveness perceptions reassured them that these goals are less disruptive to the relationship. These findings suggest that chronic concerns with promotion and prevention orient people to their relationship environment in ways that are consistent with these distinct motivational needs, especially when discussing goals that increase the salience of these needs. PMID- 25546321 TI - Failure of omalizumab in the treatment of solar urticaria. PMID- 25546317 TI - Fell-Muir Lecture: Syndecans: from peripheral coreceptors to mainstream regulators of cell behaviour. AB - In the 25 years, as the first of the syndecan family was cloned, interest in these transmembrane proteoglycans has steadily increased. While four distinct members are present in mammals, one is present in invertebrates, including C. elegans that is such a powerful genetic model. The syndecans, therefore, have a long evolutionary history, indicative of important roles. However, these roles have been elusive. The knockout in the worm has a developmental neuronal phenotype, while knockouts of the syndecans in the mouse are mild and mostly limited to post-natal rather than developmental effects. Moreover, their association with high-affinity receptors, such as integrins, growth factor receptors, frizzled and slit/robo, have led to the notion that syndecans are coreceptors, with minor roles. Given that their heparan sulphate chains can gather many different protein ligands, this gave credence to views that the importance of syndecans lay with their ability to concentrate ligands and that only the extracellular polysaccharide was of significance. Syndecans are increasingly identified with roles in the pathogenesis of many diseases, including tumour progression, vascular disease, arthritis and inflammation. This has provided impetus to understanding syndecan roles in more detail. It emerges that while the cytoplasmic domains of syndecans are small, they have clear interactive capabilities, most notably with the actin cytoskeleton. Moreover, through the binding and activation of signalling molecules, it is likely that syndecans are important receptors in their own right. Here, an overview of syndecan structure and function is provided, with some prospects for the future. PMID- 25546322 TI - The "dose" of exercise and its effects beyond weight loss. PMID- 25546323 TI - Bilateral inflammatory myofibroblastic tumor mastoiditis. AB - BACKGROUND: Inflammatory myoblastic tumors (IMTs) are rare, mesenchymal neoplasms most commonly located in areas of previous inflammation. In the temporal bone, these tumors typically present as solitary, space-occupying lesions that clinically resemble chronic otitis media. METHODS: We present a case of bilateral IMTs with facial nerve involvement, sigmoid sinus thrombosis, leptomeningeal enhancement, and seizures. RESULTS/CONCLUSION: This case demonstrates the need for a high index of suspicion of IMT when imaging reveals bilateral mastoid opacification. These tumors are more aggressive than their orbital counterparts and require multimodality therapy to prevent recurrence and alleviate severe neurotologic symptoms. PMID- 25546324 TI - Going beyond compromises in multifunctionality of biomaterials. AB - Prioritizing one function in biomaterial and biomedical device design goes hand in hand with compromises with respect to other functions. Strategies to overcome the limitations of such an approach for realizing novel fields of biomaterial application are critically evaluated to promote interdisciplinary and integrative research. PMID- 25546325 TI - Doubling absorption in nanowire solar cells with dielectric shell optical antennas. AB - Semiconductor nanowires (NWs) often exhibit efficient, broadband light absorption despite their relatively small size. This characteristic originates from the subwavelength dimensions and high refractive indices of the NWs, which cause a light-trapping optical antenna effect. As a result, NWs could enable high efficiency but low-cost solar cells using small volumes of expensive semiconductor material. Nevertheless, the extent to which the antenna effect can be leveraged in devices will largely determine the economic viability of NW-based solar cells. Here, we demonstrate a simple, low-cost, and scalable route to dramatically enhance the optical antenna effect in NW photovoltaic devices by coating the wires with conformal dielectric shells. Scattering and absorption measurements on Si NWs coated with shells of SiN(x) or SiO(x) exhibit a broadband enhancement of light absorption by ~ 50-200% and light scattering by ~ 200-1000%. The increased light-matter interaction leads to a ~ 80% increase in short-circuit current density in Si photovoltaic devices under 1 sun illumination. Optical simulations reproduce the experimental results and indicate the dielectric-shell effect to be a general phenomenon for groups IV, II-VI, and III-V semiconductor NWs in both lateral and vertical orientations, providing a simple route to approximately double the efficiency of NW-based solar cells. PMID- 25546326 TI - Upper airways in aspirin-exacerbated respiratory disease. AB - PURPOSE OF REVIEW: This review updates the status of chronic rhinosinusitis with nasal polyps (CRSwNP) in aspirin-exacerbated respiratory disease (AERD) in the contexts of epidemiology, diagnosis, pathogenesis, and treatment. RECENT FINDINGS: Recent studies have shown that prostaglandin E2 (PGE2) deficiency induces an AERD phenotype in PGE2 synthase-1 knock-out mice and also PGE2 resistance in granulocytes of AERD patients. The numbers of platelet-adherent leukocytes increase in AERD patients, enhancing production of cysteinyl leukotrienes (CysLTs) via transcellular metabolism of arachidonate. INF-gamma released from eosinophils of the sinus tissue of AERD patients promotes eosinophil maturation, increases leukotriene-associated gene expression, and releases CysLTs. The serum periostin level has been suggested to be a useful biomarker predicting the AERD/CRSwNP phenotype. Aspirin desensitization was reported to decrease the levels of CD4+ T cell-derived cytokines, including INF gamma and IL-10, in line with the newly defined role of INF-gamma in AERD. SUMMARY: Recent findings further support the notion that arachidonic acid metabolism is dysregulated in AERD patients. This is reflected by resistance to PGE2, overproduction of CysLTs by enhanced numbers of platelet-adherent leukocytes, and cellular stimulation by INF-gamma released from eosinophils. Aspirin desensitization may be a useful treatment option in AERD patients exhibiting recalcitrant CRSwNP. PMID- 25546328 TI - Novel co-enrichment method for isolation of magnetotactic bacteria. AB - A novel co-enrichment technique was designed for enrichment of magnetotactic bacteria from soil, water, and sediments. Delayed addition of iron uptake inducer and the iron source proved amenable to induce magnetosome synthesis by MTB followed by their separation from consortium using magnetic flux. We successfully enriched and isolated both North seeking as well as South seeking magnetotactic bacteria from Lonar Lake (Buldhana), Moti Lake (Jalna), Ghanewadi Lake (Jalna), Ganesh Lake (Miraj), Rankala Lake (Kolhapur), and industrial metal-contaminated glaying soils (Jalna) and a soil (Karad), (MS, India) exposed to high-voltage electric current. The hanging drop preparations and growth under magnetic stress on low-agar media allowed conformation of magnetotactic behavior of the isolates. Both Gram positive and Gram negative MTB were isolated with diverse morphologies. South seeking population was more predominant. The soil inhabitants showed little dwelling property which was more prominent in case of aquatic inhabitants. The use of in situ pH and salt concentrations during enrichment and isolation found suited. The simultaneous growth of whole consortium in the system ensured the in situ simulation of microenvironment needful for proper growth of fastidious MTB. PMID- 25546327 TI - Innate responses to pollen allergens. AB - PURPOSE OF REVIEW: The aim of the present review was to discuss the effects of pollen components on innate immune responses. RECENT FINDINGS: Pollens contain numerous factors that can stimulate an innate immune response. These include intrinsic factors in pollens such as nicotinamide adenine dinucleotide phosphate oxidases, proteases, aqueous pollen proteins, lipids, and antigens. Each component stimulates innate immune response in a different manner. Pollen nicotinamide adenine dinucleotide phosphate oxidases induce reactive oxygen species generation and recruit neutrophils that stimulate subsequent allergic inflammation. Pollen proteases damage epithelial barrier function and increase antigen uptake. Aqueous pollen extract proteins and pollen lipids modulate dendritic cell function and induce Th2 polarization. Clinical studies have shown that modulation of innate immune response to pollens with toll-like receptor 9- and toll-like receptor 4-stimulating conjugates is well tolerated and induces clear immunological effects, but is not very effective in suppressing primary clinical endpoints of allergic inflammation. SUMMARY: Additional research on innate immune pathways induced by pollen components is required to develop novel strategies that will mitigate the development of allergic inflammation. PMID- 25546330 TI - The probiotic mixture VSL#3 dampens LPS-induced chemokine expression in human dendritic cells by inhibition of STAT-1 phosphorylation. AB - VSL#3, a mixture of 8 different probiotic bacteria, has successfully been used in the clinic to treat Ulcerative Colitis. We previously identified the modulation of chemokines as a major mechanism in the protective effect of the VSL#3 in a mouse model of colitis. This was supported by in vitro studies that implicated a role for VSL#3 in the suppression of LPS-induced chemokine production by mouse bone marrow-derived dendritic cells (DC). Herein, we validated these findings employing human monocyte-derived DC. Stimulation of human DC with LPS, VSL#3, or a combination of both resulted in their maturation, evident from enhanced expression of activation markers on the cell-surface, as well as the induction of various chemokines and cytokines. Interestingly, a set of LPS-induced chemokines was identified that were suppressed by VSL#3. These included CXCL9, CXCL10, CCL2, CCL7, and CCL8. In silico approaches identified STAT-1 as a dominant regulator of these chemokines, and this was confirmed by demonstrating that LPS-induced phosphorylation of this transcription factor was inhibited by VSL#3. This indicates that VSL#3 may contribute to the control of inflammation by selective suppression of STAT-1 induced chemokines. PMID- 25546331 TI - Aeromonas hydrophila as a causative agent of blue sac fry syndrome in different trout species. PMID- 25546329 TI - GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease. AB - The chaperone GRP78/Dna K is conserved throughout evolution down to prokaryotes. The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes. Similar data with the drug combination were obtained for: HSP70, HSP90, GRP94, GRP58, HSP27, HSP40 and HSP60. OSU 03012/sildenafil treatment killed brain cancer stem cells and decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola/Marburg/Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Chikungunya, Mumps, Measles, Rubella, RSV, CMV, and Influenza viruses. OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression. The PDE5 inhibitors sildenafil or tadalafil enhanced OSU-03012 killing in N. gonorrhoeae and MRSE and low marginally toxic doses of OSU-03012 could restore bacterial sensitivity in N. gonorrhoeae to multiple antibiotics. Thus, Dna K and bacterial phosphodiesterases are novel antibiotic targets, and inhibition of GRP78 is of therapeutic utility for cancer and also for bacterial and viral infections. PMID- 25546332 TI - Epigenetic regulation of endothelial-cell-mediated vascular repair. AB - Maintenance of vascular integrity is essential for the prevention of vascular disease and for recovery following cardiovascular, cerebrovascular and peripheral vascular events including limb ischemia, heart attack and stroke. Endothelial stem/progenitor cells have recently gained considerable interest due to their potential use in stem cell therapies to mediate revascularization after ischemic injury. Therefore, there is an urgent need to understand fundamental mechanisms regulating vascular repair in specific cell types to develop new beneficial therapeutic interventions. In this review, we highlight recent studies demonstrating that epigenetic mechanisms (including post-translational modifications of DNA and histones as well as non-coding RNA-mediated processes) play essential roles in the regulation of endothelial stem/progenitor cell functions through modifying chromatin structure. Furthermore, we discuss the potential of using small molecules that modulate the activities of epigenetic enzymes to enhance the vascular repair function of endothelial cells and offer insight on potential strategies that may accelerate clinical applications. PMID- 25546333 TI - Water content differences have stronger effects than plant functional groups on soil bacteria in a steppe ecosystem. AB - Many investigations across natural and artificial plant diversity gradients have reported that both soil physicochemical factors and plant community composition affect soil microbial communities. To test the effect of plant diversity loss on soil bacterial communities, we conducted a five-year plant functional group removal experiment in a steppe ecosystem in Inner Mongolia (China). We found that the number and composition type of plant functional groups had no effect on bacterial diversity and community composition, or on the relative abundance of major taxa. In contrast, bacterial community patterns were significantly structured by soil water content differences among plots. Our results support researches that suggest that water availability is the key factor structuring soil bacterial communities in this semi-arid ecosystem. PMID- 25546334 TI - Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype. AB - Sequences of long-interspersed elements (LINE-1, L1) make up ~17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ~6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases. PMID- 25546335 TI - Color measurement of tea leaves at different drying periods using hyperspectral imaging technique. AB - This study investigated the feasibility of using hyperspectral imaging technique for nondestructive measurement of color components (DeltaL*, Deltaa* and Deltab*) and classify tea leaves during different drying periods. Hyperspectral images of tea leaves at five drying periods were acquired in the spectral region of 380 1030 nm. The three color features were measured by the colorimeter. Different preprocessing algorithms were applied to select the best one in accordance with the prediction results of partial least squares regression (PLSR) models. Competitive adaptive reweighted sampling (CARS) and successive projections algorithm (SPA) were used to identify the effective wavelengths, respectively. Different models (least squares-support vector machine [LS-SVM], PLSR, principal components regression [PCR] and multiple linear regression [MLR]) were established to predict the three color components, respectively. SPA-LS-SVM model performed excellently with the correlation coefficient (rp) of 0.929 for DeltaL*, 0.849 for Deltaa*and 0.917 for Deltab*, respectively. LS-SVM model was built for the classification of different tea leaves. The correct classification rates (CCRs) ranged from 89.29% to 100% in the calibration set and from 71.43% to 100% in the prediction set, respectively. The total classification results were 96.43% in the calibration set and 85.71% in the prediction set. The result showed that hyperspectral imaging technique could be used as an objective and nondestructive method to determine color features and classify tea leaves at different drying periods. PMID- 25546336 TI - Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Pediatric Patients: Encouragement Wrapped in Caution. PMID- 25546337 TI - Extrahepatic portal vein obstruction in Egyptian children. AB - BACKGROUND AND AIM: Extrahepatic portal vein obstruction (EHPVO) is an important cause of portal hypertension in children. The aim of this study was to describe the clinical presentation, possible risk factors, upper gastrointestinal endoscopic findings, and treatment modalities of children with EHPVO. METHODS: After ethical approval of our study protocol by our institution review board, we analyzed available data from medical records of patients with EHPVO presenting to the Pediatric Hepatology Unit, Cairo University Pediatric Hospital, Egypt, for a period of 15 years from January 1996 to December 2010. RESULTS: The study included 169 patients. Their ages at presentation ranged from 1 month to 12 years (median 2.5 years, interquartile range 5); 101 were boys. Hematemesis was a presenting symptom in 58%, splenomegaly was present in 87%, esophageal varices were present in 94%, and fundal varices were present in 23%. Possible risk factors, in the form of umbilical catheterization, umbilical sepsis, and exchange transfusion, were elicited in 18%. Propranolol was associated with reduction in bleeding episodes (P < 0.001), but was associated with increased chest symptoms (P < 0.01). Both injection sclerotherapy and band ligation were effective in the management of bleeding varices and for primary and secondary prophylaxis; however, injection sclerotherapy was associated with the development of secondary gastric varices (P = 0.03). CONCLUSIONS: This large study of children with EHPVO demonstrates the efficacy of propranolol in the reduction of gastrointestinal bleeding in children with EHPVO. Both injection sclerotherapy and band ligation were effective in the management of esophageal varices, although the former was associated with the development of secondary gastric varices. Randomized clinical trials to choose the best modalities for the management of portal hypertension in children are still lacking. PMID- 25546338 TI - Psychological and pharmacological interventions for depression in patients with diabetes mellitus: an abridged Cochrane review: some critical comments. PMID- 25546339 TI - Is dengue a disease of poverty? A systematic review. AB - Policy prescriptions for combating dengue fever tend to focus on addressing environmental and social conditions of poverty. However, while poverty has long been considered a determinant of dengue, the research evidence for such a relationship is not well established. Results of a systematic review of the research literature designed to identify and assess the current state of the empirical evidence for the dengue-poverty link reveal a mixed story. Of 260 peer reviewed articles referencing dengue-poverty relationships, only 12 English language studies empirically assessed these relationships. Our analysis covering various social and economic conditions of poverty showed no clear associations with dengue rates. While nine of the 12 studies demonstrated some positive associations between measures of dengue and poverty (measured inconsistently through income, education, structural housing condition, overcrowding, and socioeconomic status), nine also presented null results and five with negative results. Of the five studies relating to access to water and sanitation, four reported null associations. Income and physical housing conditions were more consistently correlated with dengue outcomes than other poverty indicators. The small size of this sample, and the heterogeneity of measures and scales used to capture conditions of poverty, make it difficult to assess the strength and consistency of associations between various poverty indicators and dengue outcomes. At present, the global body of eligible English-language peer-reviewed literature investigating dengue-poverty relationships is too small to support a definitive relationship. We conclude that more research, particularly using standardized measures of both outcomes and indicators, is needed to support evidence-informed policies and approaches. PMID- 25546340 TI - Predictors of response to a cognitive behavioral intervention for impulse control behaviors in Parkinson's disease. AB - BACKGROUND: Limited trial evidence suggests that cognitive-behavioral therapy (CBT) may be effective in managing impulse control behavior (ICBs) in Parkinson's disease. AIMS: To examine predictors of outcome in trial, participants (N=42) receiving treatment immediately or after a waiting time. METHODS: Dependent variables were Clinical Global Impression of Change (CGI-C) and the Neuropsychiatric Inventory (NPI). Baseline demographic and clinical variables were independent variables. RESULTS: Better CGI-C was predicted by fewer ICBs, taking a dopamine agonist, lower levodopa (l-dopa) equivalent dose (LEDD), higher social functioning, and lower NPI severity before treatment. Improvement on the NPI was predicted by lower LEDD, lower anxiety, lower baseline global clinical severity, and higher social functioning. CONCLUSIONS: Patients with lower burden of ICBs and other psychiatric symptomatology, better social functioning, and lower dose of antiparkinsonian medication may benefit more from CBT. However, we cannot yet identify individual patients with sufficient confidence at this stage to target treatment. PMID- 25546341 TI - Long-term arrhythmia follow-up of patients with myotonic dystrophy. AB - BACKGROUND: Myotonic dystrophy (MD) is the most common muscular dystrophy in adults and is associated with sudden death. Reported predictors of sudden death in this population include atrial tachyarrhythmias, a PR interval greater than 240 milliseconds, aberrant QRS conduction, and any degree of AV block. OBJECTIVE: We sought to report on the arrhythmic outcome of a cohort of patients with a new diagnosis of genetically proven MD. METHODS: We performed a retrospective review of 37 patients with genetically confirmed MD referred to our electrophysiology clinic for primary cardiac screening. RESULTS: There were 25 patients with MD type 1 (MD1) and 12 patients with MD type 2 (MD2). Eight patients with MD1 (32%) had atrial fibrillation, compared to only one patient with MD2 (8.3%). Patients with MD1 were more likely to have evidence of conduction disease abnormalities (40% vs. 8.3%, P = ns) and had a higher all-cause mortality (16% vs. 0%) than those with MD2. Criteria for recommending ICD implantation were based on sudden death risk factors suggested by published literature. Eleven patients were offered an ICD, 2 refused and died within the next year. Of the 9 patients who received an ICD, 8 had MD1. Three patients received appropriate shocks, 2 for monomorphic VT, and one for polymorphic VT. CONCLUSION: The presence of AV conduction disturbance in MD patients is associated with a greater risk for ventricular arrhythmias. MD1 was more likely to be associated with cardiac arrhythmias than MD2. The incidence of ventricular arrhythmias among those who received a primary prevention ICD was 33% over 22 months, with 2 patients experiencing monomorphic VT and one experiencing polymorphic VT. PMID- 25546342 TI - Watching language grow in the manual modality: nominals, predicates, and handshapes. AB - All languages, both spoken and signed, make a formal distinction between two types of terms in a proposition--terms that identify what is to be talked about (nominals) and terms that say something about this topic (predicates). Here we explore conditions that could lead to this property by charting its development in a newly emerging language--Nicaraguan Sign Language (NSL). We examine how handshape is used in nominals vs. predicates in three Nicaraguan groups: (1) homesigners who are not part of the Deaf community and use their own gestures, called homesigns, to communicate; (2) NSL cohort 1 signers who fashioned the first stage of NSL; (3) NSL cohort 2 signers who learned NSL from cohort 1. We compare these three groups to a fourth: (4) native signers of American Sign Language (ASL), an established sign language. We focus on handshape in predicates that are part of a productive classifier system in ASL; handshape in these predicates varies systematically across agent vs. no-agent contexts, unlike handshape in the nominals we study, which does not vary across these contexts. We found that all four groups, including homesigners, used handshape differently in nominals vs. predicates--they displayed variability in handshape form across agent vs. no-agent contexts in predicates, but not in nominals. Variability thus differed in predicates and nominals: (1) In predicates, the variability across grammatical contexts (agent vs. no-agent) was systematic in all four groups, suggesting that handshape functioned as a productive morphological marker on predicate signs, even in homesign. This grammatical use of handshape can thus appear in the earliest stages of an emerging language. (2) In nominals, there was no variability across grammatical contexts (agent vs. no-agent), but there was variability within- and across-individuals in the handshape used in the nominal for a particular object. This variability was striking in homesigners (an individual homesigner did not necessarily use the same handshape in every nominal he produced for a particular object), but decreased in the first cohort of NSL and remained relatively constant in the second cohort. Stability in the lexical use of handshape in nominals thus does not seem to emerge unless there is pressure from a peer linguistic community. Taken together, our findings argue that a community of users is essential to arrive at a stable nominal lexicon, but not to establish a productive morphological marker in predicates. Examining the steps a manual communication system takes as it moves toward becoming a fully fledged language offers a unique window onto factors that have made human language what it is. PMID- 25546343 TI - Exploring in silico prediction of the unbound brain-to-plasma drug concentration ratio: model validation, renewal, and interpretation. AB - Recently, we built an in silico model to predict the unbound brain-to-plasma concentration ratio (Kp,uu,brain), a measure of the distribution of a compound between the blood plasma and the brain. Here, we validate the previous model with new additional data points expanding the chemical space and use that data also to renew the model. The model building process was similar to our previous approach; however, a new set of descriptors, molecular signatures, was included to facilitate the model interpretation from a structure perspective. The best consensus model shows better predictive power than the previous model (R(2) = 0.6 vs. R(2) = 0.53, when the same 99 compounds were used as test set). The two-class classification accuracy increased from 76% using the previous model to 81%. Furthermore, the atom-summarized gradient based on molecular signature descriptors was proposed as an interesting new approach to interpret the Kp,uu,brain machine learning model and scrutinize structure Kp,uu,brain relationships for investigated compounds. PMID- 25546344 TI - Persistent alopecia induced by vismodegib. PMID- 25546345 TI - Rhodococcus equi infection in a patient with Crohn's disease treated with infliximab. PMID- 25546346 TI - Correction to "a generic approach to pathological lung segmentation". PMID- 25546347 TI - Reconstruction of scalp defects with exposed bone after surgical treatment of basal cell carcinoma: the use of a bilayer matrix wound dressing. AB - Treatment of scalp defects after tumor resection or traumatic events is a challenging problem. Large defects with loss of soft tissue down to the bone require complex reconstructive options, including tissue expansion, local and distal scalp flaps, and free split thickness skin graft. Nonetheless, these techniques are often disfiguring and are limited by the relatively poor elasticity and vascularity of scalp tissues after recurrent resection or previous irradiation. Moreover, comorbid conditions among elderly patients often limit anesthetic tolerance and the use of distant flaps. We report a case of a 75-year old woman with large tissue loss and bone exposure after Mohs micrographic surgery of basal cell carcinoma of the scalp which was successfully rebuilt through the use of a skin substitute. We describe the uncommon use of a bilayer matrix wound dressing as a single procedure option for the management of full thickness scalp defects with bone exposure. PMID- 25546348 TI - Haematopoietic stem cell transplantation for treatment of primary CNS lymphoma: single-centre experience and literature review. AB - Primary central nervous system lymphoma (PCNSL) is a rare and malignant tumour type. Established treatment approaches include high-dose methotrexate (HD-MTX) based chemotherapy and whole-brain radiotherapy (WBRT). WBRT is associated with significant neurotoxicity and autologous haematopoietic stem cell transplantation (ASCT) has been proposed as an alternative treatment - either in the 1st line setting after HD-MTX-based chemotherapy or as salvage treatment for relapsed/refractory PCNSL. We here report our single-centre experience with five PCNSL patients, who had achieved an objective response after a high-dose methotrexate-based induction therapy and consecutively received a high-dose chemotherapy, consisting of carmustine and thiotepa, followed by ASCT. We also provide a literature review on ASCL for PCNSL. Our data, with three of five patients in continuous complete remission and four of five patients alive after a median follow-up time of 8 months, as well as previously published results, show that ASCT is a safe treatment option that is able to induce tumour remissions in patients with PCNSL. However, controlled trials are needed to compare the long term efficacy and tolerability of ASCT with other treatment approaches and also to establish the optimal sequence of treatment regimens in PCNSL patients. PMID- 25546349 TI - Trikatu, a herbal compound mitigates the biochemical and immunological complications in adjuvant-induced arthritic rats. AB - AIM: Rheumatoid arthritis is a chronic inflammatory autoimmune disorder with multi-factorial factors influencing disease alleviation in synovial joints. The aim of this study was to investigate the anti-arthritic efficacy of trikatu, a herbal compound, on biochemical and immunological complications in adjuvant induced arthritic rats. METHODS: Arthritis was induced in rats by a single intradermal injection of complete Freund's adjuvant (0.1 mL) into the foot pad of the right hind paw. Trikatu (1000 mg/kg body weight, oral) and indomethacin (3 mg/kg body weight, intrap intraperitoneal) were administered for 8 days from days 11 to 18 after adjuvant injection. RESULTS: Our present study results evidenced a significant alteration in the activities/levels of lysosomal enzymes, protein bound carbohydrates, bone collagen, urinary constituents like hydroxyproline and total glycosaminoglycans, lipid peroxidation, antioxidant status, lipid profiles, rheumatoid factor and inflammatory mediators in adjuvant-induced arthritic rats. Trikatu treatment (1000 mg/kg/body weight) reverted back all the above biochemical and immunological parameters to near normal levels in arthritic rats as evidenced by the radiological and histopathological assessements . CONCLUSION: These results suggest that trikatu could be a promising alternative drug for the control and management of rheumatoid arthritis. PMID- 25546351 TI - Leucophore identity is more gold than silver. PMID- 25546350 TI - Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model. AB - HIV infection by sexual transmission remains an enormous global health concern. More than 1 million new infections among women occur annually. Microbicides represent a promising prevention strategy that women can easily control. Among emerging therapies, natural small molecules such as flavonoids are an important source of new active substances. In this study we report the in vitro cytotoxicity and anti-HIV-1 and microbicide activity of the following flavonoids: Myricetin, Quercetin and Pinocembrin. Cytotoxicity tests were conducted on TZM bl, HeLa, PBMC, and H9 cell cultures using 0.01-100 uM concentrations. Myricetin presented the lowest toxic effect, with Quercetin and Pinocembrin relatively more toxic. The anti-HIV-1 activity was tested with TZM-bl cell plus HIV-1 BaL (R5 tropic), H9 and PBMC cells plus HIV-1 MN (X4 tropic), and the dual tropic (X4R5) HIV-1 89.6. All flavonoids showed anti-HIV activity, although Myricetin was more effective than Quercetin or Pinocembrin. In TZM-bl cells, Myricetin inhibited >=90% of HIV-1 BaL infection. The results were confirmed by quantification of HIV 1 p24 antigen in supernatant from H9 and PBMC cells following flavonoid treatment. In H9 and PBMC cells infected by HIV-1 MN and HIV-1 89.6, Myricetin showed more than 80% anti-HIV activity. Quercetin and Pinocembrin presented modest anti-HIV activity in all experiments. Myricetin activity was tested against HIV-RT and inhibited the enzyme by 49%. Microbicide activities were evaluated using a dual-chamber female genital tract model. In the in vitro microbicide activity model, Myricetin showed promising results against different strains of HIV-1 while also showing insignificant cytotoxic effects. Further studies of Myricetin should be performed to identify its molecular targets in order to provide a solid biological foundation for translational research. PMID- 25546352 TI - ICD sees what you do not see: how does it beat you? PMID- 25546353 TI - Understanding and enhancing future infrastructure resiliency: a socio-ecological approach. AB - The resilience of any system, human or natural, centres on its capacity to adapt its structure, but not necessarily its function, to a new configuration in response to long-term socio-ecological change. In the long term, therefore, enhancing resilience involves more than simply improving a system's ability to resist an immediate threat or to recover to a stable past state. However, despite the prevalence of adaptive notions of resilience in academic discourse, it is apparent that infrastructure planners and policies largely continue to struggle to comprehend longer-term system adaptation in their understanding of resilience. Instead, a short-term, stable system (STSS) perspective on resilience is prevalent. This paper seeks to identify and problematise this perspective, presenting research based on the development of a heuristic 'scenario-episode' tool to address, and challenge, it in the context of United Kingdom infrastructure resilience. The aim is to help resilience practitioners to understand better the capacities of future infrastructure systems to respond to natural, malicious threats. PMID- 25546354 TI - Effects of suberoylanilide hydroxamic acid (SAHA) combined with paclitaxel (PTX) on paclitaxel-resistant ovarian cancer cells and insights into the underlying mechanisms. AB - BACKGROUND: Suberoylanilide hydroxamic acid (SAHA) is a member of the hydroxamic acid class of the newly developed histone deacetylase inhibitors. Recently, Suberoylanilide hydroxamic acid has attracted increasing attention because of its antitumor activity and synergistic effects in combination with a variety of traditional chemotherapeutic drugs. Paclitaxel (PTX), is a natural anticancer drugs; however, resistance to paclitaxel has become a major challenge to the efficacy of this agent. The purpose of this study was to investigate the effects of the combined application of these two drugs on the paclitaxel-resistant ovarian cancer OC3/P cell line. METHODS: In the present study, the effects of Suberoylanilide hydroxamic acid or/and paclitaxel on OC3/P cells cultured in vitro were analyzed in terms of cell viability, migration, cell-cycle progression and apoptosis by CCK-8, wound healing and flow cytometry assays. Changes in cell ultrastructure were observed by transmission electron microscopy. The expression of genes and proteins related to proliferation, apoptosis and drug resistance were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses. RESULTS: There was no cross-resistance of the paclitaxel-resistant ovarian cancer OC3/P cells to Suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid combined with paclitaxel significantly inhibited cell growth and reduced the migration of OC3/P cells compared with the effects of Suberoylanilide hydroxamic acid or paclitaxel alone. Q-PCR showed the combination of Suberoylanilide hydroxamic acid and paclitaxel reduced intracellular bcl-2 and c myc gene expression and increased bax gene expression more distinctly than the application of SAHA or paclitaxel alone. Moreover, the level of mdr1 gene expression in cells treated with Suberoylanilide hydroxamic acid was lower than that of the control group (P <0.05). Western blot analysis showed that Suberoylanilide hydroxamic acid alone or in combination with paclitaxel enhanced caspase-3 protein expression and degraded ID1 protein expression in OC3/P cells. CONCLUSION: Suberoylanilide hydroxamic acid inhibited the growth of paclitaxel resistant ovarian cancer OC3/P cells and reduced migration by the induction of cell-cycle arrest, apoptosis and autophagy. These observations indicate the possible synergistic antitumor effects of sequential Suberoylanilide hydroxamic acid and paclitaxel treatment. PMID- 25546355 TI - Sensitivity of high-risk HPV Hybrid Capture II (hrHPV HC2) test using SurePath(TM) specimens in the prediction of cervical high-grade squamous lesions. AB - INTRODUCTION: High-risk HPV (hrHPV) testing is now considered standard of care in the detection and management of cervical high-grade squamous intraepithelial lesions (HSIL/CIN 2-3) and their precursors. Recently, there has been concern in the scientific literature and lay media about the lack of data regarding the false-negative rate (FNR) of HPV testing on SurePath(TM) cytology specimens. This is a critical issue, since guidelines on the management of Pap test abnormalities rely heavily on HPV status. We undertook this study to determine whether HPV testing on SurePath(TM) specimens is less sensitive compared to reports in the literature for ThinPrep(r). METHODS: We identified women with new diagnoses of CIN 2, CIN 3, and squamous cell carcinoma (SCC) on biopsy or excision in 2009 2013. For each patient, we recorded all SurePath(TM) cytology and hrHPV HC2 (high risk HPV Hybrid Capture 2) test results from within 5 years prior to histologic diagnosis. Using the histologic diagnosis as the gold standard, we calculated the sensitivities of cytology and hrHPV HC2 tests for the detection of CIN 2, 3, and SCC. Our findings are based only on women who underwent biopsy or excision after having an abnormal cytology and/or positive HPV result. RESULTS: In our cohort, the sensitivity of testing in the 5 years prior to histologic diagnosis of CIN 2, 3, and SCC (combined as a single group) is 98.4% for SurePath(TM) cytology, 95.3% for hrHPV HC2, and 100% if both tests are used together. No conclusion can be drawn regarding testing for SCC alone, because there was only one case of SCC. CONCLUSION: Our results show that the false-negative rate of hrHPV HC2 testing on SurePath(TM) specimens for the detection of CIN 2 and CIN 3 is low and comparable to that of ThinPrep(r) specimens. PMID- 25546356 TI - Comparative biokinetics and metabolism of pure monomeric, dimeric, and polymeric flavan-3-ols: a randomized cross-over study in humans. AB - SCOPE: Flavan-3-ols are abundant polyphenols in human nutrition and are associated with beneficial health effects. The aim of this study was to comparatively investigate the metabolic fate of (-)-epicatechin, procyanidin B1, and polymeric procyanidins in a randomized cross-over study in humans. METHODS AND RESULTS: Parent compounds, conjugates, and microbial metabolites were determined in plasma, urine, and faeces by HPLC-MS and GC-MS/MS. Glucuronidated, sulfated, and methylated (-)-epicatechin and 5-(3',4'-dihydroxyphenyl) valerolactone were the dominant metabolites in blood and urine. In addition, minor amounts of procyanidin B1 and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid and their conjugated metabolites were detected. The formation of 5-(3',4' dihydroxyphenyl)-valerolactone and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid varied largely between individuals as well as with the degree of polymerization of flavan-3-ols. Monomer units were not detectable in plasma or urine after procyanidin B1 and polymeric procyanidin intake. No correlation was found between the intake of flavan-3-ols and the occurrence of phenolic acids in blood and urine or the phenolic compound profiles in faeces. CONCLUSION: In addition to conjugated metabolites derived from the absorption of monomeric flavan-3-ols, 5-(3',4'-dihydroxyphenyl)-valerolactone represents an important in vivo metabolite of (-)-epicatechin and procyanidin B1 produced by the gut microbiota. PMID- 25546357 TI - Detection of urinary creatinine using gold nanoparticles after solid phase extraction. AB - Label-free gold nanoparticles (AuNPs) were utilized in the detection of creatinine in human urine after a sample preparation by extraction of creatinine on sulfonic acid functionalized silica gel. With the proposed sample preparation method, the interfering effects of the urine matrix on creatinine detection by AuNPs were eliminated. Parameters affecting creatinine extraction were investigated. The aggregation of AuNPs induced by creatinine resulted in a change in the surface plasmon resonance signal with a concomitant color change that could be observed by the naked eye and quantified spectrometrically. The effect of AuNP concentration and reaction time on AuNP aggregation was investigated. The method described herein provides a determination of creatinine in a range of 15 40mgL(-1) with a detection limit of 13.7mgL(-1) and it was successfully used in the detection of creatinine in human urine samples. PMID- 25546358 TI - Tools for water quality monitoring and mapping using paper-based sensors and cell phones. AB - In this paper we describe a combination of paper-based sensors and a novel smart phone application for on-site quantification of colorimetric readouts as an ultra low cost solution to monitoring water quality. The system utilizes a paper-based analytical device (MUPAD) that produces a colorimetric signal that is dependent on the concentration of a specific target; a cell phone equipped with a camera for capturing images of two MUPADs - one tested with a water sample and the other tested with clean water that is used as a control; and an on-site image processing app that uses a novel algorithm for quantifying color intensity and relating this to contaminant concentration. The cell phone app utilizes a pixel counting algorithm that performs with less bias and user subjectivity than the typically used lab-based software, ImageJ. The use of a test and control strip reduces bias from variations in ambient lighting, making it possible to acquire and process images on-site. The cell phone is also able to GPS tag the location of the test, and transmit results to a newly developed website, WaterMap.ca, that displays the quantitative results from the water samples on a map. We demonstrate our approach using a previously developed MUPAD that detects the presence of organophosphate pesticides based on the inhibition of immobilized acetylcholinesterase by these contaminants. The objective of this paper is to highlight the importance and potential of developing and integrated monitoring system consisting of MUPADs, cell-phones and a centralized web portal for low cost monitoring environmental contaminants at a large-scale. PMID- 25546359 TI - Water quality and quantity investigation of green roofs in a dry climate. AB - Low-energy pollutant removal strategies are now being sought for water sensitive urban design. This paper describes investigations into the water quality and quantity of sixteen, low-maintenance and unfertilized intensive and extensive green roof beds. The factors of Slope (1 degrees and 25 degrees ), Depth (100 mm and 300 mm), Growing media (type A, type B and type C) and Species (P1, P2 and P3) were randomized according to a split-split plot design. This consisted of twelve vegetated green roof beds and four non-vegetated beds as controls. Stormwater runoff was collected from drainage points that were installed in each area. Samples of run-off were collected for five rainfall events and analysed for water retention capacity and the water quality parameters of NO2, NO3, NH4, PO4, pH, EC, TDS, Turbidity, Na, Ca, Mg and K. The results indicated significant differences in terms of stormwater water quality and quantity between the outflows of vegetated and non-vegetated systems. The water retention was between 51% and 96% and this range was attributed to the green roof configurations in the experiment. Comparing the quality of rainfall as inflow, and the quality of runoff from the systems showed that green roofs generally acted as a source of pollutants in this study. In the vegetated beds, the intensive green roofs performed better than the extensive beds with regard to outflow quality while in the non-vegetated beds, the extensive beds performed better than intensive systems. This highlights the importance of vegetation in improving water retention capacity as well as the role of vegetation in enhancing pollutant removal in green roof systems. In addition growing media with less organic matter had better water quality performance. Comparison of these results with national and international standards for water reuse confirmed that the green roof outflow was suitable for non-potable uses such as landscape irrigation and toilet flushing. PMID- 25546360 TI - An integrative proteome analysis of different seedling organs in tolerant and sensitive wheat cultivars under drought stress and recovery. AB - Roots, leaves, and intermediate sections between roots and leaves (ISRL) of wheat seedlings show different physiological functions at the protein level. We performed the first integrative proteomic analysis of different tissues of the drought-tolerant wheat cultivar Hanxuan 10 (HX-10) and drought-sensitive cultivar Chinese Spring (CS) during a simulated drought and recovery. Differentially expressed proteins (DEPs) in the roots (122), ISRLs (146), and leaves (163) showed significant changes in expression in response to drought stress and recovery. Numerous DEPs associated with cell defense and detoxifications were significantly regulated in roots and ISRLs, while in leaves, DEPs related to photosynthesis showed significant changes in expression. A significantly larger number of DEPs related to stress defense were upregulated in HX-10 than in CS. Expression of six HSPs potentially related to drought tolerance was significantly upregulated under drought conditions, and these proteins were involved in a complex protein-protein interaction network. Further phosphorylation analysis showed that the phosphorylation levels of HSP60, HSP90, and HOP were upregulated in HX-10 under drought stress. We present an overview of metabolic pathways in wheat seedlings based on abscisic acid signaling and important protein expression patterns. PMID- 25546361 TI - Markers for distinguishing cultured human corneal endothelial cells from corneal stromal myofibroblasts. AB - PURPOSE: Eliminating contamination by corneal stromal cells is critical when preparing cultured human corneal endothelial cells (CECs) transplantation. We investigated markers for the purification of cultured human CECs and markers for excluding cultured human corneal stromal myofibroblasts (CSMFs) from cultured human CECs. MATERIALS AND METHODS: CECs and CSMFs were obtained from human donor corneas by culturing separately in serum-containing medium. Candidate markers of CECs and CSMFs were screened with microarray analysis in the fourth passaged CECs and CSMFs. Then, selected factors were evaluated in reverse transcription polymerase chain reaction (RT-PCR), western blot, immunocytochemistry, and flow cytometry to investigate differential markers for each cell. RESULTS: Among the genes identified by microarray analysis, cultured human CECs, but not CSMFs, expressed integrin alpha 3 (ITGA3 and CD49c) protein according to immunocytochemistry and western blotting. Iroquois homeobox 2 (IRX2) gene was a marker that distinguished CSMFs from cultured human CECs by RT-PCR. The IRX2 gene can be used as a marker of CSMFs contaminating cultured CECs. CONCLUSION: These molecules could be important markers for the production of highly purified cultured CECs for regenerative medicine. PMID- 25546363 TI - The RUNX1 +24 enhancer and P1 promoter identify a unique subpopulation of hematopoietic progenitor cells derived from human pluripotent stem cells. AB - Derivation of hematopoietic stem cells (HSCs) from human pluripotent stem cells remains a key goal for the fields of developmental biology and regenerative medicine. Here, we use a novel genetic reporter system to prospectively identify and isolate early hematopoietic cells derived from human embryonic stem cells (hESCs) and human induced pluripotent cells (iPSCs). Cloning the human RUNX1c P1 promoter and +24 enhancer to drive expression of tdTomato (tdTom) in hESCs and iPSCs, we demonstrate that tdTom expression faithfully enriches for RUNX1c expressing hematopoietic progenitor cells. Time-lapse microscopy demonstrated the tdTom(+) hematopoietic cells to emerge from adherent cells. Furthermore, inhibition of primitive hematopoiesis by blocking Activin/Nodal signaling promoted the expansion and/or survival of the tdTom(+) population. Notably, RUNX1c/tdTom(+) cells represent only a limited subpopulation of the CD34(+) CD45(+) and CD34(+) CD43(+) cells with a unique genetic signature. Using gene array analysis, we find significantly lower expression of Let-7 and mir181a microRNAs in the RUNX1c/tdTom(+) cell population. These phenotypic and genetic analyses comparing the RUNX1c/tdTom(+) population to CD34(+) CD45(+) umbilical cord blood and fetal liver demonstrate several key differences that likely impact the development of HSCs capable of long-term multilineage engraftment from hESCs and iPSCs. PMID- 25546365 TI - Use of an ionic liquid-based surfactant as pseudostationary phase in the analysis of carbamates by micellar electrokinetic chromatography. AB - The applicability of an ionic liquid-based cationic surfactant 1-dodecyl-3-methyl imidazolium tetrafluoroborate (C12 MImBF4 ) as pseudostationary phase in MEKC has been evaluated for the analysis of 11 carbamate pesticides (promecarb, carbofuran, metolcarb, fenobucarb, aldicarb, propoxur, asulam, benomyl, carbendazim, ethiofencarb, isoprocarb) in juice samples. Under optimum conditions (separation buffer, 35 mM NaHCO3 and 20 mM C12 MImBF4 , pH 9.0; capillary temperature 25 degrees C; voltage -22 kV) the analysis was carried out in less than 12 min, using hydrodynamic injection (50 mbar for 7.5 s) and detection at 200 nm. For the extraction of these CRBs from juice samples, a dispersive liquid liquid microextraction (DLLME) procedure has been proposed, by optimization of variables affecting the efficiency of the extraction. Following this treatment, sample throughput was approximately 12 samples per hour, obtaining a preconcentration factor of 20. Matrix-matched calibration curves were established using tomato juice as representative matrix (from 5 to 250 MUg/L for CBZ, BY, PX, CF, FEN, ETH, ISP, and 25-250 MUg/L for ASL, ALD, PRC, MTL), obtaining quantification limits ranging from 1 to 18 MUg/L and recoveries from 70 to 96%, with RSDs lower than 9%. PMID- 25546364 TI - High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. AB - IMPORTANCE: Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS. OBJECTIVE: To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS: Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled. INTERVENTIONS: Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURES: The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores. CONCLUSIONS AND RELEVANCE: At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events. PMID- 25546366 TI - Strain-dependent performance in nicotine-induced conditioned place preference. AB - Nicotine addiction is most likely a result of a combination of factors including the rewarding effects of the drug; these effects, however, might be influenced by genetic background. Using a conditioned place preference (CPP) paradigm and 8 inbred mouse strains, we conducted an initial examination of the role of genetic background in the rewarding effects of nicotine. Following habituation and initial place preference test, inbred strains (A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/1J, DBA/2J, and 129/SvEv) were trained and tested in CPP for nicotine (0.35 mg/kg). Although several strains (C57BL/6J, CBA/J, and 129/SvEv) showed nicotine-induced CPP, 1 strain (DBA/1J) showed conditioned place aversion (CPA), and other strains (A/J, BALB/cByJ, C3H/HeJ, and DBA/2J) did not show CPP. Overall, these results indicate that nicotine's rewarding effects tested in CPP are differentially affected by the genetic background, and this trait has a relatively high heritability (42%-57%). This initial investigation lays the foundation for future studies examining the genetic substrates of nicotine reward. PMID- 25546367 TI - Targeted proteomic analyses of nasal lavage fluid in persulfate-challenged hairdressers with bleaching powder-associated rhinitis. AB - Hairdressers have an increased risk for developing airway symptoms, for example, asthma and rhinitis. Persulfates, which are oxidizing agents in bleaching powder, are considered important causal agents for these symptoms. However, the underlying mechanisms are unclear. The aim was therefore to measure proteomic changes in nasal lavage fluid from persulfate-challenged subjects to identify proteins potentially involved in the pathogenesis of bleaching powder-associated rhinitis or candidate effect biomarkers for persulfate. Also, oxidized peptides were measured to evaluate their usefulness as biomarkers for persulfate exposure or effect, for example, oxidative stress. Samples from hairdressers with and without bleaching powder-associated rhinitis were analyzed with liquid chromatography tandem mass spectrometry using selected reaction monitoring to target 246 proteins and five oxidized peptides. Pathway analysis was applied to obtain a functional overview of the proteins. Several proteins involved in biologically meaningful pathways, functions, or disorders, for example, inflammatory responses, oxidative stress, epithelium integrity, and dermatological disorders, changed after the persulfate challenge. A list with nine proteins that appeared to be affected by the persulfate challenge and should be followed up was defined. An albumin peptide containing oxidized tryptophan increased 2 h and 5 h after the challenge but not after 20 min, which indicates that such peptides may be useful as oxidative stress biomarkers. PMID- 25546369 TI - Differential pharmacokinetics of diclofenac potassium for oral solution vs immediate-release tablets from a randomized trial: effect of fed and fasting conditions. AB - OBJECTIVE: To compare the pharmacokinetics of, and food effect on, diclofenac potassium delivered as an oral solution vs an immediate-release tablet. BACKGROUND: Diclofenac potassium for oral solution is the only nonsteroidal anti inflammatory drug approved as monotherapy for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older. It is formulated with potassium bicarbonate as a buffering agent to raise the pH and consequently increase the aqueous solubility of diclofenac in the acidic environment of the stomach following oral administration. The dosage is 50 mg of powdered diclofenac potassium dissolved in 1 to 2 ounces (30 to 60 mL) of water prior to administration, with dosing time in relation to food intake not specified - this was the case for the pivotal efficacy and safety trials in subjects with acute migraine attacks in which the primary endpoints were achieved. For acute treatment of migraine attacks, rapid onset of pain relief is desirable and is likely related to a rapid appearance of an effective concentration of the drug in the systemic circulation. The rate at which an orally administered drug reaches the blood is affected by both its formulation and the presence of food in the stomach. The present study was designed to investigate the pharmacokinetics of 2 formulations of diclofenac potassium, an immediate-release tablet and an oral solution, and to ascertain the effect of food. METHODS: This was an open-label, randomized, single-center, crossover trial in healthy volunteers. Subjects were randomized using computer-generated list to 1:1:1:1 ratio. They received a single 50-mg dose of diclofenac potassium in 4 sequences (ABCD, BADC, CDBA, and DCAB) during each of the 4 treatment periods. The 4 treatments were: A, oral solution fasting; B, tablet fasting; C, oral solution fed; and D, tablet fed. There was a >=7-day washout period between dosing. Blood samples for pharmacokinetic analysis were taken for up to 12 hours post-dose and analyzed for diclofenac concentrations. Pharmacokinetic parameters, including peak concentration (Cmax ), time to Cmax (tmax ), area under the concentration-time curve (AUC) from time 0 to last measurable concentration (AUCt ), and extrapolation to infinity (AUCinfinity ) were obtained using non-compartmental analysis. Comparative assessments for Cmax and AUC were performed between the solution and tablet under fed and fasting conditions and between fed and fasting states for both formulations. Bioequivalent exposure was defined as the geometric mean ratio and its 90% confidence interval falling within 80.0-125.0% for Cmax and AUC. Adverse events (AEs) were monitored throughout the trial. RESULTS: Sixty-one percent of the 36 randomized subjects were male, 91.7% were Caucasian, and the mean (standard deviation [SD]) age was 31.9 (7.6) years. Thirty-three (91.7%) subjects completed all 4 treatments. SOLUTION VS TABLET: When taken under fed conditions, the oral solution resulted in an approximately 80% faster median tmax (0.17 vs 1.25 hours, P = .00015) and a 21% lower Cmax (mean +/- SD, ng/mL: 506 +/- 305 vs 835 +/- 449, P = .00061) compared with the tablet. AUC values were similar between the 2 formulations. When taken under fasting conditions, the oral solution exhibited a 50% faster median tmax (0.25 vs 0.50 hours, P = .00035) to achieve a 77% higher Cmax (mean +/- SD, ng/mL: 1620 +/- 538 vs 1160 +/- 452, P = .00032) compared with the tablet. AUCt and AUCinfinity were similar between the 2 formulations. FED VS FASTING: When taken under fed conditions, the oral solution resulted in a similar median tmax (0.17 vs 0.25 hours, P = .185) and 64% lower Cmax (mean +/- SD, ng/mL: 506 +/- 305 vs 1620 +/- 538, P < .00001) compared with fasting conditions. In comparison, the tablets under fed conditions resulted in a statistically significantly delayed median tmax (1.25 vs 0.50, P = .00143) and ~30% lower Cmax (mean +/- SD, ng/mL: 835 +/- 449 vs 1160 +/- 452, P = .00377). AUC values were similar between fed and fasting conditions for both formulations. Twelve subjects (33%) experienced >=1 treatment-emergent AE during the study. All AEs were mild and resolved without treatment; none resulted in study discontinuation. More treatment-emergent AEs were reported in subjects receiving the tablet compared with the solution formulation (20.0% vs 11.8 % in fasting and 17.1% vs 8.6% in fed conditions). CONCLUSIONS: Diclofenac potassium oral solution and tablet formulations produced statistically significantly different Cmax and tmax but similar AUC under fed and fasting conditions. Fed conditions produced significantly lower Cmax for both formulations and profoundly delayed tmax for the tablet, but had no effect on tmax for the solution formulation. These data provide insights into the importance of an earlier and greater exposure to diclofenac arising from the solution formulation than the tablet, which may account for the superiority in the onset and sustained pain reduction for the solution than the tablet formulation observed in the double-blind, efficacy/safety study in migraine patients conducted in Europe. PMID- 25546368 TI - Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II). AB - BACKGROUND: BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES: To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS: In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12-65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81 8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS: Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean +/- SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 +/- 7.2; 3-times-weekly, 4.3 +/- 6.5; combined, 4.9 +/- 6.8) vs. on-demand treatment (57.7 +/- 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment related serious AEs or inhibitors were reported. CONCLUSIONS: Twice weekly or 3 times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated. PMID- 25546370 TI - Genetic and nongenetic etiology of nonsyndromic anorectal malformations: a systematic review. AB - Congenital anorectal malformations (ARMs) are one of the most frequently observed birth defects of the digestive system. However, their etiology remains elusive. Therefore, we aim to summarize and critically appraise all existing literature on the genetic and nongenetic etiology of nonsyndromic ARM and to conclude with unifying hypotheses and directions for future research. A structured literature search on English language human studies was conducted in PubMed and Embase up to October 1, 2013, resulting in 112 included articles. Research on the identification of genes underlying nonsyndromic ARM is remarkably scarce. Most studies were focused on screening of candidate genes for mutations or single nucleotide polymorphisms, which did not yield any substantial evidence. Nongenetic factors fairly consistently found to be associated with ARM are assisted reproductive techniques, multiple pregnancy, preterm delivery, low birth weight, maternal overweight or obesity, and preexisting diabetes. This review provides indications for the involvement of both genes and nongenetic risk factors in the etiology of ARM. In future studies, large cohorts of patients with ARM from national and international collaborations are needed to acquire new hypotheses and knowledge through hypothesis-generating approaches. Challenges for future studies may also lie in the investigation of gene-gene and gene environment interactions. PMID- 25546372 TI - Eighteen years experience of granulocyte donations-acceptable donor safety? AB - BACKGROUND: Granulocyte transfusions are given to patients with life-threatening infections, refractory to treatment. The donors are stimulated with corticosteroids +/- granulocyte colony stimulating factor (G-CSF). However, data regarding the donors' safety is sparse. The objective was therefore to evaluate short- and long-term adverse events (AE) in G-CSF stimulated donors. STUDY DESIGN AND METHODS: All consecutive granulocyte donors from 1994 to 2012 were identified through our registry. From the donation records, the number of aphereses, stimulation therapy, AE, blood values post donation, and recent status were evaluated. RESULTS: One hundred fifty-four volunteer donors were mobilized for 359 collections. Age at first granulocyte donation was 43 years (median; range 19 64 years). Follow-up was 60 months (median; range 0-229 months). The dose of G CSF per collection was 3.8 ug/kg body weight (median; range 1.6-6.0 ug/kg). Sedimentation agent was HES. Short-term AE were mild. Blood values 4 weeks post donation with minor reductions/elevations mostly resolved in later donations. Fourteen donors were excluded from the registry due to hypertension (4), diabetes (2), atrial flutter (1), breast carcinoma (1), urethral carcinoma in situ (1), MGUS (1), thrombosis (1), anaphylaxis (1), primary biliary cirrhosis (1), and unknown (1). Three donors are deceased due to diabetes, acute myocardial infarction, and unknown cause. All excluded/deceased donors except one were excluded/died at least 6 months after first granulocyte donation. CONCLUSION: No serious short-term AE were observed. Due to the variability of diagnoses among excluded/deceased donors, we propose that it is less likely that granulocyte donations have a causative impact on these donors' exclusion or death. PMID- 25546374 TI - Deliberately Light Interpersonal Touch as an Aid to Balance Control in Neurologic Conditions. AB - PURPOSE: We aimed to quantify the benefit of externally provided deliberately light interpersonal touch (IPT) on body sway in neurological patients. DESIGN: IPT effect on sway was assessed experimentally across differing contacting conditions in a group of 12 patients with Parkinson's disease and a group of 11 patients with chronic hemiparetic stroke. METHODS: A pressure plate recorded sway when IPT was provided by a healthcare professional at various locations on a patient's back. FINDINGS: IPT on the back reduced anteroposterior body sway in both groups. Numerically, IPT was more effective when applied more superior on the back, specifically at shoulder level, and when applied at two contact locations simultaneously. CONCLUSION: Our findings demonstrate the benefit of deliberately light IPT on the back to facilitate patients' postural stability. CLINICAL RELEVANCE: Deliberately light IPT resembles a manual handling strategy, which minimizes load imposed on healthcare professionals when providing balance support, while it facilitates patients' own sensorimotor control of body balance during standing. PMID- 25546373 TI - In vitro kinetics of amiodarone and its major metabolite in two human liver cell models after acute and repeated treatments. AB - The limited value of in vitro toxicity data for the in vivo extrapolation has been often attributed to the lack of kinetic data. Here the in vitro kinetics of amiodarone (AMI) and its mono-N-desethyl (MDEA) metabolite was determined and modelled in primary human hepatocytes (PHH) and HepaRG cells, after single and repeated administration of clinically relevant concentrations. AMI bioavailability was influenced by adsorption to the plastic and the presence of protein in the medium (e.g. 10% serum protein reduced the uptake by half in HepaRG cells). The cell uptake was quick (within 3h), AMI metabolism was efficient and a dynamic equilibrium was reached in about a week after multiple dosing. In HepaRG cells the metabolic clearance was higher than in PHH and increased over time, as well as CYP3A4. The interindividual variability in MDEA production in PHHs was not proportional to the differences in CYP3A4 activities, suggesting the involvement of other CYPs and/or AMI-related CYP inhibition. After repeated treatment AMI showed a slight potential for bioaccumulation, whereas much higher intracellular MDEA levels accumulated over time, especially in the HepaRG cells, associated with occurrence of phospholipidosis. The knowledge of in vitro biokinetics is important to transform an actual in vitro concentration effect into an in vivo dose-effect relationship by using appropriate modelling, thus improving the in vitro-to-in vivo extrapolation. PMID- 25546375 TI - Meta-analysis on survival of patients treated with transoral surgery versus radiotherapy for early-stage squamous cell carcinoma of the oropharynx. AB - BACKGROUND: Transoral surgery (TOS) for patients with early stage oropharyngeal squamous cell carcinoma (SCC) is increasingly used, however, criticized, because of less optimal access to the tumor than open techniques and thus potentially jeopardizing tumor control in comparison with radiotherapy (RT). Therefore, we compared the currently available data on survival provided by TOS versus RT. METHODS: Survival data were extracted after a MEDLINE, Web of Science, and Google Scholar search followed by a meta-analysis. RESULTS: The analysis was based on 729 patients in the RT group versus 276 in the TOS group with similar quality of studies in both groups. The 5-year disease-specific survival (DSS)/overall survival (OS) was 90.4% (95% confidence interval [CI], 85.6% to 95.2%/58.8%; 95% CI, 52.8% to 64.7%) in the RT group versus 89.6% (95% CI, 81.8% to 97.3%/78.1%; 95% CI, 71.2% to 85.1%) in the TOS group. CONCLUSION: The data suggest equivalent efficacy of both treatments in terms of disease control for early stage oropharyngeal SCC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 2143-2150. PMID- 25546376 TI - Chemical cross-linking/mass spectrometry maps the amyloid beta peptide binding region on both apolipoprotein E domains. AB - Apolipoprotein E (apoE) binds the amyloid beta peptide (Abeta), one of the major culprits in Alzheimer's disease development. The formation of apoE:Abeta complexes is implicated in both Abeta clearance and fibrillization. However, the binding interface between apoE and Abeta is poorly defined despite substantial previous research efforts, and the exact role of apoE in the pathology of Alzheimer's disease remains largely elusive. Here, we compared the three main isoforms of apoE (E2, E3, and E4) for their interaction with Abeta1-42 in an early stage of aggregation and at near physiological conditions. Using electron microscopy and Western blots, we showed that all three isoforms are able to prevent Abeta fibrillization and form a noncovalent complex, with one molecule of Abeta bound per apoE. Using chemical cross-linking coupled to mass spectrometry, we further examined the interface of interaction between apoE2/3/4 and Abeta. Multiple high-confidence intermolecular apoE2/3/4:Abeta cross-links confirmed that Lys16 is located in the region of Abeta binding to apoE2/3/4. Further, we demonstrated that both N- and C-terminal domains of apoE2/3/4 are interacting with Abeta. The cross-linked sites were mapped onto and evaluated in light of a recent structure of apoE. Our results support binding of the hydrophobic Abeta at the apoE domain-domain interaction interface, which would explain how apoE is able to stabilize Abeta and thereby prevent its subsequent aggregation. PMID- 25546377 TI - The influence of an individual's weight perception on the acceptance of bariatric surgery. AB - OBJECTIVE: This study assessed the proportion of US adults with excess weight and obesity who consider bariatric surgery to be appropriate for themselves and how their own weight perception influences this consideration. METHODS: A stratified sample of 920 US adults in June 2014 was obtained through an online survey. The respondents were queried about bariatric surgery acceptability and personal weight perception. Average body mass index (BMI) was determined for each demographic variable, and responses were characterized according to BMI and concordance with perceived weight status. Chi-square analyses served to assess perceived weight concordance in relation to bariatric acceptance. RESULTS: Only 32% of respondents with Class III obesity indicated that bariatric surgery would be an acceptable option for them, most often because they considered it to be too risky. Respondents with Class III obesity and concordant perception of weight status were more likely (P < 0.03) than discordant Class III respondents to accept bariatric surgery. Likewise, concordant respondents with excess weight, but not obesity, were more likely (P < 0.001) to correctly consider bariatric surgery to be inappropriate for them. CONCLUSIONS: Despite good safety and efficacy, many persons still believe bariatric surgery is too risky. Weight perception concordance or discordance influences one's decision to consider this treatment option. PMID- 25546378 TI - Zofenopril attenuates injury induced by ischemia-reperfusion on rat ovary. AB - AIM: The aim of the study was to investigate the effectiveness of zofenopril in an experimental model of ovarian torsion in rats with histologic and biochemical assessments. MATERIAL AND METHODS: Experimental procedures were performed on 35 female rats (Wistar albino). Rats were randomly divided into five groups as: sham (sham operated, n = 7); vehicle group 1 (torsion-detorsion, n = 7) with 2 h ischemia and 2 h reperfusion; vehicle group 2 (torsion-detorsion, n = 7) with 2 h ischemia and 5 days' reperfusion; zofenopril group 1 (torsion-detorsion, n = 7) with 2 h ischemia, 2 h reperfusion and a signal dose of oral 15 mg/kg zofenopril; and zofenopril group 2 (torsion-detorsion, n = 7) with 2 h ischemia, 5 days' reperfusion and 5 days' oral 15 mg/kg zofenopril. A scoring of histopathologic evaluation was performed on the ovaries according to congestion, bleeding, edema, and cellular degeneration. Biochemical assessments included catalase, tissue malondialdehyde and protein carbonyl. RESULTS: Compared with the vehicle groups, histopathologic scores, tissue malondialdehyde and protein carbonyl levels, which reflect oxidative stress markers, were significantly lower in the zofenopril groups. Furthermore, catalase levels were significantly increased in the zofenopril group. CONCLUSION: Our study results revealed that zofenopril attenuates injury induced by ischemia-reperfusion on rat ovary. PMID- 25546379 TI - Efficacy and safety of a flaxseed hull extract in the symptomatic management of benign prostatic hyperplasia: a parallel, randomized, double-blind, placebo controlled, pilot study. AB - This exploratory study was designed to assess the effectiveness of a lignan-rich extract of flaxseed hulls (LinumLife EXTRA((r))) in alleviating symptoms in subjects with benign prostatic hyperplasia (BPH) compared with placebo. Two dosages of extract were compared against placebo in a double-blinded, randomized, parallel, multicenter study. Newly diagnosed cases of BPH in patients aged 45-75 years with an American Urological Association Symptom Index (AUASI) score of >=13 were included. Study treatment consisted of 500 or 1000 mg of extract containing 100 mg (low-dose active [LDA] group, n=26) or 200 mg (high-dose active [HDA] group, n=26) of secoisolariciresinol diglucoside (SDG), respectively. The placebo (P) group (n=28) received matching maltodextrin capsules. Sixty subjects (LDA [n=19], HDA [n=20], and P [n=21]) completed the study as per the protocol requirements. Change in the AUASI score within a period of 8 weeks, from baseline to end of treatment, was assessed. Significant improvement of obstructive symptoms and management of irritable BPH symptoms was achieved in all groups after treatment. Due to a strong placebo effect, there was no statistical difference between the groups that were treated with flaxseed hull extract as compared with the placebo group. Treatment with flaxseed hull extract did not lead to adverse effects compared with placebo. Supplementation with flaxseed hull extract was found to be safe and well-tolerated and may have improved the quality of life of individuals with BPH. The significant placebo effect as well as the number of subjects per treatment group and the relative short duration of the study may explain the lack of statistical significance between groups. PMID- 25546380 TI - Cerebral white matter lesions in patients with cirrhosis - causative for hepatic encephalopathy or bystanders? AB - BACKGROUND & AIMS: Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function. METHODS: 55 cirrhotic patients underwent neurological examination, psychometric testing and magnetic resonance imaging. T2-weighted images were reviewed for white matter lesions by a neuroradiologist and a neurologist, independently. Patients were allocated into three groups: (i) no or <5, (ii) 6-15 and (iii) more than 15 lesions. Allocation was confirmed by a senior neuroradiologist blinded for the clinical data. The patient groups were compared concerning age, underlying liver disease, mortality, MELD Score, history of HE, treatment for HE, cerebrovascular risk factors and psychometric test results. Regression analysis was performed to identify risk factors for the presence and extent of white matter lesions. RESULTS: Patient groups 2 and 3 were older and showed worse results in the psychometric tests than group 1 (P < 0.05). Correlation analyses showed a significant relationship between the number of white matter lesions and the grade of HE (P < 0.001) and cognitive function (P < 0.05), but no interrelationship between the lesions and cerebrovascular risk factors or other factors tested. CONCLUSIONS: Focal white matter lesions in patients with cirrhosis do not represent cerebrovascular small vessel disease but are related to the pathology of HE. Further studies are needed to clarify the mechanisms behind in detail. PMID- 25546381 TI - Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association. AB - Recent studies have shown that the protein interface sites between individual monomeric units in biological assemblies are enriched in disease-associated non synonymous single nucleotide variants (nsSNVs). To elucidate the mechanistic underpinning of this observation, we investigated the conformational dynamic properties of protein interface sites through a site-specific structural dynamic flexibility metric (dfi) for 333 multimeric protein assemblies. dfi measures the dynamic resilience of a single residue to perturbations that occurred in the rest of the protein structure and identifies sites contributing the most to functionally critical dynamics. Analysis of dfi profiles of over a thousand positions harboring variation revealed that amino acid residues at interfaces have lower average dfi (31%) than those present at non-interfaces (50%), which means that protein interfaces have less dynamic flexibility. Interestingly, interface sites with disease-associated nsSNVs have significantly lower average dfi (23%) as compared to those of neutral nsSNVs (42%), which directly relates structural dynamics to functional importance. We found that less conserved interface positions show much lower dfi for disease nsSNVs as compared to neutral nsSNVs. In this case, dfi is better as compared to the accessible surface area metric, which is based on the static protein structure. Overall, our proteome wide conformational dynamic analysis indicates that certain interface sites play a critical role in functionally related dynamics (i.e., those with low dfi values), therefore mutations at those sites are more likely to be associated with disease. PMID- 25546382 TI - What drives quality of life in patients with sporadic vestibular schwannoma? AB - OBJECTIVES/HYPOTHESIS: To investigate the influence of posttreatment audiovestibular symptoms, facial neuropathy, and headache on long-term quality-of life outcomes in patients with sporadic vestibular schwannoma (VS) utilizing the Short Form 36 (SF-36) Health Survey and the Penn Acoustic Neuroma Quality of Life (PANQOL) scale. STUDY DESIGN: Cross-sectional observation study. METHODS: Patients with sporadic small- or medium-sized VS (< 3.0 cm) who were evaluated between 1998 and 2008 at two independent tertiary academic referral centers were surveyed. Multivariable associations with the PANQOL total score and the SF-36 physical and mental component scores evaluated using regression analysis. RESULTS: A total of 538 surveyed patients returned a completed questionnaire, providing a response rate of 79%. Two hundred forty-seven (46%) patients underwent stereotactic radiosurgery, 143 (27%) microsurgery, and 148 (28%) observation. Multivariable regression analysis revealed that ongoing dizziness was associated with the greatest reduction in PANQOL total score, followed by headache. After adjusting for all examined features, ongoing dizziness and ongoing headache were the only two variables that were associated with both the SF-36 physical and mental component scores. Patient sex and treatment modality did not significantly influence PANQOL or SF-36 scores. CONCLUSIONS: Ongoing dizziness and headache are the strongest predictors of long-term quality-of-life reduction in patients with sporadic VS, while the impact of hearing loss, facial nerve function, and tinnitus are less by comparison. This information may be valuable for patient counseling, refinement of VS quality-of-life assessment instruments, and determining high-yield targets for therapy in efforts to further improve patient outcomes. PMID- 25546383 TI - Forkhead box protein O3 transcription factor negatively regulates autophagy in human cancer cells by inhibiting forkhead box protein O1 expression and cytosolic accumulation. AB - FoxO proteins are important regulators in cellular metabolism and are recognized to be nodes in multiple signaling pathways, most notably those involving PI3K/AKT and mTOR. FoxO proteins primarily function as transcription factors, but recent study suggests that cytosolic FoxO1 participates in the regulation of autophagy. In the current study, we find that cytosolic FoxO1 indeed stimulates cellular autophagy in multiple cancer cell lines, and that it regulates not only basal autophagy but also that induced by rapamycin and that in response to nutrient deprivation. These findings illustrate the importance of FoxO1 in cell metabolism regulation independent of its transcription factor function. In contrast to FoxO1, we find the closely related FoxO3a is a negative regulator of autophagy in multiple cancer cell lines, a previously unrecognized function for this protein, different from its function in benign fibroblast and muscle cells. The induction of autophagy by the knockdown of FoxO3a was found not to be mediated through the suppression of mTORC1 signaling; rather, the regulatory role of FoxO3a on autophagy was determined to be through its ability to transcriptionally suppress FoxO1. This complicated interplay of FoxO1 and FoxO3a suggests a complex checks- and balances-relationship between FoxO3a and FoxO1 in regulating autophagy and cell metabolism. PMID- 25546384 TI - Formins: linking cytoskeleton and endomembranes in plant cells. AB - The cytoskeleton plays a central part in spatial organization of the plant cytoplasm, including the endomebrane system. However, the mechanisms involved are so far only partially understood. Formins (FH2 proteins), a family of evolutionarily conserved proteins sharing the FH2 domain whose dimer can nucleate actin, mediate the co-ordination between actin and microtubule cytoskeletons in multiple eukaryotic lineages including plants. Moreover, some plant formins contain transmembrane domains and participate in anchoring cytoskeletal structures to the plasmalemma, and possibly to other membranes. Direct or indirect membrane association is well documented even for some fungal and metazoan formins lacking membrane insertion motifs, and FH2 proteins have been shown to associate with endomembranes and modulate their dynamics in both fungi and metazoans. Here we summarize the available evidence suggesting that formins participate in membrane trafficking and endomembrane, especially ER, organization also in plants. We propose that, despite some methodological pitfalls inherent to in vivo studies based on (over)expression of truncated and/or tagged proteins, formins are beginning to emerge as candidates for the so far somewhat elusive link between the plant cytoskeleton and the endomembrane system. PMID- 25546385 TI - Plasma levels of dimethylarginines in preterm very low birth weight neonates: its relation with perinatal factors and short-term outcome. AB - Endogenously produced inhibitors of nitric oxide (NO) synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various disease states characterized by reduced NO availability. We investigated the association between plasma levels of ADMA, symmetric dimethylarginine (SDMA), L-arginine, and citrulline and perinatal factors and outcome in 130 preterm (gestational age <= 30 weeks) very low birth weight (VLBW, < 1500 g) infants. Plasma samples were collected 6-12 h after birth. We did not find significant correlations between ADMA, SDMA, L-arginine, and citrulline levels and gestational age or birth weight. However, the arginine:ADMA ratio (AAR, a better indicator of NO availability than either arginine or ADMA separately) was positively correlated with gestational age. ADMA and arginine levels were not significantly different between males and females but males showed a negative correlation between ADMA levels and gestational age. Perinatal factors such as preeclampsia, chrorioamnionitis, prolonged rupture of membranes, or form of delivery did not significantly alter dimethylarginine levels or AAR. In contrast, the AAR was significantly reduced in the infants with respiratory distress, mechanical ventilation, and systemic hypotension Therefore, our data suggest that altered NO availability may play a role in the respiratory and cardiovascular adaptation in preterm VLBW infants. PMID- 25546386 TI - The role of autophagy as a mechanism of toxicity induced by multi-walled carbon nanotubes in human lung cells. AB - Carbon nanotubes (CNTs) are promising nanomaterials having unique physical and chemical properties, with applications in a variety of fields. In this review, we briefly summarize the intrinsic properties of highly purified multi-walled CNTs (MWCNTs, HTT2800) and their potential hazardous effects on intracellular and extracellular pathways, which alter cellular signaling and impact major cell functions such as differentiation, reactive oxygen species (ROS) production, apoptosis, and autophagy. A recent study suggested that the induction of autophagy by CNTs causes nanotoxicity. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with exposure to CNTs. Although autophagy is considered as a cytoprotective process, it is often observed in association with cell death, and the relationship between autophagy and cell death remains unclear. Our recent study suggests that the levels of autophagy-related genes (LC3B) and autophagosome formation are clearly up-regulated, along with an increase in numbers of autophagosome vacuoles. This review highlights the importance of autophagy as an emerging mechanism of CNT toxicity. PMID- 25546387 TI - The regulation of nitric oxide synthase isoform expression in mouse and human fallopian tubes: potential insights for ectopic pregnancy. AB - Nitric oxide (NO) is highly unstable and has a half-life of seconds in buffer solutions. It is synthesized by NO-synthase (NOS), which has been found to exist in the following three isoforms: neuro nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS). NOS activity is localized in the reproductive tracts of many species, although direct evidence for NOS isoforms in the Fallopian tubes of mice is still lacking. In the present study, we investigated the expression and regulation of NOS isoforms in the mouse and human Fallopian tubes during the estrous and menstrual cycles, respectively. We also measured isoform expression in humans with ectopic pregnancy and in mice treated with lipopolysaccharide (LPS). Our results confirmed the presence of different NOS isoforms in the mouse and human Fallopian tubes during different stages of the estrous and menstrual cycles and showed that iNOS expression increased in the Fallopian tubes of women with ectopic pregnancy and in LPS-treated mice. Elevated iNOS activity might influence ovulation, cilia beats, contractility, and embryo transportation in such a manner as to increase the risk of ectopic pregnancy. This study has provided morphological and molecular evidence that NOS isoforms are present and active in the human and mouse Fallopian tubes and suggests that iNOS might play an important role in both the reproductive cycle and infection-induced ectopic pregnancies. PMID- 25546388 TI - Exposure to non-extreme solar UV daylight: spectral characterization, effects on skin and photoprotection. AB - The link between chronic sun exposure of human skin and harmful clinical consequences such as photo-aging and skin cancers is now indisputable. These effects are mostly due to ultraviolet (UV) rays (UVA, 320-400 nm and UVB, 280-320 nm). The UVA/UVB ratio can vary with latitude, season, hour, meteorology and ozone layer, leading to different exposure conditions. Zenithal sun exposure (for example on a beach around noon under a clear sky) can rapidly induce visible and well-characterized clinical consequences such as sunburn, predominantly induced by UVB. However, a limited part of the global population is exposed daily to such intense irradiance and until recently little attention has been paid to solar exposure that does not induce any short term clinical impact. This paper will review different studies on non-extreme daily UV exposures with: (1) the characterization and the definition of the standard UV daylight and its simulation in the laboratory; (2) description of the biological and clinical effects of such UV exposure in an in vitro reconstructed human skin model and in human skin in vivo, emphasizing the contribution of UVA rays and (3) analysis of photoprotection approaches dedicated to prevent the harmful impact of such UV exposure. PMID- 25546389 TI - Transfer RNA methyltransferases from Thermoplasma acidophilum, a thermoacidophilic archaeon. AB - We investigated tRNA methyltransferase activities in crude cell extracts from the thermoacidophilic archaeon Thermoplasma acidophilum. We analyzed the modified nucleosides in native initiator and elongator tRNAMet, predicted the candidate genes for the tRNA methyltransferases on the basis of the tRNAMet and tRNALeu sequences, and characterized Trm5, Trm1 and Trm56 by purifying recombinant proteins. We found that the Ta0997, Ta0931, and Ta0836 genes of T. acidophilum encode Trm1, Trm56 and Trm5, respectively. Initiator tRNAMet from T. acidophilum strain HO-62 contained G+, m1I, and m22G, which were not reported previously in this tRNA, and the m2G26 and m22G26 were formed by Trm1. In the case of elongator tRNAMet, our analysis showed that the previously unidentified G modification at position 26 was a mixture of m2G and m22G, and that they were also generated by Trm1. Furthermore, purified Trm1 and Trm56 could methylate the precursor of elongator tRNAMet, which has an intron at the canonical position. However, the speed of methyl-transfer by Trm56 to the precursor RNA was considerably slower than that to the mature transcript, which suggests that Trm56 acts mainly on the transcript after the intron has been removed. Moreover, cellular arrangements of the tRNA methyltransferases in T. acidophilum are discussed. PMID- 25546391 TI - The ubiquitin E3 ligase NOSIP modulates protein phosphatase 2A activity in craniofacial development. AB - Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans. PMID- 25546393 TI - Optimization and determination of polycyclic aromatic hydrocarbons in biochar based fertilizers. AB - The agronomic benefit of biochar has attracted widespread attention to biochar based fertilizers. However, the inevitable presence of polycyclic aromatic hydrocarbons in biochar is a matter of concern because of the health and ecological risks of these compounds. The strong adsorption of polycyclic aromatic hydrocarbons to biochar complicates their analysis and extraction from biochar based fertilizers. In this study, we optimized and validated a method for determining the 16 priority polycyclic aromatic hydrocarbons in biochar-based fertilizers. Results showed that accelerated solvent extraction exhibited high extraction efficiency. Based on a Box-Behnken design with a triplicate central point, accelerated solvent extraction was used under the following optimal operational conditions: extraction temperature of 78 degrees C, extraction time of 17 min, and two static cycles. The optimized method was validated by assessing the linearity of analysis, limit of detection, limit of quantification, recovery, and application to real samples. The results showed that the 16 polycyclic aromatic hydrocarbons exhibited good linearity, with a correlation coefficient of 0.996. The limits of detection varied between 0.001 (phenanthrene) and 0.021 mg/g (benzo[ghi]perylene), and the limits of quantification varied between 0.004 (phenanthrene) and 0.069 mg/g (benzo[ghi]perylene). The relative recoveries of the 16 polycyclic aromatic hydrocarbons were 70.26-102.99%. PMID- 25546390 TI - Transmembrane signal transduction in oocyte maturation and fertilization: focusing on Xenopus laevis as a model animal. AB - Fertilization is a cell biological phenomenon of crucial importance for the birth of new life in a variety of multicellular and sexual reproduction species such as algae, animal and plants. Fertilization involves a sequence of events, in which the female gamete "egg" and the male gamete "spermatozoon (sperm)" develop, acquire their functions, meet and fuse with each other, to initiate embryonic and zygotic development. Here, it will be briefly reviewed how oocyte cytoplasmic components are orchestrated to undergo hormone-induced oocyte maturation and sperm-induced activation of development. I then review how sperm-egg membrane interaction/fusion and activation of development in the fertilized egg are accomplished and regulated through egg coat- or egg plasma membrane-associated components, highlighting recent findings and future directions in the studies using Xenopus laevis as a model experimental animal. PMID- 25546392 TI - Nanomiemgel--a novel drug delivery system for topical application--in vitro and in vivo evaluation. AB - AIM: The objective of this study was to formulate and evaluate a unique matrix mixture (nanomiemgel) of nanomicelle and nanoemulsion containing aceclofenac and capsaicin using in vitro and in vivo analyses and to compare it to a marketed formulation (Aceproxyvon). METHODS: Nanomicelles were prepared using Vitamin E TPGS by solvent evaporation method and nanoemulsion was prepared by high-pressure homogenization method. In vitro drug release and human skin permeation studies were performed and analyzed using HPLC. The efficiency of nanomiemgel as a delivery system was investigated using an imiquimod-induced psoriatic like plaque model developed in C57BL/6 mice. RESULTS: Atomic Force Microscopy images of the samples exhibited a globular morphology with an average diameter of 200, 250 and 220 nm for NMI, NEM and NMG, respectively. Nanomiemgel demonstrated a controlled release drug pattern and induced 2.02 and 1.97-fold more permeation of aceclofenac and capsaicin, respectively than Aceproxyvon through dermatomed human skin. Nanomiemgel also showed 2.94 and 2.09-fold greater Cmax of aceclofenac and capsaicin, respectively than Aceproxyvon in skin microdialysis study in rats. The PASI score, ear thickness and spleen weight of the imiquimod-induced psoriatic like plaque model were significantly (p<0.05) reduced in NMG treated mice compared to free drug, NEM, NMI & Aceproxyvon. CONCLUSION: Using a new combination of two different drug delivery systems (NEM+NMI), the absorption of the combined system (NMG) was found to be better than either of the individual drug delivery systems due to the utilization of the maximum possible paths of absorption available for that particular drug. PMID- 25546394 TI - Fetal-onset IPEX: report of two families and review of literature. AB - Early-life autoimmunity is an IPEX characteristic, however intrauterine forms had not yet been described. Here, two unrelated families with clear evidence of fetal onset IPEX are reported. One had 5 miscarriages of males in two generations, and a newborn presenting type-1 diabetes mellitus immediately after birth, diarrhea, thrombocytopenia, eczematous dermatitis, eosinophilia, high IgE levels and autoantibodies to pancreatic islet antigens at 4-days-old. Maternal serology was negative. He presented a FOXP3 mutation, c.1189C>T, p.Arg397Trp, previously described only in another family with IPEX at birth. The second family had several miscarriages of males in three consecutive generations and a novel FOXP3 c.319_320delTC mutation was observed in two miscarried monochorionic twin male fetuses. These twins died at 21weeks of gestation due to hydrops, and CD3+ infiltrating lymphocytes were found in their pancreas. We demonstrate that: i) IPEX may develop in fetal life; and ii) c.1189C>T and c.319_320delTC mutations are associated with early-onset phenotype. PMID- 25546396 TI - Expanding what is known of the anatomy of the spinal accessory nerve. AB - The spinal accessory nerve (SAN) is classically considered a motor nerve innervating the sternocleidomastoid and trapezius muscles. Its anatomical relevance derives from the high prevalence of lesions following head and neck surgeries. As expected, trapezius weakness and atrophy are the most common findings; however, it is also commonly accompanied by pain and other sensory deficits that have no clear explanation, suggesting other functions. We have recently seen two patients presenting with an unrecognized sign, that is, subclavicular/pectoral asymmetry secondary to the SAN lesion. Retrospectively, we reviewed other patients with similar findings in our case series and in the literature. We discuss the anatomical connections of the SAN with the superficial cervical plexus and propose an explanation for this finding. Of the 41 patients in our series, we identified this sign in all who had preoperative photographs. New insights on the anatomy and connections of the SAN may account for the diversity of symptoms and signs presented following an operative intervention as well as the variability of its severity. PMID- 25546397 TI - Wild Morchella conica Pers. from different origins: a comparative study of nutritional and bioactive properties. AB - BACKGROUND: Morchella conica Pers. is a species of fungus that belongs to the Morchellaceae family and was studied in order to obtain more information about this species, by comparing Portuguese and Serbian wild samples. Free sugars, fatty acids, tocopherols, organic and phenolic acids were analysed by chromatographic techniques. M. conica methanolic extracts were tested regarding antioxidant and antimicrobial properties. The absence of hepatotoxicity was confirmed in porcine liver primary cells. RESULTS: The nutrition value varied between the two samples and the Serbian one gave the highest energy contribution and content in sugars, polyunsaturated fatty acids and phenolic compounds, while the Portuguese sample was richer in saturated and monounsaturated fatty acids, tocopherols and organic acids. In general, the Portuguese sample revealed the highest antioxidant potential (except for lipid peroxidation inhibition), while the Serbian one displayed higher antimicrobial activity. None of the samples revealed toxicity towards liver cells. CONCLUSION: The present study provides new data concerning chemical characterization and bioactivity of Morchella conica Pers. PMID- 25546398 TI - Involvement of purinergic system in the release of cytokines by macrophages exposed to glioma-conditioned medium. AB - Macrophages are involved in cancer progression. M1 macrophages have an antitumor effect, whereas M2 phenotype are associated with tumor growth. The progression of gliomas involves the participation of an inflammatory microenvironment. Adenosine triphosphate (ATP) can act as pro-inflammatory signal, whereas adenosine has opposite properties. The biological effects of extracellular nucleotides/nucleosides mediated by purinergic receptors are controlled by ectonucleotidases. In the present work, we evaluated whether glioma-conditioned medium (GL-CM) modulates macrophage differentiation and the participation of ATP and adenosine in the release of pro-and anti-inflammatory cytokines by these cells. The results show that macrophages exposed to GL-CM were modulated to an M2 like phenotype. HPLC analysis of GL-CM demonstrated the presence of significant amounts of ATP and its metabolites. Macrophages exposed to GL-CM presented decreased ATP and AMP hydrolysis and increased IL-10 and MCP-1 secretion, effects that were diminished by P1 or P2 antagonists. GL-CM did not alter the release of IL-6 by macrophages, although treatment with ATP promoted an increase in the release of IL-6, which was prevented by a P2X7 antagonist. In summary, we found that A2A and P2X7 activation is necessary for IL-10, MCP-1, and IL-6 release by macrophages exposed to GL-CM, which, in turn, modulates the macrophages to M2 phenotype. The present study establishes a relationship between M2-like polarization, cytokine release and purinergic receptor activation in macrophages exposed to GL-CM. Therefore, the data presented herein contributes to advancing in the field of cancer-related inflammation and point specific purinergic receptors as targets for modulation of the phenotype of glioma-associated macrophages. PMID- 25546399 TI - Delivery of paclitaxel using PEGylated graphene oxide as a nanocarrier. AB - Paclitaxel (PTX) is an extensively used potent chemotherapy drug; however, low water solubility, poor bioavailability, and emergence of drug resistance in patients limited its biological application. In this report, we proposed a new drug delivery system for cancer therapy based on graphene oxide (GO), a novel 2D nanomaterial obtained from the oxidation of natural graphite, to improve the utilization rate of PTX. PTX was first connected to biocompatible 6-armed poly(ethylene glycol), followed by covalent introduction into the surface of GO sheets via a facile amidation process under mild conditions, affording the drug delivery system, GO-PEG-PTX (size 50-200 nm). GO-PEG nanosized carrier could quickly enter into human lung cancer A549 and human breast cancer MCF-7 cells verified by inverted fluorescence microscope using fluorescein isothiocyanate as probe. This nanocarrier was nontoxic to A549 and MCF-7 cells without linking with PTX. Nevertheless, GO-PEG-PTX showed remarkably high cytotoxicity to A549 and MCF 7 cells in a broad range of concentration of PTX and time compared to free PTX. This kind of nanoscale drug delivery system based on PEGylated GO may find widespread application in biomedicine. PMID- 25546401 TI - Synthesis and Structure-Activity Relationships of Triazaspirodecanone Derivatives as Nociceptin/Orphanin FQ Receptor Ligands. AB - Several spiroxatrine derivatives were synthesized and evaluated as potential NOP receptor ligands. Structural modifications of the 1,4-benzodioxane moiety of spiroxatrine have been the focus of this research project. The structure-activity relationships that emerged indicate that the presence of an H-bond donor group (hydroxyl group) is more favorable for NOP activity when it is positioned alpha with respect to the CH2 linked to the 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one portion. Moreover, cis diastereoisomers of the hydroxyl derivatives4 and 22 show a moderately higher degree of stereoselectivity than trans isomers. In particular, the spiropiperidine derivative cis-4 has submicromolar agonistic activity, and it will be the reference compound for the design and synthesis of new NOP agonists. PMID- 25546395 TI - HLA-DRB1454 and predictors of new-onset asthma in HIV-infected Thai children. PMID- 25546400 TI - Detection and evolutionary analysis of picobirnaviruses in treated wastewater. AB - Wastewater contains numerous viruses. In this study, picobirnaviruses (PBVs) were detected in the stream of a wastewater treatment plant in Changsha, Hunan province, China, and evolutionary analysis of the isolated PBVs was performed. The phylogenetic tree revealed that the PBVs were highly divergent and could be classified into six distinct groups according to their hosts. Among these groups, pairwise comparison of the six groups revealed that the nucleotide distance of group 4 (bootstrap value = 0.92; nucleotide identity = 94%) was the largest. Thus, group 4 might represent a new division of PBVs. Comprehensive analysis of the obtained PBV sequences to investigate their evolutionary history and phylodynamics revealed that group 5 (PBVs from monkey) exhibited maximum polymorphism (K = 30.582, S = 74, eta = 98, Pa = 47) and lowest nucleotide substitutions per site per year (6.54E-3 subs per site per year), except group 4. Maximum clade credibility tree indicated that group 5 appeared earlier than the other groups. In conclusion, this study detected PBVs in treated wastewater in China, and identified a new PBV group. Furthermore, among these PBVs, group 5 was found to survive longer and present a balance between PBVs and their monkey host. PMID- 25546402 TI - Type 2 wide-field amacrine cells in TH::GFP mice show a homogenous synapse distribution and contact small ganglion cells. AB - In vertebrate retinas, wide-field amacrine cells represent a diverse class of interneurons, important for the extraction of selective features, like motion or objects, from the visual scene. Most types of wide-field amacrine cells lack dedicated output processes, whereas some types spatially segregate outputs from inputs. In the tyrosine hydroxylase (TH)::green fluorescent protein (GFP) mouse line, two types of GFP-expressing wide-field amacrine cells have been described: dopaminergic type 1 and gamma-aminobutyric acid-ergic type 2 cells (TH2). TH2 cells possess short and long radial processes stratifying in the middle of the inner plexiform layer, where they collect excitatory and inhibitory inputs from bipolar cells and other amacrine cells, respectively. Although it was shown that these inputs lead to ON-OFF light responses, their spatial distribution along TH2 cell processes is unknown. Also, the postsynaptic targets of TH2 cells have not been identified so far. Here, we analysed the synapse distribution of these cells in TH::GFP mice and show that they form a weakly coupled network. Electrical synapses (made of connexin36) and chemical (excitatory and inhibitory) synapses are uniformly distributed along TH2 dendrites, independent of dendrite length or distance from soma. Moreover, we reveal that TH2 cells contact at least two types of small ganglion cells; one of them is the W3 cell, a ganglion cell sensitive to object motion. Contacts were often associated with markers of inhibitory synapses. Thus, TH2 wide-field amacrine cells likely provide postsynaptic inhibition to W3 ganglion cells and may contribute to object-motion detection in the mouse retina. PMID- 25546403 TI - Diagnostic potential of 1-step nucleic acid amplification assay in patients with head and neck squamous cell carcinoma based on CK19 expression in a primary lesion. AB - BACKGROUND: The purpose of this study was to investigate the effects of CK19 expression in the primary lesions of head and neck squamous cell carcinoma on the diagnosis of the cervical lymph node (CLN) metastasis using the 1-step nucleic acid amplification assay. METHODS: Primary lesions and 54 CLNs were resected from 21 patients with head and neck squamous cell carcinoma between 2009 and 2011. Each CLN was tested by the 1-step nucleic acid amplification assay, and the CK19 mRNA copy number obtained was compared to the corresponding histopathological results. RESULTS: In the primary lesion CK19-positive group, the sensitivity and specificity of the 1-step nucleic acid amplification assay against hematoxylin eosin staining were 86% and 100%, respectively. The p value by Fisher's exact test was < .0001, indicating statistical significance. CONCLUSION: These results suggest that 1-step nucleic acid amplification offers similar diagnostic potential to that of histopathological diagnosis of CLN biopsy in patients with a CK19-positive primary lesion. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E239 E245, 2016. PMID- 25546406 TI - Bone microarchitecture at muscle attachment sites: The relationship between macroscopic scores of entheses and their cortical and trabecular microstructural design. AB - The studies of entheses in bioarchaeology attempted to reconstruct the habitual physical activities of past populations. However, the studies of microarchitecture of the underlying bone are still lacking despite well-known potential of bone internal microarchitecture to reflect mechanical loading. It is unknown whether different morphological expressions of entheseal changes (ECs) correlate with the microstructural characteristics of the underlining bone. This study analyzed bone microstructural characteristics at the entheses. Our focus was on examining the possible successive nature of the three-stage scale of entheseal macroscopic changes by comparing EC scores with the microarchitectural features at the attachment sites. The study was based on the hypothesis that mechanical loading influences the microarchitecture of the bone at the attachment site. The bone samples were taken from 24 adult male skeletons from medieval cemeteries in Serbia, with different macroscopic expression score of EC. We evaluated the macroscopic and microscopic appearance of four entheses of the lower limbs (origin of the soleus muscle and the insertions of the adductor magnus, gluteus maximus, and iliopsoas muscles). The specimens were scanned using microcomputed tomography (Scanco uCT 40). Our data showed a lack of consistent correlation between stages of the macroscopic scoring systems with microarchitecture at the entheses, only cortical thickness was significantly different between EC stages. Analyzing relationship between trabecular and cortical bone microstructure we found correlations between cortical and trabecular variables only in Stage C. Results of our study suggest that macroscopic EC might not represent distinct successive phases in bone adaptation to mechanical loading. PMID- 25546404 TI - Subclassification of newly diagnosed glioblastomas through an immunohistochemical approach. AB - Molecular signatures in Glioblastoma (GBM) have been described that correlate with clinical outcome and response to therapy. The Proneural (PN) and Mesenchymal (MES) signatures have been identified most consistently, but others including Classical (CLAS) have also been reported. The molecular signatures have been detected by array techniques at RNA and DNA level, but these methods are costly and cannot take into account individual contributions of different cells within a tumor. Therefore, the aim of this study was to investigate whether subclasses of newly diagnosed GBMs could be assessed and assigned by application of standard pathology laboratory procedures. 123 newly diagnosed GBMs were analyzed for the tumor cell expression of 23 pre-identified proteins and EGFR amplification, together allowing for the subclassification of 65% of the tumors. Immunohistochemistry (IHC)-based profiling was found to be analogous to transcription-based profiling using a 9-gene transcriptional signature for PN and MES subclasses. Based on these data a novel, minimal IHC-based scheme for subclass assignment for GBMs is proposed. Positive staining for IDH1R132H can be used for PN subclass assignment, high EGFR expression for the CLAS subtype and a combined high expression of PTEN, VIM and/or YKL40 for the MES subclass. The application of the proposed scheme was evaluated in an independent tumor set, which resulted in similar subclass assignment rates as those observed in the training set. The IHC-based subclassification scheme proposed in this study therefore could provide very useful in future studies for stratification of individual patient samples. PMID- 25546405 TI - Identification of S100A9 as biomarker of responsiveness to the methotrexate/etanercept combination in rheumatoid arthritis using a proteomic approach. AB - OBJECTIVES: One way to optimize the drug prescription in rheumatoid arthritis (RA) is to identify predictive biomarkers of drug responsiveness. Here, we investigated the potential "theranostic" value of proteins of the S100 family by monitoring levels of both S100A8 and S100A9 in blood samples from RA patients. DESIGN: For proteomic analysis, peripheral blood mononuclear cells (PBMC) and serum samples were collected in patients prior to initiation of the methotrexate/etanercept (MTX/ETA) combination. Firstly, relative mass spectrometry (MS) quantification focusing on S100A8 and S100A9 proteins was carried out from PBMCs samples to identify potential biomarkers. The same approach was also performed from serum samples from responder (R) and non responder (NR) patients. Finally, to confirm these results, an absolute quantification of S100A8, S100A9 proteins and calprotectin (heterodimer of S100A8/S100A9) was carried out on the serum samples using ELISA. RESULTS: MS analyses revealed that both S100A8 and S100A9 proteins were significantly accumulated in PBMC from responders. In contrast to PBMC, only the S100A9 protein was significantly overexpressed in the serum of R patients. Absolute quantification by ELISA confirmed this result and pointed out a similar expression level of S100A8 protein and calprotectin in sera from both R and NR groups. Thus, the S100A9 protein revealed to be predictive of MTX/ETA responsiveness, contrarily to parameters of inflammation and auto-antibodies which did not allow significant discrimination. CONCLUSION: This is the first report of an overexpression of S100A9 protein in both PBMCs and serum of patients with subsequent response to the MTX/ETA combination. This protein thus represents an interesting biomarker candidate of therapeutic response in RA. PMID- 25546407 TI - Defining uremic arterial functional abnormalities in patients recently started on haemodialysis: combined in vivo and ex vivo assessment. AB - Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05-0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 um. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 um of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P = 0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury. PMID- 25546408 TI - A mesoporous catalytic membrane architecture for lithium-oxygen battery systems. AB - Controlling the mesoscale geometric configuration of catalysts on the oxygen electrode is an effective strategy to achieve high reversibility and efficiency in Li-O2 batteries. Here we introduce a new Li-O2 cell architecture that employs a catalytic polymer-based membrane between the oxygen electrode and the separator. The catalytic membrane was prepared by immobilization of Pd nanoparticles on a polyacrylonitrile (PAN) nanofiber membrane and is adjacent to a carbon nanotube electrode loaded with Ru nanoparticles. During oxide product formation, the insulating PAN polymer scaffold restricts direct electron transfer to the Pd catalyst particles and prevents the direct blockage of Pd catalytic sites. The modified Li-O2 battery with a catalytic membrane showed a stable cyclability for 60 cycles with a capacity of 1000 mAh/g and a reduced degree of polarization (~ 0.3 V) compared to cells without a catalytic membrane. We demonstrate the effects of a catalytic membrane on the reaction characteristics associated with morphological and structural features of the discharge products via detailed ex situ characterization. PMID- 25546410 TI - Judgments of Meaning in Life, Religious Beliefs, and the Experience of Cognitive (Dis)Fluency. AB - The primary aim of the current studies was to test whether religiousness interacted with self-reported levels of meaning in life (MIL) to predict the ease or difficulty in judging one's MIL, the search for meaning itself, and religious doubt. Undergraduate students in Study 1 (N = 111) and adult participants recruited online in Study 2 (N = 206) completed measures of religious beliefs, MIL, cognitive fluency related to MIL, and related variables. Study 3 merged these data sets. In Study 4 (N = 255), online participants completed measures of religious beliefs, cognitive fluency related to religious beliefs, and MIL. Studies 1 and 2 showed that highly religious people with lower MIL reported greater difficulty making their MIL judgments than other people. Study 3 showed that they were also more likely to search for MIL and that disfluency mediated this effect. Study 4 demonstrated that they also reported more difficult judgments of religious beliefs and more religious doubts than their religious peers with high MIL. The current studies demonstrate that the experience of ease or difficulty associated with MIL judgments represents an important yet largely unexamined aspect of MIL. Our findings have implications for understanding the cognitive mechanisms underlying responses to meaning threats. PMID- 25546409 TI - Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes. AB - BACKGROUND: Intratumoral heterogeneity may help drive resistance to targeted therapies in cancer. In breast cancer, the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of breast cancer by whole genome next generation sequencing (NGS) of a primary breast tumor, a matched locally-involved axillary lymph node and healthy normal DNA from blood. METHODS: Whole genome NGS was performed on 12 ug (range 11.1-13.3 ug) of DNA isolated from fresh-frozen primary breast tumor, axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with tumor metastasis. RESULTS: Whole genome sequencing revealed overlapping variants between the tumor and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, TGIF2 and CCNB2, which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in PDS5B, which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from tumor to node, including SNVs in TP53 and ARAP3, which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferation and can segregate breast cancers by outcome. CONCLUSION: This case study provides preliminary evidence that primary tumor and early nodal metastasis have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of patient samples. PMID- 25546411 TI - Angiopoietin-1 protects the endothelial cells against advanced glycation end product injury by strengthening cell junctions and inhibiting cell apoptosis. AB - Endothelial dysfunction is a major characteristic of diabetic vasculopathy. Protection of the vascular endothelium is an essential aspect of preventing and treating diabetic vascular complications. Although Angiopoietin-1 (Ang-1) is an important endothelial-specific protective factor, whether Ang-1 protects vascular cells undergoing advanced glycation end product (AGE) injury has not been investigated. The aim of the present study was to determine the potential effects of Ang-1 on endothelial cells after exposure to AGE. We show here that Ang-1 prevented AGE-induced vascular leakage by enhancing the adherens junctions between endothelial cells, and this process was mediated by the phosphorylation and membrane localization of VE-cadherin. Furthermore, Ang-1 also protected endothelial cells from AGE-induced death by regulating phosphatidylinositol 3 kinase (PI3K)/Akt-dependent Bad phosphorylation. Our findings suggest that the novel protective mechanisms of Ang-1 on endothelium are achieved by strengthening endothelial cell junctions and reducing endothelial cell death after AGE injury. PMID- 25546414 TI - Biochemical markers, liver biopsy, or magnetic resonance elastography to detect or exclude advanced fibrosis in patients with nonalcoholic fatty liver disease. PMID- 25546412 TI - Golgi defects enhance APP amyloidogenic processing in Alzheimer's disease. AB - Increased amyloid beta (Abeta) production by sequential cleavage of the amyloid precursor protein (APP) by the beta- and gamma-secretases contributes to the etiological basis of Alzheimer's disease (AD). This process requires APP and the secretases to be in the same subcellular compartments, such as the endosomes. Since all membrane organelles in the endomembrane system are kinetically and functionally linked, any defects in the trafficking and sorting machinery would be expected to change the functional properties of the whole system. The Golgi is a primary organelle for protein trafficking, sorting and modifications, and Golgi defects have been reported in AD. Here we hypothesize that Golgi fragmentation in AD accelerates APP trafficking and Abeta production. Furthermore, Golgi defects may perturb the proper trafficking and processing of many essential neuronal proteins, resulting in compromised neuronal function. Therefore, molecular tools that can restore Golgi structure and function could prove useful as potential drugs for AD treatment. PMID- 25546413 TI - Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism. AB - Caloric restriction has consistently been shown to extend life span and ameliorate aging-related diseases. These effects may be due to diet-induced reactive oxygen species acting to up-regulate sirtuins and related protective pathways, which research suggests may be partially inhibited by dietary anti oxidant supplementation. Because caloric restriction is not sustainable long term for most humans, we investigated an alternative dietary approach, intermittent fasting (IF), which is proposed to act on similar biological pathways. We hypothesized that a modified IF diet, where participants maintain overall energy balance by alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal), would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by anti-oxidant supplementation. To assess the tolerability of the diet and to explore effects on biological mechanisms related to aging and metabolism, we recruited a cohort of 24 healthy individuals in a double-crossover, double blinded, randomized clinical trial. Study participants underwent two 3-week treatment periods-IF and IF with anti-oxidant (vitamins C and E) supplementation. We found strict adherence to study-provided diets and that participants found the diet tolerable, with no adverse clinical findings or weight change. We detected a marginal increase (2.7%) in SIRT3 expression due to the IF diet, but no change in expression of other genes or oxidative stress markers analyzed. We also found that IF decreased plasma insulin levels (1.01 MUU/mL). Although our study suggests that the IF dieting paradigm is acceptable in healthy individuals, additional research is needed to further assess the potential benefits and risks. PMID- 25546415 TI - Immunomodulation by the Pseudomonas syringae HopZ type III effector family in Arabidopsis. AB - Pseudomonas syringae employs a type III secretion system to inject 20-30 different type III effector (T3SE) proteins into plant host cells. A major role of T3SEs is to suppress plant immune responses and promote bacterial infection. The YopJ/HopZ acetyltransferases are a superfamily of T3SEs found in both plant and animal pathogenic bacteria. In P. syringae, this superfamily includes the evolutionarily diverse HopZ1, HopZ2 and HopZ3 alleles. To investigate the roles of the HopZ family in immunomodulation, we generated dexamethasone-inducible T3SE transgenic lines of Arabidopsis for HopZ family members and characterized them for immune suppression phenotypes. We show that all of the HopZ family members can actively suppress various facets of Arabidopsis immunity in a catalytic residue-dependent manner. HopZ family members can differentially suppress the activation of mitogen-activated protein (MAP) kinase cascades or the production of reactive oxygen species, whereas all members can promote the growth of non virulent P. syringae. Localization studies show that four of the HopZ family members containing predicted myristoylation sites are localized to the vicinity of the plasma membrane while HopZ3 which lacks the myristoylation site is at least partially nuclear localized, suggesting diversification of immunosuppressive mechanisms. Overall, we demonstrate that despite significant evolutionary diversification, all HopZ family members can suppress immunity in Arabidopsis. PMID- 25546416 TI - Experiences, feelings and thoughts of women undergoing second trimester medical termination of pregnancy. AB - MAIN OBJECTIVE: The objective of this study was to explore women's expectations and experiences of undergoing second trimester abortion. METHODS: This is a cross sectional study using a screening questionnaire and semi-structured interviews for data collection. Thirty-one women filled out the questionnaire and 23 of them were later interviewed. The questionnaires were analyzed by descriptive statistics. The interviews were recorded, transcribed verbatim and analyzed with qualitative content analysis. MOST IMPORTANT FINDINGS: Indications for the abortion were fetal malformation or unintended pregnancy. The women expressed similar feelings and these were irrespective for the reason for having an abortion. Both physical and mental pain was experienced during the abortion process and described by the women. Taking the mifepristone-pill was experienced as especially emotionally difficult for many participants. Professional support from the staff together with support from the partner, a friend or relative helped in transforming the worries related to something unknown to feelings of coping with a new and hard experience. Prior to the abortion most women stated that they did not want to view the fetus but women who chose to view the fetus described this as a way of confronting the reality and an opportunity to say farewell to the pregnancy/fetus. The analysis of the interview transcripts revealed five themes mirroring the women's experiences, thoughts and feelings related to the abortion. CONCLUSIONS: The decision to undergo second trimester abortion sometimes exposes women to strong and conflicting emotions which are irrespective for the reason for having an abortion. Despite this women do not regret their decision to terminate the pregnancy. This analysis shows that their rational thinking outweighs their emotionally difficult feelings. It is important for the attending staff to be responsive to the needs of each individual woman whatever the indication is for the abortion. PMID- 25546417 TI - Gene conversion between cationic trypsinogen (PRSS1) and the pseudogene trypsinogen 6 (PRSS3P2) in patients with chronic pancreatitis. AB - Mutations of the human cationic trypsinogen gene (PRSS1) are frequently found in association with hereditary pancreatitis. The most frequent variants p.N29I and p.R122H are recognized as disease-causing mutations. Three pseudogene paralogs in the human trypsinogen family, including trypsinogen 6 (PRSS3P2), carry sequence variations in exon 3 that mimic the p.R122H mutation. In routine genetic testing of patients with chronic pancreatitis, we identified in two unrelated individuals similar gene conversion events of 24-71 nucleotides length between exon 3 of the PRSS1 (acceptor) and PRSS3P2 (donor) genes. The converted allele resulted in three nonsynonymous alterations c.343T>A (p.S115T), c.347G>C (p.R116P), and c.365_366delinsAT (p.R122H). Functional analysis of the conversion triple mutant revealed markedly increased autoactivation resulting in high and sustained trypsin activity in the presence of chymotrypsin C. This activation phenotype was identical to that of the p.R122H mutant. In addition, cellular secretion of the triple mutant from transfected HEK 293T cells was increased about twofold and this effect was attributable to mutation p.R116P. Our observations confirm and extend the notion that recombination events between members of the trypsinogen family can generate high-risk PRSS1 alleles. The pathogenic phenotype of the novel conversion is explained by a unique combination of increased trypsinogen activation and secretion. PMID- 25546418 TI - Characterization of the murine myeloid precursor cell line MuMac-E8. AB - Starting point for the present work was the assumption that the cell line MuMac E8 represents a murine cell population with stem cell properties. Preliminary studies already pointed to the expression of stem-cell associated markers and a self-regenerative potential of the cells. The cell line MuMac-E8 should be examined for their differential stage within stem cell hierarchy. MuMac-E8 cells were derived from a chimeric mouse model of arthritis. It could be shown that MuMac-E8 cells express mRNA of some genes associated with pluripotent stem cells (Nanog, Nucleostemin), of genes for hematopoietic markers (EPCR, Sca-1, CD11b, CD45), for the mesenchymal marker CD105 and of genes for the neural markers Pax-6 and Ezrin. In methylcellulose and May-Grunwald-Giemsa staining, hematopoietic colonies were obtained but the hematopoietic system of lethally irradiated mice could not be rescued. Osteogenic differentiation was not detectable. Thus, it became evident that MuMac-E8 represents not a stem cell line. However, MuMac-E8 cells expressed several myeloid surface markers (i.e. CD11b, F4/80, CD14, CD64), showed phagocytosis and is capable of producing nitric oxide. Thus, this cell line seems to be arrested an advanced stage of myeloid differentiation. Adherence data measured by impedance-based real-time cell analysis together with cell morphology data suggested that MuMac-E8 represents a new macrophage precursor cell line exhibiting weak adherence. This cell line is suitable as an in-vitro model for testing of macrophage functions. Moreover, it might be also useful for differentiation or reprogramming studies. PMID- 25546419 TI - Directional secretory response of double stranded RNA-induced thymic stromal lymphopoetin (TSLP) and CCL11/eotaxin-1 in human asthmatic airways. AB - BACKGROUND: Thymic stromal lymphoproetin (TSLP) is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state. METHODS: Primary human bronchial epithelial cells (HBEC) from control (n = 3) and asthmatic (n = 3) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC) from normal (n = 3) and asthmatic (n = 3) donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20) vs. non asthmatic uninfected controls (n = 20). Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-alpha and CXCL8 were determined with a multiplex magnetic bead assay. RESULTS: Our data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure induces unidirectional (apical) secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3) Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1. CONCLUSIONS: There are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral induced exacerbations. PMID- 25546422 TI - Giant onychomatricoma in third toe: exceptional condition with surgical resolution. PMID- 25546421 TI - An A1-A1 mutant with improved binding and inhibition of beta2GPI/antibody complexes in antiphospholipid syndrome. AB - beta2 glycoprotein I (beta2GPI) is the most common antigen for autoimmune antibodies in antiphospholipid syndrome (APS). Thrombosis is a clinical feature of APS. We created a molecule (A1-A1) that consists of two identical beta2GPI binding modules from ApoE receptor 2 (ApoER2). A1-A1 binds to beta2GPI/antibody complexes, preventing their association with ApoER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1ND) with improved affinity for beta2GPI. mA1-A1ND inhibits the binding of beta2GPI to cardiolipin in the presence of anti-beta2GPI antibodies, and inhibits the binding to phospholipids in plasma samples of APS patients, affecting the clotting time. Reduction of the clotting time demonstrates the presence of soluble beta2GPI/antibody complexes in patients' plasma. These complexes either already exist in patients' plasma or form rapidly in the proximity to phospholipids. All members of the low-density lipoprotein receptor family bind beta2GPI. Modeling studies of A1 in a complex with domain V of beta2GPI (beta2GPI-DV) revealed two possible modes of interaction of a ligand binding module from lipoprotein receptors with beta2GPI-DV. In both orientations, the ligand-binding module interferes with binding of beta2GPI to anionic phospholipids; however, it interacts with two different but overlapping sets of lysine residues in beta2GPI-DV, depending on the orientation. PMID- 25546420 TI - MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide. AB - BACKGROUND: Monoclonal antibodies (mAbs) which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied. OBJECTIVES: To assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women. DESIGN: A randomized, double blind, placebo-controlled phase 1 trial. METHODS: Twenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL) or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose. RESULTS: After adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours). In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR) between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious. CONCLUSIONS: Vaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems. TRIAL REGISTRATION: ISRCTN 64808733 UK CRN Portfolio 6470. PMID- 25546423 TI - iRhom2 mutation leads to aberrant hair follicle differentiation in mice. AB - iRhom1 and iRhom2 are inactive homologues of rhomboid intramembrane serine proteases lacking essential catalytic residues, which are necessary for the maturation of TNFalpha-converting enzyme (TACE). In addition, iRhoms regulate epidermal growth factor family secretion. The functional significance of iRhom2 during mammalian development is largely unclear. We have identified a spontaneous single gene deletion mutation of iRhom2 in Uncv mice. The iRhom2Uncv/Uncv mice exhibit hairless phenotype in a BALB/c genetic background. In this study, we observed dysplasia hair follicles in iRhom2Uncv/Uncv mice from postnatal day 3. Further examination found decreased hair matrix proliferation and aberrant hair shaft and inner root sheath differentiation in iRhom2Uncv/Uncv mutant hair follicles. iRhom2 is required for the maturation of TACE. Our data demonstrate that iRhom2Uncv cannot induce the maturation of TACE in vitro and the level of mature TACE is also significantly reduced in the skin of iRhom2Uncv/Uncv mice. The activation of Notch1, a substrate of TACE, is disturbed, associated with dramatically down-regulation of Lef1 in iRhom2Uncv/Uncv hair follicle matrix. This study identifies iRhom2 as a novel regulator of hair shaft and inner root sheath differentiation. PMID- 25546427 TI - Epidemiological cut-off values for Flavobacterium psychrophilum MIC data generated by a standard test protocol. AB - Epidemiological cut-off values were developed for application to antibiotic susceptibility data for Flavobacterium psychrophilum generated by standard CLSI test protocols. The MIC values for ten antibiotic agents against Flavobacterium psychrophilum were determined in two laboratories. For five antibiotics, the data sets were of sufficient quality and quantity to allow the setting of valid epidemiological cut-off values. For these agents, the cut-off values, calculated by the application of the statistically based normalized resistance interpretation method, were <=16 mg L(-1) for erythromycin, <=2 mg L(-1) for florfenicol, <=0.025 mg L(-1) for oxolinic acid (OXO), <=0.125 mg L(-1) for oxytetracycline and <=20 (1/19) mg L(-1) for trimethoprim/sulphamethoxazole. For ampicillin and amoxicillin, the majority of putative wild-type observations were 'off scale', and therefore, statistically valid cut-off values could not be calculated. For ormetoprim/sulphadimethoxine, the data were excessively diverse and a valid cut-off could not be determined. For flumequine, the putative wild type data were extremely skewed, and for enrofloxacin, there was inadequate separation in the MIC values for putative wild-type and non-wild-type strains. It is argued that the adoption of OXO as a class representative for the quinolone group would be a valid method of determining susceptibilities to these agents. PMID- 25546424 TI - Bovine FcRn-mediated human immunoglobulin G transfer across the milk-blood barrier in transgenic mice. AB - Maternal-fetal IgGs transport occurs either prenatally or postnatally, which confers the newborns with passive immunity before their own immune system has matured. However, little is known about the mechanisms of postnatal IgGs passage in the mammary gland. To investigate how FcRn mediates the IgGs transport in the mammary gland, we first generated bFcRn and anti-HAV mAb transgenic mice, and then obtained HF transgenic mice expressing both transgenes by mating the above two strains. Transgene expression of bFcRn in the four lines was determined by qRT-PCR and western blot. We then localized the expression of bFcRn to the acinar epithelial cells in the mammary gland, and anti-HAV mAb was mainly detected in the acini with weak staining in the acinar epithelial cells. Human IgGs could be detected in both milk and serum of HF transgenic mice by western blot and ELISA. A significantly lower milk to serum ratio of human IgGs in HF mice compared with that of anti-HAV mAb mice, indicating that bFcRn could transport human IgGs across the milk-blood barrier from milk to serum during lactation in HF mice. While, there were no transport of murine IgGs, IgAs, or IgMs. These results provide understandings about the mechanisms of maternal-fetal immunity transfer in the mammary gland. PMID- 25546429 TI - Frontline leadership, innovation and best practice: 10 hot topics every critical care nurse should be aware of. PMID- 25546428 TI - Evaluation of novel large cut-off ultrafiltration membranes for adenovirus serotype 5 (Ad5) concentration. AB - The purification of virus particles and viral vectors for vaccine and gene therapy applications is gaining increasing importance in order to deliver a fast, efficient, and reliable production process. Ultrafiltration (UF) is a widely employed unit operation in bioprocessing and its use is present in several steps of the downstream purification train of biopharmaceuticals. However, to date few studies have thoroughly investigated the performance of several membrane materials and cut-offs for virus concentration/diafiltration. The present study aimed at developing a novel class of UF cassettes for virus concentration/diafiltration. A detailed study was conducted to evaluate the effects of (i) membrane materials, namely polyethersulfone (PES), regenerated cellulose (RC), and highly cross-linked RC (xRC), (ii) nominal cut-off, and (iii) UF device geometry at different production scales. The results indicate that the xRC cassettes with a cut-off of approximately 500 kDa are able to achieve a 10 fold concentration factor with 100% recovery of particles with a process time twice as fast as that of a commercially available hollow fiber. DNA and host cell protein clearances, as well as hydraulic permeability and fouling behavior, were also assessed. PMID- 25546430 TI - Oral Solid Dosage Form Disintegration Testing - The Forgotten Test. AB - Since its inception in the 1930s, disintegration testing has become an important quality control (QC) test in pharmaceutical industry, and disintegration test procedures for various dosage forms have been described by the different pharmacopoeias, with harmonization among them still not quite complete. However, because of the fact that complete disintegration does not necessarily imply complete dissolution, much more research has been focused on dissolution rather than on disintegration testing. Nevertheless, owing to its simplicity, disintegration testing seems to be an attractive replacement to dissolution testing as recognized by the International Conference on Harmonization guidelines, in some cases. Therefore, with proper research being carried out to overcome the associated challenges, the full potential of disintegration testing could be tapped saving considerable efforts allocated to QC testing and quality assurance. PMID- 25546431 TI - Sentinel node biopsy and improved patient care. AB - Sentinel lymph node biopsy (SLNB) is based on the hypothesis that the sentinel lymph node (SLN) reflects the lymph-node status and a negative SLN might allow complete axillary lymph node dissection (ALND) to be avoided. Past and current sentinel lymph node clinical trials for breast carcinoma have addressed the prognostic and therapeutic benefits of this technique and as such, SLNB has become a standard of care for select breast cancer patients. This article reviews the history of SLNB as well as current guidelines and recent controversies. PMID- 25546432 TI - Platelet activation after presyncope by lower body negative pressure in humans. AB - Central hypovolemia elevates hemostatic activity which is essential for preventing exsanguination after trauma, but platelet activation to central hypovolemia has not been described. We hypothesized that central hypovolemia induced by lower body negative pressure (LBNP) activates platelets. Eight healthy subjects were exposed to progressive central hypovolemia by LBNP until presyncope. At baseline and 5 min after presyncope, hemostatic activity of venous blood was evaluated by flow cytometry, thrombelastography, and plasma markers of coagulation and fibrinolysis. Cell counts were also determined. Flow cytometry revealed that LBNP increased mean fluorescence intensity of PAC-1 by 1959+/-455 units (P<0.001) and percent of fluorescence-positive platelets by 27+/-18%-points (P = 0.013). Thrombelastography demonstrated that coagulation was accelerated (R time decreased by 0.8+/-0.4 min (P = 0.001)) and that clot lysis increased (LY60 by 6.0+/-5.8%-points (P = 0.034)). Plasma coagulation factor VIII and von Willebrand factor ristocetin cofactor activity increased (P = 0.011 and P = 0.024, respectively), demonstrating increased coagulation activity, while von Willebrand factor antigen was unchanged. Plasma protein C activity and tissue type plasminogen activator increased (P = 0.007 and P = 0.017, respectively), and D-dimer increased by 0.03+/-0.02 mg l(-1) (P = 0.031), demonstrating increased fibrinolytic activity. Plasma prothrombin time and activated partial thromboplastin time were unchanged. Platelet count increased by 15+/-13% (P = 0.014) and red blood cells by 9+/-4% (P = 0.002). In humans, LBNP-induced presyncope activates platelets, as evidenced by increased exposure of active glycoprotein IIb/IIIa, accelerates coagulation. LBNP activates fibrinolysis, similar to hemorrhage, but does not alter coagulation screening tests, such as prothrombin time and activated partial thromboplastin time. LBNP results in increased platelet counts, but also in hemoconcentration. PMID- 25546433 TI - Identification of SCAN domain zinc-finger gene ZNF449 as a novel factor of chondrogenesis. AB - Transcription factors SOX9, SOX5 and SOX6 are indispensable for generation and differentiation of chondrocytes. However, molecular mechanisms to induce the SOX genes are poorly understood. To address this issue, we previously determined the human embryonic enhancer of SOX6 by 5'RACE analysis, and identified the 46-bp core enhancer region (CES6). We initially performed yeast one-hybrid assay for screening other chondrogenic factors using CES6 as bait, and identified a zinc finger protein ZNF449. ZNF449 and Zfp449, a counterpart in mouse, transactivated enhancers or promoters of SOX6, SOX9 and COL2A1. Zfp449 was expressed in mesenchyme-derived tissues including cartilage, calvaria, muscle and tendon, as well as in other tissues including brain, lung and kidney. In limb cartilage of mouse embryo, Zfp449 protein was abundantly located in periarticular chondrocytes, and decreased in accordance with the differentiation. Zfp449 protein was also detected in articular cartilage of an adult mouse. During chondrogenic differentiation of human mesenchymal stem cells, ZNF449 was increased at an early stage, and its overexpression enhanced SOX9 and SOX6 only at the initial stage of the differentiation. We further generated Zfp449 knockout mice to examine the in vivo roles; however, no obvious abnormality was observed in skeletal development or articular cartilage homeostasis. ZNF449 may regulate chondrogenic differentiation from mesenchymal progenitor cells, although the underlying mechanisms are still unknown. PMID- 25546434 TI - The effects of intermittent fasting during the month of Ramadan in chronic haemodialysis patients in a tropical climate country. AB - BACKGROUND: Chronic kidney disease is an emerging problem in the majority Muslim countries. Despite the uncertainties of the risks involved, some Muslim patients undergoing chronic haemodialysis choose to observe intermittent fasting during the month of Ramadan. This study aims to investigate the effect of Ramadan fasting in haemodialysis patients residing in a tropical climate country. METHODS: This prospective cross sectional study recruited Muslim patients on regular haemodialysis from three haemodialysis centres in Kuala Lumpur from 15th July 2011 to 29th August 2011. Patients who fasted for any number of days were included (n = 35, 54% female, age 54+/-11 years). 89% of patients fasted for more than 15 days and 49% were diabetics. Dialysis parameters and blood samples were obtained one week prior to Ramadan and during the last week of Ramadan. The differences in dialysis parameters and biochemical values pre- and end-Ramadan were examined using paired t-test. RESULTS: Both pre- and post-dialysis weight were significantly decreased during Ramadan fasting compared to the month prior (p = <0.001). There was a significant decrease in the amount of ultrafiltration (p = 0.002). There were no significant differences in dry weight, inter-dialytic weight gain, mean urea reduction ratio or blood pressure measurements comparing pre- and end of Ramadan fasting. There was a significant increase in serum albumin level (p = 0.006) and decrease in serum phosphate level (p = 0.02) at the end of Ramadan. CONCLUSION: Ramadan fasting is associated with reduced weight, improved serum albumin and phosphate level in our population of haemodialysis patients. A larger multi-centre study will allow us to understand more about the effects of fasting in this population. PMID- 25546436 TI - Building disaster-resilient micro enterprises in the developing world. AB - Family-owned micro enterprises operating within the informal sector of most developing countries provide millions of citizens with a livelihood and are the economic backbone of many communities. Yet, the turbulence that emanates up or down respective supply chains following a disaster can cause these entities to fail. This study develops a model that recognises the relative weakness of micro enterprises to such disaster-related shocks. The model proposes that micro enterprises can moderate the effect of such shocks by creating resilience through cognitive preparation, continuous learning, and the generation of various forms of social capital (cognitive, relational, and structural). The propositions for the model are established through an extensive literature review, coupled with examples drawn from the documents of humanitarian agencies performing disaster relief work in India. This model also serves as a preliminary basis with which to derive metrics to set benchmarks or to assess the viability of a micro enterprise's ability to survive disaster-related shocks. PMID- 25546435 TI - The human pancreas proteome defined by transcriptomics and antibody-based profiling. AB - The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects. PMID- 25546438 TI - Ciliary neurotrophic factor promotes the activation of corneal epithelial stem/progenitor cells and accelerates corneal epithelial wound healing. AB - Ciliary neurotrophic factor (CNTF), a well-known neuroprotective cytokine, has been found to play an important role in neurogenesis and functional regulations of neural stem cells. As one of the most innervated tissue, however, the role of CNTF in cornea epithelium remains unclear. This study was to explore the roles and mechanisms of CNTF in the activation of corneal epithelial stem/progenitor cells and wound healing of both normal and diabetic mouse corneal epithelium. In mice subjecting to mechanical removal of corneal epithelium, the corneal epithelial stem/progenitor cell activation and wound healing were promoted by exogenous CNTF application, while delayed by CNTF neutralizing antibody. In cultured corneal epithelial stem/progenitor cells, CNTF enhanced the colony forming efficiency, stimulated the mitogenic proliferation, and upregulated the expression levels of corneal epithelial stem/progenitor cell-associated transcription factors. Furthermore, the promotion of CNTF on the corneal epithelial stem/progenitor cell activation and wound healing was mediated by the activation of STAT3. Moreover, in diabetic mice, the content of CNTF in corneal epithelium decreased significantly when compared with that of normal mice, and the supplement of CNTF promoted the diabetic corneal epithelial wound healing, accompanied with the advanced activation of corneal epithelial stem/progenitor cells and the regeneration of corneal nerve fibers. Thus, the capability of expanding corneal epithelial stem/progenitor cells and promoting corneal epithelial wound healing and nerve regeneration indicates the potential application of CNTF in ameliorating limbal stem cell deficiency and treating diabetic keratopathy. PMID- 25546437 TI - Conditional knockout of prolyl hydroxylase domain protein 2 attenuates high fat diet-induced cardiac dysfunction in mice. AB - Oxygen sensor prolyl hydroxylases (PHDs) play important roles in the regulation of HIF-alpha and cell metabolisms. This study was designed to investigate the direct role of PHD2 in high fat-diet (HFD)-induced cardiac dysfunction. In HFD fed mice, PHD2 expression was increased without significant changes in PHD1 and PHD3 levels in the heart. This was accompanied by a significant upregulation of myeloid differentiation factor 88 (MYD88) and NF-kappaB. To explore the role of PHD2 in HFD-induced cardiac dysfunction, PHD2 conditional knockout mice were fed a HFD for 16 weeks. Intriguingly, knockout of PHD2 significantly reduced MYD88 and NF-kappab expression in HFD mouse hearts. Moreover, knockout of PHD2 inhibited TNFalpha and ICAM-1 expression, and reduced cell apoptosis and macrophage infiltration in HFD mice. This was accompanied by a significant improvement of cardiac function. Most importantly, conditional knockout of PHD2 at late stage in HFD mice significantly improved glucose tolerance and reversed cardiac dysfunction. Our studies demonstrate that PHD2 activity is a critical contributor to the HFD-induced cardiac dysfunction. Inhibition of PHD2 attenuates HFD-induced cardiac dysfunction by a mechanism involving suppression of MYD88/NF kappab pathway and inflammation. PMID- 25546439 TI - Rapid oriented fibril formation of fish scale collagen facilitates early osteoblastic differentiation of human mesenchymal stem cells. AB - We studied the effect of fibril formation of fish scale collagen on the osteoblastic differentiation of human mesenchymal stem cells (hMSCs). We found that hMSCs adhered easily to tilapia scale collagen, which remarkably accelerated the early stage of osteoblastic differentiation in hMSCs during in vitro cell culture. Osteoblastic markers such as ALP activity, osteopontin, and bone morphogenetic protein 2 were markedly upregulated when the hMSCs were cultured on a tilapia collagen surface, especially in the early osteoblastic differentiation stage. We hypothesized that this phenomenon occurs due to specific fibril formation of tilapia collagen. Thus, we examined the time course of collagen fibril formation using high-speed atomic force microscopy. Moreover, to elucidate the effect of the orientation of fibril formation on the differentiation of hMSCs, we measured ALP activity of hMSCs cultured on two types of tilapia scale collagen membranes with different degrees of fibril formation. The ALP activity in hMSCs cultured on a fibrous collagen membrane was significantly higher than on a non-fibrous collagen membrane even before adding osteoblastic differentiation medium. These results showed that the degree of the fibril formation of tilapia collagen was essential for the osteoblastic differentiation of hMSCs. PMID- 25546440 TI - Where does chorea come from? cortical excitability findings challenge classic pathophysiological concepts. PMID- 25546441 TI - Evaluation of transmembrane helix predictions in 2014. AB - Experimental structure determination continues to be challenging for membrane proteins. Computational prediction methods are therefore needed and widely used to supplement experimental data. Here, we re-examined the state of the art in transmembrane helix prediction based on a nonredundant dataset with 190 high resolution structures. Analyzing 12 widely-used and well-known methods using a stringent performance measure, we largely confirmed the expected high level of performance. On the other hand, all methods performed worse for proteins that could not have been used for development. A few results stood out: First, all methods predicted proteins in eukaryotes better than those in bacteria. Second, methods worked less well for proteins with many transmembrane helices. Third, most methods correctly discriminated between soluble and transmembrane proteins. However, several older methods often mistook signal peptides for transmembrane helices. Some newer methods have overcome this shortcoming. In our hands, PolyPhobius and MEMSAT-SVM outperformed other methods. PMID- 25546442 TI - Gastric mesenchymal myofibroblasts maintain stem cell activity and proliferation of murine gastric epithelium in vitro. AB - Stem cells are influenced by a microenvironmental niche that includes mesenchymal cells. We established a novel long-term method for primary mouse glandular stomach culture with mesenchymal myofibroblasts to investigate gastric epithelial mesenchymal interactions. A gastric mesenchymal myofibroblast (GMF) cell line was established from mouse glandular stomach. Glandular stomach cells from neonatal mice and GMF cells were co-cultured in a collagen gel. Cultured stomach cells yielded expanding sphere-like structures. In the GMF co-culture system, the number and size of gastrospheres were increased compared with control cultures (P = 0.009 and 0.008, respectively). Immunohistochemistry showed cells positive for human gastric mucin, HIK1083, and chromogranin A, indicating differentiation into surface mucous cells, mucous neck cells, and enteroendocrine cells, respectively. RNA in situ hybridization for Lgr5 showed Lgr5(+) stem cells in the cultured gastrospheres. Lgr5(+) cells were observed persistently in the epithelium of gastrospheres in the GMF co-culture system for 2 months. GMFs allowed the cultured gastric epithelium to maintain active proliferation similar to that seen in vivo. Real-time quantitative RT-PCR showed that Gas1 expression was higher in GMFs (P = 0.0445), and Hoxc8, Notch1, and Sox10 expressions were higher in intestinal mesenchymal myofibroblasts (P = 0.0003, 0.0143, and 0.0488, respectively). We show the potential role of GMFs in sustaining Lgr5(+) stem cell activity and affecting normal gastric epithelial differentiation and proliferation. PMID- 25546443 TI - Intracerebral antioxidant ability of mature rats after neonatal hypoxic-ischemic brain injury estimated using the microdialysis-electron spin resonance method. AB - AIM: The intracerebral antioxidant ability of mature rats after neonatal hypoxic ischemic (HI) brain injury was estimated using the microdialysis-electron spin resonance method. MATERIAL AND METHODS: Seven-day-old Wistar rats were subjected to a modified Levine's procedure for producing HI brain injury. After HI insult, pups were returned and reared with their dams. Seven weeks after HI insult, their intracerebral antioxidant abilities were measured using the microdialysis electron spin resonance method after the intraperitoneal injection of 3 methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl. Ascorbic acid, L-cysteine, and glutathione (GSH) were also determined. The rats without HI insult were used as a control. RESULTS: The decay rate of 3-methoxycarbonyl-2,2,5,5 tetramethylpyrrolidine-1-oxyl in the non-ligated side of the cerebral hemisphere of the HI group was significantly larger than that of the control group. The amounts of ascorbic acid in the perfusate from the non-ligated side of the HI group were about four times larger than those of the control group. The amounts of L-cysteine and GSH of the HI group were about 10 times larger than those of the control group. CONCLUSIONS: The antioxidant ability in the non-ligated sides of the cerebral hemispheres of the mature rats 7 weeks after neonatal HI insult was higher than that of the control group. Higher amounts of ascorbic acid and GSH supported the higher antioxidant ability. The increase of the intracerebral antioxidant ability of the non-ligated side indicates the compensation of motor function for the lost side. The present results should offer important insights into the prognosis for hypoxic-ischemic encephalopathy. PMID- 25546444 TI - Dose-response of 1, 3, and 5 sets of resistance exercise on strength, local muscular endurance, and hypertrophy. AB - The study's purpose was to compare the response of performing 1, 3, and 5 sets on measures of performance and muscle hypertrophy. Forty-eight men, with no weight training experience, were randomly assigned to one of the 3 training groups, 1 SET, 3 SETS, 5 SETS, or control group. All training groups performed 3 resistance training sessions per week for 6 months. The 5 repetition maximum (RM) for all training groups increased in the bench press (BP), front lat pull down (LPD), shoulder press (SP), and leg press (LP) (p <= 0.05), with the 5 RM increases in the BP and LPD being significantly greater for 5 SETS compared with the other training groups (p <= 0.05). Bench press 20 RM in the 3-SET and 5-SET groups significantly increased with the increase being significantly greater than the 1 SET group and the 5-SET group increase being significantly greater than the 3-SET group (p <= 0.05). LP 20 RM increased in all training groups (p <= 0.05), with the 5-SETS group showing a significantly greater increase than the 1-SET group (p <= 0.05). The 3-SET and 5-SET groups significantly increased elbow flexor muscle thickness (MT) with the 5-SET increase being significantly greater than the other 2 training groups (p <= 0.05). The 5-SET group significantly increased elbow extensor MT with the increase being significantly greater than the other training groups (p <= 0.05). All training groups decreased percent body fat, increased fat free mass, and vertical jump ability (p <= 0.05), with no differences between groups. The results demonstrate a dose-response for the number of sets per exercise and a superiority of multiple sets compared with a single set per exercise for strength gains, muscle endurance, and upper arm muscle hypertrophy. PMID- 25546445 TI - The effect of on-hill active recovery performed between runs on blood lactate concentration and fatigue in alpine ski racers. AB - Alpine skiing is a high-intensity intermittent sport that results in lactate accumulation and muscle acidosis, which has been shown to contribute to peripheral neuromuscular fatigue. Active recovery influences the removal of lactate from the muscle and blood by maintaining blood flow to fatigued muscles and enhancing aerobic utilization of lactate by nonfatigued tissues. The purpose of this study was to investigate the effect of on-hill active recovery on blood lactate concentration in alpine skiers. Fourteen highly trained alpine skiers (7 women, 7 men) completed 8 training runs in a 45-gate slalom or a 25-gate giant slalom corridor at 2,600 m above sea level. Skiers were randomized to active (ACT) or static recovery (CON) performed at the top of each run. Blood lactate concentration and perceived fatigue were recorded at the top and bottom of each run. Performance was measured by time to complete each training run and rate of incomplete runs. A significant time (p < 0.01) and interaction (p = 0.001) effect was observed for blood lactate concentration measured at the top, with ACT being associated with significantly lower values. A significant time effect (p < 0.001) was observed for blood lactate concentration measured at the bottom. Training run completion time was longer (p <= 0.05), and higher rate of incomplete runs were observed in the CON group, despite no between-group differences in rating of perceived fatigue. On-hill active recovery performed between runs promotes blood lactate clearance in alpine skiers and is associated with delayed fatigue as indicated by faster training runs and fewer incomplete runs. PMID- 25546446 TI - Testing strength and power in soccer players: the application of conventional and traditional methods of assessment. AB - Soccer is a highly complex sport influenced by many physical, psychological, tactical, and technical factors. In terms of basic physical components, strength and power are considered requisites for many important actions such as tackling, jumping, and shooting. Hence, assessment of strength and power is commonly performed within a soccer club's test battery. The objective is to use valid, reliable, and sensitive measures that allow for trustworthy analysis of the physical characteristics of players. Before any credence can be placed in test results, test's validity, reliability, and sensitivity needs to be established. This will allow practitioners to make informed decisions about test selection. This review examines the reliability, validity, and sensitivity of different strength and power assessments in soccer. The suitability of conventional and functional tests is detailed and the strengths and weaknesses of isokinetic dynamometry, hand-held dynamometry (HHD), repetition maximum, and power testing are also addressed. Generally, the tests considered in this review provide moderate to high reliability in soccer players of different training level. Similarly, the consensus demonstrates test methods to be sensitive to training interventions. In comparison, test validity seems less established. Isokinetic dynamometry has often been recognized as a gold standard measure of testing strength. Other methods of assessment are emerging as viable options (e.g., HHD), likely due to functionality and suitability of testing. Given the demands within a soccer club setting, practitioners should endeavor to use testing procedures that are informative yet not time consuming or labor intensive. By providing this, practitioners may have the option to perform more regular monitoring throughout the season rather than a limited number of specific time periods. PMID- 25546447 TI - Changes in hip flexor passive compliance do not account for improvement in vertical jump performance after hip flexor static stretching. AB - To date, there is limited research investigating stretching of antagonist muscles and its effects on agonist muscle function. The purpose of this research was to investigate the effects of pre-static stretching (pre-SS) of the hip flexor musculature on passive hip extension range of motion (ROM) and vertical jump height. Fifteen subjects reported to the laboratory on 4 separate days (D1, D2, D3, and D4). D1 was for familiarization, while on D2 to D4, subjects randomly completed 1 of 3 intervention conditions; no stretch (CON), hip flexor stretch (HFS), or hip extensor stretch (HES). Subject's pre- and post-intervention hip extension ROM were measured before performing 3 sets of pre- and post-maximal counter-movement vertical jumps. Vertical jump height was normalized to baseline for data analysis. A repeated-measures ANOVA with post hoc paired sample t-tests revealed a significant increase in vertical jump height in the HFS condition (1.74% +/- 0.73; p <= 0.05) when compared with CON (-1.34% +/- 0.96) or HES ( 1.74% +/- 0.65) conditions. There was also a significant increase in hip extension ROM after the HFS stretching protocol (6.5 +/- 2.75%; p <= 0.05) when compared with the CON protocol (-1.73 +/- 3.26); however, no significant difference when compared with the HES protocol (1.84 +/- 2.79). A correlation analysis showed that the relative hip laxity of each subject had no effect on response to either condition nor did the magnitude of hip ROM change predict improvement in vertical jump. These results suggest that performing SS of the hip flexors may enhance vertical jump performance independent of changes in passive compliance of the hip flexor muscular tendon unit. PMID- 25546449 TI - Gluteus medius and scapula muscle activations in youth baseball pitchers. AB - The baseball pitching motion is a total kinetic chain activity that must efficiently use both the upper and lower extremity. Of particular importance is the scapular motion, which is critical for humeral positioning and proper alignment of shoulder musculature. It was hypothesized that scapular stability is enhanced by pelvic girdle stability. Therefore, it was the purpose of this study to determine the muscle activations of selected pelvic and scapular stabilizing muscles during a fastball pitch in youth baseball pitchers. Twenty youth baseball pitchers (age: 11.3 + 1.0 years; height: 152.4 + 9.0 cm; weight: 47.5 + 11.3 kg) were recorded throwing 4-seam fastballs for strikes. Data revealed moderate (20 39% maximum voluntary isometric contraction [MVIC]) to moderately strong (>40% MVIC) activation of the ipsilateral (throwing arm side) gluteus medius, upper trapezius, and serratus anterior throughout phases 2 (maximum shoulder external rotation to ball release) and 3 (ball release to maximum shoulder internal rotation). Moderately strong activation (>40% MVIC) of the upper trapezius and serratus anterior was noted during phases 2 and 3 of the pitching motion. Pearson's product-moment correlation revealed significant relationships between bilateral gluteus medius and the force couples about the scapula during all 3 phases of the pitching motion. The results of this study provide important data that improve the understanding of the muscular relationship between the pelvic and scapular stabilizers during the fastball pitch. Training and rehabilitation programs should consider focusing on lumbopelvic-hip and scapular muscle strengthening as well as coordinated strengthening of the pelvic and scapular stabilizers, in baseball pitchers. PMID- 25546450 TI - Specific Training Effects of Concurrent Aerobic and Strength Exercises Depend on Recovery Duration. AB - This study aimed to determine whether the duration (0, 6, or 24 hours) of recovery between strength and aerobic sequences influences the responses to a concurrent training program. Fifty-eight amateur rugby players were randomly assigned to control (CONT), concurrent training (C-0h, C-6h, or C-24h), or strength training (STR) groups during a 7-week training period. Two sessions of each quality were proposed each week with strength always performed before aerobic training. Neuromuscular and aerobic measurements were performed before and immediately after the overall training period. Data were assessed for practical significance using magnitude-based inference. Gains in maximal strength for bench press and half squat were lower in C-0h compared with that in C-6h, C 24h, and STR. The maximal voluntary contraction (MVC) during isokinetic knee extension at 60 degrees .s(-1) was likely higher for C-24h compared with C-0h. Changes in MVC at 180 degrees .s(-1) was likely higher in C-24h and STR than in C 0h and C-6h. Training-induced gains in isometric MVC for C-0h, C-6h, C-24h, and STR were unclear. V[Combining Dot Above]O2peak increased in C-0h, C-6h, and C 24h. Training-induced changes in V[Combining Dot Above]O2peak were higher in C 24h than in C-0h and C-6h. Our study emphasized that the interference on strength development depends on the recovery delay between the 2 sequences. Daily training without a recovery period between sessions (C-0h) and, to a lesser extent, training twice a day (C-6h), is not optimal for neuromuscular and aerobic improvements. Fitness coaches should avoid scheduling 2 contradictory qualities, with less than 6-hour recovery between them to obtain full adaptive responses to concurrent training. PMID- 25546451 TI - Differences in muscle mechanical properties between elite power and endurance athletes: a comparative study. AB - The aim of this study was to compare muscle mechanical properties (using tensiomyography-TMG) and jumping performance of endurance and power athletes and to quantify the associations between TMG parameters and jumping performance indices. Forty-one high-level track and field athletes from power (n = 22; mean +/- SD age, height, and weight were 27.2 +/- 3.6 years; 180.2 +/- 5.4 cm; and 79.4 +/- 8.6 kg, respectively) and endurance (endurance runners and triathletes; n = 19; mean +/- SD age, height, and weight were 27.1 +/- 6.9 years; 169.6 +/- 9.8 cm; 62.2 +/- 13.1 kg, respectively) specialties had the mechanical properties of their rectus femoris (RF) and biceps femoris (BF) assessed by TMG. Muscle displacement (Dm), contraction time (Tc), and delay time (Td) were retained for analyses. Furthermore, they performed squat jumps (SJs), countermovement jumps (CMJs), and drop jumps to assess reactive strength index (RSI), using a contact platform. Comparisons between groups were performed using differences based on magnitudes, and associations were quantified by the Spearman's rho correlation. Power athletes showed almost certain higher performance in all jumping performance indices when compared with endurance athletes (SJ = 44.9 +/- 4.1 vs. 30.7 +/- 6.8 cm; CMJ = 48.9 +/- 4.5 vs. 33.6 +/- 7.2 cm; RSI = 2.19 +/- 0.58 vs. 0.84 +/- 0.39, for power and endurance athletes, mean +/- SD, respectively; 00/00/100, almost certain, p <= 0.05), along with better contractile indices reflected by lower Dm, Tc, and Td (Tc BF = 14.3 +/- 2.3 vs. 19.4 +/- 3.3 milliseconds; Dm BF = 1.67 +/- 1.05 vs. 4.23 +/- 1.75 mm; Td BF = 16.8 +/- 1.6 vs. 19.6 +/- 1.3 milliseconds; Tc RF = 18.3 +/- 2.8 vs. 22.9 +/- 4.0 milliseconds; Dm RF = 4.98 +/- 3.71 vs. 8.88 +/- 3.45 mm; Td RF = 17.5 +/- 1.0 vs. 20.9 +/- 1.6 milliseconds, for power and endurance athletes, mean +/- SD, respectively; 00/00/100, almost certain, p <= 0.05). Moderate correlations (Spearman's rho between -0.61 and -0.72) were found between TMG and jumping performance. The power group presented better performance in vertical jumps, supporting the validity of these tests to distinguish between endurance and power athletes. Furthermore, TMG can discriminate the "athlete-type" using noninvasive indices moderately correlated with explosive lower-body performance. In summary, both vertical jump and TMG assessments could be useful in identifying and selecting young athletes. PMID- 25546453 TI - Intra-facility linkage of HIV-positive mothers and HIV-exposed babies into HIV chronic care: rural and urban experience in a resource limited setting. AB - INTRODUCTION: Linkage of HIV-infected pregnant women to HIV care remains critical for improvement of maternal and child outcomes through prevention of maternal-to child transmission of HIV (PMTCT) and subsequent chronic HIV care. This study determined proportions and factors associated with intra-facility linkage to HIV care and Early Infant Diagnosis care (EID) to inform strategic scale up of PMTCT programs. METHODS: A cross-sectional review of records was done at 2 urban and 3 rural public health care facilities supported by the Infectious Diseases Institute (IDI). HIV-infected pregnant mothers, identified through routine antenatal care (ANC) and HIV-exposed babies were evaluated for enrollment in HIV clinics by 6 weeks post-delivery. RESULTS: Overall, 1,025 HIV-infected pregnant mothers were identified during ANC between January and June, 2012; 267/1,025 (26%) in rural and 743/1,025 (74%) in urban facilities. Of these 375/1,025 (37%) were linked to HIV clinics [67/267(25%) rural and 308/758(41%) urban]. Of 636 HIV exposed babies, 193 (30%) were linked to EID. Linkage of mother-baby pairs to HIV chronic care and EID was 16% (101/636); 8/179 (4.5%)] in rural and 93/457(20.3%) in urban health facilities. Within rural facilities, ANC registration <28 weeks of-gestation was associated with mothers' linkage to HIV chronic care [AoR, 2.0 95% CI, 1.1-3.7, p = 0.019] and mothers' multi-parity was associated with baby's linkage to EID; AoR 4.4 (1.3-15.1), p = 0.023. Stigma, long distance to health facilities and vertical PMTCT services affected linkage in rural facilities, while peer mothers, infant feeding services, long patient queues and limited privacy hindered linkage to HIV care in urban settings. CONCLUSION: Post-natal linkage of HIV-infected mothers to chronic HIV care and HIV-exposed babies to EID programs was low. Barriers to linkage to HIV care vary in urban and rural settings. We recommend targeted interventions to rapidly improve linkage to antiretroviral therapy for elimination of MTCT. PMID- 25546455 TI - Properties of nucleic acid staining dyes used in gel electrophoresis. AB - Nucleic acid staining dyes are used for detecting nucleic acids in electrophoresis gels. Historically, the most common dye used for gel staining is ethidium bromide, however due to its toxicity and mutagenicity other dyes that are safer to the user and the environment are preferred. This Short Communication details the properties of dyes now available and their sensitivity for detection of DNA and their ability to permeate the cell membrane. It was found that GelRedTM was the most sensitive and safest dye to use with UV light excitation, and both GelGreenTM and DiamondTM Nucleic Acid Dye were sensitive and the safer dyes using blue light excitation. PMID- 25546454 TI - Down-regulation of KCC2 expression and phosphorylation in motoneurons, and increases the number of in primary afferent projections to motoneurons in mice with post-stroke spasticity. AB - Spasticity obstructs motor function recovery post-stroke, and has been reported to occur in spinal cord injury and electrophysiological studies. The purpose of the present study was to assess spinal cord circuit spasticity in post-stroke mice. At 3, 7, 21, and 42 d after photothrombotic ischemic cortical injury in C57BL/6J mice, we observed decreased rate-dependent depression (RDD) of the Hoffmann reflex (H reflex) in the affected forelimb of mice compared with the limbs of sham mice and the non-affected forelimb. This finding suggests a hyper excitable stretch reflex in the affected forelimb. We then performed immunohistochemical and western blot analyses to examine the expression of the potassium-chloride cotransporter 2 (KCC2) and phosphorylation of the KCC2 serine residue, 940 (S940), since this is the main chloride extruder that affects neuronal excitability. We also performed immunohistochemical analyses on the number of vesicular glutamate transporter 1 (vGluT1)-positive boutons to count the number of Ia afferent fibers that connect to motoneurons. Western bolts revealed that, compared with sham mice, experimental mice had significantly reduced KCC2 expression at 7 d post-stroke, and dephosphorylated S940 at 3 and 7 d post-stroke in motoneuron plasma membranes. We also observed a lower density of KCC2-positive areas in the plasma membrane of motoneurons at 3 and 7 d post stroke. However, western blot and immunohistochemical analyses revealed that there were no differences between groups 21 and 42 d post-stroke, respectively. In addition, at 7 and 42 d post-stroke, experimental mice exhibited a significant increase in vGluT1 boutons compared with sham mice. Our findings suggest that both the down-regulation of KCC2 and increases in Ia afferent fibers are involved in post-stroke spasticity. PMID- 25546456 TI - Clinical outcomes after bilevel positive airway pressure treatment for acute asthma exacerbations. PMID- 25546458 TI - Mass budget in two high altitude lakes reveals their role as atmospheric PCB sinks. AB - A mass budget of polychlorinated biphenyls (PCBs) was constructed for two altitude lakes located in the French Alps to (i) quantify inward and outward PCB flux over the entire year of 2012, (ii) hierarchize the dominant pathways of PCB transfers, and (iii) evaluate to what extent these pathways vary between both lakes. The annual PCB inputs were similar, and the glacial runoff and sediment-to water exchange were negligible sources of PCBs to the water column relative to atmospheric deposition. The annual inputs were primarily introduced by snow deposition and transferred into the lakes during the few weeks of spring thaw. While the dominant deposition pathways were similar, the main processes by which the water column lost pollutants differed between the two lakes. Despite these differences, the mass budget revealed that PCB inputs exceeded outputs for both studied lakes and that the lakes acted as atmospheric PCB sinks for the surrounding mountain environment. The differences in the PCB distribution between the key compartments (sediment and water column) are most likely due to differences in the lacustrine internal processes. PMID- 25546457 TI - The vitamin D receptor inhibits the respiratory chain, contributing to the metabolic switch that is essential for cancer cell proliferation. AB - We recently described the mitochondrial localization and import of the vitamin D receptor (VDR) in actively proliferating HaCaT cells for the first time, but its role in the organelle remains unknown. Many metabolic intermediates that support cell growth are provided by the mitochondria; consequently, the identification of proteins that regulate mitochondrial metabolic pathways is of great interest, and we sought to understand whether VDR may modulate these pathways. We genetically silenced VDR in HaCaT cells and studied the effects on cell growth, mitochondrial metabolism and biosynthetic pathways. VDR knockdown resulted in robust growth inhibition, with accumulation in the G0G1 phase of the cell cycle and decreased accumulation in the M phase. The effects of VDR silencing on proliferation were confirmed in several human cancer cell lines. Decreased VDR expression was consistently observed in two different models of cell differentiation. The impairment of silenced HaCaT cell growth was accompanied by sharp increases in the mitochondrial membrane potential, which sensitized the cells to oxidative stress. We found that transcription of the subunits II and IV of cytochrome c oxidase was significantly increased upon VDR silencing. Accordingly, treatment of HaCaT cells with vitamin D downregulated both subunits, suggesting that VDR may inhibit the respiratory chain and redirect TCA intermediates toward biosynthesis, thus contributing to the metabolic switch that is typical of cancer cells. In order to explore this hypothesis, we examined various acetyl-CoA-dependent biosynthetic pathways, such as the mevalonate pathway (measured as cholesterol biosynthesis and prenylation of small GTPases), and histone acetylation levels; all of these pathways were inhibited by VDR silencing. These data provide evidence of the role of VDR as a gatekeeper of mitochondrial respiratory chain activity and a facilitator of the diversion of acetyl-CoA from the energy producing TCA cycle toward biosynthetic pathways that are essential for cellular proliferation. PMID- 25546459 TI - Tracing endocrine disrupting chemicals in a coastal lagoon (Sacca di Goro, Italy): sediment contamination and bioaccumulation in Manila clams. AB - The Water Framework Directive, recently amended with new priority substances (2013/39/EU), is meant to regulate the health status of European aquatic environments, including transitional waters. Despite the ecological and economic importance of transitional water bodies and, in particular, of coastal lagoons, a relevant example of this type of environments, little is known about their contamination by priority substances, particularly by endocrine disrupting chemicals (EDCs). In this study, a wide array of priority substances, all with recognised disrupting properties, was investigated in the Sacca di Goro Lagoon (Adriatic Sea, Italy), which receives freshwater from the Po River after draining the most urbanised and industrialised Italian regions. Flame retardants, alkylphenols, bisphenol A, natural and synthetic steroids, personal care products and legacy pollutants were investigated both in sediments and in the clam Ruditapes philippinarum collected from three sites in the lagoon. Sediments showed that most of the chemicals analysed could reach the lagoon ecosystem but their concentrations were below existing quality guidelines. Clams essentially reflected this condition although some concern was raised by polybrominated diphenyl ethers (PBDEs): the limit for the sum of six congeners set for biota in the European Directive (2013/39/EU) to protect human health was exceeded 4-5 times. No significant biota-sediment accumulation factors (BSAFs) were calculated. Nonylphenol, tonalide, PBDE, polychlorinated biphenyls and bisphenol A were the most abundant chemicals in clam tissues. PMID- 25546460 TI - Sources and distribution of organic matter along the Ring of Cenotes, Yucatan, Mexico: sterol markers and statistical approaches. AB - The Yucatan Peninsula is a large low lying platform of limestone, dolomite and evaporite deposits, forming an extensive and mature karst aquifer with many sinkholes locally called cenotes. In Yucatan, the only source of drinking water is groundwater and its quality could be impaired by: (i) infiltration of contaminants and (ii) saltwater intrusion. To investigate the sources of organic matter in this aquifer, sediment samples (46) were collected from cenotes and analysed using gas chromatography-mass spectrometry. Sterol analysis, coupled with principal component analysis (PCA), allowed us to distinguish three sources of natural organic matter (e.g. marine, autotrophic and terrigenous) and to detect an anthropogenic input (e.g. fecal contamination). Good consistency was observed between the source assignment and the land use context (forest, agricultural, rural or urban areas) and the season, except for some of the samples where a direct correlation could not be made. The latter cases are most likely a result of the karstic character of the system. PMID- 25546461 TI - An omic approach for the identification of oil sands process-affected water compounds using multivariate statistical analysis of ultrahigh resolution mass spectrometry datasets. AB - Oil sands process-affected water (OSPW) is a major environmental issue due to its acute and chronic toxicity to aquatic life. Advanced oxidation processes are promising treatments to successfully degrade toxic OSPW compounds. This study applied high resolution mass spectrometry to detect over 1000 compounds in OSPW samples after treatments including general ozonation, and ozone with carbonate, tert-butyl-alcohol, carbonate/tert-butyl-alcohol, tetranitromethane, or iron. Hierarchal clustering analysis showed that samples clustered based on sampling time and principal component analysis corroborated these results while also providing information on significant markers responsible for the clustering. Some markers were uniquely present in certain treatment conditions, while others showed variable behaviors in two or more treatments due to the presence of scavengers/catalysts. This advanced approach to monitoring significant changes of markers by using multivariate analysis can be invaluable for future work on OSPW treatment by-products and their potential toxicity to receiving environment organisms. PMID- 25546462 TI - Repeated pig manure applications modify nitrate and chloride competition and fluxes in a Nitisol. AB - Solute transport was studied in a variable-charge soil (Nitisol) with two following pig manure applications. There were three identical soil columns (diameter=37.5 cm; soil depth=85 cm) equipped with TDR probes and tensiometers, one of which served as an untreated control. Dispersivities inferred using the CXTFIT 2.1 code presented inverse patterns with depth for nitrate and chloride breakthrough curves, while the normalized intensities had the same patterns with depth for both applications. For nitrates, the retardation factors steadily decreased with depth from 4.85 and 3.57 at 17 cm depth to 2.1 and 1.86 PV (pore volume) at 85 cm depth for each column, respectively. For chlorides, the retardation factor increased lineary with depth, from 1.05 at 17 cm depth to 1.76 and 1.86 PV at 85 cm depth. After the first application, the mean difference between nitrate and chloride retardation factors was 3.8 PV at 17 cm depth and it regularly decreased to 0.34 PV at 85 cm depth. For the second application, the mean difference was 2.52 PV at 17 cm depth and it regularly decreased to 0 PV at 85 cm depth. The kinetics of nitrate production by the pig manure nitrification process modified the pH, the ionic strength of the soil solution and then the anionic exchange capacity. This could explain the high nitrate retardation factors until 55 cm depth and the difference between nitrate and chloride retardation factors. The earlier chloride adsorption at anionic exchange sites, combined with a selectivity coefficient to the detriment of nitrates, counterbalanced the delay in nitrate production due to the kinetic mineralisation of pig manure. Nitrate fluxes then caught up with the chloride fluxes at the outlet. PMID- 25546463 TI - The influence of crowd density on the sound environment of commercial pedestrian streets. AB - Commercial pedestrian streets are very common in China and Europe, with many situated in historic or cultural centres. The environments of these streets are important, including their sound environments. The objective of this study is to explore the relationships between the crowd density and the sound environments of commercial pedestrian streets. On-site measurements were performed at the case study site in Harbin, China, and a questionnaire was administered. The sound pressure measurements showed that the crowd density has an insignificant effect on sound pressure below 0.05 persons/m2, whereas when the crowd density is greater than 0.05 persons/m2, the sound pressure increases with crowd density. The sound sources were analysed, showing that several typical sound sources, such as traffic noise, can be masked by the sounds resulting from dense crowds. The acoustic analysis showed that crowd densities outside the range of 0.10 to 0.25 persons/m2 exhibited lower acoustic comfort evaluation scores. In terms of audiovisual characteristics, the subjective loudness increases with greater crowd density, while the acoustic comfort decreases. The results for an indoor underground shopping street are also presented for comparison. PMID- 25546464 TI - Interspecific and geographical differences in anticoagulant rodenticide residues of predatory wildlife from the Mediterranean region of Spain. AB - We studied the prevalence of anticoagulant rodenticides (ARs) in the liver of 344 individuals representing 11 species of predatory wildlife that were found dead in the Mediterranean region of Spain (Catalonia and Majorca Island). Six different ARs (brodifacoum, bromadiolone, difenacoum, flocoumafen, difethialone, warfarin) were found in the liver of 216 (62.8%) animals and >1 AR co-occurred in 119 individuals (34.6%). The occurrence of ARs was positively correlated with the human population density. Catalonia and Majorca showed similar prevalence of AR detection (64.4 and 60.4%, respectively), but a higher prevalence was found in the resident population of Eurasian scops owl (Otus scops) from Majorca (57.7%) compared to the migratory population from Catalonia (14.3%). Birds of prey had lower levels of bromadiolone than hedgehogs, whereas no difference was found for other ARs. The risk of SGAR poisoning in wild predators in NE Spain is believed to be elevated, because 23.3% of the individuals exhibited hepatic concentration of ARs exceeding 200 ng/g. PMID- 25546465 TI - Multiple daily doses of acetyl-salicylic acid (ASA) overcome reduced platelet response to once-daily ASA after coronary artery bypass graft surgery: a pilot randomized controlled trial. AB - BACKGROUND: The efficacy of ASA for prevention of graft failure following CABG surgery may be limited by incomplete platelet inhibition due to increased post operative platelet turnover. OBJECTIVES: To determine whether acetyl-salicylic acid (ASA) 325 mg once-daily or 81 mg four-times daily overcomes the impaired response to ASA 81 mg once-daily in post-operative coronary artery bypass graft (CABG) patients. METHODS: We randomized 110 patients undergoing CABG surgery to either ASA 81 mg once-daily, 81 mg four times daily or 325 mg once-daily and compared their effects on serum thromboxane B2 (TXB2 ) suppression and arachidonate-induced platelet aggregation. RESULTS: One hundred patients were included in the final analysis. Platelet counts fell after surgery, reached a nadir on day 2, and then gradually increased. Although there was near complete suppression of TXB2 on the second or third post-operative day, TXB2 levels increased in parallel with the rise in platelet count on subsequent days. This increase was most marked in patients receiving ASA 81 mg once-daily and less evident in those receiving ASA four times daily. On post-operative day 4, (i) median TXB2 levels were lower with four times daily ASA than with either ASA 81 mg once-daily (1.1 ng/mL; Quartile(Q) Q1,Q3: 0.5, 2.4 and 13.3 ng/mL; Q1,Q3: 7.8, 30.8 ng/mL, respectively; P < 0.0001) or ASA 325 mg once-daily (3.4 ng/mL; Q1,Q3: 2.0, 8.2 ng/mL; P = 0.002), and (ii) ASA given four times daily was more effective than ASA 81 mg once-daily and 325 mg once-daily at suppressing platelet aggregation. CONCLUSIONS: Four times daily ASA is more effective than ASA 81 and 325 mg once-daily at suppressing serum TXB2 formation and platelet aggregation immediately following CABG surgery. PMID- 25546466 TI - A comparative population-based analysis of sinonasal diffuse large B-cell and extranodal NK/T-cell lymphomas. AB - OBJECTIVE/HYPOTHESIS: Diffuse large B-cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma (ENKTL) are aggressive tumors. ENTKL is very rare in the United States and often affects the nasal cavity and paranasal sinuses; DLBCL, although more common, rarely occurs in these locations. Our study aims to compare incidence and survival of these lymphomas in the sinonasal cavity. STUDY DESIGN: Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. METHODS: The SEER database was searched for patients diagnosed with sinonasal ENKTL and DLBCL between 1973 and 2011. Data analyzed included patient demographics, incidence, treatment modality, and survival. RESULTS: Three hundred and twenty-eight sinonasal ENKTL (SN-ENKTL) cases and 1,054 sinonasal DLBCL (SN-DLBCL) cases were identified. The mean ages at diagnosis for SN-ENKTL and SN-DLBCL were 51.7 and 67.8 years, respectively (P = 0.0001). Overall 1-, 5-, and 10-year disease specific survival (DSS) rates for SN-DLBCL were 85.5%, 63.5%, and 44.0%, compared to 66.4%, 30.9%, and 9.2% for SN-ENKTL, respectively (P < 0.0001). For patients matched for stage, age, and treatment modality, the 1-, 5-, and 10-year DSS for the SN-DLBCL group was 94.4%, 72.8%, and 46.8%, respectively, whereas the respective survival rates for the SN-ENKTL group were 77.6%, 38.4%, and 13.9%, respectively (P < 0.0001 at each time interval). CONCLUSIONS: To our knowledge, this study represents the only population-based comparison between SN-DLBCL and SN-ENKTL. SN-DLBCL has a better prognosis regardless of gender, stage, treatment modality, and age. LEVEL OF EVIDENCE: 2b. PMID- 25546467 TI - Noninvasive identification of two lesions with local repolarization changes using two dipoles in inverse solution simulation study. AB - BACKGROUND: The method for inverse localization and identification of two distinct simultaneous lesions with changed repolarization in the ventricular myocardium (two-vessel disease) is proposed and its robustness to errors in input data is tested in this simulation study. METHOD: The inverse solution was obtained from the difference between STT integral body surface potential map computed with repolarization changes and the STT integral map from normal activation. In a numerical model of ventricles 48 cases of two simultaneous lesions and 48 cases of a single lesion were modeled. The effect of the lesions was taken to be represented by two dipoles. The input data were disturbed by three types of added noise. Twenty three characteristics of every obtained inverse solution were defined and four of them were used as the features in discriminant analysis task distinguishing the correct inverse solutions identifying two lesions. RESULTS: The mean localization error for identified two lesions was 1.1+/-0.7cm. The sensitivity and specificity of quadratic discriminant analysis with cross-validation and feature selection was higher than 90%. CONCLUSIONS: The combination of the inverse solution with two dipoles and discriminant analysis allows the identification of two simultaneous lesions without a priori information about the number of lesions. PMID- 25546468 TI - A virtual reality based simulator for learning nasogastric tube placement. AB - Nasogastric tube (NGT) placement is a common clinical procedure where a plastic tube is inserted into the stomach through the nostril for feeding or drainage. However, the placement is a blind process in which the tube may be mistakenly inserted into other locations, leading to unexpected complications or fatal incidents. The placement techniques are conventionally acquired by practising on unrealistic rubber mannequins or on humans. In this paper, a virtual reality based training simulation system is proposed to facilitate the training of NGT placement. It focuses on the simulation of tube insertion and the rendering of the feedback forces with a haptic device. A hybrid force model is developed to compute the forces analytically or numerically under different conditions, including the situations when the patient is swallowing or when the tube is buckled at the nostril. To ensure real-time interactive simulations, an offline simulation approach is adopted to obtain the relationship between the insertion depth and insertion force using a non-linear finite element method. The offline dataset is then used to generate real-time feedback forces by interpolation. The virtual training process is logged quantitatively with metrics that can be used for assessing objective performance and tracking progress. The system has been evaluated by nursing professionals. They found that the haptic feeling produced by the simulated forces is similar to their experience during real NGT insertion. The proposed system provides a new educational tool to enhance conventional training in NGT placement. PMID- 25546469 TI - Changes in aerodynamics during vocal cord dysfunction. AB - BACKGROUND: Changes in laryngeal airflow dynamics during episodes of vocal cord dysfunction (VCD) have not been well described. Very little is known about how inspiratory airflow is impacted when the vocal cords transition from normal inhalation state to a paradoxical adducted state; and how much change in laryngeal airflow and resistance occur before symptoms of stridor and air hunger emerge. This study provides new insight on the effects of VCD on respiratory airflow using computational fluid dynamics (CFD) techniques. METHODS: Computed tomography images of a subject with normal vocal cords opening at the time of scanning were digitally modified to mimic an episode of VCD. To quantify and compare changes in inspiratory flow during VCD attack and normal inhalation, steady-state, laminar simulations were performed for three different breathing rates. RESULTS: Pressure-flow analysis during VCD revealed that increasing inspiratory effort is not as efficient as in normal inhalation. Airflow resistance at the epiglottis was higher in the normal state (0.04Pa.s/mL versus 0.02Pa.s/mL) than in VCD; while resistance at the glottis and trachea remained roughly the same (0.04Pa.s/mL) during normal inhalation, it escalated during VCD (0.11Pa.s/mL and 0.13Pa.s/mL at the glottis and trachea, respectively). Peak airflow velocity and vorticity occurred around the glottis during VCD, and at the epiglottis during normal inhalation. CONCLUSIONS: This pilot study demonstrates that attempting to force more inspired air will yield greater glottal resistance during VCD. Furthermore, there were evidence of abrupt laryngeal pressure gradient, chaotic airflow and high concentration of shear stresses in the glottal region. PMID- 25546470 TI - Effects of preharvest ultraviolet-C irradiation on fruit phytochemical profiles and antioxidant capacity in three strawberry (Fragaria * ananassa Duch.) cultivars. AB - BACKGROUND: Ultraviolet-C (UV-C) has proven effective in extending shelf-life, reducing disease incidence and increasing the levels of health-promoting compounds in several crops. While most studies were conducted at the postharvest stage, our study examined the effect of preharvest UV-C application in three strawberry cultivars (Fragaria * ananassa Duch. 'Albion', 'Charlotte' and 'Seascape'). UV-C treatment was applied from the onset of flowering until the fruits reached commercial maturity on plants grown for two consecutive seasons under greenhouse conditions. The phytochemical profiles and antioxidant capacity of the fruits were assessed at harvest. RESULTS: The ellagic acid and kaempferol 3-glucuronide contents were significantly increased only in fruits of the cultivar 'Albion' collected from UV-C-treated plants in season 1. UV-C did not consistently affect the other phenolic compounds that were measured. Based on the results of the ferric-reducing antioxidant power, oxygen radical absorbance capacity and total phenolic content assays, the antioxidant capacity of the three strawberry cultivars was not affected by UV-C. Season and cultivar had a decisive impact on these parameters. CONCLUSION: The effect of preharvest UV-C on the levels of bioactive compounds in strawberry fruits appears to be cultivar- dependent, with season or growing conditions having a significant impact. PMID- 25546472 TI - Short-term outcomes of combined implantation of diffractive multifocal intraocular lenses with different addition power. AB - PURPOSE: To compare short-term binocular visual function between patients implanted with diffractive multifocal intraocular lenses (MIOLs) of different near addition powers in each eye or the same MIOLs bilaterally. METHODS: Seventy patients scheduled for implantation of diffractive MIOLs were divided into two groups: (i) mix and match group, a MIOL with +3.0 dioptre (D) addition power implanted in the dominant eye (Alcon SN60D1) and a MIOL with +4.0D power implanted in the non-dominant eye (SN60D3) or (ii) same MIOL group, same MIOL (SN60D1) implanted bilaterally. At 3 months postoperatively, we examined binocular visual acuity (VA) at various distances, binocular contrast VA and that with a glare (glare VA), and near stereoacuity. RESULTS: Mean binocular uncorrected (UNVA) or corrected near VA (CNVA) at 0.3 m was significantly better in the mix and match group than in the same MIOL group (p <= 0.0066). Binocular uncorrected and distance-corrected VA at other distances was similar. Binocular UNVA of 0.8 or better was achieved in 77.1% of patients in the mix and match group and 45.7% in the same MIOL group (p = 0.0144). Binocular contrast and glare VA, and stereoacuity did not significantly differ between groups. Spectacle independence and patient satisfaction with near vision were significantly better in the mix and match group (p <= 0.0195). CONCLUSION: Mix and match implantation of diffractive MIOLs with different addition power provides a better binocular VA curve and spectacle independence than bilateral implantation of the same MIOLs, without compromising contrast sensitivity and stereopsis. PMID- 25546471 TI - Electroanatomic mapping guided cryoablation of Mahaim pathways in children with limited fluoroscopy exposure. AB - BACKGROUND: The presence of Mahaim accessory pathways (MAP) with anterograde decremental conduction is a disorder that leads to antidromic atrioventricular reentrant tachycardia. There are rare reports of cryoablation use in MAP. This study aims at sharing our experience with using cryoablation to treat MAP in children. METHODS: Electrophysiology study and catheter ablation were performed in 14 patients diagnosed with Mahaim tachycardia between January 2010 and December 2013. Cryoablation was used in nine of the cases. A three-dimensional navigation system with surface electrode patches (EnSite System, St. Jude Medical Inc., St. Paul, MN, USA) was used for all procedures. RESULTS: The patients (two girls and seven boys) had a median age of 11.5 years (8-18 years) and a median weight of 67 kg (31-80 kg). Mahaim conduction was localized in the right posterolateral (n = 4), right lateral region (n = 2), right posteroseptal (n = 1), right anterolateral (n = 1), and right anterior (n = 1). A pathway potential was noted in six of nine cases at the tricuspid annulus. Catheter choices and acute success rates were as follows: cryoablation in four (three of four successful), radiofrequency catheter ablation (RFA) and cryoablation in five (successful in four of five). No fluoroscopy was used in six of nine patients. The mean procedure duration was 249 +/- 90 minutes. No major complications were observed. The final long-term success rate for cryoablation was seven of nine (78%). CONCLUSIONS: Cryoablation can be used as a reliable and effective alternative to RFA in the treatment of Mahaim accessory conduction pathways in children. Prospective comparative studies are necessary in order to further evaluate the long-term efficacy of this method. PMID- 25546473 TI - Poly(L-lactic acid)-modified silica stationary phase for reversed-phase and hydrophilic interaction liquid chromatography. AB - Poly(L-lactic acid) is a linear aliphatic thermoplastic polyester that can be produced from renewable resources. A poly(L-lactic acid)-modified silica stationary phase was newly prepared by amide bond reaction between amino groups on aminopropyl silica and carboxylic acid groups at the end of the poly(L-lactic acid) chain. The poly(L-lactic acid)-silica column was characterized in reversed phase liquid chromatography and hydrophilic interaction liquid chromatography with the use of different mobile phase compositions. The poly(L-lactic acid) silica column was found to work in both modes, and the retention of test compounds depending on acetonitrile content exhibited "U-shaped" curves, which was an indicator of reversed-phase liquid chromatography/hydrophilic interaction liquid chromatography mixed-mode retention behavior. In addition, carbonyl groups included into the poly(L-lactic acid) backbone work as an electron-accepting group toward a polycyclic aromatic hydrocarbon and provide pi-pi interactions. PMID- 25546474 TI - Complete genome sequence analysis of Pseudomonas aeruginosa N002 reveals its genetic adaptation for crude oil degradation. AB - The present research work reports the whole genome sequence analysis of Pseudomonas aeruginosa strain N002 isolated from crude oil contaminated soil of Assam, India having high crude oil degradation ability. The whole genome of the strain N002 was sequenced by shotgun sequencing using Ion Torrent method and complete genome sequence analysis was done. It was found that the strain N002 revealed versatility for degradation, emulsification and metabolizing of crude oil. Analysis of cluster of orthologous group (COG) revealed that N002 has significantly higher gene abundance for cell motility, lipid transport and metabolism, intracellular trafficking, secretion and vesicular transport, secondary metabolite biosynthesis, transport and catabolism, signal transduction mechanism and transcription than average levels found in other genome sequences of the same bacterial species. However, lower gene abundance for carbohydrate transport and metabolism, replication, recombination and repair, translation, ribosomal structure, biogenesis was observed in N002 than average levels of other bacterial species. PMID- 25546476 TI - Kinetic oscillation stimulation as treatment of acute migraine: a randomized, controlled pilot study. AB - OBJECTIVE: To assess the relief of migraine pain, especially in the acute phase, by comparing active treatment, ie, kinetic oscillation stimulation (KOS) in the nasal cavity, with placebo. BACKGROUND: Exploratory trials testing the efficacy of KOS on migraine patients indicated that this treatment could be a fast-acting remedy for acute migraine pain. METHOD: Thirty-six patients were randomized 1:1 using a placebo module to active or placebo treatment in this double-blinded parallel design study. Treatment was administered with a minimally invasive inflatable tip oscillating catheter. Symptom scores (0-10 visual analog scale) were obtained before treatment, every 5 minutes during treatment, at 15 minutes, 2, and 24 hours post-treatment, as well as daily (0-3 migraine pain scale) from 30 days pretreatment until Day 60 post. Thirty-five patients were evaluated (active n=18, placebo n=17). The primary end-point was the change in average pain score from before treatment to 15 minutes after treatment. RESULTS: Patients who received active treatment reported reduced pain, eg, average visual analog scale pain scores fell from 5.5 before treatment to 1.2 15 minutes after, while the corresponding scores for recipients of placebo fell from 4.9 to 3.9. The changes in pain scores differed between the 2 treatments by 3.3 points (95% confidence interval: 2.3, 4.4), P<.001. Already 5 minutes into the treatment, the difference (1.9 points) was significant (P=.007). The difference was likewise significant at 2 hours post-treatment (3.7 points, P<.001). One patient experienced an adverse event (a vasovagal reaction with full spontaneous recovery) during placebo treatment. CONCLUSION: KOS is an effective and safe treatment for acute migraine pain. PMID- 25546475 TI - Berberine protects against neuronal damage via suppression of glia-mediated inflammation in traumatic brain injury. AB - Traumatic brain injury (TBI) triggers a series of neuroinflammatory processes that contribute to evolution of neuronal injury. The present study investigated the neuroprotective effects and anti-inflammatory actions of berberine, an isoquinoline alkaloid, in both in vitro and in vivo TBI models. Mice subjected to controlled cortical impact injury were injected with berberine (10 mg.kg(-1)) or vehicle 10 min after injury. In addition to behavioral studies and histology analysis, blood-brain barrier (BBB) permeability and brain water content were determined. Expression of PI3K/Akt and Erk signaling and inflammatory mediators were also analyzed. The protective effect of berberine was also investigated in cultured neurons either subjected to stretch injury or exposed to conditioned media with activated microglia. Berberine significantly attenuated functional deficits and brain damage associated with TBI up to day 28 post-injury. Berberine also reduced neuronal death, apoptosis, BBB permeability, and brain edema at day 1 post-injury. These changes coincided with a marked reduction in leukocyte infiltration, microglial activation, matrix metalloproteinase-9 activity, and expression of inflammatory mediators. Berberine had no effect on Akt or Erk 1/2 phosphorylation. In mixed glial cultures, berberine reduced TLR4/MyD88/NF-kappaB signaling. Berberine also attenuated neuronal death induced by microglial conditioned media; however, it did not directly protect cultured neurons subjected to stretch injury. Moreover, administration of berberine at 3 h post injury also reduced TBI-induced neuronal damage, apoptosis and inflammation in vivo. Berberine reduces TBI-induced brain damage by limiting the production of inflammatory mediators by glial cells, rather than by a direct neuroprotective effect. PMID- 25546477 TI - Benefits of fresh-frozen plasma as a replacement fluid to neutralize ABO antibodies. AB - BACKGROUND: ABO-incompatible organ transplantation requires pre-transplant conditioning to reduce ABO antibody levels in the recipients. With respect to replacement fluids used in plasma exchange, we intended to verify whether fresh frozen plasma (FFP) containing soluble ABO substance (SAS) is more effective than albumin solution in reducing ABO IgG antibody levels. METHODS: Apheresis data were retrospectively studied for in vivo effects, and in vitro plasma mixing studies were prospectively performed. The amount of ABO IgG antibodies bound to red cells was measured as the mean fluorescence intensity (MFI) using flow cytometry. Neutralization of ABO antibodies in the recipientst plasma by an ABO incompatible donornc plasma was measured using the inhibition assay principle. The MFI value of the unneutralized control tube was divided by that of the neutralized test tube (neutralizing-capacity index, NCI). RESULTS: The plasma exchange procedures replaced with group AB FFP showed a significantly greater decreased titer than those replaced with albumin (P = 0.010). The in vitro plasma mixing study simulating plasma exchange also produced consistent results. When the pooled group O plasma was neutralized for anti-A by individual group AB plasmas (AB-to-O, N = 30), the NCI was 12.8 +/- 5.4 (6.5-29.5). When this group O plasma was neutralized by pooled group AB or A plasma, the repeatedly measured NCI (N = 5) of A-to-O (11.4 +/- 1.4) was not significantly different from that of AB-to-O (9.7 +/- 1.3, P = 0.074). CONCLUSIONS: ABO antibody levels are reduced more effectively by group AB FFP than by albumin. Either group AB or donor type (group A or B) FFP can be infused to group O recipients. FFP units with higher SAS levels can be selected from multiple available candidate units using our protocol for measuring the neutralizing-capacity. PMID- 25546478 TI - In vitro study of human osteoblast proliferation and morphology on orthodontic mini-implants. AB - OBJECTIVE: To evaluate the proliferation and morphology of human osteoblasts cultured on two brands of mini-implants after 24, 48, and 72 hours, in addition to the chemical composition found on their surface. MATERIALS AND METHODS: Two brands of mini-implant (Morelli and Neodent) were evaluated; polystyrene was used as a control group (n = 3). Osteoblasts were cultured on the surface of sterilized mini-implants in a CO2 incubator at different time periods (24, 48, and 72 hours). Osteoblast proliferation was quantified by scanning electron microscopy using up to 5000* magnification, and cell morphology was analyzed by a single observer. For the chemical analysis, spectroscopy X-ray fluorescence was used to identify and quantify chemical components on the surface of the mini implants. RESULTS: Two-way ANOVA showed no significant interaction between the factors studied (P = 0.686). A Tukey test revealed no significant difference in osteoblast proliferation between the mini-implants at all studied periods; however, a difference in cell proliferation was detected between the Neodent and the control group (P = .025). For all groups, time had a direct and positive effect on osteoblast proliferation (P < .001). The significant elements present in both brands of mini-implants were titanium, aluminum, vanadium, and iron. CONCLUSIONS: Osteoblast proliferation was present on the mini-implants studied, which increased over time; however, no significant difference between brands was observed. No difference was seen between the mini-implants evaluated in terms of chemical composition. Cell adhesion after 72 hours suggests that areas of bone remodeling can be achieved, thus initiating the process of mini-implant anchorage. PMID- 25546480 TI - Common otolith microstructure related to key early life-history events in flatfishes identified in the larvae and juveniles of cresthead flounder Pseudopleuronectes schrenki. AB - Otolith microstructure of reared and wild cresthead flounder Pseudopleuronectes schrenki larvae and juveniles was used to investigate the daily periodicity of ring formation, morphological change and unique otolith structure related to important life events. By comparing microstructural features of P. schrenki with those reported for other flatfish species, it was shown that there may be microstructural features that are common to all flatfishes. In the sagittae and lapillus, a check (a distinct ring) was formed in the centre of otoliths at c. 6 days post hatching, and the daily formation of rings observed outside the check was confirmed. During metamorphosis, accessory primordia (AP) of otolith growth were formed on the outer edge of the sagittae, and the shape of the sagittae became more complex. No AP was formed on the lapilli, however, and otolith rings were concentrically formed throughout the larval and juvenile (<=51.6 mm standard length, LS ) stages. It is proposed, therefore, that lapilli are more appropriate than sagittae for analysis throughout the larval and juvenile (<=51.6 mm LS ) stages. During metamorphosis, unique rings that are relatively wide and show weak contrast are formed on lapilli (metamorphosing zone, MZ). Hence, the duration of metamorphosis, larval duration and the days of juvenile life can be estimated by the number of rings within the MZ, using rings from the check to outermost ring of the MZ, and that of rings formed outside MZ, respectively. The formation of AP on sagittae as well as the absence of AP, bilateral asymmetry and the formation of a unique structure during metamorphosis on lapilli have also been reported for other flatfishes. PMID- 25546479 TI - A comparison of intravitreal bevacizumab and steroid activity in an experimental uveitis model. AB - PURPOSE: To compare intravitreal bevacizumab (IVB) and steroid activity in an experimental uveitis (EU) model. MATERIALS AND METHODS: EU was induced by intravitreal injection of bovine serum albumin (BSA) at baseline. Rabbits were randomly divided into three groups (n = 8) according to treatment with a single dose of IVB, steroid or saline on day 3. Aqueous humor (AH) samples were collected periodically (baseline and days 1, 3, 10 and 33). Rabbits were sacrified and eyes were enucleated for histopathology on day 33. AH vascular endothelial growth factor (VEGF) levels and histopathological changes were subjected to statistical analysis. RESULTS: VEGF levels increased significantly after BSA injection (day 1) when compared with baseline in all three groups. Mean VEGF levels were 794.46 pg/mL, 777.91 pg/mL and 872 pg/mL for IVB, steroid and control groups, respectively (p = 0.002, p = 0.019 and p = 0.014). Seven days after treatment (day 10), VEGF levels decreased significantly in both treatment groups. Mean VEGF levels were 0 pg/mL, 292 pg/mL and 872 pg/mL, repectively (p < 0.001, p = 0.016 and p = 0.12). On day 33, the VEGF levels and inflammation had returned to baseline levels in both treatment groups, whereas no decrease in inflammation was observed in the control group. The histopathological evaluation revealed a mild congestion in ciliary tissue with a normal retina and choroidea in IVB group, a mild congestion in ciliary tissue with moderate inflammation in the posterior vitreus and a normal retina in steroid group and a severe inflammation in ciliary tissue with moderate inflammation in the retina in control group. CONCLUSIONS: These findings suggest that IVB may be used as an alternative to steroid treatment to reduce the acute effects of inflammation in patients with uveitis in whom intraocular steroids are contraindicated. PMID- 25546481 TI - Primary hepatocellular carcinoma in a patient with neurofibromatosis type I. PMID- 25546482 TI - Effectiveness of Vestibular Rehabilitation in Hemodialysis Patients With Dizziness. AB - PURPOSE: This study evaluated the effectiveness of vestibular rehabilitation (VR) for hemodialysis (HD) patients with chronic dizziness. DESIGN: A single-blind, randomized controlled study was performed. METHODS: Cluster-randomized sampling was used to select the experimental group from two outpatient dialysis clinics. A total of 26 patients participated in the study. Dizziness Handicap Inventory (DHI) and falls were used as outcome measures. Data were collected at baseline (T1), 3 months (T2), and 6 months (T3). FINDINGS: Two-way repeated-measures ANOVA of DHI revealed a statistically significant group and time interaction. Dizziness handicap outcome was significantly reduced over time in the experimental group (DHI total score, T1 = 35.29, T2 = 32.86, T3 = 27.86, p = .001). CONCLUSIONS: VR exercise instructed by nurses can be effective in alleviating handicap imposed by dizziness in dialysis patients. CLINICAL RELEVANCE: Nurses are encouraged to learn VR as a simple exercise to improve well-being in dialysis patients with chronic dizziness. PMID- 25546483 TI - Harnessing denatured protein for controllable bipolar doping of a monolayer graphene. AB - In this work, we demonstrated tunable p- and/or n-type doping of chemical vapor deposition-grown graphene with the use of protein bovine serum albumin (BSA) as a dopant. BSA undergoes protonation or deprotonation reaction subject to solution pH, thereby acting as either an electron donor or an electron acceptor on the graphene surface layered with denatured BSA through pi-stacking interaction. This direct annealing of graphene with denatured BSA of amphoteric nature rendered facilitated fabrication of a p- and/or n-type graphene transistor by modulating pH-dependent net charges of the single dopant. Following AFM confirmation of the BSA/graphene interface assembly, the carrier transport properties of BSA-doped graphene transistors were assessed by I-V measurement and Raman spectra to show effective charge modulation of the graphene enabled by BSA doping at various pH conditions. The protein-mediated bipolar doping of graphene demonstrated in our work is simple, scalable, and straightforward; the proposed scheme is therefore expected to provide a useful alternative for fabricating graphene transistors of novel properties and promote their implementation in practice. PMID- 25546484 TI - Intrinsic functional brain mapping in reconstructed 4D magnetic susceptibility (chi) data space. AB - BACKGROUND: By solving an inverse problem of T2*-weighted magnetic resonance imaging for a dynamic fMRI study, we reconstruct a 4D magnetic susceptibility source (chi) data space for intrinsic functional mapping. NEW METHODS: A 4D phase dataset is calculated from a 4D complex fMRI dataset. The background field and phase wrapping effect are removed by a Laplacian technique. A 3D chi source map is reconstructed from a 3D phase image by a computed inverse MRI (CIMRI) scheme. A 4D chi data space is reconstructed by repeating the 3D chi source reconstruction for each time point. A functional map is calculated by a temporal correlation between voxel signals in the 4D chi space and the timecourse of the task paradigm. RESULTS: With a finger-tapping experiment, we obtain two 3D functional mappings in the 4D magnitude data space and in the reconstructed 4D chi data space. We find that the chi-based functional mapping reveals co occurrence of bidirectional responses in a 3D activation map that is different from the conventional magnitude-based mapping. COMPARISON WITH EXISTING METHODS: The chi-based functional mapping can also be achieved by a 3D deconvolution of a phase activation map. Based on a subject experimental comparison, we show that the 4D chi tomography method could produce a similar chi activation map as obtained by the 3D deconvolution method. CONCLUSION: By removing the dipole effect and other fMRI technological contaminations, 4D chi tomography provides a 4D chi data space that allows a more direct and truthful functional mapping of a brain activity. PMID- 25546485 TI - Automated identification of neural correlates of continuous variables. AB - BACKGROUND: The electroencephalogram (EEG) may be described by a large number of different feature types and automated feature selection methods are needed in order to reliably identify features which correlate with continuous independent variables. NEW METHOD: A method is presented for the automated identification of features that differentiate two or more groups in neurological datasets based upon a spectral decomposition of the feature set. Furthermore, the method is able to identify features that relate to continuous independent variables. RESULTS: The proposed method is first evaluated on synthetic EEG datasets and observed to reliably identify the correct features. The method is then applied to EEG recorded during a music listening task and is observed to automatically identify neural correlates of music tempo changes similar to neural correlates identified in a previous study. Finally, the method is applied to identify neural correlates of music-induced affective states. The identified neural correlates reside primarily over the frontal cortex and are consistent with widely reported neural correlates of emotions. COMPARISON WITH EXISTING METHODS: The proposed method is compared to the state-of-the-art methods of canonical correlation analysis and common spatial patterns, in order to identify features differentiating synthetic event-related potentials of different amplitudes and is observed to exhibit greater performance as the number of unique groups in the dataset increases. CONCLUSIONS: The proposed method is able to identify neural correlates of continuous variables in EEG datasets and is shown to outperform canonical correlation analysis and common spatial patterns. PMID- 25546486 TI - The effect of ICD programming on inappropriate and appropriate ICD Therapies in ischemic and nonischemic cardiomyopathy: the MADIT-RIT trial. AB - INTRODUCTION: The MADIT-RIT trial demonstrated reduction of inappropriate and appropriate ICD therapies and mortality by high-rate cut-off and 60-second delayed VT therapy ICD programming in patients with a primary prophylactic ICD indication. The aim of this analysis was to study effects of MADIT-RIT ICD programming in patients with ischemic and nonischemic cardiomyopathy. METHODS AND RESULTS: First and total occurrences of both inappropriate and appropriate ICD therapies were analyzed by multivariate Cox models in 791 (53%) patients with ischemic and 707 (47%) patients with nonischemic cardiomyopathy. Patients with ischemic and nonischemic cardiomyopathy had similar incidence of first inappropriate (9% and 11%, P = 0.21) and first appropriate ICD therapy (11.6% and 14.1%, P = 0.15). Patients with ischemic cardiomyopathy had higher mortality rate (6.1% vs. 3.3%, P = 0.01). MADIT-RIT high-rate cut-off (arm B) and delayed VT therapy ICD programming (arm C) compared with conventional (arm A) ICD programming were associated with a significant risk reduction of first inappropriate and appropriate ICD therapy in patients with ischemic and nonischemic cardiomyopathy (HR range 0.11-0.34, P < 0.001 for all comparisons). Occurrence of total inappropriate and appropriate ICD therapies was significantly reduced by high-rate cut-off ICD programming and delayed VT therapy ICD programming in both ischemic and nonischemic cardiomyopathy patients. CONCLUSION: High-rate cut-off and delayed VT therapy ICD programming are associated with significant reduction in first and total inappropriate and appropriate ICD therapy in patients with ischemic and nonischemic cardiomyopathy. PMID- 25546487 TI - An in vitro priming step increases the expression of numerous epidermal growth and migration mediators in a tissue-engineering construct. AB - An FDA-approved, prototypic, living, bilayered skin construct (BSC) has been used for non-healing wounds. Using this particular construct as proof of principle, we hypothesized that an in vitro 'priming' step may enhance its repertoire of expression of key mediators and genes. The priming step used here was incubation in Dulbecco's modified Eagle's medium (DMEM) for 24 h at 37 degrees C and 5% CO2 , with or without construct meshing. Microarray and ingenuity pathway analysis (IPA) showed that >1000 genes were overexpressed by the priming step, including interleukin 6 (IL-6), which plays important roles in wound healing. Genes highly overexpressed by priming were those involved in epidermal proliferation and migration. Quantitative real-time PCR (qRT-PCR), immunostaining and western blots verified the results. An epiboly assay (epidermal migration over dermis) showed that BSC epiboly was inhibited by IL-6 neutralizing antibody. Back wounds of nude mice were treated with primed or control BSCs for 3 days prior to harvesting; primed BSCs showed a significantly (p = 0.006) greater level of epidermal migration vs unprimed. Our study demonstrates that an in vitro priming step induces wound healing-related genes in the BSC, leading to a construct that could prove more effective in stimulating wound healing. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25546488 TI - Treatment of low back pain: Second extended follow up of an original trial (NCT00600197) comparing a multidisciplinary group-based rehabilitation program with oral drug treatment alone up to 30 months. AB - BACKGROUND: The aim of this study is to investigate the effects of the extended 30-month follow-up of an original trial (NCT00600197) which has been published in the Clinical Journal of Pain. METHODS: Seventy-four percent (146/197) of the participants who had taken part in the original study, including 69 patients in the intervention group and 77 patients in the control group, were followed up to 30 months after intervention. The intervention group continued receiving monthly motivational consultation and booster classes plus oral medication but the other group received just medication. Data on measures from the Short Form 36 (SF-36), Quebec Disability Scale (QDS) and Ronald Morris Disability Questionnaire (RDQ) were collected at 3-, 6-, 12-, 18-, 24- and 30-month follow-ups and analyzed through repeated measures analysis of variance. RESULTS: The two groups were comparable regarding all baseline characteristics (P > 0.05) except for education level and mental health, which were better in the intervention group (P < 0.05). The two groups improved regarding all studied variables over time up to 30 months (P < 0.001). Moreover, the intervention group in comparison with the control group had consistently better outcomes regarding all variables. There were significant differences within each group by time in terms of mental health (P = 0.01) and disability measured through QDS (P = 0.005) and RDQ (P = 0.014). CONCLUSION: The proposed multidisciplinary program could improve mental health and disability up to 30 months in chronic low back pain patients. PMID- 25546489 TI - Extent of central neck dissection among thyroid cancer surgeons: Cross-sectional analysis. AB - BACKGROUND: It is unclear if surgeons are performing comprehensive central neck dissections for well-differentiated thyroid cancer. The purpose of this study was to determine mean lymph node retrieval in central neck dissection as well as variability across surgeons and institutions. METHODS: A prospectively collected database identified 18 surgeons performing 425 central neck dissections, 313 unilateral and 112 bilateral. Demographics, perioperative, and pathologic factors were analyzed. RESULTS: Mean lymph node yield was 7.4 and 11.9 for unilateral and bilateral central neck dissection, respectively. Although 224 central neck dissections were prophylactic, both total and pathologic lymph node yields were significantly higher in therapeutic central neck dissection. There was a significant variation in lymph node yield across individual surgeons, institutions, and regions. High-volume central neck dissection surgeons have significantly lower lymph node yield compared to low-volume surgeons. CONCLUSION: Central neck dissection seems to be performed adequately; however, there is a significant variation in lymph node yield. Future initiatives should try to standardize the central neck dissections performed, with emphasis on obtaining a sufficient yield. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E328-E332, 2016. PMID- 25546490 TI - Electron paramagnetic resonance and photoluminescence investigation on ultraviolet-emitting gadolinium-ion-doped CaAl12O19 phosphors. AB - The gadolinium doped CaAl12O19 phosphor has been prepared by a low temperature solution combustion method in a short time and characterized using powder X-ray diffraction, energy dispersive analysis of X-ray mapping, electron paramagnetic resonance (EPR) and photoluminescence spectroscopic techniques. EPR and optical analysis of the sample confirm the presence of Gd(3+) in the CaAl12O19 matrix. PMID- 25546491 TI - Microwave-assisted synthesis of CdO-ZnO nanocomposite and its antibacterial activity against human pathogens. AB - CdO-ZnO nanocomposite was prepared by microwave-assisted method and characterized by X-ray crystallography (XRD), Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FT-IR). It exhibits hexagonal cubic structure with an average crystallite size of 27 nm. From the UV-Vis spectra, the bandgap is estimated as 2.92 eV. The fluorescence spectrum shows a near band edge emission at 422 nm. In addition the antibacterial activity of CdO-ZnO nanocomposite was carried out in-vitro against two kinds of bacteria: gram negative bacteria (G -ve) i.e. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and gram positive bacteria (G +ve): Staphylococcus aureus, Proteus vulgaris and Bacillus spp. This study indicates the zone of inhibition of 40 mm has high antibacterial activity towards the gram positive bacterium S. aureus. PMID- 25546492 TI - Spectroscopic insights on selfassembly and excited state interactions between rhodamine and phthalocyanine molecules. AB - The absorption and fluorescence spectra as well as fluorescence lifetimes of tetrasulfonated zinc phthalocyanine ZnPc(SO3Na)4 were measured in the absence and presence of four rhodamine dyes, Rhodamine B (RB), Ethyl rhodamine B (ERB), Rhodamine 6G (R6G), Rhodamine 110 (R110), and Pyronine B (PYB). The ground state complexes of phthalocyanine-(Rhodamine)2 were observed which exhibit new absorption bands. The binding constants are all very large (0.86*10(5)-0.22*10(8) M(-1)), suggesting rhodamine-phthalocyanine pairs are very good combinations for efficient selfassembly. Both the fluorescence intensity and the lifetime values of ZnPc(SO3Na)4 were decreased by the presence of rhodamines. The structural effect of rhodamines on selfassembly is significant. The ground state binding and dynamic quenching capability is PYB>R6G>ERB>RB>R110. The dynamic fluorescence quenching is due to the photoinduced electron transfer (PET). The PET rate constant is very large and in the order of 10(13) M(-1) s(-1), much greater than kf and kic (in the order of 10(8) M(-1) s(-1)), which means that the PET efficiency is almost 100%. Therefore the non-covalent Pc-rhodamine is a very good pair of donor/acceptor for potential efficient solar energy conversion. PMID- 25546493 TI - Simultaneous determination of chloramphenicol, dexamethasone and naphazoline in ternary and quaternary mixtures by RP-HPLC, derivative and wavelet transforms of UV ratio spectra. AB - The application of chemometrics-assisted UV spectrophotometry and RP-HPLC to the simultaneous determination of chloramphenicol, dexamethasone and naphazoline in ternary and quaternary mixtures is presented. The spectrophotometric procedure is based on the first-order derivative and wavelet transforms of ratio spectra using single, double and successive divisors. The ratio spectra were differentiated and smoothed using Savitzky-Golay filter; whereas wavelet transform realized with wavelet functions (i.e. db6, gaus5 and coif3) to obtain highest spectral recoveries. For the RP-HPLC procedure, the separation was achieved on a ZORBAX SB C18 (150*4.6 mm; 5 MUm) column at ambient temperature and the total run time was less than 7 min. A mixture of acetonitrile - 25 mM phosphate buffer pH 3 (27:73, v/v) was used as the mobile phase at a flow rate of 1.0 mL/min and the effluent monitored by measuring absorbance at 220 nm. Calibration graphs were established in the range 20-70 mg/L for chloramphenicol, 6-14 mg/L for dexamethasone and 3-8 mg/L for naphazoline (R(2)>0.990). The RP-HPLC and ratio spectra transformed by a combination of derivative-wavelet algorithms proved to be able to successfully determine all analytes in commercial eye drop formulations without sample matrix interference (mean percent recoveries, 97.4-104.3%). PMID- 25546494 TI - Synthesis and spectral characterization of mono- and binuclear copper(II) complexes derived from 2-benzoylpyridine-N4-methyl-3-thiosemicarbazone: crystal structure of a novel sulfur bridged copper(II) box-dimer. AB - Mononuclear and binuclear copper(II) complexes of 2-benzoylpyridine-N(4)-methyl thiosemicarbazone (HL) were prepared and characterized by a variety of spectroscopic techniques. Structural evidence for the novel sulfur bridged copper(II) iodo binuclear complex is obtained by single crystal X-ray diffraction analysis. The complex [Cu2L2I2], a non-centrosymmetric box dimer, crystallizes in monoclinic C2/c space group and it was found to have distorted square pyramidal geometry (Addison parameter, tau=0.238) with the square basal plane occupied by the thiosemicarbazone moiety and iodine atom whereas the sulfur atom from the other coordinated thiosemicarbazone moiety occupies the apical position. This is the first crystallographically studied system having non-centrosymmetrical entities bridged via thiolate S atoms with Cu(II)I bond. The tridentate thiosemicarbazone coordinates in mono deprotonated thionic tautomeric form in all complexes except in sulfato complex, [Cu(HL)(SO4)].H2O (1) where it binds to the metal centre in neutral form. The magnetic moment values and the EPR spectral studies reflect the binuclearity of some of the complexes. The spin Hamiltonian and bonding parameters are calculated based on EPR studies. In all the complexes g||>g?>2.0023 and the g values in frozen DMF are consistent with the d(x2-y2) ground state. The thermal stabilities of some of the complexes were also determined. PMID- 25546496 TI - Poliosis circumscripta unmasking a scalp melanoma. AB - A 28-year-old man presented with a 1-year history of a localized patch of grey hair and an underlying darkly pigmented lesion on his right occipital area. Clinical appearance revealed poliosis overlying an asymmetrical plaque with variable degrees of brown pigmentation and white discolouration. Owing to the suspicious nature of the lesion, excision with a 2 mm margin was performed. Histology revealed an invasive melanoma with extensive regression and prominent involvement of multiple hair follicles. Scalp melanoma with associated poliosis is extremely rare, and has only been reported once in the literature to date. There have been two reports in the opthalmology literature regarding eyelash poliosis associated with orbital melanoma. The pathogenesis of poliosis still remains unclear. This is the second reported case of poliosis circmscripta unmasking a scalp melanoma, and highlights the importance of being vigilant when examining patients with poliosis of the scalp. PMID- 25546495 TI - Reflectance confocal microscopy for the diagnosis of vulvar naevi: six cases. AB - BACKGROUND AND OBJECTIVES: The differential diagnosis between vulvar naevi and melanoma is challenging. In vivo reflectance-mode confocal microscopy (RCM) is an emerging technique that allows non-invasive high-resolution imaging of the skin and mucosa. It has recently been used for the study of vulvar melanosis and melanoma, but it has not been so far employed for the diagnosis of genital naevi. The objective of this study is to evaluate RCM features of vulvar naevi and to compare them with dermoscopical and histopathological aspects. METHODS: Clinical, dermoscopical, in vivo RCM and histological features of six vulvar naevi were evaluated. RESULTS: The clinical and/or dermoscopical aspects were suspicious in all six cases. RCM showed a blue naevus, an atypical genital naevus, a junctional naevus and three compound naevi that were later confirmed by histological examination. In one compound naevus, RCM showed focal cytological atypia and architectural irregularity without clear features of malignancy, confirmed by histological examination. CONCLUSIONS: Reflectance-mode confocal microscopy can play a role in non-invasive diagnosis of vulvar naevi, but further broader studies are required to validate our observations. PMID- 25546499 TI - Yeast mitochondrial protein-protein interactions reveal diverse complexes and disease-relevant functional relationships. AB - Although detailed, focused, and mechanistic analyses of associations among mitochondrial proteins (MPs) have identified their importance in varied biological processes, a systematic understanding of how MPs function in concert both with one another and with extra-mitochondrial proteins remains incomplete. Consequently, many questions regarding the role of mitochondrial dysfunction in the development of human disease remain unanswered. To address this, we compiled all existing mitochondrial physical interaction data for over 1200 experimentally defined yeast MPs and, through bioinformatic analysis, identified hundreds of heteromeric MP complexes having extensive associations both within and outside the mitochondria. We provide support for these complexes through structure prediction analysis, morphological comparisons of deletion strains, and protein co-immunoprecipitation. The integration of these MP complexes with reported genetic interaction data reveals substantial crosstalk between MPs and non-MPs and identifies novel factors in endoplasmic reticulum-mitochondrial organization, membrane structure, and mitochondrial lipid homeostasis. More than one-third of these MP complexes are conserved in humans, with many containing members linked to clinical pathologies, enabling us to identify genes with putative disease function through guilt-by-association. Although still remaining incomplete, existing mitochondrial interaction data suggests that the relevant molecular machinery is modular, yet highly integrated with non-mitochondrial processes. PMID- 25546497 TI - Neuroendocrine-autonomic integration in the paraventricular nucleus: novel roles for dendritically released neuropeptides. AB - Communication between pairs of neurones in the central nervous system typically involves classical 'hard-wired' synaptic transmission, characterised by high temporal and spatial precision. Over the last two decades, however, knowledge regarding the repertoire of communication modalities used in the brain has notably expanded to include less conventional forms, characterised by a diffuse and less temporally precise transfer of information. These forms are best suited to mediate communication among entire neuronal populations, now recognised to be a fundamental process in the brain for the generation of complex behaviours. In response to an osmotic stressor, the hypothalamic paraventricular nucleus (PVN) generates a multimodal homeostatic response that involves orchestrated neuroendocrine (i.e. systemic release of vasopressin) and autonomic (i.e. sympathetic outflow to the kidneys) components. The precise mechanisms that underlie interpopulation cross-talk between these two distinct neuronal populations, however, remain largely unknown. The present review summarises and discusses a series of recent studies that have identified the dendritic release of neuropeptides as a novel interpopulation signalling modality in the PVN. A current working model is described in which it is proposed that the activity dependent dendritic release of vasopressin from neurosecretory neurones in the PVN acts in a diffusible manner to increase the activity of distant presympathetic neurones, resulting in an integrated sympathoexcitatory population response, particularly within the context of a hyperosmotic challenge. The cellular mechanism underlying this novel form of intercellular communication, as well as its physiological and pathophysiological implications, is discussed. PMID- 25546498 TI - Gender differences in narcissism: a meta-analytic review. AB - Despite the widely held belief that men are more narcissistic than women, there has been no systematic review to establish the magnitude, variability across measures and settings, and stability over time of this gender difference. Drawing on the biosocial approach to social role theory, a meta-analysis performed for Study 1 found that men tended to be more narcissistic than women (d = .26; k = 355 studies; N = 470,846). This gender difference remained stable in U.S. college student cohorts over time (from 1990 to 2013) and across different age groups. Study 1 also investigated gender differences in three facets of the Narcissistic Personality Inventory (NPI) to reveal that the narcissism gender difference is driven by the Exploitative/Entitlement facet (d = .29; k = 44 studies; N = 44,108) and Leadership/Authority facet (d = .20; k = 40 studies; N = 44,739); whereas the gender difference in Grandiose/Exhibitionism (d = .04; k = 39 studies; N = 42,460) was much smaller. We further investigated a less-studied form of narcissism called vulnerable narcissism-which is marked by low self esteem, neuroticism, and introversion-to find that (in contrast to the more commonly studied form of narcissism found in the DSM and the NPI) men and women did not differ on vulnerable narcissism (d = -.04; k = 42 studies; N = 46,735). Study 2 used item response theory to rule out the possibility that measurement bias accounts for observed gender differences in the three facets of the NPI (N = 19,001). Results revealed that observed gender differences were not explained by measurement bias and thus can be interpreted as true sex differences. Discussion focuses on the implications for the biosocial construction model of gender differences, for the etiology of narcissism, for clinical applications, and for the role of narcissism in helping to explain gender differences in leadership and aggressive behavior. Readers are warned against overapplying small effect sizes to perpetuate gender stereotypes. PMID- 25546500 TI - Wisdom and Psychosocial Functioning in Later Life. AB - We investigated the connection between wisdom-related performance, personality, and generativity to further the understanding of how they are interrelated. Our sample consisted of 163 men and women 68-77 years of age, mostly White, and predominantly middle class. Wisdom was assessed with the performance-based Berlin Wisdom Paradigm, with the remaining measures being mostly self-report. As hypothesized, on the zero-order level, wisdom-related performance (WRP) was positively associated with (a) growth, a personality component indexed by Openness to Experience, psychological mindedness, and a sense of well-being derived from growth, purpose in life, and autonomy; (b) adjustment, a personality component associated with life satisfaction, high levels of Agreeableness and Conscientiousness, low Neuroticism, a sense of well-being derived from positive relations with others, self-acceptance, and environmental mastery; and (c) a generative concern for the welfare of others. Latent path analysis indicated that the bivariate associations between adjustment and wisdom and between generativity and wisdom were mediated by growth. Wise individuals are characterized by their ability to balance different personal strengths and interests, an integration that occurs, however, within the context of a dominant personality style marked by the pursuit of maturity through personal growth. PMID- 25546501 TI - Suppressing a charge density wave by changing dimensionality in the ferecrystalline compounds ([SnSe]1.15)1(VSe2)n with n = 1, 2, 3, 4. AB - The compounds, ([SnSe]1.15)1(VSe2)n with n = 1, 2, 3, and 4, were prepared using designed precursors in order to investigate the influence of the thickness of the VSe2 constituent on the charge density wave transition. The structure of each of the compounds was determined using X-ray diffraction and scanning transmission electron microscopy. The charge density wave transition observed in the resistivity of ([SnSe]1.15)1(VSe2)1 was confirmed. The electrical properties of the n = 2 and 3 compounds are distinctly different. The magnitude of the resistivity change at the transition temperature is dramatically lowered and the temperature of the resistivity minimum systematically increases from 118 K (n = 1) to 172 K (n = 3). For n = 1, this temperature correlates with the onset of the charge density wave transition. The Hall-coefficient changes sign when n is greater than 1, and the temperature dependence of the Hall coefficient of the n = 2 and 3 compounds is very similar to the bulk, slowly decreasing as the temperature is decreased, while for the n = 1 compound the Hall coefficient increases dramatically starting at the onset of the charge density wave. The transport properties suggest an abrupt change in electronic properties on increasing the thickness of the VSe2 layer beyond a single layer. PMID- 25546503 TI - Review toward all RNA structures, concisely. AB - Profound insights regarding nucleic acid structure and function can be gleaned from very simple, direct, and chemistry-based strategies. Our approach strives to incorporate the elegant physical insights that Don Crothers instilled in those who trained in his laboratory. Don emphasized the advantages of focusing on direct and concise experiments even when the final objective was to understand something complex-potentially including the large-scale architectures of the genomes of RNA viruses and the transcriptomes of cells. Here, the author reviews the intellectual path, and a few detours, that led to the development of the SHAPE-MaP and RING-MaP technologies for interrogating RNA structure and function at large scales. The author also argues that greater attention to creating direct, less inferential experiments will convert "omics" investigations into lasting and definitive contributions to our understanding of biological function. PMID- 25546502 TI - Trans-fatty acid promotes thrombus formation in mice by aggravating antithrombogenic endothelial functions via Toll-like receptors. AB - SCOPE: Since excessive intake of trans-fatty acid (TFA) increases the risk of myocardial infarction, we investigated the effects of TFA on thrombus formation using animal and cell culture experiments. METHODS AND RESULTS: C57BL/6 mice were fed a diet containing TFA or cis-fatty acid (5% each of total calories) or a chow diet for 4 weeks, and thrombus formation was induced in the carotid artery by He Ne laser irradiation. The high-TFA diet significantly promoted thrombus formation in the carotid artery compared to the chow or cis-fatty acid diet. TFA activated the inflammatory signaling pathway in cultured endothelial cells and in mice; aortic gene expression levels of antithrombogenic molecules, including thrombomodulin and tissue factor pathway inhibitor, were decreased, and the expression levels of prothrombogenic molecules were increased in TFA-treated mice. TFA markedly upregulated the prothrombogenic molecules and downregulated the antithrombogenic molecules in endothelial cells. In addition, TFA induced phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor-kappaB. The TFA-activated signal pathways and prothrombogenic phenotypic changes of endothelial cells were inhibited by genetic or pharmacological inactivation of Toll-like receptors 2 and 4. CONCLUSION: TFA aggravates the antithrombogenic phenotypes of vascular endothelial cells via Toll like receptors and promotes thrombus formation in mice. PMID- 25546505 TI - VAD: heart transplant: ECMO: lung transplant? PMID- 25546504 TI - Role of Wnt/beta-Catenin Signaling in Epithelial Differentiation of Lung Resident Mesenchymal Stem Cells. AB - Accumulating evidence has demonstrated that stem cells have the ability to repair the lung tissue injuries following either injection of cultured cells or bone marrow transplantation. As a result, increasing attention has focused on the lung resident mesenchymal stem cells (LR-MSCs) for repairing damaged lung tissues. Meanwhile, some studies have revealed that Wnt/beta-catenin signaling plays an important role in the epithelial differentiation of mesenchymal stem cells (MSCs). In the current study, our aim was to explore the roles of Wnt/beta catenin signaling on cell proliferation and epithelial differentiation of LR MSCs. We have successfully isolated the stem cell antigen (Sca)-1(+) CD45(-) CD31(-) cells which were proposed to be LR-MSCs by magnetic-activated cell sorting (MACS). Furthermore, we demonstrated the expression of epithelial markers on LR-MSCs following indirect co-culture of these cells with alveolar epithelial type II (ATII) cells, confirming the epithelial phenotype of LR-MSCs following co culture. In order to clarify the regulatory mechanisms of Wnt/beta-catenin signaling in epithelial differentiation of LR-MSCs, we measured the protein levels of several important members involved in Wnt/beta-catenin signaling in the presence or absence of some canonical activators and inhibitors of the beta catenin pathways. In conclusion, our study demonstrated that Wnt/beta-catenin signaling may be an essential mechanism underlying the regulation of epithelial differentiation of LR-MSCs. PMID- 25546506 TI - Dried blood spots for therapeutic drug monitoring of tacrolimus and sirolimus in pediatric patients. PMID- 25546507 TI - The merits of sequential transplantation for hyperoxaluria type I. PMID- 25546509 TI - Self-reflection, growth goals, and academic outcomes: A qualitative study. AB - BACKGROUND: Goal-setting theory continues to be among the most popular and influential theories of motivation and performance, although there have been limited academic applications relative to applications in other domains, such as organizational psychology. AIMS: This paper summarizes existing quantitative research and then employs a qualitative approach to exploring academic growth via an in-depth reflective growth goal-setting methodology. SAMPLE: The study focuses on 92 UK final-year students enrolled in an elective advanced interpersonal skills and personal development module, with self-reflection and growth goal setting at its core. METHOD: Qualitative data in the form of regular reflective written diary entries and qualitative questionnaires were collected from students during, on completion of, and 6 months following the personal growth goal-setting programme. RESULTS: About 20% of students' self-set growth goals directly related to academic growth and performance; students reported that these had a strong impact on their achievement both during and following the reflective programme. Growth goals that were indirectly related to achievement (e.g., stress management) appeared to positively impact academic growth and other outcomes (e.g., well-being). A follow-up survey revealed that growth goal setting continued to impact academic growth factors (e.g., self-efficacy, academic performance) beyond the reflective programme itself. CONCLUSIONS: Academic growth can result from both academically direct and indirect growth goals, and growth goal setting appears to be aided by the process of simultaneous growth reflection. The implications for promoting academic growth via this unique learning and development approach are discussed. PMID- 25546508 TI - Association Between Leukocyte Telomere Length and Plasma Homocysteine in a Singapore Chinese Population. AB - RATIONALE: Leukocyte telomere length (LTL) and plasma homocysteine (HCY) have been independently associated with cardiovascular disease (CVD) morbidity and mortality. However, few studies have investigated the association between LTL and HCY levels. OBJECTIVE: This study investigated the association of LTL with CVD risk factors, including HCY, in an overt CVD-free Singapore Chinese population comprised of middle aged and elderly, the age group at risk of developing CVD. APPROACH: The association of plasma HCY and other CVD biomarkers with LTL were assessed in 100 samples drawn from the Singapore Chinese Health Study (SCHS). SCHS, a population-based cohort, recruited Chinese individuals, aged 45-74 years, between 1993 and 1998. Questionnaire data were collected via face-to-face interviews. Known CVD biomarkers were measured from the blood collected at the time of recruitment, and LTL was measured using the conventional Southern blot method. RESULTS: After adjustment for age, gender, smoking status, education, and dialect, LTL was found to be inversely associated with plasma HCY levels (p for trend=0.014). Serum urate showed a weak association (p for trend=0.056). Other CVD risk factors and nutrients, namely total cholesterol, low-density lipoprotein (LDL), triglycerides and creatinine, high-density lipoprotein (HDL), folate, and vitamin B6 showed the expected trend with LTL, but did not reach statistical significance. CONCLUSION: LTL displayed an inverse association with plasma HCY. This LTL-HCY inverse association in subjects lacking obvious cardiovascular events suggests that telomere length may be an intermediary in the biological mechanism by which elevated HCY leads to CVD. PMID- 25546510 TI - Proteome of monoclonal antibody-purified haustoria from Puccinia triticina Race 1. AB - Puccinia triticina causes leaf rust, a disease that causes annual yield losses in wheat. It is an obligate parasite that invades the host leaf and forms intracellular structures called haustoria, which obtain nutrients and suppress host immunity using secreted proteins called effectors. Since effector proteins act at the frontier between plant and pathogen and help determine the outcome of the interaction, it is critical to understand their functions. Here, we used a direct proteomics approach to identify effector candidates from P. triticina Race 1 haustoria isolated with a specific monoclonal antibody. Haustoria were >95% pure and free of host contaminants. Using high resolution MS we have identified 1192 haustoria proteins. These were quantified using normalized spectral counts and spanned a dynamic range of three orders of magnitude, with unknown proteins and metabolic enzymes as the most highly represented. The dataset contained 140 candidate effector proteins, based on the presence of a signal peptide and the absence of a known function for the protein. Some of these candidates were significantly enriched with cysteine, with up to 13 residues per protein and up to 6.8% cysteine in composition. PMID- 25546511 TI - One-way trip: influenza virus' adaptation to gallinaceous poultry may limit its pandemic potential. AB - We hypothesise that some influenza virus adaptations to poultry may explain why the barrier for human-to-human transmission is not easily overcome once the virus has crossed from wild birds to chickens. Since the cluster of human infections with H5N1 influenza in Hong Kong in 1997, chickens have been recognized as the major source of avian influenza virus infection in humans. Although often severe, these infections have been limited in their subsequent human-to-human transmission, and the feared H5N1 pandemic has not yet occurred. Here we examine virus adaptations selected for during replication in chickens and other gallinaceous poultry. These include altered receptor binding and increased pH of fusion of the haemagglutinin as well as stalk deletions of the neuraminidase protein. This knowledge could aid the delivery of vaccines and increase our ability to prioritize research efforts on those viruses from the diverse array of avian influenza viruses that have greatest human pandemic potential. Also watch the Video Abstract. PMID- 25546512 TI - Cervical spine clearance protocols in Level I, II, and III trauma centers in California. AB - BACKGROUND CONTEXT: Cervical spine clearance protocols were developed to standardize the clearance of the cervical spine after blunt trauma and prevent secondary neurologic injuries. The degree of incorporation of evidence-based guidelines into protocols at trauma centers in California is unknown. PURPOSE: To evaluate the cervical spine clearance protocols in all trauma centers of California. STUDY DESIGN: An observational cross-sectional study. PATIENT SAMPLE: Included from Level I, II, III trauma centers in California. OUTCOME MEASURES: The self-reported outcomes of each trauma center's cervical spine clearance protocols were assessed. METHODS: Level I (n=15), II (n=30), and III (n=11) trauma centers in California were contacted. Each available protocol was reviewed for four scenarios: clearing the asymptomatic patient, the initial imaging modality used in patients not amenable to clinical clearance, and the management strategies for patients with persistent neck pain with a negative computed tomography (CT) scan and those who are obtunded. Results were compared with the 2009 Eastern Association for the Surgery of Trauma (EAST) cervical spine clearance guidelines. RESULTS: The response rate was 96%. Sixty-three percent of California's trauma centers (Level I, 93%; Level II, 60%; Level III, 27%) had written cervical spine clearance protocols. For asymptomatic patients, 83% of Level I and 61% of Level II centers used National Emergency X-Radiography Utilization Study criteria with/without painless range of motion. For those requiring imaging, 67% of Level I and 56% of Level II centers stated a CT scan should be the first line of imaging. For obtunded patients and patients with persistent neck pain and a negative CT scan, more than 90% of Level I and more than 70% of Level II trauma centers incorporated the 2009 EAST recommendations. No institution recommended passive flexion-extension radiographs for the obtunded patient. CONCLUSIONS: Written cervical spine clearance protocols exist in 63% of California's trauma centers and only 51% of the centers have protocols that follow current evidence-based guidelines. Standardization and utilization of these protocols should be encouraged to prevent missed injuries and secondary neurologic injuries. PMID- 25546513 TI - Functional impact of integrin alpha5beta1 on the homeostasis of intervertebral discs: a study of mechanotransduction pathways using a novel dynamic loading organ culture system. AB - BACKGROUND CONTEXT: Intervertebral disc (IVD) degeneration, a major cause of low back pain, is considered to be induced by daily mechanical loading. Mechanical stress is widely known to affect cell survival and extracellular matrix metabolism in many cell types. Although the involvement of integrin alpha5beta1 transmembrane mechanoreceptor in IVD degeneration has been reported, the precise function of integrin alpha5beta1 remains obscure. PURPOSE: To reflect IVD tissue response to mechanical stress using a dynamic loading organ culture system and elucidate the functional impact of integrin alpha5beta1 on the pathomechanism of IVD degeneration. STUDY DESIGN: An ex vivo study using a dynamic loading organ culture system. METHODS: Ninety-six rat IVD explants were examined. Intervertebral discs were subjected to 1.3 MPa, 1.0 Hz dynamic compressive load in the presence or absence of an Arg-Gly-Asp (RGD) peptide with affinity to the fibronectin binding-site of integrin alpha5beta1. Cell viability and histomorphology were assessed. The localization of integrin alpha5beta1 in the IVD was assessed by immunohistochemistry. Gene expression levels of IVD cells were evaluated using real-time reverse transcription-polymerase chain reaction. RESULTS: In the nucleus pulposus (NP), cell density and viability were reduced by dynamic compressive load. Histologic degenerative alterations, mainly seen in the NP, were the morphologic changes of NP cells. In both NP and annulus fibrosus (AF), immunohistochemistry revealed localization of integrin alpha5beta1 and that the messenger-RNA expression of integrin alpha5beta1 was increased by dynamic load. Dynamic load induced a catabolic effect, the stimulation of matrix metalloproteinase-3 and -13 gene expressions by NP and AF cells. The RGD peptide partially blocked the histologic alterations and the catabolic effect. CONCLUSIONS: The dynamic loading organ culture system simulated cellular responses to mechanical loading of the IVD. Our results suggest that IVD cells recognize the mechanical stress through RGD integrins, particularly the alpha5beta1 subtype that is highly expressed in NP and AF cells. Further experiments using this system will provide information about pathomechanisms of IVD degeneration through the mechanotransduction pathways. PMID- 25546515 TI - Down-regulated CFTR During Aging Contributes to Benign Prostatic Hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a hyper-proliferative disease of the aging prostate; however, the exact mechanism underlying the development of BPH remains incompletely understood. The present study investigated the possible involvement of the cystic fibrosis transmembrane conductance regulator (CFTR), which has been previously shown to negatively regulate nuclear factor-kappaB (NF kappaB)/cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) pathway, in the pathogenesis of BPH. Our results showed decreasing CFTR and increasing COX2 expression in rat prostate tissues with aging. Furthermore, suppression of CFTR led to increased expression of COX2 and over-production of PGE2 in a normal human prostate epithelial cell line (PNT1A) with elevated NF-kappaB activity. PGE2 stimulated the proliferation of primary rat prostate stromal cells but not epithelial cells, with increased PCNA expression. In addition, the condition medium from PNT1A cells after inhibition or knockdown of CFTR promoted cell proliferation of prostate stromal cells which could be reversed by COX2 or NF kappaB inhibitor. More importantly, the involvement of CFTR in BPH was further demonstrated by the down-regulation of CFTR and up-regulation of COX2/NF-kappaB in human BPH samples. The present results suggest that CFTR may be involved in regulating PGE2 production through its negative regulation on NF-kappaB/COX2 pathway in prostate epithelial cells, which consequently stimulates cell growth of prostate stromal cells. The overstimulation of prostate stromal cell proliferation by down-regulation of CFTR-enhanced PGE2 production and release during aging may contribute to the development of BPH. PMID- 25546514 TI - Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times (ESCAPE) trial: methodology. AB - ESCAPE is a prospective, multicenter, randomized clinical trial that will enroll subjects with the following main inclusion criteria: less than 12 h from symptom onset, age > 18, baseline NIHSS >5, ASPECTS score of >5 and CTA evidence of carotid T/L or M1 segment MCA occlusion, and at least moderate collaterals by CTA. The trial will determine if endovascular treatment will result in higher rates of favorable outcome compared with standard medical therapy alone. Patient populations that are eligible include those receiving IV tPA, tPA ineligible and unwitnessed onset or wake up strokes with 12 h of last seen normal. The primary end-point, based on intention-to-treat criteria is the distribution of modified Rankin Scale scores at 90 days assessed using a proportional odds model. The projected maximum sample size is 500 subjects. Randomization is stratified under a minimization process using age, gender, baseline NIHSS, baseline ASPECTS (8-10 vs. 6-7), IV tPA treatment and occlusion location (ICA vs. MCA) as covariates. The study will have one formal interim analysis after 300 subjects have been accrued. Secondary end-points at 90 days include the following: mRS 0-1; mRS 0-2; Barthel 95-100, EuroQOL and a cognitive battery. Safety outcomes are symptomatic ICH, major bleeding, contrast nephropathy, total radiation dose, malignant MCA infarction, hemicraniectomy and mortality at 90 days. PMID- 25546516 TI - Marine-derived quorum-sensing inhibitory activities enhance the antibacterial efficacy of tobramycin against Pseudomonas aeruginosa. AB - Bacterial epiphytes isolated from marine eukaryotes were screened for the production of quorum sensing inhibitory compounds (QSIs). Marine isolate KS8, identified as a Pseudoalteromonas sp., was found to display strong quorum sensing inhibitory (QSI) activity against acyl homoserine lactone (AHL)-based reporter strains Chromobacterium violaceum ATCC 12472 and CV026. KS8 supernatant significantly reduced biofilm biomass during biofilm formation (-63%) and in pre established, mature P. aeruginosa PAO1 biofilms (-33%). KS8 supernatant also caused a 0.97-log reduction (-89%) and a 2-log reduction (-99%) in PAO1 biofilm viable counts in the biofilm formation assay and the biofilm eradication assay respectively. The crude organic extract of KS8 had a minimum inhibitory concentration (MIC) of 2 mg/mL against PAO1 but no minimum bactericidal concentration (MBC) was observed over the concentration range tested (MBC > 16 mg/mL). Sub-MIC concentrations (1 mg/mL) of KS8 crude organic extract significantly reduced the quorum sensing (QS)-dependent production of both pyoverdin and pyocyanin in P. aeruginosa PAO1 without affecting growth. A combinatorial approach using tobramycin and the crude organic extract at 1 mg/mL against planktonic P. aeruginosa PAO1 was found to increase the efficacy of tobramycin ten-fold, decreasing the MIC from 0.75 to 0.075 ug/mL. These data support the validity of approaches combining conventional antibiotic therapy with non-antibiotic compounds to improve the efficacy of current treatments. PMID- 25546519 TI - Favourable outcome of pregnancy in a patient with pemphigus vulgaris. PMID- 25546518 TI - Intestinal absorption of fucoidan extracted from the brown seaweed, Cladosiphon okamuranus. AB - The aim of this study was to examine the absorption of fucoidan through the intestinal tract. Fucoidan (0.1, 0.5, 1.0, 1.5 and 2.0 mg/mL) was added to Transwell inserts containing Caco-2 cells. The transport of fucoidan across Caco 2 cells increased in a dose-dependent manner up to 1.0 mg/mL. It reached a maximum after 1 h and then rapidly decreased. In another experiment, rats were fed standard chow containing 2% fucoidan for one or two weeks. Immunohistochemical staining revealed that fucoidan accumulated in jejunal epithelial cells, mononuclear cells in the jejunal lamina propria and sinusoidal non-parenchymal cells in the liver. Since we previously speculated that nitrosamine may enhance the intestinal absorption of fucoidan, its absorption was estimated in rats administered N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water. Rats were fed 0.2% fucoidan chow (BBN + 0.2% fucoidan rats), 2% fucoidan chow (BBN + 2% fucoidan rats) and standard chow for eight weeks. The uptake of fucoidan through the intestinal tract seemed to be low, but was measurable by our ELISA method. Fucoidan-positive cells were abundant in the small intestinal mucosa of BBN + 2% fucoidan rats. Most fucoidan-positive cells also stained positive for ED1, suggesting that fucoidan was incorporated into intestinal macrophages. The uptake of fucoidan by Kupffer cells was observed in the livers of BBN + 2% fucoidan rats. In conclusion, the absorption of fucoidan through the small intestine was demonstrated both in vivo and in vitro. PMID- 25546517 TI - Marine compound xyloketal B reduces neonatal hypoxic-ischemic brain injury. AB - Neonatal hypoxic-ischemic encephalopathy causes neurodegeneration and brain injury, leading to sensorimotor dysfunction. Xyloketal B is a novel marine compound isolated from a mangrove fungus Xylaria species (no. 2508) with unique antioxidant effects. In this study, we investigated the effects and mechanism of xyloketal B on oxygen-glucose deprivation-induced neuronal cell death in mouse primary cortical culture and on hypoxic-ischemic brain injury in neonatal mice in vivo. We found that xyloketal B reduced anoxia-induced neuronal cell death in vitro, as well as infarct volume in neonatal hypoxic-ischemic brain injury model in vivo. Furthermore, xyloketal B improved functional behavioral recovery of the animals following hypoxic-ischemic insult. In addition, xyloketal B significantly decreased calcium entry, reduced the number of TUNEL-positive cells, reduced the levels of cleaved caspase-3 and Bax proteins, and increased the level of Bcl-2 protein after the hypoxic-ischemic injury. Our findings indicate that xyloketal B is effective in models of hypoxia-ischemia and thus has potential as a treatment for hypoxic-ischemic brain injury. PMID- 25546520 TI - Acute herpes simplex encephalitis in pregnancy. PMID- 25546521 TI - Pubic symphysis diastasis after an uncomplicated vaginal delivery: A case report. PMID- 25546522 TI - Conservative management of a choledochal cyst during a twin pregnancy. PMID- 25546523 TI - Effect of postural changes on inferior vena cava dimensions and its influence on haemodynamics during caesarean section under spinal anaesthesia. AB - The effect of postural changes on inferior vena cava (IVC) dimensions and its influence on intra-operative haemodynamics in term parturients can be studied using abdominal ultrasound by a subcostal approach. Thirty-two term parturients scheduled to undergo elective caesarean section under spinal anaesthesia were recruited in this observational study. End expiratory diameter and collapsibility index of IVC was measured preoperatively in 3 different positions - supine, recumbent with wedge and left lateral positions. End expiratory diameter was significantly high in recumbent (10.79) and left lateral (12.27) compared with supine (9.96) position (P < 0.0001). A greater fall in systolic blood pressure (>20%) was noted in patients with collapsibility index of more than 11.5 in recumbent with wedge position with a positive predictive value of 86%. IVC dimensions change significantly with change in position and collapsibility index in recumbent position can be a useful parameter for predicting hypotension during caesarean section under spinal anaesthesia. PMID- 25546524 TI - Does bupivacaine and fentanyl combination for epidural analgesia shorten the duration of labour? AB - In this study we aimed to explore the effects of epidural analgesia achieved by a combination of low-dose bupivacaine and fentanyl infused through an epidural catheter on mother, foetus and labour process in nulliparous at-term pregnant women during vaginal delivery. This study was designed in a prospective, randomised controlled manner. Epidural analgesia was achieved in 50 nulliparous women. Fifty nulliparous women did not undergo epidural analgesia procedure. The duration of the first stage of labour was significantly shortened, while the second stage was significantly lengthened in pregnant women who underwent epidural analgesia (p < 0.05). In conclusion, starting epidural analgesia application during the active phase of the first stage of labour may shorten the duration of the first stage compared with the group of nulliparous women not undergoing epidural analgesia. The factor that has an impact on this may be the addition of fentanyl to bupivacaine used for epidural analgesia. PMID- 25546525 TI - Risk factors for adverse clinical outcomes in patients with tubo-ovarian abscess. AB - This study assessed the risk factors for poor clinical outcomes in patients with tubo-ovarian abscess (TOA). Patients managed with medical therapy and discharged within 7 days without complications constituted the favourable prognosis group (n = 22), whereas those who were managed surgically or discharged after 7 days of antibiotic therapy constituted the poor prognosis group (n = 87). Variables including age, gravidity, number of dilation and curettage procedures, caesarean delivery, smoking status, serum C-reactive protein levels, serum white blood count, body temperature, abscess diameter, presence of an intrauterine device (IUD), duration of IUD placement and length of hospitalisation were evaluated to assess their relationship with the clinical prognosis of TOA. Abscess diameter of >= 6 cm was a significant parameter that increased the risk eightfold for poor prognosis. No significant differences were observed regarding the other variables. PMID- 25546526 TI - The ovarian artery: an unusual feeding artery of uterine artery pseudoaneurysm necessitating repetitive transarterial embolisation. PMID- 25546527 TI - Near-infrared fluorescence imaging-guided surgery improves recurrence-free survival rate in novel orthotopic animal model of head and neck squamous cell carcinoma. AB - BACKGROUND: Appropriate animal models are required to test novel therapeutics for head and neck squamous cell carcinoma (HNSCC) such as near-infrared (NIR) imaging guided surgery. METHODS: We developed an optimized animal model of orthotopic HNSCC (in female athymic NMRI (Naval Medical Research Institute) nude mice) with a prolonged survival time. Resection of the orthotopic tumors was performed 30 days after implantation with or without the aid of a miniaturized clinical grade NIR optical imaging device, after systemic administration of a fluorescent RGD based probe that targets alphav beta3 integrin. RESULTS: NIR optical imaging guided surgery increased the recurrence-free survival rate by 50% through the detection of fluorescent cancer residues as small as 185 um; these fragments could remain unidentified if resection was performed exclusively under unaided visual guidance. CONCLUSION: NIR optical imaging-guided surgery showed an improved HNSCC tumor resection quality in our optimized orthotopic animal model. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E246-E255, 2016. PMID- 25546528 TI - Atomic resolution crystal structure of HV-BBI protease inhibitor from amphibian skin in complex with bovine trypsin. AB - Protease inhibitors of the Bowman-Birk (BBI) family are commonly found in plants and animals where they play a protective role against invading pathogens. Here, we report an atomic resolution (1A) crystal structure of a peptide inhibitor isolated from a skin secretion of a Chinese bamboo odorous frog Huia versabilis (HV-BBI) in complex with trypsin. HV-BBI shares significant similarities in sequence with a previously described inhibitor from a diskless-fingered odorous frog Odorrana graham (ORB). However, the latter is characterized by more than a 16,000 fold higher Ki against trypsin than HV-BBI. Comparative analysis of trypsin cocrystal structures of HV-BBI and ORB and additionally that of Sunflower Trypsin Inhibitor (SFTI-1) together with accessory information on the affinities of inhibitor variants allowed us to pinpoint the inhibitor moiety responsible for the observed large difference in activity and also to define the extent of modifications permissible within the common protease-binding loop scaffold of BBI inhibitors. We suggest that modifications outside of the inhibitory loop permit the evolution of specificity toward different enzymes characterized by trypsin like specificity. PMID- 25546529 TI - Disaster risk insurance and catastrophe models in risk-prone small Caribbean islands. AB - Post-catastrophe recovery and financial liquidity have long challenged small Caribbean islands. These states are vulnerable to multifarious natural hazards that often cause considerable socioeconomic dislocation. Such events inflict heavy losses on businesses and households, and significantly disrupt all aspects of government operations. After Hurricane Ivan devastated the economies of some islands in September 2004-with estimated losses of as much as 200 per cent of gross domestic product in some cases-regional governments, aided by the World Bank and international donors, approved the creation of a regional catastrophe insurance scheme. This parametric-based mechanism is underpinned by derivatives based catastrophe modelling whose outputs determine policy triggers and pay outs. Hazard models, particularly catastrophe models, are not widely accepted as yet. Despite recent advancements, major concerns have rendered them peripheral tools for many establishments. This paper reviews the region's vulnerabilities and examines constraints on the application of these models and suggests a means of improving their efficacy and acceptability. PMID- 25546530 TI - Can we afford to sequence every newborn baby's genome? AB - Whole-exome sequencing and whole-genome sequencing are gradually entering into the clinical arena. Drops in sequencing prices have led some to suggest that these analyses could be extended to the screening of whole populations or subsets thereof. Herein, we argue that this optimism is presently still unfounded. While cost estimates take into account the generation of sequence data, they fail to properly evaluate both the price of accurate and efficient interpretation and of the proper return of genomic information to the consulting individuals. Thus, short of inventing new, cost-effective ways of achieving these goals, the latter are likely to ruin our healthcare systems. We posit that due to lack of available resources, generalization of this practice remains, for the time being, unrealistic. PMID- 25546531 TI - Hypercapnia: clinical relevance and mechanisms of action. AB - PURPOSE OF REVIEW: Multiple clinical and laboratory studies have been conducted to illustrate the effects of hypercapnia in a range of injuries, and to understand the mechanisms underlying these effects. The aim of this review is to highlight and interpret information obtained from these recent reports and discuss how they may inform the clinical context. RECENT FINDINGS: In the last decade, several important articles have addressed key elements of how carbon dioxide interacts in critical illness states. Among them the most important insights relate to how hypercapnia affects critical illness and include the effects and mechanisms of carbon dioxide in pulmonary hypertension, infection, inflammation, diaphragm dysfunction, and cerebral ischemia. In addition, we discuss molecular insights that apply to multiple aspects of critical illness. SUMMARY: Experiments involving hypercapnia have covered a wide range of illness models with varying degrees of success. It is becoming evident that deliberate hypercapnia in the clinical setting should seldom be used, except wherever necessitated to avoid ventilator-associated lung injury. A more complete understanding of the molecular mechanisms must be established. PMID- 25546532 TI - Novel approaches to minimize ventilator-induced lung injury. AB - PURPOSE OF REVIEW: To discuss the mechanisms of ventilator-induced lung injury and the pro and cons of the different approaches proposed by literature to minimize its impact in patients with acute respiratory distress syndrome. RECENT FINDINGS: Mechanical ventilation is indispensable to manage respiratory failure. The evolution of knowledge of the physiological principles and of the clinical implementation of mechanical ventilation is characterized by the shift of interest from its capability to restore 'normal gas exchange' to its capability of causing further lung damage and multisystem organ failure. SUMMARY: If one of the essential teachings to young intensivists in the 1980s was to ensure mechanical ventilation restored being able to immediately drain a pneumothorax (barotrauma), nowadays priority we teach to young intensivists is to implement 'protective' ventilation to protect the lungs from the pulmonary and systemic effects of ventilator-induced lung injury (biotrauma). At the same time, priority of clinical research shifted from the search of optimal ventilator settings (best positive end-expiratory pressure) and to the evaluation of 'super-protective' ventilation that integrating partial or total extracorporeal support tries to minimize the use of mechanical ventilation. PMID- 25546533 TI - Monitoring and preventing diaphragm injury. AB - PURPOSE OF REVIEW: The present review summarizes developments in the field of respiratory muscle monitoring, in particular in critically ill patients. RECENT FINDINGS: Patients admitted to the ICU may develop severe respiratory muscle dysfunction in a very short time span. Among other factors, disuse and sepsis have been associated with respiratory muscle dysfunction in these patients. Because weakness is associated with adverse outcome, including prolonged mechanical ventilation and mortality, it is surprising that respiratory muscle dysfunction largely develops without being noticed by the clinician. Respiratory muscle monitoring is not standard of care in most ICUs. Improvements in technology have opened windows for monitoring the respiratory muscles in critically ill patients. Diaphragm electromyography and esophageal pressure measurement are feasible techniques for respiratory muscle monitoring, although the effect on outcome remains to be investigated. SUMMARY: Respiratory muscle dysfunction develops rapidly in selected critically ill patients and is associated with adverse outcome. Recent technological advances allow real-time monitoring of respiratory muscle activity in these patients. Although this field is in its infancy, from a physiological perspective, it is reasonable to assume that monitoring respiratory muscle activity improves outcome in these patients. PMID- 25546534 TI - Selecting the 'right' positive end-expiratory pressure level. AB - PURPOSE OF REVIEW: To compare the positive end-expiratory pressure selection aiming either to oxygenation or to the full lung opening. RECENT FINDINGS: Increasing positive end-expiratory pressure in patients with severe hypoxemia is associated with better outcome if the oxygenation response is greater and positive end-expiratory pressure tests may be performed in a few minutes. The oxygenation response to recruitment maneuvers was associated with better outcome in patients with acute respiratory distress syndrome from influenza A (H1N1). If, after recruitment maneuver, the recruitment is not sustained by sufficient positive end-expiratory pressure, the lung will unavoidably collapse. Several papers investigated the positive end-expiratory pressure selection according to the deflation limb of the pressure-volume curve. It is still questionable whether to consider oxygenation or respiratory mechanics change as the best marker for adequate selection. A growing interest is paid to the estimate of transpulmonary pressure, although no consensus is available on which methodology is preferable. Finally, the positive end-expiratory pressure adequate for full lung opening may be computed combining the computed tomography scan variables and the chest wall elastance. SUMMARY: When compared, most of the methods give the same positive end expiratory pressure values in patients with higher and lower recruitability. The positive end-expiratory pressure/inspiratory oxygen fraction tables are the only methods providing lower positive end-expiratory pressure in lower recruiters and higher positive end-expiratory pressure in higher recruiters. PMID- 25546535 TI - Discontinuation of ventilatory support: new solutions to old dilemmas. AB - PURPOSE OF REVIEW: Weaning from mechanical ventilation implies two separate but closely related aspects of care, the discontinuation of mechanical ventilation and removal of artificial airway, which implies routine clinical dilemmas. Extubation delay and extubation failure are associated with poor clinical outcomes. We sought to summarize recent evidence on weaning. RECENT FINDINGS: Tolerance to an unassisted breathing does not require routine use of weaning predictors and can be addressed using weaning protocols or by implementing automatic weaning methods. Spontaneous breathing trial can be performed on low levels of pressure support, continuous positive airway pressure, or T-piece. Echocardiographic tools may help to prevent the failure of extubation. Noninvasive ventilation can prevent respiratory failure after extubation, when used in hypercapnic patients. Recently, sedation protocols and early mobilization in ventilated critically ill patients may decrease weaning period and duration of mechanical ventilation, and prevent extubation failure and complications such as ICU-acquired weakness. New techniques have been performed to identify patients with high risk for extubation failure. SUMMARY: There is an interesting body of clinical research in the discontinuation of mechanical ventilation. Recent randomized controlled studies provide high-level evidence for the best approaches to weaning, especially in patients who fail the first spontaneous breathing trial or targeted populations. PMID- 25546536 TI - [Satisfaction with child and adolescent mental health services by user and clinician sex]. AB - Client Satisfaction with mental health services is an important aspect in the evaluation of quality of those services. In youth mental health field, a few studies had being made about this characteristic. The aim of this study is to evaluate the relationship between satisfaction of parents, children and adolescents according to sex of patients and therapists. The sample included 382 subjects who attended to Buenos Aires private services who completed the questionnaire of experiences with the service. The results in teenagers' group showed differences in the satisfaction with the service matching the sex of teenagers with the sex of therapist, however in children and parent groups we haven't found significant differences. We discuss the implications of the results in order to improve the services given in youth area. PMID- 25546537 TI - [Acute stress disorder in the emergency, its relationship with trigger factors from a gender perspective]. AB - BACKGROUND: Anxiety disorders and, in particular, acute stress disorder are one of the principal reasons for medical assistance, being the women the ones who frequently consult. AIMS: To describe and analyze, from a perspective of gender, the factors that unleash the consultation of an episode of acute stress disorder in the emergency. MATERIALS AND METHOD: An exploratory descriptive study was performed. A semi-directed interview and a socio-demographic questionnaire were assessed and scales to evaluate anxiety and depression were administered to females that consulted for an acute stress disorder. RESULTS: Sixty nine percent of the patients described the physical discomfort as trigger factor, presenting in the 85% of the cases a degree of major anxiety; associating the family conflicts as the principal cause of distress, followed by violence against women. The situation of distress, in 75% of the cases, did not correspond with an isolated episode. CONCLUSION: The physical symptomatology was the principal cause for consultation of an episode of acute stress disorder in the emergency, being the family conflicts and the violence against women the principal reasons of distress. Therefore, interdisciplinary approach for the assistance of mental disorders in emergency should be taken in consideration. PMID- 25546538 TI - [Deliberate burning with acid. New expressions of violence against women in Medellin, Colombia. Series of cases]. AB - INTRODUCTION: The deliberate burns with acid are recognized as violence against women described in the 17th century. However, in the second half of the 20th Century this practice becomes frequent in South East Asia, Africa and Middle East. In Latin America is a recent phenomena over which little has been published in the scientific literature. OBJECTIVE: To describe the clinical and psychic pathological characteristics of 8 Colombian women burned with acid in the context of violence based on gender. METHOD: retrospective series of cases, patients admitted at a university hospital in a period of 7 years after being burned with acid within the context of hetero-aggression. The patients were attended by a group of interdisciplinary health professionals, including the psychiatrists. The psychiatric analyses were carried out parting from the non structured psychiatric interview complying with diagnostic criteria of the Statistic and Diagnostic Manual. RESULTS: Eight women with an average age of 29.5 years were attacked with acid in a period of 8 years. The context for the aggression was violence based on gender. All the attackers were males. The body surface burned was 24% in average. The ocular involvement was present in 80% of the cases, two of them with bilateral blindness. The direct aggressor was the partner in three cases. The reason for the attack was jealousy and revenge due to rejection to sexual or love advancements or pretensions. CONCLUSIONS: The burns with acid constitute a new expression of the violence based on gender in Colombia. This type of aggressions generates suffering, rejection and social isolation and although, it does not have the intent to cause death to the victim, it does leave permanent scars of the aggression. PMID- 25546539 TI - [Suicide and psychiatry]. PMID- 25546540 TI - [A patient's suicide. The psychiatrist's impact]. AB - The clinical work of the psychiatrist often faces him to people who openly talk about their wish to die. However, although such thoughts did not culminate in most cases, unfortunately statistics show that suicide is a concrete possibility, more frequent than suspected. Globally, a million people die by suicide each year. The will to kill themselves is a complex phenomenon that is neither new nor modern. Suicide has crossed different times adopting different forms and meanings according to culture and history. As doctors, we tend to describe behaviors, in this case highly such a variable one, which involves various reasons and determinants. Thus, much has been written in the scientific literature about suicide in the causes, risk and protective factors, most vulnerable groups, etc. It has also been remarked the pain that the suicide causes in the family and close friends. Lots of articles propose psychotherapeutic and supporting measures for the suicide survivors to avoid the traumatic consequences of the experience. But, what about the psychiatrist? Isn't him a person who has been in close contact with the subject who has killed himself? The survivor risk of having traumatic symptoms, does it not apply to the doctor who was in charge? In this article, it will be taken into account the point of view of the psychiatrist in the grief after a patient's suicide. PMID- 25546541 TI - [Provincial public center for crisis intervention and psycho-social rehabilitation. A path towards communitary suicidology]. AB - This work on the systematic comprehensive approach towards the Prevention and Postvencion of Suicide started to develop back in mid 2011 in Rio Gallegos, capital of Santa Cruz Province. The first step on this development was a Pilot Plan for the Training of Professionals and also field intervention. The Center for Crisis Intervention and Psycho-social Rehabilitation was founded eight months later. The case-client in crisis plus family group- undergoes quantitative and qualitative evaluation by means of a triage system, all of which allows starting intensive face-to-face and also phone follow up according to the Crisis Intervention Model. Such intervention is developed by means of the participation in the "Grupo Sosten", the Adolescents Group if the client fits into that age, and also family relationship interviews as well as Multi-family meetings open to the Community. There is also a Community Team in the Center which performs collective assessment in schools, in conjunction with the "Equidad en Redes" Educational Specialty Team, belonging to the Provincial Education Council. The approach takes place on the field, and works as a screening step for the early detection of risk. Such risk is dealt with by means of short term intervention group programs involving the whole of the educational community. When facing situations of committed suicide there are interventions in communities to the interior of the province, fundamentally through the Hospital Team which works as the cluster convener for the social intersectoral frame-work. PMID- 25546542 TI - [Patients hospitalized for suicidal ideation and suicide attempt in a Mental Health Hospital: Clinicodemographical features and 6-month follow-up]. AB - BACKGROUND: Suicide is an issue of high public health impact. In Argentina there are few published studies on suicide and suicide attempt. OBJECTIVE: To determine the percentage of hospitalizations caused by suicidal attempt or suicidal ideation in a Mental Health Hospital of the City of Buenos Aires, describe the clinical and demographic characteristics of these patients and to analyze the frequency of adverse events at a 6-month follow-up. METHODS: In the present study, baseline and follow-up data of an analytical, observational, prospective cohort study are used. RESULTS: Baseline data show that of all patients who entered the Emergency Department, 27% did so for ideation or suicide attempt. The most frequent diagnoses were: borderline personality disorder (41%), major depressive disorder (38%), bipolar disorder (20%) and schizophrenia (16%). The method most commonly used during the suicide attempt was drug poisoning. In half of the patients, the suicidal process was developed in less than 10 minutes. Monitoring data show that 22% of patients had a new attempted suicide and 34% had a readmission in a 6-month period. CONCLUSIONS: Together, these results describe the characteristics of suicide patients admitted to a Mental Health Hospital and show the low efficacy of interventions and the need to devise new strategies for the management of suicidal patients. PMID- 25546543 TI - [Deliberate self-harm (DSH). Between constraint and relief]. AB - This article is the product of the research work done on "Deliberate self-harm DSH-: a constraint way to open to the world?" in which this Deliberate Self Harm was explored as from the phenomenological psychopathology and the suicidology theoretical approach, such research being done on the subjective and reflective narrations of people undergoing such problems, coming from different sources. Some discourse patterns are exposed that may be considered of great usefulness for the identification, the treatment -or postvention-, as well as for the prevention of the problem at issue. As an annex, a Survey of Self-harm is presented made for data collection and the planning of actions in communitarian interventions with adolescents form different places in Argentina, in conjunction with the Argentinean Professional Team of the Argentinean Association for Suicide Prevention. PMID- 25546544 TI - [Risk and suicide in open door institutions. Liability and forensic issues]. AB - Suicide is a complex issue and a source of discussion between different disciplines. Suicide assessment and management research had received a huge attention in the field. Argentina has a legal framework focused on protecting human rights. Malpractice and liability discussion is offered in cases of suicide in psychiatric patients recently admitted to an inpatient setting. Imminent and certain risk of damage is the legal requirement for involuntary psychiatric admission in terms of Mental Health Law in Argentina. PMID- 25546545 TI - [Suicide, damned word (death, forbidden word)]. AB - This paper addresses four main questions regarding suicide: Death, as a substitute to Sex as a Tabu, the lack of a theory capable of rendering a comprehensive concept, the dichotomy severing epidemiology from clinics; and lastly the notion of the good treatment as the best preventive approach to the individual patient. PMID- 25546546 TI - [Chronic pain and suicide attempt in the elderly through a case narration]. AB - We sought to reconstruct the case of an elderly patient who made a suicide attempt. We have isolated and identified certain risk factors which could have determined the patient's final decision, such as chronic pain, social isolation, narcissistic personality traits, depression and family suicidality. We analyze the difficulties and limitations found in the current treatment of these patients, with an aim to raise greater interest in the research and treatment of them. PMID- 25546548 TI - Letter from the editor. PMID- 25546547 TI - Recombinant adeno-associated virus-mediated inhibition of microRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and transforming growth factor beta 1 pathways. AB - Schistosomiasis is a serious parasitic disease in humans, which can lead to liver fibrosis and death. Accumulating evidence indicated that targeting the deregulated microRNAs (miRNAs) could mitigate disease outcomes. Here, we showed that progressive hepatic schistosomiasis caused elevation of miR-21 and efficient and sustained inhibition of miR-21 by using highly hepatic tropic adeno associated virus serotype 8 (rAAV8), which protected mice against lethal schistosome infection through attenuation of hepatic fibrosis (HF). We demonstrated an additive role of interleukin (IL)-13 and transforming growth factor beta 1 (TGF-beta1) in up-regulating miR-21 expression in hepatic stellate cells (HSCs) by activation of mothers against decapentaplegic (SMAD) proteins. Furthermore, down-regulation of miR-21 in HSCs reversed HF by enhancing SMAD7 expression, thus repressing TGF-beta1/Smad and IL-13/Smad pathways. CONCLUSION: This study suggests the mechanism of IL-13-mediated schistosomiasis HF by up regulation of miR-21 and highlights the potential of rAAV8-mediated miR-21 inhibition as a therapeutic intervention for hepatic fibrotic diseases, such as schistosomiasis. PMID- 25546550 TI - Novel femoral artery terminology: From inconsistent and confusing to stereostructural clarity? PMID- 25546551 TI - Lipoic-based TRPA1/TRPV1 antagonist to treat orofacial pain. AB - Inflammation of the trigeminal nerve is considered one of the most painful conditions known to humankind. The diagnosis is often difficult; moreover, safe and effective pharmacological treatments are lacking. A new molecule, ADM_12, formed by a lipoic and omotaurine residues covalently linked, is here reported. In vitro and in vivo tests showed that ADM_12 is a very attractive original compound presenting (i) a remarkable safety profile; (ii) a high binding constant versus TRPA1; (iii) an intriguing behavior versus TRPV1; and (iv) the ability to significantly and persistently reduce mechanical facial allodynia in rats. Noteworthy, by testing ADM_12, we shed light on the unprecedented involvement of TRPA1 and TRPV1 channels in orofacial pain. PMID- 25546553 TI - Stereotypic rheumatoid factors that are frequently expressed in mucosa-associated lymphoid tissue-type lymphomas are rare in the labial salivary glands of patients with Sjogren's syndrome. AB - OBJECTIVE: Among autoimmune diseases, Sjogren's syndrome (SS) is most strongly associated with the development of malignant B cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT)-type lymphoma. Previously, we have shown that in ~40% of cases of salivary gland MALT lymphoma, high-affinity stereotypic rheumatoid factor (RF) B cell receptors, specific for IgG-Fc, are expressed. This study was undertaken to investigate whether in the inflamed salivary glands of patients with SS, a similar RF-biased Ig repertoire is present. METHODS: Extensive analyses of the B cell Ig VH region repertoire were performed on microdissected tissue samples from the labial salivary glands of 4 patients with SS. RESULTS: All SS labial salivary glands harbored expanded B cell clones, of which 1 or 2 were highly expanded and detected in >50% of the microdissected samples. However, among the identified 464 distinct Ig clonotypes, only 3 stereotypic RF-expressing clones were detected. In 2 patients with SS, an RF expressing clone was detected at low frequency in 1 of the microdissected samples, whereas 1 patient with SS harbored a highly expanded RF-expressing clone that was detected in all microdissected samples and also detected in the peripheral blood. Two years after analysis of this sample, the latter patient developed a diffuse large B cell lymphoma originating from the same RF clone. CONCLUSION: Inflamed labial salivary glands in patients with SS generally harbor 1 or 2 highly expanded B cell clones. The repertoire strongly biased toward stereotypic RFs in salivary gland MALT lymphomas is not a reflection of a similar repertoire in the inflamed salivary glands of patients with SS; rather, in the latter, the repertoire is based on a strong selection advantage of incidental stereotypic RF-expressing B cells. PMID- 25546552 TI - Efficient and High-Speed Transduction of an Antibody into Living Cells Using a Multifunctional Nanocarrier System to Control Intracellular Trafficking. AB - The transduction of antibodies into living cells would represent a major contribution to both basic and applied biomedical fields, as currently available methods suffer from limitations such as low-uptake efficiency and endosomal entrapment. In this study, a liposome-based carrier was designed to overcome these issues. Liposomes were modified with octaarginine (R8), a cell penetrating peptide and GALA, a pH-sensitive fusogenic peptide. The presence of R8 enhanced the cellular uptake of antibodies, whereas GALA reduced endosomal entrapment, resulting in antibodies being released into the cytosol within 30 min. Moreover, compared with commercially available reagents for delivering antibodies, our system was superior in both cellular uptake and endosomal escape. In addition, specific antibodies delivered by R8-GALA liposomes were found to be associated with their epitope, confirming the preservation of functionality. This system for the efficient and high-speed cytosolic delivery of an antibody provides a valuable tool that can be useful in basic and applied research for analyzing the expression and function of intracellular molecules. PMID- 25546554 TI - A meta-analysis of temperament in eating disorders. AB - Although suggested as an important contributor to the development and maintenance of eating disorders, temperament has not previously been studied adopting a meta analytical approach. We therefore pooled data (N = 14 studies; N = 3315 cases, N = 3395 controls) on Cloninger's temperament traits (novelty seeking, harm avoidance, reward dependence and persistence) in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED) and eating disorders not otherwise specified. Persistence was significantly higher than in the controls in all eating disorders except for BED the highest levels being observed in AN. Correspondingly, the highest effect sizes for harm avoidance were seen in AN. Novelty seeking was significantly elevated relative to the controls only in BN. Harm avoidance was significantly lower, and reward dependence was significantly higher in individuals who had recovered from AN than in those who remained ill. Future studies with a longitudinal design are needed to explore the temporal relationships between eating disorders and temperament traits. PMID- 25546555 TI - Gestational diabetes mellitus: Confusion among medical doctors caused by multiple international criteria. AB - AIM: The aim of this study was to appraise the current regional practices of screening, diagnosis and follow-up of gestational diabetes mellitus (GDM) because the approach to GDM is frequently inconsistent. MATERIAL AND METHODS: A 21-item questionnaire was distributed to physicians taking care of pregnant women in seven hospitals in the United Arab Emirates and one hospital in Oman. Besides assessing their attitudes towards testing for GDM, the questionnaire assessed familiarity with the Hyperglycemia and Pregnancy Outcome study and the International Association of Diabetes in Pregnancy Study Groups GDM guidelines. RESULTS: One hundred and forty-eight (93%) of the 159 questionnaires distributed to the medical doctors (106 [72%] obstetricians and 42 [28%] internists) were returned. For GDM screening, six hospitals used five different tests; two hospitals utilized one single test. For GDM diagnosis, six hospitals employed the 2-h, 75-g oral glucose tolerance test (OGTT) (four different criteria) while two hospitals used the 3-h, 100-g OGTT (single criteria). For post-delivery follow up, the 2-h, 75-g OGTT and fasting plasma glucose were accepted by 103 (70%) and 38 (26%) of the 148 medical doctors, respectively. Ninety-eight (69%) of 143 responding physicians were aware of the Hyperglycemia and Pregnancy Outcome study, while 85 (61%) of 140 responders were familiar with the guidelines of the International Association of Diabetes in Pregnancy Study Groups; this knowledge was independent of specialty, seniority, academia, years in practice or country trained. CONCLUSIONS: Although this study is parochial, its implications are global; that is, further education of caregivers would make the discordant approach to GDM (within and between hospitals) more harmonious and improve the obstetric care of pregnant women. PMID- 25546557 TI - Differential diagnosis of rSr' pattern in leads V1 -V2. Comprehensive review and proposed algorithm. AB - One of the more frequent dilemmas in ECG interpretation is the differential diagnosis of an rSr' pattern in leads V1 -V2 . We often face this finding in asymptomatic and otherwise healthy individuals and the causes may vary from benign nonpathological variants to severe or life-threatening heart diseases, such as Brugada syndrome or arrhythmogenic right ventricular dysplasia. In other cases, a normal variant of rSr' pattern can be misinterpreted as pathological after the occurrence of certain clinical events such as cardiac arrest or syncope of unknown cause. In this review we analyze in detail all the possible conditions, both benign and pathological that may explain the presence of this electrocardiographic pattern. We also propose a simple electrocardiographic algorithm for differential diagnosis. PMID- 25546556 TI - Final overall survival results from a phase III, randomized, placebo-controlled, parallel-group study of gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804). AB - BACKGROUND: The results of the Iressa in NSCLC for maintenance study (NCT00770588; C-TONG 0804), which compared gefitinib and placebo as maintenance therapy in patients with advanced non-small-cell lung cancer without disease progression after first-line chemotherapy, were published previously. The objective of this report is to provide a mature analysis of overall survival (OS) for Iressa in NSCLC for maintenance study in intention to treat (ITT) population and in subgroups according to epidermal growth factor receptor (EGFR) mutation status. PATIENTS AND METHODS: A total of 296 patients were randomly assigned. EGFR mutations were detected using an amplification mutation refractory system. Seventy-nine patients were assessable for EGFR mutations. OS was analyzed by a Cox proportional hazards model adjusted for the same covariates in ITT population and subgroups according to EGFR mutation status. RESULTS: OS was similar for gefitinib and placebo arm with no significant difference between treatments in ITT population (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.68-1.14; p = 0.335) and in subgroups with wild type EGFR (HR, 1.27; 95% CI, 0.7-2.3; p = 0.431) or unknown EGFR mutations (HR, 0.92; 95% CI, 0.68, 1.25; p = 0.603). In the EGFR mutation-positive subgroup, the gefitinib arm showed a higher OS than the placebo arm (HR, 0.39; 95% CI, 0.15, 0.97; p = 0.036). CONCLUSION: EGFR mutation was the strongest predictive biomarker for OS benefit of gefitinib as maintenance treatment. The analyses of OS showed that patients achieve a clear and significant survival benefit if they receive EGFR tyrosine kinase inhibitors as maintenance treatment in EGFR mutation-positive patients. PMID- 25546558 TI - Progression of gait dysfunction in incident Parkinson's disease: impact of medication and phenotype. AB - Gait impairment in Parkinson's disease (PD) persists despite the use of dopaminergic therapy. Motor phenotype associated with greater postural instability and gait difficulty is related to a greater risk of motor decline and may be influenced by non-dopaminergic pathology. This study documents the progression of gait impairment over 18 months in an incident cohort of PD with regard to phenotype and medication. Gait characteristics were measured in 121 PD and 184 controls, and 18 months later in 108 PD participants. Sixteen gait characteristics were examined with respect to five broad domains for PD and motor phenotype. Correlations between change in levodopa (l-dopa) equivalent daily dose and gait were used to identify dopa-responsive and nonresponsive characteristics. Pace and rhythm deteriorated over 18 months in people with PD, with other gait domains remaining stable. People with a postural instability and gait difficulty phenotype had more impaired gait at baseline compared with a tremor-dominant phenotype, which was most evident in temporal characteristics. In contrast, pace and variability deteriorated over the subsequent 18 months in the tremor-dominant phenotype only. Weak but statistically significant correlations were found between increased l-dopa medication and less deterioration in pace and asymmetry. Significant gait impairment is evident in very early disease despite optimal medication. Change over 18 months is subtle and discrete, and is more pronounced in the tremor-dominant phenotype. Some features of gait are refractory to dopaminergic therapy, implicating a non-dopaminergic contribution. This may explain more temporal gait disturbance in the postural instability and gait difficulty phenotype. PMID- 25546559 TI - Development and the epigenome: the 'synapse' of gene-environment interplay. AB - This paper argues that there is a revolution afoot in the developmental science of gene-environment interplay. We summarize, for an audience of developmental researchers and clinicians, how epigenetic processes - chromatin structural modifications that regulate gene expression without changing DNA sequences - may offer a strong, parsimonious account for the convergence of genetic and contextual variation in the genesis of adaptive and maladaptive development. Epigenetic processes may play a plausible explanatory role in understanding: divergent trajectories and sexual dimorphisms in brain development; statistical interactions between genes and environments; the biological embedding of early psychosocial adversities; the linkages of such adversities to disorders of mental health; the striking individual variation in the strength of those linkages; the molecular origins of critical and sensitive periods; and the transgenerational inheritance of risk and protection. Taken together, these arguments converge in a claim that epigenetic processes constitute a promising and illuminating point of connection - a 'synapse' - between genes and environments. PMID- 25546560 TI - Accuracy of Bayley scores as outcome measures in trials of neonatal therapies. PMID- 25546561 TI - Determination of the action modes of cellulases from hydrolytic profiles over a time course using fluorescence-assisted carbohydrate electrophoresis. AB - Fluorescence-assisted carbohydrate electrophoresis (FACE) is a sensitive and simple method for the separation of oligosaccharides. It relies on labeling the reducing ends of oligosaccharides with a fluorophore, followed by PAGE. Concentration changes of oligosaccharides following hydrolysis of a carbohydrate polymer could be quantitatively measured continuously over time using the FACE method. Based on the quantitative analysis, we suggested that FACE was a relatively high-throughput, repeatable, and suitable method for the analysis of the action modes of cellulases. On account of the time courses of their hydrolytic profiles, the apparent processivity was used to show the different action modes of cellulases. Cellulases could be easily differentiated as exoglucanases, beta-glucosidases, or endoglucanases. Moreover, endoglucanases from the same glycoside hydrolases family had a variety of apparent processivity, indicating the different modes of action. Endoglucanases with the same binding capacities and hydrolytic activities had similar oligosaccharide profiles, which aided in their classification. The hydrolytic profile of Trichoderma reesei Cel12A, an endoglucanases from T. reesei, contained glucose, cellobiose, and cellotriose, which revealed that it may have a new glucosidase activity, corresponding to that of EC 3.2.1.74. A hydrolysate study of a T. reesei Cel12A N20A mutant demonstrated that the FACE method was sufficiently sensitive to detect the influence of a single-site mutation on enzymatic activity. PMID- 25546562 TI - Iatrogenic anemia/Twenty-five million liters of blood into the sewer: reply. PMID- 25546563 TI - Voice disorders in Sjogren's syndrome: Prevalence and related risk factors. AB - OBJECTIVES/HYPOTHESIS: Sjogren's Syndrome (SS) is an autoimmune disease that causes sicca (dryness) symptoms by affecting secretions most notably of the lacrimal and salivary glands. Voice disorders have been documented in patients with SS, but the true prevalence and relationships among possible contributing factors remain unknown. This preliminary epidemiological investigation examined prevalence and risk factors for voice disorders in SS. STUDY DESIGN: Self-report epidemiological questionnaire. METHODS: One hundred and one (101) patients with SS (94 females, 7 males; M age = 59.4 years; standard deviation [SD] = 14.1 years) completed an extensive interview using a previously validated questionnaire involving the patient's medical, family, occupational, psychosocial, social/lifestyle, voice use, and general health histories. Summary statistics, chi-squares, risk ratios, and multiple logistic regression were used to determine the frequency and severity of voice disorders in individuals with SS, as well as associations with demographic, lifestyle, health, disease severity, and voice use factors. RESULTS: The prevalence of a current voice disorder in individuals with SS was 59.4%. In general, voice disorders began gradually; were chronic; and correlated with SS disease severity independent of age, sex, duration of the disease, comorbid autoimmune conditions, and use of SS related medication. Specific voice symptoms including chronic throat dryness and soreness were significantly associated with SS disease severity. CONCLUSIONS: Voice disorders are relatively common in SS and are more frequent as disease severity worsens. These findings have important implications for evaluation and treatment of patients with SS. LEVEL OF EVIDENCE: 4. PMID- 25546564 TI - Identification of antioxidant peptides of Jinhua ham generated in the products and through the simulated gastrointestinal digestion system. AB - BACKGROUND: The objective of this study was to purify and identify antioxidant peptides present in the extract of Chinese dry-cured Jinhua ham. Jinhua ham extracts were separated into five fractions (A-E) by size-exclusion chromatography. Each fraction was subjected to a simulated gastrointestinal (GI) digestion system and fractions showing strong antioxidant activities were collected and subjected to liquid chromatography combined with tandem mass spectrometry (LC/MS/MS) for further purification and identification. RESULTS: Using MS/MS analysis, 33 peptides were identified in these fractions. Several key peptides were selected for synthesis and their antioxidant activity determined. The peptide showing strongest DPPH radical scavenging activity was GKFNV, which showed 92.7% antioxidant activity at a concentration of 1 mg mL(-1); the peptide LPGGGHGDL showed the highest hydroxyl radical scavenging activity; and LPGGGT and HA showed strong inhibition activity against erythrocyte hemolysis (about 45%) before digestion. On the other hand, KEER may contribute to Fe(2+) chelating ability in fraction C after GI digestion. CONCLUSION: Jinhua dry-cured ham seems to be a potential source of antioxidant peptides generated in the products and in GI digestion. PMID- 25546565 TI - Evaluating alternate biokinetic models for trace pollutant cometabolism. AB - Mathematical models of cometabolic biodegradation kinetics can improve our understanding of the relevant microbial reactions and allow us to design in situ or in-reactor applications of cometabolic bioremediation. A variety of models are available, but their ability to describe experimental data has not been systematically evaluated for a variety of operational/experimental conditions. Here five different models were considered: first-order; Michaelis-Menten; reductant; competition; and combined models. The models were assessed on their ability to fit data from simulated batch experiments covering a realistic range of experimental conditions. The simulated observations were generated by using the most complex model structure and parameters based on the literature, with added experimental error. Three criteria were used to evaluate model fit: ability to fit the simulated experimental data, identifiability of parameters using a colinearity analysis, and suitability of the model size and complexity using the Bayesian and Akaike Information criteria. Results show that no single model fits data well for a range of experimental conditions. The reductant model achieved best results, but required very different parameter sets to simulate each experiment. Parameter nonuniqueness was likely to be due to the parameter correlation. These results suggest that the cometabolic models must be further developed if they are to reliably simulate experimental and operational data. PMID- 25546566 TI - Exome sequencing reveals ADAM9 mutations in a child with cone-rod dystrophy. PMID- 25546567 TI - Extrahepatic biliary atresia in a 4-week-old Pug. AB - OBJECTIVE: To report diagnosis and surgical therapy of extrahepatic biliary atresia in a dog. STUDY DESIGN: Clinical report. ANIMAL: Dog (n = 1). METHODS: A 4-week-old female intact Pug presented with acholic feces, lethargy, and poor weight gain. On the basis of the stool color and abdominal ultrasonography findings, extrahepatic biliary atresia was suspected. Intraoperatively, no major duodenal papilla was identified and cholecystoduodenostomy was performed. RESULTS: One day postoperatively the stool color was considered normal. On ultrasonographic examinations up to 6 months after surgery, the gall bladder remained small and the stoma was functional. Serum biochemical profile after 10 months had a mild increase in alanine-aminotransferase (149 U/L; reference interval [RI], 0-85 U/L) whereas alkaline phosphatase and glutamate dehydrogenase were within normal limits. At 15 months, clinical examination was normal and blood ammonia concentration was within normal limits (43 umol/L; RI: <100 umol/L) but bile acid concentrations were still markedly elevated (fasting, 95 umol/L [RI: <20 umol/L] to postprandial, 127 umol/L [RI: <35 umol/L]). CONCLUSIONS: Ultrasonography and stool color can be helpful noninvasive diagnostic evidence in extrahepatic biliary atresia. Surgical correction with cholecystoduodenostomy with a good clinical outcome is possible even in very young dogs. Long-term prognosis in dogs with extrahepatic biliary atresia is unknown. PMID- 25546568 TI - Results of a prospective, multicenter study evaluating quality of life, safety, and efficacy of sacral neuromodulation at twelve months in subjects with symptoms of overactive bladder. AB - AIMS: This prospective, multicenter post-approval study evaluated the success rate of sacral neuromodulation (SNM) with the InterStim(r) System at 12-months. Subjects with bothersome symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) or urgency-frequency (UF), who failed at least one anticholinergic medication and had at least one not tried were included. METHODS: Subjects with successful test stimulation received an SNM implant. Therapeutic success (>=50% improvement in average leaks/day or voids/day or a return to normal voiding frequency [<8 voids/day]) and quality of life through 12 months were evaluated for implanted subjects. RESULTS: Of the 340 subjects that went through test stimulation, 272 were implanted with SNM. Of these, 91% were female, mean age was 57, UI subjects had 3.1 +/- 2.7 leaks/day, UF subjects had 12.6 +/- 4.5 voids/day. The analysis which includes all implanted subjects with diary data at baseline and 12 months showed an OAB therapeutic success rate of 85% at 12 months. UI subjects had a mean reduction of 2.2 +/- 2.7 leaks/day; UF subjects had a mean reduction of 5.1 +/- 4.1 voids/day (both P < 0.0001). Subjects showed significant improvement from baseline in all measures of ICIQ-OABqol (all P < 0.0001). 80% of subjects reported improved changes in their urinary symptom interference at 12 months. Device-related adverse events occurred in 16% (56/340) of subjects during test stimulation and 30% (82/272) of subjects post-implant. CONCLUSIONS: This multicenter study shows SNM is safe and effective and results in improved outcomes through 12 months in subjects with OAB symptoms, without requiring failure of all medications. PMID- 25546570 TI - Simultaneous determination of herbicide residues in tobacco using ultraperformance convergence chromatography coupled with solid-phase extraction. AB - A time-saving and organic solvent efficient method to simultaneously determine six kinds of herbicide residues in tobacco using solid-phase extraction for sample clean-up and preconcentration and the highly sensitive ultraperformance convergence chromatography method was developed. Parameters for ultraperformance convergence chromatography, including the choice of stationary phase and modifiers, autobackpressure regulator pressure, column temperature, and the flow rate of mobile solvents, were optimized. The herbicide residues of napropamide, alachlor, quizalofop-ethyl, diphenamid, metolachlor, and clomazone in tobacco samples were successfully separated and detected at levels as low as 0.0043 0.0086 mg/kg within 5 min using a nonpolar high strength silica C18 selectivity for bases column and methanol as the cosolvent of the mobile phase of carbon dioxide (75-99.9%, v/v). Analysis of tobacco samples had recoveries of 69.8 95.0%, limit of quantitation of 0.0127-0.0245 mg/kg, limit of detection of 0.0043 0.0086 mg/kg, and correlation coefficient of >0.9990. Results support this method as an efficient alternative to current methodologies for the determination of herbicide residues in tobacco. PMID- 25546571 TI - Species composition and aspects of the biology of Orectolobiformes from Indonesian waters. AB - The biological aspects of members of the order Orectolobiformes exploited in Indonesian waters are given. Seven species belonging to five families were recorded in the catches at various landing sites in southern Indonesia. Of these, Chiloscyllium punctatum was the most abundant species landed, contributing >50% of the number of orectolobiforms recorded. The biological data obtained varied greatly between the species listed. The total length (LT ) at maturity for some species, e.g. C. punctatum and Nebrius ferrugineus, varied from that which has been previously recorded for those species in other regions. This highlights the need for regional-specific biological data for fisheries managers and conservation assessors. PMID- 25546569 TI - The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity. AB - In vitro and ex vivo studies assessing the impact of stress hormones on immune competence commonly replace the natural milieu of leukocytes with an artificial medium, excluding plasma factors, hormones, and cytokines. Given prevalent inconsistencies between in vitro, ex vivo, and in vivo findings, we studied whether such procedures could yield misleading outcomes regarding the impact of stress hormones on NK cell cytotoxicity (NKCC), using fresh human whole blood samples. We found that in the presence of plasma 10-30-fold higher concentrations of cortisol, epinephrine, and prostaglandin-E2 (PGE2) were required to reach suppression levels evident in the context of artificial medium. Importantly, whereas the NK suppressive effects of PGE2 occurred immediately and remained stable upon prolonged exposure, the suppressive effects of cortisol slowly increased over time. Last, to simulate the exclusion of stress factors in the ex vivo approach, we subjected whole blood to stress hormones (as occurs in vivo), and abruptly removed them. We found that the effects of epinephrine and PGE2 quickly disappeared, while the effects of cortisol persisted. Overall, these findings demonstrate the potential misleading nature of in vitro and ex vivo procedures, and specifically suggest that (i) the common in vitro findings of profound suppression of NKCC by stress hormones are overestimation of their direct effects expected in vivo; and (ii) the common ex vivo approach cannot reflect the direct in vivo suppressive effects of epinephrine and PGE2 on NKCC, while inflating the effects of glucocorticoids. Some of these fallacies may be circumvented by using non-delayed whole blood NKCC assays in humans. PMID- 25546572 TI - Inflammatory bowel disease meta-evidence and its challenges: is it time to restructure surgical research? AB - AIM: The aim of this study was to compare the methodological quality and input paper characteristics of systematic reviews and meta-analyses reported in the medical and surgical literature by performing a systematic 'overview of reviews'. Ulcerative colitis (UC) and Crohn's disease (CD) were used as the framework for this comparison as they are relatively common serious conditions, with both medical and surgical options for therapy. METHOD: Medline, Embase, CINHAL and the Cochrane Database were searched to November 2013. Eligible papers were systematic reviews or meta-analyses that considered a question of therapy in CD or UC. Two independent reviewers selected the papers, extracted the data and scored their methodology using the AMSTAR scoring system. The papers were categorized into medical therapy (M), surgical therapy (S) or medical and surgical therapy (MS) groups. Following retrieval of the sample of meta-evidence papers, the original input studies used in their creation were identified and a search of Medline, Embase, CINHAL and the Cochrane Database was performed. A team of researchers then examined the collection of papers for bibliographic and financial information. RESULTS: Five hundred papers were identified in the meta-evidence search, of which 118 were deemed eligible. There was a difference in the AMSTAR rated average quality of the papers between the S and M group (S 7.36 vs M 8.75, P = 0.01). On average S papers were published in journals with a lower impact factor (S 3.26, M 5.04, MS 5.30, P < 0.001). S papers also showed more heterogeneity (I(2) ; S 37%, M 24%, MS 10%, P < 0.001). Some 25% of S meta analyses used data-sets with significant heterogeneity (I(2) > 75%), compared with 8% of M meta-analyses and 3% of the MS meta-analyses. Some 5% of S papers were done on data sets that had I(2) values > 90%. There was no difference in the average number of papers assessed in each group, the average number of patients per meta-paper, the average time covered by the reviews, the average number of papers considered within each meta-analysis, or the average number of patients considered within each meta-analysis. Considering the conclusions of each meta analysis, S meta-evidence was 50% more likely than M meta-evidence to be unable to make recommendations for practice. A total of 1499 original input papers were identified, of which 283 were used in more than one review. Within the non repeated papers (n = 1023) the average impact factor within the S group was lower than that of the M and the MS groups (3.720 vs 11.230 vs 7.563, respectively; ANOVAP < 0.001). M papers had higher rates of pharmaceutical sponsorship than S papers (M 56% vs S 1%) and twice the level of government support (M 16% vs S 8%). Of note, 21% of M papers had corporate sponsorship but did not list any conflict of interest. CONCLUSION: Compared with M meta-analyses, S meta-analyses in the UC and CD domain are more likely to be of poorer methodological quality, are of a greater degree of heterogeneity and less often offer a positive conclusion. The papers used to generate meta-evidence in M papers have a greater degree of corporate and government sponsorship, and are more likely to come from journals with higher impact factors. PMID- 25546573 TI - Endothelial function in migraine with aura - a systematic review. AB - BACKGROUND: An increased risk of ischemic stroke is repeatedly reported in young subjects with migraine with aura (MA). Such may be caused by changes in endothelial function. The present review evaluates current evidence on endothelial function in MA patients. METHODS: A systematic search of electronic databases (Medline, Embase, Cochrane library) was performed, and a search in associated reference lists of identified studies was done. RESULTS: In total, 27 studies met inclusion criteria for this review. Six studies assessed endothelial function by flow-mediated dilation; four reported no differences compared with healthy subjects, one study reported an increase and one study a decrease in migraineurs. Peripheral arterial tonometry was applied in one study where no changes were detected between groups. Likewise, applying venous occlusion plethysmography elicited comparable responses. Arterial function was investigated in six studies; increased augmentation index and decreased arterial distensibility were reported in migraineurs, whereas findings regarding pulse wave velocity were dissimilar. However, when investigating levels of endothelial progenitor cells, two studies reported reduced levels in migraineurs, and several studies on endothelial markers in the areas of inflammation, oxidative stress, and coagulation found increased endothelial activation in migraineurs, particularly in MA. One study, assessing cerebral endothelial function using transcranial Doppler sonography, reported lower cerebrovascular reactivity to L arginine in the posterior cerebral arteries in migraineurs. CONCLUSION: Endothelial dysfunction appears not to be of importance in MA patients. However, the studies were few with a wide variety of techniques applied in small groups of patients. Endothelial biomarkers were increased in patients indicating a possible subtle change in the endothelium. Further investigations on larger groups of patients combining testing of endothelial dysfunction as well as biomarkers are warranted to identify whether or not endothelial changes may play a role in the increased risk of stroke in young MA patients. PMID- 25546575 TI - Health-related quality of life among patients with primary sclerosing cholangitis. AB - BACKGROUND & AIMS: To assess health-related quality of life (HRQoL) of patients with primary sclerosing cholangitis (PSC), and to compare it with that of the general population. Also, to examine changes in HRQoL in newly diagnosed PSC patients at a follow-up 1-2 years later, and to compare their HRQoL with HRQoL of newly diagnosed inflammatory bowel disease (IBD) patients. Furthermore, sources of and need for disease-related information among PSC patients were surveyed. METHODS: Primary sclerosing cholangitis patients filled in the survey questionnaire when attending an endoscopic retrograde cholangiography examination. The 15D served as a general HRQoL instrument. The follow-up questionnaire was mailed to the newly diagnosed patients 1-2 years later. RESULTS: No significant difference was seen in 15D scores between PSC patients and general population, but the dimensions of excretion (P < 0.001), depression (P = 0.003), distress (P = 0.003) and vitality (P = 0.005) were significantly lower in PSC. Age and symptoms affected HRQoL but severity of biliary changes did not. Those with newly diagnosed IBD had lower 15D scores than those with PSC. No significant changes were observed in 15D scores of new PSC patients in the follow up. Many patients were dissatisfied with information received. CONCLUSION: Newly diagnosed PSC patients have better HRQoL than do IBD patients, and no significant HRQoL changes were observed in the mean follow-up of 1.58 years after PSC diagnosis. ERC findings did not correlate with HRQoL or symptoms. HRQoL of PSC patients was mostly comparable with that of general population, but special attention should be paid to patients' psychological well-being. PMID- 25546577 TI - High-quality RNA extraction from copepods for Next Generation Sequencing: A comparative study. AB - Despite the ecological importance of copepods, few Next Generation Sequencing studies (NGS) have been performed on small crustaceans, and a standard method for RNA extraction is lacking. In this study, we compared three commonly-used methods: TRIzol(r), Aurum Total RNA Mini Kit and Qiagen RNeasy Micro Kit, in combination with preservation reagents TRIzol(r) or RNAlater(r), to obtain high quality and quantity of RNA from copepods for NGS. Total RNA was extracted from the copepods Calanus helgolandicus, Centropages typicus and Temora stylifera and its quantity and quality were evaluated using NanoDrop, agarose gel electrophoresis and Agilent Bioanalyzer. Our results demonstrate that preservation of copepods in RNAlater(r) and extraction with Qiagen RNeasy Micro Kit were the optimal isolation method for high-quality and quantity of RNA for NGS studies of C. helgolandicus. Intriguingly, C. helgolandicus 28S rRNA is formed by two subunits that separate after heat-denaturation and migrate along with 18S rRNA. This unique property of protostome RNA has never been reported in copepods. Overall, our comparative study on RNA extraction protocols will help increase gene expression studies on copepods using high-throughput applications, such as RNA-Seq and microarrays. PMID- 25546576 TI - Displacing hexokinase from mitochondrial voltage-dependent anion channel impairs GLT-1-mediated glutamate uptake but does not disrupt interactions between GLT-1 and mitochondrial proteins. AB - The glutamate transporter GLT-1 is the major route for the clearance of extracellular glutamate in the forebrain, and most GLT-1 protein is found in astrocytes. This protein is coupled to the Na(+) electrochemical gradient, supporting the active intracellular accumulation of glutamate. We recently used a proteomic approach to identify proteins that may interact with GLT-1 in rat cortex, including the Na(+)/K(+) -ATPase, most glycolytic enzymes, and several mitochondrial proteins. We also showed that most GLT-1 puncta (~ 70%) are overlapped by mitochondria in astroglial processes in organotypic slices. From this analysis, we proposed that the glycolytic enzyme hexokinase (HK)-1 might physically form a scaffold to link GLT-1 and mitochondria because HK1 is known to interact with the outer mitochondrial membrane protein voltage-dependent anion channel (VDAC). The current study validates the interactions among HK-1, VDAC, and GLT-1 by using forward and reverse immunoprecipitations and provides evidence that a subfraction of HK1 colocalizes with GLT-1 in vivo. A peptide known to disrupt the interaction between HK and VDAC did not disrupt interactions between GLT-1 and several mitochondrial proteins. In parallel experiments, displacement of HK from VDAC reduced GLT-1-mediated glutamate uptake. These results suggest that, although HK1 forms coimmunoprecipitatable complexes with both VDAC and GLT 1, it does not physically link GLT-1 to mitochondrial proteins. However, the interaction of HK1 with VDAC supports GLT-1-mediated transport activity. PMID- 25546578 TI - Extraction protease expressed by Penicillium fellutanum from the Brazilian savanna using poly(ethylene glycol)/sodium polyacrylate/NaCl aqueous two-phase system. AB - The partitioning of protease expressed by Penicillium fellutanum from the Brazilian savanna in a novel inexpensive and stable aqueous two-phase system (ATPS) composed of poly(ethylene glycol) (PEG) and sodium polyacrylate (NaPA) was studied in this work using factorial design. The ATPS is formed by mixing both polymers with a salt (NaCl) and fermented broth of P. fellutanum. The effects of molar mass (2,000, 4,000, and 6,000 g ? mol(-1)) and concentration (6, 8, and 10 wt%) of PEG and that of NaPA concentration (6, 8, and 10 wt%) on protease partitioning (K) at 25 degrees C were studied. A two-level factorial design (2(3)) was implemented. The effect of Na2 SO4 concentration (5, 10, and 15 wt%) on the reextraction of the enzyme was also analyzed. The partition coefficient K ranged from 77.51 to 1.21, indicating the versatility of the method. The reextraction was achieved with the addition of 5% Na2 SO4 , allowing the partitioning of the protease to the upper phase, whereas total proteins were directed to the bottom phase. The results of partitioning using the PEG/NaPA/NaCl system and that of the subsequent reextraction with Na2 SO4 suggest that this method can be used to purify proteases from fermented broth of P. fellutanum. PMID- 25546579 TI - Plasmonic nanobiosensor based on hairpin DNA for detection of trace oligonucleotides biomarker in cancers. AB - MicroRNAs (miRNAs), a class of small, endogenous, noncoding RNA molecules, can serve as biomarkers for potential applications in cancer diagnosis, prognosis, and prediction due to its abnormal expression. As a result, a novel label-free biosensor with nanometer scale was prepared and employed in the detection of trace oligonucleotides based on the localized surface plasmon resonance (LSPR). The dielectric constant on the surface of DNA modified gold nanoparticle would change when probe single-strand DNA hybridized with target oligonucleotides, which resulted in the notable red shift of scattering peak position. The biosensor with excellent selectivity can be used in a real-time monitoring hybridization process. Notably, this method provided label-free detection of DNA and miRNA at single nanoparticle level with limit of detection up to 3 nM. Due to the advantages of LSPR scattering spectra, single nanoparticle biosensor can be designed for trace cancer-relevant miRNAs detection in the future. PMID- 25546580 TI - Relationship between contact force sensing technology and medium-term outcome of atrial fibrillation ablation: a multicenter study of 600 patients. AB - INTRODUCTION: Contact force sensing (CFS) technology improves acute pulmonary vein isolation durability; however, its impact on the clinical outcome of ablating atrial fibrillation (AF) is unknown. METHODS AND RESULTS: First time AF ablation procedures employing CFS from 4 centers were matched retrospectively to those without CFS in a 1:2 manner by type of AF. Freedom from atrial tachyarrhythmia was defined as the primary outcome measure, and fluoroscopy time the secondary outcome measure. Nineteen possible explanatory variables were tested in addition to CFS. A total of 600 AF ablation procedures (200 using CFS and 400 using non-CFS catheters) performed between 2010 and 2012 (46% paroxysmal, 36% persistent, 18% long-lasting persistent) were analyzed. The mean follow-up duration was 11.4 +/- 4.7 months-paroxysmal AF 11.2 +/- 4.1 CFS versus 11.3 +/- 3.9 non-CFS (P = 0.745)-nonparoxysmal AF 10.4 +/- 4.5 CFS versus 11.9 +/- 5.4 non CFS (P = 0.015). The use of a CFS catheter independently predicted clinical success in ablating paroxysmal AF (HR 2.24 [95% CIs 1.29-3.90]; P = 0.004), but not nonparoxysmal AF (HR 0.73 [0.41-1.30]; P = 0.289) in a multivariate analysis that included follow-up duration. Among all cases, the use of CFS catheters was associated with reduced fluoroscopy time in multivariate analysis (reduction by 7.7 [5.0-10.5] minutes; P < 0.001). Complication rates were similar in both groups. CONCLUSIONS: At medium-term follow-up, CFS catheter technology is associated with significantly improved outcome of first time catheter ablation of paroxysmal AF, but not nonparoxysmal AF. Fluoroscopy time was lower when CFS technology was employed in all types of AF ablation procedures. PMID- 25546581 TI - An antidote to the imager's fallacy, or how to identify brain areas that are in limbo. AB - Traditionally, fMRI data are analyzed using statistical parametric mapping approaches. Regardless of the precise thresholding procedure, these approaches ultimately divide the brain in regions that do or do not differ significantly across experimental conditions. This binary classification scheme fosters the so called imager's fallacy, where researchers prematurely conclude that region A is selectively involved in a certain cognitive task because activity in that region reaches statistical significance and activity in region B does not. For such a conclusion to be statistically valid, however, a test on the differences in activation across these two regions is required. Here we propose a simple GLM based method that defines an "in-between" category of brain regions that are neither significantly active nor inactive, but rather "in limbo". For regions that are in limbo, the activation pattern is inconclusive: it does not differ significantly from baseline, but neither does it differ significantly from regions that do show significant changes from baseline. This pattern indicates that measurement was insufficiently precise. By directly testing differences in activation, our procedure helps reduce the impact of the imager's fallacy. The method is illustrated using concrete examples. PMID- 25546574 TI - Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications. AB - Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. PMID- 25546582 TI - Related factors of fetal loss in Chinese women with systemic lupus erythematosus: data from Chinese SLE Treatment and Research Group registry IV. AB - OBJECTIVE: To study the factors associated with fetal loss in Chinese women with systemic lupus erythematosus (SLE) in a large cohort of SLE patients in the CSTAR (Chinese SLE Treatment and Research Group) registry. METHODS: We compared the clinical characteristics and auto-antibody profiles between SLE patients with fetal loss and SLE patients with normal pregnancies. The relationship between selected variables and fetal loss was examined by univariate analysis and binary logistic regression analysis. RESULTS: A total of 992 patients with 2026 pregnancies were recruited. Fifty women experienced fetal loss, including 49 spontaneous abortion, eight stillbirths and three neonatal deaths. The overall fetal loss rate was 3.0% (60/2026). Arthritis and serositis were observed significantly more frequently (P < 0.05) in normal pregnancy women. The rate of thrombocytopenia was significantly increased in patients with fetal loss (30.0% vs. 16.1%, P = 0.010), while there was no statistically significant difference in the frequency of nephropathy, central nervous system involvement between the normal pregnancy group and fetal loss group. Factors that associated with fetal loss included anti-phospholipid antibodies (aPL) (OR 2.299; 95% CI 1.058-4.993; P = 0.035) and anti-Sjogren syndrome antigen A (SSA) antibody (OR 2.283; 95% CI 1.275-4.088; P = 0.005), and thrombocytopenia (OR 2.241; 95% CI 1.192-4.213; P = 0.012). However, arthritis (OR 0.544, 95% CI 0.307-0.965, P = 0.037) was associated with favorable fetal outcome. CONCLUSIONS: Both univariate analysis and binary logistic regression analysis suggest that thrombocytopenia, aPL antibodies and anti-SSA antibody are associated with fetal loss in Chinese SLE women, while arthritis may be a possible factor related to favorable pregnancy outcome. PMID- 25546583 TI - Transcriptional profile of genes involved in ascorbate glutathione cycle in senescing leaves for an early senescence leaf (esl) rice mutant. AB - To clarify the complex relationship between ascorbate-glutathione (AsA-GSH) cycle and H2O2-induced leaf senescence, the genotype-dependent difference in some senescence-related physiological parameters and the transcript levels and the temporal patterns of genes involved in the AsA-GSH cycle during leaf senescence were investigated using two rice genotypes, namely, the early senescence leaf (esl) mutant and its wild type. Meanwhile, the triggering effect of exogenous H2O2 on the expression of OsAPX genes was examined using detached leaves. The results showed that the esl mutant had higher H2O2 level than its wild type at the initial stage of leaf senescence. At transcriptional level, the association of expression of various genes involved in the AsA-GSH cycle with leaf senescence was isoform dependent. For OsAPXs, the transcripts of two cytosolic OsAPX genes (OsAPX1 and OsAPX2), thylakoid-bound OsAPX8, chloroplastic OsAPX7 and peroxisomal OsAPX4 exhibited remarkable genotype-dependent variation in their expression levels and temporal patterns during leaf senescence, there were significantly increasing transcripts of OsAXP1 and OsAPX7, severely repressed transcripts of OsAPX4 and OsAPX8 for the esl rice at the initial leaf senescence. In contrast, the repressing transcript of OsAPX8 was highly sensitive to the increasing H2O2 level in the senescing rice leaves, while higher H2O2 concentration resulted in the enhancing transcripts of two cytosolic OsAPX genes, OsAPX7 transcript was greatly variable with different H2O2 concentrations and incubating duration, suggesting that the different OsAPXs isoforms played a complementary role in perceiving and scavenging H2O2 accumulation at various H2O2 concentrations during leaf senescence. Higher H2O2 level, increased AsA level, higher activities of APX and glutathione reductase (GR), and relatively stable GSH content during the entire sampling period in the leaves of esl mutant implied that a close interrelationship existed between AsA level and APX activity in the ongoing senescence of rice leaves. The GSH supply in rice leaves was not the limiting factor for the efficient maintenance of AsA-GSH cycle, despite the senescence related change in GR activity between the two rice genotypes. PMID- 25546584 TI - The interactive effects of simultaneous biotic and abiotic stresses on plants: mechanistic understanding from drought and pathogen combination. AB - In nature, plants are simultaneously exposed to a combination of biotic and abiotic stresses that limit crop yields. Only recently, researchers have started understanding the molecular basis of combined biotic and abiotic stress interactions. Evidences suggest that under combined stress plants exhibit tailored physiological and molecular responses, in addition to several shared responses as part of their stress tolerance strategy. These tailored responses are suggested to occur only in plants exposed to simultaneous stresses and this information cannot be inferred from individual stress studies. In this review article, we provide update on the responses of plants to simultaneous biotic and abiotic stresses, in particular drought and pathogen. Simultaneous occurrence of drought and pathogen during plant growth provokes complex pathways controlled by different signaling events resulting in positive or negative impact of one stress over the other. Here, we summarize the effect of combined drought and pathogen infection on plants and highlight the tailored strategies adapted by plants. Besides, we enumerate the evidences from pathogen derived elicitors and ABA response studies for understanding simultaneous drought and pathogen tolerance. PMID- 25546586 TI - Subcutaneous non-absorbable polypropylene (SNAP) sutures in serial excision of congenital naevi: A new time-saving technique reducing dehiscence with optimized aesthetic results. PMID- 25546587 TI - A special issue on risk factors for the development of allergic disease. PMID- 25546585 TI - Quantitative multigene FISH on breast carcinomas identifies der(1;16)(q10;p10) as an early event in luminal A tumors. AB - In situ detection of genomic alterations in cancer provides information at the single cell level, making it possible to investigate genomic changes in cells in a tissue context. Such topological information is important when studying intratumor heterogeneity as well as alterations related to different steps in tumor progression. We developed a quantitative multigene fluorescence in situ hybridization (QM FISH) method to detect multiple genomic regions in single cells in complex tissues. As a "proof of principle" we applied the method to breast cancer samples to identify partners in whole arm (WA) translocations. WA gain of chromosome arm 1q and loss of chromosome arm 16q are among the most frequent genomic events in breast cancer. By designing five specific FISH probes based on breakpoint information from comparative genomic hybridization array (aCGH) profiles, we visualized chromosomal translocations in clinical samples at the single cell level. By analyzing aCGH data from 295 patients with breast carcinoma with known molecular subtype, we found concurrent WA gain of 1q and loss of 16q to be more frequent in luminal A tumors compared to other molecular subtypes. QM FISH applied to a subset of samples (n = 26) identified a derivative chromosome der(1;16)(q10;p10), a result of a centromere-close translocation between chromosome arms 1q and 16p. In addition, we observed that the distribution of cells with the translocation varied from sample to sample, some had a homogenous cell population while others displayed intratumor heterogeneity with cell-to-cell variation. Finally, for one tumor with both preinvasive and invasive components, the fraction of cells with translocation was lower and more heterogeneous in the preinvasive tumor cells compared to the cells in the invasive component. PMID- 25546588 TI - Does air pollution really cause allergy? PMID- 25546589 TI - Antibiotics and risk of asthma: a debate that is set to continue. PMID- 25546592 TI - Language development in the early school years: the importance of close relationships with teachers. AB - This longitudinal study examined developmental links between closeness in teacher child relationships and children's receptive language ability from the end of the preschool years into the early elementary years, while controlling for changes in peer interaction quality and child behavioral functioning. The sample included children and their parents and teachers (N = 4,983) participating in the Longitudinal Study of Australian Children (LSAC) at ages 4-5, 6-7, and 8-9 years (3 waves). Teachers reported on levels of closeness in relationships with individual children. Independent assessments of receptive language were employed. Parents and teachers reported on peer interaction problems and child conduct problems. Results indicated reciprocal associations between close teacher-child relationships and receptive language development above and beyond associations with peer interaction quality and child behavioral functioning. However, the effects were only modest. PMID- 25546593 TI - Infants' emerging sensitivity to emotional body expressions: insights from asymmetrical frontal brain activity. AB - Sensitive responding to others' emotional body expressions is an essential social skill in humans. Using event-related brain potentials, it has recently been shown that the ability to discriminate between emotional body expressions develops between 4 and 8 months of age. However, it is not clear whether the perception of emotional body expressions in others evokes sensitive brain responses linked to motivational processes in infants. We therefore examined frontal EEG alpha asymmetry in response to dynamic happy and fearful body expressions presented to 4- and 8-month-old infants in 2 orientations (upright and inverted). Our results revealed that only 8-month-olds but not 4-month-olds showed significant differences in their frontal asymmetry responses between emotional expressions when presented in an upright orientation. Specifically, 8-month-old infants showed a greater lateralization to the left hemisphere in response to happy expression, indexing a greater tendency to approach, whereas they showed a greater lateralization to the right hemisphere in response to fearful expressions, indexing a greater tendency to withdraw. These findings provide further support for the notion that infants' perception of emotion undergoes a developmental tuning during this period in development. Critically, the results suggest that the infant brain becomes sensitive to the motivational significance conveyed by the emotional body expressions. PMID- 25546594 TI - Mindfulness and compassion in human development: introduction to the special section. AB - Research on contemplative practices (e.g., mindfulness or compassion training) is growing rapidly in the clinical, health and neuro-sciences, but almost none of this research takes an explicitly developmental life span perspective. At present, we know rather little about the naturalistic development of mindfulness or compassion in children and adolescents, or the processes by which parents can socialize these positive qualities in their offspring. Thus, the goal of this special section is to showcase empirical research articles that redress this absence of a developmental focus in contemplative science by focusing on issues of construct conceptualization and measurement, socialization practices in families, and the role that interventions can play in fostering mindfulness and compassion in children, adolescents, and care-givers alike. PMID- 25546595 TI - Enhancing cognitive and social-emotional development through a simple-to administer mindfulness-based school program for elementary school children: a randomized controlled trial. AB - The authors hypothesized that a social and emotional learning (SEL) program involving mindfulness and caring for others, designed for elementary school students, would enhance cognitive control, reduce stress, promote well-being and prosociality, and produce positive school outcomes. To test this hypothesis, 4 classes of combined 4th and 5th graders (N = 99) were randomly assigned to receive the SEL with mindfulness program versus a regular social responsibility program. Measures assessed executive functions (EFs), stress physiology via salivary cortisol, well-being (self-reports), prosociality and peer acceptance (peer reports), and math grades. Relative to children in the social responsibility program, children who received the SEL program with mindfulness (a) improved more in their cognitive control and stress physiology; (b) reported greater empathy, perspective-taking, emotional control, optimism, school self concept, and mindfulness, (c) showed greater decreases in self-reported symptoms of depression and peer-rated aggression, (d) were rated by peers as more prosocial, and (e) increased in peer acceptance (or sociometric popularity). The results of this investigation suggest the promise of this SEL intervention and address a lacuna in the scientific literature-identifying strategies not only to ameliorate children's problems but also to cultivate their well-being and thriving. Directions for future research are discussed. PMID- 25546596 TI - Mexican American adolescents' family obligation values and behaviors: links to internalizing symptoms across time and context. AB - Family obligation is an important aspect of family relationships among families from Mexican backgrounds and can have significant implications for adolescents' well-being. Prior research and theory regarding youths' obligations offer conflicting hypotheses about whether it is detrimental or beneficial for adolescents' well-being. In the current longitudinal study, we used a daily diary method among 428 Mexican American adolescents and their parents to closely examine the impact of adolescents' family obligation values and family assistance behaviors on internalizing symptoms over time. The authors closely examined the role of the family context in these associations. Results suggest that family obligation values relate to declines in adolescents' internalizing symptoms, whereas family assistance behaviors are both a protective and risk factor, depending on the family context. Only when youths provide family assistance in response to acute changes in parental physical and psychological distress do family assistance behaviors relate to increases in adolescents' internalizing symptoms. PMID- 25546597 TI - Latino adolescents' perceived discrimination in online and offline settings: an examination of cultural risk and protective factors. AB - Guided by a risk and resilience framework, the current study examined the associations between Latino adolescents' (n = 219; Mage = 14.35; SD = 1.75) perceptions of ethnic discrimination in multiple settings (e.g., online, school) and several domains of adjustment (e.g., mental health, academic), and tested whether developmentally salient cultural assets (i.e., ethnic identity) directly promoted youth adjustment or moderated the negative impact of discrimination on adjustment. Each of the 3 ethnic identity components (i.e., exploration, resolution, affirmation) demonstrated evidence of promoting positive outcomes among Latino youth; furthermore, there was some evidence that the promotive effects of affirmation and resolution were significantly stronger for older versus younger adolescents. In addition, with the exception of experiences with discrimination from adults outside of the school setting, there was evidence of ethnic identity interacting with each type of discrimination to predict Latino adolescents' self-esteem, depressive symptoms, and externalizing problems. Findings suggest directions for future research and identify potential targets for intervention that may prove fruitful in programming efforts with Latino adolescents. PMID- 25546598 TI - Examining executive function in the second year of life: coherence, stability, and relations to joint attention and language. AB - Several theories of executive function (EF) propose that EF development corresponds to children's ability to form representations and reflect on represented stimuli in the environment. However, research on early EF is primarily conducted with preschoolers, despite the fact that important developments in representation (e.g., language, gesture, shared joint attention) occur within the 1st years of life. In the present study, EF performance and the relationship between EF and early representation (i.e., joint attention, language) were longitudinally examined in 47 children at 14 and 18 months of age. Results suggest that the 2nd year of life is a distinct period of EF development in which children exhibit very little coherence or stability across a battery of EF tasks. However, by 18 months, a subset of child participants consistently passed the majority of EF tasks, and superior EF performance was predicted by 14 month representational abilities (i.e., language comprehension and some episodes of initiating joint attention). This research suggests that the transition from foundational behavioral control in infancy to the more complex EF observed in preschool is supported by representational abilities in the 2nd year of life. PMID- 25546599 TI - Growth in perceived control across 25 years from the late teens to midlife: the role of personal and parents' education. AB - This study examined trajectories of perceived control and their association with parents' education and personal educational experience (educational attainment and years of full-time postsecondary education) in 971 Canadian high school seniors tracked 7 times across 25 years. Latent growth models showed that, on average, perceived control increased from age 18 to age 25 and decreased by age 32, with a further slower decrease by age 43. Parents' education contributed to a growing gap in perceived control, however, such that among individuals with at least 1 university-educated parent, perceived control increased across 25 years, reaching its highest level at age 43. Personal educational attainment (completion of a university degree or not) was not associated with growth in perceived control, but individuals who were higher on perceived control at age 18 were more likely to complete a university degree. Parallel process modeling found that perceived control at age 19 predicted gains through age 32 in years of postsecondary education. Postsecondary enrollment at age 19 did not predict gains in perceived control over time. Parents' education predicted both higher levels of perceived control and enrollment in full-time postsecondary education at age 19. Family socioeconomic status contributes to perceived control early in the transition to adulthood and may lead to diverging trajectories over the next 25 years, and perceived control contributes to subsequent postsecondary educational experience. Further longitudinal research should explore the development and determinants of perceived control across the full life span. PMID- 25546601 TI - Hematopoietic stem cell transplantation following unsuccessful salvage treatment for relapsed acute lymphoblastic leukemia in children. AB - BACKGROUND: For children who experience a re-induction failure or multiple recurrences following the first relapse of acute lymphoblastic leukemia (ALL), it is uncertain whether additional intensive chemotherapy aimed at hematopoietic stem cell transplantation (SCT) in complete remission (CR) or immediate SCT even in non-CR should be performed. This study aimed to investigate the impact of disease status at SCT on the outcomes of SCT for these children, whose prognosis is considered unquestionably poor even with SCT. PROCEDURE: The medical records of 55 children with ALL who underwent SCT following the experience of re induction failure (n = 25) or multiple relapses (n = 30) were retrospectively analyzed. RESULTS: Twenty-one patients underwent SCT in CR (delayed CR2, CR3, and CR4) and 34 in non-CR (first or subsequent relapse). The probability of overall survival of patients with CR and with non-CR at SCT was 42.9% and 23.5% (P = 0.15), leukemia-free survival was 38.1% and 20.6% (P = 0.18), and the cumulative incidence of relapse at 2 years was 23.8% and 50%, respectively (P = 0.05). In multivariate analysis, non-CR at SCT was a significant risk factor for higher relapse incidence and male sex was a significant risk factor for lower survival. CONCLUSIONS: Our results indicated that in case of tolerable patient condition, further re-induction chemotherapy might be reasonable so that SCT could be performed in CR, which might result in a low incidence of relapse after SCT. Novel approaches are required to induce CR for the treatment of children with relapsed/refractory ALL. PMID- 25546602 TI - Ultrafast dynamics of defect-assisted electron-hole recombination in monolayer MoS2. AB - In this Letter, we present nondegenerate ultrafast optical pump-probe studies of the carrier recombination dynamics in MoS2 monolayers. By tuning the probe to wavelengths much longer than the exciton line, we make the probe transmission sensitive to the total population of photoexcited electrons and holes. Our measurement reveals two distinct time scales over which the photoexcited electrons and holes recombine; a fast time scale that lasts ~ 2 ps and a slow time scale that lasts longer than ~ 100 ps. The temperature and the pump fluence dependence of the observed carrier dynamics are consistent with defect-assisted recombination as being the dominant mechanism for electron-hole recombination in which the electrons and holes are captured by defects via Auger processes. Strong Coulomb interactions in two-dimensional atomic materials, together with strong electron and hole correlations in two-dimensional metal dichalcogenides, make Auger processes particularly effective for carrier capture by defects. We present a model for carrier recombination dynamics that quantitatively explains all features of our data for different temperatures and pump fluences. The theoretical estimates for the rate constants for Auger carrier capture are in good agreement with the experimentally determined values. Our results underscore the important role played by Auger processes in two-dimensional atomic materials. PMID- 25546600 TI - Self-esteem is relatively stable late in life: the role of resources in the health, self-regulation, and social domains. AB - A large body of research has documented changes in self-esteem across adulthood and individual-difference correlates thereof. However, little is known about whether people maintain their self-esteem until the end of life and what role key risk factors in the health, cognitive, self-regulatory, and social domains play. To examine these questions, we apply growth modeling to 13-year longitudinal data obtained from by now deceased participants of the Berlin Aging Study (N = 462; age 70-103, M = 86.3 years, SD = 8.3; 51% male). Results revealed that self esteem, on average, does decline in very old age and close to death, but the amount of typical decline is minor. Health-related constraints and disabilities as well as lower control beliefs and higher loneliness were each associated with lower self-esteem late in life. We obtained initial evidence that some of these associations were stronger among the oldest-old participants. Our results corroborate and extend initial reports that self-esteem is, on average, fairly stable into the last years of life. We discuss possible pathways by which common and often severe late-life challenges may undermine an otherwise relatively robust self-esteem system. PMID- 25546603 TI - Lichen planus pemphigoides associated with chronic hepatitis B virus infection. AB - Lichen planus pemphigoides (LPP) is a rare autoimmune dermatosis with the features of both lichen planus (LP) and bullous pemphigoid (BP). Although in rare cases, LPP has been associated with several medications and conditions, it is generally considered an idiopathic disorder, and its pathogenesis remains uncertain. We report a 56-year-old woman who presented with a 2-year history of flat-topped, polygonal, violaceous-colored papules and some bullae. She was diagnosed with chronic hepatitis B virus (HBV) infection, which had been treated intermittently with entecavir. Histopathological examination showed the typical features of LP with subepidermal blisters, and with linear deposits of IgG along the basement membrane zone on direct immunofluorescence. Immunoblotting revealed antibodies directed at the BP180 and BP230 antigens. We diagnosed the patient with LPP, and treated the condition with systemic steroids and dapsone. To our knowledge, this is the first report of LPP in a patient with chronic HBV infection. PMID- 25546605 TI - Regulation of hypoxia-inducible factor-1a by reactive oxygen species: new developments in an old debate. AB - Hypoxia-Inducible Factor-1 (HIF-1) has been largely studied for its role in cell survival in hypoxic conditions. The regulation of HIF-1 is a complex process and involves a number of molecules and pathways. Among these mechanisms a direct regulatory role of reactive oxygen species (ROS) on HIF-1 alpha subunit has received a great deal of attention and the existing body of literature includes many contradictory findings. Other intermediates such as nitric oxide (NO), specific microRNAs (miR), and transcriptional and post-translational modification have also been implicated as players in ROS mediated HIF-1a regulation. The focus of this review is to present the past conflicting evidence along with more recent findings in order to relate various aspects of this complex process. Aside from the direct role of ROS on HIF-1a regulation under hypoxia and normoxia, we analyzed the effect of different sources and concentrations of NO and the interplay between superoxide (SO) and NO in this process. We also present findings on transcriptional and translational regulation of HIF-1a via ROS and the interplay with microRNAs in this process. This review further provides insight on ERK and PI3K/AKT signaling as a common mechanism relating several pathways of ROS mediated HIF-1a regulation. Ultimately further research and discovery regarding HIF-1 regulation by oxidative stress is warranted for better understanding of disease development and potential therapeutics for pathologies such as cancer, inflammatory diseases, and ischemia-reperfusion injury. PMID- 25546604 TI - Gene-dietary fat interaction, bone mineral density and bone speed of sound in children: a twin study in China. AB - SCOPE: Dietary fat correlates with bone mineral density (BMD). We tested the association between fat intake and BMD, and tested if fat intake modified the degree of genetic influence on BMD and bone speed of sound (SOS). METHODS AND RESULTS: We included 622 twins aged 7-15 from South China. Data on anthropometry, dietary intake, BMD, and SOS were collected. Quantitative genetic analyses of structural equation models were fit using the Mx statistical package. The within pair intraclass correlations for BMD in dizygotic twins were nearly half of that for monozygotic twins (intraclass correlations = 0.39 versus 0.70). The heritability of BMD and SOS were 71 and 79%. Phenotypic correlation between fat intake and SOS was significant (r = -0.19, p = 0.04). SOS was negatively correlated with fat intake in boys (r = -0.11, p = 0.05), but not in girls. Full Cholesky decomposition models showed SOS has a strong genetic correlation with fat intake (rA = -0.88, 95% confidence interval = -0.94, 0.01); the environmental correlation between fat intake and SOS was weak (rE = -0.04, 95% confidence interval = -0.20, 0.13). Fat intake modified the additive genetic effects on BMD. CONCLUSION: Genetic factors explained 71 and 79% of individual variance in BMD and SOS, respectively. Low fat intake counteracts genetic predisposition to low BMD. PMID- 25546607 TI - Leiomyomatosis peritonealis disseminata of unusual course with malignant transformation: case report. AB - Leiomyomatosis peritonealis disseminata is a very rare, benign entity of unknown pathogenesis, characterized by the presence of multiple subperitoneal or peritoneal smooth muscle nodules throughout the peritoneal surface. Mostly the course is asymptomatic and it is found incidentally during laparotomy, laparoscopy or cesarean section. Non-specific symptoms such as abdominal pain, vaginal bleeding, abdominal mass or gastrointestinal signs are described. Rare cases of malignant transformation have been reported. We present a case of disseminated peritoneal leiomyomatosis with an unusual course and transformation to endometrial sarcoma in a 26-year-old previously healthy woman, where the appearance of peritoneal nodules was preceded by multiple incidents of fast fibroid growth and delivery of myomatous growth into the cervical canal. PMID- 25546606 TI - Meeting report: SMART timing--principles of single molecule techniques course at the University of Michigan 2014. AB - Four days after the announcement of the 2014 Nobel Prize in Chemistry for "the development of super-resolved fluorescence microscopy" based on single molecule detection, the Single Molecule Analysis in Real-Time (SMART) Center at the University of Michigan hosted a "Principles of Single Molecule Techniques 2014" course. Through a combination of plenary lectures and an Open House at the SMART Center, the course took a snapshot of a technology with an especially broad and rapidly expanding range of applications in the biomedical and materials sciences. Highlighting the continued rapid emergence of technical and scientific advances, the course underscored just how brightly the future of the single molecule field shines. PMID- 25546609 TI - In vivo T-cell depletion using alemtuzumab in family and unrelated donor transplantation for pediatric non-malignant disease achieves engraftment with low incidence of graft vs. host disease. AB - In vivo T-cell depletion, using alemtuzumab therapy prior to SCT, can reduce the incidence of GVHD. This treatment has a potential to delay immune reconstitution resulting in increased morbidity due to viral illnesses. We retrospectively analyzed data on all pediatric patients with non-malignant disorders who received alemtuzumab-based conditioning regimens in our center over the last 10 yr (n = 91). Our data show an OS of 91.2%. The incidence of acute (grade 2-4) GVHD was 18.7% and that of chronic GVHD 5.5%. Viremia due to adenovirus, EBV and CMV was seen in 19.8%, 64.8% and 39.6% patients, respectively, with only two deaths attributed to viral infection (adenovirus). Chimerism level at three month was predictive of graft outcome. Nine patients, who had graft failure after first SCT, were salvaged with a second SCT using RIC and same donor (if available). Based on these results, we conclude that the use of in vivo T-cell depletion is safe, achieves good chimerism and does not lead to increased morbidity and mortality due to viral infections. It is associated with a reduced incidence of chronic GVHD. PMID- 25546608 TI - Embryonic stem cells derived neuron transplantation recovery in models of parkinsonism in relation to severity of the disorder in rats. AB - 6-Hydroxydopamine (6-OHDA)- and 1-methyl-4-phenylpyridinium (MPP(+))-induced hemi parkinsonism was investigated in relation to the severity of the disorder in terms of behavioral disability and nigral neuronal loss and recovery regarding the number of stem cell-derived neurons transplanted in the striatum. Intra median forebrain bundle infusion of the parkinsonian neurotoxins and intra striatal transplantation of differentiated embryonic stem cells (ESCs) were carried out by rat brain stereotaxic surgery. The severity of the disease was determined using the number of amphetamine- or apomorphine-induced rotations, striatal dopamine levels as estimated by high-performance liquid chromatography (HPLC)-electrochemistry, and the number of surviving tyrosine hydroxylase immunoreactive dopaminergic neurons in the substantia nigra pars compacta. Rats that received unilateral infusion of 6-OHDA or MPP(+) responded with dose dependent, unilateral bias in turning behavior when amphetamine or apomorphine was administered. Rotational asymmetry in both models correlated significantly well with the loss in the number of nigral dopaminergic neurons and striatal dopamine depletion. Transplantation of 2*10(5) differentiated murine ESCs revealed remarkably similar kinds of recovery in both animal models. The survival of the grafted dopaminergic cells in the striatum was better in animals with low severity parkinsonism, but poor in the animals with severe parkinsonism. Amphetamine-induced rotational recovery correlated positively with an increasing number of cells transplanted in animals with uniform nigral neuronal lesion. These results suggest that disease severity is an important factor for determining the number of cells to be transplanted in parkinsonian rats for desirable recovery, which may be true in clinical conditions too. PMID- 25546610 TI - Advances in high-resolution accurate mass spectrometry application to targeted proteomics. AB - Targeted quantitative proteomic analyses aim at systematically measuring the abundance of proteins in large sets of samples, without biases or missing values. One typical implementation is the verification of biomarker candidates in bodily fluids, which measures extended lists of validated transitions using triple quadrupole instruments in selected reaction monitoring (SRM) mode. However, the selectivity of this mass spectrometer is limited by the resolving power of its mass analyzers, and interferences may require the reanalysis of the samples. Despite the efforts undertaken in the development of software, and resources to design SRM studies, and to analyze and validate the data, the process remains tedious and time consuming. The development of fast scanning high-resolution and accurate mass (HRAM) spectrometers, such as the quadrupole TOF and the quadrupole orbitrap instruments, offers alternatives for targeted analyses. The selectivity of HRAM measurements in complex samples is greatly improved by effectively separating co-eluting interferences. The fragment ion chromatograms are extracted from the high-resolution MS/MS data using a narrow mass tolerance. The entire process is straightforward as the selection of fragment ions is performed postacquisition. This account describes the different HRAM techniques and discusses their advantages and limitations in the context of targeted proteomic analyses. PMID- 25546611 TI - Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. AB - Salvage therapy followed by high-dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R-DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18 65 years, Eastern Cooperative Oncology Group performance score 0-2, with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) were eligible. R-Dexa-BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression-free-survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B-cell lymphoma 55, mantle cell lymphoma 7, follicular lymphoma (FL) grade 3: 5, indolent Lymphoma (iNHL): FL grade 1-2: 29, marginal zone lymphoma 6, Immunocytoma 1. The overall response rate after salvage therapy was 62% for aNHL and 78% for iNHL patients. 66% of patients with aNHL and 86% with iNHL underwent HDT. Treatment-related mortality for HDT was 1.3%. For aNHL patients, the median PFS was 0.83 years with 44% alive at the median follow-up of 7.3 years. Corresponding figures for iNHL were: median PFS 3.7 years and 72% alive after 8 years. The combination of rituximab with DexaBEAM followed by HDT resulted in high response rates and sustained remissions in responders. R-DexaBEAM followed by HDT can be considered a valid salvage option for NHL. PMID- 25546613 TI - To mutate or not to mutate: genetic and epigenetic heterogeneity contribute to bacterial adaptation (comment on DOI 10.1002/bies.201400153). PMID- 25546612 TI - Cell membrane gp96 facilitates HER2 dimerization and serves as a novel target in breast cancer. AB - HER2 receptor dimerization is a critical step in the HER2 activation process. Here, we demonstrated that heat shock protein gp96 on cell membrane interacts with HER2, facilitates HER2 dimerization and promotes cell proliferation. Cell membrane gp96 levels were observed to correlate with HER2 phosphorylation in primary breast tumors. Finally, we provide evidence that targeting gp96 with a specific monoclonal antibody led to decreased cell growth and increased apoptosis in vitro, and suppression of tumor growth in vivo. Our work represents a new therapeutic strategy for inhibiting HER2 signaling in cancer. PMID- 25546614 TI - CPAS: a trans-omics pathway analysis tool for jointly analyzing DNA copy number variations and mRNA expression profiles data. AB - Pathway-based analysis approaches provide additional insights into the pathogenesis of complex diseases. Copy number variations (CNVs) play an important role in gene expression regulation. Joint pathway analysis of CNVs and gene expression data should provide more useful information for revealing the molecular mechanism of complex diseases. To implement trans-omics pathway analysis of genome-wide CNVs and mRNA expression profiles data, we extended the gene set enrichment analysis algorithm and developed a flexible trans-omics pathway analysis tool CPAS. CPAS was developed by C to interface with R for efficient data analysis. CNV-gene and pathway-gene annotation files derived from public database were included in CPAS. We hope that CPAS could help to identify disease-relevant biological pathways that were undetectable using traditional single-omic analysis approaches. PMID- 25546615 TI - Melatonin decreases muscular oxidative stress and inflammation induced by strenuous exercise and stimulates growth factor synthesis. AB - Strenuous exercise is detrimental to athletes because of the overproduction of reactive oxygen species. Melatonin, a classic antioxidant, has been shown to exhibit beneficial effects regarding intense exercise and tissue repair. In this study, we evaluated the onset and resolution of inflammation in melatonin-treated and nontreated rats subjected to a strenuous exercise session. We also analyzed the formation of thiobarbituric acid reactive substances (TBARS) and the activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Control and treated rats were subjected to exhaustive exercise after a period of 10 days of melatonin treatment (20 mg/dL). Plasma and muscle levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1beta), interleukin 6 (IL-6), cytokine-induced neutrophil chemoattractant-2-alpha/beta (CINC-2alpha/beta), l-selectin, macrophage inflammatory protein-3-alpha (MIP 3alpha), and vascular endothelial growth factor (VEGF) were measured prior to, immediately after, and 2 hr after exercise. Our data revealed decreases in the muscle concentrations of IL-1beta (35%), TNF-alpha (13%), IL-6 (48%), and TBARS (40%) in the melatonin-treated group compared with the control group. We also observed decreases in the plasma concentrations of IL-1beta (17%) in the melatonin-treated group. VEGF-alpha concentrations and SOD activity increased by 179% and 22%, respectively, in the melatonin-treated group compared with the control group. We concluded that muscle inflammation and oxidative stress resulting from exhaustive exercise were less severe in the muscles of melatonin treated animals than in the muscles of control animals. Thus, melatonin treatment may reverse exercise-induced skeletal muscle inflammation and stimulate growth factor synthesis. PMID- 25546616 TI - Chronic oxidative stress leads to malignant transformation along with acquisition of stem cell characteristics, and epithelial to mesenchymal transition in human renal epithelial cells. AB - Oxidative injury to cellular macromolecules has been suggested as a common pathway shared by multiple etiological factors for kidney cancer. Whether the chronic oxidative stress alone is sufficient to induce malignant transformation in human kidney cells is not clear. Therefore, the objective of this study was to evaluate the effect of H2O2-induced chronic oxidative stress on growth, and malignant transformation of HK-2 normal kidney epithelial cells. This study revealed that chronic oxidative stress causes increased growth and neoplastic transformation in normal kidney epithelial cells at non-cytotoxic dose and increased adaptation to cytotoxic level. This was confirmed by gene expression changes, cell cycle analysis, anchorage independent growth assay and in vivo tumorigenicity in nude mice. Stem cells characteristics as revealed by up regulation of stem cell marker genes, and morphological changes indicative of EMT with up regulation of mesenchymal markers were also observed in cells exposed to chronic oxidative stress. Antioxidant NAC did not reverse the chronic oxidative stress-induced growth, and adaptation suggesting that perturbed biological function in these cells are permanent. Partial reversal of oxidative stress induced growth, and adaptation by silencing of Oct 4 and Snail1, respectively, suggest that these changes are mediated by acquisition of stem cell and EMT characteristics. In summary, this study for the first time suggests that chronic exposure to elevated levels of oxidative stress is sufficient to induce malignant transformation in kidney epithelial cells through acquisition of stem cell characteristics. Additionally, the EMT plays an important role in increased adaptive response of renal cells to oxidative stress. PMID- 25546617 TI - Enzymatic polymerization of cyclic monomers in ionic liquids as a prospective synthesis method for polyesters used in drug delivery systems. AB - Biodegradable or bioresorbable polymers are commonly used in various pharmaceutical fields (e.g., as drug delivery systems, therapeutic systems or macromolecular drug conjugates). Polyesters are an important class of polymers widely utilized in pharmacy due to their biodegradability and biocompatibility features. In recent years, there has been increased interest in enzyme-catalyzed ring-opening polymerization (e-ROP) of cyclic esters as an alternative method of preparation of biodegradable or bioresorbable polymers. Ionic liquids (ILs) have been presented as green solvents in enzymatic ring-opening polymerization. The activity, stability, selectivity of enzymes in ILs and the ability to catalyze polyester synthesis under these conditions are discussed. Overall, the review demonstrates that e-ROP of lactones or lactides could be an effective method for the synthesis of useful biomedical polymers. PMID- 25546618 TI - EDTA a novel inducer of pisatin, a phytoalexin indicator of the non-host resistance in peas. AB - Pea pod endocarp suppresses the growth of an inappropriate fungus or non-pathogen by generating a "non-host resistance response" that completely suppresses growth of the challenging fungus within 6 h. Most of the components of this resistance response including pisatin production can be elicited by an extensive number of both biotic and abiotic inducers. Thus this phytoalexin serves as an indicator to be used in evaluating the chemical properties of inducers that can initiate the resistance response. Many of the pisatin inducers are reported to interact with DNA and potentially cause DNA damage. Here we propose that EDTA (ethylenediaminetetraacetic acid) is an elicitor to evoke non-host resistance in plants. EDTA is manufactured as a chelating agent, however at low concentration it is a strong elicitor, inducing the phytoalexin pisatin, cellular DNA damage and defense-responsive genes. It is capable of activating complete resistance in peas against a pea pathogen. Since there is also an accompanying fragmentation of pea DNA and alteration in the size of pea nuclei, the potential biochemical insult as a metal chelator may not be its primary action. The potential effects of EDTA on the structure of DNA within pea chromatin may assist the transcription of plant defense genes. PMID- 25546619 TI - Toxicity of Fatty Acid autoxidation products: highest anti-microbial toxicity in the initial oxidative phase. AB - The autoxidation-degradation processes of polyunsaturated fatty acids give rise to toxic products, and the relative toxicity at different stages of the process is of great interest. We report here that when methyl alpha-linolenate is exposed to sunlight and air, its antimicrobial activity against yeasts and bacteria (as measured by agar diffusion) reaches its maximum during the early oxidative phase when addition of oxygen occurs and the mass increases drastically. Before exposure, the activity is minimal or zero, but it increases rapidly during the first days of the test, simultaneously with the increase of the mass of the material, and begins to decrease while the mass is still increasing and before the mass begins to decrease due to degradation and formation of volatile compounds. Thus, the products formed during the degradation phase of the process are far less toxic to the test organisms than the compounds formed at the early stages when addition of oxygen occurs with maximal rate. PMID- 25546620 TI - Synthesis and anti-Trypanosoma cruzi activity of diaryldiazepines. AB - Chagas disease is a so-called "neglected disease" and endemic to Latin America. Nifurtimox and benznidazole are drugs that have considerable efficacy in the treatment of the acute phase of the disease but cause many significant side effects. Furthermore, in the Chronic Phase its efficiency is reduced and their therapeutic effectiveness is dependent on the type of T. cruzi strain. For this reason, the present work aims to drive basic research towards the discovery of new chemical entities to treat Chagas disease. Differently substituted 5,7-diaryl 2,3-dihydro-1,4-diazepines were synthesized by cyclocondensation of substituted flavones with ethylenediamine and tested as anti-Trypanosoma cruzi candidates. Epimastigotes of the Y strain from T. cruzi were used in this study and the number of parasites was determined in a Neubauer chamber. The most potent diaryldiazepine that reduced epimastigote proliferation exhibited an IC50 value of 0.25 MUM, which is significantly more active than benznidazole. PMID- 25546621 TI - Effect of monomer dosing rate in the preparation of mesoporous polystyrene nanoparticles by semicontinuous heterophase polymerization. AB - The semicontinuous heterophase polymerization of styrene in the presence of cross linking and porogen agents was carried out. Latexes with close to 20% solid content, which contained mesoporous nanoparticles with 28 nm in average diameters, up to 0.5 cm3/g in porosity and 6-8 nm in pore diameters were obtained. By varying the monomer dosing rate over the micellar solution, an unexpected direct dependence of instantaneous conversion on the monomer dosing rate was found. This was ascribed to the higher average number of radicals per particle attained in the polymerization at the higher dosing rate, which in turn would arise from the higher gel percentage in the polymer. It is believed that the cross-linked chains prevent encounters between radicals, delaying the bimolecular termination reactions and allowing the existence of more than one radical inside the particles, which in turn increases the propagation rate. PMID- 25546622 TI - Comparison of the separation performances of cinchona alkaloid-based zwitterionic stationary phases in the enantioseparation of beta2- and beta3-amino acids. AB - The enantiomers of twelve unusual beta2- and beta3-homoamino acids containing the same side-chains were separated on chiral stationary phases containing a quinine- or quinidine-based zwitterionic ion-exchanger as chiral selector. The effects of the mobile phase composition, the nature and concentration of the acid and base additives and temperature on the separations were investigated. The changes in standard enthalpy, ?(?H degrees ), entropy, ?(?S degrees ), and free energy, ?(?G degrees ), were calculated from the linear van't Hoff plots derived from the ln alpha vs. 1/T curves in the studied temperature range (10-50 degrees C). The values of the thermodynamic parameters depended on the nature of the selectors, the structures of the analytes, and the positions of the substituents on the analytes. A comparison of the zwitterionic stationary phases revealed that the quinidine-based ZWIX(-)TM column exhibited much better selectivity for both beta2 and beta3-amino acids than the quinine-based ZWIX(+)TM column, and the separation performances of both the ZWIX(+)TM and ZWIX(-)TM columns were better for beta2-amino acids. The elution sequence was determined in some cases and was observed to be R < S and S < R on the ZWIX(+)TM and ZWIX(-)TM columns, respectively. PMID- 25546623 TI - Using dyes for evaluating photocatalytic properties: a critical review. AB - This brief review aims at analyzing the use of dyestuffs for evaluating the photocatalytic properties of novel photocatalysts. It is shown that the use of dyes as predictors for photocatalytic activity has its roots in the pre visible light activity era, when the aim was to treat effluents streams containing hazardous dyes. The main conclusion of this review is that, in general, dyes are inappropriate as model compounds for the evaluation of photocatalytic activity of novel photocatalysts claimed to operate under visible light. Their main advantage, the ability to use UV-Vis spectroscopy, is severely limited by a variety of factors, most of which are related to the presence of other species. The presence of a second mechanism, sensitization, diminishes the generality required from a model contaminant used for testing a novel photocatalyst. While it is recommended not to use dyes for general testing of novel photocatalysts, it is still understandable that a model system consisting of a dye and a semiconductor can be of large importance if the degradation of a specific dye is the main aim of the research, or, alternatively, if the abilities of a specific dye to induce the degradation of a different type of contaminant are under study. PMID- 25546624 TI - 3beta-O-tigloylmelianol from Guarea kunthiana: a new potential agent to control Rhipicephalus (Boophilus) microplus, a cattle tick of veterinary significance. AB - Chemical investigation of Guarea kunthiana fruits, guided by their effect on the reproductive cycle of engorged females of the cattle tick Rhipicephalus (Boophilus) microplus-a major economic problem to the livestock industry worldwide-led to isolation of 3beta-O-tigloylmelianol, a new protolimonoid, from the bioactive hexane phase obtained by partitioning the crude ethanol extract. An adult immersion test was performed. The compound strongly inhibited egg-laying and hatchability (99.2% effectiveness at a 0.01% concentration). Melianone, isolated from the same phase, yielded unremarkable results in the adult immersion test. From the dichloromethane phase, melianol, melianodiol, meliantriol, and a new protolimonoid, 3beta-O-tigloylmeliantriol, were isolated, all of which, in the same manner as melianone, exhibited unremarkable results in the test. The structures of new and known compounds were mostly established by 1D- and 2D-NMR analyses and mass spectrometry data. This is the first report on the bioactivity of protolimonoids on the reproductive cycle of engorged females of R. (B.) microplus. 3beta-O-Tigloylmelianol proved a promising candidate for the development of a biocontrol agent against the cattle tick investigated, as an alternative to environmentally hazardous synthetic acaricides. PMID- 25546625 TI - Xanthones from the roots of Moutabea guianensis Aubl. AB - The phytochemical investigation of Moutabea guianensis roots led to the isolation of five polyoxygenated xanthones, including two new ones named moutabeone B (1,8 dihydroxy-4,5,6,7-tetramethoxyxanthone) and moutabeone C (1-hydroxy-4,5,6,7,8 pentamethoxyxanthone), along with the three known xanthones, 1,8-dihydroxy-4,6 dimethoxyxanthone, 1,8-dihydroxy-4,5,6-trimethoxyxanthone and augustin A (1,8 dihydroxy-4,6,7-trimethoxyxanthone). Structural characterization of all compounds was established on the basis of spectroscopic methods, mainly 1D and 2D nuclear magnetic resonance (NMR) and comparison with literature data. The antioxidant activity of compounds was tested through a thin layer chromatography (TLC) bioautography assay using 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH.) as detection reagent. All tested compounds were more active (DL < 0.13-0.03 ug) than Trolox (DL < 0.15 ug), used as reference standard. PMID- 25546626 TI - In silico affinity profiling of neuroactive polyphenols for post-traumatic calpain inactivation: a molecular docking and atomistic simulation sensitivity analysis. AB - Calcium-activated nonlysosomal neutral proteases, calpains, are believed to be early mediators of neuronal damage associated with neuron death and axonal degeneration after traumatic neural injuries. In this study, a library of biologically active small molecular weight calpain inhibitors was used for model validation and inhibition site recognition. Subsequently, two natural neuroactive polyphenols, curcumin and quercetin, were tested for their sensitivity and activity towards calpain's proteolytic sequence and compared with the known calpain inhibitors via detailed molecular mechanics (MM), molecular dynamics (MD), and docking simulations. The MM and MD energy profiles (SJA6017 < AK275 < AK295 < PD151746 < quercetin < leupeptin < PD150606 < curcumin < ALLN < ALLM < MDL-28170 < calpeptin) and the docking analysis (AK275 < AK295 < PD151746 < ALLN < PD150606 < curcumin < leupeptin < quercetin < calpeptin < SJA6017 < MDL-28170 < ALLM) demonstrated that polyphenols conferred comparable calpain inhibition profiling. The modeling paradigm used in this study provides the first detailed account of corroboration of enzyme inhibition efficacy of calpain inhibitors and the respective calpain-calpain inhibitor molecular complexes' energetic landscape and in addition stimulates the polyphenol bioactive paradigm for post-SCI intervention with implications reaching to experimental in vitro, in cyto, and in vivo studies. PMID- 25546627 TI - Palliative care: reduced to a little purple pill? PMID- 25546628 TI - Should minor stroke patients be thrombolyzed? A focused review and future directions. AB - Stroke is a leading cause of morbidity and mortality worldwide. Up to 80% of ischemic stroke patients may initially present with minor symptoms. Minor stroke and transient ischemic attack patients are typically treated conservatively with antiplatelet agents and general vascular prevention strategies. Yet a high proportion develop recurrent stroke or progression of stroke and up to one in four of these patients are disabled or dead at follow-up. Minor or rapidly improving symptoms are the top reasons for withholding thrombolytic therapy to time-eligible stroke patients as they are believed to be 'too good to treat'. The benefits and risks of treating mild ischemic strokes are still unclear. The increasing use of computed tomography angiography and its ability to identify both proximal and distal intracranial occlusions may change this equation. In this review, we discuss the diagnosis and prognosis of mild strokes, the role of neurovascular imaging in treatment decision making, experience with thrombolysis in this patient population, and propose directions for future studies. PMID- 25546629 TI - The making of giant pumpkins: how selective breeding changed the phloem of Cucurbita maxima from source to sink. AB - Despite the success of breeding programmes focused on increasing fruit size, relatively little is known about the anatomical and physiological changes required to increase reproductive allocation. To address this gap in knowledge, we compared fruit/ovary anatomy, vascular structure and phloem transport of two varieties of giant pumpkins, and their smaller fruited progenitor under controlled environmental conditions. We also modelled carbon transport into the fruit of competitively grown plants using data collected in the field. There was no evidence that changes in leaf area or photosynthetic capacity impacted fruit size. Instead, giant varieties differed in their ovary morphology and contained more phloem on a cross-sectional area basis in their petioles and pedicels than the ancestral variety. These results suggest that sink activity is important in determining fruit size and that giant pumpkins have an enhanced capacity to transport carbon. The strong connection observed between carbon fixation, phloem structure and fruit growth in field-grown plants indicates that breeding for large fruit has led to changes throughout the carbon transport system that could have important implications for how we think about phloem transport velocity and carbon allocation. PMID- 25546630 TI - Electronic vs steric effects on the stability of anionic species: a case study on the ortho and para regioisomers of organofullerenes. AB - The stability of the anionic species of the ortho and para regioisomers of (MeO)BnC(2n) (Me = methyl, Bn = benzyl, n = 30 or 35) has been examined. The results show that the ortho adducts (electronically favored regioisomers) are stable upon receiving one or two electrons, while the para ones (sterically favored adducts) decompose by removing the methoxy group under similar conditions. Computational calculations indicate that the stability of the anionic species is significantly affected by the electronic structure, where the [5,6] double bond is responsible for the instability of the reduced species of the para adducts. Further study with 1,15-(MeO)2-2,4-Bn2C60, an adduct with both the ortho and para positioned methoxy, shows that the reduced species is stable, indicating that the 1,2,4,15-configuration is an electronically preferential structure even though it has a [5,6]-double bond. PMID- 25546631 TI - Tumor deposits in head and neck carcinomas. AB - BACKGROUND: Tumor deposits, nodules in the peritumoral adipose tissue with no architectural residue of lymph node, have previously been described in colorectal adenocarcinomas. To date, however, there has been no examination of tumor deposits in head and neck squamous cell carcinoma (HNSCC). METHODS: Neck dissection specimens of 140 patients with HNSCC were reevaluated for tumor deposits. RESULTS: Tumor deposits were detected in 24 cases (17%). Cases with tumor deposits had more lymphatic invasion (p = .007), higher pathological N classification (p = .00), and more frequently showed distant metastasis (p = .003). Disease-free and overall survival were significantly shorter for tumor deposit positive cases (p = .016 and p = .005, respectively). Only tumor deposits were significant for overall survival. Tumor deposits increased the risk of recurrent disease 2294 times. Tumor deposits and pericapsular invasion were identified as independent prognostic markers; tumor deposits increased the risk of death from disease 3.4 times, whereas pericapsular invasion was associated with a 2.2-fold increase in the risk of death. CONCLUSION: These results highlight the existence of tumor deposits in neck dissection specimens of HNSCC and their association with poor prognosis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E256-E260, 2016. PMID- 25546633 TI - The Interaction of Language-Specific and Universal Factors During the Acquisition of Morphophonemic Alternations With Exceptions. AB - Using the artificial language paradigm, we studied the acquisition of morphophonemic alternations with exceptions by 160 German adult learners. We tested the acquisition of two types of alternations in two regularity conditions while additionally varying length of training. In the first alternation, a vowel harmony, backness of the stem vowel determines backness of the suffix. This process is grounded in substance (phonetic motivation), and this universal phonetic factor bolsters learning a generalization. In the second alternation, tenseness of the stem vowel determines backness of the suffix vowel. This process is not based in substance, but it reflects a phonotactic property of German and our participants benefit from this language-specific factor. We found that learners use both cues, while substantive bias surfaces mainly in the most unstable situation. We show that language-specific and universal factors interact in learning. PMID- 25546632 TI - Combined computational and experimental analysis of a complex of ribonuclease III and the regulatory macrodomain protein, YmdB. AB - Ribonuclease III is a conserved bacterial endonuclease that cleaves double stranded(ds) structures in diverse coding and noncoding RNAs. RNase III is subject to multiple levels of control that in turn confer global post transcriptional regulation. The Escherichia coli macrodomain protein YmdB directly interacts with RNase III, and an increase in YmdB amount in vivo correlates with a reduction in RNase III activity. Here, a computational-based structural analysis was performed to identify atomic-level features of the YmdB RNase III interaction. The docking of monomeric E. coli YmdB with a homology model of the E. coli RNase III homodimer yields a complex that exhibits an interaction of the conserved YmdB residue R40 with specific RNase III residues at the subunit interface. Surface Plasmon Resonance (SPR) analysis provided a KD of 61 nM for the complex, corresponding to a binding free energy (DeltaG) of -9.9 kcal/mol. YmdB R40 and RNase III D128 were identified by in silico alanine mutagenesis as thermodynamically important interacting partners. Consistent with the prediction, the YmdB R40A mutation causes a 16-fold increase in K(D) (DeltaDeltaG = +1.8 kcal/mol), as measured by SPR, and the D128A mutation in both RNase III subunits (D128A/D128'A) causes an 83-fold increase in KD (DeltaDeltaG = +2.7 kcal/mol). The greater effect of the D128A/D128'A mutation may reflect an altered RNase III secondary structure, as revealed by CD spectroscopy, which also may explain the significant reduction in catalytic activity in vitro. The features of the modeled complex relevant to potential RNase III regulatory mechanisms are discussed. PMID- 25546634 TI - Sun-related behaviours among young Australians with Asian ethnic background: differences according to sociocultural norms and skin tone perceptions. AB - Deliberate tanning, poor sun protection and sun exposure increase an individual's risk for skin cancer. Recent evidence suggests that individuals of Asian heritage have lower incidence of skin cancer than Caucasians but that their post-diagnosis outcomes are often worse. In Western cultures tanning behaviours are often motivated by a desire for 'attractive' tanned skin. Conversely, a light complexion is desired in a number of Asian cultures and may consequently serve to protect this group from excessive and risky sun exposure behaviours. This possibility is yet to be tested, with little known about the sun-related behaviours of Asian people residing in Australia. The present study involves 140 South Australian young adults who report having Asian heritage. Results show that the majority of female participants, and significantly fewer males, reported participating in deliberate outdoor tanning behaviour. Perceptions of family, peer and media tanning norms influenced behaviour, with peer norms being the strongest predictor. The desire for a lighter skin tone was associated with increased sun-protective behaviour and a lower number of previous severe sunburns. As a significant proportion of participants engaged in deliberate tanning behaviour, it is recommended that future research continue to explore factors associated with tanning, including an explicit measure of culture. PMID- 25546635 TI - Concurrent nucleotide substitution mutations in the human genome are characterized by a significantly decreased transition/transversion ratio. AB - There is accumulating evidence that the number of multiple-nucleotide substitutions (MNS) occurring in closely spaced sites in eukaryotic genomes is significantly higher than would be predicted from the random accumulation of independently generated single-nucleotide substitutions (SNS). Although this excess can in principle be accounted for by the concept of transient hypermutability, a general mutational signature of concurrent MNS mutations has not so far been evident. Employing a dataset (N = 449) of "concurrent" double MNS mutations causing human inherited disease, we have identified just such a mutational signature: concurrently generated double MNS mutations exhibit a >twofold lower transition/transversion ratio (termed RTs/Tv ) than independently generated de novo SNS mutations (<0.80 vs. 2.10; P = 2.69 * 10(-14) ). We replicated this novel finding through a similar analysis employing two double MNS variant datasets with differing abundances of concurrent events (150,521 variants with both substitutions on the same haplotypic lineage vs. 94,875 variants whose component substitutions were on different haplotypic lineages) plus 5,430,874 SNS variants, all being derived from the whole-genome sequencing of seven Chinese individuals. Evaluation of the newly observed mutational signature in diverse contexts provides solid support for the postulated role of translesion synthesis DNA polymerases in transient hypermutability. PMID- 25546636 TI - Disorders of growth and development: new genetics, new endocrinology, and new environmental challenges. PMID- 25546637 TI - Vma9p need not be associated with the yeast V-ATPase for fully-coupled proton pumping activity in vitro. AB - Vacuolar-type ATPases (V-ATPases) acidify numerous intracellular compartments in all eukaryotic cells and are responsible for extracellular acidification in some specialized cells. V-ATPases are large macromolecular complexes with at least 15 different subunits, some of which are found in multiple copies. The main roles of all V-ATPase subunits have been established except for the e subunit, encoded by the gene VMA9 in Saccharomyces cerevisiae, and the Ac45 subunit, which is not found in the S. cerevisiae enzyme. Here we demonstrate that when the S. cerevisiae V-ATPase is solubilized with the detergent dodecylmaltoside (DDM), Vma9p is removed. We further demonstrate that after Vma9p has been removed by detergent the purified enzyme is still able to perform fully-coupled ATP dependent proton pumping. This observation shows that Vma9p is not necessary in vitro for this principal activity of the V-ATPase. PMID- 25546638 TI - [Reliability of the Chilean version of the Hare PCL-R and convergent validity with other assessment tools for psychopathy]. AB - INTRODUCTION: Evaluation of mental health in forensic field is relevant in order to plan interventions and diminish institutional risks. The procedure includes the evaluation of psychopathic traits, which should be assessed by reliable and valid instruments. OBJECTIVES: To evaluate the internal congruence of the Chilean version of the PCL-R, and the convergent validity with the PCL: SV, the SRP-III SF and the IM-P. To explore the utility of the PCL: SV as screening tool. MATERIAL AND METHOD: The population of sentenced inmates of the Jail of Los Andes, Chile, was evaluated in a cross sectional study (N=209 inmates of a universe of 235 eligible subjects). Data was obtained from different sources and the interviews were video-recorded. The PCL-R, PCL: SV, IM-P and SRP-III-SF were used. RESULTS: Cronbach Alpha for the PCL-R total score was 0.97. The correlation of the total PCL-R score with the PCL: SV was 0.87; 0.37 with the SRP-III-SF and 0.75 with the IM-P. Sensibility of the PCL: SV was 1 and specificity 0.90 thus concluding that it is an excellent screening test. PMID- 25546639 TI - [Theory of Mind in eating disorders: endophenotype of the disease?]. AB - Considering the clinical and empirical evidence of socio-cognitive difficulties in patients with eating disorders, this paper aims to critically review the current state of research on theory of mind in anorexia and bulimia, to evaluate if there is any alteration of it in these pathologies and to determine whether there are indicators that can be considered endophenotype. METHOD: We conducted a literature search of PubMed database, using keywords related to the topic. The papers were analyzed according to inclusion/ exclusion criteria. RESULTS: We identified seven studies of patients with anorexia, one on bulimia and four on both pathologies. Most studies reported that patients with anorexia have alterations in the theory of mind. Studies on bulimia are scarce, and their results contradictory. CONCLUSION: Research on theory of mind in eating disorders at initial level, being the most of works on anorexia. There are indicators of deficits for this pathology on ToM tasks, and they might be considered endophenotypes, although studies that evaluate unaffected first-degree relatives are still lacking. PMID- 25546640 TI - [The concept of "understanding" (Verstehen) in Karl Jaspers]. AB - This article explores the relationship between empathy and psychopathology. It deals with the concept of "understanding" in Jaspers' General Psychopathology, 100 years after the publication of its first edition. The Jaspersian proposal has the person and his/her experience as its primary object of study, just as in Ortegas' vital reason. Jaspers' understanding is not rational but empathetic, based on the co-presence of emotional content and detailed descriptions. Jaspers' methodology is essentially pluralistic, considering both explanation and understanding, necessary for psychopathology. Despite certain limits, the concept of understanding is the backbone of the psychopathological reasoning, and has proven useful over a century of clinical practice. However, it needs a review covering the recent epistemological and clinical findings. "To be understandable" is a relational property that emerges from a semiotic process. Therefore, an effective psychology should encompass an inter-subjective process, and get away from strict rationalism. PMID- 25546641 TI - [Psychogenic non-epileptic seizures. Differential diagnosis with epilepsy, clinical presentation and therapeutic approach]. AB - The current term psychogenic non-epileptic seizures were coined by contemporary neurologists and epileptologists, since the implementation of Video electroencephalogram, considered today the gold standard diagnostic tool. Patients with psychogenic non-epileptic seizures comprise a heterogeneous group from the psychiatric point of view. The diagnosis that describes the psychogenic non-epileptic seizures is "conversion disorder", often associated with dissociative disorder. These disorders are frequently co-morbid with depression, anxiety and posttraumatic stress disorder. Furthermore, usually coexist with personality disorders, especially borderline personality disorder, although dependence personality disorder has also been described. A history of trauma is very important in the pathogenesis and development of psychogenic non-epileptic seizures. The symptoms "core" of the psychogenic non-epileptic seizures (conversion and dissociation), some co-morbidities and personality disorders are treated with psychotherapy, while psychotropic drugs are used for co-morbidities such as depression and posttraumatic stress disorder. PMID- 25546642 TI - [Debates on child and adolescent psychiatry. Diagnosis, labeling, use of psychotropic drugs, treatments]. PMID- 25546643 TI - [Between the exaggerated and the exasperated clinic. Bridges, differences and rupture in child and youth mental care]. AB - This article intends to approach a series of contrasting concepts regarding different relevant issues for the Child and Youth Mental Health. Diagnosis as a temporary and unstable assessment method. Early detection and treatment as opposed to the possibility of premature diagnoses. The possible or impossible dialogues between psychoanalysis, neuroscience and cognitive sciences. The problems associated with autism and its different theoretical approach models. The development of each of these complex aspects of the practice considers the risk of treating the child as a mere "pathological entity" and dehumanizing him and his condition from the different perspectives, disciplines and discourses, which intend to address the child and his condition. Finally this proposal aims at building bridges of dialogue, overcoming differences in order to avoid rupture. PMID- 25546644 TI - [The importance of early detection and early intervention for children with autism spectrum conditions]. AB - Autism spectrum disorders are a group of neurodevelopmental disorders characterized by social communication difficulties and restrictive and repetitive patterns of behavior, interests and activities. In Argentina in 2013, legislation introduced both at national and provincial levels generated vigorous debate in relation to early detection of autism spectrum disorders, diagnosis or "pathologization" of children, and early intervention for these children. This paper provides evidence supporting the importance of systematic screening for autism spectrum disorders in toddlers, the usefulness of the new autism spectrum disorder classification provided by DSM-5, the desirability of timely and comprehensive diagnostic assessments by interdisciplinary teams specialized in development, and the critical importance of early intervention. Early intervention takes advantage of the neuroplasticity present in early life and positively impacts prognosis of children and family quality of life. Finally, the role of parent-mediated interventions in the treatment of children with autism spectrum disorders is mentioned. PMID- 25546645 TI - [Are we (child psychiatrists) pathologizing childhood?]. AB - Child psychiatry is a young discipline with great potential. Comparing the current resources that we had a few decades ago the contrast is marked. Our discipline has had a great development. The current psychiatric thinking cannot be defined based on one main theory to which all psychiatrists adhere. There is a theoretical pluralism where different models coexist in tension. The child psychiatrist requires conducting diagnostic regardless of their frame of reference without polarizing the field because not only is required to make a psychiatric diagnosis but also requires an understanding of the unique problems of the patient. Currently we have two methods of assessment and diagnosis of children with psychiatric disorders: 1) the phenomenological method (derived from DSM), and 2) the traditional method (dynamic). The best is to make use of all available resources and clinical tools. The use of psychotropic drugs in clinical practice in children and adolescents has been installed as a controversial issue in our society. These debates have great difficulty crossing ideological and clinical arguments. It is appropriate to put in discussion the use of drugs. It is remarkable the therapeutic potential of psychotropics but we must also keep in mind the great business environment underlying our practice. PMID- 25546646 TI - [Reductionist approaches of complex problems: an epistemological and ethical reflection]. AB - Reductionism is a constitutive feature of the "standard view" or inherited conception in philosophy of science, such as Enrique Mari says in his book "Elements of comparative epistemology". Whereas the "standard view" is one of the articulators of scientism - epistemological hegemonic position in the contexts of education, innovation, evaluation and application of techno-scientific knowledge imposed an analysis of this concept as a necessary condition for its overcoming. This article intends to define the meaning and scope of the epistemological reductionism within the framework of the biomedical sciences, on the basis of their genealogy, and then moving in the explicitation of the multiple ways that invest for, finally, realize the consequences of his naive acceptance - or perhaps downright accomplice, of a great part of the scientific community. The consequences are presented in the field of theory, but very particularly in the field of praxis. Establishing the ethical implications of the epistemological reductionism in the theory and practice of Biomedical Sciences is the objective of this work. PMID- 25546647 TI - [Contribution to child sexual psychopathology]. PMID- 25546648 TI - Reply: To PMID 24277679. PMID- 25546649 TI - Factors that influence soft tissue thickness over the greater trochanter: application to understanding hip fractures. AB - Fall-related hip injuries are a concern for the growing population of older adults. Evidence suggests that soft tissue overlying the greater trochanter attenuates the forces transmitted to the proximal femur during an impact, reducing mechanical risk of hip fracture. However, there is limited information about the factors that influence trochanteric soft tissue thickness. The current study used ultrasonography and electromyography to determine whether trochanteric soft tissue thickness could be quantified reproducibly and whether it was influenced by: (1) gender; (2) hip postures associated with potential falling configurations in the sagittal plane (from 30 degrees of extension to 60 degrees of flexion, at 15 degrees intervals), combined adduction-flexion, and combined adduction-extension; and (3) activation levels of the tensor fascia lata (TFL) and gluteus medius (GM) muscles. Our results demonstrated that soft tissue thickness can be measured reliably in nine hip postures and three muscle activation conditions (for all conditions, ICC >0.98). Mean (SD) thickness in quiet stance was 2.52 cm. Thickness was 27.0% lower for males than females during quiet stance. It was 16.4% greater at maximum flexion than quiet standing, 27.2% greater at maximum extension, and 12.5% greater during combined adduction flexion. However, there was no significant difference between combined adduction extension and quiet standing. Thickness was not affected by changes in muscle activity. Forces applied to the femoral neck during a lateral fall decrease as trochanteric soft tissue thickness increases; gender and postural configuration at impact could influence the loads applied to the proximal femur (and thus hip fracture risk) during falls on the hip. PMID- 25546650 TI - Control systems engineering in continuous pharmaceutical manufacturing. May 20 21, 2014 Continuous Manufacturing Symposium. AB - This white paper provides a perspective of the challenges, research needs, and future directions for control systems engineering in continuous pharmaceutical processing. The main motivation for writing this paper is to facilitate the development and deployment of control systems technologies so as to ensure quality of the drug product. Although the main focus is on small-molecule pharmaceutical products, most of the same statements apply to biological drug products. An introduction to continuous manufacturing and control systems is followed by a discussion of the current status and technical needs in process monitoring and control, systems integration, and risk analysis. Some key points are that: (1) the desired objective in continuous manufacturing should be the satisfaction of all critical quality attributes (CQAs), not for all variables to operate at steady-state values; (2) the design of start-up and shutdown procedures can significantly affect the economic operation of a continuous manufacturing process; (3) the traceability of material as it moves through the manufacturing facility is an important consideration that can at least in part be addressed using residence time distributions; and (4) the control systems technologies must assure quality in the presence of disturbances, dynamics, uncertainties, nonlinearities, and constraints. Direct measurement, first principles and empirical model-based predictions, and design space approaches are described for ensuring that CQA specifications are met. Ways are discussed for universities, regulatory bodies, and industry to facilitate working around or through barriers to the development of control systems engineering technologies for continuous drug manufacturing. Industry and regulatory bodies should work with federal agencies to create federal funding mechanisms to attract faculty to this area. Universities should hire faculty interested in developing first principles models and control systems technologies for drug manufacturing that are easily transportable to industry. Industry can facilitate the move to continuous manufacturing by working with universities on the conception of new continuous pharmaceutical manufacturing process unit operations that have the potential to make major improvements in product quality, controllability, or reduced capital and/or operating costs. Regulatory bodies should ensure that: (1) regulations and regulatory practices promote, and do not derail, the development and implementation of continuous manufacturing and control systems engineering approaches; (2) the individuals who approve specific regulatory filings are sufficiently trained to make good decisions regarding control systems approaches; (3) provide regulatory clarity and eliminate/reduce regulatory risks; (4) financially support the development of high-quality training materials for use of undergraduate students, graduate students, industrial employees, and regulatory staff; (5) enhance the training of their own technical staff by financially supporting joint research projects with universities in the development of continuous pharmaceutical manufacturing processes and the associated control systems engineering theory, numerical algorithms, and software; and (6) strongly encourage the federal agencies that support research to fund these research areas. PMID- 25546651 TI - Achenbach's syndrome (paroxysmal finger hematoma) with capillaroscopic evidence of microhemorrhages. PMID- 25546653 TI - Structural and functional assessment of skin nerve fibres in small-fibre pathology. AB - Damage to nociceptor nerve fibres may give rise to peripheral neuropathies, some of which are pain free and some are painful. A hallmark of many peripheral neuropathies is the loss of small nerve fibres in the epidermis, a condition called small-fibre neuropathy (SFN) when it is predominantly the small nerve fibres that are damaged. Historically, SFN has been very difficult to diagnose as clinical examination and nerve conduction studies mainly detect large nerve fibres, and quantitative sensory testing is not sensitive enough to detect small changes in small nerve fibres. However, taking a 3-mm punch skin biopsy from the distal leg and quantification of the nerve fibre density has proven to be a useful method to diagnose SFN. However, the correlation between the nerve fibre loss and other test results varies greatly. Recent studies have shown that it is possible not only to extract information about the nerve fibre density from the biopsies but also to get an estimation of the nerve fibre length density using stereology, quantify sweat gland innervation and detect morphological changes such as axonal swelling, all of which may be additional parameters indicating diseased small fibres relating to symptoms reported by the patients. In this review, we focus on available tests to assess structure and function of the small nerve fibres, and summarize recent advances that have provided new possibilities to more specifically relate structural findings with symptoms and function in patients with SFN. PMID- 25546654 TI - Selection and concentration of obstetric facilities in Japan: Longitudinal study based on national census data. AB - AIM: A shortage of obstetricians with increased workload is a social problem in Japan. In response, the government and professional bodies have accelerated the 'selection and concentration' of obstetric facilities. The aim of this study was to evaluate the recent trend of selection and concentration. METHODS: We used data on the number of deliveries and of obstetricians in each hospital and clinic in Japan, according to the Static Survey of Medical Institutions in 2005, 2008 and 2011. To evaluate the inter-facility equality of distribution of the number of deliveries, number of obstetricians and number of deliveries per obstetrician, Gini coefficients were calculated. RESULTS: The number of obstetric hospitals decreased by 20% and the number of deliveries per hospital increased by 26% between 2005 and 2011. Hospital obstetricians increased by 16% and the average number of obstetricians per hospital increased by 19% between 2008 and 2011. Gini coefficient of deliveries has significantly decreased. In contrast, Gini coefficient of deliveries per obstetrician has significantly increased. The degree of increase in obstetricians and of decrease in deliveries per obstetrician was largest at the hospitals with the highest proportion of cesarean sections. The proportion of obstetric hospitals with the optimal volume of deliveries and obstetricians, as defined by Japan Society of Obstetrics and Gynecology, was 4% in 2008, and it had doubled to 8.1% 3 years later. CONCLUSION: The selection and concentration of obstetric facilities is progressing rapidly and effectively in Japan. PMID- 25546655 TI - Retraction. Association study of TGFBR2 and miR-518 gene polymorphisms with age at natural menopause, premature ovarian failure and early menopause among Chinese Han women. PMID- 25546656 TI - Retraction. Rebamipide plus proton pump inhibitor versus proton pump inhibitor alone in treatment of endoscopic submucosal dissection-induced gastric ulcer: a meta-analysis of randomized controlled trials. PMID- 25546652 TI - Brain tissue responses to neural implants impact signal sensitivity and intervention strategies. AB - Implantable biosensors are valuable scientific tools for basic neuroscience research and clinical applications. Neurotechnologies provide direct readouts of neurological signal and neurochemical processes. These tools are generally most valuable when performance capacities extend over months and years to facilitate the study of memory, plasticity, and behavior or to monitor patients' conditions. These needs have generated a variety of device designs from microelectrodes for fast scan cyclic voltammetry (FSCV) and electrophysiology to microdialysis probes for sampling and detecting various neurochemicals. Regardless of the technology used, the breaching of the blood-brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. Changes to the tissue microenvironment surrounding the device can dramatically impact electrochemical and electrophysiological signal sensitivity and stability over time. This review summarizes the magnitude, variability, and time course of the dynamic molecular and cellular level neural tissue responses induced by state-of-the-art implantable devices. Studies show that insertion injuries and foreign body response can impact signal quality across all implanted central nervous system (CNS) sensors to varying degrees over both acute (seconds to minutes) and chronic periods (weeks to months). Understanding the underlying biological processes behind the brain tissue response to the devices at the cellular and molecular level leads to a variety of intervention strategies for improving signal sensitivity and longevity. PMID- 25546657 TI - Recurrent Kawasaki disease in a child with retropharyngeal involvement: a case report and literature review. AB - Kawasaki disease (KD) is a multisystemic vasculitic disease. Recurrent KD is rare and generally presents in a similar clinical picture as the first episode, and early diagnosis with prompt treatment is the key point in preventing associated cardiovascular morbidities. A 9-year-old boy, who was diagnosed with KD when he was 1.5 years' old, was referred to our hospital for surgical drainage of retropharyngeal abscess. He had a 7-day history of high fever, sore throat, left sided neck swelling, and restricted neck movements. Subsequently, he was diagnosed with recurrent KD and retropharyngeal involvement. He was successfully treated with a single dose of intravenous immunoglobulin (IVIG) and acetyl salicylic acid. Recurrence is rare and occurs most commonly in children. Atypical presentation, incomplete disease, short duration of fever, and reduced response to IVIG treatment were found to be the risk factors for recurrence. KD can occasionally present with clinical and radiographic findings of deep neck bacterial infection. Unusual presentations in KD may cause delay in diagnosis and increase the risk of life-threatening complications. We describe a case of recurrent KD presenting with a clinical picture resembling retropharyngeal infection who fully recovered after 1 dose of IVIG instead of surgical drainage and antibiotic use. PMID- 25546658 TI - Role of osteoprotegerin and its gene polymorphisms in the occurrence of left ventricular hypertrophy in essential hypertensive patients. AB - The aim of the study was to investigate the role of osteoprotegerin (OPG) in left ventricular hypertrophy (LVH) development in patients with essential hypertension (EH). A total of 1092 patients diagnosed with EH were recruited. The LVHs were determined and OPG gene polymorphisms were genotyped. Patients with LVH had a significantly higher mean serum OPG level than those without LVH. The 1181CC genotype carriers had significantly lower risk for LVH compared with GC and GG genotype carriers. The serum OPG level and OPG 1181 G>C polymorphism were found to be independent risk factors for the occurrence of LVH in hypertensive patients. In vitro study shows that OPG overexpression upregulates cell surface size, protein synthesis per cell, and hypertrophy- and fibrosis-related proteins in both cardiomyocytes and cardiac fibroblasts, whereas OPG inhibition can abolish the above-mentioned changes. Consistent with the in vitro data, our in vivo study revealed that the OPG administration induced the LVH in hypertensive rats. This study is the first to report the close association between OPG and LVH development in EH patients and the regulatory effect of OPG on cardiomyocytes and cardiac fibroblasts. PMID- 25546659 TI - Tumor PHD2 expression is correlated with clinical features and prognosis of patients with HCC receiving liver resection. AB - The role of prolyl hydroxylase domain protein 2 (PHD2) in carcinogenesis has been studied in a variety of cancer types. However, the association between PHD2 and human hepatocellular carcinoma (HCC) has not been documented. A total of 220 patients with primary HCC who underwent a curative liver resection were enrolled in this study. The tumor samples were obtained during the surgical procedure from each patient for PHD2 immunohistological staining. All the patients were followed up and the disease-free survival (DFS) and overall survival (OS) were evaluated. We found that that high PHD2 expression was significantly associated with higher stage (stages III + IV) (odds ratio [OR] = 5.576, P < 0.001), larger tumor size (> 5 cm) (OR = 6.176, P < 0.001), poorer tumor differentiation (OR = 1.424, P = 0.003), and higher serum alpha fetoprotein (AFP) level (OR = 6.861, P < 0.001). Compared to those with high PHD2 expressions, patients with low PHD2 expression had significantly longer DFS and OS periods (both P < 0.001). Cox regression analyses revealed that higher levels of PHD2, tumor size, tumor stage, as well as serum AFP level were predictors for a worse prognosis in patients with HCC. PHD2 expression in the tumors is associated with the clinical features and prognosis of patients with HCC; it may be used as a histological marker for HCC. PMID- 25546660 TI - Use of ValtracTM-secured intracolonic bypass in laparoscopic rectal cancer resection. AB - The occurrence of anastomotic leakage (AL) remains a major concern in the early postoperative stage. Because of the relatively high morbidity and mortality of AL in patients with laparoscopic low rectal cancer who receive an anterior resection, a fecal diverting method is usually introduced. The ValtracTM-secured intracolonic bypass (VIB) was used in open rectal resection, and played a role of protecting the anastomotic site. This study was designed to assess the efficacy and safety of the VIB in protecting laparoscopic low rectal anastomosis and to compare the efficacy and complications of VIB with those of loop ileostomy (LI). Medical records of the 43 patients with rectal cancer who underwent elective laparoscopic low anterior resection and received VIB procedure or LI between May 2011 and May 2013 were retrospectively analyzed, including the patients' demographics, clinical features, and operative data. Twenty-four patients received a VIB and 19 patients a LI procedure. Most of the demographics and clinical features of the groups, including Dukes stages, were similar. However, the median distance of the tumor edge from the anus verge in the VIB group was significantly longer (7.5 cm; inter-quartile range [IQR] 7.0-9.5 cm) than that of the L1 group (6.0 cm; IQR 6.0-7.0 cm). None of the patients developed clinical AL. The comparisons between the LI and the VIB groups were adjusted for the significant differences in the tumor level of the groups. After adjustment, the LI group experienced longer overall postoperative hospital stay (14.0 days, IQR: 12.0, 16.0 days; P < 0.001) and incurred higher costs ($6300 (IQR: $5900, $6600)) than the VIB group (7.0 days, $4800; P < 0.05). Stoma-related complications in the ileostomy group included dermatitis (n = 2), stoma bleeding (n = 1), and wound infection after closure (n = 2). No BAR-related complications occurred. The mean time to ValtracTM ring loosening was 14.1 +/- 3.2 days. The VIB procedure, as a good partner with the laparoscopic rectal cancer resection, appears to be a safe and effective, but time-limited, diverting technique to protect an elective low colorectal anastomosis. PMID- 25546661 TI - Locoregional outcomes in clinical stage IIB breast cancer after neoadjuvant therapy and mastectomy with or without radiation. AB - Low rates of locoregional recurrence (LRR) in patients with clinical stage IIB breast cancer (cT2N1 or cT3N0) who undergo neoadjuvant therapy (NAT) and mastectomy have been reported. We aimed to quantify the risk of LRR and the relationship between LRR and potential risk factors in this subset of patients. We conducted a retrospective review of 116 patients with clinical IIB breast cancer who underwent NAT followed by mastectomy +/- postmastectomy radiotherapy (PMRT) between 2000 and 2009. We estimated the rate of LRR by cumulative incidence. The effect of prognostic factors was examined by Gray's test and Fine and Gray's test. Median follow-up: 63 months. Median age: 49. 28.4% cT2N1 and 71.6% cT3N0. 62.1% of tumors were ER+, 22.6% HER2+, 19% triple negative (TN). All patients underwent NAT and mastectomy. The majority of patients (87%) received PMRT; 32.3% were treated to chest wall (CW) only, and 67.7% to CW plus supraclavicular (SCV) field. Compared to cT2N1, patients with cT3N0 disease were more likely to be pN0 (60% vs 27%, P = 0.005). There was no significant relationship between risk of LRR and pathologic complete response (pCR), use of PMRT, RT to SCV field, or TN status, but there was higher risk of LRR in cT2N1 than cT3N0 (HR 6.03, P = 0.015). LRR was more common in cT2N1 than in cT3N0 disease, emphasizing the negative prognostic implication of clinically node positive presentation. PMID- 25546662 TI - Instrumented reduction and monosegmental fusion for Meyerding Grade IV developmental spondylolisthesis: a report of 3 cases. AB - There are numerous reports of treatment methods for spondylolisthesis with a Meyerding Grade of more than III. In high dysplastic spondylosthesis, surgical treatment was selected because there is considered to be a high possibility of low back pain and lower limb neurological symptoms worsening if slippage progresses. Monosegmental lumbar interbody fusion (L5-S1) with a pedicle screw system (PPS) was used to treat three cases of Meyerding Grade IV developmental spondylolisthesis. Patients gave written informed consent. The spondylolisthesis was reduced to Meyerding Grade I and sagittal balance improved in all three cases. In two cases with severe spinal instability, there were no postoperative neurological complications and the course was favorable. However, in one case with little spinal mobility due to vertebral body dysplasia, despite performing sufficient decompression of the nerve root at L5 and slow reduction to avoid placing excessive tension on the nerve root, a transient neurological disorder was observed. A PPS was used to increase the reduction strength and favorable reduction was possible. However, in the case with a long clinical course and the case with poor spinal mobility, since the mobility and plasticity of the nerve root itself may have been reduced, it was considered that reduction should be performed carefully using intraoperative neurological monitoring. PMID- 25546663 TI - Intestinal pseudo-obstruction in systemic lupus erythematosus: a case report and review of the literature. AB - Intestinal pseudo-obstruction (IPO) is a rare but dangerous complication of systemic lupus erythematosus (SLE) when the patient has no other manifestations except gastrointestinal symptoms. We performed 1 patient with a 2-month history of recurrent vomiting and abdominal distension. She admitted past surgical histories of cesarean section and appendectomy. A physical examination revealed tenderness in the right lower abdominal on palpation and bowel sounds were weak, 2 to 3 bpm. An x-ray and CT of her abdomen showed intestinal obstruction. The initial diagnosis was adhesive intestinal obstruction. She received surgical treatment because her symptoms had gradually become more frequent and persistent. But she vomited again 2 weeks later after the surgery. Further immunology tests indicated that she had an IPO secondary to SLE. We treated the patient with methylprednisolone pulse for 3 days and followed by prednisone orally. The patient had a good response. Complete remission was achieved on 8 years follow up. The importance of IPO secondary to SLE lies in an early diagnosis. After the diagnosis is established, immunosuppressive therapy should be the initial and first-line treatment, and surgical intervention is often disappointing and should be carefully avoided. It is necessary to enhance awareness of doctors to IPO secondary to SLE. PMID- 25546665 TI - Early reconstruction surgery resolving visual occlusion and ocular malformation: a case report. AB - Congenital ocular malformation may lead to failure of the development of ocular regions and visual function in the pediatric population. Orbital bones are established within the first 2 months of embryogenesis. Any abnormalities may lead to failure in development of the ocular region. In this case report, we present a newborn with congenital canthus malposition, a distorted tarsus, and mild enophthalmos caused by an embryogenesis fibroma, which although rare, can result in amblyopia. Surgical resection of the fibroma followed by orbital reconstruction of the canthus, correction of malposition and tarsus extension were performed. Twelve months and 5 years follow-up showed no recurrence and the visual acuity was 20/20 in the left eye and 16/20 in the right. The deformity of the left orbit was corrected without complications and was symmetrical with the right side. This is the first known case of children with embryonic fibroma. It is likely that early reconstruction surgery may avoid visual occlusion and ocular malformation. PMID- 25546664 TI - The association of common functional polymorphisms in mir-146a and mir-196a2 and hepatocellular carcinoma risk: evidence from a meta-analysis. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that function as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) located in the miRNAs influence the function of mature miRNAs and may contribute to cancer development. Studies investigating the association between miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms and hepatocellular carcinoma (HCC) risk reported inconsistent results. We performed a meta-analysis of all available studies to summarize this situation. Eligible studies were identified by search of electronic databases including PubMed, Embase, and Cochrane library for the period up to August 2014. The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms and HCC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Finally, a total of 12 studies with 4171 cases and 4901 controls were included for miR-146a rs2910164 polymorphism and 10 studies with 4687 cases and 4990 controls were available for miR-196a2 rs11614913 polymorphism. With respect to miR-146a rs2910164 polymorphism, statistical significant increased HCC risk was found when all studies were pooled into the meta-analysis (GG+CG vs CC: OR = 1.097, 95% CI 1.005-1.197, P = 0.037). In subgroup analyses by ethnicity, source of control, and HWE in controls, significant increase of HCC risk was found in Asians, population-based studies, and studies consistent with HWE, but not in Caucasians, hospital-based studies, and studies inconsistent with HWE. With respect to miR-196a2 rs11614913 polymorphism, no significant association with HCC risk was found in the overall and subgroup analyses. The results suggest that the miR-146a rs2910164 polymorphism contributes to increased HCC susceptibility, especially in Asian populations. Further large and well-designed studies are required to validate this association. PMID- 25546666 TI - Age, arterial stiffness, and components of blood pressure in Chinese adults. AB - Blood pressure (BP) changes with age. We conducted a cross-sectional study in rural Chinese adults to investigate: (1) what is the relationship between age, arterial stiffness, and BP in Chinese men and women; and (2) to what degree can the age-BP relationship be explained by arterial stiffness, controlling for other covariables. These analyses included a total of 1688 subjects (males/females: 623/1065), aged 40 to 88 years. Among them, 353 (20.9%) had hypertension (defined as systolic blood pressure (SBP) >= 140 mm Hg or diastolic blood pressure (DBP) >= 90 mm Hg). Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV). baPWV appeared to be more strongly correlated with BP (including SBP, DBP, mean arterial pressure [MAP], pulse pressure [PP]) than age (P < 0.001 for comparisons between Spearman correlation coefficients). Furthermore, baPWV was associated with BP (including SBP, DBP, MAP, and PP) and risk of hypertension in a dose-response fashion, independent of age; in contrast, the age-BP associations were either attenuated or became negative after adjusting for baPWV. Arterial stiffness appears to be an independent contributor to hypertension, even after adjusting for age and other covariables. In contrast, age-BP associations became attenuated or negative after adjusting for baPWV. The utility of baPWV as a diagnostic, prognostic, and therapeutic indicator for hypertension warrants further investigation. PMID- 25546667 TI - D-dimer as an early marker of severity in patients with acute superior mesenteric venous thrombosis. AB - No early serum marker of disease severity contributes to the treatment decision making process of acute superior mesenteric venous thrombosis (ASMVT). This study aims to assess the value of serum D-dimer level in the first 3 days after admission as a severity marker of ASMVT patients. From May 2010 to June 2014, 50 consecutive patients of ASMVT were enrolled in this observational study. The serum D-dimer level was measured on a daily basis during the first 3 days after admission as well as other laboratory-testing parameters, clinical score, and outcome variables recorded during the same period. The maximum and mean D-dimer values were analyzed and compared with other potential markers for prediction of multiple-organ dysfunction syndrome (MODS) and short-bowel syndrome (SBS). The correlation of D-dimer level with other potential severity markers and inflammation parameters were also studied. Both maximum and mean D-dimer level during the first 3 days of admission were significantly higher in patients with several clinical variables such as death within 30 days, bowel resection, sepsis, abdominal compartment syndrome, MODS, and SBS. In addition, serum D-dimer level showed precise prediction for MODS and SBS, greater than L-lactate and intestinal type fatty acid-binding protein (I-FABP). The D-dimer level was correlated well with L-lactate, I-FABP, and APACHE II score on the first 3 days of admission. Poor correlation of D-dimer level and inflammation parameters, white blood cell count, and C-reactive protein level, was detected. D-dimer level could be an effective, early, and specific serum marker indicating the clinical evolution and outcome of ASMVT. PMID- 25546668 TI - Radiofrequency ablation versus surgical resection for small unifocal hepatocellular carcinomas. AB - We aimed to compare the effectiveness and safety of hepatic resection and radiofrequency ablation (RFA) for small hepatocellular carcinomas (HCCs) less than 5 cm in diameter. A total of 289 patients were diagnosed with a small HCC (a single tumor no larger than 5 cm). Among these patients, 133 underwent hepatic resection, and 156 received RFA. Demographic data, intraoperative data, post operative recovery data, and the baseline characteristics of the 2 groups of patients were compared. The incidence of post-operative complications; 1-, 3-, and 5-year survival rates; and tumor recurrence were determined. No statistically significant differences in the baseline characteristics were noted between the 2 groups. By contrast, operation time (P = 0.003), intraoperative blood loss (P = 0.000), and the length of post-operative hospital stay (P = 0.000) were significantly lower in the RFA group compared with the surgical resection group. The 2 groups displayed similar post-operative complication rates (12% or 16/133 in the liver resection group vs. 8.3% or 13/156 in the RFA group, P = 0.395). The 1-, 3-, and 5-year overall survival rates of the patients in the liver resection group were 88.7%, 78.2%, and 66.2%, respectively, whereas the rates in the RFA group were 90.4%, 76.3%, and 66.0%, respectively (P = 0.722). The 1-, 3-, and 5 year tumor-free survival rates of patients in the resection group were 87.2%, 69.9%, and 58.6%, respectively, whereas the rates in the RFA group were 85.9%, 66.0%, and 54.5%, respectively (P = 0.327). In addition, among HCC patients receiving RFA, patients with tumors no greater than 3 cm in diameter exhibited no significant differences regarding overall survival and tumor-free survival rates compared with patients with tumors 3 to 5 cm in diameter (all P > 0.05). RFA is an effective and safe treatment option for small HCCs and may be a preferred choice for HCC patients with small lesions. PMID- 25546669 TI - Multiple nodular lesions in spleen associated with visceral leishmaniasis: a case report of MRI-findings. AB - The spleen is one of the most commonly involved organs of visceral leishmaniasis (VL). However, there were few reports about imaging findings of splenic leishmaniasis, especially regarding MRI findings. This case report describes a 45 years old male patient from Zhejiang province of southeastern China, who was admitted for persistent fever of unknown origin, with splenomegaly and multiple hypodense/low echo nodules on CT/ultrasonography (USG) studies. MRI showed multiple nodules with concentric rings in the spleen on T2-weighted imaging (T2WI), with no obvious diffusion restriction on diffusion weighted imaging (DWI), and gradual ring-like enhancement after intravenous administration of contrast medium. So MRI suggested necrotic granulomatous lesion. By reviewing the clinical history and following positive serological leishmania antibody test, the patient was finally confirmed a recent infection with VL. The patient received antimony gluconate therapy intravenously. At 4 months follow-up, the contrast enhanced abdominal MRI showed that the size of the spleen was returned to normal and the splenic lesions were completely resolved except for reduced infarction compared with the previous MRI. This is the first case which was performed MRI examination completely. Meanwhile, it is the second case which MRI findings were reported. As for the characteristics of MRI in this case, there are several features, which are helpful for giving the diagnosis and differential diagnosis of VL. PMID- 25546670 TI - Non-union rate with stand-alone lateral lumbar interbody fusion. AB - Retrospective radiographic analysis.To determine the fusion rate of stand-alone lateral lumbar interbody fusion (LLIF). Biomechanical studies have indicated that LLIF may be more stable than anterior or transforaminal lumbar interbody fusion. Early clinical reports of stand-alone LLIF have shown success in obtaining fusion and indirectly decompressing nerve roots. A consecutive case series of stand alone LLIF was analyzed with chart and radiographic review. Non-union was determined by symptomatology consistent with non-union and absence of bridging bone on the CT scan. Thirty-nine levels of stand alone LLIF were performed in 23 patients. Eleven patients received 1-level surgery, 7 patients received 2-level surgery, 3 patients received 3-level surgery, and 1 patient received 4-level surgery. Excluding 1 infected case, we analyzed 37 levels of stand alone LLIF in 22 patients. Non-union incidence was 7 levels in 6 patients. Non-union rate was 7/37 (19%) per level and 6/22 (27%) per patient. While our study population was relatively low, a non-union rate of 19% to 27% is concerning for modern spine surgery. Currently in our practice, we occasionally still perform stand-alone LLIF utilizing 22 mm wide grafts in low-demand levels in non-smoking and non osteoporotic patients. However, in a majority of patients, we provide supplemental fixation: bilateral pedicle screws in most patients and unilateral pedicle screws or spinous process plates in some patients. PMID- 25546671 TI - Intraepithelial giardia intestinalis: a case report and literature review. AB - The giardiasis is a neglected parasitic disease. The WHO has estimated more than 280 million of human infections each year; however, intraepithelial giardiasis is a rare entity, there are only 5 reports showing invasive giardiasis. A pediatric female patient with chronic abdominal pain, diarrhea, or pasty stools, without fever, was seen in the Gastroenterology and Nutrition Service. The stool studies were negative for pathogens and lactose hydrogen breath test was positive. The presumptive clinical diagnosis was giardiasis and the patient was empirically treated with nitazoxanide. But, the patient persisted with abdominal pain and pasty stools. Endoscopy was indicated to search for Helicobacter and Giardia. Guardian and patient gave written informed consent. Hematological profile was normal. The endoscopy was performed under general anesthesia and the biopsies and duodenal aspirate were obtained. The microscopic analyses of duodenal fluid showed Giardia trophozoites. Electron microscopic analysis was negative for Helicobacter pylori, but Giardia trophozoites with a typical crescent shape within the tissue were found. The patient was treated with tinidazole, subsequent tests showed that lactose absorption was normal, stool examinations were negative for Giardia and abdominal pain had stopped. This case suggest that intraepithelial giardiasis could be a common entity but unseen because the giardiasis diagnosis is usually made on fecal samples. Future studies are necessary to determine the role of intraepithelial trophozoites in giardiasis pathogenic mechanisms. PMID- 25546672 TI - Environmental influences on daily emergency admissions in sickle-cell disease patients. AB - Previous reports have suggested a role for weather conditions and air pollution on the variability of sickle cell disease (SCD) severity, but large-scale comprehensive epidemiological studies are lacking. In order to evaluate the influence of air pollution and climatic factors on emergency hospital admissions (EHA) in SCD patients, we conducted an 8-year observational retrospective study in 22 French university hospitals in Paris conurbation, using distributed lag non linear models, a methodology able to flexibly describe simultaneously non-linear and delayed associations, with a multivariable approach. During the 2922 days of the study, there were 17,710 EHA, with a mean daily number of 6.1 +/- 2.8. Most environmental factors were significantly correlated to each other. The risk of EHA was significantly associated with higher values of nitrogen dioxide, atmospheric particulate matters, and daily mean wind speed; and with lower values of carbon monoxide, ozone, sulfur dioxide, daily temperature (minimal, maximal, mean, and range), day-to-day mean temperature change, daily bright sunshine, and occurrence of storm. There was a lag effect for 12 of 15 environmental factors influencing hospitalization rate. Multivariate analysis identified carbon monoxide, day-to-day temperature change, and mean wind speed, along with calendar factors (weekend, summer season, and year) as independent factors associated with EHA. In conclusion, most weather conditions and air pollutants assessed were correlated to each other and influenced the rate of EHA in SCD patients. In multivariate analysis, lower carbon monoxide concentrations, day-to-day mean temperature drop and higher wind speed were associated with increased risk of EHA. PMID- 25546673 TI - Concurrent oncogene mutation profile in Chinese patients with stage Ib lung adenocarcinoma. AB - Molecular characteristics in lung cancer are associated with carcinogenesis, response to targeted therapies, and prognosis. With concurrent oncogene mutations being reported more often, the adjustment of treatment based on the driver gene mutations would improve therapy. We proposed to investigate the distribution of concurrent oncogene mutations in stage Ib lung adenocarcinoma in a Chinese population and find out the correlation between survival outcome and the most frequently mutated genes in EGFR and KRAS in Chinese population. Simultaneously, we tried to validate the Sequenom method by real time fluoresce qualification reverse transcription polymerase chain reaction (RT-PCR) in oncogene detection. One hundred fifty-six patients who underwent complete surgical resection in our hospital between 1999 and 2007 were retrospectively investigated. Using time-of flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined. Genetic mutations occurred in 86 of 156 patients (55.13%). EGFR was most frequently gene contained driver mutations, with a rate of 44.23%, followed by KRAS (8.33%), PIK3CA (3.84%), KIT (3.20%), BRAF (2.56%), AKT (1.28%), MET (0.64%), NRAS (0.64%), HRAS (0.64%), and ERBB2 (0.64%). No mutations were found in the RET, PDGFRA, FGFR1, FGFR3, FLT3, ABL, CDK, or JAK2 oncogenes. Thirteen patients (8.3%) were detected in multiple gene mutations. Six patients had PIK3CA mutations in addition to mutations in EGFR and KRAS. EGFR mutations can coexist with mutations in NRAS, KIT, ERBB2, and BRAF. Only one case was found to have a KRAS mutation coexisting with the EGFR T790M mutation. Otherwise, mutations in EGFR and KRAS seem to be mutually exclusive. There is no survival benefit in favor of EGFR/KRAS mutation. Several concomitant driver gene mutations were observed in our study. None of EFGR/KRAS mutation was demonstrated as a prognostic factor. Polygenic mutation testing by time-of-flight mass spectrometry was validated by RT-PCR, which can be an alternative option to test for multiple mutations and can be widely applied to clinical practice and help to guide treatment. PMID- 25546674 TI - Long-term prognosis of adult patients with steroid-dependent minimal change nephrotic syndrome following rituximab treatment. AB - This study was to evaluate the long-term efficacy and safety of a single-dose rituximab regimen rituximab treatment in adult patients with steroid-dependent minimal change nephrotic syndrome (MCNS). We conducted a prospective cohort study with historical controls to evaluate the effect of single-dose infusions of rituximab at 375 mg/m2 BSA per dose administered at intervals of 6 months for a period of 24 months. At the end of the 24-month period, the patients were divided into the treatment continuation (n = 20) and treatment discontinuation (n = 5) groups according to their intention to continue/discontinue the treatment. A significant reduction in the total number of relapses was observed during the 24 month period after the first rituximab infusion as compared with that during the 24-month period before the first rituximab infusion (108 vs. 8, P < 0.001). Complete remission was induced/maintained in all patients from 12 to 24 months after the first rituximab infusion. In regard to the clinical course after 24 months, 4 of the 20 patients in the treatment continuation group discontinued the rituximab treatment after the fifth infusion and 2 patients discontinued the treatment after the sixth infusion. However, complete remission was maintained in all the 20 patients of this group during the 12-month observation period after the first four single-dose rituximab infusions. On the other hand, 1 of the 5 patients in the treatment discontinuation group developed relapse during the observation period after the first four rituximab infusions, and the rituximab treatment was resumed. In our trial, rituximab therapy was associated with maintenance of complete remission. Complete remission was maintained even in most of the patients who showed B-cell repletion after discontinuation of rituximab therapy. Thus, rituximab may be considered as a radical therapeutic agent for patients with steroid-dependent MCNS. PMID- 25546675 TI - Does the position or contact pressure of the stethoscope make any difference to clinical blood pressure measurements: an observational study. AB - This study aimed to investigate the effect of stethoscope position and contact pressure on auscultatory blood pressure (BP) measurement. Thirty healthy subjects were studied. Two identical stethoscopes (one under the cuff, the other outside the cuff) were used to simultaneously and digitally record 2 channels of Korotkoff sounds during linear cuff pressure deflation. For each subject, 3 measurements with different contact pressures (0, 50, and 100 mm Hg) on the stethoscope outside the cuff were each recorded at 3 repeat sessions. The Korotkoff sounds were replayed twice on separate days to each of 2 experienced listeners to determine systolic and diastolic BPs (SBP and DBP). Variance analysis was performed to study the measurement repeatability and the effect of stethoscope position and contact pressure on BPs. There was no significant BP difference between the 3 repeat sessions, between the 2 determinations from each listener, between the 2 listeners and between the 3 stethoscope contact pressures (all P > 0.06). There was no significant SBP difference between the 2 stethoscope positions at the 2 lower stethoscope pressures (P = 0.23 and 0.45), but there was a small (0.4 mm Hg, clinically unimportant) significant difference (P = 0.005) at the highest stethoscope pressure. The key result was that, DBP from the stethoscope under the cuff was significantly lower than that from outside the cuff by 2.8 mm Hg (P < 0.001, 95% confidence interval -3.5 to -2.1 mm Hg). Since it is known that the traditional Korotkoff sound method, with the stethoscope outside the cuff, tends to give a higher DBP than the true intra-arterial pressure, this study could suggest that the stethoscope position under the cuff, and closer to the arterial occlusion, might yield measurements closer to the actual invasive DBP. PMID- 25546676 TI - Relation between VE/VCO2 slope and maximum phonation time in chronic heart failure patients. AB - This study aimed to determine the relation between the regression slope relating minute ventilation to carbon dioxide output (VE/VCO2 slope) and maximum phonation time (MPT), and the MPT required to attain a threshold value for VE/VCO2 slope of <= 34 in chronic heart failure (CHF) patients. This cross-sectional study enrolled 115 CHF patients (mean age, 54.5 years; men, 84.9%). VE/VCO2 slope was assessed during cardiopulmonary exercise testing (CPX). Thereafter, patients were divided into 2 groups according to exercise capacity: VE/VCO2 slope <= 34 (VE/VCO2 <= 34 group, n = 81) and VE/VCO2 slope > 34 (VE/VCO2 > 34 group, n = 34). For MPT measurements, all patients produced a sustained vowel/a:/ for as long as possible during respiratory effort from the seated position. All subjects showed significant negative correlation between VE/VCO2 slope and MPT (r = -0.51, P < 0.001). After adjustment for clinical characteristics, MPT was significantly higher in the VE/VCO2 <= 34 group vs VE/VCO2 > 34 group (21.4 +/- 6.4 vs 17.4 +/- 4.3 s, F = 7.4, P = 0.007). The appropriate MPT cut-off value for identifying a VE/VCO2 slope <= 34 was 18.12 seconds. An MPT value of 18.12 seconds may be a useful target value for identifying CHF patients with a VE/VCO2 slope <= 34 and for risk management in these patients. PMID- 25546677 TI - Increasing the supply of kidneys for transplantation by making living donors the preferred source of donor kidneys. AB - At the present time, increasing the use of living donors offers the best solution to the organ shortage problem. The clinical questions raised when the first living donor kidney transplant was performed, involving donor risk, informed consent, donor protection, and organ quality, have been largely answered. We strongly encourage a wider utilization of living donation and recommend that living donation, rather than deceased donation, become the first choice for kidney transplantation. We believe that it is ethically sound to have living kidney donation as the primary source for organs when the mortality and morbidity risks to the donor are known and kept extremely low, when the donor is properly informed and protected from coercion, and when accepted national and local guidelines for living donation are followed. PMID- 25546678 TI - Predictors of mortality within 6 weeks after treatment of gastric variceal bleeding in cirrhotic patients. AB - Acute gastric variceal bleeding (GVB) is a catastrophic problem and accounts for one of the major causes of death in cirrhotic patients. Although, N-butyl cyanoacrylate (NBC) has been shown to control bleeding effectively, it still carries up high mortality rate. This study aimed to find the predictors of mortality within 6 weeks after emergent endoscopic treatment with NBC injection. This retrospective study recruited patients with acute GVB after emergent endoscopic NBC injection between January 2011 and June 2013 in Linkou Medical Center, Chang Gung Memorial Hospital, Linkou, Taiwan. Logistic regression analysis was applied for predictors of mortality within 6 weeks. Statistical significance was set as P < 0.05. There were 132 patients with acute GVB (83.3% men, median age 51.3 years) with endoscopic NBC injection treatments recruited. Mortality within 6 weeks was noted in 16.7% patients. By multivariate analysis, renal function impairment (odds ratio [OR]: 21.1, 95% confidence interval [CI]: 3.06-146.0, P = 0.002), higher Child-Turcotte-Pugh (CTP) score (OR: 2.49, 95% CI: 1.41-4.38, P = 0.002), higher model for end-stage liver disease (MELD) score (OR: 1.18, 95% CI: 1.03-1.35, P = 0.013), rebleeding within 5 days (OR: 16.4, 95% CI: 3.36-79.7, P = 0.001), and acute on chronic liver failure (ACLF) (OR: 4.67, 95% CI: 1.62-13.33, P = 0.004) were independent predictors of mortality within 6 weeks. A MELD score of >= 18 was associated with Area Under the Receiver Operating Characteristic (AUROC) of 0.79 (P < 0.001, 95% CI: 0.69-0.90) and a CTP score of >= 9 with AUROC of 0.85 (P < 0.001, 95% CI: 0.76-0.94) for determining 6 weeks mortality. Impaired renal function, deteriorated liver function with CTP score >= 9 as well as MELD score >= 18, rebleeding within 5 days, and ACLF are independent predictors of mortality. PMID- 25546679 TI - Antibody to hepatitis B core antigen levels in the natural history of chronic hepatitis B: a prospective observational study. AB - Previous studies have revealed antibody to hepatitis B core antigen (anti-HBc) levels as a predictor of treatment response in hepatitis B early antigen (HBeAg) positive chronic hepatitis B (CHB) patients in both interferon and nucleos(t)ide analog therapy cohorts. However, there is no information about anti-HBc levels in the natural history of CHB. This study aimed to define anti-HBc levels of different phases in the natural history of CHB. Two hundred eleven treatment naive CHB patients were included in the study. They were classified into 4 phases: immune tolerance (IT) phase (n = 39), immune clearance (IC) phase (n = 48), low or no-replicative (LR) phase (n = 55), and HBeAg-negative hepatitis (ENH, n = 69). Fifty patients who were HBsAg negative and anti-HBc positive were also recruited as past HBV infection (PBI) control group. Anti-HBc levels were measured by a newly developed double-sandwich immunoassay. Correlation of anti HBc levels with alanine aminotransferase (ALT) and other HBV-related markers within each phase was performed. Serum anti-HBc levels were statistically significant between patients in different phases of CHB (P < 0.001). The median anti-HBc levels were: IT (3.17 log 10 IU/mL), IC (4.39 log 10 IU/mL), LR (3.29 log 10 IU/mL), ENH (4.12 log 10 IU/mL), and PBI (0.61 log 10 IU/mL). There existed a strong correlation in IC (r = 0.489, P < 0.001), a poor correlation in ENH (r = 0.275, P = 0.042), and no correlation in patients with ALT reached 5 times upper limit of normal (r = 0.120, P = 0.616). Anti-HBc levels show significant differences during the natural course of CHB. These results may provide some potentially useful insights into hepatitis B pathogenesis and immune activation against hepatitis B virus. PMID- 25546680 TI - Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort. AB - Hereditary multiple intestinal atresia (HMIA) is a rare cause of intestinal obstruction in humans associated with a profound combined immune deficiency. Deleterious mutations of the tetratricopeptide repeat domain-7A (TTC7A) gene lead to HMIA, although the mechanism(s) causing the disease in TTC7A deficiency has (have) not yet been clearly identified. To evaluate the consequences of TTC7A deficiency, we studied the morphology of several organs from HMIA patients at different developmental stages, as well as the expression of the TTC7A protein. We performed histological and immunohistochemical analyses on biopsies and autopsies of 6 patients and 1 fetus with HMIA. Moreover, we characterized for the first time the expression of the TTC7A protein by immunostaining it in several organs from control (including fetal samples), infants, and 1 fetus with HMIA. Besides the gastrointestinal tract, HMIA disease was associated with morphological alterations in multiple organs: thymus, lung, spleen, and liver. Moreover, we demonstrated that normal TTC7A protein was expressed in the cytoplasm of epithelial cells of the intestine, thymus, and pancreas. Surprisingly, altered TTC7A protein was highly expressed in tissues from patients, mainly in the epithelial cells. We have established that HMIA associated with a TTC7A defect is characterized by multiorgan impairments. Overall, this report suggests that TTC7A protein is critical for the proper development, preservation, and/or function of thymic and gastrointestinal epithelium. PMID- 25546681 TI - Association between XPD Lys751Gln and Asp312Asn polymorphisms and hepatocellular carcinoma risk: a systematic review and meta-analysis. AB - Genetic polymorphisms of xeroderma pigmentosum group D (XPD) in the nucleotide excision repair pathway may influence cancer susceptibility by affecting the capacity for DNA repair. Studies investigating the association between XPD Lys751Gln and Asp312Asn polymorphisms and hepatocellular carcinoma (HCC) risk reported inconsistent results. The aim of this study was to quantitatively summarize the evidence for such an association. Eligible studies were identified by searching electronic databases including PubMed, Embase, Cochrane library, and CBM, Chinese Biomedical Literature Database, for the period up to October 2014. The association of XPD Lys751Gln and Asp312Asn polymorphisms and HCC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Finally, a total of 11 studies with 4322 cases and 4970 controls were included for XPD Lys751Gln polymorphism and 6 studies with 2223 cases and 2441 controls were available for XPD Asp312Asn polymorphism. With respect to XPD Lys751Gln polymorphism, statistically significant increased HCC risk was found when all studies were pooled into the meta-analysis (Gln/Gln vs Lys/Lys: OR = 1.363, 95% CI 1.065-1.744, P = 0.014; Lys/Gln vs Lys/Lys: OR = 1.205, 95% CI 1.099-1.321, P = 0.000; Gln/Gln+Lys/Gln vs Lys/Lys: OR = 1.300, 95% CI 1.141-1.480, P = 0.000). In subgroup analyses by ethnicity, source of control, Hardy-Weinberg equilibrium (HWE) in controls, hepatitis B virus (HBV) infection, and statistically significant increase of HCC risk was found in East Asians, population-based studies, studies consistent with HWE, and HBV-positive subjects, but not in mixed/other populations, hospital-based studies, studies deviating from HWE, and HBV-negative subjects. With respect to XPD Asp312Asn polymorphism, no significant association with HCC risk was found in the overall and subgroup analyses. The results suggest that the XPD Lys751Gln polymorphism contributes to increased HCC susceptibility, especially in East Asian populations. Further, large and well designed studies are required to validate this association. PMID- 25546682 TI - Obstructive sleep apnea and serious adverse outcomes in patients with cardiovascular or cerebrovascular disease: a PRISMA-compliant systematic review and meta-analysis. AB - Obstructive sleep apnea (OSA) is seen in approximately 60% to 70% of patients with stroke or ischemic heart disease (IHD). The relationship between OSA and recurrent vascular events and all-cause mortality remains inconclusive. We aimed to systematically evaluate the associations between OSA and serious adverse outcomes following stroke or IHD by a meta-analysis of prospective cohort studies. We searched MEDLINE and EMBASE in August 2014 for studies that evaluated the prospective associations between OSA and the risk of stroke, IHD, and death among stroke or IHD patients. Outcome data were pooled using random effects meta analysis. Subgroup, heterogeneity, and sensitivity analyses and publication bias were performed. Of 13 hospital-based cohort studies included, 5 reported results on stroke (n = 860), 6 reported on IHD (n = 1083), and 11 reported on all-cause death or cardiovascular death (n = 1930). OSA was significantly associated with the risk of stroke, IHD, and all-cause mortality after stroke or IHD. The pooled relative risks were 1.94 (95% confidence interval [CI], 1.29-2.92) for stroke, 1.83 (95% CI, 1.15-2.93) for IHD, and 1.59 (95% CI, 1.33-1.89) for all-cause mortality. There was no evidence of significant between-study heterogeneity. The results did not materially change in the sensitivity analyses for the outcomes of stroke and all-cause mortality. OSA may be a significant predictor of serious adverse outcomes following stroke or IHD. More high-quality studies are needed to determine if better treatment of OSA leads to fewer recurrent vascular events, especially a large-scale, multicenter randomized-controlled trial. PMID- 25546683 TI - Relationship between psychiatric status, self-reported outcome measures, and clinical parameters in axial spondyloarthritis. AB - This article aims to compare the risks of depression and anxiety in patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr axSpA) and investigate the relationship among self-reported outcome measures, clinical parameters, and physical variables of patients with axSpA. Patients with axSpA were recruited from Erciyes Spondyloarthritis Cohort. The patients met Assessment of Spondyloarthritis International Society classification criteria for axial SpA and were assessed in a cross-sectional study design for visual analog scale (VAS) pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Quality of Life questionnaire (ASQoL), and Ankylosing Spondylitis Disease Activity Score-C-reactive protein (ASDAS-CRP). Psychological status was evaluated using the hospital anxiety and depression scale (HADS). Multivariate logistic regression analysis was applied to determine the associations between psychological variables and clinical parameters after adjusting for confounding variables. Of the 316 patients (142 nr-axSpA, 174 AS), 139 (44%) had high risk for depression (HADS-D score >= 7) and 71 (22.5%) for anxiety (HADS-A score >= 10). HADS-D and HADS-A scores were similar between patients with AS and nr-axSpA. Patients with high risk for depression and anxiety had higher scores in BASDAI, BASFI, and ASDAS-CRP, and also poorer scores in VAS pain and ASQoL. Multivariate logistic regression analysis showed that the ASDAS-CRP, ASQoL, BASDAI, as well as educational level were factors associated with the risk of depression whereas the ASQoL and educational level were factors associated with the risk of anxiety. Patients with nr-axSpA and AS have similar burden of psychological distress. The quality of life (ASQoL) and educational level were factors associated with the risk of both depression and anxiety whereas disease activity (BASDAI and ASDAS CRP) was the independent risk factor associated with depression but not anxiety in axSpA. These findings suggest that psychological status should be examined while assessing patients with axSpA including AS and nr-axSpA. PMID- 25546684 TI - Urinary calculi and risk of cancer: a nationwide population-based study. AB - Previous studies have shown that urinary calculi are associated with increased risks of urinary tract cancers. However, the association between urinary calculi and overall cancers is a largely undefined body of knowledge. We conducted a nationwide population-based cohort study using Taiwan's National Health Insurance Research Database from 2000 and 2009. Patients were excluded if they had antecedent cancers or urinary calculi before the enrollment. All study subjects were followed until the occurrence of cancer, dropout from the NHI program, death, or the end of 2010. Patterns of cancer incidence in patients with urinary calculi were compared with those of the general population using standardized incidence ratio (SIR). A total of 43,516 patients with urinary calculi were included. After a median follow-up of 5.3 years, 1891 patients developed cancer. The risk of overall cancers was significantly increased (SIR, 1.75; 95% confidence interval [CI], 1.68-1.83). We observed that urinary calculi was associated with higher risk of cancers of kidney (4.24; 95% CI, 3.47-5.13), bladder (3.30; 95% CI, 2.69-4.00), thyroid (2.50; 95% CI, 1.78-3.40), hematologic origin (2.41; 95% CI, 1.92-2.99), breast (1.84; 95% CI, 1.54-2.20), lung (1.82; 95% CI, 1.59-2.07), digestive tract (1.69; 95% CI, 1.57-1.82), and head and neck (1.54; 95% CI, 1.32-1.79), respectively. Our study shows that urinary calculi are associated with higher risk of systemic cancers in addition to urinary tract cancers. Further study is required to validate this association. PMID- 25546685 TI - "Do not resuscitate" orders among deceased patients who received acute neurological care: an observation analysis. AB - There were many reports about the "do not resuscitate" (DNR) order while practicing in the critical care units and conducting hospice affairs but limited in the neurological issues. This study investigated the possible flaws in the execution of the DNR order among patients who received acute neurological care in Taiwan. Over a 3-year period, we retrospectively reviewed the medical records of 77 deceased patients with neurological conditions for DNR orders. Registry and analysis works included demography, hospital courses, DNR data, and clinical usefulness of the lab and image examinations. Sixty-seven DNR orders were requested by the patients' families, and more than half were signed by the patients' children or grandchildren. The main DNR items were chest compression, cardiac defibrillation, and pacemaker use, although several DNR patients received resuscitation. The mean duration from the coding date to death was 7.6 days. Two thirds of the patients with DNR requests remained in the intensive care unit, with a mean stay of 6.9 days. Several patients underwent regular roentgenography and blood tests on the day of their death, despite their DNR orders. Hospital courses and DNR items may be valuable information on dealing with the patients with DNR orders. The results of this study also suggest the public education about the DNR orders implemented for neurological illnesses. PMID- 25546686 TI - Increased risk of post-transplant malignancy and mortality in transplant tourists: a nationwide population-based cohort study in Taiwan. AB - Information on post-transplant malignancy and mortality risk in kidney transplant tourists remains controversial and is an important concern. The present study aimed to evaluate the incidence of post-transplant malignancy and mortality risk between tourists and domestic transplant recipients using the claims data from Taiwan's universal health insurance. A retrospective study was performed on 2394 tourists and 1956 domestic recipients. Post-transplant malignancy and mortality were defined from the catastrophic illness patient registry by using the International Classification of Diseases, 9th Revision. Cox proportional hazard regression and Kaplan-Meier curves were used for the analyses. The incidence for post-transplant de novo malignancy in the tourist group was 1.8-fold higher than that of the domestic group (21.8 vs 12.1 per 1000 person-years). The overall cancer recurrence rate was approximately 11%. The top 3 post-transplant malignancies, in decreasing order, were urinary tract, kidney, and liver cancers, regardless of the recipient type. Compared with domestic recipients, there was significant higher mortality risk in transplant tourists (adjusted hazard ratio = 1.2, 95% confidence interval: 1.0-1.5). In addition, those with either pre transplant or post-transplant malignancies were associated with increased mortality risk. We suggest that a sufficient waiting period for patients with pre transplant malignancies should be better emphasized to eliminate recurrence, and transplant tourists should be discouraged because of the possibility of higher post-transplant de novo malignancy occurrence and mortality. PMID- 25546687 TI - Gray matter volume abnormalities in depressive patients with and without anxiety disorders. AB - Comorbidity with anxiety disorder is a relatively common occurrence in major depressive disorder. However, the unique and shared neuroanatomical characteristics of depression and anxiety disorders have not been fully identified. The aim of this study was to identify gray matter abnormalities and their clinical correlates in depressive patients with and without anxiety disorders. We applied voxel-based morphometry and region-of-interest analyses of gray matter volume (GMV) in normal controls (NC group, n = 28), depressive patients without anxiety disorder (DP group, n = 18), and depressive patients with anxiety disorder (DPA group, n = 20). The correlations between regional GMV and clinical data were analyzed. The DP group showed decreased GMV in the left insula (INS) and left triangular part of the inferior frontal gyrus when compared to the NC group. The DPA group showed greater GMV in the midbrain, medial prefrontal cortex, and primary motor/somatosensory cortex when compared to the NC group. Moreover, the DPA group showed greater GMV than the DP group in the frontal, INS, and temporal lobes. Most gray matter anomalies were significantly correlated with depression severity or anxiety symptoms. These correlations were categorized into 4 trend models, of which 3 trend models (ie, Models I, II, and IV) revealed the direction of the correlation between regional GMV and depression severity to be the opposite of that between regional GMV and anxiety symptoms. Importantly, the left INS showed a trend Model I, which might be critically important for distinguishing depressive patients with and without anxiety disorder. Our findings of gray matter abnormalities, their correlations with clinical data, and the trend models showing opposite direction may reflect disorder-specific symptom characteristics and help explain the neurobiological differences between depression and anxiety disorder. PMID- 25546689 TI - A comparison of clinical manifestations and prognoses between patients with hepatocellular carcinoma and Child-Pugh scores of 5 or 6. AB - The objective of this work is to compare the outcomes between the Child-Pugh score 5 (A5 group) and Child-Pugh score 6 (A6 group) in patients with hepatocellular carcinoma (HCC). Whether HCC patients with A5 and A6 groups have different prognoses is still obscure. We enrolled 2462 consecutive treatment naive HCC patients from 2007 to 2012. Among them, 1486 patients had Child-Pugh grade A, including 1016 in the A5 group and 470 in the A6 group. Factors in the prognoses were analyzed by multivariate analysis. Compared with those in the A6 group, patients in the A5 group were younger, had higher proportions of tumors within the Milan criteria, and more of them underwent curative therapies. The cumulative survival rates at 5 years were 51.3% and 37.1% for patients in the A5 and A6 groups, respectively (P < 0.001). Multivariate analysis showed that the independent risk factors associated with poor overall survival were nonhepatitis C virus carrier, serum albumin <= 4 g/dL, aspartate aminotransferase > 45 U/L, alpha-fetoprotein > 20 ng/mL, multinodularity, tumor size > 3 cm, vascular invasion, and noncurative therapies, but not the Child-Pugh numeric score. The Child-Pugh numeric score had a significant prognostic effect only in patients who had tumors beyond the Milan criteria and received noncurative therapies. HCC patients with A5 group had a better overall survival rate than those with A6 group due to the early tumor stage and higher rate of receiving curative treatments. Tumor factors and treatment modalities were more important than the Child-Pugh numeric score. PMID- 25546688 TI - Neutrophilic skin lesions in autoimmune connective tissue diseases: nine cases and a literature review. AB - The pathophysiology of neutrophilic dermatoses (NDs) and autoimmune connective tissue diseases (AICTDs) is incompletely understood. The association between NDs and AICTDs is rare; recently, however, a distinctive subset of cutaneous lupus erythematosus (LE, the prototypical AICTD) with neutrophilic histological features has been proposed to be included in the spectrum of lupus. The aim of our study was to test the validity of such a classification. We conducted a monocentric retrospective study of 7028 AICTDs patients. Among these 7028 patients, a skin biopsy was performed in 932 cases with mainly neutrophilic infiltrate on histology in 9 cases. Combining our 9 cases and an exhaustive literature review, pyoderma gangrenosum, Sweet syndrome (n = 49), Sweet-like ND (n = 13), neutrophilic urticarial dermatosis (n = 6), palisaded neutrophilic granulomatous dermatitis (n = 12), and histiocytoid neutrophilic dermatitis (n = 2) were likely to occur both in AICTDs and autoinflammatory diseases. Other NDs were specifically encountered in AICTDs: bullous LE (n = 71), amicrobial pustulosis of the folds (n = 28), autoimmunity-related ND (n = 24), ND resembling erythema gyratum repens (n = 1), and neutrophilic annular erythema (n = 1). The improvement of AICTDS neutrophilic lesions under neutrophil targeting therapy suggests possible common physiopathological pathways between NDs and AICTDs. PMID- 25546691 TI - Effectiveness of ultrasound-guided carpal tunnel injection using in-plane ulnar approach: a prospective, randomized, single-blinded study. AB - The objective of this study is to evaluate the degree of symptom improvement and the change of electrophysiological and ultrasonographic findings after sonographically guided local steroid injection using an in-plane ulnar approach in carpal tunnel syndrome (CTS). Seventy-five cases of 44 patients diagnosed with CTS were included and evaluated at baseline and at 4 and 12 weeks after injection. All patients received injection with 40 mg of triamcinolone mixed with 1 mL of 1% lidocaine into the carpal tunnel using an in-plane Ultrasound (US) guided ulnar approach, out-plane US-guided approach, and blind injection. For clinical evaluation, we used the Boston Carpal Tunnel Questionnaire (BCTQ) and electrophysiological tests. The ultrasonographic findings were also evaluated with regard to cross-sectional area and the flattening ratio of the median nerve. Subjective symptoms measured by BCTQ and median nerve conduction parameters showed significant improvement at 4 weeks in the in-plane ulnar approach group compared with the out-plane ulnar approach and blind injection. This improvement was still observed at 12 weeks. The flattening ratio and cross-sectional area of the median nerve showed a more significant decrease with the in-plane ulnar approach than with the out-plane ulnar approach and blind injection (P < 0.05). US-guided local steroid injection using an in-plane ulnar approach in the CTS may be more effective than out-plane or blind injection. PMID- 25546690 TI - IFNAR1 is a predictor for overall survival in colorectal cancer and its mRNA expression correlated with IRF7 but not TLR9. AB - Toll-like receptor (TLR) 9 plays a role in intestinal inflammation that, in turn, is related to the tumorigenesis of colorectal cancer. Nuclear factor kappaB (NFkappaB), and interferon regulatory factor (IRF) 5 and IRF7 can be activated by TLR9 and induce the production of proinflammatory cytokines and type I interferon, respectively. This study investigated the mRNA expressions of TLR9 and its downstream signaling molecules in both the tumor and the normal tissues of colorectal cancer. Eighty-four subjects with colorectal cancer were consecutively recruited at a community-based hospital, and the mRNA expression of TLR9, NFkappaB, IRF5, IRF7, interleukin 6 (IL6), and interferon alpha/beta/omega receptor 1 (IFNAR1) in the tumor and normal tissue were determined by real-time reverse transcription polymerase chain reaction using TaqMan FAM-labeled MGB probes (Life Technologies, Carlsbad, CA). The tumor had higher percentages of detection of TLR9, IFNAR1, and IL6 mRNA expressions than normal tissue. The absence of detectable TLR9 mRNA expression was associated with an absence of significance in the correlation between IL6 and NFkappaB or IRF5, but not that between IRF7 and IFNAR1 in both the tumor and the normal tissues. An absence of detectable IFNAR1 mRNA expression in the tumor (hazard ratio: 3.77; 95% confidence interval: 1.22-11.60) and advanced stage (stages III and IV, 7.86; 1.76-35.40) were significant predictors for overall survival. IFNAR1 is a predictor for overall survival and mRNA expression is correlated to IRF7, but not TLR9 in colorectal cancer. The results cast doubt on the usefulness of TLR9 agonist in treating colorectal cancer. PMID- 25546692 TI - Lupus erythematosus and neutrophilic urticarial dermatosis: a retrospective study of 7 patients. AB - Neutrophilic urticarial dermatosis (NUD) resembles urticaria clinically but is a neutrophilic dermatosis histopathologically. The majority of patients with NUD have an underlying systemic condition, mainly, autoinflammatory disorders such as cryopyrin-associated periodic syndromes, Schnitzler syndrome, and adult-onset Still disease, but a few also have systemic lupus erythematosus (LE). Here, we confirm these data and we report relevant clinical and histopathological data of 7 patients with LE and NUD. We retrospectively retrieved the medical records of all patients with LE in whom skin biopsy showed NUD in registers of Strasbourg and Montpellier University hospitals since 2000. All were female and aged between 13 and 45 years. Skin lesions were typically rose or red macules or slightly elevated papules occurring in a wide distribution. Individual lesions resolved within 24 hours and were not or only slightly itchy. Every patient had associated signs, most of the time polyarthritis and/or fever. NUD was the presenting mode of LE in 2 patients. NUD was misdiagnosed as a classic lupus flare and led to therapeutic intensification with the introduction of immunosuppressive drugs in 4 patients. Histopathological findings consisted of intense neutrophilic interstitial and perivascular infiltrate with leukocytoclasia and without fibrinoid necrosis of vessel walls. Direct immunofluorescence testing showed a lupus band in 4 patients. Antinuclear antibodies were always positive, anti-dsDNA antibodies were positive in 5 patients, and anti-Ro/SSA antibodies in 6 patients. Immunosuppressive drugs such as prednisone, hydroxychloroquine, mycophenolate mofetil, and methotrexate were never effective to treat NUD. Antihistamines were effective in 1 patient and dapsone or colchicine was effective in 5 patients. NUD is not exceptional in patients with systemic LE and is easily misdiagnosed as an acute LE flare. Furthermore, we show that conventional immunosuppressive LE treatments are not efficient and we underline the major interest of dapsone and colchicine, classic neutrophil migration inhibitors, in those patients. PMID- 25546693 TI - Fatal necrotizing angiotropic Epstein-Barr virus-negative large B-cell lymphoma: a case report with unusual clinicopathological features in-between lymphomatoid granulomatosis and T-cell/histiocyte-rich large B-cell lymphoma. AB - In the spectrum of diffuse large B-cell lymphomas (DLBCL), both T-cell/histiocyte rich large B-cell lymphoma (TCHRBCL) and most lymphomatoid granulomatosis (LG) cases are characterized by the relative rarity of the neoplastic B-cell population, with respect to the overwhelming non-neoplastic counterpart of T cells or histiocytes. Here we report a case of aggressive B-cell lymphoma with unusual clinicopathological features partially overlapping these two entities. The patient was a previously healthy 55-year-old male, presenting with a computed tomography finding of a pelvic mass, inguinal lymphadenopathies, and pulmonary nodules. Two excisional lymph node biopsies resulted inconclusive for lymphoproliferative disease. Because of a colonic perforation, the patient underwent an urgent laparotomy, which disclosed a large pelvic abscess. The pathological examination of the surgical specimen could not discriminate between a primary aggressive B-cell lymphoproliferative disorder and an abnormal inflammatory hyper-reaction. The patient developed a septic state, not resolving until death, which occurred because of an abdominal hemorrhage. A second perimortem surgical specimen consisting of a nodal mass revealed a diagnosis of an Epstein-Barr virus-negative high-grade large B-cell lymphoma with massive necrosis, angiocentric pattern of growth, and prominent T-cell infiltrate. The unique clinicopathological features did not allow to classify this tumor within any of the recognized WHO entities, potentially representing a new clinicopathological variant of DLBCL in-between TCHRBCL and LG. PMID- 25546694 TI - Determinants of plasma renin activity: role of a human renin gene variant as a genetic factor. AB - The plasma renin activity (PRA) is affected by a number of environmental factors. However, significant heritability has been shown for the activity. A hypothesis that a candidate regulatory single-nucleotide polymorphism, C-5312T, of human renin gene should have a significant effect on PRA was elucidated and updating of independent determinants of PRA was attempted. Cross sectional study. Outpatient study. We enrolled consecutive 810 subjects who had consulted our hospitals for lifestyle-related diseases. Genotypes were assayed with genomic DNA for C-5312T. Among the genetic variants, the difference of PRA was evaluated. Monovariate linear regression analysis was performed to test the correlation between PRA and clinical variables. Finally, stepwise multiple regression analysis was performed to evaluate the independent determinants. On comparing 2 genotype groups, CC/CT and T allele homozygote, the geometric means of PRA were 0.778 and 0.941 ng/ml/h, respectively (F = 5.992, P = 0.015). Monovariate linear regression analysis revealed that a number of variables have a significant correlation with the activity, including urinary salt excretion. A stepwise multivariate regression analysis revealed that renin C-5312T variant (TT) is one of the independent determinants of PRA. Thus, for the first time, a human renin gene variant was associated with a significant increase in PRA as a genetic factor and the independent determinants for the activity were updated including genetic factor. PMID- 25546696 TI - Clinical implementation of cardiac resynchronization therapy-regional disparities across selected ESC member countries. AB - BACKGROUND: The present analysis aimed to estimate the penetration of cardiac resynchronization therapy (CRT) on the basis of the prevalence and incidence of eligible patients in selected European countries and in Israel. METHODS AND RESULTS: The following countries were considered: Italy, Slovakia, Greece, Israel, Slovenia, Serbia, the Czech Republic, Poland, Romania, Hungary, Ukraine, and the Russian Federation. CRT penetration was defined as the number of patients treated with CRT (CRT patients) divided by the prevalence of patients eligible for CRT. The number of CRT patients was estimated as the sum of CRT implantations in the last 5 years, the European Heart Rhythm Association (EHRA) White Book being used as the source. The prevalence of CRT indications was derived from the literature by applying three epidemiologic models, a synthesis of which indicates that 10% of heart failure (HF) patients are candidates for CRT. HF prevalence was considered to range from 1% to 2% of the general population, resulting in an estimated range of prevalence of CRT indication between 1000 and 2000 patients per million inhabitants. Similarly, the annual incidence of CRT indication, representing the potential target population once CRT has fully penetrated, was estimated as between 100 and 200 individuals per million. The results showed the best CRT penetration in Italy (47-93%), while in some countries it was less than 5% (Romania, Russian Federation, and Ukraine). CONCLUSION: CRT penetration differs markedly among the countries analyzed. The main barriers are the lack of reimbursement for the procedure and insufficient awareness of guidelines by the referring physicians. PMID- 25546695 TI - Preliminary study on electrophysiological changes after cellular autograft in age related macular degeneration. AB - Evolving atrophic macular degeneration represents at least 80% of all macular degenerations and is currently without a standardized care. Autologous fat transplantation efficacy was demonstrated by several studies, as these cells are able to produce growth factors. The aim of the work was to demonstrate possible therapeutic effect of the joined suprachoroidal graft of adipocytes, adipose derived stem cells (ADSCs) in stromal vascular fractions (SVFs) of adipose tissue, and platelet-rich plasma (PRP). Twelve eyes in 12 dry age-related macular degeneration (AMD) patients, aged 71.25 (SD +/- 6.8) between 62 and 80 years, were analyzed. A complete ocular evaluation was performed using best corrected visual acuity (BCVA), retinographic analysis, spectral-domain optical coherence tomography, microperimetry, computerized visual field, and standard electroretinogram (ERG). Each eye received a cell in graft between choroid and sclera of mature fat cells and ADSCs in SVF enriched with PRP by means of the variant second Limoli (Limoli retinal restoration technique [LRRT]). In order to test if the differences pre- and post-treatment were significant, the Wilcoxon signed-rank test has been performed. Adverse effects were not reported in the patients. After surgery with LRRT, the most significant increase in the ERG values was recorded by scotopic rod-ERG (answer coming from the rods), from 41.26 to 60.83 MUV with an average increase of 47.44% highly significant (P < 0.05). Moderately significant was the one recorded by scotopic maximal ERG (answer coming from the rods and cones), from 112.22 to 129.68 MUV with an average increase of 15.56% (P < 0.1). Cell-mediated therapy based on growth factors used appears interesting because it can improve the retinal functionality responses in the short term. The ERG could, therefore, be used to monitor the effect of cell mediated regenerative therapies. PMID- 25546697 TI - Is the Parkinson Anxiety Scale comparable across raters? AB - The Parkinson Anxiety Scale is a new scale developed to measure anxiety severity in Parkinson's disease specifically. It consists of three dimensions: persistent anxiety, episodic anxiety, and avoidance behavior. This study aimed to assess the measurement properties of the scale while controlling for the rater (self- vs. clinician-rated) effect. The Parkinson Anxiety Scale was administered to a cross sectional multicenter international sample of 362 Parkinson's disease patients. Both patients and clinicians rated the patient's anxiety independently. A many facet Rasch model design was applied to estimate and remove the rater effect. The following measurement properties were assessed: fit to the Rasch model, unidimensionality, reliability, differential item functioning, item local independency, interrater reliability (self or clinician), and scale targeting. In addition, test-retest stability, construct validity, precision, and diagnostic properties of the Parkinson Anxiety Scale were also analyzed. A good fit to the Rasch model was obtained for Parkinson Anxiety Scale dimensions A and B, after the removal of one item and rescoring of the response scale for certain items, whereas dimension C showed marginal fit. Self versus clinician rating differences were of small magnitude, with patients reporting higher anxiety levels than clinicians. The linear measure for Parkinson Anxiety Scale dimensions A and B showed good convergent construct with other anxiety measures and good diagnostic properties. Parkinson Anxiety Scale modified dimensions A and B provide valid and reliable measures of anxiety in Parkinson's disease that are comparable across raters. Further studies are needed with dimension C. PMID- 25546698 TI - Bilingualism changes children's beliefs about what is innate. AB - Young children engage in essentialist reasoning about natural kinds, believing that many traits are innately determined. This study investigated whether personal experience with second language acquisition could alter children's essentialist biases. In a switched-at-birth paradigm, 5- and 6-year-old monolingual and simultaneous bilingual children expected that a baby's native language, an animal's vocalizations, and an animal's physical traits would match those of a birth rather than of an adoptive parent. We predicted that sequential bilingual children, who had been exposed to a new language after age 3, would show greater understanding that languages are learned. Surprisingly, sequential bilinguals showed reduced essentialist beliefs about all traits: they were significantly more likely than other children to believe that human language, animal vocalizations, and animal physical traits would be learned through experience rather than innately endowed. These findings suggest that bilingualism in the preschool years can profoundly change children's essentialist biases. PMID- 25546700 TI - A microfluidic direct formate fuel cell on paper. AB - We describe the first direct formate fuel cell on a paper microfluidic platform. In traditional membrane-less microfluidic fuel cells (MFCs), external pumping consumes power produced by the fuel cell in order to maintain co-laminar flow of the anode stream and oxidant stream to prevent mixing. However, in paper microfluidics, capillary action drives flow while minimizing stream mixing. In this work, we demonstrate a paper MFC that uses formate and hydrogen peroxide as the anode fuel and cathode oxidant, respectively. Using these materials we achieve a maximum power density of nearly 2.5 mW/mg Pd. In a series configuration, our MFC achieves an open circuit voltage just over 1 V, and in a parallel configuration, short circuit of 20 mA absolute current. We also demonstrate that the MFC does not require continuous flow of fuel and oxidant to produce power. We found that we can pre-saturate the materials on the paper, stop the electrolyte flow, and still produce approximately 0.5 V for 15 min. This type of paper MFC has potential applications in point-of-care diagnostic devices and other electrochemical sensors. PMID- 25546699 TI - Electronic cigarette use and exposure in the pediatric population. AB - Electronic cigarette (e-cigarette) use has gained recent widespread popularity and acceptance in the general population. What effect e-cigarettes may have on pediatric health remains unknown. Although many jurisdictions have laws that prevent the sale of e-cigarettes to minors and the use of e-cigarettes in public places, infants, children, and adolescents are increasingly exposed to them. In this pediatric-focused review, we discuss the history of these devices, user demographics, known health effects, and current legislative efforts to protect minors from exposure. PMID- 25546701 TI - Factors associated with severe epiglottitis in adults: Analysis of a Japanese inpatient database. AB - OBJECTIVES/HYPOTHESIS: The aim of the study was to evaluate the factors associated with the development of severe epiglottitis in adults to provide information for physicians to make early decisions on airway management. STUDY DESIGN: Retrospective cohort study. METHODS: Adult patients admitted to acute care hospitals with a diagnosis of acute epiglottitis between January 2011 and December 2012 were identified in the Diagnosis Procedure Combination database of Japan. The main outcome measures were: 1) severe epiglottitis requiring airway intervention or resulting in early death within 2 days after admission and 2) 2 day mortality. Multivariable logistic regression analysis was performed to evaluate the association between patient characteristics and development of severe epiglottitis. RESULTS: A total of 6,072 epiglottitis patients from 599 hospitals were identified. The proportion of developing severe epiglottitis was 9.4%, and 2-day mortality was 0.4%. Factors significantly associated with severe epiglottitis were older age, male sex (adjusted odds ratio [OR] 1.60; 95% confidence interval [CI], 1.28-2.00; P < .001), body mass index (BMI) >25.0 kg/m(2) (OR 1.31; 95% CI, 1.05-1.63; P = .018), diabetes mellitus (OR 1.41; 95% CI, 1.06-1.86; P = .017), epiglottic cyst (OR 2.90; 95% CI, 1.46-5.78; P = .002), pneumonia (OR 2.90; 95% CI, 1.73-4.86; P < .001), and academic hospitals (OR 1.56; 95% CI, 1.21-2.00; P = .001). Epiglottitis-related admission was summer dominant, but seasonality was not significantly associated with severe epiglottitis. CONCLUSION: Development of severe epiglottitis was significantly associated with older age, BMI >25.0 kg/m(2), diabetes mellitus, epiglottic cyst, or pneumonia at admission. LEVEL OF EVIDENCE: 2b. PMID- 25546702 TI - Characterizing the metabolic trade-off in Nitrosomonas europaea in response to changes in inorganic carbon supply. AB - The link between the nitrogen and one-carbon cycles forms the metabolic basis for energy and biomass synthesis in autotrophic nitrifying organisms, which in turn are crucial players in engineered nitrogen removal processes. To understand how autotrophic nitrifying organisms respond to inorganic carbon (IC) conditions that could be encountered in engineered partially nitrifying systems, we investigated the response of one of the most extensively studied model ammonia oxidizing bacteria, Nitrosomonas europaea (ATCC19718), to three IC availability conditions: excess gaseous and excess ionic IC supply (40* stoichiometric requirement), excess gaseous IC supply (4* stoichiometric requirement in gaseous form only), and limiting IC supply (0.25* stoichiometric requirement). We found that, when switching from excess gaseous and excess ionic IC supply to excess gaseous IC supply, N. europaea chemostat cultures demonstrated an acclimation period that was characterized by transient decreases in the ammonia removal efficiency and transient peaks in the specific oxygen uptake rate. Limiting IC supply led to permanent reactor failures (characterized by biomass washout and failure of ammonia removal) that were preceded by similar decreases in the ammonia removal efficiency and peaks in the specific oxygen uptake rate. Notably, both excess gaseous IC supply and limiting IC supply elicited a previously undocumented increase in nitric and nitrous oxide emissions. Further, gene expression patterns suggested that excess gaseous IC supply and limiting IC supply led to consistent up-regulation of ammonia respiration genes and carbon assimilation genes. Under these conditions, interrogation of the N. europaea proteome revealed increased levels of carbon fixation and transport proteins and decreased levels of ammonia oxidation proteins (active in energy synthesis pathways). Together, the results indicated that N. europaea mobilized enhanced IC scavenging pathways for biosynthesis and turned down respiratory pathways for energy synthesis, when challenged with excess gaseous IC supply and limiting IC supply. PMID- 25546703 TI - Engineering of a thermostable beta-1,3-1,4-glucanase from Bacillus altitudinis YC 9 to improve its catalytic efficiency. AB - BACKGROUND: Error-prone polymerase chain reaction (PCR) is frequently used in directed evolution of enzymes to modify their quality. In this study, error-prone PCR was used to improve the catalytic efficiency of beta-1,3-1,4-glucanase from Bacillus altitudinis YC-9. RESULTS: By screening, the mutant Glu-3060 with higher activity was selected among 5000 transformants. After induction with isopropyl beta-D-1-thiogalactopyranoside (IPTG), the activity of the mutant Glu-3060 reached 474.6 U mL(-1), resulting in a 48.6% increment of the parent enzyme activity. Research on the characterization of the mutated enzyme showed the optimal pH of the mutated enzyme to be 5.0, which is lower than the parent enzyme, but thermal stability was almost the same between them. Sequence analysis of the mutated enzyme revealed that three amino acids were changed compared with the parent enzyme, including K142N, Q203L and N214D. CONCLUSION: The three dimensional structure predicted by SWISS-MODEL of the mutated enzyme Glu-3060 showed that the substitution of three amino acids had an effect on the catalytic activity, stability and optimal pH of the enzyme, through changing the charge properties or electron density, forming secondary keys, the acidity of the amino acids and the side chain group. The sum effects of all the factors were increased activity of the mutated enzyme and decreased optimal pH, while the same thermostability was maintained, thereby increasing the suitability of the enzyme for industrial use. PMID- 25546705 TI - The amoeboidal Dictyostelium aquaporin AqpB is gated via Tyr216 and aqpB gene deletion affects random cell motility. AB - BACKGROUND INFORMATION: Regulation of aquaporin (AQPs) water channels mostly occurs on the transcriptional level or by intracellular trafficking. Direct AQP gating is comparatively rare and is described mainly for fungi and plants. Earlier, we identified a gated water-specific AQP in Dictyostelium discoideum, AqpB, which is opened by truncation of an extended intracellular loop D (AqpB Delta208-219). RESULTS: We show that Tyr216 of loop D is a key residue in the gating mechanism possibly involving phosphorylation. Mutation of Tyr216 to aspartate or glutamate initiated water permeability (Pf = 69 MUm/s) to the same extent as AqpB Delta208-219, whereas neither replacement of Tyr216 by a positive arginine (Y216R) nor introduction of a negative charge in a neighbouring position (T217D) opened the channel. We overexpressed AqpB wildtype and AqpB Delta208-219 as GFP fusion constructs in Dictyostelium amoebae and found that the truncated, permanently open AqpB yielded cells with reduced capability to cope with hypotonic stress. Genetic deletion of aqpB yielded a strain with significantly reduced speed of random motility (4.5 MUm/min vs. 6.3 MUm/min of wildtype cells). Yet, chemotaxis towards folate and cAMP was unaffected. In this context, we identified a second, so-far uncharacterised amoeboidal AQP, AqpD, whose role in directed cell locomotion needs to be established. CONCLUSION: Our data add to the completion of the Dictyostelium model for cell motility and show that knowledge on the expression, permeability properties and localisation of amoeboidal AQPs are crucial for further development of the system. PMID- 25546704 TI - Cardiopulmonary bypass and intra-aortic balloon pump use is associated with higher short and long term mortality after transcatheter aortic valve replacement: a PARTNER trial substudy. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) with the balloon expandable Sapien transcatheter heart valve improves survival compared to standard therapy in patients with severe aortic stenosis (AS) and is noninferior to surgical aortic valve replacement (AVR) in patients at high operative risk. Nonetheless, a significant proportion of patients may require pre-emptive or emergent support with cardiopulmonary bypass (CPB) and/or intra-aortic balloon pump (IABP) during TAVR due to pre-existing comorbid conditions or as a result of procedural complications. OBJECTIVES: We hypothesized that patients who required CPB or IABP would have increased periprocedural complications and reduced long term survival. In addition, we sought to determine whether preprocedural variables could predict the need for CPB and IABP. METHODS: The study population included 2,525 patients in the PARTNER Trial (Cohort A and B) and the continuing access registry (CAR). Patients that received CPB or IABP were compared to patients that did not receive either, and then further divided into those that received support pre-TAVR and those that were placed on support emergently. RESULTS: One-hundred sixty-three patients (6.5%) were placed on CPB and/or IABP. The use of CPB or IABP was associated with higher 1 year mortality (49.1% vs. 21.6%, P < 0.001). In multivariable analysis, utilization of CPB or IABP was an independent predictor of 30 day (HR 6.95) and 1-year (HR 2.56) mortality. Although mortality was highest in emergent cases, mortality was also greater in planned CPB and IABP cases compared with non-CPB/IABP cases (53.3% and 40.3% vs. 21.6%, P < 0.001). CONCLUSIONS: These findings indicate that CPB and IABP use in TAVR portends a poor prognosis and its utilization, particularly in the setting of pre-emptive use, needs reconsideration. PMID- 25546706 TI - Enhanced depth imaging-optical coherence tomography of the choroid in moderate and severe primary angle-closure glaucoma. AB - PURPOSE: To compare the choroidal thickness (CT) in eyes with moderate and severe primary angle-closure glaucoma (PACG) with the eyes of healthy controls. METHODS: Fifty-nine patients (59 eyes) with PACG and 56 age-matched normal subjects underwent macular CT scanning using enhanced depth imaging-optical coherence tomography. The subjects with PACG were further classified as having moderate [ 12 dB <= visual field mean deviation (VF-MD) <= -6 dB] or severe (VF-MD < -12 dB) glaucoma. The average CT of the PACG eyes at each location was compared to that of normal eyes. RESULTS: The CT was significantly increased in moderate and severe PACG eyes compared with the normal eyes at all nine macular locations, with the exception of 1 and 3 mm superior to the fovea. The mean CT under the fovea was 292.0 +/- 48.2 MUm in the moderate PACG eyes, 277.1 +/- 58.3 MUm in the severe PACG eyes and 249.9 +/- 72.1 MUm in the normal eyes, respectively. There were no significant differences between the macular CTs in the eyes with moderate PACG and those in severe PACG eyes (all p > 0.05). Factors associated with a thinner choroid were ageing (p < 0.001), female (p = 0.036) and increasing axial length (p = 0.021). Neither the VF-MD nor pattern standard deviation was found to be associated with CT. CONCLUSIONS: The CT is greater in patients with PACG, but it does not differ between moderate and severe PACG, suggesting a lack of relationship between CT and the progression of glaucoma based on EDI-OCT measurements. PMID- 25546707 TI - Perceived barriers and difficulties of intermittent catheterization: In Korean patients with spinal dysraphism and their parents. AB - AIMS: Integrating regular intermittent catheterization (IC) into daily life is essential for good medical outcomes in patients with neurogenic bladders. The goal is to identify long-term IC-related barriers, or difficulties in Korean patients with spinal dysraphism and their parents. METHODS: The data were prospectively collected using questionnaires from spinal dysraphism patients from two sources: an online community, and those visiting the outpatient clinic of Seoul National university hospital. The questions included were barriers in general and school life, respectively. Also, an open question was included regarding suggestions for school managers or the government in order to overcome identified IC related difficulties. RESULTS: A total of 20 patients and 40 parents answered the questionnaire. Common barriers found in general life were related to lack of places, time, or helpers to perform IC. Substantial numbers of adolescent patients also complained that IC could not be adequately performed due to problems related to privacy or lack of understanding at school. However, the number and nature of barriers varied according to the developmental stage and school environments. Almost all IC barriers seemed to be significant in adolescence. Some parents requested that the government provide space and broaden insurance coverage of catheters in order to facilitate IC. CONCLUSIONS: Various perceived barriers were identified in those who need IC and differences were demonstrated over time. Both dedicated space and time are issues. In addition, patients may benefit from emotional support and enhanced communication with community agencies and government to resolve the problems related with privacy. PMID- 25546708 TI - Metazoan parasite communities and diet of the velvet belly lantern shark Etmopterus spinax (Squaliformes: Etmopteridae): a comparison of two deep-sea ecosystems. AB - By combining an examination of stomach contents yielding a snapshot of the most recent trophic niche and the structure of parasite communities reflecting a long term feeding niche, this study aimed at gaining more comprehensive information on the role of the small-sized deep-water velvet belly lantern shark Etmopterus spinax in the local food webs of the Galicia Bank and the canyon and valley system of the Aviles Canyon, which have been both proposed for inclusion in the Natura 2000 network of protected areas. As far as is known, this study provides the first comparative parasite infracommunity data for a deep-sea shark species. Component parasite communities in E. spinax were relatively rich, whereas the infracommunities were rather depauperate, with similar low diversity at both localities. The significant differences in the composition and structure of both parasite communities and prey assemblages indicate differential effects of the two deep-sea ecosystems on both long-term and most recent trophic niches of E. spinax. These results underline the importance of the use of multivariate analyses for the assessment of geographical variation in shark populations based on parasites and diet data. PMID- 25546711 TI - Medication overuse headache: inaccurate and overdiagnosed - a response. PMID- 25546709 TI - Dimerization of cAMP phosphodiesterase-4 (PDE4) in living cells requires interfaces located in both the UCR1 and catalytic unit domains. AB - PDE4 family cAMP phosphodiesterases play a pivotal role in determining compartmentalised cAMP signalling through targeted cAMP breakdown. Expressing the widely found PDE4D5 isoform, as both bait and prey in a yeast 2-hybrid system, we demonstrated interaction consistent with the notion that long PDE4 isoforms form dimers. Four potential dimerization sites were uncovered using a scanning peptide array approach, where a recombinant purified PDE4D5 fusion protein was used to probe a 25-mer library of overlapping peptides covering the entire PDE4D5 sequence. Key residues involved in PDE4D5 dimerization were defined using a site directed mutagenesis programme directed by an alanine scanning peptide array approach. Critical residues stabilising PDE4D5 dimerization were defined within the regulatory UCR1 region found in long, but not short, PDE4 isoforms, namely the Arg(173), Asn(174) and Asn(175) (DD1) cluster. Disruption of the DD1 cluster was not sufficient, in itself, to destabilise PDE4D5 homodimers. Instead, disruption of an additional interface, located on the PDE4 catalytic unit, was also required to convert PDE4D5 into a monomeric form. This second dimerization site on the conserved PDE4 catalytic unit is dependent upon a critical ion pair interaction. This involves Asp(463) and Arg(499) in PDE4D5, which interact in a trans fashion involving the two PDE4D5 molecules participating in the homodimer. PDE4 long isoforms adopt a dimeric state in living cells that is underpinned by two key contributory interactions, one involving the UCR modules and one involving an interface on the core catalytic domain. We propose that short forms do not adopt a dimeric configuration because, in the absence of the UCR1 module, residual engagement of the remaining core catalytic domain interface provides insufficient free energy to drive dimerization. The functioning of PDE4 long and short forms is thus poised to be inherently distinct due to this difference in quaternary structure. PMID- 25546712 TI - How do patients score cosmesis after laparoscopic natural orifice specimen extraction colectomy? AB - AIM: Laparoscopic colorectal resection results in improved cosmetic outcome and better presumed body image. Laparoscopic NOSE colectomy omits an incision for specimen extraction and is supposed to further improve postoperative cosmesis. This study aimed to assess the cosmetic benefit. METHOD: Forty-nine patients who underwent a NOSE colectomy for bowel endometriosis from September 2009 to September 2013 were matched for age, American Society of Anesthesiologists (ASA) grade and body mass index (BMI) with patients who underwent a conventional laparoscopic colectomy for the same indication. Patients were asked to complete a questionnaire consisting of a body scale and a cosmetic scale and the Patient Scar Assessment Questionnaire (PSAQ) including five subscales (appearance, symptoms, scar consciousness, satisfaction with appearance and satisfaction with symptoms). RESULTS: Patient demographics were similar between both groups. Patients were assessed at a median postoperative follow-up of 41 months in the NOSE colectomy group and 35 months in the conventional resection group. The median body image questionnaire score was 15 for NOSE colectomy and 18 for conventional resection (P = 0.027). The respective median PSAQ scores were 56 and 71 (P = 0.002). There was a good relationship between the PSAQ score and the body image questionnaire (Spearman correlation coefficient 0.82). CONCLUSION: Depending on the scoring system used, the cosmetic outcome may be better after NOSE colectomy than conventional laparoscopy in patients having surgery for endometriosis. The comprehensive body image questionnaire, being shorter and easier to use, could be a valid tool for assessing cosmesis after NOSE procedures. PMID- 25546713 TI - A pilot study comparing a protocol using intermittent administration of glargine and regular insulin to a continuous rate infusion of regular insulin in cats with naturally occurring diabetic ketoacidosis. AB - OBJECTIVE: The goal of this pilot study was to compare regular insulin administered by continuous rate infusion (CRI) to an approach using insulin glargine and regular insulin administered intermittently. DESIGN: Prospective randomized clinical trial. SETTING: University teaching hospital. ANIMALS: Sixteen cats with diabetic ketoacidosis (DKA). INTERVENTIONS: Cats with DKA were randomized to either low-dose regular insulin CRI (CRI group; n = 8) or intermittent short- and long-acting insulin injections (subcutaneous [SC] glargine plus intramuscular [IM] regular insulin; SC/IM group; n = 8). MEASUREMENTS AND MAIN RESULTS: Time of normalization of pH, bicarbonate, hyperglycemia, ketonemia, and appetite, as well as duration of hospitalization were recorded. Eleven of 16 cats (59%) survived to discharge, with no difference in survival between groups (P = 0.99). Times of resolution of hyperglycemia (P = 0.02) and ketonemia (P = 0.04), and normalization of pH (P = 0.04), and bicarbonate (P = 0.03) were significantly shorter in the SC/IM group. Cats in the SC/IM group also had a significantly shorter duration of hospitalization (SC/IM: median = 54 hr [range, 19-118 hr]; CRI: median = 111 hr [range, 58-271 hr]; P = 0.04). Time of first meal was not significantly different between groups. CONCLUSIONS: Although further research is required, an approach using intermittent short- and long-acting insulin injections appeared to be an effective option for treatment of DKA in cats. PMID- 25546710 TI - Mitochondrial protein quality control: the mechanisms guarding mitochondrial health. AB - SIGNIFICANCE: Mitochondria are complex dynamic organelles pivotal for cellular physiology and human health. Failure to maintain mitochondrial health leads to numerous maladies that include late-onset neurodegenerative diseases and cardiovascular disorders. Furthermore, a decline in mitochondrial health is prevalent with aging. A set of evolutionary conserved mechanisms known as mitochondrial quality control (MQC) is involved in recognition and correction of the mitochondrial proteome. RECENT ADVANCES: Here, we review current knowledge and latest developments in MQC. We particularly focus on the proteolytic aspect of MQC and its impact on health and aging. CRITICAL ISSUES: While our knowledge about MQC is steadily growing, critical gaps remain in the mechanistic understanding of how MQC modules sense damage and preserve mitochondrial welfare, particularly in higher organisms. FUTURE DIRECTIONS: Delineating how coordinated action of the MQC modules orchestrates physiological responses on both organellar and cellular levels will further elucidate the current picture of MQC's role and function in health, cellular stress, and degenerative diseases. PMID- 25546715 TI - Discrepancies in reported US pricing information for digoxin-Fab. PMID- 25546714 TI - High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide poisoning-induced cardiac depression in sheep. AB - CONTEXT: Severe H2S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication. OBJECTIVES: To determine the time course and the nature of H2S induced cardiac arrest and the effects of high-dose hydroxocobalamin administered after the end of sulfide exposure. MATERIALS AND METHODS: NaHS was infused in 16 sedated mechanically ventilated sheep to reach concentrations of H2S in the blood, which was previously found to lead to cardiac arrest within minutes following the cessation of H2S exposure. High-dose hydroxocobalamin (5 g) or saline solution was administered intravenously, 1 min after the cessation of NaHS infusion. RESULTS: All animals were still alive at the cessation of H2S exposure. Three animals (18%) presented a cardiac arrest within 90 s and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 min. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g of hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving hydroxocobalamin, as blood lactate remained elevated and even continued to rise after 1 h, despite restored hemodynamics. This, along with an unaltered recovery of H2S kinetics, suggests that hydroxocobalamin did not act through a mechanism of H2S trapping. CONCLUSION: In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 min after H2S exposure. Very high dose of hydroxocobalamin (5 g), injected very early after the cessation of H2S exposure, improved cardiac contractility and prevented PEA. PMID- 25546716 TI - Venoms and antivenoms: North American poisonous scorpion, snake, and spider information is now in the National Library of Medicine's Hazardous Substances Data Bank. PMID- 25546718 TI - Optimization of a high-resolution radical scavenging assay coupled on-line to reversed-phase liquid chromatography for antioxidant detection in complex natural extracts. AB - This paper reports the optimization of the on-line coupling of 2,2'-azinobis(3 ethylbenzothiazoline)-6-sulfonic acid based radical scavenging assays with reversed-phase high-performance liquid chromatography. The residence time in the reactor was reduced to 6.4 s to ensure minimal peak broadening and loss of separation. Peak capacity losses between compound detection and measurement of the radical scavenging potential were reduced to 10% and lower on coupled column systems. The methodology was successfully applied for the detection of the scavenging activity of molecules encompassing a broad hydrophobicity range. The method shows promise for the assessment of low-molecular-weight polyphenols in red wine by coupled-column high-resolution high-performance liquid chromatography with mass spectrometry analysis. PMID- 25546719 TI - Hydrogen-bond-mediated in situ fabrication of AgNPs/agar/PAN electrospun nanofibers as reproducible SERS substrates. AB - Reproducibility in surface enhanced Raman scattering (SERS) measurements is a challenge. This work developed a facile way to make highly dispersed uniform silver nanoparticles (AgNPs) loaded in the agar/polyacrylonitrile (PAN) nanofibers by the coupling the electrospinning technology from metal complex containing polymer solution and in situ photoreductive technique. Agar, as hydrophilic component, was introduced into the electrospinning solution considering that its abundant hydroxyl group sites could greatly improve the contents of silver ions in the polymers because of the rich silver ion chelated with the hydroxyl group, whereas hydrophilic agar was integrated with hydrophobic PAN by -OH...N=C- hydrogen bonds as a bridge. Meanwhile, the in situ photoreductive reaction was made under different light irradiations such as desk lamp, 365 nm UV-lamp, and 254 nm UV-lamp. High yield of stable AgNPs with highly uniform and dispersion are available in the agar/PAN nanofibers after the in situ photoreductive reaction, supplying the possibility of reproducible SERS signals. To identify that concept of proof, a facile approach for the determination of malachite green (MG) in three environmental practical samples was demonstrated by using the composite nanofibrous material irradiated by 365 nm UV-lamp, giving the minimum detection concentration of MG as low as 0.1 MUmol/L with a good linear response ranging from 0.1-100 MUmol/L (R(2) = 0.9960). PMID- 25546720 TI - Interrater reliability of the Neuromuscular Recovery Scale for spinal cord injury. AB - OBJECTIVE: To determine the interrater reliability of the Neuromuscular Recovery Scale (NRS), an outcome measure designed to classify people with complete or incomplete spinal cord injury (SCI) into 4 phase-of-injury groups by assessing motor performance based on normal preinjury function and disallowing use of compensation for 4 treadmill-based items and 6 overground/mat items. DESIGN: Masked comparison, multicenter observational study. SETTING: Outpatient rehabilitation. PARTICIPANTS: Raters (N=14) and a criterion standard expert assigned scores to 10 video NRS assessments of persons with SCI. The raters were volunteers from the NeuroRecovery Network. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Interrater reliability measured with the Kendall coefficient of concordance (W). RESULTS: Interrater reliability was generally strong (W=.91-.98; 95% confidence interval [CI], .65-.99), while lower reliability occurred for treadmill stand retraining (W=.87; 95% CI, .06-1) and seated trunk extension (W=.82; 95% CI, .28-.94). Less experienced raters assigned slightly lower scores than the expert for most items, but the difference was less than half a point and did not weaken concordance. CONCLUSIONS: NRS had strong interrater reliability, a necessary first step in establishing its utility as a clinical and research outcome measure. PMID- 25546721 TI - Relative recency influences object-in-context memory. AB - In two experiments rats received training on an object-in-context (OIC) task, in which they received preexposure to object A in context x, followed by exposure to object B in context y. In a subsequent test both A and B are presented in either context x or context y. Usually more exploration is seen of the object that has not previously been paired with the test context, an effect attributed to the ability to remember where an object was encountered. However, in the typical version of this task, object A has also been encountered less recently than object B at test. This is precisely the arrangement in tests of 'relatively recency' (RR), in which more remotely presented objects are explored more than objects experienced more recently. RR could contaminate performance on the OIC task, by enhancing the OIC effect when animals are tested in context y, and masking it when the test is in context x. This possibility was examined in two experiments, and evidence for superior performance in context y was obtained. The implications of this for theoretical interpretations of recognition memory and the procedures used to explore it are discussed. PMID- 25546722 TI - Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: the double neurogenic niche hypothesis. AB - Adult hippocampal neurogenesis (AHN) is involved in learning, memory, and stress, and plays a significant role in neurodegenerative and psychiatric disorders. As an age-dependent process, AHN is largely influenced by changes that occur during the pre- and postnatal stages of brain development, and constitutes an important field of research. This review examines the current knowledge regarding the regulators of AHN and the influence of prenatal and postnatal stress on later AHN. In addition, a hypothesis is presented suggesting that each kind of stress influences a specific neurogenic pool, developmental or postnatal, that later becomes a precursor with important repercussions for AHN. This hypothesis is referred to as "the double neurogenic niche hypothesis." Discovering what receptors, transcription factors, or genes are specifically activated by different stressors is proposed as an essential line of future research in the field. Such knowledge shall constitute an important starting point toward the goal of modifying AHN in neurodegenerative or psychiatric diseases. PMID- 25546723 TI - Duration- and environment-dependent effects of repeated voluntary exercise on anxiety and cued fear in mice. AB - Several studies have indicated that animal models of exercise, such as voluntary wheel running, might be endowed with anxiolytic properties. Using the light/dark test of unconditioned anxiety, we have reported that one confounding factor in the estimation of wheel running impacts on anxiety might be the housing condition of the sedentary controls. The present mouse study analyzed whether the aforementioned observation in the light/dark test (i) could be repeated in the elevated plus-maze and social interaction tests of unconditioned anxiety, (ii) extended to conditioned anxiety, as assessed during cued fear recall tests, and (iii) required unlimited daily access to the running wheel. Housing with a locked wheel or with a free wheel that allowed limited or unlimited running activity triggered anxiolysis in the light/dark test, but not in the elevated plus-maze test, compared to standard housing. In the social interaction test, the duration, but not the number, of social contacts was increased in mice provided unlimited (but not limited) access to a wheel, compared to standard housing or housing with a locked wheel. Lastly, freezing responses to a cue during fear recall tests indicated that the reduction in freezing observed in mice provided limited or unlimited access to the wheels was fully accounted for by housing with a wheel. Besides confirming that the housing condition of the sedentary controls might bias the estimation of the effects of wheel running on anxiety, this study further shows that this estimation is dependent on the test used to assess anxiety. PMID- 25546724 TI - Activation of postsynaptic D2 dopamine receptors in the rat dorsolateral striatum prevents the amnestic effect of systemically administered neuroleptics. AB - Systemically administered antipsychotics bind to dopamine (DA) D2 receptors expressed in both pre- and postsynaptic neurons of different striatal sites and present an amnestic effect on learning and memory of conditioned avoidance responses (CAR). The aim of this study was to test whether blockade of the pre- or post-synaptic D2 receptors of the dorsolateral striatum of rats is the mechanism by which systemically administered antipsychotics present this amnestic effect. CAR learning and memory was evaluated in rats that received i.p. administrations of pre- or postsynaptic doses of the antipsychotic sulpiride combined with intra-DLS infusion of the D2 agonist quinpirole. Intra-DLS quinpirole itself was not amnestic and this effect was prevented by co administration of presynaptic dose of sulpiride. However, sulpiride was amnestic when administered systemically in a post- but not presynaptic dose. This amnestic effect of sulpiride was prevented by the co-administration of quinpirole into the DLS. These results show that a blockade of postsynaptic D2 receptors in the DLS is necessary and sufficient to produce the amnestic effect of neuroleptics on CARs. PMID- 25546725 TI - Brentuximab vedotin in combination with extended field radiotherapy as salvage treatment for primary refractory Hodgkin lymphoma. PMID- 25546726 TI - Frequency of fractionated ventricular activation and atrial/ventricular electrogram amplitude ratio at successful ablation target of accessory pathways in patients with Ebstein's anomaly. AB - INTRODUCTION: Knowledge about local electrogram and atrial/ventricular electrogram amplitude ratio (A/V ratio) at the true atrioventricular ring for successful ablation of accessory pathways (APs) in patients with Ebstein's anomaly is limited. METHODS: Twenty-two adults with Ebstein's anomaly and APs were managed by 24 sessions of radiofrequency catheter ablation (RFCA). A right atrial/ventricular angiogram with or without 3-dimensional electroanatomic mapping was performed to delineate the true atrioventricular ring and atrialized right ventricle (ARV). Electrograms of successful targets were analyzed. For each right-sided AP target, 2 AP targets matched by location and conduction property from normal hearts were selected as controls, and their A/V ratios were compared. RESULTS: In 32 right-sided APs of all 22 patients, local ventricular activation at successful site presented as normal electrogram in 14, fractionated ventricular electrogram (FVE) in 16, and double ventricular potentials in 2. The bipolar voltage of ARV was markedly lower than in normal hearts. The A/V ratio at the successful target was significantly higher in APs with FVE than in control (1.64 +/- 1.34 vs. 0.47 +/- 0.19, P < 0.01), and was similar in APs with normal ventricular electrogram and in the control (0.38 +/- 0.15 vs. 0.46 +/- 0.15, P = 0.1726). The A/V ratio at the successful target with double ventricular potentials (after surgical correction) was 0.30 +/- 0.20. All APs were successfully ablated without complications. CONCLUSIONS: In patients with Ebstein's anomaly, FVE was found in 50% of the successful targets of APs. High A/V ratio at successful sites with FVE and normal A/V ratio at targets with normal ventricular electrogram can facilitate target recognition and ablation. PMID- 25546727 TI - Global transcriptome and sequenome analysis of formalin-fixed salivary epithelial myoepithelial carcinoma specimens. AB - Diverse microarray and sequencing technologies have been widely used to characterize molecular changes in malignant epithelial cells in salivary neoplasms. Such gene expression studies to identify markers and targets in tumor cells are, however, compromised by the cellular heterogeneity of these tumors and by the difficulties to accrue matching controls representing normal salivary glands. Seventeen samples of primary salivary epithelial-myoepithelial carcinoma along with tissue from six normal major salivary glands were microdissected from paraffin-embedded tissue. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using a whole-transcriptome shotgun sequencing experiment. In parallel, extracted genomic DNA was used for the 50 gene hotspot panel sequenome. KRAS mutations in three patients (18%), NRAS mutations in one patient (6%), but no HRAS, MET, PIK3CA, or BRAF mutations. Using strict and conservative criteria, 220 differentially expressed transcripts were found, with 36% up- and 64% downregulated. The transcripts were annotated using NCBI Entrez Gene, and computationally analyzed with the Ingenuity Pathway Analysis program. From these significantly changed expressions, the analysis identified 26 cancer-related transcripts and 16 transcripts related to mitochondrial dysfunction overlapping with three cancer-related genes. These 220 differentially expressed genes including microRNAs provide here a sufficiently large set to specifically define epithelial-myoepithelial carcinoma and to identify novel and potentially important targets for diagnosis, prognosis, and therapy of this cancer. PMID- 25546728 TI - Lupus erythematosus cell phenomenon in synovial and peritoneal fluids in systemic lupus erythematosus: smoking guns, crime scenes and a twist. AB - The presence of the lupus erythematosus (LE) phenomenon has been generally conceptualized as an in vitro occurrence where numerous damaged cells are present and substantial nucleo-phagocytosis has occurred. In systemic lupus erythematosus (SLE), the positive LE cell phenomenon has been shown to indicate active disease with major organ involvement which potentially warrants prompt and heavy immunosuppressive therapy. We report a 36-year-old woman with a known history of SLE who presented with fever, left knee effusion, polyserositis, pancytopenia, low complement and high anti-dsDNA antibody levels whose immunosuppressive treatment was escalated in view of the clinically and serologically active SLE, accompanied by the presence of LE cells in her inflammatory yet sterile left knee synovial fluid. Within 3 days of immunosuppressant escalation, her ascites worsened. While microscopic examination of the ascitic fluid also revealed LE cells, culture of the ascitic fluid later grew Candida parapsilosis. The patient subsequently responded to the addition of anti-fungal therapy into her augmented immunosuppressive regime. Coexistence of the LE cell phenomenon and infection in SLE patients has hitherto not been described. This case illustrates that infection remains to be meticulously excluded despite the presence of the LE phenomenon in the context of clinically and serologically active SLE. PMID- 25546729 TI - Particulate Matter deposition on Quercus ilex leaves in an industrial city of central Italy. AB - A number of studies have focused on urban trees to understand their mitigation capacity of air pollution. In this study particulate matter (PM) deposition on Quercus ilex leaves was quantitatively analyzed in four districts of the City of Terni (Italy) for three periods of the year. Fine (between 0.2 and 2.5 MUm) and Large (between 2.5 and 10 MUm) PM fractions were analyzed. Mean PM deposition value on Quercus ilex leaves was 20.6 MUg cm(-2). Variations in PM deposition correlated with distance to main roads and downwind position relatively to industrial area. Epicuticular waxes were measured and related to accumulated PM. For Fine PM deposited in waxes we observed a higher value (40% of total Fine PM) than Large PM (4% of total Large PM). Results from this study allow to increase our understanding about air pollution interactions with urban vegetation and could be hopefully taken into account when guidelines for local urban green management are realized. PMID- 25546730 TI - Risk factors for depression in community-treated epilepsy: systematic review. AB - OBJECTIVE: Depression is one of the most common psychiatric comorbidities in epilepsy; however, the factors contributing to this association remain unclear. There is a growing consensus that methodological limitations, particularly selection bias, affect many of the original studies. A systematic review focussed on community-based studies offers an alternative approach for the identification of the risk factors for depression. METHODS: Searches were performed in MEDLINE (Ovid), 2000 to 31 December 2013, EMBASE, and Google Scholar to identify studies examining risk factors for depression in epilepsy. Community-based studies of adults with epilepsy that reported at least one risk factor for depression were included. RESULTS: The search identified 17 studies that met selection criteria, representing a combined total of 12,212 people with epilepsy with a mean sample size of 718. The most consistent risk factors for depression were sociodemographic factors, despite the fact that most studies focus on epilepsy related factors. SIGNIFICANCE: Most studies lacked a systematic conceptual approach to investigating depression, and few risk factors were consistently well studied. Future community-based studies require a detailed systematic approach to improve the ability to detect risk factors for depression in epilepsy. Psychological factors were rarely studied in community-based samples with epilepsy, although the consistent association with depression in the few studies that did suggests this warrants further examination. PMID- 25546731 TI - Changes in the frequency of benign focal spikes accompany changes in central information processing speed: a prospective 2-year follow-up study. AB - We prospectively examined whether changes in the frequency of benign focal spikes accompany changes in cognition. Twenty-six children with benign focal spikes (19 with Rolandic epilepsy) and learning difficulties were examined with repeated 24 hour EEG recordings, three cognitive tests on central information processing speed (CIPS), and questionnaires on cognition and behavior at baseline, 6months, and 2years. Antiepileptic drug changes were allowed when estimated necessary by the treating physician. At baseline, a lower CIPS was correlated with a higher frequency of diurnal interictal epileptiform discharges (IEDs) and with worse academic achievement. At follow-up, there was a significant correlation between changes in CIPS and EEG changes in wakefulness (in the same direction) when the EEG outcome was dichotomized in IED frequency "increased" or "not increased". Behavioral problems were more often observed in patients with higher frequency of IEDs in sleep at baseline and in those with ongoing IEDs compared with those with EEG remission (without or with sporadic IEDs in the recording) at the end of the study period. No changes were observed in the results of the questionnaires. A lower diurnal IED frequency at baseline, lack of serial IEDs, and occurrence of only unilateral IEDs were correlated with a higher chance of EEG remission at 2 year follow-up. Electroencephalography remission could not be predicted from other epilepsy variables except from seizure freedom in the last six months. Our results confirm the nonbenign character of 'benign' focal spikes. Whether an early and stable EEG remission can be achieved through antiepileptic treatment and whether this is of benefit for cognitive development should be examined in prospective placebo-controlled randomized trials. PMID- 25546732 TI - Impaired sleep-related consolidation of declarative memories in idiopathic focal epilepsies of childhood. AB - OBJECTIVE: Declarative memory is consolidated during sleep in healthy children. We tested the hypothesis that consolidation processes are impaired in idiopathic focal epilepsies (IFE) of childhood in association with frequent interictal epileptiform discharges (IEDs) during sleep. METHODS: A verbal (word-pair association) and a nonverbal (2D object location) declarative memory task were administrated to 15 children with IFEs and 8 control children 6-12 years of age. Patients had either centrotemporal (11 patients) or occipital (4 patients) IEDs. All but 3 patients had a history of unprovoked seizures, and 6 of them were treated with valproate (VPA). The learning procedure (location of object pairs presented on a grid; association of word pairs) was executed in the evening. Retrieval was tested immediately after learning and on the next morning after a night of sleep. Participants were tested twice, once in natural home conditions and one month later in the unfamiliar conditions of the sleep unit under EEG monitoring. RESULTS: Overnight recall performance was lower in children with IFE than in control children on both tasks (ps<0.05). Performance in home conditions was similar to that in hospital conditions. Higher spike-wave index (SWI) during nonrapid eye movement (NREM) sleep was associated with poorer performance in the nonverbal task (p<0.05). Valproate treatment was not associated with overnight recall performance for both tasks (ps>0.05). CONCLUSION: Memory consolidation is impaired in IFE of childhood. The association between higher SWI during NREM sleep and poorer nonverbal declarative memory consolidation supports the hypothesis that interictal epileptic activity could disrupt sleep memory consolidation. PMID- 25546733 TI - Treatment of relapsed Wilms tumour (WT) patients: experience with topotecan. A report from the SIOP Renal Tumour Study Group (RTSG). AB - BACKGROUND: Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients. METHODS: Children who were treated with topotecan as part of their chemotherapeutic regimens for relapsed WT were identified and included in our retrospective study. Patient charts were reviewed for general patient characteristics, histology and stage at initial diagnosis, number and type of relapse, salvage treatment schedules, toxicity, response to treatment and outcome. RESULTS: From 2000 to 2012, 30 children (median age at relapse 5.5 years, range 1.6-14.5 years) were identified to have received topotecan as part of their salvage regimens (primary progressive disease n = 3, first, second and third relapse n = 13, 9 and 2 respectively, partial response n = 3). Topotecan was administered as a single agent (12 patients) or in combination with other drugs (18 patients). Sixteen patients had high-risk histology according to the SIOP classification, 15 died within 12 months because of progressive disease. Fourteen patients had SIOP intermediate-risk histology of which four patients displayed objective responses to topotecan. Overall, 6 out of 14 intermediate-risk patients survived (median follow up of 6 years), however, three of whom (stage V) had bilateral nephrectomy after topotecan treatment. CONCLUSIONS: Topotecan does not seem to show effectiveness in the treatment of relapsed WT patients with initial high-risk histology. In patients with intermediate-risk histology, the role of topotecan might deserve further attention, to prove its efficacy. PMID- 25546734 TI - Blue vitiligo following intralesional injection of psoralen combined with ultraviolet B radiation therapy. AB - A 23-year-old Chinese man presented with a 16-month history of white patches on his abdomen and neck. He had previously received an intralesional injection of psoralen along with narrowband psoralen ultraviolet B radiation (PUVB) therapy. Blue macules had appeared in and around the injection sites 1 week later. Dermoscopy revealed blue spots and reticular telangiectasia within the white patches. Histological examination revealed an absence of epidermal melanocytes and pigment in the basal layer, as well as deposition of melanophages between collagen bundles or surrounding blood vessels and appendages in the middle and lower parts of the dermis. A diagnosis of blue vitiligo was made. The blue colour faded gradually over time. Our case provides direct evidence to support the previous surmise that PUVB can contribute to blue vitiligo. To our knowledge, this is only the fourth reported case of blue vitiligo in the English literature. PMID- 25546735 TI - Robust electrodes based on coaxial TiC/C-MnO2 core/shell nanofiber arrays with excellent cycling stability for high-performance supercapacitors. AB - A coaxial electrode structure composed of manganese oxide-decorated TiC/C core/shell nanofiber arrays is produced hydrothermally in a KMnO4 solution. The pristine TiC/C core/shell structure prepared on the Ti alloy substrate provides the self-sacrificing carbon shell and highly conductive TiC core, thus greatly simplifying the fabrication process without requiring an additional reduction source and conductive additive. The as-prepared electrode exhibits a high specific capacitance of 645 F g(-1) at a discharging current density of 1 A g(-1) attributable to the highly conductive TiC/C and amorphous MnO2 shell with fast ion diffusion. In the charging/discharging cycling test, the as-prepared electrode shows high stability and 99% capacity retention after 5000 cycles. Although the thermal treatment conducted on the as-prepared electrode decreases the initial capacitance, the electrode undergoes capacitance recovery through structural transformation from the crystalline cluster to layered birnessite type MnO2 nanosheets as a result of dissolution and further electrodeposition in the cycling. 96.5% of the initial capacitance is retained after 1000 cycles at high charging/discharging current density of 25 A g(-1). This study demonstrates a novel scaffold to construct MnO2 based SCs with high specific capacitance as well as excellent mechanical and cycling stability boding well for future design of high-performance MnO2-based SCs. PMID- 25546736 TI - Logical gaps in the approximate solutions of the social learning game and an exact solution. AB - After the social learning models were proposed, finding solutions to the games becomes a well-defined mathematical question. However, almost all papers on the games and their applications are based on solutions built either upon an ad-hoc argument or a twisted Bayesian analysis of the games. Here, we present logical gaps in those solutions and offer an exact solution of our own. We also introduce a minor extension to the original game so that not only logical differences but also differences in action outcomes among those solutions become visible. PMID- 25546737 TI - Internalization of Near-Infrared Fluorescently Labeled Activatable Cell Penetrating Peptide and of Proteins into Human Fibrosarcoma Cell Line HT-1080. AB - The internalization of near-infrared fluorescently labeled cargos into living cells and tissues allows a highly sensitive detection without interference from skin, porphins or other fluorescent cell and tissue compounds. In this study, the uptake of labeled bovine serum albumin and an antibody, into fibrosarcoma (HT 1080) cells was triggered by the formation of non-covalent complexes with different cell-penetrating peptides; uptake efficiency and intracellular localization were determined. To improve selectivity of internalization into tumor cells, a fluorescent activatable cell-penetrating peptide (ACPP) was synthesized and functionally characterized. This 25-mer peptide was designed to be activatable by Matrix-Metallo-Proteases (MMPs). Its uptake selectivity was estimated using cells with different MMP activities. PMID- 25546738 TI - Review fifteen years of search for strong nucleosomes. AB - Don Crothers, Mikael Kubista, Jon Widom, and their teams have been first to look for strong nucleosomes, in a bid to reveal the nucleosome positioning pattern(s) carried by the nucleosome DNA sequences. They were first to demonstrate that the nucleosome stability correlates with 10-11 base sequence periodicity, and that the strong nucleosomes localize preferentially in centromeres. This review describes these findings and their connection to recent discovery of the strong nucleosomes (SNs) with visibly periodic nucleosome DNA sequences. PMID- 25546739 TI - Temporal patterns of orchid mycorrhizal fungi in meadows and forests as revealed by 454 pyrosequencing. AB - Orchid mycorrhizal (OrM) symbionts play a key role in the growth of orchids, but the temporal variation and habitat partitioning of these fungi in roots and soil remain unclear. Temporal changes in root and rhizosphere fungal communities of Cypripedium calceolus, Neottia ovata and Orchis militaris were studied in meadow and forest habitats over the vegetation period by using 454 pyrosequencing of the full internal transcribed spacer (ITS) region. The community of typical OrM symbionts differed by plant species and habitats. The root fungal community of N. ovata changed significantly in time, but this was not observed in C. calceolus and O. militaris. The rhizosphere community included a low proportion of OrM symbionts that exhibited a slight temporal turnover in meadow habitats but not in forests. Habitat differences in OrM and all fungal associates are largely attributable to the greater proportion of ectomycorrhizal fungi in forests. Temporal changes in OrM fungal communities in roots of certain species indicate selection of suitable fungal species by plants. It remains to be elucidated whether these shifts depend on functional differences inside roots, seasonality, climate or succession. PMID- 25546740 TI - Fecal colonization and infection with Pseudomonas aeruginosa in recipients of allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Pseudomonas aeruginosa, especially multidrug-resistant (MDR) isolates, is an important pathogen in allogeneic hematopoietic stem cell transplant (HCT) recipients. The ability to identify patients at risk for these infections and administer appropriate empiric therapy, particularly during episodes of neutropenia, may improve outcomes and also direct infection control and antimicrobial stewardship efforts. Many transplant centers obtain routine surveillance stool cultures (SSCs) from HCT recipients to test for colonization with vancomycin-resistant enterococci, and extended-spectrum beta lactamase producing Enterobacteriaceae. Our center initiated the performance of SSCs for P. aeruginosa, because of a perceived increase in the frequency of infection with MDR strains. The aim of this study was to determine the utility of this practice. METHODS: We conducted a 2-year (2010-2011) retrospective review of the medical records of all patients who underwent allogeneic HCT at our cancer center to (a) determine the frequency of fecal colonization with P. aeruginosa, including MDR strains; (b) to determine the overall frequency of subsequent P. aeruginosa infection, as well as the frequency of infection with MDR strains; (c) to ascertain the proportion of subsequent infections likely arising from the intestinal tract; and (d) to determine risk factors for progression from colonization to infection. RESULTS: Of 794 study patients, 58 (7.3%) had at least 1 positive SSC for P. aeruginosa; 19/58 (32.8%) developed a subsequent pseudomonal infection (11 with matching antimicrobial resistance patterns). On the other hand, 37/736 (5%) of the patients who were not colonized, developed a pseudomonal infection. The type of infection observed was pneumonia in 26 (46%) patients, bloodstream infection in 20 (36%), urinary tract infection in 8 (14%), and infections at other sites in 2 (4%). The incidence of MDR P. aeruginosa in the entire cohort was 2.2% (18 of 794): 12 had positive SSCs and 7 of these patients later developed MDR P. aeruginosa infections. Patients with acute myelogenous leukemia were more likely to be colonized and to develop subsequent infection. No infection-related deaths were observed during the first 30 days after infection. CONCLUSIONS: The incidence of P. aeruginosa colonization and subsequent infection was low. Patients who were not colonized had a low chance of developing P. aeruginosa infection. Most patients who developed infection did not have fecal colonization, suggesting a different source of infection. SSCs for P. aeruginosa provide incomplete information regarding the source of infection. PMID- 25546741 TI - 7th International Immunoglobulin Conference: Immunodeficiencies. AB - Most primary immunodeficiency disorders (PID) are the result of single gene defects. Based on this fact, more than 240 different entities have been identified. Those PIDs with predominant antibody deficiency are treated with immunoglobulin (Ig) replacement therapy. This review focuses on the diagnosis, clinical characteristics and treatment of patients suffering from PID, or secondary immunodeficiency disorders (SID) caused, for instance, by irradiation, immunosuppressive drugs or thymectomy. Common variable immunodeficiency (CVID) is the most commonly diagnosed and least understood form of PID, with a heterogeneous range of symptoms and genotypes, requiring individualized treatment plans. This includes adjusting the dose and treatment interval, administrating Ig by intravenous or subcutaneous injection by either pump or push, and finally deciding which treatment options are best for a given patient. Ig therapy can also be used to treat immunodeficiencies resulting from lymphoproliferative and autoimmune diseases or immunosuppression following organ transplantation; however, there is an urgent need for research in this field. Accurate and early diagnosis of PID is important to ensure that optimal treatment is started early to maintain the patient's health. Detailed patient registries have been established to increase awareness of PID, as well as provide a valuable resource for further research. PMID- 25546742 TI - Common variable immunodeficiency (CVID): new genetic insight and unanswered questions. PMID- 25546743 TI - Dose and outcomes in primary immunodeficiency disorders. PMID- 25546744 TI - Immunoglobulin G treatment of secondary immunodeficiencies in the era of novel therapies. PMID- 25546745 TI - Primary immunodeficiencies screening: neonatal screening for T/B cell disorders - a triplex PCR method for quantitation of TRECs and KRECs in newborns. PMID- 25546746 TI - The relevance of collaborative work: the Latin American Society for Immunodeficiencies (LASID) registry model. PMID- 25546748 TI - 7th International Immunoglobulin Conference: Immunodeficiencies. AB - Awareness of the challenges involved in diagnosing and treating a heterogeneous group of immunodeficiency disorders is growing. The improvements in neonatal screening offer new methods to ensure that primary immunodeficiencies (PIDs) are diagnosed as early as possible, enabling accurate treatment and the prevention of life-threatening infections and other complications. Additionally, the need to individualize patient therapy in order to optimize both clinical outcomes and quality-of-life is obvious and is exemplified by the ability to switch between intravenous and subcutaneous immunoglobulin administration offering flexible treatment regimens. However, further research is crucial in order to determine the optimal treatment for secondary immunodeficiencies, and to gain greater understanding of the underlying causes of PIDs, including common variable immunodeficiency. The information relating to the growth of patient registries is encouraging, with approximately 25 000 patients with PIDs included in the two registries discussed. Registries such as this are vital for future research, as well as providing an educational resource. PMID- 25546749 TI - 7th International Immunoglobulin Conference: Neurology. AB - Immunoglobulin (Ig) therapy has been used and studied as a treatment for a variety of neurological conditions for decades. In some of these disorders Ig therapy has a significant role as a first-line treatment. This session explores the use of Ig therapy in immune-mediated peripheral neuropathies and various central nervous system (CNS) diseases. Informative practice points relating to the management and treatment of these diseases are discussed. Potential future neurological indications for Ig therapy, as well as data on efficacy and possible mechanisms of action, are also presented. In peripheral immune-mediated neuropathies, data show good response rates to Ig therapy and it is often used as a first-line treatment. Intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) are both well tolerated, but dose and dosing frequency should be based on individual clinical responses. In Alzheimer's disease, although clinical data show no significant differences between IVIg and placebo, biomarker studies indicate that plasma-derived antibodies may be involved in clearance of amyloid aggregates from the brain. Data suggest that the use of high IVIg doses in early-stage Alzheimer's treatment may warrant further investigation. Ig therapy is considered a valuable option for autoimmune encephalitis, an antibody-mediated CNS disease. Combination treatment with IVIg and corticosteroids shows promising results and is proposed as a first-line treatment in these disorders. Until recently, very little was understood about the pathogenesis of chronic pain disorders. Data now indicate that perpetuation of the pain response may be underpinned by central immune activation. Some data suggest that Ig therapy may mitigate this effect, with good response rates in a number of studies, but these data need confirmation. PMID- 25546750 TI - Use of immunoglobulin (Ig) in peripheral neuropathies. Impact of Ig on remission rates: comparison of intravenous immunoglobulin and subcutaneous immunoglobulin. PMID- 25546751 TI - Intravenous immunoglobulin for Alzheimer's disease. PMID- 25546752 TI - Antibody-mediated central nervous system diseases: disease recognition and treatment challenges. PMID- 25546747 TI - The European Society for Immunodeficiencies (ESID) registry 2014. PMID- 25546753 TI - Peripheral neuropathies: current evidence for alternative treatment regimens and treatment combinations. PMID- 25546754 TI - Dosing and individualized treatment - patient-centric treatment: changing practice guidelines. PMID- 25546755 TI - Immune activation and autoimmunity in chronic pain conditions and response to immunoglobulin G. PMID- 25546756 TI - Immunoglobulin (Ig) in multifocal motor neuropathy (MMN): update on evidence for Ig treatment in MMN. PMID- 25546757 TI - 7th International Immunoglobulin Conference: Neurology. AB - Data presented demonstrate the versatility of immunoglobulin (Ig) therapy for a variety of neurological disorders with different pathogenesis and presentations. In indications where the efficacy of Ig is well established, the neurology community is striving to improve the use of this valuable and limited resource by perfecting best practice guidelines, individualizing dosing schemes and investigating combination therapies to enhance treatment benefit. The data showing the efficacy of Ig therapy in conditions such as chronic pain and autoimmune encephalitis are promising. Future challenges for Ig use in neurological disorders were also outlined. Ongoing and upcoming randomized controlled trials will be pivotal to the use of Ig in the future, by identifying responder groups and elucidating the most effective administration practices. As our understanding and use of the therapy increases, it is essential that we collect data on the effects of long-term Ig treatment in neurological conditions, of which very little currently exists. PMID- 25546758 TI - 7th International Immunoglobulin Conference: Transplantation. AB - In transplantation, harnessing the immune system is essential for allograft survival and function. This session explores different aspects of the immune system during transplantation, including the effect of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs), antibody-mediated rejection (AMR), B cell modulation and the role of immunoglobulin (Ig) therapy. It is well known that DSAs play a key role in the failure of allografts. Identifying and characterizing DSAs provides information that can aid in risk stratification of transplant recipients. The ability to bind complement provides additional information regarding the cytotoxic potential of these antibodies and can therefore potentially guide individualized treatment strategies. AMR presents as several phenotypes, which vary in severity. As such, potentially different treatment strategies are required, emphasizing the importance of accurate diagnosis. In patients with elevated anti-HLA antibodies, waiting times for a compatible organ are often prolonged. Desensitization protocols using intravenous immunoglobulin (IVIg), in combination with other therapies, have been developed to enhance the availability of compatible donors. Another important aspect of transplantation is the role of B cells. While B cells may be involved in AMR and forms of cellular rejection, there is evidence to suggest that regulatory B cells may also have a positive impact upon long-term graft survival. Hypogammaglobulinaemia (HGG) has been reported after solid organ transplantation and is associated with an increased risk of infections. Monitoring immunoglobulin G (IgG) levels post-transplantation may identify patients at risk for infections who could potentially benefit from pre-emptive treatment with IVIg. PMID- 25546760 TI - Chronic antibody-mediated rejection: new diagnostic tools - clinical significance of C4d deposition and improved detection and characterization of human leucocyte antigen antibodies. PMID- 25546759 TI - Benefits, efficacy, cost-effectiveness and infectious complications in transplant patients desensitized with intravenous immunoglobulin and anti-CD20 therapy. PMID- 25546761 TI - Solid organ transplantation: hypogammaglobulinaemia and infectious complications after solid organ transplantation. PMID- 25546762 TI - Complement activation in kidney transplantation: from risk stratification to therapeutic strategies. PMID- 25546763 TI - Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies. PMID- 25546764 TI - B cell modulation in transplantation. PMID- 25546765 TI - 7th International Immunoglobulin Conference: Transplantation. AB - The data presented highlight the complexity of the immune response during transplantation. Early identification and characterization of donor-specific anti HLA antibodies (DSAs) allows for identification of patients at high risk of transplant rejection and offers information regarding appropriate intervention strategies. The availability of new diagnostic tools can also detect the presence of complement-binding antibodies, providing further information as to the cytotoxic potential of these antibodies. It is particularly encouraging to note that monitoring transplant recipients for the presence of various immune cells or immunoglobulin G (IgG) levels can provide detailed information regarding those at high risk for complications and therefore increased morbidity and mortality. Intervention strategies, either before or after transplantation, may potentially increase the long-term survival of allografts, thus enhancing patient outcomes. Future trials are warranted to assess these strategies in more detail. PMID- 25546766 TI - 7th International Immunoglobulin Conference: Immunoglobulin in clinical practice. AB - Immunoglobulin (Ig) replacement therapy has been the mainstay of primary immunodeficiencies (PID) treatment for more than 30 years and has substantially changed the lives of patients. This review focuses on aspects of Ig use in clinical practice in addition to discussing prioritizing future Ig use. Despite Ig therapy, PID patients continue to be predisposed to recurrent, subclinical respiratory tract infections, which may lead to chronic lung disease. Research has shown that one of the underlying reasons for this deterioration in lung function is the differential distribution and concentration of Ig isotypes in the airway lumen. Further to this, the relationship between Ig dose and infection outcome is explored, expanding on end-of-cycle loss of efficacy (wear-off) particularly with intravenous immunoglobulin (IVIg), how this can confound the determination of optimal IgG dose and how our aim of treatment should be to improve clinical outcome. This review goes on to discuss the safety of Ig replacement therapy, which is generally well tolerated by most patients, compares the rates of systemic adverse reactions between IVIg and SCIg and highlights the advantages of SCIg administration in this respect, including the use of pre infused subcutaneous recombinant human hyaluronidase to aid subcutaneous infusion volumes. The growing demand for Ig replacement therapy is challenging physicians; here we show the development of prioritization algorithms to assist in identifying those who will benefit most from this clinically valuable therapy. PMID- 25546767 TI - Subclinical infection and dosing in primary immunodeficiencies. PMID- 25546768 TI - Effective dosing strategies for therapeutic immunoglobulin: managing wear-off effects in antibody replacement to immunomodulation. PMID- 25546769 TI - Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis. PMID- 25546770 TI - Subcutaneous immunoglobulin: facilitated infusion and advances in administration. PMID- 25546771 TI - Considering the demand for and prioritization of intravenous immunoglobulin. PMID- 25546772 TI - Immunoglobulin replacement therapy in antibody deficiency syndromes: are we really doing enough? PMID- 25546773 TI - 7th International Immunoglobulin Conference: Immunoglobulin in clinical practice. AB - Intravenous and subcutaneous immunoglobulins (IVIg and SCIg, respectively) are increasingly used in clinical practice, not only as replacement therapy but also for immunomodulation. Physicians have learned that primary immunodeficiency (PID) patients are susceptible to recurrent respiratory tract infections even when appropriately treated with immunoglobulin (Ig) therapy. Further investigation will establish whether a combined therapeutic approach including Ig dose optimization will prevent progressive lung disease in PID. The wear-off effects observed with IVIg can be minimized by adjusting the dosing regimen. It is also possible to avoid the cyclic wear-off following transition to SCIg administration. Consideration of benefit versus risk with Ig therapy includes evaluating the potential occurrence of thromboembolic and haemolytic events, which may be more frequent when Ig is administered in high doses and in the presence of pre-existing risk factors. The ability to select an administration method from IVIg, SCIg or hyaluronidase-facilitated SCIg infusions provides patient choice and alternatives if one or other administration route is not suitable for a patient. The evolution in indications, applications, and understanding of Ig therapy described here has reinforced the need for robust methods to prioritize Ig use. PMID- 25546774 TI - 7th International Immunoglobulin Conference: Mechanisms of action. AB - Although intravenous immunoglobulin (IVIg) is widely used for replacement therapy in immunodeficiencies and to treat autoimmune and inflammatory diseases, its mechanisms of action are not fully understood. Examination of immunoglobulin (Ig) receptors, including the Fc-gamma receptors (FCgammaRs) and the neonatal Fc receptor, have revealed genetic variations that are linked to autoimmune diseases and to the efficacy of IVIg treatment. However, the beneficial effect of IVIg encompasses multiple mechanisms of action. One of these is scavenging of activated complement fragments, such as C3a, C5a, C3b and C4b, by infused Ig molecules. This interaction prevents binding of complement fragments to their receptors on target cells, thus attenuating the immune damage. Additionally, anti inflammatory effects may be facilitated by IgA via specific receptors and/or complement scavenging. Glycosylation of both the Fc- and Fab-fragments has also been implicated in the anti-inflammatory action of IVIg. Although there is evidence to support a role for sialylated IgG glycovariants in mediating the effect of IVIg, evidence from animal models of inflammatory disease suggest that sialylation may not be a critical factor. However, an increase in IgG glycosylation has been observed following IVIg treatment in Guillain-Barre syndrome patients, and this has been associated with improved clinical outcomes. PMID- 25546775 TI - Fc-dependent mechanisms of action: roles of FcgammaR and FcRn. PMID- 25546776 TI - Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor. PMID- 25546777 TI - Intravenous immunoglobulin and immune response. PMID- 25546778 TI - Role of sialylation in the anti-inflammatory activity of intravenous immunoglobulin - F(ab')2 versus Fc sialylation. PMID- 25546779 TI - Will sialylation change intravenous immunoglobulin therapy in the future? PMID- 25546780 TI - Influence of FCRN expression on lung decline and intravenous immunoglobulin catabolism in common variable immunodeficiency patients. PMID- 25546781 TI - Immunoglobulin G Fc N-glycosylation in Guillain-Barre syndrome treated with intravenous immunoglobulin. PMID- 25546782 TI - Immunoglobulin A as an anti-inflammatory agent. PMID- 25546783 TI - 7th International Immunoglobulin Conference: Mechanisms of action. AB - The mechanism of action by which therapeutic administration of intravenous immunoglobulin (IVIg) is able to provide a beneficial effect in autoimmune and inflammatory diseases is not yet fully understood, but current research is providing some answers. Signalling via receptors that interact with immunoglobulin (Ig) is crucial, and genetic polymorphisms of the Fc receptors have clear links to disease and also appear to influence the outcome of IVIg treatment. Glycosylation of the IgG, Fc- or Fab-fragments has a role in enhancing or blocking the pro- and anti-inflammatory effector functions. In addition, and independently of Fc receptors and glycosylation, Fc fragment and the constant domain of the Fab fragment contain binding sites for activated complement fragments that mediate complement-scavenging based immunomodulation. Although IgG Fc sialylation may not be critical for IVIg activity, research in some diseases suggests that it is associated with improved clinical outcomes. Therefore, further investigation of how IgG and IgA receptor expression and regulation affects the outcome of IVIg treatment may further clarify the mechanisms behind IVIg, and provide valuable guidance for future treatment paradigms. PMID- 25546784 TI - 7th International Immunoglobulin Conference: Immunomodulation. AB - Immunomodulation uses synthetic, natural and recombinant preparations to modify the immune response to a desired level, typically to treat specific autoimmune diseases, as will be discussed in this section. Rheumatoid arthritis (RA) is a common systemic autoimmune disease, affecting 1% of the population worldwide. Currently, a first-line disease-modifying therapy for RA is methotrexate; however, more than 40 monoclonal antibodies are in use or under investigation for the treatment of RA. This panoply of biological disease-modifying agents means that clinicians can make use of drugs with different mechanisms of action should one type become ineffective. In autoimmune pemphigus conditions, identification of pathogenic autoantibodies against intercellular cadherin desmoglein 1 and/or 3 antigens is one of the criteria for appropriate diagnosis. In pemphigoid conditions, autoantibodies are directed against bullous pemphigoid antigens BP230 and BP180, and in both types of immunobullous disease intravenous immunoglobulin (IVIg), as adjuvant therapy in combination with a cytotoxic drug, is effective in reducing autoantibody levels, disease severity and background steroid use. Further studies are required to establish the role of monoclonal antibodies in the treatment of autoimmune bullous disease. IVIg may also be effective in another at-risk population with autoimmune disease, namely secondary recurrent miscarriage (RM). However, the mechanism of action of IVIg in secondary RM is largely unknown, although levels of natural killer cell biomarkers, particularly CD56(+) , have been shown to decline after IVIg treatment. Data from meta analyses of heterogeneous placebo-controlled trials indicate that IVIg may be effective in secondary RM, but most trials to date have used immunomodulatory doses lower than those considered to be efficient in autoimmune disease. The results of a recently completed study may help to address this question. PMID- 25546785 TI - Gammaglobulins, autoantibodies, therapeutic antibodies and anti-drug antibodies in rheumatoid arthritis. PMID- 25546786 TI - Intravenous immunoglobulin G in the treatment of autoimmune bullous disease. PMID- 25546787 TI - Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics. PMID- 25546788 TI - 7th International Immunoglobulin Conference: Immunomodulation. AB - Rheumatoid arthritis (RA) is a debilitating autoimmune disease that is usually treated aggressively to slow the rate of joint destruction. The therapeutic strategy used at the French centre, described here, is to use the non-biological disease-modifying drug, methotrexate, as first-line therapy and to add biological agents as second-line treatment. The two other autoimmune diseases discussed in this session were immunobullous skin diseases, and secondary recurrent miscarriage (RM). In the former conditions, low levels of pathogenic autoantibodies can be achieved with adjuvant intravenous immunoglobulin (IVIg) therapy, usually in combination with an immunosuppressant. Secondary RM has an autoimmune basis, as shown by high tumour necrosis factor (TNF)-alpha levels and specific human leucocyte antigen (HLA) polymorphisms. Although the mechanism is not yet known, IVIg may also be an effective treatment, despite the generally low doses used in published studies. PMID- 25546789 TI - 7th International Immunoglobulin Conference: Interlaken Leadership Awards. AB - The Interlaken Leadership Awards (ILAs), established in 2010, are monetary grants pledged annually by CSL Behring to fund research into the use of immunoglobulin (Ig) therapy, especially into its use in neurological disorders. Five recipients of the 2011/2012 Awards were invited to present their research at the 7th International Immunoglobulin Conference. Dr Honnorat reports on paraneoplastic neurological syndromes (PNS). His multi-centre Phase II trial, currently under way, will assess the efficacy of IVIg therapy in treating PNS in the first 3 months of treatment. Dr Geis shows improved disease scores after IVIg treatment in a mouse model of neuromyelitis optica (NMO). It is hoped that these promising results will translate well into human NMO. Dr Schmidt studied IVIg therapy in an mdx mouse model for Duchenne muscular dystrophy (DMD). He reports that motor function improved and myopathic changes in skeletal muscles and creatine kinase release were decreased. Dr Gamez presents the design and rationale for a Phase II clinical trial investigating the preoperative use of IVIg therapy in myasthenia gravis patients to prevent post-operative myasthenic crisis. Dr Goebel reports results from studies elucidating the immune-mediated pathogenesis of complex regional pain syndrome (CRPS), the successful IVIg therapy in a proportion of CRPS patients, and the development of a model for predicting which patients are more likely to respond to Ig therapy. PMID- 25546790 TI - Early-onset immunotherapy by intravenous immunoglobulin and corticosteroids in well characterized onconeural-antibody-positive paraneoplastic neurological syndrome. PMID- 25546791 TI - Effects of pooled human immunoglobulins in an animal model of neuromyelitis optica with chronic application of autoantibodies to aquaporin 4. PMID- 25546792 TI - Human immunoglobulin G for experimental treatment of Duchenne muscular dystrophy. PMID- 25546793 TI - Intravenous immunoglobulin for preparing myasthenia gravis patients for thymectomy and other surgical procedures preventing myasthenic crisis. PMID- 25546795 TI - 7th International Immunoglobulin Conference: Interlaken Leadership Awards. AB - The research presented in this section explores novel applications of immunoglobulin (Ig) therapy in neurological disorders. The results from the upcoming and ongoing trials of Drs Honnorat and Gamez are expected to provide meaningful insights into the treatment of two serious and disabling diseases. The results already being reported from the work of Drs Schmidt and Geis in animal models seem promising, but further proof-of-concept research is warranted to translate their significance to human diseases. Dr Goebel's work in developing animal models of complex regional pain syndrome (CRPS) may provide new insights into predicting which CRPS patients could respond to Ig therapy or other immunotherapies. The work being made possible by a number of the Interlaken Leadership Awards may provide fundamental insights in understanding neurological disorders and improving quality of life for the patients who suffer from them. PMID- 25546794 TI - Cellular and behavioural models to predict responses to immunoglobulin G treatment in complex regional pain syndrome. PMID- 25546796 TI - 7(th) International Immunoglobulin Conference: Poster presentations. AB - Immunoglobulin (Ig) therapy is the mainstay of treatment for primary antibody deficiency disorders and has proved to be efficacious in specific autoimmune and inflammatory diseases. Additionally, due to the role of Ig in complement activation, it is being used increasingly in solid organ transplantation. Furthermore, Ig is the primary or secondary treatment in some immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) or multifocal motor neuropathy (MMN). This session discusses trends of Ig use in Europe, proposed mechanisms of action, adverse effects and the potential role of Ig therapy in transplantation. Dr Sediva reported that Ig therapy is available in all European countries, although dosing is not always optimal, due partly to reimbursement plans. Subcutaneous immunoglobulin (SCIg) has become increasingly accessible in recent years; however, the chosen route of administration still varies widely between countries. Dr Berger's presentation on optimization of Ig therapy in neuropathies, and Dr Rojavin's report on a pharmacometric model to determine the serum IgG levels achieved by different dosing regimens in primary antibody deficiency (PAD) patients, led to the challenging concept of using individualized dosing strategies. Dr Klehmet reported on the potential benefit of using antigen-specific T cell responses as a biomarker of IVIg responsiveness in CIDP patients, while Dr von Gunten provided an insight into the mechanisms of action of Ig preparations, suggesting that the immunoregulatory effects of IgG may be mediated by IgG antibodies against glycans. Dr Basta reported on the potential thrombogenic adverse effects associated with Ig therapy. Although these adverse events are rare, further studies are needed to clarify the relationship between Ig replacement and immunomodulatory therapy and these adverse reactions. In transplantation, Dr Carbone described that prophylactic IVIg treatment was found to decrease the incidence of severe infection in IgG hypogammaglobulinaemia patients undergoing heart transplantations. Furthermore, Dr Clatworthy reported that inactivating polymorphisms in the inhibitory receptor FcgammaRIIB do not impact upon kidney allograft survival. PMID- 25546798 TI - Optimizing immunoglobulin G therapy in chronic autoimmune neuropathies. PMID- 25546797 TI - Europe immunoglobulin map. PMID- 25546799 TI - Subcutaneous immunoglobulin loading regimens for previously untreated patients with primary antibody deficiency. PMID- 25546800 TI - Efficiency of long-term treatment with intravenous immunoglobulins correlates with reduced autoreactive T cell responses in chronic inflammatory demyelinating polyneuropathy patients. PMID- 25546801 TI - Protein-glycan interactions as targets of intravenous/subcutaneous immunoglobulin (IVIg/SCIg) preparations. PMID- 25546802 TI - Intravenous immunoglobulin-related thromboembolic events - an accusation that proves the opposite. PMID- 25546803 TI - Intravenous immunoglobulin as an intervention strategy of risk factor modification for prevention of severe infection in heart transplantation. PMID- 25546804 TI - De-functioning polymorphism in the inhibitory receptor FcgammaRIIB does not impact upon kidney allograft survival. PMID- 25546805 TI - 7th International Immunoglobulin Conference: Poster presentations. AB - The pan-European survey provides useful information on the accessibility and trends of intravenous and subcutaneous immunoglobulin (IVIg/SCIg) therapy, which is used to treat primary immunodeficiency disorders (PIDs). Although immunoglobulin (Ig) therapy is the first-line treatment for PIDs, the mechanisms of action of Ig therapy may differ according to the condition it is used to treat. Moreover, intriguing presentations suggest that further investigation is required to understand more clearly both the haematological and immunoregulatory effects of therapeutic immunoglobulin. This can ultimately provide more information on optimizing Ig therapy efficacy, and establish whether individualized dosing regimens for patients will be conducive to better clinical outcomes. In addition to treating autoimmune and inflammatory conditions, there is evidence to suggest that immunoglobulins can potentially play a role in transplantation, which warrants further investigation for future use. PMID- 25546806 TI - Immunoglobulins: current understanding and future directions. PMID- 25546808 TI - Reflections on the lowly PVC. PMID- 25546809 TI - The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. AB - BACKGROUND: Risk stratification tools are needed to select the right candidates for catheter ablation of atrial fibrillation (AF). Both the CHADS2 and CHA2DS2 VASc scores have utility in predicting AF-related outcomes and guiding anticoagulation treatment. OBJECTIVE: We sought to determine whether these risk scores predict long-term outcomes after AF ablation and whether one risk score provides comparatively superior performance. METHODS: CHADS2 and CHA2DS2-VASc scores were calculated in 2179 patients who underwent a first ablation procedure for AF enrolled in the Intermountain Heart Collaborative Study. CHADS2 and CHA2DS2-VASc scores were categorized as 0-1, 2-4, and >=5. Patient outcomes were analyzed over 5 years for AF/atrial flutter recurrence and major adverse cardiovascular events (MACE: composite of death, stroke, and heart failure hospitalization). RESULTS: The mean age was 65.7 +/- 10.5 years, and 61.1% were men. Both scores incrementally predicted risk of AF recurrence, stroke, heart failure, and death at 5 years. Increasing CHADS2 (hazard ratio [HR] 1.19; P < .001) and CHA2DS2-VASc (HR 1.15; P < .0001) scores were both associated with AF/atrial flutter recurrence. The results were similar for MACE where increasing CHADS2 (HR 1.54; P < .0001) and CHA2DS2-VASc (HR 1.32; P < .0001) scores were associated with risk. When CHADS2 and CHA2DS2-VASc scores were modeled together, only CHA2DS2-VASc scores significantly predicted AF recurrence (HR 1.13; P = .001), but both were associated with MACE. CONCLUSION: Both the CHADS2 and CHA2DS2-VASc scores were excellent in stratifying patients for 5-year outcomes after AF ablation. However, the CHA2DS2-VASc score was superior to the CHADS2 score in predicting AF recurrence and AF-related morbidities. PMID- 25546807 TI - Studying macromolecular complex stoichiometries by peptide-based mass spectrometry. AB - A majority of cellular functions are carried out by macromolecular complexes. A host of biochemical and spectroscopic methods exists to characterize especially protein/protein complexes, however there has been a lack of a universal method to determine protein stoichiometries. Peptide-based MS, especially as a complementary method to the MS analysis of intact protein complexes, has now been developed to a point where it can be employed to assay protein stoichiometries in a routine manner. While the experimental demands are still significant, peptide based MS has been successfully applied to analyze stoichiometries for a variety of protein complexes from very different biological backgrounds. In this review, we discuss the requirements especially for targeted MS acquisition strategies to be used in this context, with a special focus on the interconnected experimental aspects of sample preparation, protein digestion, and peptide stability. In addition, different strategies for the introduction of quantitative peptide standards and their suitability for different scenarios are compared. PMID- 25546810 TI - Inhibition of IKr potentiates development of atrial-selective INa block leading to effective suppression of atrial fibrillation. AB - BACKGROUND: The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need. OBJECTIVES: The purpose of this study was to test the hypothesis that the inhibition of the rapidly activating delayed rectifier potassium current (IKr) greatly potentiates the development of atrial-selective sodium channel current (INa) block, leading to more effective suppression of AF. METHODS: Electrophysiological and anti-AF effects of highly selective INa and IKr blockers (lidocaine and E-4031) individually and in combination were determined in canine coronary-perfused atrial and ventricular preparations. Acetylcholine (1 uM) was used to induce persistent AF. RESULTS: Lidocaine (10 uM) caused a relatively small abbreviation of the action potential duration measured at 90% repolarization in both atria and ventricles, but caused atrial-selective prolongation of the effective refractory period owing to the induction of post-repolarization refractoriness. Lidocaine also caused modest atrial-selective depression of other INa-mediated parameters including excitability, maximum rate of rise of the action potential upstroke, and conduction time. E-4031 (1 uM) prolonged the action potential duration measured at 90% repolarization and effective refractory period in an atrial predominant manner. A combination of lidocaine and E-4031 caused a greater atrial selective depression of INa-mediated parameters. Persistent acetylcholine mediated AF developed in 100% of atria under control conditions, in 80% (4 of 5) after pretreatment with lidocaine (10 uM), in 100% (4 of 4) after E-4031 (1 uM), and in only 14% (1 of 7) after the combination of lidocaine and E-4031. CONCLUSION: Our results provide a proof of concept that IKr block greatly potentiates the effects of rapidly dissociating INa blockers to depress sodium channel-dependent parameters in the canine atria but not in the ventricles, thus contributing significantly to suppression of AF. PMID- 25546811 TI - Electrical dyssynchrony induced by biventricular pacing: implications for patient selection and therapy improvement. AB - BACKGROUND: Biventricular pacing (BVP) may not achieve complete electrical resynchronization. OBJECTIVE: The purpose of this study was to assess whether the resynchronizing effect of BVP varies among patients depending on the underlying electrical substrate. METHODS: High-resolution electrocardiographic mapping with invasive measurement of the maximal rate of systolic left ventricular (LV) pressure rise (LVdP/dtmax) was performed during baseline activation and during BVP in 61 patients with heart failure with various conduction delays: 13 with narrow QRS duration (<120 ms), 22 with nonspecific intraventricular conduction disturbance, and 26 with left bundle branch block. Electrical dyssynchrony, both during baseline activation and BVP, was quantified by total and LV activation times (TAT and LVTAT) and by ventricular electrical uncoupling (VEU = mean LVTAT mean right ventricular activation time). Response to BVP was defined as a >=10% increase in LVdP/dtmax. RESULTS: The electrical activation pattern during BVP was similar for all patient groups and, hence, not dependent on baseline conduction disturbance. During BVP, TAT, LVTAT, and VEU were similar for all groups and were either not correlated or weakly correlated with the change in LVdP/dtmax. In contrast, changes in electrical dyssynchrony correlated significantly with the change in LVdP/dtmax: r=0.71, 0.69, and 0.69 for ?TAT, ?LVTAT, and ?VEU, respectively (all P < .001). Responders showed higher baseline dyssynchrony levels and BVP-induced dyssynchrony reduction than did nonresponders (all P < .001); in nonresponders, BVP worsened activation times than did baseline activation. CONCLUSION: BVP does not eliminate electrical dyssynchrony, but rather brings it to a common level independent of the patient's underlying electrical substrate. Therefore, BVP is of benefit to patients with dyssynchrony but not to patients with insufficient electrical dyssynchrony in whom it induces an iatrogenic electropathy. PMID- 25546812 TI - Evolution of dynamin: modular design of a membrane remodeling machine (retrospective on DOI 10.1002/bies.201200033). PMID- 25546814 TI - Melatonin treatment improves primary progressive multiple sclerosis: a case report. AB - We describe the case of a female patient who, at the age of 28, was diagnosed with symptoms of primary progressive multiple sclerosis (PPMS). Glucocorticoid treatment was immediately initiated. The disease and the demyelinating lesions progressed during the following 9 years reaching Expanded Disability Status Scale (EDSS) 8.0 (patient essentially restricted to bed, a chair or perambulated in a wheelchair). At this point, the patient began taking melatonin at doses ranging from 50 to 300 mg per day. Melatonin was her only treatment for the next 4 years; during this interval, her EDSS progressively recovered to 6.0 (the person needs intermittent or unilateral constant assistance such as cane, crutch, or brace to walk 100 meters with or without resting). This long-lasting improvement is likely due to melatonin usage since it is related in time and because of its exceptionally long duration. PMID- 25546813 TI - Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. AB - The endoplasmic reticulum (ER) is a cellular organelle where secretory and membrane proteins, as well as lipids, are synthesized and modified. When cells are subjected to ER stress, an adaptive mechanism referred to as the Unfolded Protein Response (UPR) is triggered to allow the cells to restore homeostasis. Evidence has accumulated that the UPR pathways provide specialized and unique roles in diverse development and metabolic processes. The glucose regulated proteins (GRPs) are traditionally regarded as ER proteins with chaperone and calcium binding properties. The GRPs are constitutively expressed at basal levels in all organs, and as stress-inducible ER chaperones, they are major players in protein folding, assembly and degradation. This conventional concept is augmented by recent discoveries that GRPs can be actively translocated to other cellular locations such as the cell surface, where they assume novel functions that regulate signaling, proliferation, apoptosis and immunity. Recent construction and characterization of mouse models where the gene encoding for the UPR components and the GRPs is genetically altered provide new insights on the physiological contribution of these proteins in vivo. This review highlights recent progress towards the understanding of the role of the UPR and two major GRPs (GRP78 and GRP94) in regulating homeostasis of organs arising from the endoderm, mesoderm and ectoderm. GRP78 and GRP94 exhibit shared and unique functions, and in specific organs their depletion elicits adaptive responses with physiological consequences. PMID- 25546816 TI - Present planning versus future planning: we need a shift toward goals of care education for physicians. PMID- 25546815 TI - Rare LRP6 variants identified in spina bifida patients. AB - Several single-nucleotide variants (SNVs) in low-density lipoprotein receptor related protein 6 (Lrp6) cause neural tube defects (NTDs) in mice. We therefore examined LRP6 in 192 unrelated infants from California with the NTD, spina bifida, and found four heterozygous missense SNVs, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched nonmalformed controls. Parents and siblings could not be tested because of the study design. Like Crooked tail and Ringleschwanz mouse variants, the p.Tyr544Cys Lrp6 protein failed to bind the chaperone protein mesoderm development and impaired Lrp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p.Tyr544Cys Lrp6 variant downregulated canonical Wnt signaling in a TopFlash luciferase reporter in vitro assay. In contrast, three Lrp6 mutants (p.Ala3Val, p.Tyr544Cys, and p.Arg1574Leu) increased noncanonical Wnt/planar cell polarity (PCP) signaling in an Ap1-luciferase assay. Thus, LRP6 variants outside of YWTD repeats could potentially predispose embryos to NTDs, whereas Lrp6 modulation of Wnt/PCP signaling would be more essential than its canonical pathway role in neural tube closure. PMID- 25546817 TI - Outcomes after surgery and postoperative radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma. AB - BACKGROUND: Queensland, Australia, has the highest rates of cutaneous squamous cell carcinoma (SCC). Perineural invasion (PNI) is associated with reduced local control and survival. METHODS: A retrospective review of a prospective database of patients with clinical PNI from cutaneous SCC of the head and neck (SCCHN) treated with surgery and postoperative radiotherapy (PORT) between 2000 and 2011 and a minimum of 24 months follow-up. Patients were excluded if immunosuppressed, had non-SCC histology, or were treated palliatively. RESULTS: Fifty patients (mean age, 60 years) with median follow-up of 50 months were included in this study. A total of 54.8% of known primary tumors had incidental PNI. Ten percent had nodal disease at presentation. MRI neurogram was positive in 95.8%. Recurrence-free survival (RFS) at 5-years was 62%. Five-year disease-specific survival (DSS) and overall survival (OS) were 75% and 64%, respectively. There were no perioperative deaths. CONCLUSION: This report demonstrates that long-term survival is achievable in patients with clinical PNI from cutaneous SCCHN after surgery and PORT. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 824-831, 2016. PMID- 25546818 TI - Mechanisms underlying turgor regulation in the estuarine alga Vaucheria erythrospora (Xanthophyceae) exposed to hyperosmotic shock. AB - Aquatic organisms are often exposed to dramatic changes in salinity in the environment. Despite decades of research, many questions related to molecular and physiological mechanisms mediating sensing and adaptation to salinity stress remain unanswered. Here, responses of Vaucheria erythrospora, a turgor-regulating xanthophycean alga from an estuarine habitat, have been investigated. The role of ion uptake in turgor regulation was studied using a single cell pressure probe, microelectrode ion flux estimation (MIFE) technique and membrane potential (Em ) measurements. Turgor recovery was inhibited by Gd(3+) , tetraethylammonium chloride (TEA), verapamil and orthovanadate. A NaCl-induced shock rapidly depolarized the plasma membrane while an isotonic sorbitol treatment hyperpolarized it. Turgor recovery was critically dependent on the presence of Na(+) but not K(+) and Cl(-) in the incubation media. Na(+) uptake was strongly decreased by amiloride and changes in net Na(+) and H(+) fluxes were oppositely directed. This suggests active uptake of Na(+) in V. erythrospora mediated by an antiport Na(+) /H(+) system, functioning in the direction opposite to that of the SOS1 exchanger in higher plants. The alga also retains K(+) efficiently when exposed to high NaCl concentrations. Overall, this study provides insights into mechanisms enabling V. erythrospora to regulate turgor via ion movements during hyperosmotic stress. PMID- 25546819 TI - Adiponectin -11377C/G and +276G/T polymorphisms affect adiponectin levels but do not modify responsiveness to therapy in resistant hypertension. AB - Resistant hypertension (RHTN) is a multifactorial and polygenic disease, frequently associated with obesity. Low plasma adiponectin levels, a hormone produced by the adipose tissue, were associated with RHTN. Single nucleotide polymorphisms (SNPs) -11377C/G (rs266729) and +276G/T (rs1501299) in ADIPOQ (adiponectin gene) were associated with hypertension. This study evaluated the association between two SNPs (-11377C/G and +276G/T) and adiponectin levels in RHTN. This study comprised 109 patients with RHTN genotyped for both polymorphisms. A cross-sectional study was designed to compare features of CC homozygous versus G allele carriers for -11377C/G and GG homozygous versus T allele carriers for +276G/T. Office and ambulatory BP measurements were similar among genotypes subgroups in both SNPs as well as the markers of target organ damage (arterial stiffness, left ventricular mass index and microalbuminuria). Adiponectin concentrations were significantly higher in CC compared to G carrier for -11377C/G (CC:7.0 (4.0-10.2) versus G allele:5.5 (2.5-7.9), p = 0.04) and lower in GG compared to T carrier for +276G/T (GG:5.3 (2.3-7.7) versus T allele:7.1 (3.6-10.5), p = 0.04). Adjusting for systolic ambulatory BP, body mass index, age, gender, race and presence of type 2 diabetes, multiple linear regression analyses revealed that the minor alleles G (beta-coefficient= -0.14, SE=0.07, p = 0.03) and T (beta-coefficient=0.12, SE=0.06, p = 0.04) were independent predictors of adiponectin. The -11377C/G and +276G/T SNPs in ADIPOQ were associated with adiponectin levels in RHTN individuals. PMID- 25546820 TI - New atropisomeric amino alcohol ligands for enantioselective addition of diethylzinc to aldehydes. AB - Efficient synthesis of several new atropisomeric amino alcohols having 1-phenyl 1H-pyrrole skeleton are reported. Steric arrangements of the products were confirmed by a single-crystal X-ray measurement. The consequences of the size of the N-substituents on enantioinduction were examined by employing the enantioselective catalytic addition of diethylzinc to a series of substituted benzaldehydes (yields 91-97%, up to 85% enantiomeric excess). The special effect of the ortho methoxy group of the substrate on the enantioinduction is also interpreted. PMID- 25546821 TI - Evidence against a role of serotonin in liver regeneration in humans. PMID- 25546822 TI - The parasitic worm product ES-62 targets myeloid differentiation factor 88 dependent effector mechanisms to suppress antinuclear antibody production and proteinuria in MRL/lpr mice. AB - OBJECTIVE: The hygiene hypothesis suggests that parasitic helminths (worms) protect against the development of autoimmune disease via a serendipitous side effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. The aim of this study was to investigate whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage in an MRL/lpr mouse model of systemic lupus erythematosus (SLE). METHODS: MRL/lpr mice progressively produce high levels of autoantibodies, and the resultant deposition of immune complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria, assessment of kidney histology, determination of antinuclear antibody (ANA) production and cytokine levels, and flow cytometric analysis of relevant cellular populations. RESULTS: ES-62 restored the disrupted balance between effector and regulatory B cells in MRL/lpr mice by inhibiting plasmablast differentiation, with a consequent reduction in ANA production and deposition of immune complexes and C3a in the kidneys. Moreover, by reducing interleukin-22 production, ES-62 may desensitize downstream effector mechanisms in the pathogenesis of kidney disease. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62-treated MRL/lpr mice mimicked the protection afforded by the helminth product. Mechanistically, this reflects down regulation of myeloid differentiation factor 88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic cross-talk among Toll-like receptor-, C3a-, and immune complex-mediated effector mechanisms. CONCLUSION: This study provides the first demonstration of protection against kidney pathology by a parasitic worm-derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on the mechanism of action of ES 62. PMID- 25546824 TI - Astigmatism and early academic readiness in preschool children. AB - PURPOSE: This study investigated the relationship between uncorrected astigmatism and early academic readiness in at-risk preschool-aged children. METHODS: A vision screening and academic records review were performed on 122 three- to five year-old children enrolled in the Philadelphia Head Start program. Vision screening results were related to two measures of early academic readiness, the teacher-reported Work Sampling System (WSS) and the parent-reported Ages and Stages Questionnaire (ASQ). Both measures assess multiple developmental and skill domains thought to be related to academic readiness. Children with astigmatism (defined as >|-0.25| in either eye) were compared with children who had no astigmatism. Associations between astigmatism and specific subscales of the WSS and ASQ were examined using parametric and nonparametric bivariate statistics and regression analyses controlling for age and spherical refractive error. RESULTS: Presence of astigmatism was negatively associated with multiple domains of academic readiness. Children with astigmatism had significantly lower mean scores on Personal and Social Development, Language and Literacy, and Physical Development domains of the WSS, and on Personal/Social, Communication, and Fine Motor domains of the ASQ. These differences between children with astigmatism and children with no astigmatism persisted after statistically adjusting for age and magnitude of spherical refractive error. Nonparametric tests corroborated these findings for the Language and Literacy and Physical Health and Development domains of the WSS and the Communication domain of the ASQ. CONCLUSIONS: The presence of astigmatism detected in a screening setting was associated with a pattern of reduced academic readiness in multiple developmental and educational domains among at-risk preschool-aged children. This study may help to establish the role of early vision screenings, comprehensive vision examinations, and the need for refractive correction to improve academic success in preschool children. PMID- 25546825 TI - Refractive error and vision-related quality of life in South Indian children. AB - PURPOSE: To understand the vision-related quality of life (QoL) of schoolchildren with uncorrected refractive error (URE). METHODS: A snapshot qualitative research design and homogeneous sampling strategy was adopted. Thirty-one, 27, and 22 eye care practitioners, children, and teachers participated in four, three, and two focus group discussions, respectively. The participants were recruited from various parts of Chennai, India. The discussions were audio recorded, transcribed, coded, and analyzed. RESULTS: Eight themes emerged: complaints and symptoms of children with URE, vision-related activity limitation, coping strategies, psychological impact, social impact, the perceived difference after first time refractive correction, reasons for refractive error remaining uncorrected, and the significant amount of refractive error. CONCLUSIONS: The study gives a holistic view of the vision-related QoL of children with URE by demonstrating the difficulties and problems that they face in their day-to-day life and also by describing the perceived difference in QoL after wearing refractive correction. PMID- 25546823 TI - Tetrakis(p-carboranylthio-tetrafluorophenyl)chlorin (TPFC): application for photodynamic therapy and boron neutron capture therapy. AB - Carboranyl-containing chlorins have emerged as promising dual sensitizers for use in both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT), by virtue of their known tumor affinity, low cytotoxicity in dark conditions, and their strong absorptions in the red region of the optical spectrum. Tetrakis(p carboranylthio-tetrafluorophenyl)chlorin (TPFC) is a new synthetic carboranyl containing chlorin of high boron content (24% by weight). To evaluate TPFC's applicability as sensitizer for both PDT and BNCT, we performed an in vitro and in vivo study using F98 rat glioma cells and F98 rat glioma-bearing brain tumor models. For the in vivo BNCT study, we used boronophenylalanine (BPA), which is currently used in clinical BNCT studies, via intravenous administration (i.v.) and/or used TPFC via convection-enhanced delivery (CED), a method for local drug infusion directly into the brain. In the in vitro PDT study, the cell surviving fraction following laser irradiation (9 J/cm(2) ) was 0.035 whereas in the in vitro BNCT study, the cell surviving fraction following neutron irradiation (thermal neutron = 1.73 * 10(12) n/cm(2) ) was 0.04. In the in vivo BNCT study, the median survival time following concomitant administration of BPA (i.v.) and TPFC (CED) was 42 days (95% confidence interval; 37-43 days). PMID- 25546826 TI - Ocular surface sensitivity repeatability with Cochet-Bonnet esthesiometer. AB - PURPOSE: To determine the repeatability of ocular surface threshold measurements using the Cochet-Bonnet esthesiometer on the same day and 3 months apart. METHODS: Two separate studies were conducted to determine the repeatability of ocular surface threshold measurements made on the same day (n = 20 subjects) and 3 months apart (n = 29 subjects). The Cochet-Bonnet esthesiometer was used to measure corneal and inferior conjunctival thresholds using the ascending method of limits. The pressure exerted by the Cochet-Bonnet esthesiometer was determined using an analytical balance, for both the 0.08- and 0.12-mm-diameter filaments. This calibration was then used to convert filament length measurements to pressure. Repeatability was determined using a Bland and Altman analysis. RESULTS: The pressure exerted at each filament length differed between the two filament diameters. The measured pressure also differed from values provided by the manufacturer. Repeatability of threshold measurements at the central cornea was shown to be good, with better repeatability for same-day measurements (coefficient of repeatability [CoR] = +/-0.23 g/mm2) than for those 3 months apart (CoR = +/-0.52 g/mm2). Threshold measurements at the inferior conjunctiva, in contrast, were poorly repeatable (CoR = +/-12.78 g/mm2). CONCLUSIONS: Cochet Bonnet esthesiometry is repeatable when performed on the central cornea on the same day and 3 months apart, but this instrument is not recommended for conjunctival threshold measurements. PMID- 25546827 TI - Comparison between live and photographed slit lamp grading of corneal staining. AB - PURPOSE: To compare live and photographic (still) grades of corneal staining of the same eyes and the repeatability of grading between two investigators. METHODS: Thirty patients were recruited to participate in a contact lens study, and their level of corneal staining was graded by two investigators in situ (live images), using slit lamp biomicroscopy. Digital still images of the corneal staining were also captured during the study visits. An independent observer selected 105 of the still images graded by investigator 1 and another 105 images graded by investigator 2 and presented them to the original investigator in a random order, on three separate occasions. Grading was performed at the time of the live grading and the three still image sessions, using the Centre for Contact Lens Research corneal staining scale that combines grades of both extent and type to provide an overall "global staining score" from 0 to 10,000 for corneal staining. A comparison was made between live and still grades as well as the intrainvestigator repeatability for the multiple grading of the still images. RESULTS: The mean (+/-SD) of corneal staining grades recorded for the same eyes examined live and then later on three occasions was 1795 (+/-1083) and 714 (+/ 974), respectively, for participants examined by investigator 1 (p < 0.001) and 1854 (+/-1075) and 461 (+/-411) for those examined by investigator 2 (p < 0.001). There was a significant difference over the three repeated still grading sessions for each investigator (p < 0.001), although there was a high degree of consistency among the three still grading sessions for each of the investigators: the intraclass correlation for investigator 1 was 0.91 (confidence interval, 0.87 to 0.93) and that for investigator 2 was 0.82 (confidence interval, 0.77 to 0.87). DISCUSSION: Digital still image grading of corneal staining significantly underrepresented the amount of corneal staining observed through a slit lamp. Clinical investigators graded corneal staining with a high degree of consistency. PMID- 25546828 TI - Standard and hypoosmolar corneal cross-linking in various pachymetry groups. AB - PURPOSE: To investigate the influence of corneal thickness on the outcome of corneal cross-linking (CXL) for progressive keratoconus. METHODS: In this cohort study, 72 unilateral eyes were treated by CXL and divided into three groups according to central corneal thickness (CCT) measured by ultrasound pachymetry after 30-minute riboflavin. Group 1 (CCT <400 MUm) underwent hypoosmolar CXL; group 2 (CCT 400 to 460 MUm) and group 3 (CCT >460 MUm) underwent standard CXL. Visual acuity, refraction, topography, ultrasound and optical pachymetry, intraocular pressure, endothelial cell count, and complications were evaluated 1 year post-CXL. RESULTS: Ultrasound CCT after riboflavin instillation decreased significantly in groups 1 and 2 (-57 +/- 44 MUm and -39 +/- 23 MUm, respectively) and increased in group 3 (+15 +/- 37 MUm). One year post-CXL, maximal keratometry decreased significantly in group 2. Keratoconus progression was halted in 92% (group 1), 97% (group 2), and 86% (group 3). Optical pachymetry decreased significantly in all groups. Corrected distance visual acuity improved significantly in groups 1 and 3. No significant difference was found in visual acuity, keratometry, optical pachymetry, or endothelial cell density change between groups. Complication rates were comparable between the groups; there was no significant difference in CXL failure (p = 0.687) or corrected distance visual acuity loss (p = 0.617). CONCLUSIONS: During CXL, corneas with CCT less than or equal to 460 MUm seem to dehydrate faster than corneas with CCT greater than 460 MUm. Both standard and hypoosmolar CXL are safe and effective treatments, with comparable amounts of stabilization after 1 year. PMID- 25546829 TI - Aniseikonia induced by cataract surgery and its effect on binocular vision. AB - PURPOSE: This study measured aniseikonia before and after the first and second cataract surgeries in ametropic adults. The relationship of aniseikonia to anisometropia and its effect on stereopsis, ocular alignment, and clinical symptoms were determined. METHODS: Seventeen patients scheduled to have bilateral cataract surgery with 2 diopters or more ametropia participated. Patients were evaluated before cataract surgery and 4 weeks (+/-1 week) after the first and second surgery. Visual acuity, refractive error, aniseikonia, stereopsis, ocular alignment, and visual symptoms were determined at each visit. RESULTS: Aniseikonia increased after the first cataract surgery. The increase in aniseikonia occurred in concert with increased anisometropia and resulted in poorer stereopsis overall. Aniseikonia and anisometropia 1 month (+/-1 week) after the second cataract surgery returned to near baseline and were associated with better stereopsis. The amount of aniseikonia showed substantial variance and could not be predicted by the amount of induced anisometropia. Changes in ocular alignment were minimal. Statistically significant changes in patient symptoms between study visits were infrequent. CONCLUSIONS: Aniseikonia induced by cataract surgery may not be a substantial problem for ametropic adults with normal binocular vision, at least in the short term. PMID- 25546830 TI - Effect of axial length on diurnal IOP in cataract patients without glaucoma. AB - PURPOSE: To evaluate the effect of ocular biometrics on intraocular pressure (IOP) and diurnal IOP fluctuation in nonglaucomatous subjects. METHODS: We examined 115 subjects from May to December 2007 in Kangbuk Samsung Hospital, Seoul, Korea. Intraocular pressure was measured with a Goldmann applanation tonometer in habitual positions every 2 hours from 9 am to 11 pm. Ocular biometric values including central corneal thickness, central corneal power, axial length, anterior chamber depth, and lens thickness were measured using an ultrasound biometer and keratometer and the refractive state was determined. RESULTS: Two hundred fourteen eyes of 115 patients were included in this study; the mean (+/-SD) IOP of all eyes was 12.33 (+/-2.55) mmHg. The mean (+/-SD) diurnal IOP fluctuation was 2.72 (+/-1.43) mmHg. Central corneal thickness was positively correlated with the mean IOP (Pearson correlation, r = 0.217, p = 0.002); however, there was no relationship between central corneal thickness and the diurnal IOP fluctuation. Axial length was not related to the mean IOP (Pearson correlation, r = 0.049, p = 0.476) and the diurnal IOP fluctuation (Pearson correlation, r = 0.058, p = 0.395). The mean IOP or diurnal IOP fluctuation was not related to any of the following values: central corneal power, anterior chamber depth, refractive error, lens thickness, or vitreous chamber depth. CONCLUSIONS: Central corneal thickness is significantly related to the IOP but may not affect diurnal IOP fluctuation. The axial length was not associated with IOP profiles in this study. Our results can contribute to a broader understanding of the effects of ocular biomechanical properties on the IOP profile. PMID- 25546831 TI - Stem cell reprogramming: basic implications and future perspective for movement disorders. AB - The introduction of stem cell-associated molecular factors into human patient derived cells allows for their reprogramming in the laboratory environment. As a result, human induced pluripotent stem cells (hiPSC) can now be reprogrammed epigenetically without disruption of their overall genomic integrity. For patients with neurodegenerative diseases characterized by progressive loss of functional neurons, the ability to reprogram any individual's cells and drive their differentiation toward susceptible neuronal subtypes holds great promise. Apart from applications in regenerative medicine and cell replacement-based therapy, hiPSCs are increasingly used in preclinical research for establishing disease models and screening for drug toxicities. The rapid developments in this field prompted us to review recent progress toward the applications of stem cell technologies for movement disorders. We introduce reprogramming strategies and explain the critical steps in the differentiation of hiPSCs to clinical relevant subtypes of cells in the context of movement disorders. We summarize and discuss recent discoveries in this field, which, based on the rapidly expanding basic science literature as well as upcoming trends in personalized medicine, will strongly influence the future therapeutic options available to practitioners working with patients suffering from such disorders. PMID- 25546832 TI - Effects of alternating wetting and drying versus continuous flooding on chromium fate in paddy soils. AB - Anthropogenic chromium (Cr) pollution in soils poses a great threat to human health through the food chain. It is imperative to understand Cr fate under the range of conditions suitable for rice growth. In this study, the effects of irrigation managements on dynamics of porewater Cr(VI) concentrations in rice paddies and Cr distribution in rice were investigated with pot experiments under greenhouse conditions. Soil redox potential in continuous flooding (CF) treatments showed that reducing conditions remained for the whole duration of rice growing period, while soil redox potential in alternating wetting and drying (AWD) treatments showed that soil conditions alternately changed between reducing and oxic. As soil redox potential is an important factor affecting Cr(VI) reduction in paddy soils, dynamics of Cr(VI) concentration were clearly different under different irrigation managements. In CF treatments, porewater Cr(VI) concentrations decreased with time after planting, while in AWD treatments porewater Cr(VI) concentrations were increased and decreased alternately response to the irrigation cycles. Chromium(VI) concentrations in the CF treatments were lower than those in AWD treatments for most part of rice-growing season. Moreover, Cr concentrations in rice tissues were significantly influenced by irrigation with relatively higher values in the AWD treatments, which might be attributed to the higher porewater Cr(VI) concentrations in AWD treatments. Therefore, it would be better to use CF than AWD management in Cr-contaminated paddy soils to reduce Cr accumulation in rice, and thus to reduce the potential risk to human health. PMID- 25546833 TI - Biodegradation of nicotine by a novel strain Pusillimonas. AB - A novel strain, Pusillimonas sp. T2, which is capable of degrading nicotine, was isolated and identified. This strain could completely degrade 500 mg/L nicotine within 8 h at 30 degrees C, pH 7.0. Six intermediates were detected and identified as 6-hydroxy-nicotine, 6-hydroxy-N-methylmyosmine, 6 hydroxypseudooxynicotine, 2,6-dihydroxypyridine, 6-hydroxy-3-succinoyl-pyridine and 2,5-dihydroxypyridine. Activities of 6-hydroxy-3-succinoyl-pyridine hydroxylase and 2,6-dihydroxypyridine hydroxylase were demonstrated in the cell extracts of strain T2, indicating that this strain may employ a novel variant of the pyridine and pyrrolidine pathways that is different from those of other species. This study provides the first evidence that Pusillimonas bacteria participate in nicotine degradation. PMID- 25546834 TI - Drug release through liposome pores. AB - Electrical, ultrasound and other types of external fields are known to induce the formation of pores in cellular and model membranes. This paper examines drug release through field induced liposome pores using Monte Carlo simulations. We find that drug release rates vary as a function of pore size and spacing, as well as the overall fraction of surface area covered by pores: The rate of release from liposomes is found to increase rapidly with pore surface coverage, approaching that of the fully ruptured liposome at fractional pore areas. For a given pore surface coverage, the pore size affects the release rate in the limit of low coverage, but not when the pores cover a relatively high fraction of the liposome surface area. On the other hand, for a given pore size and surface coverage, the distribution of pores significantly affects the release in the limit of high surface coverage: The rate of release from a liposome covered with a regularly spaced array of pores is, in this limit, higher than the release rate from (most) systems where the pores are distributed randomly on the liposome surface. In contrast, there is little effect of the pore distribution on release when the pore surface coverage is low. The simulation results are in good agreement with the predictions of detailed diffusion models. PMID- 25546835 TI - Ag2Te quantum dots with compact surface coatings of multivalent polymers: ambient one-pot aqueous synthesis and the second near-infrared bioimaging. AB - In this study, we described a facile ambient one-pot aqueous synthesis of fluorescent Ag2Te quantum dots (QDs) adopting multivalent polymers (poly(maleic anhydride) homopolymers) as stabilizers. In experiments, Ag2Te QDs were synthesized via a stepwise addition of the stabilizers, precursors (AgNO3/Na2TeO3) and promoters (NaBH4/N2H4 . H2O) in ambient one-pot aqueous solution. By regulating the compositions of raw materials, water-dispersed Ag2Te QDs (3.8-4.7 nm) were achieved and exhibited tunable photoluminescence (PL) emission (995-1068 nm) in the second near-infrared (NIR-II) region, accompanying with the minimized surface coating thickness (1.5-1.9 nm). Such compact coating of multivalent polymers promoted PL emission of Ag2Te QDs, so showing high PL quantum yields (PLQYs: 13.1-15.2%). In addition to compact sizes and high PLQYs, experimental results testified that the Ag2Te QDs demonstrated high photo /colloidal stability and ultralow cytotoxicity, which implied their promising applications, especially serving as an effective nanoprobe for bioimaging in the NIR-II biological window. PMID- 25546836 TI - A feasible way for the fabrication of single walled carbon nanotube/polypyrrole composite film with controlled pore size for neural interface. AB - Single walled carbon nanotube (SWNT)/polypyrrole (PPy) composite films with controlled pore size and strong adhesive force was prepared as electrode material for improving the performance of neural electrodes. SWNT film with controlled pore size was first fabricated through electrophoresis with a merit that the pore size can be well tuned by changing the concentration of metal ions in the electrolyte. An ultrathin conformal PPy layer around SWNT bundles in a uniform manner within the entire films was subsequently obtained by pulsed electropolymerization. The adhesion of the SWNT coated electrodes was tested by repeatedly inserting the coated electrode into agar gel to demonstrate the better adhesive force of the coating. Electrochemical results showed that the SWNT/PPy coated metal electrodes have much lower impedance and higher charge storage capacity than the bare metal substrates. Further in vitro culture of rat pheochromocytoma (PC12) cells revealed that the porous SWNT/PPy composite film was non-toxic and well supported the growth of neurons. We demonstrate that the prepared composite film has potential applications in chronic implantable neural electrodes for neural stimulation and recording. PMID- 25546838 TI - Creation of Cu2O@TiO2 composite photocatalysts with p-n heterojunctions formed on exposed Cu2O facets, their energy band alignment study, and their enhanced photocatalytic activity under illumination with visible light. AB - The creation of photocatalysts with controlled facets has become an important approach to enhance their activity. However, how the formation of heterojunctions on exposed facets could affect their photocatalytic performance ranking had not yet been investigated. In this study, Cu2O@TiO2 core-shell structures were created, and Cu2O/TiO2 p-n heterojunctions were formed on various exposed facets of Cu2O cubes, Cu2O cuboctahedra, and Cu2O octahedra, respectively. These Cu2O@TiO2 polyhedra demonstrated an enhanced photocatalytic degradation effect on Methylene Blue (MB) and 4-nitrophenol (4-NP) under visible light illumination, because of the enhanced charge carrier separation by the formation of Cu2O@TiO2 p n heterojunctions. It was further found that their photocatalytic performance was also facet-dependent as pure Cu2O polyhedra, while the photocatalytic performance ranking of these Cu2O@TiO2 polyhedra was different with that of their corresponding Cu2O polyhedron cores. By the combination of optical property measurement and XPS analysis, the energy band alignments of these Cu2O@TiO2 polyhedra were determined, which demonstrated that Cu2O@TiO2 octahedra had the highest band offset for the separation of charge carriers. Thus, the charge carrier-separation-driven force in Cu2O@TiO2 polyhedra was different from their corresponding Cu2O polyhedron cores, which resulted in their different surface photovoltage spectrum (SPS) responses and different photocatalytic performance rankings. PMID- 25546837 TI - Nanotopography enhanced mobility determines mesenchymal stem cell distribution on micropatterned semiconductors bearing nanorough areas. AB - Surface micropatterns are relevant instruments for the in vitro analysis of cell cultures in non-conventional planar conditions. In this work, two semiconductors (Si and TiO2) have been micropatterned by combined ion-beam/chemical-etching processes leading to selective areas bearing nanorough features. A preferential affinity of human mesenchymal stem cells (hMSCs) for planar areas versus nanotopographic ones is observed. Fluorescence microscopy after beta-catenin staining suggests that hMSCs adhesion is inhibited on nanostructured porous silicon areas. This has a direct impact in the development of actin fibers and suggests different cell migration mechanisms on the materials of a micropattern. hMSCs organization on nanotopographic micropatterns has been modeled by using a simplified random walk approach. The model attributes preferential cell mobilities on the nanotopographic areas with respect to the planar and considers purely stochastic movement with no inertial term. Simulations of the cell distribution have been run on 1D and 2D micropatterns and compared with the real hMSC cultures. The simulations allow defining two regimes for cell organization as a function of cell density. hMSCs ordering on planar areas is diffusion induced in most micropatterns but constriction forced disorder appears for high cell densities. The relative mobility on the planar versus nanotopographic areas can be used as a quality indicator of the nanotopography contrasts in the diffusion induced ordering regime. It is shown that the relative mobility is favorable for the TiO2 versus the Si based system, and allows envisaging its use for the calibrated design of nanotopography based micropatterned materials. PMID- 25546839 TI - Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. AB - In recent decades, growing scientific evidence supports the role of ion channels in the development of different cancers. Both potassium selective pores and chloride permeabilities are considered the most active channels during tumorigenesis. High rate of proliferation, active migration, and invasiveness into non-neoplastic tissues are specific properties of neoplastic transformation. All these actions require partial or total involvement of chloride channel activity. In this context, this class of membrane proteins could represent valuable therapeutic targets for the treatment of resistant tumors. However, this encouraging premise has not so far produced any valid new channel-targeted antitumoral molecule for cancer treatment. Problematic for drug design targeting ion channels is their vital role in normal cells for essential physiological functions. By targeting these membrane proteins involved in pathological conditions, it is inevitable to cause relevant side effects in healthy organs. In light of this, a new protein family, the chloride intracellular channels (CLICs), could be a promising class of therapeutic targets for its intrinsic individualities: CLIC1 and CLIC4, in particular, not only are overexpressed in specific tumor types or their corresponding stroma but also change localization and function from hydrophilic cytosolic to integral transmembrane proteins as active ionic channels or signal transducers during cell cycle progression in certain cases. These changes in intracellular localization, tissue compartments, and channel function, uniquely associated with malignant transformation, may offer a unique target for cancer therapy, likely able to spare normal cells. This article is part of a special issue itled "Membrane Channels and Transporters in Cancers." PMID- 25546840 TI - Cholesterol stimulates and ceramide inhibits Sticholysin II-induced pore formation in complex bilayer membranes. AB - The pore forming capacity of Sticholysin II (StnII; isolated from Stichodactyla helianthus) in bilayer membranes containing 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC), palmitoylsphingomyelin (PSM) and either cholesterol or palmitoyl ceramide (PCer) has been examined. The aim of the study was to elucidate how the presence of differently ordered PSM domains affected StnII oligomerization and pore formation. Cholesterol is known to enhance pore formation by StnII, and our results confirmed this and provide kinetic information for the process. The effect of cholesterol on bilayer permeabilization kinetics was concentration-dependent. In the concentration regime used (2.5-10nmol cholesterol in POPC:PSM 80:20 by nmol), cholesterol also increased the acyl chain order in the fluid PSM domain and thus decreased bilayer fluidity, suggesting that fluidity per se was not responsible for cholesterol's effect. Addition of PCer (2.5-10nmol) to the POPC:PSM (80:20 by nmol) bilayers attenuated StnII-induced pore formation, again in a concentration-dependent fashion. This addition also led to the formation of a PCer-rich gel phase. Addition of cholesterol to PCer-containing membranes could partially reduce the inhibitory effect of PCer on StnII pore formation. We conclude that the physical state of PSM (as influenced by either cholesterol or PCer) affected StnII binding and pore formation under the conditions examined. PMID- 25546841 TI - Quantification of filamentation by uropathogenic Escherichia coli during experimental bladder cell infection by using semi-automated image analysis. AB - Several rod-shaped pathogens including Escherichia coli, Salmonella spp. and Klebsiella pneumonia are capable of adopting highly filamentous cell shapes under certain circumstances. This phenomenon occurs as a result of continued cell elongation during growth without the usual septation into single rod-shaped cells. Evidence has emerged over the past decade suggesting that this morphological transformation is controlled and reversible and provides selective advantages under certain growth conditions, such as during infection in humans. In order to identify the factors which induce filamentation of bacterial pathogens and study the advantages of bacterial morphological plasticity, methods are needed to accurately quantify changes in bacterial cell shape. In this study, we present a method for quantification of bacterial filamentation based on automatic detection and measurement of bacterial units in focus-stacked microscopy images. Used in combination with a flow-chamber based in vitro cystitis model, we study the factors involved in filament formation by uropathogenic E. coli (UPEC) during infection. The influence of substratum surface, intracellular proliferation and flow media on UPEC filamentation is evaluated. We show that reversible UPEC filamentation during cystitis is not dependent on intracellular infection, which previous studies have suggested. Instead, we find that filamentation can be induced by contact with surfaces, both biological and artificial. Lastly our data indicate that UPEC filamentation is induced by trace-amounts of specific components in urine, rather than being a generic stress-response to high urine salt concentrations. The study shows that the combined methodology is generally useful for investigation of bacterial morphological transitions during cell infection. PMID- 25546842 TI - Isolation of single Chlamydia-infected cells using laser microdissection. AB - Chlamydia are obligate intracellular parasites of humans and animals that cause a wide range of acute and chronic infections. To elucidate the genetic basis of chlamydial parasitism, several approaches for making genetic modifications to Chlamydia have recently been reported. However, the lack of the available methods for the fast and effective selection of genetically modified bacteria restricts the application of genetic tools. We suggest the use of laser microdissection to isolate of single live Chlamydia-infected cells for the re-cultivation and whole genome sequencing of single inclusion-derived Chlamydia. To visualise individual infected cells, we made use of the vital labelling of inclusions with the fluorescent Golgi-specific dye BODIPY(r) FL C5-ceramide. We demonstrated that single Chlamydia-infected cells isolated by laser microdissection and placed onto a host cell monolayer resulted in new cycles of infection. We also demonstrated the successful use of whole-genome sequencing to study the genomic variability of Chlamydia derived from a single inclusion. Our work provides the first evidence of the successful use of laser microdissection for the isolation of single live Chlamydia-infected cells, thus demonstrating that this method can help overcome the barriers to the fast and effective selection of Chlamydia. PMID- 25546843 TI - Heptaplex PCR melting curve analysis for rapid detection of plasmid-mediated AmpC beta-lactamase genes. AB - Antimicrobial resistance mediated by plasmid-borne AmpC beta-lactamase in Gram negative bacteria is an emerging event of significant clinical importance. Rapid and reliable detection of ampC is in urgent need for appropriate infection control. We described the development and evaluation of a heptaplex PCR melting curve analysis that could identify six groups of ampC, i.e., CIT, EBC, DHA, ACC, MOX and FOX, through predefined melting temperatures. The entire analysis could be finished within 2h for 96 samples after template DNA was prepared. We first evaluated the assay with 176 AmpC-producing isolates of Escherichia coli and Klebsiella pneumoniae, and the results showed that 36 isolates were positive for ampC, including 18 positive for DHA, 12 for CIT, 5 for EBC, and one for both DHA and EBC. These results were fully concordant with sequencing analysis whereas the comparison method, an electrophoresis-based singleplex PCR assay, missed four isolates. The assay was also used to analyze 429 randomly selected clinically relevant Gram-negative isolates involving 22 different species, and 34 isolates were found to be ampC-positive. The results again fully agreed with the sequencing analysis. We conclude that the established assay could be used for rapid and reliable detection of ampC. PMID- 25546844 TI - Managing uncertainty, ambiguity and ignorance in impact assessment by embedding evolutionary resilience, participatory modelling and adaptive management. AB - In the context of continuing uncertainty, ambiguity and ignorance in impact assessment (IA) prediction, the case is made that existing IA processes are based on false 'normal' assumptions that science can solve problems and transfer knowledge into policy. Instead, a 'post-normal science' approach is needed that acknowledges the limits of current levels of scientific understanding. We argue that this can be achieved through embedding evolutionary resilience into IA; using participatory workshops; and emphasising adaptive management. The goal is an IA process capable of informing policy choices in the face of uncertain influences acting on socio-ecological systems. We propose a specific set of process steps to operationalise this post-normal science approach which draws on work undertaken by the Resilience Alliance. This process differs significantly from current models of IA, as it has a far greater focus on avoidance of, or adaptation to (through incorporating adaptive management subsequent to decisions), unwanted future scenarios rather than a focus on the identification of the implications of a single preferred vision. Implementing such a process would represent a culture change in IA practice as a lack of knowledge is assumed and explicit, and forms the basis of future planning activity, rather than being ignored. PMID- 25546846 TI - A macrokinetic model-based comparative meta-analysis of recombinant protein production by Pichia pastoris under AOX1 promoter. AB - An unstructured macrokinetic model for heterologous production of Rhizopus oryzae lipase (ROL) by a Pichia pastoris PAOX1 based system was developed. Mean specific rates and state variables for various fed-batch cultures, under methanol limited and non-limited conditions were used for modeling. The most representative kinetic functions (viz., Monod, Haldane, Pirt and Luedeking-Piret) were used for the specific rates of cell growth (u), substrate consumption (qS ) and product formation (qP ). The performance of two different process models was assessed via simulation tests, using an overall validation procedure. The best model describes the cellular growth by a non-monotonic substrate function, substrate uptake via Pirt's equation and product formation through a Luedeking-Piret equation. A comparative meta-analysis of heterologous protein production of various target proteins by Pichia pastoris under AOX1 promoter was conducted and a general strategy for improving protein production from process kinetics was developed as a key to bioprocess optimization. PMID- 25546845 TI - A comparative study of the treatment of ethylene plant spent caustic by neutralization and classical and advanced oxidation. AB - The treatment of spent caustic produced from an ethylene plant was investigated. In the case of neutralization alone it was found that the maximum removal of sulfide was at pH values below 5.5. The higher percentage removal of sulfides (99% at pH = 1.5) was accompanied with the highest COD removal (88%). For classical oxidation using H2O2 the maximum COD removal percentage reached 89% at pH = 2.5 and at a hydrogen peroxide concentration of 19 mM/L. For the advanced oxidation using Fenton's process it was found that the maximum COD removal of 96.5% was achieved at a hydrogen peroxide/ferrous sulfate ratio of (7:1). PMID- 25546847 TI - Enhanced neuronal cell differentiation combining biomimetic peptides and a carbon nanotube-polymer scaffold. AB - Carbon nanotubes are attractive candidates for the development of scaffolds able to support neuronal growth and differentiation thanks to their ability to conduct electrical stimuli, to interface with cells and to mimic the neural environment. We developed a biocompatible composite scaffold, consisting of multi-walled carbon nanotubes dispersed in a poly-L-lactic acid matrix able to support growth and differentiation of human neuronal cells. Moreover, to mimic guidance cues from the neural environment, we also designed synthetic peptides, derived from L1 and LINGO1 proteins. Such peptides could positively modulate neuronal differentiation, which is synergistically improved by the combination of the nanocomposite scaffold and the peptides, thus suggesting a prototype for the development of implants for long-term neuronal growth and differentiation. From the clinical editor: The study describes the design and preparation of nanocomposite scaffolds with multi-walled carbon nanotubes in a poly-L-lactic acid matrix. This compound used in combination with peptides leads to synergistic effects in supporting neuronal cell growth and differentiation. PMID- 25546848 TI - Negligible particle-specific toxicity mechanism of silver nanoparticles: the role of Ag+ ion release in the cytosol. AB - Toxicity of silver nanoparticles (AgNPs) is supported by many observations in literature, but no mechanism details have been proved yet. Here we confirm and quantify the toxic potential of fully characterized AgNPs in HeLa and A549 cells. Notably, through a specific fluorescent probe, we demonstrate the intracellular release of Ag(+) ions in living cells after nanoparticle internalization, showing that in-situ particle degradation is promoted by the acidic lysosomal environment. The activation of metallothioneins in response to AgNPs and the possibility to reverse the main toxic pathway by Ag(+) chelating agents demonstrate a cause/effect relationship between ions and cell death. We propose that endocytosed AgNPs are degraded in the lysosomes and the release of Ag(+) ions in the cytosol induces cell damages, while ions released in the cell culture medium play a negligible effect. These findings will be useful to develop safer by-design nanoparticles and proper regulatory guidelines of AgNPs. From the clinical editor: The authors describe the toxic potential of silver nanoparticles (AgNP) in human cancer cell lines. Cell death following the application of AgNPs is dose-dependent, and it is mostly due to Ag+ ions. Further in vivo studies should be performed to gain a comprehensive picture of AgNP-toxicity in mammals. PMID- 25546849 TI - Topological modeling and classification of mammographic microcalcification clusters. AB - GOAL: The presence of microcalcification clusters is a primary sign of breast cancer; however, it is difficult and time consuming for radiologists to classify microcalcifications as malignant or benign. In this paper, a novel method for the classification of microcalcification clusters in mammograms is proposed. METHODS: The topology/connectivity of individual microcalcifications is analyzed within a cluster using multiscale morphology. This is distinct from existing approaches that tend to concentrate on the morphology of individual microcalcifications and/or global (statistical) cluster features. A set of microcalcification graphs are generated to represent the topological structure of microcalcification clusters at different scales. Subsequently, graph theoretical features are extracted, which constitute the topological feature space for modeling and classifying microcalcification clusters. k-nearest-neighbors-based classifiers are employed for classifying microcalcification clusters. RESULTS: The validity of the proposed method is evaluated using two well-known digitized datasets (MIAS and DDSM) and a full-field digital dataset. High classification accuracies (up to 96%) and good ROC results (area under the ROC curve up to 0.96) are achieved. A full comparison with related publications is provided, which includes a direct comparison. CONCLUSION: The results indicate that the proposed approach is able to outperform the current state-of-the-art methods. Significance: This study shows that topology modeling is an important tool for microcalcification analysis not only because of the improved classification accuracy but also because the topological measures can be linked to clinical understanding. PMID- 25546850 TI - Normalization of Intrinsic Neural Circuits Governing Tourette's Syndrome Using Cranial Electrotherapy Stimulation. AB - GOAL: The aim of this study was to investigate the normalization of the intrinsic functional activity and connectivity of TS adolescents before and after the cranial electrotherapy stimulation (CES) with alpha stim device. METHODS: We performed resting-state functional magnetic resonance imaging on eight adolescents before and after CES with mean age of about nine-years old who had Tourette's syndrome with moderate to severe tics symptom. Independent component analysis (ICA) with hierarchical partner matching method was used to examine the functional connectivity between regions within cortico-striato-thalamo-cortical (CSTC) circuit. Granger causality was used to investigate effective connectivity among these regions detected by ICA. We then performed pattern classification on independent components with significant group differences that served as endophenotype markers to distinguish the adolescents between TS and the normalized ones after CES. RESULTS: Results showed that TS adolescents after CES treatment had stronger functional activity and connectivity in anterior cingulate cortex (ACC), caudate and posterior cingulate cortex while had weaker activity in supplementary motor area within the motor pathway compared with TS before CES. CONCLUSION: The results suggest that the functional activity and connectivity in motor pathway was suppressed while activities in the control portions within CSTC loop including ACC and caudate were increased in TS adolescents after CES compared with adolescents before CES. SIGNIFICANCE: The normalization of the balance between motor and control portions of the CSTC circuit may result in the recovery of TS adolescents. PMID- 25546851 TI - Expiration-phase template-based motion correction of free-breathing abdominal dynamic contrast enhanced MRI. AB - This paper studies a novel method to compensate for respiratory and peristaltic motions in abdominal dynamic contrast enhanced magnetic resonance imaging. The method consists of two steps: 1) expiration-phase "template" construction and retrospective gating of the data to the template; and 2) nonrigid registration of the gated volumes. Landmarks annotated by three experts were used to directly assess the registration performance. A tri-exponential function fit to time intensity curves from regions of interest was used to indirectly assess the performance. One of the parameters of the tri-exponential fit was used to quantify the contrast enhancement. Our method achieved a mean target registration error (MTRE) of 2.12, 2.27, and 2.33 mm with respect to annotations by expert, which was close to the average interobserver variability (2.07 mm). A state-of the-art registration method achieved an MTRE of 2.83-3.10 mm. The correlation coefficient of the contrast enhancement parameter to the Crohn's disease endoscopic index of Severity (r = 0.60, p = 0.004) was higher than the correlation coefficient for the relative contrast enhancement measurements values of two observers ( r(Observer 1) = 0.29, p = 0.2; r(Observer 2) = 0.45, p = 0.04). Direct and indirect assessments show that the expiration-based gating and a nonrigid registration approach effectively corrects for respiratory motion and peristalsis. The method facilitates improved enhancement measurement in the bowel wall in patients with Crohn's disease. PMID- 25546852 TI - Probabilistic multiple sclerosis lesion classification based on modeling regional intensity variability and local neighborhood information. AB - GOAL: In this paper, a fully automatic probabilistic method for multiple sclerosis (MS) lesion classification is presented, whereby the posterior probability density function over healthy tissues and two types of lesions (T1 hypointense and T2-hyperintense) is generated at every voxel. METHODS: During training, the system explicitly models the spatial variability of the intensity distributions throughout the brain by first segmenting it into distinct anatomical regions and then building regional likelihood distributions for each tissue class based on multimodal magnetic resonance image (MRI) intensities. Local class smoothness is ensured by incorporating neighboring voxel information in the prior probability through Markov random fields. The system is tested on two datasets from real multisite clinical trials consisting of multimodal MRIs from a total of 100 patients with MS. Lesion classification results based on the framework are compared with and without the regional information, as well as with other state-of-the-art methods against the labels from expert manual raters. The metrics for comparison include Dice overlap, sensitivity, and positive predictive rates for both voxel and lesion classifications. RESULTS: Statistically significant improvements in Dice values ( ), for voxel-based and lesion-based sensitivity values ( ), and positive predictive rates ( and respectively) are shown when the proposed method is compared to the method without regional information, and to a widely used method [1]. This holds particularly true in the posterior fossa, an area where classification is very challenging. SIGNIFICANCE: The proposed method allows us to provide clinicians with accurate tissue labels for T1-hypointense and T2-hyperintense lesions, two types of lesions that differ in appearance and clinical ramifications, and with a confidence level in the classification, which helps clinicians assess the classification results. PMID- 25546854 TI - Training for planning tumour resection: augmented reality and human factors. AB - Planning surgical interventions is a complex task, demanding a high degree of perceptual, cognitive, and sensorimotor skills to reduce intra- and post operative complications. This process requires spatial reasoning to coordinate between the preoperatively acquired medical images and patient reference frames. In the case of neurosurgical interventions, traditional approaches to planning tend to focus on providing a means for visualizing medical images, but rarely support transformation between different spatial reference frames. Thus, surgeons often rely on their previous experience and intuition as their sole guide is to perform mental transformation. In case of junior residents, this may lead to longer operation times or increased chance of error under additional cognitive demands. In this paper, we introduce a mixed augmented-/virtual-reality system to facilitate training for planning a common neurosurgical procedure, brain tumour resection. The proposed system is designed and evaluated with human factors explicitly in mind, alleviating the difficulty of mental transformation. Our results indicate that, compared to conventional planning environments, the proposed system greatly improves the nonclinicians' performance, independent of the sensorimotor tasks performed ( ). Furthermore, the use of the proposed system by clinicians resulted in a significant reduction in time to perform clinically relevant tasks ( ). These results demonstrate the role of mixed-reality systems in assisting residents to develop necessary spatial reasoning skills needed for planning brain tumour resection, improving patient outcomes. PMID- 25546853 TI - Microbubbles and blood-brain barrier opening: a numerical study on acoustic emissions and wall stress predictions. AB - Focused ultrasound with microbubbles is an emerging technique for blood-brain barrier opening. Here, a comprehensive theoretical model of a bubble-fluid-vessel system has been developed which accounts for the bubble's nonspherical oscillations inside a microvessel, and its resulting acoustic emissions. Numerical simulations of unbound and confined encapsulated bubbles were performed to evaluate the effect of the vessel wall on acoustic emissions and vessel wall stresses. Using a Marmottant shell model, the normalized second harmonic to fundamental emissions first decreased as a function of pressure (>50 kPa) until reaching a minima ("transition point") at which point they increased. The transition point of unbound compared to confined bubble populations occurred at different pressures and was associated with an accompanying increase in shear and circumferential wall stresses. As the wall stresses depend on the bubble to vessel wall distance, the stresses were evaluated for bubbles with their wall at a constant distance to a flat wall. As a result, the wall stresses were bubble size and frequency dependent and the peak stress values induced by bubbles larger than resonance remained constant versus frequency at a constant mechanical index. PMID- 25546855 TI - Extracting a cardiac signal from the extracorporeal pressure sensors of a hemodialysis machine. AB - Although patients undergoing hemodialysis treatment often suffer from cardiovascular disease, monitoring of cardiac rhythm is not performed on a routine basis. Without requiring any extra sensor, this study proposes a method for extracting a cardiac signal from the built-in extracorporeal venous pressure sensor of the hemodialysis machine. The extraction is challenged by the fact that the cardiac component is much weaker than the pressure component caused by the peristaltic blood pump. To further complicate the extraction problem, the cardiac component is difficult to separate when the pump and heart rates coincide. The proposed method estimates a cardiac signal by subtracting an iteratively refined blood pump model signal from the signal measured at the extracorporeal venous pressure sensor. The method was developed based on simulated pressure signals, and evaluated on clinical pressure signals acquired during hemodialysis treatment. The heart rate estimated from the clinical pressure signal was compared to that derived from a photoplethysmographic reference signal, resulting in a difference of 0.07 +/- 0.84 beats/min. The accuracy of the heartbeat occurrence times was studied for different strengths of the cardiac component, using both clinical and simulated signals. The results suggest that the accuracy is sufficient for analysis of heart rate and certain arrhythmias. PMID- 25546856 TI - An inductive sensor for real-time measurement of plantar normal and shear forces distribution. AB - GOAL: The objective of this paper is to demonstrate a multiplexed inductive force sensor for simultaneously measuring normal force and shear forces on a foot. METHODS: The sensor measures the normal force and shear forces by monitoring the inductance changes of three planar sensing coils. Resonance frequency division multiplexing was applied to signals from the multiple sensing coils, making it feasible to simultaneously measure the three forces (normal force, shear forces in x- and y-axis) on a foot using only one set of measurement electronics with high sensitivity and resolution. RESULTS: The testing results of the prototype sensor have shown that the sensor is capable of measuring normal force ranging from 0 to 800 N and shear forces ranging from 0 to 130 N in real time. CONCLUSION: With its high resolution, high sensitivity, and the capability of monitoring forces at different positions of a foot simultaneously, this sensor can be potentially used for real-time measurement of plantar normal force and shear forces distribution on diabetes patient's foot. SIGNIFICANCE: Real-time monitoring of the normal force and shear forces on diabetes patient's foot can provide useful information for physicians and diabetes patients to take actions in preventing foot ulceration. PMID- 25546858 TI - Estimation of sunlight direction using 3D object models. AB - The direction of sunlight is an important informative cue in a number of applications in image processing, such as augmented reality and object recognition. In general, existing methods to estimate the direction of the sunlight rely on different image features (e.g., sky, texture, shadows, and shading). These features can be considered as weak informative cues as no single feature can reliably estimate the sunlight direction. Moreover, existing methods may require that the camera parameters are known limiting their applicability. In this paper, we present a new method to estimate the sunlight direction from a single (outdoor) image by inferring casts shadows through object modeling and recognition. First, objects (e.g., cars or persons) are first (automatically) recognized in images by exemplar-SVMs. Instead of training the Support Vector Machine (SVMs) using natural images (limited variation in viewpoints), we propose to train on 2D object samples generated from 3D object models. Then, the recognized objects are used as sundial cues (probes) to estimate the sunlight direction by inferring the corresponding shadows generated by 3D object models considering different illumination directions. We demonstrate the effectiveness of our approach on synthetic and real images. Experiments show that our method estimates the azimuth angle accurately within a quadrant (smaller than 45 degrees ) and compute the zenith angle with mean angular error of 23 degrees . PMID- 25546859 TI - Toward naturalistic 2D-to-3D conversion. AB - Natural scene statistics (NSSs) models have been developed that make it possible to impose useful perceptually relevant priors on the luminance, colors, and depth maps of natural scenes. We show that these models can be used to develop 3D content creation algorithms that can convert monocular 2D videos into statistically natural 3D-viewable videos. First, accurate depth information on key frames is obtained via human annotation. Then, both forward and backward motion vectors are estimated and compared to decide the initial depth values, and a compensation process is applied to further improve the depth initialization. Then, the luminance/chrominance and initial depth map are decomposed by a Gabor filter bank. Each subband of depth is modeled to produce a NSS prior term. The statistical color-depth priors are combined with the spatial smoothness constraint in the depth propagation target function as a prior regularizing term. The final depth map associated with each frame of the input 2D video is optimized by minimizing the target function over all subbands. In the end, stereoscopic frames are rendered from the color frames and their associated depth maps. We evaluated the quality of the generated 3D videos using both subjective and objective quality assessment methods. The experimental results obtained on various sequences show that the presented method outperforms several state-of-the art 2D-to-3D conversion methods. PMID- 25546860 TI - Robust action recognition via borrowing information across video modalities. AB - The recent advances in imaging devices have opened the opportunity of better solving the tasks of video content analysis and understanding. Next-generation cameras, such as the depth or binocular cameras, capture diverse information, and complement the conventional 2D RGB cameras. Thus, investigating the yielded multimodal videos generally facilitates the accomplishment of related applications. However, the limitations of the emerging cameras, such as short effective distances, expensive costs, or long response time, degrade their applicability, and currently make these devices not online accessible in practical use. In this paper, we provide an alternative scenario to address this problem, and illustrate it with the task of recognizing human actions. In particular, we aim at improving the accuracy of action recognition in RGB videos with the aid of one additional RGB-D camera. Since RGB-D cameras, such as Kinect, are typically not applicable in a surveillance system due to its short effective distance, we instead offline collect a database, in which not only the RGB videos but also the depth maps and the skeleton data of actions are available jointly. The proposed approach can adapt the interdatabase variations, and activate the borrowing of visual knowledge across different video modalities. Each action to be recognized in RGB representation is then augmented with the borrowed depth and skeleton features. Our approach is comprehensively evaluated on five benchmark data sets of action recognition. The promising results manifest that the borrowed information leads to remarkable boost in recognition accuracy. PMID- 25546857 TI - Transcranial Assessment and Visualization of Acoustic Cavitation: Modeling and Experimental Validation. AB - The interaction of ultrasonically-controlled microbubble oscillations with tissues and biological media has been shown to induce a wide range of bioeffects that may have significant impact on therapy and diagnosis of brain diseases and disorders. However, the inherently non-linear microbubble oscillations combined with the micrometer and microsecond scales involved in these interactions and the limited methods to assess and visualize them transcranially hinder both their optimal use and translation to the clinics. To overcome these challenges, we present a framework that combines numerical simulations with multimodality imaging to assess and visualize the microbubble oscillations transcranially. In the present work, microbubble oscillations were studied with an integrated US and MR imaging guided clinical FUS system. A high-resolution brain CT scan was also co-registered to the US and MR images and the derived acoustic properties were used as inputs to two- and three-dimensional Finite Difference Time Domain simulations that matched the experimental conditions and geometry. Synthetic point sources by either a Gaussian function or the output of a microbubble dynamics model were numerically excited and propagated through the skull towards a virtual US imaging array. Using passive acoustic mapping (PAM) that was refined to incorporate variable speed of sound, we were able to correct the aberrations introduced by the skull and substantially improve the PAM resolution. The good agreement between the simulations incorporating microbubble emissions and experimentally-determined PAMs suggest that this integrated approach can provide a clinically-relevant framework and more control over this nonlinear and dynamic process. PMID- 25546861 TI - An Embedded Deep Brain Stimulator for Biphasic Chronic Experiments in Freely Moving Rodents. AB - This paper describes a Deep Brain Stimulation device, portable, for chronic experiments on rodents in the context of Parkinson's disease. Our goal is to equip the animal with a device that mimics the human therapeutic conditions. It implies to respect a set of properties such as bilateral current-mode and charge balanced stimulation, as well as programmability, low power consumption and re usability to finally reach a suitable weight for long-term experiments. After the analysis of the solutions found in the literature, the full design of the device is explained. First, the stimulation front-end circuit driven by a processor unit, then the choice of supply sources which is a critical point for the weight and life-time of our system. Our low cost system has been realized using commercial discrete components and the overall power consumption was minimized. We achieved 6 days of maximal current stimulation with the chosen battery for a weight of 13.8 g . Finally, the device was carried out in vivo on rats during a 3 weeks experiment as the used implantation technique allows battery changing. This experiment also permits to emphasize the mechanical aspects including the packaging and electrodes holding. PMID- 25546862 TI - A 680 nA ECG acquisition IC for leadless pacemaker applications. AB - A sub- MUW ECG acquisition IC is presented for a single-chamber leadless pacemaker applications. It integrates a low-power, wide dynamic-range ECG readout front end together with an analog QRS-complex extractor. To save ASIC power, a current-multiplexed channel buffer is introduced to drive a 7 b-to-10 b self synchronized SAR ADC which utilizes 4 fF/unit capacitors. The ASIC consumes only 680nA and achieves CMRR > 90 dB, PSRR > 80 dB, an input-referred noise of 4.9 MUVrms in a 130 Hz bandwidth, and has rail-to-rail DC offset rejection. Low-power heartbeat detections are evaluated with the help of the ASIC acquiring nearly 20,000 beats across 10 different records from the MIT-BIH arrhythmia database. In the presence of muscle noise, both the average Sensitivity (Se) and Positive Predictivity (PP) show more than 90% when the input SNR > 6 dB. PMID- 25546863 TI - ML-Tree: a tree-structure-based approach to multilabel learning. AB - Multilabel learning aims to predict labels of unseen instances by learning from training samples that are associated with a set of known labels. In this paper, we propose to use a hierarchical tree model for multilabel learning, and to develop the ML-Tree algorithm for finding the tree structure. ML-Tree considers a tree as a hierarchy of data and constructs the tree using the induction of one against-all SVM classifiers at each node to recursively partition the data into child nodes. For each node, we define a predictive label vector to represent the predictive label transmission in the tree model for multilabel prediction and automatic discovery of the label relationships. If two labels co-occur frequently as predictive labels at leaf nodes, these labels are supposed to be relevant. The amount of predictive label co-occurrence provides an estimation of the label relationships. We examine the ML-Tree method on 11 real data sets of different domains and compare it with six well-established multilabel learning algorithms. The performances of these approaches are evaluated by 16 commonly used measures. We also conduct Friedman and Nemenyi tests to assess the statistical significance of the differences in performance. Experimental results demonstrate the effectiveness of our method. PMID- 25546864 TI - Learning-regulated context relevant topographical map. AB - Kohonen's self-organizing map (SOM) is used to map high-dimensional data into a low-dimensional representation (typically a 2-D or 3-D space) while preserving their topological characteristics. A major reason for its application is to be able to visualize data while preserving their relation in the high-dimensional input data space as much as possible. Here, we are seeking to go further by incorporating semantic meaning in the low-dimensional representation. In a conventional SOM, the semantic context of the data, such as class labels, does not have any influence on the formation of the map. As an abstraction of neural function, the SOM models bottom-up self-organization but not feedback modulation which is also ubiquitous in the brain. In this paper, we demonstrate a hierarchical neural network, which learns a topographical map that also reflects the semantic context of the data. Our method combines unsupervised, bottom-up topographical map formation with top-down supervised learning. We discuss the mathematical properties of the proposed hierarchical neural network and demonstrate its abilities with empirical experiments. PMID- 25546865 TI - Stochastic stability of delayed neural networks with local impulsive effects. AB - In this paper, the stability problem is studied for a class of stochastic neural networks (NNs) with local impulsive effects. The impulsive effects considered can be not only nonidentical in different dimensions of the system state but also various at distinct impulsive instants. Hence, the impulses here can encompass several typical impulses in NNs. The aim of this paper is to derive stability criteria such that stochastic NNs with local impulsive effects are exponentially stable in mean square. By means of the mathematical induction method, several easy-to-check conditions are obtained to ensure the mean square stability of NNs. Three examples are given to show the effectiveness of the proposed stability criterion. PMID- 25546866 TI - A statistical characterization of the finger tapping test: modeling, estimation, and applications. AB - Sensory-motor performance is indicative of both cognitive and physical function. The Halstead-Reitan finger tapping test is a measure of sensory-motor speed commonly used to assess function as part of a neuropsychological evaluation. Despite the widespread use of this test, the underlying motor and cognitive processes driving tapping behavior during the test are not well characterized or understood. This lack of understanding may make clinical inferences from test results about health or disease state less accurate because important aspects of the task such as variability or fatigue are unmeasured. To overcome these limitations, we enhanced the tapper with a sensor that enables us to more fully characterize all the aspects of tapping. This modification enabled us to decompose the tapping performance into six component phases and represent each phase with a set of parameters having clear functional interpretation. This results in a set of 29 total parameters for each trial, including change in tapping over time, and trial-to-trial and tap-to-tap variability. These parameters can be used to more precisely link different aspects of cognition or motor function to tapping behavior. We demonstrate the benefits of this new instrument with a simple hypothesis-driven trial comparing single and dual-task tapping. PMID- 25546867 TI - Unobtrusive Monitoring of Neonatal Brain Temperature Using a Zero-Heat-Flux Sensor Matrix. AB - The temperature of preterm neonates must be maintained within a narrow window to ensure their survival. Continuously measuring their core temperature provides an optimal means of monitoring their thermoregulation and their response to environmental changes. However, existing methods of measuring core temperature can be very obtrusive, such as rectal probes, or inaccurate/lagging, such as skin temperature sensors and spot-checks using tympanic temperature sensors. This study investigates an unobtrusive method of measuring brain temperature continuously using an embedded zero-heat-flux (ZHF) sensor matrix placed under the head of the neonate. The measured temperature profile is used to segment areas of motion and incorrect positioning, where the neonate's head is not above the sensors. We compare our measurements during low motion/stable periods to esophageal temperatures for 12 preterm neonates, measured for an average of 5 h per neonate. The method we propose shows good correlation with the reference temperature for most of the neonates. The unobtrusive embedding of the matrix in the neonate's environment poses no harm or disturbance to the care work-flow, while measuring core temperature. To address the effect of motion on the ZHF measurements in the current embodiment, we recommend a more ergonomic embedding ensuring the sensors are continuously placed under the neonate's head. PMID- 25546869 TI - Robust Face Clustering Via Tensor Decomposition. AB - Face clustering is a key component either in image managements or video analysis. Wild human faces vary with the poses, expressions, and illumination changes. All kinds of noises, like block occlusions, random pixel corruptions, and various disguises may also destroy the consistency of faces referring to the same person. This motivates us to develop a robust face clustering algorithm that is less sensitive to these noises. To retain the underlying structured information within facial images, we use tensors to represent faces, and then accomplish the clustering task based on the tensor data. The proposed algorithm is called robust tensor clustering (RTC), which firstly finds a lower-rank approximation of the original tensor data using a L1 norm optimization function. Because L1 norm does not exaggerate the effect of noises compared with L2 norm, the minimization of the L1 norm approximation function makes RTC robust. Then, we compute high-order singular value decomposition of this approximate tensor to obtain the final clustering results. Different from traditional algorithms solving the approximation function with a greedy strategy, we utilize a nongreedy strategy to obtain a better solution. Experiments conducted on the benchmark facial datasets and gait sequences demonstrate that RTC has better performance than the state-of the-art clustering algorithms and is more robust to noises. PMID- 25546868 TI - Personalized Multilayer Daily Life Profiling Through Context Enabled Activity Classification and Motion Reconstruction: An Integrated System Approach. AB - Profiling the daily activity of a physically disabled person in the community would enable healthcare professionals to monitor the type, quantity, and quality of their patients' compliance with recommendations for exercise, fitness, and practice of skilled movements, as well as enable feedback about performance in real-world situations. Based on our early research in in-community activity profiling, we present in this paper an end-to-end system capable of reporting a patient's daily activity at multiple levels of granularity: 1) at the highest level, information on the location categories a patient is able to visit; 2) within each location category, information on the activities a patient is able to perform; and 3) at the lowest level, motion trajectory, visualization, and metrics computation of each activity. Our methodology is built upon a physical activity prescription model coupled with MEMS inertial sensors and mobile device kits that can be sent to a patient at home. A novel context-guided activity monitoring concept with categorical location context is used to achieve enhanced classification accuracy and throughput. The methodology is then seamlessly integrated with motion reconstruction and metrics computation to provide comprehensive layered reporting of a patient's daily life. We also present an implementation of the methodology featuring a novel location context detection algorithm using WiFi augmented GPS and overlays, with motion reconstruction and visualization algorithms for practical in-community deployment. Finally, we use a series of experimental field evaluations to confirm the accuracy of the system. PMID- 25546871 TI - Can We Do Better in Unimodal Biometric Systems? A Rank-Based Score Normalization Framework. AB - Biometric systems use score normalization techniques and fusion rules to improve recognition performance. The large amount of research on score fusion for multimodal systems raises an important question: can we utilize the available information from unimodal systems more effectively? In this paper, we present a rank-based score normalization framework that addresses this problem. Specifically, our approach consists of three algorithms: 1) partition the matching scores into subsets and normalize each subset independently; 2) utilize the gallery versus gallery matching scores matrix (i.e., gallery-based information); and 3) dynamically augment the gallery in an online fashion. We invoke the theory of stochastic dominance along with results of prior research to demonstrate when and why our approach yields increased performance. Our framework: 1) can be used in conjunction with any score normalization technique and any fusion rule; 2) is amenable to parallel programming; and 3) is suitable for both verification and open-set identification. To assess the performance of our framework, we use the UHDB11 and FRGC v2 face datasets. Specifically, the statistical hypothesis tests performed illustrate that the performance of our framework improves as we increase the number of samples per subject. Furthermore, the corresponding statistical analysis demonstrates that increased separation between match and nonmatch scores is obtained for each probe. Besides the benefits and limitations highlighted by our experimental evaluation, results under optimal and pessimal conditions are also presented to offer better insights. PMID- 25546870 TI - A Genetic-Algorithm-Based Explicit Description of Object Contour and its Ability to Facilitate Recognition. AB - Shape representation is an extremely important and longstanding problem in the field of pattern recognition. Closed contour, which refers to shape contour, plays a crucial role in the comparison of shapes. Because shape contour is the most stable, distinguishable, and invariable feature of an object, it is useful to incorporate it into the recognition process. This paper proposes a method based on genetic algorithms. The proposed method can be used to identify the most common contour fragments, which can be used to represent the contours of a shape category. The common fragments clarify the particular logics included in the contours. This paper shows that the explicit representation of the shape contour contributes significantly to shape representation and object recognition. PMID- 25546872 TI - Multistep prediction of physiological tremor based on machine learning for robotics assisted microsurgery. AB - For effective tremor compensation in robotics assisted hand-held device, accurate filtering of tremulous motion is necessary. The time-varying unknown phase delay that arises due to both software (filtering) and hardware (sensors) in these robotics instruments adversely affects the device performance. In this paper, moving window-based least squares support vector machines approach is formulated for multistep prediction of tremor to overcome the time-varying delay. This approach relies on the kernel-learning technique and does not require the knowledge of prediction horizon compared to the existing methods that require the delay to be known as a priori. The proposed method is evaluated through simulations and experiments with the tremor data recorded from surgeons and novice subjects. Comparison with the state-of-the-art techniques highlights the suitability and better performance of the proposed method. PMID- 25546877 TI - Introduction: Drug-induced diseases II. PMID- 25546878 TI - Drug-induced hepatotoxicity of select herbal therapies. AB - The use of herbal botanicals and dietary supplements to treat and alleviate disease symptoms has increased over the past decades, and as a result, more research has been done to study the potential damaging effects of herbal products on the liver and other organs. Although reporting rates vary, cases have been published describing liver damage following herbal therapy. Studies have proposed multiple mechanisms of injury for these herbal preparations, and several potential risk factors have been identified including age, gender, polypharmacy, alcohol consumption, and genetic variability. Ingredients and other constituents often differ among products, and lack of standardization in manufacturing of these formulations makes it difficult to determine causality. The potential for drug-induced liver injury is often not known until the postmarketing period due to less rigorous safety testing and regulations. PMID- 25546879 TI - Fabrication of electrospun thermoplastic polyurethane blended poly (l-lactide-co e-caprolactone) microyarn scaffolds for engineering of female pelvic-floor tissue. AB - Potential scaffolds for repair of the female pelvic floor require new materials and fabrication by novel methods to improve cellular infiltration. An 'ideal' engineered scaffold for pelvic-floor tissue should mimic the three-dimensional (3D) network of the extracellular matrix (ECM), which possesses intricate macro- and nano-architecture. In this study, a series of blended poly(l-lactide-co ecaprolactone) P(LLA-CL)/thermoplastic polyurethane (TPU) microyarn/microfibrous scaffolds were produced with different weight ratios via dynamic liquid electrospinning and electrospinning. Both biopolymers were dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Our data showed the mean diameter of microyarn scaffolds to be significantly larger than that of microfibers. Microyarn scaffolds possessed large pore sizes and high porosity. There was no significant difference between the mechanical properties of microyarn and microfibrous scaffolds. Fourier-transform infrared spectroscopy suggested that intermolecular bonds were not present between the molecules of TPU and P(LLA-CL). Morphologic observations using scanning electron microscopy and inverted fluorescence microscopy showed that adipose-derived stem cells labeled with enhanced green fluorescent protein could grow well along or within blend microyarns and migrate within the novel 3D scaffolds. Hematoxylin and eosin staining demonstrated that cell infiltration on microyarn scaffolds was significantly enhanced. The CCK-8 assay showed that microyarns could significantly facilitate cell proliferation compared with microfibrous scaffolds. These results suggested that blend microyarns of P(LLA-CL)/TPU designed to mimic the ECM for female pelvic-floor tissue may be excellent macroporous scaffolds for tissue repair. PMID- 25546880 TI - Dissolution of copper mineral phases in biological fluids and the controlled release of copper ions from mineralized alginate hydrogels. AB - Here we investigate the dissolution behaviour of copper minerals contained within biocompatible alginate hydrogels. Copper has a number of biological effects and has most recently been evaluated as an alternative to expensive and controversial growth factors for applications in tissue engineering. Precise control and sustained release of copper ions are important due to a narrow therapeutic window of this potentially toxic ion, and alginate would appear to be a good material of choice for this purpose. We found that aqueously insoluble copper minerals could be precipitated during gelling within or mixed into alginate hydrogels in the form of microbeads prior to gelling to serve as depots of copper. These minerals were found to be soluble in a variety of biological fluids relevant to in vitro and in vivo investigations, and the alginate carrier served as a barrier to diffusion of these ions and therefore offered control over the rate and duration of release (Cu(2+) release rates observed between 10-750 uMol g(-1) h(-1) and duration for up to 32 d). Copper mineral and copper mineralized alginate microbeads were characterized using powder x-ray diffraction, FTIR, thermogravimetric analysis and scanning electron microscopy. Dissolution kinetics were studied based on measurements of copper ion concentrations using colourimetric methods. In addition we characterized the complexes formed between released copper ions and biological fluids by electron paramagnetic spectroscopy which offers an insight into the behaviour of these materials in the body. PMID- 25546882 TI - More accurate ways to measure tumor cellularity. The author's reply. PMID- 25546881 TI - In vitro fibroblast and pre-osteoblastic cellular responses on laser surface modified Ti-6Al-4V. AB - The success of any implant, dental or orthopaedic, is driven by the interaction of implant material with the surrounding tissue. In this context, the nature of the implant surface plays a direct role in determining the long term stability as physico-chemical properties of the surface affect cellular attachment, expression of proteins, and finally osseointegration. Thus to enhance the degree of integration of the implant into the host tissue, various surface modification techniques are employed. In this work, laser surface melting of titanium alloy Ti 6Al-4V was carried out using a CO2 laser with an argon gas atmosphere. Investigations were carried out to study the influence of laser surface modification on the biocompatibility of Ti-6Al-4V alloy implant material. Surface roughness, microhardness, and phase development were recorded. Initial knowledge of these effects on biocompatibility was gained from examination of the response of fibroblast cell lines, which was followed by examination of the response of osteoblast cell lines which is relevant to the applications of this material in bone repair. Biocompatibility with these cell lines was analysed via Resazurin cell viability assay, DNA cell attachment assay, and alamarBlue metabolic activity assay. Laser treated surfaces were found to preferentially promote cell attachment, higher levels of proliferation, and enhanced bioactivity when compared to untreated control samples. These results demonstrate the tremendous potential of this laser surface melting treatment to significantly improve the biocompatibility of titanium implants in vivo. PMID- 25546883 TI - Standards to prevent, detect, and respond to sexual abuse and sexual harassment involving unaccompanied children. Interim final rule (IFR). AB - This IFR proposes standards and procedures to prevent, detect, and respond to sexual abuse and sexual harassment involving unaccompanied children (UCs) in ORR's care provider facilities. DATES: This IFR is effective on December 24, 2014. ORR care provider facilities must be in compliance with this IFR by June 24, 2015 but encourages care provider facilities to be in compliance sooner, if possible. HHS will work with facilities to implement and enforce the standards contained in this rule. Comments on this IFR must be received on or before February 23, 2015. PMID- 25546884 TI - Management & marketing: establishing an optimal pricing strategy for your practice. PMID- 25546885 TI - Liquor license? PMID- 25546886 TI - Going without. The do's and don'ts of fasting with diabetes. PMID- 25546887 TI - Sisters and friends. PMID- 25546888 TI - People to know 2014. PMID- 25546889 TI - Picturing health. Diabetes management is really an art. But can art improve your diabetes management? PMID- 25546890 TI - Natural harvest. PMID- 25546891 TI - Food for a day. PMID- 25546892 TI - Making a meal of it. PMID- 25546893 TI - Food by the plate. A 20-minute meal. PMID- 25546895 TI - [Vaccines and nurses, key factors in prevention]. PMID- 25546894 TI - Young at heart. Could metformin help type 1 teens avoid heart disease as adults? PMID- 25546896 TI - [Who illustrates ROL? How is it done? Art and science united]. PMID- 25546897 TI - [Health promotions interventions designed and implemented in aged people over 65 years: a systematic review]. AB - BACKGROUND: To systematically review the scientific literature indexed in major databases of health sciences, about the activities or health programs, applied to persons over 65 years. METHODS: Cross-sectional descriptive study. Selecting scientific literature databases: MEDLINE, EMBASE, ISI Web of Knowledge, CINAHL, and LILACS. Descriptors used (MeSH): Health Promotion and Aging. RESULTS: 378 articles were retrieved after applying the inclusion and exclusion criteria were selected for review 28 arti- cles, of which nine randomized trials. Actions or programs implemented were: implementation and creation of scales and instruments, physical activity and education, assessment and home care, oral health, analysis of activities and strategies, vaccination and leisure and recreational activities. Made in homes, private or public institutions, residences and outdoors. U.S. stands out with 13 of the 28 interventions studied. CONCLUSIONS: There is increased interest in the study of health promotion activities for elderly people in Anglo-Saxon countries and awakening the same in Latin America. The implementation of the programs proved effective in encoura- ging changes in lifestyle and produce improvement in physical condition and maintenance of autonomy. Situation is not yet proven in home care. Subsequent monitoring showed improvement on health, but over the effect of intervention decreases. There is need to focus attention and efforts on specific groups at risk of social exclusion. PMID- 25546898 TI - [Vaccines. Some practical issues]. AB - Vaccines are a key tool in disease prevention and public health. Nurses, working in a multidisciplinary manner are essential for successful implementation of vaccination programs. We review some practical issues, useful in the clinic. We will obtain more effective and efficient in our work. PMID- 25546899 TI - [Preventing cervix uteri cancer is possible]. PMID- 25546901 TI - [Diet low in potassium]. AB - After confirming the high prevalence rates in our hemodialysis unit of the following nursing diagnoses: nutritional imbalances--both excesses and shortages, willingness to improve nutrition and fear related to the consequences of excessive intake of potassium and manifested by the inhibition in some people towards the enjoyment of food, we decided to plan an educational strategy which later resulted in a nursing intervention for these diagnoses, with the objective of providing adequate resources for the monitoring of balanced diets with a restriction of potassium. Inspired by dietary rations, as well as recognized dietary programs of learning by points, we decided to incorporate these ideas to design an educational tool to facilitate advice to our patients on how to follow diet plans as well as the choice of appropriate foods. The result was a set of cards incorporating nutritional information of various kinds, aimed at our patients covering different aspects of the diet appropriate food rations using household measurements, promoting good food preparation, appropriate dietary advice for different chronic diseases and a scoring system of foods according to their potassium content. Together they form a board game available during the hemodialysis sessions that also takes into consideration other issues of importance related to conditions such as cognitive stimulation, coping with the disease, improving the therapeutic performance or resources to increase patient motivation. Although initially it was only an educational exercise, the result has turned out to be both enjoyable and entertaining. PMID- 25546900 TI - [Papillomavirus vaccines: adverse effects]. AB - BACKGROUND: The Health Department of Catalunya laun- ched the first vaccination campaign against human papillo- mavirus (HPV) in the 2008-09 school year This study des- cribes the side effects of HPV vaccine and compared them with those of the vaccine against Hepatitis. METHODS: This is a prospective observational study Nurses of our primary health centre went to the area's schools to administer the HPV vaccine and hepatitis vaccine (when necessary). Afterwards, between 24 to 72 hours, they went back to schools in order to control the adverse effects. RESULTS: The frequency of general symptoms (syn- cope, fever, headache, muscle aches, malaise) was less than 5% with the first two doses. With the third, 9.8% of girls referred headache. Pain was the most common local symptom: 28.3% of girls reported pain with the first dose, 53.4% with the second and 53.6% with the third. Local reactions appear more often with HPV than with hepatitis vaccine, especially in the second and third doses (McNemar test p < 0.001). CONCLUSIONS: HPV vaccine was generally well tolerated. General side effects were rare. Local symptoms were com- mon and increased with each new dose. The vaccine against hepatitis produced fewer side effects. PMID- 25546902 TI - [Patients with acute kidney failure. Nursing care]. PMID- 25546903 TI - [Metabolopathies. The importance of a good performance nurse]. AB - The possibility for early detection of metabolic disorders has been a big step forward in medical history due to using a good technique by which diseases can be diagnosed, improving their outcome. The main disorders that these tests are designed to detect are hypothyroidism, congenital adrenal hyperplasia, hyperphenylalaninemia, hemoglobinopathies, and cystic fibrosis, among others. Samples can be collected by two methods: the single draw (taken on the third day of life) or the double draw (the first sample is taken at 48 hours of life and the second after the fourth day). It is important to institute a good technique in order to obtain good results and prevent erroneous samples or false positives. PMID- 25546904 TI - Emergency medicine and its development in Ethiopia with emphasis on the role of Addis Ababa University, School of Medicine, Emergency Medicine Department. AB - INTRODUCTION: Globally Emergency Medicine (EM) is young discipline and even in developed countries it is about five decades old. In Ethiopia formal pre-hospital care or hospital based Emergency department (ED) development is a recent phenomenon and this article describes development of Emergency Medicine care in Ethiopia before, around and after Ethiopia millennium. METHODOLOGY: Documents related to emergency medicine development and implementation from different government and nongovernmental data sources are used as a resource for this article. RESULTS: Emergency Medicine task force (EMTF) has been established in Addis Ababa University (AAU) school of Medicine (SOM) in June 2006 and the taskforce has closely worked with Federal Ministry of Health (FMOH) and Addis Ababa city council Health Bureau (AACCHB). In addition to the main actors many partners have contributed significantly to this initiative. Some of the developments were establishment of emergency departments in Tikur Anbessa Specialized Hospital (TASH) and the restructuring of EM service by FMOH. Emergency care has been considered as a crucial service in hospitals' service along with outpatient and inpatient services. Furthermore, Pre-hospital care initiatives have been commenced in Addis Ababa and expanded to the regions with a arrangement of one or two ambulances to small districts having 100,000 population. There have also been key achievement in human resource development, notably the establishment of EM residency and MSC in EM and critical care nursing. Prehospital care givers training programs in order to produce emergency medicine technicians (EMT) have been started in various regional health professionals training centers. Furthermore, EM module has been included in the current undergraduate medical education. The Ethiopian society of emergency professionals (ESEP) has been established with members from different categories of emergency medicine professionals. In all these developments the emergency medicine training center in the emergency department of AAU has played key role in the training of human resources in different categories. DISCUSSION AND CONCLUSION: The recent successes in EM development is due to concerted efforts of the FMOH, AAU SOM and AACCHB along with committed partners. Hence, it is concluded that consistent local efforts and relevant stakeholders support in EM has resulted in successful development of the field in the country. PMID- 25546905 TI - Development and implementation of an emergency medicine graduate training program at Addis Ababa University School of Medicine: challenges and successes. AB - BACKGROUND: Ethiopians experience high rates of acute illness and injury that have been sub-optimally addressed by the existing health care system. High rates of patient morbidity and mortality prompted the Federal Ministry of Health (FMOH) and the Addis Ababa University School of Medicine (AAU-SM) to prioritize the establishment of emergency medicine (EM) as a medical specialty in Ethiopia to meet this acute health system need. OBJECTIVES: To review the EM residency training program developed and implemented at AAU-SM in partnership with the University of Wisconsin (UW), the University of Toronto (UT) and University of Cape Town (UCT) and to evaluate the progress and challenges to date. METHODS: An EM Task Force (EMTF) at AAU-SM developed a context-specific three-year graduate EM curriculum with UW input. This curriculum has been co-implemented by faculty teachers from AAU-SM, UT and UW. The curriculum together with all documents (written, audio, video) are reviewed and used as a resource for this article. RESULTS: Seventeen residents are currently in full-time training. Five residents research projects are finalized and 100% of residents passed their year-end exams. CONCLUSION: A novel graduate EM training program has been successfully developed and implemented at AAU-SM. Interim results suggest that this curriculum and tri-institutional collaboration has been successful in addressing the emergency health needs of Ethiopians and bolstering the expertise of Ethiopian physicians. This program, at the forefront of EM education in Africa, may serve as an effective model for future EM training development throughout Africa. PMID- 25546906 TI - Development of emergency medicine and critical care masters program for nurses at Addis Ababa University, School of Medicine. AB - BACKGROUND: In Ethiopia, though all health care facilities have rooms available for ill and injured patients, emergency care has always remained suboptimal. Poor organization, lack of properly trained staff and lack of timely identification of the critically sick are the reasons. The role of nurses in the emergency rooms is very vital to im- prove patient survival. To address this pressing health care need and improve the emergency rooms (ER) nursing care, Addis Ababa University School of Medicine (AAU-SM) prioritized Emergency Medicine and Critical Care Nursing Training Program. The initial training began in September 2010 with a class of 20 students. Of these, 18 nurses successfully completed the Emergency Medicine and Critical Care Masters of Nursing program and graduated in 2012. OBJECTIVES: To review the Emergency medicine and Critical Care Masters training program for nurses developed and implemented at AAU-SM in partnership with the University of Wisconsin (UW) and the University of Toronto (UT) and to evaluate the progress and challenges to date. METHODS: An Emergency Medicine Task Force (EMTF) organized at AAU-SM developed a two years modular type of EM and Critical Care masters program curriculum for nurses that is co-implemented by faculty teachers from AAU-SM, UT and UW. In this article both the curriculum and other relevant materials are used as a resource. RESULTS: Thirty eight nurses have already graduated with Masters in Emergency Medicine and Critical Care. Equal number of trainees are currently in full-time training. Their skill and competency log book is going according to the curriculum expectation. CONCLUSION: This EM and Critical Care masters training program for nurses is successfully implemented. This program has also shown that the number and qualification of trained personnel capacity in low resource setting health care system can be effectively improved by partnership with developed training institutions. PMID- 25546907 TI - Development of pediatric emergency medicine at Addis Ababa University/Tikuranbessa Specialized Hospital, Ethiopia. AB - BACKGROUND: In the world emergencies occur everywhere, and each day they consume ressources regardless of whether there are systems capable of achieving good outcomes. Low-income countries suffer the most highest rates of every category of injury--from traffic and the highest rates of acute complications of communicable diseases including tuberculosis, malaria and HIV. OBJECTIVE: To describe the development of pediatrics emergency medicine at Tikur Anbesa Specialized Hospital METHODS: A twinning partnership model was used in developing a pediatric emergency medicine training program helps in development of pediatrics emergency system. RESULTS: Strengthening the capacity of Addis Ababa University (AAU), Tikur Anbessa Hospital (TASH) to provide pediatric emergency medical services through improved organization of the pediatrics emergency department and strengthening of continuing education opportunities for faculty and staff capacity building by this improving quality of care in pediatrics patients in the country. CONCLUSION: The Addis Ababa University, University of Wiscosin and People to People partners intend to continue working together to strengthening and developing effetive systems to deliver quality pediatrics emergency medicine care troughout all regions of Ethiopia. PMID- 25546908 TI - Enhancing emergency medicine initiatives with a quality improvement program: lessons learned in the emergency department of Tikur Anbessa Hospital, Addis Ababa Ethiopia. AB - INTRODUCTION: A Twinning Partnership between the University of Wisconsin-Madison (UW) and Addis Ababa University (AAU) in Addis Ababa, Ethiopia was formed to strengthen the development of emergency medical services at AAU's Tikur Anbessa Specialized Hospital (TASHI) through medical education and exchanges. The Twinning philosophy which emphasizes collaboration and joint learning was an ideal program in which QI program was incorporated to maximize success, promote sustainability, and reinforce basic principles for effective healthcare service delivery. This article describes the QI methodology, capacity building strategy, implementation approach, and lessons learned. METHODOLOGY: QI initiative at TASH ED started during EM fellowship in 2010 when Priority problems in the department were identified, and root cause analysis and possible strategies for improvement were devised. Then Baseline and sensitization was undertaken which was followed by Quality Improvement Projects cycles. The Federal Ministry of health key performance indicators (KPI) were used as standard and measurement tool when it was relevant. The findings were analyzed and trends presented to the ED staff and other stakeholders. RESULTS: In the past four years Since QI initiatives started in TASH EM department different achievements have been registered. The main developments were capacity building with QI training of EM fellows, EM residents and EM and critical care nurses. QI Training was also conducted to Tikur Anbessa Hospital and college of health sciences leadership. In addition, various QI projects have been designed and started, while some are finalized and the rest are on implementation. DISCUSSION: The QI experience in the department suggests that a QI program can effectively support, complement, and enhance health system strengthening partnerships, and that establishment of a QI program at the department level is feasible and beneficial, enhancing the adoption and sustainability of health care improvements such as marked improvements in triage, improved infection control and other critical improvements. Therefore, program leaders have determined that scale-up to a hospital-wide QI program is needed to fully realize the potential for increased quality, efficiency and system strengthening. PMID- 25546909 TI - The Toronto-Addis Ababa academic collaboration: emergency medicine. AB - It is common for universities to form academic partnerships to strengthen their provision of educational opportunities for the faculty and staff at both institutions. These efforts are occasionally done, particularly in north-south partnerships, by partners with different means. As such, unless a true spirit of collaboration is sought, agreed upon, and both parties given equal authority to determine its success, imbalances can prevent each from achieving its goal. Using a collaboration between Addis Ababa University and the University of Toronto as an example, the facets of what makes an appropriate and successful partnership are explored, and outcomes that are meaningful to both institutions described. PMID- 25546910 TI - The new emergency medicine building design at Tikur Anbessa Specialized Hospital (TASH), Addis Ababa University. AB - Tikur Anbessa Specialized Hospital has a new Emergency department design to fulfil the public and the hospital's demand and alleviate the crowded emergency care environment. The design development was based on various stakeholders involvement, benchmarking experiences and relevant review on current recommendations. This paper attempts to describe the new Emergency Medicine building design at Tikur Anbessa Specialized Hospital, Addis Ababa University. PMID- 25546911 TI - Results of varicocele treatment with laparoscopic Palomo technique in children and adolescents in years 2002-2012. AB - INTRODUCTION: Varicocele is caused by enlargement of internal testicular veins, including the pampiniform veno- us plexus. It is assumed that it occurs in 8% to 16% of the male population and predisposes to male infertility. The aim of our study was to assess laparoscopic treatment of the varicocele in children using the Palomo method. MATERIAL AND METHODS: In the years 2002-2012, our clinic treated 114 boys with the varicocele on the left side. In all patients the procedure involved ligation of veins, the testicular artery and lymphatic vessels with the Roeder knot. The average time of the procedure was 29 min. RESULTS: Varicocele recurrence was found in 2 out of 94 patients reporting for the follow up visit, and this corresponds to 2.1% of the studied group. The postoperative hydrocele occurred in 20 patients, of which 5 (5.3% of the studied group) required surgical treatment with the Winkelmann technique, while in 15 (15.9% of the studied group) disappeared spontaneously during the average follow-up period of 1 year. No other intra- or postoperative complications occurred in any patient. Also no case of testicular atrophy was diagnosed. CONCLUSION: The results obtained from our laparoscopy patients using the Palomo method in treatment of varicocele can be considered satisfactory. PMID- 25546912 TI - [Comparison of the iron metabolism and effectiveness of anemia treatment in patients on maintenance hemodialysis performed based on polysulfone and helixone dialyzers]. AB - INTRODUCTION: Anemia is a common complication in patients with chronic renal failure (CRF) especially on maintenance hemodialysis. There are some data that the use of biocompatible high-flux dialyzers is more efficient than low-flux dialyzers in controlling some uremia related diseases including anemia. The aim of the study was to assess the iron metabolism and degree of anemia correction in patients on maintenance hemodialysis performed based on low-flux dialyzers (HD LF), with polysulfone membrane and high- flux dialyzers (HD-HF), with helixone membrane. MATERIAL AND METHODS: The observation lasted 12 months and involved 60 patients (23 F and 37 M) aged from 24 to 84 years, mean 60.73 +/- 15.75 treated on maintenance HD. RESULTS: It was demonstrated a higher mean Hb and Ht values during period of HD-HF as compared with the HD-LF (LF-Hb = 11.09 +/- 0.89 vs. HF Hb = 11.42 +/- 0.98; p < 0.01 and LF- Ht = 33.7 +/- 2.87% vs. HF-Ht = 34.45 +/- 3.08%). Higher values of Hb and Ht during HD-HF were obtained at a comparable average doses of darbepoetin alfa (Aranesp) used in both periods (LF-Aranesp = 8.29 +/- 4.17 MUg vs. HF-Aranesp = 8.25 +/- 3.92 MUg; p <= 0.29) and statistically significantly lower average doses of intravenous iron administered during HD-HF (LF-iron iv = 17.59 +/- 10.44 mg vs. HF-iron iv 12.16 +/- 9.04 mg; p < 0.01). It was also shown a statistically significant higher mean corpuscular volume of red blood cells (MCV) in patients during HD-HF (LF-MCV = 91.15 +/- 6.6 MUm3 vs. HF- MCV = 95.03 +/- 5.38 MUm3; p <= 0.001) and lower mean ferritin values (LF-ferritin = 636.33 +/- 704.57 ng/ml vs. HF-ferritin = 538 +/- 475.92 ng/ml; p <= 0.001). CONCLUSIONS: Lower intravenous iron use during HD-HF, with higher Hb values in these period may indicate on may indicate an increased loss of folates during HD-HF and the necessity of its increased supplementation. PMID- 25546913 TI - [Acute kidney injury in patients with acute respiratory distress]. AB - Acute respiratory distress together with hypoxia could be an indication for admission to intensive care unit. It may also lead to acute kidney injury. In addition, mechanical ventilation may be an additional factor for development of acute kidney injury. The aim of the work was to assess the prevalence of acute kidney injury, including the need for renal replacement therapy in patients with acute respiratory distress treated in intensive care unit. In addition, the effect of acute kidney injury on outcome of patients with acute respiratory distress was evaluated. The studies were performed on 100 patients with acute respiratory distress treated in intensive care unit of the regional hospital. Patients were divided into 2 groups in respect to the presence or absence of acute kidney injury. Acute kidney injury was diagnosed in 22% of patients with acute respiratory distress, while 12% required renal replacement therapy, it was more often observed in patients with estimated GFR < 60 ml/min/1.73m2. Length of stay was similar irrespective of kidney function, however, the mortality was significantly higher in patients with eGFR < 60 ml/min/1.73 m2, particularly in those on hemodialyses. In addition, mortality was associated with older age and sepsis. PMID- 25546914 TI - [Clinical usefulness of heparin-coated dialyzers]. AB - Hemodialysis procedures involve activation of the coagulation system, which creates the need for heparinization to prevent clotting in the extra- corporeal circulatory system. Heparin-based anticoagulation in dialysis, increases the risk of bleeding during and after hemodialysis procedure. Patients with active bleeding or an increased its risk should be dialyzed without heparin or with limited anticoagulation, while ensuring protection against clotting in the dialyzers and dialysis lines. The search for a reliable and comfortable manner of hemodialysis in patients at risk of bleeding did not bring long-term satisfactory results. It seems that a breakthrough in this field was the introduction of dialyzers with polyacrylonitrile membrane with adsorption capacity of heparin during their pre-rinse and then membrane dialyzers with hydrogel polyacrylonitrile heparinized during the manufacturing process. The authors evaluated the clinical usefulness of heparinized dialyzers based on 1140 Evodial hemodialysis sessions performed in 11 patients with increased risk of bleeding in the Dialysis Unit of the Department of Nephrology, University Hospital, Krakow during years 2012-2014. It has been shown that heparinized dialyzers are useful not only in patients with acute bleeding organ, but also in patients with chronic bleeding or chronic bleeding risk non responding for therapeutic methods. Their use allows the individualization of anticoagulation therapy by reducing the dose of heparin. PMID- 25546915 TI - [Return to physical activity and duration of exemption from physical education classes after mild and moderate head injury in children at school age]. AB - GOAL: An attempt to explain the correlation between exemption from physical education classes at school, the length of their duration and the return to physical activity of children with mild and moderate head injury. MATERIAL AND THE METHOD: 55 patients the age of 7 to 17 years treated in two hospital centers due to mild and moderate head injury. The results were interpreted basing on an author's survey conducted among respondents in 1-2 weeks after the injury and after 12 weeks from sustained head injury. The survey was also conducted in the control group of children without head injury (55 children, age 7-17 years). RESULTS: Exemption from physical education classes at school concerned 89% of respondents and lasted on average 9.7 weeks. Only 33% of respondents did not participate in any activity during the exemption. The main problems reported and related to the head injury which correlate with physical exertion were headache, dizziness and frequent feeling of fatigue. CONCLUSIONS: Prolonged duration of exemption from physical education classes at school in the light of this research seems unnecessary. PMID- 25546916 TI - [Surveyed pregnant women's opinion concerning the importance of the participation in the school of birth as a form of preparation for childbirth]. AB - The purpose of the research was the questionnaire evaluation of 76 pregnant women primiparas concerning the importance of the participation in the school of birth as a form of preparation for childbirth. The women were planning their pregnancy at the age of between 20 and 30. The pregnant women declared the importance of physical activity during their pregnancy, however, it did not resulted in the participation in the school of birth. PMID- 25546917 TI - [Influence of right ventricular pacing on tricuspid regurgitation grade--the current state of knowledge]. AB - Tricuspid valve regurgitation (TR) caused by permanent pacemaker implantation was first described in the eight decade of XX century, however dynamical increase in frequency of pacemaker implantation makes this topic of growing importance. Pacemaker electrode in the right part of the heart could intensify TR, but this dependence is still not clearly understood. Available studies in the most of cases are not related on uniform criteria of TR, what provides difficulties in the analyses. Additional difficulty provides the fact that TR occurs in a high percentage of healthy people. Current literature shows, that risk factors for TR worsening are patients' older age and previously diagnosed valve pathologies. Results of studies concerning influence of number, type, or location of the electrode in the heart on the TR severity are unclear. This article presents current literature review regarding influence of right-sided pacing on the frequency of TR. PMID- 25546918 TI - [Postural orthostatic tachycardia syndrome (POTS)--pathophysiology, diagnostics, and treatment]. AB - Postural orthostatic tachycardia syndrome (POTS) is one of the most common presentation of orthostatic intolerance. The syndrome is described as a multifactorial affliction. Main symptoms consist of persistent orthostatic tachycardia (heart rate increase at least 30 beats/min, lasting at least 10 min after assumic vertical position) with high noradrenalin serum concentration (measured in stand-up position). Additionally patients with POTS tend to have lover total blood volume. POTS is generally classified into dysatonomia disorders Symptoms in patients affected with POTS are chronic. The syndrome occurs predominantly in young women (approximately 80%). Due to complexity and variable intensity of symptoms POTS can severely impair daily activity and quality of life in otherwise healthy people. The correct diagnosis and identification of potential pathophysiological mechanisms of POTS is necessary before treatment administration. Adequate therapy can significantly reduce symptoms giving the patients a chance for a normal life. PMID- 25546919 TI - Astrocytoma malignum in glioblastoma multiforme vertens with long term survival- case report and a literature review. AB - Glioblastoma multiforme is the most common and most lethal pri- mary malignant tumor of the central nervous system. It can develop as a primary tumor or by transformation from its precursor--anaplastic astrocytoma which occurs less frequently but the prognosis is also unfavorable. Authors report a case of a 36 year-old man with "astrocytoma malignum in glioblastoma multiforme vertens" in the left frontal lobe. The mass, around 5 cm in diameter was resected by craniotomy 8 years ago. The patient received adiuvant radiation therapy concomitanly with temozolomide. He still stays asymptomatic, with no focal neurologic defects. There is no recurrence in the magnetic resonance imaging. PMID- 25546920 TI - [Patient receiving peritoneal dialysis after treatment of ovarian cancer]. AB - Peritoneal dialysis is one of the three available options for renal replacement therapy. This method of treatment of end-stage renal disease gives patients relatively high sense of independence and control over their disease, especially in comparison with hemodialysis, and therefore is often preferable method for young individuals wishing to lead an active lifestyle. We present a case of 22 year old female patient with stage 5 of chronic kidney disease, which is a consequence of multi-agent chemotherapy for endo-dermal sinus tumor of the right ovary (diagnosed at the age of 13). Particularly important in the context of treating our patient with peritoneal dialysis is the fact of confirmed metastases into the peritoneum, which was the reason for the use of chemotherapy reserved for high-risk patients (ifosfamide + etoposide + cisplatin). The selected program of chemotherapy provided effective eradication of cancer, but a side effect of treatment was renal tubular damage. In the period from 03.2006 to 05.2007 our patient required hemodialysis (with gradually reduce dose of dialysis), at a later time to 12.2011 patient did not require renal replacement therapy (stable renal function were observed at the stage 4 of chronic kidney disease), but in 12.2011 resumption of dialysis was necessary and the patient, in accordance with her selection, is receiving peritoneal dialysis. Qualification of our patient for treatment with peritoneal dialysis was associated with reasonable concern about the ability to provide acceptable adequacy of dialysis. Apprehensions proved to be unfounded, the clinical observation of the patient presents proper ratios of dialysis adequacy. Our patient was also qualified for renal transplantation. PMID- 25546921 TI - [Bilateral ureterocele in adult--a case report and review of literature]. AB - Lower urinary tract symptoms in men are associated usually with the presence of bladder outlet obstruction, especially with benign prostatic hyperplasia. We present a case of a patient whose cause of urinary frequency, difficulty in starting micturition and feeling of incomplete emptying of the bladder was ureterocele, causing symptoms of bladder outlet obstruction. Treatment consisted of endoscopic electroresection of the cyst. Following treatment the complete resolution of symptoms reported before treatment was achieved. PMID- 25546922 TI - [Influence of chronic hypoxia on optical density of MU-opioid receptors in fetal rat brain]. AB - Fetal brain is considered to be the major body organ, critical for the future quality of human life. Offspring exposed to prenatal hypoxia has been evidenced to experience behavioral abnormalities as a result of the injury sustained by neuronal cells in the brain. The relatively early appearance of opioid receptors proved susceptible to endogenous and exogenous factors. Increased concentrations of neurotransmitters in the maternal circulation and amniotic fluid induced by hypoxic exposure imply their role in the regulation of cellular division and differentiation processes. Endogenous neuropeptides and specific opioid receptors are distributed in those brain structures that are associated with behavior and reproduction. Fetuses exposed to the adverse effects of increased opioid level incur structural brain tissue abnormalities. OBJECTIVES: The present study seeks to determine the effects of long-term hypoxic exposure during gestation on the expression of opioid receptors in specific brain regions in both sexes. MATERIAL AND METHODS: The study was conducted on pregnant Sprague-Dawley rats, (120 days old, body weight between 250 and 300 g). Experiments were carried out in order to determine the effect of long-term hypoxia on MU-opioid receptor density in selected structures of fetal central nervous system: caudate-putamen (CPu), zona germinata (ZG), nucleus accumbens (NA), olfactory tubercle (OT), Median Part Medial Preoptic Area (MMPoA) and Lateral Part Medial Preoptic Area (LMPoA). Pregnant female rats were assigned to two research groups: the control group (N=6) and the experimental group subject to prolonged hypoxia for 24 hours from the gestational day 15 to gestational day 20 (E-15-E20). At E-21 rats were sacrificed, their fetuses were removed and their brains were incubated with radioligands. The MU-opioid receptor incubation in selected brain structures was performed with a specific radioisotope [3H]DAMGO [tyrosyl-3,5,-3H(N)-D-Ala-Gly-N methyl-Phe-Gly-enkephalin]. Optical density of MU-opioid receptors was determined at E-21 of gestation during long-term exposure to chronic hypoxia induced from E 15 to E-21 of gestation. Experimental model coupled with an innovative autoradiography allowed for a precise assessment of the lesions sustained by fetal brain tissues due to hypoxia and the adaptive mechanisms of the central nervous system in reaction to hypoxic exposure. RESULTS: Statistically significant chronic hypoxia (p<0.05) downregulated the values of MU-opioid receptors optical density in relation to control group in CPu and ZG. Chronic hypoxia in ZG substantially reduces the values of MU-opioid receptors optical density in males (p<0.05). The differences among remaining groups did not show to be statistically significant. CONCLUSIONS: The obtained results of MU-opioid receptor expression can be detected in specific fetal brain regions that mediate sexual behavior and may be attributable to behavioral changes of experimental animals due to hypoxic exposure during gestation. PMID- 25546923 TI - Normal range of intracranial translucency in healthy Turkish pregnancies and its association with first trimester maternal serum biochemistry and ductus venosus pulsatility index. . AB - OBJECTIVE: To measure the intracranial translucency (IT) by establishing reference ranges in uncomplicated singleton Turkish pregnancies and to evaluate the association of IT with maternal serum biochemistry, gestational week, crown rump length (CRL) measurement, nuchal translucency (NT) and ductus venosus Doppler velocimetry. MATERIALS AND METHODS: 190 uncomplicated singleton pregnancies were included in the study. IT, NT and CRL measurements between 11-14 gestational weeks were obtained with mid-sagittal plane. Two independent measurements were taken and averaged to obtain the final measurement used in the calculations. Statistical analysis was performed with SPSS for Windows 20.0 software package. Correlation analysis was used to determine the association between IT and NT pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (beta-hCG) and CRL length. A p-value of <0.05 was considered statistically significant. RESULTS: The assessment rate of IT was 167/190 (87.89%). The mean CRL length, gestational week, NT and IT measurements were 63.63+/-10.05 mm, 12.28+/-0.75 weeks, 1.23+/-0.43 mm (range: 0.20-2.68) and 2.29+/-0.49 mm (range: 0.18-3.80), respectively There was no significant correlation between IT and maternal serum PAPP-A MoM (r=-0.34, p=0.698) or maternal serum free beta-hCG MoM (r=-0.79, p=0.363), respectively. There was weak but statistically significant correlation between IT with with maternal weight (r=0.172, p=0.047), CRL length (r =0.301, p<0.001), gestational week (r=0.286, p=0.001) and NT measurement (r=0.224, p=0.007), respectively. There was no significant association between IT with ductus venosus Doppler pulsatility index (r=0.108, p=0.213). CONCLUSION: IT can be easily measured while scanning for NT. This study shows normal range values in healthy Turkish pregnancies. Consistent with recent data, our results show positive correlation with gestational week and CRL length. Maternal serum biochemistry does not have any effect on IT. Besides, our study highlights that IT is correlated with NT and adds newly to the literature that there is no correlation of IT with ductus venosus pulsatility index. PMID- 25546924 TI - [Aberrant right subclavian artery (ARSA)--a new sonographic marker for chromosomal aberrations in the second trimester--preliminary observations]. AB - OBJECTIVES: Presentation of our own, preliminary experiences in the assessment of the right subclavian artery's (RSA) position during the second trimester scan. MATERIAL AND METHODS: Since January 2012 our center has started to conduct the assessment of the position of the right subclavian artery in the second trimester scan. Patients who were diagnosed with an aberrant right subclavian artery (ARSA) were referred to invasive method of prenatal diagnosis. Abnormal karyotype and microdeletion 22q11 were analyzed. Detailed echocardiography was conducted in each case. RESULTS: Between January 2012 and September 2013 we diagnosed 19 cases of ARSA. There were three cases of congenital heart defect (15.8%; 3/19) (ventricular septal defect--VSD, n=2, atrioventricular septal defect--AVSD, n=1). Two out of 17 cases showed an abnormal karyotype (11.8%; 2/17)--46,XY del(5) (q15q31) and 47,XX+18. No 22q11.2 deletions were observed. Two patients did not consent to invasive methods of prenatal diagnosis. CONCLUSIONS: The position of the right subclavian artery (RSA) should be routinely assessed during the second trimester of ultrasound screening. The presence of ARSA increases the risk for abnormal karyotype in the fetus and therefore, all patients who are diagnosed with ARSA should be referred to the reference center. PMID- 25546925 TI - The effect of treatment on pregnancy outcomes in women with one elevated oral glucose tolerance test value. AB - OBJECTIVE: The aim of the study was to evaluate whether dietary intervention could reduce maternal and perinatal morbidity in pregnancies with one elevated 100 g oral glucose tolerance test (OGTT) value. MATERIAL AND METHODS: The study was conducted among patients with positive 50 g glucose challenge test (GCT) and one elevated 100 g OGTT value. Plasma glucose value of 140 mg/dL was used as the threshold to define an abnormal GCT result. Carpenter and Coustan criteria were used to evaluate the OGTT results. Seventy-four women with normal GCT values comprised group I. Ninety-nine women with one elevated 100 g OGTT value who were given a caloric diet and 102 women with one elevated OGTT value in group III who received antenatal care with no special diet were randomly assigned to groups II and III, respectively. All women were followed up until the end of pregnancy. Poor maternal outcome was defined as: cesarean delivery performed due to cephalopelvic disproportion, failure to progress or fetal distress, preeclampsia, and/or preterm labor. Poor perinatal outcome was defined as: small for gestational age, large for gestational age or admission to a neonatal intensive care unit. The groups were compared in terms of maternal and perinatal outcomes. RESULTS: The rates of macrosomia and large for gestational age incidence were significantly higher in group III as compared to groups I and II. When we examined the multivariate effects of the risk factors considered to be predictive of poor maternal outcomes, group III was the only statistically significant risk factor (OR=3.90, 95% CI:1.95- 7.84; p=<0.001). In terms of poor perinatal outcome, one elevated OGTT value (group III) was the only significant risk factor (OR=2.92, 95% CI:1.56-5.46; p=<0.001). CONCLUSION: Women with one elevated OGTT value benefit from a structured program of diet therapy aimed to reduce adverse maternal and perinatal outcomes. PMID- 25546926 TI - [Endometrial cancer in young women--clinical and molecular aspects]. AB - OBJECTIVES: The aim the study was to compare two groups of endometrial cancer patients (below and above 45 years of age) in the aspect of clinicopathological and molecular data. MATERIAL AND METHODS: The study encompassed 456 primary tumour samples retrospectively collected from a cohort of endometrial cancer patients, primarily treated by surgery Molecular analysis covered: copy number variations of 10 genes (TOP2A, ERBB1, ERBB2, ERBB3, ERBB4, MYC, CCND1, ESR1, PIK3CA, RAD21) analyzed by quantitative PCR; mRNA expression of 6 genes (SCGB2A2, RAD27, RUNX1, SNAI1, SNAI2, PROM1) analyzed with the use of reverse transcription quantitative PCR; protein expression analysis of 8 markers (PGR, ESR1; ERBB1, ERBB2, ERBB3, ERBB4, TOP2A, pAKT1) performed with the use of immunohistochemistry. RESULTS: The younger group of patients was characterized by less frequent hypertension (p <0.00007), less frequent myometrial infiltration (p=0.002) and longer overall survival (p=0.003). Apart from RAD21 gene aberrations, which were more frequent in younger patients (p=0.02), the study revealed no statistically significant differences between the groups. CONCLUSIONS: The study showed no molecular differences in the profile of younger and older endometrial cancer patients. Data on both the prognostic and predictive significance of RAD21 in endometrial cancer are still insufficient. The clinical profile of younger patients with endometrial carcinoma was slightly better when compared to elderly patients. Younger patients were characterized by longer overall survival. PMID- 25546927 TI - [The influence of mesh pelvic floor reconstructive surgery on OAB symptoms]. AB - OBJECTIVES: The working hypothesis was that pelvic organs prolapse can induce overactive bladder symptoms. Therefore, restoration of pelvic anatomy with accompanying proper urodynamic parameters (cystometric volume, micturition volume, uroflow) should resolve OAB (Overactive Bladder) symptoms. MATERIALS AND METHODS: Forty eight women, aged 51-77 years (mean 62.4+/-7.32), with stage II, III or IV prolapse (POP-Q scale) were included into the study. Patients with LUTS (Lower Urinary Tract Symtoms--inflammation, infection, pain) were excluded. Each patient underwent clinical evaluation and full urodynamic examination (cystometry and uroflowmetry MMS Libra +). Depending on the type of the anatomical defect on the POP-Q scale--anterior defect, posterior defect or both anterior and posterior -a repair using polypropylene monofilament mesh was performed (TVM anterior, TVM posterior or TVM Total). Patients were asked to complete King's Health questionnaire before and after the reconstructive surgery. Statistical analysis was performed using Kolmogorov-Smirnov and U Mann-Whitney tests. RESULTS: Overactive bladder symptoms were diagnosed in 27 patients. Detrusor overactivity was found in 10 patients. In 17 patients, out of 27 with OAB before surgery overactivity symptoms completely resolved after the surgery (63%). On the other hand, post-op de novo OAB symptoms appeared in 2 patients (4.1%). Half of the patients with OAB symptoms after surgery had detrusor overactivity before mesh repair while only 30% of patients without OAB symptoms after surgery had DO (Detrusor Overactivity) before the surgical procedure. Micturition volume in group of patients with OAB significantly increased after the surgery (293.78 ml vs. 364.15 ml; p=0.006). Maximal cystometric capacity in patients with overactive bladder also significantly increased after the surgery (318.78 ml vs. 407 ml; p=0.0001). Quality of life measured by King's questionnaire improved in the group of patients with resolution of OAB symptoms in such domains as: Incontinence Impact, Role Limitations and Sleep/emotions, p<0.05. CONCLUSIONS: Correction of pelvic organ prolapse stage II, III and IV in patients with OAB symptoms leads to an improvement in bladder conditions in half of the patients. Such treatment also resulted in symptom resolution of detrusor overactivity ascertained in urodynamic studies. Overactive bladder syndrome with DO was more resistant to surgical treatment as compared to OAB without DO. Quality of life improved in patients who did not present with OAB bladder symptoms after the mesh surgery. Restoration of proper anatomy might also cure or improve bladder symptoms in patients with OAB symptoms, coexisting with advanced pelvic organ prolapse. PMID- 25546928 TI - Associations of vitamin D concentration with metabolic and hormonal indices in women with polycystic ovary syndrome presenting abdominal and gynoidal type of obesity. AB - GOAL: The aim of the study was to estimate potential associations of vitamin D concentration with metabolic and hormonal indices in women with polycystic ovary syndrome (PCOS) presenting abdominal and gynoidal type of obesity. MATERIAL AND METHODS: Twenty-six women with PCOS (19-49 years old, BMI: 26.8-53.8 kg/m2), presenting predominantly abdominal and gynoidal type of obesity were recruited. Anthropometric measures, body composition using dual-energy absorptiometry, fasting serum 25-hydroxyvitamin D, leptin, glucose, insulin, homeostatic model of assessment (HOMA), lipids, androgens and sex hormone-binding globulin (SHGB) were estimated. RESULTS: Vitamin D insufficiency was found in 2, and deficiency or deep deficiency in 12 patients. Levels of vitamin D were lower in obese than non obese women, and in patients with abdominal as compared to gynoidal obesity (9.60+/-3.7 vs. 16.02+/-3.3 ng/mL, p<0.04). In obese women, vitamin D correlated negatively with all, except for gynoidal fat, measures of obesity fasting glucose levels, and HOMA. No correlations with androgens were found. In women with abdominal obesity vitamin D correlated with luteinizing hormone/follicle stimulating hormone ratio (LH/FSH) and SHBG. CONCLUSIONS: We demonstrated that women with PCOS are often vitamin D deficient. Its concentration was lower in patients with predominantly abdominal obesity as compared to subjects with gynoidal fat excess. In overweight/obese subjects with PCOS, vitamin D correlated with fasting glucose and HOMA. The correlation with LH/FSH suggests that vitamin D status may contribute to hormonal dysregulation. Further studies are needed to elucidate a potentially different impact of abdominal and subcutaneous fat on vitamin D metabolism. PMID- 25546929 TI - Decreased large-artery stiffness in midluteal phase of the menstrual cycle in healthy women of reproductive age. AB - OBJECTIVES: Sex hormones are specific factors contributing to the regulation of cardiovascular system. Studies on the effects of hormonal fluctuations during the menstrual cycle on hemodynamics and arterial stiffness in young women are limited and provide conflicting results. AIM: The aim of the study was to assess arterial stiffness, peripheral/central blood (pBP and cBP) and pulse (pPP and cPP) pressures throughout the single, natural menstrual cycle (early follicular [EFP], late follicular [LFP] and midluteal [LP] phase). MATERIALS AND METHODS: Forty two healthy regularly menstruating women (28.6+/-5.1 yrs of age; BMI 22.0+/-3.5 kg/m2) were evaluated during EFP (Estradiol [E], FSH, LH, PRL, TSH, Testosterone [T], DHEAS, and SHBG), LFP (E, FSH, LH) and LP (Progesterone, E, FSH, LH). Transvaginal ultrasound was performed to confirm ovulatory cycle. Resting radial and aortic BP were assessed noninvasively and continuously using tonometric measurement of peripheral PP wave-PPW (Colin BMP7000, Japan) and on-line reconstruction of central PPW (Sphygmocor Mx, Australia) at EFP, LFP and LP. ANOVA and Friedman test were used in statistical analysis. RESULTS: There were no significant differences in systolic/diastolic BP and PP both at the periphery and at ascending aorta throughout the menstrual cycle. Comparable observations of no interphasal differences were noted for peripheral Augmentation Index (AI). Central AI and augmentation pressure (AP) were significantly lower in LP than in LFP (by 4%; p<0.05 and by 37%; p<0.05, respectively). CONCLUSIONS: We demonstrated significant differences in mechanical properties of large arteries at the midluteal phase of natural menstrual cycle. We conclude that sex hormones may play role in the regulation of arterial stiffness in the reproductive age women. PMID- 25546930 TI - Comparison of the second-generation Beckman Coulter IVD and first-generation AnshLabs ELISA assays for anti-Mullerian hormone in patients undergoing IVF treatment. AB - OBJECTIVES: Ovarian reserve is the main factor influencing the efficacy of infertility treatment. Currently the anti- Mullerian hormone is the main indicator of the ovarian reserve and has a wide spectrum of clinical importance. It achieved a high clinical value right after the introduction of the first commercial AMH assays in 2005. Lack further research and development of the tests and monopoly on their production have led to a significant reduction of their quality resulting in lowered veracity and usefulness. Therefore, we searched for an alternative to the Beckman Coulter assay. The objective of the study was to draw a comparison between the commonly used second-generation assay by Beckman Coulter and the ultra-sensitive first-generation assay by AnshLabs. MATERIALS AND METHODS: Serum samples (n=520) were collected from female patients undergoing routine AMH evaluation before entering an IVF program. We chose samples of patients with the lowest correlation between the AMH serum level and response to stimulation. The AMH serum levels of the patients were examined using two AMH tests, the second-generation assay by Beckman Coulter and the first-generation assay by AnshLabs. Precision and accuracy of both methods were determined and the results of AMH serum levels of 130 patients were correlated with the number of: antral follicles (AFC), follicles after stimulation, and the obtained cumulus cells. RESULTS: Both precision and accuracy of the compared methods were highly satisfactory. The coefficients of variation obtained in the study conducted on two different levels of control material were lower than 12% and the load did not exceed 9%. The study proved that both of the methods yielded comparable results. The coefficient of variation between the first-generation and the second generation AMH assays was 0.871. CONCLUSION: Both methods might be applied in the evaluation of the ovarian reserve. The first- and second-generation assays show comparable correlation with the clinical effects of stimulation, however it seems that first-generation assays are a better alternative to the unstable second generation kits. The results from the first-generation assays are distributed on a wider range, which facilitates clinical interpretation. PMID- 25546931 TI - Multiaxial changes in pregnancy: mental health--a review of the literature. AB - Pregnancy constitutes not only a challenge for the body of the woman, but also a developmental and psychological task for the mother-to-be, her partner and the entire family. Considerable amount of research has been published on the subject of the puerperal period and treatment options of various disorders emerging after pregnancy. However, data on psychiatric disorders and their treatment during that period, although available, remain insufficient. The paper reviews the literature on mental disorders occurring in pregnancy taking into account the overall emotional situation of the pregnant woman. PMID- 25546933 TI - Clear cell carcinoma derived from an endometriosis focus in a scar after a caesarean section--a case report and literature review. AB - Endometriosis is defined as the occurrence of endometrial glands and endometrial stromal cells outside their typical localization within the uterus. Malignant transformation of endometriosis foci in a scar after a caesarean section (cc) is very rare--until 2013 (in a span of 40 years), about 40 such cases have been described. In our article, we describe a case of a 42-year-old woman with a tumour localized in a scar after a caesarean section. The tumour was diagnosed as clear cell carcinoma derived from an endometriosis focus. The long time interval- 17 years in average (from 3 to 39 years) between the surgery (cesarean section in most cases) and the tumor diagnosis is characteristic. In the case we describe, the patient was diagnosed 16 years after the endometriosis focus in the scar had arised. Even though endometriosis is a benign lesion, it has many features distinctive for invasive carcinoma; it may itself undergo a malignant transformation as well as increase the risk of endometrial carcinoma or clear cell ovarian carcinoma. Maybe in future, more exhaustive studies will allow establishing a therapeutic protocol in patients with extra-ovarian malignant transformation of endometriosis foci. PMID- 25546932 TI - [Therapeutic value of lymphadenectomy in ovarian cancer patients]. AB - Ovarian cancer has the highest mortality rate among the female genital malignancies. Its incidence is steadily increasing worldwide, especially in highly industrialized countries. Scarce and non-specific clinical symptoms in the early stages, and lack of effective screening methods, are the reasons why in the majority of cases the disease is diagnosed in advanced stage. Early diagnosis and optimal therapeutic method have significant impact on the prognosis. Surgery remains the basic treatment method in all stages of ovarian cancer. The general principle is the removal of the entire tumor or maximal cytoreduction. Pelvic and para-aortic lymphadenectomy is an integral part of the operating protocol. Evaluation of the regional lymph nodes is an important element of the diagnosis in patients with ovarian cancer, as the disease stage and the decision about the method of adjuvant therapy both depend on it. The diagnostic value of lymphadenectomy is unquestionable and is the basis of proper classification, while its therapeutic value remains the subject of controversy. The aim of the paper is to review the results of the most important research concerning lymphadenectomy in ovarian cancer, based on the available literature. PMID- 25546934 TI - Vulvar angiomyofibroblastoma--a case report of rare entity mimicking Bartholin cyst. AB - Vulvar angiomyofibroblastoma is rare tumor of obscure histological origin. Here a case of 49-year old woman is described with this intriguing benign vulvar entity. The tumor developed at left vulvar labia and clinically imitated Bartholin cyst with clinical complaints of regional discomfort without pain. A macroscopic evaluation revealed well separated, encapsulated tumor of 3,5 cm in diameter. On cut surface the tumor was whitish, flesh, solid with myxoid appearance without any apparent cysts formation. There were alternating hypo- and hypercellular in the neoplasm. Microscopically the tumor comprised proliferation of small thin walled vessels that were surrounded with cuffs and islands of epithelioid, spindle and plasmacytoid cells with occasional vacuolization. Some aggregations of cells were quite dense and in such fields, vessels were compressed and ecstatic enough to mimic a bit haemangiopericytoma pattern. A production of myxoid intercellular matrix was seen in loose, hypocellular areas and was confirmed by positive pas-alcian blue stain that demonstrated prominent myxoid stroma and intracytoplasmatic globules of acid glicoproteins. The immunoprofile was remarkable enough to show strong expression of vimentin and desmin, while there was a lack of pan-keratin (CKAE1/3) and smooth muscle actin (SMA) immunoreactivities. Such an immunofentype is regarded to share some of myofibrolastic origin despite SMA negativity. Tumor cells seemed to sprout from perivascular regions giving an impression of accumulations strictly associated with neighbouring vascular branches. This configuration of cells is very often viewed as pericyte-like proliferation. Thus, our case of angiomyofibroblastoma is an example of tumor that probably derives from perivascular stem cells that acquire some of myoid features. PMID- 25546935 TI - Auxins as one of the factors of plant growth improvement by plant growth promoting rhizobacteria. AB - Plant growth promoting rhizobacteria (PGPR) promote plant growth by various mechanisms such as phytohormone production, enhanced water and nutrient uptake, improved nitrogen availability in the soil, production of ACC-deaminase for ethylene breakdown, phosphate solubilization, siderophore production etc. Microbial auxin production is the major factor not only responsible for strengthening the plant-microbe relationship but it also promotes plant growth and development in a positive manner. Thus, bacterial auxin production potential can be exploited for plant growth improvement that may be effective in reducing the hazardous effects of chemical fertilizers on the ecosystem used to obtain higher yields. The present review gives a better understanding of various factors and mechanisms involved in auxin production by PGPR that may be helpful in proper exploitation of these natural resources in a beneficial way. PMID- 25546936 TI - Fournier's gangrene--current concepts. AB - Fournier's gangrene (FG) is a rapidly progressive form of infective necrotising fasciitis of the perineal, genital, or perianal regions, leading to thrombosis of the small subcutaneous vessels and necrosis of the overlying skin. It is believed that the occurrence of the disease in women is underreported and may be unrecognised by some clinicians. Fournier's gangrene is a life-threatening condition, constituting an urological emergency. Many patients with Fournier's gangrene have medical or surgical conditions, which are predisposing factors to this disease or its more severe or fatal course. These comprise diabetes mellitus, hypertension, alcoholism and advanced age. Recent reports in the literature point to changes in the epidemiology of FG, comprising an increasing age of patients. Several authors reported that the mean age of FG patients is at present 53-55 years. Prognosis in FG patients is based on FGSI (Fournier's gangrene severity index) score. Despite the progress in medical care for FG patients, the mortality rate reported in the literature remains high--most often 20-40%, but ranges from 4% to 80%. The most common isolates cultured from FG lesions are both Gram-positive and Gram-negative, as well as strictly anaerobic bacteria. Recently community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as an etiological agent of FG with severe clinical course and even fulminant sepsis. Rarely FG may have a fungal etiology, being caused by yeast-like fungi Candida spp. or by moulds. Antibiotics should be administered parenterally and in doses high enough to reach an effective concentration in the infected tissues. PMID- 25546937 TI - Epidemiological characteristics and drug resistance analysis of multidrug resistant Acinetobacter baumannii in a China hospital at a certain time. AB - Multidrug-resistant Acinetobacter baumannii is an important bacterium causing nosocomial infections; A. baumannii infections have increased in our hospital since 2009. However, multidrug-resistant A. baumannii, which was mainly isolated from patients in each intensive care unit (ICU), rapidly increased from December 2012 to January 2013. Therefore, we described the molecular characteristics of A. baumannii by pulsed-field gel electrophoresis (PFGE). We also detected resistance genes for beta-lactam, aminoglycosides, and plasmid-mediated quinolones. Disinfectant-resistant genes were also detected in the clinical isolates of blaOXA-51-positive multidrug-resistant A. baumannii. The conjugative test was performed to detect whether or not resistance genes can be transferred to different strains. Carbonyl cyanide m-chlorophenylhydrazone (CCCP) inhibition test was conducted to analyze the factors influencing the resistance of A. baumannii to imipenem, meropenem, ceftazidime, levofloxacin, and tigecycline. PFGE profiles contained 12 strains, including 20 type C strains (47.6%), 4 type D strains (9.5%), and 1 to 3 strains of other types; 38 strains were distributed in patients in each ICU. In our test samples, the presence of blaOXA-23 was closely related to carbapenem resistance. The 16S rRNA methylase gene armA was associated with resistance to amikacin, gentamicin, and tobramycin. The multidrug-resistant A. baumannii was closely related to various resistance genes. These results indicated that multidrug-resistant A. baumannii with type C strains was predominant in our hospital in this period. PMID- 25546939 TI - Identification and assessment of genetic similarity of soil bacterial isolates of Pseudomonas spp. using molecular techniques. AB - Bacteria of the genus Pseudomonas are often components of bioproducts designed to enhance the condition of the soil and plants. The use of Pseudomonas bacteria in bioproducts must be preceded by the acquisition, characterization and selection of beneficial strains living in the soil. A prerequisite for the selection of bacterial strains for use in bioproducts is to be able to identify the isolates rapidly and accurately. To identify and differentiate 15 bacterial isolates obtained from the soil surrounding the roots of sour cherry trees and to assess their genetic similarity, the rep-PCR technique and restriction analysis of the 16S rRNA gene and the 16S-ITS-23S rRNA operon were used. In addition, a sequence analysis of the 16S rRNA gene was performed. The analyses made it possible to divide the isolates into four clusters and to confirm their affiliation with the Pseudomonas species. RFLP analysis of the 16S-ITS-23S rRNA operon enabled greater differentiation of the isolates than RFLP of the 16S rRNA gene. The greatest differentiation of isolates within the clusters was obtained after using the rep PCR technique. However, none of the techniques was able to discriminate all the isolates, which indicates very high genetic similarity of the Pseudomonas isolates found in the same sample of soil from around the roots of sour cherry trees. The tests performed will find application for distinguishing and identifying Pseudomonas strains collected from the soil in order to select the most valuable bacterial strains that produce beneficial effects on plants. PMID- 25546938 TI - Application of microsatellite-primed PCR (MSP-PCR) and PCR melting profile (PCR MP) method for intraspecies differentiation of dermatophytes. AB - In this study, two PCR-based methods (MSP-PCR and PCR-MP) were compared for their abilities to identify intraspecies variations of 23 isolates of Trichophyton rubrum, 78 isolates of Trichophyton interdigitale and 22 isolates of Microsporum canis, obtained mainly from patients in Lodz city. The results allowed to distinguish four types (containing two subtypes) characteristic for T. interdigitale and three types characteristic for T. rubrum using PCR-MP method. Analysis conducted using MSP-PCR with (GACA)4 primer revealed four types for T. rubrum and three types (containing one subtype) for T. interdigitale and with (GTG), primer showed two types (containing one subtype) for T. rubrum and six types (containing one subtype) for T. interdigitale. No differentiation was observed for the M. canis isolates with either method. PMID- 25546940 TI - Sonication as a diagnostic approach used to investigate the infectious etiology of prosthetic hip joint loosening. AB - The purpose of the study was to evaluate the usefulness of sonication for the diagnosis of prosthetic joint infections (PJIs) by its comparison with periprosthetic tissues (PTs) and synovial fluid (SV-F) cultures. The study groups included 54 patients undergoing exchange of total hip prostheses for so called "aseptic" loosening occurring without clinical manifestations of an accompanying PJI and 22 patients who developed a sinus tract communicating with the prosthesis which was indicative of an ongoing infectious process. Significant positive culture results were obtained among 10 (18.5%) patients with "aseptic" implant failure and in 18 (81.8%) patients who developed a sinus tract. Sonicate-fluid (S F) yielded bacterial growth in all culture-positive patients with "aseptic" loosening vs. 15 patients with presumed PJIs. There was a concordance in terms of bacterial species isolated from S-F and conventional cultures from individual patients. Coagulase-negative staphylococci were isolated most frequently. Sensitivity of sonication (75%) exceeded that estimated for PTs (69%) and SV-F (45%) cultures. We conclude that identification of causative agents of PJIs which is critical to further therapeutic decisions is aided by the combination of sonication and conventional culture. PMID- 25546941 TI - Phenotypical and molecular characterization of Microsporum canis strains in North Tunisia. AB - In this study, 40 Microsporum canis isolates were obtained from different patients from the Mycology Unit of the Hospital La Rabta (Tunis) during a 3 month period. The phenotypic identification was done by morphological characterization and biochemical tests. Molecular analysis was performed by amplification of the ITS region of rDNA, the amplified region was subjected to enzymatic digestion and sequenced to evaluate phylogenetic relationships. The morphological analysis showed a considerable diversity of colonies as well as different morphologies of conidia and we have noted variability in the assimilation of the nitrogen and carbon sources. The PCR-RFLP results showed only one restriction pattern for each enzyme. The phylogenetic tree proves that all the strains from Tunisian patients are clonal and related with other strains from different origins. The classical methods used in the mycological laboratories are time-consuming, the PCR-RFLP analysis of the ITS is a reliable tool for the identification of M. canis strains. M. canis from infected Tunisian patients are clonal, although the isolates had different phenotypic characteristics. PMID- 25546942 TI - Antibacterial and antioxidant capacity of polar microorganisms isolated from Arctic lichen Ochrolechia sp.. AB - Although many scientists have been studying lichens, the bacterial communities among lichens have not been fully explored. In this study, the biological activities of bacterial isolates from Arctic lichen Ochrolechia sp. were screened. Cell cultures were extracted using ethyl acetate, and these cultures were tested for antibacterial and antioxidant activities. To evaluate the antibacterial activities, we carried out a disk diffusion test and minimum inhibitory concentration assay. The inhibition zone diameter (mm) was 8 to 12, and its MIC value ranged from 222.0 to > 1000 MUg/ml (control antibiotic ampicillin ranged from 0.31 to 0.58 MUg/ml). PAMC26625 (Sphingomonas sp., sequence similarity: 99.108%) showed a high amount of total phenolic and total flavonoid contents within 5 extracts and also exhibited 77.23% and 80.02% in the 1,1-diphenyl-2-picryl-hydrazyl assay and the 2,2'-azino-bis(3-ethyl benzothiazoline-6-sulphonic acid) assay, respectively. In the ferric reducing antioxidant power assay, it was determined that PAMC26625 contained a higher amount of ferrous ion [8.72 mM Fe(II)/mg extract] than control ascorbic acid [6.21 mM Fe(II)/mg extract]. Our data indicated that they had potential to be novel sources of antibacterials and antioxidants. PMID- 25546943 TI - Laccase production by Trametes hirsuta, characterization, and its capability of decoloring chlorophyll. AB - The present study focused on laccase production, characterization, and its involvement in chlorophyll decolorization. Extracellular laccase, with the highest activity of 11 U/ml on day 8, was efficiently produced from Trametes hirsuta in 5 l bioreactor with optimized media comprising dual carbon sources, glucose and water hyacinth. A laccase was then purified from the supernatant to homogeneity with purification fold of 9.51 and recovery of 39.8% and an estimated molecular mass of 62 kDa by SDS-PAGE. The laccase showed activity at pH 2-6 and temperature 30-80 degrees C and was relatively thermally stable at below 70 degrees C and neutral pH. The laccase was applied to decolorize chlorophyll under different factors: temperature, pH, mediator, metal ions, and enzyme dosage. Other fungal laccases were also found to be able to degrade chlorophyll with rating from 52% to 88% following 1 h treatment with two laccase dosages (5 or 10 U/ml) in the absence of any other mediators at room temperature. These findings may be an important step in developing new, important, and commercially viable industrial applications for laccase enzymes. PMID- 25546944 TI - Antimicrobial properties of substituted quino[3,2-b]benzo[1,4]thiazines. AB - Our previous studies demonstrated that among phenothiazines several derivatives could be found showing strong antiproliferative actions and the property of inhibiting inducible tumor necrosis factor alpha (TNF a) production in human blood cultures. The aim of this investigation was to determine potential antimicrobial actions of forty four new phenothiazine derivatives with the quinobenzothiazine structure. The compounds showed differential antibacterial and antifungal activities against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans depending on the compound structures, concentrations and bacterial strains. More specifically, 6-(1-methyl- 2 piperidylethyl) quinobenzothiazine displayed strongest actions against S. aureus and E. coli whereas 6-methanesulfonylaminobutyl-9-methylthioquinobenzothiazine exhibited the most universal antimicrobial properties. The correlation between antimicrobial activity and the chemical structure of quinobenzothiazines was discussed. PMID- 25546945 TI - Larvicidal and repellent properties of Streptomyces sp. VITJS4 crude extract against Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae). AB - The aim of the present study was to assess the larvicidal and repellent properties of marine Streptomyces sp. VITJS4 crude extracts. The marine soil samples were collected from the Puducherry coast, Tamil Nadu, India. The isolate Streptomyces sp. VITJS4 was taxonomically characterized and identified. The ethyl acetate crude extract tested for larvicidal property showed 100% mortality for all the 3 species after 24 h exposure against the early fourth instar larvae of malarial vector--Anopheles stephensi at 50% and 90% lethal concentration (LC50 = 132.86, LC90 396.14 ppm); dengue vector--Aedes aegypti (LC50 = 112.78, LC90 336.42 ppm) and filariasis vector--Culex quinquefasciatus (LC50 = 156.53, LC90 468.37 ppm). The Streptomyces sp. VITJS4 solvent extracts of hexane, ethyl acetate, benzene, chloroform and methanol were tested for repellent activity against A. stephensi, A. aegypti and C. quinquefasciatus. The ethyl acetate extract showed complete protection for 210 min at 6 mg/cm2 against these mosquito bites. The crude extract was analyzed further for Fourier Transform-infrared spectroscopy (FT-IR) analysis. In addition to the importance of bioactive compounds, the utilization of Streptomyces sp. VITJS4 crude extracts revealed effective larvicidal and repellent activity against the vectors, which perhaps represents a promising tool in the management of mosquito control. PMID- 25546946 TI - Clonal analysis of Staphylococcus hominis strains isolated from hospitalized patients. AB - Staphylococcus hominis is a part of normal skin flora, but it is also a cause of nosocomial infections. The aim of this study was to investigate the genetic relatedness of 62 strains of S. hominis obtained from hospitalised patients during an 11-year period. For the discrimination of these clinical strains we used repetitive sequence-based PCR method (BOX-PCR) and multiple-locus variable number tandem repeat analysis (MLVA). BOX-PCR analysis revealed a large genetic diversity among clinical strains and we did not find a predominant clone with the ability to persist in a hospital environment. MLVA is not as discriminatory as BOX fingerprinting and would not be a useful method for epidemiological studies. PMID- 25546947 TI - Unusual occurrence of Salmonella Mikawasima in 2012-2013 in the Czech Republic: part of a multistate outbreak? AB - An increased number of cases of salmonellosis caused by the rare serotype Mikawasima was noted in the years 2012 and 2013 in the Czech Republic. A potential on-going outbreak caused by this serotype in European countries has also been reported. Altogether 14 human and 1 environmental isolates from the year 2012 and 11 human isolates from the year 2013 from different locations of the Czech Republic were sent to our laboratory for typing. Macrorestriction analysis together with antimicrobial susceptibility testing and PCR for ESBL and plasmid-mediated quinolone resistance detection were performed to compare our isolates. Twenty-one isolates created two very similar clusters and 5 isolates had different profiles. Twenty-five isolates were fully susceptible to all agents used. One isolate showed resistance to 12 microbial agents and possessed blaTEM, blaSHV, blaOXA, blaCTX-M and qnrB genes. PMID- 25546948 TI - PCR-based genomic deletion analysis of RD-regions in the identification of mycobacteria isolated from adverse events following BCG vaccination or TB suspected cases. AB - Early identification of mycobacterial species is crucial for early diagnosis. PCR multiplex method performed on randomly chosen 54 mycobacteria isolates originating from clinical samples was found to be an inexpensive, quick and reliable alternative for commercially available diagnostics tests. Although the results of gene probes identification performed by NTLDR were generally consistent with multiplex PCR, two mixed Mycobacterium bovis BCG/Mycobacterium tuberculosis infections and a single misdiagnosis of M. tuberculosis with M. bovis were found. The routine application of multiplex-PCR has the potential to make diagnostics surveillance studies feasible. PMID- 25546949 TI - Disc-diffusion and PCR detection of methicillin resistance in environmental airborne strains of Staphylococcus spp.. AB - The aim of this study was to assess the species composition of airborne Staphylococcus spp. in public premises, to determine the methicillin resistance of the isolates and the prevalence of mecA gene, determining resistance to beta lactams. In total 65 Staphylococcus strains were isolated from 54 sites. Four strains exhibited phenotypic methicillin resistance, while the presence of mecA gene was found in 11 strains. The results of both assays were compared, showing that the phenotypic tests revealed methicillin resistance only in 36% of the examined samples. This study revealed high species diversity among airborne Staphylococcus spp. population, which consists of multidrug resistant strains. PMID- 25546950 TI - Could a step in the isolation of mycobacteria from sputum samples be eliminated by new decontamination kits? AB - The efficacy of two mycobacterial homogenization, decontamination and concentration kits, Mycoprosafe and Decomics, were compared. A total of 146 sputum samples were examined in this study; 46 (31.5%) mycobacterial isolates were recovered with Mycoprosafe, while 39 (26.7%) mycobacterial isolates were recovered with Decomics. These results, although very preliminary, indicate that Mycoprosafe and Decomics are similar in terms of ease of use and price. However, Decomics offers several advantages, including the need for less equipment, a more rapid detection time, and an easy shipping process; thus, pre-processing can be done anywhere. PMID- 25546951 TI - [Medical rehabilitation in the Armed Forces: history, current state and prospects]. AB - Authors analyzed history, current state and prospects of medical rehabilitation in the Armed Forces of the Russian Federation. Current system of medical rehabilitation in the Armed Forces provides all categories of military personnel and members of their families complete rehabilitative and remedial measures. An integration of rehabilitative experience of the medical service of the Armed Forces of the Russian Federation into the State system of medical rehabilitation, active participation of the medical service of the Armed Forces of the Russian Federation in activity of National association of specialists of medical rehabilitation and regenerative medicine will allow to increase the effectiveness of the rehabilitation system of the Armed Forces. PMID- 25546952 TI - [Organization and delivery of therapeutic care in modern local wars and armed conflicts]. AB - The system of providing therapeutic care within a united system of staged treatment of wounded and sick and evacuation was established during the Great Patriotic War of 1941-1945 and helped to return 90,6% of casualties to duty. In terms of local wars and armed conflicts the most important task of military field therapy is to improve the provision of therapeutic support through regional and territorial principles, echeloning of forces and facilities, optimization of allocation of medical institutions in accordance with their capabilities, evacuation routes, etc. The organization of therapeutic assistance should be guided primarily by the size and structure of sanitary losses. In modern local wars cannot exclude the occurrence of massive sanitary losses with limited use of weapons of mass destruction, as a result of failure (with a conventional weapon or as a result of sabotage) of nuclear power plants, chemical plants, and transport containers containing toxic chemicals. PMID- 25546953 TI - [Main ways of improvements of the systems of medical rehabilitation of military servicemen after cardiovascular surgery]. AB - For better improvement of medical rehabilitation referred to effective restoration of functional status of servicemen after cardiovascular surgery it is necessary to introduce standards of medical rehabilitation at all stages of rehabilitation, syndrome-pathologic principle of grouping patients, multidisciplinary organisation of medical activity: cardiologist-physician, specialist of functional diagnostics, specialist of physical therapy, psychotherapist, physical therapeutic, surgeon and specialist of professional rehabilitation. Basic ways of improvement of the system of rehabilitation were organisational technologies of interaction during early and late stages of rehabilitation and persistent control of quality and effectiveness of rehabilitation. Optimization of organisation of late stage of hospitalisation allowed to reduce the average time of rehabilitation to 33,3% and at the same time to improve effectiveness of rehabilitation. PMID- 25546954 TI - [Pathology of the nervous system in conscripts with drug abuse in past medical history: symptomatology, diagnostics methods]. AB - Authors examined 60 female and male patients (average age 25.8+/-2.7 years) with confirmed diagnosis - drug abuse. Average duration of drug abuse was approximately 9+/-3.3 years. At the moment of examination patients had been fully in remission for 3 weeks. The following non-invasive procedures were undertaken: stimulation electroneuromyogrphy and brain MRI. Received results showed that drug abuse leads to diffuse lesion of the nervous system, which manifests itself as vegetative disorders, scattered neurological symptoms, polyneuropathy. Authors gave recommendations in the field of military examination with the aim of detection of nervous disorders caused by drug abuse. PMID- 25546955 TI - [Peculiarities of bronchopulmonary pathology in HIV-patients]. AB - The causes of hospitalization of HIV-infected patients during of medical treatment in a multidisciplinary health care setting (Military Medical Academy) are analyzed. Leading causes of death in medical institutions among patients with HIV are diseases, which are not associated with HIV infection: burns, combined injuries, toxic substances poisoning. It was found that HIV infection worsens prognosis for patients hospitalized with respiratory diseases and leads to earlier development of nosocomial infections, exacerbation of bronchopulmonary diseases and short-term mortality. PMID- 25546956 TI - [Problems and prospects of infectious diseases and HIV-infected military personnel register organization]. AB - An analysis of regulatory documents of the Ministry of Healthcare and the Ministry of Defence of the Russian Federation related to HIV/AIDS prevention was carried out. The current system of HIV/AIDS detection and registration among military and civil personnel was assessed. Problems and prospects of scientific and-research laboratory (the register of infectious disease pathology and HIV infected military personnel) of Scientific-and-research centre at the Kirov Military medical academy were discussed. It is proposed that the main direction of the laboratory activity will be the restoration of up-to-date records of military personnel with HIV/AIDS. This activity will provide the necessary information to responsible specialists of the Main state sanitary and epidemiological surveillance centre and the Main military medical department of the Ministry of Defence of the Russian Federation for the sanitary and epidemiological surveillance for purposeful and economically feasible management decisions in the field of military personnel infection diseases prevention. PMID- 25546957 TI - [Combat burn injury. The Afghanistan and Iraq military campaign experience]. AB - The current article briefly reviews the experience of combat burns care obtained in the course of 2001-2013 military campaign in Afghanistan and Iraq as it has been covered in the foreign scientific medical publications. The following topics are covered: statistics, the prehospital medical care, aeromedical evacuation, the Burn Center of the US Army Institute of Surgical Research. The new method.of the .initial intravenous infusion rate estimation, so called the "Rule of 10 formula, is marked: At the end, the list of freely available publications summarized the modern combat burns care experience is presented. PMID- 25546958 TI - [Russian physicians during first months of the Great War (to 100th anniversary of the beginning of the First World War)]. AB - At the beginning of the First World War professor and surgeon S.R. Mitotvortsev was appointed as a Chief Expert - Surgeon of the Western Front, there in Lyublyana he faced with difficulties such as organization of health care delivery and treatment of wounded soldiers. In the following, organized by Mirotvortsev team served in Novaya Aleksandriya, Ivan-Gorod, Radom and other towns of the Western Front. This team was named as "Collecting dressing station of professor S.R.Mirotvortsev". PMID- 25546959 TI - [Branch No. 2 of the Vishnevskiy Central Military Clinical Hospital No. 3 celebrates the 25th anniversary]. AB - Authors present a short summary about the history of 6th Central Military Clinical Hospital (now - Branch N 2 of the Vishnevskiy Central Military Clinical hospital N3), founded in September 1989. Hospital Branch N 2 is one of the first specialized applied research centres in our country, many highly-qualified, experienced and certified professional work at the hospital; they are proficient in original and unique methods of treatment based on high technologies and capable to solve any problem, even the most difficult, connected with medical rehabilitation of patients. Hospital Branch N 2 is also known as the Centre of orthopaedic and prosthetic aid to disabled servicemen. Also patients with different diseases and suffering from boardline mental disorders, psychosomatic disorders and chronic fatigue syndrome receive complete rehabilitative therapy under "late" hospital stage. PMID- 25546960 TI - [Professional psychological selection system in the Air Force - 50 years]. AB - Given the data about the establishment of the professional psychological selection system in the Air Force in 1958-1964 in the NIIIAM Air Force by the team psychological department under the leadership of K.K.Platonova. Given the names of the developers of this system and given the results of their research. The result of all made work the order of Air Force Commander about the introduction of the psychological selection in Higher Military Aviation School of Pilots, starting from a set of 1964 became. Recommendations for professional psychological selection of a wide range of aviation professionals in various fields, and in the future - and other professionals of the Armed Forces, became the results of future work. PMID- 25546961 TI - [The experience of medical information system implementation into multi-field outpatient facility]. AB - The main prospective line of development of information technologies implemented into medical facilities is working out and approbation of complex solutions for work automatiozation. It is necessary to mention the experience of implementation of industrial integrated medical information system into the 9h diagnostic and treatment centre of the Ministry of Defence of the Russian Federation. In 2008 implementation of the information systems was funded by extra budgetary accounts of the facility. The basis of medical information system for the diagnostic and treatment centre was "Interin PROMIS". The article presents the main tasks, stages and difficulties that emerged in the process of implementation. One of the main tasks was to create the database of attached contingents. Conducted work allowed to increase access to healthcare, to develop transparent technologies for providing the healthcare to patients in different subunits. Implemented system is a very prospective for other military-medical facilities and has a unique functional capacity, system customizability, provides access to all activities of the medical facility. PMID- 25546962 TI - [Wounded patients transportation during peace enforcement operation in Georgia (August 2008)]. AB - The article highlights the analysis of wounded movement during peace enforcement operation in Georgia (August 2008). 72% of incoming patients were walking wounded; 97,5% male patients, 2,5% female patients; per cent of combat surgery pathology - 90,2% including combat surgical trauma 83,2%, general surgical diseases - 7%, combat therapeutic pathology - 9,8%; leading gunshot traumas in walking wounded are lower extremities injuries - 33,6%, upper extremities injuries - 27,9% (in total 61,5%), head injuries - 25,4%. Within combat therapeutic pathology walking wounded suffered from the following classes of diseases/sicknesses - I class - 35,7%, XII class - 14,3%, V class - 10,7%. 236 military hospitals (In Vladikavkaz) had admitted 71,2% of walking wounded (of incoming traffic), 1458 military hospitals (in Mozdok) had admitted 91,7% of walking wounded from front traffic, flank traffic was 100%. 49, 7% of patients finished the treatment in military hospitals of zone level, 47,9% of patients - in hospitals of district level, 2,4% of patients - in central hospitals. The,average duration of the treatment of walking wounded in hospitals of zone level consisted 16,9+/-0,7 days, no lethal outcomes were registered. PMID- 25546963 TI - [Substantiation and search of health indicators for military servicemen and civil population]. AB - Health authorities and executives of medical organisations focused on improvement of quality index and access to health care in the process of realisation of the state policy of the Russian Federation in the healthcare field. But the figures currently used and recorded on the official statistical books don't allow to make an objective evaluation of the health status of the population and therefore to evaluate an effectiveness of medical arrangements. Thereby it is necessary to find new indicators for objective individual and public health evaluation. Performed comparative-analytical study of currently used methods and figures for public health evaluation showed that the integral health indicators obtained by the evaluation of heart rate variability are the most efficient. PMID- 25546964 TI - [The use of the new loads of expendable medical supplies by the medical service of the Armed Forces]. AB - The new loads of expendable medical supplies adopted by the Armed Forces of the Russian Federation and included into regulating documents are the most important elements of the authorized equipment system. Nine loads of expendable medical supplies, combined into two classification groups, are provided for the medical service. The use of these loads improves the effectiveness of medical supply for all stages of medical evacuation, medical continuity during medical and evacuation procedures and allows to deliver medical aid to patients on the basis of modern and innovative medical technologies. PMID- 25546965 TI - [Modern possibilities of endovascular surgery in the diagnosis and treatment of pancreatic inflammatory diseases]. AB - Demonstration of possibilities of an effective application of endovascular techniques in the diagnosis and treatment of pancreatic inflammatory diseases. Group N1 - 41 patients with severe acute pancreatitis, whose complex treatment was complemented with catheterization of the celiac trunk and subsequent regional intra-arterial drug perfusion of the pancreas and spiral celiac angiography. Group N2 - 18 patients with acute and chronic pancreatitis in whom endovascular surgery was performed with the aim of diagnosis and arresting of arrosive haemorrhage. Regional intra-arterial perfusion of the pancreas is effective as a method of prevention of septic complications, progression of pancreatic necrosis in patients with aseptic forms of severe pancreatitis, in case of infected necrotizing pancreatitis significant advantage of this method over the standard multimodality treatment was observed. Effectiveness of endovascular surgery in the diagnosis and haemostasis of arrosive arterial haemorrhage is showed. The results of this study suggest that the effective use of endovascular surgery as possible in patients with severe acute pancreatitis and late postnecrotic complications. PMID- 25546966 TI - [Epidemiological peculiarities of acute respiratory diseases and its prophylaxis in Internal Troops of the Ministry of Internal Affairs]. AB - Acute respiratory diseases is the current problem of the medical service and command of Internal Troops of the Ministry of Internal Affairs. In recent years on the background of increase of contract servicemen the total rate of these infections decreased. However, rate of acute respiratory diseases in conscripts remains high and has a tendency to increase. Due to restricted possibilities of immunization in case of acute respiratory diseases it is necessary to improve the non-specific prophylaxis. The guaranty of sanitary-and-epidemiological safety may be active participation of military-and-professional society in realization of lifesaving measures and safety of military service. PMID- 25546967 TI - [Medical approaches to development and testing of anti-mine defence for combat vehicle crews]. AB - To prevention death and serious injuries personnel must be equipped with war materiel collective and individual antimine defence. The experience gained in the establishment of protective equipment shows that modern technology can prevent serious injuries and moderately severe blast injuries in the members of the crew an ensure injury prevention not less than 95%. The solution to this problem is achieved by exception of conditions for spinal compression fractures, ankle and foot fractures, severe and moderately severe brain contusions and eardrum ruptures. Anti-mine defence effectiveness test should be carried in situ and in semi natural environment using as an analogue of the human body a biomorphic model and recording parameters and traumatic factors in the following mathematical simulation of the reaction of the human body on the effect of these factors. PMID- 25546968 TI - [Dynamics of functional status of submarine personnel during the pre-deployment period]. AB - Authors came to conclusions that during the pre-deployment period submarine personnel are stressed out. During this period submarine personnel .usually resupply, conduct maintenance and other monitoring-and-checkout measures, which leads to functional stress. Authors came to conclusion that it is necessary to use simple and easy, but at the same time informative methods for early diagnosis of worsen functional health status. One of these methods is evaluation of indicators of cardiovascular system. This method is a base for functional health status prophylaxis. PMID- 25546970 TI - [Russian Red Cross Society and its role in providing medical aid to wounded and sick people during the First World War]. AB - Russian Red Cross Society during the First World War played a significant role in health care, preservation of human life and return of millions of experienced soldiers to duty. The Red Cross Society formed and sent to the front their medical institutions (military hospitals, hospitals, hospital trains, etc.), trained medical nurses, charity nurses and orderlies of the Red Cross. Famous professor-surgeons worked as the consultants of the Red Cross Society, under their leadership were organized mobile surgical units. Society has created mobile nutrition and dressing units, X-ray units, psychiatric reception and collection points. The Red Cross Society assisted the military Department in the fight against infectious diseases. PMID- 25546969 TI - [Medical Service of the Norwegian Armed Forces]. AB - The article is a brief description of the current state of the Norwegian Armed Forces medical service and is based on the study of the open access foreign sources. At the beginning, the general information about Norway, the Norwegian Armed Forces, and their medical service is presented: Then some particular features are described with more detail, namely, the organization of the inpatient and outpatient treatment, medical supply, scientific research, combat medicine, medical staff education and training, medical service personnel income. PMID- 25546971 TI - [The First World War and medical school of Petrograd]. AB - The article is devoted to the history of higher medical education of the Petrograd just before and during the First World War. The topical issue is the lack of information concerning this period of the history of Russian medicine and medical education, and the history of development of domestic medicine during the First World War, the centenary of which is celebrated this year. On the basis of a wide range of published and archival sources the authors show the basic vectors of development of medical education and exploring the role of St. Petersburg as one of the leading academic medical centres in the country. PMID- 25546972 TI - [The head of the medical service must be the person...(To the 70th anniversary of N.G. Ryzhman)]. AB - The article is devoted to contribution of major general (rear Admiral. - navy) of medical service Nikolay Grigoryevich Ryzhman (1944-2005), the chief of the medical service of the Northern fleet (1991-1999), to development of naval medicine, who would have turn 70 years this September. The constant analysis, and experience generalization of the medical services of the fleet connections and associations and aspiration to provide fighting capacity for the fleet crew - were a keynote of Ryzhman's activity concerned development and deployment of the new forms and methods of medical support and searching of ways to increase crew efficiency. The implemented methods and forms of organization of the medical support and scientific development of the medical support are used even now in the practical activities of the medical service of the Northern fleet. PMID- 25546973 TI - The question is whether hemiparesis is more common in unilateral than bilateral chronic subdural hematoma. AB - INTRODUCTION: Chronic subdural hematoma is an intracranial hemorrhagic lesion that illustrates various expressions in clinical and radiological practice. The aim of this study was to emphasize the correlation between the brain site of chronic subdural hematoma and clinical symptoms/signs of disease. Furthermore, the study denotes the significance of hemiparesis occurrence in the patients with unilateral chronic subdural hematomas more than in those with bilateral ones, associated with time required to diagnose hematoma. MATERIAL AND METHODS: A three year study included 72 patients with chronic subdural hematoma. According to their clinical and neurological symptoms on hospital admission, all patients underwent non-contrast brain computed tomography scan, which confirmed the diagnosis. The radiological parameters, including the site of chronic subdural hematoma, a hematoma width and midline shift were recorded to give precise data about the correlation with neurological symptoms. A special focus was put on the lag time between the onset of symptoms and signs to diagnosis of chronic subdural hematoma. RESULTS: The study proved that the patients with unilateral chronic subdural hematoma had more frequent occurrence of hemiparesis than the patients with bilateral chronic subdural hematoma. It took the left-sided chronic subdural hematomas less time (about 200 hours earlier) than the right-sided ones to present its symptoms although the average hematoma diameter value was almost the same. CONCLUSION: The site and the form of intracranial lesion-chronic subdural hematoma could have a great influence on neurological and functional condition in a patient. Although the length of time required for making diagnosis as well as clinical symptoms greatly differ and the latter are not always so clear, physicians should maintain a high level of suspicion for this disease and thus contribute to prompt diagnosis and better clinical outcome of patients. PMID- 25546974 TI - Analysis of antibiotic consumption for treating respiratory tract infections in children and compliance with the national clinical guidelines. AB - INTRODUCTION: Respiratory infections are the most common infections in children. The aims of the study were to analyze the use of antibiotics for respiratory infections in the period 2008-2010 in children's population in region of Nis and to estimate the rational use of antibiotics in relation to the recommendations of the National Guidelines for physicians in primary care. MATERIAL AND METHODS: Data source was a Pharmacy Nis database. Antibiotics prescriptions were selected for the following diagnoses: H65-H75 (acute otitis media, mastoiditis), J01 (acute sinusitis), J02-J03 (tonsillopharyngitis), J12-J18 (community acquired pneumonia), J20 (acute bronchitis), J32 (chronic sinusitis), J42 (chronic bronchitis). Antibiotic consumption was expressed in defined daily dose/1000 ihhabitants/day. RESULTS: The most widely prescribed antibiotic for the treatment of upper respiratory tract infections in children during the three years was amoxicillin (34.63; 32.50 and 31.00 defined daily dose/1000 inhabitants/day in 2008, 2009 and 2010, respectively). In the treatment of infections of the middle ear and mastoid, the combination of amoxicillin and clavulanic acid, was the most prescribed antibiotics (60% of total consumption of antibiotics for this indication). Azithromycin was the most widely prescribed antibiotic for the treatment of lower respiratory tract infections in children during the observed period (6.92; 8.20 and 7.18 defined daily dose/1000 inhabitans/day in 2008, 2009 and 2010, respectively). CONCLUSION: Recommendations of national guidelines are not complied with the treatment of upper and lower respiratory infections in the children population in region of Nis. This could be a sign of potentially irrational use of antibiotics that need to be further examined. Education of physicians can influence irrational use of antibiotics. PMID- 25546975 TI - Hormonal contraception--habits and awareness female students of the University of Novi Sad, Vojvodina, Serbia. AB - INTRODUCTION: Despite a large number of modern contraceptive methods available in the market today, numerous studies have shown insufficient awareness of young women about these forms for birth control. The aim of this study was to compare characteristics of common use of contraceptives as well as the awareness of hormonal contraception among female students of the Faculty of Medicine and the Faculty of Technical Sciences in Novi Sad. MATERIALS AND METHODS: In the study which was conducted in 2012 240 female students of the Faculty of Medicine and the Faculty of Technical Sciences participated. The average age of students of the Faculty of Medicine and the Faculty of Technical Sciences was 24.06 +/- 3.24 and 22.72 +/- 0.90 years, respectively. They completed an anonymous questionnaire, which consisted of three parts. The first part comprised general questions, the second part included characteristics of the sexual life of students and their contraceptive habits, while in the third part students were asked to evaluate the accuracy of statements about hormonal contraception. The obtained data were statistically processed by using appropriate methods. RESULTS: The average age when the students of the Faculty of Medicine and the Faculty of Technical Sciences had the first sexual intercourse was 18.74 +/- 2.61 and 18.75 +/- 2.59, respectively. One third of students from both faculties (30.91% from the Faculty of Medicine and 35% from the Faculty of Technical Sciences) had only one sexual partner. Modern contraception was used by 83.64% of the medical students and by 80% of those from the Faculty of Technical Sciences. Contraception was used regularly by 54.54% of the medical students and 43% of those from the Faculty of Technical Sciences. The most frequently applied contraceptive method was condom (90% of the medical students and 93% of the Faculty of Technical Sciences students, respectively). Oral contraceptives were used by 24.54% of the medical students and 11% of those from the Faculty of Technical Sciences. There was a statistically significant difference in the knowledge level between the two groups since the medical students gave quantitatively higher range of expected responses than the students from the Faculty of Technical Sciences. CONCLUSION: It is necessary to increase the availability of adequate information on various types of contraception to student population in Vojvodina. PMID- 25546977 TI - Thyroid-stimulation hormone-receptor antibodies as a predictor of thyrosuppressive drug therapy outcome in Graves' disease patients. AB - INTRODUCTION: Graves' disease is autoimmune hyperthyroidism caused by pathological stimulation of thyroid-stimulation hormone-receptor antibodies. The decision on changing the therapy can be made on time by determining the prognostic factors of thyrosuppressive drug therapy outcome. The aim of the study was to determine the significance of thyroid-stimulation hormone-receptor antibodies level on the prediction of therapy outcome. MATERIAL AND METHODS: The study was prospective and involved 106 drug-treated patients with newly diagnosed Graves' disease. Thyroid-stimulation hormone-receptor antibodies level was measured at the beginning of therapy, during therapy and 12 months after it had been introduced. RESULTS: No statistically significant difference in the level of thyroid-stimulation hormone-receptor antibodies was found at the beginning of disease and 12 months after the introduction of thyrosuppressive drug therapy among the patients who had been in remission and those who had not. Regardless of the outcome, thyroid-stimulation hormone-receptor antibodies level significantly decreased in all patients 12 months after the therapy had been introduced. CONCLUSION: The level of thyroid-stimulation hormone-receptor antibodies at the beginning of disease and 12 months after the introduction of therapy cannot predict the outcome of thyrosuppressive drug therapy. PMID- 25546976 TI - Polymorphism of angiotensin converting enzyme in hemodialysis patients- association with cardiovascular morbidity. AB - INTRODUCTION: Cardiovascular morbidity and mortality are the major concern in dialysis patients and many risk factors are thought to be involved in its pathogenesis. Apart from traditional and non-traditional risk factors, the genetic susceptibility may be of importance, including renin-angiotensin system gene polymorphism. The aim of this study was to analyse renin-angiotensin system polymorphism in our group of hemodialysis patients and to correlate the findings with cardiovascular morbidity. MATERIAL AND METHODS: The study included 196 patients on regular hemodialysis on polysulphone membrane three times per week for more than six months. Genetic analysis was performed by using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Out of 196 patients, 55% had I/D genotype, 35% had D/D and 10% had I/I, including angiotensin-converting enzyme polymorphism. It was shown that the patients with D allele genotype developed a significantly higher incidence of left ventricular hypertrophy and peripheral vascular disease. The angiotensin-converting enzyme polymorphism showed a significant association with the incidence of cerebrovascular accident and hyperlipoproteinemia in our group of hemodialysis patients. CONCLUSION: The angiotensin-converting enzyme gene polymorphism is associated with the development of cerebrovascular accidents and hyperlipoproteinemia. Allele D of this gene increases the risk for the development of left ventricular hypertrophy and peripheral vascular disease significantly in hemodialysis patients. A longer follow-up is needed to make the definitive conclusion about the influence of angiotensin-converting enzyme polymorphism on cardiovascular morbidity and its importance in everyday clinical practice. PMID- 25546978 TI - The question is whether intake of folic acid from diet alone during pregnancy is sufficient. AB - PREGNANCY AND FOLIC ACID: Pregnancy is the most important period in life of every woman, partially for the number of physiological adaptations she is going through, partially for the expectance of new life. In addition, pregnancy is the "critical window" for development later in childhood, as a period of foetal programming during which nutrition plays one of crucial roles. Despite the general belief that nutrition through pregnancy is adequate and characterized by better nutritional habits, a number of studies do not corroborate this belief. ROLE OF FOLIC ACID: An adequate folate blood level is necessary for normal cell growth, synthesis of several compounds including deoxyribonucleic acid and ribonucleic acid, proper brain and neurologic functions; it is included in the regulation of homocysteine level, and closely related to the vitamin B12 metabolism. Folate deficiency in pregnancy is related to neural tube defects, other neurological disorders, preterm delivery and low birth weight. FOOD SOURCES: A correlation between folate and the prevention of broad spectrum of chronic diseases has been confirmed. Emerging evidence from the epigenetic studies is now bringing even more light on the level of significance of folic acid. A wide range of plant and animal foods are the natural sources of folate; liver, yeast, mushrooms, and green leafy vegetables being the most significant. Different ways of food preparation influence the folate stability and its bioavailability varies from 25 to 50% from foods, 85% from enriched foods or 100% from supplements. CONCLUSION: A great amount of scientific results has led to official recommendations for folic acid supplementation in pregnant women as well as in a number of obligatory or voluntary fortification programmes in order to prevent the folate deficiency on the level of different population groups. Nevertheless, there must be a certain level of precaution for elderly because folate can mask the vitamin B12 deficiency with possible fatal outcomes. PMID- 25546979 TI - Articulation of sounds in Serbian language in patients who learned esophageal speech successfully. AB - INTRODUCTION: Articulation of pronounced sounds during the training and subsequent use of esophageal speech is very important because it contributes significantly to intelligibility and aesthetics of spoken words and sentences, as well as of speech and language itself. The aim of this research was to determine the quality of articulation of sounds of Serbian language by groups of sounds in patients who had learned esophageal speech successfully as well as the effect of age and tooth loss on the quality of articulation. MATERIAL AND METHODS: This retrospective-prospective study included 16 patients who had undergone total laryngectomy. Having completed the rehabilitation of speech, these patient used esophageal voice and speech. The quality of articulation was tested by the "Global test of articulation." RESULTS: Esophageal speech was rated with grade 5, 4 and 3 in 62.5%, 31.3% and one patient, respectively. Serbian was the native language of all the patients. The study included 30 sounds of Serbian language in 16 subjects (480 total sounds). Only two patients (12.5%) articulated all sounds properly, whereas 87.5% of them had incorrect articulation. CONCLUSION: The articulation of affricates and fricatives, especially sound /h/ from the group of the fricatives, was found to be the worst in the patients who had successfully mastered esophageal speech. The age and the tooth loss of patients who have mastered esophageal speech do not affect the articulation of sounds in Serbian language. PMID- 25546980 TI - Clinical characteristics of first venous thrombosis among women under and over 45 years of age. AB - INTRODUCTION: Venous thromboembolism is a multifactorial disease defined by multiple interactions between genetic and acquired risk factors. After coronary heart disease and stroke, venous thromboembolism is the most common cause of cardiovascular death and disability. MATERIAL AND METHODS: In order to investigate the clinical characteristics of first venous thromboembolism, 447 women younger than 45 and 174 over 45 years of age with confirmed venous thromboembolism, who had been tested for the presence of thrombophilia in the period 1998-2012, were included in the study. RESULTS: Proximal deep vein thrombosis occurred most often among young women, while distal deep vein thrombosis was the most frequent in the older group. The most common reported risk for venous thromboembolism observed in 49.8% of the young women was pregnancy and puerperium, while 25.2% of them developed venous thromboembolism without any obvious cause. Among women over the age of 45, venous thromboembolism developed without an obvious cause in 38.5%, while malignant disease was identified as the most important risk factor in 23% of them. Thrombophilia was observed in 48.7% of the young women in comparison to 28.7% of the older ones (p < 0.0001). As for venous thromboembolism recurrence, it developed in 26.3% of young women and 17.8% of the older ones (p = 0.03). CONCLUSION: Younger women developed more severe forms of thrombosis than the older ones. Inherited risk factor for thrombosis was detected in almost half of all young women, and in every fourth elderly women. With the exception of factor V Leiden mutation, other types of congenital thrombophilia are almost negligible among older women. Therefore, thrombophilia testing in case of first thrombosis is fully justified only in young women. PMID- 25546981 TI - Drug induced lung disease--amiodarone in focus. AB - More than 380 medications are known to cause pulmonary toxicity. Selected drugs that are important causes of pulmonary toxicity fall into the following classes: cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit drugs, miscellaneous. The adverse reactions can involve the pulmonary parenchyma, pleura, the airways, pulmonary vascular system, and mediastinum. Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic or histological findings. A drug-induced lung disease is usually considered a diagnosis of exclusion of other diseases. The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis. High-resolution computed tomography scanning is more sensitive than chest radiography for defining radiographic abnormalities. The treatment of drug-induced lung disease consists of immediate discontinuation of the offending drug and appropriate management of the pulmonary symptoms. Glucocorticoids have been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities. Before starting any medication, patients should be educated about the potential adverse effects of the drug. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia. Amiodarone-caused pulmonary toxicity is a well-known side effect (complication) of this medication. The incidence of amiodarone-induced lung disease is approximately 5-7%. PMID- 25546982 TI - Glycated hemoglobin A1c as a modern biochemical marker of glucose regulation. AB - GLYCATED HEMOGLOBIN STRUCTURE AND SYNTHESIS OF MOLECULE: Glycated hemoglobin A1c, the major fraction of glycated hemoglobin, is formed by irreversible nonenzymatic glycation. Its concentration depends only on the life span of red blood cells and blood glucose levels. CLINICAL SIGNIFICANCE OF GLYCATED HEMOGLOBIN A1c: It is the key parameter for monitoring the regulation of diabetes and for assessing the risk of microvascular complications. It is a diagnostic criterion for diabetes as well. Its concentration reflects the average value of blood glucose over the last two to three months. The estimated average glucose, a new parameter which facilitates the patient's self-monitoring of diabetes, can be calculated from its value. METHODS FOR DETERMINING GLYCATED HEMOGLOBIN A1c AND THEIR STANDARDIZATION: Immunoassay and ion-exchange chromatography are commonly used methods for the glycated hemoglobin determination in routine laboratory practice. The advantage of immunoassay is that there is no need for the sample pre-treatment in order to eliminate unstable glycated hemoglobin A1c intermediary forms, and the possibility of false positive results is lower. The current program of standardization requires traceability to the International Federation of Clinical Chemistry and Laboratory Medicine reference method. REPORTING AND INTERPRETATION OF RESULTS OF GLYCATED HEMOGLOBIN A1c DETERMINATION: Glycated Hemoglobin A1c can be reported as % or as mmol/mol. In our country, it is recommended to use the International Federation of Clinical Chemistry and Laboratory Medicine units (mmol/mol). When interpreting the results, the potential causes of falsely high or low values must always be taken into consideration. RECOMMENDATIONS FOR CLINICAL PRACTICE: Periodic determinations of glycated hemoglobin A1c are recommended for monitoring of diabetes regulation. Additionally, the determination is recommended for the diagnosis of diabetes. The target value for the prevention of microvascular complications is < 7% and the diagnostic criterion for diabetes is 6.5%. PMID- 25546983 TI - Modulatory role of nitric oxide in cardiac performance. AB - Nitric oxide is produced by almost all cardiac cells, endothelial cells, cardiomyocytes and nerve fibers. It is synthesized by an enzyme, a nitric oxide synthase, which occurs in endothelial, neural and inducible form. The distribution of nitric oxide synthase in the heart is characterized by a pronounced non-uniformity. Nitric oxide exerts its effects in physiological and pathophysiological conditions. The physiological effects of low concentrations of nitric oxide, which is released in the normal conditions under the influence of constituent enzymes, occur via cyclic guanosine monophosphate. The synthesized nitric oxide exhibits its effect in the cells where it is produced, in an autocrine manner, or by diffusing into the neighboring cells, in a paracrine manner. Nitric oxide acts by regulating the coronary vessel tonus, affecting the contractility of cardiomyocytes, generating an inotropic effect in a dose dependent manner and controlling the cellular respiration. Other effects of nitric oxide in the cardiovascular system include the hyperpolarization of the smooth muscle cells in blood vessels, the inhibition of the monocyte adhesion, the inhibition of platelet migration, adhesion and aggregation and the proliferation of smooth muscle cells and fibroblasts. The anti-atherosclerotic effects of nitric oxide are based on these effects. Nitric oxide is a weak free radical in gaseous state, and the cytotoxic and/or the cytoprotective effects of the higher concentrations of nitric oxide are related to the chemical structure of nitric oxide as a free radical. The excessive production of nitric oxide by the activation of inducible nitric oxide synthase can lead to major irregularities in the function of cardiomyocytes and cardiac insufficiency. Understanding the nitric oxide molecular mechanisms of signaling pathways in the heart can provide a new strategic approach to prevention and treatment of cardiovascular diseases. PMID- 25546984 TI - [Modern threat of Ebola virus]. AB - Since the detection of Ebola virus in 1976. recorded 13 major epidemics in Africa. The current threat in Guinea, Liberia and Sierra Leone absorbs another victims and threatened pandemic. Picture of the disease is initially very non characteristic (influenza-like symptoms) and quickly leads to dehydration, shock and disseminated intravascular coagulation syndrome, which is responsible for high mortality. Lack of effective antibiotic therapy and vaccine hampers the existing situation. For this reason, there is an absolute necessity to introduce regimes sanitation, quarantine at the suspects and maintain the highest safety measures for emergency responders. Developed procedures require absolute compliance. PMID- 25546985 TI - [Comparison of the safety of rivaroxaban versus dabigatran therapy in patients with persistent atrial fibrillation]. AB - For 60 years, vitamin K antagonists have been used in prevention of thromboembolic complications in the course of atrial fibrillation (AF), however such therapy is associated with many inconveniences. New oral anticoagulants (NOAC), rivaroxaban and dabigatran, represent an attractive alternative to VKA. THE AIM OF THE STUDY: Yo evaluate the safety of a 6-month therapy with rivaroxaban and dabigatran in patients (pts) with persistent AF. MATERIALS AND METHODS: The analysis included 24 pts (14 females, 10 males) with nonvalvular AF and indications for oral anticoagulant therapy (CHA2DS2-VASc > or = 2, HAS-BLED < 3), hospitalized in the Clinic of Internal Diseases and Clinical Pharmacology of the Medical University of Lodz between July 2012 and September 2013. In the group of patients treated chronically with VKA, laboratory tests (GFR, creatinine, ALT AST, coagulation) were performed during their stay in the clinic. The patients were randomly assigned to the treatment with one of the new NOACs, rivaroxaban or dabigatran. After a 6-month period, the patients completed a questionnaire on their general health condition and follow-up laboratory tests were performed. RESULTS: In the group of pts. receiving dabigatran INR increased by 23% (p = 0.0002) and APTT prolongation by 91% was noted (p = 0.0004) whereas in the group of pts receiving rivaroxaban an INR increase by 17% (p = 0.04) and APTT prolongation by 32% (p = 0.0043) were observed. After a 6-month therapy, dabigatran prolongs APTT significantly more, as compared to rivaroxaban (p=0.0002). Among patients using dabigatran, 16.7% experienced the following symptoms: abdominal pain, gastritis, nausea. 8.3% patients experienced bleeding from haemorrhoids, easier bruising. In the group of patients receiving rivaroxaban, 16.7% experienced the following symptoms: nosebleeds and easier bruising; 8.3%: bleeding from gums, haematuria. 25%: pruritus, rash: 8.3%. The hazard ratio (HR) for occurrence of dyspeptic symptoms was 1.13 for dabigatran. Minor bleeding is 3.6 times more common when using rivaroxaban. CONCLUSIONS: Significant increase of INR and prolongation of APTT are observed after a 6-month therapy with rivaroxaban or dabigatran. Additionally, dabigatran significantly prolongs the prothrombin time. Despite the fact that dabigatran caused larger prolongation of APTT minor bleeding episodes occurred more frequently in patients treated with rivaroxaban. No worsening of kidney or liver function was observed during the 6-month therapy with rivaroxaban or dabigatran. Rywaroxaban more frequently causes minor bleeding, whereas treatment with dabigatran is associated with more frequent gastrointestinal adverse symptoms. PMID- 25546986 TI - [Smoking among patients with obstructive sleep apnea syndrome--preliminary report]. AB - Association of smoking with the occurrence and severity of the obstructive sleep apnea syndrome (OSAS) is poorly understood. THE AIM OF THE STUDY: The evaluation of smoking habits among the patients hospitalized with the suspicion and diagnosis of the OSAS. The possible relationship between smoking and severity of OSAS and the occurrence of concomitant diseases occurrence was also evaluated. MATERIAL AND METHODS: 82 patients has been included into the study: 11 without OSAS (apnea/hypopnea index-AHI < 5/hour) and 71 with OSAS of varying severity (AHI 7-74/hours). RESULTS: Forty six patients with OSAS were smokers or ex smokers, and 5 persons from a group without OSAS were ex-smokers. Patients with OSAS who smoked at least 20 pack years had significant higher AHI (54.5/h) than non-smokers (38.5/h) and patients smoking less than 20 pack years (35.9/h). These groups of patients did not differ according to BMI (36.8 kg/m2, 38.8 kg/m2, 36.3 kg/ms). Smokers with OSAS more frequently had concomitant cardiovascular diseases than non-smokers with OSAS (86.1% and 23.1% respectively). CONCLUSION: Smoking influences the severity of OSAS independently of the degree of obesity. PMID- 25546987 TI - [Incidence of complex metabolic disorders among young people--preliminary report]. AB - The incidence of metabolic disorders and predispositions to development of civilization diseases in general population is well known, but there is a little data about presence of these disorders among young, potentially healthy people. THE AIM OF STUDY: To conduct an assessment of incidence metabolically disorders among young people. MATERIALS AND METHODS: In examination 45 young volunteers, students of Wroclaw Medical University were included. At the beginning, each participant filled the questionnaire, then anthropometric measurements were made, and carbohydrate and lipid related laboratory parameters were determined in fasting serum or plasma. RESULTS: According to Polish Diagnostics Laboratory Association (PTDL), Polish Cardiology Association (PTK), Polish Diabetes Association (PTD), International Diabetes Federation (IDF) recommendations and data from publications, we have shown that the most participants (90%) had appropriate body mass (BMI<25 kg/m2), but more than one fourth of them characterized overly large waist circumference. The rarest observed disorder was the increased blood pressure and too low HDL cholesterol concentration (depending on the applied criteria), whereas insulin resistance was identified the most frequent. Occurrence of at least one of "classic" metabolic disorders was indicated in more than half of participants, whereas coexistence three or more these disorders in the same person was observed in 7% of volunteers. Metabolic syndrome was identified with the same frequency, while one fourth of participants showed features which enabled to diagnose MONW (metabolically obese normal weight). CONCLUSIONS: The complex metabolic disturbances were observed at very large percent of young, potentially health and not family burdened people. We concluded that it is necessary to undertake various actions, like screening examinations, including insulin resistance parameters, in purpose to early identification of these metabolic disturbances, especially towards diagnosis of MONW syndrome. PMID- 25546988 TI - [Welfare as the goal of the analgesic pharmacotherapy accompanying biological treatment in patients with rheumatoid arthritis and ankylosing spondylitis]. AB - Therapy of chronic rheumatic diseases, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS) needs a comprehensive approach to the patient, based on the control of pain and improvement in overall condition, which affects the quality-of-life. This requires optimizing the treatment with non-steroidal anti inflammatory drugs (NSAIDs) or analgesics and control of adverse drug reactions. The aim of the study was to evaluate the efficacy and safety of pain pharmacotherapy in patients with rheumatoid arthritis and ankylosing spondylitis treated as the basic pharmacotherapy-biological drugs, the analysis of awareness of pharmacovigilance and evaluation of analgesic treatment costs. Material and methods. Examined group consisted of 102 people with RA or AS received biological therapy. Test method was questionnaire with closed and open questions. Results. 86.2% of respondents used a pain medication (41%--an ad hoc basis, but 23%--at least once a day), while 79.4%--NSAIDs (33%--an ad hoc basis and 17%--at least once a day). In 85.3% of those not observed adverse effects of pain pharmacotherapy. 5 persons declared abdominal pain. Most of the patients complied with the recommendations of the doctor in the pain treatment. For the third respondents the cost of pharmacotherapy of pain was monthly 1-10 zl, but 6% of patients paying for drugs from 50-60 and above 60 zl monthly. Conclusions. Biological treatment in RA and AS is effective but requires additional analgesic therapy. Adverse effects seen during pharmacological treatment of chronic pain in rheumatic diseases are, in practice sporadic. Therapeutic patient education with chronic diseases is proper. Costs borne by the patient's pain relief in this group are not too high. PMID- 25546989 TI - [Impact of military service in Afghanistan on mental health of Polish soldiers]. AB - Many of the challenges they have to face the soldiers in Afghanistan acts as a specific stressors. They have been identified and defined during the past armed conflict. THE AIM OF THE STUDY: A preliminary analysis of the factors affecting the mental health of soldiers during their service in Afghanistan and determining ways to cope with stress by them, including the motivation to take medication. MATERIAL AND METHODS: The study was conducted under the conditions of the mission in Afghanistan and involved a group of 100 men aged 21-54 years (Wed 37.7 years). Analyses were based on questionnaires completed by soldiers twice in the conditions of the mission. RESULTS: Studies show that 73.3% of men in the study group were directly exposed to the loss of life, 40% knew someone who was injured or killed, 60% were direct witnesses of the death or life-threatening injury. 25% of soldiers deployed in Afghanistan led fire on the enemy, 3.3% were perpetrators of the death of enemy combatants. Furthermore, only 2% of the soldiers who have experienced health problems and seemed aware of them, were interested in receiving help. It seems that this was due to fear of soldiers before them as the perception of the mentally ill, which might be considered prejudicial to their career. CONCLUSIONS: The soldiers undergoing military service in Afghanistan are subject to the influence of multiple stressors of combat and operational, with a significant proportion of stressors carrying a direct threat to health and life. Stressors of the battlefield have modulatory effects on the process of adaptation by increasing the use of such coping styles that lead to developing a sense of security. Wrong attitudes and beliefs about the stress soldiers translate negatively to search for assistance and additional help in overcoming the effects of stress. Recognizing the impact of stressors and injuries resulting from the new course of the service can help to raise awareness of soldiers returning home, as well as families prepare for their return. PMID- 25546990 TI - Cardiac arrest and electrical storm due to recurrent torsades de pointes caused by concomitant clarithromycin, cotrimoxazole and amiodarone treatment. AB - Torsades de pointes (TdP) is a rapid, polymorphic and usually self-terminating ventricular tachycardia associated with the long QT syndrome. Many drugs may cause prolongation of QT interval and be the trigger for TdP occurrence. We present the case of 52-year-old male who was treated with clarithromycin due to bilateral atypical pneumonia. However, on the fourth day of hospitalization he deteriorated, developed pulmonary edema and short cardiac arrest. After successful resuscitation, unfortunately amiodarone and co-trimoxazole were given causing the arrhythmic storm which required many defibrillations. The case highlights the importance of careful QT measurement, appropriate TdP treatment and difficulties resulting from the patient's disagreement for invasive treatment. We think, that knowledge of drug-induced long QT syndrome and its consequences should be widely spread not only in cardiologists, but also in others doctors. PMID- 25546991 TI - [Difficulty in diagnosis of primary hyperaldosteronism as the cause of resistant hypertension and severe hypokalemia--case report]. AB - The most common endocrinological cause of secondary hypertension is primary hyperaldosteronism. Despite great progress in laboratory and imaging techniques, its identification is often difficult. We report the case of the 52-year-old man with resistant hypertension and severe hypokalemia. Renovascular hypertension, Cushing syndrome and pheochromocytoma were excluded as potential causes of drug resistant hypertension in the presented case. Renal potassium excretion was significantly high. The results of plasma aldosterone concentration measured in supine position as well as in standing position were ambiguous. Computed tomography revealed abnormal round solid mass with a maximum diameter of 11 mm in the left adrenal. As there were not diagnostic results of laboratory research and ambiguous character of pathological structure in research computed tomography we have decided to carry adrenal cortex scintigraphy with iodomethyl-norcholesterol 131I. The result of this research was consistent with left adrenal scan of computed tomography and left adrenal adenoma has been confirmed. Normal blood pressure and normokalemia were restored after surgical treatment. PMID- 25546992 TI - [Atrial fibrillation in athletes]. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting up to 1 1.5% of the population. Regular physical activity reduces the risk of cardiovascular diseases, however several studies have shown paradoxically increased incidence of AF in people practicing sport, especially in elite athletes. The results of studies suggest a U-shape relationship between sport and risk of arrhythmia. Minor regular exertion protects from arrhythmia through reduction in AF risk factors, while intense physical activity increases the risk of arrhythmia. The etiopathogenesis of arrhythmia in athletes has not been fully elucidated yet, but it is definitely multifactorial. Arrhythmia's occurrence may be related to adaptative remodeling of a heart, autonomic nervous system alteration as well as may be associated with other factors like inflammation or dyselectrolitaemia. Atrial Fibrillation in athletes should always be considered as an abnormality which requires further investigation as in small percentage of cases arrhythmia may be the first manifestation of a structural heart disease or chanellopathy potentially leading to sudden cardiac death. Taking into account several problems related to pharmacotherapy, AF ablation has become the first line treatment in athletes. PMID- 25546993 TI - [The ability to pharmacological control of anemia and thrombocytopenia in patients with acute coronary syndromes]. AB - Recently, attention has been paid to anemia (decreased number of red blood cells in peripheral blood and less than the normal quantity of hemoglobin) apart from the traditional methods used in determining prognosis in patients with acute cardiac syndrome (ACS). Thrombocytopenia and increased mean platelet volume (MPV) are listed among other--yet simple--laboratory blood tests which have prognostic significance in patients with ACS. In ACS patients it is necessary to distinguish between anemia which is established on admission to hospital (chronic anemia) and that acquired in the hospital (HAA). Anemia diagnosed on admission is an independent predictor of in-hospital mortality, short term and long term. In tum, hospital-acquired anemia is associated with the increase of in-hospital mortality, which further increases with greater decrease in Hb concentration. The prognostic value of Hb concentration was evaluated among others in patients with myocardial infarction. There was no beneficial effect of erythropoietin in patients with STEMI undergoing PCI, on the contrary, the increase of the adverse cardiovascular events and the risk of thromboembolic events was observed in selected groups of patients. The need of the administration of iron preparations is indicated in the case of anemia associated with iron deficiency or due to major bleeding. It was found that in patients with ACS even mild thrombocytopenia increases the risk of bleeding complications and in-hospital mortality, the risk of reinfarction, cardiogenic shock and stroke. Worse prognosis in patients with ACS is also associated with a decreased platelet count on admission to hospital and with increased mean platelet volume. In patients with ACS, we deal with heparin-induced thrombocytopenia or thrombocytopenia caused by the use of antiplatelet agents. The treatment of these causes of thrombocytopenia is an important issue. Increased platelet reactivity is observed in patients with increased MPV. This results in the development of restenosis, worse blood flow after PCI, in the increase in mortality and a higher incidence of the phenomenon of "no-reflow". The use of abciximab in STEMI and NSTEMI was associated with a decrease in MPV. Statins also caused a significant decrease in MPV. PMID- 25546994 TI - [Stigmatization in psoriasis patients]. AB - Psoriasis is a chronic disease that affects the skin, nail plates and/or joints in which correlation between the onset of skin changes or more severe symptoms and the psychical condition of a patient is observed. At present it is assumed that stigmatization are events and situations in a person's life that are recognized by the society as those that stigmatize a given person and lead to their rejection and finally downgrade and ruin their social status. Opinions and behaviour patterns of the members of the society create the sigma feeling in a patient and affect his/her psyche. The aim of the present paper is the analysis of the latest data presented in the literature on the sigma feeling in psoriasis patients. In the study, the analysis of the types of stigmatization experienced by patients has been carried out. Life events influence the severity of psoriatic changes, but also psoriasis as a somatic disease affects the everyday life of a patient. Some reactions and behaviours of other people may create the feeling of rejection in social situations and the subjective feeling of being stigmatized. Then, as a result of the sigma feeling, the general health condition, functioning in the society and quality of life are affected. PMID- 25546995 TI - [Modern immunological and clinical determinants of virus dengue infection]. AB - The growing problem of widespread viral infections is a challenge for modern medicine. Emerging reports of dengue virus infections in Europe create a new epidemic problem. The virus responsible for causing the symptoms of the disease is transmitted by mosquitoes. Over 50% of the world's population lives in areas where the risk of dengue feveris high. In total, according to WHO, infected with dengue is 2.4 million people and outbreaks of endemic diseases are present in 100 countries that threaten the 2.5 billion population. There are four serotypes of dengue virus, which belong to the family Flaviviridae and the type of Flavirus. Serotypes are known as DENV-1, DENV-2, DENV-3 and DENV-4. Contact each of the serotypes of the virus causes long-lasting resistance to the other, and each of them is responsible for the induction of disease epidemics, including severe cases. In the first stage of the disease should seek to replace lost fluids and electrolytes. Because of the elevated body temperature is recommended to administer paracetamol formulations and the use of cold compresses. Contraindicated is the use of aspirin and non-steroidal anti-inflammatory drugs. In severe forms of dengue patients absolutely should be hospitalized and treatment in the intensive care centers. In the treatment of shock, it is recommended that the administration of isotonic crystalloid fluids at 5-10 ml/kg/hr. under the control of hematocrit and fill peripheral microcirculation. The administration of blood products for the large current is required to control bleeding. Dengue vaccine containing DEN-DEN chimeras is still at the stage of preclinical studies. PMID- 25546996 TI - [The story of biosimilars--chance or threat?]. AB - Patent protection on some key biologic drugs is going to expire soon. Therefore, chances are rising for biopharmaceutical manufacturers to develop and market biosimilars (follow-on biologics). These drugs are approved when similarity to reference biological medicine is proven: in terms of quality, safety or efficacy. In September 2013 European Medicines Agency authorized the first biosimilar monoclonal antibody-infliximab. Doubts considering follow-on biologics are related to their safety and efficacy. The majority of them are associated with the new phenomenon for biological products in clinical use and drug approval processes. These are: extrapolation of indications, immunogenicity and interchangeability. The case of interchangeability poses a threat that it would be impossible to determine which drug is responsible for adverse event, even if brand names and batch numbers of reference and biosimilar products are known. Biosimilar product is authorized if it has shown efficacy and safety in some of indications. When approved, its use will be extrapolated on other indications of the reference product. The aim of following article is to describe some current issues on biosimilars safety, approval procedures and legal solutions in Poland. PMID- 25546997 TI - Hansteen's magnetometer and the origin of the magnetic crusade. AB - In the early nineteenth century, Norwegian mathematician and astronomer Christopher Hansteen (1784-1873) contributed significantly to international collaboration in the study of terrestrial magnetism. In particular, Hansteen was influential in the origin and orientation of the magnetic lobby in Britain, a campaign which resulted in a global network of fixed geomagnetic observatories. In retrospect, however, his contribution was diminished, because his four-pole theory in Untersuchungen der Magnetismus der Erde (1819) was ultimately refuted by Carl Friedrich Gauss in Allgemeine Theorie des Erdmagnetismus (1839). Yet Hansteen's main contribution was practical rather than theoretical. His major impact was related to the circulation of his instruments and techniques. From the mid-1820s, 'Hansteen's magnetometer' was distributed all over the British Isles and throughout the international scientific community devoted to studying terrestrial magnetism. Thus in the decades before the magnetic crusade, Hansteen had established an international system of observation, standardization and representation based on measurements with his small and portable magnetometers. PMID- 25546998 TI - A British national observatory: the building of the New Physical Observatory at Greenwich, 1889-1898. AB - Over its long history, the buildings of the Royal Observatory in Greenwich were enlarged and altered many times, reflecting changing needs and expectations of astronomers and funders, but also the constraints of a limited site and small budgets. The most significant expansion took place in the late nineteenth century, overseen by the eighth Astronomer Royal, William Christie, a programme that is put in the context of changing attitudes toward scientific funding, Christie's ambitious plans for the work and staffing of the Observatory and his desire to develop a national institution that could stand with more recently founded European and American rivals. Examination of the archives reveals the range of strategies Christie was required to use to acquire consent and financial backing from the Admiralty, as well as his opportunistic approach. While hindsight might lead to criticism of his decisions, Christie eventually succeeded in completing a large building - the New Physical Observatory - that, in its decoration, celebrated Greenwich's past while, in its name, style, structure and contents, it was intended to signal the institution's modernization and future promise. PMID- 25546999 TI - 'A thorn in the side of European geodesy': measuring Paris-Greenwich longitude by electric telegraph. AB - The difference in longitude between the observatories of Paris and Greenwich was long of fundamental importance to geodesy, navigation and timekeeping. Measured many times and by many different means since the seventeenth century, the preferred method of the later nineteenth and early twentieth centuries made use of the electric telegraph. I describe here for the first time the four Paris Greenwich telegraphic longitude determinations made between 1854 and 1902. Despite contemporary faith in the new technique, the first was soon found to be inaccurate; the second was a failure, ending in Anglo-French dispute over whose result was to be trusted; the third failed in exactly the same way; and when eventually the fourth was presented as a success, the evidence for that success was far from clear-cut. I use this as a case study in precision measurement, showing how mutual grounding between different measurement techniques, in the search for agreement between them, was an important force for change and improvement. I also show that better precision had more to do with the gradually improving methods of astronomical, time determination than with the singular innovation of the telegraph, thus emphasizing the importance of what have been described as 'observatory techniques' to nineteenth-century practices of precision measurement. PMID- 25547000 TI - Paolo Sarpi and the first Copernican tidal theory. AB - Despite his demanding religious responsibilities, Paolo Sarpi maintained an active involvement in science between 1578 and 1598- as his Pensieri reveal. They show that from 1585 onwards he studied the Copernican theory and recorded arguments in its favour. The fact that for 1595 they include an outline of a Copernican tidal theory resembling Galileo's Dialogue theory is well known. But examined closely, Sarpi's theory is found to be different from that of the Dialogue in several important respects. That Sarpi was a Copernican by 1592 is revealed by other of his pensieri, whereas at that time we know that Galileo was not. The examination of Sarpi's tidal theory and of the work of Galileo in this period indicates that the theory Sarpi recorded in 1595 was of his own creation. The appreciation that the theory was Sarpi's and that Galileo subsequently came to change his views on the Copernican theory and adopted the tidal theory has major implications for our understanding of the significance of Sarpi's contribution to the Scientific Revolution. Moreover, it appears that several of the most significant theoretical features of the tidal theory published by Galileo in the Dialogue - and which proved of lasting value - were in reality Sarpi's. PMID- 25547001 TI - The power of partnerships: the Liverpool school of butterfly and medical genetics. AB - From the 1950s to the 1970s, a group of physician-researchers forming the 'Liverpool school' made groundbreaking contributions in such diverse areas as the genetics of Lepidoptera and human medical genetics. The success of this group can be attributed to the several different, but interconnected, research partnerships that Liverpool physician Cyril Clarke established with Philip Sheppard, Victor McKusick at Johns Hopkins University, the Nuffield Foundation, and his wife FCo. Despite its notable successes, among them the discovery of the method to prevent Rhesus haemolytic disease of the newborn, the Liverpool School began to lose prominence in the mid-1970s, just as the field of medical genetics that it had helped pioneer began to grow. This paper explores the role of partnerships in making possible the Liverpool school's scientific and medical achievements, and also in contributing to its decline. PMID- 25547002 TI - Elite science and the BBC: a 1950s contest of ownership. AB - In the late 1950s and early 1960s, the elite world of institutional British science attempted to take control of the BBC's management of science broadcasting. Delegations of scientists met BBC managers to propose an increased role for scientists in planning science broadcasts to a degree that threatened to compromise the BBC's authority and autonomy. The culmination was a set of proposals to the Pilkington Committee in 1960, principally from the Royal Society and the British Association for the Advancement of Science, under which a scientist-manager was to be appointed head of a unified science division in the BBC. BBC managers resisted these proposals. The outcome, in 1964, was a compromise giving the scientists little of what they wanted, and proving practically and strategically useful for the BBC. The article frames the story as a contest of jurisdiction between elite science and the BBC, and draws on scholarship relating to the social nature of authority and professions, and to the popularization of science. It shows the fundamentally different beliefs held by the scientists and the BBC about the purpose of science broadcasts and about the nature of the audience. The historical narrative is based on unpublished archive documents, and it contributes to the small but growing body of work on the historical background to the presentation of science in the broadcast media. PMID- 25547004 TI - First report of Kocuria marina spontaneous peritonitis in a child. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a rare affection in the pediatric population. It usually occurs when concurrent conditions are present, such as nephrotic syndrome, peritoneal dialysis or liver disease. We report a case of spontaneous bacterial peritonitis due to Kocuria marina in a 2-year-old child with no underlying risk factor. This is both the first description of an infection caused by this rare pathogen in a child and the first reported case of primary peritonitis caused by K. marina in a patient with no predisposing condition. CASE PRESENTATION: A 2 year-old boy presented to the Pediatric Emergency Department with clinical signs of peritonitis. Laparoscopic surgical exploration confirmed purulent, generalized peritonitis without perforation. Culture of the peritoneal fluid revealed the presence of Kocuria marina, a Gram positive coccoid environmental bacteria. After peritoneal lavage and appropriate antibiotic treatment, the patient improved and was discharged without sequel. CONCLUSION: The present report illustrates the first clinical presentation of Kocuria marina SBP in a child with no underlying risk factor. Although never previously described in healthy patients, this pathogen may therefore be considered as a possible cause of SBP in a child. This unusual finding extends the spectrum of infectious diseases caused by Kocuria marina beyond the scope of the previously described susceptible population. PMID- 25547003 TI - Preliminary investigation of intraperitoneal raltitrexed in patients with gastric cancer. AB - BACKGROUND: Peritoneal implantation metastasis of gastric cancer is the major reason for cancer recurrence after radical operations. As a new chemotherapeutic agent, raltitrexed has been widely used in intravenous chemotherapy for many kinds of cancers. However, no study has reported the efficacy and safety of raltitrexed in intraperitoneal chemotherapy. This study aimed to explore the safety of intraperitoneal chemotherapy with raltitrexed during gastric cancer operation compared to normal saline (NS) rinsing of the abdominal cavity. METHODS: In this prospective study, 91 gastric cancer patients undergoing surgery and reconstruction were consecutively enrolled and randomly assigned into two groups. Raltitrexed in NS (500 ml) was injected into the abdominopelvic cavity for the patients in the RT group (n = 48), while for the patients in the group NS (n = 43), only NS (500 ml) was injected. The postoperative complications, gas passage time, and adverse effects, according to NCI-CTCAE v3.0, were compared between the two groups. RESULTS: There were no significant differences in age, sex, cancer pathological type, clinical stage or operation method between the two groups (all P >0.05). No significant difference was observed in adverse effects and postoperative complications between the two groups (all P >0.05). No significant change was found in the levels of red blood cells, white blood cells, platelets, lactate dehydrogenase, blood urea nitrogen, and alanine aminotransferase before and after the operation for both groups (all P >0.05). All adverse events were mild or moderate by NCI-CTCAE v3.0 (National Cancer Institute common terminology criteria for adverse events) grade. CONCLUSIONS: The findings of the present study demonstrate that intraperitoneal chemotherapy with raltitrexed after gastric cancer operation is safe and could be used for patients. PMID- 25547005 TI - Yeast cells-derived hollow core/shell heteroatom-doped carbon microparticles for sustainable electrocatalysis. AB - The use of renewable resources to make various synthetic materials is increasing in order to meet some of our sustainability challenges. Yeast is one of the most common household ingredients, which is cheap and easy to reproduce. Herein we report that yeast cells can be thermally transformed into hollow, core-shell heteroatom-doped carbon microparticles that can effectively electrocatalyze the oxygen reduction and hydrazine oxidation reactions, reactions that are highly pertinent to fuel cells or renewable energy applications. We also show that yeast cell walls, which can easily be separated from the cells, can produce carbon materials with electrocatalytic activity for both reactions, albeit with lower activity compared with the ones obtained from intact yeast cells. The results reveal that the intracellular components of the yeast cells such as proteins, phospholipids, DNAs and RNAs are indirectly responsible for the latter's higher electrocatalytic activity, by providing it with more heteroatom dopants. The synthetic method we report here can serve as a general route for the synthesis of (electro)catalysts using microorganisms as raw materials. PMID- 25547006 TI - Are antagonistic salts surfactants? AB - It is well known that surfactants decrease both water/air and water/oil interfacial tensions whereas in contrast inorganic salts increase both. We study a new, third class of surface-active ionic solutes, which have been called antagonistic salts, consisting of an organic group with a small inorganic counterion. These show decreased interfacial tension at the oil/water interface due to a redistribution of the organic group in the oil but do not show any surface activity at the air/water interface and are consequently different from surfactants that lower both tensions. We use a simple modeling using Poisson Boltzmann theory that accounts for the surface activity of the antagonistic salt at the water/oil interface. PMID- 25547007 TI - Unusual imaging finding of a "fluid-fluid" level in a neurenteric cyst at anterior margin of the cervico-medullary junction. AB - Intracranial neurenteric cysts are rare. Diagnosis can only be established on histopathology with the demonstration of mucin-secreting cells in cyst wall. We report a midline, ventral, cystic lesion at the cervico-medullary junction, with the unusual radiological finding of a "fluid-fluid" level. Intraoperatively, the cyst contained fluid along with pus-like material with white flakes and specks of calcification, suggesting a dermoid cyst. However, histopathology confirmed the diagnosis of neurenteric cyst. The patient was managed with right lateral inferior suboccipital approach and near-total excision of the lesion. PMID- 25547009 TI - Hearing impairment among adults: the impact of cardiovascular diseases and cardiovascular risk factors. AB - OBJECTIVE: To investigate the influence of cardiovascular diseases on hearing impairment (HI) among adults. Furthermore, to seek other potential risk factors for HI, such as smoking, obesity, and socioeconomic class. DESIGN: A cross sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Cardiovascular diseases did not increase the risk for HI in a propensity-score adjusted logistic regression model: OR 1.24, 95% CI 0.79 to 1.96 for HI defined by better ear hearing level (BEHL), and OR 1.48, 95% CI 0.96 to 2.28 for HI defined by worse ear hearing level (WEHL), in the 0.5-4 kHz frequency range. Heavy smoking is a risk factor for HI among men (BEHL: OR 1.96, WEHL: OR 1.88) and women (WEHL: OR 2.4). Among men, obesity (BEHL, OR 1.85) and lower socioeconomic class (BEHL: OR 2.79, WEHL: OR 2.28) are also risk factors for HI. CONCLUSION: No significant association between cardiovascular disease and HI was found. PMID- 25547008 TI - An engineered autotransporter-based surface expression vector enables efficient display of Affibody molecules on OmpT-negative E. coli as well as protease mediated secretion in OmpT-positive strains. AB - BACKGROUND: Cell display technologies (e.g. bacterial display) are attractive in directed evolution as they provide the option to use flow-cytometric cell sorting for selection from combinatorial libraries. The aim of this study was to engineer and investigate an expression vector system with dual functionalities: i) recombinant display of Affibody libraries on Escherichia coli for directed evolution and ii) small scale secreted production of candidate affinity proteins, allowing initial downstream characterizations prior to subcloning. Autotransporters form a class of surface proteins in Gram-negative bacteria that have potential for efficient translocation and tethering of recombinant passenger proteins to the outer membrane. We engineered a bacterial display vector based on the E. coli AIDA-I autotransporter for anchoring to the bacterial surface. Potential advantages of employing autotransporters combined with E. coli as host include: high surface expression level, high transformation frequency, alternative promoter systems available, efficient translocation to the outer membrane and tolerance for large multi-domain passenger proteins. RESULTS: The new vector was designed to comprise an expression cassette encoding for an Affibody molecule, three albumin binding domains for monitoring of surface expression levels, an Outer membrane Protease T (OmpT) recognition site for potential protease-mediated secretion of displayed affinity proteins and a histidine-tag for purification. A panel of vectors with different promoters were generated and evaluated, and suitable cultivation conditions were investigated. The results demonstrated a high surface expression level of the different evaluated Affibody molecules, high correlation between target binding and surface expression level, high signal-to-background ratio, efficient secretion and purification of binders in OmpT-positive hosts as well as tight regulation of surface expression for the titratable promoters. Importantly, a mock selection using FACS from a 1:100,000 background yielded around 20,000-fold enrichment in a single round and high viability of the isolated bacteria after sorting. CONCLUSIONS: The new expression vectors are promising for combinatorial engineering of Affibody molecules and the strategy for small-scale production of soluble recombinant proteins has the potential to increase throughput of the entire discovery process. PMID- 25547010 TI - College students' personal listening device usage and knowledge. AB - OBJECTIVE: To determine the usage and knowledge of safe limits on personal listening devices (PLD) among college students. DESIGN: First, information on health history was collected. Second, microphone in real ear techniques determined eardrum to free-field correction factors. Third, hearing levels were evaluated and information gathered about knowledge of safe listening behaviors. STUDY SAMPLE: 180 college students participated in a one-hour session using their PLDs and earphones set to their personal preference. RESULTS: Virtually all participants reported knowledge of hearing loss risk due to PLD use and accurately recognized their own PLD listening levels (p = .01) as either within or exceeding safe sound limits. Forty-four subjects listened at greater than 80 dBA free-field equivalent levels. Only 7% of these participants were aware of these hazardous levels and 15% of participants' exposure surpassed free-field equivalent levels normalized to eight hours. CONCLUSIONS: Despite reported knowledge of hearing loss risk due to PLD use in virtually all college students, 1 in 4 were found to listen to their PLDs at free-field equivalent levels greater than 80-dBA, with 94% unaware of their potential risk. Further research is needed to provide accurate PLD listening information and evaluate the possibility of long term PLD intensities that surpass recommended safety levels on hearing loss in adults over time. PMID- 25547011 TI - An integrated network visualization framework towards metabolic engineering applications. AB - BACKGROUND: Over the last years, several methods for the phenotype simulation of microorganisms, under specified genetic and environmental conditions have been proposed, in the context of Metabolic Engineering (ME). These methods provided insight on the functioning of microbial metabolism and played a key role in the design of genetic modifications that can lead to strains of industrial interest. On the other hand, in the context of Systems Biology research, biological network visualization has reinforced its role as a core tool in understanding biological processes. However, it has been scarcely used to foster ME related methods, in spite of the acknowledged potential. RESULTS: In this work, an open-source software that aims to fill the gap between ME and metabolic network visualization is proposed, in the form of a plugin to the OptFlux ME platform. The framework is based on an abstract layer, where the network is represented as a bipartite graph containing minimal information about the underlying entities and their desired relative placement. The framework provides input/output support for networks specified in standard formats, such as XGMML, SBGN or SBML, providing a connection to genome-scale metabolic models. An user-interface makes it possible to edit, manipulate and query nodes in the network, providing tools to visualize diverse effects, including visual filters and aspect changing (e.g. colors, shapes and sizes). These tools are particularly interesting for ME, since they allow overlaying phenotype simulation results or elementary flux modes over the networks. CONCLUSIONS: The framework and its source code are freely available, together with documentation and other resources, being illustrated with well documented case studies. PMID- 25547017 TI - MicroRNA-130b regulates scleroderma fibrosis by targeting peroxisome proliferator activated receptor gamma. AB - OBJECTIVES: To investigate the role of microRNA-130b (miR-130b) in systemic sclerosis (SSc) skin fibrosis and its regulatory effect on peroxisome proliferator-activated receptor gamma (PPARgamma). METHODS: miR-130b was identified from microarray analyses in our previous studies. The expression of miR-130b, PPARgamma, and fibrosis-related genes were determined by real-time PCR analysis. PPARgamma protein levels were detected by immunohistochemistry and Western blot. Cells were transfected with microRNA mimics/inhibitor/scramble of miR-130b using Lipofectamine. Luciferase reporter gene assays were used to identify the direct target of miR-130b. Transforming growth factor beta (TGF beta) was used for stimulation. RESULTS: The expression of miR-130b was significantly upregulated and level of PPARgamma was decreased in the dermis of the SSc skin biopsy samples and fibroblasts. Similar to human SSc, the same expression patterns of miR-130b, PPARgamma, and fibrosis-related genes were observed in the bleomycin-induced skin fibrosis model; TGF-beta induced the expression of miR-130b and fibrosis-related genes expression, but downregulated the expression of PPARgamma. Overexpression of miR-130b in normal or SSc skin fibroblasts significantly decreased, and accordingly, knockdown of miR-130b increased the levels of PPARgamma and fibrosis-related genes. In the reporter gene assay, cotransfection with miR-130b mimics significantly decreased the relative luciferase activity, which suggested a direct regulation of PPARgamma by miR-130b. CONCLUSIONS: These studies demonstrated that miR-130b played important profibrotic roles in SSc fibrosis, and enhanced TGF-beta signaling through negative regulation of PPARgamma expression. MiR-130b may be a potential therapeutic target in SSc fibrosis. PMID- 25547018 TI - Cost-effectiveness of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, versus methotrexate in patients with rheumatoid arthritis using real-world data from the IORRA observational cohort study. AB - OBJECTIVES: To evaluate the cost-effectiveness of tocilizumab in patients with rheumatoid arthritis (RA) in a real-world setting in Japan. METHODS: The cost effectiveness was determined using a Markov model-based probabilistic simulation. Data from RA patients registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study between April 2007 and April 2011 were extracted using a pair-matching method: tocilizumab group (n = 104), patients who used at least 1 disease-modifying anti- rheumatic drug and in whom tocilizumab treatment was initiated; methotrexate group (n = 104), patients in whom methotrexate treatment was initiated for the first time or after an interruption of 6 or more months. Assuming a 6-month cycle length, health benefits and costs were measured over a lifetime and discounted at an annual rate of 3%. RESULTS: Compared with methotrexate treatment, lifetime costs and quality-adjusted life years (QALYs) for tocilizumab treatment were approximately 1.5- and 1.3-times higher, respectively. Incremental cost per QALY gained with tocilizumab was $49,359, which was below the assumed cost-effectiveness threshold of $50,000 per QALY. The probability of tocilizumab being cost- effective was 62.2%. CONCLUSION: The simulation model using real-world data from Japan showed that tocilizumab (at a certain price) may improve treatment cost-effectiveness in patients with moderate to-severe RA by enhancing quality-adjusted life expectancy. PMID- 25547019 TI - Immunohistological analysis for immunological response and mechanism of interstitial fibrosis in IgG4-related kidney disease. AB - OBJECTIVES: Our study aimed to clarify the immunological characteristics and the mechanism of interstitial fibrosis in immunoglobulin G4-related kidney disease (IgG4-RKD) by the immunohistological analysis. METHODS: Immunohistological study was performed in the biopsied renal tissues of 16 IgG4-RKD, 16 Sjogren syndrome (SJS), and 17 idiopathic tubulointerstitial nephritis (ITIN) patients using antibodies against IgG; IgG1; IgG4; CD38; CD3; C-X-C chemokine receptor type 3 (CXCR3); chemokine (C-C motif) receptor 4 (CCR4); forkhead box 3 (Foxp3); Type I, Type III, Type IV, and Type VI collagens; and transforming growth factor (TGF) beta1. RESULTS: Interstitial lymphoplasmacytic and eosinophilic infiltration and the severity of interstitial fibrosis were greater in IgG4-RKD than SJS and ITIN. The ratio of CXCR3+/CD3 + cells was greater in SJS as compared with that in IgG4 RKD and ITIN. The ratio of CCR4+/CD3 + cells was not different among the three diseases. The ratio of interstitial IgG4+/IgG+ plasma cells, Foxp3+/CD3 + cells, and TGF-beta1 + cells/total infiltrating cells was higher in IgG4-RKD than SJS and ITIN. There was a positive correlation between the ratio of Foxp3+/CD3 + cells and that of IgG4+/IgG+ plasma cells in IgG4-RKD. Significant correlation was found between the ratio of Foxp3+/CD3 + cells and that of TGF-beta1 + cells/total infiltrating cells in IgG4-RKD. Foxp3 + cells and TGF-beta1 + cells were colocalized in the interstitium in IgG4-RKD. The significant correlation between the ratio of TGF-beta1 + cells/total infiltrating cells and the severity of fibrosis was noticed in IgG4-RKD. The interstitial distribution of type III collagen and type IV collagen was higher in IgG4-RKD than in SJS. CONCLUSIONS: Our results suggest that regulatory T-cells (Tregs) may play a central role in IgG4 production in the interstitium and TGF-beta1 induced by Tregs may play a pivotal role in the interstitial fibrosis including type III and type IV collagens in IgG4-RKD. PMID- 25547020 TI - Chalcogen bonds in complexes of SOXY (X, Y = F, Cl) with nitrogen bases. AB - SOF2, SOFCl, and SOCl2 were each paired with a series of N bases. The potential energy surface of the binary complexes were characterized by MP2 calculations with double and triple-xi basis sets, extrapolated to complete sets. The most stable configurations contained a S...N chalcogen bond with interaction energies as high as 6.8 kcal/mol. These structures are stabilized by a Nlp -> sigma*(S-Z) electron transfer (Z = O, F, Cl), complemented by Coulombic attraction of N to the sigma-hole opposite the Z atom. N...S-F and N...S-Cl chalcogen bonds are stronger than N...S?O interactions. Formation of each chalcogen bond elongates all of the internal covalent bonds within SOXY, especially the S-Cl bond. Halogen bonded (N...Cl-S) complexes were also observed, but these are more weakly bound, by less than 3 kcal/mol. PMID- 25547021 TI - Experiences of older adults in transition from hospital to community. AB - This study examined how patients experience transitions to community from hospitals, inclusive of daily living problems and medical concerns. Analysing qualitative data from interviews with 36 individuals including 17 high-risk older adults with multiple chronic health conditions recently discharged from hospital, and 19 family members who provided the patients with ongoing care, we asked (1) What are the challenges that patients experience in transitioning home from the hospital, and (2) What are the system and policy solutions that can address the challenges these patients experience? Our findings reveal both short- and long term challenges associated with transitions back home. Short-term challenges include preparing the dwelling for the patient and understanding the organization of care at home. Long-term challenges are associated with practical and emotional concerns. Reflecting on our findings, we suggest that patients' social needs may be equally important to their medical needs during post-discharge recovery, and we discuss implications for policy. PMID- 25547022 TI - Patient-specific bone modeling and analysis: the role of integration and automation in clinical adoption. AB - Patient-specific analysis of bones is considered an important tool for diagnosis and treatment of skeletal diseases and for clinical research aimed at understanding the etiology of skeletal diseases and the effects of different types of treatment on their progress. In this article, we discuss how integration of several important components enables accurate and cost-effective patient specific bone analysis, focusing primarily on patient-specific finite element (FE) modeling of bones. First, the different components are briefly reviewed. Then, two important aspects of patient-specific FE modeling, namely integration of modeling components and automation of modeling approaches, are discussed. We conclude with a section on validation of patient-specific modeling results, possible applications of patient-specific modeling procedures, current limitations of the modeling approaches, and possible areas for future research. PMID- 25547023 TI - In memory of Rik Huiskes. PMID- 25547024 TI - Numerical analysis of hemodynamic changes in the left atrium due to atrial fibrillation. AB - Atrial fibrillation (AF) disrupts movement of the left atrium (LA) and worsens the vital prognosis by causing thromboembolism. Ultrasound Doppler measurement, phase-contrast magnetic resonance imaging (PC MRI), as well as computational fluid dynamics (CFD) have revealed hemodynamic changes in the LA due to AF, such as stagnation of blood flow in the left atrial appendage (LAA). However, quantitative evaluation of the hemodynamics during AF has not been conducted, and the effects of important AF characteristics, such as a lack of active contraction of the LA (atrial kick) in late diastole and the occurrence of high-frequency fibrillation (>400bpm) of the atrial wall, on blood flow field and concomitant hemodynamic stresses have not been completely understood. In this study, the effects of the above-mentioned two characteristic phenomena of AF on blood flow and hemodynamic parameters were quantitatively investigated. Based on MRI of a healthy volunteer heart, one healthy LA model and two AF models (one without atrial kick, and one without atrial kick and with high-frequency fibrillation) were constructed to perform hemodynamic analysis, and the computational results were compared. The results revealed that each characteristic phenomenon of AF influenced hemodynamics. Especially, atrial wall movement by high-frequency fibrillation had a large impact on the stagnation of blood flow. The relative residence time (RRT), which is an indicator of stagnation of blood flow, increased in the upper part of the LAA during AF. This result implies that there is a local thrombus-prone site in LAA when AF occurs. PMID- 25547025 TI - Centre of pressure or centre of mass feedback in mediolateral balance assessment. AB - The mediolateral balance assessment method (MELBA) consists of tracking a sinusoidal or multisine target with the center of pressure as feedback (CoPfb). The aim of the CoP trajectory is to elicit weight-shifting, i.e. movement of the center of mass (CoM). However, it is not known whether CoPfb elicits consistent mediolateral displacements of the CoM, whether CoM feedback (CoMfb) is required to achieve this and whether CoPfb or CoMfb elicit different kinematic strategies. The aims of this study were to determine (1) the extent to which CoP imposes CoM displacements (CoMd) during CoPfb, (2) whether larger CoMd are elicited by CoMfb and (3) whether different kinematic strategies arise when using CoPfb or CoMfb. Nineteen young adults performed MELBA with CoPfb and CoMfb from which coherence, gain and phase-shift between CoP-CoM and leg-trunk kinematics were calculated. CoMd and CoPd and leg and trunk excursions were also calculated. Results show that for CoPfb tasks, CoP-CoM coherence was high, while the gain dropped with increasing frequency. The drop in gain was highly consistent between subjects. Reasonable trunk-leg coherence (~.6) was found over all frequencies and tasks. The leg-trunk angle gain increased with frequency in all tasks and was significantly higher in the CoMfb compared to the CoPfb. Significant interaction indicated that this difference increased with frequency. CoPfb in MELBA elicits consistent CoMd. However, different kinematics are employed in CoMfb with more trunk movement and an ankle-to-hip shift as frequency increases. Hence CoMfb may be preferable over CoPfb despite the larger measurement effort involved. PMID- 25547026 TI - Non-invasive assessment of functional strain lines in the real human left ventricle via speckle tracking echocardiography. AB - A mechanics-based analysis of data from three-dimensional speckle tracking echocardiography is proposed, aimed at investigating deformations in myocardium and at assessing shape and function of distinct strain lines corresponding to the principal strain lines of the cardiac tissue. The analysis is based on the application of a protocol of measurement of the endocardial and epicardial principal strain lines, which was already tested on simulated left ventricles. In contrast with similar studies, it is established that endocardial principal strain lines cannot be identified with any structural fibers, not even along the systolic phase and is suggested that it is due to the capacity of the endocardial surface to contrast the dilation of the left ventricle. PMID- 25547027 TI - Genetic relatedness among indigenous rice varieties in the Eastern Himalayan region based on nucleotide sequences of the Waxy gene. AB - BACKGROUND: Indigenous rice varieties in the Eastern Himalayan region of Northeast India are traditionally classified into sali, boro and jum ecotypes based on geographical locality and the season of cultivation. In this study, we used DNA sequence data from the Waxy (Wx) gene to infer the genetic relatedness among indigenous rice varieties in Northeast India and to assess the genetic distinctiveness of ecotypes. FINDINGS: The results of all three analyses (Bayesian, Maximum Parsimony and Neighbor Joining) were congruent and revealed two genetically distinct clusters of rice varieties in the region. The large group comprised several varieties of sali and boro ecotypes, and all agronomically improved varieties. The small group consisted of only traditionally cultivated indigenous rice varieties, which included one boro, few sali and all jum varieties. The fixation index analysis revealed a very low level of differentiation between sali and boro (F(ST) = 0.005), moderate differentiation between sali and jum (F(ST) = 0.108) and high differentiation between jum and boro (F(ST) = 0.230) ecotypes. CONCLUSION: The genetic relatedness analyses revealed that sali, boro and jum ecotypes are genetically heterogeneous, and the current classification based on cultivation type is not congruent with the genetic background of rice varieties. Indigenous rice varieties chosen from genetically distinct clusters could be used in breeding programs to improve genetic gain through heterosis, while maintaining high genetic diversity. PMID- 25547028 TI - Genome-wide association study of Fusarium ear rot disease in the U.S.A. maize inbred line collection. AB - BACKGROUND: Resistance to Fusarium ear rot of maize is a quantitative and complex trait. Marker-trait associations to date have had small additive effects and were inconsistent between previous studies, likely due to the combined effects of genetic heterogeneity and low power of detection of many small effect variants. The complexity of inheritance of resistance hinders the use marker-assisted selection for ear rot resistance. RESULTS: We conducted a genome-wide association study (GWAS) for Fusarium ear rot resistance in a panel of 1687 diverse inbred lines from the USDA maize gene bank with 200,978 SNPs while controlling for background genetic relationships with a mixed model and identified seven single nucleotide polymorphisms (SNPs) in six genes associated with disease resistance in either the complete inbred panel (1687 lines with highly unbalanced phenotype data) or in a filtered inbred panel (734 lines with balanced phenotype data). Different sets of SNPs were detected as associated in the two different data sets. The alleles conferring greater disease resistance at all seven SNPs were rare overall (below 16%) and always higher in allele frequency in tropical maize than in temperate dent maize. Resampling analysis of the complete data set identified one robust SNP association detected as significant at a stringent p value in 94% of data sets, each representing a random sample of 80% of the lines. All associated SNPs were in exons, but none of the genes had predicted functions with an obvious relationship to resistance to fungal infection. CONCLUSIONS: GWAS in a very diverse maize collection identified seven SNP variants each associated with between 1% and 3% of trait variation. Because of their small effects, the value of selection on these SNPs for improving resistance to Fusarium ear rot is limited. Selection to combine these resistance alleles combined with genomic selection to improve the polygenic background resistance might be fruitful. The genes associated with resistance provide candidate gene targets for further study of the biological pathways involved in this complex disease resistance. PMID- 25547029 TI - Prevalence of common and atypical melanocytic nevi in young adults and its relationship with sun protection and exposure habits. AB - Background: The incidence of melanoma in young adults is rising. The design of appropriate preventive measures requires the analysis of risk factors, including the prevalence of common and atypical melanocytic nevi (MN) and sun protection and exposure habits. OBJECTIVES: To establish the prevalence and density of common and atypical MN in young adults (18-25 yrs) and their relationship with sun exposure and protection habits. METHODS: Cross-sectional descriptive study was undertaken in 535 university students from southern Spain to gather data on: the number, density, body localization, and characteristics of common and atypical nevi; phototype; sunburn history; sun protection and exposure habits; and family history of skin cancer. RESULTS: Means of 94.28 common MN and 0.06 atypical MN were detected; most MN were <=2 mm in diameter; MN were more frequently detected on upper (p<0.01) and lower (p<0.0001 limbs in females versus males and on the trunk (p = 0.08) in males versus females. Nevus density was higher in females in all body areas. Sunburns (in the previous summer) were reported by 88.2% of participants, while cream with SPF >=15 was not used by 75.8%. Mean number of atypical MN was higher in those with low phototypes and a family history of skin cancer. CONCLUSIONS: Mean number of common MN was elevated and atypical MN were associated with a low phototype and a family history of skin cancer. Sunburn history was significantly associated with younger age and with sun exposure between mid-day and 6 pm. PMID- 25547030 TI - Effect of CETP polymorphism on atorvastatin lipid-regulating effect and clinical prognosis of patients with coronary heart disease. AB - BACKGROUND: The aim of this study was to investigate the influence of genetic polymorphism of cholesteryl ester transfer protein (CETP) gene polymorphism 629C/A on the therapeutic effect of atorvastatin and clinical outcome in Han Chinese patients with coronary heart disease (CHD). MATERIAL AND METHODS: From October 2011 to December 2012, 348 patients with angiographically confirmed CHD were recruited. CETP gene polymorphism was determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method. Serum level of CETP was determined with enzyme-1inked immunosorbent assay (ELISA). Lipid 1evel in all patients was determined at baseline and after 12 months of treatment with 20 mg/d of atorvastatin. All the patients were followed-up at least 12 months. Major adverse cardiac events, including death, non-fatal infarction, revascularization, and stroke (MACE), were recorded. RESULTS: The frequency of the -629A allele was 0.412. Compared with CC or CA genotypes, individuals with AA genotype had lower CETP levels (P=0.026) and higher high-density lipoprotein cholesterol (HDL-C) levels (P=0.035). After 12 months of atorvastatin therapy, carriers with CC genotype had greater reduction of low-density lipoprotein cholesterol (LDL-C) (P<0.001), reduced LP (a) (P=0.005), and elevated HDL-C (P=0.045) compared with CA or AA genotypes. The incidence of MACE after a mean follow-up of 17.3+/-5.2 months was 8.8%. The cumulative MACE-free survival rates were 90.1%, 85.2%, and 71.1% for CC, CA, and AA genotypes, respectively. CONCLUSIONS: Our results suggest that the AA variant of the -629A allele of CETP gene had higher HDL-C levels and reduced CETP levels, but patients with CC genotype appeared to have benefited more from statin therapy with reduction in LDL-C and LP (a) levels. Long-term clinical prognosis was, however, not affected by the 3 genotypes. PMID- 25547031 TI - Cryoglobulinemic vasculitis and skin ulcers. Our therapeutic strategy and review of the literature. AB - OBJECTIVE: Cryoglobulinemic vasculitis (CV) involving small- and medium-sized vessels is very frequently associated with hepatitis C virus and may be responsible for multiple organ involvement and skin ulcers (SU). Skin ulcers are often non-healing cutaneous lesions, possibly complicated by local infection and gangrene; they may severely affect the patients' quality of life and the overall prognosis. Therefore, the treatment of cryoglobulinemic SU is particularly challenging in the clinical practice. The present work evaluated the prevalence and correlations of cryoglobulinemic SU with other clinico-epidemiological features of CV; moreover, our long-term experience with the management strategies of these cutaneous lesions was compared with the world literature on this topic. METHODS: The study included 126 CV patients (24 male and 102 female, aged 69 +/- 11.2 SD years, disease duration 7 +/- 6.9 SD years), followed at our Rheumatology Unit during the past decade. All patients were carefully evaluated regarding the entire cryoglobulinemic syndrome with particular concern for clinical characteristics and treatment of SU. RESULTS: Among 126 CV patients, 36 individuals (29%) experienced at least one episode of SU, more commonly localized at the lower limbs. Patients with complicating SU showed significantly higher percentage of purpuric manifestations (p < 0.01) and liver (p < 0.001), peripheral nerve (p < 0.02), and/or thyroid involvement (p = 0.019). Therapeutic approach to SU included both systemic (immunosuppressors, corticosteroids, and/or plasma exchange) and local treatments. Local treatments consisted of sharp or surgical debridement as well as interactive dressing according to the condition of wound bed, perilesional skin, and the possible presence of infection, detected in 29 of 36 (81%) individuals in our Rheumatology unit. All patients underwent analgesic treatment for SU-related background pain as well as procedural pain, which was critical for an effective local SU management. The large majority of patients with SU healed at a variable time interval according to the severity of the single lesion; only five patients with very severe, non-healing SU needed amputation. The updated review of the literature revealed the presence of SU in around a quarter of CV patients. Among systemic treatments, the anti-CD20 monoclonal antibody rituximab represents one of the most effective and frequently employed therapies; however, the available data focusing on local therapeutic approach are generally limited to anecdotal observations. CONCLUSIONS: Overall, the treatment of cryoglobulinemic SU should be tailored to the single patient's conditions using combined systemic and local treatments; lesional sharp debridement and interactive dressing as well as procedural pain management were decisive, particularly for more severe, non-healing cutaneous lesions. PMID- 25547033 TI - Polysomnography using abbreviated signal montages: impact on sleep and cortical arousal scoring. AB - OBJECTIVE: This study examined the impact of using two abbreviated signal montages on the accuracy, precision and inter-scorer reliability of polysomnography (PSG) sleep and arousal scoring, compared to a standard reference montage, in a cohort of patients investigated for obstructive sleep apnoea (OSA). One abbreviated montage incorporated two signals dedicated to sleep and arousal scoring, and the other incorporated a single signal. METHODS: Four scorers from two laboratories each scored 15 PSGS four times in random order: once using each abbreviated montage and twice using the reference montage. RESULTS: Use of the two-signal montage resulted in small changes in the distribution of sleep stages, a reduction in the arousal index and resultant reductions in sleep and arousal scoring agreement. For the one-signal montage, although similar magnitude sleep stage distribution changes were observed, there were larger reductions in the arousal index, and sleep and arousal scoring accuracy. Additionally, using the one-signal montage, there were statistically significant reductions in the precision of summary statistics including total sleep time (TST) and the amount of rapid eye movement (REM) sleep scored, and reductions in the inter-scorer reliability of REM sleep and arousal scoring. CONCLUSIONS: These findings demonstrate that abbreviated signal montages may result in underestimation of the arousal index and, depending on the montage, poorer precision in TST and REM sleep scoring, with potential consequences for apnoea-hypopnoea index (AHI) measures and OSA diagnosis. The results highlight the importance of careful evaluation of PSG results when using portable devices that have restricted signals, and they offer guidance for future PSG and portable monitoring standards. PMID- 25547032 TI - Identification of putative interactions between swine and human influenza A virus nucleoprotein and human host proteins. AB - BACKGROUND: Influenza A viruses (IAVs) are important pathogens that affect the health of humans and many additional animal species. IAVs are enveloped, negative single-stranded RNA viruses whose genome encodes at least ten proteins. The IAV nucleoprotein (NP) is a structural protein that associates with the viral RNA and is essential for virus replication. Understanding how IAVs interact with host proteins is essential for elucidating all of the required processes for viral replication, restrictions in species host range, and potential targets for antiviral therapies. METHODS: In this study, the NP from a swine IAV was cloned into a yeast two-hybrid "bait" vector for expression of a yeast Gal4 binding domain (BD)-NP fusion protein. This "bait" was used to screen a Y2H human HeLa cell "prey" library which consisted of human proteins fused to the Gal4 protein's activation domain (AD). The interaction of "bait" and "prey" proteins resulted in activation of reporter genes. RESULTS: Seventeen positive bait-prey interactions were isolated in yeast. All of the "prey" isolated also interact in yeast with a NP "bait" cloned from a human IAV strain. Isolation and sequence analysis of the cDNAs encoding the human prey proteins revealed ten different human proteins. These host proteins are involved in various host cell processes and structures, including purine biosynthesis (PAICS), metabolism (ACOT13), proteasome (PA28B), DNA-binding (MSANTD3), cytoskeleton (CKAP5), potassium channel formation (KCTD9), zinc transporter function (SLC30A9), Na+/K+ ATPase function (ATP1B1), and RNA splicing (TRA2B). CONCLUSIONS: Ten human proteins were identified as interacting with IAV NP in a Y2H screen. Some of these human proteins were reported in previous screens aimed at elucidating host proteins relevant to specific viral life cycle processes such as replication. This study extends previous findings by suggesting a mechanism by which these host proteins associate with the IAV, i.e., physical interaction with NP. Furthermore, this study revealed novel host protein NP interactions in yeast. PMID- 25547034 TI - Sleep disorders increase the risk of venous thromboembolism in individuals without sleep apnea: a nationwide population-based cohort study in Taiwan. AB - OBJECTIVE: Studies investigating the relationship between sleep disorders (SDs) and the risk of venous thromboembolism (VTE) are scarce. The present study from Taiwan evaluated whether the risk of VTE was associated with SDs other than sleep apnea. METHODS: The present study investigated the incidence and risk of VTE in 46,371 people with SDs, compared with 92,742 controls without SDs. The follow-up period began from the date of entering the study cohort to the date of a VTE event, censoring, or December 31, 2011. A Cox proportional hazards regression analysis was conducted to estimate the effects of SDs on the risk of VTE. RESULTS: The SD cohort had a 1.79-fold adjusted hazard ratio (HR) of subsequent VTE, compared with the non-SD cohort (95% CI 1.49-2.16). The incidence of VTE increased with age for both cohorts but was higher for those in the SD cohort. However, the adjusted HRs for VTE were significantly higher for the people with SDs aged ?49 years (HR 3.29, 95% CI 2.12-5.12) and 50-64 years (HR 2.43, 95% CI 1.76-3.35), but were not significant for the oldest group (HR 1.11, 95% CI 0.84 1.47), compared with the controls. The multiplicative increased risk of VTE was significant for the people with SDs with any comorbidity. CONCLUSION: This nationwide cohort study determined that the VTE risk significantly increased in people with SDs compared with those of the general population. PMID- 25547035 TI - Actigraphic assessment of sleep/wake behavior in central disorders of hypersomnolence. AB - OBJECTIVE: To evaluate the reliability of actigraphy to distinguish the features of estimated daytime and nighttime sleep between patients with central disorders of hypersomnolence and healthy controls. METHODS: Thirty-nine drug-naive patients with Narcolepsy Type 1, twenty-four drug-naive patients with Idiopathic Hypersomnia, and thirty age- and sex- matched healthy controls underwent seven days of actigraphic and self-report monitoring of sleep/wake behavior. The following variables were examined: estimated time in bed (eTIB), estimated total sleep time, estimated sleep latency (eSOL), estimated sleep efficiency, estimated wake after sleep onset, number of estimated awakenings (eAwk), number of estimated awakenings longer than 5 minutes, estimated sleep motor activity (eSMA), number of estimated naps, mean duration of the longest estimated nap (eNapD), and daytime motor activity. RESULTS: All actigraphic parameters significantly differentiated the three groups, except eTIB and eSOL. A discriminant score computed combining actigraphic parameters from nighttime (eSMA, eAwk) and daytime (eNapD) periods showed a wide area under the curve (0.935) and a good balance between positive (95%) and negative predictive (87%) values in Narcolepsy Type 1 cases. CONCLUSION: Actigraphy provided a reliable objective measurement of sleep quality and daytime napping behavior able to distinguish central disorders of hypersomnolence and in particular Narcolepsy Type 1. The nycthemeral profile, combined with a careful clinical evaluation, may be an ecological information, useful to track disease course. PMID- 25547036 TI - Obstructive sleep apnea is independently associated with worse diastolic function in coronary artery disease. AB - BACKGROUND: Diastolic dysfunction is common in patients with coronary artery disease (CAD). We hypothesize that patients with CAD and preserved left ventricular ejection fraction (LVEF) and obstructive sleep apnea (OSA) will have worse diastolic function than similar patients without OSA. MATERIAL AND METHODS: We analyzed sleep-study recordings and echocardiographic measurements obtained at baseline in a randomized controlled trial (RICCADSA) of revascularized patients with CAD who had LVEF of at least 50%. OSA was defined as an apnea-hypopnea-index (AHI) >=15 events/h, and, no OSA, as an AHI <5. Worse diastolic function was defined as assumed elevated left ventricular filling pressure based on peak flow velocity in early diastole/Tissue Doppler of early diastolic ventricular filling (E/e) of >13 (or >9 in patients with an enlarged left atrial diameter [>=39 mm for women and >=40 mm for men]). RESULTS: Data from 431 patients were evaluated (mean age: 63.7 +/- 8.8 y; men: 82.5%; OSA: n = 331). Worse diastolic function was more common among the patients with OSA than those without (54.4% vs 41.0%, p = 0.019). In multivariate analysis, OSA was associated with worse diastolic function (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.13; 3.18) adjusted for female sex (OR 2.28, 95% CI 1.28; 4.07), hypertension (OR 1.84, 95% CI 1.20; 2.82), and diabetes mellitus (OR 2.45, 95% CI 1.42; 4.23). Age >=60 years, obesity, and current smoking were nonsignificant. CONCLUSIONS: In this cohort with CAD and preserved LVEF, OSA was associated with worse diastolic function independent of the traditionally recognized risk indicators. PMID- 25547037 TI - The effects of an anxiety sensitivity intervention on insomnia symptoms. AB - OBJECTIVE: Recent work suggests a link between a transdiagnostic vulnerability factor, anxiety sensitivity (AS), and sleep disturbance. Although research has indicated that AS is malleable through brief interventions, no studies have yet examined whether interventions targeting AS will reduce symptoms of insomnia. Considering this gap in previous research, the current study tested the direct and indirect effects of a brief, computerized intervention targeting AS on self reported insomnia symptoms. METHODS: Community participants (N = 97) were randomized into either the AS intervention (consisting of psychoeducation and interoceptive exposure) or a health information control condition, and they were assessed at baseline and at 1-month follow-up. RESULTS: Findings indicated that symptoms of insomnia were related to AS and its subfactors at baseline and follow up. Moreover, there was an indirect effect of the treatment on insomnia symptoms through AS and its subfactors, which held after covarying for baseline symptoms of anxiety and depression. CONCLUSIONS: These preliminary findings suggest that targeting AS may be a brief and effective way to reduce symptoms of insomnia, but it should be replicated in a clinical sample of individuals with a diagnosis of insomnia disorder. PMID- 25547038 TI - Review of self-reported instruments that measure sleep dysfunction in patients suffering from temporomandibular disorders and/or orofacial pain. AB - Patients with temporomandibular disorders (TMD) and/or orofacial pain (OFP) frequently experience poor sleep quality or suffer from comorbid sleep disorders. Study results suggest that in chronic pain patients, an improvement in sleep quality critically influences the outcomes of interventions on mood and pain. Yet, only a few studies have systematically sought to evaluate the sleep quality of TMD/OFP patients. Standardized and validated self-reported instruments designed for screening sleep disturbances or for the evaluation of treatment outcomes in this population would therefore enhance evidence and improve treatment options. The objectives of the present study were: (1) to review the self-reported instruments that measure sleep dysfunction in studies on TMD/OFP patients, by conducting a systematic literature search; (2) to evaluate their clinimetric evidence; and (3) to provide guidance for future research using such instruments. A total of 26 papers, using eight different instruments, were identified. The most frequently used questionnaires and the only ones with good clinimetric properties were the Insomnia Severity Index followed by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. They were most reliable, valid and time-effective for measuring sleep dysfunctions in patients with TMD/OFP, with only a few practical constraints. Yet, in future studies, an assessment of the relationship between sleep disturbances and chronic pain will have to include instruments measuring the effect of mediator variables such as cognitive or emotional arousal. Research is required to clarify if existing self reported questionnaires measuring these aspects will promote further insights or if there is a need for new instruments. This future research direction would blend into the overall biopsychosocial concept of TMD/OFP diagnoses and treatment. PMID- 25547039 TI - Do patients prefer face-to-face or internet-based therapy? PMID- 25547040 TI - Carnitine deficiency: Risk factors and incidence in children with epilepsy. AB - BACKGROUND: Carnitine deficiency is relatively common in epilepsy; risk factors reportedly include combination antiepileptic drug (AED) therapy with valproic acid (VPA), young age, intellectual disability, diet and enteral or parenteral feeding. Few studies have examined the correlation between each risk factor and carnitine deficiency in children with epilepsy. We examined the influence of these risk factors on carnitine deficiency, and identified a formula to estimate plasma free carnitine concentration in children with epilepsy. METHODS: Sixty five children with epilepsy and 26 age-matched controls were enrolled. Plasma carnitine concentrations were measured using an enzyme cycling assay, and correlations were sought with patients' other clinical characteristics. RESULTS: Carnitine deficiency was found in approximately 17% of patients with epilepsy and was significantly associated with carnitine-free enteral formula only by tube feeding, number of AEDs taken (independent of VPA use), body weight (BW), body height and Gross Motor Function Classification System (GMFCS) score. Stepwise multiple linear regression analysis indicated that carnitine concentration (in MUmol/L) could be accurately estimated from a formula that does not require blood testing: 42.44+0.14*(BW in kg)-18.16*(feeding)-3.19*(number of AEDs), where feeding was allocated a score of 1 for carnitine-free enteral formula only by tube feeding and 0 for taking food orally (R(2)=0.504, P<0.001). CONCLUSIONS: Carnitine-free enteral formula only by tube feeding, multiple AED treatment and low BW are risk factors for carnitine deficiency in children with epilepsy. l carnitine should be administered to children at risk of deficiency to avoid complications. Treatment decisions can be informed using an estimation formula that does not require blood tests. PMID- 25547042 TI - Early onset of moyamoya syndrome in a Down syndrome patient with the genetic variant RNF213 p.R4810K. AB - Moyamoya syndrome is a unique progressive occlusive cerebrovascular disease that predisposes affected patients to stroke. We describe the case of a 2-year-old girl presenting with early onset of moyamoya syndrome with concurrent Down syndrome. Genetic testing revealed a heterozygous missense variant of RNF213. RNF213 was recently identified as the first susceptibility gene for moyamoya disease in patients with no known associated risk factors. The reported median age at the onset of idiopathic moyamoya disease with a heterozygous RNF213 risk variant is 7 years, while, the average age at onset of moyamoya syndrome in Down syndrome is 7-16 years. Down syndrome and RNF213 variant contribute to the development of moyamoya vasculopathy in different ways. Although the underlying mechanism is not fully understood, an additive effect was observed with the early onset seen in this patient. Little is known about the potential association between RNF213 and moyamoya syndrome. Based on these observations, we hypothesize that the RNF213 risk variant has a modifier effect in steno-occlusive vasculopathy, even in medical conditions known to be associated with moyamoya syndrome. PMID- 25547041 TI - Evolution of a symptomatic diffuse developmental venous anomaly with progressive cerebral atrophy in an atypical case of Sturge-Weber syndrome. AB - A 2-year-old boy had glaucoma, bilateral facial haemangioma and widespread blue nevi on the trunk and extremities since birth. Dilated medullary veins were detected in the left cerebral periventricular white matter on magnetic resonance imaging (MRI). Macrocephaly and delayed psychomotor development were observed during late infancy, and susceptibility-weighted angiography revealed an extensive developmental venous anomaly with multiple caput medusae throughout bilateral hemispheres, accompanied by periventricular hyperintense alterations on MRI and progressive diffuse atrophy of the cerebral mantle with left-sided predominance. Hypoperfusion in the left cerebral and cerebellar hemisphere was also uncovered. No meningeal haemangioma was observed. This patient may represent a novel subgroup of phakomatosis cases that can be regarded as a variant of Sturge-Weber syndrome. PMID- 25547043 TI - Cortical ischemic lesion burden measured by DIR is related to carotid artery disease severity. AB - BACKGROUND: Over time, exposure to cerebrovascular risk factors and carotid artery disease may cause multiple asymptomatic brain cortical and subcortical microinfarcts, which are commonly found at brain autopsy. So far, lack of convenient neuroimaging tools limited the investigation of grey matter ischemic damage in vivo. We applied the Double Inversion Recovery (DIR) sequence to explore the impact of carotid artery disease on intracortical ischemic lesion load in vivo, taking into account the impact of demographic characteristics and vascular risk factors. METHODS: DIR was acquired in 62 patients with common cerebrovascular risk factors stratified in three groups according to carotid artery disease severity. Intracortical lesions scored on DIR (DIRlns) were classified by vascular territory, lobe and hemisphere. White matter hyperintensities (WMHs) volume was also quantified on Fluid Attenuated Inversion Recovery sequence (FLAIR). RESULTS: Among demographic characteristics and cerebrovascular risk variables explored, General Linear Model indicated that age and carotid artery disease were significantly associated to DIRlns. After correcting for age, DIRlns load was found to be significantly dependent on carotid artery stenosis severity (F(2, 58) = 5.56, p = 0.006). A linear positive correlation between DIRlns and WMHs was found after correcting for age (p = 0.003). CONCLUSIONS: Carotid disease severity is associated with DIRlns accrual. Microembolism and impaired cerebral hemodynamics may act as physiopathological mechanisms underlying cortical ischemic damage. The role of other factors, such as small vessel disease and the possible interaction with carotid disease, remains to be further explored. PMID- 25547044 TI - An active city approach for urban development. AB - With an increasing percentage of the global population living in cities and the concurrent decrease in physical activity in daily life, public health issues for urban development have arisen. This study responds to that trend by presenting an approach to measure city-wide physical activity levels. Comparing of city indices for active sports and the active transportation shows differences between subject cities and activity level of age groups in sports as well as walking and cycling. Therefore, our study lends itself to implications for urban development towards creating a healthier city. PMID- 25547045 TI - Attenuation of glomerular endothelial cells from high glucose-induced injury by blockade of MAD2B. AB - BACKGROUND/AIMS: To assess the role of mitotic arrest-deficient 2-like protein 2 (MAD2B) in high glucose-induced injury in mouse glomerular endothelial cells (GEnCs). METHODS: GEnCs were cultured in vitro, and MAD2B protein levels were measured by Western blot in cells stimulated with high glucose (30 mM) for various periods of time. MAD2B and scrambled shRNA were introduced into GEnCs by liposomal transfection. Cell proliferation, apoptosis, nitric oxide (NO) production, and monolayer permeability were then measured in cells grown in the following conditions: control, high glucose treatment, MAD2B shRNA transfection with high glucose treatment, and scrambled shRNA transfection with high glucose treatment. RESULTS: High glucose increased the protein levels of MAD2B in GEnCs. Compared with control cells, apoptosis was increased by high glucose treatment, which was attenuated by transfection with MAD2B shRNA transfection. Cells treated with high glucose produced less NO than control cells, whereas MAD2B shRNA transfection increased NO production. Cell monolayer permeability was enhanced in high glucose treated cells, but MAD2B shRNA transfection reduced permeability. CONCLUSION: High glucose levels induced the expression of MAD2B in GEnCs, whereas suppressing its expression reduced high glucose-induced endothelial cell apoptosis and high permeability, and promoted cell proliferation and NO production. PMID- 25547046 TI - Comparison between clinical indicators of transmembrane oxygenator thrombosis and multidetector computed tomographic analysis. AB - This study aims to assess whether multidetector computed tomography (MDCT) could accurately confirm the clinical suspicion of transmembrane oxygenator thrombosis (MOT) during extracorporeal membrane oxygenation (ECMO). Twenty-seven oxygenators were examined using MDCT at the end of patient treatment. Transmembrane oxygenator thrombosis was suspected in 15 of them according to the presence of at least 2 of the following clinical indicators: (1) increase in d-dimer, (2) decrease in platelet count, (3) decrease in oxygenator performance, and (4) presence of clots on the surface of the oxygenator. Transmembrane oxygenator thrombosis was confirmed by MDCT in 5 (33%) of them. Transmembrane oxygenator thrombosis was unexpectedly found in 5 (41%) of the remaining 12 oxygenators not suspected for MOT. Eight (80%) of these oxygenators had clots accounting for less than 1% of total volume. Clots were mainly detectable at the apical corner of the oxygenator, most likely due to greater blood stasis. We found a significant increase in d-dimer and in membrane oxygenator shunt and a decrease in platelet count from the start to the discontinuation of ECMO. Hemostatic abnormalities significantly reverted 48 hours after oxygenator removal, suggesting the role of ECMO in activation of the coagulation cascade. Multidetector computed tomographic scan could not accurately confirm the clinical suspicion of MOT. PMID- 25547047 TI - Predictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department. AB - PURPOSE: To investigate changes in circulating complement component C3, membrane attack complex (MAC), and mannose-binding lectin (MBL) in patients with sepsis induced disseminated intravascular coagulation (DIC). MATERIALS AND METHODS: Adult septic patients admitted to the emergency department (ED) of Beijing Chao Yang Hospital were enrolled. A DIC score of 5 or higher was considered sepsis induced DIC. Circulating C3, MAC, and MBL levels were detected on ED arrival and compared between patients with and without DIC. The predictive value of C3, MAC, and MBL for sepsis-induced DIC at ED arrival and development of DIC after admission were assessed by receiver operating characteristic curve and logistic regression. RESULTS: We enrolled 267 septic patients between February and December 2013. Complement 3, MAC, and MBL were higher in the DIC group (P < .01). Membrane attack complex was the independent predictor of sepsis-induced DIC. The area under the curve of MAC in predicting sepsis-induced DIC was 0.793. During hospitalization, 25 patients without DIC at enrollment developed DIC. Membrane attack complex and Sequential Organ Failure Assessment independently predicted progress to DIC. The area under the curve of MAC was 0.741. CONCLUSIONS: Complement 3, MAC, and MBL were significantly increased in septic patients with DIC. Membrane attack complex independently predicted sepsis-induced DIC and development of DIC after ED admission. PMID- 25547048 TI - A meta-analysis of bone-patellar tendon-bone autograft versus four-strand hamstring tendon autograft for anterior cruciate ligament reconstruction. AB - BACKGROUND: There is a lack of comprehensive studies comparing the clinical outcome of anterior cruciate ligament (ACL) reconstruction with either a bone patellar tendon-bone (BPTB) or four-strand hamstring tendon (4SHT) autografts. The optimal choice of graft for anterior cruciate ligament reconstruction remains controversial. PURPOSE: The objective of this study was to evaluate the effectiveness of BPTB autografts versus 4SHT autografts for the reconstruction of ACL. METHODS: A systematical search of literature was performed in Pubmed, Embase, and the Cochrane library to identify published clinical prospective studies relevant to ACL reconstruction comparing BPTB and 4SHT autografts. The results of the eligible studies were analysed in terms of instrumented laxity measurements, Lachman test, pivot shift test, objective International Knee Documentation Committee (IKDC) scores, return to preinjury activity level, and morbidity of graft failure, anterior knee pain, kneeling pain, extension deficit, and flexion deficit. Study quality was assessed by using the Jadad scale for randomized clinical trial (RCT) and the Newcastle-Ottawa Scale (NOS) for prospective cohort study (PCS). Two reviewers independently assessed each study for quality and extracted data. Subgroup analysis of the primary outcomes was conducted according to the type of study design (RCT or PCS). RESULTS: Twenty-two studies, with 931 patients in the BPTB group and 999 patients in the 4SHT group, met the inclusion criteria. Fourteen studies were randomized controlled trials, and eight were prospective cohort studies. The results of the meta-analysis showed that there were no significant differences between BPTB and 4SHT in terms of instrumented laxity measurements (P=0.06), Lachman test (P=0.58), objective IKDC scores (P=0.31), graft failure (P=0.45), extension deficit (P=0.06) and flexion deficit (P=0.63). However, outcomes in favour of BPTB were found in terms of pivot shift test (P=0.01) and return to preinjury activity level (P=0.03); outcome measures that favours 4SHT included anterior knee pain (P<0.01) and kneeling pain (P<0.01). These findings were still robust during the sensitivity analysis. Results from subgroup analysis of the primary outcomes were consistent with the overall analysis. CONCLUSION: Based on the results above, ACL reconstruction with BPTB autografts might be superior in resuming rotation stability of the knee joint and allow patients to return to higher levels of activity in comparison with 4SHT autografts. Whereas, postoperative complications of the knee joint were lower for 4SHT autografts than for BPTB autografts. There was insufficient evidence to identify which of the two types of grafts was significantly better for ACL reconstruction considering the limitations of this study. More high-quality randomized controlled trials with strictly specified inclusion criteria are highly required before drawing a reliable conclusion. PMID- 25547049 TI - Quercetin protects against acetaminophen-induced hepatorenal toxicity by reducing reactive oxygen and nitrogen species. AB - High or toxic doses of acetaminophen (APAP), a mild analgesic and antipyretic drug, can cause life-threatening hepatic and renal dysfunction. This study is designed to investigate the potential protective role of quercetin to attenuate the hepatorenal toxicity induced by a high single oral dose (3g/kg) of APAP in rats. Three main groups of Sprague-Dawley rats were used: quercetin, APAP and quercetin plus APAP-receiving animals. Corresponding control animals were also used. Interestingly, oral supplementation of quercetin (15mg/kg/day) prior to APAP intoxication dramatically reduced APAP-induced hepatorenal toxicity as evidenced by measuring serum lipid profile, total protein, urea, creatinine, ALT, AST, ALP, G-GT and liver tissue content of TC and TG. Quercetin treatment markedly prevented the generation of TBARS and PCC with substantial improvement in terms of GSH and activities of antioxidant enzymes in both liver and kidney homogenates. The relationship between quercetin and NO levels which is still a matter of debate, was also investigated. NO levels in serum, liver and kidney tissues were significantly inhibited in quercetin pre-treated animals. Furthermore, quercetin administration significantly inhibited the reduction of liver and kidney contents of ATP parcels associated with this hepatorenal toxicity. These results suggest that the protective role of quercetin in the prevention of APAP-induced hepatorenal toxicity in rats was associated with the decrease of oxidative and nitrosative stress in hepatic and renal tissues as well as its capacity to improve the mitochondrial energy production. However, clinical studies are warranted to investigate such an effect in human subjects. PMID- 25547050 TI - Exploring the impact of bariatric surgery on high density lipoprotein. AB - Low HDL cholesterol is an independent cardiac risk factor. A general efficacy gradient exists for the resolution of cardiovascular risk factors after bariatric surgery (i.e., biliopancreatic diversion [BPD]>Roux-en-Y gastric bypass [RYGB]>sleeve gastrectomy [SG]>adjustable gastric banding [AGB]). However, a review of high level of evidence clinical studies shows a different hierarchy for the effect of bariatric surgery on HDL (i.e., RYGB=SG>BPD, AGB). Surgically induced weight loss effectively reverses many steps in HDL metabolism that have been altered with obesity. Furthermore, enterocytes contribute to HDL levels through the synthesis of apolipoproteins A-IV and A-I. RYGB and SG that preserve the small intestine (particularly the jejunum) lead to a significant rise in HDL. However, when the small intestinal contribution does not reinforce the weight loss dependent mechanisms (e.g., after BPD and AGB), only a modest rise in HDL occurs. Further experimental and clinical studies are required to better delineate the issue. PMID- 25547051 TI - Ethnic variation in weight loss, but not co-morbidity remission, after laparoscopic gastric banding and Roux-en-Y gastric bypass. AB - BACKGROUND: Demographic factors such as ethnicity may affect bariatric surgery outcomes. We examined weight loss and co-morbidities outcomes in African American, Caucasian, and Hispanic patients who underwent laparoscopic gastric banding (LAGB) and Roux-en-Y gastric bypass (RYGB). The primary aim was to investigate demographic differences in weight loss and co-morbidities outcomes. METHODS: We retrospectively examined weight change and co-morbidities outcomes in our prospective database. A total of 1,903 patients underwent LAGB or RYGB between January 1, 2005 and March 31, 2012. Of those, 1828 completed their 1-year follow-up visit (9-15 mo) and had complete data. We excluded patients who were missing ethnicity information, resulting in a final cohort of 1,684 patients. Multivariate analyses and chi2 tests were used to examine demographic variables in body mass index (BMI) change, percent excess weight loss (%EWL), and remission of co-morbidities. We also examined weight loss outcomes at 2- and 3-year follow up. RESULTS: Overall, those who underwent RYGB had a lower BMI and greater %EWL at 1, 2, and 3 years compared to those who had undergone LAGB. Overall, African American patients had a higher postoperative BMI than either Caucasian or Hispanic patients. African American patients also showed less %EWL than Caucasian and Hispanic patients. When we examined within surgery type, ethnic differences between African American and Caucasian patients were present across all 3 years in RYGB, but there were no ethnic differences by year 3 in LAGB. Additionally, African American and Hispanic patients no longer differed by year 3 in RYGB and by year 2 in LAGB. There were no significant ethnic differences in remission of diabetes, hyperlipidemia, hypertension, and sleep apnea at 1 year. CONCLUSION: Our study found significant ethnic differences in the postoperative BMI and %EWL, which were more pronounced in patients undergoing RYGB than LAGB at the 3-year time point. These weight loss differences did not translate to a lower rate of co morbidities remission. PMID- 25547052 TI - Changes in liver volume and body composition during 4 weeks of low calorie diet before laparoscopic gastric bypass. AB - BACKGROUND: Weight loss before laparoscopic Roux-en-Y gastric bypass (LRYGB) is desirable, because it can reduce liver volume and thereby facilitate the procedure. The optimal duration of a low-calorie diet (LCD) has not been established. The objective of this study was to assess changes in liver volume and body composition during 4 weeks of LCD. METHODS: Ten women (aged 43+/-8.9 years, 114+/-12.1 kg, and body mass index 42+/-2.6 kg/m(2)) were examined on days 0, 3, 7, 14, and 28 after commencing the LCD. At each evaluation, body composition was assessed through bioelectric impedance analysis, and liver volume and intrahepatic fat content were assessed by magnetic resonance imaging. Serum and urine samples were obtained. Questionnaires regarding quality of life and LCD related symptoms were administered. RESULTS: In total, mean weight decreased by 7.4+/-1.2 kg (range 5.7-9.1 kg), and 71% of the weight loss consisted of fat mass according to bioelectric impedance analysis. From day 0 to day 3, the weight loss (2.0 kg) consisted mainly of water. Liver volume decreased by 18%+/-6.2%, from 2.1 to 1.7 liters (P<.01), during the first 2 weeks with no further change thereafter. A continuous 51%+/-16% decrease was seen in intrahepatic fat content. Systolic blood pressure, insulin, and lipids improved, while liver enzymes, glucose levels, and quality of life were unaffected. CONCLUSION: A significant decrease in liver volume (18%) occurred during the first 2 weeks of LCD treatment, and intrahepatic fat gradually decreased throughout the study period. A preoperative 2-week LCD treatment seems sufficient in similar patients. PMID- 25547053 TI - Is preoperative manometry necessary for evaluating reflux symptoms in sleeve gastrectomy patients? AB - BACKGROUND: The effect of laparoscopic sleeve gastrectomy (LSG) in gastroesophageal reflux disease (GERD) is controversial. However, it has been reported that up to 22% of patients presented with symptomatic GERD after LSG. The aim of our study was to evaluate the necessity of preoperative manometric testing in LSG patients. METHODS: We prospectively collected the data on LSG candidate patients who underwent preoperative manometric testing. The normal range for the lower esophageal sphincter (LES) pressure is 10.0-45.0 mmHg. Each patient was interviewed for the GERD score questionnaire (scaled severity and frequency of heartburn, regurgitation, epigastric pain, epigastric fullness, dysphagia and cough) at the time of the manometric study. RESULTS: Forty-nine patients were studied. The mean preoperative LES pressure was 13.2+/-7.7 mmHg (range, 1.0-34.4). Eleven patients responded that they had 1 or more moderate to severe GERD symptoms >2-4 times a week, of which 9 had competent LES pressures. Thirteen (26.5%) patients had decreased LES pressures, and only 3 (23.1%) of these reported moderate to severe symptoms of GERD. In 26 LSG patients with postoperative results, the mean preoperative LES pressure was 14.8+/-8.0 mmHg (range, 3.5-34.4), and the mean GERD score did not show a significant difference at 9 months after LSG. Twenty-two had normal LES pressures, and 16 (72.8%) of these patients reported reflux symptoms preoperatively. Only 2 (12.5%) of these symptomatic patients reported a higher GERD score postoperatively, but the difference was not significant. Of the 4 patients who had low LES pressures, only 1 patient complained of mild GERD symptoms preoperatively. However, this patient and another without preoperative symptoms developed severe GERD symptoms postoperatively. CONCLUSION: Manometric study may be necessary in LSG patients to accurately evaluate GERD and the LES pressure. PMID- 25547054 TI - Visceral fat area as a new predictor of short-term diabetes remission after Roux en-Y gastric bypass surgery in Chinese patients with a body mass index less than 35 kg/m2. AB - BACKGROUND: Metabolic surgery has been proposed for inadequately controlled type 2 diabetes mellitus (T2DM) in association with obesity. However, prediction of successful T2DM remission after surgery has not been clearly studied in Chinese patients. The objective of this study was to predict the outcome in those with T2DM after metabolic surgery to help in patient selection. METHODS: A retrospective review of prospectively collected data of 68 ethnic Chinese with mean body mass index (BMI) of 31.5 and T2DM were examined for the metabolic outcomes at 1 year after Roux-en-Y gastric bypass (RYGB). Visceral and abdominal subcutaneous fat areas were assessed using magnetic resonance imaging before and 1 year after RYGB. Remission was defined as a glycated hemoglobin (HbA1 c)<6.5% and no medications at 1 year. Binary logistic regression analysis was used to identify predictors. RESULTS: At 1 year after surgery, the BMI in the study group decreased from 31.5+/-3.6 to 24.5+/-2.5 kg/m2. Remission was achieved in 50 patients (73.5%) at 1 year. Compared with patients in the nonremission group, patients in the remission group had a shorter duration of diabetes, lower preoperative HbA1 c level, higher fasting C-peptide level, and more visceral fat area (VFA). Preoperative BMI and waist circumference did not differ between the 2 groups. CONCLUSION: The metabolic improvement in T2DM after RYGB in the mildly obese is greater with a shorter duration of diabetes, higher fasting C-peptide. Those who have more visceral adiposity may obtain greater benefit from RYGB. PMID- 25547055 TI - Robotic single-site cholecystectomy in the obese: outcomes from a single institution. AB - BACKGROUND: Robotic single-site cholecystectomy (RSSC) has been shown to be a safe alternative to the laparoscopic approach in selected patients. Patient exclusion criteria have prevented RSSC as a surgical option in many obese patients. This study reports the feasibility of performing RSSC in obese patients (body mass index [BMI] >= 30). METHODS: Between November 2012 and February 2014, a total of 200 patients underwent RSSC at our institution. All patients were offered the robotic procedure regardless of their BMI, age, previous surgery, and acuity of their disease with no exclusion criteria. All patients with BMI >= 30 were included in the study and were compared to nonobese patients for demographic characteristics, co-morbidities, and postoperative outcomes. Data were compared to RSSC performed in nonobese patients by the same surgeon, as well to published data for standard laparoscopic cholecystectomy (LC). RESULTS: A total of 112 cholecystectomies were successfully performed with the robotic approach in patients with BMI >= 30 without conversion to open, laparoscopic, or multiport procedures. The mean BMI was 39.5 (range 30.1-62.3). Twenty-eight patients had a BMI >= 40 (25%), and 13 patients had a BMI >= 50 (11.6%). Fifty-two patients (46.4%) had a history of prior abdominal surgery. Most procedures were nonelective (78.6%) with patients presenting with acute symptoms. Pathology showed chronic cholecystitis and cholelithiasis in 79 patients (70.5%), acute cholecystitis in 26 patients (23.3%), cholelithiasis in 4 patients (3.5%), and gangrenous cholecystitis in 3 patients (2.7%). Total mean operative time was 69.8 (26) minutes for obese patients compared to 59.2 (19.7) minutes in the nonobese, which was statistically significant (P = .0012). After a mean follow-up of 6 months, there were no major complications recorded including bile leak, hematoma, or ductal injury. There was 1 umbilical (incisional) hernia (0.9%) reported, and zero wound infections. When comparing RSSC performed in obese patients, RSSC in nonobese patients, and published data for standard LC, we found no difference in operative time, with less conversion to open. CONCLUSIONS: Robotic single-site cholecystectomy is a feasible option in the obese patient population with excellent short-term outcomes. Patients should not be excluded based on their high BMI although further study is needed to determine long-term outcomes. PMID- 25547056 TI - Management of staple line leaks following sleeve gastrectomy. AB - BACKGROUND: Leaks after laparoscopic sleeve gastrectomy (LSG) are not very frequent but are a difficult complication that can become chronic. Various treatment options have been suggested but no definitive treatment regimen has been established. The aim of our study is to report leak complications after LSG, their management, and outcomes. METHODS: Between June 2008 and October 2013, a total of 539 patients underwent laparoscopic and robot-assisted laparoscopic sleeve gastrectomy at our institution. A retrospective review of a prospectively collected database was performed for all LSG patients, noting the outcomes and complications of the procedure. RESULTS: Fifteen (2.8%) patients presented with a leak after LSG. The diagnosis was made at a mean of 27.2+/-29.9 days (range, 1 102) after LSG. Eight (53.3%) patients underwent conservative treatment initially and 6 (75.0%) of these patients required stenting as secondary treatment. Although leaks from 3 patients resolved with stenting, the other 3 required restenting and 2 eventually underwent conversion to gastric bypass. Five (33.3%) patients underwent endoscopic intervention, closing the leak with fibrin glue (n=3) or hemoclips (n=2). Two (13.3%) patients who were diagnosed with a leak immediately after LSG before discharge had their leak oversewn laparoscopically with an omental patch. Leaks in 9 (60.0%) patients did not heal after the first intervention, and the mean number of intervention required was 2.3+/-1.7 times (range, 1-7) for the treatment of this condition. CONCLUSION: Management of leaks after LSG can be challenging. Early diagnosis and treatment is important in the management of a leak. However, it can be treated safely via various management options depending on the time of diagnosis and size of the leak. PMID- 25547057 TI - The role of bariatric surgery in morbidly obese patients with inflammatory bowel disease. AB - BACKGROUND: Bariatric surgery is considered as being contraindicated for morbidly obese patients who also have inflammatory bowel disease (IBD). The aim of our study was to report the outcomes of bariatric surgery in morbidly obese IBD patients. METHODS: The prospectively collected data of all the patients diagnosed as having IBD who underwent bariatric operations in 2 medical centers between October 2006 and January 2014 were retrieved and analyzed. RESULTS: One male and 9 female morbidly obese IBD patients (8 with Crohn's disease and 2 with ulcerative colitis) underwent bariatric surgery. Their mean age was 40 years, and their mean body mass index was 42.6 kg/m2. Nine of them underwent a laparoscopic sleeve gastrectomy and 1 underwent a laparoscopic adjustable gastric band. Eight patients had obesity-related co-morbidities, including type 2 diabetes, hypertension, sleep apnea, osteoarthropathy, etc. After a median follow-up of 46 months (range 9-67), all of the patients lost weight, with an excess weight loss of 71%, and 10 out of 16 obesity-related co-morbidities were resolved. There was 1 complication not related to IBD, and no IBD exacerbation. CONCLUSION: Bariatric surgery was safe and effective in our morbidly obese IBD patients. The surgical outcome in this selected patient group was similar to that of comparable non-IBD patients. PMID- 25547058 TI - Comment on: A case-matched study of the differences in bone mineral density 1 year after 3 different bariatric procedures. PMID- 25547059 TI - Papillary Cystadenoma of Minor Salivary Glands: Report of 11 Cases and Review of the English Literature. AB - Papillary cystadenoma is a rare, benign salivary gland tumor which is well circumscribed, containing cystic cavities with intraluminal papillary projections. Only 19 cases arising within minor salivary glands (MnSG) from the oral cavity sites have been reported in the English literature (PubMed 1958 2014). We report 11 new cases of MnSG papillary cystadenomas in conjunction with a review of the literature. Demographic information, clinical and histologic features, treatment and prognosis are compiled and discussed for all 30 cases reported in the English literature. PMID- 25547060 TI - Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs. AB - PURPOSE: To compare the effects of metformin with insulin on maternal and neonatal outcomes in gestational diabetes mellitus (GDM). METHODS: A literature search in PUBMED, EMBASE, Science Direct, Springer link, and Cochrane library was conducted using the following search terms: "Gestational Diabetes" or "GDM", and "insulin" and "metformin". Quality assessment of included studies was determined with Quality Assessment of Diagnostic Accuracy Studies. Review Manger 5.2 was used to analyze mean difference (MD)/risk ratio (RR) and 95 % confidence interval (CI) in random-effects model or fixed-effects model depending on the level of heterogeneity. RESULTS: A total of 11 studies were identified. There was no significant difference of the effect on maternal outcomes between the two treatments in glycohemoglobin A1c levels (P = 0.37), fasting blood glucose (P = 0.66), and the incidence of preeclampsia (P = 0.26); whereas, significantly reduced results were found in the metformin group in pregnancy-induced hypertension (PIH) rate (RR = 0.53, 95 % CI 0.31-0.90, P = 0.02), average weight gains after enrollment (MD = -1.28, 95 % CI -1.54 to -1.01, P < 0.0001), and average gestational ages at delivery (MD = 0.94, 95 % CI -0.21 to -0.01, P = 0.03). Regarding neonatal outcomes, when compared with insulin group, metformin presented significantly lower average birth weights (MD = -44.35, 95 % CI -85.79 to -2.90, P = 0.04), incidence of hypoglycemia (RR = 0.69, 95 % CI 0.55-0.87, P = 0.001) and neonatal intensive care unit (NICU) (RR = 0.82, 95 % CI 0.67-0.99, P = 0.04). CONCLUSION: Metformin can significantly reduce several adverse maternal and neonatal outcomes including PIH rate, incidence of hypoglycemia and NICU, thus it may be an effective and safe alternative or additional treatment to insulin for GDM women. PMID- 25547061 TI - Congenital HCMV and assisted reproduction: Why not use the chance for primary screening? AB - HCMV is the leading cause of congenital infection, with 0.5-0.9% of infants affected in Europe, and primary maternal infection from the preconceptional phase to the first half of pregnancy bears the highest risk for long-term sequelae-like mental retardation, visual impairment, and progressive sensorineural hearing loss. As compared to couples conceiving spontaneously those under infertility treatment are well accessible to primary HCMV prevention. Since they face higher risk pregnancies this chance should be considered. The concept comprises serological screening for HCMV-IgG, including the partner where appropriate, defining individual risk factors, and counselling on hygiene at the initial assessment of infertility treatment. If seroconversion occurs, the subsequent treatment cycles should be postponed by 6 months. Uncertainties of diagnosis in early pregnancy which may lead to precautious elective termination can be prevented. A newborn at risk of congenital HCMV infection can be identified and scheduled for laboratory and paediatric evaluation within the first 2 weeks of life. PMID- 25547062 TI - Annexin A2 plays a critical role in epithelial ovarian cancer. AB - PURPOSE: This study aimed at investigating the potential role and prognostic significance of Annexin A2 in human epithelial ovarian cancer (EOC). METHODS: Western blot was used to evaluate the expression of Annexin A2 in nine fresh EOC tissues, and immunohistochemical analysis was performed on formalin-fixed paraffin-embedded sections of 119 cases of ovarian cancers. Then, we used Fisher exact test to analyze the correlation between Annexin A2 and clinicopathological parameters. Starvation refeeding was used to detect the alteration of Annexin A2 in HO8910 cell cycle. RESULTS: Annexin A2 was overexpressed in carcinoma tissues compared with normal tissue, and the expression levels gradually increased from G1 to G3. Moreover, the staining of tissue microarray was consistent with the result we got from western blot, increasing from G1 to G3 gradually, and it was related to the Figo stage (P = 0.005), histologic grade (P = 0.002), ascite (P < 0.001), malignant tumor cells (P < 0.001), residual tumor size (P = 0.044), Ki-67 (P = 0.003). Kaplan-Meier analysis revealed that high Annexin A2 expression was significantly associated with poor prognoses of the patients (P < 0.001). Multivariate analysis demonstrated that Annexin A2 was an independent prognostic indicator for overall survival. Starvation refeeding indicated that Annexin A2 was related to EOC cell proliferation. CONCLUSIONS: We could hypothesize that Annexin A2 acted a critical role in EOC cell proliferation, and may be used as a potential and novel therapeutic target for EOC. These data suggest that Annexin A2 may promote the progression of EOC and be a therapeutic target for EOC therapy. PMID- 25547063 TI - Associations between pregnancy outcomes and unexplained high and low maternal serum alpha-fetoprotein levels. AB - OBJECTIVE: To determine the relationship between adverse pregnancy outcomes and maternal serum alpha-fetoprotein (MSAFP) levels. MATERIALS AND METHODS: A retrospective cohort study was conducted on consecutive singleton pregnancies, screened for fetal Down syndrome, in the northern part of Thailand. The prospective database of our fetal Down screening program was assessed to recruit all consecutive records. Pregnancies with medical complication and fetal abnormality were excluded. The recruited women were categorized into three groups: normal (>=0.76 to <=2.0 MoM), low (<0.76 MoM) and high (>2.0 MoM) MSAFP levels. RESULTS: Of 7,110 screened women, 5,486 met inclusion criteria, including 240; 5,016 and 230 in the group of high, normal and low MSAFP levels, respectively. The rates of preterm birth, pregnancy-induced hypertension (PIH), fetal growth restriction (FGR), fetal death, low birth weight (LBW) and low APGAR scores were significantly higher in women with high MSAFP levels (11.7 vs. 6.6 %, 7.5 vs. 3.3 %, 7.5 vs. 3.3 %, 2.1 vs. 0.3 %, 15.8 vs. 6.7 %, and 2.9 vs. 0.5 % respectively), with relative risk of 1.76, 2.28, 2.27, 7.46, 2.35 and 6.09, respectively. The rates of preterm birth, FGR and LBW were significantly lower in low MSAFP levels with relative risk of 0.39, 0.26 and 0.26, respectively, whereas the rates of PIH and fetal death and low Apgar scores were not significantly different. CONCLUSIONS: Pregnant women with high MSAFP levels had an increased risk of poor pregnancy outcomes, while those with low MSAFP levels had a significantly lower risk of such outcomes. PMID- 25547064 TI - Conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis: a randomized clinical trial. AB - OBJECTIVE: Efficacy of the conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis was compared. METHODS: In a randomized clinical trial 44 patients with acute bacterial meningitis were randomly assigned to the conventional- or high-dose vancomycin groups. Clinical and laboratory parameters were used for evaluation of response to the treatment regimens. RESULTS: In the high-dose group, leukocytosis and fever resolved significantly faster than those in the conventional group. Furthermore, the length of hospitalization was shorter and Glasgow Coma Scale at the end of 10th day was significantly lower in the high dose compared to the conventional group. Trend of creatinine clearance changes did not differ significantly between the two groups. CONCLUSION: In comparison to the conventional-dose regimen, the high-dose vancomycin regimen was associated with significantly more favorable clinical response without increase in the incidence of nephrotoxicity in patients with acute bacterial meningitis. PMID- 25547065 TI - RC3/neurogranin negatively regulates extracellular signal-regulated kinase pathway through its interaction with Ras. AB - RC3/neurogranin is a postsynaptic protein and plays pivotal roles in spatial learning and emotional anxiety as well as synaptic plasticity. The expression level of RC3 is dynamically changed during developmental stages, but the function of RC3 in brain development is not well understood yet. Neurotrophins interact with tropomyosin-related kinase receptors to activate Ras-extracellular signal regulated kinase (ERK) pathway and can also induce neuronal differentiation. In this study, we demonstrate that RC3 inhibits Ras-ERK pathway by interaction with Ras and controls neurite outgrowth induced by neurotrophins. In PC12 cells, RC3 inhibits nerve growth factor (NGF)-induced activation of Ras and thereby ERK1/2 signaling cascade as well as neurite outgrowth induced by NGF. We found Ras is the target of the inhibitory function of RC3, because RC3 interacts with Ras and suppresses the elevated affinity of Ras to Ras-binding domain of Raf-1. Meanwhile, already activated Raf-1 by Ras activity is not affected by RC3. Furthermore, depletion of RC3 by RNA interference drastically enhances the stimulation of ERK1/2 and neurite outgrowth induced by brain-derived neurotrophic factor in hippocampal neurons. These findings suggest that RC3 is a novel natural inhibitor of Ras-ERK1/2 signaling axis, leading to negatively regulate neuronal differentiation induced by neurotrophins. PMID- 25547066 TI - Rutin stimulates sarcoplasmic reticulum Ca(2+)-ATPase activity (SERCA1) and protects SERCA1 from peroxynitrite mediated injury. AB - In this study we analyzed the protective action of the flavonoid rutin on peroxynitrite (ONOO(-)) mediated impairment of sarcoplasmic reticulum Ca(2+) ATPase (SERCA1 isoform), especially related to posttranslational and conformational changes. Rutin concentration dependently protected ONOO(-) induced SERCA1 activity decrease with effective concentration EC50 of 18 +/- 1.5 uM. Upon treatment with ONOO(-), this flavonoid also prevented SERCA1 from thiol group oxidation and significantly reduced tyrosine nitration and protein carbonyl formation. In the absence of ONOO(-), rutin (250 and 350 uM) stimulated SERCA1 activity at 2.1 mM [ATP] and 10 uM [Ca(2+)]free. According to changes in the kinetic parameters V max and K m with regard to [ATP], rutin (250 uM) increased the rate of enzyme catalysis and decreased the affinity of SERCA1 to ATP. FITC fluorescence decreased in the presence of rutin (150 and 250 uM), indicating conformational changes in the cytosolic ATP binding region of SERCA1. In silico study confirmed the binding of rutin in the cytosolic region of SERCA1, in the vicinity of the ATP binding site. Residue Glu183 localized within the conserved TGES loop was identified to play a key role in rutin-SERCA1 interaction (H-bond length of 1.7 A), elucidating the ability of rutin to affect the affinity of SERCA1 to ATP. The binding of rutin in the proximity of Lys515 is likely to cause a decrease in FITC fluorescence. PMID- 25547068 TI - Cricothyrotomy training increases adherence to the ASA difficult airway algorithm in a simulated crisis: a randomized controlled trial. AB - PURPOSE: Non-adherence to airway guidelines in a 'cannot intubate-cannot oxygenate' (CICO) crisis situation is associated with adverse patient outcomes. This study investigated the effects of hands-on training in cricothyrotomy on adherence to the American Society of Anesthesiologists difficult airway algorithm (ASA-DAA) during a simulated CICO scenario. METHODS: A total of 21 postgraduate second-year anesthesia residents completed a pre-test teaching session during which they reviewed the ASA-DAA, became familiarized with the Melker cricothyrotomy kit, and watched a video on cricothyrotomy. Participants were randomized to either the intervention 'Trained' group (n = 10) (taught and practiced cricothyrotomy) or the control 'Non-Trained' group (n = 11) (no extra training). After two to three weeks, performances of the groups were assessed in a simulated CICO scenario. The primary outcome measure was major deviation from the ASA-DAA. Secondary outcome measures were (1) performance of the four categories of non-technical behaviours using the validated Anaesthetists' Non Technical Skills scale (ANTS) and (2) time to perform specific tasks. RESULTS: Significantly more non-trained than trained participants (6/11 vs 0/10, P = 0.012) committed at least one major ASA-DAA deviation, including failure to insert an oral airway, failure to call for help, bypassing the laryngeal mask airway, and attempting fibreoptic intubation. ANTS scores for all four categories of behaviours, however, were similar between the groups. Trained participants called for help faster [26 (2) vs 63 (48) sec, P = 0.012] but delayed opening of the cricothyrotomy kit [130 (50) vs 74 (36) sec, P = 0.014]. CONCLUSION: Hands-on training in cricothyrotomy resulted in fewer major ASA-DAA deviations in a simulated CICO scenario. Training in cricothyrotomy may play an important role in complying with the ASA-DAA in a CICO situation but does not appear to affect non technical behaviours such as decision-making. PMID- 25547067 TI - Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKalpha-mediated reduction of DNA methyltransferase 1. AB - Hepatocellular carcinoma (HCC), the major histological subtype of primary liver cancer, remains one of the most common malignancies worldwide. Due to the complicated pathogenesis of this malignancy, the outcome for comprehensive treatment is limited. Chinese herbal medicine (CHM) is emerging as a promising choice for its multi-targets and coordinated intervention effects against HCC. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid found in CHM, exerts anti-tumor effects and is emerging as an effective compound for cancer prevention and therapy. However, the molecular mechanisms underlying the action of UA remain largely unknown. In this study, we showed that UA inhibited the growth of HCC cells and induced apoptosis in the dose- and time-dependent fashion. Furthermore, we found that UA induced phosphorylation of AMP-activated protein kinase alpha (AMPKalpha) and suppressed the protein expression of DNA methyltransferase 1 (DNMT1) in the dose-dependent manner. The inhibitor of AMPK, compound C blocked, while an activator of AMPK, metformin augmented the effect of UA on DNMT1 expression. In addition, UA suppressed the expression of transcription factor Sp1. Conversely, overexpression of Sp1 reversed the effect of UA on DNMT1 expression and cell growth. Collectively, our results show for the first time that UA inhibits growth of HCC through AMPKalpha-mediated inhibition of Sp1; this in turn results in inhibition of DNMT1. This study reveals a potential novel mechanism by which UA controls growth of HCC cells and suggests that DNMT1 could be novel target for HCC chemoprevention and treatment. PMID- 25547069 TI - Abstracts of the Canadian Anesthesiologists' Society Annual Meeting, June 13-16, 2014, St John's, Canada. PMID- 25547071 TI - The induction of cell death by phosphine silver(I) thiocyanate complexes in SNO esophageal cancer cells. AB - Esophageal cancer is one of the least studied cancers and is found to be prominent in black South African males. It is mainly diagnosed in the late stages, and patients tend to have a low 5-year survival rate of only 10%. Silver is generally used as an antimicrobial agent, with limited reports on anticancer studies. In this study, dimeric silver(I) thiocyanate complexes were used containing a variation of 4-substitued triphenylphosphines, including [AgSCN(PPh(3))(2)](2) (1), [AgSCN{P(4-MeC(6)H(4))(3)}(2)](2) (2), [AgSCN{P(4 FC(6)H(4))(3)}(2)](2) (3) and [AgSCN{P(4-ClC(6)H(4))(3)}(2)](2) (4). All four complexes, with their respective phosphine ligands, PPh(3) (L1), P(4 MeC(6)H(4))(3) (L2), P(4-FC(6)H(4))(3) (L3) and P(4-ClC(6)H(4))(3) (L4), were subjected to in vitro toxicity studies in SNO-esophageal cancer cells, using an alamarBlue((r)) assay. Morphological changes, including blebbing and apoptotic body formation, were observed. Phosphatidylserine externalization, a marker of apoptosis, was quantified by flow cytometry. The phosphine ligands L1-L4, on their own, had minimal effect on the malignant while complexes 1-4 resulted in significant cell death. A 10x decreased concentration of these complexes had similar effects than cisplatin, used as the positive control. These complexes show promise as anticancer agents. PMID- 25547072 TI - Survival characteristics of composite restorations in primary teeth. AB - OBJECTIVES: This retrospective study analyzed restoration survival of composite fillings in children with at high caries risk in relation to age, sex, operator, tooth type, filling extension, and material used. MATERIALS AND METHODS: Among 667 children treated in 2004-2012 in a university setting without sedation or general anesthesia, 2388 composite fillings were included. Relevant data from regular recall intervals were retrieved from patients' records. Either total-etch or a self-etch adhesive combined with flowable and/or (nano)hybrid composite was used. The Kaplan-Meier estimator and Cox proportional hazard analysis with backward elimination model were applied for survival analysis. RESULTS: For the observation period of 8 years (mean 1.7 years), the cumulative failure rate was 17.2 % with annual failure rates of 10.0 %. In 8.8 % of the cases, fillings failed due to secondary caries. In 8.3 % technical failure due to total filling loss, loosening, marginal gaps, or tooth fracture occurred. Tooth type, filling extension, age, operator, dental dam, and type of adhesive were significant for survival (p < 0.05). CONCLUSIONS: Filling survival was comparably lower to composite restorations observed in prospective clinical studies on permanent teeth and other tooth-colored restoratives used in primary teeth. Due to the very high caries risk and young age of the population, frequent loss due to secondary caries was observed. With respect to the high caries risk, composite restorations can be used to treat carious primary teeth, though a strict caries prevention regimen should be followed to minimize restoration failure. CLINICAL RELEVANCE: Filling loss of composites in the primary dentition is associated with secondary caries on the long term. PMID- 25547070 TI - Anterior cruciate ligament biomechanics during robotic and mechanical simulations of physiologic and clinical motion tasks: a systematic review and meta-analysis. AB - Investigators use in vitro joint simulations to invasively study the biomechanical behaviors of the anterior cruciate ligament. The aims of these simulations are to replicate physiologic conditions, but multiple mechanisms can be used to drive in vitro motions, which may influence biomechanical outcomes. The objective of this review was to examine, summarize, and compare biomechanical evidence related to anterior cruciate ligament function from in vitro simulations of knee motion. A systematic review was conducted (2004 to 2013) in Scopus, PubMed/Medline, and SPORTDiscus to identify peer-reviewed studies that reported kinematic and kinetic outcomes from in vitro simulations of physiologic or clinical tasks at the knee. Inclusion criteria for relevant studies were articles published in English that reported on whole-ligament anterior cruciate ligament mechanics during the in vitro simulation of physiologic or clinical motions on cadaveric knees that were unaltered outside of the anterior-cruciate-ligament intact, -deficient, and -reconstructed conditions. A meta-analysis was performed to synthesize biomechanical differences between the anterior-cruciate-ligament intact and reconstructed conditions. 77 studies met our inclusion/exclusion criteria and were reviewed. Combined joint rotations have the greatest impact on anterior cruciate ligament loads, but the magnitude by which individual kinematic degrees of freedom contribute to ligament loading during in vitro simulations is technique-dependent. Biomechanical data collected in prospective, longitudinal studies corresponds better with robotic-manipulator simulations than mechanical impact simulations. Robotic simulation indicated that the ability to restore intact anterior cruciate ligament mechanics with anterior cruciate ligament reconstructions was dependent on loading condition and degree of freedom examined. PMID- 25547073 TI - Assessment of algorithms for mitosis detection in breast cancer histopathology images. AB - The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues. In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists. PMID- 25547074 TI - Inaccurate and incomplete diagnoses of malignant polyps as a cause of pathologic tumor stage T0 colectomy. AB - The purpose of this study was to retrospectively review cases of pathologic tumor stage T0 (pT0) colectomy for colon cancer to determine whether any cases could be attributed to inaccurate (false-positive) or incomplete biopsy diagnoses. We conducted a search of our laboratory archives for all biopsy diagnoses of invasive colonic adenocarcinoma over a period of 11 years. Rectal carcinomas and those treated neoadjuvantly were excluded. The subset of interest consisted of those biopsies that were followed up by a colectomy specimen with no invasive malignancy. There were 762 biopsy diagnoses of invasive colon cancer, of which 564 (74.0%) had subsequent colectomy. Thirty-two resection cases (5.7%) were classified as pT0 on resection. After review, 2 gastrointestinal pathologists determined that 4 (0.7%) of the original biopsies represented false-positive diagnoses of invasive malignancy. They agreed that 24 cases represented malignant polyps containing invasive adenocarcinoma and disagreed on the presence of invasion in 4 cases. Less than half (15/32, 46.9%) of reviewed cases had included all parameters required, when diagnosing early colon cancer in a polypectomy. We are not aware of any other published quality assurance studies looking specifically at false diagnosis of invasion as a cause of pT0 colon cancer resections. In this retrospective review, most biopsy diagnoses were accurate. However, false-positive biopsy diagnoses of colon cancer do occur and may lead to pT0 colectomy. PMID- 25547075 TI - First detection of an ignored parasite, Encephalitozoon cuniculi, in different animal hosts in Egypt. AB - Encephalitozoon cuniculi is an obligate intracellular microsporidian parasite that infects a wide range of mammalian hosts. The present study investigated the prevalence of E. cuniculi in different animal hosts from different provinces of Egypt (Alexandria, Behera, and Assuit) using serological (IFAT and ELISA) and molecular (PCR) assays. A total of 324 serum and 274 urine samples were collected from seven different species of animals (cattle, buffaloes, sheep, goat, rabbit, dog, and rat). The results of serological examination confirmed the occurrence of antibodies against E. cuniculi in 38.9 % (126 out of 324) of the examined animals. The significant (P < 0.01) highest positivity was observed in goats (67 %) followed by buffaloes, rabbits, dogs, rat, and cattle (46.42, 41, 40, 36.2, and 28.1 %, respectively), while the least was recorded in sheep (9 %). Behera province showed the highest (P < 0.01) infection rate (40.68 %) followed by Alexandria and Assuit (39.2 and 22.73 %, respectively). The infection rate was significantly higher (P < 0.01) in females (45.34 %) than that in males (30.47 %). Positive cases were observed in all age categories. The highest infection rate (64.66 %) was recorded in the age group 1-5 years and the least was recorded in the age group <1 year (34.85 %).On the other hand, only five positive out of 274 urine samples (1.82 %) were detected by PCR. Our study provides a wide database on prevalence and epidemiology of an ignored parasite (E. cuniculi) for the first time in Egypt. PMID- 25547077 TI - Five-month comparative efficacy evaluation of three ectoparasiticides against adult cat fleas (Ctenocephalides felis), flea egg hatch and emergence, and adult brown dog ticks (Rhipicephalus sanguineus sensu lato) on dogs housed outdoors. AB - This study was designed to compare the efficacy of three topical combinations on dogs in outdoor conditions against adult cat fleas (Ctenocephalides felis), flea egg hatch and emergence, and against adult brown dog ticks (Rhipicephalus sanguineus sensu lato). Treatment was performed on day 0 with a placebo; dinotefuran, pyriproxifen and permethrin (DPP); fipronil and (S)-methoprene (FM) or imidacloprid and permethrin (IP). Dogs (n = 32), housed outdoors for 7 months, were treated monthly for four consecutive months (on days 0, 30, 60 and 90) and infested with ~100 unfed adult fleas on days 14, 55, 74, 115 and 150 and with ~50 unfed adult ticks on days 28, 44, 88 and 104. Adult fleas were counted and removed 24 h after infestation. Immediately after flea removal, dogs were reinfested with ~100 new adult fleas 72 h prior to egg collection for up to 48 h. Flea eggs were incubated for 32 days, and newly emerged adults were counted. Ticks were counted and removed 48 h after each infestation. FM had >90 % efficacy against fleas at each time point and variable efficacy against ticks (38.0-99.6 %). Efficacy of IP was <90 % against fleas at day 64 and against ticks at day 30 of the first post-treatment. No flea eggs were laid in the treated groups until infestation was carried out >60 days after the last treatment. Despite challenging weather conditions, DPP was highly effective, providing >90 % efficacy against adult ticks as well as adult and immature fleas at every time point of the study. PMID- 25547078 TI - Population identification of Sarcoptes hominis and Sarcoptes canis in China using DNA sequences. AB - There has been no consistent conclusion on whether Sarcoptes mites parasitizing in humans and animals are the same species. To identify Sarcoptes (S.) hominis and S. canis in China, gDNA was extracted from individual mites (five from patients with scabies and five from dogs with mange) for amplification of rDNA ITS2, mtDNA 16S, and cox1 fragment sequences. Then, the sequences obtained were aligned with those from different hosts and geographical locations retrieved from GenBank and sequence analyses were conducted. Phylogenetic trees based on 317-bp mtDNA cox1 showed five distinctive branches (species) of Sarcoptes mites, four for S. hominis (S. hominis Chinese, S. nr. hominis Chinese, S. hominis Australian, and S. hominis Panamanian) and one for S. animal (S. animal). S. animal included mites from nine animal species, with S. canis China, S. canis Australia, and S. canis USA clustering as a subbranch. Further sequence divergence analysis revealed no overlap between intraspecific (<= 2.6 %) and interspecific (2.6-10.5 %) divergences in 317-bp mtDNA cox1. However, overlap was detected between intra- and interspecific divergences in 311-bp rDNA ITS2 or 275 bp mtDNA 16S when the divergences exceeded 1.0 %, which resulted in failure in identification of Sarcoptes. The results showed that the 317-bp mtDNA cox1 could be used as a DNA barcode for molecular identification of Sarcoptes mites. In addition, geographical isolation was observed between S. hominis Chinese, S. hominis Australian, and S. hominis Panamanian, but not between all S. canis. S. canis and the other S. animal belonged to the same species. PMID- 25547080 TI - Anaphylactic shock ensuing therapeutic puncture of an echinococcal cyst. AB - Cystic echinococcosis (CE) is a widespread zoonosis. For treating single echinococcal cysts during the last decades, therapeutic puncture of the cyst, aspiration, injection of a scolicide, and re-aspiration (PAIR) has been established as a minimal-invasive alternative method to surgery. A recent review on the complications of therapeutic cyst punctures has shown that dangerous complications occur much less frequently than previously assumed. A case is described where an allergic acute bronchospasm and arterial hypotension led to a life-threatening shock immediately after echinococcal cyst puncture. Fortunately, the situation could be managed by an experienced and well-equipped anesthesiology team. Life-threatening allergic phenomena after puncture of echinococcal cysts may occur less frequently than generally assumed; nevertheless, they must be taken into account, and precautions must be taken to manage serious adverse events. PMID- 25547079 TI - Integrated fly management in European ruminant operations from the perspective of directive 2009/128/EC on sustainable use of pesticides. AB - Integrated pest management (IPM) in agriculture animals remains undeveloped as compared to IPM in crops. With respect to the range of external nuisance arthropods that may bother farm animals, development and implementation of systematic IPM strategies are difficult to carry out. However, recurrent outbreaks of blue tongue disease in sheep and cattle, the public threats regarding the prophylactic use of veterinary insecticides and the need to preserve the efficacy of available actives have to lead the reflexion on new control strategies for arthropod pests of livestock. A recent extension of EU regulation on the use of pesticides in crops provides an opportunity to compare IPM strategies and to suggest new lines of reflection for the control of nuisance pests in ruminants under European conditions. In this paper, actions suggested by the Annex III of the Directive 2009/128/CE on Sustainable Use of Pesticides and related National Action Plans from 28 member states of the EU were reviewed from an animal production perspective by a group of veterinary entomologists. Eight lines of action have been identified and thus challenged with respect to current husbandry practices in modern European ruminant operations. Many IPM strategies for crops were identified to be unsuitable for large animals. Suggestions for implementing tools, opportunities and constraint assessment, and needs for support were also discussed. Only control of pest development sites and monitoring of harmful organisms were considered achievable in the near future; both in conjunction with the use of topical insecticides. Complementary actions such as alternatives to chemical control require further researches and industrial development. Marketing of IGR-based feed additives would be of great interest, but development of new compounds for veterinary medicines is very unlikely with respect to the European regulatory environment and associated cost of development. PMID- 25547081 TI - Embolisation of a proximal type I endoleak post-Nellix aortic aneurysm repair complicated by reflux of Onyx into the Nellix endograft limb. AB - We report the first case of intervention for a proximal type 1 endoleak following Nellix endovascular aneurysm sealing repair of an aortic aneurysm. This was complicated by migration of Onyx into one of the Nellix graft limbs causing significant stenosis. Subsequent placement of a covered stent to affix the Onyx between the stent and the wall of the Nellix endograft successfully restored stent patency. PMID- 25547082 TI - Acute stroke and obstruction of the extracranial carotid artery combined with intracranial tandem occlusion: results of interventional revascularization. AB - PURPOSE: Due to high thrombus load, acute stroke patients with tandem obstructions of the extra- and intracranial carotid arteries or the middle cerebral artery show a very limited response to systemic thrombolysis. Interventional treatment with mechanical thrombectomy-often in combination with acute stenting of underlying atherosclerotic stenosis or dissection-is increasingly used. It has been shown that such complex interventions are technically feasible. The lack of optimal management strategies and clinical data encouraged us to review our acute stroke interventions in patient with anterior circulation tandem lesions to determine lesion patterns, interventional approaches, and angiographic or clinical outcomes. PATIENTS AND METHODS: We retrospectively analyzed a series of 39 consecutive patients with intracranial vessel occlusion of the anterior circulation simultaneously presenting with high grade cervical internal carotid artery (ICA) stenosis or occlusion. RESULTS: Emergency ICA stent implantation was technically feasible in all patients, and intracranial recanalization with TICI >= 2b was reached in a large number of patients (64 %). Good clinical outcomes (mRS <= 2 at 3 months) were achieved in one third of the patients (36 %). Symptomatic hemorrhages occurred in four patients (10 %). Mortality was 10 %. CONCLUSION: Endovascular recanalization of acute cervical carotid artery occlusion was technically feasible in all patients, and resulted in high extra- and intracranial revascularization rates. A trend for favorable clinical outcome was seen in a higher TICI score, younger age, good collateral status, and combined IV rTPA and endovascular therapy. PMID- 25547076 TI - Helminthes and insects: maladies or therapies. AB - By definition, parasites cause harm to their hosts. But, considerable evidence from ancient traditional medicine has supported the theory of using parasites and their products in treating many diseases. Maggots have been used successfully to treat chronic, long-standing, infected wounds which failed to respond to conventional treatment by many beneficial effects on the wound including debridement, disinfection, and healing enhancement. Maggots are also applied in forensic medicine to estimate time between the death and discovery of a corpse and in entomotoxicology involving the potential use of insects as alternative samples for detecting drugs and toxins in death investigations. Leeches are segmented invertebrates, famous by their blood-feeding habits and used in phlebotomy to treat various ailments since ancient times. Leech therapy is experiencing resurgence nowadays in health care principally in plastic and reconstructive surgery. Earthworms provide a source of medicinally useful products with potential antimicrobial, antiviral, and anticancer properties. Lumbrokinases are a group of fibrinolytic enzymes isolated and purified from earthworms capable of degrading plasminogen-rich and plasminogen-free fibrin and so can be used to treat various conditions associated with thrombotic diseases. Helminth infection has been proved to have therapeutic effects in both animal and human clinical trials with promising evidence in treating many allergic diseases and can block the induction of or reduce the severity of some autoimmune disorders as Crohn's disease or ulcerative colitis. What is more, venomous arthropods such as scorpions, bees, wasps, spiders, ants, centipedes, snail, beetles, and caterpillars. The venoms and toxins from these arthropods provide a promising source of natural bioactive compounds which can be employed in the development of new drugs to treat diseases as cancer. The possibility of using these active molecules in biotechnological processes can make these venoms and toxins a valuable and promising source of natural bioactive compounds. The therapeutic use of helminthes and insects will be of great value in biomedicine and further studies on insect toxins will contribute extensively to the development of Biomedical Sciences. PMID- 25547084 TI - The elderly also deserves to undergo therapeutic endoscopy safely under sedation with propofol by gastroenterologists. PMID- 25547083 TI - Consumers' questions about antipsychotic medication: revealing safety concerns and the silent voices of young men. AB - PURPOSE: Little is known about consumer information needs regarding antipsychotic medicines. Medicines call centre (MCC)-derived data are underutilised; and could provide insight into issues of importance to consumers. This study aimed to explore consumers' information needs about antipsychotic medication sought from a national MCC in Australia. METHODS: Questions received by the National Prescribing Service Medicines Line relating to antipsychotic medication from September 2002 to June 2010 were examined by antipsychotic subclass and in relation to other medication queries. RESULTS: We identified 6,295 calls related to antipsychotic medication. While female callers predominated, the percentage of males with antipsychotic questions was statistically significantly higher than for other medication calls (33.9 vs 22.6 %; p < 0.001). There were distinct gender differences in medicines information seeking across age ranges. Younger men asked about second-generation antipsychotics, shifting toward first generation antipsychotics after 45 years of age. Female interest in both subclasses was comparable, irrespective of age. Most callers asking about antipsychotics sought information for themselves (69.4 %). Callers were primarily concerned about safety (57.0 %), especially adverse drug reactions (28.8 %), and were more often prompted by a worrying symptom (23.8 %) compared with the rest of calls (17.2 %). Trends of antipsychotic questions received corresponded with antipsychotic prescription data. CONCLUSIONS: The number of calls received by this MCC over time reveals an ongoing consumer need for additional, targeted information about antipsychotics. Noticeable was the relatively high frequency of young male callers asking about antipsychotics, indicating that call centres could be a way to reach these traditionally poor users of health services. PMID- 25547085 TI - Benign colorectal stricture: an answer to the balloon or stent question? PMID- 25547087 TI - Current and emerging biologics for ulcerative colitis. AB - Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are be ing investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are be-ing used for treating ulcerative colitis. Recently, golimumab, another anti TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage. PMID- 25547086 TI - Diagnosis and management of high risk group for gastric cancer. AB - Gastric cancer is associated with high morbidity and mortality worldwide. To reduce the socioeconomic burden related to gastric cancer, it is very important to identify and manage high risk group for gastric cancer. In this review, we describe the general risk factors for gastric cancer and define high risk group for gastric cancer. We discuss strategies for the effective management of patients for the prevention and early detection of gastric cancer. Atrophic gastritis (AG) and intestinal metaplasia (IM) are the most significant risk factors for gastric cancer. Therefore, the accurate selection of individuals with AG and IM may be a key strategy for the prevention and/or early detection of gastric cancer. Although endoscopic evaluation using enhanced technologies such as narrow band imaging-magnification, the serum pepsinogen test, Helicobacter pylori serology, and trefoil factor 3 have been evaluated, a gold standard method to accurately select individuals with AG and IM has not emerged. In terms of managing patients at high risk of gastric cancer, it remains uncertain whether H. pylori eradication reverses and/or prevents the progression of AG and IM. Although endoscopic surveillance in high risk patients is expected to be beneficial, further prospective studies in large populations are needed to determine the optimal surveillance interval. PMID- 25547089 TI - Successful stone removal by endoscopic retrograde cholangiopancreatography in situs inversus totalis with Billroth-II gastrectomy. PMID- 25547090 TI - Use of electronic health records to support smoking cessation. AB - BACKGROUND: Health information systems such as electronic health records (EHR), computerized decision support systems, and electronic prescribing are potentially valuable components to improve the quality and efficiency of clinical interventions for tobacco use. OBJECTIVES: To assess the effectiveness of electronic health record-facilitated interventions on smoking cessation support actions by clinicians, clinics, and healthcare delivery systems and on patient smoking cessation outcomes. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, and reference lists and bibliographies of included studies. We searched for studies published between January 1990 and July 2014. SELECTION CRITERIA: We included both randomized studies and non-randomized studies that reported interventions targeting tobacco use through an EHR in healthcare settings. The intervention could include any use of an EHR to improve smoking status documentation or cessation assistance for patients who use tobacco, either by direct action or by feedback of clinical performance measures. DATA COLLECTION AND ANALYSIS: Characteristics and content of the interventions, participants, outcomes and methods of the included studies were extracted by one author and checked by a second. Because of wide variation in measurement of outcomes, we were not able to conduct a meta-analysis. MAIN RESULTS: We included six group randomized trials, one patient randomized study, and nine non-randomized observational studies of fair to good quality that tested the use of an existing EHR to improve documentation and/or treatment of tobacco use. None of the studies included a direct assessment of patient quit rates. Overall, these studies found only modest improvements in some of the recommended clinician actions on tobacco use. AUTHORS' CONCLUSIONS: Documentation of tobacco status and referral to cessation counselling appears to increase following EHR modifications designed to prompt the recording and treating of tobacco use at healthcare visits. There is a need for additional research to enhance the potential of EHRs to prompt additional tobacco use treatment and cessation outcomes in healthcare settings. PMID- 25547088 TI - Celiac disease: a disorder emerging from antiquity, its evolving classification and risk, and potential new treatment paradigms. AB - Celiac disease is a chronic genetically based gluten-sensitive immune-mediated enteropathic process primarily affecting the small intestinal mucosa. The disorder classically presents with diarrhea and weight loss; however, more recently, it has been characterized by subclinical occult or latent disease associated with few or no intestinal symptoms. Diagnosis depends on the detection of typical histopathological biopsy changes followed by a gluten-free diet response. A broad range of clinical disorders may mimic celiac disease, along with a wide range of drugs and other therapeutic agents. Recent and intriguing archeological data, largely from the Gobleki Tepe region of the Fertile Crescent, indicate that celiac disease probably emerged as humans transitioned from hunter gatherer groups to societies dependent on agriculture to secure a stable food supply. Longitudinal studies per-formed over several decades have suggested that changes in the prevalence of the disease, even apparent epidemic disease, may be due to superimposed or novel environmental factors that may precipitate its appearance. Recent therapeutic approaches are being explored that may supplement, rather than replace, gluten-free diet therapy and permit more nutritional options for future management. PMID- 25547091 TI - Extended distal pancreatectomy for pancreatic adenocarcinoma with splenic vein thrombosis and/or adjacent organ invasion. AB - BACKGROUND: Patients with adenocarcinoma of the pancreatic body/tail and associated vascular thrombosis or adjacent organ invasion are suboptimal candidates for resection. We hypothesized that extended distal pancreatectomy (EDP) for locally advanced adenocarcinoma is associated with a survival benefit. METHODS: We retrospectively reviewed a prospectively collected database of patients who underwent distal pancreatectomy (DP) for adenocarcinoma at a single academic institution (1996 to 2011) with greater than or equal to 2 years of follow-up. RESULTS: Among 680 DP patients, 93 were indicated for pancreatic adenocarcinoma. Splenic vein thrombosis (n = 26) did not significantly affect morbidity, mortality, or survival. Standard DP was performed in 70 patients and 23 underwent EDP with no difference in morbidity/mortality. Patients with EDP had a survival comparable with patients with standard DP (disease-free survival 18 vs 12 months = .8; overall survival 23 vs 17 months, P =.6). There was no difference in survival between EDP patients with versus without pathologic invasion of adjacent organs, but a trend favored those without. CONCLUSION: EDP is safe and should be considered in fit patients with locally advanced adenocarcinoma. PMID- 25547092 TI - Outcomes and charges associated with outpatient inguinal hernia repair according to method of anesthesia and surgical approach. AB - BACKGROUND: We conducted this study to compare short-term outcomes and charges between methods of hernia repair and anesthesia in the outpatient setting. METHODS: Using New York's state ambulatory surgery databases, we identified discharges for patients who underwent inguinal hernia repair. Patients were grouped by method of hernia repair. We compared hospital-based acute care encounters and total charges across groups. RESULTS: Locoregional anesthesia (5.2%) experienced a similar frequency of hospital-based acute care encounters within 30 days of discharge when compared with patients receiving general (6.0%) or having a laparoscopic procedure (6.0%). Risk-adjusted charges increased across groups (locoregional = $6,845 vs general = $7,839 vs laparoscopic = $11,340, P < .01). CONCLUSION: Open inguinal hernia repair under local anesthesia reduces healthcare charges. PMID- 25547093 TI - Single incision versus conventional multiport laparoscopic appendectomy: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: The efficacy of single incision laparoscopic appendectomy (SILA) in comparison with conventional multiport laparoscopic appendectomy (CMLA) has not been conclusively determined. METHODS: A systematic literature review (Medline, EMBASE, Science Citation Index, and Cochrane Central Register of Controlled Trials) was performed. Meta-analyses of randomized controlled trials (RCTs) comparing SILA with CMLA were carried out by RevMan 5.0 software. RESULTS: Eleven RCTs comparing SILA and CMLA were included. Overall, 1,216 patients were operated on: 611 cases by SILA versus 605 cases by CMLA. Compared with CMLA, SILA was associated with increased procedural difficulty, prolonged procedural duration, shorter length of hospital stay, earlier return to normal activity and better cosmesis. There were no significant differences in postoperative pain scores and complication rates between SILA and CMLA. CONCLUSION: The current best evidence shows SILA holds the promise of improving postoperative recovery and cosmetic result with equal efficacy and safety, whereas it is associated with higher surgical difficulty with longer surgical time when compared with CMLA. PMID- 25547096 TI - Antioxidant Supplementation on Cancer Risk and Concurrent Use of Antioxidants during Cancer Therapy: An Update. AB - Some chemotherapeutic agents and radiation therapy generate reactive oxygen species (ROS), which diminish the cellular antioxidant capacity, and a ROS level beyond a threshold leads to apoptosis and cancer cell death. Cancer patients take antioxidant supplements widely in order to prevent toxic side effects of chemotherapy and radiation therapy to normal tissues.. However, recent studies have demonstrated that the effects of antioxidant supplementation in cancer therapy were largely disappointing. Despite nearly two decades of research investigating the use of dietary antioxidant supplementation during conventional chemotherapy and radiation therapy, controversy remains about the efficacy and safety of these complementary treatments. Most studies found that antioxidant supplements do not reduce the risk for cancer or prevent tumour growth; at the contrary, these interventions resulted in some cases to be harmful to the patients. There is an urgent need to develop an evidence-based guidance on antioxidant supplementation, in order to obtain the best possible care and to avoid risky treatments for cancer patients. PMID- 25547094 TI - Correspondence. PMID- 25547095 TI - Antioxidant capacities of flavones and benefits in oxidative-stress related diseases. AB - Flavonoids, a group of secondary metabolites widely distributed in the plant kingdom, have been acknowledged for their interesting medicinal properties. Among them, natural flavones, as well as some of their synthetic derivatives, have been shown to exhibit several biological activities, including antioxidant, anti inflammatory, antitumor, anti-allergic, neuroprotective, cardioprotective and antimicrobial. The antioxidant properties of flavones allow them to demonstrate potential application as preventive and attenuating agents in oxidative stress, i.e., a biological condition that is closely associated to aging process and several diseases. Some flavones interfere in distinct oxidative-stress related events by directly reducing the levels of intracellular free radicals (hydroxyl, superoxide and nitric oxide) and/or of reactive species (e.g. hydrogen peroxide, peroxynitrite and hypochlorous acid) thus preventing their amplification and the consequent damage of other biomolecules such as lipids, proteins and DNA. Flavones can also hinder the activity of central free radical-producing enzymes, such as xanthine oxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) or inducible nitric oxide synthase (iNOS) and can even modulate the intracellular levels of pro-oxidant and/or antioxidant enzymes. The evaluation of flavones antioxidant ability has been extensively determined in chemical or biological in vitro models, but in vivo therapy with individual flavones or with flavones-enriched extracts has also been reported. The present manuscript revises relevant studies focusing the preventive effects of flavones on stress-related diseases, namely the neurological and cardiovascular diseases, and diabetes and its associated complications. PMID- 25547097 TI - Overlapping the Tryptophan Catabolite (TRYCAT) and Melatoninergic Pathways in Alzheimer's Disease. AB - Activation of the trptophan catabolite (TRYCAT) pathways by oxidative and nitrosative stress and proinflammatory cytokine-driven indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) leads to the synthesis of a number of neuroregulatory TRYCATs, such as kynurenic acid and quinolinic acid. Such TRYCATs have significant impacts on neuronal functioning and survival contributing to the changes seen in Alzheimer's disease (AD), including in its association with depression as well as alterations in the reactivity of immune and glia cells. By decreasing the availability of tryptophan for serotonin synthesis, such IDO and TDO-driven TRYCATs, also decrease the availability of serotonin for N-acetylserotonin (NAS) and melatonin synthesis. The loss of NAS and melatonin has significant consequences for the etiology, course and treatment of AD, including via interactions with altered TRYCATs, but also by changing the levels of trophic support and modulating the patterning of immune activity. In this review, we look at how such interactions of the TRYCAT and melatoninergic pathways link a plethora of previously diffuse data in AD as well as the treatment implications and future research directions that such data would suggest. PMID- 25547099 TI - Electrochemically Driven Supramolecular Interaction of Quinones and Ferrocifens: An Example of Redox Activation of Bioactive Compounds. AB - This review discusses the state of the art, challenges and perspectives in recent applications of electrochemistry in the life sciences. It deals mainly with the elucidation of molecular mechanisms of drug action, drug design and development, involving electron transfer, pharmaco-electrochemistry (the combination of electrochemical and pharmacological assays), and electrochemical studies of membrane models and drug delivery. It aims to shed light on the question: does electrochemistry really contribute to this area? It includes a general introduction for the use of electrochemistry in the life sciences, with a focus on how electrochemistry can uniquely provide both kinetic and thermodynamic information. A number of studies are reported in the literature and from the authors' laboratories, including the investigation of biooxidative/bioreductive activation of pro-drugs, DNA alkylation, electrochemically-based release of reactive oxygen and nitrogen species, with a particular emphasis on quinones, ferrocifens and compounds with mixed-functionality. Within the context of drug delivery and bioavailability, the electrochemical investigation of supramolecular interactions of the chosen classes of compounds with cyclodextrins and lipid bilayers, in relation to their solubilization and vectorization was also carried out. The updated examples herein illustrate how relevant and challenging the integration of electrochemistry, supramolecular and materials chemistry, biochemistry and medical knowledge for the design and development of redox selective molecular approaches is. Many questions related to these fields are still unclear and the search for selectivity toward redox therapeutic agents remains of expanding interest. This review hopes to stimulate researchers to become more involved in this fruitful interface between electrochemistry and the life sciences. PMID- 25547100 TI - Emerging potential of citrus flavanones as an antioxidant in diabetes and its complications. AB - A proper balance between oxidants and antioxidants is necessary in maintaining health and longevity. Alterations in this balance may result in oxidative stress causing functional disorders and diseases. Oxidative stress is considered to play a vital role in the pathogenesis of diabetes and its complications. Flavanones and flavanones-rich botanical extracts have been a subject of great interest for scientific research. Citrus flavanones like naringin and hesperidin exert a variety of biological activities such as anti-oxidant, anti-inflammatory, antihyperglycemic, anti-apoptotic etc. Naringin and hesperidin along with their respective aglycones, naringenin and hesperetin have been shown to attenuate diabetes and its related complications. This review discusses the role of flavanones as a possible emerging treatment for diabetes and its complications along with the possible mechanistic explanations. PMID- 25547101 TI - Is there a Role For Antioxidants in the Prevention of Infection-Associated Carcinogenesis and in the Treatment of Infection-Driven Tumors? AB - Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL related apoptosis and the induction of intracellular oxidative stress. PMID- 25547098 TI - Computational studies of free radical-scavenging properties of phenolic compounds. AB - For more than half a century free radical-induced alterations at cellular and organ levels have been investigated as a probable underlying mechanism of a number of adverse health conditions. Consequently, significant research efforts have been spent for discovering more effective and potent antioxidants / free radical scavengers for treatment of these adverse conditions. Being by far the most used antioxidants among natural and synthetic compounds, mono- and polyphenols have been the focus of both experimental and computational research on mechanisms of free radical scavenging. Quantum chemical studies have provided a significant amount of data on mechanisms of reactions between phenolic compounds and free radicals outlining a number of properties with a key role for the radical scavenging activity and capacity of phenolics. The obtained quantum chemical parameters together with other molecular descriptors have been used in quantitative structure-activity relationship (QSAR) analyses for the design of new more effective phenolic antioxidants and for identification of the most useful natural antioxidant phenolics. This review aims at presenting the state of the art in quantum chemical and QSAR studies of phenolic antioxidants and at analysing the trends observed in the field in the last decade. PMID- 25547102 TI - Melatonin Redox Activity. Its Potential Clinical Application in Neurodegenerative Disorders. AB - Neurodegeneration is the hallmark of many chronic progressive neurogical disorders characterized by specific clinical, morphological and biochemical features. Central nervous system is very sensitive to oxidative stress, which is considered as a key factor of neurodegenerative disorders. Therefore, many therapeutical strategies are focused on molecules with redox activity to re establish the equilibrium between pro and antioxidants. Due to the fact that melatonin readily crosses the blood- brain-barrier, concomitant with its safety profile at the highest dosages makes this dietary supplement very useful in possible clinical application in neurodegeneration. Melatonin is currently marketed in several countries as a dietary supplement with no prescription. Clinical trials have shown different effectiveness of melatonin supplementation in several disorders, including neurodegenerative disorders. Melatonin has unique biochemical properties such as scavenging of hydroxyl, carbonate, alkoxyl, peroxyl and aryl cation radicals and stimulation of activities main antioxidative enzymes (glutathione peroxidase, superoxide dismutase etc.). Moreover, it can suppress nitric oxide synthase. The present paper highlighted the potential clinical role of melatonin in main neurodegenerative diseases including Alzheimer disease, Parkinson disease, amylotrophic lateral sclerosis and multiple sclerosis. Moreover, in this review the main molecular aspects of melatonin in brain cell protection and survival mechanisms were discussed. Therefore, melatonin is regarded as a potential therapeutical agent in clinical application in neurodegenerative disorders, but this findings needs to be confirmed by the larger, more well-designed clinical trials. PMID- 25547103 TI - Oxidative Stress and Neurodegenerative Diseases: Looking for a Therapeutic Solution Inspired on Benzopyran Chemistry. AB - Reactive species are continuously produced in vivo by all body tissues. However, when an imbalance between the reactive species production and the endogenous pool of antioxidants occurs, the resulting oxidative stress can somehow intensify the pathophysiological mechanisms of several diseases, such as neurodegenerative diseases. Although the aetiology of Parkinson's and Alzheimer's diseases is not yet completely understood, it is accepted by the scientific community that the oxidative stress can act as a trigger or can be involved in the course of both diseases. Therefore, the development of an antioxidant-based therapy could be a helpful approach to ameliorate the deleterious effects of oxidative stress in neurodegenerative diseases. Coumarins and chromones are natural or synthetic chemical entities described as privileged structures with diverse biological activities that have been used to design new drugs with potential anti-Alzheimer and anti-Parkinson profiles. Since some of these compounds also displayed potent antioxidant activity, the rationale approach to developing new drugs based on the benzopyran scaffold, as therapeutic alternatives for neurodegenerative diseases, is a valid and compelling topic. This review provides a medicinal chemistry overview on the discovery and development of benzopyran-based compounds endowed with antioxidant, neuroprotective and anti-Alzheimer or anti-Parkinson activities. PMID- 25547104 TI - The Competence of 7,8-Diacetoxy-4-Methylcoumarin and Other Polyphenolic Acetates in Mitigating the Oxidative Stress and their Role in Angiogenesis. AB - The potential role of polyphenolic acetate (PA) in causing diverse biological and pharmacological actions has been well studied in our laboratory. Our investigations, for the first time, established the role of calreticulin transacetylase (CRTAase) in catalyzing the acetylation of nitric oxide synthase (NOS) by Pas leading to robust activation of NOS. 7, 8- Diacetoxy-4 methylcoumarin (DAMC) and other acetoxycoumarins augmented the expression of thioredoxin (TRX) and vascular endothelial growth factor (VEGF) in human peripheral blood mononuclear cells (PBMCs). These findings substantiated our earlier observations that DAMC was a superb inducer of angiogenesis. The enhanced expression of thioredoxin reductase (TRXR) and diminished expression of thioredoxin interacting protein (TRXIP) leading to increased expression and activity of TRX in PBMCs due to the action of DAMC was revealed by real time RT PCR analysis. The possible activation of TRX due to acetylation was confirmed by the fact that TRX activity of PBMCs was enhanced by various acetoxycoumarins in tune with their affinities to CRTAase as substrates. DAMC caused enhanced production of NO by way of acetylation of NOS as mentioned above and thereby acted as an inducer of VEGF. Real time RT-PCR and VEGF ELISA results also revealed the overexpression of TRX. DAMC and other PAs were found to reduce the oxidative stress in cells as proved by significant reduction of intracellular ROS levels. Thus, the crucial role of TRX in DAMC-induced angiogenesis with the involvement of VEGF was established. PMID- 25547105 TI - Development of normative data for the Brazilian adaptation of the University of Pennsylvania Smell Identification Test. AB - It is well established that olfactory dysfunction has significant implications for safety, nutrition, and quality of life. The more reliable standardized tests of olfactory function, such as the University of Pennsylvania Smell Identification Test (UPSIT), assess odor identification ability. Unfortunately, cultural factors can influence such tests, as a number of odors are not universally recognized. In this study, a Portuguese language version of the UPSIT was administered to an age- and sex-stratified prospective sample of 1820 Brazilian subjects. Normative data were developed for a subset of 1578 subjects who reported having no difficulties smelling or tasting. Individuals with a history of head trauma or, in the case of those over the age of 64 years, Mini Mental State Examination Scores <24, were excluded from analysis. As in other populations, the test scores were significantly influenced by age and sex. The median overall difference between the North American and Brazilian UPSIT scores was 2.2 points for men and 0.8 points for women, although subtle age-related differences were also apparent. This research represents that largest clinical study of olfaction ever performed in South America. Correction factors based upon age and sex are provided to allow for direct comparisons of Brazilian test scores to those based upon North American norms. PMID- 25547106 TI - Government must act now or miss chance to legislate on plain tobacco packs, say campaigners. PMID- 25547107 TI - Impact of Medicare Part D on coverage, access, and disparities among new jersey seniors. AB - The authors used a population-based survey of New Jersey residents to assess outcomes associated with implementation of the Medicare Part D program. Between 2001 and 2009, there was a 24% increase in prescription drug coverage among elderly individuals, but also an increase in cost-related access problems. Compared with the pre-Part D period, seniors reporting access problems post-Part D were less likely to be uninsured and more likely to be publicly insured. Cost related access disparities among elderly Blacks and Hispanics relative to elderly Whites persisted from 2001 to 2009, and were partly driven by ongoing disparities related to low income. Such cost-based access problems 3 years into implementation implies that they are not transitory and may reflect inadequate subsidy levels alongside the importance of physician advice about prescriptions in ensuring low-cost medication options for vulnerable patients. Finally, the findings, may also reflect success in enrolling high-need seniors into Part D. PMID- 25547111 TI - Comparative transcriptome profiling in human bicuspid aortic valve disease using RNA sequencing. AB - Intrinsic valvular degeneration and dysfunction is the most common complication of bicuspid aortic valve (BAV) disease. Phenotypically, it ranges from calcific aortic stenosis to redundant or prolapsing regurgitant leaflets. The underlying molecular mechanism underpinning phenotype heterogeneity of valvular degeneration in BAV is poorly understood. We used RNA sequencing (RNA-seq) to identify genes and pathways responsible for the development of valvular degeneration in BAV, compared with tricuspid aortic valve (TAV). Comparative transcriptome analysis was performed on total RNA of aortic valve tissues of patients with diseased BAV (n = 5) and calcified TAV (n = 3). RNA-seq findings were validated by RT-qPCR. A total of 59 and 177 genes were significantly up- and downregulated, respectively, in BAV compared with TAV. Hierarchical clustering indicated heterogeneity within the BAV group, separating those with heavy calcification (BAVc) from those with redundant leaflets and/or minimal calcification (BAVr). Interestingly, the gene expression profile of the BAVc group closely resembled the TAV, with shared up- and downregulation of inflammatory and NOTCH1 signaling pathways, respectively. Downregulation of matrix protease ADAMTS9 and protein aggrecan were observed in BAVr compared with TAV. Dysregulation of fetal gene programs were also present, with notable downregulation of SEMA6B and SEMA3F in BAVr and BAVc compared with TAV, respectively. Upregulation of TBX20 was observed exclusively in BAVr compared with BAVc. In conclusion, diverging molecular mechanisms underpin phenotype heterogeneity of valvular degeneration in BAV and data from the present study suggest that there may be shared mechanisms leading to calcification in BAV and TAV. Recognition of these pathways is fundamental to improve our understanding of the molecular basis of human BAV disease. PMID- 25547110 TI - Temporal analysis of reciprocal miRNA-mRNA expression patterns predicts regulatory networks during differentiation in human skeletal muscle cells. AB - microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through posttranscriptional repression of target genes. miRNAs exert a fundamental level of control over many developmental processes, but their role in the differentiation and development of skeletal muscle from myogenic progenitor cells in humans remains incompletely understood. Using primary cultures established from human skeletal muscle satellite cells, we performed microarray profiling of miRNA expression during differentiation of myoblasts (day 0) into myotubes at 48 h intervals (day 2, 4, 6, 8, and 10). Based on a time-course analysis, we identified 44 miRNAs with altered expression [false discovery rate (FDR) < 5%, fold change > +/-1.2] during differentiation, including the marked upregulation of the canonical myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206. Microarray profiling of mRNA expression at day 0, 4, and 10 identified 842 and 949 genes differentially expressed (FDR < 10%) at day 4 and 10, respectively. At day 10, 42% of altered transcripts demonstrated reciprocal expression patterns in relation to the directional change of their in silico predicted regulatory miRNAs based on analysis using Ingenuity Pathway Analysis microRNA Target Filter. Bioinformatic analysis predicted networks of regulation during differentiation including myomiRs miR-1/206 and miR-133a/b, miRNAs previously established in differentiation including miR-26 and miR-30, and novel miRNAs regulated during differentiation of human skeletal muscle cells such as miR-138-5p and miR-20a. These reciprocal expression patterns may represent new regulatory nodes in human skeletal muscle cell differentiation. This analysis serves as a reference point for future studies of human skeletal muscle differentiation and development in healthy and disease states. PMID- 25547112 TI - Effects of interactive visual feedback training on post-stroke pusher syndrome: a pilot randomized controlled study. AB - OBJECTIVE: We investigated the effects of a computer-generated interactive visual feedback training program on the recovery from pusher syndrome in stroke patients. DESIGN: Assessor-blinded, pilot randomized controlled study. PARTICIPANTS: A total of 12 stroke patients with pusher syndrome were randomly assigned to either the experimental group (N = 7, computer-generated interactive visual feedback training) or control group (N = 5, mirror visual feedback training). MAIN OUTCOME MEASURES: The scale for contraversive pushing for severity of pusher syndrome, the Berg Balance Scale for balance performance, and the Fugl-Meyer assessment scale for motor control were the outcome measures. Patients were assessed pre- and posttraining. RESULTS: A comparison of pre- and posttraining assessment results revealed that both training programs led to the following significant changes: decreased severity of pusher syndrome scores (decreases of 4.0 +/- 1.1 and 1.4 +/- 1.0 in the experimental and control groups, respectively); improved balance scores (increases of 14.7 +/- 4.3 and 7.2 +/- 1.6 in the experimental and control groups, respectively); and higher scores for lower extremity motor control (increases of 8.4 +/- 2.2 and 5.6 +/- 3.3 in the experimental and control groups, respectively). Furthermore, the computer generated interactive visual feedback training program produced significantly better outcomes in the improvement of pusher syndrome (p < 0.01) and balance (p < 0.05) compared with the mirror visual feedback training program. CONCLUSIONS: Although both training programs were beneficial, the computer-generated interactive visual feedback training program more effectively aided recovery from pusher syndrome compared with mirror visual feedback training. PMID- 25547113 TI - Effectiveness of a training package for implementing a community-based occupational therapy program in dementia: a cluster randomized controlled trial. AB - OBJECTIVE: Evaluate the effectiveness of a training package to implement a community occupational therapy program for people with dementia and their caregiver (COTiD). DESIGN: Cluster randomized controlled trial. SUBJECTS: A total of 45 service units including 94 occupational therapists, 48 managers, 80 physicians, treating 71 client-caregiver couples. INTERVENTIONS: Control intervention: A postgraduate course for occupational therapists only. EXPERIMENTAL INTERVENTION: A training package including the usual postgraduate course, additional training days, outreach visits, regional meetings, and access to a reporting system for occupational therapists. Physicians and managers received newsletters, had access to a website, and were approached by telephone. MAIN MEASURES: PRIMARY OUTCOME: The intended adherence of therapists to the COTiD program. This was assessed using vignettes. SECONDARY OUTCOMES: clients' daily functioning, caregivers' sense of competence, quality of life, and self perceived performance of daily activities of both clients and caregivers. Between group differences were assessed using multilevel analyses with therapist and intervention factors as covariates. RESULTS: No significant between-group differences between baseline and 12 months were found for adherence (1.58, 95% CI -0.10 to 3.25), nor for any client or caregiver outcome. A higher number of coaching sessions and higher self-perceived knowledge of dementia at baseline positively correlated with adherence scores. In contrast, experiencing more support from occupational therapy colleagues or having conducted more COTiD treatments at baseline negatively affected adherence scores. CONCLUSION: The training package was not effective in increasing therapist adherence and client caregiver outcomes. This study suggests that coaching sessions and increasing therapist knowledge on dementia positively affect adherence. CLINICAL TRIAL NUMBER: NCT01117285. PMID- 25547114 TI - Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2. AB - Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2 dependent methylation and activation by ERK1/2-dependent phosphorylation. PMID- 25547116 TI - Exploring the ecology of Canada's publicly funded residential long-term care bed supply. AB - Despite Canada's increasing population of seniors and the varying long-term care (LTC) strategies that provinces have implemented, little research has focused on understanding the extent to which publicly funded residential LTC bed supply varies across provinces, or the factors influencing this variation. Our study involved an analysis in which we examined the association of three select jurisdictional characteristics with LTC bed supply: population age demographics, provincial wealth, and provincial investments in home care. No significant cross jurisdictional "ecology" or inter-relatedness was found between the variation in LTC bed supply and any of the examined variables. Interprovincial variation in bed supply also did not statistically influence alternate level of care days specific to LTC waits, suggesting that these days were not influenced simply by differences in LTC bed supply and that other provincial-level factors were in play. PMID- 25547115 TI - Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth. AB - PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN-AKT pathway that can be explored further for cancer treatment. PMID- 25547117 TI - Pemphigus vulgaris: approach to treatment. AB - The therapeutic management of pemphigus vulgaris (PV) is centered around immunosuppression, which can be generalized, as in the use of corticosteroids or steroid sparing agents, or specific, as in therapeutic blockage of autoantibody production, certain cytokines, or signaling pathways. Currently, the backbone of treatment for PV, particularly, first line therapy, remains systemic corticosteroids. Although very effective, the significant side effects of long term corticosteroid usage are well documented. Adjunctive therapies aim to eliminate, or at least decrease, the necessary dose of corticosteroids. Specifically, azathioprine, cyclophosphamide, methotrexate, cyclosporine, mycophenolate mofetil and dapsone are now widely used in PV. Intravenous immunoglobulin (IVIG), plasmapheresis, immunoadsorption, and most recently, rituximab, are other members of the therapeutic armamentarium. However, despite the widening range of treatment options in PV, well-controlled clinical trials and consensus guidelines are lacking. PMID- 25547118 TI - Personalized one-two punches for lung cancer. AB - Discovery of individualized therapies to address resistance to tyrosine kinase inhibitors (TKIs) has been hampered by the inability to test drug combinations on patient samples before and after TKI resistance. A recent study published in Science by Crystal et al. describes a methodology for pharmacological screening using a panel of 76 targeted agents and cell lines made directly from patient biopsies. PMID- 25547120 TI - Highly conductive single-walled carbon nanotube thin film preparation by direct alignment on substrates from water dispersions. AB - A safe, scalable method for producing highly conductive aligned films of single walled carbon nanotubes (SWNTs) from water suspensions is presented. While microfluidic assembly of SWNTs has received significant attention, achieving desirable SWNT dispersion and morphology in fluids without an insulating surfactant or toxic superacid is challenging. We present a method that uniquely produces a noncorrosive ink that can be directly applied to a device in situ, which is different from previous fabrication techniques. Functionalized SWNTs (f SWNTs) are dispersed in an aqueous urea solution to leverage binding between the amine group of urea and the carboxylic acid group of f-SWNTs and obtain urea SWNT. Compared with SWNTs dispersed using conventional methods (e.g., superacid and surfactants), the dispersed urea-SWNT aggregates have a higher aspect ratio with a rodlike morphology as measured by light scattering. The Mayer rod technique is used to prepare urea-SWNT, highly aligned films (two-dimensional nematic order parameter of 0.6, 5 MUm spot size, via polarized Raman) with resistance values as low as 15-1700 Omega/sq in a transmittance range of 2-80% at 550 nm. These values compete with the best literature values for conductivity of SWNT-enabled thin films. The findings offer promising opportunities for industrial applications relying on highly conductive thin SWNT films. PMID- 25547119 TI - Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B. AB - As a gram-positive, spore-forming anaerobic bacillus, Clostridium difficile (C. difficile) is responsible for severe and fatal pseudomembranous colitis, and poses the most urgent antibiotic resistance threat worldwide. Epidemic C. difficile is the leading cause of antibiotic-associated diarrhoea globally, especially diarrhoea due to the emergence of hypervirulent strains associated with high mortality and morbidity. TcdB, one of the key virulence factors secreted by this bacterium, enters host cells through a poorly understood mechanism to elicit its pathogenic effect. Here we report the first identification of the TcdB cellular receptor, chondroitin sulfate proteoglycan 4 (CSPG4). CSPG4 was initially isolated from a whole-genome human shRNAmir library screening, and its role was confirmed by both TALEN- and CRISPR/Cas9-mediated gene knockout in human cells. CSPG4 is critical for TcdB binding to the cell surface, inducing cytoskeleton disruption and cell death. A direct interaction between the N-terminus of CSPG4 and the C-terminus of TcdB was confirmed, and the soluble peptide of the toxin-binding domain of CSPG4 could protect cells from the action of TcdB. Notably, the complete loss of CSPG4/NG2 decreased TcdB-triggered interleukin-8 induction in mice without significantly affecting animal mortality. Based on both the in vitro and in vivo studies, we propose a dual-receptor model for TcdB endocytosis. The discovery of the first TcdB receptor reveals a previously unsuspected role for CSPG4 and provides a new therapeutic target for the treatment of C. difficile infection. PMID- 25547121 TI - Influence of modified atmosphere packaging on 'Star Ruby' grapefruit phytochemicals. AB - Modified atmosphere packaging (MAP) can extend the shelf life of salads, vegetables, and fruits by generating a storage environment with low O2, high CO2, and high humidity. The current study investigates the effect of modified atmosphere and humidity generated by two plastic films, microperforated bags (MIPBs) and macroperforated bags (MAPBs), on the levels of phytochemicals present in 'Star Ruby' grapefruits (Citrus paradisi, Macf.) stored for 16 weeks at 10 degrees C. Control fruits were stored without any packaging film. Juice samples were analyzed every 4 weeks for ascorbic acid, carotenoids, limonoids, flavonoids, and furocoumarins and assessed for quality parameters. MAP significantly reduced weight loss compared to control grapefruits. Control fruits had more beta-carotene, lycopene, and furocoumarin compared with the fruits in MAP. Flavonoid content was highest in fruits stored in MAPB (P < 0.05), while fruits stored in MIPB showed no significant difference in flavonoid content compared to control (P > 0.05). The MAP treatments did not significantly affect ascorbic acid, limonoids, or fruit quality parameters, including total soluble solids, acidity, ripening ratio, decay and disorders, fruit taste, and off flavors after 16 weeks of storage. These results suggest that MAP can be used to maintain the quality of 'Star Ruby' grapefruit with no detrimental effect on health-promoting phytochemicals. PMID- 25547122 TI - Harnessing tunable scanning probe techniques to measure shear enhanced adhesion of gecko-inspired fibrillar arrays. AB - The hierarchical arrays of mesoscale to nanoscale fibrillar structures on a gecko's foot enable the animal to climb surfaces of varying roughness. Adhesion force between the fibrillar structures and various surfaces is maximized after the gecko drags its foot in one direction, which has also been demonstrated to improve the adhesion forces of artificial fibrillar arrays. Essential conditions that influence the magnitude of these interactions include the lateral distance traveled and velocity between the contacting surfaces, as well as the velocity at which the two surfaces are subsequently separated. These parameters have, however, not been systematically investigated to assess the adhesion properties of artificial adhesives. We introduce a systematic study that investigates these conditions using a scanning probe microscope to measure the adhesion forces of artificial adhesives through a process that mimics the mechanism by which a gecko climbs. The measured adhesion response was different for arrays of shorter and longer fibrils. These results from 9000 independent measurements also provide further insight into the dynamics of the interactions between fibrillar arrays and contacting surfaces. These studies establish scanning probe microscopy techniques as a versatile approach for measuring a variety of adhesion properties of artificial fibrillar adhesives. PMID- 25547127 TI - Tribute to David R. Yarkony. PMID- 25547125 TI - Pancreatic metastases originating from uterine leiomyosarcoma: a case report. AB - In this report, we describe the case of a 67-year-old woman with metastatic pancreatic uterine leiomyosarcoma. She underwent a total hysterectomy and adnexectomy in December 2009. The resected uterine specimen was characterized as a leiomyosarcoma. The patient was free of disease until November 2010, when three pulmonary tumoral lesions detected by follow-up chest computed tomography were diagnosed as metastatic lesions. Wedge resections and enucleoresection of the pulmonary tumoral nodules were performed, and the patient received adjuvant chemotherapy. Ten months after the lung resection, an abdominal examination showed two tumoral masses in the pancreas and no extrapancreatic recurrence. In April 2014, a pylorus-preserving pancreaticoduodenectomy was performed. To date, the patient is alive, without any evidence of recurrence, and she has received chemotherapy. Surgery can be considered in cases in which the pancreas is a unique metastatic site or even in cases with resectable oligometastases. PMID- 25547126 TI - Prediction of plant pre-microRNAs and their microRNAs in genome-scale sequences using structure-sequence features and support vector machine. AB - BACKGROUND: MicroRNAs (miRNAs) are a family of non-coding RNAs approximately 21 nucleotides in length that play pivotal roles at the post-transcriptional level in animals, plants and viruses. These molecules silence their target genes by degrading transcription or suppressing translation. Studies have shown that miRNAs are involved in biological responses to a variety of biotic and abiotic stresses. Identification of these molecules and their targets can aid the understanding of regulatory processes. Recently, prediction methods based on machine learning have been widely used for miRNA prediction. However, most of these methods were designed for mammalian miRNA prediction, and few are available for predicting miRNAs in the pre-miRNAs of specific plant species. Although the complete Solanum lycopersicum genome has been published, only 77 Solanum lycopersicum miRNAs have been identified, far less than the estimated number. Therefore, it is essential to develop a prediction method based on machine learning to identify new plant miRNAs. RESULTS: A novel classification model based on a support vector machine (SVM) was trained to identify real and pseudo plant pre-miRNAs together with their miRNAs. An initial set of 152 novel features related to sequential structures was used to train the model. By applying feature selection, we obtained the best subset of 47 features for use with the Back Support Vector Machine-Recursive Feature Elimination (B-SVM-RFE) method for the classification of plant pre-miRNAs. Using this method, 63 features were obtained for plant miRNA classification. We then developed an integrated classification model, miPlantPreMat, which comprises MiPlantPre and MiPlantMat, to identify plant pre-miRNAs and their miRNAs. This model achieved approximately 90% accuracy using plant datasets from nine plant species, including Arabidopsis thaliana, Glycine max, Oryza sativa, Physcomitrella patens, Medicago truncatula, Sorghum bicolor, Arabidopsis lyrata, Zea mays and Solanum lycopersicum. Using miPlantPreMat, 522 Solanum lycopersicum miRNAs were identified in the Solanum lycopersicum genome sequence. CONCLUSIONS: We developed an integrated classification model, miPlantPreMat, based on structure-sequence features and SVM. MiPlantPreMat was used to identify both plant pre-miRNAs and the corresponding mature miRNAs. An improved feature selection method was proposed, resulting in high classification accuracy, sensitivity and specificity. PMID- 25547128 TI - Preface. Autobiography of David R. Yarkony: my life as a scientist. PMID- 25547132 TI - Twenty-five-year changing pattern of gonococcal antimicrobial susceptibility in Shanghai: surveillance and its impact on treatment guidelines. AB - BACKGROUND: Antimicrobial resistance of Neisseria gonorrhoeae is a serious health problem in China. Gonococcal antimicrobial susceptibility has been monitored in Shanghai since 1988. In this study, we examined the changing pattern of gonococcal antimicrobial susceptibility based on data from N. gonorrhoeae isolates collected over the past 25 years. METHODS: Approximately 100-200 isolates each year (1988-2013) were tested for their susceptibility to penicillin (PEN), tetracycline (TET), ciprofloxacin (CIP), ceftriaxone (CRO) and spectinomycin (SPT), using the agar dilution method. Plasmid-mediated N. gonorrhoeae antimicrobial resistance, comprising penicillinase-producing N. gonorrhoeae (presumed PPNG) and high-level tetracycline resistance N. gonorrhoeae (presumed TRNG), were also determined. Breakpoints for susceptibilities followed those described by the Clinical and Laboratory Standard Institute and the European Committee on Antimicrobial Susceptibility Testing. RESULTS: A high proportion of isolates were resistant to PEN, TET and CIP, ranging from less than 20% at the beginning of the survey, increasing in the late 1990s and reaching over 90% in recent years. The proportion of isolates exhibiting plasmid-mediated resistance exceeded 38% for presumed PPNG and 20% for presumed TRNG in recent years. The proportion of CRO nonsusceptible isolates (MIC >= 0.125 mg/L) ranged from 7% to 13% in most of the study years. Almost all isolates were susceptible to SPT. The SPT MIC90 was 16-32 mg/L for 2008-2013. The proportion of CRO nonsusceptible-associated multiple-drug-resistant (MDR) isolates was over 5% in most of the study years. CONCLUSIONS: N. gonorrhoeae isolates in Shanghai were resistant to PEN, TET and CIP. Furthermore, CRO nonsusceptible and MDR isolates were prevalent. N. gonorrhoeae isolates were also found to be susceptible to SPT. It is recommended that the CRO dose be increased from currently recommended 250 mg to 500 mg and that SPT be an alternative in treating urogenital gonorrhea. Our findings highlight the importance of both regional and national surveillance programs for the prompt modification of treatment guidelines, vital in responding to the changing pattern of gonococcal antimicrobial susceptibility. PMID- 25547133 TI - Outcomes of children exposed in utero to chemotherapy for breast cancer. AB - INTRODUCTION: The incidence of breast cancer diagnosed during pregnancy is expected to increase as more women delay childbearing in the United States. Treatment of cancer in pregnant women requires prudent judgment to balance the benefit to the cancer patient and the risks to the fetus. Prospective data on the outcomes of children exposed to chemotherapy in utero are limited for the breast cancer population. METHODS: Between 1992 and 2010, 81 pregnant patients with breast cancer were treated in a single-arm, institutional review board-approved study with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in the adjuvant or neoadjuvant setting. Labor and delivery records were reviewed for each patient and neonate. In addition, the parents or guardians were surveyed regarding the health outcomes of the children exposed to chemotherapy in utero. RESULTS: In total, 78% of the women (or next of kin) answered a follow-up survey. At a median age of 7 years, most of the children exposed to chemotherapy in utero were growing normally without any significant exposure-related toxicity or health problems. Three children were born with congenital abnormalities: one each with Down syndrome, ureteral reflux or clubfoot. The rate of congenital abnormalities in the cohort was similar to the national average of 3%. CONCLUSIONS: During the second and third trimesters, pregnant women with breast cancer can be treated with FAC safely without concerns for serious complications or short-term health concerns for their offspring who are exposed to chemotherapy in utero. Continued long-term follow-up of the children in this cohort is required. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00510367. Other Study ID numbers: ID01-193, NCI-2012-01578. Registration date: 31 July 2007. PMID- 25547134 TI - Quality assessment and optimization of purified protein samples: why and how? AB - Purified protein quality control is the final and critical check-point of any protein production process. Unfortunately, it is too often overlooked and performed hastily, resulting in irreproducible and misleading observations in downstream applications. In this review, we aim at proposing a simple-to-follow workflow based on an ensemble of widely available physico-chemical technologies, to assess sequentially the essential properties of any protein sample: purity and integrity, homogeneity and activity. Approaches are then suggested to optimize the homogeneity, time-stability and storage conditions of purified protein preparations, as well as methods to rapidly evaluate their reproducibility and lot-to-lot consistency. PMID- 25547137 TI - The changing model. PMID- 25547135 TI - Major haplotype divergence including multiple germin-like protein genes, at the wheat Sr2 adult plant stem rust resistance locus. AB - BACKGROUND: The adult plant stem rust resistance gene Sr2 was introgressed into hexaploid wheat cultivar (cv) Marquis from tetraploid emmer wheat cv Yaroslav, to generate stem rust resistant cv Hope in the 1920s. Subsequently, Sr2 has been widely deployed and has provided durable partial resistance to all known races of Puccinia graminis f. sp. tritici. This report describes the physical map of the Sr2-carrying region on the short arm of chromosome 3B of cv Hope and compares the Hope haplotype with non-Sr2 wheat cv Chinese Spring. RESULTS: Sr2 was located to a region of 867 kb on chromosome 3B in Hope, which corresponded to a region of 567 kb in Chinese Spring. The Hope Sr2 region carried 34 putative genes but only 17 were annotated in the comparable region of Chinese Spring. The two haplotypes differed by extensive DNA sequence polymorphisms between flanking markers as well as by a major insertion/deletion event including ten Germin-Like Protein (GLP) genes in Hope that were absent in Chinese Spring. Haplotype analysis of a limited number of wheat genotypes of interest showed that all wheat genotypes carrying Sr2 possessed the GLP cluster; while, of those lacking Sr2, some, including Marquis, possessed the cluster, while some lacked it. Thus, this region represents a common presence-absence polymorphism in wheat, with presence of the cluster not correlated with presence of Sr2. Comparison of Hope and Marquis GLP genes on 3BS found no polymorphisms in the coding regions of the ten genes but several SNPs in the shared promoter of one divergently transcribed GLP gene pair and a single SNP downstream of the transcribed region of a second GLP. CONCLUSION: Physical mapping and sequence comparison showed major haplotype divergence at the Sr2 locus between Hope and Chinese Spring. Candidate genes within the Sr2 region of Hope are being evaluated for the ability to confer stem rust resistance. Based on the detailed mapping and sequencing of the locus, we predict that Sr2 does not belong to the NB-LRR gene family and is not related to previously cloned, race non-specific rust resistance genes Lr34 and Yr36. PMID- 25547138 TI - The need is now... Sleep education and the dentist. PMID- 25547136 TI - Expression pattern of NLRP3 and its related cytokines in the lung and brain of avian influenza virus H9N2 infected BALB/c mice. AB - BACKGROUND: H9N2 avian influenza virus (AIV) becomes the focus for its ability of transmission to mammals and as a donor to provide internal genes to form the new epidemic lethal influenza viruses. Residue 627 in PB2 has been proven the virulence factor of H9N2 avian influenza virus in mice, but the detailed data for inflammation difference between H9N2 virus strains with site 627 mutation is still unclear. The inflammasome NLRP3 is recently reported as the cellular machinery responsible for activation of inflammatory processes and plays an important role during the development of inflammation caused by influenza virus infection. METHODS: In this study, we investigated the expression pattern of NLRP3 and its related cytokines of IL-1beta and TNF-alpha in BALB/c mice infected by H9N2 AIV strains with only a site 627 difference at both mRNA and protein levels at different time points. RESULTS: The results showed that the expression level of NLRP3, IL-1beta and TNF-alpha changed in the lung and brain of BALB/c mice after infection by VK627 and rVK627E. The immunohistological results showed that the positive cells of NLRP3, IL-1beta and TNF-alpha altered the positive levels of original cells in tissues and infiltrated inflammatory cells which caused by H9N2 infection. CONCLUSIONS: Our results provided the basic data at differences in expression pattern of NLRP3 and its related cytokines in BALB/c mice infected by H9N2 influenza viruses with only a site 627 difference. This implied that NLRP3 inflammasome plays a role in host response to influenza virus infection and determines the outcome of clinical manifestation and pathological injury. This will explain the variable of pathological presentation in tissues and enhance research on inflammation process of the AIV H9N2 infection. PMID- 25547139 TI - One-leg standing time with eyes open: comparison between the mouth-opened and mouth-closed conditions. AB - OBJECTIVE: Many studies report a significant relationship between the one-leg standing time with the eyes open and the occlusal relationship. To determine the association between proprioception (the periodontal membrane vs muscle spindle) to the one-leg standing time, the authors compared the one-leg standing time with eyes open between mouth-opened and mouth-closed conditions. METHODS: The study participants were 107 healthy, elderly patients. The authors measured the one-leg standing time with eyes open between mouth-opened and mouth-closed conditions. RESULTS: The one-leg standing time was significantly shorter with the mouth opened (21.1+/-19.1 seconds) than with the mouth closed (25.1+/-21.4 seconds). Patients whose one-leg standing time was equal or shorter with the mouth opened than with the mouth closed were not different from the other patients with regard to age, handgrip strength, BMI, and the number of remaining teeth. DISCUSSION: The vertical mandibular position may affect body balance. PMID- 25547140 TI - Thinking of a maladaptive occlusion as an orthopedic cumulative trauma disorder. AB - AIM: The authors review the possible connection between a dental malocclusion and a temporal mandibular disorder (TMD). METHODOLOGY: The authors have reflected on several patient case histories to remind us that there may be instances when a simple case of dental malocclusion could be blamed for instigating the signs and symptoms of TMD. The common denominator for this discussion is the situation of joint pain, dysfunction and/or myalgia. Patient-reported signs and symptoms, along with treatment results and progress notes were evaluated. RESULTS: The onset of TMD signs could be traced to an altered dental occlusion, which, upon maximum closure drives the mandible in a posterior direction, forcing the condylar head to now impinge upon retrodiscal tissue and the resultant muscle reflex protective response. Correction for the dentally induced malocclusion obviated the symptoms of TMD with patient-reported improved health. CONCLUSIONS: When a patient presents with signs consistent with those of a TMD, the clinician should include a review of recently placed dental restorations or occlusal equilibration to assess the patient's adaptive occlusion. Overlooking this quick evaluation on the exam checklist may lead to the clinician missing a simple treatment modality to address a TMD. PMID- 25547141 TI - Craniofacial growth: evolving paradigms. AB - AIMS: Numerous theories about craniofacial growth have been formulated in the last century. The most influential hypotheses were: genetic, synthetic and functional matrix revisited. Moreover, a large number of experts from different fields tried to explain craniofacial growth and its developmental mechanisms, in order to deliver the best treatment possible to orthodontic patients. The aim of this review is to summarize recent concepts on craniofacial growth, overlap these theories with the development of the general scientific knowledge, and suggest a more integrated multidisciplinary person-based approach. METHODOLOGY: MEDLINE, EMBASE, Pubmed, CINAHL and Google Scholar were screened from inception to February 2014 for relevant papers. Grey literature was considered as part of the search. CONCLUSIONS: The influence of new scientific discoveries and intuitions about craniofacial growth produced further insights in orthodontics care, shifting the paradigm from a pre-determined, sectorial treatment to an individualized, multidisciplinary patient-centered approach aiming to enhance the quality of orthodontic assistance. PMID- 25547142 TI - The craniofacial morphology and maximum bite force in sleep bruxism patients with signs and symptoms of temporomandibular disorders. AB - OBJECTIVES: The purpose of the present study was to compare craniofacial morphology and bite force of bruxist patients with signs and symptoms of temporomandibular disorders. METHOD: Fourteen subjects with sleep bruxism and 14 healthy subjects participated. The signs and symptoms of the temporomandibular disorders were identified according to the Craniomandibular Index (CMI). Maximum bite force was measured using strain-gage transducers. Lateral cephalometric films were taken, and linear and angular measurements were performed. RESULTS: Bite force between bruxist and non-bruxist females was not significant, whereas males with bruxism revealed higher bite forces. None of the linear and angular measurements differed significantly between bruxist and non-bruxist males. However, higher mandibular corpus length and anterior cranial base length, and lower gonial angle were observed in bruxist females compared to non-bruxist females. Negative correlation between bite force and CMI values was found in both genders. DISCUSSION: Bruxist females had higher CMI values than bruxist males, which could lead to relatively lower bite forces. PMID- 25547143 TI - Sleep bruxism associated with nocturnal enuresis in a 6-year-old child. AB - BACKGROUND: Bruxism is the involuntary grinding of teeth that occurs during sleep or wake time. The prevalence of bruxism in children and adolescents is high when compared to the adult population. CLINICAL PRESENTATION: This article presents a case report of sleep bruxism in a 6-year-old child. The interesting finding here was its association with nocturnal enuresis (NE)/bedwetting. CONCLUSION/CLINICAL RELEVANCE: NE could be a predisposing factor for sleep bruxism in children, as it causes emotional stress and has a negative impact on a child's self esteem. Psychological support and techniques for overcoming NE, like a scheduled waking program at night helps children with these problems by alleviating the associated stress. In addition, NE and bruxism are often associated with other sleep disorders, such as obstructive sleep apnea syndrome, and hence, child bruxers require careful medical evaluation to rule out such potential interactions. PMID- 25547144 TI - Spindle cell carcinoma arising at the buccal mucosa: a case report and review of the literature. AB - AIMS: Spindle cell carcinoma (SPCC) is a subtype of squamous cell carcinoma, and it mainly occurs in the upper aerodigestive duct. On the other hand, it rarely arises in the head and neck region. The prognosis of this tumor is usually poor because of its highly malignant behavior, such as its high incidence of recurrence or metastasis to cervical lymph nodes. However, the number of accumulated cases is still too low to provide the full details of SPCC. METHODOLOGY: The case of SPCC was counted by using database, PubMed. The authors also present a case of SPCC arising at the left buccal mucosa in a 72-year-old Japanese female in the current study. RESULTS: Only six cases of SPCC arising at the buccal mucosa have been reported previously. The authors' patient died from a recurrent tumor 15 months after the first operation. CONCLUSION: The authors have added this case to the previous knowledge of SPCC arising at the buccal mucosa, and discuss the clinical behavior of SPCC to help suggest a standard treatment strategy for the disease. PMID- 25547146 TI - Letter to the Editor regarding TMDes(TM) Ear System article from CRANIO Volume 30 Issue 3, by Alejandro Tsuchiya Tavera, et al. PMID- 25547147 TI - Dr. Roger N. Wixtrom's Reply. PMID- 25547150 TI - Ischaemic strokes with reversible vasoconstriction and without thunderclap headache: a variant of the reversible cerebral vasoconstriction syndrome? AB - BACKGROUND: Reversible vasoconstriction (RV) may cause ischaemic stroke (IS) in the absence of any other defined stroke aetiology. The three objectives of our study were to evaluate the frequency of RV in a prospective series of young IS patients, to describe the detailed clinical-radiological features in the patients with RV and IS, and to compare these characteristics with those of reversible cerebral vasoconstriction syndrome (RCVS). METHODS: We identified between October 2005 and December 2010, 159 consecutive young patients (<45 years) hospitalized for an acute IS confirmed by cerebral magnetic resonance imaging. An extensive diagnostic work-up was performed including toxicological urinary screening for cannabis, cocaine and amphetamines, and the usual biological, cardiac and vascular investigations for an IS in the young. We specifically studied patients with IS and RV, which was defined as multifocal intracranial arterial stenoses confirmed by intracranial arterial imaging that resolved within 3-6 months. RESULTS: Out of 159 patients with IS, 21 (13%, 12 males, 9 females; mean age 32 years) had multifocal cerebral arterial stenoses that were fully reversible at 3 6 months, and no other cause for stroke. IS were located on posterior territory in 71% of cases, and vasoconstriction predominated on posterior cerebral and superior cerebellar arteries. Precipitating factors of IS and RV were the use of cannabis resin (n = 14), nasal decongestants (n = 2) and triptan (n = 1). Most cases (74%) had unusual severe headache, but none had thunderclap headache. None of 21 cases had reversible posterior leukoencephalopathy, cortical subarachnoid or intracerebral haemorrhage. CONCLUSION: RV was the sole identified cause of IS in 13% of our cohort. These young patients with IS and RV may have a variant of RCVS, related to an increased susceptibility to vasoactive agents in some individuals. RV in our patients differs from the classical characteristics of RCVS by the absence of thunderclap headache, reversible brain oedema and subarachnoid or intracranial haemorrhage. Intracranial arteries should be looked for, by appropriate vascular imaging, in young patients with IS at the acute stage and during the follow-up period. PMID- 25547152 TI - Retraction. AB - [This retracts the article on p. 2105 in vol. 7, PMID: 24179960.]. PMID- 25547151 TI - MiR-146b-5p promotes metastasis and induces epithelial-mesenchymal transition in thyroid cancer by targeting ZNRF3. AB - BACKGROUND/AIMS: Micro-RNA (miR)-146b-5p is overexpressed in papillary thyroid carcinoma (PTC) and associated with extrathyroidal invasion and advanced tumor stage. In the present study, we showed that miR-146b-5p is upregulated in PTC with lymph node metastasis. METHODS: A computational search and luciferase assay identified zinc RING finger 3 (ZNRF3), a negative regulator of Wnt/beta-catenin signaling, as a direct target of miR-146b-5p in PTC. RESULTS: MiR-146b-5p promoted migration and invasiveness and induced epithelial-mesenchymal transition (EMT) of PTC cells, whereas ZNRF3 overexpression reversed this effect. MiR-146b 5p increased the cell surface levels of the Wnt receptors Frizzled-6 and LRP6 and enhanced Wnt/beta-catenin signaling by downregulating ZNRF3, whereas an inhibitor of Wnt/beta-catenin suppressed the effect of miR-146b-5p on migration, invasiveness and EMT of PTC cells. CONCLUSION: These results indicate that miR 146b-5p induces EMT and may promote PTC metastasis through the regulation of Wnt/beta-catenin signaling, and suggest novel potential therapeutic targets for the treatment of PTC. PMID- 25547149 TI - Targeting the neurophysiology of cognitive systems with transcranial alternating current stimulation. AB - Cognitive impairment represents one of the most debilitating and most difficult symptom to treat of many psychiatric illnesses. Human neurophysiology studies have suggested that specific pathologies of cortical network activity correlate with cognitive impairment. However, we lack demonstration of causal relationships between specific network activity patterns and cognitive capabilities and treatment modalities that directly target impaired network dynamics of cognition. Transcranial alternating current stimulation (tACS), a novel non-invasive brain stimulation approach, may provide a crucial tool to tackle these challenges. Here, we propose that tACS can be used to elucidate the causal role of cortical synchronization in cognition and, eventually, to enhance pathologically weakened synchrony that may underlie cognitive deficits. To accelerate such development of tACS as a treatment for cognitive deficits, we discuss studies on tACS and cognition performed in healthy participants, according to the Research Domain Criteria of the National Institute of Mental Health. PMID- 25547153 TI - Fast-track programs versus traditional care in hepatectomy: a meta-analysis of randomized controlled trials. AB - BACKGROUND/AIMS: The role of fast-track programs in hepatectomy is unclear. This meta-analysis aimed to evaluate the efficacy and safety of fast-track programs versus traditional care. METHODS: We searched Pubmed, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar for relevant randomized controlled trials (RCTs) comparing fast-track with traditional care in hepatectomy. Length of hospital stay, time to first flatus, postoperative complications, operating time, and intraoperative blood loss were assessed. Meta analyses were performed using RevMan 5.2 software. RESULTS: Four original RCTs with 372 patients were included: 187 in the fast-track and 185 in the traditional care group. Fast-track patients had shorter hospital stay (WMD -2.32; 95% CI, 3.54 to -1.11; p < 0.001) and time to first flatus (WMD -0.99; 95% CI, -1.15 to 0.84; p < 0.001), and less postoperative complications (RR 0.66; 95% CI, 0.47 to 0.93; p < 0.05). However, there was significant heterogeneity between the studies regarding hospital stay (I(2) = 88%; p < 0.001). Operating time and intraoperative blood loss were not different. CONCLUSIONS: Patients in fast-track programs had less time to first flatus and postoperative complications compared to traditional care. Fast-track programs may reduce the length of hospital stay. Larger, higher quality prospective RCTs are necessary to draw more robust conclusions. PMID- 25547154 TI - Absence of Dap12 and the alphavbeta3 integrin causes severe osteopetrosis. AB - In vitro, ligand occupancy of alphavbeta3 integrin induces phosphorylation of Dap12, which is essential for osteoclast function. Like mice deleted of only alphavbeta3, Dap12(-/-) mice exhibited a slight increase in bone mass, but Dap12( /-) mice, lacking another ITAM protein, FcRgamma, were severely osteopetrotic. The mechanism by which FcRgamma compensates for Dap12 deficiency is unknown. We find that co-deletion of FcRgamma did not exacerbate the skeletal phenotype of beta3(-/-) mice. In contrast, beta3/Dap12 double-deficient (DAP/beta3(-/-)) mice (but not beta1/Dap12 double-deficient mice) were profoundly osteopetrotic, reflecting severe osteoclast dysfunction relative to those lacking alphavbeta3 or Dap12 alone. Activation of OSCAR, the FcRgamma co-receptor, rescued Dap12(-/-) but not DAP/beta3(-/-)osteoclasts. Thus, the absence of alphavbeta3 precluded compensation for Dap12 deficiency by FcRgamma. In keeping with this, Syk phosphorylation did not occur in OSCAR-activated DAP/beta3(-/-) osteoclasts. Thus, FcRgamma requires the osteoclast alphavbeta3 integrin to normalize the Dap12-deficient skeleton. PMID- 25547155 TI - Transient assembly of F-actin on the outer mitochondrial membrane contributes to mitochondrial fission. AB - In addition to established membrane remodeling roles in various cellular locations, actin has recently emerged as a participant in mitochondrial fission. However, the underlying mechanisms of its participation remain largely unknown. We report that transient de novo F-actin assembly on the mitochondria occurs upon induction of mitochondrial fission and F-actin accumulates on the mitochondria without forming detectable submitochondrial foci. Impairing mitochondrial division through Drp1 knockout or inhibition prolonged the time of mitochondrial accumulation of F-actin and also led to abnormal mitochondrial accumulation of the actin regulatory factors cortactin, cofilin, and Arp2/3 complexes, suggesting that disassembly of mitochondrial F-actin depends on Drp1 activity. Furthermore, down-regulation of actin regulatory proteins led to elongation of mitochondria, associated with mitochondrial accumulation of Drp1. In addition, depletion of cortactin inhibited Mfn2 down-regulation- or FCCP-induced mitochondrial fragmentation. These data indicate that the dynamic assembly and disassembly of F actin on the mitochondria participates in Drp1-mediated mitochondrial fission. PMID- 25547156 TI - Mouse BRWD1 is critical for spermatid postmeiotic transcription and female meiotic chromosome stability. AB - Postmeiotic gene expression is essential for development and maturation of sperm and eggs. We report that the dual bromodomain-containing protein BRWD1, which is essential for both male and female fertility, promotes haploid spermatid-specific transcription but has distinct roles in oocyte meiotic progression. Brwd1 deficiency caused down-regulation of ~300 mostly spermatid-specific transcripts in testis, including nearly complete elimination of those encoding the protamines and transition proteins, but was not associated with global epigenetic changes in chromatin, which suggests that BRWD1 acts selectively. In females, Brwd1 ablation caused severe chromosome condensation and structural defects associated with abnormal telomere structure but only minor changes in gene expression at the germinal vesicle stage, including more than twofold overexpression of the histone methyltransferase MLL5 and LINE-1 elements transposons. Thus, loss of BRWD1 function interferes with the completion of oogenesis and spermatogenesis through sexually dimorphic mechanisms: it is essential in females for epigenetic control of meiotic chromosome stability and in males for haploid gene transcription during postmeiotic sperm differentiation. PMID- 25547157 TI - A protein complex containing Epo1p anchors the cortical endoplasmic reticulum to the yeast bud tip. AB - The cortical endoplasmic reticulum (cER) of yeast underlies the plasma membrane (PM) at specific contact sites to enable a direct transfer of information and material between both organelles. During budding, directed movement of cER to the young bud followed by subsequent anchorage at its tip ensures the faithful inheritance of this organelle. The ER membrane protein Scs2p tethers the cER to the PM and to the bud tip through so far unknown receptors. We characterize Epo1p as a novel member of the polarisome that interacts with Scs2p exclusively at the cell tip during bud growth and show that Epo1p binds simultaneously to the Cdc42p guanosine triphosphatase-activating protein Bem3p. Deletion of EPO1 or deletion of BEM3 in a polarisome-deficient strain reduces the amount of cER at the tip. This analysis therefore identifies Epo1p as a novel and important component of the polarisome that promotes cER tethering at sites of polarized growth. PMID- 25547159 TI - Abdominal aorta interruption and CHD. AB - We report a rare case of CHD and abdominal aorta interruption. Renal hypertension was the first sign of the abdominal aortic malformation. The aetiology of abdominal aortic interruption remains unclear, it could be congenital or acquired. PMID- 25547158 TI - Correction: genomic comparison of 93 Bacillus phages reveals 12 clusters, 14 singletons and remarkable diversity. AB - BACKGROUND: The Bacillus genus of Firmicutes bacteria is ubiquitous in nature and includes one of the best characterized model organisms, B. subtilis, as well as medically significant human pathogens, the most notorious being B. anthracis and B. cereus. As the most abundant living entities on the planet, bacteriophages are known to heavily influence the ecology and evolution of their hosts, including providing virulence factors. Thus, the identification and analysis of Bacillus phages is critical to understanding the evolution of Bacillus species, including pathogenic strains. RESULTS: Whole genome nucleotide and proteome comparison of the 83 extant, fully sequenced Bacillus phages revealed 10 distinct clusters, 24 subclusters and 15 singleton phages. Host analysis of these clusters supports host boundaries at the subcluster level and suggests phages as vectors for genetic transfer within the Bacillus cereus group, with B. anthracis as a distant member. Analysis of the proteins conserved among these phages reveals enormous diversity and the uncharacterized nature of these phages, with a total of 4,442 protein families (phams) of which only 894 (20%) had a predicted function. In addition, 2,583 (58%) of phams were orphams (phams containing a single member). The most populated phams were those encoding proteins involved in DNA metabolism, virion structure and assembly, cell lysis, or host function. These included several genes that may contribute to the pathogenicity of Bacillus strains. CONCLUSIONS: This analysis provides a basis for understanding and characterizing Bacillus and other related phages as well as their contributions to the evolution and pathogenicity of Bacillus cereus group bacteria. The presence of sparsely populated clusters, the high ratio of singletons to clusters, and the large number of uncharacterized, conserved proteins confirms the need for more Bacillus phage isolation in order to understand the full extent of their diversity as well as their impact on host evolution. PMID- 25547161 TI - A many-body Hamiltonian for nanoparticles immersed in a polymer solution. AB - We developed an analytical theory for the many-body potential of mean force (POMF) between N spheres immersed in a continuum chain fluid. The theory is almost exact for a Theta polymer solution in the protein limit (small particles, long polymers), where N-body effects are important. Polydispersity in polymer length according to a Schulz-Flory distribution emerges naturally from our analysis, as does the transition to the monodisperse limit. The analytical expression for the POMF allows for computer simulations employing the complete N body potential (i.e., without n-body truncation; n < N). These are compared with simulations of an explicit particle/polymer mixture. We show that the theory produces fluid structure in excellent agreement with the explicit model simulations even when the system is strongly fluctuating, e.g., at or near the spinodal region. We also demonstrate that other commonly used theoretical approaches, such as truncation of the POMF at the pair level or the Asakura Oosawa model, are extremely inaccurate for these systems. PMID- 25547160 TI - Isolated flushes without permanent, fixed or other skin lesions in patients with systemic mastocytosis: a case series of 9 patients. PMID- 25547162 TI - High-throughput simultaneous analysis of pesticides by supercritical fluid chromatography coupled with high-resolution mass spectrometry. AB - Recently, a generally applicable screening method for multiresidue pesticide analysis, which is simple, quick, and accurate and has a reliable performance, is becoming increasingly important for food safety and international trade. This paper proposes a high-throughput screening methodology that enables the detection of multiresidue pesticides using supercritical fluid chromatography coupled to a high-performance benchtop quadrupole Orbitrap mass spectrometry (SFC/Q Exactive) and an automated library-based detection. A total of 444 chemicals covering a wide polarity range (logPow from -4.2 to 7.7) and a wide molecular weight range (from 99.0 to 872.5) were analyzed simultaneously through a combination of high mass resolution (a value of m/Deltam = 70000), high mass accuracy (<5 ppm) with positive/negative polarity switching, and highly efficient separation by SFC. A total of 373 pesticides were detected in QuEChERS spinach extracts without dispersive solid phase extraction at the 10 MUg kg(-1) level (provisional maximum residue limits in Japan). In conclusion, the developed analytical system is a potentially useful tool for practical multiresidue pesticide screening with high throughput (time for data acquisition, 72 samples per day; and time for data processing of 72 samples, approximately 45 min). PMID- 25547163 TI - Mammary myofibroblastoma: a clinico- pathologic study of six cases. AB - BACKGROUND: Mammary myofibroblastoma is a rare and benign neoplasm of the breast stroma, showing features of fibroblasts and myofibroblasts. It has also been noted to exhibit smooth muscle cell characteristics. OBJECTIVE: The aim of this study was to describe the clinical and pathological features of mammary myofibroblastoma reported at our institution. METHODS: Cases of mammary myofibroblastoma reported in our laboratory were retrieved by electronic search. H&E slides were reviewed and clinico-pathologic features were noted. Immunohistochemistery was performed by Envision method. Only CD34 and CKAE1/AE3 were performed in all 6 cases. ASMA, desmin and S-100 were performed in 5, 4 and 2 cases, respectively. Vimentin and Bcl-2 were performed in one case. RESULTS: A total of 6 cases were identified. Five were female and one was male. The mean age of patients was 45.5 years. The mean size of tumors was 7.7 cm in the largest dimension. Histologically, four cases showed clusters of uniform bipolar spindle shaped cells separated by broad bands of hyalinized collagen. Mitotic figures ranged from none to 3 mitoses/10 HPFs. One case showed combined features of cellular and fibrous areas. Another case was epithelioid-cell type. On immunohistochemistry, CD34 stain was positive in 5/6 cases, ASMA in 3/5 cases, desmin in 2/4 cases, S-100 in none and vimentin and Bcl-2 in 1/6 cases. None of the cases stained positive for CKAE1/AE3. CONCLUSIONS: Due to the varying degree of fibro-myofibroblastic differentiation, myofibroblastoma shows multiple morphologies and several intratumoral and intertumoral types. It is essential to distinguish each variant from the other to avoid inaccurate diagnosis of other benign or malignant breast conditions, becoming a noteworthy diagnostic dilemma for histopathologists. PMID- 25547166 TI - The jigsaw puzzles. PMID- 25547164 TI - Role of PRL-3, Snail, Cytokeratin and Vimentin expression in epithelial mesenchymal transition in breast carcinoma. AB - AIM: To study epithelial mesenchymal transition (EMT) in breast cancer, molecules such as PRL-3, Snail, Cytokeratin and Vimentin involved in EMT were evaluated. MATERIALS AND METHODS: In this study, m-RNA expression of PRL3 and Snail by RT PCR, protein expression of PRL-3, Snail, Cytokeratin and Vimentin by immunohistochemistry were evaluated on paraffin-embedded tissue sections of 100 patients with breast cancer. RESULTS: PRL3 m-RNA expression (above cut off level > 2487301.00) and PRL-3 protein expression was noted in 52% and 70% of breast carcinoma patients, respectively. The higher incidence of PRL3 protein than m-RNA expression could be due to post translation modification. Further, Snail m-RNA expression (above cut off level > 1285142.00) and Snail protein expression was noted in 53% and 54% of breast cancer patients respectively and Snail protein expression was found significantly higher in patients with pre-menopausal status. The loss of cytokeratin expression in 32% and gain of vimentin expression in 17% was noted in these patients. Vimentin expression was found significantly higher in patients with stage IV disease, BR score 4 and PR negativity. In multivariate survival analysis, Vimentin expression found as strong indicator of biologically aggressive breast cancer predicting reduced disease free survival (DFS) and overall survival (OS). CONCLUSION: In our study reveals that Vimentin expression emerged as significant biomarker for predicting reduced DFS and OS in breast cancer. The study proposes routine evaluation of Vimentin with other predictive parameters can allow use of EMT inhibitors with conventional therapy to revert EMT in breast cancer. PMID- 25547165 TI - Solution structure, aggregation behavior, and flexibility of human relaxin-2. AB - Relaxin is a member of the relaxin/insulin peptide hormone superfamily and is characterized by a two-chain structure constrained by three disulfide bonds. Relaxin is a pleiotropic hormone and involved in a number of physiological and pathogenic processes, including collagen and cardiovascular regulation and tissue remodelling during pregnancy and cancer. Crystallographic and ultracentrifugation experiments have revealed that the human form of relaxin, H2 relaxin, self associates into dimers, but the significance of this is poorly understood. Here, we present the NMR structure of a monomeric, amidated form of H2 relaxin and compare its features and behavior in solution to those of native H2 relaxin. The overall structure of H2 relaxin is retained in the monomeric form. H2 relaxin amide is fully active at the relaxin receptor RXFP1 and thus dimerization is not required for biological activity. Analysis of NMR chemical shifts and relaxation parameters identified internal motion in H2 relaxin at the pico-nanosecond and milli-microsecond time scales, which is commonly seen in other relaxin and insulin peptides and might be related to function. PMID- 25547167 TI - A brief introduction to the military workplace culture. AB - BACKGROUND: Military culture and workplace are areas of interest for researchers across disciplines. However, few publications on military culture exist. OBJECTIVE: The purpose of this article is to introduce general concepts regarding the structure and culture of the United States Military and discuss how this creates challenges for reintegrating into the civilian world. METHOD: Topics that will be covered in this article include an overview of the Department of Defense (DoD) and Department of Veterans Affairs (VA), socialization to military culture, the unique features of the military as a workplace, the cultural experiences of military personnel reintegrating back into the community, and the challenges faced by military members and their spouses. RESULTS: The provided information on military culture will expand military cultural competency so that civilian employers can enhance their ability to create supportive workplaces for veterans and military spouses during times of transition and reintegration. DISCUSSION: The unique characteristics of the military culture should be understood by those who work with or plan to work with military populations. PMID- 25547169 TI - Cerebrospinal fluid prohormone processing and neuropeptides stimulating feed intake of dairy cows during early lactation. AB - After parturition, feed intake of dairy cows increases within the first weeks of lactation, but the molecular mechanisms stimulating or delaying the slope of increase are poorly understood. Some of the molecules controlling feed intake are neuropeptides that are synthesized as propeptides and subsequently processed before they bind to specific receptors in feeding centers of the brain. Cerebrospinal fluid surrounds most of the feed intake regulatory centers and contains numerous neuropeptides. In the present study, we used a proteomic approach to analyze the neuropeptide concentrations in cerebrospinal fluid taken from dairy cows between day -18 and -10, and between day +10 and +20 relative to parturition. We found 13 proteins which were only present in samples taken before parturition, 13 proteins which were only present in samples taken after parturition, and 25 proteins which were commonly present, before and after parturition. Among them, differences in pro-neuropeptide Y, proenkephalin-A, neuroendocrine convertase-2, neurosecretory protein VGF, chromogranin-A, and secretogranin-1 and -3 concentrations relative to parturition highlight propeptides and prohormone processings involved in the control of feed intake and energy homeostasis. Scaffold analysis further emphasized an increased tone of endogenous opioids associated with the postparturient increase of feed intake. PMID- 25547168 TI - Global medical education partnerships to expand specialty expertise: a case report on building neurology clinical and research capacity. AB - BACKGROUND: Neurological disorders are a common cause of morbidity and mortality in sub-Saharan African, but resources for their management are scarce. Collaborations between training institutions in developed and resource-limited countries can be a successful model for supporting specialty medical education and increasing clinical and research capacity. CASE REPORT: This report describes a US National Institutes of Health (NIH) funded Medical Education Partnership Initiative (MEPI) to enhance expertise in neurology, developed between Makerere University College of Health Sciences in Kampala, Uganda, and Case Western Reserve University School of Medicine in Cleveland, OH, USA. This collaborative model is based on a successful medical education and research model that has been developed over the past two decades. The Ugandan and US teams have accumulated knowledge and 'lessons learned' that facilitate specialty expertise in neurological conditions, which are widespread and associated with substantial disability in resource-limited countries. Strengths of the model include a focus on community health care settings and a strong research component. Key elements include strong local leadership; use of remote technology, templates to standardize performance; shared exchanges; mechanisms to optimize sustainability and of dissemination activities that expand impact of the original initiative. Efficient collaborations are further enhanced by external and institutional support, and can be sequentially refined. CONCLUSION: Models such as the Makerere University College of Health Sciences - Case Western Reserve University partnership may help other groups initiate collaborative education programmes and establish successful partnerships that may provide the opportunity to expand to other chronic diseases. A benefit of collaboration is that learning is two directional, and interaction with other international medical education collaborators is likely to be of benefit to the larger global health community. PMID- 25547170 TI - Western white pine SNP discovery and high-throughput genotyping for breeding and conservation applications. AB - BACKGROUND: Western white pine (WWP, Pinus monticola Douglas ex D. Don) is of high interest in forest breeding and conservation because of its high susceptibility to the invasive disease white pine blister rust (WPBR, caused by the fungus Cronartium ribicola J. C. Fisch). However, WWP lacks genomic resource development and is evolutionarily far away from plants with available draft genome sequences. Here we report a single nucleotide polymorphism (SNP) study by bulked segregation-based RNA-Seq analysis. RESULTS: A collection of resistance germplasm was used for construction of cDNA libraries and SNP genotyping. Approximately 36-89 million 2 * 100-bp reads were obtained per library and de novo assembly generated the first shoot-tip reference transcriptome containing a total of 54,661 unique transcripts. Bioinformatic SNP detection identified >100,000 high quality SNPs in three expressed candidate gene groups: Pinus highly conserved genes (HCGs), differential expressed genes (DEGs) in plant defense response, and resistance gene analogs (RGAs). To estimate efficiency of in-silico SNP discovery, genotyping assay was developed by using Sequenom iPlex and it unveiled SNP success rates from 40.1% to 61.1%. SNP clustering analyses consistently revealed distinct populations, each composed of multiple full-sib seed families by parentage assignment in the WWP germplasm collection. Linkage disequilibrium (LD) analysis identified six genes in significant association with major gene (Cr2) resistance, including three RGAs (two NBS-LRR genes and one receptor-like protein kinase -RLK gene), two HCGs, and one DEG. At least one SNP locus provided an excellent marker for Cr2 selection across P. monticola populations. CONCLUSIONS: The WWP shoot tip transcriptome and those validated SNP markers provide novel genomic resources for genetic, evolutionary and ecological studies. SNP loci of those candidate genes associated with resistant phenotypes can be used as positional and functional variation sites for further characterization of WWP major gene resistance against C. ribicola. Our results demonstrate that integration of RNA-seq-based transcriptome analysis and high throughput genotyping is an effective approach for discovery of a large number of nucleotide variations and for identification of functional gene variants associated with adaptive traits in a non-model species. PMID- 25547171 TI - Effect of elevated oxygen concentration on bacteria, yeasts, and cells propagated for production of biological compounds. AB - The response of bacteria, yeast, and mammalian and insects cells to oxidative stress is a topic that has been studied for many years. However, in most the reported studies, the oxidative stress was caused by challenging the organisms with H2O2 and redox-cycling drugs, but not by subjecting the cells to high concentrations of molecular oxygen. In this review we summarize available information about the effect of elevated oxygen concentrations on the physiology of microorganisms and cells at various culture conditions. In general, increased oxygen concentrations promote higher leakage of reactive oxygen species (superoxide and H2O2) from the respiratory chain affecting metalloenzymes and DNA that in turn cause impaired growth and elevated mutagenesis. To prevent the potential damage, the microorganisms and cells respond by activating antioxidant defenses and repair systems. This review described the factors that affect growth properties and metabolism at elevated oxygen concentrations that cells may be exposed to, in bioreactor sparged with oxygen enriched air which could affect the yield and quality of the recombinant proteins produced by high cell density schemes. PMID- 25547172 TI - Breast vibro-acoustography: initial experience in benign lesions. AB - BACKGROUND: Vibro-acoustography (VA) is a newly developed imaging technology that is based on low-frequency vibrations induced in the object by the radiation force of ultrasound. VA is sensitive to the dynamic characteristics of tissue. Here, we evaluate the performance of VA in identifying benign lesions and compare the results to those of mammography. METHODS: An integrated mammography-VA system designed for in vivo breast imaging was tested on a group of female volunteers, age >= 18 years, with suspected breast lesions based on clinical examination. A set of VA scans was acquired after each corresponding mammography. Most lesions were classified as benign based on their histological results. However, in 4 cases, initial diagnosis based on clinical imaging determined that the lesions were cysts. These cysts were aspirated with needle aspiration and disappeared completely under direct ultrasound visualization. Therefore, no biopsies were performed on these cases and lesions were classified as benign based on clinical findings per clinical standards. To define the VA characteristics of benign breast masses, we adopted the features that are normally attributed to such masses in mammography. In a blinded assessment, three radiologists evaluated the VA images independently. The diagnostic accuracy of VA for detection of benign lesions was assessed by comparing the reviewers' evaluations with clinical data. RESULTS: Out of a total 29 benign lesions in the group, the reviewers were able to locate all lesions on VA images and mammography, 100% with (95% confidence interval (CI): 88% to 100%). Two reviewers were also able to correctly classify 83% (95% CI: 65% to 92%), and the third reviewer 86% (95% CI: 65% to 95%) of lesions, as benign on VA images and 86% (95% CI: 69% to 95%) on mammography. CONCLUSIONS: The results suggest that the mammographic characteristics of benign lesion may also be used to identify such lesions in VA. Furthermore, the results show the ability of VA to detect benign breast abnormalities with a performance comparable to mammography. Therefore, the VA technology has the potential to be utilized as a complementary tool for breast imaging applications. Additional studies are needed to compare the capabilities of VA and traditional ultrasound imaging. PMID- 25547173 TI - A framework for feature extraction from hospital medical data with applications in risk prediction. AB - BACKGROUND: Feature engineering is a time consuming component of predictive modeling. We propose a versatile platform to automatically extract features for risk prediction, based on a pre-defined and extensible entity schema. The extraction is independent of disease type or risk prediction task. We contrast auto-extracted features to baselines generated from the Elixhauser comorbidities. RESULTS: Hospital medical records was transformed to event sequences, to which filters were applied to extract feature sets capturing diversity in temporal scales and data types. The features were evaluated on a readmission prediction task, comparing with baseline feature sets generated from the Elixhauser comorbidities. The prediction model was through logistic regression with elastic net regularization. Predictions horizons of 1, 2, 3, 6, 12 months were considered for four diverse diseases: diabetes, COPD, mental disorders and pneumonia, with derivation and validation cohorts defined on non-overlapping data-collection periods. For unplanned readmissions, auto-extracted feature set using socio demographic information and medical records, outperformed baselines derived from the socio-demographic information and Elixhauser comorbidities, over 20 settings (5 prediction horizons over 4 diseases). In particular over 30-day prediction, the AUCs are: COPD-baseline: 0.60 (95% CI: 0.57, 0.63), auto-extracted: 0.67 (0.64, 0.70); diabetes-baseline: 0.60 (0.58, 0.63), auto-extracted: 0.67 (0.64, 0.69); mental disorders-baseline: 0.57 (0.54, 0.60), auto-extracted: 0.69 (0.64,0.70); pneumonia-baseline: 0.61 (0.59, 0.63), auto-extracted: 0.70 (0.67, 0.72). CONCLUSIONS: The advantages of auto-extracted standard features from complex medical records, in a disease and task agnostic manner were demonstrated. Auto-extracted features have good predictive power over multiple time horizons. Such feature sets have potential to form the foundation of complex automated analytic tasks. PMID- 25547175 TI - Retained drugs in the gastrointestinal tracts of deceased victims of oral drug overdose. AB - CONTEXT: The extent of non-absorbed drug burden in the GI tract following overdose is unknown. Patients who present with clinical signs of toxicity may not undergo decontamination due to assumption that the drug has already been completely absorbed and because of limited scientific evidence of benefit for routine GI decontamination in poisoned patients. OBJECTIVE: The goal of this study was to assess whether people who die of an oral overdose have unabsorbed drug present in the GI tract. The secondary goal was to analyze pharmacologic characteristics of retained drugs when present. MATERIALS AND METHODS: Retrospective review of autopsy reports from 2008 to 2010, whose cause of death was determined as "intoxication" or "overdose, was performed at the Office of Chief Medical Examiner of the City of New York (OCME NYC)." Decedents of all ages were identified via electronic OCME database. Inclusion criteria were as follows: 1) cause of death "intoxication" or "overdose" noted by forensic autopsy, 2) ingestion of a solid drug formulation. RESULTS: 92 out of 1038 autopsies (9%) that met inclusion criteria had documentation of retained pill fragments, granules, paste, sludge, slurry, or whole pills in the GI tract. The most common drugs found were opioids and anticholinergics. Ninety-eight percent (98%) of the retained drugs were either modified-release preparations or drugs known to slow GI transit. Most decedents were dead on arrival; there were twelve in-hospital deaths and eleven patients died in the Emergency Department. Bupropion and venlafaxine were responsible for four deaths in those who received medical care. One person died in the ICU following bupropion ingestion. DISCUSSION AND CONCLUSION: Overdose of an oral drug that either has modified-release properties or slows GI tract motility may result in substantial unabsorbed drug burden remaining in the GI tract. PMID- 25547174 TI - Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis. AB - INTRODUCTION: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) recruits actin regulatory proteins to invadopodia, and promotes breast tumor metastasis. Since metastatic breast tumors frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. METHODS: Normal mammary epithelial cells (HBL-100, MCF10A) and breast cancer cell lines expressing wild-type (WT) p53 (DU4475, MTLn3) were treated with camptothecin or Nutlin-3 to stabilize p53 to test effects on Toca-1 mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assays were performed to identify p53 binding site in Toca-1 gene. Stable silencing of p53 and Toca-1 were performed in MTLn3 cells to test effects on invadopodia and cell invasion in vitro, and tumor metastasis in vivo. RESULTS: We observed that breast cancer cell lines with mutant p53 have high levels of Toca-1 compared to those with WT p53. Stabilization of WT p53 led to further reduction in Toca-1 mRNA and protein levels in normal breast epithelial cells and breast cancer cells. ChIP assays revealed p53 binding within intron 2 of toca1, and reduced histone acetylation within its promoter region upon p53 upregulation or activation. Stable silencing of WT p53 in MTLn3 cells led to increased extracellular matrix degradation and cell invasion compared to control cells. Interestingly, the combined silencing of p53 and Toca-1 led to a partial rescue of these effects of p53 silencing in vitro and reduced lung metastases in mice. In human breast tumors, Toca-1 levels were high in subtypes with frequent p53 mutations, and high Toca-1 transcript levels correlated with increased risk of relapse. CONCLUSIONS: Based on these findings, we conclude that loss of p53 tumor suppressor function in breast cancers leads to upregulation of Toca-1, and results in enhanced risk of developing metastatic disease. PMID- 25547176 TI - Hypovitaminosis D in adolescent females--an analytical cohort study in the United Arab Emirates. AB - BACKGROUND: Despite living in a sunny country, hypovitaminosis D is common in women of reproductive age in Al Ain, United Arab Emirates (UAE). AIMS AND OBJECTIVES: To establish the prevalence of hypovitaminosis D in adolescent female Emirati nationals and its risk factors. METHODS: This was an analytical prospective cohort study of 350 female Emirati nationals aged 11-18 years attending public schools in Al Ain. Socio-economic status, diet and amount of sun exposure were evaluated by face-to-face interviews. Serum total 25 (OH) vitamin D (D2 + D3) levels were measured by electrochemiluminescence assay. The prevalence of hypovitaminosis D was calculated and the association with risk factors analysed. RESULTS: Data were complete for 293 girls. Only one girl [prevalence 0.3%, 95% confidence interval (CI) 0.01-1.9] had vitamin D sufficiency (serum vitamin D levels >75 nmol/L). Three girls (1.0%, 95% CI 0.2-2.9) had vitamin D insufficiency (50-75 nmol/L), 58 (19.8%, 95% CI 15.0-25.5) were deficient (27.5 50 nmol/L) and 231 (78.8%, 95% CI 68.9-89.6) had severe deficiency (<27.5 nmol/L). Serum vitamin D levels declined between the ages of 11 and 13 years before progressively rising until the age of 18 years but without regaining the levels they were at the age of 11. There was no statistically significant difference between the vitamin D status groups in age, body mass index, accommodation type, family income, percentage of surface area unexposed to the sun when outdoors, consumption of oily fish or total vitamin D intake. CONCLUSION: The finding of a high prevalence of hypovitaminosis D in adolescent females in UAE is of serious concern for their health and that of their infants during their reproductive lives. Adolescent girls with a similar social and cultural background currently living in less sunny, industrialised countries might also be at risk. PMID- 25547177 TI - There is no difference in nitric oxide metabolites and neonatal outcome between premature infants born to pre-eclamptic and those born to normotensive women. AB - BACKGROUND: The pathophysiology of pre-eclampsia (PE) is complex, and nitric oxide (NO) may be a factor. The neonatal outcome in pregnancies complicated by PE is controversial, and the PE/NO/neonatal diseases relationship has not been well established. AIMS: To measure nitrate and nitrite levels in the placenta, umbilical cord blood, blood and urine of preterm neonates born to pre-eclamptic and normotensive women and to investigate the relationship between placental, fetal and neonatal NO metabolites and neonatal outcome. METHODS: A prospective study was undertaken of 30 preterm infants <34 weeks of gestation, born to pre eclamptic mothers and matched by gestational age with 30 infants born to normotensive mothers. Samples from the placental tissue, venous cord blood and the newborns' blood on day 4 and urine on days 1 and 4 were assayed for NO metabolites (nitrate and nitrite). Clinical variables and NO metabolites were compared between the groups. Generalised linear models were fitted to associate NO metabolites levels with adverse neonatal outcomes. RESULTS: There were no differences in NO metabolites and neonatal outcomes between the two groups. Increased levels of NO metabolites were found in the placenta and cord blood of small-for-gestational-age infants, and in the cord blood of newborns with necrotising enterocolitis and those who died. CONCLUSION: NO metabolite levels in the placenta and fetal and neonatal circulation were not associated with PE; however, cord blood levels of NO metabolites differed according to fetal growth and neonatal outcome. PMID- 25547178 TI - Congenital toxoplasmosis: an uncommon disease in Thailand. AB - BACKGROUND: The seroprevalence of toxoplasma antibodies in pregnant women and the prevalence of congenital infection differ widely between countries. A few cases of congenital toxoplasmosis diagnosed after the neonatal period, with long-term sequelae, have been reported in Thailand. No data on the prevalence of congenital toxoplasmosis have been documented and no screening for toxoplasmosis during pregnancy has been undertaken in Thailand. SUBJECTS AND METHODS: A questionnaire enquiring about cases of congenital toxoplasmosis during 1995-2013 was distributed to paediatricians in referral and university hospitals in Thailand and the responses were analysed. Specific toxoplasma IgM antibody and clinical features were used for diagnosis. RESULTS: There were 20 cases - 13 most likely and seven suspected cases of congenital toxoplasmosis. Most patients had systemic manifestations, but only 25% of diagnosed patients exhibited the classic triad of hydrocephalus, cerebral calcification and chorioretinitis. One of the five deceased patients lived beyond the age of 13 years and died of a pulmonary infection. All 15 surviving cases developed deafness, visual impairment or developmental delay. CONCLUSIONS: Twenty cases of congenital toxoplasmosis are reported. Delayed diagnosis and treatment resulted in a poor outcome. The prevention of toxoplasmosis in pregnant women and prompt diagnosis and appropriate treatment of congenital toxoplasmosis should be a priority in order to prevent a poor outcome in infected children. PMID- 25547180 TI - Erratum: correction of prevalence of falls by sex in article 'risk factors for falls in older korean adults: the 2011 community health survey'. AB - [This corrects the article on p. 1482 in vol. 29, PMID: 25408578.]. PMID- 25547179 TI - Which clinical signs predict hypoxaemia in young Senegalese children with acute lower respiratory tract disease? AB - BACKGROUND: Acute lower respiratory tract diseases are an important cause of mortality in children in resource-limited settings. In the absence of pulse oximetry, clinicians rely on clinical signs to detect hypoxaemia. OBJECTIVE: To assess the diagnostic value of clinical signs of hypoxaemia in children aged 2 months to 5 years with acute lower respiratory tract disease. METHODS: Seventy children with a history of cough and signs of respiratory distress were enrolled. Three experienced physicians recorded clinical signs and oxygen saturation by pulse oximetry. Hypoxaemia was defined as oxygen saturation <90%. Clinical predictors of hypoxaemia were evaluated using adjusted diagnostic odds ratios (aDOR). RESULTS: There was a 43% prevalence of hypoxaemia. An initial visual impression of poor general status [aDOR 20.0, 95% CI 3.8-106], severe chest indrawing (aDOR 9.8, 95% CI 1.5-65), audible grunting (aDOR 6.9, 95% CI 1.4-25) and cyanosis (aDOR 26.5, 95% CI 1.1-677) were significant predictors of hypoxaemia. CONCLUSION: In children under 5 years of age, several simple clinical signs are reliable predictors of hypoxaemia. These should be included in diagnostic guidelines. PMID- 25547182 TI - Fabrication of nanopatterned poly(ethylene glycol) brushes by molecular transfer printing from poly(styrene-block-methyl methacrylate) films to generate arrays of Au nanoparticles. AB - This article presents a soft lithographic approach using block copolymer (BCP) films to fabricate functional chemically patterned polymer brushes on the nanoscale. Hydroxyl-terminated poly(ethylene glycol) (PEG-OH) was transfer printed from the poly(methyl methacrylate) (PMMA) domains of self-assembled poly(styrene-block-methyl methacrylate) films to a substrate in conformal contact with the film to generate patterned PEG brushes mirroring the pattern of BCP domains. A key point in the study is that the chemistry of the functional transferred brushes is different from the chemistry of either block of the copolymer; PEG-OH is miscible only in the PMMA block and therefore transferred only from PMMA domains. The functionality of the PEG brushes was demonstrated by the selective immobilization of citrate-stabilized Au NPs (15 nm) and validated the generation of high-quality chemical patterns with sub-30-nm feature sizes. PMID- 25547181 TI - IL-22-producing Th22 cells play a protective role in CVB3-induced chronic myocarditis and dilated cardiomyopathy by inhibiting myocardial fibrosis. AB - BACKGROUND: A new subset of T helper (Th) cells, named IL-22-producing Th22 cells, was identified recently. Th22 cells have been implicated in immunity and inflammation. However, the role of these cells in the progression from acute viral myocarditis (AVMC) to dilated cardiomyopathy (DCM) and myocardial fibrosis remains unknown. METHODS: BALB/c mice were repeatedly i.p. infected with Coxsackie virus B3 (CVB3) to establish models of AVMC, chronic myocarditis and DCM. On week 2, 12 and 24 post initial injection, the percentage of splenic Th22 cells, the levels of plasma IL-22, cardiac IL-22 receptor (IL-22R) expression, and indicators of myocardial fibrosis were measured. Further, mice with AVMC and chronic myocarditis were treated with an anti-IL-22 neutralizing antibody (Ab). The collagen volume fraction (CVF), the percentage of splenic Th22 cells, plasma IL-22 levels, cardiac IL-22R expression and indicators of myocardial fibrosis were then monitored. RESULTS: Compared to control mice at the same time points, AVMC, chronic myocarditis and DCM mice have higher percentage of splenic Th22 cells, higher plasma IL-22 levels, increased cardiac IL-22R, as well as increased collagen typeI-A1 (COL1-A1), collagen type III-A1 (COL3-A1) and matrix metalloproteinase-9 (MMP9) expression. However, the expression of tissue inhibitor of metalloproteinase-1(TIMP-1) was decreased. Treatment of AVMC and chronic myocarditis mice with an anti-IL-22 Ab decreased the survival rate and exacerbated myocardial fibrosis. The percentage of splenic Th22 cells, plasma IL 22 levels and cardiac IL-22R expression also decreased in anti-IL-22 Ab treatment group as compared to IgG and PBS treated groups of AVMC and chronic myocarditis mice. Moreover, increased expression of COL1-A1, COL3-A1, MMP9 but decreased expression of TIMP-1 were observed in anti-IL-22 Ab mouse group. CONCLUSIONS: Th22 cells play an important role in the pathogenesis of CVB3-induced mouse chronic myocarditis and DCM. IL-22 is a myocardium-protective cytokine by inhibiting myocardial fibrosis. Therefore, Th 22 cells may be considered as potential therapeutic targets for DCM. PMID- 25547183 TI - Lessons for molecular diagnostics in oncology from the Cancer Research UK Stratified Medicine Programme. AB - The implementation of stratified medicine in modern cancer care presents substantial opportunity to refine diagnosis and treatment but also numerous challenges. Through experience in a UK tumor profiling initiative, we have gained valuable insights into the complexities and possible solutions for routine delivery of stratified cancer medicine. PMID- 25547184 TI - Pemphigoid gestationis with IgG autoantibodies to both the 120 kDa LAD-1 and the BP180 NC16a domain. PMID- 25547185 TI - Wearable sensor-based in-home assessment of gait, balance, and physical activity for discrimination of frailty status: baseline results of the Arizona frailty cohort study. AB - BACKGROUND: Frailty is a geriatric syndrome resulting from age-related cumulative decline across multiple physiologic systems, impaired homeostatic reserve, and reduced capacity to resist stress. Based on recent estimates, 10% of community dwelling older individuals are frail and another 41.6% are prefrail. Frail elders account for the highest health care costs in industrialized nations. Impaired physical function is a major indicator of frailty, and functional performance tests are useful for the identification of frailty. Objective instrumented assessments of physical functioning that are feasible for home frailty screening have not been adequately developed. OBJECTIVE: To examine the ability of wearable sensor-based in-home assessment of gait, balance, and physical activity (PA) to discriminate between frailty levels (nonfrail, prefrail, and frail). METHODS: In an observational cross-sectional study, in-home visits were completed in 125 older adults (nonfrail: n=44, prefrail: n=60, frail: n=21) living in Tucson, Ariz., USA, between September 2012 and November 2013. Temporal-spatial gait parameters (speed, stride length, stride time, double support, and variability of stride velocity), postural balance (sway of hip, ankle, and center of mass), and PA (percentage of walking, standing, sitting, and lying; mean duration and variability of single walking, standing, sitting, and lying bouts) were measured in the participant's home using validated wearable sensor technology. Logistic regression was used to assess the most sensitive gait, balance, and PA variables for identifying prefrail participants (vs. nonfrail). Multinomial logistic regression was used to identify variables sensitive to discriminate between three frailty levels. RESULTS: Gait speed (area under the curve, AUC=0.802), hip sway (AUC=0.734), and steps/day (AUC=0.736) were the most sensitive parameters for the identification of prefrailty. Multinomial regression revealed that stride length (AUC=0.857) and double support (AUC=0.841) were the most sensitive gait parameters for discriminating between three frailty levels. Interestingly, walking bout duration variability was the most sensitive PA parameter for discriminating between three frailty levels (AUC=0.818). No balance parameter discriminated between three frailty levels. CONCLUSION: Our results indicate that unique parameters derived from objective assessment of gait, balance, and PA are sensitive for the identification of prefrailty and the classification of a subject's frailty level. The present findings highlight the potential of wearable sensor technology for in-home assessment of frailty status. PMID- 25547187 TI - The clinical utility of sonographic cervical length in the management of preterm parturition at 28-32 weeks of gestation. AB - OBJECTIVES: The aim of this study was to evaluate the role of cervical length measurement in early third trimester (28-32 weeks) as a predictor of preterm delivery (PTD), in women presenting with preterm parturition. METHODS: Cervical length was measured prospectively, in singleton pregnancies at 28-32 weeks with preterm contractions (PTC). A multivariate linear regression model was performed to assess the association between cervical length and gestational age at delivery. Logistic regression analysis with PTD before 34 and 37 weeks of gestation as the outcome variable was performed to control for confounders. RESULTS: Fifty-six women were included, mean gestational week at presentation and at delivery were 29.88 +/- 1.13 and 37.05 +/- 2.86, respectively. There was a direct association between short cervical length at admission and gestational week at delivery (p = 0.027). This association remained significant even after controlling for confounders. Short cervical length was significantly associated with PTD before 34 (p = 0.045) or 37 (p = 0.046) weeks of gestation. CONCLUSIONS: Third trimester cervical length measurement in patients with PTC is associated with gestational week at delivery, as well as PTD prior to 34 and 37 weeks of gestation. Therefore, examining cervical length is clinically valuable and probably cost-effective during early third trimester. PMID- 25547186 TI - Transcriptomic and proteomic dynamics in the metabolism of a diazotrophic cyanobacterium, Cyanothece sp. PCC 7822 during a diurnal light-dark cycle. AB - BACKGROUND: Cyanothece sp. PCC 7822 is an excellent cyanobacterial model organism with great potential to be applied as a biocatalyst for the production of high value compounds. Like other unicellular diazotrophic cyanobacterial species, it has a tightly regulated metabolism synchronized to the light-dark cycle. Utilizing transcriptomic and proteomic methods, we quantified the relationships between transcription and translation underlying central and secondary metabolism in response to nitrogen free, 12 hour light and 12 hour dark conditions. RESULTS: By combining mass-spectrometry based proteomics and RNA-sequencing transcriptomics, we quantitatively measured a total of 6766 mRNAs and 1322 proteins at four time points across a 24 hour light-dark cycle. Photosynthesis, nitrogen fixation, and carbon storage relevant genes were expressed during the preceding light or dark period, concurrent with measured nitrogenase activity in the late light period. We describe many instances of disparity in peak mRNA and protein abundances, and strong correlation of light dependent expression of both antisense and CRISPR-related gene expression. The proteins for nitrogenase and the pentose phosphate pathway were highest in the dark, whereas those for glycolysis and the TCA cycle were more prominent in the light. Interestingly, one copy of the psbA gene encoding the photosystem II (PSII) reaction center protein D1 (psbA4) was highly upregulated only in the dark. This protein likely cannot catalyze O2 evolution and so may be used by the cell to keep PSII intact during N2 fixation. The CRISPR elements were found exclusively at the ends of the large plasmid and we speculate that their presence is crucial to the maintenance of this plasmid. CONCLUSIONS: This investigation of parallel transcriptional and translational activity within Cyanothece sp. PCC 7822 provided quantitative information on expression levels of metabolic pathways relevant to engineering efforts. The identification of expression patterns for both mRNA and protein affords a basis for improving biofuel production in this strain and for further genetic manipulations. Expression analysis of the genes encoded on the 6 plasmids provided insight into the possible acquisition and maintenance of some of these extra-chromosomal elements. PMID- 25547188 TI - Cardio-STIC (spatio-temporal image correlation) as genetic ultrasound of fetal Down syndrome. AB - OBJECTIVE: To evaluate efficacy of cardio-STIC in detection of fetal Down syndrome. METHODS: Cardio-STIC volume datasets (VDS) were prospectively collected from women during 16-22 weeks, consisting of 40 VDS acquired from fetuses with Down syndrome and 400 VDS from normal fetuses. All VDS were blindly analyzed. RESULTS: Between both groups, most dimensions were comparable but the right-sided dimensions were significantly greater in fetuses with Down syndrome. Interestingly, shortening fraction was also significantly higher in affected fetuses. Right-to-left disproportion and shortening fraction were used as cardiac markers as well as other eight structural markers to predict fetal Down syndrome. Tricuspid regurgitation had highest sensitivity (30%); followed by VSD (27.5%), right-to-left disproportion (20.0%), and echogenic intra-cardiac foci (EIF; 17.5%). If the test was considered positive in case of the presence of any cardiac marker, cardio-STIC had a detection rate of 72.5% and false-positive rate of 19.5%. Likelihood ratio of each marker for modifying priori risk was also provided. CONCLUSION: Cardio-STIC as genetic ultrasound for Down syndrome had a detection rate of about 70% and false-positive rate 20%. Cardio-STIC analysis can be helpful in estimation of fetal risk for Down syndrome and counseling when the prenatal diagnosis of the syndrome is made. PMID- 25547189 TI - The clinical inadequacy of evidence-based medicine and the need for a conceptual framework based on clinical judgment. PMID- 25547191 TI - Lifestyle is blamed for half a million UK cancers in past five years. PMID- 25547190 TI - [A case of community acquired Elisabethkingia meningoseptica meningitis in an infant]. PMID- 25547192 TI - Transcranial direct current stimulation to enhance cognitive remediation in schizophrenia. PMID- 25547194 TI - Medical documentation: part of the solution, or part of the problem? A narrative review of the literature on the time spent on and value of medical documentation. AB - BACKGROUND: Even though it takes up such a large part of all clinicians' working day the medical literature on documentation and its value is sparse. METHODS: Medline searches combining the terms medical records, documentation, time, and value or efficacy or benefit yielded only 147 articles. This review is based on the relevant articles selected from this search and additional studies gathered from the personal experience of the authors and their colleagues. RESULTS: Documentation now occupies a quarter to half of doctors' time yet much of the information collected is of dubious or unproven value. Most medical records departments still use the traditional paper chart, and there is considerable debate on the benefits of electronic medical records (EMRs). Although EMRs contains a lot more information than a paper record clinicians do not find it easy to getting useful information out of them. Unlike the paper chart narrative is difficult to enter into most EMRs so that they do not adequately communicate the patient's "story" to clinicians. Recent innovations have the potential to address these issues. CONCLUSION: Although documentation is widespread throughout the health care industry there has been almost no formal research into its value, on how to enhance its value, or on whether the time spent on it has negative effects on patient care. PMID- 25547196 TI - Production and characterization of refined oils obtained from Indian oil sardine (Sardinella longiceps). AB - Crude Sardinella longiceps oil was refined in different stages such as degumming, neutralization, bleaching, and deodorization. The efficiency of these processes was evaluated on the basis of free fatty acid (FFA), peroxide (PV), p-anisidine (pAV), total oxidation (TOTOX), thiobarbituric acid reactive species (TBARS) values, Lovibond CIE-L*a*b* color analyses, and (1)H NMR or GC-MS experiments. The utilities of NMR-based proton signal characteristics as new analytical tools to understand the signature peaks and relative abundance of different fatty acids and monitoring the refining process of fish oil have been demonstrated. Phosphoric acid (1%) was found to be an effective degumming reagent to obtain oil with the lowest FFA, PV, pAV, TOTOX, and TBARS values and highest color reduction. Significant reduction in the contents of hydrocarbon functionalities as shown by the decrease in proton integral in the characteristic (1)H NMR region was demonstrated by using 1% H3PO4 during the course of the degumming process. A combination (1.25:3.75%) of activated charcoal and Fuller's earth at 3% concentration for a stirring time of 40 min was found to be effective in bleaching the sardine oil. This study demonstrated that unfavorable odor-causing components, particularly low molecular weight carbonyl compounds, could successfully be removed by the refining process. The alkane-dienals/alkanes, which cause unfavorable fishy odors, were successfully removed by distillation (100 degrees C) under vacuum with aqueous acetic acid solution (0.25 N) to obtain greater quality of refined sardine oil, a rich source of essential fatty acids and improved oxidative stability. The present study demonstrated that the four-stage refinement process of sardine oil resulted in a significant improvement in quality characteristics and nutritional values, particularly n-3 PUFAs, with improved fish oil characteristics for use in the pharmaceutical and functional food industries. PMID- 25547195 TI - Cerebral small vessel disease and renal function: systematic review and meta analysis. AB - BACKGROUND: The small vessel disease (SVD) that appears in the brain may be part of a multisystem disorder affecting other vascular beds such as the kidney and retina. Because renal failure is associated with both stroke and white matter hyperintensities we hypothesised that small vessel (lacunar) stroke would be more strongly associated with renal failure than cortical stroke. Therefore, we performed a systematic review and meta-analysis to establish first if lacunar stroke was associated with the renal function, and second, if cerebral small vessel disease seen on the MRI of patients without stroke was more common in patients with renal failure. METHODS: We searched Medline and EMBASE for studies in adults with cerebral SVD (lacunar stroke or white matter hyper intensities (WMH) on Magnetic Resonance Imaging (MRI)), in which renal function was assessed (estimated glomerular filtration rate (eGFR) or proteinuria). We extracted data on SVD diagnosis, renal function, demographics and comorbidities. We performed two meta-analyses: first, we calculated the odds of renal impairment in lacunar (small vessel) ischaemic stroke compared to other ischaemic stroke subtypes (non small vessel disease); and second, we calculated the odds of renal impairment in non-stroke individuals with WMH on MRI compared to individuals without WMH. We then performed a sensitivity analysis by excluding studies with certain characteristics and repeating the meta-analysis calculation. RESULTS: After screening 11,001 potentially suitable titles, we included 37 papers reporting 32 studies of 20,379 subjects: 15 of stroke patients and 17 of SVD features in non stroke patients. To diagnose lacunar stroke, 13/15 of the studies used risk factor-based classification (none used diffusion-weighted MRI). 394/1,119 (35%) of patients with lacunar stroke had renal impairment compared with 1,443/4,217 (34%) of patients with non-lacunar stroke, OR 0.88, (95% CI 0.6-1.30). In individuals without stroke the presence of SVD was associated with an increased risk of renal impairment (whether proteinuria or reduced eGFR) OR 2.33 (95% CI 1.80-3.01), when compared to those without SVD. After adjustment for age and hypertension, 15/21 studies still reported a significant association between renal impairment and SVD. CONCLUSION: We found no specific association between renal impairment and lacunar stroke, but we did find that in individuals who had not had a stroke, having more SVD features on imaging was associated with a worse renal function, which remained significant after controlling for hypertension. However, this finding does not exclude a powerful co-associate effect of age or vascular risk factor exposure. Future research should subtype lacunar stroke sensitively and control for major risk factors. PMID- 25547197 TI - An epigenetic escape route. AB - Some of our fate is predetermined, by genetics and by the environment in the womb. Gestational environments are reflected in the DNA methylomes of newborns, in a manner that is often influenced by genotype. Therefore, DNA methylation serves as molecular mechanism linking the interplay of early life environments and genetics to later life health. As such, methylation marks are potential biomarkers of suboptimal developmental trajectories. Can DNA methylation also be used to construct an escape route from biological fate? PMID- 25547193 TI - [Monitoring network for vulnerable children in the Pays de la Loire ("Grandir ensemble" - Cohort LIFT): 10 years of activity 2003-2013]. AB - INTRODUCTION: Vulnerable children are at-risk newborns including premature infants and some children with pathologies presented by fear anomalies and deficiencies, most particularly neurological. Monitoring is based on the detection of these abnormalities and their early management. The organization of this monitoring system is based on a network of doctors, mostly pediatricians, trained regularly. The objective of this review was to assess the resources, means, and results of 10 years of follow-up. METHODS: The Pays de la Loire network includes 24 maternity wards and 13 neonatal departments. Annual admissions are around 5000 newborns to approximately 45,000 annual births. Upon discharge of newborns, born prematurely at 34 weeks of gestation (WG) or less, or term infants with neurological problems, parents are asked to have their child monitored by a referring doctor. During the consultation, a reference document is filled out by the doctor and sent to the project manager for data collection and specific compensation for private practitioners. Standardized questionnaires were used such as the ASQ (Ages and Stage Questionnaire) completed by parents, the developmental quotient (DQ) with the Lezine Brunet-Revised test (BLR), the intelligence quotient (IQ) with the Wechsler Preschool and Primary Scale of Intelligence (WIPPSI III) completed by psychologists employed in the network, and a questionnaire completed by the teacher at 5 years of age. RESULTS: The network started on 1st March 2003, and 28th February 2013, after 10 years of inclusion, 10,800 children had been included. This population accounts for 2.4% of all annual births: 1.1% were included for prematurity less than 33 weeks and 0.25% were term-born infants. The characteristics of children are presented with gestational age, birth weight, and obstetric and neonatal pathologies. The percentage of these children followed was 80% at 2 years and 63% at 5 years. At 2 years, the results are presented according to gestational age with approximately 60% of children without disabilities at 25-26 WG, 73% at 27-28 WG, 77% at 29-30 WG, and 86% at 31-32 WG. Absorptions are diverse and vary according to the age of the child with physical therapy, psychomotor skill work, speech therapy, hearing and vision consultations, and psychology/psychiatry. Assessment tools were refined by specific analyses: the ASQ 24 months (completed by parents) was deemed valid and predictive with respect to IQ (abandoned in 2012), and the grid completed by the teacher was found to predict abnormalities in 5 years. CONCLUSION: The Pays de la Loire monitoring network has met its initial objective, namely to detect disabilities early and provide practical help to parents in a population of vulnerable children. Benefits for professionals and other children not followed in the network were observed, with an increase in pediatricians' skills. The benefits of the evaluation results are more difficult to assess with the care than neonatal care in obstetrics. The sustainability of such a network seems assured for healthcare professionals, provided that funding is maintained by the health authorities. PMID- 25547198 TI - Clinical characteristics, treatment outcomes, and resource utilization in children and adults with eosinophilic gastroenteritis. AB - BACKGROUND: Eosinophilic gastroenteritis is a rare condition where eosinophilic inflammation occurs in the gastrointestinal tract in the absence of secondary causes. Little is known regarding aetiology, pathogenesis, or natural history. AIMS: To characterize the clinical, endoscopic, and histopathologic features of eosinophilic gastroenteritis and to summarize treatment outcomes. METHODS: Pathology reports of all patients who had undergone upper endoscopy with biopsy between January 1, 2000 and June 20, 2013 were reviewed. Eosinophilic gastroenteritis was diagnosed if there were >=20 eosinophils/hpf on either gastric of duodenal biopsy, symptoms attributable to the gastrointestinal tract, and no known secondary cause of eosinophilia. Descriptive statistics characterized patients diagnosed with eosinophilic gastroenteritis and bivariate analysis compared adults and children. RESULTS: There were 44 patients diagnosed with eosinophilic gastrointestinal disease. The most common symptoms were vomiting (71%) and abdominal pain (62%). Of the eosinophilic gastroenteritis cases, 12 (30%) had esophageal involvement, and 11 (28%) had colonic involvement. For treatment, 36 (80%) received corticosteroids. Overall, 27 (60%) had symptom resolution and 23 (51%) had endoscopic resolution. Cases underwent a mean of five endoscopic procedures per year. CONCLUSION: Eosinophilic gastroenteritis presents with non-specific gastrointestinal symptoms and in almost one-third of cases has concomitant esophageal or colonic involvement. It remains difficult to treat, with high rates of endoscopic utilization. PMID- 25547200 TI - Standardised ("plain") packaging of cigarettes regulations must be passed before the general election. PMID- 25547199 TI - N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues. AB - A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5 dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca(2+) mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5 HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor. PMID- 25547201 TI - Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications. AB - BACKGROUND: At the interface of the external environment and the mucosal surface of the female reproductive tract (FRT) lies a first-line defense against pathogen invasion that includes antimicrobial peptides (AMP). Comprised of a unique class of multifunctional, amphipathic molecules, AMP employ a wide range of functions to limit microbial invasion and replication within host cells as well as independently modulate the immune system, dampen inflammation and maintain tissue homeostasis. The role of AMP in barrier defense at the level of the skin and gut has received much attention as of late. Given the far reaching implications for women's health, maternal and fetal morbidity and mortality, and sexually transmissible and polymicrobial diseases, we herein review the distribution and function of key AMP throughout the female reproductive mucosa and assess their role as an essential immunological barrier to microbial invasion throughout the reproductive cycle of a woman's lifetime. METHODS: A comprehensive search in PubMed/Medline was conducted related to AMP general structure, function, signaling, expression, distribution and barrier function of AMP in the FRT, hormone regulation of AMP, the microbiome of the FRT, and AMP in relation to implantation, pregnancy, fertility, pelvic inflammatory disease, complications of pregnancy and assisted reproductive technology. RESULTS: AMP are amphipathic peptides that target microbes for destruction and have been conserved throughout all living organisms. In the FRT, several major classes of AMP are expressed constitutively and others are inducible at the mucosal epithelium and by immune cells. AMP expression is also under the influence of sex hormones, varying throughout the menstrual cycle, and dependent on the vaginal microbiome. AMP can prevent infection with sexually transmissible and opportunistic pathogens of the female reproductive tissues, although emerging understanding of vaginal dysbiosis suggests induction of a unique AMP profile with increased susceptibility to these pathogens. During pregnancy, AMP are key immune effectors of the fetal membranes and placenta and are dysregulated in states of intrauterine infection and other complications of pregnancy. CONCLUSIONS: At the level of the FRT, AMP serve to inhibit infection by sexually and vertically transmissible as well as by opportunistic bacteria, fungi, viruses, and protozoa and must do so throughout the hormone flux of menses and pregnancy. Guarding the exclusive site of reproduction, AMP modulate the vaginal microbiome of the lower FRT to aid in preventing ascending microbes into the upper FRT. Evolving in parallel with, and in response to, pathogenic insults, AMP are relatively immune to the resistance mechanisms employed by rapidly evolving pathogens and play a key role in barrier function and host defense throughout the FRT. PMID- 25547202 TI - Polymer and surfactant-templated synthesis of hollow and porous ZnS nano- and microspheres in a spray pyrolysis reactor. AB - Nanostructured zinc sulfide can provide unique photonic, electronic, and catalytic properties that are of interest for applications ranging from bioimaging to photocatalysis. Here we report an easily controllable continuous method to produce porous and hollow ZnS nano- and microspheres. We used poly(ethylene glycol) methyl ether (PEG), polyvinylpyrrolidone (PVP), ethylene oxide/propylene oxide block copolymer (Pluronic F-38), and cetyltrimethylammonium bromide (CTAB) as templates to synthesize ZnS nano- and microspheres with controlled internal morphology in a spray pyrolysis process, starting from an aqueous solution of chemical precursors and templating agents. Spherical particles were produced by droplet-to-particle conversion of droplets. Zinc acetate and thiourea, used here as precursors for ZnS, react in solution to form bis-thiourea zinc acetate (BTZA), which precipitates with the evaporation of solvent. Upon further heating, BTZA decomposes to yield ZnS. During solvent evaporation, PEG and Pluronic precipitate after BTZA, driving formation of a shell of ZnS and a hollow core. In contrast, PVP and CTAB interact strongly with BTZA and ZnS, such that the PVP and ZnS remain intermixed. After evaporation of solvent, the templating agents can be pyrolyzed at high temperature to leave behind porous or hollow ZnS microspheres composed of many much smaller nanocrystals. PMID- 25547203 TI - Association of CD40 -1C/T polymorphism in the 5'-untranslated region with chronic HBV infection. AB - BACKGROUND: CD40 is an important costimulatory molecule in both cellular and humoral immune responses, involved in the pathogenic processes of chronic inflammatory diseases. Few studies were performed on the association of CD40 single nucleotide polymorphism (SNP) with chronic hepatitis B virus (HBV) infection. In this study, we studied whether the CD40-1C/T polymorphism had any effect on the progression of chronic HBV infection in Chinese population. METHODS: CD40 -1C/T polymorphism in the 5'-untranslated region was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 453 chronic HBV carriers, who were divided into asymptomatic HBV carriers (ASC), moderate chronic hepatitis B group (MCHB) and severe chronic hepatitis B group (SCHB). 202 healthy individuals in the same region were enrolled in this study as the controls. The CD40 expression on B lymphocytes was detected by flow cytometry. The concentrations of soluble CD40 (sCD40) in sera were assayed by a commercial ELISA kit. RESULTS: Our results showed the frequencies of TT genotype and T allele of CD40-1C/T polymorphism were higher significantly in ASC than those in controls (P< 0.05), while this result was not found in either MCHB or SCHB. On the surface of B lymphocytes, the CD40 expression levels in the individuals with TT genotype were significantly lower than those with CC and CT genotypes in either ASC group or healthy controls (P<0.001). The sCD40 levels in the sera of ASC, MCHB and SCHB groups were significantly higher than the controls (P<0.001). CONCLUSIONS: The CD40 -1C/T polymorphism may contribute to the susceptibility of asymptomatic HBV carriers through its effect on cell-surface CD40 expression, which indicated CD40 signaling was involved in immune tolerance of chronic HBV infection. PMID- 25547204 TI - Association of MTHFR A1298C polymorphism with conotruncal heart disease. AB - Congenital heart diseases are common congenital anomalies with 1% prevalence worldwide and are associated with significant childhood morbidity and mortality. Among a wide range of aetiologically heterogeneous conditions, conotruncal anomalies account for approximately one-third of all congenital heart defects. The aetiology of conotruncal heart diseases is complex, with both environmental and genetic causes. Hyperhomocysteinaemia, which is often accompanied by the defects of folic acid metabolism, is known to cause conotruncal heart anomalies. In this study, we have evaluated three polymorphisms in the following two hyperhomocysteinaemia-related genes: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and nicotinamide N-methyl transferase (NNMT rs694539) in 79 children with conotruncal heart disease and 99 children without conotruncal heart disease. Genotype distribution of the MTHFR A1298C polymorphism showed a statistically significant difference between the two groups. In the case group, AC and CC genotypes were higher than the control group (p<0.05). We have found that MTHFR A1298C polymorphism is associated with conotruncal heart disease; C allele (p=0.028), AC (OR[95% CI]=2.48[1.24-4.95], p=0.010), CC (OR[95% CI]=3.01[1.16-7.83], p=0.023), and AC+CC (OR[95% CI]=2.60[1.36-4.99], p=0.004) genotypes are more frequent in the patient group. Genotype distributions of the MTHFR C677T and NNMT rs694539 polymorphisms were similar in the two groups when evaluated separately and also according to the dominant genetic model (p>0.05). Our results suggest that MTHFR 1298C allele is a risk factor for conotruncal heart disease. PMID- 25547205 TI - Addressing the challenges of pancreatic cancer: future directions for improving outcomes. AB - Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease. PMID- 25547207 TI - The politics of relative deprivation: A transdisciplinary social justice perspective. AB - Relative deprivation was defined by Townsend (1987, p. 125) as "a state of observable and demonstrable disadvantage, relative to the local community or the wider society or nation to which an individual, family or group belongs". This definition is widely used within social and health sciences to identify, measure, and explain forms of inequality in human societies based on material and social conditions. From a multi-disciplinary social science perspective, we conducted a systematic literature review of published material in English through online database searches and books since 1966. We review the concept and measurement of relative 'deprivation' focussing on area-based deprivation in relation to inequities in health and social outcomes. This paper presents a perspective based in Aotearoa/New Zealand where colonisation has shaped the contours of racialised health inequities and current applications and understandings of 'deprivation'. We provide a critique of Townsend's concept of deprivation and area-based deprivation through a critical, structural analysis and suggest alternatives to give social justice a better chance. Deprivation measures used without critical reflection can lead to deficit framing of populations and maintain current inequities in health and social outcomes. We contend therefore that the lack of consideration of (bio)power, privilege, epistemology and (bio)politics is a central concern in studies of deprivation. Our review highlights the need for the academy to balance the asymmetry between qualitative and quantitative studies of deprivation through trans-disciplinary approaches to understanding deprivation, and subsequently, social and health inequities. We recommend that deprivation research needs be critically applied through a decolonising lens to avoid deficit framing and suggest that there is space for a tool that focuses on measuring the unequal distribution of power and privilege in populations. PMID- 25547206 TI - Preventive care in older cancer survivors. AB - OBJECTIVE: To study factors that influence receipt of preventive care in older cancer survivors. METHODS: We analyzed a nationally representative sample of 12,458 older adults from the 2003 Medicare Current Beneficiary Survey. Factors associated with non-receipt of preventive care were explored among cancer and non cancer survivors, using logistic regression. RESULTS: Among the cancer survivors, 1883 were diagnosed >1 year at survey completion. A cancer history was independently associated with receipt of mammogram (AOR = 1.57, 95% CI = 1.34 1.85), flu shot (AOR = 1.33, 95% CI = 1.16-1.53), measurement of total cholesterol in the previous six months (AOR = 1.20, 95% CI = 1.07-1.34), pneumonia vaccination (AOR = 1.33, 95% CI = 1.18-1.49), bone mineral density (BMD) testing (AOR = 1.38, 95% CI = 1.21-1.56), and lower endoscopy (AOR = 1.46, 95% CI = 1.29-1.65). However, receipt of preventive care was not optimal among older cancer survivors with only 51.2% of the female cancer survivors received a mammogram, 63.8% of all the cancer survivors received colonoscopy, and 42.5% had BMD testing. Among the cancer survivors, factors associated with non-receipt of mammogram included age >=85 years (AOR = 0.43, 95% CI = 0.26-0.74), and scoring >=three points on the Vulnerable Elders Survey-13 (AOR = 0.94, 95% CI = 0.80 1.00). Factors associated with non-receipt of colonoscopy included low education (AOR= 0.43, 95% CI = 0.27-0.68) and rural residence (AOR = 0.51, 95% CI = 0.34 0.77). Factors associated with non-receipt of BMD testing included age >=70 (AOR = 0.59, 95% CI = 0.39-0.90), African American race (AOR = 0.51, 95% CI= 0.27 0.95), low education (AOR = 0.23, 95% CI = 0.14-0.38), and rural residence (AOR = 0.43, 95% CI = 0.27-0.70). CONCLUSION: Although older cancer survivors are more likely to receive preventive care services than other older adults, factors other than health status considerations (e.g., education, rural residence) are associated with non-receipt of preventive care services. PMID- 25547208 TI - The positive aspects of caregiving in dementia: A critical review of the qualitative literature. AB - Positive aspects of caregiving in dementia have been identified as important in understanding the experiences of carers, yet the research base lacks clear definitions of key concepts. Qualitative research explores carers' experiences of positive aspects of caregiving in rich detail which lends itself to supporting theory development. The aim of the present review was to critically evaluate the empirical findings of qualitative studies that have explored positive aspects of caregiving in dementia. A systematic search of the literature revealed 14 studies that met this aim. Carers described multiple positive dimensions of caregiving and identified several factors that were important in supporting their positive caregiving experience. The present review evidences a solid base of understanding of the positive aspects of caregiving in dementia from which concepts and theories can be further developed. Clinical and research implications are discussed. PMID- 25547209 TI - The "not yet" horizon: Understandings of the future amongst couples living with dementia. AB - The way in which persons with dementia and their spouses regard the future could influence how they experience the disease itself. This study aims to explore how the future is understood by couples living with dementia. The analysis reveals different ways in which couples understand the future. The findings show that persons with dementia describe the here and now in ways that take the gloomy future they dread as a point of reference, and as a result of this, they operate in what we term "the not yet horizon". But while they take for granted that there is a horizon that they have not yet reached, their spouses always seem to focus on the horizons that they have already crossed. The article discusses the findings in relation to ideas such as critical periods, existential coordinates and possible selves, and problematizes the implicit assumptions about the future that dementia researchers tend to operate from. PMID- 25547214 TI - Effects of mandibular setback surgery on upper airway dimensions and their influence on obstructive sleep apnoea - a systematic review. AB - BACKGROUND: Mandibular setback used to be the traditional treatment of choice for correcting mandibular prognathism. Nowadays, bimaxillary surgery is preferred. Several authors have asserted that mandibular setback causes a relative narrowing of the upper airway (UA) that could trigger obstructive sleep apnoea (OSA); however, its potential role in OSA development is still much debated. Another controversial subject is whether changes in airway space caused by the procedure are permanent. OBJECTIVES: To ascertain the consequences for UA size and shape of mandibular setback surgery in comparison with bimaxillary surgery (maxillary advancement with Le Fort I and mandibular setback), and to analyse the changes in oximetric indices and their relationship with OSA. SEARCH METHODS: A systematic review was made of the bibliography in 4 databases: Medline, Scopus, Embase and Cochrane. SELECTION CRITERIA: Systematic reviews, meta-analyses, clinical trials and cohort and case-control studies of adults published in the past 15 years were included. DATA COLLECTION AND ANALYSIS: The initial search yielded 668 articles, of which 498 were eliminated because of duplication and 123 on the basis of their titles and abstracts or summaries. The remaining 47 papers were read in their entirety, and 14 were included in the final selection. RESULTS: According to our observations, the nasopharyngeal space does not undergo significant changes after either of the two surgical procedures. In the oropharynx and hypopharynx, none of the measurements changed significantly with maxillary advancement; however, persistent and significant decreases in the area, horizontal linear dimensions, and volume of these spaces are encountered after mandibular setback alone. No long-term changes in oximetric indices were found. CONCLUSIONS: Morphological changes are more pronounced following exclusively mandibular surgery. A decrease in the UA does take place but appears not to affect the patient's sleep quality. This study found no evidence to confirm that bimaxillary or mandibular orthognathic surgery predisposes to obstructive sleep apnoea development. PMID- 25547213 TI - Risk of site-specific cancer in incident venous thromboembolism: a population based study. AB - BACKGROUND: The risk of venous thromboembolism (VTE) by cancer site is uncertain. OBJECTIVE: To estimate VTE risk by tumor site. METHODS: We enumerated observed active cancers by cancer site for Olmsted County, MN residents with incident VTE over the 13-year period, 1988-2000 (n = 345 of 1417). We used 1988-2000 Iowa State Surveillance, Epidemiology, and End Results (SEER) data to estimate the expected age-specific prevalence of cancer by cancer site for all VTE cases; standardized Morbidity Ratios (SMR) for each cancer site were estimated by dividing the observed number of cancers in the VTE incident cohort by the expected number. Relative risk regression was used to model the observed number of cancers of each site, adjusting for the expected value based on SEER prevalence data, using generalized linear regression with a Poisson error and the natural log of the age- and sex-group expected count as an offset. RESULTS: For men and women with VTE, all cancer sites had an increased SMR, ranging from 4.1 for head neck cancer to 47.3 for brain cancer. Among women, the SMR for breast, ovarian and other gynecologic cancers were 8.4, 13.0 and 8.4, respectively; for men, prostate cancer SMR was 7.9. Adjusting for age and sex, the relative risk (RR) of cancer in VTE cases was associated with cancer site in a multivariable model (p < 0.001). Adjusting for age and sex, pancreatic, brain, other digestive cancers, and lymphoma had significantly higher RRs than the grouped comparison cancers. CONCLUSIONS: Incident VTE risk can be stratified by cancer site. PMID- 25547216 TI - Lingual concavities in the mandible: a morphological study using cross-sectional analysis determined by CBCT. AB - BACKGROUND: Lingual undercuts are common in the edentulous mandible and pose the risk of perforating the lingual cortical bone during insertion of dental implants, which may lead to hemorrhage or infections of the parapharyngeal space. The aim of our study was to determine the occurrence and extent of lingual undercuts in the molar and premolar/canine region of the mandible. METHODS: We analyzed 716 cross-sections of the edentulous molar region and 215 cross-sections of the edentulous first premolar/canine region. Mandibular morphology was classified into a U-configuration (undercut), P-configuration (parallel), and C configuration (convex), depending on the shape of the alveolar ridge. Depth of the lingual concavity, concavity angle, and further parameters were measured to describe the mandibular morphology. RESULTS: Lingual undercuts had a prevalence of 68% in the molar region. The prevalence was significantly higher in the second molar region (90%) than in the first molar region (56%). A deep position of the inferior alveolar nerve close to the basal cortical bone was significantly associated with the presence of lingual undercuts. CONCLUSION: Lingual undercuts are a frequent in the edentulous mandible. Cross-sectional analysis of three dimensional radiographs provides the opportunity to determine a lingual undercut and to prevent complications of perforating the lingual cortical bone. PMID- 25547215 TI - Retrospective analysis of 301 patients with orbital floor fracture. AB - The purpose of this study was to retrospectively analyse patients with orbital floor fracture who were treated at the Department of Odontostomatology and Maxillofacial Surgery, Policlinico Umberto I, Sapienza University of Rome, Italy, between 2008 and 2013. Patients were evaluated by age, sex, aetiology, clinical findings, fracture pattern, ocular injury, treatment, complications, and sequelae. We evaluated surgical outcomes and complications with the use of different surgical approaches and various materials used to reconstruct the orbital floor. In total, there were 301 orbital fractures. Two hundred and seventeen patients were men (72.1%) and 84 were women (27.9%). The average age of the patients was 37.2 years (range, 9-90 years). The leading cause of these fractures was violent assault (27.3%). Pure blow-out fractures (50.2%) were the most represented pattern, followed by zygomatic complex (46.5%). The most common symptom was hypoesthesia extending through the territory of the second trigeminal branch (TBH; 32.9%). Diplopia was present in 20.2% of patients followed by enophthalmos (2.3%) and extraocular movement limitation (1.7%). Ocular symptoms significantly improved following surgical repair. The most common postoperative complications included TBH in 34.2%, scarring 26%, and diplopia in 16.4% of the patients. PMID- 25547217 TI - Connexins: junctional and non-junctional modulators of proliferation. AB - Mounting evidence indicates that dysregulation of gap junctions and their structural subunits-connexins-often occurs in, and sometimes causes, a variety of proliferative disorders, including cancer. Connexin-mediated regulation of cell proliferation is complex and may involve modulation of gap junction intercellular communication (GJIC), hemichannel signalling, or gap junction-independent paths. However, the exact mechanisms linking connexins to proliferation remain poorly defined and a number of contradictory studies report both pro- and anti proliferative effects, effects that often depend on the cell or tissue type or the microenvironment. The present review covers junctional and non-junctional regulation of proliferation by connexins, with a particular emphasis on their association with cancer. PMID- 25547218 TI - Instrument contributions to resolution and sensitivity in ultra high performance liquid chromatography using small bore columns: comparison of diode array and triple quadrupole mass spectrometry detection. AB - UHPLC with DAD-UV detection or in combination with mass spectrometry (MS) has proven to be a robust and widely applicable platform for high sensitivity analyses of many types of chemical compounds. The majority of users employ narrow bore columns with 2.1mm internal diameter (ID) typically exhibiting very high efficiencies (>200,000 plates/m). This ultimately sets stringent demands upon the chromatographic system as the separation efficiency can be compromised by external contributions to dispersion caused by connection capillaries, auto sampler and/or the detection device. Sample limited applications often use reduced column diameters down to capillary- or even nano-column format. Capillary (ID<=0.5mm) or small-bore columns (ID<=1mm) can be a good compromise between system robustness and enhanced sensitivity. Yet in this case, extra-column dispersion gains additional importance due to reduced peak volumes. To design an optimized system configuration for specific column dimensions and applications it is crucial to understand the dispersion contributions of individual extra-column components. This was subject to many studies done within our group and by others. Here, we employed a fully optimized UHPLC/UV system to investigate the contribution to peak dispersion obtained from columns ranging from capillary to narrow bore (0.3, 0.5, 1, 2.1mm) using a set of small molecules that were analyzed in gradient mode. Further UV detection was replaced by a triple quadrupole (QQQ) MS in order to evaluate its contribution to band broadening. In this context the impact of column-ID upon MS sensitivity when interfaced with an Agilent Jet Stream source was investigated. Data obtained from our test suite of compounds shows mostly mass-sensitive behavior of this advanced electrospray technology. PMID- 25547224 TI - Acromegaly and aging: a comparative cross-sectional study. AB - OBJECTIVE: Cognitive and functional geriatric assessment may change in acromegaly. Herein we aimed to determine at which points geriatric assessment of the cases with acromegaly differs from that of general elderly population. DESIGN: In this comparative cross-sectional study, a total of 30 cases with acromegaly (controlled n = 14, uncontrolled n = 16) and 30 gender and body-mass index-matched cases without acromegaly (control group, CG) above 60 years old were included. Cognitive functions were evaluated on the basis of the mini-mental state exam (MMSE). Affective status was determined using the geriatric depression scale. Activities of daily living (ADL) were ranked according to the Barthel index while instrumental activities of daily living (IADL) were graded on the basis of the Lawton scale. Nutritional status was evaluated using the mini nutritional assessment (MNA). Body composition was measured through bioimpedance analysis. Functional mobility was determined using the Timed Up and Go test (TUG) and muscle strength with the handgrip strength test. RESULTS: Scores on the MMSE were significantly lower in the elderly cases with acromegaly than in the cases without acromegaly (p < 0.001). Dementia was more frequent in the acromegaly group than in the CG (p = 0.04). Total MNA scores were significantly lower in cases with acromegaly than in the CG (p = 0.006). More subjects in the acromegaly group (33%) were at greater risk of malnutrition than in the CG (3%) (p = 0.003). There was greater moderate functional impairment based on Barthel ADL in the acromegaly group than in the CG (p = 0.04). CONCLUSION: Acromegaly may impair cognitive functions, functional mobility and instrumental daily living activities in the geriatric population. With acromegaly, the risk of malnutrition may also increase. PMID- 25547219 TI - Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer. AB - The objective of this study was to assess the efficacy and tolerability of YM155, a survivin suppressor, in combination with docetaxel, compared with docetaxel alone in patients with HER2-negative metastatic breast cancer. This phase II, multicenter, open-label, 2-arm study randomized patients (>=18 years) with histologically or cytologically confirmed stage IV HER2-negative metastatic breast cancer and >=1 measurable lesion, to receive docetaxel alone or docetaxel plus YM155. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR), biomarker assessment, and analysis of circulating tumor cells. Patients were women diagnosed with HER2-negative breast cancer; most had received prior drug therapies. The median PFS was 8.4 months with YM155 plus docetaxel (n = 50) and 10.5 months with docetaxel alone (n = 51; HR 1.53; 95 % CI 0.83, 2.83; P = 0.176). No statistically significant differences were observed for secondary endpoints, although slightly greater OS (630 vs 601 days; P = 0.768), CBR (84.3 vs 82.0 %; P = 0.855), DOR, and TTR were observed with docetaxel alone compared with YM155 plus docetaxel, whereas ORR was similar (25.5 vs 26.0). The most common TEAEs observed with YM155 plus docetaxel compared with docetaxel alone were neutropenia (83.3 vs 84.3 %), alopecia (62.5 vs 52.9 %), fatigue (50 vs 41.2 %), and nausea (37.5 vs 41.2 %). Although YM155 is a novel drug that suppresses survivin, YM155 plus docetaxel exhibited no statistically significant differences in endpoints compared with docetaxel alone. The combination regimen was well tolerated. PMID- 25547225 TI - Type 1 diabetes stigma in China: a call to end the devaluation of individuals living with a manageable chronic disease. AB - Stigma is a significant barrier to improving care for individuals with type 1 diabetes mellitus (T1DM). This commentary describes this phenomenon in China, where stigma has led to labeling and devaluing of individuals with T1DM. Difficulties finding a spouse and regulations restricting admission to universities and government employment have forced many individuals to hide their diabetes. The shame, fear, and guilt stemming from stigma may preclude the use of insulin pumps; multiple daily injections, which require pre-meal insulin dosing at school or the workplace; participation in research studies; and general health seeking behaviors. A multifaceted, multilevel approach is urgently needed and should involve improving public awareness and understanding of T1DM; adoption by health care providers of holistic rather than biomedical approaches to disease management; patient counseling on positive coping skills; and expansion of the scope of research to consider the psychosocial realities of diabetes care in China. Recent media attention in the form of a nationally broadcasted documentary on T1DM is an important step in the right direction. We believe that coordinated action by multiple stakeholders can lead to meaningful improvements in treatment, ultimately leading to better physical and emotional health outcomes for individuals living with this manageable chronic disease. PMID- 25547227 TI - One size does not fit all: a qualitative content analysis of the importance of existing quality improvement capacity in the implementation of Releasing Time to Care: the Productive WardTM in Saskatchewan, Canada. AB - BACKGROUND: Releasing Time to Care: The Productive WardTM (RTC) is a method for conducting continuous quality improvement (QI). The Saskatchewan Ministry of Health mandated its implementation in Saskatchewan, Canada between 2008 and 2012. Subsequently, a research team was developed to evaluate its impact on the nursing unit environment. We sought to explore the influence of the unit's existing QI capacity on their ability to engage with RTC as a program for continuous QI. METHODS: We conducted interviews with staff from 8 nursing units and asked them to speak about their experience doing RTC. Using qualitative content analysis, and guided by the Organizing for Quality framework, we describe the existing QI capacity and impact of RTC on the unit environment. RESULTS: The results focus on 2 units chosen to highlight extreme variation in existing QI capacity. Unit B was characterized by a strong existing environment. RTC was implemented in an environment with a motivated manager and collaborative culture. Aided by the structural support provided by the organization, the QI capacity on this unit was strengthened through RTC. Staff recognized the potential of using the RTC processes to support QI work. Staff on unit E did not have the same experience with RTC. Like unit B, they had similar structural supports provided by their organization but they did not have the same existing cultural or political environment to facilitate the implementation of RTC. They did not have internal motivation and felt they were only doing RTC because they had to. Though they had some success with RTC activities, the staff did not have the same understanding of the methods that RTC could provide for continuous QI work. CONCLUSIONS: RTC has the potential to be a strong tool for engaging units to do QI. This occurs best when RTC is implemented in a supporting environment. One size does not fit all and administrative bodies must consider the unique context of each environment prior to implementing large-scale QI projects. Use of an established framework, like Organizing for Quality, could highlight the distinctive supports needed in particular care environments to increase the likelihood of successful engagement. PMID- 25547226 TI - Expression of turtle riboflavin-binding protein represses mitochondrial electron transport gene expression and promotes flowering in Arabidopsis. AB - BACKGROUND: Recently we showed that de novo expression of a turtle riboflavin binding protein (RfBP) in transgenic Arabidopsis increased H2O2 concentrations inside leaf cells, enhanced the expression of floral regulatory gene FD and floral meristem identity gene AP1 at the shoot apex, and induced early flowering. Here we report that RfBP-induced H2O2 presumably results from electron leakage at the mitochondrial electron transport chain (METC) and this source of H2O2 contributes to the early flowering phenotype. RESULTS: While enhanced expression of FD and AP1 at the shoot apex was correlated with early flowering, the foliar expression of 13 of 19 METC genes was repressed in RfBP-expressing (RfBP+) plants. Inside RfBP+ leaf cells, cytosolic H2O2 concentrations were increased possibly through electron leakage because similar responses were also induced by a known inducer of electron leakage from METC. Early flowering no longer occurred when the repression on METC genes was eliminated by RfBP gene silencing, which restored RfBP+ to wild type in levels of FD and AP1 expression, H2O2, and flavins. Flowering was delayed by the external riboflavin application, which brought gene expression and flavins back to the steady-state levels but only caused 55% reduction of H2O2 concentrations in RfBP+ plants. RfBP-repressed METC gene expression remedied the cytosolic H2O2 diminution by genetic disruption of transcription factor NFXLl and compensated for compromises in FD and AP1 expression and flowering time. By contrast, RfBP resembled a peroxisomal catalase mutation, which augments the cytosolic H2O2, to enhance FD and AP1 expression and induce early flowering. CONCLUSIONS: RfBP-repressed METC gene expression potentially causes electron leakage as one of cellular sources for the generation of H2O2 with the promoting effect on flowering. The repressive effect on METC gene expression is not the only way by which RfBP induces H2O2 and currently unappreciated factors may also function under RfBP+ background. PMID- 25547228 TI - New insight into HCV E1/E2 region of genotype 4a. AB - INTRODUCTION: Hepatitis C virus (HCV) genome contains two envelope proteins (E1 and E2) responsible for the virus entry into the cell. There is a substantial lack of sequences covering the full length of E1/E2 region for genotype 4. Our study aims at providing new sequences as well as characterizing the genetic divergence of the E1/E2 region of HCV 4a using our new sequences along with all publicly available datasets. METHODS: The genomic segments covering the whole E1/E2 region were isolated from Egyptian HCV patients and sequenced. The resulting 36 sequences 36 were analyzed using sequence analysis techniques to study variability within and among hosts in the same time point. Furthermore, previously published HCV E1/E2 sequence datasets for genotype 4a were retrieved and categorized according to the geographical location and date of isolation and were used for further analysis of variability among Egyptian over a period of 15 years, also compared with non-Egyptian sequences to figure out region-specific variability. RESULTS: Phylogenetic analysis of the new sequences has shown variability within the host and among different individuals in the same time point. Analysis of the 36 sequences along with the Egyptian sequences (254 sequences in E1 in the period from 1997 to 2010 and 8 E2 sequences in the period from 2006 to 2010) has shown temporal change over time. Analysis of the new HCV sequences with the non-Egyptian sequences (182 sequences in E1 and 155 sequences in the E2) has shown region specific variability. The molecular clock rate of E1 was estimated to be 5E-3 per site per year for Egyptian and 5.38E-3 for non Egyptian. The clock rate of E2 was estimated to be 8.48E per site per year for Egyptian and 6.3E-3 for non-Egyptian. CONCLUSION: The results of this study support the high rate of evolution of the Egyptian HCV genotype 4a. It has also revealed significant level of genetic variability among sequences from different regions in the world. PMID- 25547230 TI - A pooled analysis of the IL-10-1082 A/G polymorphism and the nasopharyngeal carcinoma susceptibility. AB - It has been reported that IL-10-1082 A/G polymorphism might influence the transcription and secretion of IL10 and tumor development. While many studies have been conducted to investigate the association between IL-10-1082 A/G polymorphism and risk of nasopharyngeal carcinoma (NPC) in various populations, the results of these studies are still controversial. We aimed to explore this relationship through a cumulative meta-analysis. A search of the literature was performed using the Cochrane Library, PubMed, and EMBASE databases. The odds ratio (OR) and corresponding 95 % confidence interval (CI) were calculated to assess this possible association. Six studies were included in the study. The meta-analysis reveals a significant effect in the allelic model (G vs. A: OR 1.516, 95 % CI 1.077-2.133, P heterogeneity = 0.003), dominant model (AG + GG vs. AA: OR = 1.770, 95 % CI 1.415-2.212, P heterogeneity = 0.169), and co-dominant model (AG vs. AA: OR = 1.747, 95 % CI 1.377-2.216, P heterogeneity = 0.491). Similarly, in the stratified analyses, significant effects were reported in studies of Asian populations. Our meta-analysis results suggest that the IL-10 1082 A/G variant is associated with increased risk of NPC in Asian populations. PMID- 25547231 TI - The ileocolic vein passing through the ring-shaped part of ileocolic artery. AB - PURPOSE: The purpose of this case report is to report vascular variations in the abdomen because of its clinical importance for the surgeries like acute abdominal emergencies and symptomatic aneurysms. Here, we report an extremely rare case with an ileocolic vein passing through the annulus of the ileocolic artery. METHODS: During the routine dissection, we found an ileocolic vein perforating through a ring-shaped ileocolic artery. RESULTS: A ring-shaped ileocolic artery was originating from the superior mesenteric artery as a single branch. After forming the circle, it maintained the regular branching patterns. The ileocolic vein was drained from the ascending colon, cecum, appendix and the distal part of the ileum and passed the center of the ring-shaped part of the ileocolic artery from posterior to anterior. Other structures of the abdomen were normal. CONCLUSIONS: We reported this rare variation and suggest that the clinicians should be aware of this variation for succeeding surgery and making a good diagnosis for the patients. PMID- 25547232 TI - Musculoskeletal disorders among a group of Iranian general dental practitioners. AB - BACKGROUND: Dentists have to remain in a fixed position during dental practices for the accuracy required, therefore they are susceptible to musculoskeletal disorders (MSDs). OBJECTIVES: Considering the infrequency of ergonomics studies in general dental practitioners (GDPs), especially in cervical region, this study aimed to reviews MSDs in the neck region among GDPs. METHODS: An analytic cross sectional study was carried out among the GDPs in 2011. A total of 60 dentists (40 males and 20 females) were examined through a combination of questionnaires (concerning their demographic information) such as the Nordic standardized musculoskeletal disorder questionnaire (NMQ) and Body Discomfort Assessment questionnaire (BDA). Each dentist's working posture was assessed using Rapid Upper Limb Assessment (RULA) and deep cervical flexor muscle endurance through a Craniocervical Flexion test (CCFT). Descriptive statistical indexes and Chi square test were used for statistical analysis, while considering p< 0.05. RESULTS: The mean dental practice experience was 16.9 +/- 5.6 years with average 41.2 +/- 13.4 working hours per week. About 45% of dentists took regular exercises weekly. Some 83.3% of these dentists expressed to be suffering from the cervical pain, whereas, 56.7% complained about back pains and 41% shoulder problems. Female dentists were found more at risk of neckache, discomfort and pain in shoulder and hand than males. Greater pain frequency in knee was found in more experienced and older age dentists (P= 0.07). Results from the CCF test showed that the deep cervical flexor muscles endurance increased with regular exercise and decreased with aging. CONCLUSION: Many dentists experience the MSDs, especially in cervical region, as a consequence of occupational stresses. Therefore, detecting occupational risk factors, standards of work position, regular exercise and following ergonomic policy are intensely recommended. PMID- 25547233 TI - Quality of life and related factors in degenerative lumbar spinal stenosis: A controlled study. AB - OBJECTIVE: The purpose of this study was to compare the quality of life of patients with lumbar spinal stenosis (LSS) with that of the controls' and to investigate the factors related with the quality of life in LSS. METHODS: Fifty four patients with LSS were included in the study whose diagnosis were made by clinically and magnetic resonance imaging (MRI). Control group consisted of age and sex matched 54 individuals. Both of the patient and control groups were evaluated with the Short Form-36 (SF-36) health survey and Hospital Anxiety Depression Scale (HADS). The Oswestry Pain and Disability Index (ODI) was used for the assessment of the disability. RESULTS: SF-36 scores in the LSS group was lower than that of the controls'. There was a significantly positive correlation between the SF-36 scores and walking distance in LSS group. A moderately negative correlation was found between the SF-36 and the ODI, HADS anxiety and depression scores. There was a significantly positive correlation between the ODI and the HADS anxiety and depression scores. HADS anxiety and depression scores in the patient group were significantly higher than that of the controls'. CONCLUSIONS: As a result, quality of life was decreased in subjects with LSS. The factors related with the quality of life were the walking distance, severity of the disability and emotional status in LSS. PMID- 25547234 TI - Exercise and gait training in persons with paraplegia and its effect on muscle properties. AB - BACKGROUND: Upper extremity strengthening and gait training with orthoses form a major part of inpatient rehabilitation of paraplegic patients in developing countries. This helps to overcome architectural barriers and limited wheelchair accessible environment in the community. OBJECTIVES: To evaluate the changes in physiological properties of the Triceps Brachii muscle following exercise training in individuals with paraplegia. The authors also explored the correlation between muscle property changes and gait parameters using orthoses in paraplegic persons. METHODS: Twelve subjects with complete paraplegia and neurological level of injury (NLI) from T9 to L1, underwent exercise training for a mean 64.1 +/- 4.1 days. Triceps brachii was chosen as the sample muscle. Variables like arm circumference, time to fatigue and mean power frequency (MF) (surface EMG parameter), were recorded at the beginning and the end of training, during a sub-maximal isometric elbow extension. Non-parametric tests were used to assess statistical significance between the two recordings. Additionally, gait parameters like walking speed and distance (with the help of orthoses) were obtained and compared with the above variables, to determine impact of upper extremity strengthening on gait improvements in such patients. RESULTS: Statistically significant changes were noted in bilateral arm circumferences (p= 0.003 bilaterally) and MF drop, expressed as percentage (right p= 0.04, left p= 0.01), indicative of better muscle resilience and adaptation. Significant positive correlation was observed between 'time to fatigue' and the orthoses aided total walking distance (right rho = 0.65, left rho = 0.69). CONCLUSIONS: Exercise training induces noticeable changes in the muscles of upper extremities favoring better muscle adaptation. Furthermore, positive correlation between 'time to fatigue' and (orthotic) aided walking distance highlights the positive impact of strengthening program on gait parameters in paraplegic patients. These findings are important and relevant in developing countries with environmental barriers. Upper extremity strengthening should be included in the rehabilitation of paraplegic patients who are being trained for ambulation with orthoses. PMID- 25547235 TI - Antecedent anterior cruciate ligament reconstruction surgery and optimal duration of supervised physiotherapy. AB - A 22-year-old patient undergoing unilateral surgical reconstruction of the anterior cruciate ligament (ACL) of the right knee volunteered for the research project and followed an established contemporary hospital-based rehabilitation programme. The patient was supervised post-surgically by an experienced and clinically specialized physiotherapist. The clinical outcomes of rehabilitation were assessed by selected validated patient-reported and objectively-measured outcomes of functional performance capability on four different occasions (pre surgery, 6th, 12th and 24th week post-surgery). The patient scored 30, 56, 60 and 85 on IKDC (maximum score, 100); 46, 53, 90 and 91 on Lysholm (maximum score, 100); 141, 73, 128 and 175 on K-SES (maximum score, 220); 17, 12, 6 and 6 on the symptom subsection of KOOS (maximum score, 28); 7, 7, 5 and 5 on the pain subsection (maximum score, 36); 1, 0, 3 and 1 on the daily function subsection (maximum score, 68); 0, 0, 5 and 5 on the sport and recreation function subsection (maximum score, 20); 13, 11, 15 and 13 on the quality of life subsection (maximum score, 16) of KOOS at pre-surgery and at the 6th, 12th and 24th week following ACL reconstruction, respectively. Moreover, the patient scored 1.96 m, 1.92 m and 1.99 m on single-leg hop (injured leg) when assessed at pre-surgery and at the 12th and 24th week post-surgery, respectively, following ACL reconstruction. The total time spent in supervised rehabilitation by the patient (675 minutes) was computed as the aggregate patient-reported time spent in exercise during each hospital-based rehabilitation session (verified by physiotherapist evaluation) across the total number of sessions. The patient managed to return to the sport in which he had participated prior to the injury, immediately after the completion of the contemporary rehabilitation programme, at 24 weeks post-surgery. A total of fifteen physiotherapy sessions supervised by the physiotherapist, were attended by the patient during the 24 week rehabilitation period. The latter number of physiotherapy sessions was substantially less than the average supervised physiotherapy sessions reported in the literature. PMID- 25547236 TI - Dorsal scapular neuropathy causing rhomboids palsy and scapular winging. AB - Most cases of scapular winging (SW) are attributed to either long thoracic or spinal accessory nerve lesions. Dorsal scapular nerve lesions are quite rare and the literature contains very few case reports of SW secondary to rhomboid paralysis. We are reporting the unusual case of a young patient who developed right-side scapular winging due to dorsal scapular neuropathy and rhomboids palsy, and we highlight the role of conservative treatment and rehabilitation for cases of mild/medium injury to the dorsal scapular nerve or to the rhomboid muscles. For those cases, physiotherapy is recommended, and this is mainly aimed at strengthening the trapezius in order to compensate for rhomboids weakness. PMID- 25547237 TI - Comparison of static wrist splint with static wrist and metacarpophalangeal splint in carpal tunnel syndrome. AB - BACKGROUND: The position of metacarpophalangeal (MCP) joints may be an important factor affecting the efficacy of splinting in patients with carpal tunnel syndrome (CTS). OBJECTIVE: The aim of the present study was to compare the efficacy of a neutral volar static wrist splint with a neutral volar static wrist and MCP splint in patients with CTS. METHODS: Fifty-four hands were included into the study. A neutral volar static wrist splint was given to the symptomatic hands of the patients in group 1 while a neutral volar static wrist and MCP splint was given to the symptomatic hands of the patients in group 2. Evaluation parameters were Visual Analog Scale for pain severity (VASp), grip strength, pinch strength, electrophysiologic tests and CTS Questionnaire (CTSQ) at baseline and four weeks later. RESULTS: At baseline there was no difference between groups. The intergroup comparison of the improvement showed significant differences in VASp at rest, grip strength, pinch strength and CTSQ functional capacity scores between groups in favor of wrist MCP splint. Although there were significant improvements with regard to sensory amplitude and motor latency in both groups after therapy, the differences between groups were not at the level of significance. CONCLUSIONS: The position of MCP joints seems to be an important factor for the treatment of CTS and should be considered while prescribing a splint to the patients with CTS. PMID- 25547238 TI - Cross-cultural adaptation and validation of the Portuguese survey of musculoskeletal conditions, playing characteristics and warm-up patterns of golfers. AB - BACKGROUND: The University of Western Ontario Questionnaire for Musculoskeletal Conditions in Senior Golfers (MSK Golfers) was developed in Canada because of a lack of knowledge concerning musculoskeletal conditions directly related to golf play and warm-up, although the high injury incidence in golf practice. This lack of epidemiological measures also exists for the Portuguese golf population. OBJECTIVE: The purpose of this study was to translate and cross-culturally adapt the MSK Golfers questionnaire into Portuguese and to test its construct validity and reproducibility. METHODS: The MSK Golfers was translated from English to Portuguese and tested for psychometric properties. Sixty-one golfers, aged between 14 and 70 years and with at least 1 year of practice in golf, were recruited. The validity of the MSK Golfers was assessed by evaluating data quality (missing, floor and ceiling effects). Reproducibility analysis included intra-class correlation coefficients (ICC) (2,1) and Cohen's Kappa coefficient. RESULTS: The ICC values for continuous items ranged from 0.634 to 0.998 with the exception of one item on golf activity. Kappa statistics for the categorical items ranged between 0.714 and 1.00. CONCLUSIONS: The Portuguese version of the MSK Golfers, including playing characteristics and warm-up patterns of golfers, showed a high reliability for a golfing population with an age range of 14 to 70 years. PMID- 25547240 TI - Erratum: correction of 1.3 investigators in supplementary materials. AB - [This corrects the article on p. 1308 in vol. 29, PMID: 25246752.]. PMID- 25547239 TI - Breast cancer detection using sonography in women with mammographically dense breasts. AB - BACKGROUND: Mammography, the gold standard for breast cancer screening misses some cancers, especially in women with dense breasts. Breast ultrasonography as a supplementary imaging tool for further evaluation of symptomatic women with mammographically dense breasts may improve the detection of mass lesions otherwise missed at mammography. The purpose of this study was to determine the incremental breast cancer detection rate using US scanning in symptomatic women with mammographically dense breasts in a resource poor environment. METHODS: A cross sectional descriptive study. Women referred for mammography underwent bilateral breast ultrasound, and mammography for symptom evaluation. The lesions seen by both modalities were described using sonographic BI-RADS lexicon and categorized. Ultrasound guided core biopsies were performed. IRB approval was obtained and all participants provided informed written consent. RESULTS: In total 148 women with mammographically dense breasts were recruited over six months. The prevalence of breast cancer in symptomatic women with mammographically dense breasts was 22/148 (15%). Mammography detected 16/22 (73%) of these cases and missed 6/22 (27%). The six breast cancer cases missed were correctly diagnosed on breast ultrasonography. Sonographic features typical of breast malignancy were irregular shape, non-parallel orientation, non circumscribed margin, echogenic halo, and increased lesion vascularity (p values < 0.005). Typical sonofeatures of benign mass lesions were: oval shape, parallel orientation and circumscribed margin (p values <0.005). CONCLUSION: Breast ultrasound scan as a supplementary imaging tool detected 27% more malignant mass lesions otherwise missed by mammography among these symptomatic women with mammographically dense breasts. We recommend that ultra sound scanning in routine evaluation of symptomatic women with mammographically dense breasts. PMID- 25547241 TI - Practical implementation of incretin-based therapy in hospitalized patients with type 2 diabetes. AB - Hyperglycemia in patients with and without a prior history of diabetes is an independent marker of morbidity and mortality in critically and noncritically ill patients. Improvement of glycemic control with insulin therapy has been shown to reduce hospital complications in patients with diabetes, but also results in increased rates of hypoglycemia, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, stimulate insulin secretion in a glucose-dependent fashion, thus not causing hypoglycemia. Alternative points of view exist regarding insulin versus incretin therapy for the care of these patients. We have brought together the authors on the opposite sides of this discussion with the objective of providing a rational synthesis on how to achieve the best possible control of glycemia in the hospital, using both standard insulin approaches and incretin-based therapies to improve patient outcomes. This review examines the benefits of incretin-based therapy in improving glycemic control in hospitalized patients with stress-induced diabetes and in diabetic patients in critical care and non-critical care settings. PMID- 25547243 TI - Glucose oxidase adsorption performance of carbonaceous mesocellular foams prepared with different carbon sources. AB - Several carbonaceous mesocellular foams (C-MCFs) were prepared with MCF-silica as template using the carbon precursors of sucrose, furfuryl alcohol and lab-made phenolic resin, and the corresponding C-MCFs were named as C-MCF-Suc, C-MCF-FA and C-MCF-PR, respectively. The results of SEM, transmission electron microscopy, N2 adsorption-desorption and energy-dispersive X-ray measurements indicated that the C-MCFs prepared from different carbon source appeared morphologically with different degree of order and different pore distribution. The C-MCF-FA exhibited the highest ordered structure and the smallest pore distribution among the foams. The optimum conditions for adsorption of C-MCFs on glucose oxidase (GOD) were also studied, and the maximum adsorbance was determined. The adsorption of GOD on C-MCF-FA was performed at different pH with different GOD concentrations. The maximum adsorption (423.3 mg g(-1)) was observed near the isoelectric point of the GOD (pI ~ 5.0) with a GOD concentration of 6.0 mg mL(-1), suggesting that the GOD adsorption on C-MCFs might be affected strongly by the electric repulsion between the GOD molecules. Moreover, GOD adsorption performances on different C MCFs revealed that both the pore size and the pore volume played important roles in the adsorption process, and the window size of C-MCFs dominated the residual immobilized amounts of GOD. Compared to the other two C-MCFs, the C-MCF-FA with a smaller window pore (10 nm) and higher volume (1.40 cm(3) g(-1)) exhibited the highest GOD adsorption and catalytic activity. Furthermore, the immobilized GOD exhibited improved thermal and storable stabilities. Thus the C-MCF-FA could be served as the prospective GOD carrier material used in enzymatic fuel cells. PMID- 25547244 TI - Improving xylitol production through recombinant expression of xylose reductase in the white-rot fungus Phanerochaete sordida YK-624. AB - We generated an expression construct consisting of the xylose reductase (XR) gene (xr) from Phanerochaete chrysosporium. Transformant X7 exhibited increased xylitol production and markedly higher XR activities than the wild-type strain. RT-PCR analysis demonstrated that the increased XR activity was associated with constant expression of the recombinant xr gene. PMID- 25547242 TI - WEBnm@ v2.0: Web server and services for comparing protein flexibility. AB - BACKGROUND: Normal mode analysis (NMA) using elastic network models is a reliable and cost-effective computational method to characterise protein flexibility and by extension, their dynamics. Further insight into the dynamics-function relationship can be gained by comparing protein motions between protein homologs and functional classifications. This can be achieved by comparing normal modes obtained from sets of evolutionary related proteins. RESULTS: We have developed an automated tool for comparative NMA of a set of pre-aligned protein structures. The user can submit a sequence alignment in the FASTA format and the corresponding coordinate files in the Protein Data Bank (PDB) format. The computed normalised squared atomic fluctuations and atomic deformation energies of the submitted structures can be easily compared on graphs provided by the web user interface. The web server provides pairwise comparison of the dynamics of all proteins included in the submitted set using two measures: the Root Mean Squared Inner Product and the Bhattacharyya Coefficient. The Comparative Analysis has been implemented on our web server for NMA, WEBnm@, which also provides recently upgraded functionality for NMA of single protein structures. This includes new visualisations of protein motion, visualisation of inter-residue correlations and the analysis of conformational change using the overlap analysis. In addition, programmatic access to WEBnm@ is now available through a SOAP-based web service. Webnm@ is available at http://apps.cbu.uib.no/webnma . CONCLUSION: WEBnm@ v2.0 is an online tool offering unique capability for comparative NMA on multiple protein structures. Along with a convenient web interface, powerful computing resources, and several methods for mode analyses, WEBnm@ facilitates the assessment of protein flexibility within protein families and superfamilies. These analyses can give a good view of how the structures move and how the flexibility is conserved over the different structures. PMID- 25547245 TI - Expression of interleukin-34 and colony stimulating factor-1 in the stimulated periodontal ligament cells with tumor necrosis factor-alpha. AB - Tumor necrosis factor-alpha (TNF-alpha) directly and indirectly plays a crucial role in osteoclastogenesis. However, the indirect effects of TNF-alpha on colony stimulating factor-1 receptor (CSF-1R)-mediated osteoclastogenesis achieved via periodontal ligament (PDL) cells are not fully understood. We herein examined the potency of osteoclast differentiation and maturation induced by fivefold supernatants in the stimulated human PDL cells with a physiologically high concentration (10 ng/mL) of recombinant TNF-alpha to human peripheral blood monocytes/macrophages in the simultaneous presence of the receptor activator of nuclear factor kappa-B ligand. The number of tartrate-resistant acid phosphatase positive cells with multiple nuclei, but not those with a single nucleus, was decreased by approximately 50% by neutralization with rabbit IgG against either interleukin-34 (IL-34) or CSF-1. Small and large amounts of IL34 and CSF1 transcripts were measured in the stimulated PDL cells using real-time polymerase chain reaction. The corresponding amounts of proteins to IL34 and CSF1 transcripts were observed in the stimulated PDL cells on immunohistochemical staining or Western blotting. Moreover, 0.13 ng/mL of IL-34 and 5.0 ng/mL of CSF 1 were measured in the supernatants of the stimulated PDL cells using an enzyme linked immunosorbent assay. IL-34 derived from the stimulated PDL cells with TNF alpha appeared to synergistically function with CSF-1 in the CSF-1R-mediated maturation of osteoclastogenesis. PMID- 25547246 TI - Leptin rapidly induces the expression of metabolic and myokine genes in C2C12 muscle cells to regulate nutrient partition and oxidation. AB - BACKGROUND: Skeletal muscle can experience pronounced metabolic adaptations in response to extrinsic stimuli, and expresses leptin receptor (OB-Rb). We aimed to further the understanding of leptin effects on muscle cells, by studying the expression of key energy metabolism genes in C2C12 myotubes. METHODS: We performed a dose-time-dependent study with physiological concentrations of leptin: 5, 10 and 50 ng/ml, for 0, 30', 3h, 6h, 12h and 24h, also monitoring time course changes in non-treated cells. mRNA levels were analyzed by RT-qPCR and peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC1alpha) protein levels by western blot. RESULTS: The most significant effects were observed with 50 ng/ml leptin. In the short-term (30' and/or 3h), leptin significantly induced the expression of PGC1alpha, muscle carnitine palmitoyl transferase 1 (mCPT1), uncoupling protein 3 (UCP3), OB-Rb, Insulin receptor (InsR) and interleukins 6 and 15 (IL6, IL15). There was a decrease in mRNA levels of pyruvate dehydrogenase kinase 4 (PDK4) and mCPT1 in the long-term (24h). PGC1alpha protein levels were increased (24h). CONCLUSION: Leptin rapidly induces the expression of genes important for its own response and the control of metabolic fuels, with the rapid responses of the genes encoding the master regulator PGC1alpha, mCPT1, UCP3, PDK4 and the signaling secretory molecule IL6 particularly interesting. PMID- 25547248 TI - When professional forceps are not available: Efficient tick removal using a no. 15 scalpel as a spade. PMID- 25547249 TI - The Journal's Progress. PMID- 25547247 TI - Short-term influence of cataract surgery on circadian biological rhythm and related health outcomes (CLOCK-IOL trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Light information is the most important cue of circadian rhythm which synchronizes biological rhythm with external environment. Circadian misalignment of biological rhythm and external environment is associated with increased risk of depression, insomnia, obesity, diabetes, cardiovascular disease, and cancer. Increased light transmission by cataract surgery may improve circadian misalignment and related health outcomes. Although some observational studies have shown improvement of depression and insomnia after cataract surgery, randomized controlled trials are lacking. We will conduct a parallel-group, assessor-blinded, simple randomized controlled study comparing a cataract surgery group at three months after surgery with a control group to determine whether cataract surgery improves depressive symptoms, sleep quality, body mass regulation, and glucose and lipid metabolism. METHODS/DESIGN: We will recruit patients who are aged 60 years and over, scheduled to receive their first cataract surgery, and have grade 2 or higher nuclear opacification as defined by the lens opacities classification system III. Exclusion criteria will be patients with major depression, severe corneal opacity, severe glaucoma, vitreous haemorrhage, proliferative diabetic retinopathy, macular oedema, age-related macular degeneration, and patients needing immediate or combined cataract surgery. After baseline participants will be randomized to two groups. Outcomes will be measured at three months after surgery among the intervention group, and three months after baseline among the control group. We will assess depressive symptoms as a primary outcome, using the short version geriatric depression scale (GDS-15). Secondary outcomes will be subjective and actigraph-measured sleep quality, sleepiness, glycated haemoglobin, fasting plasma glucose and triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index, abdominal circumference, circadian rhythms of physical activity and wrist skin temperature, and urinary melatonin metabolite. Chronotype and visual function will be assessed using the 'morningness eveningness' questionnaire, the Munich chronotype questionnaire, and the National Eye Institute Visual Function Questionnaire. DISCUSSION: Although there are potential limitations due to the difference in duration from baseline survey to outcome measurements between two groups, any seasonal effect on the outcome measurement will be balanced as a result of continuous inclusion of participants through the year, and outcomes will be adjusted for day length at outcome measurements at analysis. TRIAL REGISTRATION: UMIN000014559, UMIN Clinical Trials Registry, registered on 15 July 2014. PMID- 25547250 TI - Thrombocytopenia in neonates with polycythemia: incidence, risk factors and clinical outcome. AB - BACKGROUND: Polycythemia occurs in 1 to 5% of neonates and is associated with complications, including an increased risk of thrombocytopenia. OBJECTIVE: To evaluate incidence, risk factors, management and outcome of thrombocytopenia in neonates with polycythemia. STUDY DESIGN: All neonates with polycythemia admitted to our neonatal intensive care unit between 2006 and 2013 were included in this retrospective study. We evaluated the incidence of thrombocytopenia (platelet count <150 * 10(9)/l) and severe thrombocytopenia (platelet count <50 * 10(9)/l) and the correlation between platelet counts and hematocrit values. RESULTS: The incidence of thrombocytopenia and severe thrombocytopenia was 51 (71/140) and 9% (13/140), respectively. Platelet count was negatively correlated with hematocrit (spearman correlation coefficient -0.233, p = 0.007). After multiple regression analysis, we found an independent association between thrombocytopenia and being small for gestational age (OR: 10.0; 95%; CI: 1.2-81.7; p = 0.031). CONCLUSION: Thrombocytopenia occurs in 51% of neonates with polycythemia and is independently associated with growth restriction. Increased hematocrit is associated with decreased platelet count. PMID- 25547251 TI - Radioanatomy of the retroperitoneal space. AB - The retroperitoneum is a space situated behind the parietal peritoneum and in front of the transversalis fascia. It contains further spaces that are separated by the fasciae, between which communication is possible with both the peritoneal cavity and the pelvis, according to the theory of interfascial spread. The perirenal space has the shape of an inverted cone and contains the kidneys, adrenal glands, and related vasculature. It is delineated by the anterior and posterior renal fasciae, which surround the ureter and allow communication towards the pelvis. At the upper right pole, the perirenal space connects to the retrohepatic space at the bare area of the liver. There is communication between these two spaces through the Kneeland channel. The anterior pararenal space contains the duodenum, pancreas, and the ascending and descending colon. There is free communication within this space, and towards the mesenteries along the vessels. The posterior pararenal space, which contains fat, communicates with the preperitoneal space at the anterior surface of the abdomen between the peritoneum and the transversalis fascia, and allows communication with the contralateral posterior pararenal space. This space follows the length of the ureter to the pelvis, which explains the communication between these areas and the length of the pelvic fasciae. PMID- 25547252 TI - Development of a novel method to create double-strand break repair fingerprints using next-generation sequencing. AB - Efficient DNA double-strand break (DSB) repair is a critical determinant of cell survival in response to DNA damaging agents, and it plays a key role in the maintenance of genomic integrity. Homologous recombination (HR) and non homologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. We now understand that HR and NHEJ repair are composed of multiple sub-pathways, some of which still remain poorly understood. As such, there is great interest in the development of novel assays to interrogate these key pathways, which could lead to the development of novel therapeutics, and a better understanding of how DSBs are repaired. Furthermore, assays which can measure repair specifically at endogenous chromosomal loci are of particular interest, because of an emerging understanding that chromatin interactions heavily influence DSB repair pathway choice. Here, we present the design and validation of a novel, next-generation sequencing-based approach to study DSB repair at chromosomal loci in cells. We demonstrate that NHEJ repair "fingerprints" can be identified using our assay, which are dependent on the status of key DSB repair proteins. In addition, we have validated that our system can be used to detect dynamic shifts in DSB repair activity in response to specific perturbations. This approach represents a unique alternative to many currently available DSB repair assays, which typical rely on the expression of reporter genes as an indirect read-out for repair. As such, we believe this tool will be useful for DNA repair researchers to study NHEJ repair in a high throughput and sensitive manner, with the capacity to detect subtle changes in DSB repair patterns that was not possible previously. PMID- 25547253 TI - Effect of prior hemorrhage on intracranial arteriovenous malformation radiosurgery outcomes. AB - BACKGROUND: Intracerebral hemorrhage is simultaneously the most frequent and most debilitating manifestation of intracranial arteriovenous malformations (AVM), but its impact on success and complications of radiosurgery has not been rigorously assessed. In this case-control study, we define the effect of prior hemorrhage on AVM radiosurgery outcomes. METHODS: From a prospective, institutional database of 1,400 AVM patients treated with Gamma Knife radiosurgery, unruptured and ruptured AVMs were matched in a 1:1 fashion, blinded to outcome, based on patient demographics, prior embolization (26.6% of each cohort), AVM size (mean volume of unruptured AVMs 3.7 cm(3) versus ruptured AVMs 3.5 cm(3), p = 0.195), Spetzler Martin grade (Grade I 17.0%, Grade II 37.8%, Grade III 34.8%, Grade IV 10.4% for each cohort), and radiosurgical treatment parameters (mean prescription dose for unruptured AVMs 20.9 Gy versus ruptured AVMs 21.0 Gy, p = 0.837). There were 270 patients in each cohort. Matched statistical analyses were used to compare the baseline characteristics, obliteration rates, post-radiosurgery latency period hemorrhage risks, and incidences of radiation-induced changes (RIC) between the two cohorts. RESULTS: The actuarial obliteration rates of the two cohorts were similar (unruptured AVMs: 38, 58, and 76% at 3, 5, 10 years, respectively; ruptured AVMs: 40, 60, and 73% at 3, 5, 10 years, respectively; p = 0.592). However, for embolized AVMs, complete obliteration was more likely to be achieved in unruptured lesions (unruptured AVMs: 25, 32, and 54% at 3, 5, 10 years, respectively; ruptured AVMs: 18, 27, and 42% at 3, 5, 10 years, respectively; p = 0.038). Prior AVM rupture resulted in a higher annual risk of post-radiosurgery latency period hemorrhage (ruptured AVMs 2.3% versus unruptured AVMs 1.1%, p = 0.025) but a lower rate of cumulative and symptomatic RIC (cumulative RIC: ruptured AVMs 30.4% versus unruptured AVMs 48.9%, p < 0.0001; symptomatic RIC: ruptured AVMs 7.0% versus unruptured AVMs 12.2%, p = 0.041, respectively). The rates of permanent RIC were similar between the unruptured (2.2%) and ruptured (1.9%) AVM cohorts (p = 0.761). The mean time interval to onset of RIC (unruptured AVMs 13.3 months versus ruptured AVMs 12.1 months, p = 0.783), and the mean duration of RIC (unruptured AVMs 22.0 months versus ruptured AVMs 21.7 months, p = 0.599) were not significantly different between the two cohorts. CONCLUSIONS: Prior AVM rupture significantly alters the risk of latency period hemorrhage and RIC following radiosurgery. These effects should be taken into consideration with the multidisciplinary management of AVM patients. Radiosurgery does not significantly alter the natural history of the hemorrhage risks of unruptured and ruptured AVMs unless obliteration is achieved. PMID- 25547254 TI - Role of (18)F-fluoride PET/CT over dual-phase bone scintigraphy in evaluation and management of lesions causing foot and ankle pain. AB - OBJECTIVE: The purpose of this study was to assess the potential role of (18)F fluoride PET/CT over dual-phase bone scintigraphy (DBS) in evaluation and management of lesions causing foot and ankle pain. METHODS: (99m)Tc-HDP DBS and (18)F-fluoride PET/CT were performed in consecutive patients who visited rehabilitation department due to foot or ankle pain. Focal painful lesions in fore, mid, and hindfoot or ankle, and diffuse pain in foot were evaluated on DBS and (18)F-fluoride PET/CT (conclusive, inconclusive, nonvisible) and lesions on each modality were correlated. The clinical course was followed to see if the results of (18)F-fluoride PET/CT affected the decision of patient management. RESULTS: Sixty-one painful lesions in 31 patients included 16 forefoot (26.2 %), 11 midfoot (18.0 %), 19 hindfoot (31.2 %), 6 ankle (9.8 %), and 9 diffuse footpain (14.8 %). Forty lesions (40/61, 65.6 %) were detected on DBS, including 21 conclusive diagnostic (21/40, 52.5 %), mainly including hindfoot lesions (n = 11). The inconclusive 19 lesions (19/40, 47.5 %) on DBS showed conclusive diagnostic findings on (18)F-fluoride PET/CT, mainly in fore and midfoot lesions (n = 15). Twenty-one painful lesions (21/61, 34.4 %) which were nonvisible on DBS revealed conclusive diagnostic findings on (18)F-fluoride PET/CT in 7 lesions (7/21, 33.3 %), including 5 hindfoot lesions. Fourteen nonvisible lesions (14/21, 66.7 %) on both modalities included all 9 diffuse painful foot lesions. Patient management was affected by findings of (18)F-fluoride PET/CT in 31 lesions (31/61, 50.8 %). CONCLUSIONS: (18)F-fluoride PET/CT provided more confirmative diagnostic information in painful foot and ankle over DBS, and influenced patient management in many inconclusive or nonvisible cases on DBS. Increasing role of (18)F-fluoride PET/CT in benign diseases including foot and ankle pain is expected in the near future. PMID- 25547255 TI - Alpha-substituted derivatives of cinnamaldehyde as tyrosinase inhibitors: inhibitory mechanism and molecular analysis. AB - Alpha-substituted derivatives of cinnamaldehyde (alpha-bromocinnamaldehyde, alpha chlorocinnamaldehyde, and alpha-methylcinnamaldehyde) were used as inhibitors on mushroom tyrosinase. The result showed that three compounds can reduce both monophenolase and diphenolase activity on tyrosinase, and the inhibition was reversible. The IC50 values of alpha-bromocinnamaldehyde, alpha chlorocinnamaldehyde, and alpha-methylcinnamaldehyde were 0.075, 0.140, and 0.440 mM on monophenolase and 0.049, 0.110, and 0.450 mM on diphenolase, respectively. The inhibition types and constants on diphenolase for these inhibitors were further studied. The molecular inhibition mechanisms of tyrosinase by the derivatives were investigated by UV-scanning study, fluorescence quenching, and molecular docking. These assays demonstrated that the derivatives could decrease the formation of o-quinones, and all derivatives were static quenchers of mushroom tyrosinase. Docking results implied that they could not form metal interactions with the copper ions of the enzyme, whereas they could interact with the amino acid residues of active site center. This research on alpha-substituted derivatives of cinnamaldehyde as tyrosinase inhibitors would lead to advances in the field of antityrosinase. PMID- 25547256 TI - Assessment of feasibility of running RSNA's MIRC on a Raspberry Pi: a cost effective solution for teaching files in radiology. AB - PURPOSE: The value of a teaching case repository in radiology training programs is immense. The allocation of resources for putting one together is a complex issue, given the factors that have to be coordinated: hardware, software, infrastructure, administration, and ethics. Costs may be significant and cost effective solutions are desirable. METHODS: We chose Medical Imaging Resource Center (MIRC) to build our teaching file. It is offered by RSNA for free. For the hardware, we chose the Raspberry Pi, developed by the Raspberry Foundation: a small control board developed as a low cost computer for schools also used in alternative projects such as robotics and environmental data collection. Its performance and reliability as a file server were unknown to us. For the operational system, we chose Raspbian, a variant of Debian Linux, along with Apache (web server), MySql (database server) and PHP, which enhance the functionality of the server. A USB hub and an external hard drive completed the setup. Installation of software was smooth. RESULTS: The Raspberry Pi was able to handle very well the task of hosting the teaching file repository for our division. Uptime was logged at 100 %, and loading times were similar to other MIRC sites available online. We setup two servers (one for backup), each costing just below $200.00 including external storage and USB hub. CONCLUSION: It is feasible to run RSNA's MIRC off a low-cost control board (Raspberry Pi). Performance and reliability are comparable to full-size servers for the intended purpose of hosting a teaching file within an intranet environment. PMID- 25547257 TI - Pulmonary artery catheter entrapment in cardiac surgery: a simple percutaneous solution. AB - Pulmonary artery catheter entrapment is a reported complication after cardiac surgery from inadvertent suturing of the catheter to the vena-caval wall during surgery. This article reports a simple percutaneous technique to retrieve the trapped catheter. PMID- 25547258 TI - Below-the-elbow intervention for Buerger's disease. AB - An increasing attention has been paid to endovascular therapy for lower limb ischemia in patients with Buerger's disease. However, critical hand ischemia in Buerger's disease patients has been underappreciated despite a tremendous advancement of endovascular therapy for peripheral arterial disease. Herein, we describe endovascular "hand" salvage with a below-the-elbow intervention. PMID- 25547259 TI - [A Paediatric Orthopaedic outpatient clinic referral patterns]. AB - INTRODUCTION: The aim of this study was to identify the commonest referrals to a paediatric orthopaedic outpatient clinic and, therefore, to be able to improve the paediatric residency program in managing musculoskeletal problems. MATERIAL AND METHODS: Demographic data, referrals and final diagnosis were collected prospectively on all patients that were evaluated in a paediatric orthopaedic outpatient clinic. RESULTS: The majority of referrals were to evaluate musculoskeletal pain (37%), foot deformity (20%), spine deformity (15%), walking pattern (11%), alignment of the lower limbs (4%), and development of the hip (4%). A normal physical examination or a normal variation was observed in 42% of patients. A mild condition was observed in 17% of patients that should have only been referred to a paediatric orthopaedic clinic after failing to resolve pain with anti-inflammatories or physiotherapy. A mild deformity that only needed treatment if it became symptomatic was seen in 8% of patients. CONCLUSIONS: The majority of referrals were due to a normal variation or mild conditions that only required symptomatic treatment. Paediatric residency programs do not reflect the prevalence of musculoskeletal conditions in clinical practice. PMID- 25547260 TI - [Risk factors for cerebrovascular accident in a university hospital. Author's response]. PMID- 25547261 TI - Fine-needle aspiration cytology of disseminated Kaposi sarcoma of the bone in an AIDS patient. AB - BACKGROUND: Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8). Skin and mucous membranes are the most common sites, but other organs may be involved. Skeletal KS is rare and occurs either by direct spread of mucocutaneous lesions or through dissemination. Patients present with bone pain and lytic lesions for which they may undergo fine-needle aspiration (FNA). While there are about 70 published case reports of skeletal KS, there is limited literature specifically describing its cytomorphology. Our literature search yielded only a single prior reported case of FNA biopsy of skeletal KS in a Nigerian AIDS patient. CASE: We present a case of disseminated KS of the axial skeleton in a 45-year-old African-American man with AIDS which was diagnosed on FNA cytologic examination. The patient presented with multiple lytic lesions in the axial skeleton. The aspirate, core-needle biopsy and touch imprint cytology of a bone lesion demonstrated clusters of spindle and epithelioid cells in radial and streaming arrangement with indistinct intercytoplasmic borders, elongated nuclei, fine chromatin and inconspicuous nucleoli. Immunohistochemical studies revealed positivity for HHV-8 and vascular markers. The cytomorphologic and ancillary features of the case are presented and discussed. PMID- 25547262 TI - Unexpected deaths and unplanned re-admissions in infants discharged home after cardiac surgery: a systematic review of potential risk factors. AB - BACKGROUND: Babies with CHDs are a particularly vulnerable population with significant mortality in their 1st year. Although most deaths occur in the hospital within the early postoperative period, around one-fifth of postoperative deaths in the 1st year of life may occur after hospital discharge in infants who have undergone apparently successful cardiac surgery. Aim To systematically review the published literature and identify risk factors for adverse outcomes, specifically deaths and unplanned re-admissions, following hospital discharge after infant surgery for life-threatening CHDs. METHODS: A systematic search was conducted in MEDLINE, EMBASE, CINAHL, Cochrane Library, Web of Knowledge, and PsycINFO electronic databases, supplemented by manual searching of conference abstracts. RESULTS: A total of 15 studies were eligible for inclusion. Almost exclusively, studies were conducted in single US centres and focussed on children with complex single ventricle diagnoses. A wide range of risk factors were evaluated, and those more frequently identified as having a significant association with higher mortality or unplanned re-admission risk were non Caucasian ethnicity, lower socio-economic status, co-morbid conditions, age at surgery, operative complexity and procedure type, and post-operative feeding difficulties. CONCLUSIONS: Studies investigating risk factors for adverse outcomes post-discharge following diverse congenital heart operations in infants are lacking. Further research is needed to systematically identify higher risk groups, and to develop interventions targeted at supporting the most vulnerable infants within an integrated primary and secondary care pathway. PMID- 25547263 TI - Solid-phase synthesis of 2-aryl-3-alkylamino-1H-indoles from 2-nitro-N-(2-oxo-2 arylethyl)benzenesulfonamides via base-mediated C-arylation. AB - Polymer-supported 2-nitro-N-(2-oxo-2-arylethyl)benzenesulfonamides, prepared from resin-bound amines by sulfonylation with 2-nitrobenzenesulfonyl chlorides followed by alkylation with alpha-bromoacetophenones, represent advanced intermediates for the synthesis of different nitrogenous heterocycles. We report their application for the synthesis of 2-aryl-3-alkylamino-1H-indoles via base mediated C-arylation reactions followed by the reduction of the C-arylated intermediates. Linear precursors for C-arylation were prepared on solid-phase support from simple, commercially available building blocks. The effects of different substituents on the amino and aryl groups were addressed. PMID- 25547264 TI - The influence of different factors including fnbA and mecA expression on biofilm formed by MRSA clinical isolates with different genetic backgrounds. AB - Biofilm formation is considered an important virulence factor in implanted device associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Recent studies demonstrated that the ica-independent biofilms produced by MRSA are multifactorial. Despite the recent progress achieved in this field, the bacterial factors associated with biofilm formation/accumulation and regulation among clinical MRSA isolates remain largely unknown. In this study, using MRSA isolates from diverse multilocus sequence typing (MLST) clonal complexes that produce different amounts of biofilm, and a number of phenotypic and molecular approaches, we investigated the correlation between biofilm-associated factors and the ability of the bacteria to accumulate biofilm. PMID- 25547266 TI - Self-focusing therapeutic gene delivery with intelligent gene vector swarms: intra-swarm signalling through receptor transgene expression in targeted cells. AB - BACKGROUND: Gene delivery in vivo that is tightly focused on the intended target cells is essential to maximize the benefits of gene therapy and to reduce unwanted side-effects. Cell surface markers are immediately available for probing by therapeutic gene vectors and are often used to direct gene transfer with these vectors to specific target cell populations. However, it is not unusual for the choice of available extra-cellular markers to be too scarce to provide a reliable definition of the desired therapeutically relevant set of target cells. Therefore, interrogation of intra-cellular determinants of cell-specificity, such as tissue-specific transcription factors, can be vital in order to provide detailed cell-guiding information to gene vector particles. An important improvement in cell-specific gene delivery can be achieved through auto-buildup in vector homing efficiency using intelligent 'self-focusing' of swarms of vector particles on target cells. Vector self-focusing was previously suggested to rely on the release of diffusible chemo-attractants after a successful target-specific hit by 'scout' vector particles. HYPOTHESIS: I hypothesize that intelligent self focusing behaviour of swarms of cell-targeted therapeutic gene vectors can be accomplished without the employment of difficult-to-use diffusible chemo attractants, instead relying on the intra-swarm signalling through cells expressing a non-diffusible extra-cellular receptor for the gene vectors. In the proposed model, cell-guiding information is gathered by the 'scout' gene vector particles, which: (1) attach to a variety of cells via a weakly binding (low affinity) receptor; (2) successfully facilitate gene transfer into these cells; (3) query intra-cellular determinants of cell-specificity with their transgene expression control elements and (4) direct the cell-specific biosynthesis of a vector-encoded strongly binding (high affinity) cell-surface receptor. Free members of the vector swarm loaded with therapeutic cargo are then attracted to and internalized into the intended target cells via the expressed cognate strongly binding extra-cellular receptor, causing escalation of gene transfer into these cells and increasing the copy number of the therapeutic gene expression modules. Such self-focusing swarms of gene vectors can be either homogeneous, with 'scout' and 'therapeutic' members of the swarm being structurally identical, or, alternatively, heterogeneous (split), with 'scout' and 'therapeutic' members of the swarm being structurally specialized. CONCLUSIONS: It is hoped that the proposed self-focusing cell-targeted gene vector swarms with receptor-mediated intra-swarm signalling could be particularly effective in 'top-up' gene delivery scenarios, achieving high-level and sustained expression of therapeutic transgenes that are prone to shut-down through degradation and silencing. Crucially, in contrast to low-precision 'general location' vector guidance by diffusible chemo-attractants, ear-marking non diffusible receptors can provide high-accuracy targeting of therapeutic vector particles to the specific cell, which has undergone a 'successful cell-specific hit' by a 'scout' vector particle. Opportunities for cell targeting could be expanded, since in the proposed model of self-focusing it could be possible to probe a broad selection of intra-cellular determinants of cell-specificity and not just to rely exclusively on extra-cellular markers of cell-specificity. By employing such self-focusing gene vectors for the improvement of cell-targeted delivery of therapeutic genes, e.g., in cancer therapy or gene addition therapy of recessive genetic diseases, it could be possible to broaden a leeway for the reduction of the vector load and, consequently, to minimize undesired vector cytotoxicity, immune reactions, and the risk of inadvertent genetic modification of germline cells in genetic treatment in vivo. PMID- 25547265 TI - Colonization with extended-spectrum beta-lactamase-producing and carbapenemase producing Enterobacteriaceae in international travelers returning to Germany. AB - Two hundred and twenty-five healthy German volunteers traveling to 53 different countries (mostly in Asia, Africa and South America) were enrolled in a prospective cohort study. Stool samples and data on potential travel-associated risk factors (such as type of travel, nutritional habits, occurrence of gastroenteritis) were collected before and after traveling. Screening for extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) and carbapenemase-producing Enterobacteriaceae (CPE) was performed using selective media (CHROMagarTM ESBL/CPE plates). Isolates with confirmed ESBL-phenotype were examined for the presence of blaCTX-M, blaTEM, blaSHV, and blaVIM, blaIMP, blaNDM, blaKPC, blaOXA-48 genes by PCR amplification and sequencing. Antimicrobial susceptibility testing was performed using conventional microbroth dilution. Pre-travel analysis of 205 fully evaluable participants revealed an ESBL-PE prevalence rate of 6.8% (14/205). Among 191 participants that were ESBL negative before travel, 58 (30.4%) were colonized by ESBL-producing Escherichia coli, and 5 (8.6%) additionally carried ESBL-producing Klebsiella pneumoniae upon return. However, no carbapenem-resistant Enterobacteriaceae were detected. ESBL genotyping revealed that 52/54 (96.6%) E. coli and 4/4 (100%) K. pneumoniae strains available for sequencing produced CTX-M enzymes, mostly CTX-M-15 (33/56, 58.9%), and 2/54 (3.7%) E. coli strains produced SHV-12 enzymes. Travel to India was associated with the highest ESBL-PE acquisition rate (11/15, 73.3%; p=0.015), followed by South East Asia (22/46, 47.8%; p=0.038). Evaluation of travel associated risk factors demonstrated significance for the occurrence of gastroenteritis (p=0.011). Strictly practiced hand hygiene and exclusive consumption of packaged beverages showed no protective effect. The ESBL-PE persistence rate after 6 months was 8.6% (3/35). We conclude that global efforts are needed to address the further spread of ESBL-PE in the community. Active surveillance and contact isolation precautions may be recommended at admission to medical facilities especially for patients who traveled to India and South East Asia in the previous 6 months. PMID- 25547267 TI - Development of electroencephalographic pattern classifiers for real and imaginary thumb and index finger movements of one hand. AB - OBJECTIVE: This study aimed to find effective approaches to electroencephalographic (EEG) signal analysis and resolve problems of real and imaginary finger movement pattern recognition and categorization for one hand. METHODS AND MATERIALS: Eight right-handed subjects (mean age 32.8 [SD=3.3] years) participated in the study, and activity from sensorimotor zones (central and contralateral to the movements/imagery) was recorded for EEG data analysis. In our study, we explored the decoding accuracy of EEG signals using real and imagined finger (thumb/index of one hand) movements using artificial neural network (ANN) and support vector machine (SVM) algorithms for future brain computer interface (BCI) applications. RESULTS: The decoding accuracy of the SVM based on a Gaussian radial basis function linearly increased with each trial accumulation (mean: 45%, max: 62% with 20 trial summarizations), and the decoding accuracy of the ANN was higher when single-trial discrimination was applied (mean: 38%, max: 42%). The chosen approaches of EEG signal discrimination demonstrated differential sensitivity to data accumulation. Additionally, the time responses varied across subjects and inside sessions but did not influence the discrimination accuracy of the algorithms. CONCLUSION: This work supports the feasibility of the approach, which is presumed suitable for one-hand finger movement (real and imaginary) decoding. These results could be applied in the elaboration of multiclass BCI systems. PMID- 25547268 TI - Smoking Cessation Clinics as an Aid for Early Diagnosis of Chronic Obstructive Pulmonary Disease. PMID- 25547269 TI - Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis. AB - The aims of the present study were to develop a colon-specific gel formulation of melatonin with sodium alginate and to evaluate its in vitro characteristics and intracolonic performance on oxidative stress parameters, such as nitric oxide (NOx), malondialdehyde (MDA) and glutathione (GSH) levels in rats with acetic acid-induced colitis. The melatonin-alginate gel formulations were prepared and their physico-pharmaceutical properties were determined. Formulation M5, which contained 3% of sodium alginate and 20% polyethylene glycol, was used for in vivo studies. The in vivo studies were conducted in rats with acetic acid-induced colitis. NOx, MDA and GSH levels were determined and histological investigations were performed. It was found that formulation M5 was the most suitable formulation for the colon-specific melatonin gel, in terms of pH, viscosity, drug release and mucoadhesion properties. The MDA levels in the tissues of Group 2 (treated with an intracolonic gel formulation without melatonin) were found to be significantly higher than in Group 1 (the untreated group). NOx levels decreased with the intracolonic and systemic melatonin treatment in the colitis-induced rats. Neither intracolonic nor intra-peritoneal (IP) melatonin treatment affected GSH levels. The epitelization of the colon tissues in groups administered with intracolonic melatonin, IP melatonin, and the intracolonic gel formulation without melatonin was much better than that found in the untreated group. It was concluded that melatonin participated in various defense mechanisms against the colonic inflammatory process, and that the dose, route and formulation type were the most important parameters in the effectiveness of melatonin. PMID- 25547270 TI - Development of lipid nanoparticles for a histone deacetylases inhibitor as a promising anticancer therapeutic. AB - BACKGROUND: Vorinostat (VRS), a histone deacetylases inhibitor, has significant cytotoxic potential in a large number of human cancer cell lines. OBJECTIVE: To clarify its promising anticancer potential and to improve its drawback related to physical properties and in vivo performance of VRS. METHODS: VRS was successfully incorporated into nanostructured lipid carriers (NLCs) by the hot microemulsion method using sonication following a homogenization technique. RESULTS: After the optimization process, VRS-loaded NLCs (VRS-NLCs) were obtained as ideal quality nanoparticles with a spherical shape, small size (~150 nm), negative charge (~-22 mV), and narrow size distribution. In addition, the high entrapment efficiency (~99%) and sustained drug release profile were recorded. Cytotoxicity study in three different cell lines (A549, MCF-7, and SCC-7) demonstrated higher cytotoxicity of VRS-NLCs than free drug. Finally, the AUC of VRS (118.16 +/- 17.35 ugh/mL) was enhanced ~4.4 times compared with that of free drug (27.03 +/- 3.25 ugh/mL). CONCLUSION: These results suggest the potential of NLCs as an oral delivery system for enhancement of cellular uptake, in vitro cytotoxicity in cancer cell lines and the oral bioavailability of VRS. PMID- 25547271 TI - Autonomy and paternalism in medical e-commerce. AB - One of the overriding interests of the literature on health care economics is to discover where personal choice in market economies end and corrective government intervention should begin. Our study addresses this question in the context of John Stuart Mill's utilitarian principle of harm. Our primary objective is to determine whether public policy interventions concerning more than 35,000 online pharmacies worldwide are necessary and efficient compared to traditional market oriented approaches. Secondly, we seek to determine whether government interference could enhance personal utility maximization, despite its direct and indirect (unintended) costs on medical e-commerce. This study finds that containing the negative externalities of medical e-commerce provides the most compelling raison d'etre of government interference. It asserts that autonomy and paternalism need not be mutually exclusive, despite their direct and indirect consequences on individual choice and decision-making processes. Valuable insights derived from Mill's principle should enrich theory-building in health care economics and policy. PMID- 25547272 TI - The hypermobile lateral meniscus: a retrospective review of presentation, imaging, treatment, and results. AB - PURPOSE: Hypermobility of the posterior portion of the lateral meniscus has been reported in several recent case reports and small case series. Pathophysiology and optimal treatment have not been fully elucidated. Our purpose was to evaluate results following arthroscopic stabilization. METHODS: Over a 10-year period, 13 knees were diagnosed at the time of arthroscopy as having hypermobility of the posterior portion of the lateral meniscus in the absence of a discrete tear or discoid morphology. Clinical presentation, pre-operative MRI findings, arthroscopic findings, and repair technique were retrospectively reviewed. Most recent outcomes data were gathered via a telephone interview utilizing the IKDC-9 questionnaire. RESULTS: Eleven of 12 patients presented primarily with mechanical symptoms. Duration of symptoms ranged from 7 months to over 10 years. Eight of 12 patients did not recall any history of trauma. Twelve of 13 pre-operative MRIs did not identify a meniscal tear. Stabilization was obtained by fixation of the meniscus to the posterior capsule by various techniques. Average follow-up was 4 years (range 6 months to 10.7 years). Subjective current knee function averaged 8.0 (range 3.5-10) on a scale of 0-10. Knee pain severity averaged 2.2 (range 0 4) on a scale of 0-10. Pain frequency averaged 3.3 (range 0-9) on a scale of 0 10. Better results were seen in younger patients. CONCLUSION: Hypermobility of the posterior portion of the lateral meniscus can successfully be treated with arthroscopic repair to the posterior capsule. LEVEL OF EVIDENCE: IV. PMID- 25547274 TI - Full-thickness nasal defect: place of prosthetic reconstruction. AB - Extensive rhinectomy or full-thickness defects are not uncommon, in particular in the treatment of skin cancer. The present study lays out the principles of choice and creation of prostheses for nasal reconstruction. Prosthetic nasal reconstruction in France depends on a specialist prescription drawn up under the "Ocular and Facial Prostheses" rubric of the official List of Products and Procedures. National health insurance cover is 100% on condition that the prosthesis is produced by an approved prosthetist. The present study describes production stages, forms and means of fixation, and the timeline of implantation. Nasal prosthetic repair is simple, fast and functional, allowing social rehabilitation despite full respect of carcinologic margins, and without ruling out subsequent multilayer reconstruction. Benefits and drawbacks, and the factors determining repair options according to pathologic context are discussed. Nasal prostheses are an integral option in the repair of full-thickness nasal defects and total rhinectomies. The head and neck surgeon needs expertise in indications and techniques of reconstruction, so as to prescribe nasal prostheses as the context demands. PMID- 25547273 TI - Differences in acromial morphology of shoulders in patients with degenerative and traumatic supraspinatus tendon tears. AB - PURPOSE: Distinct characteristics of acromial morphology seem to be one factor for the development of degenerative supraspinatus tendon tears. Thus, it is questionable whether patients with traumatic tendon tears also present these parameters. The hypothesis of the present study was that the acromial morphology of patients with degenerative supraspinatus tendon tears differs from patients with traumatic tears. METHODS: One hundred and thirty-six patients that were treated by arthroscopic rotator cuff repair from 2010 to 2013 were included in this study. Seventy-two patients had degenerative (group 1), and 64 had traumatic (group 2) supraspinatus tendon tears. On preoperative radiographs the Bigliani type, acromial slope, acromiohumeral (AH) distance, lateral acromial angle (LAA), acromion index (AI), and critical shoulder angle (CSA) were measured. Medians of these parameters as well as of age of both groups were compared using the t test. RESULTS: The percentaged distribution of the Bigliani type differed (group 1 vs. 2: type 1: 18/38, type 2: 56/55, type 3: 26/8). All parameters showed significant differences between degenerative and traumatic tears. Slope: 21.2 degrees (SD 7.6 degrees ) versus 19.2 degrees (SD 7.9 degrees , p = 0.026), AH distance: 8.4 mm (SD 2.3 mm) versus 9.9 mm (SD 1.9 mm, p = 0.0006), LAA: 77.0 degrees (SD 4.0 degrees ) versus 82.5 degrees (SD 4.7 degrees , p < 0.0001), AI: 0.77 (SD 0.07) versus 0.73 (0.06, p = 0.0239), and CSA: 36.8 degrees (SD 3.6 degrees ) versus 35.3 degrees (SD 2.9 degrees , p = 0.007). An LAA <70 degrees or an AH distance of <5 mm only occurred in degenerative tears. Patients with degenerative tears were significantly older (60 vs. 54 years). CONCLUSIONS: The hypothesis that the acromial morphology of patients with degenerative supraspinatus tendon tears differs from patients with traumatic tears was confirmed. Shoulders with degenerative tears show a narrower subacromial space and a larger lateral extension as well as a steeper angulation of the acromion than with traumatic tears. Thus, the results of this study support the theory of external impingement as a cause for degenerative rotator cuff tears. LEVEL OF EVIDENCE: IV. PMID- 25547275 TI - The longitudinal exercise trend among older Swedes aged 53-84 years - a 16-year follow-up study. AB - BACKGROUND: Many older adults are physically inactive and inactivity increases with age. This knowledge comes from cross-sectional studies. Cross-sectional studies may miss important trajectories within the older adults as a result of retirements, and poor health impact of promotional efforts. The aim of this study was to analyse, longitudinally, the annual effects of age group and birth cohort on self-reported regular exercise in the Swedish population aged 53-84 years during a 16-year period, for each sex separately. METHODS: A random sample of non institutionalized persons was interviewed three times from 1988 to 2004 by professional interviewers. In addition to three time-related variables - year of interview, age at the time of the interview, and year of birth - we included the following explanatory variables in the analyses: educational level, body mass index, smoking, and self-reported health status. The data were analysed by a mixed model with a random intercept. RESULTS: The total prevalence of self reported regular exercise increased between 1988/89 and 2004/05 among both men and women, from 27.1 to 43.1% and from 21.1 to 41.1%, respectively. There was a mean annual change in all age-groups in exercise of between 0.76 and 1.24% among men and between 0.86 and 1.38% among women. Low prevalence of self-reported regular exercise was associated with low educational level, obesity, smoking, and poor self-reported health, although those with poor self-reported health the greatest increase of physical activity. CONCLUSIONS: There was a steady, albeit inadequate, increase in self-reported regular exercise in older adults between 1988 and 2004. Physical activity promotion in older adults should be of high priority for both primary and secondary prevention of diseases, especially among groups with known risk factors for low levels of exercise. PMID- 25547276 TI - Commentary on "The clinical significance of persistent prostate cancer cells on prostate biopsy after high-dose-rate brachytherapy boost for intermediate-risk prostate cancer". PMID- 25547283 TI - Metabolism Study of Veratramine Associated with Neurotoxicity by Using HPLC-MSn. AB - Veratramine (VAM) is the major lipid-soluble alkaloid existing in Veratrum nigrum L. that has been demonstrated to exert neurotoxic effects. To better understand the potential mechanism of neurotoxicity of VAM, VAM-induced DNA damage was measured in the cerebellum and cerebral cortex of mice after a 7-day repetitive oral dose by using single-cell gel electrophoresis (comet assay). A method based on high-performance liquid chromatography-electrospray ionization tandem mass spectrometry was developed for the determination of VAM and its in vivo and in vitro metabolites, to establish the potential correlation between metabolites and neurotoxicity. In vitro experiment was carried out using rat liver microsomes, whereas the in vivo study was conducted on rats at a single dose of 3 mg/kg. The results showed that VAM caused DNA damage in the cerebellum and cerebral cortex of mice in a dose-dependent manner. Phenyl mono-oxidation, sulfate conjugation and phenyl di-oxidation were proposed to be the main in vivo metabolic pathways of VAM, whereas the major in vitro metabolic pathways were phenyl mono-oxidation, hydroxylation and methylation. Phenyl-oxidation reaction was likely to be associated with reactive oxygen species production, leading to the DNA damage in the mouse brain. PMID- 25547284 TI - Kate Granger: quiet, determined, compassionate. PMID- 25547282 TI - Maternal obesity is associated with a reduction in placental taurine transporter activity. AB - BACKGROUND/OBJECTIVES: Maternal obesity increases the risk of poor pregnancy outcome including stillbirth, pre-eclampsia, fetal growth restriction and fetal overgrowth. These pregnancy complications are associated with dysfunctional syncytiotrophoblast, the transporting epithelium of the human placenta. Taurine, a beta-amino acid with antioxidant and cytoprotective properties, has a role in syncytiotrophoblast development and function and is required for fetal growth and organ development. Taurine is conditionally essential in pregnancy and fetal tissues depend on uptake of taurine from maternal blood. We tested the hypothesis that taurine uptake into placental syncytiotrophoblast by the taurine transporter protein (TauT) is lower in obese women (body mass index (BMI)?30 kg m(-)(2)) than in women of ideal weight (BMI 18.5-24.9 kg m(-)(2)) and explored potential regulatory factors. SUBJECTS/METHODS: Placentas were collected from term (37-42 week gestation), uncomplicated, singleton pregnancies from women with BMI 19-49 kg m(-)(2). TauT activity was measured as the Na(+)-dependent uptake of (3)H taurine into placental villous fragments. TauT expression in membrane-enriched placental samples was investigated by western blot. In vitro studies using placental villous explants examined whether leptin or IL-6, adipokines/cytokines that are elevated in maternal obesity, regulates TauT activity. RESULTS: Placental TauT activity was significantly lower in obese women (BMI?30) than women of ideal weight (P<0.03) and inversely related to maternal BMI (19-49 kg m( )(2); P<0.05; n=61). There was no difference in TauT expression between placentas of ideal weight and obese class III (BMI?40) subjects. Long-term exposure (48 h) of placental villous explants to leptin or IL-6 did not affect TauT activity. CONCLUSIONS: Placental TauT activity at term is negatively related to maternal BMI. We propose that the reduction in placental TauT activity in maternal obesity could lower syncytiotrophoblast taurine concentration, compromise placental development and function, and reduce the driving force for taurine efflux to the fetus, thereby increasing the risk of poor pregnancy outcome. PMID- 25547285 TI - Oocyte-derived Smad4 is not required for development of the oocyte or the preimplantation embryo. AB - The generation of a competent egg requires complex molecular interactions between the oocyte and the ovary, and transforming growth factor beta (TGF-beta) is a major signaling pathway. Smad4 is a central regulator of the TGF-beta signaling pathway as it mediates gene expression triggered by activation of TGF-beta receptors. Deletion of Smad4 in granulosa cells disrupts follicle development; however, the role of Smad4 in the oocyte has not been confirmed. Furthermore, the role of Smad4 in embryo development has not been confirmed because previous studies of Smad4(del/del) embryos were generated from heterozygous parents, and thus it is possible that maternal transcripts rescue development before embryonic day 6.5 (E6.5) when Smad4(del/del) embryos die. To determine the role of TGF-beta signaling in oocyte and embryo development, mice with oocyte-specific deletion of Smad4 were studied. Fertility was evaluated in Mutant (Smad4(F/F):ZP3Cre) and CONTROL (Smad4(F/F)) females mated continuously with control males during a 6 month period. Surprisingly, Mutant females were fertile with the same litter size (Mutants, 9.23 +/- 0.4; CONTROLs, 9.42 +/- 0.4) and interlitter period as CONTROLs. Ovulation rate induced using a superovulation regime did not differ between CONTROLs and Mutants at both 6 weeks and 6 months. Embryo development was assessed at E6.5 using CONTROL and Mutant females mated with heterozygous males. Development of Smad4(del/del) embryos at E6.5 was retarded consistent with previous studies of embryos generated from heterozygous parents indicating that there is no rescue of preimplantation development by maternal transcripts. The numbers of implanted embryos at 6.5 dpc also did not differ ( CONTROL: 9.1 +/- 0.4; Mutant: 7.0 +/- 0.9). However, only 26.3% of E6.5 embryos carried by Mutant females were Smad4(del/del) compared with the expected ratio of 50%. Since litter size was not decreased, this indicates that either the number of Smad4(del) sperm fertilizing the oocytes is reduced or implantation of Smad4(del/del) embryos is suboptimal. In summary, we have shown that Smad4 in the oocyte, and thus TGF-beta signaling, is not required for oocyte or follicle development, ovulation, fertilization, preimplantation development, or implantation. PMID- 25547286 TI - Spermatozoa cryopreservation alters pronuclear formation and zygotic DNA demethylation in mice. AB - This study was conducted to investigate the effects of spermatozoa cryopreservation on DNA demethylation in mouse zygotes. Global methylation was studied in zygotes fertilized with cryopreserved sperm by immunostaining, and relative transcript abundance of Tet3, a key gene responsible for zygotic DNA demethylation, was examined by real-time quantitative polymerase chain reaction. Fresh sperm group served as control. Results indicated spermatozoa cryopreservation decreased fertilization rate (68.2% vs. 86.9%; P < 0.01) and delayed pronuclear formation (P < 0.05), compared with the control group. The percentages of embryos developed to cleavage and blastocyst stages in the freezing group (52.9% and 66.8%, respectively) were lower (P < 0.01 and P < 0.05, respectively) than those of the control group (83.4% and 81.1%, respectively). Furthermore, embryos obtained from cryopreserved sperm had higher relative methylation levels (P < 0.05) and less Tet3 mRNA concentrations (P < 0.01) in advanced pronuclear stages. Hence, we reported that spermatozoa cryopreservation disturbed the Tet3-mediated DNA demethylation progression in the zygotic paternal genome, which could be detrimental to the development of early mouse embryos, and most of the differences observed might be explained by delayed fertilization when using cryopreserved sperm. PMID- 25547287 TI - Chemical, electrochemical and photochemical molecular water oxidation catalysts. AB - Hydrogen release from the splitting of water by simply using sunlight as the only energy source is an old human dream that could finally become a reality. This process involves both the reduction and oxidation of water into hydrogen and oxygen, respectively. While the first process has been fairly overcome, the conversion of water into oxygen has been traditionally the bottleneck process hampering the development of a sustainable hydrogen production based on water splitting. Fortunately, a revolution in this field has occurred during the past decade, since many research groups have been conducting an intense research in this area. Thus, while molecular, well-characterized catalysts able to oxidize water were scarce just five years ago, now a wide range of transition metal based compounds has been reported as active catalysts for this transformation. This review reports the most prominent key advances in the field, covering either examples where the catalysis is triggered chemically, electrochemically or photochemically. PMID- 25547288 TI - Customized optimization of cellulase mixtures for differently pretreated rice straw. AB - Lignocellulose contains a large amount of cellulose but is recalcitrant to enzymatic hydrolysis, which yields sugars for fuels or chemicals. Various pretreatment methods are used to improve the enzymatic digestibility of cellulose in lignocellulose. Depending on the lignocellulose types and pretreatment methods, biomass compositions and physical properties significantly vary. Therefore, customized enzyme mixtures have to be employed for the efficient hydrolysis of pretreated lignocellulose. Here, using three recombinant model enzymes consisting of endoglucanase, cellobiohydrolase, and xylanase with a fixed amount of beta-glucosidase, the optimal formulation of enzyme mixtures was designed for two differently pretreated rice straws (acid-pretreated or alkali pretreated rice straw) by the mixture design methodology. As a result, different optimal compositions for the enzyme mixtures were employed depending on the type of pretreatment of rice straw. These results suggest that customized enzyme mixtures for pretreated lignocellulosic biomass are necessary to obtain increased sugar yields and should be considered in the industrial utilization of lignocellulose. PMID- 25547289 TI - Contractile reserve in systemic sclerosis patients as a major predictor of global cardiac impairment and exercise tolerance. AB - Several studies have evidenced high prevalence of myocardial systolic and diastolic dysfunction among patients with systemic sclerosis (SSc). Exercise echocardiography has shown a diagnostic and prognostic role in identifying early left ventricular (LV) dysfunction in several myocardial pathological settings. The aim of our study was to evaluate early signs of LV impairment under exercise and their correlation to patient's exercise tolerance. Forty-five patients (age 60.4 +/- 10.3 years) with SSc and 20 age and sex comparable controls were enrolled in the study. All patients underwent clinical evaluation, 2D echocardiography associated with Tissue Doppler and speckle tracking to evaluate LV deformation indexes, and an exercise echocardiography to evaluate left ventricle contractile reserve (LVCR) and exercise pulmonary pressures. Finally, a 6-minute walking test (6MWT) to evaluate exercise tolerance was also performed. Compared to controls, SSc patients showed an impaired diastolic function (E/E' 10.9 +/- 3.7 vs 8.36 +/- 2.01; p < 0.01) associated with larger left atrial dimensions (LAVI 28.4 +/- 8.7 vs 19.3 +/- 4.6 mL/m(2); p < 0.01). During exercise echocardiography, a reduced global longitudinal strain at peak exercise (S-GLS) was highlighted compared to controls (15.7 +/- 3.6 vs 18.2 +/- 2.2; p = 0.001). A S-GLS cutoff <18%, identified by ROC analysis, identified SSc patients with a reduced diastolic function, exercise tolerance at the 6MWT and higher pulmonary pressures. Our data show that in SSc patients a reduced LVCR characterizes the patients with a more extensive cardiovascular impairment in terms of LV diastolic function, pulmonary pressures and exercise tolerance. These data underline the importance of exercise echocardiography for the preclinical screening of the LV impairment in this population. PMID- 25547291 TI - Distinct amino acid compositional requirements for formation and maintenance of the [PSI+] prion in yeast. AB - Multiple yeast prions have been identified that result from the structural conversion of proteins into a self-propagating amyloid form. Amyloid-based prion activity in yeast requires a series of discrete steps. First, the prion protein must form an amyloid nucleus that can recruit and structurally convert additional soluble proteins. Subsequently, maintenance of the prion during cell division requires fragmentation of these aggregates to create new heritable propagons. For the Saccharomyces cerevisiae prion protein Sup35, these different activities are encoded by different regions of the Sup35 prion domain. An N-terminal glutamine/asparagine-rich nucleation domain is required for nucleation and fiber growth, while an adjacent oligopeptide repeat domain is largely dispensable for prion nucleation and fiber growth but is required for chaperone-dependent prion maintenance. Although prion activity of glutamine/asparagine-rich proteins is predominantly determined by amino acid composition, the nucleation and oligopeptide repeat domains of Sup35 have distinct compositional requirements. Here, we quantitatively define these compositional requirements in vivo. We show that aromatic residues strongly promote both prion formation and chaperone dependent prion maintenance. In contrast, nonaromatic hydrophobic residues strongly promote prion formation but inhibit prion propagation. These results provide insight into why some aggregation-prone proteins are unable to propagate as prions. PMID- 25547296 TI - Short communication: Estimation of the financial benefit of using Jersey milk at different inclusion rates for Cheddar cheese production using partial budgeting. AB - Partial budgeting was used to estimate the net benefit of blending Jersey milk in Holstein-Friesian milk for Cheddar cheese production. Jersey milk increases Cheddar cheese yield. However, the cost of Jersey milk is also higher; thus, determining the balance of profitability is necessary, including consideration of seasonal effects. Input variables were based on a pilot plant experiment run from 2012 to 2013 and industry milk and cheese prices during this period. When Jersey milk was used at an increasing rate with Holstein-Friesian milk (25, 50, 75, and 100% Jersey milk), it resulted in an increase of average net profit of 3.41, 6.44, 8.57, and 11.18 pence per kilogram of milk, respectively, and this additional profit was constant throughout the year. Sensitivity analysis showed that the most influential input on additional profit was cheese yield, whereas cheese price and milk price had a small effect. The minimum increase in yield, which was necessary for the use of Jersey milk to be profitable, was 2.63, 7.28, 9.95, and 12.37% at 25, 50, 75, and 100% Jersey milk, respectively. Including Jersey milk did not affect the quantity of whey butter and powder produced. Although further research is needed to ascertain the amount of additional profit that would be found on a commercial scale, the results indicate that using Jersey milk for Cheddar cheese making would lead to an improvement in profit for the cheese makers, especially at higher inclusion rates. PMID- 25547290 TI - Retroviral transcriptional regulation and embryonic stem cells: war and peace. AB - Retroviruses have evolved complex transcriptional enhancers and promoters that allow their replication in a wide range of tissue and cell types. Embryonic stem (ES) cells, however, characteristically suppress transcription of proviruses formed after infection by exogenous retroviruses and also of most members of the vast array of endogenous retroviruses in the genome. These cells have unusual profiles of transcribed genes and are poised to make rapid changes in those profiles upon induction of differentiation. Many of the transcription factors in ES cells control both host and retroviral genes coordinately, such that retroviral expression patterns can serve as markers of ES cell pluripotency. This overlap is not coincidental; retrovirus-derived regulatory sequences are often used to control cellular genes important for pluripotency. These sequences specify the temporal control and perhaps "noisy" control of cellular genes that direct proper cell gene expression in primitive cells and their differentiating progeny. The evidence suggests that the viral elements have been domesticated for host needs, reflecting the wide-ranging exploitation of any and all available DNA sequences in assembling regulatory networks. PMID- 25547297 TI - Evaluation of conductive cooling of lactating dairy cows under controlled environmental conditions. AB - Cooling systems used to reduce heat stress in dairy operations require high energy, water usage, or both. Steady increases in electricity costs and reduction of water availability and an increase in water usage regulations require evaluation of passive cooling systems to cool cows and reduce use of water and electricity. A study was conducted to evaluate the use of heat exchangers buried 25 cm below the surface as components in a conductive system for cooling cows. Six cows were housed in environmentally controlled rooms with tie-stall beds, which were equipped with a heat exchanger and filled with 25 cm of either sand or dried manure. Beds were connected to supply and return lines and individually controlled. Two beds (one per each kind of bedding material) constituted a control group (water off), and the other 4 (2 sand and 2 dried manure) used water at 7 degrees C passing through the heat exchangers (water on). The experiment was divided in 2 periods of 40 d, and each period involved 3 repetitions of 3 different climates (hot and dry, thermo neutral, and hot and humid). Each cow was randomly assigned to a different treatment after each repetition was over. Sand bedding remained cooler than dried manure bedding in all environments and at all levels of cooling (water on or off). Bed temperatures were lower and heat flux higher during the bed treatment with sand and water on. We also detected a reduction in core body temperatures, respiration rates, rectal temperatures, and skin temperatures of those cows during the sand and water on treatment. Feed intake and milk yield numerically increased during the bed treatment with sand and water on for all climates. No major changes were observed in the lying time of cows or the composition of the milk produced. We conclude that use of heat exchangers is a viable adjunct to systems that employ fans, misters, and evaporative cooling methods to mitigate effects of heat stress on dairy cows. Sand was superior to dried manure as a bedding material in combination with heat exchangers. PMID- 25547292 TI - 2-Deoxyglucose impairs Saccharomyces cerevisiae growth by stimulating Snf1 regulated and alpha-arrestin-mediated trafficking of hexose transporters 1 and 3. AB - The glucose analog 2-deoxyglucose (2DG) inhibits the growth of Saccharomyces cerevisiae and human tumor cells, but its modes of action have not been fully elucidated. Yeast cells lacking Snf1 (AMP-activated protein kinase) are hypersensitive to 2DG. Overexpression of either of two low-affinity, high capacity glucose transporters, Hxt1 and Hxt3, suppresses the 2DG hypersensitivity of snf1Delta cells. The addition of 2DG or the loss of Snf1 reduces HXT1 and HXT3 expression levels and stimulates transporter endocytosis and degradation in the vacuole. 2DG-stimulated trafficking of Hxt1 and Hxt3 requires Rod1/Art4 and Rog3/Art7, two members of the alpha-arrestin trafficking adaptor family. Mutations in ROD1 and ROG3 that block binding to the ubiquitin ligase Rsp5 eliminate Rod1- and Rog3-mediated trafficking of Hxt1 and Hxt3. Genetic analysis suggests that Snf1 negatively regulates both Rod1 and Rog3, but via different mechanisms. Snf1 activated by 2DG phosphorylates Rod1 but fails to phosphorylate other known targets, such as the transcriptional repressor Mig1. We propose a novel mechanism for 2DG-induced toxicity whereby 2DG stimulates the modification of alpha-arrestins, which promote glucose transporter internalization and degradation, causing glucose starvation even when cells are in a glucose-rich environment. PMID- 25547299 TI - Incremental amounts of Ascophyllum nodosum meal do not improve animal performance but do increase milk iodine output in early lactation dairy cows fed high-forage diets. AB - The objective of this study was to investigate the effects of incremental amounts of Ascophyllum nodosum meal (ANOD) on milk production, milk composition including fatty acids and I, blood metabolites, and nutrient intake and digestibility in early lactation dairy cows fed high-forage diets. Twelve multiparous Jersey cows averaging (mean+/-standard deviation) 40+/-21 d in milk and 464+/-35 kg of body weight and 4 primiparous Jersey cows averaging 75+/-37 d in milk and 384+/-17kg of body weight were randomly assigned to treatment sequences in a replicated 4*4 Latin square design. Each period lasted 21 d with 14 d for diet adaptation and 7 d for data and sample collection. Cows were fed a total mixed ration (64:36 forage-to-concentrate ratio) supplemented (as fed) with 0, 57, 113, or 170 g/d of ANOD. Milk yield as well as concentrations and yields of milk components (fat, protein, lactose, milk urea N) were not affected by increasing dietary amounts of ANOD. Concentration (from 178 to 1,370 ug/L) and yield (from 2.8 to 20.6 mg/d) of milk I increased linearly in cows fed incremental amounts of ANOD as a result of the high concentration of I (820 mg/kg of dry matter) in ANOD. Overall, only minor changes were observed in the proportion of milk fatty acids with ANOD supplementation. Quadratic trends were observed for dry matter intake and total tract digestibilities of organic matter and neutral detergent fiber, whereas negative linear trends were observed for serum concentration of cortisol and crude protein digestibility with ANOD supplementation. Serum concentrations of triiodothyronine and thyroxine were not affected by ANOD supplementation and averaged 1.1 and 48.4 ng/mL, respectively. However, feeding increasing amounts of ANOD linearly reduced the plasma concentration of nonesterified fatty acids (from 164 to 132 mEq/L). Quadratic effects were found for the total-tract digestibility of ADF and urinary output of purine derivatives, suggesting that ANOD supplementation may stimulate growth of ruminal cellulolytic bacteria in a dose dependent fashion. In general, feeding incremental amounts of ANOD to early lactation dairy cows dramatically increased milk I concentration and output with no effect on animal performance. PMID- 25547298 TI - Fat and starch as additive risk factors for milk fat depression in dairy diets containing corn dried distillers grains with solubles. AB - Two experiments were conducted to evaluate the additive effects of starch and fat as risk factors associated with milk fat depression in dairy diets containing corn dried distillers grains with solubles. In experiment 1, 4 multiparous ruminally cannulated Holstein cows, averaging 114+/-14 d in milk and 662+/-52 kg of body weight, were randomly assigned to 4 treatments in a 4*4 Latin square to determine the effect of these risk factors on rumen fermentation and milk fatty acid profile. In each 21-d period, cows were assigned to 1 of 4 dietary treatments: a control diet (CON; ether extract 5.2%, starch 19%); CON with added oil (OL; ether extract 6.4%, starch 18%); CON with added starch (STR; ether extract 5.5%, starch 22%); and CON with added oil and starch (COMBO; ether extract 6.5%, starch 23%). After completion of experiment 1, milk production response was evaluated in a second experiment with a similar approach to diet formulation. Twenty Holstein cows, 12 primiparous and 8 multiparous, averaging 117+/-17 d in milk and 641+/-82 kg, were used in replicated 4*4 Latin squares with 21-d periods. Results from experiment 1 showed that ruminal pH was not affected by treatment averaging 5.87+/-0.08. Molar proportion of propionate in rumen fluid was greatest on the COMBO diet, followed by OL and STR, and lowest for CON. The concentration of trans-10,cis-12 conjugated linoleic acid in milk fat increased with the COMBO diet. Adding oil, starch, or a combination of both resulted in lower concentration and yield of fatty acids<16 carbons. Compared with the control, OL and STR resulted in 13% lower concentration, whereas the COMBO diet resulted in a 27% reduction; similarly yield was reduced by 24% with the OL and STR treatments and 54% with the COMBO diet. In experiment 2, milk yield, milk protein percentage, and milk protein yield were similar across treatments, averaging 26.6+/-1.01 kg/d, 3.2+/-0.05%, and 0.84+/-0.03 kg/d, respectively. Fat-corrected milk was greatest for CON, 26.5+/-1.12 kg/d; no differences were detected among the remaining treatments, which averaged 23.5+/ 1.12 kg/d. Milk fat percentage was greatest when cows consumed CON, 3.3+/-0.15%; OL and STR averaged 3.0+/-0.15% and COMBO resulted in the lowest milk fat percentage, 2.73+/-0.15%. Milk fat yield was 0.25+/-0.05 kg/d greater for the CON diet compared with the other 3 treatments, which were similar. These results suggest that fat and starch are additive risk factors that will likely induce milk fat depression in diets containing high inclusion of dried distillers grains with solubles. PMID- 25547300 TI - Production technology and characterization of Fior di latte cheeses made from sheep and goat milks. AB - Innovation in the small ruminant dairy sector faces structural challenges because dairies are often involved in breeding and produce cheeses that appeal essentially to local markets using traditional technologies and facilities. An investigation was carried out to produce Fior di latte, a traditional, soft pasta filata cheese, from sheep and goat milks at the farm level. Fior di latte is an Italian high-moisture, round mozzarella currently produced from cow and water buffalo milks; it is very popular in Europe. Cheesemaking trials were performed and the most appropriate technology proved to be a combination of direct acidification and lactic fermentation, with some modifications to the milk coagulation phase. The gross composition of the experimental cheeses was similar to that of bovine Fior di latte, and the overall hygienic quality was satisfactory even though the milk had not been pasteurized. The new cheeses were similar in appearance to the bovine type, but some specific features were detected. Besides the typical "goaty" and "sheepy" flavors, some novel and distinctive descriptors of odor, flavor, and texture were noted. Our experiment showed that good quality Fior di latte cheese that complies with microbiological requirements of the European legislation can be obtained from sheep and goat milks by appropriately modifying the cheesemaking technology. PMID- 25547301 TI - Effect of summer season on milk protein fractions in Holstein cows. AB - Milk characteristics are affected by heat stress, but very little information is available on changes of milk protein fractions and their relationship with cheesemaking properties of milk. The main objective of the study was to evaluate the effect of hot season on milk protein fractions and cheesemaking properties of milk for Grana Padano cheese production. The study was carried out in a dairy farm with a cheese factory for transforming the milk to Grana Padano cheese. The study was carried out from June 2012 to May 2013. Temperature and relative humidity of the inside barn were recorded daily during the study period using 8 electronic data loggers programmed to record every 30 min. Constant managerial conditions were maintained during the experimental periods. During the experimental period, feed and diet characteristics, milk yield, and milk characteristics were recorded in summer (from June 29 to July 27, 2012), winter (from January 25 to March 8, 2013), and spring (from May 17 to May 31, 2013). Milk yield was recorded and individual milk samples were taken from 25 cows selected in each season during the p.m. milking. Content of fat, proteins, caseins (CN), lactose and somatic cell count (SCC), titratable acidity, and milk rennet coagulation properties were determined on fresh samples. Milk protein fraction concentrations were determined by the sodium dodecyl sulfate-PAGE. Data were tested for nonnormality by the Shapiro-Wilk test. In case of nonnormality, parameters were normalized by log or exponential transformation. The data were analyzed with repeated measures ANOVA using a mixed model procedure. For all the main milk components (fat, protein, total solids, and solids-not-fat), the lowest values were observed in the summer and the greatest values were observed in the winter. Casein fractions, with the exception of gamma-CN, showed the lowest values in the summer and the greatest values in the winter. The content of IgG and serum albumin was greater in summer than in the winter and spring. A mild effect of season was observed for milk SCC, with greater values in summer than in the winter and spring. A worsening of milk coagulation properties was observed in summer season. The alteration of cheesemaking properties during hot season seems strictly linked with changes of milk protein fractions mainly with the decrease of alphaS-CN and beta-CN and the increase of undefined proteins. PMID- 25547303 TI - Reductions in milk Delta9-desaturation ratios to oral dosing of cobalt-acetate are accompanied by the downregulation of SCD1 in lactating ewes. AB - Oral administration of cobalt has been proven to alter milk fatty acid (FA) composition consistent with an inhibition of mammary stearoyl-coenzyme A desaturase (SCD) activity in ruminants, but the mechanisms explaining its mode of action remain uncertain. In this study, Co (as Co-acetate) was dosed to lactating ewes with the aims of examining mammary gene expression during Co-induced changes in milk FA composition, and estimating the endogenous synthesis of SCD products in milk of sheep fed an 18:3n-3-enriched diet. Twelve Assaf ewes fed a diet supplemented with 2% linseed oil were allocated to 2 experimental groups and received an oral drench supplying either 0 (control) or 9 mg of Co/kg of body weight per day. Treatments were administered in 3 equal doses at 8-h intervals for 6 d. No effects of Co administration on animal performance were observed. The changes in milk FA (namely, reductions in most cis-9-containing FA) were consistent with an inhibition of SCD in the absence of detectable effects on the relative importance of mammary de novo synthesis and FA uptake. The high proportion of endogenous cis-9 trans-11 18:2 observed in this study (89%) would agree with a greater supply of trans-11 18:1 of ruminal origin in ewes fed linseed oil, compared with previous estimates in sheep fed a diet without lipid supplementation. Differences between studies could also be related to diet induced changes in SCD activity. Altogether, both mechanisms would support that basal diet composition is a major determinant of the relative contribution of Delta9-desaturation to milk FA profile. Similarly, the consumption of a diet rich in 18:3n-3 might also explain the low proportion of milk cis-9 18:1 estimated to derive from Delta9-desaturation (29%). The administration of Co to ewes fed linseed oil allowed to discriminate minor 18:3 isomers in milk, such as cis-9 trans-12 cis-15 18:3, as SCD products. Finally, Co dosing lowered the mRNA abundance of SCD1 in the mammary secretory tissue (33%), whereas no changes were detected in the SCD5 isoform or in the studied transcription factors (SREBF1, PPARG, SP1, and EGR2). These results suggest that the mode of action of Co in dairy ewes would be at least partly mediated by the downregulation of SCD1. PMID- 25547302 TI - Effect of dietary protein level and rumen-protected amino acid supplementation on amino acid utilization for milk protein in lactating dairy cows. AB - This study investigated the effect of metabolizable protein (MP) supply and rumen protected (RP) Lys and Met supplementation on productivity, nutrient digestibility, urinary N losses, apparent total-tract digestibility of dietary AA, and the efficiency of AA utilization for milk protein synthesis in dairy cows. The experiment was conducted with 8 ruminally cannulated Holstein cows in a replicated 4*4 Latin square design trial with 21-d periods. Treatments were (1) MP-adequate diet (AMP; MP balance of -24 g/d); (2) MP-deficient diet (DMP; MP balance of -281 g/d); (3) DMP supplemented with 100 g of RPLys/cow per day (estimated digestible Lys supply=24 g/d; DMPL; MP balance of -305g/d); and (4) DMPL supplemented with 24 g of RPMet/cow per day (estimated digestible Met supply=15 g/d; DMPLM; MP balance of -256g/d). Diet had no effect on total-tract nutrient digestibility, milk production, and milk composition, but the DMP diets decreased urinary N excretion and the ammonia emitting potential of manure. Plasma Met concentration was increased by DMPLM compared with AMP. Supplementation with RPLys had no effect on plasma Lys. Concentration of most AA in milk protein was increased or tended to be increased by DMPLM compared with DMPL. Except for the AA supplemented as RPAA (i.e., Met and Lys), apparent total tract digestibility of all dietary AA was generally greater for the DMP diets and ranged from 33% (Arg, AMP diet) to 67% (Thr, DMPL diet). Apparent recovery of dietary AA in milk protein followed the same trends, being greater for the DMP diets than AMP and generally lower for Lys and Met with the RPAA-supplemented diets versus AMP and DMP. The RPAA were apparently not used for milk protein synthesis in the conditions of this experiment. The AA recoveries in milk protein varied from around 17% (Ala) to 70% (Pro). Milk protein recoveries of essential AA (EAA) were around 54% for the DMP diet and 49% for AMP. The estimated efficiency of utilization of digestible EAA for milk protein synthesis was generally greater for the DMP diets compared with AMP. In this trial, blood plasma Lys and Met were labeled by abomasal pulse-dose of 15N-Lys and 13C-Met (respectively). Analysis of the 15N-Lys and 13C-Met decay curves in plasma indicated trends for a faster extraction of Lys and Met from plasma for the MP deficient diets, compared with AMP. Overall, this study confirmed conclusions from previous analyses that the efficiency of utilization of dietary EAA will increase with decreasing MP-AA supply. PMID- 25547304 TI - Rapid detection of Staphylococcus aureus in dairy and meat foods by combination of capture with silica-coated magnetic nanoparticles and thermophilic helicase dependent isothermal amplification. AB - Staphylococcus aureus is one of the main pathogens in dairy and meat products; therefore, developing a highly sensitive and rapid method for its detection is necessary. In this study, a quantitative detection method for Staph. aureus was developed using silica-coated magnetic nanoparticles and thermophilic helicase dependent isothermal amplification. First, genomic DNA was extracted from lysed bacteria using silica-coated magnetic nanoparticles and amplified using thermophilic helicase-dependent isothermal amplification. After adding the nucleic-acid dye SYBR Green I to the amplicons, the fluorescence intensity was observed using a UV lamp or recorded using a fluorescence spectrophotometer. This detection system had a detection limit of 5*10(0) cfu/mL in pure culture and milk powder samples and 5*10(1) cfu/mL in pork samples using a UV light in less than 2h. In addition, a good linear relationship was obtained between fluorescence intensity and bacterial concentrations ranging from 10(2) to 10(4) cfu/mL under optimal conditions. Furthermore, the results from contaminated milk powder and pork samples suggested that the detection system could be used for the quantitative analysis of Staph. aureus and applied potentially to the food industry for the detection of this pathogen. PMID- 25547305 TI - Short communication: Pharmacokinetics of intramammary hetacillin in dairy cattle milked 3 times per day. AB - Mastitis remains a critical disease in the dairy industry and the use of intramammary antibiotics plays a critical role in mastitis treatment. Hetacillin is currently approved as an intramammary antibiotic that is used to treat mastitis in dairy cows. It is approved for once a day administration and can be used for a total of 3 d. An increasing number of dairy farms are milking 3 times per day (instead of the traditional 2 times per day) and very little pharmacokinetic data exists on the use of intramammary drugs in a 3*system. The primary purpose of this study was to determine if once a day intramammary infusion of hetacillin is sufficient to maintain therapeutic drug concentrations in cattle milked 3 times per day. Eight Holstein cattle milked 3 times per day were used in this study. After collecting a baseline milk sample, each cow received intramammary infusions of hetacillin in the left front and right rear quarters once a day for 3 d. Milk samples from each of the treated quarters were collected at each milking and frozen until analysis. Milk samples were analyzed for ampicillin concentrations using an ultra-performance liquid chromatography method. All treated quarters had antibiotic concentrations well above the minimum inhibitory concentration (MIC) for gram-positive mastitis pathogens at 8 and 16 h postinfusion. Milk concentrations had fallen well below the MIC by the 24-h period (before the next infusion). All 8 cows in this study consistently had individual quarter milk ampicillin concentrations below the FDA tolerance of 0.01 MUg/mL (10 ppb) within 48 h of the last infusion. Based on this study, milk ampicillin concentrations exceed the minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC90) for at least 65% of the dosing interval, which is sufficient for once-daily dosing with most cases of gram positive mastitis. Therefore, intramammary hetacillin should be an effective treatment for the vast majority of gram-positive mastitis pathogens when used according to label (once per day) in cows milked 3 times per day. PMID- 25547306 TI - Behavioral changes in freestall-housed dairy cows with naturally occurring clinical mastitis. AB - Dairy cows exhibit classic signs of sickness behavior during mastitis. However, knowledge about the consequences of naturally occurring mastitis in freestall housed dairy cows, milked in automatic milking systems, is lacking. The aim of the present study was to describe the behavior of dairy cows after diagnosis and antibiotic treatment of mastitis. In the days before and after antibiotic treatment, the milking behavior, feeding, and activity were examined in 30 mastitic and 30 control Danish Holstein-Friesian cows kept in freestalls and milked by an automatic milking system. Sickness behavior was evident in the mastitic dairy cows and local clinical signs in the udder as well as behavioral changes persisted beyond the 3 d of antibiotic treatment. In the days before diagnosis and treatment, feed intake was reduced compared with the control animals. Although reduced by the antibiotic treatment, this difference persisted until at least 10 d after diagnosis. Sick cows spent less time lying in the initial days after treatment, reversing to the level of the control cows within the 10 d posttreatment period. In the 48 h before antibiotic treatment, the mastitic cows showed increased restlessness during milking, as seen by a higher frequency of tripping and kicking. Mastitic cows continued to show increased kicking during milking even after the antibiotic treatment period. These results show that the behavioral changes induced by naturally occurring mastitis persisted beyond the days of antibiotic treatment, thereby calling for further investigation into management of mastitic dairy cows to optimize recovery and ensure animal welfare during the recovery period after clinical mastitis. PMID- 25547307 TI - Effects of dry period length on milk production, body condition, metabolites, and hepatic glucose metabolism in dairy cows. AB - Dry period (DP) length affects energy metabolism around calving in dairy cows as well as milk production in the subsequent lactation. The aim of the study was to investigate milk production, body condition, metabolic adaptation, and hepatic gene expression of gluconeogenic enzymes in Holstein cows (>10,000 kg milk/305 d) with 28- (n=18), 56- (n=18), and 90-d DP (n=22) length (treatment groups) in a commercial farm. Cows were fed total mixed rations ad libitum adjusted for far off (not for 28-d DP) and close-up DP and lactation. Milk yield was recorded daily and body condition score (BCS), back fat thickness (BFT), and body weight (BW) were determined at dry off, 1 wk before expected and after calving, and on wk 2, 4, and 8 postpartum (pp). Blood samples were taken on d -56, -28, -7, 1, 7, 14, 28, and 56 relative to calving to measure plasma concentrations of metabolites and hormones. Liver biopsies (n=11 per treatment) were taken on d -10 and 10 relative to calving to determine glycogen and total liver fat concentration (LFC) and to quantify mRNA levels of pyruvate carboxylase (PC), cytosolic phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase. Time course of milk yield during first 8 wk in lactation differed among treatment. Milk protein content was higher in 28-d than in 90-d DP cows. Milk fat to protein ratio was highest and milk urea was lowest in 90-d DP cows. Differences in BW, BFT, and BCS were predominantly seen before calving with greatest BW, BFT, and BCS in 90-d DP cows. Plasma concentrations of NEFA and BHBA were elevated during the transition period in all cows, and the greatest increase pp was seen in 90-d DP cows. Plasma glucose concentration decreased around calving and was greater in 28-d than in 90-d DP cows. Dry period length also affected plasma concentrations of urea, cholesterol, aspartate transaminase, and glutamate dehydrogenase. Plasma insulin concentration decreased around calving in all cows, but insulin concentration pp was greater in 28-d than in 56-d DP cows. Hepatic glycogen concentration decreased and LFC increased after calving in all cows, and LFC was greater pp in 90-d DP than in 28-d DP cows. Hepatic PC mRNA abundance pp tended to increase most in 90-d DP cows. Changes on glucose metabolism were more balanced in cows with a reduced DP, whereas cows with extended DP and elevated body condition indicated greatest metabolic changes according to lipid and glucose metabolism during the transition period. PMID- 25547308 TI - Effect of in situ exopolysaccharide production on physicochemical, rheological, sensory, and microstructural properties of the yogurt drink ayran: an optimization study based on fermentation kinetics. AB - Exopolysaccharide (EPS)-producing starter cultures are preferred for the manufacture of fermented milk products to improve rheological and technological properties. However, no clear correlation exists between EPS production and the rheological and technological properties of fermented milk products such as the yogurt drink ayran. In this study, 4 different strain conditions (EPS- and EPS+ Streptococcus thermophilus strains) were tested as a function of incubation temperature (32, 37, or 42 degrees C) and time (2, 3, or 4 h) to determine the effect of culture type and in situ EPS production on physicochemical, rheological, sensory, and microstructural properties of ayran. Furthermore, we assessed the effect of fermentation conditions on amounts of EPS production by different EPS-producing strains during ayran production. A multifactorial design of response surface methodology was used to model linear, interaction, and quadratic effects of these variables on steady shear rheological properties of ayran samples and in situ EPS production levels. The physicochemical and microbiological characteristics of ayran samples altered depending on incubation conditions and strain selection. Steady shear tests showed that ayran samples inoculated with EPS+ strains exhibited pseudoplastic flow behavior. Production of ayran with EPS- strain (control sample) resulted in the lowest apparent viscosity values (eta50), whereas those produced with the combination of 2 EPS+ strains yielded ayran with notably increased eta50 values. We concluded that incubation time was the variable with the greatest effect on eta50, consistency coefficient (K), and flow behavior index (n) values. In situ EPS production was also affected by these conditions during ayran fermentation in which strain-specific metabolism conditions were found to be the most important factor for EPS production. In addition, these findings correlated the amount of in situ EPS produced with the rheological properties of ayran. Scanning electron microscopy images of the samples showed differences in structural features, revealing a prominent network strand structure in the ayran samples inoculated with the admixture of 2 EPS producing strains incubated at 37 degrees C for 3 h. These results provide useful information for large-scale production of ayran by the dairy industry. PMID- 25547309 TI - Development of a rapid SNP-typing assay to differentiate Bifidobacterium animalis ssp. lactis strains used in probiotic-supplemented dairy products. AB - Identification at the genus, species, and strain levels is desirable when a probiotic microorganism is added to foods. Strains of Bifidobacterium animalis ssp. lactis (BAL) are commonly used worldwide in dairy products supplemented with probiotic strains. However, strain discrimination is difficult because of the high degree of genome identity (99.975%) between different genomes of this subspecies. Typing of monomorphic species can be carried out efficiently by targeting informative single nucleotide polymorphisms (SNP). Findings from a previous study analyzing both reference and commercial strains of BAL identified SNP that could be used to discriminate common strains into 8 groups. This paper describes development of a minisequencing assay based on the primer extension reaction (PER) targeting multiple SNP that can allow strain differentiation of BAL. Based on previous data, 6 informative SNP were selected for further testing, and a multiplex preliminary PCR was optimized to amplify the DNA regions containing the selected SNP. Extension primers (EP) annealing immediately adjacent to the selected SNP were developed and tested in simplex and multiplex PER to evaluate their performance. Twenty-five strains belonging to 9 distinct genomic clusters of B. animalis ssp. lactis were selected and analyzed using the developed minisequencing assay, simultaneously targeting the 6 selected SNP. Fragment analysis was subsequently carried out in duplicate and demonstrated that the assay yielded 8 specific profiles separating the most commonly used commercial strains. This novel multiplex PER approach provides a simple, rapid, flexible SNP-based subtyping method for proper characterization and identification of commercial probiotic strains of BAL from fermented dairy products. To assess the usefulness of this method, DNA was extracted from yogurt manufactured with and without the addition of B. animalis ssp. lactis BB-12. Extracted DNA was then subjected to the minisequencing protocol, resulting in a SNP profile matching the profile for the strain BB-12. PMID- 25547310 TI - Effect of linseed feeding on blood metabolites, incidence of cystic follicles, and productive and reproductive performance in fresh Holstein dairy cows. AB - This study was done to investigate the effect of feeding linseed on blood metabolites, incidence of cystic follicles, resumption of postpartum ovarian cyclicity, pregnancy rate, milk production, and composition in fresh Holstein dairy cows. A total of 399 dairy cows were assigned randomly to 2 diets. Diets contained either protected palm oil (CON) or extruded linseed (LIN) and were fed from calving to d 40 postpartum. Ovaries of each cow were examined on d 10, 20, 30, and 40 after parturition (parturition=d 0) by transrectal ultrasonography to determine follicular development, ovarian disorders, and cyclicity. Blood samples were collected at 14-d intervals for 6 wk starting on the day of parturition to determine plasma concentrations of glucose, beta-hydroxybutyrate (BHBA), nonesterified fatty acids (NEFA), and blood urea N (BUN). Results showed plasma glucose concentration was affected by the diets and was greater in the LIN treatment, but BHBA, NEFA, and BUN concentrations were similar among treatments. Dietary treatments had no significant effect on milk production and composition except milk fat percentage that significantly decreased in cows fed LIN (3.55%) compared with those fed with CON (4.17%). Plasma progesterone concentrations were greater in LIN treatment than CON treatment (1.31+/-0.09 vs. 0.87+/-0.09) at early postpartum. The resumption of cyclicity and onset of estrus were influenced by treatments and reduced by 7 d in LIN treatment compared with CON treatment. Cows fed diets enriched in LIN fatty acids had a lesser incidence of cystic follicles. Treatments did not differ significantly in terms of the number of days open, number of services per pregnancy, and pregnancy rate. In conclusion, feeding linseed immediately after parturition decreased milk fat and incidence of cystic follicles, increased progesterone concentrations early postpartum, and caused earlier resumption of cyclicity but did not affect pregnancy rate. PMID- 25547311 TI - Effects of various starch feeding regimens on responses of dairy cows to intramammary lipopolysaccharide infusion. AB - Endotoxin tolerance (ET) can develop in mammals that have been challenged repeatedly with sublethal amounts of lipopolysaccharide (LPS). Previous research has shown that subclinical ruminal acidosis can increase circulating concentrations of LPS. We investigated whether ET would develop in Holstein cows that were subjected to chronic subacute ruminal acidosis (SARA) or acute SARA followed by intramammary infusion of LPS. Twenty-four cows, both primiparous and multiparous, were assigned to 8 blocks of 3 cows. Cows within blocks were randomly assigned to 1 of 3 treatments: (1) control (diet DM was 24% starch and 35% NDF), (2) high starch (formulated to induce chronic milk fat depression with 29% starch and 32% NDF), and (3) acidosis (designed to cause acute bouts of milk fat depression by short-term feeding of a diet with 32% starch, some of which came from wheat grain, and 30% NDF). Cows on the control and high-starch treatments were fed their respective diets throughout the 24-d trial. The acidosis cows were fed the control diet during most of the experiment, except during two 2-d bouts (d 10 and 11 and 17 and 18 of the experiment) in which a high-starch diet was fed. Cows on the high-starch and acidosis treatments produced milk fat with an altered fatty acid profile indicative of SARA (e.g., increased concentrations of specific trans, and odd-, and branched-chain fatty acids), but only cows on the high-starch treatment had milk fat depression. Concentrations of serum amyloid A were elevated in cows on the acidosis treatment, but did not differ between control and high-starch cows. On d 20 of the experiment, all cows were given an intramammary infusion of 10 ug of LPS into 1 mammary quarter 3h after morning milking. Milk yield and DMI decreased the day of the infusion, but the response was not affected by dietary treatment. No systemic indicators of ET were observed among treatments, but evidence of an ET response at the local level of the mammary gland was observed. Cows fed the control diet had higher concentrations of serum amyloid A in milk 12 and 24h postinfusion than did cows fed the high-starch diet and higher concentrations than cows on the acidosis treatment at 12h postinfusion. Our data suggest cows that experienced varying degrees of SARA (based on altered milk fatty acid profile) and subsequent experimental endotoxin mastitis experienced a blunted inflammatory response at the level of the mammary gland, but not a systemic reduction in some inflammatory mediators. PMID- 25547312 TI - Quantitative analysis of the lactic acid and acetaldehyde produced by Streptococcus thermophilus and Lactobacillus bulgaricus strains isolated from traditional Turkish yogurts using HPLC. AB - The present study was conducted to evaluate the lactic acid- and acetaldehyde producing abilities of lactic acid bacterial species isolated from traditionally manufactured Turkish yogurts using HPLC. The lactic acid bacterial species purified from the yogurts were the 2 most widely used species in industrial yogurt production: Streptococcus thermophilus and Lactobacillus bulgaricus. These bacteria have the ability to ferment hexose sugars homofermentatively to generate lactic acid and some carbonyl compounds, such as acetaldehyde through pyruvate metabolism. The levels of the compounds produced during fermentation influence the texture and the flavor of the yogurt and are themselves influenced by the chemical composition of the milk, processing conditions, and the metabolic activity of the starter culture. In the study, morphological, biochemical, and molecular characteristics were employed to identify the bacteria obtained from homemade yogurts produced in different regions of Turkey. A collection of 91 Strep. thermophilus and 35 L. bulgaricus strains were investigated for their lactic acid- and acetaldehyde-formation capabilities in various media such as cow milk, LM17 agar, and aerobic-anaerobic SM17 agar or de Man, Rogosa, and Sharpe agar. The amounts of the metabolites generated by each strain in all conditions were quantified by HPLC. The levels were found to vary depending on the species, the strain, and the growth conditions used. Whereas lactic acid production ranged between 0 and 77.9 mg/kg for Strep. thermophilus strains, it ranged from 0 to 103.5 mg/kg for L. bulgaricus. Correspondingly, the ability to generate acetaldehyde ranged from 0 to 105.9 mg/kg in Strep. thermophilus and from 0 to 126.9 mg/kg in L. bulgaricus. Our study constitutes the first attempt to determine characteristics of the wild strains isolated from traditional Turkish yogurts, and the approach presented here, which reveals the differences in metabolite production abilities of the wild lactic acid bacteria strains, holds the potential for the selection of the most desirable strains to be used as starters in commercial yogurt manufacture in the future. PMID- 25547314 TI - China's role as a global health donor in Africa: what can we learn from studying under reported resource flows? AB - BACKGROUND: There is a growing recognition of China's role as a global health donor, in particular in Africa, but there have been few systematic studies of the level, destination, trends, or composition of these development finance flows or a comparison of China's engagement as a donor with that of more traditional global health donors. METHODS: Using newly released data from AidData on China's development finance activities in Africa, developed to track under reported resource flows, we identified 255 health, population, water, and sanitation (HPWS) projects from 2000-2012, which we descriptively analyze by activity sector, recipient country, project type, and planned activity. We compare China's activities to projects from traditional donors using data from the OECD's Development Assistance Committee (DAC) Creditor Reporting System. RESULTS: Since 2000, China increased the number of HPWS projects it supported in Africa and health has increased as a development priority for China. China's contributions are large, ranking it among the top 10 bilateral global health donors to Africa. Over 50% of the HPWS projects target infrastructure, 40% target human resource development, and the provision of equipment and drugs is also common. Malaria is an important disease priority but HIV is not. We find little evidence that China targets health aid preferentially to natural resource rich countries. CONCLUSIONS: China is an important global health donor to Africa but contrasts with traditional DAC donors through China's focus on health system inputs and on malaria. Although better data are needed, particularly through more transparent aid data reporting across ministries and agencies, China's approach to South South cooperation represents an important and distinct source of financial assistance for health in Africa. PMID- 25547315 TI - Schwannomatosis on a single foot: a case report. AB - Schwannomatosis has been recently recognized as the third major type of neurofibromatosis. It causes multiple schwannomas without the vestibular tumors that are diagnostic of neurofibromatosis type 2. Schwannoma is rarely found in the foot, and it is still rarer to find multiple schawannomas in a single peripheral nerve on the foot. In this article, we describe a case of schwannomatosis case on a single foot. LEVELS OF EVIDENCE: Case report, Level IV. PMID- 25547313 TI - CenH3 evolution in diploids and polyploids of three angiosperm genera. AB - BACKGROUND: Centromeric DNA sequences alone are neither necessary nor sufficient for centromere specification. The centromere specific histone, CenH3, evolves rapidly in many species, perhaps as a coevolutionary response to rapidly evolving centromeric DNA. To gain insight into CenH3 evolution, we characterized patterns of nucleotide and protein diversity among diploids and allopolyploids within three diverse angiosperm genera, Brassica, Oryza, and Gossypium (cotton), with a focus on evidence for diversifying selection in the various domains of the CenH3 gene. In addition, we compare expression profiles and alternative splicing patterns for CenH3 in representatives of each genus. RESULTS: All three genera retain both duplicated CenH3 copies, while Brassica and Gossypium exhibit pronounced homoeologous expression level bias. Comparisons among genera reveal shared and unique aspects of CenH3 evolution, variable levels of diversifying selection in different CenH3 domains, and that alternative splicing contributes significantly to CenH3 diversity. CONCLUSIONS: Since the N terminus is subject to diversifying selection but the DNA binding domains do not appear to be, rapidly evolving centromere sequences are unlikely to be the primary driver of CenH3 sequence diversification. At present, the functional explanation for the diversity generated by both conventional protein evolution in the N terminal domain, as well as alternative splicing, remains unexplained. PMID- 25547316 TI - Noise power associated with decreased task-induced variability of brain electrical activity in schizophrenia. AB - In schizophrenia, both increased baseline metabolic and electroencephalographic (EEG) activities as well as decreased task-related modulation of neural dynamics have been reported. Noise power (NP) can measure the background EEG activity during task performance, and Shannon entropy (SE) is useful for quantifying the global modulation of EEG activity with a high temporal resolution. In this study, we have assessed the possible relationship between increased NP in theta and gamma bands and decreased SE modulation in 24 patients with schizophrenia and 26 controls over the parietal and central regions during a P300 task. SE modulation was calculated as the change from baseline to the active epoch (i.e., 150-550 ms following the target stimulus onset). Patients with schizophrenia displayed statistically significant higher NP values and lower SE modulation than healthy controls. We found a significant association between gamma NP and SE in all of the participants. Specifically, a NP increase in the gamma band was followed by a decrease in SE change. These results support the notion that an excess of gamma activity, unlocked to the task being performed, is accompanied by a decreased modulation of EEG activity in schizophrenia. PMID- 25547318 TI - A 17-year-old female with secondary amenorrhea, galactorrhea, and headaches. PMID- 25547317 TI - Dopamine transporter gene may be associated with bipolar disorder and its personality traits. AB - Dopamine transporter and its genetic factors have been suggested to play a critical role in the development of bipolar disorder (BPD). However, the importance of the dopamine transporter gene (DAT1) in the pathogenesis of BPD remains unclear. The aims of this study were to assess 18 polymorphisms of the DAT1 gene to determine whether this gene is associated with BPD and whether it influences personality traits of patients with BPD. DAT1 polymorphisms were analyzed in 492 BPD (374 BPDI and 118 BPDII) patients and 436 controls. All participants were screened using the same assessment tool, and all met the criteria for BPD. The Tridimensional Personality Questionnaire was used to assess personality traits in both patients and controls. Several polymorphisms had a weak association with BPD, including rs2550948, rs2652511, and rs2975226 in allele distribution analysis (P < 0.05). Furthermore, the promoter G-A-C-G haplotype (rs6350-rs2975226-rs2652511-rs6413429) was over-represented in the BPD patients compared to the controls (P = 0.007). In personality assessment, the BPDII patients had the highest harm avoidance score, followed by the BPDI patients and controls (P = 3.7 * 10(-32)). In addition, a significant association between rs40184 and harm avoidance was found in the patients with BPD. The DAT1 promoter may be associated with vulnerabilities in BPD. The BPD patients had a higher rate of harm avoidance personality traits than the controls, and DAT1 variants may influence personality traits in patients with BPD. PMID- 25547319 TI - OHEP: an oral health education program for mothers of newborns. AB - INTRODUCTION: The purposes of the study were to determine (a) the knowledge base of mothers of newborns on oral health for newborns and young infants and (b) the effectiveness of an oral health education program provided to mothers of newborns prior to discharge from the postpartum unit. METHODS: Ninety-four mothers of healthy newborns on a postpartum unit were randomized to the treatment or control group. A pretest was administered to each mother to assess the mother's knowledge of infant oral health. The treatment intervention was a DVD designed collaboratively by an interprofessional team of nurse practitioners and dental faculty to educate the mothers on oral health care for their newborns. The control intervention was a DVD on newborn nutrition. All participants received routine newborn nursery discharge instructions by the postpartum nurses and physicians. Follow-up appointments were scheduled 6 and 12 months later for administration of the posttest to the mothers and for oral health assessments of the infants. RESULTS: Pretest questionnaire results revealed that most mothers lacked knowledge about oral health care for infants and young children, especially concerning vertical transmission of streptococcus mutans through food sharing practices. In addition, 28.4% of the mothers were not aware of the benefits of fluoride as a prevention strategy for dental caries. A significant no show rate for the planned follow-up visits in the dental clinic hindered our plans to evaluate the effectiveness of the oral health educational program on prevention of dental white spots or decay when the study infants were 6 and 12 months old, respectively. DISCUSSION: The knowledge deficit of mothers of newborns regarding oral health care for infants may be one of the contributing factors to the high prevalence rate of dental caries in children younger than 71 months. An oral health educational program provided to mothers on the postpartum unit prior to discharge from the hospital may help increase mothers' knowledge about oral health care and prevention of dental caries in infants and young children. PMID- 25547320 TI - Evaluation of bone marrow involvement in extranodal NK/T cell lymphoma by FDG PET/CT. AB - Evaluation of bone marrow involvement (BMI) by conventional bone marrow biopsy (BMB) can generate false-negative results if marrow disease is focal. The sensitivity of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) in assessing BMI in extranodal NK/T cell lymphoma (ENKL) has not been determined. We retrospectively collected clinical data from a series of 55 patients with newly diagnosed ENKL, who have received both FDG-PET/CT and BMB prior to treatment. BMB results were used as reference standard. Twelve patients (21.8 %) were considered positive lymphomatous infiltration by FDG-PET/CT (PET-CT/BM+), and five patients (9 %) were identified positive by BMB (BMB/BM+). There was a discordant result in seven patients who were PET-CT/BM+ but BMB/BM-. The sensitivity and specificity of FDG PET/CT for identifying BMI were 100 and 86 %, respectively. Then, we analyzed the overall survival (OS) and progression-free survival (PFS) of patients who were PET-CT/BM+ and PET-CT/BM-. The median follow-up time was 16 months (range, 3 to 43 months). PET-CT/BM+ patients possessed worse 2-year OS than PET-CT/BM- patients (84.8 vs 67.9 %, P < 0.05). The estimated 2-year PFS for PET-CT/BM- and PET-CT/BM+ patients were 72.7 and 41.9 % (P < 0.05), respectively. However, it was hard to conclude that patients who were PET-CT/BM+ had similar survivals to advanced-stage patients due to the low number of patients who were PET-CT/BM+. In conclusion, FDG-PET/CT can complementally detect positive BMI patients missed by BMB in ENKL. The utility of FDG-PET/CT for defining bone marrow status has important prognostic value. PMID- 25547321 TI - A decomposition analysis of change in skilled birth attendants, 2003 to 2008, Ghana Demographic and Health Surveys. AB - BACKGROUND: The single most critical intervention to improve maternal and neonatal survival is to ensure that a competent health worker with midwifery skills is present at every birth, and transport is available to a referral facility for obstetric care in case of an emergency. This study aims to describe changes in percentage of skilled birth attendants in Ghana and to identify causes of the observed changes as well as the contribution of different categories of mother's characteristics to these changes. METHOD: This study uses two successive nationally representative household surveys: the 2003 and 2008 Ghana Demographic and Health Surveys (GDHS). The two datasets have comparable information on household characteristics and skilled attendants at birth at the time of the survey. The 2003 GDHS database includes information on 6,251 households and 3639 live births in the five years preceding the survey, whereas the 2008 GDHS database had information on11, 778 households and 2909 live births in the five years preceding the survey. A decomposition approach was used to explain the observed change in percentage of skilled birth attendants. Random-effects generalized least square regression was used to explore the effect of changes in population structure in respect of the mother's characteristics on percentage of skilled birth attendants over the period. RESULTS: Overall, the data showed absolute gain in the proportion of births attended by a health professional from 47.1% in 2003 to 58.7% in 2008, which represents 21.9% of gap closed to reach universal coverage. The increase in skilled birth attendants was found to be caused by changes in general health behaviour. The gain is regardless of the mother's characteristics. The structural change in the proportion of births in respect of birth order and mother's education had little effect on the change in percentage of skilled birth attendants. CONCLUSION: Improvement in general health behaviour can potentially contribute to an accelerated increase in proportion of births attended by skilled personnel in Ghana. PMID- 25547322 TI - The use of circulating microRNAs as diagnostic biomarkers in colorectal cancer. AB - BACKGROUND: Abnormal levels of microRNAs (miRNAs) have been found in the blood or its components in a number of different cancers including colorectal cancer. In addition to being abundant in circulation, miRNAs show remarkable stability in both plasma and serum making miRNAs ideal markers for early detection in colorectal cancer. Several miRNAs have been identified as potential circulating biomarkers although none have been incorporated into clinical practice. OBJECTIVE: To identify the most consistently dysregulated circulating miRNAs in colorectal cancer patients according to current literature and postulate reasons for heterogeneity in results. METHODS: A literature review was performed using the electronic databases PubMed, Embase and the Cochrane Library. RESULTS: The 6 circulating miRNAs most frequently found to be dysregulated in colorectal cancer are miR-18a-5p, miR-21-5p, miR-29a-5p, miR-92a-5p, miR-143-5p and miR-378-5p. There are, however, multiple studies with conflicting findings. Studies vary significantly in ethnicity of populations, use of endogenous controls, source of miRNAs (whole blood, serum and plasma) and methods of detection. CONCLUSIONS: Circulating miRNAs are promising diagnostic biomarkers in colorectal cancer. Further studies identifying the source of tumour derived miRNAs in circulation, including identification of exosomal miRNA content, are required. Identifying pre profiling factors affecting miRNA expression and determining stable endogenous controls will expedite the incorporation of miRNAs into clinical practice. PMID- 25547323 TI - Clinical report: the joint obstetric and psychiatric management of phobic anxiety disorders in pregnancy. AB - Women who struggle with distressing pregnancy-related phobic anxiety disorders are regularly encountered in maternity services, and their management poses particular challenges. Early identification is crucial in order to offer an opportunity to treat and manage their fears and enable a positive birth experience. In this article, women with different phobias (tokophobia, emetophobia and ante-cubital fossa phobia) describe their first pregnancy experience, and the ways in which the Chelsea and Westminster Hospital offered them joint maternity and psychiatric care. A multidisciplinary hospital-based approach can be effective in managing mental health problems in pregnancy. Despite maternal preconceptions and professional misgivings, this approach can work for women with phobias and enable a good birth experience and successful mother and infant bonding. The lead obstetrician for mental health and perinatal psychiatrist describe their roles in enabling successful outcomes for both the current and subsequent pregnancies. The case is made for training of maternity staff in both the identification of severe pregnancy phobias and the prompt referral for shared psychiatric and maternity care. Even if previous treatments have failed, adequate coping strategies for childbirth may be achieved in a short time frame. Long-term improvements in the phobia itself may also be found. PMID- 25547324 TI - FogBank: a single cell segmentation across multiple cell lines and image modalities. AB - BACKGROUND: Many cell lines currently used in medical research, such as cancer cells or stem cells, grow in confluent sheets or colonies. The biology of individual cells provide valuable information, thus the separation of touching cells in these microscopy images is critical for counting, identification and measurement of individual cells. Over-segmentation of single cells continues to be a major problem for methods based on morphological watershed due to the high level of noise in microscopy cell images. There is a need for a new segmentation method that is robust over a wide variety of biological images and can accurately separate individual cells even in challenging datasets such as confluent sheets or colonies. RESULTS: We present a new automated segmentation method called FogBank that accurately separates cells when confluent and touching each other. This technique is successfully applied to phase contrast, bright field, fluorescence microscopy and binary images. The method is based on morphological watershed principles with two new features to improve accuracy and minimize over segmentation. First, FogBank uses histogram binning to quantize pixel intensities which minimizes the image noise that causes over-segmentation. Second, FogBank uses a geodesic distance mask derived from raw images to detect the shapes of individual cells, in contrast to the more linear cell edges that other watershed like algorithms produce. We evaluated the segmentation accuracy against manually segmented datasets using two metrics. FogBank achieved segmentation accuracy on the order of 0.75 (1 being a perfect match). We compared our method with other available segmentation techniques in term of achieved performance over the reference data sets. FogBank outperformed all related algorithms. The accuracy has also been visually verified on data sets with 14 cell lines across 3 imaging modalities leading to 876 segmentation evaluation images. CONCLUSIONS: FogBank produces single cell segmentation from confluent cell sheets with high accuracy. It can be applied to microscopy images of multiple cell lines and a variety of imaging modalities. The code for the segmentation method is available as open source and includes a Graphical User Interface for user friendly execution. PMID- 25547325 TI - Erratum: efficacy and tolerability of anticholinergics in korean children with overactive bladder: a multicenter retrospective study. AB - [This corrects the article on p. 1550 in vol. 29, PMID: 25408588.]. PMID- 25547326 TI - Can ultrasound of plantar plate have normal appearance with a positive drawer test? AB - OBJECTIVES: The aims of this study were (1) to evaluate the reliability of ultrasound (US) examination in the identification and measurement of the metatarsophalangeal plantar plate (MTP-PP) in asymptomatic subjects and (2) to establish the correlation of US findings with those of physical examination and magnetic resonance imaging (MRI), once it is an important tool in the evaluation of the instability syndrome of the second and third rays. MATERIALS AND METHODS: US examinations of the second and third MTP-PPs were performed in eight asymptomatic volunteers, totaling 32 MTP joints, by three examiners with different levels of experience in musculoskeletal US. Plantar plate dimensions, integrity and echogenicity, the presence of ruptures, and confidence level in terms of structure identification were determined using conventional US. Vascular flow was assessed using power Doppler. US data were correlated with data from physical examination and MRI. RESULTS: MTP-PPs were ultrasonographically identified in 100% of cases, always showing homogeneous hyperechoic features and no detectable vascular flow on power Doppler, with 100% certainty in identification for all examiners. There was excellent US inter-observer agreement for longitudinal measures of second and third toe MTP-PPs and for transverse measures of the second toe MTP-PP. The MTP drawer test was positive for grade 1 MTP instability in 34.4% of joints with normal US results. Transverse MTP-PP measures were significantly higher in individuals with positive MTP drawer test. US measures and characteristics of MPT-PPs were positively correlated with those of MRI. CONCLUSIONS: US is efficient in identifying and measuring MPT-PPs and may complement physical examination. A grade 1 positive MTP drawer test may be found in asymptomatic individuals with normal MPT-PPs, as assessed by imaging. PMID- 25547327 TI - Double-echo gradient chemical shift MR imaging fails to differentiate minimal fat renal angiomyolipomas from other homogeneous solid renal tumors. AB - OBJECTIVES: The purpose of this retrospective study was to evaluate the diagnostic performance of double-echo gradient chemical shift (GRE) magnetic resonance (MR) imaging for the differentiation of angiomyolipomas with minimal fat (mfAML) from other homogeneous solid renal tumors. METHODS: Between 2005 and 2010 in two institutions, all histologically proven homogenous solid renal tumors imaged with computed tomography and MR imaging, including GRE sequences, have been retrospectively selected. A total of 118 patients (mean age: 61 years; range: 20-87) with 119 tumors were included. Two readers measured independently the signal intensity (SI) on GRE images and calculated SI index (SII) and tumor to-spleen ratio (TSR) on in-phase and opposed-phase images. Intra- and interreader agreement was obtained. Cut-off values were derived from the receiver operating characteristic (ROC) curve analysis. RESULTS: Twelve mfAMLs in 11 patients were identified (mean size: 2.8cm; range: 1.2-3.5), and 107 non-AML tumors (3.2cm; 1-7.8) in 107 patients. The intraobserver reproducibility of SII and TSR was excellent with an intraclass correlation coefficient equal to 0.99 [0.98-0.99]. The coefficient of correlation between the readers was 0.99. The mean values of TSR for mfAMLs and non-mfAMLs were -7.0+/-22.8 versus -8.2+/-21.2 for reader 1 and -6.7+/-22.8 versus -8.4+/-20.9 for reader 2 respectively. No significant difference was noticed between the two groups for SII (p=0.98) and TSR (p=0.86). Only 1 out of 12 mfAMLs and 11 of 107 non-AML tumors presented with a TSR inferior to -30% (p=0.83). CONCLUSION: In a routine practice, GRE sequences cannot be a confident tool to differentiate renal mfAMLs from other homogeneous solid renal tumors. PMID- 25547328 TI - Using quantitative image analysis to classify axillary lymph nodes on breast MRI: a new application for the Z 0011 Era. AB - PURPOSE: To assess the performance of computer extracted feature analysis of dynamic contrast enhanced (DCE) magnetic resonance images (MRI) of axillary lymph nodes. To determine which quantitative features best predict nodal metastasis. METHODS: This institutional board-approved HIPAA compliant study, in which informed patient consent was waived, collected enhanced T1 images of the axilla from patients with breast cancer. Lesion segmentation and feature analysis were performed on 192 nodes using a laboratory-developed quantitative image analysis (QIA) workstation. The importance of 28 features were assessed. Classification used the features as input to a neural net classifier in a leave-one-case-out cross-validation and evaluated with receiver operating characteristic (ROC) analysis. RESULTS: The area under the ROC curve (AUC) values for features in the task of distinguishing between positive and negative nodes ranged from just over 0.50 to 0.70. Five features yielded AUCs greater than 0.65: two morphological and three textural features. In cross-validation, the neural net classifier obtained an AUC of 0.88 (SE 0.03) for the task of distinguishing between positive and negative nodes. CONCLUSION: QIA of DCE MRI demonstrated promising performance in discriminating between positive and negative axillary nodes. PMID- 25547330 TI - Charcot-Marie-Tooth 2F: phenotypic presentation of the Arg136Leu HSP27 mutation in a multigenerational family. AB - Mutations in the small heat-shock protein HSP27 gene are associated with distal hereditary motor neuropathy and with the axonal form of Charcot-Marie-Tooth disease type 2. We present the clinical and electrophysiological data on a multigenerational family with the p.Arg136Leu HSP27 mutation. Atypical features such as deafness and pyramidal signs were present in our cases adding new data to the large spectrum of HSP27-related phenotype. PMID- 25547329 TI - Triptolide (TPL) improves locomotor function recovery in rats and reduces inflammation after spinal cord injury. AB - In this study, we studied the effect of triptolide (TPL) on locomotor function in rats with spinal cord injury. A total of 40 rats were studied after dividing them in two major groups, one was experimental group denoted as TPL group while other was control group denoted as PBS group. Each group was subdivided in four subgroups having five rats each (n = 5). TPL was given intraperitonially at the rate of 5 mg/kg/day in TPL group while PBS was given at the same time interval in the same manner in control group for comparison. A reduction in the cavity area of tissue sections was observed by bright field microscopy from 0.22 +/- 0.05 to 0.12 +/- 0.05 mm(2) in experimental group after 28 days of treatment while BBB score also improved from 1 to 5 after 14 days of treatment. SPSS software, one way ANOVA, was used for recording statistical analysis and values were expressed as mean +/- SEM where P value of <0.01 was considered significant. The expression of I-kBalpha and NF-kB p65 was also studied using western blotting and after recording optical density (OD) values of western blots. It was observed that treatment with TPL significantly reduced the expression of these factors after 28 days of treatment compared with controls. PMID- 25547331 TI - The role of ephrins-B1 and -B2 during fetal rat lung development. AB - BACKGROUND/ AIMS: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis. METHODS: Ephrins B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed. RESULTS: Ephrin-B1 presents mesenchymal expression, whereas ephrin B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development. CONCLUSION: Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters. PMID- 25547332 TI - Superficial epithelioma with sebaceous differentiation involving the eyelid: a case report. AB - INTRODUCTION: Superficial epithelioma with sebaceous differentiation is a rare benign epithelial neoplasm. It usually involves the head, neck or the back of a middle-age person. To the best of our knowledge, two ocular cases have been reported in the literature. CASE PRESENTATION: A 46-year-old man of Italian descent, with a known history of testicular seminoma treated by orchiectomy with chemotherapy and radiotherapy, presented with a tan-colored lesion measuring 4mm in diameter in his right upper lid that had been growing over 10 months. It was clinically diagnosed as papilloma. An excisional biopsy was done. On histological examination, the lesion was a well-circumscribed and sharply demarcated epithelial tumor attached to the overlying epidermis and characterized by plate like proliferation of basaloid to squamous cells with clusters of mature sebaceous cells and foci of ductal differentiation. After a follow-up period of 5 months, no recurrence of the lesion has been documented. CONCLUSIONS: Superficial epithelioma with sebaceous differentiation is part of the differential diagnoses of eyelid lesions. Arguments in the literature about the correct nomenclature of superficial epithelioma with sebaceous differentiation have resulted in under diagnosed cases. The benign histological features and the lack of recurrence support its benign nature. Although no clear association has linked superficial epithelioma with sebaceous differentiation with Muir-Torre syndrome, further clinical correlation and close follow up for patients are recommended. PMID- 25547333 TI - Changes of serum lipocalin-2 and retinol binding protein-4 levels in patients with psoriasis and Behcet's disease. PMID- 25547334 TI - Cost-utility analyses of cognitive-behavioural therapy of depression: a systematic review. AB - BACKGROUND: Major depressive disorder (MDD) causes a massive disease burden worldwide. Cognitive behavioural therapy (CBT) is an important treatment approach for depression. Cost-utility analysis (CUA) is a method to support decisions on efficient allocation of resources in health policy. The objective of our study was to systematically review CUA of CBT in the treatment of patients suffering from MDD. METHODS: We conducted a systematic literature search in Medline, Embase, PsycINFO and National Health Service Economic Evaluation Database (NHS EED) to identify CUA of CBT for MDD. Cost data were inflated to the year 2011 and converted into USD using purchasing power parities (USD PPP) to ensure comparability of the data. Quality assessment of CUA was performed. RESULTS: Twenty-two studies were included in this systematic review. No study employed a time horizon of more than 5 years. In most studies, individual and group CBT as well as CBT for maintenance showed acceptable incremental cost-utility ratios (<50,000 USD PPP/quality-adjusted life year). The CUA results of CBT for children and adolescents and of computerized CBT were inconsistent. DISCUSSION: We found consistent evidence that individualized CBT is cost-effective from the perspective of a third-party payer for short-term treatment and for relapse prevention of MDD in the adult population. PMID- 25547335 TI - Invasive pulmonary aspergillosis in patients with influenza infection: report of two cases and systematic review of the literature. AB - Superinfection or coinfections are major causes of morbidity and mortality in patients with influenza. There are limited data on invasive pulmonary aspergillosis (IPA) in this setting. We conducted a systematic review of the literature for patients with IPA following influenza infection. A total of 68 patients (two reported from our institution and 66 identified by literature review) were analyzed. The majority of patients had underlying comorbid illnesses. Overall, the mortality rate in this cohort was 47%. On multivariate analysis, H1N1 infection was associated with better outcome (odds ratio [OR]: 0.19; 95% CI: 0.05-0.67; p = 0.010), whereas corticosteroid therapy during hospitalization was associated with worse outcome (OR: 13.5; 95% CI: 3.65-49.67; p < 0.0001). In conclusion, IPA is an emerging serious infection in patients with influenza. A high index of suspicion is necessary for the timely identification and treatment of these patients. PMID- 25547336 TI - Nutrition management of the post-bariatric surgery patient. AB - Bariatric surgery is considered one of the most effective methods of achieving long-term weight loss when all other medical treatments have failed. The number of bariatric procedures increases each year. Nevertheless, bariatric procedures are associated with a number of complications that require careful multidisciplinary management. Nutrition supervision is of substantial value, as malnutrition, vitamin, and micro- and macronutrient deficiencies may lead to deleterious consequences. In this review, we provide essential information on nutrition management, both before and after bariatric surgical procedures. PMID- 25547337 TI - Nutrient intake from thickened beverages and patient-specific implications for care. AB - Dysphagia, or difficulty swallowing, affects more than 15 million Americans and can result in adverse and potentially fatal consequences, including poor quality of life, depression, dehydration, malnutrition, aspiration pneumonia, and airway obstruction. Although many treatment options are available, provision of thickened liquids is a common intervention for achieving slower, more controlled bolus manipulation and propulsion. To meet this therapeutic demand, commercially available products containing starch and/or gum-based components have been developed for use by patients and institutions. The nutrient content of thickened products has been neglected, although dysphagic patients are often at significant nutrition risk. Thus, there are no clinical guidelines for selection of thickened products based on patient characteristics. To consider whether such guidelines are warranted, it is necessary to quantify nutrition differences among common thickened beverages. An analysis was conducted to quantify energy, carbohydrate, and sodium provided through daily consumption of thickened beverages. To determine the relevance of these nutrition contributions in the context of total dietary intake, we compared values with dietary recommended intakes. This analysis revealed that there are substantial disparities in the nutrient content of thickened beverages. These differences suggest that product selection can be optimized based on patient-specific characteristics such as weight status and presence of comorbidities. Future research focusing on the effect of this strategy on patient outcomes will facilitate the development of evidence-based recommendations to elevate the standard of care for this population. PMID- 25547338 TI - Nutrition adequacy in enhanced recovery after surgery: a single academic center experience. AB - BACKGROUND: A prospective observational study was initiated to determine the prevalence of nutrition risk before surgery and assess nutrition adequacy of food choices after elective colorectal surgery. MATERIALS AND METHODS: Patient Generated Subjective Global Assessment was used to screen all preoperative clinic patients (n = 70) scheduled for elective colorectal surgery. Adequacy of dietary intake (n = 40) was determined for the first 3 postoperative days by estimating total energy and protein intake from leftover food at each meal based on standard hospital portions with food composition tables. Food access questionnaire provided a rationale for observed food intake. All patients received Enhanced Recovery After Surgery (ERAS) and room service system care. RESULTS: Before surgery, 63% of patients were considered well-nourished, 29% suspected or moderately undernourished, and 8% severely undernourished. Fifty-one percent of patients scored > 4 on the Patient-Generated Subjective Global Assessment, indicating requirement for dietary intervention or symptom management. On average, 77% +/- 27%, 63% +/- 28%, and 92% +/- 39% of energy requirements were met on postoperative days 1, 2, and 3, respectively; conversely, 55% +/- 24%, 43% +/- 16%, and 45% +/- 12% of protein requirements were met. Most common reasons for missed meals included loss of appetite and feelings of fatigue or worry. Preoperative nutrition risk tended to result in a greater 30-day hospital readmission rate compared to well-nourished patients (P = .07). CONCLUSIONS: A third of patients scheduled for elective colorectal surgery were at nutrition risk. An acceptable intake of dietary protein was not achieved during the first 3 days of hospitalization. Preoperative nutrition education, as part of Enhanced Recovery Programs, may be useful to optimize nutrition status before surgery to mitigate clinical consequences associated with undernutrition and empower patients to make adequate food choices for recovery. NCT 01727570. PMID- 25547340 TI - Going against the flow: the connexin connection in hypertension. PMID- 25547339 TI - Decrease in Glycemic Index Associated with Improved Glycemic Control among Latinos with Type 2 Diabetes. AB - BACKGROUND: Glycemic index and glycemic load are used to facilitate glucose control among adults with type 2 diabetes, with a low glycemic index diet associated with improved glycemic control. OBJECTIVE: To examine long-term longitudinal associations between changes in glycemic index and glycemic load with glycemic and metabolic control among Latino adults with diabetes. DESIGN: Secondary data from intervention and comparison participants in the Latinos en Control trial (2006 to 2008) were analyzed. PARTICIPANTS/SETTING: Data on dietary intake and metabolic characteristics were from low-income, Latino adults (N=238; 87.7% Puerto Rican) with type 2 diabetes. INTERVENTION: The Latinos en Control trial was a randomized clinical trial targeting diabetes self-management among Latinos with type 2 diabetes. Participants were randomized to a group-based behavioral intervention or usual care and followed through 12 months. MAIN OUTCOME MEASURES: Outcomes included hemoglobin A1c (HbA1c) levels, fasting blood glucose, lipid profiles, anthropometrics, and blood pressure. STATISTICAL ANALYSIS: Glycemic index and load were analyzed using data from three 24-hour dietary recalls conducted at baseline, 4 months, and 12 months. Repeated measures regression models were used to examine change in glycemic index and load associated with metabolic characteristics at 12 months. Covariates included sex, age, body mass index, blood pressure, total energy intake, medication use and intensity, physical activity, intervention status (intervention vs usual care), and time. RESULTS: Increases in glycemic index from baseline to 12 months were associated with increased logarithm of HbA1c levels (beta=0.003; P=0.034) and waist circumference (beta=0.12; P=0.026) over time, but not with fasting glucose, blood lipids, or body mass index. There was modest evidence to support small, positive associations between glycemic load and HbA1c levels and waist circumference. CONCLUSIONS: Lowering glycemic index is associated with improvements in certain metabolic risk factors among Latinos with diabetes. Targeting glycemic index may be an important component of dietary strategies for diabetes self-management. PMID- 25547341 TI - Loss of functional endothelial connexin40 results in exercise-induced hypertension in mice. AB - During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity. PMID- 25547342 TI - Contribution of Kv7 channels to natriuretic peptide mediated vasodilation in normal and hypertensive rats. AB - The Kv7 family of voltage-gated potassium channels are expressed within the vasculature where they are key regulators of vascular tone and mediate cAMP linked endogenous vasodilator responses, a pathway that is compromised in hypertension. However, the role of Kv7 channels in non-cAMP-linked vasodilator pathways has not been investigated. Natriuretic peptides are potent vasodilators, which operate primarily through the activation of a cGMP-dependent signaling pathway. This study investigated the putative role of Kv7 channels in natriuretic peptide-dependent relaxations in the vasculature of normal and hypertensive animals. Relaxant responses of rat aorta to both atrial and C-type natriuretic peptides and the nitric oxide donor sodium nitroprusside were impaired by the Kv7 blocker linopirdine (10 MUmol/L) but not by the Kv7.1-specific blocker HMR1556 (10 MUmol/L) and other K(+) channel blockers. In contrast, only the atrial natriuretic peptide response was sensitive to linopirdine in the renal artery. These Kv7-mediated responses were attenuated in arteries from hypertensive rats. Quantitative polymerase chain reaction showed that A- and B-type natriuretic peptide receptors were expressed at high levels in the aorta and renal artery from normal and spontaneously hypertensive rats. This study provides the first evidence that natriuretic peptide responses are impaired in hypertension and that recruitment of Kv7 channels is a key component of natriuretic peptide-dependent vasodilations. PMID- 25547343 TI - Risk factors assessed in adolescence and the later risk of stroke in men: a 33 year follow-up study. AB - BACKGROUND: Stroke is a common cause of death, and a leading contributor to long term disability. The cost associated with the disease is great. Several modifiable risk factors for stroke have been found in older cohorts; however, no study to date has investigated the effects of these risk factors from late adolescence. METHODS: The study cohort comprised 811,579 Swedish men (mean age, 18 years) that participated in the mandatory military conscription service in Sweden between 1969 and 1986. Some risk factors for stroke, such as body mass index, systolic and diastolic blood pressure, and cognitive function, were assessed at conscription. Aerobic fitness was also assessed at conscription, using a braked ergometer cycle test. Other risk factors for stroke, including stroke in subjects' parents, and socioeconomic factors including highest achieved level of education and annual income 15 years after conscription, were collected through national register linkage using the personal identification number. Stroke diagnosis among the study participants was tracked in the National Hospital Discharge Patient Register. RESULTS: During a median follow-up period of 33 years 6,180 ischemic strokes and 2,104 hemorrhagic strokes were diagnosed in the cohort at a mean age of 47.9 years. Strong independent risk factors (all p <1.0 * 10-(6)) for ischemic stroke included low aerobic fitness (hazard ratio [HR], 0.84 per standard deviation [SD] increase), high BMI (HR, 1.15 per SD increase), diabetes (HR, 2.85), alcohol intoxication (HR, 1.93), low annual income (HR, 0.85 per SD decrease), and stroke in the mother (HR, 1.31). Similar risk factors were found for hemorrhagic stroke including low aerobic fitness (HR, 0.82 per SD increase), high BMI (HR, 1.18 per SD increase) alcohol intoxication (HR, 2.92), diabetes (HR, 2.06), and low annual income (HR, 0.75). The population attributable risks associated with all evaluated risk factors were 69% for ischemic stroke and 88% for hemorrhagic stroke (p < 0.001 for both). CONCLUSIONS: In the present study we have shown that several known risk factors for stroke are present already in late adolescence, and that they are independent of each other. The strongest risk factors were low physical fitness, high BMI, diabetes, low annual income and a maternal history of stroke. Several of the aforementioned risk factors are potentially modifiable. PMID- 25547344 TI - Mindfully considering treatment of fibromyalgia: a comment on Cash et Al. PMID- 25547345 TI - Colloidal quantum dot solar cells exploiting hierarchical structuring. AB - Extremely thin-absorber solar cells offer low materials utilization and simplified manufacture but require improved means to enhance photon absorption in the active layer. Here, we report enhanced-absorption colloidal quantum dot (CQD) solar cells that feature transfer-stamped solution-processed pyramid-shaped electrodes employed in a hierarchically structured device. The pyramids increase, by up to a factor of 2, the external quantum efficiency of the device at absorption-limited wavelengths near the absorber band edge. We show that absorption enhancement can be optimized with increased pyramid angle with an appreciable net improvement in power conversion efficiency, that is, with the gain in current associated with improved absorption and extraction overcoming the smaller fractional decrease in open-circuit voltage associated with increased junction area. We show that the hierarchical combination of micron-scale structured electrodes with nanoscale films provides for an optimized enhancement at absorption-limited wavelengths. We fabricate 54.7 degrees pyramid-patterned electrodes, conformally apply the quantum dot films, and report pyramid CQD solar cells that exhibit a 24% improvement in overall short-circuit current density with champion devices providing a power conversion efficiency of 9.2%. PMID- 25547347 TI - Chalcogenophene comonomer comparison in small band gap diketopyrrolopyrrole-based conjugated polymers for high-performing field-effect transistors and organic solar cells. AB - The design, synthesis, and characterization of a series of diketopyrrolopyrrole based copolymers with different chalcogenophene comonomers (thiophene, selenophene, and tellurophene) for use in field-effect transistors and organic photovoltaic devices are reported. The effect of the heteroatom substitution on the optical, electrochemical, and photovoltaic properties and charge carrier mobilities of these polymers is discussed. The results indicate that by increasing the size of the chalcogen atom (S < Se < Te), polymer band gaps are narrowed mainly due to LUMO energy level stabilization. In addition, the larger heteroatomic size also increases intermolecular heteroatom-heteroatom interactions facilitating the formation of polymer aggregates leading to enhanced field-effect mobilities of 1.6 cm(2)/(V s). Bulk heterojunction solar cells based on the chalcogenophene polymer series blended with fullerene derivatives show good photovoltaic properties, with power conversion efficiencies ranging from 7.1 8.8%. A high photoresponse in the near-infrared (NIR) region with excellent photocurrents above 20 mA cm(-2) was achieved for all polymers, making these highly efficient low band gap polymers promising candidates for use in tandem solar cells. PMID- 25547346 TI - Laparoscopic intragastric surgery and laparoscopic roux-y gastric bypass were performed simultaneously on a morbidly obese patient with a gastric submucosal tumor: a report of a case and review. AB - BACKGROUND: Obesity patients sometimes have gastric submucosal tumors (SMTs). Surgical excision is recommended in cases of SMTs with suspected malignancy or other reasons making follow-up difficult. Laparoscopic intragastric surgery (LIGS) has recently achieved good results in the treatment of gastric SMTs, especially near the esophagogastric junction (EGJ). This procedure has enabled either preservation of the stomach or minimization of the extent of partial resection. METHODS: The patient is a 43-year-old female with BMI of 48.2 kg/m(2) who is a candidate for LRYGB. A small SMT was found just below the EGJ. A follow up with an endoscopy would be needed but difficult because the pouch was too small to observe the lesion. We decided to resect the tumor with LIGS and perform LRYGB simultaneously. RESULTS: We put the trocars as is our usual LRYGB practice. Observing with laparoscopy and endoscopy, three trocars were inserted into the stomach. After marking the margin of the tumor and injecting normal saline to the submucosal layer, resection of the tumor was performed. Suturing of the defects of the mucosa and the holes of the trocars on the stomach was performed. Then, we performed LRYGB as usual. The patient was discharged uneventfully. The pathological findings showed that the tumor was resected completely. Weight loss has succeeded as her BMI is 32.7 at 1 year after the surgery. CONCLUSIONS: We performed LIGS and LRYGB simultaneously and safely for a morbidly obese patient with a gastric SMT, and our case is the first case of LIGS during a bariatric procedure. PMID- 25547349 TI - Ability of hydroxypropyl chitosan nail lacquer to protect against dermatophyte nail infection. AB - The development of a topical agent that would strengthen the nail, improve the natural barrier, and provide better drug penetration to the nail bed is needed. In this study, we examined the effects of a hydroxypropyl chitosan (HPCH)-based nail solution using a bovine hoof model. Following application of the nail solution, changes in the hardness of the hoof samples were measured using the Vickers method. Tensile and flexural strengths were tested by stretching or punching the samples, respectively. The ultrastructure was examined using scanning electron microscopy (SEM), and samples stained with periodic acid-Schiff (PAS) stain were used to determine the fungal penetration depth. The comparators included 40% urea and 70% isopropyl alcohol solutions. The HPCH nail solution increased hoof sample hardness in comparison to the untreated control sample (mean, 22.3 versus 19.4 Vickers pyramid number [HV]). Similarly, the HPCH solution increased the tensile strength (mean, 33.07 versus 28.42 MPa) and flexural strength (mean, 183.79 versus 181.20 MPa) compared to the untreated control. In contrast, the comparators had adverse effects on hardness and strength. SEM showed that the HPCH solution reduced the area of sample crumbling following abrasion compared to the untreated control (7,418 versus 17,843 pixels), and the PAS-stained images showed that the HPCH solution reduced penetration of the dermatophyte hyphae (e.g., penetration by Trichophyton mentagrophytes was <25 MUm at day 9 versus 275 MUm in the untreated control). Unlike chemicals normally used in cosmetic treatments, repeated application of the HPCH nail solution may help prevent the establishment of new or recurring fungal nail infection. PMID- 25547348 TI - Tn6249, a new Tn6162 transposon derivative carrying a double-integron platform and involved with acquisition of the blaVIM-1 metallo-beta-lactamase gene in Pseudomonas aeruginosa. AB - The In70.2 integron platform appears to be a conserved structure involved in the dissemination of the blaVIM-1 metallo-beta-lactamase gene in Pseudomonas aeruginosa. The genetic context of the In70.2 integron platform from P. aeruginosa VR-143/97, the VIM-1-producing index strain isolated in Italy in 1997, was fully characterized by a next-generation sequencing approach refined by conventional sequencing. The In70.2 integron platform from VR-143/97 was found to be associated with a defective Tn402-like transposon inserted into the urf2 gene of a Tn3 family transposon of an original structure, named Tn6249, which also carried a partially deleted mer operon and an In90 integron platform in a tail-to tail orientation. Tn6249 was inserted into a PACS171b-like genomic island, which was in turn inserted into the endA gene of the Pseudomonas chromosomal backbone. Tn6249 showed a similar structure and a conserved location with respect to that of Tn6060, a Tn3 family transposon associated with In70.2 and carrying a double integron platform, which was detected in a VIM-1-producing P. aeruginosa strain isolated in Australia in 2008. Both Tn6249 and Tn6060 are apparently derived from Tn6162, a mercury resistance transposon carrying an integron platform, which was found in P. aeruginosa isolates from different geographic locations. The conservation of the genetic context of Tn6249 and Tn6060 suggests an in situ evolution of these elements after the insertion of a Tn6162-like ancestor into the PACS171b-like genomic island (GI) present in the genome of a successful widespread P. aeruginosa clonal lineage. PMID- 25547350 TI - Effect of reduced oxygen on the antifungal susceptibility of clinically relevant aspergilli. AB - The influence of hypoxia on the in vitro activities of amphotericin B, azoles, and echinocandins against Aspergillus spp. was evaluated by comparing MICs, minimal fungicidal concentrations (MFCs), and epidemiological cutoffs (ECOFFs). Changes of MIC distributions due to hypoxia largely depend on the method, the species, and the growth ability under hypoxia. The activities of antifungals were not significantly altered under hypoxia, except for Aspergillus terreus, for which the activity changed from fungicidal to fungistatic. PMID- 25547351 TI - Cardiac effects of echinocandins after central venous administration in adult rats. AB - Echinocandins have become the agents of choice for early and specific antifungal treatment in critically ill patients. In vitro studies and clinical case reports revealed a possible impact of echinocandin treatment on cardiac function. The aim of our study was to evaluate echinocandin-induced cardiac failure. Using an in vivo rat model, we assessed hemodynamic parameters and time to hemodynamic failure after central venous application (vena jugularis interna) of anidulafungin (low-dose group, 2.5 mg/kg body weight [BW]; high-dose group, 25 mg/kg BW), caspofungin (low-dose group, 0.875 mg/kg BW; high-dose group, 8.75 mg/kg BW), micafungin (low-dose group, 3 mg/kg BW; high-dose group, 30 mg/kg BW), and placebo (0.9% sodium chloride). Left ventricular heart tissue was collected to determine mitochondrial enzyme activity via spectrophotometric measurements. mRNA expression of transcriptional regulators and primary mitochondrial transcripts, mitochondrial DNA (mtDNA) content, and citrate synthase activity were also explored. Animals receiving high-dose anidulafungin or caspofungin showed an immediate decrease in hemodynamic function. All of the subjects in these groups died during the observation period. Every animal in the untreated control group survived (P < 0.001). Hemodynamic failure was not noticed in the anidulafungin and caspofungin low-dose groups. Micafungin had no impact on cardiac function. In analyzing mitochondrial enzyme activity and mitochondrial transcripts, we found no association between echinocandin administration and the risk for hemodynamic failure. Further experimental studies are needed to elucidate the underlying mechanisms involved in cardiotoxic echinocandin effects. In addition, randomized controlled clinical trials are needed to explore the clinical impact of echinocandin treatment in critically ill patients. PMID- 25547352 TI - Effects of tigecycline and vancomycin administration on established Clostridium difficile infection. AB - The glycylcycline antibiotic tigecycline was approved in 2005 for the treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections. Tigecycline is broadly active against both Gram-negative and Gram positive microorganisms, including Clostridium difficile. Tigecycline has a low MIC against C. difficile in vitro and thus may represent an alternate treatment for C. difficile infection (CDI). To assess the use of tigecycline for treatment of established CDI, 5- to 8-week-old C57BL/6 mice were colonized with C. difficile strain 630. After C. difficile colonization was established, mice (n = 10 per group) were treated with either a 5-day course of tigecycline (6.25 mg/kg every 12 h subcutaneously) or a 5-day course of vancomycin (0.4 mg/ml in drinking water) and compared to infected, untreated control mice. Mice were evaluated for clinical signs of CDI throughout treatment and at 1 week posttreatment to assess potential for disease development. Immediately following a treatment course, C. difficile was not detectable in the feces of vancomycin-treated mice but remained detectable in feces from tigecycline-treated and untreated control mice. Toxin activity and histopathological inflammation and edema were observed in the ceca and colons of untreated mice; tigecycline- and vancomycin-treated mice did not show such changes directly after treatment. One week after the conclusion of either antibiotic treatment, C. difficile load, toxin activity, and histopathology scores increased in the cecum and colon, indicating that C. difficile-associated disease occurred. In vitro growth studies confirmed that subinhibitory concentrations of tigecycline were able to suppress toxin activity and spore formation of C. difficile, whereas vancomycin did not. Taken together, these data show how tigecycline is able to alter C. difficile pathogenesis in a mouse model of CDI. PMID- 25547353 TI - Rapid testing using the Verigene Gram-negative blood culture nucleic acid test in combination with antimicrobial stewardship intervention against Gram-negative bacteremia. AB - Rapid identification of microorganisms and antimicrobial resistance is paramount for targeted treatment in serious bloodstream infections (BSI). The Verigene Gram negative blood culture nucleic acid test (BC-GN) is a multiplex, automated molecular diagnostic test for identification of eight Gram-negative (GN) organisms and resistance markers from blood culture with a turnaround time of approximately 2 h. Clinical isolates from adult patients at the University Maryland Medical Center with GN bacteremia from 1 January 2012 to 30 June 2012 were included in this study. Blood culture bottles were spiked with clinical isolates, allowed to incubate, and processed by BC-GN. A diagnostic evaluation was performed. In addition, a theoretical evaluation of time to effective and optimal antibiotic was performed, comparing actual antibiotic administration times from chart review ("control") to theoretical administration times based on BC-GN reporting and antimicrobial stewardship team (AST) review ("intervention"). For organisms detected by the assay, BC-GN correctly identified 95.6% (131/137), with a sensitivity of 97.1% (95% confidence interval [CI], 90.7 to 98.4%) and a specificity of 99.5% (95% CI, 98.8 to 99.8%). CTX-M and OXA resistance determinants were both detected. Allowing 12 h from Gram stain for antibiotic implementation, the intervention group had a significantly shorter duration to both effective (3.3 versus 7.0 h; P < 0.01) and optimal (23.5 versus 41.8 h; P < 0.01) antibiotic therapy. BC-GN with AST intervention can potentially decrease time to both effective and optimal antibiotic therapy in GN BSI. PMID- 25547354 TI - In vitro activity of fosfomycin alone and in combination with ceftriaxone or azithromycin against clinical Neisseria gonorrhoeae isolates. AB - New therapeutic strategies are needed to combat the emergence of infections due to multidrug-resistant Neisseria gonorrhoeae. In this study, fosfomycin (FOS) was tested against 89 N. gonorrhoeae isolates using the Etest method, showing MIC50/MIC90s of only 8/16 MUg/ml (range, <=1 to 32 MUg/ml). FOS in combination with ceftriaxone (CRO) or azithromycin (AZT) was then evaluated using the checkerboard method for eight strains, including N. gonorrhoeae F89 (CRO resistant) and AZT-HLR (high-level AZT-resistant). All combinations that included FOS gave indifferent effects (fractional inhibitory concentration [FIC] index values, 1.2 to 2.3 for FOS plus CRO, 1.8 to 3.2 for FOS plus AZT). Time-kill experiments for FOS, CRO, AZT, and their combinations (at 0.5*, 1*, 2*, and 4* the MIC) were performed against N. gonorrhoeae strain ATCC 49226, one N. gonorrhoeae multiantigen sequence typing (NG-MAST) sequence type 1407 (ST1407) strain, F89, and AZT-HLR. For all strains, at 24 h, the results indicated that (i) FOS was bactericidal at 2* the MIC, but after >24 h, there was regrowth of bacteria; (ii) CRO was bactericidal at 0.5* the MIC; (iii) AZT was bactericidal at 4* the MIC; (iv) CRO plus AZT was less bactericidal than was CRO alone; (v) FOS plus AZT was bactericidal at 2* the MIC; and (vi) CRO plus AZT and FOS plus CRO were both bactericidal at 0.5* the MIC, but FOS plus CRO had more rapid effects. FOS is appealing for use in the management of N. gonorrhoeae infections because of its single and oral formulation. However, our results suggest it be used in combination with CRO. After the appropriate clinical trials are conducted, this strategy could be implemented for the treatment of infections due to isolates possessing resistance to CRO and/or AZT. PMID- 25547355 TI - Inhibition of nucleic acid biosynthesis makes little difference to formation of amphotericin B-tolerant persisters in Candida albicans biofilm. AB - Candida albicans persisters constitute a small subpopulation of biofilm cells and play a major role in recalcitrant chronic candidiasis; however, the mechanism underlying persister formation remains unclear. Persisters are often described as dormant, multidrug-tolerant, nongrowing cells. Persister cells are difficult to isolate and study not only due to their low levels in C. albicans biofilms but also due to their transient, reversible phenotype. In this study, we tried to induce persister formation by inducing C. albicans cells into a dormant state. C. albicans cells were pretreated with 5-fluorocytosine (planktonic cells, 0.8 MUg ml(-1); biofilm cells, 1 MUg ml(-1)) for 6 h at 37 degrees C, which inhibits nucleic acid and protein synthesis. Biofilms and planktonic cultures of eight C. albicans strains were surveyed for persisters after amphotericin B treatment (100 MUg ml(-1) for 24 h) and CFU assay. None of the planktonic cultures, with or without 5-fluorocytosine pretreatment, contained persisters. Persister cells were found in biofilms of all tested C. albicans strains, representing approximately 0.01 to 1.93% of the total population. However, the persister levels were not significantly increased in C. albicans biofilms pretreated with 5-fluorocytosine. These results suggest that inhibition of nucleic acid synthesis did not seem to increase the formation of amphotericin B-tolerant persisters in C. albicans biofilms. PMID- 25547356 TI - Tigecycline treatment causes a decrease in fibrinogen levels. AB - The objective of this study was to assess the impact of tigecycline treatment on coagulation parameters, specifically fibrinogen, in patients with severe infections. We examined 20 cases of tigecycline-treated patients with severe infections, including hospital-acquired pneumonia, complicated intra-abdominal infections, complicated skin and soft tissue infections, and bloodstream infections. We monitored the relative markers of coagulation and renal and liver function before, during, and after treatment. Fibrinogen (FIB) levels decreased significantly after the use of tigecycline and normalized after the cessation of treatment. FIB levels significantly decreased in the patients treated with the recommended dose or a higher treatment dose. The FIB levels decreased more in the higher-treatment-dose group. There was no difference in the decrease in FIB levels or the FIB level recovery by age. Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) were prolonged after tigecycline use. The TT decreased after the cessation of treatment, and the PT and APTT also decreased but not to a significant level. There was no change in platelet, alanine aminotransferase (ALT), or creatinine (Cr) levels associated with treatment. The use of tigecycline was associated with decreased FIB levels, which returned to normal after the cessation of treatment. A high-dose treatment group showed greater decreases in FIB levels than did patients treated with the recommended dose. The decline in FIB was not related to patient age. The use of tigecycline was associated with prolonged PT, APTT, and TT. PMID- 25547357 TI - Influenza viral load and peramivir kinetics after single administration and proposal of regimens for peramivir administration against resistant variants. AB - We estimated the efficacy of the current single administration of peramivir on the basis of peramivir pharmacokinetics in the upper respiratory tract (URT) and determined the predictive peramivir concentration-time curve to assess its efficacy against viruses with decreased susceptibility to neuraminidase inhibitors. Serum, nasal swab, or aspiration samples were collected from 28 patients treated with 10 mg/kg body weight peramivir. The sequential influenza viral RNA load and susceptibility after peramivir administration were measured using a quantitative real-time reverse transcription-PCR and neuraminidase inhibition assay. The peramivir concentrations in the serum and URT after a single administration at 10 mg/kg were measured, and the predictive blood and URT peramivir concentration-time curves were determined to assess various administration regimens against resistant variants. The peramivir concentration decreased to <0.1% of the maximum concentration of drug in serum (Cmax) at 24 h after administration. Rapid elimination of peramivir from the URT by 48 h after administration may contribute to an increase in the influenza A viral load after day 3 but not to a decrease in the influenza B viral load, despite the absence of a decrease in the susceptibility to peramivir. A longer maintenance of a high level of peramivir in the URT is expected by divided administration rather than once-daily administration. When no clinical improvement is observed in patients with normal susceptibility influenza A and B, peramivir readministration should be considered. In severe cases caused by resistant variants, better inhibitory effectiveness and less frequent adverse events are expected by divided administration rather than once-daily administration with an increased dosage. PMID- 25547358 TI - Clavanin A improves outcome of complications from different bacterial infections. AB - The rapid increase in the incidence of multidrug-resistant infections today has led to enormous interest in antimicrobial peptides (AMPs) as suitable compounds for developing unusual antibiotics. In this study, clavanin A, an antimicrobial peptide previously isolated from the marine tunicate Styela clava, was selected as a purposeful molecule that could be used in controlling infection and further synthesized. Clavanin A was in vitro evaluated against Staphylococcus aureus and Escherichia coli as well as toward L929 mouse fibroblasts and skin primary cells (SPCs). Moreover, this peptide was challenged here in an in vivo wound and sepsis model, and the immune response was also analyzed. Despite displaying clear in vitro antimicrobial activity toward Gram-positive and -negative bacteria, clavanin A showed no cytotoxic activities against mammalian cells, and in acute toxicity tests, no adverse reaction was observed at any of the concentrations. Moreover, clavanin A significantly reduced the S. aureus CFU in an experimental wound model. This peptide also reduced the mortality of mice infected with E. coli and S. aureus by 80% compared with that of control animals (treated with phosphate-buffered saline [PBS]): these data suggest that clavanin A prevents the start of sepsis and thereby reduces mortality. These data suggest that clavanin A is an AMP that could improve the development of novel peptide-based strategies for the treatment of wound and sepsis infections. PMID- 25547359 TI - Characterization of a novel metallo-beta-lactamase variant, GIM-2, from a clinical isolate of Enterobacter cloacae in Germany. PMID- 25547360 TI - Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. AB - VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. PMID- 25547361 TI - Pharmacokinetic-pharmacodynamic model to evaluate intramuscular tetracycline treatment protocols to prevent antimicrobial resistance in pigs. AB - High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent to which resistant strains outcompete susceptible strains under antimicrobial pressure may depend not only on the antimicrobial treatment strategies but also on the epidemiological parameters, such as the composition of the bacterial strains in a pig. This study evaluated how variation in the dosing protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma concentration profiles of tetracycline. All dosing regimens result in a clear growth advantage for resistant strains. Short treatment duration was found to be preferable, since it allowed less time for resistant strains to outcompete the susceptible ones. Dosing frequency appeared to be ineffective at reducing the resistance levels. The number of competing strains had no apparent effect on the resistance level during treatment, but possession of fewer strains reduced the time to reach equilibrium after the end of treatment. To sum up, epidemiological parameters may have more profound influence on growth dynamics than dosing regimens and should be considered when designing improved treatment protocols. PMID- 25547363 TI - Crystal structure of human Fanconi-associated nuclease 1. PMID- 25547362 TI - Crystal structures of GI.8 Boxer virus P dimers in complex with HBGAs, a novel evolutionary path selected by the Lewis epitope. AB - Human noroviruses (huNoVs) recognize histo-blood group antigens (HBGAs) as attachment factors, in which genogroup (G) I and GII huNoVs use distinct binding interfaces. The genetic and evolutionary relationships of GII huNoVs under selection by the host HBGAs have been well elucidated via a number of structural studies; however, such relationships among GI NoVs remain less clear due to the fact that the structures of HBGA-binding interfaces of only three GI NoVs with similar binding profiles are known. In this study the crystal structures of the P dimers of a Lewis-binding strain, the GI.8 Boxer virus (BV) that does not bind the A and H antigens, in complex with the Lewis b (Le(b)) and Le(y) antigens, respectively, were determined and compared with those of the three previously known GI huNoVs, i.e. GI.1 Norwalk virus (NV), GI.2 FUV258 (FUV) and GI.7 TCH060 (TCH) that bind the A/H/Le antigens. The HBGA binding interface of BV is composed of a conserved central binding pocket (CBP) that interacts with the beta galactose of the precursor, and a well-developed Le epitope-binding site formed by five amino acids, including three consecutive residues from the long P-loop and one from the S-loop of the P1 subdomain, a feature that was not seen in the other GI NoVs. On the other hand, the H epitope/acetamido binding site observed in the other GI NoVs is greatly degenerated in BV. These data explain the evolutionary path of GI NoVs selected by the polymorphic human HBGAs. While the CBP is conserved, the regions surrounding the CBP are flexible, providing freedom for changes. The loss or degeneration of the H epitope/acetamido binding site and the reinforcement of the Le binding site of the GI.8 BV is a typical example of such change selected by the host Lewis epitope. PMID- 25547364 TI - Comment on the paper by Kuniyoshi et al. entitled 'multifocal electroretinograms in Stargardt's disease/fundus flavimaculatus'. PMID- 25547365 TI - Statistical analysis and interpolation of compositional data in materials science. AB - Compositional data are ubiquitous in chemistry and materials science: analysis of elements in multicomponent systems, combinatorial problems, etc., lead to data that are non-negative and sum to a constant (for example, atomic concentrations). The constant sum constraint restricts the sampling space to a simplex instead of the usual Euclidean space. Since statistical measures such as mean and standard deviation are defined for the Euclidean space, traditional correlation studies, multivariate analysis, and hypothesis testing may lead to erroneous dependencies and incorrect inferences when applied to compositional data. Furthermore, composition measurements that are used for data analytics may not include all of the elements contained in the material; that is, the measurements may be subcompositions of a higher-dimensional parent composition. Physically meaningful statistical analysis must yield results that are invariant under the number of composition elements, requiring the application of specialized statistical tools. We present specifics and subtleties of compositional data processing through discussion of illustrative examples. We introduce basic concepts, terminology, and methods required for the analysis of compositional data and utilize them for the spatial interpolation of composition in a sputtered thin film. The results demonstrate the importance of this mathematical framework for compositional data analysis (CDA) in the fields of materials science and chemistry. PMID- 25547366 TI - Reversible diaphragmatic paralysis caused by a malpositioned chest tube. AB - We report a case of reversible diaphragmatic paralysis caused by a malpositioned chest tube, a diagnosis to consider when unexplained respiratory failure occurs following drainage of pleural effusion. Prompt recognition and removal of the tube led to full recovery of diaphragm function. PMID- 25547367 TI - Prenatal diagnosis based on HPRT1 gene mutation in a Lesch-Nyhan family. AB - We explored the feasibility of applying gene diagnosis in prenatal diagnosis by analysis of hypoxanthine-guanine phosphoribosyltransferase-1 (HPRT1) gene mutation in a Chinese Lesch-Nyhan family. A homozygous mutation of p.R170X (c.508C>T) in HPRT1 gene was detected in the proband, and a heterozygous mutation of p.R170X was detected in his mother. This mutation failed to be found in the 50 unrelated healthy individuals. Prenatal diagnosis indicated that the foetus was male and also carried p.R170X (c.508C>T) mutation, same as the proband. Parents of the foetus decided termination of pregnancy, and the result of gene analysis for the aborted tissue was consistent with that of prenatal diagnosis. We can see that Lesch-Nyhan syndrome (LNS) is caused by non-sense mutation p.R170X(c.508C>T)in HPRT1 gene in this family. Prenatal gene diagnosis is a valid strategy to prevent LNS because it can avoid the birth of LNS foetuses. PMID- 25547368 TI - Internal exposure to organochlorine pollutants and cadmium and self-reported health status: a prospective study. AB - In this paper, based on the Flemish biomonitoring programs, we describe the associations between internal exposure to organochlorine pollutants and to cadmium (measured in 2004-2005 for adults aged 50-65 years) and self-reported health status obtained through a questionnaire in November 2011. Dioxin-like activity in serum showed a significant positive association with risk of cancer for women. After adjustment for confounders and covariates, the odds ratio for an exposure equal to the 90th percentile was 2.4 times higher than for an exposure equal to the 10th percentile. For both men and women dioxin-like activity and serum hexachlorobenzene (HCB) showed a significant positive association with risk of diabetes and of hypertension. Detailed analysis suggested that an increase in BMI might be part of the mechanism through which HCB contributes to diabetes and hypertension. Serum dichlorodiphenyldichloroethylene (p,p'-DDE) concentration showed a significant positive association with diabetes and hypertension in men, but not in women. Serum polychlorinated biphenyl (PCB) 118 showed a significant positive association with diabetes in both men and women, and after adjustment for correlated exposures, also with hypertension in men. Urinary cadmium concentrations showed a significant positive association with hypertension. Urinary cadmium concentrations were (in 2004-2005) significantly higher in persons who felt in less than good health (in 2011) than in persons who felt in very good health. After adjustment for correlated exposures (to HCB, p,p'-DDE and PCB118) marker PCBs showed a significant negative association with diabetes and hypertension. Serum p,p'-DDE showed in men a significant negative association with risk of diseases based on atheromata. Our findings suggest that exposure to pollutants can lead to an important increase in the risk of diseases such as cancer, diabetes and hypertension. Some pollutants may possibly also decrease the risk of some health problems, although this requires confirmation by other approaches. PMID- 25547369 TI - PEG-lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication. AB - PEG-lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG-DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG-lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG lipid micelles and their relevance to the inherent advantages and applications of PEG-lipid micelles for drug delivery. PMID- 25547370 TI - Possible role of GABA-B receptor modulation in MPTP induced Parkinson's disease in rats. AB - Accumulating evidence strongly suggests that gamma amino butyric acid (GABA) receptors play a crucial role in the pathogenesis of Parkinson's disease (PD). Therefore, the present study was designed to investigate the role of GABA-B receptor modulation in experimental models of MPTP-induced PD. MPTP was administered repeatedly on 1st, 7th and 14th day intranigrally for the induction of PD in Male Wistar rats. Baclofen (10 and 20mg/kg) and GABA-B antagonist CGP35348 (10mg/kg) were given after induction of PD for 14 days. Different behavioural tasks were performed during 1st, 14th, 21st, 28th days after MPTP injection and biochemical parameters were estimated on day 28th. Central administration of MPTP showed significant impairment of motor behaviour and marked increase of oxidative damage LPO and GSH in striatum and cortex. Pro inflammatory cytokines like TNF-alpha and IL-beta were significantly increased in striatum region of MPTP treated rats. However, post treatment with baclofen significantly improved the motor abnormalities and attenuated the oxidative damage and neuro-inflammation in MPTP treated rats. CGP35348, GABA-B receptor antagonist, reversed the protective effect of baclofen GABA-B receptor play role in the neuroprotection. The present study concluded that baclofen produce beneficial effect against MPTP induced PD like symptoms rats through GABAergic mechanism. PMID- 25547371 TI - Stability of class II subdivision malocclusion treatment with 3 and 4 premolar extractions. AB - BACKGROUND: The purpose of this study was to compare the occlusal stability of class II subdivision malocclusion treatment with 3 and 4 first premolar extractions. A sample of 156 dental casts from 52 patients with class II subdivision malocclusion was divided into two groups according to the extraction protocol. Group 1 comprised 24 patients treated with 3 premolar extractions and group 2 included 28 patients treated with 4 premolar extractions. METHODS: Peer assessment rating (PAR) indexes were measured on the dental casts obtained before (T1) and after treatment (T2) and at a mean of 6.9 years after the end of treatment (T3). The groups were matching regarding sex distribution, pretreatment, posttreatment and long-term posttreatment ages, and treatment and long-term posttreatment times. They were also comparable concerning the initial malocclusion severity and the occlusal results at the end of treatment. Stability evaluation was calculated by subtracting the posttreatment from the long-term posttreatment index values (T3 - T2). T tests were used to compare the amount and percentage of long-term posttreatment changes. RESULTS: There were no intergroup differences regarding the amount and percentage of long-term posttreatment changes. CONCLUSION: Treatment of class II subdivision malocclusion with 3 and 4 premolar extractions have a similar long-term posttreatment occlusal stability. PMID- 25547372 TI - Inhibition of telomerase activity by NME2: impact on metastasis suppression? AB - Though anti-metastatic function of non-metastatic 2 (NME2) has been implicated in multiple cancers, mechanisms of metastases control by NME2 are not clearly understood. Recent observations indicating the involvement of telomerase, the ribonucleoprotein required for telomere synthesis, in metastatic outcome are interesting. Notably, though the role of telomerase dysfunction in tumorigenesis is relatively well studied, involvement in metastasis progression is poorly understood. Recent findings demonstrate NME2 presence at telomere ends, association with telomerase, and NME2's role in inhibition of telomerase activity in cancer cells. These present a novel opportunity to investigate mechanisms underlying NME2-mediated metastasis suppression. PMID- 25547374 TI - Systemic review of published literature on Candida infection following total hip arthroplasty. AB - Candida species (Candida spp.) infection following total hip arthroplasty (THA) is a rare but potentially devastating complication. The purpose of this study was to provide an evidence-based summarization of the treatment and outcome of Candida spp. infection after THA. We conducted a systemic review of the literature and pooled analysis of Candida spp. infection after THA published between 1950 and 2014. A total of 20 articles with 37 patients were identified. Median time between THA and readmission for Candida spp. infection was 25 months (range 0.5-184 months). Thirty-two patients (87%) underwent removal of the prosthesis for initial surgical treatment. All patients were treated with systemic antifungal medication therapy for various durations after the surgical procedure or primary therapy without surgical procedures except for one patient who was treated with only amphotericin B joint cavity irrigation after removal of the prosthesis. Relapse of the infection occurred in three patients who had retention of the original prosthesis. There were three deaths related to the Candida spp. infection following THA owing to uncontrolled Candida spp. infection and deteriorating candidemia sepsis. Of note, among 15 patients who underwent two stage exchange arthroplasty, there was one patient (7%) who developed complication (death) while other 14 patients had uncomplicated recovery. In conclusion, surgical debridement with removal of the original prosthesis or two stage exchange arthroplasty with combination of adequate systemic antifungal therapy is highly recommended in the treatment of Candida spp. infection following THA. PMID- 25547373 TI - Synergistic effects of GSK-3beta and HDAC inhibitors in intracerebroventricular streptozotocin-induced cognitive deficits in rats. AB - Recent studies suggest the importance of combined treatment of glycogen synthase kinase-3beta (GSK-3beta) and histone deacetylase (HDAC) inhibition in various in vitro and in vivo models of neurological diseases. Lithium chloride (LiCl) and valproate (VPA), two well-known mood stabilizers, have been reported to act through GSK-3beta and HDAC inhibition, respectively. The present study was designed to investigate the potential of low-dose combination of LiCl and VPA in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficits in rats. STZ was injected twice (3 mg/kg ICV) on alternate days (day 1 and day 3) in rats. The ICV-STZ-treated rats received LiCl (60 mg/kg, i.p.), VPA (200 mg/kg, i.p.), and combination of both LiCl (60 mg/kg, i.p.) and VPA (200 mg/kg, i.p.) drugs for a period of 3 weeks. The ICV-STZ administration results in significant memory impairment, elevated oxidative-nitrosative stress, and reduced brain derived neurotrophic factor (BDNF) levels. Using a battery of behavioral and biochemical tests, we observed that co-treatment of both drugs showed synergistic effect in improving the spatial learning and memory impairment as well as significantly attenuated the oxidative stress markers in STZ-treated rats as compared to either drug alone. Moreover, the combination of both drugs reversed the hyperinsulinemic brain condition and improved the BDNF levels in STZ-treated rats. Based upon these results, it could be suggested that a low-dose combination of LiCl and VPA produces synergistic and more consistent neuroprotective effects in ICV-STZ-induced cognitive deficits in rats. PMID- 25547375 TI - Update on cardiac imaging techniques 2014. AB - In this article, we review the contributions of the most important imaging techniques used in cardiology, reported in 2014. Echocardiography remains the cornerstone for diagnosing and monitoring valvular heart disease, and there has been a continuing effort to improve quantification of this condition and obtain prognostic parameters for follow-up. The study of regional myocardial function is anchored in the diagnosis of subclinical ventricular dysfunction, and 3 dimensional transesophageal echocardiography has become the perfect ally in interventional procedures for structural heart disease. Cardiac magnetic resonance imaging and cardiac computed tomography are the focus of most publications on cardiac imaging in ischemic heart disease, reflecting their consolidated use in clinical practice. Nuclear medicine excels in the study of myocardial viability after interventional treatment of acute coronary syndromes and its performance is validated in the diagnosis of ischemic heart disease. PMID- 25547376 TI - Comments on exercise echocardiography and multidetector computed tomography for the evaluation of acute chest pain. Response. PMID- 25547377 TI - Design of non-pharmaceutical intervention strategies for pandemic influenza outbreaks. AB - BACKGROUND: As seen during past pandemic influenza outbreaks, pharmaceutical interventions (PHIs) with vaccines and antivirals are the most effective methods of mitigation. However, availability of PHIs is unlikely to be adequate during the early stages of a pandemic. Hence, for early mitigation and possible containment, non-pharmaceutical interventions (NPIs) offer a viable alternative. Also, NPIs may be the only available interventions for most underdeveloped countries. In this paper we present a comprehensive methodology for design of effective NPI strategies. METHODS: We develop a statistical ANOVA-based design approach that uses a detailed agent-based simulation as an underlying model. The design approach obtains the marginal effect of the characteristic parameters of NPIs, social behavior, and their interactions on various pandemic outcome measures including total number of contacts, infections, and deaths. We use the marginal effects to establish regression equations for the outcome measures, which are optimized to obtain NPI strategies. Efficacy of the NPI strategies designed using our methodology is demonstrated using simulated pandemic influenza outbreaks with different levels of virus transmissibility. RESULTS: Our methodology was able to design effective NPI strategies, which were able to contain outbreaks by reducing infection attack rates (IAR) to below 10% in low and medium virus transmissibility scenarios with 33% and 50% IAR, respectively. The level of reduction in the high transmissibility scenario (with 65% IAR) was also significant. As noted in the published literature, we also found school closure to be the single most effective intervention among all NPIs. CONCLUSIONS: If harnessed effectively, NPIs offer a significant potential for mitigation of pandemic influenza outbreaks. The methodology presented here fills a gap in the literature, which, though replete with models on NPI strategy evaluation, lacks a treatise on optimal strategy design. PMID- 25547378 TI - Impact of the California breast density law on primary care physicians. AB - PURPOSE: To investigate primary physician awareness of the California Breast Density Notification Law and its impact on primary care practice. METHODS: An online survey was distributed to 174 physicians within a single primary care network system 10 months after California's breast density notification law took effect. The survey assessed physicians' awareness of the law, perceived changes in patient levels of concern about breast density, and physician comfort levels in handling breast density management issues. RESULTS: The survey was completed by 77 physicians (45%). Roughly half of those surveyed (49%) reported no knowledge of the breast density notification legislation. Only 32% of respondents noted an increase in patient levels of concern about breast density compared to prior years. The majority were only "somewhat comfortable" (55%) or "not comfortable" (12%) with breast density questions, and almost one-third (32%) had referred patients to a breast health clinic for these discussions. A total of 75% of those surveyed would be interested in more specific education on the subject. CONCLUSIONS: Awareness among primary care clinicians of the California Breast Density Notification Law is low, and many do not feel comfortable answering breast density-related patient questions. Breast imagers and institutions may need to devote additional time and resources to primary physician education in order for density notification laws to have significant impact on patient care. PMID- 25547379 TI - Medical physics at the crossroads. PMID- 25547380 TI - Legal Ramifications of Computer-Aided Detection in Mammography. PMID- 25547381 TI - Fluorescent carbon dots as an efficient siRNA nanocarrier for its interference therapy in gastric cancer cells. AB - BACKGROUND: Fluorescent carbon dots (Cdots) have attracted increasing attention due to their potential applications in sensing, catalysis, and biomedicine. Currently, intensive research has been concentrated on the synthesis and imaging guided therapy of these benign photoluminescent materials. Meanwhile, Cdots have been explored as nonviral vector for nucleic acid or drug delivery by chemical modification on purpose. RESULTS: We have developed a microwave assisted one-step synthesis of Cdots with citric acid as carbon source and tryptophan (Trp) as both nitrogen source and passivation agent. The Cdots with uniform size show superior water solubility, excellent biocompatibility, and high quantum yield. Afterwards, the PEI (polyethylenimine)-adsorbed Cdots nanoparticles (Cdots@PEI) were applied to deliver Survivin siRNA into human gastric cancer cell line MGC-803. The results have confirmed the nanocarrier exhibited excellent biocompatibility and a significant increase in cellular delivery of siRNA, inducing efficient knockdown for Survivin protein to 6.1%. In addition, PEI@Cdots complexes mediated Survivin silencing, the arrested cell cycle progression in G1 phase as well as cell apoptosis was observed. CONCLUSION: The Cdots-based and PEI-adsorbed complexes both as imaging agents and siRNA nanocarriers have been developed for Survivin siRNA delivery. And the results indicate that Cdots-based nanocarriers could be utilized in a broad range of siRNA delivery systems for cancer therapy. PMID- 25547389 TI - Candesartan improves ischemia-induced impairment of the blood-brain barrier in vitro. AB - Candesartan has been reported to have a protective effect on cerebral ischemia in vivo and in human ischemic stroke. We studied the direct effects of candesartan on blood-brain barrier (BBB) function with our in vitro monolayer model generated using rat brain capillary endothelial cells (RBECs). The in vitro BBB model was subjected to normoxia or 6-h oxygen glucose deprivation (OGD)/24-h reoxygenation, with or without candesartan. 6-h OGD/24-h reoxygenation decreased transendothelial electrical resistance and increased the endothelial permeability for sodium fluorescein in RBEC monolayers. Candesartan (10 nM) improved RBEC barrier dysfunction induced by 6-h OGD/24-h reoxygenation. Immunostaining and immunoblotting analysis indicated that the effect of candesartan on barrier function under 6-h OGD/24-h reoxygenation was not related to the expression levels of tight junction proteins. However, candesartan affected RBEC morphological changes induced by 6-h OGD/24-h reoxygenation. We analyzed oxidative stress and cell viability using chemical reagents. Candesartan improved cell viability following 6-h OGD/24-h reoxygenation, whereas candesartan had no effect on oxidative stress. These results show that candesartan directly improves cell function and viability of brain capillary endothelial cells under OGD/reoxygenation, suggesting that the protective effects of candesartan on ischemic stroke are related to protection of the BBB. PMID- 25547391 TI - The non-vitamin K oral anticoagulants (NOACs): Have all questions been answered? PMID- 25547390 TI - The mGluR5 positive allosteric modulator CDPPB inhibits SO2-induced protein radical formation and mitochondrial dysfunction through activation of Akt in mouse hippocampal HT22 cells. AB - Sulfur dioxide (SO2) is a common gas pollutant that is detrimental to many organs. Previous studies have shown that SO2 exposure is involved in neurotoxicity and increased risk of many brain disorders; however, our understanding of the mechanisms underlying SO2-induced cytotoxicity on neuronal cells remains elusive. The group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. In the present study, we showed that SO2 derivatives exposure induced protein radical formation, mitochondrial dysfunction, and apoptotic cell death in neuronal HT22 cells. Pretreatment with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) (CDPPB), a positive allosteric modulator of mGluR5, significantly attenuated SO2-induced neurotoxicity, which was fully prevented by the mGluR5 antagonist MPEP. CDPPB reduced the protein radical formation and inducible nitric oxide synthase (iNOS) derived generation of nitric oxide, and inhibited mitochondrial dysfunction in both HT22 cells and isolated mitochondria after SO2 treatment. Moreover, CDPPB increased the activation of Akt in the presence and absence of SO2 treatment. Blocking Akt activation using the selective inhibitor LY294002 partially reversed the CDPPB-induced protection against SO2-induced neurotoxicity. This study provides mechanistic experimental support for oxidative stress and mitochondrial dysfunction after SO2 exposure in neuronal cells, and also introduces a novel therapeutic approach for SO2-induced neurotoxicity. PMID- 25547388 TI - The biology of castration-resistant prostate cancer. PMID- 25547392 TI - ARVD: "What would you do?". PMID- 25547393 TI - [Diagnostic yield and postoperative management of patients submitted to brain biopsy in a university hospital]. AB - OBJECTIVE: To assess the diagnostic yield and the incidence of perioperative complications in patients undergoing an open or closed cerebral biopsy and to determine the length of intensive care monitoring, for early diagnosis and fast management of perioperative complications. MATERIAL AND METHOD: This was a retrospective analysis of all the patients that underwent brain biopsy between January 2006 and July 2012. We recorded demographic data, comorbidities, modality of biopsy, intraoperative clinical data, histological results, computed tomography scanning findings and occurrence, and type of perioperative complications and moment of appearance. RESULTS: Seventy-six brain biopsies in 75 consecutive patients (51 closed and 25 open) were analysed. Diagnostic yield was 98% for closed biopsies and 96% for open biopsies. Mortality related to the procedures was 3.9 and 4%, respectively. The incidence of major complications was 3.9% for closed biopsies and 8% for open biopsies; half of these appeared within the first 24 postoperative hours, during patient stay in the Intensive Care Unit. Age was the only risk factor for complications (P=.04) in our study. No differences in morbimortality were found between the studied groups. CONCLUSIONS: Diagnostic yield was very high in our series. Because the importance of early diagnosis of complications for preventing long-term sequelae, we recommend overnight hospital stay for observation after open or closed brain biopsy. PMID- 25547397 TI - Evaluation of the relationship between 5-HTT and MAO gene polymorphisms, mood and level of anxiety among postmenopausal women. AB - OBJECTIVE: The aim of this study was to analyze how mood and anxiety level are related to the functional genetic polymorphism in the promoter region of SLC6A4 (5-HTTLPR) and the 30-bp VNTR polymorphism in the MAO A promoter region. METHODS: The study involved 272 postmenopausal women from Poland. The authors employed the State-Trait Anxiety Inventory for measuring levels of anxiety, the Mood Adjective Check List for measuring mood, and genetic tests. RESULTS: Analysis did not show any statistically significant differences in the mean levels of anxiety, and mood disorders in women in relation to genotypes of the 5-HTTLPR (SLC6A4) polymorphism and the 30-bp VNTR polymorphism in the MAO A promoter region. However, these problems were more severe among women with s/s genotype. In the case of MAO A gene polymorphism, the level of anxiety was higher in women with a 4/4 genotype. CONCLUSIONS: The study did not prove the possibility of the identification of homogeneous groups of women with an elevated risk of developing anxiety and mood disorders during the post-menopausal period. Nevertheless, it showed that respondents with s/s genotype of the 44-bp polymorphism in the 5-HTT (SLC6A4) promoter region had the highest average anxiety levels both as a state and as a trait. Furthermore, the analysis of the 30-bp VNTR polymorphism in the MAO A promoter region demonstrated slight differences in anxiety levels between the women, indicating that those with a 4/4 genotype had higher severity of anxiety symptoms. PMID- 25547398 TI - Electronic cigarettes and indoor air quality: a simple approach to modeling potential bystander exposures to nicotine. AB - There has been rapid growth in the use of electronic cigarettes ("vaping") in Europe, North America and elsewhere. With such increased prevalence, there is currently a debate on whether the aerosol exhaled following the use of e cigarettes has implications for the quality of air breathed by bystanders. Conducting chemical analysis of the indoor environment can be costly and resource intensive, limiting the number of studies which can be conducted. However, this can be modelled reasonably accurately based on empirical emissions data and using some basic assumptions. Here, we present a simplified model, based on physical principles, which considers aerosol propagation, dilution and extraction to determine the potential contribution of a single puff from an e-cigarette to indoor air. From this, it was then possible to simulate the cumulative effect of vaping over time. The model was applied to a virtual, but plausible, scenario considering an e-cigarette user and a non-user working in the same office space. The model was also used to reproduce published experimental studies and showed good agreement with the published values of indoor air nicotine concentration. With some additional refinements, such an approach may be a cost-effective and rapid way of assessing the potential exposure of bystanders to exhaled e cigarette aerosol constituents. PMID- 25547399 TI - Health impact assessment of urban waterway decisions. AB - Health impact assessments (HIA) promote the consideration of health in a wide range of public decisions. Although each HIA is different, common pathways, evidence bases, and strategies for community engagement tend to emerge in certain sectors, such as urban redevelopment, natural resource extraction, or transportation planning. To date, a limited number of HIAs have been conducted on decisions affecting water resources and waterfronts. This review presents four recent HIAs of water-related decisions in the United States and Puerto Rico. Although the four cases are topically and geographically diverse, several common themes emerged from the consideration of health in water-related decisions. Water resource decisions are characterized by multiple competing uses, inter institutional and inter-jurisdictional complexity, scientific uncertainty, long time scales for environmental change, diverse cultural and historical human values, and tradeoffs between private use and public access. These four case studies reveal challenges and opportunities of examining waterfront decisions through a "health lens". This review analyzes these cases, common themes, and lessons learned for the future practice of HIA in the waterfront zone and beyond. PMID- 25547401 TI - A roadmap for comparing readmission policies with application to Denmark, England, Germany and the United States. AB - Hospital readmissions receive increasing interest from policy makers because reducing unnecessary readmissions has the potential to simultaneously improve quality and save costs. This paper reviews readmission policies in Denmark, England, Germany and the United States (Medicare system). The suggested roadmap enables researchers and policy makers to systematically compare and analyse readmission policies. We find considerable differences across countries. In Germany, the readmission policy aims to avoid unintended consequences of the introduction of DRG-based payment; it focuses on readmissions of individual patients and hospitals receive only one DRG-based payment for both the initial and the re-admission. In Denmark, England and the US readmission policies aim at quality improvement and focus on readmission rates. In Denmark, readmission rates are publicly reported but payments are not adjusted in relation to readmissions. In England and the US, financial incentives penalise hospitals with readmission rates above a certain benchmark. In England, this benchmark is defined through local clinical review, while it is based on the risk-adjusted national average in the US. At present, not enough evidence exists to give recommendations on the optimal design of readmission policies. The roadmap can be a tool for systematically assessing how elements of other countries' readmission policies can potentially be adopted to improve national policies. PMID- 25547400 TI - Polycyclic aromatic hydrocarbon residues in serum samples of autopsied individuals from Tennessee. AB - This study reports the concentrations of polycyclic aromatic hydrocarbons (PAHs) in human blood sera samples (n = 650) obtained at autopsy from individuals who died of drug abuse, alcohol toxicity, homicide, suicide and other unknown causes. The analyzed samples from decedents revealed the presence of PAHs of which B(a)P was the most predominant one, followed by benzo(b)fluoranthene and benzo(k)fluoranthene. The other PAHs detected sporadically and measured were benzo(g,h,i)perylene, acenaphthene, anthracene, phenanthrene, and fluoranthene The mean concentrations of PAHs were greater in the twenties to fifties age groups compared to others. The PAH residue levels detected were high in African Americans compared to Caucasians, Asians, and Hispanics. It appears that environmental exposure, dietary intake and in some cases occupational exposure may have contributed to the PAH body burden. While the PAH residue concentrations measured fall within the range of those reported for healthy adults elsewhere, in isolated cases, the concentrations detected were high, calling the need for a reduction in PAH emissions and human biomonitoring studies for purposes of risk assessment. PMID- 25547402 TI - A comparison of induced and developmental cell death morphologies in lace plant (Aponogeton madagascariensis) leaves. AB - BACKGROUND: Programmed cell death (PCD) is an important process for the development and maintenance of multicellular eukaryotes. In animals, there are three morphologically distinct cell death types: apoptosis, autophagic cell death, and necrosis. The search for an all-encompassing classification system based on plant cell death morphology continues. The lace plant is a model system for studying PCD as leaf perforations form predictably via this process during development. This study induced death in cells that do not undergo developmental PCD using various degrees and types of stress (heat, salt, acid and base). Cell death was observed via live cell imaging and compared to the developmental PCD pathway. RESULTS: Morphological similarities between developmental and induced PCD included: disappearance of anthocyanin from the vacuole, increase in vesicle formation, nuclear condensation, and fusing of vesicles containing organelles to the vacuole prior to tonoplast collapse. Plasma membrane retraction was a key feature of developmental PCD but did not occur in all induced modes of cell death. CONCLUSIONS: Regardless of the causal agent in cell death, the vacuole appeared to play a central role in dying cells. The results indicated that within a single system, various types and intensities of stress will influence cell death morphology. In order to establish a plant cell death classification system, future research should combine morphological data with biochemical and molecular data. PMID- 25547403 TI - The Bucentaur (BCNT) protein family: a long-neglected class of essential proteins required for chromatin/chromosome organization and function. AB - The evolutionarily conserved Bucentaur (BCNT) protein superfamily was identified about two decades ago in bovines, but its biological role has long remained largely unknown. Sparse studies in the literature suggest that BCNT proteins perform important functions during development. Only recently, a functional analysis of the Drosophila BCNT ortholog, called YETI, has provided evidence that it is essential for proper fly development and plays roles in chromatin organization. Here, we introduce the BCNT proteins and comprehensively review data that contribute to clarify their function and mechanistic clues on how they may control development in multicellular organisms. PMID- 25547405 TI - Novel in silico-designed estradiol analogues are cytotoxic to a multidrug resistant cell line at nanomolar concentrations. AB - PURPOSE: 2-Methoxyestradiol (2ME) is a promising anti-cancer agent that disrupts the integrity and dynamics of the spindle network. In order to overcome the pharmacokinetic constraints of this compound, a panel of sulphamoylated estradiol analogues were in silico-designed by our laboratory. In this study, we analysed the potential of each analogue to induce cell death on a panel of cancer cell lines. Moreover, the mechanism of action of the most effective compounds was determined. METHODS: Cytotoxicity screening of the compounds and intermediates was performed on five different cancer cell lines to determine IG50 values. An in vitro tubulin polymerization assay was done to determine the effect of the drugs on tubulin polymerization while their intracellular effects on the microtubule network were assessed by immunofluorescence microscopy. RESULTS: IG50 calculations showed that the sulphamoylated analogues induce cytotoxicity at nanomolar concentrations in all cell lines, including the P-glycoprotein pump overexpressing multidrug-resistant uterine sarcoma cell line. The non sulphamoylated compounds were only cytotoxic at micromolar ranges, if at all. The sulphamoylated compounds inhibited pure tubulin polymerization in a dose dependent manner and induced microtubule destruction in cells after 24-h exposure. CONCLUSION: Results revealed that the novel sulphamoylated 2ME derivatives have potential as anti-cancer drugs, possibly even against chemoresistant cancer cells. These compounds disrupt the intracellular microtubule integrity which leads to mitotic block of the cells. PMID- 25547404 TI - Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. AB - RATIONALE: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. OBJECTIVE: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST segment resolution, and infarct size. METHODS AND RESULTS: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. CONCLUSIONS: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size. PMID- 25547406 TI - CEACAM1 and hollow spheroid formation modulate the chemosensitivity of colorectal cancer to 5-fluorouracil. AB - PURPOSE: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) re expressed and promoted hollow spheroid (HS) formation beyond the invasion front of colorectal cancer. The aim of the present study was to clarify whether CEACAM1 cytoplasmic domain isoform balance and HS are associated with resistance to 5 fluorouracil (5FU). METHODS: Two-dimensional (D) or 3D culture systems were employed to evaluate the effects of CEACAM1 cytoplasmic isoform balance and HS formation on the chemosensitivity of colorectal cancer cells to 5FU. The risk factors for postoperative recurrence were calculated based on the presence of HS and various clinicopathological characteristics in 82 patients with Stage III colorectal cancer who had undergone curative surgery followed by 5FU-based chemotherapy. RESULTS: CEACAM1-4L-transfected HT29 and CEACAM1-4L and 4S expressing parental LS174T cells had significantly higher resistance to 5FU in comparison with CEACAM1-4S- or vector control-transfected cells. In 3D culture, HS formation induced by CEACAM1-4L induced chemoresistance to 5FU, whereas the solid spheres formed in response to CEACAM1-4S were destroyed by 5FU treatment. HS was identified as an independent factor for recurrence of Stage III colorectal cancer after curative resection followed by 5FU-based chemotherapy. Kaplan-Meier survival curves demonstrated that patients with HS had lower recurrence-free survival rate. CONCLUSIONS: CEACAM1 long cytoplasmic domain isoform dominance and HS formation are phenotypes associated with chemoresistance to 5FU. PMID- 25547407 TI - Retrospective analysis of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) as salvage chemotherapy in patients with gemcitabine refractory advanced pancreatic cancer: inflammation-based prognostic score predicts survival. AB - PURPOSE: The purpose of this study was to assess the efficacy and safety of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) in patients with gemcitabine (GEM)-refractory pancreatic cancer (PC) and to explore independent variables associated with survival. METHODS: We retrospectively reviewed consecutive patients with GEM-refractory PC who received FGS at our institution from March 2009 to December 2013. GEM was administered by fixed dose rate intravenous infusion of 1,200 mg/m(2) as a 120-min infusion on day 1, and S 1 was administered orally twice a day at a dose of 40 mg/m(2) on days 1-7. Cycles were repeated every 14 days. RESULTS: Sixty-one patients with GEM-refractory PC received FGS. Sixteen patients received FGS as third-line treatment. Twenty-nine patients (48 %) had a history of S-1 administration. The objective response rate was 13 %, and the disease control rate was 49 %. The median progression-free survival time was 2.7 months, and the median overall survival time was 6.0 months. Major Grade 3 or 4 adverse events included neutropenia (15 %), diarrhea (3 %), anorexia (2 %), and fatigue (2 %). A high inflammation-based prognostic score (modified Glasgow prognostic score (mGPS), which incorporates C-reactive protein and albumin), a performance status >0, and serum carbohydrate antigen 19 9 level >2,000 IU/ml were independently associated with a poor outcome. CONCLUSIONS: FGS might be effective and well tolerated as salvage chemotherapy in a practical setting. The inflammation-based prognostic score is a simple and reliable indicator of survival in the setting of salvage chemotherapy. PMID- 25547409 TI - Effect of Adeli suit treatment on gait in a child with cerebral palsy: a single subject report. AB - The purpose of this research report is to investigate the long-term effect of Adeli suit treatment (AST) in a child with cerebral palsy (CP) on spatial temporal gait parameters, 10-meter walking speed, gross motor functional measure (GMFM) and performance on the pediatric balance scale (PBS). An eight-year-old girl with spastic diplegia classified as level III on the Gross Motor Function Classification System participated in this single-subject A-B design study, with a baseline and an intervention phase. The baseline phase was collected at one week intervals for six weeks and then the AST intervention phase was carried out with 18 AST sessions, 50 min per session, once a week for an 18-week period. Spatial-temporal gait parameters significantly improved after the completion of 18 sessions. Furthermore, 10-meter walking speed, GMFM and PBS changed significantly from the baseline measurement (p < 0.05). In conclusion, the AST was effective in improving gait, gross motor function and balance in a child with diplegic CP. Clinically, neuro-rehabilitation with AST provided a complementary and alternative treatment for lower extremity rehabilitation in this child with CP. These findings provide preliminary evidence supporting the effectiveness of AST in children with spastic CP, and thus underscore the need for additional research in this area. PMID- 25547410 TI - IMF policy is blamed for contributing to Ebola epidemic. PMID- 25547408 TI - The Clinical Education Partnership Initiative: an innovative approach to global health education. AB - BACKGROUND: Despite evidence that international clinical electives can be educationally and professionally beneficial to both visiting and in-country trainees, these opportunities remain challenging for American residents to participate in abroad. Additionally, even when logistically possible, they are often poorly structured. The Universities of Washington (UW) and Nairobi (UoN) have enjoyed a long-standing research collaboration, which recently expanded into the UoN Medical Education Partnership Initiative (MEPI). Based on MEPI in Kenya, the Clinical Education Partnership Initiative (CEPI) is a new educational exchange program between UoN and UW. CEPI allows UW residents to partner with Kenyan trainees in clinical care and teaching activities at Naivasha District Hospital (NDH), one of UoN's MEPI training sites in Kenya. METHODS: UW and UoN faculty collaborated to create a curriculum and structure for the program. A Chief Resident from the UW Department of Medicine coordinated the program at NDH. From August 2012 through April 2014, 32 UW participants from 5 medical specialties spent between 4 and 12 weeks working in NDH. In addition to clinical duties, all took part in formal and informal educational activities. Before and after their rotations, UW residents completed surveys evaluating clinical competencies and cross-cultural educational and research skills. Kenyan trainees also completed surveys after working with UW residents for three months. RESULTS: UW trainees reported a significant increase in exposure to various tropical and other diseases, an increased sense of self-reliance, particularly in a resource limited setting, and an improved understanding of how social and cultural factors can affect health. Kenyan trainees reported both an increase in clinical skills and confidence, and an appreciation for learning a different approach to patient care and professionalism. CONCLUSIONS: After participating in CEPI, both Kenyan and US trainees noted improvement in their clinical knowledge and skills and a broader understanding of what it means to be clinicians. Through structured partnerships between institutions, educational exchange that benefits both parties is possible. PMID- 25547411 TI - Identifying tandem Ankyrin repeats in protein structures. AB - BACKGROUND: Tandem repetition of structural motifs in proteins is frequently observed across all forms of life. Topology of repeating unit and its frequency of occurrence are associated to a wide range of structural and functional roles in diverse proteins, and defects in repeat proteins have been associated with a number of diseases. It is thus desirable to accurately identify specific repeat type and its copy number. Weak evolutionary constraints on repeat units and insertions/deletions between them make their identification difficult at the sequence level and structure based approaches are desired. The proposed graph spectral approach is based on protein structure represented as a graph for detecting one of the most frequently observed structural repeats, Ankyrin repeat. RESULTS: It has been shown in a large number of studies that 3-dimensional topology of a protein structure is well captured by a graph, making it possible to analyze a complex protein structure as a mathematical entity. In this study we show that eigen spectra profile of a protein structure graph exhibits a unique repetitive profile for contiguous repeating units enabling the detection of the repeat region and the repeat type. The proposed approach uses a non-redundant set of 58 Ankyrin proteins to define rules for the detection of Ankyrin repeat motifs. It is evaluated on a set of 370 proteins comprising 125 known Ankyrin proteins and remaining non-solenoid proteins and the prediction compared with UniProt annotation, sequence-based approach, RADAR, and structure-based approach, ConSole. To show the efficacy of the approach, we analyzed the complete PDB structural database and identified 641 previously unrecognized Ankyrin repeat proteins. We observe a unique eigen spectra profile for different repeat types and show that the method can be easily extended to detect other repeat types. It is implemented as a web server, AnkPred. It is freely available at 'bioinf.iiit.ac.in/AnkPred'. CONCLUSIONS: AnkPred provides an elegant and computationally efficient graph-based approach for detecting Ankyrin structural repeats in proteins. By analyzing the eigen spectra of the protein structure graph and secondary structure information, characteristic features of a known repeat family are identified. This method is especially useful in correctly identifying new members of a repeat family. PMID- 25547412 TI - Influences of high-voltage electrical burns on the pulmonary microcirculation in rabbits. AB - This study was performed to investigate the effects of high-voltage electrical burns (HEB) on the pulmonary microcirculation in rabbits. Total of 120 rabbits were randomly divided into control and HEB group using a random number table. HEB model was developed with a voltage regulator and experimental transformer. Laser Doppler perfusion imager was utilized to monitor and quantify the blood perfusion in pulmonary microcirculation. The microvascular morphologic changes of the lung were observed using light microscopy and transmission electron microscope (TEM). The lung wet/dry weight ratio and the PaO2 were determined. The values of blood perfusion in rabbit pulmonary microcirculation in the HEB group were decreased at 5 min, but increased at 1 h after burn (P < 0.01) and then decreased gradually. Light microscopy reveals microthrombus formation in pulmonary venules and bleeding in venous capillaries in HEB group. We found the number of microvilli in the capillary endothelial cells decreased, the rough endoplasmic reticulum expanded and severe degranulation occurred, the mitochondrial cristae fused or disappeared, and severe edema surrounded the capillary endothelial cells by TEM. The values of lung wet/dry weight ratio were higher and the PaO2 were lower than that of before burn group (P < 0.01). These results demonstrated that microcirculatory disorders play a major role in the development of progressive lung damage after high-voltage electrical burns. PMID- 25547413 TI - Protective effects of 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors on oxidative modification of human low density lipoproteins in vitro. AB - It has been suggested that 2,3-diaryl-substituted indole-based cyclooxygenase-2 (COX-2) inhibitors (2,3-diaryl-indole coxibs) do not only appear as potent anti inflammatory agents but also show the ability to scavenge reactive oxygen species (ROS). This led to the hypothesis that 2,3-diaryl-indole coxibs also may act as potent inhibitors of oxidative modification of low-density lipoprotein (LDL), which is considered a key factor in atherogenesis. The aim of this study was to explore i) the reactivity of a series of new synthesized 2,3-diaryl-indoles with several well characterized LDL oxidation systems and ii) subsequent effects on an inflammatory/atherogenic microenvironment. The results demonstrate that under the present experimental conditions 2,3-diaryl-indoles showed potent ROS scavenging activity and were able to markedly inhibit LDL oxidation. Subsequently, this led to a substantial decrease of modified LDL uptake by scavenger receptors in THP-1 macrophages in vitro and in rats in vivo. Moreover, modified LDL-mediated monocyte/neutrophil adhesion to endothelial cells, macrophage NFkappaB activation, as well as macrophage and endothelial cell cytokine release was diminished in vitro. The reduction of modified LDL-induced atherogenic effects by antioxidant 2,3-diaryl-indole coxibs may widen the therapeutic window of COX-2 targeted treatment. PMID- 25547415 TI - Respiratory hospitalizations of children living near a hazardous industrial site adjusted for prevalent dust: a case-control study. AB - The Neot Hovav Industrial Park (IP), located in southern Israel, hosts 23 chemical industry facilities and the national site for treatment of hazardous waste. Yet, information about its impact on the health of local population has been mostly ecological, focused on Bedouins and did not control for possible confounding effect of prevalent dust storms. This case-control study examined whether living near the IP could lead to increased risk of pediatric hospitalization for respiratory diseases. Cases (n=3608) were residents of the Be'er Sheva sub-district aged 0-14 years who were admitted for respiratory illnesses between 2004 and 2009. These were compared to children admitted for non respiratory conditions (n=3058). Home addresses were geocoded and the distances from the IP to the child's residence were calculated. The association between hospitalization and residential distance from the IP was examined for three age groups (0-1, 2-6, 7-14) by logistic regressions adjusting for gender, socioeconomic status, urbanity and temperature. We found that infants in the first year of life who lived within 10 km of the IP had increased risk of respiratory hospitalization when compared with those living >20 km from the IP (adjusted odds ratio, OR=2.07, 95% confidence interval, CI: 1.19-3.59). In models with both distance from the IP and particulate matter with aerodynamic diameter <10 MUm (PM(10)) the estimated risk was modestly attenuated (OR=1.96, 95% CI: 1.09-3.51). Elevated risk was also observed for children 2-5 years of age but with no statistical significance (OR=1.16, 95% CI: 0.76-1.76). Our findings suggest that residential proximity to a hazardous industrial site may contribute to early life respiratory admissions, beyond that of prevailing PM(10). PMID- 25547414 TI - RTS,S vaccination is associated with serologic evidence of decreased exposure to Plasmodium falciparum liver- and blood-stage parasites. AB - The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood stage parasites remains unclear. We hypothesized that vaccination with RTS,S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood stage parasites that go undetected and untreated, which in turn boosts pre existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican children 6 months after receiving a full course of RTS,S (n = 291) versus comparator vaccine (n = 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual blood-stage antigens was significantly lower in RTS,S vaccinees, with the exception of only four antigens, including the RTS,S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS,S confers protection against clinical malaria by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible children during the subsequent 12-month follow-up period but were strongly associated with exposure. Together, these data provide insight into the mechanism by which RTS,S protects from malaria. PMID- 25547416 TI - Rapamycin attenuates aldosterone-induced tubulointerstitial inflammation and fibrosis. AB - BACKGROUND/AIM: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. METHODS: Uninephrectomized, Sprague Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 MUg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-alpha mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. RESULTS: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-beta1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-alpha mRNA expression and secretion in cultured HK-2 cells. CONCLUSIONS: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process. PMID- 25547417 TI - In vitro efficacy of various antibiotic combinations against Pseudomonas aeruginosa isolates. AB - OBJECTIVE: Pseudomonas aeruginosa is one of the leading causes of nosocomial infection. The present study tested the in vitro efficacy of ceftazidime or imipenem combined with amikacin, levofloxacin and colistin in P.aeruginosa isolates. METHODS: P.aeruginosa strains, isolated from clinical samples, were assessed for antibiotic susceptibility using the disc diffusion method. Antibiotic combination tests were performed using minimum inhibitory concentration (MIC) test strips and the sum of the Fractional Inhibitory Concentration (SigmaFIC) index was used to assess synergy. RESULTS: Out of 60 isolated P.aeruginosa strains, 100% were susceptible to colistin and 26.7% (16 strains) were multidrug resistant. MIC50 and MIC90 values were 2 and 32 ug/ml for imipenem; 1.5 and 24 ug/ml for ceftazidime; 3 and 8 ug/ml for amikacin; 0.38 and 32 ug/ml for levofloxacin; 1 and 1.5 ug/ml for colistin, respectively. Antagonism was not found in any of the antibiotic combinations tested. The amikacin ceftazidime combination was found to have a synergistic effect in 15% of the strains, but no synergistic effect was detected for other combinations. CONCLUSIONS: In Pseudomonas infection, alternative treatment options using different antibiotic combinations should be tested in vitro and findings should be confirmed by clinical studies. PMID- 25547418 TI - Water-induced blister formation in a thin film polymer. AB - A failure mechanism of thin film polymers immersed in water is presented: the formation of blisters. The growth of blisters is counterintuitive as the substrates were noncorroding and the polymer does not swell in water. We identify osmosis as the driving force behind the blister formation. The dynamics of the blister formation is studied experimentally as well as theoretically, and a quantitative model describing the blister growth is developed, which accurately describes the temporal evolution of the blisters. PMID- 25547419 TI - Intraparenchymal meningioma mimicking cavernous malformation: a case report and review of the literature. AB - INTRODUCTION: A primary intraparenchymal meningioma located in the subcortical region of the brain without a dural attachment is extremely rare. To the best of our knowledge, this is the first report showing that meningioma can mimic cavernous malformations. CASE PRESENTATION: We present the case of a 42-year-old German man who presented to our institution with seizure. Both computed tomography and magnetic resonance imaging scans showed characters of an intra axial subcortical lesion with a 'popcorn' appearance and hemosiderin deposits in the right parietal lobe. The initial diagnosis was cavernous malformation. Intraoperatively, the lesion presented as a subcortical mass that had no connection to the dura or the ventricle. The histological diagnosis showed a WHO Grade 1 'raddled' psammomatous meningioma with extensive metaplastic ossification. A literature review of 29 cases of intraparenchymal meningiomas regarding their clinical presentations, location and management was performed. CONCLUSIONS: Meningiomas can be found in any region of the brain with and without dural attachment. Intraparenchymal meningiomas can have multiple entities mimicking their presentation. Caution must be used regarding the preoperative differential diagnosis. PMID- 25547420 TI - Leukocytoclastic vasculitis due to duloxetine. PMID- 25547421 TI - Mood and anxiety disorders as early manifestations of medical illness: a systematic review. AB - BACKGROUND: Affective disturbances involving alterations of mood, anxiety and irritability may be early symptoms of medical illnesses. The aim of this paper was to provide a systematic review of the literature with qualitative data synthesis. METHODS: MEDLINE, PsycINFO, EMBASE, Cochrane, and ISI Web of Science were systematically searched from inception to February 2014. Search terms were 'prodrome/early symptom', combined using the Boolean 'AND' operator with 'anxiety/depression/mania/hypomania/irritability/irritable mood/hostility', combined with the Boolean 'AND' operator with 'medical illness/medical disorder'. PRISMA guidelines were followed. RESULTS: A total of 21 studies met the inclusion criteria and were analyzed. Depression was found to be the most common affective prodrome of medical disorders and was consistently reported in Cushing's syndrome, hypothyroidism, hyperparathyroidism, pancreatic and lung cancer, myocardial infarction, Wilson's disease, and AIDS. Mania, anxiety and irritability were less frequent. CONCLUSIONS: Physicians may not pursue medical workup of cases that appear to be psychiatric in nature. They should be alerted that disturbances in mood, anxiety and irritability may antedate the appearance of a medical disorder. PMID- 25547422 TI - Glycopyrronium bromide for the treatment of chronic obstructive pulmonary disease. AB - Glycopyrronium bromide is a new long-acting muscarinic antagonist to be used once daily, which is approved as a bronchodilator for the symptomatic maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD). In the Glycopyrronium bromide in chronic Obstructive pulmonary disease airWays trials, treatment with inhaled glycopyrronium bromide at 50 MUg once daily achieved a significantly better lung function than placebo, as measured by the trough forced expiratory volume in 1 s in patients with moderate-to-severe COPD. The lung function improvement was maintained for up to 52 weeks. Other improved indexes were dyspnea scores, health status, exacerbation rates and time of exercise endurance. Studies comparing the efficacy of glycopyrronium versus tiotropium bromide found substantial equivalence of the two drugs. Glycopyrronium was generally well tolerated. These data add inhaled glycopyrronium bromide to the treatment of patients with moderate to severe COPD as an effective once-daily LAMA. PMID- 25547423 TI - Blepharoconjunctivitis and an unusual location of metastatic breast carcinoma. PMID- 25547424 TI - Cervical Artery Dissection (CeAD) in physicians. PMID- 25547425 TI - Microcytic anemia in a pregnant woman: beyond iron deficiency. AB - Sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severity and the presence of ringed sideroblasts in bone marrow. The most common form of inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA). In many XLSA patients, anemia responds variably to supplementation with pyridoxine (vitamin B6). We describe the case of a pregnant female with XLSA who had a novel mutation on the ALAS2 gene (c.1218G > T, p.Leu406Phe). Oral chelation therapy was contraindicated and high-dose vitamin B6 would have possible side effects in pregnancy. Serum hepcidin level was very low, indicating increased absorption of iron secondary to ineffective erythropoiesis. Therapy was begun with a low dose of pyridoxine that was increased post-partum. The patient's liver showed moderate iron deposits. During a subsequent 3-month period of pyridoxine supplementation, serum ferritin level and transferrin saturation decreased, hemoglobin content and serum hepcidin level normalized, and morphologic red cell abnormalities improved markedly. The patient responded well to treatment, showing the pyridoxine responsiveness of this novel ALAS2 mutation. The baby girl had the same mutation heterozygously, and although she was neither anemic nor showed abnormalities in a peripheral blood smear, she had a mild increment in RDW and her condition is now being followed. PMID- 25547426 TI - Regioselective formation of 2,4,5-trisubstituted oxazoles through transition metal free heterocyclization of 1,3-diynes with N,O-bis(trimethylsiyl)acetamide. AB - Transition-metal free heterocyclization reaction of 1,3-diynes with N,O bis(trimethylsiyl)acetamide was accomplished in the presence of t-BuOK and acetonitrile at 120 degrees C. This method regioselectively gave 2,4,5 trisubstituted oxazoles in yields up to 97%. PMID- 25547427 TI - Dietary ALA, but not LNA, increase growth, reduce inflammatory processes, and increase anti-oxidant capacity in the marine finfish Larimichthys crocea: dietary ALA, but not LNA, increase growth, reduce inflammatory processes, and increase anti-oxidant capacity in the large yellow croaker. AB - Whilst aquaculture feed is increasingly formulated with the inclusion of plant oils replacing fish oil, and increasing research effort has been invested in understanding the metabolic effects of reduced dietary n-3 long chain poly unsaturated fatty acids (n-3 LC-PUFA), relatively little information is available on the potential direct metabolic roles of dietary alpha-linolenic acid (ALA, 18:3n-3) and alpha-linolenic acid/linoleic acid (LNA, 18:2n-6) ratio in cultured marine finfish species. In this study, four plant oil based diets, with varying ALA/LNA ratio (0.0, 0.5, 1.0 and 1.5) were fed to juvenile large yellow croakers (Larimichthys crocea) and compared to a fish oil-based control diet (CD) to evaluate the resulting effects on growth, nonspecific immunity, anti-oxidant capacity and related gene expression. High dietary LNA negatively impacted fish growth performance, nonspecific immunity and antioxidant capacity, but growth and immunity were maintained to levels comparable to CD by increasing the ratio of dietary ALA/LNA. The over-expression of genes associated with inflammation (cyclooxygenase-2 and interleukin-1beta) and fatty acid oxidation (carnitine palmitoyl transferase I and acyl CoA oxidase) in croakers fed high concentrations of LNA were reduced to levels comparable to those fed CD by increasing dietary ALA/LNA. This study showed that dietary ALA, by increasing the overall n-3/n-6 PUFA ratio, exerts direct anti-inflammatory and antioxidant effects, similar to those exerted by dietary n-3 LC-PUFA. PMID- 25547429 TI - Lipids: 50th anniversary celebration and the future. PMID- 25547428 TI - The safety and anti-hypercholesterolemic effect of coptisine in Syrian golden hamsters. AB - Current work was conducted to evaluate the cholesterol-lowering effect of coptisine extracted from Rhizoma coptidis in Syrian golden hamsters. The safety results indicated that coptisine was a safe and low-toxic compound. Coptisine showed a beneficial effect in the abnormal serum lipid levels induced by a high fat and high-cholesterol diet (HFHC): at a concentration of 70.05 mg/kg, coptisine significantly led to a decrease in total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-c) levels by 26.70, 15.38, and 22.22 %, respectively, and high-density lipoprotein cholesterol (HDL-c) was increased by 41.74 % in serum of hamsters (p < 0.01). In addition, total bile acid (TBA) levels in feces of hamsters were elevated after coptisine administration. Further investigation has suggested that the mRNA and protein expression of 3-hydroxy-3 methyl-glutaryl-CoA reductase (HMGCR) in the liver of hamsters was down-regulated by high-dosage coptisine treatment (p < 0.05); mRNA and protein expression of low density lipoprotein receptor (LDLR) and cholesterol 7alpha-hydroxylase (CYP7A1) were dramatically up-regulated by coptisine administration. The apical sodium dependent bile salt transporter expression was down-regulated in the coptisine treated animals, but showed no significant differences from the HFHC groups. Taken together, our results demonstrate that a high dosage of coptisine could inhibit cholesterol synthesis via suppressing the HMGCR expression and promoting the use and excretion of cholesterol via up-regulating LDLR and CYP7A1 expression. These findings suggest a critical role for coptisine in anti- hypercholesterolemia, and thus it needs to be considered as a potential natural cholesterol lowering agent. PMID- 25547430 TI - Activation of B-H, Si-H, and C-F bonds with Tp'Rh(PMe3) complexes: kinetics, mechanism, and selectivity. AB - The photochemical reactions of Tp'Rh(PMe3)H2 (1) and thermal reactions of Tp'Rh(PMe3)(CH3)H (1a, Tp' = tris(3,5-dimethylpyrazolyl)borate) with substrates containing B-H, Si-H, C-F, and C-H bonds are reported. Complexes 1 and 1a are known activators of C-H bonds, including those of alkanes. Kinetic studies of reactions with HBpin and PhSiH3 show that photodissociation of H2 from 1 occurs prior to substrate attack, whereas thermal reaction of 1a proceeds by bimolecular reaction with the substrate. Complete intramolecular selectivity for B-H over C-H activation of HBpin (pin = pinacolate) leading to Tp'Rh(PMe3)(Bpin)H is observed. Similarly, the reaction with Et2SiH2 shows a strong preference for Si-H over C-H activation, generating Tp'Rh(PMe3)(SiEt2H)H. The Rh(Bpin)H and Rh(SiEt2H)H products were stable to heating in benzene in accord with DFT calculations that showed that reaction with benzene is endoergic. The intramolecular competition with PhSiH3 yields a ~1:4 mixture of Tp'Rh(PMe3)(C6H4SiH3)H and Tp'Rh(PMe3)(SiPhH2)H, respectively. Reaction with pentafluoropyridine generates Tp'Rh(PMe3)(C5NF4)F, while reaction with 2,3,5,6-tetrafluoropyridine yields a mixture of C-H and C-F activated products. Hexafluorobenzene proves unreactive. Crystal structures are reported for B-H, Si-H, and C-F activated products, but in the latter case a bifluoride complex Tp'Rh(PMe3)(C5NF4)(FHF) was crystallized. Intermolecular competition reactions were studied by photoreaction of 1 in C6F6 with benzene and another substrate (HBpin, PhSiH3, or pentafluoropyridine) employing in situ laser photolysis in the NMR probe, resulting in a wide-ranging map of kinetic selectivities. The mechanisms of intramolecular and intermolecular selection are analyzed. PMID- 25547431 TI - Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections? AB - Investigators have hypothesized a range of subcortical neuropathology in the genesis of bilirubin-induced neurologic dysfunction (BIND). The current review builds on this speculation with a specific focus on the cerebellum and its connections in the development of the subtle neuromotor disabilities of BIND. The focus on the cerebellum derives from the following observations: (i) the cerebellum is vulnerable to bilirubin-induced injury; perhaps the most vulnerable region within the central nervous system; (ii) infants with cerebellar injury exhibit a neuromotor phenotype similar to BIND; and (iii) the cerebellum has extensive bidirectional circuitry projections to motor and non-motor regions of the brainstem and cerebral cortex that impact a variety of neurobehaviors. Future study using advanced magnetic resonance neuroimaging techniques have the potential to shed new insights into bilirubin's effect on neural network topology via both structural and functional brain connectivity measurements. PMID- 25547432 TI - Macular electroretinogram in Stargardt's disease/fundus flavimaculatus. PMID- 25547434 TI - AURKA is a predictor of chemotherapy response and prognosis for patients with advanced oral squamous cell carcinoma. AB - Increasing evidence proposes the benefits of cisplatin-based chemotherapy in a subpopulation of patients with oral squamous cell carcinoma (OSCC), yet reliable indicators for this subpopulation are poorly explored. AURKA, also known as aurora kinase A, playing important functions in cell mitosis and making cells resistant to cisplatin through dysregulation of DNA damage repair networks, has been reported to be upregulated in OSCC, making AURKA a promising indicator. In this study, we recruited 78 patients with advanced OSCC to examine the expression of AURKA and the correlation with chemotherapy response and clinical outcomes. We found that AURKA was strongly expressed in 31 (39.74 %) of the 78 advanced OSCC samples and its expression was significantly associated with cisplatin resistance (P = 0.023), clinical recurrence (P = 0.021), and 5-year survival (P = 0.019). Chemotherapy increased AURKA expression in post-chemotherapy samples, yet with no significance (P = 0.101). Multivariate Cox proportional hazards regression model analysis demonstrated that lymph node samples with positive, strong AURKA staining, and poor chemotherapy response were independently associated with the 5 year survival and disease-free survival. Inhibiting AURKA expression in OSCC cell lines remarkably increased their sensitivity to cisplatin treatment by 2.5-fold difference. Our results imply that the overexpression of AURKA in advanced OSCC not only plays a role in the disease course but also shows an involvement in cisplatin treatment response. AURKA level may be a valuable predictor for patients with advanced OSCC, with downregulation of AURKA being a promising adjuvant therapy in this patient population. PMID- 25547435 TI - HOTAIR enhanced aggressive biological behaviors and induced radio-resistance via inhibiting p21 in cervical cancer. AB - We previously reported the frequent overexpression of HOX Antisense Intergenic RNA (HOTAIR) in human cervical cancer, which was significantly correlated with tumor progression and poor prognosis. In the present study, we investigated the detailed biological functions of HOTAIR in cervical cancer. In vitro, upregulation of HOTAIR inhibited apoptosis and promoted cellular proliferation, cell cycle progression, migration, and invasion; on the contrast, downregulation of HOTAIR induced more apoptosis, suppressed cellular proliferation, cell cycle, migration, and invasion. Moreover, a high level of HOTAIR was notably associated with radio-resistance and downregulation of p21 in the primary cultured cervical cancer cells. Further, we demonstrated that elevated HOTAIR could induce radio resistance via inhibiting p21 in HeLa cells, while knockdown of HOTAIR upregulated p21 and consequentially increased the radio-sensitivity of C33A cells. Consistently, stable knockdown of HOTAIR significantly suppressed tumor growth and sensitized cervical cancer to radiotherapy in vivo. In conclusion, HOTAIR served as an onco-lncRNA in cervical cancer which could enhance various aggressive biological behaviors. Moreover, we proved that HOTAIR execute its functions mainly through inhibiting the p21 expression. These results proposed that targeting HOTAIR might be a potent therapeutic strategy in cervical cancer, especially for those patients who accepted radiotherapy. PMID- 25547433 TI - RKIP promotes cisplatin-induced gastric cancer cell death through NF-kappaB/Snail pathway. AB - The objectives of this study were to explore the expression profiles of Raf kinase inhibitor protein (RKIP) in human gastric cancer cell line (SGC-7901) and cisplatin-resistant cell line (SGC-7901/DDP) and investigate the role of RKIP in the sensitivity of human gastric cancer cells to cisplatin and its signaling pathways, with an attempt to identify new approaches and strategies for the management of gastric cancer. The human gastric cancer cell line (SGC-7901) and cisplatin-resistant cell line (SGC-7901/DDP) were separately cultured in vitro. The expression profiles of RKIP in these two cell lines were detected by Western blotting. Forty-eight hours after the transfection of RKIP siRNA in SGC-7901 cells, the change of RKIP expression in the cells was detected using Western blotting, and the change of cell viability after the interference of RKIP expression was determined using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide (MTT) method. The effect of the ectopic expression of RKIP on the cisplatin-induced viability of gastric cancer cell was detected using MTT method. The effect of the ectopic expression of RKIP on the cisplatin-induced apoptosis of gastric cancer cell was detected using flow cytometry after having been double stained with Annexin V/PI. The effect of the ectopic expression of RKIP on the NF-kappaB and Snail expressions in cisplatin-induced gastric cancer cells was detected using Western blotting. As shown by the Western blotting, the expression of RKIP in SGC-7901/DDP cells significantly decreased when compared with that in SGC-7901 cells (P < 0.05). Compared with the control group, the expression of RKIP in SGC-7901 cells significantly decreased 48 h after the transfection of RKIP siRNA (P < 0.01). After the SGC-7901 cells were transfected with RKIP siRNA, the cell viability was significantly increased (P < 0.05); after the SGC-7901/DDP cells were transfected with RKIP recombinant plasmid, the cell viability was significantly decreased (P < 0.05). After the RKIP expression was suppressed in the cisplatin-treated SGC-7901 cells, the cell viability significantly increased (P < 0.05), and the amount of apoptotic cells significantly decreased (P < 0.05). In contrast, after the RKIP overexpression in the cisplatin-treated SGC-7901/DDP cells, the cell viability significantly decreased (P < 0.05), and the amount of apoptotic cells significantly increased (P < 0.05). The suppression of RKIP expression in SGC-7901 cells could significantly promote the increase of NF-kappaB expression (P < 0.05); in contrast, the increased expression of RKIP in SGC-7901/DDP cells significantly inhibited the expression of Snail (P < 0.05). The expression of RKIP is downregulated in cisplatin-resistant cell line (SGC-7901/DDP). The overexpression of RKIP can enhance the sensitivity of human gastric cancer cells to cisplatin, which may be achieved via the NF-kappaB/Snail signaling pathway. PMID- 25547436 TI - Calcitriol induced redox imbalance and DNA breakage in cells sharing a common metabolic feature of malignancies: Interaction with cellular copper (II) ions leads to the production of reactive oxygen species. AB - Calcitriol is known to selectively kill malignant cells, however, not much is known about the mechanism by which it kills malignant cells and spares the "normal" cells. Since elevation of cellular copper is a metabolic condition common to all malignancies, we developed a mouse model to mimic this condition and treated the animals with calcitriol. It was observed that calcitriol-copper interaction in vivo causes severe fluctuations in cellular enzymatic and nonenzymatic scavengers of reactive oxygen species (ROS). Lipid peroxidation, a well-established marker of oxidative stress, was found to increase, and a substantial cellular DNA breakage was observed. Calcitriol-copper interaction in vivo was observed to lead the cells to an apoptosis like cell death. We propose that the interaction of calcitriol and copper within malignant cells and the consequent redox scavenger fluctuations and ROS-mediated DNA breakage may be one of the several mechanisms by which calcitriol causes selective cell death of malignant cells, while sparing normal cells. PMID- 25547437 TI - Report of the WPA section of pharmacopsychiatry on the relationship of antiepileptic drugs with suicidality in epilepsy. AB - INTRODUCTION: This report from the World Psychiatric Association Section on Pharmacopsychiatry examines the possible relationship of antiepileptic drugs with suicide-related clinical features and behaviors in patients with epilepsy. MATERIALS AND METHODS: A systematic review of the MEDLINE search returned 1039 papers, of which only 8 were considered relevant. A critical analysis of the Food and Drug Administration (FDA) report on the increase risk for patients under antiepileptics to manifest suicidality is also included in this report. RESULTS: The analysis of these studies revealed that the data are not supportive of the presence of a "class effect" on suicide-related behavior; on the contrary, there are some data suggesting such an effect concerning treatment with topiramate, lamotrigine, and levetiracetam for which further research is needed. DISCUSSION: For the majority of people with epilepsy, anticonvulsant treatment is necessary and its failure for any reason is expected to have deleterious consequences. Therefore, clinicians should inform patients and their families of this increased risk of suicidal ideation and behavior, but should not overemphasize the issue. Specific subgroups of patients with epilepsy might be at a higher risk, and deserve closer monitoring and follow-up. Future research with antiepileptics should specifically focus on depression and suicidal thoughts. PMID- 25547438 TI - "Long-acting" olanzapine in maintenance therapy of schizophrenia: A study with plasma levels. AB - INTRODUCTION: This prospective study was performed to evaluate clinical efficacy and tolerability of olanzapine long-acting injection (OLZ-LAI) and the relation between OLZ plasma level (PL) and the clinical outcome in maintenance therapy of schizophrenia. MATERIAL AND METHODS: Twenty-five chronic schizophrenic outpatients with age ranging from 18 to 65 years were included in this 9-month study. Patients were given a dosage of either 210 or 300 or 405 mg of OLZ-LAI every 28 days. Patients were evaluated at baseline and every four weeks by Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Symptom Scale (PANSS); at the same time, PL of OLZ was determined. The metabolic profile (aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein, low-density lipoprotein, total cholesterol, and glucose levels) was analyzed every two months. RESULTS: BPRS and total PANSS showed a statistically significant improvement from T2 with a clinical stabilization of psychopathological picture. PL ranged from 4.0 to 78.9 ng/ml (mean 20.59 ng/ml +/- 14.66 standard deviation). The coefficient of variation of PLs was related to clinical stabilization. No post-injection delirium sedation syndrome occurred. CONCLUSIONS: Our data reveal the efficacy of OLZ-LAI in maintenance treatment of schizophrenia at lower dosages also in comparison with that of oral therapy. OLZ-LAI seems to be useful for guaranteeing constant PL of the drug. A lesser variation of PL was the most predictable factor associated with maintenance of clinical benefit. PMID- 25547439 TI - Religiousness and spirituality in patients with bipolar disorder. AB - BACKGROUND: Religiousness and spirituality (R/S) are often neglected features among psychiatric patients but important both for quality of life and coping strategies for mental disorders. In patients affected by bipolar disorder (BD), R/S can sometimes be confused with symptoms related to the psychiatric disorder. This study aimed to perform a clinical review of the relationship between R/S and BD. METHODS: Data sources included Medline (OvidSP), CINAHL (Ebsco), EMBASE (Ovid), PsychINFO (Ebsco), Angeline, Cochrane Database of Systematic Reviews and Database of Abstract of Reviews of Effects, searching for pertinent Keywords: 'religiousness', 'spirituality' and 'bipolar disorder'. RESULTS: Nine works were found but only five used homogeneous samples with BD patients. R/S were important when facing symptoms and relapses in the lifeworld. These beliefs influenced the relationship with psychiatrists and spiritual figures of reference. CONCLUSIONS: R/S play a role as a psychosocial variable in the course of BD. However, the hypothesis that the R/S factor can be relevant both in terms of providing a protective effect as well as a provocative element in depressive or hypomanic phases was not fully supported at the moment. PMID- 25547440 TI - Towards a pragmatic and operational definition of relapse in schizophrenia: A Delphi consensus approach. AB - OBJECTIVE: To develop pragmatic and operational definitions of relapse in schizophrenia. METHODS: A two-round Delphi consensus approach was used. The final questionnaire based on seven pre-established definition relapse models developed by a panel of eight experts was presented to 33 general psychiatrists who attended an "ad hoc" meeting. RESULTS: The most frequent components of the pragmatic definition were the psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), and impairment in functioning and social behavior (67%). In the operational definition, reappearance of symptoms was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was considered recommendable by 67%. Between 46% and 53% rated worsening of severity status and worsening of functioning as indispensable or recommendable. An increase of >= 10 points in the positive subscale of Positive and Negative Symptom Scale was rated by 51% of the participants, a score of 6 points in the Clinical Global Impression scale (much worse) by 89%, and a reduction of >= 20 points in the Global Assessment of Functioning scale by 62%. CONCLUSIONS: A better understanding of the definition of relapse in schizophrenia is necessary to improve effective prevention strategies. PMID- 25547441 TI - [The 30th anniversary of percutaneous coronary intervention in China: history and future prospective]. PMID- 25547442 TI - [Comprehensive prevention and treatment of infective endocarditis by implement consensus]. PMID- 25547443 TI - [Expert consensus on the prevention, diagnosis, and treatment of infective endocarditis in adults]. PMID- 25547444 TI - [The impact of pre-primary percutaneous coronary intervention beta blocker use on the no-reflow phenomenon in patients with acute myocardial infarction]. AB - OBJECTIVE: To investigate the impact of pre-primary percutaneous coronary intervention (PCI) beta blocker use on the development of no-reflow in ST-segment elevation myocardial infarction (STEMI) patients post PCI. METHODS: We retrospectively evaluated 1 615 outpatients with STEMI who underwent primary primary PCI with in 12 hours from symptom onset admitted to Beijing Anzhen Hospital and Chinese people's liberation army general hospital from January 2007 to June 2011. The study population was divided into the following 2 groups: beta blocker group (pretreatment with beta blockers >= one month before admission, n = 257) and non-beta blockers group (pretreatment with beta blockers < one month before admission or had no beta blocker, n = 1 358). No-reflow was defined as TIMI grade < 3 in last imaging of coronary artery after stenting. Multivariable logistic regression analyses were used to identify independent predictors for the no-reflow after primary PCI. RESULTS: Incidence of the no-reflow was significantly lower in the beta blocker group than in non-beta blockers group (13.6% (35/257) vs. 21.2% (289/1 358), P = 0.017). Multivariable logistic regression analysis revealed that pre-PCI beta blocker use was a protective predictor of the no-reflow (OR = 0.594, 95%CI:0.394-0.893, P = 0.012), while age >= 55 years old (OR = 2.734, 95%CI:1.959-3.817, P < 0.001), high neutrophil count (OR = 1.257, 95%CI: 1.169-1.351, P < 0.001), admission plasma glucose (OR = 1.060, 95%CI:1.018-1.103, P = 0.004), Killip classes IV (OR = 3.383, 95%CI:1.924 5.948, P < 0.001) and reperfusion time >= 4 h(OR = 1.503, 95%CI:1.124-2.009, P = 0.006) were risk factors for the development of no-reflow post PCI. CONCLUSION: Previous long term beta blockers use before STEMI is associated with lower incidence of no-reflow in patients with STEMI treated with primary PCI. PMID- 25547445 TI - [Pulmonary vein stenting for the treatment of severe pulmonary vein stenosis after catheter ablation of atrial fibrillation]. AB - OBJECTIVE: To evaluate the feasibility, safety, and effectiveness of pulmonary vein stenting in patients with severe pulmonary vein stenosis (PVS) after catheter ablation of atrial fibrillation (AF). METHODS: This retrospective analysis included 5 PVS patients (3 males, (54.1 +/- 11.2) years old) confirmed by computed tomography angiography after catheter ablation of AF in Shanghai Chest Hospital from April 2010 to April 2013. After selective pulmonary vein angiography, stents were implanted in the pulmonary vein. Operation results were analyzed after the procedure. RESULTS: All of 14 serious pulmonary vein stenosis from these 5 patients were treated with primary stent implantation (diameter: 7 or 8 mm, length: 12-23 mm). After stenting, degree of pulmonary vein stenosis decreased from (83 +/- 16) % to (12 +/- 4) % (P < 0.01), the minimal diameter of the stenosis was significantly increased from (1.7 +/- 0.6) mm to (8.1 +/- 0.7) mm (P < 0.01), trans-stenotic gradient decreased from (15 +/- 5) mmHg (1 mmHg = 0.133 kPa) to (3 +/- 2) mmHg (P < 0.05), mean pulmonary pressure measured by cardiac catheter decreased from (47 +/- 5) mmHg to (28 +/- 4) mmHg (P < 0.05). Dyspnea was improved after the procedure. There was no serious operation related complications. Six months after stenting, three patients still complained mild to moderate dyspnea, and in-stent restenosis was evidenced in seven pulmonary veins by computed tomography angiography. These stenosis was successfully dilated by repeated interventions with balloon dilation. CONCLUSIONS: Stenting for severe pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation may be feasible and safe, and can improve hemodynamics and symptoms. In-stent stenosis is relatively frequent, and larger stents and early intervention may reduce the rates of in-stent restenosis. PMID- 25547446 TI - [Clinical efficacy and outcome of endovascular therapy for complex arteriosclerosis obliterans of the lower extremities]. AB - OBJECTIVE: To evaluate efficacy and outcome of endovascular therapy for complex arteriosclerosis obliterans of the lower extremities. METHODS: In this single center retrospective study, the clinical data of consecutive 114 cases with TASC II type C/D lower extremity obstructive disease and clinical stage of Fontaine >= IIb and ankle brachial index <0.9 underwent endovascular therapy from December 2011 to January 2013 were collected. Telephone or clinic interviews were conducted to investigate the clinical outcomes. RESULTS: There were 39 TASC II type C patients and 75 TASC II type D patients, 78 patients were in Fontaine IIb, 30 patients in Fontaine III and 6 patients in Fontaine IV stages. Immediate procedural success rate was 94.9% (131/138). Ankle brachial index was increased from 0.54 +/- 0.26 at baseline to 0.83 +/- 0.30 at discharge (P < 0.01). No adverse event was observed during the perioperative period. During (15.7 +/- 8.7) months follow-up, cumulative patency rate of 6, 12 and 18 months was 75.8% (94/124) , 68.7% (68/99) and 39.2% (20/51) respectively and limb salvage rate was 100%. CONCLUSION: Endovascular therapy for complex arteriosclerosis obliterans of the lower extremities is effective and safe. PMID- 25547448 TI - [Prevalence and risk factors of arrhythmias after transcatheter closure of ventricular septal defect in children]. AB - OBJECTIVE: To evaluate the prevalence and risk factors of arrhythmia after transcatheter closure of ventricular septal defect (VSD) in children. METHODS: A total 1 069 children (583 males, mean age (7.7 +/- 3.6) years) underwent transcatheter closure of VSD from January 2002 to December 2010 in our hospital were enrolled and retrospectively analyzed.VSD diameters were (4.0 +/- 1.8)mm, 336 cases accompanied membranous aneurysm. Electrocardiogram were performed at 1, 3 days after the procedure.Once arrhythmias recorded, electrocardiogram was performed daily till discharge. All cases were followed up by ECG at 1, 3, 6, 12 months after the procedure in outpatient department and then in a year interval. The risk factors were identified by multivariable logistical analysis. RESULTS: All VSDs were closed successfully and the diameters of occluder was (7.2 +/- 2.1)mm. The median follow-up time was 2.2 (1.0-4.2) years. Mortality was zero during follow up.Incidence of early ( < 1 month) post-procedure arrhythmias was 24.6 % (263 cases), and severe arrhythmias were recorded in 50 cases (4.7%). There were 43 late ( >= 1 month) post-procedure arrhythmias (4.0%) including 4 (0.4%) complete atrioventricular block. Multivariable logistic analysis revealed that VSD treated with thin-waist-big-side occluder (OR = 2.426, 95%CI:1.835 3.208, P < 0.001) , male gender (OR = 1.267, 95%CI:1.055-1.523, P = 0.011) were the risk factors while higher body weight (OR = 0.838, 95%CI:0.737-0.951, P = 0.006) was protective factor for early onset arrhythmia. Placement of asymmetrical occluder (OR = 4.777, 95%CI:2.079-10.978, P < 0.001) , longer procedure time (OR = 1.011, 95%CI:1.002-1.020, P = 0.012) , occluder from foreign countries (OR = 2.621, 95%CI:1.143-6.014, P = 0.021) were the risks factors for early onset severe conduct block. Treatment with thin-waist-big-side occluder (OR = 2.654, 95%CI: 1.042-6.760, P = 0.041) was the risk factor while higher body weight (OR = 0.373, 95%CI:0.159-0.875, P = 0.023) was a protective factor for late onset conduct block. CONCLUSIONS: Arrhythmia after transcatheter closure of VSD is common in children, and late onset severe conduct block is rare. The weight of patients should not too light and symmetrical occluder should be chosen if possible in the transcatheter closure VSD procedure to minimize the risk of late onset conduct block. PMID- 25547447 TI - [Value of preoperative assessment on transcatheter aortic valve implantation procedure with high-pitch dual-source computed tomography angiography]. AB - OBJECTIVE: To evaluate the value of preoperative assessment on transcatheter aortic valve implantation (TAVI) procedure with high-pitch dual-source computed tomography angiography (CTA). METHODS: Seventeen consecutive patients with severe symptomatic aortic stenosis underwent TAVI in our department from December 2012 to December 2013 were examined by 128-slice prospective ECG-triggered high-pitch spiral CTA and the clinical data were analyzed. Aortic annulus, sinus of Valsalva, sinotubular junction, ascending aorta and native leaflet to coronary ostium length were measured. Peripheral vascular access was evaluated. Then the patients were assessed on the suitability for TAVI procedure and prosthetic valve sizes. RESULTS: Mean diameter of the aortic annulus was (25.7 +/- 2.0) mm, perimeter mean diameter was (26.4 +/- 2.0) mm, area mean diameter was (25.4 +/- 1.9) mm. Mean diameter of sinus of Valsalva was (34.0 +/- 3.8) mm. Mean diameter of sinotubular junction was (30.5 +/- 3.2) mm. Mean diameter of ascending aorta was (37.8 +/- 2.8) mm. The length from native leaflet to left coronary ostium was (14.0 +/- 2.0) mm, and the length from native leaflet to right coronary ostium was (15.9 +/- 3.6) mm. Mean diameter of left iliac arteries was (7.5 +/- 1.4) mm. Mean diameter of right iliac arteries was (7.4 +/- 1.2) mm. Mean diameter of left femoral arteries was (7.4 +/- 1.2) mm. Mean diameter of right femoral arteries was (7.3 +/- 1.3) mm. One patient was considered ineligible for TAVI because of large aortic annulus diameter. Three patients died prior to TAVI. Two patients refused to undergo TAVI. Eleven patients underwent TAVI, 26# prosthetic valve was implanted in 1 patient, 29# prosthetic valve implanted in 6 patients, 31# prosthetic valve implanted in 4 patients. Prosthetic valve implantation was successful in 9 patients and only mild or trace perivalvular leakage was observed in these patients. Moderate perivalvular leakage were observed in 2 patients because of the location of implantation was too low, and perivalvular leakage was significantly reduced after re-implantation with same size prosthetic valve at a higher location. CONCLUSIONS: CTA can be used to evaluate the aortic root anatomy and vascular access, and help to choose the right size of prosthetic valve. CTA has an important practical value in preoperative screening of TAVI procedure. PMID- 25547449 TI - [Frequency and predictors of recovery of normal left ventricular ejection fraction and end-diastolic diameter in patients with dilated cardiomyopathy]. AB - OBJECTIVE: To observe the frequency and predictors of recovery of normal left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD) in patients with dilated cardiomyopathy (DCM). METHODS: A consecutive cohort of 296 patients with DCM were reviewed and followed up for at least 12 months or to death or cardiac transplantation, to identify those with recovery of normal LVEF, defined as LVEF >= 50%, or recovery of normal LVEDD, defined as LVEDD <= 55/50 mm for male/female, or both by follow up echocardiography.Variables regarded as potentially relevant to left ventricular function and dimension recovery were evaluated to identify predictors using multivariable logistic regression analysis. RESULTS: After a median follow-up of 28 months, normal LVEF was evidenced in 81 patients (27.4%), normal LVEDD was found in 63 patients (21.3%) and both parameters were recovered in 52 patients (17.6%), LVEF was increased from (31.7 +/- 6.3)% to ( 57.5 +/- 5.2)% (P < 0.01) and LVEDD decreased from (62.7 +/- 4.3) mm to (50.2 +/- 3.7) mm (P < 0.01) in these 52 patients. Multivariable logistic regression analysis showed that shorter symptom duration, higher systolic blood pressure at admission, smaller LVEDD and lower LVEF by echocardiography at baseline were independent predictors of subsequent recovery of normal LVEF and LVEDD. CONCLUSION: Current therapy for heart failure could lead to recovery of normal LVEF and LVEDD in part of DCM patients, especially for DCM patients with short symptom duration, higher systolic blood pressure at admission, less enlarged LVEDD and less reduced LVEF at baseline echocardiography. PMID- 25547450 TI - [Myocardial changes in heart transplantation recipients with primary restrictive cardiomyopathy]. AB - OBJECTIVE: To investigate the histopathological features of primary restrictive cardiomyopathy (PRCM). METHODS: Nine extransplanted hearts from heart transplantation recipients were examined. Gross and histopathological findings were observed, photographed and final pathological diagnosis was compared to clinical diagnosis. The myocardial ultrastructure changes were determined using transmission electron microscopy. RESULTS: The hallmark pathologic feature of PRCM was distinguished by myocardial cell degeneration and hyperplastic collagen fibrils around the myocardial cells.Fibrosis was severer in left ventricle free wall than in ventricular septum and right ventricle. The degree of myocardial cell degeneration and poloidal disorder were severer in patients with reduced ejection fraction (EF) than in patients with preserved EF. Transmission electron microscope evidenced severe interstitial fibrosis, myofibrillar changes of sarcomere structure, abnormalities both on intercalated disc number and distribution. CONCLUSIONS: PRCM is characterized by hyperplastic collagen fibrils around the cardiomyocytes. Fibrosis is severer in left ventricle than in right ventricle. Sarcomere dysplasia is the main cause of PRCM, and ultrastructural examination is helpful for PRCM diagnosis. PMID- 25547451 TI - [Impact of resting heart rate on the progression to hypertension in prehypertension patients]. AB - OBJECTIVE: To observe the effect of resting heart rate (RHR) on the progression to hypertension in patients with prehypertension. METHODS: People who participated the physical examination between 2006 and 2007 at Kailuan medical group and diagnosed as prehypentension were selected as the observation cohort. The second and the third physical examination were conducted between 2008 and 2009 and between 2010 and 2011. The observation population was divided into five groups according to the different levels of RHR at baseline: the first group ( <=69 beats/min), the second group (70-74 beats/min), the third group (75-79 beats/min), the fourth group (80-84 beats/min) and the fifth group ( >=85 beats/min). The rate of the progression to hypertension was compared among five groups, and the relationship between RHR and the progression to hypertension was estimated using Cox proportional hazard analysis. RESULTS: A total of 34 512 patients with prehypentension were recruited and 25 392 patients were involved in the final statistics after excluding patients who died or were lost to follow-up. A total of 13 228 (52.1%) patients with prehypentension developed hypertension during follow-up. The rate of the progression to hypertension increased with the RHR (first group: 51.2%, second group: 50.1%, third group: 52.9%, fourth group: 53.5%, fifth group: 57.5%). Multiple Cox regression models showed that the risk of the progression to hypertension increased with the RHR levels. Patients in the fifth group carried 1.25 times higher risk for developing hypertension than patients in the second group after adjustment for age, gender, systolic blood pressure, diastolic blood pressure, waist circumference, body mass index, triglyceride, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, fasting blood glucose, serum uric acid, C reactive protein, smoking, drinking, physical exercise and family history of hypertension at baseline. CONCLUSION: Elevated RHR is an independent risk factor for the progression to hypertension in patients with prehypertension. PMID- 25547452 TI - [kappa-opioid receptor agonist U50, 488H attenuates myocardial ischemia reperfusionvia modulating Toll-like receptor 4/nuclear factor-kappaB signaling in rat]. AB - OBJECTIVE: To observe the effects of kappa-opioid receptor agonist U50, 488H on myocardial ischemia and reperfusion injury and related mechanism. METHODS: Rats were randomly divided into sham operation, myocardial ischemia and reperfusion(I/R, 30 min ischemia followed by 120 min reperfusion), and MI/R+U50, 488H (1.5 mg/kg) and I/R+U50, 488H+ selective kappa-opioid receptor antagonist Nor-BNI (2 mg/kg, n = 8 each). The infarction size and the incidence of ventricular arrhythmias were observed.Real-time PCR and DAB staining were used to define the myocardium Toll-like receptor 4(TLR4) expression. Myeloperoxidase level, TNF-alpha induction and the expression of NF-kappaB were also examined in rats. RESULTS: After I/R, the expressions of myocardial TLR4 and NF-kappaB increased significantly both in ischemia area and area at risk. Compared with I/R, kappa-opioid receptor stimulation with U50, 488H significantly attenuated the expressions of TLR4 and NF-kappaB and reduced myeloperoxidase (MPO) levels, myocardial TNF-alpha production, myocardial infarct sizes and the incidence of ventricular arrhythmias and arrhythmia score (2.9 +/- 0.7 vs. 4.4 +/- 0.9, P < 0.05) , above effects of U50, 488H were partly abolished by co-treatment with Nor BNI. CONCLUSION: These data provide evidence for the first time that kappa-opioid receptor stimulation could attenuate myocardial I/R injury via downregulating TLR4/NF-kappaB signaling in rats. PMID- 25547454 TI - [Successful coronary intractable thrombus aspiration with sub-5 F catheter in three patients]. PMID- 25547453 TI - [Experimental study of transcatheter aortic valve implantation assisted with snare to fix the delivery system]. AB - OBJECTIVE: To evaluate the feasibility and effectiveness of transcatheter aortic valve implantation assisted with snare to fix the delivery system. METHODS: This study was made in 5 healthy goats. After the abdomen was opened and the abdominal aorta was exposed, a stiff guide wire was advanced into the apex of the left ventricle through abdominal arterial puncture points. The delivery catheter equipped with valved stent was inserted into the descending aorta under fluoroscopy along the stiff guide wire. A minimal thoracic surgery approach was used to access the apex of the heart. A J-type guidewire and 5 F multifunction catheter were placed transapically and across the aortic valve down to the descending aorta. The snare was introduced through the 5 F catheter into the ascending aorta and was controlled to seize the head of stent delivery catheter. Then the delivery catheter was advanced into the left ventricle. The valved stent was positioned in the desired position under aortography and then the balloon was dilated and the valved stent was deployed into the aortic annulus assisted with snare to fix the catheter to prevent stent dispositions. Aortic angiography and echocardiography were performed to evaluate of valve performance post procedure. RESULTS: The interventional procedure was completed successfully in all 5 goats. The mean aortic annulus diameter was (23.8 +/- 2.6) mm, two valved stent of 23 mm diameter and three valved stent of 26 mm in diameter were implanted. The operation duration and X-ray exposure time were (112.3 +/- 19.5) min and (16.8 +/ 5.2) min, respectively. Immediate observation after procedure showed that the valved stents were in the desired position after implantation by angiography and echocardiography. No moderate to severe aortic regurgitation was observed. All goats were alive at 1 month post procedure. CONCLUSIONS: The procedure of transcatheter implantation of a balloon-expandable valved stent into the aortic valve position of goats assisted with snare to fix the delivery catheter is feasible and effective. This procedure might be suitable also for patients with noncalcified aortic stenosis. PMID- 25547455 TI - [Recent advances on the role of cytophagy in atherosclerotic plaques]. PMID- 25547456 TI - [Progress on the genetics of calcific aortic valve disease]. PMID- 25547457 TI - Patient experiences at diagnosis and psychological well-being in prostate cancer: A Finnish national survey. AB - PURPOSE: Most cases of prostate cancer are diagnosed at an early stage, and men live for many years after diagnosis. Thus, their well-being and quality of life are of great importance. This study investigated patient experiences and psychological well-being in a Finnish national sample of prostate cancer patients who received various types of treatment. METHOD: In a national sample (50%) of prostate cancer patients diagnosed in Finland in 2004, information was collected on the patients' experiences at diagnosis and choice of treatment (e.g. treatment selection, patient satisfaction with care and information, psychological reactions). In 2009, participants were asked about their experiences, and psychological well-being (psychological symptoms, satisfaction with life) was measured. In total, 1239 completed questionnaires (73%) were accepted for the study. Differences between treatments and predictors of psychological well-being were investigated using descriptive statistics and regression analysis. RESULTS: Half of the respondents were satisfied with the care and information they received about the cancer and side effects of treatment. Experiences and psychological well-being were most positive among patients who received brachytherapy and poorest among patients who received hormonal therapy. Patients who underwent prostatectomy or brachytherapy were most likely to have been involved in treatment selection. Negative experiences, such as learning of the diagnosis in an impersonal way and dissatisfaction with the information and care received, were predictive of poorer well-being. CONCLUSIONS: Unmet supportive care and informational needs were common. Experiences and well-being varied between treatments. Patients tended to prefer prostatectomy and brachytherapy. Unmet needs, which would probably be reduced by improvements in care, appear to have a long-lasting impact on patients' psychological well-being. PMID- 25547458 TI - Comorbid diseases in aspirin-exacerbated respiratory disease, and asthma. AB - BACKGROUND: Asthma, persistent rhinosinusitis, and/or nasal polyposis accompanying non-steroidal anti-inflammatory drug (NSAID) intolerance is defined as aspirin-exacerbated respiratory disease (AERD). Although the literature includes considerable data on comorbidities in asthma, data on comorbidities in AERD have not been previously published. OBJECTIVE: This study aimed to determine the prevalence of comorbidities in AERD and compare the findings to those in asthmatic patients. MATERIALS AND METHODS: The records for 330 AERD patients that presented to our allergy clinic were reviewed. Patients with urticaria/angio oedema type reactions to NSAIDs were included in the pseudo Samter's group (n=83) and 338 randomly selected NSAID-tolerant asthma patients constituted the control group. RESULTS: Gender, age at presentation, age at onset of asthma, and follow up periods were similar in all groups. Hypertension (P=0.035), diabetes mellitus (P=0.323), gastro-oesophageal reflux (P<0.001), psychological disorders (P=0.099), obesity (P=0.003), and hyperlipidaemia (P=0.002) were significantly more prevalent in the asthma group. Interestingly, coronary artery disease (CAD) and congestive heart failure (CHF) were more common in the AERD group (P=0.178); CAD/CHF was associated with AERD (OR: 4.5; 95% CI: 1.206-16.93). CONCLUSION: AERD and asthma are associated with several comorbidities. Even though systemic steroid dependency and severe asthma were significantly more common in the AERD group, comorbidities occurred more frequently in the asthma group. Additional longitudinal studies are needed to more clearly discern if the risk of CAD/CHF is increased in AERD. PMID- 25547459 TI - Development and application of PI3K assays for novel drug discovery. AB - INTRODUCTION: Phosphoinositide 3-kinases (PI3Ks) constitute one of the most important signaling pathways, playing a vital role in cellular differentiation and proliferation with a key function in cellular receptor triggered signal transduction downstream of tyrosine kinase receptors and/or G-protein coupled receptors. PI3K promotes cell survival proliferation, protein synthesis and glucose metabolism by generating secondary messengers phospholipid phosphatidyl 3,4,5-triphosphate and signaling via AKT/mTOR regulation. Deregulation of PI3K pathways have been observed in cancer, diabetes, neurological and inflammatory diseases and is an attractive target for pharmaceutical industries. AREAS COVERED: In this review, the authors explain different PI3K assay methodologies. Furthermore, the authors summarize the techno-scientific principles and their utility in profiling novel chemical entities against PI3Ks. Specifically, the authors compare different PI3K assay formats explaining their mode of detection as well as their advantages and limitations for drug discovery efforts. EXPERT OPINION: Developing lipid (PI3K) kinase assays involves significant effort and a rational understanding is needed due to the intrinsic lipidic nature of phospholipid phosphatidyl 4,5-biphosphate, which is used as an in vitro substrate for assays with PI3K isoforms. The assay of choice should be versatile, homogenous and definitely adaptable for high-throughput screening campaigns. Additionally, these assays are expected to dissect the mechanism of action of novel compounds (inhibitor characterization) against PI3K. Existing methods provide the versatility to medicinal chemists such that they can choose one or more assay platform to progress their compounds while profiling and/or inhibitor characterization. PMID- 25547460 TI - Increased fibroblast proliferation and activity after applying intense pulsed light 800-1200 nm. AB - BACKGROUND AND OBJECTIVES: Light devices emitting near infrared have been shown to be highly effective for the skin rejuvenation but biochemical and molecular mechanism or optimum dose treatment are not well-known. In our study we try to elucidate why systems emitting near infrared produce skin improvement such as fibroblasts proliferation, increase in gene expression or extracellular matrix (ECM) protein production. STUDY DESIGN/MATERIALS AND METHODS: 1BR3G human skin fibroblasts were used to test the effects of an intense pulsed light device emitting with an 800-1200 nm filter (MiniSilk FT manufactured by Deka((r))). In our protocol, fibroblasts were irradiated twice successively with a 10 Hz frequency, with a total fluence up to 60 J/cm(2) for 15s each pass. After incubating for 48 h, fibroblasts were harvested from the culture plates to test cell proliferation by flow cytometer. To determine changes in gene expression (mRNA levels for collagen types I and III and metalloproteinase 1 (MMP-1)) and protein production (hyaluronic acid, versican and decorin) tests were performed after irradiation. RESULTS: After 48 h irradiation, 1BR3G human skin fibroblasts were observed to proliferate at a fast rate. The study of ECM macromolecules production using ELISA showed an increase of hyaluronic acid and versican production but no changes were observed for decorin. With RT-PCR assays, an increase in mRNA for collagen type I, type III and MMP-1 were observed. CONCLUSION: Intense pulsed light emitting near infrared applied in vitro cultured cells increases fibroblasts proliferation and activity, which can be a possible mechanism of action for these devices in aging skin treatment. PMID- 25547461 TI - A 15-month evaluation of bond failures of orthodontic brackets bonded with direct versus indirect bonding technique: a clinical trial. AB - BACKGROUND: The purpose of this clinical longitudinal study was to investigate the effectiveness of indirect bonding technique evaluating the number of bond failures which occurred during treatment. METHODS: Fifty-two patients were selected and divided into two groups: group A (33 patients) bonded with the direct technique and group B (19 patients) bonded with the indirect technique. The number and date of bracket failure were recorded for over 15 months. Moreover, also the effect of crowding level on bracket failures was calculated. Statistical analysis was performed by means of t-test, Kaplan-Meier survival estimates and chi-squared test. RESULTS: No statistically significant differences were found in the total bond failure rate between direct and indirect techniques, also when comparing the upper and lower arches. The only significant difference was found comparing the posterior segment of the lower arches, in which a higher percentage of detachments were recorded in group B, bonded with the indirect technique. Moreover, no significant differences between direct and indirect bonding were found when evaluating crowding level. CONCLUSIONS: Orthodontic practitioners can safely use the indirect bonding technique, even in patients with severe crowding, because it does not influence the adhesive quality and the bracket survival rate. PMID- 25547462 TI - Involvement of 2-arachidonoylglycerol signaling in social challenge responding of male CD1 mice. AB - RATIONALE: Endocannabinoids are strong modulators of emotionality and present a novel target for psychotropic drug development. Increasing evidence suggests that endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) affect behavior differentially. While the roles of anandamide have been investigated extensively, studies regarding the specific roles of 2-AG became possible only recently, and its involvement in social behaviors has not yet been studied. OBJECTIVE: We studied the impact of 2-AG signaling on aggression as a first attempt to characterize the role of this endocannabinoid in social behaviors. METHODS: 2-AG signaling was enhanced by the monoacylglycerol lipase inhibitor JZL184 (8, and 16 mg/kg) in mice later submitted to the resident/intruder paradigm. RESULTS: JZL184 near completely abolished aggressiveness in residents and increased victimization (i.e., attacks by the opponent). Interestingly, the level of defensiveness remained unaltered, despite the large increase in bites received. The CB1 receptor blocker AM251 (0.5 mg/kg) did not influence the effects of JZL184. In intruders, JZL184 near completely suppressed bites and offensive behavior in a fashion similar to residents, but it also increased agitation and defensiveness during, and the corticosterone response to, aggressive encounters. Experiments involving the corticosterone synthesis inhibitor metyrapone (30 mg/kg) suggest that the suppression of biting and offensive behavior is directly influenced by JZL184, whereas increased agitation and defensiveness (seen in intruders only) are a secondary development of the stress-endocrine effects of JZL184. CONCLUSIONS: 2-AG signaling emerges as a surprisingly strong negative modulator of aggressiveness, which warrants further studies into its general role in social behavior and the target receptors involved. PMID- 25547463 TI - Loss of ICA69 potentiates long-lasting hyperalgesia after subcutaneous formalin injection into the mouse hindpaw. AB - Islet-cell autoantigen 69 kDa (ICA69) plays an important role in many diseases and physiological activities by forming heteromeric complexes with protein interacts with C-kinase 1 (PICK1). PICK1 is critical for inflammatory pain hypersensitivity by regulating trafficking of AMPA receptor subunit GluA2 in spinal neurons. However, the role of ICA69 in inflammatory pain has not yet been investigated. Here we reported that expression of PICK1 in spinal cord was reduced largely in ICA69 knockout mice. The pain hypersensitivity was enhanced in the second phase 7 days after formalin administration. Meanwhile, increased Ser880 phosphorylation in GluA2 and decreased surface GluA2 were concordant with the pain. Furthermore, the number of activated microglia in spinal dorsal horn increased in line with pain hypersensitivity. Together, ICA69 deficiency promoted the internalization of GluA2 and FML-induced long-lasting pain hypersensitivity. In addition, microglia activation might be an important factor in the development of the pain hypersensitivity. PMID- 25547465 TI - On orthopedic surgical skill prediction--the limited value of traditional testing. AB - OBJECTIVES: Primary: to assess the utility of our distal radius fracture repair model as a tool for examining residents' surgical skills. Secondary: to compare the residents' ability to achieve specific biomechanically measured fracture stability with traditional test scores. DESIGN: Our laboratory pioneered a model that measures biomechanical qualities of a repaired distal radius fracture. Before participation, all residents to be tested completed specified knowledge examinations. During the laboratory exercise, proctors observed each resident and completed Objective Structured Assessment of Technical Skills forms. At the completion of the laboratory, each specimen was tested biomechanically. Written examinations were completed in a proctored setting and computer examinations at home following the honor system. The laboratory exercise had adequate space and materials and allowed 60 minutes to complete the procedure. Residents had equal access to x-ray imaging. SETTING: The examination environment of the study resembled an operating room. PARTICIPANTS: Postgraduate years 3 and 4 orthopedic residents in our program were asked to participate. The institutional review board reviewed and approved the study as exempt. RESULTS: Fracture repair constructs capable of resisting loads expected during rehabilitation were created by approximately half the residents tested. However, traditional written and computer-based testing methods failed to predict which resident's fracture construct would pass the biomechanical testing. Prior in vivo similar case experience was not predictive. CONCLUSIONS: The idea that "book smart does not equal street smart" applies to the tested model. To measure surgical skill acquisition and increase public safety related to surgery, it will be necessary to employ new and specific examination methods that identify the skill to be acquired and test the acquisition of this skill as precisely as possible. PMID- 25547464 TI - The Fifth German Oral Health Study (Funfte Deutsche Mundgesundheitsstudie, DMS V) - rationale, design, and methods. AB - BACKGROUND: Oral diseases rank among the most prevalent non-communicable diseases in modern societies. In Germany, oral epidemiological data show that both dental caries and periodontal diseases are highly prevalent, though significant improvements in oral health has been taking in the population within the last decades, particularly in children. It is, therefore, the aim of the Fifth German Oral Health Study (DMS V) to actualize the data on current oral health status and to gather information on oral health behavior and risk factors. In addition to current oral health monitoring, the study will also permit conclusions about trends in the development of oral health in Germany between 1989 and 2014. METHODS/DESIGN: DMS V is a cross-sectional, multi-center, nationwide representative, socio-epidemiological study to investigate the oral health status und behavior of the German resident population in four age cohorts. Study participants are children (12-year-olds), adults (35- to 44-year-olds), young olds (65- to 74-year-olds), and old olds (75- to 100-year-olds) who are drawn from local residents' registration offices. Social-science investigation parameters concern subjective perceptions and attitudes regarding oral health and nutrition, sense of coherence, and socio-demographic data. Clinical oral parameters are tooth loss, caries and periodontitis, prosthodontic status, further developmental and acquired dental hard tissue and mucosal lesions. To ensure reproducibility, the dental investigators are trained and calibrated by experts and multiple reliability checks are performed throughout the field phase. Statistical analyses are calculated according to a detailed statistical analysis plan. DISCUSSION: The DMS studies first performed in 1989, 1992 and repeated in 1997 and 2005 are the only cross-sectional oral health studies conducted in Germany on a population-based national representative level. Updated prevalence and trend analyses of key oral diseases are, therefore, of major epidemiological and health services research interest. TRIAL REGISTRATION: German Health Services Research Data Bank VfD_DMSV_13_002152. PMID- 25547466 TI - Validity of an adapted scoring method for a Modified Six Elements Test in individuals with brain injury. AB - The Modified Six Elements Test (MSET) assesses several executive functions. We examined whether an adapted scoring method is appropriate for discriminating between brain-injured persons with and without executive deficits. A MSET was administered to 70 participants with acquired brain injury in the chronic phase. The group was divided into individuals with and without executive impairments based on several other executive tests. The discriminative value for both the conventional raw score and the adapted scoring method was evaluated using receiver operating characteristic analyses. Both scoring methods discriminated significantly between persons with impaired and unimpaired executive functions (raw score: area under the curve, AUC = 0.703, p = .004; adapted score: AUC = 0.780, p = .000). Only the adapted scoring method proved sensitive (81%) and specific (67%) within a clinically useful range. Within this range, an acceptable cut-off score could be determined. Altogether, the proposed MSET scoring index is a potentially clinically useful contribution to the measurement of executive functions. PMID- 25547471 TI - A collaborative pipeline. PMID- 25547467 TI - Bioimprinted polymer platforms for cell culture using soft lithography. AB - BACKGROUND: It is becoming recognised that traditional methods of culture in vitro on flat substrates do not replicate physiological conditions well, and a number of studies have indicated that the physical environment is crucial to the directed functioning of cells in vivo. In this paper we report the development of a platform with cell-like features that is suitable for in vitro investigation of cell activity. Biological cells were imprinted in hard methacrylate copolymer using soft lithography. The cell structures were replicated at high nanometre scale resolution, as confirmed by atomic force microscopy. Optimisation of the methacrylate-based co-polymer mixture for transparency and biocompatibility was performed, and cytotoxicity and chemical stability of the cured polymer in cell culture conditions were evaluated. Cells of an endometrial adenocarcinoma cell line (Ishikawa) were cultured on bioimprinted substrates. RESULTS: The cells exhibited differential attachment on the bioimprint substrate surface compared to those on areas of flat surface and preferentially followed the pattern of the original cell footprint. CONCLUSIONS: The results revealed for the first time that the cancer cells distinguished between behavioural cues from surfaces that had features reminiscent of themselves and that of flat areas. Therefore the imprinted platform will lend itself to detailed studies of relevant physical substrate environments on cell behaviour. The material is not degraded and its permanency allows reuse of the same substrate in multiple experimental runs. It is simple and does not require expensive or specialised equipment. In this work cancer cells were studied, and the growth behaviour of the tumour-derived cells was modified by alterations of the cells' physical environment. Implications are also clear for studies in other crucial areas of health, such as wound healing and artificial tissues. PMID- 25547472 TI - Attentional flexibility in the thalamus: now we're getting SOMwhere. PMID- 25547474 TI - A place for motion in mapping. PMID- 25547473 TI - Change the neural code, change the message. PMID- 25547475 TI - Gain from your own (moving) perspective. PMID- 25547476 TI - Using register data to examine patterns of compulsory addiction treatment care in Sweden: program planning and methodological implications. PMID- 25547477 TI - Building effective partnerships to improve birth outcomes by reducing obesity: The B'more Fit for healthy babies coalition of Baltimore. AB - Obesity affects a large percentage of Baltimore City's population with repercussions on maternal health and birth outcomes. Approaches to ameliorate its impact must be comprehensive and include stakeholder involvement at all levels of influence including policy makers, service providers, and community residents. In this article, we examine the evolution of the B'more Fit for Healthy Babies Coalition in Baltimore, Maryland, with a specific focus on how the public health alliance was formed, the strategies employed, and how partners continually evaluated themselves. This study offers the opportunity to understand the extent and complexity undergirding the collaborative processes of community coalitions as they strive to find innovative solutions to major public health concerns. PMID- 25547478 TI - Restoration of sodic soils involving chemical and biological amendments and phytoremediation by Eucalyptus camaldulensis in a semiarid region. AB - Salt-affected soils in semiarid regions impede the agricultural productivity and degrade the ecosystem health. In South India, several hectares of land are salt affected, where the evapotranspiration exceeds the annual precipitation. This study is an attempt to ameliorate sodic soils, by an experiment involving chemical treatment (addition of gypsum), organic amendments (decomposed bagasse pith and green manuring with Sesbania rostrata) and phytoremediation by plantation of Eucalyptus camaldulensis. The prime focus is to minimize the use of gypsum and improve the soil health in terms of nutrients, microbial population and enzyme activity in addition to sodicity reclamation. At the end of the third year, a reduction of 10 % in soil pH, 33 % in electrical conductivity and 20 % in exchangeable sodium percentage was achieved compared to the initial values. Three to fourfold increases in organic carbon content were observed. Significant improvement in the available major and micronutrients of soil, microbial growth and enzyme activity was observed, suggesting phytoremediation by E. camaldulensis as a sustainable option for restoration of similar kind of degraded lands. PMID- 25547479 TI - Seroprevalence of HSV-1/2 and correlation with aggravation of oral mucositis in patients with squamous cell carcinoma of the head and neck region submitted to antineoplastic treatment. AB - PURPOSE: Oral mucositis (OM) is a frequent side effect resulting from antineoplastic treatment and is described as an acute alteration characterized by ulcerative lesions, with the presence of a persistent chronic inflammatory infiltrate, erythema, and pain. AIMS: The purpose of the study was to evaluate the presence of the herpes simplex virus (HSV-1/2) in patients with squamous cell carcinoma of the head and neck region (SCC) and its influence on the aggravation of oral mucositis after radiotherapy or radio/chemotherapy treatment. METHODS: In this prospective cohort study, 91 patients were evaluated with regard to their serological status for IgG before treatment (initial time interval--TI) and for IgM before treatment (T1) and on the 30th day after the first day of radiotherapy application/radiation therapy (final time interval--TF), using immunoenzymatic assay (ELISA), and the results were correlated with the intensity of OM. RESULTS: The seroprevalence for IgG was 97.8 %. IgM (TI) was positive in 18.7% and IgM (TF) in 20.9% of patients. All the patients developed some degree of oral mucositis; however, there was statistically significant correlation between positivity for IgM and degree of severity of OM, irrespective of the type of treatment to which the patient was submitted. CONCLUSION: The reactivation of HSV 1/2 was shown to be relatively infrequent and there was no correlation between presence of the virus and aggravation of oral mucositis resulting from antineoplastic treatment. PMID- 25547480 TI - Unique characteristics of informal hospice cancer caregiving. AB - PURPOSE: The purpose of this study was to describe the unique characteristics of informal hospice cancer caregiving. METHODS: Researchers conducted a secondary analysis of data drawn from a randomized clinical trial of an informal hospice caregiving intervention (N = 348). Demographic characteristics and measures of the informal caregiving experience of hospice patients and their informal caregivers were compared based on the patient's diagnosis using chi-square tests for association of categorical variables and t tests for continuous variables. RESULTS: Informal caregivers of cancer patients differed from their non-cancer counterparts in a number of respects including patient age, caregiver age, patient residence, relationship between patient and caregiver, amount and duration of care provided, likelihood to incur out-of-pocket expenses related to patient care, caregiver problem-solving style, and impact on caregiver daily schedule. There were no statistically significant differences between cancer and non-cancer caregivers in terms of gender, race, employment status, anxiety, and quality of life. CONCLUSIONS: While cancer and non-cancer caregivers are similar in many respects, a number of unique features characterize the informal hospice cancer caregiving experience. Attention to these unique features will allow hospice providers to tailor supportive care interventions to better address cancer caregivers' needs. PMID- 25547481 TI - Opioid-taking self-efficacy affects the quality of life of Taiwanese patients with cancer pain. AB - GOALS: Quality of life is an important indicator for evaluating the outcome of treatment for patients with cancer pain. Perceived self-efficacy has been reported to play an important role in controlling quality of life (QOL). Limited studies have focused on opioid-taking self-efficacy effects on the patients' QOL, which is caused by cancer pain. The purpose of this study was to evaluate how much of the variance in QOL among Taiwanese cancer patients with pain could be accounted for by opioid-taking self-efficacy. MATERIALS AND METHODS: This cross sectional study included 109 cancer patients who had taken prescribed opioid analgesics for cancer-related pain in the past week and completed the Opioid Taking sSelf-Efficacy Scale and European Organization for Research and Treatment of Cancer Quality of Life Group Questionnaire. MAIN RESULTS: There was a significant correlation between scores on self-efficacy total scale and functional QOL (r = 0.30, p < 0.01) and symptomatic QOL (r = -0.22, p < 0.05). The opioid-taking self-efficacy total scale accounted for 8% (R (2) = 0.08, p < 0.01) of the variance in predicting the patients' functional QOL and 7% (R (2) = 0.07, p < 0.01) of the variance in predicting the patients' symptomatic QOL. CONCLUSIONS: This study highlights the potential importance of a patient's opioid taking self-efficacy beliefs in their quality of life, which is relevant to cancer pain. PMID- 25547482 TI - Relationship of the urine cortisol level with the performance status of patients with lung cancer: a retrospective study. AB - PURPOSE: Cortisol plays an important role in the physical status of patients with end-stage lung cancer, but the association of urine cortisol levels with TNM stage/performance status (PS) is unclear in patients with advanced lung cancer receiving chemotherapy. The objective of this study was to examine this association. METHODS: In this single-center, retrospective, observational study, cortisol concentrations in 24-h pooled urine from 22 patients with advanced lung cancer were measured over 2 days. The mean concentration in each patient was compared with PS, TNM stage, and serum sodium and potassium ion levels. RESULTS: The 24-h urine cortisol levels were higher in PS2 or PS3 cases compared to PS1 (p < 0.05) and increased proportionally with PS. Urine cortisol also increased in N2 or N3 cases compared to N1 (p < 0.01) and also increased in M1 cases (p < 0.05). Urine cortisol levels were negatively correlated with serum sodium (R = -0.49, p < 0.05) and had a tendency for a positive correlation with serum potassium (R = 0.40, p = 0.06). CONCLUSION: The 24-h urine cortisol level increased in patients with advanced lung cancer undergoing chemotherapy. Low serum levels of potassium and high levels of sodium may indicate relative adrenal insufficiency. PMID- 25547483 TI - Enhanced visual awareness for morality and pajamas? Perception vs. memory in 'top down' effects. AB - A raft of prominent findings has revived the notion that higher-level cognitive factors such as desire, meaning, and moral relevance can directly affect what we see. For example, under conditions of brief presentation, morally relevant words reportedly "pop out" and are easier to identify than morally irrelevant words. Though such results purport to show that perception itself is sensitive to such factors, much of this research instead demonstrates effects on visual recognition -which necessarily involves not only visual processing per se, but also memory retrieval. Here we report three experiments which suggest that many alleged top down effects of this sort are actually effects on 'back-end' memory rather than 'front-end' perception. In particular, the same methods used to demonstrate popout effects for supposedly privileged stimuli (such as morality-related words, e.g. "punishment" and "victim") also yield popout effects for unmotivated, superficial categories (such as fashion-related words, e.g. "pajamas" and "stiletto"). We conclude that such effects reduce to well-known memory processes (in this case, semantic priming) that do not involve morality, and have no implications for debates about whether higher-level factors influence perception. These case studies illustrate how it is critical to distinguish perception from memory in alleged 'top-down' effects. PMID- 25547484 TI - Quantification of drug transport function across the multiple resistance associated protein 2 (Mrp2) in rat livers. AB - To understand the transport function of drugs across the canalicular membrane of hepatocytes, it would be important to measure concentrations in hepatocytes and bile. However, these concentration gradients are rarely provided. The aim of the study is then to measure these concentrations and define parameters to quantify the canalicular transport of drugs through the multiple resistance associated protein 2 (Mrp2) in entire rat livers. Besides drug bile excretion rates, we measured additional parameters to better define transport function across Mrp2: (1) Concentration gradients between hepatocyte and bile concentrations over time; and (2) a unique parameter (canalicular concentration ratio) that represents the slope of the non-linear regression curve between hepatocyte and bile concentrations. This information was obtained in isolated rat livers perfused with gadobenate dimeglumine (BOPTA) and mebrofenin (MEB), two hepatobiliary drugs used in clinical liver imaging. Interestingly, despite different transport characteristics including excretion rates into bile and hepatocyte clearance into bile, BOPTA and MEB have a similar canalicular concentration ratio. In contrast, the ratio was null when BOPTA was not excreted in bile in hepatocytes lacking Mrp2. The canalicular concentration ratio is more informative than bile excretion rates because it is independent of time, bile flows, and concentrations perfused in portal veins. It would be interesting to apply such information in human liver imaging where hepatobiliary compounds are increasingly investigated. PMID- 25547485 TI - Systemic delivery of protein nanocages bearing CTT peptides for enhanced imaging of MMP-2 expression in metastatic tumor models. AB - Matrix metalloproteinase 2 (MMP-2) in metastatic cancer tissue, which is associated with a poor prognosis, is a potential target for tumor imaging in vivo. Here, we describe a metastatic cancer cell-targeted protein nanocage. An MMP-2-binding peptide, termed CTT peptide (CTTHWGFTLC), was conjugated to the surface of a naturally occurring heat shock protein nanocage by genetic modification. The engineered protein nanocages showed a binding affinity for MMP 2 and selective uptake in cancer cells that highly expressed MMP-2 in vitro. In near-infrared fluorescence imaging, the nanocages showed specific and significant accumulation in tumor tissue after intravenous injection in vivo. These protein nanocages conjugated with CTT peptide could be potentially applied to a noninvasive near-infrared fluorescence detection method for imaging gelatinase activity in metastatic tumors in vivo. PMID- 25547486 TI - Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. AB - Toll-like receptors (TLRs) not only form an important part of the innate immune system but also serve to activate the adaptive immune system in response to cancer. Real-time PCR; immunohistochemical stain and Western blotting analyses were performed to clarify molecular alterations in colorectal cancer (CRC) patients. We identified Toll-like receptor 1 (TLR1), TLR2, TLR4 and TLR8 gene expression levels and downstream gene, i.e., interleukin-6 (IL-6), IL-8, interferon-alpha (IFN-alpha) and myeloid differentiation primary-response protein 88 (MyD88), expression levels in CRC patients and in cancer cell lines. CRC tissues have higher TLR1, TLR2, TLR4, TLR8, IL-6 and IL-8 gene expression levels than do the normal colon mucosa (p < 0.05). TLR2 expression varied in different cell types (mucosa and lymphocytes). There was no difference in the MyD88 and IFN alpha gene expression levels between cancerous and normal colon mucosa. CRC patients had higher levels of IL-6 (p = 0.002) and IL-8 (p = 0.038) expression than healthy volunteers did; and higher IL-6 and IL-8 expression was also found to signify a higher risk of recurrence. CL075 (3M002) treatments can reduce the production of IL-8 in different cancer cell lines. The signaling pathway of TLRs in cancer tissue is different from that in normal cells; and is MyD88 independent. Higher expression levels of TLR1, TLR2, TLR 4 and TLR 8 mRNA were related to upregulation inflammatory cytokines IL-6 and IL-8 gene expression in tissue and to the upregulation of IL-6 in blood. The concentration of IL-6 in serum can be used as an indicator of the possibility of CRC recurrence. Treatment with 3M002 can reduce IL-6 production in vitro and may prevent CRC recurrence. Our findings provide evidence that TLR1, TLR2, TLR4 and TLR8 gene expression induce downstream IL-6 and IL-8 gene expression; detection of these expression levels can serve as a CRC marker. PMID- 25547487 TI - Increased ARPP-19 expression is associated with hepatocellular carcinoma. AB - The cAMP-regulated phosphoprotein 19 (ARPP-19) plays a key role in cell mitotic G2/M transition. Expression of ARPP-19 was increased in human hepatocellular carcinoma (HCC) compared to adjacent non-tumorous liver tissues in 36 paired liver samples, and the level of ARPP-19 in HCC tissues was positively correlated with the tumor size. To determine the interrelationship between ARPP-19 expression and HCC, we silenced ARPP-19 expression in the human hepatocarcinoma HepG2 and SMMC-7721 cells using lentivirus encoding ARPP-19 siRNA. HepG2 and SMMC 7721 cells with ARPP-19 knockdown displayed lowered cell growth rate, retarded colony formation and increased arrest at the G2/M phase transition. Silencing ARPP-19 in HCC cells resulted in decreased protein levels of phospho-(Ser) CDKs substrates and increased levels of inactivated cyclin division cycle 2 (Cdc2). Therefore, ARPP-19 may play a role in HCC pathogenesis through regulating cell proliferation. PMID- 25547489 TI - Compartmentalization role of A-kinase anchoring proteins (AKAPs) in mediating protein kinase A (PKA) signaling and cardiomyocyte hypertrophy. AB - The Beta-adrenergic receptors (beta-ARs) stimulation enhances contractility through protein kinase-A (PKA) substrate phosphorylation. This PKA signaling is conferred in part by PKA binding to A-kinase anchoring proteins (AKAPs). AKAPs coordinate multi-protein signaling networks that are targeted to specific intracellular locations, resulting in the localization of enzyme activity and transmitting intracellular actions of neurotransmitters and hormones to its target substrates. In particular, mAKAP (muscle-selective AKAP) has been shown to be present on the nuclear envelope of cardiomyocytes with various proteins including: PKA-regulatory subunit (RIIalpha), phosphodiesterase-4D3, protein phosphatase-2A, and ryanodine receptor (RyR2). Therefore, through the coordination of spatial-temporal signaling of proteins and enzymes, mAKAP controls cyclic-adenosine monophosphate (cAMP) levels very tightly and functions as a regulator of PKA-mediated substrate phosphorylation leading to changes in calcium availability and myofilament calcium sensitivity. The goal of this review is to elucidate the critical compartmentalization role of mAKAP in mediating PKA signaling and regulating cardiomyocyte hypertrophy by acting as a scaffolding protein. Based on our literature search and studying the structure-function relationship between AKAP scaffolding protein and its binding partners, we propose possible explanations for the mechanism by which mAKAP promotes cardiac hypertrophy. PMID- 25547488 TI - Oxidative stress and its significant roles in neurodegenerative diseases and cancer. AB - Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and oxysterols in the development of neurodegenerative diseases and inflammation-related cancer. Our recent studies identifying and characterizing carbonylated proteins reveal oxidative damage to heat shock proteins in neurodegenerative disease models and inflammation-related cancer, suggesting dysfunction in their antioxidative properties. In neurodegenerative diseases, DNA damage may not only play a role in the induction of apoptosis, but also may inhibit cellular division via telomere shortening. Immunohistochemical analyses showed co-localization of oxidative/nitrative DNA lesions and stemness markers in the cells of inflammation-related cancers. Here, we review oxidative stress and its significant roles in neurodegenerative diseases and cancer. PMID- 25547490 TI - The potential of liposomes with carbonic anhydrase IX to deliver anticancer ingredients to cancer cells in vivo. AB - Drug delivery nanocarriers, especially targeted drug delivery by liposomes are emerging as a class of therapeutics for cancer. Early research results suggest that liposomal therapeutics enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumors and active cellular uptake. Here, we highlight the features of immunoliposomes that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While a large number of studies has been published, the emphasis here is placed on the carbonic anhydrase IX (CA-IX) and the conjugated liposomes that are likely to open a new chapter on drug delivery system by using immunoliposomes to deliver anticancer ingredients to cancer cells in vivo. PMID- 25547493 TI - USP22 promotes NSCLC tumorigenesis via MDMX up-regulation and subsequent p53 inhibition. AB - Increasing evidence suggests that ubiquitin-specific protease 22 (USP22) has great clinicopathologic significance in oncology. In this study, we investigated the role of USP22 in human NSCLC tumorigenesis along with the underlying mechanisms of action. First, we determined the expression of USP22 in human NSCLC, as well as normal tissues and cell lines. We then studied the effects of USP22 silencing by shRNA on NSCLC cell growth in vitro and tumorigenesis in vivo, along with the effect on the p53 pathway. We found that USP22 is overexpressed in human NSCLC tissues and cell lines. USP22 silencing by shRNA inhibits proliferation, induces apoptosis and arrests cells at the G0/G1 phases in NSCLC cells and curbs human NSCLC tumor growth in a mouse xenograft model. Additionally, USP22 silencing downregulates MDMX protein expression and activates the p53 pathway. Our co-immunoprecipitation analysis shows that USP22 interacts with MDMX in NSCLC cells. Furthermore, MDMX silencing leads to growth arrest and apoptosis in NSCLC cells, and over-expression of MDMX reverses the USP22 silencing-induced effects. Taken together, our results suggest that USP22 promotes NSCLC tumorigenesis in vitro and in vivo through MDMX upregulation and subsequent p53 inhibition. USP22 may represent a novel target for NSCLC treatment. PMID- 25547492 TI - The anticancer drug ellipticine activated with cytochrome P450 mediates DNA damage determining its pharmacological efficiencies: studies with rats, Hepatic Cytochrome P450 Reductase Null (HRNTM) mice and pure enzymes. AB - Ellipticine is a DNA-damaging agent acting as a prodrug whose pharmacological efficiencies and genotoxic side effects are dictated by activation with cytochrome P450 (CYP). Over the last decade we have gained extensive experience in using pure enzymes and various animal models that helped to identify CYPs metabolizing ellipticine. In this review we focus on comparison between the in vitro and in vivo studies and show a necessity of both approaches to obtain valid information on CYP enzymes contributing to ellipticine metabolism. Discrepancies were found between the CYP enzymes activating ellipticine to 13-hydroxy- and 12 hydroxyellipticine generating covalent DNA adducts and those detoxifying this drug to 9-hydroxy- and 7-hydroellipticine in vitro and in vivo. In vivo, formation of ellipticine-DNA adducts is dependent not only on expression levels of CYP3A, catalyzing ellipticine activation in vitro, but also on those of CYP1A that oxidize ellipticine in vitro mainly to the detoxification products. The finding showing that cytochrome b5 alters the ratio of ellipticine metabolites generated by CYP1A1/2 and 3A4 explained this paradox. Whereas the detoxification of ellipticine by CYP1A and 3A is either decreased or not changed by cytochrome b5, activation leading to ellipticine-DNA adducts increased considerably. We show that (I) the pharmacological effects of ellipticine mediated by covalent ellipticine-derived DNA adducts are dictated by expression levels of CYP1A, 3A and cytochrome b5, and its own potency to induce these enzymes in tumor tissues, (II) animal models, where levels of CYPs are either knocked out or induced are appropriate to identify CYPs metabolizing ellipticine in vivo, and (III) extrapolation from in vitro data to the situation in vivo is not always possible, confirming the need for these animal models. PMID- 25547491 TI - Molecular targets of antihypertensive peptides: understanding the mechanisms of action based on the pathophysiology of hypertension. AB - There is growing interest in using functional foods or nutraceuticals for the prevention and treatment of hypertension or high blood pressure. Although numerous preventive and therapeutic pharmacological interventions are available on the market, unfortunately, many patients still suffer from poorly controlled hypertension. Furthermore, most pharmacological drugs, such as inhibitors of angiotensin-I converting enzyme (ACE), are often associated with significant adverse effects. Many bioactive food compounds have been characterized over the past decades that may contribute to the management of hypertension; for example, bioactive peptides derived from various food proteins with antihypertensive properties have gained a great deal of attention. Some of these peptides have exhibited potent in vivo antihypertensive activity in both animal models and human clinical trials. This review provides an overview about the complex pathophysiology of hypertension and demonstrates the potential roles of food derived bioactive peptides as viable interventions targeting specific pathways involved in this disease process. This review offers a comprehensive guide for understanding and utilizing the molecular mechanisms of antihypertensive actions of food protein derived peptides. PMID- 25547495 TI - Stable hydrogen production from ethanol through steam reforming reaction over nickel-containing smectite-derived catalyst. AB - Hydrogen production through steam reforming of ethanol was investigated with conventional supported nickel catalysts and a Ni-containing smectite-derived catalyst. The former is initially active, but significant catalyst deactivation occurs during the reaction due to carbon deposition. Side reactions of the decomposition of CO and CH4 are the main reason for the catalyst deactivation, and these reactions can relatively be suppressed by the use of the Ni-containing smectite. The Ni-containing smectite-derived catalyst contains, after H2 reduction, stable and active Ni nanocrystallites, and as a result, it shows a stable and high catalytic performance for the steam reforming of ethanol, producing H2. PMID- 25547498 TI - Adaptive marker-free registration using a multiple point strategy for real-time and robust endoscope electromagnetic navigation. AB - Registration of pre-clinical images to physical space is indispensable for computer-assisted endoscopic interventions in operating rooms. Electromagnetically navigated endoscopic interventions are increasingly performed at current diagnoses and treatments. Such interventions use an electromagnetic tracker with a miniature sensor that is usually attached at an endoscope distal tip to real time track endoscope movements in a pre-clinical image space. Spatial alignment between the electromagnetic tracker (or sensor) and pre-clinical images must be performed to navigate the endoscope to target regions. This paper proposes an adaptive marker-free registration method that uses a multiple point selection strategy. This method seeks to address an assumption that the endoscope is operated along the centerline of an intraluminal organ which is easily violated during interventions. We introduce an adaptive strategy that generates multiple points in terms of sensor measurements and endoscope tip center calibration. From these generated points, we adaptively choose the optimal point, which is the closest to its assigned the centerline of the hollow organ, to perform registration. The experimental results demonstrate that our proposed adaptive strategy significantly reduced the target registration error from 5.32 to 2.59 mm in static phantoms validation, as well as from at least 7.58 mm to 4.71 mm in dynamic phantom validation compared to current available methods. PMID- 25547499 TI - Proteomic analysis of anthers from wild-type and photosensitive genetic male sterile mutant cotton (Gossypium hirsutum L.). AB - BACKGROUND: Male sterility is a common phenomenon in flowering plant species, and it has been successfully developed in several crops by taking advantage of heterosis. Using space mutation breeding of upland cotton, a novel photosensitive genetic male sterile (PGMS) mutant was isolated. To take advantage of the PGMS lines in cotton hybrid breeding, it is of great importance to study the molecular mechanisms of its male sterility. RESULTS: Delayed degradation of the PGMS anther tapetum occurred at different developmental stages as shown by analysis of anther cross-sections. To gain detailed insights into the cellular defects that occurred during PGMS pollen development, we used a differential proteomic approach to investigate the protein profiles of mutant and wild-type anthers at the tetrad, uninucleate and binucleate pollen stages. This approach identified 62 differentially expressed protein spots, including 19 associated with energy and metabolic pathways, 7 involved with pollen tube growth, 5 involved with protein metabolism, and 4 involved with pollen wall development. The remaining 27 protein spots were classified into other functional processes, such as protein folding and assembly (5 spots), and stress defense (4 spots). These differentially expressed proteins strikingly affected pollen development in the PGMS mutant anther and resulted in abnormal pollen grain formation, which may be the key reason for its male sterility. CONCLUSIONS: This work represents the first study using comparative proteomics between fertile and PGMS cotton plants to identify PGMS-related proteins. The results demonstrate the presence of a complicated metabolic network in anther development and advance our understanding of the molecular mechanisms of microgamete formation, providing insights into the molecular mechanisms of male sterility. PMID- 25547500 TI - Psychiatric morbidity and survival after surgery for esophageal cancer: a population-based cohort study. AB - PURPOSE: To determine the cumulative incidence of and risk factors for psychiatric morbidity and establish the impact on survival among surgically treated patients with esophageal cancer. PATIENTS AND METHODS: A nationwide Swedish cohort of 1,615 patients who underwent surgery for esophageal cancer between 1987 and 2010 with follow-up until 2012 was linked to national health registries for information on psychiatric morbidity (inferred from mental health care use). Multivariable logistic regressions were used to determine potential risk factors for postoperative psychiatric morbidity. A multivariable-adjusted Cox proportional hazard model was used to analyze overall survival. RESULTS: In patients without a history of psychiatric morbidity, the 2-year cumulative incidence for treatment in psychiatric in-patient care was 2.5%, for psychiatric out-patient care was 4.2%, and for treatment with psychotropic drugs was 32.3%. Married patients were less likely to be treated postoperatively in psychiatric in patient care (odds ratio [OR], 0.42; 95% CI, 0.22 to 0.80) or out-patient care (OR, 0.41; 95% CI, 0.17 to 1.02), whereas patients with higher tumor stage were more likely to be treated in psychiatric out-patient care (OR, 4.99; 95% CI, 1.16 to 21.38) or with psychotropic drugs (OR, 2.78; 95% CI, 1.10 to 7.01). Bearing in mind possible residual confounding, new-onset psychiatric morbidity was associated with mortality (hazard ratio [HR], 1.65 [95% CI, 1.17 to 2.33] for treatment in psychiatric in-patient care; HR, 1.93 [95% CI, 1.18 to 3.16] for treatment in psychiatric out-patient care; and HR, 2.77 [95% CI, 1.72 to 4.44] for treatment with psychotropic drugs). CONCLUSION: These results highlight the importance of recognizing and addressing psychiatric morbidity in surgically treated patients with esophageal cancer. PMID- 25547494 TI - tRNAs as antibiotic targets. AB - Transfer RNAs (tRNAs) are central players in the protein translation machinery and as such are prominent targets for a large number of natural and synthetic antibiotics. This review focuses on the role of tRNAs in bacterial antibiosis. We will discuss examples of antibiotics that target multiple stages in tRNA biology from tRNA biogenesis and modification, mature tRNAs, aminoacylation of tRNA as well as prevention of proper tRNA function by small molecules binding to the ribosome. Finally, the role of deacylated tRNAs in the bacterial "stringent response" mechanism that can lead to bacteria displaying antibiotic persistence phenotypes will be discussed. PMID- 25547501 TI - Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial. AB - PURPOSE: The presence of a mutated nucleophosmin-1 gene (NPM1(mut)) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1(mut) AML eligible for allogeneic SCT in a donor versus no-donor analysis. PATIENTS AND METHODS: Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1(mut) patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor. RESULTS: Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3 year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300). CONCLUSION: Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1(mut) AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1(mut) patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1(mut) AML with a sibling donor. PMID- 25547502 TI - Exploring the burden of inpatient readmissions after major cancer surgery. AB - PURPOSE: Travel distances to care have increased substantially with centralization of complex cancer procedures at high-volume centers. We hypothesize that longer travel distances are associated with higher rates of postoperative readmission and poorer outcomes. METHODS: SEER-Medicare patients with bladder, lung, pancreas, or esophagus cancer who were diagnosed in 2001 to 2007 and underwent extirpative surgery were included. Readmission rates and survival were calculated using Kaplan-Meier functions. Multivariable negative binomial models were used to examine factors associated with readmission. RESULTS: Four thousand nine hundred forty cystectomies, 1,573 esophagectomies, 20,362 lung resections, and 2,844 pancreatectomies were included. Thirty- and 90 day readmission rates ranged from 13% to 29% and 23% to 43%, respectively, based on tumor type. Predictors of readmission were discharge to somewhere other than home, longer length of stay, comorbidities, higher stage at diagnosis, and longer travel distance (P < .001 for each). Patients who lived farther from the index hospital also had increased emergency room visits and were more likely to be readmitted to a hospital other than the index hospital (P < .001). Of readmitted patients, 31.9% were readmitted more than once. Long-term survival was worse and costs of care higher for patients who were readmitted (P < .001 for all). CONCLUSION: The burden of readmissions after major cancer surgery is high, resulting in substantially poorer patient outcomes and higher costs. Risk of readmission was most strongly associated with length of stay and discharge destination. Travel distance also has an impact on patterns of readmission. Interventions targeted at higher risk individuals could potentially decrease the population burden of readmissions after major cancer surgery. PMID- 25547503 TI - SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. AB - PURPOSE: To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. PATIENTS AND METHODS: Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). RESULTS: Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. CONCLUSION: Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC. PMID- 25547505 TI - Time to reconsider the role of allogeneic transplantation for patients with acute myeloid leukemia and NPM1 mutation? PMID- 25547504 TI - Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. AB - PURPOSE: The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose -> 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose -> 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS: From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION: Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. PMID- 25547506 TI - Intrathecal Trastuzumab Halts Progression of CNS Metastases in Breast Cancer. PMID- 25547507 TI - Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risks of second malignancy and early menopause. AB - PURPOSE: To assess the risks of second malignancy and early menopause in a large cohort of patients with gestational trophoblastic tumor who were treated with chemotherapy. PATIENTS AND METHODS: A survey of patients treated at Charing Cross Hospital between 1958 and 2000 was performed in 2006 to assemble incidence data for subsequent malignancies and the age at menopause. Treatment records were reviewed for the regimens and durations, and the incidence of subsequent malignancies was compared with that in the national age-matched population. RESULTS: Data were obtained for 1,903 patients, with a mean follow-up of 16.9 years. Eighty-six patients developed a subsequent malignancy compared with an expected number of 79 (standardized incidence ratio [SIR], 1.1; 95% CI, 0.9 to 1.3). The overall risk was low for patients treated with single-agent methotrexate and folinic acid (MTX-FA; SIR, 0.7; 95% CI, 0.5 to 1.1) and also for patients treated with etoposide, methotrexate, and dactinomycin followed by cyclophosphamide and vincristine on alternating weeks (EMA-CO) with an SIR of 0.9 (95% CI, 0.4 to 2.2), but there were significantly increased risks of oral cancer, melanoma, meningioma, and leukemia. The cumulative risk of early menopause was low after MTX-FA but was substantial after EMA-CO, reaching 13% by age 40 years and 36% by age 45 years. CONCLUSION: Subsequent cancer risks for patients cured of gestational trophoblastic tumors with modern chemotherapy appear similar to those of the normal population with no overall increased risk of malignancy after MTX-FA or EMA-CO. However, there was evidence of an increased risk of leukemia after EMA-CO and some evidence of other site-specific increased risks based on small patient numbers. All major treatments except MTX-FA increased the risk of early menopause. PMID- 25547508 TI - Imatinib-Sensitizing KIT Mutation in a Carney-Stratakis-Associated GI Stromal Tumor. PMID- 25547509 TI - Hair, hormones, and high-risk prostate cancer. PMID- 25547510 TI - Age-dependent changes in health status in the Childhood Cancer Survivor cohort. AB - PURPOSE: To compare age-dependent changes in health status among childhood cancer survivors and a sibling cohort. METHODS: Adult survivors of childhood cancer and siblings, all participants of the Childhood Cancer Survivor Study, completed three surveys assessing health status. At each of three time points, participants were classified as having poor outcomes in general health, mental health, function, or daily activities if they indicated moderate to extreme impairment. Generalized linear mixed models were used to compare survivors with siblings for each outcome as a function of age and to identify host- and treatment-related factors associated with age-dependent worsening health status. RESULTS: Adverse health status outcomes were more frequent among survivors than siblings, with evidence of a steeper trajectory of age-dependent change among female survivors with impairment in at least one health status domain (P = .01). In adjusted models, survivors were more likely than siblings to report poor general health (prevalence ratio [PR], 2.37; 95% CI, 2.09 to 2.68), adverse mental health (PR, 1.66; 95% CI, 1.52 to 1.80), functional impairment (PR, 4.53; 95% CI, 3.91 to 5.24), activity limitations (PR, 2.38; 95% CI, 2.12 to 2.67), and an adverse health status outcome in any domain (PR, 2.10; 95% CI, 1.97 to 2.23). Cancer treatment and health behaviors influence the magnitude of differences by age groups. Chronic conditions were associated with adverse health status outcomes across organ systems. CONCLUSION: The prevalence of poor health status is higher among survivors than siblings, increases rapidly with age, particularly among female participants, and is related to an increasing burden of chronic health conditions. PMID- 25547511 TI - Distinguishing Susac's syndrome from multiple sclerosis. AB - Susac's syndrome is considered a rare differential diagnosis in the work-up of suspected multiple sclerosis. Over the last decade or so, significant advances in our understanding of Susac's syndrome mean that it can now be readily distinguished from multiple sclerosis in the majority of cases with a careful history and close attention to MR imaging. Supporting investigations such as CSF examination, fluorescein angiogram, visual field perimetry and audiology often yield important clues. In milder cases, however, diagnostic uncertainty can exist, and forme frustes of the disease are recognised. In this article, we discuss the clinical features of Susac's syndrome with emphasis on the findings and investigations that help to differentiate it from MS. PMID- 25547512 TI - Dissection of the PHO pathway in Schizosaccharomyces pombe using epistasis and the alternate repressor adenine. AB - In Saccharomyces cerevisiae, intracellular phosphate levels are maintained by the PHO pathway, activation of which is assayed by increased phosphatase activity. The PHO pathway of Schizosaccharomyces pombe upregulates phosphatase activity (encoded by pho1 (+)) during low extracellular phosphate levels, but the underlying mechanism is poorly understood. We utilized an alternate repressor of pho1 (+) expression (adenine supplementation) along with epistasis analysis to develop a model of how S. pombe PHO pathway components interact. Analyzing Pho1 activity in S. pombe PHO pathway deletion mutants during adenine starvation, we observed most mutants with a phosphatase defect in phosphate starvation also had a defect in adenine starvation. Pho7, a transcription factor in the PHO pathway, is necessary for an adenine starvation-mediated increase in Pho1 activity. Comparing adenine starvation to phosphate starvation, there are differences in the degree to which individual mutants regulate the two responses. Through epistasis studies, we identified two positive regulatory arms and one repressive arm of the PHO pathway. PKA activation is a positive regulator of Pho1 activity under both environmental conditions and is critical for transducing adenine concentrations in the cell. The synthesis of IP7 also appears critical for the induction of Pho1 activity during adenine starvation, but IP7 is not critical during phosphate starvation, which differs from S. cerevisiae. Finally, Csk1 is critical for repression of pho1 (+) expression during phosphate starvation. We believe all of these regulatory arms converge to increase transcription of pho1 (+) and some of the regulation acts through pho7 (+). PMID- 25547513 TI - Identifying and enhancing risk thresholds in the detection of elder financial abuse: a signal detection analysis of professionals' decision making. AB - BACKGROUND: Financial abuse of elders is an under acknowledged problem and professionals' judgements contribute to both the prevalence of abuse and the ability to prevent and intervene. In the absence of a definitive "gold standard" for the judgement, it is desirable to try and bring novice professionals' judgemental risk thresholds to the level of competent professionals as quickly and effectively as possible. This study aimed to test if a training intervention was able to bring novices' risk thresholds for financial abuse in line with expert opinion. METHODS: A signal detection analysis, within a randomised controlled trial of an educational intervention, was undertaken to examine the effect on the ability of novices to efficiently detect financial abuse. Novices (n = 154) and experts (n = 33) judged "certainty of risk" across 43 scenarios; whether a scenario constituted a case of financial abuse or not was a function of expert opinion. Novices (n = 154) were randomised to receive either an on-line educational intervention to improve financial abuse detection (n = 78) or a control group (no on-line educational intervention, n = 76). Both groups examined 28 scenarios of abuse (11 "signal" scenarios of risk and 17 "noise" scenarios of no risk). After the intervention group had received the on-line training, both groups then examined 15 further scenarios (5 "signal" and 10 "noise" scenarios). RESULTS: Experts were more certain than the novices, pre (Mean 70.61 vs. 58.04) and post intervention (Mean 70.84 vs. 63.04); and more consistent. The intervention group (mean 64.64) were more certain of abuse post-intervention than the control group (mean 61.41, p = 0.02). Signal detection analysis of sensitivity (A') and bias (C) revealed that this was due to the intervention shifting the novices' tendency towards saying "at risk" (C post intervention .34) and away from their pre intervention levels of bias (C-.12). Receiver operating curves revealed more efficient judgments in the intervention group. CONCLUSION: An educational intervention can improve judgements of financial abuse amongst novice professionals. PMID- 25547515 TI - APP: an Automated Proteomics Pipeline for the analysis of mass spectrometry data based on multiple open access tools. AB - BACKGROUND: Mass spectrometry analyses of complex protein samples yield large amounts of data and specific expertise is needed for data analysis, in addition to a dedicated computer infrastructure. Furthermore, the identification of proteins and their specific properties require the use of multiple independent bioinformatics tools and several database search algorithms to process the same datasets. In order to facilitate and increase the speed of data analysis, there is a need for an integrated platform that would allow a comprehensive profiling of thousands of peptides and proteins in a single process through the simultaneous exploitation of multiple complementary algorithms. RESULTS: We have established a new proteomics pipeline designated as APP that fulfills these objectives using a complete series of tools freely available from open sources. APP automates the processing of proteomics tasks such as peptide identification, validation and quantitation from LC-MS/MS data and allows easy integration of many separate proteomics tools. Distributed processing is at the core of APP, allowing the processing of very large datasets using any combination of Windows/Linux physical or virtual computing resources. CONCLUSIONS: APP provides distributed computing nodes that are simple to set up, greatly relieving the need for separate IT competence when handling large datasets. The modular nature of APP allows complex workflows to be managed and distributed, speeding up throughput and setup. Additionally, APP logs execution information on all executed tasks and generated results, simplifying information management and validation. PMID- 25547516 TI - Exploiting stoichiometric redundancies for computational efficiency and network reduction. AB - Analysis of metabolic networks typically begins with construction of the stoichiometry matrix, which characterizes the network topology. This matrix provides, via the balance equation, a description of the potential steady-state flow distribution. This paper begins with the observation that the balance equation depends only on the structure of linear redundancies in the network, and so can be stated in a succinct manner, leading to computational efficiencies in steady-state analysis. This alternative description of steady-state behaviour is then used to provide a novel method for network reduction, which complements existing algorithms for describing intracellular networks in terms of input output macro-reactions (to facilitate bioprocess optimization and control). Finally, it is demonstrated that this novel reduction method can be used to address elementary mode analysis of large networks: the modes supported by a reduced network can capture the input-output modes of a metabolic module with significantly reduced computational effort. PMID- 25547517 TI - An innovative approach to teaching bioethics in management of healthcare. AB - BACKGROUND: Bioethical courses were introduced in the curricula in medical universities in Bulgaria in 1990s. In the beginning, the courses were mainly theoretical, and systematic case analyses and discussions of movies were introduced later on. The benefits of using films to teach ethics have been previously analyzed in the literature; however, to our knowledge such studies in Bulgaria are yet lacking. OBJECTIVE: The aim of this study was to survey the opinions of students and analyze the results from the application of movies in bioethics teaching in a medical university in the north of Bulgaria. METHODOLOGY: A survey was carried out among 92 students in the management of healthcare. Two movies were used, and separate protocols for film discussion were developed. ETHICAL CONSIDERATIONS: The study was conducted anonymously and with students' free informed consent. RESULTS AND DISCUSSION: The students distinguished in total 21 different dilemmas and concepts in the first movie. The ethical dilemmas were classified into five groups: general ethical issues, deontological issues, special ethical issues, principles of bioethics, and theories of ethics. The second movie focused students' attention on the issues of death and dying. In total, 18 elements of palliative care were described by the students. The range of different categories was a positive indicator of an increased ethical sensitivity. The students evaluated the movies' discussions as a generally positive educational approach. They perceived the experience as contributing to their better understanding of bioethical issues. CONCLUSION: The innovative approach was well accepted by the students. The introduction of movies in the courses of bioethics had the potential to provide vivid illustrations of bioethical issues and to contribute to the exploration of specific theses and arguments. The presentation and discussion should be preceded by accumulation of theoretical knowledge. The future of effective bioethics education lays in the interactive involvement of students. PMID- 25547514 TI - Engineering artificial machines from designable DNA materials for biomedical applications. AB - Deoxyribonucleic acid (DNA) emerges as building bricks for the fabrication of nanostructure with complete artificial architecture and geometry. The amazing ability of DNA in building two- and three-dimensional structures raises the possibility of developing smart nanomachines with versatile controllability for various applications. Here, we overviewed the recent progresses in engineering DNA machines for specific bioengineering and biomedical applications. PMID- 25547518 TI - Alternatives for the enforcement of the right to health in Brazil. AB - In this article, the right to health is discussed as a social right and an essential requisite in the construction and guarantee of human rights, more precisely human dignity, considering this right as a complex but effective process in the transformation of the social reality. In the first place, the activities of the public power and its difficulties to guarantee universal access to health are highlighted. This scenario ends up inhibiting the practice of the right to health and prevents users from enjoying and using it. In that sense, this article challenges and explores some alternatives to solidify and put in practice the right to health in Brazil. Departing from the analysis of the Unified Health System (SUS) and social participation in Brazil, this article discusses the judicialization of health in the country, highlighting the difficulties the State faces to equitably offer universal healthcare to society. This context offers an opportunity for reflection and a paradigm change, from the "judicialization of health" to the "judicialization of health policies." Finally, the public health policies adopted by other countries are emphasized, in the attempt to construct the empowerment of human beings in the practice of their rights, particularly social participation and the discussion about the States' responsibility to put their citizens' right to health in practice. In conclusion, the political and collective construction of the right to health needs to be encouraged, distinguishing the legitimate interests of the different interlocutors involved. PMID- 25547519 TI - 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). PMID- 25547520 TI - Campaigners criticise India's new system for compensating clinical trial deaths. PMID- 25547521 TI - Stakeholder perceptions and practices regarding Prosopis (mesquite) invasions and management in South Africa. AB - Invasive alien trees impact the environment and human livelihoods. The human dimensions of such invasions are less well understood than the ecological aspects, and this is hindering the development of effective management strategies. Semi-structured interviews were undertaken to investigate the knowledge and perceptions of Prosopis between different stakeholder groups. Chi squared tests, Welch ANOVAs, and Principle Component Analyses were run. Factors such as land tenure and proximity to invasions were especially important for explaining differences in perceptions and practices relating to Prosopis among different stakeholder groups. Most respondents were aware of Prosopis and considered it to be invasive (i.e., spreading). Costs associated with Prosopis were perceived to exceed benefits, and most stakeholders wanted to see a reduction in the abundance of Prosopis stands. The mean total cost for the management of Prosopis was US$ 1914 year(-1) per farm, where costs ranged from under US$ 10 to over UD$ 500 per ha based on invasion densities and objectives for control. The findings highlight the need for more effective management interventions. PMID- 25547522 TI - A meta-analysis of the efficacy of acceptance and commitment therapy for clinically relevant mental and physical health problems. AB - BACKGROUND: The current study presents the results of a meta-analysis of 39 randomized controlled trials on the efficacy of acceptance and commitment therapy (ACT), including 1,821 patients with mental disorders or somatic health problems. METHODS: We searched PsycINFO, MEDLINE and the Cochrane Central Register of Controlled Trials. Information provided by the ACBS (Association of Contextual Behavioral Science) community was also included. Statistical calculations were conducted using Comprehensive Meta-Analysis software. Study quality was rated using a methodology rating form. RESULTS: ACT outperformed control conditions (Hedges' g = 0.57) at posttreatment and follow-up assessments in completer and intent-to-treat analyses for primary outcomes. ACT was superior to waitlist (Hedges' g = 0.82), to psychological placebo (Hedges' g = 0.51) and to treatment as usual (TAU) (we defined TAU as the standard treatment as usual; Hedges' g = 0.64). ACT was also superior on secondary outcomes (Hedges' g = 0.30), life satisfaction/quality measures (Hedges' g = 0.37) and process measures (Hedges' g = 0. 56) compared to control conditions. The comparison between ACT and established treatments (cognitive behavioral therapy) did not reveal any significant differences between these treatments (p = 0.140). CONCLUSIONS: Our findings indicate that ACT is more effective than treatment as usual or placebo and that ACT may be as effective in treating anxiety disorders, depression, addiction, and somatic health problems as established psychological interventions. More research that focuses on quality of life and processes of change is needed to understand the added value of ACT and its transdiagnostic nature. PMID- 25547523 TI - Low rates of fimbrial excision at tubal ligation: room for improvement? PMID- 25547524 TI - Predicting treatment response in castration-resistant prostate cancer: could androgen receptor variant-7 hold the key? AB - There is an emerging interest in understanding mechanisms of response and resistance to next-generation hormonal therapies: abiraterone and enzalutamide. While many explanations for resistance to these agents have been postulated, the importance of androgen receptor splice variants is gaining momentum. Androgen receptor (AR) splice variants are constitutively active isoforms of the AR that lack the ligand-binding domain yet retain their transcriptional activity in a ligand-independent fashion. Of these, AR variant-7 may be the most important, and has been implicated in primary resistance to abiraterone and enzalutamide in men with advanced prostate cancer. In this editorial, the clinical relevance of AR splice variant-7 (AR-V7) will be reviewed within the context of AR-directed therapies, and next steps for the analytical and clinical validation of this potential biomarker will be proposed. PMID- 25547525 TI - Reply to the comment by Ilhan et al. on our paper entitled 'effect of macular ischemia on intravitreal ranibizumab treatment for diabetic macular edema'. PMID- 25547526 TI - Skin bridge on a nail plate caused by distal onychocryptosis. PMID- 25547528 TI - Double transseptal puncture adjacent to multiple Amplatzer atrial septal occluders: case report. AB - Successful transseptal puncture adjacent to a single Amplatzer atrial septal closure device is well described. Rarely multiple Amplatzer devices may be required to close defects in the interatrial septum. We report on successful double transseptal puncture adjacent to multiple Amplatzer atrial septal occluder devices for the purposes of catheter ablation for atrial fibrillation. PMID- 25547527 TI - Growth and differentiation factor-5 contributes to the structural and functional maintenance of the intervertebral disc. AB - Intervertebral disc degeneration (IDD) is a widely recognized contributor to low back pain (LBP). The Prevention or reversal of IDD is a potential treatment for LBP. Unfortunately, current treatments for IDD are aimed at relieving symptoms rather than regenerating disc structure or function. Recently, the injection of growth factors and mesenchymal stem cell (MSC) transplantation have been shown to be promising biological therapies for IDD. Growth factors stimulate the proliferation of and matrix synthesis by intervertebral disc (IVD) cells, leading to the regeneration of degenerative discs. Growth factors, hypoxia and co-culture with nucleus pulposus (NP) cells induce MSCs to differentiate toward an NP-like phenotype, which can increase the number of functional cells in the IVD or enhance the function of endogenous disc cells to facilitate IVD regeneration. Therefore, the emerging roles of growth factors in IVD regeneration have piqued the interest of researchers. Growth factors including transforming growth factor beta (TGF-beta), fibroblast growth factor (FGF), insulin-like growth factor-1 (IGF-1) and growth and differentiation factor-5 (GDF-5), among others, have been demonstrated to enhance anabolism in IVD cells and to induce NP-like differentiation of MSCs. However, the injection of TGF, IGF and FGF into human IVDs may induce unwanted blood vessel ingrowth, which accelerates the process of IDD, the injection of GDF-5 may not have the same effect. This finding suggests that GDF-5 is a preferable growth factor for use in IDD treatment compared with TGF, IGF and FGF. The GDF-5 gene is one of the few growth factor genes that have been found to be associated with IDD thus far; moreover, the GDF-5 gene defects lead to collagen and proteoglycan abnormalities in discs in mice, suggesting that GDF-5 contributes to the structural and functional maintenance of the IVD. This review is focused on the functions of GDF-5 in the IVD and on the association between GDF-5 and a genetic predisposition to IDD. The effects of GDF-5 on IVD regeneration and on MSC differentiation are also discussed. GDF-5 plays a crucial role in the pathogenesis of IDD and is a promising therapeutic agent for IDD. Additionally, stem cell transplantation has been shown to be a promising biological therapy for IDD. PMID- 25547529 TI - Kounis syndrome: a stinging case of ST-elevation myocardial infarction. AB - Kounis syndrome is not a rare but an infrequently diagnosed non-thrombogenic cause of angina or myocardial infarction triggered by the release of inflammatory mediators following an allergic or anaphylactic reaction. This so-called "allergic angina" is seen in the setting of anaphylactic reactions and is believed to be due to mast cell release causing coronary vasospasm. The treatment of such cases is often with epinephrine, which has also been described in the literature as another rare cause of coronary vasospasm. We present a case of Kounis syndrome seen in a 46 year-old male who suffered two bee stings while landscaping in his yard. He developed an anaphylactic reaction and was promptly treated with IM epinephrine injection by paramedics at arrival and developed marked ST elevations on EKG in the inferior leads with reciprocal ST depressions in the anterior leads. His troponin peaked at 13 ng/mL and tryptase level was 15 ng/mL (normal <10 ng/mL). Coronary catheterisation showed non-diseased coronary arteries and a normal ejection fraction without evidence of vasospasm. He was afterwards treated with an epinephrine drip for distributive shock. Interestingly this syndrome was not provoked when re-challenged with this therapy, suggestive of an allergic reaction rather than epinephrine as the aetiology of his presumed vasospasm. This patient's ST segment elevation and troponin elevation was due to Kounis syndrome. Awareness that anaphylactic reactions can lead to Kounis syndrome can lead to prompt appropriate treatment for this life threatening condition. PMID- 25547530 TI - Thoracoscope-assisted Right Vertical Infra-axillary Mini-incision for Cardiac Surgery. AB - BACKGROUND: The thoracoscope and minimally invasive techniques have been effectively used in cardiac surgery. METHODS: The study included 27 consecutive patients (aged 24.8+/-17.6 years), who underwent cardiac surgery from January 2012 to July 2013. Six patients were diagnosed with mitral valve stenosis (MS), 17 patients with atrial septal defects (ADSs), and four with ventricular septal defects (VSDs). All the patients underwent thoracoscope-assisted right vertical infra-axillary mini-incision (TARVAI). RESULTS: The procedure was successfully performed in all patients. For the patients with ASDs or VSDs, the times for cardiopulmonary bypass, aortic cross-clamping, operating (skin-to-skin), ventilation, ICU stay, postoperative hospital stay were 63+/-25 min, 28.1+/-15.5 min, 167.1+/-35.7 min, 5.2+/-2.7 h, 25.3+/-10.5 h, 8.7+/-3.6 days, and for the patients with MS, these were 143.3+/-25.2 min, 88.2+/-15.4 min, 236.5+/-48.5 min, 7.3+/-1.5 h, 36.7+/-9.1 h, and 13.5+/-4.4 days, respectively. The median postoperative drainage (total) for the ASD/VSD and MS patients was 136.3+/-54.5 ml and 203.8+/-94.4 ml, respectively. CONCLUSIONS: In our institution, the TARVAI approach is feasible and safe in cardiac surgery. It may be particularly useful in young patients with simple congenital heart disease and mitral valve disease. PMID- 25547531 TI - Target-vessel versus multivessel revascularisation in ST-elevation myocardial infarction: a meta-analysis of randomised trials. AB - INTRODUCTION: In acute ST-segment elevation myocardial infarction (STEMI), coronary reperfusion with percutaneous coronary intervention (PCI) to treat the culprit lesion responsible for infarction improves clinical outcomes in nearly all patients. The concurrent treatment of non-infarct vessels with significant stenoses during initial angiography remains an area of controversy. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane Library, Google Scholar, Science Direct, and Web of Science. Original data were abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Only four randomised trials comprising 775 patients met full criteria for analysis. The incidence of non-fatal MI (3.25% vs 8.51%, OR: 0.376, 95% CI: 0.192-0.763), refractory angina (4.01% vs 9.57%, OR: 0.400, 95% CI: 0.241-0.741) and repeat revascularisation (10.52% vs 24.20%, OR: 0.336, 95% CI: 0.202-0.661) was lower in the multivessel revascularisation cohort. Death from cardiac causes or refractory angina or non fatal MI (11.78% vs 28.86%, OR: 0.336, 95% CI: 0.223-0.505) and death from cardiac causes or non-fatal MI (5.26% vs 12.76%, OR: 0.420, 95% CI: 0.245-0.722) were significantly lower in the multivessel revascularisation cohort. The Median Contrast Volume and Procedure Length were similar in both cohorts. CONCLUSIONS: In patients with acute STEMI who undergo primary PCI, a strategy of treatment of significant non-infarct stenosis (preventive PCI) in addition to the culprit lesion responsible for infarction may result in improved cardiovascular outcomes and reduced overall mortality; however there is insufficient data to fully validate this from currently published literature. PMID- 25547532 TI - Microarray identification of bacterial species in peritonsillar abscesses. AB - Peritonsillar abscess (PTA) is the most common otorhinolaryngological infection, requiring management at the special healthcare level. The microbiological findings vary due to geographical, etiological, and methodological factors. This study aimed to identify the bacterial species of PTAs by using a novel polymerase chain reaction (PCR)- and microarray-based assay, and to find causative cofactors among patients with different pathogens. We determined the bacterial findings of aspirates of pus prospectively collected from 180 PTA patients. Samples were pretreated prior to nucleic acid extraction and analyzed with a PCR- and microarray-based assay or DNA sequencing. Both methods were based on the gyrB/parE topoisomerase genes. Patients answered symptom questionnaires at admission, and their medical records were reviewed later. Altogether, 160 (89 %) aspirates of pus tested positive for bacteria, and a bacterial species was identified in 149 (83 %) of the samples. A polybacterial species was detected in 20 (13 %) and anaerobic bacteria in 77 (52 %) of the 149 samples. Fusobacterium necrophorum patients were younger (p < 0 .001) and had more severe symptoms (p = 0.04) than patients with other pathogens. Gender, smoking, or preadmission antibiotics showed no correlation with any of the pathogens. Although requiring some optimization, this microarray assay seems feasible and fast for bacterial identification directly from pus samples, and confirms the diversity of PTA pathogens. Young patients with more severe symptoms may require special attention. Species-specific antibiotic treatment of PTA remains challenging due to bacterial variations; the present assay may aid in specifying PTA antibiotic treatment in the future. PMID- 25547533 TI - Magnetic bead-based salivary peptidome profiling analysis for severe early childhood caries. AB - OBJECTIVE: To investigate the differential salivary protein expression profiles between children with severe early childhood caries (S-ECC) and caries-free (CF) children at the age of 3 years. METHODS: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with weak cation exchange magnetic beads, and peptide mass fingerprints were created by scanning mass spectrometry signals. Salivary samples from 20 children were analyzed (10 for each group). RESULTS: Eleven protein peaks were significantly different (p < 0.05) between the two groups. Eight of these peaks were higher in the S-ECC group and three were higher in the CF group. To establish a diagnostic model for discrimination between the two groups, we chose three peptides (3,186.2, 3,195.8 and 3,324.8 Da) that exhibited the best fitted curve, by which the two groups were better separated when compared with other combinations. CONCLUSIONS: The salivary biomarkers identified revealed significant differences between the CF and the S-ECC group. Our results provide novel insight into the salivary protein profile of preschool-age children with dental caries and may lead to the development of a new strategy for screening high-risk populations. PMID- 25547534 TI - State of the art of immunoassay methods for B-type natriuretic peptides: An update. AB - The aim of this review article is to give an update on the state of the art of the immunoassay methods for the measurement of B-type natriuretic peptide (BNP) and its related peptides. Using chromatographic procedures, several studies reported an increasing number of circulating peptides related to BNP in human plasma of patients with heart failure. These peptides may have reduced or even no biological activity. Furthermore, other studies have suggested that, using immunoassays that are considered specific for BNP, the precursor of the peptide hormone, proBNP, constitutes a major portion of the peptide measured in plasma of patients with heart failure. Because BNP immunoassay methods show large (up to 50%) systematic differences in values, the use of identical decision values for all immunoassay methods, as suggested by the most recent international guidelines, seems unreasonable. Since proBNP significantly cross-reacts with all commercial immunoassay methods considered specific for BNP, manufacturers should test and clearly declare the degree of cross-reactivity of glycosylated and non glycosylated proBNP in their BNP immunoassay methods. Clinicians should take into account that there are large systematic differences between methods when they compare results from different laboratories that use different BNP immunoassays. On the other hand, clinical laboratories should take part in external quality assessment (EQA) programs to evaluate the bias of their method in comparison to other BNP methods. Finally, the authors believe that the development of more specific methods for the active peptide, BNP1-32, should reduce the systematic differences between methods and result in better harmonization of results. PMID- 25547535 TI - Mosaicism and uniparental disomy in prenatal diagnosis. AB - Chromosomal mosaicism is the presence of numerous cell lines with different chromosomal complements in the same individual. Uniparental disomy (UPD) is the inheritance of two homologous chromosomes from the same parent. These genetic anomalies arise from errors in meiosis and/or mitosis and can occur independently or in combination. Due to the formation mechanisms of UPD, low-level or undetected mosaicisms are assumed for a significant number of UPD cases. The pre- and postnatal clinical consequences of mosaicism for chromosomal aberrations and/or UPD depend on the gene content of the involved chromosome. In prenatal evaluation of chromosomal mosaicism and UPD, genetic counseling should be offered before any laboratory testing. PMID- 25547536 TI - Semi-automated nanoprecipitation-system--an option for operator independent, scalable and size adjustable nanoparticle synthesis. AB - The preparation of nano-sized carrier systems increasingly moved into focus of pharmaceutical research and industry in the past decades. Besides the drug load and properties of the selected polymer/lipid, the size of such particles is one of the most important parameters regarding their use as efficient drug delivery systems. However, the preparation of nanoparticles with different sizes in a controlled manner is challenging, especially in terms of reproducibility and scale-up possibility. To overcome these hurdles we developed a system relying on nanoprecipitation, which meets all these requirements of an operator independent, scalable and size-adjustable nanoparticle synthesis-the Semi-Automated Nanoprecipitation-System. This system enables the adaption of the particle size to specific needs based on the process parameters-injection rate, flow rate and polymer concentration-identified within this study. The basic set-up is composed of a syringe pump and a gear pump for a precise control of the flow and injection speed of the system. Furthermore, a home-made tube-straightener guarantees a curvature-free injection point. Thus it could be shown that the production of poly(lactide-co-glycolide) nanoparticles from 150 to 600 nm with a narrow size distribution in a controlled semi-automatic manner is possible. PMID- 25547537 TI - Antibacterial and antibiofilm surfaces through polydopamine-assisted immobilization of lysostaphin as an antibacterial enzyme. AB - Antibiotic resistance and the colonization of bacteria on surfaces, often as biofilms, prolong hospitalization periods, increase mortality, and are thus major concerns for health care providers. There is an urgent need for antimicrobial and antibiofilm surface treatments that are permanent, can eradicate both biofilms and planktonic pathogens over long periods of time, and do not select for resistant strains. In this study, we have demonstrated a simple, robust, and biocompatible method that utilizes the adhesive property of polydopamine (PDA) to covalently attach the antimicrobial enzyme lysostaphin (Lst) to a variety of surfaces to generate antibacterial and antibiofilm interfaces. The immobilization of the recombinant Lst onto PDA-coated surfaces was carried out under physiological conditions, most probably through the C-terminal His6-tag fragment of the enzyme, minimizing the losses of bioagent activity. The modified surfaces were extensively characterized by X-ray photoelectron spectroscopy and peak force quantitative nanomechanical mapping (PeakForce QNM) AFM-based method, and the presence of Lst on the surfaces was further confirmed immunochemically using anti Lst antibody. We also found that, in contrast to the physically adsorbed Lst, the covalently attached Lst does not leach from the surfaces and maintains its endopeptidase activity to degrade the staphylococcal cell wall, avoiding most intracellular bacterial resistance mechanisms. Moreover, the Lst-coated surfaces kill hospital strains of Staphylococcus aureus in less than 15 min and prevent biofilm formation. This immobilization method should be applicable also to other proteins and enzymes that are recombinantly expressed to include the His6-tag fragment. PMID- 25547538 TI - A decade of building massage therapy services at an academic medical center as part of a healing enhancement program. AB - The use of complementary and integrative medicine therapies is steadily becoming an integral part of health care. Massage therapy is increasingly offered to hospitalized patients for various conditions to assist with the management of common symptoms such as pain, anxiety, and tension. This article summarizes a decade of building the massage therapy service at a large tertiary care medical center, from the early pilot studies and research to the current program offerings, and the hopes and dreams for the future. PMID- 25547539 TI - Copper-catalyzed enantioselective intramolecular aryl C-N coupling: synthesis of enantioenriched 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamides via an asymmetric desymmetrization strategy. AB - The differentiation of two nucleophilic amide groups in malonamides through a copper-catalyzed enantioselective intramolecular aryl C-N coupling reaction is demonstrated based on an asymmetric desymmetrization strategy. Such a method afforded enantioenriched 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamides in high yields and moderate to good enantioselectivity. PMID- 25547540 TI - Multiple colonization with highly resistant bacteria: carbapenemase-producing Enterobacteriaceae, carbapenemase-producing Pseudomonas aeruginosa, carbapenemase producing Acinetobacter baumannii, and glycopeptide-resistant Enterococcus faecium. PMID- 25547541 TI - Head and neck myxofibrosarcoma: a case report and review of the literature. AB - INTRODUCTION: Myxofibrosarcoma is the most common soft tissue sarcoma that occurs in late adult life, peaking in the seventh decade, and it is mainly encountered in the lower extremities. Myxofibrosarcoma of the head and neck are extremely rare. To the best of our knowledge, only 19 cases have been described in the head and neck so far. This is a literature review and retrospective chart review of our experience in head and neck myxofibrosarcoma treatment in our department. CASE PRESENTATION: In this case report we describe a 35-year-old Caucasian man who presented the first case of myxofibrosarcoma arising from the pterygopalatine fossa. The peculiar anatomical location and the extent in the midcheek region make this case a hard "challenge" for the surgeon, in order to guarantee wide surgical margins of resection. A total right maxillectomy was accomplished by means of the Weber-Ferguson approach, preserving the orbital floor. The excised portion was reconstructed using the free rectus abdominis myocutaneous flap. Postoperative radiotherapy was given to the area adjacent to the lesion, with a total dose of 60 Gy. No relapse occurred in the 27-month postoperative follow-up. CONCLUSIONS: The case described suggests the importance of combined surgical and adjuvant radiotherapy to avoid local and distant recurrences of the tumor. In our opinion, combined surgical and adjuvant radiotherapy followed by close clinical observation to search for a metastatic disease is advisable in all cases. Further studies are needed to confirm the efficacy of combined radio-chemotherapy for head and neck myxofibrosarcoma in terms of long-term disease-free survival. PMID- 25547542 TI - Endovascular repair of thoracic aortic aneurysm associated with right-sided aortic arch: report of two cases. AB - Right-sided aortic arch (RAA) is a rare congenital disorder. We describe herein two cases of thoracic aortic aneurysm with a right aortic arch and right-sided descending aorta treated with thoracic endovascular aortic repair (TEVAR). In one case, a 70-year-old man with Edwards type 1 RAA underwent TEVAR using a Relay stent-graft (Bolton Medical, Barcelona, Spain). In another case, a 72-year-old woman with Edwards type 3 RAA underwent TEVAR using a Kawasumi Najuta stent-graft (Kawasumi Laboratories, Inc., Tokyo, Japan) with the "buffalo horn chimney technique", our original method for left subclavian artery flow preservation. The postoperative courses were uneventful. Postoperative computed tomography showed complete exclusion of the aneurysm without endoleakage. Compared to conventional open surgical repair, TEVAR is challenging in patients with a RAA and right-sided descending aorta. However, our results showed that TEVAR might be feasible and a treatment option even in a patient with a RAA and right-sided descending aorta. PMID- 25547543 TI - Canadian Cardiovascular Society 2014 algorithm for anticoagulation therapy in atrial fibrillation debated. PMID- 25547544 TI - When it comes to atrial fibrillation recurrence, perhaps we should look both left and right. PMID- 25547545 TI - The new Canadian Cardiovascular Society algorithm for antithrombotic therapy of atrial fibrillation is appropriately based on current epidemiologic data. PMID- 25547546 TI - Atrial fibrillation patients categorized as "not for anticoagulation" according to the 2014 Canadian Cardiovascular Society algorithm are not "low risk". AB - BACKGROUND: Oral anticoagulation (OAC) is highly effective for stroke prevention in nonvalvular atrial fibrillation. We explored rates of stroke/thromboembolism/transient ischemic attack among the "OAC not recommended" patient group defined according to the 2014 Canadian Cardiovascular Society (CCS) algorithm (based on the Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack [CHADS2] score) who would have been offered OAC using the European Society of Cardiology (ESC) guidelines approach (based on the Congestive Heart Failure, Hypertension, Age [>=75 years], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 years], Sex [Female]; CHA2DS2-VASc score). METHODS: We identified 22,582 nonanticoagulated patients age < 65 years with a CHADS2 score of 0 who were stratified according to the CHA2DS2-VASc score, except female sex, which would be an indication for OAC according to the ESC guidelines. Event rates for each risk strata were compared using Cox proportional hazard ratios. RESULTS: The overall rate of the combined end point of ischemic stroke/systemic embolism/transient ischemic attack was 4.32 per 100 person-years (95% confidence interval [CI], 3.26-5.74) at 1 year, among the patients who would have had an indication for OAC therapy according to ESC guidelines and "OAC not recommended" according to CCS algorithm. This corresponded to an adjusted hazard ratio of 3.08 (95% CI, 2.21-4.29) relative to the subgroup with no indication for OAC according to the ESC guidelines. A subgroup of patients with previous vascular disease and CHADS2 score of 0 (ie, recommended only aspirin treatment according to the CCS algorithm) had an event rate of 4.84 (95% CI, 3.53-6.62) per 100 person-years at 1-year follow-up. CONCLUSIONS: Based on the 2014 CCS algorithm, the "OAC not recommended" subgroup can have a high 1-year stroke rate overall, showing that such patients are not "low risk." Use of the ESC guideline approach (based on the CHA2DS2-VASc) offers refinement of stroke risk stratification in such patients. PMID- 25547547 TI - Right atrial volume is superior to left atrial volume for prediction of atrial fibrillation recurrence after direct current cardioversion. AB - BACKGROUND: The value of right atrial volume as a predictor for recurrence of atrial fibrillation (AF) after direct current cardioversion (DCCV) is unknown. METHODS: We sought to compare the performance of right atrial volume indexed to body surface area (RAVI), left atrial diameter, left atrial volume indexed to body surface area (LAVI), and biatrial volume index (BAVI) for the prediction of AF recurrence at 6 months after DCCV. This study included the first 95 consecutive patients from the AF Clinic at a large tertiary care hospital who underwent DCCV and who had an echocardiogram available within 6 months before DCCV. Maximal LAVI, RAVI, and BAVI were determined from the echocardiogram before DCCV. Electrocardiographic and clinical data were acquired at baseline, before cardioversion, and at each clinic visit. RESULTS: Of the 95 patients (64 male; mean age, 63 +/- 12 years), history of systemic hypertension, diabetes mellitus, heart failure, and transient ischemic attack/stroke was present in 60 (63%), 14 (15%), 27 (28%), and 5 (5%) patients, respectively. Mean duration from AF diagnosis to DCCV was 3.5 +/- 5.0 years. At 6 months after DCCV, 53 (56%) had reverted to AF. RAVI had superior predictive ability (area under the receiver operator characteristic curve: RAVI, 0.77; left atrial diameter, 0.54; LAVI, 0.64; and BAVI, 0.70). RAVI >= 42 mL/m(2) provided the best accuracy for prediction of recurrence (76% accuracy, 71% sensitivity, 83% specificity, 90% positive predictive value, and 56% negative predictive value). Best accuracy for LAVI was >= 48 mL/m(2) (70% accuracy, 53% sensitivity, 79% specificity, 85% positive predictive value; 43% negative predictive value). CONCLUSIONS: RAVI is superior to LAVI for the prediction of AF recurrence at 6 months after DCCV. PMID- 25547548 TI - Effects of sinus rhythm maintenance on left heart function after electrical cardioversion of atrial fibrillation: implications for tachycardia-induced cardiomyopathy. AB - BACKGROUND: The role of tachycardia-induced cardiomyopathy vs tachycardia-related short diastolic filling period and reduced atrial contraction in decline of left ventricular ejection fraction (LVEF) in atrial fibrillation (AF) is uncertain. We aimed to characterize left heart changes over time in patients with AF who undergo electrical cardioversion (ECV). METHODS: Consecutive AF patients who were to undergo ECV were enrolled. Patients with unstable or acute heart failure, severe valvular diseases, recent open-heart surgery, major disorders, or an unsuccessful ECV were excluded. Transthoracic echocardiography, including 3 dimensional left atrial and ventricular volume acquisitions, was performed 1-2 hours before and after ECV, and 4-6 weeks later. RESULTS: In 73 patients (77% male, 66 +/- 11 years), ECV resulted in an immediate increase in LVEF (from 43 [interquartile range (IQR), 33-50%] to 48 [IQR, 40-53%]; P < 0.0001). Four to 6 weeks after ECV, ejection fraction increased further in patients who remained in sinus rhythm (SR) (n = 55) to 55 (IQR, 44-62)%; P < 0.001. In patients with AF relapse, LVEF returned to values comparable to pre-ECV (n = 18) (44 [IQR, 32 51]%; P = 0.03). The atrial emptying fraction did not significantly change immediately after ECV (n = 69; from 20 [IQR, 13-25]% to 20 [IQR, 15-28]%; P = 0.14). Only patients who remained in SR showed an increase in atrial emptying fraction after 4-6 weeks (n = 51; to 37 [IQR, 26-48]%; P < 0.0001 vs post-ECV). CONCLUSIONS: Immediate improvement in LVEF after ECV explains approximately 50% of total LVEF increase over time. However, in SR, LVEF, and atrial function continuously increase over 4-6 weeks after ECV. This might be attributable to recovery of tachycardia-induced cardiomyopathy. PMID- 25547549 TI - Glycated hemoglobin vs fasting plasma glucose as a predictor of left ventricular dysfunction after ST-elevation myocardial infarction. AB - BACKGROUND: The World Health Organization and the American Diabetes Association recommend a level of glycated hemoglobin (HbA1c) >= 6.5% as diagnostic for diabetes. However, concordance between fasting plasma glucose (FPG) and HbA1c levels in acutely unwell patients is unknown. Furthermore, the prognostic value of HbA1c for left ventricular (LV) dysfunction is unclear. This study aimed to evaluate the concordance between HbA1c levels and FPG in consecutive patients with acute ST-elevation MI (STEMI) and compare their prognostic value in predicting LV dysfunction and elevated filling pressures on echocardiography. METHODS: A total of 142 patients with a first incidence of STEMI were prospectively recruited. LV diastolic function was defined as mean septal and lateral early diastolic velocities (average e'); filling pressure was the ratio of transmitral E velocity to average e' (average E/e'). RESULTS: Mean FPG and HbA1c levels were 7.7 +/- 2.8 mmol/L and 6.5% +/- 1.6%, respectively. Of 109 patients without previous diabetes, HbA1c levels identified an additional 18 patients (16.5%) as having diabetes, and the concordance with FPG was poor. Between diabetic and nondiabetic patients, there were no differences in LV end diastolic volume (116 +/- 37 vs 118 +/- 43 mL; P = 0.78), end-systolic volume (69 +/- 33 vs 68 +/- 35 mL; P = 0.93), and ejection fraction (42 +/- 12 vs 44 +/- 11%; P = 0.49). On multivariable analyses, average e' was independently associated with HbA1c (beta = -0.161; P = 0.045) but not FPG (P = 0.82). Similarly, average E/e' was independently associated with HbA1c (beta = 0.168; P = 0.04) but not FPG (P = 0.32). Receiver operating characteristic curve analysis showed that an HbA1c cutoff of 6.4% (area under the curve, 0.68; P = 0.002) was associated with an elevated LV filling pressure. CONCLUSIONS: Only HbA1c was independently associated with impaired LV diastolic function and increased filling pressures after STEMI. PMID- 25547551 TI - Periprocedural bleeding, acute kidney injury, and long-term mortality after transcatheter aortic valve implantation. AB - BACKGROUND: Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) is frequent and is associated with adverse outcomes. Past studies have attributed AKI to impaired kidney function at baseline, amount of contrast medium used, major bleeding, and hemodynamic instability during the procedure. Because major bleeding might play a role in the development of AKI, we analyzed the relationship between periprocedural bleeding and the development of AKI and assessed the impact of these 2 important procedure-related complications on outcome. METHODS: Consecutive patients undergoing transfemoral TAVI for severe aortic stenosis were prospectively recruited. AKI and bleeding events during hospitalization were recorded, defined, and classified according to the Valve Academic Research Consortium 2 definitions. Logistic and Cox regression was used for predictor and survival analyses. RESULTS: We recruited 422 consecutive patients who underwent TAVI; the mean follow-up duration was 576 +/- 400 days. AKI occurred in 66 (15.6%) patients. No patient required dialysis. Fifty patients (12%) had major or life-threatening bleeding. Periprocedural major or life threatening bleeding was a strong predictor of the development of AKI (odds ratio, 3.19; 95% confidence interval [CI], 1.38-7.1; P = 0.006). Major bleeding was a strong independent predictor for both 30-day and long-term mortality (hazard ratio [HR], 6.67; 95% CI, 2.2-19.8; P = 0.001 and HR, 3.3, 95% CI, 1.2 9.0; P = 0.02, respectively), whereas AKI was not independently associated with increased mortality after TAVI. CONCLUSIONS: In patients undergoing transfemoral TAVI, periprocedural bleeding is a strong risk factor for the development of AKI and a major determinant of short- and long-term mortality. PMID- 25547550 TI - Association of admission hemoglobin levels and acute kidney injury among myocardial infarction patients treated with primary percutaneous intervention. AB - BACKGROUND: Anemia on admission is associated with an increased risk for contrast induced nephropathy, however, its association with acute kidney injury (AKI) after ST segment elevation myocardial infarction (STEMI) in patients undergoing primary percutaneous coronary intervention (PPCI) has not been studied. Our aim was to evaluate whether admission hemoglobin levels might increase the risk of AKI among STEMI patients who undergo PPCI. METHODS: We performed a retrospective analysis of 1248 consecutive patients admitted with the diagnosis of STEMI between January 2008 and January 2014, and treated with PPCI. Patient medical records were reviewed for admission hemoglobin levels and for the occurrence of AKI. RESULTS: The mean age of patients was 61 +/- 13 years and 1009 (81%) were male. AKI occurred in 115 patients (9.2%). Patients with AKI were more likely to be older, female, with more comorbidities, had longer symptom duration, and more likely to be in a critical state. Patients with AKI had significantly lower admission hemoglobin levels (13.6 +/- 1.7 g/dL vs 14.4 +/- 1.5 g/dL; P < 0.001) and were more likely to be anemic (27% vs 12%; P < 0.001). In a multivariate logistic regression model, a lower admission hemoglobin level (odds ratio, 0.86; 95% confidence interval, 0.74-0.98; P = 0.04) and the presence of anemia on admission (odds ratio, 1.76; 95% confidence interval, 1.02-3.02; P = 0.04) emerged as independent predictors of AKI. CONCLUSIONS: Among STEMI patients who underwent PPCI, a lower admission level of hemoglobin and anemia (hemoglobin < 12 in women or < 13 in men) were independent predictors of AKI. Precautions to prevent AKI should be particularly considered in anemic patients. PMID- 25547552 TI - Sutureless aortic valve replacement: a Canadian multicentre study. AB - BACKGROUND: Sutureless aortic valve replacement (AVR) has recently been introduced as an alternative to standard AVR in elderly high-risk surgical patients. The purpose of this study was to report the early Canadian experience with sutureless AVR. METHODS: A Canadian multicenter study included 215 consecutive patients from 6 centres who underwent sutureless AVR using the Perceval S bioprosthesis (Sorin Group, Saluggia, Italy) between June 2011 and May 2013. Perioperative clinical and echocardiographic outcomes were assessed in all patients. RESULTS: Mean age was 79 +/- 6 years, and 116 patients (54%) were women. Concomitant procedures included coronary artery bypass grafting in 86 patients (40%), multiple valve procedures in 24 (11%) patients, and septal myectomy in 9 (4%) patients. A full sternotomy was used in 173 cases (80%), a minithoracotomy in 23 (11%) cases, and a partial sternotomy in 19 (9%) cases. Nineteen cases (9%) were redo procedures. For isolated AVR, mean aortic cross clamp time was 41 +/- 12 minutes. In-hospital mortality occurred in 9 patients (4%). No postoperative valve migration was reported. A total of 37 patients (17%) underwent postoperative implantation of a permanent pacemaker, including 20 patients (9%) who had complete atrioventricular block. Postoperative stroke occurred in 7 patients (3%). Echocardiographic evaluation demonstrated well seated valves with no significant (2+) valvular or paravalvular aortic insufficiency and a mean aortic gradient of 13 +/- 6 mm Hg. CONCLUSIONS: Sutureless AVR using the Perceval S prosthesis is safe and reproducible and results in short operative times. Echocardiographic results are encouraging, with low gradients and no paravalvular aortic insufficiency. However, in this series, sutureless AVR was associated with a high risk of permanent pacemaker implantation. PMID- 25547553 TI - Predictors of late improvement of significant remnant tricuspid regurgitation detected early after tricuspid annuloplasty. AB - BACKGROUND: In some patients with severe tricuspid regurgitation (TR) who undergo tricuspid annuloplasty (TAP), significant remnant TR is detected early after TAP but diminishes after long-term follow-up. We sought to investigate the outcome of significant residual TR early after TAP and the predictors for late improvement of TR. METHODS: A total of 58 consecutive patients presenting with moderate to severe TR early (5.7 +/- 2.0 days) after TAP and before discharge were enrolled in this study. Echocardiography was repeated for 32.3 +/- 28.6 months after TAP, and improvements in TR were defined as mild or less TR. Clinical data and echocardiographic studies were retrospectively analyzed. RESULTS: Twenty-nine (50%) patients showed late improvement in TR during follow-up. Multivariate Cox regression analysis revealed that tricuspid valve (TV) tenting height measured early after TAP (P = 0.020) and execution of the Maze procedure with TAP (P = 0.049) were independent predictors for late improvement of significant early remnant TR. The rates of late TR improvement were higher in patients with an early postoperative TV tenting height >= 9.1 mm (P = 0.026) and in patients who underwent a Maze procedure (P = 0.033) than in other groups of patients. CONCLUSIONS: Half of patients with significant remnant TR early after TAP show late improvement in TR. Evaluation of a combined Maze procedure and TV tenting height early after TAP will help identify patients for whom repeated TV surgery may be deferred. PMID- 25547554 TI - In situ postconditioning with neuregulin-1beta is mediated by a PI3K/Akt dependent pathway. AB - BACKGROUND: The myocardial infarct size can be reduced by pharmacological postconditioning using cardioprotective agents. Neuregulin-1beta is a potential candidate, but previous studies in an isolated heart model of ischemia and reperfusion displayed controversial results. An in situ model of ischemia/reperfusion was used to clarify whether the remote application of neuregulin-1beta can reduce the reperfusion injury. A second aim was to evaluate, if the effects are specific for reperfused tissue or if this is a general antiapoptotic effect. In addition, the contributing molecular mechanisms were investigated. METHODS: In an open chest model, mouse hearts were subjected to a regional ischemia (45-minute) using ligature of the left anterior descending artery. Neuregulin-1beta (80 ng/kg) was given using an intraperitoneal bolus injection 5 minutes before reopening of the ligature followed by a 30-minute reperfusion. RESULTS: Remote application of recombinant neuregulin-1beta protected the heart from reperfusion injury without influencing hemodynamics. This beneficial effect specifically targets reperfusion injury. In contrast, nonreperfused needle trauma was not reduced by neuregulin-1beta when applied remotely. Pharmacological blocking experiments and enzyme activation analysis using Western blot analysis revealed a crucial involvement of the antiapoptotic reperfusion injury salvage kinase cascade. In contrast, contribution of the survivor activating factor enhancement pathways to this early cardioprotection was not observed. CONCLUSIONS: Remote application of neuregulin-1beta protects hearts from early reperfusion injury by activation of the reperfusion injury salvage kinase pathway without relevant effects on intracardiac pressures in myocardial infarction. Besides its potential pharmacological application, neuregulin-1beta might act as an endogenously produced mediator in remote postconditioning. PMID- 25547555 TI - Cardiogenic shock in Takotsubo cardiomyopathy: a focus on management. AB - Takotsubo cardiomyopathy has become a well recognized mimicker of acute coronary syndrome. Patients generally do well, although a minority can develop life threatening complications. We present a case of 1 such patient in a branched self assessment format designed to challenge the reader's clinical management skills. PMID- 25547556 TI - Early diagnosis and management of myocardial rupture. AB - Left ventricular free wall rupture is a catastrophic mechanical complication of myocardial infarction. We present an 82-year-old woman with an anterolateral ST segment elevation myocardial infarction treated with thrombolysis. Because of unexplained hypotension, echocardiography was performed and contrast (Definity; Lantheus Medical Imaging) was used to improve visualization. Findings included a small- to moderate-sized circumferential pericardial effusion without frank tamponade, however, there was significant intramyocardial tracking of the contrast into the epicardial space, localized to the mid to apical portion of the anterior septum, consistent with rupture or disruption of the wall segment. The patient was promptly taken to the operating room where fresh blood and clots were evacuated from the pericardial space with immediate hemodynamic improvement. The patient underwent successful surgical repair. PMID- 25547557 TI - Can diagnostic and procedural skills required to practice cardiology as a specialist be mastered in 3 years? AB - Cognitive and procedural skills required of cardiologists have increased in the past 10 years. What is unknown is whether residents consistently meet recommended volumes during training and what their own subjective assessments of their competency are after training. The purpose of this study was to (1) determine whether current training provides residents with opportunities to develop skills to function independently and (2) identify whether residents perceive gaps in their skills. We surveyed current and recent graduates of adult cardiology programs in Canada. One hundred ten responses from 425 surveys were received. Procedural and diagnostic test interpretation volumes were recorded, as were the optimum number the respondents believed were important to complete to function independently. These volumes were compared with the 2008 American College of Cardiology Core Cardiology Training Symposium (COCATS 3) and the Canadian Cardiovascular Society (CCS) recommendations for training. The proportion of residents meeting recommended volumes for diagnostic test interpretation ranged from 7% (Holter monitors) to 91% (echocardiograms). For procedures, the range was from 71% (echocardiography) to 100% (cardioversion). The ratio of residents' perceived minimum numbers believed to be required for proficiency for diagnostic test interpretation to those recommended ranged from 14% (electrocardiograms) to 116% (echocardiograms), and for procedures, the ratio was 66% (temporary pacemaker placement) to 116% (echocardiography). Recent graduates' perception of minimum required numbers to achieve competency is underestimated compared with COCATS 3 and CCS recommendations. Few graduates achieved the recommended volume targets suggested for diagnostic test interpretation. PMID- 25547559 TI - An integrated approach for vascular health: a call to action. AB - Vascular diseases such as stroke, myocardial infarction, most causes of heart failure, dementia, peripheral arterial disease, certain kidney, and many lung and eye conditions are a result of disorders in the blood vessels (large and small) throughout the entire human body. Vascular diseases are the leading cause of preventable death and disability in Canada. Most vascular diseases share common risk factors (high blood pressure, diabetes, dyslipidemia, and obesity), which can be influenced by modifiable health behaviours such as unhealthy diet, smoking, lack of physical activity, and stress. Ninety percent of Canadians face an increased risk, which could be modified by managing these health behaviours and risk factors. Canada's aging population, combined with alarming trends in obesity, physical inactivity, high blood pressure, and diabetes are expected to further increase the social and economic effect of vascular diseases in the coming decades, unless there are major changes in health policy. Even more concerning is the increase in vascular risk factors among Canada's youth, and ethnically diverse populations. Vascular diseases affect not only the patient, but also place burdens on their spouses, families, friends, and communities. Tremendous potential exists to reduce the effects of vascular diseases through healthy public policy, supporting Canadians to make healthy lifestyle changes, and coordinating efforts across the continuum of care in a patient-focused manner. Vascular health requires partnerships for action across many sectors including government, health care practitioners, academia, not-for-profit organizations, and the private sector. The health sector alone cannot solve this problem. PMID- 25547558 TI - Trends in pediatric cardiology referrals, testing, and satisfaction at a Canadian tertiary centre. AB - Anecdotal and European evidence suggests that outpatient pediatric referrals and their diagnostic testing burden are increasing. We sought to characterize new pediatric cardiology referrals, testing performed, outcomes, and patient satisfaction in a Canadian academic hospital and how these had changed over time. Clinical data were extracted from new outpatient consultations to the IWK Children's Heart Centre between August 1, 2011 and August 17, 2012 and compared with similar local data collected in July-February 2002 using chi(2) testing. Predictors of significant differences were sought using regression analysis. Satisfaction data were collected from a validated patient questionnaire, and 620 new outpatients were evaluated. Organic disease was more likely in younger patients (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.8-4.0) or in patients referred by pediatricians (OR, 2.3; 95% CI, 1.6-3.3). Odds of echocardiography being performed were significantly increased if patients were younger than 1 year (OR, 2.0; 95% CI, 1.3-3.0), were seen at outreach clinics (OR, 1.7; 95% CI, 1.2-2.3), or were referred by pediatricians (OR, 3.7; 95% CI, 2.6-5.3). Cardiologists differed significantly in ordering echocardiograms for referred patients (P = 0.002). The patients referred in the current era have significantly less organic disease than did those in 2002 (27% vs 37%; P = 0.007), but they underwent significantly more echocardiography (58% vs 38%; P < 0.001) and Holter monitoring (12% vs 4%; P = 0.001). Satisfaction results were high and unrelated to diagnostic testing. Pediatric cardiology referrals in Maritime Canada have increased in volume, consistent with changes seen at other centres. This, coupled with changing cardiac investigations, has increased testing burden. Individual cardiologists affected the odds of echocardiography being ordered. Satisfaction with services was high, with no predictors identified. PMID- 25547560 TI - A novel MYH7 gene mutation in a fetus with left ventricular noncompaction. AB - Left ventricular noncompaction (LVNC) is a recently defined cardiomyopathy characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses. LVNC is rarely described in fetal life, and a small number of cases have been reported. We report the first fetal case, to our knowledge, of LVNC associated with a novel mutation in the MYH7 gene (c.1625A>C; p.Lys542Thr). This patient showed cardiomegaly on prenatal ultrasonographic examinations, with features indicating noncompaction of the myocardium apparent in the second trimester. This case highlights the importance of prenatal ultrasonography for the diagnosis of LVNC and suggests that abnormal myocardial development underlies the pathogenesis of LVNC. PMID- 25547561 TI - Macro-reentrant atrial tachycardia conducting through a left superior vena cava after catheter ablation in a patient with paroxysmal atrial fibrillation. AB - A left superior vena cava can be a cause of cardiac rhythm or conduction abnormalities, and can also be the arrhythmogenic source of atrial fibrillation (AF) with connections to the coronary sinus and left atrium. In the present study, we report a case with a macro re-entrant atrial tachycardia that coursed through the left superior vena cava after a previous AF ablation, which successfully ablated paroxysmal AF. PMID- 25547562 TI - Pulmonary valvuloplasty in a pregnant woman using sole transthoracic echo guidance: technical considerations. AB - An 18-year-old pregnant woman with severe pulmonary valve stenosis and exertional dyspnea underwent balloon dilation during pregnancy using sole echocardiographic guidance to protect the baby from radiation. The main technical difficulty encountered was during advancement of the catheter across the right ventricular outflow tract into the pulmonary valve. This was overcome using a wedge balloon catheter over a percutaneous transluminal coronary angioplasty (PTCA) wire. Using echo guidance, the balloon was positioned across the pulmonary valve and inflated. Pulmonary balloon valvuloplasty can be performed safely using sole transthoracic echocardiography guidance without fluoroscopy. PMID- 25547563 TI - The role of a multimodality imaging approach in diagnosis and stratification of aborted sudden cardiac death. AB - A 34-year-old man was admitted after an episode of aborted sudden cardiac death. The initial investigation including electrocardiogram, chest x-ray, transthoracic echocardiogram, and biomarkers were normal. Although coronary angiography showed nonsevere stenosis, optical coherence tomography revealed severe obstruction in the artery with a layered appearance of the vessel wall; it was consistent with the presence of mural thrombus. PMID- 25547564 TI - Left atrial tachycardia after atrial fibrillation ablation: can magnetic resonance imaging assist the ablation? AB - We present a case of a magnetic resonance imaging-assisted ablation of an atrial tachycardia in a patient with previous atrial fibrillation ablation. A 3-D reconstruction of the delayed-enhanced cardiac magnetic resonance (CMR; CMR model) was created to identify previous ablation lesions and gaps. Multiple gaps around right-sided pulmonary veins were observed. The activation map identified a dual-loop re-entry around both right-sided pulmonary veins, confirming that the substrate identified using delayed-enhanced CMR was critical to sustain the tachycardia. Ablation at this site converted to sinus rhythm. The present case shows the usefulness of delayed-enhanced CMR substrate characterization to complement activation mapping of the tachycardia and more accurately define the anatomical circuit. PMID- 25547565 TI - Spindle cell sarcoma of the left atrium: an extremely rare and challenging tumour often masquerading as left atrial myxoma. AB - Spindle-cell sarcoma of the left atrium is an extremely rare diagnosis, with only 4 cases reported in the literature worldwide. We report on a 42-year-old man, who presented to the emergency department with dyspnea and decreased exercise tolerance. A computed tomography chest scan showed a large mass in the left atrium. Echocardiography demonstrated a significant gradient across the mitral valve. The patient had the mass excised in the operating room. He did well postoperatively. Eight months later, a repeat cardiac magnetic resonance imaging scan showed a recurrence. Right pneumonectomy was performed to ensure margins were clear. Although he has done well after surgery, his prognosis remains guarded. PMID- 25547566 TI - Phagocytic efficiency and cytotoxic responses of Indian freshwater sponge (Eunapius carteri) cells isolated by density gradient centrifugation and flow cytometry: a morphofunctional analysis. AB - The freshwater sponge Eunapius carteri (Porifera: Demospongiae: Spongillidae), a resident of Indian freshwater ecosystems, has pharmaceutical and ecological potential, but there is inadequate information on its cellular spectrum and cell mediated immune responses. Microscopical analysis revealed the existence of eight distinct cellular variants, i.e. blast-like cells, choanocytes, small amoebocytes, granular cells, pinacocytes, large amoebocytes, archaeocytes and sclerocytes. The cells were isolated by density gradient centrifugation and flow cytometry and used for a morphofunctional analysis. We investigated the phagocytic efficiency of E. carteri cells under the challenge of yeast particles in vitro and spectrophotometrically quantified the generation of cytotoxic molecules (superoxide anions and nitric oxide) in different isolated cellular fractions. The two cell separating technologies did not yield any significant differences in the major findings on morphology, phagocytic response and generation of superoxide anions and nitric oxide. Archaeocytes, granular cells and large amoebocytes were identified as chief phagocytes with a high phagocytic potential as recorded by light microscopy. Archaeocytes were the principal generators of superoxide anions, whereas nitric oxide was recorded in the fractions rich in archaeocytes and large amoebocytes. The present investigation thus provides useful information regarding cellular variation, cytotoxic status and innate phagocytic response of the cells of E. carteri, a common but less studied sponge of India. PMID- 25547567 TI - The role of vibrissal sensing in forelimb position control during travelling locomotion in the rat (Rattus norvegicus, Rodentia). AB - In the stem lineage of therians, a comprehensive reorganization of limb and body mechanics took place to provide dynamic stability for rapid locomotion in a highly structured environment. At what was probably the same time, mammals developed an active sense of touch in the form of movable mystacial vibrissae. The rhythmic movements of the limbs and vibrissae are controlled by central pattern-generating networks which might interact with each other in sensorimotor control. To test this possible interaction, we studied covariation between the two by investigating speed-dependent adjustments in temporal and spatial parameters of forelimb and vibrissal kinematics in the rat. Furthermore, the possible role of carpal vibrissae in connecting the two oscillating systems was explored. We compared locomotion on continuous and discontinuous substrates in the presence and absence of the mystacial or/and carpal vibrissae across a speed range of 0.2-0.5m/s and found that a close coupling of the kinematics of the two oscillating systems appears to be precluded by their differential dependence on the animal's speed. Speed-related changes in forelimb kinematics mainly occur in temporal parameters, whereas vibrissae change their spatial excursion. However, whisking frequency is always high enough that at least one whisk cycle falls into the swing phase of the limb, which is the maximum critical period for sensing the substrate on which the forepaw will be placed. The influence of tactile cues on forelimb positional control is more subtle than expected. Tactile cues appear to affect the degree of parameter variation but not average parameters or the failure rate of limbs during walking on a perforated treadmill. The carpal vibrissae appear to play a role in sensing the animal's speed by measuring the duration of the stance phase. The absence of this cue significantly reduces speed related variation in stride frequency and vibrissal protraction. PMID- 25547568 TI - Prenatal exposure to anxiolytics and hypnotics and language competence at 3 years of age. AB - PURPOSE: The aim of the study was to examine if there was an association between use of anxiolytics and hypnotics in pregnancy and language competence in the offspring at age 3 years. METHODS: The Norwegian Mother and Child Cohort Study (MoBa) is a prospective pregnancy cohort where the mothers were asked to report on their medication use at pregnancy week 17-18, 30, and at 6 months postpartum. A woman was defined as a user of anxiolytics and hypnotics during pregnancy if she had reported use of benzodiazepines or benzodiazepine-related drugs during pregnancy. Children's language competence was measured at age three by maternal report on a validated language grammar scale. We used ordinal logistic regression with estimated standard errors allowing for clustering of multiple pregnancies. RESULTS: Forty-five thousand and two hundred sixty-six women with 51,748 pregnancies were included in the study. The women reported use of anxiolytics and/or hypnotics in 395 pregnancies (0.8 %). The odds ratios of being in a group with lower language competence were 1.2 (0.9-1.5) and 1.7 (1.0-2.8) for short term and long-term anxiolytics and hypnotics use, respectively. When adjusting for SSRI use during pregnancy, the odds ratios were 1.1 (0.83-1.41) and 1.4 (0.84 2.33), respectively. Children whose mothers took no anxiolytics and hypnotics during or before pregnancy were reference group. CONCLUSION: The results refute any strong association between prenatal use of anxiolytics and hypnotics and lower language competence in the offspring at age 3 years. PMID- 25547569 TI - Salvage supracricoid laryngectomy after failed radiotherapy and partial laryngectomy. AB - BACKGROUND: A case of salvage supracricoid laryngectomy with cricohyoidoepiglottopexy after failed radiation therapy and vertical partial laryngectomy had successful oncological and functional outcomes. This is the first reported application of salvage supracricoid laryngectomy with cricohyoidoepiglottopexy after the failure of two major treatments. CASE REPORT: A 65-year-old man was referred for salvage supracricoid laryngectomy with cricohyoidoepiglottopexy. The right recurrent hemilarynx was successfully resected. After pexis, the right lobe of the thyroid gland was repositioned to overlap and reinforce the pexis gap and fill the devoid portion of the strap muscular closure. Multiple scattered foci (recurrent tumour-node-metastasis stage T2) were identified around the arytenoid cartilage and beneath the musculocutaneous flap. Four years after supracricoid laryngectomy with cricohyoidoepiglottopexy, the patient's recovery was following a favourable course and he had satisfactory laryngeal function. CONCLUSION: Appropriate case selection and proficient surgical skills were essential for a successful outcome. Head and neck surgeons should not be afraid to adopt functional preservation open surgical procedures in well-selected and well-motivated patients. A requirement for more challenging surgical procedures and meticulous rehabilitation processes should not exclude appropriate treatments from a surgeon's repertoire. PMID- 25547570 TI - [To attach importance to expert commentary and to grasp the orientation in academic development]. AB - The purpose of this article is to make authors and readers master some writing and reading skills by elaborating the definition, characteristics, the comparison of style and writing technique of expert commentary. Expert commentary is journal editorial that is not only author's personal point of view, but also the collective opinions of Ophthalmology Branch of the Chinese Medical Association and editorial board of the magazine. Therefore, it should be view clear, clear cut stand and having certain academic orientation. It is our common responsibility to promote the academic development of ophthalmology in China, by mobilizing various aspects strength, carefully written and read expert commentary. PMID- 25547571 TI - [Academic status and development direction of Chinese ocular pathology]. AB - Along with the development of cell biology and molecular biology, the application of molecular biotechnology has brought new vitality into traditional pathology. Recently, hot research topics of ocular pathology field mainly focus on diabetic ophthalmopathy, dry eye syndrome, age-related macular degeneration and ocular tumors. Base on hot research topics, we analyzed the present status and existing problems in ocular pathology field of China. PMID- 25547572 TI - [The importance of evaluating histopathologic high risk factors in retinoblastoma and the related issues]. AB - Histopathologic high risk factors are core content in the histopathologic examination of enucleated retinoblastoma. Histopathologic high risk factors indicate that the patient has high risk of tumor spreading and metastasizing and should be given systemic adjuvant chemotherapy. Therefore, histopathologic high risk factors can provide important basis for clinicians to determine treatment plan and serve as the important foundation for clinical trials and studies to validate the proposed criteria. The focus of our discussion includes three aspects as follows. How to evaluate histopathologic high risk factors? Can clinical characteristics be used to predict histopathologic high risk factors? Do histopathologic high risk factors have any hint for intra-arterial chemotherapy? The importance of evaluating histopathologic high risk factors in retinoblastoma is emphasized in this article. PMID- 25547573 TI - [Retinoblastoma spontaneous regression: clinical and histopathologic analysis]. AB - OBJECTIVE: To analyze the clinicopathologic characteristics of retinoblastoma spontaneous regression. METHODS: Retrospective case series study. The clinic and pathologic data of 52 cases of retinoblastoma spontaneous regression were analyzed retrospectively. All the cases came from 579 cases of retinoblastoma (without pre-enucleation chemotherapy) archived in Ophthalmic Pathology Laboratory of Beijing Tongren Eye Centre from Jan. 2007 to Dec. 2013. The analyzed factors included tumor activity, tumor invasion, and tissue changes of uveal and lens. RESULTS: In this study, the patients' average age was (14.0 +/- 8.7) months. There were 33 (63.5%) male and 19 (36.5%) female patients. The rate of retinoblastoma spontaneous regression was 9.0% (52/579), of which the rate of complete regression was 1.4% (8/579). The most common symptom was leucocoria coupled with red eye 55.8% (29/52). The typical clinicopathologic characteristics were as follows: (1) all or most of all tumor cells suffered coagulation necrosis and only tumor cell remains were left; (2)most eyeballs showed atrophiabulbi or phthisis bulbi; (3) severe atrophy occurred in uvea, especially in iris and ciliary body combined with pigment cells disintegrating; (4) cataract formed coupled with lens swelling, displacement, or wrapped by fibrous connective tissue; (5) in a small number of cases, there were alive tumor cells in the retrolaminar optic nerve or choroid in spite of most tumor cells had suffered regression, indicating the patients had histopathologic high risk factors and had the dispositions of tumor diffusion and metastasis. CONCLUSIONS: Some untypical clinical manifestation such as leukocoria coupled with red eye or atrophia bulbi should be paid close attention. The possibility of retinoblastoma spontaneous regression should be considered. Meanwhile, some cases of retinoblastoma spontaneous regression with histopathologic high risk factors should be given post-enucleation systemic adjuvant chemotherapy combined with close observations and follow-ups. PMID- 25547574 TI - [Clinical analysis of orbital exenteration for orbital retinoblastoma]. AB - OBJECTIVE: To analyze the reasons of orbital exenteration for orbital retinoblastoma (RB) patients. METHODS: Retrospective case series study. Clinical records were reviewed retrospectively of 17 orbital RB patients who had undergone exenteration from November 1999 to November 2010 at Armed Police General Hospital. The clinical records included ophthalmic history, process of diagnosis and treatment, symptom and signs, surgical approach, pathological diagnosis and follow-up results. The reasons of orbital exenteration for orbital RB patients according to medical history, process of diagnosis and treatment were analyzed. RESULTS: The average age of patient was 3.2 years old. The ratio of male versus female was 1.1: 1. The common clinical findings were as following: 11 cases of orbital mass, 7 cases of exophthalmos, 6 cases with palpebral edema, 4 cases of conjunctival congestion and edema with conjunctival mass, and 2 cases with orbital pain. Reasons for orbital exenteration were as following: 7 patients who lost the opportunity of the treatment because of concernning about the cost of treatment and poor prognosis and caused worst outcome. Exenteration had to be done eventually. Five cases of orbital recurrence happened after enucleation. Three patients' Rb invaded into orbit after conservative treatment intravenous chemotherapy or radio therapy alone. Two cases were misdiagnosed and mishandled causing rapidly tumor spread into the orbit. CONCLUSIONS: The major reasons of orbital exenteration for orbital RB patients lies in the following: giving up treatment from patients, tumor recurrence in the orbit after enucleation, progressing of orbital RB after simple conservative treatment, misdiagnosis and mishandling to let RB invade into orbit rapidly. PMID- 25547575 TI - [Clinical and pathological observation of seven cases of spontaneous sub-retinal hemorrhage]. AB - OBJECTIVE: To improve pathological understanding of massive sub-retinal hemorrhage. METHODS: Retrospective case series study. The clinical and pathological data of 7 cases of massive sub-retinal hemorrhage which were examined in the Pathological Department of Tianjin Eye Hospital from May 1988 to April 2012 were collected. The serial section of eyeball specimens were made with HE and PAS staining. The pathological section were reviewed under the light microscope. Analysis were made again combining with patients' clinical history, imaging findings and the pathological features. RESULTS: In 7 patients, 6 patients were male, 1 patient was female. The age range was from 60 to 82 years old and the average age was 71.7 years old. Four cases were on the right eye and 3 cases were on the left eye. The main clinical feature was sudden loss of vision and 2 cases had acute glaucoma symptoms. Ultrasound examination showed choroidal tumor in 6 cases and retinal detachment with vitreous hemorrhage in one case. The color Doppler ultrasound examination demonstrated choroidal substantive occupying lesion in 3 cases and two of them were detected with blood flow signal. The MRI were examined in 3 cases which showed iso-high signal in T1W1 and iso-low signal in T2W1 suggesting the choroidal melanoma in 2 cases and sub-retinal hemorrhage in 1 case. Six cases were diagnosed clinically as choroidal tumor or melanoma and 1 case was diagnosed as acute angle-closure glaucoma. The enucleation were performed in 7 cases. In these cases, 6 cases were diagnosed pathologically as vitreous hemorrhage, hemorrhagic RPE detachment and massive subretinal hemorrhage. The related choroidal lesions included soft drusen of Bruch membrane in 3 cases, choriocapillaris wall degeneration in 2 cases, fibrovascular membrane formation under RPE in 2 cases, choroidal chronic non-granulomatous inflammation in 4 cases, choroidal vessels wall thickening and sclerosis in 2 cases and choroidal vessels anomaly in one case. The secondary angle-closure glaucoma or angle-open glaucoma were accompanied respectively in 2 cases. Another case of 7 cases was diagnosed pathologically as the rupture of retinal macroaneurysm with massive sub-retinal hemorrhage. CONCLUSIONS: Massive sub-retinal hemorrhage liked to occur in the elderly male patients. The main manifestations were sudden visual loss. A small number of patients had symptoms of acute glaucoma. Ophthalmic ultrasound and imaging characteristics were usually similar to the choroidal substantive neoplasm and were easily misdiagnosed as choroidal melanoma. Pathological examination revealed that the main reasons of massive hemorrhage were from the hemorrhagic RPE detachment and the rupture of retinal macroaneurysm. PMID- 25547576 TI - [Clinical short-term outcome of brachytherapy for the treatment of choroidal metastasis]. AB - OBJECTIVE: To observe and evaluate the therapeutic effect of brachytherapy for choroidal metastasis. METHODS: A restrospective case-series study. The data of 22 patients with 23 eyes of choroidal metastasis undergoing ruthenium 106 radioactive applicator brachytherapy were retrospectively analyzed from the Eye Center of People Hospital of Peking University from Feb. 2004 and Sep. 2012. Ocular tumor control, globe salvage rate and the visual acuity of the patients were observed and analyzed. RESULTS: Eighteen patients of 18 eyes were followed up. The median age of the 18 patients was 59 years and the median time of follow up was 13 months. The remission of tumors with decreasing of subretinal fluid volume were obviously achieved and the globes were all reserved. At follow-up, 13 patients' visual acuity was above or equal to 0.3, one patient's visual acuity was under 0.05, 4 patients' visual acuity was between 0.05 and 0.3. CONCLUSION: Brachytherapy was an effective option for the treatment of choroidal metastasis. PMID- 25547577 TI - [The clinical and pathological characteristics of 14 cases of primary iris stromal cysts]. AB - OBJECTIVE: To analysis the clinical and pathological characteristics of primary iris stromal cyst. METHODS: Retrospective cases series study. 14 cases of primary iris stromal cyst which were treated in Tianjin Eye Hospital from Jan.1979 to Dec. 2012 were collected. They were all proved by pathological results. Their clinical and pathological features were analyzed. RESULTS: The age of 14 patients were 5 months to 50 years old, the median is 10 years old.10 patients (71.4%) were attacked from children or adolescence, among which onset age of 8 patients were less than 1-year-old. 4 patients (28.6%) occurs when they were adults. 10 cases were female and 4 cases were males. 10 cases were left eyes, 4 cases were right eyes. All cases were unilateral involvement. In these cases, 11 cases appeared as a single translucent or gray-white cystic mass on the iris surface, which 6 cases located in the inferior aspect of the iris, 2 cases appeared with diffused iris cyst and another 1 case's cyst was found occasionally in the eyeball enucleating specimen. 8 cases had corneal opacity or leucoma, 7 cases had secondary glaucoma, and 3 cases had complicated cataract. Pathological features showed: cysts located on the iris surface or in the stroma layer. The cysts of 9 cases were constructed of non-cuticular stratified squamous epithelium cells. 3 cases' cysts were constructed of lens epithelium cells and lens capsular analogical tissues, and the cysts adhesion to the lenstightly. The other 2 cysts were constructed of single or stratified epithelium cells, similar to ciliary epithelium cells. 2 cases complicated with crystalline lens dysplasia, 3 cases complicated with iris tissue dysplasia, 2 cases complicated with ciliary cysts and 1 case had chamber angle dysplasia. CONCLUSIONS: Primary iris stoma cyst is rare and it usually occurs in infant, more often in the children less than 1-year old. Pathological examination showed that most of the cysts originated from the conjunctivaepithelium, minority cysts originated from crystalline lens epithelium or ciliary epithelium. Some cases complicated with iris, ciliary or crystalline lens malformation. PMID- 25547578 TI - [Isolation and identification of cancer stem cells from human LACC cell line]. AB - OBJECTIVE: To find ways to isolate and culture lacrimal adenoid cystic carcinoma (LACC) stem cells from human LACC cell line and to identify their biological properties. METHODS: Experimental research. LACC cells were digested, centrifuged and suspended in specific serum free medium (SFM) to get LACC cancer stem cell spheres. Limiting dilution analysis and monoclonal formation assay were performed to determine the proportion of cancer stem cells in LACC cell line. MTT assay was used to determine the proliferation and chemotherapeutic drug resistance of stem cell spheres. The expressions of cell surface markers CD44+/CD24- were detected by flow cytometry. Stem cell spheres differentiation were induced by dropping serum medium into SFM and the morphologic changes were observed. The IC50 and UV optical density of two kinds of cells were tested by Student's t-test. RESULTS: About (0.92 +/- 0.02) % cells were clonogenic in LACC cell line. They could survive and proliferate to form free-floating cell spheres in SFM, which could stably passaged. The IC50 values of cancer stem cells and LACC cell line were 22.53 mg/L and 11.06 mg/L (t = 37.94, P < 0.05), which suggested that cancer stem cells were more resistant to cis-platinum than LACC cell line. In flow cytometry assay, 84.25% stem cell spheres were CD44+/CD24- cells, comparing with 23.77% in LACC cell line. Stem cell spheres could differentiate into normal adenoid cystic carcinoma cells in medium with serum. CONCLUSION: LACC stem cell spheres, containing a large number of cancer stem cells, could be obtained by serum free suspension culture. This provide us an ideal model system for cancer stem cell research. PMID- 25547579 TI - [Establishment mice model of radiation-injured lacrimal gland and pathophysiological exploration]. AB - OBJECTIVE: To establish a radiation-injured model of lacrimal gland in mice and explore its pathophysiology. METHOD: Experimental research. According to the random number table, 50 healthy mice were divided into five groups:one control group (n = 10) and four experimental groups (n = 40). The experimental mice (n = 40) were exposed to different dosages of irradiation 12, 15, 18 and 21 Gy, respectively. The sham-irradiated controls (n = 10) were anesthetized in parallel with the irradiated rats but not irradiated. The mice were placed laterally and covered with a bolus material, then the X-ray irradiation was performed under general anaesthesia from above towards the mice' orbital region. The schirmer tests, Single- photon emission computed tomography/Computed tomography (SPECT/CT), HE, immunohistological, and ultrastructural examinations were conducted prior and 3 days, 7 days as well as 30 days after irradiation.Using t test to compare the differentiation of each group at the same time point. RESULTS: In 12 Gy group, there is no statistically significant decline in tear secretion (3 days after radiation, t = 2.137, P = 0.061;7 days after radiation, t = 1.137, P = 0.243).In 15 Gy group, Schirmer I test showed significantly reduced lachrymal secretion and the difference was statistically significant(3 days after radiation:t = 3.228, P = 0.011;7 days after radiation:t = 4.781, P = 0.001;30 days after radiation:t = 3.162, P = 0.011). Immunohistochemical findings include a significant loss in the expression of alpha-SMA (3 days after radiation, t = 4.395, P = 0.013; 30 days after radiation, t = 3.049, P = 0.035) , aquaporin (AQP 5) (3 days after radiation, t = 3.587, P = 0.028;30 days after radiation, t = 5.598, P = 0.005) , and an excessive expression of Tenascin-C (3 days after radiation, t = 2.964, P = 0.046;30 days after radiation, t = 4.028, P = 0.017) and CK8 (3 days after radiation, t = 5.103, P = 0.008;30 days after radiation, t = 6.178, P = 0.004) , which were statistically significant. Ultrastructural changes include a retention of secretory granules and an increase of apoptotic acinar nuclei as well as macrophage phagocytosis. Disturbance in the tracer uptake as well as reduction of the lacrimal ejection fraction was assessed under SPET/CT test and the difference was statistically significant (3 days after radiation:t = 2.796, P = 0.029;30 days after radiation:t = 2.641, P = 0.038). This radiation dosage didn't cause obvious eye complications (cataract, radiation retinopathy, etc.). At the dosages of 18 and 21 Gy, the lacrimal gland inflammation and tissue apoptosis expand obviously. CONCLUSIONS: The model of radiation-injured lacrimal gland was successfully constructed. Pathophysiological manifestation include the impaired structures of lacrimal gland cells and infiltration of inflammatory cells, as well as damaged function of tear secretion. These changes may prerequisites for further study on radiological protection of lacrimal glands during radiotherapy of the periorbital region for orbital tumors. PMID- 25547580 TI - [Preliminary study on CT retrograde intubation dacryosystography (CT-RIDC) and its impact factors]. AB - OBJECTIVE: To observe practicality and safety of CT-RIDC for the patients with presaccular lacrimal obstruction and study the related factors. To provide guidance for the diagnosis and treatment of the patients with presaccular lacrimal obstruction. METHODS: Fifty-four patients (75 eyes) with presaccular lacrimal obstruction, including 3 cases (5 eyes) of upper and lower lacrimal punctum atresia, 15 cases (24 eyes) of superior and inferior canalicular obstruction, 18 cases (28 eyes) of common canaliculus obstruction, 18 cases (18 eyes) of old laceration of superior and inferior canalicular, were recruited. All patients underwent the examination by using 0 degrees and 30 degrees ear endoscope and the imaging characteristics of the inferior orifice of nasolacrimal duct were obtained. Fifty-three cases (65 eyes) with the opening inferior orifice were randomly divided into four groups (15 eyes, 17 eyes, 17 eyes, 16 eyes) according to different angle of head hypsokinesis in the supine position. The OM lines back along the sagittal plane of the head back 10 degrees , 20 degrees , 30 degrees , 40 degrees were measured. The angles of head hypsokinesis were set in accordance with the OM line measurement results.Intubation was successful when the intubation guided needle within the set of epidural anesthetic catheter aided with endoscopy was inserted into the inferior orifice of nasolacrimal duct and then the epidural anesthetic catheter was inserted into the lacrimal duct 6 mm. The angle (theta) between the long axis of the curved part of the intubation guided needle and the long axis of the guided needle was measured. The numbers of intubation success cases in each group were recorded.chi2 test was used to compare intubation success rate under the different angle of head hypsokinesis.Scheffe method was used to compare intubation success rate between each group. Contrast medium was then injected into lacrimal duct through the epidural anesthetic catheter for patients with successful intubation and CT scan was carried out. 3D model of lacrimal passage was reconstructed with CT axial scanning. RESULTS: The intubation guided needle was successfully inserted into the inferior orifice of nasolacrimal duct in 44 eyes among 65 eyes with the opening orifice. The number of successful intubation cases were 4 eyes, 15 eyes, 13 eyes, 12 eyes and the intubation success rate was 26.67%, 88.24%, 76.74%, 75.00% according the angle of head hypsokinesis 10 degrees group (15 eyes), 20 degrees group (17 eyes), 30 degrees group (17 eyes), 40 degrees group (16 eyes). The intubation success rate of head hypsokinesis 10 degrees group was significantly lower than that of the other groups. Multiple Comparison by Scheffe Test demonstrated that there was a remarkable difference (P < 0.05) in the intubation success rate between head hypsokinesis 10 degrees group and the other three groups. There were no significant differences in the intubation success rate among head hypsokinesis 20 degrees group, head hypsokinesis 30 degrees group and head hypsokinesis 40 degrees group. The mean of theta was 108 degrees with a range of 93.2 degrees -120.5 degrees by measuring the angle theta of the successful intubation cases. According to the frequency distribution plot, most theta was in 104 degrees -115 degrees . The successful intubation cases (44 eyes) underwent CT scan in the same position immediately after injected contrast medium (Optiray) through the epidural anesthetic catheter. CT images of 28 eyes showed retained contrast medium in the nasolacrimal duct and lacrimal sac. The findings from CT-DCG images were basically agreed with the operation. CONCLUSIONS: CD-RIDC may apply to pre-operative examination for the patients with the opening orifice and presaccular lacrimal obstruction.It provideed imaging evidence for diagnosis and therapy and it was safe and practical. Many factors could affect CD-RIDC. The main verified facors were the shape of the inferior orifice of nasolacrimal duct, head position of the patient and the bending angle of the tip of intubation guided needle. PMID- 25547581 TI - [Clinical analysis on children uveitis complicated cataract surgery]. AB - OBJECTIVE: To explore the efficacy of operation on children's complicated cataract induced by uveitis and discuss the therapeutic methods in perioperative period and the influencing factor of effect in treatment. METHOD: Retrospective case series study. Thirteen cases (17 eyes) children's complicated cataract induced by uveitis who were treated by phacoemulsification with intraocular lens implantation in Peking union medical college hospital from Feb.2002 to Dec.2011 were collected. The characteristics, perioperative medical managements, surgical approach, postoperative visual, complications and follow-up states postoperatively were observed. RESULT: Total of 13 cases (17 eyes) of children uveitis, which including 4 cases (4 eyes) of male, 9 cases (13 eyes) of female, and 1 (1 eye) Reiter's symptom and 2 (3 eyes) juvenile idiopathic arthritis (JIA) were collected. The average operative age was (9.6 +/- 2.4) years. The average time of inflammation fully controlled was (6.44 +/- 5.88) months. All 17 eyes were received phacoemulsification with intraocular lens implantation, among them 12 eyes were received pupil forming meanwhile. Prednisolone 0.8-1.0 mg * kg-1 * d 1 was used 3 days pre-operatively or on the operation day, 6 serious patients were given additional systemic immunosuppressive treatments. All patients were followed up from 8-72 months; the average follow-up time was (36.4 +/- 19.8) months. The average using time of prednisolone was (5.4 +/- 6.5) months. At the final point, 14 eyes got the best corrected visual acuity (BCVA) of 0.3 or better. Among those, 12 eyes BCVA were 0.6 or better. All BCVA were improved significantly compared with pre-operative which was lower than 0.3. During the follow up periods, Neodymium: YAG (Nd:YAG) laser posterior capsulotomy was performed in 14 eyes because of the posterior capsular opacity (PCO). Other postoperative complications were seen as macular edema (3 eyes), uveitis recurrence (9 eyes), secondary glaucoma (5 eyes) and IOL reduction (2 eyes). CONCLUSIONS: The method of phacoemulsification with intraocular lens on children's complicated cataract induced by uveitis could improve the visual acuity effectively. The opportunity of the operation, properly medical applications perioperatively and follow-up postoperatively was crucial for a successful operation. PMID- 25547582 TI - [Resveratrol alleviates oxidative injury from high glucose-induced human lens epithelial cells and its possible mechanism]. AB - OBJECTIVE: To investigate the effects and its mechanism of resveratrol against human lens epithelial cells (LEC) apoptosis mediated by high glucose-induced oxidative injury. METHODS: An experimental study. LEC were cultured in different concentrations (5.5, 15.0, 25.0, 35.0, 45.0 mmol/L) of glucose medium or 25.0 mmol/L glucose medium at different time (0, 6, 12, 24, 48, 72 h), and established an interventional models of (5.0, 15.0, 25.0, 35.0 mg/L) resveratrol. Av-FITC-PI (annexin V-fluorescein isothiocyanate-propidium iodium) was used to detect apoptosis. The amount of ROS was calculated by flow cytometry. The expression of apoptosis of the protein Bcl-2 and Bax, iNOS, NF-kappaB, IkappaB and MnSOD were showed by Western blotting and the amount of oxidative damage marker MDA was explored by Spectrometers and Analytical Photometers. Differences between the two groups were evaluated by One-way ANOVA. RESULTS: The apoptosis of LEC induced by high glucose was time-and dose-dependent obviously. As the glucose concentration increased and duration prolonged, the expression of anti-apoptotic protein Bcl-2 was decreased and pro-apoptotic protein Bax was increased.Intracellular ROS and MDA induced by high glucose were increased significantly with dose-and time dependence. Compared with 5.5 mmol/L group, ROS generation increased significantly in the concentration of 15.0 mmol/L (F = 14.06, P = 0.035), 25.0 mmol/L (F = 17.46, P = 0.000), 35.0 mmol/L (F = 16.58, P = 0.001), 45.0 mmol/L (F = 12.88, P = 0.000) and were statistically significant. Compared with 5.5 mmol/L glucose cultured group, ROS generation increased significantly at 6 h (F = 6.778, P = 0.014), 12 h (F = 6.551, P = 0.001), 24 h (F = 7.327, P = 0.001), 48 h (F = 10.84, P = 0.000), 72 h (F = 13.36, P = 0.000) in LEC cultured group by 25.0 mmol/L glucose and were statistically significant. Compared with 5.5 mmol/L group, the content of MDA were significantly increased in 15.0 mmol/L (F = 1.177, P = 0.035), 25.0 mmol/L (F = 1.704, P = 0.000), 35.0 mmol/L (F = 2.412, P = 0.001) and 45.0 mmol/L (F = 2.347, P = 0.000) glucose medium and were statistically significant. Compared with 5.5 mmol/L cultured group, the content of MDA were significantly increased at 6 h (F = 1.704, P = 0.014), 12 h (F = 5.676, P = 0.001), 24 h (F = 3.325, P = 0.001), 48 h (F = 6.669, P = 0.000), 72 h (F = 3.011, P = 0.000) in LEC cultured group by 25.0 mmol/L high glucose and were statistically significant. When resveratrol (5.0, 15.0, 25.0, 35.0 mg/L) was added to 25.0 mmol/L glucose medium, respectively, the apoptotic cells were decreased, the expression of pro-apoptotic protein Bax was decreased and anti apoptotic protein Bcl-2 was increased.Intracellular ROS (compared with the basic concentration of 5.5 mmol/L, F values were 14.76, 7.018, 13.96, 4.733, 1.921, P values were 0.000, 0.000, 0.003, 0.086, 0.100 respectively) and MDA (compared with the basic concentration of 5.5 mmol/L, F values were 2.454, 1.108, 1.630, 1.563, 2.250, P values were 0.000, 0.001, 0.026, 0.068, 0.183 respectively) were decreased. MnSOD expression was increased, iNOS and NF-kappaB activation were inhibited. CONCLUSION: Resveratrol could alleviates oxidative injury from high glucose-induced LEC, and inhibited of iNOS-mediated oxidative damage through inhibiting the activities of NF-kappaB could be the mechanism of this effect. PMID- 25547583 TI - [Top ten research progresses of ocular pathology in China in the past five years]. AB - Ten researches that may represent the progresses of clinical and basic ocular pathological studies in China in the past 5 years, were voted by specialists from Chinese Ocular Pathology Group. These researches were concentrated in following 5 fields: Stem cell therapy for retinal disease, Molecular imaging approach for detection of ocular fundus disease, Pathogenesis and comprehensive therapy of ocular tumors, Study of thyroid-associated opthalmopathy and Study of diabetic retinopathy. These studies, in a certain extent, represented the current level of research and the influence of our national ocular pathology specialists in the international ocular pathology field. PMID- 25547584 TI - [Research advances of animal models of retinoblastoma]. AB - Advances in animal models of retinoblastoma have accelerated the research in understanding tumor biology and assessing therapeutic modalities. At present, there are two types of models:transgenic models and xenograft models. The transgenic models have experienced a developmental process from LH-beta-Tag models to conditional gene knock-out models. The xenograft models included intraocular transplantation models and subcutaneous transplantation models. The two types of RB models both have their merits and drawbacks. The combination of genetic and xenograft models in retinoblastoma research has and will help to pave way for better understanding tumor progression and searching more effective diagnosis and treatment modalities. In this review, we summarized the recent research progress in animal models of retinoblastoma and their application in assessing therapeutic modalities. PMID- 25547585 TI - [Mechanism study on trans-lamina cribrosa pressure difference correlated with optic neuropathy in glaucoma]. AB - Glaucomatous optic neuropathy is among the most common causes of blindness worldwide. Elevated intraocular pressure (IOP) has long being considered to be the major risk factors for the development and progression of glaucomatous optic nerve damage. However, numerous studies have shown that a relatively large number of patients with typical glaucomatous optic neuropathy, in whom the IOP measurements have always been in the normal range (<21 mmHg, 1 mmHg = 0.133 kPa). Thus, the role of IOP in the pathogenesis of POAG becomes vague and controversial. Based on prospective clinical observations, Beijing iCOP (Intracranial and Intraocular Pressure) Study has found that the orbital cerebrospinal fluid pressure (CSF-P) may be of importance for the physiology and patho-physiology of the optic nerve head and may play a role in the pathogenesis of glaucomatous optic neuropathy. A low CSF-P in the retrobulbar region of the orbit may act as the counter-pressure against IOP and theoretically have a similar effect as an increased IOP on the trans-lamina cribrosa pressure difference which may be more relevant to the glaucomatous optic neuropathy than IOP alone. Moreover, an experimental and chronic reduction in CSF-P in monkeys was associated with the development of optic nerve damage morphologically typical for glaucomatous optic neuropathy. The findings support the hypothesis the CSF-P may play a role in the pathogenesis of glaucomatous optic neuropathy. PMID- 25547586 TI - Left-sided approach video-assisted thymectomy for the treatment of thymic diseases. AB - BACKGROUND: Video-assisted thoracoscopic thymectomy was developed more than 10 years ago and has become a widely accepted surgical approach. Most published reports regarding this procedure have focused on the right-sided approach. Since left-sided approach chest surgery is the first choice in cases of right pleural adhesion, large left thymus tumors, and tumors in close contact with the great vessels of the left pericardium, we performed thoracoscopic thymectomy using the left-sided approach in 52 cases and summarize herein its technical feasibility, indications, and operative steps. METHODS: Between February 2004 and October 2014, 52 patients (24 men, 28 women, median age: 50 years, ranging from 18 to 85 years), underwent a video-assisted thoracoscopic thymectomy using the left-sided approach. All procedures were performed under general anesthesia with single-lung ventilation. Patients were placed in the right lateral decubitus position and three ports were made. The entire hemithorax was carefully examined, then mediastinal pleura was incised, and the thymus was bluntly dissected from the inferior polar extending to the superior polar. The thymic venous was clipped. RESULTS: All procedures were carried out safely, including simple thymectomy (n = 43) and extended thymectomy (n = 9). There were no operative deaths or serious complications, and there were seven cases of conversion to open thoracotomy. The mean operative duration was 105.3 minutes (ranging from 80 to 140 minutes). The mean blood loss was 78.5 ml (ranging from 20 to 200 ml), and there was no blood transfusion required. All patients were well throughout the follow-up period. CONCLUSIONS: The left-sided approach for video-assisted thoracoscopic thymectomy was a safe approach and could be an alternative procedure to the right-sided approach for the same procedure. PMID- 25547587 TI - Skeletal muscle atrophy in sedentary Zucker obese rats is not caused by calpain mediated muscle damage or lipid peroxidation induced by oxidative stress. AB - BACKGROUND: Skeletal muscle undergoes significant atrophy in Type 2 diabetic patients and animal models. We aimed to determine if atrophy of Zucker rat skeletal muscle was due to the activation of intracellular damage pathways induced by excess reactive oxygen species production (specifically those associated with the peroxidation of lipid membranes) and calpain activity. 14 week old obese Zucker rats and littermate lean controls were injected with 1% Evan's Blue Dye. Animals were anaesthetised and extensor digitorum longus and soleus muscles were dissected, snap frozen and analysed for ROS-mediated F2 isoprostane production and calpain activation/autolysis. Contralateral muscles were histologically analysed for markers of muscle membrane permeability and atrophy. RESULTS: Muscle mass was lower in extensor digitorum longus and soleus of obese compared with lean animals, concomitant with reduced fibre area. Muscles from obese rats had a higher proportional area of Evan's Blue Dye fluorescence, albeit this was localised to the interstitium/external sarcolemma. There were no differences in F2-isoprostane production when expressed relative to arachidonic acid content, which was lower in the obese EDL and soleus muscles. There were no differences in the activation of either MU-calpain or calpain-3. CONCLUSIONS: This study highlights that atrophy of Zucker rat skeletal muscle is not related to sarcolemmal damage, sustained hyperactivation of the calpain proteases or excessive lipid peroxidation. As such, establishing the correct pathways involved in atrophy is highly important so as to develop more specific treatment options that target the underlying cause. This study has eliminated two of the potential pathways theorised to be responsible. PMID- 25547588 TI - Recent advances in the role of supramolecular hydrogels in drug delivery. AB - INTRODUCTION: Supramolecular hydrogels, formed by noncovalent crosslinking of polymeric chains in water, constitute an interesting class of materials that can be developed specifically for drug delivery and biomedical applications. The biocompatibility, stimuli responsiveness to various external factors, and powerful functionalization capacity of these polymeric networks make them attractive candidates for novel advanced dosage form design. AREAS COVERED: This review summarizes the significance of supramolecular hydrogels in various biomedical and drug delivery applications. The recent advancement of these hydrogels as potential advanced drug delivery systems (for gene, protein, anticancer and other drugs) is discussed. The importance of these hydrogels in biomedical applications, particularly in tissue engineering, biosensing, cell culture research and wound treatment is briefly described. EXPERT OPINION: The use of supramolecular hydrogels in drug delivery is still in very early stages. However, the potential of such a system is undeniably important and very promising. A number of recent studies have been conducted, which mainly focus on the use of cyclodextrin-based host-guest complex as well as other supramolecular motifs to form supramolecular hydrogels for delivery of various classes of drugs, therapeutic agents, proteins and genes. However, there are still plenty of opportunities for further development in this area for drug delivery and other biomedical applications. PMID- 25547594 TI - Modeling transcriptional regulation. AB - Systems models of the ways transcription factor networks operate and evolve are essential for understanding cell identity, developmental commitment and regulatory variation. Terminologies from different techniques and disciplines may need to be adapted or put aside to make and test these models effectively. PMID- 25547596 TI - A genome to unveil the mysteries of orchids. AB - Orchids have captured imaginations worldwide for hundreds of years. The publication of the moth orchid genome sequence opens the door to a greater understanding of orchid morphological evolution and physiological adaptation. PMID- 25547595 TI - Pseudomonas aeruginosa adaptation to human hosts. AB - Bacterial whole-genome sequencing of longitudinally collected isolates enables the investigation of evolutionary trajectories, which may inform both the prevention and treatment of human-associated pathogen infections. A new study explores the adaptation of multiple lineages of Pseudomonas aeruginosa to the lungs of young patients with cystic fibrosis and finds evidence of convergent molecular evolution and historical contingencies. PMID- 25547597 TI - Swapping one red pigment for another. AB - Betalains are bright red and yellow pigments, which are produced in only one order of plants, the Caryophyllales, and replace the more familiar anthocyanin pigments. The evolutionary origin of betalain production is a mystery, but a new study has identified the first regulator of betalain production and discovered a previously unknown link between the two pigment pathways. PMID- 25547603 TI - What are super-enhancers? AB - The term 'super-enhancer' has been used to describe groups of putative enhancers in close genomic proximity with unusually high levels of Mediator binding, as measured by chromatin immunoprecipitation and sequencing (ChIP-seq). Here we review the identification and composition of super-enhancers, describe links between super-enhancers, gene regulation and disease, and discuss the functional significance of enhancer clustering. We also provide our perspective regarding the proposition that super-enhancers are a regulatory entity conceptually distinct from what was known before the introduction of the term. Our opinion is that there is not yet strong evidence that super-enhancers are a novel paradigm in gene regulation and that use of the term in this context is not currently justified. However, the term likely identifies strong enhancers that exhibit behaviors consistent with previous models and concepts of transcriptional regulation. In this respect, the super-enhancer definition is useful in identifying regulatory elements likely to control genes important for cell type specification. PMID- 25547607 TI - Considering affinity: an ethereal conversation (part two of three). AB - In 1840 Hugh Strickland published a diagram showing the relationships of genera of birds in the kingfisher family. Three years later he applied this mapping idea to genera of birds of prey and songbirds, creating a large wall chart that he displayed to colleagues but never published. Both of his diagrams featured a scale of degrees of affinity. The meaning of taxonomic affinity was something Darwin thought about deeply. Details in the chart undermine Strickland's claim that his method was purely inductive. PMID- 25547606 TI - Changes on digestive enzymes during initial ontogeny in the three-spot cichlid Cichlasoma trimaculatum. AB - A study was performed in order to understand the development of digestive enzymes during initial ontogeny of Cichlasoma trimaculatum, for which the activity of acidic and alkaline proteases, lipases, amylases and phosphatases was determined by means of biochemical and electrophoretic analysis. Our results showed that the activity of alkaline proteases, trypsin and chymotrypsin is present from day 6 after hatching (dah) during exogenous feeding with Artemia nauplii. The activities of carboxypeptidase A and leucine aminopeptidase are present from the first days, increasing at 6 dah and reaching their maximum activity at 9 dah while acid protease activity started at 9 dah. Furthermore, the lipase activity is detected on 6 dah and keeps increasing and decreasing on 17 dah. Amylase activity is detected on 3 dah, presenting fluctuations until 45 dah, where it reaches its maximum activity. Acid and alkaline phosphatases are detected from 3 dah and reach a maximum activity between 13 and 19 dah. The SDS-PAGE electrophoresis revealed six types of bands in the alkaline proteases, with molecular weight between 113.4 and 20.4 kDa. First three bands appear on 6 dah, but it is until 11 dah when all isoforms appear. Based on these results, it is considered that this species completes its digestive enzymatic machinery from day 9 after hatching, therefore is recommended to perform the transition from live feed to inert feed at 15 dah. PMID- 25547608 TI - Complete and sustained remission of spondyloarthritis after allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome. PMID- 25547609 TI - Galectin-3 is expressed in the myocardium very early post-myocardial infarction. AB - BACKGROUND: Galectin-3 (GAL-3) plays a regulatory role in several diverse biological processes and disease states. It is associated with heart failure and increased risk of death in a number of studies. We aim to study the direct effects of ischemia on GAL-3 levels in the heart very early in the course of events following myocardial infarction (MI). METHODS: Male C57B6/J mice were used for permanently ligating the left anterior descending artery of the heart to create ischemia/infarction in the anterior wall of left ventricle (LV). Heart samples were processed for immunohistochemical and immunofluorescent labeling, enzyme-linked immunosorbent assay, and quantitative reverse transcriptase polymerase chain reaction to identify GAL-3 levels in the heart during the first 24 h following MI. RESULTS: GAL-3 mRNA was significantly increased at 60min (P=.032), 4 h (P=.012), and 24 h (P=.00) post-MI groups in the infarcted LV as compared to sham. Thirty minutes post-MI GAL-3 mRNA is higher than the sham and almost reaching statistical significance (P=.056). GAL-3 protein was significantly increased in the LV at 30 min (P=.021), 60 min (P=.029), 4 h (P=.015), and 24 h (P=.01) post-MI compared to corresponding sham-operated mice. Plasma GAL-3 levels are also significantly raised at 24-h post-MI. GAL-3 is colocalized with cardiomyocytes and endothelial cells in the ischemic area of the LV. GAL-3 is also colocalized with hypoxia-inducible factor-1 alpha (HIF-1alpha). CONCLUSIONS: We show for the first time that GAL-3 is increased at both transcriptional and translational levels in the LV in early ischemic period, which can possibly be a part of the prosurvival gene expression profile transcribed by HIF-1alpha. This is significant because it can help in understanding the mechanism of very early response of the myocardium following acute infarction and help devise ways to save the viable tissue before permanent damage sets in. PMID- 25547610 TI - Pneumoperitoneum affects stroke volume variation in humans. AB - PURPOSE: Stroke volume variation (SVV) is affected by many factors. Although elevated intra-abdominal pressure and a pneumoperitoneum have been shown to increase SVV in animals, a recent human study showed that SVV did not change as a pneumoperitoneum was established. However, we considered the results of this study questionable, and we therefore attempted to study whether SVV changes both before and after pneumoperitoneums in humans. METHODS: We performed a prospective observational study in 19 patients undergoing cholecystectomy or colectomy while on mechanical ventilation. Immediately before pneumoperitoneum, baseline registrations of variables were obtained (baseline I), which were measured every min for 5 min after the pneumoperitoneum was initiated. Immediately before the pneumoperitoneum was released, another baseline registration of variables was obtained (baseline II); these variables were then measured every min for 5 min. RESULTS: After the pneumoperitoneum was initiated, there were significant increases in SVV at the 2- to 5-min time points. After release of the pneumoperitoneum, there were significant decreases in SVV at the 1- to 5-min time points. CONCLUSION: A pneumoperitoneum increased SVV, which is similar to the findings of previous animal studies but is different from a previous clinical study. Upon release of the pneumoperitoneum, SVV decreased significantly, which is new information. SVV values must be estimated cautiously during a pneumoperitoneum. PMID- 25547615 TI - Spatial distribution and historical trends of heavy metals in the sediments of petroleum producing regions of the Beibu Gulf, China. AB - The concentrations of As, Sb, Hg, Pb, Cd, and Ba in the surface and core sediments of the oil and gas producing region of the Beibu Gulf were measured by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Atomic Fluorescence Spectrometry (AFS), and the spatial distribution and historical trends of these elements are discussed. The results show that the concentrations of these elements are highest near the platforms. The results of Enrichment Factor (EF) and Potential Ecological Risk Index (PERI) also reveal significantly higher enrichment around the platforms, which imply that the offshore petroleum production was the cause of the unusual distribution and severe enrichment of these elements in the study area. The environment around the platforms was highly laden with toxic elements, thereby representing a very high ecological risk to the environment of the study area. PMID- 25547614 TI - Nitrogen-driven stem elongation in poplar is linked with wood modification and gene clusters for stress, photosynthesis and cell wall formation. AB - BACKGROUND: Nitrogen is an important nutrient, often limiting plant productivity and yield. In poplars, woody crops used as feedstock for renewable resources and bioenergy, nitrogen fertilization accelerates growth of the young, expanding stem internodes. The underlying molecular mechanisms of nitrogen use for extension growth in poplars are not well understood. The aim of this study was to dissect the nitrogen-responsive transcriptional network in the elongation zone of Populus trichocarpa in relation to extension growth and cell wall properties. RESULTS: Transcriptome analyses in the first two internodes of P. trichocarpa stems grown without or with nitrogen fertilization (5 mM NH4NO3) revealed 1037 more than 2 fold differentially expressed genes (DEGs). Co-expression analysis extracted a network containing about one-third of the DEGs with three main complexes of strongly clustered genes. These complexes represented three main processes that were responsive to N-driven growth: Complex 1 integrated growth processes and stress suggesting that genes with established functions in abiotic and biotic stress are also recruited to coordinate growth. Complex 2 was enriched in genes with decreased transcript abundance and functionally annotated as photosynthetic hub. Complex 3 was a hub for secondary cell wall formation connecting well-known transcription factors that control secondary cell walls with genes for the formation of cellulose, hemicelluloses, and lignin. Anatomical and biochemical analysis supported that N-driven growth resulted in early secondary cell wall formation in the elongation zone with thicker cell walls and increased lignin. These alterations contrasted the N influence on the secondary xylem, where thinner cell walls with lower lignin contents than in unfertilized trees were formed. CONCLUSION: This study uncovered that nitrogen-responsive elongation growth of poplar internodes is linked with abiotic stress, suppression of photosynthetic genes and stimulation of genes for cell wall formation. Anatomical and biochemical analysis supported increased accumulation of cell walls and secondary metabolites in the elongation zone. The finding of a nitrogen responsive cell wall hub may have wider implications for the improvement of tree nitrogen use efficiency and opens new perspectives on the enhancement of wood composition as a feedstock for biofuels. PMID- 25547616 TI - Selective extraction and concentration of mebendazole in seawater samples using molecularly imprinted polymer as sorbent. AB - A high selective pre-treatment method for the extraction and analysis of mebendazole in environmental water samples was developed based on molecularly imprinted solid-phase extraction (MISPE). The mebendazole imprinted polymers were synthesized in acetonitrile using methacrylic acid and ethylene glycol dimethacrylate as functional monomer and cross-linker respectively. The imprinted materials showed high adsorption ability for mebendazole and were applied as special solid-phase extraction sorbents for selective separation of mebendazole. An off-line MISPE procedure was developed for the purification and enrichment of mebendazole from natural seawater samples prior to high-performance liquid chromatography analysis. The recoveries of spiked seawater on the MISPE cartridges were from 83.0% to 90.6%, and the values of the relative standard deviation were in the range of 2.78-4.13% (n=3). The satisfied results showed that this pre-treatment methodology for extracting mebendazole in seawater was simple and effective. PMID- 25547617 TI - Intravitreal aflibercept for choroidal neovascularisation complicating chronic central serous chorioretinopathy. PMID- 25547618 TI - The use of Argus(r) II retinal prosthesis by blind subjects to achieve localisation and prehension of objects in 3-dimensional space. AB - BACKGROUND: The Argus(r) II retinal prosthesis system has entered mainstream treatment for patients blind from Retinitis Pigmentosa (RP). We set out to evaluate the use of this system by blind subjects to achieve object localisation and prehension in 3-dimensional space. METHODS: This is a single-centre, prospective, internally-controlled case series involving 5 blind RP subjects who received the Argus(r) II implant. The subjects were instructed to visually locate, reach and grasp (i.e. prehension) a small white cuboid object placed at random locations on a black worktop. A flashing LED beacon was attached to the reaching index finger (as a finger marker) to assess the effect of enhanced finger visualisation on performance. Tasks were performed with the prosthesis switched "on" or "off" and with the finger marker switched "on" or "off". Forty eight trials were performed per subject. Trajectory of each subject's hand movement during the task was recorded by a 3D motion-capture unit (Qualysis(r), see supplementary video) and analysed using a MATLAB script. RESULT: Percentage of successful prehension+/-standard deviation was: 71.3 +/- 27.1 % with prosthesis on and finger marker on; 77.5 +/- 24.5 % with prosthesis on and finger marker off; 0.0 +/- 0.0 % with prosthesis off and finger marker on, and 0.00 +/- 0.00 % with prosthesis off and finger marker off. The finger marker did not have a significant effect on performance (P = 0.546 and 1, Wilcoxon Signed Rank test, with prosthesis on and off respectively). With prosthesis off, none of the subjects were able to visually locate the target object and no initiation of prehension was attempted. With prosthesis on, prehension was initiated on 82.5 % (range 59-100 %) of the trials with 89.0 % (range 66.7-100 %) achieving successful prehension. CONCLUSION: Argus(r) II subjects were able to achieve object localisation and prehension better with their prosthesis switched on than off. PMID- 25547619 TI - Exercises in anatomy: holes between the ventricles. AB - Holes between the ventricles are the commonest congenital cardiac malformations. As yet, however, there is no consensus as to how they can best be described and categorized. In this, our third exercise in cardiac anatomy, we address the issue of classification of ventricular septal defects. We begin our demonstration by analysing the normal heart. We show that the larger part of the ventricular septum is made up of its muscular component. The membranous part accounts for only a small portion, which is located centrally within the cardiac base. This small membranous part forms a boundary between the right-sided chambers and the aortic root. Holes at this site, therefore, which account for the commonest defects closed surgically, will open centrally in the cardiac base, being located postero-inferiorly relative to the supraventricular crest. We then show that the larger part of the crest itself is a free-standing muscular sleeve, which lifts the leaflets of the pulmonary valve away from the cardiac base. Only a very small part of the muscle forming the right ventricular outlet is located in the septal position. Turning our attention to malformed hearts, we show how holes between the ventricles can open centrally at the cardiac base, open to the inlet or outlet of the right ventricle or open within the substance of the apical muscular septum. We demonstrate, however, that description of such geographical location of the defects does not paint the full picture, since lesions with markedly different phenotypic features can open in comparable geographic locations. We illustrate how it is the phenotypic features, as seen from the right ventricle, which convey the crucial information for the surgeon with regard to the location of the atrioventricular conduction axis, using hearts with holes opening to the inlet of the right ventricle with muscular as opposed to partially fibrous borders to emphasize this point. We continue by showing how holes with different phenotypes can also open to the outlet of the right ventricle, the key feature in this regard being malalignment between the apical muscular septum relative to the muscular outlet septum or its fibrous remnant. Malalignment can also be found between the apical ventricular septum and the atrial septum, this being shown in a defect opening to the inlet of the right ventricle. We conclude by emphasizing that, so as to bring together all the information of surgical significance, it is necessary to take note of the geographical location of holes between the ventricles, their phenotypic features and the presence or absence of malalignment between the septal components. PMID- 25547620 TI - Exercises in anatomy: cardiac isomerism. AB - It is well recognized that the patients with the most complex cardiac malformations are those with so-called visceral heterotaxy. At present, it remains a fact that most investigators segregate these patients on the basis of their splenic anatomy, describing syndromes of so-called asplenia and polysplenia. It has also been known for quite some time, nonetheless, that the morphology of the tracheobronchial tree is usually isomeric in the setting of heterotaxy. And it has been shown that the isomerism found in terms of bronchial arrangement correlates in a better fashion with the cardiac anatomy than does the presence of multiple spleens, or the absence of any splenic tissue. In this exercise in anatomy, we use hearts from the Idriss archive of Lurie Children's Hospital in Chicago to demonstrate the isomeric features found in the hearts obtained from patients known to have had heterotaxy. We first demonstrate the normal arrangements, showing how it is the extent of the pectinate muscles in the atrial appendages relative to the atrioventricular junctions that distinguishes between morphologically right and left atrial chambers. We also show the asymmetry of the normal bronchial tree, and the relationships of the first bronchial branches to the pulmonary arteries supplying the lower lobes of the lungs. We then demonstrate that diagnosis of multiple spleens requires the finding of splenic tissue on either side of the dorsal mesogastrium. Turning to hearts obtained from patients with heterotaxy, we illustrate isomeric right and left atrial appendages. We emphasize that it is only the appendages that are universally isomeric, but point out that other features support the notion of cardiac isomerism. We then show that description also requires a full account of veno-atrial connections, since these can seemingly be mirror-imaged when the arrangement within the heart is one of isomerism of the atrial appendages. We show how failure to recognize the presence of such isomeric appendages can lead to spurious diagnoses of discordant atrioventricular connections. Overall, we show that the finding of isomeric atrial appendages, guided by the finding of bronchial isomerism, is but the prelude to full segmental sequential analysis. PMID- 25547621 TI - Evaluating the guideline enhancement tool (GET): an innovative clinical training tool to enhance the use of hypertension guidelines in general practice. AB - BACKGROUND: This project aims to evaluate the effectiveness of an innovative educational intervention in enhancing clinical decision making related to the management of hypertension in general practice. The relatively low level of uptake of clinical practice guidelines by clinicians is widely recognised as a problem that impacts on clinical outcomes. This project addresses this problem with a focus on hypertension guidelines. Hypertension is the most frequently managed problem in general practice but evidence suggests that management of Hypertension in general practice is sub-optimal. METHODS/DESIGN: This study will explore the effectiveness of an educational intervention named the 'Guideline Enhancement Tool (GET)'. The intervention is designed to guide clinicians through a systematic process of considering key decision points related to the management of hypertension and provides a mechanism for clinicians to engage with the hypertension clinical guidelines. The intervention will be administered within the Australian General Practice Training program, via one of the regional training providers. Two cohorts of trainees will participate as the intervention and delayed intervention groups. This process is expected to improve clinicians' engagement with the hypertension guidelines in particular, and enhance their clinical reasoning abilities in general. The effectiveness of the intervention in improving clinical reasoning will be evaluated using the 'Script Concordance Test'. DISCUSSION: The study design presented in this protocol aims to achieve two major outcomes. Firstly, the trial and evaluation of the educational intervention can lead to the development of a validated clinical education strategy that can be used in GP training to enhance the decision-making processes related to the management of hypertension. This has the potential to be adapted to other clinical conditions and training programs and can benefit clinicians in their clinical decision-making. Secondly, the study explores features that influence the effective use of clinical practice guidelines. The study thus addresses a significant problem in clinical education. PMID- 25547622 TI - Polymyositis, a very uncommon isolated disease: clinical and histological re evaluation after long-term follow-up. AB - The aim of the present study was to explore whether polymyositis may be considered as an isolated, organ-specific disease or more suitably as a secondary or associated entity. A retrospective re-evaluation of all the muscle biopsies performed at the Hospital Clinic of Barcelona showing histopathological pattern of polymyositis from January 1997 to May 2012 was carried out. The medical records of the patients with the aforementioned pathological pattern were also reviewed. From 1.290 muscle biopsies performed during the period evaluated, 36 with polymyositis pattern were identified. At the time of muscle biopsy, polymyositis pattern was secondary or associated with other disease in 26 patients and was classified as isolated in the remaining ten patients. After pathological re-evaluation and long-term clinical follow-up, only one patient remained with this diagnosis. Overall, the main final diagnosis related to the initial polymyositis pattern was inflammatory myopathy associated with connective tissue disease. Several other associated conditions were also identified. Isolated polymyositis is highly uncommon. Ruling out potential associated or confusing entities, like inclusion body myositis, overlap syndromes, infections, and cancer, is mandatory. PMID- 25547623 TI - Cat scratch disease during infliximab therapy: a case report and literature review. AB - Cat scratch disease may occur during etanercept therapy, but there has been no report on infliximab-associated cat scratch disease. We report a case of a 23 year-old woman who developed right inguinal lymph node enlargement following a cat scratch. The patient had received infliximab therapy for spondyloarthropathy. She was successfully managed by discontinuing infliximab and by treatment with moxifloxacin and amikacin. PMID- 25547624 TI - Primary central nervous system lymphoma and glioblastoma: differentiation using dynamic susceptibility-contrast perfusion-weighted imaging, diffusion-weighted imaging, and (18)F-fluorodeoxyglucose positron emission tomography. AB - OBJECTIVE: The objective was to evaluate diagnostic performance of dynamic susceptibility-contrast perfusion-weighted imaging, diffusion-weighted imaging, and (18)F-fluorodeoxyglucose positron emission tomography in differentiating primary central nervous system lymphoma (PCNSL) and glioblastoma. MATERIALS AND METHODS: Twenty-three glioblastomas and 11 PCNSLs were analyzed with uncorrected cerebral blood volume (CBV) ratio, fifth percentile value of cumulative apparent diffusion coefficient histogram (ADC5%), and maximum standardized uptake value (SUVmax) using regions of interest created semiautomatically on enhancing areas. RESULTS: Uncorrected CBV ratio was highly capable of differentiating PCNSL from glioblastoma, as well as SUVmax and ADC5%. CONCLUSIONS: Uncorrected CBV ratio demonstrates high diagnostic performance comparable to SUVmax. PMID- 25547625 TI - Imaging of extraosseous intracranial and intraspinal multiple myeloma, including central nervous system involvement. AB - Involvement of the central nervous system by multiple myeloma is rare and has a very poor prognosis. Magnetic resonance imaging of the head and spine plays an important role in diagnosing central nervous system involvement with multiple myeloma. We retrospectively analyzed the imaging features of pathology-proven extraosseous intracranial and intraspinal multiple myeloma from 2002 to 2013. The most common imaging manifestations were extraaxial nonosseous spinal lesions, cranial nerve involvement, and intracranial extraaxial nonosseous lesions. Different sites in the central nervous system may be affected by multiple myeloma, often simultaneously, producing a variety of imaging appearances. PMID- 25547626 TI - Biotransformation and mass balance of the SGLT2 inhibitor empagliflozin in healthy volunteers. AB - 1. The absorption, biotransformation and excretion of empagliflozin, an SGLT2 inhibitor, were evaluated in eight healthy subjects following a single 50 mg oral dose of empagliflozin containing ~100 uCi [(14)C]-empagliflozin. 2. Radioactivity was rapidly absorbed, with plasma levels peaking 1 h post-dose. Total exposure was lower in blood versus plasma, consistent with moderate (28.6-36.8%) red blood cell partitioning. Protein binding was 80.3-86.2%. 3. Most of the radioactive dose was recovered in urine (54.4%) and faeces (41.1%). Unchanged empagliflozin was the most abundant drug-related component in plasma, representing 75.5-77.4% of plasma radioactivity and 79.6% plasma radioactivity AUC0-12 h. Unchanged empagliflozin was the most abundant drug-related component in urine and faeces, representing 43.5% (23.7% of dose) and 82.9% (34.1% of dose) of radioactivity in urine and faeces, respectively. Six metabolites were identified in plasma: three glucuronide conjugates representing 4.7-7.1% of AUC0-12 h and three less abundant metabolites (<0.2-1.9% AUC0-12 h). The most abundant metabolites in urine were two glucuronide conjugates (7.8-13.2% of dose) and in faeces was a tetrahydrofuran ring-opened carboxylic acid metabolite (1.9% of dose). 4. To conclude, empagliflozin was rapidly absorbed and excreted primarily unchanged in urine and faeces. Unchanged parent was the major drug-related component in plasma. Metabolism was primarily via glucuronide conjugation. PMID- 25547627 TI - Identification and functional characterization of novel feline cytochrome P450 2A. AB - 1. Cytochrome P450s are the major metabolizing enzymes for xenobiotics in humans and other mammals. Although the domestic cat Felis catus, an obligate carnivore, is the most common companion animal, the properties of cytochrome P450 subfamilies are largely unknown. 2. We newly identified the feline CYP2A13, which consists of 494 deduced amino acids, showing the highest identity to CYP2As of dogs, followed by those of pigs, cattle and humans. 3. The feline CYP2A13 transcript and protein were expressed almost exclusively in the liver without particular sex-dependent differences. 4. The feline CYP2A13 protein heterogeneously expressed in Escherichia coli showed metabolic activity similar to those of human and canine CYP2As for coumarin, 7-ethoxycoumarin and nicotine. 5. The results indicate the importance of CYP2A13 in systemic metabolism of xenobiotics in cats. PMID- 25547628 TI - Differences in the glucuronidation of bisphenols F and S between two homologous human UGT enzymes, 1A9 and 1A10. AB - 1. Bisphenol S (BPS) and bisphenol F (BPF) are bisphenol A (BPA) analogues commonly used in the manufacturing of industrial and consumer products. 2. Bisphenols are often detoxified through conjugation with glucuronic acid or sulfate. In this work, we have examined the glucuronidation of BPS and BPF by recombinant human UDP-glucuronosyltransferase (UGT) enzymes. In addition, we have reexamined BPA glucuronidation, using extra-hepatic UGTs that were not tested previously. 3. The results revealed that UGT1A9, primarily a hepatic enzyme, is mainly responsible for BPS glucuronidation, whereas UGT1A10, an intestine enzyme that is highly homologous to UGT1A9 at the protein level, is by far the most active UGT in BPF glucuronidation. In contrast to the latter two UGTs that display significant specificity in the glucuronidation of BPS and BPF, UGT2A1 that is mainly expressed in the airways, exhibited high activity toward all the tested bisphenols, BPS, BPF and BPA. UGT1A10 exhibited somewhat higher BPA glucuronidation activity than UGT1A9, but it was lower than UGT2A1 and UGT2B15. 4. The new findings demonstrate interesting differences in the glucuronidation patterns of bisphenols and provide new insights into the role of extra-hepatic tissues in their detoxification. PMID- 25547629 TI - Quasispecies in population of compositional assemblies. AB - BACKGROUND: The quasispecies model refers to information carriers that undergo self-replication with errors. A quasispecies is a steady-state population of biopolymer sequence variants generated by mutations from a master sequence. A quasispecies error threshold is a minimal replication accuracy below which the population structure breaks down. Theory and experimentation of this model often refer to biopolymers, e.g. RNA molecules or viral genomes, while its prebiotic context is often associated with an RNA world scenario. Here, we study the possibility that compositional entities which code for compositional information, intrinsically different from biopolymers coding for sequential information, could show quasispecies dynamics. RESULTS: We employed a chemistry-based model, graded autocatalysis replication domain (GARD), which simulates the network dynamics within compositional molecular assemblies. In GARD, a compotype represents a population of similar assemblies that constitute a quasi-stationary state in compositional space. A compotype's center-of-mass is found to be analogous to a master sequence for a sequential quasispecies. Using single-cycle GARD dynamics, we measured the quasispecies transition matrix (Q) for the probabilities of transition from one center-of-mass Euclidean distance to another. Similarly, the quasispecies' growth rate vector (A) was obtained. This allowed computing a steady state distribution of distances to the center of mass, as derived from the quasispecies equation. In parallel, a steady state distribution was obtained via the GARD equation kinetics. Rewardingly, a significant correlation was observed between the distributions obtained by these two methods. This was only seen for distances to the compotype center-of-mass, and not to randomly selected compositions. A similar correspondence was found when comparing the quasispecies time dependent dynamics towards steady state. Further, changing the error rate by modifying basal assembly joining rate of GARD kinetics was found to display an error catastrophe, similar to the standard quasispecies model. Additional augmentation of compositional mutations leads to the complete disappearance of the master-like composition. CONCLUSIONS: Our results show that compositional assemblies, as simulated by the GARD formalism, portray significant attributes of quasispecies dynamics. This expands the applicability of the quasispecies model beyond sequence-based entities, and potentially enhances validity of GARD as a model for prebiotic evolution. PMID- 25547630 TI - Identifying target processes for microbial electrosynthesis by elementary mode analysis. AB - BACKGROUND: Microbial electrosynthesis and electro fermentation are techniques that aim to optimize microbial production of chemicals and fuels by regulating the cellular redox balance via interaction with electrodes. While the concept is known for decades major knowledge gaps remain, which make it hard to evaluate its biotechnological potential. Here we present an in silico approach to identify beneficial production processes for electro fermentation by elementary mode analysis. Since the fundamentals of electron transport between electrodes and microbes have not been fully uncovered yet, we propose different options and discuss their impact on biomass and product yields. RESULTS: For the first time 20 different valuable products were screened for their potential to show increased yields during anaerobic electrically enhanced fermentation. Surprisingly we found that an increase in product formation by electrical enhancement is not necessarily dependent on the degree of reduction of the product but rather the metabolic pathway it is derived from. We present a variety of beneficial processes with product yield increases of maximal 36% in reductive and 84% in oxidative fermentations and final theoretical product yields up to 100%. This includes compounds that are already produced at industrial scale such as succinic acid, lysine and diaminopentane as well as potential novel bio commodities such as isoprene, para-hydroxybenzoic acid and para-aminobenzoic acid. Furthermore, it is shown that the way of electron transport has major impact on achievable biomass and product yields. The coupling of electron transport to energy conservation could be identified as crucial for most processes. CONCLUSIONS: This study introduces a powerful tool to determine beneficial substrate and product combinations for electro-fermentation. It also highlights that the maximal yield achievable by bio electrochemical techniques depends strongly on the actual electron transport mechanisms. Therefore it is of great importance to reveal the involved fundamental processes to be able to optimize and advance electro fermentations beyond the level of lab-scale studies. PMID- 25547631 TI - Amyloid-beta1-42 Disrupts Synaptic Plasticity by Altering Glutamate Recycling at the Synapse. AB - Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorders characterized by neuritic plaques containing amyloid-beta peptide (Abeta) and neurofibrillary tangles. Evidence has been reported that Abeta(1-42) plays an essential pathogenic role in decreased spine density, impairment of synaptic plasticity, and neuronal loss with disruption of memory-related synapse function, all associated with AD. Experimentally, Abeta(1-42) oligomers perturb hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory. Abeta was also reported to perturb synaptic glutamate (Glu) recycling by inhibiting excitatory-amino-acid-transporters. Elevated level of extracellular Glu leads to activation of perisynaptic receptors, including NR2B subunit containing NMDARs. These receptors were shown to induce impaired LTP and enhanced long-term depression and proapoptotic pathways, all central features of AD. In the present study, we investigated the role of Glu-recycling on Abeta(1 42)-induced LTP deficit in the CA1. We found that Abeta-induced LTP damage, which was mimicked by the Glu-reuptake inhibitor TBOA, could be rescued by blocking the NR2B subunit of NMDA receptors. Furthermore, decreasing the level of extracellular Glu using a Glu scavenger also restores TBOA or Abeta induces LTP damage. Overall, these results suggest that reducing ambient Glu in the brain can be protective against Abeta-induced synaptic disruption. PMID- 25547632 TI - Cognitive-motor intervention in Alzheimer's disease: long-term results from the Maria Wolff trial. AB - BACKGROUND: Little is known about the long-term acceptance and effects of cognitive and motor stimulation interventions (CMSI) in Alzheimer's disease (AD). OBJECTIVE: To evaluate a replicable CMSI program for mild cognitive impairment (MCI) and mild-to-moderate AD persons. METHODS: Eighty-four non-institutionalized subjects with AD were randomized to receive either CMSI, administered by a single care provider, or standard support. Cognition, activities of daily living (ADL), mood, and study partner's subjective burden were assessed by blinded raters. Data on institutionalization, psychiatric medications, and demise were collected by the study physicians. Random effects model and survival analyses were conducted, after 2 and 3 years of study. RESULTS: Three-year assessments could be performed by the physician in 85% and by the blinded rater in 66% of subjects. Significant benefits were observed in basic ADL at the 2- and 3-year assessments, whereas instrumental ADL showed benefits only up to the second year of intervention (p < 0.05). CONCLUSION: Long-term cognitive-motor stimulation is well accepted and produces functional benefits in subjects with AD, with no extra subjective burden in the partner. PMID- 25547633 TI - Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-beta and Tau Pathology in Alzheimer's Disease. AB - A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer's disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tau(HYP)) appears early in these neurons. In an attempt to find out if both heavy metals and tau(HYP) could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tau(HYP) using AT8 immunostaining. Heavy metals or tau(HYP) were usually seen in separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tau(HYP). Heavy metals therefore appear to occupy a mostly different population of LC neurons to those containing tau(HYP), indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-beta deposition, and tau(HYP) in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-beta and tau pathologies of AD. PMID- 25547634 TI - Amyloid-beta oligomers relate to cognitive decline in Alzheimer's disease. AB - BACKGROUND: Amyloid-beta (Abeta)-oligomers are neurotoxic isoforms of Abeta and are a potential diagnostic biomarker for Alzheimer's disease (AD). OBJECTIVES: 1) Analyze the potential of Abeta-oligomer concentrations in cerebrospinal fluid (CSF) to diagnose and predict progression to AD in a large clinical study sample. 2) Monitor Abeta-oligomer concentrations over-time, both in early and advanced stages of AD. 3) Examine the relation between Abeta-oligomer levels in CSF and cognitive functioning. METHODS: 24 non-demented, 61 mild cognitive impairment (MCI), and 64 AD patients who underwent lumbar puncture and cognitive testing at baseline and follow-up were selected from the memory clinic based Amsterdam Dementia Cohort. CSF samples were analyzed for standard AD-biomarkers and Abeta oligomer levels using a validated in-house Abeta-oligomer specific enzyme-linked immunosorbent assay. Abeta-oligomer levels were analyzed as indicators of disease progression (follow-up AD diagnosis) and cognitive decline, respectively. RESULTS: Patient groups did not differ in Abeta-oligomer concentrations at baseline or follow-up. Baseline CSF Abeta-oligomer levels were similar in MCI patients that develop AD as in stable MCI patients. MCI and AD patients showed an annual decrease in Abeta-oligomer levels of 9.4% and 6.8%, respectively. A decrease in Abeta-oligomer levels over time was strongly associated with more severe cognitive decline in AD patients. CONCLUSION: Despite the limited diagnostic potential of Abeta-oligomer levels in CSF to differentiate between patient groups, and between MCI-AD and MCI-stable patients, changes in CSF Abeta oligomer levels were related to cognitive decline. Therefore, CSF Abeta-oligomers may aid in the selection of patients with a more aggressive disease course. PMID- 25547635 TI - Neuron Loss and Behavioral Deficits in the TBA42 Mouse Model Expressing N Truncated Pyroglutamate Amyloid-beta3-42. AB - Pyroglutamate-modified amyloid-beta (Abeta) at amino acid position three (Abeta(pE3-42)) is gaining considerable attention as a potential key player in the pathogenesis of Alzheimer's disease (AD). Abeta(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability, and cellular toxicity. The aim of the present work was to study the effect of Abeta(pE3-42) expression on neuron loss and associated behavioral deficits using the TBA42 transgenic mouse model. Expression of pyroglutamate Abeta(3-42) triggers hippocampal CA1 neuron loss and behavioral deficits in the TBA42 mouse model. Mice elicited significant neuron death (-35% at the age of 12 months), deficits in the spatial reference memory, working memory, loss of anxiety, and severe motor deficits in an age-dependent manner. These results support a major pathological function of pyroglutamate Abeta in AD. PMID- 25547636 TI - Increased functional connectivity in the default mode network in mild cognitive impairment: a maladaptive compensatory mechanism associated with poor semantic memory performance. AB - Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population. PMID- 25547638 TI - Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid beta of Peptides in Cerebrospinal Fluid Specimens from Alzheimer's Disease Studies. AB - The aim of this study was to validate assays for measurement of amyloid-beta (Abeta) peptides in cerebrospinal fluid (CSF)specimens according to regulatory guidance and demonstrate their utility with measurements in specimens from Alzheimer's disease (AD) studies. Methods based on INNOTEST((r))beta-AMYLOID(1 42) and prototype INNOTEST((r))beta-AMYLOID(1-40) ELISAkits were developed involving pre-analytical sample treatment with Tween-20 for reliable analyte recovery.Validation parameters were evaluated by repeated testing of CSF pools collected and stored in the same manner as clinical specimens. Intra- and interassay coefficients of variation were <=11% and relative accuracy was within +/- 10% for both analytes. Dilutional linearity was demonstrated for both analytes from a spiked CSF pool, but not from a non-spiked native CSF pool. Recovery of standard Abeta peptide spikes standard ranged from 77% to 93%. No interference was observed from the investigational drugs LY2811376, LY2886721, LY3002813, or semagacestat. Abeta(1-40) and Abeta(1-42) were stable in CSF for up to 8 hours at room temperature and during 5 f reeze-thaw cycles from <=-20?C and <=-70?C. In frozen native CSF specimens, Abeta(1-40) was mostly stable up to 3 years at <=-70?C, whereas stability of Abeta(1-42) was limited to 221 days. Dose dependent changes in measured CSF Abeta were observed in healthy volunteers up to 36 hours after treatment with the-site cleavage enzyme inhibitor LY2886721. In conclusion, rigorous validation tests have successfully demonstrated the strengths and operational limitations of these INNOTEST((r))-based assays.They have proved to be robust and reliable tools for pharmacodynamic evaluations of investigational AD therapeutics in clinical trials. PMID- 25547639 TI - Pharmacokinetic and biodistribution study of eserine and pralidoxime chloride in rabbits following a single application of a transdermal patch. AB - In the present study, a simple reverse-phase high-performance liquid chromatography method with diode array detection has been developed and validated for the simultaneous determination and quantification of eserine and pralidoxime chloride in rabbit plasma and its application to pharmacokinetic study. The pharmacokinetic study was performed after transdermal application of single patch in rabbits. The plasma levels of both drugs following transdermal application of single patch were maintained for 72 h after removal of the patch. The maximal concentrations (C max) of both drugs were significantly reduced while the mean areas under the plasma concentration vs. time moment curve and mean residence times were evidently increased and extended, respectively. A sustained activity was observed over a period of 3 days. This sustained activity was due to the controlled release of drug into the systemic circulation following transdermal application. Linear correlation was also observed when fraction of drug permeated was correlated with the fraction of drug absorbed at the same time point. Gamma scintigraphy imaging on rabbit following transdermal patch application was performed to ascertain the localization of drugs in rabbit brain. PMID- 25547641 TI - Efficacy of psychosocial interventions on psychological and physical health outcomes in chronic obstructive pulmonary disease: a systematic review and meta analysis. AB - BACKGROUND: Psychosocial intervention has been suggested as a potentially effective supplement to medical treatment in chronic obstructive pulmonary disease (COPD), but no reviews so far have quantified the existing research in terms of both psychological and physical health outcomes. We therefore conducted a systematic review and meta-analysis of controlled trials evaluating the effects of psychosocial interventions on psychological and physical health outcomes in COPD. METHODS: Two independent raters screened 1,491 references for eligibility. Twenty independent studies investigating a total of 1,361 patients were included, assessed for their methodological quality, and subjected to meta-analytic evaluation. RESULTS: After adjusting for potential publication bias, a statistically significant overall effect was found for psychological (Hedges' g = 0.38, 95% confidence interval, CI = 0.19-0.58; p < 0.001) outcomes. When analyzing individual intervention types, cognitive behavioral therapy appeared to be effective (g = 0.39, CI = 0.15-0.62; p = 0.001) for improving psychological outcomes. In contrast, for physical outcomes, only mind-body interventions (e.g. mindfulness-based therapy, yoga, and relaxation) revealed a statistically significant effect (g = 0.40; CI = 0.01-0.79; p = 0.042). CONCLUSIONS: Taken together, the results lend support to psychosocial intervention as a tool in the management of COPD. However, due to indications of possible publication bias towards positive findings, the results should be interpreted with some caution, and more high quality research is needed. PMID- 25547640 TI - Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice. AB - The aim of the current investigation was to assess the ability GFJ to modulate the pharmacokinetic profile of paracetamol following single or repeated administrations of GFJ in Sprague-Dawley rats. Diclofenac and carbamazepine were both used as positive controls. Rats received single GFJ or single distilled water doses or pretreated with three doses of GFJ prior to test drug administration. Blood samples were collected, processed and analyzed using validated HPLC methods, and pharmacokinetic data were constructed for each group. Increase in the bioavailability of both diclofenac and carbamazepine following multiple GFJ ingestion was revealed. Conversely, the bioavailability of paracetamol was significantly reduced following multiple GFJ administration. The percentage of reduction in the C max and AUC of paracetamol were calculated as 31 and 51 %, respectively, compared to none-GFJ-treated control (P < 0.05). The T(max) was not essentially changed. In conclusion, frequent administration of GFJ was confirmed to modulate the pharmacokinetics of paracetamol in rats by reducing its bioavailability. Meanwhile, it may be advisable not to ingest large amounts of GFJ along with paracetamol to avoid a possible potential loss of the efficacy. PMID- 25547642 TI - Skin sensitisation to fragrance ingredients: is there a role for household cleaning/maintenance products? AB - The induction of contact allergy to fragrance ingredients and the consequent risk of allergic contact dermatitis (ACD) present a human health concern that cannot be ignored. The problem arises when exposure exceeds safe levels, but the source(s) of exposure which lead to induction often remain unclear. This contrasts with the elicitation of ACD, where the eczema frequently can be traced to specific source(s) of skin exposure. Cosmetic products are often implicated, both for induction and elicitation. However, other products contain fragrance ingredients, including household cleaning products. In this paper, the risk assessment concerning the ability of these products to induce fragrance contact allergy is considered and the clinical evidence for the induction and/or elicitation of ACD is reviewed. It can be concluded that the risk of the induction of fragrance contact allergy from household cleaning products is low. Especially where more potent fragrance allergens are used in higher exposure products, the aggregated exposure from such products can augment the risk for the elicitation of ACD. This supports the need to manage this risk via the provision of information to consumers. PMID- 25547643 TI - Environmental determinants of the spatial distribution of Angiostrongylus vasorum, Crenosoma vulpis and Eucoleus aerophilus in Hungary. AB - Angiostrongylus vasorum, Crenosoma vulpis and Eucoleus aerophilus (syn. Capillaria aerophila) are the most important lungworm species infecting wild and domesticated canids in Europe. To investigate the spatial distribution of these parasites and the factors influencing their circulation in the fox populations, 937 red foxes (Vulpes vulpes) were tested for lungworm infection in Hungary. The prevalence of A. vasorum, C. vulpis and E. aerophilus infection was high (17.9, 24.6 and 61.7%). The distribution pattern of infection in foxes and the relationship of this pattern with landscape and climate was analyzed by geographic information system. Based on the analysis, the annual precipitation was the major determinant of the spatial distribution of A. vasorum and C. vulpis and E. aerophilus. Nevertheless, the mean annual temperature also influenced the distribution of A. vasorum and E. aerophilus. The positive relationship with annual precipitation and the negative relationship with mean annual temperature can be attributed to the sensitivity of larvae, eggs and intermediate hosts (snails and slugs) of lungworms for desiccation. Based on the highly clumped distribution of A. vasorum and C. vulpis, the indirect life cycle (larvae, slugs and snails) of these parasites seems to be particularly sensitive for environmental effects. The distribution of E. aerophilus was considerably less clumped indicating a lower sensitivity of the direct life cycle (eggs) of this parasite for environmental factors. Based on these results, lungworm infections in canids including dogs can be expected mainly in relatively wet and cool areas. PMID- 25547645 TI - Stem cell terminology and 'synthetic' embryos: a new debate on totipotency, omnipotency, and pluripotency and how it relates to recent experimental data. AB - The rapid progress in the stem cell field, in particular in cell reprogramming, combined with certain recent observations from experimental embryology, has ignited a new discussion on stem cell terminology. The current use of terms describing stem cell potentiality is inconsistent and can be confusing, in particular the widely used term pluripotency and its distiction from totipotency. For cells possessing a complete differentiation potential (but lacking an autonomous embryo-structuring capacity) the term omnipotency (or, as recently proposed, plenipotency) has been coined. The present commentary takes up this discussion and confronts it with recent reports on 'engineering' viable fish embryos or gastrulating human germ disc models using 'pluripotent'/omnipotent cells, as well as on symmetry breaking in aggregates of mouse embryonic stem cells. It is concluded that we should start contemplating not only the terminology but also, even more urgently, the ethical implications of the perspective of constructing embryonic anlagen in humans. PMID- 25547644 TI - New insights of nociceptor sensitization in bone cancer pain. AB - INTRODUCTION: Numerous studies have shown that an intact CNS is required for the conscious perception of cancer-induced bone pain (CIBP) and that changes in the CNS are clearly evident. Accordingly, the blockage of nociceptive stimulus into the CNS can effectively relieve or markedly attenuate CIBP, revealing the clinical implication of the blockage of ongoing peripheral inputs for the control of CIBP. AREAS COVERED: In this review, the heterogeneity and excitability of nociceptors in bone are covered. Furthermore, their role in initiating and maintaining CIBP is also described. EXPERT OPINION: Developing mechanistic therapies to treat CIBP is a challenge, but they have the potential to fundamentally change our ability to effectively block/relieve CIBP and increase the functional status and quality of life of patients with bone metastasis. Further studies are desperately needed at both the preclinical and clinical levels to determine whether the targets as mentioned in this review are viable and feasible for patient populations. PMID- 25547646 TI - Experimental and computational investigation on the gas phase reaction of p cymene with Cl atoms. AB - The rate coefficient for the gas-phase reaction of Cl atoms with p-cymene was determined as a function of temperature (288-350 K) and pressure (700-800 Torr) using the relative rate technique, with 1,3-butadiene and ethylene as reference compounds. Cl atoms were generated by UV photolysis of oxalyl chloride ((COCl)2) at 254 nm, and nitrogen was used as the diluent gas. The rate coefficient for the reaction of Cl atoms with p-cymene at 298 K was measured to be (2.58 +/- 1.55) * 10(-10) cm(3) molecule(-1) s(-1). The kinetic data obtained over the temperature range 288-350 K were used to derive an Arrhenius expression: k(T) = (9.36 +/- 2.90) * 10(-10) exp[-(488 +/- 98)/T] cm(3) molecule(-1) s(-1). Theoretical kinetic calculations were also performed for the title reaction using canonical variational transition state theory (CVT) with small curvature tunneling (SCT) between 250 and 400 K. The calculated rate coefficients obtained over the temperature range 250-400 K were used to derive an Arrhenius expression: k(T) = 5.41 * 10(-13) exp[1837/T] cm(3) molecule(-1) s(-1). Theoretical study indicated that addition channels contribute maximum to the total reaction and H-abstraction channels can be neglected. The atmospheric lifetime (tau) of p-cymene due to its reactions with various tropospheric oxidants was estimated, and it was concluded that the reactions of p-cymene with Cl atoms may compete with OH radicals in the marine boundary layer and in coastal urban areas where the concentration of Cl atoms is high. PMID- 25547647 TI - Increasing the health literacy of learning disability and mental health nurses in physical care skills: a pre and post-test evaluation of a workshop on diabetes care. AB - This paper presents the pre- and post-test results of the outcomes of a workshop designed to increase learning disability and mental health nurses' knowledge and skill to undertake interventions for service users at risk of, or with a diagnosis of, type 2 diabetes. Health literacy is also discussed as a way of explaining why such nurses may lack expertise in physical health care. Findings from the workshop show that learning disability and mental health nurses have the motivation to increase their health literacy (skills and knowledge) in diabetes care. The potential of such workshops, and how organisations looking forward to the future can build health literacy, is discussed. PMID- 25547648 TI - SalA attenuates hypoxia-induced endothelial endoplasmic reticulum stress and apoptosis via down-regulation of VLDL receptor expression. AB - BACKGROUND: Salvianolic acid A (SalA) has been shown to display robust protection against endothelial injury. VLDL receptor (VLDLr) is expressed at high levels in the endothelial cells. However its endothelial biological function has not been completely elucidated. Here, we investigated molecular effects of SalA on endothelial VLDLr expression, ER stress, and apoptosis under hypoxia condition. METHODS: Human umbilical vein endothelial cells (HUVECs) pretreated with SalA were subjected to hypoxia stimulation. Endothelial ER stress and apoptosis were examined. The mRNA levels were tested by real-time RT-PCR, and the protein levels were determined by immunoblot analysis. RESULTS: Pretreatment of HUVECs with SalA markedly attenuated hypoxia-induced endothelial ER stress and apoptosis. Hypoxia resulted in enhancement of VLDLr expression, which was effectively inhibited by SalA pretreatment. Furthermore, luciferase reporter gene assays indicated that SalA inhibited vldlr gene promoter activity, and ChIP assays showed that hypoxia increase the recruitment of HIF-1alpha to the vldlr gene promoter, and this process was hampered markedly by pretreatment of SalA. Finally, overexpression of VLDLr abolished SalA-mediated protection of endothelial cells from ER stress and apoptosis. Knockdown of VLDLr mimicked SalA protective effect. CONCLUSION: These results for the first time demonstrate that SalA protects against hypoxia-induced endothelial ER stress and apoptosis through inhibiting recruitment of HIF-1alpha to vldlr gene promoter and thus suppressing VLDLr expression. PMID- 25547649 TI - Pompholyx-like manifestation in Churg-Strauss syndrome. PMID- 25547652 TI - VLA-4 and CXCR4 overexpression in bone marrow of an aleukemic B-cell acute lymphoblastic leukemia presenting with osteolytic bone lesions. PMID- 25547653 TI - Lenalidomide differently modulates CD20 antigen surface expression on chronic lymphocytic leukemia B-cells. PMID- 25547651 TI - Low plasma ApoE levels are associated with smaller hippocampal size in the Alzheimer's disease neuroimaging initiative cohort. AB - Apolipoprotein E (APOE) genotype is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD), but the utility of plasma ApoE levels for assessing the severity of underlying neurodegenerative changes remains uncertain. Here, we examined cross-sectional associations between plasma ApoE levels and volumetric magnetic resonance imaging indices of the hippocampus from 541 participants [57 with normal cognition (NC), 375 with mild cognitive impairment (MCI), and 109 with mild AD] who were enrolled in the Alzheimer's Disease Neuroimaging Initiative. Across the NC and MCI groups, lower plasma ApoE levels were significantly correlated with smaller hippocampal size, as measured by either hippocampal volume or hippocampal radial distance. These associations were driven primarily by findings from carriers of an APOE epsilon4 allele and are consistent with prior reports that lower plasma ApoE levels correlate with greater global cortical Pittsburgh Compound B retention. In this high-risk group, plasma ApoE levels may represent a peripheral marker of underlying AD neuropathology in nondemented elderly individuals. PMID- 25547650 TI - White matter tract-oriented deformation predicts traumatic axonal brain injury and reveals rotational direction-specific vulnerabilities. AB - A systematic correlation between finite element models (FEMs) and histopathology is needed to define deformation thresholds associated with traumatic brain injury (TBI). In this study, a FEM of a transected piglet brain was used to reverse engineer the range of optimal shear moduli for infant (5 days old, 553-658 Pa) and 4-week-old toddler piglet brain (692-811 Pa) from comparisons with measured in situ tissue strains. The more mature brain modulus was found to have significant strain and strain rate dependencies not observed with the infant brain. Age-appropriate FEMs were then used to simulate experimental TBI in infant (n=36) and preadolescent (n=17) piglets undergoing a range of rotational head loads. The experimental animals were evaluated for the presence of clinically significant traumatic axonal injury (TAI), which was then correlated with FEM calculated measures of overall and white matter tract-oriented tissue deformations, and used to identify the metric with the highest sensitivity and specificity for detecting TAI. The best predictors of TAI were the tract-oriented strain (6-7%), strain rate (38-40 s(-1), and strain times strain rate (1.3-1.8 s( 1) values exceeded by 90% of the brain. These tract-oriented strain and strain rate thresholds for TAI were comparable to those found in isolated axonal stretch studies. Furthermore, we proposed that the higher degree of agreement between tissue distortion aligned with white matter tracts and TAI may be the underlying mechanism responsible for more severe TAI after horizontal and sagittal head rotations in our porcine model of nonimpact TAI than coronal plane rotations. PMID- 25547654 TI - Thrombotic microangiopathy complicating bortezomib-based therapy for multiple myeloma. PMID- 25547655 TI - A case of acute erythroleukemia with concurrence of BCR-ABL and FLT3-TKD (D835E) mutation. PMID- 25547656 TI - Results of therapy in children with acute lymphoblastic leukemia in over 50 years of experience in a single center in Poland. PMID- 25547658 TI - Massachusetts requires doctors to inform patients about end of life options. PMID- 25547657 TI - ubiA (Rv3806c) encoding DPPR synthase involved in cell wall synthesis is associated with ethambutol resistance in Mycobacterium tuberculosis. AB - OBJECTIVES: Ethambutol (EMB) is a frontline antituberculosis drug for the treatment of tuberculosis (TB). The embB gene is responsible for EMB resistance in only about 50-60% clinical isolates of Mycobacterium tuberculosis, and the mechanism of resistance in the remaining EMB-resistant strains is not clear. We assessed the role of the ubiA gene encoding 5-phospho-alpha-d-ribose-1 diphosphate: decaprenyl-phosphate 5-phosphoribosyltransferase (DPPR synthase, UbiA) involved in decaprenylphosphoryl-d-arabinose (DPA) pathway for cell wall synthesis in EMB resistance. METHODS: Antimicrobial susceptibility testing was performed using broth colorimetric method or an agar proportion method to compare the MICs of recombinant M. tuberculosis strains that overexpressed the wild type or mutant ubiA gene. PCR and DNA sequencing were used to detect ubiA mutations in EMB-resistant M. tuberculosis clinical isolates with or without embB mutations. ubiA mRNA expression levels were measured by qRT-PCR. Enzymatic activity of UbiA in different M. tuberculosis strains was analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). RESULTS: Overexpression of the wild type M. tuberculosis ubiA led to increased resistance to EMB in M. tuberculosis. In addition, novel ubiA mutations were found in some EMB-resistant XDR-TB isolates without common embB mutations. Topological modeling analysis showed that the mutation sites in ubiA were mainly localized in the sixth transmembrane domain of the UbiA protein. Moreover, mutated ubiA when overexpressed led to higher level of EMB resistance and increased DPA levels, compared to wild type ubiA in M. tuberculosis. CONCLUSIONS: Our results indicate that ubiA is involved in EMB resistance in M. tuberculosis and that ubiA mutations that caused elevated DPA levels may be responsible for EMB resistance. The essentiality of UbiA, its involvement in EMB resistance, and lack of human homologs make UbiA an attractive target for new drug development. PMID- 25547659 TI - Future orientation and health quality of life in primary care: vitality as a mediator. AB - PURPOSE: Temporal perspective, including views about future goals, may influence motivational processes related to health. An adaptive sense of future orientation is linked to better health, but little research has examined potential underlying factors, such as vitality. METHOD: In a sample of 101 primary care patients, we examined whether belief in the changeability of the future was related to mental and physical energization and, in turn, to health-related quality of life. Participants were working, uninsured primary care patients, who completed self report measures of future orientation, vitality, and health-related quality of life. RESULTS: Mediation models, covarying age, sex, and race/ethnicity indicated that vitality significantly mediated the association between future orientation and the outcomes of general health, mental health, social functioning, bodily pain, and role limitations due to emotional and physical reasons. Vitality exerted an indirect-only effect on the relation between future orientation and physical functioning. CONCLUSIONS: Our findings suggest that adaptive beliefs about the future may promote, or allow access to, physical and mental energy and, in turn, may result in better mental and physical health functioning. Individual level and public health interventions designed to promote future orientation and vitality may beneficially influence quality of life and well-being. PMID- 25547660 TI - How recent health-related life events affected my perspective on quality-of-life research. PMID- 25547661 TI - New type of redox nanoprobe: C60-based nanomaterial and its application in electrochemical immunoassay for doping detection. AB - Carbon nanomaterials were usually exploited as nanocarriers in an electrochemical immunosensor but rarely acted as redox nanoprobes. Herein, our motivation is to adequately utilize the inner redox activity of fullerene (C60) to obtain a new type of redox nanoprobe based on a hydrophilic C60 nanomaterial. First, C60 nanoparticles (C60NPs) were prepared by phase-transfer method and functionalized with amino-terminated polyamidoamine (PAMAM) to obtain the PAMAM decorated C60NPs (PAMAM-C60NPs) which have better hydrophilicity compared to that of unmodified C60NPs and possesses abundant amine groups for further modification. Following that, gold nanoparticles (nano-Au) were absorbed on the PAMAM-C60NPs surface, and the resultant Au-PAMAM-C60NPs were employed as a new type of redox nanoprobe and nanocarrier to label detection antibodies (Ab2). Doping control has become the biggest problem facing international sport. Erythropoietin (EPO) as a blood doping agent has been a hotspot in doping control. After sandwich-type immunoreaction between EPO (as a model) and Ab2-labeled Au-PAMAM-C60NPs, the resultant immunosensor was further incubated with a drop of tetraoctylammonium bromide (TOAB) which acts as booster to arouse the inner redox activity of Au PAMAM-C60NPs, thus a pair of reversible redox peaks is observed. As a result, the proposed immunosensor shows a wide linear range and a relatively low detection limit for EPO. This strategy paves a new avenue for exploring the redox nanoprobe based on carbon nanomaterials in the electrochemical biosensor field. PMID- 25547662 TI - Echocardiographic assessment of right ventricular systolic function in conscious healthy dogs: repeatability and reference intervals. AB - OBJECTIVES: To determine the feasibility, repeatability, intra- and interobserver variability, and reference intervals for 5 echocardiographic indices of right ventricular (RV) systolic function: tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), pulsed wave tissue Doppler imaging-derived systolic myocardial velocity of the lateral tricuspid annulus (S'), and speckle tracking echocardiography-derived global longitudinal RV free wall strain and strain rate. To explore statistical relationships between RV systolic function and age, gender, heart rate, and bodyweight. ANIMALS: 80 healthy adult dogs. METHODS: Dogs underwent 2 echocardiographic examinations. Repeatability and intra observer and inter-observer measurement variability were quantified by average coefficient of variation (CV). Relationships between RV function and age, heart rate and bodyweight were estimated by regression analysis. RESULTS: All indices were acquired with clinically acceptable repeatability and intra- and inter observer variability (CVs < 10%). No differences were identified between male and female dogs. Allometric scaling by bodyweight demonstrated significant, clinically relevant correlations between RV function and bodyweight (all p <= 0.001) as follows: TAPSE - strong positive correlation (r(2) = 0.75); S' - moderate positive correlation (r(2) = 0.31); strain rate - moderate negative correlation (r(2) = 0.44); FAC and strain - weak negative correlations (r(2) = 0.22 and 0.14, respectively). Strain rate and FAC were positively correlated with heart rate (r(2) = 0.35 and 0.31, respectively). Allometric scaling generated bodyweight-based reference intervals for these RV systolic function indices. CONCLUSIONS: Echocardiographic indices of RV systolic function are feasible to obtain, repeatable, and affected by bodyweight. Studies of these indices in dogs with cardiovascular disease are needed. PMID- 25547663 TI - The effects of storage conditions on measurements of canine N-terminal pro-B-type natriuretic peptide. AB - OBJECTIVES: The study aims were to assess the temporal stability following storage at room temperature, the effect of up to 4 freeze-thaw cycles and the effect of simulated freezer failure on measurements of canine N-terminal pro-B type natriuretic peptide (NT-proBNP) in serum and protease-inhibited (PI) plasma. ANIMALS: Twenty-five blood samples were collected from 16 dogs with myxomatous mitral valve disease. METHODS: Aliquots of canine serum and PI plasma were stored at room temperature (17-26 degrees C) for 30 min, 6, 24, 48 and 72 h, respectively. Further aliquots were subjected to between 1 and 4 freeze-thaw cycles. A further aliquot was transferred to storage at 4 degrees C for 24 h while a paired aliquot remained at -80 degrees C. All samples were returned to storage at -80 degrees C until subsequent analysis. N-terminal pro-B-type natriuretic peptide was measured in serum and PI plasma samples using first- and second-generation versions of a commercially-available ELISA. Repeated measures models were used to assess change in NT-proBNP measurements. Wilcoxon signed ranks were used to compare paired measurements. RESULTS: N-terminal pro-B-type natriuretic peptide concentrations declined over time in all samples stored at room temperature. Of the four situations tested, the rate of decrease was lowest for PI plasma samples measured using the second-generation assay. N-terminal pro B-type natriuretic peptide is stable in samples subjected to up to 4 freeze-thaw cycles and in previously-frozen samples stored at 4 degrees C for 24 h. CONCLUSIONS: Use of the second-generation assay, compared with the first generation, resulted in significantly higher recovery of NT-proBNP measured in PI plasma stored at room temperature. Transport of serum at room temperature for NT proBNP measurement is not recommended. PMID- 25547664 TI - High turnover frequency of hydrogen evolution reaction on amorphous MoS2 thin film directly grown by atomic layer deposition. AB - Recently amorphous MoS2 thin film has attracted great attention as an emerging material for electrochemical hydrogen evolution reaction (HER) catalyst. Here we prepare the amorphous MoS2 catalyst on Au by atomic layer deposition (ALD) using molybdenum hexacarbonyl (Mo(CO)6) and dimethyl disulfide (CH3S2CH3) as Mo and S precursors, respectively. Each active site of the amorphous MoS2 film effectively catalyzes the HER with an excellent turnover frequency of 3 H2/s at 0.215 V versus the reversible hydrogen electrode (RHE). The Tafel slope (47 mV/dec) on the amorphous film suggests the Volmer-Heyrovsky mechanism as a major pathway for the HER in which a primary discharging step (Volmer reaction) for hydrogen adsorption is followed by the rate-determining electrochemical desorption of hydrogen gas (Heyrovsky reaction). In addition, the amorphous MoS2 thin film is electrically evaluated to be rather conductive (0.22 Omega(-1) cm(-1) at room temperature) with a low activation energy of 0.027 eV. It is one of origins for the high catalytic activity of the amorphous MoS2 catalyst. PMID- 25547665 TI - Seminal quality in the first fraction of ejaculate. AB - Semen samples from 40 patients were collected in consecutive fractions. The variability in semen quality of each fraction was then determined. The first ejaculated fraction (FEF) primarily contained prostatic secretions, while the second ejaculate fraction (SEF) held the majority of the spermatozoa suspended in the secretions from the seminal vesicle. Differences in sperm quality were observed when the FEF was compared to the SEF and the total ejaculate fraction (TEF). These included the seminal parameters (volume, sperm concentration, motility) and sperm DNA fragmentation (SDF). When compared to TEF and SEF, the FEF presented a lower volume, higher sperm concentration, higher motility rates, and lower SDF. The data suggest that the first fraction renders an improved subpopulation of spermatozoa, with lower SDF. Spermatozoa from this fraction and hence their use for ART may have a positive effect on fertilization and embryo development. PMID- 25547666 TI - Performances of the heart fatty acid protein assay for the rapid diagnosis of acute myocardial infarction in ED patients. AB - OBJECTIVE: We sought to evaluate the added value of heart fatty acid protein assay (HFABP) for rapid diagnosis of acute myocardial infarction in a prospective cohort of emergency department (ED) patients with acute chest pain. METHODS: High sensitivity cardiac troponin T (hs-cTnT; Roche Diagnostics, Meylan, France) and HFABP (Randox, Mauguio, France) were blindly assayed from venous blood samples obtained at admission. Diagnosis was made by 2 ED physicians using all available data and serial cardiac troponin I as the biochemical standard. Diagnostic performances of HFABP combined with hs-cTnT were assessed using logistic regression. Analysis was conducted in all patients and in patients without ST elevation myocardial infarction. RESULTS: A total of 181 patients were included (age, 61 +/-17 years; male sex, 66%). Acute myocardial infarction occurred in 47 (25.9%) patients, including non-ST-elevation myocardial infarction in 31 (17.1%). The receiver operating characteristic area under the curve was 0.893 for hs-cTnT levels at presentation (95% confidence interval, 0.812-0.974) and 0.908 (95% confidence interval, 0.839-0.977) for the combination of hs-cTnT and HFABP, with no significant (P=.07). Adding HFABP to hs-cTnT increased both sensitivity and negative predictive value (NPV) for non-ST-elevation myocardial infarction diagnosis, with about 13% and 3% increase, respectively, leading to a sensitivity of 97% and an NPV of 99%. CONCLUSION: The assessment of HFABP at ED admission adds incremental value to initial hs-cTnT. The increase of sensitivity and NPV without sacrificing the specificity and positive predictive value in patients with chest pain with noncontributive electrocardiogram could potentially allow safe and early rule out of acute myocardial infarction without the need for further serial troponin testing. PMID- 25547667 TI - [Compliance with the PECARN and AEP guidelines in diagnostic approach of mild head trauma in patients younger than 24 months old]. AB - INTRODUCTION: Mild head trauma is a frequent complaint in Pediatric Emergency Departments. Several guidelines have been published in the last few years. However, significant variability can be appreciated in terms of the demand for image tests. The aim of this study is to determine the level of compliance with PECARN and AEP guidelines in the management of patients younger than 24 months old in four different hospitals. PATIENTS AND METHODS: A multicenter retrospective study was conducted on patients presenting with mild head trauma between October 1st, 2011 and March 31st, 2013 in the Emergency Departments of four hospitals. RESULTS: In the analysis of the results obtained, only one of the four hospitals complied with the AEP guidelines in more than 50% of the patients. The other three hospitals had a level of compliance lower than 50%. Management was more suitable according to PECARN guidelines, with 3 of the 4 hospitals having a level of compliance greater than 50%. However, the best compliance achieved by a hospital was only of 70%. CONCLUSIONS: The study shows that the level of compliance with guidelines for management of mild head trauma in patients younger than 24 months old is low. PMID- 25547668 TI - [Intestinal failure and transplantation in microvillous inclusion disease]. AB - INTRODUCTION: Microvillous inclusion disease is a rare autosomal recessive condition, characterized by severe secretory diarrhea that produces a permanent intestinal failure and dependency on parenteral nutrition. It usually begins in the neonatal period, and the only treatment at present is intestinal transplantation. PATIENTS AND METHODS: A retrospective review was conducted on 6 patients (three males and three females) diagnosed with microvillous inclusion disease between 1998 and 2013. RESULTS: All debuted in the first month of life, with a median age of three days (range, 3-30 days), and had secretory diarrhea dependent on parenteral nutrition, with fasting fecal volume of 150-200ml/kg/day. Light microscopy of duodenal biopsy samples showed varying degrees of villous atrophy without cryptic hyperplasia, accumulation of PAS positive material in the cytoplasm of enterocytes brush border, and anti-CD10 immunostaining was suggestive of intracytoplasmic inclusions. Diagnostic confirmation was performed with electron microscopy. Two of them had a genetic study, and showed mutations in MYO5B gene. Three died and three are alive; two of them with an intestinal transplantation and the third waiting for a multivisceral transplantation. PMID- 25547669 TI - Acquired haemophilia A associated with autoimmune thyroiditis: a case report. AB - INTRODUCTION: Acquired haemophilia A is a rare life- and limb-threatening bleeding disorder if left untreated. Autoimmune thyroiditis is an autoimmune disorder that can be rarely associated with acquired haemophilia. Here we report a case of a 60-year-old woman presenting with cutaneous and muscle haematomas secondary to acquired haemophilia A in association with autoimmune thyroiditis, who was successfully treated with recombinant activated factor VII and immunosuppression. CASE PRESENTATION: A 60-year-old Sri Lankan woman with a background of longstanding hypothyroidism, diabetes mellitus, hypertension, hyperlipidaemia and bronchial asthma developed spontaneous cutaneous purpura and a limb-threatening intramuscular haematoma. Initial coagulation screening revealed prolonged activated partial thromboplastin time of 66.4 seconds (normal range 26 to -36 seconds) and time-dependent inhibitors against factor VIII. She had positive antinuclear antibody and antithyroid peroxidase (microsomal) antibody titre of over 1/80 and 1000IU/mL respectively. The diagnosis was therefore made of acquired haemophilia A in association with autoimmune thyroiditis. Acute limb-threatening bleeding was managed with recombinant activated factor VII (NovoSeven(r)). Immunosuppressive treatment consisting of oral prednisone 60mg/day and cyclophosphamide 100mg/day was administered in order to remove the factor VIII inhibitor. This treatment led to normalisation of her haemostatic parameters. This case illustrates a very rare association of acquired haemophilia and autoimmune thyroiditis as well as the importance of considering acquired haemophilia as a differential diagnosis of spontaneous bleeding. CONCLUSIONS: Acquired haemophilia should be considered in the differential diagnosis of unexplained bleeding in adults. Treatment of the acute coagulopathy with recombinant activated factor VII and immunosuppressive therapy was successful in this case. PMID- 25547670 TI - Characterization of prostate cancer using T2 mapping at 3T: a multi-scanner study. AB - RATIONALE AND OBJECTIVES: To assess the prostate T2 value as a predictor of malignancy on two different 3T scanners. PATIENTS AND METHODS: Eighty-three pre prostatectomy multiparametric MRIs were retrospectively evaluated [67 obtained on a General Electric MRI (scanner 1) and 16 on a Philips MRI (scanner 2)]. After correlation with prostatectomy specimens, readers measured the T2 value of regions-of-interest categorized as "cancers", "false positive lesions", or "normal tissue". RESULTS: On scanner 1, in PZ, cancers had significantly lower T2 values than false positive lesions (P=0.02) and normal tissue (P=2*10(-9)). Gleason>=6 cancers had similar T2 values than false positive lesions and significantly higher T2 values than Gleason>=7 cancers (P=0.009). T2 values corresponding to a 25% and 75% risk of Gleason>=7 malignancy were respectively 132 ms (95% CI: 129-135 ms) and 77 ms (95% CI: 74-81 ms). In TZ, cancers had significantly lower T2 values than normal tissue (P=0.008), but not than false positive findings. Mean T2 values measured on scanner 2 were not significantly different than those measured on scanner 1 for all tissue classes. CONCLUSION: All tested tissue classes had similar mean T2 values on both scanners. In PZ, the T2 value was a significant predictor of Gleason>=7 cancers. PMID- 25547671 TI - Ultrasonographic renal volume measurements in early autosomal dominant polycystic disease: comparison with CT-scan renal volume calculations. AB - PURPOSE: To investigate the correlation and concordance between the ellipsoid volume calculated by ultrasonography measurements (Vol3DUS) and the reference kidney volume measured by CT (VolTDM) in early autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: Prospective study of the correlation and concordance of renal volumes in 24 patients with early ADPKD (48 kidneys analysed separately), with calculation of Vol3DUS using the formula for an ellipsoid in three different manners and VolTDM measurement by manual contouring. Calculations of correlation coefficients (r) and coefficients of intra-class correlation (ICC) with confidence intervals at 95%. RESULTS: The US volume was strongly correlated with the CT volume by using the maximum width in a transverse section (r=0.83) with a mean Vol3DUS=692+/-348ml [180; 2069]. The most reproducible ultrasonography measurement was the height. When the kidney volume exceeded 800ml, US underestimated the volume. However, the median error was 57.5ml [-1090; 183] and 85% of the Vol3DUS calculated differed by more than 5% from the reference measurement. CONCLUSION: The correlation between the US calculated volumes and the CT volumes was strong. However, the median error with ellipsoid US volume was too high to detect a small renal variation in early ADPKD. PMID- 25547672 TI - The development of an ELISA for group IVA phospholipase A2 in human red blood cells. AB - An immunoassay for IVA phospholipase A2 in human red blood cells is described. The assay is a non-competitive sandwich assay in which increasing amounts of the measured protein produce increased luminescence. The antibodies used in the assay are directed against two unique epitopes of the molecule, which sequentially trap and detect the protein. The standard curve covers the range 0.7ng to 23ng/mL (0.07 to 2.3ng/well). The intra-assay and inter-assay coefficients of variation were 9% and 12%, respectively. Evidence is presented that the assay is specific for the alpha paralog of IV PLA2. The assay allows simple and rapid quantification of IVAPLA2 in red blood cell lysates and other biological fluids. PMID- 25547673 TI - Cdc42 is a key regulator of B cell differentiation and is required for antiviral humoral immunity. AB - The small Rho GTPase Cdc42, known to interact with Wiskott-Aldrich syndrome (WAS) protein, is an important regulator of actin remodeling. Here, we show that genetic ablation of Cdc42 exclusively in the B cell lineage is sufficient to render mice unable to mount antibody responses. Indeed Cdc42-deficient mice are incapable of forming germinal centers or generating plasma B cells upon either viral infection or immunization. Such severe immune deficiency is caused by multiple and profound B cell abnormalities, including early blocks during B cell development; impaired antigen-driven BCR signaling and actin remodeling; defective antigen presentation and in vivo interaction with T cells; and a severe B cell-intrinsic block in plasma cell differentiation. Thus, our study presents a new perspective on Cdc42 as key regulator of B cell physiology. PMID- 25547676 TI - Cardiovascular mortality in patients with metastatic prostate cancer exposed to androgen deprivation therapy: a population-based study. AB - INTRODUCTION: The aim of our study was to reexamine the prevalence of baseline cardiovascular (CV) morbidity and the rates of CV mortality in a contemporary cohort of patients with prostate cancer (PCa) exposed to androgen deprivation therapy (ADT). MATERIALS AND METHODS: Records of patients aged 65 years and older with metastatic PCa who received ADT were abstracted from the Surveillance, Epidemiology, and End Results-Medicare database between 1991 and 2009. The primary end points comprised 5-year CV mortality rates. Survival rates were stratified according to age and Charlson comorbidity index (CCI). Competing-risks Poisson regression methodologies were performed. RESULTS: Overall, 9596 patients with metastatic PCa treated with ADT were identified. At baseline, 3049 patients (31.8%) had preexisting CV disease. The 5-year CV mortality rates were 9.8% and 14.8% in the overall population and in patients with preexisting CV disease, respectively. The 5-year CV mortality rates increased with advanced age and higher CCI score. In multivariate competing-risks regression analyses, age, year of diagnosis, CV comorbidities, CCI, and marital status represented independent predictors of CV mortality, after accounting for the risk of dying from other causes (all P <= .04). Of those, preexisting CV disease contributed to the highest risk of CV mortality. Our study is limited by its retrospective nature. CONCLUSION: CV mortality represents a common event in patients with metastatic PCa treated with ADT. Preexisting CV disease represented the strongest risk factor. PMID- 25547674 TI - Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation. AB - Hematopoietic stem cells (HSCs) are generated via a natural transdifferentiation process known as endothelial to hematopoietic cell transition (EHT). Because of small numbers of embryonal arterial cells undergoing EHT and the paucity of markers to enrich for hemogenic endothelial cells (ECs [HECs]), the genetic program driving HSC emergence is largely unknown. Here, we use a highly sensitive RNAseq method to examine the whole transcriptome of small numbers of enriched aortic HSCs, HECs, and ECs. Gpr56, a G-coupled protein receptor, is one of the most highly up-regulated of the 530 differentially expressed genes. Also, highly up-regulated are hematopoietic transcription factors, including the "heptad" complex of factors. We show that Gpr56 (mouse and human) is a target of the heptad complex and is required for hematopoietic cluster formation during EHT. Our results identify the processes and regulators involved in EHT and reveal the surprising requirement for Gpr56 in generating the first HSCs. PMID- 25547677 TI - Direct serum assay for cell-free bmi-1 mRNA and its potential diagnostic and prognostic value for colorectal cancer. AB - PURPOSE: Cell-free Bmi-1 mRNA is stably detectable in the serum/plasma and is associated with the development and progression of some tumors. Previous methods detecting extracellular Bmi-1 mRNA with RNA extraction are inefficient. This study developed a novel reverse transcription quantitative PCR (RT-qPCR) approach directly applied in serum (RT-qPCR-D) to quantify Bmi-1 mRNA, and assessed its diagnostic and prognostic potential in colorectal cancer. EXPERIMENTAL DESIGN: The feasibility of the RT-qPCR-D method was first analyzed in 50 serum samples. Then, using the RT-qPCR-D method, Bmi-1 mRNA expression was validated in serum from an independent cohort of patients with 87 normal colonoscopy, 76 hyperplastic polyp, 82 inflammatory bowel disease, 68 adenoma, and 158 colorectal cancer. Receiver operating characteristic (ROC) curves and Cox analyses were used to evaluate its diagnosis and prognosis value, respectively. RESULTS: In a pilot study, levels of Bmi-1 mRNA were increased in colorectal cancer serum samples detected by RT-qPCR-D and significantly associated with results obtained by RT qPCR. In a validation cohort, serum Bmi-1 mRNA levels were significantly elevated in the colorectal cancer group and the adenoma group when compared with other groups. The area under ROC curve distinguishing colorectal cancer from benign colorectal diseases was 0.888, with 72.2% sensitivity and 94.9% specificity, which was superior to carcinoembryogenic antigen. Bmi-1 mRNA levels were significantly associated with survival. Cox analysis indicated Bmi-1 mRNA was an independent prognostic factor for overall survival. CONCLUSIONS: Detection of cell-free Bmi-1 mRNA in serum by RT-qPCR-D is a simple and noninvasive approach and may be used for colorectal cancer diagnosis and prognosis. PMID- 25547678 TI - A serum microRNA signature predicts tumor relapse and survival in triple-negative breast cancer patients. AB - PURPOSE: Triple-negative breast cancers (TNBC) are associated with high risk of early tumor recurrence and poor outcome. Common prognostic biomarkers give very restricted predictive information of tumor recurrences in TNBC. Human serum contains stably expressed microRNAs (miRNAs), which have been discovered to predict prognosis in patients with cancer. The purpose of this study was to identify circulating biomarkers able to predict clinical outcome in TNBC. EXPERIMENTAL DESIGN: We performed genome-wide serum miRNA expression and real time PCR analyses to investigate the ability of miRNAs in predicting tumor relapse in serum samples from 60 primary TNBC. Patients were divided into training and testing cohorts. RESULTS: By Cox regression analysis, we identified a four-miRNA signature (miR-18b, miR-103, miR-107, and miR-652) that predicted tumor relapse and overall survival. This miRNA signature was further validated in an independent cohort of 70 TNBC. A high-risk signature score was developed and significantly associated with tumor recurrence and reduced survival. Multivariate Cox regression models indicated that the risk score based on the four-miRNA signature was an independent prognostic classifier of patients with TNBC. CONCLUSIONS: This signature may serve as a minimally invasive predictor of tumor relapse and overall survival for patients with TNBC. This prediction model may ultimately lead to better treatment options for patients with TNBC. PMID- 25547680 TI - Ocular herpes: the pathophysiology, management and treatment of herpetic eye diseases. AB - Herpesviruses are a prominent cause of human viral disease, second only to the cold and influenza viruses. Most herpesvirus infections are mild or asymptomatic. However, when the virus invades the eye, a number of pathologies can develop and its associated sequelae have become a considerable source of ocular morbidity. The most common culprits of herpetic eye disease are the herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). While primary infection can produce ocular disease, the most destructive manifestations tend to arise from recurrent infection. These recurrent infections can wreck devastating effects and lead to irreversible vision loss accompanied by a decreased quality of life, increased healthcare usage, and significant cost burden. Unfortunately, no method currently exists to eradicate herpesviruses from the body after infection. Treatment and management of herpes-related eye conditions continue to revolve around antiviral drugs, although corticosteroids, interferons, and other newer therapies may also be appropriate depending on the disease presentation. Ultimately, the advent of effective vaccines will be crucial to preventing herpesvirus diseases altogether and cutting the incidence of ocular complications. PMID- 25547681 TI - Recent progress in dengue vaccine development. AB - Dengue virus (DENV) has four distinct serotypes. DENV infection can result in classic dengue fever and life-threatening dengue hemorrhagic fever/dengue shock syndrome. In recent decades, DENV infection has become an important public health concern in epidemic-prone areas. Vaccination is the most effective measure to prevent and control viral infections. However, several challenges impede the development of effective DENV vaccines, such as the lack of suitable animal models and the antibody-dependent enhancement phenomenon. Although no licensed DENV vaccine is available, significant progress has been made. This review summarizes candidate DENV vaccines from recent investigations. PMID- 25547682 TI - Nucleoprotein-based indirect enzyme-linked immunosorbent assay (indirect ELISA) for detecting antibodies specific to Ebola virus and Marbug virus. AB - Full-length nucleoproteins from Ebola and Marburg viruses were expressed as His tagged recombinant proteins in Escherichia coli and nucleoprotein-based enzyme linked immunosorbent assays (ELISAs) were established for the detection of antibodies specific to Ebola and Marburg viruses. The ELISAs were evaluated by testing antisera collected from rabbit immunized with Ebola and Marburg virus nucleoproteins. Although little cross-reactivity of antibodies was observed in anti-Ebola virus nucleoprotein rabbit antisera, the highest reactions to immunoglobulin G (IgG) were uniformly detected against the nucleoprotein antigens of homologous viruses. We further evaluated the ELISA's ability to detect antibodies to Ebola and Marburg viruses using human sera samples collected from individuals passing through the Guangdong port of entry. With a threshold set at the mean plus three standard deviations of average optical densities of sera tested, the ELISA systems using these two recombinant nucleoproteins have good sensitivity and specificity. These results demonstrate the usefulness of ELISA for diagnostics as well as ecological and serosurvey studies of Ebola and Marburg virus infection. PMID- 25547679 TI - Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations. AB - PURPOSE: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL(+) leukemias or acute myelogenous leukemia (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myelogenous leukemia (CML) cells upon BCR-ABL inhibition. Here, we examined the role of mitochondrial metabolism in the survival of Ph(+) leukemia and AML upon TK inhibition. EXPERIMENTAL DESIGN: Ph(+) cancer cell lines, AML cell lines, leukemia xenografts, cord blood, and patient samples were examined. RESULTS: We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations of 100- to 1,000-fold below those required for inhibition of respiration. Oligomycin-A treatment rapidly led to mitochondrial membrane depolarization and reduced ATP levels, and promoted superoxide production and leukemia cell apoptosis when combined with TKI. Importantly, oligomycin-A enhanced elimination of BCR-ABL(+) leukemia cells by TKI in a mouse model and in primary blast crisis CML samples. Moreover, oligomycin-A also greatly potentiated the elimination of FLT3-dependent AML cells when combined with an FLT3 TKI, both in vitro and in vivo. CONCLUSIONS: TKI therapy in leukemia cells creates a novel metabolic state that is highly sensitive to particular mitochondrial perturbations. Targeting mitochondrial metabolism as an adjuvant therapy could therefore improve therapeutic responses to TKI for patients with BCR-ABL(+) and FLT3(ITD) leukemias. PMID- 25547684 TI - Generation of hepatitis B virus PreS2-S antigen in Hansenula polymorpha. AB - Despite the long availability of a traditional prophylactic vaccine containing the HBV surface antigen (HBsAg) and aluminum adjuvant, nearly 10% of the population remains unable to generate an effective immune response. Previous studies have indicated that hepatitis B virus (HBV) PreS2-S is abundant in T/B cell epitopes, which induces a stronger immune response than HBsAg, particularly in terms of cytotoxic T lymphocyte (CTL) reaction. In the current study, the HBV PreS2-S gene encoding an extra 26 amino acids (PreS2 C-terminus) located at the N terminus of HBsAg was cloned into the pVCH1300 expression vector. PreS2-S expressed in the methylotrophic yeast, Hansenula polymorpha, was produced at a yield of up to 250 mg/L. Subsequent purification steps involved hydrophobic adsorption to colloidal silica, ion-exchange chromatography and density ultracentrifugation. The final product was obtained with a total yield of ~ 15% and purity of ~ 99%. In keeping with previous studies, ~ 22 nm viruslike particles were detected using electron microscopy. The generated PreS2-S antigen will be further studied for efficacy and safty in animals. PMID- 25547685 TI - Distribution and relationship of uranium and radium along an allochthonously dominated wetland gradient. AB - Uranium mining may pose a large threat for freshwater ecosystems, caused by elevated concentrations of metals/radionuclides in drainage water. Important pollutants of such waters are uranium (U) and radium (Ra), because of their impact due to both radio- as well as chemo-toxicity. Despite the comprehensive knowledge about specific element speciation as well as fixation processes, less is known about the retention of U and Ra at a higher level of complexity (within allochthonous ecosystems as predominant for low order streams). Consequently, we investigated the distribution and retention potential of allochthonous ecosystems regarding U and Ra as well as changing U/Ra ratios. We found U predominantly transported over long distances, whereas Ra mainly precipitates immediately after reaching the surface, i.e. in the spring area. Although high U accumulation in organic rich sediments is found, still high transport rates are detected. Low overall fixation of U within the allochthonously dominated wetland results in an U transport over long distances. Consequently, large areas are affected by U mining activities and its post-mining impact, with U being more relevant compared to Ra. PMID- 25547683 TI - Coronavirus MHV-A59 infects the lung and causes severe pneumonia in C57BL/6 mice. AB - It remains challenging to develop animal models of lung infection and severe pneumonia by severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome cornavirus (MERS-CoV) without high level of containment. This inevitably hinders understanding of virushost interaction and development of appropriate countermeasures. Here we report that intranasal inoculation of sublethal doses of murine coronavirus mouse hepatitis virus A-59 (MHV-A59), a hepatic and neuronal tropic coronavirus, can induce acute pneumonia and severe lung injuries in C57BL/6 mice. Inflammatory leukocyte infiltrations, hemorrhages and fibrosis of alveolar walls can be observed 2-11 days after MHV A59 infection. This pathological manifestation is associated with dramatical elevation of tissue IP-10 and IFN-gamma and moderate increase of TNF-alpha and IL 1beta, but inability of anti-viral type I interferon response. These results suggest that intranasal infection of MHV-A59 would serve as a surrogate mouse model of acute respiratory distress syndrome by SARS-CoV and MERS-CoV infections. PMID- 25547686 TI - Dermatofibrosarcoma protuberans of the vulva: margins assessment and reconstructive options - a report of two cases. AB - BACKGROUND: Dermatofibrosarcoma Protuberans (DFSP) of the vulva is rare and oncologic surgery with free margins may lead to severe functional damage, requiring multidisciplinary approach regarding resection, margin assessment and reconstruction.Case Report: Two cases of DFSP in vulva were treated in a single institution. A 28-year-old patient with an incisional biopsy in the vulvar region revealing DFSP underwent a partial vulvectomy with clitoris preservation. Pathological studies revealed free margins and reconstructive surgery was performed. This patient is disease free in a 40 months follow up. The other, a 57 year-old patient was also referred after an incomplete resection of a DFSP in the vulvar region. A 1-cm margim resection followed by Complete Circumferential and Peripheral Deep Margin Assessment (CCPDMA) was performed. Although the upper lateral margin was positive, it was possible to perform another wide local excision with preservation of the clitoris and primary closure. CONCLUSION: DFSP of the vulva requires an accurate evaluation of margins, resections following oncological principles and reconstruction. Although being a very challenging lesion that usually implies difficult surgical management, if treated in a multidisciplinary environment, with surgical oncologists, experienced dermatopathologists and reconstructive surgeons can achieve good results. Even in difficult cases that presents with large lesions and compromising challenging areas, a complete oncologic resection can be performed minimizing functional damage for the patient. PMID- 25547687 TI - Does hepatitis B virus therapy reduce the risk of hepatocellular carcinoma? AB - INTRODUCTION: Liver cancer is one of the most common cancers. Hepatocellular carcinoma (HCC) represents > 90% of primary liver cancers and is a major global health problem today. Chronic hepatitis B virus (HBV) infection is associated with more than half of HCCs. AREAS COVERED: Long-term therapy with nucleos(t)ide analogues (NUCs) improves outcomes in HBV-infected patients by slowing the progression of liver disease. It is associated with improvements in histological and clinical outcomes, improved patient survival, reduced need for liver transplantation and improved liver function in patients with decompensated liver disease. This review highlights the results of previous studies conducted on HCC prevention with long-term NUC therapy. Studies include the use of all available drugs in different clinical scenarios, and the comparison between treated and untreated patients. EXPERT OPINION: NUCs have been studied extensively in HCC prevention. A comprehensive review of the literature has shown that they can be safely and effectively used for this purpose. Despite some discrepancies between studies, most of the evidence favors using NUC therapy for HCC prevention. PMID- 25547691 TI - Outcomes in Patients Hospitalized for Periapical Abscess in the United States. AB - BACKGROUND.: Severe infections resulting from periapical abscesses may warrant hospitalization. The authors conducted a study to investigate the factors affecting outcomes for patients hospitalized for periapical abscess in the United States in 2007. METHODS.: The authors used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project for 2007. They selected for analysis all hospitalizations attributed primarily to periapical abscess. Outcomes examined included hospitalization charges, length of stay and type of admission (emergency or urgent versus elective). They used multivariable regression analysis to examine the effects of patient-related factors (including age, sex, presence of comorbid conditions, insurance status, type of periapical abscess and discharge disposition) on outcomes. RESULTS.: In 2007, 7,886 hospitalizations were attributed primarily to periapical abscess. Total hospital charges were $105.8 million. Periapical abscess also resulted in a total of 23,001 hospitalization days. The mean hospitalization charges and length of stay were $13,590 and 2.92 days, respectively. The authors found an association between patients with comorbid conditions and higher charges and longer length of stay (P < .05). Of all hospitalizations, 91 percent occurred on an emergency or urgent basis. The percentage was significantly higher among uninsured patients than among those with private insurance (P < .05). CONCLUSION.: The study provides nationally representative estimates of outcomes associated with hospitalizations due to periapical abscess, and it highlights the substantial resources needed to treat patients hospitalized for this condition. PMID- 25547693 TI - [Focus on promoting a rapid development in the area of noninvasive positive pressure ventilation in China]. PMID- 25547694 TI - [Application of nonconventional noninvasive positive pressure ventilation]. PMID- 25547695 TI - [Indications of noninvasive positive pressure ventilation in the treatment of acute hypoxemic respiratory failure]. PMID- 25547696 TI - [Efficacy of auto-trilevel positive airway ventilation in hypercapnic patients with overlap syndrome]. AB - OBJECTIVE: To observe the efficacy of auto-trilevel positive airway pressure (Auto-trilevel PAP) ventilation in overlap syndrome (OS) patients with hypercapnia. METHODS: From October 2012 to May 2014, 21 OS patients with a PaCO2> 45 mmHg (1 mmHg = 0.133 kPa) and coexisting stable chronic obstructive pulmonary diseases (COPD) and moderate-to-severe OSAS were recruited. Three different positive airway pressure (PAP) modes of ventilators (SOMNOvent auto-S, Weinmann Inc, Germany) were employed for 8 hours per night with each mode at each night and two nights' interval without any treatment among different modes. Under mode one, the expiratory positive airway pressure (EPAP) issued by bilevel positive airway pressure (BiPAP) was titrated as the minimal positive pressure for a disappearance of snoring. The same inspiratory positive airway pressure (IPAP) titrated by end tidal CO2 levels under mode 1 was used under modes 2 and 3 as well. However, the EPAP issued by BiPAP under mode 2 was 3 cmH2O (1 cmH2O = 0.098 kPa) higher than that under mode 1. Under mode 3 with autotrilevel PAP, the beginning of EPAP was set the same as that under mode 1 while the end of EPAP (EEPAP) was automatically adjusted based on upper airway patency condition. Comparisons were made for parameters before and after treatment as well as among different ventilation modes. The following parameters were compared such as nocturnal apnea hypopnea index (AHI), minimal SpO2 (miniSpO2), arousal index, sleep efficiency, morning PaCO2 and Epworth sleepiness score (ESS). RESULTS: Compared with the parameters pre-therapy, modes 1-3 showed a significant decrease in nocturnal AHI (6.3 +/- 1.3), (3.1 +/- 1.0), (3.6 +/- 0.6) vs (38.6 +/- 11.3) events/h), arousal index ((7.0 +/- 1.1), (5.1 +/- 0.9), (4.2 +/- 1.7) vs (27.5 +/ 5.4) events/h), morning PaCO2 (42.4 +/- 3.8), (47.9 +/- 2.6) and (43.2 +/- 3.3) vs (57.3 +/- 4.3) mmHg and daytime ESS (7.2 +/- 1.3, 7.4 +/- 1.3 and 5.3 +/- 1.5 vs 11.4 +/- 2.7), but a significant increase in nocturnal miniSpO2 (82.3 +/- 5.4), (89.6 +/- 3.9) and (90.3 +/- 3.2) vs (62.4 +/- 11.3) mmHg and sleep efficiency caused (71.3 +/- 5.2)%, (79.4 +/- 4.3)% and (83.2 +/- 4.4)% vs (59.8 +/- 6.3)% (all P < 0.01). Comparison of 3 modes demonstrated that, with the same IPAP, mode 3 resulted in the lowest arousal index, daytime ESS and the highest sleep efficiency. Comparison of modes 1 and 2 revealed a statistically lower AHI but higher miniSpO2 and morning PaCO2 under mode 2 (all P < 0.01). Compared with mode 1, mode 3 showed a lower AHI, higher miniSpO2 (all P < 0.01), but there was no significant difference in PaCO2 at the end of therapy. Compared with mode 2, mode 3 showed a significant lower PaCO2 (P < 0.01), but there was no significant difference in AHI and miniSpO2. CONCLUSION: Auto-trilevel PAP ventilation is superior to fixed BiPAP ventilation in the treatment of hypercapnic OS since this novel PAP mode can achieve a higher efficacy in simultaneous removal of residual apnea hypopnea events and correction of hypercapnia and yield a higher sleep quality and lower daytime sleepiness. PMID- 25547697 TI - [Efficacies of continuous positive airway pressure on mixed sleep respiratory events in patients with sleep apnea]. AB - OBJECTIVE: To explore the efficacies of continuous positive airway pressure (CPAP) for mixed sleep apnea (MSA) events in patients with sleep apnea. METHODS: A total of 21 patients with sleep apnea whose MSA events >10 events/h on overnight polysomnography (PSG) were studied. They were selected from the Sleep Center, Guangzhou Institute of Respiratory Disease. Ten of them were diagnosed only by conventional polysomnography (PSG group) while the diagnosis of another 11 patients was further confirmed by diaphragm electromyogram (EMG) (EMG group). All of them were treated by CPAP titrated manually on PSG. RESULTS: Manual CPAP titrating pressure in PSG group was (8.1 +/- 2.2) cmH2O (1 cmH2O = 0.098 kPa) and it was similar to that in EMG group ((8.9 +/- 1.5) cmH2O). Apnea-hypopnea index (AHI) decreased significantly after CPAP in both PSG group (6.9 (3.5, 10.2) vs 62.2 (54.7, 71.4) events/h) and EMG group (1.5 (0.5, 5.5) vs 71.3 (59.5, 79.5) events/h) (both P < 0.01). CPAP could eliminate MSA diagnosed either by conventional PSG (0.1 (0.0, 0.4) vs 29.6 (19.6, 32.4) events/h) or by diaphragm EMG (0.0 (0.0, 0.2) vs 18.1 (9.1, 19.3) events/h) (both P < 0.01). CONCLUSION: CPAP can effectively treat MSA events in patients with sleep apnea. PMID- 25547698 TI - [Effect on inspiratory cycling-off synchronization with different expiratory trigger sensitivity level during pressure-support ventilation: a lung model study]. AB - OBJECTIVE: To compare the inspiratory cycling-off synchronization with different expiratory trigger sensitivity (ETS) setting during noninvasive pressure support ventilation (PSV) under the conditions of system leak. METHODS: Ventilators were connected to a lung model (Hans Rudolph Series1101 simulator). And its mechanics was set in two models of obstructive and restrictive ventilatory dysfunction. All ventilators were set at 15 cmH2O (1 cmH2O = 0.098 kPa) pressure support and 5 cmH2O positive end-expiratory pressure (PEEP). Tests were conducted at the level of air leaks (24-28 L/min). Cycling delay time, tidal volume and airflow were collected. RESULTS: Compared with Curative Flexo ST 30 with the ETS setting at the most sensitive level, the use of digital Auto-Trak(TM) system (Respironics Synchrony) was associated with milder delay cycling ((68.9 +/- 13.3) vs (121.4 +/ 13.2) ms, P < 0.05) in obstructive condition. The tidal volume (VT), inspiratory time (TI vent) and peak expiratory flow (PEF) increased after adjusting the ETS level. Premature cycling was detected in restrictive condition with both ventilators. Peak inspiratory flow (PIF) and PEF significantly increased as VT and TI vent decreased. Delay cycling ((64.3 +/- 15.3) ms) was present in Flexo ST 30 when ETS was at most insensitive level. CONCLUSIONS: There are significant differences in performances and cycling-off in obstructive and restrictive conditions among 2 bilevel ventilators. And it may be due to the software of algorithm. Modifications of ETS can affect the ventilatory parameters to improve patient-ventilator synchrony in the presence of air leaks. The Auto-Trak system during PSV show similar results and better synchronzation compared with conventional adjustments. PMID- 25547699 TI - [Clinical characteristics and risk factors of refractory Crohn's disease]. AB - OBJECTIVE: To analyze the clinical characteristics and risk factors of refractory Crohn's disease (CD). METHODS: All clinical data of confirmed consecutive CD patients were collected from our hospital between January 2003 and June 2013. The patients' demographic data, clinical features, therapeutic regimens and laboratory examinations were analyzed. A multivariate Logistic regression was performed to identify the risk factors of refractory CD. RESULTS: (1) A total of 402 confirmed CD patients were recruited for analysis. The prevalence of refractory CD was 33.8% (136/402). The rates of steroid-dependency was 37.0% (97/262) in 262 patients with a history of steroid use and the rate of thiopurines ineffectiveness was 26.9% (79/294) in 294 patients with a history of thiopurines-use; (2) Univariate analysis showed that disease location (L3 type), abdominal pain, diarrhea, fever, abdominal tenderness, perianal lesion, steroid use, AZA/6-MP use, leucocyte, hemoglobin (Hb), platelet level and high sensitivity C-reactive protein (HsCRP) were significantly different between refractory and non-refractory CD patients (all P < 0.05) . Multivariate Logistic regression showed that steroid use (OR = 6.516, 95% CI: 2.884-14.722, P = 0.000) and low Hb (OR = 1.023, 95% CI: 1.008-1.037, P = 0.002) were independent risk factors related to refractory CD; (3) Univariate analysis showed that Hb level, erythrocyte sedimentation rate (ESR) were significantly different between steroid dependent and non-steroid-dependent groups (all P < 0.05) . Multivariate Logistic regression showed that only low Hb level (OR = 1.021, 95% CI: 1.006-1.036, P = 0.005) was an independent risk factor related to steroid-dependency; (4) Univariate analysis showed that disease location (L3 type), perianal lesion, abdominal pain, diarrhea, fever, abdominal tenderness, platelet level, steroid use, steroid-dependency were significantly different between thiopurines ineffective and thiopurines-effective groups (all P < 0.05) . Multivariate Logistic regression showed that perianal lesion (OR = 2.085, 95% CI: 1.007-4.039, P = 0.029), abdominal tenderness (OR = 2.943, 95% CI: 1.452-5.964, P = 0.003) and steroid-dependency (OR = 3.599, 95% CI: 1.847-7.013, P = 0.000) were independent risk factors related to thiopurines-ineffectiveness. CONCLUSIONS: Nearly one third CD patients became refractory during the course of disease. Low Hb and steroid use are independent risk factors. Low Hb is an independent risk factor related to steroid-dependency. Perianal disease, abdominal tenderness and steroid dependency are independent risk factors related to thiopurines- ineffectiveness. PMID- 25547700 TI - [Genetic polymorphisms of PDGFR associated with thrombocytopenia in Chinese patients with clear-cell metastatic renal cell carcinoma treated with sunitinib]. AB - OBJECTIVE: To explore the genetic polymorphisms of PDGFR associated with thrombocytopenia in Chinese patients with metastatic clear-cell renal cell carcinoma (mcc-RCC) treated with sunitinib. METHODS: A total of 93 mcc-RCC patients treated with sunitinib were enrolled. Genotype analyses were performed before treatment and thrombocytopenia was recorded on the first three cycles of treatment. Genetic polymorphisms of PDGFR (rs35597368, rs1800810) were analyzed for a possible association with thrombocytopenia. RESULTS: The genotypes of rs35597368 and rs1800810 conformed to the Hardy-Weinberg law. No significant difference existed in grade 3/4 thrombocytopenia between rs35597368 TC and TT genotypes (29.6% vs 29.4%, P = 0.313). The rs1800810 CG genotype was associated with a higher risk for grade 3/4 thrombocytopenia as compared with CC genotype (45.8% vs 34.2%, P = 0.048). CONCLUSIONS: The risk for grade 3/4 thrombocytopenia increases in the presence of allele genotype in PDGFR 1171C/G. And a biomarker may be customized for patients with mcc-RCC treated with sunitinib. PMID- 25547701 TI - [Effects of insulin on pigment epithelium-derived factor expression in adipocytes of type 2 diabetic mellitus in rats]. AB - OBJECTIVE: To explore the effects of insulin therapy on the expression of pigment epithelium-derived factor (PEDF) in adipocytes of type 2 diabetic mellitus (T2DM) in rats. METHODS: A total of 22 newly diagnosed type 2 diabetics received a 2 week intensive insulin therapy. The levels of fasting plasma glucose (FPG), serum triglyceride and PEDF were measured before and after therapy. T2DM was induced by a high-fat diet and a low-dose streptozotocin (STZ). The Spraque-Dawley rats were divided randomly into diabetic, insulin treatment and gliclazide treatment groups. Another group with a chow diet was designated as normal controls. Differentiated 3T3-L1 adipocytes were then incubated with tumor necrosis factor alpha (TNF-alpha) and (or) insulin for 24 h. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of PEDF in adipose tissue or adipocytes. The PEDF levels in both sera and cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Glucose uptake was detected after treatment of PEDF or anti-PEDF antibody simultaneously together with insulin in mature 3T3-L1 adipocytes. RESULTS: Insulin therapy decreased the serum levels of FPG and triglyceride of T2DM patients ((12.9 +/- 2.8) vs (5.9 +/- 1.4) mmol/L, (3.1 +/- 1.8) vs (1.7 +/- 0.8) mmol/L, P < 0.05) while the serum level of PEDF decreased significantly after therapy ((22.85 +/- 5.73) vs (18.38 +/- 5.28) ug/L, P < 0.05). Consistently the serum level of PEDF of diabetic rats was remarkably higher than that of normal controls and insulin-treated group ((28.6 +/- 0.5) vs (25.4 +/- 0.6) and (25.3 +/ 0.6) ug/L, P < 0.05). And the elevated levels of PEDF, TNF-alpha mRNA and protein in adipose tissue (P < 0.05) could be reduced by insulin treatment (P < 0.05). However, no obvious change was detected in gliclazide treatment group. Further evidences suggested that TNF-alpha could induce more secretion and expression of PEDF in 3T3-L1 adipocyte while this effect became ameliorated by insulin treatment. Furthermore, decreased capacity of glucose uptake by PEDF might be reversed by anti-PEDF antibody in 3T3-L1 adipocytes (P < 0.05). CONCLUSIONS: Insulin can down-regulate the expression of PEDF in adipocytes of T2DM and improve the glucose uptake of adipocytes. It may be one of the mechanisms through which insulin therapy improves peripheral insulin resistance. PMID- 25547702 TI - [Clinical value of flow cytometry in assessing bone marrow involvement of non Hodgkin's lymphoma]. AB - OBJECTIVE: To evaluate the value of flow cytometry (FCM) in the diagnosis of bone marrow involvement in patients with non-Hodgkin's lymphoma (NHL). METHODS: The cytomorphology, biopsy and FCM tests were performed concurrently on bone marrow samples from 206 patients who were consecutively diagnosed as NHL from March 2013 to August 2013 at Peking University Cancer Hospital. The results were analyzed and compared. RESULTS: Totally bone marrow involvement occurred in 25.7% (53/206) patients. The detection positivity of bone marrow involvement by cytomorphology, biopsy and flow cytometry were 6/14, 6/14 and 9/14 respectively in 14 T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (T-LBL/ALL) patients; 9.2% (14/152) , 19.1% (29/152) and 23.7% (36/152) respectively in 152 mature B-cell NHL patients; 0 (0/40) , 15.0% (6/40) and 2.5% (1/40) in 40 cases of mature T/NK-cell NHL. The overall rate of concordance of biopsy and flow cytometry was 88.3%. CONCLUSIONS: FCM has a high sensitivity in detecting bone marrow involvement in NHL patients, especially those with T-LBL/ALL and B-cell NHL. And a combination of morphology, biopsy and FCM may improve the sensitivity and accuracy in the detection of bone marrow involvement in NHL patients. PMID- 25547703 TI - [Risk factors and management of systemic reactions induced by subcutaneous immunotherapy]. AB - OBJECTIVE: To explore the risk factors (causes or possible causes) of systemic reactions induced by subcutaneous immunotherapy (SCIT) through clinical observations and develop countermeasures for preventing further SCIT-induced systemic reactions. METHODS: Each patient on SCIT at our department from December 1993 to September 2013 was inquired about systemic reactions induced by SCIT. Individuals with systemic reactions immediately after SCIT were included. Clinical history and manifestations were inquired and recorded carefully. Risk factors of systemic reactions were probed and analyzed. SCIT schedule was adjusted according to the risk factors and the patients on continuous SCIT were followed up until the end of SCIT course. RESULTS: A total of 70 reactions were observed in 35 patients during the observation period. A large majority (97.1% (68/70) ) of systemic reactions occurred at a maximal concentration of 10(-2). Risk factor included an injection of maximal dosage (0.6-1.0 ml of 10(-2) vial, 27.2% (28/103) ), a further injection of large dosage (0.1-0.5 ml of 10(-2) vial) during pollen season (20.4% (21/103) ), incremental dose regardless of marked local reaction (12.6% (13/103) ), suspected incorrect injection procedure(12.6% (13/103) ) and an injection with a wrong vial of higher concentration (9.7% (10/103) ). Countermeasures were taken accordingly, include stopping injection of maximal dosage, avoiding SCIT of 10(-2) vial on pollen season, decreasing SCIT dosage on existence of large local reactions, performing SCIT only at medical institutions capable of managing anaphylaxis and implementing normalized injection procedures. Most patients (n = 29) finished the course of SCIT successfully without further systemic reactions. Six patients ceased SCIT for personal reasons or on medical advice. CONCLUSIONS: Probing the risk factors of systemic reactions induced by SCIT and adopting countermeasures accordingly prevent further systemic reactions. It may provide rationales for preventing or minimizing systemic reactions during SCIT. PMID- 25547704 TI - [Expression and correlation of CIP2A and OPN in bladder cancer]. AB - OBJECTIVE: To explore the expressions of cancerous inhibitor of protein phosphatase 2A (CIP2A) and osteopontin (OPN) and evaluate their roles in bladder cancer. METHODS: RNA was isolated from 38 cases of patients with bladder cancer and 12 cases of normal bladder tissue by TRIzol method from May 2010 to December 2012. And reverse transcription (RT)-PCR was used to detect the expressions of CIP2A and OPN. The expression levels of CIP2A and OPN in 99 cases of patients with bladder cancer and 12 cases of normal tissue were detected by immunohistochemical staining. RESULTS: The positive expression rate of CIP2A mRNA and OPN mRNA were 76.32% (29/38) and 92.11% (35/38) in bladder cancer while there was no expression in normal tissue (both P < 0.05). The positive rates of CIP2A and OPN protein were 63.64% (63/99)and 84.85% (84/99)in cases of bladder cancer tissues while CIP2A was not detected in normal tissues. The positive expression rate of OPN in normal tissues was 2/12 (both P < 0.05). The CIP2A and OPN proteins were both expressed in 58/99 cases of bladder cancer tissues while neither of them was expressed in 13 cases. In 8 cases, CIP2A was expressed while OPN was not. In another 20 cases, OPN was expressed while CIP2A was not (r = 0.300, P < 0.05). CONCLUSIONS: The expression levels of CIP2A and OPN in tissue of bladder cancer are higher than those of normal controls. And CIP2A and OPN may be used as indicators of biological behaviors and serve as new molecular diagnostic markers for bladder cancer. PMID- 25547705 TI - [Laparoscopic versus open mesh rectopexy for total rectal prolapse]. AB - OBJECTIVE: To evaluate the efficacy and safety of laparoscopic versus open mesh rectopexy for total rectal prolapse. METHODS: A retrospective review was conducted for 34 patients undergoing laparoscopic versus open mesh rectopexy for total rectal prolapse between January 2006 and December 2013. RESULTS: Laparoscopic rectopexy (n = 15) and open surgery (n = 19) were performed. Two groups were matched with regards to age, gender, body mass index (BMI) and American Society of Anesthesiologists (ASA) score. Mortality was zero in each group. There were insignificant inter-group differences in operative duration, postoperative complication, rate of long-term recurrence and improvement of incontinence and constipation. Perioperative blood loss, time to first flatus and hospital stay were significantly shorter in laparoscopic rectopexy group. CONCLUSIONS: Laparoscopic mesh rectopexy is as safe and efficient as open rectopexy. And both are suitable for senile patients. Long-term outcomes are similar for two groups, but laparoscopic group has better short-term outcome. PMID- 25547706 TI - [Absence of response to rituximab in patients with refractory primary immune thrombocytopenia]. AB - OBJECTIVE: To explore the possible causes for an absence of response to rituximab (RTX) in patients with refractory immune thrombocytopenia (ITP). METHODS: A total of 20 refractory ITP patients on RTX therapy and 10 health volunteers were recruited from 2008 to 2013. Memory T lymphocytes (Tm) (CD4(+)CD45RO(+)) and B lymphocytes (CD19(+)CD20(+)) in peripheral blood (PB) were examined by flow cytometry (FCM). And enzyme-linked immunosorbent assay (ELISA) was employed for detecting the platelet-associated antibodies IgG/IgM (PAIgG/IgM). RESULTS: (1) 12 patients with refractory ITP achieved a good response after therapy with RTX (effective RTX group) and 8 cases failed to respond (ineffective RTX group). The PB levels of CD4(+)CD45RO(+)Tm were 41.33% +/- 9.62% and 45.36% +/- 8.57% respectively at pre-therapy and post-therapy in ineffective RTX group. And significant differences existed between ineffective and effective RTX groups (22.36% +/- 11.57%, 26.65% +/- 6.32%) versus health volunteers (19.72% +/- 7.35%, 20.64% +/- 7.35%) (all P < 0.05) . No statistical differences existed in the PB level of CD4(+)CD45RO(+)Tm between pre-therapy and post-therapy in ineffective or effective RTX group (both P > 0.05); (2) The PB level of CD19(+)CD20(+)B lymphocytes in RTX ineffective group was lower than that at pre-therapy in RTX effective group (16.36% (6.17%-27.53%) vs 45.72% (35.80%-57.19%), P < 0.05) . No significant difference existed in the level of CD19(+)CD20(+)B at post-therapy between ineffective and effective RTX groups (6.67% (4.09%-19.17%) vs 5.19% (3.78%-17.39%), P > 0.05). And significant differences existed in the PB level of CD19(+)CD20(+)B between pre-therapy and post-therapy in ineffective or effective RTX group (both P > 0.05); (3) PAIgG/IgM was not detected in RTX ineffective group. And PAIgG/IgM was found in 11 cases at pre-therapy versus 1 case at post therapy in RTX effective group. CONCLUSION: CD4(+)CD45RO(+)Tm is probably associated with an absence of response to RTX in patients with refractory ITP. PMID- 25547707 TI - [Clinical analyses of hepatocellular carcinoma and nasopharyngeal multiple primary cancers]. AB - OBJECTIVE: To explore the clinicopathological characteristics, diagnosis, treatment outcomes and survival of hepatocellular carcinoma (HCC) and nasopharyngeal multiple primary cancers. METHODS: The clinical data of 12 male patients with hepatocellular and nasopharyngeal multiple primary cancers were retrospectively analyzed. RESULTS: Second primary cancer was diagnosed with a median age of 54.5 years. Hepatitis B surface antigen (HBsAg) was detected in 7 patients (58.3%) and 6 cases (50.0%) had a family history of cancer. The treatments included radiochemotherapy (n = 5), radiotherapy (n = 6) and non therapy (n = 1). And the interventions included hepatic surgery (n = 6), interventional treatment (n = 4) and conservative (n = 2). The 1, 3 and 5-year overall survival rates were 90.9%, 81.8% and 58.4% and the HCC-specific survival rates 80.0% at 1 year and 57.1% at 3 years respectively. The HCC-specific survival rates of surgery group were significantly better than those of the non surgical group. The 1, 3-year HCC-specific survival rates were 100.0%, and 100.0%vs 50.0% and 0 respectively (P = 0.002). CONCLUSIONS: HCC and nasopharyngeal multiple primary cancers are not rare and careful follow-ups are necessary . The co-existence of HCC and nasopharyngeal multiple primary cancers does not imply a worse prognosis. And radical resection of HCC is considered. PMID- 25547708 TI - [Clinicopathological characteristics, diagnosis and treatment of Castleman's disease]. AB - OBJECTIVE: To explore the clinicopathological characteristics, diagnosis and treatment of Castleman's disease. METHODS: Seven teen cases of castleman's disease confirmed by surgery and pathology were presented, with the helping of relevant literatures, to discuss its clinical presentation, CT findings, pathology, diagnosis, treatment and prognosis, especially the cases with PNP. RESULTS: There were 10 males and 7 females with an age range of 28-56 years. They were all of local hyaline-vascular types according to histopathology. All cases were cured by surgical resection. CONCLUSIONS: Castleman's disease is a rare lyphoproliferative disorder with giant lymph node hyperplasia. Its diagnosis depends on its histopathological characteristics and clinical manifestations should also be taken into account. Surgical resection is the first choice and other treatments may be effective. PMID- 25547709 TI - [Effects of propofol on miR-181a and Bcl-2 expression in glucose deprivation cultured astrocytes]. AB - OBJECTIVE: To explore the propofol regulation of Bcl-2 protein expression through miR-181a in glucose deprivation (GD) cultured astrocytes. METHODS: Primary cultured murine astrocytes were treated with 0, 1, 5, 10, 15, 20 umol/L propofol for 12 h and then cultured with GD medium for 24 h. The cell survival rate was recorded with microscope. Reactive oxygen species (ROS) formation and mitochondrial membrane stabilization were observed. And the expression levels of miR-181a and Bcl-2 protein were recorded to analyze the protection effects of propofol on astrocytes. RESULTS: After the treatments of propofol and GD, the survival rates of 0, 1, 5, 10, 15, 20 umol/L propofol groups were (0.51 +/- 0.03)%, (0.52 +/- 0.02) %, (0.52 +/- 0.02) %, (0.73 +/- 0.04) %, (0.31 +/- 0.02) % and (0.21 +/- 0.02)%. And there were statistical significance (F = 118.62, P < 0.001). Compared with 0 umol/L propofol group, the survival rate was much higher in 10 umol/L propofol group while much lower in 15 umol/L and 20 umol/L propofol groups. 10 umol/L propofol could decrease ROS formation and stabilize mitochondrial membrane. And Bcl-2 protein expression was up-regulated while miR 181a expression inhibited by 10 umol/L propofol. CONCLUSION: The protection of 10 umol/L propofol against GD stress in astrocytes is correlated with inhibiting miR 181a and up-regulating Bcl-2 protein expression. PMID- 25547710 TI - [Effects of hydrogen-rich saline on endoplasmic reticulum stress during myocardial ischemia-reperfusion in rats]. AB - OBJECTIVE: To explore the effects of hydrogen-rich saline on endoplasmic reticulum stress during myocardial ischemia-reperfusion (I/R) in rats. METHODS: A total of 150 healthy male Sprague-Dawley rats were selected and then randomly divided into 5 groups of normal control (I), sham operation (II), myocardial ischemia-reperfusion (III), hydrogen-rich saline (IV) and normal saline (V) (n = 30 each). Group I had no treatment. In group II, anterior descending branch was merely exposed but not ligated. Myocardial I/R was induced by an occlusion of anterior descending branch of left coronary artery for 30 min followed by 12 h and 24 h of reperfusion with bimbaum. Hydrogen-rich saline 1 ml/100 g was injected intraperitoneally 5 min before reperfusion in group IV. Normal saline 1 ml/100 g was injected intraperitoneally 5 min before reperfusion in group V. The rats were sacrificed at 12 h and 24 h of reperfusion and heart tissues harvested. The pathological changes of myocardial tissue were detected by hematoxylin & eosin staining. The apoptotic cardiomyocytes of myocardial tissue were tested by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). And the expressions of GRP78, Caspase-12, Bcl-2 and Bax in myocardial tissue were detected by Western blot. RESULTS: Compared with groups I and II, the numbers of apoptotic cardiomyocytes, the expression of GRP78, Caspase-12 and Bax in myocardial tissue significantly increased and the expression of Bcl-2 in myocardial tissue significantly decreased in groups III, IV and V. Compared with group III and V, the numbers of apoptotic cardiomyocytes, the expression of GRP78, Caspase-12 and Bax in myocardial tissue significantly decreased while the expression of Bcl-2 in myocardial tissue significantly increased in group IV. CONCLUSIONS: Hydrogen-rich saline may decrease cell apoptosis and attenuate myocardial reperfusion injury through inhibiting endoplasmic reticulum stress. The mechanism may be associated with decreasing the expression of GRP78, Caspase 12 and Bax and increasing the expression of Bcl-2 in myocardial tissue. PMID- 25547711 TI - A cognitive-emotional biomarker for predicting remission with antidepressant medications: a report from the iSPOT-D trial. AB - Depression involves impairments in a range of cognitive and emotional capacities. It is unknown whether these functions can inform medication choice when considered as a composite predictive biomarker. We tested whether behavioral tests, grounded in the neurobiology of cognitive and emotional functions, predict outcome with common antidepressants. Medication-free outpatients with nonpsychotic major depressive disorder (N=1008; 665 completers) were assessed before treatment using 13 computerized tests of psychomotor, executive, memory attention, processing speed, inhibitory, and emotional functions. Matched healthy controls (N=336) provided a normative reference sample for test performance. Depressed participants were then randomized to escitalopram, sertraline, or venlafaxine-extended release, and were assessed using the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) and the 17-item Hamilton Rating Scale for Depression. Given the heterogeneity of depression, analyses were furthermore stratified by pretreatment performance. We then used pattern classification with cross-validation to determine individual patient-level composite predictive biomarkers of antidepressant outcome based on test performance. A subgroup of depressed participants (approximately one-quarter of patients) were found to be impaired across most cognitive tests relative to the healthy norm, from which they could be discriminated with 91% accuracy. These patients with generally impaired cognitive task performance had poorer treatment outcomes. For this impaired subgroup, task performance furthermore predicted remission on the QIDS SR16 at 72% accuracy specifically following treatment with escitalopram but not the other medications. Therefore, tests of cognitive and emotional functions can form a clinically meaningful composite biomarker that may help drive general treatment outcome prediction for optimal treatment selection in depression, particularly for escitalopram. PMID- 25547712 TI - Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues. AB - A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse. PMID- 25547713 TI - Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation. AB - Glucocorticoid hormones are known to act synergistically with other stress activated neuromodulatory systems, such as norepinephrine and corticotropin releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation. PMID- 25547715 TI - The bovine model for elucidating the role of gammadelta T cells in controlling infectious diseases of importance to cattle and humans. AB - There are several instances of co-investigation and related discoveries and achievements in bovine and human immunology; perhaps most interesting is the development of the BCG vaccine, the tuberculin skin test and the more recent interferon-gamma test that were developed first in cattle to prevent and diagnosis bovine tuberculosis and then applied to humans. There are also a number of immune-physiological traits that ruminant share with humans including the development of their immune systems in utero which increases the utility of cattle as a model for human immunology. These are reviewed here with a particular focus on the use of cattle to unravel gammadelta T cell biology. Based on the sheer number of gammadelta T cells in this gammadelta T cell high species, it is reasonable to expect gammadelta T cells to play an important role in protective immune responses. For that reason alone cattle may provide good models for elucidating at least some of the roles gammadelta T cells play in protective immunity in all species. This includes fundamental research on gammadelta T cells as well as the responses of ruminant gammadelta T cells to a variety of infectious disease situations including to protozoan and bacterial pathogens. The role that pattern recognition receptors (PRR) play in the activation of gammadelta T cells may be unique relative to alphabeta T cells. Here we focus on that of the gammadelta T cell specific family of molecules known as WC1 or T19 in ruminants, which are part of the CD163 scavenger receptor cysteine rich (SRCR) family that includes SCART1 and SCART2 expressed on murine gammadelta T cells. We review the evidence for WC1 being a PRR as well as an activating co-receptor and the role that gammadelta T cells bearing these receptors play in immunity to leptospirosis and tuberculosis. This includes the generation of memory responses to vaccines, thereby continuing the tradition of co-discovery between cattle and humans. PMID- 25547716 TI - Asthma "of horses and men"--how can equine heaves help us better understand human asthma immunopathology and its functional consequences? AB - Animal models have been studied to unravel etiological, immunopathological, and genetic attributes leading to asthma. However, while experiments in which the disease is artificially induced have helped discovering biological and molecular pathways leading to allergic airway inflammation, their contribution to the understanding of the causality of the disease has been more limited. Horses naturally suffer from an asthma-like condition called "heaves" which presents sticking similarities with human asthma. It is characterized by reversible airway obstruction, airway neutrophilic inflammation, and a predominant Th2 immune response. This model allows one to investigate the role of neutrophils in asthma, which remains contentious, the regulation of chronic neutrophilic inflammation, and their possible implication in pulmonary allergic responses. Furthermore, the pulmonary remodeling features in heaves closely resemble those of human asthma, which makes this model unique to investigate the kinetics, reversibility, as well as the physiological consequences of tissue remodeling. In conclusion, heaves and asthma share common clinical presentation and also important immunological and tissue remodeling features. This makes heaves an ideal model for the discovery of novel pathways implicated in the asthmatic inflammation and associated tissue remodeling. PMID- 25547714 TI - Adult AMPA GLUA1 receptor subunit loss in 5-HT neurons results in a specific anxiety-phenotype with evidence for dysregulation of 5-HT neuronal activity. AB - Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5 hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while alpha1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5 HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5 HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior. PMID- 25547718 TI - Usefulness of dual protection combined with blood aspiration for distal embolic protection during carotid artery stenting. AB - BACKGROUND: We describe dual protection (simultaneous flow reversal and distal filter) combined with blood aspiration as a novel technique to provide distal embolic protection during carotid artery stenting (CAS). METHODS: Between July 2011 and August 2014, 190 patients with internal carotid artery (ICA) stenosis underwent 190 CAS procedures as follows. After post-dilation of the stent using dual protection, the aspiration catheter was placed between the distal filter and the proximal end of the stent, and the blood was aspirated several times from the ICA. We assessed hyper-intensity spots in diffusion-weighted images (DWI), and major adverse events (MAE) defined as major stroke, myocardial infarction and death after CAS. We then assessed visible debris captured in aspirated blood, the distal filter and a blood filter during flow reversal. RESULTS: The overall technical success rate was 100 %, and all stenoses were dilated. Hyper-intense spots were found in 33 (17.3 %) of 190 DWI. The rate of MAE within 30 days was 1.05 % (2/190). Visible debris in 175 of 190 CAS procedures was captured in 92 (52.5 %) of these 175. In 25 (27.2 %) of these 92, visible debris was captured in all of aspirated blood, the distal filter and the blood filter during flow reversal, only the blood filter during flow reversal (n = 19; 20.7 %), only the distal filter (n = 14; 15.2 %), only aspirated blood (n = 11; 12 %), aspirated blood and the blood filter during flow reversal (n = 10; 10.8 %), aspirated blood and the distal filter (n = 7; 7.6 %) and the distal filter and blood filter during flow reversal (n = 6; 6.5 %). CONCLUSIONS: Adding a distal filter and blood aspiration to flow reversal during CAS could provide effective distal embolic protection. PMID- 25547719 TI - 5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy. AB - BACKGROUND: The 5-aminolevulinic acid (5-ALA) fluorescence-guided resection of recurrent malignant glioma is a standard surgical procedure at many neuro oncological centers and is considered to be equally reliable as the primary resection of these tumors. 5-ALA induced fluorescence (5-AIF)-guided resection has been demonstrated to be highly predictive for tumor tissue. As pseudoprogression and radiation-induced necrosis are critical differential diagnoses of glioma recurrence, the purpose of the present analysis was to analyze 5-AIF behavior in resected tissue specimens histopathologically showing regressive and reactive changes but lacking active, that is, cellular recurrent tumor tissue after adjuvant treatment of malignant glioma. METHODS: A retrospective analysis was performed in patients suffering from malignant glioma who underwent surgical resection for suspected contrast-enhancing tumor recurrence (according to RANO criteria) at our institution between 2007 and 2013, but in whom histopathological analysis only revealed reactive changes. The presence of AIF in the resected tissue samples was intraoperatively assessed and classified by the surgeon, using the categories (1) no, (2) vague and (3) solid AIF. RESULTS: A total of 13 out of 313 patients who underwent AIF-guided surgical resection of tissue suspicious for recurrent glioma histologically demonstrated only reactive changes without active recurrent tumor tissue after adjuvant therapy. Pretreatment was chemotherapy with temozolomide in 1 patient and combined radio-/chemotherapy in 12 patients. Six patients had suffered previous tumor recurrence with a subsequently intensified adjuvant therapy. Seven of the 13 patients displayed solid, 5 patients vague and 1 patient no 5-AIF of the resected tissue specimens. However, all 5-AIF-positive lesions exhibited heterogeneous fluorescence patterns with vaguely or solidly fluorescent as well as nonfluorescent regions. CONCLUSIONS: Resection of reactive tissue without active recurrent tumor after multimodal treatment for glioblastoma is frequently associated with solid or vague 5-AIF. Therefore, neurosurgeons should remain cautious when attempting to employ intraoperative 5-AIF to discriminate radiation and chemotherapy-induced tissue changes from true disease progression. Nevertheless, 5-AIF-guided resection remains a valid tool in the neurosurgical treatment of recurrent gliomas. PMID- 25547720 TI - Influence of home care on life satisfaction, loneliness, and perceived life stress. AB - Strong evidence has established the medical and health services utilization benefits of home care services for older adults. However, sparse research has been conducted on potential psychosocial benefits. Older adults (65 and over) receiving home care with their needs met are compared with persons who have unmet needs (whether they received home care or not) on three key indicators of quality of life - life satisfaction, loneliness, and perceived life stress. Data are drawn from the 2008-2009 Canadian Community Health Survey respondents who met the study criteria (n = 3,244). Regression analyses showed that older adults who had their home care needs met reported higher levels of life satisfaction, and lower levels of loneliness and perceived life stress, than those with unmet needs, net of co-variates. The results suggest that filling this home care gap would significantly raise quality of life by increasing social and environmental resilience to age in place. PMID- 25547717 TI - Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy. AB - AIMS: To determine leg intermuscular (IMAT) and subcutaneous (SQAT) adipose tissue and their relationships with muscle performance and function in obese adults with and without type 2 diabetes and peripheral neuropathy (T2DMPN). METHODS: Seventy-nine age-matched obese adults were studied, 13 T2DM, 54 T2DMPN, and 24 obese controls. Leg fat (%IMAT, %SQAT) volumes were quantified using MRI. Ankle plantar flexion (PF) torque and power were assessed with isokinetic dynamometry. Physical function was assessed with 9-item Physical Performance Test (PPT), 6-minute walk distance, single-limb balance, and time to ascend 10 stairs. One-way ANOVAs determined group differences, and multiple regression predicted PPT score from disease status, % IMAT, and PF power. RESULTS: T2DMPN participants had 37% greater IMAT volumes and 15% lower SQAT volumes than controls (p =. 01). T2DMPN and T2DM showed reduced PF torque and power compared to controls. T2DMPN participants had lower PPT score, 6-minute walk, single-limb balance, and stair climbing than controls (all p<.05). %IMAT volume correlated inversely, and %SQAT correlated directly, with PPT. Leg %IMAT and disease status predicted 49% of PPT score. CONCLUSIONS: T2DMPN may represent a shift in adipose tissue accumulation from SQAT to IMAT depots, which is inversely associated with muscle performance and physical function. PMID- 25547721 TI - [Uveitic macular edema]. AB - Macular edema may complicate anterior, intermediate, and posterior uveitis, which may be due to various infectious, tumoral, or autoimmune etiologies. Breakdown of the internal or external blood-retinal barrier is involved in the pathogenesis of inflammatory macular edema. Optical coherence tomography has become standard in confirming the diagnosis of macular thickening, due to its non-invasive, reproducible and sensitivity characteristics. Fluorescein and indocyanine green angiography allows for, in addition to study of the macula, screening for associated vasculitis, detection of ischemic areas, easy diagnosis of preretinal, prepaillary or choroidal neovascular complications, and it can provide etiological information and may be required to evaluate the therapeutic response. Treatment of inflammatory macular edema requires specific treatment in cases of infectious or tumoral etiologies. If it remains persistent, or occurs in other etiologies, anti-inflammatory treatments are needed. Steroid treatment, available in intravitreal, subconjunctival and sub-Tenon's routes, are widely used. Limitations of local use include induced cataract and glaucoma, and their short lasting action. Such products may reveal retinal infection. Thus, bilateral chronic sight-threatening posterior uveitis often requires systemic treatment, and steroids represent the classic first-line therapy. In order to reduce the daily steroid dose, immunosuppressant or immunomodulatory drugs may be added. Certain of these compounds are now available intravitreally. PMID- 25547722 TI - Steric stabilization of "charge-free" cellulose nanowhiskers by grafting of poly(ethylene glycol). AB - A sterically stabilized aqueous suspension of "charge-free" cellulose nanowhiskers was prepared by hydrochloric acid hydrolysis of cotton powders and subsequent surface grafting of monomethoxy poly(ethylene glycol) (mPEG). The preparation scheme included carboxylation of the terminal hydroxyl groups in mPEG via oxidation with silica gel particles carrying 2,2,6,6-tetramethyl-1 pyperidinyloxyl (TEMPO) moieties and subsequent esterification between terminal carboxyls in mPEG and surface hydroxyl groups of cellulose nanowhiskers, mediated by 1,1'-carbonyldiimidazole (CDI) in dimethyl sulfoxide or dimethylacetamide. Some of the prepared PEG-grafted samples showed remarkable flow birefringence and enhanced stability after 24 h, even in 0.1 M NaCl, suggesting successful steric stabilization by efficient mPEG grafting. Actual PEG grafting via ester linkages was confirmed by attenuated total reflectance-Fourier transform infrared spectrometry. In a typical example, the amount of grafted mPEG was estimated as ca. 0.3 g/g cellulose by two measurements, i.e., weight increase after grafting and weight loss after alkali cleavage of ester linkages. Transmission electron microscopy indicated unchanged nanowhisker morphology after mPEG grafting. PMID- 25547723 TI - Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses. AB - Curcumin (diferuloylmethane), a golden pigment from turmeric, has been linked with antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antidiabetic properties. Most of the these activities have been assigned to methoxy, hydroxyl, alpha,beta-unsaturated carbonyl moiety or to diketone groups present in curcumin. One of the major metabolites of curcumin is tetrahydrocurcumin (THC), which lacks alpha,beta-unsaturated carbonyl moiety and is white in color. Whether THC is superior to curcumin on a molecular level is unclear and thus is the focus of this review. Various studies suggest that curcumin is a more potent antioxidant than THC; curcumin (but not THC) can bind and inhibit numerous targets including DNA (cytosine-5)-methyltransferase-1, heme oxygenase-1, Nrf2, beta-catenin, cyclooxygenase-2, NF-kappaB, inducible nitric oxide synthase, nitric oxide, amyloid plaques, reactive oxygen species, vascular endothelial growth factor, cyclin D1, glutathione, P300/CBP, 5-lipoxygenase, cytosolic phospholipase A2, prostaglandin E2, inhibitor of NF-kappaB kinase-1, 2, P38MAPK, p-Tau, tumor necrosis factor-alpha, forkhead box O3a, CRAC; curcumin can inhibit tumor cell growth and suppress cellular entry of viruses such as influenza A virus and hepatitis C virus much more effectively than THC; curcumin affects membrane mobility; and curcumin is also more effective than THC in suppressing phorbol-ester-induced tumor promotion. Other studies, however, suggest that THC is superior to curcumin for induction of GSH peroxidase, glutathione-S-transferase, NADPH: quinone reductase, and quenching of free radicals. Most studies have indicated that THC exhibits higher antioxidant activity, but curcumin exhibits both pro-oxidant and antioxidant properties. PMID- 25547724 TI - Structure-based virtual screening of novel natural alkaloid derivatives as potential binders of h-telo and c-myc DNA G-quadruplex conformations. AB - Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex structures, G-binders are generally characterized by a large aromatic core involved in pi-pi stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding affinity with G-quadruplex, such as berbamine and many other alkaloids. Using the structural information available on G-quadruplex structures, we performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG3(T2AG3)3] and the c-myc promoter structure. We identified 69 best hits reporting an improved theoretical binding affinity with respect to the active set. Among them, a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc. PMID- 25547725 TI - Phenolic profile of Potentilla anserina L. (Rosaceae) herb of siberian origin and development of a rapid method for simultaneous determination of major Phenolics in P. anserina pharmaceutical products by microcolumn RP-HPLC-UV. AB - A chemical study of Potentilla anserina L. herb (Rosaceae) of Siberian origin led to the isolation of 17 compounds. Three ellagitannins-potentillin, agrimonic acid A and B-are reported for the first time in this species. With a view to rapid quantitative analysis, a new method was developed for simultaneous determination of major phenolic compounds in P. anserina, including caffeic acid, myricetin-3-O glucuronide, agrimoniin, ellagic acid, miquelianin, isorhamnetin-3-O-glucuronide, and kaempferol-3-O-rhamnoside. The quantitative determination was conducted by microcolumn reversed phase high-performance liquid chromatography with UV detection. Separation was performed using a ProntoSIL-120-5-C18 AQ column (60 mm * 1 mm * 5 MUm) with six-step gradient elution of aqueous 0.2 M LiClO4 in 0.006 M HClO4 and acetonitrile as mobile phases. The components were quantified by HPLC UV at 270 nm. All calibration curves showed good linearity (r2 > 0.999) within test ranges. The reproducibility was evaluated by intra- and inter-day assays, and RSD values were less than 2.8%. The recoveries were between 97.15 and 102.38%. The limits of detection ranged from 0.21 to 1.94 MUg/mL, and limits of quantification ranged from 0.65 to 5.88 MUg/mL, respectively. Various solvents, extraction methods, temperatures, and times were evaluated to obtain the best extraction efficiency. The developed method was successfully applied for the analysis of selected pharmaceutical products: 12 batches of P. anserina herb collected from three Siberian regions (Yakutia, Buryatia, Irkutsk), two commercial samples of P. anserina herb, and some preparations (liquid extract, tincture, decoction, infusion, and dry extract). PMID- 25547727 TI - Protective effects of Lycium barbarum polysaccharide on 6-OHDA-induced apoptosis in PC12 cells through the ROS-NO pathway. AB - Oxidative stress plays an important role in Parkinson's disease and other neurodegenerative disorders. Lycium barbarum polysaccharides (LBP), the main active ingredients extracted from the fruits of Lycium barbarum L., have been shown to be a potent antioxidant. In the present study, we investigated the protective effects, and the possible mechanism of action of LBP against 6 hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells. Our data demonstrated that LBP significantly reversed the 6-OHDA-induced decrease in cell viability, prevented 6-OHDA-induced changes in condensed nuclei and decreased the percentage of apoptotic cells in a dose-dependent manner. Furthermore, LBP also slowed the accumulation of reactive oxygen species (ROS) and nitric oxide (NO), decreased the level of protein-bound 3-nitrotyrosine (3-NT) and intracellular free Ca2+, and inhibiting the overexpression of nuclear factor kappaB (NF-kappaB), neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). These results demonstrate that LBP prevents 6-OHDA-induced apoptosis in PC12 cells, at least in part through the ROS-NO pathway. PMID- 25547728 TI - Ag+ as a more effective elicitor for production of tanshinones than phenolic acids in Salvia miltiorrhiza hairy roots. AB - Phenolic acids and tanshinones are two groups of bioactive ingredients in Salvia miltiorrhiza Bunge. As a heavy metal elicitor, it has been reported that Ag+ can induce accumulations of both phenolic acids and tanshinones in S. miltiorrhiza hairy roots. In this study, the effects of Ag+ treatment on accumulations of six phenolic acids and four tanshinones in S. miltiorrhiza hairy roots were investigated. To further elucidate the molecular mechanism, expressions of key genes involved in the biosynthesis of these ingredients were also detected. The results showed that although the total phenolic acids content was almost not affected by Ag+, accumulations of rosmarinic acid (RA), caffeic acid and ferulic acid were significantly increased, while accumulations of salvianolic acid B (LAB), danshensu (DSU) and cinnamic acid were decreased. We speculate that LAB probably derived from the branch pathway of DSU biosynthesis. Contents of four tanshinones were enhanced by Ag+ and their accumulations were more sensitive to Ag+ than phenolic acids. Genes in the upstream biosynthetic pathways of these ingredients responded to Ag+ earlier than those in the downstream biosynthetic pathways. Ag+ probably induced the whole pathways, upregulated gene expressions from the upstream pathways to the downstream pathways, and finally resulted in the enhancement of ingredient production. Compared with phenolic acids, tanshinone production was more sensitive to Ag+ treatments. This study will help us understand how secondary metabolism in S. miltiorrhiza responds to elicitors and provide a reference for the improvement of the production of targeted compounds in the near future. PMID- 25547726 TI - Eliminating the heart from the curcumin molecule: monocarbonyl curcumin mimics (MACs). AB - Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin's Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin's assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10-20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer's disease and malaria. PMID- 25547729 TI - Asperaculanes A and B, two sesquiterpenoids from the fungus Aspergillus aculeatus. AB - Six sesquiterpenoids 1-6, including two new ones, an ent-daucane-type sesquiterpenoid, asperaculane A (1), and a nordaucane one, asperaculane B (2), and four known nordaucane derivatives, aculenes A-D 3-6, together with the known secalonic acid D (7), were isolated from a fermentation culture of the fungus Aspergillus aculeatus. Their structures and absolute configurations were established by analyses of their spectroscopic data, including 1D and 2D-NMR spectra, HR-ESIMS, electronic circular dichroism (ECD) data, and quantum chemical calculations. These metabolites were evaluated for in vitro cytotoxic activity against two cell lines, human cancer cell lines (HeLa) and one normal hamster cell line (CHO). PMID- 25547734 TI - The ethics of animal research: a survey of pediatric health care workers. AB - INTRODUCTION: Pediatric health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR). We aim to determine whether HCW consider common arguments (and counterarguments) in support (or not) of AR convincing. DESIGN: After development and validation, an e-mail survey was sent to all pediatricians and pediatric intensive care unit nurses and respiratory therapists (RTs) affiliated with a Canadian University. We presented questions about demographics, support for AR, and common arguments (with their counterarguments) to justify the moral permissibility (or not) of AR. Responses are reported using standard tabulations. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. RESULTS: Response rate was 53/115(46%) (pediatricians), and 73/120(61%) (nurses/RTs). Pediatricians and nurses/RTs are supportive of AR. Most considered 'benefits arguments' sufficient to justify AR; however, most acknowledged that counterarguments suggesting alternative research methods may be available, or that it is unclear why the same 'benefits arguments' do not apply to using humans in research, significantly weakened 'benefits arguments'. Almost all were not convinced of the moral permissibility of AR by 'characteristics of non-human animals arguments', including that non-human-animals may not be sentient, or are simply property. Most were not convinced of the moral permissibility of AR by 'human exceptionalism' arguments, including that humans have more advanced mental abilities, are of a special 'kind', can enter into social contracts, or face a 'lifeboat situation'. Counterarguments explained much of this, including that not all humans have these more advanced abilities [the argument from species overlap], and that the notion of 'kind' is arbitrary [e.g., why are we not of the kind 'sentient animal' or 'subject-of-a-life']. Pediatrician and nurse/RT responses were similar. CONCLUSIONS: Most respondents were not convinced of the moral permissibility of AR when given common arguments and counterarguments from the literature. HCW should seriously consider arguments on both sides of the AR debate. PMID- 25547733 TI - AtROP1 negatively regulates potato resistance to Phytophthora infestans via NADPH oxidase-mediated accumulation of H2O2. AB - BACKGROUND: Small GTPases are monomeric guanine nucleotide-binding proteins. In plants, ROPs regulate plant cell polarity, plant cell differentiation and development as well as biotic and abiotic stress signaling pathways. RESULTS: We report the subcellular localization of the AtRop1 protein at the plasma membrane in tobacco epidermal cells using GFP fusions. Additionally, transient and stable expression of a dominant negative form (DN) of the Arabidopsis AtRop1 in potato led to H2O2 accumulation associated with the reduced development of Phytophthora infestans Montagne de Bary and smaller lesions on infected potato leaves. The expression of the Strboh-D gene, a NADPH oxidase homologue in potato, was analyzed by RT-PCR. Expression of this gene was maintained in DN-AtRop1 transgenic plants after infection with P. infestans. In transgenic potato lines, the transcript levels of salicylic acid (SA) and jasmonic acid (JA) marker genes (Npr1 and Lox, respectively) were analyzed. The Lox gene was induced dramatically whereas expression of Npr1, a gene up-regulated by SA, decreased slightly in DN AtRop1 transgenic plants after infection with P. infestans. CONCLUSIONS: In conclusion, our results indicate that DN-AtROP1 affects potato resistance to P. infestans. This is associated with increased NADPH oxidase-mediated H2O2 production and JA signaling. PMID- 25547735 TI - Who would students ask for help in academic cheating? Cross-sectional study of medical students in Croatia. AB - BACKGROUND: Academic cheating does not happen as an isolated action of an individual but is most often a collaborative practice. As there are few studies that looked at who are collaborators in cheating, we investigated medical students' readiness to engage others in academic dishonest behaviours. METHODS: In a cross-sectional survey study in Zagreb, Croatia, 592 medical students from the first, 3rd and 6th (final) study year anonymously answered a survey of readiness to ask family, friends, colleagues or strangers for help in 4 different forms of academic cheating or for 2 personal material favours. Stepwise multiple linear regression models (MLR) were used to evaluate potential factors influencing propensity for engaging others in these two types of behaviour. RESULTS: Many students would ask another person for help in academic cheating, from 88.8% to 26.9% depending on a cheating behaviour. Students would most often ask a family member or friend for help in academic cheating. The same "helpers" were identified for non-academic related behaviour - asking for personal material favours. More respondents, however, would include three or four persons for asking help in academic cheating than for routine material favours. Score on material favours survey was the strongest positive predictor of readiness for asking help in academic cheating (stepwise MLR model; beta = 0.308, P < 0.0001) followed by extrinsic motivation (compensation) and male gender, whereas intrinsic motivation, year of study and grade point average were weak negative predictors. CONCLUSIONS: Our study indicates that medical students are willing to engage more than one person in either close or distant relationships in academic cheating. In order to develop effective preventive measures to deter cheating at medical academic institutions, factors surrounding students' preference towards academic cheating rather than routine favours should be further investigated. PMID- 25547736 TI - VO2 kinetics and metabolic contributions during full and upper body extreme swimming intensity. AB - PURPOSE: Our purpose was to characterize the oxygen uptake ([Formula: see text]) kinetics, assess the energy systems contributions and determine the energy cost when swimming front crawl at extreme intensity. Complementarily, we compared swimming full body with upper body only. METHODS: Seventeen swimmers performed a 100 m maximal front crawl in two conditions: once swimming with full body and other using only the upper propulsive segments. The [Formula: see text] was continuously measured using a telemetric portable gas analyser (connected to a respiratory snorkel), and the capillary blood samples for lactate concentration analysis were collected. RESULTS: A sudden increase in [Formula: see text] in the beginning of exercise, which continuously rose until the end of the bout (time: 63.82 +/- 3.38 s; [Formula: see text]: 56.07 +/- 5.19 ml min(-1) kg(-1); [Formula: see text] amplitude: 41.88 +/- 4.74 ml min(-1) kg(-1); time constant: 12.73 +/- 3.09 s), was observed. Aerobic, anaerobic lactic and alactic pathways were estimated and accounted for 43.4, 33.1 and 23.5 % of energy contribution and 1.16 +/- 0.10 kJ m(-1) was the energy cost. Complementarily, the absence of lower limbs lead to a longer time to cover 100 m (71.96 +/- 5.13 s), slower [Formula: see text] kinetics, lower aerobic and anaerobic (lactic and alactic) energy production and lower energy cost. CONCLUSION: Despite the short duration of the event, the aerobic energy contribution covers about 50 % of total metabolic energy liberation, highlighting that both aerobic and anaerobic energy processes should be developed to improve the 100 m swimming performance. Lower limbs action provided an important contribution in the energy availability in working muscles being advised its full use in this short duration and very high-intensity event. PMID- 25547737 TI - [Subacute cutaneous lupus erythematosus induced by golimumab]. PMID- 25547738 TI - [Rythm disturbances as Emery-Dreifuss muscular dystrophy onset]. PMID- 25547739 TI - Severity of morphological lesion complexity affects fractional flow reserve in intermediate coronary stenosis. AB - BACKGROUND: Although functional ischemia identification is important when determining revascularization, angiographic assessment alone is challenging in intermediate coronary stenosis. Previous studies have reported that lesion specific characteristics affected the fractional flow reserve (FFR). However, the relationship between morphological lesion complexity and FFR has not yet been fully evaluated. This study aimed to evaluate the impact of morphological lesion complexity on FFR in intermediate coronary stenosis. METHODS: A total of 109 consecutive patients with 136 intermediate coronary stenoses (visually estimated diameter stenosis: 40-70%) were assessed via quantitative coronary angiography, lesion-specific characteristics, and FFR. Indexed lesions were assessed according to 6 morphological lesion characteristics: eccentricity, bend, irregularity, calcification, bifurcation, and diffuse. The lesions were then classified into 3 groups according to the morphological severity count represented by the number of present characteristics (mild-complex: 0-1, moderate-complex: 2-3, and severe complex: 4-6), and their functional severities were evaluated. Lesions with an FFR <0.80 were considered functionally significant coronary stenoses. RESULTS: Of the 136 lesions, 51% were located in the left anterior descending artery (LAD) and 47% had an FFR <0.80. The FFR differed significantly among the 3 lesion complexity groups (0.84+/-0.10 vs. 0.79+/-0.10 vs. 0.73+/-0.07, for mild-, moderate-, and severe-complex, respectively; p<0.01). In a multivariate logistic analysis, LAD lesions, moderate- and severe-complex, and diameter stenosis were independently associated with an FFR <0.80 [odds ratio (OR): 5.65, 95% confidence interval (CI): 2.50-12.80, p<0.01; OR: 2.96, 95% CI: 1.30-6.72, p<0.01; OR: 7.11, 95% CI: 1.25-40.37, p=0.03, and OR: 2.65, 95% CI: 1.04-6.72, p=0.04, respectively]. CONCLUSIONS: Both indexed vessels and the degree of diameter stenosis affected the FFR. In addition, the severity of morphological lesion complexity correlated with the degree of functional severity in intermediate coronary stenosis. PMID- 25547740 TI - Impact of hypoalbuminemia, frailty, and body mass index on early prognosis in older patients (>=85 years) with ST-elevation myocardial infarction. AB - BACKGROUND: The optimal treatment strategies for acute ST-elevation myocardial infarction (STEMI) in older patients are unclear because of the high risk of mortality in this population. Hypoalbuminemia, frailty, and body mass index (BMI) have been reported to worsen the prognosis of some older patients with cardiovascular disease, but the specific impact of these factors on the prognosis after STEMI is poorly understood. The aim of this study was to investigate the impact of these factors on early outcomes in patients aged >=85 years with acute STEMI. METHODS: Sixty-two consecutive eligible patients aged >=85 years (mean age, 88.1+/-2.5 years; age range, 85-94 years; female, 41.9%; primary percutaneous coronary intervention, 67.7%) who were admitted to our hospital with STEMI were retrospectively reviewed. Baseline patient characteristics, echocardiographic, electrocardiographic, and laboratory findings, and the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS) score were assessed. The primary endpoint was in-hospital mortality and the secondary endpoint was failure of discharge to home. Independent baseline variables with a p-value of <0.15 in the univariate analyses were included in the multivariate analyses. RESULTS: Multivariate analysis identified a higher baseline serum troponin I level [p=0.046; odds ratio (OR): 1.02], lower baseline albumin level (p=0.035, OR: 0.16), and CSHA-CFS score >=6 (p=0.028, OR: 6.38) as independent predictors of in-hospital mortality. Lower BMI (p<0.001, OR: 0.49) and CSHA-CFS frailty score >=6 (p=0.002, OR: 16.69) were identified as independent predictors of failure of discharge to home. CONCLUSIONS: These findings indicate that the serum albumin level, CSHA-CFS score, and BMI, in addition to serum troponin I level, have an impact on the early prognosis of older patients with STEMI. PMID- 25547741 TI - A novel ultrasound predictor of pulmonary capillary wedge pressure assessed by the combination of left atrial volume and function: A speckle tracking echocardiography study. AB - BACKGROUND: We hypothesized that a development of a novel index based on the combination of left atrial volume (LAV) and left atrial (LA) function evaluated by the time-LA volume curve using speckle tracking echocardiography (STE) would be accurate and useful to estimate pulmonary capillary wedge pressure (PCWP). Our goal was to develop a novel index of PCWP based on a combination of LAV and LA function using STE. METHODS: A cross-validation study was performed with the patients divided into a training study to define the novel index (n=50) and a testing study to validate the index (n=196). PCWP was measured by right heart catheterization, and phasic LAV and emptying function (EF) were measured by STE. RESULTS: Simple linear regression analysis in the training study revealed that the novel index that best estimated PCWP was the kinetics-tracking index [KT index=log10 (active LAEF/minimum LAV index)]. Multiple regression analysis revealed that the KT index was the most reliable predictor of PCWP. It had the strongest correlation with PCWP (r=-0.86, p<0.001) among all echocardiographic parameters. In the testing study, PCWP estimated by the KT index was also strongly correlated with measured PCWP (r=0.92, p<0.001). These correlations were also strong in the patients with reduced left ventricular ejection fraction (<50%), chronic heart failure, and chronic atrial fibrillation (r=0.92, r=0.91, r=0.79, p<0.001, respectively). CONCLUSIONS: A novel index (KT index) using a combination of LAV and LA function was a powerful and useful predictor of PCWP and may be valuable in routine clinical practice. PMID- 25547743 TI - Ocular vestibular evoked myogenic potentials in response to air conducted stimuli: clinical application in healthy adults. AB - OBJECTIVES: This study aims to determine the normal values for ocular vestibular evoked myogenic potentials in response to air conducted stimuli in healthy adults. PATIENTS AND METHODS: Thirty-six healthy adult participants with no ear complaints were enrolled. Ocular vestibular evoked myogenic potential tests were performed to all participants. Latency and amplitude values of the waves were recorded. RESULTS: The mean N1 latency was 9.62+/-2.02 (4.30-16.00) msec and the mean P1 latency was 14.90+/-2.33 (9.0-21.00) msec. The mean amplitude was 3.36+/ 1.36 (1.06-8.48) uV. There was a positive correlation between N1 and P1 latencies and age (r=242, p=0.0359 for N1; r=250, p=0.030 for P1). CONCLUSION: Ocular vestibular evoked myogenic potentials can be obtained easily and can be used in the evaluation of vestibular disorders. However, the effect of age should be considered when interpreting results. PMID- 25547742 TI - De novo transcriptome sequencing in Pueraria lobata to identify putative genes involved in isoflavones biosynthesis. AB - KEY MESSAGE: Using Illumina sequencing technology, we have generated the large scale transcriptome sequencing data and indentified many putative genes involved in isoflavones biosynthesis in Pueraria lobata. Pueraria lobata, a member of the Leguminosae family, is a traditional Chinese herb which has been used since ancient times. P. lobata root has extensive clinical usages, because it contains a rich source of isoflavones, including daidzin and puerarin. However, the knowledge of isoflavone metabolism and the characterization of corresponding genes in such a pathway remain largely unknown. In this study, de novo transcriptome of P. lobata root and leaf was sequenced using the Solexa sequencing platform. Over 140 million high-quality reads were assembled into 163,625 unigenes, of which about 43.1% were aligned to the Nr protein database. Using the RPKM (reads per kilo bases per million reads) method, 3,148 unigenes were found to be upregulated, and 2,011 genes were downregulated in the leaf as compared to those in the root. Towards a further understanding of these differentially expressed genes, Gene ontology enrichment and metabolic pathway enrichment analyses were performed. Based on these results, 47 novel structural genes were identified in the biosynthesis of isoflavones. Also, 22 putative UDP glycosyltransferases and 45 O-methyltransferases unigenes were identified as the candidates most likely to be involved in the tailoring processes of isoflavonoid downstream pathway. Moreover, MYB transcription factors were analyzed, and 133 of them were found to have higher expression levels in the roots than in the leaves. In conclusion, the de novo transcriptome investigation of these unique transcripts provided an invaluable resource for the global discovery of functional genes related to isoflavones biosynthesis in P. lobata. PMID- 25547744 TI - [Our results of postoperative radiation therapy in patients with salivary gland cancer]. AB - OBJECTIVES: This study aims to evaluate our single center experience in patients with a salivary gland tumor receiving postoperative radiation therapy (RT). PATIENTS AND METHODS: Between January 1996 and December 2011, the records of 34 salivary gland tumor patients who were operated and referred to our clinic for adjuvant RT were retrospectively analyzed. Radiation therapy was applied to the primary tumor and lymphatics at a median dose of 60 Gy (54 to 60 Gy) with 1.8-2 Gy/fraction. RESULTS: The median follow-up was 38 months (range, 3 to 204 months). The most common site of involvement was the parotid gland in 21 patients (62%), followed by the submandibular gland in 11 patients (%24) and minor salivary gland in two patients (9%). Five-year overall survival (OS) was 49% (range, 3 to 206 months) and disease free survival (DFS) was 61% (range, 1 to 173 months). Six patients had local or regional recurrences (18%), while 13 patients (38%) had distant metastasis. A tumor size larger than 4 cm, over six weeks referral time to RT, and existence of metastatic lymph node were found to be poor prognostic factors for OS (p=0.023, p=0.039, respectively), and DFS (p=0.046). While extracapsular involvement significantly reduced the DFS and OS (p=0.022, p=0.050, respectively), overall RT time affected DFS alone (p=0.046). CONCLUSION: We recommend adjuvant RT in high-risk patients operated due to a salivary gland tumor. PMID- 25547745 TI - [Evaluation of music department students who passed the entrance exam with phonetogram (Voice Range Profile)]. AB - OBJECTIVES: This study aims to evaluate phonetogram data of the students in the department of music who passed the entrance exam. PATIENTS AND METHODS: The phonetogram data of 44 individuals with a good voice quality in the department of music and age-matched individuals who were not trained in the field of music or not involved in music amateurish as the control group were compared. The voice of both groups were recorded using the voice range profile within the scope of Kay Elemetrics CSL (Model 4300 B) programmed. RESULTS: There was a significant difference in the voice range profile parameters including max Fo, Fo range, Fo range (St), min dB SPL, and max dB sound pressure level (p<0.05). CONCLUSION: Our study results suggest that the voice interval of the department of music is higher than the control group and that plays a major role in their acceptance to the department of music. PMID- 25547746 TI - [Transcanal endoscopic tympanoplasty in the treatment of chronic otitis media]. AB - OBJECTIVES: This study aims to report early postoperative complications and hearing results in patients with chronic otitis media undergoing endoscopic transcanal tympanoplasty. PATIENTS AND METHODS: Twenty-four patients (6 males, 18 females; mean age 25.9 years; range 9 to 46 years) who were operated with endoscopic transcanal tympanoplasty in the Department of Otorhinolaryngology, Faculty of Medicine, Cukurova University between December 2012 and January 2014 were included. Postoperative complication rates, graft success, and hearing outcomes (mean air-bone gap) were evaluated. RESULTS: The mean preoperative air bone gap was found 25.1 dB and the mean postoperative air bone gap was found 20.3 dB. Postoperative duration of hospital was 24 hours. Reperforation was seen in one patient and medialization of the anterior quadrant of the graft was seen in one patient. The mean follow-up time was 7.3 months. CONCLUSION: Endoscopic transcanal tympanoplasty can be easily applied, cheap and safe method and can be given successful results in challenging cases. PMID- 25547747 TI - The effect of adenoid hypertrophy on tympanometric findings in children without hearing loss. AB - OBJECTIVES: This study aims to investigate the effects of adenoid hypertrophy on negative middle ear pressure and diagnostic efficiency of tympanogram in the detection of otitis media with effusion in children without parental suspicion of hearing loss. PATIENTS AND METHODS: Fifty-six children (26 boys, 30 girls; mean age 5.9+/-2.2 years; range, 3 to 12 years) who underwent adenoidectomy were analyzed using otoscopy, nasal endoscopy, and tympanometry (before 1 week and 3 months after adenoidectomy). RESULTS: The median negative middle ear pressure before the adenoidectomy was significantly higher from after adenoidectomy (p=0.045). Type B tympanogram were detected in 13 of the 112 ears preoperatively. About 17.9% (n=20) of the ears with otitis media with effusion were confirmed by myringotomy. CONCLUSION: Our study findings suggest that the adenoid hyperthrophy is associated with increased negative pressure in the middle ear. We believe that it is necessary to perform the middle ear examination and tympanometry in children before adenoidectomy and in children without parental suspicion of hearing loss, even. PMID- 25547748 TI - [Provox 2 use for voice restoration after total laryngectomy]. AB - OBJECTIVES: This study aims to determine the problems of patients applied provox 2 voice prosthesis for speech rehabilitation with their prosthesis and our treatment modalities to increase the quality of life of these patients. PATIENTS AND METHODS: A total of 210 patients (180 males, 30 females; mean age 58+/-11.9 years; range 37 to 83 years) who underwent total laryngectomy, applied and changed provox 2 voice prosthesis for voice restoration were included in the study. For speech restoration of the patients with a primary (intraoperative) and secondary (postoperative) tracheoesophageal fistula was opened. In the 15th postoperative day, provox 2 voice prosthesis was placed to approximately 0.5 cm inferior and midline fistula line of the tracheostoma. The patients underwent speech exercises. RESULTS: The mean change time of prosthesis was 7.5 months (range 1 to 48 months). Fungal colonization was detected in 141 patients (66%) who had voice prostheses. Granulation tissue developed around the voice prosthesis in 30 patients (14%), three patients (1%) swallowed their voice prosthesis, tracheoesophageal fistula width remained permanently in two patients (1%), and these patients were abandoned to use their voice prosthesis. Mediastinitis occurred in one patient (1%). CONCLUSION: Due to several reasons such as success of high speech despite of complications and being easy to fight with these complications, provox voice prosthesis is an effective method to use for voice restoration. PMID- 25547749 TI - [A rare late complication of radiation therapy: bilaterally recurrent laryngeal nerve paralysis]. AB - Peripheral neuropathy is a late complication of radiation therapy, which is least and probably threatening. As it occurs many years after the remission is achieved with a usually irreversible clinical presentation, it significantly increases morbidity in cancer survivors and has an adverse effect on the quality of life. In this article, we report a 39-year-old male patient of bilateral recurrent laryngeal nerve paralysis which developed eight years after the treatment of stage T1b glottic laryngeal carcinoma with primary radiation therapy and was treated by transverse laser cordotomy. PMID- 25547750 TI - [Bilateral inverted papilloma originating from the frontal sinus]. AB - Inverted papilloma is a benign neoplasm characterized by its high rate of recurrence, local aggressiveness, and malignancy potential. Nasal obstruction is the most frequent presenting complaint. Bilateral inverted papillom involving both sides of the frontal sinus is extremely rare. Herein, we present a 64-year old male case with a bilateral inverted papilloma involving the frontal sinus which was removed by an endoscopic surgery. PMID- 25547751 TI - [Sphenoid sinus agenesis]. AB - Agenesis of paranasal sinuses is an uncommon finding mainly seen in the frontal and maxillary sinuses. Agenesis of sphenoid sinuses is an extremely rare condition. In this article, we present an 18-year-old female patient suffering from headache and nasal obstruction without any skeletal or cranial anomalies. Axial, coronal and sagittal computed tomography revealed absent sphenoid sinuses. Surgeons should be aware of sphenoid sinus agenesis, when transsphenoidal hypophysectomy and endoscopic sinus surgery are scheduled, in particular. PMID- 25547753 TI - Angiokeratoma of the nasal vestibule: a case report. AB - Angiokeratomas are benign mucocutaneous lesions which are composed of enlarged veins in the dermis of the skin. Although angiokeratomas may be part of a systemic disease, it is important to distinguish them from other vascular lesions. In this report, we present a rare case of angiokeratoma of the nasal vestibule. To our knowledge, this is the first nasal angiokeratoma case in the literature. The diagnostic and treatment features of this case and the association of angiokeratoma with systemic diseases like Fabry disease were discussed. PMID- 25547752 TI - Bifid inferior turbinate: a report of two cases. AB - Nasal turbinates are functionally important structures which extend from the lateral nasal walls to the nasal cavity. Lateral nasal wall anomalies are usually asymptomatic lesions which are incidentally detected. The most common variation of the lateral nasal wall is the pneumatization of turbinates. Anatomical variations of paranasal structures may present confusing intranasal landmarks. This may cause challenges in endoscopic sinus surgery. Bifid inferior turbinate is an extremely rare condition. In this article, we present two cases with bifid inferior turbinate. This variation should be kept in mind as a rare cause of nasal obstruction. PMID- 25547754 TI - Nasal type natural killer T-cell lymphoma involving nasooropharynx and larynx. AB - Lymphoma is one of the malignant non-squamous tumors involving the head and neck. Lymphomas in this region are mostly B-cell type in origin and usually seen in Waldeyer's ring. In this article, we report a 45-year-old female case of primary natural killer T cell lymphoma-nasal type involving the nasooropharynx and larynx. This is a very rare entity with poor prognosis. PMID- 25547755 TI - Concatenated alignments and the case of the disappearing tree. AB - BACKGROUND: Analyzed individually, gene trees for a given taxon set tend to harbour incongruent or conflicting signals. One popular approach to deal with this circumstance is to use concatenated data. But especially in prokaryotes, where lateral gene transfer (LGT) is a natural mechanism of generating genetic diversity, there are open questions as to whether concatenation amplifies or averages phylogenetic signals residing in individual genes. Here we investigate concatenations of prokaryotic and eukaryotic datasets to investigate possible sources of incongruence in phylogenetic trees and to examine the level of overlap between individual and concatenated alignments. RESULTS: We analyzed prokaryotic datasets comprising 248 invidual gene trees from 315 genomes at three taxonomic depths spanning gammaproteobacteria, proteobacteria, and prokaryotes (bacteria plus archaea), and eukaryotic datasets comprising 279 invidual gene trees from 85 genomes at two taxonomic depths: across plants-animals-fungi and within fungi. Consistent with previous findings, the branches in trees made from concatenated alignments are, in general, not supported by any of their underlying individual gene trees, even though the concatenation trees tend to possess high bootstrap proportions values. For the prokaryote data, this observation is independent of phylogenetic depth and sequence conservation. The eukaryotic data show much better agreement between concatenation and single gene trees. LGT frequencies in trees were estimated using established methods. Sequence length in individual alignments, but not sequence divergence, was found to correlate with the generation of branches that correspond to the concatenated tree. CONCLUSIONS: The weak correspondence of concatenation trees with single gene trees gives rise to the question where the phylogenetic signal in concatenated trees is coming from. The eukaryote data reveals a better correspondence between individual and concatenation trees than the prokaryote data. The question of whether the lack of correspondence between individual genes and the concatenation tree in the prokaryotic data is due to LGT or phylogenetic artefacts remains unanswered. If LGT is the cause of incongruence between concatenation and individual trees, we would have expected to see greater degrees of incongruence for more divergent prokaryotic data sets, which was not observed, although estimated rates of LGT suggest that LGT is responsible for at least some of the observed incongruence. PMID- 25547756 TI - Mammalian transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes and are predicted to act as transcriptional activator hubs. AB - BACKGROUND: Transcriptional hotspots are defined as genomic regions bound by multiple factors. They have been identified recently as cell type specific enhancers regulating developmentally essential genes in many species such as worm, fly and humans. The in-depth analysis of hotspots across multiple cell types in same species still remains to be explored and can bring new biological insights. RESULTS: We therefore collected 108 transcription-related factor (TF) ChIP sequencing data sets in ten murine cell types and classified the peaks in each cell type in three groups according to binding occupancy as singletons (low occupancy), combinatorials (mid-occupancy) and hotspots (high-occupancy). The peaks in the three groups clustered largely according to the occupancy, suggesting priming of genomic loci for mid occupancy irrespective of cell type. We then characterized hotspots for diverse structural functional properties. The genes neighbouring hotspots had a small overlap with hotspot genes in other cell types and were highly enriched for cell type specific function. Hotspots were enriched for sequence motifs of key TFs in that cell type and more than 90% of hotspots were occupied by pioneering factors. Though we did not find any sequence signature in the three groups, the H3K4me1 binding profile had bimodal peaks at hotspots, distinguishing hotspots from mono-modal H3K4me1 singletons. In ES cells, differentially expressed genes after perturbation of activators were enriched for hotspot genes suggesting hotspots primarily act as transcriptional activator hubs. Finally, we proposed that ES hotspots might be under control of SetDB1 and not DNMT for silencing. CONCLUSION: Transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes. In ES cells, they are predicted to act as transcriptional activator hubs and might be under SetDB1 control for silencing. PMID- 25547758 TI - ICF and neurorehabilitation. PMID- 25547757 TI - Social influences on adaptive criterion learning. AB - People adaptively shift decision criteria when given biased feedback encouraging specific types of errors. Given that work on this topic has been conducted in nonsocial contexts, we extended the literature by examining adaptive criterion learning in both social and nonsocial contexts. Specifically, we compared potential differences in criterion shifting given performance feedback from social sources varying in reliability and from a nonsocial source. Participants became lax when given false positive feedback for false alarms, and became conservative when given false positive feedback for misses, replicating prior work. In terms of a social influence on adaptive criterion learning, people became more lax in response style over time if feedback was provided by a nonsocial source or by a social source meant to be perceived as unreliable and low-achieving. In contrast, people adopted a more conservative response style over time if performance feedback came from a high-achieving and reliable source. Awareness that a reliable and high-achieving person had not provided their feedback reduced the tendency to become more conservative, relative to those unaware of the source manipulation. Because teaching and learning often occur in a social context, these findings may have important implications for many scenarios in which people fine-tune their behaviors, given cues from others. PMID- 25547759 TI - The use of ICF in the neurorehabilitation process. AB - INTRODUCTION: Rehabilitation is often described as a process that starts when the diagnosis is made and continues as long as the person needs interventions. This process comprises four steps: assessment, goal setting, interventions and outcome measurement. In each step, the WHO International Classification of Functioning, Disability and Health (ICF) can be used and the results can be summarized in a rehabilitation plan. OBJECTIVES: In this brief review, we describe the use of the ICF in the neurorehabilitation process in the form of an ICF based rehabilitation plan and how the rehabilitation plan can facilitate interdisciplinary team work in each of the four steps that comprise the rehabilitation process. CONCLUSION: An ICF based rehabilitation plan that comprises a common language, understood by team members, patients and their family, is a valuable tool in the rehabilitation of persons with injuries and diseases to the nervous system. The use of the ICF has thereby enabled the development of a common framework for our neurorehabilitation methodology, regardless of diagnosis or disability. PMID- 25547760 TI - Engaging with clinicians to implement and evaluate the ICF in neurorehabilitation practice. AB - INTRODUCTION: Although deemed a globally accepted framework, there remains scare evidence on the process and outcome of implementing the International Classification of Functioning, Disability and Health (ICF) within neurorehabilitation. OBJECTIVES: This review briefly explores the existing, broader literature and then reports on two action research projects, undertaken in England, specifically within stroke and neurorehabilitation. Working with participants, including clinicians from in-patient and community settings, there are now 35 different ways identified for the use of the ICF. CONCLUSION: The outcome of the first project highlights that using the ICF enhances communication within and beyond the acute stroke service, fosters holistic thinking and clarifies team roles. To adopt it into clinical practice, the ICF must be adapted to meet local service needs. The use of action research has facilitated the knowledge translation process which has enabled the ICF to become a clinical reality in neurorehabilitation, with clinicians identifying a range of potential uses. PMID- 25547761 TI - The ICF as a framework to collect and interpret data on the extent and variety of disability in neurological conditions. AB - INTRODUCTION: Neurological conditions are associated with high levels of disability. OBJECTIVES: The aim of this study was to describe, using the International Classification of Functioning, Disability and Health (ICF), the most relevant aspects of disability in patients with neurological conditions. We collated data from previous studies on myasthenia gravis, migraine, Parkinson's disease, multiple sclerosis, traumatic brain injury, stroke, epilepsy, vegetative state and minimally conscious state, and identified as relevant those ICF categories reported by at least 50% of patients in each condition. CONCLUSIONS: Records from 1310 patients were available. A total of 97 ICF categories were reported, and 21 were commonly addressed in more than five conditions. Approximately half of the categories in body functions were related to mental and movement-related functions and more than 25% of the activities-related categories involved activities that require the support from a caregiver. Environmental factors were mostly reported as facilitators. Our data indicate a residual mind body dichotomy, the relevance of disability not only for the patients but also for their caregivers, and the difficulties in addressing barriers in the environment. PMID- 25547762 TI - Pediatric neurorehabilitation and the ICF. AB - INTRODUCTION: One of the major intended uses of the International Classification of Functioning, Disability and Health (ICF) is the clinical world of rehabilitation. The intrinsic qualities of ICF, especially in its children and youth version (ICF-CY) seem to perfectly match the needs for the complex process of pediatric neurorehabilitation. OBJECTIVES: We here report on the effect that the implementation of ICF-CY had on team members and families when it was used as a guiding structure in framing the rehabilitation project in a pediatric outpatient clinic dealing with adolescents with cerebral palsy and complex needs. The two-year experience was positive and an ad-hoc questionnaire delivered to team members and families returned very positive remarks. CONCLUSION: The main messages coming from this experience is on the feasibility of the introduction of ICF-CY language and the bio-psycho-social model in the described setting and on the positive response by the stakeholders. PMID- 25547763 TI - Determinants of disability using count-based approaches to ICF-based definition of neurological disability. AB - INTRODUCTION: The aim of this study was to explore the most relevant determinants of severe disability in a heterogeneous sample of patients with neurological conditions. OBJECTIVES: We used data from previous studies on patients with myasthenia gravis (MG), migraine, Parkinson's disease (PD), multiple sclerosis, traumatic brain injury (TBI), stroke and epilepsy (349 patients, aged 18-74 years; mean 48.0, SD 11.7). We calculated count-based extension indexes to address severe disability, and hierarchical logistic regression to assess the association between severe disability, sociodemographic and health status information. CONCLUSIONS: Results show that sociodemographic variables played a minor role, while health state information was a stronger determinant of severe disability. Compared to the reference value of TBI patients, those with MG, PD and epilepsy had higher odds to have severe difficulties undertaking daily activities despite the presence of environmental factors. Our results contrast with those of previous studies, mostly derived from general populations, showing the different impact of clinical and sociodemographic variables. PMID- 25547764 TI - How are the activity and participation aspects of the ICF used? Examples from studies of people with intellectual disability. AB - INTRODUCTION: Interdisciplinary differences regarding understanding the International Classification of Functioning, Disability and Health (ICF) concepts activity/participation may hinder its unifying purpose. In the ICF model, functioning (and disability) is described as a tripartite concept: 1) Body structures/functions, 2) Activities, and 3) Participation. Activities refer to an individual perspective on disability that does not tally with the basic structure of social models. OBJECTIVE: To review how activity and participation are actually used in studies of intellectual disability (ID). CONCLUSION: Based on 16 papers, four different usages of activity/participation were found. 1) Theoretical reference to tripartite ICF concept with attempts to use it. 2) Theoretical reference to tripartite ICF concept without actual use of activities. 3) "Atheoretical" approach with implicit focus on participation. 4) Theoretical reference to bipartite concept with corresponding use of terms. The highlighted studies have in common a focus on participation. However, the usage of the term "activity" differs both within and between studies. Such terminology will probably confuse interdisciplinary communication rather than facilitating it. Also, the use of an explicit underlying theory differs, from references to a tripartite to references to a bipartite concept of disability. This paper is focused on ID, but the discussed principles regarding the ICF and interdisciplinary disability theory are applicable to other diagnostic groups within rehabilitation practices. PMID- 25547765 TI - Rehabilitation of traumatic brain injury in the light of the ICF. AB - INTRODUCTION: Traumatic brain injury is a sudden and unexpected condition that gives rise to different impairments in body functions and structures leading to dramatic life changes, not only to the patient but also to his or her family and ultimately in the wider society. As a health strategy, rehabilitation aims to reduce disability and increasing the quality of life of those people that suffer from TBI but also to reduce the social burden associated with it. Functioning is the starting point of rehabilitation and the use of measurement instruments and classifications are commonly used tools for its definition. Within the endorsement of the ICF by WHO, there is now a classification and a conceptual framework for the description of functioning providing an opportunity of a full understanding of the experience of TBI. OBJECTIVE: This paper aims to identify the utility of ICF in TBI as well as bringing new challenges for further clinical practice and research. CONCLUSIONS: ICF has shown itself to be useful in the content comparison of measurement instruments. It has also been used to describe the functional profile of individuals with TBI in both acute and chronic phases making it possible to draw comparisons across other health conditions. Furthermore, the development of the TBI ICF Core Sets provided an item bank to describe not only functional status but also to set goals and plan interventions. Overall, we now have a potentially useful tool in rehabilitation of TBI that allows us to understand the full burden of traumatic brain injury. PMID- 25547766 TI - Dry needling for the treatment of poststroke muscle spasticity: a prospective case report. AB - BACKGROUND: Spasticity is a common symptom that can be detrimental to the quality of life and daily function of patients with stroke. OBJECTIVE: To introduce the use of dry needling (DN) as a novel method for the treatment of affected upper limb spasticity in a patient with chronic ischemic stroke who was admitted at the Stroke Physiotherapy Clinic. METHODS: The pronator teres (PT), flexor carpi radialis (FCR), and flexor carpi ulnaris (FCU) on the affected side were needled. The patient received deep DN for 1 session, and the duration of needling for each muscle was 1 minute. The main outcomes were the Modified Modified Ashworth Scale (MMAS) muscle spasticity score, and the Hmax/Mmax ratio which were measured before (T0), immediately after (T1), and 15 minutes after the end of needling (T2). RESULTS: The case was a 53-year-old man with a 13-year history of right hemiparesis poststroke. After DN, the spasticity scores improved and maintained as indicated in the MMAS grades (PT 3 to 2, finger flexors 1 to 0) and the Hmax/Mmax ratio (0.39, 0. 29, and 0.32 at T0, T1, and T2, respectively). The patient was able to voluntarily extend the wrist and fingers slightly after DN. The upper limb Brunnstrom recovery stage (3 to 4) and hand function (2 to 3) improved and maintained. The passive supination increased at T1 (75 degrees ) and T2 (50 degrees ) compared to T0 (38 degrees ). CONCLUSIONS: This prospective case report presents dry needling as a novel method in neurorehabilitation for the treatment of poststroke spasticity. Further research is recommended. PMID- 25547767 TI - A single blind, clinical trial to investigate the effects of a single session extracorporeal shock wave therapy on wrist flexor spasticity after stroke. AB - BACKGROUND: Spasticity is a common, serious symptom after stroke. Extracorporeal shock wave therapy (ESWT) has been suggested for the treatment of muscle spasticity. OBJECTIVE: To investigate the effects of ESWT on post stroke wrist flexor spasticity. METHODS: Fifteen patients with poststroke wrist flexor spasticity (12 male and 3 female with a mean age of 54 years) were enrolled. Patients received 1 sham ESWT followed by 1 active ESWT 1 week later. The outcome measures were the Modified Modified Ashworth Scale (MMAS), the Hmax/Mmax ratio, and the Brunnstrom motor recovery stage. RESULTS: The sham ESWT had not effects on the outcome measures. After active ESW, the MMAS scores of spasticity and the Hmax/Mmax ratio improved. The improvements were maintained 5 weeks after active ESWT. No significant improvements were observed for the motor recovery after sham or active ESWT. CONCLUSIONS: In adult patients after stroke, a single session of active ESWT resulted in significant improvement in the wrist flexor spasticity and alpha motor neuron excitability. PMID- 25547768 TI - Long-term effects of contralesional rTMS in severe stroke: safety, cortical excitability, and relationship with transcallosal motor fibers. AB - BACKGROUND: Contralesional hemispheric repetitive transcranial magnetic stimulation (rTMS) may improve motor function in mild to moderate stroke and effects are considered to be mediated through transcallosal motor fibers. OBJECTIVE: This study aimed to investigate the safety of contralesional rTMS in a selected group of severe chronic stroke patients. METHODS: Ten sessions of 1 Hz rTMS were applied to contralesional primary motor cortex (M1) using neuronavigated stimulation and changes in motor impairment were evaluated before, during and after rTMS applications and at 4-weeks follow-up. Neurophysiological response to stimulation was assessed through cortical excitability evaluations. The relationship between functional and neurophysiological response to rTMS and microstructural integrity of transcallosal motor fibers were searched using diffusion tensor imaging (DTI) based fractional anisotropy (FA). RESULTS: rTMS was well-tolerated with high compliance and no dropouts; no seizures or motor worsening occurred. Transcallosal FA values revealed a positive linear relationship with the mild motor improvement detected after rTMS while higher FA values were observed in subjects with better motor outcome. Cortical excitability showed a significant change in contralesional short-interval intracortical inhibition indicating altered plasticity following rTMS. CONCLUSIONS: Our results suggest that noninvasive neuromodulation of the contralesional hemisphere may present a possibility to assist adaptive neuroplastic changes in severe chronic stroke. Implementation of DTI-derived measures of transcallosal microstructural integrity may allow for individually-tailored interventions to guide processes of interhemispheric neuroplasticity. Further research is warranted to establish the clinical value of these findings in neurorehabilitation settings for subjects with chronic severe stroke. PMID- 25547769 TI - Gait parameters predicted by Timed Up and Go performance in stroke patients. AB - BACKGROUND: The Timed Up and Go (TUG) is a test of functional mobility which is routinely used in the assessment of hemiparetic patients. This easy and rapid to perform test includes motor tasks which occur frequently in daily life (stand up, walk, turn, sit down). Correlations between TUG performance and kinematic and kinetic gait parameters have never been studied. OBJECTIVE: The aim of this study was to determine whether kinematic and kinetic gait parameters would be more related to TUG performance than spatio-temporal parameters in stroke patients. METHODS: Sixty hemiparetic patients able to walk alone performed the TUG test and underwent 3D gait analysis and a clinical evaluation. A stepwise regression analysis was used to select the gait variables that best explained the variability in TUG performance. RESULTS: The percentage of the gait cycle spent in single support phase on the paretic limb was the factor which was the most predictive and correlated with TUG performance, explaining 67% of the variance. No kinematic or kinetic gait parameters explained TUG performance. The results also suggested that TUG performance is mainly related to paretic lower limb motor function. CONCLUSIONS: TUG performance in hemiparetic patients mainly depends on the motor ability of the paretic lower limb, particularly the single support phase on the paretic side. Kinematic and kinetic gait parameters do not predict the TUG performance in stroke patients. PMID- 25547770 TI - Robotic gait training improves motor skills and quality of life in hereditary spastic paraplegia. AB - BACKGROUND: Gait impairment, balance problems and falls have a negative impact on independence in ADL and quality of life of patients affected by Hereditary Spastic Paraplegia (HSP). Since no pharmacological options are available, treatments rely mostly on rehabilitation therapy, although almost no data on this topic exist. Given the demonstrated effectiveness of robotics in improving gait and balance in various neurological diseases, aim of this study is to test the effectiveness of a robotic-aided program of gait training on balance, walking ability and quality of life in adult subjects affected by uncomplicated HSP. METHODS: Thirteen patients affected by uncomplicated HSP were subjected to a six week robotic-aided gait training protocol. Participants underwent a battery of 3 walking test, 1 balance test and 2 quality of life questionnaires. RESULTS: At the end of the treatment a significant improvement of balance, walking ability and quality of life was observed in almost all the tests. The improvements were maintained over a two-month follow-up period. CONCLUSIONS: Our study indicates that a robotic gait training is long term effective in improving balance and walking ability with a positive impact on quality of life in patients affected by uncomplicated form of HSP. As currently there is no specific treatment to prevent or reverse HSP progression, our contribution would be significant for the development of exercise recommendations in this rare disease. PMID- 25547771 TI - Effects on facial dysfunction and swallowing capacity of intraoral stimulation early and late after stroke. AB - BACKGROUND: Most patients with post-stroke dysphagia are also affected by facial dysfunction in all four facial quadrants. Intraoral stimulation can successfully treat post-stroke dysphagia, but its effect on post-stroke facial dysfunction remains unknown. OBJECTIVE: This study aimed to investigate whether intraoral stimulation after stroke has simultaneous effects on facial dysfunction in the contralateral lower facial quadrant and in the other three facial quadrants, on lip force, and on dysphagia. METHODS: Thirty-one stroke patients were treated with intraoral stimulation and assessed with a facial activity test, lip force test, and swallowing capacity test at three time-points: before treatment, at the end of treatment, and at late follow-up (over one year after the end of treatment). RESULTS: Facial activity, lip force, and swallowing capacity scores were all improved between baseline and the end of treatment (P < 0.001 for each), with these improvements remaining at late follow-up. Baseline and treatment data did not significantly differ between patients treated short and late after stroke. CONCLUSIONS: Treatment with intraoral stimulation significantly improved post-stroke dysfunction in all four facial quadrants, swallowing capacity, and lip force even in cases of long-standing post-stroke dysfunction. Furthermore, such improvement remained for over one year after the end of treatment. PMID- 25547772 TI - Body weight support during robot-assisted walking: influence on the trunk and pelvis kinematics. AB - BACKGROUND: Efficacy studies concerning robot assisted gait rehabilitation showed limited clinical benefits. A changed kinematic pattern might be responsible for this. Little is known about the kinematics of the trunk and pelvis during robot assisted treadmill walking (RATW). OBJECTIVE: The aim of this study was to assess the trunk and pelvis kinematics of healthy subjects during RATW, with different amounts of body weight support (BWS) compared to regular treadmill walking (TW). METHOD: Eighteen healthy participants walked on a treadmill, while kinematics were registered by an electromagnetic tracking device. Hereafter, the kinematics of pelvis and trunk were registered during RATW (guidance force 30%) with 0%, 30% and 50% BWS. RESULTS: Compared to TW, RATW showed a decrease in the following trunk movements: axial rotation, anteroposterior flexion, lateral and anteroposterior translation. Besides, a decrease in lateral tilting and all translation of the pelvis was found when comparing RATW with TW. Furthermore, the anteroposterior tilting of the pelvis increased during RATW. CONCLUSION: In general, there was a decrease in trunk and pelvis movement amplitude during RATW compared with regular TW. Though, it is not known if these changes are responsible for the limited efficacy of robot assisted gait rehabilitation. Further research is indicated. PMID- 25547773 TI - Therapeutic effect of repetitive magnetic stimulation combined with speech and language therapy in post-stroke non-fluent aphasia. AB - OBJECTIVE: To investigate the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS) and speech and language therapy (SLT) on the improvement of performance on the Korean-version of the Western Aphasia Battery (K-WAB) in post-stroke non-fluent aphasic patients. METHODS: Twenty post-stroke, non-fluent aphasic patients were enrolled and assigned to one of two groups: a case group (n = 10) or a control group (n = 10). Participants were recruited from the inpatient clinic of the Physical and Rehabilitation Medicine Department of Bundang Jesaeng General Hospital from March 2011 to January 2012. The case group received rTMS and SLT and the control group received SLT; both groups received these therapies for four weeks. Language functioning was evaluated using K-WAB before and after treatment. RESULTS: There were no significant differences between the groups' baseline characteristics and initial values (p > 0.05). After four weeks of therapy, there were significant improvements in repetition and naming in the case group (p < 0.05). However, there was no significant improvement in the control group (p > 0.05). CONCLUSIONS: rTMS combined with SLT can be an effective therapeutic method for treating aphasia in post-stroke non fluent aphasic patients, although additional controlled and more systemic studies should be conducted. PMID- 25547774 TI - Dysarthria and dysphagia in Amyotrophic Lateral Sclerosis with spinal onset: a study of quality of life related to swallowing. AB - BACKGROUND: Dysarthria and dysphagia are the most common clinical problems encountered in Amyotrophic Lateral Sclerosis and may reduce the quality of life. OBJECTIVE: Evaluate the association of dysarthria and dysphagia and to evaluate the impact of dysphagia on swallowing quality of life in patients with ALS with spinal onset. METHODS: Seventeen patients underwent to speech and swallowing evaluation and filled out self-report assessment of the Swallowing Quality of Life (SWAL-QOL). The dysarthria severity was graded using the Speech Subscale of ALS Severity Scale. The dysphagia severity was graded using a scale proposed by Dziweas et al., and the Functional Oral Intake Scale. RESULTS: Over 70% of the ALS patients with spinal onset had dysarthria and dysphagia. The correlation of dysarthria and dysphagia scales was statistically significant (p < 0.001). The correlation between dysarthria and dysphagia severity and SWAL-QOL outcomes was significant for the same domains: "symptom frequency", "communication" and "fear of eating". The SWAL-QOL domains presented a mild to moderate impact on quality of life. Disease duration did not impact on SWAL-QOL. CONCLUSIONS: Dysarthria and dysphagia were common symptoms in patients with spinal onset of ALS and the swallowing quality of life decrease was directly related to with severity of dysarthria and dysphagia. PMID- 25547775 TI - A pilot study on behavioral and cognitive effects of Cognitive Stimulation Training based on 3R Mental Stimulation. The Treviso Dementia (TREDEM) Study. AB - OBJECTIVES: Cognitive Stimulation (CS) trainings are non-pharmacological treatments widely used in dementia care. 3R Mental Stimulation is a particular type of CS, which consists of sequential association of ROT, Reminiscence and Remotivation during the same session. This pilot study sought to investigate whether CS, based on 3R program, could benefit cognitive functions, autonomy and behavioral disorders. METHOD: 3R-CS treatment was applied to 36 patients, which are part of the "TREDEM" study sample, and their caregivers. All patients received a multidimensional assessment consisting of a socio-demographic, clinical and neuropsychological data collection. RESULTS: After CS treatment a significant improvement was detected in cognition and autonomy in basic activities of daily living. Caregiver distress was decreased. Behavioral disturbances were reduced even when considering a potential confounding factor such as treatment with anticholinesterase or NMDA receptor antagonist drugs. CONCLUSION: The findings demonstrated that 3R-CS can benefit cognitive functions and level of autonomy in the basic activities of daily living and also it can reduce behavioral disorders and caregiver's distress. PMID- 25547777 TI - Experienced usability of assistive technology for cognitive support with respect to user goals. AB - BACKGROUND: Studies have shown that Assistive Technology (AT) for cognitive support can support users in everyday activities. However, whether the AT actually supports the user to achieve their individual goals must further be examined. OBJECTIVE: The study objective was to examine the experienced usability of features in AT for cognitive support for users with cognitive impairment. METHODS: A content analysis was applied on data from interviews and field notes collected during two six-month interventions in which persons with cognitive impairment tested AT for cognitive support. RESULTS: Features, included in the AT support that enhanced the user's sense of control, were identified as promotional for the achievement of user goals, and some features, such as reminders, were more sensitive to the specific user's perceptions and motives. Also, features related to how the AT was maintained and communicated with other technology were very influential. CONCLUSIONS: The results show that easily maintained AT that fits in to the context of use increases the user's sense of control of the AT and thereby promotes the goal achievement and usability of the AT. Further, the usability of the AT is very influenced by contextual factors such as the ordinary mobile network, the Internet, and the operators. PMID- 25547778 TI - Overcoming treatment resistance in chronic depression: a pilot study on outcome and feasibility of the cognitive behavioral analysis system of psychotherapy as an inpatient treatment program. AB - BACKGROUND: The Cognitive Behavioral Analysis System of Psychotherapy (CBASP), initially developed as an outpatient treatment for chronic depression (CD), has been adapted as a multidisciplinary 12-week inpatient program for CD. METHODS: Seventy inpatients with CD and treatment resistance were included in a noncontrolled trial. The Hamilton Depression Rating Scale served as the primary outcome measure. Prospective naturalistic follow-up assessments were conducted 6 and 12 months after discharge. RESULTS: Dropout rate was 7.1%; 90.4% perceived the program as helpful. Pre-post comparisons yielded strong effect sizes; 75.7% of the intention-to-treat sample responded, and 40.0% remitted. Nonremission was associated with experiencing temporary deterioration of symptoms during treatment. After 6 months 75.0% and after 12 months 48.0% of patients sustained response. CONCLUSIONS: The CBASP program appears as a feasible acute treatment for treatment-resistant CD inpatients with promising outcome. However, the continuation of treatment after discharge should be optimized especially for patients with subjective deterioration during treatment. PMID- 25547776 TI - Feasibility of using high-definition transcranial direct current stimulation (HD tDCS) to enhance treatment outcomes in persons with aphasia. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) enhances treatment outcomes post-stroke. Feasibility and tolerability of high-definition (HD) tDCS (a technique that increases current focality and intensity) for consecutive weekdays as an adjuvant to behavioral treatment in a clinical population has not been demonstrated. OBJECTIVE: To determine HD-tDCS feasibility outcomes: 1) ability to implement study as designed, 2) acceptability of repeated HD-tDCS administration to patients, and 3) preliminary efficacy. METHODS: Eight patients with chronic post-stroke aphasia participated in a randomized crossover trial with two arms: conventional sponge-based (CS) tDCS and HD-tDCS. Computerized anomia treatment was administered for five consecutive days during each treatment arm. RESULTS: Individualized modeling/targeting procedures and an 8-channel HD tDCS device were developed. CS-tDCS and HD-tDCS were comparable in terms of implementation, acceptability, and outcomes. Naming accuracy and response time improved for both stimulation conditions. Change in accuracy of trained items was numerically higher (but not statistically significant) for HD-tDCS compared to CS tDCS for most patients. CONCLUSIONS: Regarding feasibility, HD-tDCS treatment studies can be implemented when designed similarly to documented CS-tDCS studies. HD-tDCS is likely to be acceptable to patients and clinicians. Preliminary efficacy data suggest that HD-tDCS effects, using only 4 electrodes, are at least comparable to CS-tDCS. PMID- 25547779 TI - Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target. AB - INTRODUCTION: Fibroblast growth factor 19 (FGF19) is a member of the hormone-like FGF family and has activity as an ileum-derived postprandial hormone. It shares high binding affinity with beta-Klotho and together with the FGF receptor (FGFR) 4, is predominantly targeted to the liver. The main function of FGF19 in metabolism is the negative control of bile acid synthesis, promotion of glycogen synthesis, lipid metabolism and protein synthesis. AREAS COVERED: Drawing on in vitro and in vivo studies, this review discusses FGF19 and some underlying mechanisms of action of FGF19 as an endocrine hormone in several liver diseases. The molecular pathway of the FGF19-FGFR4 axis in non-alcoholic liver disease and hepatocellular carcinoma are discussed. Furthermore, definition of function and pharmacological effects of FGF19 for liver disease are also presented. EXPERT OPINION: A series of studies have highlighted a crucial role of FGF19 in liver disease. However, the conclusions of these studies are partly paradoxical and controversial. An understanding of the underlying biological mechanisms which may explain inconsistent findings is especially important for consideration of potential biomarker strategies and an exploration of the putative therapeutic efficacy of FGF19 for human liver disease. PMID- 25547781 TI - Intermittent hypoxic resistance training: is metabolic stress the key moderator? AB - Traditionally, researchers and practitioners have manipulated acute resistance exercise variables to elicit the desired responses to training. However, recent research indicates that altering the muscular environment during resistance training, namely by implementing a hypoxic stimulus, can augment muscle hypertrophy and strength. Intermittent hypoxic resistance training (IHRT), whereby participants inspire hypoxic air during resistance training, has been previously demonstrated to increase muscle cross-sectional area and maximum strength by significantly greater amounts than the equivalent training in normoxia. However, some recent evidence has provided conflicting results, reporting that the use of systemic hypoxia during resistance training provided no added benefit. While the definitive mechanisms that may augment muscular responses to IHRT are not yet fully understood, an increased metabolic stress is thought to be important for moderating many downstream processes related to hypertrophy. It is likely that methodological differences between conflicting IHRT studies have resulted in different degrees of metabolic stress during training, particularly when considering the inter-set recovery intervals used. Given that the most fundamental physiological stresses resulting from hypoxia are disturbances to oxidative metabolism, it becomes apparent that resistance training may only benefit from additional hypoxia if the exercise is structured to elicit a strong metabolic response. We hypothesize that for IHRT to be more effective in producing muscular hypertrophy and increasing strength than the equivalent normoxic training, exercise should be performed with relatively brief inter-set recovery periods, with the aim of providing a potent metabolic stimulus to enhance anabolic responses. PMID- 25547780 TI - Differential expression profile of Th1/Th2-associated chemokines characterizes Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) as distinct entities. PMID- 25547782 TI - Molecular imaging of carotid plaque vulnerability. AB - BACKGROUND: Carotid endarterectomy (CEA) has been shown to be beneficial in patients with high-grade symptomatic carotid artery stenosis. Patients with high grade asymptomatic stenosis may only exceptionally benefit from CEA during periods of increased plaque vulnerability. Imaging modalities to characterize unstable, vulnerable plaques are strongly needed for better risk stratification in these patients. SUMMARY: Contrast-enhanced ultrasound (CEUS) is a novel and noninvasive technique capable to identify several surrogate markers of vulnerable carotid plaques. The use of specific ultrasound microbubbles allows a reliable detection of microulcerations due to an optimized visualization of the plaque lumen border. As microbubbles are strictly intravascular tracers, the detection of individual microbubbles within the plaque corresponds to intraplaque neovessels. The accuracy of CEUS in the visualization of newly formed microvessels has been confirmed in histological studies on carotid endarterectomy specimens. Together with the formation of adventitial vasa vasorum, intraplaque neovascularization is a strong predictor for symptomatic disease. The phenomenon of late phase contrast enhancement is based on the adherence of microbubble containing monocytes on inflamed endothelium. Recent studies suggest that late phase contrast enhancement may reflect endothelial inflammation or activation within carotid plaques. The development of conjugated microbubbles that bind to specific ligands such as thrombotic material or neovessels has led to the term 'molecular imaging'. CEUS with microbubbles targeted to P-selectin and VCAM-1, key molecules in leukocyte trafficking, was used to detect an inflammatory plaque phenotype, whereas microbubbles coupled to the VEGF-receptor may allow for a detection of neovascularization. Even though imaging with targeted microbubbles is yet in an experimental stage, this technique can visualize active plaque reorganization with increased vulnerability leading to generation of arterio arterial embolism. Key Messages: The use of contrast-enhanced ultrasound can be recommended to assess atherosclerotic carotid lesions at risk for rupture. Prospective clinical studies are needed to validate the use of CEUS in patients with high risks of recurrent large artery strokes. In particular, this applies to the detection of intraplaque neovascularization, a well-established marker in preclinical and observational studies, while the clinical significance of late phase contrast enhancement still needs to be determined.. PMID- 25547783 TI - Labile capping bonds in lanthanide(III) complexes: shorter and weaker. AB - For a wide range of trivalent lanthanide ion coordination complexes of tricapped trigonal prism or monocapped square antiprism configurations, the bonds between the central lanthanide ions and the capping ligands are found to violate Badger's rule: they can get weaker as they get shorter. We demonstrate that this observation originates from the screening and repulsion effect of the prism ligands. Both effects enhance as the electric field of the central ion or the softness of the prism ligands increases. Thus, for heavier lanthanides, despite the fact that the capping bond could be shorter, it is more efficient to be weakened by the prism ligands, being inherently labile. This concept of "labile capping bonds phenomenon" is then successfully used to interpret many problems in lanthanide(III) hydration, e.g., why the water exchange rate of a lanthanide(III) complex is much higher in a twisted square antiprism than in square antiprism configuration. Thus, the theory proposed in this paper offers new insights in understanding chemical problems. PMID- 25547784 TI - [Buruli ulcer in the health districts of the Democratic Republic of Congo from 1950 to 2013: literature review and new distribution map]. AB - This paper describes the current distribution of cases of Buruli ulcer (BU) by highlighting health districts that are endemic and suspected to be endemic, based on the studies, surveys, and activity reports published from 1950 to 2013. We define as endemic any health district with BU patients positive by PCR, whether or not positive on a Ziehl-Neelsen (ZN) test, culture or histologic sample. A district is defined as suspected to be endemic when it is a historical BU area, has BU clinical cases and/or patients with positive ZN, but negative PCR. Of the 515 health districts in the DRC, 17 were found to be endemic (3%) and 26 suspected to be endemic (5%). In most cases, former focal areas, described before 1974, remain currently active. New focal points were found along the Kwango River in the province of Bandundu. We also discovered the extension of former BU focal areas to neighboring health districts in the provinces of Bas-Congo, Bandundu, and Maniema. The need for diagnostic confirmation by PCR appears to be a requirement and a priority, not only in all former historical focal areas but also in the health districts newly suspected to be endemic. PMID- 25547785 TI - Reproductive toxicity to male mice of nose only exposure to water- pipe smoke. AB - BACKGROUND/AIMS: Water-pipe smoking (WPS) is popular in the Middle East and is starting to gain popularity in several Western countries as well. It is widely and erroneously perceived to be less harmful than other forms of tobacco use. The reproductive adverse effects of cigarette smoking have been studied before with conflicting results, but data on the possible adverse reproductive effects of WPS are lacking. Here, we assessed the effects of nose-only exposure to mainstream WPS generated by commercially available honey-flavored "moasel" tobacco in mice. METHODS: The duration of the session was 30 min/day for one month. Control mice were exposed to air. Twenty-four h after the last exposure, mice were killed and the testes and plasma removed for analysis. In testicular homogenates total protein, alkaline phosphatase activity, several indices of oxidative damage and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) were quantified. The plasma concentrations of leptin, testosterone, estrogen and luteinizing hormone (LH) were also measured. Histological analysis of testes and lungs was also conducted. RESULTS: WPS caused statistically significant decreases in the plasma concentrations of leptin, testosterone, and LH, and in the concentrations of total protein and the antioxidant indices measured. A statistically non significant decrease in VEGFR2 protein in the WPS--exposed mice compared to the control mice was also found. The body and testicular weights of mice exposed to WPS, as well as their testicular alkaline phosphatase activity and light microscopic histology, and plasma estrogen concentration were all not significantly affected by WPS. CONCLUSION: Further studies on the functional implications of these findings in mice exposed to WPS for longer durations are warranted. PMID- 25547786 TI - Comparison of levofloxacin- and moxifloxacin-based triple therapies with standard treatment in eradication of Helicobacter pylori as first-line therapy. AB - AIM: It is recommended that treatments that include clarithromycin should be avoided in eradication of Helicobacter pylori (HP) in cases where clarithromycin resistance is higher than 20%. We aimed to compare levofloxacin- and moxifloxacin based triple therapies with standard treatment and with each other in eradication of helicobacter pylori as first-line therapy. MATERIALS AND METHODS: Patients were randomized prospectively as three groups. There were 102 patients in the levofloxacin group, 101 patients in the moxifloxacin group, and 103 patients in the standard treatment group. The patients received levofloxacin 500 mg daily, amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. for ten days (LAL) in the levofloxacin group; moxifloxacin 400 mg daily, amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. (MAL) in the moxifloxacin group; and clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. (CAL) in the standard treatment group. At post-treatment week 6, HP was checked by using stool antigen test. RESULTS: In the eradication of Helicobacter pylori, the success rate as determined by per protocol (PP) analysis was 92% in the LAL group, 91.8% in the MAL group, and 82.4% in the CAL group. A statistically significant difference was found in the LAL and MAL groups compared to the CAL group (p < 0.05). There was no difference between the LAL and MAL groups. CONCLUSIONS: It was determined that levofloxacin- and moxifloxacin-based triple therapies were more effective than the standard treatment in first-line setting in the eradication of Helicobacter pylori. In addition, no difference was found between levofloxacin- and moxifloxacin-based triple therapies. Currently observed high efficacy may be evaluated in treatment. Although quinolon resistance is not considered a major problem, it appears to be a factor that may reduce treatment success over a period of time. PMID- 25547787 TI - Cloning and expression of a novel prolyl endopeptidase from Aspergillus oryzae and its application in beer stabilization. AB - A novel prolyl endopeptidase gene from Aspergillus oryzae was cloned and expressed in Pichia pastoris. Amino acid sequence analysis of the prolyl endopeptidase from Aspergillus oryzae (AO-PEP) showed that this enzyme belongs to a class serine peptide S28 family. Expression, purification and characterization of AO-PEP were analyzed. The optimum pH and temperature were pH 5.0 and 40 degrees C, respectively. The enzyme was activated and stabilized by metal ion Ca(2+) and inhibited by Zn(2+), Mn(2+), Al(3+), and Cu(2+). The K m and k cat values of the purified enzyme for different substrates were evaluated. The results implied that the recombinant AO-PEP possessed higher affinity for the larger substrate. A fed-batch strategy was developed for the high-cell-density fermentation and the enzyme activity reached 1,130 U/l after cultivation in 7 l fermentor. After addition of AO-PEP during the fermentation phase of beer brewing, demonstrated the potential application of AO-PEP in the non-biological stability of beer, which favor further industrial development of this new enzyme in beer stabilization, due to its reducing operational costs, as well as no beer losses unlike regeneration process and beer lost with regenerated polyvinylpolypyrrolidone system. PMID- 25547788 TI - Monkey models of tuberculosis: lessons learned. AB - The use of animal models has been invaluable for studying the pathogenesis of Mycobacterium tuberculosis infection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. Among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. As such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. This review focuses on published major studies which illustrate how the rhesus and cynomolgus macaques have enriched and may continue to advance the field of global tuberculosis research. PMID- 25547789 TI - Nuclease activity of Legionella pneumophila Cas2 promotes intracellular infection of amoebal host cells. AB - Legionella pneumophila, the primary agent of Legionnaires' disease, flourishes in both natural and man-made environments by growing in a wide variety of aquatic amoebae. Recently, we determined that the Cas2 protein of L. pneumophila promotes intracellular infection of Acanthamoeba castellanii and Hartmannella vermiformis, the two amoebae most commonly linked to cases of disease. The Cas2 family of proteins is best known for its role in the bacterial and archeal clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein (Cas) system that constitutes a form of adaptive immunity against phage and plasmid. However, the infection event mediated by L. pneumophila Cas2 appeared to be distinct from this function, because cas2 mutants exhibited infectivity defects in the absence of added phage or plasmid and since mutants lacking the CRISPR array or any one of the other cas genes were not impaired in infection ability. We now report that the Cas2 protein of L. pneumophila has both RNase and DNase activities, with the RNase activity being more pronounced. By characterizing a catalytically deficient version of Cas2, we determined that nuclease activity is critical for promoting infection of amoebae. Also, introduction of Cas2, but not its catalytic mutant form, into a strain of L. pneumophila that naturally lacks a CRISPR-Cas locus caused that strain to be 40- to 80-fold more infective for amoebae, unequivocally demonstrating that Cas2 facilitates the infection process independently of any other component encoded within the CRISPR-Cas locus. Finally, a cas2 mutant was impaired for infection of Willaertia magna but not Naegleria lovaniensis, suggesting that Cas2 promotes infection of most but not all amoebal hosts. PMID- 25547790 TI - Nonbinding site-directed mutants of transferrin binding protein B exhibit enhanced immunogenicity and protective capabilities. AB - Host-adapted Gram-negative bacterial pathogens from the Pasteurellaceae, Neisseriaceae, and Moraxellaceae families normally reside in the upper respiratory or genitourinary tracts of their hosts and rely on utilizing iron from host transferrin (Tf) for growth and survival. The surface receptor proteins that mediate this critical iron acquisition pathway have been proposed as ideal vaccine targets due to the critical role that they play in survival and disease pathogenesis in vivo. In particular, the surface lipoprotein component of the receptor, Tf binding protein B (TbpB), had received considerable attention as a potential antigen for vaccines in humans and food production animals but this has not translated into the series of successful vaccine products originally envisioned. Preliminary immunization experiments suggesting that host Tf could interfere with development of the immune response prompted us to directly address this question with site-directed mutant proteins defective in binding Tf. Site directed mutants with dramatically reduced binding of porcine transferrin and nearly identical structure to the native proteins were prepared. A mutant Haemophilus parasuis TbpB was shown to induce an enhanced B-cell and T-cell response in pigs relative to native TbpB and provide superior protection from infection than the native TbpB or a commercial vaccine product. The results indicate that binding of host transferrin modulates the development of the immune response against TbpBs and that strategies designed to reduce or eliminate binding can be used to generate superior antigens for vaccines. PMID- 25547791 TI - Reassessment of the role of aromatic amino acid hydroxylases and the effect of infection by Toxoplasma gondii on host dopamine. AB - Toxoplasma gondii infection has been described previously to cause infected mice to lose their fear of cat urine. This behavioral manipulation has been proposed to involve alterations of host dopamine pathways due to parasite-encoded aromatic amino acid hydroxylases. Here, we report successful knockout and complementation of the aromatic amino acid hydroxylase AAH2 gene, with no observable phenotype in parasite growth or differentiation in vitro and in vivo. Additionally, expression levels of the two aromatic amino acid hydroxylases were negligible both in tachyzoites and in bradyzoites. Finally, we were unable to confirm previously described effects of parasite infection on host dopamine either in vitro or in vivo, even when AAH2 was overexpressed using the BAG1 promoter. Together, these data indicate that AAH enzymes in the parasite do not cause global or regional alterations of dopamine in the host brain, although they may affect this pathway locally. Additionally, our findings suggest alternative roles for the AHH enzymes in T. gondii, since AAH1 is essential for growth in nondopaminergic cells. PMID- 25547793 TI - New role for human alpha-defensin 5 in the fight against hypervirulent Clostridium difficile strains. AB - Clostridium difficile infection (CDI), one of the most common hospital-acquired infections, is increasing in incidence and severity with the emergence and diffusion of hypervirulent strains. CDI is precipitated by antibiotic treatment that destroys the equilibrium of the gut microbiota. Human alpha-defensin 5 (HD5), the most abundant enteric antimicrobial peptide, is a key regulator of gut microbiota homeostasis, yet it is still unknown if C. difficile, which successfully evades killing by other host microbicidal peptides, is susceptible to HD5. We evaluated, by means of viability assay, fluorescence-activated cell sorter (FACS) analysis, and electron microscopy, the antimicrobial activities of alpha-defensins 1 and 5 against a panel of C. difficile strains encompassing the most prevalent epidemic and hypervirulent PCR ribotypes in Europe (012, 014/020, 106, 018, 027, and 078). Here we show that (i) concentrations of HD5 within the intestinal physiological range produced massive C. difficile cell killing; (ii) HD5 bactericidal activity was mediated by membrane depolarization and bacterial fragmentation with a pattern of damage peculiar to C. difficile bacilli, compared to commensals like Escherichia coli and Enterococcus faecalis; and (iii) unexpectedly, hypervirulent ribotypes were among the most susceptible to both defensins. These results support the notion that HD5, naturally present at very high concentrations in the mucosa of the small intestine, could indeed control the very early steps of CDI by killing C. difficile bacilli at their germination site. As a consequence, HD5 can be regarded as a good candidate for the containment of hypervirulent C. difficile strains, and it could be exploited in the therapy of CDI and relapsing C. difficile-associated disease. PMID- 25547792 TI - Design of glycoconjugate vaccines against invasive African Salmonella enterica serovar Typhimurium. AB - Nontyphoidal salmonellae, particularly Salmonella enterica serovar Typhimurium, are a major cause of invasive disease in Africa, affecting mainly young children and HIV-infected individuals. Glycoconjugate vaccines provide a safe and reliable strategy against invasive polysaccharide-encapsulated pathogens, and lipopolysaccharide (LPS) is a target of protective immune responses. With the aim of designing an effective vaccine against S. Typhimurium, we have synthesized different glycoconjugates, by linking O-antigen and core sugars (OAg) of LPS to the nontoxic mutant of diphtheria toxin (CRM(197)). The OAg-CRM(197) conjugates varied in (i) OAg source, with three S. Typhimurium strains used for OAg extraction, producing OAg with differences in structural specificities, (ii) OAg chain length, and (iii) OAg/CRM(197) ratio. All glycoconjugates were compared for immunogenicity and ability to induce serum bactericidal activity in mice. In vivo enhancement of bacterial clearance was assessed for a selected S. Typhimurium glycoconjugate by challenge with live Salmonella. We found that the largest anti OAg antibody responses were elicited by (i) vaccines synthesized from OAg with the highest glucosylation levels, (ii) OAg composed of mixed- or medium-molecular weight populations, and (iii) a lower OAg/CRM(197) ratio. In addition, we found that bactericidal activity can be influenced by S. Typhimurium OAg strain, most likely as a result of differences in OAg O-acetylation and glucosylation. Finally, we confirmed that mice immunized with the selected OAg-conjugate were protected against S. Typhimurium colonization of the spleen and liver. In conclusion, our findings indicate that differences in the design of OAg-based glycoconjugate vaccines against invasive African S. Typhimurium can have profound effects on immunogenicity and therefore optimal vaccine design requires careful consideration. PMID- 25547794 TI - Two-component regulators control hilA expression by controlling fimZ and hilE expression within Salmonella enterica serovar Typhimurium. AB - Salmonellae initiate disease through the invasion of host cells within the intestine. This ability to invade requires the coordinated action of numerous genes, many of which are found within Salmonella pathogenicity island 1 (SPI-1). The key to this process is the ability of the bacteria to respond to the environment, thereby upregulating the necessary genes under optimal conditions. Central to the control of SPI-1 is the transcriptional activator hilA. Work has identified at least 10 different activators and 8 different repressors responsible for the control of hilA. We have previously shown that hilE is a Salmonella-specific negative regulator that is able to repress hilA expression and invasion. Additionally, fimZ, a transcriptional activator responsible for the expression of type I fimbriae as well as flagellar genes, has also been implicated in this process. fimZ is homologous to response regulators from other two-component regulatory systems, although a sensor for the system has not been identified. The phoPQ and phoBR regulons are both two-component systems that negatively affect hilA expression, although the mechanism of action has not been determined. Our results show that PhoBR is capable of inducing fimZ expression, whereas PhoPQ does not affect fimZ expression but does upregulate hilE in an FimZ dependent manner. Therefore, phosphate (sensed by PhoBR) and magnesium (sensed by PhoPQ) levels are important in controlling hilA expression levels when Salmonella is in the intestinal environment. PMID- 25547795 TI - Identification of host proteins involved in rickettsial invasion of tick cells. AB - Tick-borne spotted fever group (SFG) Rickettsia species are obligate intracellular bacteria capable of infecting both vertebrate and invertebrate host cells, an essential process for subsequent bacterial survival in distinct hosts. The host cell signaling molecules involved in the uptake of Rickettsia into mammalian and Drosophila cells have been identified; however, invasion into tick cells is understudied. Considering the movement of SFG Rickettsia between vertebrate and invertebrate hosts, the hypothesis is that conserved mechanisms are utilized for host cell invasion. The current study employed biochemical inhibition assays to determine the tick proteins involved in Rickettsia montanensis infection of tick-derived cells from a natural host, Dermacentor variabilis. The results revealed several tick proteins important for rickettsial invasion, including actin filaments, actin-related protein 2/3 complex, phosphatidylinositol-3'-kinase, protein tyrosine kinases (PTKs), Src family PTK, focal adhesion kinase, Rho GTPase Rac1, and neural Wiskott-Aldrich syndrome protein. Delineating the molecular mechanisms of rickettsial infection is critical to a thorough understanding of rickettsial transmission in tick populations and the ecology of tick-borne rickettsial diseases. PMID- 25547797 TI - CX3CR1 is dispensable for control of mucosal Candida albicans infections in mice and humans. AB - Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections. PMID- 25547796 TI - New aspects of RpoE in uropathogenic Proteus mirabilis. AB - Proteus mirabilis is a common human pathogen causing recurrent or persistent urinary tract infections (UTIs). The underlying mechanisms for P. mirabilis to establish UTIs are not fully elucidated. In this study, we showed that loss of the sigma factor E (RpoE), mediating extracytoplasmic stress responses, decreased fimbria expression, survival in macrophages, cell invasion, and colonization in mice but increased the interleukin-8 (IL-8) expression of urothelial cells and swarming motility. This is the first study to demonstrate that RpoE modulated expression of MR/P fimbriae by regulating mrpI, a gene encoding a recombinase controlling the orientation of MR/P fimbria promoter. By real-time reverse transcription-PCR, we found that the IL-8 mRNA amount of urothelial cells was induced significantly by lipopolysaccharides extracted from rpoE mutant but not from the wild type. These RpoE-associated virulence factors should be coordinately expressed to enhance the fitness of P. mirabilis in the host, including the avoidance of immune attacks. Accordingly, rpoE mutant-infected mice displayed more immune cell infiltration in bladders and kidneys during early stages of infection, and the rpoE mutant had a dramatically impaired ability of colonization. Moreover, it is noteworthy that urea (the major component in urine) and polymyxin B (a cationic antimicrobial peptide) can induce expression of rpoE by the reporter assay, suggesting that RpoE might be activated in the urinary tract. Altogether, our results indicate that RpoE is important in sensing environmental cues of the urinary tract and subsequently triggering the expression of virulence factors, which are associated with the fitness of P. mirabilis, to build up a UTI. PMID- 25547798 TI - Role of BrnQ1 and BrnQ2 in branched-chain amino acid transport and virulence in Staphylococcus aureus. AB - The branched-chain amino acids (BCAAs; Ile, Leu, and Val) not only are important nutrients for the growth of Staphylococcus aureus but also are corepressors for CodY, which regulates virulence gene expression, implicating BCAAs as an important link between the metabolic state of the cell and virulence. BCAAs are either synthesized intracellularly or acquired from the environment. S. aureus encodes three putative BCAA transporters, designated BrnQ1, BrnQ2, and BrnQ3; their functions have not yet been formally tested. In this study, we mutated all three brnQ paralogs so as to characterize their substrate specificities and their roles in growth in vitro and in vivo. We demonstrated that in the community associated, methicillin-resistant S. aureus (CA-MRSA) strain USA300, BrnQ1 is involved in uptake of all three BCAAs, BrnQ2 transports Ile, and BrnQ3 does not have a significant role in BCAA transport under the conditions tested. Of the three, only BrnQ1 is essential for USA300 to grow in a chemically defined medium that is limited for Leu or Val. Interestingly, we observed that a brnQ2 mutant grew better than USA300 in media limited for Leu and Val, owing to the fact that this mutation leads to overexpression of brnQ1. In a murine infection model, the brnQ1 mutant was attenuated, but in contrast, brnQ2 mutants had significantly increased virulence compared to that of USA300, a phenotype we suggest is at least partially linked to enhanced in vivo scavenging of Leu and Val through BrnQ1. These data uncover a hitherto-undiscovered connection between nutrient acquisition and virulence in CA-MRSA. PMID- 25547801 TI - High-throughput methods for screening liposome-macrophage cell interaction. AB - Abstract Carriers are often an essential element of drug delivery, bestowing attributes to their cargo such as biocompatibility, enhanced delivery, extended half-life and efficacy as well as mediating specific targeting at a tissue, cell or intracellular level. Liposomes and lipid-based carriers have been investigated for decades for this purpose, many achieving clinical approval including products such as Doxil(r) and MyocetTM. Large-scale compound screens are routinely carried out in the field of drug discovery; however, less work has been done on harnessing high-throughput methods for carrier material screening. Screening the interaction of drug carriers and materials with cells is particularly critical for the development of emerging therapies, including biomedicines, in order to facilitate the development of safe and efficient drug products. Herein, a range of liposomes of neutral, anionic and cationic charge and others that are surface modified with mannose residues were screened for cell interaction, toxicity and immune reactivity in THP-1-derived macrophages using a high-throughput format. Liposomes were seen to be efficacious in a concentration-dependent and, for mannosylated liposomes, mannosylated cholesterol linker length-dependent manner. PMID- 25547800 TI - Nanoethosomal formulation for skin targeting of amphotericin B: an in vitro and in vivo assessment. AB - The present study is envisaged to develop nanoethosomal formulation for enhanced topical delivery of amphotericin B (AmB) for the treatment of cutaneous fungal infections. AmB encapsulated nanoethosomes were prepared using mechanical dispersion method in a strength of 0.1% w/w similar to the strength of marketed topical formulation. Vesicle size of nanoethosomal formulations was found to be in the range of 186 +/- 2 to 298 +/- 4 nm. The optimized nanoethosomal formulation was further incorporated in gel base to form AmB nanoethogel formulation. Rheological characterization study of nanoethogel demonstrated its viscoelastic nature with high elasticity and resistance to deformation at 37 degrees C. The yield stress value was found to be 108.05 +/- 2.4 and 52.15 +/- 0.9 Pa for nanoethogel and marketed gel formulation, respectively. The nanoethogel formulation exhibited 2.7- and 3.5-fold higher steady state transdermal flux and skin deposition of AmB, respectively, in comparison to marketed formulation. Confocal laser scanning microscopy (CLSM) study also revealed enhanced skin permeation and deposition with nanoethogel formulation. In vivo study showed that topical application of nanoethogel does not exhibit any skin irritation as tested by Draize test. The developed formulation, in comparison to the marketed gel, demonstrated a remarkable increase in the antifungal activity against Candida albicans. It is thus corroborated from the above results that nanoethosomal formulation represents an efficacious carrier for effective topical delivery of AmB. PMID- 25547799 TI - Role of the nuclease of nontypeable Haemophilus influenzae in dispersal of organisms from biofilms. AB - Nontypeable Haemophilus influenzae (NTHI) forms biofilms in the middle ear during human infection. The biofilm matrix of NTHI contains extracellular DNA. We show that NTHI possesses a potent nuclease, which is a homolog of the thermonuclease of Staphylococcus aureus. Using a biofilm dispersal assay, studies showed a biofilm dispersal pattern in the parent strain, no evidence of dispersal in the nuclease mutant, and a partial return of dispersion in the complemented mutant. Quantitative PCR of mRNA from biofilms from a 24-h continuous flow system demonstrated a significantly increased expression of the nuclease from planktonic organisms compared to those in the biofilm phase of growth (P < 0.042). Microscopic analysis of biofilms grown in vitro showed that in the nuclease mutant the nucleic acid matrix was increased compared to the wild-type and complemented strains. Organisms were typically found in large aggregates, unlike the wild-type and complement biofilms in which the organisms were evenly dispersed throughout the biofilm. At 48 h, the majority of the organisms in the mutant biofilm were dead. The nuclease mutant formed a biofilm in the chinchilla model of otitis media and demonstrated a propensity to also form similar large aggregates of organisms. These studies indicate that NTHI nuclease is involved in biofilm remodeling and organism dispersal. PMID- 25547802 TI - Risk factors for post-ERCP pancreatitis: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Pancreatitis is the most common and serious complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). Prevention strategies targeting risk factors could be important to reduce the rate of post-ERCP pancreatitis. However, the risk factors for post-ERCP pancreatitis (PEP) are still debated. This systematic review and meta-analysis was performed to identify risk factors for PEP. METHODS: Medline (PubMed and Ovid), Cochrane Central Register of Controlled trials & Database of Systematic Reviews, Embase, Scopus, ScienceDirect, Springer links and WEB OF SCIENCE were searched for published studies in all languages. Inclusion and exclusion criteria were defined a priori. Eighteen probable risk factors were evaluated, and outcomes were expressed in the case of dichotomous variables, as an odds ratio (OR) (with a 95% confidence interval, (CI)). RESULTS: When patient-related risk factors were analyzed, the ORs for female gender was 1.46 (95%CI: 1.30-1.64); for previous pancreatitis 2.03 (95%CI: 1.31-3.14); for previous PEP was 2.90 (95%CI: 1.87-4.48); for Sphincter of Oddi dysfunction (SOD) was 2.04 (95%CI: 1.73-2.33) and for Intraductal papillary mucinous neoplasm (IPMN) was 3.01 (95%CI: 1.34 6.77). Four endoscopy-related factors were confirmed: the OR for difficult cannulation was 3.49 (95%CI: 1.364-8.925); for endoscopic sphincterotomy (EST) it was 1.39 (95%CI: 1.09-1.79); for precut sphincterotomy it was 2.25 (95%CI: 1.70_2.96); and for main pancreatic duct injection it was 1.58 (95%CI: 1.21 2.08). CONCLUSIONS: Female gender, previous pancreatitis, previous PEP, SOD, IPMN, difficult cannulation, EST, precut sphincterotomy and main pancreatic duct injection are risk factors for post-ERCP pancreatitis. PMID- 25547803 TI - Genotype effect on distribution pattern of maternally derived antibody against Newcastle disease in Nigerian local chickens. AB - This study was conducted to evaluate the variation in antibody from Newcastle disease (ND) vaccinated breeder birds and their progenies. The chicks were evaluated for maternally derived antibody (MDA) against ND virus and also the MDA transfer rate for each genotype. The local parent stocks were Frizzle-feathered, Normal-feathered, and Naked neck while an exotic parent stock (Anak Titan) was used for the purpose of comparison. Sera samples were collected from chicks generated at day 3 post-hatch, and sera were also collected from the parent stocks. The sera samples were stored at -20 degrees C until analysed. Enzyme linked immuno-sorbent assay (ELISA) test was used for the detection and quantification of antibodies to ND in the parent stocks and the chicks using IDEXX Newcastle Disease ELISA test kit. The least squares means of antibody titers for parent stocks were 413.333 +/- 68.853, 426.333 +/- 121.949, 481.667 +/ 145.454, and 1148.333 +/- 532.843 for Frizzle-feathered, Normal-feathered, Naked Neck, and Anak Titan, and the calculated MDA transfer rate was 96.4, 93.8, 88.7, and 34.7 % for Frizzle-feathered, Normal-feathered, Naked neck, and Anak Titan, respectively. The mean antibody titers for chicks were 398.6 +/- 43.871, 400.0 +/ 53.952, 427.0 +/- 89.353, and 398.8 +/- 57.593 for Frizzle-feathered, Normal feathered, Naked neck, and Anak Titan, respectively. The antibody titers from parent stocks were higher than those observed in chicks for all the genotypes. The values obtained in this study indicated that parent stocks with their progenies were below protective level. The local parent stocks had higher transfer rate when compared to their exotic counterpart. Hence, there is an indication from this finding that the local chickens had a better transfer rate in relation to Anak Titan which is an exotic breed. Therefore, there is the presence of genetic variability for antibody transfer in the Nigerian local chickens and can be incorporated in designing a breeding program for better adaptive potential. PMID- 25547804 TI - Erratum to: Neospora caninum causes severe economic losses in cattle in the humid pampa region of Argentina. PMID- 25547805 TI - Serological evidence of camel exposure to peste des petits ruminants virus (PPRV) in Nigeria. AB - Peste des petits ruminants (PPR), a viral disease of sheep and goats, is endemic in Nigeria. There are reports indicating the involvement of peste des petits ruminants virus (PPRV), the causative agent of PPR, in a camel respiratory syndrome in Africa. Considering that camels share the same grazing land and drinking points with other ruminants, this study was undertaken to determine the seroprevalence and extent of PPRV antibodies in Nigerian camels. A total of 1517 camel sera samples were collected from four states (Borno, Kano, Kastina and Sokoto). The seroprevalence was determined by the H-protein-based competitive ELISA. The overall prevalence was 3.36% (51/1517, 95% confidence interval of 2.51 4.39%). There was no significant differences in prevalence between states (p = 0.8921) and between male and female camels (p = 0.7424). The prevalence differed significantly (p < 0.00001) by body condition score; camels with poor body condition score has higher (16.67%) antibody seroprevalence to PPR compared to those with fair and good body condition score. There was a statistically significant difference between camels aged <= 5 years and those >5 years (p = 0.0042). These results show occasional transient PPRV infection of camels in Nigeria, and there is the need to include camels among species to be studied in elucidating the epidemiology of the disease in sheep and goats. PMID- 25547806 TI - Passive transfer of maternal immunity in the dromedary (Camelus dromedarius), involvement of heavy chain antibodies. AB - In many mammalian species, newborns are agammaglobulinemic; thus, colostrum and milk are the main sources of early protective antibodies. These antibodies are produced in the mother's serum and transferred to mammalian glands a few days before parturition. Here, we have studied the transfer of immunity from a she camel immunized with human serum albumin (HSA) to her calf via colostrum and milk. Our results show that HSA-specific antibodies are produced in the mother's serum and are subsequently transferred to her colostrum. These specific antibodies are then transferred by suckling to the calf. The calf serum did not contain HSA-reactive antibodies at parturition and before the first feed, after suckling, a rise in reactivity was observed peaking at 24 h postpartum. The involvement of heavy chain antibodies (HCAbs) in the process of immunity transfer was also examined, and it was found that they were also transferred from the colostrum to the calf serum like conventional antibodies. PMID- 25547807 TI - Resistance to antimicrobials and biofilm formation in Staphylococcus spp. isolated from bovine mastitis in the Northeast of Brazil. AB - Mastitis is the principal disease affecting dairy herds worldwide. The aim of the present study was to characterize phenotypic and genotypic features associated with resistance to antimicrobials in Staphylococcus spp. isolated from 2064 milk samples of 525 lactating cows in the Northeast of Brazil. Of the 218 isolates analyzed, 57.8% were characterized as Staphylococcus aureus, 28% as coagulase positive staphylococci other than S. aureus (oCPS), and 14.2% as coagulase negative staphylococci (CNS). The test for susceptibility to antimicrobials showed amoxicillin (32.6%) to be the less effective drug in vitro, and the multi drug resistance (MDR) rate for beta-lactams varied from 0 to 0.75. The genotypic characterization showed that 93.1% of the samples were tested positive for the blaZ gene, while none amplified mecA. The antibiotic efflux mechanism was observed in 0.9% of isolates. The biofilm formation was found in 3.7 and 96.3% of samples, respectively, on Congo red agar and on the microplate adhesion test, while the icaD gene was present in 92.2% of Staphylococcus spp. The high frequency of blaZ gene observed in this study was associated with the resistance of most Staphylococcus spp. to one or more of the beta-lactams tested, which are routinely used in Brazilian herds for mastitis treatment. The biofilm formation was also detected in the isolates analyzed being an important characteristic for pathogenicity and antimicrobial resistance of bacteria. PMID- 25547809 TI - [Management of idiopathic membranous nephropathy: evaluation of a standardized strategy in a Lorraine health network]. AB - INTRODUCTION: The evolution of idiopathic membranous membranous (MNi) is variable, treatment is discussed. Our work's main objective was to evaluate the results of a standardized management strategy proposed in 2006 in Lorraine (Nephrolor health network). The secondary objective was to evaluate the professional practices. PATIENTS ET METHODS: This study compared the evolution of incident MNi between 2002 and 2005 (Before) and between 2007 and 2010 (After), the respective dates point to 31/12/2011 and 31/12/2006. In nephrotics patients without renal failure, the risk assessment of end stage renal disease based on urinary beta2-microglobulin (ubeta2 m, threshold to 0,5 MUg/min). Patients at high risk should receive immunosuppressive therapy (IS). RESULTS: Seventy-four biopsy-proven MNi were diagnosed with 50 nephrotic (22 Before and 28 After) of which 20 had normal renal function. In these nephrotic, there was no significant difference in the probability and the average time of remission between the two groups (P=0.26). Dosage of ubeta2m was performed in 35% of cases. Fifty percent were treated with IS respecting strategy. CONCLUSION: Despite differences between the strategy and practices, which may explain these non-significant results, we observed changes in thinking and therapeutic attitude of the clinician. The implementation of this strategy tends to standardize and improve practices about MNi in Lorraine, which seems to improve results in remission. We encourage to generalize the application of this strategy and to continue this cohort follow. PMID- 25547810 TI - Photophysical study of a self-assembled donor-acceptor two-layer film on TiO2. AB - The self-assembled monolayer (SAM) technique was employed to fabricate a two layer donor-acceptor film on the surface of TiO2. The approach is based on using donor and acceptor compounds with anchoring groups of different lengths. The acceptor, a fullerene derivative, has a carboxyl anchor attached to the fullerene moiety via a short linker that places the fullerene close to the surface. The donor, a porphyrin derivative, is equipped with a long linker that can penetrate between the fullerenes and keep porphyrin on top of the fullerene layer. The two layer fullerene-porphyrin structures were deposited on a mesoporous film of TiO2 nanoparticles by immersing the TiO2 film sequentially into fullerene and porphyrin solutions. Transient absorption spectroscopy studies of the samples revealed that after the selective photoexcitation of porphyrin a fast (<5 ps) intermolecular electron transfer (ET) takes place from porphyrin to the fullerene layer, which confirms the formation of the interlayer donor-acceptor interface. Furthermore, in the second step of ET the fullerene anions donate electrons to the TiO2 nanoparticles. The latter reaction is relatively slow with an average time constant of 230 ps. It involves roughly half of the primary generated charges, and the second half relaxes by the interlayer charge recombination. The resulting state with a porphyrin cation and electron in TiO2 has an extremely long lifetime and recombines with an average time constant of 23 ms. PMID- 25547808 TI - Dual peptide conjugation strategy for improved cellular uptake and mitochondria targeting. AB - Mitochondria are critical regulators of cellular function and survival. Delivery of therapeutic and diagnostic agents into mitochondria is a challenging task in modern pharmacology because the molecule to be delivered needs to first overcome the cell membrane barrier and then be able to actively target the intracellular organelle. Current strategy of conjugating either a cell penetrating peptide (CPP) or a subcellular targeting sequence to the molecule of interest only has limited success. We report here a dual peptide conjugation strategy to achieve effective delivery of a non-membrane-penetrating dye 5-carboxyfluorescein (5-FAM) into mitochondria through the incorporation of both a mitochondrial targeting sequence (MTS) and a CPP into one conjugated molecule. Notably, circular dichroism studies reveal that the combined use of alpha-helix and PPII-like secondary structures has an unexpected, synergistic contribution to the internalization of the conjugate. Our results suggest that although the use of positively charged MTS peptide allows for improved targeting of mitochondria, with MTS alone it showed poor cellular uptake. With further covalent linkage of the MTS-5-FAM conjugate to a CPP sequence (R8), the dually conjugated molecule was found to show both improved cellular uptake and effective mitochondria targeting. We believe these results offer important insight into the rational design of peptide conjugates for intracellular delivery. PMID- 25547811 TI - Medication list assessment in Spanish hospital emergency departments. AB - BACKGROUND: Medication errors lead to morbidity and mortality among emergency department (ED) patients. An inaccurate medication history is one of the underlying causes of these errors. OBJECTIVES: This study was performed to determine the prevalence of patients with discrepancies between the medical list information contained in the clinical history compiled on admission to the ED and the list of medications patients are actually taking, to characterize the discrepancies found, and to analyze whether certain factors are associated with the risk of discrepancies. METHODS: We conducted a cross-sectional, descriptive, observational, multicenter study with an analytic component in the EDs of 11 hospitals in Spain. We compared pharmacist-obtained medication lists (PML) with ED-obtained medication lists (EDML). Discrepancy was defined as one or more differences (in drug or dosage or route of administration) between the EDML and PML. The endpoints were the proportion of patients with discrepancies in their home medical lists, and the prevalence of certain factors among patients with discrepancies and those without. RESULTS: We detected 1476 discrepancies in 387 patients; no discrepancies were found in 20.7%. The most frequent discrepancies involved incomplete information (44.2%) and omission (41.8%). In the bivariate analysis, age, number of medications, and Charlson comorbidity score were significantly associated with discrepancy. In the multivariate analysis, number of medications and hospital were the variables associated with discrepancy. CONCLUSIONS: The EDML differed from the list of medications patients were actually taking in 79.3% of cases. Incomplete information and omission were the most frequent discrepancies. Age, number of medications, and comorbidities were related to the risk of discrepancies. PMID- 25547812 TI - In response to letter to the editor. PMID- 25547813 TI - Bowel obstruction caused by an internal hernia that developed after laparoscopic subtotal colectomy: a case report. AB - INTRODUCTION: Laparoscopic surgery is a minimally invasive approach with good treatment outcomes and is currently the standard surgery for colorectal cancer in Japan. Mesenteric closure is considered unnecessary in laparoscopic colorectal surgery because it can damage the bowel and blood vessels. However, an internal hernia may develop if the mesentery is not repaired. CASE PRESENTATION: We report a case of internal hernia in a 61-year-old male of Japanese ethnicity. The patient had advanced sigmoid colon cancer, early-stage transverse colon cancer, and multiple adenomatous polyposis, and underwent laparoscopically-assisted subtotal colectomy. Bowel obstruction developed six days postoperatively and did not improve with conservative treatment. Abdominal computed tomography detected an internal hernia, prompting emergency surgery in which the ileum protruding into the mesenteric defect and an anastomotic stricture were detected. Reanastomosis, mesentery closure, and ileostomy were performed after hernia repair. CONCLUSION: In this case, open surgery was necessary due to bowel obstruction after laparoscopic colectomy. This outcome indicated that mesenteric closure should have been performed. Thus, the benefits of mesenteric closure require assessment in future cases. PMID- 25547815 TI - Metal complex of the first-generation quinolone antimicrobial drug nalidixic acid: structure and its biological evaluation. AB - A novel binuclear squire planar complex of nalidixic acid with Ag(I) metal ion with the formula [Ag(Nal)2] has been synthesized. The synthesized metal complex was characterized using CHN analysis, Fourier-transformed infra-red (FT-IR), thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), ultra violet-visible (Uv-vis) and single-crystal X-ray diffraction (XRD). The newly synthesized complex shows more advanced antifungal activity compared to the parent quinolone against four fungi, namely Pythium aphanidermatum, Sclerotinia rolfsii, Rhizoctonia solani and Rhizoctonia bataticola. PMID- 25547814 TI - Polygalacturonase production by calcium alginate immobilized Enterobacter aerogenes NBO2 cells. AB - Bacterial cells of Enterobacter aerogenes NBO2 were entrapped in calcium alginate beads in order to enhance polygalacturonase production compared to free cells. The optimized condition of 5 % (w/v) sodium alginate concentration, agitation speed of 250 rpm, and 15 beads of calcium alginate with inoculum size of 4 % (v/v; 5.4 * 10(7) cells/ml) produced 23.48 U/mL of polygalacturonase compared to free cells of 18.54 U/ml. There was about 26.6 % increment in polygalaturonase production. However, in this study, there was 296.6 % of increment in polygalacturonase production after improvement parameters compared to before improvement parameters of calcium alginate bead immobilization cells (5.92 U/ml). This research has indicated that optimized physical parameters of calcium alginate bead immobilization cells have significantly enhanced the production of polygalacturonase. PMID- 25547816 TI - Biotransformation of 1,3-propanediol cyclic sulfate and its derivatives to diols by toluene-permeabilized cells of Bacillus sp. CCZU11-1. AB - In this study, it was the first report that Bacillus sp. CCZU11-1 was used for the biotransformation of 1,3-propanediol cyclic sulfate (1,3-PDS) and its derivatives. The catalytic performance of Bacillus sp. sulfatase in the biotransformation of 1,3-PDS was significantly improved by biocatalyst permeabilization and immobilization. Using cell permeabilization, the hydrolytic activity of the whole-cell biocatalyst was increased by 3.5-fold after 1.5 h of pretreatment with 10 % (v/v) toluene at 30 degrees C and pH 7.0. Biotransformation of 20 mM 1,3-PDS for 24 h, 1,3-propanediol (1,3-PD) could be obtained in the yield of 97.4 % under the optimized reaction condition. Additionally, the immobilized biocatalysts, permeabilized cells entrapped in calcium alginate, and cross-linked enzyme aggregates were further employed to biotansform 1,3-PDS. Moreover, the total operational time of the immobilized biocatalysts could reach above 240 h with high conversion rate (>90 %). PMID- 25547817 TI - Ni3Mo3C as anode catalyst for high-performance microbial fuel cells. AB - Ni3Mo3C was prepared by a modified organic colloid method and explored as anode catalyst for high-performance microbial fuel cell (MFC) based on Klebsiella pneumoniae (K. pneumoniae). The prepared sample was characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), and Brunauer-Emmett-Teller (BET). The activity of the sample as anode catalyst for MFC based on K. pneumoniae was investigated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and polarization curve measurement. The results show that the adding of nickel in Mo2C increases the BET surface area of Mo2C and improves the electrocatalytic activity of Mo2C towards the oxidation of microbial fermentation products. The power density of MFC with 3 mg cm(-2) Ni3Mo3C anode is far higher than that of the MFC with carbon felt as anode without any catalyst, which is 19 % higher than that of Mo2C anode and produced 62 % as much as that of Pt anode, indicating that Ni3Mo3C is comparative to noble metal platinum as anode electrocatalyst for MFCs by increasing the loading. PMID- 25547818 TI - Reply: To PMID 25103986. PMID- 25547820 TI - Overview of Ebola virus disease in 2014. AB - In late December 2013, a deadly infectious epidemic, Ebola virus disease (EVD), emerged from West Africa and resulted in a formidable outbreak in areas including Guinea, Liberia, Sierra Leone and Nigeria. EVD is a zoonotic disease with a high mortality rate. Person-to-person transmission occurs through blood or body fluid exposure, which can jeopardize first-line healthcare workers if there is a lack of stringent infection control or no proper personal protective equipment available. Currently, there is no standard treatment for EVD. To promptly identify patients and prevent further spreading, physicians should be aware of travel or contact history for patients with constitutional symptoms. PMID- 25547819 TI - 2015 guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society for the management of hypertension. AB - It has been almost 5 years since the publication of the 2010 hypertension guidelines of the Taiwan Society of Cardiology (TSOC). There is new evidence regarding the management of hypertension, including randomized controlled trials, non-randomized trials, post-hoc analyses, subgroup analyses, retrospective studies, cohort studies, and registries. More recently, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) published joint hypertension guidelines in 2013. The panel members who were appointed to the Eighth Joint National Committee (JNC) also published the 2014 JNC report. Blood pressure (BP) targets have been changed; in particular, such targets have been loosened in high risk patients. The Executive Board members of TSOC and the Taiwan Hypertension Society (THS) aimed to review updated information about the management of hypertension to publish an updated hypertension guideline in Taiwan. We recognized that hypertension is the most important risk factor for global disease burden. Management of hypertension is especially important in Asia where the prevalence rate grows faster than other parts of the world. In most countries in East Asia, stroke surpassed coronary heart disease (CHD) in causing premature death. A diagnostic algorithm was proposed, emphasizing the importance of home BP monitoring and ambulatory BP monitoring for better detection of night time hypertension, early morning hypertension, white-coat hypertension, and masked hypertension. We disagreed with the ESH/ESH joint hypertension guidelines suggestion to loosen BP targets to <140/90 mmHg for all patients. We strongly disagree with the suggestion by the 2014 JNC report to raise the BP target to <150/90 mmHg for patients between 60-80 years of age. For patients with diabetes, CHD, chronic kidney disease who have proteinuria, and those who are receiving antithrombotic therapy for stroke prevention, we propose BP targets of <130/80 mmHg in our guidelines. BP targets are <140/90 mmHg for all other patient groups, except for patients >=80 years of age in whom a BP target of <150/90 mmHg would be optimal. For the management of hypertension, we proposed a treatment algorithm, starting with life style modification (LSM) including S-ABCDE (Sodium restriction, Alcohol limitation, Body weight reduction, Cigarette smoke cessation, Diet adaptation, and Exercise adoption). We emphasized a low-salt strategy instead of a no-salt strategy, and that excessively aggressive sodium restriction to <2.0 gram/day may be harmful. When drug therapy is considered, a strategy called "PROCEED" was suggested (Previous experience, Risk factors, Organ damage, Contraindications or unfavorable conditions, Expert's or doctor's judgment, Expenses or cost, and Delivery and compliance issue). To predict drug effects in lowering BP, we proposed the "Rule of 10" and "Rule of 5". With a standard dose of any one of the 5 major classes of anti-hypertensive agents, one can anticipate approximately a 10-mmHg decrease in systolic BP (SBP) (Rule of 10) and a 5-mmHg decrease in diastolic BP (DBP) (Rule of 5). When doses of the same drug are doubled, there is only a 2-mmHg incremental decrease in SBP and a 1-mmHg incremental decrease in DBP. Preferably, when 2 drugs with different mechanisms are to be taken together, the decrease in BP is the sum of the decrease of the individual agents (approximately 20 mmHg in SBP and 10 mmHg in DBP). Early combination therapy, especially single-pill combination (SPC), is recommended. When patient's initial treatment cannot get BP to targeted goals, we have proposed an adjustment algorithm, "AT GOALs" (Adherence, Timing of administration, Greater doses, Other classes of drugs, Alternative combination or SPC, and LSM + Laboratory tests). Treatment of hypertension in special conditions, including treatment of resistant hypertension, hypertension in women, and perioperative management of hypertension, were also mentioned. The TSOC/THS hypertension guidelines provide the most updated information available in the management of hypertension. The guidelines are not mandatory, and members of the task force fully realize that treatment of hypertension should be individualized to address each patient's circumstances. Ultimately, the decision of the physician decision remains of the utmost importance in hypertension management. PMID- 25547821 TI - Expansive jaw lesions in chronic kidney disease: review of the literature and a report of two cases. AB - Chronic kidney disease is an increasing public health problem, with a worldwide prevalence estimated to be between 8% and 16%. The metabolic alterations induce bone and soft tissue changes, and the encompassing term chronic kidney disease mineral and bone disorder syndrome (CKD-MBD) is used to describe them. The cardinal manifestations of the syndrome are bone catabolism and soft tissue calcifications, which ultimately compromise the cardiovascular and skeletal systems. In rare cases, tumorous enlargement of the craniofacial bones occurs. This article provides a brief review of the pathogenesis and imaging of craniofacial changes in CKD-MBD and reports on two cases of expansive jaw lesions. The term expansive renal osteitis fibrosa is recommended to describe these lesions. PMID- 25547822 TI - Nodular swelling of the tongue. PMID- 25547823 TI - Oral squamous cell carcinoma associated with proliferative verrucous leukoplakia compared with conventional squamous cell carcinoma--a clinical, histologic and immunohistochemical study. AB - OBJECTIVE: Proliferative verrucous leukoplakia (PVL), a potentially malignant disorder, often undergoes malignant transformation to oral squamous cell carcinoma. The aim of our study was to document and compare the histologic, immunohistochemical, and clinical features and the survival rates of carcinoma arising in patients with PVL (p-scca) with conventional squamous cell carcinoma (c-scca) in order to determine if p-scca should be categorized as a separate clinical entity. MATERIALS AND METHODS: A retrospective review of 11 patients with PVL, 38 with p-scca tumors and 49 with c-scca tumors: buccal mucosa (n = 28) and gingiva or palate (n = 21). Immunohistochemistry was performed by using antibodies directed against p16, p53, and ki67. RESULTS: P-scca had lower clinical stage (P = .0001), smaller tumor size (P = .0033), no lymph node metastasis (P = .0002) or distant metastasis (P = .05), and better short term (P = .03), but not long term (P = .12) survival. Microscopically, p-scca tumor thickness was significantly less (P = .0001). P-53 overexpression was more common in p-scca (P = .0043) but not ki67 or p16 overexpression. CONCLUSIONS: P-scca, compared with c-scca, presented with significantly better prognostic factors and short-term survival rates and longer duration of disease. Our results suggest that p-scca may represent a distinct entity, which may have practical implications when deciding on treatment. Further studies on a larger cohort of patients are recommended. PMID- 25547824 TI - Half of over 75s in US are taking cholesterol lowering drugs, report says. PMID- 25547825 TI - Anesthetic management of a patient with Hermansky-Pudlak syndrome undergoing video-assisted bullectomy. AB - The Hermansky-Pudlak syndrome (HPS) is a rare set of disorders characterized by oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, with the latter 2 conditions presenting major challenges in anesthetic management. We report a 53-year-old woman with pulmonary fibrosis secondary to HPS who underwent video-assisted bullectomy to treat recurrent pneumothorax. Preoperative bleeding time and platelet count were within normal limits, but the surgeons had difficulty with continuous oozing from the incision site; the surgical blood loss was 270 mL, which was a relatively large amount for this surgery. Because of her restrictive lung disease, the patient's tidal volume was only 250 mL under pressure-controlled ventilation, with a peak inspiratory pressure of 30 cm H2O and a positive end-expiratory pressure of 5 cm H2O. She also had postoperative respiratory insufficiency, with a partial pressure of arterial CO2 of 112 mm Hg and a pH of 7.08 on arterial blood gas analysis. Then, the patient needed mechanical ventilation for 4 days. In conclusion, patients with HPS require strict respiratory management to support their restrictive pulmonary dysfunction, and, also, we should consider preventive management for hemostasis and adequate analgesia to reduce the patient's work of breathing. PMID- 25547826 TI - The versatility of intraosseous vascular access in perioperative medicine: a case series. AB - Intraosseous vascular access is a time-tested procedure that is reemerging in popularity. This is primarily a result of the emphasis on intraosseous access in the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Advanced Cardiac Life Support. Modern intraosseous insertion devices are easy to learn and use, suggesting the possibility of use beyond the resuscitation setting. We present a case series of recent intraosseous insertions for a variety of indications by anesthesiologists at our institution to demonstrate the potential utility of this alternative access technique. PMID- 25547827 TI - Correlations between prognosis and regional biomarker profiles in head and neck squamous cell carcinomas. AB - Head and neck squamous cell carcinomas (HNSCC) show diverse clinicopathological features and are mostly linked with poor outcome. In this study, we tested if the expression of tumor growth, cell cycle and basement membrane anchorage related biomarkers allow prognostic and clinicopathological stratification of HNSCC. Archived HNSCC samples from 226 patients included into tissue microarrays (TMA) were tested using immunohistochemistry. Histopathological evaluation and the analysis of immunostaining for EGFR, Ki67, p53, p16(ink4) and Collagen XVII proteins were carried out in digital whole slides. Statistical evaluation was carried out using Pearson's Chi-square test and Kaplan-Meier survival analysis. In the tested cohort, hypopharyngeal cancers had the least favorable, and glottic cancers had the most favorable prognosis. High Ki67 positive tumor cell fractions were associated with significantly worse prognosis and elevated rate of lymph node metastasis. Both Ki67 and EGFR expression correlated significantly with the tumor localization. Ki67 index was the highest in the hypopharyngeal region and it proved to be the lowest in the glottic region. EGFR expression was the highest in the oral cavity and the lowest in the glottic region. The survival rate of patients with p16(ink4)-negative cancer was significantly lower than of those with p16(ink4)-positive disease. A significant inverse correlation was found between histological grade and the prognosis of HNSCC. Our data support that elevated Ki67 positive proliferating cell fractions contribute to the unfavorable prognosis of hypopharyngeal cancers, while glottic cancers have the most favorable prognosis because of the lowest Ki67 expression rate. PMID- 25547828 TI - HPV-type distribution and reproducibility of histological diagnosis in cervical neoplasia in Poland. AB - This study was performed to assess attribution of high grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) to human papillomavirus (HPV) genotypes and secondarily to assess reproducibility of HG CIN/ICC diagnosis obtained in Poland. Formaldehyde fixed, paraffin embedded blocks of HG-CIN/ICC from two distant institutions were sent to a central laboratory together with original histological diagnoses. Central/expert review of histopathological specimens was performed and agreement between local and central/expert diagnoses was calculated. HPV detection and genotyping in the samples was carried out with the use of SPF10-LiPA25 technology. Results were analyzed for 205 HG-CIN and 193 ICC cases with centrally confirmed diagnoses. Kappa coefficients and 95 % confidence intervals for HG-CIN and ICC diagnoses were: 0.13 (0.09;0.17) and 0.19 (0.11;0.26) respectively. Cohen's kappa coefficients for lesions with representative number of samples ranged from 0.01 for cervical intraepithelial neoplasia grade 2 to 0.75 for adenocarcinoma. HPV DNA was detected in 96.1 and 91.2 % of the confirmed HG-CIN and ICC specimens respectively. HPV positive HG-CIN was most commonly attributed to HPV types: 16 (62.8), 33 (7.8), 31 (6.6), 52 (3.7), 45 (2.6) and 58 (2.6 %). HPV positive ICC was most commonly attributed to HPV types: 16 (72.1), 18 (10.8), 33 (5.7), 45 (3.4) and 31 (1.7 %). Reproducibility of histological diagnosis of HG-CIN/ICC obtained in Poland generally increases with the severity of lesion and is lowest for cervical intraepithelial neoplasia grade 2 and highest for adenocarcinoma. Over 80 % of ICC cases are vaccine-preventable in Poland. PMID- 25547830 TI - RETRACTED ARTICLE: Cell-specific delivery of messenger RNA and microRNA by recombinant MS2 virus-like particles carrying cell-penetrating peptide. PMID- 25547831 TI - The stability of Pb species during the Pb removal process by growing cells of Phanerochaete chrysosporium. AB - Extensive studies have been operated on the biosorption of heavy metal using white-rot fungi, whereas information on the stability of the sorbed metal species has never been taken into consideration, which is important for the later disposal of the used biomass. In this study, the growing cells of Phanerochaete chrysosporium were used to remove Pb from the fungal living environment. The bioremoval of Pb proceeded continually until 121 h. The bioremoved Pb was found to be stabilized at the first time P. chrysosporium was exposed to Pb ions. The extractable rate of removed Pb decreased constantly and kept at a stable level around 20 % after 121 h. The results indicated that the growing biomass is efficient for the stabilization of Pb, and the used biomass was suitable to be separated for further disposal at 121 h. With environment scanning electron microscopy coupled with energy-dispersive X-ray analysis (ESEM-EDAX) and X-ray powder diffraction (XRD) analysis, the stabilized Pb species were identified to be lead oxalate and lead chloride phosphate. Further, it is found that the stabilization of Pb by growing P. chrysosporium is not strictly limited in the aspect of pH when pH in the environment is in the range of 4-6. PMID- 25547829 TI - Testicular yolk sac tumors in children: a review of 61 patients over 19 years. AB - BACKGROUND: To describe 19 years of clinical experience managing pediatric patients with testicular yolk sac tumors at the Chongqing Medical University Affiliated Children's Hospital. METHODS: This study involved a retrospective review of the records of 61 pediatric patients who presented with testicular yolk sac tumor at our institution between 1995 and 2014. RESULTS: All patients presented with a painless scrotal mass. Serum alpha-fetoprotein (AFP) levels were elevated (n = 15). Ultrasonography identified the yolk sac tumors as solid masses. Color Doppler flow imaging showed rich blood flow inside and around the masses in 84.8% cases. X-ray of the scrotum showed no intrascrotal calcification (n = 38). Inguinal orchiectomy was performed in 60 patients, one case was treated with testis-sparing surgery. In 11 cases, radical dissection of the inguinal lymph nodes was performed. Histological analysis showed pathologies typical of yolk sac tumor including microcapsule and reticular structures, gland tube-gland bubble structures, an embryo sinus structure, and papillary structures. All patients received postoperative chemotherapy. Serum AFP levels returned to normal 1 to 2 months after surgery. No patients treated with surgery in our hospital relapsed. CONCLUSION: Testicular yolk sac tumor presents as a painless scrotal mass, increased serum AFP levels, and a solid mass on ultrasound. Chest radiography and abdominal ultrasound should be used to accurately stage the tumor. We advocate for inguinal orchiectomy for Stage I disease and postoperative chemotherapy to prevent recurrence in the ipsilateral or contralateral testis. PMID- 25547832 TI - Biosynthesized silver nanoparticles as a nanoweapon against phytopathogens: exploring their scope and potential in agriculture. AB - The beneficial use of silver nanoparticles (AgNPs) in agroecosystems is not fully explored with partial information available, of which most of the studies are limited to laboratory conditions and only few involve natural ecosystems. AgNPs, being the most popular metallic nanoparticles exhibiting antimicrobial property, are predominantly used for plant disease management. Owing to the ill hazards of chemically synthesized AgNPs, their biosynthesis using environment-friendly biomolecules is gaining noteworthy attention. In addition, considering the advantages of nanoformulations over biopesticides, there is no doubt that biosynthesized AgNP-based biopesticides could revolutionize the agricultural sector in the future. Though enhanced commercial use of AgNPs has generated biosafety issues in modern scenario but expecting their significant contribution towards agricultural sector, it is too early to predict the risk factor associated with their usage. To unveil the toxicity factor of AgNPs, we need to focus and understand the major interactions of AgNPs in agroecosytems. Hence, the present review highlights (i) the potential application of AgNPs in the agricultural sector particularly for plant disease management, (ii) significance of biosynthesized AgNPs using microbes and plants over their chemical synthesis, (iii) major interactions of AgNPs in agroecosystems (with soil, soil biota, and plants) with emphasis to deal with toxicity-determining factors, and (iv) identifying future research work holding promising applications of biosynthesized AgNPs in agroecosystems. PMID- 25547833 TI - Toward metabolic engineering in the context of system biology and synthetic biology: advances and prospects. AB - Metabolic engineering facilitates the rational development of recombinant bacterial strains for metabolite overproduction. Building on enormous advances in system biology and synthetic biology, novel strategies have been established for multivariate optimization of metabolic networks in ensemble, spatial, and dynamic manners such as modular pathway engineering, compartmentalization metabolic engineering, and metabolic engineering guided by genome-scale metabolic models, in vitro reconstitution, and systems and synthetic biology. Herein, we summarize recent advances in novel metabolic engineering strategies. Combined with advancing kinetic models and synthetic biology tools, more efficient new strategies for improving cellular properties can be established and applied for industrially important biochemical production. PMID- 25547834 TI - Design of N-acyl homoserine lactonase with high substrate specificity by a rational approach. AB - N-Acyl homoserine lactone (AHL) is a major quorum-sensing signaling molecule in many bacterial species. Quorum-quenching (QQ) enzymes, which degrade such signaling molecules, have attracted much attention as an approach to controlling and preventing bacterial virulence and pathogenesis. However, naturally occurring QQ enzymes show a broad substrate spectrum, raising the concern of unintentionally attenuating beneficial effects by symbiotic bacteria. Here we report the rational design of acyl homoserine lactonase with high substrate specificity. Through docking analysis, we identified three key residues which play a key role in the substrate preference of the enzyme. The key residues were changed in a way that increases hydrophobic contact with a substrate having a short acyl chain (C4-AHL) while generating steric clashes with that containing a long acyl chain (C12-AHL). The resulting mutants exhibited a significantly shifted preference toward a substrate with a short acyl chain. Molecular dynamics simulations suggested that the mutations affect the behavior of a flexible loop, allowing tighter binding of a substrate with a short acyl chain. PMID- 25547835 TI - Functional expression of L-lysine alpha-oxidase from Scomber japonicus in Escherichia coli for one-pot synthesis of L-pipecolic acid from DL-lysine. AB - L-Pipecolic acid is a key component of biologically active molecules and a pharmaceutically important chiral building block. It can be stereoselectively produced from L-lysine by a two-step bioconversion involving L-lysine alpha oxidase and ?(1)-piperideine-2-carboxylae (Pip2C) reductase. In this study, we focused on an L-lysine alpha-oxidase from Scomber japonicus that was originally identified as an apoptosis-inducing protein (AIP) and applied the enzyme to one pot fermentation of L-pipecolic acid in Escherichia coli. A synthetic gene coding for an AIP was expressed in E. coli, and the recombinant enzyme was purified and characterized. The purified enzyme was determined to be a homodimer with a molecular mass of 133.9 kDa. The enzyme essentially exhibited the same substrate specificity as the native enzyme. Optimal temperature and pH for the enzymatic reaction were 70 degrees C and 7.4, respectively. The enzyme was stable below 60 degrees C and at a pH range of 5.5-7.5 but was markedly inhibited by Co(2+). To establish a one-pot fermentation system for the synthesis of optically pure L pipecolic acid from DL-lysine, an E. coli strain carrying a plasmid encoding AIP, Pip2C reductase from Pseudomonas putida, lysine racemase from P. putida, and glucose dehydrogenase from Bacillus subtilis was constructed. The one-pot process produced 45.1 g/L of L-pipecolic acid (87.4 % yield from DL-lysine) after a 46-h reaction with high optical purity (>99.9 % enantiomeric excess). PMID- 25547836 TI - The antioxidant hydroxytyrosol: biotechnological production challenges and opportunities. AB - Hydroxytyrosol (HT) is a highly potent antioxidant originating in nature as a second metabolite of plants, most abundantly in olives (Olea europaea). In the last decade, numerous research studies showed the health benefits of antioxidants in general and those of HT in particular. As olive oil is a prime constituent of the health-promoting Mediterranean diet, HT has obtained recognition for its attributes, supported by a recent health claim of the European Food Safety Authority. HT is already used as a food supplement and in cosmetic products, but it has the potential to be used as a food additive and drug, based on its anticarcinogenic, anti-inflammatory, antiapoptotic and neuroprotective activity. Nevertheless, there is a large gap between the potential of HT and its current availability in the market due to its high price tag. In this review, the challenges of producing HT using biotechnological methods are described with an emphasis on the substrate source, the biocatalyst and the process parameters, in order to narrow the gap towards an efficient bio-based industrial process. PMID- 25547837 TI - One-pot production of fructooligosaccharides by a Saccharomyces cerevisiae strain expressing an engineered invertase. AB - We describe a simple, efficient process for the production of 6-kestose, a trisaccharide with well-documented prebiotic properties. A key factor is the use of a yeast transformant expressing an engineered version of Saccharomyces invertase with enhanced transfructosylating activity. When the yeast transformant was grown with 30 % sucrose as the carbon source, 6-kestose accumulated up to ca. 100 g/L in the culture medium. The 6-kestose yield was significantly enhanced (up to 200 g/L) using a two-stage process carried out in the same flask. In the first stage, the culture was grown in 30 % sucrose at physiological temperature (30 degrees C) to allow overexpression of the invertase. In the second stage, sucrose was added to the culture at high concentration (60 %) and the temperature shifted to 50 degrees C. In both cases, 6-kestose was synthesized with high specificity, representing more than 95 % of total FOS. PMID- 25547838 TI - An organic solvent-tolerant phenolic acid decarboxylase from Bacillus licheniformis for the efficient bioconversion of hydroxycinnamic acids to vinyl phenol derivatives. AB - A new phenolic acid decarboxylase gene (blpad) from Bacillus licheniformis was cloned and overexpressed in Escherichia coli. The full-length blpad encodes a 166 amino acid polypeptide with a predicted molecular mass and pI of 19,521 Da and 5.02, respectively. The recombinant BLPAD displayed maximum activity at 37 degrees C and pH 6.0. This enzyme possesses a broad substrate specificity and is able to decarboxylate p-coumaric, ferulic, caffeic, and sinapic acids at the relative ratios of specific activities 100:74.59:34.41:0.29. Kinetic constant K m values toward p-coumaric, ferulic, caffeic, and sinapic acids were 1.64, 1.55, 1.93, and 2.45 mM, and V max values were 268.43, 216.80, 119.07, and 0.78 U mg( 1), respectively. In comparison with other phenolic acid decarboxylases, BLPAD exhibited remarkable organic solvent tolerance and good thermal stability. BLPAD showed excellent catalytic performance in biphasic organic/aqueous systems and efficiently converted p-coumaric and ferulic acids into 4-vinylphenol and 4 vinylguaiacol. At 500 mM of p-coumaric and ferulic acids, the recombinant BLPAD produced a total 60.63 g l(-1) 4-vinylphenol and 58.30 g l(-1) 4-vinylguaiacol with the conversion yields 97.02 and 70.96 %, respectively. The low yield and product concentration are the crucial drawbacks to the practical bioproduction of vinyl phenol derivatives using phenolic acid decarboxylases. These unusual properties make BLPAD a desirable biocatalyst for commercial use in the bioconversion of hydroxycinnamic acids to vinyl phenol derivatives via enzymatic decarboxylation in a biphasic organic/aqueous reaction system. PMID- 25547840 TI - What renders Bacilli genetically competent? A gaze beyond the model organism. AB - Natural genetic competence enables bacteria to take in and establish exogenously supplied DNA and thus constitutes a valuable tool for strain improvement. Extensively studied in the Gram-positive model organism Bacillus subtilis genetic competence has indeed proven successful for genetic manipulation aiming at enhancement of handling, yield, and biosafety. The majority of Bacilli, particularly those relevant for industrial application, do not or only poorly develop genetic competence, although rather homologous DNA-uptake machineries are routinely encoded. Establishing the competent state solely due to high cell densities (quorum sensing dependency) appears to be restricted to the model organism, in which the small signalling peptide ComS initiates the regulatory pathway that ultimately leads to the expression of all genes necessary for reaching the competent state. Agreeing with the lack of a functional ComS peptide, competence-mediated transformation of other Bacilli depends on nutrient exhaustion rather than cell density. Genetically, competent strains of the model organism B. subtilis, cultivated for a long time and selected for laboratory purposes, display probably not least to such selection a point mutation in the promoter of a regulatory gene that favors competence development whereas the wild type progenitor only poorly displays genetic competence. Consistent with competence being a matter of deregulation, all strains of Bacillus licheniformis displaying efficient DNA uptake were found to carry mutations in regulator genes, which are responsible for their genetic competence. Thus, strain-specific genetic equipment and regulation as well as the proven role of domestication for the well established laboratory strains ought to be considered when attempting to broaden the applicability of competence as a genetic tool for strains other than the model organism. PMID- 25547841 TI - Fundamental role of cobalamin biosynthesis in the developmental growth of Streptomyces coelicolor A3 (2). AB - Cobalamin (Cbl) (synonym, vitamin B12) is the cobalt-containing cofactor produced only by some prokaryotes. Streptomyces is an effective Cbl producer. To study the role of Cbl production in Streptomyces, a knockout mutant for Cbl biosynthesis (cob) was generated in Streptomyces coelicolor A3 (2). The growth of the mutant was similar to that of the wild type in a rich medium, but inhibited in minimal medium, suggesting the involvement of Cbl in some step of primary metabolism. Methionine synthesis catalyzed by MetH, the Cbl-dependent methionine synthase, is a candidate. However, supplementing the minimal medium with methionine did not rescue the growth of the cob mutant, indicating that the availability of Cbl affects another primary function. Transcriptional analysis confirmed that the mutant induced metE encoding an alternative Cbl-independent methionine synthase, probably due to the Cbl-dependent riboswitch mechanism. The cob mutant produced low levels of pigment antibiotics and formed fewer aerial mycelium and spores in a rich medium, suggesting that a Cbl-dependent mechanism controls development. A similar developmental defect was observed for a knockout mutant for SCO4800, encoding the putative Cbl-dependent isobutyryl-CoA mutase (Icm) small subunit. Since the knockout of the Icm large subunit (SCO5415) did not affect the developmental phenotype, SCO4800 likely regulates development independently from SCO5415. Effective Cbl production is fundamental to the diverse functions underlying the complex developmental life cycle of S. coelicolor A3 (2). PMID- 25547839 TI - Cloning, expression, and purification of insect (Sitophilus oryzae) alpha amylase, able to digest granular starch, in Yarrowia lipolytica host. AB - Raw-starch-digesting enzymes (RSDE) are of major importance for industrial applications, as their usage greatly simplifies the starch processing pipeline. To date, only microbial RSDE have gained considerable attention, since only microbial production of enzymes meets industrial demands. In this study, alpha amylase from rice weevil (Sitophilus oryzae), the major rice pest, was cloned and expressed in Yarrowia lipolytica Po1g strain. The enzyme was secreted into the culture medium, and the peak activity (81 AU/L) was reached after only 29 h of culturing in 5-L bioreactors. Through simple purification procedure of ammonium sulfate precipitation and affinity chromatography, it was possible to purify the enzyme to apparent homogeneity (25-fold purification factor, at 5 % yield). The optimal conditions for the alpha-amylase activity were pH 5.0 and a temperature of 40 degrees C. The alpha-amylase studied here did not show any obligate requirement for Ca(2+) ions. The recombinant alpha-amylase appeared to efficiently digest granular starch from pea, amaranth, waxy corn, and waxy rice. PMID- 25547842 TI - Continuous nitrous oxide abatement in a novel denitrifying off-gas bioscrubber. AB - The potential of a bioscrubber composed of a packed bed absorption column coupled to a stirred tank denitrification bioreactor (STR) was assessed for 95 days for the continuous abatement of a diluted air emission of N2O at different liquid recycling velocities. N2O removal efficiencies of up to 40 +/- 1 % were achieved at the highest recirculation velocity (8 m h(-1)) at an empty bed residence time of 3 min using a synthetic air emission containing N2O at 104 +/- 12 ppmv. N2O was absorbed in the packed bed column and further reduced in the STR at efficiencies >80 % using methanol as electron donor. The long-term operation of the bioscrubber suggested that the specialized N2O degrading community established was not able to use N2O as nitrogen source. Additional nitrification assays showed that the activated sludge used as inoculum was not capable of aerobically oxidizing N2O to nitrate or nitrite, regardless of the inorganic carbon concentration tested. Denitrification assays confirmed the ability of non acclimated activated sludge to readily denitrify N2O at a specific rate of 3.9 mg N2O g VSS h(-1) using methanol as electron donor. This study constitutes, to the best of our knowledge, the first systematic assessment of the continuous abatement of N2O in air emission. A characterization of the structure of the microbial population in the absorption column by DGGE-sequencing revealed a high microbial diversity and the presence of heterotrophic denitrifying methylotrophs. PMID- 25547843 TI - Fermentative production of 1-propanol from sugars using wild-type and recombinant Shimwellia blattae. AB - Shimwellia blattae is an enteric bacterium and produces endogenous enzymes that convert 1,2-propanediol (1,2-PD) to 1-propanol, which is expected to be used as a fuel substitute and a precursor of polypropylene. Therefore, if S. blattae could be induced to generate its own 1,2-PD from sugars, it might be possible to produce 1-propanol from sugars with this microorganism. Here, two 1,2-PD production pathways were constructed in S. blattae, resulting in two methods for 1-propanol production with the bacterium. One method employed the L-rhamnose utilization pathway, in which L-rhamnose is split into dihydroxyacetone phosphate and 1,2-PD. When wild-type S. blattae was cultured with L-rhamnose, an accumulation of 1,2-PD was observed. The other method for producing 1,2-PD was to introduce an engineered 1,2-PD production pathway from glucose into S. blattae. In both cases, the produced 1,2-PD was then converted to 1-propanol by 1,2-PD converting enzymes, whose production was induced by the addition of glycerol. PMID- 25547844 TI - Early to Phase II drugs currently under investigation for the treatment of liver fibrosis. AB - INTRODUCTION: Chronic liver diseases represent a high unmet medical need and are characterized by persistent inflammation, parenchymal damage and fibrotic remodeling, leading eventually to cirrhosis and hepatic failure. Besides the persisting high prevalence of chronic viral hepatitis B and C, the dramatic increase in nonalcoholic steatohepatitis is now considered to be a major pathophysiologic driver for fibrosis development and subsequently cirrhosis. Increasing evidence suggests that also liver cirrhosis can regress when treated adequately. AREAS COVERED: Herein, the authors review the underlying pathophysiologic mechanisms leading to fibrotic remodeling in the liver. They also highlight the options for novel treatment strategies by using molecular targeted agents. EXPERT OPINION: New in vitro and preclinical animal models, and the careful selection of patients with high disease dynamics for clinical studies, provide a sound basis for the clinical development of antifibrotic agents in humans. Surrogate parameters of liver function, inflammation, tissue remodeling and damage, as well as noninvasive imaging techniques, can be applied in clinical trials to provide fast readouts and novel and reliable endpoints for trial design, and provide an attractive regulatory environment for this emerging disease area. PMID- 25547848 TI - Immunometabolism. ILC2s skew the fat. AB - Group 2 innate lymphoid cells promote beiging of adipose tissue and protect against obesity. PMID- 25547849 TI - Extensive spreading of interstitial telomeric sites on the chromosomes of Characidium (Teleostei, Characiformes). AB - Characidium comprises several species of small freshwater fish that display conserved diploid chromosome numbers and karyotypic formulae. In this study, a comparative cytogenetic analysis using telomeric DNA probes was carried out in nine species of Characidium; a molecular phylogenetic analysis with mitochondrial DNA was also performed in order to investigate the direction of the evolutionary chromosome changes observed here. Our results showed the existence of species with several and variable interstitial telomeric sites (ITSs), with other species showing only terminal signals in their chromosomes. Molecular phylogenetic data suggested that these ITSs emerged once in the evolutionary history of Characidium and were later differentially spread in distinct species/populations of this clade. Additionally, the origin of an exclusive acrocentric pair found in C. pterostictum, C. serrano and C. timbuiense was also investigated, revealing that this pair possibly had a common origin to these species. These results evidence the occurrence of intense and continuous genomic changes among species of Characidium. PMID- 25547851 TI - Enabling technologies built on a sonochemical platform: challenges and opportunities. AB - Scientific and technological progress now occurs at the interface between two or more scientific and technical disciplines while chemistry is intertwined with almost all scientific domains. Complementary and synergistic effects have been found in the overlay between sonochemistry and other enabling technologies such as mechanochemistry, microwave chemistry and flow-chemistry. Although their nature and effects are intrinsically different, these techniques share the ability to significantly activate most chemical processes and peculiar phenomena. These studies offer a comprehensive overview of sonochemistry, provide a better understanding of correlated phenomena (mechanochemical effects, hot spots, etc.), and pave the way for emerging applications which unite hybrid reactors. PMID- 25547850 TI - Serum uric acid levels and different phases of illness in bipolar I patients treated with lithium. AB - Recent findings support the role of purinergic system dysfunction in the pathophysiology of bipolar disorder (BD). The present study aimed to evaluate the pattern of serum uric acid levels in a sample of 98 BD I patients followed-up prospectively in a naturalistic study and treated with lithium monotherapy or in association with other mood stabilizers (valproate or carbamazepine), in relation to different phases of illness and to pharmacological treatment. The results showed that uric acid levels were significantly higher in patients suffering from a manic/mixed episode, than in those euthymic or during a depressive phase. Further, these levels were related to the Clinical Global Impression-Bipolar Version (CGI-BP) scale score for the severity of manic symptoms. A positive correlation was found also with male sex and with serum lithium levels. These findings suggest that a dysregulation of the purinergic system may occur during manic/mixed episodes, and they support a possible role of serum uric acid levels as a state-dependent marker of BD manic phases. PMID- 25547852 TI - Graphene-oxide (GO)-Fe3+ hybrid nanosheets with effective sonocatalytic degradation of Reactive Red 120 and study of their kinetics mechanism. AB - This work demonstrates the preparation of graphene-oxide (GO)-Fe(3+) hybrids nanosheets and their high bleaching efficiency on the dye "Reactive Red 120 (RR 120)" by using sonocatalytic degradation. Sonocatalytic degradation was enhanced by using oxidants like PMS (peroxomonosulphate), PDS (peroxodisulphate), H2O2 (hydrogen peroxide) and KIO4 (potassium periodate). Our observations manifested that the degradation of the dye "RR 120" was found to be multiplied by addition of oxidants in the order of PMS>H2O2>PDS>KIO4. The effect of inorganic ions was studied by the addition of SO4(2-), Cl(-), H2PO4(-) and HCO3(-). These results revealed that an addition of inorganic anionic decreases the degradation efficiency of RR 120 at high concentration. The trend of decreased degradation efficiency was SO(-)4 .8). Passive internal rotation was reduced with increased diameter at both neutral and lateralized glenosphere positions (-6 degrees +/- 6 degrees and -12 degrees +/- 6 degrees ; P < .002); however, external rotation was not affected (P > .05). At neutral glenosphere position, increasing diameter increased the maximum angles of both adduction (+1 degrees +/- 1 degrees ; P = .03) and abduction (+8 degrees +/- 9 degrees ; P < .05). Lateralization also increased abduction range of motion compared with neutral (P < .01). CONCLUSIONS: Although increasing glenosphere diameter significantly increased joint load and deltoid force, the clinical impact of these changes is presently unclear. Internal rotation, however, was reduced, which contradicts previous bone modeling studies, which we postulate is due to increased posterior capsular tension as it is forced to wrap around a larger 42 mm implant assembly. PMID- 25547854 TI - New endoprosthesis suspension method with polypropylene monofilament knitted mesh after resection of bone tumors in proximal humerus. AB - BACKGROUND: Endoprosthetic reconstruction of the proximal humerus is one of the standard procedures after resection of tumors of the proximal humerus and has been considered a reliable method to reconstruct the proximal humerus in recent reports. However, instability of the shoulder joint caused by loss of the rotator cuff and deltoid muscle function is often observed after such an endoprosthetic reconstruction. METHODS: We performed the endoprosthesis suspension method with polypropylene monofilament knitted mesh. This suspension method, by which the endoprosthesis is suspended from the bone structure, was used after resection of tumors in 9 patients. We assessed postoperative stability of the shoulder joint by comparing these patients with 12 patients who underwent the conventional surgical technique, by which the mesh-wrapped endoprosthesis is attached only to soft tissue. RESULTS: In radiographic and physical evaluation, 4 of the 12 patients in the soft tissue reconstruction group showed shoulder joint instability. No patient in the suspension method group showed subluxation of the humeral prosthesis. The mean shoulder flexion was 35 degrees and 65 degrees and the mean shoulder abduction was 40 degrees and 40 degrees for the soft tissue reconstruction group and the suspension method group, respectively. DISCUSSION: Shoulder joint subluxation sometimes occurs because of elongation of the attached soft tissue in the conventional reconstruction with mesh, whereas no shoulder joint subluxation occurs after endoprosthetic reconstruction in the suspension method because the bone structure has no leeway for elongation. Excellent stability of our new method enables exercise of the surgical shoulder at an early stage, leading to improved range of shoulder joint motion. PMID- 25547855 TI - Arthroscopic repair of a significant (>50%) partial-thickness subscapularis tear concomitant with a full-thickness supraspinatus tear: technical considerations for subscapularis repair (transtendon technique versus tear completion). AB - BACKGROUND: The purpose of this study was to compare clinical outcomes and structural integrity of arthroscopic repair by either transtendon repair or tear completion for a significant (>50%) partial-thickness articular-side subscapularis tear associated with a full-thickness supraspinatus tear. METHODS: The study population comprised 109 patients who underwent arthroscopic repair for partial-thickness subscapularis tears associated with full-thickness supraspinatus tears with either a transtendon technique (81 patients, group T) or tear completion (28 patients, group C). Pain on a visual analog scale; the Subjective Shoulder Value; the American Shoulder and Elbow Surgeons score; and the University of California, Los Angeles shoulder score were used to compare clinical outcomes between the 2 groups. At 6 months after surgery, magnetic resonance arthrography or computed tomographic arthrography was performed to assess structural integrity. RESULTS: At the 2-year follow-up, there were no significant differences in functional outcomes between groups. In group T, external rotation was reduced significantly from 55 degrees to 51 degrees (P < .001). The subscapularis and overall retear rates were 8% and 19%, respectively, in group T and 12% and 23%, respectively, in group C. There were no significant differences in retear rates between groups. CONCLUSIONS: Arthroscopic repair of partial-thickness subscapularis tears associated with full-thickness supraspinatus tears using either the transtendon technique or tear completion resulted in significant functional improvements in both groups except for postoperative external rotation in group T, and there were no significant differences between groups. The retear rates were also not significantly different between groups. However, after subscapularis repair using the transtendon technique, some patients may have decreased external rotation. PMID- 25547856 TI - Does fracture of the dominant shoulder have any effect on functional and quality of life outcome compared with the nondominant shoulder? AB - HYPOTHESIS: Proximal humeral fractures involving the dominant arm are not predisposed to worsen the functional outcome and the quality of life compared with proximal humeral fractures of the nondominant arm. METHODS: This was a retrospective study including 179 consecutive proximal humeral fractures divided into 2 groups: fractures involving the dominant arm (n = 97) and fractures involving the nondominant arm (n = 82). Both groups were prospectively assessed for 2 years, and at the end of the follow-up, all patients underwent functional assessment by Constant score and quality of life assessment through the 36-Item Short Form Health Survey (SF-36). RESULTS: At the 2-year follow-up, the mean Constant score of the whole series was 65.5 (64.1 in the dominant group and 66.8 in the nondominant group). No significant differences were noted between groups in the total Constant score or among any of the items of the Constant score (total Constant score, P = .43; pain, P = .63; activities of daily living, P = .70; forward elevation, P = .57; abduction, P = .52; lateral rotation; P = .90; internal rotation, P = .32; and strength, P = .24). The mean physical component summary score of the SF-36 at the 2-year follow-up was 40.8 (39.7 in the dominant group and 41.9 in the nondominant group). The mean mental component summary score of the SF-36 at the 2-year follow-up was 43.5 (44.2 in the dominant group and 42.7 in the nondominant group). No significant differences were noted between groups in any item of the SF-36 (physical component summary score, P = .29; mental component summary score, P = .51). CONCLUSION: No significant difference could be found relating to dominance in functional outcome and in the quality of life perception in proximal humeral fractures. Dominance of the affected shoulder has no influence and should not be used to make treatment decisions. PMID- 25547857 TI - Rapidly destructive arthrosis of the shoulder joints: radiographic, magnetic resonance imaging, and histopathologic findings. AB - BACKGROUND: Rapidly destructive arthrosis of the humeral head is a rare condition with an elusive pathophysiologic mechanism. In this study, radiographic and histopathologic findings were analyzed to determine the clinical characteristics of this rare condition. METHODS: We retrospectively analyzed 189 patients who underwent total shoulder arthroplasty from January 2001 to August 2012. Among them, 9 patients showed a particular pattern of rapid collapse of the humeral head on plain radiography and magnetic resonance imaging (MRI) within 12 months from symptom onset. Patients with trauma, rheumatoid arthritis, steroid intake, neurologic osteoarthropathy, osteonecrosis, renal osteoarthropathy, or gout were excluded. RESULTS: All patients were women, with a mean age of 72.0 years (range, 63-85 years). The right side was involved in 7 cases and the left in 2 cases. The mean duration of humeral head collapse was 5.6 months (range, 2-11 months) from the onset of shoulder pain. Plain radiographs of all patients showed a unique pattern of humeral head flattening, which appeared like a clean surgical cut with bone debris around the humeral head. MRI findings revealed significant joint effusion and bone marrow edema in the humeral head, without involvement of the glenoid. Pathologic findings showed both fragmentation and regeneration of bone matrix, representing fracture healing. CONCLUSION: The important features of rapidly destructive shoulder arthrosis are unique flattened humeral head collapse with MRI showing massive joint effusion and bone marrow edema in the remnant humeral head. This condition should be considered in the differential diagnosis of elderly women with insidious shoulder pain. PMID- 25547858 TI - Propionibacterium can be isolated from deep cultures obtained at primary arthroplasty despite intravenous antimicrobial prophylaxis. AB - BACKGROUND: Propionibacterium organisms are commonly recovered from deep cultures obtained at the time of revision arthroplasty. This study sought to determine whether deep cultures obtained at the time of primary arthroplasty can be substantially positive for Propionibacterium despite thorough skin preparation and preoperative intravenous antibiotic prophylaxis. METHODS: After timely administration of preoperative antibiotics chosen specifically for their activity against Propionibacterium and after double skin preparation, specimens from the dermis, fascia, capsule, synovium, and glenoid tissue were sterilely harvested from 10 male patients undergoing primary shoulder arthroplasty and were submitted for culture for Propionibacterium. RESULTS: Of the 50 specimens, 7 were positive for Propionibacterium: 3 in each of 2 patients and 1 in 1 patient. The specimen sources having positive anaerobic cultures were the dermis (1 of 10), fascia (2 of 10), synovium (1 of 10), and glenoid tissue (3 of 10). None of these patients had evidence of infection at the time of the arthroplasty. DISCUSSION AND CONCLUSION: Preoperative antibiotics and skin preparation do not always eliminate Propionibacterium from the surgical field of primary shoulder arthroplasty. The presence of these bacteria in the arthroplasty wound may pose a risk of delayed shoulder arthroplasty failure from the subtle type of periprosthetic infection typically associated with Propionibacterium. PMID- 25547859 TI - High specificity of MMSE pentagon scoring for diagnosis of prodromal dementia with Lewy bodies. AB - BACKGROUND: Patients with dementia with Lewy bodies (DLB) may display a different cognitive pattern from Alzheimer's disease (AD) with more severe impairment performing visuospatial/visuoconstructive tasks. The aim of this study was to investigate whether the analysis of the MMSE pentagon copy could be a useful diagnostic screening tool in prodromal DLB. METHODS: Fifty-three patients with Mild Cognitive Impairment (MCI) were followed over 3-years until a diagnosis of DLB (MCI-DLB: n = 30) and AD (MCI-AD: n = 23) were made according to standard criteria. At the first assessment patients underwent a thorough cognitive assessment including the Qualitative Scoring MMSE Pentagon Test (QSPT), the NPI, the UPDRS as well as questionnaires to determine fluctuations and sleep disorders. RESULTS: The percentage of subjects who were unable to determine the correct number of angles in the pentagon copy test was 45.1% of MCI-DLB and 8.3% of MCI-AD patients (sensitivity 41.1%; specificity 91%). Attentive/executive functions and visual-spatial abilities were worse in the MCI-DLB group, while episodic memory impairment was greater in MCI-AD. Subtle extrapyramidal signs (63%) and RBD symptoms (56%) were the most frequent clinical features supporting the diagnosis of MCI-DLB. CONCLUSIONS: We suggest that a poor performance in determining the number of angles when performing the pentagon copying test, together with the presence of subtle extrapyramidal signs and symptoms of RBD may serve as a predictive tool for early DLB. PMID- 25547860 TI - Dysfunctional action control as a specific feature of Parkinson's disease. AB - Parkinson's disease (PD) is characterised by motor deficits as well as cognitive alterations, particularly concerning frontal lobe control. Here, we were interested in whether executive function is abnormal already early in PD, as well as whether this dysfunction worsens as a part of the dementia in PD. The following groups engaged in tasks addressing action control: PD patients with mild and advanced motor symptoms (aPD) without dementia, PD patients with dementia (PDD), patients with Alzheimer's disease (AD) and healthy subjects (CON). Subjects either had to perform or inhibit button presses upon go and no-go cues, respectively. These cues were preceded by pre-cues, either randomly instructive of right or left hand preparation (switch condition), or repetitively instructive for one side only (non-switch condition). PDD and aPD omitted more go responses than CON. Furthermore, PDD disproportionally committed failures upon no go cues compared to CON. In the non-switch condition, PDD performed worse than AD, whose deficits increased to the level of PDD in the switch condition. Over all PD patients, task performance correlated with disease severity. Under the switch condition, task performance was low in both PDD and AD. In the non-switch condition, this also held true for advanced PD patients (with and without dementia), but not for AD. Thus, the deficits evident in PDD appear to develop from imbalanced inhibitory-to-excitatory action control generally inherent to PD. These results specify the concept of dysexecution in PD and differentiate the cognitive profile of PDD from that of AD patients. PMID- 25547861 TI - Relevance of sonography for botulinum toxin treatment of cervical dystonia: an expert statement. AB - Botulinum neurotoxin A (BoNT A) is the first-line treatment for cervical dystonia. However, although BoNT A has a favorable safety profile and is effective in the majority of patients, in some cases the treatment outcome is disappointing or side effects occur when higher doses are used. It is likely that in such cases either the target muscles were not injected accurately or unintended weakness of non-target muscles occurred. It has been demonstrated in clinical trials for spastic movement disorders that sonography-guided BoNT A injections could improve treatment outcome. As the published evidence for a benefit of sonography-guided BoNT injection in patients with cervical dystonia is scarce, it is the aim of this review to discuss the relevance of sonography in this indication and provide a statement from clinical experts for its use. The clear advantage of sonography-guided injections is non-invasive, real-time visualization of the targeted muscle, thus improving the precision of injections and potentially the treatment outcomes as well as avoiding adverse effects. Other imaging techniques are of limited value due to high costs, radiation exposure or non-availability in clinical routine. In the hands of a trained injector, sonography is a quick and non-invasive imaging technique. Novel treatment concepts of cervical dystonia considering the differential contributions of distinct cranial and cervical muscles can reliably be implemented only by use of imaging-guided injection protocols. PMID- 25547862 TI - Efficacy and safety of galantamine treatment for patients with Alzheimer's disease: a meta-analysis of randomized controlled trials. AB - Cholinesterase inhibitors treatment is considered as a common therapeutic approach for Alzheimer's disease (AD) by numerous reported studies, but the role of currently available drugs for AD is still controversial. Our study aimed to evaluate the efficacy and safety of galantamine for the treatment of AD, and provide the basis and reference for clinical rational drug use. Randomized controlled trials (RCTs) of galantamine for AD published up to April 30, 2014 were searched. A random or fixed-effect model was used to analyze outcomes which were expressed as risk ratios (RRs) or mean difference (MD) with a 95 % confidence interval (CI). Heterogeneity was assessed by Q test and I(2) statistic. The outcome measurements were as follows: the changes of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), Neuropsychiatric Inventory (NPI), Clinicians' Interview-Based Impression of Change with Caregiver's Input (CIBIC+), adverse effects and dropouts. Eleven articles with 4,074 participants were included. Administration of galantamine for 8-28 weeks (16-40 mg daily) led to significant improvements in ADAS-cog score [P < 0.00001, MD = -2.95, 95 % CI ( 3.32, -2.57)], MMSE score [P = 0.003, MD = 2.50, 95 % CI (0.86, 4.15)], NPI score [P = 0.001, MD = -1.58, 95 % CI (-2.54, -0.62)], and CIBIC+ scale [P < 0.00001, RR = 1.26, 95 % CI (1.15, 1.39)], but not in ADL score [P = 0.43, MD = 0.71, 95 % CI (-1.07, 2.48)]. More adverse events and dropouts occurred in the galantamine group than that in the placebo group, the differences were statistically significant (all P < 0.05). Galantamine could significantly improve cognitive, behavioral, and global performances in patients with AD. In addition, we need to use it with caution in the clinical treatment. PMID- 25547863 TI - The effect of a "surveillance nurse" telephone support intervention in a home care program. AB - This study is an evaluation of a unique "surveillance nurse" telephone support intervention for community-dwelling elderly individuals in a home care program. A combined propensity-based covariate-matching procedure was used to pair each individual who received the intervention ("treatment" condition, nT = 930) to a similar individual who did not receive the intervention ("control" condition, nC1 = 930) from among a large pool of potential control individuals (nC0 = 4656). The intervention consisted of regularly scheduled telephone calls from a surveillance nurse to proactively assess the individual's well-being, care plan status, use of and need for services (home support, adult day program, physiotherapy, etc.) and home environment (e.g., informal caregiver support). Treatment and control conditions were compared with respect to four service utilization outcomes: (1) rate of survival in the community before institutionalization in an assisted living or nursing home facility or death, (2) rate of emergency room registrations, (3) rate of acute care hospitalizations, and (4) rate of days in hospital, during home care enrollment. Results indicated a beneficial effect of the surveillance nurse intervention on reducing rate of service utilization by increasing the duration of the home care episode. PMID- 25547864 TI - Do statins cause dementia? PMID- 25547865 TI - Measuring acculturation and enculturation among Chinese Canadian older adults. AB - Cultural adaptation is important to assess; however, most acculturation measures are unidimensional with little psychometric data for older immigrants. This study assessed a bidimensional measure, the Vancouver Index of Acculturation (VIA; Ryder, Alden, & Paulhus, 2000), among 149 (mean age: 73.92 years) Chinese Canadians. Internal consistencies were .84 and .83 for the Mainstream and Heritage subscales respectively, and they were orthogonal. Convergent and discriminant validity were demonstrated by predicted correlations between the VIA subscales and age at immigration, years in Canada, English fluency, and the Belief in Chinese Culture and Values Scale (BCCV; Lai & Chau, 2007). The VIA accounted for significantly more variance in language ability than the BCCV, above and beyond acculturation proxies. Exploratory factor analysis replicated the two-factor structure reported by Ryder et al. (2000). A confirmatory factor analysis indicated poor fit. This study supports a bidimensional model of cultural adaptation among older Chinese Canadians. PMID- 25547867 TI - Are capecitabine and the active metabolite 5-Fu CNS penetrable to treat breast cancer brain metastasis? AB - Brain metastasis (BM) is increasingly diagnosed in Her2 positive breast cancer (BC) patients. Lack of effective treatment to breast cancer brain metastases (BCBMs) is probably due to inability of the current therapeutic agents to cross the blood-brain barrier. The central nervous system (CNS) response rate in BCBM patients was reported to improve from 2.6%-6% (lapatinib) to 20%-65% (lapatinib in combination with capecitabine). Lapatinib is a poor brain penetrant. In this study, we evaluated the CNS penetration of capecitabine and hoped to interpret the mechanism of the improved CNS response from the pharmacokinetic (PK) perspective. Capecitabine does not have antiproliferative activity and 5 fluorouracil (5-FU) is the active metabolite. Capecitabine was orally administered to mouse returning an unbound brain-to-blood ratio (Kp,uu,brain) at 0.13 and cerebrospinal fluid (CSF)-to-unbound blood ratio (Kp,uu,CSF) at 0.29 for 5-FU. Neither free brain nor CSF concentration of 5-FU can achieve antiproliferative concentration for 50% of maximal inhibition of cell proliferation of 4.57 uM. BCBM mice were treated with capecitabine monotherapy or in combination with lapatinib. The Kp,uu,brain value of 5-FU increased to 0.17 in the brain tumor in the presence of lapatinib, which is still far below unity. The calculated free concentration of 5-FU and lapatinib in the brain tumor did not reach the antiproliferative potency and neither treatment showed antitumor activity in the BCBM mice. The CNS penetration of 5-FU in human was predicted based on the penetration in preclinical brain tumor, CSF, and human PK and the predicted free CNS concentration was below the antiproliferative potency. These results suggest that CNS penetration of 5-FU and lapatinib are not desirable and development of a true CNS penetrable therapeutic agent will further improve the response rate for BCBM. PMID- 25547866 TI - [French Society for Biological Psychiatry and Neuropsychopharmacology task force. Formal consensus for the treatment of bipolar disorder: an update (2014)]. AB - As part of a process to improve the quality of care, the French Society for Biological Psychiatry and Neuropsychopharmacology developed in 2010 formal consensus guidelines for the treatment of bipolar disorder. The evolution of therapeutic options available in France for the treatment of bipolar disorder has justified the update of this guideline. The purpose of this work was to provide an updated and ergonomic document to promote its use by clinicians. This update focuses on two of the six thematic previously published (acute treatment and long term treatment). Aspects of the treatment of bipolar patients sparking debate and questions of clinicians (use of antidepressant, place of the bitherapy, interest of long-acting antipsychotics...) were also covered. Finally, we proposed graded recommendations taking into account specifically the risk-benefit balance of each molecule. PMID- 25547868 TI - Identification of 2-aminothiazolobenzazepine metabolites in human, rat, dog, and monkey microsomes by ion-molecule reactions in linear quadrupole ion trap mass spectrometry. AB - 2-Aminothiazolobenzazepine (2-ATBA), 7-[(1-methyl-1H-pyrazol-4-yl)methyl]-6,7,8,9 tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepin-2-amine, is a D2 partial agonist that has demonstrated antipsychotic effects in a rodent in vivo efficacy model. The metabolite profile showed that 2-ATBA is mainly metabolized by oxidation. However, identification of the oxidation site(s) in the 2-aminothiazole group presents a challenge for the traditional metabolite identification methods such as liquid chromatography/mass spectrometry and NMR due to the lack of unique tandem mass spectrometry fragmentation patterns for ions with the 2-aminothiazole group oxidized at different sites and the lack of stability for purification or reference standard synthesis. We describe the characterization of the oxidized heteroatoms of the 2-aminothiazole group via gas-phase ion-molecule reactions (GPIMR) in a modified linear quadrupole ion trap mass spectrometer. The GPIMR reagents used were dimethyl disulfide, tert-butyl peroxide, and tri(dimethylamino)borane. Each reagent was introduced into the ion trap through the helium line and was allowed to react with the protonated metabolites. The ionic ion-molecule reaction products and their fragmentation profiles were compared with the profiles of the ionic ion-molecule reaction products of protonated reference compounds that had specific heteroatom functionalities. The oxidized 2-aminothiazole metabolite of 2-ATBA showed a similar GPIMR profile to that of the reference compounds with a tertiary N-oxide functionality and distinct from the profiles of the reference compounds with N-aryl hydroxylamine, nitroso, or pyridine N-oxide functionalities. This study demonstrates the feasibility of fingerprinting the chemical nature of oxidized nitrogen functional groups via GPIMR profiling for metabolite structure elucidation. PMID- 25547871 TI - Ultrasound imaging of the anterior section of the eye of five different snake species. AB - BACKGROUND: Nineteen clinically normal snakes: six ball pythons (Python regius), six Burmese pythons (Python bivittatus), one Children's python (Antaresia childreni), four Amazon tree boas (Corallus hortulanus), and two Malagasy ground boas (Acrantophis madagascariensis) were subjected to ultrasound imaging with 21 MHz (ball python) and 50 MHz (ball python, Burmese python, Children's python, Amazon tree boa, Malagasy ground boa) transducers in order to measure the different structures of the anterior segment in clinically normal snake eyes with the aim to review baseline values for clinically important ophthalmic structures. The ultrasonographic measurements included horizontal spectacle diameter, spectacle thickness, depth of sub-spectacular space and corneal thickness. For comparative purposes, a formalin-fixed head of a Burmese python was subjected to micro computed tomography. RESULTS: In all snakes, the spectacle was thinner than the cornea. There was significant difference in spectacle diameter, and spectacle and corneal thickness between the Amazon tree boa and the Burmese and ball pythons. There was no difference in the depth of the sub-spectacular space. The results obtained in the Burmese python with the 50 MHz transducer were similar to the results obtained with micro computed tomography. Images acquired with the 21 MHz transducer included artifacts which may be misinterpreted as ocular structures. CONCLUSIONS: Our measurements of the structures in the anterior segment of the eye can serve as orientative values for snakes examined for ocular diseases. In addition, we demonstrated that using a high frequency transducer minimizes the risk of misinterpreting artifacts as ocular structures. PMID- 25547869 TI - Pain, distress, and anticipated recovery for older versus younger emergency department patients after motor vehicle collision. AB - BACKGROUND: Motor vehicle collisions (MVCs) are the second most common injury mechanism resulting in emergency department (ED) visits by older adults. MVCs result in substantial pain and psychological distress among younger individuals, but little is known about the occurrence of these symptoms in older individuals. We describe the frequency of and characteristics associated with pain, distress, and anticipated time for physical and emotional recovery for older adults presenting to the ED after MVC in comparison to younger adults. METHODS: In person interviews were conducted for adults presenting to one of eight EDs after MVC without an obvious fracture or injury requiring admission as part of two prospective studies. Pain severity was assessed using a 0-10 verbal scale. Distress was assessed using the Peritraumatic Distress Inventory (range 0-52). Patients were asked to estimate their expected time for physical and emotional recovery; these responses were dichotomized to <30 or >=30 days. ED pain and distress and associations between patient and collision characteristics and ED pain and distress were examined for patients age 65 years and older and patients age 18 to 64. RESULTS: Older (n = 96) and younger (n = 943) adults had the same mean pain scores (5.5, SD 2.5 vs. 5.5, SD 2.4). Distress scores were lower in older than in younger adults (15.5, SD 9 vs. 19.2, SD 10). A higher percentage of older adults than younger adults had an anticipated time to physical recovery >=30 days (41%, 95% confidence interval [CI] 28%-55% vs. 11%, 95% CI 9%-13%). Similarly, older adults were more likely to have an anticipated time for emotional recovery >=30 days (45%, 95% CI 35%-55% vs. 17%, 95% CI 15%-20%). Older adults were less likely than younger adults to have moderate or severe neck pain (score >=4) (25%, 95% CI 23% to 41% vs. 54%, 95% CI 48% to 60%) or back pain (31%, 95% CI 23% to 46% vs. 56%, 95% CI 51 to 62%) but more likely to have moderate or severe chest pain (42%, 95% CI 32% to 50% vs. 20%, 95% CI 16 to 23%). Pre-MVC depressive symptoms and pain catastrophizing were positively associated with pain and distress in both older and younger adults. CONCLUSIONS: In our cohort, older adults who presented to the ED after MVC experienced similar pain severity as younger patients and less distress but were more likely to estimate their times for physical and emotional recovery to be 30 days or more. Increased emergency provider awareness of acute pain and distress symptoms among older patients experiencing MVC may improve outcomes for these patients. PMID- 25547872 TI - Salt and sugar: their effects on blood pressure. AB - Both dietary salt and sugar are related to blood pressure (BP). The evidence for salt is much stronger, and various types of studies have consistently shown that salt is a major cause of raised BP, and a reduction from the current intake of ~ 9-12 g/day in most countries of the world to the recommended level of 5-6 g/day lowers BP in both hypertensive and normotensive individuals, in men and women, in all age groups and in all ethnic groups. Countries such as Finland and the UK that have successfully reduced salt intake have demonstrated a reduction in population BP and cardiovascular mortality, with major cost savings to the health service. The mechanisms whereby salt raises BP are not fully understood. The traditional concepts focus on the tendency for an increase in extracellular fluid volume. Increasing evidence suggests that small increases in plasma sodium may play an important role. There are several other factors that also increase BP, one of which is added sugars. The current high intake of added sugars increases obesity which, in turn, raises BP. Recent studies also suggest that added sugars, particularly those in soft drinks, may have a direct effect on BP. However, the relationship between soft drink consumption and BP could be, at least partially, mediated by the effect of salt intake on increasing soft drink consumption. Actions to reduce salt and sugar intake across the whole population will have major beneficial effects on health along with major cost savings. PMID- 25547873 TI - Murine cardiac growth, TRPC channels, and cGMP kinase I. AB - Signaling via cGMP-dependent protein kinase I (cGKI) and canonical transient receptor potential (TRPC) channels appears to be involved in the regulation of cardiac hypertrophy. Recent evidence suggests that TRPC channels are targets for cGKI, and phosphorylation of these channels may mediate the antihypertrophic effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on angiotensin II (A II)-induced cardiac hypertrophy using a control group (Ctr), trpc6(-/-), trpc3(-/-), trpc3(-/-)/6(-/-), betaRM mice, and trpc3(-/-)/6(-/-) * betaRM mice. betaRM mice express cGKIbeta only in the smooth muscle on a cGKI(-/-) background. The control group was composed of littermate mice that contained at least one wild type gene of the respective genotype. A II was infused by minipumps (7 days; 2 mg/kg/day) in Ctr, trpc6(-/-), trpc3(-/-), trpc3(-/-)/6(-/-), betaRM, and trpc3(-/-)/6(-/-) * betaRM mice. Hypertrophy was assessed by measuring heart weight per tibia length (HW/TL) and fibrosis by staining of heart slices. A II-induced increase in HW/TL and fibrosis was absent in trpc3 (-/-) mice, whereas an increase in HW/TL and fibrosis was evident in Ctr and trpc6(-/-), minimal or absent in trpc3(-/-), moderate in betaRM, and dramatic in trpc3(-/-)/6(-/-) betaRM mice. These results suggest that TRPC3 may be necessary for A II-induced cardiac hypertrophy. On the other hand, hypertrophy and fibrosis were massively increased in betaRM mice on a TRPC3/6 * cGKI(-/-)KO background, indicating an "additive" coupling between both signaling pathways. PMID- 25547874 TI - Pediatric anterior visual pathway gliomas: trends in fluid and electrolyte dynamics and their management nuances. AB - PURPOSE: Trends in pre- and postoperative fluid, electrolyte and osmolarity changes, and incidence of diabetes insipidus (DI) were assessed in pediatric patients with anterior visual pathway gliomas (AVPGs). METHODS: Thirty-three patients with AVPGs (age < 16 years) were divided into two groups: (1) no hypothalamic involvement [NHI; n = 17 (51.5 %) including optic (5, 15.2 %); chiasmal (5, 15.2 %); and optico-chiasmal (7, 21.2 %)] and (2) hypothalamic involvement [HI; n = 16 (48.5 %) including chiasmal-hypothalamic (12, 36.4 %) and optico-chiasmal-hypothalamic (4, 12.1 %)]. Frontotemporal transylvian decompression/biopsy was undertaken in 32 patients, while one patient (with severe diencephalic syndrome) was treated conservatively. Their endocrinal and fluid/electrolyte balance, serum osmolarity, and DI status were noted. Chi-square test compared clinical/endocrinological parameters, and unpaired T test evaluated mean daily water/electrolyte changes (p value < 0.05: significant). RESULTS: Significant visual deterioration (perception of light (PL) positive (left: n = 4; right: n = 4) and PL negative (left: n = 5; right: n = 5) was encountered due to optic atrophy. Larger lesions (>3 cm), hydrocephalus [(NHI: n = 7, 41.18 %; HI: n = 12, 75 %), endocrinopathies (p = 0.047), Na(+)/K(+) derangements, and preoperative DI (n = 8, p = 0.004)] were present in the group HI. Increased postoperative urine output (almost double in those with hypothalamic involvement) and hypernatremia/hyperkalemia were seen in group HI until the sixth postoperative day (p < 0.05). Two patients with progressive hypernatremia without increased urine output showed dehydration on central venous pressure monitoring and improved with vasopressin administration. Five patients [NHI: n = 4 (23.5 %); HI: n = 1 (6.3 %)] had neurofibromatosis types I and 3 (NHI: n = 1, 5.9 %; HI: n = 2, 12.5 %) had a diencephalic syndrome. CONCLUSIONS: Hypothalamic infiltration significantly increases the incidence of DI and fluid and electrolyte disturbances. Strict vigilance over postoperative fluid balance is mandatory during the first postoperative week. Rapidly rising serial serum sodium values without increased urine output mandates immediate central venous pressure measurement to detect DI associated with dehydration. PMID- 25547876 TI - Colony size is linked to paternity frequency and paternity skew in yellowjacket wasps and hornets. AB - BACKGROUND: The puzzle of the selective benefits of multiple mating and multiple paternity in social insects has been a major focus of research in evolutionary biology. We examine paternity in a clade of social insects, the vespine wasps (the yellowjackets and hornets), which contains species with high multiple paternity as well as species with single paternity. This group is particularly useful for comparative analyses given the wide interspecific variation in paternity traits despite similar sociobiology and ecology of the species in the genera Vespula, Dolichovespula and Vespa. We describe the paternity of 5 species of yellowjackets (Vespula spp.) and we perform a phylogenetically controlled comparative analysis of relatedness, paternity frequency, paternity skew, colony size, and nest site across 22 vespine taxa. RESULTS: We found moderate multiple paternity in four small-colony Vespula rufa-group species (effective paternity 1.5 - 2.1), and higher multiple paternity in the large-colony Vespula flavopilosa (effective paternity ~3.1). Our comparative analysis shows that colony size, but not nest site, predicts average intracolony relatedness. Underlying this pattern, we found that greater colony size is associated with both higher paternity frequency and reduced paternity skew. CONCLUSIONS: Our results support hypotheses focusing on the enhancement of genetic diversity in species with large colonies, and run counter to the hypothesis that multiple paternity is adaptively maintained due to sperm limitation associated with large colonies. We confirm the patterns observed in taxonomically widespread analyses by comparing closely related species of wasps with similar ecology, behavior and social organization. The vespine wasps may be a useful group for experimental investigation of the benefits of multiple paternity in the future. PMID- 25547875 TI - Is there an ideal shunt? A panoramic view of 110 years in CSF diversions and shunt systems used for the treatment of hydrocephalus: from historical events to current trends. AB - OBJECT: The goal of this study is to evaluate whether an "ideal shunt" exists. METHODS: This is a retrospective analysis based on original papers in the field of Hydrocephalus and Shunts. Patients of all age groups, who had hydrocephalus, and underwent some form of CSF diversion were included. The study has been divided into four stages: from 1900 to 1949, 1950 to 1974, 1975 to 1999, and from 2000 to 2010. RESULTS: In stage 1 (historical era): Saphenous vein grafts, rubber conduits, and other materials were used in CSF diversions. In 1949, the first implantable shunt tube was developed by Nulsen. In stage 2 (experimental stage): the Holter valve was developed. Newer innovations were developed in relation to the ventriculo-atrial shunt, which was the preferred CSF diversion. In stage 3 (developmental stage), a large number of different design shunt systems were developed, with the aim of reducing complications. The ventriculo-peritoneal shunt had become the preferred CSF diversion. Also, the programmable valve was born. In stage 4 (era of programmable valve, there is a preference for the use of programmable shunt systems. However, shunt failure rate at 1 year being around 25 to 40%, and shunt survival at 1 and 2 years are 50-70 and 47-53% in most series. CONCLUSION: Every shunt is an ideal shunt provided the choice of the shunt used should be made by the matching performance of the shunt system to the altered profile of CSF dynamics of a given patient. The most important factor being the opening pressure. PMID- 25547879 TI - Dignity therapy and its effect on the survival of terminally ill Portuguese patients. PMID- 25547877 TI - JRC GMO-Matrix: a web application to support Genetically Modified Organisms detection strategies. AB - BACKGROUND: The polymerase chain reaction (PCR) is the current state of the art technique for DNA-based detection of Genetically Modified Organisms (GMOs). A typical control strategy starts by analyzing a sample for the presence of target sequences (GM-elements) known to be present in many GMOs. Positive findings from this "screening" are then confirmed with GM (event) specific test methods. A reliable knowledge of which GMOs are detected by combinations of GM-detection methods is thus crucial to minimize the verification efforts. DESCRIPTION: In this article, we describe a novel platform that links the information of two unique databases built and maintained by the European Union Reference Laboratory for Genetically Modified Food and Feed (EU-RL GMFF) at the Joint Research Centre (JRC) of the European Commission, one containing the sequence information of known GM-events and the other validated PCR-based detection and identification methods. The new platform compiles in silico determinations of the detection of a wide range of GMOs by the available detection methods using existing scripts that simulate PCR amplification and, when present, probe binding. The correctness of the information has been verified by comparing the in silico conclusions to experimental results for a subset of forty-nine GM events and six methods. CONCLUSIONS: The JRC GMO-Matrix is unique for its reliance on DNA sequence data and its flexibility in integrating novel GMOs and new detection methods. Users can mine the database using a set of web interfaces that thus provide a valuable support to GMO control laboratories in planning and evaluating their GMO screening strategies. The platform is accessible at http://gmo crl.jrc.ec.europa.eu/jrcgmomatrix/ . PMID- 25547878 TI - Nociception and role of immune system in pain. AB - Both pain and inflammation are protective responses. However, these self-limiting conditions (with well-established negative feedback loops) become pathological if left uncontrolled. Both pain and inflammation can interact with each other in a multi-dimensional manner. These interactions are known to create an array of 'difficult to manage' pathologies. This review explains in detail the role of immune system and the related cells in peripheral sensitization and neurogenic inflammation. Various neuro-immune interactions are analyzed at peripheral, sensory and central nervous system levels. Innate immunity plays a critical role in central sensitization and in establishing acute pain as chronic condition. Moreover, inflammatory mediators also exhibit psychological effects, thus contributing towards the emotional elements associated with pain. However, there is also a considerable anti-inflammatory and analgesic role of immune system. This review also attempts to enlist various novel pharmacological approaches that exhibit their actions through modification of neuro-immune interface. PMID- 25547880 TI - Rehabilitation and medical issues of brain tumors. Editorial. PMID- 25547881 TI - Early and late endocrine effects in pediatric central nervous system diseases. AB - Endocrinopathies are frequently linked to central nervous system disease, both as early effects prior to the disease diagnosis and/or late effects after the disease has been treated. In particular, tumors and infiltrative diseases of the brain and pituitary, such as craniopharyngioma, optic pathway and hypothalamic gliomas, intracranial germ cell tumor, and Langerhans cell histiocytosis, can present with abnormal endocrine manifestations that precede the development of neurological symptoms. Early endocrine effects include diabetes insipidus, growth failure, obesity, and precocious or delayed puberty. With improving prognosis and treatment of childhood brain tumors, many survivors experience late endocrine effects related to medical and surgical interventions. Chemotherapeutic agents and radiation therapy can affect the hypothalamic-pituitary axes governing growth, thyroid, gonadal, and adrenal function. In addition, obesity and metabolic alterations are frequent late manifestations. Diagnosing and treating both early and late endocrine manifestations can dramatically improve the growth, well-being, and quality of life of patients with childhood central nervous system diseases. PMID- 25547882 TI - Facial paralysis reconstruction in children and adolescents with central nervous system tumors. AB - Facial paralysis remains a vexing problem in the treatment of posterior cranial fossa tumors in children. Fortunately, current techniques are available to reconstruct the paralyzed face in restoring balance, symmetry, and amelioration of functional sequelae. The restoration of structure and function of the paralyzed face is tantamount to proper social integration and psychosocial rehabilitation. In addition, the facial nerve is important in preventing drying of the eyes, drooling, and speech abnormalities, among other functions. The most visible evidence of facial paralysis is stark asymmetry, especially with animation. This is perhaps the most troubling aspect of facial paralysis and the one that leads to the greatest amount of psychosocial stress for the child and family members. Management strategies include early and late intervention. Early reconstructive goals focus on preservation and strengthening of intact motor end plates through native stimulatory pathways. Late reconstructive efforts are centered on surgically reconstructing permanently lost function based on each third of the face. Use of adjunct modalities such as chemical or surgical denervation and myectomies are also critical tools in restoring symmetry. Physical therapy plays a large role in both early and late facial nerve paralysis in optimizing cosmetic and functional outcome. PMID- 25547883 TI - Supporting students with brain tumors in obtaining school intervention services: the clinician's role from an educator's perspective. AB - With an increase in the number of pediatric patients surviving the diagnosis and treatment of brain tumors, many children are returning to school with an alteration in their physical, cognitive, and social-emotional functioning and thus requiring school intervention or services. Physicians and clinicians in hospital and rehabilitation settings serving this population can play a key role in communicating the medical and functional needs these children present as a result of diagnosis and treatment as they transition to an educational setting. Medical and allied health personnel can best support successful school transition when they are aware of the information schools require in order to open the door for students to easily access the interventions, supports, and services available through 504 Accommodation Plans and special education supports and services under the Individuals with Disabilities Education Act. Clear communication between medical and school personnel is vital in improving educational, social, and vocational outcomes for students with brain tumors. A streamlined approach to accomplish this task is offered for consideration. PMID- 25547884 TI - Neurosurgical care of pediatric brain tumor patients in a rehabilitation unit. AB - As brain tumor patients are transferred to a rehabilitation unit in a stable condition, subsequent neurosurgical involvement is needed to address later developing complications. Problems of cerebrospinal fluid circulation are the most common and include shunt malfunction. Infection is the next in frequency, with wound and shunt infection the most likely. Bleeding rarely occurs, especially acutely, and is more apt to be seen with chronic subdural hematomas. PMID- 25547885 TI - Cerebellar mutism: the rehabilitation challenge in pediatric neuro-oncology: case studies. AB - Cerebellar Mutism Syndrome (CMS), also known as posterior fossa syndrome (CMS/PFS), refers to a transient loss of speech followed by dysarthria and is a common complication in the pediatric population following resection of a cerebellar tumor. Recognition and rehabilitation of CMS is critical in the post operative phases of recovery. Two case studies, including neuropsychological assessments, along with the family and patient's perspectives are reviewed. PMID- 25547886 TI - Depressive symptoms in parents of adolescents with myelomeningocele: the association of clinical, adolescent neuropsychological functioning, and family protective factors. AB - PURPOSE: The purpose of this study is to determine if neuropsychological functioning and family protective factors are related to depressive symptoms in parents of adolescents with myelomeningocele (MMC). METHODS: Fifty adolescents (28 females, 22 males; predominately Caucasian; ages 12-21 years, M=15.7, SD=2.4) and their parents from a large Midwestern MMC Program participated in a cross sectional descriptive mixed-methods study. Participants completed measures of adolescent clinical status (WeeFIM(r), Demographic and Clinical Information Form), neuropsychological (NP) functioning, family protective factors and parents' depressive symptoms. RESULTS: Parents' depressive symptoms correlated significantly with NP functioning in the domains of Mental Processing Speed, Psychomotor Speed, Executive Functioning, Fine Motor Skills, and Language, and with each self-reported family protective factor. Multiple regression analysis revealed independent main effects for the NP variable, Executive Functioning and the Family Protective Factors Composite (p< 0.05); there was no interaction (p> 0.10). CONCLUSION: Clinicians are especially encouraged to include assessment of parental depressive symptoms if the adolescent has executive functioning impairments or if the parents have few family protective factors. PMID- 25547888 TI - Conservative management of lymphoedema in children: a systematic review. AB - PURPOSE: A systematic literature review was conducted to determine best practice conservative management of pediatric lymphoedema. METHOD: The PRISMA protocol was followed; a search of Ovid Medline, Cinahl and Scopus was conducted using the search terms children OR pediatric OR adolescent AND lymphoedema OR lymphedema. Studies about management or treatment of lymphoedema in children were included while studies about filariasis, imaging, pathology, secondary lymphoedema, surgical techniques, central lymphoedema and those with participants with a median age greater than 18 years were excluded. RESULTS: Of 738 possible studies identified, eight studies were eligible for inclusion in the review: four case reports, two retrospective service reviews and two prospective studies investigating different interventions. All studies were rated using the NHMRC hierarchy of evidence and appraised by both authors using the McMaster University Critical Review Form. Studies were of low quality with poor descriptions of management, small sample size, unclear and inconsistent methodology and irreproducible outcome measures. CONCLUSION: This review identified low level evidence to support the use of pneumatic compression in the management of pediatric lymphoedema. Further research is required to identify optimal parameters for application of pneumatic compression and to investigate the use of other interventions for conservative management of pediatric lymphoedema. PMID- 25547887 TI - Isokinetic muscle strength differences in patients with mucopolysaccharidosis I, II, and VI. AB - PURPOSE: To determine muscular strength differences in patients with MPS-I, II, and VI versus age- and sex-matched healthy controls. METHODS: Dominant leg isokinetic knee extension strength was measured at 90 and 120 degrees per second (d/s) using a dynamometer in 30 subjects with MPS and 42 controls (5-16 yrs). MPS I was further divided into MPS-IA (attenuated) and MPS-IH (severe). Strength measures analyzed were peak torque (PkT), peak torque per unit body weight (PkT/BW) and per unit lean body mass (PkT/LBM), and average power (AP). RESULTS: Following adjusting strength measures for age, MPS-IH and MPS-II had significantly lower strength measures for all variables at both angular velocities. MPS-VI had significantly lower PkT, PkT/LBM, and AP compared to controls at 90 and 120d/s. In contrast, MPS-IA was not significantly different from controls for any strength variable at either angular velocity. CONCLUSION: The results of this study suggest that decrements in skeletal muscle strength depend on MPS diagnosis and severity of disease. Children with MPS-IH demonstrate the greatest difference in muscular strength compared to healthy controls. PMID- 25547889 TI - Bilateral congenital deficiency of tibia: a case report. AB - INTRODUCTION: Tibial hemimelia/amelia is a rare congenital anomaly characterized by deficiency of the tibia with relatively intact fibula. They can be identified as an isolated disorder or as part of malformation syndromes. This presentation expands the spectrum of tibial hemimelia characterizing its great clinical and radiological variability. OBSERVATION: A five year old female child, born to unaffected and non-consanguineous parents, presented with deformity and shortening of both legs. There was no other structural anomaly except in both lower limbs. Radiological imaging showed absence of the tibia, angulation of fibula and tarsal coalition of right side. Femur was seen to be normal in both lower limbs while patella, tibia and talus were absent on left side along with 1st ray deficiency. Severe varus deformity was seen in both feet. The parents were not willing for corrective surgery, therefore extension prosthesis was devised. DISCUSSION AND CONCLUSION: We report a case of tibial hemimelia as well as to suggest methods to manage and rehabilitate such patients. A congenital malformations surveillance and record system needs to be developed to identify the demographic parameters, etiology, risk factors and associations of all types of limb deficiencies. Need is felt of a classification system which includes broader spectrum of limb malformations. PMID- 25547895 TI - Hybrid neurofibroma/schwannoma in neurofibromatosis type I exhibiting high FDG uptake in PET imaging. PMID- 25547896 TI - Monitoring changes in thioredoxin and over-oxidised peroxiredoxin in response to exercise in humans. AB - INTRODUCTION: Peroxiredoxin (PRDX) and thioredoxin (TRX) are antioxidant proteins that control cellular signalling and redox balance, although their response to exercise is unknown. This study aimed to assess key aspects of the PRDX-TRX redox cycle in response to three different modes of exercise. METHODS: Healthy males (n = 10, mean +/- SD: 22 +/- 3 yrs) undertook three exercise trials on separate days: two steady-state cycling trials at moderate (60% [Formula: see text]O2MAX; 27 min, MOD) and high (80% [Formula: see text]O2MAX; 20 min, HIGH) intensities, and a low-volume high-intensity interval training trial (10 * 1 min 90% [Formula: see text]O2MAX, LV-HIIT). Peripheral blood mononuclear cells were assessed for TRX-1 and over-oxidised PRDX (isoforms I-IV) protein expression before, during, and 30 min following exercise (post + 30). The activities of TRX reductase (TRX R) and the nuclear factor kappa B (NF-kappaB) p65 subunit were also assessed. RESULTS: TRX-1 increased during exercise in all trials (MOD, + 84.5%; HIGH, + 64.1%; LV-HIIT, + 205.7%; p < 05), whereas over-oxidised PRDX increased during HIGH only (MOD, - 28.7%; HIGH, + 202.9%; LV-HIIT, - 22.7%; p < .05). TRX-R and NF kappaB p65 activity increased during exercise in all trials, with the greatest response in TRX-R activity seen in HIGH (p < 0.05). DISCUSSION: All trials stimulated a transient increase in TRX-1 protein expression during exercise. Only HIGH induced a transient over-oxidation of PRDX, alongside the greatest change in TRX-R activity. Future studies are needed to clarify the significance of heightened peroxide exposure during continuous high-intensity exercise and the mechanisms of PRDX-regulatory control. PMID- 25547897 TI - Transglutaminase 2 is involved in homocysteine-induced activation of human THP-1 monocytes. AB - Aberrant transglutaminase 2 (TG2) expression and protein cross-linking activity have been associated with several chronic neurodegenerative disorders in which inflammatory processes triggered by activated microglia and monocytes play a key role, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Interestingly, mild-to-moderate hyperhomocysteinemia (HHcy), corresponding to increased plasma homocysteine (Hcy) concentrations in the range 16-60 MUM, have recently been associated with the above-cited diseases. Using THP-1 monocytes, here we investigated the role of TG2 in cell response to mildly elevated Hcy concentrations. A five-day incubation with Hcy (~25 MUM) increased reactive oxygen species, peroxide lipids, as well as 8-hydroxyguanosine levels by twofold, and decreased the endogenous cell antioxidant defenses, that is reduced glutathione, by 50% in Hcy-exposed cultures compared with controls (p < 0.01). Hcy-induced oxidative stress was associated with increases in TG2 expression and activity, as well as nuclear factor kappa B activation. Notably, the latter was reduced in the presence of the TG-specific inhibitor R283. Hcy exposure also significantly increased the mRNA levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-1beta, as well as the level of Hcy-inducible endoplasmic reticulum (ER) stress protein, a marker of ER stress, in Hcy-exposed cultures compared with controls. Notably, these effects were dramatically reduced by R283. These preliminary findings indicate that TG2 plays a key role in Hcy-induced activation of THP-1 monocytes, involving oxidative as well as ER stress and inflammation. This underlines the potential of TG2 inhibition in the therapeutic management of inflammatory processes contributing to neurodegenerative disorders associated with mild HHcy. PMID- 25547898 TI - Theoretical study on the composition location of the best glass formers in Cu-Zr amorphous alloys. AB - This study combines the molecular dynamics (MD) simulations and first-principles approach to explain the experimental observation that the best glass formers of Cu-Zr bulk metallic glasses (BMGs) have the compositions Cu50Zr50 and Cu64Zr36. These two best glass formers are first calculated to be most abundantly composed of Cu6Zr7 and Cu8Zr5 icosahedral clusters when compared in the compositional range of CuxZr100-x (45 <= x <= 70), and then these two icosahedral clusters are calculated to have the lowest formation energy among the icosahedral clusters CuxZr13-x (3 <= x <= 10), as well as possessing some characteristics in electronic structure and chemical hardness. Through understanding the properties of specific icosahedral clusters in metallic glasses, the structural and energetic contribution to the glass-forming ability are systematically discussed. PMID- 25547899 TI - High expression of vacuolar protein sorting 4B (VPS4B) is associated with accelerated cell proliferation and poor prognosis in human hepatocellular carcinoma. AB - Vacuolar protein sorting 4B (VPS4B) is a member of ATPase family proteins that have been shown to play important roles in the formation of MVBs, virus budding and abscission of cytokinesis. In this study, we investigated the prognostic role of VPS4B in human hepatocellular carcinoma (HCC) and its effect on the growth of HCC cells. Western blot and immunohistochemistrical analyses revealed that VPS4B was significantly upregulated in 98 HCC tissues, compared with adjacent nontumorous samples. Meanwhile, clinicopathological variables and univariate and multivariate survival analyses showed that high VPS4B expression was correlated with multiple clinicopathological factors, including AJCC stage, microvascular invasion, Ki-67 and a poor prognosis. More importantly, univariate and multivariate survival analyses demonstrated that VPS4B served as an independent prognostic factor for survival in HCC patients. Furthermore, we found that VPS4B was lowly expressed in serum-starved Huh7 and HepG2 HCC cells, and was progressively increased after serum-refeeding. To study whether VPS4B could regulate the proliferation of HCC cells, VPS4B was knocked down in both Huh7 and HepG2 cells through the transfection of VPS4B-siRNA oligos. Flow cytometry and CCK-8 assay results indicated that interference of VPS4B led to cell cycle arrest and reduced cell proliferation of HCC cells. Taken together, our results implied that VPS4B could be a candidate prognostic biomarker as well as a potential therapeutical target of HCC. PMID- 25547900 TI - Aspirin plus clopidogrel as secondary prevention after stroke or transient ischemic attack: a systematic review and meta-analysis. AB - BACKGROUND: Antiplatelet agents are the mainstay for secondary prevention of non cardioembolic stroke. This systematic review examined the safety and efficacy of short-, middle-, and long-term aspirin in combination with clopidogrel as secondary prevention of stroke or transient ischemic attack (TIA) of presumed arterial origin. METHODS: PubMed, EmBase, and CENTRAL were searched up to May 2014. Randomized controlled trials (RCTs) that compared aspirin plus clopidogrel versus aspirin or clopidogrel as secondary prevention of stroke or TIA of arterial origin were included. The analyses were stratified into short-term (<=3 months), middle-term (>3 months and <1 year), and long-term (>=1 year). Outcomes were compared using risk ratio (RR) and 95% confidence interval (95% CI). RESULTS: Eight RCTs (20,728 patients) were included in the overall analysis. Compared with aspirin or clopidogrel alone, the complete analysis of all the data indicated that the combination therapy significantly reduced the risk of stroke recurrence (RR, 0.82; 95% CI 0.70-0.96, p = 0.01) and major vascular events (RR, 0.84; 95% CI 0.73-0.96, p < 0.01). But the risk of hemorrhagic stroke (RR, 1.59; 95% CI 1.08-2.33, p = 0.02) and major bleeding (RR, 1.83; 95% CI 1.37-2.45, p < 0.01) was increased. No RCT studied middle-term combination therapy. The analyses were therefore stratified into only two subgroups, short- and long-term treatment. Stratified analysis of short-term treatment showed that relative to monotherapy, the drug combination reduced the risk of stroke recurrence (RR, 0.69; 95% CI 0.59-0.81, p < 0.01) and did not increase the risk of hemorrhagic stroke (RR, 1.23; 95% CI 0.50-3.04, p = 0.65) and major bleeding events (RR, 2.17; 95% CI 0.18-25.71, p = 0.54). Short-term combination therapy was associated with a significantly lower risk of major vascular events (RR, 0.70; 95% CI 0.69 to 0.82, p < 0.01). Stratified analysis of long-term treatment revealed that the combination treatment did not decrease the risk of stroke recurrence (RR, 0.92; 95% CI 0.83-1.03, p = 0.15), but was associated with a significantly higher risk of hemorrhagic stroke (RR, 1.67; 95% CI 1.10-2.56, p = 0.02) and major bleeding events (RR, 1.90; 95% CI 1.46-2.48, p < 0.01). Long-term combination therapy failed to reduce the risk of major vascular events (RR, 0.92; 95% CI 0.84-1.03, p = 0.09). CONCLUSIONS: Compared with monotherapy, short-term aspirin in combination with clopidogrel is more effective as secondary prevention of stroke or TIA without increasing the risk of hemorrhagic stroke and major bleeding events. Long-term combination therapy does not reduce the risk of stroke recurrence, and is associated with increased major bleeding events. The clinical applicability of the findings of this systematic review, however, needs to be confirmed in future clinical trials. PMID- 25547901 TI - Should Tyrosine Kinase Inhibitors Be Considered for Advanced Non-Small-Cell Lung Cancer Patients With Wild Type EGFR? Two Systematic Reviews and Meta-Analyses of Randomized Trials. AB - Guidance concerning tyrosine kinase inhibitors (TKIs) for patients with wild type epidermal growth factor receptor (EGFR) and advanced non-small-cell lung cancer (NSCLC) after first-line treatment is unclear. We assessed the effect of TKIs as second-line therapy and maintenance therapy after first-line chemotherapy in two systematic reviews and meta-analyses, focusing on patients without EGFR mutations. Systematic searches were completed and data extracted from eligible randomized controlled trials. Three analytical approaches were used to maximize available data. Fourteen trials of second-line treatment (4388 patients) were included. Results showed the effect of TKIs on progression-free survival (PFS) depended on EGFR status (interaction hazard ratio [HR], 2.69; P = .004). Chemotherapy benefited patients with wild type EGFR (HR, 1.31; P < .0001), TKIs benefited patients with mutations (HR, 0.34; P = .0002). Based on 12 trials (85% of randomized patients) the benefits of TKIs on PFS decreased with increasing proportions of patients with wild type EGFR (P = .014). Six trials of maintenance therapy (2697 patients) were included. Results showed that although the effect of TKIs on PFS depended on EGFR status (interaction HR, 3.58; P < .0001), all benefited from TKIs (wild type EGFR: HR, 0.82; P = .01; mutated EGFR: HR, 0.24; P < .0001). There was a suggestion that benefits of TKIs on PFS decreased with increasing proportions of patients with wild type EGFR (P = .11). Chemotherapy should be standard second-line treatment for patients with advanced NSCLC and wild type EGFR. TKIs might be unsuitable for unselected patients. TKIs appear to benefit all patients compared with no active treatment as maintenance treatment, however, direct comparisons with chemotherapy are needed. PMID- 25547903 TI - Creation of a metric for faculty effort in teaching in the veterinary curriculum. AB - A teaching-effort metric was generated using information from health sciences literature and self-reported data from faculty members. This metric was used to verify faculty effort based on teaching assignments, to equalize teaching between faculty members within disciplines, and to help faculty members understand the ramifications of new teaching opportunities on their overall effort. PMID- 25547902 TI - Intercalated Dosing Schedule of Erlotinib and Docetaxel as a Therapeutic Strategy to Avoid Antagonism and Optimize Its Benefits in Advanced Non-Small-Cell Lung Cancer. A Randomized Phase II Clinical Trial. AB - INTRODUCTION: The purpose of this study was to assess whether an intercalated dosing schedule of erlotinib and docetaxel could avoid possible negative interactions and optimize the benefit obtained as second-line therapy in non small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A phase II randomized clinical trial was designed for advanced NSCLC patients in whom previous chemotherapy treatment had failed. The experimental arm with 33 patients consisted of erlotinib 150 mg/d orally, intermittent administration on days 2 to 16 every 21 days, combined with docetaxel 75 mg/m(2) every 21 days; the control arm with 35 patients consisted of erlotinib 150 mg/d orally, administered continuously. The study's primary end point was the proportion of patients who remained progression-free at 6 months in the 2 arms. RESULTS: The proportion of patients who remained progression-free at 6 months was of 5 patients (15%) in the intercalated arm and 3 patients (9%) in the erlotinib monotherapy arm respectively. Median progression-free survival (PFS) was 3.0 versus 2.1 months (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.39-1.06; P = .086). Median overall survival (OS) was 7.5 and 5.2 months (HR, 0.70; 95% CI, 0.41-1.19; P = .19). Disease control rates were 51.7% and 36.4%, respectively. No new safety signals were observed. CONCLUSION: Erlotinib and docetaxel with intermittent administration of erlotinib improved PFS, OS, and disease control rates compared with erlotinib alone. All of our results indicated that an intercalated dosing schedule of erlotinib and docetaxel could be more efficient than erlotinib treatment alone. Therefore, further studies should be developed in a larger number of patients. This study has shown the absence of antagonism between docetaxel and erlotinib when given in an intercalated fashion. PMID- 25547904 TI - Validation of an effective, easy-to-make hemostasis simulator. AB - The purpose of this study is to describe the construction method of a cost effective, easy-to-make hemostasis simulator and to compare its effectiveness as a training tool to cadaver training. The simulator is made of materials commonly found in hospitals and clinics. These include a column manometer, a 500-ml saline bag, two intravenous fluid lines, a three-way stopcock, and a 6-mm-diameter Penrose drain. The device was tested on 10 final-year veterinary students. All participants tied 40 knots on the simulator and 40 knots on equine jejunal arteries sourced from a local abattoir. They were then asked to fill out a questionnaire comparing both methods. Participants assigned an overall assessment median score of 8.5/10 to the simulator and of 6.2/10 to cadaver practice. The simulator provided reliable haptic feedback, giving trainees a lifelike feel very close to that experienced when actually closing a blood vessel. In addition, it was effective in objectively evaluating students' ability to place ligatures on vessels. After adequate training, students' skills had significantly improved, alongside their confidence in placing hemostatic sutures. This proves our model is also useful in teaching basic open-surgery skills. Finally, its low production cost makes it ideally suited for self-practice. PMID- 25547906 TI - Assessment literacy: definition, implementation, and implications. AB - This paper explores the current notion of assessment literacy and describes delivery and evaluation of an intervention to support its development in two different cohorts in a veterinary curriculum. Before the intervention, two cohorts (Cohort A, first-year students; Cohort B, third-year students) were surveyed on their expectations and understanding of assessment. The new students expressed uncertainty about their understanding of the assessment process: 51% disagreed that they had a good understanding. As expected, more experienced students had a better understanding, although 30% still disagreed that they had a good understanding of the process. A workshop supporting the development of assessment literacy was implemented, giving students an opportunity to evaluate authentic student work of differing standards. Most of the students in both cohorts found the session helpful in terms of their understanding of different standards in assessments (92% and 97%), and most found it helped them understand how to prepare for the degree examination better (75% and 87%). Student grades were recorded in the workshop involving Cohort B, revealing a large variation in students' ability to grade other students' work accurately, with bias ranging from 22% to -25%. Finally, faculty views on student preparedness for assessment were also explored and compared to student views. Disagreement existed between faculty regarding perceived student preparedness for assessment, and significantly more faculty than students thought that students had a good understanding of how their assessments would be graded. The implications of these results for future work and faculty development are discussed. PMID- 25547905 TI - Associations among depressive symptoms, drinking motives, and risk for alcohol related problems in veterinary students. AB - Hazardous alcohol consumption among medical students appears to occur at a level comparable to the general population; however, among medical students, it has been found that the motivation to use alcohol partially stems from unique stressors related to their professional training. Although veterinary students may also experience psychological distress in association with their training, little work has focused on the way that these students use alcohol to cope with their distress. The current study sought to examine the severity of depressive symptoms and alcohol consumption among veterinary students as well as students' specific motives for drinking alcohol. The majority of our sample reported experiencing at least one depressive symptom, and a significant proportion engaged in high-risk drinking, with men reporting more harmful alcohol use patterns. Drinking motives related to managing internal bodily and emotional states accounted for variance in drinking patterns. Further, drinking to ameliorate negative emotions partially accounted for the relationship between psychological distress and high-risk drinking. The results of this study suggest that depressive symptoms among veterinary students may be related to harmful drinking patterns, due to alcohol being used as a coping mechanism to regulate emotions. The findings from this study can be used to develop targeted interventions to promote psychological well-being among veterinary students. PMID- 25547907 TI - A novel role for the calcium sensing receptor in rat diabetic encephalopathy. AB - BACKGROUND: Diabetic encephalopathy is a common complication of diabetes, and it may be involved in altering intracellular calcium concentrations ([Ca(2+)]i) at its onset. The calcium sensing receptor (CaSR) is a G-protein coupled receptor, however, the functional involvement of CaSR in diabetic encephalopathy remains unclear. METHODS: In this study, diabetic rats were modeled by STZ (50 mg/kg). At the end of 4, 8 and 12 weeks, the CaSR expression in hippocampus was analyzed by Western blot. In neonatal rat hippocampal neurons, the [Ca(2+)]i was detected by laser scanning confocal microscopy, the production of reactive oxygen species (ROS) in mitochondria, the level of NO and the mitochondrial transmembrane potential were measured by MitoSOX, DAF-FM and JC-1, respectively. RESULTS: Our results showed in hippocampal neurons treated with high glucose, CaSR regulated [Ca(2+)]i through the PLC-IP3 pathway. CaSR expression was decreased and was involved in the changes in [Ca(2+)]i. Mitochondrial membrane potential, NO release and expression of p-eNOS decreased, while the production of ROS in mitochondria increased. CONCLUSION: Down-regulation of CaSR expression was accompanied by neuronal injury, calcium disturbance, increased ROS production and decreased release of NO. Up-regulation of CaSR expression attenuated these changes through a positive compensatory protective mechanism to inhibit and delay diabetic encephalopathy in rats. PMID- 25547908 TI - CXCR3, CXCR5, CXCR6, and CXCR7 in Diabetes. AB - Many studies have suggested that CXCR3, CXCR5, CXCR6 and CXCR7 chemokine receptors are determinant in type 1 diabetes (T1D), expecially in autoimmunity and beta-cell destruction. In particular circulating CXCL10 level (the ligand of CXCR3) is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Blocking the CXCL10/CXCR3 axis in newly onset of diabetes seems to be a potential strategy for the therapy of T1D. Attempts have been done in modulating or blocking CXCR5, CXCR6 and CXCR7 chemokine receptors in experimental settings of T1D. More researches are necessary to evaluate the interplay among cytokines, chemokines and the pathogenesis and therapy of T1D. PMID- 25547909 TI - Inflammasome, inflammation and cancer: an interrelated pathobiological triad. AB - Cancer represents a major health problem worldwide, therefore on the basis of current research results constantly more effective therapeutic strategies are expected. Chronic, unchecked inflammation has widely been suggested to trigger carcinogenesis. The innate immune system ensures a first line host defense in which the inflammasome is essential maintaining a delicate balance betweeen pro- and anti-inflammatory signals in order to generate an appropriate immune response without harming the host. Studies have revealed a remarkable, but contradictory link of host inflammatory responses to tumorigenesis. Indeed, activation of the multiprotein complex inflammasome by danger signals seems to play diverse and sometimes conflicting, suppressive or stimulatory role in cancer development and progression with a significant context-dependency. The pleitropic inflammasomes may act at cell-autonomous level to eliminate malignant cells via the programmed cell death type of inflammatory pyroptosis, but on the contrary, may favor the production of gowth and trophic factors for tumor cells and their microenvironment. Further, upon caspase-1 activation the inflammasome can provoke sterile inflammation, and thus facilitate carcinogenesis, though in antigen presenting cells it can elicit anti-tumor immune responses. Clarifying the exact, context-specific impact of inflammasomes on tumorigenesis represents a new research area with the potential to introduce promising novel targets for cancer therapeutics. PMID- 25547910 TI - Molecular foundations for personalized therapy in prostate cancer. AB - Prostate cancer is the most common and second most lethal cancer in men. The majority of prostate cancers are histologically similar to acinar adenocarcinomas and rely on androgen-dependent signaling for their development and progression. Androgen deprivation therapy is a mainstay of treatment regimens and we discuss the recent advancements in androgen-deprivation therapy. Recent advances in defining the genetic landscape of prostate cancer have shown that the depth of genetic heterogeneity surpasses what can be seen histologically and has the ability to redefine treatments. TMPRSS2-ETS family fusion proteins are unique to prostate cancer and we discuss their role in carcinogenesis, prognosis, and the development of TMPRSS2-ETS family gene fusion targeted therapy. Inactivation of the tumor suppressor PTEN leads to activation of the PI3K/Akt/mTOR pathway and we discuss the prognostic and treatment implications. Molecular genetic analysis has recently demonstrated that clinically aggressive high grade neuroendocrine prostate carcinomas contain a high prevalence of overexpression of Aurora A kinase and N-myc. We discuss the role of Aurora A kinase and N-myc in the development of the aggressive neuroendocrine phenotype and the development of targeted inhibitors of this specific genetic subtype. Lastly, we briefly discuss emerging genetic subtypes defined by either SPINK1 overexpression, CHD1 inactivation, or SPOP mutations. By reviewing the associations between the morphologic features and the molecular genetics of prostate cancer we hope to provide insight and guidance to the emerging options for targeted therapy. PMID- 25547913 TI - Thy28 protects against anti-CD3-mediated thymic cell death in vivo. AB - Apoptotic cell death plays a pivotal role in the development and/or maintenance of several tissues including thymus. Deregulated thymic cell death is associated with autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), a prototype murine model for analysis of human multiple sclerosis. Because Thy28 expression is modulated during thymocyte development, we tested whether Thy28 affects induction of EAE as effectively as antigen-induced thymocyte deletion using Thy28 transgenic (TG) mice. Thy28 TG mice showed partial resistance to anti-CD3 monoclonal antibody (mAb)-induced thymic cell death in vivo, as assessed by annexin V-expression and loss of mitochondrial membrane potential. The resistance to anti-CD3 mAb-induced cell death in Thy28 TG mice appeared to correlate with a decreased c-Jun N-terminal kinase phosphorylation and reduced down-regulation of Bcl-xL. Moreover, thymic hyperplasia was detected in Thy28 TG mice, although thymocyte development was unaltered. Development of peripheral lymphoid tissues including spleen and lymph nodes was also unaltered. Thy28 TG spleen T cells showed an increased production of IFN-gamma, but not IL 17, in response to both anti-CD3 and anti-CD28 mAbs. Finally, Thy28 TG mice displayed accelerated induction of EAE as assessed by disease incidence, clinical score, and pathology following immunization with myelin oligodendrocyte glycoprotein compared with control WT mice. These findings suggest that modulation of Thy28 expression plays a crucial role in the determination of thymic cell fate, which may contribute to the development of EAE through proinflammatory cytokine production. PMID- 25547914 TI - Analysis of different strategies adapted by two cassava cultivars in response to drought stress: ensuring survival or continuing growth. AB - Cassava is one of the most drought-tolerant crops, however, the underlying mechanism for its ability to survive and produce under drought remains obscure. In this study, two cassava cultivars, SC124 and Arg7, were treated by gradually reducing the soil water content. Their responses to the drought stress were examined through their morphological and physiological traits and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis. SC124 plants adapted a 'survival' mode under mild drought stress as evidenced by early stomatal closure and a reduction in the levels of various photosynthetic proteins and photosynthetic capacity, resulting in early growth quiescence. In contrast, Arg7 plants underwent senescence of older leaves but continued to grow, although at a reduced rate, under mild drought. SC124 plants were more capable of surviving prolonged severe drought than Arg7. The iTRAQ analysis identified over 5000 cassava proteins. Among the drought-responsive proteins identified in the study were an aquaporin, myo-inositol 1-phosphate synthases, and a number of proteins involved in the antioxidant systems and secondary metabolism. Many proteins that might play a role in signalling or gene regulation were also identified as drought-responsive proteins, which included several protein kinases, two 14-3-3 proteins, several RNA-binding proteins and transcription factors, and two histone deacetylases. Our study also supports the notion that linamarin might play a role in nitrogen reallocation in cassava under drought. PMID- 25547915 TI - Increasing leaf hydraulic conductance with transpiration rate minimizes the water potential drawdown from stem to leaf. AB - Leaf hydraulic conductance (k leaf) is a central element in the regulation of leaf water balance but the properties of k leaf remain uncertain. Here, the evidence for the following two models for k leaf in well-hydrated plants is evaluated: (i) k leaf is constant or (ii) k leaf increases as transpiration rate (E) increases. The difference between stem and leaf water potential (DeltaPsistem leaf), stomatal conductance (g s), k leaf, and E over a diurnal cycle for three angiosperm and gymnosperm tree species growing in a common garden, and for Helianthus annuus plants grown under sub-ambient, ambient, and elevated atmospheric CO2 concentration were evaluated. Results show that for well-watered plants k leaf is positively dependent on E. Here, this property is termed the dynamic conductance, k leaf(E), which incorporates the inherent k leaf at zero E, which is distinguished as the static conductance, k leaf(0). Growth under different CO2 concentrations maintained the same relationship between k leaf and E, resulting in similar k leaf(0), while operating along different regions of the curve owing to the influence of CO2 on g s. The positive relationship between k leaf and E minimized variation in DeltaPsistem-leaf. This enables leaves to minimize variation in Psileaf and maximize g s and CO2 assimilation rate over the diurnal course of evaporative demand. PMID- 25547916 TI - Local root abscisic acid (ABA) accumulation depends on the spatial distribution of soil moisture in potato: implications for ABA signalling under heterogeneous soil drying. AB - Patterns of root abscisic acid (ABA) accumulation ([ABA]root), root water potential (Psiroot), and root water uptake (RWU), and their impact on xylem sap ABA concentration ([X-ABA]) were measured under vertical partial root-zone drying (VPRD, upper compartment dry, lower compartment wet) and horizontal partial root zone drying (HPRD, two lateral compartments: one dry, the other wet) of potato (Solanum tuberosum L.). When water was withheld from the dry compartment for 0-10 d, RWU and Psiroot were similarly lower in the dry compartment when soil volumetric water content dropped below 0.22cm(3) cm(-3) for both spatial distributions of soil moisture. However, [ABA]root increased in response to decreasing Psiroot in the dry compartment only for HPRD, resulting in much higher ABA accumulation than in VPRD. The position of the sampled roots (~4cm closer to the surface in the dry compartment of VPRD than in HPRD) might account for this difference, since older (upper) roots may accumulate less ABA in response to decreased Psiroot than younger (deeper) roots. This would explain differences in root ABA accumulation patterns under vertical and horizontal soil moisture gradients reported in the literature. In our experiment, these differences in root ABA accumulation did not influence [X-ABA], since the RWU fraction (and thus ABA export to shoots) from the dry compartment dramatically decreased simultaneously with any increase in [ABA]root. Thus, HPRD might better trigger a long-distance ABA signal than VPRD under conditions allowing simultaneous high [ABA]root and relatively high RWU fraction. PMID- 25547918 TI - The complete mitochondrial genome of Acleris fimbriana (Lepidoptera: Tortricidae). AB - The yellow tortrix, Acleris fimbriana belongs to Tortricidae in Lepidoptera. We described the complete mitogenome of A. fimbriana, which is typical circular duplex molecules and 15,933 bp in length containing the standard metazoan set of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and an A + T-rich region with macro-repeat sequences. All the inferred tRNA secondary structures show the common cloverleaf pattern, with the exception of trnS1(AGN) which lacks the DHU arm. The A. fimbriana mitochondrial genome has the same gene order with other lepidopterans. PMID- 25547919 TI - Families' Views of Pediatric Palliative Aquatics: A Qualitative Study. AB - Although pediatric palliative care policies and services have been developed, research in this area continues to lag. An integrated model of palliative care has been suggested by the American Academy of Pediatrics and includes complementary and alternative services aimed at improving the well-being of children and their families. The first-known pediatric palliative aquatics program (PPAP) in California uses several techniques to decrease pain and promote well-being through relaxation and interaction between patients, specialists, and family members. This study investigates the perceptions of family members of their children's experiences with a PPAP. Researchers from an outside institution conducted focus groups and interviews. Themes were extracted from the focus group transcripts using Braun and Clarke's method of inductive thematic analysis. Data were collected at the host site, local libraries, and participant homes. Participants were primary caregivers and siblings (n = 23) of children in a PPAP, an independent children's respite, transitional, and end-of-life care facility in California. The research described and drew implications from the diverse perceptions that family members expressed about the benefits of having a child in the PPAP, including sensory, physical, and social experiences. Although the PPAP aims to promote well-being through relaxation, several other benefits were expressed by family members of children going through the program, including pain relief. PMID- 25547917 TI - New insights into root gravitropic signalling. AB - An important feature of plants is the ability to adapt their growth towards or away from external stimuli such as light, water, temperature, and gravity. These responsive plant growth movements are called tropisms and they contribute to the plant's survival and reproduction. Roots modulate their growth towards gravity to exploit the soil for water and nutrient uptake, and to provide anchorage. The physiological process of root gravitropism comprises gravity perception, signal transmission, growth response, and the re-establishment of normal growth. Gravity perception is best explained by the starch-statolith hypothesis that states that dense starch-filled amyloplasts or statoliths within columella cells sediment in the direction of gravity, resulting in the generation of a signal that causes asymmetric growth. Though little is known about the gravity receptor(s), the role of auxin linking gravity sensing to the response is well established. Auxin influx and efflux carriers facilitate creation of a differential auxin gradient between the upper and lower side of gravistimulated roots. This asymmetric auxin gradient causes differential growth responses in the graviresponding tissue of the elongation zone, leading to root curvature. Cell biological and mathematical modelling approaches suggest that the root gravitropic response begins within minutes of a gravity stimulus, triggering genomic and non-genomic responses. This review discusses recent advances in our understanding of root gravitropism in Arabidopsis thaliana and identifies current challenges and future perspectives. PMID- 25547921 TI - A 25-year study of chordal replacement with expanded polytetrafluoroethylene in mitral valve repair?. AB - OBJECTIVES: This study examines the outcome of mitral valve repair with chordal replacement using expanded polytetrafluoroethylene over the past 25 years. METHODS: From July 1988 to February 2013, 224 consecutive patients (mean age 57 years, 34% women) underwent mitral valve repair with chordal replacement using expanded polytetrafluoroethylene sutures at our institution. Isolated anterior leaflet prolapse was observed in 134 patients (60%), isolated posterior leaflet prolapse was observed in 13 patients (6%) and bileaflet prolapse was observed in 77 patients (34%). The number of replaced artificial chordae ranged from 2 to 12 (mean 3.7) per patient. Transthoracic echocardiography was performed pre- and postoperatively and in the follow-up period. The follow-up period ranged from 0.3 to 25.3 years (mean 7.4, median 6.2). RESULTS: There was 1 early death and 15 late deaths, of which 7 were cardiac related. The actuarial survival rates at 10 and 20 years were 92 and 81%, respectively. Thirty-three patients (15%) developed recurrent moderate or severe mitral regurgitation during the follow-up period and 30 patients (13%) required reoperation on the mitral valve. Rates of freedom from reoperation and freedom from recurrent moderate or severe mitral regurgitation were 84 and 82% at 10 years, and 74 and 59% at 20 years, respectively. Multivariate analysis revealed that the independent predictors of recurrent mitral regurgitation were mitral valve repair without annuloplasty ring and greater than mild postoperative mitral regurgitation; and the independent predictors of mitral reoperation were previous cardiac surgery and greater than mild postoperative mitral regurgitation. Histopathological analysis of the expanded polytetrafluoroethylene sutures removed during reoperation revealed complete endothelialization without calcification or microthrombi. CONCLUSIONS: Our 25-year follow-up demonstrated reliable long-term outcomes of chordal replacement with expanded polytetrafluoroethylene sutures. PMID- 25547920 TI - Peritoneal dialysis catheter placement in the right lower quadrant is associated with a lower risk of catheter tip migration: a retrospective single-center study. AB - PURPOSE: The aim of this study was to investigate the effect of a modified technique for peritoneal dialysis catheter placement in the right lower quadrant with respect to catheter tip migration. METHODS: This retrospective study included 237 patients with end-stage renal disease who underwent implantation of a two-cuff straight-end swan-neck catheter for peritoneal dialysis. Ninety-eight patients received conventional catheter placement in the left quadrant (beside the umbilicus 12-13 cm above the pubic symphysis) with catheter exit site on the left, and 139 patients received modified catheter placement in the right lower quadrant (beside the umbilicus 6-7 cm above the pubic symphysis) with catheter exit site on the right. Dialysate inflow time, dialysate outflow time, ultrafiltration volume, infection, hemorrhage, intestinal obstruction, and catheter tip migration were recorded. RESULTS: There were no significant differences in dialysate inflow time, dialysate outflow time, ultrafiltration volume, infection, hemorrhage, or intestinal obstruction between the conventional and modified groups. Catheter tip migration occurred in 19 (19.3%) of the 98 patients in the conventional group, and in 5 (3.6%) of the 139 patients in the modified group. The frequency of occurrence of catheter tip migration was significantly less in the modified group compared with the conventional group (p < 0.01). In addition, repositioning of the catheter occurred in all five patients with catheter tip migration in the modified group after conservative treatment, whereas 12 patients required surgical repositioning of the catheter in the conventional group. CONCLUSIONS: The modified technique is superior to the conventional technique in reducing catheter tip migration. This technique can be widely performed in the clinic. PMID- 25547922 TI - Emerging drugs for migraine treatment. AB - INTRODUCTION: Migraine is a highly prevalent and disabling neurological condition whose personal, social and economic impact is substantial. Abortive and preventative treatments of this condition are still unsatisfactory, with poor control of the acute symptoms of the single attacks in many cases and a frequent progression towards chronicity. AREAS COVERED: The major drug classes recently developed and/or in current development for migraine treatment are discussed. These include: Calcitonin-Gene-Related Peptide (CGRP) receptor antagonists, mAbs against CGRP or its receptor, selective 5 hydroxytryptamine (5-HT)1F receptor agonists, drugs targeting Acid-Sensing Ion Channels, Transient Receptor Potential channels and Nitric Oxide. EXPERT OPINION: The most convincing results appear those obtained with mAbs against CGRP, particularly in migraine preventative treatment, given the absence of serious adverse events, and the good response in terms of pain relief. If these results are confirmed in larger studies, these compounds have the potential to significantly improve the pharmacological control of migraine and also its evolution towards chronicity. PMID- 25547923 TI - Static public health funding will increase pressure on local government. PMID- 25547924 TI - Solena amplexicaulis induces cell cycle arrest, apoptosis and inhibits angiogenesis in hepatocarcinoma cells and HUVECs. AB - Solena amplexicaulis (Lam.) Gandhi (SA) has been used as a traditional medicine for the treatment of dysentery, multiple abscess, gastralgia, urethritis, and eczema in the minority area of China. This study was aimed to examine the cell proliferation inhibitory activity of the SA extract (SACE) and its mechanism of action in human hepatoma cell line (HepG2) and evaluate its anti-angiogenesis activity in human umbilical vein endothelial cell line (HUVEC). SACE could inhibit the growth of HepG2 cells in a dose- and time-dependent manner. FCM analysis showed that SACE could induce G2/M phase arrest, cell apoptosis, the mitochondrial membrane potential loss (DeltaPsim) and increase the production of intracellular ROS of HepG2 cells. After treatment with SACE, topical morphological changes of apoptotic body formation, obvious increase of apoptosis related protein expressions, such as Bax, cytochrome c, caspase-3, PARP-1, and decrease of Bcl-2, procaspase-9 protein expressions were observed at the same time. Moreover, SACE caused the significant inhibition of endothelial cell migration and tube formation in HUVEC cells. The results suggested that SACE could act as an angiogenesis inhibitor and induce cell apoptosis via a caspase dependent mitochondrial pathway. Therefore, SACE could be a potent candidate for the prevention and treatment of liver cancer. PMID- 25547926 TI - Colon cancer screening for Colorado's underserved: a community clinic/academic partnership. AB - BACKGROUND: Colorectal cancer (CRC) is largely preventable by finding and removing adenomas, but many people have not been screened, especially the uninsured with low income. PURPOSE: To establish a statewide infrastructure to ensure that low-income Coloradans receive colonoscopy for CRC screening and diagnostic evaluation. DESIGN: In 2006, a statewide program to provide free colonoscopy to uninsured Coloradans was developed as a partnership between the University of Colorado Cancer Center and Colorado safety-net clinics. Funded by excise tax revenues, the Colorado Colorectal Screening Program (CCSP) successfully embedded screening into primary care, providing patient navigation support and reimbursement that allowed primary care providers to refer patients for colonoscopy. SETTING/PARTICIPANTS: More than 50 safety-net clinics joined the CCSP to provide colonoscopies to uninsured Coloradans with low income, aged >=50 years or <50 years at elevated risk, lawfully present and needing CRC screening by American Cancer Society consensus guidelines. MAIN OUTCOME MEASURES: Process and clinical outcomes included people screened, show rates, patient satisfaction, and quality measures, such as adenoma detection rate, bowel cleansing quality, and timeliness of care. Program costs and benefits were estimated. The 2013 analysis was completed using 2006-2012 data on 13,252 of 13,774 people receiving colonoscopy. RESULTS: In 2006-2012, the CCSP screened 13,774 people, with 38% minorities and 39% men. Patient navigators ensured >90% of those referred attended their colonoscopy. Adenomas were removed from 27% of patients and 1% had cancers diagnosed. Total direct medical services cost was $998/person receiving colonoscopy. About 325 fewer future incident CRCs were predicted due to adenoma removal, projecting substantial future cost savings. CONCLUSIONS: The CCSP, a successful community clinic/academic partnership provides cost-effective CRC screening and prevention services to low-income uninsured Coloradans and establishes the infrastructure to support screening low-income Coloradans as Affordable Care Act reforms provide payer coverage for them. PMID- 25547927 TI - Pregnancy outcomes among women with intellectual and developmental disabilities. AB - BACKGROUND: There is currently no population-based research on the maternal characteristics or birth outcomes of U.S. women with intellectual and developmental disabilities (IDDs). Findings from small-sample studies among non U.S. women indicate that women with IDDs and their infants are at higher risk of adverse health outcomes. PURPOSE: To describe the maternal characteristics and outcomes among deliveries to women with IDDs and compare them to women with diabetes and the general obstetric population. METHODS: Data from the 1998-2010 Massachusetts Pregnancy to Early Life Longitudinal database were analyzed between November 2013 and May 2014 to identify in-state deliveries to Massachusetts women with IDDs. RESULTS: Of the 916,032 deliveries in Massachusetts between 1998 and 2009, 703 (<0.1%) were to women with IDDs. Deliveries to women with IDDs were to those who were younger, less educated, more likely to be black and Hispanic, and less likely to be married. They were less likely to identify the father on the infant's birth certificate, more likely to smoke during pregnancy, and less likely to receive prenatal care during the first trimester compared to deliveries to women in the control groups (p<0.01). Deliveries to women with IDDs were associated with an increased risk of adverse outcomes, including preterm delivery, very low and low birth weight babies, and low Apgar scores. CONCLUSIONS: Women with IDDs are at a heightened risk for adverse pregnancy outcomes. These findings highlight the need for a systematic investigation of the pregnancy-related risks, complications, costs, and outcomes of women with IDDs. PMID- 25547928 TI - Passive commuting and dietary intake in fourth and fifth grade students. AB - BACKGROUND: Promoting active commuting by walking or biking to and from school could increase physical activity and reduce obesity among youth. However, exposure to the retail food environment while commuting may lead to greater dietary intake among active commuters. PURPOSE: To examine the relationship between commute patterns and dietary intake and quality in elementary students. METHODS: Fourth and fifth grade students (N=3,316) in 44 California schools reported commute modes to and from school and dietary intake for the same 24-hour period in 2012. Differences between active and passive commuters in total energy intake (kcal), energy from purchased foods, and energy from sweets and snack-type foods were compared, stratified by after-school program (ASP) participation (analysis conducted in 2013). RESULTS: Twenty-three percent of youth actively commuted to school; 27% actively commuted from school. Passive commuters, 87% of whom traveled by car, consumed 78 more kcal from purchased foods (p<0.01) than active commuters in the 24-hour period, though total energy intake did not differ by commute mode overall or by ASP participation. Among the 72% of students who did not attend an ASP, passive commuters consumed 56 more kcal from purchased foods (p<0.01) and 25 more kcal from sweets and snack-type foods (p=0.02) than active commuters. CONCLUSIONS: Passive commuters consumed more sweets and snack type foods and more purchased foods than active commuters. These results, which suggest that parents are providing unhealthy foods for their children during the school commute, reinforce the need for multilevel strategies to promote energy balance in youth. PMID- 25547929 TI - Use of online safety decision aid by abused women: effect on decisional conflict in a randomized controlled trial. AB - BACKGROUND: An Internet safety decision aid was developed to help abused women understand their risk for repeat and near-lethal intimate partner violence, clarify priorities related to safety, and develop an action plan customized to these priorities. PURPOSE: To test the effectiveness of a safety decision aid compared with usual safety planning (control) delivered through a secure website, using a multistate RCT design. The paper evaluates the effectiveness of the safety decision aid in reducing decisional conflict after a single use by abused women. DESIGN: RCT referred to as Internet Resource for Intervention and Safety (IRIS). SETTING/PARTICIPANTS: Abused women who spoke English (n=708) were enrolled in a four-state RCT. INTERVENTION: The intervention was an interactive safety decision aid with personalized safety plan; the control condition was usual safety planning resources. Both were delivered to participants through the secure study website. MAIN OUTCOME MEASURES: This paper compares women's decisional conflict about safety: total decisional conflict and the four subscales of this measure (feeling: uninformed, uncertain, unsupported, and unclear about safety priorities) between intervention/control conditions. Data were collected from March 2011 to May 2013 and analyzed from January to March 2014. RESULTS: Immediately following the first use of the interactive safety decision aid, intervention women had significantly lower total decisional conflict than control women, controlling for baseline value of decisional conflict (p=0.002, effect size=0.12). After controlling for baseline values, the safety decision aid group had significantly greater reduction in feeling uncertain (p=0.006, effect size=0.07) and in feeling unsupported (p=0.008, effect size=0.07) about safety than the usual safety planning group. CONCLUSIONS: Abused women randomized to the safety decision aid reported less decisional conflict about their safety in the abusive intimate relationship after one use compared to women randomized to the usual safety planning condition. PMID- 25547930 TI - The benefits and potential drawbacks in the approval of EVZIO for lay reversal of opioid overdose. PMID- 25547931 TI - Bio-inspired low frictional surfaces having micro-dimple arrays prepared with honeycomb patterned porous films as wet etching masks. AB - Some kinds of snakes have micro-dimple arrays on their skins and show low frictional properties. Cost-effective and simple preparation methods of surfaces having micro-dimple arrays without burrs have been required. In this study, micro dimple arrays were successfully prepared on aluminum plates and pipes by using honeycomb patterned porous films as wet etching masks. Resulting surfaces having 5 and 8 MUm dimple diameters show low frictional coefficients compared with polished surfaces at a fluid lubrication regime. PMID- 25547932 TI - Clinical and molecular findings in a Moroccan patient with popliteal pterygium syndrome: a case report. AB - INTRODUCTION: Popliteal pterygium syndrome is a congenital malformation that includes orofacial, musculoskeletal and genitourinary anomalies. It is a rare autosomal dominant disorder due to a mutation of the IRF6 gene on 1q32.2. CASE PRESENTATION: A one-month-old Moroccan baby boy was diagnosed with typical features of popliteal pterygium syndrome and carried the c.250C>T; p.Arg84Cys mutation of the IRF6 gene. CONCLUSIONS: We report on the first description of a Moroccan popliteal pterygium syndrome patient. This diagnosis allowed us to provide an appropriate course of management to the patient and offer genetic counseling to his family. PMID- 25547933 TI - Identification of VP1 peptides diagnostic of encephalomyocarditis virus from swine. AB - BACKGROUND: Encephalomyocarditis virus (EMCV) can cause myocarditis, respiratory failure, reproductive failure, and sudden death in pre-weaned piglets, which has been isolated in China. EMCV VP1 protein was one of the most important structural proteins and played an important role in the protective immunity. In this study, 10 monoclonal antibodies (McAbs) against EMCV VP1 were screened and identified. RESULTS: Epitope mapping results indicated that McAbs (6E11, 7A7, 7C9) specifically recognized the linear epitopes V(2)ENAEK(7), McAbs (1D1, 2A2, 5A1, 5A11, 5G1) recognized the epitope F(19)VAQPVY(25), and McAbs 1G8 and 3A9 recognized P(42)IGAFTVK(49). Protein sequence alignment of VP1 with 16 EMCV isolates indicated that the epitope F(19)VAQPVY(25) was conserved in all the reference strains. The epitopes P(42)IGAFTVK(49) and V(2)ENAEK(7) only had 1 or 2 variable amino acid among the reference strains. The 3D model analysis results showed that these epitopes presented as spheres were shown within the context of the complete particle. CONCLUSIONS: In this study, ten McAbs against EMCV VP1 were developed and three B-cells epitopes (2-7aa, 19-25aa and 42-49aa) were defined in VP1. All the results herein will promote the future investigations into the function of VP1 of EMCV and development of diagnostic methods of EMCV. PMID- 25547934 TI - Exploring in vitro and in vivo Hsp90 inhibitors activity against human protozoan parasites. AB - A set of compounds, previously selected as potent Hsp90alpha inhibitors, has been studied on a panel of human parasites. 5-Aryl-3,4-isoxazolediamide derivatives (1) were active against two protozoa, Trypanosoma brucei rhodesiense and Plasmodium falciparum, with a good tolerability toward cytotoxicity on non malignant L6 rat myoblast cell line, unlike the 1,5-diaryl,4-carboxamides-1,2,3 triazole derivatives (2) which, while showing a single-digit nM range activity against the same protozoa, were also highly cytotoxic on L6 cells. In a subsequent in vivo study, two isoxazolediamide derivatives, 1a and 1b, were very efficacious on the sleeping sickness-causing agent with a clear parasitaemia during treatment. These data, however, showed that not all protozoa are sensitive to Hsp90 inhibitors, as well as not all Hsp90 inhibitors are equally active on parasites. PMID- 25547935 TI - Uncovering potential 'herbal probiotics' in Juzen-taiho-to through the study of associated bacterial populations. AB - Juzen-taiho-to (JTT) is an immune-boosting formulation of ten medicinal herbs. It is used clinically in East Asia to boost the human immune functions. The active factors in JTT have not been clarified. But, existing evidence suggests that lipopolysaccharide (LPS)-like factors contribute to the activity. To examine this possibility, JTT was subjected to a series of analyses, including high resolution mass spectrometry, which suggested the presence of structural variants of LPS. This finding opened a possibility that JTT contains immune-boosting bacteria. As the first step to characterize the bacteria in JTT, 16S ribosomal RNA sequencing was carried out for Angelica sinensis (dried root), one of the most potent immunostimulatory herbs in JTT. The sequencing revealed a total of 519 bacteria genera in A. sinensis. The most abundant genus was Rahnella, which is widely distributed in water and plants. The abundance of Rahnella appeared to correlate with the immunostimulatory activity of A. sinensis. In conclusion, the current study provided new pieces of evidence supporting the emerging theory of bacterial contribution in immune-boosting herbs. PMID- 25547936 TI - Ultrasound-guided scraping of fibrous capsule plus bilayered negative pressure wound therapy for treatment of refractory postmastectomy seroma. AB - INTRODUCTION: Seroma is a frequent complication of breast cancer surgery. Treatment of prolonged or refractory seroma remains a clinical challenge. This study aimed to evaluate the efficacy of a novel approach for refractory seroma treatment; the method combines minimally invasive scraping for fibrous capsule removal and self-designed bilayered negative pressure wound therapy (b-NPWT) to achieve favorable wound healing. METHODS: Twenty-four patients with refractory seroma received ultrasound-guided scraping of fibrous capsule around the refractory seroma, and then a bilayered NPWT system simultaneously allowing for fluid drainage and dynamic topical pressure was manually implemented immediately. The time of NPWT application and wound healing was recorded, and pathological examination was conducted for the removed fibrous tissues. RESULTS: Removal of the fibrous capsule was securely achieved by minimally invasive scraping through a 1.5-cm incision guided with ultrasound scanning. All refractory seromas in the 24 patients healed uneventfully after an average application of NPWT for 7.2+/ 3.3 days without recurrence during the 3-12 months of follow-up. Biopsy of the removed fibrous tissue demonstrated that single-layered endothelial cells stained with CD31, D2-40, and Ki-67 existed both on the surface of and inside the fibrous tissue. CONCLUSIONS: The combination of fibrous capsule removal by ultrasound guided scraping with successive bilayered NPWT therapy is effective and minimally invasive for promoting wound healing of refractory postmastectomy seroma. PMID- 25547937 TI - A meta-analysis of randomized controlled trials of the risk of bleeding with apixaban versus vitamin K antagonists. AB - Apixaban is one of the new oral anticoagulants, which is prescribed as an alternative to vitamin K antagonists (VKAs). Concerns regarding its bleeding profile persist and require further evaluation. Therefore, we conducted a meta analysis of randomized controlled trials (RCTs) to compare the risks of bleeding and all-cause mortality between apixaban and VKAs. The MEDLINE, EMBASE, and Cochrane Library of Clinical Trials databases were systematically searched for RCTs comparing the risks of bleeding and all-cause mortality of apixaban (2.5 or 5 mg twice daily) with those of VKAs. We included RCTs conducted in adults and published in English or French. Data were pooled across RCTs using random-effects meta-analytical models. Our systematic search identified 5 RCTs meeting our inclusion criteria (n = 24,435). They included patients with atrial fibrillation (n = 18,358), total knee replacement surgery (n = 458), and venous thromboembolism (n = 5,619). Data pooled across RCTs revealed that apixaban was associated with reduced risks of any bleeding (relative risk [RR] 0.73, 95% confidence interval [CI] 0.59 to 0.90) and a composite of major or clinically relevant nonmajor bleeding (RR 0.60, 95% CI 0.40 to 0.88). Apixaban was also associated with a lower risk of intracranial bleeding (RR 0.42, 95% CI 0.31 to 0.58) whereas analyses of major and minor bleeding were inconclusive. Moreover, apixaban was associated with decreased all-cause mortality (RR 0.89, 95% CI 0.81 to 0.99) although this finding was driven by the results of the ARISTOTLE trial. In conclusion, our meta-analysis found that apixaban is associated with a lower risk of bleeding than VKAs, providing some reassurance regarding its safety. PMID- 25547938 TI - A new, intriguing hypothesis: does bivalirudin reduce the risk of acute kidney disease? PMID- 25547939 TI - Usefulness of cardiac magnetic resonance-guided management in patients with recurrent pericarditis. AB - Recurrent pericarditis (RP) affects 10% to 50% of patients with acute pericarditis. The use of steroids has been associated with increased recurrence rate of pericarditis, along with known major side effects. Cardiac magnetic resonance imaging (CMR) is more frequently used to assess pericardial inflammation and less commonly to guide therapy. The aim of this study was to assess the utility of CMR in the management of RP compared with standard therapy. A total of 507 consecutive patients with RP after the first attack, all of whom were treated with colchicine and nonsteroidal anti-inflammatory drugs as first line therapy, were retrospectively evaluated. There were 257 patients who were treated with medications and received CMR-guided therapy (group 1) and 250 patients who were treated with medications without CMR (group 2). The 2 groups had similar baseline characteristics and follow-up periods (17 +/- 7.9 vs 16.3 +/ 16.2 months, respectively, p = 0.97). CMR was used to assess the presence of pericardial inflammation, and on the basis of the results, the clinician made changes to the steroid dose dictated by the severity of inflammation. There was no significant difference in the incidence of constrictive pericarditis, pericardial window, or pericardiectomy between groups during the follow-up. However, group 2 patients had a larger number of steroid pulse therapies (defined as prednisone 50 mg/day orally for 10 days and tapering to none over 4 weeks), and higher overall total milligrams of steroid administered compared with the CMR group (p = 0.003 and p = 0.001, respectively). Recurrence and pericardiocentesis rates were lower in group 1 (p <0.0001). In conclusion, CMR-guided therapy modulates the management of RP. This approach decreased pericarditis recurrence and exposure to steroids. PMID- 25547940 TI - Relation of body mass index to bleeding during percutaneous coronary interventions. AB - The relation between body mass index (BMI) and bleeding after percutaneous coronary intervention (PCI) remains incompletely understood. This study aimed to assess the association between BMI and bleeding and mortality after PCI. The study included 14,178 patients with coronary artery disease treated by PCI. Bleeding within 30 days of PCI was defined using the Bleeding Academic Research Consortium criteria. The primary outcome was 1-year all-cause mortality. BMI quartiles were 14.1 to 24.8 kg/m(2) (first quartile [Q1]), >24.8 to 27.1 kg/m(2) (second quartile [Q2]), >27.1 to 29.8 kg/m(2) (third quartile [Q3]), and >29.8 to 56.3 kg/m(2) (fourth quartile [Q4]). In BMI Q1, Q2, Q3, and Q4, the frequency of bleeding was 13.8%, 10.1%, 10.8%, and 7.7%, respectively (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.63 to 2.23, p <0.001, for Q1 vs Q4). Multiple logistic regression showed that BMI was independently associated with bleeding (adjusted OR 1.05, 95% CI 1.04 to 1.07, p <0.001, for any bleeding; adjusted OR 1.07, 95% CI 1.04 to 1.09, p <0.001, for access site bleeding; and adjusted OR 1.03, 95% CI 1.01 to 1.05, p = 0.039, for non-access site bleeding with all 3 risk estimates calculated per 1 kg/m(2) decrease in BMI). Analysis by sex showed an increase in the frequency of bleeding with the decrease in BMI for women and men (p for trend <0.001 for women and men) with no sex-by-BMI interaction (p = 0.90). The Cox proportional hazards model showed that bleeding (adjusted hazard ratio [HR] 2.17, 95% CI 1.67 to 2.82, p <0.001) and BMI (HR 1.03, 95% CI 1.01 to 1.06, p = 0.048, per 1 kg/m(2) decrease in the BMI) were independently associated with increased risk of 1-year mortality with no bleeding-by-BMI interaction (p = 0.81). In conclusion, BMI is inversely associated with the increased risk of bleeding and mortality after PCI. PMID- 25547947 TI - Metastasis of prostate carcinoma in the mandible manifesting as numb chin syndrome. AB - BACKGROUND: Numb chin syndrome is an uncommon but well-recognized symptom in medical oncology. This condition can be related to metastatic neurological manifestation of malignancy, often with no clinically visible pathology. About 1% of oral cancers, which are located in the soft tissues and jaws, are metastases of primary tumors located elsewhere in the body. The posterior mandible is the most common site of metastasis of the oral region because of its rich blood supply in active areas of hematopoiesis. This article describes prostate carcinoma metastasis located in the mandible and temporomandibular joint of a 78 year-old male. CASE PRESENTATION: A 78-year-old male patient presented to our outpatient clinic with a complaint of numbness and pain on the left site of the mandible. The patient stated that he had been suffering from this numbness for 1 to 2 months. In the medical anamnesis, it was discovered that patient had prostate carcinoma (CA) 5 years previous, and since then, he had visited his doctor periodically for an annual examination. In these examinations and on the basis of tests carried out at the hospital 1 year previous, it was stated that no CA relapse traces were detected. The patient had visited his dentist 2 months previous for pain and numbness of the left molar region. CONCLUSIONS: We report numb chin syndrome, which is an uncommon neurological manifestation of metastatic malignancy. The clinical course and rapid deterioration after the initial presentation of this syndrome is discussed. This clinical situation illustrates the importance of good medical history review prior to all procedures by the medical professions dealing with oncology patients. An awareness of this condition is crucial, especially in symptoms with unexplained facial pain and numbness. PMID- 25547948 TI - Quitting smoking: an early non-motor feature of Parkinson's disease? AB - INTRODUCTION: Epidemiological studies report a 60-70% reduced risk of Parkinson's disease (PD) in smokers as compared to non-smokers. However, relationships between former smoking and PD have been poorly investigated. METHODS: We recruited 116 de novo PD subjects, and investigated current, former and never smoking, and reasons for smoking cessation among former smokers. Two hundred and thirty-two controls were matched by Propensity Score. RESULTS: PD subjects and controls were found to be current smokers (7.7 vs. 39.6%), former smokers (43.9 vs. 6.5%) and never smokers (48.2 vs. 53.9%). Logistic regression showed that current smokers were less likely to have PD (p < 0.001; OR: 0.22; 95% CI: 0.10 0.46), while former smokers were more likely to have PD (p < 0.001; OR: 7.6; 95% CI: 4.09-15.75), as compared to never smokers. Fifty-one PD patients reported quitting smoking before PD diagnosis (mean time since cessation 9.4 +/- 7.3 years). Most important reasons to quit smoking in PD group were illness different from PD (26 subjects, 51.0%), knowledge of the harmful effects of smoking (24 subjects, 47.0%), and physician's advice (1 subject, 2.0%). CONCLUSION: The reduced prevalence of current smokers among PD subjects as compared to healthy controls is consistent with previous findings, suggesting a possible neuroprotective effect of smoking. However, it could be due, at least in part, to the increased prevalence of former smokers among PD patients, that were more prone to quit smoking as compared to healthy controls. We suggest that smoking cessation could be an early preclinical condition occurring in PD. PMID- 25547946 TI - Statins impair survival of primary human mesenchymal progenitor cells via mevalonate depletion, NF-kappaB signaling, and Bnip3. AB - Circulating progenitor cells of bone marrow origin have been implicated in transplant cardiac allograft vasculopathy (CAV) and cardiac fibrosis. HMG-CoA reductase inhibitors, called "statins," have been shown to impair the progression of CAV and improve patient survival. We examined the in vitro effects of three HMG-CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin on the viability of MSCs and expression of nuclear factor kappa B (NF-kappaB). Mesenchymal stem cells (MSCs) isolated from human patients were treated with atorvastatin, simvastatin, and pravastatin at 0.1, 1.0, or 10 MUM +/- mevalonate. Human MSC treatment with 1 and 10 MUM simvastatin or atorvastatin resulted in progressively reduced cell viability, which was associated with a decline in NF kappaB p65. Viability was rescued by co-incubation with mevalonate or by pretreatment with Inhibitor of nuclear factor kappa-B kinase subunit beta (Ikappakappa-beta). Pravastatin did not affect MSC viability or NF-kappaB expression. Mevalonate depletion through HMG-CoA reductase inhibition impairs the viability of primary human MSC through down-regulating NF-kappaB. PMID- 25547949 TI - Deep brain stimulation in early stage Parkinson's disease. PMID- 25547951 TI - Is it time to consider patients suffering from endometriosis-related infertility as "novel candidates" for targeted peri-conceptional D-chiro inositol supplementation? Hypothesis, rationale and some considerations. PMID- 25547952 TI - To ICSI or not to ICSI? That was the question. PMID- 25547950 TI - Vitamin D and assisted reproduction: should vitamin D be routinely screened and repleted prior to ART? A systematic review. AB - PURPOSE: To review the current literature regarding the role of vitamin D status in pregnancy outcomes in women undergoing assisted reproductive technology (ART) and to assess cost-effectiveness of routine vitamin D deficiency screening and repletion prior to initiation of ART. METHODS: A systematic literature review was conducted using PubMed. Relevant study outcomes were compared among the selected studies. A cost-benefit analysis was performed using a decision tree mathematical model with sensitivity analyses from the perspective of direct societal cost. Published data were used to estimate probabilities and costs in 2014 US dollars. RESULTS: Thirty-four articles were retrieved, of which eight met inclusion criteria. One study demonstrated a negative relationship between vitamin D status and ART outcomes, while two studies showed no association. The remaining five studies concluded that ART outcomes improved after vitamin D repletion. CONCLUSION: The majority of reviewed studies reported a decrement in ART outcomes in patients with vitamin D deficiency. Cost-benefit analyses suggested that screening and supplementing vitamin D prior to ART might be cost effective, but further evidence is needed. Given the absence of Level I evidence regarding vitamin D status and ART outcomes, full endorsement of routine vitamin D screening and supplementation prior to ART is premature. PMID- 25547953 TI - Right thigh pain. Atypical femoral fracture (AFF). PMID- 25547954 TI - French health insurance databases: What interest for medical research? AB - French health insurance databases are organized since 2003 into a huge digital data warehouse, the Systeme national d'information inter-regime de l'assurance maladie (SNIIR-AM). It covers the entire French population (65 million inhabitants). In order to facilitate studies on more frequent conditions, a random sample of 1/97th of national health system beneficiaries has been built since 2005, called the echantillon generaliste des beneficiaires (EGB). The aim of this article is to describe the main characteristics of the SNIIR-AM and the EGB, to detail their accessibility according to French law, and to present their strengths and limits. It is illustrated with the most recent studies conducted in these databases. These databases include demographic, out-hospital reimbursement (including drug dispensing), medical (costly long-term diseases, occupational diseases, sick-leaves...), and in-hospital data. All these data are prospectively recorded, individualized, made anonymous and linkable. Consequently, the SNIIR-AM is a very useful data source for epidemiological, pharmacoepidemiological and health economics studies, particularly for rare diseases. The EGB is appropriate for long-term research on more frequent diseases. PMID- 25547955 TI - [Considerations for an end-of-life ethic]. PMID- 25547956 TI - [The revolution of monoclonal antibodies in the treatment of thrombotic microangiopathy]. AB - Thrombotic microangiopathies (TMA) define a syndrome characterized by the association of microangiopathic haemolytic anaemia with schistocytes, peripheral thrombocytopenia, and organ injury of variable severity. Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uremic syndrome (HUS) are the main forms of TMA. Recent advances in the pathophysiology of those two diseases, which include in HUS the identification of a deregulation of the alternative complement pathway, and in TTP a severe deficiency in ADAMTS-13, allowed to develop specific, pathophysiology-based therapies. Therefore, rituximab and eculizumab tends to be increasingly used, and there is an urgent need to define consensual modes of administration at the international level, as well as common definitions of response evaluation and follow-up explorations. PMID- 25547958 TI - Migration of a cochlear implant ground electrode through the calvarium of a pediatric patient. AB - Cochlear implantation has been performed safely several hundred thousand times, although a variety of complications have been reported including surgical site infection, device failure, migration of the receiver/stimulator or electrode array. Here we report the asymptomatic migration of the ground electrode through the squamous temporal bone, which was discovered at the time of device explantation. The incidence of this phenomenon is not known since it may remain asymptomatic and delayed postoperative imaging is not routinely performed. This finding should motivate implant surgeons to consider placement of the ground electrode into a subperiosteal pocket in a region with greater skull thickness. PMID- 25547957 TI - [Cannabinoid hyperemesis syndrome: about 6 cases]. AB - INTRODUCTION: The cannabinoid hyperemesis syndrome (CHS) is characterized by cyclic episodes of nausea, vomiting, and abdominal pain, and occurs in young adults with long-term cannabis use. The feature of this syndrome is the relief of symptoms with hot showers. We report here six cases report. CASE REPORTS: Three women and 3 men, chronic consumers of cannabis, presented with typical features of the CHS, but the syndrome remained undiagnosed until then: nausea, vomiting, abdominal pain with morning ascendancy and loss of weight occurring in adult's of less than 50 years. The symptoms were improved by taking repeated hot showers. The medical investigations were negative. After addictologist care and cannabis weaning, digestive symptoms disappeared. CONCLUSION: The CHS is based on a clinical diagnosis. When undiagnosed, clinical presentation leads to a medical wandering and to the realization of repeated, expensive, and sometimes invasive exams. The physiopathology is not clear. The treatment relies on the definitive cannabis weaning. PMID- 25547959 TI - The delivered promise of prenatal imaging and a challenge to the utility of sildenafil for severe lymphatic malformations. AB - We report the case of an infant with severe lymphatic malformation necessitating ex-utero intrapartum treatment (EXIT) procedure and examine recent advances in high resolution ultrasonography and magnetic resonance imaging, which allow for improved prenatal diagnosis of lesions that cause critical airway obstruction in the neonate. Treatments for lymphatic malformations including surgical resection, sclerotherapy, coblation, and sildenafil are discussed. Our patient did not have any reduction in the size of the lymphatic malformation from sildenafil as suggested in another series. PMID- 25547960 TI - Post tonsillectomy hemorrhage: who needs intervention? AB - BACKGROUND: Post-tonsillectomy hemorrhage (PTH) remains a significant complication. There are no guidelines for Pediatric Emergency Department (PED) disposition of children with secondary PTH. OBJECTIVES: To describe the incidence, clinical characteristics and interventions required by children presenting to a PED with secondary PTH. To identify patient and clinical characteristics associated with need for operative/inpatient intervention. METHODS: Retrospective chart review of healthy children 1-18 years with secondary PTH from 2005 to 2012. Demographics, clinical and oropharynx findings, laboratory data, intervention type and ED disposition were recorded. RESULTS: We encountered 181 children with 193 episodes of PTH. One hundred and twenty one patients were included in the final analysis. Secondary PTH rate was 2.3%. Only a minority of patients were hypotensive (3.3%) or had hemoglobin<10g/dl (9.5%) at presentation. 65.3% Children had positive oropharyngeal exam: clot 39 (49.4%) patients; ooze 17 (21.5%) patients; ooze+clot in 5 (6.3%) patients or active bleeder in 18 (22.8%) patients. Eighty seven (71.9%) patients were admitted; 74 (61.1%) patients required active intervention: medical 14.8%, surgical 74.4% or both 10.8%. Thirty seven children needed immediate operative intervention. Only positive oropharyngeal exam and age >=6 years were significantly associated with need for intervention. None of the patients with a confirmed normal oropharyngeal exam at the initial visit required any intervention either medical or surgical. The rate of return visit for recurrent PTH was found to be similar for both the admitted and the discharged group. No patient returned with a life threatening hemorrhage. CONCLUSIONS: Majority of children with secondary PTH were admitted and nearly 3/5th of them required an intervention. Our data suggests that healthy children <6 years with a confirmed normal oropharyngeal exam are less likely to require an intervention and may be candidates for safe discharge from the ED provided reliability of return for recurrence can be assured. PMID- 25547961 TI - Prediction of piRNAs using transposon interaction and a support vector machine. AB - BACKGROUND: Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNA primarily expressed in germ cells that can silence transposons at the post transcriptional level. Accurate prediction of piRNAs remains a significant challenge. RESULTS: We developed a program for piRNA annotation (Piano) using piRNA-transposon interaction information. We downloaded 13,848 Drosophila piRNAs and 261,500 Drosophila transposons. The piRNAs were aligned to transposons with a maximum of three mismatches. Then, piRNA-transposon interactions were predicted by RNAplex. Triplet elements combining structure and sequence information were extracted from piRNA-transposon matching/pairing duplexes. A support vector machine (SVM) was used on these triplet elements to classify real and pseudo piRNAs, achieving 95.3 +/- 0.33% accuracy and 96.0 +/- 0.5% sensitivity. The SVM classifier can be used to correctly predict human, mouse and rat piRNAs, with overall accuracy of 90.6%. We used Piano to predict piRNAs for the rice stem borer, Chilo suppressalis, an important rice insect pest that causes huge yield loss. As a result, 82,639 piRNAs were predicted in C. suppressalis. CONCLUSIONS: Piano demonstrates excellent piRNA prediction performance by using both structure and sequence features of transposon-piRNAs interactions. Piano is freely available to the academic community at http://ento.njau.edu.cn/Piano.html . PMID- 25547962 TI - He-Ne laser preillumination improves the resistance of tall fescue (Festuca arundinacea Schreb.) seedlings to high saline conditions. AB - In this paper, we explored the protective effect and physiochemical mechanism of He-Ne laser preillumination in enhancement of tall fescue seedlings tolerance to high salt stress. The results showed that salt stress greatly reduced plant growth, plant height, biomass, leaf development, ascorbate acid (AsA) and glutathione (GSH) concentration, the enzymatic activities, and gene expression levels of antioxidant enzymes such as catalase (CAT) and glutathione reductase (GR) and enhanced hydrogen peroxide (H2O2) content, superoxide radical (O2 (.-)) generation rates, membrane lipid peroxidation, relative electrolyte leakage, the enzymatic activities, and gene expression levels of superoxide dismutase (SOD), ascorbate peroxidase (APX), and peroxidase (POD), compared with controls. However, He-Ne laser preillumination significantly reversed plant growth retardation, biomass loss, and leaves development decay induced by salt stress. And the values of the physiochemical parameters observed in salt-stressed plants were partially reverted or further increased by He-Ne laser. Salt stress had no obvious effect on the transcriptional activity of phytochromeB, whereas He-Ne laser markedly enhanced its transcriptional level. Preillumination with white fluorescent lamps (W), red light (RL) of the same wavelength, or RL, then far-red light (FRL) had not alleviated the inhibitory effect of salt stress on plant growth and antioxidant enzymes activities, suggesting that the effect of He-Ne laser on improved salt tolerance was most likely attributed to the induction of phytochromeB transcription activities by the laser preillumination, but not RL, FRL or other light sources. In addition, we also utilized sodium nitroprusside (SNP) as NO donor to pre-treat tall fescue seedlings at the same conditions, and further evaluated the differences of physiological effects between He-Ne laser and NO in increasing salt resistance of tall fescue. Taken together, our data illustrated that He-Ne laser preillumination contributed to conferring an increased tolerance to salt stress in tall fescue seedlings due to alleviating oxidative damage through scavenging free radicals and inducing transcriptional activities of some genes involved in plant antioxidant system, and the induction of phytochromeB transcriptional level by He-Ne laser was probably correlated with these processes. Moreover, this positive physiochemical effect seemed more effective with He-Ne laser than NO molecule. PMID- 25547963 TI - Na+ and Cl(-) ions show additive effects under NaCl stress on induction of oxidative stress and the responsive antioxidative defense in rice. AB - Despite the fact that when subjected to salinity stress most plants accumulate high concentrations of sodium (Na(+)) and chloride (Cl(-)) ions in their tissues, major research has however been focused on the toxic effects of Na(+). Consequently, Cl(-) toxicity mechanisms in annual plants, particularly in inducing oxidative stress, are poorly understood. Here, the extent to which Na(+) and/or Cl(-) ions contribute in inducing oxidative stress and regulating the adaptive antioxidant defense is shown in two Indica rice genotypes differing in their salt tolerance. Equimolar (100 mM) concentrations of Na(+), Cl(-), and NaCl (EC ~ 10 dS m(-1)) generated free-radical (O2 (*-), (*)OH) and non-radical (H2O2) forms of reactive oxygen species (ROS) and triggered cell death in leaves of 21 day-old hydroponically grown rice seedlings as evident by spectrophotometric quantifications and histochemical visualizations. The magnitude of ROS-mediated oxidative damage was higher in sensitive cultivar, whereas NaCl proved to be most toxic among the treatments. Salt treatments significantly increased activities of antioxidant enzymes and their isozymes including superoxide dismutase, catalase, peroxidase, ascorbate peroxidase, and glutathione reductase. Na(+) and Cl(-) ions showed additive effects under NaCl in activating the antioxidant enzyme machinery, and responses were more pronounced in tolerant cultivar. The expression levels of SodCc2, CatA, and OsPRX1 genes were largely consistent with the activities of their corresponding enzymes. Salt treatments caused an imbalance in non-enzymatic antioxidants ascorbic acid, alpha-tocopherol, and polyphenols, with greater impacts under NaCl than Na(+) and Cl(-) separately. Results revealed that though Cl(-) was relatively less toxic than its counter cation, its effects cannot be totally ignored. Both the cultivars responded in the same manner, but the tolerant cultivar maintained lower Na(+)/K(+) and ROS levels coupled with better antioxidant defense under all three salt treatments. PMID- 25547964 TI - Cytological and molecular analysis of nonhost resistance in rice to wheat powdery mildew and leaf rust pathogens. AB - Cereal powdery mildews caused by Blumeria graminis and cereal rusts caused by Puccinia spp. are constant disease threats that limit the production of almost all important cereal crops. Rice is an intensively grown agricultural cereal that is atypical because of its immunity to all powdery mildew and rust fungi. We analyzed the nonhost interactions between rice and the wheat powdery mildew fungus B. graminis f. sp. tritici (Bgt) and the wheat leaf rust fungus Puccinia triticina (Ptr) to identify the basis of nonhost resistance (NHR) in rice against cereal powdery mildew and rust fungi at cytological and molecular levels. No visible symptoms were observed on rice leaves inoculated with Bgt or Ptr. Microscopic observations showed that both pathogens exhibited aberrant differentiation and significantly reduced penetration frequencies on rice compared to wheat. The development of Bgt and Ptr was also completely arrested at early infection stages in cases of successful penetration into rice leaves. Attempted infection of rice by Bgt and Ptr induced similar defense responses, including callose deposition, accumulation of reactive oxygen species, and hypersensitive response in rice epidermal and mesophyll cells, respectively. Furthermore, a set of defense-related genes were upregulated in rice against Bgt and Ptr infection. Rice is an excellent monocot model for genetic and molecular studies. Therefore, our results demonstrate that rice is a useful model to study the mechanisms of NHR to cereal powdery mildew and rust fungi, which provides useful information for the development of novel and durable strategies to control these important pathogens. PMID- 25547965 TI - Inhibitive effects of nickel chloride (NiCl2) on thymocytes. AB - The purpose of this study was to define the inhibitive effects of dietary nickel chloride (NiCl2) on thymocytes in broilers fed on diets supplemented with 0, 300, 600, and 900 mg/kg of NiCl2 for 42 days. We examined the changes of cell cycle phase, percentages of apoptotic cells, T cell subsets, cytokines, and mRNA expression of apoptotic proteins (bcl-2, bax, and caspase-3) in thymocytes by flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). In the NiCl2-treated broilers, the percentages of thymocytes in G0/G1 phase were increased, whereas thymocytes in the S phase and the proliferation index were decreased. The percentages of apoptotic thymocytes were increased. Also, the mRNA expression levels of bax and caspase-3 were increased, and mRNA expression levels of bcl-2 were decreased. The percentages of CD3(+), CD3(+)CD4(+), and CD3(+)CD8(+) T lymphocytes in the thymus and peripheral blood were diminished. Concurrently, thymic cytokine (interleukin-1 beta (IL-1beta), interleukin-2 (IL 2), interleukin-10 (IL-10), interleukin-12 p35 subunit (IL-12p35), interleukin-12 p40 subunit (IL-12p40), interleukin-21 (IL-21), interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), thymosin beta4, thymosin beta10, and thymosin beta15) mRNA expression levels were decreased. The abovementioned results showed that dietary NiCl2 in excess of 300 mg/kg inhibited thymocyte growth by arresting cell cycle, increasing apoptosis percentage, altering apoptotic protein mRNA expression levels, and downregulating cytokine expression levels. PMID- 25547966 TI - Combining inkjet printing and sol-gel chemistry for making pH-sensitive surfaces. AB - Today biomedical sciences are experiencing the importance of imaging biological parameters with luminescence methods. Studying 2D pH distribution with those methods allows building knowledge about complex cellular processes. Immobilizing pH sensitive nanoparticles inside hydrogel matrixes, in order to guarantee a proper SNR, could easily make stable and biocompatible 2D sensors. Inkjet printing is also well known as tool for printing images onto porous surfaces. Recently it has been used as a free-form fabrication method for building three dimensional parts, and now is being explored as a way of printing electrical and optical devices. Inkjet printing was used either as a rapid prototyping method for custom biosensors. Sol-gel method is naturally bound with inkjet, because the picoliter-sized ink droplets evaporate quickly, thus allowing quick sol-gel transitions on the printed surface. In this work will be shown how to merge those technologies, in order to make a nanoparticles doped printable hydrogel, which could be used for making 2D/3D smart scaffolds able to monitor cell activities. An automated image analysis system was developed in order to quickly have the pH measurements from pH nanosensors fluorescence images. PMID- 25547967 TI - Controlled release of nafcillin using biocompatible "dummy" molecularly imprinted sol-gel nanospheres. AB - Different silicon-based xero-gel molecularly imprinted spheres in the nano boundary range with recognition capabilities for nafcillin have been synthesised, using tetraethylorthosilicate (TEOS) and (3- aminopropyl) triethoxysilane (APTEOS) as precursors. Imprinting has been achieved using both nafcillin (NAF) or structural analogous 'dummies' such as (+)-6-aminopenicillenic acid (APA), or ampicillin ((+)-6- aminobenzylpenicillin)sodium salt (AMP). Materials were fully characterized using ATR-FTIR, (29)Si solidstate NMR, TGA, TEM and BET. Adsorption isotherms for all the materials fit with a continuous Freundlich model with correlation coefficients better than 0.988 and mean affinity constants between 10(5) and 10(6) L.mol(-1). The use of 'dummies' as well as the template itself in the imprinting process resulted in materials with different release speed. Combinations of these materials allow designing mixtures with a continuous, controlled and constant release longer than four days. Thus, the non-imprinted and the AMP-imprinted material have a rapid release during the first five hours, nafcillin and APA imprinted ones release antibiotic mainly after a latency-period of 24 hours. PMID- 25547968 TI - Molecularly imprinted sol-gel materials for medical applications. AB - The present review deals with the sol-gel imprinting of both drug and non-drug templates of medical relevance, namely neurotransmitters, biomarkers, hormones, proteins and cells. Nearly a hundred recent works, either developmental or applied in a medical-related context, were critically analyzed. It may be concluded that, although research is still at an early stage, the potential of these sol-gel materials was well demonstrated in a few applications of critical interest for medicinal/biomedical science. The vast room left for expansion and improvement envisages a continuously growing interest by researchers in the future, eventually resulting in important medical applications able to enter the professional and consumer medical markets. PMID- 25547969 TI - Sol-gel chemistry in biosensing devices of electrical transduction: application to CEA cancer biomarker. AB - Sol-gel chemistry allows the immobilization of organic molecules of biological origin on suibtable solid supports, permitting their integration into biosensing devices widening the possibility of local applications. The present work is an application of this principle, where the link between electrical receptor platform and the antibody acting as biorecognition element is made by sol-gel chemistry. The immunosensor design was targeted for carcinoembryonic antigen (CEA), an important biomarker for screening the colorectal cancer, by electrochemical techniques, namely electrochemical impedance spectroscopy (EIS) and square wave voltammetry (SVW). The device displayed linear behavior to CEA in EIS and in SWV assays ranging from 0.50 to 1.5ng/mL, and 0.25 to 1.5ng/mL, respectively. The corresponding detection limits were 0.42 and 0.043 ng/mL. Raman spectroscopy was used to characterize the surface modifications on the conductive platform (FTO glass). Overall, simple sol-gel chemistry was effective at the biosensing design and the presented approach can be a potential method for screening CEA in point-of-care, due to the simplicity of fabrication, short response time and low cost. PMID- 25547970 TI - Sol-gel encapsulation of biomolecules and cells for medicinal applications. AB - The sol-gel process provides a robust and versatile technology for the immobilization of biologicals. A wide range of inorganic, composites and hybrid materials can be prepared to encapsulate molecular drugs, proteins, antibodies/antigens, enzymes, nucleic acids, prokaryotic and eukaryotic cells into bulk gels, particles and films. This review describes the applications of sol-gel encapsulation relevant to medicinal chemistry focusing on the recent development of biosensors as well as systems for production, screening and delivery of bioactive compounds and biomaterials. PMID- 25547971 TI - Sol-gel-based biosensing applied to medicinal science. AB - Biosensors have opened new horizons in biomedical analysis, by ensuring increased assay speed and flexibility, and allowing point-of-care applications, multi target analyses, automation and reduced costs of testing. This has been a result of many studies merging nanotechnology with biochemistry over the years, thereby enabling the creation of more suitable environments to biological receptors and their substitution by synthetic analogue materials. Sol-gel chemistry, among other materials, is deeply involved in this process. Sol-gel processing allows the immobilization of organic molecules, biomacromolecules and cells maintaining their properties and activities, permitting their integration into different transduction devices, of electrochemical or optical nature, for single or multiple analyses. Sol-gel also allows to the production of synthetic materials mimicking the activity of natural receptors, while bringing advantages, mostly in terms of cost and stability. Moreover, the biocompatibility of sol-gel materials structures of biological nature allowed the use of these materials in emerging in vivo applications. In this chapter, biosensors for biomedical applications based on sol-gel derived composites are presented, compared and described, along with current emerging applications in vivo, concerning drug delivery or biomaterials. Sol-gel materials are shown as a promising tool for current, emerging and future medical applications. PMID- 25547972 TI - Sol-gel chemistry applied to medicinal science. PMID- 25547974 TI - The role of extended pelvic lymphadenectomy with radical prostatectomy for high risk prostate cancer. AB - INTRODUCTION: The role of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) for prostate cancer (PCa) is controversial. Despite extensive research in both patterns of lymphatic drainage and the clinical effect of lymph node involvement, the exact role of PLND in PCa is yet to be defined. METHODS: A systematic search of the MEDLINE database was performed, and all relevant articles were reviewed in depth. RESULTS: We included 84 relevant articles in our review and subdivided the information into the following categories: preoperative patient evaluation, procedure/extent of dissection, complications, and robotic surgery era. Most authors agree that the greatest benefit is seen in patients with high-risk PCa undergoing RP. Multiple imaging modalities have been evaluated for assistance in patient selection, but the use of preoperative nomograms appears to be the most helpful selection tool. The role of limited PLND vs. extended PLND (e-PLND) is yet to be defined, though many authors agree that e PLND is preferred in the setting of high-risk PCa. Although PLND is associated with a higher incidence of complications, especially lymphocele formation, it is unclear whether e-PLND leads to more complications than limited PLND. The introduction of minimally invasive surgery may have had a negative effect on implementation of PLND in the appropriate patients undergoing RP. CONCLUSION: Despite a lack of prospective, randomized trials evaluating PLND in RP, there does appear to be a consistent benefit in patients with high-risk disease. PMID- 25547973 TI - Soy and isoflavone consumption and risk of gastrointestinal cancer: a systematic review and meta-analysis. AB - PURPOSE: Evidence suggests that soy foods have chemoprotective properties that may reduce the risk of certain cancers such as breast and prostate cancer. However, data involving gastrointestinal (GI) have been limited, and the evidence remains controversial. This study aims to determine the potential relationship between dietary soy intake and GI cancer risk with an evaluation of the effects of isoflavone as an active soy constituent. METHODS: Relevant studies were identified after literature search via electronic databases through May 2014. Subgroup analysis for isoflavone intake (studies n = 10) was performed. Covariants including gender types, anatomical subsites and preparation methods were also evaluated. Pooled adjusted odds ratios (ORs) comparing highest and lowest categories of dietary pattern scores were calculated using a random effects model. RESULTS: Twenty-two case-control and 18 cohort studies were included for meta-analysis, which contained a total of 633,476 participants and 13,639 GI cancer cases. The combined OR was calculated as 0.93 (95% CI 0.87-0.99; p value heterogeneity = 0.01), showing only a slight decrease in risk, the association was stronger for colon cancer (OR 0.92; 95% CI 0.96-0.99; p value heterogeneity = 0.163) and colorectal cancer (CRC) (OR 0.92; 95% CI 0.87-0.97; p value heterogeneity = 0.3). Subgroup analysis for isoflavone intake showed a statistically significant risk reduction with a risk estimate of 0.73 (95% CI 0.59-0.92; p value heterogeneity = 0), and particularly for CRC (OR 0.76; 95% CI 0.59-0.98; p value heterogeneity = 0). CONCLUSION: This study provides evidence that soy intake as a food group is only associated with a small reduction in GI cancer risk. Separate analysis for dietary isoflavone intakes suggests a stronger inverse association. PMID- 25547975 TI - The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that is strongly associated with a particular phenotype of inflammatory bowel disease (IBD) with right-sided colonic involvement. In IBD, several studies demonstrated significant aberrancies in the intestinal microbiota in comparison with healthy controls. We aimed to explore the link between IBD and PSC by studying the intestinal mucosa-adherent microbiota in PSC and ulcerative colitis (UC) patients and noninflammatory controls. METHODS: We included 12 PSC patients, 11 UC patients, and nine noninflammatory controls. The microbiota composition was determined in ileocecal biopsies from each patient by 16S rRNA-based analyses using the human intestinal tract chip. RESULTS: Profiling of the mucosa-adherent microbiota of PSC patients, UC patients, and noninflammatory controls revealed that these groups did not cluster separately based on microbiota composition. At the genus-like level, the relative abundance of uncultured Clostridiales II was significantly lower (almost 2-fold) in PSC (0.26 +/- 0.10%) compared with UC (0.41 +/- 0.29%) and controls (0.49 +/- 0.25%) (p = 0.02). Diversity and richness in the microbiota composition differed across the groups and were significantly lower in PSC patients compared with noninflammatory controls (p = 0.04 and p = 0.02, respectively). No significant differences were found in evenness. CONCLUSIONS: Reduced amounts of uncultured Clostridiales II in PSC biopsies in comparison with UC and healthy controls can be considered a signature of a compromised gut, as we have recently observed that this group of as yet uncultured Firmicutes correlates significantly with health. PMID- 25547976 TI - Back/joint pain, illness perceptions and coping are important predictors of quality of life and work productivity in patients with inflammatory bowel disease: a 12-month longitudinal study. AB - BACKGROUND AND AIMS: Back and joint pain are the most common extraintestinal symptoms reported by patients with inflammatory bowel disease (IBD). We assessed the impact of back/joint pain, illness perceptions, and coping on quality of life (QOL) and work productivity in patients with IBD. METHODS: Our cohort included 155 IBD patients with and 100 without arthropathy. Arthropathy was defined as daily back pain for >=3 months and/or peripheral joint pain and/or joint swelling over the last year. At baseline and at 12 months, patients completed questionnaires on the extent of back/joint pain, IBD disease activity, illness perceptions, coping, QOL, and work productivity. The impact of back/joint pain, illness perceptions and coping on QOL and work productivity was determined, using linear mixed models. RESULTS: In total, 204 IBD patients (72% Crohn's disease, 40% male, mean age 44 +/- 14 years) completed questionnaires at both time points. At both time points, IBD patients with back/joint pain reported a significantly lower QOL and work productivity compared with IBD patients without back/joint pain. Predictors of low QOL were back/joint pain (beta = -1.04, 95% confidence interval [CI] -1.40, -0.68), stronger beliefs about the illness consequences (beta = -0.39, 95% CI -0.59, -0.18) and emotional impact of IBD (beta = -0.47, 95% CI -0.66, -0.28), and the coping strategy 'decreasing activity' (beta = 0.26, 95% CI -0.48, -0.03). Predictors of work productivity were back/joint pain (beta = 0.22, 95% CI 0.07, 0.37) and illness consequences (beta = 0.14, 95% CI 0.06, 0.22). CONCLUSION: Back/joint pain, illness perceptions, and coping are significant predictors of QOL and work productivity, after controlling for disease activity. PMID- 25547977 TI - Benefit of infliximab reintroduction after successive failure of infliximab and adalimumab in Crohn's disease. AB - BACKGROUND: Infliximab [IFX] and adalimumab [ADA] are effective in Crohn's disease [CD] for induction and maintenance therapy. However, high annual rate of discontinuation for loss of response or intolerance may lead to a switch to another anti-tumor necrosis factor agent. Patients with successive failure to IFX and ADA are becoming more frequent. The aim of this study was to assess the efficacy and the tolerance of re-treatment with IFX in CD patients who successively failed IFX and ADA. METHODS: A total of 61 patients with CD who received and discontinued successively IFX and ADA, and who were re-exposed to IFX, were identified in four French tertiary centers and retrospectively analyzed. Clinical data, follow-up and outcome were abstracted from medical records. RESULTS: Median treatment duration after reintroduction was 16 months, and probability of remaining under IFX was 60% and 51%, respectively, at 12 and 24 months. In all 29 patients discontinued the second IFX treatment due to intolerance [13], primary non-response [8], loss of response [7] or patient's wish [1]. Remission was achieved in 42% at week 6-8 after IFX re-induction, and was predictive of better long-term response [p = 0.006]. In multivariate analysis, receiving co-immunosuppression in both first and second IFX treatments [p = 0.04] and shorter interval between first and second IFX treatments [p = 0.017] were independently associated with longer duration of second IFX treatment. CONCLUSION: For CD patients who successively failed IFX and ADA, reintroducing IFX is feasible and often clinically efficient, particularly in patients who received co-immunosuppression during both first and second IFX treatments. PMID- 25547978 TI - Use of action planning to increase provision of smoking cessation care by general practitioners: role of plan specificity and enactment. AB - BACKGROUND: Strategies are needed to help general practitioners (GPs) promote smoking cessation as recommended by guidelines. This study examines whether the quality of action planning among GPs improves their provision of smoking cessation care. METHODS: The effectiveness of a 1-h training programme was examined in a cluster randomised controlled trial in which 49 GPs participated. GPs who followed the training (intervention group; n = 25) formulated action plans related to i) enquiring about smoking, ii) advising to quit smoking, and iii) arranging follow-up for smokers motivated to quit. GPs also formulated a coping plan for encountering smokers not motivated to quit. The quality of these plans (plan specificity) was rated and, 6 weeks after the training, GPs reported on the performance of these plans (plan enactment). Multilevel regression analyses were used to examine the effects of plan specificity and plan enactment on patient-reported smoking cessation activities of the GPs in the intervention group (n = 1,632 patients) compared with the control group (n = 1,769 patients). RESULTS: Compared to the control group, GPs who formulated a highly specific action plan during the training asked their patients about smoking more often after the training compared to prior to the training (OR 2.11, 95% CI 1.51-2.95). GPs were most likely to have asked patients about smoking after the training compared to prior to the training when they had enacted a highly specific formulated action plan (OR 3.08, 95% CI 2.04-4.64). The effects of GP plan specificity and plan enactment on asking patient about smoking were most prominent among GPs who, at baseline, intended to provide smoking cessation care. CONCLUSIONS: A highly specific action plan formulated by a GP on when, how, and by whom patients will be asked about smoking had a positive effect on GPs' asking patients about smoking, especially when these professionals also reported to have enacted this plan. This effect was most prominent among GPs who intended to provide smoking cessation care prior to the intervention. Training in devising personalised coping plans is recommended to further increase GPs' provision of advice to quit smoking and arranging follow-up support to quit smoking. PMID- 25547979 TI - Choice of therapeutic strategies in intrathoracic anastomotic leak following esophagectomy. AB - BACKGROUND: The aim of this study was to analyze our experience with management of intrathoracic anastomotic leak after esophagectomy. METHODS: Clinical data from 33 patients who developed intrathoracic anastomotic leak were evaluated retrospectively. These patients were selected from 1867 patients undergoing resection carcinoma of the esophagus and reconstruction between January 2003 and December 2012. RESULTS: Surgical intervention and the reformed "three-tube method" were applied in 13 and 20 patients, respectively. The overall incidence of intrathoracic anastomotic leakage was 1.8%. The median time interval from esophagectomy to diagnosis of leak was 9.7 days. Sixteen patients were confirmed as having leakage by oral contrast computed tomography (CT). Age and interval from surgery to diagnosis of leak were identified as statistically significant parameters between contained and uncontained groups. Moreover, patients with hypoalbuminemia had a longer time to leak closure than patients without hypoalbuminemia. Six patients died from intrathoracic anastomotic leak, with a mortality rate of 18.2%. There was no statistically significant difference in the time to leak closure between patients who underwent surgical exploration and those who received conservative treatment. CONCLUSIONS: Intrathoracic anastomotic leak after esophagectomy was associated with significant mortality. Once intrathoracic anastomotic leakage following esophagectomy was diagnosed or highly suspected, individualized management strategies should be implemented according to the size of the leak, extent of the abscess, and status of the patient. In the majority of patients with anastomotic leak, we preferred the strategy of conservative treatment. PMID- 25547981 TI - Metabolism of ginsenosides Rk3 and Rh4 from steamed notoginseng in zebrafish by ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - In this work, the metabolite profiles of ginsenosides Rk3 and Rh4 from steamed notoginseng in zebrafish were qualitatively investigated, and their possible metabolic pathways were subsequently proposed. Metabolites of ginsenosides Rk3 and Rh4 after exposing to zebrafish for 24 h were identified by Ultraperformance Liquid Chromatography/Quadrupole -Time-of-Flight Mass Spectrometry (UPLC-TOF/MS). The separation was performed with a UPLC BEH C18 column using a binary gradient elution of 0.1 % formic acetonitrile -0.1 % formic acid water. The quasi molecular ions of compounds were detected in negative mode. According to the quasi-molecular ions and MS2 spectra, after comparison with reference standards, molecular mass information and the potential structures about metabolites of ginsenosides Rk3 and Rh4 were obtained. In all, 5 and 6 metabolites of ginsenoside Rk3 and Rh4 including M1(M6), M2(M7), M3-M5 and N1, N2(N7), N3-N6 were identified in zebrafish respectively, which were to our knowledge reported for the first time. The results indicated that ginsenosides Rk3 and Rh4 were metabolized via desugarization, glucuronidation, sulfation, dehydroxylation, and loss of C-17 and C-23 residue pathways in zebrafish. Loss of glucose at position C-6 and glucuronidation at position C-3 or C-6 in zebrafish were considered as the main physiologic processes of ginsenosides Rk3 and Rh4. PMID- 25547980 TI - Anti-angiogenic activity of macrolactin A and its succinyl derivative is mediated through inhibition of class I PI3K activity and its signaling. AB - In the current study, macrolactin compounds, macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), were investigated for their anti-angiogenic activities and action mechanism. MA and SMA inhibited in vitro and in vivo angiogenesis induced by three different classes of pro-angiogenic factors, VEGF, IL-8, and TNF-alpha. SMA exhibited stronger anti-angiogenic activity than MA, and such anti-angiogenic activity of SMA was consistently observed in MDA-MB-231 human breast cancer cell inoculated CAM assay showing dose-dependent suppression of tumor growth and tumor induced angiogenesis. In an in vitro PI3K competitive activity assay, SMA induced concentration-dependent inhibition of class I PI3K isoforms, p110alpha, p110beta, p110delta, and p110gamma. In addition, non-receptor tyrosine kinase c-Src, which is involved in the activation of PI3K heterodimer, was suppressed by MA and SMA. Correspondingly, MA and SMA significantly inhibited the stimulus-induced phosphorylation of Akt, mTOR, p70S6K, and ribosomal S6 in human umbilical vein endothelial cells (HUVECs). At the same time, the stimulus-induced production of reactive oxygen species (ROS) and activation of NF-kappaB were significantly suppressed by MA and SMA. Moreover, the macrolactins suppressed NF-kappaB regulated HSP90 protein expression, which stabilizes phosphorylated Akt and NADPH oxidase. Suppression of NF-kappaB in macrolactin-treated HUVECs with concurrent inhibition of rS6 indicates that MAs effectively block angiogenesis through down regulation of genes related to angiogenesis at both transcriptional and translational levels. Taken together, the results demonstrate that anti angiogenic effect of MA and SMA is mediated through inhibition of PI3K/Akt and NADPH oxidase-derived ROS/NF-kappaB signaling pathways. These results further indicate that MA and SMA may be applicable for treatment of various diseases associated with angiogenesis. PMID- 25547984 TI - The prognostic value of radiologic parameters for long-term outcome assessment after an isolated unilateral calcaneus fracture. AB - OBJECTIVE: The current retrospective case-control study examines the prognostic value of radiologic parameters for long-term clinical outcome assessment after a calcaneus fracture. METHODS: In the authors' trauma department 262 adult patients with an isolated calcaneus fracture were treated from 1995 to 2005. Using conventional x-ray and computed tomography imaging. the calcaneal fractures were classified according to Sanders system. In addition, Boehler's and Gissane's angles were measured before and after therapy and the Larsen stage of subtalar arthrosis was determined. After a mean follow-up interval of 9.5 years, 44 patients were available for clinical and radiological assessment. RESULTS: At the time of trauma the average age of the study group was 52 (range, 29-79) years. Thirty-seven patients were treated operatively and seven conservatively. Patients with a negative Boehler's angle, upon admission, exhibited significantly worse results using four of the five clinical scoring systems than patients with a preserved or slight reduced Boehler's angle. Operative treatment in patients whose Boehler's angle was elevated to normal range or beyond exhibited %worse better results than patients with an over-correction of Boehler's angle. In 11 cases, two primary and nine secondary subtalar arthrodeses were performed. The degree of subtalar arthrosis as per Larsen was increased 2.54 +/- 1.14 in the course of hospital admission, arthrodesis and/or follow up examination. The results show no significant difference between operative and conservative treatment. CONCLUSIONS: Boehler's angle at time of admission appears to be a valuable prognosticator for functional long-term results after calcaneus fracture. An operative over-correction of a reduced Boehler's angle should be avoided. PMID- 25547982 TI - The GRAS gene family in pine: transcript expression patterns associated with the maturation-related decline of competence to form adventitious roots. AB - BACKGROUND: Adventitious rooting is an organogenic process by which roots are induced from differentiated cells other than those specified to develop roots. In forest tree species, age and maturation are barriers to adventitious root formation by stem cuttings. The mechanisms behind the respecification of fully differentiated progenitor cells, which underlies adventitious root formation, are unknown. RESULTS: Here, the GRAS gene family in pine is characterized and the expression of a subset of these genes during adventitious rooting is reported. Comparative analyses of protein structures showed that pine GRAS members are conserved compared with their relatives in angiosperms. Relatively high GRAS mRNA levels were measured in non-differentiated proliferating embryogenic cultures and during embryo development. The mRNA levels of putative GRAS family transcription factors, including Pinus radiata's SCARECROW (SCR), PrSCR, and SCARECROW-LIKE (SCL) 6, PrSCL6, were significantly reduced or non-existent in adult tissues that no longer had the capacity to form adventitious roots, but were maintained or induced after the reprogramming of adult cells in rooting-competent tissues. A subset of genes, SHORT-ROOT (PrSHR), PrSCL1, PrSCL2, PrSCL10 and PrSCL12, was also expressed in an auxin-, age- or developmental-dependent manner during adventitious root formation. CONCLUSIONS: The GRAS family of pine has been characterized by analyzing protein structures, phylogenetic relationships, conserved motifs and gene expression patterns. Individual genes within each group have acquired different and specialized functions, some of which could be related to the competence and reprogramming of adult cells to form adventitious roots. PMID- 25547985 TI - Assessing the nutritional status of older individuals in family practice: Evaluation and implications for management. AB - BACKGROUND & AIMS: Malnutrition is emerging as a multidimensional concern of ageing with a high prevalence among nursing home residents. This study investigated the extent of malnutrition among old subjects in family practice and its relationship with major complications. METHODS: Over 75 years old subjects (n = 274) filled the Mini Nutritional Assessment questionnaire. Appearance of major events in the following 6 months were registered. RESULTS: MNA scored were 11.5 +/- 3.1, with 175 (64%) subjects showing no malnutrition, 69 (25%) resulted at risk, and 30 (11%) malnourished. Within at risk group, 1.4% was resident, 7% bed rested, 8% had a history of major bone fracture, 33% was demented and 24.6% hospitalized at least once in the last year. Among malnourished patients, 10% was resident, ten bed rested with 70% showing multiple bedsores, 20% have had bone fractures, 60% were demented and 13% hospital admitted in the previous year. In over 90% of them, malnutrition had neither diagnosed nor considered before. During follow-up, a significantly higher number of major events including death occurred in the malnourished group. By multivariate logistic regression, n = 56 (20.4%) patients resulted at risk of major complications. The sensitivity of the questionnaire in identifying these patients was 84% with the cut-off value of 7 associated with the highest prediction (positive predictive value, 0.92; negative predictive value, 0.71) yielding a specificity of 92%. CONCLUSIONS: The prevalence of malnutrition is high among older subjects in the setting of family practice. The Mini Nutritional Assessment allows to identify malnourished subjects better than BMI and effectively predicts the risk of major events. PMID- 25547983 TI - Efficacy and safety of autologous platelet rich plasma for the treatment of vascular ulcers in primary care: Phase III study. AB - BACKGROUND: Vascular ulcers are commonly seen in daily practice at all levels of care and have great impact at personal, professional and social levels with a high cost in terms of human and material resources. Given that the application of autologous platelet rich plasma has been shown to decrease healing times in various different studies in the hospital setting, we considered that it would be interesting to assess the efficacy and feasibility of this treatment in primary care. The objectives of this study are to assess the potential efficacy and safety of autologous platelet rich plasma for the treatment of venous ulcers compared to the conventional treatment (moist wound care) in primary care patients with chronic venous insufficiency (C, clinical class, E, aetiology, A, anatomy and P, pathophysiology classification C6). DESIGN: We will conduct a phase III, open-label, parallel-group, multicentre, randomized study. The subjects will be 150 patients aged between 40 and 100 years of age with an at least 2-month history of a vascular venous ulcer assigned to ten primary care centres. For the treatment with autologous platelet rich plasma, all the following tasks will be performed in the primary care setting: blood collection, centrifugation, separation of platelet rich plasma, activation of coagulation adding calcium chloride and application of the PRP topically after gelification. The control group will receive standard moist wound care. The outcome variables to be measured at baseline, and at weeks 5 and 9 later include: reduction in the ulcer area, Chronic Venous Insufficiency Quality of Life Questionnaire score, and percentage of patients who require wound care only once a week. DISCUSSION: The results of this study will be useful to improve the protocol for using platelet rich plasma in chronic vascular ulcers and to favour wider use of this treatment in primary care. TRIAL REGISTRATION: Current Controlled Trials NCT02213952. PMID- 25547986 TI - Erratum to "prostate cancer in South Africa: pathology based national cancer registry data (1986-2006) and mortality rates (1997-2009)". AB - [This corrects the article DOI: 10.1155/2014/419801.]. PMID- 25547987 TI - Effects of tobacco smoking during pregnancy on oxidative stress in the umbilical cord and mononuclear blood cells of neonates. AB - BACKGROUND: Although cigarette smoke is known to be a complex mixture of over 4000 substances that can lead to damage through active or passive smoking, its mechanisms and biochemical consequences in pregnancy and neonates are not yet fully understood. Therefore, in the present study, we propose to study the impact of smoking during gestation on the viability of blood mononuclear cells (MNC) from umbilical cords of newborns to assess the degree of oxidative stress and cell viability. After childbirth, the cord blood and the umbilical cord were immediately collected in public hospitals in Greater Vitoria, ES, Brazil. Flow cytometry was used to analyze the cord blood followed by biochemical and histological tests to analyze possible changes in the umbilical cord. RESULTS: Pregnant smokers had a reduction of MNC viability from the umbilical cord (10%), an increase in the production of reactive oxygen species (ROS) and an increase in cell apoptosis (~2-fold) compared to pregnant non-smokers. In the umbilical cord, it was observed an increase of advanced oxidation protein products - AOPP (~2.5 fold) and a loss of the typical architecture and disposition of endothelial cells from the umbilical artery. CONCLUSIONS: These data suggest that maternal cigarette smoking during pregnancy (even in small amounts) may compromise the viability of MNC cells and damage the umbilical cord structure, possibly by excessive ROS bioavailability. PMID- 25547989 TI - Flower bouquet variation in four species of Crocus ser. Verni. AB - Flowering plants employ a wide variety of signals, including scent, to attract pollinators. The aim of this work was to examine whether flower volatiles in four closely related Crocus species are linked to species divergence and to the current knowledge on their pollination syndromes. Fragrances of freshly opened flowers in Crocus etruscus, C. ilvensis, C. neglectus, and C. vernus, all belonging to ser. Verni, were analyzed using GC/MS. Results coincide with present knowledge about systematic relationships among taxa. The four species fall into two main fragrance types, based on similarities of their volatile compounds. In C. etruscus, C. ilvensis, and C. neglectus, oxygenated monoterpenes (lilac aldehyde B and A) are most abundant, while C. vernus has a fragrance rich in monoterpene hydrocarbons (alpha-pinene and limonene). Our results point towards outcrossing mating strategies for C. etruscus, C. ilvensis, and C. neglectus, whose volatile compounds are known as pollinator attractants. This is in line with their flower architecture, showing a style of variable height, often overtopping stamens. On the other hand, a self-pollination strategy was repeatedly suggested in the literature for C. vernus, marked by flowers with the style deeply inserted in the stamens and also by a completely different flower bouquet. PMID- 25547990 TI - On intuition and the discovery of interferon. PMID- 25547988 TI - Expression analysis of two P450 monooxygenase genes of the tobacco cutworm moth (Spodoptera litura) at different developmental stages and in response to plant allelochemicals. AB - Cytochrome P450 monooxygenases (P450s) of insects are known to be involved in the metabolism or detoxification of plant allelochemicals and insecticides. Spodoptera litura (Lepidoptera, Noctuidae) is a polyphagous moth responsible for severe yield losses in many crops. In this study, two full-length P450 genes, CYP6B48 and CYP6B58, were cloned from S. litura. The cDNA sequences encode proteins with 503 and 504 amino acids, respectively. Phylogenetic analysis revealed that CYP6B48 and CYP6B58 belong to the CYP6B subfamily of P450s. Quantitative real-time PCR analyses showed that CYP6B48 and CYP6B58 were expressed only at larval stage, but not at pupal and adult stages. The highest levels of transcripts were found in the midguts and fat bodies of the larvae. No expression was detected in the ovary or hemolymph. Feeding with diets containing cinnamic acid, quercetin, or coumarin did not affect expression of CYP6B48. In contrast, diet supplemented with xanthotoxin dramatically increased the levels of CYP6B48 transcript in the midgut and fat bodies. Larvae fed with flavone had high levels of transcript of CYP6B48 in the midgut, whereas only slightly elevated levels were found in the fat bodies. Effects of the tested allelochemicals on CYP6B58 expression were minor. Hence, our findings show that S. litura responds to specific allelochemicals such as xanthotoxin with the accumulation of CYP6B48 transcripts, suggesting that specific signals in the food control the insect's ability to convert toxic allelochemicals to less harmful forms at the transcriptional level. PMID- 25547992 TI - [Blood transfusion: control of infectious risks]. AB - From blood donor collection to transfusion of the recipient, there are several layers of protection of the blood supply. These measures combined with huge progresses over the three past decades in pathogen discovery and blood testing for specific pathogens (human immunodeficiency virus (HIV), hepatitis B (HBV) and C (HCV) viruses, Human T-cell leukemia virus (HTLV)), provide the greatest safety. With the implementation of serological and molecular testing, at least in high-income countries, transfusion-transmitted infections have become extremely rare. However, for pathogen agents, which are not tested and especially those which are responsible for emerging infectious disease, it became apparent that full control of infectious disease had not been achieved. In addition, the immune status of the recipient has also an impact in the outcome of infectious diseases transmitted by transfusion. Blood safety is based on several measures: education and deferral of donors with risk factors for transmissible disease, blood testing, pathogen reduction interventions, and patient blood management. This paper proposes a review of the residual risk of transmission of infectious diseases by transfusion and of the additional interventions able to further reduce it. PMID- 25547991 TI - Advances in pharmacotherapy for the treatment of gout. AB - INTRODUCTION: Gout is a common inflammatory arthritis affecting almost 6% of US males and 2% of US females. The central cause of gout is deposition of monosodium urate crystals, and the focus of treatment is aimed at crystal dissolution using urate-lowering therapy. AREAS COVERED: The review describes the current treatments for urate-lowering therapy including allopurinol, febuxostat, probenecid, benzbromarone and pegloticase. Anti-inflammatory treatment of acute flares and prophylaxis of flares with NSAIDs, colchicine, corticosteroids and anti-IL-1 agents is also reviewed. In addition, drugs in Phase III clinical trials for gout indications are reviewed. EXPERT OPINION: In the last decade, there has been major progress in the pharmacotherapy of gout. Management guidelines have emphasized the importance of a therapeutic serum urate target for effective gout management. Studies have identified the safe and effective dosing strategies for 'old' drugs such as allopurinol and colchicine. New therapeutic agents have been developed and approved for both urate-lowering therapy and anti inflammatory treatment of acute flares. However, quality of care remains a major challenge in gout management, and strategies to ensure best practice require further focus to ensure that the progress of the last decade translates into clinical benefit for people with gout. PMID- 25547993 TI - Disability trajectories and associated disablement process factors among older adults in Taiwan. AB - OBJECTIVES: We aimed to identify disability trajectories and examine whether the predisposing, intra-individual, and extra-individual factors in the disablement process predicted different disability trajectories among older adults in Taiwan. METHODS: Data were from the Taiwan Longitudinal Study on Aging (TLSA) Survey in 1996-2007 (n=3186). Disability trajectories for activities of daily living (ADLs) and instrumental activities of daily living (IADLs) were identified by using latent class growth curves modeling. Factors including demographics, health conditions, health behaviors, social relations, and use of assistive devices were significantly predicted different disability trajectories of older adults over the following 11 years by applying hierarchical logistic regression. RESULTS: Three disability trajectories--maintained function, progressive disability, and consistent disability--were identified. Predisposing factors such as younger age, more educational attainment, and better health conditions had protective effects of leading to a later healthier maintained function trajectory. Intra-individual factors such as engaging in leisure time activities (LTAs) were positively related to the maintained function trajectory but negatively related to the consistent disability trajectory; decreasing social networks was common to those on consistent disability trajectory; dissatisfaction with social support was noted in maintained function trajectory group. An extra-individual factor, using assistive devices, was significantly related to maintaining older adults' disability levels, even for those who started disabled. CONCLUSIONS: The findings suggested that predisposing, intra-individual, and extra-individual factors play different roles in the development of later disability trajectories. More educational attainment, better health conditions, active in LTAs, and using assistive devices might benefit the maintenance of functioning in Taiwanese older adults. PMID- 25547994 TI - Quality of life (QOL) of the community-dwelling elderly and associated factors: a population-based study in urban areas of China. AB - OBJECTIVE: China has the most elderly people. Maintaining and improving the QOL of the elderly has emerged as a particularly important issue. This population based study aimed to examine the QOL of the urban elderly and to clarify the associated factors. METHODS: A cross-sectional study was performed in Liaoning Province. The elderly people without senile dementia composed our study population and were interviewed from March to November, 2012 with questionnaires pertaining to QOL (SF-36), cognitive ability, demographic characteristics, health status, behavioral factors, and social-psychological factors. 4067 effective responses were received (effective response rate: 86.0%). After further cognitive screening, 3714 participants were included as the subjects. RESULTS: The mean scores of physical component summary (PCS) and mental component summary (MCS) were 53.7+/-21.5 (mean+/-SD) and 58.9+/-18.9, respectively. With adjustment for age and sex, general linear model analysis showed that, in standardized estimate (beta) sequence, PCS was significantly associated with chronic disease, taking a walk, visual ability, sleeping quality, marital status, alcohol consumption, hearing ability, smoking, neighborhood relationships, filial piety, ethnicity, and regular diet, and MCS was associated with chronic disease, sleeping quality, taking a walk, visual ability, marital status, ethnicity, filial piety, regular diet, alcohol consumption, smoking, and hearing ability. CONCLUSIONS: The community-dwelling elderly in urban areas had a low level of QOL. To improve QOL, the maintenance of health conditions was crucial. Efforts to encourage the elderly to perform feasible exercise and develop good lifestyles should be focused on. Also, children's filial duty to their parents should be enhanced. PMID- 25547995 TI - Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma. AB - BACKGROUND/AIMS: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment. METHODS: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. RESULTS: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. CONCLUSION: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM. PMID- 25547996 TI - Atopic dermatitis: professional orientation. AB - Atopic dermatitis is often exacerbated by the working environment. In order to reduce the risk of allergy, young people must receive better medical guidance when they choose a career. This is all the more relevant for young atopic patients. PMID- 25547997 TI - Psychosomatic medicine in China. PMID- 25547999 TI - Taurine resumed neuronal differentiation in arsenite-treated N2a cells through reducing oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. AB - The goal of the study is to investigate the preventive effect of taurine against arsenite-induced arrest of neuronal differentiation in N2a cells. Our results revealed that taurine reinstated the neurite outgrowth in arsenite-treated N2a cells. Meanwhile, arsenite-induced oxidative stress and mitochondrial dysfunction as well as degradation of mitochondria DNA (mtDNA) were also inhibited by co treatment of taurine. Since oxidative stress and mitochondrial dysfunction is closely associated with endoplasmic reticulum (ER) stress, we further examined indicators of ER stress, 78 kDa glucose-regulated protein (GRP78), and C/EBP homologous protein (CHOP) protein expression. The results demonstrated that taurine significantly reduced arsenite-induced ER stress in N2a cells. In the parallel experiment, arsenite-induced disruption of intracellular calcium homeostasis was also ameliorated by taurine. The proven bio-function of taurine preserved a preventive effect against deleteriously cross-talking between oxidative stress, mitochondria, and ER. Overall, the results of the study suggested that taurine reinstated neuronal differentiation by inhibiting oxidative stress, ER stress, and mitochondrial dysfunction in arsenite-treated N2a cells. PMID- 25547998 TI - Performance characteristics of long-track speed skaters: a literature review. AB - Speed skating is an intriguing sport to study from different perspectives due to the peculiar way of motion and the multiple determinants for performance. This review aimed to identify what is known on (long-track) speed skating, and which individual characteristics determine speed skating performance. A total of 49 studies were included. Based on a multidimensional performance model, person related performance characteristics were categorized in anthropometrical, technical, physiological, tactical, and psychological characteristics. Literature was found on anthropometry, technique, physiology, and tactics. However, psychological studies were clearly under-represented. In particular, the role of self-regulation might deserve more attention to further understand mechanisms relevant for optimal performance and for instance pacing. Another remarkable finding was that the technically/biomechanically favourable crouched skating technique (i.e. small knee and trunk angle) leads to a physiological disadvantage: a smaller knee angle may increase the deoxygenation of the working muscles. This is an important underlying aspect for the pacing tactics in speed skating. Elite speed skaters need to find the optimal balance between obtaining a fast start and preventing negative technical adaptations later on in the race by distributing their available energy over the race in an optimal way. More research is required to gain more insight into how this impacts on the processes of fatigue and coordination during speed skating races. This can lead to a better understanding on how elite speed skaters can maintain the optimal technical characteristics throughout the entire race, and how they can adapt their pacing to optimize all identified aspects that determine performance. PMID- 25548001 TI - HPV16E7-specific siRNA inhibits cell proliferation in CaSki cells. AB - High-risk human papilloma virus (HPV) infection is the main cause for the genesis of cervical carcinomas. After infection, E6 and E7 genes of HPV were integrated to the genome of the cervical epithelium. Continued expression of the transforming oncoproteins E6 and E7 not only drives the neoplastic progression in cervical epithelium, but also plays an important role in maintaining the malignant phenotype of cervical cancer cells. The aim of this study is to explore the effects of liposomal transfection of HPV16E7 siRNA on the proliferation of cervical carcinoma cell line CaSki. The siRNA interfering HPV16E7 gene was synthesized and transfected into CaSki cells by liposome to observe the cell morphology changes under microscope. The cell proliferation index was detected by flow cytometry; HPV16E7 mRNA expression was determined by RT-PCR and its protein level was determined by Western blot. After transfection of the CaSki cell by siRNA, cell proliferation was inhibited significantly, and the expression of HPV16E7 mRNA and protein level of HPV16E7 decreased. HPV16E7 siRNA is able to inhibit growth of CaSki cells. HPV16E7 might become a new target for genetic therapy of cervical carcinoma. PMID- 25548000 TI - The application of Arabidopsis thaliana in studying tripartite interactions among plants, beneficial fungal endophytes and biotrophic plant-parasitic nematodes. AB - MAIN CONCLUSION: The research demonstrated that Arabidopsis can be used as a model system for studying plant-nematode-endophyte tripartite interactions; thus, opening new possibilities for further characterizing the molecular mechanisms behind these interactions. Arabidopsis has been established as an important model system for studying plant biology and plant-microbe interactions. We show that this plant can also be used for studying the tripartite interactions among plants, the root-knot nematode Meloidogyne incognita and a beneficial endophytic isolate of Fusarium oxysporum, strain Fo162. In various plant species, Fo162 can systemically reduce M. incognita infection development and fecundity. Here it is shown that Fo162 can also colonize A. thaliana roots without causing disease symptoms, thus behaving as a typical endophyte. As observed for other plants, this endophyte could not migrate from the roots into the shoots and leaves. Direct inoculation of the leaves also did not result in colonization of the plant. A significant increase in plant fresh weight, root length and average root diameter was observed, suggesting the promotion of plant growth by the endophyte. The inoculation of A. thaliana with F. oxysporum strain Fo162 also resulted in a significant reduction in the number of M. incognita juveniles infecting the roots and ultimately the number of galls produced. This was also observed in a split root experiment, in which the endophyte and nematode were spatially separated. The usefulness of Arabidopsis opens new possibilities for further dissecting complex tripartite interactions at the molecular and biochemical level. PMID- 25548002 TI - The Clinical Research of Serum VEGF, TGF-beta1, and Endostatin in Non-small Cell Lung Cancer. AB - The aim of the study was to analyze the expressions of vascular endothelial growth factor (VEGF), transforming growth factor beta1 (TGF-beta1) and endostatin in non-small cell lung caner (NSCLC), and to explore their correlations with NSCLC. 80 NSCLC patients during January 2013 to June 2014 were selected. The expression levels of VEGF, TGF-beta1, and endostatin before surgeries were detected, and compared with 40 healthy individuals and 40 patients with benign pulmonary diseases. Serum VEGF, TGF-beta1, and endostatin levels were (573.6 +/- 25.4) pg/mL, (36.2 +/- 10.5) ng/mL, and (20.3 +/- 7.8) ng/mL, respectively, in NSCLC group, which were obviously higher than those in healthy individuals and patients with benign pulmonary diseases, and the difference was statistically significant (p < 0.05); there was no statistical difference of the VEGF, TGF beta1, and endostatin levels between the healthy individuals and patients with benign pulmonary diseases (p > 0.05), or among patients with different physiological characteristics such as gender, age, and smoking history in NSCLC group (p > 0.05). Serum VEGF, TGF-beta1, and endostatin levels also showed no statistical difference among patients with different pathological characteristics such as histological types, with or without lymphatic metastasis (p > 0.05). However, the three indicators were significantly different among patients with different TNM stages, with or without distant metastasis and different cell differentiation degrees (p < 0.05). Serum VEGF and TGF-beta1 were positively related (r = 0.479, p < 0.05), endostatin was negatively related to both VEGF and TGF-beta1 (r = -0.392, -0.354, p < 0.05 in both comparisons). The expression levels of VEGF, TGF-beta1, and endostatin significantly contributed to the poor cell differentiation in NSCLC. They had important effects on the occurrence, development, and metastasis of NSCLC, which could be applied as the indicators to predict the malignancy of NSCLC. PMID- 25548003 TI - Improving the Management of Appointment Registration and Exploring an Innovative Medical Service. AB - Improving levels of healthcare service to enhance patient care are not only what patients' demands of medical staff, but also what the medical staff demands of the hospital managers. The practical experiences of Xuzhou Central Hospital have proved that a carefully designed hospital culture helps to mobilize the enthusiasm of medical staff, improve patient satisfaction, and lead to an increase in the pace of a hospital's integrated development. PMID- 25548004 TI - Study on the Mechanisms of Cartilage Tissue Damage Caused by Hydrogen Peroxide. AB - Hydrogen peroxide (H2O2), normally used in the prevention of local bacterial infection, is also used for clinical debridement in bone and joint surgery. Studies show that treatment with H2O2 can cause cartilage damage, leading to postoperative complications. H2O2 can induce apoptosis because of its strong oxidation activity. To investigate the molecular mechanisms of H2O2-induced chondrocyte apoptosis, the rat chondrocytes from the knee joint were used as a cell model for this study. The results showed that the H2O2-treated cells survived at a decreased rate, with apoptosis in a great number of chondrocytes. The expression of pro-apoptotic factors of chondrocytes, Bcl-2 and Bcl-xl, were downregulated, while the pro-apoptotic factor Bax upregulated. Two important factors ERK and p38 in MAPK signaling pathway were phosphorylated at a higher level, leading to apoptosis of chondrocytes. This study described the molecular mechanism of H2O2-induced chondrocyte apoptosis, providing a theoretical basis for the rational and clinical use of H2O2 as a disinfectant. PMID- 25548005 TI - Process Reengineering for Quality Improvement in ICU Based on Taylor's Management Theory. AB - Using methods including questionnaire-based surveys and control analysis, we analyzed the improvements in the efficiency of ICU rescue, service quality, and patients' satisfaction, in Xuzhou Central Hospital after the implementation of fine management, with an attempt to further introduce the concept of fine management and implement the brand construction. Originating in Taylor's "Theory of Scientific Management" (1982), fine management uses programmed, standardized, digitalized, and informational approaches to ensure each unit of an organization is running with great accuracy, high efficiency, strong coordination, and at sustained duration (Wang et al., Fine Management, 2007). The nature of fine management is a process that breaks up the strategy and goal, and executes it. Strategic planning takes place at every part of the process. Fine management demonstrates that everybody has a role to play in the management process, every area must be examined through the management process, and everything has to be managed (Zhang et al., The Experience of Hospital Nursing Precise Management, 2006). In other words, this kind of management theory demands all people to be involved in the entire process (Liu and Chen, Med Inf, 2007). As public hospital reform is becoming more widespread, it becomes imperative to "build a unified and efficient public hospital management system" and "improve the quality of medical services" (Guidelines on the Pilot Reform of Public Hospitals, 2010). The execution of fine management is of importance in optimizing the medical process, improving medical services and building a prestigious hospital brand. PMID- 25548006 TI - Association of Serum Levels of Adipocyte Fatty Acid-Binding Protein and High Sensitivity C Reactive Protein with Severity of Acute Ischemic Stroke. AB - To evaluate the serum levels of adipocyte fatty acid-binding protein (A-FABP) and high-sensitivity C reactive protein (hs-CRP) in patients with acute ischemic stroke (AIS), and correlations among A-FABP, hs-CRP, and AIS, 108 patients with AIS and 86 healthy controls were examined. The levels of hs-CRP and A-FABP were detected by ELISAs. The stroke severity was determined using the modified Rankin scale (mRS). Patients with AIS were divided into those with mild (mRS <= 3) and severe disease (mRS > 3). Regression analysis was performed to test association between hs-CRP and A-FABP. Serum levels of hs-CRP and A-FABP were significantly higher in patients with AIS compared with healthy controls. Furthermore, more severe AIS was associated with higher levels of these markers. Regression analysis demonstrated a weak but significant association between A-FABP and hs CRP. A-FABP and hs-CRP are associated with AIS, and may be involved in the pathogenesis of AIS. PMID- 25548007 TI - All-Round Marketing Increases Hospital Popularity. AB - Xuzhou Center Hospital is in a competing medical market in Xuzhou city. This hospital has been dedicating to improve the medical skills and provide professional and individualized service to the patients in order to improve the patient's experience and increase the patient's satisfaction. On the other side, this hospital has provided an all-round marketing campaign to build up the social influence and public reputation through public-praise marketing, web marketing, media marketing, and scholar marketing. Besides, this hospital has been cooperating with foreign medical institutions and inviting foreign medical specialists to academic communication. With the combined effects of improving medical service and all-round marketing, the hospital's economic performance has been enhanced significantly and laid a solid foundation for its ambition to become the first-class hospital in Huaihai Economic Zone. PMID- 25548008 TI - Gastrointestinal manifestations of systemic disease: a multimodality review. AB - Systemic diseases have many different presentations, including imaging findings in the bowel. Recognizing the imaging findings in these diseases is important in making the correct diagnosis. Although certain imaging features overlap, knowledge of specific findings along with the clinical presentation aid in narrowing the differential or in making an imaging diagnosis. The pictorial review will focus on the gastrointestinal manifestations of systemic diseases, including amyloidosis, angiotensin converter enzyme inhibitor-induced angioedema, celiac sprue, distal intestinal obstruction syndrome, graft-versus-host disease, hemolytic uremic syndrome, hemophilia, Henoch-Schonlein purpura, intestinal lymphangiectasia, mastocytosis, scleroderma, systemic lupus erythematosus, Wegener's granulomatosis, and Whipple's disease. The aforementioned diseases can be subdivided based upon the underlying process leading to the disease. The diseases discussed are categorized into autoimmune, infiltrative, treatment related, congenital/hereditary, and infectious etiologies. PMID- 25548009 TI - MEK/ERK signaling pathway is required for enterovirus 71 replication in immature dendritic cells. AB - BACKGROUND: The mitogen-activated protein kinase kinase/extracellular-signal regulated kinase (MEK/ERK) signaling pathway is involved in viral life cycle. However, the effect of MEK/ERK pathway in enterovirus 71(EV71)-infected immature dendritic cells (iDCs) is still unclear. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated and induced to generate iDCs. Unifected iDCs and EV71-infected iDCs with a multiplicity of infection (MOI = 5) were analyzed by flow cytometry. Differential gene expressions of MEK/ERK signaling pathway molecules in EV71-infected iDCs were performed by PCR arrays. The phosphorylation of MEK/ERK pathway molecules in EV71-infected iDCs preincubated without or with U0126 (20 MUM) at indicated times was detected by Western blot. The concentrations of IL-1alpha, IL-2, IL-6, IL-12, TNF-alpha, IFN-alpha1, IFN beta and IFN-gamma in culture supernatant were analyzed by the luminex fluorescent technique. RESULTS: When iDCs were infected with EV71 for 24 h, the percentage of CD80, CD83, CD86 and HLA-DR expressed on iDCs significantly increased. PCR arrays showed that gene expressions of molecules in MEK/ERK signaling pathway were remarkably upregulated in EV71-infected iDCs. EV71 infection activated both MEK1/2 and ERK1/2, which phosphorylated their downstream transcription factor c-Fos, c-Jun, c-myc and Elk1. Importantly, the treatment of U0126 significantly inhibited MEK/ERK signaling pathway molecules and severely impaired virus replication., Additionally, EV71 infection promoted the expression of son of sevenless (SOS1) and increased the secretion of IL-1alpha, IL-2, IL-6, IL-12, TNF-alpha,IFN-beta and IFN-gamma. Furthermore,the release of IL-1alpha, IL 2,IL-6 and TNF-alpha could be effectively suppressed by inhibitor U0126. CONCLUSIONS: Our data suggest that the MEK/ERK signaling pathway plays an important role in EV71-infected iDCs and these molecules may be potential targets for the development of new anti-EV71 drugs. PMID- 25548010 TI - Influence of microbubble in physical cleaning of MF membrane process for wastewater reuse. AB - Currently, there is a growing emphasis on wastewater reclamation and reuse all over the world due to restricted water resources. Among a variety of wastewater reuse technologies, the use of microfiltration membranes (MF) is one of the popular processes because it has the ability to successfully eliminate particulates and colloidal matters. However, successful fouling control is not easy because effluents from the activated sludge process still contain small particulates and colloidal matters such as extracellular polymeric substance (EPS) and soluble microbial products (SMP). On the other hand, microbubbles have advantageous properties compared to common bubbles, but there hasn't been reporting of the use of microbubbles in physical cleaning instead of aeration. Encouraging results were obtained herein through the application of microbubbles for physical cleaning. In evaluation of the cleaning efficiency, the efficiency of microbubbles was observed to be twice as high as that of aeration, except during the course of the initial 30 min. Total organic carbon (TOC) concentration of the membrane tank after treatment with microbubbles was more than twice as high as that after aeration for physical cleaning. The membrane cleaned with microbubbles also had the smoothest surface, with a roughness of 42.5 nm. In addition, microbubbles were found to effectively remove EPS and make the structure of the gel layer loose. In particular, the microbubbles had the ability to remove proteins through the effect of pyrolytic decomposition. Therefore, in FT-IR spectra of the membrane surfaces taken before and after physical cleaning, while each treatment showed similar peak positions, the peak values of the membrane treated with microbubbles were the lowest. Through various analyses, it was confirmed that microbubbles can remove foulants on the gel layer in spite of their very low shear force. This means that microbubble cleaning has full potential for use as a physical cleaning method in the wastewater reclamation process. PMID- 25548012 TI - Optimization of a bioremediation system of soluble uranium based on the biostimulation of an indigenous bacterial community. AB - High concentrations of uranium(VI) in the Witwatersrand Basin, South Africa from mining leachate is a serious environmental concern. Treatment systems are often ineffective. Therefore, optimization of a bioremediation system that facilitates the bioreduction of U(VI) based on biostimulation of indigenous bacterial communities can be a viable alternative. Tolerance of the indigenous bacteria to high concentrations of U and the amount of citric acid required for U removal was optimized. Two bioreactor studies which showed effective U(VI) removal more than 99 % from low (0.0037 mg L(-1)) and high (10 mg L(-1)) concentrations of U to below the limit allowed by South African National Standards for drinking water (0.0015 mg L(-1)). The second bioreactor was able to successfully adapt even with increasing levels of U(VI) feed water up to 10 mg L(-1), provided that enough electron donor was available. Molecular biology analyses identified Desulfovibrio sp. and Geobacter sp. among known species, which are known to reduce U(VI). The mineralogical analysis determined that part of the uranium precipitated intracellularly, which meant that the remaining U(VI) was precipitated as U(IV) oxides and TEM-EDS also confirmed this analysis. This was predicted with the geochemical model from the chemical data, which demonstrated that the treated drainage was supersaturated with respect to uraninite > U4O9 > U3O8 > UO2(am). Therefore, the tolerance of the indigenous bacterial community could be optimized to remediate up to 10 mg L(-1), and the system can thus be upscaled and employed for remediation of U(VI) impacted sites. PMID- 25548011 TI - Bisphenol A, nonylphenols, benzophenones, and benzotriazoles in soils, groundwater, surface water, sediments, and food: a review. AB - Contaminants of emerging concern (CECs) are not commonly monitored in the environment, but they can enter the environment from a variety of sources. The most worrying consequence of their wide use and environmental diffusion is the increase in the possible exposure pathways for humans. Moreover, knowledge of their behavior in the environment, toxicity, and biological effects is limited or not available for most CECs. The aim of this work is to edit the state of the art on few selected CECs having the potential to enter the soil and aquatic systems and cause adverse effects in humans, wildlife, and the environment: bisphenol A (BPA), nonylphenol (NP), benzophenones (BPs), and benzotriazole (BT). Some reviews are already available on BPA and NP, reporting about their behavior in surface water and sediments, but scarce and scattered information is available about their presence in soil and groundwater. Only a few studies are available about BPs and BT in the environment, in particular in soil and groundwater. This work summarizes the information available in the literature about the incidence and behavior of these compounds in the different environmental matrices and food. In particular, the review focuses on the physical-chemical properties, the environmental fate, the major degradation byproducts, and the environmental evidence of the selected CECs. PMID- 25548014 TI - Assessment of occurrence and concentrations of paraquat dichloride in water, sediments and fish from Warri River Basin, Niger Delta, Nigeria. AB - The distribution of Paraquat dichloride in different matrices of Warri River, Western Niger Delta, Nigeria was examined. The samplings and physicochemical parameters of the river were carried out during the dry and wet seasons, and stations were visited on monthly basis. The downstream stations had significant (p < 0.05) higher values than the control station. Seasonal variation revealed that, in water, the pesticide level was higher in the dry season than in wet season, and there was no significant difference between the seasons (p > 0.05). The reverse was the case for sediments and fish. The physicochemical parameters of the river's water were within the recommended limits accepted by Federal Environmental Protection Agency, Nigeria. The observed Paraquat dichloride concentrations were above ecological bench, an observation that calls for regular monitoring and strict law enforcement to develop a strategy to manage environmental hazards and to improve environmental protection of this area. PMID- 25548013 TI - Comparison of essential and toxic elements in esophagus, lung, mouth and urinary bladder male cancer patients with related to controls. AB - There is a compelling evidence in support of negative associations between essential trace and toxic elements in different types of cancer. The aim of the present study was to investigate the relationship between carcinogenic (As, Cd, Ni) and anti-carcinogenic (Se, Zn) trace elements in scalp hair samples of different male cancerous patients (esophagus, lung, mouth, and urinary bladder). For comparative purposes, the scalp hair samples of healthy males of the same age group (ranged 35-65 years) as controls were analyzed. Both controls and patients have the same socioeconomic status, localities, dietary habits, and smoking locally made cigarette. The scalp hair samples were oxidized by 65% nitric acid: 30% hydrogen peroxide (2:1) ratio in microwave oven followed by atomic absorption spectrometry. The validity and accuracy of the methodology were checked using certified reference material of human hair BCR 397. The mean concentrations of As, Cd, and Ni were found to be significantly higher in scalp hair samples of patients having different cancers as compared to the controls, while reverse results were obtained in the case of Se and Zn levels (p < 0.01). The study revealed that the carcinogenic processes are significantly affecting the trace elements burden and mutual interaction of essential trace and toxic elements in the cancerous patients. PMID- 25548016 TI - Effect of bromide ion on the reaction pathway between hydroxyl radical and glycine. AB - Br(-) and nitrogen-containing organic pollutants, such as amino acids, protein, etc., were often detected in water and wastewater treatment plants using advanced oxidation technologies. All these technologies have one common characteristic, that is, the removal processes involve .OH. Therefore, it is necessary to study the different reaction pathways among .OH, Br(-), and amino acids. In this research, glycine was chosen as the representative of amino acids and H2O2 was selected as .OH precursor. Results showed that Br(-) had a shielding effect on [Formula: see text] of alpha-carbon in glycine, when it was abstracted by .OH. The main reaction pathway in the system containing Br(-) was the abstraction of H from amino group in glycine by .OH, contributing 85 % of total abstracted H. This system had a prominent phenomenon of decarboxylation and performed as alkali production dominating. However, in the system not containing Br(-), the main reaction pathway was the abstraction of H from alpha-carbon in glycine by .OH, contributing 97 % of total abstracted H. This system performed as acid production dominating. By laser flash photolysis, the second-order rate constants of abstraction of H from both alpha-carbon and amino group in glycine by .OH were obtained as (3.3 +/- 0.5) * 10(7) M(-1).s(-1) and (8.2 +/- 0.8) * 10(8) M(-1).s( 1), respectively. The second-order rate constants of the reaction between [Formula: see text], HNCH2COO(-) and H2O2 were (1.5 +/- 1.1) * 10(7) M(-1).s(-1) and (4.4 +/- 0.3) * 10(7) M(-1).s(-1), respectively. In addition, Br(-) was found to play a catalytic role in the decomposition of H2O2 under UV radiation. The results mentioned above were significant for the application of advanced oxidation technologies for water containing both amino acids and Br(-) in water and wastewater treatment plants. PMID- 25548015 TI - Impact of nanoparticles on human and environment: review of toxicity factors, exposures, control strategies, and future prospects. AB - Nanotechnology has revolutionized the world through introduction of a unique class of materials and consumer products in many arenas. It has led to production of innovative materials and devices. Despite of their unique advantages and applications in domestic and industrial sectors, use of materials with dimensions in nanometers has raised the issue of safety for workers, consumers, and human environment. Because of their small size and other unique characteristics, nanoparticles have ability to harm human and wildlife by interacting through various mechanisms. We have reviewed the characteristics of nanoparticles which form the basis of their toxicity. This paper also reviews possible routes of exposure of nanoparticles to human body. Dermal contact, inhalation, and ingestion have been discussed in detail. As very limited data is available for long-term human exposures, there is a pressing need to develop the methods which can determine short and long-term effects of nanoparticles on human and environment. We also discuss in brief the strategies which can help to control human exposures to toxic nanoparticles. We have outlined the current status of toxicological studies dealing with nanoparticles, accomplishments, weaknesses, and future challenges. PMID- 25548017 TI - Effects of Fructus ligustri lucidi on the growth, cell integrity, and metabolic activity of the Microcystis aeruginosa. AB - Agricultural waste has been used in the treatment of cyanobacterial bloom because of its environmental friendly and cost-efficient characteristics. In this work, the effects of Fructus ligustri lucidi (FLL) on the growth inhibition, physiological properties, algicidal property, and cell ultrastructure of Microcystis aeruginosa were investigated for the first time. The alga was efficiently inhibited by FLL at the dosages from 0.25 to 4.0 g L(-1), and the Chl a fluorescence and metabolic activity of cells also declined gradually. During 25 days incubation time, the inhibition ratio of 0.25 g L(-1) dosage increased from 8 to 68 %, the percentage of intact cells decreased from 94.4 to 59.8 %, the inhibition ratio of 2.0 and 4.0 g L(-1) dosages was nearly 100 %, and the cell membranes were completely broken. The results of Chl-a, propidium iodide (PI) staining, fluorescein diacetate (FDA) staining, and transmission electron microscopy (TEM) assays were consistent with that of growth inhibition tests. The new medium test with the PI staining test suggested that FLL may act as an algicidal agent which can inhibit the growth of M. aeruginosa in the acute time. Consequently, FLL could be an excellent choice in the treatment of eutrophic water. PMID- 25548018 TI - The physiological responses of Vallisneria natans to epiphytic algae with the increase of N and P concentrations in water bodies. AB - To reveal the mechanism of submerged plants decline in progressively eutrophicated freshwaters, physiological responses of Vallisneria natans to epiphytic algae were studied in simulation lab by measuring plant physiological indexes of chlorophyll content, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity based on a 2 * 4 factorial design with two epiphytic conditions (with epiphytic algae and without) and four levels of N and P concentrations in water (N-P[mg.L(-1)]: 0.5, 0.05; 2.5, 0.25; 4.5, 0.45; 12.5, 1.25). Compared with control (non-presence of epiphytic algae), chlorophyll contents of V. natans were significantly decreased (p < 0.01) for the presence of epiphytic algae under any concentrations of N and P in water bodies. While the presence of epiphytic algae induced peroxidation of membrane lipids, MDA contents of V. natans had significantly increased (p < 0.05) by comparing with control. SOD activity significantly enhanced (p < 0.05) with the presence of epiphytic algae in the treatments of T2 and T3 in the whole culture process by comparing with control, sometimes reaching an extremely significant level (p < 0.01). However, in the treatments of T1 and T4, SOD activity had no obvious change with the presence of epiphytic algae (p < 0.05) by comparing with control. At the end of the experiment, the effects of epiphytic algae on chlorophyll content and SOD activity in the leaves of V. natans were increased at first and then decreased with the concentrations of N and P in water, and MDA content became higher with the increase of N and P. concentrations. Repeated measurement data testing showed that the effects of epiphytic algae on the chlorophyll content and MDA content and SOD activity were significant, respectively (p < 0.001), the effects of epiphytic algae were combining with effects of concentrations of N and P (p < 0.001), respectively, and their interaction (p < 0.001). Our observations confirmed that this prediction: the growth of epiphytic algae directly produced adverse effects on physiology of V. natans and epiphytic algal biomass were positively correlated with nutrient available in the water column. PMID- 25548019 TI - Heritage materials and biofouling mitigation through UV-C irradiation in show caves: state-of-the-art practices and future challenges. AB - Biofouling, i.e., colonization of a given substrate by living organisms, has frequently been reported for heritage materials and particularly on stone surfaces such as building facades, historical monuments, and artworks. This also concerns subterranean environments such as show caves, in which the installation of artificial light for tourism has led to the proliferation of phototrophic microorganisms. In Europe nowadays, the use of chemicals in these very sensitive environments is scrutinized and regulated by the European Union. New and environmentally friendly processes must be developed as alternative methods for cave conservation. For several years, the UV irradiation currently used in medical facilities and for the treatment of drinking water has been studied as a new innovative method for the conservation of heritage materials. This paper first presents a review of the biofouling phenomena on stone materials such as building facades and historical monuments. The biological disturbances induced by tourist activity in show caves are then examined, with special attention given to the methods and means to combat them. Thirdly, a general overview is given of the effects of UV-C on living organisms, and especially on photosynthetic microorganisms, through different contexts and studies. Finally, the authors' own experiments and findings are presented concerning the study and use of UV-C irradiation to combat algal proliferation in show caves. Both laboratory and in situ results are summarized and synthesized from their previously published works. The application of UV in caves is discussed and further experiments are proposed to enhance research in this domain. PMID- 25548021 TI - Risk of phosphorus leaching from phosphorus-enriched soils in the Dianchi catchment, Southwestern China. AB - As an important pathway for phosphorus (P) transport from soil to water body, P leaching has aroused attention. This study aimed to investigate the degree of risk and forms of P leaching from P-enriched soils. Surface soils were collected from forest land (FL) and open agricultural land (OAL) in typical P-enriched area of the Dianchi catchment, China. Based on analysis of soil P and water-soluble P using chemical methods and (31)P-NMR analysis, combined with a soil column leaching experiment, P forms and risk of P leaching were identified. CaCl2 extractable water-soluble organic P (CaCl2-Po), inorganic P (CaCl2-Pi), and total P (CaCl2-P) extracted using 0.01-M CaCl2 solution were found to be useful for predicting potential organic and inorganic P leaching, given a linear, positive correlation between CaCl2-P, CaCl2-Pi, and CaCl2-Po in soils and accumulated amounts of corresponding P forms in soil leachates. The majority of investigated FL was at or above the change points of 46, 46, and 42 mg AP kg(-1) for CaCl2-Pi, CaCl2-Po, and CaCl2-P, respectively, and thus at a risk of P leaching. Organic and inorganic P leaching was present in nearly all investigated OAL. CaCl2-Po accounted for 66.0 % of CaCl2-P in FL and 56.1 % in OAL. Signals of (31)P-NMR spectra were mainly attributable to orthophosphate, orthophosphate monoesters, and orthophosphate diesters in FL and OAL soils. It is important to consider P loss due to leaching of inorganic and organic P in P-enriched areas. PMID- 25548020 TI - The content of selected metals in muscles of the red deer (Cervus elaphus) from Poland. AB - The aim of this study was to evaluate the concentrations of Pb, Cu, Zn, Rb, Cs, Sr and Ba in the muscles of red deer that were hunted in two regions of Poland (south-western and north-eastern). The data obtained were evaluated with regards to benefits and potential risk to consumers' health. Samples for the investigations were collected in 2008 and 2009 from 50 female red deer, and the metal concentrations were determined by using the inductively coupled plasma-mass spectrometric (ICP-MS) method. The mean concentrations of Pb did not differ statistically between regions and were equal to that permitted for farm animals. The results of this study support the conclusion that the meat of the analysed animals does not pose a risk of lead intoxication. Statistically higher mean concentrations of Cu and Zn were found in the muscles of red deer from the south western region (namely, 2.99 and 25.78 mg kg(-1)) than those in animals from north-eastern Poland (namely, 2.61 and 23.39 mg kg(-1) wet weight). In terms of human nutritional needs, the meat of red deer can be considered as a good source of Cu and Zn. Furthermore, Rb, Cs, Sr and Ba concentrations did not differ statistically between regions. Their mean concentrations were 4.50, 0.09, 0.16 and 0.31 mg kg(-1) wet weight, respectively. Although high Cs, Sr and Ba concentrations were found, the meat of red deer does not pose a risk for adult consumers. Only high Ba content may potentially result in negative health effects for children. PMID- 25548022 TI - Cultivar variations in cadmium and lead accumulation and distribution among 30 wheat (Triticum aestivum L.) cultivars. AB - In recent years, heavy metal pollution in agricultural soil in China has received public concern. The concept of low-accumulation cultivars (LACs) was proposed to minimize the influx of pollutants to the human food chain. Variations in Cd and Pb accumulation, distribution, and tolerance among 30 wheat (Triticum aestivum L.) cultivars were studied in a hydroponic experiment to preliminary identify LACs of Cd or Pb for further field experiments. Of the 30 wheat cultivars tested, 27 and 26 wheat cultivars showed no effect of the Cd/Pb treatments on the shoot and root biomass, respectively. The results showed that the tested wheat cultivars had considerable tolerance to Cd and Pb toxicity. Significant (p < 0.05) differences in shoot Cd concentration were observed among the tested wheat cultivars under treatments Cd1.0 and Cd1.0Pb15, ranging from 0.91 to 6.74 and from 0.87 to 5.96, with the mean of 3.83 and 2.94 mg kg(-1) DW, respectively. Significant (p < 0.05) differences in shoot Pb concentration were also observed among the tested wheat cultivars under treatments Pb15 and Cd1.0Pb15, ranging from 22.18 to 94.03 and from 18.30 to 76.88, with the mean of 50.38 and 41.20 mg kg(-1) DW, respectively. Low accumulation and internal distribution may both affect the cultivar differences in Cd and Pb accumulation in wheat shoots. Overall, wheat cultivars LF-13, LF-16, and LF-21 had lower Cd-accumulating abilities in their shoots. Wheat cultivars LF-13, LF-23, LF-26, and LF-27 showed low Pb accumulation characteristics in their shoots. An antagonistic interaction occurred between Cd and Pb in accumulation in wheat roots and shoots, which will be further studied in field experiments. PMID- 25548023 TI - Correlating concentrations of heavy metals in atmospheric deposition with respective accumulation in moss and natural surface soil for ecological land classes in Norway between 1990 and 2010. AB - This study investigated whether statistical correlation of modeled atmospheric heavy metal deposition and respective accumulation in moss and natural surface soil varies across natural landscapes in Norway. Target metals were cadmium, lead, and mercury, and analyses were run between 1990 and 2010 on a 5-year interval. The landscape information was derived from the Ecological Land Classification of Europe. Correlations between concentration and respective deposition data were computed for each land class. The strongest correlations between heavy metal concentrations in atmospheric deposition and corresponding levels in moss and natural surface soil were observed for lead. Correlations for mercury were weaker compared to those calculated for cadmium and lead, indicating that atmospheric transport of mercury occurs at a larger spatial scale, while accumulation additionally seems to be influenced by factors operating on smaller scales. The correlation between concentrations in atmospheric deposition and moss is landscape-specific and metal-specific. The same holds true for the relations between heavy metal concentration in modeled atmospheric deposition and natural surface soil. The results of this investigation are in line with similar calculations from across Europe. They further confirm previous studies indicating that for Norway atmospheric transport is a main source of lead and cadmium accumulation in moss as well as in natural surface soil. PMID- 25548024 TI - Using fluorescence spectroscopy coupled with chemometric analysis to investigate the origin, composition, and dynamics of dissolved organic matter in leachate polluted groundwater. AB - Groundwater was collected in 2011 and 2012, and fluorescence spectroscopy coupled with chemometric analysis was employed to investigate the composition, origin, and dynamics of dissolved organic matter (DOM) in the groundwater. The results showed that the groundwater DOM comprised protein-, fulvic-, and humic-like substances, and the protein-like component originated predominantly from microbial production. The groundwater pollution by landfill leachate enhanced microbial activity and thereby increased microbial by-product-like material such as protein-like component in the groundwater. Excitation-emission matrix fluorescence spectra combined with parallel factor analysis showed that the protein-like matter content increased from 2011 to 2012 in the groundwater, whereas the fulvic- and humic-like matter concentration exhibited no significant changes. In addition, synchronous-scan fluorescence spectra coupled with two dimensional correlation analysis showed that the change of the fulvic- and humic like matter was faster than that of the protein-like substances, as the groundwater flowed from upstream to downstream in 2011, but slower than that of the protein-like substance in 2012 due to the enhancement of microbial activity. Fluorescence spectroscopy combined with chemometric analysis can investigate groundwater pollution characteristics and monitor DOM dynamics in groundwater. PMID- 25548025 TI - Prevalence and correlates of substance use among trans female youth ages 16-24 years in the San Francisco Bay Area. AB - BACKGROUND: Substance use is highly prevalent among transgender (trans*) females and has been associated with negative health outcomes, including HIV infection. Little is known about psychosocial risk factors that may influence the onset of substance use among trans*female youth, which can contribute to health disparities during adulthood. METHODS: We conducted a secondary data analysis of a study on HIV risk and resilience among trans*female youth (N=292). Prevalence of substance use was assessed and multivariable logistic regression models were used to examine the relationship between posttraumatic stress disorder (PTSD), psychological distress, gender-related discrimination, parental drug or alcohol problems (PDAP) and multiple substance use outcomes. RESULTS: Most (69%) of the trans*female youth reported recent drug use. In multivariable analyses, those with PTSD had increased odds of drug use [AOR=1.94 (95% CI=1.09-3.44)]. Those who experienced gender-related discrimination had increased odds of drug use [AOR=2.28 (95% CI=1.17-4.44)], drug use concurrent with sex [AOR=2.35 (95% CI=1.11-4.98)] and use of multiple drugs [AOR=3.24 (95% CI=1.52-6.88)]. Those with psychological distress had increased odds of using multiple heavy drugs [AOR=2.27 (95% CI=1.01-5.12)]. Those with PDAP had increased odds of drugs use [AOR=2.62 (95% CI=1.43-4.82)], drug use concurrent with sex [AOR=2.01 (95% CI, 1.15-3.51)] and use of multiple drugs [AOR=2.10 (95% CI=1.22-3.62)]. CONCLUSIONS: Substance use is highly prevalent among trans*female youth and was significantly associated with psychosocial risk factors. In order to effectively address substance use among trans*female youth, efforts must address coping related to gender-based discrimination and trauma. Furthermore, structural level interventions aiming to reduce stigma and gender-identity discrimination might also be effective. PMID- 25548027 TI - Clonal relatedness is a predictor of spontaneous multidrug efflux pump gene overexpression in Staphylococcus aureus. AB - Increased expression of genes encoding multidrug resistance efflux pumps (MDR EPs) contributes to antimicrobial agent and biocide resistance in Staphylococcus aureus. Previously identified associations between norA overexpression and spa type t002 meticillin-resistant S. aureus (MRSA), and a similar yet weaker association between mepA overexpression and type t008 meticillin-susceptible S. aureus (MSSA), in clinical isolates are suggestive of clonal dissemination. It is also possible that related strains are prone to mutations resulting in overexpression of specific MDR-EP genes. Exposure of non-MDR-EP-overexpressing clinical isolates to biocides and dyes can select for MDR-EP-overexpressing mutants. spa types t002 and t008 isolates are predominated by multilocus sequencing typing sequence types (STs) 5 and 8, respectively. In this study, non MDR-EP gene-overexpressing clinical isolates (MRSA and MSSA) representing ST5 and ST8 were subjected to single exposures of ethidium bromide (EtBr) to select for EtBr-resistant mutants. Measurements of active EtBr transport among mutants were used to demonstrate an efflux-proficient phenotype. Using quantitative reverse transcription PCR, it was found that EtBr-resistant mutants of ST5 and ST8 parental strains predominantly overexpressed mepA (100%) and mdeA (83%), respectively, regardless of meticillin sensitivity. Associations between clonal lineage and MDR-EP gene overexpression differed from those previously observed and suggest the latter is due to clonal spread of efflux-proficient strains. The predilection of in vitro-selected mutants of related strains to overexpress the same MDR-EP gene indicates the presence of a consistent mutational process. PMID- 25548028 TI - Defining sarcopenia in terms of incident adverse outcomes. AB - OBJECTIVES: The objectives of this study were to compare the performance of different diagnoses of sarcopenia using European Working Group on Sarcopenia in Older People, International Working Group on Sarcopenia, and the US Foundation of National Institutes of Health (FNIH) criteria, and the screening tool SARC-F, against the Asian Working Group for Sarcopenia consensus panel definitions, in predicting physical limitation, slow walking speed, and repeated chair stand performance, days of hospital stay and mortality at follow up. DESIGN: Longitudinal study. SETTING: Community survey in Hong Kong. PARTICIPANTS: Participants were 4000 men and women 65 years and older living in the community. MEASUREMENTS: Information from questionnaire regarding activities of daily living, physical functioning limitations, and constituent questions of SARC-F; body mass index (BMI), grip strength (GS), walking speed, and appendicular muscle mass (ASM). RESULTS: FNIH, consensus panel definitions, and the screening tool SARC-F all have similar AUC values in predicting incident physical limitation and physical performance measures at 4 years, walking speed at 7 years, days of hospital stay at 7 years, and mortality at 10 years. None of the definitions predicted increase in physical limitation at 4 years or mortality at 10 years in women, and none predicted all the adverse outcomes. The highest AUC values were observed for walking speed at 4 and 7 years. CONCLUSION: When applied to a Chinese elderly population, criteria used for diagnosis of sarcopenia derived from European, Asian, and international consensus panels, from US cutoff values defined from incident physical limitation, and the SARC-F screening tool, all have similar performance in predicting incident physical limitation and mortality. PMID- 25548026 TI - Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. AB - BACKGROUND: Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies. METHODS: This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective. RESULTS: Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of Drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters. CONCLUSIONS: Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse. PMID- 25548029 TI - Exposure to atropinic drugs and frailty status. AB - BACKGROUND: Atropinic drugs can increase the risk of falls, cognitive impairment, and mortality in older patients; however, whether exposure to atropinic drugs is associated with frailty status remains unknown. Our aim was to assess the association between frailty status and exposure to atropinic drugs in a geriatric day hospital population. METHODS: We carried out a cross-sectional study that included all the patients consulting for the first time at the Geriatric Frailty Clinic for Assessment of Frailty and Prevention of Disability in Toulouse, France, from January 2013 to October 2013. Frailty was defined by 3 or more of Fried et al's criteria. Atropinic drugs were those with clinical antimuscarinic effect from the Anticholinergic Drug Scale (excluding drugs weighted 1 point and not listed by Duran et al) and from Laroche et al list (to include drugs marketed in France not present in the Anticholinergic Drug Scale). To explore a dose effect relationship, we calculated the atropinic burden using the Anticholinergic Drug Scale weights. We performed logistic regression models adjusted for age, gender, comorbidities, being community dwelling or not, cognitive status, educational level, and polypharmacy (>=6 drugs). RESULTS: We included 437 patients (227 frail and 210 robust or prefrail). Exposure to at least one atropinic drug was associated with frailty (odds ratio 1.97, 95% confidence interval 1.10-3.53, P = .02). Due to a statistically significant interaction between age and atropinic burden, a dose-effect relationship for atropinic burden was explored in patients younger than 85 years, showing a significant association between atropinic burden score and frailty (P = .01). The Odds ratio for an atropinic burden greater than or equal to 3 versus 0 was 3.84, 95% confidence interval 1.43-10.34 (P < .01). CONCLUSIONS: In a geriatric day hospital, population frailty is associated with a high atropinic burden. PMID- 25548030 TI - Insulinlike Growth Factor-1 and Its Binding Protein-3 Polymorphisms Predict Circulating IGF-1 Level and Appendicular Skeletal Muscle Mass in Chinese Elderly. AB - BACKGROUND: Previous studies have demonstrated the polymorphisms of insulinlike growth factor-1 (IGF-1) and its binding protein-3 (IGFBP3) genes could affect the circulating IGF-1 level. Moreover, the serum IGF-1 level was correlated with muscle size. OBJECTIVES: This study aimed to explore the effect of polymorphisms of IGF1, IGFBP3, and IGFBP5 genes on appendicular skeletal muscle mass in Taiwanese older adults in a metropolitan area. DESIGN: A community-based cross sectional study. SETTING AND SUBJECTS: A random sample of 472 elders with complete information of dual energy X-ray absorptiometry examination, genotyping analysis, and serum IGF-1 level from Taichung Community Health Study for Elders (TCHS-E) was included. MEASUREMENTS: Low appendicular skeletal muscle mass index (ASMI) was defined as 2 SDs below the mean of young adults from our TCHS study (n = 471). Seven polymorphisms of IGF1, IGFBP3, and IGFBP5 were analyzed by using Illumina GoldenGate Genotyping Assay. The chi(2) test, Student t test, and multiple logistic regression were applied for statistical analysis. RESULTS: The prevalence of low ASMI was 7.1%, 8.8%, and 23.0% in those aged 70 or younger, 71 to 75, and older than 75 years, respectively. We found that serum IGF-1 level (natural logarithmic transformation) was significantly lower in the low ASMI group compared with the normal ASMI group and the SNP rs2854744 near IGFBP3 gene was significantly associated with low ASMI. Moreover, we discovered the SNP rs6214 on the IGF1 gene would significantly affect the serum IGF-1 level. Therefore, the joint effect of rs6214 and rs2854744 was analyzed. Elders with GG genotype of rs6214 and AC or CC genotypes of rs2854744 had a 3.18-fold (95% CI 1.02-9.89) risk of having low ASMI compared with those with the AA and AA genotype, after adjusting for age, gender, smoking, exercise, hyperlipidemia, and albumin level. CONCLUSIONS: Our results suggest that rs6214 on the IGF1 gene and rs2854744 near the IGFBP3 gene potentially play an important role with ASMI in Taiwanese older adults in a metropolitan area. PMID- 25548031 TI - Searching for a polypharmacy threshold associated with frailty. PMID- 25548032 TI - Reappraisal of the inferior right hepatic vein preserving liver resection. AB - BACKGROUND: To resect tumors infiltrating to the right hepatic vein at its root, right hemihepatectomy or that following portal vein embolization (PVE) is applied. If the IRHV is sizable, the IRHV preserving liver resection can be another option. METHODS: Between 1994 and 2007, the IRHV preserving liver resection was performed in 21 patients (IRHV group). The short-term outcomes after surgery of them p. RESULTS: There were no mortality and no significant difference between the IRHV and RH groups concerning the blood loss, the morbidity rates and the duration of hospital stay. The median operation time was shorter in the IRHV group than in the RH group (393 vs. 480 min, p = 0.0409). The median weight of resected specimen of the IRHV group was 293 g (range: 20-982), which was significantly lighter than that of the RH group (median: 680 g [250 4,300], p < 0.001). The median percentage of resected volume to standard liver volume was significantly smaller in the IRHV group than in the RH group (25.8 vs. 52.2%, p < 0.001). CONCLUSION: The IRHV preserving liver resection remains a safe and useful procedure. PMID- 25548034 TI - Evaluation of potential for reuse of industrial wastewater using metal immobilized catalysts and reverse osmosis. AB - This report describes a novel technology of reusing the wastewater discharged from the display manufacturing industry through an advanced oxidation process (AOP) with a metal-immobilized catalyst and reverse osmosis (RO) in the pilot scale. The reclaimed water generated from the etching and cleaning processes in display manufacturing facilities was low-strength organic wastewater and was required to be recycled to secure a water source. For the reuse of reclaimed water to ultrapure water (UPW), a combination of solid-phase AOP and RO was implemented. The removal efficiency of TOC by solid-phase AOP and RO was 92%. Specifically, the optimal acid, pH, and H2O2 concentrations in the solid-phase AOP were determined. With regard to water quality and operating costs, the combination of solid-phase AOP and RO was superior to activated carbon/RO and ultraviolet AOP/anion polisher/coal carbon. PMID- 25548033 TI - Gas-phase and particulate products from the atmospheric degradation of the organothiophosphorus insecticide chlorpyrifos-methyl. AB - The phosphorothioate structure is highly present in several organophosphorus pesticides. However, there is insufficient information about its degradation process after the release to the atmosphere and the secondary pollutants formed. Herein, the atmospheric reaction of chlorpyrifos-methyl (o,o-dimethyl o-(3,5,6 trichloropyridin-2-yl) phosphorothioate), is described for semi-urban or rural locations. The photo-oxidation under low NOx conditions (5-55 ppbV) was reproduced in a large outdoor simulation chamber, observing a rapid degradation (lifetime<3.5 h). The formation of gaseous products and particulate matter (aerosol yield 2-8%) was monitored. The chemical composition of minor products (gaseous and particulate) was studied, identifying 15 multi-oxygenated derivatives. The most abundant products were ring-retaining molecules such as o,o dimethyl o-(3,5,6-trichloropyridin-2-yl) phosphorothioate, dimethyl 3,5,6 trichloropyridin-2-yl phosphate, o-methyl o-(3,5,6-trichloropyridin-2-yl) hydrogen phosphorothioate, 3,5,6-trichloropyridin-2-yl dihydrogen phosphate, 3,5,6-trichloropyridin-2-ol, and 3,5,6-trichloropyridine-2,4-diol. An atmospheric degradation mechanism has been proposed based on an oxidation started with OH nucleophilic attack to P=S bond. The results have been extrapolated to other organothiophosphorus molecules, such as malathion, parathion, diazinon and methidathion, among many others, to estimate their photo-oxidative degradation and the expected products. PMID- 25548035 TI - Insights into spatially and temporally co-occurring polybrominated diphenyl ethers in sediments of the East China Sea. AB - In this study, twenty-four core sediment samples were collected from monitoring stations in the East China Sea (ECS) to investigate the spatial and temporal distributions of polybrominated diphenyl ethers (PBDEs) and their potential sources. In surface sediment samples (the top 0-3 cm segment), the concentrations of Sigma8PBDEs (sum of BDE15, 28, 47, 99, 100, 153, 154 and 183) and BDE209 were between 0.03 and 1.26 ng g(-1) d.w., and 0.20 and 3.15 ng g(-1) d.w., respectively. The PBDEs concentrations were decreased generally from the shore towards the sea, indicating that PBDEs are mainly derived from anthropogenic sources. As the predominant congener, BDE209 was primarily distributed in the nearshore regions, suggesting that it might be derived from runoff and sewage. In contrast, higher levels of BDE99 and BDE47 were detected in the offshore samples, and the concentrations of BDE47 were higher than those of BDE99. All of their concentrations were poorly correlated with TOC, suggesting BDE47 and BDE99 might be transferred mainly along with the atmosphere. In most sediment cores, the Sigma8PBDEs and BDE209 concentrations increased from the bottom (18-30 cm), reached their maximum concentrations in the middle (6-15 cm) or upper (0-6 cm) sections, and leveled off near the surface (0-3 cm). This trend is consistent with the phasing-out of PBDEs and the strict management of recycling e-waste. This is the first study for network used to analyze the distribution properties of pollutant congeners in environment, which facilitates the visualization of cluster results among multivariable data and helps in tracing the potential sources of pollutants. PMID- 25548036 TI - Seasonal and spatial distribution of 4-nonylphenol and 4-tert-octylphenol in the sediment of Kaohsiung Harbor, Taiwan. AB - The 4-nonylphenol (4-NP) and 4-tert-octylphenol (4-t-OP) were investigated in the surface sediments of Kaohsiung Harbor, Taiwan. The concentrations were between 18 and 27,882 ng g(-1)dw (average 101 +/- 3,580 ng g(-1)dw) and 1.1 and 1,150 ng g( 1)dw (average 44 +/- 174 ng g(-1)dw) for 4-NP and 4-t-OP, respectively. The concentrations of 4-NP and 4-t-OP in the river mouths' sediments are apparently higher and gradually decrease nearer the Harbor. The results showed that the river mouths' alkylphenol (AP) concentration in the wet season was higher than that in the dry season; in the channels and Harbor entrances, the AP values in the dry season were similar or even higher than those in the wet season. The correlation analysis indicated that total organic carbon (TOC) and organic matter (OM) played an important role in controlling the concentration level of 4-NP and 4-t-OP in the sediments. However, in the pollution hotspot, the direct inflow of pollutants would be the crucial factor that determines the concentration and distribution of organic pollutants in sediments. According to the evaluation of the potential ecological risk, the 4-NP concentration in the harbor had an 87% probability of exceed PNEC (39 ng g(-1), predicted no effect concentration) which means that the sediments of Kaohsiung Harbor probably pose a potential ecological risk to aquatic life, as is especially the case with those in the river mouths with relatively high EEQ values (estrogen equivalent concentration). PMID- 25548037 TI - Evaluation of the in vitro estrogenicity of emerging bisphenol analogs and their respective estrogenic contributions in municipal sewage sludge in China. AB - There is a potential risk to the environment from persistent estrogenic compounds in sewage sludge. In this study, eight bisphenols (BPs) were identified in sewage sludge collected from wastewater treatment plants in 15 cities in China. The estrogenic potencies of the eight BPs and the estrogenic activities of sludge samples were evaluated using a bioluminescence yeast estrogen screen (BLYES) assay. All sludge samples elicited considerable estrogenic activity at a range of 2.8-4.7 ng E2 g(-1) dry weight (dw). All BPs exhibited estrogenic activity in the BLYES assay, but there were significant differences between the potency of individual chemicals. Bisphenol AF had the highest activity, followed by tetrachlorobisphenol A, bisphenol F, bisphenol A, bisphenol E, bisphenol S and 2,4-dihydroxybenzophenone. Tetrabromobisphenol A showed weak estrogenic activity at 1*10(4)nM, but significant cytotoxicity above this concentration. The total estradiol equivalency quantities (EEQs) of BPs were in the range of 2.16-49.13 pg E2 g(-1) dw, accounting for 0.05-1.47% of the total EEQs in sewage sludge samples. The results indicate that BPs made a minor contribution to the estrogenic activity of the investigated sewage sludge. Nevertheless, our results suggest that considerable attention should be directed to the estrogenic potentials of emerging organic pollutants because of their widespread use and their potential to persist in the environment. PMID- 25548038 TI - Comparison of two different electrodialytic cells for separation of phosphorus and heavy metals from sewage sludge ash. AB - With decreasing availability of phosphorus from primary resources its recovery from waste streams becomes increasingly more important. Sewage sludge ash is rich in phosphorus, but the direct use as fertilizer is limited because of inorganic contaminants such as heavy metals and strong bonding of phosphorous in the ash. Electrodialysis (ED) can be used to recover phosphorus and simultaneously remove heavy metals. The present work is an experimental screening of different options for ED in relation to experimental setup and combination with acid addition. Experiments for stirred ash suspensions utilizing a three compartment cell setup where the anode, cathode and stirred suspension are separated by ion exchange membranes are reported. Simplifying this experimental setup by removing the anion exchange membrane brings the anode in direct contact with the stirred ash suspension. Through this adjustment, half-reactions at the anode contribute to the acidity of the stirred suspension resulting in increased dissolution of both phosphorus and heavy metals (Cd, Cu, Cr, Pb, Zn, Ni) and better separation of most heavy metals from the stirred ash suspension. When the ash is suspended in an acidic solution, these effects increase significantly in early stages of the experiments. The combination of ED in a two compartment setup and initial acidification of the stirred suspension is most effective in dissolving of phosphorus and separation of heavy metals. In this setup, up to 96% of the phosphorus in the ash was dissolved after 7 d. Using the three compartment setup and initially suspending the ash in distilled water, resulted in 53% dissolution of the total recovered phosphorus after 7 d. PMID- 25548039 TI - Primer-introduced restriction analysis polymerase chain reaction method for non invasive prenatal testing of beta-thalassemia. AB - We have developed a new method for non-invasive prenatal testing (NIPT) of paternally inherited fetal mutants for beta-thalassemia (beta-thal). Specially designed primer-introduced restriction analysis-polymerase chain reaction (PIRA PCR) were used to detect four major mutations [IVS-II-654, HBB: c.316-197C > T; codon 17 (A > T), HBB: c.52A > T; -28 (A > G), HBB: c.-78A > G and codons 41/42 ( TTCT), HBB: c.126_129delCTTT] causing beta-thal in China. The PIRA-PCR assay was first tested in a series of mixed DNA with different concentrations and mixed proportions. Subsequently, this assay was further tested in 10 plasma DNA samples collected from pregnant women. In the DNA mixture simulation test, the PIRA-PCR assay was able to detect 3.0% target genomic DNA (gDNA) mixed in 97.0% wild-type gDNA isolated from whole blood. For plasma DNA testing, the results detected by PIRA-PCR assay achieved 100.0% consistency with those obtained from the amniocentesis analysis. This new method could potentially be used for NIPT of paternally inherited fetal mutants for beta-thal. PMID- 25548040 TI - Evaluating the occurrence of Escherichia albertii in chicken carcass rinses by PCR, Vitek analysis, and sequencing of the rpoB gene. AB - Escherichia albertii is a recently described species that has been associated with gastroenteritis in humans and with healthy and ill birds. Most recently, it has been identified as the causative agent in a food-borne outbreak in Japan. The distribution and clinical importance of E. albertii are not well studied because its importance is unclear. Culture methods for clinical isolation frequently miss E. albertii or incorrectly identify it as Shigella spp., Escherichia coli, or Hafnia alvei. This study was designed to determine if E. albertii could be recovered from chicken carcass rinses collected at slaughter during a 1-year period from November 2009 until October 2010. Colonies were isolated from chicken carcass rinses and tested by PCR for the presence or absence of clpX, lysP, mdh, intimin (eae), Shiga toxins 1 and 2 (stx1, stx2, and stx2f), heat-stable enterotoxin A (staA), and cytolethal distending toxins 1 and 2 (cdtB) genes. Sixty-five isolates were analyzed by sequencing a section of the rpoB gene. Analysis of the rpoB gene sequences revealed 14 fixed differences between E. albertii and other, closely related organisms. The fixed differences found in the rpoB gene could aid in future discrimination of E. albertii from closely related bacteria. PMID- 25548041 TI - A chlorogenic acid esterase with a unique substrate specificity from Ustilago maydis. AB - An extracellular chlorogenic acid esterase from Ustilago maydis (UmChlE) was purified to homogeneity by using three separation steps, including anion-exchange chromatography on a Q Sepharose FF column, preparative isoelectric focusing (IEF), and, finally, a combination of affinity chromatography and hydrophobic interaction chromatography on polyamide. SDS-PAGE analysis suggested a monomeric protein of ~71 kDa. The purified enzyme showed maximal activity at pH 7.5 and at 37 degrees C and was active over a wide pH range (3.5 to 9.5). Previously described chlorogenic acid esterases exhibited a comparable affinity for chlorogenic acid, but the enzyme from Ustilago was also active on typical feruloyl esterase substrates. Kinetic constants for chlorogenic acid, methyl p coumarate, methyl caffeate, and methyl ferulate were as follows: Km values of 19.6 MUM, 64.1 MUM, 72.5 MUM, and 101.8 MUM, respectively, and kcat/Km values of 25.83 mM(-1) s(-1), 7.63 mM(-1) s(-1), 3.83 mM(-1) s(-1) and 3.75 mM(-1) s(-1), respectively. UmChlE released ferulic, p-coumaric, and caffeic acids from natural substrates such as destarched wheat bran (DSWB) and coffee pulp (CP), confirming activity on complex plant biomass. The full-length gene encoding UmChlE consisted of 1,758 bp, corresponding to a protein of 585 amino acids, and was functionally produced in Pichia pastoris GS115. Sequence alignments with annotated chlorogenic acid and feruloyl esterases underlined the uniqueness of this enzyme. PMID- 25548042 TI - Bacterial diversity in the South Adriatic Sea during a strong, deep winter convection year. AB - The South Adriatic Sea is the deepest part of the Adriatic Sea and represents a key area for both the Adriatic Sea and the deep eastern Mediterranean. It has a role in dense water formation for the eastern Mediterranean deep circulation cell, and it represents an entry point for water masses originating from the Ionian Sea. The biodiversity and seasonality of bacterial picoplankton before, during, and after deep winter convection in the oligotrophic South Adriatic waters were assessed by combining comparative 16S rRNA sequence analysis and catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH). The picoplankton communities reached their maximum abundance in the spring euphotic zone when the maximum value of the chlorophyll a in response to deep winter convection was recorded. The communities were dominated by Bacteria, while Archaea were a minor constituent. A seasonality of bacterial richness and diversity was observed, with minimum values occurring during the winter convection and spring postconvection periods and maximum values occurring under summer stratified conditions. The SAR11 clade was the main constituent of the bacterial communities and reached the maximum abundance in the euphotic zone in spring after the convection episode. Cyanobacteria were the second most abundant group, and their abundance strongly depended on the convection event, when minimal cyanobacterial abundance was observed. In spring and autumn, the euphotic zone was characterized by Bacteroidetes and Gammaproteobacteria. Bacteroidetes clades NS2b, NS4, and NS5 and the gammaproteobacterial SAR86 clade were detected to co-occur with phytoplankton blooms. The SAR324, SAR202, and SAR406 clades were present in the deep layer, exhibiting different seasonal variations in abundance. Overall, our data demonstrate that the abundances of particular bacterial clades and the overall bacterial richness and diversity are greatly impacted by strong winter convection. PMID- 25548043 TI - A vector system for ABC transporter-mediated secretion and purification of recombinant proteins in Pseudomonas species. AB - Pseudomonas fluorescens is an efficient platform for recombinant protein production. P. fluorescens has an ABC transporter secreting endogenous thermostable lipase (TliA) and protease, which can be exploited to transport recombinant proteins across the cell membrane. In this study, the expression vector pDART was constructed by inserting tliDEF, genes encoding the ABC transporter, along with the construct of the lipase ABC transporter recognition domain (LARD), into pDSK519, a widely used shuttle vector. When the gene for the target protein was inserted into the vector, the C-terminally fused LARD allowed it to be secreted through the ABC transporter into the extracellular medium. After secretion of the fused target protein, the LARD containing a hydrophobic C terminus enabled its purification through hydrophobic interaction chromatography (HIC) using a methyl-Sepharose column. Alkaline phosphatase (AP) and green fluorescent protein (GFP) were used to validate the expression, export, and purification of target proteins by the pDART system. Both proteins were secreted into the extracellular medium in P. fluorescens. In particular, AP was secreted in several Pseudomonas species with its enzymatic activity in extracellular media. Furthermore, purification of the target protein using HIC yielded some degree of AP and GFP purification, where AP was purified to almost a single product. The pDART system will provide greater convenience for the secretory production and purification of recombinant proteins in Gram-negative bacteria, such as Pseudomonas species. PMID- 25548044 TI - Genotypic and phenotypic characterization of Escherichia coli isolates from feces, hands, and soils in rural Bangladesh via the Colilert Quanti-Tray System. AB - The increased awareness of the role of environmental matrices in enteric disease transmission has resulted in the need for rapid, field-based methods for fecal indicator bacteria and pathogen detection. Evidence of the specificity of beta glucuronidase-based assays for detection of Escherichia coli from environmental matrices relevant to enteric pathogen transmission in developing countries, such as hands, soils, and surfaces, is limited. In this study, we quantify the false positive rate of a beta-glucuronidase-based E. coli detection assay (Colilert) for two environmental reservoirs in Bangladeshi households (hands and soils) and three fecal composite sources (cattle, chicken, and humans). We investigate whether or not the isolation source of E. coli influences phenotypic and genotypic characteristics. Phenotypic characteristics include results of biochemical assays provided by the API-20E test; genotypic characteristics include the Clermont phylogroup and the presence of enteric and/or environmental indicator genes sfmH, rfaI, and fucK. Our findings demonstrate no statistically significant difference in the false-positive rate of Colilert for environmental compared to enteric samples. E. coli isolates from all source types are genetically diverse, representing six of the seven phylogroups, and there is no difference in relative frequency of phylogroups between enteric and environmental samples. We conclude that Colilert, and likely other beta-glucuronidase-based assays, is appropriate for detection of E. coli on hands and in soils with low false-positive rates. Furthermore, E. coli isolated from hands and soils in Bangladeshi households are diverse and indistinguishable from cattle, chicken, and human fecal isolates, using traditional biochemical assays and phylogrouping. PMID- 25548045 TI - Field and experimental evidence of Vibrio parahaemolyticus as the causative agent of acute hepatopancreatic necrosis disease of cultured shrimp (Litopenaeus vannamei) in Northwestern Mexico. AB - Moribund shrimp affected by acute hepatopancreatic necrosis disease (AHPND) from farms in northwestern Mexico were sampled for bacteriological and histological analysis. Bacterial isolates were molecularly identified as Vibrio parahaemolyticus by the presence of the tlh gene. The tdh-negative, trh-negative, and tlh-positive V. parahaemolyticus strains were further characterized by repetitive extragenic palindromic element-PCR (rep-PCR), and primers AP1, AP2, AP3, and AP and an ems2 IQ2000 detection kit (GeneReach, Taiwan) were used in the diagnostic tests for AHPND. The V. parahaemolyticus strains were used in immersion challenges with shrimp, and farmed and challenged shrimp presented the same clinical and pathological symptoms: lethargy, empty gut, pale and aqueous hepatopancreas, and expanded chromatophores. Using histological analysis and bacterial density count, three stages of AHNPD (initial, acute, and terminal) were identified in the affected shrimp. The pathognomonic lesions indicating severe desquamation of tubular epithelial cells of the hepatopancreas were observed in both challenged and pond-infected shrimp. The results showed that different V. parahaemolyticus strains have different virulences; some of the less virulent strains do not induce 100% mortality, and mortality rates also rise more slowly than they do for the more virulent strains. The virulence of V. parahaemolyticus strains was dose dependent, where the threshold infective density was 10(4) CFU ml(-1); below that density, no mortality was observed. The AP3 primer set had the best sensitivity and specificity. Field and experimental results showed that the V. parahaemolyticus strain that causes AHPND acts as a primary pathogen for shrimp in Mexico compared with the V. parahaemolyticus strains reported to date. PMID- 25548046 TI - Exploring the diversity of Listeria monocytogenes biofilm architecture by high throughput confocal laser scanning microscopy and the predominance of the honeycomb-like morphotype. AB - Listeria monocytogenes is involved in food-borne illness with a high mortality rate. The persistence of the pathogen along the food chain can be associated with its ability to form biofilms on inert surfaces. While most of the phenotypes associated with biofilms are related to their spatial organization, most published data comparing biofilm formation by L. monocytogenes isolates are based on the quantitative crystal violet assay, which does not give access to structural information. Using a high-throughput confocal-imaging approach, the aim of this work was to decipher the structural diversity of biofilms formed by 96 L. monocytogenes strains isolated from various environments. Prior to large scale analysis, an experimental design was created to improve L. monocytogenes biofilm formation in microscopic-grade microplates, with special emphasis on the growth medium composition. Microscopic analysis of biofilms formed under the selected conditions by the 96 isolates revealed only weak correlation between the genetic lineages of the isolates and the structural properties of the biofilms. However, a gradient in their geometric descriptors (biovolume, mean thickness, and roughness), ranging from flat multilayers to complex honeycomb-like structures, was shown. The dominant honeycomb-like morphotype was characterized by hollow voids hosting free-swimming cells and localized pockets containing mixtures of dead cells and extracellular DNA (eDNA). PMID- 25548047 TI - Malonic semialdehyde reductase from the archaeon Nitrosopumilus maritimus is involved in the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle. AB - The recently described ammonia-oxidizing archaea of the phylum Thaumarchaeota are highly abundant in marine, geothermal, and terrestrial environments. All characterized representatives of this phylum are aerobic chemolithoautotrophic ammonia oxidizers assimilating inorganic carbon via a recently described thaumarchaeal version of the 3-hydroxypropionate/4-hydroxybutyrate cycle. Although some genes coding for the enzymes of this cycle have been identified in the genomes of Thaumarchaeota, many other genes of the cycle are not homologous to the characterized enzymes from other species and can therefore not be identified bioinformatically. Here we report the identification and characterization of malonic semialdehyde reductase Nmar_1110 in the cultured marine thaumarchaeon Nitrosopumilus maritimus. This enzyme, which catalyzes the reduction of malonic semialdehyde with NAD(P)H to 3-hydroxypropionate, belongs to the family of iron-containing alcohol dehydrogenases and is not homologous to malonic semialdehyde reductases from Chloroflexus aurantiacus and Metallosphaera sedula. It is highly specific to malonic semialdehyde (Km, 0.11 mM; Vmax, 86.9 MUmol min(-1) mg(-1) of protein) and exhibits only low activity with succinic semialdehyde (Km, 4.26 mM; Vmax, 18.5 MUmol min(-1) mg(-1) of protein). Homologues of N. maritimus malonic semialdehyde reductase can be found in the genomes of all Thaumarchaeota sequenced so far and form a well-defined cluster in the phylogenetic tree of iron-containing alcohol dehydrogenases. We conclude that malonic semialdehyde reductase can be regarded as a characteristic enzyme for the thaumarchaeal version of the 3-hydroxypropionate/4-hydroxybutyrate cycle. PMID- 25548048 TI - Iron corrosion induced by nonhydrogenotrophic nitrate-reducing Prolixibacter sp. strain MIC1-1. AB - Microbiologically influenced corrosion (MIC) of metallic materials imposes a heavy economic burden. The mechanism of MIC of metallic iron (Fe(0)) under anaerobic conditions is usually explained as the consumption of cathodic hydrogen by hydrogenotrophic microorganisms that accelerates anodic Fe(0) oxidation. In this study, we describe Fe(0) corrosion induced by a nonhydrogenotrophic nitrate reducing bacterium called MIC1-1, which was isolated from a crude-oil sample collected at an oil well in Akita, Japan. This strain requires specific electron donor-acceptor combinations and an organic carbon source to grow. For example, the strain grew anaerobically on nitrate as a sole electron acceptor with pyruvate as a carbon source and Fe(0) as the sole electron donor. In addition, ferrous ion and l-cysteine served as electron donors, whereas molecular hydrogen did not. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain MIC1-1 was a member of the genus Prolixibacter in the order Bacteroidales. Thus, Prolixibacter sp. strain MIC1-1 is the first Fe(0)-corroding representative belonging to the phylum Bacteroidetes. Under anaerobic conditions, Prolixibacter sp. MIC1-1 corroded Fe(0) concomitantly with nitrate reduction, and the amount of iron dissolved by the strain was six times higher than that in an aseptic control. Scanning electron microscopy analyses revealed that microscopic crystals of FePO4 developed on the surface of the Fe(0) foils, and a layer of FeCO3 covered the FePO4 crystals. We propose that cells of Prolixibacter sp. MIC1-1 accept electrons directly from Fe(0) to reduce nitrate. PMID- 25548049 TI - Genetic tools for the industrially promising methanotroph Methylomicrobium buryatense. AB - Aerobic methanotrophs oxidize methane at ambient temperatures and pressures and are therefore attractive systems for methane-based bioconversions. In this work, we developed and validated genetic tools for Methylomicrobium buryatense, a haloalkaliphilic gammaproteobacterial (type I) methanotroph. M. buryatense was isolated directly on natural gas and grows robustly in pure culture with a 3-h doubling time, enabling rapid genetic manipulation compared to many other methanotrophic species. As a proof of concept, we used a sucrose counterselection system to eliminate glycogen production in M. buryatense by constructing unmarked deletions in two redundant glycogen synthase genes. We also selected for a more genetically tractable variant strain that can be conjugated with small incompatibility group P (IncP)-based broad-host-range vectors and determined that this capability is due to loss of the native plasmid. These tools make M. buryatense a promising model system for studying aerobic methanotroph physiology and enable metabolic engineering in this bacterium for industrial biocatalysis of methane. PMID- 25548050 TI - A novel CO-responsive transcriptional regulator and enhanced H2 production by an engineered Thermococcus onnurineus NA1 strain. AB - Genome analysis revealed the existence of a putative transcriptional regulatory system governing CO metabolism in Thermococcus onnurineus NA1, a carboxydotrophic hydrogenogenic archaeon. The regulatory system is composed of CorQ with a 4-vinyl reductase domain and CorR with a DNA-binding domain of the LysR-type transcriptional regulator family in close proximity to the CO dehydrogenase (CODH) gene cluster. Homologous genes of the CorQR pair were also found in the genomes of Thermococcus species and "Candidatus Korarchaeum cryptofilum" OPF8. In frame deletion of either corQ or corR caused a severe impairment in CO-dependent growth and H2 production. When corQ and corR deletion mutants were complemented by introducing the corQR genes under the control of a strong promoter, the mRNA and protein levels of the CODH gene were significantly increased in a DeltaCorR strain complemented with integrated corQR (DeltaCorR/corQR(?)) compared with those in the wild-type strain. In addition, the DeltaCorR/corQR(?) strain exhibited a much higher H2 production rate (5.8-fold) than the wild-type strain in a bioreactor culture. The H2 production rate (191.9 mmol liter(-1) h(-1)) and the specific H2 production rate (249.6 mmol g(-1) h(-1)) of this strain were extremely high compared with those of CO-dependent H2-producing prokaryotes reported so far. These results suggest that the corQR genes encode a positive regulatory protein pair for the expression of a CODH gene cluster. The study also illustrates that manipulation of the transcriptional regulatory system can improve biological H2 production. PMID- 25548051 TI - The mannitol utilization system of the marine bacterium Zobellia galactanivorans. AB - Mannitol is a polyol that occurs in a wide range of living organisms, where it fulfills different physiological roles. In particular, mannitol can account for as much as 20 to 30% of the dry weight of brown algae and is likely to be an important source of carbon for marine heterotrophic bacteria. Zobellia galactanivorans (Flavobacteriia) is a model for the study of pathways involved in the degradation of seaweed carbohydrates. Annotation of its genome revealed the presence of genes potentially involved in mannitol catabolism, and we describe here the biochemical characterization of a recombinant mannitol-2-dehydrogenase (M2DH) and a fructokinase (FK). Among the observations, the M2DH of Z. galactanivorans was active as a monomer, did not require metal ions for catalysis, and featured a narrow substrate specificity. The FK characterized was active on fructose and mannose in the presence of a monocation, preferentially K(+). Furthermore, the genes coding for these two proteins were adjacent in the genome and were located directly downstream of three loci likely to encode an ATP binding cassette (ABC) transporter complex, suggesting organization into an operon. Gene expression analysis supported this hypothesis and showed the induction of these five genes after culture of Z. galactanivorans in the presence of mannitol as the sole source of carbon. This operon for mannitol catabolism was identified in only 6 genomes of Flavobacteriaceae among the 76 publicly available at the time of the analysis. It is not conserved in all Bacteroidetes; some species contain a predicted mannitol permease instead of a putative ABC transporter complex upstream of M2DH and FK ortholog genes. PMID- 25548053 TI - Accumulation of reserve carbohydrate by rumen protozoa and bacteria in competition for glucose. AB - The aim of this study was to determine if rumen protozoa could form large amounts of reserve carbohydrate compared to the amounts formed by bacteria when competing for glucose in batch cultures. We separated large protozoa and small bacteria from rumen fluid by filtration and centrifugation, recombined equal protein masses of each group into one mixture, and subsequently harvested (reseparated) these groups at intervals after glucose dosing. This method allowed us to monitor reserve carbohydrate accumulation of protozoa and bacteria individually. When mixtures were dosed with a moderate concentration of glucose (4.62 or 5 mM) (n = 2 each), protozoa accumulated large amounts of reserve carbohydrate; 58.7% (standard error of the mean [SEM], 2.2%) glucose carbon was recovered from protozoal reserve carbohydrate at time of peak reserve carbohydrate concentrations. Only 1.7% (SEM, 2.2%) was recovered in bacterial reserve carbohydrate, which was less than that for protozoa (P < 0.001). When provided a high concentration of glucose (20 mM) (n = 4 each), 24.1% (SEM, 2.2%) of glucose carbon was recovered from protozoal reserve carbohydrate, which was still higher (P = 0.001) than the 5.0% (SEM, 2.2%) glucose carbon recovered from bacterial reserve carbohydrate. Our novel competition experiments directly demonstrate that mixed protozoa can sequester sugar away from bacteria by accumulating reserve carbohydrate, giving protozoa a competitive advantage and stabilizing fermentation in the rumen. Similar experiments could be used to investigate the importance of starch sequestration. PMID- 25548052 TI - Population biology of intestinal enterococcus isolates from hospitalized and nonhospitalized individuals in different age groups. AB - The diversity of enterococcal populations from fecal samples from hospitalized (n = 133) and nonhospitalized individuals (n = 173) of different age groups (group I, ages 0 to 19 years; group II, ages 20 to 59 years; group III, ages >=60 years) was analyzed. Enterococci were recovered at similar rates from hospitalized and nonhospitalized persons (77.44% to 79.77%) of all age groups (75.0% to 82.61%). Enterococcus faecalis and Enterococcus faecium were predominant, although seven other Enterococcus species were identified. E. faecalis and E. faecium (including ampicillin-resistant E. faecium) colonization rates in nonhospitalized persons were age independent. For inpatients, E. faecalis colonization rates were age independent, but E. faecium colonization rates (particularly the rates of ampicillin-resistant E. faecium colonization) significantly increased with age. The population structure of E. faecium and E. faecalis was determined by superimposing goeBURST and Bayesian analysis of the population structure (BAPS). Most E. faecium sequence types (STs; 150 isolates belonging to 75 STs) were linked to BAPS groups 1 (22.0%), 2 (31.3%), and 3 (36.7%). A positive association between hospital isolates and BAPS subgroups 2.1a and 3.3a (which included major ampicillin-resistant E. faecium human lineages) and between community-based ampicillin-resistant E. faecium isolates and BAPS subgroups 1.2 and 3.3b was found. Most E. faecalis isolates (130 isolates belonging to 58 STs) were grouped into 3 BAPS groups, BAPS groups 1 (36.9%), 2 (40.0%), and 3 (23.1%), with each one comprising widespread lineages. No positive associations with age or hospitalization were established. The diversity and dynamics of enterococcal populations in the fecal microbiota of healthy humans are largely unexplored, with the available knowledge being fragmented and contradictory. The study offers a novel and comprehensive analysis of enterococcal population landscapes and suggests that E. faecium populations from hospitalized patients and from community-based individuals differ, with a predominance of certain clonal lineages, often in association with elderly individuals, occurring in the hospital setting. PMID- 25548054 TI - Transcriptional analysis of Deinococcus radiodurans reveals novel small RNAs that are differentially expressed under ionizing radiation. AB - Small noncoding RNAs (sRNAs) are posttranscriptional regulators that have been identified in multiple species and shown to play essential roles in responsive mechanisms to environmental stresses. The natural ability of specific bacteria to resist high levels of radiation has been of high interest to mechanistic studies of DNA repair and biomolecular protection. Deinococcus radiodurans is a model extremophile for radiation studies that can survive doses of ionizing radiation of >12,000 Gy, 3,000 times higher than for most vertebrates. Few studies have investigated posttranscriptional regulatory mechanisms of this organism that could be relevant in its general gene regulatory patterns. In this study, we identified 199 potential sRNA candidates in D. radiodurans by whole-transcriptome deep sequencing analysis and confirmed the expression of 41 sRNAs by Northern blotting and reverse transcriptase PCR (RT-PCR). A total of 8 confirmed sRNAs showed differential expression during recovery after acute ionizing radiation (15 kGy). We have also found and confirmed 7 sRNAs in Deinococcus geothermalis, a closely related radioresistant species. The identification of several novel sRNAs in Deinococcus bacteria raises important questions about the evolution and nature of global gene regulation in radioresistance. PMID- 25548055 TI - Impact of the use of beta-lactam antimicrobials on the emergence of Escherichia coli isolates resistant to cephalosporins under standard pig-rearing conditions. AB - The aim of this study was to evaluate if the treatments with ceftiofur and amoxicillin are risk factors for the emergence of cephalosporin resistant (CR) E. coli in a pig farm during the rearing period. One hundred 7-day-old piglets were divided into two groups, a control (n = 50) group and a group parenterally treated with ceftiofur (n = 50). During the fattening period, both groups were subdivided in two. A second treatment with amoxicillin was administered in feed to two of the four groups, as follows: group 1 (untreated, n = 20), group 2 (treated with amoxicillin, n = 26), group 3 (treated with ceftiofur, n = 20), and group 4 (treated with ceftiofur and amoxicillin, n = 26). During treatment with ceftiofur, fecal samples were collected before treatment (day 0) and at days 2, 7, 14, 21, and 42 posttreatment, whereas with amoxicillin, the sampling was extended 73 days posttreatment. CR E. coli bacteria were selected on MacConkey agar with ceftriaxone (1 mg/liter). Pulsed-field gel electrophoresis (PFGE), MICs of 14 antimicrobials, the presence of cephalosporin resistance genes, and replicon typing of plasmids were analyzed. Both treatments generated an increase in the prevalence of CR E. coli, which was statistically significant in the treated groups. Resistance diminished after treatment. A total of 47 CR E. coli isolates were recovered during the study period; of these, 15 contained blaCTX-M 1, 10 contained blaCTX-M-14, 4 contained blaCTX-M-9, 2 contained blaCTX-M-15, and 5 contained blaSHV-12. The treatment with ceftiofur and amoxicillin was associated with the emergence of CR E. coli during the course of the treatment. However, by the time of finishing, CR E. coli bacteria were not recovered from the animals. PMID- 25548056 TI - The Bacillus cereus group is an excellent reservoir of novel lanthipeptides. AB - Lantibiotics are ribosomally synthesized peptides that contain multiple posttranslational modifications. Research on lantibiotics has increased recently, mainly due to their broad-spectrum antimicrobial activity, especially against some clinical Gram-positive pathogens. Many reports about various bacteriocins in the Bacillus cereus group have been published, but few were about lantibiotics. In this study, we identified 101 putative lanthipeptide gene clusters from 77 out of 223 strains of this group, and these gene clusters were further classified into 20 types according to their gene organization and the homologies of their functional genes. Among them, 18 types were novel and have not yet been experimentally verified. Two novel lantibiotics (thuricin 4A-4 and its derivative, thuricin 4A-4D) were identified in the type I-1 lanthipeptide gene cluster and showed activity against all tested Gram-positive bacteria. The mode of action of thuricin 4A-4 was studied, and we found that it acted as a bactericidal compound. The transcriptional analysis of four structural genes (thiA1, thiA2, thiA3, and thiA4) in the thuricin 4A gene cluster showed that only one structural gene, thiA4, showed efficient transcription in the exponential growth phase; the other three structural genes did not. In addition, the putative transmembrane protein ThiI was responsible for thuricin 4A-4 immunity. Genome analysis and functional verification illustrated that B. cereus group strains were a prolific source of novel lantibiotics. PMID- 25548057 TI - Production of buttery-odor compounds and transcriptome response in Leuconostoc gelidum subsp. gasicomitatum LMG18811T during growth on various carbon sources. AB - Leuconostoc gelidum subsp. gasicomitatum is a common spoilage bacterium in meat products packaged under oxygen-containing modified atmospheres. Buttery off-odors related to diacetyl/acetoin formation are frequently associated with the spoilage of these products. A whole-genome microarray study, together with gas chromatography (GC)-mass spectrometry (MS) analyses of the pathway end products, was performed to investigate the transcriptome response of L. gelidum subsp. gasicomitatum LMG18811(T) growing on semidefined media containing glucose, ribose, or inosine, which are essential carbon sources in meat. Generally, the gene expression patterns with ribose and inosine were quite similar, indicating that catabolism of ribose and nucleosides is closely linked. Diacetyl/acetoin concentrations as high as 110 or 470 MUM were measured when growth was based on inosine or ribose, respectively. The gene expression results for pyruvate metabolism (upregulation of alpha-acetolactate synthase, downregulation of l lactate dehydrogenase and pyruvate dehydrogenase) were as expected when diacetyl and acetoin were the end products. No diacetyl production (<7.5 MUM) was detected with the glucose-containing medium, even though the cell counts of LMG18811(T) was 6 or 10 times higher than that on inosine or ribose, respectively. Although glucose was the most effective carbon source for the growth of L. gelidum subsp. gasicomitatum, utilization of inosine and ribose resulted in the production of the unwanted buttery-odor compounds. These results increase our understanding of which compounds are likely to enhance the formation of buttery odors during meat spoilage caused by L. gelidum subsp. gasicomitatum. PMID- 25548058 TI - Comparative proteome analysis reveals four novel polyhydroxybutyrate (PHB) granule-associated proteins in Ralstonia eutropha H16. AB - Identification of proteins that were present in a polyhydroxybutyrate (PHB) granule fraction isolated from Ralstonia eutropha but absent in the soluble, membrane, and membrane-associated fractions revealed the presence of only 12 polypeptides with PHB-specific locations plus 4 previously known PHB-associated proteins with multiple locations. None of the previously postulated PHB depolymerase isoenzymes (PhaZa2 to PhaZa5, PhaZd1, and PhaZd2) and none of the two known 3-hydroxybutyrate oligomer hydrolases (PhaZb and PhaZc) were significantly present in isolated PHB granules. Four polypeptides were found that had not yet been identified in PHB granules. Three of the novel proteins are putative alpha/beta-hydrolases, and two of those (A0671 and B1632) have a PHB synthase/depolymerase signature. The third novel protein (A0225) is a patatin like phospholipase, a type of enzyme that has not been described for PHB granules of any PHB-accumulating species. No function has been ascribed to the fourth protein (A2001), but its encoding gene forms an operon with phaB2 (acetoacetyl coenzyme A [CoA] reductase) and phaC2 (PHB synthase), and this is in line with a putative function in PHB metabolism. The localization of the four new proteins at the PHB granule surface was confirmed in vivo by fluorescence microscopy of constructed fusion proteins with enhanced yellow fluorescent protein (eYFP). Deletion of A0671 and B1632 had a minor but detectable effect on the PHB mobilization ability in the stationary growth phase of nutrient broth (NB) gluconate cells, confirming the functional involvement of both proteins in PHB metabolism. PMID- 25548059 TI - Pathogenic potential, genetic diversity, and population structure of Escherichia coli strains isolated from a forest-dominated watershed (Comox Lake) in British Columbia, Canada. AB - Escherichia coli isolates (n = 658) obtained from drinking water intakes of Comox Lake (2011 to 2013) were screened for the following virulence genes (VGs): stx1 and stx2 (Shiga toxin-producing E. coli [STEC]), eae and the adherence factor (EAF) gene (enteropathogenic E. coli [EPEC]), heat-stable (ST) enterotoxin (variants STh and STp) and heat-labile enterotoxin (LT) genes (enterotoxigenic E. coli [ETEC]), and ipaH (enteroinvasive E. coli [EIEC]). The only genes detected were eae and stx2, which were carried by 37.69% (n = 248) of the isolates. Only eae was harbored by 26.74% (n = 176) of the isolates, representing potential atypical EPEC strains, while only stx2 was detected in 10.33% (n = 68) of the isolates, indicating potential STEC strains. Moreover, four isolates were positive for both the stx2 and eae genes, representing potential EHEC strains. The prevalence of VGs (eae or stx2) was significantly (P < 0.0001) higher in the fall season, and multiple genes (eae plus stx2) were detected only in fall. Repetitive element palindromic PCR (rep-PCR) fingerprint analysis of 658 E. coli isolates identified 335 unique fingerprints, with an overall Shannon diversity (H') index of 3.653. Diversity varied among seasons over the years, with relatively higher diversity during fall. Multivariate analysis of variance (MANOVA) revealed that the majority of the fingerprints showed a tendency to cluster according to year, season, and month. Taken together, the results indicated that the diversity and population structure of E. coli fluctuate on a temporal scale, reflecting the presence of diverse host sources and their behavior over time in the watershed. Furthermore, the occurrence of potentially pathogenic E. coli strains in the drinking water intakes highlights the risk to human health associated with direct and indirect consumption of untreated surface water. PMID- 25548060 TI - Triglycerides on the rise: should we swap seats on the seesaw? PMID- 25548061 TI - Misperceptions of aspirin efficacy and safety may perpetuate anticoagulant underutilization in atrial fibrillation. PMID- 25548062 TI - Risk of early recurrent stroke in symptomatic carotid stenosis. AB - OBJECTIVES: The risk of recurrent stroke in patients with symptomatic carotid artery stenosis is highest in the first weeks after a transient ischemic attack (TIA) or minor stroke and can be reduced with carotid endarterectomy (CEA). The optimal timing of CEA remains a controversial issue since very urgent CEA is associated with an increased procedural risk. The aim of this study was to determine the risk of very early recurrent stroke in a population with symptomatic high grade carotid stenosis. METHODS: Data were analyzed on all patients with ocular TIA, TIA, or minor stroke with >70% carotid stenosis as assessed by carotid ultrasound at Sahlgrenska University Hospital during the periods 2004-2006 and 2010-2012. The two time periods were chosen to minimize selection bias and to analyze changes over time. The risk of recurrent stroke within 30 days of the referring event was assessed. RESULTS: 397 patients with symptomatic carotid stenosis were identified. The risk of recurrent stroke in the total cohort was 2.0% (CI 95% 0.6-3.4) by day 2, 4.0% (CI 95% 2.0-5.9) by day 7, and 7.5% (CI 95% 4.4-10.6) by day 30. There was no significant difference between the two time periods. Patients with minor stroke had a significantly higher risk of recurrent stroke than patients with TIA or ocular TIA as the referring event. CONCLUSIONS: The data suggest that the early risk of recurrent stroke in symptomatic significant carotid stenosis is not as high as some earlier studies have shown. The risk is similar to several studies in which a modern medical treatment regime could be assumed. PMID- 25548063 TI - Management strategies for patients with varicose veins (C2-C6): results of a worldwide survey. AB - OBJECTIVES: This study evaluated how patient characteristics and duplex ultrasound findings influence management decisions of physicians with specific expertise in the field of chronic venous disease. METHODS: Worldwide, 346 physicians with a known interest and experience in phlebology were invited to participate in an online survey about management strategies in patients with great saphenous vein (GSV) reflux and refluxing tributaries. The survey included two basic vignettes representing a 47 year old healthy male with GSV reflux above the knee and a 27 year old healthy female with a short segment refluxing GSV (CEAP classification C2sEpAs2,5Pr in both cases). Participants could choose one or more treatment options. Subsequently, the basic vignettes were modified according to different patient characteristics (e.g. older age, morbid obesity, anticoagulant treatment, peripheral arterial disease), clinical class (C4, C6), and duplex ultrasound findings (e.g. competent terminal valve, larger or smaller GSV diameter, presence of focal dilatation). The authors recorded the distribution of chosen management strategies; adjustment of strategies according to characteristics; and follow up strategies. RESULTS: A total of 211 physicians (68% surgeons, 12% dermatologists, 12% angiologists, and 8% phlebologists) from 36 different countries completed the survey. In the basic case vignettes 1 and 2, respectively, 55% and 40% of participants proposed to perform endovenous thermal ablation, either with or without concomitant phlebectomies (p < .001). Looking at the modified case vignettes, between 20% and 64% of participants proposed to adapt their management strategy, opting for either a more or a less invasive treatment, depending on the modification introduced. The distribution of chosen management strategies changed significantly for all modified vignettes (p < .05). CONCLUSIONS: This study illustrates the worldwide variety in management preferences for treating patients with varicose veins (C2-C6). In clinical practice, patient related and duplex ultrasound related factors clearly influence therapeutic options. PMID- 25548065 TI - Freedom, invisibility, and community: a qualitative study of self-identification with asexuality. AB - A significant body of research is now emerging on the subjective meaning of asexuality. This study explored how self-identification as asexual is managed, both as a threat to the self-concept and a source of personal meaning. A total of 66 self-identified asexuals were recruited from an asexuality internet community and responded to open-ended questions on an online survey. Of these, 31 participants identified as female, 15 as male, 18 gave a different label such as genderqueer or androgynous, and two did not provide information on gender. A thematic analysis of the transcripts resulted in three themes. Socially, asexuality attracted denial and resistance due to incompatibility with heteronormative societal expectations. Despite the threat to self-integrity arising from asexuality being socially rejected, it was typically assimilated as a valued and meaningful orientation on an intra-personal level, aided by information and support from the online community. A second level of threat to self arose whereby other self-identifications, especially gender, had to be reconciled with a non-sexual persona. The accommodation made to other elements of the self was reflected in complex sub-identities. The findings were interpreted using identity process theory to understand how threats arising from self identifying as asexual are managed. Although asexuality emerges as an orientation to sexuality that can be reconciled with the self, its invisibility or outright rejection in society constitute an on-going challenge. PMID- 25548064 TI - Correlates of unprotected anal intercourse: the influence of anal sex position among men who have sex with men in Beijing, china. AB - Understanding barriers to consistent condom use among men who have sex with men (MSM) requires consideration of the context in which risk behaviors occur. Anal sex position is one such context. This pooled cross-sectional study used survey data from 1,230 MSM and their 2,618 reported male sexual partnerships. Overall, nearly half of the participants engaged in unprotected anal intercourse (UAI) with at least one of upto three partners in the past 6 months. "Insertive" men engaged in less UAI (39 %) than "receptive" (53 %) or "versatile" (51 %) men. Regardless of sexual position, UAI was associated with cohabiting with a male or female partner and perceiving great or moderate risk of HIV from male contact at the individual level, and steady (vs. casual) partnership at the dyad level. However, early MSM anal sex debut, high number of male partners, alcohol use, receiving and buying condoms, HIV testing, and MSM sex-seeking venues were found to be only statistically significantly correlated with UAI among some but not all sexual positions, implying that interventions to increase condom use should take into account how anal sex position may influence willingness and ability to engage in safer sex. Dyad level data appear to provide additional insight into the influence of sexual positions, and should be used to complement individual data for future intervention designs. PMID- 25548066 TI - Gender Nonconformity, Sexual Orientation, and Dutch Adolescents' Relationship with Peers. AB - Same-sex attraction and gender nonconformity have both been shown to negatively affect the relationships of adolescents with their peers. It is not clear, though, whether same-sex attracted adolescents are more likely to have negative peer relationships because they are same-sex attracted or because they are more likely to be gender nonconforming. It is also possible that both stressors affect peer relationships independently or amplify each other in their impact. We explored these questions in a sample of 486 Dutch adolescents (M age = 14.02 years). We found that same-sex attraction and gender nonconformity both had an independent effect and that gender nonconformity moderated, but not mediated, the associations between same-sex attraction and peer relationships at school. Same sex attraction was more strongly associated with poorer relationships with peers in adolescents who were more gender nonconforming. These findings indicate the importance of including gender nonconformity in the understanding of same-sex attracted adolescents' relationships and suggest that in order to improve same sex attracted adolescents' social position at school, acceptance of gender diversity should be promoted as well. PMID- 25548067 TI - Mechanisms of daughter cell-size control during cell division. AB - Daughter cell size is tightly regulated during cell division. In animal cells, the position of the anaphase spindle specifies the cell cleavage site to dictate the relative size of the daughter cells. Although spindle orientation is regulated by dynein-dependent cortical pulling forces exerted on astral microtubules in many cell types, it was unclear how these forces are precisely regulated to center or displace the spindle. Recently, intrinsic signals derived from chromosomes or spindle poles have been demonstrated to regulate dynein dependent pulling forces in symmetrically dividing cells. Unexpectedly, myosin dependent contractile forces have also been shown to control spindle position by altering the cellular boundaries during anaphase. In this review, I discuss how dynein- and myosin-dependent forces are coordinately regulated to control daughter cell size. PMID- 25548068 TI - Identification of complications in mastectomy with immediate reconstruction using tissue expanders and permanent implants for breast cancer patients. AB - BACKGROUND: Since complications of postmastectomy breast reconstruction may reduce patient satisfaction, we investigated complications of reconstruction with tissue expanders (TEs), particularly surgical site infections requiring TE/permanent implant (PI) removal. PATIENTS AND METHODS: A retrospective review was performed of 234 primary breast cancer patients undergoing 239 postmastectomy breast reconstructions with TEs/PIs from 1997 to 2009. Clinicopathological findings and postoperative complications, particularly infections, were analyzed. Data were analyzed by the Chi-square test and a multivariate logistic regression model. TE infection risk factors considered for model inclusion were excisional biopsy, (neo) adjuvant chemotherapy, lymph node resection, body mass index (BMI), simultaneous bilateral reconstructions, and seroma aspiration. RESULTS: Removal of TEs/PIs was observed in 15.5% (37/239) of reconstructions, and 18/37 underwent re-reconstructions. Of the 19/37 reconstructions that were not achieved completely, the most frequent reason was TE infection (11 reconstructions). The completion rate was 92% (220/239 reconstructions) and it was significantly higher in reconstructions without TE infection than with infection (96 vs. 54%, p < 0.0001). Patients with BMI >= 25 kg/m2 and seroma aspiration were more likely to develop TE infections (p = 0.0019, p < 0.001, respectively). By multivariate logistic regression analysis, seroma aspiration was a significant independent risk factor for TE infection (odds ratio 28.75, 95% confidence interval 5.71 40.03, p < 0.0001). CONCLUSION: To improve completion rates of breast reconstruction, prevention of TE infection plays a key role. We should reduce unnecessary seroma aspirations and delay elevation/exercise of the ipsilateral arm. PMID- 25548069 TI - The association of cognitive fatigue with menopause, depressive symptoms, and quality of life in ambulatory breast cancer patients. AB - BACKGROUND: The causes of cancer-related fatigue, which can influence patients' activities, are multidimensional; however, little is known about the cognitive dimension. We examined the association of cognitive fatigue with menopause, depressive symptoms, and quality of life in ambulatory breast cancer patients after primary treatment. METHODS: This descriptive, cross-sectional study recruited 20-64-year-old breast cancer patients in an outpatient setting. The patients (N = 93; mean age = 53 years) were divided into low (L-CogF) and high cognitive fatigue (H-CogF) groups according to their scores on the cognitive fatigue subscale of the Cancer Fatigue Scale. We compared the groups on their sociodemographic and medical characteristics and scores on the Functional Assessment of Cancer Therapy-Breast (FACT-B) [a measure of quality of life (QOL)], Simplified Menopausal Index (SMI), and Self-Rating Questionnaire for Depression (SRQ-D). RESULTS: The L-CogF (n = 55) and H-CogF (n = 38) patients did not differ in age, years since diagnosis, marital status, educational background, or treatment history. Total and subscale FACT-B scores, except for physical well being, were significantly lower in H-CogF participants than in L-CogF participants. SMI and SRQ-D scores were significantly higher in H-CogF participants. Employed H-CogF participants were concerned about keeping their jobs (p < 0.05). CONCLUSIONS: Breast cancer patients with high-cognitive fatigue suffer from severe menopause and depressive symptoms, and deteriorating QOL. Cognitive fatigue should be considered when interpreting patients' cognitive complaints. PMID- 25548073 TI - Neutrophil recruitment to the brain in mouse and human ischemic stroke. AB - Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow-Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion. PMID- 25548074 TI - Synthesis, characterization, antimicrobial, DNA binding and cleavage studies of mixed ligand Cu(II), Co(II) complexes. AB - The mixed ligand complexes MLA of Cu(II) and Co(II) with Schiff base derived from 4-amino antipyrine and 5-NO(2) salicylaldehyde (2,3 -dimethyl-1-phenyl-4-(2 hydroxy-5-nitro benzylideneamino)-pyrazol-5-one) as ONO donor (L) and A = 2,2 bipyridine (bpy),1,10 phenonthroline (1,10 phen) as N, N donor ligands have been prepared, owing to their biological and other applications. The structural features have arrived from their elemental analyses, magnetic susceptibility, molar conductance, Mass, IR, UV-VIS, powdered XRD and ESR spectral studies, that established MLA type of composition for the metal complexes. The electronic absorption spectral data of the complexes suggest an octahedral geometry around the central metal ion. The interaction of the complexes with Calf Thymus (CT) DNA has been studied using absorption spectra, viscosity measurements and fluorescence spectra. The binding constants (K(b)) of the complexes were determined as 2.1 * 10(6) M(-1) for complex 1, 2.5x10(6)M(-1) for complex 2, 1.16 * 10(6) M(-1) for complex 3,1.25x10(6)M(-1) for complex 4, DNA cleavage experiments performed on pBR-322 plasmids using metal complexes in the presence of H(2)O(2) showed that all the complexes afford a pronounced DNA cleavage. Molecular modelling studies were also performed to confirm the geometries of the complexes. The ligand and their metal complexes were screened for their antimicrobial activity against bacteria. The results showed that the metal complexes are biologically active. PMID- 25548075 TI - Time to adjuvant chemotherapy and survival outcomes among patients with stage 2 to 3 rectal cancer treated with preoperative chemoradiation. AB - BACKGROUND: Previous studies have evaluated the impact of time to adjuvant chemotherapy (AC) on survival in early-stage colon cancer. However, the optimal time to adjuvant chemotherapy (TTAC) in rectal cancer remains unclear. The objective of this study was to identify an optimal TTAC and determine its prognostic effect in stage 2 to 3 rectal cancer. METHODS: Patients with stage 2 to 3 rectal cancer treated with preoperative chemoradiation and postoperative AC between 1999 and 2008 were included. Predetermined time points of 4, 6, 8, and 12 weeks from date of surgery were analyzed. Cut-point analysis was then used to determine an optimal TTAC, and overall survival at the identified cut-point was evaluated. RESULTS: A total of 328 eligible patients were identified with a median age of 61 years (range 22-85 years), 70% male, and 75% stage 3 disease. The median TTAC was 7.0 weeks. Initiation of AC at 6 weeks from date of surgery was associated with a significant survival benefit (hazard ratio 0.52, 95% confidence interval 0.31-0.90, P = .017), while no significant association was seen at 4, 8 or 12 weeks (P > .05). The cut-point analysis identified an optimal TTAC of 5.6 weeks association with improved survival compared to those with a TTAC greater than 5.6 weeks (hazard ratio 0.42, 95% confidence interval 0.22 0.82, P = .0087). This cut-point was also found to be a significant prognostic factor in multivariable analysis (P = .04) adjusted for Eastern Cooperative Oncology Group performance status, age, gender, stage, margin status, and grade. CONCLUSIONS: This study suggests that initiation of AC within an earlier time frame is associated with improved overall survival. PMID- 25548076 TI - Adjunct screening of cervical or vaginal samples using careHPV testing with Pap and aided visual inspection for detecting high-grade cervical intraepithelial neoplasia. AB - OBJECTIVE: To evaluate the performance of careHPV DNA testing for human papillomavirus (HPV) on cervical and vaginal samples (CHPV and VHPV respectively) in adjunct screening together with visual inspection of the cervix by acetic acid (VIA) or Papanicolaou (Pap) tests in the detection of high-grade cervical intraepithelial neoplasia (CIN). SUBJECTS AND METHODS: A cross-sectional study examined 4658 women 30-59 years of age by performing screening tests for HPV using careHPV on cervical and vaginal samples together with Pap and VIA. The CHPV and VHPV test results were presented as a ratio of viral load expressed in relative light units (RLUs) to the mean RLU from a positive control set at 1 pg/mL cut-off (CO). Performances of various pairs of screening tests in parallel and sequential settings were computed through the detection rates of CIN, percentages of unnecessary colposcopic referrals of screen positives, and compared with stand-alone tests. RESULTS: The screening positivity of CHPV, VHPV, Pap and VIA ranged from 2.4% to 5.5%. The highest sensitivity (72%) was observed for the combination of CHPV and VIA in parallel, followed by 65.6% for CHPV and Pap, and 59% for all other combinations (VHPV and Pap, VHPV and VIA, and VIA and Pap). The percentage of unnecessary colposcopic referrals in the parallel setting of CINII+ detection ranged from 2.8% to 6.0%. Sequential testing of CHPV or VHPV with other tests yielded very low sensitivities with a reduction in unnecessary colposcopic referrals. CONCLUSION: Cervical careHPV testing (CHPV) in parallel with VIA was the option that performed best in the detection of high-grade CIN and could be a feasible option for low-resource countries (LRCs). PMID- 25548077 TI - Parental cancer diagnosis and child mortality--a population-based cohort study in Sweden. AB - OBJECTIVE: Cancer diagnosis is known to induce severe psychological stress for the diagnosed patients; however, how it affects the next-of-kin is less well documented. This study aimed to assess the impact of parental cancer on the risk of childhood death. METHODS: A population-based cohort study was conducted using the Swedish national registries, including 2,871,242 children followed during the period of 1991-2009. Parental cancer diagnosis was defined as a time-varying exposure. We used Cox proportional hazards regression to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) as an estimate of the association between parental cancer and childhood mortality. We adjusted for attained age, sex, gestational age, mode of delivery and birth weight of the child, maternal age at child's birth, as well as educational level and socio economic classification of the parents in the analyses. RESULTS: Among 113,555 children with parental cancer, 127 deaths occurred during 561,198 person-years of follow-up. A parental cancer diagnosis was associated with an increased rate of death among children at the age of 1-18 (HR for all-cause death: 1.39; 95% CI: 1.16-1.66). For young children (aged 1-12), an increased rate was only noted for death due to cancer (HR: 2.06; 95% CI: 1.13-3.75) after parental cancer diagnosis. Among adolescents (aged 13-18), an increased rate was noted for all cause death (HR: 1.52; 95% CI: 1.25-1.86), and for both non-cancer-related (HR: 1.43; 95% CI: 1.14-1.79) and cancer-related (HR: 2.07; 95% CI: 1.33-3.24) death in the exposed children. CONCLUSION: Children have an increased rate of death if they have a parent diagnosed with cancer as compared to children without such experience; this association appears to be slightly stronger among adolescents. PMID- 25548078 TI - Erratum: Drug-Use Evaluation Comparing Dexmedetomidine Use at 3 Health Authority Sites Relative to Manufacturer's Recommended Directions (DECODE Study): Correction. AB - [This corrects the article on p. 379 in vol. 67, PMID: 25364021.]. PMID- 25548079 TI - No difference between intra-articular injection of hyaluronic acid and placebo for mild to moderate knee osteoarthritis: a randomized, controlled, double-blind trial. AB - The main goal of our study was to examine the effectiveness and safety of Fermathron plus, a specific brand of hyaluronic acid (HA), in patients with mild to moderate knee osteoarthritis. In a randomized, controlled, double-blind trial, 196 patients with symptomatic knee osteoarthritis (mean age +/- SD, 59.4 +/- 9.9 years, Kellgren-Lawrence grade 1-3) were given either 3 weekly intra-articular injections of HA or saline (placebo). Although pain and functional scores (WOMAC scale) improved significantly from baseline up to 6 months, HA was not superior to placebo at any follow-up (VAS pain 50 m walking from 56.4 to 38.1, P < .001, and 58.2 to 39.6, P < .001, respectively). No subgroup analysis resulted in superior outcomes. No serious adverse events were noticed. PMID- 25548080 TI - Economic analysis of vaccination to control bovine brucellosis in the States of Sao Paulo and Mato Grosso, Brazil. AB - Brucellosis is a zoonotic disease that causes important economic losses in Brazil, and the country has therefore established a national program for its control and eradication. Using data generated in the last national brucellosis survey, we conducted an economic analysis in two Brazilian States with different brucellosis status, Mato Grosso (with high prevalence) and Sao Paulo (with low prevalence). The economic analysis was based on the calculation of the additional benefits and costs of controlling bovine brucellosis through the vaccination of heifers aged between 3 and 8 months with S19 vaccine, considering maximal and minimal impacts of the disease. The analysis showed that vaccinating 90% of the replacement heifers aged 3-8 months of age offers the best economic performance in a vaccination program against bovine brucellosis if compared to vaccination rates of 70% and 80%. Moreover, regions with higher prevalences of bovine brucellosis would experience significant economic advantages when implementing a vaccination strategy to control the disease. This economic analysis will allow decision makers to plan more economically effective vaccination programs. PMID- 25548081 TI - The impact of obesity on consumer bankruptcy. AB - Over the last two decades, both bankruptcy and obesity rates in the U.S. have seen a steady rise. As obesity is one of the leading causes of medical and morbidity related economic costs, its influence on personal bankruptcy is analyzed in this study. Using the National Longitudinal Survey of Youth 1979, we employ a duration model to investigate the relative importance of obesity on the timing of bankruptcy. Even after accounting for possible endogeneity of BMI and controlling for a wide variety of individual and aggregate-level confounding factors, being obese puts one at a greater risk of filing for bankruptcy. PMID- 25548083 TI - Erratum to: Less depressed or less forthcoming? Self-report of depression symptoms in women preparing for in vitro fertilization. AB - Erratum to: Arch Womens Ment Health (2013) 16:87-92 DOI 10.1007/s00737-012-0317 8. The original version of this article unfortunately missed the Acknowledgment which is stated below: "This work was partially supported by a grant from the NICHD (K12-HD063117)." PMID- 25548082 TI - [123I]ICF01012 melanoma imaging and [131I]ICF01012 dosimetry allow adapted internal targeted radiotherapy in preclinical melanoma models. AB - BACKGROUND: Melanin-targeting radiotracers are interesting tools for imaging and treatment of pigmented melanoma metastases. However, variation of the pigment concentration may alter the efficiency of such targeting. OBJECTIVES: A clear assessment of both tumor melanin status and dosimetry are therefore prerequisites for internal radiotherapy of disseminated melanoma. MATERIALS & METHODS: The melanin tracer ICF01012 was labelled with iodine-123 for melanoma imaging in pigmented murine B16F0 and human SK-Mel 3 melanomas. RESULTS: In vivo imaging showed that the uptake of [(123)I]ICF01012 to melanomas correlated significantly with melanin content. Schedule treatment of 3 * 25 MBq [(131)I]ICF01012 significantly reduced SK-Mel 3 tumor growth and significantly increased the median survival in treated mice. For this protocol, the calculated delivered dose was 53.2 Gy. CONCLUSION: Radio-iodinated ICF01012 is a good candidate for both imaging and therapeutic purposes for patients with metastatic pigmented melanomas. PMID- 25548084 TI - Gene inactivation using the CRISPR/Cas9 system in the nematode Pristionchus pacificus. AB - The diplogastrid nematode Pristionchus pacificus is a nematode model system for comparative studies to Caenorhabditis elegans and integrative evolutionary biology aiming for interdisciplinary approaches of evo-devo, population genetics, and ecology. For this, fieldwork can be combined with laboratory studies, and P. pacificus has a well-developed methodological toolkit of forward genetics, whole genome sequencing, DNA-mediated transformation, and various -omics platforms. Here, we establish CRISPR/Cas9-based gene inactivation and describe various boundary conditions of this methodology for P. pacificus. Specifically, we demonstrate that most mutations arise within the first 9 hours after injections. We systematically tested the efficiency of sgRNAs targeting different exons in Ppa-dpy-1 and characterized the molecular nature of the induced mutations. Finally, we provide a protocol that might also be useful for researchers working with other non-Caenorhabditis nematodes. PMID- 25548086 TI - Out-of-home behavior and cognitive impairment in older adults: findings of the SenTra Project. AB - This study explores differences in the out-of-home behavior of community-dwelling older adults with different cognitive impairment. Three levels of complexity of out-of-home behavior were distinguished: (a) mostly automatized walking behavior (low complexity), (b) global out-of-home mobility (medium complexity), and (c) defined units of concrete out-of-home activities, particularly cognitively demanding activities (high complexity). A sample of 257 older adults aged 59 to 91 years (M = 72.9 years, SD = 6.4 years) included 35 persons with early-stage Alzheimer's disease (AD), 76 persons with mild cognitive impairment (MCI), and 146 cognitively healthy persons (CH). Mobility data were gathered by using a GPS tracking device as well as by questionnaire. Predicting cognitive impairment status by out-of-home behavior and a range of confounders by means of multinomial logistic regression revealed that only cognitively demanding activities showed at least a marginally significant difference between MCI and CH and were highly significant between AD and CH. PMID- 25548087 TI - Daily mood and out-of-home mobility in older adults: does cognitive impairment matter? AB - This study explores the relationship between out-of-home behavior and daily mood of community-dwelling older adults with different levels of cognitive impairment across four consecutive weeks. The sample included 16 persons with early stage Alzheimer's disease (AD), 30 persons with mild cognitive impairment (MCI), and 95 cognitively healthy persons (CH). Using a multi-method approach, GPS tracking and daily-diary data were combined on a day-to-day basis. AD and MCI adults showed lower mood than the CH group. Whereas stronger positive links between mood and out-of-home behavior were found for AD compared to the total sample on an aggregate level, predicting daily mood by person (i.e., cognition) and occasion specific characteristics (i.e., mobility and weekday), using multilevel regression analysis revealed no corresponding effect. In conclusion, cognitive status in old age appears to impact on mobility and mood as such, rather than on the mood and out-of-home behavior connection. PMID- 25548088 TI - Sleep and everyday functioning in older adulthood. AB - As individuals age they report increasing numbers of sleep problems (e.g., increased nighttime wakings) and this poorer sleep quality has been associated with increased risk for various medical conditions; however limited research has focused on the implications of sleep quality on everyday functioning in older adulthood. We compared three methods of sleep data collection (wrist actigraphy, self-report questionnaires, and sleep diary) and evaluated their relationships with three approaches to assessing everyday functioning (direct observation, self report, and paper-and-pencil-based problem-solving tasks) in cognitively healthy older adults. Consistent with previous research, subjective sleep measures correlated significantly with each other but did not correlate with objective sleep measures. Multiple regression analyses revealed neither objective nor subjective sleep measures predicted everyday functioning. Individual variability in sleep may affect prediction of everyday functioning using a cross-sectional sample. Future research should investigate the combined influence of sleep and cognitive factors on everyday functioning in older adults. PMID- 25548085 TI - The gut sensor as regulator of body weight. AB - The gastrointestinal (GI) tract comprises a large endocrine organ that regulates not only nutrient sensing and metabolising but also satiety and energy homeostasis. More than 20 hormones secreted from the stomach, intestine, and pancreas as well as signaling mediators of the gut microbiome are involved in this process. A better understanding of how related pathways affect body weight and food intake will help us to find new strategies and drugs to treat obesity. For example, weight loss secondary to lifestyle intervention is often accompanied by unfavorable changes in multiple GI hormones, which may cause difficulties in maintaining a lower body weight status. Conversely, bariatric surgery favorably changes the hormone profile to support improved satiety and metabolic function. This partially explains stronger sustained body weight reduction resulting in better long-term results of improved metabolic functions. This review focuses on GI hormones and signaling mediators of the microbiome involved in satiety regulation and energy homeostasis and summarizes their changes following weight loss. Furthermore, the potential role of GI hormones as anti-obesity drugs is discussed. PMID- 25548089 TI - Factors buffering against the effects of job demands: how does age matter? AB - Given the increasing role that paid work is likely to play in older adulthood in the coming decades, the goal of this study was to understand the circumstances under which work is related to mental health for older adults and whether these circumstances differ by age. Using a multiworksite sample of 1,812 U.S. workers age 18 to 81, we use the life-span theory of control to hypothesize that older and younger workers may benefit differentially from job and personal control in the context of high job demands. Results suggest that for younger workers with high personal control, job control buffers the impact of job demands on mental health. For older workers, personal control alone buffers the impact of job demands on mental health. This study adds to previous research by addressing how the factors thought to buffer against the effects of job demands differ cross sectionally by age. PMID- 25548090 TI - Waist circumference cutoff points for central obesity in the Korean elderly population. AB - The aim is to determine the appropriate cutoff values of waist circumference (WC) for an increased risk of the metabolic syndrome in the Korean elderly population. We analyzed the WC cutoff values of four groups divided according to sex and age with a total of 2,224 elderly participants aged 65 years old and above from the Fourth Korean National Health and Nutrition Examination Survey using the receiver operating characteristic curve and multiple logistic regression. The WC cutoff values associated with an increased risk of metabolic syndrome were 89.6 cm for men and 90.5 cm for women for those who were 65 to 74 years old, and 89.9 cm for men and 87.9 cm for women for those who were 75 years old or older. WC cutoff points for estimating metabolic risk are similar in elderly men and women. Age specific optimal WC cutoff points should be considered especially for elderly women in screening for metabolic syndrome. PMID- 25548091 TI - The effect of therapeutic horseback riding on balance in community-dwelling older adults: a pilot study. AB - Equine assisted activities (hippotherapy and therapeutic riding) improve balance in patients with disabilities such as cerebral palsy, but have not been systematically studied in older adults, at risk of falls due to balance deficits. We conducted a 10-week, single blind, controlled trial of the effect of a therapeutic horseback riding course on measures of balance in community-dwelling adults 65 years and older. Nine riders and six controls completed the trial. Controls were age matched to riders and all participants were recruited from the local community. Both groups showed improvements in balance during the trial, but did not reach statistical significance. Sample size was small, participants had relatively high initial balance scores, and controls tended to increase their physical activities, likely influencing outcomes. No adverse events occurred and the supervised therapeutic riding program appeared to be a safe and effective form of exercise to improve balance in older adults. A power analysis was performed to estimate numbers of participants needed for a larger study. PMID- 25548094 TI - The importance of comparative oncology in translational medicine. AB - Human cancer is so complex that in vivo preclinical models are needed if effective therapies are to be developed. Naturally occurring cancers in companion animals are therefore a great resource, as shown by the remarkable growth that comparative oncology has seen over the last 30 years. Cancer has become a leading cause of death in companion animals now that more pets are living long enough to develop the disease. Furthermore, more owners are seeking advanced and novel therapies for their pets as they are very much considered family members. Living in the same environments, pets and humans are often afflicted by the same types of cancer which show similar behavior and, in some species, express the same antigen molecules. The treatment of pet tumors using novel therapies is of compelling translational significance. PMID- 25548092 TI - Long-term clinical outcome of melanoma patients treated with messenger RNA electroporated dendritic cell therapy following complete resection of metastases. AB - PURPOSE: Melanoma patients with a high risk of recurrence may benefit from immunotherapy with mRNA-electroporated autologous monocyte-derived dendritic cells (DCs). Further benefit may be found in combining DC-therapy with interferon alfa-2b. PATIENTS AND METHODS: The long-term clinical outcome of AJCC stage III/IV melanoma patients who had no evidence of disease at the time of treatment with autologous mRNA-electroporated DCs in a single-center pilot clinical trial was analyzed. Antigen loading was accomplished by co-electroporation of mRNA encoding a fusion protein between MAGE-A1, -A3, -C2, Tyrosinase, MelanA/MART-1, or gp100, and an HLA class II-targeting sequence. DCs were administered by 4-6 bi weekly intradermal injections. IFN-alpha-2b (5 MIU TIW) was initiated either at recurrence (cohort 1), concomitant with DCs (cohorts 2 and 3), or following the fourth DC administration (cohort 4). RESULTS: Thirty melanoma patients were recruited between April 2006 and June 2009. DC-related adverse events included grade 2 local injection site reactions in all patients, grade 2 fever and flu like symptoms in one patient, and skin depigmentation in seven patients. After a median follow-up of over 6 years, the median relapse-free survival is 22 months (95% CI 12-32 months). Twelve patients have died. The median overall survival has not been reached; the 2-year and 4-year survival rates are 93 and 70%, respectively. CONCLUSIONS: Adjuvant therapy following the resection of melanoma metastases with autologous mRNA-electroporated DCs, combined with interferon alfa 2b, is tolerable and results in encouraging long-term overall survival rates justifying further evaluation in a randomized clinical trial. PMID- 25548093 TI - Cancer immunotherapy achieves breakthrough status: 12th annual meeting of the association for cancer immunotherapy (CIMT), Mainz, Germany, May 6-8, 2014. PMID- 25548095 TI - Tumor-induced CD14+HLA-DR (-/low) myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. AB - Myeloid-derived suppressor cells (MDSCs) are heterogeneous, immature, myeloid progenitor cells, which suppress immune responses against tumors. CD14(+)HLA-DR( /low) monocytic MDSCs (M-MDSC) are increased in patients suffering from multiple myeloma (MM). However, the frequency and function of M-MDSCs with the relationship between the tumor development and outcome of therapy in MM remain unclear. In this study, we analyzed the changes in M-MDSCs in newly diagnosed, relapsed and remission MM patients. In addition, we also assessed the response of M-MDSCs in MM patients treated with a bortezomib-based therapy as well as the impact of bortezomib on the modulation of M-MDSCs in vitro. The levels of M-MDSCs in newly diagnosed and relapsed MM patients were significantly increased compared with those in remission MM patients and healthy donors. Moreover, the levels of M MDSCs were shown to correlate with tumor progression. The decrease in M-MDSCs after proteasome inhibitory therapy suggested that M-MDSCs could be considered as an indicator for the efficacy of therapy. Finally, we found the plasma from newly diagnosed MM patients, and MM cells were able to induce the accumulation of M MDSCs in vitro. These results indicated that M-MDSCs could be considered as a prognostic predictor and an important cell type contributing to immune suppressive microenvironment in MM patients. Treatments targeting for M-MDSCs may improve therapeutic outcomes for MM patients. PMID- 25548096 TI - Psychiatry's dilemma: a poorly valid symptom based classification versus a yet infantile neuroscience based classification. PMID- 25548098 TI - Aerobic training attenuates nicotinic acethylcholine receptor changes in the diaphragm muscle during heart failure. AB - INTRODUCTION: Heart failure (HF) is a progressive myopathy, with clinical signs of fatigue and limb weakness that can damage the nerve-muscle interaction, altering synaptic transmission and nicotinic acetylcholine receptors (nAChR) in neuromuscular junctions (NMJs). The diaphragm is composed of a mixed proportion of muscle fibres, and during HF, this muscle becomes slower and can alter its function. As exercise training is an accepted practice to minimise abnormalities of skeletal muscle during HF, in this study, we evaluated the hypothesis that aerobic training attenuates alterations in the expression of nAChR subunits in NMJs diaphragm during heart failure. OBJECTIVE: The aim of this study was to evaluate the distribution and expression of nAChR subunits in the diaphragm muscle fibres of rats subjected to an aerobic training programme during HF. METHODS: Control (Sham), control training (ShamTR), aortic stenosis (AS) and aortic stenosis training (ASTR) groups were evaluated. The expression of nAChR subunits (gamma, alpha1, epsilon, beta1 and delta) was determined by qRT-PCR, and NMJs were analysed using confocal microscopy. RESULTS: We observed increased expression of the gamma, alpha1 and beta1 subunits in the AS group compared with the ASTR group. The distribution of NMJs was modulated in these groups. DISCUSSION: HF alters the mRNA expression of nAChR subunits and the structural characteristics of diaphragm NMJs. In addition, aerobic training did not alter NMJs morphology but attenuated the alterations in heart structure and function and in nAChR subunit mRNA expression. Our findings demonstrate the beneficial effects of aerobic exercise training in maintaining the integrity of the neuromuscular system in the diaphragm muscle during HF and may be critical for non-pharmacological therapy to improve the quality of life for patients with this syndrome. PMID- 25548097 TI - The influence of intraluminal thrombus on noninvasive abdominal aortic aneurysm wall distensibility measurement. AB - Abdominal aortic aneurysm wall distensibility can be estimated by measuring pulse pressure and the corresponding sac volume change, which can be obtained by measuring wall displacement. This approach, however, may introduce error if the role of thrombus in assisting the wall in bearing the pulse pressure loading is neglected. Our aim was to introduce a methodology for evaluating and potentially correcting this error in estimating distensibility. Electrocardiogram-gated computed tomography images of eleven patients were obtained, and the volume change between diastole and systole was measured. Using finite element procedures, we determined the equivalent pulse pressure loading that should be applied to the wall of a model where thrombus was digitally removed, to yield the same sac volumetric increase caused by applying the luminal pulse pressure to the model with thrombus. The equivalent instead of the measured pulse pressure was used in the distensibility expression. For a relative volumetric thrombus deposition (V ILT) of 50 %, a 62 % distensibility underestimation resulted when thrombus role was neglected. A strong linear correlation was observed between distensibility underestimation and V ILT. To assess the potential value of noninvasive wall distensibility measurement in rupture risk stratification, the role of thrombus on wall loading should be further investigated. PMID- 25548099 TI - Salt-inducible kinase 2 regulates mitotic progression and transcription in prostate cancer. AB - Salt-inducible kinase 2 (SIK2) is a multifunctional kinase of the AMPK family that plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell-cycle progression and a negative regulator of CREB1 activity. Knockdown of SIK2 inhibited cell growth, delayed cell-cycle progression, induced cell death, and enhanced CREB1 activity. Expression of a kinase-dead mutant of SIK2 also inhibited cell growth, induced cell death, and enhanced CREB1 activity. Treatment with a small-molecule SIK2 inhibitor (ARN 3236), currently in preclinical development, also led to enhanced CREB1 activity in a dose- and time-dependent manner. Because CREB1 is a transcription factor and proto-oncogene, it was posited that the effects of SIK2 on cell proliferation and viability might be mediated by changes in gene expression. To test this, gene expression array profiling was performed and while SIK2 knockdown or overexpression of the kinase-dead mutant affected established CREB1 target genes; the overlap with transcripts regulated by forskolin (FSK), the adenylate cyclase/CREB1 pathway activator, was incomplete. IMPLICATIONS: This study demonstrates that targeting SIK2 genetically or therapeutically will have pleiotropic effects on cell-cycle progression and transcription factor activation, which should be accounted for when characterizing SIK2 inhibitors. PMID- 25548100 TI - Reversal of Mutant KRAS-Mediated Apoptosis Resistance by Concurrent Noxa/Bik Induction and Bcl-2/Bcl-xL Antagonism in Colon Cancer Cells. AB - KRAS mutations are frequently detected in human colorectal cancer and contribute to de novo apoptosis resistance and ultimately therapeutic failure. To overcome KRAS-mediated apoptosis resistance, the irreversible proteasome inhibitor, carfilzomib, was evaluated and found to potently induce Noxa, which was dependent upon c-Myc, and Bik. Isogenic mutant versus wild-type KRAS carcinoma cells showed elevated Bcl-xL, confirmed by KRAS siRNA or ectopic expression. Upregulated Bcl xL by mutant KRAS was mediated by ERK as indicated by ERK knockdown. Bcl-xL expression was regulated at the level of mRNA and protein as shown using actinomycin D and cyclohexamide, respectively. Suppression of Bcl-xL by shRNA sensitized mutant KRAS cells to carfilzomib. Concurrent Bcl-xL antagonism by the BH3 mimetic ABT-263 combined with carfilzomib synergistically enhanced apoptosis that was dependent on Bax or p53, and was attenuated by Noxa or Bik shRNA. In support of this strategy, ectopically expressed Noxa enhanced apoptosis by ABT 263. Carfilzomib-induced Noxa and Bik sequestered Mcl-1 and ABT-263 released Bik and Bak from Bcl-xL, suggesting a mechanism for drug synergy. These preclinical findings establish mutant KRAS-mediated Bcl-xL upregulation as a key mechanism of apoptosis resistance in KRAS-mutant colorectal cancer. Furthermore, antagonizing Bcl-xL enabled carfilzomib-induced Noxa and Bik to induce synergistic apoptosis that reversed KRAS-mediated resistance. IMPLICATIONS: This novel study reveals a promising treatment strategy to overcome apoptosis resistance in KRAS-mutant colorectal cancer by concurrent upregulation of Noxa/Bik and antagonism of Bcl xL. PMID- 25548101 TI - Membrane-to-Nucleus Signals and Epigenetic Mechanisms for Myofibroblastic Activation and Desmoplastic Stroma: Potential Therapeutic Targets for Liver Metastasis? AB - Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment (TME), are a key source of the extracellular matrix (ECM) that constitutes the desmoplastic stroma. Through remodeling of the reactive tumor stroma and paracrine actions, CAFs regulate cancer initiation, progression, and metastasis, as well as tumor resistance to therapies. The CAFs found in stroma rich primary hepatocellular carcinomas (HCC) and liver metastases of primary cancers of other organs predominantly originate from hepatic stellate cells (HSTC), which are pericytes associated with hepatic sinusoids. During tumor invasion, HSTCs transdifferentiate into myofibroblasts in response to paracrine signals emanating from either tumor cells or a heterogeneous cell population within the hepatic tumor microenvironment. Mechanistically, HSTC-to-myofibroblast transdifferentiation, also known as, HSTC activation, requires cell surface receptor activation, intracellular signal transduction, gene transcription, and epigenetic signals, which combined ultimately modulate distinct gene expression profiles that give rise to and maintain a new phenotype. The current review defines a paradigm that explains how HSTCs are activated into CAFs to promote liver metastasis. Furthermore, a focus on the most relevant intracellular signaling networks and epigenetic mechanisms that control HSTC activation is provided. Finally, we discuss the feasibility of targeting CAF/activated HSTCs, in isolation or in conjunction with targeting cancer cells, which constitutes a promising and viable therapeutic approach for the treatment of primary stroma rich liver cancers and liver metastasis. PMID- 25548102 TI - A vascular model of Tsc1 deficiency accelerates renal tumor formation with accompanying hemangiosarcomas. AB - Tuberous sclerosis complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumor suppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mouse model (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age, the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Because paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug testing for therapies of TSC-related tumors. IMPLICATIONS: These findings provide a strong rationale for simultaneous use of this conditional knockout mouse as an in vivo genetic model while seeking new cancer therapies for TSC-related tumors. PMID- 25548103 TI - Capillary compared to venous blood sampling in clozapine treatment: patients' and healthcare practitioners' experiences with a point-of-care device. AB - Underuse of the antipsychotic clozapine for schizophrenia is an impediment to improving outcomes for patients. Because of its possible severe side effects, including granulocytopenia or even agranulocytosis, clozapine treatment entails regular WBC monitoring, which can be a major drawback for patients and practitioners. The HemoCue WBC DIFF system is a point-of-care device using capillary blood sampling which provides WBC counts with differentials, including granulocytes. We investigated if capillary sampling instead of conventional venous sampling might diminish the burden for patients and practitioners and motivate them to continue clozapine treatment. A randomized cross-over trial design was used to compare the two sampling methods. Patients' subjective experiences of various aspects of blood sampling were rated on a 10-cm visual analogue scale (VAS). Patients and practitioners were also asked if they had any preference for venous or capillary sampling and patients were asked if the sampling method influenced their motivation to continue clozapine treatment. Seventy-three patients were included in this study. Three dropped out before completion. The VAS ratings on all five aspects and the total burden experienced showed a consistent pattern favouring capillary blood sampling (p<0.001). This pattern was more pronounced for inpatients than for outpatients. Patients strongly preferred capillary testing (p<0.001). The method used moderately influenced their motivation for clozapine therapy. In this study patients tolerated capillary blood testing with a point-of-care device better than traditional venous sampling at a laboratory and practitioners also preferred it. Using this method might therefore boost clozapine prescription rates. PMID- 25548104 TI - Combination therapy with cholinesterase inhibitors and memantine for Alzheimer's disease: a systematic review and meta-analysis. AB - BACKGROUND: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer's disease. METHODS: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. RESULTS: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference=-0.13), activity of daily living scores (standardized mean difference=-0.10), and global assessment scores (standardized mean difference=-0.15). In addition, cognitive function scores (standardized mean difference=-0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer's disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. CONCLUSIONS: Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer's disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated. PMID- 25548105 TI - Increased excitability of lateral habenula neurons in adolescent rats following cocaine self-administration. AB - BACKGROUND: The lateral habenula is a brain region that has been critically implicated in modulating negative emotional states and responses to aversive stimuli. Exposure to addictive drugs such as cocaine negatively impacts affective states, an effect persisting longer than acute drug effects. However, the mechanisms of this effect are poorly understood. We hypothesized that drugs of abuse, such as cocaine, may contribute to drug-induced negative affective states by altering the firing properties of lateral habenula neurons, thus changing the signaling patterns from the lateral habenula to downstream circuits. METHODS: Using whole-cell current-clamp recording of acutely prepared brain slices of rats after various periods of withdrawal from cocaine self-administration, we characterized an important heterogeneous subregion of the lateral habenula based on membrane properties. RESULTS: We found two major relevant neuronal subtypes: burst firing neurons and regular spiking neurons. We also found that lateral habenula regular spiking neurons had higher membrane excitability for at least 7 days following cocaine self-administration, likely due to a greater membrane resistance. Both the increase in lateral habenula excitability and membrane resistance returned to baseline when tested after a more prolonged period of 45 days of withdrawal. CONCLUSION: This is the first study to look at intrinsic lateral habenula neuron properties following cocaine exposure beyond acute drug effects. These results may help to explain how cocaine and other drugs negatively impact affect states. PMID- 25548107 TI - Cannabinoid modulation of amygdala subregion functional connectivity to social signals of threat. AB - BACKGROUND: Delta(9)-Tetrahydrocannabinol has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex is implicated in affective processes, it is possible that Delta(9)-tetrahydrocannabinol affects amygdala-prefrontal cortex functional connectivity in ways that differ across amygdala subregions: basolateral, centromedial, and superficial. METHODS: The aim of the study was to examine the effects of Delta(9)-tetrahydrocannabinol on functional connectivity between amygdala subregions and the prefrontal cortex during socio-emotional threat in healthy adults using a double-blind, placebo controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging task designed to probe amygdala responses to social threat. Amygdala subregion-prefrontal cortex functional connectivity was compared between Delta(9)-tetrahydrocannabinol and placebo using generalized psychophysiological interaction analyses. RESULTS: Findings indicated that Delta(9)-tetrahydrocannabinol enhanced basolateral and superficial amygdala connectivity to the rostral anterior cingulate/medial prefrontal cortex. CONCLUSION: These effects, including Delta(9)-tetrahydrocannabinol's potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect. PMID- 25548106 TI - Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats. AB - BACKGROUND: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile. METHODS: We tested whether oleoylethanolamide/palmitoylethanolamide (10 mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5 mg/kg, i.p.) in rats. RESULTS: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, nuclear transcription factor-kappaB activity, and the expression of its inhibitory protein IkappaBalpha in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2(-)) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor alpha levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-alpha mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-kappaB (NF-kappaB)/IkappaBalpha upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1beta, cyclooxygenase-2, and prostaglandin E2, and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test. CONCLUSIONS: Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinflammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinflammatory component. PMID- 25548108 TI - Association study indicates a protective role of phosphatidylinositol-4-phosphate 5-kinase against tardive dyskinesia. AB - BACKGROUND: Tardive dyskinesia is a disorder characterized by involuntary muscle movements that occur as a complication of long-term treatment with antipsychotic drugs. It has been suggested to be related to a malfunctioning of the indirect pathway of the motor part of the cortical-striatal-thalamic-cortical circuit, which may be caused by oxidative stress-induced neurotoxicity. METHODS: The purpose of our study was to investigate the possible association between phosphatidylinositol-4-phosphate-5-kinase type IIa (PIP5K2A) function and tardive dyskinesia in 491 Caucasian patients with schizophrenia from 3 different psychiatric institutes in West Siberia. The Abnormal Involuntary Movement Scale was used to assess tardive dyskinesia. Individuals were genotyped for 3 single nucleotide polymorphisms in PIP5K2A gene: rs10828317, rs746203, and rs8341. RESULTS: A significant association was established between the functional mutation N251S-polymorphism of the PIP5K2A gene (rs10828317) and tardive dyskinesia, while the other 2 examined nonfunctional single nucleotide polymorphisms were not related. CONCLUSIONS: We conclude from this association that PIP5K2A is possibly involved in a mechanism protecting against tardive dyskinesia-inducing neurotoxicity. This corresponds to our hypothesis that tardive dyskinesia is related to neurotoxicity at striatal indirect pathway medium-sized spiny neurons. PMID- 25548110 TI - DeltaNp63 (p40) expression in prostatic adenocarcinoma with diffuse p63 positivity. AB - Basal cells of benign prostate glands are typically p63 positive, whereas malignant glands are usually p63 negative. A rare subset of prostatic adenocarcinoma (PCa) demonstrates aberrant diffuse p63 expression but is negative for high-molecular-weight cytokeratin. Strong p63 staining of the tumor cells can obscure the loss of high-molecular-weight cytokeratin when using a cocktail of basal cell markers and create a diagnostic pitfall. The p63 protein has 6 major isoforms; of these, TAp63 and DeltaNp63 (p40) are the best characterized N terminal variants. In an attempt to aid in the diagnosis of p63-positive PCas, we studied DeltaNp63 expression in tumors with aberrant p63. Immunohistochemistry was performed on 31 cores of aberrant p63-positive PCas from 24 patients and on a tissue microarray containing 125 cores of conventional PCas from 40 radical prostatectomy cases using a DeltaNp63-specific polyclonal (p40) antibody and a TAp63-specific monoclonal antibody (p63, clone 4A4) that recognizes both TAp63 and DeltaNp63. Most of the aberrant p63-positive tumors showed diffuse positivity for p40 (29/31 cores, 93.5%; 23/24 cases, 96%). All 40 conventional PCa (125 cores) were negative for p40 and p63 in the tumor cells. In summary, p40 is expressed in most p63-positive PCas but negative in p63-negative conventional PCas. From a diagnostic perspective, the use of immunohistochemistry for DeltaNp63/p40 provides only a small advantage over the more widely used p63 assays. Our 1 DeltaNp63-negative p63-positive case may represent expression of the TAp63 isoform in the tumor. PMID- 25548109 TI - The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress. AB - BACKGROUND: Evidence suggests that mammalian target of rapamycin activation mediates ketamine's rapid but transient antidepressant effects and that glycogen synthase kinase-3beta inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects. METHODS: Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated. RESULTS: Subtherapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by postketamine treatment with 1200 mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium. CONCLUSIONS: Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine. PMID- 25548111 TI - Medium-term outcomes following limb salvage for severe open tibia fracture are similar to trans-tibial amputation. AB - Extremity injuries define the surgical burden of recent conflicts. Current literature is inconclusive when assessing the merits of limb salvage over amputation. The aim of this study was to determine medium term functional outcomes in military casualties undergoing limb salvage for severe open tibia fractures, and compare them to equivalent outcomes for unilateral trans-tibial amputees. Cases of severe open diaphyseal tibia fractures sustained in combat between 2006 and 2010, as described in a previously published series, were contacted. Consenting individuals conducted a brief telephone interview and were asked to complete a SF-36 questionnaire. These results were compared to a similar cohort of 18 military patients who sustained a unilateral trans-tibial amputation between 2004 and 2010. Forty-nine patients with 57 severe open tibia fractures met the inclusion criteria. Telephone follow-up and SF-36 questionnaire data was available for 30 patients (61%). The median follow-up was 4 years (49 months, IQR 39-63). Ten of the 30 patients required revision surgery, three of which involved conversion from initial fixation to a circular frame for non- or mal-union. Twenty-two of the 30 patients (73%) recovered sufficiently to complete an age standardised basic military fitness test. The median physical component score of SF-36 in the limb salvage group was 46 (IQR 35-54) which was similar to the trans tibial amputation cohort (p=0.3057, Mann-Whitney). Similarly there was no difference in mental component scores between the limb salvage and amputation groups (p=0.1595, Mann-Whitney). There was no significant difference in the proportion of patients in either the amputation or limb salvage group reporting pain (p=0.1157, Fisher's exact test) or with respect to SF-36 physical pain scores (p=0.5258, Mann-Whitney). This study demonstrates that medium term outcomes for military patients are similar following trans-tibial amputation or limb salvage following combat trauma. PMID- 25548112 TI - Impact of combat events on first responders: experiences of the armed conflict in Uruzgan, Afghanistan. AB - INTRODUCTION: Care for battle casualties demands special skills from medics, nurses, and tactical commanders. To date, no inventory has been performed evaluating the first responders (medics, nurses and tactical commanders) around battle casualties. METHOD: This observational cohort study was conducted amongst the first responders (n=195) who were deployed to Southern Afghanistan (2009 2010) in three Marine companies. The survey focused on four main topics: (1) participants general background, (2) exposure to combat (casualty) situations, (3) self-perceived quality of care (1 [low]-10 [high]) in the pre-hospital phase, and (4) the effects of combat stressors on professional skills and social environment using the Post Deployment Reintegration Scale (PDRS) and the Impact of Event Scale-Revised (IES-R). RESULTS: 71% of the eligible Dutch tactical commanders, medics, and nurses participated in this survey. Most (14/16) medics and nurses scored their pre-deployment training as sufficient The overall self perceived quality of care score was above average (7.8). Most (80%) of the participants were exposed to battle casualties. There were no significant differences regarding rank, gender, age and military task using the impact of event scale and PDRS, except for a worse score on the work negative, family positive and personal positive subscales (p<0.05) in the PDRS for the first responders in comparison to the armed forces norm score. CONCLUSION: The quality of care in the pre-hospital phase was considered adequate, symptoms of post traumatic stress in this group was low. Active involvement of co-combatants and the social support network are essential in adaption after exposure to combat events. Further research is necessary to identity predisposing preventable high stress factors, and to compose a "waterproof" aftercare programme. PMID- 25548114 TI - Managing AVN following internal fixation: treatment options and clinical results. AB - Avascular necrosis (AVN) after internal fixation of intracapsular hip fractures is a progressive multifactorial disease that ultimately results in local ischemia with ensuing osteocyte necrosis and structural compromise. This disease can cause significant clinical morbidity and affects patients of any age, including young and active patients. Effective treatment of this condition among young adults is challenging due to their high functional demands. The aim of managing AVN is to relieve pain, preserve range of movement and improve function. Treatment methods vary depending on the stage of the disease and can be broadly categorised into two options, hip preserving surgery and hip arthroplasty. Although, hip preserving techniques are attractive in the young adult, they may alter the morphology of the proximal femur and make subsequent arthroplasty more challenging. Conversely, arthroplasty in the young adult may require repeat revision procedures throughout the patient's life. Current evidence suggests that modifications of prevailing treatments, in addition to new technologies, have led to the development of management strategies that may be able to alter the course of femoral head osteonecrosis. This review aims to summarise the options available for treatment of AVN in the young adult and review the clinical results. PMID- 25548113 TI - The effect of becoming a major trauma centre on outcomes for elderly hip fracture patients. AB - Twenty-two major trauma centres (MTCs) became operational across England on 1st April 2012. The aim of this study was to ascertain whether becoming an MTC has affected outcomes for elderly hip fracture patients at our institution. Eight hundred and twenty-four patients aged >=60 years who sustained 841 consecutive hip fractures over a two-year period were included. There were 381 fractures during the year prior to (pre-MTC group), and 460 fractures during the year after (post-MTC group) becoming an MTC. Outcomes analysed were time to theatre, length of acute hospital stay, post-operative complications, and mortality at 30, 120 and 365 days. No statistically significant difference was found in median length of stay between the two groups (13 days vs 14 days, p=0.2888). In the post-MTC group there was a significant increase in median delay to theatre for medically fit patients (25.5h vs 31.5h, p<0.0001), and there was a significant increase in post-operative medical complications (29.7% vs 37.6%, p=0.0160). There was no statistically significant difference in overall mortality rates, however 30-day mortality rose from 4.7% to 8.0% (p=0.0678). These results suggest that becoming an MTC has led to a significant increase in the delay to surgical management of our hip fracture patients with consequent increases in morbidity and mortality. PMID- 25548115 TI - Combined lateral femoral epicondylar osteotomy and a submeniscal approach for the treatment of a tibial plateau fracture involving the posterolateral quadrant. AB - Exposure of a tibial plateau fracture involving the posterolateral quadrant is challenging, and several approaches for treating these fractures have been introduced. However, these approaches may have limited applicability, and they can potentially cause neurovascular, musculotendinous, or ligamentous injury of the posterolateral corner. Lateral femoral epicondylar osteotomy has been used for meniscal transplantation, total knee arthroplasty, and the treatment of posterolateral articular disorders of the femur and tibia. We encountered a case of a tibial plateau fracture involving the posterolateral quadrant without an anterior-extending fracture line. We successfully exposed, reduced, and fixed the fracture using combined lateral femoral epicondylar osteotomy and a submeniscal approach. This combined modality can be used as an alternative surgical technique for the treatment of tibial plateau fractures involving the posterolateral quadrant. PMID- 25548116 TI - Vertigo in childhood: a retrospective series of 100 children. AB - OBJECTIVE: Evaluation and management of vertigo in children vary between institutions and medical specialties. The aim of this study is to describe the characteristics of vertigo in children presenting to a pediatric neurology referral center and to investigate the relationship between vertigo and migraine. STUDY DESIGN: Patients <18 years old presenting with vertigo to Hacettepe University Ihsan Dogramaci Children's Hospital Neurology Unit between January 1996-January 2012 were included (n = 100). Data were obtained from patient files and phone interviews. RESULTS: Mean age was 7.5 years. The most common etiological groups were benign paroxysmal vertigo of childhood (BPVC) (39%), psychogenic vertigo (21%), epileptic vertigo (15%), and migraine-associated vertigo (MAV) (11%). BPVC was the most common diagnosis in children <=5 years of age while psychogenic vertigo prevailed in children >5 years. Staring episodes characterized epileptic vertigo patients (p = 0.021) while headache was more often described by MAV patients (p < 0.001). Vertigo attacks >5 min were uncommon in BPVC patients compared to others (p = 0.013). Twenty percent of BPVC patients contacted through phone interviews were experiencing migraine type headaches that started at a median age of 7.5 years. An algorithm for evaluation of children with vertigo was formed based on data obtained from this study and the literature. When this algorithm was applied to 100 cases of this series, 88 (88%) were correctly diagnosed. CONCLUSION: While most vertigo cases in children can be diagnosed accurately by a detailed medical history, physical and neurological examination, a standard algorithm can help with the correct classification. PMID- 25548117 TI - Proteomics analysis for enhanced lipid accumulation in oleaginous Chlorella vulgaris under a heterotrophic-Na+ induction two-step regime. AB - A heterotrophic-Na(+) induction (HNI) two-step regime was developed to enhance lipid accumulation in oleaginous Chlorella vulgaris. C. vulgaris was cultivated heterotrophically to a biomass of 7.8 g l(-1) in 120 h. The cells were re suspended in fresh media supplemented with 0.5 M NaCl followed by 12 h growth to accumulate lipid to 53.4 % (w/w). The lipid productivity (625 mg l(-1) day(-1)) achieved with HNI was better than that using heterotrophy alone (405 mg l(-1) day(-1)). To promote possible applications of HNI strategy in other microalgal species, the lipid triggers and potential molecular pathways associated with lipid biosynthesis were investigated. Malic enzyme and acyl-CoA-binding protein were key metabolic checkpoints found to modulate lipid biosynthesis in cells. These results provide the foundation to develop high-lipid engineering miroalgae for industrialization of biodiesel. PMID- 25548118 TI - Deletion of D-ribulose-5-phosphate 3-epimerase (RPE1) induces simultaneous utilization of xylose and glucose in xylose-utilizing Saccharomyces cerevisiae. AB - Simultaneous co-utilization of xylose and glucose is a key issue in engineering microbes for cellulosic ethanol production. We coupled xylose utilization with glucose metabolism by deletion of D-ribulose-5-phosphate 3-epimerase (RPE1) through pentose phosphate pathway flux. Simultaneous utilization of xylose and glucose then occurred in the engineered Saccharomyces cerevisiae strain with the xylose utilization pathway. Xylose consumption occurred at the beginning of glucose consumption by the engineered yeast without RPE1 in a mixed sugar fermentation. About 3.2 g xylose l(-1) was utilized simultaneously with consumption of 40.2 g glucose l(-1) under O2-limited conditions. In addition, an approximate ratio (~1:10) for xylose and glucose consumption was observed in the fermentation with different sugar concentration by the engineered strain without RPE1. Simultaneous utilization of xylose is realized by the coupling of glucose metabolism and xylose utilization through RPE1 deletion in xylose-utilizing S. cerevisiae. PMID- 25548119 TI - Sex differences in whole body gait kinematics at preferred speeds. AB - Studies on human perception have identified pelvis and torso motion as key discriminators between male and female gaits. However, while most observers would advocate that men and women walk differently, consistent findings and explanations of sex differences in gait kinematics across modern empirical studies are rare. In the present study we evaluated sex differences in whole body gait kinematics from a large sample of subjects (55 men, 36 women) walking at self selected speeds. We analyzed the data through comparisons of discrete metrics and whole curve analyses. Results showed that in the frontal plane, women walked with greater pelvic obliquity than men, but exhibited a more stable torso and head. Women had greater transverse plane pelvis and torso rotation as well as greater arm swing. Additional sex differences were noted at the hip and ankle. These kinematic results are in line with anectdotal observations and qualitative studies. In order to understand these observations and substantiate some of the explanations previously set forth in the biomechanics literature, we also explored possible reasons for dynamic sex effects, and suggested applications that may benefit from their consideration. PMID- 25548120 TI - Serious complications associated with regadenoson administration for myocardial perfusion imaging. PMID- 25548121 TI - Clinical topic: Nuclear imaging in hypertrophic cardiomyopathy. AB - Non-invasive cardiac imaging plays a central role in the diagnosis and management of patients with hypertrophic cardiomyopathy. Transthoracic echocardiography is the imaging technique of first choice to evaluate wall thickness, left ventricular systolic and diastolic function, presence of left ventricular outflow tract obstruction, and abnormal mitral anatomy, whereas cardiac magnetic resonance provides additional information on tissue characterization (replacement fibrosis) using late gadolinium enhancement. Nuclear imaging techniques permit also the assessment of left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy but are more frequently used to evaluate myocardial ischemia (particularly assessment of microvascular dysfunction using positron emission tomography) and abnormal sympathetic myocardial innervation. This review article provides an overview of the use of nuclear imaging techniques to refine the phenotyping and risk stratification of patients with hypertrophic cardiomyopathy with particular focus on prediction of progression to overt heart failure, detection of myocardial ischemia, and evaluation of the arrhythmogenic substrate and risk of sudden cardiac death. PMID- 25548122 TI - Matrix-induced autologous mesenchymal stem cell implantation versus matrix induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. AB - BACKGROUND: Cell-based strategies that combine in vitro- expanded autologous chondrocytes with matrix scaffolds are currently preferred for full-thickness cartilage lesions of the knee >=2 cm(2). Although this approach is reasonable, continuing advances in the field of cartilage repair will further expand the options available to improve outcomes. HYPOTHESIS/PURPOSE: In the present clinical study, we compared the outcomes of matrix-induced autologous mesenchymal stem cell implantation (m-AMI) with matrix-induced autologous chondrocyte implantation (m-ACI) for the treatment of isolated chondral defects of the knee. STUDY DESIGN: Prospective, single-site, randomized, single-blind pilot study. METHODS: Fourteen patients with isolated full-thickness chondral lesions of the knee >2 cm(2) were randomized into two treatment groups: m-AMI and m-ACI. Outcomes were assessed pre-operatively and 3, 6, 12 and 24 months post operatively. RESULTS: Clinical evaluations revealed that improvement from pre operation to 24 months post-operation occurred in both groups (p < 0.05). At all follow-up intervals, m-AMI demonstrated significantly better functional outcomes (motion deficit and straight leg raise strength) than did m-ACI (p < 0.05). At all follow-up intervals, m-AMI demonstrated significantly better subjective sub scale scores for pain, symptoms, activities of daily living and sport and recreation of the knee injury and osteoarthritis outcome score (KOOS) than did m ACI (p < 0.05). Additionally, m-AMI demonstrated significantly better (p < 0.05) scores than m-ACI for the quality of life sub-scale of the KOOS and visual analog scale (VAS) severity at the 6-month follow-up. The Tegner activity score and VAS frequency were not significantly different between the two groups. Graft failure was not observed on magnetic resonance imaging at the 24-month follow-up. m-AMI and m-ACI demonstrated very good-to-excellent and good-to-very good infill, respectively, with no adverse effects from the implant, regardless of the treatment. CONCLUSION: For the treatment of isolated full-thickness chondral lesion of the knee, m-AMI can be used effectively and may potentially accelerate recovery. A larger patient cohort and follow-up supported by histological analyses are necessary to determine long-term outcomes. PMID- 25548123 TI - Rapid evaluation of N-glycosylation status of antibodies with chemiluminescent lectin-binding assay. AB - We constructed an assay system for the rapid detection of the glycosylation status of antibodies with a chemiluminescence-based lectin-binding assay, and investigated the glycosylation dynamics during the culture of recombinant Chinese hamster ovary cells. This rapid detection system is applicable to the high throughput evaluation of therapeutic glycoproteins. PMID- 25548124 TI - The effect of nurse-led problem-solving therapy on coping, self-efficacy and depressive symptoms for patients with chronic obstructive pulmonary disease: a randomised controlled trial. AB - OBJECTIVE: to examine the effects of nurse-led, problem-solving therapy (PST) on coping, self-efficacy and depressive symptoms for patients with chronic obstructive pulmonary disease (COPD) using a randomised controlled trial. SUBJECTS: a total of 254 patients with COPD were recruited, screened and randomly allocated into the intervention group with nurse-led PST or the comparison group with usual care. A total of 151 patients (intervention = 78 and comparison = 73) completed the study for 6 months. METHODS: the nurse-led PST was an individualised and patient-centred intervention to improve patients' problem solving skills related to symptom management and lifestyle modification. Twelve telephone-based PST sessions were provided to the intervention group, while the control group received usual care from their primary care providers. RESULTS: there were no group differences of post-test scores in problem-oriented coping, self-efficacy and depressive symptoms between the two groups. However, despite the lack of group differences, the nurse-led PST was effective for clinically depressed patients with COPD, who experienced decreased depressive symptoms (mean difference = 6.8, P = 0.009) and increased self-efficacy (mean difference = -0.6, P = 0.041) in the intervention group (n = 12). CONCLUSION: the nurse-led PST offered to patients with COPD did not demonstrate any different effects compared with usual care over 6 months; however, a subgroup analysis with clinically depressed subjects showed improved self-efficacy and decreased depressive symptoms in the intervention group. PMID- 25548125 TI - Reply to comments by Li et al.: "Do the specialist hip unit surgeons have no significant influence on reducing rates of surgical site infection?". PMID- 25548126 TI - Obesity is no longer a risk factor for dislocation after total hip arthroplasty with a double-mobility cup. AB - PURPOSE: Dislocation is one of the most feared complications after total hip arthroplasty (THA). This risk is greater in obese patients compared with the general population. METHODS: We performed a retrospective cohort study in which the main objective was to compare the dislocation rate between obese patients (BMI > 30 kg/m2) (exposed group) and non-obese patients (BMI <= 30 kg/m2) (unexposed group) after primary THA with a double-mobility acetabular cup. The patients had a minimum follow-up of 24 months. RESULTS: The 'obese' group consisted of 77 THA cases and the 'non-obese' group of 425 cases; the two groups were similar in terms of age, gender and ASA score. After a mean follow-up of 58.3 +/- 27 months (range 27-159), 43 patients had been lost to follow-up and 56 had died; the two groups had similar mean values. One patient in the 'obese' group had suffered a dislocation due to a fall 16 months after the THA. One patient in the 'non-obese' group had suffered a dislocation after a periprosthetic femur fracture with stem subsidence two months after the THA procedure. Both patients underwent surgical revision where the double-mobility cup was preserved; there were no further dislocation events as of the last follow up. The dislocation rate in the two groups was similar (1.3 % versus 0.23%, p > 0.05). No cases of loosening were found. Revisions were secondary to deep or superficial infection (n = 22), periprosthetic femur fracture (n = 10) or haematoma (n = 3). CONCLUSION: These findings imply that double-mobility cups are a reliable way of reducing the risk of dislocation in obese patients after primary THA. PMID- 25548127 TI - Consensus for physiotherapy for shoulder pain. AB - PURPOSE: Shoulder pain is a common disorder. Despite growing evidence of the importance of physiotherapy, in particular active exercise therapy, little data is available to guide treatment. The aim of this project was to contribute to the development of an internationally accepted assessment and treatment algorithm for patients with shoulder pain. METHODS: Nine physiotherapists with expertise in the treatment of shoulder dysfunction met in Sweden 2012 to begin the process of developing a treatment algorithm. A questionnaire was completed prior to the meeting to guide discussions. Virtual conferences were thereafter the platform to reach consensus. RESULTS: Consensus was achieved on a clinical reasoning algorithm to guide the assessment and treatment for patients presenting with local shoulder pain, without significant passive range of motion deficits and no symptoms or signs of instability. The algorithm emphasises that physiotherapy treatment decisions should be based on physical assessment findings and not structural pathology, that active exercises should be the primary treatment approach, and that regular re-assessment is performed to ensure that all clinical features contributing to the presenting shoulder pain are addressed. Consensus was also achieved on a set of guiding principles for implementing exercise therapy for shoulder pain, namely, a limited number of exercises, performed with appropriate scapulo-humeral coordination and humeral head alignment, in a graduated manner without provoking the presenting shoulder pain. CONCLUSION: The assessment and treatment algorithm presented could contribute to a more formal, extensive process aimed at achieving international agreement on an algorithm to guide physiotherapy treatment for shoulder pain. PMID- 25548128 TI - Reverse shoulder arthroplasty in acute fractures provides better results than in revision procedures for fracture sequelae. AB - PURPOSE: The purpose of this study was to evaluate functional outcomes of reverse shoulder arthroplasty (RSA) in patients with acute fracture and sequelae of the proximal humeral fractures. METHODS: Thirty-seven patients were treated with RSA for acute fracture and sequelae of a proximal humeral fracture. The average age was 73 years (range 50-87 years). Twenty-one patients had had no previous surgery, seven patients had acute fractures and 14 patients had chronic fractures. Sixteen patients had had previous surgery. Active range of motion and Constant score were evaluated at a minimum follow-up of two years. RESULTS: Active elevation was 102 degrees , external rotation 24 degrees , and internal rotation was up to L4 in all patients. In the group of patients without previous surgery treated with RSA, elevation was 116 degrees , external rotation 24 degrees , and internal rotation up to L3. In the group of patients with previous surgery treated with RSA, elevation was 84 degrees , external rotation 19 degrees , and internal rotation up to L4. In the group of patients with acute fracture treated with RSA, elevation was 124 degrees , external rotation 28 degrees , and internal rotation up to L4. In the group of patients with chronic or sequel of the fractures treated with RSA elevation was 114 degrees , external rotation 28 degrees , and internal rotation up to L3. Constant score in all patients was 54. Constant score in patients without previous surgery treated with RSA was 68 and with previous surgery it was 42. CONCLUSION: Patients without previous surgery treated with RSA for fractures had better functional results than patients who had undergone previous surgery. PMID- 25548129 TI - Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy. AB - PURPOSE: Cells deficient in argininosuccinate synthetase (ASS) must absorb the arginine they need for growth from circulating blood. Treatment with pegylated arginine deiminase (ADI-PEG 20) selectively eliminates arginine from the circulation and has shown some efficacy against ASS-deficient tumors including small cell lung cancer (SCLC). We sought to assess ASS expression in a cohort of high-grade pulmonary neuroendocrine carcinomas (PNEC) which include SCLC and large cell neuroendocrine carcinoma (LCNEC). METHODS: Sixty-nine PNEC (49 SCLC and 20 LCNEC) were retrieved from our pathology archives. Formalin-fixed paraffin embedded sections of the 54 primary tumors, 15 metastases and appropriate positive and negative controls were immunostained using an ASS-specific monoclonal antibody. Positive staining in <30 % of the tumor was scored as weak; staining in >=30 % of the tumor was scored as strong. The absence of staining in the tumor was recorded as ASS negative. RESULTS: 58 % of the PNEC including 61.2 % of the SCLC and 50 % of the LCNEC were ASS negative. These ASS-negative tumors included 63 % of the primary and 40 % of the metastatic lesions tested. CONCLUSIONS: More than 50 % of the high-grade PNEC tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. PNEC comprise about 25 % of primary lung cancers and have a 5-year overall survival of only 5 10 %, underscoring the need for new and more effective therapies. Immunostaining for ASS has potential to improve the selection of patients with PNEC for arginine deprivation therapy with ADI-PEG 20. PMID- 25548130 TI - Regorafenib: start low and go slow. PMID- 25548131 TI - Repeated lung volume reduction surgery is successful in selected patients. AB - OBJECTIVES: Lung volume reduction surgery (LVRS) improves dyspnoea, quality of life and may even prolong survival in carefully selected patients with end-stage emphysema. The benefit may be sustained for several years and vanishes with the natural progression of the disease. Data on repeated surgical treatment of emphysema are scarce. The aim of this study was to evaluate the safety, effects and outcomes of repeated LVRS (Re-LVRS) in patients no longer benefiting from their initial LVRS. METHODS: Between June 2002 and December 2013, 22 patients (9 females) with advanced emphysema underwent Re-LVRS at a median of 60 months (25 196) after their initial LVRS. While initial LVRS was performed thoracoscopically as a bilateral procedure, Re-LVRS was performed unilaterally by a video-assisted thoracoscopic technique in 19 patients and, due to adhesions, by thoracotomy in 3 patients. Pulmonary function test (PFT) was performed at 3 and 12 months postoperatively. RESULTS: Lung function at Re-LVRS was similar to that prior to the first LVRS. The 90-day mortality rate was 0%. The first patient died 15 months postoperatively. The median hospitalization time after Re-LVRS was significantly longer compared with the initial LVRS [14 days, interquartile range (IQR): 11-19, vs 9 days, IQR: 8-14; P = 0.017]. The most frequent complication was prolonged air leak with a median drainage time of 11 days (IQR: 6-13); reoperations due to persistent air leak were necessary in 7 patients (32%). Five patients (23%) had no complications. Lung function and Medical Research Council (MRC) score improved significantly for up to 12 months after Re-LVRS, with results similar to those after initial bilateral LVRS. The average increase in the forced expiratory volume in 1 s (FEV1) was 25% (a 7% increase over the predicted value or 0.18 l) at 3 months, and the mean reduction in hyperinflation, assessed by relative decrease in RV/TLC (residual volume/total lung capacity), was 12% at 3 months (a decrease of 8% in absolute ratios). The mean MRC breathlessness score decreased significantly after 3 months (from 3.7 to 2.2). CONCLUSIONS: Re-LVRS can be performed successfully in carefully selected patients as a palliative treatment. It may be performed as a bridge to transplantation or in patients with newly diagnosed intrapulmonary nodules or during elective cardiac surgery. Morbidity is acceptable and outcomes may be satisfactory with significantly improved lung function and reduced dyspnoea for at least 12 months postoperatively. PMID- 25548132 TI - Inflammation-based scoring is a useful prognostic predictor of pulmonary resection for elderly patients with clinical stage I non-small-cell lung cancer. AB - OBJECTIVES: The number of elderly lung cancer patients requiring surgery has been increasing due to the ageing society and less invasive perioperative procedures. Elderly people usually have various comorbidities, but there are few simple and objective tools that can be used to determine prognostic factors for elderly patients with clinical stage I non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the prognostic factors of surgically treated, over 80-year old patients with clinical stage I NSCLC. METHODS: The preoperative data of 97 over 80-year old patients with clinical stage I NSCLC were collected at Nagasaki University Hospital from 1990 to 2012. As prognostic factors, inflammation-based scoring systems, including the Glasgow Prognostic Score (GPS) determined by serum levels of C-reactive protein and albumin, the neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) were evaluated, as well as other clinicopathological factors, including performance status, body mass index, carcinoembryonic antigen, Charlson comorbidity index and type of surgical procedure. RESULTS: The median age was 82 (range, 80-93) years. There were 62 (64.0%) clinical stage IA cases and 35 IB cases. Operations included 64 (66.0%) lobectomies, 15 segmentectomies and 18 wedge resections. The pathological stage was I in 76 (78.4%) patients, II in 12 (12.4%), III in 8 (8.2%) and IV in 1 (1.0%). Twelve (12.4%) patients underwent mediastinal lymph node dissection. Overall survival and disease-specific 5-year survival rates were 55.5 and 70.0%, respectively. The average GPS score was 0.4 (0-2). Disease specific 5-year survival was significantly longer with GPS 0 than with GPS 1-2. (74.2%, 53.7%, respectively, P = 0.03). Overall 5-year survival was significantly longer with GPS 0 than with GPS 1-2. (59.7%, 43.1%, respectively, P = 0.005). Both the NLR (median value = 1.9) and the PLR (median value = 117) were not correlated with disease-specific and overall 5-year survival. On multivariate analysis, pathological stage I (P = 0.01) and GPS 0 (P = 0.04, hazard ratio: 2.13, 95% confidence interval 1.036-4.393) were significant prognostic factors. CONCLUSIONS: The preoperative GPS appears to be a useful predictor of overall survival and could be a simple prognostic tool for elderly patients with clinical stage I NSCLC. PMID- 25548133 TI - Variability and sources of surface ozone at rural sites in Nevada, USA: Results from two years of the Nevada Rural Ozone Initiative. AB - Ozone (O3) has been measured at Great Basin National Park (GBNP) since September 1993. GBNP is located in a remote, rural area of eastern Nevada. Data indicate that GBNP will not comply with a more stringent National Ambient Air Quality Standard (NAAQS) for O3, which is based upon the 3-year average of the annual 4th highest Maximum Daily 8-h Average (MDA8) concentration. Trend analyses for GBNP data collected from 1993 to 2013 indicate that MDA8 O3 increased significantly for November to February, and May. The greatest increase was for May at 0.38, 0.35, and 0.46 ppb yr(-1) for the 95th, 50th, and 5th percentiles of MDA8 O3 values, respectively. With the exception of GBNP, continuous O3 monitoring in Nevada has been limited to the greater metropolitan areas. Due to the limited spatial detail of O3 measurements in rural Nevada, a network of rural monitoring sites was established beginning in July 2011. For a period ranging from July 2011 to June 2013, maximum MDA8 O3 at 6 sites occurred in the spring and summer, and ranged from 68 to 80ppb. Our analyses indicate that GBNP, in particular, is ideally positioned to intercept air containing elevated O3 derived from regional and global sources. For the 2 year period considered here, MDA8 O3 at GBNP was an average of 3.1 to 12.6 ppb higher than at other rural Nevada sites. Measured MDA8 O3 at GBNP exceeded the current regulatory threshold of 75 ppb on 7 occasions. Analyses of synoptic conditions, model tracers, and air mass back-trajectories on these days indicate that stratospheric intrusions, interstate pollution transport, wildfires, and Asian pollution contributed to elevated O3 observed at GBNP. We suggest that regional and global sources of ozone may pose challenges to achieving a more stringent O3 NAAQS in rural Nevada. PMID- 25548134 TI - Of ELIC and evolution. PMID- 25548135 TI - Mechanism of activation of the prokaryotic channel ELIC by propylamine: a single channel study. AB - Prokaryotic channels, such as Erwinia chrysanthemi ligand-gated ion channel (ELIC) and Gloeobacter violaceus ligand-gated ion channel, give key structural information for the pentameric ligand-gated ion channel family, which includes nicotinic acetylcholine receptors. ELIC, a cationic channel from E. chrysanthemi, is particularly suitable for single-channel recording because of its high conductance. Here, we report on the kinetic properties of ELIC channels expressed in human embryonic kidney 293 cells. Single-channel currents elicited by the full agonist propylamine (0.5-50 mM) in outside-out patches at -60 mV were analyzed by direct maximum likelihood fitting of kinetic schemes to the idealized data. Several mechanisms were tested, and their adequacy was judged by comparing the predictions of the best fit obtained with the observable features of the experimental data. These included open-/shut-time distributions and the time course of macroscopic propylamine-activated currents elicited by fast theta-tube applications (50-600 ms, 1-50 mM, -100 mV). Related eukaryotic channels, such as glycine and nicotinic receptors, when fully liganded open with high efficacy to a single open state, reached via a preopening intermediate. The simplest adequate description of their activation, the "Flip" model, assumes a concerted transition to a single intermediate state at high agonist concentration. In contrast, ELIC open-time distributions at saturating propylamine showed multiple components. Thus, more than one open state must be accessible to the fully liganded channel. The "Primed" model allows opening from multiple fully liganded intermediates. The best fits of this type of model showed that ELIC maximum open probability (99%) is reached when at least two and probably three molecules of agonist have bound to the channel. The overall efficacy with which the fully liganded channel opens was ~ 102 (~ 20 for alpha1beta glycine channels). The microscopic affinity for the agonist increased as the channel activated, from 7 mM for the resting state to 0.15 mM for the partially activated intermediate state. PMID- 25548137 TI - Does calmodulin regulate the bicarbonate permeability of ANO1/TMEM16A or not? PMID- 25548136 TI - Hydrophobic interaction between contiguous residues in the S6 transmembrane segment acts as a stimuli integration node in the BK channel. AB - Large-conductance Ca(2+)- and voltage-activated K(+) channel (BK) open probability is enhanced by depolarization, increasing Ca(2+) concentration, or both. These stimuli activate modular voltage and Ca(2+) sensors that are allosterically coupled to channel gating. Here, we report a point mutation of a phenylalanine (F380A) in the S6 transmembrane helix that, in the absence of internal Ca(2+), profoundly hinders channel opening while showing only minor effects on the voltage sensor active-resting equilibrium. Interpretation of these results using an allosteric model suggests that the F380A mutation greatly increases the free energy difference between open and closed states and uncouples Ca(2+) binding from voltage sensor activation and voltage sensor activation from channel opening. However, the presence of a bulky and more hydrophobic amino acid in the F380 position (F380W) increases the intrinsic open-closed equilibrium, weakening the coupling between both sensors with the pore domain. Based on these functional experiments and molecular dynamics simulations, we propose that F380 interacts with another S6 hydrophobic residue (L377) in contiguous subunits. This pair forms a hydrophobic ring important in determining the open-closed equilibrium and, like an integration node, participates in the communication between sensors and between the sensors and pore. Moreover, because of its effects on open probabilities, the F380A mutant can be used for detailed voltage sensor experiments in the presence of permeant cations. PMID- 25548138 TI - Purified human brain calmodulin does not alter the bicarbonate permeability of the ANO1/TMEM16A channel. PMID- 25548139 TI - iScreen: Image-Based High-Content RNAi Screening Analysis Tools. AB - High-throughput RNA interference (RNAi) screening has opened up a path to investigating functional genomics in a genome-wide pattern. However, such studies are often restricted to assays that have a single readout format. Recently, advanced image technologies have been coupled with high-throughput RNAi screening to develop high-content screening, in which one or more cell image(s), instead of a single readout, were generated from each well. This image-based high-content screening technology has led to genome-wide functional annotation in a wider spectrum of biological research studies, as well as in drug and target discovery, so that complex cellular phenotypes can be measured in a multiparametric format. Despite these advances, data analysis and visualization tools are still largely lacking for these types of experiments. Therefore, we developed iScreen (image Based High-content RNAi Screening Analysis Tool), an R package for the statistical modeling and visualization of image-based high-content RNAi screening. Two case studies were used to demonstrate the capability and efficiency of the iScreen package. iScreen is available for download on CRAN (http://cran.cnr.berkeley.edu/web/packages/iScreen/index.html). The user manual is also available as a supplementary document. PMID- 25548140 TI - A fully automated primary screening system for the discovery of therapeutic antibodies directly from B cells. AB - For a therapeutic antibody to succeed, it must meet a range of potency, stability, and specificity criteria. Many of these characteristics are conferred by the amino acid sequence of the heavy and light chain variable regions and, for this reason, can be screened for during antibody selection. However, it is important to consider that antibodies satisfying all these criteria may be of low frequency in an immunized animal; for this reason, it is essential to have a mechanism that allows for efficient sampling of the immune repertoire. UCB's core antibody discovery platform combines high-throughput B cell culture screening and the identification and isolation of single, antigen-specific IgG-secreting B cells through a proprietary technique called the "fluorescent foci" method. Using state-of-the-art automation to facilitate primary screening, extremely efficient interrogation of the natural antibody repertoire is made possible; more than 1 billion immune B cells can now be screened to provide a useful starting point from which to identify the rare therapeutic antibody. This article will describe the design, construction, and commissioning of a bespoke automated screening platform and two examples of how it was used to screen for antibodies against two targets. PMID- 25548141 TI - Correlation of Central Blood Pressure to Hypertensive Target Organ Damages During Antihypertensive Treatment: The J-TOP Study. AB - BACKGROUND: Some previous studies have shown that central blood pressure (BP) is more closely related to cardiovascular risks than brachial BP. This study compared the correlations between asymptomatic organ damages and each of central BP, brachial clinic BP, and home BP during antihypertensive treatment. METHODS: In the Japan Morning Surge-Target Organ Protection (J-TOP) study, which compared bedtime or awakening dosing of candesartan (+diuretics as needed) among subjects with home systolic BP (SBP) higher than 135 mm Hg, we evaluated 180 hypertensive patients who successfully underwent pulse wave analysis by HEM-9000AI and measured their urinary albumin/creatinine ratio (UACR) and left ventricular mass index (LVMI) (n = 144) at baseline and after 6 months of treatment. RESULTS: During antihypertensive treatment, significant reductions were found in central SBP, UACR, and LVMI (all P < 0.001). Multiple regression analyses showed that the decrease in central SBP was associated with those of log-transformed UACR (beta = 0.24, P < 0.01) and LVMI (beta = 0.23, P = 0.04), independently of the decrease in both clinic and home SBP. The goodness-of-fit of the association between the reduction in SBP and the UACR (P < 0.01) or LVMI (P = 0.04) was improved by adding central SBP to the SBP measurement. CONCLUSION: These findings suggest that the change in central BP could be an important therapeutic target during antihypertensive treatment, in addition to peripheral clinic and home BP. PMID- 25548142 TI - A National Descriptive Portrait of Adolescent Relationship Abuse: Results From the National Survey on Teen Relationships and Intimate Violence. AB - This article reports results from the National Survey on Teen Relationships and Intimate Violence (STRiV) for 12- to 18-year-old youth (n = 1,804). STRiV provides the first nationally representative household survey focused on adolescent relationship abuse (ARA), covering perpetration and victimization. Among respondents (37%) reporting current- or past-year dating, 69% reported lifetime ARA victimization (63% lifetime ARA perpetration). Although psychological abuse was most common for these youth (more than 60%), the rates of sexual abuse (18%) and physical abuse victimization (18%), as well as 12% reporting perpetrating physical abuse and/or sexual abuse (12%) were substantial as well. Other than differences by age and gender, ARA rates were consistent by race/ethnicity, geographic region, urbanicity, and household characteristics, highlighting the importance of universal prevention programs. Compared with youth aged 15 to 18, those 12 to 14 years old reported lower rates of psychological and sexual ARA victimization. Similarly, we found lower ARA perpetration rates for those 12 to 14. We found no gender differences for ARA victimization but found that girls perpetrated more physical ARA than boys. Girls aged 15 to 18 reported perpetrating moderate threats/physical violence at more than twice the rate of younger girls and 3 times the rate compared with boys aged 15 to 18; girls aged 15 to 18 reported perpetrating more than 4 times the rate of serious psychological abuse than boys 15 to 18. Finally, these data document the significant positive correlation between ARA victimization and perpetration. Findings suggest that when working with youth in prevention services, interventions should not be designed for monolithic groups of "victims" or "perpetrators." PMID- 25548143 TI - Is the relationship between major depressive disorder and self-reported alcohol use disorder an artificial one? AB - AIMS: Many studies have suggested a close relationship between alcohol use disorder (AUD) and major depressive disorder (MDD). This study aimed to test whether the relationship between self-reported AUD and MDD was artificially strengthened by the diagnosis of MDD. This association was tested comparing relationships between alcohol use and AUD for depressive people and non depressive people. METHODS: As part of the Cohort Study on Substance Use Risk Factors, 4352 male Swiss alcohol users in their early twenties answered questions concerning their alcohol use, AUD and MDD at two time points. Generalized linear models for cross-sectional and longitudinal associations were calculated. RESULTS: For cross-sectional associations, depressive participants reported a higher number of AUD symptoms (beta = 0.743, P < 0.001) than non-depressive participants. Moreover, there was an interaction (beta = -0.204, P = 0.001): the relationship between alcohol use and AUD was weaker for depressive participants rather than non-depressive participants. For longitudinal associations, there were almost no significant relationships between MDD at baseline and AUD at follow-up, but the interaction was still significant (beta = -0.249, P < 0.001). CONCLUSION: MDD thus appeared to be a confounding variable in the relationship between alcohol use and AUD, and self-reported measures of AUD seemed to be overestimated by depressive people. This result brings into question the accuracy of self-reported measures of substance use disorders. Furthermore, it adds to the emerging debate about the usefulness of substance use disorder as a concept, when heavy substance use itself appears to be a sensitive and reliable indicator. PMID- 25548145 TI - Periodontal health during clear aligners treatment: a systematic review. AB - BACKGROUND: Clear aligner treatment (CAT) has been cited as a safe and comfortable orthodontic procedure for adult patients. However, the available evidence is scarce. OBJECTIVE: To perform a systematic review of the existing literature in order to assess periodontal health during CAT. SEARCH METHODS AND SELECTION CRITERIA: Pubmed, Pubmed Central, National Library of Medicine's Medline, Embase, Cochrane Central Register of Controlled Clinical trials, Web of Knowledge, Scopus, Google Scholar, and LILACS were searched from January 1945 to September 2014 to identify all peer-reviewed papers potentially relevant to the review. DATA COLLECTION AND ANALYSIS: After duplicate selection and extraction procedures, the risk of bias was assessed according to the Centre for Reviews and Dissemination criteria, and a 3-point grading system, as described by the Swedish Council on Technology Assessment in Health Care (SBU), was used to rate the methodological quality of the selected papers. A PICOS table was used for data extraction. RESULTS: Five relevant articles were selected from the 1247 identified articles. The level of evidence was moderate for all the studies. A significant improvement of the periodontal health indexes was revealed, in particular when CAT was compared to fixed appliances. No periodontal CAT adverse effects were observed in the selected studies. CONCLUSIONS: Periodontal health indexes were significantly improved during CAT. The results of this review should be interpreted with some caution because of the number, quality, and heterogeneity of the included studies. PMID- 25548144 TI - Debonding and adhesive remnant cleanup: an in vitro comparison of bond quality, adhesive remnant cleanup, and orthodontic acceptance of a flash-free product. AB - BACKGROUND/OBJECTIVES: A new flash-free adhesive promises to eliminate the need to clean up excess adhesive upon orthodontic bracket bonding. This study evaluated this new adhesive with regard to microleakage at the enamel-bracket interface, amount of adhesive remaining on the tooth after bracket debonding, time required for adhesive remnant cleanup, and clinical practitioners' preference in comparison to a conventional adhesive. MATERIALS/METHODS: A total of 184 bovine incisors were bonded with ceramic brackets using either the flash free adhesive (APC Flash-Free Adhesive Coated Appliance System, 3M Unitek [3M], Monrovia, California, USA) or a conventional adhesive (APCII Adhesive Coated Appliance System, 3M). Twenty-four of the teeth were scanned using microcomputed tomography to quantify microleakage into the adhesive layer. Twenty orthodontists debonded the brackets, removed the remaining adhesive, and then completed a survey regarding their preference for one of the two adhesives. The adhesive remnant was quantified and the time required for its removal recorded. Differences between the adhesives were tested for statistical significance. RESULTS: For both adhesives, the microleakage was minimal with no significant differences between the two adhesives. The adhesive remnant was significantly larger for the flash-free adhesive, whereas there was no significant difference in adhesive cleanup time. Fourteen out of the 20 orthodontists preferred the flash-free adhesive over the conventional adhesive. LIMITATIONS: In vitro testing cannot replicate the actual clinical situation during in vivo debonding. CONCLUSIONS: With regard to bond quality and adhesive remnant cleanup, the new flash-free adhesive performs just as well as the conventional adhesive, and, of the two products, is the one preferred by most orthodontists. PMID- 25548146 TI - Effects of cleft lip and palate on the development of permanent upper central incisors: a cone-beam computed tomography study. AB - OBJECTIVE: The aim of this study was to evaluate 1. the differences among the cleft sides of unilateral cleft lip and palate (UCLP) patients, non-cleft sides of the same UCLP patients and well matched control patients in the root development and position of permanent upper central incisors and 2. possible gender differences. MATERIALS AND METHODS: The study sample consisted of 40 patient (20 males and 20 females; mean age: 14.84+/-3.2 years) with non-syndromic UCLP patients, and 40 control patients (20 males and 20 females; mean age: 13.38+/-1.6 years). Cone-beam computed tomography (CBCT) images were taken off from all patients. All tomographs were obtained in supine position by using CBCT (NewTom 5G, QR, Verona, Italy). RESULTS: Significant smaller root volume of central incisor was observed on the cleft side than on the non-cleft side of UCLP patients (P < 0.05). No significant difference in the root development and position of the central incisors was found between the non-cleft side of the UCLP and the control group (P > 0.05). There were no statistically significant gender differences in any linear, angular, or volumetric measurements (P > 0.05). Only the root volume of the cleft side was smaller in females than in males (P < 0.05). CONCLUSIONS: In general, root volumes of central incisors on the cleft side were 12.15 per cent smaller than non-cleft side. Root development of the central incisor was much more influenced by the cleft in females than in males. PMID- 25548147 TI - Effect of adhesive resin flexibility on enamel fracture during metal bracket debonding: an ex vivo study. AB - OBJECTIVE: To test the null hypothesis that neither the flexural properties of orthodontic adhesive resins nor the enamel pre-treatment methods would affect metal bracket debonding behaviours, including enamel fracture. MATERIALS AND METHODS: A dimethacrylate-based resin (Transbond XT, TX) and two methyl methacrylate (MMA)-based resins (Super-Bond C&B, SB; an experimental light-cured resin, EXP) were tested. Flexural strength and flexural modulus for each resin were measured by a three-point-bending test. Metal brackets were bonded to human enamel pretreated with total-etch (TE) or self-etch adhesive using one of the three resins (a total of six groups, n = 15). After 24 hours of storage in water at 37 degrees C, a shear bond strength (SBS) test was performed using the wire loop method. After debonding, remaining resin on the enamel surfaces and occurrence of enamel fracture were assessed. Statistical significance was set at P < 0.05. RESULTS: The two MMA resins exhibited substantially lower flexural strength and modulus values than the TX resin. The mean SBS values of all groups (10.15-11.09MPa) were statistically equivalent to one another (P > 0.05), except for the TE-TX group (13.51MPa, P < 0.05). The two EXP groups showed less resin remnant. Only in the two TX groups were enamel fractures observed (three cases for each group). LIMITATIONS: The results were drawn only from ex vivo experiments. CONCLUSIONS: The hypothesis is rejected. This study suggests that a more flexible MMA resin is favourable for avoiding enamel fracture during metal bracket debonding. PMID- 25548148 TI - Risk factors associated with revision and contralateral anterior cruciate ligament reconstructions in the Kaiser Permanente ACLR registry. AB - BACKGROUND: Patients generally choose to undergo anterior cruciate ligament reconstruction (ACLR) to return to their active lifestyles. However, returning to their previous activity level may result in a retear of their reconstructed knee or an injury to their contralateral anterior cruciate ligament (CACL). PURPOSE: To determine the risk factors associated with revision ACLR and contralateral ACLR (CACLR), compare the survival of the reconstructed ACL with the CACL, and determine how the risk factors associated with revision ACLR compare with those for CACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective cohort study of prospectively collected data from the Kaiser Permanente ACLR registry between February 1, 2005, and September 30, 2012, was conducted. Primary ACLR cases without history of contralateral knee ACL injury were included. The study endpoints included revision ACLR and CACLR. Graft type (bone-patellar tendon-bone [BPTB] autograft, hamstring autograft, and allograft) was the main exposure of interest, and patient characteristics were evaluated as risk factors for revision ACLR and CACLR. Survival analyses were conducted. RESULTS: A total of 17,436 ACLRs were evaluated. The median age was 27.2 years (interquartile range, 18.7-37.7 years), and 64% were males. The 5-year survival for index ACLR was 95.1% (95% CI, 94.5%-95.6%), and for CACL it was 95.8% (95% CI, 95.2%-96.3%). Overall, the cohort had a mean of 2.4 +/- 1.7 years of follow up; 18.2% were lost to follow-up. There were fewer CACLRs per 100 years of observation (0.83) than there were revision ACLRs (1.05) during the study period (P < .001). There was a statistically significant difference in the density of revision ACLR and CACL in BPTB autografts (0.74 vs 1.06, respectively; P = .010), hamstring autografts (1.07 vs 0.81; P = .042), and allografts (1.26 vs 0.67; P < .001). The risk factors for revision ACLR and contralateral surgery were different (P < .05). After adjusting for covariates, factors associated with higher risk of revision ACLR were as follows: allografts, hamstring autografts, male sex, younger age, lower body mass index (BMI), and being white as opposed to black. Factors associated with higher risk of CACLR were as follows: younger age, female sex, and lower BMI. CONCLUSION: The 5-year revision-free and CACLR-free survival rate in this study was 95.1% and 95.8%, respectively. Allografts and hamstring autografts had a higher risk of revision ACLR surgery, and BPTB autografts had a higher risk of CACLR. Males were found to have a higher risk of revision ACLR, and females had a higher risk of CACLR. Increasing age and increasing BMI decreased the risk of both revision and CACLR. PMID- 25548149 TI - Hamstring Tendon Regeneration After Harvesting: A Systematic Review. AB - BACKGROUND: Hamstring tendons are often used as autografts for anterior cruciate ligament (ACL) reconstruction. However, no systematic review has been performed describing consequences such as hamstring tendon regeneration rate and determinants of hamstring tendon regeneration. PURPOSE: To summarize the current literature regarding hamstring tendon rate regeneration, the time course of regeneration, and determinants of hamstring regeneration. STUDY DESIGN: Systematic review. METHODS: A search was performed in the Embase, Medline (OvidSP), Web of Science, Cochrane, PubMed, and Google Scholar databases up to June 2014 to identify relevant articles. A study was eligible if it met the following inclusion criteria: tendons were harvested, regeneration at harvest site was assessed, population size was at least 10 human subjects, full-text article was available, and the study design was either a randomized controlled trial, prospective cohort study, retrospective cohort study, or case control study. A risk of bias assessment of the eligible articles was determined. Data describing hamstring tendon regeneration rates were pooled per time period. RESULTS: A total of 18 publications met the inclusion criteria. The mean regeneration rate for the semitendinosus and gracilis tendons was, in all cases, 70% or higher. More than 1 year after harvesting, 79% (median [IQR], 80 [75.5 90]) of the semitendinosus tendons and 72% (median [IQR], 80 [61-88.5]) of the gracilis tendons were regenerated. No significant differences in regeneration rate could be found considering patient sex, age, height, weight, or duration of immobilization. Results did not clearly show whether absence of regeneration disadvantages the subsequent hamstring function. Five studies measured the regeneration rate at different moments in time. CONCLUSION: Hamstring tendons regenerated in the majority of patients after ACL reconstruction. The majority of the hamstring tendon regeneration was found to occur between 1 month and 1 year after harvest. No significant determinants for hamstring tendon regeneration could be identified because of a lack of research. The function and strength of the regenerated hamstring remained unclear. PMID- 25548150 TI - Identification and characterization of Rvs162/Rvs167-3, a novel N-BAR heterodimer in the human fungal pathogen Candida albicans. AB - Membrane reshaping resides at the core of many important cellular processes, and among its mediators are the BAR (Bin, Amphiphysin, Rvs) domain-containing proteins. We have explored the diversity and function of the Rvs BAR proteins in Candida albicans and identified a novel family member, Rvs167-3 (orf19.1861). We show that Rvs167-3 specifically interacts with Rvs162 to form a stable BAR heterodimer able to bind liposomes in vitro. A second, distinct heterodimer is formed by the canonical BAR proteins Rvs161 and Rvs167. Purified Rvs161/Rvs167 complex also binds liposomes, indicating that C. albicans expresses two functional BAR heterodimers. We used live-cell imaging to localize green fluorescent protein (GFP)-tagged Rvs167-3 and Rvs167 and show that both proteins concentrate in small cortical spots. However, while Rvs167 strictly colocalizes with the endocytic marker protein Abp1, we do not observe any colocalization of Rvs167-3 with sites of endocytosis marked by Abp1. Furthermore, the rvs167 3Delta/Delta mutant is not defective in endocytosis and strains lacking Rvs167-3 or its partner Rvs162 do not display increased sensitivity to high salt concentrations or decreased cell wall integrity, phenotypes which have been observed for rvs167Delta/Delta and rvs161Delta/Delta strains and which are linked to endocytosis defects. Taken together, our results indicate different roles for the two BAR heterodimers in C. albicans: the canonical Rvs161/Rvs167 heterodimer functions in endocytosis, whereas the novel Rvs162/Rvs167-3 heterodimer seems not to be involved in this process. Nevertheless, despite their different roles, our phenotypic analysis revealed a genetic interaction between the two BAR heterodimers, suggesting that they may have related but distinct membrane associated functions. PMID- 25548151 TI - The selenocysteine tRNA gene in leishmania major is transcribed by both RNA polymerase II and RNA polymerase III. AB - Eukaryotic tRNAs, transcribed by RNA polymerase III (Pol III), contain boxes A and B as internal promoter elements. One exception is the selenocysteine (Sec) tRNA (tRNA-Sec), whose transcription is directed by an internal box B and three extragenic sequences in vertebrates. Here we report on the transcriptional analysis of the tRNA-Sec gene in the protozoan parasite Leishmania major. This organism has unusual mechanisms of gene expression, including Pol II polycistronic transcription and maturation of mRNAs by trans splicing, a process that attaches a 39-nucleotide miniexon to the 5' end of all the mRNAs. In L. major, tRNA-Sec is encoded by a single gene inserted into a Pol II polycistronic unit, in contrast to most tRNAs, which are clustered at the boundaries of polycistronic units. 5' rapid amplification of cDNA ends and reverse transcription-PCR experiments showed that some tRNA-Sec transcripts contain the miniexon at the 5' end and a poly(A) tail at the 3' end, indicating that the tRNA Sec gene is polycistronically transcribed by Pol II and processed by trans splicing and polyadenylation, as was recently reported for the tRNA-Sec genes in the related parasite Trypanosoma brucei. However, nuclear run-on assays with RNA polymerase inhibitors and with cells that were previously UV irradiated showed that the tRNA-Sec gene in L. major is also transcribed by Pol III. Thus, our results indicate that RNA polymerase specificity in Leishmania is not absolute in vivo, as has recently been found in other eukaryotes. PMID- 25548152 TI - Ancestral duplications and highly dynamic opsin gene evolution in percomorph fishes. AB - Single-gene and whole-genome duplications are important evolutionary mechanisms that contribute to biological diversification by launching new genetic raw material. For example, the evolution of animal vision is tightly linked to the expansion of the opsin gene family encoding light-absorbing visual pigments. In teleost fishes, the most species-rich vertebrate group, opsins are particularly diverse and key to the successful colonization of habitats ranging from the bioluminescence-biased but basically dark deep sea to clear mountain streams. In this study, we report a previously unnoticed duplication of the violet-blue short wavelength-sensitive 2 (SWS2) opsin, which coincides with the radiation of highly diverse percomorph fishes, permitting us to reinterpret the evolution of this gene family. The inspection of close to 100 fish genomes revealed that, triggered by frequent gene conversion between duplicates, the evolutionary history of SWS2 is rather complex and difficult to predict. Coincidentally, we also report potential cases of gene resurrection in vertebrate opsins, whereby pseudogenized genes were found to convert with their functional paralogs. We then identify multiple novel amino acid substitutions that are likely to have contributed to the adaptive differentiation between SWS2 copies. Finally, using the dusky dottyback Pseudochromis fuscus, we show that the newly discovered SWS2A duplicates can contribute to visual adaptation in two ways: by gaining sensitivities to different wavelengths of light and by being differentially expressed between ontogenetic stages. Thus, our study highlights the importance of comparative approaches in gaining a comprehensive view of the dynamics underlying gene family evolution and ultimately, animal diversification. PMID- 25548155 TI - Oxidation-driven surface dynamics on NiAl(100). AB - Atomic steps, a defect common to all crystal surfaces, can play an important role in many physical and chemical processes. However, attempts to predict surface dynamics under nonequilibrium conditions are usually frustrated by poor knowledge of the atomic processes of surface motion arising from mass transport from/to surface steps. Using low-energy electron microscopy that spatially and temporally resolves oxide film growth during the oxidation of NiAl(100) we demonstrate that surface steps are impermeable to oxide film growth. The advancement of the oxide occurs exclusively on the same terrace and requires the coordinated migration of surface steps. The resulting piling up of surface steps ahead of the oxide growth front progressively impedes the oxide growth. This process is reversed during oxide decomposition. The migration of the substrate steps is found to be a surface-step version of the well-known Hele-Shaw problem, governed by detachment (attachment) of Al atoms at step edges induced by the oxide growth (decomposition). By comparing with the oxidation of NiAl(110) that exhibits unimpeded oxide film growth over substrate steps we suggest that whenever steps are the source of atoms used for oxide growth they limit the oxidation process; when atoms are supplied from the bulk, the oxidation rate is not limited by the motion of surface steps. PMID- 25548153 TI - miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic gammac cytokines. AB - Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic "cytokine sinks." These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor specific CD8(+) T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic gammac cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers. PMID- 25548154 TI - Directional selection can drive the evolution of modularity in complex traits. AB - Modularity is a central concept in modern biology, providing a powerful framework for the study of living organisms on many organizational levels. Two central and related questions can be posed in regard to modularity: How does modularity appear in the first place, and what forces are responsible for keeping and/or changing modular patterns? We approached these questions using a quantitative genetics simulation framework, building on previous results obtained with bivariate systems and extending them to multivariate systems. We developed an individual-based model capable of simulating many traits controlled by many loci with variable pleiotropic relations between them, expressed in populations subject to mutation, recombination, drift, and selection. We used this model to study the problem of the emergence of modularity, and hereby show that drift and stabilizing selection are inefficient at creating modular variational structures. We also demonstrate that directional selection can have marked effects on the modular structure between traits, actively promoting a restructuring of genetic variation in the selected population and potentially facilitating the response to selection. Furthermore, we give examples of complex covariation created by simple regimes of combined directional and stabilizing selection and show that stabilizing selection is important in the maintenance of established covariation patterns. Our results are in full agreement with previous results for two-trait systems and further extend them to include scenarios of greater complexity. Finally, we discuss the evolutionary consequences of modular patterns being molded by directional selection. PMID- 25548156 TI - Effect of increasing CO2 on the terrestrial carbon cycle. AB - Feedbacks from the terrestrial carbon cycle significantly affect future climate change. The CO2 concentration dependence of global terrestrial carbon storage is one of the largest and most uncertain feedbacks. Theory predicts the CO2 effect should have a tropical maximum, but a large terrestrial sink has been contradicted by analyses of atmospheric CO2 that do not show large tropical uptake. Our results, however, show significant tropical uptake and, combining tropical and extratropical fluxes, suggest that up to 60% of the present-day terrestrial sink is caused by increasing atmospheric CO2. This conclusion is consistent with a validated subset of atmospheric analyses, but uncertainty remains. Improved model diagnostics and new space-based observations can reduce the uncertainty of tropical and temperate zone carbon flux estimates. This analysis supports a significant feedback to future atmospheric CO2 concentrations from carbon uptake in terrestrial ecosystems caused by rising atmospheric CO2 concentrations. This feedback will have substantial tropical contributions, but the magnitude of future carbon uptake by tropical forests also depends on how they respond to climate change and requires their protection from deforestation. PMID- 25548157 TI - Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. AB - Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1alpha in Fnip1 null skeletal muscle. Genetic disruption of PGC1alpha rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases. PMID- 25548158 TI - Natural diversity in daily rhythms of gene expression contributes to phenotypic variation. AB - Daily rhythms of gene expression provide a benefit to most organisms by ensuring that biological processes are activated at the optimal time of day. Although temporal patterns of expression control plant traits of agricultural importance, how natural genetic variation modifies these patterns during the day and how precisely these patterns influence phenotypes is poorly understood. The circadian clock regulates the timing of gene expression, and natural variation in circadian rhythms has been described, but circadian rhythms are measured in artificial continuous conditions that do not reflect the complexity of biologically relevant day/night cycles. By studying transcriptional rhythms of the evening-expressed gene gigantea (GI) at high temporal resolution and during day/night cycles, we show that natural variation in the timing of GI expression occurs mostly under long days in 77 Arabidopsis accessions. This variation is explained by natural alleles that alter light sensitivity of GI, specifically in the evening, and that act at least partly independent of circadian rhythms. Natural alleles induce precise changes in the temporal waveform of GI expression, and these changes have detectable effects on phytochrome interacting factor 4 expression and growth. Our findings provide a paradigm for how natural alleles act within day/night cycles to precisely modify temporal gene expression waveforms and cause phenotypic diversity. Such alleles could confer an advantage by adjusting the activity of temporally regulated processes without severely disrupting the circadian system. PMID- 25548159 TI - Stac adaptor proteins regulate trafficking and function of muscle and neuronal L type Ca2+ channels. AB - Excitation-contraction (EC) coupling in skeletal muscle depends upon trafficking of CaV1.1, the principal subunit of the dihydropyridine receptor (DHPR) (L-type Ca(2+) channel), to plasma membrane regions at which the DHPRs interact with type 1 ryanodine receptors (RyR1) in the sarcoplasmic reticulum. A distinctive feature of this trafficking is that CaV1.1 expresses poorly or not at all in mammalian cells that are not of muscle origin (e.g., tsA201 cells), in which all of the other nine CaV isoforms have been successfully expressed. Here, we tested whether plasma membrane trafficking of CaV1.1 in tsA201 cells is promoted by the adapter protein Stac3, because recent work has shown that genetic deletion of Stac3 in skeletal muscle causes the loss of EC coupling. Using fluorescently tagged constructs, we found that Stac3 and CaV1.1 traffic together to the tsA201 plasma membrane, whereas CaV1.1 is retained intracellularly when Stac3 is absent. Moreover, L-type Ca(2+) channel function in tsA201 cells coexpressing Stac3 and CaV1.1 is quantitatively similar to that in myotubes, despite the absence of RyR1. Although Stac3 is not required for surface expression of CaV1.2, the principle subunit of the cardiac/brain L-type Ca(2+) channel, Stac3 does bind to CaV1.2 and, as a result, greatly slows the rate of current inactivation, with Stac2 acting similarly. Overall, these results indicate that Stac3 is an essential chaperone of CaV1.1 in skeletal muscle and that in the brain, Stac2 and Stac3 may significantly modulate CaV1.2 function. PMID- 25548160 TI - Structure of CrgA, a cell division structural and regulatory protein from Mycobacterium tuberculosis, in lipid bilayers. AB - The 93-residue transmembrane protein CrgA in Mycobacterium tuberculosis is a central component of the divisome, a large macromolecular machine responsible for cell division. Through interactions with multiple other components including FtsZ, FtsQ, FtsI (PBPB), PBPA, and CwsA, CrgA facilitates the recruitment of the proteins essential for peptidoglycan synthesis to the divisome and stabilizes the divisome. CrgA is predicted to have two transmembrane helices. Here, the structure of CrgA was determined in a liquid-crystalline lipid bilayer environment by solid-state NMR spectroscopy. Oriented-sample data yielded orientational restraints, whereas magic-angle spinning data yielded interhelical distance restraints. These data define a complete structure for the transmembrane domain and provide rich information on the conformational ensembles of the partially disordered N-terminal region and interhelical loop. The structure of the transmembrane domain was refined using restrained molecular dynamics simulations in an all-atom representation of the same lipid bilayer environment as in the NMR samples. The two transmembrane helices form a left-handed packing arrangement with a crossing angle of 24 degrees at the conserved Gly39 residue. This helix pair exposes other conserved glycine and alanine residues to the fatty acyl environment, which are potential sites for binding CrgA's partners such as CwsA and FtsQ. This approach combining oriented-sample and magic-angle spinning NMR spectroscopy in native-like lipid bilayers with restrained molecular dynamics simulations represents a powerful tool for structural characterization of not only isolated membrane proteins, but their complexes, such as those that form macromolecular machines. PMID- 25548161 TI - Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) consists of a polygonal network of sheets and tubules interconnected by three-way junctions. This network undergoes continual remodeling through competing processes: the branching and fusion of tubules forms new three-way junctions and new polygons, and junction sliding and ring closure leads to polygon loss. However, little is known about the machinery required to generate and maintain junctions. We previously reported that yeast Lnp1 localizes to ER junctions, and that loss of Lnp1 leads to a collapsed, densely reticulated ER network. In mammalian cells, only approximately half the junctions contain Lnp1. Here we use live cell imaging to show that mammalian Lnp1 (mLnp1) affects ER junction mobility and hence network dynamics. Three-way junctions with mLnp1 are less mobile than junctions without mLnp1. Newly formed junctions that acquire mLnp1 remain stable within the ER network, whereas nascent junctions that fail to acquire mLnp1 undergo rapid ring closure. These findings imply that mLnp1 plays a key role in stabilizing nascent three-way ER junctions. PMID- 25548162 TI - CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. AB - Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4-deficient mice show spontaneous T follicular helper (T(FH)) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elicit T(FH) generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T(FH) differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T(FH) generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T(FH) differentiation by graded control of CD28 engagement. PMID- 25548163 TI - Cryptic carbon and sulfur cycling between surface ocean plankton. AB - About half the carbon fixed by phytoplankton in the ocean is taken up and metabolized by marine bacteria, a transfer that is mediated through the seawater dissolved organic carbon (DOC) pool. The chemical complexity of marine DOC, along with a poor understanding of which compounds form the basis of trophic interactions between bacteria and phytoplankton, have impeded efforts to identify key currencies of this carbon cycle link. Here, we used transcriptional patterns in a bacterial-diatom model system based on vitamin B12 auxotrophy as a sensitive assay for metabolite exchange between marine plankton. The most highly up regulated genes (up to 374-fold) by a marine Roseobacter clade bacterium when cocultured with the diatom Thalassiosira pseudonana were those encoding the transport and catabolism of 2,3-dihydroxypropane-1-sulfonate (DHPS). This compound has no currently recognized role in the marine microbial food web. As the genes for DHPS catabolism have limited distribution among bacterial taxa, T. pseudonana may use this sulfonate for targeted feeding of beneficial associates. Indeed, DHPS was both a major component of the T. pseudonana cytosol and an abundant microbial metabolite in a diatom bloom in the eastern North Pacific Ocean. Moreover, transcript analysis of the North Pacific samples provided evidence of DHPS catabolism by Roseobacter populations. Other such biogeochemically important metabolites may be common in the ocean but difficult to discriminate against the complex chemical background of seawater. Bacterial transformation of this diatom-derived sulfonate represents a previously unidentified and likely sizeable link in both the marine carbon and sulfur cycles. PMID- 25548164 TI - Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. AB - An inborn error of metabolism associated with mutations in the human methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene has been identified. The proband presented with SCID, megaloblastic anemia, and neurologic abnormalities, but the causal metabolic impairment is unknown. SCID has been associated with impaired purine nucleotide metabolism, whereas megaloblastic anemia has been associated with impaired de novo thymidylate (dTMP) biosynthesis. MTHFD1 functions to condense formate with tetrahydrofolate and serves as the primary entry point of single carbons into folate-dependent one-carbon metabolism in the cytosol. In this study, we examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency. The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected. Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts. These results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and SCID in MTHFD1 deficiency. PMID- 25548165 TI - Direct measurement of oxidative and nitrosative stress dynamics in Salmonella inside macrophages. AB - Many significant bacterial pathogens have evolved virulence mechanisms to evade degradation and exposure to reactive oxygen (ROS) and reactive nitrogen species (RNS), allowing them to survive and replicate inside their hosts. Due to the highly reactive and short-lived nature of ROS and RNS, combined with limitations of conventional detection agents, the mechanisms underlying these evasion strategies remain poorly understood. In this study, we describe a system that uses redox-sensitive GFP to nondisruptively measure real-time fluctuations in the intrabacterial redox environment. Using this system coupled with high-throughput microscopy, we report the intrabacterial redox dynamics of Salmonella enterica Typhimurium (S. Typhimurium) residing inside macrophages. We found that the bacterial SPI-2 type III secretion system is required for ROS evasion strategies and this evasion relies on an intact Salmonella-containing vacuole (SCV) within which the bacteria reside during infection. Additionally, we found that cytosolic bacteria that escape the SCV experience increased redox stress in human and murine macrophages. These results highlight the existence of specialized evasion strategies used by intracellular pathogens that either reside inside a vacuole or "escape" into the cytosol. Taken together, the use of redox-sensitive GFP inside Salmonella significantly advances our understanding of ROS and RNS evasion strategies during infection. This technology can also be applied to measuring bacterial oxidative and nitrosative stress dynamics under different conditions in a wide variety of bacteria. PMID- 25548166 TI - Structure of the Pseudomonas aeruginosa transamidosome reveals unique aspects of bacterial tRNA-dependent asparagine biosynthesis. AB - Many prokaryotes lack a tRNA synthetase to attach asparagine to its cognate tRNA(Asn), and instead synthesize asparagine from tRNA(Asn)-bound aspartate. This conversion involves two enzymes: a nondiscriminating aspartyl-tRNA synthetase (ND AspRS) that forms Asp-tRNA(Asn), and a heterotrimeric amidotransferase GatCAB that amidates Asp-tRNA(Asn) to form Asn-tRNA(Asn) for use in protein synthesis. ND-AspRS, GatCAB, and tRNA(Asn) may assemble in an ~400-kDa complex, known as the Asn-transamidosome, which couples the two steps of asparagine biosynthesis in space and time to yield Asn-tRNA(Asn). We report the 3.7-A resolution crystal structure of the Pseudomonas aeruginosa Asn-transamidosome, which represents the most common machinery for asparagine biosynthesis in bacteria. We show that, in contrast to a previously described archaeal-type transamidosome, a bacteria specific GAD domain of ND-AspRS provokes a principally new architecture of the complex. Both tRNA(Asn) molecules in the transamidosome simultaneously serve as substrates and scaffolds for the complex assembly. This architecture rationalizes an elevated dynamic and a greater turnover of ND-AspRS within bacterial-type transamidosomes, and possibly may explain a different evolutionary pathway of GatCAB in organisms with bacterial-type vs. archaeal-type Asn-transamidosomes. Importantly, because the two-step pathway for Asn-tRNA(Asn) formation evolutionarily preceded the direct attachment of Asn to tRNA(Asn), our structure also may reflect the mechanism by which asparagine was initially added to the genetic code. PMID- 25548167 TI - HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL). AB - The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy. PMID- 25548168 TI - The global distribution of diet breadth in insect herbivores. AB - Understanding variation in resource specialization is important for progress on issues that include coevolution, community assembly, ecosystem processes, and the latitudinal gradient of species richness. Herbivorous insects are useful models for studying resource specialization, and the interaction between plants and herbivorous insects is one of the most common and consequential ecological associations on the planet. However, uncertainty persists regarding fundamental features of herbivore diet breadth, including its relationship to latitude and plant species richness. Here, we use a global dataset to investigate host range for over 7,500 insect herbivore species covering a wide taxonomic breadth and interacting with more than 2,000 species of plants in 165 families. We ask whether relatively specialized and generalized herbivores represent a dichotomy rather than a continuum from few to many host families and species attacked and whether diet breadth changes with increasing plant species richness toward the tropics. Across geographic regions and taxonomic subsets of the data, we find that the distribution of diet breadth is fit well by a discrete, truncated Pareto power law characterized by the predominance of specialized herbivores and a long, thin tail of more generalized species. Both the taxonomic and phylogenetic distributions of diet breadth shift globally with latitude, consistent with a higher frequency of specialized insects in tropical regions. We also find that more diverse lineages of plants support assemblages of relatively more specialized herbivores and that the global distribution of plant diversity contributes to but does not fully explain the latitudinal gradient in insect herbivore specialization. PMID- 25548170 TI - Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells. AB - The mitochondrial enzyme glutaminase C (GAC) catalyzes the hydrolysis of glutamine to glutamate plus ammonia, a key step in the metabolism of glutamine by cancer cells. Recently, we discovered a class of allosteric inhibitors of GAC that inhibit cancer cell growth without affecting their normal cellular counterparts, with the lead compound being the bromo-benzophenanthridinone 968. Here, we take advantage of mouse embryonic fibroblasts transformed by oncogenic Dbl, which hyperactivates Rho GTPases, together with (13)C-labeled glutamine and stable-isotope tracing methods, to establish that 968 selectively blocks the enhancement in glutaminolysis necessary for satisfying the glutamine addiction of cancer cells. We then determine how 968 inhibits the catalytic activity of GAC. First, we developed a FRET assay to examine the effects of 968 on the ability of GAC to undergo the dimer-to-tetramer transition necessary for enzyme activation. We next demonstrate how the fluorescence of a reporter group attached to GAC provides a direct read-out of the binding of 968 and related compounds to the enzyme. By combining these fluorescence assays with newly developed GAC mutants trapped in either the monomeric or dimeric state, we show that 968 has the highest affinity for monomeric GAC and that the dose-dependent binding of 968 to GAC monomers directly matches its dose-dependent inhibition of enzyme activity and cellular transformation. Together, these findings highlight the requirement of tetramer formation as the mechanism of GAC activation and shed new light on how a distinct class of allosteric GAC inhibitors impacts the metabolic program of transformed cells. PMID- 25548169 TI - Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization. AB - Pulmonary immunization enhances local humoral and cell-mediated mucosal protection, which are critical for vaccination against lung-specific pathogens such as influenza or tuberculosis. A variety of nanoparticle (NP) formulations have been tested preclinically for pulmonary vaccine development, yet the role of NP surface charge on downstream immune responses remains poorly understood. We used the Particle Replication in Non-Wetting Templates (PRINT) process to synthesize hydrogel NPs that varied only in surface charge and otherwise maintained constant size, shape, and antigen loading. Pulmonary immunization with ovalbumin (OVA)-conjugated cationic NPs led to enhanced systemic and lung antibody titers compared with anionic NPs. Increased antibody production correlated with robust germinal center B-cell expansion and increased activated CD4(+) T-cell populations in lung draining lymph nodes. Ex vivo treatment of dendritic cells (DCs) with OVA-conjugated cationic NPs induced robust antigen specific T-cell proliferation with ~ 100-fold more potency than soluble OVA alone. Enhanced T-cell expansion correlated with increased expression of surface MHCII, T-cell coactivating receptors, and key cytokines/chemokine expression by DCs treated with cationic NPs, which were not observed with anionic NPs or soluble OVA. Together, these studies highlight the importance of NP surface charge when designing pulmonary vaccines, and our findings support the notion that cationic NP platforms engender potent humoral and mucosal immune responses. PMID- 25548171 TI - beta-Catenin-related protein WRM-1 is a multifunctional regulatory subunit of the LIT-1 MAPK complex. AB - Vertebrate beta-catenin has two functions, as a structural component of the adherens junction in cell adhesion and as the T-cell factor (TCF) transcriptional coactivator in canonical Wnt (wingless-related integration site) signaling. These two functions are split between three of the four beta-catenin-related proteins present in the round worm Caenorhabditis elegans. The fourth beta-catenin-related protein, WRM-1, exhibits neither of these functions. Instead, WRM-1 binds the MAPK loss of intestine 1 (LIT-1), and these two proteins have been shown to be essential for the transcription of Wnt target genes by phosphorylating and regulating the nuclear level of the sole worm TCF protein. We showed previously that WRM-1 binds to worm TCF and functions as the substrate-binding subunit for LIT-1. In this study, we show that phosphorylation of T220 in the activation loop is essential for LIT-1 kinase activity in vivo and in vitro. T220 can be phosphorylated either through LIT-1 autophosphorylation or directly by the upstream MAP3K MOM-4. Our data support a model in which WRM-1, which can undergo homotypic interaction, binds LIT-1 and thereby generates a kinase complex in which LIT-1 molecules are situated in a conformation enabling autophosphorylation as well as promoting phosphorylation of the T220 residue by MOM-4. In addition, we show that WRM-1 is essential for the translocation of the LIT-1 kinase complex to the nucleus, the site of its TCF substrate. To our knowledge, this is the first report of a MAP3K directly activating a MAPK by phosphorylation within the activation loop. This study should help uncover novel and as yet underappreciated functions of vertebrate beta-catenin. PMID- 25548172 TI - Antiviral immunity of Anopheles gambiae is highly compartmentalized, with distinct roles for RNA interference and gut microbiota. AB - Arboviruses are transmitted by mosquitoes and other arthropods to humans and animals. The risk associated with these viruses is increasing worldwide, including new emergence in Europe and the Americas. Anopheline mosquitoes are vectors of human malaria but are believed to transmit one known arbovirus, o'nyong-nyong virus, whereas Aedes mosquitoes transmit many. Anopheles interactions with viruses have been little studied, and the initial antiviral response in the midgut has not been examined. Here, we determine the antiviral immune pathways of the Anopheles gambiae midgut, the initial site of viral infection after an infective blood meal. We compare them with the responses of the post-midgut systemic compartment, which is the site of the subsequent disseminated viral infection. Normal viral infection of the midgut requires bacterial flora and is inhibited by the activities of immune deficiency (Imd), JAK/STAT, and Leu-rich repeat immune factors. We show that the exogenous siRNA pathway, thought of as the canonical mosquito antiviral pathway, plays no detectable role in antiviral defense in the midgut but only protects later in the systemic compartment. These results alter the prevailing antiviral paradigm by describing distinct protective mechanisms in different body compartments and infection stages. Importantly, the presence of the midgut bacterial flora is required for full viral infectivity to Anopheles, in contrast to malaria infection, where the presence of the midgut bacterial flora is required for protection against infection. Thus, the enteric flora controls a reciprocal protection tradeoff in the vector for resistance to different human pathogens. PMID- 25548173 TI - Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation. AB - The differentiation of effector CD8(+) T cells is critical for the development of protective responses to pathogens and for effective vaccines. In the first few hours after activation, naive CD8(+) T cells initiate a transcriptional program that leads to the formation of effector and memory T cells, but the regulation of this process is poorly understood. Investigating the role of specific transcription factors (TFs) in determining CD8(+) effector T-cell fate by gene knockdown with RNAi is challenging because naive T cells are refractory to transduction with viral vectors without extensive ex vivo stimulation, which obscures the earliest events in effector differentiation. To overcome this obstacle, we developed a novel strategy to test the function of genes in naive CD8(+) T cells in vivo by creating bone marrow chimera from hematopoietic progenitors transduced with an inducible shRNA construct. Following hematopoietic reconstitution, this approach allowed inducible in vivo gene knockdown in any cell type that developed from this transduced progenitor pool. We demonstrated that lentivirus-transduced progenitor cells could reconstitute normal hematopoiesis and develop into naive CD8(+) T cells that were indistinguishable from wild-type naive T cells. This experimental system enabled induction of efficient gene knockdown in vivo without subsequent manipulation. We applied this strategy to show that the TF BATF is essential for initial commitment of naive CD8(+) T cells to effector development but becomes dispensable by 72h. This approach makes possible the study of gene function in vivo in unperturbed cells of hematopoietic origin that are refractory to viral transduction. PMID- 25548175 TI - Plasmonic photonic crystals realized through DNA-programmable assembly. AB - Three-dimensional dielectric photonic crystals have well-established enhanced light-matter interactions via high Q factors. Their plasmonic counterparts based on arrays of nanoparticles, however, have not been experimentally well explored owing to a lack of available synthetic routes for preparing them. However, such structures should facilitate these interactions based on the small mode volumes associated with plasmonic polarization. Herein we report strong light-plasmon interactions within 3D plasmonic photonic crystals that have lattice constants and nanoparticle diameters that can be independently controlled in the deep subwavelength size regime by using a DNA-programmable assembly technique. The strong coupling within such crystals is probed with backscattering spectra, and the mode splitting (0.10 and 0.24 eV) is defined based on dispersion diagrams. Numerical simulations predict that the crystal photonic modes (Fabry-Perot modes) can be enhanced by coating the crystals with a silver layer, achieving moderate Q factors (~10(2)) over the visible and near-infrared spectrum. PMID- 25548174 TI - Immunological consequences of intragenus conservation of Mycobacterium tuberculosis T-cell epitopes. AB - A previous unbiased genome-wide analysis of CD4 Mycobacterium tuberculosis (MTB) recognition using peripheral blood mononuclear cells from individuals with latent MTB infection (LTBI) or nonexposed healthy controls (HCs) revealed that certain MTB sequences were unexpectedly recognized by HCs. In the present study, it was found that, based on their pattern of reactivity, epitopes could be divided into LTBI-specific, mixed reactivity, and HC-specific categories. This pattern corresponded to sequence conservation in nontuberculous mycobacteria (NTMs), suggesting environmental exposure as an underlying cause of differential reactivity. LTBI-specific epitopes were found to be hyperconserved, as previously reported, whereas the opposite was true for NTM conserved epitopes, suggesting that intragenus conservation also influences host pathogen adaptation. The biological relevance of this observation was demonstrated further by several observations. First, the T cells elicited by MTB/NTM cross-reactive epitopes in HCs were found mainly in a CCR6(+)CXCR3(+) memory subset, similar to findings in LTBI individuals. Thus, both MTB and NTM appear to elicit a phenotypically similar T-cell response. Second, T cells reactive to MTB/NTM-conserved epitopes responded to naturally processed epitopes from MTB and NTMs, whereas T cells reactive to MTB-specific epitopes responded only to MTB. Third, cross-reactivity could be translated to antigen recognition. Several MTB candidate vaccine antigens were cross-reactive, but others were MTB-specific. Finally, NTM-specific epitopes that elicit T cells that recognize NTMs but not MTB were identified. These epitopes can be used to characterize T-cell responses to NTMs, eliminating the confounding factor of MTB cross-recognition and providing insights into vaccine design and evaluation. PMID- 25548177 TI - Detecting nanoscale vibrations as signature of life. AB - The existence of life in extreme conditions, in particular in extraterrestrial environments, is certainly one of the most intriguing scientific questions of our time. In this report, we demonstrate the use of an innovative nanoscale motion sensor in life-searching experiments in Earth-bound and interplanetary missions. This technique exploits the sensitivity of nanomechanical oscillators to transduce the small fluctuations that characterize living systems. The intensity of such movements is an indication of the viability of living specimens and conveys information related to their metabolic activity. Here, we show that the nanomotion detector can assess the viability of a vast range of biological specimens and that it could be the perfect complement to conventional chemical life-detection assays. Indeed, by combining chemical and dynamical measurements, we could achieve an unprecedented depth in the characterization of life in extreme and extraterrestrial environments. PMID- 25548176 TI - Cohort of birth modifies the association between FTO genotype and BMI. AB - A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this hypothesis, we use longitudinal data from the Framingham Heart Study collected over 30 y from a geographically relatively localized sample to test whether the well-documented association between the rs993609 variant of the FTO (fat mass and obesity associated) gene and body mass index (BMI) varies across birth cohorts, time period, and the lifecycle. Such cohort and period effects integrate many potential environmental factors, and this gene-by-environment analysis examines interactions with both time-varying contemporaneous and historical environmental influences. Using constrained linear age-period-cohort models that include family controls, we find that there is a robust relationship between birth cohort and the genotype-phenotype correlation between the FTO risk allele and BMI, with an observed inflection point for those born after 1942. These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance. PMID- 25548178 TI - Distinct dopamine neurons mediate reward signals for short- and long-term memories. AB - Drosophila melanogaster can acquire a stable appetitive olfactory memory when the presentation of a sugar reward and an odor are paired. However, the neuronal mechanisms by which a single training induces long-term memory are poorly understood. Here we show that two distinct subsets of dopamine neurons in the fly brain signal reward for short-term (STM) and long-term memories (LTM). One subset induces memory that decays within several hours, whereas the other induces memory that gradually develops after training. They convey reward signals to spatially segregated synaptic domains of the mushroom body (MB), a potential site for convergence. Furthermore, we identified a single type of dopamine neuron that conveys the reward signal to restricted subdomains of the mushroom body lobes and induces long-term memory. Constant appetitive memory retention after a single training session thus comprises two memory components triggered by distinct dopamine neurons. PMID- 25548179 TI - Direct coupling of haptic signals between hands. AB - Although motor actions can profoundly affect the perceptual interpretation of sensory inputs, it is not known whether the combination of sensory and movement signals occurs only for sensory surfaces undergoing movement or whether it is a more general phenomenon. In the haptic modality, the independent movement of multiple sensory surfaces poses a challenge to the nervous system when combining the tactile and kinesthetic signals into a coherent percept. When exploring a stationary object, the tactile and kinesthetic signals come from the same hand. Here we probe the internal structure of haptic combination by directing the two signal streams to separate hands: one hand moves but receives no tactile stimulation, while the other hand feels the consequences of the first hand's movement but remains still. We find that both discrete and continuous tactile and kinesthetic signals are combined as if they came from the same hand. This combination proceeds by direct coupling or transfer of the kinesthetic signal from the moving to the feeling hand, rather than assuming the displacement of a mediating object. The combination of signals is due to perception rather than inference, because a small temporal offset between the signals significantly degrades performance. These results suggest that the brain simplifies the complex coordinate transformation task of remapping sensory inputs to take into account the movements of multiple body parts in haptic perception, and they show that the effects of action are not limited to moving sensors. PMID- 25548180 TI - Bacterial growth laws reflect the evolutionary importance of energy efficiency. AB - We are interested in the balance of energy and protein synthesis in bacterial growth. How has evolution optimized this balance? We describe an analytical model that leverages extensive literature data on growth laws to infer the underlying fitness landscape and to draw inferences about what evolution has optimized in Escherichia coli. Is E. coli optimized for growth speed, energy efficiency, or some other property? Experimental data show that at its replication speed limit, E. coli produces about four mass equivalents of nonribosomal proteins for every mass equivalent of ribosomes. This ratio can be explained if the cell's fitness function is the the energy efficiency of cells under fast growth conditions, indicating a tradeoff between the high energy costs of ribosomes under fast growth and the high energy costs of turning over nonribosomal proteins under slow growth. This model gives insight into some of the complex nonlinear relationships between energy utilization and ribosomal and nonribosomal production as a function of cell growth conditions. PMID- 25548181 TI - Arrival of the Fukushima radioactivity plume in North American continental waters. AB - The large discharge of radioactivity into the northwest Pacific Ocean from the 2011 Fukushima Dai-ichi nuclear reactor accident has generated considerable concern about the spread of this material across the ocean to North America. We report here the first systematic study to our knowledge of the transport of the Fukushima marine radioactivity signal to the eastern North Pacific. Time series measurements of (134)Cs and (137)Cs in seawater revealed the initial arrival of the Fukushima signal by ocean current transport at a location 1,500 km west of British Columbia, Canada, in June 2012, about 1.3 y after the accident. By June 2013, the Fukushima signal had spread onto the Canadian continental shelf, and by February 2014, it had increased to a value of 2 Bq/m(3) throughout the upper 150 m of the water column, resulting in an overall doubling of the fallout background from atmospheric nuclear weapons tests. Ocean circulation model estimates that are in reasonable agreement with our measured values indicate that future total levels of (137)Cs (Fukushima-derived plus fallout (137)Cs) off the North American coast will likely attain maximum values in the 3-5 Bq/m(3) range by 2015-2016 before declining to levels closer to the fallout background of about 1 Bq/m(3) by 2021. The increase in (137)Cs levels in the eastern North Pacific from Fukushima inputs will probably return eastern North Pacific concentrations to the fallout levels that prevailed during the 1980s but does not represent a threat to human health or the environment. PMID- 25548182 TI - Adaptive simplification and the evolution of gecko locomotion: morphological and biomechanical consequences of losing adhesion. AB - Innovations permit the diversification of lineages, but they may also impose functional constraints on behaviors such as locomotion. Thus, it is not surprising that secondary simplification of novel locomotory traits has occurred several times among vertebrates and could potentially lead to exceptional divergence when constraints are relaxed. For example, the gecko adhesive system is a remarkable innovation that permits locomotion on surfaces unavailable to other animals, but has been lost or simplified in species that have reverted to a terrestrial lifestyle. We examined the functional and morphological consequences of this adaptive simplification in the Pachydactylus radiation of geckos, which exhibits multiple unambiguous losses or bouts of simplification of the adhesive system. We found that the rates of morphological and 3D locomotor kinematic evolution are elevated in those species that have simplified or lost adhesive capabilities. This finding suggests that the constraints associated with adhesion have been circumvented, permitting these species to either run faster or burrow. The association between a terrestrial lifestyle and the loss/reduction of adhesion suggests a direct link between morphology, biomechanics, and ecology. PMID- 25548183 TI - MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs. AB - Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGFbeta, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications. PMID- 25548184 TI - A red meat-derived glycan promotes inflammation and cancer progression. AB - A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of "red meat" of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption. PMID- 25548185 TI - Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase. AB - Intradiol aromatic ring-cleaving dioxygenases use an active site, nonheme Fe(3+) to activate O2 and catecholic substrates for reaction. The inability of Fe(3+) to directly bind O2 presents a mechanistic conundrum. The reaction mechanism of protocatechuate 3,4-dioxygenase is investigated here using the alternative substrate 4-fluorocatechol. This substrate is found to slow the reaction at several steps throughout the mechanistic cycle, allowing the intermediates to be detected in solution studies. When the reaction was initiated in an enzyme crystal, it was found to halt at one of two intermediates depending on the pH of the surrounding solution. The X-ray crystal structure of the intermediate at pH 6.5 revealed the key alkylperoxo-Fe(3+) species, and the anhydride-Fe(3+) intermediate was found for a crystal reacted at pH 8.5. Intermediates of these types have not been structurally characterized for intradiol dioxygenases, and they validate four decades of spectroscopic, kinetic, and computational studies. In contrast to our similar in crystallo crystallographic studies of an Fe(2+) containing extradiol dioxygenase, no evidence for a superoxo or peroxo intermediate preceding the alkylperoxo was found. This observation and the lack of spectroscopic evidence for an Fe(2+) intermediate that could bind O2 are consistent with concerted formation of the alkylperoxo followed by Criegee rearrangement to yield the anhydride and ultimately ring-opened product. Structural comparison of the alkylperoxo intermediates from the intra- and extradiol dioxygenases provides a rationale for site specificity of ring cleavage. PMID- 25548187 TI - Granular impact cratering by liquid drops: Understanding raindrop imprints through an analogy to asteroid strikes. AB - When a granular material is impacted by a sphere, its surface deforms like a liquid yet it preserves a circular crater like a solid. Although the mechanism of granular impact cratering by solid spheres is well explored, our knowledge on granular impact cratering by liquid drops is still very limited. Here, by combining high-speed photography with high-precision laser profilometry, we investigate liquid-drop impact dynamics on granular surface and monitor the morphology of resulting impact craters. Surprisingly, we find that despite the enormous energy and length difference, granular impact cratering by liquid drops follows the same energy scaling and reproduces the same crater morphology as that of asteroid impact craters. Inspired by this similarity, we integrate the physical insight from planetary sciences, the liquid marble model from fluid mechanics, and the concept of jamming transition from granular physics into a simple theoretical framework that quantitatively describes all of the main features of liquid-drop imprints in granular media. Our study sheds light on the mechanisms governing raindrop impacts on granular surfaces and reveals a remarkable analogy between familiar phenomena of raining and catastrophic asteroid strikes. PMID- 25548188 TI - Coral host cells acidify symbiotic algal microenvironment to promote photosynthesis. AB - Symbiotic dinoflagellate algae residing inside coral tissues supply the host with the majority of their energy requirements through the translocation of photosynthetically fixed carbon. The algae, in turn, rely on the host for the supply of inorganic carbon. Carbon must be concentrated as CO2 in order for photosynthesis to proceed, and here we show that the coral host plays an active role in this process. The host-derived symbiosome membrane surrounding the algae abundantly expresses vacuolar H(+)-ATPase (VHA), which acidifies the symbiosome space down to pH ~ 4. Inhibition of VHA results in a significant decrease in average H(+) activity in the symbiosome of up to 75% and a significant reduction in O2 production rate, a measure of photosynthetic activity. These results suggest that host VHA is part of a previously unidentified carbon concentrating mechanism for algal photosynthesis and provide mechanistic evidence that coral host cells can actively modulate the physiology of their symbionts. PMID- 25548186 TI - Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. AB - Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies. PMID- 25548190 TI - Warfare and reproductive success in a tribal population. AB - Intergroup conflict is a persistent feature of many human societies yet little is known about why individuals participate when doing so imposes a mortality risk. To evaluate whether participation in warfare is associated with reproductive benefits, we present data on participation in small-scale livestock raids among the Nyangatom, a group of nomadic pastoralists in East Africa. Nyangatom marriages require the exchange of a significant amount of bridewealth in the form of livestock. Raids are usually intended to capture livestock, which raises the question of whether and how these livestock are converted into reproductive opportunities. Over the short term, raiders do not have a greater number of wives or children than nonraiders. However, elders who were identified as prolific raiders in their youth have more wives and children than other elders. Raiders were not more likely to come from families with fewer older maternal sisters or a greater number of older maternal brothers. Our results suggest that in this cultural context raiding provides opportunities for increased reproductive success over the lifetime. PMID- 25548189 TI - Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus. AB - The emergence of human infection with a novel H7N9 influenza virus in China raises a pandemic concern. Chicken H9N2 viruses provided all six of the novel reassortant's internal genes. However, it is not fully understood how the prevalence and evolution of these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that over more than 10 y of cocirculation of multiple H9N2 genotypes, a genotype (G57) emerged that had changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens in China, caused widespread outbreaks in 2010-2013 before the H7N9 viruses emerged in humans, and finally provided all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential. PMID- 25548191 TI - Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. AB - Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep. PMID- 25548192 TI - Enhancing long-term memory with stimulation tunes visual attention in one trial. AB - Scientists have long proposed that memory representations control the mechanisms of attention that focus processing on the task-relevant objects in our visual field. Modern theories specifically propose that we rely on working memory to store the object representations that provide top-down control over attentional selection. Here, we show that the tuning of perceptual attention can be sharply accelerated after 20 min of noninvasive brain stimulation over medial-frontal cortex. Contrary to prevailing theories of attention, these improvements did not appear to be caused by changes in the nature of the working memory representations of the search targets. Instead, improvements in attentional tuning were accompanied by changes in an electrophysiological signal hypothesized to index long-term memory. We found that this pattern of effects was reliably observed when we stimulated medial-frontal cortex, but when we stimulated posterior parietal cortex, we found that stimulation directly affected the perceptual processing of the search array elements, not the memory representations providing top-down control. Our findings appear to challenge dominant theories of attention by demonstrating that changes in the storage of target representations in long-term memory may underlie rapid changes in the efficiency with which humans can find targets in arrays of objects. PMID- 25548193 TI - Remodeling of intermediate metabolism in the diatom Phaeodactylum tricornutum under nitrogen stress. AB - Diatoms are unicellular algae that accumulate significant amounts of triacylglycerols as storage lipids when their growth is limited by nutrients. Using biochemical, physiological, bioinformatics, and reverse genetic approaches, we analyzed how the flux of carbon into lipids is influenced by nitrogen stress in a model diatom, Phaeodactylum tricornutum. Our results reveal that the accumulation of lipids is a consequence of remodeling of intermediate metabolism, especially reactions in the tricarboxylic acid and the urea cycles. Specifically, approximately one-half of the cellular proteins are cannibalized; whereas the nitrogen is scavenged by the urea and glutamine synthetase/glutamine 2 oxoglutarate aminotransferase pathways and redirected to the de novo synthesis of nitrogen assimilation machinery, simultaneously, the photobiological flux of carbon and reductants is used to synthesize lipids. To further examine how nitrogen stress triggers the remodeling process, we knocked down the gene encoding for nitrate reductase, a key enzyme required for the assimilation of nitrate. The strain exhibits 40-50% of the mRNA copy numbers, protein content, and enzymatic activity of the wild type, concomitant with a 43% increase in cellular lipid content. We suggest a negative feedback sensor that couples photosynthetic carbon fixation to lipid biosynthesis and is regulated by the nitrogen assimilation pathway. This metabolic feedback enables diatoms to rapidly respond to fluctuations in environmental nitrogen availability. PMID- 25548194 TI - Spatiotemporal variations of seismicity before major earthquakes in the Japanese area and their relation with the epicentral locations. AB - Using the Japan Meteorological Agency earthquake catalog, we investigate the seismicity variations before major earthquakes in the Japanese region. We apply natural time, the new time frame, for calculating the fluctuations, termed beta, of a certain parameter of seismicity, termed kappa1. In an earlier study, we found that beta calculated for the entire Japanese region showed a minimum a few months before the shallow major earthquakes (magnitude larger than 7.6) that occurred in the region during the period from 1 January 1984 to 11 March 2011. In this study, by dividing the Japanese region into small areas, we carry out the beta calculation on them. It was found that some small areas show beta minimum almost simultaneously with the large area and such small areas clustered within a few hundred kilometers from the actual epicenter of the related main shocks. These results suggest that the present approach may help estimation of the epicentral location of forthcoming major earthquakes. PMID- 25548195 TI - Experiment, monitoring, and gradient methods used to infer climate change effects on plant communities yield consistent patterns. AB - Inference about future climate change impacts typically relies on one of three approaches: manipulative experiments, historical comparisons (broadly defined to include monitoring the response to ambient climate fluctuations using repeat sampling of plots, dendroecology, and paleoecology techniques), and space-for time substitutions derived from sampling along environmental gradients. Potential limitations of all three approaches are recognized. Here we address the congruence among these three main approaches by comparing the degree to which tundra plant community composition changes (i) in response to in situ experimental warming, (ii) with interannual variability in summer temperature within sites, and (iii) over spatial gradients in summer temperature. We analyzed changes in plant community composition from repeat sampling (85 plant communities in 28 regions) and experimental warming studies (28 experiments in 14 regions) throughout arctic and alpine North America and Europe. Increases in the relative abundance of species with a warmer thermal niche were observed in response to warmer summer temperatures using all three methods; however, effect sizes were greater over broad-scale spatial gradients relative to either temporal variability in summer temperature within a site or summer temperature increases induced by experimental warming. The effect sizes for change over time within a site and with experimental warming were nearly identical. These results support the view that inferences based on space-for-time substitution overestimate the magnitude of responses to contemporary climate warming, because spatial gradients reflect long-term processes. In contrast, in situ experimental warming and monitoring approaches yield consistent estimates of the magnitude of response of plant communities to climate warming. PMID- 25548196 TI - Reply to Brush et al.: Wake-up call for crop conservation science. PMID- 25548197 TI - Assessing maize genetic erosion. PMID- 25548198 TI - The typology and function of private speech in a young man with intellectual disabilities: An empirical case study. AB - A naturalistic observational single case study was carried out to investigate the form and function of private speech (PS) in a young man with Dandy-Walker variant syndrome and trisomy 22. Video recordings were observed, transcribed and coded to identify all combinations of type and form of PS. Through comparison between theories of PS and the results, five putative functions were identified in this case. In contrast to the predominant theoretical models of inner and PS, it is proposed that PS cannot necessarily be reduced to a single functional definition. PMID- 25548199 TI - Teaching Algebra to Students With Learning Disabilities: Where Have We Come and Where Should We Go? AB - This review investigates effective interventions for teaching algebra to students with learning disabilities and evaluates the complexity and alignment of skills with the Common Core State Standards in math. The review includes the results of 10 experimental and 5 single-subject designs (N = 15) producing a moderate overall effect size (g = 0.48). A total of five interventions were identified and analyzed across the studies using effect size data. PMID- 25548200 TI - Effect of zinc-bearing zeolite clinoptilolite on growth performance, zinc accumulation, and gene expression of zinc transporters in broilers. AB - This study investigated Zn-bearing zeolite clinoptilolite (Zn-ZCP) as a Zn supplement on performance, organ or tissue development, Zn accumulation in tissues, and gene expression of Zn transporters in the duodenum of broilers. A total of 300 1-d-old Arbor Acres chickens were randomly allocated to 5 dietary treatments with 6 replicate cages of 10 birds per treatment for a 21-d feeding period. The treatments comprised a basal corn-soybean meal diet without supplemental Zn (the control) or similar diets supplemented with 80 mg/kg Zn from ZnSO4 or 20, 40, or 80 mg/kg Zn from Zn- ZCP, respectively. Supplementation of Zn ZCP had a positive effect on G:F (linear, P < 0.05) and had tendency difference on ADG (linear, P < 0.1) of broilers during 1 to 21 d. Incremental Zn-ZCP inclusion in the diet increased the fresh weight of the pancreas (linear, P < 0.05) and tibia (linear, P < 0.05) in broilers on d 14. The same trend to the fresh weight of the tibia (linear, P < 0.05) and pancreas (linear, P < 0.05) was observed on d 21. Increasing Zn-ZCP level showed a linear response on Zn concentration in the liver (linear, P < 0.001), pancreas (linear, P < 0.05), and tibia (linear, P < 0.05) on d 14. The same trend of Zn concentrations in pancreas (linear, P < 0.05) and tibia (linear, P < 0.001) was observed on d 21. The mRNA levels of Zn transporter 2 (ZnT-2) and Zn transporter 5 (ZnT-5) in the duodenum of chicks fed the diet with 80 mg/kg Zn from Zn-ZCP did not differ from those of chicks fed the control diet, but both were lower (P < 0.05) than those of chicks fed ZnSO4 diet. Metallothionein (MT) mRNA levels of broilers fed the diet supplemented with 80 mg/kg Zn from Zn-ZCP or ZnSO4 was higher (P < 0.05) than that in the control group. Dietary treatments did not affect the mRNA expression of Zn transporter 1 (ZnT-1) or metal response element-binding transcription factor-1 (MTF-1). In conclusion, as a Zn supplement, Zn-ZCP was comparable to ZnSO4 for enhancing Zn accumulation and growth performance of broilers during 1 to 21 d. Broilers fed the diet with 80 mg/kg Zn from Zn-ZCP had different expressions of ZnT-2 and ZnT-5 in the duodenum compared with those fed the ZnSO4 diet. PMID- 25548201 TI - Effect of replacing corn with hulled and hulless or low-amylose hulless barley varieties on growth performance and carcass quality of Italian growing-finishing pig. AB - A study was conducted to evaluate the effect of diets based on hulled or hulless (normal- and low-amylose) barley varieties on growth performance and carcass characteristics in heavy growing-finishing pigs for the production of protected designation of origin (PDO) Italian products. The study was performed with 40 gilts and 40 barrows (Italian Duroc * Italian Large White). Four diets were formulated: 1) corn-based diet (control), 2) control diet with 80% of a normal amylose hulled barley variety named Cometa (Cometa), 3) control diet with 80% of a normal-amylose hulless barley variety named Astartis (Astartis), and 4) control diet with 80% of a low-amylose hulless barley variety named Alamo (Alamo). The diets were formulated according to 3 growth phases (P1, 40 to 80 kg BW; P2, 80 to 120 kg BW; and P3, 120 to 170 kg BW), with the same Lys:DE ratio (2.60, 2.20, and 1.80, respectively in P1, P2, and P3) according to the NRC requirements for P1 and P2 and according to requirements for high-performing pigs for P3. The diets were analyzed for their in vitro starch digestion potentials (predicted glycemic index, pGI) and for their resistant starch (RS) contents. In P1, P2, and P3, the Alamo diet had the numerically lowest RS contents and greatest pGI values, whereas the control diet had the numerically greatest RS contents and the lowest pGI values. Throughout the study, the pigs fed Cometa and Alamo diets grew faster (P < 0.01) than those fed the control diet, whereas pigs receiving Astartis diet grew in a similar manner to those receiving all the other diets. Pigs fed Cometa and Alamo achieved greater final BW (P < 0.01) compared with those fed the control diet. The pigs receiving the Astartis diet had a mean final BW similar to that of the pigs fed other diets. Throughout the study, the control group had a lower grams per megacalorie DE (P < 0.01) compared with the pigs fed diets with barley, whereas the gain per megacalorie of DE (G/Mcal DE) was greater (P < 0.01) for the pigs fed hulled barley compared with the pig fed hulless barleys. No difference in carcass characteristics was found among treatments (P > 0.05). This study showed that diets based both on hulled and hulless barley might be suitable for the heavy pig breeding intended to the production of Italian PDO products. In addition, hulled or low-amylose hulless barley could be valuable to support maximum pig growth performance without affecting carcass composition. PMID- 25548202 TI - Feeding distiller's grains as an energy source to gestating and lactating beef heifers: Impact on female progeny growth, puberty attainment, and reproductive processes. AB - This study compared postweaning growth, puberty attainment, and reproductive processes of female progeny (n = 33) born to Angus-Simmental beef heifers treated with either a control diet or a diet in which dried distiller's grains with solubles (DDGS) were fed as an energy source during late gestation and early lactation. From 192 d of gestation through 118 +/- 4 d in lactation, dams were fed either a corn silage-based control diet (CON) orcorn residue with DDGS, where DDGS were supplemented as an energy source (DG). Diets were formulated to provide similar daily NEg between diets, but CP requirements were drastically exceeded in the DG treatment. Heifer progeny (n = 33) were weaned, commingled at 191 +/- 4 d of age, and similarly managed for the remainder of the project. Heifer BW and blood samples for progesterone assessment to determine onset of puberty were collected weekly beginning at weaning. At 255 +/- 4 d of age, a single follicular wave was mapped via ultrasonography in 10 prepubertal heifers per treatment. Prepubertal antral follicle count and ovarian size were determined at 253 +/- 4 d of age. Hip height was recorded at 213,297, and 437 +/- 4 d of age. Estrous synchronization and AI was initiated at 447 +/- 4 d of age. Binary data were analyzed with the GLIMMIX procedures of SAS and all other data were analyzed with the MIXED procedures of SAS. Progeny from DG-treated dams tended to be heavier (P = 0.08) than progeny from CON-treated dams from weaning until breeding. In addition, DG progeny had a greater (P < 0.01) frame score than CON throughout the developmental period. Ovarian size, antral follicle count, and follicular growth parameters did not differ between treatments. Age at puberty did not differ between CON (303 +/- 10 d) and DG (320 +/- 10 d) progeny; however, BW at puberty was greater (P = 0.01) for DG (326 +/- 7 kg) than CON (298 +/- 8 kg) progeny. Pregnancy rates to AI were greater (P = 0.05) in DG progeny (70.6%) than CON (33.3%), but overall breeding season pregnancy rate did not differ (P = 0.97). Moreover, rate of dystocia in female progeny at first parturition and grand offspring birth BW did not differ due to treatment (P >= 0.74). In summary, feeding DDGS as an energy source during late gestation and early lactation to first-parity heifers resulted in female progeny with greater skeletal growth that were heavier at onset of puberty and had increased AI pregnancy rates. PMID- 25548203 TI - The influence of maternal energy status during midgestation on beef offspring carcass characteristics and meat quality. AB - Research has suggested that maternal undernutrition may cause the development of a thrifty phenotype in the offspring, potentially resulting in greater adiposity and reduced muscle mass. These alterations in adipose and muscle development could have lasting impacts on offspring growth, carcass characteristics, and meat quality. However, limited research exists evaluating the impact of maternal energy status on these economically important traits of the offspring. Therefore, the objective of this study was to determine the influence of maternal energy status during midgestation on offspring carcass characteristics and meat quality. To alter maternal energy status, cows either grazed dormant, winter range (positive energy status [PES]) or were fed in a drylot at 80% of the energy requirements for BW maintenance (negative energy status [NES]) during a mean period of 102 +/- 10.9 to 193 +/- 10.9 d of gestation. Changes in BCS, BW, LM area (LMA), and 12th rib backfat were measured throughout midgestation. At the end of midgestation, cows in the NES group had a reduction (P <= 0.05) in BCS, BW, LMA, and 12th rib backfat when compared with PES dams. Cows and calves were managed similarly after midgestation through weaning and calves were managed and fed a common diet through the receiving, backgrounding, and finishing phases in the feedlot. Calves were harvested after 208 d in the feedlot, carcass characteristics were recorded, and strip loins were recovered for analysis of objective color and Warner-Bratzler shear force (WBSF). Maternal energy status had no influence on offspring HCW, dressing percent, LMA, percent KPH, marbling score, percent intramuscular fat, objective color, or WBSF (P > 0.10). Progeny of NES cows tended to have improvements in 12th rib backfat and USDA yield grade (P < 0.10). Greater ratio of marbling score to 12th rib fat thickness and ratio of percent intramuscular fat to 12th rib fat thickness (P < 0.05) were discovered in progeny from cows experiencing a NES during midgestation. These results suggest that maternal energy status during midgestation may impact fat deposition in intramuscular and subcutaneous fat depots without impacting muscle mass. PMID- 25548204 TI - Effect of grinding intensity and pelleting of the diet on indoor particulate matter concentrations and growth performance of weanling pigs. AB - This study evaluated the effect of feed form and grinding intensity of the pig diet and the interaction between both on the particulate matter (PM) concentrations inside a pig nursery and the growth performances of weanling pigs. Four diets were compared: finely ground meal, coarsely ground meal, finely ground pellets, and coarsely ground pellets. Four weaning rounds with 144 pigs per weaning round, divided over 4 identical compartments, were monitored. Within each weaning round, each compartment was randomly assigned to 1 of 4 treatments. A hammer mill with a screen of 1.5 or 6 mm was used to grind the ingredients of the finely ground and coarsely ground feeds, respectively. Indoor concentrations of the following PM fractions were measured: PM that passes through a size-selective inlet with a 50 % efficiency cutoff at 10 (PM10) , 2.5 (PM2.5), or 1 (PM1) MUm aerodynamic diameter, respectively (USEPA, 2004). Feeding pelleted diets instead of meal diets gave rise to higher PM10 (P < 0.001), PM2.5 (P < 0.001), and PM1 (P < 0.001) concentrations. Grinding intensity had an effect only on PM10 (P < 0.05) concentrations. No interaction between feed form and grinding intensity was found for any of the PM fractions. Interactions (P < 0.05) between feed form and grinding intensity on ADFI and ADG were found. Grinding intensity had an effect only on the meal diets with higher ADFI for the coarsely ground meal. Pigs fed the finely ground meal had a lower (P < 0.001) ADG than the other 3 diets. Feed efficiency was influenced only by the feed form (P < 0.001) and not by the grinding intensity. Pelleting the feed gave rise to a higher G:F. In conclusion, a contradiction between environmental concerns and performance results was found. Feeding pelleted diets to the piglets improved growth performance but also increased indoor PM concentrations. PMID- 25548205 TI - Source of metabolizable energy affects gene transcription in metabolic pathways in adipose and liver tissue of nonlactating, pregnant dairy cows. AB - The objective of this experiment was to determine if transcript abundance of genes involved in metabolic pathways in adipose and liver tissue could provide some explanation for the low efficiency with which ME in autumn pasture is used for BW gain. Nonlactating, pregnant (208 +/- 19 d of gestation or approximately 75 d precalving) dairy cows (n = 90) were randomly allocated to either a control diet (i.e., offered fresh autumn pasture to maintenance requirements: 0.55 MJ ME/kg of measured metabolic BW [BW0.75] per day) or, in addition to the control diet, 1 of 2 supplement amounts (2.5 and 5.0 kg DM/d) of autumn pasture or 1 of 4 supplementary feeds (i.e., a control and 2 levels of feeding for each of 5 feeds: 11 groups of cows). Along with autumn pasture, evaluated feeds included spring pasture silage, maize silage, maize grain, and palm kernel expeller. Adipose and liver tissues were biopsied in wk 4 of the experiment and transcript abundance of genes involved in metabolic pathways associated with energy metabolism, lipolysis, and lipogenesis was determined. Additional feed, irrespective of type, increased BW gain (P < 0.01) and this effect was reflected in the expression of genes in adipose and liver tissue. However, autumn pasture had lower energy-use efficiency than the other feeds. Genes involved in both lipogenesis (ACACA, THRSP, GPAM, GPD1, and LPL) and lipolysis (PNPLA2) were upregulated (P < 0.05) in adipose tissue in response to increased ME intake/kilogram BW0.75. Hepatic expression of APOA1 decreased and that of APOB increased (P < 0.05) in cows offered maize grain and maize silage (i.e., starch-containing feeds). In comparison, pasture-fed cows demonstrated a degree of uncoupling of the somatotropic axis, with lower hepatic transcript abundance of both GHR1A and IGF 1 compared with cows offered any of the other 4 feeds. Changes to gene transcription indicate a possible molecular mechanism for the poor BW gain evident in ruminants consuming autumn pasture. PMID- 25548206 TI - Digestibility and performance of steers fed low-quality crop residues treated with calcium oxide to partially replace corn in distillers grains finishing diets. AB - Two studies were conducted to identify methods for treating crop residues to improve digestibility and value in finishing diets based on corn grain and corn wet distillers grain with solubles (WDGS). In Exp. 1, 336 yearling steers (initial BW 356 +/- 11.5 kg) were used in a 2 * 3 + 1 factorial arrangement of treatments with 6 pens per treatment. Factors were 3 crop residues (corn cobs, wheat straw, and corn stover) and 2 treatments where crop residues were either fed (20% diet DM) in their native form (NT) or alkaline treated with 5% CaO (DM basis) and hydrated to 50% DM before anaerobic storage (AT). Intakes were not affected by diet (F test; P = 0.30). An interaction between chemical treatment and residue (P < 0.01) was noted for final BW, ADG, G:F, and HCW. Greater final BW was observed for treated stover (4.6%) and straw (5.6%) compared with NT residues; however, AT and NT cobs were similar. Treated straw (9.7%) and stover (12.5%) resulted in greater ADG (P < 0.01) and improved G:F (10.7% and 5.0%, respectively; P < 0.01) compared with NT forms. In Exp. 2, ruminally fistulated steers (n = 5) were used in an unbalanced 5 * 7 incomplete Latin square design with a 2 * 3 + 1 factorial arrangement of treatments. Factors were crop residue (corn cobs, wheat straw, and corn stover) and chemical treatment (NT or AT) fed at 25% of diet DM. Greater DM (73.7% vs. 66.1%; P < 0.01), OM (77.0% vs. 68.5%; P < 0.01), fat (89.2 vs. 85.2; P = 0.02), and NDF (66.8% vs. 51.5%; P < 0.01) digestibilities were noted for AT than for NT. However, no difference (P > 0.10) was observed between control (46% corn; DM basis) and AT (31% corn; DM basis) for DM digestibility (70.7% vs. 73.7%) or OM digestibility (72.1% vs. 77.0%). Dry matter intakes were not different between treated and untreated diets (P = 0.38), but lower (P < 0.01) NDF intake was observed for treated diets (3.1 vs. 3.5 kg/d), suggesting that CaO treatment was effective in solubilizing some carbohydrate. These data suggest that 15% replacement of corn and 10% untreated residue with treated forage result in a nutrient supply of OM similar to that of the control. The improvements in total tract fiber digestibility that occurred when treated forages were fed may have been related to increased digestibility of recoverable NDF and not to increased ruminal pH. Feeding chemically treated crop residues and WDGS is an effective strategy for replacing a portion of corn grain and roughage in feedlot diets. PMID- 25548207 TI - Multitrial analysis of the effects of copper level and source on performance in nursery pigs. AB - A multitrial analysis was conducted to evaluate the effect of different levels of Cu from either Cu(2-hydroxy-4-(methylthio)butanoic acid [HMTBa])2 or CuSO4 on growth performance in nursery pigs. Six nursery trials were conducted from 2007 to 2012 under the same commercial conditions with initial BW of 5.75 +/- 0.41 kg at 21 +/- 3 d of age; the trials lasted for 42 d with a 3-phase feeding program (7 d in Phase I, 14 d in Phase II, and 21 d in Phase III). Diets were medicated with antibiotics and supplemented with 3,000 mg/kg Zn as ZnO during phases I and/or II. Treatments included a basal diet without added Cu or according to the NRC (1998) and supplemental levels of Cu (50 to 250 mg Cu/kg diet) from either Cu(HMTBa)2 or CuSO4; HMTBa was supplemented to make diets isomethionine. Treatments from each trial included 6 or 9 replicate pens/treatment with 22 to 25 piglets/pen. Mixed model analysis was conducted in which trial was considered a random effect, Cu level was considered a continuous fixed effect, and Cu source was a fixed effect. The basal diet within trial and statistical tests of the intercept between sources were not different, resulting in fitting a common intercept mixed model to the overall responses across phases. Cumulative ADG and ADFI quadratically responded (P < 0.05) with increasing Cu supplementation; predicted optimal ADG and ADFI occurred at 174 and 119 mg/kg, respectively. Increasing Cu supplementation linearly improved G:F (P = 0.054). No differences between sources were observed in ADG or ADFI. Numerically, pigs fed Cu(HMTBa)2 had higher ADG and lower ADFI compared to pigs fed CuSO4, resulting in better G:F for pigs supplemented with Cu(HMTBa)2 compared to pigs supplemented with CuSO4 (P < 0.01). The linear slope for increasing Cu supplementation on G:F was 2.1-fold higher for Cu(HMTBa)2 than that of CuSO4, with larger differences occurring in Phase II. In conclusion, Cu supplementation in nursery diets resulted in improved performance and Cu(HMTBa)2 is more effective than CuSO4 in improving feed efficiency. PMID- 25548208 TI - Impact of cow size on dry matter intake, residual feed intake, metabolic response, and cow performance. AB - Thirty-eight Angus-cross beef cows were used to evaluate differences in DMI, residual feed intake (RFI), and endocrine markers on the basis of cow size and RFI ranking during 2 stages of production. Cows housed in individual pens (2.2 * 9.1 m) were fed, over a 70-d feeding period, 30% Bermuda grass hay and 70% ryegrass baleage diet during lactation (LACT) and a 100% ryegrass hay diet during postweaning (NOLACT). Individual daily feed intake, BW, and BCS were recorded, and hip height was used to determine frame score (FS). Feed intake was used to calculate RFI for each cow, and cow was the experimental unit. Blood samples were obtained on d 0 and 70 and were analyzed for glucose, insulin, leptin, triiodothyronine (T3), and thyroxine (T4). Cows were assigned to a light (LIT) or heavy (HEV) BW groups on the basis of mean BW at the beginning of the LACT period. On the basis of RFI values for each feeding period, cows were placed into a negative (NEG; RFI < 0.00) or positive (POS; RFI > 0.00) RFI group and into a low (LOW; <=0.2 SD mean RFI), medium (MED; within +/-0.19 SD), or high (HI; >=0.2 SD mean RFI) RFI group. During LACT, DMI was 4.8% greater (P = 0.03) and FS was greater (P < 0.01; 6.4 and 5.5 +/- 0.16) for the HEV compared with LIT BW cows. No RFI by day interaction or RFI group main effect occurred for endocrine markers during LACT; however, a negative relationship (P = 0.04) existed between BW group and combined T3 data, and a positive relationship (P = 0.04) existed between RFI and combined insulin data. For both LACT and NOLACT, RFI was similar (P > 0.05) among BW groups; however, DMI was 6.5% and 8.9% greater (P < 0.01) for POS compared with NEG RFI in the LACT and NOLACT periods. In LACT, DMI was greater (P < 0.01) for HI and MED RFI compared with LOW RFI, and in NOLACT, DMI was greater (P < 0.01) for the HI compared with MED and LOW RFI cows and MED compared with LOW RFI cows. During NOLACT, DMI was 8.9% greater (P < 0.01) for the HEV (12.4 +/ 0.22 kg) compared with LIT (11.3 +/- 0.19 kg) BW cows. Change in BCS was greater (P <= 0.03) in higher RFI cows in both RFI groups only in the NOLACT period. Differences in T3 and T4 on d 0 and 70 were 25% and 15% greater (P <= 0.04) for the LIT BW group compared with the HEV BW group. A negative correlation existed (P <= 0.04) between BW group and T3 and T4, as well as leptin and RFI (P = 0.03). Although cow BW was independent of RFI and T3 and T4 levels tended to be greater in lighter BW cows, DMI was consistently greater for cows with heavier BW and higher RFIvalues. PMID- 25548209 TI - Kinetics of lithium as a lithium chloride dose suitable for conditioned taste aversion in lactating goats and dry sheep. AB - Lithium chloride (LiCl) is widely used for inducing conditioned taste aversion (CTA) so that livestock will reduce or avoid ingestion of toxic plants and graze groundcover mingled with valuable crops. However, pharmacokinetic studies of LiCl at effective CTA doses are lacking. With this aim, 6 Murciano-Grandina dairy does during late lactation and 6 dry Manchega dairy ewes were orally dosed with 200 and 225 mg LiCl/kg BW, respectively. Does were placed in metabolism cages whereas ewes were group fed in pens. Lithium was measured over 168 (does) and 192 h (ewes) at predefined intervals in plasma, urine, feces, and milk using flame atomic absorption spectroscopy. Plasma Li concentrations reached a maximum at 4 h in does (13.4 +/- 1.35 mg Li/L) and 12 h in ewes (17.7 +/- 0.8 mg Li/L). The calculated plasma half-lives were 40.3 +/- 3.8 and 30.9 +/- 2.1 h for does and ewes, respectively. In goats, all Li administered was recovered at 96 h (92 +/- 4% in urine, 6.5 +/- 1.3% in feces, and 2.8 +/- 0.4% in milk); however, the estimated clearance time in feces was 11 and 9 d for does and ewes, respectively. Additionally, maximum Li excretion in doe milk was 15.6 +/- 0.5 mg/L, which was approximately half of the calculated effective dose for a 5-kg BW sucking kid. In conclusion, Li kinetics in goats and sheep were similar to cattle and elimination took longer than in monogastric species. The low concentration of Li in feces, urine, and milk, as well as the complete elimination of Li from the body after 1.5 wk allows us to conclude that LiCl is safe and suitable for inducing CTA in ruminants. PMID- 25548211 TI - Highlights from the current issue: January 2015. PMID- 25548212 TI - Association of focal choroidal excavation with age-related macular degeneration. PMID- 25548213 TI - Author response: Association of focal choroidal excavation with age-related macular degeneration. PMID- 25548214 TI - ALSPAC study does not support a role for vitamin D in the prevention of myopia. PMID- 25548215 TI - The endoplasmic reticulum adaptor protein ERAdP initiates NK cell activation via the Ubc13-mediated NF-kappaB pathway. AB - NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-kappaB pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-kappaB essential modulator ubiquitination to trigger the Ubc13-mediated NF kappaB pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases. PMID- 25548216 TI - Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. AB - Innate immune pattern recognition receptors sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. In this study, we use a model of inflammation resulting from accrual of self DNA (DNase II(-/-) type I IFN receptor [Ifnar](-/-)) to understand the role of pattern recognition receptor sensing pathways in arthritis and autoantibody production. Using triple knockout (TKO) mice deficient in DNase II/IFNaR together with deficiency in either stimulator of IFN genes (STING) or absent in melanoma 2 (AIM2), we reveal central roles for the STING and AIM2 pathways in arthritis. AIM2 TKO mice show limited inflammasome activation and, similar to STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, whereas DNase II(-/-) Ifnar(-/-) mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid-sensing pathways in disease manifestations. PMID- 25548218 TI - Complement component C5 recruits neutrophils in the absence of C3 during respiratory infection with modified vaccinia virus Ankara. AB - Efficient leukocyte migration is important for an effective host response to viral infection and the development of adaptive immunity. The poxvirus strain modified vaccinia virus Ankara (MVA), a safe and efficient viral vector, rapidly induces chemokine expression and respiratory recruitment of leukocytes, which is unique among vaccinia viruses. In addition to chemokines, the complement system contributes to the attraction and activation of different types of leukocytes. Using a murine model of intranasal infection, we show in this study that MVA induced neutrophil recruitment depends on complement component C5. Remarkably, we find that C5 mediates neutrophil recruitment to the lung, even in the absence of the central complement component C3. Our findings argue for complement C5 activation during MVA infection of the lung via a C3-independent pathway, which enables rapid recruitment of neutrophils. PMID- 25548217 TI - Distinct cellular sources of hepoxilin A3 and leukotriene B4 are used to coordinate bacterial-induced neutrophil transepithelial migration. AB - Neutrophilic infiltration is a leading contributor to pathology in a number of pulmonary disease states, including cystic fibrosis. Hepoxilin A3 (HXA3) is a chemotactic eicosanoid shown to mediate the transepithelial passage of neutrophils in response to infection in several model systems and at multiple mucosal surfaces. Another well-known eicosanoid mediating general neutrophil chemotaxis is leukotriene B4 (LTB4). We sought to distinguish the roles of each eicosanoid in the context of infection of lung epithelial monolayers by Pseudomonas aeruginosa. Using human and mouse in vitro transwell model systems, we used a combination of biosynthetic inhibitors, receptor antagonists, as well as mutant sources of neutrophils to assess the contribution of each chemoattractant in driving neutrophil transepithelial migration. We found that following chemotaxis to epithelial-derived HXA3 signals, neutrophil-derived LTB4 is required to amplify the magnitude of neutrophil migration. LTB4 signaling is not required for migration to HXA3 signals, but LTB4 generation by migrated neutrophils plays a significant role in augmenting the initial HXA3-mediated migration. We conclude that HXA3 and LTB4 serve independent roles to collectively coordinate an effective neutrophilic transepithelial migratory response. PMID- 25548219 TI - Knockdown of the antiapoptotic Bcl-2 family member A1/Bfl-1 protects mice from anaphylaxis. AB - Many forms of hypersensitivity reactions and allergic responses depend on deregulated mast cell activity. Several reports suggested that the antiapoptotic Bcl-2 family protein Bcl2a1/Bfl-1/A1 plays a critical role in mast cell survival upon activation. However, its in vivo relevance is poorly understood because of quadruplication of the Bcl2a1 gene locus in mice, hindering conventional knockout studies. In this study, we used a mouse model allowing traceable constitutive knockdown of all A1 isoforms expressed in the hematopoietic system by RNA interference. Knockdown of A1 reduced mast cell numbers in the skin and impaired connective tissue-like mast cell survival upon FcepsilonRI-mediated activation in vitro. In contrast, A1 was dispensable for mucosa-like mast cell differentiation and survival. Moreover, knockdown of A1 prevented IgE-mediated passive systemic and cutaneous anaphylaxis in vivo. Our findings demonstrate that A1 is essential for the homeostasis of connective tissue mast cells, identifying A1 as a possible therapeutic target for therapy of certain types of mast cell-driven allergy symptoms. PMID- 25548221 TI - IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid. AB - Mice lacking the IL-1R-associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d galactosamine-challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist-, IL-1alpha-, or high-mobility group box-1-stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF kappaB or AP-1. CGA consequently attenuated protein or mRNA levels of NF kappaB/AP-1 target genes encoding TNF-alpha, IL-1alpha, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity-related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses. PMID- 25548220 TI - TRIF-dependent innate immune activation is critical for survival to neonatal gram negative sepsis. AB - Current evidence suggests that neonatal immunity is functionally distinct from adults. Although TLR signaling through the adaptor protein, MyD88, has been shown to be critical for survival to sepsis in adults, little is known about the role of MyD88 or TRIF in neonatal sepsis. We demonstrate that TRIF(-/-) but not MyD88( /-) neonates are highly susceptible to Escherichia coli peritonitis and bacteremia. This was associated with decreased innate immune recruitment and function. Importantly, we found that the reverse was true in adults that MyD88(-/ ) but not TRIF(-/-) or wild-type adults are susceptible to E. coli peritonitis and bacteremia. In addition, we demonstrate that TRIF but not MyD88 signaling is critical for the TLR4 protective adjuvant effect we have previously demonstrated. These data suggest a differential requirement for the survival of neonates versus adults to Gram-negative infection, and that modulation of TRIF in neonates can be used to augment survival to neonatal sepsis. PMID- 25548222 TI - Cutting edge: progesterone directly upregulates vitamin d receptor gene expression for efficient regulation of T cells by calcitriol. AB - The two nuclear hormone receptor ligands progesterone and vitamin D (vit.D) play important roles in regulating T cells. The mechanism that connects these two hormones in regulating T cells has not been established. In this study, we report that progesterone is a novel inducer of vit.D receptor (VDR) in T cells and makes T cells highly sensitive to calcitriol. At the molecular level, the induction by progesterone is mediated by two progesterone receptor-binding elements in the intron region after the first noncoding exon of the human VDR gene. Increased expression of VDR by progesterone allows highly sensitive regulation of T cells by vit.D even when vit.D levels are suboptimal. This novel regulatory pathway allows enhanced induction of regulatory T cells but suppression of Th1 and Th17 cells by the two nuclear hormones. The results have significant ramifications in effective regulation of T cells to prevent adverse immune responses during pregnancy. PMID- 25548223 TI - Endogenous intracellular cathelicidin enhances TLR9 activation in dendritic cells and macrophages. AB - Cathelicidins are a gene family best known for their antimicrobial action, but the diverse mature peptides they encode also have other host defense functions. The human cathelicidin peptide LL-37 enhances recognition of nucleic acids, an action whose significance is seen in human diseases such as psoriasis where it is associated with increased type 1 IFN production. This function has been attributed to the extracellular action of the peptide to facilitate uptake of nucleic acids. In this study, we demonstrate that the murine mature cathelicidin peptide (CRAMP), encoded by the mouse gene (Camp), is functionally distinct from the human mature peptide (LL-37), as it does not facilitate CpG entry. However, mouse cathelicidin does influence recognition of CpG as bone marrow-derived dendritic cells from Camp(-/-) mice have impaired CpG responses and Camp(-/-) mice had impaired response to CpG given i.v. or s.c. We show that cathelicidin concentrates in Lamp1 positive compartments, is colocalized with CpG in the endolysosome, can be immunoprecipitated with TLR9, and binds to CpG intracellulary. Collectively, these results indicate that the functions of cathelicidin in control of TLR9 activation may include both intracellular and extracellular effects. PMID- 25548224 TI - Protective role for caspase-11 during acute experimental murine colitis. AB - Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1beta and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis. We find that caspase-11(-/-) mice display enhanced susceptibility to DSS, because of impaired IL-18 production. The impaired IL-18 levels observed are shown to result in reduced intestinal epithelial cell proliferation and increased cell death. We also suggest that a novel type II IFN-dependent, type I IFN-TRIF independent signaling pathway is required for in vivo caspase-11 production in intestinal epithelial cells during DSS colitis. Collectively, these data suggest that IFN-gamma-mediated caspase-11 expression has a key role maintaining intestinal epithelial barrier integrity in vivo during experimentally induced acute colitis. PMID- 25548225 TI - Modulating DNA methylation in activated CD8+ T cells inhibits regulatory T cell induced binding of Foxp3 to the CD8+ T Cell IL-2 promoter. AB - We have previously demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) activated during the course of feline immunodeficiency virus (FIV) infection suppress CD8(+) CTL function in a TGF-beta-dependent fashion, inhibiting IFN gamma and IL-2 production and inducing G1 cell-cycle arrest. In this article, we describe the molecular events occurring at the IL-2 promoter leading to suppression of IL-2 production. These experiments demonstrate that Foxp3 induced by lentivirus-activated Tregs in the CD8(+) target cells binds to the IL-2 promoter, actively repressing IL-2 transcription. We further demonstrate that the chronic activation of CD8(+) T cells during FIV infection results in chromatin remodeling at the IL-2 promoter, specifically, demethylation of CpG residues. These DNA modifications occur during active transcription and translation of IL 2; however, these changes render the IL-2 promoter permissive to Foxp3-induced transcriptional repression. These data help explain, in part, the seemingly paradoxical observations that CD8(+) T cells displaying an activation phenotype exhibit altered antiviral function. Further, we demonstrate that blocking demethylation of CpG residues at the IL-2 promoter inhibits Foxp3 binding, suggesting a potential mechanism for rescue and/or reactivation of CD8(+) T cells. Using the FIV model for lentiviral persistence, these studies provide a framework for understanding how immune activation combined with Treg-mediated suppression may affect CD8(+) T cell IL-2 transcription, maturation, and antiviral function. PMID- 25548227 TI - A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection. AB - Staphylococcus aureus can cause difficult-to-treat chronic infections. We recently reported that S. aureus chronic infection was associated with a profound inhibition of T cell responses. In this study, we investigated the mechanisms responsible for the suppression of T cell responses during chronic S. aureus infection. Using in vitro coculture systems, as well as in vivo adoptive transfer of CFSE-labeled OT-II cells, we demonstrated the presence of immunosuppressive mechanisms in splenocytes of S. aureus-infected mice that inhibited the response of OT-II cells to cognate antigenic stimulation. Immunosuppression was IL-10/TGF beta independent but required cell-cell proximity. Using DEREG and Foxp3(gfp) mice, we demonstrated that CD4(+)CD25(+)Foxp3(+) regulatory T cells contributed, but only to a minor degree, to bystander immunosuppression. Neither regulatory B cells nor tolerogenic dendritic cells contributed to immunosuppression. Instead, we found a significant expansion of granulocytic (CD11b(+)Ly6G(+)Ly6C(low)) and monocytic (CD11b(+)Ly6G(-)Ly6C(high)) myeloid-derived suppressor cells (MDSC) in chronically infected mice, which exerted a strong immunosuppressive effect on T cell responses. Splenocytes of S. aureus-infected mice lost most of their suppressive activity after the in vivo depletion of MDSC by treatment with gemcitabine. Furthermore, a robust negative correlation was observed between the degree of T cell inhibition and the number of MDSC. An increase in the numbers of MDSC in S. aureus-infected mice by adoptive transfer caused a significant exacerbation of infection. In summary, our results indicate that expansion of MDSC and, to a minor degree, of regulatory T cells in S. aureus-infected mice may create an immunosuppressive environment that sustains chronic infection. PMID- 25548226 TI - Antibody-mediated trapping of helminth larvae requires CD11b and Fcgamma receptor I. AB - Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MPhi) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MPhi adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow-derived MPhi, we now identify CD11b as the major complement receptor mediating MPhi adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcgammaRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcgammaRI signaling also contributed to the upregulation of MPhi Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcgammaRI on the MPhi surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MPhi in vitro. Our findings reveal a novel role for IgG2a/c FcgammaRI-driven MPhi activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti helminth vaccine development. PMID- 25548228 TI - Survival of human circulating antigen-induced plasma cells is supported by plasma cell-niche cytokines and T follicular helper lymphocytes. AB - Human circulating Ag-induced plasma cells (PCs) contain a high proportion of cycling cells. This study reveals that these PCs spontaneously proliferate in culture during 72 h, as determined by BrdU-uptake detection. Transcriptome analysis indicates that, in comparison with tonsil and bone marrow (BM) PCs, these PCs distinctively upregulate genes involved in cell division. Blood PC proliferation occurs simultaneously with increasing apoptosis rates, and is associated with PC survival. In addition, the proliferating activity of these PCs is enhanced by the addition of cytokines present in PC survival niches. Moreover, blood Ag-induced, but not BM, PCs exhibit the expression of molecules involved in the interaction between memory B cells and T follicular helper (Tfh) cells. In fact, purified circulating and tonsil Tfh cells increased IgG secretion by blood Ag-induced, but not by BM, PCs. This effect is exerted by augmenting blood PC survival through a mechanism partly dependent on cell contact. These results strongly suggest that the proliferating capacity of circulating Ag-induced PCs contributes to their competitive migration to survival niches, either to long living PC niches or to temporal niches present in reactive lymphoid organs and inflamed tissues, structures where Tfh cells appear to participate. PMID- 25548231 TI - Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans. AB - CD4(+) regulatory T cells (Tregs) are critical for maintaining self-tolerance and function to prevent autoimmune disease. High densities of intratumoral Tregs are generally associated with poor patient prognosis, a correlation attributed to their broad immune-suppressive features. Two major populations of Tregs have been defined, thymically derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs). However, the relative contribution of nTregs versus iTregs to the intratumoral Treg compartment remains controversial. Demarcating the proportion of nTregs versus iTregs has important implications in the design of therapeutic strategies to overcome their antagonistic effects on antitumor immune responses. We used epigenetic, phenotypic, and functional parameters to evaluate the composition of nTregs versus iTregs isolated from mouse tumor models and primary human tumors. Our findings failed to find evidence for extensive intratumoral iTreg induction. Rather, we identified a population of Foxp3-stable nTregs in tumors from mice and humans. PMID- 25548229 TI - Complement deficiency promotes cutaneous wound healing in mice. AB - Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3(-/-) mice exhibit accelerated early stages of wound healing. Reconstitution of C3(-/-) mice with serum from C3(+/+) mice or purified human C3 abrogated the accelerated wound-healing phenotype. Wound histology of C3(-/-) mice revealed a reduction in inflammatory infiltrate compared with C3(+/+) mice. C3 deficiency also resulted in increased accumulation of mast cells and advanced angiogenesis. We further show that mice deficient in the downstream complement effector C5 exhibit a similar wound-healing phenotype, which is recapitulated in C5aR1(-/-) mice, but not C3aR(-/-) or C5aR2(-/-) mice. Taken together, these data suggest that C5a signaling through C5aR may in part play a pivotal role in recruitment and activation of inflammatory cells to the wound environment, which in turn could delay the early stages of cutaneous wound healing. These findings also suggest a previously underappreciated role for complement in wound healing, and may have therapeutic implications for conditions of delayed wound healing. PMID- 25548230 TI - IFN-gamma production by memory helper T cells is required for CD40-independent alloantibody responses. AB - Cognate T-B cell interactions and CD40-CD154 costimulation are essential for productive humoral immunity against T-dependent Ags. We reported that memory CD4 T cells can deliver help to B cells and induce pathogenic IgG alloantibodies in the absence of CD40-CD154 interactions. To determine cytokine requirements for CD40-independent help, we used CD40(-/-) mice containing differentiated subsets of donor-reactive memory Th cells as heart allograft recipients. Th1 and Th17, but not Th2, memory CD4 T cells elicited high titers of anti-donor Ab. Abs induced by Th17 memory CD4 T cells had decreased reactivity against donor MHC class I molecules and inferior ability to cause complement deposition in heart allografts compared with Abs induced by Th1 cells, suggesting a requirement for IFN-gamma during CD40-independent help. IFN-gamma neutralization inhibited helper functions of memory CD4 T cells in both CD40(-/-) recipients and wild type recipients treated with anti-CD154 mAb. Our results suggest that IFN-gamma secreted by pre-existing memory helper cells determines both isotype and specificity of donor-reactive alloantibodies and can thus affect allograft pathology. This information may be valuable for identifying transplant patients at risk for de novo development of pathogenic alloantibodies and for preventing alloantibody production in T cell-sensitized recipients. PMID- 25548232 TI - CD26-mediated induction of EGR2 and IL-10 as potential regulatory mechanism for CD26 costimulatory pathway. AB - CD26 is associated with T cell signal transduction processes as a costimulatory molecule, and CD26(+) T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Although the cellular and molecular mechanisms involved in CD26-mediated T cell activation have been extensively evaluated by our group and others, potential negative feedback mechanisms to regulate CD26-mediated activation still remain to be elucidated. In the present study, we examine the expression of inhibitory molecules induced via CD26-mediated costimulation. We show that coengagement of CD3 and CD26 induces preferential production of IL-10 in human CD4(+) T cells, mediated through NFAT and Raf-MEK-ERK pathways. A high level of early growth response 2 (EGR2) is also induced following CD26 costimulation, possibly via NFAT and AP-1-mediated signaling, and knockdown of EGR2 leads to decreased IL-10 production. Furthermore, CD3/CD26-stimulated CD4(+) T cells clearly suppress proliferative activity and effector cytokine production of bystander T cells in an IL-10 dependent manner. Taken together, our data suggest that robust CD26 costimulatory signaling induces preferential expression of EGR2 and IL-10 as a potential mechanism for regulating CD26-mediated activation. PMID- 25548233 TI - Effector T cells boost regulatory T cell expansion by IL-2, TNF, OX40, and plasmacytoid dendritic cells depending on the immune context. AB - CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a major role in peripheral tolerance. Multiple environmental factors and cell types affect their biology. Among them, activated effector CD4(+) T cells can boost Treg cell expansion through TNF or IL-2. In this study, we further characterized this effector T (Teff) cell-dependent Treg cell boost in vivo in mice. This phenomenon was observed when both Treg and Teff cells were activated by their cognate Ag, with the latter being the same or different. Also, when Treg cells highly proliferated on their own, there was no additional Treg cell boost by Teff cells. In a condition of low inflammation, the Teff cell-mediated Treg cell boost involved TNF, OX40L, and plasmacytoid dendritic cells, whereas in a condition of high inflammation, it involved TNF and IL-2. Thus, this feedback mechanism in which Treg cells are highly activated by their Teff cell counterparts depends on the immune context for its effectiveness and mechanism. This Teff cell-dependent Treg cell boost may be crucial to limit inflammatory and autoimmune responses. PMID- 25548235 TI - Tools for readers: Getting the most from the Neurology electronic platforms. PMID- 25548236 TI - Drawing perseveration in the behavioral variant of frontotemporal dementia. PMID- 25548234 TI - CD40L induces functional tunneling nanotube networks exclusively in dendritic cells programmed by mediators of type 1 immunity. AB - The ability of dendritic cells (DC) to mediate CD4(+) T cell help for cellular immunity is guided by instructive signals received during DC maturation, as well as the resulting pattern of DC responsiveness to the Th signal, CD40L. Furthermore, the professional transfer of antigenic information from migratory DC to lymph node-residing DC is critical for the effective induction of cellular immune responses. In this study we report that, in addition to their enhanced IL 12p70 producing capacity, human DC matured in the presence of inflammatory mediators of type 1 immunity are uniquely programmed to form networks of tunneling nanotube-like structures in response to CD40L-expressing Th cells or rCD40L. This immunologic process of DC reticulation facilitates intercellular trafficking of endosome-associated vesicles and Ag, but also pathogens such HIV 1, and is regulated by the opposing roles of IFN-gamma and IL-4. The initiation of DC reticulation represents a novel helper function of CD40L and a superior mechanism of intercellular communication possessed by type 1 polarized DC, as well as a target for exploitation by pathogens to enhance direct cell-to-cell spread. PMID- 25548237 TI - Medullary cap dysplasia: MRI and diffusion tensor imaging of a hindbrain malformation. PMID- 25548238 TI - Cognitive training in Parkinson disease: Cognition-specific vs nonspecific computer training. PMID- 25548239 TI - Influenza vaccination and cardiovascular risk in patients with recent TIA and stroke. PMID- 25548240 TI - MRI measurement of brain iron in patients with restless legs syndrome. PMID- 25548241 TI - Child Neurology: PRRT2-associated movement disorders and differential diagnoses. PMID- 25548242 TI - CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing remitting MS. PMID- 25548244 TI - Teaching NeuroImages: Primary Sjogren syndrome presenting as isolated lesion of medulla oblongata. PMID- 25548243 TI - Opinion and special articles: An interdisciplinary neuroinfectious diseases clinic to improve patient care and training. PMID- 25548245 TI - Teaching NeuroImages: Posttraumatic lumbar epidural hematoma. PMID- 25548246 TI - Analysis of metabolism in dormant spores of Bacillus species by 31P nuclear magnetic resonance analysis of low-molecular-weight compounds. AB - This work was undertaken to obtain information on levels of metabolism in dormant spores of Bacillus species incubated for weeks at physiological temperatures. Spores of Bacillus megaterium and Bacillus subtilis strains were harvested shortly after release from sporangia and incubated under various conditions, and dormant spore metabolism was monitored by (31)P nuclear magnetic resonance (NMR) analysis of molecules including 3-phosphoglyceric acid (3PGA) and ribonucleotides. Incubation for up to 30 days at 4, 37, or 50 degrees C in water, at 37 or 50 degrees C in buffer to raise the spore core pH from ~6.3 to 7.8, or at 4 degrees C in spent sporulation medium caused no significant changes in ribonucleotide or 3PGA levels. Stage I germinated spores of Bacillus megaterium that had slightly increased core water content and a core pH of 7.8 also did not degrade 3PGA and accumulated no ribonucleotides, including ATP, during incubation for 8 days at 37 degrees C in buffered saline. In contrast, spores incubated for up to 30 days at 37 or 50 degrees C in spent sporulation medium degraded significant amounts of 3PGA and accumulated ribonucleotides, indicative of RNA degradation, and these processes were increased in B. megaterium spores with a core pH of ~7.8. However, no ATP was accumulated in these spores. These data indicate that spores of Bacillus species stored in water or buffer at low or high temperatures exhibited minimal, if any, metabolism of endogenous compounds, even when the spore core pH was 7.8 and core water content was increased somewhat. However, there was some metabolism in spores stored in spent sporulation medium. PMID- 25548247 TI - Modulation of decoding fidelity by ribosomal proteins S4 and S5. AB - Ribosomal proteins S4 and S5 participate in the decoding and assembly processes on the ribosome and the interaction with specific antibiotic inhibitors of translation. Many of the characterized mutations affecting these proteins decrease the accuracy of translation, leading to a ribosomal-ambiguity phenotype. Structural analyses of ribosomal complexes indicate that the tRNA selection pathway involves a transition between the closed and open conformations of the 30S ribosomal subunit and requires disruption of the interface between the S4 and S5 proteins. In agreement with this observation, several of the mutations that promote miscoding alter residues located at the S4-S5 interface. Here, the Escherichia coli rpsD and rpsE genes encoding the S4 and S5 proteins were targeted for mutagenesis and screened for accuracy-altering mutations. While a majority of the 38 mutant proteins recovered decrease the accuracy of translation, error-restrictive mutations were also recovered; only a minority of the mutant proteins affected rRNA processing, ribosome assembly, or interactions with antibiotics. Several of the mutations affect residues at the S4-S5 interface. These include five nonsense mutations that generate C-terminal truncations of S4. These truncations are predicted to destabilize the S4-S5 interface and, consistent with the domain closure model, all have ribosomal ambiguity phenotypes. A substantial number of the mutations alter distant locations and conceivably affect tRNA selection through indirect effects on the S4-S5 interface or by altering interactions with adjacent ribosomal proteins and 16S rRNA. PMID- 25548248 TI - Another look at mutations in ribosomal protein S4 lends strong support to the domain closure model. AB - Ribosomes employ a "kinetic discrimination" mechanism, in which correct substrates are incorporated more rapidly than incorrect ones. The structural basis of this mechanism may involve 30S domain closure, a global conformational change that coincides with codon recognition. In a direct screen for fidelity altering mutations, Agarwal and coworkers (D. Agarwal, D. Kamath, S. T. Gregory, and M. O'Connor, J Bacteriol 197:1017-1025, 2015, doi:10.1128/JB.02485-14) isolated mutations that progressively truncate the C terminus of S4. All of these promote miscoding and undoubtedly destabilize the S4-S5 interface, consistent with the domain closure model. PMID- 25548249 TI - Cj1386, an atypical hemin-binding protein, mediates hemin trafficking to KatA in Campylobacter jejuni. AB - Catalase enzymes detoxify H2O2 by the dismutation of H2O2 into O2 and H2O through the use of hemin cofactors. While the structure and biochemical properties of catalase enzymes have been well characterized over many decades of research, it remained unclear how catalases acquire hemin. We have previously reported that Cj1386 is essential for ensuring proper hemin content in Campylobacter jejuni catalase (KatA) (A. Flint, Y. Q. Sun, and A. Stintzi, J Bacteriol 194: 334-345, 2012). In this report, an in-depth molecular characterization of Cj1386 was performed to elucidate the mechanistic details of this association. Coimmunoprecipitation assays revealed that KatA-Cj1386 transiently interact in vivo, and UV-visible spectroscopy demonstrated that purified Cj1386 protein binds hemin. Furthermore, hemin titration experiments determined that hemin binds to Cj1386 in a 1:1 ratio with hexacoordinate hemin binding. Mutagenesis of potential hemin-coordinating residues in Cj1386 showed that tyrosine 57 was essential for hemin coordination when Cj1386 was overexpressed in Escherichia coli. The importance of tyrosine 57 in hemin trafficking in vivo was confirmed by introducing the cj1386(Y57A) allele into a C. jejuni Deltacj1386 mutant background. The cj1386(Y57A) mutation resulted in increased sensitivity toward H2O2 relative to the wild type, suggesting that KatA was not functional in this strain. In support of this finding, KatA immunoprecipitated from the Deltacj1386+cj1386(Y57A) mutant had significantly reduced hemin content compared to that of the cj1386(WT) background. Overall, these findings indicate that Cj1386 is involved in directly trafficking hemin to KatA and that tyrosine 57 plays a key role in this function. PMID- 25548252 TI - An essential role of syntaxin 3 protein for granule exocytosis and secretion of IL-1alpha, IL-1beta, IL-12b, and CCL4 from differentiated HL-60 cells. AB - Besides their roles in the killing of pathogens, neutrophils have the capacity to package a variety of cytokines into cytoplasmic granules for subsequent release upon inflammatory conditions. Because the rapid secretion of cytokines orchestrates the action of other immune cells at the infection site and thus, can contribute to the development and chronicity of inflammatory diseases, we aimed to determine the intracellular SNARE machinery responsible for the regulation of cytokine secretion and degranulation. From a constructed gene-expression network, we first selected relevant cytokines for functional validation by the CBA approach. We established a cytokine-secretion profile for human neutrophils and dHL-60 cells, underlining their similar ability to secrete a broad variety of cytokines within proinflammatory conditions mimicked by LPS stimulation. Secondly, after screening of SNARE genes by microarray experiments, we selected STX3 for further functional studies. With the use of a siRNA strategy, we show that STX3 is clearly required for the maximal release of IL-1alpha, IL-1beta, IL 12b, and CCL4 without alteration of other cytokine secretion in dHL-60 cells. In addition, we demonstrate that STX3 is involved in MMP-9 exocytosis from gelatinase granules, where STX3 is partly localized. Our results suggest that the secretion of IL-1alpha, IL-1beta, IL-12b, and CCL4 occurs during gelatinase degranulation, a process controlled by STX3. In summary, these findings provide first evidence that STX3 has an essential role in trafficking pathways of cytokines in neutrophil granulocytes. PMID- 25548251 TI - Cytokine crowdsourcing: multicellular production of TH17-associated cytokines. AB - In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-gamma). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17 associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17 associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues. PMID- 25548254 TI - A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8alphaalpha+ dendritic cells. AB - CD8 coreceptor expression is dynamically regulated during thymocyte development and is tightly controlled by the activity of at least 5 different cis-regulatory elements. Despite the detailed characterization of the Cd8 loci, the regulation of the complex expression pattern of CD8 cannot be fully explained by the activity of the known Cd8 enhancers. In this study, we revisited the Cd8ab gene complex with bioinformatics and transgenic reporter gene expression approaches to search for additional Cd8 cis-regulatory elements. This led to the identification of an ECR (ECR-4), which in transgenic reporter gene expression assays, directed expression preferentially in CD44(hi)CD62L(+) CD8(+) T cells, including innate like CD8(+) T cells. ECR-4, designated as Cd8 enhancer E8VI, was bound by Runx/CBFbeta complexes and Bcl11b, indicating that E8VI is part of the cis regulatory network that recruits transcription factors to the Cd8ab gene complex in CD8(+) T cells. Transgenic reporter expression was maintained in LCMV-specific CD8(+) T cells upon infection, although short-term, in vitro activation led to a down-regulation of E8VI activity. Finally, E8VI directed transgene expression also in CD8alphaalpha(+) DCs but not in CD8alphaalpha-expressing IELs. Taken together, we have identified a novel Cd8 enhancer that directs expression in CD44(hi)CD62L(+) CD8(+) T cells, including innate-like and antigen-specific effector/memory CD8(+) T cells and in CD8alphaalpha(+) DCs, and thus, our data provide further insight into the cis-regulatory networks that control CD8 expression. PMID- 25548255 TI - Context-dependent role of IL-18 in cancer biology and counter-regulation by IL 18BP. AB - IL-18 is a proinflammatory and immune regulatory cytokine, member of the IL-1 family. IL-18 was initially identified as an IFN-gamma-inducing factor in T and NK cells, involved in Th1 responses. IL-18 is produced as an inactive precursor (pro-IL-18) that is enzymatically processed into a mature form by Casp1. Different cells, such as macrophages, DCs, microglial cells, synovial fibroblasts, and epithelial cells, express pro-IL-18, and the production of bioactive IL-18 is mainly regulated at the processing level. PAMP or DAMP molecules activate inflammasomes, which trigger Casp1 activation and IL-18 conversion. The natural inhibitor IL-18BP , whose production is enhanced by IFN gamma and IL-27, further regulates IL-18 activity in the extracellular environment. Inflammasomes and IL-18 represent double-edged swords in cancer, as their activation may promote tumor development and progression or oppositely, enhance anti-tumor immunity and limit tumor growth. IL-18 has shown anti-tumor activity in different preclinical models of cancer immunotherapy through the activation of NK and/or T cell responses and has been tested in clinical studies in cancer patients. However, the dual role of IL-18 in different experimental tumor models and human cancers raises critical issues on its therapeutic use in cancer. This review will summarize the biology of the IL-18/IL-18R/IL-18BP system and will address the role of IL-18 and its inhibitor, IL-18BP, in cancer biology and immunotherapy. PMID- 25548256 TI - Estimating cross-price elasticity of e-cigarettes using a simulated demand procedure. AB - INTRODUCTION: Our goal was to measure the cross-price elasticity of electronic cigarettes (e-cigarettes) and simulated demand for tobacco cigarettes both in the presence and absence of e-cigarette availability. METHOD: A sample of New Zealand smokers (N = 210) completed a Cigarette Purchase Task to indicate their demand for tobacco at a range of prices. They sampled an e-cigarette and rated it and their own-brand tobacco for favorability, and indicated how many e-cigarettes and regular cigarettes they would purchase at 0.5*, 1*, and 2* the current market price for regular cigarettes, assuming that the price of e-cigarettes remained constant. RESULTS: Cross-price elasticity for e-cigarettes was estimated as 0.16, and was significantly positive, indicating that e-cigarettes were partially substitutable for regular cigarettes. Simulated demand for regular cigarettes at current market prices decreased by 42.8% when e-cigarettes were available, and e cigarettes were rated 81% as favorably as own-brand tobacco. However when cigarettes cost 2* the current market price, significantly more smokers said they would quit (50.2%) if e-cigarettes were not available than if they were available (30.0%). CONCLUSION: Results show that e-cigarettes are potentially substitutable for regular cigarettes and their availability will reduce tobacco consumption. However, e-cigarettes may discourage smokers from quitting entirely as cigarette price increases, so policy makers should consider maintaining a constant relative price differential between e-cigarettes and tobacco cigarettes. PMID- 25548253 TI - Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis. AB - Once viewed as simply antibacterial effector cells packed with antimicrobials, neutrophils are now increasingly appreciated for their regulatory roles in immunity and inflammation. The homeostatic regulation of neutrophils is thus crucial for optimal operation of the immune system. An attractive model to understand mechanistically the role of neutrophils is periodontitis, an oral inflammatory disease that is particularly sensitive to neutrophil alterations in numbers or function. The recruitment and proper activation of neutrophils are largely dependent on leukocyte integrins and complement. This review discusses how these processes are affected by host genetic or microbial factors leading to the development of periodontitis. For instance, both hypo- and hyper-recruitment of neutrophils as a result of deficiencies in the expression of beta2 integrins or their negative regulators, respectively, causes unwarranted IL-17-dependent inflammatory bone loss. Moreover, microbial hijacking of C5aR (CD88) signaling in neutrophils impairs their antimicrobial function while promoting destructive inflammatory responses. These studies not only support the concept that neutrophil homeostasis is key to periodontal health but also reveal promising, new therapeutic targets as discussed in the review. PMID- 25548257 TI - Duties performed by occupational physicians in Norway. AB - BACKGROUND: Occupational health care for all is a global aim but has not yet been achieved. Further development should be based on knowledge of specific alternative models of occupational health services (OHS). Little is published on different OHS models and work as a physician in these services. AIMS: To describe duties for Norwegian physicians working in two different OHS models: internal and external. In the internal model, the physician is employed in an OHS located at the company served, whereas in the external model, OHS time is shared between several companies and the physician is often located outside the companies. METHODS: A web-based survey was sent to all members of the Norwegian Occupational Medicine Association. RESULTS: There were 206 responses (response rate of 73%). Only those working as OHS physicians were included (54%). Physicians in external OHS performed individual health examinations to a greater extent, otherwise few differences between physicians working in internal and external OHS were found. Changes in the priority of the physicians' duties through a period of 20 years seem to be related to changes in legislation and official guidelines related to OHS practice. CONCLUSIONS: In this study, OHS physicians in Norway performed a large number of individual-based health examinations but this was seen more in the external OHS model. Otherwise physicians' duties had similar priority in the external and internal models. Legislation and official guidelines seem to be of major importance to the duties performed. PMID- 25548258 TI - Sharps injuries in a teaching hospital: changes over a decade. AB - BACKGROUND: Sharps injuries create a high volume of occupational health (OH) workload in the health care setting. The deadline for implementation of the European Sharps Directive was 11 May 2013. AIMS: To compare the epidemiology of sharps injuries reported in a large Irish teaching hospital in 2008-10 with those reported between 1998 and 2000. METHODS: We compared data from electronic and paper OH records of sharps injuries reported between 1 January 2008 and 31 December 2010 with those from a previous study of sharps injuries reported between 1 January 1998 and 31 December 2000. RESULTS: A total of 325 sharps injuries were reported in 2008-10, compared with 332 in 1998-2000 (P = 0.568). Hepatitis B immunity in sharps injury recipients in 2008-10 was 87% compared to 86% in 1998-2000 (P = 0.32). Glove use was reported in 80% of reported injuries in 2008-10 compared with 74% in 1998-2000 (P = 0.32). In 2008-10, 49% of injuries occurred during disposal or following improper disposal of sharps, compared with 42% in 1998-2000. CONCLUSIONS: There was no significant change in the epidemiology of sharps injuries reported between 2008 and 2010 compared with 1998 2000. Further education in standard precautions, safe disposal of sharps, the use of safety-engineered devices and the benefits of hepatitis B immunization is needed. PMID- 25548259 TI - ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content. AB - ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60-70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-epsilon and PKCtheta in liver and muscle, respectively, and increased insulin-stimulated AKT2 pho-sphory-lation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle. PMID- 25548260 TI - Nucleoredoxin promotes adipogenic differentiation through regulation of Wnt/beta catenin signaling. AB - Nucleoredoxin (NRX) is a member of the thioredoxin family of proteins that controls redox homeostasis in cell. Redox homeostasis is a well-known regulator of cell differentiation into various tissue types. We found that NRX expression levels were higher in white adipose tissue of obese ob/ob mice and increased in the early adipogenic stage of 3T3-L1 preadipocyte differentiation. Knockdown of NRX decreased differentiation of 3T3-L1 cells, whereas overexpression increased differentiation. Adipose tissue-specific NRX transgenic mice showed increases in adipocyte size as well as number compared with WT mice. We further confirmed that the Wingless/int-1 class (Wnt)/beta-catenin pathway was also involved in NRX promoted adipogenesis, consistent with a previous report showing NRX regulation of this pathway. Genes involved in lipid metabolism were downregulated, whereas inflammatory genes, including those encoding macrophage markers, were significantly upregulated, likely contributing to the obesity in Adipo-NRX mice. Our results therefore suggest that NRX acts as a novel proadipogenic factor and controls obesity in vivo. PMID- 25548262 TI - Characterizing dilute combustion instabilities in a multi-cylinder spark-ignited engine using symbolic analysis. AB - Spark-ignited internal combustion engines have evolved considerably in recent years in response to increasingly stringent regulations for emissions and fuel economy. One new advanced engine strategy ustilizes high levels of exhaust gas recirculation (EGR) to reduce combustion temperatures, thereby increasing thermodynamic efficiency and reducing nitrogen oxide emissions. While this strategy can be highly effective, it also poses major control and design challenges due to the large combustion oscillations that develop at sufficiently high EGR levels. Previous research has documented that combustion instabilities can propagate between successive engine cycles in individual cylinders via self generated feedback of reactive species and thermal energy in the retained residual exhaust gases. In this work, we use symbolic analysis to characterize multi-cylinder combustion oscillations in an experimental engine operating with external EGR. At low levels of EGR, intra-cylinder oscillations are clearly visible and appear to be associated with brief, intermittent coupling among cylinders. As EGR is increased further, a point is reached where all four cylinders lock almost completely in phase and alternate simultaneously between two distinct bi-stable combustion states. From a practical perspective, it is important to understand the causes of this phenomenon and develop diagnostics that might be applied to ameliorate its effects. We demonstrate here that two approaches for symbolizing the engine combustion measurements can provide useful probes for characterizing these instabilities. PMID- 25548263 TI - Strategies of symbolization in cardiovascular time series to test individual gestational development in the fetus. AB - The analysis of symbolic dynamics applied to physiological time series retrieves dynamical properties of the underlying regulation which are robust against the symbolic transformation. In this study, three different transformations to produce a symbolic series were applied to fetal RR interval series to test whether they reflect individual changes of fetal heart rate variability in the course of pregnancy. Each transformation was applied to 215 heartbeat datasets obtained from 11 fetuses during the second and the third trimester of pregnancy (at least 10 datasets per fetus, median 17). In the symbolic series, the occurrence of symbolic sequences of length 3 was categorized according to the amount of variations in the sequence: no variation of the symbols, one variation, two variations. Linear regression with respect to gestational age showed that the individual course during pregnancy performed best using a binary transformation reflecting whether the RR interval differences are below or above a threshold. The median goodness of fit of the individual regression lines was 0.73 and also the variability among the individual slopes was low. Other transformations to symbolic dynamics performed worse but were still able to reflect the individual progress of fetal cardiovascular regulation. PMID- 25548261 TI - CETP genotype and changes in lipid levels in response to weight-loss diet intervention in the POUNDS LOST and DIRECT randomized trials. AB - Little is known about whether cholesteryl ester transfer protein (CETP) genetic variation may modify the effect of weight-loss diets varying in fat content on changes in lipid levels. We analyzed the interaction between the CETP variant rs3764261 and dietary interventions on changes in lipid levels among 732 overweight/obese adults from a 2 year randomized weight-loss trial [Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST)], and replicated the findings in 171 overweight/obese adults from an independent 2 year weight-loss trial [Dietary Intervention Randomized Controlled Trial (DIRECT)]. In the POUNDS LOST, participants with the CETP rs3764261 CC genotype on the high-fat diet had larger increases in HDL cholesterol (P = 0.001) and decreases in triglycerides (P = 0.007) than those on the low-fat diet at 6 months, while no significant difference between these two diets was observed among participants carrying other genotypes. The gene-diet interactions on changes in HDL-cholesterol and tri-glyc erides were replicated in the DIRECT (pooled P for interaction <= 0.01). Similar results on trajectory of changes in HDL cholesterol and triglycerides over the 2 year intervention were observed in both trials. Our study provides replicable evidence that individuals with the CETP rs3764261 CC genotype might derive greater effects on raising HDL cholesterol and lowering triglycerides by choosing a low-carbohydrate/high-fat weight-loss diet instead of a low-fat diet. PMID- 25548264 TI - Ordinal symbolic analysis and its application to biomedical recordings. AB - Ordinal symbolic analysis opens an interesting and powerful perspective on time series analysis. Here, we review this relatively new approach and highlight its relation to symbolic dynamics and representations. Our exposition reaches from the general ideas up to recent developments, with special emphasis on its applications to biomedical recordings. The latter will be illustrated with epilepsy data. PMID- 25548265 TI - Enhancing dynamical signatures of complex systems through symbolic computation. PMID- 25548266 TI - High-resolution joint symbolic analysis to enhance classification of the cardiorespiratory system in patients with schizophrenia and their relatives. AB - Schizophrenia as a mental illness is one of the most serious in the world. Patients with schizophrenia have an increased cardiac mortality rate, but the reasons for this remain unclear. In addition to other factors, the role of impaired autonomic regulation during acute psychosis has become more evident in different studies applying heart rate (HR) variability analyses. But, until now, respiration and cardiorespiratory regulation, which are important for homeostatic control, have not been considered. In this study, short-term cardiorespiratory couplings (CRCs) of 23 unmedicated patients with paranoid schizophrenia (SZO), 20 of their healthy first-degree relatives (REL) and 20 healthy subjects (CON) matched according to age and sex of SZO and REL were investigated by applying high-resolution joint symbolic dynamics (HRJSD) analysis. We found a significantly (p<0.0061) altered HR pattern, respiratory pattern and CRCs in SZO and only marginal alterations for the REL group in comparison with the CON group when we applied HRJSD. These results might be an indication of decreased vagal activity within the brainstem, an altered or suppressed interaction of the brainstem and higher regulatory centres, or panic- and anxiety-related changes in the brainstem associated with the acute psychosis of these patients. PMID- 25548267 TI - Assessing directionality and strength of coupling through symbolic analysis: an application to epilepsy patients. AB - Inferring strength and direction of interactions from electroencephalographic (EEG) recordings is of crucial importance to improve our understanding of dynamical interdependencies underlying various physiological and pathophysiological conditions in the human epileptic brain. We here use approaches from symbolic analysis to investigate--in a time-resolved manner- weighted and directed, short- to long-ranged interactions between various brain regions constituting the epileptic network. Our observations point to complex spatial-temporal interdependencies underlying the epileptic process and their role in the generation of epileptic seizures, despite the massive reduction of the complex information content of multi-day, multi-channel EEG recordings through symbolization. We discuss limitations and potential future improvements of this approach. PMID- 25548268 TI - Symbolic dynamics to discriminate healthy and ischaemic dilated cardiomyopathy populations: an application to the variability of heart period and QT interval. AB - Myocardial ischaemia is hypothesized to stimulate the cardiac sympathetic excitatory afferents and, therefore, the spontaneous changes of heart period (approximated as the RR interval), and the QT interval in ischaemic dilated cardiomyopathy (IDC) patients might reflect this sympathetic activation. Symbolic analysis is a nonlinear and powerful tool for the extraction and classification of patterns in time-series analysis, which implies a transformation of the original series into symbols and the construction of patterns with the symbols. The aim of this work was to investigate whether symbolic transformations of RR and QT cardiac series can provide a better separation between IDC patients and healthy control (HC) subjects compared with traditional linear measures. The variability of these cardiac series was studied during daytime and night-time periods and also during the complete 24 h recording over windows of short data sequences of approximately 5 min. The IDC group was characterized by an increase in the occurrence rate of patterns without variations (0 V%) and a reduction in the occurrence rate of patterns with one variation (1 V%) and two variations (2 V%). Concerning the RR variability during the daytime, the highest number of patterns had 0 V%, whereas the rates of 1 V% and 2 V% were lower. During the night, 1 V% and 2 V% increased at the expense of diminishing 0 V%. Patterns with and without variations between consecutive symbols were able to increase the separation between the IDC and HC groups, allowing accuracies higher than 80%. With regard to entropy measures, an increase in RR regularity was associated with cardiac disease described by accuracy >70% in the RR series and by accuracy >60% in the QTc series. These results could be associated with an increase in the sympathetic tone in IDC patients. PMID- 25548269 TI - Conditional symbolic analysis detects nonlinear influences of respiration on cardiovascular control in humans. AB - We propose a symbolic analysis framework for the quantitative characterization of complex dynamical systems. It allows the description of the time course of a single variable, the assessment of joint interactions and an analysis triggered by a conditioning input. The framework was applied to spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and integrated muscle sympathetic nerve activity (MSNA) with the aim of characterizing cardiovascular control and nonlinear influences of respiration at rest in supine position, during orthostatic challenge induced by 80 degrees head-up tilt (TILT) and about 3 min before evoked pre-syncope signs (PRESY). The approach detected (i) the exaggerated sympathetic modulation and vagal withdrawal from HP variability and the increased presence of fast MSNA variability components during PRESY compared with TILT; (ii) the increase of the SAP-HP coordination occurring at slow temporal scales and a decrease of that occurring at faster time scales during PRESY compared with TILT; (iii) the reduction of the coordination between fast MSNA and SAP patterns during TILT and PRESY; (iv) the nonlinear influences of respiration leading to an increased likelihood to observe the abovementioned findings during expiration compared with inspiration one. The framework provided simple, quantitative indexes able to distinguish experimental conditions characterized by different states of the autonomic nervous system and to detect the early signs of a life threatening situation such as postural syncope. PMID- 25548270 TI - Detecting event-related recurrences by symbolic analysis: applications to human language processing. AB - Quasi-stationarity is ubiquitous in complex dynamical systems. In brain dynamics, there is ample evidence that event-related potentials (ERPs) reflect such quasi stationary states. In order to detect them from time series, several segmentation techniques have been proposed. In this study, we elaborate a recent approach for detecting quasi-stationary states as recurrence domains by means of recurrence analysis and subsequent symbolization methods. We address two pertinent problems of contemporary recurrence analysis: optimizing the size of recurrence neighbourhoods and identifying symbols from different realizations for sequence alignment. As possible solutions for these problems, we suggest a maximum entropy criterion and a Hausdorff clustering algorithm. The resulting recurrence domains for single-subject ERPs are obtained as partition cells reflecting quasi stationary brain states. PMID- 25548271 TI - Changes of sleep-stage transitions due to ageing and sleep disorder. AB - Transition patterns between different sleep stages are analysed in terms of probability distributions of symbolic sequences for young and old subjects with and without sleep disorder. Changes of these patterns due to ageing are compared with variations of transition probabilities due to sleep disorder. PMID- 25548273 TI - Assessing levels of consciousness with symbolic analysis. AB - 'Covert consciousness' is a state in which consciousness is present without the capacity for behavioural response, and it can occur in patients with intraoperative awareness or unresponsive wakefulness syndrome. To detect and prevent this undesirable state, it is critical to develop a reliable neurobiological assessment of an individual's level of consciousness that is independent of behaviour. One such approach that shows potential is measuring surrogates of cortical communication in the brain using electroencephalography (EEG). EEG is practicable in clinical application, but involves many fundamental signal processing problems, including signal-to-noise ratio and high dimensional complexity. Symbolic analysis of EEG can mitigate these problems, improving the measurement of brain connectivity and the ability to successfully assess levels of consciousness. In this article, we review the problem of covert consciousness, basic neurobiological principles of consciousness, current methods of measuring brain connectivity and the advantages of symbolic processing, with a focus on symbolic transfer entropy (STE). Finally, we discuss recent advances and clinical applications of STE and other symbolic analyses to assess levels of consciousness. PMID- 25548272 TI - Joint symbolic dynamics for the assessment of cardiovascular and cardiorespiratory interactions. AB - Beat-to-beat variations in heart period provide information on cardiovascular control and are closely linked to variations in arterial pressure and respiration. Joint symbolic analysis of heart period, systolic arterial pressure and respiration allows for a simple description of their shared short-term dynamics that are governed by cardiac baroreflex control and cardiorespiratory coupling. In this review, we discuss methodology and research applications. Studies suggest that analysis of joint symbolic dynamics provides a powerful tool for identifying physiological and pathophysiological changes in cardiovascular and cardiorespiratory control. PMID- 25548274 TI - Lignin-rich enzyme lignin (LREL), a cellulase-treated lignin-carbohydrate derived from plants, activates myeloid dendritic cells via Toll-like receptor 4 (TLR4). AB - Lignin-carbohydrates, one of the major cell wall components, are believed to be the structures that form chemical linkage between lignin and cell wall polysaccharides. Due to the molecular complexity of lignin-containing substances, their isolation and the assignment of their biological activities have so far remained a difficult task. Here, we extracted two lignin-containing carbohydrates, lignin-rich enzyme lignin (LREL) and pure enzyme lignin (PEL), from barley husk and demonstrated that they act as immune stimulators of dendritic cells (DCs), which are particularly important in linking innate and adaptive immunity. Thioacidolysis, acid hydrolysis, and mild alkali hydrolysis of both LREL and PEL revealed that their immunostimulatory activities depended on the lignin structure and/or content, neutral sugar content (especially the characteristic distribution of galactose and mannose), and presence of an ester bond. Furthermore, we showed that the immunostimulatory potency of the lignin carbohydrate depended on its molecular weight and degree of polymerization. We also demonstrated that the LREL-induced activation of DCs was mediated via TLR4. Thus, LREL-induced increases in the expression levels of several cell surface marker proteins, production of inflammatory cytokines IL-12p40 and TNF-alpha, and activation and nuclear translocation of transcription factors, as was observed in the WT DCs, were completely abrogated in DCs derived from the TLR4(-/-) mice but not in DCs derived from the TLR2(-/-), TLR7(-/-), and TLR9(-/-) mice. We further demonstrated that LRELs isolated from other plant tissues also activated DCs. These immunostimulatory activities of lignin-carbohydrates, extracted from edible plant tissues, could have potential relevance in anti-infectious immunity and vaccine adjuvants. PMID- 25548275 TI - Induction and activation of latent transforming growth factor-beta1 are carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1). AB - Pregnancy-specific glycoproteins (PSGs) are a family of Ig-like proteins secreted by specialized placental cells. The PSG1 structure is composed of a single Ig variable region-like N-terminal domain and three Ig constant region-like domains termed A1, A2, and B2. Members of the human and murine PSG family have been shown to induce anti-inflammatory cytokines from monocytes and macrophages and to stimulate angiogenesis. We recently showed that recombinant forms of PSG1 (PSG1 Fc and PSG1-His) and PSG1 purified from the serum of pregnant women are associated with the immunoregulatory cytokine TGF-beta1 and activated latent TGF beta1. Here, we sought to examine the requirement of specific PSG1 domains in the activation of latent TGF-beta1. Plasmon surface resonance studies showed that PSG1 directly bound to the small latent complex and to the latency-associated peptide of TGF-beta1 and that this binding was mediated through the B2 domain. Furthermore, the B2 domain alone was sufficient for activating the small latent complex. In separate experiments, we found that the PSG1-mediated induction of TGF-beta1 secretion in macrophages was dependent on the N-terminal domain. Mutagenesis analysis revealed that four amino acids (LYHY) of the CC' loop of the N-terminal domain were required for induction of latent TGF-beta1 secretion. Together, our results show that two distinct domains of PSG1 are involved in the regulation of TGF-beta1 and provide a mechanistic framework for how PSGs modulate the immunoregulatory environment at the maternal-fetal interface for successful pregnancy outcome. PMID- 25548276 TI - A cyclooxygenase-2-dependent prostaglandin E2 biosynthetic system in the Golgi apparatus. AB - Cyclooxygenases (COXs) catalyze the committed step in prostaglandin (PG) biosynthesis. COX-1 is constitutively expressed and stable, whereas COX-2 is inducible and short lived. COX-2 is degraded via endoplasmic reticulum (ER) associated degradation (ERAD) following post-translational glycosylation of Asn 594. COX-1 and COX-2 are found in abundance on the luminal surfaces of the ER and inner membrane of the nuclear envelope. Using confocal immunocytofluorescence, we detected both COX-2 and microsomal PGE synthase-1 (mPGES-1) but not COX-1 in the Golgi apparatus. Inhibition of trafficking between the ER and Golgi retarded COX 2 ERAD. COX-2 has a C-terminal STEL sequence, which is an inefficient ER retention signal. Substituting this sequence with KDEL, a robust ER retention signal, concentrated COX-2 in the ER where it was stable and slowly glycosylated on Asn-594. Native COX-2 and a recombinant COX-2 having a Golgi targeting signal but not native COX-1 exhibited efficient catalytic coupling to mPGES-1. We conclude that N-glycosylation of Asn-594 of COX-2 occurs in the ER, leading to anterograde movement of COX-2 to the Golgi where the Asn-594-linked glycan is trimmed prior to retrograde COX-2 transport to the ER for ERAD. Having an inefficient ER retention signal leads to sluggish Golgi to ER transit of COX-2. This permits significant Golgi residence time during which COX-2 can function catalytically. Cytosolic phospholipase A2alpha, which mobilizes arachidonic acid for PG synthesis, preferentially translocates to the Golgi in response to physiologic Ca(2+) mobilization. We propose that cytosolic phospholipase A2alpha, COX-2, and mPGES-1 in the Golgi comprise a dedicated system for COX-2-dependent PGE2 biosynthesis. PMID- 25548277 TI - Inhibition of transforming growth factor beta (TGF-beta) signaling can substitute for Oct4 protein in reprogramming and maintain pluripotency. AB - Mouse pluripotent stem cells (PSCs), such as ES cells and induced PSCs (iPSCs), are an excellent system to investigate the molecular and cellular mechanisms involved in early embryonic development. The signaling pathways orchestrated by leukemia inhibitor factor/STAT3, Wnt/beta-catenin, and FGF/MEK/ERK play key roles in the generation of pluripotency. However, the function of TGF-beta signaling in this process remains elusive. Here we show that inhibiting TGF-beta signaling with its inhibitor SB431542 can substitute for Oct4 during reprogramming. Moreover, inhibiting TGF-beta signaling can sustain the pluripotency of iPSCs and ES cells through modulating FGF/MEK/ERK signaling. Therefore, this study reveals a novel function of TGF-beta signaling inhibition in the generation and maintenance of PSCs. PMID- 25548278 TI - NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1beta. AB - Supplemental oxygen inhalation is frequently used to treat severe respiratory failure; however, prolonged exposure to hyperoxia causes hyperoxic acute lung injury (HALI), which induces acute respiratory distress syndrome and leads to high mortality rates. Recent investigations suggest the possible role of NLRP3 inflammasomes, which regulate IL-1beta production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In this study, we investigated the role of NLRP3 inflammasomes in mice with HALI. Under hyperoxic conditions, NLRP3(-/-) mice died at a higher rate compared with wild-type and IL-1beta(-/-) mice, and there was no difference in IL 1beta production in their lungs. Under hyperoxic conditions, the lungs of NLRP3( /-) mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, as well as increased and decreased expression of MMP-9 and Bcl-2, respectively. NLRP3(-/-) mice exhibited diminished expression and activation of Stat3, which regulates MMP-9 and Bcl-2, in addition to increased numbers of apoptotic alveolar epithelial cells. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils and chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independent of IL-1beta production and contributes to the pathophysiology of HALI. PMID- 25548279 TI - Cyclin E-CDK2 protein phosphorylates plant homeodomain finger protein 8 (PHF8) and regulates its function in the cell cycle. AB - Cyclin E-CDK2 is a key regulator in G1/S transition. Previously, we identified a number of CDK2-interacting proteins, including PHF8 (plant homeodomain finger protein 8). In this report, we confirmed that PHF8 is a novel cyclin E-CDK2 substrate. By taking the approach of mass spectrometry, we identified that PHF8 Ser-844 is phosphorylated by cyclin E-CDK2. Immunoblotting analysis indicated that WT PHF8 demethylates histone H3K9me2 more efficiently than the cyclin E-CDK2 phosphorylation-deficient PHF8-S844A mutant. Furthermore, flow cytometry analysis showed that WT PHF8 promotes S phase progression more robustly than PHF8-S844A. Real-time PCR results demonstrated that PHF8 increases transcription of cyclin E, E2F3, and E2F7 to significantly higher levels compared with PHF8-S844A. Further analysis by ChIP assay indicated that PHF8 binds to the cyclin E promoter stronger than PHF8-S844A and reduces the H3K9me2 level at the cyclin E promoter more efficiently than PHF8-S844A. In addition, we found that cyclin E-CDK2 mediated phosphorylation of PHF8 Ser-844 promotes PHF8-dependent rRNA transcription in luciferase reporter assays and real-time PCR. Taken together, these results indicate that cyclin E-CDK2 phosphorylates PHF8 to stimulate its demethylase activity to promote rRNA transcription and cell cycle progression. PMID- 25548280 TI - Regulated in development and DNA damage 1 is necessary for hyperglycemia-induced vascular endothelial growth factor expression in the retina of diabetic rodents. AB - Vascular endothelial growth factor (VEGF) is considered a major role player in the pathogenesis of diabetic retinopathy, yet the mechanisms regulating its expression are not fully understood. Our laboratory previously demonstrated that diabetes-induced VEGF expression in the retina was dependent on the repressor of mRNA translation 4E-BP1. Interaction of 4E-BP1 with the cap-binding protein eIF4E regulates protein expression by controlling the selection of mRNAs for translation. The process is regulated by the master kinase mTOR in complex 1 (mTORC1), which phosphorylates 4E-BP1, thus promoting its disassociation from eIF4E. In the present study, we investigated the role of the Akt/mTORC1 repressor REDD1 (regulated in development and DNA damage) in diabetes-induced VEGF expression. REDD1 expression was induced by hyperglycemia in the retina of diabetic rodents and by hyperglycemic conditions in Muller cells concomitant with increased VEGF expression. In Muller cells, hyperglycemic conditions attenuated global rates of protein synthesis and cap-dependent mRNA translation concomitant with up-regulated cap-independent VEGF mRNA translation, as assessed by a bicistronic luciferase reporter assay. Hyperglycemic conditions also attenuated mTORC1 signaling and enhanced 4E-BP1 binding to eIF4E. Furthermore, ectopic expression of REDD1 in Muller cells was sufficient to promote both increased 4E BP1 binding to eIF4E and VEGF expression. Whereas the retina of wild-type mice exhibited increased expression of VEGF and tumor necrosis factor alpha (TNF alpha) 4 weeks after streptozotocin administration, the retina of REDD1 knock-out mice failed to do so. Overall, the results demonstrate that REDD1 contributes to the pathogenesis of diabetes in the retina by mediating the pathogenic effects of hyperglycemia. PMID- 25548281 TI - The carboxyl tail of connexin32 regulates gap junction assembly in human prostate and pancreatic cancer cells. AB - Connexins, the constituent proteins of gap junctions, are transmembrane proteins. A connexin (Cx) traverses the membrane four times and has one intracellular and two extracellular loops with the amino and carboxyl termini facing the cytoplasm. The transmembrane and the extracellular loop domains are highly conserved among different Cxs, whereas the carboxyl termini, often called the cytoplasmic tails, are highly divergent. We have explored the role of the cytoplasmic tail of Cx32, a Cx expressed in polarized and differentiated cells, in regulating gap junction assembly. Our results demonstrate that compared with the full-length Cx32, the cytoplasmic tail-deleted Cx32 is assembled into small gap junctions in human pancreatic and prostatic cancer cells. Our results further document that the expression of the full-length Cx32 in cells, which express the tail-deleted Cx32, increases the size of gap junctions, whereas the expression of the tail-deleted Cx32 in cells, which express the full-length Cx32, has the opposite effect. Moreover, we show that the tail is required for the clustering of cell-cell channels and that in cells expressing the tail-deleted Cx32, the expression of cell surface-targeted cytoplasmic tail alone is sufficient to enhance the size of gap junctions. Our live-cell imaging data further demonstrate that gap junctions formed of the tail-deleted Cx32 are highly mobile compared with those formed of full-length Cx32. Our results suggest that the cytoplasmic tail of Cx32 is not required to initiate the assembly of gap junctions but for their subsequent growth and stability. Our findings suggest that the cytoplasmic tail of Cx32 may be involved in regulating the permeability of gap junctions by regulating their size. PMID- 25548282 TI - Inhibition of autophagic turnover in beta-cells by fatty acids and glucose leads to apoptotic cell death. AB - Autophagy, a cellular recycling process responsible for turnover of cytoplasmic contents, is critical for maintenance of health. Defects in this process have been linked to diabetes. Diabetes-associated glucotoxicity/lipotoxicity contribute to impaired beta-cell function and have been implicated as contributing factors to this disease. We tested the hypothesis that these two conditions affect beta-cell function by modulating autophagy. We report that exposure of beta-cell lines and human pancreatic islets to high levels of glucose and lipids blocks autophagic flux and leads to apoptotic cell death. EM analysis showed accumulation of autophagy intermediates (autophagosomes), with abundant engulfed cargo in palmitic acid (PA)- or glucose-treated cells, indicating suppressed autophagic turnover. EM studies also showed accumulation of damaged mitochondria, endoplasmic reticulum distention, and vacuolar changes in PA treated cells. Pulse-chase experiments indicated decreased protein turnover in beta-cells treated with PA/glucose. Expression of mTORC1, an inhibitor of autophagy, was elevated in beta-cells treated with PA/glucose. mTORC1 inhibition, by treatment with rapamycin, reversed changes in autophagic flux, and cell death induced by glucose/PA. Our results indicate that nutrient toxicity-induced cell death occurs via impaired autophagy and is mediated by activation of mTORC1 in beta-cells, contributing to beta-cell failure in the presence of metabolic stress. PMID- 25548283 TI - Essential role of mitochondrial Ca2+ uniporter in the generation of mitochondrial pH gradient and metabolism-secretion coupling in insulin-releasing cells. AB - In pancreatic beta-cells, ATP acts as a signaling molecule initiating plasma membrane electrical activity linked to Ca(2+) influx, which triggers insulin exocytosis. The mitochondrial Ca(2+) uniporter (MCU) mediates Ca(2+) uptake into the organelle, where energy metabolism is further stimulated for sustained second phase insulin secretion. Here, we have studied the contribution of the MCU to the regulation of oxidative phosphorylation and metabolism-secretion coupling in intact and permeabilized clonal beta-cells as well as rat pancreatic islets. Knockdown of MCU with siRNA transfection blunted matrix Ca(2+) rises, decreased nutrient-stimulated ATP production as well as insulin secretion. Furthermore, MCU knockdown lowered the expression of respiratory chain complexes, mitochondrial metabolic activity, and oxygen consumption. The pH gradient formed across the inner mitochondrial membrane following nutrient stimulation was markedly lowered in MCU-silenced cells. In contrast, nutrient-induced hyperpolarization of the electrical gradient was not altered. In permeabilized cells, knockdown of MCU ablated matrix acidification in response to extramitochondrial Ca(2+). Suppression of the putative Ca(2+)/H(+) antiporter leucine zipper-EF hand containing transmembrane protein 1 (LETM1) also abolished Ca(2+)-induced matrix acidification. These results demonstrate that MCU-mediated Ca(2+) uptake is essential to establish a nutrient-induced mitochondrial pH gradient which is critical for sustained ATP synthesis and metabolism-secretion coupling in insulin releasing cells. PMID- 25548284 TI - Overexpression of heparanase lowers the amyloid burden in amyloid-beta precursor protein transgenic mice. AB - Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-beta (Abeta) deposits in Alzheimer disease brain and in Abeta precursor protein (AbetaPP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Abeta pathogenesis in vivo. We therefore generated a double transgenic mouse model overexpressing both human heparanase and human AbetaPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AbetaPP processing because the steady-state levels of Abeta1-40, Abeta1 42, and soluble AbetaPP beta were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the Abeta burden, measured by Abetax-40 and Abetax-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Abetax-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Abeta1-42 aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Abeta fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Abeta-HSPG interactions might be a potential strategy for Alzheimer disease treatment. PMID- 25548286 TI - WITHDRAWN: Novel role of LeuO in HNS mediated silencing of the Vibrio cholerae virulence regulatory gene toxT. AB - This manuscript has been withdrawn by the author. PMID- 25548285 TI - Free fatty acids shift insulin-induced hepatocyte proliferation towards CD95 dependent apoptosis. AB - Insulin is known to induce hepatocyte swelling, which triggers via integrins and c-Src kinase an activation of the epidermal growth factor receptor (EGFR) and subsequent cell proliferation (1). Free fatty acids (FFAs) are known to induce lipoapoptosis in liver cells in a c-Jun-NH2-terminal kinase (JNK)-dependent, but death receptor-independent way (2). As non-alcoholic steatohepatitis (NASH) is associated with hyperinsulinemia and increased FFA-blood levels, the interplay between insulin and FFA was studied with regard to hepatocyte proliferation and apoptosis in isolated rat and mouse hepatocytes. Saturated long chain FFAs induced apoptosis and JNK activation in primary rat hepatocytes, but did not activate the CD95 (Fas, APO-1) system, whereas insulin triggered EGFR activation and hepatocyte proliferation. Coadministration of insulin and FFAs, however, abolished hepatocyte proliferation and triggered CD95-dependent apoptosis due to a JNK-dependent association of the activated EGFR with CD95, subsequent CD95 tyrosine phosphorylation and formation of the death-inducing signaling complex (DISC). JNK inhibition restored the proliferative insulin effect in presence of FFAs and prevented EGFR/CD95 association, CD95 tyrosine phosphorylation and DISC formation. Likewise, in presence of FFAs insulin increased apoptosis in hepatocytes from wild type but not from Alb-Cre-FAS(fl/fl) mice, which lack functional CD95. It is concluded that FFAs can shift insulin-induced hepatocyte proliferation toward hepatocyte apoptosis by triggering a JNK signal, which allows activated EGFR to associate with CD95 and to trigger CD95-dependent apoptosis. Such phenomena may contribute to the pathogenesis of NASH. PMID- 25548287 TI - O-linked glycosylation of the mucin domain of the herpes simplex virus type 1 specific glycoprotein gC-1 is temporally regulated in a seed-and-spread manner. AB - The herpes simplex virus type 1 (HSV-1) glycoprotein gC-1, participating in viral receptor interactions and immunity interference, harbors a mucin-like domain with multiple clustered O-linked glycans. Using HSV-1-infected diploid human fibroblasts, an authentic target for HSV-1 infection, and a protein immunoaffinity procedure, we enriched fully glycosylated gC-1 and a series of its biosynthetic intermediates. This fraction was subjected to trypsin digestion and a LC-MS/MS glycoproteomics approach. In parallel, we characterized the expression patterns of the 20 isoforms of human GalNAc transferases responsible for initiation of O-linked glycosylation. The gC-1 O-glycosylation was regulated in an orderly manner initiated by synchronous addition of one GalNAc unit each to Thr-87 and Thr-91 and one GalNAc unit to either Thr-99 or Thr-101, forming a core glycopeptide for subsequent additions of in all 11 GalNAc residues to selected Ser and Thr residues of the Thr-76-Lys-107 stretch of the mucin domain. The expression patterns of GalNAc transferases in the infected cells suggested that initial additions of GalNAc were carried out by initiating GalNAc transferases, in particular GalNAc-T2, whereas subsequent GalNAc additions were carried out by followup transferases, in particular GalNAc-T10. Essentially all of the susceptible Ser or Thr residues had to acquire their GalNAc units before any elongation to longer O-linked glycans of the gC-1-associated GalNAc units was permitted. Because the GalNAc occupancy pattern is of relevance for receptor binding of gC-1, the data provide a model to delineate biosynthetic steps of O linked glycosylation of the gC-1 mucin domain in HSV-1-infected target cells. PMID- 25548288 TI - Monoubiquitination of histone H2B is intrinsic to the Bre1 RING domain-Rad6 interaction and augmented by a second Rad6-binding site on Bre1. AB - Ubiquitin signaling on chromatin is linked to diverse aspects of genome regulation, including gene expression and DNA repair. The yeast RING E3 ligase Bre1 combines with the E2 Rad6 to monoubiquitinate histone H2B during transcription. Little is known about how Bre1 directs Rad6 toward transferring only a single ubiquitin to a specific lysine residue. Using a defined in vitro system, we show that the Bre1 RING domain interaction with Rad6 is minimally sufficient to monoubiquitinate nucleosomes at histone H2B Lys-123. In addition, we reveal a cluster of charged residues on the Bre1 RING domain that is critical for recognizing the nucleosome surface. Notably, a second Rad6 binding domain of Bre1 interacts with the E2 backside and potentiates ubiquitin transfer to the substrate. Taken together, our study establishes a molecular framework for how distinct RING and non-RING E3 elements cooperate to regulate E2 reactivity and substrate selection during gene expression. PMID- 25548291 TI - New Year's Resolutions. PMID- 25548290 TI - p38 MAPK down-regulates fibulin 3 expression through methylation of gene regulatory sequences: role in migration and invasion. AB - p38 MAPKs regulate migration and invasion. However, the mechanisms involved are only partially known. We had previously identified fibulin 3, which plays a role in migration, invasion, and tumorigenesis, as a gene regulated by p38alpha. We have characterized in detail how p38 MAPK regulates fibulin 3 expression and its role. We describe here for the first time that p38alpha, p38gamma, and p38delta down-regulate fibulin 3 expression. p38alpha has a stronger effect, and it does so through hypermethylation of CpG sites in the regulatory sequences of the gene. This would be mediated by the DNA methylase, DNMT3A, which is down-regulated in cells lacking p38alpha, but once re-introduced represses Fibulin 3 expression. p38alpha through HuR stabilizes dnmt3a mRNA leading to an increase in DNMT3A protein levels. Moreover, by knocking-down fibulin 3, we have found that Fibulin 3 inhibits migration and invasion in MEFs by mechanisms involving p38alpha/beta inhibition. Hence, p38alpha pro-migratory/invasive effect might be, at least in part, mediated by fibulin 3 down-regulation in MEFs. In contrast, in HCT116 cells, Fibulin 3 promotes migration and invasion through a mechanism dependent on p38alpha and/or p38beta activation. Furthermore, Fibulin 3 promotes in vitro and in vivo tumor growth of HCT116 cells through a mechanism dependent on p38alpha, which surprisingly acts as a potent inducer of tumor growth. At the same time, p38alpha limits fibulin 3 expression, which might represent a negative feed-back loop. PMID- 25548292 TI - Cardiovascular risk prediction: balancing complexity against simple practicality. PMID- 25548293 TI - Beyond the placebo: understanding the therapeutic context. PMID- 25548289 TI - Mechanistic heterogeneity in contractile properties of alpha-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. AB - The most frequent known causes of primary cardiomyopathies are mutations in the genes encoding sarcomeric proteins. Among those are 30 single-residue mutations in TPM1, the gene encoding alpha-tropomyosin. We examined seven mutant tropomyosins, E62Q, D84N, I172T, L185R, S215L, D230N, and M281T, that were chosen based on their clinical severity and locations along the molecule. The goal of our study was to determine how the biochemical characteristics of each of these mutant proteins are altered, which in turn could provide a structural rationale for treatment of the cardiomyopathies they produce. Measurements of Ca(2+) sensitivity of human beta-cardiac myosin ATPase activity are consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca(2+) activation, and dilated cardiomyopathies are hyposensitive. We also report correlations between ATPase activity at maximum Ca(2+) concentrations and conformational changes in TnC measured using a fluorescent probe, which provide evidence that different substitutions perturb the structure of the regulatory complex in different ways. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally, we examined a computationally designed mutant, E181K, that is hypersensitive, confirming predictions derived from in silico structural analysis. PMID- 25548294 TI - Licensing exams and judicial review: the closing of one door and opening of others? PMID- 25548295 TI - Practice nursing: what do we know? PMID- 25548297 TI - Why doesn't anyone want to be a GP? PMID- 25548298 TI - Physical health indicators in SMI. PMID- 25548299 TI - Common sense or cognitive bias and groupthink: does it belong in our clinical reasoning? PMID- 25548300 TI - International primary care snapshots: Sweden and Lebanon. PMID- 25548301 TI - Dangerous ideas: improving the quality of significant event audit by involving the patients. PMID- 25548302 TI - URTI, menopause, universal health coverage, and chocolate cravings. PMID- 25548303 TI - An A-Z of medical philosophy: Y is for You and I: the philosophy of Martin Buber. PMID- 25548307 TI - My vision for a new GP frontier. PMID- 25548308 TI - William Pickles Lecture 2014: Cum Scientia Caritas - compassion with knowledge. PMID- 25548309 TI - The increasing demand for knee replacements: a hostage to fortune. PMID- 25548310 TI - What can GPs do for adult patients disclosing recent sexual violence? PMID- 25548311 TI - Measurement of ECG abnormalities and cardiovascular risk classification: a cohort study of primary care patients in the Netherlands. AB - BACKGROUND: GPs need accurate tools for cardiovascular (CV) risk assessment. Abnormalities in resting electrocardiograms (ECGs) relate to increased CV risk. AIM: To determine whether measurement of ECG abnormalities on top of established risk estimation (SCORE) improves CV risk classification in a primary care population. DESIGN AND SETTING: A cohort study of patients enlisted with academic general practices in the Netherlands (the Utrecht Health Project [UHP]). METHOD: Incident CV events were extracted from the GP records. MEANS algorithm was used to assess ECG abnormalities. Cox proportional hazards modelling was applied to relate ECG abnormalities to CV events. For a prediction model only with SCORE variables, and a model with SCORE+ECG abnormalities, the discriminative value (area under the receiver operator curve [AUC]) and the net reclassification improvement (NRI) were estimated. RESULTS: A total of 2370 participants aged 38 74 years were included, all eligible for CV risk assessment. During a mean follow up of 7.8 years, 172 CV events occurred. In 19% of the participants at least one ECG abnormality was found (Lausanne criteria). Presence of atrial fibrillation/flutter (AF) and myocardial infarction (MI) were significantly related to CV events. The AUC of the SCORE risk factors was 0.75 (95% CI = 0.71 to 0.79). Addition of MI or AF resulted in an AUC of 0.76 (95% CI = 0.72 to 0.79) and 0.75 (95% CI = 0.72 to 0.79), respectively. The NRI with the addition of ECG abnormalities was small (MI 1.0%; 95% CI = -3.2% to 6.9%; AF 0.5%; 95% CI = -3.5% to 3.3%). CONCLUSION: Performing a resting ECG in a primary care population does not seem to improve risk classification when SCORE information - age, sex, smoking, systolic blood pressure, and total cholesterol/HDL ratio - is already available. PMID- 25548312 TI - Optimising stroke prevention in patients with atrial fibrillation: application of the GRASP-AF audit tool in a UK general practice cohort. AB - BACKGROUND: Oral anticoagulation (OAC) is recommended for effective stroke prevention in the majority of atrial fibrillation patients but is often under utilised. AIM: To use the Guidance on Risk Assessment and Stroke Prevention in the Atrial Fibrillation (GRASP-AF) tool to risk stratify patients, identify antithrombotic therapy received, and determine predictors of stroke and death in a UK general practice cohort. DESIGN AND SETTING: Retrospective-observational cohort study in 11 general practices in Darlington, England, with 105 000 patients. METHOD: The study included patients with atrial fibrillation (AF) identified from GP databases using the GRASP-AF tool. Stroke risk was determined by CHADS2 and CHA2DS2-VASc scores. RESULTS: A total of 2259 (2.15%) patients with AF (mean age 76 years [SD 12]; 46% female) were identified. Use of CHA2DS2-VASc rather than CHADS2 increased the proportion eligible for OAC from 86.0% to 92.5%. Of those with CHA2DS2-VASc score of >=2, 39.7% were not receiving appropriate OAC, and of those with CHADS2 score of >=1, 39.5% were not receiving appropriate OAC. Antiplatelet monotherapy was utilised in 33-40% of patients at high risk of stroke. During 12-month follow-up, 67 (3.0%) patients experienced a stroke and 214 (9.5%) died. Use of OAC significantly reduced stroke risk (odds ratio [OR] 0.60, 95% confidence intervals [CI] = 0.45 to 0.81) and death (OR = 0.54, 95% CI = 0.38 to 0.75, P<0.001) among patients at moderate-high risk of stroke. Use of antiplatelet agents also independently predicted death (OR = 0.69, 95% CI = 0.50 to 0.94; P = 0.020). CONCLUSION: Most patients with AF in general practice are at high risk of stroke, but OAC is under-utilised in about 40%. Risk of stroke and death was significantly reduced by OAC, yet antiplatelet monotherapy was inappropriately used in approximately 25% of patients at risk of stroke. Optimal implementation of the CHA2DS2-VASc score in the GRASP-AF tool could help prevent more strokes annually. PMID- 25548313 TI - Patients' responses to transient ischaemic attack symptoms: a cross-sectional questionnaire study in Australian general practices. AB - BACKGROUND: Consensus guidelines for transient ischaemic attack (TIA) recommend urgent investigation and management, but delays in management occur and are attributable to patient and health system factors. AIM: To establish general practice patients' anticipated responses to TIA symptoms, and associations of appropriate responses. DESIGN AND SETTING: A cross-sectional questionnaire-based study in Australian general practices. METHOD: Consecutive patients attending general practices completed questionnaires that contained the Stroke Action Test (STAT) adapted for TIA about demographic, health system use, and stroke risk factors. STAT elicits appropriate or inappropriate anticipated responses to 28 symptom complexes. Anticipated actions in-hours and out-of-hours were elicited. Associations of independent variables with adapted-STAT scores were tested with multiple linear regression. RESULTS: There were 854 participants (response rate 76.9%). Urgent healthcare-seeking responses to transient neurological symptoms ranged from 96.8% for right-sided weakness with dysphasia to 59.1% for sudden dizziness. Associations of higher adapted-STAT scores were older age, Indigenous status, previous after-hours services use, self-perception of health as poor, and familiarity with a stroke public awareness campaign. A personal or family history of stroke, smoking status, and time of event (in-hours/out-of-hours) were not significantly associated with adapted-STAT scores. CONCLUSION: Most general practice attendees expressed intentions to seek health care urgently for most symptoms suggestive of TIA, with highest levels of urgency observed in high stroke-risk scenarios. Intentions were not associated with a number of major risk factors for TIA and might be improved by further educational interventions, either targeted or at population level. PMID- 25548314 TI - A cardiovascular educational intervention for primary care professionals in Spain: positive impact in a quasi-experimental study. AB - BACKGROUND: Routine general practice data collection can help identify patients at risk of cardiovascular disease. AIM: To determine whether a training programme for primary care professionals improves the recording of cardiovascular disease risk factors in electronic health records. DESIGN AND SETTING: A quasi experimental study without random assignment of professionals. This was an educational intervention study, consisting of an online-classroom 1-year training programme, and carried out in the Valencian community in Spain. METHOD: The prevalence rates of recording of cardiovascular factors (recorded every 6 months over a 4-year period) were compared between intervention and control group. Clinical relevance was calculated by absolute risk reduction (ARR), relative risk reduction (RRR), and number of patients needed-to-attend (NNA), to avoid under recording, with their 95% confidence intervals (CIs). Linear regression models were used for each of the variables. RESULTS: Of the 941 professionals initially registered, 78.1% completed the programme. The ARR ranged from 1.87% (95% CI = 1.79 to 1.94) in the diagnosis of diabetes to 15.27% (95% CI = 15.14 to 15.40) in the recording of basal blood glucose. The NNA ranged from 7 in blood pressure, cholesterol, and blood glucose recording to 54 in the diagnosis of diabetes. The RRR ranged from 26.7% in the diagnosis of diabetes to 177.1% in the recording of the Systematic Coronary Risk Evaluation (SCORE). The rates of change were greater in the intervention group and the differences were significant for recording of cholesterol (P<0.001), basal blood glucose (P<0.001), smoking (P<0.001), alcohol (P<0.001), microalbuminuria (P = 0.001), abdominal circumference (P<0.001), and SCORE (P<0.001). CONCLUSION: The education programme had a beneficial effect at the end of the follow-up that was significant and clinically relevant. PMID- 25548315 TI - Perspectives of older people engaging in nurse-led cardiovascular prevention programmes: a qualitative study in primary care in the Netherlands. AB - BACKGROUND: Cardiovascular prevention programmes are increasingly being offered to older people. To achieve the proposed benefits, adherence is crucial. Understanding the reasons for adherence and non-adherence can improve preventive care. AIM: To gain insight into what motivates older people living in the community to partake in a cardiovascular prevention programme, and reasons for subsequent continuation or withdrawal. DESIGN AND SETTING: Qualitative study of current and former participants of the ongoing >=6 year PreDIVA (prevention of dementia by intensive vascular care) trial in primary care practices in suburban areas in the Netherlands. METHOD: Semi-structured interviews were conducted with a purposive sample of 15 participants (aged 76-82 years). Interviews were audiorecorded and analysed by two independent researchers using a thematic approach. Participants were asked about their motivation for participating in the programme, along with the facilitators and barriers to continue doing so. RESULTS: Responders reported that regular check-ups offered a feeling of safety, control, or being looked after, and were an important motivator for participation. For successful continuation, a personal relationship with the nurse and a coaching approach were both essential; the lack of these, along with frequent changes of nursing staff, were considered to be barriers. Participants considered general preventive advice unnecessary or patronising, but practical support was appreciated. CONCLUSION: To successfully engage older people in long term, preventive consultations, the approach of the healthcare provider is crucial. Key elements are to offer regular check-ups, use a coaching approach and to build a personal relationship with the patient. PMID- 25548317 TI - Clinically led or clinically fronted? An alternative view of leadership. PMID- 25548316 TI - Early diagnostic suggestions improve accuracy of GPs: a randomised controlled trial using computer-simulated patients. AB - BACKGROUND: Designers of computerised diagnostic support systems (CDSSs) expect physicians to notice when they need advice and enter into the CDSS all information that they have gathered about the patient. The poor use of CDSSs and the tendency not to follow advice once a leading diagnosis emerges would question this expectation. AIM: To determine whether providing GPs with diagnoses to consider before they start testing hypotheses improves accuracy. DESIGN AND SETTING: Mixed factorial design, where 297 GPs diagnosed nine patient cases, differing in difficulty, in one of three experimental conditions: control, early support, or late support. METHOD: Data were collected over the internet. After reading some initial information about the patient and the reason for encounter, GPs requested further information for diagnosis and management. Those receiving early support were shown a list of possible diagnoses before gathering further information. In late support, GPs first gave a diagnosis and were then shown which other diagnoses they could still not discount. RESULTS: Early support significantly improved diagnostic accuracy over control (odds ratio [OR] 1.31; 95% confidence interval [95%CI] = 1.03 to 1.66, P = 0.027), while late support did not (OR 1.10; 95% CI = 0.88 to 1.37). An absolute improvement of 6% with early support was obtained. There was no significant interaction with case difficulty and no effect of GP experience on accuracy. No differences in information search were detected between experimental conditions. CONCLUSION: Reminding GPs of diagnoses to consider before they start testing hypotheses can improve diagnostic accuracy irrespective of case difficulty, without lengthening information search. PMID- 25548318 TI - Dental evaluation prior to medical treatment: who to refer? PMID- 25548319 TI - Predicting blood pressure outcomes using single-item physician-administered measures: a retrospective pooled analysis of observational studies in Belgium. AB - BACKGROUND: Patient adherence is often not monitored because existing methods of evaluating adherence are either burdensome or do not accurately predict treatment outcomes. AIM: To examine whether two simple, single-item physician-administered measures of patient adherence to antihypertensive medication are predictive of blood pressure outcomes. DESIGN AND SETTING: Retrospective database analysis of patients with hypertension treated in Belgian primary care. METHOD: Using pooled data from five observational studies, a sample was identified of 9725 patients who were assessed using two single-item physician-administered measures of adherence to antihypertensive medication: the first item of the Basel Assessment of Adherence Scale (BAAS) and the Visual Analogue Scale (VAS). These two assessment tools were administered by GPs during regular appointments with patients. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and combined SBP/DBP were measured at baseline and at 90 days. RESULTS: BAAS identified adherent patients achieved lower mean SBP and DBP compared with non adherent patients at 90 days (P<0.001), and had odds ratios of achieving blood pressure control of 0.66 (95% confidence intervals (CI) = 0.61 to 0.73, P<0.001) for SBP, 0.69 (95% CI = 0.62 to 0.76, P<0.001) for DBP, and 0.65 (95% CI = 0.59 to 0.72, P<0.001) for combined SBP/DBP. For VAS-identified adherent patients, the odds ratios of achieving blood pressure control were 0.93 (95% CI = 0.86 to 1.00, P<0.001) for SBP, 0.79 (95% CI = 0.73 to 0.85, P<0.001) for DBP, and 0.91 (95% CI = 0.84 to 0.99, P<0.001) for combined SBP/DBP. CONCLUSIONS: The first item of the BAAS and the VAS are independent predictors of blood pressure control. These methods can be integrated seamlessly into routine clinical practice by allowing GPs to quickly evaluate a patient's adherence and tailor treatment recommendations accordingly. PMID- 25548320 TI - C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia. AB - Immune-mediated platelet destruction is most frequently caused by allo- or autoantibodies via Fcgamma receptor-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating that other factors play a role. Here we show that the acute phase protein C-reactive protein (CRP), a ligand for Fc receptors on phagocytes, enhances antibody-mediated platelet destruction by human phagocytes in vitro and in vivo in mice. Without antiplatelet antibodies, CRP was found to be inert toward platelets, but it bound to phosphorylcholine exposed after oxidation triggered by antiplatelet antibodies, thereby enhancing platelet phagocytosis. CRP levels were significantly elevated in patients with allo- and autoantibody-mediated thrombocytopenias compared with healthy controls. Within a week, intravenous immunoglobulin treatment in children with newly diagnosed immune thrombocytopenia led to significant decrease of CRP levels, increased platelet numbers, and clinically decreased bleeding severity. Furthermore, the higher the level of CRP at diagnosis, the longer it took before stable platelet counts were reached. These data suggest that CRP amplifies antibody-mediated platelet destruction and may in part explain the aggravation of thrombocytopenia on infections. Hence, targeting CRP could offer new therapeutic opportunities for these patients. PMID- 25548321 TI - Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma. AB - TOX is a nuclear factor essential for the development of CD4(+) T cells in the thymus. It is normally expressed in low amounts in mature CD4(+) T cells of the skin and the peripheral blood. We have recently discovered that the transcript levels of TOX were significantly increased in mycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL), as compared to normal skin or benign inflammatory dermatoses. However, its involvement in advanced CTCL and its biological effects on CTCL pathogenesis have not been explored. In this study, we demonstrate that TOX expression is also enhanced significantly in primary CD4(+)CD7(-) cells from patients with Sezary syndrome, a leukemic variant of CTCL, and that high TOX transcript levels correlate with increased disease specific mortality. Stable knockdown of TOX in CTCL cells promoted apoptosis and reduced cell cycle progression, leading to less cell viability and colony-forming ability in vitro and to reduced tumor growth in vivo. Furthermore, TOX knockdown significantly increased 2 cyclin-dependent kinase (CDK) inhibitors, CDKN1B and CDKN1C. Lastly, blocking CDKN1B and CDKN1C reversed growth inhibition of TOX knockdown. Collectively, these findings provide strong evidence that aberrant TOX activation is a critical oncogenic event for CTCL. PMID- 25548322 TI - Improving delivery of Bright Futures preventive services at the 9- and 24-month well child visit. AB - OBJECTIVES: To determine if clinicians and staff from 21 diverse primary care practice settings could implement the 2008 Bright Futures Guidelines for Health Supervision of Infants, Children, and Adolescents, 3rd edition recommendations, at the 9- and 24-month preventive services visits. METHODS: Twenty-two practice settings from 15 states were selected from 51 applicants to participate in the Preventive Services Improvement Project (PreSIP). Practices participated in a 9 month modified Breakthrough Series Collaborative from January to November 2011. Outcome measures reflect whether the 17 components of Bright Futures recommendations were performed at the 9- and 24-month visits for at least 85% of visits. Additional measures identified which office systems were in place before and after the collaborative. RESULTS: There was a statistically significant increase for all 17 measures. Overall participating practices achieved an 85% completion rate for the preventive services measures except for discussion of parental strengths, which was reported in 70% of the charts. The preventive services score, a summary score for all the chart audit measures, increased significantly for both the 9-month (7 measures) and 24-month visits (8 measures). CONCLUSIONS: Clinicians and staff from various practice settings were able to implement the majority of the Bright Futures recommended preventive services at the 9- and 24-month visits at a high level after participation in a 9-month modified Breakthrough Series collaborative. PMID- 25548323 TI - Mobile and interactive media use by young children: the good, the bad, and the unknown. PMID- 25548324 TI - Maintaining tradition while fostering change: Pediatrics in 2015. PMID- 25548325 TI - Use of electronic health record systems by office-based pediatricians. AB - BACKGROUND AND OBJECTIVES: The American Recovery and Reinvestment Act of 2009 accelerated the implementation of electronic health records (EHRs) in pediatric offices. We sought to determine the prevalence and functionalities of EHRs, as well as pediatricians' perceptions of EHRs. METHODS: An 8-page self-administered questionnaire was sent randomly to 1621 nonretired US members of the American Academy of Pediatrics from July to December 2012. Responses were compared with a similar survey in 2009. RESULTS: The percent of pediatricians, who are using EHRs, increased significantly from 58% in the 2009 survey to 79% in 2012. Only 31% used an EHR considered to have basic functionality, and only 14% used a fully functional EHR. Providers with equal or greater than 20% public insurance patients (threshold for meaningful use eligibility) were more likely to have an EHR. Solo/2-physician practices were least likely to have adopted an EHR. Younger physicians were more likely to consider an EHR important to quality care and perceived the presence of an EHR as more important in recruiting. CONCLUSIONS: The number of office-based pediatricians who are using an EHR has steadily risen to almost 80%. EHR cost and reduction in productivity remain serious concerns. Despite the widespread adoption of EHRs by pediatricians, only few use a basic or fully functional EHR and even fewer have added pediatric functionality. There is a role for the EHR certification process to advance functionalities used by pediatricians and to increase efficiency, data exchange capability, and general EHR functionality. PMID- 25548326 TI - Increasing pediatrician participation in EHR incentive programs. PMID- 25548327 TI - Type B lactic acidosis secondary to thiamine deficiency in a child with malignancy. AB - Type B lactic acidosis is an underrecognized clinical entity that must be distinguished from type A (hypoxic) lactic acidosis. We present the case of a 4 year-old boy with medulloblastoma who presented with lactic acidosis in the setting of septic shock. His hyperlactatemia persisted to high levels even after his hemodynamic status improved. After administration of intravenous thiamine, his lactate level rapidly normalized and remained stable. It was determined that his total parenteral nutrition was deficient in vitamins due to a national shortage. Because thiamine is an important cofactor for pyruvate dehydrogenase, he was unable to use glucose through aerobic metabolism pathways. We briefly review type A versus type B lactic acidosis in this case report. PMID- 25548328 TI - Eradicating polio: how the world's pediatricians can help stop this crippling illness forever. AB - The American Academy of Pediatrics strongly supports the Polio Eradication and Endgame Strategic Plan of the Global Polio Eradication Initiative. This plan was endorsed in November 2012 by the Strategic Advisory Group of Experts on Immunization of the World Health Organization and published by the World Health Organization in April 2013. As a key component of the plan, it will be necessary to stop oral polio vaccine (OPV) use globally to achieve eradication, because the attenuated viruses in the vaccine rarely can cause polio. The plan includes procedures for elimination of vaccine-associated paralytic polio and circulating vaccine-derived polioviruses (cVDPVs). cVDPVs can proliferate when vaccine viruses are transmitted among susceptible people, resulting in mutations conferring both the neurovirulence and transmissibility characteristics of wild polioviruses. Although there are 3 different types of wild poliovirus strains, the polio eradication effort has already resulted in the global elimination of type 2 poliovirus for more than a decade. Type 3 poliovirus may be eliminated because the wild type 3 poliovirus was last detected in 2012. Thus, of the 3 wild types, only wild type 1 poliovirus is still known to be circulating and causing disease. OPV remains the key vaccine for eradicating wild polioviruses in polio infected countries because it induces high levels of systemic immunity to prevent paralysis and intestinal immunity to reduce transmission. However, OPV is a rare cause of paralysis and the substantial decrease in wild-type disease has resulted in estimates that the vaccine is causing more polio-related paralysis annually in recent years than the wild virus. The new endgame strategic plan calls for stepwise removal of the type 2 poliovirus component from trivalent oral vaccines, because type 2 wild poliovirus appears to have been eradicated (since 1999) and yet is the main cause of cVDPV outbreaks and approximately 40% of vaccine associated paralytic polio cases. The Endgame and Strategic Plan will be accomplished by shifting from trivalent OPV to bivalent OPV (containing types 1 and 3 poliovirus only). It will be necessary to introduce trivalent inactivated poliovirus vaccine (IPV) into routine immunization programs in all countries using OPV to provide population immunity to type 2 before the switch from trivalent OPV to bivalent OPV. The Global Polio Eradication Initiative hopes to achieve global eradication of polio by 2018 with this strategy, after which all OPV use will be stopped. Challenges expected for adding IPV into routine immunization schedules include higher cost of IPV compared with OPV, cold-chain capacity limits, more complex administration of vaccine because IPV requires injections as opposed to oral administration, and inferior intestinal immunity conferred by IPV. The goal of this report is to help pediatricians understand the change in strategy and outline ways that pediatricians can help global polio eradication efforts, including advocating for the resources needed to accomplish polio eradication and for incorporation of IPV into routine immunization programs in all countries. PMID- 25548330 TI - Telemedicine for evaluation of retinopathy of prematurity. AB - Retinopathy of prematurity (ROP) remains a significant threat to vision for extremely premature infants despite the availability of therapeutic modalities capable, in most cases, of managing this disorder. It has been shown in many controlled trials that application of therapies at the appropriate time is essential to successful outcomes in premature infants affected by ROP. Bedside binocular indirect ophthalmoscopy has been the standard technique for diagnosis and monitoring of ROP in these patients. However, implementation of routine use of this screening method for at-risk premature infants has presented challenges within our existing care systems, including relative local scarcity of qualified ophthalmologist examiners in some locations and the remote location of some NICUs. Modern technology, including the development of wide-angle ocular digital fundus photography, coupled with the ability to send digital images electronically to remote locations, has led to the development of telemedicine based remote digital fundus imaging (RDFI-TM) evaluation techniques. These techniques have the potential to allow the diagnosis and monitoring of ROP to occur in lieu of the necessity for some repeated on-site examinations in NICUs. This report reviews the currently available literature on RDFI-TM evaluations for ROP and outlines pertinent practical and risk management considerations that should be used when including RDFI-TM in any new or existing ROP care structure. PMID- 25548329 TI - Text message reminders for second dose of influenza vaccine: a randomized controlled trial. AB - OBJECTIVE: To determine whether provision of vaccine-health-literacy-promoting information in text message vaccine reminders improves receipt and timeliness of the second dose of influenza vaccine within a season for children in need of 2 doses. METHODS: During the 2012-2013 season, families of eligible 6-month through 8-year-old children were recruited at the time of their first influenza vaccination from 3 community clinics in New York City. Children (n = 660) were randomly assigned to "educational" text message, "conventional" text message, and "written reminder-only" arms. At enrollment, all arms received a written reminder with next dose due date. Conventional messages included second dose due date and clinic walk-in hours. Educational messages added information regarding the need for a timely second dose. Receipt of second dose by April 30 was assessed by using chi(2) tests. Timeliness was assessed by receipt of second dose by 2 weeks after due date (day 42) using chi(2) and over time using a Kaplan-Meier analysis. RESULTS: Most families were Latino and publicly insured with no significant between-arm differences between groups. Children in the educational arm were more likely to receive a second dose by April 30 (72.7%) versus conventional (66.7%) versus written reminder-only arm (57.1%; P = .003). They also had more timely receipt by day 42 (P < .001) and over time (P < .001). CONCLUSIONS: In this low income, urban, minority population, embedding health literacy information improved the effectiveness of text message reminders in promoting timely delivery of a second dose of influenza vaccine, compared with conventional text messages and written reminder only. PMID- 25548331 TI - Registry-linked electronic influenza vaccine provider reminders: a cluster crossover trial. AB - OBJECTIVE: To determine the impact of a vaccination reminder in an electronic health record supplemented with data from an immunization information system (IIS). METHODS: A noninterruptive influenza vaccination reminder, based on a real time query of hospital and city IIS, was used at 4 urban, academically affiliated clinics serving a low-income population. Using a randomized cluster-crossover design, each study site had "on" and "off" period during the fall and winter of 2011-2012. Influenza vaccination during a clinic visit was assessed for 6-month to 17-year-old patients. To assess sustainability, the reminder was active at all sites during the 2012-2013 season. RESULTS: In the 2011-2012 season, 8481 unique non-up-to-date children had visits. Slightly more non-up-to-date children seen when the reminder was 'on' were vaccinated than when 'off' (76.2% vs 73.8%; P = .027). Effects were seen in the winter (67.9% vs 62.2%; P = .005), not fall (76.8% vs 76.5%). The reminder also increased documentation of the reason for vaccine non-administration (68.1% vs 41.5%; P < .0001). During the 2011-2012 season, the reminder displayed for 8630 unique visits, and clinicians interacted with it in 83.1% of cases where patients required vaccination. During the 2012 2013 season, it displayed for 22 248 unique visits; clinicians interacted with it in 84.8% of cases. CONCLUSIONS: An IIS-linked influenza vaccination reminder increased vaccination later in the winter when fewer vaccine doses are usually given. Although the reminder did not require clinicians to interact with it, they frequently did; utilization did not wane over time. PMID- 25548332 TI - Early childhood neurodevelopment after intrauterine growth restriction: a systematic review. AB - BACKGROUND AND OBJECTIVE: Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse developmental outcomes in early childhood. The objective of this study was to carry out a systematic review of neurodevelopmental outcomes from 6 months to 3 years after IUGR. METHODS: PubMed, Embase, PsycINFO, Maternity and Infant Care, and CINAHL databases were searched by using the search terms intrauterine, fetal, growth restriction, child development, neurodevelopment, early childhood, cognitive, motor, speech, language. Studies were eligible for inclusion if participants met specified criteria for growth restriction, follow-up was conducted within 6 months to 3 years, methods were adequately described, non-IUGR comparison groups were included, and full English text of the article was available. A specifically designed data extraction form was used. The methodological quality of included studies was assessed using well-documented quality-appraisal guidelines. RESULTS: Of 731 studies reviewed, 16 were included. Poorer neurodevelopmental outcomes after IUGR were described in 11. Ten found motor, 8 cognitive, and 7 language delays. Other delays included social development, attention, and adaptive behavior. Only 8 included abnormal Doppler parameters in their definitions of IUGR. CONCLUSIONS: Evidence suggests that children are at risk for poorer neurodevelopmental outcomes following IUGR from 6 months to 3 years of age. The heterogeneity of primary outcomes, assessment measures, adjustment for confounding variables, and definitions of IUGR limits synthesis and interpretation. Sample sizes in most studies were small, and some examined preterm IUGR children without including term IUGR or AGA comparison groups, limiting the value of extant studies. PMID- 25548333 TI - Intrapulmonary recombinant factor VIIa for diffuse alveolar hemorrhage in children. AB - Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders, and it has a high mortality rate. The current treatment options of corticosteroids, transfusions, and immunosuppressants have been limited and largely unsuccessful, and they can be accompanied by multiple complications. Intrapulmonary administration of recombinant activated factor VII (rFVIIa) has been reported in adults, but there are scarce data on its use in children. The present article reviews our institutional experience with intrapulmonary rFVIIa for the treatment of DAH in children. The study included 6 pediatric patients with acute, bronchoscopically confirmed DAH treated between 2011 and 2013. The median age was 11 years, and patient diagnoses were as follows: acute myeloid leukemia (2 patients), myelodysplastic syndrome (1 patient), hemophagocytic lymphohistiocytosis (1 patient), T-cell lymphoblastic lymphoma (1 patient), and idiopathic pulmonary hemosiderosis (1 patient). These patients were treated with intrapulmonary rFVIIa concurrent with methylprednisolone, fresh-frozen plasma, and maintenance of the platelet count >50 000/mm(3). Complete and sustained hemostasis after rFVIIa treatment and an absence of adverse events were observed in all patients. The PaO2/fraction of inspired oxygen ratio increased significantly, and rapid clinical improvements were observed. Two patients who received hematopoietic stem cell transplantation died of subsequent respiratory syncytial virus and Acinetobacter baumannii infections, but the other 4 patients exhibited rapid improvement, were successfully weaned from ventilators, and experienced long-term survival. Our findings indicate that intrapulmonary administration of rFVIIa is an effective and safe treatment option for children with DAH; however, further clinical studies are needed. PMID- 25548335 TI - Patient- and family-centered care of children in the emergency department. AB - Patient- and family-centered care is an approach to the planning, delivery, and evaluation of health care that is grounded in a mutually beneficial partnership among patients, families, and health care professionals. Providing patient- and family-centered care to children in the emergency department setting presents many opportunities and challenges. This revised technical report draws on previously published policy statements and reports, reviews the current literature, and describes the present state of practice and research regarding patient- and family-centered care for children in the emergency department setting as well as some of the complexities of providing such care. PMID- 25548334 TI - Best practices for improving flow and care of pediatric patients in the emergency department. AB - This report provides a summary of best practices for improving flow, reducing waiting times, and improving the quality of care of pediatric patients in the emergency department. PMID- 25548336 TI - Race, ethnicity, and socioeconomic status in research on child health. AB - An extensive literature documents the existence of pervasive and persistent child health, development, and health care disparities by race, ethnicity, and socioeconomic status (SES). Disparities experienced during childhood can result in a wide variety of health and health care outcomes, including adult morbidity and mortality, indicating that it is crucial to examine the influence of disparities across the life course. Studies often collect data on the race, ethnicity, and SES of research participants to be used as covariates or explanatory factors. In the past, these variables have often been assumed to exert their effects through individual or genetically determined biologic mechanisms. However, it is now widely accepted that these variables have important social dimensions that influence health. SES, a multidimensional construct, interacts with and confounds analyses of race and ethnicity. Because SES, race, and ethnicity are often difficult to measure accurately, leading to the potential for misattribution of causality, thoughtful consideration should be given to appropriate measurement, analysis, and interpretation of such factors. Scientists who study child and adolescent health and development should understand the multiple measures used to assess race, ethnicity, and SES, including their validity and shortcomings and potential confounding of race and ethnicity with SES. The American Academy of Pediatrics (AAP) recommends that research on eliminating health and health care disparities related to race, ethnicity, and SES be a priority. Data on race, ethnicity, and SES should be collected in research on child health to improve their definitions and increase understanding of how these factors and their complex interrelationships affect child health. Furthermore, the AAP believes that researchers should consider both biological and social mechanisms of action of race, ethnicity, and SES as they relate to the aims and hypothesis of the specific area of investigation. It is important to measure these variables, but it is not sufficient to use these variables alone as explanatory for differences in disease, morbidity, and outcomes without attention to the social and biologic influences they have on health throughout the life course. The AAP recommends more research, both in the United States and internationally, on measures of race, ethnicity, and SES and how these complex constructs affect health care and health outcomes throughout the life course. PMID- 25548337 TI - Tribute to a patriarch: Adib Domingos Jatene, 1929-2014. PMID- 25548338 TI - Late outcomes of infants supported by extracorporeal membrane oxygenation following the Norwood operation. AB - BACKGROUND: Hospital survival for infants who require extracorporeal membrane oxygenation (ECMO) following the Norwood operation is 30% to 60%. However, little is known about late outcomes of hospital survivors and their ability to progress through subsequent palliative stages. METHODS: Between 2002 and 2012, 38 (13.4%) of the 284 neonates with hypoplastic left heart syndrome or other single ventricle variants received ECMO support following Norwood. We examined factors affecting hospital death and compared postdischarge events between hospital survivors who received postoperative ECMO (n = 16 of 38) and a control of hospital survivors who did not receive ECMO (220 of 246). RESULTS: Unplanned cardiac reoperation was the only predictor of postoperative ECMO requirement. Overall, 22 (58%) of the 38 patients were weaned from ECMO support and 16 (42%) of the 38 survived to hospital discharge. The ECMO duration was a significant factor for hospital mortality (odds ratio = 1.52 per 1-day increase [1.03-2.24], P = .035). Following discharge, 15 (94%) of the 16 underwent Glenn and 1 (6%) of the 16 had interstage mortality. In the control group, 194 (88%) of the 220 underwent Glenn and 26 (12%) of the 220 had interstage mortality or received transplantation (P = .499). Following Glenn, 3 (20%) of the 15 patients had interstage mortality or received transplantation and 12 (80%) of the 15 proceeded to Fontan or were alive awaiting Fontan. In the control group, 23 (12%) of the 194 had interstage mortality or received transplantation and 171 (88%) proceeded to Fontan or were alive awaiting Fontan (P = .357). Overall, 81% of hospital survivors were alive 5 years following discharge in both ECMO and non-ECMO groups. CONCLUSIONS: ECMO support following Norwood is associated with high probability of hospital death. Nonetheless, interstage mortality, progression to subsequent palliative stages, intermediate survival, and freedom from heart transplantation are comparable to those in patients who did not require postoperative ECMO support. PMID- 25548339 TI - Pediatric cardiac surgery Parent Education Discharge Instruction (PEDI) program: a pilot study. AB - BACKGROUND: In developing countries, more children with complex cardiac defects now receive treatment for their condition. For successful long-term outcomes, children also need skilled care at home after discharge. The Parent Education Discharge Instruction (PEDI) program was developed to educate nurses on the importance of discharge teaching and to provide them with a structured process for conducting parent teaching for home care of children after cardiac surgery. The aim of this pilot study was to generate preliminary data on the feasibility and acceptability of the nurse-led structured discharge program on an Indian pediatric cardiac surgery unit. METHODS: A pre-/post-design was used. Questionnaires were used to evaluate role acceptability, nurse and parent knowledge of discharge content, and utility of training materials with 40 nurses and 20 parents. Retrospective audits of 50 patient medical records (25 pre and 25 post) were performed to evaluate discharge teaching documentation. RESULTS: Nurses' discharge knowledge increased from a mean of 81% to 96% (P = .001) after participation in the training. Nurses and parents reported high levels of satisfaction with the education materials (3.75-4 on a 4.00-point scale). Evidence of discharge teaching documentation in patient medical records improved from 48% (12 of 25 medical records) to 96% (24 of 25 medical records) six months after the implementation of the PEDI program. CONCLUSION: The structured nurse led parent discharge teaching program demonstrated feasibility, acceptability, utility, and sustainability in the cardiac unit. Future studies are needed to examine nurse, parent, child, and organizational outcomes related to this expanded nursing role in resource-constrained environments. PMID- 25548340 TI - Mixed type total anomalous pulmonary venous connection: early results and surgical techniques. AB - INTRODUCTION: The mixed total anomalous pulmonary connection is a rare type of congenital cardiopathy. The occurrence of multiple connections of the pulmonary veins has important implication in the diagnosis and surgical planning. These types of total anomalous pulmonary venous connection (TAPVC) and the infracardiac have higher surgical mortality. METHODS: Between December 1994 and July 2013, a total of 58 children underwent surgical treatment of TAPVC. Twenty-five (43.1%) patients had supracardiac connection, 15 (25.8%) patients had intracardiac type, 12 (20.6%) patients had a mixed type, and 6 (10.3%) patients had an infracardiac type. In children with mixed TAPVC, four (33.3%) patients had type I, five (41.6%) patients had type II, and three (25.0%) patients had type III. The diagnosis of TAPVC was performed in all patients using Doppler echocardiography, and they underwent cardiopulmonary bypass with aorta-bicaval cannulation and lately we use mild hypothermia with normal flow. The drainage channels were ligated in all patients. RESULTS: The immediate surgical results were as follows: one (16.6%) death in the infracardiac group, four (16.0%) deaths in the supracardiac group, one (8.3%) death in the mixed group, and no death in the cardiac group (no statistical difference, P = .488). CONCLUSION: In this series of patients, the mixed TAPVC could be corrected only with preoperative two dimensional Doppler echocardiography with good immediate results, and we believe that the use of computed angiotomography combined with three-dimensional reconstruction may improve the surgical outcome mainly in the mixed and infracardiac group of TAPVC. PMID- 25548341 TI - Surgical cardiac denervation therapy for treatment of congenital ion channelopathies in pediatric patients: a contemporary, single institutional experience. AB - BACKGROUND: Congenital ion channel disorders, including congenital long QT syndrome (LQTS), cause significant morbidity in pediatric patients. When medication therapy does not control symptoms or arrhythmias, more invasive treatment strategies may be necessary. This study examines our institution's clinical experience with surgical cardiac denervation therapy for management of these arrhythmogenic disorders in children. METHODS: An institutional review board-approved retrospective review identified ten pediatric patients with congenital ion channelopathies who underwent surgical cardiac denervation therapy at a single institution between May 2011 and April 2014. Eight patients had a diagnosis of congenital LQTS, two patients were diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT). All patients underwent sympathectomy and partial stellate ganglionectomy via video-assisted thoracoscopic surgery (VATS). RESULTS: Six of the ten patients had documented ventricular arrhythmias preoperatively, and 70% of the patients had preoperative syncope. The corrected QT interval decreased in 75% of patients with LQTS following sympathectomy. Postoperative arrhythmogenic symptoms were absent in 88% of congenital LQTS patients, but both patients with CPVT continued to have symptoms throughout the duration of follow-up. All patients were alive after a median follow-up period of 10 months. CONCLUSIONS: Surgical cardiac denervation therapy via VATS is a useful treatment strategy for congenital LQTS patients who fail medical management, and its potential benefit in the management of CPVT is unclear. A prospective comparison of the efficacy of surgical cardiac denervation therapy and implantable cardioverter-defibrillator use in congenital ion channelopathies is timely and crucial. PMID- 25548342 TI - Closure of tubular patent ductus arteriosus with the Amplatzer Vascular Plug IV: feasibility and safety. AB - BACKGROUND: Closure of tubular patent ductus arteriosus remains a challenging procedure. Anecdotal use of Amplatzer Vascular Plug IV for tubular ductus closure has been reported but feasibility and safety in a consecutive patients' series remain unknown. METHODS: We performed a monocenter prospective study at the Marie Lannelongue Hospital in Paris, France. From 2009 to 2014, a total of 47 patients (39 infants, 3 children, and 5 adults) underwent ductus closure with the Plug IV. RESULTS: Ductus morphology was a type E in 34 (72.3%) patients and a type C in 13 (27.7%) patients. Ductus closure occurred in 39 (83.0%) infants at a median age of seven months (range: 3-23 months) and a median weight of 6.9 kg (range: 4.1 17.0 kg). A past history of prematurity and very low birth weight was found in 33 (70.2%) of them. Twelve (25.5%) patients had pulmonary hypertension. Mean Plug IV diameter was 1.9 +/- 0.1 mm larger than the mean maximal ductus diameter. Early complete closure of the ductus was obtained in all patients. Early migration of an undersized Plug IV occurred in one (2.1%) patient and was suitable for percutaneous device retrieval. After a mean follow-up of 3.4 +/- 1.4 years, all patients are alive and asymptomatic, no late complication occurred. CONCLUSION: Transcatheter closure of tubular ductus with the Amplatzer Vascular Plug IV can be safe and effective, with a 100% early occlusion rate. This device, suitable for a 4F sheath, is a new alternative for tubular ductus closure in low-body weight infants. PMID- 25548343 TI - Current outcomes of the Norwood operation in patients with single-ventricle malformations other than hypoplastic left heart syndrome. AB - BACKGROUND: Subsequent to increased experience with the Norwood operation in children with hypoplastic left heart syndrome (HLHS), its application has expanded to allow palliation of single-ventricle (SV) malformations other than HLHS. We describe current palliation outcomes in this group of SV patients. METHODS: Between 2002 and 2012, 65 of the 303 Norwood operations were performed in non-HLHS SV patients. Competing risk analysis modeled events after Norwood and after subsequent Glenn and examined risk factors affecting outcomes. RESULTS: Competing risk analysis showed that one year following Norwood, 24% of patients had died or received transplantation, 72% had undergone Glenn, and 4% were alive awaiting Glenn/Kawashima. Five years following Glenn, 9% of patients had died, 68% had undergone Fontan, and 23% were alive awaiting Fontan. Overall seven-year survival following Norwood was 68%. On multivariable analysis, mortality risk factors were unplanned cardiac reoperation (hazard ratio [HR]: 4.0 [1.5-10.6], P = .006), right dominant ventricle morphology (HR: 3.3 [1.3-8.3], P = .012), and postoperative extracorporeal membrane oxygenation (HR: 3.1 [1.1-9.0], P = .035). CONCLUSIONS: Operative death and interstage mortality continue to be problematic following Norwood palliation for non-HLHS SV variants. Outcomes seem comparable to those reported for HLHS, however they are influenced by underlying pathology; children with dominant left ventricle morphology (tricuspid atresia and double inlet left ventricle) have superior survival compared to those with dominant right ventricle morphology (mitral atresia, unbalanced atrioventricular septal defect, and most patients with atrial isomerism). Unplanned reoperations for technical imperfections diminish survival. Large multicenter studies might be warranted to better identify high-risk patients and provide guidance toward improving their survival. PMID- 25548344 TI - Adult congenital heart disease registry at Cairo University: a report of the first 100 patients. AB - AIMS: To establish a clinical registry for adult patients with congenital heart disease (CHD) managed in Cairo University Hospitals, aiming at description of the pattern and clinical profile of such patients. METHODS: Patients were recruited from both Cardiovascular Medicine Department Outpatient Clinic and inpatient wards of Cairo University Hospitals. Clinical data were collected from hospital records and directly from patients by treating cardiologists. Collected data were then registered in a dedicated database system and subsequently analyzed. RESULTS: Patients (49% males) ranged in age from 16 to 63 years, with a median of 25 years. Fifty-one patients were in the age-group from 20 to 30 years, with only 9% aged 50 years or older. Seventy-eight patients had acyanotic lesions, with atrial septal defect being the most common primary diagnosis (20% of total lesions). The remaining 22 patients had cyanotic heart disease, with tetralogy of Fallot being the predominant diagnosis (45% of cyanotic lesions). Six patients presented with infective endocarditis in the setting of CHD. Four women (8% of females) presented during pregnancy. Forty-six patients were sent for surgical correction/repair, while percutaneous intervention was planned in 20 patients. CONCLUSIONS: A new registry of adult patients with CHD managed in Cairo University Hospitals provides useful information, including the extent to which congenital heart defects are underdiagnosed and undertreated during infancy and childhood. In addition, those who were previously treated early in life require long-term follow-up in specialized centers. Establishment of a multidisciplinary team with expert physicians (cardiologists, dentists, obstetricians, and psychiatrists), cardiac surgeons, and nurses may be facilitated by development of a dedicated database system. Continuous financial support is a major challenge. PMID- 25548345 TI - Fluorescein dye-guided intraoperative identification and closure of muscular ventricular septal defect. AB - OBJECTIVE: Various techniques for intraoperative identification of muscular ventricular septal defects (VSDs) are cumbersome, difficult to use in infants, and inefficient in confirming the completeness of closure. We used simple technique of intraoperative fluorescein saline injection into the left ventricle to locate the muscular VSDs and to confirm their closure. METHODS: This is a prospective observational study conducted between April 2013 to December 2013, involving 22 patients with multiple VSDs either in isolated form or in association with other congenital cardiac anomalies. Following the closure of all visible VSDs, an 8F infant feeding tube was introduced into the left ventricle through the fossa ovalis and fluorescein saline was injected. Right ventricle was observed for saline leakage and VSD site tracking. Saline injection was repeated till appearance of no significant leak. RESULTS: A total of 63 defects were closed in 22 patients. Only two patients required re-endocardialization or septal exclusion technique for Swiss cheese septum. None of them required division of moderator band or major trabeculae. Eleven patients had insignificant residual shunting found on postoperative echocardiography. There were two deaths. In the remaining 20 patients, the mean of intensive care unit (ICU) and hospital stay was 5.4 +/- 3.72 and 10.2 +/- 4.64 days, respectively. Comparative study between patients with and without residual VSD showed no significant difference in mean inotropic score, ICU, and hospital stay, confirming the absence of significant residual shunting. CONCLUSIONS: Intraoperative fluorescein saline injection into the left ventricle is safe, effective in precisely localizing muscular VSDs and confirming the completeness of their closure. PMID- 25548346 TI - Disease-specific outcome analysis of palliation with the modified Blalock-Taussig shunt. AB - BACKGROUND: Albeit being a simple surgical procedure, adverse outcomes with the modified Blalock-Taussig shunt (MBTS) are commonly reported in generalizing terms, independent of the underlying heart disorder. METHODS: From August 1995 to December 2013, a total of 150 children underwent an MBTS for tetralogy of Fallot (TOF; n = 44, 29%), pulmonary atresia with ventricular septal defect (PA/VSD; n = 28, 19%), pulmonary atresia with intact ventricular septum (PA/IVS; n = 17, 11%), transposition of the great arteries with ventricular septal defect (TGA/VSD) with pulmonary stenosis (PS; n = 12, 8%), Ebstein malformation (n = 2, 1%), and complex univentricular anomalies (n = 47, 31%). Outcome analysis focused on operative mortality and survival until shunt takedown, adjusted to the underlying disease. RESULTS: In-hospital mortality was 8.7% (n = 13), and interstage mortality was 5.1% (n = 7), resulting in 86.1% survival to the next surgery. Hospital mortality was 14% in PA/VSD, 13% in univentricular heart, and 18% in PA/IVS, while no mortality was observed in TOF, TGA/VSD/PS, and Ebstein disease. A shunt-related complication was observed in 18% (n = 27) of the children, including acute thrombosis (n = 7, 5%), shunt stenosis (n = 3, 2%), overshunting (n = 7, 5%), and pulmonary artery stenosis (n = 10, 7%). Multivariate analysis of shunt-dependent time survival identified a shunt complication occurring in a univentricular circulation (hazard ratio [HR] 4.10, 95% confidence interval [CI] = 1.05-17.43, P = .01) and increased shunt size-to-weight ratio (HR 2.72, 95% CI = 0.80-9.18, P = .04) as risk factors. Shunt thrombosis was also a negative outcome predictor in PA/VSD, when requiring associated unifocalization (P = .05). CONCLUSION: This study shows that the outcome of palliation with the MBTS is importantly affected by the occurrence of a shunt-related complication, whose circulatory effect is even more dismal in single ventricle hearts. Since an increased shunt size-to-weight ratio additionally compromises the shunt-dependent survival, it emphasizes that the choice of the shunt with regard to size as well as surgical approach remains critical. PMID- 25548347 TI - External counterpulsation of a systemic-to-pulmonary artery shunt increases coronary blood flow in neonatal piglets. AB - BACKGROUND: Systemic-to-pulmonary artery shunt (SPS) palliation reduces coronary blood flow (CBF), which may precipitate myocardial ischemia postoperatively. HYPOTHESIS: Counterpulsation (CP) of SPS augments CBF. METHODS: Seven neonatal piglets (4.3 +/- 0.23 kg) underwent sternotomy and ductus ligation. With a 5-mm polytetrafluoroethylene graft, SPS was created from innominate to pulmonary artery. A rigid shell holding a 9.5-mm diameter balloon was placed around the graft for CP. Using electrocardiographic signal, CP was initiated to trigger balloon inflation/deflation during the diastolic/systolic intervals, respectively. Instantaneous proximal and distal pulmonary artery and mid-anterior descending coronary artery flow rates were measured using transit time flow probes. Blood pressure and flow rates were recorded during three states: shunt closed, shunt open, and shunt open with CP. STATISTICAL COMPARISON: Friedman's test and repeated measures analysis of variance. RESULTS: Diastolic pressure decreased significantly with the shunt open (39 +/- 8.4 to 28 +/- 4.5 mm Hg, P = .05), then increased with CP (33 +/- 2.3 mm Hg, P = .03). Median ratio of pulmonary to systemic flow (Qp/Qs) was 1.19, 1.9, and 1.53 with shunt closed, open, and open with CP, respectively. With CP, both diastolic coronary flow per minute (P = .018) and average diastolic flow rate per diastolic interval (P = .03) increased as well as total coronary flow per minute (P = .066; 19.6% +/- 11.7%, 25.2% +/- 17.0%, and 15.4% +/- 13.9% change from shunt open, respectively). The percentage increase in average diastolic flow rate per diastolic interval correlated strongly with Qp/Qs (R (2) = .838). CONCLUSIONS: In this model of SPS, CP increased diastolic blood pressure and CBF while maintaining significant augmentation of pulmonary blood flow (Qp/Qs). Shunt CP may aid in early postoperative management of palliative congenital heart disease. PMID- 25548348 TI - Unusual presentation of unroofed coronary sinus with cyanosis after ventricular septal defect closure. AB - Cyanosis after surgical closure of ventricular and/or atrial septal defect is very unusual. We report a case of unroofed coronary sinus in a six-month-old boy who developed cyanosis after surgical closure of ventricular and atrial septal defects. Clinical presentation, diagnosis, and management are discussed. PMID- 25548349 TI - Horseshoe lung with cor triatriatum and partial atrioventricular canal defect. AB - Cor triatriatum with partial atrioventricular canal defect is a rare congenital cardiac anomaly. We report a case of cor triatriatum and partial atrioventricular canal defect in association with horseshoe lung. PMID- 25548350 TI - Chest pain on exertion after the Takeuchi repair of anomalous origin of the left coronary artery: right ventricular ischemia due to severe pulmonary outflow tract obstruction. AB - Right ventricular (RV) outflow obstruction (in the form of valvar or supravalvular pulmonary stenosis) is a well-known complication of the Takeuchi procedure. We describe a 13-year-old male with exertional chest pain, pulmonary stenosis, RV hypertrophy, and consequent RV ischemia, which was confirmed using stress echocardiography and single-photon emission tomography. PMID- 25548351 TI - Neonatal repair of common arterial trunk with intact ventricular septum. AB - We report a rare case of common arterial trunk with intact ventricular septum, a large patent arterial duct, and normally developed aortic arch. We discuss its possible embryology, emphasizing the phenotypic differences from aortopulmonary window, and describe our surgical management. PMID- 25548352 TI - Absent pulmonary valve, tricuspid atresia, and congenital heart block. AB - We describe management of a patient with a prenatal diagnosis of absent pulmonary valve, tricuspid atresia, ventricular septal defect, and congenital heart block. Initial treatment consisted of temporary pacemaker implantation, and subsequent palliation included a central shunt during the neonatal period and placement of a permanent pacemaker. At seven months of age, a bidirectional Glenn anastomosis was performed. Cardiac catheterization revealed high cavopulmonary pressures and ventricular dysfunction precluding Fontan completion. Heart transplantation was performed at 3.75 years of age. The patient is alive and well 26 months posttransplantation. PMID- 25548353 TI - Elective ECMO support for pulmonary artery stent placement in a 4.9-kg shunt dependent patient. AB - Although extracorporeal membrane oxygenation (ECMO) is traditionally used to emergently manage respiratory and/or cardiovascular failure, ECMO can also support cardiorespiratory function in nonemergent settings. Here we present the elective use of ECMO to support a 4.9-kg pediatric patient undergoing a complex percutaneous catheter-based intervention. PMID- 25548354 TI - Right juxtaposition and a tunnel between the atrial appendages in a patient with atrial septal defect and pulmonary valve stenosis. AB - A 13-month-old boy with a diagnosis of atrial septal defect and pulmonary valve stenosis was admitted for corrective surgery. Right juxtaposition of the atrial appendages with a tunnel between the atrial appendages was detected during the surgery. The patient was operated successfully and had an uneventful recovery. Once right juxtaposition of the atrial appendages has been identified, the possibility of a "tunnel" communication between the appendages must be considered and ruled out. PMID- 25548355 TI - Anomalous origin of single coronary artery from pulmonary artery: serendipitous diagnosis and successful surgical treatment. AB - Anomalous origin of a single coronary artery from the pulmonary artery is a rare and potentially fatal congenital heart malformation. Although the actual incidence is not known, it is rarer than anomalous left coronary artery from pulmonary artery. In the absence of other important congenital cardiac anomalies, patients with anomalous origin of a single coronary artery from the pulmonary artery typically experience myocardial ischemia in association with the physiological decrease in the pulmonary vascular resistance that typically occurs over the first few months of life. To our knowledge, there have been only three reported cases of successful surgical correction. We describe a very unusual case in which the diagnosis was made intraoperatively during surgery to close a ventricular septal defect. PMID- 25548356 TI - Contained rupture of mycotic aneurysm of the left circumflex coronary artery in a child. AB - Coronary artery aneurysm (CAA) is defined as dilatation of a coronary artery segment to a diameter of more than 1.5-fold normal size. Rupture of CAA is a catastrophic event and may result in sudden death or myocardial infarction. We report this unusual case of contained rupture of the left circumflex CAA. PMID- 25548357 TI - Successful lysis of bilateral renal vein thrombosis following neonatal truncus repair. AB - Renal vein thrombosis (RVT) is the most common noncatheter-related thrombosis encountered in infancy, most of which occurs in neonates. The optimal management strategy for neonatal RVT is unclear. Fibrinolytic and heparin therapy may play a role in preventing chronic renal failure in neonates with bilateral RVT. However, the use of fibrinolytics early after any major surgery requires tremendous caution. In this report, we describe the successful use of fibrinolysis in a neonate with bilateral RVT after repair of truncus arteriosus in the early postoperative period. PMID- 25548358 TI - Plasma exchange on venovenous extracorporeal membrane oxygenation with bivalirudin anticoagulation. AB - A pediatric patient requiring venovenous (VV) extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation developed heparin-induced thrombocytopenia. Unfractionated heparin was discontinued, and a bivalirudin infusion was started. During the lung transplant evaluation, he was found to have allosensitization, requiring treatment with plasma exchange along with pulse methylprednisolone, rituximab, bortezomib, and pooled immunoglobulin infusion. We describe our experience with successful plasma exchange for allosensitization during bivalirudin anticoagulation on VV ECMO in a pediatric patient. PMID- 25548359 TI - Intrapleural fibrinolysis during pediatric extracorporeal life support. AB - Pediatric patients who require extracorporeal life support (ECLS) for refractory cardiorespiratory failure are at increased risk for intrapleural hemorrhage due to the effects of systemic anticoagulation and frequent occurrence of pneumothorax. Surgical evacuation is standard therapy for retained hemothorax to prevent secondary empyema, pulmonary compression, and development of fibrothorax. However, surgical interventions during ECLS are hazardous and place patients at increased risk for surgical site bleeding. Intrapleural fibrinolysis with tissue plasminogen activator may be used to facilitate nonsurgical evacuation of retained hemothorax. We present two pediatric patients who were safely and successfully managed with intrapleural fibrinolysis of retained hemothorax during ECLS. PMID- 25548360 TI - Vascular access for pediatric coronary angiography on extracorporeal membrane oxygenation. AB - Vascular access for catheterization of a pediatric patient on extracorporeal membrane oxygenation (ECMO) was facilitated by adding an accessory limb to the ECMO circuit. This limb was terminated with a hemostatic valve allowing insertion of a catheter. Changes in support parameters compensated for the change in the effective diameter of the ECMO cannula on insertion of the catheter. This method can overcome difficulties in obtaining vascular access for patients on ECMO. PMID- 25548361 TI - An unusual cause of persisting hyperlactatemia in a neonate undergoing open heart surgery. AB - Being a reflection of the degree of global tissue anoxia, serum lactate levels therefore can be used as a marker of organ damage and eventual outcome. A statistically significant association was observed between serum lactate levels and subsequent mortality and morbidity in critically ill adults, children, and neonates. In cardiac critical care, hyperlactatemia is usually multifactorial in origin, resulting from a combination of etiologies. Many centers are using serial lactate levels in conjugation with other parameters of cellular oxygen delivery, consumption, or extraction to monitor prognosis after pediatric cardiac surgery. A single initial lactate level has a lesser predictive value for morbidity and mortality after pediatric cardiac surgery than its failure to fall within 48 hours of surgery. In case of persistently high lactate levels with no other evidence of cellular hypoperfusion, other possibilities must be considered. There has been an established association of lactic acidosis with thiamine deficiency, but this has not yet been reported in newborns undergoing congenital cardiac surgery. We present one such rare case. PMID- 25548362 TI - Recurrent neoaortic insufficiency after the switch back operation with previous repair of transposition with ventricular septal defect and aortic arch hypoplasia. AB - Neoaortic insufficiency is not uncommon after the arterial switch operation (ASO) for d-Transposition, yet surgery is rarely required. In a patient with worsening neoaortic regurgitation post-arterial switch and ventricular septal defect (VSD) closure, we performed a successful "switch back" operation with documented aortic valve competence on discharge echocardiography. However, recurrent severe aortic insufficiency required valve replacement, and histopathology of the excised valve indicated abnormal leaflet/vascular wall structure. We question whether the switch back operation is a viable option for neoaortic insufficiency after an ASO in patients with previous d-Transposition and VSD, when the native pulmonary valve may have structural deficiencies. PMID- 25548363 TI - Hybrid palliation for a neonate with functional single ventricle and restrictive atrial septal defect: a case report. AB - We present the case of a neonate who was successfully treated with emergency hybrid palliation soon after birth, including a stent insertion into a severely thickened atrial septum and bilateral pulmonary artery banding. The patient was prenatally diagnosed with severe pulmonary venous hypertension owing to mitral atresia and intact atrial septum associated with functional single ventricle and coarctation of the aorta. PMID- 25548364 TI - Double aortic arch associated with bronchopulmonary sequestration: a rare dual anomaly. AB - We report two isolated and rare congenital malformations, namely double aortic arch and bronchopulmonary sequestration occurring as coexisting lesions in an infant. Clinical presentation leading up to a detailed anatomic diagnosis, using echocardiography and multidetector computerized tomographic angiographic imaging are described. To our knowledge, our patient is the second case reported with this dual pathology, making it an exceedingly rare occurrence. PMID- 25548366 TI - Recanalization of an acute neonatal life-threatening superior vena cava syndrome. PMID- 25548365 TI - Right aortic arch with retroesophageal left innominate artery and left patent ductus arteriosus: a rare vascular ring. PMID- 25548367 TI - Hypoplastic left heart syndrome and ventriculocoronary connections. PMID- 25548369 TI - Indwelling pleural catheters for pleural effusions associated with end-stage renal disease: a case series. AB - BACKGROUND: Pleural effusions are a common complication of end-stage renal disease.These effusions are occasionally refractory to medical management, but few options are then available. Indwelling pleural catheter insertion (IPC) has been well described for the management of malignant pleural effusions and, more recently, of nonmalignant effusions of other origin. We aimed to analyze our experience and to evaluate the safety and feasibility of using IPCs for pleural effusion associated with end-stage renal disease. METHODS: We constructed a cohort of patients who underwent IPC insertion for pleural effusions associated with end-stage renal disease. The IPCs were inserted as a palliative measure in patients who had thoracentesis twice within the preceding 2 weeks, no evidence of infection and either failure to respond, complications or intolerance to maximal medical therapy, or if IPC insertion would enable discharge when the patient was hospitalized mainly for dyspnea due to pleural effusion. RESULTS: There were nine IPCs inserted in eight patients. Patients had significant dyspnea at baseline with a median baseline dyspnea index of 1.5 [interquartile range (IQR) 0-3]. Dyspnea improved significantly 2 weeks after catheter insertion with a median transitional dyspnea index of 6 (IQR 4.5-7.0). There was no occurrence of empyema or other major complications.Serum albumin did not decrease after catheter insertion. IPCs were removed in four patients(50%) and successful spontaneous pleurodesis occurred in three patients (37.5%) after a median of 77 days (IQR 9 208). CONCLUSION: IPC insertion for pleural effusions associated with end-stage renal disease appears safe and effective. Larger studies are needed, particularly regarding the impact of this intervention on quality of life. PMID- 25548370 TI - Cigarette smoke-induced cell cycle arrest in spermatocytes [GC-2spd(ts)] is mediated through crosstalk between Ahr-Nrf2 pathway and MAPK signaling. AB - Our earlier studies have demonstrated that the cigarette smoke in the form of cigarette smoke condensate (CSC) causes growth arrest of a mouse spermatocyte cell line [GC-2spd(ts)] through activation of the AHR-NRF2 pathway. The present study demonstrates the CSC-activated p38 and ERK MAPK signaling in GC-2spd(ts) via arylhydrocarbon receptor (AHR). Pharmacological inhibition by using AHR antagonist, or p38 MAPK and ERK (MEK1) inhibitors significantly abrogates CSC induced growth arrest by AHR and MAPK inactivation. QRT-PCR, western blot, and immunofluorescence of Ahr-target of Nrf2, and stress-inducible growth suppressive Atf3 and E2f4 following treatments indicate a crosstalk among these pathways. Regulation of Atf3 by Nrf2 and Ahr through RNA interference suggests the existence of a cross-regulatory loop between the targets. CSC induction of E2f4 via Atf3 and its regulation by pharmacological inhibitors reveal a possible regulatory mechanism of growth inhibitory CSC. SiRNA silencing of Ahr, Nrf2, Atf3, and E2f4 genes and downregulation of cyclins by CSC corroborate the growth inhibitory effect of cigarette smoke. Thus, the data obtained suggest that the CSC-mediated MAPKs and AHR-NRF2 crosstalks lay the molecular basis for the growth arrest and cell death of spermatocytes. PMID- 25548371 TI - Protein kinase C-delta and -beta coordinate flow-induced directionality and deformation of migratory human blood T-lymphocytes. AB - T-lymphocyte migration under flow is critical for immune responses, but the mechanisms by which flow modulates the migratory behaviors of T-lymphocytes remain unclear. Human peripheral blood T-lymphocytes (PBTLs), when stimulated with phorbol 12-myristate 13-acetate (PMA), stretched their cell bodies dramatically and moved along the flow direction. In contrast, stromal cell derived factor-1alpha-stimulated PBTLs deformed and migrated in a random manner. Here we elucidated the molecular mechanisms underlying flow-induced directionality and deformation of PMA-stimulated PBTLs. PMA primed PBTLs for polarization under flow, with protein kinase C (PKC)-delta enriched in the leading edge, PKC-betaI in the microtubule organizing center, and PKC-betaII in the uropod and peripheral region. PKC-delta regulated cell protrusions in the leading edge through Tiam1/Rac1/calmodulin, whereas PKC-beta regulated RhoA/Rho associated kinase activity and microtubule stability to modulate uropod contractility and detachment. Our findings indicate that PKC-delta and -beta coordinate in the cell leading edge and uropod, respectively, to modulate the directionality and deformability of migratory T-lymphocytes under flow. PMID- 25548372 TI - Ameliorative effect of Allolobophora caliginosa extract on hepatotoxicity induced by silicon dioxide nanoparticles. AB - This study aims to evaluate the possible ameliorative effect of earthworm (Allolobophora caliginosa) extract (EE) against silicon dioxide nanoparticles (SiNPs)-induced liver injury in male albino rats. The effectiveness of EE was compared with silymarin as a standard hepatoprotective drug. The present work demonstrates the antioxidant activity of EE by 1,1-diphenyl-2-picrylhydrazyl assay. Administration of SiNPs, for 15 consecutive days, caused changes in most of the biochemical parameters, namely, serum aminotransferase enzymes activities (alanine transaminase and aspartate transaminase), alkaline phosphatase activity, total protein, total and direct bilirubin level, malondialdehyde, glutathione reduced, catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase. In addition, administration of SiNPs induced changes in liver tissue architecture. Administration of EE, for subsequent 30 days, to SiNPs exposure demonstrated significant ameliorative effects on nearly all the studied parameters, and such effects were compatible with those of silymarin. In addition, the administration of EE repairs, to some extent, the abnormal architecture of the liver tissue induced by SiNPs. PMID- 25548373 TI - Oxidative stress following exposure to silver and gold nanoparticles in mice. AB - Silver (Ag) and gold nanoparticles (Au NPs) have wide applications. They are increasingly being used in the medical devices, biosensors, cancer cell imaging, and cosmetics. Increased applications of these NPs in the technological advances have also led to the risk of exposure to these particles. This study investigated the toxic effects of Ag and Au NPs (1 MUM and 2 MUM, oral) on mouse erythrocytes and tissues after 14 consecutive days' exposure. Our results demonstrate significant increase in reactive oxygen species (ROS) and depletion of antioxidant enzyme status in erythrocytes and tissues. Hepatic and renal toxicity was evident from liver and kidney function tests. Inflammatory markers, interleukin-6 and nitric oxide synthase increased in plasma on administration following exposure to these NPs at both the doses. A more pronounced increase was noted in kidney metallothionein (MT) compared to liver MT on exposure to these NPs. Toxic potential of these NPs was further confirmed by increased 8-hydroxy-2' deoxyguanosine levels in urine, a biomarker of DNA damage. Among the two NPs, Ag NP was more toxic at 2 MUM dose compared to lower dose of 1 MUM. The study suggests oxidative stress as the major mechanism responsible for the toxic manifestations induced by Ag and Au NPs. PMID- 25548374 TI - Induction of hsp70, hsp90, and catalase activity in planarian Dugesia japonica exposed to cadmium. AB - The hsp70 and hsp90 expression patterns and catalase (CAT) activity in the freshwater planaria Dugesia japonica exposed to cadmium (Cd) under laboratory conditions were investigated. Planaria were exposed to a range of Cd concentrations (0-150 MUg Cd/L) for 24 h. The expression levels of hsp70 and hsp90 were determined by relative quantitative real-time polymerase chain reaction. Within the overall dose range in the experiment, the expression level of hsp70 and the activity of CAT in D. japonica were altered significantly. Hsp70 was induced in D. japonica upon Cd exposure concentrations as low as 9.375 MUg Cd/L. No significant effect on the expression level of hsp90 was observed. Our findings demonstrated that stress gene hsp70, but not hsp90, was responsive to Cd contamination in D. japonica CAT activity was significantly induced at concentrations of 18.75, 37.5, and 75 MUg Cd/L after 24-h exposure. We recommend that the use of hsp70 as a biomarker should be complemented by evidence of changes in other parameters, such as CAT activity, in D. japonica. PMID- 25548375 TI - Influence of alpha-tocopherol and alpha-lipoic acid on bisphenol-A-induced oxidative damage in liver and ovarian tissue of rats. AB - Bisphenol A (BPA) is a commonly used material in daily life, and it is argued to cause oxidative stress in liver and ovarian tissue. alpha-Lipoic acid (ALA) and alpha-tocopherol (ATF), two of the most effective antioxidants, may play a role in preventing the toxic effect. Therefore, the purpose of this study was to examine the beneficial effects of ALA, ATF, and that of ALA + ATF combination on oxidative damage induced by BPA. Female Wistar rats were divided into five groups (control, BPA, BPA + ALA, BPA + ATF, and BPA + ALA + ATF). BPA (25 mg/kg/day), ALA (100 mg/kg/day), and ATF (20 mg/kg/day) were administered for 30 days. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), liver malondialdehyde (L-MDA) and glutathione peroxidase (L-GPx), and ovarian malondialdehyde (Ov-MDA) and nitric oxide (Ov-NO) were significantly higher in the BPA-treated groups compared with the control group. The levels of AST and ALT decreased in the BPA + ALA, BPA + ATF, and BPA + ALA + ATF groups compared with the BPA group. Similarly, BPA + ALA or BPA + ATF led to decreases in L-MDA and Ov-MDA levels compared with the BPA group. However, the BPA + ALA + ATF group showed a significant decrease in L-MDA levels compared with the BPA + ALA group and the BPA + ATF group. The levels of L-GPx decreased in the BPA + ATF and the BPA + ALA + ATF groups compared with the BPA group. The administration of ATF and ALA + ATF significantly decreased the Ov-NO levels. This study demonstrates that BPA causes oxidative damage in liver and ovarian tissues. ALA, ATF, or their combination were found to be beneficial in preventing BPA-induced oxidative stress. PMID- 25548376 TI - Economic abuse in the lives of women abused by an intimate partner: a qualitative study. AB - This article presents qualitative findings of a study that examined the role of financial issues and economic factors in the lives of women who have experienced intimate partner violence (IPV). Eight themes emerged in discussions with women about the ways in which money and economic issues played a role in their experiences of abuse. Taken together, women's discussions clearly support an "economic abuse" dimension of IPV. Implications for safely advancing the economic well-being of low-income survivors are discussed. PMID- 25548377 TI - Abducens nerve palsy and meningitis by Rickettsia typhi. AB - Patients with rickettsial infection may present with encephalitis or meningitis but neurologic involvement is rare in murine typhus. Here, we report two patients with Rickettsia typhi meningitis who presented with cranial neuropathy, presumably caused by two distinct disease processes. Recognition of the disease manifestations is important because rickettsial infections are potentially associated with significant morbidity. Simple effective treatments are available. PMID- 25548378 TI - Malaria in the Americas: trends from 1959 to 2011. AB - Malaria has declined in recent years in countries of the American continents. In 2011, 12 of 21 endemic countries had already met their 2015 Millennium Development Goal. However, this declining trend has not been adequately evaluated. An analysis of the number of cases per 100,000 people (annual parasite index [API]) and the percentage of positive blood slides (slide positivity rate [SPR]) during the period of 1959-2011 in 21 endemic countries was done using the joinpoint regression methodology. During 1960-1979, API and SPR increased significantly and peaked in the 1980s. Since the 1990s, there have been significant declining trends in both API and SPR. Additionally, both Plasmodium vivax and P. falciparum species-specific incidence have declined. With the exception of two countries, such a collectively declining malaria trend was not observed in previous decades. This presents a unique opportunity for the Americas to seriously consider malaria elimination as a final goal. PMID- 25548379 TI - Five cases of recurrent meningitis associated with chronic strongyloidiasis. AB - Although meningitis secondary to chronic strongyloidiasis is a rare complication, it is associated with a high mortality rate. Recurrent meningitis can occur if the underlying parasitic infection is left untreated. We report five cases of recurrent meningitis related to chronic strongyloidiasis that were associated with human T-lymphotropic virus type 1 (HTLV-1) infection. Common causative organisms are Escherichia coli, Streptococcus bovis, and Klebsiella pneumonia. One patient died during the second episode of meningitis. Three patients showed significant gastrointestinal and respiratory symptoms before developing headache and fever. In four cases, patients developed multiple recurrences even with the treatment of thiabendazol. Ivermectin seems to be a better agent compared with thiabendazol to achieve eradication of strongyloidiasis. PMID- 25548380 TI - Relative frequency, characteristics, and antimicrobial susceptibility patterns of Vibrio spp., Aeromonas spp., Chromobacterium violaceum, and Shewanella spp. in the northern territory of Australia, 2000-2013. AB - Vibrio, Aeromonas, Chromobacterium violaceum, and Shewanella (VACS) are water associated Gram-negative organisms that can cause a variety of infections. The frequency, patient characteristics, and antimicrobial susceptibilities for 468 isolates from 442 patients from the Northern Territory were reviewed. Aeromonas spp. (312 of 468; 67%) were most commonly isolated followed by Vibrio spp. (71 of 468; 15%), Shewanella spp. (61 of 468; 13%), and C. violaceum (24 of 468; 5%). A strong male predominance was found (male to female ratio of 2.3:1). Skin and soft tissue isolations (373 of 468; 80%) from lower limb infections (222 of 371; 60%) were the most common clinical manifestation. The episodes were usually polymicrobial (281 of 468; 60%). Coisolates included Staphylococcus aureus (137 of 468; 29%), beta-hemolytic streptococci (74 of 468; 16%), enterobacteriaceae (111 of 468; 24%), non-fermentative Gram-negative bacilli (35 of 468; 7%), and other VACS organisms (37 of 468; 8%). Antimicrobial resistance of VACS organisms to ciprofloxacin (0-4%), cefepime (0-3%), and gentamicin (0-0.8%) and Vibrio spp., Aeromonas spp., and Shewanella to cotrimoxazole (0-3%) was rarely shown. For water-associated lower limb skin and soft tissue infections in the tropics, clinicians should consider empirical antimicrobial therapy with agents active against S. aureus and VACS organisms. PMID- 25548381 TI - Deficiency in mannose-binding lectin-associated serine protease-2 does not increase susceptibility to Trypanosoma cruzi infection. AB - Trypanosoma cruzi is the causative agent of Chagas' disease, a chronic illness affecting 10 million people around the world. The complement system plays an important role in fighting microbial infections. The recognition molecules of the lectin pathway of complement activation, mannose-binding lectin (MBL), ficolins, and CL-11, bind to specific carbohydrates on pathogens, triggering complement activation through MBL-associated serine protease-2 (MASP-2). Previous in vitro work showed that human MBL and ficolins contribute to T. cruzi lysis. However, MBL-deficient mice are only moderately compromised in their defense against the parasite, as they may still activate the lectin pathway through ficolins and CL 11. Here, we assessed MASP-2-deficient mice, the only presently available mouse line with total lectin pathway deficiency, for a phenotype in T. cruzi infection. Total absence of lectin pathway functional activity did not confer higher susceptibility to T. cruzi infection, suggesting that it plays a minor role in the immune response against this parasite. PMID- 25548382 TI - Prevalence of Borrelia burgdorferi sensu lato in ticks from eastern China. AB - To explore the tick distribution and prevalence of Borrelia in Zhejiang Province, we performed a survey in nine sites. A total of 447 adult ticks of 11 species were captured and the dominant tick species were Haemaphysalis longicornis and Ixodes sinensis and the abundance of tick species in different areas varied significantly. Overall, 4.70% of the ticks were polymerase chain reaction (PCR) positive for Borrelia. The average PCR positive rates were 5.19% for H. longicornis, 3.45% for Amblyomma testudinarium, 1.06% for I. sinensis, 5.00% for Rhipicephalus (Boophilus) microplus, and 19.44% for Ixodes granulatus, respectively. No Borrelia DNA was detected in Rhiphicephalus haemaphysaloides, Haemaphysalis yeni, Dermacentor taiwanensis, Haemaphysalis hystricis, Hyalomna asiaticum, and Ixodes ovatus. The prevalence of Borrelia was significantly different among tick species and the prevalence in I. granulatus was significantly higher than that in other tick species. Of note, experimentally confirmed vectors for B. burgdorferi s.l. including I. sinensis and I. granulatus were found in Zhejiang Province. Two species of B. burgdorferi s.l. exist in Zhejiang Province of which 12 sequences were most similar to the sequence of Borrelia garinii and nine sequences were most similar to the sequence of Borrelia valaisiana or Borrelia yangtze sp. nov. PMID- 25548383 TI - Formation of infectious dengue virus-antibody immune complex in vivo in marmosets (Callithrix jacchus) after passive transfer of anti-dengue virus monoclonal antibodies and infection with dengue virus. AB - Infection with a dengue virus (DENV) serotype induces cross-reactive, weakly neutralizing antibodies to different dengue serotypes. It has been postulated that cross-reactive antibodies form a virus-antibody immune complex and enhance DENV infection of Fc gamma receptor (FcgammaR)-bearing cells. We determined whether infectious DENV-antibody immune complex is formed in vivo in marmosets after passive transfer of DENV-specific monoclonal antibody (mAb) and DENV inoculation and whether infectious DENV-antibody immune complex is detectable using FcgammaR-expressing cells. Marmosets showed that DENV-antibody immune complex was exclusively infectious to FcgammaR-expressing cells on days 2, 4, and 7 after passive transfer of each of the mAbs (mAb 4G2 and mAb 6B6C) and DENV inoculation. Although DENV-antibody immune complex was detected, contribution of the passively transferred antibody to overall viremia levels was limited in this study. The results indicate that DENV cross-reactive antibodies form DENV antibody immune complex in vivo, which is infectious to FcgammaR-bearing cells but not FcgammaR-negative cells. PMID- 25548385 TI - Schizotypy from a developmental perspective. AB - The schizotypy construct focuses attention on the liability to develop schizophrenia-spectrum disorders, yet traditionally, the schizotypy models have put more emphasis on stress-vulnerability interactions rather than developmental dynamics of emerging risk for psychopathology. Indeed, developmental accounts of this emerging personality trait have rarely been explicitly formulated. In this position article, we wish to convey some of the basic developmental tenets of schizotypy, and how they can inform high-risk research. Firstly, we tackle the state vs trait issue to outline the possible relationship between high-risk states and trait schizotypy. Second, we review the evidence suggesting that the consolidation of schizotypy, encompassing its 3 main dimensions, could be considered as a developmental mediator between very early risk factors and transition into high-risk states. Importantly, developmental dynamics between endophenotypes, as well as transactional and epigenetics mechanisms should enter modern conceptualizations of schizotypy. Finally, we present a developmental psychopathology perspective of schizotypy sensitive to both the multifinality and equifinality of schizophrenia-spectrum disorders. We conclude that schizotypy represents a crucial construct in a fully-developmental study of schizophrenia spectrum disorders. PMID- 25548384 TI - Patterns of Gray Matter Abnormalities in Schizophrenia Based on an International Mega-analysis. AB - Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects. PMID- 25548387 TI - Schizotypy: looking back and moving forward. AB - This article introduces and reviews the history of the construct of schizotypy for the special section appearing in the journal. Schizotypy offers a useful construct for understanding the etiology, development, and expression of schizophrenia-spectrum psychopathology and a unifying construct for linking a broad continuum of clinical and subclinical manifestations. The article reviews the descriptive psychopathology roots of schizotypy, Meehl and Claridge's classical formulations of the construct (including the debate about dimensional vs taxonic structure), and the need for a comprehensive, multidimensional model of schizotypy. The article briefly reviews the wide empirical literature supporting schizotypy and also examines several criticisms and misconceptions about the construct and research methods used to assess it. Finally, the article offers several suggested goals for future schizotypy research. PMID- 25548386 TI - Developing psychosis and its risk states through the lens of schizotypy. AB - Starting from the early descriptions of Kraepelin and Bleuler, the construct of schizotypy was developed from observations of aberrations in nonpsychotic family members of schizophrenia patients. In contemporary diagnostic manuals, the positive symptoms of schizotypal personality disorder were included in the ultra high-risk (UHR) criteria 20 years ago, and nowadays are broadly employed in clinical early detection of psychosis. The schizotypy construct, now dissociated from strict familial risk, also informed research on the liability to develop any psychotic disorder, and in particular schizophrenia-spectrum disorders, even outside clinical settings. Against the historical background of schizotypy it is surprising that evidence from longitudinal studies linking schizotypy, UHR, and conversion to psychosis has only recently emerged; and it still remains unclear how schizotypy may be positioned in high-risk research. Following a comprehensive literature search, we review 18 prospective studies on 15 samples examining the evidence for a link between trait schizotypy and conversion to psychosis in 4 different types of samples: general population, clinical risk samples according to UHR and/or basic symptom criteria, genetic (familial) risk, and clinical samples at-risk for a nonpsychotic schizophrenia-spectrum diagnosis. These prospective studies underline the value of schizotypy in high-risk research, but also point to the lack of evidence needed to better define the position of the construct of schizotypy within a developmental psychopathology perspective of emerging psychosis and schizophrenia-spectrum disorders. PMID- 25548388 TI - Concise review: hematopoietic stem cell aging and the prospects for rejuvenation. AB - Because of the continuous increases in lifetime expectancy, the incidence of age related diseases will, unless counteracted, represent an increasing problem at both the individual and socioeconomic levels. Studies on the processes of blood cell formation have revealed several shortcomings as a consequence of chronological age. They include a reduced ability to mount adaptive immune responses and a blood cell composition skewed toward myeloid cells, with the latter coinciding with a dramatically increased incidence of myelogenous diseases, including cancer. Conversely, the dominant forms of acute leukemia affecting children associate with the lymphoid lineages. A growing body of evidence has suggested that aging of various organs and cellular systems, including the hematopoietic system, associates with a functional demise of tissue resident stem cell populations. Mechanistically, DNA damage and/or altered transcriptional landscapes appear to be major drivers of the hematopoietic stem cell aging state, with recent data proposing that stem cell aging phenotypes are characterized by at least some degree of reversibility. These findings suggest the possibility of rejuvenating, or at least dampening, stem cell aging phenotypes in the elderly for therapeutic benefit. PMID- 25548389 TI - Clinical research skills development program in cell-based regenerative medicine. AB - Cell-based therapy aimed at restoring organ function is one of the most exciting and promising areas of medical research. However, a novel intervention like cell based therapy requires physician education and training. An increasing number of physicians untrained in regenerative medicine are using cell-based therapy to treat patients for a wide variety of chronic illnesses. The current lack of training for physicians in this area combined with the sharply increasing practice of regenerative medicine is concerning for a number of reasons, namely potential harm to patients and avoidable conflicts between governmental regulatory agencies and physicians. Academic medical fellowship training programs are needed that specifically prepare physicians for treating patients with cell based therapies for various organ systems and chronic diseases. The National Heart, Lung, and Blood Institute established the Cardiovascular Cell Therapy Network to design and conduct clinical trials that advance the field of cell based therapy for patients with cardiovascular disease. As part of the network, a two-year Clinical Research Skills Development Program was supported at two centers with the goal of training early career investigators in cell-based clinical and translational research. In this review, we describe the implementation of this training program at our institution with the purpose of promoting the further development of academic fellowship programs in cell-based regenerative medicine. PMID- 25548391 TI - Sudden Advanced Illness: An Emerging Concept Among Palliative Care and Surgical Critical Care Physicians. AB - BACKGROUND: End-of-life discussions in critically-ill patients with acute surgical conditions may be rushed and occur earlier during hospitalization. This study explores the concept of sudden advanced illness (SAI) and its relevance to patients requiring Palliative and Surgical Critical Care. METHODS: Semi structured interviews were completed with 16 physicians, querying each about (1) definitional components, (2) illustrative cases, and (3) comfort with SAI. Analysis was done by grounded theory. RESULTS: SAI was characterized as unforeseen, emerging abruptly and producing devastating injury, often in healthy, younger patients. There is (1) prognostic uncertainty, (2) loss of capacity, and (3) unprepared surrogate decision-making. Cases are emotionally-charged and often personal. CONCLUSION: The emerging concept of SAI is important for understanding how Palliative Care can enhance care for this subset of patients. PMID- 25548390 TI - Adipose-derived mesenchymal stem cells reduce neuronal death after transient global cerebral ischemia through prevention of blood-brain barrier disruption and endothelial damage. AB - Global cerebral ischemia (GCI) is the leading cause of a poor prognosis even after successful resuscitation from cardiac arrest. Therapeutic induction of hypothermia (TH) is the only proven therapy-and current standard care-for GCI after cardiac arrest; however, its application has been significantly limited owing to technical difficulties. Mesenchymal stem cells (MSCs) are known to suppress neuronal death after cerebral ischemia. The prevention of blood-brain barrier (BBB) disruption has not been suggested as a mechanism of MSC treatment but has for TH. We evaluated the therapeutic effect of MSC administration on BBB disruption and neutrophil infiltration after GCI. To evaluate the therapeutic effects of MSC treatment, rats were subjected to 7 minutes of transient GCI and treated with MSCs immediately after reperfusion. Hippocampal neuronal death was evaluated at 7 days after ischemia using Fluoro-Jade B (FJB). BBB disruption, endothelial damage, and neutrophil infiltration were evaluated at 7 days after ischemia by immunostaining for IgG leakage, Rat endothelial antigen-1, and myeloperoxidase (MPO). Rats treated with MSCs showed a significantly reduced FJB+ neuron count compared with the control group. They also showed reduced IgG leakage, endothelial damage, and MPO+ cell counts. The present study demonstrated that administration of MSCs after transient GCI provides a dramatic protective effect against hippocampal neuronal death. We hypothesized that the neuroprotective effects of MSC treatment might be associated with the prevention of BBB disruption and endothelial damage and a decrease in neutrophil infiltration. PMID- 25548392 TI - Reading interventions with behavioral and social skill outcomes: a synthesis of research. AB - Research findings have suggested that reading deficits and problem behaviors are positively related. This synthesis investigated how reading interventions impact behavioral/social skill outcomes by reviewing studies that included (a) a reading intervention without behavioral/social skill components, (b) behavioral/social skill dependent variables, and (c) students in Grades K-12. Fifteen articles were evaluated by the type of reading intervention, associations between positive reading effects and behavioral/social skill outcomes, and The What Works Clearinghouse (WWC) determinants of study ratings. Findings suggested that reading interventions tended to have positive reading outcomes, while behavioral/social skill outcomes were small or negative. Research did not suggest an association between improved reading and behavioral performance, regardless of the WWC study determinants rating. Implications include reading instruction may not be sufficient to improve behavioral and social skill outcomes. Additional research is warranted to investigate the long-term impact of reading on behavioral and social skill outcomes. PMID- 25548394 TI - Psychosocial factors associated with self-efficacy for managing chronic disease in patients with chronic heart failure. AB - BACKGROUND: Self-efficacy is crucial to the management of chronic disease. However, little is known about self-efficacy for managing chronic disease in patients with chronic heart failure. AIM: The purpose of this study was to determine the incidence of inadequate self-efficacy for managing chronic disease and to identify the associated psychosocial factors in Chinese patients with chronic heart failure. METHODS: A cross-sectional design was used. One hundred and fifty-nine chronic heart failure patients (mean age 63 years, 53% female) completed instruments related to self-efficacy for managing chronic disease, general self-efficacy, anxiety and depression, perceived social support, and demographic/clinical variables. RESULTS: Of 159 patients, 46 patients (29%) had inadequate self-efficacy for managing chronic disease (the mean score on the Self efficacy for Managing Chronic Disease Six-Item Scale (SECD6) was<7). The scores for general self-efficacy and perceived social support were positively correlated with the mean SECD6 score (p<0.01), whereas the scores for anxiety and depression were negatively correlated with the mean SECD6 score (p<0.01). Multiple linear regression analysis revealed that the factors associated with self-efficacy for managing chronic disease were general self-efficacy, depression and perceived social support, and three factors accounted for 29% of the variance. CONCLUSIONS: In Chinese patients with chronic heart failure, the prevalence of inadequate self efficacy for managing chronic disease is high; general self-efficacy, depression and perceived social support are independent factors associated with self efficacy for managing chronic disease. The screening of patients' self-efficacy and the implementation of relevant interventions may be beneficial to the promotion of self-management. PMID- 25548393 TI - Plasma Estrogen Levels Are Associated With Severity of Injury and Outcomes After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Biochemical mediators alter cerebral perfusion and have been implicated in delayed cerebral ischemia (DCI) and poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Estrogens (estrone [E1] and estradiol [E2]) are mediators with neuroprotective properties that could play a role in DCI. This study explored associations between plasma estrogen levels and outcomes following aSAH. METHODS: Plasma samples from 1-4, 4-6, and 7-10 days after hemorrhage from 99 adult aSAH patients were analyzed for estrogen levels using liquid chromatography tandem mass spectrometry. DCI was operationalized as radiographic/ultrasonic evidence of impaired cerebral blood flow accompanied by neurological deterioration. Outcomes were assessed using the Modified Rankin Scale at 3 and 12 months after hemorrhage. Statistical analysis included correlation, regression, and group-based trajectory. RESULTS: Higher E1 and E2 levels were associated with higher Hunt and Hess grade (E1, p = .01; E2, p = .03), the presence of DCI (E1, p = .02; E2, p = .02), and poor 3-month outcomes (E1, p = .002; E2, p = .002). Trajectory analysis identified distinct populations over time for E1 (61% E1 high) and E2 (68% E2 high). Patients in higher trajectory groups had higher Fisher grades (E1, p = .008; E2, p = .01), more frequent DCI (E1, p = .04; E2, p = .08), and worse 3-month outcomes (E1, p = .01; E2, p = .004) than low groups. CONCLUSIONS: These results provide the first clinical evidence that plasma E1 and E2 concentrations are associated with severity of injury and outcomes after aSAH. PMID- 25548395 TI - Electrocardiogram interpretation skills among ambulance nurses. AB - BACKGROUND: To describe ambulance nurses' practical electrocardiogram (ECG) interpretation skills and to measure the correlation between these skills and factors that may impact on the level of knowledge. METHODS: This study was conducted using a prospective quantitative survey with questionnaires and a knowledge test. A convenience sample collection was conducted among ambulance nurses in three different districts in western Sweden. The knowledge test consisted of nine different ECGs. The score of the ECG test were correlated against the questions in the questionnaire regarding both general ECG interpretation skill and ability to identify acute myocardial infarction using Mann-Whitney U test, Kruskal-Wallis test and Spearman's rank correlation. RESULTS: On average, the respondents had 54% correct answers on the test and identified 46% of the ECGs indicating acute myocardial infarction. The median total score was 9 of 16 (interquartile range 7-11) and 1 of 3 (IQR 1-2) in infarction points. No correlation between ECG interpretation skill and factors such as education and professional experience was found, except that coronary care unit experience was associated with better results on the ECG test. CONCLUSIONS: Ambulance nurses have deficiencies in their ECG interpretation skills. This also applies to conditions where the ambulance crew has great potential to improve the outcome of the patient's health, such as myocardial infarction and cardiac arrest. Neither education, extensive experience in ambulance service nor in nursing contributed to an improved result. The only factor of importance for higher ECG interpretation knowledge was prior experience of working in a coronary care unit. PMID- 25548396 TI - Forty-Five Years of the CJHP: Never Closed, Always Renovating. PMID- 25548397 TI - Decreasing medication turnaround time with digital scanning technology in a canadian health region. AB - BACKGROUND: Reducing medication turnaround time can improve efficiency, patient safety, and quality of care in the hospital setting. Digital scanning technology (DST) can be used to electronically transmit scanned prescriber orders to a pharmacy computer queue for verification and processing, which may help to improve medication turnaround time. OBJECTIVES: To evaluate medication turnaround time before and after implementation of DST for all medications and for antibiotics only. METHODS: Medication turnaround times were evaluated retrospectively for periods before (June 6-10, 2011) and after (September 26-30, 2011) implementation of DST at 2 hospital sites in 1 health region. Medication turnaround time was defined as the time from composition of a medication order by the prescriber to its verification by the pharmacy (phase 1) and the time from prescriber composition to administration to the patient by a nurse (total). Median turnaround times were analyzed with SPSS software using the Mann-Whitney U test. RESULTS: In total, 304 and 244 medication orders were audited before and after DST implementation, respectively. Median phase 1 turnaround time for all medications declined significantly, from 2 h 23 min before DST implementation to 1 h 33 min after DST implementation (p < 0.001). Antibiotics were also processed significantly faster (1 h 51 min versus 1 h 9 min, p = 0.015). However, total turnaround time for all medications did not differ significantly (5 h 15 min versus 5 h 0 min, p = 0.42). CONCLUSIONS: Implementation of DST was associated with a 50-min decrease in medication turnaround time for the period from when an order was prescribed to the time it was processed by the pharmacy. Regular evaluation of medication turnaround times is recommended to compare with benchmarks, to ensure that hospital standards are being met, and to measure the effects of policy changes and implementation of new technology on medication-use processes. PMID- 25548398 TI - Achieving therapeutic vancomycin levels in pediatric patients. AB - BACKGROUND: Vancomycin is widely used to treat infections caused by methicillin resistant Staphylococcus aureus. Data for dosing and monitoring of this drug in pediatric patients are lacking, and clinicians who are treating children often follow guidelines established for adults. OBJECTIVES: To examine the total daily doses of vancomycin required to reach therapeutic trough levels (i.e., 10-20 mg/L) in infants, children, and adolescents, and to assess the number of pediatric patients in whom therapeutic trough levels are achieved with current empiric doses (40-60 mg/kg daily). METHODS: This chart review evaluated patients 1 month to 18 years of age for whom vancomycin was prescribed at a single institution between November 2011 and October 2012. Patients' demographic characteristics, vancomycin dosing parameters, and subsequent steady-state trough concentrations were analyzed. RESULTS: Overall, the proportion of patients who reached therapeutic trough levels with current empiric doses was 39% (74 of 188). The mean total daily dose (+/- standard deviation) required to achieve therapeutic trough levels was 57.8 +/- 11.5 mg/kg for patients 1 to 5 months of age, 68.9 +/- 15.4 mg/kg for those 6 to 23 months of age, 65.8 +/- 13.0 mg/kg for those 2 to 12 years of age, and 55.7 +/- 11.8 mg/kg for those 13 to 18 years of age. CONCLUSIONS: Common empiric vancomycin dosing regimens (40-60 mg/kg daily) are not high enough to achieve trough levels of 10-20 mg/L in the majority of pediatric patients. Given these data, the authors suggest a starting dose of 60 mg/kg daily for patients 1 to 5 months of age and those 13 to 18 years of age and a starting dose of 70 mg/kg daily for patients 6 months to 12 years of age. PMID- 25548399 TI - Measuring adverse drug events on hospital medicine units with the institute for healthcare improvement trigger tool: a chart review. AB - BACKGROUND: An adverse drug event (ADE) is a noxious, unintended response to a drug, occurring at doses used in humans for prophylaxis, diagnosis, or treatment of disease or for modification of physiological function. ADEs account for about one-quarter of all adverse events in Canadian hospitals. Canadian data on specific types of ADEs and commonly implicated drugs are lacking. In particular, there is a paucity of data on ADEs that occur during hospital admissions. OBJECTIVES: The primary objective was to identify the incidence of ADEs in a sample of adult general medicine inpatients over a 1-year period. The secondary objective was to identify the 5 drugs most frequently responsible for ADEs in this setting. METHODS: A retrospective chart analysis was conducted for general medicine patients discharged from St Paul's Hospital in Vancouver, British Columbia, from January to December 2011. ADEs were identified using the Institute for Healthcare Improvement (IHI) Trigger Tool for Measuring Adverse Drug Events. The Naranjo criteria were applied to assess causality, and a physician independently authenticated the ADEs for preventability and harm using the categories of harm set out by the US National Coordinating Council for Medication Error Reporting and Prevention. RESULTS: Of the 204 patient encounters reviewed, 15 involved ADEs, which represented an incidence of 7% over the 1-year study period. The 5 drugs most frequently implicated in ADEs were vancomycin, ciprofloxacin, ceftriaxone, piperacillin-tazobactam, and moxifloxacin. CONCLUSIONS: The rate of ADEs during hospital admissions was substantial. These events may necessitate additional investigations and interventions and may prolong the hospital stay. The authors do not recommend the IHI Trigger Tool for Measuring Adverse Drug Events for efficient prospective detection of ADEs in manual chart reviews. Possible modifications to improve the utility of this tool might include incorporating it into a compatible electronic health record system with automated trigger detection. PMID- 25548400 TI - Influence of Admission to a Tertiary Care Hospital after a Fall on Use of Potentially Inappropriate Medications among Older Patients. AB - BACKGROUND: Each year, about one-third of individuals over the age of 65 years will experience a fall, and half of these will experience a subsequent fall in the following year. The use of potentially inappropriate medications (PIMs) is an important factor contributing to increased fall risk in geriatric patients. OBJECTIVE: To determine the proportion of patients over the age of 65 admitted to orthopedics and general medicine services with diagnosis of a fall who experienced a change in the total number or dosage of PIMs, as defined by the Beers criteria, upon discharge from hospital. METHODS: This retrospective observational study involved patients admitted to a tertiary care hospital with diagnosis of a fall between January 1 and December 31, 2011. Those aged 65 years or older with at least one PIM on admission were eligible for inclusion. Data analysis included chi(2) and Fisher testing, as well as multivariate analysis. RESULTS: A total of 148 patients were included, of whom 63 (43%) had an overall change in the dosage or number of PIMs during their hospital stay. Forty patients (27%) had an overall reduction in the dosage or number of PIMs upon discharge from hospital, whereas 23 (16%) experienced an overall increase in the dosage or total number of PIMs. The mean number (+/- standard deviation) of PIMs decreased during the hospital stay, from 1.6 +/- 0.8 on admission to 1.4 +/- 0.9 on discharge (p = 0.03). Benzodiazepines were the class of PIMs most frequently discontinued or reduced in dosage. CONCLUSION: One-quarter of patients admitted with falls had de-escalation of PIMs upon hospital discharge. Although dosage reduction or drug discontinuation may not be appropriate for all patients, a standardized approach to medication review during the hospital stay and improved prescriber education and awareness of PIM use among elderly individuals are warranted. PMID- 25548401 TI - Qualitative research: getting started. PMID- 25548402 TI - Domperidone-associated sudden cardiac death in the general population and implications for use in patients undergoing hemodialysis: a literature review. AB - BACKGROUND: Domperidone, an effective prokinetic agent, is commonly used to manage symptoms of gastroparesis. Health regulatory agencies have issued warnings about an increased risk of sudden cardiac death associated with use of this drug. OBJECTIVE: To evaluate the evidence for domperidone-associated sudden cardiac death and to determine whether this drug can be safely used for gastroparesis in patients undergoing dialysis. DATA SOURCES: Two databases (MEDLINE [1965 to September 2014] and Embase [1980 to September 2014]) were searched using the Medical Subject Headings "domperidone", "sudden cardiac death", and "cardiac arrhythmia". The search was limited to studies conducted in humans and published in English. Advisories from health regulatory agencies (Health Canada, the European Medicines Agency, and the US Food and Drug Administration) were identified and reviewed. STUDY SELECTION: Studies eligible for inclusion in this narrative review were randomized controlled trials and cohort, case-control, cross-sectional, and other epidemiological studies comparing use and non-use of domperidone for the outcome of sudden cardiac death in adults. Abstracts of eligible case reports and case series were also included. DATA SYNTHESIS: Despite inconsistencies in their decisions, the various drug regulatory authorities have acknowledged the potential safety concern of increased risk of sudden cardiac death associated with domperidone. To date, no randomized controlled studies have shown an increased risk of this outcome secondary to domperidone use. Current regulatory recommendations and approval decisions are based on 2 large observational epidemiological studies that generated a signal of increased risk. The strengths and limitations of these studies were evaluated in detail. No direct evidence applicable to patients with end-stage renal disease was found. In vitro evidence suggests that the risk of sudden cardiac death is dose-related. CONCLUSIONS: Given gaps in the literature, use of domperidone for patients undergoing dialysis should be assessed on a case-by-case basis. Extreme caution should be used for patients taking more than 30 mg/day of this drug. PMID- 25548403 TI - Patients' physical response to thiopental and alternative anesthetic agents in the setting of electroconvulsive therapy. PMID- 25548404 TI - Urinary Tract Infection in a Preterm Neonate Caused by Lactococcus lactis. PMID- 25548405 TI - Should Hospital Pharmacies That Are Not Fully Compliant with USP General Chapter <797> Standards Outsource, to the Fullest Extent Possible, the Preparation of Compounded Sterile Products to a Facility That Is Compliant? PMID- 25548406 TI - Does pulse dosing of methylprednisolone have an acute effect on serum creatinine concentrations? PMID- 25548407 TI - More Information about Postbaccalaureate PharmD Training. PMID- 25548408 TI - Change: the future of pharmacy. PMID- 25548410 TI - Trichomonas vaginalis metalloproteinase induces mTOR cleavage of SiHa cells. AB - Trichomonas vaginalis secretes a number of proteases which are suspected to be the cause of pathogenesis; however, little is understood how they manipulate host cells. The mammalian target of rapamycin (mTOR) regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. We detected various types of metalloproteinases including GP63 protein from T. vaginalis trophozoites, and T. vaginalis GP63 metalloproteinase was confirmed by sequencing and western blot. When SiHa cells were stimulated with live T. vaginalis, T. vaginalis excretory-secretory products (ESP) or T. vaginalis lysate, live T. vaginalis and T. vaginalis ESP induced the mTOR cleavage in both time- and parasite load-dependent manner, but T. vaginalis lysate did not. Pretreatment of T. vaginalis with a metalloproteinase inhibitor, 1,10-phenanthroline, completely disappeared the mTOR cleavage in SiHa cells. Collectively, T. vaginalis metallopeptidase induces host cell mTOR cleavage, which may be related to survival of the parasite. PMID- 25548409 TI - Recent advances in Toxoplasma gondii immunotherapeutics. AB - Toxoplasmosis is an opportunistic infection caused by the protozoan parasite Toxoplasma gondii. T. gondii is widespread globally and causes severe diseases in individuals with impaired immune defences as well as congenitally infected infants. The high prevalence rate in some parts of the world such as South America and Africa, coupled with the current drug treatments that trigger hypersensitivity reactions, makes the development of immunotherapeutics intervention a highly important research priority. Immunotherapeutics strategies could either be a vaccine which would confer a pre-emptive immunity to infection, or passive immunization in cases of disease recrudescence or recurrent clinical diseases. As the severity of clinical manifestations is often greater in developing nations, the development of well-tolerated and safe immunotherapeutics becomes not only a scientific pursuit, but a humanitarian enterprise. In the last few years, much progress has been made in vaccine research with new antigens, novel adjuvants, and innovative vaccine delivery such as nanoparticles and antigen encapsulations. A literature search over the past 5 years showed that most experimental studies were focused on DNA vaccination at 52%, followed by protein vaccination which formed 36% of the studies, live attenuated vaccinations at 9%, and heterologous vaccination at 3%; while there were few on passive immunization. Recent progress in studies on vaccination, passive immunization, as well as insights gained from these immunotherapeutics is highlighted in this review. PMID- 25548411 TI - Prominent IL-12 production and tumor reduction in athymic nude mice after Toxoplasma gondii lysate antigen treatment. AB - Toxoplasma gondii is an intracellular protozoan parasite that causes a Th1 cellular immunity. Our previous study showed that T. gondii lysate antigen (TLA) treatment in S180 tumor-bearing mice resulted in tumor reduction by suppressing CD31 expression, a marker of angiogenesis. In the present study, to investigate tumor suppressive effect of TLA under the absence of T lymphocytes, athymic nude mice were compared with euthymic mice in the anti-tumorigenic effect triggered by TLA in CT26 tumors. According to the results, intratumorally injected TLA reduced tumor growth and TIMP-1 level, a metastatic marker, in both euthymic and athymic mice. TLA treatment led to a sharp increase in IL-12 expression in serum cytokine profiling of athymic mice, and increased MyD88 signals in macrophages derived from the bone marrow, implying the activation of innate immunity. The selective induction of IL-12 by TLA treatment had an anti-tumorigenic effect. PMID- 25548412 TI - Flavonoids modulate the proliferation of Neospora caninum in glial cell primary cultures. AB - Neospora caninum (Apicomplexa; Sarcocystidae) is a protozoan that causes abortion in cattle, horses, sheep, and dogs as well as neurological and dermatological diseases in dogs. In the central nervous system of dogs infected with N. caninum, cysts were detected that exhibited gliosis and meningitis. Flavonoids are polyphenolic compounds that exhibit antibacterial, antiparasitic, antifungal, and antiviral properties. In this study, we investigated the effects of flavonoids in a well-established in vitro model of N. caninum infection in glial cell cultures. Glial cells were treated individually with 10 different flavonoids, and a subset of cultures was also infected with the NC-1 strain of N. caninum. All of the flavonoids tested induced an increase in the metabolism of glial cells and many of them increased nitrite levels in cultures infected with NC-1 compared to controls and uninfected cultures. Among the flavonoids tested, 3',4' dihydroxyflavone, 3',4',5,7-tetrahydroxyflavone (luteolin), and 3,3',4',5,6 pentahydroxyflavone (quercetin), also inhibited parasitophorous vacuole formation. Taken together, our findings show that flavonoids modulate glial cell responses, increase NO secretion, and interfere with N. caninum infection and proliferation. PMID- 25548413 TI - Prevalence and clinical manifestations of malaria in Aligarh, India. AB - Malaria is one of the most widespread infectious diseases of tropical countries with an estimated 207 million cases globally. In India, there are endemic pockets of this disease, including Aligarh. Hundreds of Plasmodium falciparum and P. vivax cases with severe pathological conditions are recorded every year in this district. The aim of this study is to find out changes in liver enzymes and kidney markers. Specific diagnosis for P. falciparum and P. vivax was made by microscopic examination of Giemsa stained slides. Clinical symptoms were observed in both of these infections. Liver enzymes, such as AST, ALT, and ALP, and kidney function markers, such as creatinine and urea, were estimated by standard biochemical techniques. In Aligarh district, P. vivax, P. falciparum, and mixed infections were 64%, 34%, and 2%, respectively. In case of P. falciparum infection, the incidences of anemia, splenomegaly, renal failure, jaundice, and neurological sequelae were higher compared to those in P. vivax infection. Recrudescence and relapse rates were 18% and 20% in P. falciparum and P. vivax infections, respectively. Liver dysfunctions and renal failures were more common in P. falciparum patients, particularly in elderly patients. Artesunate derivatives must, therefore, be introduced for the treatment of P. falciparum as they resist to chloroquine as well as sulfadoxine-pyrimethamine combinations. PMID- 25548414 TI - Plasmodium falciparum genotype diversity in artemisinin derivatives treatment failure patients along the Thai-Myanmar border. AB - Genetic characteristics of Plasmodium falciparum may play a role in the treatment outcome of malaria infection. We have studied the association between diversity at the merozoite surface protein-1 (msp-1), msp-2, and glutamate-rich protein (glurp) loci and the treatment outcome of uncomplicated falciparum malaria patients along the Thai-Myanmar border who were treated with artemisinin derivatives combination therapy. P. falciparum isolates were collected prior to treatment from 3 groups of patients; 50 cases of treatment failures, 50 recrudescences, and 56 successful treatments. Genotyping of the 3 polymorphic markers was analyzed by nested PCR. The distribution of msp-1 alleles was significantly different among the 3 groups of patients but not the msp-2 and glurp alleles. The allelic frequencies of K1 and MAD20 alleles of msp1 gene were higher while RO33 allele was significantly lower in the successful treatment group. Treatment failure samples had a higher median number of alleles as compared to the successful treatment group. Specific genotypes of msp-1, msp-2, and glurp were significantly associated with the treatment outcomes. Three allelic size variants were significantly higher among the isolates from the treatment failure groups, i.e., K1270-290, 3D7610-630, G650-690, while 2 variants, K1150-170, and 3D7670-690 were significantly lower. In conclusion, the present study reports the differences in multiplicity of infection and distribution of specific alleles of msp-1, msp-2, and glurp genes in P. falciparum isolates obtained from treatment failure and successful treatment patients following artemisinin derivatives combination therapy. PMID- 25548415 TI - Congenital malaria in newborns selected for low birth-weight, anemia, and other possible symptoms in Maumere, Indonesia. AB - Congenital malaria is assumed to be a risk factor for infant morbidity and mortality in endemic areas like Maumere, Indonesia. Infected infants are susceptible to its impact such as premature labor, low birth weight, anemia, and other unspecified symptoms. The aim of this study was to investigate the prevalence of congenital malaria and the influence of mother-infant paired parasite densities on the clinical outcome of the newborns at TC Hillers Hospital, Maumere. An analytical cross sectional study was carried out in newborns which showed criteria associated with congenital malaria. A thick and thin blood smear confirmed by nested PCR was performed in both mothers and infants. The association of congenital malaria with the newborn's health status was then assessed. From 112 mother-infant pairs included in this study, 92 were evaluated further. Thirty-nine infants (42.4%) were found to be infected and half of them were asymptomatic. Infected newborns had a 4.7 times higher risk in developing anemia compared to uninfected newborns (95% CI, 1.3-17.1). The hemoglobin level, erythrocyte amount, and hematocrit level were affected by the infants' parasite densities (P<0.05). Focusing on newborns at risk of congenital malaria, the prevalence is almost 3 times higher than in an unselected collective. Low birth weight, anemia, and pre-term birth were the most common features. Anemia seems to be significantly influenced by infant parasite densities but not by maternal parasitemia. PMID- 25548416 TI - Fasciola hepatica in snails collected from water-dropwort fields using PCR. AB - Fasciola hepatica is a trematode that causes zoonosis mainly in cattle and sheep and occasionally in humans. Fascioliasis has been reported in Korea; however, determining F. hepatica infection in snails has not been done recently. Thus, using PCR, we evaluated the prevalence of F. hepatica infection in snails at 4 large water-dropwort fields. Among 349 examined snails, F. hepatica-specific internal transcribed space 1 (ITS-1) and/or ITS-2 markers were detected in 12 snails and confirmed using sequence analysis. Morphologically, 213 of 349 collected snails were dextral shelled, which is the same aperture as the lymnaeid snail, the vectorial host for F. hepatica. Among the 12 F. hepatica-infected snails, 6 were known first intermediate hosts in Korea (Lymnaea viridis and L. ollula) and the remaining 6 (Lymnaea sp.) were potentially a new first intermediate host in Korea. It has been shown that the overall prevalence of the snails contaminated with F. hepatica in water-dropwort fields was 3.4%; however, the prevalence varied among the fields. This is the first study to estimate the prevalence of F. hepatica infection using the vectorial capacity of the snails in Korea. PMID- 25548417 TI - Scolicidal effects of black cumin seed (Nigella sativa) essential oil on hydatid cysts. AB - Surgery remains the preferred treatment for hydatid cyst (cystic echinococcosis, CE). Various scolicidal agents have been used for inactivation of protoscolices during surgery, but most of them are associated with adverse side effects. The present study aimed to evaluate the in vitro scolicidal effect of Nigella sativa (Ranunculaceae) essential oil and also its active principle, thymoquinone, against protoscolices of hydatid cysts. Protoscolices were aseptically aspirated from sheep livers having hydatid cysts. Various concentrations of the essential oil (0.01-10 mg/ml) and thymoquinone (0.125-1.0 mg/ml) were used for 5 to 60 min. Viability of protoscolices was confirmed by 0.1% eosin staining. Furthermore, the components of the N. sativa essential oil were identified by gas chromatography/mass spectroscopy (GC/MS). Our study revealed that the essential oil of N. sativa at the concentration of 10 mg/ml and its main component, thymoquinone, at the concentration of 1 mg/ml had potent scolicidal activities against protoscolices of Echinococcus granulosus after 10 min exposure. Moreover, thymoquinone (42.4%), p-cymene (14.1%), carvacrol (10.3%), and longifolene (6.1%) were found to be the major components of N. sativa essential oil by GC/MS analysis. The results of this study indicated the potential of N. sativa as a natural source for production of a new scolicidal agent for use in hydatid cyst surgery. However, further studies will be needed to confirm these results by checking the essential oil and its active component in in vivo models. PMID- 25548418 TI - Prevalence of intestinal helminths among inhabitants of Cambodia (2006-2011). AB - In order to investigate the status of intestinal helminthic infections in Cambodia, epidemiological surveys were carried out on a national scale, including 19 provinces. A total of 32,201 fecal samples were collected from schoolchildren and adults between 2006 and 2011 and examined once by the Kato-Katz thick smear technique. The overall egg positive rate of intestinal helminths was 26.2%. The prevalence of hookworms was the highest (9.6%), followed by that of Opisthorchis viverrini/minute intestinal flukes (Ov/MIF) (5.7%), Ascaris lumbricoides (4.6%), and Trichuris trichiura (4.1%). Other types of parasites detected were Enterobius vermicularis (1.1%), Taenia spp. (0.4%), and Hymenolepis spp. (0.2%). The northwestern regions such as the Siem Reap, Oddar Meanchey, and Banteay Meanchey Provinces showed higher prevalences (17.4-22.3%) of hookworms than the other localities. The southwestern areas, including Koh Kong and Preah Sihanouk Provinces showed higher prevalences of A. lumbricoides (17.5-19.2%) and T. trichiura (6.1-21.0%). Meanwhile, the central and southern areas, in particular, Takeo and Kampong Cham Provinces, showed high prevalences of Ov/MIF (23.8-24.0%). The results indicate that a considerably high prevalence of intestinal helminths has been revealed in Cambodia, and thus sustained national parasite control projects are necessary to reduce morbidity due to parasitic infections in Cambodia. PMID- 25548420 TI - Three cases of Diphyllobothrium nihonkaiense infection in Korea. AB - Until 2012, a total of 48 cases of diphyllobothriasis had been reported in Korea, all of which were morphologically identified as Diphyllobothrium latum. However, some of these specimens were analyzed by nucleotide sequencing of the mitochondrial cox1 gene, which showed that all were D. nihonkaiense, not D. latum. After that, 3 further cases of diphyllobothriasis were confirmed as D. nihonkaiense. In the present study, 3 new cases of D. nihonkaiense were detected from 2011 through 2013. The hosts were infected through consumption of salmonid fishes, such as the trout or salmon, and 2 of them experienced severe diarrhea prior to proglottid passage. All of the tapeworms were confirmed to be D. nihonkaiense by genetic identification. This proved again that most diphyllobothriasis in Korea have been caused by D. nihonkaiense. PMID- 25548419 TI - An imported case of severe falciparum malaria with prolonged hemolytic anemia clinically mimicking a coinfection with babesiosis. AB - While imported falciparum malaria has been increasingly reported in recent years in Korea, clinicians have difficulties in making a clinical diagnosis as well as in having accessibility to effective anti-malarial agents. Here we describe an unusual case of imported falciparum malaria with severe hemolytic anemia lasting over 2 weeks, clinically mimicking a coinfection with babesiosis. A 48-year old Korean man was diagnosed with severe falciparum malaria in France after traveling to the Republic of Benin, West Africa. He received a 1-day course of intravenous artesunate and a 7-day course of Malarone (atovaquone/proguanil) with supportive hemodialysis. Coming back to Korea 5 days after discharge, he was readmitted due to recurrent fever, and further treated with Malarone for 3 days. Both the peripheral blood smears and PCR test were positive for Plasmodium falciparum. However, he had prolonged severe hemolytic anemia (Hb 5.6 g/dl). Therefore, 10 days after the hospitalization, Babesia was considered to be potentially coinfected. A 7-day course of Malarone and azithromycin was empirically started. He became afebrile within 3 days of this babesiosis treatment, and hemolytic anemia profiles began to improve at the completion of the treatment. He has remained stable since his discharge. Unexpectedly, the PCR assays failed to detect DNA of Babesia spp. from blood. In addition, during the retrospective review of the case, the artesunate-induced delayed hemolytic anemia was considered as an alternative cause of the unexplained hemolytic anemia. PMID- 25548421 TI - Extracorporeal worm extraction of Diphyllobothrium nihonkaiense with amidotrizoic acid in a child. AB - Infection cases of diphyllobothriid tapeworms are not much in the below teen-age group. We report a case of Diphyllobothrium nihonkaiense infection in a 13-year old boy. He presented with severe fatigue, occasional abdominal pain at night time. He also had several episodes of tapeworm segment discharge in his stools. By his past history, he had frequently eaten raw fish including salmon and trout with his families. Numerous eggs of diphyllobothriid tapeworm were detected in the fecal examination. We introduced amidotrizoic acid as a cathartic agent through nasogastroduodenal tube and let nearly whole length (4.75 m) of D. nihonkaiense be excreted through his anus. After a single dose of praziquantel, the child's stool showed no further eggs, and his symptoms disappeared. The evacuated worm was identified as D. nihonkaiense by mitochondrial cox1 gene analysis. Here we report a successful extracorporeal worm extraction from an infection case of D. nihonkaiense by the injection of amidotrizoic acid. PMID- 25548422 TI - Human sting of Cephalonomia gallicola (Hymenoptera: Bethylidae) in Korea. AB - Hymenoptera stings can cause serious injury to humans. We report the clinical findings of 6 cases of Hymenoptera stings. All patients developed painful erythematous papules at the sting sites and had a past history of parasitoid wasp sting. This is the first clinical report of the parasitoid wasp, Cephalonomia gallicola, causing human stings in Korea. PMID- 25548423 TI - Perianal tick-bite lesion caused by a fully engorged female Amblyomma testudinarium. AB - A perianal tick and the surrounding skin were surgically excised from a 73-year old man residing in a southwestern costal area of the Korean Peninsula. Microscopically a deep penetrating lesion was formed beneath the attachment site. Dense and mixed inflammatory cell infiltrations occurred in the dermis and subcutaneous tissues around the feeding lesion. Amorphous eosinophilic cement was abundant in the center of the lesion. The tick had Y-shaped anal groove, long mouthparts, ornate scutum, comma-shaped spiracular plate, distinct eyes, and fastoons. It was morphologically identified as a fully engorged female Amblyomma testudinarium. This is the third human case of Amblyomma tick infection in Korea. PMID- 25548424 TI - Prevalence of Dirofilaria immitis infection in stray cats by nested PCR in Korea. AB - The purpose of this study was to conduct a survey of Dirofilaria immitis infection among stray cats in Korea using nested PCR. We included 235 stray cats (121 females and 114 males) and evaluated each for the presence of feline heartworm infection. Blood samples were collected from 135 cats in Daejeon, 50 cats in Seoul, and 50 cats from Gyeonggi-do (Province). Of the 235 DNA samples, 14 (6.0%) were positive for D. immitis. The prevalence of infection in male cats (8/114, 7.0%) tended to be higher than that in female cats (6/121, 5.0%), but the difference was not statistically significant. In each location, 8, 2, and 4 cats were positive for infection, respectively, based on DNA testing. No significant differences in the prevalence were observed among the geographic regions, although the rate of infection was higher in Gyeonggi-do (8.0%) than Daejeon (5.9%) and Seoul (4.0%). We submitted 7 of the 14 D. immitis DNA-positive samples for sequencing analysis. All samples corresponded to partial D. immitis cytochrome c oxidase subunit I gene sequences with 99% homology to the D. immitis sequence deposited in GenBank (accession no. FN391553). To the best of our knowledge, this is the first survey using nested PCR to analyze the prevalence of D. immitis in stray cats in Korea. PMID- 25548425 TI - Chronic Opisthorchis viverrini infection and associated hepatobiliary disease is associated with iron loaded M2-like macrophages. AB - Chronic Opisthorchis viverrini-induced hepatobiliary disease is associated with significant leukocyte infiltration, including activated macrophages; however, the polarization of infiltrating macrophages remains to be fully characterized. In this study, we characterized macrophage polarization and phenotype in chronic O. viverrini-induced hepatobiliary disease in humans and hamsters using gene expression and histochemical analysis. Chronic O. viverrini infection and associated hepatobiliary diseases were associated with iron loaded M2-like macrophages in both humans and hamsters. This study provides suggestive evidence that iron loaded M2-like macrophages promote hepatobiliary disease in chronic O. viverrini infection. PMID- 25548426 TI - Molecular characterization of Gastrothylax crumenifer (Platyhelminthes: Gastrothylacidae) from goats in the western part of India by LSU of nuclear ribosomal DNA. AB - The rumen parasite, Gastrothylax crumenifer (Platyhelminthes: Gastrothylacidae), is a highly pathogenic trematode parasite of goat (Capra hircus). It sucks blood that causes acute disease like anemia, and severe economic losses occur due to morbidity and mortality of the ruminant infected by these worms. The study of these rumen paramphistomes, their infection, and public health importance remains unclear in India especially in the western part of state Uttar Pradesh (U.P.), Meerut, India, where the goat meat consumption is very high. This paper provides the molecular characterization of G. crumenifer recovered from the rumen of Capra hircus from Meerut, U.P., India by the partial sequence of 28S rDNA. Nucleotide sequence similarity searching on BLAST of 28S rDNA from parasites showed the highest identity with those of G. crumenifer from the same host Capra hircus. This is the first report of molecular identification of G. crumenifer from this part of India. PMID- 25548427 TI - RNA-Seq data mining: downregulation of NeuroD6 serves as a possible biomarker for alzheimer's disease brains. AB - Alzheimer's disease (AD) is the most common cause of dementia worldwide with no curative therapies currently available. Previously, global transcriptome analysis of AD brains by microarray failed to identify the set of consistently deregulated genes for biomarker development of AD. Therefore, the molecular pathogenesis of AD remains largely unknown. Whole RNA sequencing (RNA-Seq) is an innovative technology for the comprehensive transcriptome profiling on a genome-wide scale that overcomes several drawbacks of the microarray-based approach. To identify biomarker genes for AD, we analyzed a RNA-Seq dataset composed of the comprehensive transcriptome of autopsized AD brains derived from two independent cohorts. We identified the core set of 522 genes deregulated in AD brains shared between both, compared with normal control subjects. They included downregulation of neuronal differentiation 6 (NeuroD6), a basic helix-loop-helix (bHLH) transcription factor involved in neuronal development, differentiation, and survival in AD brains of both cohorts. We verified the results of RNA-Seq by analyzing three microarray datasets of AD brains different in brain regions, ethnicities, and microarray platforms. Thus, both RNA-Seq and microarray data analysis indicated consistent downregulation of NeuroD6 in AD brains. These results suggested that downregulation of NeuroD6 serves as a possible biomarker for AD brains. PMID- 25548428 TI - Transporter TAP1-637G and immunoproteasome PSMB9-60H variants influence the risk of developing vitiligo in the Saudi population. AB - We evaluated whether TAP1-rs1135216 (p.637D>G) and PSMB9-rs17587 (p.60R>H) were significantly associated with the risk and severity of vitiligo among Saudi patients. One hundred seventy-two subjects were genotyped for the TAP1-rs1135216 and PSMB9-rs17587 variants using endonuclease digestions of amplified genomic DNA. The TAP1-rs1135216 and PSMB9-rs17587 mutant alleles were strongly associated with vitiligo, with odds ratios showing five fold and two fold risks (P < 0.0001 and P = 0.007, resp.). In TAP1-rs1135216, the 637G mutant allele was more frequent in cases (74%) than in healthy controls. In cases, the 60H mutant allele PSMB9-rs17587 was less frequent (42%) than the wild-type 60R allele (58%). Vitiligo vulgaris was the most common type of disease, associated with the DG (55%) and GG (46%) genotypes for rs1135216 and with the RH genotype (59%) for rs17587. The heterozygous 637DG and 60RH genotypes were each linked with active phenotypes in 64% of cases. In conclusion, the TAP1-rs1135216 and PSMB9-rs17587 variants are significantly associated with vitiligo, and even one copy of these mutant alleles can influence the risk among Saudis. Vitiligo vulgaris is associated with genotypes containing the mutant G and H alleles. PMID- 25548429 TI - CLCA2 as a novel immunohistochemical marker for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the lung. AB - Recent progress in targeted therapy for lung cancer has revealed that accurate differential diagnosis between squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lung is essential. To identify a novel immunohistochemical marker useful for differential diagnosis between the two subtypes of lung cancer, we first selected 24 SCC-specific genes and 6 ADC-specific genes using data (case number, 980) from the Cancer Genome Atlas (TCGA) database. Among the genes, we chose the CLCA2 gene, which is involved in chloride conductance and whose protein expression in lung cancer is yet to be characterized, and evaluated its protein expression status in 396 cases of primary lung cancer at Hamamatsu University Hospital. Immunohistochemical analysis revealed a significantly higher CLCA2 expression level in the SCCs than in the ADCs (P < 0.0001) and also a significantly higher frequency of CLCA2 protein expression in the SCCs (104/161, 64.6%) as compared with that in the ADCs (2/235, 0.9%) (P < 0.0001; sensitivity 64.6%, specificity 99.1%). The CLCA2 protein expression status was associated with the histological tumor grade in the SCCs. These results suggest that CLCA2 might be a novel excellent immunohistochemical marker for differentiating between primary SCC and primary ADC of the lung. PMID- 25548430 TI - The CCR5Delta32 polymorphism in Brazilian patients with sickle cell disease. AB - BACKGROUND: Previous studies on the role of inflammation in the pathophysiology of sickle cell disease (SCD) suggested that the CCR5Delta32 allele, which is responsible for the production of truncated C-C chemokine receptor type 5 (CCR5), could confer a selective advantage on patients with SCD because it leads to a less efficient Th1 response. We determined the frequency of the CCR5Delta32 polymorphism in 795 Afro-Brazilian SCD patients followed up at the Pernambuco Hematology and Hemotherapy Center, in Northeastern Brazil, divided into a pediatric group (3 months-17 years, n = 483) and an adult group (18-70 years, n = 312). The adult patients were also compared to a healthy control group (blood donors, 18-61 years, n = 247). METHODS: The CCR5/CCR5Delta32 polymorphism was determined by allele-specific PCR. RESULTS: No homozygous patient for the CCR5Delta32 allele was detected. The frequency of heterozygotes in the study population (patients and controls) was 5.8%, in the total SCD patients 5.1%, in the children 5.4%, in the adults with SCD 4.8%, and in the adult controls 8.1%. These differences did not reach statistical significance. CONCLUSIONS: Our findings failed to demonstrate an important role of the CCR5Delta32 allele in the population sample studied here. PMID- 25548432 TI - Laparoscopic versus Open Liver Resection: Differences in Intraoperative and Early Postoperative Outcome among Cirrhotic Patients with Hepatocellular Carcinoma-A Retrospective Observational Study. AB - Introduction. Laparoscopic liver resection is considered risky in cirrhotic patients, even if minor surgical trauma of laparoscopy could be useful to prevent deterioration of a compromised liver function. This study aimed to identify the differences in terms of perioperative complications and early outcome in cirrhotic patients undergoing minor hepatic resection for hepatocellular carcinoma with open or laparoscopic technique. Methods. In this retrospective study, 156 cirrhotic patients undergoing liver resection for hepatocellular carcinoma were divided into two groups according to type of surgical approach: laparoscopy (LS group: 23 patients) or laparotomy (LT group: 133 patients). Perioperative data, mortality, and length of hospital stay were recorded. Results. Groups were matched for type of resection, median number of nodules, and median diameter of largest lesions. Groups were also homogeneous for preoperative liver and renal function tests. Intraoperative haemoglobin decrease and transfusions of red blood cells and fresh frozen plasma were significantly lower in LS group. MELD score lasted stable after laparoscopic resection, while it increased in laparotomic group. Postoperative liver and renal failure and mortality were all lower in LS group. Conclusions. Lower morbidity and mortality, maintenance of liver function, and shorter hospital stay suggest the safety and benefit of laparoscopic approach. PMID- 25548431 TI - Peroxisome proliferator-activated receptors family is involved in the response to treatment and mild clinical course in patients with ulcerative colitis. AB - BACKGROUND: PPARs play an important role in the regulation of intestinal inflammation. METHODS: We included a total of 46 UC patients and 31 controls. The gene expression of PPARs was measured by RT-PCR and protein expression by immunohistochemistry. RESULTS: PPARalpha gene expression was significantly decreased in patients with active UC compared with remission UC group (P = 0.001) and controls (P = 0.001). We found that low gene expression of PPARalpha in mucosa confers a higher risk of UC activity (P <= 0.0001, OR = 22.6). We observed an increase of PPARalpha expression in patients with UC who were treated with 5 aminosalicylates compared with those who received any other combined therapy (P = 0.03, OR = 0.08). PPARgamma gene expression was decreased in the active UC group compared with UC in remission (P = 0.001) and control group (P = 0.001). An increased expression of PPARgamma gene was associated with mild clinical course of the disease (P <= 0.001, OR = 0.05). No gene expression of PPARbeta/delta was found in the colonic mucosa from UC patients and controls. CONCLUSION: Our results suggest that patients with high gene expression of PPARs have a better response to medical treatment and a mild clinical course of the disease. PMID- 25548433 TI - On the significance of new biochemical markers for the diagnosis of premature labour. AB - Preterm labour is defined as a birth taking place between 22nd and 37th weeks of gestation. Despite numerous studies on the aetiology and pathogenesis of preterm labour, its very cause still remains unclear. The importance of the cytokines and acute inflammation in preterm labour aetiology is nowadays well-proven. However, chronic inflammation as an element of the pathogenesis of premature labour is still unclear. This paper presents a literature review on the damage-associated molecular patterns (DAMPs), receptors for advanced glycation end products (RAGE), negative soluble isoforms of RAGE, chemokine-stromal cell-derived factor-1 (SDF 1) and one of the adipokines, resistin, in the pathogenesis of preterm labour. We conclude that the chronic inflammatory response can play a much more important role in the pathogenesis of preterm delivery than the acute one. PMID- 25548434 TI - Effect of proinflammatory cytokines (IL-6, TNF-alpha, and IL-1beta) on clinical manifestations in Indian SLE patients. AB - Systemic lupus erythematosus (SLE) is an inflammatory rheumatic disease characterized by production of autoantibodies and organ damage. Elevated levels of cytokines have been reported in SLE patients. In this study we have investigated the effect of proinflammatory cytokines (IL-6, TNF-alpha, and IL 1beta) on clinical manifestations in 145 Indian SLE patients. One hundred and forty-five healthy controls of the same ethnicity served as a control group. Clinical disease activity was scored according to SLEDAI score. Accordingly, 110 patients had active disease and 35 patients had inactive disease. Mean levels of IL-6, TNF-alpha, and IL-1beta were found to be significantly higher in SLE patients than healthy controls (P < 0.001). Mean level of IL-6 for patients with active disease (70.45+/-68.32 pg/mL) was significantly higher (P = 0.0430) than those of inactive disease patients (43.85+/-63.36 pg/mL). Mean level of TNF-alpha was 44.76+/-68.32 pg/mL for patients with active disease while it was 25.97+/ 22.03 pg/mL for those with inactive disease and this difference was statistically significant (P = 0.0161). Similar results were obtained for IL-1beta (P = 0.0002). Correlation between IL-6, TNF-alpha, and IL-1beta serum levels and SLEDAI score was observed (r = 0.20, r = 0.27, and r = 0.38, resp.). This study supports the role of these proinflammatory cytokines as inflammatory mediators in active stage of disease. PMID- 25548435 TI - Elevated serum IgG4 defines specific clinical phenotype of rheumatoid arthritis. AB - OBJECTIVES: To explore the correlation of serum IgG4 (sIgG4) with clinical manifestations or therapeutic response in rheumatoid arthritis (RA). METHODS: Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. RESULTS: Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P < 0.05). Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18) of patients with elevated sIgG4 and 85% (23/27) of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2) at 6-month visit (chi(2) = 6.508, P = 0.011). IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P < 0.05). CONCLUSIONS: Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy. PMID- 25548436 TI - Optimized "in vitro" culture conditions for human rheumatoid arthritis synovial fibroblasts. AB - The composition of synovial fluid in rheumatoid arthritis (RA) is complex and strongly influences the microenvironment of joints and it is an inseparable element of the disease. Currently, "in vitro" studies are performed on RA cells cultured in the presence of either recombinant proinflammatory cytokines conditioned medium or medium alone. In this study, we evaluated the use of synovial fluid, derived from RA patients, as optimal culture condition to perform "in vitro" studies on RA synovial fibroblasts. We observed that synovial fluid is more effective in inducing cell proliferation with respect to TNF-alpha or culture medium alone. Spontaneous apoptosis in fibroblasts was also decreased in response to synovial fluid. The expression of proinflammatory cytokines in the presence of synovial fluid was significantly elevated with respect to cells cultured with TNF-alpha or medium, and the overall morphology of cells was also modified. In addition, modulation of intracellular calcium dynamics elicited in response to synovial fluid or TNF-alpha exposure is different and suggests a role for the purinergic signalling in the modulation of the effects. These results emphasize the importance of using RA synovial fluid in "in vitro" studies involving RA cells, in order to reproduce faithfully the physiopathological environmental characteristic of RA joints. PMID- 25548437 TI - Improving Outcome of Aplastic Anaemia with HLA-Matched Sibling Donor Hematopoietic Stem Cell Transplantation: An Experience of Gujarat Cancer and Research Institute (GCRI). AB - Fifteen patients, with a median age of 19 years having severe aplastic anaemia (SAA) underwent human leucocyte antigen (HLA) identical sibling donor hematopoietic stem cell transplantation (HSCT) using conditioning regimens containing cyclophosphamide with antithymocyte globulin (ATG) or a combination of fludarabine and cyclophosphamide with or without ATG during December 2007 to May 2013. Cyclosporine and mini methotrexate were used as graft versus host disease (GVHD) prophylaxis. Graft source included peripheral blood stem cells in 11, bone marrow in 3 and both in 1. One patient had primary graft failure while 14 patients were engrafted with a median neutrophil and platelet engraftment time of 13.5 days. One patient had secondary graft rejection. Acute GVHD occurred in 3 patients and chronic GVHD in 4. One year death rate in engrafted patients was 14.28 %. At a mean follow-up of 21.2 months, 12 (80 %) are alive and well. One of the donors was a patient of haemophilia but the disease did not occur in the recipient. The graft was successful and the recipient is alive till date. PMID- 25548438 TI - Unrelated Umbilical Cord Blood Transplant for Children with beta-Thalassemia Major. AB - Beta thalassemia major, one of the most prevalent hemoglobinopathy throughout the word, can be cured by allogenic stem cell transplantation (SCT) (Bone Marrow Transplant 36:971-975, 2005). Many patients, however, lack a suitably matched related sibling donor. Unrelated umbilical cord blood (UCB) can be used as an alternative stem cell source for these patients. This report describes SCT for nine children with beta-thalassemia major using partially HLA-matched unrelated UCB. Conditioning included oral busulfan 16 mg/kg (day -10 to -7), cyclophosphamide (Cy) 200 mg/kg (day -5 to -2), fludarabine 90 mg/kg (day -13 to 11), and antithymocyte globulin (rabbit) 7.5 mg/kg (day -3 to -1). The infused cell dose was 10.71 * 10(7)/kg total nucleated cells (TNC) (range 6.5-17 * 10(7)/kg TNC). The patients ranged in age from 1.5 to 7 years, in weight from 10.5 to 17 kg. A second transplant with two unrelated cord blood units was attempted in two patients who had primary graft failure. The retransplant recipients were preconditioned with i.v Cy 120 mg/kg (day -3 to -2). Five of the nine patients engrafted promptly with 50-100 % donor chimerism (56 %). They engrafted at a median of 17 days (range 12-19). One patient is transfusion free for 36 months; a second patient is transfusion free for 18 months and a third is transfusion free for 9 months. There was no transplant related mortality. Four of the nine children had autologous recovery without engraftment. Primary graft rejection is the major complication. Post transplant complications were mild hepatic veno-occlusive disease, acute GVHD grade II, and CMV interstitial pneumonia. The chronic GVHD was limited and could be controlled by Methylprednisolone combined with Mycophenolate. The lack of a marrow donor registry in India makes UCBT from related and unrelated donors a good alternative. Transplant should be delayed until the child is at least 18 months of age. The dose of UCB stem cells is the most important factor for engraftment. UCB has the advantages of rapid availability and low risk of severe GVHD despite donor-recipient HLA disparity (Transplant Proc 37:2667-2669, 2005). We demonstrate the feasibility of this procedure in the setting of a developing country. PMID- 25548439 TI - Treatment of High-Risk T-NHL with Stem Cell Transplantation: A Single Center Experience. AB - Prognosis of peripheral and other advanced T cell lymphomas is poor. 20 patients with a median age of 46.4 (range 20.5-64.1) years were treated with autoSCT (n = 6) or alloSCT (n = 14) from 1996 to 2013. All patients were at high risk either due to the IPI-score or to the fact that SCT was part of a salvage therapy. Conditioning prior to alloSCT was myeloablative in seven cases (50 %). The patients were pretreated with 8.5 (median, range 2-38) cycles of chemotherapy. Ten patients are alive in CR after a median follow-up of 1.3 years (range 0.1 13.3). OS was 53 % after one and 40 % after 10 years. Best survival was reached after related alloSCT (80 % at 10 years) compared to other modalities. GvHD did not influence survival. AlloSCT from related donors can cure patients from T-cell lymphomas. Unrelated alloSCT or high-dose therapy and autoSCT are an option for patients without a familiar donor. PMID- 25548440 TI - The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia. AB - Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). About 45 % of de novo adult AML and 20 % of pediatric AML lack cytogenetic abnormalities, so identification of predictive molecular markers might improve therapy. Mutation status of FLT3, NPM1 genes and gene expression levels of ERG, BAALC have been postulated as possible prognostic markers in pediatric AML with normal karyotype. Pretreatment blood samples from 47 cytogenetically normal AML patients were analysed for BAALC and ERG expression using real time RT-PCR. The patients were dichotomized at BAALC and ERG mean expression into low and high expression based on the median expression as cutoff. BAALC showed high expression in (24/47; 51.1 %) of patients and ERG high expression was detected in (22/47; 46.6 %). With follow-up for 1 year, patients with high BAALC and high ERG had inferior EFS (P = 0.001, P = 0.017 respectively), overall survival (P = 0.001, 0.08 respectively), and low rates of induction remission (P = 0.001, P = 0.0017 respectively) as compared to those with low expression. Also there was significant positive association between high expression of BAALC; ERG and FLT-ITD mutations (P = 0.016; P = 0.007 respectively). Multivariable analysis confirmed that high BAALC expression is an independent risk factor for EFS [HR for EFS 1.9(1.04-3.46) P = 0.037]; and OS [HR OS 1.55(1.7-3.36) P = 0.03]. IN CONCLUSION: Over expression of BAALC could predict adverse clinical outcome and may define important risk factor in cytogenetically normal pediatric AML. PMID- 25548441 TI - Lack of Correlation Between the CCR5-Delta32 Mutation and Acute Myeloid Leukemia in Iranian Patients. AB - Chemokines and their receptors are crucially important in the pathogenesis of acute myeloblastic leukemia (AML). The CC chemokine receptor 5 (CCR5) is a specific chemokine receptor for CC chemokine ligand 3 (CCL3), CCL4 and CCL5 which all play key roles in identifying cancer properties and localization of leukemia cells. It has been demonstrated that the known mutation in CCR5 gene (CCR5 Delta32) leads to mal-expression of the receptor and affect its function. The aim of this study was to determine the rate of CCR5-Delta32 mutation within Iranian AML patients. In this study, blood samples were obtained from 60 AML patients and 300 healthy controls. The CCR5-Delta32 mutation was evaluated using Gap-PCR technique. Our results showed that CCR5-Delta32 mutation was not found in the patients, while three out of the controls had hetrozygotic form of this mutation. The rest of studied samples had the wild form of the gene. According to these findings, it can probably be concluded that the CCR5-Delta32 is not associated with susceptibility to AML in Iranian patients. PMID- 25548442 TI - Children Diagnosed as Mixed-Phenotype Acute Leukemia Didn't Benefit from the CCLG 2008 Protocol, Retrospective Analysis from Single Center. AB - Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia with a poor clinical outcome which lacks specific therapy. To evaluate the therapeutic efficiency of CCLG-2008 protocol used for acute lymphoblastic leukemia (ALL) in China on MPAL children who were initially diagnosed as ALL by morphology, we reviewed patients' database diagnosed as ALL and MPAL according to WHO classification and compared their outcomes from July 2008 to June 2012. Total newly enrolled ALL in this study were 309 cases by morphology, in which ten cases were identified as MPAL mainly by immunophenotyping: B+ myeloid (3/10), T+ myeloid (2/10), B + T (4/10), trilineage (1/10). Two cases were classified as intermediate risk (IR) and 8 cases were high risk (HR) according to the CCLG-2008 criteria. Only one case of IR survived and others died due to primary resistance of chemotherapy and relapse. Compared with MPAL, ALL children in IR and HR had a longer survival (28.1 vs 9.5 months, p < 0.0001) and lower relapse (16.3 vs 85.7 %, p = 0.0002). In a summary, our result indicated that MPAL in children is a poor-risk disease which needs personalized therapy to improve outcome. PMID- 25548444 TI - Micro-organisms Associated with Febrile Neutropenia in Patients with Haematological Malignancies in a Tertiary Care Hospital in Eastern India. AB - There is paucity of information from eastern India with regard to observed dominant micro-organisms causing febrile neutropenia (FN) in patients with haematological malignancies. To identify the prevalence of pathogenic microorganisms associated with FN. A total number of 268 episodes of FN were analysed from September'2010 to October'2013. The blood samples were inoculated into brain heart infusion broth, glucose broth, Hicombi dual performance media (Himedia, LQ-12) at 37 degrees C for 168 h and Bactec method was also performed for these samples. Blood agar, chocolate agar, MacConkey's agar and cystine lactose electrolyte deficient agar were used for isolation of the microorganisms. A total number of 78 (29.10 %) episodes revealed positive growths. Gram negative bacilli and Gram positive cocci were isolated in 61.53 and 34.61 % cases respectively. The eight commonest isolates were Pseudomonas aeruginosa (14.10 %), methicillin resistant Staphylococcus aureus (MRSA-12.82 %), Acinetobacter sps (11.53 %), coagulase negative Staphylococcus (10.25 %), Klebsiella pneumoniae (8.97 %), Escherichia coli (8.97 %), ESBL E. coli (6.41 %), methicillin sensitive S. aureus (MSSA-6.41 %). Amongst other less common isolates were Citrobacter kosseri (3.84 %), Citrobacter freundii (2.56 %), Ralstonia paucula (2.56 %), Cedecia neteri (1.28 %), methicillin resistant coagulase negative Staphylococcus (2.56 %). Candida spp. including two cases of Candida non-albicans was isolated in 3.84 % of cases. P. aeruginosa was the commonest pathogenic isolates in FN patients associated with haematological malignancies in this study. Gram negative bacteria were the commonest isolates in FN including significant numbers of rare opportunistic micro-organisms. PMID- 25548443 TI - PCR Analysis of IgH and TCR-gamma Gene Rearrangements as a Confirmatory Diagnostic Tool for Lymphoproliferative Disorders. AB - This study investigates PCR analysis of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements on paraffin-embedded tissue sections and bone marrow aspirates of patients suspected to have lymphoproliferative disorders but with inconclusive diagnosis in histopathological examination. 130 samples of patients with inconclusive immunohistochemistry results were evaluated for clonal rearrangement of IgH and TCR genes. Based on histopathology examination, the patients were divided into three groups: the first group without any definite diagnosis of lymphoproliferative disorders (60 cases, 46.2 %), the second group suspected to have a lymphoproliferative disorder but in favor of benign disorders (19 cases, 14.6 %) and the third group suspect to lymphoproliferative disorders but relatively in favor of malignant disorders (51 cases, 39.2 %). After DNA extraction and quality control, semi-nested PCR was performed using consensus primers for amplification of TCR-gamma and CDR-3 regions of IgH genes. PCR products were analyzed after heteroduplex analysis using polyacrylamide gel electrophoresis, and were subject to silver staining. Totally, in over half of the cases (55.4 %), a monoclonal pattern was found in IgH or TCR-gamma genes rearrangements. Monoclonal IgH gene rearrangement was detected in 48.1 % of patients, whereas monoclonal TCR-gamma gene rearrangement was found in 33.6 % of them, which was not statistically significant (P = 0.008). Only in 32 patients (24.6 %) were the results of TCR-gamma and IgH gene rearrangements consistent with respect to the presence (2.3 %) or absence (22.3 %) of monoclonality. Finally, PCR analysis of TCR-gamma and IgH gene rearrangements led to definite diagnosis in 105 patients (80.8 %), and only 25 cases (19.2 %) remained inconclusive. Our results emphasize the usefulness of gene rearrangement study in cases without a definite diagnosis in immunohistochemistry studies. Multiple PCR analysis results when combined with patient's clinical course and immunohistochemistry can lead to early diagnosis and subsequent therapy. PMID- 25548445 TI - Which Multidrug-Resitant Bacteria are Emerging in Patients with Hematological Malignancies?: One-Year Report. AB - The aim of this retrospective, observational study was to evaluate the outcomes of bacteremia attacks during neutropenic episodes caused by chemotherapy in patients with hematological cancers by assessing mortality, involved pathogens, antimicrobial therapy and treatment responses. Patients who were older than 14 years of age and developed at least one neutropenic episode after chemotherapy to treat hematological cancer between November 2011 and November 2012 were included in the study. We retrospectively collected demographic, treatment, and survival data for 68 patients with 129 neutropenic episodes. The mean age was 59.36 +/- 15.22 years (range 17-80 years), and 41 cases were male. The mean Multinational Association of Supportive Care in Cancer score was 19.56 +/- 9.04. A total of 37 (28 %) bacteremia attacks were recorded in 20 cases (29 %). Fatality rates were 50 % in the six cases with bacteremia caused by carbapenem-resistant Gram negative bacteria; death occurred in two patients with carbapenem-resistant Acinetobacter baumannii and in one patient with carbapenem-resistant Pseudomonas aeruginosa. Clinical and microbiological responses were achieved using PIP-TAZ or CEP-SUL treatment in 80 % (16/20) of the cases with bacteremia caused by carbapenem-sensitive Gram-negative bacteria (CS-GNB). During 547 colonization days in 21 (30 %) vancomycin-resistant enterococci (VRE)-colonized cases among 68 patients, vancomycin-resistant Enterococcus faecium bacteremia developed in two patients. Non-carbapenem-based therapy can cure most bacteremia attacks caused by CS-GNB in patients with hematological cancer. However, bacteremia and other infections caused by drug-resistant pathogens, such as A. baumannii, P. aeruginosa, and VRE, are a growing concern in hematological patients. PMID- 25548446 TI - Bone Marrow Involvement in Neuroblastoma: A Study of Hemato-morphological Features. AB - Bone marrow involvement in neuroblastoma indicates advanced stage of disease. The recent use of autologous bone marrow "rescue", has provided an additional important reason for accurate assessment of bone marrow status in newly diagnosed patients. In this study, we analyzed 44 cases of neuroblastoma for bone marrow infiltration status and their hematological parameters. Eighty-eight bone marrow aspirate and trephine touch imprint smears and 44 trephine biopsy sections were examined in these 44 patients. Of these, 24 cases (54.5 %) showed marrow infiltration. Leucopenia and bicytopenia were significantly (p < 0.05) associated with marrow infiltration. Both bone marrow aspirate and biopsy were positive for infiltration in 16 out of 24 positive cases. Only aspirate smears were positive in 4 and only trephine biopsy in another 4 cases. The pattern of infiltration consisted of rosette formation in 40.7 % cases on aspirate smears and 22.2 % cases in trephine biopsies. Remaining cases showed diffuse and interstitial presence of tumor cells and cases positive only on trephine biopsy, showed marked stromal reaction. Bilateral trephine biopsies combined with aspirate smears picked up all positive cases compared to when they were assessed alone. PMID- 25548447 TI - Macrothrombocytopenia in north India: role of automated platelet data in the detection of an under diagnosed entity. AB - Congenital macrothrombocytopenia is being increasingly recognised because of the increasing availability of automated platelet counts during routine complete blood count. If not recognised, these patients may be unnecessarily investigated or treated. The study was done to assess the occurrence of macrothrombocytopenia in the North Indian population and the role of automated platelet parameters in its detection. This prospective study was done on patients whose blood samples were sent for CBC to the hematology laboratory of a tertiary care hospital. Samples were run on Advia-120, a 5-part differential automated analyzer. Routine blood parameters including platelet count, mean platelet volume (MPV), platelet cytogram pattern and platelet flagging was studied along with peripheral blood smear examination. ANOVA was used to compare difference in mean MPV in patients with macrothrombocytopenia, and those with secondary thrombocytopenia and ITP. Seventy five (0.6 %) patients with CBC evaluation were detected to have macrothrombocytopenia, majority (96 %) of North Indian origin. The MPV (fl) in the 75 patients ranged from 10.9 to 23.3 (mean 15.1 +/- 3.1 fl) with a dispersed cytogram pattern distinct from that seen in patients with normal platelet count, raised platelet count or low platelets due to secondary thrombocytopenia (MPV 10.9 +/- 2.6) or ITP (10.8 +/- 3.5). The difference in mean MPV in these patients was statistically significant (p < 0.00001). Macrothrombocytopenia is an under diagnosed condition and may be initially suspected on automated blood counts. Along with a blood smear examination, automated data (MPV and platelet cytogram pattern) aids the diagnosis and can avoid unnecessary investigations and interventions for these patients. PMID- 25548448 TI - Pediatric lupus: varied haematological picture and presentation. AB - Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease characterized by periods of increased disease activity caused by inflammation of blood vessels and connective tissue. Pediatric patients with SLE have a more severe clinical course when compared with adults. Patients commonly present with rash, fever, and arthritis, although the presentation may be unpredictable. Hematological findings are more predominant in children than adults. Thirty-nine percent of children with SLE will develop hematological abnormalities, one of the American Rheumatic Association criteria for classifying the disease. In our case series we found varied hematological picture and presentation. We present here four case reports of SLE cases with interesting hematological features. Our first case is a 13 month old female child who was initially diagnosed as Evans syndrome and 2 years later diagnosed as SLE. Second case is a 3 year old male child who had SLE with warm antibody AIHA. Third case is a 6 year old female child who presented with AIHA and was diagnosed with SLE 6 years later. Fourth case is a 6 year old female child diagnosed as SLE with aplastic anemia. Hematological findings should be carefully assessed and treated in order to decrease disease related morbidity. PMID- 25548449 TI - Value of platelet indices in identifying complete resolution of thrombus in deep venous thrombosis patients. AB - We aimed to evaluate whether mean platelet volume (MPV) and platelet distribution width (PDW) are helpful to identify complete thrombus resolution (CTR) after acute deep venous thrombosis (DVT). Patients who had first-time episode of acute proximal DVT were included in this retrospective study. 100 patients with DVT were divided into two groups according to absence (group 1; n = 68) or presence (group 2; n = 32) of CTR on doppler ultrasonography at month 6. There were no significant difference in admission MPV and PDW levels between group 1 and group 2. MPV (p = 0.03) and PDW (p < 0.001) levels at month 6 were significantly higher in group 1 than in group 2. CTR showed a moderate negative correlation with PDW at month 6 (rho = -0.47) and a weak negative correlation with MPV at month 6 (rho = -0.26). Logistic regression analysis showed that PDW (OR, 2.2; p = 0.004) at month 6 was an independent risk factor for the presence of residual venous thrombosis in DVT patients. Receiver operating characteristics analysis revealed that a 8.4 % decrease in admission MPV at month 6 provided 62 % sensitivity and 62 % specificity (AUC: 0.64) and a 15.4 % decrease in admission PDW at month 6 provided 87 % sensitivity and 94 % specificity (AUC: 0.89) for prediction of CTR in DVT patients. Percent change in admission MPV and PDW levels at month 6 may be used to identify the patients with CTR after a first episode of acute proximal DVT. PMID- 25548450 TI - Detection and Identification of Platelet-Associated Alloantibodies by a Solid Phase Modified Antigen Capture Elisa (MACE) Technique and Its Correlation to Platelet Refractoriness in Multi platelet Concentrate Transfused Patients. AB - Platelets express glycoproteins (IIb/IIIa, Ib/IX, Ia/IIa, IV, and HLA-1) that are polymorphic and can become targets for antibody responses. Patients at threat are those who received multiple platelet transfusions. Modified antigen capture elisa (MACE) is a qualitative solid phase Elisa designed to detect IgG antibodies against platelet specific antigens. The study has been carried out over a period of 2 years. A total of 100 patients were selected, who had been transfused with at least 15 units of platelet concentrate. All patients were having either hematological malignancies or bone marrow failure syndromes. Platelet antibodies were identified using MACE-1&2. Data was analysed statistically, using odds ratio (OR) with 95 % confidence interval. 39 % of the patients were found to be alloimmunized against platelet antigens, of which eleven showed refractoriness. Six patients (54.5 %) with HLA-1, two patients (9.5 %) with GPIb/IX, two patients (40 %) with both HLA-1 and GPIIb/IIIa, and one patient with GPIIb/IIIa antibodies showed refractoriness. Production of HLA-1 antibody and the development of refractoriness was found to be significant with OR 14.05 and P value 0.0025. MACE 1&2 enabled specific detection and identification of platelet antibodies, which in turn correlated well with the development of refractoriness in multi transfused patients. GPIb/IX was detected as the commonest antibody in our patient population, which is in variance with Europian studies where it is GPIa/IIIa (HPA-1a/5b). This technique should be utilised in patients who are at an increased risk of developing alloimmunisation due to repeated platelet transfusions. PMID- 25548451 TI - Clinical significance of positive platelet immunofluorescence assay in adult immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is a relatively common hematologic disorder manifested by low platelet count due to immune-mediated platelet destruction and/or suppression of platelet production. This study aim was to evaluate characteristics and clinical presentation of adult patients with ITP and exploring the clinical value of platelet antibodies assay in proposed cases in Iranian population. In this prospective case series 46 adult patients with ITP and platelet count of <100 * 10(9)/L, referred to the Taleghani Medical Center, Tehran, Iran between 2007 and 2009 were evaluated. There were 26 females and 20 males (1.3:1) with mean age of 38.9 +/- 19.7 years. The platelet autoantibodies were measured by means of indirect platelet suspension immunofluorescence test. According to our results, 7 patients (15.2 %) displayed a positive platelet antibody assay. There was a significant negative correlation between platelet count and antibody level (r = -0 0.59; p < 0.001). Additionally, a positive correlation between platelet count and patients' age (r = 0.302; p = 0.042) was detected. 20 patients (56.5 %) were symptomatic at presentation and the most common bleeding signs were petechia, purpura and epistaxis. Results indicated no significant correlation between increased platelet antibody level and bleeding manifestations except for hematuria (r = 0.435; p = 0.02) and epistaxis (r = 0.382; p = 0.015). Disclosure of platelet autoantibodies and the consequential thrombocytopenia associated to some extent but not completely with the propensity to bleed which necessitates more factors to be evaluated. PMID- 25548452 TI - In Vitro Susceptibility of Wistar Rat Platelets to Hydrogen Peroxide and AAPH Induced Oxidative Stress. AB - Hydroxyl and peroxyl radicals are biologically active species because of their likelihood to damage cellular constituents. An in vitro study on Wistar rats was conducted to investigate the influence of hydrogen peroxide (H2O2) and 2,2' azobis(2-amidinopropane) dihydrochloride (AAPH) on platelets and compare the vulnerability of platelets to oxidative stress (OS) induced by these two free radical initiators. Isolated platelets were divided into controls (without free radical initiators; n = 5) and experimentals (with free radical initiators; n = 5). Different concentrations (0.5, 1.0 and 2.0) of free radical initiators H2O2 and AAPH were used to treat the platelets and incubated for 5, 15 and 30 min. Biomarkers such as platelet aggregation, superoxide generation, lipid peroxidation (thiobarbituric acid reactive substances, conjugate dienes), protein oxidation (protein carbonyls, sulfhydryls) and antioxidant enzymes were assessed. In H2O2 and AAPH treated platelets, though OS was observed at concentrations of 0.5 and 1.0 mM, platelets could tolerate the oxidative insult. Treatment of platelets with 2.0 mM H2O2 demonstrated the onset of irreversible changes in platelets as observed in the results of increased superoxide generation and lipid peroxidation products. In 2.0 mM AAPH platelets, the oxidative damage was evident as indicated through increased aggregation, superoxide generation and conjugate dienes and lower protein sulfhydryls. Platelets were more susceptible to AAPH than H2O2, as AAPH acted on both lipids and proteins whereas H2O2 acted only on lipids. This study gives insight on platelet survival under different OS situations. PMID- 25548453 TI - Spectrum of Hemoglobinopathies in West Bengal, India: A CE-HPLC Study on 10407 Subjects. AB - Hemoglobinopathies are common genetic disorders of haemoglobin. Identification of these disorders is immensely important epidemiologically and they can be prevented by population screening. The present study was carried out to evaluate the spectrum of hemoglobinopathies in the state of West Bengal by the cation exchange high-performance liquid chromatography (CE-HPLC). A retrospective, single-center, cross-sectional study was conducted on consecutive 10,407 participants. Out of 10,407 subjects, 8,898 (85.5 %) were diagnosed as normal, 579 (5.6 %) were as beta-thalassemia trait (BTT) and 522 (5.0 %) were detected as HbE carrier on HPLC study. Apart from BTT and HbE carrier ten additional variants were encountered. The present study showed that CE-HPLC is a convenient, high throughput, labour-saving and objective screening tool for early detection and management of hemoglobinopathies. PMID- 25548455 TI - HPLC in characterization of hemoglobin profile in thalassemia syndromes and hemoglobinopathies: a clinicohematological correlation. AB - High-performance liquid chromatography (HPLC) is a technique introduced for the accurate diagnosis of hemoglobinopathies and thalassemias. The advantage of the HPLC system is the excellent resolution, reproducibility & quantification of several normal & abnormal hemoglobin resulting in accurate diagnosis of thalassemia syndromes. The purpose of this study is to evaluate the HPLC technique in diagnosis of thalassemia syndromes and also correlate it with clinicohematological profile in these cases. A total of 110 cases were diagnosed as thalassemias and hemoglobinopathies by Bio- Rad variant II HPLC system by beta thal short program. The retention times, proportion of the haemoglobin (%), and peak characteristics for all hemoglobin (Hb) fractions were recorded. Alkaline Hb electrophoresis was performed in each case. Other tests performed were HbF estimation by Betke's method, brilliant cresyl blue preparation for HbH inclusion bodies, sickling tests using 2 % metabisulphite and serum Ferritin estimation. Family studies were carried out wherever necessary. Of 110 cases included in the study, 87 cases were of thalassemic disorders and 23 cases were of hemoglobinopathies. Four Hb variants were identified including HbD, HbE, HbS, HbJ Oxford. There was a significant decrease in the level of HbA2 associated with iron deficiency anemia. The mean HbA2 levels in both iron deplete and iron replete groups were clearly >4 %, suggesting that HPLC identified nearly all high HbA2 beta-thalassemia trait even in spite of iron deficiency. PMID- 25548454 TI - The screening and morbidity pattern of sickle cell anemia in chhattisgarh. AB - Our objective was to find out prevalence of sickle cell anemia among the population of three districts (Kanker, Dantewada and Raigarh) of Chhattisgarh with clinical and hematological profile of sickle cell disease patients. A cross sectional study was done. A total of 15,701 persons collectively from three districts voluntarily attended the mobile camp and were screened for sickle cell anemia. First solubility test were done and were confirmed by Hb electrophoresis. The prevalence of sickle cell trait (HbAS) was 1,672 (10.6 %), sickle cell disease (HbSS) and inconclusive band was 97 (0.66 %). The HbSS and inconclusive band were subjected to HPLC. Among them 12 (0.076 %) cases were double heterozygous for Hb-S and beta thalassemia minor (SB+), 2 (0.012 %) cases were double heterozygous for Hb-S and Hb-E (S/HBE), 1 (0.006 %) case was double heterozygous for Hb-S and Hb-D Punjab (S/HBD) and 22 (0.14 %) cases had Hb-S with Hb-F level more than 20 % (SSF). Maximum number of HbSS cases were 13 (2.29 %) out of 567 children in the age group 0-5 years and HbAS cases were 124 (15.6 %) out of 794 persons in the age group 21-25 years. On comparison between vaso occlusive and steady state, homozygous patients showed decrease in Hb, HCT, MCH, RBC in vaso-occlusive crises (p < 0.001) than steady state. Also there was one moderate negative correlation in number of blood transfusion (r = 0.46) with fetal hemoglobin (HbF) level. Patients with high HbF can have severe disease. This happens due to uneven distribution of fetal hemoglobin in F-cells with mean HbF remaining constant but in our study, those who had HbF level above 15-20 % were having fewer crises. PMID- 25548456 TI - The Prognostic Significance of HbF in Childhood Haematological Malignancies. AB - The degree of increase in foetal haemoglobin (HbF) synthesis in haematological malignancies may be associated with the degree of malignancy. The aim of the present study was to quantify HbF levels in various childhood haematological malignancies and also, to ascertain its prognostic significance by comparing the results with the already established standard prognostic factors. Newly diagnosed cases of haematological malignancies in the paediatric age group were included in the study. HbF levels were estimated in each case of the study group along with HbF levels of control group comprising healthy children of same age group. The estimation was done by HPLC and Modified Betke's method. 50 cases of newly diagnosed haematological malignancies were studied out of which most of the cases were of acute lymphoblastic leukaemia (ALL) [n = 30(60 %)] followed by acute myeloid leukaemia (AML) [n = 8(16 %)], Hodgkin's lymphoma [n = 7(14%)], non Hodgkin's lymphoma [n = 5(10 %)]. Raised HbF levels were found in 43.3 % cases of ALL (13/30) and 37.5 % cases of AML (3/8). No significant rise in HbF level was found in cases of lymphomas. There was correlation between raised HbF level and poor prognostic factors in cases of ALL but no such correlation was found in cases of AML. HbF levels are often elevated in childhood leukaemias as compared to childhood lymphomas. Thus, the concentration of HbF in acute childhood leukaemia may be considered as a prognostic factor. PMID- 25548457 TI - Clinicoinvestigational and demographic profile of children with thalassemia major. AB - There are an estimated 200 million carriers of the beta-thalassemia gene worldwide, 20 million being in India. The mean prevalence in India is 3.3 %. Objective To evaluate the clinico-investigational profile and the demographic characteristics of patients with thalassemia major (TM). Methods This was a retrospective analysis of the clinico-demographic profile at presentation of patients of TM diagnosed in the Paediatric Hematology Clinic of our hospital. Results The clinical profile of 964 patients of TM was analyzed. The mean age at presentation of untransfused children was 13.2 +/- 9.7 months. Nearly 2/3(rd) children presented before 1 year of age. Almost 40 % had symptoms for 3 months prior to presentation. The manifestations at presentation included pallor and failure to thrive. About 40 % presented with severe anemia, with a hemoglobin of <5.0 gm/dl. A large number received blood transfusions prior to establishment of the diagnosis. Half of the families had ancestors who hailed originally from Pakistan. Approximately 50 % belonged to the Khatri/Arora castes. The parental literacy rate was about 90 %. Conclusions Thalassemia needs greater public awareness and prevention strategies in our country. Some communities are at high risk as compared to others. Education programs and compulsory antenatal screening appear to be the order of the day. PMID- 25548458 TI - Hereditary spherocytosis: evaluation of 68 children. AB - To determine the clinical and hematologic features of 68 children with hereditary spherocytosis (HS). In this retrospective study, we analyzed recorded information of 68 HS patients diagnosed between March 1997 and March 2007, including clinical manifestations at admission, gender, median age at diagnosis, family history, hematologic and biochemical data, patient management, complications, median age of splenectomy, and median follow-up time. Sixty-eight patients with HS (36 male and female) were investigated. The median age at diagnosis was 5.6 years (range 3 months to 18 years). Twenty-seven (39.7 %) had parents with consanguineous marriages, and 20 (29.4 %) had parents with first-degree consanguinity. Predominant clinical manifestations at admission were anemia in 59 patients (86.76 %), splenomegaly in 49 (72.05 %), and jaundice in 33 (48.52 %). Patients were classified as mild, moderate, or severe in 29.4, 61.7, and 8.8 % of patients, respectively. Five patients (7.3 %) underwent splenectomy. Major complications of HS were hemolytic, aplastic, and megaloblastic crises and cholelithiasis in 7 (10.2 %), 1 (1.4 %), 7 (10.2 %), and 6 (8.8 %) of patients, respectively. There were no deaths during follow-up. HS should be considered in evaluating possible diagnoses in patients with hemolytic anemia. In this study, the clinical course of patients with HS was relatively benign, with low proportions of patients having splenectomized and aplastic crises. PMID- 25548459 TI - Molecular Characterization of G6PD Deficient Variants in Nineveh Province, Northwestern Iraq. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency considered to be the commonest inherited enzymopathies disorders worldwide including Iraq. Studies have addressed its prevalence and molecular characterization in several parts of the country, but no data were available from Nineveh province, northwestern-Iraq regarding molecular basis of this inherited enzymopathy. To determine the molecular basis of G6PD deficient variants in Nineveh province. A total of 61 G6PD deficient male individuals from Nineveh province were enrolled in this study. DNA from all enrolled individuals were extracted and analyzed for four deficient molecular variants using a polymerase chain reaction-restriction fragment polymorphism method. These deficient variants were G6PD-Mediterranean (563 C->T), G6PD-Chatham (1003 G->A), G6PD-A-(202 G->A) and G6PD-Cosenza (1376 G >C). Also enrolled individuals were screened for silent 1311 (C->T) mutation. It was found that 46 (75.41 %) were G6PD-Mediterranean, 1(1.64 %) were G6PD-Chatham, another 1(1.64 %) were G6PD-A-, and 13 (21.31 %) were remained uncharacterized. Also all G6PD-Mediterranean as well as one uncharacterized individuals were carriers of silent 1311 (C->T) mutation. This study documented that G6PD Mediterranean constitute the bulk of G6PD deficient variants in this province and G6PD-Chatham and A- were encountered less frequently. Also that silent 1311 (C >T) mutation were common among G6PD-Mediterranean deficient variants individuals. PMID- 25548460 TI - Antenatal Maternal Serum IAT Titer and Fetal Outcome in Rh Isoimmunized Pregnancies. AB - The incidence of Rh negativity in India is about 1-5 % and the rate of Rh sensitization to be approximately 0.79 % of live births. This study evaluated the role of antenatal maternal serum Indirect Antiglobulin Test (IAT) titre in predicting the feto-neonatal outcome. The study was conducted from Jan 2007 to Dec 2012 at our centre in Pune, Maharashtra, India. This study reports our experience with 75 IUTs carried out for 42 cases of severe Rh isoimmunization. IAT was performed by ID gel cards and test tube method was utilized for titration. Results were analysed by odds ratio (OR) with 95 % Confidence Interval. IAT titre was found to have a direct correlation with the maternal parity, requirement of number of IUT's and adverse fetal outcome. Of the 42 cases of severe Rhisoimmunization who underwent IUT, 11 (26.2 %) had hydropic fetus resulting in 08 (73 %) live babies, two intrauterine and one neonatal death. The remaining 31 (73.8 %) non-hydropic fetuses who received IUT, one intrauterine and one neonatal death were observed. In the 11 hydropic cases, who received IUTs, two intrauterine and one neonatal death were observed in which the IAT titre was >=512, which was found statistically significant with OR of 9.77 & P value of 0.05. The overall survival rate was 37/42 (88.1 %). Severity and fetal outcome in Rh isoimmunized pregnancies, showed a significant association with antenatal maternal serum IAT titre. More the antibody titre more would be the fetal and/or neonatal severity with respect to immune hemolytic anemia. Requirement of multiple IUTs are also associated with high antenatal serum IAT titre. PMID- 25548461 TI - Study of adverse whole blood donor reactions in normal healthy blood donors: experience of tertiary health care centre in jammu region. AB - Whole blood donation is generally a safe procedure, but sometimes adverse reactions of varying severity may occur during or at completion of blood donation process. The aim of the present study was to estimate the frequency and type of adverse events during blood donation. This retrospective study conducted from November 2011 to December 2012 at Department of Blood Transfusion Medicine GMC Jammu. All whole blood donations at our Department was analyzed. All adverse events occurring during or at end of donation were noted using standardized format. Overall 108 adverse events were reported in relation to 29,524 donations, resulting in overall adverse event rate of 0.365 %. Presyncopal reactions in other words vasovagal reactions of mild intensity, were the most commonly observed adverse reactions and accounted for approximately 58/108 (53.70 %) of all adverse reactions noted. Only 0.365 % of blood donations were complicated by adverse events and most of these events were presyncopal symptoms. Our study reinforces that blood donation is a very safe procedure which could be made even more event free by following certain friendly, reassuring and tactful practices. PMID- 25548462 TI - Infantile Acute Monoblastic Leukemia with MLL Gene Rearrangements. AB - A 7 month infant presented with fever and breathlessness with raised total counts. Examination revealed 90 % blasts with prominent nucleoli. Flow cytometry revealed a tight cluster in the monocytic region. The blasts showed homogenous bright CD 33/4/64/HLA D with heterogeneous expression of CD14/15/11c. Blasts were negative for CD13/MPO/Cytoplasmic CD3/19/7/34/117/5/22/TdT/CD 61/41. FISH revealed MLL gene rearrangements in the blasts. No evidence of Down's syndrome on cytogenetic studies was noted. Diagnosis of Infantile acute monoblastic leukemia was made. These leukemias are rare in infants and are associated with a poor outcome. PMID- 25548463 TI - Unusual Case of ALL with Ovarian Relapse. AB - Patients with acute lymphoblastic leukemia (ALL) can develop relapse in sanctuary sites like brain, ovary or testis even when the bone marrow is in remission. Pelvic recurrence is rarely reported during the follow up of successfully treated ALL in females. We report here a very unusual case of a large pelvic lump which the patient herself could feel, that was probably an ovarian relapse of ALL, successfully treated with re-induction chemotherapy alone and achieved complete remission. PMID- 25548464 TI - Management of acquired haemophilia bleed in the backdrop of multiple myeloma. AB - Acquired haemophilia A is an uncommon, potentially life-threatening disorder caused by onset of auto-antibodies against coagulation factor VIII. The association of acquired haemophilia and multiple myeloma is extremely rare. Prompt diagnosis of this acquired bleeding disorder is essential for management, aimed at haemorrhage control and inhibitor suppression. We describe a case of acquired haemophilia in a patient with multiple myeloma. PMID- 25548465 TI - Philadelphia chromosome positive precursor T acute lymphoblastic leukemia. PMID- 25548466 TI - Granular ALL in an Elderly Woman Diagnosed by Flow Cytometric Immunophenotyping. PMID- 25548467 TI - Spontaneous remission of adult acute lymphoblastic leukemia: a very rare event. AB - A middle aged male presented to us with an unusual problem when his acute lymphoblastic leukemia (ALL) disappeared without any chemotherapy. We faced a dilemma whether to go ahead and treat his initial diagnosis or wait. Eventually he did relapse and was treated, albeit with a fatal outcome. Such spontaneous remission in acute leukemia are a very rare event, more common in acute myeloid leukemia and in children. Spontaneous remission in adult ALL is rarely described in literature. PMID- 25548468 TI - Genetic polymorphism in pathogenesis of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdominal pain or discomfort that has at least two of the following symptoms for 3 d per month in the past 3 mo according to ROME III: relief by defecation, onset associated with a change in stool frequency or onset with change in appearance or form of stool. Recent discoveries revealed genetic polymorphisms in specific cytokines and neuropeptides may possibly influence the frequencies and severity of symptoms, as well as the therapeutic responses in treating IBS patients. This review gives new insights on how genetic determinations influence in clinical manifestations, treatment responses and potential biomarkers of IBS. PMID- 25548469 TI - Toll-like receptor signaling in colorectal cancer: carcinogenesis to cancer therapy. AB - Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-kappaB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-kappaB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy. PMID- 25548470 TI - Achieving the best bowel preparation for colonoscopy. AB - Bowel preparation is a core issue in colonoscopy, as it is closely related to the quality of the procedure. Patients often find that bowel preparation is the most unpleasant part of the examination. It is widely accepted that the quality of cleansing must be excellent to facilitate detecting neoplastic lesions. In spite of its importance and potential implications, until recently, bowel preparation has not been the subject of much study. The most commonly used agents are high volume polyethylene glycol (PEG) electrolyte solution and sodium phosphate. There has been some confusion, even in published meta-analyses, regarding which of the two agents provides better cleansing. It is clear now that both PEG and sodium phosphate are effective when administered with proper timing. Consequently, the timing of administration is recognized as one of the central factors to the quality of cleansing. The bowel preparation agent should be administered, at least in part, a few hours in advance of the colonoscopy. Several low volume agents are available, and either new or modified schedules with PEG that usually improve tolerance. Certain adjuvants can also be used to reduce the volume of PEG, or to improve the efficacy of other agents. Other factors apart from the choice of agent can improve the quality of bowel cleansing. For instance, the effect of diet before colonoscopy has not been completely clarified, but an exclusively liquid diet is probably not required, and a low-fiber diet may be preferable because it improves patient satisfaction and the quality of the procedure. Some patients, such as diabetics and persons with heart or kidney disease, require modified procedures and certain precautions. Bowel preparation for pediatric patients is also reviewed here. In such cases, PEG remains the most commonly used agent. As detecting neoplasia is not the main objective with these patients, less intensive preparation may suffice. Special considerations must be made for patients with inflammatory bowel disease, including safety and diagnostic issues, so that the most adequate agent is chosen. Identifying neoplasia is one of the main objectives of colonoscopy with these patients, and the target lesions are often almost invisible with white light endoscopy. Therefore excellent quality preparation is required to find these lesions and to apply advanced methods such as chromoendoscopy. Bowel preparation for patients with lower gastrointestinal bleeding represents a challenge, and the strategies available are also reviewed here. PMID- 25548471 TI - Impact of the gut microbiota on rodent models of human disease. AB - Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 10(14) organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation. PMID- 25548473 TI - Per-oral endoscopic myotomy: major advance in achalasia treatment and in endoscopic surgery. AB - Per-oral endoscopic myotomy (POEM) represents a natural orifice endoscopic surgery (NOTES) approach to laparoscopy Heller myotomy (LHM). POEM is arguably the most successful clinical application of NOTES. The growth of POEM from a single center in 2008 to approximately 60 centers worldwide in 2014 with several thousand procedures having been performed attests to the success of POEM. Initial efficacy, safety and acid reflux data suggest at least equivalence of POEM to LHM, the previous gold standard for achalasia therapy. Adjunctive techniques used in the West include impedance planimetry for real-time intraprocedural luminal assessment and endoscopic suturing for challenging mucosal defect closures during POEM. The impact of POEM extends beyond the realm of esophageal motility disorders as it is rapidly popularizing endoscopic submucosal dissection in the West and spawning offshoots that use the submucosal tunnel technique for a host of new indications ranging from resection of tumors to pyloromyotomy for gastroparesis. PMID- 25548472 TI - Intestinal microbiota and type 2 diabetes: from mechanism insights to therapeutic perspective. AB - The incidence of type 2 diabetes (T2DM) is rapidly increasing worldwide. However, the pathogenesis of T2DM has not yet been well explained. Recent evidence suggests that the intestinal microbiota composition is associated with obesity and T2DM. In this review, we provide an overview about the mechanisms underlying the role of intestinal microbiota in the pathogenesis of T2DM. There is clear evidence that the intestinal microbiota influences the host through its effect on body weight, bile acid metabolism, proinflammatory activity and insulin resistance, and modulation of gut hormones. Modulating gut microbiota with the use of probiotics, prebiotics, antibiotics, and fecal microbiota transplantation may have benefits for improvement in glucose metabolism and insulin resistance in the host. Further studies are required to increase our understanding of the complex interplay between intestinal microbiota and the host with T2DM. Further studies may be able to boost the development of new effective therapeutic approaches for T2DM. PMID- 25548475 TI - Procalcitonin and intestinal ischemia: a review of the literature. AB - Intestinal ischemia is common after emergency gastrointestinal or cardiovascular surgery. At present, there are no diagnostic tools for the early diagnosis of intestinal ischemia. In the last decade, procalcitonin (PCT) has been suggested as a marker of this condition. Here, we review the use of PCT as a diagnostic tool for intestinal ischemia. Two reviewers independently searched the PubMed and EMBASE databases for articles on intestinal ischemia and PCT. They then considered (1) the criteria applicable to preclinical and clinical data; and (2) PCT's predictive value in the diagnosis of intestinal ischemia. Article quality was rated according to the STAndards for Reporting of Diagnostic accuracy. Between 1993 and 2014, seven studies (including two preclinical studies and five clinical studies) dealt with the use of PCT to diagnose intestinal ischemia. Procalcitonin's sensitivity, specificity, positive predictive value and negative predictive value ranged between 72% and 100%; 68% and 91%; 27% and 90% and 81% and 100%, respectively. The area under the receiver operating characteristic curve ranged from 0.77 to 0.92. In view of the preclinical and clinical data, we consider that PCT can be used in daily practice as a tool for diagnosing intestinal ischemia. PMID- 25548476 TI - Helicobacter heilmannii sensu lato: an overview of the infection in humans. AB - Helicobacter heilmannii sensu lato (H. heilmannii s.l.) is a group of gastric non Helicobacter pylori Helicobacter species that are morphologically indistinguishable from each other. H. heilmannii s.l. infect the stomach of several animals and may have zoonotic potential. Although the prevalence of these infections in humans is low, they are associated with gastric pathology, including mucosa-associated lymphoid tissue lymphoma, making them a significant health issue. Here, the taxonomy, epidemiology, microbiology, diagnosis, and treatment of these infections will be reviewed. The gastric pathology associated with H. heilmannii s.l. infections in humans will also be addressed. Finally, the features of the complete bacterial genomes available and studies on species specific pathogenesis will be reviewed. The understanding of the mechanisms that underlie gastric disease development mediated by the different bacterial species that constitute H. heilmannii s.l. is essential for developing strategies for prevention and treatment of these infections. PMID- 25548477 TI - Probiotics for antibiotic-associated diarrhea: do we have a verdict? AB - Probiotics use has increased tremendously over the past ten years. This was coupled with a surge of data relating their importance in clinical practice. Antibiotic-associated diarrhea, whose frequency has risen recently, was one of the earliest targets with data published more than ten years ago. Unfortunately, available trials suffer from severe discrepancies associated with variability and heterogeneity of several factors. Most published randomized controlled trials and subsequent meta-analyses suggest benefit for probiotics in the prevention of antibiotic-associated diarrhea. The same seems to also apply when the data is examined for Clostridium difficile-associated colitis. However, the largest randomized double-blind placebo-controlled trial to date examining the use of a certain preparation of probiotics in antibiotic-associated diarrhea showed disappointing results, but it was flawed with several drawbacks. The commonest species of probiotics studied across most trials is Lactobacillus; however, other types have also shown similar benefit. Probiotics have enjoyed an impeccable safety reputation. Despite a few reports of severe infections sometimes leading to septicemia, most of the available trials confirm their harmless behavior and show similar adverse events compared to placebo. Since a consensus dictating its use is still lacking, it would be advisable at this point to suggest prophylactic use of probiotics to certain patients at risk for antibiotic-associated diarrhea or to those who suffered previous episodes. PMID- 25548474 TI - Pathogenesis of alcoholic liver disease: role of oxidative metabolism. AB - Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-beta-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. PMID- 25548478 TI - Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients. AB - To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future. PMID- 25548480 TI - Enterolithiasis. AB - Enterolithiasis or formation of gastrointestinal concretions is an uncommon medical condition that develops in the setting of intestinal stasis in the presence of the intestinal diverticula, surgical enteroanastomoses, blind pouches, afferent loops, incarcerated hernias, small intestinal tumors, intestinal kinking from intra-abdominal adhesions, and stenosing or stricturing Crohn's disease and intestinal tuberculosis. Enterolithiasis is classified into primary and secondary types. Its prevalence ranges from 0.3% to 10% in selected populations. Proximal primary enteroliths are composed of choleic acid salts and distal enteroliths are calcified. Clinical presentation includes abdominal pains, distention, nausea, and vomiting of occasionally sudden but often fluctuating subacute nature which occurs as a result of the enterolith tumbling through the bowel lumen. Thorough history and physical exam coupled with radiologic imaging helps establish a diagnosis in a patient at risk. Complications include bowel obstruction, direct pressure injury to the intestinal mucosa, intestinal gangrene, intussusceptions, afferent loop syndrome, diverticulitis, iron deficiency anemia, gastrointestinal hemorrhage, and perforation. Mortality of primary enterolithiasis may reach 3% and secondary enterolithiasis 8%. Risk factors include poorly conditioned patients with significant obstruction and delay in diagnosis. Treatment relies on timely recognition of the disease and endoscopic or surgical intervention. With advents in new technology, improved outcome is expected for patients with enterolithiasis. PMID- 25548479 TI - Cancer-associated fibroblasts in digestive tumors. AB - The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells including tumor vascular composing cells, inflammatory cells and fibroblasts. As a major and important component in tumor stroma, increasing evidence has shown that spindle-shaped cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution, and promote tumorigenesis, tumor invasion and metastasis by stimulating angiogenesis, malignant cell survival, epithelial-mesenchymal transition (EMT) and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors. CAFs are thought to be activated, characterized by the expression of alpha-smooth muscle actin, fibroblast activated protein, fibroblast specific protein, vimentin, fibronectin, etc. They are hypothesized to originate from normal or aged fibroblasts, bone marrow-derived mesenchymal cells, or vascular endothelial cells. EMT may also be an important process generating CAFs, and most probably, CAFs may originate from multiple cells. A close link exists between EMT, tumor stem cells, and chemo resistance of tumor cells, which is largely orchestrated by CAFs. CAFs significantly induce immunosuppression, and may be a prognostic marker in various malignancies. Targeted therapy toward CAFs has displayed promising anticancer efficacy, which further reinforces the necessity to explore the relationship between CAFs and their hosts. PMID- 25548483 TI - Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration. AB - AIM: To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype (SASP). METHODS: Hydrogen peroxide treatment was used to induce senescence in the human HepG2 hepatocyte cell line. Senescence was confirmed by cytochemical staining for a panel of markers including Ki67, p21, heterochromatin protein 1beta, and senescence-associated beta-galactosidase activity. Senescent hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction (qPCR), and conditioned media was used in proteomic analyses, a human chemokine protein array, and cell migration assays to characterise the composition and function of the hepatocyte SASP. RESULTS: Senescent hepatocytes induced classical markers of senescence (p21, heterochromatin protein 1beta, and senescence-associated-beta galactosidase activity); and downregulated the proliferation marker, Ki67. Hepatocyte senescence induced a 4.6-fold increase in total secreted protein (P = 0.06) without major alterations in the protein profile. Senescence-induced genes were identified by microarray (Benjamini Hochberg-corrected P < 0.05); and, consistent with the increase in secreted protein, gene ontology analysis revealed a significant enrichment of secreted proteins among inducible genes. The hepatocyte SASP included characteristic factors such as interleukin (IL)-8 and IL 6, as well as novel components such as SAA4, IL-32 and Fibrinogen, which were validated by qPCR and/or chemokine protein array. Senescent hepatocyte conditioned medium elicited migration of inflammatory (granulocyte-macrophage colony stimulating factor, GM-CSF-derived), but not non-inflammatory (CSF-1 derived) human macrophages (P = 0.022), which could contribute to a pro inflammatory microenvironment in vivo, or facilitate the clearance of senescent cells. CONCLUSION: Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis. PMID- 25548481 TI - Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. AB - Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general. PMID- 25548484 TI - Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells. AB - AIM: To investigate the role of claudin 1 in the regulation of genes involved in cell migration and tumor necrosis factor alpha (TNF-alpha)-induced gene expression in human gastric adenocarcinoma cells. METHODS: Knockdown experiments were conducted with claudin 1 small interfering RNA (siRNA), and the effects on the cell cycle, apoptosis, migration and invasion were analyzed in human gastric adenocarcinoma MKN28 cells. The gene expression profiles of cells were analyzed by microarray and bioinformatics. RESULTS: The knockdown of claudin 1 significantly inhibited cell proliferation, migration and invasion, and increased apoptosis. Microarray analysis identified 245 genes whose expression levels were altered by the knockdown of claudin 1. Pathway analysis showed that the top ranked molecular and cellular function was the cellular movement related pathway, which involved MMP7, TNF-SF10, TGFBR1, and CCL2. Furthermore, TNF- and nuclear frctor-kappaB were the top-ranked upstream regulators related to claudin 1. TNF alpha treatment increased claudin 1 expression and cell migration in MKN28 cells. Microarray analysis indicated that the depletion of claudin 1 inhibited 80% of the TNF-alpha-induced mRNA expression changes. Further, TNF-alpha did not enhance cell migration in the claudin 1 siRNA transfected cells. CONCLUSION: These results suggest that claudin 1 is an important messenger that regulates TNF-alpha induced gene expression and migration in gastric cancer cells. A deeper understanding of these cellular processes may be helpful in establishing new therapeutic strategies for gastric cancer. PMID- 25548482 TI - Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis. AB - AIM: To characterize how insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol. METHODS: Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatography-mass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-kappaB) subunit p65 was examined in frozen tissues. RESULTS: Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-kappaB and expression of NF-kappaB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis. Filipin staining revealed increased free cholesterol in p62 transgenic livers, which were not diet-derived. The mRNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3 methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) were not significantly upregulated, potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2 (SREBF2) gene expression and increased iron deposition in transgenic animals. CONCLUSION: This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol. PMID- 25548485 TI - Study of pruritus in chronic hepatitis C patients. AB - AIM: To investigate the occurrence and severity of pruritus in chronic hepatitis C patients treated with or without interferon (IFN) therapy. METHODS: A total of 89 patients with chronic hepatitis C and 55 control (non-hepatitis) patients were asked to rate their experience of diurnal and nocturnal pruritus in the preceding week using a visual analogue scale (VAS) and a five-point scale, respectively. Blood samples were taken and serum thymus and activation-regulated chemokine (TARC) levels were measured by enzyme-linked immunosorbent assay. RESULTS: A significantly greater proportion of chronic hepatitis C patients experienced nocturnal pruritus compared with control (58.4% vs 5.5%, P < 0.0001). Chronic hepatitis C patients also had more severe pruritus compared with control patients, indicated by the higher mean VAS scores in both the IFN-treated and non IFN-treated groups. In particular, patients who received combined peginterferon alfa-2b and ribavirin had significantly higher mean VAS scores than those receiving peginterferon alfa-2a or no IFN treatment. Serum TARC levels did not correlate with pruritus scores, and no significant differences in TARC levels were observed between the IFN-treated and non-IFN-treated groups. CONCLUSION: Patients with chronic hepatitis C experience pruritus more than those without. Serum TARC levels do not correlate with pruritus severity in chronic hepatitis C patients. PMID- 25548486 TI - Differential gene expression profiling of gastric intraepithelial neoplasia and early-stage adenocarcinoma. AB - AIM: To investigate the differentiated whole genome expression profiling of gastric high- and low-grade intraepithelial neoplasia and early-stage adenocarcinoma. METHODS: Gastric specimens from an upper magnifying chromoendoscopic targeted biopsy were collected from March 2010 to May 2013. Whole genome expression profiling was performed on 19 low-grade intraepithelial neoplasia (LGIN), 20 high-grade intraepithelial neoplasia (HGIN), 19 early-stage adenocarcinoma (EGC), and 19 chronic gastritis tissue samples using Agilent 4 * 44K Whole Human Genome microarrays. Differentially expressed genes between different types of lesions were identified using an unpaired t-test and corrected with the Benjamini and Hochberg false discovery rate algorithm. A gene ontology (GO) enrichment analysis was performed using the GeneSpring software GX 12.6. The differentially expressed gene was verified using a real-time TaqMan(r) PCR assay with independent tissue samples, including 26 LGIN, 15 HGIN, 14 EGC, and 20 chronic gastritis. The expression of G0S2 were further validated by immunohistochemical staining (IHC) in 24 LGIN, 40 HGIN, 30 EGC and 61 chronic gastritis specimens. RESULTS: The gene expression patterns of LGIN and HGIN tissues were distinct. There were 2521 significantly differentially expressed transcripts in HGIN, with 951 upregulated and 1570 downregulated. A GO enrichment analysis demonstrated that the most striking overexpressed transcripts in HGIN compared with LGIN were in the category of metabolism, defense response, and nuclear factor kappaB (NF-kappaB) cascade. While the vast majority of transcripts had barely altered expression in HGIN and EGC tissues, only 38 transcripts were upregulated in EGC. A GO enrichment analysis revealed that the alterations of the immune response were most prominent in the progression from HGIN to EGC. It is worth noting that, compared with LGIN, 289 transcripts were expressed at higher levels both in HGIN and EGC. A characteristic gene, G0/G1 switch 2 (G0S2) was one of the 289 transcripts and related to metabolism, the immune response, and the NF kappaB cascade, and its expression was validated in independent samples through real-time TaqMan(r) PCR and immunohistochemical staining. In real-time PCR analysis, the expression of G0S2 was elevated both in HGIN and EGC compared with that in LGIN (P < 0.01 and P < 0.001, respectively). In IHC analysis, G0S2 immunoreactivity was detected in the cytoplasmic of neoplastic cells, but was undetectable in chronic gastritis cells. The G0S2 expression in HGIN was higher than that of LGIN (P = 0.012, chi (2) = 6.28) and EGC (P = 0.008, chi (2) = 6.94). CONCLUSION: A clear biological distinction between gastric high- and low grade intraepithelial neoplasia was identified, and provides molecular evidence for clinical application. PMID- 25548487 TI - HIF-1alpha induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells. AB - AIM: To investigate whether hypoxia inducible factor (HIF)-1alpha modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC). METHODS: Esophageal squamous cancer cell lines Eca109 and TE13 were transfected with plasmids harboring small interfering RNAs targeting HIF-1alpha or VE-cadherin. The proliferation and invasion of esophageal carcinoma cells were detected by MTT and Transwell migration assays. The formation of tubular networks of cells was analyzed by 3D culture in vitro. BALB/c nude mice were used to observe xenograft tumor formation. The relationship between the expression of HIF-1alpha and VE-cadherin, ephrinA2 (EphA2) and laminin5gamma2 (LN5gamma2) was measured by Western blot and real-time polymerase chain reaction. RESULTS: Knockdown of HIF-1alpha inhibited cell proliferation (32.3% +/- 6.1% for Eca109 cells and 38.6% +/- 6.8% for TE13 cells, P < 0.05). Both Eca109 and TE13 cells formed typical tubular networks. The number of tubular networks markedly decreased when HIF-1alpha or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5gamma2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1alpha silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5gamma2 (P < 0.05), while HIF-1alpha expression was unchanged. The time for xenograft tumor formation was 6 +/- 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1alpha Neo control short hairpin RNA (shRNA) vector, and 8.4 +/- 2.1 d for Eca109 cells transfected with an shRNA against HIF 1alpha. Knockdown of HIF-1alpha inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo. CONCLUSION: HIF-1alpha may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5gamma2. PMID- 25548488 TI - Protective effects of terminal ileostomy against bacterial translocation in a rat model of intestinal ischemia/reperfusion injury. AB - AIM: To investigate the effects of terminal ileostomy on bacterial translocation (BT) and systemic inflammation after intestinal ischemia/reperfusion (I/R) injury in rats. METHODS: Thirty-two rats were assigned to either the sham-operated group, I/R group, I/R + resection and anastomosis group, or the I/R + ileostomy group. The superior mesenteric artery was occluded for 60 min. After 4 h, tissue samples were collected for analysis. BT was assessed by bacteriologic cultures, intestinal permeability and serum levels of endotoxin; systemic inflammation was assessed by serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10, as well as by the activity of myeloperoxidase (MPO) and by intestinal histopathology. RESULTS: Intestinal I/R injury not only caused morphologic damage to ileal mucosa, but also induced BT, increased MPO activity and promoted the release of TNF-alpha, IL-6, and IL-10 in serum. BT and ileal mucosa injuries were significantly improved and levels of TNF-alpha and IL-6 in serum were decreased in the I/R + ileostomy group compared with the I/R + resection and anastomosis group. CONCLUSION: Terminal ileostomy can prevent the detrimental effects of intestinal I/R injury on BT, intestinal tissue, and inflammation. PMID- 25548489 TI - MicroRNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease. AB - AIM: To assess the regulatory effect of microRNA-185 (miR-185) on lipid metabolism and the insulin signalling pathway in human HepG2 hepatocytes and a high-fat diet mouse model. METHODS: Quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA levels of lipogenic genes after loss or gain of miR-185. In addition, the amounts of insulin signalling intermediates were determined after transfection of HepG2 cells with pre-miR-185. RESULTS: MiR 185 levels decreased in a time- and dose-dependent manner in response to palmitic acid in human HepG2 hepatocytes. Transfection of HepG2 cells with miR-185 significantly decreased the mRNA levels of fatty acid synthase, 3-hydroxy-3 methylglutaryl-CoA reductase, sterol-regulatory element binding protein-2, and sterol-regulatory element binding protein-1c, whereas inhibition of miR-185 using an anti-miR-185 oligonucleotide produced the opposite effect in HepG2 cells. In a high-fat diet mouse model, the accumulation of lipids was significantly improved after treatment with miR-185, compared with control animals. Induction of miR-185 enhanced the insulin signalling pathway by up-regulating the insulin-receptor substrate-2. CONCLUSION: These findings suggest that miR-185 plays an important role in regulating fatty-acid metabolism and cholesterol homeostasis in hepatocytes, as well as in improving insulin sensitivity, both in vitro and in vivo. PMID- 25548490 TI - Proinflammatory effects and molecular mechanisms of interleukin-17 in intestinal epithelial cell line HT-29. AB - AIM: To evaluate the proinflammatory effects and molecular mechanisms of interleukin (IL)-17 in intestinal epithelial cell line HT-29. METHODS: HT-29 cells were cultured with IL-17, tumor necrosis factor (TNF)-alpha, or the combination of both IL-17 and TNF-alpha. Real-time PCR and Western blot were used to measure the gene expression levels of neutrophil chemokines CXCL1, CXCL2, CXCL5, CXCL6, IL-8 and TH-17 cell chemokine CCL20, the phosphorylation levels of p38 and TNF-alpha, and the expression level of IL-8, after using the p38 inhibitor in HT-29 cells. The stable Act1 knockdown HT-29 cell line was established to further test the phosphorylation changes of p38, after using IL-17 and TNF-alpha. RESULTS: After HT-29 cells were cultured with IL-17 and TNF-alpha, the expression levels of neutrophil chemokines (CXCL1, CXCL2, CXCL5, CXCL6, IL-8) and Th17 chemokine (CCL20) significantly improved (24.96 +/- 2.53, 28.47 +/- 2.87, 38.08 +/- 2.72, 33.47 +/- 2.41, 31.7 +/- 2.38, 44.37 +/- 2.73, respectively), and the differences were all statistically significant (P < 0.01). Western blot results showed that IL-17 obviously enhanced the phosphorylation level of p38, which was induced by TNF-alpha. Compared with the control group, the expression level of IL-8 significantly declined (9.47 +/- 1.36 vs 3.06 +/- 0.67, P < 0.01) when TH-29 cells were cultured with IL-17 and TNF-alpha. p38 inhibition assay showed that the p38 pathway played an essential role in the inflammatory response induced by IL-17. p38 phosphorylation levels could not be changed after using IL-17 and TNF-alpha in the stable Act1 knockdown HT-29 cell line. CONCLUSION: IL-17 significantly promoted the gene expression levels of TNF alpha-induced neutrophil chemokines and Th17 cell chemokine. It is obvious that IL-17 and TNF-alpha have synergistic effects on p38. PMID- 25548491 TI - Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. AB - AIM: To study the prevalence and clinical biochemical, blood cell and metabolic features of lean-non-alcoholic fatty liver disease (lean-NAFLD) and its association with other diseases. METHODS: Demographic, biochemical and blood examinations were conducted in all the subjects in this study. We classified the subjects into four groups according to their weight and NAFLD status: lean control, lean-NAFLD [body mass index (BMI) < 24 kg/m(2)], overweight-obese control and overweight-obese NAFLD. One-way analysis of variance (ANOVA) was used to compare the means of continuous variables (age, BMI, blood pressure, glucose, lipid, insulin, liver enzymes and blood cell counts) and the chi (2) test was used to compare the differences in frequency of categorical variables (sex, education, physical activity, smoking, alcohol consumption and prevalence of hypertension, hyperlipidemia, diabetes, metabolic syndrome central obesity and obesity). Both univariate and multivariate logistic regression models were adopted to calculate odds ratios (ORs) and predict hyperlipidemia, hypertension, diabetes and metabolic syndrome when we respectively set all controls, lean control and overweight-obese-control as references. In multivariate logistic regression models, we adjusted potential confounding factors, including age, sex, smoking, alcohol consumption and physical activity. RESULTS: The prevalence of NAFLD was very high in China. NAFLD patients were older, had a higher BMI, waist circumference, blood pressure, fasting blood glucose, insulin, blood lipid, liver enzymes and uric acid than the controls. Although lean-NAFLD patients had lower BMI and waist circumstance, they had significantly higher visceral adiposity index than overweight-obese controls. Lean-NAFLD patients had comparable triglyceride, cholesterin and low-density lipoprotein cholesterin to overweight obese NAFLD patients. In blood cell examination, both lean and overweight-obese NAFLD was companied by higher white blood cell count, red blood cell count, hemoglobin and hematocrit value. All NAFLD patients were at risk of hyperlipidemia, hypertension, diabetes and metabolic syndrome (MetS). Lean-NAFLD was more strongly associated with diabetes (OR = 2.47, 95%CI: 1.14-5.35), hypertension (OR = 1.72, 95%CI: 1.00-2.96) and MetS (OR = 3.19, 95%CI: 1.17-4.05) than overweight-obese-NAFLD (only OR for MetS was meaningful: OR = 1.89, 95%CI: 1.29-2.77). NAFLD patients were more likely to have central obesity (OR = 1.97, 95%CI: 1.38-2.80), especially in lean groups (OR = 2.17, 95%CI: 1.17-4.05). CONCLUSION: Lean-NAFLD has unique results in demographic, biochemical and blood examinations, and adds significant risk for diabetes, hypertension and MetS in lean individuals. PMID- 25548492 TI - Risk factors for early rebleeding and mortality in acute variceal hemorrhage. AB - AIM: To investigate the risk factors for 6-wk rebleeding and mortality in acute variceal hemorrhage (AVH) patients treated by percutaneous transhepatic variceal embolization (PTVE). METHODS: A retrospective cohort study of AVH patients who had undergone PTVE treatment was conducted between January 2010 and December 2012. Demographic information, medical histories, physical examination findings, and laboratory test results were collected. The PTVE procedure was performed as a rescue therapy for patients who failed endoscopic and pharmacologic treatment. Survival analysis was estimated using the Kaplan-Meier method and compared using the log-rank test. The multivariate analysis was performed using the Cox regression test to identify independent risk factors for rebleeding and mortality. RESULTS: One hundred and one patients were included; 71 were males and the average age was 51 years. Twenty-one patients rebled within 6 wk. Patients with high-risk stigmata, PTVE with trunk obliteration, and a hepatic vein pressure gradient (HVPG) >= 20 mmHg were at increased risk for rebleeding (OR = 5.279, 95%CI: 2.782-38.454, P = 0.003; OR = 4.309, 95%CI: = 2.144-11.793, P < 0.001; and OR = 1.534, 95%CI: 1.062-2.216, P = 0.022, respectively). Thirteen patients died within 6 wk. A model for end-stage liver disease (MELD) score >= 18 and an HVPG >= 20 mmHg were associated with 6-wk mortality (OR = 2.162, 95%CI: 1.145-4.084, P = 0.017 and OR = 1.423, 95%CI: 1.222-1.657, P < 0.001, respectively). CONCLUSION: MELD score and HVPG in combination allow for early identification of patients with AVH who are at substantially increased risk of death over the short term. PMID- 25548493 TI - Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors. AB - AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs). METHODS: The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed. RESULTS: All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis. CONCLUSION: Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation. PMID- 25548494 TI - Interventional digital subtraction angiography for small bowel gastrointestinal stromal tumors with bleeding. AB - AIM: To retrospectively evaluate the diagnostic efficacy of interventional digital subtraction angiography (DSA) for bleeding small bowel gastrointestinal stromal tumors (GISTs). METHODS: Between January 2006 and December 2013, small bowel tumors in 25 consecutive patients undergoing emergency interventional DSA were histopathologically confirmed as GIST after surgical resection. The medical records of these patients and the effects of interventional DSA and the presentation and management of the condition were retrospectively reviewed. RESULTS: Of the 25 patients with an age range from 34- to 70-year-old (mean: 54 +/- 12 years), 8 were male and 17 were female. Obscure gastrointestinal bleeding, including tarry or bloody stool and intermittent melena, was observed in all cases, and one case also involved hematemesis. Nineteen patients required acute blood transfusion. There were a total of 28 small bowel tumors detected by DSA. Among these, 20 were located in the jejunum and 8 were located in the ileum. The DSA characteristics of the GISTs included a hypervascular mass of well-defined, homogeneous enhancement and early developed draining veins. One case involved a complication of intussusception of the small intestine that was discovered during surgery. No pseudoaneurysms, arteriovenous malformations or fistulae, or arterial rupture were observed. The completely excised size was approximately 1.20 to 5.50 cm (mean: 3.05 +/- 1.25 cm) in maximum diameter based on measurements after the resection. There were ulcerations (n = 8), erosions (n = 10), hyperemia and edema (n = 10) on the intra-luminal side of the tumors. Eight tumors in patients with a large amount of blood loss were treated with transcatheter arterial embolization with gelfoam particles during interventional DSA. CONCLUSION: Emergency interventional DSA is a useful imaging option for locating and diagnosing small bowel GISTs in patients with bleeding, and is an effective treatment modality. PMID- 25548495 TI - Small sphincterotomy combined with endoscopic papillary large balloon dilation vs sphincterotomy alone for removal of common bile duct stones. AB - AIM: To evaluate the efficacy and safety of endoscopic papillary large diameter balloon dilation (EPLBD) following limited endoscopic sphincterotomy (EST) and EST alone for removal of large common bile duct (CBD) stones. METHODS: We retrospectively compared EST + EPLBD (group A, n = 64) with EST alone (group B, n = 89) for the treatment of large or multiple bile duct stones. The success rate of stone clearance, procedure-related complications and incidents, frequency of mechanical lithotripsy use, and recurrent stones were recorded. RESULTS: There was no statistically significant difference between the two groups regarding periampullary diverticula (35.9% vs 34.8%, P > 0.05), pre-cut sphincterotomy (6.3% vs 6.7%, P > 0.05), size (12.1 +/- 2.0 mm vs 12.9 +/- 2.6 mm, P > 0.05) and number (2.2 +/- 1.9 vs 2.4 +/- 2.1, P > 0.05) of stones or the diameters of CBD (15.1 +/- 3.3 mm vs 15.4 +/- 3.6 mm, P > 0.05). The rates of overall stone removal and stone removal in the first session were not significantly different between the two groups [62/64 (96.9%) vs 84/89 (94.4%), P > 0.05; and 58/64 (90.6%) vs 79/89 (88.8%), P > 0.05, respectively]. The rates of post-endoscopic retrograde cholangiopancreatography pancreatitis and hyperamylasemia were not significantly different between the two groups [3/64 (4.7%) vs 4/89 (4.5%), P > 0.05; 7/64 (10.9%) vs 9/89 (10.1%), P > 0.05, respectively]. There were no cases of perforation, acute cholangitis, or cholecystitis in the two groups. The rate of bleeding and the recurrence of CBD stones were significantly lower in group A than in group B [1/64 (1.6%) vs 5/89 (5.6%), P < 0.05; 1/64 (1.6%) vs 6/89 (6.7%), P < 0.05, respectively]. CONCLUSION: EST + EPLBD is an effective and safe endoscopic approach for removing large or multiple CBD stones. PMID- 25548496 TI - Effect of bilateral supraclavicular postoperative radiotherapy in middle and lower thoracic esophageal carcinoma. AB - AIM: To evaluate whether postoperative radiotherapy is an alternative to neck lymph node surgery and if it provides a survival benefit for those receiving two field, chest and abdomen, lymphadenectomy. METHODS: A total of 530 cases with middle and lower thoracic esophageal carcinoma in our hospital from January 2008 to April 2009 were selected and analyzed, of which 219 cases received right chest, upper abdominal incision Ivor-Lewis surgery and simultaneously underwent mediastinal and abdominal two-field lymphadenectomy. If regional lymph node metastasis occurred within the recurrent laryngeal nerve, the patients would receive bilateral supraclavicular radiotherapy (DT = 5000cGy) to be adopted at postoperative 4-5 wk (Group A) or cervical lymphadenectomy at postoperative 3-4 wk (Group B). If there were no regional lymph node metastases within the recurrent laryngeal nerve, the patients only underwent two-field, chest and abdomen, lymphadenectomy (Group C). RESULTS: In 219 cases who underwent two-field lymphadenectomy, 91 cases were diagnosed with regional lymph node metastasis within the recurrent laryngeal nerve. Of them, 48 cases received cervical radiotherapy, and 43 cases underwent staging lymphadenectomy; 128 patients were not given the follow-up treatment of cervical radiotherapy because there was no regional lymph node metastasis within the recurrent laryngeal nerve. Five-year survival rates in group A and B were 47% and 50%, respectively, with no statistical difference between them, and the rate in group C was 58%. CONCLUSION: For patients with middle and lower thoracic esophageal carcinoma combined with lymph node metastasis within the recurrent laryngeal nerve, cervical radiotherapy can be a substitute for surgery and provide benefit. PMID- 25548497 TI - Cost-effectiveness analysis of colon cancer treatments from MOSIAC and No. 16968 trials. AB - AIM: To compare XELOX and FOLFOX4 as colon cancer adjuvant chemotherapy based on MOSAIC and No. 16968 trails from Chinese cost-effectiveness perspective. METHODS: A decision-analytic Markov model was developed to compare the FOLFOX4 and XELOX regimens based MOSAIC and No. 16968 trial. Five states were included in our Markov model: well (state 1), minor toxicity (state 2), major toxicity (state 3), quitting adjuvant chemotherapy (state 4), and death due to adjuvant chemotherapy (state 5). Transitions among the 5 states were assumed to be Markovian. Costs were calculated from the perspective of the Chinese health-care payer. The utility data were taken from published studies. Sensitivity analyses were used to explore the impact of uncertainty factors in this cost-effectiveness analysis. RESULTS: Total direct costs of FOLFOX4 and XELOX per patient were $19884.96 +/- 4280.30 and $18113.25 +/- 3122.20, respectively. The total fees related to adverse events per patient during the entire treatment were $204.75 +/- 16.80 for the XELOX group, and $873.72 +/- 27.60 for the FOLFOX4 group, and the costs for travel and absenteeism per patient were $18495.00 for the XELOX group and $21,352.68 for the FOLFOX4 group. The base-case analysis showed that FOLFOX4 was estimated to produce an additional 0.06 in quality adjusted life years (QALYs) at an additional cost of $3950.47 when compared to the XELOX regimen over the model time horizon. The cost per QALY gained was $8047.30 in the XELOX group, which was $900.98 less than in the FOLFOX4 group ($8948.28). The one way sensitivity analysis demonstrated that the utility for the well state and minor toxicity state greatly influenced the incremental cost-effectiveness ratio of FOLFOX4. CONCLUSION: In term of cost-comparison, XELOX is expected to dominate FOLFOX4 regimes; Therefore, XELOX provides a more cost-effective adjuvant chemotherapy for colon cancer patients in China. PMID- 25548498 TI - Ultrasound hepatic/renal ratio and hepatic attenuation rate for quantifying liver fat content. AB - AIM: To establish and validate a simple quantitative assessment method for nonalcoholic fatty liver disease (NAFLD) based on a combination of the ultrasound hepatic/renal ratio and hepatic attenuation rate. METHODS: A total of 170 subjects were enrolled in this study. All subjects were examined by ultrasound and (1)H-magnetic resonance spectroscopy ((1)H-MRS) on the same day. The ultrasound hepatic/renal echo-intensity ratio and ultrasound hepatic echo intensity attenuation rate were obtained from ordinary ultrasound images using the MATLAB program. RESULTS: Correlation analysis revealed that the ultrasound hepatic/renal ratio and hepatic echo-intensity attenuation rate were significantly correlated with (1)H-MRS liver fat content (ultrasound hepatic/renal ratio: r = 0.952, P = 0.000; hepatic echo-intensity attenuation r = 0.850, P = 0.000). The equation for predicting liver fat content by ultrasound (quantitative ultrasound model) is: liver fat content (%) = 61.519 * ultrasound hepatic/renal ratio + 167.701 * hepatic echo-intensity attenuation rate -26.736. Spearman correlation analysis revealed that the liver fat content ratio of the quantitative ultrasound model was positively correlated with serum alanine aminotransferase, aspartate aminotransferase, and triglyceride, but negatively correlated with high density lipoprotein cholesterol. Receiver operating characteristic curve analysis revealed that the optimal point for diagnosing fatty liver was 9.15% in the quantitative ultrasound model. Furthermore, in the quantitative ultrasound model, fatty liver diagnostic sensitivity and specificity were 94.7% and 100.0%, respectively, showing that the quantitative ultrasound model was better than conventional ultrasound methods or the combined ultrasound hepatic/renal ratio and hepatic echo-intensity attenuation rate. If the (1)H-MRS liver fat content had a value < 15%, the sensitivity and specificity of the ultrasound quantitative model would be 81.4% and 100%, which still shows that using the model is better than the other methods. CONCLUSION: The quantitative ultrasound model is a simple, low-cost, and sensitive tool that can accurately assess hepatic fat content in clinical practice. It provides an easy and effective parameter for the early diagnosis of mild hepatic steatosis and evaluation of the efficacy of NAFLD treatment. PMID- 25548499 TI - Poor agreement between endoscopists and gastrointestinal pathologists for the interpretation of probe-based confocal laser endomicroscopy findings. AB - AIM: To compare the interpretation of probe-based confocal laser endomicroscopy (pCLE) findings between endoscopists and gastrointestinal (GI)-pathologists. METHODS: All pCLE procedures were undertaken and the endoscopist rendered assessment. The same pCLE videos were then viewed offline by an expert GI pathologist. Histopathology was considered the gold standard for definitive diagnosis. The sensitivity, specificity and accuracy for diagnosis of dysplastic/ neoplastic GI lesions and interobserver agreement between endoscopists and experienced gastrointestinal pathologist for pCLE findings were analyzed. RESULTS: Of the 66 included patients, 40 (60.6%) had lesions in the esophagus, 7 (10.6%) in the stomach, 15 (22.7%) in the biliary tract, 3 (4.5%) in the ampulla and 1 (1.5%) in the colon. The overall sensitivity, specificity and accuracy for diagnosing dysplastic/neoplastic lesions using pCLE were higher for endoscopists than pathologist at 87.0% vs 69.6%, 80.0% vs 40.0% and 84.8% vs 60.6% (P = 0.0003), respectively. Area under the ROC curve (AUC) was greater for endoscopists than the pathologist (0.83 vs 0.55, P = 0.0001). Overall agreement between endoscopists and pathologist was moderate for all GI lesions (K = 0.43; 95%CI: 0.26-0.61), luminal lesions (K = 0.40; 95%CI: 0.20-0.60) and those of dysplastic/neoplastic pathology (K = 0.55; 95%CI: 0.37-0.72), the agreement was poor for benign (K = 0.13; 95%CI: -0.097-0.36) and pancreaticobiliary lesions (K = 0.19; 95%CI: -0.26-0.63). CONCLUSION: There is a wide discrepancy in the interpretation of pCLE findings between endoscopists and pathologist, particularly for benign and malignant pancreaticobiliary lesions. Further studies are needed to identify the cause of this poor agreement. PMID- 25548500 TI - Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer: a meta-analysis. AB - AIM: To investigate the efficacy and safety of gemcitabine (Gem)-based combination chemotherapies for the treatment of advanced biliary tract cancer. METHODS: Clinical trials were identified by searching scientific literature databases (PubMed, EMBASE and the Cochrane Library) for studies published between 1975 and 2013. Two reviewers independently evaluated the relevant studies and manually searched references from these reports to locate additional eligible studies. The disease response and control rates, progression-free and overall survivals, and the grade 3-4 toxicities were evaluated by a meta-analysis. Odds ratios (ORs) of the disease response and control rates and grade 3-4 toxicities, and the mean difference (MD) of both progression-free and overall survivals were calculated and used for statistical analysis. RESULTS: Seven randomized trials with a total of 858 patients were selected and included in the final analysis. The studies were divided into subgroups based on the chemotherapy regimens, including Gem-based and non-Gem-based chemotherapies. The overall analyses revealed that the patients treated with Gem-based combination chemotherapy had significantly higher disease response rates [OR = 1.69, 95% confidence interval (CI): 1.17-2.43; P = 0.01], a longer progression-free survival (MD = 1.95, 95%CI: 0.90-3.00; P = 0.00) and a longer overall survival (MD = 1.85, 95%CI: 0.26-3.44; P = 0.02). A higher incidence of grade 3-4 hematological toxicities, including leukopenia (OR = 2.98, 95%CI: 1.44-6.20; P = 0.00), anemia (OR = 2.96, 95%CI: 1.79-4.92; P = 0.00) and neutropenia (OR = 2.80, 95%CI: 1.39-5.64; P = 0.00) was found in the Gem-based combination chemotherapy group compared with the Gem monotherapy and non-Gem-based chemotherapy groups. CONCLUSION: Gem-based combination chemotherapy is a potential first-line treatment for advanced biliary tract cancer as a result of improved survival, though with additional toxicity. PMID- 25548501 TI - Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy. AB - AIM: To evaluate the role of probiotics in the standard triple Helicobacter pylori therapy. METHODS: In this meta-analysis, we investigated the efficacy of probiotics in a standard triple H. pylori therapy in adults. Searches were mainly conducted in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Fourteen studies met our criteria, and the quality of these studies was assessed using the Jadad scale. We used STATA version 12.0 to extract data and to calculate the odds ratios (ORs), which are presented with the corresponding 95% confidence intervals (CIs). The data are presented as forest plots. RESULTS: The pooled ORs for the eradication rates calculated by intention to-treat analysis and per-protocol analysis in the probiotic group vs the control group were 1.67 (95%CI: 1.38-2.02) and 1.68 (95%CI: 1.35-2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40-2.26; Caucasian: OR = 1.48, 95%CI: 1.06-2.05). The pooled OR for the incidence of total adverse effects was significantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26-0.94), using the random effects model, with significant heterogeneity (I (2) = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06-0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group. CONCLUSION: Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects. PMID- 25548502 TI - Three-field vs two-field lymph node dissection for esophageal cancer: a meta analysis. AB - AIM: To assess the effects of 3-field lymphadenectomy for esophageal carcinoma. METHODS: We conducted a computerized literature search of the PubMed, Cochrane Controlled Trials Register, and EMBASE databases from their inception to present. Randomized controlled trials (RCTs) or observational epidemiological studies (cohort studies) that compared the survival rates and/or postoperative complications between 2-field lymphadenectomy (2FL) and 3-field lymphadenectomy (3FL) for esophageal carcinoma with R0 resection were included. Meta-analysis was conducted using published data on 3FL vs 2FL in esophageal carcinoma patients. End points were 1-, 3-, and 5-year overall survival rates and postoperative complications, including recurrent nerve palsy, anastomosis leak, pulmonary complications, and chylothorax. Subgroup analysis was performed on the involvement of recurrent laryngeal lymph nodes. RESULTS: Two RCTs and 18 observational studies with over 7000 patients were included. There was a clear benefit for 3FL in the 1- (RR = 1.16; 95%CI: 1.09-1.24; P < 0.01), 3- (RR = 1.44; 95%CI: 1.19-1.75; P < 0.01), and 5-year overall survival rates (RR = 1.37; 95%CI: 1.18-1.59; P < 0.01). For postoperative complications, 3FL was associated with significantly more recurrent nerve palsy (RR = 1.43; 95%CI: 1.28-1.60; P = 0.02) and anastomosis leak (RR = 1.26; 95%CI: 1.05-1.52; P = 0.09). In contrast, there was no significant difference for pulmonary complications (RR = 0.93; 95%CI: 0.75 1.16, random-effects model; P = 0.27) or chylothorax (RR = 0.77; 95%CI: 0.32 1.85; P = 0.69). CONCLUSION: This meta-analysis shows that 3FL improves overall survival rate but has more complications. Because of the high heterogeneity among outcomes, definite conclusions are difficult to draw. PMID- 25548503 TI - Role of protective stoma in low anterior resection for rectal cancer: a meta analysis. AB - AIM: To provide a comprehensive evaluation of the role of a protective stoma in low anterior resection (LAR) for rectal cancer. METHODS: The PubMed, EMBASE, and MEDLINE databases were searched for studies and relevant literature published between 2007 and 2014 regarding the construction of a protective stoma during LAR. A pooled risk ratio (RR) with 95% confidence intervals (CIs) was used to assess the outcomes of the studies, including the rate of postoperative anastomotic leakage and reoperations related to leakage. Funnel plots and Egger's tests were used to evaluate the publication biases of the studies. P values < 0.05 were considered statistically significant. RESULTS: A total of 11 studies were included in the meta-analysis. In total, 5612 patients were examined, 2868 of whom had a protective stoma and 2744 of whom did not. The sample size of the studies varied from 34 to 1912 patients. All studies reported the number of patients who developed an anastomotic leakage and required a reoperation related to leakage. A random effects model was used to calculate the pooled RR with the corresponding 95%CI because obvious heterogeneity was observed among the 11 studies (I (2) = 77%). The results indicated that the creation of a protective stoma during LAR significantly reduces the rate of anastomotic leakage and the number of reoperations related to leakage, with pooled RRs of 0.38 (95%CI: 0.30 0.48, P < 0.00001) and 0.37 (95%CI: 0.29-0.48, P < 0.00001), respectively. The shape of the funnel plot did not reveal any evidence of obvious asymmetry. CONCLUSION: The presence of a protective stoma effectively decreased the incidences of anastomotic leakage and reoperation and is recommended in patients undergoing low rectal anterior resections for rectal cancer. PMID- 25548504 TI - Eosinophilic esophagitis in patients with esophageal atresia and chronic dysphagia. AB - Esophageal atresia (EA) is defined as a discontinuity of the lumen of the esophagus repaired soon after birth. Dysphagia is a common symptom in these patients, usually related to stricture, dysmotility or peptic esophagitis. We present 4 cases of patients with EA who complained of dysphagia and the diagnosis of Eosinophilic esophagitis (EoE) was made, ages ranging from 9 to 16 years. Although our patients were on acid suppression years after their EA repair, they presented with acute worsening of dysphagia. Esophogastroduodenoscopy and/or barium swallow did not show stricture and biopsies revealed elevated eosinophil counts consistent with EoE. Two of 4 patients improved symptomatically with the topical steroids. It is important to note that all our patients have asthma and 3 out of 4 have tested positive for food allergies. One of our patients developed recurrent anastomotic strictures that improved with the treatment of the EoE. A previous case report linked the recurrence of esophageal strictures in patients with EA repair with EoE. Once the EoE was treated the strictures resolved. On the other hand, based on our observation, EoE could be present in patients without recurrent anastomotic strictures. There appears to be a spectrum in the disease process. We are suggesting that EoE is a frequent concomitant problem in patients with history of congenital esophageal deformities, and for this reason any of these patients with refractory reflux symptoms or dysphagia (with or without anastomotic stricture) may benefit from an endoscopic evaluation with biopsies to rule out EoE. PMID- 25548505 TI - Signet-ring cell carcinoma arising from a fundic gland polyp in the stomach. AB - Fundic gland polyps (FGPs) are currently the most common type of gastric polyps and are usually benign. However, although rare, gastric adenocarcinoma of FGP has been recently proposed as a new variant of gastric adenocarcinoma. Here we report the first case of a 49-year-old woman with focal signet ring cell carcinoma that arose from an FGP of the stomach. The tumor was completely excised by endoscopic snare polypectomy. FGPs should therefore be evaluated for malignant changes although they occur rarely, if the FGP has an erosive or irregular surface. PMID- 25548506 TI - Primary large cell neuroendocrine carcinoma in the common bile duct: first Asian case report. AB - Large cell neuroendocrine carcinoma (LCNEC) in the biliary system is a poorly differentiated, high-grade neuroendocrine tumor. These tumors exhibit aggressive behavior and an increased tendency for early nodal and distant metastases. Herein, we report an unusual case of a pure primary LCNEC of the common bile duct (CBD). A 75-year-old female presented with nausea and jaundice. The patient underwent a CBD excision with lymph node dissection. Upon histological and immunohistochemical examination, the tumor exhibited pure large cell-type neuroendocrine features. Metastases were noted in two of the eight lymph nodes. The patient was administered adjuvant chemotherapy. The patient's cancer recurred 7 mo after surgery, and the patient died from liver failure 5 mo after recurrence. The prognosis of LCNEC of CBD remains poor despite curative resection and adjuvant chemotherapy. The role of additional therapies, such as multimodal treatment including radiation therapy, must be further studied to improve the prognoses of patients. PMID- 25548507 TI - Acute pancreatitis associated with herpes zoster: case report and literature review. AB - Varicella-zoster virus (VZV) is a type of herpes virus known to cause varicella, mainly in young children, and herpes zoster in adults. Although generally non lethal, VZV infection can be associated with serious complications, particularly in adults. Acute pancreatitis caused by VZV infection is a rare event, with reports primarily concerning immunocompromised individuals. Here we report a 44 year-old immunocompetent female who developed acute pancreatitis associated with VZV infection. The patient presented with vomiting and persistent pain in the upper quadrant less than one week after diagnosis and treatment for a herpes zoster-related rash with stabbing pain on the abdomen and dorsal right trunk side. A diagnosis of acute pancreatitis was confirmed based on abdominal pain, elevated levels of urine and serum amylase, and findings of peri-pancreatic exudation and effusions by computed tomography and magnetic resonance cholangiopancreatography. This case highlights that, though rare, acute pancreatitis should be considered in VZV patients who complain of abdominal pain, especially in the epigastric area. Early detection and proper treatment are needed to prevent the condition from deteriorating further and to minimize mortality. PMID- 25548508 TI - Helicobacter, gamma-glutamyltransferase and cancer: further intriguing connections. AB - Virulence of Helicobacter pylori, Helicobacter suis and other bacteria appears to be partly mediated through a release of gamma-glutamyltransferase (GGT), an enzyme activity capable of promoting biochemical reactions ultimately resulting in damage to gastric epithelium and suppression of immune response. Recently published studies show that secretion of bacterial GGT occurs in the form of exosome-like vesicles. Very similar GGT-rich exosomes have been described to originate from human cancer cells, and the hypothesis is thus forwarded that in the resistant and invasive phenotype of malignant cells such vesicular/exosomal GGT may play roles akin to those described for Helicobacter infection, thus providing a significant contribution to the establishment of cancer metastases. PMID- 25548509 TI - Hepatocellular carcinoma review: current treatment, and evidence-based medicine. AB - We read with great interest the recent article entitled "Hepatocellular carcinoma review: Current treatment, and evidence-based medicine" by Raza et al, published in World Journal of Gastroenterology. Authors evaluated treatments for early and advanced stage hepatocellular carcinoma based on an extensive review of the relevant literature. They reported that radiofrequency ablation is the most effective local ablative therapy. They concluded that RF ablation is equivalent to surgical resection in well selected patients with early stage hepatocellular carcinoma. In addition, we want to mention microwave ablation besides RF ablation. PMID- 25548510 TI - Antiviral treatment among pregnant women with chronic hepatitis B. AB - OBJECTIVE: To describe the antiviral treatment patterns for chronic hepatitis B (CHB) among pregnant and nonpregnant women. METHODS: Using 2011 MarketScan claims, we calculated the rates of antiviral treatment among women (aged 10-50 years) with CHB. We described the pattern of antiviral treatment during pregnancy and >=1 month after delivery. RESULTS: We identified 6274 women with CHB during 2011. Among these, 64 of 507 (12.6%) pregnant women and 1151 of 5767 (20.0%) nonpregnant women received antiviral treatment (P < 0.01). Pregnant women were most commonly prescribed tenofovir (73.4%) and lamivudine (21.9%); nonpregnant women were most commonly prescribed tenofovir (50.2%) and entecavir (41.3%) (P < 0.01). Among 48 treated pregnant women with an identifiable delivery date, 16 (33.3%) were prescribed an antiviral before pregnancy and continued treatment for at least one month after delivery; 14 (29.2%) started treatment during the third trimester and continued at least one month after delivery. CONCLUSION: Among this insured population, pregnant women with CHB received an antiviral significantly less often than nonpregnant women. The most common antiviral prescribed for pregnant women was tenofovir. These data provide a baseline for assessing changes in treatment patterns with anticipated increased use of antivirals to prevent breakthrough perinatal hepatitis B virus infection. PMID- 25548512 TI - Long-lasting effects of anti-VEGF/photodynamic combination therapy in the treatment of exudative age-related macular degeneration: a retrospective chart review. AB - PURPOSE: To examine the potential long-term benefit of an anti-VEGF/photodynamic therapy (PDT) combination on patients treated for wet age-related macular degeneration (AMD). METHODS: A retrospective chart review was conducted on 29 eyes (subjects) from 26 patients (eight male and 18 female) that showed sustained, positive response to combination therapy for exudative AMD for a minimum of 1 year. Collected data included: visual acuity, central retinal thickness, intraocular pressure and history of glaucoma, wet AMD onset and treatment history, concomitant use of anticoagulants and past history or development of cerebrovascular or cardiovascular disease while receiving combination therapy. RESULTS: Subjects underwent an average of five injections and two PDT treatments in total over 16 months before the choroidal neovascular membrane (CNVM) stabilized and became inactive for at least 1 year. Prior to the effective anti-VEGF/PDT combination therapy the median Snellen visual acuity ranged from 20/200 to 20/250 and presented at no worse than 20/200 at 1 year after treatment. Some subjects were followed for up to 5 years and remained inactive. CONCLUSION: Combination therapy can cause long-lasting closure of the CNVM, even with advanced disease resistant to anti-VEGF monotherapy. PMID- 25548511 TI - Loss of ion transporters and increased unfolded protein response in Fuchs' dystrophy. AB - PURPOSE: Fuchs' endothelial corneal dystrophy (FECD), which affects approximately 5% of the population over 40 in the U.S.A., is a major cause of corneal transplantation. FECD is associated with mutations of a variety of unrelated genes: SLC4A11, COL8A2, TCF8, and LOXHD1. The current pathological description of the dystrophy includes deficiency of corneal endothelium (CE) pump function and induction of the unfolded protein response (UPR). This study aims to determine the contribution of the two mechanisms by assessing the expression levels of (1) seven endothelial ion transporters known to regulate stromal hydration and (2) UPR related genes in a set of six CE samples obtained from FECD patients compared to that of normal controls. METHODS: CE samples collected during FECD keratoplasty or from an eye bank (normal control) were transferred into an RNA stabilizing agent and refrigerated. Total RNA from each CE specimen was individually extracted. The expression levels of ion transporters and UPR genes were tested using quantitative real-time (RT) PCR and a UPR specific PCR array, respectively. RESULTS: In normal CE, the comparative expression levels of ion transporters in decreasing order were SLC4A11, Na(+)/K(+) ATPase, pNBCe1, and NHE1, followed by the isoforms of monocarboxylate transporters (MCTs). In FECD samples, Na(+)/K(+) ATPase and MCTs 1 and 4 were significantly downregulated compared to normal controls (p<0.05). The PCR array tested 84 UPR related genes. Data analysis showed upregulation of 39 genes and downregulation of three genes, i.e., approximately 51% of the tested genes had their expression altered in FECD samples with a difference greater than +/- twofold regulation. Thirteen of the altered genes showed significant changes (p<0.05). The PCR array results were validated by quantitative RT-PCR. CONCLUSIONS: FECD samples had evident UPR with significant changes in the expression of the protein processing pathway genes. The significant downregulation of ion transporters indicates simultaneous compromised CE pump function in Fuchs' dystrophy. PMID- 25548513 TI - A new recombinant factor VIII: from genetics to clinical use. AB - Advances in recombinant technology and knowledge about coagulation factor VIII (FVIII) are building a platform for new therapeutic options in patients with hemophilia A. The development of turoctocog alfa, a novel, high-purity, third generation, B-domain truncated recombinant FVIII, has been produced and formulated without the use of animal-derived or human serum-derived components, in the wake of understanding of the new biochemical characteristics of FVIII, namely its protein structure, and glycosylation and sulfating patterns. Culture conditions and a five-step purification process have been developed to optimize the safety of turoctocog alfa. The results of two pilot clinical trials using turoctocog alfa confirmed high safety levels, with no patient developing inhibitors during the period of observation. The purpose of this review is to describe briefly the molecular and biological properties of turoctocog alfa, together with details of its clinical development, with emphasis on the needs of patients with hemophilia A. PMID- 25548514 TI - Sequential treatment with AT-101 enhances cisplatin chemosensitivity in human non small cell lung cancer cells through inhibition of apurinic/apyrimidinic endonuclease 1-activated IL-6/STAT3 signaling pathway. AB - AT-101, known as R-(-)-gossypol, is a potent anticancer agent, but its chemosensitizing effects remain elusive. The present study aimed to examine whether AT-101 could increase the sensitivity of non-small cell lung cancer A549 cells to cisplatin (CDDP) and the underlying mechanisms. We evaluated the efficacy of the sequential treatment with AT-101 and CDDP using both in vitro and in vivo models. Our results showed that as compared to AT-101 or CDDP monotherapy, or AT-101 plus CDDP concurrent treatment, the sequential treatment significantly inhibited cell proliferation and migration and induced tumor cell death. Moreover, the efficacy of the sequential treatment was also confirmed in a mouse A549 xenograft model. Our study revealed that AT-101 inhibited the reduced status of apurinic/apyrimidinic endonuclease 1 (APE1) and attenuated APE1 mediated IL-6/STAT3 signaling activation by decreasing IL-6 protein expression; suppressing the STAT3-DNA binding; and reducing the expression of the downstream antiapoptotic proteins Bcl-2 and Bcl-xL. In conclusion, AT-101 enhances the sensitivity of A549 cells to CDDP in vitro and in vivo through the inhibition of APE1-mediated IL-6/STAT3 signaling activation, providing a rationale for the combined use of AT-101 and CDDP in non-small cell lung cancer chemotherapy. PMID- 25548515 TI - Treatment of port wine stains with pulsed dye laser: a retrospective study of 848 cases in Shandong Province, People's Republic of China. AB - BACKGROUND: Currently, 595 nm pulsed dye laser (PDL) therapy is offered as one of the effective treatments of port wine stains (PWSs). However, the efficacy of PDL differs in different populations. OBJECTIVE: The purpose of the study was to investigate the efficacy, and related factors, of 595 nm PDL in the treatment of PWSs in Chinese patients with skin type III to IV. METHODS: A total of 848 cases that were treated with PDL were enrolled and analyzed in this study. An independent dermatologist evaluated these lesions according to the before and after photographs. RESULTS: The response rate (RR) of all the 848 PWS patients was 69.9%, within which the cure rate was 6.3%. The patients aged <=1 year had the highest RR (93.9%), whereas those treated after age 50 reacted the worst (RR =25%). We analyzed the anatomical distribution of the lesion and found that the temporal region had the highest lesion clearance (RR =75.3%), while the extremities had the lowest clearance (RR =44.5%). Compared with the patients whose lesion size was larger than 80 cm(2), the patients with small lesion size, of 0-20 cm(2), had better clinical effect (RR =73.8% vs 53.2%). The reactions of the patients with hyperplastic lesion were worse than those with red patches (RR =36.4% vs 71.7%). As well, increasing treatment numbers could achieve higher clearance rates (P=0.005). CONCLUSION: The PDL had a relatively high RR but a low clearance rate in Chinese patients with PWS, although the earlier the intervention, the better was the efficacy. The response of PDL was, not only related to the anatomical area, but also, to the lesion size, type of lesion (ie, the presence of existing hyperplastic lesions), and the number of treatment, all of which are essential for the evaluation of therapeutic effect and acquisition of patients consent before treatment. PMID- 25548517 TI - Curative treatment can be an option for patients with metastatic squamous cell cancer of the head and neck. AB - BACKGROUND: No specific study has focused on patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) at diagnosis. Due to high response rates of induction chemotherapy in chemo-naive patients with localized disease, their prognosis should be better than patients with recurrent disease. METHODS: From January 1, 2008 to July 1, 2012, we retrospectively collected all patients' records with SCCHN diagnosed as metastatic. Patients, disease, treatment and its results were analyzed. Survival was calculated using the Kaplan-Meier method. RESULTS: Of the 749 new patients treated for SCCHN in our institution, 16 (2.1%) were metastatic at diagnosis, of whom five had cytological results to prove it. Six patients died before treatment or had palliative care and ten received initial chemotherapy and then surgery and/or radiotherapy according to the primary response. Four patients treated with first-line chemotherapy with docetaxel-5FU-cisplatin (TPF) showed a complete response of metastatic lesions allowing locoregional treatment. The overall survival at 1 year and 3 years was 50% and 24%, respectively. The median survival was 7 months (1-72 months). Seven patients (43.7%) had a higher survival at 12 months, including five (31.5%) who are still alive without recurrence with a mean follow-up of 30 months. There was a significant difference in overall survival (P<0.01) between patients who had chemotherapy with TPF versus other therapeutic protocols. The median survival of patients with lung metastases only was 15 months (1-72 months), significantly higher than that of patients with liver and/or bone localizations, which was 2 months (1-9 months). CONCLUSION: Patients with metastatic SCCHN treated by TPF followed by multimodal treatment could achieve long survival. PMID- 25548516 TI - Stevens-Johnson Syndrome and toxic epidermal necrolysis: a multi-aspect comparative 7-year study from the People's Republic of China. AB - BACKGROUND: Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous drug reactions. They are differentiated based on the fraction of the body surface area affected. Optimal therapy for SJS and TEN is a controversial issue. OBJECTIVE: We compared the treatments given to and the clinical outcomes of 39 cases of SJS and 48 cases of TEN seen at a single institution between January 2007 and December 2013 for better understanding of the clinical characteristics and development of the two conditions. METHODS: Demographic data, clinical characteristics, treatments given, and therapeutic responses observed were retrospectively collected. RESULTS: The incidence rates of hypoproteinemia and secondary infections are significantly higher in TEN than in SJS (P=0.001 and P=0.002, respectively). The corticosteroid dose did not influence the time from the initiation of therapy to control of the lesions in SJS, but increasing the dosage of corticosteroids progressively decreased the time from the initiation of therapy to control of the lesions in TEN. With increases in the utilization ratio of intravenous immunoglobulin (IVIG), the length of the hospital stay became shorter, whereas the time from the initiation of therapy to control of the lesions remained the same in SJS. However, for TEN, both the length of the hospital stay and the time from the initiation of therapy to control of the lesions became shorter with increases in the utilization ratio of IVIG. CONCLUSION: SJS and TEN are two variants of the same spectrum, and they differ from each other not only in the severity of epidermal detachment but also in other clinical parameters and their distinct clinical courses. Thus, differential treatment of both conditions may have benefits for their prognosis. PMID- 25548519 TI - Use of time in people with chronic obstructive pulmonary disease--a systematic review. AB - "Physical inactivity" and "sedentary lifestyles" are phrases often used when describing lifestyles of people with chronic obstructive pulmonary disease (COPD). Evidence suggests activity types, independent of energy expenditure, influence health outcomes, so understanding patterns of time use is important, particularly in chronic disease. We aimed to identify reports of time use in people with COPD. Predefined search strategies were used with six electronic databases to identify individual activity reports (including frequencies and/or durations) in which community-dwelling people with COPD engaged. Eligible studies were assessed independently against predefined criteria and data were extracted by two reviewers. Data synthesis was achieved by aggregating activity reports into activity domains (sports/exercise, screen time, transport, quiet time, self care, sociocultural, work/study, chores, and sleep). Twenty-six publications reported 37 specific daily activities. People with COPD were found to spend extended periods in sedentary behaviors (eg, standing [194 min/day]; sitting [359 min/day]; lying [88 min/day]), have limited engagement in physical activity (eg, walking [51 min/day]; exercising [1.2 episodes per week {ep/w}, 13 min/day]), have high health care needs (medical appointments [1.0 ep/w]), and experience difficulties associated with activities of daily living (eg, showering [2.5 ep/w, 60 minutes per episode]; preparing meals [4.7 ep/w]). Little data could be found describing how people with COPD use their time, and data synthesis was problematic because of variations in methodologies, population differences, and research emphases. Identified data largely referred to posture and were skewed according to country, assessment methods, and disease severity. Comparisons with age-matched population data showed people with COPD spent less time engaged in personal-care activities (self-care and sleeping) and chores than people in similar age groups. The incorporation of time-use outcomes in future research designs should be encouraged. Ideally, these tools should use consistent frameworks and comparable outcome measures in order to provide clearer descriptions of time use in chronic disease. PMID- 25548521 TI - The concept of control of COPD in clinical practice. AB - Treatment of chronic obstructive pulmonary disease (COPD) requires a personalized approach according to the clinical characteristics of the patients, the level of severity, and the response to the different therapies. Furthermore, patients with the same level of severity measured by the degree of airflow obstruction or even with multidimensional indices may have very different symptoms and limitations for daily activities. The concept of control has been extensively developed in asthma but has not been defined in COPD. Here, we propose a definition of COPD control based on the concepts of impact and stability. Impact is a cross sectional concept that can be measured by questionnaires such as the COPD Assessment Test or the Clinical COPD Questionnaire. Alternatively, impact can be assessed by the degree of dyspnea, the use of rescue medication, the level of physical activity, and sputum color. Stability is a longitudinal concept that requires the absence of exacerbations and deterioration in the aforementioned variables or in the COPD Assessment Test or Clinical COPD Questionnaire scores. Control is defined by low impact (adjusted for severity) and stability. The concept of control in COPD can be useful in the decision making regarding an increase or decrease in medication in the stable state. PMID- 25548518 TI - Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study. AB - Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown. Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects. However, its molecular targets and effects on drug-metabolizing enzymes are unknown. This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe. DDI-CPI, a server that can predict drug-drug interactions via the chemical-protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB. Homology modeling was performed using the Discovery Studio program 3.1. The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days. Rat plasma concentrations of midazolam and its metabolite 1'-OH-midazolam were determined using a validated high-performance liquid chromatographic method. Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB. A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds. The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1'-OH-midazolam over midazolam. Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats. Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats. XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members. More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members. PMID- 25548522 TI - Efficacy of sorafenib in advanced differentiated and medullary thyroid cancer: experience in a Turkish population. AB - BACKGROUND: Antivascular endothelial growth factor tyrosine kinase inhibitors have been used recently in the treatment of advanced differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). Off-label sorafenib is used in Turkey with special permission by the Ministry of Health for this indication. PATIENTS AND METHODS: Patients with advanced DTC and MTC were retrospectively identified from the Turkish Ministry of Health database. Data on these patients were prospectively collected before permission is granted to use sorafenib. RESULTS: Thirty patients with complete data were analyzed: 14 DTC (papillary number [n] =10; follicular n=4) and 16 MTC. The median age of the patients was 57 years (range: 28-79 years), and there were 18 males and 12 females. All DTC patients were iodine refractory and had received a median three doses of radioactive iodine (range: 1-7 doses). Sorafenib was used for a median of 12 months (range: 1-49 months). The overall response rate was 20%, all partial responses, with no complete response. The overall response rate was 14% in DTC and 25% in MTC patients. The median progression-free survival (PFS) was 17.1 months (95% confidence interval [CI]: 7.3-26.8) and overall survival (OS) was not reached. The 2-year PFS and OS were 39% and 68%, respectively. DTC and MTC patients had similar survival outcomes: median PFS of 21.3 months (95% CI: 5.8 36.7) versus 14.5 months (95% CI: 3.7-25.2), respectively (P=0.36), with the median OS not reached in either group (P=0.17). Tumor marker levels did not have any prognostic or predictive role. The toxicity profile was similar to that of other sorafenib trials. CONCLUSION: Sorafenib is an effective and well-tolerated treatment in advanced thyroid cancers. PMID- 25548520 TI - The clinical use of regenerative therapy in COPD. AB - Regenerative or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues. Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury. Animal and human studies have demonstrated that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for chronic obstructive pulmonary disease. The use of bone marrow-derived stem cells could allow repairing and regenerate the damaged tissue present in chronic obstructive pulmonary disease by means of their engraftment into the lung. Another approach could be the stimulation of resident stem cells by means of humoral factors or photobiostimulation. PMID- 25548524 TI - The costs of fluid overload in the adult intensive care unit: is a small-volume infusion model a proactive solution? AB - PURPOSE: Fluid overload (FO) in critically ill patients remains a challenging clinical dilemma, and many continuous intravenous (IV) medications in the US are being delivered as a dilute solution, adding significantly to a patient's daily intake. This study describes the costs and outcomes of FO in patients receiving multiple continuous infusions. MATERIALS AND METHODS: A retrospective study was conducted using a hospital administrative database covering >500 US hospitals. An FO cohort included adult intensive care unit (ICU) patients with a central line receiving IV loop diuretics and 2+ continuous IV infusions on 50%+ of their ICU days; a directly matched non-FO cohort included patients without IV diuretic use. The primary outcome of the study was total hospitalization costs per visit. Additional outcomes were ICU costs, mortality, total and ICU length of stay (LOS), 30-day readmission rates, and ventilator use. Unadjusted descriptive analysis was performed using chi-squared or paired t-tests to compare outcomes between the two cohorts. RESULTS: A total of 63,974 patients were identified in each cohort. The total hospitalization cost per visit for the FO cohort was US$15,344 higher than the non-FO cohort (US$42,386 vs US$27,042), and the ICU cost for the FO cohort was US$5,243 higher than the non-FO cohort (US$10,902 vs US$5,659). FO patients had higher mortality (20% vs 16.8%), prolonged LOS (11.5 vs 8.0 days), longer ICU LOS (6.2 vs 3.6 days), higher risk of 30-day readmission (21.8% vs 21.3%), and ventilator usage (47.7% vs 28.3%) than the non-FO cohort (all P<0.05). CONCLUSION: In patients receiving multiple continuous infusions, FO is associated with increased health care resources and costs. Maximally concentrating medications and proactively providing continuous medications in small-volume infusions (SVI) could be a potential solution to prevent iatrogenic FO in critically ill patients. Further prospective research is warranted to assess the impact of the SVI dispensing model on patient outcomes and health care costs. PMID- 25548523 TI - Antibiotic lock therapy: review of technique and logistical challenges. AB - Antibiotic lock therapy (ALT) for the prevention and treatment of catheter related bloodstream infections is a simple strategy in theory, yet its real-world application may be delayed or avoided due to technical questions and/or logistical challenges. This review focuses on these latter aspects of ALT, including preparation information for a variety of antibiotic lock solutions (ie, aminoglycosides, beta-lactams, fluoroquinolones, folate antagonists, glycopeptides, glycylcyclines, lipopeptides, oxazolidinones, polymyxins, and tetracyclines) and common clinical issues surrounding ALT administration. Detailed data regarding concentrations, additives, stability/compatibility, and dwell times are summarized. Logistical challenges such as lock preparation procedures, use of additives (eg, heparin, citrate, or ethylenediaminetetraacetic acid), timing of initiation and therapy duration, optimal dwell time and catheter accessibility, and risks of ALT are also described. Development of local protocols is recommended in order to avoid these potential barriers and encourage utilization of ALT where appropriate. PMID- 25548525 TI - Economic evaluation of first-line and maintenance treatments for advanced non small cell lung cancer: a systematic review. AB - During these last years, there have been an increased number of new drugs for non small cell lung cancer (NSCLC), with a growing financial effect on patients and society. The purpose of this article was to review the economics of first-line and maintenance NSCLC treatments. We reviewed economic analyses of NSCLC therapies published between 2004 and 2014. In first-line settings, in unselected patients with advanced NSCLC, the cisplatin gemcitabine doublet appears to be cost-saving compared with other platinum doublets. In patients with nonsquamous NSCLC, the incremental cost-effectiveness ratios (ICERs) per life-year gained (LYG) were $83,537, $178,613, and more than $300,000 for cisplatin-pemetrexed compared with, respectively, cisplatin-gemcitabine, cisplatin-carboplatin paclitaxel, and carboplatin-paclitaxel-bevacizumab. For all primary chemotherapy agents, use of carboplatin is associated with slightly higher costs than cisplatin. In all the analysis, bevacizumab had an ICER greater than $150,000 per quality-adjusted life-year (QALY). In epidermal growth factor receptor mutated advanced NSCLC, compared with carboplatin-paclitaxel doublet, targeted therapy based on testing available tissue yielded an ICER of $110,644 per QALY, and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Compared with the triplet carboplatin-paclitaxel-bevacizumab, testing and rebiopsy strategies had ICERs of $25,547 and $44,036 per QALY, respectively. In an indirect comparison, ICERs per LYG and QALY of erlotinib versus gefitinib were $39,431 and $62,419, respectively. In anaplastic lymphoma kinase-positive nonsquamous advanced NSCLC, the ICER of first-line crizotinib compared with that of chemotherapy was $255,970 per QALY. For maintenance therapy, gefitinib had an ICER of $19,214 per QALY, erlotinib had an ICER of $127,343 per LYG, and pemetrexed had an ICER varying between $183,589 and $205,597 per LYG. Most recent NSCLC strategies are based on apparently no cost-effective strategies if we consider an ICER below $50,000 per QALY an acceptable threshold. We need, probably on a countrywide level, to have a debate involving public health organizations and pharmaceutical companies, as well as clinicians and patients, to challenge the rising costs of managing lung cancer. PMID- 25548527 TI - Paracetamol and analgesic nephropathy: Are you kidneying me? AB - INTRODUCTION: Analgesic nephropathy is a disease resulting from the frequent use of combinations of analgesic medications over many years, leading to significant impairment of renal function. The observation of a large number of cases of renal failure in patients abusing analgesic mixtures containing phenacetin led to the initial recognition of the nephrotoxicity from the use of analgesics. Phenacetin was subsequently exclusively blamed for this disease. However, the role of a single analgesic as a sole cause of analgesic nephropathy was challenged, and a number of researchers have since attempted to determine the extent of involvement of other analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and paracetamol. CASE PRESENTATION: We present the case of an 83-year old woman with a history of NSAID-induced nephropathy with poor pain control and reluctance to use paracetamol. We attempt to briefly review the evidence of paracetamol being implicated in the development of analgesic-induced nephropathy. CONCLUSION: There is a lack of concrete data regarding causative analgesics, including paracetamol. Patients should therefore not be withheld paracetamol, an effective and commonly recommended agent, for fear of worsening renal function. PMID- 25548526 TI - Diabetic retinopathy: variations in patient therapeutic outcomes and pharmacogenomics. AB - Diabetes and its microvascular complications in patients poses a significant challenge and constitutes a major health problem. When it comes to manifestations in the eye, each case of diabetic retinopathy (DR) is unique, in terms of the phenotype, genotype, and, more importantly, the therapeutic response. It is therefore important to identify factors that distinguish one patient from another. Personalized therapy in DR is a new trend aimed at achieving maximum therapeutic response in patients by identifying genotypic and phenotypic factors that may result in less than optimal response to conventional therapy, and consequently, lead to poorer outcome. With advances in the identification of these genetic markers, such as gene polymorphisms and human leucocyte antigen associations, as well as development of drugs that can target their effects, the future of personalized medicine in DR is promising. In this comprehensive review, data from various studies have been analyzed to present what has been achieved in the field of pharmacogenomics thus far. An insight into future research is also provided. PMID- 25548528 TI - Hypothesis: somatic mosaicism and Parkinson disease. AB - Mutations causing genetic disorders can occur during mitotic cell division after fertilization, which is called somatic mutations. This leads to somatic mosaicism, where two or more genetically distinct cells are present in one individual. Somatic mutations are the most well studied in cancer where it plays an important role and also have been associated with some neurodegenerative disorders. The study of somatic mosaicism in Parkinson disease (PD) is only in its infancy, and a case with somatic mutation has not yet been described. However, we can speculate that a somatic mutation affecting cells in the central nervous system including substantia nigra dopaminergic neurons could lead to the development of PD through the same pathomechanisms of genetic PD even in the absence of a germ-line mutation. Theoretically, a number of genes could be candidates for genetic analysis for the presence of somatic mosaicism. Among them, SNCA and PARK2 could be the best candidates to analyze. Because analyzing brain tissues in living patients is impossible, alternative tissues could be used to indicate the genetic status of the brain. Performance of the technology is another factor to consider when analyzing the tissues. PMID- 25548529 TI - Multiple system atrophy: genetic or epigenetic? AB - Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of alpha synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis. PMID- 25548531 TI - ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy. AB - Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions. Thus, two different hypotheses have emerged supporting a role of ATP13A2 and asyn in metal homeostasis or in autophagy. Interestingly, an appealing theory might combine these two cellular pathways. Here we review the novel findings in the interaction between these two proteins and debate the exciting roads still ahead. PMID- 25548532 TI - Protein Transmission, Seeding and Degradation: Key Steps for alpha-Synuclein Prion-Like Propagation. AB - Converging lines of evidence suggest that cell-to-cell transmission and the self propagation of pathogenic amyloidogenic proteins play a central role in the initiation and the progression of several neurodegenerative disorders. This "prion-like" hypothesis has been recently reported for alpha-synuclein, a presynaptic protein implicated in the pathogenesis of Parkinson's disease (PD) and related disorders. This review summarizes recent findings on alpha-synuclein prion-like propagation, focusing on its transmission, seeding and degradation and discusses some key questions that remain to be explored. Understanding how alpha synuclein exits cells and propagates from one brain region to another will lead to the development of new therapeutic strategies for the treatment of PD, aiming at slowing or stopping the disease progression. PMID- 25548530 TI - Alpha-synuclein function and dysfunction on cellular membranes. AB - Alpha-synuclein is a small neuronal protein that is closely associated with the etiology of Parkinson's disease. Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites that are composed primarily of alpha synuclein deposited in an aggregated amyloid fibril state. The normal function of alpha-synuclein is poorly understood, and the precise mechanisms by which it leads to toxicity and cell death are also unclear. Although alpha-synuclein is a highly soluble, cytoplasmic protein, it binds to a variety of cellular membranes of different properties and compositions. These interactions are considered critical for at least some normal functions of alpha-synuclein, and may well play critical roles in both the aggregation of the protein and its mechanisms of toxicity. Here we review the known features of alpha-synuclein membrane interactions in the context of both the putative functions of the protein and of its pathological roles in disease. PMID- 25548533 TI - Exploring myelin dysfunction in multiple system atrophy. AB - Multiple system atrophy (MSA) is a rare, yet fatal neurodegenerative disease that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. MSA impacts on the autonomic nervous system affecting blood pressure, heart rate and bladder function, and the motor system affecting balance and muscle movement. The cause of MSA is unknown, no definitive risk factors have been identified, and there is no cure or effective treatment. The definitive pathology of MSA is the presence of alpha-synuclein aggregates in the brain and therefore MSA is classified as an alpha-synucleinopathy, together with Parkinson's disease and dementia with Lewy bodies. Although the molecular mechanisms of misfolding, fibrillation and aggregation of alpha-synuclein partly overlap with other alpha-synucleinopathies, the pathological pathway of MSA is unique in that the principal site for alpha-synuclein deposition is in the oligodendrocytes rather than the neurons. The sequence of pathological events of MSA is now recognized as abnormal protein redistributions in oligodendrocytes first, followed by myelin dysfunction and then neurodegeneration. Oligodendrocytes are responsible for the production and maintenance of myelin, the specialized lipid membrane that encases the axons of all neurons in the brain. Myelin is composed of lipids and two prominent proteins, myelin basic protein and proteolipid protein. In vitro studies suggest that aberration in protein distribution and lipid transport may lead to myelin dysfunction in MSA. The purpose of this perspective is to bring together available evidence to explore the potential role of alpha-synuclein, myelin protein dysfunction, lipid dyshomeostasis and ABCA8 in MSA pathogenesis. PMID- 25548534 TI - Mitochondrial homeostasis molecules: regulation by a trio of recessive Parkinson's disease genes. AB - Mitochondria are small organelles that produce the majority of cellular energy as ATP. Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD), and rare familial forms of PD provide valuable insight into the pathogenic mechanism underlying mitochondrial impairment, even though the majority of PD cases are sporadic. The regulation of mitochondria is crucial for the maintenance of energy-demanding neuronal functions in the brain. Mitochondrial biogenesis and mitophagic degradation are the major regulatory pathways that preserve optimal mitochondrial content, structure and function. In this mini-review, we provide an overview of the mitochondrial quality control mechanisms, emphasizing regulatory molecules in mitophagy and biogenesis that specifically interact with the protein products of three major recessive familial PD genes, PINK1, Parkin and DJ-1. PMID- 25548535 TI - What is the Clinical Significance of Cerebrospinal Fluid Biomarkers in Parkinson's disease? Is the Significance Diagnostic or Prognostic? AB - The clinical diagnostic criteria of Parkinson's disease (PD) have limitations in detecting the disease at early stage and in differentiating heterogeneous clinical progression. The lack of reliable biomarker(s) for early diagnosis and prediction of prognosis is a major hurdle to achieve optimal clinical care of patients and efficient design of clinical trials for disease-modifying therapeutics. Numerous efforts to discover PD biomarkers in CSF were conducted. In this review, we describe the molecular pathogenesis of PD and discuss its implication to develop PD biomarkers in CSF. Next, we summarize the clinical utility of CSF biomarkers including alpha-synuclein for early and differential diagnosis, and prediction of PD progression. Given the heterogeneity in the clinical features of PD and none of the CSF biomarkers for an early diagnosis have been developed, research efforts to develop biomarkers to predict heterogeneous disease progression is on-going. Notably, a rapid cognitive decline followed by the development of dementia is a risk factor of poor prognosis in PD. In connection to this, CSF levels of Alzheimer's disease (AD) biomarkers have received considerable attention. However, we still need long-term longitudinal observational studies employing large cohorts to evaluate the clinical utility of CSF biomarkers reflecting Lewy body pathology and AD pathology in the brain. We believe that current research efforts including the Parkinson's Progression Markers Initiative will resolve the current needs of early diagnosis and/or prediction of disease progression using CSF biomarkers, and which will further accelerate the development of disease-modifying therapeutics and optimize the clinical management of PD patients. PMID- 25548536 TI - ATP13A2/PARK9 Deficiency Neither Cause Lysosomal Impairment Nor Alter alpha Synuclein Metabolism in SH-SY5Y Cells. AB - Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis. Here, we set out to investigate the role of ATP13A2 in lysosomal function and in metabolism of alpha-synuclein, another PD-linked protein whose accumulation is implicated in the pathogenesis. We generated non-sense mutations in both copies of ATP13A2 gene in SH-SY5Y human neuroblastoma cells. We examined lysosomal function of ATP13A2-/- cells by measuring the accumulation of lysosomal substrate proteins, such as p62 and polyubiquitinated proteins, induction of acidic compartments, and degradation of ectopically introduced dextran. None of these measures were altered by ATP13A2 deficiency. The steady-state levels of alpha-synuclein in cells or secretion of this protein were unaltered either in ATP13A2-/- compared to the normal cells. Therefore, the proposed roles of ATP13A2 in lysosomal functions may not be generalized and may depend on the cellular context. The ATP13A2-/- cells generated in the current study may provide a useful control for studies on the roles of PD genes in lysosomal functions. PMID- 25548537 TI - Involvement of endoplasmic reticulum stress response in orofacial inflammatory pain. AB - Endoplasmic reticulum (ER) stress is involved in many neurological diseases and inflammatory responses. Inflammatory mediators induce neuronal damage and trigger the neuropathic or inflammatory pain. But there is very little data on the role of the ER stress response in pain mechanisms. In this study, we explored whether the ER stress response is involved in orofacial inflammatory pain by using a complete Freund's adjuvant (CFA)-injected rat model. The thermal pain hypersensitivity increased significantly after CFA injection. We found that the protein and mRNA levels of ER stress response genes, GRP78/Bip and p-eIF2alpha, increased significantly in trigeminal ganglion (TG) of CFA-injected rats compared to control animals. In immunofluorescence analysis, a significant increase of GRP78 and p-eIF2alpha immunopositive neurons was observed in CFA-injected TG compared to control TG. When we administered an ER stress modulator, salubrinal, CFA-induced thermal pain hypersensitivity was temporally reduced. Thus, our study suggests that ER stress responses in TG neurons contribute to CFA-induced inflammatory pain, and may comprise an important molecular mechanism underlying the orofacial inflammatory pain pathway. PMID- 25548538 TI - Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosarcoma. AB - Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma. Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012. Results. We identified 14 patients with a total of 27 lesions from osteosarcoma (n = 19) or ES (n = 8). The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30-60 Gy in 3-10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16-50 Gy in 1-10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation. Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity. PMID- 25548539 TI - A cross-sectional study of the differences in diabetes knowledge, attitudes, perceptions and self-care practices as related to assessment of chronic illness care among people with diabetes consulting in a family physician-led hospital based first line health service and local government health unit-based health centers in the Philippines. AB - BACKGROUND: The purpose of this study was to investigate differences in diabetes knowledge, attitudes and perceptions (KAP), self-care practices as related to assessment of chronic illness care among people with diabetes consulting in a family physician-led tertiary hospital-based out-patient clinic versus local government health unit-based health centers in the Philippines. METHODS: People with diabetes consulting in the said primary care services were interviewed making use of questionnaires adapted from previously tested and validated KAP questionnaires and the patients' assessment of chronic illness care (PACIC) questionnaire. Adherence to medications, diabetes diet, and exercise and the number of diabetes consultations were asked. Analysis of variance was used to determine differences in KAP, self-care practices, and PACIC and regression analysis was used to determine any associations of the abovementioned variables to the PACIC ratings. RESULTS: A total of 549 respondents were included in the study. Differences in knowledge, attitudes, perceptions, PACIC, utilization of health services, and adherence to medications and exercise were all statistically significant. Ratings for diabetes knowledge, positive attitudes, and the perceptions of support attitudes and the abilities to perform self care, and the proportions of those properly utilizing health services and adhering to medications and exercise were higher while ratings for negative attitudes, perceived support needs, perceived support received and PACIC were lower among those consulting in the family physician-led health service. CONCLUSIONS: Combining family medicine-based approaches with culturally competent diabetes care may improve knowledge, attitudes, perceptions and self-care practices of and collaborative care with people with diabetes. PMID- 25548540 TI - A descriptive study of knowledge, beliefs and practices regarding osteoporosis among female medical school entrants in Sri Lanka. AB - BACKGROUND: Osteoporosis is a significant problem in rapidly ageing populations in Asian regions. It causes a significant personal and societal impact and increases the burden on health care services. OBJECTIVES: Aim of this study is to determine the knowledge, beliefs and practices regarding osteoporosis among young females entering medical schools in Sri Lanka. METHODS: This is a descriptive cross sectional study conducted amongst 186 female medical school entrants of the Faculties of Medicine, Universities of Colombo and Kelaniya from September to December 2010. A self administered questionnaire was used to assess knowledge, beliefs and practices on osteoporosis, including a food frequency chart to assess the calcium intake. RESULTS: The mean age was 20.7 +/- 2.1 years. Majority of the participants (51.6%, n = 96) had an average score (40-60) on the knowledge test, while 40.8% (n = 76) had a poor score (<40). However, in depth knowledge on risk factors, and protective factors was lacking. Perceived susceptibility for osteoporosis was low with only 13.9% (n = 26) of women agreeing that their chances of getting osteoporosis are high. The mean calcium intake was 528 mg/day and only 18.8% (n = 35) of the participants achieved the Recommended Daily Allowances (RDA) for Calcium. Exercise was grossly inadequate in the majority and only 13.6%( n = 23) engaged in the recommended exercises. Only 3.8% (n =7) of the participants currently engaged in specific behaviours to improve bone health while 10.8% (n = 20) had thought of routinely engaging in such behaviours. CONCLUSIONS: Although majority of participants had a modest level of knowledge on osteoporosis, there were gaps in their knowledge in relation to risk factors, protective factors and on the insidious nature of osteoporosis. Perceived susceptibility for osteoporosis was low. Practices towards preventing Osteoporosis were inadequate. PMID- 25548541 TI - Altered expression of T cell Immunoglobulin-Mucin (Tim) molecules in peripheral blood mononuclear cells in aplastic anemia. AB - To evaluate the balance between T-cell immunoglobulin and mucin domain (Tim) molecules(Tim)-1 and Tim-3 in patients with aplastic anemia (AA), plasma IFN gamma and IL-4 levels were measured in patients with active AA (n = 41), AA in remission (n = 29) and in healthy subjects (n = 40) by enzyme linked immunosorbent assay (ELISA). Using real-time quantitative polymerase chain reaction (RT-PCR), the mRNA expression of IFN-gamma, IL-4, Tim-1 and Tim-3 were studied in all subjects. The results showed that the expression of Tim-3 in newly diagnosed patients was significantly deceased, compared with the controls. Meanwhile, Tim-1 mRNA expression in the active AA group was not significantly reduced, which resulted in a declined ratio of Tim-3/Tim-1 in patients with active disease. During the remission stages, the levels of these transcription factors were comparable with those observed in the healthy controls. These findings are the first data on the expression of the Tim-1 and Tim-3 molecules in AA. The reduced levels of Tim-3/Tim-1 in PBMCs during the active stages of disease suggest that they may play a possible role in the pathogenesis and course of AA. PMID- 25548542 TI - Extent of pelvic lymph node dissection during radical cystectomy: is bigger better? AB - Pelvic lymph node dissection (PLND) is a standard component of radical cystectomy (RC) for bladder cancer. The optimal anatomic PLND template remains undefined. An extended PLND template can potentially improve survival through the eradication of micrometastatic disease and improved pathologic staging. However, this benefit could be compromised by a potential increase in perioperative complications and cost. Two randomized controlled clinical trials that will clarify this question are ongoing. Many important retrospective studies have provided insights into the optimal PLND extent. Here the authors review the key evidence that informs how urologists may tailor the PLND template during RC depending on patient and tumor characteristics. PMID- 25548544 TI - A guide for clinicians in the evaluation of emerging molecular diagnostics for newly diagnosed prostate cancer. AB - Prostate-specific antigen (PSA) screening is associated with a decline in prostate cancer-related mortality. However, screening has also led to overdiagnosis and overtreatment of clinically insignificant tumors. Recently, certain national guidelines (eg, US Preventive Services Task Force) have recommended against PSA screening, which may lead to a reverse-stage migration. Although many prostate tumors are indolent at presentation, others are aggressive and are appropriate targets for treatment interventions. Utilization of molecular markers may improve our ability to measure tumor biology and allow better discrimination of indolent and aggressive tumors at diagnosis. Many emerging commercial molecular diagnostic assays have been designed to provide more accurate risk stratification for newly diagnosed prostate cancer. Unfamiliarity with molecular diagnostics may make it challenging for some clinicians to navigate and interpret the medical literature to ascertain whether particular assays are appropriately developed and validated for clinical use. Herein, the authors provide a framework for practitioners to use when assessing new tissue based molecular assays. This review outlines aspects of assay development, clinical and analytic validation and clinical utility studies, and regulatory issues, which collectively determine whether tests (1) are actionable for specific clinical indications, (2) measurably influence treatment decisions, and (3) are sufficiently validated to warrant incorporation into clinical practice. PMID- 25548543 TI - Erectile Dysfunction and Essential Hypertension: The Same Aging-related Disorder? AB - An erection is a mechanical event dependent primarily on corporeal vascular dynamics wherein arterial inflow and storage of blood within the corpora is greater than the egress of blood from the corpora. The most common cause of erectile dysfunction (ED) is the inability of the corporal tissue to store the blood within the corporal sinusoids once inflow into the corpora begins. This failure to store is primarily due to a corporal smooth muscle dysfunction and, in most men, is most likely an aging-related occurrence. Because the corporal smooth muscle is embryologically and physiologically indistinguishable from the smooth muscle within our arterial system, the authors hypothesize that the aging-related dysfunction that occurs within the penis also occurs within the arterial system, and that this smooth muscle dysfunction within the arterial media is most likely the cause of what is called essential hypertension. This panvascular smooth muscle myopathy could explain why hypertension is the most common comorbidity associated with ED and appears to indicate that both ED and essential hypertension are the same disorder, albeit in two different organ systems. PMID- 25548546 TI - From the President's Desk: Looking Ahead at 2015. PMID- 25548545 TI - Post-radical prostatectomy incontinence: etiology and prevention. AB - All patients undergoing a radical prostatectomy (RP) using any surgical approach, be it open, laparoscopic, or robotic, are at risk of developing postprostatectomy urinary incontinence. This side effect of RP has an effect on the patient's quality of life and can be associated with moderate to severe postoperative morbidity. The authors present a review of the etiology and prevention strategies of postprostatectomy urinary incontinence. Based on the current literature, the authors conclude that there is a paucity of studies that can accurately answer the exact anatomic and physiologic etiologies of postprostatectomy urinary incontinence. The aim of urologic surgeons performing RP should be to reduce the rate of postoperative incontinence rather than attempting to treat it once it has occurred. Further studies aimed at providing a detailed anatomic map of the pelvic anatomy related to continence will help to improve surgical techniques and reduce postoperative urinary incontinence following RP. PMID- 25548547 TI - Testicular sclerosing sertoli cell tumor: a case report and review of the literature. AB - Sertoli cell tumors are very rare testicular tumors, representing 0.4% to 1.5% of all testicular malignancies. They are subclassified as classic, large-cell calcifying, and sclerosing Sertoli cell tumors (SSCT) based on distinct clinical features. Only 42 cases of SSCTs have been reported in the literature. We present a case of a 23-year-old man diagnosed with SSCT. PMID- 25548548 TI - The use of botulinum neurotoxin type a in a patient with refractory urge incontinence to facilitate the intravesical treatment of bladder carcinoma. AB - Intravesical Bacillus Calmette-Guerin (BCG) has become the preferred initial treatment after resection of high-grade T1 urothelial carcinoma and carcinoma in situ (CIS). We report the case of a patient with high-grade T1 urothelial carcinoma and CIS who was treated with intravesical BCG. Due to the patient's severe urge incontinence, however, the BCG solution leaked from the bladder immediately upon instillation. We describe our experience of using botulinum neurotoxin A intradetrusor injections to facilitate successful intravesical therapy by increasing bladder capacity to enable the BCG to remain in the patient's bladder for the appropriate treatment duration. PMID- 25548549 TI - Intratesticular epidermoid cyst masquerading as testicular torsion. AB - Epidermoid cysts are benign tumors that comprise approximately 1% of all testicular masses. They usually present as painless masses that can be identified on scrotal ultrasound as well-demarcated intratesticular lesions with mixed echogenicity. This case report describes a rare presentation of an extremely large intratesticular epidermoid cyst with clinical and radiologic findings more consistent with testicular torsion. The sizeable cyst obliterated the surrounding testicular parenchyma, causing it to appear on scrotal Doppler ultrasound as a testicle devoid of blood flow. This obliteration also resulted in failure to identify a testicular mass on physical examination or imaging. The current literature contains previous reports of extratesticular epidermoid cysts presenting as torsion; however, this is the first report of an intratesticular epidermoid cyst presenting in this manner. Though smaller cysts may be managed effectively with testicular-sparing surgery, optimal management of a cyst this size requires orchiectomy. PMID- 25548550 TI - Heterogeneity in active surveillance protocols worldwide. PMID- 25548551 TI - Synthesis, Characterization, Semiempirical and Biological Activities of Organotin(IV) Carboxylates with 4-Piperidinecarboxylic Acid. AB - Organotin (IV) carboxylates with the general formulae R2Sn(Cl)L [R = Me (1), n-Bu (2), Ph (3)] and R3SnL [R = Me (4), Ph (5)] have been synthesized by the reaction of 4-piperidinecarboxylic acid (HL) with KOH and R2SnCl2 (R = Me, n-Bu, Ph)/R3SnCl (R = Me, Ph) in methanol under stirring conditions. The metal ligand binding site, structure, and stability of complexes have been verified by FT-IR, ((1)H, (13)C) NMR, EI-MS technique, and semiempirical study. The FT-IR data indicate the bidentate chelating mode of the carboxylate ligand which is also confirmed by semiempirical study. In solution state, five and four coordinated geometry around tin was confirmed by NMR spectroscopy. The EI-MS data agreed well with the molecular structure of the complexes. Thermodynamic parameters and molecular descriptors were calculated by using semiempirical PM3 method. HOMO LUMO calculations show that chlorodiorganotin complexes are more susceptible to nucleophilic attack as compared to triorganotin complexes. Computed negative heat of formation indicates that complexes 1-4 are thermodynamically stable. The organotin(IV) carboxylates displayed powerful antimicrobial activities against various strains of bacteria and fungi and their minimal inhibitory concentration were also evaluated. The complexes exhibited comparatively higher hemolytic activity as compared to free ligand. PMID- 25548552 TI - High frequency of symptomatic zinc deficiency in infants in northern ethiopia. AB - Background. Zinc deficiency occurs in infants when its demand exceeds its supply. It presents with cutaneous signs which, in severe cases, are associated with diarrhea, alopecia, and irritability. Genetic and acquired forms of zinc deficiency have been reported and often overlap clinical features. Malnutrition, prematurity, malabsorption syndromes, and burns may cause an increased demand for zinc. Methods. Cases of acquired transient infantile zinc deficiency (TIZD) observed during a period of 3 years at Ayder Referral Hospital of Mekelle, Northern Ethiopia, are reported here. Since no sophisticated tests were available at our center, the diagnosis was based on the clinical signs and prompt response to oral zinc supplementation. Results. We observed 18 cases of TIZD at our center. All patients were full-term and breastfeeding infants with no relevant associated diseases. Conclusions. In this region, a high incidence of this condition is observed. We could not rule out whether heterozygosity for the genetic mutation was present or that the disease was caused by a nutritional deficiency in the mothers or more probably because both the factors coexisted together. However, further studies are necessary to better understand the causes of the increased incidence of this disease in Northern Ethiopia. PMID- 25548553 TI - VAWCM-Instillation Improves Delayed Primary Fascial Closure of Open Septic Abdomen. AB - Background. Failure to achieve delayed primary fascial closure (DPFC) is one of the main complications of open abdomen (OA), certainly when abdominal sepsis is present. This retrospective cohort study aims to evaluate the effect of combined therapy of vacuum-assisted mesh-mediated fascial traction and topical instillation (VAWCM-instillation) on DPFC in the open septic abdomen. Methods. The patients with abdominal sepsis who underwent OA using VAWCM were included and divided into the instillation and noninstillation (control) groups. The DPFC rate and other outcomes were compared between the two groups. Results. Between 2007 and 2013, 73 patients with open septic abdomen were treated with VAWCM instillation and 61 cases with VAWCM-only. The DPFC rate in the instillation group was significantly increased (63% versus 41%, P = 0.011). The mortality with OA was similar (24.6% versus 23%, P = 0.817) between the two groups. However, time to DPFC (P = 0.003) and length of stay in hospital (P = 0.022) of the survivals were significantly decreased in the instillation group. In addition, VAWCM-instillation (OR 1.453, 95% CI 1.222-4.927, P = 0.011) was an independent influencing factor related to successful DPFC. Conclusions. VAWCM-instillation could improve the DPFC rate but could not decrease the mortality in the patients with open septic abdomen. PMID- 25548554 TI - Endoscopic management of diverticular bleeding. AB - Diverticular hemorrhage is the most common reason for lower gastrointestinal bleeding (LGIB) with substantial cost of hospitalization and a median length of hospital stay of 3 days. Bleeding usually is self-limited in 70-80% of cases but early rebleeding is not an uncommon problem that can be reduced with proper endoscopic therapies. Colonoscopy is recommended as first-line diagnostic and therapeutic approach. In the vast majority of patients diverticular hemorrhage can be readily managed by interventional endotherapy including injection, heat cautery, clip placement, and ligation to achieve endoscopic hemostasis. This review will serve to highlight the various interventions available to endoscopists with specific emphasis on superior modalities in the endoscopic management of diverticular bleeding. PMID- 25548555 TI - Increased risk for vitamin d deficiency in obese children with both celiac disease and type 1 diabetes. AB - Background. It is unknown whether the coexistence of type 1 diabetes (T1D) and celiac disease (CD) increases the risk for vitamin D deficiency. Aims. To determine the vitamin D status and the risk for vitamin D deficiency in prepubertal children with both T1D and CD compared to controls, TID, and CD. Subjects and Methods. Characteristics of 62 prepubertal children of age 2-13 y with either CD + T1D (n = 22, 9.9 +/- 3.1 y), CD only (n = 18, 8.9 +/- 3.3 y), or T1D only (n = 22, 10.1 +/- 2.8 y) were compared to 49 controls of the age of 8.0 +/- 2.6 years. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L, overweight as BMI of >85th but <95th percentile, and obesity as BMI > 95th percentile. Results. The 4 groups had no difference in 25(OH)D (ANOVA P = 0.123) before stratification into normal-weight versus overweight/obese subtypes. Following stratification, 25(OH)D differed significantly between the subgroups (F (3,98) = 10.109, ANOVA P < 0.001). Post-hoc analysis showed a significantly lower 25(OH)D in the overweight/obese CD + T1D compared to the overweight/obese controls (P = 0.039) and the overweight/obese CD (P = 0.003). Subjects with CD + T1D were 3 times more likely to be vitamin D deficient (OR = 3.1 [0.8-11.9], P = 0.098), compared to controls. Conclusions. The coexistence of T1D and CD in overweight/obese prepubertal children may be associated with lower vitamin D concentration. PMID- 25548556 TI - Optimal timing for resuming antithrombotic agents and risk factors for delayed bleeding after endoscopic resection of colorectal tumors. AB - Aim. To examine optimal timing for resuming antithrombotic agents and risk factors for delayed bleeding after endoscopic resection of colorectal tumors. Method. Of 1,970 polyps larger than 10 mm removed by polypectomy, endoscopic mucosal resection, or endoscopic submucosal dissection, delayed bleeding, which was designated as bleeding that occurred 6 or more hours after endoscopic treatment, occurred in 52 cases (2.6%); 156 nonbleeding cases matched for age and gender were controls in this single-institution retrospective case-control study. We investigated (1) patient-factors: resuming antithrombotic agents within 5 days following endoscopic resection, hypertension, and diabetes mellitus; and (2) tumor-factors: morphology, size, location, and resection technique by conditional logistic regression. Results. By multivariate analysis resumption of anticoagulants within 5 days was a significant risk factor for delayed bleeding (OR 10.2; 95% CI = 2.7-38.3; P = 0.0006). But resuming a thienopyridine within 5 days was not (OR 0.9; 95% CI = 0.1-2.6; P = 0.40). Other patient- and tumor factors were not significant. Conclusion. Resuming anticoagulants within 5 days after endoscopic treatment was associated with delayed bleeding whereas resuming thienopyridines was not. PMID- 25548557 TI - Scheduling in Sensor Grid Middleware for Telemedicine Using ABC Algorithm. AB - Advances in microelectromechanical systems (MEMS) and nanotechnology have enabled design of low power wireless sensor nodes capable of sensing different vital signs in our body. These nodes can communicate with each other to aggregate data and transmit vital parameters to a base station (BS). The data collected in the base station can be used to monitor health in real time. The patient wearing sensors may be mobile leading to aggregation of data from different BS for processing. Processing real time data is compute-intensive and telemedicine facilities may not have appropriate hardware to process the real time data effectively. To overcome this, sensor grid has been proposed in literature wherein sensor data is integrated to the grid for processing. This work proposes a scheduling algorithm to efficiently process telemedicine data in the grid. The proposed algorithm uses the popular swarm intelligence algorithm for scheduling to overcome the NP complete problem of grid scheduling. Results compared with other heuristic scheduling algorithms show the effectiveness of the proposed algorithm. PMID- 25548558 TI - Seroprevalence and seroconversion of dengue and implications for clinical diagnosis in amazonian children. AB - This study aimed to evaluate the prevalence of serum IgG dengue in children in an Amazonian population, to assess the seroconversion rate in 12 months, and to estimate how many seropositive children had a prior clinical diagnosis of dengue. We conducted a population-based study between 2010 and 2011, with children aged 6 months to 12 years that were living in the urban area of a small town in the Brazilian Amazon. The prevalence of IgG antibodies against dengue antigens was determined by indirect ELISA technique, and seronegative children were reexamined after 12 months to determine seroconversion rates. Results showed seroprevalence of IgG antibodies against dengue type of 2.9%, with no significant association between age, race, and sex. In seropositive children, only 8.4% had received a clinical diagnosis of dengue, and the ratio of clinically diagnosed cases and subclinical cases was 1 : 11. The seroconversion rate between 2010 and 2011 was 1.4% (CI 3.8% to 35.1%). The seroprevalence of dengue in this pediatric population was low, and the vast majority of cases were not clinically detected, suggesting a difficulty in making the clinical diagnosis in children and a high frequency of asymptomatic infections. PMID- 25548559 TI - Effect of Calcium Ion Removal, Ionic Strength, and Temperature on the Conformation Change in Calmodulin Protein at Physiological pH. AB - The response of the calmodulin (CaM) protein as a function of calcium ion removal, ionic strength, and temperature at physiological pH condition was investigated using classical molecular dynamics simulations. Changing the ionic strength and temperature came out to be two of the possible routes for observing a conformation change in the protein. This behavior is similar to the conformation change observed in our previous study where a change in the pH was observed to trigger a conformation change in this protein. In the present study, as the calcium ions are removed from the protein, the protein is observed to acquire more flexibility. This flexibility is observed to be more prominent at a higher ionic strength. At a lower ionic strength of 150 mM with all the four calcium ions intact, the N- and C-lobes are observed to come close to a distance of 30 A starting from an initial separation distance of 48 A. This conformation change is observed to take place around 50 ns in a simulation of 100 ns. As a second parameter, temperature is observed to play a key role in the conformation change of the protein. With an increase in the temperature, the protein is observed to acquire a more compact form with the formation of different salt bridges between the residues of the N- and the C-lobes. The salt bridge formation leads to an overall lowering of the energy of the protein thus favoring the bending of the two lobes towards each other. The improper and dihedral terms show a significant shift thus leading to a more compact form on increasing the temperature. Another set of simulations is also performed at an increased temperature of 500 K to verify the reproducibility of the results. Thus a set of three possible alterations in the environmental conditions of the protein CaM are studied, with two of them giving rise to a conformation change and one adding flexibility to the protein. PMID- 25548560 TI - Anion Gap Toxicity in Alloxan Induced Type 2 Diabetic Rats Treated with Antidiabetic Noncytotoxic Bioactive Compounds of Ethanolic Extract of Moringa oleifera. AB - Moringa oleifera (MO) is used for a number of therapeutic purposes. This raises the question of safety and possible toxicity. The objective of the study was to ascertain the safety and possible metabolic toxicity in comparison with metformin, a known drug associated with acidosis. Animals confirmed with diabetes were grouped into 2 groups. The control group only received oral dose of PBS while the test group was treated with ethanolic extract of MO orally twice daily for 5-6 days. Data showed that the extract significantly lowered glucose level to normal values and did not cause any significant cytotoxicity compared to the control group (P = 0.0698); there was no gain in weight between the MO treated and the control groups (P > 0.8115). However, data showed that treatment with an ethanolic extract of MO caused a decrease in bicarbonate (P < 0.0001), and more than twofold increase in anion gap (P < 0.0001); metformin treatment also decreased bicarbonate (P < 0.0001) and resulted in a threefold increase in anion gap (P < 0.0001). Conclusively, these data show that while MO appears to have antidiabetic and noncytotoxic properties, it is associated with statistically significant anion gap acidosis in alloxan induced type 2 diabetic rats. PMID- 25548561 TI - Cytotoxicity and genotoxicity of panel of single- and multiwalled carbon nanotubes: in vitro effects on normal Syrian hamster embryo and immortalized v79 hamster lung cells. AB - Carbon nanotubes (CNTs) belong to a specific class of nanomaterials with unique properties. Because of their anticipated use in a wide range of industrial applications, their toxicity is of increasing concern. In order to determine whether specific physicochemical characteristics of CNTs are responsible for their toxicological effects, we investigated the cytotoxic and genotoxic effects of eight CNTs representative of each of the commonly encountered classes: single- SW-, double- DW-, and multiwalled (MW) CNTs, purified and raw. In addition, because most previous studies of CNT toxicity were conducted on immortalized cell lines, we decided to compare results obtained from V79 cells, an established cell line, with results from SHE (Syrian hamster embryo) cells, an easy-to-handle normal cell model. After 24 hours of treatment, MWCNTs were generally found to be more cytotoxic than SW- or DWCNTs. MWCNTs also provoked more genotoxic effects. No correlation could be found between CNT genotoxicity and metal impurities, length, surface area, or induction of cellular oxidative stress, but genotoxicity was seen to increase with CNT width. The toxicity observed for some CNTs leads us to suggest that they might also act by interfering with the cell cycle, but no significant differences were observed between normal and immortalized cells. PMID- 25548563 TI - Assessment of the common risk factors associated with type 2 diabetes mellitus in jeddah. AB - Risk factor management is important in avoiding life-threatening complications and preventing new-onset diabetes. We performed a case-control study in 2013 at ten primary health care centers in Jeddah, Saudi Arabia to determine the common risk factors of diabetes mellitus type 2 (DM2) and the demographic background of adult Saudi patients with DM2. Known diabetic patients were recruited as cases, while nondiabetic attendants were selected as controls. A pretested designed questionnaire was used to collect data from 159 cases and 128 controls. Cases were more likely than controls to be men (P < 0.0001), less educated (P < 0.0001), natives of eastern Saudi Arabia (P < 0.0001), retired (P < 0.0001), lower-salaried (P < 0.0001), or married or divorced (P < 0.0001). By univariate analysis cases were likely to be current smokers (P < 0.0001), hypertensive (P < 0.0001), or overweight/obese (P < 0.0001). Cases were also more likely to have a history of DM in a first-degree relative (P = 0.020). By multivariate analysis, cases were more likely to be older than 40 years (P < 0.0001), less educated (P = 0.05), married or divorced (P = 0.04), jobless/housewives (P < 0.0001), or current smokers (P = 0.002). They were also more likely to have salaries <7000 Saudi riyals (P = 0.01). Overall, prediabetic and high risk groups should be identified and counseled early before the occurrence of diabetes. PMID- 25548562 TI - MicroRNAs in Human Pituitary Adenomas. AB - MicroRNAs (miRNAs) are a class of recently identified noncoding RNAs that regulate gene expression at posttranscriptional level. Due to the large number of genes regulated by miRNAs, miRNAs play important roles in many cellular processes. Emerging evidence indicates that miRNAs are dysregulated in pituitary adenomas, a class of intracranial neoplasms which account for 10-15% of diagnosed brain tumors. Deregulated miRNAs and their targets contribute to pituitary adenomas progression and are associated with cell cycle control, apoptosis, invasion, and pharmacological treatment of pituitary adenomas. To provide an overview of miRNAs dysregulation and functions of these miRNAs in pituitary adenoma progression, we summarize the deregulated miRNAs and their targets to shed more light on their potential as therapeutic targets and novel biomarkers. PMID- 25548564 TI - Clinical evaluation of various thyroid hormones on thyroid function. AB - To clarify the clinical value of serums total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4) and provide a more eligible and economic strategy to assess thyroid function. A total of 2,673 participants (500 patients with hyperthyroidism, 500 patients with hypothyroidism, and 1,673 healthy people) were involved in our study. Serums TT3, TT4, FT3, and FT4 and thyrotropin (TSH) were measured with VIDAS fluorescent enzyme immunoassay. The Pearson correlation between TT3, TT4, FT3, and FT4 and TSH was determined to identify the most important indicator for thyroid function besides TSH. The correlation of TT4, and FT4 with TSH was statistically significant in healthy individuals (P < 0.01), and the R-values were -0.065 and 0.152, respectively. The correlation of TT4, FT4, TT3, and FT3 with TSH was statistically significant in patients with hyperthyroidism, and the R-values were -0.241, -0.225, -0.195, and -0.176, respectively. The correlation of TT4, FT4, TT3, and FT3 with TSH was statistically significant in patients with hypothyroidism, and the R-values were -0.322, -0.262, -0.179, and -0.136, respectively. In our opinion, TSH and FT4 are the most valuable indicators in assessing thyroid function in a healthy population, and TSH and TT4 are the most meaningful in hyperthyroidism and hypothyroidism. PMID- 25548565 TI - Computed tomography features of incidentally detected diffuse thyroid disease. AB - Objective. This study aimed to evaluate the CT features of incidentally detected DTD in the patients who underwent thyroidectomy and to assess the diagnostic accuracy of CT diagnosis. Methods. We enrolled 209 consecutive patients who received preoperative neck CT and subsequent thyroid surgery. Neck CT in each case was retrospectively investigated by a single radiologist. We evaluated the diagnostic accuracy of individual CT features and the cut-off CT criteria for detecting DTD by comparing the CT features with histopathological results. Results. Histopathological examination of the 209 cases revealed normal thyroid (n = 157), Hashimoto thyroiditis (n = 17), non-Hashimoto lymphocytic thyroiditis (n = 34), and diffuse hyperplasia (n = 1). The CT features suggestive of DTD included low attenuation, inhomogeneous attenuation, increased glandular size, lobulated margin, and inhomogeneous enhancement. ROC curve analysis revealed that CT diagnosis of DTD based on the CT classification of "3 or more" abnormal CT features was superior. When the "3 or more" CT classification was selected, the sensitivity, specificity, positive and negative predictive values, and accuracy of CT diagnosis for DTD were 55.8%, 95.5%, 80.6%, 86.7%, and 85.6%, respectively. Conclusion. Neck CT may be helpful for the detection of incidental DTD. PMID- 25548566 TI - Identification of new metabolites of bacterial transformation of indole by gas chromatography-mass spectrometry and high performance liquid chromatography. AB - Arthrobacter sp. SPG transformed indole completely in the presence of an additional carbon source. High performance liquid chromatography and gas chromatography-mass spectrometry detected indole-3-acetic acid, indole-3 glyoxylic acid, and indole-3-aldehyde as biotransformation products. This is the first report of the formation of indole-3-acetic acid, indole-3-glyoxylic acid, and indole-3-aldehyde from indole by any bacterium. PMID- 25548567 TI - Quantitation of alpha-Lactalbumin by Liquid Chromatography Tandem Mass Spectrometry in Medicinal Adjuvant Lactose. AB - Lactose is a widely used pharmaceutical excipient, sometimes irreplaceable. Traces of residual proteins left during production of lactose are potential allergen to body. The present paper describes a sensitive and specific LC-MS method for the determination of alpha-lactalbumin (alpha-La) in lactose samples. Chromatographic separation was performed on an Acquity UPLC BEH300 C18 column (2.1 * 150 mm, 1.7 MUm) with an isocratic mobile phase consisting of water containing 0.1% TFA and acetonitrile containing 0.1% TFA (80 : 20, v/v). Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an ESI interface operating in positive ionization mode. Quantitation was performed using selected ion monitoring of m/z 2364 for alpha La. The calibration curve was linear from 0.2 to 10 ug/mL. The intra- and interday precisions were less than 7.6% and the accuracy ranged from 96.4 to 104.5%. The limit of quantification (LOQ) was 0.15 ug/mL and the limit of detection (LOD) was 0.05 ug/mL. This method was then successfully applied to investigate 6 different lactose samples. The application can provide technical preparation for the development of specification of lactose. PMID- 25548568 TI - Aromatic Amines Exert Contrasting Effects on the Anticoagulant Effect of Acetaldehyde upon APTT. AB - The pharmacological effects of amphetamine, procaine, procainamide, DOPA, isoproterenol, and atenolol upon activated partial thromboplastin time in the absence and presence of acetaldehyde have been investigated. In the absence of acetaldehyde, amphetamine and isoproterenol exhibit a procoagulant effect upon activated partial thromboplastin time, whereas atenolol and procaine display anticoagulant effects upon activated partial thromboplastin time. DOPA and procainamide do not alter activated partial thromboplastin time. Premixtures of procaine with acetaldehyde produce an additive anticoagulant effect on activated partial thromboplastin time, suggesting independent action of these compounds upon clotting factors. Premixtures of amphetamine with acetaldehyde, as well as atenolol with acetaldehyde, generate a detoxication of the anticoagulant effect of acetaldehyde upon activated partial thromboplastin time. A similar statistically significant decrease in activated partial thromboplastin time is seen when procainamide is premixed with acetaldehyde for 20 minutes at room temperature. Premixtures of DOPA and isoproterenol with acetaldehyde do not affect an alteration in activated partial thromboplastin time relative to acetaldehyde alone. Hence, a selective interaction of atenolol, procaine, and amphetamine with acetaldehyde to produce detoxication of the acetaldehyde is suggested, undoubtedly due to the presence of amino, hydroxyl, or amide groups in these drugs. PMID- 25548569 TI - Nasal involvement in obstructive sleep apnea syndrome. AB - Numerous studies have reported an association between nasal obstruction and obstructive sleep apnea syndrome (OSAS), but the precise nature of this relationship remains to be clarified. This paper aimed to summarize data and theories on the role of the nose in the pathophysiology of sleep apnea as well as to discuss the benefits of surgical and medical nasal treatments. A number of pathophysiological mechanisms can potentially explain the role of nasal pathology in OSAS. These include the Starling resistor model, the unstable oral airway, the nasal ventilatory reflex, and the role of nitric oxide (NO). Pharmacological treatment presents some beneficial effects on the frequency of respiratory events and sleep architecture. Nonetheless, objective data assessing snoring and daytime sleepiness are still necessary. Nasal surgery can improve the quality of life and snoring in a select group of patients with mild OSAS and septal deviation but is not an effective treatment for OSA as such. Despite the conflicting results in the literature, it is important that patients who are not perfectly adapted to CPAP are evaluated in detail, in order to identify whether there are obstructive factors that could be surgically corrected. PMID- 25548570 TI - Pain mystery score beliefs: a comparison of fibromyalgia and rheumatoid arthritis. AB - Objectives. To compare the mysteriousness scores of the Pain Beliefs and Perceptions Inventory in fibromyalgia. Methods. Two cohorts of patients, one with fibromyalgia (FM) and one with rheumatoid arthritis (RA), completed the Mystery Scale component of the Pain Beliefs and Perceptions Inventory to determine whether subjects in the two diagnostic groups had significantly different scores on the Mystery Scale. Results. A total of 126 subjects (64 FM, 62 RA) completed all questionnaires. The FM group had a greater percentage of female subjects, more severe pain, more severe anxiety, more severe depression, and a higher perceived injustice score. When the RA and FM group scores for the Mystery Scale were adjusted for age, sex, pain severity, HADS scores, and perceived injustice scores, the FM group still had a higher Mystery Scale score. Discussion. Fibromyalgia is associated with a higher level of perception of mysteriousness in the Pain Beliefs and Perceptions Inventory than is seen with rheumatoid arthritis. This difference appears to be independent of levels of pain, depression, anxiety, and perceived injustice. This sense of mysteriousness may reflect a lack of understanding of pain in fibromyalgia as previously reported and may be an area to be addressed in therapy. PMID- 25548571 TI - Aneurysms of the P2P Segment of Posterior Cerebral Artery: Case Report and Surgical Steps. AB - The posterior cerebral artery (PCA) is divided into 4 segments: precommunicating segment (P1), postcommunicating segment (P2), quadrigeminal segment (P3), and calcarine segment (P4). Small aneurysms are more prevalent than large aneurysms in patients with ruptured aneurysms. P2 and P3 aneurysms are usually managed by the subtemporal approach. This is a case report of rupture saccular aneurysm of posterior cerebral artery on P2P segment. The authors show the surgical steps of these rare aneurysms with an illustrative case. PMID- 25548572 TI - Fecal transplantation treatment of antibiotic-induced, noninfectious colitis and long-term microbiota follow-up. AB - Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI) and is considered as a treatment for other gastrointestinal (GI) diseases. We followed up the relief of symptoms and long term, over-a-year microbiota stabilization in a 46-year-old man, who underwent FMT for antibiotic-induced, non-CDI colitis nine months after being treated for CDI by FMT. Fecal and mucosal microbiota was analyzed before the second FMT and during 14 months after FMT by using a high-throughput phylogenetic microarray. FMT resolved the symptoms and restored normal GI-function. Microbiota analysis revealed increased bacterial diversity in the rectal mucosa and a stable fecal microbiota up to three months after FMT. A number of mucosa-associated bacteria increased after FMT and some of these bacteria remained increased in feces up to 14 months. Notably, the increased bacteria included Bifidobacterium spp. and various representatives of Clostridium clusters IV and XIVa, such as Clostridium leptum, Oscillospira guillermondii, Sporobacter termitidis, Anaerotruncus colihominis, Ruminococcus callidus, R. bromii, Lachnospira pectinoschiza, and C. colinum, which are presumed to be anti-inflammatory. The presented case suggests a possible role of microbiota in restoring and maintaining normal GI functionality and improves our knowledge on the etiology of antibiotic-induced, noninfectious colitis. PMID- 25548573 TI - Current perspectives in mesenchymal stem cell therapies for osteoarthritis. AB - Osteoarthritis (OA) is a degenerative joint disease most commonly occurring in the ageing population. It is a slow progressive condition resulting in the destruction of hyaline cartilage followed by pain and reduced activity. Conventional treatments have little effects on the progression of the condition often leaving surgery as the last option. In the last 10 years tissue engineering utilising mesenchymal stem cells has been emerging as an alternative method for treating OA. Mesenchymal stem cells (MSCs) are multipotent progenitor cells found in various tissues, most commonly bone marrow and adipose tissue. MSCs are capable of differentiating into osteocytes, adipocytes, and chondrocytes. Autologous MSCs can be easily harvested and applied in treatment, but allogenic cells can also be employed. The early uses of MSCs focused on the implantations of cell rich matrixes during open surgeries, resulting in the formation of hyaline-like durable cartilage. More recently, the focus has completely shifted towards direct intra-articular injections where a great number of cells are suspended and injected into affected joints. In this review the history and early uses of MSCs in cartilage regeneration are reviewed and different approaches in current trends are explained and evaluated. PMID- 25548574 TI - Cell therapy for chemically induced ovarian failure in mice. AB - Cell therapy has been linked to an unexplained return of ovarian function and fertility in some cancer survivors. Studies modeling this in mice have shown that cells transplantation generates donor-derived oocytes in chemotherapy-treated recipients. This study was conducted to further clarify the impact of cell transplantation from different sources on female reproductive function after chemotherapy using a preclinical mouse model. Methods. Female mice were administered 7.5 mg/kg cisplatin followed by cell transplantation (one week later) using GFP+ female cell donors. For cell tracking, adipose derived stem cell GFP+ (ADSC), female germline stem cell GFP+/MVH+ (FGSC), or ovary cell suspension GFP+ mice were transplanted into cisplatin-treated wild-type recipients. After 7 or 14 days animals were killed and histological analysis, IHQ for GFP cells, and ELISA for estradiol were performed. Results. Histological examinations showed that ADSC, ovary cell suspension, and FGSC transplant increase the number of follicles with apparent normal structure in the cells recipient group euthanized on day 7. Cell tracking showed GFP+ samples 7 days after transplant. Conclusion. These data suggest that intraovarian injection of ADSCs and FGSC into mice with chemotherapy-induced ovarian failure diminished the damage caused by cisplatin. PMID- 25548575 TI - Effectiveness of Palivizumab in Preventing RSV Hospitalization in High Risk Children: A Real-World Perspective. AB - Infection with respiratory syncytial virus (RSV) is one of the major causes globally of childhood respiratory morbidity and hospitalization. Palivizumab, a humanized monoclonal antibody, has been recommended for high risk infants to prevent severe RSV-associated respiratory illness. This recommendation is based on evidence of efficacy when used under clinical trial conditions. However the real-world effectiveness of palivizumab outside of clinical trials among different patient populations is not well established. We performed a systematic review focusing on postlicensure observational studies of the protective effect of palivizumab prophylaxis for reducing RSV-associated hospitalizations in infants and children at high risk of severe infection. We searched studies published in English between 1 January 1999 and August 2013 and identified 420 articles, of which 20 met the inclusion criteria. This review supports the recommended use of palivizumab for reducing RSV-associated hospitalization rates in premature infants born at gestational age < 33 weeks and in children with chronic lung and heart diseases. Data are limited to allow commenting on the protective effect of palivizumab among other high risk children, including those with Down syndrome, cystic fibrosis, and haematological malignancy, indicating further research is warranted in these groups. PMID- 25548577 TI - Meeting highlights: the first korean breast cancer treatment consensus conference. AB - The first Korean Breast Cancer Treatment Consensus Conference Expert Panel reviewed and endorsed new evidence on aspects of local and regional therapies and diagnostic procedures that support the conservative application of results from recent clinical trials. This conference clarified the barriers that limit the application of recent clinical trial results, such as questions about level of evidence, differences between the setting of clinical trials and that of daily clinical practice, and medical necessities and environment. Detailed decisions recommended for the treatment and diagnosis, according to the from the consensus conference, are recorded including details of the votes. These recommendations differed in the degree of support for clinical consideration of disease extent and host factors, medical necessities, and environment. PMID- 25548578 TI - Anticancer Activity of Cobra Venom Polypeptide, Cytotoxin-II, against Human Breast Adenocarcinoma Cell Line (MCF-7) via the Induction of Apoptosis. AB - PURPOSE: Breast cancer is a significant health problem worldwide, accounting for a quarter of all cancer diagnoses in women. Current strategies for breast cancer treatment are not fully effective, and there is substantial interest in the identification of novel anticancer agents especially from natural products including toxins. Cytotoxins are polypeptides found in the venom of cobras and have various physiological effects. In the present study, the anticancer potential of cytotoxin-II against the human breast adenocarcinoma cell line (MCF 7) was investigated. METHODS: The cytotoxic effects of cytotoxin-II were determined by morphological analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. The mode and mechanism of cell death were investigated via acridine orange/ethidium bromide (AO/EtBr) double staining, flow cytometric analysis of cell death, detection of mitochondrial membrane potential, measurement of intracellular reactive oxygen species (ROS), annexin V/propidium iodide staining, and caspase-9 activity assays. RESULTS: The half maximal inhibitory concentration (IC50) of cytotoxin-II in MCF-7 cells was 4.18+/-1.23 ug/mL, while the value for cisplatin was approximately 28.02+/-1.87 ug/mL. Morphological analysis and AO/EtBr double staining showed typical manifestations of apoptotic cell death (in doses lower than 8 ug/mL). Dose- and time-dependent ROS generation, loss of mitochondrial membrane potential, caspase-9 activation, and cell cycle arrest were observed in their respective tests. CONCLUSION: In conclusion, cytotoxin-II has potent anticancer effects in the MCF-7 cell line, which are induced via the intrinsic pathways of apoptosis. Based on these findings, cytotoxin-II is a suitable choice for breast cancer treatment. PMID- 25548576 TI - Unique features of young age breast cancer and its management. AB - Young age breast cancer (YABC) has unique clinical and biological features that are not seen in older patients. Breast tumor biology is more aggressive and is associated with an unfavorable prognosis in younger women. The diagnosis of breast cancer is often delayed, resulting in their initial presentation with more advanced disease. Together, these characteristics lead to a poorer prognosis in younger women than in older women. Young women who receive breast-conserving therapy have a higher rate of local recurrence. Therefore, it is important to secure sufficient resection margins and consider boost radiotherapy to prevent local treatment failure. Based on age alone, patients with YABC should be regarded as high-risk cases, and they should be treated with adjuvant chemotherapy. Special considerations regarding psychosocial factors and fertility should be taken into account for young patients. This review discusses the major considerations and principles concerning the management of patients with YABC. PMID- 25548579 TI - Expression of Histone Deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in Invasive Ductal Carcinomas of the Breast. AB - PURPOSE: DNA deacetylation by histone deacetylase (HDAC) is an important mechanism involved in the oncogenic tumorigenesis of breast cancer. Previous studies have reported an association of the estrogen receptor (ER) with HDACs and demonstrated the efficacy of HDAC inhibitors for the treatment of breast cancers via in vitro experiments. In this study, we examined the association of HDAC expression with clinicopathological parameters and disease-specific survival. METHODS: Immunohistochemical (IHC) analysis of HDAC1, HDAC2, HDAC3, and HDAC6 was performed using tissue microarrays in 300 invasive ductal carcinomas. IHC scoring was determined by multiplication of the intensity (0 to 3) and the proportion (0 to 4) of staining, and we classified tumors into low- and high-HDAC expression groups. RESULTS: High expression of HDAC1 was correlated with the molecular subtype (p=0.001) and human epidermal growth factor 2 (HER2) amplification (p=0.012). High expression of HDAC6 was correlated with a younger age (p<0.001), ER expression (p=0.025), progesterone receptor expression (p=0.034), molecular subtype (p=0.023), and HER2 amplification (p=0.011). High HDAC1 expression was correlated with luminal A tumors (p=0.001), while high HDAC6 expression was more common in luminal B tumors (p=0.023). Although the expression of HDACs did not exhibit prognostic significance in the entire cohort, high expression of HDAC1 and HDAC6 was associated with improved overall survival (OS) in patients with ER positive tumors (p=0.017 and p=0.029, respectively), and high expression of HDAC2 was correlated with improved OS in ER-negative tumors (p=0.048) on univariate analysis. Furthermore, high HDAC6 expression was associated with improved disease free survival (p=0.048) on multivariate analysis. CONCLUSION: HDAC1 expression is significantly correlated with the molecular subtypes of tumors, with the highest expression being observed in luminal A tumors. HDAC6 is a significantly correlated with ER expression and the molecular subtype, thereby supporting the estrogen regulatory property of HDAC6. HDAC1 and HDAC6 expression are good prognostic factors for ER-positive tumors. PMID- 25548580 TI - Transient receptor potential vanilloid 1 expression and functionality in mcf-7 cells: a preliminary investigation. AB - PURPOSE: Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel belonging to the transient receptor potential family, and it is expressed in different neoplastic tissues. Its activation is associated with regulation of cancer growth and progression. The aim of this research was to study the expression and pharmacological characteristics of TRPV1 in cells derived from human breast cancer MCF-7 cells. METHODS: TRPV1 presence was assessed by binding studies and Western blotting. Receptor binding characteristics were evaluated through competition assays, while 3-(4,5 dimethylthiazol-2-yl)-2,5,-dipheyltetrazolium bromide reduction assays were performed to confirm an early hypothesis regarding the modulation of cancer cell proliferation. The functionality of TRPV1 was evaluated by measuring Ca(2+) uptake in the presence of increasing concentrations of TRPV1 agonists and antagonists. RESULTS: Binding studies identified a single class of TRPV1 (Bmax 1,492+/-192 fmol/mg protein), and Western blot showed a signal at 100 kDa corresponding to the molecular weight of human TRPV1. Among the different tested agonists and antagonists, anandamide (Ki: 2.8*10(-11) M) and 5 iodoresiniferatoxin (5-I-RTX) (Ki: 5.6*10(-11) M) showed the highest degrees of affinity for TRPV1, respectively. All tested TRPV1 agonists and antagonists caused a significant (p<0.05) decrease in cell growth rate in MCF-7 cells. For agonists and antagonists, the efficacy of tested compounds displayed the following rank order: resiniferatoxin>anandamide>capsaicin and 5-I RTX=capsazepine, respectively. CONCLUSION: These data indicate that both TRPV1 agonists and antagonists induce significant inhibition of MCF-7 cell growth. Even though the mechanisms involved in the antiproliferative effects of TRPV1 agonists and antagonists should be further investigated, it has been suggested that agonists cause desensitization of the receptor, leading to alteration in Ca(2+) influx regulation. By contrast, antagonists cause a functional block of the receptor with consequent fatal dysregulation of cell homeostasis. PMID- 25548581 TI - Outcomes of palliative weekly low-dose gemcitabine-Cisplatin chemotherapy in anthracycline- and taxane- pretreated metastatic breast cancer patients. AB - PURPOSE: The combination of gemcitabine and cisplatin (GP) has been shown to be safe and efficacious for patients with metastatic breast cancer (MBC), pretreated with anthracyclines and taxanes. We assessed the efficacy and safety of weekly low-dose GP in patients with MBC. METHODS: We collected clinicopathological data from MBC patients who had been treated with gemcitabine, 800 mg/m(2) plus cisplatin, 30 mg/m(2) intravenously, on days 1 and 8 every 3 weeks, between January 2001 and November 2011 in Korea. RESULTS: The analysis included 294 patients previously treated anthracycline-xand taxane-based chemotherapies prior to GP (median age, 48 years [range, 28-78 years]; median follow-up duration, 63.9 months). Seventeen patients (5.8%) discontinued GP because of toxicities. The median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI], 3.394.4 months) and the median overall survival (OS) was 27.7 months (95% CI, 17.6-37.8 months) months. Statistically significant factors for PFS were performance status (Eastern Cooperative Oncology Group, >=2 vs. <2; hazard ratio [HR], 1.37; 95% CI, 1.02-1.85; p=0.037), distant disease-free interval (DDFI; <=2 years vs. >2 years; HR, 1.66; 95% CI, 1.28-1.95, p<0.001), time interval from the diagnosis of metastasis to GP therapy (<=1 year vs. >1 year; HR, 1.48; 95% CI, 1.13-1.95, p<0.001), and presence of brain metastasis (HR, 1.47; 95% CI, 1.03 2.10; p=0.031). Similarly, DDFI (<=2 years vs. >2 years; HR, 2.07; 95% CI, 1.36 3.14; p<0.001) and the presence of brain metastasis (HR, 2.14; 95% CI, 1.27-3.61; p=0.004) were important factors for OS after GP treatment. CONCLUSION: Weekly low dose GP chemotherapy appears safe and effective for heavily pretreated MBC patients. PMID- 25548582 TI - A Phase II Trial of Neoadjuvant Chemotherapy with Genexol(r) (Paclitaxel) and Epirubicin for Locally Advanced Breast Cancer. AB - PURPOSE: Neoadjuvant chemotherapy (NC) is yet to be established as the definitive treatment regimen for locally advanced breast cancer (LABC). The aim of this study was to determine the efficacy and toxicity of NC with epirubicin and paclitaxel. METHODS: Between March 2007 and January 2009, 50 patients with LABC were enrolled in an open-label, phase II, multicenter study carried out at five distinct institutions. All patients were scheduled to receive four cycles of 60 mg/m(2) epirubicin and 175 mg/m(2) paclitaxel every 3 weeks, preoperatively, unless they developed profound side effects or disease progression. After curative surgery, two additional cycles of chemotherapy were administered to patients who had shown a positive response to NC. RESULTS: In all, 196 cycles of chemotherapy were administered preoperatively; 47 of the 50 patients (94%) underwent all four cycles of designated treatment. Complete disappearance of invasive foci of the primary tumor, and negative axillary lymph nodes were confirmed in eight patients (16.0%), post operation. The cumulative 5-year disease-free survival rate was 70.0% for patients with complete remission (CR) and partial remission (PR), and 33.3% for patients with stable disease (SD) and progressive disease (PD) (p=0.018). The cumulative 5-year overall survival was 90.0% for patients who achieved CR and PR and 55.6% for patients who had SD and PD (p=0.001). Neutropenia (42.0%) was the most common grade 3/4 toxicity. However, none of the toxicities resulted in cessation of the treatment. CONCLUSION: The encouraging pathologic response observed in the patients treated with epirubicin plus paclitaxel NC in this study suggests that epirubicin could be a substitute for doxorubicin, which is the most cardiotoxic agent. PMID- 25548583 TI - Survival benefit of zoledronic Acid in postmenopausal breast cancer patients receiving aromatase inhibitors. AB - PURPOSE: A growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors. METHODS: Between January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines. RESULTS: The baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99). CONCLUSION: Our findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment. PMID- 25548584 TI - Safety and tolerability of docetaxel, cyclophosphamide, and trastuzumab compared to standard trastuzumab-based chemotherapy regimens for early-stage human epidermal growth factor receptor 2-positive breast cancer. AB - PURPOSE: We evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared to the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCaH). METHODS: We retrospectively reviewed early stage, resectable, HER2-positive breast cancer patients treated with trastuzumab based chemotherapy at a single comprehensive cancer center between 2004 and 2011. Patient characteristics, comorbidities, relative dose intensity (RDI) of each regimen, tolerability, and cardiac toxicity were evaluated. RESULTS: One hundred seventy-seven patients were included in the study (AC-TH, n=114; TCaH, n=39; TCyH, n=24). TCyH was solely administered in the adjuvant setting, whereas two thirds of the AC-TH and TCaH groups were administered postoperatively. Patients treated with TCyH tended to have a more significant underlying cardiac history, higher Charlson comorbidity index, and were of an earlier stage. All patients treated with TCyH received granulocyte colony stimulating factor primary prophylaxis. No febrile neutropenia or grade >=3 hematologic toxicity was observed in the TCyH group as compared to the AC-TH and TCaH groups. There were no significant differences in the rates of early termination, hospitalization, dose reduction, or RDI between the regimens. The symptomatic congestive heart failure rate between AC-TH, TCaH, and TCyH groups was not significantly different (4.4% vs. 2.6% vs. 8.3%, respectively, p=0.57). There was also no significant difference in the rate of early trastuzumab termination between patients treated with each regimen. CONCLUSION: TCyH is well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab-containing regimens. Larger clinical trials are necessary to support the wider use of TCyH as an adjuvant regimen. PMID- 25548585 TI - Risk of trastuzumab-related cardiotoxicity in early breast cancer patients: a prospective observational study. AB - PURPOSE: In the present study, we investigated the incidence of cardiotoxicity within 5 years of trastuzumab treatment and evaluated potential risk factors in clinical practice. METHODS: The study cohort included 415 patients diagnosed with early breast cancer (EBC). Cardiotoxicity incidence was evaluated in patients receiving trastuzumab and those who did not. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals of potential risk factors for trastuzumab-related cardiotoxicity after appropriate adjustments. RESULTS: Incidence of cardiotoxicity in patients treated with trastuzumab was significantly higher than that in controls (23.7% vs. 10.8%, p<0.001). This result was adjusted for factors that might increase the risk of cardiotoxicity, such as history of coronary artery diseases or the use of anthracyclines for more than four cycles. CONCLUSION: Our findings indicated that treatment with trastuzumab was strongly associated with cardiotoxicity in EBC patients. PMID- 25548586 TI - Subtype is a predictive factor of nonsentinel lymph node involvement in sentinel node-positive breast cancer patients. AB - PURPOSE: This study aimed to identify the effect of breast cancer subtype on nonsentinel lymph node (NSLN) metastasis in patients with a positive sentinel lymph node (SLN). METHODS: The records of 104 early breast cancer patients with a positive SLN between April 2009 and September 2013 were retrospectively evaluated. All patients underwent axillary lymph node dissection. The effects of the tumor subtype (luminal A, luminal/HER2+, human epidermal growth factor receptor 2 [HER2] overexpression, and triple-negative) and other clinicopathological factors on NSLN metastasis were examined by univariate and multivariate statistical analyses. RESULTS: Fifty of 104 patients (48%) exhibited NSLN metastasis. Univariate and multivariate analyses revealed that tumor size and the ratio of positive SLNs were significant risk factors of NSLN metastasis in patients with a positive SLN. The rate of NSLN metastasis was higher in patients with luminal/HER2+ and HER2 overexpression subtypes than that in patients with other subtypes in the univariate analysis (p<0.001). In the multivariate analysis, both patients with luminal/HER2+ (p<0.006) and patients with HER2 overexpression (p<0.031) subtypes had a higher risk of NSLN metastasis than patients with the luminal A subtype. CONCLUSION: Subtype classification should be considered as an independent factor when evaluating the risk of NSLN metastasis in patients with a positive SLN. This result supports the development of new nomograms including breast cancer subtype to increase predictive accuracy. PMID- 25548587 TI - Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients. AB - PURPOSE: We aimed to determine the rate of pathological complete response (pCR), clinicopathological factors associated with pCR, and clinical outcomes following neoadjuvant chemotherapy in locally advanced breast cancer. METHODS: Medical records of patients who had undergone neoadjuvant chemotherapy for breast cancer between January 2007 and September 2011 were retrospectively reviewed, and the pCR rates were calculated according to three sets of criteria: the National Surgical Adjuvant Breast and Bowel Project (NSABP), the MD Anderson Cancer Center (MDACC), and the German Breast Group (GBG). Tumors were classified as luminal A like, luminal B like, human epidermal growth factor receptor 2 (HER2), or triple negative. pCR and clinical outcome, including overall survival (OS) and disease free survival (DFS) rates were analyzed at the median follow-up of 54.2 months. RESULTS: Of a total of 179 patients who had received neoadjuvant chemotherapy, 167 patients (93.3%) had locally advanced breast cancer and 12 patients (6.7%) had early-stage breast cancer. The majority of patients (152 patients, 89.4%) received anthracycline-based neoadjuvant chemotherapy. The objective clinical response rate was 61.5%, comprising clinical partial response in 5.5% and clinical complete response in 3.9% of patients. Twenty-one (11.7%), 20 (11.2%), and 17 patients (9.5%) achieved pCR according to NSABP, MDACC, and GBG definitions, respectively. pCR rates, as defined by NSABP, according to breast cancer subtype were 4.4%, 9.7%, 24.2%, and 19.2% in luminal A like, luminal B like, HER2, and triple-negative subtypes, respectively. Patients who achieved pCR had significantly better DFS (5-year DFS rates, 80% vs. 53%, p=0.030) and OS (5 year OS rates, 86% vs. 54%, p=0.042) than those who did not. CONCLUSION: The pCR rate following neoadjuvant chemotherapy for breast cancer in Thai women attending our institution was 11.7%; pCR was more frequently observed in HER2 and triple negative breast tumor subtypes. Patients who achieved pCR had significantly improved survival. PMID- 25548588 TI - Magnetic resonance imaging and clinicopathological factors for the detection of occult nipple involvement in breast cancer patients. AB - PURPOSE: Nipple sparing mastectomy provides good cosmetic results and low local recurrence rates for breast cancer patients. However, there is a potential risk of leaving an occult tumor within the nipple, which could lead to cancer relapse and poor prognosis for the patient. The objective of this study was to investigate the occult nipple involvement rate in mastectomy specimens, and to identify preoperative magnetic resonance imaging (MRI) findings and the clinicopathological characteristics of the primary tumor that may correlate with nipple invasion. METHODS: Four hundred sixty-six consecutive mastectomy samples with grossly unremarkable nipples were evaluated. Demographic and clinicopathological data were collected. Nipple involvement was evaluated using serial histological sections. The tumor size and tumor-nipple distance were measured using preoperative MRI images. RESULTS: Thirty-six of the 466 therapeutic mastectomy specimens (7.7%) were found to have occult nipple involvement. In univariate analysis, tumor size, tumor-nipple distance, lymph node status, p53 mutation, and lymphovascular invasion (LVI) were found to influence the likelihood of nipple involvement. Multivariate logistic regression analysis, adjusted by lymph node status, p53 mutation, and LVI, showed that tumor size and tumor-nipple distance were predictive factors indicating nipple involvement. With regard to tumor location, only tumors in the central area of the breast showed a significant association with nipple involvement. CONCLUSION: In this study, a statistically significant association was found between occult nipple involvement and tumor size, tumor-nipple distance, axillary lymph node status, LVI, and p53 mutation. A cutoff point of 2.2 cm for tumor size and 2 cm for tumor-nipple distance could be used as parameters to predict occult nipple involvement. PMID- 25548589 TI - Ductal carcinoma arising from ectopic breast tissue following microcalcification observed on screening mammography: a case report and review of the literature. AB - Ectopic breast tissue can occur anywhere along the incompletely regressed mammary ridge. Among the various types of breast choristoma, ectopic breast tissue, which has only glandular tissue without a nipple or areola, is most commonly detected in axillary areas. However, ectopic breast cancer is often not detected until significant clinical symptoms have been revealed, or diagnosis is delayed. Furthermore, an examination of ectopic breast tissue tends to be omitted from a screening mammography. Especially, the microcalcifications of ectopic breast tissue are difficult to delineate on mammography. Herein, the authors report a case of ectopic breast carcinoma that showed clustered microcalcifications on screening mammography, and discuss the interpretation and implications of microcalcification in ectopic breast tissue. PMID- 25548590 TI - Multiple Symmetric Lipomatosis (Madelung's Disease) Presenting as Bilateral Huge Gynecomastia. AB - Multiple symmetric lipomatosis (MSL), or Madelung's disease, is a rare disease of unknown etiology. It is characterized by the presence of loose adipose tissue deposits localized in the cervical region and upper body. MSL presenting as bilateral huge gynecomastia is an extremely rare phenomenon. The present report describes a case of MSL in a 66-year-old man. The patients presented with bilateral breast bulging. He had a history of cigarette and alcohol use. His condition was treated with a bilateral nipple-sparing mastectomy. MSL can present as a form of gynecomastia, for its accurate diagnosis and proper treatment of MSL, increasing awareness of the clinical characteristics of the disease is required, especially amongst breast surgeons. Herein, we review the literature and discuss the clinical characteristics, pathology, and surgical treatment of MSL. PMID- 25548591 TI - Ethyl Acetate Extract from Celastrus aculeatus Merr. Suppresses Synovial Inflammation in Adjuvant Arthritis Rats through Apoptosis Induction of CD4(+)CD25(+)FOXP3(+) T Cells. AB - Celastrus aculeatus Merr. has been widely used in traditional Chinese medicine to treat rheumatoid arthritis (RA) in clinic. However, the main active fraction of this plant is still unclear. In this study, we attempted to evaluate the suppressive effect of ethyl acetate extract (EAE) from Celastrus aculeatus Merr. on synovial inflammation in adjuvant arthritis (AA) rats induced by Mycobacterium tuberculosis H37Ra (Mtb) and to explore the underlying mechanisms. SD rats immunized with heat-killed Mtb were fed with EAE and observed for erythema, swelling, and induration of each paw. The pathologic changes in joint synovium were tested by hematoxylin-eosin staining. Apoptosis induction of synoviocytes was tested immunohistochemically. Apoptosis of peripheral lymphocytes and the level of regulatory T cells were analyzed by flow cytometry. After treatment with EAE, the joint inflammation in rats with AA was alleviated. Both apoptotic ratios of synoviocytes and peripheral lymphocytes and the ratio of CD4(+)CD25(+)FOXP3(+) to CD4 regulatory T cells were significantly increased. In summary, we first demonstrated that EAE of Celastrus aculeatus Merr. can inhibit synovial inflammation in AA rats through apoptosis induction of CD4(+)CD25(+)FOXP3(+) T cells. Our study provides a rationale for the application of Celastrus aculeatus Merr. to treat RA. PMID- 25548592 TI - Tetrahydrobiopterin improves endothelial function in cardiovascular disease: a systematic review. AB - Background. Tetrahydrobiopterin (BH4) is a cofactor of nitric oxide synthase (NOS). Nitric oxide (NO) bioavailability is reduced during the early stage of vascular diseases, such as coronary artery disease, hypercholesterolemia, hypertension, and diabetic vasculopathy, and even throughout the entire progression of atherosclerosis. Methods. A literature search was performed using electronic databases (up to January 31, 2014), including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), using an established strategy. Results. Fourteen articles were selected with a total of 370 patients. Ten of the fourteen studies showed a significant improvement in the endothelial dysfunction of various cardiovascular disease groups with BH4 supplementation compared with the control groups or placebos. Three studies showed no positive outcome, and one study showed that low-dose BH4 had no effect but that high-dose BH4 did have a significantly different result. Conclusions. This review concludes that supplementation with BH4 and/or augmentation of the endogenous levels of BH4 will be a novel approach to improve the endothelial dysfunction observed in various cardiovascular diseases. BH4 might be considered to be a new therapeutic agent to prevent the initiation and progression of cardiovascular disease. PMID- 25548593 TI - Circulating MicroRNA Profiles Differ between Qi-Stagnation and Qi-Deficiency in Coronary Heart Disease Patients with Blood Stasis Syndrome. AB - We compared the circulating microRNA profiles of Qi-stagnation (QSB) and Qi deficiency (QDB) in coronary heart disease (CHD) patients with blood stasis syndrome. Twenty-nine CHD patients were divided into QSB group and QDB group. The analysis was carried out through comparing their circulating microRNA profiles and the following bioinformatics analysis. The number of differential miRNAs in QDB group was much more than that in QSB group. Functional annotations of the differentially expressed miRNAs target genes in the QSB group and QDB group were, respectively, related to regulation of cellular component organization, regulation of glucose metabolic process, and so forth and protein kinase cascade, phosphate metabolic process, and so forth. KEGG pathway analysis showed that the process Qi-deficiency was associated with phagocytosis including endocytosis and mTOR signaling pathway. Specifically, pathway of cell adhesion molecules played the crucial role in the pathological process of Qi-stagnation, with a unique upregulation except for pathways associated with cancer signal. MicroRNA-gene-net analysis indicated that let-7c, miR-4487, miR-619, miR-8075, miR-6735, and miR-32 5p and miR-17-5p, miR-130a, and miR 320 family had the most important and extensive regulatory function for Qi-stagnation syndromes and Qi-deficiency syndromes, respectively. Differentially expressed miRNAs and concerned pathways suggest different molecular mechanisms that may mediate the pathological process of QSB and QDB syndromes. PMID- 25548594 TI - Acupuncture for refractory epilepsy: role of thalamus. AB - Neurostimulation procedures like vagus nerve stimulation (VNS) and deep brain stimulation have been used to treat refractory epilepsy and other neurological disorders. While holding promise, they are invasive interventions with serious complications and adverse effects. Moreover, their efficacies are modest with less seizure free. Acupuncture is a simple, safe, and effective traditional healing modality for a wide range of diseases including pain and epilepsy. Thalamus takes critical role in sensory transmission and is highly involved in epilepsy genesis particularly the absence epilepsy. Considering thalamus serves as a convergent structure for both acupuncture and VNS and the thalamic neuronal activities can be modulated by acupuncture, we propose that acupuncture could be a promising therapy or at least a screening tool to select suitable candidates for those invasive modalities in the management of refractory epilepsy. PMID- 25548595 TI - Effect of integrated cognitive therapy on hippocampal functional connectivity patterns in stroke patients with cognitive dysfunction: a resting-state FMRI study. AB - Objective. This study aimed to identify abnormal hippocampal functional connectivity (FC) following ischemic stroke using resting-state fMRI. We also explored whether abnormal hippocampal FC could be modulated by integrated cognitive therapy and tested whether these alterations were associated with cognitive performance. Methods. 18 right-handed cognitively impaired ischemic stroke patients and 18 healty control (HC) subjects were included in this study. Stroke subjects were scanned at baseline and after integrated cognitive therapy, while HCs were only scanned at baseline, to identify regions that show significant correlations with the seed region. Behavioral and cognitive assessments were obtained before each scan. Results. During the resting state, we found abnormal hippocampal FC associated with temporal regions, insular cortex, cerebellum, and prefrontal cortex in stroke patients compared to HCs. After integrated cognitive therapy, however, the stroke group showed increased hippocampal FC mainly located in the prefrontal gyrus and the default mode network (DMN). Altered hippocampal FC was associated with cognitive improvement. Conclusion. Resting-state fMRI may provide novel insight into the study of functional networks in the brain after stroke. Furthermore, altered hippocampal FC may be a compensatory mechanism for cognitive recovery after ischemic stroke. PMID- 25548596 TI - Current pre-hospital traumatic brain injury management in China. AB - BACKGROUND: Traumatic brain injury (TBI) is associated with most trauma-related deaths. Secondary brain injury is the leading cause of in-hospital deaths after traumatic brain injury. By early prevention and slowing of the initial pathophysiological mechanism of secondary brain injury, pre-hospital service can significantly reduce case-fatality rates of TBI. In China, the incidence of TBI is increasing and the proportion of severe TBI is much higher than that in other countries. The objective of this paper is to review the pre-hospital management of TBI in China. DATA SOURCES: A literature search was conducted in January 2014 using the China National Knowledge Infrastructure (CNKI). Articles on the assessment and treatment of TBI in pre-hospital settings practiced by Chinese doctors were identified. The information on the assessment and treatment of hypoxemia, hypotension, and brain herniation was extracted from the identified articles. RESULTS: Of the 471 articles identified, 65 met the selection criteria. The existing literature indicated that current practices of pre-hospital TBI management in China were sub-optimal and varied considerably across different regions. CONCLUSION: Since pre-hospital care is the weakest part of Chinese emergency care, appropriate training programs on pre-hospital TBI management are urgently needed in China. PMID- 25548597 TI - Emergency bedside ultrasound for the diagnosis of pediatric intussusception: a retrospective review. AB - BACKGROUND: Ultrasound diagnosis of pediatric intussusception is feasible with limited operator training. The authors report the test characteristics of bedside ultrasound (BUS) for the diagnosis of pediatric intussusception at a single institution. METHODS: Inclusion criteria were: 1) patients of 0-18 years old were seen in the pediatric emergency department (ED) with a clinical presentation suspicious for intussusception; 2) BUS was performed to identify intussusception and bedside impression documented in the medical record; 3) a "formal" diagnostic study (such as computed tomography, ultrasound, or barium enema) was performed by the radiology department after BUS was completed. Electronic medical record and ED BUS archive were screened for potentially eligible ED visits between January 1(st) 2009 to October 3(rd) 2012. These records were then reviewed to identify patients for inclusion in the study. All emergency physicians who performed the BUS had undergone a minimum of 1-hour didactic training on the use of BUS to diagnose pediatric intussusception. RESULTS: A total of 1 631 charts were reviewed, with 49 meeting inclusion criteria. Five of those were later excluded for incomplete documentation or lack of saved BUS images. The prevalence of intussusception was 23%. The mean age of the subjects was 31 months. BUS was 100% sensitive (95%CI 66%-100%) and 94% specific (95%CI 79%-99%) for detection of pediatric intussusception compared to radiology study results. Positive and negative likelihood ratios were 16.5 (95%CI 4.30%-63.21%) and 0 (95%CI 0-0) respectively. CONCLUSIONS: BUS is an accurate means of diagnosing acute intussusception in pediatric patients. Further study might be indicated to confirm such benefits. PMID- 25548598 TI - How to secure the connection between thoracostomy tube and drainage system? AB - BACKGROUND: Thoracostomy tube insertion is one of the common bedside procedures in emergency medicine and many acute specialties. Dislodgement of thoracostomy tube from the connection tube of chest drainage system is an important problem with potential complications such as contamination, infection and pneumothorax. Besides, mere loosening can also lead to malfunction. It is a common practice to tape the connection of the system. This study aimed to evaluate the materials and methods of connection of chest drain system to minimize drainage dislodgement. METHODS: We conducted an experimental study to assess the tightness of the connection with various taping materials and methods. We selected three commonly used adhesive materials (3MTM TransporeTM Medical tape, 3MTM MicroporeTM Medical tape, 3MTM Soft Cloth Tape on Liner) and three different methods (cross method, straight method, nylon band) to secure the junction between the thoracostomy tube and the bi-conical adaptor in the drainage system. The measured outcome was the weight causing visible loosening of the junction between thoracotomy tube and the adaptor. RESULTS: For each taping material and taping method, 10 trials were performed. The median weight required to disconnect the junction is 26.22 lb for TransporeTM, 31.29 lb for MicroporeTM and 32.44 lb for Soft Cloth Tape on Liner. A smaller force was required to disconnect if TransporeTM is used (P<0.001). There was no statistical significant difference between MicroporeTM and Soft Cloth Tape on Liner (P=0.98). The median disconnecting force is 32.44 lb for straight taping method, 40.55 lb for cross taping method and 21.15 lb for plastic band. The cross-taping method was the more secure method (P<0.0001 when compared with plastic band) (P=0.033 when compared with straight method). CONCLUSION: Cross-taping is the most secure method among the tested varieties in connecting the thoracostomy tube to the chest drainage system. TransporeTM is not a recommended material for thoracostomy tube taping. PMID- 25548599 TI - Clinical probability and risk analysis of patients with suspected pulmonary embolism. AB - BACKGROUND: Pulmonary embolism (PE) is one of the most frequent diseases that could be missed in overcrowded emergency departments as in Turkey. Early and accurate diagnosis could decrease the mortality rate and this standard algorithm should be defined. This study is to find the accurate, fast, non-invasive, cost effective, easy-to-access diagnostic tests, clinical scoring systems and the patients who should be tested for clinical diagnosis of PE in emergency department. METHODS: One hundred and forty patients admitted to the emergency department with the final diagnosis of PE regarding to anamnesis, physical examination and risk factors, were included in this prospective, cross-sectional study. The patients with a diagnosis of pulmonary embolism, acute coronary syndrome or infection and chronic obstructive pulmonary disease (COPD) were excluded from the study. The demographics, risk factors, radiological findings, vital signs, symptoms, physical-laboratory findings, diagnostic tests and clinical scoring systems of patients (Wells and Geneva) were noted. The diagnostic criteria for pulmonary emboli were: filling defect in the pulmonary artery lumen on spiral computed tomographic angiography and perfusion defect on perfusion scintigraphy. RESULTS: Totally, 90 (64%) of the patients had PE. Age, hypotension, having deep vein thrombosis were the risk factors, and oxygen saturation, shock index, BNP, troponin and fibrinogen levels as for the biochemical parameters were significantly different between the PE (+) and PE (-) groups (P<0.05). The Wells scoring system was more successful than the other scoring systems. CONCLUSION: Biochemical parameters, clinical findings, and scoring systems, when used altogether, can contribute to the diagnosis of PE. PMID- 25548600 TI - Thyroid hormone alterations in trauma patients requiring massive transfusion: An observational study. AB - BACKGROUND: Although non-thyroidal illness syndrome (NTIS) is considered a negative prognostic factor, the alterations in free triiodothyronine (fT3) levels in trauma patients requiring massive transfusion have not been reported. METHODS: A prospective observational study comparing 2 groups of trauma patients was conducted. Group M comprised trauma patients requiring massive transfusions (>10 units of packed red blood cells) within 24 hours of emergency admission. Group C comprised patients with an injury severity score >9 but not requiring massive transfusions. Levels of fT3, free thyroxine (fT4), and thyroid-stimulating hormone (TSH) were evaluated on admission and on days 1, 2, and 7 after admission. The clinical backgrounds and variables measured including total transfusion amounts were compared and the inter-group prognosis was evaluated. Results are presented as mean+/-standard deviation. RESULTS: Nineteen patients were enrolled in each group. In both groups, 32 were men, and the mean age was 50+/-24 years. In group C one patient died from respiratory failure. The initial fT3 levels in group M (1.95+/-0.37 pg/mL) were significantly lower than those in group C (2.49+/-0.72 pg/mL; P<0.01) and remained low until 1 week after admission. Initial inter-group fT4 and TSH levels were not significantly different. TSH levels at 1 week (1.99+/-1.64 uIU/mL) were higher than at admission (1.48+/-0.5 uIU/mL) in group C (P<0.05). CONCLUSION: Typical NTIS was observed in trauma patients requiring massive transfusions. When initial resuscitation achieved circulatory stabilization, prognosis was not strongly associated with NTIS. PMID- 25548601 TI - A single subcutaneous dose of tramadol for mild to moderate musculoskeletal trauma in the emergency department. AB - BACKGROUND: Mild to moderate musculoskeletal trauma is a common cause for an emergency room visit, and frequent pain is one of the cardinal symptoms of consultation. The objective of this study is to assess the perception of a single subcutaneous dose of 50 mg tramadol for pain management in patients with mild to moderate musculoskeletal trauma, likewise to appraise the perception of pain by subcutaneous injection. METHODS: A total of 77 patients, who met inclusion criteria, received a single subcutaneous dose of tramadol. Pain control was evaluated based on the verbal numerical pain scale (0-10) at baseline, 20 and 60 minutes; similarly, pain perception was evaluated secondary to subcutaneous injection of the analgesic. RESULTS: On admission, the average pain perceived by patients was 8; twenty minutes later, 89% of the patients reported five or less, and after sixty minutes, 94% had three or less on the verbal numerical pain scale. Of the patients, 88% reported pain perception by verbal numeric scale of 3 or less by injection of the drug, and 6.5% required a second analgesic for pain control. Two events with drug administration (soft tissue infection and mild abdominal rectus injection) were reported. CONCLUSION: We conclude that a single subcutaneous dose of tramadol is a safe and effective option for the management of patients with mild to moderate pain and musculoskeletal disease in the emergency department. PMID- 25548602 TI - The incidence of oxygen desaturation during rapid sequence induction and intubation. AB - BACKGROUND: Rapid sequence induction and intubation (RSII) is an emergency airway management technique for patients with a risk of pulmonary aspiration. It involves preoxygenation, administration of predetermined doses of induction and paralytic drugs, avoidance of mask ventilation, and laryngoscopy followed by tracheal intubation and keeping cricoid pressure applied till endotracheal tube cuff be inflated. Oxygen desaturation has been seen during RSII. We assessed the incidence of oxygen desaturation during RSII. METHODS: An institution-based observational study was conducted from March 3 to May 4, 2014 in our hospital. All patients who were operated upon under general anesthesia with RSII during the study period were included. A checklist was prepared for data collection. RESULTS: A total of 153 patients were included in this study with a response rate of 91.6%. Appropriate drugs for RSII, equipments for RSII, equipments for difficult intubation, suction machine with a catheter, a monitor and an oxygen backup such as ambu bag were not prepared for 41 (26.8%), 50 (32.7%), 51 (33.3%), 38 (24.8%) and 25 (16.3%) patients respectively. Cricoid pressure was not applied at all for 17 (11.1%) patients and 53 (34.6%) patients were ventilated after induction of anesthesia but before intubation and endotracheal cuff inflation. A total of 55 (35.9%) patients desaturated during RSII (SPO2<95%). The minimum, maximum and mean oxygen desaturations were 26%, 94% and 70.9% respectively. The oxygen desaturation was in the range of <50%, 50%-64%, 65%-74%, 75%-84%, 85%-89 % and 90%-94% for 6 (3.9%), 7 (4.6%), 5 (3.3%), 10 (6.5%), 13 (8.5%) and 14 (9.2%) patients respectively. CONCLUSION: The incidence of oxygen desaturation during RSII was high in our hospital. Preoperative patient optimization and training about the techniques of RSII should be emphasized. PMID- 25548603 TI - Heat-related illness in Jinshan District of Shanghai: A retrospective analysis of 70 patients. AB - BACKGROUND: This study aimed to investigate the epidemiological and clinical characteristics of patients with heat-related illness, and guide the prevention, diagnosis and treatment of heat-related illness. METHODS: From June 2013 to August 2013, seventy patients with heat-related illness were treated at Jinshan Hospital of Fudan University, and their epidemiological characteristics, laboratory results, treatment and prognosis were retrospectively analyzed. RESULTS: In the 70 patients, 18 patients suffered from heat stroke and 52 patients from non-heat stroke. When the environmnent temperature was above 35 degrees C, the body temperature of the patients began to increase markedly. The patients with heat stroke were significantly older than those with non-heat stroke (P<0.05). The body temperature, heart rate, blood glucose, blood lactate dehydrogenase and blood creatine kinase in the patients with heat stroke were higher than those in the patients with non-heat stroke (P<0.05). Blood lactate dehydrogenase and blood creatine kinase were positively correlated with body temperature (r=0.801). CONCLUSION: When the environmental temperature goes above 35 degrees C, heat-related illness should be prevented, especially in the elderly. The body temperature, heart rate, blood glucose, blood lactate dehydrogenase and blood creatine kinase in patients with heat stroke are higher than those in patients with non-heat stroke. Blood lactate dehydrogenase and blood creatine kinase are positively correlated with body temperature, but their relationship with heat-related illness awaits further study. PMID- 25548604 TI - Simvastatin inhibits apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. AB - BACKGROUND: Many studies have showed that apoptosis of endothelial cells plays a curial role in the progress of sepsis. But the role of simvastatin in apoptosis of endothelial cells induced by sepsis is not clear. The present study aimed to investigate the role of simvastatin in apoptosis of endothelial cells induced by sepsis and its mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) were randomly divided into three groups: control group, sepsis serum intervention group (sepsis group) and simvastatin+sepsis serum intervention group (simvastatin group). After 24-hour incubation with corresponding culture medium, the relative growth rate of HUVECS in different groups was detected by MTT assay; the apoptosis of HUVECs was detected by Hoechst33258 assay and flow cytometry; and the expression of the Bcl-2 and Bax genes of HUVECs was detected by PCR. RESULTS: Compared with the sepsis group, HUVECs in the simvastatin group had a higher relative growth rate. Apoptotic HUVECs decreased significantly in the simvastatin group in comparison with the sepsis group. Expression of the Bcl-2 gene in HUVECs decreased obviously, but the expression of the Bax gene increased obviously after 24-hour incubation with sepsis serum; however, the expression of the Bcl-2 and Bax genes was just the opposite in the simvastatin group. CONCLUSIONS: Our study suggests that simvastatin can inhibit apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. It may be one of the mechanisms for simvastatin to treat sepsis. PMID- 25548605 TI - Effects of mild hypothermia on the ROS and expression of caspase-3 mRNA and LC3 of hippocampus nerve cells in rats after cardiopulmonary resuscitation. AB - BACKGROUND: Cardiac arrest (CA) is a common and serious event in emergency medicine. Despite recent improvements in resuscitation techniques, the survival rate of patients with CA is unchanged. The present study was undertaken to observe the effect of mild hypothermia (MH) on the reactive oxygen species (ROS) and the effect of neurological function and related mechanisms. METHODS: Sixty five healthy male Sprague Dawley (SD) adult rats were randomly (random number) divided into 2 groups: blank control group (n=5) and CPR group (n=60). CA was induced by asphyxia. The surviving rats were randomly (random number) divided into two groups: normothermia CPR group (NT) and hypothermia CPR group (HT). Normothermia of 37 degrees C was maintained in the NT group after return of spontaneous circulation (ROSC), hypothermal intervention of 32 degrees C was carried out in the HT group for 4 hours immediately after ROSC. Both the NT and HT groups were then randomly divided into 2 subgroups 12 hours and 24 hours after ROSC (NT-12, NT-24, HT-12, HT-24 subgroups). During observation, the neurological deficit scores (NDSs) was recorded, then the bilateral hippocampi were obtained from rats' head, and monoplast suspension of fresh hippocampus tissue was made immediately to determine the level of intracellular ROS by flow cytometry. Transmission electron microscope was used to observe the ultramicro changes of cellular nucleus and mitochondria. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression of caspase-3 mRNA, and western-blotting (WB) was used to determine the level of LC3 in frozen hippocampus tissue. Measured data were analyzed with paired sample t test and One Way ANOVA. RESULTS: Of 60 rats with CA, 44 (73%) were successfully resuscitated and 33 (55%) survived until the end of the experiment. The NDSs of rats in the NT and HT groups were more significantly reduced than those in the BC group (F=8.107, P<0.05), whereas the NDSs of rats in the HT-12 and HT-24 subgroups were significantly increased in comparison with those NDSs of rats in the NT-12 and NT 24 subgroups, respectively (t=9.692, P<0.001; t=14.374, P<0.001). The ROS in hippocampus nerve cells in the NT and HT groups significantly increased compared to the BC group (F=16.824, P<0.05), whereas the ROS in the HT-12 and HT-24 subgroups significantly reduced compared with that ROS in the NT-12 and NT-24 subgroups, respectively (t=9.836, P<0.001; t=7.499, P<0.001). The expression of caspase-3 mRNA in hippocampus nerve cells in the NT and HT groups were significantly increased compared to the BC group (F=24.527, P<0.05), whereas the expression of caspase-3 mRNA in rats of the HT-12 and HT-24 subgroups was significantly reduced compared to the NT-12 and NT-24 subgroups, respectively (t=6.935, P<0.001; t=4.317, P<0.001). The expression of LC3B-II/I in hippocampus nerve cells of rats in the NT and HT groups significantly increased compared to the BC group (F=6.584, P<0.05), whereas the expression of LC3B-II/I in rats of the HT-12 and HT-24 subgroups significantly reduced compared to the NT-12 and NT 24 subgroups, respectively (t=10.836, P<0.001; t=2.653, P=0.02). Ultrastructure damage of nucleus and mitochondria in the NT group was more evident than in the BC group, and eumorphism of nucleus and mitochondria were maintained in rats of the HT group compared with the NT group. CONCLUSION: Mild hypothermia lessened the injury of nerve cells and improved the neurological function of rats that survived from cardiac arrest by reducing the ROS production of nerve cells and inhibiting the expression of caspase-3 mRNA and LC3, leading to cellular apoptosis and massive autophagy in rats that survived from cardiac arrest after CPR. PMID- 25548606 TI - A man with a fracture from minor trauma. AB - BACKGROUND: We commonly encounter fractures secondary to trauma on and off in our daily practice. While it is not uncommon to see fractures due to underlying pathology, we need to be on the alert when patients present atypically because the treatment for pathological fractures is far different from that for simple fractures. METHODS: We presented a case of left clavicle fracture secondary to minor trauma, in which the initial X-ray shows suspicious lesion around the fracture site and further investigation reveals multiple myeloma. The patient received treatment at the clinical oncology department upon diagnosis. Since he was relatively young and fit, he was started on the induction therapy of VTD, which was followed by high dose melphalan and autologous stem cell transplant. RESULTS: He is currently free from symptoms and on maintenance thalidomide. CONCLUSIONS: Though multiple myeloma is not commonly encountered in emergency practice, earlier identification of relatively subtle symptoms can allow early treatment. Missing this diagnosis will delay treatment and produce severe outcome to the patient. We should be on the alert for such important condition. PMID- 25548607 TI - A minimally invasive multiple percutaneous drainage technique for acute necrotizing pancreatitis. AB - BACKGROUND: In approximately 20% of patients, necrotizing pancreatitis is complicated with severe acute pancreatitis, with high morbidity and mortality rates. Minimally invasive step-up approach is both safe and effective, but sometimes requires multiple access sites. METHODS: A 62-year-old woman was admitted with diabetic ketoacidosis, and initial computed tomography (CT) revealed no evidence of acute pancreatitis. She was clinically improved with insulin therapy, fluid administration, and electrolyte replacement. However, on the 14(th) day of admission, she developed a high-grade fever, and CT demonstrated evidence of acute necrotizing pancreatitis with a large collection of peripancreatic fluid. Percutaneous transgastric drainage was performed and a 14 French gauge (Fr) pigtail catheter was placed 1 week later, which drained copious pus. Because of persistent high-grade fever and poor clinical improvement, multiple 8 and 10 Fr pigtail catheters were placed via the initial drainage route, allowing the safe and effective drainage of the extensive necrotic tissue that was occupying the bilateral anterior pararenal space. RESULTS: After drainage, the patient recovered well and the last catheter was removed on day 123 of admission. CONCLUSIONS: Multiple percutaneous drainage requires both careful judgment and specialist skills. The perforation of the colon and small bowel as well as the injury of the kidney and major vessels can occur. The current technique appears to be safe and minimally invasive compared with other drainage methods in patients with extended, infected necrotic pancreatic pseudocysts. PMID- 25548608 TI - Intrathoracic esophagojejunostomy using OrVilTM for gastric adenocarcinoma involving the esophagus. AB - AIM: To demonstrate a new surgical technique of lower mediastinal lymphadenectomy and intrathoracic anastomosis of esophagojejunostomy using OrVilTM. METHODS: After a total median phrenotomy, the supradiaphragmatic and lower thoracic paraesophageal lymph nodes were transhiatally dissected. The esophagus was cut off using a liner stapler and OrVilTMwas inserted. Finally, end-to-side esophagojejunostomy was created by using a circular stapler. From July 2009, we adopted this surgical technique for five patients with gastric cancer involving the lower esophagus. RESULTS: The median operation time was 314 min (range; 210 367 min), and median blood loss was 210 mL (range; 100-838 mL). The median numbers of dissected lower mediastinal nodes were 3 (range; 1-10). None of the patients had postoperative complications including anastomotic leakage and stenosis. The median hospital stay was 16 d (range: 15-20 d). The median length of esophageal involvement was 14 mm (range: 6-48 mm) and that of the resected esophagus was 40 mm (range: 35-55 mm); all resected specimens had tumor-free margins. CONCLUSION: This surgical technique is easy and safe intrathoracic anastomosis for the patients with gastric adenocarcinoma involving the lower esophagus. PMID- 25548609 TI - Systematic review of absorbable vs non-absorbable sutures used for the closure of surgical incisions. AB - AIM: To report a systematic review of published randomized controlled trials (RCTs) investigating the role of absorbable suture (AS) against non-AS (NAS) used for the closure of surgical incisions. METHODS: RCTs investigating the use of AS vs NAS for the closure of surgical incisions were statistically analysed based upon the principles of meta-analysis and the summated outcomes were represented as OR. RESULTS: The systematic search of medical literature yielded 10 RCTs on 1354 patients. Prevalence of wound infection (OR = 0.97; 95%CI: 0.56, 1.69; Z = 0.11; P = 0.92) and operative morbidity (P = 0.45) was comparable in both groups. Nonetheless, the use of AS lead to lower risk of wound break-down (OR = 0.12; 95%CI: 0.04, 0.39; Z = 3.52; P < 0.0004). CONCLUSION: This meta-analysis of 10 RCTs demonstrates that the use of AS is similar to NAS for skin closure for surgical site infection and other operative morbidities. AS do not increase the risk of skin wound dehiscence, rather lead to a reduced risk of wound dehiscence compared to NAS. PMID- 25548611 TI - Case of bronchoesophageal fistula with gastric perforation due to multidrug resistant tuberculosis. AB - Gastric perforation and tuberculous bronchoesophageal fistula (TBEF) are very rare complications of extrapulmonary tuberculosis (TB). We present a case of pulmonary TB with TBEF and gastric perforation caused by a multidrug-resistant tuberculosis strain in a non-acquired immune deficiency syndrome male patient. The patient underwent total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy and feeding jejunostomy during intravenous treatment with anti-TB medication, and esophageal reconstruction with colonic interposition and jejunocolostomy were performed successfully after a full course of anti-TB medication. Though recent therapies for TBEF have favored medication, patients with severe stenosis or perforation require surgery and medication with anti-TB drugs based upon adequate culture and drug susceptibility testing. PMID- 25548610 TI - Inflammatory pseudotumour of the spleen associated with splenic tuberculosis. AB - Inflammatory pseudotumor (IPT) of the spleen is an uncommon entity with an uncertain aetiology. Inflammatory pseudotumors present diagnostic difficulties because the clinical and radiological findings tend to suggest a malignancy. The symptoms include weight loss, fever, and abdominal pain. Most cases of splenic IPT present solitary relatively large well circumscribed masses on imaging. The diagnosis in the majority of the cases is made after histopathologic study of splenectomy specimens. The IPTs that occur in the spleen and liver are typically associated with Epstein-Barr virus. Thirty-seven percent of all new cases of active tuberculosis infection are extrapulmonary tuberculosis and tuberculous lymphadenitis the most commonly occurring form of extrapulmonary tuberculosis. We report the case of an inflammatory pseudotumor of the spleen associated with splenic tuberculous lymphadenitis in a 50-year-old female patient who was preoperatively diagnosed with a malignant spleen tumour based on her history of breast of carcinoma. PMID- 25548612 TI - Etiology of bicuspid aortic valve disease: Focus on hemodynamics. AB - The bicuspid aortic valve (BAV) is the most common form of inheritable cardiac defect. Although this abnormality may still achieve normal valvular function, it is often associated with secondary valvular and aortic complications such as calcific aortic valve disease and aortic dilation. The clinical significance and economic burden of BAV disease justify the need for improved clinical guidelines and more robust therapeutic modalities, which address the root-cause of those pathologies. Unfortunately, the etiology of BAV valvulopathy and aortopathy is still a debated issue. While the BAV anatomy and its secondary complications have been linked historically to a common genetic root, recent advances in medical imaging have demonstrated the existence of altered hemodynamics near BAV leaflets prone to calcification and BAV aortic regions vulnerable to dilation. The abnormal mechanical stresses imposed by the BAV on its leaflets and on the aortic wall could be transduced into cell-mediated processes, leading ultimately to valvular calcification and aortic medial degeneration. Despite increasing evidence for this hemodynamic etiology, the demonstration of the involvement of mechanical abnormalities in the pathogenesis of BAV disease requires the investigation of causality between the blood flow environment imposed on the leaflets and the aortic wall and the local biology, which has been lacking to date. This editorial discusses the different hypothetical etiologies of BAV disease with a particular focus on the most recent advances in cardiovascular imaging, flow characterization techniques and tissue culture methodologies that have provided new evidence in support of the hemodynamic theory. PMID- 25548613 TI - Arrhythmogenic right ventricular cardiomyopathy: From genetics to diagnostic and therapeutic challenges. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disease characterized by myocyte loss and fibro-fatty tissue replacement. Diagnosis of ARVC remains a clinical challenge mainly at its early stages and in patients with minimal echocardiographic right ventricular (RV) abnormalities. ARVC shares some common features with other cardiac diseases, such as RV outflow ventricular tachycardia, Brugada syndrome, and myocarditis, due to arrhythmic expressivity and biventricular involvement. The identification of ARVC can be often challenging, because of the heterogeneous clinical presentation, highly variable intra- and inter-family expressivity and incomplete penetrance. This genotype phenotype "plasticity" is largely unexplained. A familial history of ARVC is present in 30% to 50% of cases, and the disease is considered a genetic cardiomyopathy, usually inherited in an autosomal dominant pattern with variable penetrance and expressivity; in addition, autosomal recessive forms have been reported (Naxos disease and Carvajal syndrome). Diagnosis of ARVC relays on a scoring system, with major or minor criteria on the Revised Task Force Criteria. Implantable cardioverter defibrillators (ICDs) are increasingly utilized in patients with ARVC who have survived sudden death (SD) (secondary prevention). However, there are few data available to help identifying ARVC patients in whom the prophylactic implantation of an ICD is truly warranted. Prevention of SD is the primary goal of management. Pharmacologic treatment of arrhythmias, catheter ablation of ventricular tachycardia, and ICD are the mainstay of treatment of ARVC. PMID- 25548614 TI - Experimental models of inherited cardiomyopathy and its therapeutics. AB - Cardiomyopathy is a disease of myocardium categorized into three major forms, hypertrophic (HCM), dilated (DCM) and restrictive cardiomyopathy (RCM), which has recently been demonstrated to be a monogenic disease due to mutations in various proteins expressed in cardiomyocytes. Mutations in HCM and RCM typically increase the myofilament sensitivity to cytoplasmic Ca(2+), leading to systolic hyperfunction and diastolic dysfunction. In contrast, mutations in DCM typically decrease the myofilament sensitivity to cytoplasmic Ca(2+) and/or force generation/transmission, leading to systolic dysfunction. Creation of genetically manipulated transgenic and knock-in animals expressing mutant proteins exogenously and endogenously, respectively, in their hearts provides valuable animal models to discover the molecular and cellular mechanisms for pathogenesis and promising therapeutic strategy in vivo. Recently, cardiomyocytes have been differentiated from patient's induced pluripotent stem cells as a model of inherited cardiomyopathies in vitro. In this review, we provide overview of experimental models of cardiomyopathies with a focus on revealed molecular and cellular pathogenic mechanisms and potential therapeutics. PMID- 25548615 TI - Arginine vasopressin as a target in the treatment of acute heart failure. AB - Congestive heart failure (CHF) is one of the most common reasons for hospitalization in the United States. Despite multiple different beneficial medications for the treatment of chronic CHF, there are no therapies with a demonstrated mortality benefit in the treatment of acute decompensated heart failure. In fact, studies of inotropes used in this setting have demonstrated more harm than good. Arginine vasopressin has been shown to be up regulated in CHF. When bound to the V1a and/or V2 receptors, vasopressin causes vasoconstriction, left ventricular remodeling and free water reabsorption. Recently, two drugs have been approved for use that antagonize these receptors. Studies thus far have indicated that these medications, while effective at aquaresis (free water removal), are safe and not associated with increased morbidity such as renal failure and arrhythmias. Both conivaptan and tolvaptan have been approved for the treatment of euvolemic and hypervolemic hyponatremia. We review the results of these studies in patients with heart failure. PMID- 25548617 TI - Cardiac resynchronization therapy: Dire need for targeted left ventricular lead placement and optimal device programming. AB - Cardiac resynchronization therapy (CRT) effected via biventricular pacing has been established as prime therapy for heart failure patients of New York Heart Association functional class II, III and ambulatory IV, reduced left ventricular (LV) function, and a widened QRS complex. CRT has been shown to improve symptoms, LV function, hospitalization rates, and survival. In order to maximize the benefit from CRT and reduce the number of non-responders, consideration should be given to target the optimal site for LV lead implantation away from myocardial scar and close to the latest LV site activation; and also to appropriately program the device paying particular attention to optimal atrioventricular and interventricular intervals. We herein review current data related to both optimal LV lead placement and device programming and their effects on CRT clinical outcomes. PMID- 25548616 TI - Implications of Klotho in vascular health and disease. AB - Cardiovascular disease (CVD) is a prevalent condition in general population and the first cause of death overall. Klotho, a pleiotropic protein related to longevity that acts as a co-receptor of the fibroblast growth factor 23, has been proposed as a key regulator of the development of CVD. In the few clinical studies made, it has been observed a relationship between low levels of soluble Klotho and the occurrence and severity of CVD, as well as a reduction of cardiovascular risk when they are high. Also, different polymorphisms of human Klotho gene have been related to the incidence of cardiovascular events. Moreover, several experimental studies indicate that this protein acts in the maintenance of vascular homeostasis. Klotho improves endothelial dysfunction through promotion of NO production and mediates anti-inflammatory and anti-aging effects such as suppression of adhesion molecules expression, attenuation of nuclear factor-kappa B or inhibition of Wnt signaling. Furthermore, this protein is related to the attenuation of vascular calcification as well as prevention of cardiac hypertrophy. The expression of this protein in the vascular wall implies a new scenario for the treatment of vascular disorders. The purpose of this review is to provide an overview of the relationship between the Klotho protein and CVD, in addition to its role in the maintenance of functional vascular integrity. PMID- 25548619 TI - Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome. AB - Polycystic ovary syndrome is characterized by ovulatory dysfunction, androgen excess and polycystic ovaries and is associated with hypertension, diabetes, metabolic syndrome and cardiovascular events. Oral contraceptives constitute first-line treatment, particularly when symptomatic hyperandrogenism is present. However, these drugs are associated with cardiovascular events and hypersensitivity reactions that pose problem in differential diagnosis and therapy. We present a 14 year-old female with polycystic ovary syndrome taking oral contraceptive and suffering from recurrent coronary ischemic attacks with increased eosinophils, and troponin levels suggesting Kounis syndrome. PMID- 25548618 TI - Complicated Whipple's disease and endocarditis following tumor necrosis factor inhibitors. AB - AIM: To test whether treatment with tumor necrosis factor inhibitors (TNFI) is associated with complications of Tropheryma whipplei (T. whipplei) infection. METHODS: Because unexplained arthritis is often the first Whipple's disease (WD) symptom, patients may undergo treatment with TNFI before diagnosis. This may influence the course of infection with T. whipplei, which causes WD, because host immune defects contribute to the pathogenesis of WD. A literature search and cross referencing identified 19 reports of TNFI treatment prior to WD diagnosis. This case-control study compared clinical data in patients receiving TNFI therapy (group I, n = 41) with patients not receiving TNFI therapy (group II, n = 61). Patients from large reviews served as controls (group III, n = 1059). RESULTS: The rate of endocarditis in patient group I was significantly higher than in patient group II (12.2% in group I vs 1.6% in group II, P < 0.05), and group III (12.2% in group I vs 0.16% in group III, P < 0.01). Other, severe systemic or local WD complications such as pericarditis, fever or specific organ manifestations were increased also in group I as compared to the other patient groups. However, diarrhea and weight loss were somewhat less frequent in patient group I. WD is typically diagnosed with duodenal biopsy and periodic acid Schiff (PAS) staining. PAS-stain as standard diagnostic test had a very high percentage of false negative results (diagnostic failure in 63.6% of cases) in group I. Polymerase chain reaction (PCR) for T. whipplei was more accurate than PAS stainings (diagnostic accuracy, rate of true positive tests 90.9% for PCR vs 36.4% for PAS, P < 0.01). CONCLUSION: TNFI trigger severe WD complications, particularly endocarditis, and lead to false-negative PAS-tests. In case of TNFI treatment failure, infection with T. whipplei should be considered. PMID- 25548620 TI - Spontaneous coronary artery dissection as a cause of myocardial infarction. AB - Spontaneous coronary artery dissection (SCAD) is a rare disease that is usually seen in young women in left descending coronary artery and result in events like sudden cardiac death and acute myocardial infarction. A 70-year-old man was admitted to the emergency department with chest pain which started 1 h ago during a relative's funeral. The initial electrocardiography demonstrated 2 mm ST segment depression in leads V1-V3 and the patient underwent emergent coronary angiography. SCAD simultaneously in two different coronary arteries [left anterior descending (LAD) artery and left circumflex (LCx)] artery was detected and SCAD in LCx artery was causing total occlusion which resulted in acute myocardial infarction. Successful stenting was performed thereafter for both lesions. In addition to the existence of SCAD simultaneously in two different coronary arteries, the presence of muscular bridge and SCAD together at the same site of the LAD artery was another interesting point which made us report this case. PMID- 25548621 TI - Clinical Case Reports in mental health: the need for nuance and context. PMID- 25548622 TI - Vulval cancer and HPV vaccination in recurrent disease. AB - KEY CLINICAL MESSAGE: A woman diagnosed with a recurrent vulval carcinoma after initial treatment with radiochemotherapy is presented. After three additional relapses she was vaccinated with Gardasil. She has had no relapses in her vulvar area for 39 months and an overall progression-free survival of almost 24 months. PMID- 25548623 TI - Herniorrhaphy: an unusual cause of ureteral injury in Nigeria. AB - KEY CLINICAL MESSAGE: Herniorrhaphy is a common surgery worldwide. Common complications include hemorrhage, infection, chronic pain, and recurrence. Ureteric injury from herniorrhaphy is unusual. We present a case of ureteric injury complicating an inguinal herniorrhaphy for a huge right inguino-scrotal hernia. Patient had primary uretero-neocystostomy but died from septicemia in the postoperative period. PMID- 25548624 TI - Skinfold over toenail is pathognomonic for the popliteal pterygium syndrome in a Congolese family with large intrafamilial variability. AB - KEY CLINICAL MESSAGE: We report on three related Congolese popliteal pterygium syndrome (PPS) patients concordant only for the skinfold over the toenail. Mutation analysis revealed that the three affected individuals carried a heterozygous missense mutation in the Exon 4, NM_006147.2:c.250C>T; p.Arg84Cys. This is the first molecularly confirmed PPS family from central Africa. PMID- 25548625 TI - Giant left-sided inguinoscrotal hernia containing the cecum and appendix (giant left-sided Amyand's hernia). AB - KEY CLINICAL MESSAGE: The present case involved a 62-year-old male with a large left-sided inguinoscrotal hernia. A CT scan and a clinical examination led to a diagnosis of a giant left-sided Amyand's hernia. The hernia was repaired using the ULTRAPRO Hernia System (UHS), and the patient exhibited an uneventful postoperative course. PMID- 25548626 TI - Significance of pharmaceutical excipients in prescribed medicines: a case report. AB - KEY CLINICAL MESSAGE: Pharmaceutical excipients need careful observation as they play a significant role in treatment outcomes. It is imperative for a physician to collect complete patient profile before prescribing new medications for current treatment. We present a case report on the significance of pharmaceutical excipients in prescribed medicines. PMID- 25548627 TI - Placenta percreta managed by transverse uterine fundal incision with retrograde cesarean hysterectomy: a novel surgical approach. AB - KEY CLINICAL MESSAGE: Placenta percreta (with bladder invasion) is a rare obstetric condition with the risk of massive intraoperative hemorrhage. In these cases, the combination of a transverse uterine fundal incision and retrograde cesarean hysterectomy could be useful to minimize maternal hemorrhage and avoid severe bladder injury. PMID- 25548628 TI - Natural history of chronic myelomonocytic leukemia: gene sequencing identifies multiple clonal molecular abnormalities associated with rapid progression to acute myeloid leukemia. AB - KEY CLINICAL MESSAGE: Gene panel sequencing in a CMML patient without any detectable genetic abnormality by conventional genetic studies identified four concurrent somatic mutations in three genes. Gene panel mutation analysis is a rapidly emerging clinical tool to demonstrate the clonality in hematologic malignancies, and to identify the potential targets for therapy. PMID- 25548629 TI - Umbilical vein thrombosis: to deliver or not to deliver at the time of diagnosis? AB - KEY CLINICAL MESSAGE: Umbilical vein thrombosis is a rare anomaly with high mortality that frequently occurs in association with fetomaternal conditions. The unfavorable outcome of our case highlights the need for consensus on severity criteria, including the percentage of vascular occlusion determined by power Doppler, in order to improve outcome. PMID- 25548630 TI - Oral infection control to assist infliximab therapy in a Behcet's disease patient with severe eye inflammation in response to dental treatment: a case report. AB - KEY CLINICAL MESSAGE: We report a case of Behcet's disease which was aggravated by psychological stress and oral infection. The control of oral infection under medical and dental collaboration is important for providing Behcet's disease patients with the optimal medical care and for facilitating the relief of the primary disease. PMID- 25548631 TI - Transcatheter CoreValve valve-in-valve implantation in a stentless porcine aortic valve for severe aortic regurgitation. AB - KEY CLINICAL MESSAGE: We describe the first valve-in-valve Corevalve transcatheter aortic valve replacement in the St. Jude Toronto stentless porcine aortic valve in the United States, which enabled this 59-year-old patient with a history of bacterial endocarditis and aortic regurgitation to avoid heart transplant with complete resolution of his severe left ventricular dysfunction. PMID- 25548632 TI - Gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection: a case report. AB - It has been suggested that vitamin C deficiency/scurvy is associated with gingival inflammatory changes; however, the disorder is very infrequently encountered in the modern era. Here, we report a case of extensive gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection. PMID- 25548633 TI - Induced negative pressure proposed as a new method for diagnosing hepatic hydrothorax involving minor leaks. AB - KEY CLINICAL MESSAGE: Hepatic hydrothorax is known as pleural effusion of hepatic origin, and is difficult to diagnose. We herein report the novel strategy combining radioisotope scintigraphy with chest drainage to definitively diagnose hepatic hydrothorax of an 85-year-old patient which would have been missed with conventional diagnostic methods. PMID- 25548634 TI - Two interstitial rearrangements (16q deletion and 17p duplication) in a child with MR/MCA. AB - KEY CLINICAL MEASSAGE: Patients with rare deletions in 16q12 and a duplication of 17p, both interstitial and de novo. Only seven cases have been described with these deletions and none of them presented other chromosomal abnormalities. The proband showed a complex phenotype with features found in patients with dup17p11.2 syndrome, deletions in 16q12. PMID- 25548635 TI - Reiter's syndrome and hearing loss: a possible association? AB - KEY CLINICAL MESSAGE: Patient complained of hearing loss and tinnitus after the onset of Reiter's syndrome. Audiometry confirmed the hearing loss on the left ear; blood work showed increased erythrocyte sedimentation rate and C3 fraction of the complement. Genotyping for HLA-B27 was positive. Treatment with prednisolone did not improve the hearing levels. PMID- 25548636 TI - Melanoma of the gallbladder: appropriate surgical management and review of the literature. AB - KEY CLINICAL MESSAGE: Melanomas of the gallbladder (GB) are extremely rare with a very poor prognosis. They feature in the literature as a few case reports and the method of their management is not clear. We report a case of patient with metastatic cutaneous melanoma to the GB, and our treatment suggestion. PMID- 25548637 TI - Aplastic anemia associated with systemic lupus erythematosus in children - case report and review of the literature. AB - KEY CLINICAL MESSAGE: Systemic lupus erythematosus should be included in the differential diagnosis of every adolescent with pancytopenia. An accurate diagnosis with the appropriate therapy is vital and can cause lasting reversal of this condition. Systemic lupus erythematosus should be included in the differential diagnosis of every adolescent with pancytopenia. An accurate diagnosis with the appropriate therapy is vital and can cause lasting reversal of this condition. PMID- 25548638 TI - An interesting case of primary squamous cell carcinoma of the colon with synchronous metastatic adenocarcinoma. AB - KEY CLINICAL MESSAGE: We present a case of primary squamous cell carcinoma of the colon with synchronous metastatic adenocarcinoma. This case highlights the poor prognosis of these late presenting cancers. Furthermore, the unusual dual pathology raises questions about its potential etiology. PMID- 25548639 TI - Phenotypic variation of autosomal recessive pseudohypoaldosteronism type I: a case in point. AB - KEY CLINICAL MASSAGE: We present a 27-month-old male infant with pseudohypoaldosteronism, with two novel alpha-subunits, epithelial sodium channel (ENaC) mutations. Despite the presence of the ENaC in the lungs, kidneys, and exocrine glands, he continues to only have renal and exocrine involvement, stressing differential effects of the mutation in each organ. PMID- 25548640 TI - First case of pulmonary tuberculosis and visceral leishmaniasis coinfection successfully treated with antituberculosis drug and liposomal amphotericin B. AB - KEY CLINICAL MESSAGE: Successful management of cases with visceral leishmaniasis (VL) and tuberculosis is a challenge for clinicians, because a guideline for that is currently unavailable. We report the first case in Bangladesh who developed VL during her treatment for pulmonary tuberculosis and was treated successfully with multidose liposomal amhptericin B for VL. PMID- 25548641 TI - De novo acute myeloid leukemia with monocytoid blasts and erythrophagocytosis. AB - KEY CLINICAL MESSAGE: Acute myeloid leukemia (AML) with t(8:16) is an infrequent acute leukemia subtype. It can occur de novo or more frequently therapy-related. The presence of blasts with monocytoid morphology and erythrophagocytosis suggest the presence of the t(8;16). PMID- 25548642 TI - A case of feverish neutropenia. AB - KEY CLINICAL MESSAGE: A case of feverish benign neutropenia occurring in a diabetic patient receiving pregabalin for peripheral neuropathy is reported. Although pregabalin-induced neutropenia is very rare, it is important to keep in mind that this drug like other anticonvulsants used for neuropathic pain, can cause severe neutropenia. PMID- 25548643 TI - Snapshots in surgery: small bowel intussusception following ileojejunal bypass. AB - KEY CLINICAL MESSAGE: Jejunal intussusception is a known complication of ileojejunal bypass surgery for obesity that may present as an acute abdomen. It can be avoided if the jejunum is anchored to the transverse mesocolon intra operatively. PMID- 25548644 TI - Itch itch with not a wink of sleep. AB - KEY CLINICAL MESSAGE: A 55-year-old man of dark complexion presented with multiple extensive swellings over the chest, right upper arm, and left shoulder for 10 years. Swellings were hyperpigmented, firm, and intensely pruritic especially over the chest region. The swellings progressed in size, extended, and developed satellite lesions over its 10 years history. PMID- 25548646 TI - Association between sexual health and delivery mode. AB - INTRODUCTION: Female sexual function changes considerably during pregnancy and the postpartum period. In addition, women's physical and mental health, endocrine secretion, and internal and external genitalia vary during these times. However, there are limited studies on the relationship between delivery and sexual function. AIM: The present study aimed to demonstrate the association between sexual function and delivery mode. METHODS: Mothers who delivered a single baby at term were recruited for the study, and 435 mothers were analyzed. MAIN OUTCOME MEASURES: The Female Sexual Function Questionnaire (SFQ28) scores and mothers' backgrounds were assessed at 6 months after delivery. RESULTS: The delivery mode affected the SFQ28 partner domain. Episiotomy affected the arousal (sensation) domain. Multiple regression analysis revealed that maternal age and cesarean section were significantly associated with several SHQ28 domains. CONCLUSION: This study suggests that routine episiotomies at delivery should be avoided to improve postpartum maternal sexual function. Maternal age and cesarean section were found to affect postpartum sexual health. PMID- 25548647 TI - Sexual Function before and after Total Hip Replacement: Narrative Review. AB - BACKGROUND: More than 1 million total hip replacements (THRs) are performed every year worldwide. Achieving decreased pain, increased mobility, and improved quality of life (QoL) are key factors in the decision to undergo THR. Sexual activity is a valued component of QoL; however, little is known about how THR affects sexual functioning or the extent to which health care providers address sexuality in THR patients. AIM: The aim of the study was to assess the literature regarding sexuality and sexual function in patients before and after THR. METHODS: PubMed, Google Scholar, and PEDro databases were searched without search limitations from inception until December 2013 for terms relating to sexual function and THR. RESULTS: Sexual activity before and after a THR is an important QoL issue. In patients with end-stage hip osteoarthritis, THR has been reported to have beneficial effects in restoring sexual satisfaction and performance. While research has recently been conducted to determine the range of motion of the hip joints necessary to execute certain sexual positions, there remains a lack of validated guidelines and the risks related to sexual activity after THR is rarely discussed between patients and medical staff. CONCLUSIONS: The ability to move comfortably is included among the many physical and psychosocial factors influencing sexual functioning. Practitioners should be encouraged to question their THR patients about sexual concerns and to provide counseling related to physical and functional aspects of sexual activity. Rehabilitation that focuses specifically on activities of daily living of sex should include sexual counseling, therapeutic exercise, and advice regarding sexual positions. Rehabilitation provided by physical therapists may help decrease pain, and facilitate greater self-awareness, self-confidence, and improved body image, all of which encourage and affirm optimal sexual health. Meiri R, Rosenbaum TY, and Kalichman L. Sexual function before and after total hip replacement: Narrative review. PMID- 25548649 TI - Suprapubic cystostomy for the management of urethral injuries during penile prosthesis implantation. AB - INTRODUCTION: Urethral injury is an uncommon surgical complication of penile prosthesis (PP) surgery. Conventional dogma requires abortion of the procedure if the adjacent corporal body is involved or delayed implantation to avert device infection associated with urinary extravasation. Besides the setback of the aborted surgery, this management approach also presents the possible difficulty of encountering corporal fibrosis at the time of reoperation. AIM: We report an approach using primary urethral repair and temporary suprapubic cystostomy for the management of incidental urethral injuries in a cohort of patients allowing for successful completion of unaborted PP implantation. MATERIALS AND METHODS: We performed a retrospective analysis of all patients receiving PPs from 1990 to 2014 in which incidental urethral injuries were repaired and PP implantation was completed with suprapubic cystostomy (suprapubic tube [SPT] insertion). After allowing for urethral healing and urinary diversion via SPT for 4-8 weeks, the PP was activated. MAIN OUTCOME MEASURES: Successful management was determined by the absence of perioperative complications within 6 months of implantation. RESULTS: We identified four cases, all receiving inflatable PPs, managed with temporary suprapubic cystostomy. These patients sustained urethral injuries during corporal dissection (one patient), corporal dilation (one patient), and penile straightening (two patients). All patients were managed safely and successfully. CONCLUSION: Primary urethral repair followed by temporary suprapubic cystostomy offers a surgical approach to complete PP implantation successfully in patients who sustain urethral injury complications, particularly for complex PP surgeries. Anele UA, Le BV, and Burnett AL. Suprapubic cystostomy for the management of urethral injuries during penile prosthesis implantation. PMID- 25548648 TI - Psychosexual Symptoms and Treatment of Peyronie's Disease Within a Collaborative Care Model. AB - INTRODUCTION: Peyronie's disease (PD) can be emotionally and sexually debilitating for patients and may negatively impact partner relationships. AIMS: This study aims to present an ongoing collaborative care model for patients with PD and to discuss the critical need for integration of patient care among sexual medicine physicians and mental health practitioners or sex therapists. METHODS: PubMed searches using the terms "Peyronie's disease" and "natural history," "treatment," "psychosexual," "depression," "relationship," and "partner" were conducted. Expert opinion based on review of the relevant published literature and clinical experience was used to identify meaningful treatment targets for patients with PD within a collaborative care model. MAIN OUTCOME MEASURE: Characteristics of PD, medical treatment, and important assessment and treatment targets, including physical, emotional, psychosexual, and relationship concerns, from peer-reviewed published literature and clinical experience. RESULTS: PD can result in significant patient and partner distress and relationship disruption. Sex therapy interventions may be directed at acute emotional, psychosexual, and relationship problems that occur during the initial diagnosis of PD, the period following minimally invasive or surgical treatment for PD, or recurring problems over the lifelong course of the disease. Sex therapy to improve self-acceptance, learn new forms of sexual intimacy, and improve communication with partners provides comprehensive treatment targeting emotional, psychosexual, and relationship distress. Ongoing communication between the mental health practitioner and physician working with the patient with PD about key assessments, treatment targets, and treatment responses is necessary for coordinated treatment planning and patient care. CONCLUSIONS: Men with PD are more likely now than in the past to see both a sexual medicine physician and a mental health practitioner or sex therapist, and the integration of assessments and treatment planning is essential for optimal patient outcomes. PMID- 25548650 TI - Superficial dorsal vein injury/thrombosis presenting as false penile fracture requiring dorsal venous ligation. AB - INTRODUCTION: Conditions mimicking penile fracture are extremely rare and have been seldom described. AIM: To describe a patient with false penile fracture who presented with superficial dorsal vein injury/thrombosis managed with ligation. METHODS: A 33-year-old male presented with penile swelling and ecchymosis after intercourse. A penile ultrasound demonstrated a thrombosed superficial dorsal vein but also questionable fracture of the tunica albuginea. As the thrombus was expanding, he was emergently taken to the operating room for exploration and required only dorsal venous ligation. RESULTS: Postoperatively, patient's Sexual Health Inventory for Men score was 23, and he had no issues with erections or sexual intercourse. CONCLUSION: Early exploration of patients with suspected penile fracture provides excellent results with maintenance of erectile function. Also, in the setting of dorsal vein thrombosis, ligation preserves the integrity of the penile tissues and avoids unnecessary complications from conservative management. Rafiei A, Hakky TS, Martinez D, Parker J, and Carrion R. Superficial dorsal vein injury/thrombosis presenting as false penile fracture requiring dorsal venous ligation. PMID- 25548653 TI - Torsion of epiploic appendix presenting as acute pancreatitis. AB - Epiploic appendagitis is a little-diagnosed condition capable of mimicking various pathologies. Here, we present a case presenting as acute pancreatitis. PMID- 25548652 TI - A panel of DNA methylation markers reveals extensive methylation in histologically benign prostate biopsy cores from cancer patients. AB - BACKGROUND: Men with a negative first prostate biopsy will undergo one or more additional biopsies if they remain at high suspicion of prostate cancer. To date, there are no diagnostic tests capable of identifying patients at risk for a positive diagnosis with the predictive power needed to eliminate unnecessary repeat biopsies. Efforts to develop clinical tests using the epigenetic signature of cores recovered from first biopsies have been limited to a few markers and lack the sensitivity and specificity needed for widespread clinical adoption. METHODS: We developed methylation-specific quantitative polymerase chain reaction assays for a panel of 24 markers that are preferentially methylated in prostate cancer. We modified the bisulfite conversion conditions to allow the integration of the methylation information from multiple markers. We determined the methylation status of the 24 markers in 213 prostate biopsy cores from 104 patients, 37 prostate cancer patients and 67 controls. We performed logistic regression on combinations of markers as well as the entire panel of 24 markers to identify the best candidates for a diagnostic test. RESULTS: The marker panel differentiated between cancer cores and benign cores from non-cancer patients with 100% sensitivity and 97% specificity. Furthermore, the panel detected significant methylation in benign cores from prostate cancer patients that was not present in controls. Using methylation of 5 out of 24 to define a cancer case, the analysis of a single benign biopsy core identified 62% of prostate cancer patients undergoing repeat biopsies. ROC curve analysis showed that markers commonly methylated in benign cores from cancer patients are the best candidates for a diagnostic test. The results suggest that 5 to 10 markers will be needed to achieve optimal predictive power. CONCLUSIONS: This study shows that epigenetic field effects differ significantly between cancer patients and controls. Their detection in benign biopsy cores can form the basis of diagnostic tests to identify patients in need of repeat biopsies, reducing the cost of continued PCA screening by up to 40%. They could also be used to identify prostate cancer patients with low grade disease who are likely candidates for active surveillance or focal therapy. PMID- 25548654 TI - A questionnaire survey comparing the educational priorities of patients and medical students in the management of multiple sclerosis. AB - OBJECTIVE: To compare the educational priorities patients and students raise concerning the management of multiple sclerosis (MS). DESIGN/SETTING: A single centre comparative questionnaire survey conducted in a foundation trust hospital which provides teaching for one UK medical school. PARTICIPANTS: A total of 255 people with multiple sclerosis (pwMS) and 125 final year medical students attending a mandatory module were invited to participate. MAIN OUTCOME MEASUREMENTS: Questionnaires were developed and piloted for this study and analysed on the basis of the International Classification of Functioning, Disability and Health terminology. RESULTS: Questionnaires were returned by 125 (50%) pwMS (age range 36-86 years; median 58) and 96 (77%) medical students (age range 22-37 years; median 23). The most commonly reported priority listed by people with MS and students concerned 'environmental contextual factors' (95.5% and 99%, respectively). PwMS focused primarily on the 'social and attitudinal aspects' of the environment (53.6%), while students expressed greater interest in the use of medications (91.7%) and investigations (14.6%) (p < 0.001). People with greater psychological or physical impact of the condition were more likely to prioritise 'health condition' topics. CONCLUSIONS: PwMS and medical students identify different topics when asked to list aspects of management of MS which they deem to be important for medical student teaching. These differences in educational priorities should be taken into consideration when teaching students about MS. The findings may also apply to other long-term neurological conditions and warrant further investigation. PMID- 25548655 TI - A case of chronic anorexia nervosa with child-bearing by in vitro fertilization necessitating comprehensive team support. AB - Generalists should be aware of the issues surrounding pregnancy in patients with anorexia nervosa and discuss well with patients and their families before in vitro fertilization. PMID- 25548656 TI - Primary anti-phospholipid antibody syndrome causing recurrent venous thrombosis and thrombocytopenia in a patient with Addison's disease. AB - We report a case of Addison's disease presenting with recurrent deep venous thrombosis and thrombocytopenia and proved to have primary anti-phospholipid antibody syndrome. The case report highlights the shared autoimmune nature of both diseases. PMID- 25548657 TI - Comparison of mycotic keratitis with nonmycotic keratitis: an epidemiological study. AB - Purpose. This work aims to study the problems encountered with and the different epidemiological features of patients with fungal keratitis. Patients and Methods. All cases with keratitis attending the Outpatient Clinic of Ophthalmology Department at Tanta University Hospital during three years from the first of January 2011 to the end of December 2013 were selected and carefully examined and cases with mycotic keratitis were further examined and investigated. Results. From 66303 attendants during this period with different complaints, there were 361 cases (0.54%) with mycotic keratitis and 473 cases (0.71%) of nonmycotic origin. Mycotic keratitis is common between 40 and 60 years, more in farmers (64%), families with large number and large crowding index, rural than urban residence, and patients with outdoor water sources and insanitary sewage disposal. Positive fungal cultures were obtained in 84.5% and were negative in 15.5% of cases in spite of their typical clinical findings for diagnosis and their improvement with antifungal therapy. Conclusion. Mycotic keratitis is more frequent in farmers, rural areas, outdoor water supply, insanitary sewage disposal, and patients preceded with organic trauma. Atypical clinical findings were found in some cases and not all cases improved with specific antifungal therapy. PMID- 25548658 TI - Photon atomic parameters of nonessential amino acids for radiotherapy and diagnostics. AB - The total mass attenuation coefficients (MU t ) (cm(2)/g) and atomic, molecular, and electronic effective cross sections have been calculated for nonessential amino acids that contain H, C, N, and O such as tyrosine, aspartate, glutamine, alanine, asparagine, aspartic acid, cysteine, and glycine in the wide energy region 0.015-15 MeV. The variations with energy of total mass attenuation coefficients and atomic, molecular, and electronic cross sections are shown for all photon interactions. PMID- 25548659 TI - Adapting and Implementing a Community Program to Improve Retention in Care among Patients with HIV in Southern Haiti: "Group of 6". AB - Objective. In Mozambique, a patient-led Community ART Group model developed by Medecins Sans Frontieres improved retention in care and adherence to antiretroviral therapy (ART) among persons with HIV. We describe the adaptation and implementation of this model within the HIV clinic located in the largest public hospital in Haiti's Southern Department. Methods. Our adapted model was named Group of 6. Hospital staff enabled stable patients with HIV receiving ART to form community groups with 4-6 members to facilitate monthly ART distribution, track progress and adherence, and provide support. Implementation outcomes included recruitment success, participant retention, group completion of monthly monitoring forms, and satisfaction surveys. Results. Over one year, 80 patients from nine communities enrolled into 15 groups. Six participants left to receive HIV care elsewhere, two moved away, and one died of a non-HIV condition. Group members successfully completed monthly ART distribution and returned 85.6% of the monthly monitoring forms. Members reported that Group of 6 made their HIV management easier and hospital staff reported that it reduced their workload. Conclusions. We report successful adaptation and implementation of a validated community HIV-care model in Southern Haiti. Group of 6 can reduce barriers to ART adherence, and will be integrated as a routine care option. PMID- 25548660 TI - Heliox Improves Carbon Dioxide Removal during Lung Protective Mechanical Ventilation. AB - Introduction. Helium is a noble gas with low density and increased carbon dioxide (CO2) diffusion capacity. This allows lower driving pressures in mechanical ventilation and increased CO2 diffusion. We hypothesized that heliox facilitates ventilation in patients during lung-protective mechanical ventilation using low tidal volumes. Methods. This is an observational cohort substudy of a single arm intervention study. Twenty-four ICU patients were included, who were admitted after a cardiac arrest and mechanically ventilated for 3 hours with heliox (50% helium; 50% oxygen). A fixed protective ventilation protocol (6 mL/kg) was used, with prospective observation for changes in lung mechanics and gas exchange. Statistics was by Bonferroni post-hoc correction with statistical significance set at P < 0.017. Results. During heliox ventilation, respiratory rate decreased (25 +/- 4 versus 23 +/- 5 breaths min(-1), P = 0.010). Minute volume ventilation showed a trend to decrease compared to baseline (11.1 +/- 1.9 versus 9.9 +/- 2.1 L min(-1), P = 0.026), while reducing PaCO2 levels (5.0 +/- 0.6 versus 4.5 +/- 0.6 kPa, P = 0.011) and peak pressures (21.1 +/- 3.3 versus 19.8 +/- 3.2 cm H2O, P = 0.024). Conclusions. Heliox improved CO2 elimination while allowing reduced minute volume ventilation in adult patients during protective mechanical ventilation. PMID- 25548661 TI - Episodic and semantic autobiographical memory in temporal lobe epilepsy. AB - Autobiographical memory (AM) is understood as the retrieval of personal experiences that occurred in specific time and space. To date, there is no consensus on the role of medial temporal lobe structures in AM. Therefore, we investigated AM in medial temporal lobe epilepsy (TLE) patients. Twenty TLE patients candidates for surgical treatment, 10 right (RTLE) and 10 left (LTLE), and 20 healthy controls were examined with a version of the Autobiographical Interview adapted to Spanish language. Episodic and semantic AM were analyzed during five life periods through two conditions: recall and specific probe. AM scores were compared with clinical and cognitive data. TLE patients showed lower performance in episodic AM than healthy controls, being significantly worst in RTLE group and after specific probe. In relation to semantic AM, LTLE retrieved higher amount of total semantic details compared to controls during recall, but not after specific probe. No significant differences were found between RTLE and LTLE, but a trend towards poorer performance in RTLE group was found. TLE patients obtained lower scores for adolescence period memories after specific probe. Our findings support the idea that the right hippocampus would play a more important role in episodic retrieval than the left, regardless of a temporal gradient. PMID- 25548662 TI - Hypertension education intervention with ugandan nurses working in hospital outpatient clinic: a pilot study. AB - Noncommunicable diseases (NCDs) pose a significant global burden in both developed and developing countries. It is estimated that, by 2025, 41.7% of males and 38.7% of females in Sub-Saharan Africa will develop high blood pressure (HBP). This is particularly true in Uganda with hypertensive prevalence rates estimated to range from 22.5% to 30.5%. Coupled with low levels of detection, treatment, and control, hypertension represents a Ugandan public health crisis. An innovative WHO-ISH education program culturally was adapted in a pilot study and focused on knowledge, skills, and attitudes (KSA) of nurses caring for hypertensive patients in an outpatient clinic. Pre-post intervention data was collected and analyzed in which significant improvements were noted on all the three outcome measures. This pilot study demonstrated that nurses' knowledge, skills, and attitudes could be significantly improved with a multimodal education program implemented in a low resource environment. PMID- 25548663 TI - Comment on "video-assisted thoracic surgery for tubercular spondylitis". PMID- 25548664 TI - Changing trends in use of laparoscopy: a clinical audit. AB - Aim. To find out the changing trends in indications for use of laparoscopy for diagnostic or operative procedures in gynaecology. Methods. This was a clinical audit of 417 women who underwent laparoscopic procedures over a period of 8 years from January 2005 to December 2012 in the Department of Obstetrics and Gynaecology at a tertiary care centre in Delhi. Results. A total of 417 diagnostic and operative laparoscopic procedures were performed during the period from January 2005 to December 2012. Out of 417 women, 13 women were excluded from the study due to inadequate data. 208 (51.4%) women had only diagnostic laparoscopy whereas 196 (48.6%) patients had operative laparoscopy after the initial diagnostic procedure. Change in trend of diagnostic versus operative procedures was observed from 2005 to 2012. There was increase in operative procedures from 10 (37.03%) women in 2005 as compared to 51 (73.91%) in 2012. The main indication for laparoscopy was infertility throughout the study period (61.38%), followed by chronic pelvic pain (CPP) (11.38%) and abnormal uterine bleeding (AUB) (9.4%). Conclusion. Over the years, there has been a rise in the rate of operative laparoscopy. Though the indications for laparoscopy have remained almost similar during the years, laparoscopy for diagnosis and treatment of CPP and AUB has now increased. PMID- 25548665 TI - The efficacy of intranasal desmopressin as an adjuvant in the acute renal colic pain management. AB - The aim of this study was to compare analgesic effect of intramuscular (IM) sodium diclofenac and intranasal desmopressin combination with IM sodium diclofenac alone in patients with acute renal colic. In this randomized double blind clinical trial, all patients aged 18 to 55 years who were diagnosed as acute renal colic and met the inclusion and exclusion criteria were randomized into two groups to receive 40 MUg intranasal desmopressin spray and 75 mg IM sodium diclofenac combination (Group A) or 75 mg IM sodium diclofenac alone (Group B). The pain score of patients was assessed using a visual analogue scale (VAS) at baseline, 15, 30, 45, and 60 minutes after administration. Of all 159 patients who were assessed for eligibility finally, the results of 120 patients were analyzed. There was no significant difference regarding age and gender between two groups. The baseline VAS score was not significantly different between two groups (P = 0.44). The Mean +/- SD scores of two groups reduced 15 minutes after drug administration, but this decrease was significantly more in Group A compared with Group B (P = 0.02). This pattern continued in minutes 30, 45, and 60 of drug administration. Our results showed that desmopressin could be used as an effective adjuvant in acute renal colic pain management. PMID- 25548666 TI - Sarcoidosis treatment with antifungal medication: a follow-up. AB - INTRODUCTION: The aim of the study was to compare treatment of sarcoidosis with antifungal or corticosteroid medication. METHODS: In patients with sarcoidosis antifungal medication (n = 29), corticosteroids (n = 21) or a combination (n = 27) was given. Nine patients allotted to antifungal medication were later given corticosteroids because of the lack of regression of the disease. X-ray scores for the severity of granuloma infiltration were determined. Chitotriosidase and angiotensin converting enzyme were determined. The time in months till remission was observed as well as the number of recurrences. PMID- 25548668 TI - The outcome of agitation in poisoned patients in an Iranian tertiary care university hospital. AB - Introduction. This study was conducted to evaluate and document the frequency and causes of agitation, the symptoms accompanying this condition in intoxications, relationship between agitation score on admission and different variables, and the outcome of therapy in a tertiary care referral poisoning center in Iran. Methods. In this prospective observational study which was done in 2012, 3010 patients were screened for agitation at the time of admission using the Richmond Agitation Sedation Scale. Demographic data including age, gender, and the drug ingested were also recorded. The patients' outcome was categorized as recovery without complications, recovery with complications (hyperthermia, renal failure, and other causes), and death. Results. Agitation was observed in 56 patients (males, n = 41), mostly aged 19-40 years (n = 38) and more frequently in illegal substance (stimulants, opioids and also alcohol) abusers. Agitation score was not significantly related to the age, gender, and previous history of psychiatric disorders. Forty nine patients had recovery without any complication. The need for mechanical ventilation was the most frequent complication. None of the patients died. Conclusion. Drug abuse seems to be a must-to-consider etiology for patients presenting with acute agitation and its morbidity and mortality could be low in agitated poisoning cases if prompt supportive care is performed. PMID- 25548667 TI - Accuracy of the Hospital Anxiety and Depression Scale for identifying depression in chronic obstructive pulmonary disease patients. AB - Psychological morbidity is common in chronic respiratory diseases. The diagnostic accuracy of the Hospital Anxiety and Depression Scale (HADS) and risk factors for comorbid depression in chronic obstructive pulmonary disease (COPD) are addressed. Consecutive COPD patients (GOLD stage I-IV, 40-75 years old) were enrolled in a multicentre, cross-sectional cohort study. Diagnosis of depression was ascertained through clinical records. Lung function, HADS score, 6-minute walking test (6-MWT), MRC dyspnoea score, and COPD Assessment Test (CAT) were evaluated. Two hundred fifty-nine COPD patients (mean age 62.5 years; 32% female; mean FEV1 48% predicted) were included. Patients diagnosed with depression (29/259; 11.2%) had significantly higher HADS-D and HADS-Total scores than nondepressed patients (median (quartiles) HADS-D 6 [4; 9] versus 4 [2; 7], median HADS-Total 14 [10; 20] versus 8 [5; 14]). Receiver-operating characteristic plots showed moderate accuracy for HADS-D, AUC 0.662 (95%CI 0.601-0.719), and HADS Total, AUC 0.681 (95%CI 0.620-0.737), with optimal cut-off scores of >5 and >9, respectively. Sensitivity and specificity were 62.1% and 62.6% for HADS-D compared to 75.9% and 55.2% for HADS-Total. Age, comorbidities, sex, and lower airflow limitation predicted depression. The HADS exhibits low diagnostic accuracy for depression in COPD patients. Younger men with comorbidities are at increased risk for depression. PMID- 25548669 TI - Partial block by riluzole of muscle sodium channels in myotubes from amyotrophic lateral sclerosis patients. AB - Denervated muscles undergo fibrillations due to spontaneous activation of voltage gated sodium (Na(+)) channels generating action potentials. Fibrillations also occur in patients with amyotrophic lateral sclerosis (ALS). Riluzole, the only approved drug for ALS treatment, blocks voltage-gated Na(+) channels, but its effects on muscle Na(+) channels and fibrillations are yet poorly characterized. Using patch-clamp technique, we studied riluzole effect on Na(+) channels in cultured myotubes from ALS patients. Needle electromyography was used to study fibrillation potentials (Fibs) in ALS patients during riluzole treatment and after one week of suspension. Patients were clinically characterized in all recording sessions. In myotubes, riluzole (1 MUM, a therapeutic concentration) reduced Na(+) current by 20%. The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced. Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect. Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing. In line with this in vitro finding, muscle Fibs in ALS patients appear to be largely unaffected by riluzole. PMID- 25548670 TI - In Vivo MR Microneurography of the Tibial and Common Peroneal Nerves. AB - MR microneurography is a noninvasive technique that provides visualization of the microanatomy of peripheral nerves, otherwise available only with histopathology. The objective of this study was to present a protocol to visualize the microstructure of peripheral nerves in vivo, using a 3T MRI scanner with a clinical set of coils and sequences. The tibial and the common peroneal nerves of healthy volunteers were imaged above the medial malleolus and at the level of the fibular head, respectively. The acquired images provided details about the internal structure of peripheral nerves, with visualization of the fascicles, the interfascicular fat, the epineurium, and the perineurium. MR microneurography can be performed in a clinical setting with acceptable imaging times and can be a potentially powerful tool that complements standard MR neurography. PMID- 25548671 TI - Multisite Kinetic Modeling of (13)C Metabolic MR Using [1-(13)C]Pyruvate. AB - Hyperpolarized (13)C imaging allows real-time in vivo measurements of metabolite levels. Quantification of metabolite conversion between [1-(13)C]pyruvate and downstream metabolites [1-(13)C]alanine, [1-(13)C]lactate, and [(13)C]bicarbonate can be achieved through kinetic modeling. Since pyruvate interacts dynamically and simultaneously with its downstream metabolites, the purpose of this work is the determination of parameter values through a multisite, dynamic model involving possible biochemical pathways present in MR spectroscopy. Kinetic modeling parameters were determined by fitting the multisite model to time-domain dynamic metabolite data. The results for different pyruvate doses were compared with those of different two-site models to evaluate the hypothesis that for identical data the uncertainty of a model and the signal-to-noise ratio determine the sensitivity in detecting small physiological differences in the target metabolism. In comparison to the two-site exchange models, the multisite model yielded metabolic conversion rates with smaller bias and smaller standard deviation, as demonstrated in simulations with different signal-to-noise ratio. Pyruvate dose effects observed previously were confirmed and quantified through metabolic conversion rate values. Parameter interdependency allowed an accurate quantification and can therefore be useful for monitoring metabolic activity in different tissues. PMID- 25548673 TI - The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC Patients. AB - Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), P = 0.029. Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone. PMID- 25548675 TI - Using structured observation and content analysis to explore the presence of older people in public fora in developing countries. AB - There is a lack of research on the everyday lives of older people in developing countries. This exploratory study used structured observation and content analysis to examine the presence of older people in public fora and considered the methods' potential for understanding older people's social integration and inclusion. Structured observation occurred of public social spaces in six cities each located in a different developing country and in one city in the United Kingdom, together with content analysis of the presence of people in newspaper pictures and on television in the selected countries. Results indicated that across all fieldwork sites and data sources, there was a low presence of older people, with women considerably less present than men in developing countries. There was variation across fieldwork sites in older people's presence by place and time of day and in their accompanied status. The presence of older people in images drawn from newspapers was associated with the news/non-news nature of the source. The utility of the study's methodological approach is considered, as is the degree to which the presence of older people in public fora might relate to social integration and inclusion in different cultural contexts. PMID- 25548672 TI - Gender identity disorder and schizophrenia: neurodevelopmental disorders with common causal mechanisms? AB - Gender identity disorder (GID), recently renamed gender dysphoria (GD), is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization. Various mechanisms, such as Toxoplasma infection, reduced levels of brain-derived neurotrophic factor (BDNF), early childhood adversity, and links with autism spectrum disorders, may account for some of this overlap. The implications of this association for further research are discussed. PMID- 25548674 TI - Interleukin-6 c.-174G>C Polymorphism and Periodontitis in a Brazilian Population. AB - Aim. Periodontitis is an inflammatory disease that affects the teeth supporting structures, triggered by periodontal pathogens, and is influenced by environmental and genetic factors. Genes encoding molecules related to the immune response, such as cytokine, are the main candidates for polymorphisms analysis and may be possibly associated with this pathology. A G/C promoter polymorphism on the IL6 gene has been shown to affect basal IL-6 levels. The aim of this study was to investigate the association between the IL6 c.-174G>C polymorphism and periodontitis in individuals from Vitoria da Conquista, Bahia, Brazil. Material and Methods. Three hundred and thirty individuals (134 cases, 196 controls) were genotyped for the IL6 c.-174G>C by MS-PCR technique. Concentrations of salivary IL-6 were determined by ELISA method. Results. The IL6 c.-174G>C polymorphism was associated with periodontitis when comparing the distribution of genotypes between patients with periodontitis and control subjects. The GC genotype appeared as a protective factor for periodontitis. Results showed increased levels of salivary IL-6 in periodontitis patients. Nevertheless, there was no relationship between the concentrations of IL-6 and genotypes when comparing the case and control groups. Conclusions. Our data indicate an association between IL6 c.-174G>C polymorphism and periodontitis and showed that IL-6 may be considered an important marker for periodontitis. PMID- 25548676 TI - The frequency of anti-aquaporin-4 Ig g antibody in neuromyelitis optica and its spectrum disorders at a single tertiary referral center in malaysia. AB - Background. In the past the occurrence of neuromyelitis optica in Malaysia was thought to be uncommon and the frequency of anti-aquaporin-4 Ig G antibody was unknown. Objective. To evaluate the frequency of anti-aquaporin-4 Ig G antibody (Anti-AQP4 antibody) amongst patients with neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) and the differences between the seropositive and seronegative groups. Methods. Retrospectively, 96 patients with NMO/high risk syndromes for NMOSD (HRS-NMOSD) were identified out of 266 patients with idiopathic inflammatory demyelinating disease from a single center hospital based registry. Anti-AQP4 seropositivity was found in 38/48 (79.2%) with NMO, 12/21 (57.1%) with brain involvement at high risk for NMOSD, 12/15 (80%) with transverse myelitis (i.e., 11/15 with relapsing transverse myelitis and one with monophasic transverse myelitis), and 3/7 (42.8%) with relapsing optic neuritis. Sixty-five out of 96 patients, that is, 67.7%, with NMO/HRS for NMOSD were seropositive. Seropositivity was significantly associated with female gender, a higher number of mean relapses, that is, 5.15 +/- 4.42 versus 2.10 +/- 1.68, longer length of spinal cord lesions, that is, 6.6 +/- 4.9 versus 2.9 +/- 2.5, vertebral bodies, higher EDSS, 4.5 +/- 2.4 versus 2.4 +/- 2.6, presence of paroxysmal tonic spasms, and blindness (unilateral/bilateral); P < 0.001. Longitudinally extensive cord lesions (contiguous or linear), presence of lesions in the cervical and thoracic regions, and involvement of the central gray matter or holocord regions on axial scans, were also significantly associated with seropositivity; P < 0.001. Conclusion. NMO and HRS for NMOSD are present in larger numbers than previously thought in Malaysia. More than 2/3rds are seropositive. Seropositive and seronegative NMO/NMOSD have differences that are useful in clinical practice. PMID- 25548678 TI - Validity and stability of the decisional balance for sun protection inventory. AB - The 8-item Decisional Balance for sun protection inventory (SunDB) assesses the relative importance of the perceived advantages (Pros) and disadvantages (Cons) of sun protective behaviors. This study examined the psychometric properties of the SunDB measure, including invariance of the measurement model, in a population based sample of N = 1336 adults. Confirmatory factor analyses supported the theoretically based 2-factor (Pros, Cons) model, with high internal consistencies for each subscale (alpha >= .70). Multiple-sample CFA established that this factor pattern was invariant across multiple population subgroups, including gender, racial identity, age, education level, and stage of change subgroups. Multivariate analysis by stage of change replicated expected patterns for SunDB (Pros eta (2) = .15, Cons eta (2) = .02). These results demonstrate the internal and external validity and measurement stability of the SunDB instrument in adults, supporting its use in research and intervention. PMID- 25548679 TI - Carboxymethyl cellulose acetate butyrate: a review of the preparations, properties, and applications. AB - Carboxymethyl cellulose acetate butyrate (CMCAB) has gained increasing importance in several fields, particularly in coating technologies and pharmaceutical research. CMCAB is synthesized by esterification of CMC sodium salt with acetic and butyric anhydrides. CMCAB mixed esters are relatively high molecular weight (MW) thermoplastic polymers with high glass transition temperatures (Tg). CMCAB ester is dispersible in water and soluble in a wide range of organic solvents, allowing varied opportunity to the solvent choice. It makes application of coatings more consistent and defect-free. Its ability to slow down the release rate of highly water-soluble compounds and to increase the dissolution of poorly soluble compounds makes CMCAB a unique and potentially valuable tool in pharmaceutical and amorphous solid dispersions (ASD) formulations. PMID- 25548680 TI - Long-term efficacy and tolerability of abdominal once-yearly histrelin acetate subcutaneous implants in patients with advanced prostate cancer. AB - Objectives. Long-term assessment of the efficacy and tolerability of subcutaneous abdominal histrelin acetate implants that have been inserted for more than two years. Materials and Methods. Retrospective data collected over a six-year period at a single center from charts of 113 patients who received the subcutaneous abdominal histrelin acetate implant. Results. Following insertion of the first implant, 92.1% and 91.8% of patients had a serum testosterone level of <=30 ng/dL at 24 and 48 weeks, respectively. Serum testosterone levels remained at <30 ng/dL for 96% of patients at two years and for 100% of patients at 3, 4, and 5 years. The testosterone levels remained significantly less than baseline (P < 0.05). Six patients (5.3%) had androgen-independent progression when followed up on the long term, increasing the mean serum PSA at 3, 4, and 5 years to 35.0 ug/L (n = 22), 30.7 ug/L (n = 13), and 132.9 ug/L (n = 8), respectively. The mean serum PSA was significantly greater than baseline during these years (P < 0.05). Eight patients (7.1%) experienced minor, but not serious, adverse events from the histrelin acetate. Conclusion. Subcutaneous abdominal histrelin acetate implants are an effective long-term and well-tolerated administration method for treating patients with advanced prostate cancer. PMID- 25548677 TI - IUGR management: new perspectives. AB - AIM OF THE STUDY: Analyzing velocimetric (umbilical artery, UA; ductus venosus, DV; middle cerebral artery, MCA) and computerized cardiotocographic (cCTG) (fetal heart rate, FHR; short term variability, STV; approximate entropy, ApEn) parameters in intrauterine growth restriction, IUGR, in order to detect early signs of fetal compromise. POPULATION STUDY: 375 pregnant women assisted from the 28th week of amenorrhea to delivery and monitored through cCTG and Doppler ultrasound investigation. The patients were divided into three groups according to the age of gestation at the time of delivery, before the 34th week, from 34th to 37th week, and after the 37th week. Data were analyzed in relation to the days before delivery and according to the physiology or pathology of velocimetry. Statistical analysis was performed through the t-test, chi-square test, and Pearson correlation test (P < 0.05). Our results evidenced an earlier alteration of UA, DV, and MCA. The analysis between cCTG and velocimetric parameters (the last distinguished into physiological and pathological values) suggests a possible relation between cCTG alterations and Doppler ones. The present study emphasizes the need for an antenatal testing in IUGR fetuses using multiple surveillance modalities to enhance prediction of neonatal outcome. PMID- 25548682 TI - The mind and liver test: a new approach to the diagnosis of minimal hepatic encephalopathy in resource-poor settings. AB - Background and Aims. Minimal hepatic encephalopathy (MHE) is diagnosed using neuropsychometric tests or neurophysiological tests that are either inapplicable to illiterate patient population in resource-poor settings or require sophisticated and expensive equipment. The available tests assess discrete domains of mental impairment. Our aim was (a) to design a neuropsychometric test that measures all domains of mental impairment in MHE using one metric; (b) to evaluate its sensitivity, specificity, and reproducibility. Methods. The mind and liver test (MALT), a psychometric test assessing cognition, memory, and psychometric impairment, each on a scale of 20, was designed keeping in mind the requirements of a universal test. 40 cirrhotics and 36 controls were subjected to critical flicker frequency (CFF) and MALT in same sitting. ROC curve was plotted for MALT using CFF as gold standard. Bland-Altman plot was used to find test retest agreement. Results. CFF values and MALT scores varied significantly between the cases and the controls (P < 0.05). MALT was 94% sensitive and 83% specific. Using ROC with CFF as gold standard, the AUC for diagnosis of MHE using MALT score was 0.89. Test-retest agreement was high (ICC = 0.89). Conclusion. In this pilot study, MALT proved to be highly sensitive, specific, inexpensive, and reproducible. PMID- 25548683 TI - IFNL4 ss469415590 Variant Is Associated with Treatment Response in Japanese HCV Genotype 1 Infected Individuals Treated with IFN-Including Regimens. AB - Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens. PMID- 25548684 TI - Triad of Idiopathic Thrombocytopenic Purpura, Preeclampsia, and HELLP Syndrome in a Parturient: A Rare Confrontation to the Anesthetist. AB - Idiopathic thrombocytopenic purpura (ITP) with HELLP represents a rare complication that requires combined care of obstetrician, anesthesiologist, hematologist, and neonatologist. At 37-week gestation a 35-year-old parturient (G2A1P0) a known case of chronic ITP presented with severe pregnancy induced hypertension (PIH), thrombocytopenia, and elevated liver enzymes. We describe successful anesthetic management of this patient who was taken for emergency caesarean section. PMID- 25548681 TI - An Introspective Update on the Influence of miRNAs in Breast Carcinoma and Neuroblastoma Chemoresistance. AB - Chemoresistance to conventional cytotoxic drugs may occur in any type of cancer and this can either be inherent or develop through time. Studies have linked this acquired resistance to the abnormal expression of microRNAs (miRNAs) that normally silence genes. At abnormal levels, miRNAs can either gain ability to silence tumour suppressor genes or else lose ability to silence oncogenes. miRNAs can also affect pathways that are involved in drug metabolism, such as drug efflux pumps, resulting in a resistant phenotype. The scope of this review is to provide an introspective analysis on the specific niches of breast carcinoma and neuroblastoma research. PMID- 25548685 TI - Treatment algorithm for ameloblastoma. AB - Ameloblastoma is the second most common benign odontogenic tumour (Shafer et al. 2006) which constitutes 1-3% of all cysts and tumours of jaw, with locally aggressive behaviour, high recurrence rate, and a malignant potential (Chaine et al. 2009). Various treatment algorithms for ameloblastoma have been reported; however, a universally accepted approach remains unsettled and controversial (Chaine et al. 2009). The treatment algorithm to be chosen depends on size (Escande et al. 2009 and Sampson and Pogrel 1999), anatomical location (Feinberg and Steinberg 1996), histologic variant (Philipsen and Reichart 1998), and anatomical involvement (Jackson et al. 1996). In this paper various such treatment modalities which include enucleation and peripheral osteotomy, partial maxillectomy, segmental resection and reconstruction done with fibula graft, and radical resection and reconstruction done with rib graft and their recurrence rate are reviewed with study of five cases. PMID- 25548686 TI - Camouflage of Severe Skeletal Class II Gummy Smile Patient Treated Nonsurgically with Mini Implants. AB - Skeletal class II has always been a challenge in orthodontics and often needs assistance of surgical orthodontics in nongrowing patients when it presents with severe discrepancy. Difficulty increases more when vertical dysplasia is also associated with sagittal discrepancy. The advent of mini implants in orthodontics has broadened the spectrum of camouflage treatment. This case report presents a 16-year-old nongrowing girl with severe class II because of retrognathic mandible, and anterior dentoalveolar protrusion sagittally and vertically resulted in severe overjet of 13 mm and excessive display of incisors and gums. Both maxillary central incisors were trimmed by general practitioner few years back to reduce visibility. Treatment involved use of micro implant for retraction and intrusion of anterior maxillary dentoalveolar segment while lower incisors were proclined to obtain normal overjet, and overbite and pleasing soft tissue profile. Smile esthetics was further improved with composite restoration of incisal edges of both central incisors. PMID- 25548687 TI - Familial case of cherubism from South India: differential diagnosis and report of 2 cases. AB - Cherubism is a rare familial multilocular cystic lesion of the jaws. The condition clinically appears as a bilateral symmetric swelling of the cheeks in children and is the primary reason for referral. It is a rare lesion of the jaws that has a dominant pattern of inheritance. We report two cases of cherubism, that of a boy and his mother suggestive of a strong familial incidence. A variety of lesions of the jaw mimic this condition and hence the differential diagnosis has been emphasised. PMID- 25548688 TI - Cutaneous sinus formation is a rare complication of thyroid fine needle aspiration biopsy. AB - Fine needle aspiration biopsy (FNAB) is essential in the diagnosis and management of thyroid nodules. In this paper, we report a rare complication, cutaneous sinus formation, after diagnostic FNAB guided by palpation. Sixty-three-year-old female patient was admitted with the complaints of hoarseness and discharge from the anterior neck wall which were present for the last 6 months. The patient underwent a near total thyroidectomy 17 years ago. Recurrent nodular goiter was detected six months before and a diagnostic FNAB guided by palpation was performed. Two weeks later the patient had wound discharge and hoarseness. Physical examination of the patient revealed a sinus, which was located superior to the thyroidectomy incision. A 1 cm nodule was palpated in the left side of her neck. A cervical ultrasonography (USG) showed a 9 * 7 mm nodule in the remnant thyroid and a 9.5 * 3.5 mm fistulized fluid collection. The patient underwent sinus tract and remnant thyroid removal. This case report presents a cutaneous sinus formation deriving from the granulation tissue, probably due to the silk suture reaction in the previous surgery, by the FNAB guided by palpation procedure. We suggest USG guided FNAB to achieve more accurate and safe diagnosis in evaluating the thyroid nodules. PMID- 25548689 TI - Response to "Acute Hepatitis Induced by Lyprinol, the Lipid Extract of the Green Lipped Mussel (Perna canaliculus), in a Patient with Polyarthrosis". PMID- 25548690 TI - Successful management of insulin allergy and autoimmune polyendocrine syndrome type 4 with desensitization therapy and glucocorticoid treatment: a case report and review of the literature. AB - Introduction. Insulin allergy is a rare complication of insulin therapy, especially in type 1 diabetes mellitus (T1DM). Key manifestations are hypersensitivity-related symptoms and poor metabolic control. T1DM, as well as insulin allergy, may develop in the context of autoimmune polyendocrine syndrome (APS), further complicating management. Case Report. A 17-year-old male patient, diagnosed with T1DM, was treated with various insulin therapy schemes over several months, which resulted in recurrent anaphylactoid reactions and poor glycemic control, after which he was referred to our Endocrinology and Immunology Department. A prick test was carried out for all commercially available insulin presentations and another insulin scheme was designed but proved unsuccessful. A desensitization protocol was started with Glargine alongside administration of Prednisone, which successfully induced tolerance. Observation of skin lesions typical of vitiligo prompted laboratory workup for other autoimmune disorders, which returned positive for autoimmune gastritis/pernicious anemia. These findings are compatible with APS type 4. Discussion. To our knowledge, this is the first documented case of insulin allergy in type 4 APS, as well as this particular combination in APS. Etiopathogenic components shared by insulin allergy and APS beg for further research in immunogenetics to further comprehend pathophysiologic aspects of these diseases. PMID- 25548691 TI - Mucocutaneous Leishmaniasis/HIV Coinfection Presented as a Diffuse Desquamative Rash. AB - Leishmaniasis is an infectious disease that is endemic in tropical areas and in the Mediterranean. This condition spreads to 98 countries in four continents, surpassing 12 million infected individuals, with 350 million people at risk of infection. This disease is characterized by a wide spectrum of clinical syndromes, caused by protozoa of the genus Leishmania, with various animal reservoirs, such as rodents, dogs, wolves, foxes, and even humans. Transmission occurs through a vector, a sandfly of the genus Lutzomyia. There are three main clinical forms of leishmaniasis: visceral leishmaniasis, cutaneous leishmaniasis, and mucocutaneous leishmaniasis. The wide spectrum of nonvisceral forms includes: localized cutaneous leishmaniasis, a papular lesion that progresses to ulceration with granular base and a large framed board; diffuse cutaneous leishmaniasis; mucocutaneous leishmaniasis, which can cause disfiguring and mutilating injuries of the nasal cavity, pharynx, and larynx. Leishmaniasis/HIV coinfection is considered an emerging problem in several countries, including Brazil, where, despite the growing number of cases, a problem of late diagnosis occurs. Clinically, the cases of leishmaniasis associated with HIV infection may demonstrate unusual aspects, such as extensive and destructive lesions. This study aims to report a case of mucocutaneous leishmaniasis/HIV coinfection with atypical presentation of diffuse desquamative eruption and nasopharyngeal involvement. PMID- 25548692 TI - Motor Neuron Syndrome as a New Phenotypic Manifestation of Mutation 9185T>C in Gene MTATP6. AB - Background. The mutation 9185T>C in ATP6 gene, associated with Leigh syndrome, was reported in only few families. Motor neuron disease (MND), both clinically and electrophysiologically, was not previously described in association with this mutation. Case Report. 33-year-old male, with family history of mitochondrial disease, presented with cognitive impairment, exercise intolerance, and progressive muscle weakness. Examination revealed global hypotonia, and proximal tetraparesis, without atrophy or fasciculation, pyramidal signs, or sensory symptoms. The laboratory findings revealed an increase of lactate and lactate/pyruvate ratio; electromyogram showed chronic neurogenic compromise; muscle biopsy was suggestive of spinal muscular atrophy and mitochondriopathy; genetic study of SMN1 was negative but detected a homoplasmic mutation 9185T>C in ATP6 gene. His younger sister, with the same mutation, had cognitive impairment, ataxia, and muscle weakness. EMG showed axonal peripheral neuropathy. Conclusion. This case is unique because of the benignity and the coexistence of clinical, neurophysiological, and pathological findings suggestive of MND that, although described in mitochondrial disease, have not yet been reported in association with 9185T>C mutation. The present case contributes to the expansion of the phenotypic expressions of this particular mutation. PMID- 25548693 TI - Perforation of the Pregnant Uterus during Laparoscopy for Suspected Internal Herniation after Gastric Bypass. AB - We report perforations of a pregnant uterus during laparoscopy for suspected internal herniation after gastric bypass at 24 weeks of gestation. Abdominal access and gas insufflation were achieved by the use of a 12 mm optic trocar. An additional 5 mm trocar was positioned. The perforations were handled by suturing following laparotomy and mobilisation of the high located uterus. The uterine fundus was located in the subcostal area. Internal herniation was not verified. A cesarean section was made 6 weeks later due to acute low abdominal pain. During delivery the uterus was found normal. At 5 months of age the child has developed normal and seems healthy. Optical trocars should be used with caution for abdominal access during laparoscopy in pregnancy. Open access should probably be preferred in most cases. Accidental perforations of the uterine cavity may be handled in selected cases with simple closure even following the use of large trocars under close postoperative surveillance throughout the pregnancy. PMID- 25548694 TI - Radical Abdominal Trachelectomy for IB1 Cervical Cancer at 17 Weeks of Gestation: A Case Report and Literature Review. AB - Background. With regard to the therapy for early invasive cervical carcinoma during pregnancy, radical trachelectomy is also a treatment of choice, along with its advantages and disadvantages. Case Report. A 28-year-old woman, para 1-0-0-1, was diagnosed with FIGO stage IB1 squamous cell carcinoma of the cervix at 12 weeks of gestation. The patient underwent radical abdominal trachelectomy with pelvic lymphadenectomy at 17 weeks of gestation. Her pregnancy was successfully maintained after the surgery. The patient underwent a planned cesarean section at 38 weeks of gestation. A healthy baby girl weighing 2970 g was born with an Apgar score of 8/9. The mother and child in overall good health were discharged. Ten months after the delivery, there was no clinical evidence of recurrence. Conclusions. We believe that it is appropriate to perform radical abdominal trachelectomy in the early second trimester with preserving uterine arteries, although it is a technically challenging approach. It may be possible that radical abdominal trachelectomy during pregnancy can help women avoid the triple losses of a desired pregnancy, fertility, and motherhood. PMID- 25548695 TI - MYST3/CREBBP Rearranged Acute Myeloid Leukemia after Adjuvant Chemotherapy for Breast Cancer. AB - Although rare, clinicians and patients must be aware that therapy related malignancies, specifically acute myeloid leukemia (AML), can occur as a complication of adjuvant chemotherapy for breast cancer. Vigilance for signs and symptoms is appropriate. AML with t (8;16) is a specific translocation leading to formation of a fusion protein (MYST3/CREBBP). The MYST3/CREBBP AML tends to develop within 2 years of adjuvant chemotherapy, especially for breast cancer, without preceding myelodysplasia. It usually presents with disseminated intravascular coagulation and osteolytic lesions and has a poor prognosis despite aggressive resuscitation and therapy. With the increasing use of adjuvant chemotherapy for breast cancer, we are seeing a definite increase in the incidence of therapy related myelodysplastic syndromes and AML. One must keep this complication in mind while counseling and following up breast cancer patients who have received adjuvant chemotherapy. New osteolytic bone lesions in a patient with history of breast cancer do not necessarily mean metastatic disease and should be fully evaluated. PMID- 25548696 TI - Giant malignant phyllodes tumour of breast. AB - The term phyllodes tumour includes lesions ranging from completely benign tumours to malignant sarcomas. Clinically phyllodes tumours are smooth, rounded, and usually painless multinodular lesions indistinguishable from fibroadenomas. Percentage of phyllodes tumour classified as malignant ranges from 23% to 50%. We report a case of second largest phyllodes tumour in a 35-year-old lady who presented with swelling of right breast since 6 months, initially small in size, that progressed gradually to present size. Examination revealed mass in the right breast measuring 36*32 cms with lobulated firm surface and weighing 10 kgs. Fine needle aspiration cytology was reported as borderline phyllodes; however core biopsy examination showed biphasic neoplasm with malignant stromal component. Simple mastectomy was done and specimen was sent for histopathological examination which confirmed the core biopsy report. Postoperatively the patient received chemotherapy and radiotherapy. The patient is on follow-up for a year and has not shown any evidence of metastasis or recurrence. PMID- 25548697 TI - Inner segment ellipsoid band and cone outer segment tips changes preceding macular hole development in a young patient. AB - Purpose. Pathophysiology of macular hole (MH) is not yet well defined but the advances of spectral domain optical coherence tomography (SD-OCT) give us access to further detailed imaging. We report a case with macular inner segment ellipsoid (ISe) band loss and cone outer segment tips (COST) line changes seen in SD-OCT preceding MH appearance in a young patient. Methods. 21-year-old woman presented with a partial central scotoma, metamorphopsia, and a 20/25 vision in her right eye. Past medical history was positive for laser assisted in situ keratomileusis (LASIK) surgery 7 months ago with no complications. Macular SD-OCT showed ISe band loss and COST line elevation. She was followed a month later with visual acuity deteriorating to 20/200 and a full thickness MH. Results. The patient underwent a pars plana vitrectomy with internal limiting membrane peeling. Her visual acuity 2 months later was 20/20. Conclusion. SD-OCT can identify preliminary changes, yet to be described, preceding MH formation. Our patient demonstrated ISe band loss and COST abnormalities on SD-OCT a month prior to MH development. SD-OCT should be considered in young patients with subtle visual symptoms and mild changes in visual acuity that are not readily explained by ophthalmological exam. PMID- 25548698 TI - Spontaneous absorption of extensive subinternal limiting membrane hemorrhage in shaken baby syndrome. AB - The Shaken Baby Syndrome (SBS) is characterized by subdural hematomas (SH), retinal hemorrhages (RH), and multiple fractures of long bones without external evidence of head trauma. Subinternal limiting membrane (ILM) hemorrhage, also known as macular schisis, is a characteristic finding of this entity. There is no guideline on the right time to indicate surgical treatment. This report describes an abused child with massive sub-ILM hemorrhage, which showed spontaneous absorption after less than two months of follow-up. Due to the possible spontaneous resolution, we suggest an initial conservative treatment in cases of sub-ILM hemorrhage related to SBS. PMID- 25548699 TI - Isolated Pulmonary Embolism following Shoulder Arthroscopy. AB - Pulmonary embolism (PE) following shoulder arthroscopy is a rare complication. We present a unique case report of a 43-year-old right-hand dominant female who developed a PE 41 days postoperatively with no associated upper or lower extremity DVT. The patient had minimal preoperative and intraoperative risk factors. Additionally, she had no thromboembolic symptoms postoperatively until 41 days following surgery when she developed sudden right-hand swelling, labored breathing, and abdominal pain. A stat pulmonary computed tomography (CT) angiogram of the chest revealed an acute PE in the right lower lobe, and subsequent extremity ultrasounds showed no upper or lower extremity deep vein thrombosis. After a thorough review of the literature, we present the first documented isolated PE following shoulder arthroscopy. Although rare, sudden development of an isolated PE is possible, and symptoms such as sudden hand swelling, trouble breathing, and systemic symptoms should be evaluated aggressively with a pulmonary CT angiogram given the fact that an extremity ultrasound may be negative for deep vein thrombosis. PMID- 25548700 TI - Familial discoid medial meniscus tear in three members of a family: a case report and review of literature. AB - Background. A discoid meniscus is a thickened variant of the normal C-shaped meniscus prone to injury. Discoid medial meniscal tears have rarely been reported within families and may suggest familial or developmental origins. Methods. We report the cases of two Caucasian brothers with symptomatic discoid medial meniscus tears. A literature review was conducted addressing discoid medial meniscus and cases of familial meniscus tears. Case Presentation. Physically active brothers presented with progressively worsening knee pain. MRI revealed medial meniscus tears in both brothers. The family history of medial meniscus tears in their mother and the discoid medial meniscus injuries found on arthroscopy suggested evidence for familial discoid medial meniscus tears. Conclusions. Discoid medial meniscus tears within a family have not been previously reported. Two cases of families with discoid lateral meniscus tears have been reported. Discoid medial meniscus is rare relative to the discoid lateral meniscus and predisposes children to symptomatic tears. PMID- 25548701 TI - Chondroblastoma of the knee treated with resection and osteochondral allograft reconstruction. AB - Case. This case report describes the operative management of 16-year-old male with a symptomatic chondroblastoma of the distal femur with breach of the chondral surface. Following appropriate imaging and core needle biopsy, the diagnosis was confirmed histologically. The patient then underwent intralesional curettage and osteochondral allograft reconstruction of the defect. At one-year follow-up the patient was pain-free and has obtained excellent range of motion. There is radiographic evidence of allograft incorporation and no evidence of local recurrence. Conclusion. Osteochondral allograft reconstruction is an effective option following marginal resection and curettage of chondroblastoma involving the chondral surface of the distal femur. PMID- 25548702 TI - Wholly endoscopic permeatal removal of a petrous apex cholesteatoma. AB - We report a case of a petrous apex cholesteatoma which was managed with a wholly endoscopic permeatal approach. A 63-year-old Caucasian male presented with a 10 year history of right-sided facial palsy and profound deafness. On examination in our clinic, the patient had a grade VI House-Brackmann paresis, otoscopic evidence of attic cholesteatoma behind an intact drum, and extensive scarring of the face from previous facial reanimation surgery. Imaging review was suggestive of petrous apex cholesteatoma. An initial decision to manage the patient conservatively was later reviewed on account of the patient suffering recurrent epileptic seizures. A wholly endoscopic permeatal approach was used with successful outcomes. In addition to the case report we also provide a brief description of the technique and a review of the relevant literature. PMID- 25548703 TI - Malignant peripheral nerve sheath tumors of the head and neck: a case series and literature review. AB - Background. Malignant peripheral nerve sheath tumors (MPNSTs) of the head and neck are rare aggressive neoplasms with a poor prognosis. This study describes the management and outcomes of 3 of our patients with MPNSTs of the head and neck. Methods. We identified 3 patients presenting with MPNST of the head and neck and treated at the University of North Carolina. We compared our results to the literature from 1963 to 2014. Results. Mean follow-up was 31 months. Average age at diagnosis was 44.7 years of age. All patients received wide-local excision and adjuvant radiotherapy. No patients recurred during the series. Recurrence free survival time for the patients was 45, 37, and 3 months, respectively. Conclusions. Our data series confirms that a combined-modality approach with complete surgical resection and adjuvant radiotherapy leads to improved outcomes in MPNSTs of the head and neck. Nonetheless, due to historically poor outcomes, continued research into newer therapies needs to be explored. PMID- 25548704 TI - Cervical cystic hygroma in an adult. AB - Cystic hygromas/lymphangiomas are extremely rare malformations in adults. They are usually seen in infants and children under 2 years of age. En bloc resection is difficult due to the adhesive characteristics of the tumors. Inadequate surgical intervention often leads to recurrent disease. We report herein the case of a cystic hygroma/lymphangioma that presented as an uncommon mass on the cervical region in an adult, together with its histopathological, radiologic, and operative features. PMID- 25548705 TI - Oral verruciform xanthoma: a case report and literature review. AB - Oral verruciform xanthoma represents an uncommon entity, which affects mainly oral mucosa. This paper presents the major clinical and histological features of oral verruciform xanthoma and reports a case on the tongue. The differential diagnosis and a literature review are also provided in light of recent information. PMID- 25548706 TI - Pleomorphic Invasive Ductal Carcinoma of the Breast in a Patient with Huntington's Disease. AB - A pleomorphic invasive ductal carcinoma developed in a patient with Huntington's disease. The tumour showed marked nuclear pleomorphism and contained large number of bizarre tumour giant cells and abundant abnormal mitoses. Tumour cells showed nuclear vesicles and inclusions similar to those described in nuclei of neural cells in patients with Huntington's disease. The case suggests that, in some patients, tumour morphology may reflect specific individual features. PMID- 25548707 TI - Symptomatic Floor-of-Mouth Swelling with Neck Extension in a 14-Year-Old Girl. AB - A plunging ranula is a soft-tissue mass stemming from a mucous extravasation cyst of the sublingual gland which can herniate through the mylohyoid muscle. We describe a case in which a 14-year-old girl presented with a rapidly expanding mass on the floor of her mouth affecting her ability to swallow and speak and causing tracheal compression. The patient was initially managed conservatively with antibiotics and steroids; however, the mass continued to expand necessitating emergent bedside incision and drainage and subsequent surgical intervention. The pathophysiology and management options for ranulas are also discussed herein. PMID- 25548709 TI - Bilateral maxillary sinus hypoplasia. AB - Maxillary sinus hypoplasia (MSH) is an uncommon abnormality of paranasal sinuses noted in clinical practice. Computed tomography (CT) scan helps in diagnosing the anomaly along with any anatomical variation that may be associated with it. MSH is usually associated with other anomalies like uncinate process hypoplasia. Three types of MSH have been described. Type 1 MSH shows mild maxillary sinus hypoplasia, type 2 shows significant sinus hypoplasia with narrowed infundibular passage and hypoplastic or absent uncinate process, and type 3 is cleft like maxillary sinus hypoplasia with absent uncinate process. CT and endoscopic examination usually complement each other in diagnosing MSH. PMID- 25548708 TI - Multiphasic multidetector computed tomography study of a rare tracheal tumor: granular cell tumor. AB - Our aim is to present the case report of a woman affected by tracheal granular cell tumor analysed by multiphasic contrast-enhanced multidetector CT. The tumor presents as polypoid lesion (diameter 13 mm), with smooth and well-defined margins, elevated contrast enhancement in arterial phase, and a modest release of contrast in venous phase. This pattern is quite different from the other tracheal tumours. We have performed a comprehensive review of literature to assess all cases of granular cell tumors of the trachea; only 40 cases are reported. Of these, no one focused on the contrast enhancement aspect, so our work is the first showing a specific pattern in multidetector computed tomography (MDCT) of the tracheal granular cell tumour and may help in differential diagnosis. PMID- 25548710 TI - Transient antiphospholipid syndrome associated with primary cytomegalovirus infection: a case report and literature review. AB - Viral infection is known to induce transient autoimmunity in humans. Acute cytomegalovirus (CMV) infection is implicated in occasional thrombosis formation. We here, for the first time, report a 19-year-old female who had an acute CMV infection, leading to a deep venous thrombosis and a pulmonary embolism along with transient appearance of lupus anticoagulant. The pathological role of antiphospholipid antibodies in CMV-mediated thrombosis is discussed. PMID- 25548711 TI - Prune belly syndrome with overlapping presentation of partial urorectal septum malformation sequence in a female newborn with absent perineal openings. AB - Prune belly syndrome (PBS) is a rare congenital anomaly characterized in males by a triad of anomalous genitourinary tract, deficient development of abdominal wall muscles, and bilateral cryptorchidism. Although similar anomalies have been reported in females, by definition they do not full fill the classical triad. Urorectal septum malformation sequence (URSM) is a lethal condition characterized by presence of ambiguous genitalia, absent perineal openings (urogenital and anal), and lumbosacral abnormalities. In this original case report, the authors discuss the presentation and management of what would be analogous to a Woodhouse category 1 PBS in a female newborn associated with an overlapping presentation of URSM. PMID- 25548713 TI - Improving hip fracture care in ireland: a preliminary report of the irish hip fracture database. AB - Introduction. Hip fractures are common injuries in the older persons, with significant associated morbidity and mortality. The Irish Hip Fracture Database (IHFD) was implemented to monitor standards of care against international standards. Methods. The IHFD is a clinically led web-based audit. We summarize the data collected on hip fractures from April 2012 to March 2013 from 8 centres. Results. There were 843 patients with the majority being (70%) female. The 80-89 year age group accounted for the majority of fractures (44%). Most (71%) sustained a fall at home. Intertrochanteric fractures (40%) were most common. Only 28% were admitted to an orthopaedic ward within 4 hours. The majority (97%) underwent surgery with 44% having surgery within 36 hours. Medical optimization (35%) and lack of theatre space (26%) accounted for most of the surgical delay. While 29% were discharged home, 33% were discharged to a nursing home or other long-stay facilities. There was a 4% in-hospital mortality rate. Conclusions. Several key areas in both the database and aspects of patient care needing improvement have been highlighted. The implementation of similar databases has led to improved hip fracture care in other countries and we believe this can be replicated in Ireland. PMID- 25548712 TI - Dystrophic calcification of the prostate after cryotherapy. AB - We present a previously undocumented complication of dystrophic calcification of the prostate after cryotherapy. An 87-year-old male presented with recurrent lower urinary tract infections and was found to have an obstructing large calcified mass in the right lobe of the prostate. Subsequently, he underwent transurethral resection of the prostate (TURP) and bladder neck with laser lithotripsy to remove the calculus. We propose that chronic inflammation and necrosis of the prostate from cryotherapy resulted in dystrophic calcification of the prostate. As the use of cryotherapy for the treatment of localized prostate cancer continues to increase, it is important that clinicians be aware of this scenario and the technical challenges it poses. PMID- 25548714 TI - Changes in Dickkopf-1 (DKK1) and Sclerostin following a Loading Dose of Vitamin D 2 (300,000 IU). AB - Background. Vitamin D is important for bone health, although high loading doses have been associated with an increase in fracture risk. The mechanisms remain uncertain. Aim. We hypothesize that supraphysiological concentrations of 1,25 (OH)2 vitamin D may inhibit formation by increasing the production of Wnt inhibitors: sclerostin and DKK1. Subjects and Methods. We measured serum sclerostin and DKK1 in 34 patients (21 F, 13 M) aged mean (SD) 61.3 (15.6) years with vitamin D deficiency/insufficiency treated with a loading dose of vitamin D2 (300,000 IU) intramuscularly. Blood samples were taken at baseline and serially up to 3 months. Results. Serum 1,25 (OH)2 vitamin D increased markedly at 3 months (mean (SD) baseline 116 (63), 3 months : 229 (142) pmol/L, P < 0.001). There was a significant correlation between sclerostin and DKK1 at baseline (r = 0.504, P = 0.002) and at 3 months (r = 0.42, P = 0.013). A significant inverse correlation was observed between sclerostin and eGFR at 3 months (r = -0.494, P = 0.007). Sclerostin increased significantly at 3 months (P = 0.033). In a multilinear regression analysis with % change in sclerostin and DKK1 as dependent variable, a positive significant association was observed with % change in 1,25 (OH)2 vitamin D (P = 0.038), independent of changes in PTH and following correction for confounders such as age, gender, BMI, BMD and eGFR. Conclusions. Supraphysiological concentration in 1,25 (OH)2 vitamin D achieved following a loading dose of vitamin D increases sclerostin and may inhibit Wnt signalling. This may have detrimental effects on bone. PMID- 25548715 TI - Imported malaria in portugal 2000-2009: a role for hospital statistics for better estimates and surveillance. AB - Background. Although eradicated in Portugal, malaria keeps taking its toll on travelers and migrants from endemic countries. Disease notification is mandatory but is compromised by underreporting. Methods. A retrospective study on malaria hospitalizations for 10 consecutive years (2000-2009) was conducted. Data on hospitalizations and notifications were obtained from Central Administration of Health System and Health Protection Agency, respectively. For data selection ICD 9 CM and ICD-10 were used: codes 084(*), 647.4, and B50-B54. Variables were gender, age, agent and origin of infection, length of stay (LOS), lethality, and comorbidities. Analysis included description, hypothesis testing, and regression. Results. There were 2003 malaria hospitalizations and 480 notified hospitalized cases, mainly in young male adults. P. falciparum was the main agent of infection acquired mainly in sub-Saharan Africa. Lethality was 1.95% and mean LOS was 8.09 days. Older age entailed longer LOS and increased lethality. Discussion. From 2000 to 2009, there were 2003 malaria hospitalizations with decreasing annual incidence, these numbers being remarkably higher than those notified. The national database of diagnosis related groups, reflecting hospitalizations on NHS hospitals, may be an unexplored complementary source for better estimates on imported malaria. PMID- 25548716 TI - Multiple Antimicrobial Resistance of Escherichia coli Isolated from Chickens in Iran. AB - Antimicrobial agents are used extremely in order to reduce the great losses caused by Escherichia coli infections in poultry industry. In this study, 318 pathogenic Escherichia coli (APEC) strains isolated from commercial broiler flocks with coli-septicemia were examined for antimicrobials of both veterinary and human significance by disc diffusion method. Multiple resistances to antimicrobial agents were observed in all the isolates. Resistance to the antibiotics was as follows: Tylosin (88.68%), Erythromycin (71.70%), Oxytetracycline (43.40%), Sulfadimethoxine-Trimethoprim (39.62%), Enrofloxacin (37.74%), Florfenicol (35.85%), Chlortetracycline (33.96%), Doxycycline (16.98%), Difloxacin (32.08%), Danofloxacin (28.30%), Chloramphenicol (20.75%), Ciprofloxacin (7.55%), and Gentamicin (5.66%). This study showed resistance against the antimicrobial agents that are commonly applied in poultry, although resistance against the antibiotics that are only applied in humans or less frequently used in poultry was significantly low. This study emphasizes on the occurrence of multiple drug resistant E. coli among diseased broiler chickens in Iran. The data revealed the relative risks of using antimicrobials in poultry industry. It also concluded that use of antibiotics must be limited in poultry farms in order to reduce the antibiotic resistances. PMID- 25548717 TI - Research of Recognition Method of Discrete Wavelet Feature Extraction and PNN Classification of Rats FT-IR Pancreatic Cancer Data. AB - Sprague-Dawley (SD) rats' normal and abnormal pancreatic tissues are determined directly by attenuated total reflectance Fourier transform infrared (ATR-FT-IR) spectroscopy method. In order to diagnose earlier stage of SD rats pancreatic cancer rate with FT-IR, a novel method of extraction of FT-IR feature using discrete wavelet transformation (DWT) analysis and classification with the probability neural network (PNN) was developed. The differences between normal pancreatic and abnormal samples were identified by PNN based on the indices of 4 feature variants. When error goal was 0.01, the total correct rates of pancreatic early carcinoma and advanced carcinoma were 98% and 100%, respectively. It was practical to apply PNN on the basis of ATR-FT-IR to identify abnormal tissues. The research result shows the feasibility of establishing the models with FT-IR DWT-PNN method to identify normal pancreatic tissues, early carcinoma tissues, and advanced carcinoma tissues. PMID- 25548718 TI - Detection of beta -Lactamases and Outer Membrane Porins among Klebsiella pneumoniae Strains Isolated in Iran. AB - This descriptive study was accomplished on 83 K. pneumoniae strains isolated from two hospitals in Tehran, Iran. Antibiotic susceptibility tests were performed by disc diffusion and broth microdilution methods. ESBLs, MBL, Amp-C, and KPC producing strains were detected by phenotypic confirmatory test, combination disk diffusion test (CDDT), Amp-C detection kit, and modified Hodge test, respectively. OXA-48, NDM-1, and CTX-M-15 genes were detected by PCR and sequencing methods. The outer membrane porins such as OmpK35 and OmpK36 were analysed by SDS-PAGE, PCR, and sequencing methods. From 83 K. pneumoniae isolates, 48 (57.5%), 3 (3.5%), 23 (28%), and 5 (6%) were ESBL, MBL, Amp-C, and KPC positive, respectively. The CTX-M-15 gene was detected in 30 (62.5%) and OXA 48 gene was found in 2 (4.1%) of the 48 ESBL-producing isolates. Two isolates harboured both OXA-48 and CTX-M-15; NDM-1 gene was not detected in this study. Outer membrane porin, OmpK35, was detected in 30 (62.5%) of 48 ESBL-producing isolates while OmpK36 was found in 35 (72.91%) of 48 ESBL-producing isolates. In this study, fosfomycin and tigecycline were more effective than other antibiotics. The high prevalence of beta-lactamase-producing K. pneumoniae detected in this study is of great concern, which requires infection control measures including antibacterial management and identification of beta-lactamases producing isolates. PMID- 25548719 TI - Microarray analysis after umbilical cord blood derived mesenchymal stem cells injection in monocrotaline-induced pulmonary artery hypertension rats. AB - Pulmonary arterial hypertension (PAH) is associated with structural alterations of lung vasculature. PAH is still a devastating disease needing an aggressive therapeutic approach. Despite the therapeutic potential of human umbilical cord mesenchymal stem cells (MSCs), the molecular parameters to define the stemness remain largely unknown. Using high-density oligonucleotide microarrays, the differential gene expression profiles between a fraction of mononuclear cells of human umbilical cord blood (UCB) and its MSC subpopulation were obtained. Of particular interest was a subset of 46 genes preferentially expressed at 7-fold or higher in the group treated with human UCB-MSCs. This subset contained numerous genes involved in the inflammatory response, immune response, lipid metabolism, cell adhesion, cell migration, cell differentiation, apoptosis, cell growth, transport, cell proliferation, transcription, and signal transduction. Our results provide a foundation for a more reproducible and reliable quality control using genotypic analysis for the definition of human UCB-MSCs. Therefore, our results will provide a basis for studies on molecular mechanisms controlling the core properties of human MSCs. PMID- 25548720 TI - Mesoesophagus and other fascial structures of the abdominal and lower thoracic esophagus: a histological study using human embryos and fetuses. AB - A term "mesoesophagus" has been often used by surgeons, but the morphology was not described well. To better understand the structures attaching the human abdominal and lower thoracic esophagus to the body wall, we examined serial or semiserial sections from 10 embryos and 9 fetuses. The esophagus was initially embedded in a large posterior mesenchymal tissue, which included the vertebral column and aorta. Below the tracheal bifurcation at the fifth week, the esophagus formed a mesentery-like structure, which we call the "mesoesophagus," that was sculpted by the enlarging lungs and pleural cavity. The pneumatoenteric recess of the pleuroperitoneal canal was observed in the lowest part of the mesoesophagus. At the seventh week, the mesoesophagus was divided into the upper long and lower short parts by the diaphragm. Near the esophageal hiatus, the pleural cavity provided 1 or 2 recesses in the upper side, while the fetal adrenal gland in the left side was attached to the lower side of the mesoesophagus. At the 10th and 18th week, the mesoesophagus remained along the lower thoracic esophagus, but the abdominal esophagus attached to the diaphragm instead of to the left adrenal. The mesoesophagus did not contain any blood vessels from the aorta and to the azygos vein. The posterior attachment of the abdominal esophagus seemed to develop to the major part of the phrenoesophageal membrane with modification from the increased mass of the left fetal adrenal. After postnatal degeneration of the fetal adrenal, the abdominal esophagus might again obtain a mesentery. Consequently, the mesoesophagus seemed to correspond to a small area containing the pulmonary ligament and aorta in adults. PMID- 25548721 TI - Upper terminal of the inferior vena cava and development of the heart atriums: a study using human embryos. AB - In the embryonic heart, the primitive atrium is considered to receive the bilateral sinus horns including the upper terminal of the inferior vena cava (IVC). To reveal topographical anatomy of the embryonic venous pole of the heart, we examined horizontal serial paraffin sections of 15 human embryos with crown rump length 9-31 mm, corresponding to a gestational age of 6-7 weeks or Carnegie stage 14-16. The IVC was often fixed to the developing right pulmonary vein by a mesentery-like fibrous tissue. Rather than the terminal portion of the future superior vena cava, the IVC contributed to form a right-sided atrial lumen at the stage. The sinus venosus or its left horn communicated with the IVC in earlier specimens, but in later specimens, the left atrium extended caudally to separate the sinus and IVC. In contrast, the right atrium consistently extended far caudally, even below the sinus horn, along the IVC. A small (or large) attachment between the left (or right) atrium and IVC in adult hearts seemed to be derived from the left (or right) sinus valve. This hypothesis did not contradict with the incorporation theory of the sinus valves into the atrial wall. Variations in topographical anatomy around the IVC, especially of the sinus valves, might not always depend on the stages but partly in individual differences. PMID- 25548722 TI - Stable isotope analysis of Joseon people skeletons from the cemeteries of Old Seoul City, the capital of Joseon Dynasty. AB - Stable carbon and nitrogen isotope analysis reveals the diets of different human populations in history. In this study, we performed stable isotope analysis on human skeletons from Joseon-period cemeteries discovered around Old Seoul City (Hansung). Our data clearly showed that Joseon individuals consumed more C3-based than C4-based foods as the main staples, and that the proteins they ate were mainly of terrestrial, but not of marine origin. Stable isotope values exhibited unique patterns in each of our sample subgroups. Whereas the delta(13)C values did not show any statistical differences among the subgroups, significantly higher values of delta(15)N were found in males than in females, which might reflect dietary differences between the sexes. For a fuller understanding of the dietary patterns of pre-industrial (pre-20th century) Koreans, additional studies on Joseon samples from Korean archaeological sites will be necessary. PMID- 25548723 TI - Morphological variations of the lungs: a study conducted on Indian cadavers. AB - Awareness of anatomical variations in lungs is essential during segmental or lobar resections of lungs. We studied the variations of fissures, lobes and hilar structures in 65 right and 73 left isolated lungs from the dissection hall. Horizontal fissure was absent in 3.07% and incomplete in 35.38% of right lungs. Four point six one percentage of right lungs had 3 fissures and 4 lobes. Three point zero seven percentage of right lungs had 3 arteries, 67.69% had 2 arteries, and 29.23% had only one artery in the hilum. Sixty-three point zero seven percentage of right lungs had two veins in the hilum; 32.30% had 3 veins in the hilum; and 4.61% had more than 3 veins in the hilum. Ninety-eight point four six percentage of right lungs showed 2 bronchi in the hilum, and 1.53% of them showed 3 bronchi in the hilum. Two of the right lungs (3.07%) had an artery passing across the oblique fissure. Fifteen point zero six percentage of left lungs showed incomplete oblique fissure and 2.73% showed 2 fissures and 3 lobes. Five point four seven percentage of left lungs showed 2 arteries and 94.52% had only one artery in the hilum. Eighty point eight two percentage of left lungs had two veins in the hilum and 19.17% had 3 veins in the hilum. Twenty-one point nine one percent of left lungs had 2 bronchi and 78.08% had only one bronchus in the hilum. The knowledge of variations in the lobar and hilar anatomy of the lung presented in this study is clinically important while interpreting the radiological images and performing surgical procedures. PMID- 25548724 TI - Outcome-based self-assessment on a team-teaching subject in the medical school. AB - We attempted to investigate the reason why the students got a worse grade in gross anatomy and the way how we can improve upon the teaching method since there were gaps between teaching and learning under recently changed integration curriculum. General characteristics of students and exploratory factors to testify the validity were compared between year 2011 and 2012. Students were asked to complete a short survey with a Likert scale. The results were as follows: although the percentage of acceptable items was similar between professors, professor C preferred questions with adequate item discrimination and inappropriate item difficulty whereas professor Y preferred adequate item discrimination and appropriate item difficulty with statistical significance (P<0.01). The survey revealed that 26.5% of total students gave up the exam on gross anatomy of professor Y irrespective of years. These results suggested that students were affected by the corrected item difficulty rather than item discrimination in order to obtain academic achievement. Therefore, professors in a team-teaching subject should reach a consensus on an item difficulty with proper teaching methods. PMID- 25548725 TI - Unilateral ureteric stone associated with gross hydronephrosis and kidney shrinkage: a cadaveric report. AB - Ureteric stones are a common cause of obstruction of the urinary tract, usually presenting with characteristic signs and symptoms, such as acute ureteric colic and hematuria. Occasionally, stones may present with non-specific symptoms such as low back pain and remain unidentified, leading to stone growth, chronic ureteric obstruction and complications such as hydronephrosis and renal damage. Here, we report a large ureteric stone in a cadaver with complete obstruction at the left ureterovesical junction, resulting in severe dilatation of the left ureter and renal pelvis. PMID- 25548726 TI - Unusual morphology of the superior belly of omohyoid muscle. AB - Though anomalies of the superior belly of the omohyoid have been described in medical literature, absence of superior belly of omohyoid is rarely reported. Herein, we report a rare case of unilateral absence of muscular part of superior belly of omohyoid. During laboratory dissections for medical undergraduate students, unusual morphology of the superior belly of the omohyoid muscle has been observed in formalin embalmed male cadaver of South Indian origin. The muscular part of the superior belly of the omohyoid was completely absent. The inferior belly originated normally from the upper border of scapula, and continued with a fibrous tendon which ran vertically lateral to sternohyoid muscle and finally attached to the lower border of the body of hyoid bone. The fibrous tendon was about 1 mm thick and received a nerve supply form the superior root of the ansa cervicalis. As omohyoid mucle is used to achieve the reconstruction of the laryngeal muscles and bowed vocal folds, the knowledge of the possible anomalies of the omohyoid muscle is important during neck surgeries. PMID- 25548727 TI - Multiple absences of the branches of abdominal aorta with congenital absence of the portal vein, unilateral adrenal agenesis and persistent ductus arteriosus in a female cadaver. AB - We report on an extremely rare case of multiple absences of the branches of abdominal aorta with congenital absence of the portal vein, unilateral adrenal agenesis and persistent ductus arteriosus in an adult female cadaver. Specifically, instead of celiac trunk, superior and inferior mesenteric arteries, solely a single arterial trunk aroused from the anterior aspect of abdominal aorta, inferior phrenic and ovarian arteries were absent in both sides. Left kidneys drained by two veins. There were not superior, splenic and mesenteric veins, while left renal vein received an additional vein, which run downward and drained primarily all parts of digestive tract and its associated glands (portal vein did not exist). Right adrenal gland was absent. To the best of our knowledge, it is the only reported case with such widespread anomalies. We think the importance of this case is beyond the surgical consideration and needs more profound developmental studies. PMID- 25548728 TI - Absence of transverse colon, persistent descending mesocolon, displaced small and large bowels: a rare congenital anomaly with a high risk of volvulus formation. AB - Congenital anomalies such as positional anomalies of the right half of the colon are more common when compared to its left half. We report a rare case of congenital anomaly where the transverse colon was totally absent. Ascending colon continued as descending colon at the right colic flexure. Ascending and descending colons formed an inverted U shaped loop which was situated in the right half of the abdomen. The sigmoid colon began from the descending colon, on the right side of the midline and coursed to the left iliac fossa. The terminal part of ascending colon and entire descending colon had a persistent mesocolon. The jejunum and ileum were situated in the upper left part of the abdominal cavity. This anomaly can cause volvulus of the colon at any stage of life. Furthermore, the knowledge of this anomaly is very useful for radiologists, gastroenterologists and surgeons. PMID- 25548729 TI - Missing checkerboards? An absence of competitive signal in Alnus-associated ectomycorrhizal fungal communities. AB - A number of recent studies suggest that interspecific competition plays a key role in determining the structure of ectomycorrhizal (ECM) fungal communities. Despite this growing consensus, there has been limited study of ECM fungal community dynamics in abiotically stressful environments, which are often dominated by positive rather than antagonistic interactions. In this study, we examined the ECM fungal communities associated with the host genus Alnus, which live in soils high in both nitrate and acidity. The nature of ECM fungal species interactions (i.e., antagonistic, neutral, or positive) was assessed using taxon co-occurrence and DNA sequence abundance correlational analyses. ECM fungal communities were sampled from root tips or mesh in-growth bags in three monodominant A. rubra plots at a site in Oregon, USA and identified using Illumina-based amplification of the ITS1 gene region. We found a total of 175 ECM fungal taxa; 16 of which were closely related to known Alnus-associated ECM fungi. Contrary to previous studies of ECM fungal communities, taxon co occurrence analyses on both the total and Alnus-associated ECM datasets indicated that the ECM fungal communities in this system were not structured by interspecific competition. Instead, the co-occurrence patterns were consistent with either random assembly or significant positive interactions. Pair-wise correlational analyses were also more consistent with neutral or positive interactions. Taken together, our results suggest that interspecific competition does not appear to determine the structure of all ECM fungal communities and that abiotic conditions may be important in determining the specific type of interaction occurring among ECM fungi. PMID- 25548730 TI - Positive affect and age as predictors of exercise compliance. AB - Physical exercise is linked to individuals whose affect profiles are invariably positive and it induces anti-apoptotic and anti-excitotoxic effects, buttressing blood-brain barrier intactness in both healthy individuals and those suffering from disorders accompanying overweight and obesity. In this regard, exercise offers a unique non-pharmacologic, non-invasive intervention that incorporates different regimes, whether dynamic or static, endurance, or resistance. In this brief report we present a self-reported study carried out on an adolescent and adult population (N = 280, 144 males and 136 females), which indicated that the propensity and compliance for exercise, measured as the "Archer ratio", was predicted by a positive affect. This association is discussed from the perspective of health, well-being, affect dimensions, and age. PMID- 25548731 TI - Metabolic diversity and niche structure in sponges from the Miskito Cays, Honduras. AB - Hosting symbionts provides many eukaryotes with access to the products of microbial metabolism that are crucial for host performance. On tropical coral reefs, many (High Microbial Abundance [HMA]) but not all (Low Microbial Abundance [LMA]) marine sponges host abundant symbiont communities. Although recent research has revealed substantial variation in these sponge-microbe associations (termed holobionts), little is known about the ecological implications of this diversity. We investigated the expansion of diverse sponge species across isotopic niche space by calculating niche size (as standard ellipse area [SEA c ]) and assessing the relative placement of common sponge species in bivariate (delta (13)C and delta (15)N) plots. Sponges for this study were collected from the relatively isolated reefs within the Miskito Cays of Honduras. These reefs support diverse communities of HMA and LMA species that together span a gradient of photosymbiont abundance, as revealed by chlorophyll a analysis. HMA sponges occupied unique niche space compared to LMA species, but the placement of some HMA sponges was driven by photosymbiont abundance. In addition, photosymbiont abundance explained a significant portion of the variation in isotope values, suggesting that access to autotrophic metabolism provided by photosymbionts is an important predictor in the location of species within isotopic space. Host identity accounted for over 70% of the variation in isotope values within the Miskito Cays and there was substantial variation in the placement of individual species within isotopic niche space, suggesting that holobiont metabolic diversity may allow taxonomically diverse sponge species to utilize unique sources of nutrients within a reef system. This study provides initial evidence that microbial symbionts allow sponges to expand into novel physiochemical niche space. This expansion may reduce competitive interactions within coral reefs and promote diversification of these communities. PMID- 25548733 TI - Combining physical and virtual contexts through augmented reality: design and evaluation of a prototype using a drug box as a marker for antibiotic training. AB - Introduction. Antimicrobial resistance is a global health issue. Studies have shown that improved antibiotic prescription education among healthcare professionals reduces mistakes during the antibiotic prescription process. The aim of this study was to investigate novel educational approaches that through the use of Augmented Reality technology could make use of the real physical context and thereby enrich the educational process of antibiotics prescription. The objective is to investigate which type of information related to antibiotics could be used in an augmented reality application for antibiotics education. Methods. This study followed the Design-Based Research Methodology composed of the following main steps: problem analysis, investigation of information that should be visualized for the training session, and finally the involvement of the end users the development and evaluation processes of the prototype. Results. Two of the most important aspects in the antibiotic prescription process, to represent in an augmented reality application, are the antibiotic guidelines and the side effects. Moreover, this study showed how this information could be visualized from a mobile device using an Augmented Reality scanner and antibiotic drug boxes as markers. Discussion. In this study we investigated the usage of objects from a real physical context such as drug boxes and how they could be used as educational resources. The logical next steps are to examine how this approach of combining physical and virtual contexts through Augmented Reality applications could contribute to the improvement of competencies among healthcare professionals and its impact on the decrease of antibiotics resistance. PMID- 25548732 TI - Population expansions shared among coexisting bacterial lineages are revealed by genetic evidence. AB - Comparative population studies can help elucidate the influence of historical events upon current patterns of biodiversity among taxa that coexist in a given geographic area. In particular, comparative assessments derived from population genetics and coalescent theory have been used to investigate population dynamics of bacterial pathogens in order to understand disease epidemics. In contrast, and despite the ecological relevance of non-host associated and naturally occurring bacteria, there is little understanding of the processes determining their diversity. Here we analyzed the patterns of genetic diversity in coexisting populations of three genera of bacteria (Bacillus, Exiguobacterium, and Pseudomonas) that are abundant in the aquatic systems of the Cuatro Cienegas Basin, Mexico. We tested the hypothesis that a common habitat leaves a signature upon the genetic variation present in bacterial populations, independent of phylogenetic relationships. We used multilocus markers to assess genetic diversity and (1) performed comparative phylogenetic analyses, (2) described the genetic structure of bacterial populations, (3) calculated descriptive parameters of genetic diversity, (4) performed neutrality tests, and (5) conducted coalescent-based historical reconstructions. Our results show a trend of synchronic expansions across most populations independent of both lineage and sampling site. Thus, we provide empirical evidence supporting the analysis of coexisting bacterial lineages in natural environments to advance our understanding of bacterial evolution beyond medical or health-related microbes. PMID- 25548734 TI - Public stigma associated with mental illnesses in Pakistani university students: a cross sectional survey. AB - Background. The objectives of the study were to explore the knowledge and attitudes of Pakistani university students toward mental illnesses. People with mental illnesses are challenged not only by their symptoms but also by the prejudices associated with their illness. Acknowledging the stigma of mental illness should be the first essential step toward devising an appropriate treatment plan. Methods. A cross-sectional survey was conducted at the University of Punjab, Lahore, CMH Lahore Medical and Dental College, Lahore, and University of Sargodha, Sub-campus Lahore, from February to May 2014. The self-administered questionnaire consisted of three sections: demographics, general knowledge of psychiatric illnesses, and Community Attitudes towards Mental Illnesses (CAMI) Scale. The questionnaire was distributed to 650 participants enrolled in different disciplines (Social Sciences, Medicine and Formal Sciences). Results. Response rate was 81% (527/650 respondents). Mean age was 20.98 years. Most of the students (331, 62.8%) had an urban background and studied Social Sciences (238, 45.2%). Four hundred and eighteen respondents (79.3%) considered religion very important and most respondents considered psychiatrists (334, 63.4%) and spiritual leaders (72, 13.7%) to be best able to treat mental illnesses. One hundred and sixty nine respondents (32.1%) considered black magic to be a cause of mental illness. Only 215 (41%) respondents had ever read an article on mental illnesses. Multiple regression analysis revealed study discipline, exposure, perceived causes of mental illnesses and superstitions to be significantly associated with attitudes towards mental illnesses (p < .05). Conclusion. Although low awareness and exposure were found in this sample of Pakistani university students, their attitude towards mental illnesses was generally positive. Most respondents gave supernatural explanations for mental illnesses but only a few believed that spiritual leaders can play a role in treatment. PMID- 25548735 TI - Plasticity of gene expression according to salinity in the testis of broodstock and F1 black-chinned tilapia, Sarotherodon melanotheron heudelotii. AB - The black-chinned tilapia Sarotherodon melanotheron heudelotii Ruppell 1852 (Teleostei, Cichlidae) displays remarkable acclimation capacities. When exposed to drastic changes of salinity, which can be the case in its natural habitat, it develops quick physiological responses and keeps reproducing. The present study focused on the physiological impact of salinity on male reproductive capacities, using gene expression as a proxy of acclimation process. Two series of experimental fish were investigated: the first one was composed of fish maintained in freshwater for several generations and newly acclimated to salinities of 35 and 70, whereas the second one consisted of the descendants of the latter born and were raised under their native salinity. Expression patterns of 43 candidate genes previously identified from the testes of wild males was investigated in the three salinities and two generations. Twenty of them showed significant expression differences between salinities, and their predicted function revealed that most of them are involved in the osmotic tolerance of sperm cells and/or in the maintenance of sperm motility. A high level of expression variation was evidenced, especially for fish maintained in freshwater. In spite of this, gene expression patterns allowed the differentiation between fish raised in freshwater and those maintained in hypersaline water in both generations. Altogether, the results presented here suggest that this high variability of expression is likely to ensure the reproductive success of this species under varying salinities. PMID- 25548736 TI - A statistical assessment of population trends for data deficient Mexican amphibians. AB - Background. Mexico has the world's fifth largest population of amphibians and the second country with the highest quantity of threatened amphibian species. About 10% of Mexican amphibians lack enough data to be assigned to a risk category by the IUCN, so in this paper we want to test a statistical tool that, in the absence of specific demographic data, can assess a species' risk of extinction, population trend, and to better understand which variables increase their vulnerability. Recent studies have demonstrated that the risk of species decline depends on extrinsic and intrinsic traits, thus including both of them for assessing extinction might render more accurate assessment of threats. Methods. We harvested data from the Encyclopedia of Life (EOL) and the published literature for Mexican amphibians, and used these data to assess the population trend of some of the Mexican species that have been assigned to the Data Deficient category of the IUCN using Random Forests, a Machine Learning method that gives a prediction of complex processes and identifies the most important variables that account for the predictions. Results. Our results show that most of the data deficient Mexican amphibians that we used have decreasing population trends. We found that Random Forests is a solid way to identify species with decreasing population trends when no demographic data is available. Moreover, we point to the most important variables that make species more vulnerable for extinction. This exercise is a very valuable first step in assigning conservation priorities for poorly known species. PMID- 25548737 TI - Cost-of-illness studies: concepts, scopes, and methods. AB - Liver diseases are one of the main causes of death, and their ever-increasing prevalence is threatening to cause significant damage both to individuals and society as a whole. This damage is especially serious for the economically active population in Korea. From the societal perspective, it is therefore necessary to consider the economic impacts associated with liver diseases, and identify interventions that can reduce the burden of these diseases. The cost-of-illness study is considered to be an essential evaluation technique in health care. By measuring and comparing the economic burdens of diseases to society, such studies can help health-care decision-makers to set up and prioritize health-care policies and interventions. Using economic theories, this paper introduces various study methods that are generally applicable to most disease cases for estimating the costs of illness associated with mortality, morbidity, disability, and other disease characteristics. It also presents concepts and scopes of costs along with different cost categories from different research perspectives in cost estimations. By discussing the epidemiological and economic grounds of the cost of-illness study, the reported results represent useful information about several evaluation techniques at an advanced level, such as cost-benefit analysis, cost effectiveness analysis, and cost-utility analysis. PMID- 25548739 TI - Angiotensin receptor blocker add-on therapy in portal hypertension: to use angiotensin receptor blocker or not to use, that is the question. PMID- 25548738 TI - Management of viral hepatitis in liver transplant recipients. AB - Recurrence of viral hepatitis after liver transplantation (LT) can progress to graft failure and lead to a decrease in long-term survival. Recently, there have been remarkable improvement in the treatment of chronic hepatitis B (CHB) using potent antiviral agents. Combination of hepatitis B immunoglobulin and potent antiviral therapy has brought marked advances in the management of CHB for liver transplant recipients. Post-transplant antiviral therapy for hepatitis C virus infection is generally reserved for patients showing progressive disease. Acheiving a sustained virological response in patients with LT greatly ameliorates graft and overall survival, however this only occurs in 30% of transplant recipient using pegylated interferon and ribavirin (RBV). Direct acting antivirals such as protease inhibitors, polymerase or other non-structural proteins inhibitors are anticipated to establish the new standard of care for transplant recipients. In liver transplant recipients, hepatitis E virus infection is an uncommon disease. However, it can lead to chronic hepatitis and cirrhosis and may require retransplantation. Recently, 3-month course of RBV monotherapy has been reported as an effective treatment. This review focuses on the recent management and therapeutic approaches of viral hepatitis in liver transplant recipient. PMID- 25548740 TI - Serum transferrin as a liver fibrosis biomarker in patients with chronic hepatitis B. AB - BACKGROUND/AIMS: Transferrin and alpha-1 antitrypsin are reportedly associated with liver fibrosis. We evaluated the usefulness of serum transferrin and alpha-1 antitrypsin as new liver fibrosis markers in patients with chronic hepatitis B. METHODS: The study included 293 patients with chronic hepatitis B who underwent a liver biopsy between October 2005 and June 2009, and who had no history of hepatocellular carcinoma. Serum markers and liver fibrosis stages were compared. RESULTS: Univariate analysis revealed that age (P<0.001), serum platelet count (P<0.001), and serum alkaline phosphatase level (P=0.003) differed significantly between the patients with and without liver cirrhosis. Serum transferrin levels were significantly lower in advanced fibrosis than in mild fibrosis in both univariate analysis (P=0.002) and multivariate analysis (P=0.009). In addition, the serum transferrin level was significantly lower in cirrhotic patients than in noncirrhotic patients (P=0.020). However, the serum level of alpha-1 antitrypsin was not significantly associated with liver cirrhosis in patients with chronic hepatitis B. CONCLUSIONS: Serum transferrin could be promising serum marker for predicting advanced liver fibrosis in patients with chronic hepatitis B. PMID- 25548741 TI - Is it necessary to delay antiviral therapy for 3-6 months to anticipate HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B in endemic areas of HBV genotype C? AB - BACKGROUND/AIMS: Spontaneous HBeAg seroconversion occurs frequently in the immune reactive phase in HBeAg-positive chronic hepatitis B (CHB). Therefore, observation for 3-6 months before commencing antiviral therapy is recommended in patients with alanine aminotransferase (ALT) levels that exceed twice the upper limit of normal (ULN). However, HBeAg seroconversion occurs infrequently in patients infected with hepatitis B virus (HBV) genotype C. The aim of the present study was to determine whether the waiting policy is necessary in endemic areas of HBV genotype C infection. METHODS: Ninety patients with HBeAg-positive CHB were followed prospectively without administering antiviral therapy for 6 months. Antiviral therapy was initiated promptly at any time if there was any evidence of biochemical (i.e., acute exacerbation of HBV infection or aggravation of jaundice) or symptomatic deterioration. After 6 months of observation, antiviral therapy was initiated according to the patient's ALT and HBV DNA levels. RESULTS: Only one patient (1.1%) achieved spontaneous HBeAg seroconversion. Biochemical and symptomatic deterioration occurred before 6 months in 17 patients (18.9%) and 5 patients, respectively. High ALT and HBV DNA levels were both independent risk factors for biochemical deterioration. Of 15 patients with HBV DNA >= 5.1 * 10(7) IU/mL and ALT >= 5 * ULN, biochemical deterioration occurred in 7 (46.7%), including 1 patient receiving liver transplantation due to liver failure. CONCLUSIONS: Spontaneous HBeAg seroconversion in patients with HBeAg-positive CHB is rare within 6 months. Biochemical deterioration was common and may lead to liver failure. Immediate antiviral therapy should be considered, especially in patients with high ALT and HBV DNA levels in endemic areas of genotype C infection. PMID- 25548742 TI - Geographic differences in the epidemiological features of HCV infection in Korea. AB - BACKGROUND/AIMS: The prevalence of hepatitis C virus (HCV) infection in Korea exhibits significant geographic variation, with it being higher in Busan and Jeonam than in other areas. The reason for this intranational geographic difference was investigated in this study by conducting a comparative analysis of the risk factors related to HCV infection among three geographic areas: the capital (Seoul), Busan, and the province of Jeolla. METHODS: In total, 990 patients with chronic HCV infection were prospectively enrolled at 5 university hospitals located in Seoul (n=374), Busan (n=264), and Jeolla (n=352). A standardized questionnaire survey on the risk factors for HCV infection was administered to these three groups of patients, and a comparative analysis of the findings was performed. RESULTS: The analysis revealed significant regional differences in exposure to the risk factors of HCV infection. By comparison with patients in Seoul as a control group in the multivariate analysis, patients in Busan had significantly more experience of invasive medical procedures, acupuncture, cosmetic procedures, and multiple sex partners. In contrast, patients in Jeolla were significantly older, and they had a higher prevalence of hepatocellular carcinoma, a lower prevalence of multiple sex partners, and had experienced fewer invasive procedures. CONCLUSIONS: There was a significant geographic difference in the exposure to potential risk factors of HCV infection between patients from the three studied regions. This may explain the regional variation of the prevalence of HCV infection in Korea, and should be taken into account when planning strategies for the prevention and management of HCV infection. PMID- 25548743 TI - Predictors of spontaneous viral clearance and outcomes of acute hepatitis C infection. AB - BACKGROUND/AIMS: This study evaluated the predictors of spontaneous viral clearance (SVC), as defined by two consecutive undetectable hepatitis C virus (HCV) RNA tests performed >= 12 weeks apart, and the outcomes of acute hepatitis C (AHC) demonstrating SVC or treatment-induced viral clearance. METHODS: Thirty two patients with AHC were followed for 12-16 weeks without administering antiviral therapy. RESULTS: HCV RNA was undetectable at least once in 14 of the 32 patients. SVC occurred in 12 patients (37.5%), among whom relapse occurred in 4. SVC was exhibited in 8 of the 11 patients exhibiting undetectable HCV RNA within 12 weeks. HCV RNA reappeared in three patients (including two patients with SVC) exhibiting undetectable HCV RNA after 12 weeks. SVC was more frequent in patients with low viremia than in those with high viremia (55.6% vs. 14.3%; P=0.02), and in patients with HCV genotype non-1b than in those with HCV genotype 1b (57.1% vs. 22.2%; P=0.04). SVC was more common in patients with a >= 2 log reduction of HCV RNA at 4 weeks than in those with a smaller reduction (90% vs. 9.1%, P<0.001). A sustained viral response was achieved in all patients (n=18) receiving antiviral therapy. CONCLUSIONS: Baseline levels of HCV RNA and genotype non-1b were independent predictors for SVC. A >= 2 log reduction of HCV RNA at 4 weeks was a follow-up predictor for SVC. Undetectable HCV RNA occurring after 12 weeks was not sustained. All patients receiving antiviral therapy achieved a sustained viral response. Antiviral therapy should be initiated in patients with detectable HCV RNA at 12 weeks after the diagnosis. PMID- 25548744 TI - Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension. AB - BACKGROUND/AIMS: Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial. METHODS: Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders. RESULTS: The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12 27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P = 0.674]. The response rate (55.6% vs. 61.5%, P = 0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups. CONCLUSIONS: The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended. PMID- 25548745 TI - Safety, efficacy, and response predictors of anticoagulation for the treatment of nonmalignant portal-vein thrombosis in patients with cirrhosis: a propensity score matching analysis. AB - BACKGROUND/AIMS: Portal-vein thrombosis (PVT) develops in 10-25% of cirrhotic patients and may aggravate portal hypertension. There are few data regarding the effects of anticoagulation on nonmalignant PVT in liver cirrhosis. The aim of this study was to elucidate the safety, efficacy, and predictors of response to anticoagulation therapy in cirrhotic patients. METHODS: Patients with liver cirrhosis and nonmalignant PVT were identified by a hospital electronic medical record system (called BESTCARE). Patients with malignant PVT, Budd-Chiari syndrome, underlying primary hematologic disorders, or preexisting extrahepatic thrombosis were excluded from the analysis. Patients were divided into two groups (treatment and nontreatment), and propensity score matching analysis was performed to identify control patients. The sizes of the thrombus and spleen were evaluated using multidetector computed tomography. RESULTS: Twenty-eight patients were enrolled in this study between 2003 and 2014: 14 patients who received warfarin for nonmalignant PVT and 14 patients who received no anticoagulation. After 112 days of treatment, 11 patients exhibited significantly higher response rates (complete in 6 and partial in 5) compared to the control patients, with decreases in thrombus size of >30%. Compared to nonresponders, the 11 responders were older, and had a thinner spleen and fewer episodes of previous endoscopic variceal ligations, whereas pretreatment liver function and changes in prothrombin time after anticoagulation did not differ significantly between the two groups. Two patients died after warfarin therapy, but the causes of death were not related to anticoagulation. CONCLUSIONS: Warfarin can be safely administered to cirrhotic patients with nonmalignant PVT. The presence of preexisting portal hypertension is a predictor of nonresponse to anticoagulation. PMID- 25548746 TI - A case of focal nodular hyperplasia with growth progression during pregnancy. AB - Focal nodular hyperplasia (FNH) is the second most common benign solid tumor of the liver and is usually found in young females. In FNH, spontaneous bleeding or rupture rarely occurs and malignant transformation is unlikely. The etiology of FNH is unclear, but because of female predominance and young age at onset, it seems that female hormone has an important role for the development of FNH. Although the development and the complications of hepatocellular adenomas have been related to the use of oral contraceptives and pregnancy, the influence of oral contraceptives and pregnancy on the growth and complications of FNH is controversial. Most FNH are stable in size and rarely complicated during pregnancy. We describe here a case of FNH with growth progression during pregnancy in a 27-year-old female. Her course of pregnancy and delivery was uneventful. Two months after delivery, the size of FNH was decreased. PMID- 25548747 TI - Reversible splenial lesion on the corpus callosum in nonfulminant hepatitis A presenting as encephalopathy. AB - Reversible focal lesions on the splenium of the corpus callosum (SCC) have been reported in patients with mild encephalitis/encephalopathy caused by various infectious agents, such as influenza, mumps, adenovirus, Varicella zoster, Escherichia coli, Legionella pneumophila, and Staphylococcus aureus. We report a case of a reversible SCC lesion causing reversible encephalopathy in nonfulminant hepatitis A. A 30-year-old healthy male with dysarthria and fever was admitted to our hospital. After admission his mental status became confused, and so we performed electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain, which revealed an intensified signal on diffusion-weighted imaging (DWI) at the SCC. His mental status improved 5 days after admission, and the SCC lesion had completely disappeared 15 days after admission. PMID- 25548748 TI - Intrahepatic cholangiocarcinoma arising in Caroli's disease. PMID- 25548750 TI - Here comes the cord. PMID- 25548749 TI - Composite liver tumors: a radiologic-pathologic correlation. AB - Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis. PMID- 25548751 TI - The puzzle of myeloproliferative neoplasms: novel disease-specific mutations and new proposals for diagnostic criteria. PMID- 25548753 TI - Visceral leishmaniasis in an Afghan woman with systemic lupus erythematosus. PMID- 25548752 TI - Spontaneous intramural hemorrhage in a patient with severe hemophilia A. PMID- 25548755 TI - Transplant physicians' perceptions of cord blood transplantation in Korea: a questionnaire survey. AB - BACKGROUND: Although bone marrow (BM) or mobilized peripheral blood (PB) is frequently used as the source of hematopoietic stem cells, hematopoietic stem cell transplantation (HSCT) using cord blood (CB) is gradually gaining popularity in many countries. However, BM or PB is still preferred over CB in Korea. Therefore, we tried to assess the awareness of CB transplantation (CBT) among domestic HSCT physicians and develop strategies for boosting its utilization by administering questionnaires to some of these physicians. METHODS: A direct questionnaire survey was conducted using the "Audience Response System" among 301 members who attended the annual meeting of the Korean Society of Blood and Marrow Transplantation. The data were analyzed for only 67 board certified physicians who were directly involved in HSCT activities. RESULTS: The poor outcomes resulting from insufficient experience in CBT was designated by the physicians as the main reason for the low domestic implementation of HSCT using CB. Other reasons identified in the survey were distrust in the quality and management of domestic CB and the high cost of obtaining CB. CONCLUSION: Increasing the use of donated CB would foremost require increasing the inventory of donated CB containing a sufficient cell number for CBT and securing structured quality control of the CB banks. In addition, it would be necessary to minimize CB supply costs and continue to provide academic data, including CBT guidelines, so that clinicians could perform CBT with more confidence. PMID- 25548754 TI - Pathogenesis of myelodysplastic syndromes: an overview of molecular and non molecular aspects of the disease. AB - Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells generally characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, and variable degrees of cytopenias. Most MDS patients are diagnosed in their late 60s to early 70s. The estimated incidence of MDS in the United States and in Europe are 4.3 and 1.8 per 100,000 individuals per year, respectively with lower rates reported in some Asian countries and less well estimated in other parts of the world. Evolution to acute myeloid leukemia can occur in 10-15% of MDS patients. Three drugs are currently approved for the treatment of patients with MDS: immunomodulatory agents (lenalidomide), and hypomethylating therapy [HMT (decitabine and 5 azacytidine)]. All patients will eventually lose their response to therapy, and the survival outcome of MDS patients is poor (median survival of 4.5 months) especially for patients who fail (refractory/relapsed) HMT. The only potential curative treatment for MDS is hematopoietic cell transplantation. Genomic/chromosomal instability and various mechanisms contribute to the pathogenesis and prognosis of the disease. High throughput genetic technologies like single nucleotide polymorphism array analysis and next generation sequencing technologies have uncovered novel genetic alterations and increased our knowledge of MDS pathogenesis. We will review various genetic and non-genetic causes that are involved in the pathogenesis of MDS. PMID- 25548756 TI - Monosomal and complex karyotypes as prognostic parameters in patients with International Prognostic Scoring System higher risk myelodysplastic syndrome treated with azacitidine. AB - BACKGROUND: Azacitidine (AZA) is standard care for patients with myelodysplastic syndrome (MDS) who have not had allogeneic stem cell transplantation. Chromosomal abnormalities (CA) including complex karyotype (CK) or monosomal karyotype (MK) are associated with clinical outcome in patients with MDS. METHODS: We investigated which prognostic factors including CAs would predict clinical outcomes in patients with International Prognostic Scoring System (IPSS) higher risk MDS treated with AZA, retrospectively. CK was defined as the presence of three or more numerical or structural CAs. MK was defined as the presence of two or more distinct autosomal monosomies or single autosomal monosomy with at least one additional structural CA. RESULTS: A total of 243 patients who treated with AZA, were enrolled. CK was present in 124 patients and MK was present in 90 patients. Bone marrow blasts >=15% and CK were associated with poorer response (P=0.038, P=0.007) and overall survival (OS) (P<0.001, P<0.001) independently. Although MK in CK group was not associated with prognosis, non-MK status in non CK group reflected favorable OS (P=0.005). The group including >3 CAs was associated with poorer OS (group including <3 CAs vs. only three CAs, P=0.001; group with >3 CAs vs. only three CAs, P=0.001). CONCLUSION: CK was an important prognostic parameter associated with worse outcome. MK may predict poor survival in only non-CK status. The higher number of CAs was associated with poorer survival. PMID- 25548757 TI - Aberrant myeloid antigen co-expression is correlated with high percentages of CD34-positive cells among blasts of acute lymphoblastic leukemia patients: an Indian tertiary care center perspective. AB - BACKGROUND: Aberrant myeloid antigen (MA) co-expression and high expression of CD34 antigen on the blasts of acute lymphoblastic leukemia (ALL) patients are independently reported to have a role in pathogenesis and prognosis. This study was conducted to determine whether these two parameters are related. METHODS: A total of 204 cases of ALL were included in an analysis of blast immunophenotypic data. CD34 expression was categorized as low when less than 50% of blasts were CD34-positive (CD34(low)) and as high when 50% or more were CD34-positive (CD34(high)). RESULTS: Of 204 cases of ALL, 163 and 41 were of B-cell origin (B ALL) and T-cell origin (T-ALL), respectively. Of all cases, 132 (64.7%) showed co expression of MA and among these, 101 (76.51%) were CD34(high), while the remaining 31 (23.48%) were CD34(low). Of 72 cases without MA co-expression, 25 (34.72%) were CD34(high) and 47 (67.25%) were CD34(low). Furthermore, of 163 cases of B-ALL, 111 showed co-expression of MA and 84 of these were CD34(high). Of 52 cases of B-ALL without MA expression, 22 were CD34(high). Among 41 cases of T-ALL, 21 co-expressed MA, 17 of which were CD34(high). Moreover, all 20 cases of T-ALL without co-expression of MA were CD34(low). These differences were statistically significant. CONCLUSION: We observed a strong correlation between aberrant MA expression and CD34(high) expression on the blasts of ALL. We hypothesize that these different patient subsets may represent unique prognostic characteristics. PMID- 25548758 TI - Clinical characteristics and treatment outcomes of children with anaplastic large cell lymphoma: a single center experience. AB - BACKGROUND: Anaplastic large cell lymphoma (ALCL) is uncommon in children, accounting for approximately 15% of all cases of childhood non-Hodgkin lymphoma. Despite many studies attempting new treatment strategies, treatment outcomes have not significantly improved, and the optimal treatment for pediatric ALCL has not been established. METHODS: The records of newly diagnosed ALCL patients at our institute between July 1998 and April 2013 were reviewed. We evaluated the general characteristics of the patients, chemotherapy regimens, overall survival (OS) rates, and event-free survival (EFS) rates. RESULTS: Twenty-eight ALCL patients were eligible. The median age at diagnosis was 10.8 years. Lymph node involvement was the most common presentation (79%). CCG-5941, a multi-agent T cell lineage chemotherapy, was the predominant treatment regimen (57%). The five year OS and EFS rates were 88% and 69%, respectively. Stage, the presence of B symptoms, lung involvement, and bone marrow involvement were significant prognostic factors for EFS (P=0.02, 0.01, 0.01, and 0.02, respectively). Eight patients relapsed, and three died during the study period. Four of the eight patients who relapsed were treated with high-dose chemotherapy and autologous stem cell transplantation (HDCT-ASCT). Two of the four who had undergone HDCT ASCT developed secondary relapses and were subsequently treated with allogeneic SCT or brentuximab. CONCLUSION: We found that treatment outcomes with multi-agent chemotherapy in children with ALCL were similar to those of previous reports, and that relapsed patients could be salvaged with HDCT-ASCT or allogeneic SCT. A prospective, larger cohort study is warranted to define the optimal treatment for pediatric ALCL. PMID- 25548759 TI - Clinical features and outcomes in patients with human immunodeficiency virus negative, multicentric Castleman's disease: a single medical center experience. AB - BACKGROUND: Multicentric Castleman's disease (CD) is commonly associated with poor prognosis, and well-known prognostic factors are scarce. We performed a retrospective analysis to define the clinical features and prognostic factors for patients with multicentric CD. METHODS: Between 1990 and 2013, 32 patients with multicentric CD were identified from the database of the Asan Medical Center, Seoul, Korea. Clinicopathologic data were collected by reviewing the medical records. With the exclusion of 4 patients because of unknown human immunodeficiency virus infection status, 28 human immunodeficiency virus-negative patients with multicentric CD were included in this analysis. RESULTS: Most of the patients were male (76%) and had a median age of 54 years. Hyaline vascular variant was the most common subtype (N=11, 39%). Hepatosplenomegaly (61%), fever (39%), edema (29%), and ascites (18%) were the most frequently reported symptoms and signs at diagnosis. With a median follow-up of 67 months, the 5-year overall survival (OS) was 77%. Patients with extravascular fluid accumulation (i.e., peripheral edema, ascites, and/or pleural effusions) were significantly associated with a poor survival rate (5-year OS, 94% vs. 56%; P=0.04). The extent of disease involvement was also a significant prognostic factor (5-year OS, 91% for involvement on a single side vs. 73% on both sides of the diaphragm; P=0.03). Other clinicopathologic factors were not significantly associated with patient survival. CONCLUSION: Our findings suggest that the hyaline vascular variant is not a rare subtype of multicentric CD. Extravascular fluid accumulation and disseminated disease involvement seem to be significant prognostic factors. PMID- 25548760 TI - Can we predict neonatal thrombocytopenia in offspring of women with idiopathic thrombocytopenic purpura? AB - BACKGROUND: We aimed to investigate which factors in the clinical profile of mothers with idiopathic thrombocytopenic purpura (ITP) can predict neonatal risk of thrombocytopenia. METHODS: Data was retrospectively collected from all pregnant women with ITP who presented to our institution between 2001 and 2013. Neonatal offspring of these women were classified into 2 groups based on the presence or absence of neonatal thrombocytopenia (platelet count <100*10(9)/L). Several parameters were compared between the 2 groups, including maternal age, maternal platelet count, maternal treatment history, and thrombocytopenia in siblings. We further examined the correlation between maternal platelet count at the time of delivery and neonatal platelet count at birth; we also examined the correlation between the minimum platelet counts of other children born to multiparous women. RESULTS: Sixty-six neonates from 49 mothers were enrolled in the study. Thrombocytopenia was observed in 13 (19.7%) neonates. Maternal treatment for ITP such as splenectomy did not correlate with a risk of neonatal thrombocytopenia. Sibling thrombocytopenia was more frequently observed in neonates with thrombocytopenia than in those without (7/13 vs. 4/53, P<0.01). No association was observed between maternal and neonatal platelet counts. However, the nadir neonatal platelet counts of first- and second-born siblings were highly correlated (r=0.87). CONCLUSION: Thrombocytopenia in neonates of women with ITP cannot be predicted by maternal treatment history or platelet count. However, the presence of an older sibling with neonatal thrombocytopenia is a reliable risk factor for neonatal thrombocytopenia in subsequent pregnancies. PMID- 25548761 TI - Progress of in vitro factor VIII coagulant activity from 0 to 8 hours after reconstitution. AB - BACKGROUND: Continuous infusion of factor VIII (FVIII) is a more cost-effective method for treating hemophilia A than intermittent bolus injection. However, there is currently no specific data in Korea about the progress of in vitro FVIII coagulant activity (FVIII:C) after reconstitution from its lyophilized form. METHODS: Three commercial FVIII concentrate products (two recombinant FVIII and one plasma-derived) were used. In vitro FVIII:C was measured at 0, 2, 4, 6, and 8 hours following reconstitution in both the indoor light-exposed and light shielded groups. RESULTS: For the three drugs, in vitro FVIII:C decreased over the 8 hours following reconstitution (P<0.001). The decline of FVIII:C was linear (P<0.001). In vitro FVIII:C for the indoor light-exposed groups was 95.3+/-1.9% and 90.6+/-2.5% after 4 and 8 hours following reconstitution, respectively, compared to baseline activity. In the light-shielded group, FVIII:C was 95.4+/ 1.1% and 90.9+/-1.7% of the baseline activity after 4 and 8 hours, respectively. There was no statistical difference between FVIII:C in the indoor light-exposed and light-shielded groups (P=0.849). CONCLUSION: In vitro FVIII:C decreased after reconstitution, but activity was maintained at over 90% of the baseline value during 8 hours. Exposure to indoor light did not accelerate the loss of FVIII:C over the experimental time. This result indicates that CI with FVIII is available in 8-hour intervals, with no indoor light-exposure precautions needed. PMID- 25548763 TI - Nodal involvement of extranodal marginal zone lymphoma with extreme plasmacytic differentiation (Mott cell formation) simulating plasma cell neoplasm and lymphoplasmacytic lymphoma. PMID- 25548764 TI - Tumor flare reaction in a patient with mantle cell lymphoma. PMID- 25548762 TI - Case series of precursor B-cell lymphoblastic lymphoma. AB - Precursor B-cell lymphoblastic lymphoma (B-LBL) is an uncommon subtype of Non Hodgkin lymphoma (NHL), accounting for only 0.3% of NHL in adults and less than 10% of all LBL cases. Unlike T-cell LBL, it usually presents with extranodal involvement while sparing the bone marrow (BM). Among the 27 patients with LBL treated in the Asan Medical Center between January 2007 and March 2012, 3 had B LBL. All had a good performance status and low International Prognostic Index. However, unlike most previously reported cases, the patients had lymphoma in their bone marrow and extranodal sites such as bone and lung. After intensive combination chemotherapy, one patient achieved a complete response and the other 2 patients, a partial response. Our experience suggests that multiple extranodal sites may be involved in B-LBL and BM involvement may not be as infrequent as previously thought. Furthermore, intensive chemotherapy seems to be effective. PMID- 25548765 TI - Extramedullary plasmacytoma of the thyroid: report of a rare case. PMID- 25548766 TI - JAK2 V617F-positive polycythemia vera accompanied by renal artery stenosis. PMID- 25548767 TI - Protective effect of a lipid-based preparation from Mycobacterium smegmatis in a murine model of progressive pulmonary tuberculosis. AB - A more effective vaccine against tuberculosis (TB) is urgently needed. Based on its high genetic homology with Mycobacterium tuberculosis (Mtb), the nonpathogenic mycobacteria, Mycobacterium smegmatis (Ms), could be an attractive source of potential antigens to be included in such a vaccine. We evaluated the capability of lipid-based preparations obtained from Ms to provide a protective response in Balb/c mice after challenge with Mtb H37Rv strain. The intratracheal model of progressive pulmonary TB was used to assess the level of protection in terms of bacterial load as well as the pathological changes in the lungs of immunized Balb/c mice following challenge with Mtb. Mice immunized with the lipid based preparation from Ms either adjuvanted with Alum (LMs-AL) or nonadjuvanted (LMs) showed significant reductions in bacterial load (P < 0.01) compared to the negative control group (animals immunized with phosphate buffered saline (PBS)). Both lipid formulations showed the same level of protection as Bacille Calmette and Guerin (BCG). Regarding the pathologic changes in the lungs, mice immunized with both lipid formulations showed less pneumonic area when compared with the PBS group (P < 0.01) and showed similar results compared with the BCG group. These findings suggest the potential of LMs as a promising vaccine candidate against TB. PMID- 25548768 TI - Vinpocetine and pyritinol: a new model for blood rheological modulation in cerebrovascular disorders-a randomized controlled clinical study. AB - Blood and plasma viscosity are the major factors affecting blood flow and normal circulation. Whole blood viscosity is mainly affected by plasma viscosity, red blood cell deformability/aggregation and hematocrit, and other physiological factors. Thirty patients (twenty males + ten females) with age range 50-65 years, normotensive with history of cerebrovascular disorders, were selected according to the American Heart Stroke Association. Blood viscosity and other rheological parameters were measured after two-day abstinence from any medications. Dual effects of vinpocetine and pyritinol exhibit significant effects on all hemorheological parameters (P < 0.05), especially on low shear whole blood viscosity (P < 0.01), but they produced insignificant effects on total serum protein and high shear whole blood viscosity (P > 0.05). Therefore, joint effects of vinpocetine and pyritinol improve blood and plasma viscosity in patients with cerebrovascular disorders. PMID- 25548769 TI - Dental wear: a scanning electron microscope study. AB - Dental wear can be differentiated into different types on the basis of morphological and etiological factors. The present research was carried out on twelve extracted human teeth with dental wear (three teeth showing each type of wear: erosion, attrition, abrasion, and abfraction) studied by scanning electron microscopy (SEM). The study aimed, through analysis of the macro- and micromorphological features of the lesions (considering the enamel, dentin, enamel prisms, dentinal tubules, and pulp), to clarify the different clinical and diagnostic presentations of dental wear and their possible significance. Our results, which confirm current knowledge, provide a complete overview of the distinctive morphology of each lesion type. It is important to identify the type of dental wear lesion in order to recognize the contributing etiological factors and, consequently, identify other more complex, nondental disorders (such as gastroesophageal reflux, eating disorders). It is clear that each type of lesion has a specific morphology and mechanism, and further clinical studies are needed to clarify the etiological processes, particularly those underlying the onset of abfraction. PMID- 25548770 TI - Interfractional variations of tumor centroid position and tumor regression during stereotactic body radiotherapy for lung tumor. AB - PURPOSE: To determine interfractional changes of lung tumor centroid position and tumor regression during stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: 34 patients were treated by SBRT in 4-5 fractions to a median dose of 50 Gy. The CT scans acquired for verification were registered with simulation CT scans. The gross target volume (GTV) was contoured on all verification CT scans and compared to the initial GTV in treatment plan system. RESULTS: The mean (+/ standard deviation, SD) three-dimension vector shift was 5.2 +/- 3.1 mm. The mean (+/-SD) interfractional variations of tumor centroid position were -0.7 +/- 4.5 mm in anterior-posterior (AP) direction, 0.2 +/- 3.1 mm in superior-inferior (SI) direction, and 0.4 +/- 2.4 mm in right-left (RL) direction. Large interfractional variations (>=5 mm) were observed in 5 fractions (3.3%) in RL direction, 16 fractions (10.5%) in SI direction, and 36 fractions (23.5%) in AP direction. Tumor volume did not decrease significantly during lung SBRT. CONCLUSIONS: Small but insignificant tumor volume regression was observed during lung SBRT. While the mean interfractional variations of tumor centroid position were minimal in three directions, variations more than 5 mm account for approximately a third of all, indicating additional margin for PTV, especially in AP direction. PMID- 25548771 TI - Microfluidic method of pig oocyte quality assessment in relation to different follicular size based on lab-on-chip technology. AB - Since microfollicular environment and the size of the follicle are important markers influencing oocyte quality, the aim of this study is to present the spectral characterization of oocytes isolated from follicles of various sizes using lab-on-chip (LOC) technology and to demonstrate how follicle size may affect oocyte quality. Porcine oocytes (each, n = 100) recovered from follicles of different sizes, for example, from large (>5 mm), medium (3-5 mm), and small (<3 mm), were analyzed after preceding in vitro maturation (IVM). The LOC analysis was performed using a silicon-glass sandwich with two glass optical fibers positioned "face-to-face." Oocytes collected from follicles of different size classes revealed specific and distinguishable spectral characteristics. The absorbance spectra (microspectrometric specificity) for oocytes isolated from large, medium, and small follicles differ significantly (P < 0.05) and the absorbance wavelengths were between 626 and 628 nm, between 618 and 620 nm, and less than 618 nm, respectively. The present study offers a parametric and objective method of porcine oocyte assessment. However, up to now this study has been used to evidence spectral markers associated with follicular size in pigs, only. Further investigations with functional-biological assays and comparing LOC analyses with fertilization and pregnancy success and the outcome of healthy offspring must be performed. PMID- 25548772 TI - The effect of Helicobacter pylori eradication on the levels of essential trace elements. AB - OBJECTIVE: This study was designed to compare the effect of Helicobacter pylori (H. pylori) infection treatment on serum zinc, copper, and selenium levels. PATIENTS AND METHODS: We measured the serum zinc, copper, and selenium levels in H. pylori-positive and H. pylori-negative patients. We also evaluated the serum levels of these trace elements after H. pylori eradication. These serum copper, zinc, and selenium levels were determined by inductively coupled plasma mass spectrometry. RESULTS: Sixty-three H. pylori-positive patients and thirty H. pylori-negative patients were studied. Serum copper, zinc, and selenium levels had no significant difference between H. pylori-positive and H. pylori-negative groups. There were 49 patients with successful H. pylori eradication. The serum selenium levels were lower after successful H. pylori eradication, but not significantly (P = 0.06). There were 14 patients with failed H. pylori eradication. In this failed group, the serum selenium level after H. pylori eradication therapy was significantly lower than that before H. pylori eradication therapy (P < 0.05). The serum zinc and copper levels had no significant difference between before and after H. pylori eradication therapies. CONCLUSION: H pylori eradication regimen appears to influence the serum selenium concentration (IRB number: KMUH-IRB-20120327). PMID- 25548774 TI - Scotopic microperimetry in the early diagnosis of age-related macular degeneration: preliminary study. AB - BACKGROUND: Recent clinical studies have shown that, in some degenerative retinal diseases, like age-related macular degeneration (AMD), the sensitivity of the rods decreases more rapidly than the sensitivity of the cones. The aim of this study was to evaluate if there is a correlation between the presence of hard drusen at the macular level and the rod damage responsible for the reduction in scotopic retinal sensitivity in subjects at risk for AMD. METHODS: The authors selected 24 subjects (14 men and 10 women) with an average age of 67.25 +/- 5.7 years. Macular hard drusen were present in 50% of the subjects at the fundus oculi exam. The researchers evaluated the retinal sensitivity to light in mesopic and scotopic conditions of each subject with an MP-1 scotopic microperimeter (MP 1S). RESULTS: In subjects with hard drusen in the fundus oculi examination, there was a statistically significant reduction in scotopic retinal sensitivity, while the mesopic retinal sensitivity was not compromised. CONCLUSION: This study revealed how the presence of hard drusen at the macular level is associated with a reduction in scotopic retinal sensitivity compared to a control group of healthy subjects. Retinal functionality in a scotopic setting examined with MP-1S could be useful in early diagnosis of AMD. PMID- 25548775 TI - Barcoding melting curve analysis for rapid, sensitive, and discriminating authentication of saffron (Crocus sativus L.) from its adulterants. AB - Saffron (Crocus sativus L.) is one of the most important and expensive medicinal spice products in the world. Because of its high market value and premium price, saffron is often adulterated through the incorporation of other materials, such as Carthamus tinctorius L. and Calendula officinalis L. flowers, Hemerocallis L. petals, Daucus carota L. fleshy root, Curcuma longa L. rhizomes, Zea may L., and Nelumbo nucifera Gaertn. stigmas. To develop a straightforward, nonsequencing method for rapid, sensitive, and discriminating detection of these adulterants in traded saffron, we report here the application of a barcoding melting curve analysis method (Bar-MCA) that uses the universal chloroplast plant DNA barcoding region trnH-psbA to identify adulterants. When amplified at DNA concentrations and annealing temperatures optimized for the curve analysis, peaks were formed at specific locations for saffron (81.92 degrees C) and the adulterants: D. carota (81.60 degrees C), C. tinctorius (80.10 degrees C), C. officinalis (79.92 degrees C), Dendranthema morifolium (Ramat.) Tzvel. (79.62 degrees C), N. nucifera (80.58 degrees C), Hemerocallis fulva (L.) L. (84.78 degrees C), and Z. mays (84.33 degrees C). The constructed melting curves for saffron and its adulterants have significantly different peak locations or shapes. In conclusion, Bar-MCA could be a faster and more cost-effective method to authenticate saffron and detect its adulterants. PMID- 25548776 TI - Screening dementia in the outpatient department: patients at risk for dementia. AB - The targeted screening for individuals at the risks of having dementia would be crucial to the further public health issues for dementia. This study aimed to conduct a screening study in an outpatient department of a regional hospital to screen people who were at risk of developing comorbid dementia. Patients who visited Kaohsiung Municipal Ta-Tung Hospital (KMTTH) clinics during the period from June 1, 2013, to May 31, 2014, were invited to participate in this screening voluntarily. The trained interviewer collected all participants' demographic characteristics and used the instrument of ascertainment of dementia 8 (AD8) to find out suspected dementia ones. The result showed a higher ratio (24.1%) of suspected dementia in the outpatient department of a hospital, 500 out of 2017 subjects, than that in the general population. The median (interquartile range) age was significantly higher in the suspected dementia participants (70, (62, 77)) compared to that in nonsuspected dementia ones (65, (60, 73)), and the probability of suspected dementia was significantly increasing with age (P<0.001). Instead of screening dementia in general population, screening people at the risk of dementia could be the practicable and important issues in the care of dementia. PMID- 25548773 TI - Molecular and cellular basis of autosomal recessive primary microcephaly. AB - Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development. PMID- 25548777 TI - The use of D-optimal mixture design in optimising okara soap formulation for stratum corneum application. AB - Okara, soybean waste from tofu and soymilk production, was utilised as a natural antioxidant in soap formulation for stratum corneum application. D-optimal mixture design was employed to investigate the influence of the main compositions of okara soap containing different fatty acid and oils (virgin coconut oil A (24 28% w/w), olive oil B (15-20% w/w), palm oil C (6-10% w/w), castor oil D (15-20% w/w), cocoa butter E (6-10% w/w), and okara F (2-7% w/w)) by saponification process on the response hardness of the soap. The experimental data were utilized to carry out analysis of variance (ANOVA) and to develop a polynomial regression model for okara soap hardness in terms of the six design factors considered in this study. Results revealed that the best mixture was the formulation that included 26.537% A, 19.999% B, 9.998% C, 16.241% D, 7.633% E, and 7.000% F. The results proved that the difference in the level of fatty acid and oils in the formulation significantly affects the hardness of soap. Depending on the desirable level of those six variables, creation of okara based soap with desirable properties better than those of commercial ones is possible. PMID- 25548778 TI - Comparative analysis of cardiovascular development related genes in stem cells isolated from deciduous pulp and adipose tissue. AB - Human exfoliated deciduous teeth (SHED) and adipose stem cells (ASC) were suggested as alternative cell choice for cardiac regeneration. However, the true functionability of these cells toward cardiac regeneration is yet to be discovered. Hence, this study was carried out to investigate the innate biological properties of these cell sources toward cardiac regeneration. Both cells exhibited indistinguishable MSCs characteristics. Human stem cell transcription factor arrays were used to screen expression levels in SHED and ASC. Upregulated expression of transcription factor (TF) genes was detected in both sources. An almost equal percentage of >2-fold changes were observed. These TF genes fall under several cardiovascular categories with higher expressions which were observed in growth and development of blood vessel, angiogenesis, and vasculogenesis categories. Further induction into cardiomyocyte revealed ASC to express more significantly cardiomyocyte specific markers compared to SHED during the differentiation course evidenced by morphology and gene expression profile. Despite this, spontaneous cellular beating was not detected in both cell lines. Taken together, our data suggest that despite being defined as MSCs, both ASC and SHED behave differently when they were cultured in a same cardiomyocytes culture condition. Hence, vigorous characterization is needed before introducing any cell for treating targeted diseases. PMID- 25548780 TI - Feasibility and acceptability of the informant AD8 for cognitive screening in primary healthcare: a pilot study. AB - OBJECTIVES: The utility of informant AD8 for case finding of cognitive impairment at primary healthcare settings is unknown and therefore its feasibility and acceptability for targeted screening at a primary healthcare clinic should be investigated. METHODS: The informants of older adult patients attending a primary healthcare clinic in Singapore were administered the AD8. Positive screening findings were provided to patients' primary care physicians for referrals to specialist memory clinics. The acceptability of AD8 was evaluated by collecting feedbacks from the informants and primary care physicians. RESULTS: 205 patients and their informants were recruited. However, 6 (2.9%) informants were uncontactable, while the majority of the remaining 199 patients with completed AD8 (96.5%, n=192) found it acceptable where 59 (29.6%) patients were deemed cognitively impaired (AD8>=2). Clinicians (100%, n=5) found the AD8 helpful in facilitating referrals to memory clinics. However, most referral recommendations (81.4%, n=48) were declined by patients and/or informant due to limited insight of implications of cognitive impairment. CONCLUSIONS: The AD8 can be easily administered and is well tolerated. It detected cognitive impairment in one-third of older adult patients and therefore may be useful for case finding of cognitive impairment in the primary healthcare. PMID- 25548779 TI - Synthesis, characterization, and anticancer activity of new quinazoline derivatives against MCF-7 cells. AB - Two new synthesized and characterized quinazoline Schiff bases 1 and 2 were investigated for anticancer activity against MCF-7 human breast cancer cell line. Compounds 1 and 2 demonstrated a remarkable antiproliferative effect, with an IC50 value of 6.246*10(-6) mol/L and 5.910*10(-6) mol/L, respectively, after 72 hours of treatment. Most apoptosis morphological features in treated MCF-7 cells were observed by AO/PI staining. The results of cell cycle analysis indicate that compounds did not induce S and M phase arrest in cell after 24 hours of treatment. Furthermore, MCF-7 cells treated with 1 and 2 subjected to apoptosis death, as exhibited by perturbation of mitochondrial membrane potential and cytochrome c release as well as increase in ROS formation. We also found activation of caspases-3/7, -8, and -9 in compounds 1 and 2. Moreover, inhibition of NF-kappaB translocation in MCF-7 cells treated by compound 1 significantly exhibited the association of extrinsic apoptosis pathway. Acute toxicity results demonstrated the nontoxic nature of the compounds in mice. Our results showed significant activity towards MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway and are potential candidate for further in vivo and clinical breast cancer studies. PMID- 25548781 TI - Evaluation models for soil nutrient based on support vector machine and artificial neural networks. AB - Soil nutrient is an important aspect that contributes to the soil fertility and environmental effects. Traditional evaluation approaches of soil nutrient are quite hard to operate, making great difficulties in practical applications. In this paper, we present a series of comprehensive evaluation models for soil nutrient by using support vector machine (SVM), multiple linear regression (MLR), and artificial neural networks (ANNs), respectively. We took the content of organic matter, total nitrogen, alkali-hydrolysable nitrogen, rapidly available phosphorus, and rapidly available potassium as independent variables, while the evaluation level of soil nutrient content was taken as dependent variable. Results show that the average prediction accuracies of SVM models are 77.87% and 83.00%, respectively, while the general regression neural network (GRNN) model's average prediction accuracy is 92.86%, indicating that SVM and GRNN models can be used effectively to assess the levels of soil nutrient with suitable dependent variables. In practical applications, both SVM and GRNN models can be used for determining the levels of soil nutrient. PMID- 25548782 TI - Screening of dementia. PMID- 25548783 TI - Flow cytometric enumeration of parasitemia in cultures of Plasmodium falciparum stained with SYBR Green I and CD235A. AB - A flow cytometric (FACS) detection method for Plasmodium falciparum cultures (P. falciparum) was developed using SYBR Green I and CD235A and compared against the Giemsa stained microscopic examination. The cultured P. falciparum were spiked into red blood cells (RBCs) to yield parasitemia, ranging from 0.01% to 22.0%. FACS analysis demonstrated a clear separation between P. falciparum infected and uninfected RBCs. The measured percentage of parasitemia by FACS revealed higher precision (CV of 2.2-37.2%) with the sensitivity of 0.01% parasitemia than Giemsa stained microscopic examination (CV of 7.2-66.0%). High correlation of measured parasitaemia (r=0.98, P<0.05) was observed between FACS and Giemsa stained microscopic analyses. The higher levels of parasitaemia detection were observed in all ranges by FACS in comparison to Giemsa stained microscopic analysis. The currently reported FACS method using SYBR Green I and CD235A is potentially useful for measuring parasitemia in treating patients. PMID- 25548784 TI - Classifying lupus nephritis: an ongoing story. AB - The role of the renal biopsy in lupus nephritis is to provide the diagnosis and to define the parameters of prognostic and therapeutic significance for an effective clinicopathological correlation. Various classification schemas initiated by World Health Organization in 1974 have been proposed until the most recent update by International Society of Nephrology/Renal Pathology Society in 2004. In this paper, we reviewed the new classification system with the associated literature to highlight the benefits and the weak points that emerged so far. The great advantage of the classification emerged to provide a uniform reporting for lupus nephritis all over the world. It has provided more reproducible results from different centers. However, the studies indicated that the presence of glomerular necrotizing lesion was no longer significant to determine the classes of lupus nephritis leading to loss of pathogenetic diversity of the classes. Another weakness of the classification that also emerged in time was the lack of discussions related to the prognostic significance of tubulointerstitial involvement which was not included in the classification. Therefore, the pathogenetic diversity of the classification still needs to be clarified by additional studies, and it needs to be improved by the inclusion of the tubulointerstitial lesions related to prognosis. PMID- 25548785 TI - A method for the simultaneous determination of chlorogenic acid and sesquiterpene lactone content in industrial chicory root foodstuffs. AB - A method for the simultaneous determination of free chlorogenic acids (CGA) and sesquiterpene lactones (STL) in chicory root and its dried (flour) and roasted (grain) forms is described. The method uses one extraction and one analysis for all chicory root products. Various solvents with low to high polarity, such as methanol, chloroform, or n-hexane, were tested alone, in combination in different proportions or with acidified or neutral aqueous solvent. The water/chloroform/methanol (30/30/40, v/v/v) mixture generated the best extraction yield, 21% higher than alcohol mixtures. The profiling of CGA and STL content was performed through a conventional HPLC-DAD method using a PFP core shell column in a fast single run. Good retention time and area repeatability (RDD mean % 0.46 and 5.6, resp.) and linearity (R2>=0.96) were obtained. The STL and chlorogenic acids levels determined were 254.7 and 100.2 MUg/g of dry matter in the root, 792.5 and 1,547 MUg/g in flour, and 160.4 and 822.5 MUg/g in the roasted grains, respectively. With an average recovery of 106% and precision of 90%, this method is rapid, reproducible, and straightforward way to quantify the chlorogenic acids and STL in chicory raw material and end products. PMID- 25548786 TI - Is overweight a risk factor for adverse events during removal of impacted lower third molars? AB - Being overweight is recognised as a significant risk factor for several morbidities; however, the experience of the dentistry faculties focusing on this population is still low. The aim of the present study was to determine the occurrence of adverse events during removal of impacted lower third molars in overweight patients. A prospective cohort study was carried out involving overweight patients subjected to surgical removal of impacted lower third molar as part of a line of research on third molar surgery. Predictor variables indicative of the occurrence of adverse events during surgery were classified by their demographic, clinical, radiographic, and surgical aspects. Descriptive and bivariate statistics were computed. In total, 140 patients fulfilled the eligibility criteria, and 280 surgeries were performed. Patients' mean age was 25.1+/-2.2 years, and the proportion of women to men was 3:1. Eight different adverse events during surgery were recorded. These events occurred in approximately 29.3% of cases and were significantly associated with predictor variables (P<0.05). Excess weight is recognised as a risk factor for the high rate of adverse events in impacted third molar surgery. The study suggests that overweight patients are highly likely to experience morbidities. PMID- 25548787 TI - Impacts of biochar on physical properties and erosion potential of a mudstone slopeland soil. AB - Food demand and soil sustainability have become urgent issues recently because of the global climate changes. This study aims to evaluate the application of a biochar produced by rice hull, on changes of physiochemical characteristics and erosion potential of a degraded slopeland soil. Rice hull biochar pyrolized at 400 degrees C was incorporated into the soil at rates of 2.5%, 5%, and 10% (w/w) and was incubated for 168 d in this study. The results indicated that biochar application reduced the Bd by 12% to 25% and the PR by 57% to 92% after incubation, compared with the control. Besides, porosity and aggregate size increased by 16% to 22% and by 0.59 to 0.94 mm, respectively. The results presented that available water contents significantly increased in the amended soils by 18% to 89% because of the obvious increase of micropores. The water conductivity of the biochar-amended soils was only found in 10% biochar treatment, which might result from significant increase of macropores and reduction of soil strength (Bd and PR). During a simulated rainfall event, soil loss contents significantly decreased by 35% to 90% in the biochar-amended soils. In conclusion, biochar application could availably raise soil quality and physical properties for tilth increasing in the degraded mudstone soil. PMID- 25548788 TI - Comparative evaluation of effectiveness of IAVchip DNA microarray in influenza A diagnosis. AB - The paper describes comparative evaluation of IAVchip DNA microarray, reverse transcription PCR (RT-PCR), and real-time RT-PCR versus virus isolation in chicken embryos and shows their diagnostic effectiveness in detection and subtyping of influenza A virus. The tests were evaluated with use of 185 specimens from humans, animals, and birds. IAVchip DNA microarray demonstrates higher diagnostic effectiveness (99.45%) in early influenza A diagnosis as compared to the real-time PCR (98.38%) and RT-PCR (96.22%), thus showing its clear superiority. Diagnostic sensitivity of IAVchip DNA microarray (100%) exceeds the same of RT-PCR (95.95%) and real-time RT-PCR (97.96%) in the range of estimated confidence intervals. IAVchip DNA microarray and real-time RT-PCR displayed equal diagnostic specificity (98.85%), while diagnostic specificity of RT-PCR was 96.40%. IAVchip DNA microarray has an advantage over the other tests for influenza A diagnosis and virus identification as a more rapid method that allows performing simultaneous detection and subtyping of about tens of specimens within one experiment during 8-10 hours. The developed IAVchip DNA microarray is a general test tool that enables identifying simultaneously 16 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes of influenza A virus and also to screen the influenza A viruses from humans, animals, and birds by M and NP genes. PMID- 25548789 TI - Effects of subchronic exposure to cadmium and diazinon on testis and epididymis in rats. AB - The present study aimed to elucidate the structural changes in testis and epididymis of adult rats following subchronic peroral administration of cadmium at 30 mg/L, diazinon at 40 mg/L, cadmium at 30 mg/L, and diazinon at 40 mg/L, respectively. At the end of 90-day experiment, the samples of the testes and epididymis were assayed by qualitative and quantitative histological methods. The testis and epididymis weights increased following exposure to cadmium and simultaneous exposure to cadmium and diazinon. Testicular damage following cadmium and diazinon coexposure was significantly less expressive than in groups with individual administration of these compounds. Cadmium caused a significant thickening of seminiferous epithelium, cellular degeneration, and necrosis. Desquamation of immature germ cells resulted in a significant increase of intraepithelial spaces and reduced tubule volume in all experimental groups. Vascular dilation and congestion were detected in the interstitial tissue. The changes in epididymal histology in the group exposed to cadmium and group exposed simultaneously included a reduction of epithelium, necrotic epithelial cells, vasoconstriction, and interstitial edema together with mononuclear cell infiltration. Results did not indicate a synergistic or any additional effect from the simultaneous administration of both toxicants. Further research is needed to determine the significance and the mechanism of the adverse effects. PMID- 25548790 TI - Phantom eye syndrome: a review of the literature. AB - The purpose of this literature review was to describe the main features of phantom eye syndrome in relation to their possible causes, symptoms, treatments, and influence of eye amputation on quality of life of anophthalmic patients. For this, a bibliographical research was performed in Pubmed database using the following terms: "eye amputation," "eye trauma," "phantom eye syndrome," "phantom pain," and "quality of life," associated or not. Thirteen studies were selected, besides some relevant references contained in the selected manuscripts and other studies hallowed in the literature. Thus, 56 articles were included in this review. The phantom eye syndrome is defined as any sensation reported by the patient with anophthalmia, originated anophthalmic cavity. In phantom eye syndrome, at least one of these three symptoms has to be present: phantom vision, phantom pain, and phantom sensations. This syndrome has a direct influence on the quality of life of the patients, and psychological support is recommended before and after the amputation of the eyeball as well as aid in the treatment of the syndrome. Therefore, it is suggested that, for more effective treatment of phantom eye syndrome, drug therapy should be associated with psychological approach. PMID- 25548791 TI - Retroperitoneal laparoscopic ureterolithotomy for proximal ureteral calculi in selected patients. AB - OBJECTIVES: To summarize our experience of retroperitoneal laparoscopic ureterolithotomy for ureteral calculi and evaluate the safety and efficiency of this procedure. METHODS: We conducted a retrospective analysis of 197 patients with proximal ureteral calculi who accepted retroperitoneal laparoscopic ureterolithotomy from June 2005 to June 2014. RESULTS: All procedures were performed successfully and the mean operating time and estimated blood loss were 87 min and 64 mL. The clearance rate was 98.5% and the rates of urine leak and ureteral stricture were 2.5% and 1.0%. CONCLUSIONS: Retroperitoneal laparoscopic ureterolithotomy is a safe and effective procedure for patients with complex stones or anatomic abnormalities, and, with experience of high volume series, it is also a reasonable choice as the primary treatment for such selected patients. PMID- 25548792 TI - The societal impact of herpes zoster and postherpetic neuralgia on patients, life partners, and children of patients in Germany. AB - The aim of this study was to assess the impact of herpes zoster (HZ) and postherpetic neuralgia (PHN) on the daily activities of patients and family members who care for them. Some former patients and family members participated in face-to-face interviews or in a T-group meeting (qualitative phase) and some participated in telephone interviews (quantitative phase). They all expressed feelings of helplessness and frustration mixed with depression, sadness, or rage. Many of the former patients said their lives stopped, in contrast to family members who said that their lives were busy and stressful. Family members caring for patients with PHN were more psychologically stressed than those caring for patients with HZ. Although former patients appreciated the psychological and emotional support given by their family members, they underestimated the impact that their disease had on them. Former patients and their family never forgot this illness and its considerable impact on their lives, particularly when PHN occurred. We need to raise the awareness of the general public about the real life impact of HZ and PHN and their often severe, debilitating consequences and the potential benefits from vaccination. PMID- 25548793 TI - Anticoagulation strategies in venovenous hemodialysis in critically ill patients: a five-year evaluation in a surgical intensive care unit. AB - Renal failure is a common complication among critically ill patients. Timing, dosage, and mode of renal replacement (RRT) are under debate, but also anticoagulation strategies and vascular access interfere with dialysis success. We present a retrospective, five-year evaluation of patients requiring RRT on a multidisciplinary 50-bed surgical intensive care unit of a university hospital with special regard to anticoagulation strategies and vascular access. Anticoagulation was preferably performed with unfractionated heparin or regional citrate application (RAC). Bleeding and suspected HIT-II were most common causes for RAC. In CVVHD mode filter life span was significantly longer under RAC compared to heparin or other anticoagulation strategies (P=0.001). Femoral vascular access was associated with reduced filter life span (P=0.012), especially under heparin anticoagulation (P=0.015). Patients on RAC had higher rates of metabolic alkalosis (P=0.001), required more transfusions (P=0.045), and showed higher illness severity measured by SOFA scores (P=0.001). RRT with unfractionated heparin represented the most common anticoagulation strategy in this study population. However, patients with bleeding risk and severe organ dysfunction were more likely placed on RAC. Citrate provided longer filter life spans regardless of vascular access site. Attention has to be paid to metabolic disturbances. PMID- 25548794 TI - Renal function and ultrasound imaging in elderly subjects. AB - We evaluated in elderly subjects (a) the ability of GFR formulas to discriminate chronic kidney disease (CKD), (b) the correlation between renal morphology and function, and (c) the usefulness of combined r-US and GFR formulas to detect CKD. A total of 72 patients were enrolled (mean age 80+/-7 years, male sex 44%, serum creatinine 0.98+/-0.42 mg/dL, and CKD 57%). Cockcroft-Gault showed the highest sensitivity (78%) and specificity (94%) for CKD and was correlated with kidney volume (R=0.68, P<0.001). All formulas failed to provide a reliable estimate of GFR. In multivariate analysis, Cockcroft-Gault<52 mL/min and kidney sinus section area<28 cm2 showed the highest accuracy for the identification of CKD subjects (AUC 0.90, P<0.001). MDRD and CKD-EPI differed significantly for GFR>=90 mL/min. CONCLUSIONS: Cockcroft-Gault<52 mL/min was able to discriminate subjects with CKD but all formulas failed to provide a reliable estimate of GFR. The combined use of r-US and Cockcroft-Gault formula improved the ability to discriminate CKD in elderly subjects. PMID- 25548795 TI - Antidiabetic activity of benzopyrone analogues in nicotinamide-streptozotocin induced type 2 diabetes in rats. AB - Benzopyrones are proven antidiabetic drug candidate in diabetic drug discovery. In this view novel synthetic benzopyrone analogues were selected for testing in experimental diabetes. Type 2 diabetes (T2D) was induced in Wistar rats by streptozotocin (60 mg/kg, i.p.) followed by nicotinamide (120 mg/kg i.p.). Rats having fasting blood glucose (FBG)>200 mg/dL, 7 days after T2D-induction, are selected for the study. Test compounds and standard treatment were continued for 15 days. FBG, oral glucose tolerance test (OGTT), and insulin tolerance test (ITT) were determined on 21st day after induction of T2D. Plasma lipids and serum insulin were estimated. Homeostatic model assessment (HOMA-IR) was then calculated from serum insulin. Rats were sacrificed and pancreas was isolated for histopathological observations. Oxidative stress markers were estimated in liver homogenate. Quercetin, a natural product with benzopyrone ring, showed significant hypoglycemic activity comparable to glibenclamide. Treatment with test compounds lowered the FBG and insulin resistance was significant alleviated as determined by OGTT, HOMA-IR, and ITT. There was significant normalisation of liver antioxidant enzymes compared to diabetic rats indicating that all the synthesised benzopyrone analogues are beneficial in reducing oxidative stress and are on par with the standard quercetin and glibenclamide in experimental T2D. PMID- 25548796 TI - Factors associated with violent behavior among adolescents in northeastern Brazil. AB - The aim of this study was to identify prevalence and factors associated with violent behavior among adolescents in Aracaju and Metropolitan region. The study included 2207 adolescents (16.03+/-1.08 years old) enrolled in high schools of the State Public Network. Violent behavior was identified from question 14 of the YRBS-2007 questionnaire with responses categorized as "never" and "one or more times." Higher prevalence in males in relation to risk factors for adoption of violent behavior was found: cigarette consumption (7.3%), alcohol consumption (39.1%), and marijuana use (3.4%). Data analysis used descriptive statistics and logistic regression with hierarchical model at two levels: (a) sociodemographic variables and (b) behavioral variables. For both sexes, association between violent behavior and cigarette smoking (OR=3.77, CI 95%=2.06-6.92 and OR=1.99, CI 95%=1.04 to 3.81, male and female, resp.) and alcohol consumption (OR=3.38, CI 95%=2.22 to 5.16 and OR=1.83, CI 95%=1.28 to 2.63, male and female, resp.) was verified. It was concluded that violent behavior is associated with the consumption of alcoholic beverages and cigarettes among adolescents. PMID- 25548798 TI - Does aerobic exercise improve or impair cardiorespiratory fitness and health among cleaners? A cluster randomized controlled trial. AB - OBJECTIVE: It is unknown if aerobic exercise overloads or improves the cardiovascular system among workers with high occupational physical activity. This was investigated in a worksite randomized controlled trial (RCT) of aerobic exercise among cleaners. METHODS: We randomized 116 cleaners between 18-65 years. The aerobic exercise group (N=57) performed worksite aerobic exercise (30 minutes twice a week) and the reference group (N=59) received lectures. Cardiorespiratory fitness, blood pressure (BP) and diurnal heart rate (HR) for measuring aerobic workload [% HR reserve (% HRR)] were collected at baseline and after four months. A repeated measure 2*2 multi-adjusted mixed-model design was applied to compare the between-group differences in an intention-to-treat analysis. RESULTS: Between group differences (P<0.01) were found: cardiorespiratory fitness 2.2 [standard error (SE) 0.8] ml O 2 * min -1 * kg -1 [95% confidence interval (95% CI) 0.6 3.8], aerobic workload - 3.5 (SE 1.2) % HRR (95% CI - 5.9- -1.0), resting HR -3.8 (SE 1.2) bpm (95 % CI -6.1- - 1.4), sleeping HR -3.8 (SE 1.1) bpm (95% CI - 5.9- 1.7), and systolic BP 3.6 (SE 1.3) mmHg (95% CI 1.1-6.0). CONCLUSIONS: Worksite aerobic exercise seems to improve cardiorespiratory fitness, aerobic workload, and resting and sleeping HR, but increase systolic BP among cleaners. Beneficial physiological cardiovascular effects are seen from aerobic exercise, but also a harmful effect is evident. Therefore, recommendations should take into consideration the potential cardiovascular overload from additional aerobic exercise on workers with high levels of occupational physical activity. PMID- 25548797 TI - Correlation of ischemia-modified albumin with SOFA and APACHE II scores in preoperative patients with colorectal cancer. AB - PURPOSE: Critical illnesses are assessed according to the sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II. Circulating ischemia-modified albumin (IMA) is a biomarker generated under ischemic and oxidative conditions and may reflect disease severity in preoperative patients. This study investigated the correlations of IMA with SOFA and APACHE II scores in inpatients admitted for colorectal surgery. METHODS: We examined 27 patients with advanced colorectal cancers (mean age 69 years, men/women=15/12). Correlations between SOFA and APACHE II scores in addition to preoperative serum IMA and C-reactive protein (CRP) levels were analyzed. RESULTS: The mean IMA level was 0.5 AU, and the median CRP level was 0.6 mg/dL. Median scores for SOFA and APACHE II were 2 and 12 points, respectively. Significant positive correlations between IMA and SOFA (r=0.45, P<0.05) and IMA and APACHE II (r=0.45, P<0.05) were identified which remained significant in confounder-adjusted analyses. In contrast, weak correlations were observed between CRP and the SOFA and APACHE II scores. CONCLUSIONS: The positive correlations between IMA and both SOFA and APACHE II scores suggest that serum IMA measurements reflect the severity of systemic failure in patients admitted for colorectal surgery in the preoperative phase. PMID- 25548799 TI - Chemerin/chemR23 axis in inflammation onset and resolution. AB - Chemerin is an adipokine secreted by adipocytes and associated with obesity, insulin resistance and metabolic syndrome. Different chemerin fragments with pro- or anti-inflammatory action can be produced, depending on the class of proteases predominating in the microenvironment. Chemerin binds to three receptors, especially to chemR23, expressed on various cells, as dendritic cells, macrophages and natural killer cells, regulating chemotaxis towards the site of inflammation and activation status. Recently, the chemerin/chemR23 axis has attracted particular attention for the multiple roles related to the control of inflammation, metabolism and cancerogenesis in different organs and systems as lung (allergy and cancer), skin (psoriasis, lupus, cancer, wound repair), cardiovascular system (lipid profile and atherosclerosis), reproductive apparatus (polycystic ovary syndrome, follicular homoeostasis), and digestive tract (inflammatory bowel diseases and cancer). This pathway may regulate immune responses by contributing both to the pathogenesis of inflammatory diseases and to the resolution of acute inflammation. Thus, chemerin-derived peptides or other substances that may affect the chemerin/chemR23 axis could be used in the future for the treatment of many diseases, including cancer at different sites. PMID- 25548800 TI - Whole genome sequencing as a means to assess pathogenic mutations in medical genetics and cancer. AB - The past decade has seen the emergence of next-generation sequencing (NGS) technologies, which have revolutionized the field of human molecular genetics. With NGS, significant portions of the human genome can now be assessed by direct sequence analysis, highlighting normal and pathological variants of our DNA. Recent advances have also allowed the sequencing of complete genomes, by a method referred to as whole genome sequencing (WGS). In this work, we review the use of WGS in medical genetics, with specific emphasis on the benefits and the disadvantages of this technique for detecting genomic alterations leading to Mendelian human diseases and to cancer. PMID- 25548802 TI - Molecular mechanism of mitochondrial calcium uptake. AB - Mitochondrial calcium uptake plays a critical role in various cellular functions. After half a century of extensive studies, the molecular components and important regulators of the mitochondrial calcium uptake complex have been identified. However, the mechanism by which these protein molecules interact with one another and coordinate to regulate calcium passage through mitochondrial membranes remains elusive. Here, we summarize recent progress in the structural and functional characterization of these important protein molecules, which are involved in mitochondrial calcium uptake. In particular, we focus on the current understanding of the molecular mechanism underlying calcium through two mitochondrial membranes. Additionally, we provide a new perspective for future directions in investigation and molecular intervention. PMID- 25548801 TI - Metabolic effects of resveratrol: addressing the controversies. AB - Resveratrol, a polyphenol found in a number of plant-based foods such as red wine, has received a great deal of attention for its diverse array of healthful effects. Beneficial effects of resveratrol are diverse; they include improvement of mitochondrial function, protection against obesity and obesity-related diseases such as type-2 diabetes, suppression of inflammation and cancer cell growth and protection against cardiovascular dysfunction, just to name a few. Investigations into the metabolic effects of resveratrol are furthest along and now include a number of clinical trials, which have yielded mixed results. There are a number of controversies surrounding resveratrol that have not been resolved. Here, we will review these controversies with particular emphasis on its mechanism of metabolic action and how lessons from resveratrol may help develop therapies that harness the effects of resveratrol but without the undesirable properties of resveratrol. PMID- 25548805 TI - Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension. AB - Exercise limitation comes from a close interaction between cardiovascular and skeletal muscle impairments. To better understand the implication of possible peripheral oxidative metabolism dysfunction, we studied the proteomic signature of skeletal muscle in pulmonary arterial hypertension (PAH). Eight idiopathic PAH patients and eight matched healthy sedentary subjects were evaluated for exercise capacity, skeletal muscle proteomic profile, metabolism, and mitochondrial function. Skeletal muscle proteins were extracted, and fractioned peptides were tagged using an iTRAQ protocol. Proteomic analyses have documented a total of 9 downregulated proteins in PAH skeletal muscles and 10 upregulated proteins compared to healthy subjects. Most of the downregulated proteins were related to mitochondrial structure and function. Focusing on skeletal muscle metabolism and mitochondrial health, PAH patients presented a decreased expression of oxidative enzymes (pyruvate dehydrogenase, p < 0.01) and an increased expression of glycolytic enzymes (lactate dehydrogenase activity, p < 0.05). These findings were supported by abnormal mitochondrial morphology on electronic microscopy, lower citrate synthase activity (p < 0.01) and lower expression of the transcription factor A of the mitochondria (p < 0.05), confirming a more glycolytic metabolism in PAH skeletal muscles. We provide evidences that impaired mitochondrial and metabolic functions found in the lungs and the right ventricle are also present in skeletal muscles of patients. KEY MESSAGE: * Proteomic and metabolic analysis show abnormal oxidative metabolism in PAH skeletal muscle. * EM of PAH patients reveals abnormal mitochondrial structure and distribution. * Abnormal mitochondrial health and function contribute to exercise impairments of PAH. * PAH may be considered a vascular affliction of heart and lungs with major impact on peripheral muscles. PMID- 25548808 TI - Preface. Parasite genomics protocols. PMID- 25548807 TI - Preface. Mast cells. PMID- 25548804 TI - Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma. AB - Resistance to cell death is the major cause of chemotherapy failure in most kinds of cancers, including Burkitt lymphoma (BL). When analyzing therapy resistance in Burkitt lymphoma (BL), we discovered a link between apoptosis resistance and ploidy control. We therefore studied systematically a panel of 15 BL lines for apoptosis induction upon treatment with microtubule inhibitors and compared three types of microtubule toxins, i.e., paclitaxel, nocodazole and vincristine. We found an inverse relationship between apoptosis sensitivity and ploidy control. Thus, cells resistant to paclitaxel- or nocodazole-induced apoptosis underwent mitotic catastrophe and developed polyploidy (>4N). Mechanistically, apoptosis resistance was linked to failure of caspase activation, which was most pronounced in cells lacking the pro-apoptotic multidomain Bcl-2 homologs Bax and Bak. Pharmacological caspase inhibition promoted polyploidy upon exposure to paclitaxel and nocodazole supporting the relationship between resistance to apoptosis and polyploidization. Of note, vincristine induced persistent mitotic arrest but no loss of ploidy control. Considering targets to facilitate Bax/Bak independent cell death and to avoid drug-induced mitotic catastrophe and consecutive mitotic catastrophe should be of great importance to overcome therapy resistance and therapy-related events that result in ploidy changes and tumor progression. KEY MESSAGE: Inverse relation of apoptosis and polyploidy induction by paclitaxel or nocodazole in BL. Resistant cells undergo mitotic catastrophe and develop polyploidy. Lack of Bax/Bak confers resistance and leads to induction of polyploidy in BL. Intact apoptosis response protects from polyploidy as a result of mitotic catastrophe. PMID- 25548809 TI - Preface. Stem cell protocols. PMID- 25548806 TI - Multi-environment multi-QTL association mapping identifies disease resistance QTL in barley germplasm from Latin America. AB - KEY MESSAGE: Multi-environment multi-QTL mixed models were used in a GWAS context to identify QTL for disease resistance. The use of mega-environments aided the interpretation of environment-specific and general QTL. Diseases represent a major constraint for barley (Hordeum vulgare L.) production in Latin America. Spot blotch (caused by Cochliobolus sativus), stripe rust (caused by Puccinia striiformis f.sp. hordei) and leaf rust (caused by Puccinia hordei) are three of the most important diseases that affect the crop in the region. Since fungicide application is not an economically or environmentally sound solution, the development of durably resistant varieties is a priority for breeding programs. Therefore, new resistance sources are needed. The objective of this work was to detect genomic regions associated with field level plant resistance to spot blotch, stripe rust, and leaf rust in Latin American germplasm. Disease severities measured in multi-environment trials across the Americas and 1,096 SNPs in a population of 360 genotypes were used to identify genomic regions associated with disease resistance. Optimized experimental design and spatial modeling were used in each trial to estimate genotypic means. Genome-Wide Association Mapping (GWAS) in each environment was used to detect Quantitative Trait Loci (QTL). All significant environment-specific QTL were subsequently included in a multi-environment-multi-QTL (MEMQ) model. Geographical origin and inflorescence type were the main determinants of population structure. Spot blotch severity was low to intermediate while leaf and stripe rust severity was high in all environments. Mega-environments were defined by locations for spot blotch and leaf rust. Significant marker-trait associations for spot blotch (9 QTL), leaf (6 QTL) and stripe rust (7 QTL) and both global and environment specific QTL were detected that will be useful for future breeding efforts. PMID- 25548803 TI - Interactions between host factors and the skin microbiome. AB - The skin is colonized by an assemblage of microorganisms which, for the most part, peacefully coexist with their hosts. In some cases, these communities also provide vital functions to cutaneous health through the modulation of host factors. Recent studies have illuminated the role of anatomical skin site, gender, age, and the immune system in shaping the cutaneous ecosystem. Alterations to microbial communities have also been associated with, and likely contribute to, a number of cutaneous disorders. This review focuses on the host factors that shape and maintain skin microbial communities, and the reciprocal role of microbes in modulating skin immunity. A greater understanding of these interactions is critical to elucidating the forces that shape cutaneous populations and their contributions to skin homeostasis. This knowledge can also inform the tendency of perturbations to predispose and/or bring about certain skin disorders. PMID- 25548810 TI - ECOSEP: bringing the European SEM family together. PMID- 25548811 TI - Dr Chou and colleagues respond. PMID- 25548812 TI - Incidental thyroid nodules in patients with primary hyperparathyroidism. AB - BACKGROUND: It is desirable to detect neoplastic thyroid disease before proceeding with surgical therapy for hyperparathyroidism so that both conditions can be treated with a single operation. METHODS: Between March 1998 and June 2009, 227 patients with primary hyperparathyroidism were treated with surgical therapy. Of these, 217 were evaluated preoperatively with a modified 4 dimensional CT and ultrasonography. The medical records of these patients were reviewed in order to document the incidence and significance of thyroid pathology in this cohort of patients. RESULTS: Thyroid nodules were identified in 159 of the 217 patients (73.3%). Nine of 217 patients (4.1%) were treated with either a partial or a total thyroidectomy at the time of parathyroidectomy. Three of these patients had papillary thyroid carcinoma, 1 had a Hurthle cell carcinoma, and 1 had an incidental micropapillary thyroid carcinoma. CONCLUSION: The rate of clinically significant thyroid malignancy in patients undergoing surgical treatment of primary hyperparathyroidism was 1.8%. PMID- 25548813 TI - N-methylnitrosourea-induced carcinoma as a model for laryngeal carcinogenesis. AB - BACKGROUND: Preclinical animal models to study laryngeal cancer are nonexistent. The purpose of this study was to describe a novel mice laryngeal cancer model. METHODS: A total of 18 six-week-old A/J mice were used. Animals underwent microdirect laryngoscopy, superficial larynx scratching, and instillation of N methyl-N-nitrosourea (MNU) at 2 different concentrations (15 MUL and 30 MUL) or dimethyl sulfoxide (DMSO) to the control group directly to the larynx. Mice received a total of 5 instillations of MNU or DMSO at 1-week intervals. Mice were euthanized at 20 and 30 weeks after the last intervention and laryngeal histology was analyzed. RESULTS: Laryngeal instillation of MNU caused a 60% cancer conversion in the study group. CONCLUSION: Our findings demonstrate the feasibility of developing a murine laryngeal carcinogenesis model using direct topical instillation of MNU. This is the first murine model of laryngeal cancer and has great potential for evaluating new agents for chemoprevention and treatment for laryngeal carcinoma. PMID- 25548814 TI - Immunotherapy for tuberculous pericarditis. PMID- 25548815 TI - Author's reply: refining and expanding the proposal of an inherence heuristic in human understanding. PMID- 25548817 TI - Puzzles in practice: acquired hepatocerebral (or hepatolenticular) degeneration (AHD). PMID- 25548816 TI - Gannet: A batch-processing tool for the quantitative analysis of gamma aminobutyric acid-edited MR spectroscopy spectra. AB - PURPOSE: The purpose of this study is to describe the Gannet toolkit for the quantitative batch analysis of gamma-aminobutyric acid (GABA) -edited MRS data. MATERIALS AND METHODS: Using MEGA-PRESS editing and standard acquisition parameters, four MEGA-PRESS spectra were acquired in three brain regions in 10 healthy volunteers. These 120 datasets were processed without user intervention with Gannet, a Matlab-based tool that takes raw time-domain data input, processes it to generate the frequency-domain edited spectrum, and applies a simple modeling procedure to estimate GABA concentration relative to the creatine or, if provided, the unsuppressed water signal. A comparison of four modeling approaches is also presented. RESULTS: All data were successfully processed by Gannet. Coefficients of variation across subjects ranged from 11% for the occipital region to 17% for the dorsolateral prefrontal region. There was no clear difference in fitting performance between the simple Gaussian model used by Gannet and the other more complex models presented. CONCLUSION: Gannet, the GABA Analysis Toolkit, can be used to process and quantify GABA-edited MRS spectra without user intervention. PMID- 25548818 TI - A port-wine stain in association with underlying syndrome. AB - Klippel-Trenaunay syndrome (KTS) is a capillary-venous vascular malformation condition characterized by capillary malformation, soft tissue and bone hypertrophy, and varicosities. Here we present the case of a 29-year-old man who presented with port wine stain and recurrent ulcerations on his right leg. This leg was also larger than the left one. His condition was consistent with KTS. We discuss the pathogenesis, clinical presentation, complications, and treatment modalities of KTS. PMID- 25548819 TI - [Not Available]. PMID- 25548820 TI - [Arrhythmias]. PMID- 25548821 TI - Guest Editorial-special issue on selected papers from IEEE BioCAS 2013. PMID- 25548822 TI - Visualizing 20 years of applications. PMID- 25548823 TI - The next big thing. PMID- 25548824 TI - Reply: To PMID 24930458. PMID- 25548825 TI - Colorimetric screening for high-throughput discovery of light absorbers. AB - High-throughput screening is a powerful approach for identifying new functional materials in unexplored material spaces. With library synthesis capable of producing 10(5) to 10(6) samples per day, methods for material screening at rates greater than 1 Hz must be developed. For the discovery of new solar light absorbers, this throughput cannot be attained using standard instrumentation. Screening certain properties, such as the bandgap, are of interest only for phase pure materials, which comprise a small fraction of the samples in a typical solid state material library. We demonstrate the utility of colorimetric screening based on processing photoscanned images of combinatorial libraries to quickly identify distinct phase regions, isolate samples with desired bandgap, and qualitatively identify samples that are suitable for complementary measurements. Using multiple quaternary oxide libraries containing thousands of materials, we compare colorimetric screening and UV-vis spectroscopy results, demonstrating successful identification of compounds with bandgap suitable for solar applications. PMID- 25548826 TI - Atomic layer deposition encapsulated activated carbon electrodes for high voltage stable supercapacitors. AB - Operating voltage enhancement is an effective route for high energy density supercapacitors. Unfortunately, widely used activated carbon electrode generally suffers from poor electrochemical stability over 2.5 V. Here we present atomic layer deposition (ALD) encapsulation of activated carbons for high voltage stable supercapacitors. Two-nanometer-thick Al2O3 dielectric layers are conformally coated at activated carbon surface by ALD, well-maintaining microporous morphology. Resultant electrodes exhibit excellent stability at 3 V operation with 39% energy density enhancement from 2.5 V operation. Because of the protection of surface functional groups and reduction of electrolyte degradation, 74% of initial voltage was maintained 50 h after full charge, and 88% of capacitance was retained after 5000 cycles at 70 degrees C accelerated test, which correspond to 31 and 17% improvements from bare activated carbon, respectively. This ALD-based surface modification offers a general method to enhance electrochemical stability of carbon materials for diverse energy and environmental applications. PMID- 25548827 TI - Nonlinear photoluminescence spectrum of single gold nanostructures. AB - We investigate the multiphoton photoluminescence characteristics of gold nanoantennas fabricated from single crystals and polycrystalline films. By exciting these nanostructures with ultrashort pulses tunable in the near-infrared range, we observe distinct features in the broadband photoluminescence spectrum. By comparing antennas of different crystallinity and shape, we demonstrate that the nanoscopic geometry of plasmonic devices determines the shape of the emission spectra. Our findings rule out the contribution of the gold band structure in shaping the photoluminescence. PMID- 25548828 TI - Ferrocenyl-appended aurone and flavone: which possesses higher inhibitory effects on DNA oxidation and radicals? AB - The aim of the present work was to compare the antioxidative effect of the ferrocenyl-appended aurone with that of ferrocenyl-appended flavone; therefore, nine aurones together with the flavone-type analogues were synthesized by using chalcone as the reactant. The radical-scavenging property was evaluated by reacting with the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+.)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively. The cytotoxicity was estimated by inhibiting 2,2'-azobis(2 amidinopropane hydrochloride) (AAPH)-induced oxidation of DNA. It was found that the introduction of the ferrocenyl group remarkably increased the radical scavenging activities of aurone and flavone. Especially, the ferrocenyl group in flavones can quench radicals even in the absence of the phenolic hydroxyl group, while ferrocenyl-appended aurones can efficiently protect DNA against AAPH induced oxidation. Therefore, the antioxidative effect was generated by the ferrocenyl group and enhanced by the electron-donating group attaching to the para-position of the ferrocenyl group. Introducing the ferrocenyl group into natural compounds may be a useful strategy for increasing the antioxidative effectiveness. PMID- 25548829 TI - Stocks and flows of PBDEs in products from use to waste in the U.S. and Canada from 1970 to 2020. AB - The time-dependent stock of PBDEs contained in in-use products (excluding building materials and large vehicles) was estimated for the U.S. and Canada from 1970 to 2020 based on product consumption patterns, PBDE contents, and product lifespan. The stocks of penta- and octaBDE peaked in in-use products at 17,000 (95% confidence interval: 6000-70,000) and 4,000 (1,000-50,000) tonnes in 2004, respectively, and for decaBDE at 140,000 (40,000-300,000) tonnes in 2008. Products dominating PBDE usage were polyurethane foam used in furniture (65% of pentaBDE), casings of electrical and electronic equipment or EEE (80% of octaBDE), and EEE and automotive seating (35% of decaBDE for each category). The largest flow of PBDEs in products, excluding automotive sector, to the waste phase occurred between 2005 and 2008 at ~10,000 tonnes per year. Total consumption of penta-, octa-, and decaBDE from 1970 to 2020 in products considered was estimated at ~46,000, ~25,000, and ~380,000 tonnes, respectively. Per capita usage was estimated at 10-250, 10-150, and 200-2000 g.capita(-1).y(-1) for penta-, octa-, and decaBDE, respectively, over the time span. Considering only the first use (no reuse and/or storage) of PBDE-containing products, approximately 60% of the stock of PBDEs in 2014 or ~70,000 tonnes, of which 95% is decaBDE, will remain in the use phase in 2020. Total emissions to air of all PBDEs from the in-use product stock was estimated at 70-700 tonnes between 1970 and 2020, with annual emissions of 0.4-4 tonnes.y(-1) for each of penta- and octaBDE and 0.35-3.5 tonnes.y(-1) for decaBDE in 2014. PMID- 25548830 TI - Structural ordering of self-assembled clusters with competing interactions: transition from faceted to spherical clusters. AB - The self-assembly of nanoparticles into clusters and the effect of the different parameters of the competing interaction potential on it are investigated. For a small number of particles, the structural organization of the clusters is almost unaffected by the attractive part of the potential, and for an intermediate number of particles the configuration strongly depends on the strength of it. The cluster size is controlled by the range of the interaction potential, and the structural arrangement is guided by the strength of the potential: i.e., the self assembled cluster transforms from a faceted configuration at low strength to a spherical shell-like structure at high strength. Nonmonotonic behavior of the cluster size is found by increasing the interaction range. An approximate analytical expression is obtained that predicts the smallest cluster for a specific set of potential parameters. A Mendeleev-like table is constructed for different values of the strength and range of the attractive part of the potential in order to understand the structural ordering of the ground-state configuration of the self-assembled clusters. PMID- 25548831 TI - Community-based adapted tango dancing for individuals with Parkinson's disease and older adults. AB - Adapted tango dancing improves mobility and balance in older adults and additional populations with balance impairments. It is composed of very simple step elements. Adapted tango involves movement initiation and cessation, multi directional perturbations, varied speeds and rhythms. Focus on foot placement, whole body coordination, and attention to partner, path of movement, and aesthetics likely underlie adapted tango's demonstrated efficacy for improving mobility and balance. In this paper, we describe the methodology to disseminate the adapted tango teaching methods to dance instructor trainees and to implement the adapted tango by the trainees in the community for older adults and individuals with Parkinson's Disease (PD). Efficacy in improving mobility (measured with the Timed Up and Go, Tandem stance, Berg Balance Scale, Gait Speed and 30 sec chair stand), safety and fidelity of the program is maximized through targeted instructor and volunteer training and a structured detailed syllabus outlining class practices and progression. PMID- 25548832 TI - Soluble ligands and their receptors in human embryo development and implantation. AB - Extensive evidence suggests that soluble ligands and their receptors mediate human preimplantation embryo development and implantation. Progress in this complex area has been ongoing since the 1980s, with an ever-increasing list of candidates. This article specifically reviews evidence of soluble ligands and their receptors in the human preimplantation stage embryo and female reproductive tract. The focus will be on candidates produced by the human preimplantation embryo and those eliciting developmental responses in vitro, as well as endometrial factors related to implantation and receptivity. Pathways to clinical translation, including innovative diagnostics and other technologies, are also highlighted, drawing from this collective evidence toward facilitating joint improvements in embryo quality and endometrial receptivity. This strategy could not only benefit clinical outcomes in reproductive medicine but also provide broader insights into the peri-implantation period of human development to improve fetal and neonatal health. PMID- 25548833 TI - Absolute prompt-gamma yield measurements for ion beam therapy monitoring. AB - Prompt-gamma emission detection is a promising technique for hadrontherapy monitoring purposes. In this regard, obtaining prompt-gamma yields that can be used to develop monitoring systems based on this principle is of utmost importance since any camera design must cope with the available signal. Herein, a comprehensive study of the data from ten single-slit experiments is presented, five consisting in the irradiation of either PMMA or water targets with lower and higher energy carbon ions, and another five experiments using PMMA targets and proton beams. Analysis techniques such as background subtraction methods, geometrical normalization, and systematic uncertainty estimation were applied to the data in order to obtain absolute prompt-gamma yields in units of prompt-gamma counts per incident ion, unit of field of view, and unit of solid angle. At the entrance of a PMMA target, where the contribution of secondary nuclear reactions is negligible, prompt-gamma counts per incident ion, per millimetre and per steradian equal to (124 +/- 0.7stat +/- 30sys) * 10(-6) for 95 MeV u(-1) carbon ions, (79 +/- 2stat +/- 23sys) * 10(-6) for 310 MeV u(-1) carbon ions, and (16 +/ 0.07stat +/- 1sys) * 10(-6) for 160 MeV protons were found for prompt gammas with energies higher than 1 MeV. This shows a factor 5 between the yields of two different ions species with the same range in water (160 MeV protons and 310 MeV u(-1) carbon ions). The target composition was also found to influence the prompt gamma yield since, for 300/310 MeV u(-1) carbon ions, a 42% greater yield ((112 +/- 1stat +/- 22sys) * 10(-6) counts ion(-1) mm(-1) sr(-1)) was obtained with a water target compared to a PMMA one. PMID- 25548834 TI - Surgical vertebral body cementoplasty as spinal cancer metastasis management. AB - Spinal metastases of cancer are frequent and their treatment strategy remains a problem. The aim of the present paper is to present the technique of cementoplasty and its originality. Spine corporeal cementoplasty techniques were performed in 9 patients with spine metastasis treated at Neurosurgery Department between 2002 and 2005. This series is composed of four women and five men. The average age of patients was 54 years. All patients were admitted for treatment of metastasis of breast carcinoma, metastasis of breast adenocarcinoma (three cases), colon cancer (two cases), pulmonary adenocarcinoma (one case) and melanoma (three cases). Metastasis was located on the cervical spine (3 cases), thoracic spine (4 cases) and lumbar spine (2 cases). No case of cement leaking was observed. In eight patients neurological deficit and pain were decreased. In one patient we noted a persistence of neurological deficit but pain decreased. A post-operative radiological analysis showed good spine stability. Before their death this treatment had improved their quality of life. The technique of surgical cementoplasty described in this paper may be used for a surgical treatment of metastasis and spinal stabilisation. It is an alternative to a palliative treatment of metastasis when it is not possible to perform vertebroplasty. PMID- 25548835 TI - Use of allogeneic stem cell transplantation for moderate-severe Glanzmann thrombasthenia. AB - Glanzmann thrombasthenia (GT) is a rare, autosomal recessive coagulopathy characterized by either qualitative or quantitative abnormalities of the membrane glycoprotein alphaIIbbeta3 complex leading to bleeding tendencies, ranging from purpura to life-threatening hemorrhage. Although patients can be managed with supportive measures including platelet transfusions, complications such as alloimmunization are possible. Allogeneic stem cell transplantation (ASCT) can be indicated in severe cases of GT. We report the case of an eight-month-old girl diagnosed with moderate-severe GT, who was successfully treated with a reduced intensity, human leukocyte antigen (HLA)-identical ASCT. PMID- 25548836 TI - Maternal and fetal outcome in de novo preeclampsia in comparison to superimposed preeclampsia: a two-year observational study. AB - AIM: To assess the maternal and fetal outcome in women with de novo preeclampsia (PE) in comparison to superimposed PE. STUDY DESIGN: This was a prospective 2 year observational study carried out at Menoufia University Hospital, Egypt, in which 164 patients out of 6472 pregnant women were diagnosed with PE (78 with de novo PE and 86 with superimposed PE). Enrolled patients were followed to assess the maternal and fetal outcome. RESULTS: There was a significant higher women with liver impairment and delivery by caesarean section in the de novo PE group (p < 0.05), with more women with renal impairment and ECG changes in the superimposed PE group (p < 0.05). No significant difference between the two groups regarding the occurrence of eclampsia, blood transfusion, admission to ICU and venous thromboembolism (p > 0.05). There was a significantly higher small for gestational age, prematurity, NICU admission and perinatal mortality in the superimposed PE group (p < 0.05). No significant difference between the two groups regarding the occurrence of placental abruption and intrauterine fetal demise (p > 0.05). CONCLUSIONS: Women with de novo PE have higher risks of liver impairment and delivery by cesarean section. On the other hand, women with superimposed PE have higher risks of poorer fetal outcome. PMID- 25548837 TI - Introduction to Dermatologic Surgery special issue on neuromodulators. PMID- 25548838 TI - Prolonging the duration of masseter muscle reduction by adjusting the masticatory movements after the treatment of masseter muscle hypertrophy with botulinum toxin type a injection. AB - BACKGROUND: Botulinum toxin type A (BTX-A) is widely used for the clinical treatment of masseteric hypertrophy. Until now, few reports have discussed how to prolong the duration of its effectiveness. OBJECTIVE: This study evaluated that purposely adjusting the masticatory movements is possible of postponing the masseter muscle rehypertrophy. METHODS: Ninety-eight patients were randomly and equally divided into 2 groups, and 35 U BTX-A per side was injected into the masseters. The thickness and volume of the masticatory muscles were measured by ultrasound and computerized tomography, respectively. Patients in Group 1 were instructed to strengthen their masticatory effort during the denervated atrophic stage of the masseter (the interval was evaluated by real-time ultrasound monitoring), whereas patients in Group 2 were not given this instruction. When the masseter muscle began to recover, patients in both groups were instructed to reduce their chewing. RESULTS: The duration of the masseter muscle rehypertrophy was significantly prolonged in Group 1 patients. The thickness and the volume of the other masticatory muscles were significantly increased in Group 1 but were either slightly decreased or insignificantly different in Group 2. CONCLUSION: Purposely strengthening masticatory muscle movement during the denervated atrophic stage of the masseter can prolong the duration of masseter rehypertrophy. PMID- 25548839 TI - Fields of muscular and anhidrotic effects of 2 botulinum toxin-A commercial preparations: a prospective, double-blind, randomized, multicenter study. AB - BACKGROUND: Longevity of effects and dose equivalence of different botulinum toxin type A (BoNT-A) preparations need to be better clarified because BoNT-A units are manufacturer-specific. These points are of particular importance for new brands emerging in the market. OBJECTIVE: To assess the field of muscular and anhidrotic effects of 2 commercial preparations of BoNT-A (incobotulinumtoxinA: Xeomin [XEO]; abobotulinumtoxinA: Dysport [DYS]) administered to the upper third of the face. METHODS: Patients were randomized for the side of the forehead (left or right) in which the products were administered. All were treated receiving BoNT-A injections in 10 points (5 on each side) at a dose equivalence of 1.0:2.5 U (XEO:DYS). Clinical assessments and Minor test were performed at baseline and Days 28, 84, 112, and 140. Electromyography was performed at baseline and Days 28 and 140, and ultrasound was performed only at baseline. RESULTS: Eighty patients were enrolled in 2 research centers. Xeomin and DYS presented similar results regarding fields of muscular effects. However, a larger field of anhidrotic effects was found for DYS. There was a positive correlation between the muscle thickness and electromyography results. CONCLUSION: The results of this study suggest that a lower dose equivalence between DYS and XEO could be established. PMID- 25548840 TI - New frontiers and clinical applications for botulinum neuromodulators. PMID- 25548841 TI - Patient satisfaction and safety with aesthetic onabotulinumtoxinA after at least 5 years: a retrospective cross-sectional analysis of 4,402 glabellar treatments. AB - BACKGROUND: Despite extensive clinical experience with onabotulinumtoxinA, few data exist on patient satisfaction or safety with continuous treatment. OBJECTIVE: This international multicenter study evaluated patient satisfaction and safety with long-term continuous facial aesthetic treatment with onabotulinumtoxinA. METHODS: Retrospective chart review with a cross-sectional design was used to assess onabotulinumtoxinA treatment, including dosing, concomitant facial aesthetic medications and procedures, and adverse events (AEs). Validated Facial Line Satisfaction Questionnaire, Self-Perception of Age measure, and Facial Line Outcomes questionnaire instruments, and a de novo questionnaire were used to determine patient satisfaction. RESULTS: A total of 207 patients consisted of the intent-to-treat population, with 194 in the per protocol analyses. Patients received a total of 4,402 glabellar treatments over a mean of 9.1 years, with a mean dose of 21.6 U per treatment. Overall, 92.3% of patients were mostly or very satisfied. Among the 89.7% of patients who reported looking younger, the mean perceived age was 6.9 years younger. Documented AEs were infrequent, mostly mild in severity, and declined in frequency over time. LIMITATIONS: This population was self-selecting as they chose to continue treatment for 5 or more years to be eligible. CONCLUSION: Continuous treatment with onabotulinumtoxinA for a mean of 9.1 years was associated with very high patient satisfaction. PMID- 25548842 TI - You want to inject what? AB - BACKGROUND: This article is a review of the authors' 32 years' experience with botulinum toxin type A (BoNTA), especially its cosmetic use. It includes a review of the relevant literature and pointers to the future. OBJECTIVE: To provide readers with a history of the cosmetic use of BoNTA and future directions. METHODS: This article is written from the authors' experience. RESULTS: The readers will be aware of the results of the interaction with BoNTA. CONCLUSION: Botulinum toxin type A is a safe and effective treatment for some cosmetic problems. Side effects are minimal and short lived. The future of this therapeutic modality continues to be exciting. PMID- 25548843 TI - Patient-reported outcomes after incobotulinumtoxinA treatment for upper facial wrinkles. AB - BACKGROUND: Botulinum toxins are used for facial rejuvenation. OBJECTIVE: To investigate the efficacy, patient satisfaction, and skin physiology after incobotulinumtoxinA treatment of the upper face. MATERIALS AND METHODS: Thirty women aged 35 to 55 were enrolled in this single-center prospective 16-week study. Patients and an investigator blinded to visit number assessed wrinkle severity after incobotulinumtoxinA treatment of glabellar, periorbital, and forehead lines using Validated Assessment Scales at Days 0 (baseline), 2, 7, 14, 28, and 112. Responder rates (for each region) and mean wrinkle scores (whole upper face) were calculated. Treatment satisfaction was self-assessed by questionnaire. Transepidermal water loss (TEWL), stratum corneum hydration, and skin pH were measured to assess skin barrier function. RESULTS: Wrinkle severity decreased rapidly after treatment. Responder rates generally peaked at Days 7 to 14. At 112 days, mean scores remained significantly lower than baseline (p < .05). Patients were significantly more satisfied with their appearance after treatment; most felt "younger" and "more attractive" (p < .05). Transepidermal water loss decreased significantly throughout (p < .05), and stratum corneum hydration increased. No treatment-related adverse events occurred. CONCLUSION: IncobotulinumtoxinA rapidly improved wrinkle severity, and improvements were maintained for up to 112 days. Increased stratum corneum hydration and reduced TEWL may improve skin quality. IncobotulinumtoxinA was well tolerated and improved patients' self-perception. PMID- 25548844 TI - A prospective rater- and subject-blinded study comparing the efficacy of incobotulinumtoxinA and onabotulinumtoxinA to treat crow's feet: a clinical crossover evaluation. AB - BACKGROUND: Botulinum toxin A products have been used in aesthetics for more than 20 years. OBJECTIVE: To compare incobotulinumtoxinA with onabotulinumtoxinA in the treatment of crow's feet. METHODS: This single-center, randomized, prospective, split-face, subject- and rater-blinded study with a clinical crossover evaluation comprised 2 consecutive treatment cycles, each of 3 months' duration separated by 6 months (i.e., a 9-month treatment interval). Fourteen subjects with symmetrical crow's feet were assessed using the Merz 5-point scale for crow's feet, after each treatment with incobotulinumtoxinA (right side of the face) and onabotulinumtoxinA (left side), or vice versa (1:1 dose conversion ratio). The treatment applied to each side of the face was reversed in Cycle 2. RESULTS: Crow's feet severity at rest and maximum contraction was improved to a similar extent by both treatments, in both cycles and on both sides of the face. Pooled data confirmed these results. Improvements were maintained at the final visit, 3 months after treatment (e.g., left side at maximum contraction onabotulinumtoxinA mean score: 2.21 [baseline] vs 0.93 [1 month] vs 1.71 [3 months]; incobotulinumtoxinA mean score: 2.21 vs 0.86 vs 1.50). CONCLUSION: IncobotulinumtoxinA and onabotulinumtoxinA (1:1 dose conversion ratio) were well tolerated, showing comparable efficacy and duration of treatment effect for crow's feet. PMID- 25548847 TI - Long-term effects of onabotulinumtoxinA on facial lines: a 19-year experience of identical twins. PMID- 25548845 TI - Safety and efficacy of RT002, an injectable botulinum toxin type A, for treating glabellar lines: results of a phase 1/2, open-label, sequential dose-escalation study. AB - BACKGROUND: RT002 is a new injectable BoNTA product. This formulation limits the spread of BoNTA, potentially permitting safe administration of larger doses and possibly extending its duration of action. OBJECTIVE: This phase 1/2 clinical study was designed to establish the safety of RT002 for the treatment of moderate to-severe glabellar lines. MATERIALS AND METHODS: Subjects were randomized into four groups (N=12/group). Cohorts 1-3 received escalating doses of RT002 ranging from half the equivalent dose of approved toxins up to twice the current dose levels. The safety of each dose was confirmed prior to administering the next dose. Subjects in Cohort 4 were treated with the highest dose and observed for 36 weeks or until GLSS returned to baseline. RESULTS: All doses of RT002 were well tolerated. Common AEs were headache and mild injection site reactions. At Week 4, all doses of RT002 were highly effective at maximum frown. Cohort 4 achieved 7 month median duration. At 6 months, 80% of subjects maintained a >=1-point improvement in Investigator GLSS and 60% maintained WSS of None or Mild. Study limitations include an open-label design and modest number of subjects. CONCLUSION: RT002 is a safe and effective BoNTA product with an extended duration of action. PMID- 25548846 TI - Optimal dosage of botulinum toxin type A for treatment of glabellar frown lines: efficacy and safety in a clinical trial. AB - BACKGROUND: Various preparations of botulinum toxin type A (BTX-A) are used to reduces glabellar (frown) lines. However, dose-related safety and efficacy of intramuscular injections of a widely used, locally produced BTX-A in China has not been established. OBJECTIVE: Assessment of dose-dependent safety and efficacy of Chinese botulinum toxin type A (Hengli BTX-A [HBTX-A]) intramuscular injections on glabellar lines. METHODS: Four hundred eighty-eight BTX-A-naive participants were included in the double-blind trial and randomly divided into placebo (n = 122), low-dose (n = 183), and high-dose (n = 183) treatment groups for injection with saline solution, 10 units and 20 units of HBTX-A, respectively, at 4 sites in the corrugator muscle and 1 site in the procerus muscle. Outcomes were recorded before treatment and after 7, 30, 60, and 120 days, including glabellar line severity at maximum contraction and relaxation. RESULTS: Significantly greater improvement was observed in both HBTX-A groups in comparison with the placebo group (p < .05). Better efficacy was obtained in the high-dose treatment group. More participants developed adverse events after treatment with HBTX-A doses, than with the placebo (p < .05). CONCLUSION: Twenty unit HBTX-A provided optimal improvement in glabellar lines, and its use might minimize injection frequency while maintaining acceptable safety. PMID- 25548848 TI - Effects of OnabotulinumtoxinA treatment for crow's feet lines on patient-reported outcomes. AB - BACKGROUND: Although millions of aesthetic procedures are performed annually, few patient-reported outcome (PRO) measures have been used in this setting. OBJECTIVE: To evaluate the impact of onabotulinumtoxinA treatment for crow's feet lines (CFL) on relevant psychological variables and self-perception of age/appearance in subgroup populations. MATERIALS AND METHODS: Facial Lines Outcomes (FLO-11) Questionnaire, Self-Perception of Age (SPA), and Subject Global Assessment of Change in CFL (SGA-CFL) were PRO measures administered in 2 Phase 3, double-blind placebo-controlled trials for the treatment of CFL alone or CFL/glabellar lines (GL). Patient-reported outcome measures were analyzed by subgroups (age, gender, and baseline CFL severity). Subject satisfaction with appearance was also analyzed. RESULTS: Most subgroups receiving onabotulinumtoxinA demonstrated significant improvements in psychological impact (FLO-11 Items 2, 5, and 8) versus placebo at Day 30 (p <= .05). OnabotulinumtoxinA-treated subjects consistently rated themselves as looking younger on SPA versus placebo in all subgroups at Day 30 (p <= .05) and showed significant improvements in CFL appearance versus placebo at all time points on SGA-CFL. Overall, subjects were satisfied with their appearance. CONCLUSION: OnabotulinumtoxinA-treated subjects experienced significant improvements in perceived appearance, attractiveness, tiredness, age, and satisfaction versus placebo. Subjects treated for CFL and GL experienced even greater effects. PMID- 25548849 TI - Prospective randomized controlled study to determine the effect of topical application of botulinum toxin A for crow's feet after treatment with ablative fractional CO2 laser. AB - BACKGROUND: Botulinum toxin Type A (BoNT A) for the treatment of facial wrinkles is delivered through local injection. We previously demonstrated that topical surface application of BoNT A has negligible cutaneous bioavailability and is not effective in treating wrinkles. OBJECTIVE: To determine the effect of BoNT A solution applied topically on the skin surface immediately after ablative fractional CO2 laser treatment. METHODS: We conducted a randomized controlled trial for patients with periorbital wrinkles (crow's feet) (n = 10). Treatment was performed on both sides of the face with fractional ablative CO2 laser followed by the application of topical solutions of BoNT A on one side and normal saline as control on the other side. Pretreatment assessment was performed, and at 1 and 4 weeks after treatment. RESULTS: There was a clinically significant greater degree of improvement in wrinkles after treatment with CO2 laser, on the topically applied BoNT A side. Also, the difference between the 2 treatment types (laser followed by topical BoNT A vs laser followed by saline) at 1 week and at 1 month was statistically significant. CONCLUSION: Topically, noninjectable form of BoNT A applied on the surface of the skin after ablative fractional CO2 laser is effective in the treatment of lateral periorbital wrinkles. PMID- 25548850 TI - Injecting botulinum toxin at different depths is not effective for the correction of eyebrow asymmetry. AB - BACKGROUND: It is theorized that brow elevation after treatment with botulinum toxin Type A (BoNT-A) results from inactivation of the brow depressors. Expert consensus is that increased injection depth delivers more BoNT-A to these depressors and causes increased elevation. This technique is applied to the correction of brow height asymmetry. OBJECTIVE: To compare changes in brow height after deep versus shallow BoNT-A in patients with brow asymmetry. METHODS: A prospective split-face analysis was performed on 23 women with eyebrow-height asymmetry. Subjects received 64 units of BoNT-A, divided among 16 injection sites in the glabella, forehead, and lateral canthal area. On the side where increased brow lift was desired, deep injections were performed and shallow injections on the opposite side. Photographs were taken at baseline and Week 4 for comparison measurements. RESULTS: All 23 women enrolled completed baseline injections and returned for the 4-week follow-up. There was no significant difference at 4 weeks in the change in brow height between the sides that received deep versus shallow BoNT-A injection. CONCLUSION: Because of the diffusion of the BoNT-A between muscle layers, the eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies. PMID- 25548851 TI - IncobotulinumtoxinA for the treatment of platysmal bands: a single-arm, prospective proof-of-concept clinical study. AB - BACKGROUND: IncobotulinumtoxinA improves the appearance of facial rhytides and the aging neck. OBJECTIVE: To investigate the efficacy, safety, and subject satisfaction of incobotulinumtoxinA for platysmal band treatment. METHODS: Subjects (n = 23) with 2 to 4 platysmal bands (scoring >=1 on a newly validated 5 point assessment scale) were enrolled. IncobotulinumtoxinA (15 U) was administered to each band. Assessments, using the 5-point scale, occurred at 6 posttreatment visits over 5 months. Adverse events were recorded and subjects self-assessed the appearance of their platysmal bands versus baseline. RESULTS: At maximum tension, a response (>=1-point improvement from baseline score) was observed in 65.2% of subjects 3 (+/-1) days posttreatment, rising to 100% on Day 8 (+/-1). The change from baseline in the mean score was significant at each time point, including the final visit (Weeks 20-21). Response rates were higher at maximum tension than at rest. The peak effect occurred later at rest than at maximum tension. No serious adverse event occurred. At maximum tension, 69.6%, 73.9%, and 68.2% of subjects rated their platysmal bands as "improved" or "markedly improved" at Visits 2, 3, and 4, respectively. CONCLUSION: IncobotulinumtoxinA is an effective and well-tolerated treatment for platysmal bands, with a rapid onset and long duration of effect. PMID- 25548852 TI - Impact of intradermal abobotulinumtoxinA on facial erythema of rosacea. AB - BACKGROUND: Facial erythema is a frequent and often distressing complaint of patients with rosacea. Treatment of facial erythema with botulinum toxin has previously been proposed and reported. However, the current literature has mixed results. OBJECTIVE: The primary objective of this study was to evaluate the safety and efficacy of intradermal abobotulinumtoxinA on facial erythema of rosacea. MATERIALS AND METHODS: Twenty-five subjects aged 35 to 70 years with Fitzpatrick skin Types I to IV and facial erythema of erythematotelangiectatic rosacea were enrolled in the trial. Subjects received 15 to 45 units of intradermal injections of abobotulinumtoxinA to the nasal tip, nasal bridge, and nasal alae. A nontreating investigator assessed the facial erythema of rosacea using a standardized grading system (0 = absent, 1 = mild erythema, 2 = moderate erythema, and 3 = severe erythema) to evaluate digital photographs at baseline, 1, 2, and 3 months after treatment. Statistical analysis of erythema grade included one-way repeated-measures analysis of variance and pairwise comparisons using SPSS (IBM Corporation) software. RESULTS: Fifteen of the 25 enrolled subjects completed all the appropriate follow-up visits. Only the 15 subjects with complete data were included in analysis. The subjects were of Fitzpatrick skin Types I to III, a mean age of 54 years, and 80% women. The mean baseline erythema grade was 1.80 (+/-0.56), and the mean erythema grade at 3 months after treatment was 1.00 (+/-0.38). The treatment resulted in statistically significant improvement in erythema grade at 1, 2, and 3 months after treatment when compared with baseline (p < .05, p < .001, and p < .05, respectively). Pairwise comparison to baseline showed a mean erythema grade improvement of 0.80 (p < .001) at 3 month follow-up. CONCLUSION: Intradermal injection of botulinum toxin for the treatment of facial erythema of rosacea seems both effective and safe. Larger, randomized, blinded, placebo-controlled studies are warranted. Additionally, further investigation is needed to elucidate the mechanism of action by which botulinum toxin improves facial flushing of rosacea. PMID- 25548853 TI - Fields of anhidrotic effects of abobotulinumtoxinA in patients with compensatory hyperhidrosis. AB - BACKGROUND: Botulinum toxin type A can be used to treat compensatory hyperhidrosis (CHH), which presents areas of different intensity of sweating. More information about the anhidrotic effects is needed. OBJECTIVE: To evaluate the fields of anhidrotic effects (FAEs) resulting from different doses (5 and 10 U), dilution, and depths of injection of abobotulinumtoxinA in patients with CHH. METHODS: This was a prospective, single-center, pilot study. Ten patients suffering from CHH received 20 different injections of abobotulinumtoxinA on their backs. Midline received higher doses because of more intense sweating. The diameters of the FAEs were measured at 7, 30, and 180 days after the procedure. RESULTS: Diameters of the FAEs were significantly larger at Day 30 (p < .0001) and did not significantly differ when compared with different injection depths and volumes. Points injected with 10 U exhibited significantly larger vertical diameters at 7, 30, and 180 days (p values .05, <.0001, and .043, respectively) than those injected with 5 U, but no statistical significance was observed for the horizontal diameters. CONCLUSION: Areas of more intense sweating need higher doses to present similar diameters of the FAEs. Depth and volume of injections do not play a remarkable role on the FAEs diameters in patients suffering from CHH. PMID- 25548854 TI - Sex/gender disparities and women's eye health. AB - Our eyes are, both literally and figuratively, windows to the world, and ophthalmic approaches offer a tremendous space for conducting research to learn more. Male/female differences in ocular health and disease are prevalent but we know far too little about root causes to design and implement diagnostic, preventive, and treatment strategies to address sex- and gender-based disparities in eye health. Herein, we discuss several ophthalmic diseases and other conditions with ocular manifestations, with a focus upon those that disproportionately affect women. Because the vast majority of biomedical research in this area comes from studies of mixed-gender populations, or of male predominant populations, there is a pressing need for sex- and/or gender-based research at various points along the basic to clinical biomedical research continuum. Moreover, the multitude of factors that affect eye health call for a balanced look at the influence of biology, culture, and societal contributors. As clinicians, we owe our patients the best care for their needs, and that care must be derived from research that shows what is effective, for whom, and under what conditions. PMID- 25548855 TI - A dual task procedure combined with rapid serial visual presentation to test attentional blink for nontargets. AB - When viewers search for targets in a rapid serial visual presentation (RSVP) stream, if two targets are presented within about 500 msec of each other, the first target may be easy to spot but the second is likely to be missed. This phenomenon of attentional blink (AB) has been widely studied to probe the temporal capacity of attention for detecting visual targets. However, with the typical procedure of AB experiments, it is not possible to examine how the processing of non-target items in RSVP may be affected by attention. This paper describes a novel dual task procedure combined with RSVP to test effects of AB for nontargets at varied stimulus onset asynchronies (SOAs). In an exemplar experiment, a target category was first displayed, followed by a sequence of 8 nouns. If one of the nouns belonged to the target category, participants would respond 'yes' at the end of the sequence, otherwise participants would respond 'no'. Two 2-alternative forced choice memory tasks followed the response to determine if participants remembered the words immediately before or after the target, as well as a random word from another part of the sequence. In a second exemplar experiment, the same design was used, except that 1) the memory task was counterbalanced into two groups with SOAs of either 120 or 240 msec and 2) three memory tasks followed the sequence and tested remembrance for nontarget nouns in the sequence that could be anywhere from 3 items prior the target noun position to 3 items following the target noun position. Representative results from a previously published study demonstrate that our procedure can be used to examine divergent effects of attention that not only enhance targets but also suppress nontargets. Here we show results from a representative participant that replicated the previous finding. PMID- 25548856 TI - Reflective practice in speech-language pathology: a scoping review. AB - PURPOSE: Within the profession of speech-language pathology, there is limited information related to both conceptual and empirical perspectives of reflective practice. This review considers the key concepts and approaches to reflection and reflective practice that have been published in the speech-language pathology literature in order to identify potential research gaps. METHOD: A scoping review was conducted using Arksey and O'Malley's (2005) framework. RESULT: A total of 42 relevant publications were selected for review. The resulting literature mapping revealed that scholarship on reflection and reflective practice in speech language pathology is limited. Our conceptual mapping pointed to the use of both multiple and generic terms and a lack of conceptual clarity about reflection and reflective practice in speech-language pathology. Two predominant approaches to reflection and reflective practice were identified: written reflection and reflective discussion. Both educational and clinical practice contexts were associated with reflection and reflective practice. Publications reviewed were primarily concerned with reflection and reflective practice by novices and expert practitioners. CONCLUSION: Based on this review, we posit that there is considerable need for conceptual and empirical work with a goal to support university- and work-based educational initiatives involving reflection and reflective practice in speech-language pathology. PMID- 25548857 TI - Reproductive history and chronic hepatic steatosis in the Michigan Study of Women's Health Across the Nation. AB - BACKGROUND: Reproductive history, particularly maternal age at most recent birth, may reflect lower risk for chronic disease and mortality due to socioeconomic factors, lifestyle behaviors, or genetics. Reproductive history has not been examined with respect to hepatic steatosis, the most common liver disease in the United States. Our objective was to examine the association between reproductive history and hepatic steatosis. METHODS: We examined the association between reproductive history characteristics--specifically age at most recent birth--and the odds of moderate to severe hepatic steatosis using a population-based retrospective cohort study of women who underwent hepatic ultrasound at the Michigan site of the Study of Women's Health Across the Nation (n=331). RESULTS: Women who gave birth at >= 35 years of age comprised 19% of the study population and were similar to other women regarding sociodemographic history and health behaviors. In multivariable analyses adjusting for age, race/ethnicity, chronic disease, and medications associated with hepatic steatosis, age at birth >= 35 years was associated with significantly decreased odds of hepatic steatosis (adjusted odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.87), which was attenuated after adjustment for waist circumference (OR 0.51, 95% CI 0.24 1.10). Other reproductive factors including gravidity, parity, miscarriages and abortions, recall of gestational weight gain, breastfeeding, age at first birth, and age at final menstrual period were not associated with hepatic steatosis. CONCLUSIONS: Women who were older at their most recent birth had a reduced odds of hepatic steatosis, possibly associated with their lower waist circumference. PMID- 25548858 TI - Independent validation of six melanoma risk prediction models. AB - Identifying people at high risk of melanoma is important for targeted prevention activities and surveillance. Several tools have been developed to classify melanoma risk, but few have been independently validated. We assessed the discriminatory performance of six melanoma prediction tools by applying them to individuals from two independent data sets, one comprising 762 melanoma cases and the second a population-based sample of 42,116 people without melanoma. We compared the model predictions with actual melanoma status to measure sensitivity and specificity. The performance of the models was variable with sensitivity ranging from 97.7 to 10.5% and specificity from 99.6 to 1.3%. The ability of all the models to discriminate between cases and controls, however, was generally high. The model developed by MacKie et al. (1989) had higher sensitivity and specificity for men (0.89 and 0.88) than women (0.79 and 0.72). The tool developed by Cho et al. (2005) was highly specific (men, 0.92; women, 0.99) but considerably less sensitive (men, 0.64; women, 0.37). Other models were either highly specific but lacked sensitivity or had low to very low specificity and higher sensitivity. Poor performance was partly attributable to the use of non standardized assessment items and various differing interpretations of what constitutes "high risk". PMID- 25548860 TI - Design optimization of multi-pinhole micro-SPECT configurations by signal detection tasks and system performance evaluations for mouse cardiac imaging. AB - An optimized configuration of multi-pinhole aperture can improve the spatial resolution and the sensitivity of pinhole SPECT simultaneously. In this study, an optimization strategy of the multi-pinhole configuration with a small detector is proposed for mouse cardiac imaging. A 14 mm-diameter spherical field-of-view (FOV) is used to accommodate the mouse heart. To accelerate the optimization process, the analytic models are applied to rapidly obtain the projection areas of the FOV, the sensitivities and the spatial resolutions of numerous system designs. The candidates of optimal multi-pinhole configuration are then decided by the preliminary evaluations with the analytic models. Subsequently, the pinhole SPECT systems equipped with the designed multi-pinhole apertures are modeled in GATE to generate the imaging system matrices (H matrices) for the system performance assessments. The area under the ROC curves (AUC) of the designed systems is evaluated by signal-known-exactly/background-known statistically detection tasks with their corresponding H matrices. In addition, the spatial resolutions are estimated by the Fourier crosstalk approach, and the sensitivities are calculated with the H matrices of designed systems, respectively. Furthermore, a series of OSEM reconstruction images of synthetic phantoms, including the hot-rod phantom, mouse heart phantom and Defrise phantom, are reconstructed with the H matrices of designed systems. To quantify the sensitivity and resolution competition in the optimization process, the AUC from the detection tasks and the resolution estimated by the Fourier crosstalk are used as the figure of merits. A trade-off function of AUC and resolution is introduced to find the optimal multi-pinhole configuration. According to the examining results, a 22.5 degrees rotated detector plus a 4-pinhole aperture with 22.5 degrees rotation, 20% multiplexing and 1.52X magnification is the optimized multi-pinhole configuration for the micro pinhole-SPECT applied to mouse cardiac imaging with a camera of 49 * 49 mm(2) active area. PMID- 25548859 TI - Implantation of fibrin gel on mouse lung to study lung-specific angiogenesis. AB - Recent significant advances in stem cell research and bioengineering techniques have made great progress in utilizing biomaterials to regenerate and repair damage in simple tissues in the orthopedic and periodontal fields. However, attempts to regenerate the structures and functions of more complex three dimensional (3D) organs such as lungs have not been very successful because the biological processes of organ regeneration have not been well explored. It is becoming clear that angiogenesis, the formation of new blood vessels, plays key roles in organ regeneration. Newly formed vasculatures not only deliver oxygen, nutrients and various cell components that are required for organ regeneration but also provide instructive signals to the regenerating local tissues. Therefore, to successfully regenerate lungs in an adult, it is necessary to recapitulate the lung-specific microenvironments in which angiogenesis drives regeneration of local lung tissues. Although conventional in vivo angiogenesis assays, such as subcutaneous implantation of extracellular matrix (ECM)-rich hydrogels (e.g., fibrin or collagen gels or Matrigel - ECM protein mixture secreted by Engelbreth-Holm-Swarm mouse sarcoma cells), are extensively utilized to explore the general mechanisms of angiogenesis, lung-specific angiogenesis has not been well characterized because methods for orthotopic implantation of biomaterials in the lung have not been well established. The goal of this protocol is to introduce a unique method to implant fibrin gel on the lung surface of living adult mouse, allowing for the successful recapitulation of host lung-derived angiogenesis inside the gel. This approach enables researchers to explore the mechanisms by which the lung-specific microenvironment controls angiogenesis and alveolar regeneration in both normal and pathological conditions. Since implanted biomaterials release and supply physical and chemical signals to adjacent lung tissues, implantation of these biomaterials on diseased lung can potentially normalize the adjacent diseased tissues, enabling researchers to develop new therapeutic approaches for various types of lung diseases. PMID- 25548861 TI - Remind to move - A novel treatment on hemiplegic arm functions in children with unilateral cerebral palsy: A randomized cross-over study. AB - OBJECTIVE: To investigate the effects of 'remind to move' treatment on hemiplegic arm function in children with unilateral cerebral palsy (CP). METHODOLOGY: Twelve students with unilateral CP aged 6-18 were recruited from a special school and randomly assigned into two groups. Participants in the experimental group underwent a 3-week sensory cueing treatment followed by a 3-week sham treatment. Participants in the waitlist group completed the sham treatment first followed by the sensory-cueing treatment. There was a 4-week washout period between treatments. RESULTS: Both functional hand use and arm impairment level significantxly improved after the 3-week sensory cueing treatment for the combined sample between groups. However, no significant carryover effects were found for either treatment. CONCLUSION: Three weeks of 'remind to move' treatment is useful in improving hemiplegic arm function and quantity of hand use in children with unilateral CP but the long-term carryover effect requires further investigation. PMID- 25548862 TI - Isolating intestinal stem cells from adult Drosophila midguts by FACS to study stem cell behavior during aging. AB - Aging tissue is characterized by a continuous decline in functional ability. Adult stem cells are crucial in maintaining tissue homeostasis particularly in tissues that have a high turnover rate such as the intestinal epithelium. However, adult stem cells are also subject to aging processes and the concomitant decline in function. The Drosophila midgut has emerged as an ideal model system to study molecular mechanisms that interfere with the intestinal stem cells' (ISCs) ability to function in tissue homeostasis. Although adult ISCs can be easily identified and isolated from midguts of young flies, it has been a major challenge to study endogenous molecular changes of ISCs during aging. This is due to the lack of a combination of molecular markers suitable to isolate ISCs from aged intestines. Here we propose a method that allows for successful dissociation of midgut tissue into living cells that can subsequently be separated into distinct populations by FACS. By using dissociated cells from the esg-Gal4, UAS GFP fly line, in which both ISCs and the enteroblast (EB) progenitor cells express GFP, two populations of cells are distinguished based on different GFP intensities. These differences in GFP expression correlate with differences in cell size and granularity and represent enriched populations of ISCs and EBs. Intriguingly, the two GFP-positive cell populations remain distinctly separated during aging, presenting a novel technique for identifying and isolating cell populations enriched for either ISCs or EBs at any time point during aging. The further analysis, for example transcriptome analysis, of these particular cell populations at various time points during aging is now possible and this will facilitate the examination of endogenous molecular changes that occur in these cells during aging. PMID- 25548863 TI - Emerging technologies for electronic monitoring of adherence, inhaler competence, and true adherence. AB - Despite the availability of effective treatments for respiratory disorders, disease control is often suboptimal, due in part to the failure of patients to adhere to prescribed regimens, or to demonstrate competence with the often complex steps in the administration of inhaled medications. The cost of poor true adherence, a combined measure of adherence and inhaler competence, is considerable, both economically and in terms of health-related impact. While patient education is recognized as essential, there exist many barriers to healthcare professional-led monitoring and promotion of true adherence. Successful intervention remains a challenging task, dependent upon understanding and addressing the distinct issues associated with poor adherence and inhaler competence, and lessening the perceived burden on healthcare professionals. Electronic monitors provide an accurate and objective indication of adherence and may also be of value in assessing inhaler competence. The information provided by such devices is a helpful aid to understanding the challenging nature of true adherence, and may be crucial to the development and assessment of true adherence promoting interventions. This article provides a background to the impact of suboptimal adherence and inhaler competence, and the challenges associated with the promotion of true adherence, with an emphasis on respiratory therapies. Contemporary electronic monitors of adherence and inhaler competence are critically reviewed, and case studies of emerging technologies are provided to illustrate the use of innovative monitoring devices in the promotion of true adherence in practice. Potential future directions, including increased targeting and individualization, enhanced coordination of care, and a greater focus on inhaler competence are considered to be important additions to currently available technologies in this rapidly evolving field. PMID- 25548865 TI - Iridium-catalyzed asymmetric hydrogenation of 2-pyridyl cyclic imines: a highly enantioselective approach to nicotine derivatives. AB - A highly efficient asymmetric hydrogenation of cyclic imines containing a pyridyl moiety was established by using iridium catalysts with chiral spiro phosphine oxazoline ligands. This process will facilitate the development of new nicotine related pharmaceuticals. The introduction of a substituent at the ortho position of the pyridyl ring to reduce its coordinating ability ensures the success of the hydrogenation and excellent enantioselectivity. PMID- 25548864 TI - A procedure for implanting a spinal chamber for longitudinal in vivo imaging of the mouse spinal cord. AB - Studies in the mammalian neocortex have enabled unprecedented resolution of cortical structure, activity, and response to neurodegenerative insults by repeated, time-lapse in vivo imaging in live rodents. These studies were made possible by straightforward surgical procedures, which enabled optical access for a prolonged period of time without repeat surgical procedures. In contrast, analogous studies of the spinal cord have been previously limited to only a few imaging sessions, each of which required an invasive surgery. As previously described, we have developed a spinal chamber that enables continuous optical access for upwards of 8 weeks, preserves mechanical stability of the spinal column, is easily stabilized externally during imaging, and requires only a single surgery. Here, the design of the spinal chamber with its associated surgical implements is reviewed and the surgical procedure is demonstrated in detail. Briefly, this video will demonstrate the preparation of the surgical area and mouse for surgery, exposure of the spinal vertebra and appropriate tissue debridement, the delivery of the implant and vertebral clamping, the completion of the chamber, the removal of the delivery system, sealing of the skin, and finally, post-operative care. The procedure for chronic in vivo imaging using nonlinear microscopy will also be demonstrated. Finally, outcomes, limitations, typical variability, and a guide for troubleshooting are discussed. PMID- 25548866 TI - PbS/Cd3P2 quantum heterojunction colloidal quantum dot solar cells. AB - Here, we demonstrated the quantum heterojunction colloidal quantum dot (CQD) solar cells employing the PbS CQDs/Cd3P2 CQDs architecture in which both the p type PbS and n-type Cd3P2 CQD layers are quantum-tunable and solution-processed light absorbers. We synthesized well-crystallized and nearly monodispersed tetragonal Cd3P2 CQDs and then engineered their energy band alignment with the p type PbS by tuning the dot size and hence the bandgap to achieve efficient light absorbing and charge separation. We further optimized the device through the Ag doping strategy of PbS CQDs that may leverage an expanded depletion region in the n-layer, which greatly enhances the photocurrent. The resulting devices showed an efficiency of 1.5%. PMID- 25548867 TI - Rapid and robust analysis of cellular and molecular polarization induced by chemokine signaling. AB - Cells respond to chemokine stimulation by losing their round shape in a process called polarization, and by altering the subcellular localization of many proteins. Classic imaging techniques have been used to study these phenomena. However, they required the manual acquisition of many cells followed by time consuming quantification of the morphology and the co-localization of the staining of tens of cells. Here, a rapid and powerful method is described to study these phenomena on samples consisting of several thousands of cells using an imaging flow cytometry technology that combines the advantages of a microscope with those of a cytometer. Using T lymphocytes stimulated with CCL19 and staining for MHC Class I molecules and filamentous actin, a gating strategy is presented to measure simultaneously the degree of shape alterations and the extent of co localization of markers that are affected by CCL19 signaling. Moreover, this gating strategy allowed us to observe the segregation of filamentous actin (at the front) and phosphorylated Ezrin-Radixin-Moesin (phospho-ERM) proteins (at the rear) in polarized T cells after CXCL12 stimulation. This technique was also useful to observe the blocking effect on polarization of two different elements: inhibition of actin polymerization by a pharmacological inhibitor and expression of mutants of the Par6/atypical PKC signaling pathway. Thus, evidence is shown that this technique is useful to analyze both morphological alterations and protein redistributions. PMID- 25548869 TI - Dog Models for Blinding Inherited Retinal Degenerations. AB - Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials. PMID- 25548868 TI - Recovery of adult zebrafish hearts for high-throughput applications. AB - Use of the zebrafish model system for studying development, regeneration, and disease is expanding toward use of adult hearts for cell dissociation and purification of RNA, DNA, and proteins. All of these applications demand the rapid recovery of significant numbers of zebrafish hearts to avoid gene regulatory, metabolic, and other changes that begin after death. Adult zebrafish hearts are also required for studying heart structure for a variety of mutants and for studying heart regeneration. However, the traditional zebrafish heart dissection is slow and difficult and requires specialized tools, making large scale dissection of adult zebrafish hearts tedious. Traditional methods also harbor the risk of damaging the heart during the dissection. Here, we describe a method for dissection of adult zebrafish hearts that is fast, reproducible, and preserves heart architecture. Furthermore, this method does not require specialized tools, is painless for the zebrafish, can be performed on fresh or fixed specimens, and can be performed on zebrafish as young as one month old. The approach described expands the use of adult zebrafish for cardiovascular research. PMID- 25548870 TI - Homogeneous assay for whole blood folate using photon upconversion. AB - Red blood cell folate is measured for folate deficiency diagnosis, because it reflects the long-term folate level in tissues, whereas serum folate only represents the dietary intake. Direct homogeneous assay from whole blood would be ideal but conventional fluorescence techniques in blood suffer from high background and strong absorption of light at ultraviolet and visible wavelengths. In this study, a new photon upconversion-based homogeneous assay for whole blood folate is introduced based on resonance energy transfer from upconverting nanophosphor donor coated with folate binding protein to a near-infrared fluorescent acceptor dye conjugated to folate analogue. The sensitized acceptor emission is measured at 740 nm upon 980 nm excitation. Thus, optically transparent wavelengths are utilized for both donor excitation and sensitized acceptor emission to minimize the sample absorption, and anti-Stokes detection completely eliminates the Stokes-shifted autofluorescence. The IC50 value of the assay was 6.0 nM and the limit of detection (LOD) was 1 nM. The measurable concentration range was 2 orders of magnitude between 1.0-100 nM, corresponding to 40-4000 nM folate in the whole blood sample. Recoveries of added folic acid were 112%-114%. A good correlation was found when compared to a competitive heterogeneous assay based on the DELFIA-technology. The introduced assay provides a simple and fast method for whole blood folate measurement. PMID- 25548872 TI - Does mean platelet volume predict the location of the infarct-related artery in non-ST-segment elevation myocardial infarction patients? PMID- 25548871 TI - Cellulose, chitosan, and keratin composite materials. Controlled drug release. AB - A method was developed in which cellulose (CEL) and/or chitosan (CS) were added to keratin (KER) to enable [CEL/CS+KER] composites to have better mechanical strength and wider utilization. Butylmethylimmidazolium chloride ([BMIm(+)Cl( )]), an ionic liquid, was used as the sole solvent, and because the [BMIm(+)Cl( )] used was recovered, the method is green and recyclable. Fourier transform infrared spectroscopy results confirm that KER, CS, and CEL remain chemically intact in the composites. Tensile strength results expectedly show that adding CEL or CS into KER substantially increases the mechanical strength of the composites. We found that CEL, CS, and KER can encapsulate drugs such as ciprofloxacin (CPX) and then release the drug either as a single or as two- or three-component composites. Interestingly, release rates of CPX by CEL and CS either as a single or as [CEL+CS] composite are faster and independent of concentration of CS and CEL. Conversely, the release rate by KER is much slower, and when incorporated into CEL, CS, or CEL+CS, it substantially slows the rate as well. Furthermore, the reducing rate was found to correlate with the concentration of KER in the composites. KER, a protein, is known to have secondary structure, whereas CEL and CS exist only in random form. This makes KER structurally denser than CEL and CS; hence, KER releases the drug slower than CEL and CS. The results clearly indicate that drug release can be controlled and adjusted at any rate by judiciously selecting the concentration of KER in the composites. Furthermore, the fact that the [CEL+CS+KER] composite has combined properties of its components, namely, superior mechanical strength (CEL), hemostasis and bactericide (CS), and controlled drug release (KER), indicates that this novel composite can be used in ways which hitherto were not possible, e.g., as a high-performance bandage to treat chronic and ulcerous wounds. PMID- 25548873 TI - Application of mechanosynthesized azine-decorated zinc(II) metal-organic frameworks for highly efficient removal and extraction of some heavy-metal ions from aqueous samples: a comparative study. AB - The three zinc(II) metal-organic frameworks [Zn2(oba)2(4-bpdb)].(DMF)x (TMU-4), [Zn(oba)(4-bpdh)0.5]n.(DMF)y (TMU-5), and [Zn(oba)(4-bpmb)0.5]n.(DMF)z (TMU-6) [DMF = dimethylformamide, H2oba = 4,4'-oxybisbenzoic acid, 4-bpdb = 1,4-bis(4 pyridyl)-2,3-diaza-1,3-butadiene, 4-bpdh = 2,5-bis(4-pyridyl)-3,4-diaza-2,4 hexadiene, and 4-bpmb = N(1),N(4)-bis((pyridin-4-yl)methylene)benzene-1,4 diamine], which contain azine-functionalized pores, have been successfully synthesized by mechanosynthesis as a convenient, rapid, low-cost, solventless, and green process. These MOFs were studied for the removal and extraction of some heavy-metal ions from aqueous samples, and the effects of the basicity and void space of these MOFs on adsorption efficiency were evaluated. The results showed that, for trace amounts of metal ions, the basicity of the N-donor ligands in the MOFs determines the adsorption efficiency of the MOFs for the metal ions. In contrast, at high concentrations of metal ions, the void space of the MOFs plays a main role in the adsorption process. The studies conducted revealed that, among the three MOFs, TMU-6 had a lower adsorption efficiency for metal ions than the other two MOFs. This result can be attributed to the greater basicity of the azine groups on the TMU-4 and TMU-5 pore walls as compared to the imine groups on the N-donor ligands on the TMU-6 pore walls. Subsequently, TMU-5 was chosen as an efficient sorbent for the extraction and preconcentration of trace amounts of some heavy-metal ions including Cd(II), Co(II), Cr(III), Cu(II), and Pb(II), followed by their determination by flow injection inductively coupled plasma optical emission spectrometry. Several variables affecting the extraction efficiency of the analytes were investigated and optimized. The optimized methodology exhibits a good linearity between 0.05 and 100 MUg L(-1) (R(2) > 0.9935) and detection limits in the range of 0.01-1.0 MUg L(-1). The method has enhancement factors between 42 and 225 and relative standard deviations (RSDs) of 2.9-6.2%. Subsequently, the potential applicability of the proposed method was evaluated for the extraction and determination of target metal ions in some environmental water samples. PMID- 25548874 TI - The supraclavicular fossa ultrasound view for central venous catheter placement and catheter change over guidewire. AB - The supraclavicular fossa ultrasound view can be useful for central venous catheter (CVC) placement. Venipuncture of the internal jugular veins (IJV) or subclavian veins is performed with a micro-convex ultrasound probe, using a neonatal abdominal preset with a probe frequency of 10 Mhz at a depth of 10-12 cm. Following insertion of the guidewire into the vein, the probe is shifted to the right supraclavicular fossa to obtain a view of the superior vena cava (SVC), right pulmonary artery and ascending aorta. Under real-time ultrasound view, the guidewire and its J-tip is visualized and pushed forward to the lower SVC. Insertion depth is read from guidewire marks using central venous catheter. CVC is then inserted following skin and venous dilation. The supraclavicular fossa view is most suitable for right IJV CVC insertion. If other insertion sites are chosen the right supraclavicular fossa should be within the sterile field. Scanning of the IJVs, brachiocephalic veins and SVC can reveal significant thrombosis before venipuncture. Misplaced CVCs can be corrected with a change over guidewire technique under real-time ultrasound guidance. In conjunction with a diagnostic lung ultrasound scan, this technique has a potential to replace chest radiograph for confirmation of CVC tip position and exclusion of pneumothorax. Moreover, this view is of advantage in patients with a non-p-wave cardiac rhythm were an intra-cardiac electrocardiography (ECG) is not feasible for CVC tip position confirmation. Limitations of the method are lack of availability of a micro-convex probe and the need for training. PMID- 25548875 TI - Production of chlorogenic acid and its derivatives in hairy root cultures of Stevia rebaudiana. AB - Chlorogenic acid and its derivatives (CADs) are valuable bioactive plant secondary metabolites with many health benefits. In the present study, Stevia rebaudiana hairy root cultures were established, and the culture conditions for the production of CADs were optimized. The hairy roots were induced by coculture of S. rebaudiana leaves and Agrobacterium rhizogenes (C58C1) after infection, which were further verified by PCR detection of rolB and rolC genes. HPLC-MS and HPLC analysis showed that chlorogenic acid (3-caffeoylquinic acid, 3-CQA), 3,5 dicaffeoylquinic acid (3,5-CQA), and 4,5-dicaffeoylquinic acid (4,5-CQA) were the major CADs in the hairy roots. Eight single roots with rapid growth rate were selected. Among them, T3 had the highest yield of CADs. B5 medium supplemented with 40 g/L sucrose was more suitable for the production of CADs than others. Under optimal culture conditions, the total content of these three compounds reached 105.58 mg/g and total yield was 234.40 mg/100 mL. PMID- 25548876 TI - Spontaneous nematic alignment of a lipid nanotube in aqueous solutions. AB - The dispersibility and liquid crystal formation of a self-assembled lipid nanotube (LNT) was investigated in a variety of aqueous solutions. As the lipid component, we chose a bipolar lipid with glucose and tetraglycine headgroups, which self-assembled into an LNT with a small outer diameter of 16 to 17 nm and a high axial ratio of more than 310. The LNT gave a stable colloidal dispersion in its dilute solutions and showed spontaneous liquid crystal (LC) alignment at relatively low concentrations and in a pH region including neutral pH. The LNT samples with shorter length distributions were prepared by sonication, and the relationship between the LNT axial ratio and the minimum LC formation concentration was examined. The robustness of the LNT made the liquid crystal stable in mixed solvents of water/ethanol, water/acetone, and water/tetrahydrofuran (1:1 by volume) and at a temperature of up to 90 degrees C in water. The observed colloidal behavior of the LNT was compared to those of similar 1D nanostructures such as a phospholipid tubule. PMID- 25548877 TI - Use of gnotobiotic zebrafish to study Vibrio anguillarum pathogenicity. AB - We evaluated the use of the gnotobiotic zebrafish system to study the effects of bacterial infection, and analyzed expression of genes involved in zebrafish innate immunity. Using a GFP-labeled strain of Vibrio anguillarum, we fluorescently monitored colonization of the zebrafish intestinal tract and used gene expression analysis to compare changes in genes involved in innate immunity between nongnotobiotic and gnotobiotic larvae. The experiments performed with the gnotobiotic zebrafish reveal new insights into V. anguillarum pathogenesis. Specifically, an alteration of the host immune system was detected through the suppression of a number of innate immune genes (NFKB, IL1B, TLR4, MPX, and TRF) during the first 3 h post infection. This immunomodulation can be indicative of a "stealth mechanism" of mucus invasion in which the pathogen found a sheltered niche, a typical trait of intracellular pathogens. PMID- 25548878 TI - Position-dependent performance of copper phthalocyanine based field-effect transistors by gold nanoparticles modification. AB - A facile fabrication and characteristics of copper phthalocyanine (CuPc)-based organic field-effect transistor (OFET) using the gold nanoparticles (Au NPs) modification is reported, thereby achieving highly improved performance. The effect of Au NPs located at three different positions, that is, at the SiO2/CuPc interface (device B), embedding in the middle of CuPc layer (device C), and on the top of CuPc layer (device D), is investigated, and the results show that device D has the best performance. Compared with the device without Au NPs (reference device A), device D displays an improvement of field-effect mobility (MU(sat)) from 1.65 * 10(-3) to 5.51 * 10(-3) cm(2) V(-1) s(-1), and threshold voltage decreases from -23.24 to -16.12 V. Therefore, a strategy for the performance improvement of the CuPc-based OFET with large field-effect mobility and saturation drain current is developed, on the basis of the concept of nanoscale Au modification. The model of an additional electron transport channel formation by FET operation at the Au NPs/CuPc interface is therefore proposed to explain the observed performance improvement. Optimum CuPc thickness is confirmed to be about 50 nm in the present study. The device-to-device uniformity and time stability are discussed for future application. PMID- 25548879 TI - Psychiatric comorbidity, suicidality, and in-home firearm access among a nationally representative sample of adolescents. AB - IMPORTANCE: Suicide is the second leading cause of death among US adolescents, and in-home firearm access is an independent risk factor for suicide. Given recommendations to limit firearm access by those with mental health risk factors for suicide, we hypothesized that adolescents with such risk factors would be less likely to report in-home firearm access. OBJECTIVES: To estimate the prevalence of self-reported in-home firearm access among US adolescents, to quantify the lifetime prevalence of mental illness and suicidality (ie, suicidal ideation, planning, or attempt) among adolescents living with a firearm in the home, and to compare the prevalence of in-home firearm access between adolescents with and without specific mental health risk factors for suicide. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of data from the National Comorbidity Survey-Adolescent Supplement, a nationally representative survey of 10,123 US adolescents (age range, 13-18 years) who were interviewed between February 2001 and January 2004 (response rate 82.9%). EXPOSURES: Risk factors for suicide, including a history of any mental health disorder, suicidality, or any combination of the 2. MAIN OUTCOMES AND MEASURES: Self-reported access to a firearm in the home. RESULTS: One in three respondents (2778 [29.1%]) of the weighted survey sample reported living in a home with a firearm and responded to a question about firearm access; 1089 (40.9%) of those adolescents reported easy access to and the ability to shoot that firearm. Among adolescents with a firearm in home, those with access were significantly more likely to be older (15.6 vs 15.1 years), male (70.1% vs 50.9%), of non-Hispanic white race/ethnicity (86.6% vs 78.3%), and living in high-income households (40.0% vs 31.8%), and in rural areas (28.1% vs 22.6%) (P < .05 for all). Adolescents with firearm access also had a higher lifetime prevalence of alcohol abuse (10.1% vs 3.8%, P < .001) and drug abuse (11.4% vs 6.9%, P < .01) compared with those without firearm access. In multivariable analyses, adolescents with a history of mental illness without a history of suicidality (prevalence ratio [PR], 1.13; 95% CI, 0.98-1.29) and adolescents with a history of suicidality with or without a history of mental illness (PR, 1.20; 95% CI, 0.96-1.51) were as likely to report in-home firearm access as those without such histories. CONCLUSIONS AND RELEVANCE: Adolescents with risk factors for suicide were just as likely to report in-home firearm access as those without such risk factors. Given that firearms are the second most common means of suicide among adolescents, further attention to developing and implementing evidence-based strategies to decrease firearm access in this age group is warranted. PMID- 25548880 TI - Patterning via optical saturable transitions--fabrication and characterization. AB - This protocol describes the fabrication and characterization of nanostructures using a novel nanolithographic technique called Patterning via Optical Saturable Transitions (POST). In this technique the chemical properties of organic photochromic molecules that undergo single-photon reactions are exploited, enabling rapid top-down nanopatterning over large areas at low light intensities, thereby, allowing for the circumvention of the far-field diffraction barrier.(4) Simple, cost-effective, high throughput and resolution alternatives to nanopatterning are being explored, such as, two-photon polymerization(5,6), beam pen lithography (BPL)(7), scanning electron beam lithography (SEBL), and focused ion beam (FIB) patterning. However, multi-photon approaches require high light intensities, which limit their potential for high throughput and offer low image contrast. Although, electron and ion beam lithographic processes offer increased resolution, the serial nature of the process is limited to slow writing speeds, which also prevents patterning of features over large areas. Beam-pen lithography is an approach towards parallel near-field optical lithography. However, the gap between the source of the beam and the surface of the photoresist needs to be controlled extremely precisely for good pattern uniformity and this is very challenging to accomplish for large arrays of beams. Patterning via Optical Saturable Transitions (POST) is an alternative optical nanopatterning technique for patterning sub-wavelength features(1-3). Since this technique uses single photons instead of electrons, it is extremely fast and does not require high light intensities(1-3), opening the door to massive parallelization. PMID- 25548882 TI - Chalcogenide perovskites for photovoltaics. AB - Chalcogenide perovskites are proposed for photovoltaic applications. The predicted band gaps of CaTiS3, BaZrS3, CaZrSe3, and CaHfSe3 with the distorted perovskite structure are within the optimal range for making single-junction solar cells. The predicted optical absorption properties of these materials are superior compared with other high-efficiency solar-cell materials. Possible replacement of the alkaline-earth cations by molecular cations, e.g., (NH3NH3)(2+), as in the organic-inorganic halide perovskites (e.g., CH3NH3PbI3), are also proposed and found to be stable. The chalcogenide perovskites provide promising candidates for addressing the challenging issues regarding halide perovskites such as instability in the presence of moisture and containing the toxic element Pb. PMID- 25548881 TI - Vibratome sectioning mouse retina to prepare photoreceptor cultures. AB - The retina is a part of the central nervous system that has organized architecture, with neurons in layers from the photoreceptors, both rods and cones in contact with the retinal pigmented epithelium in the most distant part on the retina considering the direction of light, and the ganglion cells in the most proximal distance. This architecture allows the isolation of the photoreceptor layer by vibratome sectioning. The dissected neural retina of a mouse aged 8 days is flat-embedded in 4% gelatin on top of a slice of 20% gelatin photoreceptor layer facing down. Using a vibratome and a double edged razor blade, the 100 um thick inner retina is sectioned. This section contains the ganglion cells and the inner layer with notably the bipolar cells. An intermediary section of 15 um is discarded before 200 um of the outer retina containing the photoreceptors is recovered. The gelatin is removed by heating at 37 degrees C. Pieces of outer layer are incubated in 500 ul of Ringer's solution with 2 units of activated papain for 20 min at 37 degrees C. The reaction is stopped by adding 500 ul 10% fetal calf serum (FCS) in Dulbecco's Modified Eagle Medium (DMEM), then 25 units of DNAse I is added before centrifugation at RT, washed several times to remove serum and the cells are resuspended in 500 ul of DMEM and seeded at 1 x 10(5) cells/cm(2). The cells are grown to 5 days in vitro and their viability scored using live/dead assay. The purity of the culture is first determined by microscopic observation during the experiment. The purity is then validated by seeding and fixing cells on a histological slide and analyzing using a rabbit polyclonal anti-SAG, a photoreceptor marker and mouse monoclonal anti-RHO, a rod photoreceptor specific marker. Alternatively, the photoreceptor layer (97% rods) can be used for gene or protein expression analysis and for transplantation. PMID- 25548883 TI - Magnetoresistance and charge transport in graphene governed by nitrogen dopants. AB - We identify the influence of nitrogen-doping on charge- and magnetotransport of single layer graphene by comparing doped and undoped samples. Both sample types are grown by chemical vapor deposition (CVD) and transferred in an identical process onto Si/SiO2 wafers. We characterize the samples by Raman spectroscopy as well as by variable temperature magnetotransport measurements. Over the entire temperature range, the charge transport properties of all undoped samples are in line with literature values. The nitrogen doping instead leads to a 6-fold increase in the charge carrier concentration up to 4 * 10(13) cm(-2) at room temperature, indicating highly effective doping. Additionally it results in the opening of a charge transport gap as revealed by the temperature dependence of the resistance. The magnetotransport exhibits a conspicuous sign change from positive Lorentz magnetoresistance (MR) in undoped to large negative MR that we can attribute to the doping induced disorder. At low magnetic fields, we use quantum transport signals to quantify the transport properties. Analyses based on weak localization models allow us to determine an orders of magnitude decrease in the phase coherence and scattering times for doped samples, since the dopants act as effective scattering centers. PMID- 25548884 TI - Correlation between the length reduction of carbon nanotubes and the electrical percolation threshold of melt compounded polyolefin composites. AB - The objectives of this work are to quantify the degree of multiwalled carbon nanotube (MWCNT) length reduction upon melt compounding and to demonstrate unambiguously that the length reduction is mainly responsible for the increase in electrical percolation threshold of the resulting composites. Polyolefin matrices of varying viscosities and different functional groups are melt compounded with MWCNTs. A simple method is developed to solubilize the polymer matrix and isolate the MWCNTs, enabling detailed imaging analysis. In spite of the perceived strength of the MWCNTs, the results demonstrate that the shear forces developed during melt mixing are sufficient to cause significant nanotube breakage and length reduction. Breakage is promoted when higher MWCNT contents are used, due to increased probability of particle collisions. Furthermore, the higher shear forces transmitted to the nanotubes in the presence of higher matrix viscosities and functional groups that promote interfacial interactions, shift the nanotube distribution toward smaller sizes. The length reduction of the MWCNTs causes significant increases in the percolation threshold, due to the loss of interconnectivity, which results in fewer conductive pathways. These findings are validated by comparing the experimental percolation threshold values with those predicted by the improved interparticle distance theoretical model. PMID- 25548885 TI - Sleep problems among clinically depressed adults in China. AB - BACKGROUND: The aim of the study was to explore which variables predict poor sleep among clinically depressed Chinese adults. METHODS: In total, 100 participants were recruited from Shanghai Mental Health Centre. The dependent variables were number of hours spent sleeping as well as the quality of sleep and number of times the participants woke during the night. The independent variables were gender, age, length of depression and severity of depression. The use of antipsychotic medication was controlled for in all analyses. RESULTS: The results demonstrated that depression severity was the most important predictor of sleep quality and night waking. Gender and age were also found to be predictors of sleep problems. CONCLUSIONS: The findings demonstrated that depressed Chinese patients experienced similar relationships between sleep disturbance and depression to Westerners. Future studies should include other measures of sleep quality as well as variables consistently found to be associated with both depression and sleep difficulty, such as the use of addictive substances and psychosocial factors. PMID- 25548886 TI - Effects of parental socio-economic conditions on facial attractiveness. AB - Socio-economic conditions during early life are known to affect later life outcomes such as health or social success. We investigated whether family socio economic background may also affect facial attractiveness. We used the Wisconsin Longitudinal Study (n = 8434) to analyze the association between an individual's parental socio-economic background (in terms of father's highest education and parental income) and that individual's facial attractiveness (estimated by rating of high school yearbook photographs when subjects were between 17 and 20 years old), controlling for subjects' sex, year of birth, and father's age at subjects' birth. Subjects' facial attractiveness increased with increasing father's highest educational attainment as well as increasing parental income, with the latter effect being stronger for female subjects as well. We conclude that early socio economic conditions predict, to some extent, facial attractiveness in young adulthood. PMID- 25548888 TI - A method for generating pulmonary neutrophilia using aerosolized lipopolysaccharide. AB - Acute lung injury (ALI) is a severe disease characterized by alveolar neutrophilia, with limited treatment options and high mortality. Experimental models of ALI are key in enhancing our understanding of disease pathogenesis. Lipopolysaccharide (LPS) derived from gram positive bacteria induces neutrophilic inflammation in the airways and lung parenchyma of mice. Efficient pulmonary delivery of compounds such as LPS is, however, difficult to achieve. In the approach described here, pulmonary delivery in mice is achieved by challenge to aerosolized Pseudomonas aeruginosa LPS. Dissolved LPS was aerosolized by a nebulizer connected to compressed air. Mice were exposed to a continuous flow of LPS aerosol in a Plexiglas box for 10 min, followed by 2 min conditioning after the aerosol was discontinued. Tracheal intubation and subsequent bronchoalveolar lavage, followed by formalin perfusion was next performed, which allows for characterization of the sterile pulmonary inflammation. Aerosolized LPS generates a pulmonary inflammation characterized by alveolar neutrophilia, detected in bronchoalveolar lavage and by histological assessment. This technique can be set up at a small cost with few appliances, and requires minimal training and expertise. The exposure system can thus be routinely performed at any laboratory, with the potential to enhance our understanding of lung pathology. PMID- 25548889 TI - Polarity establishment, asymmetric division and segregation of fate determinants in early C. elegans embryos. AB - Polarity establishment, asymmetric division, and acquisition of cell fates are critical steps during early development. In this review, we discuss processes that set up the embryonic axes, with an emphasis on polarity establishment and asymmetric division. We begin with the first asymmetric division in the C. elegans embryo, where symmetry is broken by the local inactivation of actomyosin cortical contractility. This contributes to establishing a polarized distribution of PAR proteins and associated components on the cell cortex along the longitudinal embryonic axis, which becomes the anterior-posterior (AP) axis. Thereafter, AP polarity is maintained through reciprocal negative interactions between the anterior and posterior cortical domains. We then review the mechanisms that ensure proper positioning of the centrosomes and the mitotic spindle in the one-cell embryo by exerting pulling forces on astral microtubules. We explain how a ternary complex comprised of Galpha (GOA-1/GPA-16), GPR-1/GPR-2, and LIN-5 is essential for anchoring the motor protein dynein to the cell cortex, where it is thought to exert pulling forces on depolymerizing astral microtubules. We proceed by providing an overview of cell cycle asynchrony in two cell embryos, as well as the cell signaling and spindle positioning events that underly the subsequent asymmetric divisions, which establish the dorsal-ventral and left-right axes. We then discuss how AP polarity ensures the unequal segregation of cell fate regulators via the cytoplasmic proteins MEX-5/MEX-6 and other polarity mediators, before ending with an overview of how the fates of the early blastomeres are specified by these processes. PMID- 25548890 TI - Preoperative headband assessment for semi-implantable bone conduction hearing devices in conductive hearing loss: is it useful or misleading? AB - OBJECTIVE: To establish whether preoperative assessment using a conventional, percutaneous bone conducting implant (pBCI) processor on a headband accurately represents postoperative performance of a semi-implantable BCI (siBCI). STUDY DESIGN: Retrospective case series. SETTING: Tertiary otology unit. PATIENTS: Five patients with chronic otitis media (implanted unilaterally) and one with bilateral congenital ossicular fixation (implanted bilaterally). INTERVENTION(S): Semi-implantable bone conduction hearing implant. MAIN OUTCOME MEASURE(S): Functional hearing gain; preoperative (headband) versus postoperative (aided) speech discrimination; unaided bone conduction (BC) versus postoperative (aided) soundfield threshold. RESULTS: Significant functional gain was seen at all frequencies (one-tailed t test p G 0.01; n = 7). There was a 50 dB improvement in median speech reception threshold (SRT) from 70 dB unaided to 20 dB aided. Compared to the preoperative BC, aided siBCI thresholds were worse at 0.5 kHz, but at frequencies from 1 to 6 kHz, the siBCI closely matched the bone curve ( p G 0.01). The siBCI performed better than both pBCI processors on a headband at 3 to 4 kHz, except 1 kHz ( p G 0.01). CONCLUSIONS: BC thresholds may be a better indicator of implant performance than headband assessment. Candidacy assessment for siBCI implantation that relies on headband testing with pBCI processors should be interpreted with caution because the headband may under-represent the implanted device. This seems to be especially true at 3 kHz and above and may make it difficult for surgeons to conduct accurate informed consent discussions with patients about the realistic anticipated outcomes and benefits of the procedure. PMID- 25548891 TI - Epidemiology of balance symptoms and disorders in the community: a systematic review. AB - INTRODUCTION: Balance disorders presenting with symptoms of dizziness or vertigo may have significant impact on quality of life and are a recognized risk factor for falls. OBJECTIVE: The objective of this review was to systematically synthesize the published literature on the epidemiology of balance symptoms and disorders in the adult community population. METHODS: A search was carried out across PubMed, Medline, and Cochrane databases to identify suitable studies. Studies were eligible for inclusion if they contained data on the epidemiology of symptoms of balance disorders (dizziness and vertigo) or balance disorders sampled from community-based adult populations. Data were collected on prevalence and incidence of balance symptoms and on specific balance disorders. A validated risk-of-bias assessment was carried out. RESULTS: Twenty eligible studies were identified. The lifetime prevalence estimates of significant dizziness ranged between 17 and 30%, and for vertigo between 3 and 10%. Published point prevalence data exist for Meniere's disease (0.12-0.5%) and for vestibular migraine (0.98%). For benign paroxysmal positional vertigo, 1-year incidence estimates range from 0.06 to 0.6%. There are no community-based studies on the prevalence or incidence of chronic uncompensated peripheral vestibular disorders or vestibular neuritis. CONCLUSION: Symptoms of dizziness and vertigo are common in the adult population, and data give a coherent picture of community epidemiology. These data can inform rational service planning and much-needed clinical trials in this field. There are insufficient data on specific balance disorders, especially peripheral vestibular disorders such as vestibular neuritis and its long-term sequelae. PMID- 25548892 TI - Decisive criteria between stapedotomy and cochlear implantation in patients with far advanced otosclerosis. AB - OBJECTIVES: To describe the hearing outcomes in patients with far-advanced otosclerosis and to identify the best initial approach based on preoperative word recognition scores (WRS), pure tone averages (PTA), and radiological classification. STUDY DESIGN: Retrospective case review. SETTING: Academic neurotology tertiary referral center. PATIENTS: All patients (n = 58) with preoperative air conduction PTA less than 85 dB (HL), disyllabic WRS less than or equal to 50% at 60 dB (HL) with well-fitted hearing aids, and evidence of otosclerosis on CT scan, treated in our department over the past 20 years. INTERVENTIONS: Stapedotomy, cochlear implantation, or both. MAIN OUTCOME MEASURES: Postoperative WRS after a minimum of 12 months' follow-up, percentage of patients with WRS greater than 50%. Reliability of air and bone conduction PTAs and WRS in predicting failure of stapedotomy. RESULTS: Fifty-eight patients were divided into three groups: group I, primary stapedotomy (n = 32); group II, primary cochlear implantation (n = 9); and group III, secondary cochlear implantation (with a previous history of stapedotomy) (n = 25). The mean postoperative WRS were 50.6% (+/- 34), 75% (+/- 17), and 72% (+/- 20), respectively. Sixty percent of patients in the stapedotomy group had a postoperative WRS greater than 50% requiring no further treatment, compared to 85% for cochlear implant recipients. No specific predictive factors for stapedotomy outcome could be identified. Surgical difficulties during cochlear implantation were significantly higher in patients with advanced radiological stage. CONCLUSION: Although cochlear implantation gives better overall results, stapedotomy with hearing aids can still be very effective in the management of patients with far-advanced otosclerosis. It should therefore be proposed as a first-line treatment. PMID- 25548893 TI - Pediatric cartilage tympanoplasty with primary intubation. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to analyze the anatomical and audiologic results in pediatric Type I cartilage tympanoplasties with primary intubation. Our hypothesis was that the outcome of patients with tubes placed would be similar to those without tubes, even though the ears that received tubes were in worse condition. STUDY DESIGN: Retrospective chart review of patients undergoing cartilage tympanoplasty with intubation between 2007 and 2012. METHODS: All surgeries were performed or supervised by the senior author as the surgeon, using a modification of the perichondrium/cartilage island flap. All patients had a tube placed through the cartilage to allow for middle ear aeration. Hearing results were reported using a four-frequency (500, 1,000, 2,000, 3,000 Hz) pure-tone average and a pure-tone average air-bone gap (PTA ABG). Postoperative complications were recorded. RESULTS: During the study period, cartilage with intubation was used for tympanic membrane reconstruction in 20 patients. Of these, 10 (50.0%) had craniofacial abnormalities, and the remainder had documented Eustachian tube dysfunction with mucoid effusion present at the time of surgery. The average patient age was 8 years, and the average follow-up was 39 months. The average pre- and postoperative PTA-ABGs were 25.1 +/ 11.2 dB (standard deviation, SD) and 15.1 +/- 10.2 dB (p < 0.05), respectively, and the average pre- and postoperative PTAs were 36.6 +/- 12.4 and 24.9 +/- 12.0 dB (p < 0.05), respectively. Only one case had to undergo revision, which was a result of a cholesteatoma. Of the 20 patients, 15 still had patent tubes at last follow-up, three had their tubes removed, and two had tube extrusion. CONCLUSIONS: Cartilage tympanoplasty with intubation achieves good anatomical and audiologic results when Eustachian tube dysfunction or craniofacial abnormalities are present. Significant hearing improvement was realized in a patient population that is characteristically more prone to problems. PMID- 25548894 TI - Subtotal cholecystectomy for "difficult gallbladders": systematic review and meta analysis. AB - IMPORTANCE: Subtotal cholecystectomy (SC) is a procedure that removes portions of the gallbladder when structures of the Calot triangle cannot be safely identified in "difficult gallbladders." OBJECTIVE: To conduct a systematic review and meta analysis to evaluate current studies and present an evidence-based assessment of the outcomes for the techniques available for SC. DATA SOURCES: A literature search of the PubMed/MEDLINE (1954 to November 2013) and EMBASE (1974 to November 2013) databases was conducted. Search criteria included the words subtotal, partial, insufficient or incomplete, and cholecystectomy. STUDY SELECTION: Inclusion criteria were all randomized, nonrandomized, and retrospective studies with data on SC techniques and outcomes. Exclusion criteria were studies that reported data on SC along with other interventions (eg, cholecystostomy) without the possibility to discriminate results specific to SC. DATA EXTRACTION AND SYNTHESIS: This systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome of the study was the occurrence of common bild duct injury. Secondary outcomes included the occurrence of other SC-related morbidities, such as hemorrhage, subhepatic collection, bile leak, retained stones, postoperative endoscopic retrograde cholangiopancreatography, wound infection, reoperation, and mortality. RESULTS: Thirty articles were included. Subtotal cholecystectomy was typically performed using the laparoscopic technique (72.9%), followed by the open (19.0%) and laparoscopic converted to open (8.0%) techniques. The most common indications were severe cholecystitis (72.1%), followed by cholelithiasis in liver cirrhosis and portal hypertension (18.2%) and empyema or perforated gallbladder (6.1%). Morbidity rates were relatively low (postoperative hemorrhage, 0.3%; subhepatic collections, 2.9%; bile duct injury, 0.08%; and retained stones, 3.1%); the rate for bile leaks was higher (18.0%). Reoperations were necessary in 1.8% of the cases; the 30-day mortality rate was 0.4%. The laparoscopic approach produced less risk of subhepatic collection (odds ratio [OR], 0.4; 95% CI, 0.2-0.9), retained stones (OR, 0.5; 95% CI, 0.3-0.9), wound infection (OR, 0.07; 95% CI, 0.04-0.2), reoperation (OR, 0.5; 95% CI, 0.3 0.9), and mortality (OR, 0.2; 95% CI, 0.05-0.9) but more bile leaks (OR, 5.3; 95% CI, 3.9-7.2) compared with the open approach. CONCLUSIONS AND RELEVANCE: Subtotal cholecystectomy is an important tool for use in difficult gallbladders and achieves morbidity rates comparable to those reported for total cholecystectomy in simple cases. The various technical differences appear to influence outcomes only for the laparoscopic approach. PMID- 25548895 TI - High levels of KAP1 expression are associated with aggressive clinical features in ovarian cancer. AB - KAP1 is an universal corepressor for Kruppel-associated box zinc finger proteins in both normal and tumor cells. In this study, the biological function and clinical significance of KAP1 expression in ovarian cancer were investigated. Immunohistological staining of KAP1 was evaluated in 111 patients with ovarian epithelial cancer, 15 with ovarian borderline tumor, and 20 normal ovarian tissue. The correlations of KAP1 expression with clinicopathological features were studied. Kaplan-Meier analysis and Cox proportional hazard modeling were used to assess overall survival to analyze the effect of KAP1 expression on the prognosis of ovarian cancer. The positive rates of KAP1 were significantly higher in ovarian epithelial cancer (55.7%) and borderline tumor (20.0%) than in normal ovarian tissue (5.0%) (all p < 0.01). KAP1 expression correlated significantly with clinical stage (chi2 = 14.57, p < 0.0001), pathological grade (chi2 = 6.06, p = 0.048) and metastases (chi2 =10.38, p = 0.001). Patients with high KAP 1 levels showed poor survival (p < 0.0001). Multivariate analysis showed that KAP1 high expression was an independent predictor for ovarian cancer patients (hazard ratio = 0.463; 95% confidence interval = 0.230-0.9318, p = 0.031). Functionally, depletion of KAP1 by siRNA inhibited ovarian cancer cell proliferation, cell migration. KAP1 expression correlated with aggressive clinical features in ovarian cancer. High KAP1 expression was a prognostic factor of ovarian cancer. PMID- 25548898 TI - Effects of different sera conditions on olfactory ensheathing cells in vitro. AB - Transplantation of olfactory ensheathing cells (OEC) is a promising therapy in spinal cord injury (SCI) treatment. However, the therapeutic efficacy of this method is unstable due to unknown reasons. Considering the alterations in the culture environment that occur during OEC preparation for transplantation, we hypothesize that these changes may cause variations in the curative effects of this method. In this study, we compared OEC cultured in medium containing different types and concentrations of serum. After purification and passage, the OEC were cultured for 7 days in different media containing 5%, 10%, 15% or 20% fetal bovine serum (FBS) or rat serum (RS), or the cells were cultured in FBS containing medium first, followed by medium containing RS. In another group, the OEC were first cultured in 10% FBS for 3 days and then cultured with rat spinal cord explants with 10% RS for another 4 days. An MTT assay and P75 neurotrophin receptor immunofluorescence staining were used to examine cell viability and OEC numbers, respectively. The concentration of neurotrophin-3 (NT-3), which is secreted by OEC into the culture supernatant, was detected using the enzyme linked immunosorbent assay (ELISA). RT-PCR was applied to investigate the NT-3 gene expression in OEC according to different groups. Compared with FBS, RS reduced OEC proliferation in relation to OEC counts (chi2 = 166.279, df = 1, p < 0.01), the optical density (OD) value in the MTT assay (chi2 = 34.730, df = 1, p < 0.01), and NT-3 concentration in the supernatant (chi2 = 242.997, df = 1, p < 0.01). OEC cultured with spinal cord explants secreted less NT-3 than OEC cultured alone (F = 9.611, df = 5.139, p < 0.01). Meanwhile, the order of application of different sera was not influential. There was statistically significant difference in NT-3 gene expression among different groups when the serum concentration was 15% (chi2 = 64.347, df = 1, p < 0.01). In conclusion, different serum conditions may be responsible for the variations in OEC proliferation and function. PMID- 25548897 TI - Lipoprotein-associated oxidative stress: a new twist to the postprandial hypothesis. AB - Oxidative stress is recognized as one of the primary processes underlying the initiation and progression of atherosclerotic vascular disease. Under physiological conditions, the balance between reactive oxygen species (ROS) generation and ROS scavenging is tightly controlled. As part of normal cellular metabolism, regulated oxidative stress is responsible for a variety of cellular responses. Excess generation of ROS that could not be compensated by antioxidant system has been suggested to be responsible for a number of pathological conditions. Due to their short biological half-lives, direct measurement of ROS is not available and surrogate measures are commonly used. Plasma lipoproteins, by virtue of their close interactions with endothelial cells in the vasculature and the susceptibility of their surface lipids to oxidative modification, are perfect biological sensors of oxidative stress in the arterial wall. In particular, with each consumed meal, triglyceride-rich lipoproteins, secreted by the intestine into the circulation, are responsible for the delivery of 20-40 grams of fat to the peripheral tissues. This flux of dietary lipids is accompanied by concomitant increases in glucose, insulin and other meal associated metabolites. The contribution of postprandial lipemia to the pathogenesis of atherosclerosis has been previously suggested by several lines of investigation. We have extended this hypothesis by demonstrating the acute generation of oxidative epitopes on plasma lipoproteins as well as transient changes in the oxidative susceptibility of plasma lipoproteins. PMID- 25548896 TI - Oxidative stress in obesity: a critical component in human diseases. AB - Obesity, a social problem worldwide, is characterized by an increase in body weight that results in excessive fat accumulation. Obesity is a major cause of morbidity and mortality and leads to several diseases, including metabolic syndrome, diabetes mellitus, cardiovascular, fatty liver diseases, and cancer. Growing evidence allows us to understand the critical role of adipose tissue in controlling the physic-pathological mechanisms of obesity and related comorbidities. Recently, adipose tissue, especially in the visceral compartment, has been considered not only as a simple energy depository tissue, but also as an active endocrine organ releasing a variety of biologically active molecules known as adipocytokines or adipokines. Based on the complex interplay between adipokines, obesity is also characterized by chronic low grade inflammation with permanently increased oxidative stress (OS). Over-expression of oxidative stress damages cellular structures together with under-production of anti-oxidant mechanisms, leading to the development of obesity-related complications. The aim of this review is to summarize what is known in the relationship between OS in obesity and obesity-related diseases. PMID- 25548899 TI - Connexin 43 suppresses tumor angiogenesis by down-regulation of vascular endothelial growth factor via hypoxic-induced factor-1alpha. AB - Previous work showed that connexin 43 (Cx43) reduced the expression of hypoxic induced factor-1alpha (HIF-1alpha) in astrocytes. HIF-1alpha is a master transcription factor for angiogenesis in tumor. Angiogenesis is essential for tumor progression. Here, we investigated the role of Cx43 in vascular endothelial growth factor (VEGF) production and angiogenesis in murine tumor. In the study, mouse B16F10 and 4T1 cells were overexpressed or knockdown with Cx43. The expression profiles as well as activity of the treated cells were examined. Furthermore, reduced Cx43 expression in B16F10 and 4T1 cells causes increased expression of VEGF and enhanced the proliferation of endothelial cells. On the contrary, the expression of VEGF and the proliferation of endothelial were increased in the conditioned medium of Cx43-knockdown tumor cells. We subcutaneously transplanted Cx43-overexpressing B16F10 cells into mice to evaluate the roles of Cx43 in the tumor angiogenesis. Both tumor size and the number of vessels growing in the tumor were markedly decreased compare with control group. Our findings suggest that Cx43 inhibited tumor growth by reducing angiogenesis. PMID- 25548900 TI - Rickettsial diseases and ectoparasites from military bases in Japan. AB - Ectoparasitic arthropods are often vectors of rickettsiosis. We conducted a survey of ectoparasites on U.S. military facilities throughout Japan with the use of specimens submitted by pest control, public health, and veterinary personnel. Over 1,600 individual ectoparasites were collected. Fifteen species were identified, including several significant vectors of human diseases such as scrub typhus and rickettsial spotted fevers. These ectoparasites included Ctenocephalides felis , Haemaphysalis longicornis, Ixodes persulcatus , Leptotrombidium fuji, Leptotrombidium pallidum, and Rhipicephalus sanguineus . Rickettsial agents were detected by PCR and DNA sequencing. These included Bartonella henselae , Bartonella japonica, a novel Bartonella, Coxiella burnetii , an unnamed Coxiella, Ehrlichia canis , Orientia tsutsugamushi , Rickettsia typhi , and "Rickettsia Rf2125"/"Rickettsia cf1and5". PMID- 25548901 TI - Effect of water on the local structure and phase behavior of imidazolium-based protic ionic liquids. AB - We report on the effect of water on local structure and phase behavior of two protic ionic liquids, C2HImTFSI and C2HImTfO. Raman and infrared spectroscopy are employed to investigate the local coordination state. We find that water interacts weakly with TFSI(-) while more specifically with TfO(-) through the SO3 group. Additionally, we observe that upon addition of water the -NH stretching frequency does not change in C2HImTFSI, while it red-shifts in C2HImTfO, indicative of different hydrogen bonding configurations. Supported by the appearance of some additional features in the 800-1000 cm(-1) frequency range where ring out-of-plane bending (gamma) modes are found, we hypothesize that in C2HImTFSI water interacts only with the cation coordinating to the ring C(2)H and the N(3)H sites, while it interacts with both cation and anion in C2HImTfO forming hydrogen bonds that involve the cationic N-H site as well as the anionic SO3 group. These different local structures also reflect in the phase behavior investigated by DSC, which reveals a more homogeneous solution when water is added to C2HImTfO, as compared to H2O/C2HImTFSI mixtures. Finally we report that the addition of water also significantly affects both Tm and Tg. PMID- 25548903 TI - Spice/K2 synthetic marijuana-induced toxic hepatitis treated with N acetylcysteine. AB - BACKGROUND: Spice/K2 is one of several street names for synthetic marijuana. These hallucinogens are increasingly sold over the internet and in "head" shops. They are usually household herbs that are sprayed with chemicals that become centrally active compounds when burned together and inhaled by smoking. CASE REPORT: We present a case of a 45-year-old male substance abuser who was admitted with evidence of hepatocellular necrosis and worsening liver failure. Tests for acetaminophen were negative, as were tests for alcohol. The patient was empirically treated with N-acetylcysteine. Hepatocellular damage was abated and the patient made a full recovery. Upon regaining consciousness, the patient admitted to smoking Spice/K2. Other toxicities have been reported with synthetic marijuana use, but not liver toxicity. CONCLUSIONS: Physicians need to have a high index of suspicion for unknown hepatotoxins in substance abusers. N acetylcysteine can be given if there is no contraindication. PMID- 25548902 TI - The effects of ROCK inhibitor Y-27632 on injectable spheroids of bovine corneal endothelial cells. AB - The spheroids of 3-dimensional culture and Rho-associated kinase (ROCK) inhibitor Y-27632 have shown many advantages for the promotion of cellular viability and proliferation. The objective of this study was to investigate the effect of Y 27632 on the growth and injectability of bovine corneal endothelial cells (B CECs) maintained in vitro as spheroid cultures. Immunofluorescence staining showed that Y-27632 did not alter the cell type specificity of B-CECs, but it significantly enhanced B-CEC spherical viability and proliferation by a Live/Dead assay, 5-ethynyl-2'-deoxyuridine (EdU) labeling assay, and Cell Counting Kit-8 (CCK-8) assay. The uniform B-CEC spheroids could easily form in multiwall agarose micromolds and had a higher stemness potential than single B-CECs. Injectable B CEC spheroids were able to form monolayer growth, and polygonal B-CECs completely covered culture plates or Descemet's membrane of decellularized corneas under inverted microscopy and scanning electron microscopy (SEM). B-CEC spheroids were generated from agarose microwells on day 1 and then adherent culture with Y-27632 for day 5. However, small B-CEC spheroids still existed on culture plates or decellularized corneas when B-CEC spheroids were cultured in the same condition except for absence of Y-27632. Our findings that CEC spheroids with Y-27632 are injectable in vitro have important implications for the favorable treatment of CEC deficiency. PMID- 25548904 TI - A stronger post-publication culture is needed for better science. AB - Hilda Bastian considers post-publication commenting and the cultural changes that are needed to better capture this intellectual effort. Please see later in the article for the Editors' Summary. PMID- 25548905 TI - Isolation, cryopreservation and culture of human amnion epithelial cells for clinical applications. AB - Human amnion epithelial cells (hAECs) derived from term or pre-term amnion membranes have attracted attention from researchers and clinicians as a potential source of cells for regenerative medicine. The reason for this interest is evidence that these cells have highly multipotent differentiation ability, low immunogenicity, and anti-inflammatory functions. These properties have prompted researchers to investigate the potential of hAECs to be used to treat a variety of diseases and disorders in pre-clinical animal studies with much success. hAECs have found widespread application for the treatment of a range of diseases and disorders. Potential clinical applications of hAECs include the treatment of stroke, multiple sclerosis, liver disease, diabetes and chronic and acute lung diseases. Progressing from pre-clinical animal studies into clinical trials requires a higher standard of quality control and safety for cell therapy products. For safety and quality control considerations, it is preferred that cell isolation protocols use animal product-free reagents. We have developed protocols to allow researchers to isolate, cryopreserve and culture hAECs using animal product-free reagents. The advantage of this method is that these cells can be isolated, characterized, cryopreserved and cultured without the risk of delivering potentially harmful animal pathogens to humans, while maintaining suitable cell yields, viabilities and growth potential. For researchers moving from pre-clinical animal studies to clinical trials, these methodologies will greatly accelerate regulatory approval, decrease risks and improve the quality of their therapeutic cell population. PMID- 25548906 TI - Universal stem-loop primer method for screening and quantification of microRNA. AB - RT-qPCR is the accepted technique for the quantification of microRNA (miR) expression: however, stem-loop RT-PCR, the most frequently used method for quantification of miRs, is time- and reagent-consuming as well as inconvenient for scanning. We established a new method called 'universal stem-loop primer' (USLP) with 8 random nucleotides instead of a specific sequence at the 3' end of the traditional stem-loop primer (TSLP), for screening miR profile and to semi quantify expression of miRs. Peripheral blood samples were cultured with phytohaemagglutinin (PHA), and then 87 candidate miRs were scanned in cultured T cells. By USLP, our study revealed that the expression of miR-150-5p (miR-150) decreased nearly 10-fold, and miR-155-5p (miR-155) increased more than 7-fold after treated with PHA. The results of the dissociation curve and gel electrophoresis showed that the PCR production of the USLP and TSLP were specificity. The USLP method has high precision because of its low ICV (ICV<2.5%). The sensitivity of the USLP is up to 103 copies/ul miR. As compared with the TSLP, USLP saved 75% the cost of primers and 60% of the test time. The USLP method is a simple, rapid, precise, sensitive, and cost-effective approach that is suitable for screening miR profiles. PMID- 25548907 TI - Expression of tumor necrosis factor-alpha-mediated genes predicts recurrence-free survival in lung cancer. AB - In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-alpha-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-alpha/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-alpha. After matching the TNF-alpha-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF alpha-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-alpha-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence. PMID- 25548908 TI - A meta-analysis of zilpaterol and ractopamine effects on feedlot performance, carcass traits and shear strength of meat in cattle. AB - This study is a meta-analysis of the effects of the beta-agonists zilpaterol hydrochloride (ZH) and ractopamine hydrochloride (RAC) on feedlot performance, carcase characteristics of cattle and Warner Bratzler shear force (WBSF) of muscles. It was conducted to evaluate the effect of the use of these agents on beef production and meat quality and to provide data that would be useful in considerations on the effect of these agents on meat quality in Meat Standards Australia evaluations. We conducted a comprehensive literature search and study assessment using PubMed, Google Scholar, ScienceDirect, Scirus, and CAB and identification of other studies from reference lists in papers and searches. Searches were based on the key words: zilpaterol, zilmax, ractopamine, optaflexx, cattle and beef. Studies from theses obtained were included. Data were extracted from more than 50 comparisons for both agents and analysed using meta-analysis and meta-regression. Both agents markedly increased weight gain, hot carcase weight and longissimus muscle area and increased the efficiency of gain:feed. These effects were particularly large for ZH, however, fat thickness was decreased by ZH, but not RAC. Zilpaterol also markedly increased WBSF by 1.2 standard deviations and more than 0.8 kg, while RAC increased WBSF by 0.43 standard deviations and 0.2 kg. There is evidence in the ZH studies, in particular, of profound re-partitioning of nutrients from fat to protein depots. This work has provided critically needed information on the effects of ZH and RAC on production, efficiency and meat quality. PMID- 25548909 TI - A novel erythromycin resistance plasmid from Bacillus sp. strain HS24, isolated from the marine sponge Haliclona simulans. AB - A better understanding of the origin and natural reservoirs of resistance determinants is fundamental to efficiently tackle antibiotic resistance. This paper reports the identification of a novel 5.8 kb erythromycin resistance plasmid, from Bacillus sp. HS24 isolated from the marine sponge Haliclona simulans. pBHS24B has a mosaic structure and carries the erythromycin resistance gene erm(T). This is the first report of an erythromycin resistance plasmid from a sponge associated bacteria and of the Erm(T) determinant in the genus Bacillus. PMID- 25548910 TI - Self-efficacy beliefs are associated with visual height intolerance: a cross sectional survey. AB - BACKGROUND: Responses to height may range from indifference to minor distress to severe symptoms of fear of heights (acrophobia); visual height intolerance (vHI) denotes the whole spectrum of symptoms. Although there are options to manage vHI, only a small part of persons affected by vHI are willing to seek professional help or confront their problem. Purpose of this study was to determine if persons with vHI, specifically those who show avoidant behavior towards heights (avoiders), score lower in their general self-efficacy (GSE) than those who confront vHI (confronters). METHOD: Cross-sectional survey in 607 individuals living in the urban region of Munich, Germany, using a mailed questionnaire on presence or absence of vHI, confronting or avoiding behaviour, and GSE. RESULTS: Of all participants (mean age 53.9, 50.3% female), 407 reported life-time presence of vHI. Participants with vHI had a mean GSE score of 31.8 (SD 4.3) points (participants without vHI: 32.5, SD 4.3, p = 0.008 for difference). Among individuals with vHI, 23% reported confronting behavior. Confronters were significantly younger (p<.0001, 50.2 vs. 55.7 years), more likely to be female (p = 0.0039, 64.3% female), and had a higher GSE score (p = 0.0049, 32.5 vs. 31.1). Associations remained significant after multiple adjustment. CONCLUSIONS: Our study provides evidence for the association of GSE and vHI. These findings may have consequences for strategies of alleviation and therapy of vHI. PMID- 25548911 TI - Exercises in hot and humid environment caused liver injury in a rat model. AB - OBJECTIVE: To investigate injury pattern during intense exercises in hot and humid environment particularly on liver in a rat exertional heat stroke model. METHODS: We randomly divided 30 rats into a control group (CG), a normal temperature (25+/-2 degrees C, 60%+/-5% humidity) exercise group (NTEG) and a high temperature and high humidity (35+/-2 degrees C, 80%+/-10% humidity) exercising group (HTEG), each comprising 10 animals. The NTEG and HTEG rats were forced to run in a treadmill for 1 hour maximum at 20 rpm. We analyzed liver cells of all three groups with JC-1 dye and flow cytometry for apoptosis rates in addition to liver tissue 8 - hydroxy deoxyguanosine (8 - OhdG) and blood serum IL 6, tumor necrosis factor alpha (TNF-alpha), alanine aminotransferase ALT, aspartate amino transferase (AST), serum creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), creatine phosphate kinase (CK) concentrations. RESULT: Compared with NTEG rats, beside reduced exercise tolerance (60+/-5 vs. 15+/-3 minutes) (p = 0.002) the 8-OhdG liver tissue concentrations were significantly higher (p = 0.040) in the HTEG rats. The HTEG developed more organ tissue damage and cellular fragmentations of liver cells. In both exercise groups TNF-alpha and IL-6 serum concentrations were enhanced significantly (p<0.001) being highest in the HTEG animals. Serum ALT, AST, LDH, CREA, BUN and CK concentrations were significantly enhance in both exercise groups. CONCLUSION: In our exertional heat stroke rat model, we found tissue damage particularly in livers during exercises in hot and humid environment that was related to inflammation, oxidative stress and apoptosis. PMID- 25548912 TI - Phantom based evaluation of CT to CBCT image registration for proton therapy dose recalculation. AB - The ability to perform dose recalculation on the anatomy of the day is important in the context of adaptive proton therapy. The objective of this study was to investigate the use of deformable image registration (DIR) and cone beam CT (CBCT) imaging to generate the daily stopping power distribution of the patient. We investigated the deformation of the planning CT scan (pCT) onto daily CBCT images to generate a virtual CT (vCT) using a deformable phantom designed for the head and neck (H & N) region. The phantom was imaged at a planning CT scanner in planning configuration, yielding a pCT and in deformed, treatment day configuration, yielding a reference CT (refCT). The treatment day configuration was additionally scanned at a CBCT scanner. A Morphons DIR algorithm was used to generate a vCT. The accuracy of the vCT was evaluated by comparison to the refCT in terms of corresponding features as identified by an adaptive scale invariant feature transform (aSIFT) algorithm. Additionally, the vCT CT numbers were compared to those of the refCT using both profiles and regions of interest and the volumes and overlap (DICE coefficients) of various phantom structures were compared. The water equivalent thickness (WET) of the vCT, refCT and pCT were also compared to evaluate proton range differences. Proton dose distributions from the same initial fluence were calculated on the refCT, vCT and pCT and compared in terms of proton range. The method was tested on a clinical dataset using a replanning CT scan acquired close in time to a CBCT scan as reference using the WET evaluation. Results from the aSIFT investigation suggest a deformation accuracy of 2-3 mm. The use of the Morphon algorithm did not distort CT number intensity in uniform regions and WET differences between vCT and refCT were of the order of 2% of the proton range. This result was confirmed by proton dose calculations. The patient results were consistent with phantom observations. In conclusion, our phantom study suggests the vCT approach is adequate for proton dose recalculation on the basis of CBCT imaging. PMID- 25548913 TI - Comparison of combined general-epidural anesthesia with general anesthesia effects on survival and cancer recurrence: a meta-analysis of retrospective and prospective studies. AB - OBJECTIVE: Animals underwent combined general-epidural anesthesia (EGA) is reported to have better long-time outcome than general anesthesia (GA). This study aimed to make overall evaluation of the association between these two anesthetic techniques and prognosis of cancer patients undergoing surgery. METHODS: Related databases such as PubMed and EMbase were searched for eligible studies that evaluated the influence of EGA and GA on the prognosis of cancer patients undergoing surgery. Selected studies were evaluated according to the inclusion criteria by two reviewers respectively, followed by data extraction and quality assessment. The odds ratio (OR) with their 95% confidence intervals (CIs) were calculated to assess the influence strength of EGA and GA on prognosis of cancer patients. RESULTS: A total of ten studies involving 3254 patients were included. The overall results demonstrated that there was no significant difference between EGA and GA group (OR = 0.88, 95% CI 0.73 to 1.06, P = 0.187) concerning postoperative recurrence and metastasis rate. In regard to the following two factors: cancer category and time of follow-up, subgroup analysis identified significant differences between EGA and GA in the group of patients with prostate cancer and the group with follow-up less than or equal to two years (OR = 0.66, 95% CI 0.46 to 0.95, P = 0.027; OR = 0.70, 95% CI 0.51 to 0.98, P = 0.035; respectively) concerning postoperative recurrence and metastasis rate. However, no significant difference was found in the group of patients with colorectal cancer (OR = 1.06, 95% CI 0.84-1.33, P = 0.62). CONCLUSIONS: This meta analysis showed that EGA might be associated with improvement in prognosis of patients with operable prostate cancer and the cancer patients with follow-up less than or equal to two years. However, no obvious relationship between the improvement in prognosis of colorectal cancer and EGA were detected, comparing to GA. Furthermore, all the results should be interpreted cautiously, as heterogeneous data were used for analyzing. PMID- 25548914 TI - The incidence of sexually dimorphic gene expression varies greatly between tissues in the rat. AB - The sexually dimorphic expression of genes across 26 somatic rat tissues was using Affymetrix RAE-230 genechips. We considered probesets to be sexually dimorphically expressed (SDE) if they were measurably expressed above background in at least one sex, there was at least a two-fold difference in expression (dimorphism) between the sexes, and the differences were statistically significant after correcting for false discovery. 14.5% of expressed probesets were SDE in at least one tissue, with higher expression nearly twice as prevalent in males compared to females. Most were SDE in a single tissue. Surprisingly, nearly half of the probesets that were (SDE) in multiple tissues were oppositely sex biased in different tissues, and most SDE probesets were also expressed without sex bias in other tissues. Two genes were widely SDE: Xist (female-only) and Eif2s3y (male-only). The frequency of SDE probesets varied widely between tissues, and was highest in the duodenum (6.2%), whilst less than 0.05% in over half of the surveyed tissues. The occurrence of SDE probesets was not strongly correlated between tissues. Within individual tissues, however, relational networks of SDE genes were identified. In the liver, networks relating to differential metabolism between the sexes were seen. The estrogen receptor was implicated in differential gene expression in the duodenum. To conclude, sexually dimorphic gene expression is common, but highly tissue-dependent. Sexually dimorphic gene expression may provide insights into mechanisms underlying phenotypic sex differences. Online data are provided as a resource for further analyses (GEO reference GSE63362). PMID- 25548915 TI - Sodium butyrate promotes the differentiation of rat bone marrow mesenchymal stem cells to smooth muscle cells through histone acetylation. AB - Establishing an effective method to improve stem cell differentiation is crucial in stem cell transplantation. Here we aimed to explore whether and how sodium butyrate (NaB) induces rat bone marrow mesenchymal stem cells (MSCs) to differentiate into bladder smooth muscle cells (SMCs). We found that NaB significantly suppressed MSC proliferation and promoted MSCs differentiation into SMCs, as evidenced by the enhanced expression of SMC specific genes in the MSCs. Co-culturing the MSCs with SMCs in a transwell system promoted the differentiation of MSCs into SMCs. NaB again promoted MSC differentiation in this system. Furthermore, NaB enhanced the acetylation of SMC gene-associated H3K9 and H4, and decreased the expression of HDAC2 and down-regulated the recruitment of HDAC2 to the promoter regions of SMC specific genes. Finally, we found that NaB significantly promoted MSC depolarization and increased the intracellular calcium level of MSCs upon carbachol stimulation. These results demonstrated that NaB effectively promotes MSC differentiation into SMCs, possibly by the marked inhibition of HDAC2 expression and disassociation of HDAC2 recruitment to SMC specific genes in MSCs, which further induces high levels of H3K9ace and H4ace and the enhanced expression of target genes, and this strategy could potentially be applied in clinical tissue engineering and cell transplantation. PMID- 25548916 TI - Expression of thrombospondin-1 modulates the angioinflammatory phenotype of choroidal endothelial cells. AB - The choroidal circulation plays a central role in maintaining the health of outer retina and photoreceptor function. Alterations in this circulation contribute to pathogenesis of many eye diseases including exudative age-related macular degeneration. Unfortunately, very little is known about the choroidal circulation and its molecular and cellular regulation. This has been further hampered by the lack of methods for routine culturing of choroidal endothelial cells (ChEC), especially from wild type and transgenic mice. Here we describe a method for isolation and culturing of mouse ChEC. We show that expression of thrombospondin 1 (TSP1), an endogenous inhibitor of angiogenesis and inflammation, has a significant impact on phenotype of ChEC. ChEC from TSP1-deficient (TSP1-/-) mice were less proliferative and more apoptotic, less migratory and less adherent, and failed to undergo capillary morphogenesis in Matrigel. However, re-expression of TSP1 was sufficient to restore TSP1-/- ChEC migration and capillary morphogenesis. TSP1-/- ChEC expressed increased levels of TSP2, phosphorylated endothelial nitric oxide synthase (NOS) and inducible NOS (iNOS), a marker of inflammation, which was associated with significantly higher level of NO and oxidative stress in these cells. Wild type and TSP1-/- ChEC produced similar levels of VEGF, although TSP1-/- ChEC exhibited increased levels of VEGF-R1 and pSTAT3. Other signaling pathways including Src, Akt, and MAPKs were not dramatically affected by the lack of TSP1. Together our results demonstrate an important autocrine role for TSP1 in regulation of ChEC phenotype. PMID- 25548917 TI - A Western-fed diet increases plasma HDL and LDL-cholesterol levels in apoD-/- mice. AB - OBJECTIVE: Plasma apolipoprotein (apo)D, a ubiquitously expressed protein that binds small hydrophobic ligands, is found mainly on HDL particles. According to studies of human genetics and lipid disorders, plasma apoD levels positively correlate with HDL-cholesterol and apoAI levels. Thus, we tested the hypothesis that apoD was a regulator of HDL metabolism. METHODS & RESULTS: We compared the plasma lipid and lipoprotein profiles of wild-type (WT) C57BL/6 mice with apoD-/- mice on a C57BL/6 background after receiving a high fat-high cholesterol diet for 12 weeks. ApoD-/- mice had higher HDL-cholesterol levels (61+/-13-apoD-/- vs. 52+/-10-WT-males; 37+/-11-apoD-/- vs. 22+/-2 WT-female) than WT mice with sex specific changes in total plasma levels of cholesterol and other lipids. Compared to WT, the HDL of apoD-/- mice showed an increase in large, lipid-rich HDL particles and according to size various quantities and sizes of LDL particles. Plasma levels of lecithin:cholesterol acyltransferase in the control and apoD-/- mice were not different, however, plasma phospholipid transfer protein activity was modestly elevated (+10%) only in male apoD-/- mice. An in vivo HDL metabolism experiment with isolated Western-fed apoD-/- HDL particles showed that female apoD-/- mice had a 36% decrease in the fractional catabolic rate of HDL cholesteryl ester. Hepatic SR-BI and LDLR protein levels were significantly decreased; accordingly, LDL-cholesterol and apoB levels were increased in female mice. CONCLUSION: In the context of a high fat-high cholesterol diet, apoD deficiency in female mice is associated with increases in both plasma HDL and LDL cholesterol levels, reflecting changes in expression of SR-BI and LDL receptors, which may impact diet-induced atherosclerosis. PMID- 25548919 TI - Functional near infrared spectroscopy of the sensory and motor brain regions with simultaneous kinematic and EMG monitoring during motor tasks. AB - There are several advantages that functional near-infrared spectroscopy (fNIRS) presents in the study of the neural control of human movement. It is relatively flexible with respect to participant positioning and allows for some head movements during tasks. Additionally, it is inexpensive, light weight, and portable, with very few contraindications to its use. This presents a unique opportunity to study functional brain activity during motor tasks in individuals who are typically developing, as well as those with movement disorders, such as cerebral palsy. An additional consideration when studying movement disorders, however, is the quality of actual movements performed and the potential for additional, unintended movements. Therefore, concurrent monitoring of both blood flow changes in the brain and actual movements of the body during testing is required for appropriate interpretation of fNIRS results. Here, we show a protocol for the combination of fNIRS with muscle and kinematic monitoring during motor tasks. We explore gait, a unilateral multi-joint movement (cycling), and two unilateral single-joint movements (isolated ankle dorsiflexion, and isolated hand squeezing). The techniques presented can be useful in studying both typical and atypical motor control, and can be modified to investigate a broad range of tasks and scientific questions. PMID- 25548918 TI - Irreversible denaturation of maltodextrin glucosidase studied by differential scanning calorimetry, circular dichroism, and turbidity measurements. AB - Thermal denaturation of Escherichia coli maltodextrin glucosidase was studied by differential scanning calorimetry, circular dichroism (230 nm), and UV-absorption measurements (340 nm), which were respectively used to monitor heat absorption, conformational unfolding, and the production of solution turbidity. The denaturation was irreversible, and the thermal transition recorded at scan rates of 0.5-1.5 K/min was significantly scan-rate dependent, indicating that the thermal denaturation was kinetically controlled. The absence of a protein concentration effect on the thermal transition indicated that the denaturation was rate-limited by a mono-molecular process. From the analysis of the calorimetric thermograms, a one-step irreversible model well represented the thermal denaturation of the protein. The calorimetrically observed thermal transitions showed excellent coincidence with the turbidity transitions monitored by UV-absorption as well as with the unfolding transitions monitored by circular dichroism. The thermal denaturation of the protein was thus rate-limited by conformational unfolding, which was followed by a rapid irreversible formation of aggregates that produced the solution turbidity. It is thus important to note that the absence of the protein-concentration effect on the irreversible thermal denaturation does not necessarily means the absence of protein aggregation itself. The turbidity measurements together with differential scanning calorimetry in the irreversible thermal denaturation of the protein provided a very effective approach for understanding the mechanisms of the irreversible denaturation. The Arrhenius-equation parameters obtained from analysis of the thermal denaturation were compared with those of other proteins that have been reported to show the one-step irreversible thermal denaturation. Maltodextrin glucosidase had sufficiently high kinetic stability with a half-life of 68 days at a physiological temperature (37 degrees C). PMID- 25548920 TI - Evaluation of in vitro anticancer activity of Ocimum basilicum, Alhagi maurorum, Calendula officinalis and their parasite Cuscuta campestris. AB - The present investigation was carried out to study the relationship between presence of cytotoxic compounds in Ocimum basilicum, Alhagi maurorum, Calendula officinalis and their parasite Cuscuta campestris. The cytotoxic activity of the pure compounds was performed by MTT assay against breast cancer cell lines (MCF-7 and MDA-MB-231) and normal breast cell line (MCF 10A). The induction of apoptosis was measured by the expression levels of p53, bcl-2, bax and caspase-3 genes using quantitative Real Time PCR. Three active fractions were detected by nuclear magnetic resonance as lutein, lupeol and eugenol, respectively, in C. officinalis, A. maurorum and O. basilicum. These compounds and their epoxidized forms were also detected in their parasite C. campestris. The cytotoxic activity of lutein epoxide, lupeol epoxide and eugenol epoxide was significantly more than lutein, lupeol and eugenol. The mRNA expression level of p53, caspase-3 and bax genes were increased in both cancer cells treated with all pure compounds. However, bcl-2 gene expression decreased in treated breast cancer cells. In conclusion, all the data indicated that the epoxide forms of lupeol, lutein and eugenol are potential drug candidates for inducing apoptosis in human breast cancer cells. PMID- 25548921 TI - Activation of the RhoB signaling pathway by thyroid hormone receptor beta in thyroid cancer cells. AB - Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-associated carcinogenesis are still not clear. To establish the function of TRbeta in thyroid cancer cell proliferation, we constructed a recombinant adenovirus vector, AdTRbeta, which expresses human TRbeta1 cDNA. Thyroid cancer cell lines in which TRbeta protein levels were significantly decreased as compared to intact thyroid tissues were infected with AdTRbeta and the function of TRbeta on cell proliferation and migration was analyzed. Ligand-bound TRbeta induced HDAC1 and HDAC3 dissociation from, and histone acetylation associated with the RhoB promoter and enhanced the expression of RhoB mRNA and protein. In AdTRbeta-infected cells, T3 and farnesyl transferase inhibitor (FTI)-treatment induced the distribution of RhoB on the cell membrane and enhanced the abundance of active GTP-bound RhoB. This RhoB protein led to p21-associated cell-cycle arrest in the G0/G1 phase, following inhibition of cell proliferation and invasion. Conversely, lowering cellular RhoB by small interfering RNA knockdown in AdTRbeta-infected cells led to downregulation of p21 and inhibited cell-cycle arrest. The growth of BHP18-21v tumor xenografts in vivo was significantly inhibited by AdTRbeta injection with FTIs-treatment, as compared to control virus-injected tumors. This novel signaling pathway triggered by ligand-bound TRbeta provides insight into possible mechanisms of proliferation and invasion of thyroid cancer and may provide new therapeutic targets for thyroid cancers. PMID- 25548922 TI - Inflammatory micro-environmental cues of human atherothrombotic arteries confer to vascular smooth muscle cells the capacity to trigger lymphoid neogenesis. AB - BACKGROUND: Experimental atherosclerosis is characterized by the formation of tertiary lymphoid structures (TLOs) within the adventitial layer, which involves the chemokine-expressing aortic smooth muscle cells (SMCs). TLOs have also been described around human atherothrombotic arteries but the mechanisms of their formation remain poorly investigated. Herein, we tested whether human vascular SMCs play the role of chemokine-expressing cells that would trigger the formation of TLOs in atherothrombotic arteries. RESULTS: We first characterized, by flow cytometry and immunofluorescence analysis, the prevalence and cell composition of TLOs in human abdominal aneurysms of the aorta (AAAs), an evolutive form of atherothrombosis. Chemotaxis experiments revealed that the conditioned medium from AAA tissues recruited significantly more B and T lymphocytes than the conditioned medium from control (N-AAA) tissues. This was associated with an increase in the concentration of CXCL13, CXCL16, CCL19, CCL20, and CCL21 chemokines in the conditioned medium from AAA tissues. Immunofluorescence analysis of AAA cryosections revealed that alpha-SMA-positive SMCs were the main contributors to the chemokine production. These results were confirmed by RT-qPCR assays where we found that primary vascular SMCs from AAA tissues expressed significantly more chemokines than SMCs from N-AAA. Finally, in vitro experiments demonstrated that the inflammatory cytokines found to be increased in the conditioned medium from AAA were able to trigger the production of chemokines by primary SMCs. CONCLUSION: Together, these results suggest that human vascular SMCs in atherothrombotic arteries, in response to inflammatory signals, are converted into chemokine-expressing cells that trigger the recruitment of immune cells and the formation of aortic TLOs. PMID- 25548924 TI - Biased transmission of sex chromosomes in the aphid Myzus persicae is not associated with reproductive mode. AB - Commonly, a single aphid species exhibits a wide range of reproductive strategies including cyclical parthenogenesis and obligate parthenogenesis. Sex determination in aphids is chromosomal; females have two X chromosomes, while males have one. X chromosome elimination at male production is generally random, resulting in equal representation of both X chromosomes in sons. However, two studies have demonstrated deviations from randomness in some lineages. One hypothesis to account for such deviations is that recessive deleterious mutations accumulate during bouts of asexual reproduction and affect male viability, resulting in overrepresentation of males with the least deleterious of the two maternal X chromosomes. This hypothesis results in a testable prediction: X chromosome transmission bias will increase with time spent in the asexual phase and should therefore be most extreme in the least sexual aphid life cycle class. Here we test this prediction in Myzus persicae. We used multiple heterozygous X linked microsatellite markers to screen 1085 males from 95 lines of known life cycle. We found significant deviations from equal representation of X chromosomes in 15 lines; however, these lines included representatives of all life cycles. Our results are inconsistent with the hypothesis that deviations from randomness are attributable to mutation accumulation. PMID- 25548923 TI - Electrochemical regulation of budding yeast polarity. AB - Cells are naturally surrounded by organized electrical signals in the form of local ion fluxes, membrane potential, and electric fields (EFs) at their surface. Although the contribution of electrochemical elements to cell polarity and migration is beginning to be appreciated, underlying mechanisms are not known. Here we show that an exogenous EF can orient cell polarization in budding yeast (Saccharomyces cerevisiae) cells, directing the growth of mating projections towards sites of hyperpolarized membrane potential, while directing bud emergence in the opposite direction, towards sites of depolarized potential. Using an optogenetic approach, we demonstrate that a local change in membrane potential triggered by light is sufficient to direct cell polarization. Screens for mutants with altered EF responses identify genes involved in transducing electrochemical signals to the polarity machinery. Membrane potential, which is regulated by the potassium transporter Trk1p, is required for polarity orientation during mating and EF response. Membrane potential may regulate membrane charges through negatively charged phosphatidylserines (PSs), which act to position the Cdc42p based polarity machinery. These studies thus define an electrochemical pathway that directs the orientation of cell polarization. PMID- 25548926 TI - Editorial: current progress in structural bioinformatics of protein-biomolecule interactions. PMID- 25548925 TI - The transcription map of human papillomavirus type 18 during genome replication in U2OS cells. AB - The human osteosarcoma cell line U2OS is useful for studying genome replication of human papillomavirus (HPVs) subtypes that belong to different phylogenetic genera. In this study, we defined the HPV18 transcription map in U2OS cells during transient replication, stable maintenance and vegetative amplification by identifying viral promoter regions, transcription polyadenylation and splicing sites during HPV18 genome replication. Mapping of the HPV18 transcription start sites in U2OS cells revealed five distinct promoter regions (P102, P520, P811, P1193 and P3000). With the exception of P3000, all of these regions have been previously identified during productive HPV18 infection. Collectively, the data suggest that U2OS cells are suitable for studying the replication and transcription properties of HPVs and to serve as a platform for conducting high throughput drug screens to identify HPV replication inhibitors. In addition, we have identified mRNA species that are initiated from the promoter region P3000, which can encode two E2C regulator proteins that contain only the C-terminal hinge and DNA-binding and dimerization domains of E2. We show that these proteins regulate the initial amplification of HPV18 by modulating viral transcription. Moreover, we show that one of these proteins can act as a transcriptional activator of promoter P102. PMID- 25548927 TI - Some remarks on prediction of protein-protein interaction with machine learning. AB - Protein-protein interactions (PPIs) play a key role in many cellular processes. Uncovering the PPIs and their function within the cell is a challenge of post genomic biology and will improve our understanding of disease and help in the development of novel methods for disease diagnosis and forensics. The experimental methods currently used to identify PPIs are both time-consuming and expensive, and high throughput experimental results have shown both high false positive beside false negative information for protein interaction. These obstacles could be overcome by developing computational approaches to predict PPIs and validate the obtained experimental results. In this work, we will describe the recent advances in predicting protein-protein interaction from the following aspects: i) the benchmark dataset construction, ii) the sequence representation approaches, iii) the common machine learning algorithms, and iv) the cross-validation test methods and assessment metrics. PMID- 25548928 TI - Advances in protein contact map prediction based on machine learning. AB - A protein contact map is a simplified, two-dimensional version of the three dimensional protein structure. Protein contact map is proved to be crucial in forming the three-dimensional structure. Contact map prediction has now become an indispensable and promising intermediate step towards final three-dimensional structure prediction, while directed sequence-structure prediction hits its bottlenecks. In this article, different evaluation scores of prediction efficiency are compared. Next, the state of the art and future perspectives of contact map methods are reviewed and special attention is paid to those relying on machine learning algorithms. Details of neural network based methods as well as a list of machine learning based methods are given. Finally, bottlenecks and potential improvements of contact map predictions are discussed. PMID- 25548929 TI - Overview of binding free energy calculation techniques for elucidation of biological processes and for drug discovery. AB - The elucidation of the interactions between a protein and a ligand or proteins is a key issue for understanding of functional processes of various proteins, enzymes and receptors in biological organisms, system biology and drug design. One of the most important matters in these problems is the accurate estimation of binding free energy between a protein and a ligand or proteins. In the present review, we overview various techniques and introduce a new technique for estimation of binding free energy calculations. We also discuss possible ways to incorporate the effect of fect of solvent. PMID- 25548930 TI - Impacts of bioinformatics to medicinal chemistry. AB - Facing the explosive growth of biological sequence data, such as those of protein/peptide and DNA/RNA, generated in the post-genomic age, many bioinformatical and mathematical approaches as well as physicochemical concepts have been introduced to timely derive useful informations from these biological sequences, in order to stimulate the development of medical science and drug design. Meanwhile, because of the rapid penetrations from these disciplines, medicinal chemistry is currently undergoing an unprecedented revolution. In this minireview, we are to summarize the progresses by focusing on the following six aspects. (1) Use the pseudo amino acid composition or PseAAC to predict various attributes of protein/peptide sequences that are useful for drug development. (2) Use pseudo oligonucleotide composition or PseKNC to do the same for DNA/RNA sequences. (3) Introduce the multi-label approach to study those systems where the constituent elements bear multiple characters and functions. (4) Utilize the graphical rules and "wenxiang" diagrams to analyze complicated biomedical systems. (5) Recent development in identifying the interactions of drugs with its various types of target proteins in cellular networking. (6) Distorted key theory and its application in developing peptide drugs. PMID- 25548931 TI - Recent development of peptide drugs and advance on theory and methodology of peptide inhibitor design. AB - Due to the low toxicity, easy synthesis, rapid elimination, and less side effect, more and more peptide inhibitors are emerging as the effective drugs that are clinically used in therapies of a number of diseases. At the same time the computer-aided drug design (CADD) methods have remarkably developed. In this mini review the newly developed peptide inhibitors and drugs are introduced, including peptide vaccines for cancers, peptide inhibitors for HIV, Alzheimer's disease and related diseases, and the peptides as the leading compounds of drugs. The recent progress in the theory and methodology of peptide inhibitor design is reviewed. (1) The flexible protein-peptide docking model is introduced, in which the peptide structures are treated as segment-flexible chains using genetic algorithm and special force field parameters. (2) The "Wenxiang diagram" is illustrated for protein-peptide interaction analysis that has been successfully used in the coiled-coil interaction analysis. (3) The "Distorted key" theory is reviewed, which is an effective method to convert the peptide inhibitors to the small chemical drugs. (4) The amino acid property-based peptide prediction method (AABPP) is described that is a twolevel QSAR prediction network for the bioactivity prediction of peptide inhibitors. (5) Finally, several types of molecular interactions between protein and peptide ligands are summarized, including cation-pi interactions; polar hydrogen-pi interactions; and pi-pi stocking interactions. PMID- 25548932 TI - Quantitative immunofluorescence assay to measure the variation in protein levels at centrosomes. AB - Centrosomes are small but important organelles that serve as the poles of mitotic spindle to maintain genomic integrity or assemble primary cilia to facilitate sensory functions in cells. The level of a protein may be regulated differently at centrosomes than at other .cellular locations, and the variation in the centrosomal level of several proteins at different points of the cell cycle appears to be crucial for the proper regulation of centriole assembly. We developed a quantitative fluorescence microscopy assay that measures relative changes in the level of a protein at centrosomes in fixed cells from different samples, such as at different phases of the cell cycle or after treatment with various reagents. The principle of this assay lies in measuring the background corrected fluorescent intensity corresponding to a protein at a small region, and normalize that measurement against the same for another protein that does not vary under the chosen experimental condition. Utilizing this assay in combination with BrdU pulse and chase strategy to study unperturbed cell cycles, we have quantitatively validated our recent observation that the centrosomal pool of VDAC3 is regulated at centrosomes during the cell cycle, likely by proteasome mediated degradation specifically at centrosomes. PMID- 25548933 TI - Monte-Carlo-derived insights into dose-kerma-collision kerma inter-relationships for 50 keV-25 MeV photon beams in water, aluminum and copper. AB - The relationships between D, K and Kcol are of fundamental importance in radiation dosimetry. These relationships are critically influenced by secondary electron transport, which makes Monte-Carlo (MC) simulation indispensable; we have used MC codes DOSRZnrc and FLURZnrc. Computations of the ratios D/K and D/Kcol in three materials (water, aluminum and copper) for large field sizes with energies from 50 keV to 25 MeV (including 6-15 MV) are presented. Beyond the depth of maximum dose D/K is almost always less than or equal to unity and D/Kcol greater than unity, and these ratios are virtually constant with increasing depth. The difference between K and Kcol increases with energy and with the atomic number of the irradiated materials. D/K in 'sub-equilibrium' small megavoltage photon fields decreases rapidly with decreasing field size. A simple analytical expression for X, the distance 'upstream' from a given voxel to the mean origin of the secondary electrons depositing their energy in this voxel, is proposed: X(emp) ~ 0.5R(csda)(E(0)), where E(0) is the mean initial secondary electron energy. These X(emp) agree well with 'exact' MC-derived values for photon energies from 5-25 MeV for water and aluminum. An analytical expression for D/K is also presented and evaluated for 50 keV-25 MeV photons in the three materials, showing close agreement with the MC-derived values. PMID- 25548934 TI - Electrophoretic mobility shift assay (EMSA) for the study of RNA-protein interactions: the IRE/IRP example. AB - RNA/protein interactions are critical for post-transcriptional regulatory pathways. Among the best-characterized cytosolic RNA-binding proteins are iron regulatory proteins, IRP1 and IRP2. They bind to iron responsive elements (IREs) within the untranslated regions (UTRs) of several target mRNAs, thereby controlling the mRNAs translation or stability. IRE/IRP interactions have been widely studied by EMSA. Here, we describe the EMSA protocol for analyzing the IRE binding activity of IRP1 and IRP2, which can be generalized to assess the activity of other RNA-binding proteins as well. A crude protein lysate containing an RNA-binding protein, or a purified preparation of this protein, is incubated with an excess of(32) P-labeled RNA probe, allowing for complex formation. Heparin is added to preclude non-specific protein to probe binding. Subsequently, the mixture is analyzed by non-denaturing electrophoresis on a polyacrylamide gel. The free probe migrates fast, while the RNA/protein complex exhibits retarded mobility; hence, the procedure is also called "gel retardation" or "bandshift" assay. After completion of the electrophoresis, the gel is dried and RNA/protein complexes, as well as free probe, are detected by autoradiography. The overall goal of the protocol is to detect and quantify IRE/IRP and other RNA/protein interactions. Moreover, EMSA can also be used to determine specificity, binding affinity, and stoichiometry of the RNA/protein interaction under investigation. PMID- 25548935 TI - Detecting glycogen in peripheral blood mononuclear cells with periodic acid schiff staining. AB - Periodic acid Schiff (PAS) staining is an immunohistochemical technique used on muscle biopsies and as a diagnostic tool for blood samples. Polysaccharides such as glycogen, glycoproteins, and glycolipids stain bright magenta making it easy to enumerate positive and negative cells within the tissue. In muscle cells PAS staining is used to determine the glycogen content in different types of muscle cells, while in blood cell samples PAS staining has been explored as a diagnostic tool for a variety of conditions. Blood contains a proportion of white blood cells that belong to the immune system. The notion that cells of the immune system possess glycogen and use it as an energy source has not been widely explored. Here, we describe an adapted version of the PAS staining protocol that can be applied on peripheral blood mononuclear immune cells from human venous blood. Small cells with PAS-positive granules and larger cells with diffuse PAS staining were observed. Treatment of samples with amylase abrogates these patterns confirming the specificity of the stain. An alternate technique based on enzymatic digestion confirmed the presence and amount of glycogen in the samples. This protocol is useful for hematologists or immunologists studying polysaccharide content in blood-derived lymphocytes. PMID- 25548936 TI - Magnetic apatite for structural insights on the plasma membrane. AB - The iron oxide-hydroxyapatite (FeOxHA) nanoparticles reported here differ from those reported before by their advantage of homogeneity and simple preparation; moreover, the presence of carboxymethyldextran (CMD), together with hydroxyapatite (HA), allows access to the cellular membrane, which makes our magnetic apatite unique. These nanoparticles combine magnetic behavior, Raman label ability and the property of interaction with the cellular membrane; they therefore represent an interesting material for structural differentiation of the cell membrane. It was observed by Raman spectroscopy, scanning electron microscopy (SEM) and fluorescence microscopy that FeOxHA adheres to the plasma membrane and does not penetrate the membrane. These insights make the nanoparticles a promising material for magnetic cell sorting, e.g. in microfluidic device applications. PMID- 25548937 TI - Neural stem cell transplantation in experimental contusive model of spinal cord injury. AB - Spinal cord injury is a devastating clinical condition, characterized by a complex of neurological dysfunctions. Animal models of spinal cord injury can be used both to investigate the biological responses to injury and to test potential therapies. Contusion or compression injury delivered to the surgically exposed spinal cord are the most widely used models of the pathology. In this report the experimental contusion is performed by using the Infinite Horizon (IH) Impactor device, which allows the creation of a reproducible injury animal model through definition of specific injury parameters. Stem cell transplantation is commonly considered a potentially useful strategy for curing this debilitating condition. Numerous studies have evaluated the effects of transplanting a variety of stem cells. Here we demonstrate an adapted method for spinal cord injury followed by tail vein injection of cells in CD1 mice. In short, we provide procedures for: i) cell labeling with a vital tracer, ii) pre-operative care of mice, iii) execution of a contusive spinal cord injury, and iv) intravenous administration of post mortem neural precursors. This contusion model can be utilized to evaluate the efficacy and safety of stem cell transplantation in a regenerative medicine approach. PMID- 25548938 TI - Casting protocols for the production of open cell aluminum foams by the replication technique and the effect on porosity. AB - Metal foams are interesting materials from both a fundamental understanding and practical applications point of view. Uses have been proposed, and in many cases validated experimentally, for light weight or impact energy absorbing structures, as high surface area heat exchangers or electrodes, as implants to the body, and many more. Although great progress has been made in understanding their structure properties relationships, the large number of different processing techniques, each producing material with different characteristics and structure, means that understanding of the individual effects of all aspects of structure is not complete. The replication process, where molten metal is infiltrated between grains of a removable preform material, allows a markedly high degree of control and has been used to good effect to elucidate some of these relationships. Nevertheless, the process has many steps that are dependent on individual "know how", and this paper aims to provide a detailed description of all stages of one embodiment of this processing method, using materials and equipment that would be relatively easy to set up in a research environment. The goal of this protocol and its variants is to produce metal foams in an effective and simple way, giving the possibility to tailor the outcome of the samples by modifying certain steps within the process. By following this, open cell aluminum foams with pore sizes of 1-2.36 mm diameter and 61% to 77% porosity can be obtained. PMID- 25548940 TI - Study of bacterial adhesion on biomimetic temperature responsive glycopolymer surfaces. AB - Pseudomonas aeruginosa is an opportunistic pathogen responsible for diseases such as bacteremia, chronic lung infection, and acute ulcerative keratitis. P. aeruginosa induced diseases can be fatal as the exotoxins and endotoxins released by the bacterium continue to damage host tissues even after the administration of antibiotics. As bacterial adhesion on cell surfaces is the first step in bacterial based pathogen infections, the control of bacteria-cell interactions is a worthwhile research target. In this work, thermally responsive poly(N isopropylacrylamide) [P(NIPAAm)] based biomimetic surfaces were developed to study the two major bacterial infection mechanisms, which is believed to be mediated by hydrophobic or lectin-carbohydrate interactions, using quartz crystal microbalance with dissipation. Although, a greater number of P. aeruginosa adhered to the NIPAAm homopolymer modified surfaces at temperatures higher than the lower critical solution temperature (LCST), the bacterium-substratum bond stiffness was stronger between P. aeruginosa and a galactose based P(NIPAAm) surface. The high bacterial adhesion bond stiffness observed on the galactose based thermally responsive surface at 37 degrees C might suggest that both hydrophobic and lectin-carbohydrate interactions contribute to bacterial adhesion on cell surfaces. Our investigation also suggests that the lectin-carbohydrate interaction play a significant role in bacterial infections. PMID- 25548939 TI - A hybrid DNA extraction method for the qualitative and quantitative assessment of bacterial communities from poultry production samples. AB - The efficacy of DNA extraction protocols can be highly dependent upon both the type of sample being investigated and the types of downstream analyses performed. Considering that the use of new bacterial community analysis techniques (e.g., microbiomics, metagenomics) is becoming more prevalent in the agricultural and environmental sciences and many environmental samples within these disciplines can be physiochemically and microbiologically unique (e.g., fecal and litter/bedding samples from the poultry production spectrum), appropriate and effective DNA extraction methods need to be carefully chosen. Therefore, a novel semi-automated hybrid DNA extraction method was developed specifically for use with environmental poultry production samples. This method is a combination of the two major types of DNA extraction: mechanical and enzymatic. A two-step intense mechanical homogenization step (using bead-beating specifically formulated for environmental samples) was added to the beginning of the "gold standard" enzymatic DNA extraction method for fecal samples to enhance the removal of bacteria and DNA from the sample matrix and improve the recovery of Gram-positive bacterial community members. Once the enzymatic extraction portion of the hybrid method was initiated, the remaining purification process was automated using a robotic workstation to increase sample throughput and decrease sample processing error. In comparison to the strict mechanical and enzymatic DNA extraction methods, this novel hybrid method provided the best overall combined performance when considering quantitative (using 16S rRNA qPCR) and qualitative (using microbiomics) estimates of the total bacterial communities when processing poultry feces and litter samples. PMID- 25548941 TI - Symmetric and asymmetric meniscus collapse in wetting transition on submerged structured surfaces. AB - The wetting transition from the Cassie-Baxter to the Wenzel state is a phenomenon critically pertinent to the functionality of microstructured superhydrophobic surfaces. This work focuses on the last stage of the transition, when the liquid gas interface touches the bottom of the microstructure, which is also known as the "collapse" phenomenon. The process was examined in situ on a submerged surface patterned with cylindrical micropores using confocal microscopy. Both symmetric and asymmetric collapses were observed. The latter significantly shortens the progression of the metastable state prior to the collapse when compared with the former and hence may affect the lifespan of superhydrophobicity. Further experiments identified that asymmetric collapse were induced by impurities due to prior use of the structure. The problem is thus of broad relevance, since endurance through cycles is a practical requirement for these functional surfaces. Finally, the use of hierarchical structures is proposed as a remedy. The embedded self-cleaning mechanism serves to effectively remove the impurities, so as to avoid the triggering mechanism for asymmetric collapses. PMID- 25548942 TI - Detection of Listeria monocytogenes with short peptide fragments from class IIa bacteriocins as recognition elements. AB - We employed a direct peptide-bacteria binding assay to screen peptide fragments for high and specific binding to Listeria monocytogenes. Peptides were screened from a peptide array library synthesized on cellulose membrane. Twenty four peptide fragments (each a 14-mer) were derived from three potent anti-listerial peptides, Leucocin A, Pediocin PA1, and Curvacin A, that belong to class IIa bacteriocins. Fragment Leu10 (GEAFSAGVHRLANG), derived from the C-terminal region of Leucocin A, displayed the highest binding among all of the library fragments toward several pathogenic Gram-positive bacteria, including L. monocytogenes, Enterococcus faecalis, and Staphylococcus aureus. The specific binding of Leu10 to L. monocytogenes was further validated using microcantilever (MCL) experiments. Microcantilevers coated with gold were functionalized with peptides by chemical conjugation using a cysteamine linker to yield a peptide density of ~4.8*10(-3) MUmol/cm2 for different peptide fragments. Leu10 (14-mer) functionalized MCL was able to detect Listeria with same sensitivity as that of Leucocin A (37-mer) functionalized MCL, validating the use of short peptide fragments in bacterial detection platforms. Fragment Leu10 folded into a helical conformation in solution, like that of native Leucocin A, suggesting that both Leu10 and Leucocin A may employ a similar mechanism for binding target bacteria. The results show that peptide-conjugated microcantilevers can function as highly sensitive platforms for Listeria detection and hold potential to be developed as biosensors for pathogenic bacteria. PMID- 25548943 TI - Quantitative spatial analysis of the mouse brain lipidome by pressurized liquid extraction surface analysis. AB - Here we describe a novel surface sampling technique termed pressurized liquid extraction surface analysis (PLESA), which in combination with a dedicated high resolution shotgun lipidomics routine enables both quantification and in-depth structural characterization of molecular lipid species extracted directly from tissue sections. PLESA uses a sealed and pressurized sampling probe that enables the use of chloroform-containing extraction solvents for efficient in situ lipid microextraction with a spatial resolution of 400 MUm. Quantification of lipid species is achieved by the inclusion of internal lipid standards in the extraction solvent. The analysis of lipid microextracts by nanoelectrospray ionization provides long-lasting ion spray which in conjunction with a hybrid ion trap-orbitrap mass spectrometer enables identification and quantification of molecular lipid species using a method with successive polarity shifting, high resolution Fourier transform mass spectrometry (FTMS), and fragmentation analysis. We benchmarked the performance of the PLESA approach for in-depth lipidome analysis by comparing it to conventional lipid extraction of excised tissue homogenates and by mapping the spatial distribution and molar abundance of 170 molecular lipid species across different anatomical mouse brain regions. PMID- 25548944 TI - Efficient and ultrafast formation of long-lived charge-transfer exciton state in atomically thin cadmium selenide/cadmium telluride type-II heteronanosheets. AB - Colloidal cadmium chalcogenide nanosheets with atomically precise thickness of a few atomic layers and size of 10-100 nm are two-dimensional (2D) quantum well materials with strong and precise quantum confinement in the thickness direction. Despite their many advantageous properties, excitons in these and other 2D metal chalcogenide materials are short-lived due to large radiative and nonradiative recombination rates, hindering their applications as light harvesting and charge separation/transport materials for solar energy conversion. We showed that these problems could be overcome in type-II CdSe/CdTe core/crown heteronanosheets (with CdTe crown laterally extending on the CdSe nanosheet core). Photoluminesence excitation measurement revealed that nearly all excitons generated in the CdSe and CdTe domains localized to the CdSe/CdTe interface to form long-lived charge transfer excitons (with electrons in the CdSe domain and hole in the CdTe domain). By ultrafast transient absorption spectroscopy, we showed that the efficient exciton localization efficiency could be attributed to ultrafast exciton localization (0.64 +/- 0.07 ps), which was facilitated by large in-plane exciton mobility in these 2D materials and competed effectively with exiton trapping at the CdSe or CdTe domains. The spatial separation of electrons and holes across the CdSe/CdTe heterojunction effectively suppressed radiative and nonradiative recombination processes, leading to a long-lived charge transfer exciton state with a half-life of ~ 41.7 +/- 2.5 ns, ~ 30 times longer than core only CdSe nanosheets. PMID- 25548945 TI - Effect of polyethylene glycol conjugation on conformational and colloidal stability of a monoclonal antibody antigen-binding fragment (Fab'). AB - We have investigated the effects of site specific "hinge" polyethylene glycol conjugation (PEGylation) on thermal, pH, and colloidal stability of a monoclonal antibody antigen-binding fragment (Fab') using a variety of biophysical techniques. The results obtained by circular dichroism (CD), ultraviolet (UV) absorbance, and fluorescence spectroscopy suggested that the physical stability of the Fab' is maximized at pH 6-7 with no apparent differences due to PEGylation. Temperature-induced aggregation experiments revealed that PEGylation was able to increase the transition temperature, as well as prevent the formation of visible and subvisible aggregates. Statistical comparison of the three-index empirical phase diagram (EPD) revealed significant differences in thermal and pH stability signatures between Fab' and PEG-Fab'. Upon mechanical stress, micro flow imaging (MFI) and measurement of the optical density at 360 nm showed that the PEG-Fab' had significantly higher resistance to surface-induced aggregation compared to the Fab'. Analysis of the interaction parameter, kD, indicated repulsive intermolecular forces for PEG-Fab' and attractive forces for Fab'. In conclusion, PEGylation appears to protect Fab' against thermal and mechanical stress-induced aggregation, likely due to a steric hindrance mechanism. PMID- 25548946 TI - Modeling aerobic biodegradation in the capillary fringe. AB - Vapor intrusion from volatile subsurface contaminants can be mitigated by aerobic biodegradation. Laboratory column studies with contaminant sources of chlorobenzene and a mixture of chlorobenzene, 1,2-dichlorobenzene, and 1,4 dichlorobenzene showed that contaminants were rapidly degraded in thin reactive zones with high biomass and low substrate concentrations in the vicinity of the capillary fringe. Such behavior was well characterized by a model that includes oxygen-, substrate-, and biomass-dependent biodegradation kinetics along with diffusive transport processes. An analytical solution was derived to provide theoretical support for the simplification of reaction kinetics and the approximation of reactive zone location and mass flux relationships at steady state. Results demonstrate the potential of aerobic natural attenuation in the capillary fringe for preventing contaminant migration in the unsaturated zone. The solution indicates that increasing contaminant mass flux into the column creates a thinner reactive zone and pushes it toward the oxygen boundary, resulting in a shorter distance to the oxygen source and a larger oxygen mass flux that balances the contaminant mass flux. As a consequence, the aerobic biodegradation can reduce high contaminant concentrations to low levels within the capillary fringe and unsaturated zone. The results are consistent with the observations of thin reactive layers at the interface in unsaturated zones. The model considers biomass while including biodegradation in the capillary fringe and unsaturated zone and clearly demonstrates that microbial communities capable of using the contaminants as electron donors may lead to instantaneous degradation kinetics in the capillary fringe and unsaturated zone. PMID- 25548948 TI - Fluorescence activation imaging of cytochrome c released from mitochondria using aptameric nanosensor. AB - We have developed an aptameric nanosensor for fluorescence activation imaging of cytochrome c (Cyt c). Fluorescence imaging tools that enable visualization of key molecular players in apoptotic signaling are essential for cell biology and clinical theranostics. Cyt c is a major mediator in cell apoptosis. However, fluorescence imaging tools allowing direct visualization of Cyt c translocation in living cells have currently not been realized. We report for the first time the realization of a nanosensor tool that enables direct fluorescence activation imaging of Cyt c released from mitochondria in cell apoptosis. This strategy relies on spatially selective cytosolic delivery of a nanosensor constructed by assembly of a fluorophore-tagged DNA aptamer on PEGylated graphene nanosheets. The cytosolic release of Cyt c is able to dissociate the aptamer from graphene and trigger an activated fluorescence signal. The nanosensor is shown to exhibit high sensitivity and selectivity, rapid response, large signal-to-background ratio for in vitro, and intracellular detection of Cyt c. It also enables real time visualization of the Cyt c release kinetics and direct identification of the regulators for apoptosis. The developed nanosensor may provide a very valuable tool for apoptotic studies and catalyze the fundamental interrogations of Cyt c mediated biology. PMID- 25548950 TI - A testing platform for durability studies of polymers and fiber-reinforced polymer composites under concurrent hygrothermo-mechanical stimuli. AB - The durability of polymers and fiber-reinforced polymer composites under service condition is a critical aspect to be addressed for their robust designs and condition-based maintenance. These materials are adopted in a wide range of engineering applications, from aircraft and ship structures, to bridges, wind turbine blades, biomaterials and biomedical implants. Polymers are viscoelastic materials, and their response may be highly nonlinear and thus make it challenging to predict and monitor their in-service performance. The laboratory scale testing platform presented herein assists the investigation of the influence of concurrent mechanical loadings and environmental conditions on these materials. The platform was designed to be low-cost and user-friendly. Its chemically resistant materials make the platform adaptable to studies of chemical degradation due to in-service exposure to fluids. An example of experiment was conducted at RT on closed-cell polyurethane foam samples loaded with a weight corresponding to ~50% of their ultimate static and dry load. Results show that the testing apparatus is appropriate for these studies. Results also highlight the larger vulnerability of the polymer under concurrent loading, based on the higher mid-point displacements and lower residual failure loads. Recommendations are made for additional improvements to the testing apparatus. PMID- 25548949 TI - Expansion of bisindole biosynthetic pathways by combinatorial construction. AB - Cladoniamides are indolotryptoline natural products that derive from indolocarbazole precursors. Here, we present a microbial platform to artificially redirect the cladoniamide pathway to generate unnatural bisindoles for drug discovery. Specifically, we target glycosyltransferase, halogenase, and oxidoreductase genes from the phylogenetically related indolocarbazole rebeccamycin and staurosporine pathways. We generate a series of novel compounds, reveal details about the substrate specificities of a number of enzymes, and set the stage for future efforts to develop new catalysts and compounds by engineering of bisindole genes. The strategy for structural diversification we use here could furthermore be applied to other natural product families with known biosynthetic genes. PMID- 25548947 TI - A journey in science: early lessons from the hemoglobin field. AB - Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by David J Weatherall, Founder, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital. A visionary in the field of hemoglobin, this is the story of Professor Weatherall's scientific journey. PMID- 25548951 TI - Contact angle distribution of particles at fluid interfaces. AB - Recent measurements have implied a distribution of interfacially adsorbed particles' contact angles; however, it has been impossible to measure statistically significant numbers for these contact angles noninvasively in situ. Using a new microscopy method that allows nanometer-scale resolution of particle's 3D positions on an interface, we have measured the contact angles for thousands of latex particles at an oil/water interface. Furthermore, these measurements are dynamic, allowing the observation of the particle contact angle with high temporal resolution, resulting in hundreds of thousands of individual contact angle measurements. The contact angle has been found to fit a normal distribution with a standard deviation of 19.3 degrees , which is much larger than previously recorded. Furthermore, the technique used allows the effect of measurement error, constrained interfacial diffusion, and particle property variation on the contact angle distribution to be individually evaluated. Because of the ability to measure the contact angle noninvasively, the results provide previously unobtainable, unique data on the dynamics and distribution of the adsorbed particles' contact angle. PMID- 25548952 TI - Optically transparent thin-film transistors based on 2D multilayer MoS2 and indium zinc oxide electrodes. AB - We report on optically transparent thin film transistors (TFTs) fabricated using multilayered molybdenum disulfide (MoS2) as the active channel, indium tin oxide (ITO) for the back-gated electrode and indium zinc oxide (IZO) for the source/drain electrodes, respectively, which showed more than 81% transmittance in the visible wavelength. In spite of a relatively large Schottky barrier between MoS2 and IZO, the n-type behavior with a field-effect mobility (MU(eff)) of 1.4 cm(2) V(-1) s(-1) was observed in as-fabricated transparent MoS2 TFT. In order to enhance the performances of transparent MoS2 TFTs, a picosecond pulsed laser was selectively irradiated onto the contact region of the IZO electrodes. Following laser annealing, MU(eff) increased to 4.5 cm(2) V(-1) s(-1), and the on off current ratio (I(on)/I(off)) increased to 10(4), which were attributed to the reduction of the contact resistance between MoS2 and IZO. PMID- 25548953 TI - Nanopore fabrication by heating Au particles on ceramic substrates. AB - We found that gold nanoparticles, when heated to close to their melting point on substrates of amorphous SiO2 or amorphous Si3N4, move perpendicularly into the substrate. Dependent on applied temperatures, particles can become buried or leave nanopores of extreme aspect ratio (diameter ? 25 nm, length up to 800 nm). The process can be understood as driven by gold evaporation and controlled by capillary forces and can be controlled by temperature programming and substrate choice. PMID- 25548954 TI - Computational biotransformation profile of paracetamol catalyzed by cytochrome P450. AB - The P450-catalyzed biotransformation of the analgesic drug paracetamol (PAR) is a long-debated topic, involving different mechanistic hypotheses as well as experimental evidence for the metabolites N-acetyl-p-benzoquinone imine (NAPQI), p-benzoquinone, acetamide, and 3-hydroxy-PAR. During the catalytic cycle of P450, a high-valent iron(IV)-oxo species known as Compound I (Cpd I) is formed as the ultimate oxidant, featuring two energetically close-lying ground states in the doublet (low-spin) and quartet (high-spin) spin states, respectively. In order to clarify the catalytic mechanism, a computational chemistry analysis has been undertaken for both the high- and low-spin routes, employing density functional theory (DFT) including PCM (polarized continuum-solvation model) that yields an approximate simulation of the bulk polarization exerted through the protein. The results demonstrate that hydrogen abstraction transfer (HAT) by the P450 oxidant Cpd I (FeO) is kinetically strongly preferred over the alternative pathways of an oxygen addition reaction (OAR) or two consecutive single-electron transfers (SET). Moreover, only the respective high-spin route yields N-acetyl-p semiquinone imine (NAPSQI) as an intermediate that is converted to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). By contrast, 3-hydroxy-PAR, acetamide, and p-benzoquinone as electrophilic and redox-active agent are formed predominantly in the low-spin state through reactions that do not involve NAPSQI. Thus, all experimentally observed PAR metabolites are in accord with an initial HAT from the phenolic oxygen, and NAPSQI should indeed be the precursor of NAPQI, both of which are generated only via the high-spin pathway. PMID- 25548955 TI - Methods for skin wounding and assays for wound responses in C. elegans. AB - The C. elegans epidermis and cuticle form a simple yet sophisticated skin layer that can repair localized damage resulting from wounding. Studies of wound responses and repair in this model have illuminated our understanding of the cytoskeletal and genomic responses to tissue damage. The two most commonly used methods to wound the C. elegans adult skin are pricks with microinjection needles, and local laser irradiation. Needle wounding locally disrupts the cuticle, epidermis, and associated extracellular matrix, and may also damage internal tissues. Laser irradiation results in more localized damage. Wounding triggers a succession of readily assayed responses including elevated epidermal Ca(2+) (seconds-minutes), formation and closure of an actin-containing ring at the wound site (1-2 hr), elevated transcription of antimicrobial peptide genes (2 24 hr), and scar formation. Essentially all wild type adult animals survive wounding, whereas mutants defective in wound repair or other responses show decreased survival. Detailed protocols for needle and laser wounding, and assays for quantitation and visualization of wound responses and repair processes (Ca dynamics, actin dynamics, antimicrobial peptide induction, and survival) are presented. PMID- 25548956 TI - Mixed pentele-chalcogen cationic chains from aluminum and gallium halide melts. AB - The reactions of tellurium or selenium with bismuth or antimony in chloridogallate and iodidoaluminate melts in the presence of group 15 trihalides as weak oxidants yielded the compounds (Sb2Te2)[GaCl4] (1), (Sb2Te2)I[AlI4] (2), (Bi2Te2)Cl[GaCl4] (3a), (Bi2Se2)Cl[GaCl4] (3b), (Sb3Te4)[GaCl4] (4), and (SbTe4)[Ga2Cl7] (5). In the crystal structures one-dimensional polymeric cations (Sb2Te2(+))n (1), (Sb2Te2(2+))n (2), (Bi2Te2(2+))n (3a), (Bi2Se2(2+))n (3b), (Sb3Te4(+))n (4), and (SbTe4(+))n (5) are present. The polymeric cationic strands in 2, 3a, 3b, and 4 consist of pentele/chalcogen dumbbells, which are connected to ladder-shaped bands. The strands in 1 and 5 consist of condensed rings that involve four-membered Sb2Te2 rings for 1, and five-membered SbTe4 rings for 5. The counteranions are the weakly coordinating [GaCl4](-), [AlI4](-), and [Ga2Cl7](-) in addition to Cl(-) and I(-) anions, which are coordinated to the atoms of the cations. The crystal structures of 1-4 are characterized by a statistical disorder in the anions with alternatively occupied positions for the Al and Ga atoms. For 4 superstructure reflections appear in the diffractions patterns, indicating a partial order. A correct assignment of the Sb and Te positions in the cation of 5 was achieved by periodic quantum-chemical calculations, which were performed via a Hartree-Fock density functional theory hybrid method. A clear preference of the 4-fold coordinated site was obtained for Sb. PMID- 25548958 TI - Plasmon-induced efficiency enhancement on dye-sensitized solar cell by a 3D TNW AuNP layer. AB - A new 3D TNW-AuNP plasmonic electrode consists of antireflective (AR) TiO2 nanowires (TNWs) (~600 nm thickness) serving as light-harvesting antennae coupling with Au nanoparticles (NPs). A huge red-shift of 55 nm is observed in surface plasmon spectra for the Au (11 nm) plasmonic electrode that has 11 nm size Au NPs, whereby (111) lattice planes have a specific bonding with the TiO2 (101) planes. Remarkable red-shift is mainly attributed to the localized electric field improvement resulting from the plasmonic coupling effect between the Au NPs and the Au-TiO2 hybrids. After TiCl4 treatment, this favorable Au (11 nm) nanostructure takes advantage of harvesting photons to increase the conversion efficiency of dye-sensitized solar cells (DSSCs) from 6.25% to 9.73%. PMID- 25548957 TI - Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients. AB - Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials. PMID- 25548959 TI - Tailor-made polyamide membranes for water desalination. AB - Independent control of the extrinsic and intrinsic properties of the polyamide (PA) selective layer is essential for designing thin-film composite (TFC) membranes with performance characteristics required for water purification applications besides seawater desalination. Current commercial TFC membranes fabricated via the well-established interfacial polymerization (IP) approach yield materials that are far from ideal because their layer thickness, surface roughness, polymer chemistry, and network structure cannot be separately tailored. In this work, tailor-made PA-based desalination membranes based on molecular layer-by-layer (mLbL) assembly are presented. The mLbL technique enables the construction of an ultrathin and highly cross-linked PA selective layer in a precisely and independently controlled manner. The mLbL-assembled TFC membranes exhibit significant enhancements in performance compared to their IP assembled counterparts. A maximum sodium chloride rejection of 98.2% is achieved along with over 2.5 times higher water flux than the IP-assembled counterpart. More importantly, this work demonstrates the broad applicability of mLbL in fabricating a variety of PA-based TFC membranes with nanoscale control of the selective layer thickness and roughness independent of the specific polyamide chemistry. PMID- 25548960 TI - A novel model of mild traumatic brain injury for juvenile rats. AB - Despite growing evidence that childhood represents a major risk period for mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls, a reliable animal model of mTBI had previously not been developed for this important aspect of development. The modified weight-drop technique employs a glancing impact to the head of a freely moving rodent transmitting acceleration, deceleration, and rotational forces upon the brain. When applied to juvenile rats, this modified weight-drop technique induced clinically relevant behavioural outcomes that were representative of post concussion symptomology. The technique is a rapidly applied procedure with an extremely low mortality rate, rendering it ideal for high-throughput studies of therapeutics. In addition, because the procedure involves a mild injury to a closed head, it can easily be used for studies of repetitive brain injury. Owing to the simplistic nature of this technique, and the clinically relevant biomechanics of the injury pathophysiology, the modified weight-drop technique provides researchers with a reliable model of mTBI that can be used in a wide variety of behavioural, molecular, and genetic studies. PMID- 25548961 TI - Preconception care policy, guidelines, recommendations and services across six European countries: Belgium (Flanders), Denmark, Italy, the Netherlands, Sweden and the United Kingdom. AB - OBJECTIVES: Preconception care is important for the screening, prevention and management of risk factors that affect pregnancy outcomes. We aimed to investigate pre-pregnancy care policies, guidelines, recommendations and services in six European countries. METHODS: In 2013, an electronic search and investigation was undertaken of preconception policy, guidelines, recommendations and services available to healthcare professionals and the general public in six European countries: Belgium (Flanders), Denmark, Italy, the Netherlands, Sweden and the United Kingdom. Findings were compared within five categories: Governmental policy and legislation; Professional bodies and organisations; Healthcare providers; Charitable organisations; Web-based public information and internet sites. RESULTS: All countries had preconception recommendations for women with chronic diseases, such as diabetes and epilepsy. Recommendations for healthy women and men were fragmented and inconsistent. Preconception guidance was often included in antenatal and pregnancy guidelines. Differences between countries were seen with regard to nutritional and lifestyle advice particularly in relation to fish, caffeine and alcohol consumption, and vitamin supplementation. CONCLUSIONS: Current guidelines are heterogeneous. Collaborative research across Europe is required in order to develop evidence-based guidelines for preconception health and care. There is a need to establish a clear strategy for promoting advice and guidance within the European childbearing population. PMID- 25548962 TI - Computational study of the "DFG-flip" conformational transition in c-Abl and c Src tyrosine kinases. AB - Protein tyrosine kinases are crucial to cellular signaling pathways regulating cell growth, proliferation, metabolism, differentiation, and migration. To maintain normal regulation of cellular signal transductions, the activities of tyrosine kinases are also highly regulated. The conformation of a three-residue motif Asp-Phe-Gly (DFG) near the N-terminus of the long "activation" loop covering the catalytic site is known to have a critical impact on the activity of c-Abl and c-Src tyrosine kinases. A conformational transition of the DFG motif can switch the enzyme from an active (DFG-in) to an inactive (DFG-out) state. In the present study, the string method with swarms-of-trajectories was used to computationally determine the reaction pathway connecting the two end-states, and umbrella sampling calculations were carried out to characterize the thermodynamic factors affecting the conformations of the DFG motif in c-Abl and c-Src kinases. According to the calculated free energy landscapes, the DFG-out conformation is clearly more favorable in the case of c-Abl than that of c-Src. The calculations also show that the protonation state of the aspartate residue in the DFG motif strongly affects the in/out conformational transition in c-Abl, although it has a much smaller impact in the case of c-Src due to local structural differences. PMID- 25548963 TI - Metformin reduces serum CA199 levels in type 2 diabetes Chinese patients with time-effect and gender difference. AB - BACKGROUND: This study was designed to clarify the influence of metformin on serum carbohydrate antigen 199 (CA199) levels and its associated factors in Chinese type 2 diabetes mellitus (T2DM) patients. SUBJECTS AND METHODS: In total, 1,253 T2DM patients were enrolled, including a non-metformin group (n = 616), a short-term metformin group (at least 1 week to 2 years; n=325), and a long-term metformin group (>= 2 years; n = 312). Their clinical and biochemical characteristics were collected and compared. After 1 year, the biochemical parameters were re-examined in 296 patients. Sex hormones were determined, and associations between CA199 and other variables were assessed. RESULTS: At baseline, the incidence of abnormal CA199 levels was 14.7%, 8.9%, and 4.7% in the non-metformin, short-term metformin, and long-term metformin groups, respectively. CA199 levels in females were significantly higher than in males (P < 0.01) and decreased significantly with the time of taking metformin (25.60 +/- 13.68 U/mL in non-metformin controls vs. 17.62 +/- 10.87 U/mL in the short-term group vs. 10.54 +/- 8.14 U/mL in the long-term group; P = 0.000). The correlation and multiple stepwise regression analysis revealed that glycosylated hemoglobin, metformin, gender, total cholesterol, and follicle-stimulating hormone were independent impact factors on CA199 concentrations (all P < 0.05). Binary logistic regression revealed that the risk of abnormal CA199 concentrations of the total population with short-term metformin or long-term metformin treatment decreased 11% (odds ratio = 0.89; P = 0.001) and 30% (odds ratio = 0.70; P = 0.000), respectively, at baseline. After a 1-year follow-up, the incidence of high CA199 level decreased in both the short-term and the long-term metformin group compared with that of controls (P < 0.05). The extent of CA199 decrease in the long-term metformin group was the greatest (-17% vs. -4.9% in the short-term group vs. 3% in controls, P = 0.000), and the group's risk of high blood CA199 level was reduced 67% (odds ratio = 0.33; P = 0.023). The reduction in women was more apparent than that in men (-18% vs. -5%, P = 0.000). CONCLUSIONS: Metformin therapy reduced the CA199 level in Chinese T2DM patients, and its greatest decrease occurred in women with longer therapeutic time. PMID- 25548964 TI - Management of appendiceal stump in laparoscopic appendectomy--clips or ligature: a systematic review and meta-analysis. AB - BACKGROUND: Appendicular stump closure is a crucial step during laparoscopic appendectomy. Recently, endoclips (ECs) have been described for ligation of the appendicular stump. The objective of this review was to compare outcomes with EC versus endoligature (EL) for appendiceal stump closure during laparoscopic appendectomy. MATERIALS AND METHODS: A literature search of Medline, Embase, Cochrane Database, and Google Scholar was performed to identify studies comparing use of EL versus EC in laparoscopic appendectomy between January 1992 and September 2013. Reviews of each study were conducted, and data were extracted. The random-effects model was used to combine data, and between-study heterogeneity was assessed. RESULTS: Seven of the 101 identified studies met the inclusion criteria: four randomized controlled trials and three case controlled series. For the primary outcome of perioperative and postoperative complications, there was no significant difference between the EC versus EL groups. No differences were noted in length of hospital stay. However, a significant reduction in operative time was observed with EC as opposed to EL (standardized mean difference=-0.90, 95% confidence interval=-1.26 to -0.54, P=.001). Moreover, EC procedures were less expensive than EL procedures. CONCLUSIONS: EC application in the management of appendiceal stump during laparoscopic appendectomy appears to be simple, efficacious, safe, and a cost-effective alternative. PMID- 25548965 TI - The association between ambulatory blood pressure profile and brachial-ankle pulse wave velocity in untreated hypertensive subjects. AB - The study aim was to investigate the relationship between blood pressure (BP) profile of ambulatory BP monitoring (ABPM) and brachial-ankle pulse wave velocity (baPWV). A total of 196 untreated hypertensive subjects (103 women, age 54.7 +/- 12.4 years) who underwent both baPWV measurement and ABPM were analyzed. Systolic dipping of < 10% was defined as a non-dipper. Eighty subjects (40.8%) were non dippers. The baPWV values were similar between dippers and non-dippers (1609 +/- 293 vs 1539 +/- 240, p = 0.070). In multiple regression analyses, after controlling age, height and heart rate, daytime systolic BP (SBP) (beta = 0.346, p < 0.001) and night-time SBP (beta = 0.244, p = 0.006) had significant positive associations with baPWV in women but not in men. Diastolic BP and dipping status were not associated with baPWV in either gender. Univariate analysis after further stratification of women according to postmenopausal status showed significant correlations of daytime SBP (beta = 0.317, p = 0.007) and night-time SBP (beta = 0.339, p = 0.004) with baPWV in postmenopausal women but not in premenopausal women. These results suggest that age and gender effects should be considered in the interpretation of the association between BP and arterial stiffness. PMID- 25548966 TI - Evaluating measurement error in readings of blood pressure for adolescents and young adults. AB - Readings of blood pressure are known to be subject to measurement error, but the optimal method for combining multiple readings is unknown. This study assesses different sources of measurement error in blood pressure readings and assesses methods for combining multiple readings using data from a sample of adolescents/young adults who were part of a longitudinal epidemiological study based in Cebu, Philippines. Three sets of blood pressure readings were collected at 2-year intervals for 2127 adolescents and young adults as part of the Cebu National Longitudinal Health and Nutrition Study. Multi-trait, multi-method (MTMM) structural equation models in different groups were used to decompose measurement error in the blood pressure readings into systematic and random components and to examine patterns in the measurement across males and females and over time. The results reveal differences in the measurement properties of blood pressure readings by sex and over time that suggest the combination of multiple readings should be handled separately for these groups at different time points. The results indicate that an average (mean) of the blood pressure readings has high validity relative to a more complicated factor-score-based linear combination of the readings. PMID- 25548967 TI - LATCH scores and milk intake in preterm and term infants: a prospective comparative study. AB - OBJECTIVES: We aimed to detect the breastmilk intake in preterm and term infants and to determine if the LATCH scoring system (latch; audible swallowing; type of nipple; comfort [breast/nipple]; hold [positioning]) could be helpful to denote that infants have taken enough breastmilk according to their postnatal age and weight. MATERIALS AND METHODS: Sixty-six breastfeeding sessions were monitored and scored simultaneously by using the LATCH scoring system. The weight of the 66 infants (33 preterm, 33 term) was measured before and after a breastfeeding session, and thereby milk intake by breastfeeding was determined. The expected amount of milk volume that infants should receive for each feeding session was calculated according to the postnatal age and weight. The breastmilk intake by breastfeeding was compared with LATCH scores and the expected milk volume for each feeding. RESULTS: We observed that 25 term infants (75.8%) took 100% of the expected milk volume for each feeding session, compared with two preterm infants (2.1%) (p=0.009). The median LATCH scores were 7.0 (minimum-maximum=5-9) in preterm babies and 9 (minimum-maximum=7-10) in term babies (p<0.0001). Term babies could consume 95.4% of the expected milk volume for each feeding session, whereas this ratio was only 45% in preterm babies. In each group, babies receiving a score of >=7 took at least 50% of the expected milk volume for each feeding session. In each group, higher LATCH scores were associated with higher median intake, but the minimum and maximum intake for each LATCH score revealed marked variability. CONCLUSIONS: High LATCH scores (7-10) may be helpful to determine that infants take at least 50% of the expected breastmilk volume for each feeding in both preterm and term infants. However, LATCH scores cannot substitute for test weights in premature infants because of variability in minimum and maximum milk intake per LATCH score. PMID- 25548968 TI - Inhibitory effects of Cyperus digitatus extract on human platelet function in vitro. AB - The purpose of this research was to investigate the mechanisms of antiplatelet action of Cyperus digitatus. The antiplatelet action of C. digitatus was studied on platelet function: secretion, adhesion, aggregation, and sCD40L release. The platelet ATP secretion and aggregation were significantly inhibited by CDA (ethyl acetate extract) at 0.1 mg/ml and after the incubation of whole blood with CDA, the platelet coverage was inhibited by 96 +/- 3% (p < 0.001). At the same concentration, CDA significantly decreased sCD40L levels. The mechanism of antiplatelet action of CDA could be by NF-kappaB inhibition and that is cAMP independent. In conclusion, C. digitatus extract may serve as a new source of antiplatelet agents for food and nutraceutical applications. PMID- 25548971 TI - Translational Data from AAV-Mediated Gene Therapy of Hemophilia B in Dogs. AB - Pre-clinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). With regards to pre-clinical studies of AAV-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% factor IX, FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible endpoints in these dogs. This review compares the pre-clinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle and liver -based approaches. PMID- 25548969 TI - Pigment epithelium-derived factor regulates glutamine synthetase and l glutamate/l-aspartate transporter in retinas with oxygen-induced retinopathy. AB - PURPOSE: A predominant function of Muller cells is to regulate glutamate levels, but these cells are compromised in oxygen-induced retinopathy. The aim of this study was to investigate the role of pigment epithelium-derived factor (PEDF) in regulating glutamate levels in retina under hypoxia. MATERIALS AND METHODS: One week-old C57BL/6J mice were exposed to 75% oxygen for 5 days and then kept in room air for another 5 days to establish the oxygen-induced retinopathy (OIR) mouse model. Mice received intravitreous injections of 2 MUg PEDF or vehicle on postnatal (P)12 and P14, respectively. Antibody against interleukin-1Beta (IL 1beta) (IL-1ab) was used to neutralize the activity of IL-1beta, mice received intravitreous injections of 500 ng IL-1ab or vehicle on P12 and P14, respectively, too. At P17, the mice were euthanized and their eyes were enucleated. The expression levels of IL-1beta, glutamine synthetase (GS) and l glutamate/l-aspartate transporter (GLAST) in retinas with different treatments were detected. In addition, wild-type C57BL/6J mice received intravitreous injections of IL-1beta or PEDF. After 24 h, the expression of GS and GLAST in the retinas was also detected. Furthermore, high-performance liquid chromatography (HPLC) was performed to determine the glutamate concentrations in retinas with different treatments. RESULTS: The expression of IL-1beta and levels of glutamate were increased in retinas with OIR, while the expression of GS and GLAST was decreased. Administration of PEDF ameliorated the characteristic changes in retinas of OIR mice. And neutralization of IL-1beta by administration of IL-1ab increased GS and GLAST expression in retinas with OIR. Moreover, the effects of IL-1beta on GS and GLAST expression and unbalanced glutamate levels were inhibited after receiving intravitreous injections of PEDF in retinas of normal mice. CONCLUSIONS: These results suggested that PEDF might up-regulate GS and GLAST expression and decrease glutamate levels by suppressing the role of IL 1beta as an anti-inflammatory factor under hypoxia, and these functions may underlie the neuroprotective effects of PEDF. PMID- 25548970 TI - Developing authentic clinical simulations for effective listening and communication in pediatric rehabilitation service delivery. AB - PURPOSE: To describe the creation and validation of six simulations concerned with effective listening and interpersonal communication in pediatric rehabilitation. METHODS AND FINDINGS: The simulations involved clinicians from various disciplines, were based on clinical scenarios related to client issues, and reflected core aspects of listening/communication. Each simulation had a key learning objective, thus focusing clinicians on specific listening skills. The article outlines the process used to turn written scenarios into digital video simulations, including steps taken to establish content validity and authenticity, and to establish a series of videos based on the complexity of their learning objectives, given contextual factors and associated macrocognitive processes that influence the ability to listen. A complexity rating scale was developed and used to establish a gradient of easy/simple, intermediate, and hard/complex simulations. CONCLUSIONS: The development process exemplifies an evidence-based, integrated knowledge translation approach to the teaching and learning of listening and communication skills. PMID- 25548972 TI - Is the level of maternal serum prohepcidin associated with preeclampsia? AB - OBJECTIVE: The objective of the study was to compare pro-hepcidin, hemoglobin (Hb) concentration, hematocrit (Hct), C-reactive protein (CRP), IL-6 and iron status parameters in preeclamptic (PE) and healthy pregnant women, and to examine the relationship between serum pro-hepcidin levels and iron parameters of preeclampsia (PE). METHODS: In a prospective controlled study, we collected serum from women with normal pregnancy (n = 37) and from women with PE (n = 30) at the Department of Obstetrics and Gynecology at Turgut Ozal University between February 2010 and January 2013. Pro-hepcidin, hemoglobin (Hb) concentration, hematocrit (Hct), CRP, IL-6 and iron status parameters were measured in all patients and compared between groups. RESULTS: Levels of serum prohepcidin in PE and control groups were similar and amount 69.4 +/- 19.7 and 71.9 +/- 22.1 ng/ml, respectively. The difference was not statistically significant (p: 0.694). On the other hand, the study group had a statistically lower iron binding capacity (IBC), total iron binding capacity, transferin, total protein, albumin levels (p < 0.05). No significant differences were found among prohepcidin, Hb concentration, Hct, iron, ferritin, IL-6, urea and creatine in both the groups. CONCLUSION: In pregnancies complicated by PE with normal values of hemoglobin and hematocrit, serum prohepcidin concentrations are similar to those observed in healthy pregnant women. The analysis revealed no significant correlations between prohepcidin level and serum iron, serum ferritin or transferrin in the PE. PMID- 25548973 TI - Peer reactions to early childhood aggression in a preschool setting: Defenders, encouragers, or neutral bystander. AB - PURPOSE: The purpose of the current study was to determine if peer reactions to aggression among preschool youth were consistent with those conceptualized in the adolescent bullying literature as defenders, encouragers, and neutral bystanders. RESEARCH DESIGN: Direct observations were used to document patterns for types of peer-directed aggression in early childhood settings to ascertain interaction differences between individuals involved within the bullying dynamic. METHODS AND PROCEDURES: Observations of 50 students in preschool were conducted over 5.5 months. Event recording procedures were used to document aggressive behaviors and reactions from peers and teachers. RESULTS: Results indicated that the majority of aggression was physical. Additionally, peer reactions, as described in the bullying literature for school-aged youth, occurred very infrequently. CONCLUSION: Peer aggression tended to be more physical, suggesting that early childhood educators should attend to these physical interactions, and cultivate a classroom community that emphasizes social supports and appropriate interactions. PMID- 25548974 TI - Augmenting anti-cancer natural products with a small molecule adjuvant. AB - Aquatic microbes produce diverse secondary metabolites with interesting biological activities. Cytotoxic metabolites have the potential to become lead compounds or drugs for cancer treatment. Many cytotoxic compounds, however, show undesirable toxicity at higher concentrations. Such undesirable activity may be reduced or eliminated by using lower doses of the cytotoxic compound in combination with another compound that modulates its activity. Here, we have examined the cytotoxicity of four microbial metabolites [ethyl N-(2-phenethyl) carbamate (NP-1), Euglenophycin, Anabaenopeptin, and Glycolipid 652] using three in vitro cell lines [human breast cancer cells (MCF-7), mouse neuroblastoma cells (N2a), and rat pituitary epithelial cells (GH4C1)]. The compounds showed variable cytotoxicity, with Euglenophycin displaying specificity for N2a cells. We have also examined the modulatory power of NP-1 on the cytotoxicity of the other three compounds and found that at a permissible concentration (125 ug/mL), NP-1 sensitized N2a and MCF-7 cells to Euglenophycin and Glycolipid 652 induced cytotoxicity. PMID- 25548975 TI - Sulfated galactofucan from the brown alga Saccharina latissima--variability of yield, structural composition and bioactivity. AB - The fucose-containing sulfated polysaccharides (SP) from brown algae exhibit a wide range of bioactivities and are, therefore, considered promising candidates for health-supporting and medicinal applications. A critical issue is their availability in high, reproducible quality. The aim of the present study was to fractionate and characterize the SP extracted from Saccharina latissima (S.l.-SP) harvested from two marine habitats, the Baltic Sea and North Atlantic Ocean, in May, June and September. The fractionation of crude S.l.-SP by anion exchange chromatography including analytical investigations revealed that S.l.-SP is composed of a homogeneous fraction of sulfated galactofucan (SGF) and a mixture of low-sulfated, uronic acid and protein containing heteropolysaccharides. Furthermore, the results indicated that S.l. growing at an intertidal zone with high salinity harvested at the end of the growing period delivered the highest yield of S.l.-SP with SGF as the main fraction (67%). Its SGF had the highest degree of sulfation (0.81), fucose content (86.1%) and fucose/galactose ratio (7.8) and was most active (e.g., elastase inhibition: IC50 0.21 MUg/mL). Thus, S.l. from the North Atlantic harvested in autumn proved to be more appropriate for the isolation of S.l.-SP than S.l. from the Baltic Sea and S.l. harvested in spring, respectively. In conclusion, this study demonstrated that habitat and harvest time of brown algae should be considered as factors influencing the yield as well as the composition and thus also the bioactivity of their SP. PMID- 25548977 TI - Diabetes, myocardial infarction and stroke are distinct and duration-dependent predictors of subsequent cardiovascular events and all-cause mortality in older men. AB - CONTEXT: The impact of older age and duration of diabetes mellitus on macrovascular complications is unclear. OBJECTIVE: We tested the hypothesis that in older men, diabetes duration predicts incident cardiovascular events and death, differently from prior myocardial infarction (MI) or stroke. DESIGN, SETTING, AND PARTICIPANTS: This was a longitudinal cohort study of 11 728 community-dwelling men aged >= 65 years in Perth, Western Australia, recruited in 1996-1999. MAIN OUTCOME MEASURES: We assessed all-cause mortality, and deaths or hospital admissions with MI or stroke between recruitment and December 2010, analyzing age-specific hazard and adjusting for smoking, education, alcohol, exercise, BMI, hypertension, and hypercholesterolemia. RESULTS: Among 1433 (12.2%) men with diabetes, 208 (14.5%) reported age of onset of diabetes < 55 years, 451 (31.5%) 55-64 years, 679 (47.4%) 65-74 years with 95 (6.6%) > 74 years. Diabetes independently predicted increased all-cause mortality with hazard ratio (HR) of 1.37 (95% confidence interval [CI] = 1.15-1.62) for a duration of 5 9 years, 1.35 (1.18-1.55) for 10-14 years, 1.42 (1.22-1.66) for 15-19 years, and 1.75 (1.45-2.11) for 20-24 years. Mortality from MI was increased for diabetes duration up to 25 years, while stroke-specific mortality increased progressively with diabetes duration. Prior MI or stroke predicted increased risk of subsequent events peaking after 10-20 years. CONCLUSIONS: In older men, increasing duration of diabetes predicts stable increases in all-cause and MI-related mortality and a progressively higher risk of stroke deaths. Prior MI was associated with increased risk of subsequent MI, and prior stroke with subsequent stroke, particularly in the 10-20 years following the first event. Diabetes is a duration dependent risk factor for cardiovascular events which influences outcomes differently from prior vascular disease. PMID- 25548976 TI - Oxamflatin treatment enhances cloned porcine embryo development and nuclear reprogramming. AB - Faulty epigenetic reprogramming of somatic nuclei is thought to be the main reason for low cloning efficiency by somatic cell nuclear transfer (SCNT). Histone deacetylase inhibitors (HDACi), such as Scriptaid, improve developmental competence of SCNT embryos in several species. Another HDACi, Oxamflatin, is about 100 times more potent than Scriptaid in the ability to inhibit nuclear specific HDACs. The present study determined the effects of Oxamflatin treatment on embryo development, DNA methylation, and gene expression. Oxamflatin treatment enhanced blastocyst formation of SCNT embryos in vitro. Embryo transfer produced more pigs born and fewer mummies from the Oxamflatin-treated group compared to the Scriptaid-treated positive control. Oxamflatin also decreased DNA methylation of POU5F1 regulatory elements and centromeric repeat elements in day-7 blastocysts. When compared to in vitro-fertilized (IVF) embryos, the methylation status of POU5F1, NANOG, and centromeric repeat was similar in the cloned embryos, indicating these genes were successfully reprogrammed. However, compared to the lack of methylation of XIST in day-7 IVF embryos, a higher methylation level in day-7 cloned embryos was observed, implying that X chromosomes were activated in day-7 IVF blastocysts, but were not fully activated in cloned embryos, i.e., reprogramming of XIST was delayed. A time-course analysis of XIST DNA methylation on day-13, -15, -17, and -19 in vivo embryos revealed that XIST methylation initiated at about day 13 and was not completed by day 19. The methylation of the XIST gene in day-19 control cloned embryos was delayed again when compared to in vivo embryos. However, methylation of XIST in Oxamflatin treated embryos was comparable with in vivo embryos, which further demonstrated that Oxamflatin could accelerate the delayed reprogramming of XIST gene and thus might improve cloning efficiency. PMID- 25548979 TI - Pectoral fin breeding tubercle clusters: a method to determine zebrafish sex. PMID- 25548980 TI - Midazolam in palliative care: at what cost? PMID- 25548978 TI - Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials. AB - CONTEXT: The prevalence of sexual dysfunction, low vitality, and poor physical function increases with aging, as does the prevalence of low total and free testosterone (TT and FT) levels. However, the relationship between sex hormones and age-related alterations in older men is not clear. OBJECTIVE: To test the hypotheses that baseline serum TT, FT, estradiol (E2), and sex hormone-binding globulin (SHBG) levels are independently associated with sexual function, vitality, and physical function in older symptomatic men with low testosterone levels participating in the Testosterone Trials (TTrials). DESIGN: Cross sectional study of baseline measures in the TTrials. SETTING: The study was conducted at 12 sites in the United States. PARTICIPANTS: The 788 TTrials participants were >= 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT < 275 ng/dL. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Question 4 of Psychosocial Daily Questionnaire (PDQ-Q4), the FACIT-Fatigue Scale, and the 6-minute walk test. RESULTS: Baseline serum TT and FT, but not E2 or SHBG levels had small, but statistically significant associations with validated measures of sexual desire, erectile function, and sexual activity. None of these hormones was significantly associated within or across trials with FACIT-Fatigue, PHQ-9 Depression or Physical Function-10 scores, or gait speed. CONCLUSIONS: FT and TT levels were consistently, independently, and positively associated, albeit to a small degree, with measures of sexual desire, erectile function, and sexual activity, but not with measures of vitality or physical function in symptomatic older men with low T who qualified for the TTrials. PMID- 25548981 TI - IgG4-related Disease Masquerading as Recurrent Scleritis and Chronic Conjunctivitis. AB - PURPOSE: To report atypical ophthalmologic manifestations and complications of IgG4-related disease (IgG4-RD). METHODS: Patients with isolated ophthalmologic involvement of IgG4-RD other than lacrimal or orbital infiltration seen between 2009 and 2011 in a single tertiary center were retrospectively reviewed and their clinical and histological features, treatment, and prognosis were studied. CASE REPORTS: Two patients (mean age 56.5 years) were included. One patient presented with recurrent anterior and posterior scleritis, and one patient had chronic conjunctival infiltration. Histopathology demonstrated lymphoplasmacytic proliferation with overexpression of IgG4(+) plasma cells. Both patients initially responded to a high dose of oral corticosteroids (1 mg/kg/d). However, one patient required the adjunction of methotrexate and one patient developed an intra-epithelial conjunctival carcinoma on the site of the initial lesion. CONCLUSION: Patients with atypical presentation of IgG4-RD, such as chronic conjunctival infiltration or scleritis, can suffer from considerable diagnostic delay leading to fibrosis or malignancy development. We report the first case of conjunctival carcinoma in a patient with IgG4-RD. PMID- 25548983 TI - Lessons for tumor biomarker trials: vicious cycles, scientific method & developing guidelines. AB - Interview with Daniel Hayes, by Claire Raison (Commissioning Editor) Daniel F Hayes, M.D. is the Stuart A Padnos Professor of Breast Cancer Research and co Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center (Ann Arbor, MI, USA). Dr Hayes has extensive experience in clinical and translational breast cancer biomarker research, and in drug development and clinical trials. Around 30 years ago, he led the discovery of the circulating breast tumor biomarker, CA15-3, which started his career into further tumor biomarker work. The main thrust of his work since then has been in clinical trials, tumor biomarkers and trying to integrate the two. Dr Hayes is Chair of the Correlative Sciences Committee of the North American Breast Cancer Group (now called the Breast Cancer Steering Committee), and co-chairs the Expert Panel for Tumor Biomarker Practice Guidelines for the American Society of Clinical Oncology. PMID- 25548982 TI - Morphological variability and molecular identification of Uncinaria spp. (Nematoda: Ancylostomatidae) from grizzly and black bears: new species or phenotypic plasticity? AB - The hookworms Uncinaria rauschi Olsen, 1968 and Uncinaria yukonensis ( Wolfgang, 1956 ) were formally described from grizzly ( Ursus arctos horribilis) and black bears ( Ursus americanus ) of North America. We analyzed the intestinal tracts of 4 grizzly and 9 black bears from Alberta and British Columbia, Canada and isolated Uncinaria specimens with anatomical traits never previously documented. We applied morphological and molecular techniques to investigate the taxonomy and phylogeny of these Uncinaria parasites. The morphological analysis supported polymorphism at the vulvar region for females of both U. rauschi and U. yukonensis. The hypothesis of morphological plasticity for U. rauschi and U. yukonensis was confirmed by genetic analysis of the internal transcribed spacers (ITS-1 and ITS-2) of the nuclear ribosomal DNA. Two distinct genotypes were identified, differing at 5 fixed sites for ITS-1 (432 base pairs [bp]) and 7 for ITS-2 (274 bp). Morphometric data for U. rauschi revealed host-related size differences: adult U. rauschi were significantly larger in black bears than in grizzly bears. Interpretation of these results, considering the historical biogeography of North American bears, suggests a relatively recent host-switching event of U. rauschi from black bears to grizzly bears which likely occurred after the end of the Wisconsin glaciation. Phylogenetic maximum parsimony (MP) and maximum likelihood (ML) analyses of the concatenated ITS-1 and ITS-2 datasets strongly supported monophyly of U. rauschi and U. yukonensis and their close relationship with Uncinaria stenocephala (Railliet, 1884), the latter a parasite primarily of canids and felids. Relationships among species within this group, although resolved by ML, were unsupported by MP and bootstrap resampling. The clade of U. rauschi, U. yukonensis, and U. stenocephala was recovered as sister to the clade represented by Uncinaria spp. from otariid pinnipeds. These results support the absence of strict host-parasite co-phylogeny for Uncinaria spp. and their carnivore hosts. Phylogenetic relationships among Uncinaria spp. provided a framework to develop the hypothesis of similar transmission patterns for the closely related U. rauschi, U. yukonensis, and U. stenocephala. PMID- 25548984 TI - A novel inflammatory role for platelets in sickle cell disease. AB - The severe pain, ischemia and organ damage that characterizes sickle cell disease (SCD) is caused by vaso-occlusion, which is the blockage of blood vessels by heterotypic aggregates of sickled erythrocytes and other cells. Vaso-occlusion is also a vasculopathy involving endothelial cell dysfunction, leukocyte activation, platelet activation and chronic inflammation resulting in the multiple adhesive interactions between cellular elements. Since platelets mediate inflammation as well as thrombosis via release of pro- and anti-inflammatory molecules, we hypothesized that platelets may play an active inflammatory role in SCD by secreting increased amounts of cytokines. Since platelets have been shown to contain mRNA and actively produce proteins, we also hypothesized that SCD platelets may contain increased cytokine mRNA. In this cross-sectional study, we sought to compare both the quantity of cytokines secreted and the cytokine mRNA content, between SCD and control platelets. We measured the secretion of Th1, Th2, and Th17-related cytokines from platelets in a cohort of SCD patients. We simultaneously measured platelet mRNA levels of those cytokines. Platelets from SCD patients secreted increased quantities of IL-1beta, sCD40L, and IL-6 compared to controls. Secretion was increased in patients with alloantibodies. Additionally, mRNA of those cytokines was increased in SCD platelets. Platelets from sickle cell patients secrete increased amounts of inflammatory cytokines, and contain increased cytokine mRNA. These findings suggest a novel immunological role for platelets in SCD vasculopathy, in addition to their thrombotic role, and strengthen the rationale for the use of anti-platelet therapy in SCD. PMID- 25548985 TI - Nedaplatin or oxaliplatin combined with paclitaxel and docetaxel as first-line treatment for patients with advanced non-small cell lung cancer. AB - BACKGROUND: Both nedaplatin and oxaliplatin combined with paclitaxel or docetaxel have demonstrated potent activity in advanced non-small cell lung cancer (NSCLC) patients, but there is no study comparing the difference between these 2 chemotherapy regimens. The aim of this study was to evaluate and compare the efficacy and safety between the combination chemotherapy of nedaplatin or oxaliplatin plus paclitaxel and docetaxel in patients with advanced NSCLC. MATERIAL AND METHODS: We retrospectively reviewed patients with stage III-IV unresectable NSCLC from 1 January 2010 to 31 December 2013 at Southwest Hospital. They all received nedaplatin (80 mg/m2, nedaplatin group) or oxaliplatin (130 mg/m2, oxaliplatin group) combined with paclitaxel (175 mg/m2) or docetaxel (75 mg/m2) as first-line treatment. RESULTS: There are 174 patients enrolled - 123 patients in the nedaplatin group and 51 patients in the oxaliplatin group. The objective response rates were 47.3% and 34.1% and the disease control rates were 87.5% and 79.5% in nedaplatin and oxaliplatin groups, respectively. The progression-free survival time was 10.4 months and 9.6 months (p=0.722) and the overall survival time was 18.5 months and 25.5 months in the nedaplatin and oxaliplatin groups, respectively (p=0.09). Total toxicity was greater in the oxaliplatin group (p=0.008), but there is no significant difference among 3/4 grade adverse events between the 2 groups (P=0.595). CONCLUSIONS: The effect of nedaplatin plus paclitaxel and docetaxel is the same as oxaliplatin plus paclitaxel and docetaxel, and the toxicity of nedaplatin is well tolerate as first-line treatment for patients with advanced NSCLC. PMID- 25548987 TI - Improving school immunization rates may be as basic as record reconciliation and policy enforcement: a report from a rural Colorado public health/school district initiative. AB - The aim of this report was to assess the coverage rate of required immunizations for kindergarten-12 students in the Eagle County School District and to create a process for annual, district-wide immunization assessments to inform immunization campaigns. All kindergarten-12 student records were reviewed, and immunization rates during the 2012-2014 years were compiled. At baseline, only 2096 (34%) were in compliance with the Colorado School Immunization Law. After reconciliation of records and instituting a recall system in year 1 and enforcement of the Colorado School Immunization Law suspension rule in year 2, a total of 5862 (98.8%; P < .001) students were in compliance. Immunization rates for Eagle County School District students were unknown due to the lack of a process to assess a compliance rate and the lack of reconciliation of records. Although initially time-intensive, the project has impacted the community through the creation of a sustainable process of collecting and reporting student immunization records through a centralized state immunization registry. PMID- 25548986 TI - Large-scale purification of porcine or bovine photoreceptor outer segments for phagocytosis assays on retinal pigment epithelial cells. AB - Analysis of one of the vital functions of retinal pigment epithelial (RPE) cells, the phagocytosis of spent aged distal fragments of photoreceptor outer segments (POS) can be performed in vitro. Photoreceptor outer segments with stacks of membranous discs containing the phototransduction machinery are continuously renewed in the retina. Spent POS are eliminated daily by RPE cells. Rodent, porcine/bovine and human RPE cells recognize POS from various species in a similar manner. To facilitate performing large series of experiments with little variability, a large stock of POS can be isolated from porcine eyes and stored frozen in aliquots. This protocol takes advantage of the characteristic of photopigments that display an orange color when kept in the dark. Under dim red light, retinae are collected in a buffer from opened eyecups cut in halves. The retinal cell suspension is homogenized, filtered and loaded onto a continuous sucrose gradient. After centrifugation, POS are located in a discrete band in the upper part of the gradient that has a characteristic orange color. POS are then collected, spun, resuspended sequentially in wash buffers, counted and aliquoted. POS obtained this way can be used for phagocytosis assays and analysis of protein activation, localization or interaction at various times after POS challenge. Alternatively, POS can be labeled with fluorophores, e.g., FITC, before aliquoting for subsequent fluorescence quantification of POS binding or engulfment. Other possible applications include the use of modified POS or POS challenge combined with stress conditions to study the effect of oxidative stress or aging on RPE cells. PMID- 25548988 TI - Evaluation of a community immunization outreach program--Philadelphia, Pennsylvania. AB - CONTEXT: Every year the Philadelphia Department of Public Health selects roughly 5000 10-month olds not up-to-date (UTD) for their 6-month vaccinations for a community-based outreach program. OBJECTIVE: To evaluate the outreach program's effectiveness from 2008 to 2012. DESIGN: Outreach children from 2008 to 2012 were compared with children not selected for outreach on UTD rates and median UTD age in a retrospective cohort study. SETTING: Philadelphia, Pennsylvania PARTICIPANTS: : 10- to 15-month olds from targeted Philadelphia ZIP codes. INTERVENTION: Outreach workers investigated immunization status, educated families on the importance of timely immunizations, and assisted patients in securing health care services to bring children UTD on their 6-month vaccinations. MAIN OUTCOME MEASURES: Outcomes included UTD status for recommended vaccinations due by 6, 15, and 18 months and median age at which 15- and 18-month vaccinations were completed for outreach versus nonoutreach children. RESULTS: Outreach children had significantly higher UTD rates for 6-month vaccinations than nonoutreach children. Outreach children also had significantly higher UTD rates for 15- and 18-month vaccinations, and therefore the effect of outreach is lasting. From 2008 to 2012, median UTD ages for 15- and 18-month vaccinations were significantly lower for outreach than for nonoutreach children. CONCLUSIONS: Outreach was effective in increasing immunization UTD rates and is a useful tool for improving childhood immunization rates in urban settings. PMID- 25548989 TI - Racial and ethnic differences in diurnal cortisol rhythms: are they consistent over time? AB - BACKGROUND: Prior research indicates that blacks and Hispanics/Latinos have flatter diurnal cortisol declines across the day, a profile associated with poorer health. The stability of racial and ethnic differences in cortisol levels over time is not well understood, and additional research is needed to establish racial and ethnic differences in psychosocial stress levels as related to changes in cortisol levels. METHODS: With data from a community-based study of 152 adults (mean age = 58 years; 53% women; 34% black, 26% Hispanic/Latino), we examined the magnitude of racial and ethnic differences over a 5-year period. Salivary cortisol samples were obtained 3 times per day for 3 days in Years 1, 3, 4, and 5. Life events and chronic stress were assessed by questionnaires in which participants reported on whether they had experienced specific types of events or stress within the past year. Depressive symptoms scales (Center for Epidemiologic Studies of Depression Scale) were also administered annually. Daily cortisol slopes were calculated by subtracting wakeup cortisol from bedtime levels and dividing by hours awake. RESULTS: Increases in psychosocial stress were associated with flatter cortisol slopes among blacks (beta = 0.010) and Hispanics/Latinos (beta = 0.014), although including cardiovascular disease risk factors attenuates associations in blacks (beta = 0.007; p = .125). Higher income predicts a steepening of cortisol rhythms across the study (beta = -0.003; p = .019). CONCLUSIONS: Racial and ethnic differences in diurnal cortisol rhythms are stable over time. However, the magnitude of changes in cortisol levels associated with chronic stress levels may vary by racial and ethnic subgroups. PMID- 25548990 TI - Geometrically undistorted MRI in the presence of field inhomogeneities using compressed sensing accelerated broadband 3D phase encoded turbo spin-echo imaging. AB - In this study, we explore the potential of compressed sensing (CS) accelerated broadband 3D phase-encoded turbo spin-echo (3D-PE-TSE) for the purpose of geometrically undistorted imaging in the presence of field inhomogeneities. To achieve this goal 3D-PE-SE and 3D-PE-TSE sequences with broadband rf pulses and dedicated undersampling patterns were implemented on a clinical scanner. Additionally, a 3D multi-spectral spin-echo (ms3D-SE) sequence was implemented for reference purposes. First, we demonstrated the influence of susceptibility induced off-resonance effects on the spatial encoding of broadband 3D-SE, ms3D SE, 3D-PE-SE and 3D-PE-TSE using a grid phantom containing a titanium implant (Deltachi = 182 ppm) with x-ray CT as a gold standard. These experiments showed that the spatial encoding of 3D-PE-(T)SE was unaffected by susceptibility induced off-resonance effects, which caused geometrical distortions and/or signal hyper intensities in broadband 3D-SE and, to a lesser extent, in ms3D-SE frequency encoded methods. Additionally, an SNR analysis was performed and the temporally resolved signal of 3D-PE-(T)SE sequences was exploited to retrospectively decrease the acquisition bandwidth and obtain field offset maps. The feasibility of CS acceleration was studied retrospectively and prospectively for the 3D-PE-SE sequence using an existing CS algorithm adapted for the reconstruction of 3D data with undersampling in all three phase encoded dimensions. CS was combined with turbo-acceleration by variable density undersampling and spherical stepwise T2 weighting by randomly sorting consecutive echoes in predefined spherical k-space layers. The CS-TSE combination resulted in an overall acceleration factor of 60, decreasing the original 3D-PE-SE scan time from 7 h to 7 min. Finally, CS accelerated 3D-PE-TSE in vivo images of a titanium screw were obtained within 10 min using a micro-coil demonstrating the feasibility of geometrically undistorted MRI near severe field inhomogeneities. PMID- 25548991 TI - Comparison of the expression of vimentin and actin in spitz nevi and spitzoid malignant melanomas. AB - INTRODUCTION: The differentiation between Spitz nevi (SN) and Spitzoid malignant melanomas (SMM) represents a challenge to dermatopathologists. We recently demonstrated differential expression of vimentin and Actin in SN and SMM by mass spectrometry (MS). We sought to investigate whether this differential expression could be detected using conventional immunohistochemistry or automated quantitative analysis (AQUA) of histological sections. METHODS: Cases of SN and SMM, which were previously studied by MS and have readily available blocks and enough material in the block, were selected from the Yale Spitzoid Neoplasm Repository. The cases were stained for vimentin and muscle-specific actin using standard protocols. H-scores were calculated by multiplying the percentage of cells staining and the intensity of staining. Selected cases were also studied for quantitative immunofluorescent staining using the AQUA method. RESULTS: All 21 cases of SN showed strong and diffuse staining for vimentin; 19 of 21 (91%) cases had an H-score of 300 (average, 294). Similar staining results were observed in SMM; 13 of 14 (93%) cases had an H-score of 300 (average, 297). Muscle-specific actin was weakly and focally positive in 5 of 21 (24%) SN (H score = 3.3) and 5 of 14 (39%) SMM (H-score = 3.5). The AQUA method showed no significant difference in the staining intensity of SN and SMM for both vimentin and actin. CONCLUSIONS: There was no difference in the expression of vimentin and actin in SN and SMM shown by conventional immunohistochemistry or the AQUA method. This study shows that MS has much grater sensitivity in detecting the differential expression of these proteins. PMID- 25548992 TI - An asymptomatic nodule on the arm of a 46-year-old man. PMID- 25548993 TI - Transformation of Sezary syndrome into CD30+ anaplastic large T-cell lymphoma after alemtuzumab therapy with evidence of clonal unity. AB - Alemtuzumab is a humanized mouse antibody targeting the CD52 cell surface, which has been effective in patients with advanced stage mycosis fungoides (MF) including erythrodermic MF and Sezary syndrome. There are a few descriptions of large cell transformation after its administration. A young patient with an acute onset of Sezary syndrome treated initially unsuccessfully with fludarabine and cyclophosphamide and later on successfully with alemtuzumab has been described. Three weeks after the beginning of therapy, however, she developed transformed T cell lymphoma indistinguishable from CD30 anaplastic large-cell lymphoma. After bone marrow transplantation, the transformed CD30 cutaneous T-cell lymphoma recurred as a transformed CD30 plaque MF. All 3 types of lesions showed the same T-cell receptor clonal gene rearrangement, which supports the notion that Sezary syndrome, CD30 anaplastic large-cell lymphoma, and MF are interrelated. PMID- 25548995 TI - A simple and rapid protocol to non-enzymatically dissociate fresh human tissues for the analysis of infiltrating lymphocytes. AB - The ability of malignant cells to evade the immune system, characterized by tumor escape from both innate and adaptive immune responses, is now accepted as an important hallmark of cancer. Our research on breast cancer focuses on the active role that tumor infiltrating lymphocytes play in tumor progression and patient outcome. Toward this goal, we developed a methodology for the rapid isolation of intact lymphoid cells from normal and abnormal tissues in an effort to evaluate them proximate to their native state. Homogenates prepared using a mechanical dissociator show both increased viability and cell recovery while preserving surface receptor expression compared to enzyme-digested tissues. Furthermore, enzymatic digestion of the remaining insoluble material did not recover additional CD45(+) cells indicating that quantitative and qualitative measurements in the primary homogenate likely genuinely reflect infiltrating subpopulations in the tissue fragment. The lymphoid cells in these homogenates can be easily characterized using immunological (phenotype, proliferation, etc.) or molecular (DNA, RNA and/or protein) approaches. CD45(+) cells can also be used for subpopulation purification, in vitro expansion or cryopreservation. An additional benefit of this approach is that the primary tissue supernatant from the homogenates can be used to characterize and compare cytokines, chemokines, immunoglobulins and antigens present in normal and malignant tissues. This protocol functions extremely well for human breast tissues and should be applicable to a wide variety of normal and abnormal tissues. PMID- 25548997 TI - A national review of the frequency of minimally invasive surgery among general surgery residents: assessment of ACGME case logs during 2 decades of general surgery resident training. AB - IMPORTANCE: Minimally invasive surgery (MIS) has created a shift in how many surgical diseases are treated. Examining the effect on resident operative experience provides valuable insight into trends that may be useful for restructuring the requirements of resident training. OBJECTIVE: To evaluate changes in general surgery resident operative experience regarding MIS. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of the frequency of MIS relative to open operations among general surgery residents using the Accreditation Council for Graduate Medical Education case logs for academic years 1993-1994 through 2011-2012. EXPOSURES: General surgery residency training among accredited programs in the United States. MAIN OUTCOMES AND MEASURES: We analyzed the difference in the mean number of MIS techniques and corresponding open procedures across training periods using 2-tailed t tests with statistical significance set at P < .05. RESULTS: Of 6,467,708 operations with the option of MIS, 2,393,030 (37.0%) were performed with the MIS approach. Of all MIS operations performed, the 5 most common were cholecystectomy (48.5%), appendectomy (16.2%), groin hernia repair (10.0%), abdominal exploration (nontrauma) (4.4%), and antireflux procedures (3.6%). During the study period, there was a transition from a predominantly open to MIS approach for appendectomy, antireflux procedures, thoracic wedge resection, and partial gastric resection. Cholecystectomy is the only procedure for which MIS was more common than the open technique throughout the study period (P < .001). The open approach is more common for all other procedures, including splenectomy (0.7% MIS), common bile duct exploration (24.9% MIS), gastrostomy (25.9% MIS), abdominal exploration (33.1% MIS), hernia (20.3% MIS), lung resection (22.3% MIS), partial or total colectomy (39.1%), enterolysis (19.0% MIS), ileostomy (9.0% MIS), enterectomy (5.2% MIS), vagotomy (1.8% MIS), and pediatric antireflux procedures (35.9% MIS); P < .001. CONCLUSIONS AND RELEVANCE: Minimally invasive surgery has an increasingly prominent role in contemporary surgical therapy for many common diseases. The open approach, however, still predominates in all but 5 procedures. Residents today must become efficient at performing multiple techniques for a single procedure, which demands a broader skill set than in the past. PMID- 25548999 TI - Generation of fluoroscopic 3D images with a respiratory motion model based on an external surrogate signal. AB - Respiratory motion during radiotherapy can cause uncertainties in definition of the target volume and in estimation of the dose delivered to the target and healthy tissue. In this paper, we generate volumetric images of the internal patient anatomy during treatment using only the motion of a surrogate signal. Pre treatment four-dimensional CT imaging is used to create a patient-specific model correlating internal respiratory motion with the trajectory of an external surrogate placed on the chest. The performance of this model is assessed with digital and physical phantoms reproducing measured irregular patient breathing patterns. Ten patient breathing patterns are incorporated in a digital phantom. For each patient breathing pattern, the model is used to generate images over the course of thirty seconds. The tumor position predicted by the model is compared to ground truth information from the digital phantom. Over the ten patient breathing patterns, the average absolute error in the tumor centroid position predicted by the motion model is 1.4 mm. The corresponding error for one patient breathing pattern implemented in an anthropomorphic physical phantom was 0.6 mm. The global voxel intensity error was used to compare the full image to the ground truth and demonstrates good agreement between predicted and true images. The model also generates accurate predictions for breathing patterns with irregular phases or amplitudes. PMID- 25548998 TI - Vascular balloon injury and intraluminal administration in rat carotid artery. AB - The carotid artery balloon injury model in rats has been well established for over two decades. It remains an important method to study the molecular and cellular mechanisms involved in vascular smooth muscle dedifferentiation, neointima formation and vascular remodeling. Male Sprague-Dawley rats are the most frequently employed animals for this model. Female rats are not preferred as female hormones are protective against vascular diseases and thus introduce a variation into this procedure. The left carotid is typically injured with the right carotid serving as a negative control. Left carotid injury is caused by the inflated balloon that denudes the endothelium and distends the vessel wall. Following injury, potential therapeutic strategies such as the use of pharmacological compounds and either gene or shRNA transfer can be evaluated. Typically for gene or shRNA transfer, the injured section of the vessel lumen is locally transduced for 30 min with viral particles encoding either a protein or shRNA for delivery and expression in the injured vessel wall. Neointimal thickening representing proliferative vascular smooth muscle cells usually peaks at 2 weeks after injury. Vessels are mostly harvested at this time point for cellular and molecular analysis of cell signaling pathways as well as gene and protein expression. Vessels can also be harvested at earlier time points to determine the onset of expression and/or activation of a specific protein or pathway, depending on the experimental aims intended. Vessels can be characterized and evaluated using histological staining, immunohistochemistry, protein/mRNA assays, and activity assays. The intact right carotid artery from the same animal is an ideal internal control. Injury-induced changes in molecular and cellular parameters can be evaluated by comparing the injured artery to the internal right control artery. Likewise, therapeutic modalities can be evaluated by comparing the injured and treated artery to the control injured only artery. PMID- 25548996 TI - Familial pathways to early-onset suicide attempt: a 5.6-year prospective study. AB - IMPORTANCE: Suicide attempts are strong predictors of suicide, a leading cause of adolescent mortality. Suicide attempts are highly familial, although the mechanisms of familial transmission are not understood. Better delineation of these mechanisms could help frame potential targets for prevention. OBJECTIVE: To examine the mechanisms and pathways by which suicidal behavior is transmitted from parent to child. DESIGN, SETTING, AND PARTICIPANTS: In this prospective study conducted from July 15, 1997, through June 21, 2012, a total of 701 offspring aged 10 to 50 years (mean age, 17.7 years) of 334 clinically referred probands with mood disorders, 191 (57.2%) of whom had also made a suicide attempt, were followed up for a mean of 5.6 years. MAIN OUTCOMES AND MEASURES: The primary outcome was a suicide attempt. Variables were examined at baseline, intermediate time points, and the time point proximal to the attempt. Participants were assessed by structured psychiatric assessments and self-report and by interview measures of domains hypothesized to be related to familial transmission (eg, mood disorder and impulsive aggression). RESULTS: Among the 701 offspring, 44 (6.3%) had made a suicide attempt before participating in the study, and 29 (4.1%) made an attempt during study follow-up. Multivariate logistic regression revealed that proband suicide attempt was a predictor of offspring suicide attempt (odds ratio [OR], 4.79; 95% CI, 1.75-13.07), even controlling for other salient offspring variables: baseline history of mood disorder (OR, 4.20; 95% CI, 1.37-12.86), baseline history of suicide attempt (OR, 5.69; 95% CI, 1.94-16.74), and mood disorder at the time point before the attempt (OR, 11.32; 95% CI, 2.29-56.00). Path analyses were consistent with these findings, revealing a direct effect of proband attempt on offspring suicide attempt, a strong effect of offspring mood disorder at each time point, and impulsive aggression as a precursor of mood disorder. CONCLUSIONS AND RELEVANCE: Parental history of a suicide attempt conveys a nearly 5-fold increased odds of suicide attempt in offspring at risk for mood disorder, even after adjusting for the familial transmission of mood disorder. Interventions that target mood disorder and impulsive aggression in high-risk offspring may attenuate the familial transmission of suicidal behavior. PMID- 25549000 TI - Atomically defined templates for epitaxial growth of complex oxide thin films. AB - Atomically defined substrate surfaces are prerequisite for the epitaxial growth of complex oxide thin films. In this protocol, two approaches to obtain such surfaces are described. The first approach is the preparation of single terminated perovskite SrTiO3 (001) and DyScO3 (110) substrates. Wet etching was used to selectively remove one of the two possible surface terminations, while an annealing step was used to increase the smoothness of the surface. The resulting single terminated surfaces allow for the heteroepitaxial growth of perovskite oxide thin films with high crystalline quality and well-defined interfaces between substrate and film. In the second approach, seed layers for epitaxial film growth on arbitrary substrates were created by Langmuir-Blodgett (LB) deposition of nanosheets. As model system Ca2Nb3O10(-) nanosheets were used, prepared by delamination of their layered parent compound HCa2Nb3O10. A key advantage of creating seed layers with nanosheets is that relatively expensive and size-limited single crystalline substrates can be replaced by virtually any substrate material. PMID- 25549001 TI - 3-D imaging and analysis of neurons infected in vivo with Toxoplasma gondii. AB - Toxoplasma gondii is an obligate, intracellular parasite with a broad host range, including humans and rodents. In both humans and rodents, Toxoplasma establishes a lifelong persistent infection in the brain. While this brain infection is asymptomatic in most immunocompetent people, in the developing fetus or immunocompromised individuals such as acquired immune deficiency syndrome (AIDS) patients, this predilection for and persistence in the brain can lead to devastating neurologic disease. Thus, it is clear that the brain-Toxoplasma interaction is critical to the symptomatic disease produced by Toxoplasma, yet we have little understanding of the cellular or molecular interaction between cells of the central nervous system (CNS) and the parasite. In the mouse model of CNS toxoplasmosis it has been known for over 30 years that neurons are the cells in which the parasite persists, but little information is available about which part of the neuron is generally infected (soma, dendrite, axon) and if this cellular relationship changes between strains. In part, this lack is secondary to the difficulty of imaging and visualizing whole infected neurons from an animal. Such images would typically require serial sectioning and stitching of tissue imaged by electron microscopy or confocal microscopy after immunostaining. By combining several techniques, the method described here enables the use of thick sections (160 um) to identify and image whole cells that contain cysts, allowing three dimensional visualization and analysis of individual, chronically infected neurons without the need for immunostaining, electron microscopy, or serial sectioning and stitching. Using this technique, we can begin to understand the cellular relationship between the parasite and the infected neuron. PMID- 25549002 TI - Towards double-functionalized small diamondoids: selective electronic band-gap tuning. AB - Diamondoids are nanoscale diamond-like cage structures with hydrogen terminations, which can occur in various sizes and with a diverse type of modifications. In this work, we focus on the structural alterations and the effect of doping and functionalization on the electronic properties of diamondoids, from the smallest adamantane to heptamantane. The results are based on quantum mechanical calculations. We perform a self-consistent study, starting with doping the smallest diamondoid, adamantane. Boron, nitrogen, silicon, oxygen, and phosphorus are chosen as dopants at sites which have been previously optimized and are also consistent with the literature. At a next step, an amine- and a thiol- group are separately used to functionalize the adamantane molecule. We mainly focus on a double functionalization of diamondoids up to heptamantane using both these atomic groups. The effect of isomeration in the case of tetramantane is also studied. We discuss the higher efficiency of a double functionalization compared to doping or a single-functionalization of diamondoids in tuning the electronic properties, such as the electronic band-gap, of modified small diamondoids in view of their novel nanotechnological applications. PMID- 25549003 TI - Automating ChIP-seq experiments to generate epigenetic profiles on 10,000 HeLa cells. AB - Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) is a technique of choice for studying protein-DNA interactions. ChIP-seq has been used for mapping protein-DNA interactions and allocating histones modifications. The procedure is tedious and time consuming, and one of the major limitations is the requirement for high amounts of starting material, usually millions of cells. Automation of chromatin immunoprecipitation assays is possible when the procedure is based on the use of magnetic beads. Successful automated protocols of chromatin immunoprecipitation and library preparation have been specifically designed on a commercially available robotic liquid handling system dedicated mainly to automate epigenetic assays. First, validation of automated ChIP-seq assays using antibodies directed against various histone modifications was shown, followed by optimization of the automated protocols to perform chromatin immunoprecipitation and library preparation starting with low cell numbers. The goal of these experiments is to provide a valuable tool for future epigenetic analysis of specific cell types, sub-populations, and biopsy samples. PMID- 25549005 TI - Tetramer model of leukoemeraldine-emeraldine electrochemistry in the presence of trihalogenoacetic acids. DFT approach. AB - First results of the application of the DFT computational approach to the reversible electrochemistry of polyaniline are presented. A tetrameric chain was used as the simplest model of the polyaniline polymer species. The system under theoretical investigation involved six tetramer species, two electrons, and two protons, taking part in 14 elementary reactions. Moreover, the tetramer species were interacting with two trihalogenoacetic acid molecules. Trifluoroacetic, trichloroacetic, and tribromoacetic acids were found to impact the redox transformation of polyaniline as shown by cyclic voltammetry. The theoretical approach was considered as a powerful tool for investigating the main factors of importance for the experimental behavior. The DFT method provided molecular structures, interaction energies, and equilibrium energies of all of the tetramer acid complexes. Differences between the energies of the isolated tetramer species and their complexes with acids are discussed in terms of the elementary reactions, that is, ionization potentials and electron affinities, equilibrium constants, electrode potentials, and reorganization energies. The DFT results indicate a high impact of the acid on the reorganization energy of a particular elementary electron-transfer reaction. The ECEC oxidation path was predicted by the calculations. The model of the reacting system must be extended to octamer species and/or dimeric oligomer species to better approximate the real polymer situation. PMID- 25549004 TI - Mouse pneumonectomy model of compensatory lung growth. AB - In humans, disrupted repair and remodeling of injured lung contributes to a host of acute and chronic lung disorders which may ultimately lead to disability or death. Injury-based animal models of lung repair and regeneration are limited by injury-specific responses making it difficult to differentiate changes related to the injury response and injury resolution from changes related to lung repair and lung regeneration. However, use of animal models to identify these repair and regeneration signaling pathways is critical to the development of new therapies aimed at improving pulmonary function following lung injury. The mouse pneumonectomy model utilizes compensatory lung growth to isolate those repair and regeneration signals in order to more clearly define mechanisms of alveolar re septation. Here, we describe our technique for performing mouse pneumonectomy and sham pneumonectomy. This technique may be utilized in conjunction with lineage tracing or other transgenic mouse models to define molecular and cellular mechanism of lung repair and regeneration. PMID- 25549006 TI - Localization, identification, and excision of murine adipose depots. AB - Obesity has increased dramatically in the last few decades and affects over one third of the adult US population. The economic effect of obesity in 2005 reached a staggering sum of $190.2 billion in direct medical costs alone. Obesity is a major risk factor for a wide host of diseases. Historically, little was known regarding adipose and its major and essential functions in the body. Brown and white adipose are the two main types of adipose but current literature has identified a new type of fat called brite or beige adipose. Research has shown that adipose depots have specific metabolic profiles and certain depots allow for a propensity for obesity and other related disorders. The goal of this protocol is to provide researchers the capacity to identify and excise adipose depots that will allow for the analysis of different factorial effects on adipose; as well as the beneficial or detrimental role adipose plays in disease and overall health. Isolation and excision of adipose depots allows investigators to look at gross morphological changes as well as histological changes. The adipose isolated can also be used for molecular studies to evaluate transcriptional and translational change or for in vitro experimentation to discover targets of interest and mechanisms of action. This technique is superior to other published techniques due to the design allowing for isolation of multiple depots with simplicity and minimal contamination. PMID- 25549007 TI - Degradation of methylene blue using porous WO3, SiO2-WO3, and their Au-loaded analogs: adsorption and photocatalytic studies. AB - A facile sonochemical approach was used to deposit 3-5 nm monodisperse gold nanoparticles on porous SiO2-WO3 composite spheres, as confirmed by powder X-ray diffraction (XRD) and transmission electron microscopy (TEM). High-resolution TEM (HR-TEM) and energy dispersive X-ray spectroscopy (EDS) further characterized the supported Au nanoparticles within the Au-SiO2-WO3 composite. These analyses showed isolated Au nanoparticles within both SiO2- and WO3-containing regions. Selective etching of the SiO2 matrix from Au-SiO2-WO3 yielded a pure Au-WO3 material with well-dispersed 10 nm Au nanoparticles and moderate porosity. This combined sonochemical-nanocasting technique has not been previously used to synthesize Au-WO3 photocatalysts. Methylene blue (MB) served as a probe for the adsorption capacity and visible light photocatalytic activity of these WO3 containing catalysts. Extensive MB demethylation (azures A, B, C, and thionine) and polymerization of these products occurred over WO3 under dark conditions, as confirmed by electrospray ionization mass spectrometry (ESI-MS). Photoirradiation of these suspensions led to further degradation primarily through demethylation and polymerization pathways, regardless of the presence of Au nanoparticles. Ring opening sulfur oxidation to the sulfone was a secondary photocatalytic pathway. According to UV-vis spectroscopy, pure WO3 materials showed superior MB adsorption compared to SiO2-WO3 composites. Compared to their respective nonloaded catalysts, Au-SiO2-WO3 and Au-WO3 catalysts exhibited enhanced visible light photocatalytic activity toward the degradation of MB. Specifically, the rates of MB degradation over Au-WO3 and Au-SiO2-WO3 during 300 min of irradiation were faster than those over their nonloaded counterparts (WO3 and SiO2-WO3). These studies highlight the ability of Au-WO3 to serve as an excellent adsorbant and photodegradation catalyst toward MB. PMID- 25549008 TI - Hydrophobicity is the governing factor in the interaction of human serum albumin with bile salts. AB - The present study demonstrates a detailed characterization of the interaction of a series of bile salts, sodium deoxycholate (NaDC), sodium cholate (NaC), and sodium taurocholate (NaTC), with a model transport protein, human serum albumin (HSA). Here, steady-state and time-resolved fluorescence spectroscopic techniques have been used to characterize the interaction of the bile salts with HSA. The binding isotherms constructed from steady-state fluorescence intensity measurements demonstrate that the interaction of the bile salts with HSA can be characterized by three distinct regions, which were also successfully reproduced from the significant variation of the emission wavelength (lambda(em)) of the intrinsic tryptophan (Trp) moiety of HSA. The time-resolved fluorescence decay behavior of the Trp residue of HSA was also found to corroborate the steady-state results. The effect of interaction with the bile salts on the native conformation of the protein has been explored in a circular dichroism (CD) study, which reveals a decrease in alpha-helicity of HSA induced by the bile salts. In accordance with this, the esterase activity of the protein-bile salt aggregates is found to be reduced in comparison to that of the native protein. Our results exclusively highlight the fact that it is the hydrophobic character of the bile salt that governs the extent of interaction with the protein. Isothermal titration calorimetry (ITC) and molecular docking studies further substantiate our other experimental findings. PMID- 25549009 TI - Autocorrelation analysis for the unbiased determination of power-law exponents in single-quantum-dot blinking. AB - We present an unbiased and robust analysis method for power-law blinking statistics in the photoluminescence of single nanoemitters, allowing us to extract both the bright- and dark-state power-law exponents from the emitters' intensity autocorrelation functions. As opposed to the widely used threshold method, our technique therefore does not require discriminating the emission levels of bright and dark states in the experimental intensity timetraces. We rely on the simultaneous recording of 450 emission timetraces of single CdSe/CdS core/shell quantum dots at a frame rate of 250 Hz with single photon sensitivity. Under these conditions, our approach can determine ON and OFF power-law exponents with a precision of 3% from a comparison to numerical simulations, even for shot noise-dominated emission signals with an average intensity below 1 photon per frame and per quantum dot. These capabilities pave the way for the unbiased, threshold-free determination of blinking power-law exponents at the microsecond time scale. PMID- 25549010 TI - Economic and environmental assessment of office building rainwater harvesting systems in various U.S. cities. AB - Rainwater harvesting (RWH) systems implemented in office buildings under heterogeneous urban settings in the United States, including combined and separated storm sewer systems, will result in varying environmental and economic costs and benefits across multiple water sectors. The potable water saving and stormwater abatement potentials were found to strongly correlate with the local annual precipitation totals and patterns, specifically the long-period antecedent dry weather period. Given the current water rates and stormwater fees in large U.S. cities, RWH systems implemented in office buildings may not be cost effective compared to the municipal supplies over their lifetime, except in Seattle, which has the highest stormwater fees in the country ($77.50/1000 sf impervious surface/month). The minimum net life cycle costs range from -$1.60 (Seattle) to $11.9 (Phoenix) per m(3) of rainwater yield, resulting in a potential economic gain of over $520 (Seattle) to a net loss of $800 (Phoenix) per building annually. By preventing the rooftop runoff from entering the wastewater treatment plant, between 3 and 9 kg N eq per year could be reduced in combined sewer systems depending on local conditions. This N reduction comes at the expense 0.7-4.6 kg CO2 eq per m(3) rainwater yield. In separate sewer systems, eutrophication reduction benefits result from reducing N loading associated with stormwater runoff. The overall sustainability of implementing RWH depends on the site-specific functional, economic, and environmental benefits, impacts, and trade-offs. PMID- 25549011 TI - Complex columnar hexagonal polymorphism in supramolecular assemblies of a semifluorinated electron-accepting naphthalene bisimide. AB - Simple synthetic methods for a strongly electron-accepting naphthalene bisimide (NBI) derivative functionalized with a new environmentally friendly chiral racemic semifluorinated alkyl group and with AB3 minidendrons containing the same semifluorinated group are reported. The semifluorinated dendron was attached to the imide groups of the NBI via one, two, and three (m = 1, 2, 3) methylenic units. The NBI-containing semifluorinated groups and the dendronized NBI with m = 1 and 2 self-organize into lamellar crystals. The dendronized NBI with m = 3 self assembles into an unprecedentedly complex and ordered column that self-organizes in a columnar hexagonal periodic array. This array undergoes a continuous transition to a columnar hexagonal superlattice that does not display a first order phase transition during analysis by differential scanning calorimetry at heating and cooling rates of 10 and 1 degrees C/min. These complex columnar hexagonal periodic arrays with intramolecular order could be elucidated only by a combination of powder and fiber X-ray diffraction studies and solid-state NMR experiments. The lamellar crystals self-organized from m = 1 and the two highly ordered columnar hexagonal periodic arrays of m = 3 are assembled via thermodynamically controlled processes. Since strongly electron-accepting derivatives are of great interest to replace fullerene acceptors in organic photovoltaics and for other supramolecular electronic materials, the multitechnique structural analysis methodology elaborated here must be taken into consideration in all related studies. PMID- 25549012 TI - Valproate fetopathy. PMID- 25549013 TI - Selected ion flow tube-mass spectrometry for online monitoring of submerged fermentations: a case study of sourdough fermentation. AB - Selected ion flow tube-mass spectrometry (SIFT-MS) has recently gained interest as an alternative method to traditional GC-MS for the detection of targeted volatile sample compounds, due to its ease of use, its speed and sensitivity, and its potential for real-time quantification. The feasibility of this technique was demonstrated using the case of the production of ethanol during sourdough fermentation. The potential of SIFT-MS as an online monitoring device for food fermentations was further demonstrated by the detection of acetoin in certain sourdough fermentations. This allowed discrimination between sourdough fermentation processes and illustrated the importance of real-time monitoring of food fermentations. PMID- 25549014 TI - Hypocoprins A-C: new sesquiterpenoids from the coprophilous fungus Hypocopra rostrata. AB - Studies of the coprophilous fungus Hypocopra rostrata (TTI-0009, NRRL 66178) isolated from a sample of horse dung collected in Texas led to the isolation of three new sesquiterpenoids that we named hypocoprins A-C (1-3), together with the known fungal metabolite helvolic acid. The new metabolites have a distinctive ring system consisting of fused cyclopropane and cyclodecene units not previously reported from a fungal source. Compounds 1 and 3 moderately inhibited growth of Staphylococcus aureus. The structures of these metabolites were assigned mainly by analysis of 2D NMR and HRESITOFMS data. Relative and absolute configurations were assigned by interpretation of NMR J-values and NOESY data and by application of Mosher's method. These results represent the first report of chemistry from any strain of the genus Hypocopra. PMID- 25549015 TI - How to study placebo responses in motion sickness with a rotation chair paradigm in healthy participants. AB - Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates. PMID- 25549016 TI - Interaction of L-Phenylalanine with a Phospholipid Monolayer at the Water-Air Interface. AB - The interaction of L-phenylalanine with a 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) monolayer at the air-water interface was explored using a combination of experimental techniques and molecular dynamics (MD) simulations. By means of Langmuir trough methods and Brewster angle microscopy, L phenylalanine was shown to significantly alter the interfacial tension and the surface domain morphology of the DPPC film. In addition, confocal microscopy was used to explore the aggregation state of L-phenylalanine in the bulk aqueous phase. Finally, MD simulations were performed to gain molecular-level information on the interactions of L-phenylalanine and DPPC at the interface. Taken together, these results show that L-phenylalanine intercalates into a DPPC film at the air water interface, thereby affecting the surface tension, phase morphology, and ordering of the DPPC film. The results are discussed in the context of biological systems and the mechanism of diseases such as phenylketonuria. PMID- 25549017 TI - Stable self-compliance resistive switching in AlOdelta/Ta2O(5-x)/TaOy triple layer devices. AB - Stable self-compliance property was observed in the AlOdelta/Ta2O(5-x)/TaOy triple-layer resistive random access memory structure. The impact of AlOdelta barrier layer was studied with different thicknesses. Endurance of more than 10(10) cycles and data retention for more than 3 h at 125 degrees C were demonstrated. All the measurements were carried out without external current compliance and no hard breakdown was observed. Systematic analysis reveals the self-compliance property is due to the built-in series resistance of the thin AlOdelta barrier layer. A model is proposed to explain this self-compliance property. PMID- 25549018 TI - Kinetics and cluster morphology evolution of shear-driven aggregation of well stabilized colloids. AB - We investigate the shear-driven aggregation of polystyrene colloids that are stabilized by both fixed and surfactant charges, using a microchannel device, in various particle volume fractions. The objective is to understand how the primary particles evolve to clusters with shearing time, how the cluster morphology develops along the aggregation with the effect of breakage and restructuring, and whether non-Derjaguin-Landau-Verwey-Overbeek (DLVO) interactions are present, affecting the kinetics. The time evolution of the primary particle conversion to big clusters is characterized by an induction time, followed by an explosive increase when the cluster size reaches a certain critical value, which confirms the self-acceleration kinetics developed in the literature. The size of the critical clusters has been quantified for the first time, and its scaling with the shear rate follows the literature prediction well. Moreover, analysis of the shear-driven kinetics confirms the presence of substantial non-DLVO interactions in the given system. PMID- 25549019 TI - Purely electric-field-driven perpendicular magnetization reversal. AB - If achieved, magnetization reversal purely with an electric field has the potential to revolutionize the spintronic devices that currently utilize power dissipating currents. However, all existing proposals involve the use of a magnetic field. Here we use phase-field simulations to study the piezoelectric and magnetoelectric responses in a three-dimensional multiferroic nanostructure consisting of a perpendicularly magnetized nanomagnet with an in-plane long axis and a juxtaposed ferroelectric nanoisland. For the first time, we demonstrate a full reversal of perpendicular magnetization via successive precession and damping, driven purely by a perpendicular electric-field pulse of certain pulse duration across the nanoferroelectric. We discuss the materials selection and size dependence of both nanoferroelctrics and nanomagnets for experimental verification. These results offer new inspiration to the design of spintronic devices that simultaneously possess high density, high thermal stability, and high reliability. PMID- 25549021 TI - Nanocellulose-assisted formation of porous hematite nanostructures. AB - We report the formation of porous iron oxide (hematite) nanostructures via sol gel transformations of molecular precursors in the confined space of self organized nanocrystalline cellulose (NCC) used as a shape-persistent template. The obtained structures are highly porous alpha-Fe(2)O(3) (hematite) morphologies with a well-defined anisotropic porosity. The character of the porous nanostructure depends on the iron salt used as the precursor and the heat treatment. Moreover, a postsynthetic hydrothermal treatment of the NCC/iron salt composites strongly affects the crystal growth as well as the porous nanomorphology of the obtained hematite scaffolds. We demonstrate that the hydrothermal treatment alters the crystallization mechanism of the molecular iron precursors, which proceeds via the formation of anisotropic iron oxyhydroxide species. The nanocellulose templating technique established here enables the straightforward fabrication of a variety of mesoporous crystalline iron oxide scaffolds with defined porous structure and is particularly attractive for the processing of porous hematite films on different substrates. PMID- 25549020 TI - Utilizing custom-designed galvanotaxis chambers to study directional migration of prostate cells. AB - The physiological electric field serves specific biological functions, such as directing cell migration in embryo development, neuronal outgrowth and epithelial wound healing. Applying a direct current electric field to cultured cells in vitro induces directional cell migration, or galvanotaxis. The 2-dimensional galvanotaxis method we demonstrate here is modified with custom-made poly(vinyl chloride) (PVC) chambers, glass surface, platinum electrodes and the use of a motorized stage on which the cells are imaged. The PVC chambers and platinum electrodes exhibit low cytotoxicity and are affordable and re-useable. The glass surface and the motorized microscope stage improve quality of images and allow possible modifications to the glass surface and treatments to the cells. We filmed the galvanotaxis of two non-tumorigenic, SV40-immortalized prostate cell lines, pRNS-1-1 and PNT2. These two cell lines show similar migration speeds and both migrate toward the cathode, but they do show a different degree of directionality in galvanotaxis. The results obtained via this protocol suggest that the pRNS-1-1 and the PNT2 cell lines may have different intrinsic features that govern their directional migratory responses. PMID- 25549023 TI - Leptin and adiponectin in chronic obstructive pulmonary disease. Has the fat lady sung? PMID- 25549022 TI - Transformation pathways of isomeric perfluorooctanesulfonate precursors catalyzed by the active species of P450 enzymes: in silico investigation. AB - As evidenced from various in vitro and in vivo studies, metabolism of perfluorooctanesulfonate (PFOS) precursors by cytochrome P450 enzymes (CYPs) acts as an important indirect pathway for mammal PFOS exposure. Nevertheless, the mechanism of this transformation remains largely unclarified. In this study, in silico investigations adopting density functional theory (DFT) were performed to reveal the biotransformation of a typical PFOS precursor, N-ethyl perfluorooctane sulfonamide (N-EtPFOSA), catalyzed by the active species of CYPs (Compound I). Results unveil that in the enzymatic environment, N-EtPFOSA is hydroxylated feasibly (reaction energy barriers DeltaE = 11.4-14.5 kcal/mol) with a H atom transfer (HAT) from the ethyl Calpha to Compound I. The HAT derived Calpha radical then barrierlessly combines with the OH radical to produce a ferric ethanolamine intermediate. Subsequently, the ethanolamine intermediate decomposes via N-dealkylation to perfluorooctane sulfonamide (PFOSA) and acetaldehyde products nonenzymatically with the assistance of water molecules. The rate limiting O-addition (DeltaE = 21.2-34.0 kcal/mol) of Compound I to PFOSA initiated a novel deamination pathway that comprises O-S bond formation and S-N bond cleavage. The resulting hydroxylamine is then hydrolyzed to PFOS. In addition, the results reveal that both the N-dealkylation and deamination pathways are isomeric-specific, which is consistent with experimental observations. Accordingly, DFT calculations may help uncover possible toxicological effects by predicting the biotransformation mechanisms and products of xenobiotics by CYPs. PMID- 25549024 TI - From research to clinical practice. Cognitive trajectory after lung transplantation. PMID- 25549025 TI - Adult survivors of preterm birth. What spirometry conceals, exercise tests reveal. PMID- 25549026 TI - The black box of out-of-pocket cost communication. A path toward illumination. PMID- 25549027 TI - We need an additional seat at the critical care multidisciplinary team table for our speech-language pathologists. PMID- 25549028 TI - Manners of dying in ICU clinical trials. PMID- 25549029 TI - ATS core curriculum 2014: part IV. Pediatric pulmonary medicine. PMID- 25549030 TI - Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. AB - DESCRIPTION: The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF. METHODS: A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B). PMID- 25549031 TI - Exercise-induced bronchoconstriction. PMID- 25549032 TI - 69-year-old woman with rheumatoid arthritis presents with shortness of breath and cough. PMID- 25549033 TI - Dyspnea of unknown cause. Think about diaphragm. PMID- 25549034 TI - A patient with unusual electroencephalographic findings during rapid eye movement sleep. PMID- 25549035 TI - Respiratory bronchiolitis with fibrosis: prevalence and progression. PMID- 25549036 TI - Acute eosinophilic pneumonia associated with ingestion of Ulomoides dermestoides larvae ("Chinese beetles"). PMID- 25549037 TI - Fatal post-bronchoscopy bleeding in a patient with essential thrombocytosis. PMID- 25549038 TI - Airway training for critical care fellows: more than just video laryngoscopy. PMID- 25549039 TI - Reply: Airway training for critical care fellows: more than just video laryngoscopy. PMID- 25549041 TI - Probing structural determinants of ATP-binding cassette exporter conformational transition using coarse-grained molecular dynamics. AB - ATP-binding cassette (ABC) exporters pump various substrates across the cell membrane by alternating between inward-facing (IF) and outward-facing (OF) conformations of the transmembrane domains (TMDs). However, the structural determinants of the conformational transition and their functional roles are not fully understood. In this study, we carried out coarse-grained molecular dynamics (CG-MD) simulations with umbrella sampling for the multidrug transporter P glycoprotein from Caenorhabditis elegans in the presence of the membrane and explicit water molecules. The potential of mean force (PMF) is obtained to identify a reliable pathway where the predicted OF and IF structures are in good agreement with available experiments. The CG-MD simulations reveal that the different transmembrane (TM) helices play distinct but highly cooperative roles in the large-scale conformational changes. Most notably, the CG-MD trajectories show that the periplasmic gate is closed before the cytoplasmic gate is opened during the OF to IF conformational transition in response to the dissociation of the nucleotide-binding domains (NBDs), capturing the unidirectional feature of substrate translocation through the exporter. The structural and dynamical analyses identify the structural determinants and their functional roles in the structural transition. The present work sheds light on how the mechanical force generated upon the NBD dissociation is transferred to the periplasmic end at a distance over 70 A to close the gate, and subsequently to open the cytoplasmic gate. These results extend our understanding of the ABC transport mechanism. PMID- 25549040 TI - Artificial micromotors in the mouse's stomach: a step toward in vivo use of synthetic motors. AB - Artificial micromotors, operating on locally supplied fuels and performing complex tasks, offer great potential for diverse biomedical applications, including autonomous delivery and release of therapeutic payloads and cell manipulation. Various types of synthetic motors, utilizing different propulsion mechanisms, have been fabricated to operate in biological matrices. However, the performance of these man-made motors has been tested exclusively under in vitro conditions (outside the body); their behavior and functionalities in an in vivo environment (inside the body) remain unknown. Herein, we report an in vivo study of artificial micromotors in a living organism using a mouse model. Such in vivo evaluation examines the distribution, retention, cargo delivery, and acute toxicity profile of synthetic motors in mouse stomach via oral administration. Using zinc-based micromotors as a model, we demonstrate that the acid-driven propulsion in the stomach effectively enhances the binding and retention of the motors as well as of cargo payloads on the stomach wall. The body of the motors gradually dissolves in the gastric acid, autonomously releasing their carried payloads, leaving nothing toxic behind. This work is anticipated to significantly advance the emerging field of nano/micromotors and to open the door to in vivo evaluation and clinical applications of these synthetic motors. PMID- 25549042 TI - Psychosocial assessment of artificial pancreas (AP): commentary and review of existing measures and their applicability in AP research. AB - AIM: This study aimed to systematically review the evidence base for the use of existing psychological and psychosocial measures suitable for use in artificial pancreas (AP) research. MATERIALS AND METHODS: This systematic review of published literature, gray literature, previous systematic reviews, and qualitative and economic studies was conducted using terms and abbreviations synonymous with diabetes, AP, and quality of life (QoL). RESULTS: Two hundred ninety-two abstracts were identified that reported psychosocial assessment of diabetes-related technologies. Of these, nine met the inclusion criteria and were included. Only four of 103 ongoing trials evaluated psychosocial aspects as an outcome in the trial. Of these, treatment satisfaction, acceptance and use intention of AP, fear of hypoglycemia episodes, satisfaction with AP, and an unspecified QoL measure were used. CONCLUSIONS: A better understanding of the psychosocial side of AP systems and the extent to which human factors play a role in the uptake and efficient use of these systems will ultimately lead to the most benefit for people with diabetes. PMID- 25549043 TI - Glial cell line-derived neurotrophic factor induces cell proliferation in the mouse urogenital sinus. AB - Glial cell line-derived neurotrophic factor (GDNF) is a TGFbeta family member, and GDNF signals through a glycosyl-phosphatidylinositol-linked cell surface receptor (GFRalpha1) and RET receptor tyrosine kinase. GDNF signaling plays crucial roles in urogenital processes, ranging from cell fate decisions in germline progenitors to ureteric bud outgrowth and renal branching morphogenesis. Gene ablation studies in mice have revealed essential roles for GDNF signaling in urogenital development, although its role in prostate development is unclear. We investigated the functional role of GDNF signaling in the urogenital sinus (UGS) and the developing prostate of mice. GDNF, GFRalpha1, and RET show time-specific and cell-specific expression during prostate development in vivo. In the UGS, GDNF and GFRalpha1 are expressed in the urethral mesenchyme (UrM) and epithelium (UrE), whereas RET is restricted to the UrM. In each lobe of the developing prostate, GDNF and GFRalpha1 expression declines in the epithelium and becomes restricted to the stroma. Using a well-established organ culture system, we determined that exogenous GDNF increases proliferation of UrM and UrE cells, altering UGS morphology. With regard to mechanism, GDNF signaling in the UrM increased RET expression and phosphorylation of ERK1/2. Furthermore, inhibition of RET kinase activity or ERK kinases suppressed GDNF-induced proliferation of UrM cells but not UrE cells. We therefore propose that GDNF signaling in the UGS increases proliferation of UrM and UrE cells by different mechanisms, which are distinguished by the role of RET receptor tyrosine kinase and ERK kinase signaling, thus implicating GDNF signaling in prostate development and growth. PMID- 25549045 TI - CXCR4 promotes renal tubular cell survival in male diabetic rats: implications for ligand inactivation in the human kidney. AB - Binding of the receptor CXCR4 to its ligand stromal cell-derived factor 1 (SDF-1) promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase 9 (MMP-9). In light of the pivotal role that the SDF 1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death. In cultured cells, CXCR4 blockade promoted tubular cell apoptosis, up-regulated Bcl-2-associated death promoter, and prevented high glucose/SDF-1-augmented phosphorylation of the pro-survival kinase, Akt. Although CXCR4 expression was also increased in biopsy tissue from patients with diabetic nephropathy, serine 339 phosphorylation of the receptor, indicative of ligand engagement, was unaffected. Coincident with these changes in receptor expression but not activity, MMP-9 was also up-regulated in diabetic nephropathy biopsies. Supporting a ligand-inactivating effect of the endopeptidase, exposure of cultured cells to recombinant MMP-9 abrogated SDF-1 induced Akt phosphorylation. These observations demonstrate a potentially reno-protective role for CXCR4 in diabetes that is impeded in its actions in the human kidney by the coincident up regulation of ligand-inactivating endopeptidases. Therapeutically intervening in this interplay may limit tubulointerstitial injury, the principal determinant of renal decline in diabetes. PMID- 25549046 TI - Limited mitochondrial capacity of visceral versus subcutaneous white adipocytes in male C57BL/6N mice. AB - Accumulation of visceral fat is associated with metabolic risk whereas excessive amounts of peripheral fat are considered less problematic. At the same time, altered white adipocyte mitochondrial bioenergetics has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. We therefore investigated whether the metabolic risk of visceral vs peripheral fat coincides with a difference in mitochondrial capacity of white adipocytes. We assessed bioenergetic parameters of subcutaneous inguinal and visceral epididymal white adipocytes from male C57BL/6N mice employing a comprehensive respirometry setup of intact and permeabilized adipocytes as well as isolated mitochondria. Inguinal adipocytes clearly featured a higher respiratory capacity attributable to increased mitochondrial respiratory chain content compared with epididymal adipocytes. The lower capacity of mitochondria from epididymal adipocytes was accompanied by an increased generation of reactive oxygen species per oxygen consumed. Feeding a high-fat diet (HFD) for 1 week reduced white adipocyte mitochondrial capacity, with stronger effects in epididymal when compared with inguinal adipocytes. This was accompanied by impaired body glucose homeostasis. Therefore, the limited bioenergetic performance combined with the proportionally higher generation of reactive oxygen species of visceral adipocytes could be seen as a candidate mechanism mediating the elevated metabolic risk associated with this fat depot. PMID- 25549047 TI - Baseline anandamide levels and body weight impact the weight loss effect of CB1 receptor antagonism in male rats. AB - The individual weight loss response to obesity treatment is diverse. Here we test the hypothesis that the weight loss response to the CB1 receptor antagonist rimonabant is influenced by endogenous levels of receptor agonists. We show that baseline anandamide levels and body weight independently contribute to predict the treatment response to rimonabant in rodents, demonstrating that addition of biomarkers related to mode of action is relevant for a personalized health care approach to obesity treatment. PMID- 25549048 TI - Low levels of Galphas and Ric8b in testicular sertoli cells may underlie restricted FSH action during infancy in primates. AB - FSH acts via testicular Sertoli cells (Sc) bearing FSH receptor (FSH-R) for regulating male fertility. Despite an adult-like FSH milieu in infant boys and monkeys, spermatogenesis is not initiated until the onset of puberty. We used infant and pubertal monkey Sc to reveal the molecular basis underlying developmental differences of FSH-R signaling in them. Unlike pubertal Sc, increasing doses of FSH failed to augment cAMP production by infant Sc. The expression of Galphas subunit and Ric8b, which collectively activate adenylyl cyclase (AC) for augmenting cAMP production and gene transcription, were significantly low in infant Sc. However, forskolin, which acts directly on AC bypassing FSH-R, augmented cAMP production and gene transcription uniformly in both infant and pubertal Sc. FSH-induced Galphas mRNA expression was higher in pubertal Sc. However, Galphai-2 expression was down-regulated by FSH in pubertal Sc, unlike infant Sc. FSH failed, but forskolin or 8-Bromoadenosine 3',5'-cyclic monophosphate treatment to infant Sc significantly augmented the expression of transferrin, androgen binding protein, inhibin-beta-B, stem cell factor, and glial-derived neurotropic factor, which are usually up-regulated by FSH in pubertal Sc during spermatogenic onset. This suggested that lack of FSH mediated down-regulation of Galphai-2 expression and limited expression of Galphas subunit as well as Ric8b may underlie limited FSH responsiveness of Sc during infancy. This study also divulged that intracellular signaling events downstream of FSH-R are in place and can be activated exogenously in infant Sc. Additionally, this information may help in the proper diagnosis and treatment of infertile individuals having abnormal G protein-coupled FSH-R. PMID- 25549044 TI - Minireview: nuclear receptor regulation of osteoclast and bone remodeling. AB - Osteoclasts are bone-resorbing cells essential for skeletal remodeling and regeneration. However, excessive osteoclasts often contribute to prevalent bone degenerative diseases such as osteoporosis, arthritis, and cancer bone metastasis. Osteoclast dysregulation is also associated with rare disorders such as osteopetrosis, pycnodysostosis, Paget's disease, and Gorham-Stout syndrome. The nuclear receptor (NR) family of transcription factors functions as metabolic sensors that control a variety of physiological processes including skeletal homeostasis and serves as attractive therapeutic targets for many diseases. In this review, we highlight recent findings on the new players and the new mechanisms for how NRs regulate osteoclast differentiation and bone resorption. An enhanced understanding of NR functions in osteoclastogenesis will facilitate the development of not only novel osteoprotective medicine but also prudent strategies to minimize the adverse skeletal effects of certain NR-targeting drugs for a better treatment of cancer and metabolic diseases. PMID- 25549050 TI - Unilateral pyramidotomy of the corticospinal tract in rats for assessment of neuroplasticity-inducing therapies. AB - The corticospinal tract (CST) can be completely severed unilaterally in the medullary pyramids of the rodent brainstem. The CST is a motor tract that has great importance for distal muscle control in humans and, to a lesser extent, in rodents. A unilateral cut of one pyramid results in loss of CST innervation of the spinal cord mainly on the contralateral side of the spinal cord leading to transient motor disability in the forelimbs and sustained loss of dexterity. Ipsilateral projections of the corticospinal tract are minor. We have refined our surgical method to increase the chances of lesion completeness. We describe postsurgical care. Deficits on the Montoya staircase pellet reaching test and the horizontal ladder test shown here are detected up to 8 weeks postinjury. Deficits on the cylinder rearing test are only detected transiently. Therefore, the cylinder test may only be suitable for detection of short term recovery. We show how, electrophysiologically and anatomically, one may assess lesions and plastic changes. We also describe how to analyse fibers from the uninjured CST sprouting across the midline into the deprived areas. It is challenging to obtain >90% complete lesions consistently due to the proximity to the basilar artery in the medulla oblongata and survival rates can be low. Alternative surgical approaches and behavioural testing are described in this protocol. The pyramidotomy model is a good tool for assessing neuroplasticity-inducing treatments, which increase sprouting of intact fibers after injury. PMID- 25549049 TI - Central Sirt1 regulates body weight and energy expenditure along with the POMC derived peptide alpha-MSH and the processing enzyme CPE production in diet induced obese male rats. AB - In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of hypothalamic Sirt1 in body weight and energy balance regulation is debated. The first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague Dawley rats. Central inhibition of Sirt1 decreased body weight and food intake as a result of a forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which in turn increased phosphorylated FoxO1 via improved insulin/phosphorylated AKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the alpha melanocyte-stimulating hormone (alpha-MSH) maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product alpha-MSH released into the paraventricular nucleus. Increased in alpha-MSH led to augmented TRH levels and circulating T3 levels (triiodothyronine, thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics. PMID- 25549051 TI - Breastfeeding outcome comparison by parity. AB - OBJECTIVE: Anecdotally, breastfeeding experiences differ between those who have previously nursed an infant and those who are primiparous. This analysis contrasted breastfeeding outcomes between primiparous women and those with previous experience spanning from maternity stay through 6 months postpartum. STUDY DESIGN: A secondary analysis was conducted of data collected in a randomized, controlled trial with mothers and "well" newborns >=34 weeks of gestation comparing two post-hospital discharge care models. Mothers completed an in-person interview during the postpartum stay and phone surveys at 2 weeks, 2 months, and 6 months where questionnaires related to breastfeeding were completed. All participants intended to breastfeed. Chi-squared and Wilcoxon rank sum tests were used to test for differences between parity groups. Breastfeeding duration by parity group was compared using a Kaplan-Meier plot and a logrank test. A Cox proportional hazards model was used to evaluate the relationship between breastfeeding duration and parity after adjusting for covariates. RESULTS: Among 1,099 mothers available for analysis, 542 (49%) were primiparous. Multiparous mothers had a longer intended breastfeeding duration (median, 9 vs. 6 months; p<0.001). Following delivery, primiparous mothers had a longer median time to first breastfeeding attempt (119 vs. 96 minutes; p<0.001) and were more likely to have eight or fewer feeding attempts in the first 24 hours (33% vs. 44%; p<0.001)). More primiparous women reported early breastfeeding problems (35% vs. 20%; p<0.001) and mixed feeding at hospital discharge (39% vs. 23%; p<0.001) despite reporting less breastfeeding-associated pain during the first week (p=0.04). Multiparous women were more likely to breastfeed through 6 months (p<0.001). In a multivariable Cox model for breastfeeding duration, an interaction existed between intended breastfeeding duration and parity (p=0.006); among those intending to breastfeed for 12 months, multiparous mothers had a significantly lower hazard of stopping breastfeeding (hazard ratio=0.66; p=0.03) than primiparous mothers. CONCLUSIONS: Women who have breastfed previously have significantly different breastfeeding experiences than primiparous women. Pre- and postdelivery breastfeeding support should differentially target primiparous women to improve breastfeeding outcomes. PMID- 25549052 TI - The association between platelet count and metabolic syndrome in children and adolescents. AB - The goal of this study was to evaluate the association between platelet count and metabolic syndrome (MetS) in children and adolescents in Korea. This study included data from 2228 subjects (1201 boys and 1027 girls) who participated in the 2010-2012 Korean National Health and Nutrition Examination Survey (KNHANES V). We used the modified National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria to define MetS. Odds ratios (95% confidence intervals [CIs]) for MetS were calculated with a multiple logistic regression analysis after adjusting for confounding factors across platelet count quartiles. The overall prevalence of MetS according to the modified NCEP-ATP III criteria was 4.9% (+/- 0.7%) in boys and 5.7% (+/- 0.9%) in girls. The prevalence of MetS significantly increased with increasing platelet quartiles in both boys and girls. In a multiple logistic regression analysis, the adjusted ORs (95% CIs) for the highest vs. the lowest quartile were 5.03 (1.30-19.48) in boys and 4.08 (1.20 13.93) in girls after adjusting for age and total cholesterol. CONCLUSIONS: Higher platelet count was associated with increased prevalence and risk of MetS in children and adolescents. PMID- 25549053 TI - Future prospects: assessment of intraoperative optical coherence tomography in ab interno glaucoma surgery. AB - PURPOSE: Ab interno glaucoma surgery, such as trabecular aspiration or ab interno trabeculotomy, has been introduced as an alternative, non-filtering procedure to lower intraocular pressure in glaucoma patients. The purpose of the present study was to assess the feasibility of intraoperative spectral domain optical coherence tomography (iOCT) for improving ab interno glaucoma surgery. MATERIALS AND METHODS: Intraoperative optical coherence tomography was performed to visualize the anterior chamber angle, the aspiration canula during trabecular aspiration, and the trabectome device during ab interno trabeculotomy. A commercially available 840-nm iOCT was used in a clinical setting, a 1310-nm spectral-domain OCT in an experimental setting. RESULTS: In the clinical setting using the 840-nm iOCT, visualization of the aspiration canula and the trabectome device was possible, however, with rather limited visibility of the chamber angle and the trabecular meshwork. In the experimental setting, the 1310-nm OCT enabled excellent visualization of the chamber angle and detailed evaluation of the instrument-trabecular meshwork relation. CONCLUSIONS: Intraoperative use of optical coherence tomography may be helpful for ab interno glaucoma surgery. Adjustments of the commercially available iOCT, including longer wavelengths and oblique scanning options, are necessary for the clinical use. PMID- 25549054 TI - The value of the CoughAssist(r) in the daily lives of children with neuromuscular disorders: Experiences of families, children and physiotherapists. AB - OBJECTIVES: We explored parents', children's and physiotherapists' experiences of regular CoughAssist(r) use, along with their perceptions of its value as an adjunct to in their daily, home respiratory management. METHODS: All children in the care of a specialist neuromuscular service who regularly used a CoughAssist(r) device at home participated. Qualitative case study methods involved semi-structured interviews with three children with neuromuscular disorders (NMD), their parents and physiotherapist. Data were analysed using thematic content analysis. RESULTS: Participants (n = 9) perceived the CoughAssist(r) held benefits for physical, social and emotional aspects of living with NMD. Poor adherence was identified as the major barrier to effective use, governed by factors including child's resistance, time constraints, treatment preference, practitioner support and fear of pressure trauma. CONCLUSIONS: Barriers to regular CoughAssist(r) use must be identified and individually addressed to enable uptake into respiratory care, accurately measure its effectiveness and realise its perceived benefits to children with NMD. PMID- 25549056 TI - Factors associated with vaginal delivery in hypertensive and normotensive pregnant women submitted to labor induction with misoprostol: a cohort study. AB - OBJECTIVE: To determine the factors associated with vaginal delivery in hypertensive and normotensive pregnant women submitted to induction of labor with misoprostol. METHODS: A cohort study. RESULTS: The factors associated with vaginal delivery in both normotensive and hypertensive women were, respectively, Bishop score >= 4 (OR = 1.87; 95% CI: 1.06-3.29; p = 0.03) and (OR = 2.31; 95% CI: 1.25-4.28; p = 0.008) and parity >= 1 (OR = 4.36; 95% CI: 2.16-8.80; p < 0.0001) and (OR = 2.61; 95% CI: 1.36-5.04; p = 0.004). CONCLUSION: The factors associated with vaginal delivery were Bishop score >= 4 and parity >= 1 irrespective of whether or not the women were hypertensive. PMID- 25549057 TI - A retrospective review to assess whether spinal fusion and scoliosis correction improved activity and participation for children with Angelman syndrome. AB - OBJECTIVE: This study investigates outcome of scoliosis treatment for 11 children with Angelman syndrome (AS), with particular focus on activity, participation and the musculoskeletal factors that may affect these outcomes. METHODS: Retrospective review of medical records, radiographs and questionnaires administered to caregivers of 11 children (8M:3F) with AS and scoliosis. Six underwent observational treatment during childhood and five underwent spinal fusion. The Activities Scale for Kids (ASKp) questionnaire was used to measure activity and participation. Questionnaire and radiographic data were recorded over a 2 year period. RESULTS: In the observational group, scoliosis increased from 31 degrees to 46 degrees . Mean ASKp decreased from 13.8 to 11.9 (p = 0.06). In the operative group, scoliosis decreased from 68 degrees to 29 degrees . Mean ASKp increased from 11.4 to 15.9 (p < 0.01). There was also a reduction in spinal-related pain and mean number of hospital admissions for chest infection. However, there was a 60% major complication rate. There was no difference in mobility, GMFCS level, feeding or communication in either group before or after treatment. CONCLUSION: In children with significant scoliosis and AS, spinal fusion was associated with a small improvement in activity and participation, reduction in pain and a decrease in frequency of severe chest infections. Non operative treatment resulted in progression of scoliosis during childhood and decrease in activity. PMID- 25549058 TI - Anti-inflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: a review of the literature. AB - Immune responses play an important role in the pathophysiology of atherosclerosis and ischemic stroke. Atherosclerosis is a common condition that increases the risk of stroke. Hyperlipidemia damages endothelial cells, thus initiating chemokine pathways and the release of inflammatory cytokines-this represents the first step in the inflammatory response to atherosclerosis. Blocking blood flow in the brain leads to ischemic stroke, and deprives neurons of oxygen and energy. Damaged neurons release danger-associated molecular patterns, which promote the activation of innate immune cells and the release of inflammatory cytokines. The nuclear factor kappa-light-chain-enhancer of activated B cells kappaB (NF-kappaB) pathway plays a key role in the pathogenesis of atherosclerosis and ischemic stroke. Vinpocetine is believed to be a potent anti-inflammatory agent and has been used to treat cerebrovascular disorders. Vinpocetine improves neuronal plasticity and reduces the release of inflammatory cytokines and chemokines from endothelial cells, vascular smooth muscle cells, macrophages, and microglia, by inhibiting the inhibitor of the NF-kappaB pathway. This review clarifies the anti inflammatory role of vinpocetine in atherosclerosis and ischemic stroke. PMID- 25549059 TI - Marine sponge lectins: actual status on properties and biological activities. AB - Marine sponges are primitive metazoans that produce a wide variety of molecules that protect them against predators. In studies that search for bioactive molecules, these marine invertebrates stand out as promising sources of new biologically-active molecules, many of which are still unknown or little studied; thus being an unexplored biotechnological resource of high added value. Among these molecules, lectins are proteins that reversibly bind to carbohydrates without modifying them. In this review, various structural features and biological activities of lectins derived from marine sponges so far described in the scientific literature are discussed. From the results found in the literature, it could be concluded that lectins derived from marine sponges are structurally diverse proteins with great potential for application in the production of biopharmaceuticals, especially as antibacterial and antitumor agents. PMID- 25549060 TI - Flavonoids from Symplocos racemosa. AB - A novel isoflavone glycoside, peseudobatigenin 7-O-[beta-d-apiofuranosyl-(1'''' >5''')-O-beta-d-apiofuranosyl-(1'''->6'')]-beta-d-glucopyranoside, namely sympracemoside (1), was isolated from the aerial parts of Symplocos racemosa along with 15 known flavonoids (2-16). Their structures were characterized by Q TOF mass, optical rotation, UV, 1D and 2D-NMR spectroscopic data. Compounds 3, 9, 16 showed moderate inhibitory activities against NO production with IC50 value of 88.2, 42.1 and 74.3 MUM, respectively. PMID- 25549061 TI - Assessment of difference in gene expression profile between embryos of different derivations. AB - Researchers have exerted sustained efforts to improve the viability of somatic cell nuclear transfer (SCNT) embryos, testing their experimental designs and probing the resultant embryos. However, the lack of a reliable method to estimate the efficacy of these experimental attempts is a chief hindrance to tackling the low-viability problem in SCNT. Here, we introduce a procedure that assesses the degree of difference in gene expression profiles (GEPs) of blastocysts from each other as a representative control of good quality. We first adapted a multiplex reverse transcription-polymerase chain reaction strategy to obtain GEPs for 15 reprogramming-related genes from single mouse blastocysts. GEPs of individual blastocysts displayed a broad range of variations, the extent of which was calculated using a weighted root mean square deviation (wRMSD). wRMSD-based quantitation of GEP difference (qGEP) found that GEP difference between in vivo derived blastocysts (in vivo) and SCNT blastocysts was greater than the difference between in vivo blastocysts and in vitro-produced (IVP) blastocysts, demonstrating that the SCNT group was more distantly related to the in vivo group than the IVP group. Our qGEP approach for grading individual blastocysts would be useful for selecting a better protocol to derive embryos of better quality prior to field applications. PMID- 25549062 TI - Out-of-range international normalized ratio values and healthcare cost among new warfarin patients with non-valvular atrial fibrillation. AB - BACKGROUND: Patients with out-of-range international normalized ratio (INR) values <2.0 and >3.0 have been associated with increased risk of thromboembolic and bleeding events. INR monitoring is costly, because of associated physician and nurse time, laboratory resource use, and dose adjustments. OBJECTIVES: This study assessed the healthcare cost burden associated with out-of-range INR among warfarin initiator patients diagnosed with non-valvular atrial fibrillation (NVAF) in the US Veterans Health Administration (VHA) population. METHODS: Adult NVAF patients (>=18 years) initiating warfarin were selected from the VHA dataset for the study period October 1, 2007-September 30, 2012. Only valid INR measurements (0.5 <= INR <= 20) were examined for the follow-up period, from the index date (warfarin initiation date) until the end of warfarin exposure or death. All-cause healthcare costs within 30 days were measured starting from the second month (31 days post-index date) to the end of the study period. Costs for inpatient stays, emergency room, outpatient facility, physician office visits, and other services were computed separately. Multiple regression was performed using the generalized linear model for overall cost analysis. RESULTS: In total, 29,463 patients were included in the study sample. Mean costs for out-of-range INR ranged from $3419 to $5126. Inpatient, outpatient, outpatient pharmacy, and total costs were significantly higher after patients experienced out-of-range results (INR < 2, INR > 3), compared with in-range INR (2 <= INR <= 3). When exposed to out-of-range INR, patients also incurred higher mean total costs within 2-6 months ($3840-$5820) than after the first 6 months ($2789-$3503) of warfarin therapy. CONCLUSION: In the VHA population, INR measures outside of the 2-3 range were associated with significantly higher healthcare costs. Increased costs were especially apparent when INR values were below 2, although INR measures above 3 were also associated with higher costs relative to in-range values. PMID- 25549063 TI - Intravitreal Adalimumab in Active Noninfectious Uveitis: A Pilot Study. AB - PURPOSE: To evaluate the short-term efficacy of intravitreal adalimumab (IVA) for the treatment of eyes with active noninfectious uveitis. METHODS: Consecutive eyes with active noninfectious uveitis were injected with IVA at 0, 2, then every 4 weeks for total of 26 weeks. RESULTS: Six out of 7 patients (12 of 13 eyes) completed 26 weeks of treatment. One patient (1 eye) failed treatment. Seven out of 12 eyes had improvement of >=2 ETDRS lines. Three out of three eyes had resolution of anterior chamber cells. And 9 of 10 eyes with vitreous haze had zero haze at 26 weeks. Five out of 8 eyes with macular edema had complete resolution. Median fluorescein angiography score improved from 14 to 4 on last follow-up. CONCLUSIONS: IVA was effective in controlling the inflammation, decreasing the macular edema, and improving the best corrected visual acuity in the majority of eyes in this series. PMID- 25549064 TI - Chromosomal microstructure diversity in three Astyanax (Characiformes, Characidae) species: comparative analysis of the chromosomal locations of the 18S and 5S rDNAs. AB - The species of genus Astyanax is widely distributed in freshwater neotropical zones. Astyanax is considered to be taxonomically confused, similar to other genera placed incertae sedis in Characidae. The cytogenetics of this genus is well characterized; species vary widely in diploid number, from 2n=36 chromosomes in Astyanax schubarti to 2n=50 for most species studied. The size, number, and position of different cytological markers vary among species and populations of Astyanax. We analyzed the karyotypes of individuals from three Astyanax species (Astyanax abramis, Astyanax altiparanae, and Astyanax eigenmanniorum) from populations not previously analyzed. We describe variations in several cytogenetic markers and the karyotypic relationships between them, specifically focusing on the characteristics of the conserved and divergent locations of the ribosomal genes. Our data are useful for establishing relationships between species and for investigating the karyotype evolution within the genus. PMID- 25549065 TI - Curricular innovations for medical students in palliative and end-of-life care: a systematic review and assessment of study quality. AB - BACKGROUND: Recent focus on palliative and end-of-life care has led medical schools worldwide to enhance their palliative care curricula. OBJECTIVE: The objective of the study was to describe recent curricular innovations in palliative care for medical students, evaluate the quality of studies in the field, and inform future research and curricular design. METHODS: The authors searched Medline, Scopus, and Educational Resource Information Center (ERIC) for English-language articles published between 2007 and 2013 describing a palliative care curriculum for medical students. Characteristics of the curricula were extracted, and methodological quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI). RESULTS: The sample described 48 curricula in 12 countries. Faculty were usually interdisciplinary. Palliative care topics included patient assessment, communication, pain and symptom management, psychosocial and spiritual needs, bioethics and the law, role in the health care system, interdisciplinary teamwork, and self-care. Thirty-nine articles included quantitative evaluation, with a mean MERSQI score of 9.9 (on a scale of 5 to 18). The domain most likely to receive a high score was data analysis (mean 2.51 out of 3), while the domains most likely to receive low scores were validity of instrument (mean 1.05) and outcomes (mean 1.31). CONCLUSIONS: Recent innovations in palliative care education for medical students represent varied settings, learner levels, instructors, educational modalities, and palliative care topics. Future curricula should continue to incorporate interdisciplinary faculty. Studies could be improved by integrating longitudinal curricula and longer-term outcomes; collaborating across institutions; using validated measures; and assessing higher-level outcomes including skills, behaviors, and impact on patient care. PMID- 25549067 TI - Vaginal health prescription: possible next step in the management of genitourinary syndrome of menopause. PMID- 25549066 TI - Poor sleep in relation to natural menopause: a population-based 14-year follow-up of midlife women. AB - OBJECTIVE: This study aims to estimate the prevalence and predictors of moderate/severe poor sleep in relation to the final menstrual period (FMP) in midlife women. METHODS: Annual assessments were conducted in a population-based cohort of 255 women. All were premenopausal at cohort enrollment and reached natural menopause during the 16-year follow-up. The outcome measure was severity of poor sleep, as reported by participants in annual interviews for 16 years and as evaluated in relation to the FMP. RESULTS: The annual prevalence of moderate/severe poor sleep largely ranged from about 28% to 35%, with no significant differences in any year relative to the FMP for the sample overall. When sleep status was stratified at premenopausal baseline, premenopausal sleep status strongly predicted poor sleep around the FMP. Women with moderate/severe poor sleep in premenopause were approximately 3.5 times more likely to have moderate/severe poor sleep around menopause than those with no poor sleep at baseline in adjusted analysis (odds ratio, 3.58; 95% CI, 2.50-5.11; P < 0.0001), whereas mild poor sleepers in premenopause were approximately 1.5 times more likely to have moderate/severe poor sleep around menopause (odds ratio, 1.57; 95% CI, 0.99-2.47; P = 0.053). There was no significant association between poor sleep and time relative to the FMP among women who had no poor sleep at premenopausal baseline. Hot flashes were significantly associated with poor sleep (odds ratio, 1.79; 95% CI, 1.44-2.21; P < 0.0001 in adjusted analysis) but had no interaction with baseline sleep severity (interaction P = 0.25), indicating that hot flashes contributed to poor sleep regardless of baseline sleep status. CONCLUSIONS: Findings show a high prevalence of moderate/severe poor sleep in midlife women, with only a small "at-risk" subgroup having a significant increase in poor sleep in relation to the FMP. Sleep status at premenopausal baseline and concurrent hot flashes strongly and consistently predict poor sleep in the menopausal transition. Overall, poor sleep does not increase around the FMP and frequently occurs in the absence of hot flashes, indicating that sleep difficulties in the menopausal transition in generally healthy women are not simply associated with ovarian decline. PMID- 25549068 TI - The infiltration-centrifugation technique for extraction of apoplastic fluid from plant leaves using Phaseolus vulgaris as an example. AB - The apoplast is a distinct extracellular compartment in plant tissues that lies outside the plasma membrane and includes the cell wall. The apoplastic compartment of plant leaves is the site of several important biological processes, including cell wall formation, cellular nutrient and water uptake and export, plant-endophyte interactions and defence responses to pathogens. The infiltration-centrifugation method is well established as a robust technique for the analysis of the soluble apoplast composition of various plant species. The fluid obtained by this method is commonly known as apoplast washing fluid (AWF). The following protocol describes an optimized vacuum infiltration and centrifugation method for AWF extraction from Phaseolus vulgaris (French bean) cv. Tendergreen leaves. The limitations of this method and the optimization of the protocol for other plant species are discussed. Recovered AWF can be used in a wide range of downstream experiments that seek to characterize the composition of the apoplast and how it varies in response to plant species and genotype, plant development and environmental conditions, or to determine how microorganisms grow in apoplast fluid and respond to changes in its composition. PMID- 25549069 TI - Magnetic Resonance Imaging of Human Tissue-Engineered Adipose Substitutes. AB - Adipose tissue (AT) substitutes are being developed to answer the strong demand in reconstructive surgery. To facilitate the validation of their functional performance in vivo, and to avoid resorting to excessive number of animals, it is crucial at this stage to develop biomedical imaging methodologies, enabling the follow-up of reconstructed AT substitutes. Until now, biomedical imaging of AT substitutes has scarcely been reported in the literature. Therefore, the optimal parameters enabling good resolution, appropriate contrast, and graft delineation, as well as blood perfusion validation, must be studied and reported. In this study, human adipose substitutes produced from adipose-derived stem/stromal cells using the self-assembly approach of tissue engineering were implanted into athymic mice. The fate of the reconstructed AT substitutes implanted in vivo was successfully followed by magnetic resonance imaging (MRI), which is the imaging modality of choice for visualizing soft ATs. T1-weighted images allowed clear delineation of the grafts, followed by volume integration. The magnetic resonance (MR) signal of reconstructed AT was studied in vitro by proton nuclear magnetic resonance ((1)H-NMR). This confirmed the presence of a strong triglyceride peak of short longitudinal proton relaxation time (T1) values (200 +/- 53 ms) in reconstructed AT substitutes (total T1=813 +/- 76 ms), which establishes a clear signal difference between adjacent muscle, connective tissue, and native fat (total T1 ~300 ms). Graft volume retention was followed up to 6 weeks after implantation, revealing a gradual resorption rate averaging at 44% of initial substitute's volume. In addition, vascular perfusion measured by dynamic contrast enhanced-MRI confirmed the graft's vascularization postimplantation (14 and 21 days after grafting). Histological analysis of the grafted tissues revealed the persistence of numerous adipocytes without evidence of cysts or tissue necrosis. This study describes the in vivo grafting of human adipose substitutes devoid of exogenous matrix components, and for the first time, the optimal parameters necessary to achieve efficient MRI visualization of grafted tissue-engineered adipose substitutes. PMID- 25549071 TI - Phospholipase A2 group v in benign familial fleck retina in a set of triplets. AB - PURPOSE: To evaluate the association of phospholipase A2, Group V (PLA2G5), with benign familial fleck retina in a consanguineous family with triplets. METHODS: Clinical eye examination, including fundus examination and spectral domain optical coherence tomography, was performed for all the family members. After blood sample collection and DNA extraction, polymerase chain reaction was performed to amplify regions spanning Exons 2, 3, 4, and 5 of PLA2G5. The amplified products were sequenced to observe the presence of any mutations. RESULTS: Fundus examination in two of the triplets revealed discrete yellow-white flecks and both had good vision and absence of night blindness, consistent with benign familial fleck retina. The flecks were hyperautofluorescent. Furthermore, spectral domain optical coherence tomography showed focal thickening of the retinal pigment epithelium because of the presence of these flecks. Molecular investigations showed that PLA2G5 Exons 2, 4, and 5 harbored no misalignments among all family members. However, PLA2G5 Exon 3 showed a p.Gly45Cys mutation for the father and the third triplet who was affected. CONCLUSION: The clinical findings in this family suggest a diagnosis of benign familial fleck retina with excellent prognosis, in which the PLA2G5 gene may play a role. PMID- 25549070 TI - Generation of genomic deletions in mammalian cell lines via CRISPR/Cas9. AB - The prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 system may be re-purposed for site-specific eukaryotic genome engineering. CRISPR/Cas9 is an inexpensive, facile, and efficient genome editing tool that allows genetic perturbation of genes and genetic elements. Here we present a simple methodology for CRISPR design, cloning, and delivery for the production of genomic deletions. In addition, we describe techniques for deletion, identification, and characterization. This strategy relies on cellular delivery of a pair of chimeric single guide RNAs (sgRNAs) to create two double strand breaks (DSBs) at a locus in order to delete the intervening DNA segment by non-homologous end joining (NHEJ) repair. Deletions have potential advantages as compared to single-site small indels given the efficiency of biallelic modification, ease of rapid identification by PCR, predictability of loss-of-function, and utility for the study of non-coding elements. This approach can be used for efficient loss-of-function studies of genes and genetic elements in mammalian cell lines. PMID- 25549072 TI - Correlation between foveal interdigitation zone band defect and visual acuity after surgery for macular pseudohole. AB - PURPOSE: To determine the correlation between the integrity of the foveal microstructures and the best-corrected visual acuity (BCVA) after pars plana vitrectomy for a macular pseudohole. METHODS: Thirty-one eyes of 31 patients with a macular pseudohole underwent vitrectomy with internal limiting membrane removal. The foveal area was examined by spectral domain optical coherence tomography preoperatively and postoperatively. The correlations between the BCVA and the lengths of the photoreceptor interdigitation zone (IZ), the ellipsoid zone, and the external limiting membrane band defects, and central foveal thickness were determined. RESULTS: The BCVA improved significantly and the length of the IZ band defect decreased significantly after the surgery. Simple linear regression analyses showed that the BCVA was significantly correlated with the length of the IZ band defect preoperatively and also at 1 to 12 months postoperatively (P < 0.001 for all). The BCVA was not significantly correlated with the length of the ellipsoid zone, external limiting membrane band defect, and the central foveal thickness. CONCLUSION: The significant correlation between the length of the foveal IZ band defect and the BCVA preoperatively and postoperatively indicates that the foveal IZ band is related to the visual recovery in patients with macular pseudohole. PMID- 25549073 TI - One-year outcomes of eyes treated with a sutureless scleral fixation technique for intraocular lens placement or rescue. AB - PURPOSE: To report the 1 year results of a novel surgical technique for sutureless scleral fixation of a 3-piece intraocular lens. METHODS: Retrospective consecutive series of patients who underwent sutureless scleral fixation of a three-piece intraocular lens. All patients were required to have at least 1 year of follow-up to be included in the series. Outcomes data were obtained and treated with simple statistical analyses. RESULTS: A total of 24 patients were included in the study population. The average age was 75 years (range, 44-87). Short-term complications were few and included vitreous hemorrhage (n = 2), elevated intraocular pressure (n = 1), and hypotony (n = 1). Long-term complications included intraocular lens dislocation (n = 3) and cystoid macular edema (n = 1). Mean visual acuity improved from logMAR 1.30 (Snellen 20/399) to 0.52 (Snellen 20/66) at 1 year. CONCLUSION: This novel technique for sutureless scleral fixation of a three-piece intraocular lens was well-tolerated 1 year after surgery. PMID- 25549074 TI - Simple surgeon-controlled method of safe, cost-effective, and efficient application of chromovitrectomy agents through reflux. PMID- 25549075 TI - Capecitabine-Induced Takotsubo Cardiomyopathy: A Case Report and Literature Review. AB - Capecitabine is an orally administered chemotherapeutic agent that is metabolized at the tumor site to 5-fluorouracil and thought to be without significant cardiac toxicity. We report a rare case of takotsubo cardiomyopathy that is thought to be related to capecitabine where the patient presented with chest pain, and ST elevation within 48 hours of capecitabine therapy. Workup included cardiac catheterization and coronary angiogram that showed nonobstructive coronary artery disease and anteroapical left ventricular wall motion abnormality with left ventricular ejection fraction of 35%. The drug was stopped, and the patient was treated with beta-blocker and angiotensin-converting enzymes inhibitor. Six weeks later, she had a repeat echocardiogram that was normal. Capecitabine-related cardiomyopathy seems to be very rare because only 5 cases have been reported in the literature (including our case). The condition has to be anticipated and treated to prevent the serious consequence of cardiac dysfunction. All reported cases have eventually recovered after stopping capecitabine. PMID- 25549076 TI - Novel Pharmacotherapies for B-Cell Lymphomas and Leukemias. AB - Novel pharmacotherapeutic agents were recently approved for treatment of low grade B-cell neoplasms, and many other agents are under investigation. Several agents have demonstrated impressive activity in targeting malignant B-cell processes and specific pathways, all with the potential to expand our ability to effectively treat B-cell malignancies. The inhibitors of several cell regulatory proteins, including Bruton tyrosine kinase (Btk), phosphoinositide 3-kinase (PI3 K), B-cell lymphoma/leukemia-2 (Bcl-2), and histone deacetylases, as well as immunomodulatory agents are a few of the many pharmacotherapeutic agents under study. A comprehensive review and assessment is presented of the current pharmacotherapies under investigation targeting B-cell lymphomas and leukemias. PMID- 25549077 TI - A Literature Review Revisiting Phenytoin-Induced Sinus Arrest. AB - Classically, phenytoin (PTN) infusion for the treatment of status epilepticus has been proven to be associated with cardiovascular toxicity, including dysrhythmias, hypotension, and cardiovascular collapse. Subsequently, fosphenytoin (FOS) was introduced on the market in 1997 with claims of having less cardiac toxicity. However, since then, many accounts of cardiac events have been reported undermining these claims. FOS gained popularity due to its water solubility, which allows 3 times faster infusion in comparison with PTN with less venous irritation and local toxicity. FOS is the phosphate ester prodrug of PTN and is rapidly converted to PTN independent of the dose and rate of administration. Intravenous FOS and PTN are bioequivalent. Adverse cardiac effects of both intravenous FOS and PTN have been correlated to the rate of infusion, concentration of the agent, known risk factors, or pre-existing hypersensitivity, and most cases have been identified after infusing a loading dose of these medications. This case report is unique, in that, the patient developed sinus arrest while concurrently receiving oral PTN and intravenous FOS. Clinicians should be more cognizant of the association of FOS and PTN with adverse cardiac events. Baseline electrocardiogram should be obtained on all patients prescribed FOS or PTN to identify underlying cardiac problems that may place the patient in a higher risk category. Telemetry should be performed on all patients receiving PTN in an inpatient setting. PMID- 25549078 TI - Seizures as a Potential Complication of Treatment With Simeprevir and Sofosbuvir. AB - Newer direct-acting antiviral agents have revolutionized the medical management of chronic hepatitis C. In addition to being extremely efficacious, they report very mild adverse drug reactions from experience in clinical trials. However, because they are relatively new on the horizon, postmarketing surveillance studies refining the safety profile are not yet available. We present a case of seizures as a potential side effect of antiviral therapy with sofosbuvir and simeprevir. PMID- 25549079 TI - Characterizing a proton beam scanning system for Monte Carlo dose calculation in patients. AB - The presented work has two goals. First, to demonstrate the feasibility of accurately characterizing a proton radiation field at treatment head exit for Monte Carlo dose calculation of active scanning patient treatments. Second, to show that this characterization can be done based on measured depth dose curves and spot size alone, without consideration of the exact treatment head delivery system. This is demonstrated through calibration of a Monte Carlo code to the specific beam lines of two institutions, Massachusetts General Hospital (MGH) and Paul Scherrer Institute (PSI). Comparison of simulations modeling the full treatment head at MGH to ones employing a parameterized phase space of protons at treatment head exit reveals the adequacy of the method for patient simulations. The secondary particle production in the treatment head is typically below 0.2% of primary fluence, except for low-energy electrons (<0.6 MeV for 230 MeV protons), whose contribution to skin dose is negligible. However, there is significant difference between the two methods in the low-dose penumbra, making full treatment head simulations necessary to study out-of-field effects such as secondary cancer induction. To calibrate the Monte Carlo code to measurements in a water phantom, we use an analytical Bragg peak model to extract the range dependent energy spread at the two institutions, as this quantity is usually not available through measurements. Comparison of the measured with the simulated depth dose curves demonstrates agreement within 0.5 mm over the entire energy range. Subsequently, we simulate three patient treatments with varying anatomical complexity (liver, head and neck and lung) to give an example how this approach can be employed to investigate site-specific discrepancies between treatment planning system and Monte Carlo simulations. PMID- 25549081 TI - Square wave voltammetry of TNT at gold electrodes modified with self-assembled monolayers containing aromatic structures. AB - Square wave voltammetry for the reduction of 2,4,6-trinitrotoluene (TNT) was measured in 100 mM potassium phosphate buffer (pH 8) at gold electrodes modified with self-assembled monolayers (SAMs) containing either an alkane thiol or aromatic ring thiol structures. At 15 Hz, the electrochemical sensitivity (uA/ppm) was similar for all SAMs tested. However, at 60 Hz, the SAMs containing aromatic structures had a greater sensitivity than the alkane thiol SAM. In fact, the alkane thiol SAM had a decrease in sensitivity at the higher frequency. When comparing the electrochemical response between simulations and experimental data, a general trend was observed in which most of the SAMs had similar heterogeneous rate constants within experimental error for the reduction of TNT. This most likely describes a rate limiting step for the reduction of TNT. However, in the case of the alkane SAM at higher frequency, the decrease in sensitivity suggests that the rate limiting step in this case may be electron tunneling through the SAM. Our results show that SAMs containing aromatic rings increased the sensitivity for the reduction of TNT when higher frequencies were employed and at the same time suppressed the electrochemical reduction of dissolved oxygen. PMID- 25549080 TI - Moderate prenatal alcohol exposure and quantification of social behavior in adult rats. AB - Alterations in social behavior are among the major negative consequences observed in children with Fetal Alcohol Spectrum Disorders (FASDs). Several independent laboratories have demonstrated robust alterations in the social behavior of rodents exposed to alcohol during brain development across a wide range of exposure durations, timing, doses, and ages at the time of behavioral quantification. Prior work from this laboratory has identified reliable alterations in specific forms of social interaction following moderate prenatal alcohol exposure (PAE) in the rat that persist well into adulthood, including increased wrestling and decreased investigation. These behavioral alterations have been useful in identifying neural circuits altered by moderate PAE(1), and may hold importance for progressing toward a more complete understanding of the neural bases of PAE-related alterations in social behavior. This paper describes procedures for performing moderate PAE in which rat dams voluntarily consume ethanol or saccharin (control) throughout gestation, and measurement of social behaviors in adult offspring. PMID- 25549082 TI - A neuroscientific approach to the examination of concussions in student-athletes. AB - Concussions are occurring at alarming rates in the United States and have become a serious public health concern. The CDC estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities annually. Concussion as defined by the 2013 Concussion Consensus Statement "may be caused either by a direct blow to the head, face, neck or elsewhere on the body with an 'impulsive' force transmitted to the head." Concussions leave the individual with both short- and long-term effects. The short-term effects of sport related concussions may include changes in playing ability, confusion, memory disturbance, the loss of consciousness, slowing of reaction time, loss of coordination, headaches, dizziness, vomiting, changes in sleep patterns and mood changes. These symptoms typically resolve in a matter of days. However, while some individuals recover from a single concussion rather quickly, many experience lingering effects that can last for weeks or months. The factors related to concussion susceptibility and the subsequent recovery times are not well known or understood at this time. Several factors have been suggested and they include the individual's concussion history, the severity of the initial injury, history of migraines, history of learning disabilities, history of psychiatric comorbidities, and possibly, genetic factors. Many studies have individually investigated certain factors both the short-term and long-term effects of concussions, recovery time course, susceptibility and recovery. What has not been clearly established is an effective multifaceted approach to concussion evaluation that would yield valuable information related to the etiology, functional changes, and recovery. The purpose of this manuscript is to show one such multifaceted approached which examines concussions using computerized neurocognitive testing, event related potentials, somatosensory perceptual responses, balance assessment, gait assessment and genetic testing. PMID- 25549084 TI - Dwell time modulation restrictions do not necessarily improve treatment plan quality for prostate HDR brachytherapy. AB - Inverse planning algorithms for dwell time optimisation in interstitial high-dose rate (HDR) brachytherapy may produce solutions with large dwell time variations within catheters, which may result in undesirable selective high-dose subvolumes. Extending the dwell time optimisation model with a dwell time modulation restriction (DTMR) that limits dwell time differences between neighboring dwell positions has been suggested to eliminate this problem. DTMRs may additionally reduce the sensitivity for uncertainties in dwell positions that inevitably result from catheter reconstruction errors and afterloader source positioning inaccuracies. This study quantifies the reduction of high-dose subvolumes and the robustness against these uncertainties by applying a DTMR to template-based prostate HDR brachytherapy implants. Three different DTMRs were consecutively applied to a linear dose-based penalty model (LD) and a dose-volume based model (LDV), both obtained from literature. The models were solved with DTMR levels ranging from no restriction to uniform dwell times within catheters in discrete steps. Uncertainties were simulated on clinical cases using in-house developed software, and dose-volume metrics were calculated in each simulation. For the assessment of high-dose subvolumes, the dose homogeneity index (DHI) and the contiguous dose volume histogram were analysed. Robustness was measured by the improvement of the lowest D90% of the planning target volume (PTV) observed in the simulations. For (LD), a DTMR yields an increase in DHI of approximately 30% and reduces the size of the largest high-dose volume by 2-5 cc. However, this comes at a cost of a reduction in D90% of the PTV of 10%, which often implies that it drops below the desired minimum of 100%. For (LDV), none of the DTMRs were able to improve high-dose volume measures. DTMRs were not capable of improving robustness of PTV D90% against uncertainty in dwell positions for both models. PMID- 25549083 TI - Metabolomics data normalization with EigenMS. AB - Liquid chromatography mass spectrometry has become one of the analytical platforms of choice for metabolomics studies. However, LC-MS metabolomics data can suffer from the effects of various systematic biases. These include batch effects, day-to-day variations in instrument performance, signal intensity loss due to time-dependent effects of the LC column performance, accumulation of contaminants in the MS ion source and MS sensitivity among others. In this study we aimed to test a singular value decomposition-based method, called EigenMS, for normalization of metabolomics data. We analyzed a clinical human dataset where LC MS serum metabolomics data and physiological measurements were collected from thirty nine healthy subjects and forty with type 2 diabetes and applied EigenMS to detect and correct for any systematic bias. EigenMS works in several stages. First, EigenMS preserves the treatment group differences in the metabolomics data by estimating treatment effects with an ANOVA model (multiple fixed effects can be estimated). Singular value decomposition of the residuals matrix is then used to determine bias trends in the data. The number of bias trends is then estimated via a permutation test and the effects of the bias trends are eliminated. EigenMS removed bias of unknown complexity from the LC-MS metabolomics data, allowing for increased sensitivity in differential analysis. Moreover, normalized samples better correlated with both other normalized samples and corresponding physiological data, such as blood glucose level, glycated haemoglobin, exercise central augmentation pressure normalized to heart rate of 75, and total cholesterol. We were able to report 2578 discriminatory metabolite peaks in the normalized data (p<0.05) as compared to only 1840 metabolite signals in the raw data. Our results support the use of singular value decomposition-based normalization for metabolomics data. PMID- 25549085 TI - Age-related loss of lumbar spinal lordosis and mobility--a study of 323 asymptomatic volunteers. AB - BACKGROUND: The understanding of the individual shape and mobility of the lumbar spine are key factors for the prevention and treatment of low back pain. The influence of age and sex on the total lumbar lordosis and the range of motion as well as on different lumbar sub-regions (lower, middle and upper lordosis) in asymptomatic subjects still merits discussion, since it is essential for patient specific treatment and evidence-based distinction between painful degenerative pathologies and asymptomatic aging. METHODS AND FINDINGS: A novel non-invasive measuring system was used to assess the total and local lumbar shape and its mobility of 323 asymptomatic volunteers (age: 20-75 yrs; BMI <26.0 kg/m2; males/females: 139/184). The lumbar lordosis for standing and the range of motion for maximal upper body flexion (RoF) and extension (RoE) were determined. The total lordosis was significantly reduced by approximately 20%, the RoF by 12% and the RoE by 31% in the oldest (>50 yrs) compared to the youngest age cohort (20-29 yrs). Locally, these decreases mostly occurred in the middle part of the lordosis and less towards the lumbo-sacral and thoraco-lumbar transitions. The sex only affected the RoE. CONCLUSIONS: During aging, the lower lumbar spine retains its lordosis and mobility, whereas the middle part flattens and becomes less mobile. These findings lay the ground for a better understanding of the incidence of level- and age-dependent spinal disorders, and may have important implications for the clinical long-term success of different surgical interventions. PMID- 25549086 TI - Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial. AB - BACKGROUND: Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5-5 y. METHODS AND FINDINGS: An open-label, randomized, parallel-group trial of artemether lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI -3.0% to 8.4%] versus -5.0% non inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%-87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing. CONCLUSIONS: Artemisinin-naphthoquine is non inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000913077. Please see later in the article for the Editors' Summary. PMID- 25549087 TI - MiR-29a reduces TIMP-1 production by dermal fibroblasts via targeting TGF-beta activated kinase 1 binding protein 1, implications for systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterised by skin and internal organs fibrosis due to accumulation of extra cellular matrix (ECM) proteins. Tissue inhibitor of metalloproteinases 1 (TIMP-1) plays a key role in ECM deposition. AIM: To investigate the role of miR-29a in regulation of TAB1-mediated TIMP-1 production in dermal fibroblasts in systemic sclerosis. METHODS: Healthy control (HC) and SSc fibroblasts were cultured from skin biopsies. The expression of TIMP-1, MMP-1 and TGF-beta activated kinase 1 binding protein 1 (TAB1) was measured following miR-29a transfection using ELISA, qRT-PCR, and Western Blotting. The functional effect of miR-29a on dermal fibroblasts was assessed in collagen gel assay. In addition, HeLa cells were transfected with 3'UTR of TAB1 plasmid cloned downstream of firefly luciferase gene to assess TAB1 activity. HC fibroblasts and HeLa cells were also transfected with Target protectors in order to block the endogenous miR-29a activity. RESULTS: We found that TAB1 is a novel target gene of miR-29a, also regulating downstream TIMP-1 production. TAB1 is involved in TGF-beta signal transduction, a key cytokine triggering TIMP-1 production. To confirm that TAB1 is a bona fide target gene of miR-29a, we used a TAB1 3'UTR luciferase assay and Target protector system. We showed that miR-29a not only reduced TIMP-1 secretion via TAB1 repression, but also increased functional MMP-1 production resulting in collagen degradation. Blocking TAB1 activity by pharmacological inhibition or TAB1 knockdown resulted in TIMP-1 reduction, confirming TAB1-dependent TIMP-1 regulation. Enhanced expression of miR-29a was able to reverse the profibrotic phenotype of SSc fibroblasts via downregulation of collagen and TIMP-1. CONCLUSIONS: miR-29a repressed TAB1-mediated TIMP-1 production in dermal fibroblasts, demonstrating that miR-29a may be a therapeutic target in SSc. PMID- 25549088 TI - Validation of network communicability metrics for the analysis of brain structural networks. AB - Computational network analysis provides new methods to analyze the brain's structural organization based on diffusion imaging tractography data. Networks are characterized by global and local metrics that have recently given promising insights into diagnosis and the further understanding of psychiatric and neurologic disorders. Most of these metrics are based on the idea that information in a network flows along the shortest paths. In contrast to this notion, communicability is a broader measure of connectivity which assumes that information could flow along all possible paths between two nodes. In our work, the features of network metrics related to communicability were explored for the first time in the healthy structural brain network. In addition, the sensitivity of such metrics was analysed using simulated lesions to specific nodes and network connections. Results showed advantages of communicability over conventional metrics in detecting densely connected nodes as well as subsets of nodes vulnerable to lesions. In addition, communicability centrality was shown to be widely affected by the lesions and the changes were negatively correlated with the distance from lesion site. In summary, our analysis suggests that communicability metrics that may provide an insight into the integrative properties of the structural brain network and that these metrics may be useful for the analysis of brain networks in the presence of lesions. Nevertheless, the interpretation of communicability is not straightforward; hence these metrics should be used as a supplement to the more standard connectivity network metrics. PMID- 25549089 TI - Epidemiology of pathogen-specific respiratory infections among three US populations. AB - BACKGROUND: Diagnostic tests for respiratory infections can be costly and time consuming. Improved characterization of specific respiratory pathogens by identifying frequent signs, symptoms and demographic characteristics, along with improving our understanding of coinfection rates and seasonality, may improve treatment and prevention measures. METHODS: Febrile respiratory illness (FRI) and severe acute respiratory infection (SARI) surveillance was conducted from October 2011 through March 2013 among three US populations: civilians near the US-Mexico border, Department of Defense (DoD) beneficiaries, and military recruits. Clinical and demographic questionnaire data and respiratory swabs were collected from participants, tested by PCR for nine different respiratory pathogens and summarized. Age stratified characteristics of civilians positive for influenza and recruits positive for rhinovirus were compared to other and no/unknown pathogen. Seasonality and coinfection rates were also described. RESULTS: A total of 1444 patients met the FRI or SARI case definition and were enrolled in this study. Influenza signs and symptoms varied across age groups of civilians. Recruits with rhinovirus had higher percentages of pneumonia, cough, shortness of breath, congestion, cough, less fever and longer time to seeking care and were more likely to be male compared to those in the no/unknown pathogen group. Coinfections were found in 6% of all FRI/SARI cases tested and were most frequently seen among children and with rhinovirus infections. Clear seasonal trends were identified for influenza, rhinovirus, and respiratory syncytial virus. CONCLUSIONS: The age-stratified clinical characteristics associated with influenza suggest that age-specific case definitions may improve influenza surveillance and identification. Improving identification of rhinoviruses, the most frequent respiratory infection among recruits, may be useful for separating out contagious individuals, especially when larger outbreaks occur. Overall, describing the epidemiology of pathogen specific respiratory diseases can help improve clinical diagnoses, establish baselines of infection, identify outbreaks, and help prioritize the development of new vaccines and treatments. PMID- 25549090 TI - Applicability of preoperative nuclear morphometry to evaluating risk for cervical lymph node metastasis in oral squamous cell carcinoma. AB - BACKGROUND: We previously reported the utility of preoperative nuclear morphometry for evaluating risk for cervical lymph node metastases in tongue squamous cell carcinoma. The risk for lymph node metastasis in oral squamous cell carcinoma, however, is known to differ depending on the anatomical site of the primary tumor, such as the tongue, gingiva, mouth floor, and buccal mucosa. In this study, we evaluated the applicability of this morphometric technique to evaluating the risk for cervical lymph node metastasis in oral squamous cell carcinoma. METHODS: A digital image system was used to measure the mean nuclear area, mean nuclear perimeter, nuclear circular rate, ratio of nuclear length to width (aspect ratio), and nuclear area coefficient of variation (NACV). Relationships between these parameters and nodal status were evaluated by t-test and logistic regression analysis. RESULTS: Eighty-eight cases of squamous cell carcinoma (52 of the tongue, 25 of the gingiva, 4 of the buccal mucosa, and 7 of the mouth floor) were included: 46 with positive node classification and 42 with negative node classification. Nuclear area and perimeter were significantly larger in node-positive cases than in node-negative cases; however, there were no significant differences in circular rate, aspect ratio, or NACV. We derived two risk models based on the results of multivariate analysis: Model 1, which identified age and mean nuclear area and Model 2, which identified age and mean nuclear perimeter. It should be noted that primary tumor site was not associated the pN-positive status. There were no significant differences in pathological nodal status by aspect ratio, NACV, or primary tumor site. CONCLUSION: Our method of preoperative nuclear morphometry may contribute valuable information to evaluations of the risk for lymph node metastasis in oral squamous cell carcinoma. PMID- 25549091 TI - Vitamin intake reduce the risk of gastric cancer: meta-analysis and systematic review of randomized and observational studies. AB - AIM: The association between vitamin intake and gastric cancer (GC) has been widely debated due to the relatively weak evidence. In this study, a meta analysis of prospective and well designed observational studies were performed to explore this association. METHODS: MEDLINE, Cochrane Library, and Sciencedirect were searched for studies of vitamin consumption and gastric cancer. This produced 47 relevant studies covering 1,221,392 human subjects. Random effects models were used to estimate summary relative risk (RR). Dose-response, subgroup, sensitivity, meta-regression, and publication bias analyses were conducted. RESULTS: The RR of gastric cancer in the group with the highest vitamin intake was compared to that of the lowest intake group. Total vitamin intake was 0.78 (95% CI, 0.71-0.83). In 9 studies that individuals were given doses at least 4 times above the tolerable upper intake (UL) vitamins, the RR was 1.20 (95% CI, 0.99-1.44). However, in 17 studies that individuals received doses below the UL, the RR was 0.76 (95% CI, 0.68-0.86). Dose-response analysis was conducted on different increments in different types of vitamins (vitamin A: 1.5 mg/day, vitamin C: 100 mg/day, vitamin E: 10 mg/day) intake with a significant reduction in the risk of gastric cancer, respectively, 29% in vitamin A, 26% in vitamin C, and 24% in vitamin E. CONCLUSION: This meta-analysis clearly demonstrated that low doses of vitamins can significantly reduce the risk of GC, especially vitamin A, vitamin C, vitamin E. PMID- 25549092 TI - Expression characteristics of beta-catenin in scallop Chlamys farreri gonads and its role as a potential upstream gene of Dax1 through canonical Wnt signalling pathway regulating the spermatogenesis. AB - beta-catenin is a key signaling molecule in the canonical Wnt pathway, which is involved in animal development. However, little information has been reported for beta-catenin in bivalves. In the present study, we cloned a homolog of beta catenin from the scallop Chlamys farreri and determined its expression characteristics. The full-length cDNA of beta-catenin was 3,353 bp, including a 2,511 bp open reading frame that encoded a predicted 836 amino acid protein. Level of the beta-catenin mRNA increased significantly (P<0.05) with C. farreri gonadal development and presented a sexually dimorphic expression pattern in the gonads, which was significantly high in ovaries detected by quantitative real time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis revealed that the beta-catenin was mainly located in germ cells of the gonads, with obvious positive immune signals in the oogonia and oocytes of ovaries as well as in the spermatogonia and spermatocytes of testes, implying beta-catenin might be involved in the gametogenesis of C. farreri. Furthermore, when 0.1 ug/mL and 0.2 ug/mL DKK-1 (an inhibitor of the canonical Wnt pathway) were added in vitro to culture medium containing testis cells of C. farreri, the expression of beta catenin decreased significantly detected by qRT-PCR (P<0.05), suggesting the canonical Wnt signal pathway exists in the scallop testis. Similarly, when 50 uM and 100 uM quercetin (an inhibitor of beta-catenin) were added in vitro to the culture system, Dax1 expression was significantly down-regulated compared with controls (P<0.05), implying the beta-catenin is an upstream gene of Dax1 and is involved in the regulation of C. farreri spermatogenesis. PMID- 25549093 TI - Pharmacotherapy for adverse events reduces the length of hospital stay in patients admitted to otolaryngology ward: a single arm intervention study. AB - BACKGROUND: To determine whether adverse events extend the duration of hospitalization, and to evaluate the effectiveness of medical intervention in ameliorating adverse events and reducing the prolonged hospital stay associated with adverse events. METHODS: A single arm intervention study was conducted from October 2012 to March 2014 in the otolaryngology ward of a 614-bed, university affiliated hospital. Adverse events were monitored daily by physicians, pharmacists and nurses, and recorded in the electronic medical chart for each patient. Appropriate drug management of adverse events was performed by physicians in liaison with pharmacists. The Kaplan-Meier method was used to assess the length of hospitalization of patients who underwent medical intervention for adverse events. RESULTS: Of 571 patients admitted to the otolaryngology ward in a year, 219 patients (38.4%) experienced adverse events of grade >=2. The duration of hospitalization was affected by the grade of adverse events, with a mean duration of hospital stay of 9.2, 17.2, 28.3 and 47.0 days for grades 0, 1, 2, and 3-4, respectively. Medical intervention lowered the incidence of grade >=2 adverse events to 14.5%. The length of hospitalization was significantly shorter in patients who showed an improvement of adverse events after medical intervention than those who did not (26.4 days vs. 41.6 days, hazard ratio 1.687, 95% confidence interval: 1.260-2.259, P<0.001). A multivariate Cox proportional hazard analysis indicated that insomnia, constipation, nausea/vomiting, infection, non-cancer pain, oral mucositis, odynophagia and neutropenia were significant risk factors for prolongation of hospital stay. CONCLUSION: Patients who experienced adverse events are at high risk of prolonged hospitalization. Medical intervention for adverse events was found to be effective in reducing the length of hospital stay associated with adverse events. PMID- 25549094 TI - Phenylalanine is required to promote specific developmental responses and prevents cellular damage in response to ultraviolet light in soybean (Glycine max) during the seed-to-seedling transition. AB - UV-radiation elicits a suite of developmental (photomorphogenic) and protective responses in plants, but responses early post-germination have received little attention, particularly in intensively bred plants of economic importance. We examined germination, hypocotyl elongation, leaf pubescence and subcellular responses of germinating and/or etiolated soybean (Glycine max (L.) Merr.) seedlings in response to treatment with discrete wavelengths of UV-A or UV-B radiation. We demonstrate differential responses of germinating/young soybean seedlings to a range of UV wavelengths that indicate unique signal transduction mechanisms regulate UV-initiated responses. We have investigated how phenylalanine, a key substrate in the phenylpropanoid pathway, may be involved in these responses. Pubescence may be a key location for phenylalanine-derived protective compounds, as UV-B irradiation increased pubescence and accumulation of UV-absorbing compounds within primary leaf pubescence, visualized by microscopy and absorbance spectra. Mass spectrometry analysis of pubescence indicated that sinapic esters accumulate in the UV-irradiated hairs compared to unirradiated primary leaf tissue. Deleterious effects of some UV-B wavelengths on germination and seedling responses were reduced or entirely prevented by inclusion of phenylalanine in the growth media. Key effects of phenylalanine were not duplicated by tyrosine or tryptophan or sucrose, nor is the specificity of response due to the absorbance of phenylalanine itself. These results suggest that in the seed-to-seedling transition, phenylalanine may be a limiting factor in the development of initial mechanisms of UV protection in the developing leaf. PMID- 25549095 TI - Hearing loss as a function of aging and diabetes mellitus: a cross sectional study. AB - BACKGROUND: Although hearing loss may be caused by various factors, it is also a natural phenomenon associated with the aging process. This study was designed to assess the contributions of diabetes mellitus (DM) and hypertension, both chronic diseases associated with aging, as well as aging itself, to hearing loss in health screening examinees. METHODS: This study included 37,773 individuals who underwent health screening examinations from 2009 to 2012. The relationships between hearing threshold and subject age, hearing threshold at each frequency based on age group, the degree of hearing loss and the presence or absence of hypertension and DM were evaluated. RESULTS: The prevalence of hearing loss increased with age, being 1.6%, 1.8%, 4.6%, 14.0%, 30.8%, and 49.2% in subjects in their twenties, thirties, forties, fifties, sixties, and seventies, respectively (p<0.05). Hearing value per frequency showed aging-based changes, in the order of 6000, 4000, 2000, 1000 and 500 Hz, indicating greater hearing losses at high frequencies. The degree of hearing loss ranged from mild to severe. Aging and DM were correlated with the prevalence of hearing loss (p<0.05). There was no statistically significant association between hearing loss and hypertension after adjusting for age and DM. CONCLUSIONS: The prevalence of hearing loss increases with age and the presence of DM. Hearing loss was greatest at high frequencies. In all age groups, mild hearing loss was the most common form of hearing loss. PMID- 25549096 TI - Effects of standard humic materials on relative bioavailability of NDL-PCBs in juvenile swine. AB - Young children with their hand-to-mouth activity may be exposed to contaminated soils. However few studies assessing exposure of organic compounds sequestrated in soil were realized. The present study explores the impact of different organic matters on retention of NDL-PCBs during digestive processes using commercial humic substances in a close digestive model of children: the piglet. Six artificial soils were used. One standard soil, devoid of organic matter, and five amended versions of this standard soil with either fulvic acid, humic acid, Sphagnum peat, activated carbon or a mix of Sphagnum peat and activated carbon (95?5) (SPAC) were prepared. In order to compare the different treatments, we use spiked oil and negative control animals. Forty male piglets were randomly distributed in 7 contaminated and one control groups (n = 5 for each group). During 10 days, the piglets were fed artificial soil or a corn oil spiked with 19,200 ng of Aroclor 1254 per g of dry matter (6,000 ng.g-1 of NDL-PCBs) to achieve an exposure dose of 1,200 ng NDL-PCBs.Kg-1 of body weight per day. NDL PCBs in adipose tissue were analyzed by GC-MS. Fulvic acid reduced slightly the bioavailability of NDL-PCBs compared to oil. Humic acid and Sphagnum peat reduced it significantly higher whereas activated carbon reduced the most. Piglets exposed to soil containing both activated carbon and Shagnum peat exhibited a lower reduction than soil with only activated carbon. Therefore, treatment groups are ordered by decreasing value of relative bioavailability as following: oil >= fulvic acid>Sphagnum peat >= Sphagnum peat and activated carbon >= Humic acid>>activated carbon. This suggests competition between Sphagnum peat and activated carbon. The present study highlights that quality of organic matter does have a significant effect on bioavailability of sequestrated organic compounds. PMID- 25549097 TI - Long term health-related quality of life in survivors of sepsis in South West Wales: an epidemiological study. AB - INTRODUCTION: Survivors of sepsis report persistent problems that can last years after hospital discharge. The main aim of this study was to investigate long-term health-related quality of life in survivors of SIRS and sepsis compared with Welsh normative data, controlling for age, length of stay and pre-existing conditions. The second aim was to investigate any differences in long-term health related quality of life specifically with the patients categorised into three groups; SIRS, uncomplicated sepsis and severe sepsis/septic shock. METHODS: A prospective study design was used in order to investigate all sepsis patients either presenting to the Emergency Department or admitted to the Intensive Care Unit of a regional trauma centre. Baseline demographics, clinical characteristics and outcomes were collected and surviving patients were sent a SF-12v2 survey at between six months to two years post-hospital discharge. RESULTS: Quality of life was significantly reduced in all patients when compared to local normative data (all p<0.0001). Reductions in the physical components of health-related quality of life were more pronounced in severe sepsis/septic shock patients when compared to uncomplicated sepsis and SIRS patients, when controlling for age, pre-existing conditions, hospital and ICU length of stay. CONCLUSIONS: This is the first observational study to specifically focus on the different groups of SIRS and sepsis patients to assess long-term quality of life. Local population norms were used for comparison, rather than UK-wide norms that fail to reflect the intricacies of a country's population. PMID- 25549100 TI - Determining charge state of graphene vacancy by noncontact atomic force microscopy and first-principles calculations. AB - Graphene vacancies are engineered for novel functionalities, however, the charge state of these defects, the key parameter that is vital to charge transfer during chemical reactions and carrier scattering, is generally unknown. Here, we carried out atomic resolution imaging of graphene vacancy defects created by Ar plasma using noncontact atomic force microscopy, and made the first determination of their charge state by local contact potential difference measurements. Combined with density functional theory calculations, we show that graphene vacancies are typically positively charged, with size-dependent charge states that are not necessarily integer-valued. These findings provide new insights into carrier scattering by vacancy defects in graphene, as well as its functionalization for chemical sensing and catalysis, and underline the tunability of these functions by controlling the size of vacancy defect. PMID- 25549099 TI - Detection and analysis of DNA damage in mouse skeletal muscle in situ using the TUNEL method. AB - Terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) is the method of using the TdT enzyme to covalently attach a tagged form of dUTP to 3' ends of double- and single-stranded DNA breaks in cells. It is a reliable and useful method to detect DNA damage and cell death in situ. This video describes dissection, tissue processing, sectioning, and fluorescence-based TUNEL labeling of mouse skeletal muscle. It also describes a method of semi-automated TUNEL signal quantitation. Inherent normal tissue features and tissue processing conditions affect the ability of the TdT enzyme to efficiently label DNA. Tissue processing may also add undesirable autofluorescence that will interfere with TUNEL signal detection. Therefore, it is important to empirically determine tissue processing and TUNEL labeling methods that will yield the optimal signal-to-noise ratio for subsequent quantitation. The fluorescence-based assay described here provides a way to exclude autofluorescent signal by digital channel subtraction. The TUNEL assay, used with appropriate tissue processing techniques and controls, is a relatively fast, reproducible, quantitative method for detecting apoptosis in tissue. It can be used to confirm DNA damage and apoptosis as pathological mechanisms, to identify affected cell types, and to assess the efficacy of therapeutic treatments in vivo. PMID- 25549098 TI - Involvement of the P2X7 purinergic receptor in colonic motor dysfunction associated with bowel inflammation in rats. AB - BACKGROUND AND PURPOSE: Recent evidence indicates an involvement of P2X7 purinergic receptor (P2X7R) in the fine tuning of immune functions, as well as in driving enteric neuron apoptosis under intestinal inflammation. However, the participation of this receptor in the regulation of enteric neuromuscular functions remains undetermined. This study was aimed at investigating the role of P2X7Rs in the control of colonic motility in experimental colitis. EXPERIMENTAL APPROACH: Colitis was induced in rats by 2,4-dinitrobenzenesulfonic acid. P2X7R distribution was examined by immunofluorescence analysis. The effects of A804598 (selective P2X7R antagonist) and BzATP (P2X7R agonist) were tested on contractions of longitudinal smooth muscle evoked by electrical stimulation or by carbachol in the presence of tetrodotoxin. KEY RESULTS: P2X7Rs were predominantly located in myenteric neurons, but, in the presence of colitis, their expression increased in the neuromuscular layer. In normal preparations, A804598 elicited a negligible increase in electrically induced contractions, while a significant enhancement was recorded in inflamed tissues. In the presence of Nomega-propyl-L arginine (NPA, neuronal nitric oxide synthase inhibitor) the A804598 effects were lost. P2X7R stimulation with BzATP did not significantly affect electrical induced contractions in normal colon, while a marked reduction was recorded under inflammation. The inhibitory effect of BzATP was antagonized by A804598, and it was also markedly blunted by NPA. Both P2X7R ligands did not affect carbachol induced contractions. CONCLUSIONS AND IMPLICATIONS: The purinergic system contributes to functional neuromuscular changes associated with bowel inflammation via P2X7Rs, which modulate the activity of excitatory cholinergic nerves through a facilitatory control on inhibitory nitrergic pathways. PMID- 25549101 TI - Role of high mobility group box 1 (HMGB1) in SCA17 pathogenesis. AB - Spinocerebellar ataxia type 17 (SCA17) involves the expression of a polyglutamine (polyQ) expanded TATA-binding protein (TBP), a general transcription initiation factor. TBP interacts with other protein factors, including high mobility group box 1 (HMGB1), to regulate gene expression. Previously, our proteomic analysis of soluble proteins prepared from mutant TBP (TBP/Q61) expressing cells revealed a reduced concentration of HMGB1. Here, we show that HMGB1 can be incorporated into mutant TBP aggregates, which leads to reduced soluble HMGB1 levels in TBP/Q(61~79) expressing cells. HMGB1 overexpression reduced mutant TBP aggregation. HMGB1 cDNA and siRNA co-transfection, as well as an HSPA5 immunoblot and luciferase reporter assay demonstrated the important role of HMGB1 in the regulation of HSPA5 transcription. In starvation-stressed TBP/Q36 and TBP/Q79 cells, increased reactive oxygen species generation accelerated the cytoplasmic translocation of HMGB1, which accompanied autophagy activation. However, TBP/Q79 cells displayed a decrease in autophagy activation as a result of the reduction in the cytoplasmic HMGB1 level. In neuronal SH-SY5Y cells with induced TBP/Q(61~79) expression, HMGB1 expression was reduced and accompanied by a significant reduction in the total outgrowth and branches in the TBP/Q(61~79) expressing cells compared with the non-induced cells. The decreased soluble HMGB1 and impaired starvation-induced autophagy in cells suggest that HMGB1 may be a critical modulator of polyQ disease pathology and may represent a target for drug development. PMID- 25549102 TI - Measurement of mRNA decay rates in Saccharomyces cerevisiae using rpb1-1 strains. AB - mRNA steady state levels vary depending on environmental conditions. Regulation of the steady state accumulation levels of an mRNA ensures that the correct amount of protein is synthesized for the cell's specific growth conditions. One approach for measuring mRNA decay rates is inhibiting transcription and subsequently monitoring the disappearance of the already present mRNA. The rate of mRNA decay can then be quantified, and an accurate half-life can be determined utilizing several techniques. In S. cerevisiae, protocols that measure mRNA half lives have been developed and include inhibiting transcription of mRNA using strains that harbor a temperature sensitive allele of RNA polymerase II, rpb1-1. Other techniques for measuring mRNA half-lives include inhibiting transcription with transcriptional inhibitors such as thiolutin or 1,10-phenanthroline, or alternatively, by utilizing mRNAs that are under the control of a regulatable promoter such as the galactose inducible promoter and the TET-off system. Here, we describe measurement of S. cerevisiae mRNA decay rates using the temperature sensitive allele of RNA polymerase II. This technique can be used to measure mRNA decay rates of individual mRNAs or genome-wide. PMID- 25549103 TI - Disrupting reconsolidation of fear memory in humans by a noradrenergic beta blocker. AB - The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a beta-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders. PMID- 25549104 TI - Structured inquiry-based learning: Drosophila GAL4 enhancer trap characterization in an undergraduate laboratory course. AB - We have developed and tested two linked but separable structured inquiry exercises using a set of Drosophila melanogaster GAL4 enhancer trap strains for an upper-level undergraduate laboratory methods course at Bucknell University. In the first, students learn to perform inverse PCR to identify the genomic location of the GAL4 insertion, using FlyBase to identify flanking sequences and the primary literature to synthesize current knowledge regarding the nearest gene. In the second, we cross each GAL4 strain to a UAS-CD8-GFP reporter strain, and students perform whole mount CNS dissection, immunohistochemistry, confocal imaging, and analysis of developmental expression patterns. We have found these exercises to be very effective in teaching the uses and limitations of PCR and antibody-based techniques as well as critical reading of the primary literature and scientific writing. Students appreciate the opportunity to apply what they learn by generating novel data of use to the wider research community. PMID- 25549105 TI - Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. AB - IMPORTANCE: Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide. OBJECTIVES: To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. MAIN OUTCOMES AND MEASURES: The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. RESULTS: Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin(1A) BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). CONCLUSIONS AND RELEVANCE: Higher brainstem raphe serotonin(1A)BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin(1A) BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin(1A) BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts. PMID- 25549106 TI - MRI mapping of cerebrovascular reactivity via gas inhalation challenges. AB - The brain is a spatially heterogeneous and temporally dynamic organ, with different regions requiring different amount of blood supply at different time. Therefore, the ability of the blood vessels to dilate or constrict, known as Cerebral-Vascular-Reactivity (CVR), represents an important domain of vascular function. An imaging marker representing this dynamic property will provide new information of cerebral vessels under normal and diseased conditions such as stroke, dementia, atherosclerosis, small vessel diseases, brain tumor, traumatic brain injury, and multiple sclerosis. In order to perform this type of measurement in humans, it is necessary to deliver a vasoactive stimulus such as CO2 and/or O2 gas mixture while quantitative brain magnetic resonance images (MRI) are being collected. In this work, we presented a MR compatible gas delivery system and the associated protocol that allow the delivery of special gas mixtures (e.g., O2, CO2, N2, and their combinations) while the subject is lying inside the MRI scanner. This system is relatively simple, economical, and easy to use, and the experimental protocol allows accurate mapping of CVR in both healthy volunteers and patients with neurological disorders. This approach has the potential to be used in broad clinical applications and in better understanding of brain vascular pathophysiology. In the video, we demonstrate how to set up the system inside an MRI suite and how to perform a complete experiment on a human participant. PMID- 25549109 TI - Anchoring the Gas-Phase Acidity Scale from Hydrogen Sulfide to Pyrrole. Experimental Bond Dissociation Energies of Nitromethane, Ethanethiol, and Cyclopentadiene. AB - A meta-analysis of experimental information from a variety of sources is combined with statistical thermodynamics calculations to refine the gas-phase acidity scale from hydrogen sulfide to pyrrole. The absolute acidities of hydrogen sulfide, methanethiol, and pyrrole are evaluated from literature R-H bond energies and radical electron affinities to anchor the scale. Relative acidities from proton-transfer equilibrium experiments are used in a local thermochemical network optimized by least-squares analysis to obtain absolute acidities of 14 additional acids in the region. Thermal enthalpy and entropy corrections are applied using molecular parameters from density functional theory, with explicit calculation of hindered rotor energy levels for torsional modes. The analysis reduces the uncertainties of the absolute acidities of the 14 acids to within +/ 1.2 to +/-3.3 kJ/mol, expressed as estimates of the 95% confidence level. The experimental gas-phase acidities are compared with calculations, with generally good agreement. For nitromethane, ethanethiol, and cyclopentadiene, the refined acidities can be combined with electron affinities of the corresponding radicals from photoelectron spectroscopy to obtain improved values of the C-H or S-H bond dissociation energies, yielding D298(H-CH2NO2) = 423.5 +/- 2.2 kJ mol(-1), D298(C2H5S-H) = 364.7 +/- 2.2 kJ mol(-1), and D298(C5H5-H) = 347.4 +/- 2.2 kJ mol(-1). These values represent the best-available experimental bond dissociation energies for these species. PMID- 25549108 TI - Universal strategy for homogeneously doping noble metals into cyano-bridged coordination polymers. AB - Coordination polymers with large surface areas and uniform but tunable cavities have attracted extensive attention because of their unique properties and potential applications in numerous fields. The introduction of noble metal into coordination polymers, which may enhance or display new behaviors beyond their parent counterparts, presents great challenges in maintaining the fragile coordination structures and meeting the compatibility. Here, cyano-bridged coordination polymers are robust and show very nice compatibilities with a series of noble metals, such as Pd, Pt, Au, Ag. Those noble elements partially take the place of the transition metal ions under room temperature (for Au and Ag) or a mild hydrothermal environment (for Pd and Pt) without damaging the framework. By using this universal simple synthetic procedure, we prepared a series of noble metal containing metal hexacyanoferrate (MHCF) with various morphologies and structures, including Pd/Pt/Ag/Au-MnHCF, Pd/Pt/Ag/Au-CoHCF, and Pd/Pt/Ag/Au NiHCF. Among them, Pd-MnHCF demonstrates the control of morphologies by adjusting operational details, and notably, it shows very unique, enhanced catalytic performance, reflecting the superiority of cyano-connected positive-valent Pd as a single-atom catalyst. PMID- 25549107 TI - Simultaneous quantification of T-cell receptor excision circles (TRECs) and K deleting recombination excision circles (KRECs) by real-time PCR. AB - T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs) are circularized DNA elements formed during recombination process that creates T- and B-cell receptors. Because TRECs and KRECs are unable to replicate, they are diluted after each cell division, and therefore persist in the cell. Their quantity in peripheral blood can be considered as an estimation of thymic and bone marrow output. By combining well established and commonly used TREC assay with a modified version of KREC assay, we have developed a duplex quantitative real-time PCR that allows quantification of both newly-produced T and B lymphocytes in a single assay. The number of TRECs and KRECs are obtained using a standard curve prepared by serially diluting TREC and KREC signal joints cloned in a bacterial plasmid, together with a fragment of T-cell receptor alpha constant gene that serves as reference gene. Results are reported as number of TRECs and KRECs/10(6) cells or per ml of blood. The quantification of these DNA fragments have been proven useful for monitoring immune reconstitution following bone marrow transplantation in both children and adults, for improved characterization of immune deficiencies, or for better understanding of certain immunomodulating drug activity. PMID- 25549110 TI - Ultrathin, biomimetic, superhydrophilic layers of cross-linked poly(phosphobetaine) on polyethylene by photografting. AB - Ultrathin, biomimetic, superhydrophilic hydrogel layers, composed of cross-linked poly(2-methacryloyloxyethyl phosphorylcholine), are formed on low-density polyethylene films via ultraviolet-initiated surface graft polymerization. The layers are 19-58 nm thick as revealed by electron microscopy and have three dimensional networks; the unique network structure, along with its zwitterionic nature, rather than surface roughness results in superhydrophilicity, that is, the water contact angle around 5 degrees . This superhydrophilicity depends on a variety of factors, including the concentration of the monomer and cross-linker, the type of reaction solvents, the reaction and drying time, the intensity of UV light, and the way of measurement of water contact angles. Superhydrophilicity is obtained under a fixed ratio (e.g., 1/1) of the monomer to cross-linker, a reaction time over 120 s, a short drying time, (75%) ethanol as the reaction solvent, and low-intensity UV light, largely because these factors together generate optimal three-dimensional networks of cross-links. PMID- 25549113 TI - Vacuum-assisted thermal annealing of CH3NH3PbI3 for highly stable and efficient perovskite solar cells. AB - Solar cells incorporating lead halide-based perovskite absorbers can exhibit impressive power conversion efficiencies (PCEs), recently surpassing 15%. Despite rapid developments, achieving precise control over the morphologies of the perovskite films (minimizing pore formation) and enhanced stability and reproducibility of the devices remain challenging, both of which are necessary for further advancements. Here we demonstrate vacuum-assisted thermal annealing as an effective means for controlling the composition and morphology of the CH(3)NH(3)PbI(3) films formed from the precursors of PbCl(2) and CH(3)NH(3)I. We identify the critical role played by the byproduct of CH(3)NH(3)Cl on the formation and the photovoltaic performance of the perovskite film. By completely removing the byproduct through our vacuum-assisted thermal annealing approach, we are able to produce pure, pore-free planar CH(3)NH(3)PbI(3) films with high PCE reaching 14.5% in solar cell device. Importantly, the removal of CH(3)NH(3)Cl significantly improves the device stability and reproducibility with a standard deviation of only 0.92% in PCE as well as strongly reducing the photocurrent hysteresis. PMID- 25549111 TI - Evaluation of methods to improve the extraction and recovery of DNA from cotton swabs for forensic analysis. AB - Samples for forensic DNA analysis are often collected from a wide variety of objects using cotton or nylon tipped swabs. Testing has shown that significant quantities of DNA are retained on the swab, however, and subsequently lost. When processing evidentiary samples, the recovery of the maximum amount of available DNA is critical, potentially dictating whether a usable profile can be derived from a piece of evidence or not. The QIAamp DNA Investigator extraction kit was used with its recommended protocol for swabs (one hour incubation at 56 degrees C) as a baseline. Results indicate that over 50% of the recoverable DNA may be retained on the cotton swab tip, or otherwise lost, for both blood and buccal cell samples when using this protocol. The protocol's incubation time and temperature were altered, as was incubating while shaking or stationary to test for increases in recovery efficiency. An additional step was then tested that included periodic re-suspension of the swab tip in the extraction buffer during incubation. Aliquots of liquid blood or a buccal cell suspension were deposited and dried on cotton swabs and compared with swab-less controls. The concentration of DNA in each extract was quantified and STR analysis was performed to assess the quality of the extracted DNA. Stationary incubations and those performed at 65 degrees C did not result in significant gains in DNA yield. Samples incubated for 24 hours yielded less DNA. Increased yields were observed with three and 18 hour incubation periods. Increases in DNA yields were also observed using a swab re-suspension method for both cell types. The swab re-suspension method yielded an average two-fold increase in recovered DNA yield with buccal cells and an average three-fold increase with blood cells. These findings demonstrate that more of the DNA collected on swabs can be recovered with specific protocol alterations. PMID- 25549114 TI - Cancer risk assessment of polycyclic aromatic hydrocarbon contaminated soils determined using bioassay-derived levels of benzo[a]pyrene equivalents. AB - Here we evaluate the excess lifetime cancer risk (ELCR) posed by 10 PAH contaminated soils using (i) the currently advocated, targeted chemical-specific approach that assumes dose additivity for carcinogenic PAHs and (ii) a bioassay based approach that employs the in vitro mutagenic activity of the soil fractions to determine levels of benzo[a]pyrene equivalents and, by extension, ELCR. Mutagenic activity results are presented in our companion paper.1 The results show that ELCR values for the PAH-containing fractions, determined using the chemical-specific approach, are generally (i.e., 8 out of 10) greater than those calculated using the bioassay-based approach; most are less than 5-fold greater. Only two chemical-specific ELCR estimates are less than their corresponding bioassay-derived values; differences are less than 10%. The bioassay-based approach, which permits estimation of ELCR without a priori knowledge of mixture composition, proved to be a useful tool to evaluate the chemical-specific approach. The results suggest that ELCR estimates for complex PAH mixtures determined using a targeted, chemical-specific approach are reasonable, albeit conservative. Calculated risk estimates still depend on contentious PEFs and cancer slope factors. Follow-up in vivo mutagenicity assessments will be required to validate the results and their relevance for human health risk assessment of PAH-contaminated soils. PMID- 25549115 TI - Regulation of target protein knockdown and labeling using ligand-directed Ru(bpy)3 photocatalyst. AB - Ligand-directed Ru(bpy)3 photocatalysts induce chromophore-assisted light inactivation (CALI) of target proteins under visible light irradiation in vitro and within cells. Here, histidine, methionine, and tryptophan residues were oxidized by the singlet oxygen ((1)O2) generated by Ru(bpy)3 with light. The addition of a tyrosyl radical trapper (TRT), such as N'-acyl-N,N-dimethyl phenylenediamine, inhibited peptide/protein oxidation and induced labeling on the tyrosine residue. This mechanistic study suggests that TRT scavenges (1)O2, concomitant with the coupling reaction to the tyrosyl radical generated by Ru(bpy)3. Both CALI and labeling can be regulated by the Ru(bpy)3 photocatalysts in the absence or presence of TRT. Ligand-conjugated Ru(bpy)3 photocatalysts (local environmental single-electron transfer catalysts: LSCs) were used not only for target-selective protein labeling, but also for protein knockdown by CALI. PMID- 25549117 TI - Gabriel Richet (1916-2014). PMID- 25549119 TI - Intravenous iron administration: new observations and time for the next steps. AB - In this issue of Kidney International, the Dialysis Outcomes and Practice Patterns Study reports that hemodialysis patients with monthly intravenous iron supplementation of 300-399 mg or ?400 mg had a 13 or 18% higher risk of dying, respectively, compared with those receiving 100-199 mg per month, with no obvious differences in cause-specific mortalities. This study supports that randomized controlled trials are urgently needed to identify optimized iron supplementation strategies for anemic dialysis patients. PMID- 25549120 TI - Revisiting inflammation in diabetic nephropathy: the role of the Nlrp3 inflammasome in glomerular resident cells. AB - Inflammation is a protective response to remove dangerous stimuli from the body. The multiprotein complex called the inflammasome regulates inflammation through the cleavage of proinflammatory cytokines into mature forms. Shahzad et al. unravel the importance of the Nlrp3 inflammasome, especially activated in glomerular resident cells, in diabetic nephropathy. They also show the role of mitochondrial reactive oxygen species as a mediator to activate the inflammasome in diabetic conditions. Targeting the inflammasome could be a promising approach for diabetic nephropathy. PMID- 25549121 TI - Apolipoprotein L1: from obscurity to consistency to controversy. AB - Apolipoprotein L1 (APOL1) is associated with increased incidence of chronic kidney disease (CKD) and end-stage renal disease, and with faster progression of CKD, in African Americans. APOL1 is expressed in intra- and extrarenal vascular tissue, making it a candidate to explain the increased incidence of cardiovascular disease in CKD. This Commentary discusses the disparate results from three studies showing that APOL1 renal risk genotypes are either harmful, neutral, or protective in the context of cardiovascular disease. PMID- 25549122 TI - New lessons from randomized trials in steroid-sensitive nephrotic syndrome: clear evidence against long steroid therapy. AB - The best initial therapy for steroid-sensitive nephrotic syndrome (SSNS) in children is subject to ongoing debate. Systematic reviews and meta-analyses have concluded that at least 3 months and up to 7 months of treatment would reduce the number of relapses by 30%. But summarizing small underpowered studies cannot eliminate the basic flaws in design. Two well-powered randomized prospective trials now come to the opposite conclusion, and these results should impact the management of children with SSNS. PMID- 25549123 TI - On vascular calcification and plasma levels of pyrophosphate. PMID- 25549124 TI - The use of bioimpedance to aid volume assessment in dialysis patients. PMID- 25549125 TI - The authors reply. PMID- 25549126 TI - Histologic classification of glomerular diseases: clinicopathologic correlations, limitations exposed by validation studies, and suggestions for modification. PMID- 25549127 TI - Renal sarcoid-like granulomatosis during anti-TNF therapy. PMID- 25549128 TI - Individuals of Pacific Asian origin with IgA nephropathy have an increased risk of progression to end-stage renal disease. PMID- 25549129 TI - Microalbuminuria: target for renoprotective therapy PRO. PMID- 25549130 TI - The renin-aldosterone axis in kidney transplant recipients and its association with allograft function and structure. PMID- 25549131 TI - Urinary obstruction from lymphocele. PMID- 25549132 TI - End-stage renal disease from renal metastases. PMID- 25549133 TI - The case | Hypertension and neuropathy after travel. PMID- 25549134 TI - Comprehensive NMR analysis of compositional changes of black garlic during thermal processing. AB - Black garlic is a processed food product obtained by subjecting whole raw garlic to thermal processing that causes chemical reactions, such as the Maillard reaction, which change the composition of the garlic. In this paper, we report a nuclear magnetic resonance (NMR)-based comprehensive analysis of raw garlic and black garlic extracts to determine the compositional changes resulting from thermal processing. (1)H NMR spectra with a detailed signal assignment showed that 38 components were altered by thermal processing of raw garlic. For example, the contents of 11 l-amino acids increased during the first step of thermal processing over 5 days and then decreased. Multivariate data analysis revealed changes in the contents of fructose, glucose, acetic acid, formic acid, pyroglutamic acid, cycloalliin, and 5-(hydroxymethyl)furfural (5-HMF). Our results provide comprehensive information on changes in NMR-detectable components during thermal processing of whole garlic. PMID- 25549135 TI - Conditional genetic transsynaptic tracing in the embryonic mouse brain. AB - Anatomical path tracing is of pivotal importance to decipher the relationship between brain and behavior. Unraveling the formation of neural circuits during embryonic maturation of the brain however is technically challenging because most transsynaptic tracing methods developed to date depend on stereotaxic tracer injection. To overcome this problem, we developed a binary genetic strategy for conditional genetic transsynaptic tracing in the mouse brain. Towards this end we generated two complementary knock-in mouse strains to selectively express the bidirectional transsynaptic tracer barley lectin (BL) and the retrograde transsynaptic tracer Tetanus Toxin fragment C from the ROSA26 locus after Cre mediated recombination. Cell-specific tracer production in these mice is genetically encoded and does not depend on mechanical tracer injection. Therefore our experimental approach is suitable to study neural circuit formation in the embryonic murine brain. Furthermore, because tracer transfer across synapses depends on synaptic activity, these mouse strains can be used to analyze the communication between genetically defined neuronal populations during brain development at a single cell resolution. Here we provide a detailed protocol for transsynaptic tracing in mouse embryos using the novel recombinant ROSA26 alleles. We have utilized this experimental technique in order to delineate the neural circuitry underlying maturation of the reproductive axis in the developing female mouse brain. PMID- 25549136 TI - Distorted colloidal arrays as designed template. AB - In this paper, a novel type of colloidal template with broken symmetry was generated using commercial, inductively coupled plasma reactive ion etching (ICP RIE). With proper but simple treatment, the traditional symmetric non-close packed colloidal template evolves into an elliptical profile with high uniformity. This unique feature can add flexibility to colloidal lithography and/or other lithography techniques using colloidal particles as building blocks to fabricate nano-/micro-structures with broken symmetry. Beyond that the novel colloidal template we developed possesses on-site tunability, i.e. the transformability from a symmetric into an asymmetric template. Sandwich-type particles with eccentric features were fabricated utilizing this tunable template. This distinguishing feature will provide the possibility to fabricate structures with unique asymmetric features using one set of colloidal template, providing flexibility and broad tunability to enable nano-/micro-structure fabrication with colloidal templates. PMID- 25549137 TI - Surface-functionalized nanoparticle permeation triggers lipid displacement and water and ion leakage. AB - Functionalized nanoparticles (NPs) are considered suitable carriers for targeted drug delivery systems. However, the ion and water leakage induced by permeation of these nanoparticles is a challenge in these drug delivery methods because of cytotoxic effects of some ions. In this study, we have carried out a series of coarse-grained molecular dynamics simulations to investigate the effect of length of ligands on permeation of a nanoparticle across a protein-free phospholipid bilayer membrane. Water and ion penetration as well as incidence of lipid flip flop events and loss of lipid molecules from the membrane are explored in this study while varying the nanoparticle size, length of ligand, ion concentration gradient, pressure differential across the membrane, and nanoparticle permeation velocity. Some results from our studies include (1) the number of water molecules in the interior of the membrane during ligand-coated nanoparticle permeation increases with nanoparticle size, ligand length, pressure differential, and permeation velocity but is not sensitive to the ion concentration gradient; (2) some lipid molecules leave the membrane by being entangled with ligands of the NP instead of completing the flip-flop that permits them to rejoin the membrane, thereby leading to fewer flip-flop events; and (3) the formation of water columns or water "fingers" provides a mechanism of ion transport across lipid bilayer membranes, but such ion penetration events are less likely for sodium ions than chloride ions and less likely for nanoparticles with longer-ligands. PMID- 25549140 TI - Electrical detection of millimeter-waves by magnetic tunnel junctions using perpendicular magnetized L10-FePd free layer. AB - Spin dynamics excited by spin-polarized current in magnetic tunnel junctions (MTJs) is potentially useful in nanoscale electrical oscillation sources and detection devices. A spin oscillator/detector should work at a high frequency, such as that of a millimeter-wave, where the quality of a semiconductor device is restricted by carrier mobility, the CR time constant, and so on. Developers of spin systems for practical use need to find out how to excite spin dynamics (i) in the millimeter-wave region, (ii) with low power consumption (ex: no external magnetic field, low damping material), and (iii) for broad frequency modulation. Here L10-ordered FePd alloy with perpendicular magnetocrystalline anisotropy (PMA) and a low damping constant, 0.007, was used for the free layer in the MTJs, and a homodyne-detected ferromagnetic resonance (FMR) signal was obtained at around 30 GHz together with the possibility of one-octave frequency modulation. The FMR signal in out-of-plane magnetized L10-ordered FePd free layer could be excited without an external magnetic field by injecting in-plane spin polarized alternating current. This study shows the potential utility of L10-ordered alloy materials such as FePt, CoPt, MnAl, and MnGa in a variety of millimeter-wave spin devices. PMID- 25549139 TI - Endohedral metal-induced regioselective formation of bis-Prato adduct of Y3N@I(h) C80 and Gd3N@I(h)-C80. AB - Regioselective bisaddition of M3N@Ih-C80 (M = Y, Gd) was observed for the first time in the Prato reaction with N-ethylglycine and formaldehyde. The main kinetic bisadduct of Y3N@C80 was determined to be a [6,6],[6,6] adduct by (1)H and (13)C NMR and vis/NIR spectroscopy, and it converted to a mixture of regioisomers upon heating via a sigmatropic rearrangement. The main kinetic bisadduct of Gd3N@C80 (the [6,6],[6,6] adduct on the basis of vis/NIR data) existed stably under thermal conditions without isomerization. The likely position of the second addition of the Gd3N@C80 bisadduct was predicted by DFT calculations. PMID- 25549138 TI - A method for screening and validation of resistant mutations against kinase inhibitors. AB - The discovery of BCR/ABL as a driver oncogene in chronic myeloid leukemia (CML) resulted in the development of Imatinib, which, in fact, demonstrated the potential of targeting the kinase in cancers by effectively treating the CML patients. This observation revolutionized drug development to target the oncogenic kinases implicated in various other malignancies, such as, EGFR, B-RAF, KIT and PDGFRs. However, one major drawback of anti-kinase therapies is the emergence of drug resistance mutations rendering the target to have reduced or lost affinity for the drug. Understanding the mechanisms employed by resistant variants not only helps in developing the next generation inhibitors but also gives impetus to clinical management using personalized medicine. We reported a retroviral vector based screening strategy to identify the spectrum of resistance conferring mutations in BCR/ABL, which has helped in developing the next generation BCR/ABL inhibitors. Using Ruxolitinib and JAK2 as a drug target pair, here we describe in vitro screening methods that utilizes the mouse BAF3 cells expressing the random mutation library of JAK2 kinase. PMID- 25549141 TI - Application of immunohistochemistry in gastrointestinal and liver neoplasms: new markers and evolving practice. AB - CONTEXT: Diagnosis of primary gastrointestinal and liver neoplasms is usually straightforward. Immunohistochemistry is most helpful to differentiate metastatic carcinomas with morphologic similarity and to resolve tumors of unknown origin. Recently, several new markers highly sensitive and specific for primary liver and gastrointestinal tumors have been discovered. Their potential diagnostic application has not been widely appreciated by general practicing pathologists. In addition, a new trend in immunohistochemistry application has started, focusing on assessing predictive markers (such as human epidermal growth factor receptor 2) and mutation-specific markers (v-raf murine sarcoma viral oncogene homolog B V600E) to directly guide clinical management. Practicing pathologists need to be aware of and prepared for this evolving trend. OBJECTIVES: To summarize the usefulness of several recently discovered immunohistochemical markers in the study of gastrointestinal and liver tumors; to suggest the most current and effective immunohistochemical panels addressing common diagnostic challenges for these tumors; to share practical experience and useful tips for human epidermal growth factor receptor 2 testing in gastric and gastroesophageal junction adenocarcinoma and v-raf murine sarcoma viral oncogene homolog B V600E immunohistochemistry in colorectal carcinoma. DATA SOURCES: Sources include literature review, and authors' research data and practice experience. The cases illustrated are selected from the pathology archives of the Geisinger Medical Center (Danville, Pennsylvania). CONCLUSIONS: Application of immunohistochemistry in gastrointestinal and liver tumors continues to evolve. New tumor-specific markers constantly emerge and help pathologists to further improve diagnostic accuracy. Assessment of predictive and prognostic markers by immunohistochemistry in routine pathologic diagnosis is a new trend and will greatly facilitate the advancement of personalized cancer therapy. PMID- 25549142 TI - Utility of immunohistochemistry in the pancreatobiliary tract. AB - CONTEXT: Immunohistochemistry has become a useful ancillary study in the identification and classification of pancreatic neoplasms. The diagnostic accuracy has been significantly improved because of the continuous discoveries of tumor-associated biomarkers and the development of effective immunohistochemical panels. OBJECTIVES: To identify and classify pancreatic neoplasms by immunohistochemistry. DATA SOURCES: Literature review and authors' research data and personal practice experience were used. CONCLUSIONS: To better guide therapeutic decisions and predict the prognostic outcome, it is crucial to make an accurate diagnosis of a pancreatic neoplasm. Application of appropriate immunohistochemical panels enables pathologists to differentiate pancreaticobiliary adenocarcinomas from reactive conditions and to identify rare types of pancreatic neoplasms. Knowing the utilities and pitfalls of each tumor associated biomarker is essential to avoiding a potential diagnostic error because an absolutely cancer-specific biomarker does not exist. This article reviews frequently used tumor-associated biomarkers, provides lists of effective immunohistochemical panels, and recommends a diagnostic algorithm as a standard approach to pancreatic neoplasms. PMID- 25549144 TI - Review and updates of immunohistochemistry in selected salivary gland and head and neck tumors. AB - CONTEXT: Immunohistochemistry is a useful tool for diagnosing salivary gland and head and neck tumors. OBJECTIVE: To review immunohistochemical markers, which can aid in the diagnosis of selected salivary gland and head and neck tumors. DATA SOURCES: Literature review and authors' personal practice experience. CONCLUSIONS: Salivary gland and head and neck tumors include a large diverse group of tumors with complex and overlapping histologic features. Immunohistochemistry plays an important role in resolving the differential diagnosis of some salivary gland and head and neck tumors and can provide information for the prognosis of certain tumors. PMID- 25549143 TI - The utility of immunohistochemistry in the differential diagnosis of gynecologic disorders. AB - CONTEXT: Immunohistochemistry has assumed an increasing role in the identification and characterization of gynecologic disorders including lesions with deceptively bland morphology, uncommon and underdiagnosed neoplasms, and neoplasms with specific genetic alterations associated with overexpression or loss of expression of specific proteins. The diagnostic accuracy has been significantly improved owing to the discovery and increasing experience with the tumor-associated biomarkers, and the increasing demand for precise tumor classification to assess suitability for the expanding therapeutic modalities including clinical trials. OBJECTIVE: To differentiate lesions of the gynecologic tract through the use of effective immunohistochemical panels. DATA SOURCES: Literature review and authors' personal practice experience. CONCLUSIONS: The application of diagnostic and prognostic immunohistochemical panels has enabled pathologists to better guide therapeutic decisions and to better predict the clinical outcome. It is now well established that the use of ancillary testing, including immunohistochemistry, has a significant power in the identification, differentiation, and classification of reactive, premalignant, and malignant gynecologic disorders. This article discusses the utilities and pitfalls of the commonly used immunohistochemical markers in the context of overlapping morphologic features encountered in the uterus, ovaries, and fallopian tubes. PMID- 25549145 TI - Application of immunohistochemistry in thyroid pathology. AB - CONTEXT: Accurate classification of follicular-patterned thyroid lesions is not always an easy task on routine surgical hematoxylin-eosin-stained or cytologic fine-needle aspiration specimens. The diagnostic challenges are partially due to differential diagnostic criteria that are often subtle and subjective. In the past decades, tremendous advances have been made in molecular gene profiling of tumors and diagnostic immunohistochemistry, aiding in diagnostic accuracy and proper patient management. OBJECTIVE: To evaluate the diagnostic utility of the most commonly studied immunomarkers in the field of thyroid pathology by review of the literature, using the database of indexed articles in PubMed (US National Library of Medicine) from 1976-2013. DATA SOURCES: Literature review, authors' research data, and personal practice experience. CONCLUSIONS: The appropriate use of immunohistochemistry by applying a panel of immunomarkers and using a standardized technical and interpretational method may complement the morphologic assessment and aid in the accurate classification of difficult thyroid lesions. PMID- 25549146 TI - Immunohistochemistry in dermatopathology. AB - CONTEXT: Immunohistochemistry is not a diagnostic test but a highly valuable tool that requires interpretation within a context. OBJECTIVE: To review the current status and limitations of immunohistochemistry in dermatopathology. DATA SOURCES: English-language literature published between 1980 and 2014. CONCLUSIONS: Although immunohistochemistry is rarely completely specific or sensitive, it is an important adjunctive technique in dermatopathology and can be helpful in a series of diagnostic dilemmas. PMID- 25549147 TI - An update on the application of newly described immunohistochemical markers in soft tissue pathology. AB - CONTEXT: During the last 5 to 10 years, significant progress has been made in the molecular characterization of soft tissue tumors, predominantly with the identification of recurrent translocations or amplification of certain genes in different tumor types. Alongside this, translational efforts have identified many novel and diagnostically useful immunohistochemical markers for many of these tumor types. OBJECTIVE: This article reviews a select group of recently described immunohistochemical markers of particular use in the evaluation of mesenchymal neoplasms; the underlying biology of the protein product, practical utility, and limitations of each marker are discussed in detail. DATA SOURCES: Literature review, authors' research data, and personal practice experience serve as sources. CONCLUSIONS: There are many diagnostically useful immunohistochemical markers to help confirm the diagnosis of many different soft tissue tumor types, some of which have reduced the need for additional, and more costly, studies, such as fluorescence in situ hybridization. However, no one marker is 100% specific for a given tumor, and knowledge of potential pitfalls and overlap in patterns of staining among other tumor types is crucial to ensure the appropriate application of these markers in clinical practice. PMID- 25549148 TI - The pulmonary histopathology of anti-KS transfer RNA synthetase syndrome. AB - CONTEXT: The clinical spectrum of the antisynthetase syndromes (AS) has been poorly defined, although some frequently present with pulmonary manifestations. The anti-KS anti-asparaginyl-transfer RNA synthetase syndrome is one in which pulmonary interstitial lung disease is almost always present and yet the histopathologic spectrum is not well described. OBJECTIVE: To define the morphologic manifestations of pulmonary disease in those patients with anti-KS antiasparaginyl syndrome. DESIGN: We reviewed the connective tissue disorder registry of the University of Pittsburgh and identified those patients with anti KS autoantibodies who presented with interstitial lung disease and had surgical lung biopsies. RESULTS: The 5 patients with anti-KS antisynthetase syndrome were usually women presenting with dyspnea and without myositis, but with mechanic's hands (60%) and Raynaud phenomenon (40%). They most often presented with a usual interstitial pneumonia pattern of fibrosis (80%), with the final patient displaying organizing pneumonia. CONCLUSIONS: Pulmonary interstitial lung disease is a common presentation in patients with the anti-KS-antisynthetase syndrome, who are often women with rather subtle or subclinical connective tissue disease, whereas the literature emphasizes the nonspecific interstitial pneumonia pattern often diagnosed clinically. Usual interstitial pneumonia and organizing pneumonia patterns of interstitial injury need to be added to this clinical differential diagnosis. PMID- 25549149 TI - Neurogenic polyps of the gastrointestinal tract: a clinicopathologic review with emphasis on differential diagnosis and syndromic associations. AB - Primary neurogenic gastrointestinal polyps are encountered relatively frequently in routine pathology practice. They encompass a variety of neoplastic entities with clinical, morphologic, and molecular features that reflect the diversity of neural elements within the gastrointestinal system. Although most are benign and encountered incidentally, accurate diagnosis may have important clinical implications because of the associations of certain neurogenic polyps with familial syndromes or other conditions. We review the pathology of these polyps with an emphasis on the diagnostic challenges that they pose and on newly described subtypes. PMID- 25549152 TI - Ionic liquid-assisted fabrication of copper hydroxyphosphate nanocrystals with exposed {100} facets for enhanced photocatalytic activity. AB - Libethenite Cu2PO4OH nanocrystals with different morphologies were prepared by an ionic liquid-assisted hydrothermal route, and were further investigated as photocatalysts under visible-light irradiation. The Cu2PO4OH elongated truncated bipyramids exposing {100} facets exhibit superior photocatalytic activity compared to other particles, which can be attributed to the presence of 100% Cu5c atoms on {100} facets. It is highly expect this research can provide a useful fundamental understanding of shape-dependent photocatalytic performance of copper hydroxyphosphate. PMID- 25549151 TI - Spatial resolution and image qualities of Zr-89 on Siemens Biograph TruePoint PET/CT. AB - PURPOSE: Zirconium-89 (t(1/2)=78.41 hours) is an ideal metallic radioisotope for immuno-positron emission tomography (PET), given that its physical half-life closely matches the biological half-life of monoclonal antibodies. In this study, the authors measured the spatial resolution and image quality of Zr-89 PET and compared the results against those obtained using F-18 PET, which is widely regarded as the gold standard for comparison of imaging characteristics. MATERIALS AND METHODS: The spatial resolution and image qualities of Zr-89 were measured on the Siemens Biograph Truepoint TrueV PET/CT scanner, partly according to NEMA NU2-2007 standards. For spatial resolution measurement, the Zr-89 point source was located at the center of the axial field of view (FOV) and offset 1/4 axial FOV from the center. For image quality measurements, an NEMA IEC Phantom was used. The NEMA IEC Phantom consists of six hot spheres that were filled with Zr-89 solution. Spatial resolution and image quality (%contrast, %background variability [BV], and source to background ratio [SBR]) were assessed to compare the imaging characteristics of F-18 with those of Siemens Biograph Truepoint TrueV. RESULTS: The transverse and axial spatial resolutions at 1 cm were 4.5 and 4.7 mm for Zr-89, respectively. The %contrast of Zr-89 was 25.5% for the smallest 10 mm sized sphere and 89.8% for the largest 37 mm sized sphere, and for F-18, it was 32.5% for the smallest 10 mm sized sphere and 103.9% for the largest 37 mm sized sphere using the ordered subset expectation maximization (OSEM) reconstruction method. The %BV of F-18 PET was 6.4% for the smallest 10 mm sized sphere and 3.5% for the largest 37 mm sized sphere using the OSEM reconstruction. The SBR of Zr-89 was 1.8 for the smallest 10 mm sized sphere and 3.7 for the largest 37 mm sized sphere, and for F-18, it was 2.0 for the smallest 10 mm sized sphere and 4.1 for the largest 37 mm sized sphere using the OSEM reconstruction method. CONCLUSIONS: This study assessed Zr-89 imaging characteristics using a Siemens Biograph Truepoint TrueV PET/CT scanner and compared the results with those obtained for F-18 PET. Although spatial resolution and image quality of Zr 89 PET were lower compared with F-18 PET, due to longer positron range and low positron branching ratio, Zr-89 is advantageous for immuno-PET due to well matched half-life with monoclonal antibodies. PMID- 25549153 TI - Development of lead iodide perovskite solar cells using three-dimensional titanium dioxide nanowire architectures. AB - Three-dimensional (3D) nanowire (NW) architectures are considered as superior electrode design for photovoltaic devices compared to NWs or nanoparticle systems in terms of improved large surface area and charge transport properties. In this paper, we report development of lead iodide perovskite solar cells based on a novel 3D TiO2 NW architectures. The 3D TiO2 nanostructure was synthesized via surface-reaction-limited pulsed chemical vapor deposition (SPCVD) technique that also implemented the Kirkendall effect for complete ZnO NW template conversion. It was found that the film thickness of 3D TiO2 can significantly influence the photovoltaic performance. Short-circuit current increased with the TiO2 length, while open-circuit voltage and fill factor decreased with the length. The highest power conversion efficiency (PCE) of 9.0% was achieved with ~ 600 nm long 3D TiO2 NW structures. Compared to other 1D nanostructure arrays (TiO2 nanotubes, TiO2 coated ZnO NWs and ZnO NWs), 3D TiO2 NW architecture was able to achieve larger amounts of perovskite loading, enhanced light harvesting efficiency, and increased electron-transport property. Therefore, its PCE is 1.5, 2.3, and 2.8 times higher than those of TiO2 nanotubes, TiO2-coated ZnO NWs, and ZnO NWs, respectively. The unique morphological advantages, together with the largely suppressed hysteresis effect, make 3D hierarchical TiO2 a promising electrode selection in designing high-performance perovskite solar cells. PMID- 25549154 TI - Differential effect of race, education, gender, and language discrimination on glycemic control in adults with type 2 diabetes. AB - BACKGROUND: Discrimination has been linked to negative health outcomes, but little research has investigated different types of discrimination to determine if some have a greater impact on outcomes. We examined the differential effect of discrimination based on race, level of education, gender, and language on glycemic control in adults with type 2 diabetes. PATIENTS AND METHODS: Six hundred two patients with type 2 diabetes from two adult primary care clinics in the southeastern United States completed validated questionnaires. Questions included perceived discrimination because of race/ethnicity, level of education, sex/gender, or language. A multiple linear regression model assessed the differential effect of each type of perceived discrimination on glycemic control while adjusting for relevant covariates, including race, site, gender, marital status, duration of diabetes, number of years in school, number of hours worked per week, income, and health status. RESULTS: The mean age was 61.5 years, and the mean duration of diabetes was 12.3 years. Of the sample, 61.6% were men, and 64.9% were non-Hispanic black. In adjusted models, education discrimination remained significantly associated with glycemic control (beta=0.47; 95% confidence interval, 0.03, 0.92). Race, gender and language discrimination were not significantly associated with poor glycemic control in either unadjusted or adjusted analyses. CONCLUSIONS: Discrimination based on education was found to be significantly associated with poor glycemic control. The findings suggest that education discrimination may be an important social determinant to consider when providing care to patients with type 2 diabetes and should be assessed separate from other types of discrimination, such as that based on race. PMID- 25549155 TI - Prescribing practice and off-label use of psychotropic medications in post-acute brain injury rehabilitation centres: a cross-sectional survey. AB - OBJECTIVE: Guidance on pharmacotherapy of neurobehavioural sequelae post-acquired brain injury (ABI) is limited. Clinicians face the choice of prescribing off label. This survey assesses prescribing practice and off-label use of psychotropic medications in Italian brain injury rehabilitation centres and factors associated with atypical antipsychotics use. MATERIALS AND METHODS: Centres were identified through the roster of the Italian Society for Rehabilitation Medicine. Information was collected through a structured questionnaire. This study calculated the prevalence of centres reporting to use off-label individual medications and unconditional logistic regression Odds Ratio (OR), with 95% confidence interval (95% CI) of atypical antipsychotics use. RESULTS: Psychotropic medications were commonly used. More than 50% of the 35 centres (participation ratio 87.5%) reported to use off-label selected antipsychotics, mostly for agitation (90.5%) and behavioural disturbances (19.0%), and antidepressants, mostly for insomnia (37.5%) and pain (25.0%). Atypical antipsychotic use was directly associated with age <40 years (OR = 2.68; 95% CI = 1.25-5.76), recent ABI (1.74; 0.74-4.09), not with reported off-label use (0.98; 0.44-2.18). CONCLUSION: In clinical practice, the effectiveness and safety of medications, in particular off-label, should be systematically monitored. Studies are needed to improve the quality of evidence guiding pharmacotherapy and to evaluate effectiveness and safety of off-label prescribing. PMID- 25549157 TI - Human cell lines as tools of our trade: "laying it on the (cell) line". PMID- 25549158 TI - Erratum. PMID- 25549156 TI - Olfactory neurons obtained through nasal biopsy combined with laser-capture microdissection: a potential approach to study treatment response in mental disorders. AB - Bipolar disorder (BD) is a severe neuropsychiatric disorder with poorly understood pathophysiology and typically treated with the mood stabilizer, lithium carbonate. Animal studies as well as human genetic studies indicate that lithium affects molecular targets that are involved in neuronal growth, survival and maturation, and notably molecules involved in Wnt signaling. Given the ethical challenge to obtaining brain biopsies for investigating dynamic molecular changes associated with lithium-response in the central nervous system (CNS), one may consider the use of neurons obtained from olfactory tissues to achieve this goal.The olfactory epithelium contains olfactory receptor neurons at different stages of development and glial-like supporting cells. This provides a unique opportunity to study dynamic changes in the CNS of patients with neuropsychiatric diseases, using olfactory tissue safely obtained from nasal biopsies. To overcome the drawback posed by substantial contamination of biopsied olfactory tissue with non-neuronal cells, a novel approach to obtain enriched neuronal cell populations was developed by combining nasal biopsies with laser-capture microdissection. In this study, a system for investigating treatment-associated dynamic molecular changes in neuronal tissue was developed and validated, using a small pilot sample of BD patients recruited for the study of the molecular mechanisms of lithium treatment response. PMID- 25549161 TI - Properties of soluble glycoprotein VI, a potential platelet activation biomarker. AB - Glycoprotein VI (GPVI) plays a critical role in the platelet response to collagen. Clinical studies suggest that the plasma level of soluble GPVI (sGPVI) is a highly specific and useful platelet activation marker. However, many properties of sGPVI have not been fully characterized, such as its sensitivity in detecting platelet activation and its elimination rate from the blood. In this study we established a sandwich enzyme-linked immunosorbent assay for human sGPVI, which cross-reacts to cynomolgus monkey sGPVI, and evaluated the time course of sGPVI production in a cynomolgus monkey model of lipopolysaccharide (LPS)-induced thrombocytopenia. The sGPVI levels in this model were dramatically elevated and returned to baseline by 24 hours after LPS injection, the change was more pronounced than the existing platelet activation biomarker, soluble P selectin (sP-selectin) levels. The elimination half-life of recombinant human sGPVI was about 2.5 hours following intravenous administration to monkeys. These results suggest that plasma sGPVI closely reflects platelet activation in the bloodstream and has a short half-life. sGPVI would be a useful biomarker for disorders marked by platelet activation and for monitoring anti-platelet therapy. PMID- 25549162 TI - Mutation analysis in Chinese families with autosomal dominant hereditary cataracts. AB - PURPOSE: To identify the molecular basis and clinical phenotype in three Chinese families with hereditary cataracts. METHODS: Detailed family history and clinical data were recorded. The phenotypes were documented using slit-lamp photography. Candidate genes sequencing was performed to screen out the disease causing mutation. Bioinformatics analysis was performed to predict the function of mutant genes. RESULTS: The phenotypes of the families were identified as nuclear cataract in Family 1, pulverulent cataract in Family 2, and nuclear cataract in Family 3. Direct sequencing revealed transversions of C > T at c.218 (p. S73F) in GJA8 in Family 1, A > C at c.125 (p. E42A) in GJA3 in Family 2, and C > T at c.268 (p. L90F) in GJA3 in Family 3. These mutations co-segregated with all affected individuals in the family and were not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that S73F in GJA8, E42A and L90F in GJA3 are highly conserved. S73F in GJA8, E42A and L90F in GJA3 could possibly be damaging predicted by PolyPhen-2, with score of 0.858, 1.000, 1.000, respectively. CONCLUSIONS: This study identified three mutations in three Chinese families with hereditary cataracts. Of the three mutations, two were novel (c.125 A > C in GJA3 and c.268 C > T in GJA3), one was previously reported (c.218 C > T in GJA8). PMID- 25549163 TI - Effect of 457 nm diode-pumped solid state laser on the polymerization composite resins: microhardness, cross-link density, and polymerization shrinkage. AB - OBJECTIVE: The purpose of the present study was to test the usefulness of 457 nm diode-pumped solid state (DPSS) laser as a light source to cure composite resins. MATERIALS AND METHODS: Five different composite resins were light cured using three different light-curing units (LCUs): a DPSS 457 nm laser (LAS), a light emitting diode (LED), and quartz-tungsten-halogen (QTH) units. The light intensity of LAS was 560 mW/cm(2), whereas LED and QTH LCUs was ~900 mW/cm(2). The degree of polymerization was tested by evaluating microhardness, cross-link density, and polymerization shrinkage. RESULTS: Before water immersion, the microhardness of laser-treated specimens ranged from 40.8 to 84.7 HV and from 31.7 to 79.0 HV on the top and bottom surfaces, respectively, and these values were 3.3-23.2% and 2.9-31.1% lower than the highest microhardness obtained using LED or QTH LCUs. Also, laser-treated specimens had lower top and bottom microhardnesses than the other LCUs treated specimens by 2.4-19.4% and 1.4-27.8%, respectively. After ethanol immersion for 24 h, the microhardness of laser treated specimens ranged from 20.3 to 63.2 HV on top and bottom surfaces, but from 24.9 to 71.5 HV when specimens were cured using the other LCUs. Polymerization shrinkage was 9.8-14.7 MUm for laser-treated specimens, and these were significantly similar or lower (10.2-16.0 MUm) than those obtained using the other LCUs. CONCLUSIONS: The results may suggest that the 457 nm DPSS laser can be used as a light source for light-curing dental resin composites. PMID- 25549164 TI - Stimulus and transducer effects on threshold. AB - OBJECTIVE: This study examined differences in thresholds obtained under Sennheiser HDA200 circumaural earphones using pure tone, equivalent rectangular noise bands, and 1/3 octave noise bands relative to thresholds obtained using Telephonics TDH-39P supra-aural earphones. DESIGN: Thresholds were obtained via each transducer and stimulus condition six times within a 10-day period. STUDY SAMPLE: Forty-nine adults were selected from a prior study to represent low, moderate, and high threshold reliability. RESULTS: The results suggested that (1) only small adjustments were needed to reach equivalent TDH-39P thresholds, (2) pure-tone thresholds obtained with HDA200 circumaural earphones had reliability equal to or better than those obtained using TDH-39P earphones, (3) the reliability of noise-band thresholds improved with broader stimulus bandwidth and was either equal to or better than pure-tone thresholds, and (4) frequency specificity declined with stimulus bandwidths greater than one equivalent rectangular band, which could complicate early detection of hearing changes that occur within a narrow frequency range. CONCLUSIONS: These data suggest that circumaural earphones such as the HDA200 headphones provide better reliability for audiometric testing as compared to the TDH-39P earphones. These data support the use of noise bands, preferably ERB noises, as stimuli for audiometric monitoring. PMID- 25549165 TI - To measure the impact of hearing protectors on the perception of speech in noise. AB - OBJECTIVE: To propose and evaluate a new method for assessing the potential impact on speech intelligibility when wearing a hearing protection device (HPD) in a noisy environment. DESIGN: The method is based on a self adaptive method for finding the speech reception threshold (SRT) using speech material from the Callsign acquisition test (CAT) presented at a constant level while adjusting the level of a background noise. A key point is to primarily examine the impact of the HPD; i.e. the difference between occluded and unoccluded SRTs, presented as the speech intelligibility impact level. STUDY SAMPLE: A total of 31 test subjects. RESULTS: The method is shown to be stable, with a minimum amount of learning effect, and capable of detecting differences between hearing protection devices. It is also shown that low-attenuation passive HPDs are likely to have a very small effect on speech intelligibility in noise, and that an electronic HPD with a level-dependant function has the potential to improve intelligibility. CONCLUSIONS: The results are encouraging regarding the precision, repeatability, and applicability of the proposed method. PMID- 25549166 TI - Effects of user training with electronically-modulated sound transmission hearing protectors and the open ear on horizontal localization ability. AB - OBJECTIVE: To determine if training with electronically-modulated hearing protection (EMHP) and the open ear results in auditory learning on a horizontal localization task. DESIGN: Baseline localization testing was conducted in three listening conditions (open-ear, in-the-ear (ITE) EMHP, and over-the-ear (OTE) EMHP). Participants then wore either an ITE or OTE EMHP for 12, almost daily, one hour training sessions. After training was complete, participants again underwent localization testing in all three listening conditions. A computer with a custom software and hardware interface presented localization sounds and collected participant responses. STUDY SAMPLE: Twelve participants were recruited from the student population at Virginia Tech. Audiometric requirements were 35 dBHL at 500, 1000, and 2000 Hz bilaterally, and 55 dBHL at 4000 Hz in at least one ear. RESULTS: Pre-training localization performance with an ITE or OTE EMHP was worse than open-ear performance. After training with any given listening condition, including open-ear, performance in that listening condition improved, in part from a practice effect. However, post-training localization performance showed near equal performance between the open-ear and training EMHP. Auditory learning occurred for the training EMHP, but not for the non-training EMHP; that is, there was no significant training crossover effect between the ITE and the OTE devices. CONCLUSION: It is evident from this study that auditory learning (improved horizontal localization performance) occurred with the EMHP for which training was performed. However, performance improvements found with the training EMHP were not realized in the non-training EMHP. Furthermore, localization performance in the open-ear condition also benefitted from training on the task. PMID- 25549167 TI - Short-term music-induced hearing loss after sound exposure to discotheque music: the effectiveness of a break in reducing temporary threshold shift. AB - OBJECTIVE: To investigate the effect of a break in music exposure on temporary threshold shifts. DESIGN: A cross-over design where subjects are exposed to dance music for either two hours consecutively, or exposed to two hours of dance music with a one-hour break in between. Outcome measure was the change in hearing threshold, measured in 1-dB steps at different time points after ending the music. STUDY SAMPLE: Eighteen normal-hearing subjects participated in this study. RESULTS: Changes in pure-tone threshold were observed in both conditions and were similar, regardless of the break. Threshold shifts could be averaged for 1000, 2000, and 4000 Hz. The shift immediately after the ending of the music was 1.7 dB for right ears, and 3.4 dB for left ears. The difference between left and right ears was significant. One hour after the exposure, right ears were recovered to baseline conditions whereas left ears showed a small but clinically irrelevant remaining shift of approximately 1 dB. CONCLUSIONS: The advice to use chill-out zones is still valid, because this helps to reduce the duration to the exposure. This study does not provide evidence that a rest period gives an additional reduction of temporary threshold shifts. PMID- 25549169 TI - The interaction of hearing loss and level-dependent hearing protection on speech recognition in noise. AB - OBJECTIVES: To determine the effects of different control settings of level dependent hearing protectors on speech recognition performance in interaction with hearing loss. DESIGN: Controlled laboratory experiment with two level dependent devices (Peltor(r) PowerCom PlusTM and Nacre QuietPro(r)) in two military noises. STUDY SAMPLE: Word recognition scores were collected in protected and unprotected conditions for 45 participants grouped into four hearing profile categories ranging from within normal limits to moderate-to severe hearing loss. RESULTS: When the level-dependent mode was switched off to simulate conventional hearing protection, there were large differences across hearing profile categories regarding the effects of wearing the devices on speech recognition in noise; participants with normal hearing showed little effect while participants in the most hearing-impaired category showed large decrements in scores compared to unprotected listening. Activating the level-dependent mode of the devices produced large speech recognition benefits over the passive mode at both low and high gain pass-through settings. The category of participants with the most impaired hearing benefitted the most from the level-dependent mode. CONCLUSIONS: The findings indicate that level-dependent hearing protection circuitry can provide substantial benefits in speech recognition performance in noise, compared to conventional passive protection, for individuals covering a wide range of hearing losses. PMID- 25549168 TI - Does tinnitus, hearing asymmetry, or hearing loss predispose to occupational injury risk? AB - OBJECTIVE: To determine the relative contributions of tinnitus, asymmetrical hearing loss, low frequency hearing loss (pure tone average of 0.5, 1, 2, 3 kHz; PTA.5123), or high frequency hearing loss (pure tone average of 4, 6 kHz; PTA46), to acute injury risk among a cohort of production and maintenance workers at six aluminum manufacturing plants, adjusting for ambient noise exposure and other recognized predictors of injury risk. DESIGN: Retrospective analysis. STUDY SAMPLE: The study considered 9920 workers employed during 2003 to 2008. The cohort consisted of 8818 workers (89%) whose complete records were available. RESULTS: Adjusting for noise exposure and other recognized injury predictors, a 25% increased acute injury risk was observed among workers with a history of tinnitus in conjunction with high-frequency hearing loss (PTA46). Low frequency hearing loss may be associated with minor, yet less serious, injury risk. We did not find evidence that asymmetry contributes to injury risk. CONCLUSION: These results provide evidence that tinnitus, combined with high-frequency hearing loss, may pose an important safety threat to workers, especially those who work in high-noise exposed environments. These at risk workers may require careful examination of their communication and hearing protection needs. PMID- 25549170 TI - Lifelong occupational exposures and hearing loss among elderly Latino Americans aged 65-75 years. AB - OBJECTIVE: The purpose of this study is to determine the relationship between occupational exposures and hearing among elderly Latino Americans. DESIGN: A descriptive, correlational design used for this secondary analysis with the data from the Sacramento Area Latino Study of Aging (SALSA). STUDY SAMPLE: A total of 547 older adults were included. RESULTS: A majority of participants (58%) reported occupational exposures to loud noise and/or ototoxic chemicals. About 65% and over 90% showed hearing loss at low and high frequencies, respectively. Participants with occupational exposure to loud noise and/or ototoxic chemicals were, significantly, two times more likely to have hearing loss at high frequencies compared to those without exposure (OR = 2.29; 95% CI: 1.17 = 4.51, p = .016), after controlling for other risk factors of hearing loss such as age, gender, household income, current smoking, and diabetes. However, lifelong occupational exposure was not significantly associated with hearing loss at low frequencies (OR = 1.43; 95% CI: 0.94 = 2.18, p = .094). CONCLUSION: Lifelong occupational exposure to loud noise and/or ototoxic chemicals was significantly associated with hearing loss among elderly Latino Americans. Healthy work life through protection from harmful auditory effects of occupational exposures to noise and chemicals will have a positive impact on better hearing in later life. PMID- 25549171 TI - Dietary habits and hearing. AB - Abstract Objective: Study groups from three age cohorts of 70-75 year-olds were investigated to search for possible correlations between dietary habits and auditory function. DESIGN: A cross-sectional, epidemiological study. STUDY SAMPLE: A total number of 524 people (275 women, 249 men) were recruited from three age cohorts. The study sample was representative of the general population. All participants answered a diet history and were tested with pure-tone audiometry. Eleven categories of food consumption were related to pure-tone averages of low-mid frequency hearing, and high frequency hearing. RESULTS: Two consistent correlations between diet and hearing were observed. One was a correlation between good hearing and a high consumption of fish in the male group. The other was a correlation between poor high frequency hearing and a high consumption of food rich in low molecular carbohydrates in both genders; a larger effect size was seen in females. CONCLUSIONS: The study indicates that diet is important for aural health in aging. According to this study fish is beneficial to hearing, whereas consumption of "junk food", rich in low molecular carbohydrates, is detrimental. Other correlations, e.g. between high consumption of antioxidants, were not demonstrated here, but cannot be excluded. PMID- 25549172 TI - Limited evidence for calcium supplementation in preeclampsia prevention: a meta analysis and systematic review. AB - OBJECTIVE: This article synthesises evidence for calcium supplementation in preeclampsia prevention. METHODS: Major databases and trial registries were searched, and comparisons were made against other meta-analyses. RESULTS: Calcium supplementation reduced the overall risk of preeclampsia in 10 trials (n = 24 787; risk ratio (RR) 0.62; 95% confidence interval [CI] 0.47-0.81). Its effect was larger in two subgroups: low-baseline calcium intake (RR 0.42 [0.23-0.76]) and increased risk of developing hypertensive disorders (RR 0.36 [0.10-0.98]). This effect was not significant amongst larger studies (RR 0.93 [0.83-1.04]). Funnel plotting suggested possible publication bias. CONCLUSION: Some evidence for calcium supplementation exists, but its utility is limited by the possibility of publication bias and a lack of large trials. PMID- 25549173 TI - Application of wavelet packet entropy flow manifold learning in bearing factory inspection using the ultrasonic technique. AB - For decades, bearing factory quality evaluation has been a key problem and the methods used are always static tests. This paper investigates the use of piezoelectric ultrasonic transducers (PUT) as dynamic diagnostic tools and a relevant signal classification technique, wavelet packet entropy (WPEntropy) flow manifold learning, for the evaluation of bearing factory quality. The data were analyzed using wavelet packet entropy (WPEntropy) flow manifold learning. The results showed that the ultrasonic technique with WPEntropy flow manifold learning was able to detect different types of defects on the bearing components. The test method and the proposed technique are described and the different signals are analyzed and discussed. PMID- 25549174 TI - Fabrication of a SnO2-based acetone gas sensor enhanced by molecular imprinting. AB - This work presents a new route to design a highly sensitive SnO2-based sensor for acetone gas enhanced by the molecular imprinting technique. Unassisted and acetone-assisted thermal synthesis methods are used to synthesis SnO2 nanomaterials. The prepared SnO2 nanomaterials have been characterized by X-ray powder diffraction, scanning electron microscopy and N2 adsorption-desorption. Four types of SnO2 films were obtained by mixing pure deionized water and liquid acetone with the two types of as-prepared powders, respectively. The acetone gas sensing properties of sensors coated by these films were evaluated. Testing results reveal that the sensor coated by the film fabricated by mixing liquid acetone with the SnO2 nanomaterial synthesized by the acetone-assisted thermal method exhibits the best acetone gas sensing performance. The sensor is optimized for the smooth adsorption and desorption of acetone gas thanks to the participation of acetone both in the procedure of synthesis of the SnO2 nanomaterial and the device fabrication, which results in a distinct response recovery behavior. PMID- 25549175 TI - A Low-Noise DC seismic accelerometer based on a combination of MET/MEMS sensors. AB - Molecular-electronic transducers (MET) have a high conversion coefficient and low power consumption, and do not require precision mechanical components thus allowing the construction of cost- and power-efficient seismic accelerometers. Whereas the instrumental resolution of a MET accelerometer within the 0.1-100 Hz frequency range surpasses that of the best Micro-Electro Mechanical Systems (MEMS) and even some force-balanced accelerometers, the fundamental inability to register gravity or, in other words, zero frequency acceleration, significantly constrains the further spread of MET-based accelerometers. Ways of obviating this inherent zero frequency insensitivity within MET technology have so far, not been found. This article explores a possible approach to the construction of a hybrid seismic accelerometer combining the superb performance of a MET sensor in the middle and high frequency range with a conventional on chip MEMS accelerometer covering the lower frequencies and gravity. Though the frequency separation of a signal is widely used in various applications, the opposite task, i.e., the combining of two signals with different bandwidths is less common. Based on theoretical research and the analysis of actual sensors' performance, the authors determined optimal parameters for building a hybrid sensor. Description and results for implementation of the hybrid sensor are given in the Experimental section of the article. Completing a MET sensor with a cost-effective MEMS permitted the construction of a low noise DC accelerometer preserving the noise performance of a MET sensing element. The work presented herein may prove useful in designing other combined sensors based on different technologies. PMID- 25549176 TI - Modification of graphene on ultramicroelectrode array and its application in detection of dissolved oxygen. AB - This paper investigated two different modification methods of graphene (GN) on ultramicroelectrode array (UMEA) and applied the GN modified UMEA for the determination of dissolved oxygen (DO). The UMEAs were fabricated by Micro Electro-Mechanical System (MEMS) technique and the radius of each ultramicroelectrode is 10 MUm. GN-NH2 and GN-COOH were modified on UMEA by using self-assembling method. Compared with GN-NH2 modified UMEA, the GN-COOH modified UMEA showed better electrochemical reduction to DO, owing to better dispersing and more active sites. The GN-COOH on UMEA was electroreduced to reduced GN-COOH (rGN-COOH) to increase the conductivity and the catalysis performance. Finally, the palladium nanoparticles/rGN-COOH composite was incorporated into DO microsensor for the detection of DO. PMID- 25549178 TI - Preliminary effects of parent-implemented behavioural interventions for stereotypy. AB - OBJECTIVE: The purpose of our study was to replicate and extend previous research on using multicomponent behavioural interventions designed to reduce engagement in stereotypy by examining their effects when implemented by parents over several months. METHODS: We used an alternating treatment design to examine the effects of the parent-implemented interventions on engagement in stereotypy and appropriate behaviour in three children with autism and other developmental disabilities. RESULTS: The parent-implemented multicomponent treatments reduced vocal stereotypy in all three participants and increased engagement in appropriate behaviour in two participants. These effects persisted up to 24 weeks following the parent training sessions. CONCLUSIONS: Altogether, our preliminary results support (a) the involvement of parents as behaviour change agents to reduce engagement in stereotypy and (b) the scheduling of regular, but infrequent (i.e. weekly to monthly), follow-up meetings to monitor the effects of behavioural interventions in outpatient and home-based service delivery models. PMID- 25549177 TI - A highly optimized protocol for reprogramming cancer cells to pluripotency using nonviral plasmid vectors. AB - In spite of considerable interest in the field, reprogramming induced pluripotent stem cells (iPSCs) directly from cancer cells has encountered considerable challenges, including the extremely low reprogramming efficiency and instability of cancer-derived iPSCs (C-iPSCs). In this study, we aimed to identify the main obstacles that limit cancer cell reprogramming. Through a detailed multidimensional kinetic optimization, a highly optimized protocol is established for reprogramming C-iPSCs using nonviral plasmid vectors. We demonstrated how the initial cancer cell density seeded could be the most critical factor ultimately affecting C-iPSCs reprogramming. We have consistently achieved an unprecedented high C-iPSC reprogramming efficiency, establishing stable colonies with typical iPSC morphology, up to 50% of which express the iPSC phenotypic (Oct3/4, Sox2, Nanog) and enzymatic (alkaline phosphatase) markers. Furthermore, established C iPSC lines were shown to be capable of forming teratomas in vivo, containing cell types and tissues from each of the embryonic germ layers, fully consistent with their acquisition of pluripotency. This protocol was tested and confirmed in two completely unrelated human lung adenocarcinoma (A549) and mouse melanoma (B16f10) cancer cell lines and thus offers a potentially valuable method for generating effectively virus-free C-iPSCs for future applications. PMID- 25549179 TI - Psychometric validation of the Clubhouse climate questionnaire as an autonomy support measure for people with severe mental illness. AB - BACKGROUND: Self-determination represents a paradigm shift from "shoulds" to "decisions and behaviors" as the best options for helping people with mental illness achieving recovery goals. Autonomy support plays an important role in self-determination. AIMS: The purpose of this study was to validate the Clubhouse climate questionnaire (CCQ) as an autonomy support measure. METHOD: One hundred and twenty-four participants were recruited from eight Clubhouse programs in Hawaii. Measurement structure of the CCQ was evaluated using exploratory and confirmatory factor analysis. FINDINGS: CCQ is a unidimensional scale with good reliability and acceptable levels of divergent and convergent validity. CONCLUSIONS: CCQ is a brief, reliable and valid instrument for assessing autonomy support and contributes to the use of self-determination as a paradigm for improving recovery outcomes in psychiatric rehabilitation. PMID- 25549180 TI - Inflammatory Papillitis in Uveitis: Response to Treatment and Use of Optic Nerve Optical Coherence Tomography for Monitoring. AB - PURPOSE: To describe the clinical course of uveitis-associated inflammatory papillitis and evaluate the utility and reproducibility of optic nerve spectral domain optical coherence tomography (SD-OCT). METHODS: Data on 22 eyes of 14 patients with uveitis-related papillitis and optic nerve imaging were reviewed. SD-OCT measure reproducibility was determined and parameters were compared in active vs. inactive uveitis. RESULTS: Papillitis resolution lagged behind uveitis resolution in three patients. For SD-OCT measures, the intraclass correlation coefficients were 99.1-100% and 86.9-100% for intraobserver and interobserver reproducibility, respectively. All SD-OCT optic nerve measures except inferior and nasal peripapillary retinal thicknesses were significantly higher in active vs. inactive uveitis after correction for multiple hypotheses testing. Mean optic nerve central thickness decreased from 545.1 to 362.9 um (p = 0.01). CONCLUSIONS: Resolution of inflammatory papillitis can lag behind resolution of uveitis. SD OCT assessment of papillitis is reproducible and correlates with presence vs. resolution of uveitis. PMID- 25549182 TI - Coordinated public health initiatives to address violence against women and adolescents. AB - Intimate partner violence (IPV) is a well-recognized public health problem. IPV affects women's physical and mental health through direct pathways, such as injury, and indirect pathways, such as a prolonged stress response that leads to chronic health problems. The influence of abuse can persist long after the violence has stopped and women of color are disproportionately impacted. Successfully addressing the complex issue of IPV requires multiple prevention efforts that target specific risk and protective factors across individual, interpersonal, institutional, community, and societal levels. This paper includes examples of community-based, state led and federally funded public health programs focused on IPV along this continuum. Two community-based efforts to increase access to mental health care for low income, women of color who had experienced IPV, Mindfulness-Based Stress Reduction, and a telehealth intervention are discussed. Core tenets of a patient-centered comprehensive approach to assessment and responses and strategies for supporting a statewide comprehensive response are described in Project Connect: A Coordinated Public Health Initiative to Prevent Violence Against Women. Project Connect provides technical assistance to grantees funded through the Violence Against Women Act's health title and involves developing, implementing, and evaluating new ways to identify, respond to, and prevent domestic and sexual violence and promote an improved public health response to abuse in states and Native health programs. Health care partnerships with domestic violence experts are critical in order to provide training, develop referral protocols, and to link IPV victims to advocacy services. Survivors need a comprehensive response that addresses their safety concerns and may require advocacy around housing or shelter, legal assistance, and safety planning. Gaps in research knowledge identified are health system readiness to respond to IPV victims in health care settings and partner with domestic violence programs, effects of early IPV intervention, and models for taking interventions to scale. PMID- 25549181 TI - Ethnic differences in the association of thrombophilic polymorphisms with obstetric complications in Slovak and Roma (Gypsy) populations. AB - AIMS: Hereditary as well as acquired thrombophilia is associated with a higher incidence of severe obstetric complications such as preeclampsia, spontaneous pregnancy loss, placental abruption, and fetal growth retardation. The aim of our study was to examine the association of selected thrombophilic polymorphisms (factor V Leiden, MTHFR C677T, and MTHFR A1298C) with pregnancy complications in the Slovak majority population and the Roma (Gypsy) ethnic population. The study included 354 women; 120 patients and 105 controls from the Slovak majority population, 50 patients and 79 controls from the Slovak Roma population. Genotyping was performed by the real-time polymerase chain reaction method using TaqMan((r)) MGB probes. RESULTS: A statistically significant higher frequency of factor V Leiden (p=0.001, odds ratio [OR]=5.9) and MTHFR C677T polymorphism (p=0.011, OR=1.7) was observed in the Slovak majority patient group compared to the control group. The incidence of MTHFR A1298C polymorphism between patients and controls did not differ significantly. None of the three polymorphisms studied was in association with pregnancy complications in the group of Roma women. CONCLUSIONS: Our study has confirmed the variable distribution of selected thrombophilic polymorphisms in different ethnic groups as well as their various effects on the clinical phenotype. PMID- 25549183 TI - Mortality in the United States, 2013. AB - This report presents 2013 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among U.S. residents by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population (1). Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, 10 leading causes of death, and 10 leading causes of infant death were analyzed by comparing 2013 final data with 2012 final data. In 2013, a total of 2,596,993 resident deaths were registered in the United States. PMID- 25549185 TI - Influence of body mass index and age on functional outcomes in patients with subarachnoid hemorrhage. AB - BACKGROUND: Recent studies have highlighted the obesity paradox where patients with obesity have a greater chance of survival than patients with normal weight. OBJECTIVE: To investigate the association between body mass index (BMI) and age with severity of subarachnoid hemorrhage (SAH) and functional outcome. METHODS: We retrospectively reviewed the charts of 274 consecutive patients admitted with SAH between June 2008 and June 2012. Data collected included patient demographic features (age, sex, BMI), severity of SAH at admission (Fisher grade, Hunt and Hess grade, Glasgow Coma Scale score, and the World Federation of Neurosurgeons Scale score), as well as functional outcome measured by the modified Rankin Scale (mRS) by death or discharge. RESULTS: The median age was 57 years (range, 18-99), and 62% were female; the median BMI was 27 (range, 14.3-55.1). On multivariate analysis adjusting for age and sex, there was no evidence of an association between BMI and Hunt and Hess grade, Fisher grade, World Federation of Neurosurgeons Scale score, Glasgow Coma Scale score, or mRS score (all P>=.17). On multivariate analysis adjusting for BMI and sex, there was evidence of a higher mRS score (P<.001) and lower WFNS grade (P=.016) in older patients, with no significant association observed between age and the remaining 3 measures of SAH severity (all P>=.10). CONCLUSION: The results of our study indicate that BMI is not noticeably associated with severity of bleeding or functional outcome in patients with SAH. This finding was discovered after performing a multivariate analysis adjusting for age where older age was associated with worsened severity and outcome. PMID- 25549186 TI - Rational design and engineering of a modified adeno-associated virus (AAV1)-based vector system for enhanced retrograde gene delivery. AB - BACKGROUND: After injection into muscle and peripheral nerves, a variety of viral vectors undergo retrograde transport to lower motor neurons. However, because of its attractive safety profile and durable gene expression, adeno-associated virus (AAV) remains the only vector to have been applied to the human nervous system for the treatment of neurodegenerative disease. Nonetheless, only a very small fraction of intramuscularly injected AAV vector arrives at the spinal cord. OBJECTIVE: To engineer a novel AAV vector by inserting a neuronal targeting peptide (Tet1), with binding properties similar to those of tetanus toxin, into the AAV1 capsid. METHODS: Integral to this approach was the use of structure based design to increase the effectiveness of functional capsid engineering. This approach allowed the optimization of scaffolding regions for effective display of the foreign epitope while minimizing disruption of the native capsid structure. We also validated an approach by which low-titer tropism-modified AAV vectors can be rescued by particle mosaicism with unmodified capsid proteins. RESULTS: Importantly, our rationally engineered AAV1-based vectors exhibited markedly enhanced transduction of cultured motor neurons, diminished transduction of nontarget cells, and markedly superior retrograde delivery compared with unmodified AAV1 vector. CONCLUSION: This approach promises a significant advancement in the rational engineering of AAV vectors for diseases of the nervous system and other organs. PMID- 25549187 TI - Treatment of ruptured intracranial aneurysms with the pipeline embolization device. AB - BACKGROUND: The pipeline embolization device (PED) has been used for treatment of unruptured aneurysms. Little is known about the use of the PED in ruptured aneurysms. OBJECTIVE: To assess the safety and efficacy of the PED in ruptured intracranial aneurysms. METHODS: This is a case series with prospective data collection on 20 patients with freshly ruptured aneurysms who were treated with PED (with or without adjunctive coiling) at 2 cerebrovascular centers. Patients were loaded with aspirin and clopidogrel or received an infusion of tirofiban intraoperatively. RESULTS: Hunt and Hess grades were I in 7 patients (35%), II in 9 (45%), and III in 4 (20%). The mean duration from hemorrhage to PED placement was 7+/-7.0 days. A single device was used in all but 1 patient (95%). The procedure was staged in 20%. There was only 1 complication (5%); this was a fatal intraoperative aneurysm dome rupture that occurred during adjunctive coil deployment. Adjunctive coiling was used in 30%. No patient required an invasive procedure after PED placement. Follow-up angiography (mean, 5.3+/-4.2 months; range, 2-12 months) showed 100% occlusion in 12 (80%) and incomplete occlusion in 3 patients (20%). At latest follow-up, 19 patients achieved a favorable outcome (modified rankin scale 0-2). CONCLUSION: In our preliminary experience, treatment of ruptured aneurysms with the PED was associated with low complication rates, high occlusion rates, and favorable outcomes. These findings suggest that PED may be a safe and effective option for patients with favorable Hunt and Hess grades and aneurysms difficult to treat with conventional methods. PMID- 25549184 TI - Purifying the impure: sequencing metagenomes and metatranscriptomes from complex animal-associated samples. AB - The accessibility of high-throughput sequencing has revolutionized many fields of biology. In order to better understand host-associated viral and microbial communities, a comprehensive workflow for DNA and RNA extraction was developed. The workflow concurrently generates viral and microbial metagenomes, as well as metatranscriptomes, from a single sample for next-generation sequencing. The coupling of these approaches provides an overview of both the taxonomical characteristics and the community encoded functions. The presented methods use Cystic Fibrosis (CF) sputum, a problematic sample type, because it is exceptionally viscous and contains high amount of mucins, free neutrophil DNA, and other unknown contaminants. The protocols described here target these problems and successfully recover viral and microbial DNA with minimal human DNA contamination. To complement the metagenomics studies, a metatranscriptomics protocol was optimized to recover both microbial and host mRNA that contains relatively few ribosomal RNA (rRNA) sequences. An overview of the data characteristics is presented to serve as a reference for assessing the success of the methods. Additional CF sputum samples were also collected to (i) evaluate the consistency of the microbiome profiles across seven consecutive days within a single patient, and (ii) compare the consistency of metagenomic approach to a 16S ribosomal RNA gene-based sequencing. The results showed that daily fluctuation of microbial profiles without antibiotic perturbation was minimal and the taxonomy profiles of the common CF-associated bacteria were highly similar between the 16S rDNA libraries and metagenomes generated from the hypotonic lysis (HL)-derived DNA. However, the differences between 16S rDNA taxonomical profiles generated from total DNA and HL-derived DNA suggest that hypotonic lysis and the washing steps benefit in not only removing the human-derived DNA, but also microbial derived extracellular DNA that may misrepresent the actual microbial profiles. PMID- 25549188 TI - Self-expanding stent placement for anterior circulation intracranial artery dissection presenting with ischemic symptoms. AB - BACKGROUND: The prognosis of ischemic anterior circulation intracranial dissection (AC-ICD) is poor and its optimal management is still controversial. OBJECTIVE: To evaluate the safety and efficacy of a self-expanding stent for ischemic AC-ICD. METHODS: Eight patients (mean age, 36 years) underwent self expanding stenting for ischemic AC-ICD. Imaging findings of ischemic AC-ICD, the reason for stenting, and the clinical and angiographic outcomes were retrospectively evaluated. RESULTS: AC-ICD involved intracranial internal carotid artery to middle cerebral artery (MCA) in 2, intracranial internal carotid artery alone in 3, and MCA alone in 3 patients. Six AC-ICDs showed complete or near occlusions while 2 had a severe degree of stenosis. Six AC-ICDs showed an intimal flap and 3 had intramural hematomas. Six patients underwent emergent stenting for acute stroke within 6 hours (n=2) or crescendo-type stroke within 24 hours (n=4), while 2 patients had stenting for recurrent ischemia on dual antiplatelet and/or anticoagulation after the initial attack. The mean dissection-related stenosis improved from 93.1% to 20.3% after stenting (P<.05). The mean National Institutes of Health Stroke Scale score improved from 7.5 to 1.4 (P<.05). All patients had excellent or favorable outcomes at 3 months: modified Rankin Scale score, 0 in 3, 1 in 3, and 2 in 1 patient(s). No patients had subarachnoid hemorrhage or ischemic symptom recurrence during the clinical follow-up (mean, 27 months). All stented arteries were patent without significant in-stent stenosis on angiographic follow-up (range, 3-12 months). CONCLUSION: Self-expanding stents seem to be safe and effective for AC-ICD presenting with acute/crescendo-type stroke or recurrent ischemia despite adequate medication. PMID- 25549189 TI - Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection. AB - BACKGROUND: Postoperative stereotactic radiosurgery for brain metastases potentially offers similar local control rates and fewer long-term neurocognitive sequelae compared to whole brain radiation therapy, although patients remain at risk for distant brain failure (DBF). OBJECTIVE: To describe clinical outcomes of adjuvant stereotactic radiosurgery for large brain metastases and identify predictors of intracranial failure and their implications on optimal patient selection criteria. METHODS: We performed a retrospective review on 100 large (>3 cm) brain metastases in 99 patients managed by resection followed by postoperative stereotactic radiosurgery to a median dose of 22 Gy (range, 10-28) in 1 to 5 fractions (median, 3). Primary histology was nonsmall cell lung in 40%, breast cancer in 18%, and melanoma in 17%. Forty (40%) patients had uncontrolled systemic disease. RESULTS: With a median follow-up of 12.2 months (range, 0.6 87.4), the 1-year Kaplan-Meier local control was 72%, DBF 64%, and overall survival 55%. Nine patients (9%) developed evidence of radiation injury, and 6 (6%) developed leptomeningeal disease. Uncontrolled systemic disease (P=.03), melanoma histology (P=.04), and increasing number of brain metastases (P<.001) were significant predictors of DBF on Cox multivariate analysis. Patients with <4 metastases, controlled systemic disease, and nonmelanoma primary (n=47) had a 1 year DBF of 48.6% vs 80.1% for all others (P=.01). CONCLUSION: Postoperative stereotactic radiosurgery to the resection cavity safely and effectively augments local control of large brain metastases. Patients with <4 metastases and controlled systemic disease have significantly lower rates of DBF and are ideal treatment candidates. PMID- 25549190 TI - Incidence and clinical implications of carotid branch occlusion following treatment of internal carotid artery aneurysms with the pipeline embolization device. AB - BACKGROUND: The use of flow diverters such as the pipeline embolization device (PED) for treatment of intracranial aneurysms carries the risk of side branch occlusion. OBJECTIVE: To determine the incidence and clinical outcomes associated with supraclinoid internal carotid artery (ICA) branch occlusion after deployment of PEDs for ICA aneurysms. METHODS: We reviewed patients who underwent endovascular treatment with PEDs for ICA aneurysms between June 2011 and March 2013. Forty-nine patients (43 women, mean age 56.3+/-1.8 years, 68 aneurysms) in whom PEDs traversed the origin of supraclinoid ICA branches (ophthalmic [OA], posterior communicating [PcommA], and anterior choroidal artery [AChA]) were selected for this study. Follow-up angiograms (mean follow-up, 12.8+/-0.8 months) were studied to determine the location of PEDs and the patency of ICA branches. RESULTS: PEDs were placed across the ostia of 49 OAs, 14 PcommAs, and 11 AChAs. Multiple PEDs were deployed in 16 patients. Rate of branch occlusion was 4% (2/49) for the OA, 7.1% (1/14) for the PcommA, and 0% for the AChA. Patients with branch occlusion did not endure new neurological deficits. ICA branch occlusion was not associated with the number of PEDs covering the ostia (P=.76) or the origin of ICA branches from the aneurysm (P=.24). CONCLUSION: The incidence of major supraclinoid ICA branch occlusion after treatment with PEDs was low. These events were not associated with new neurological deficits nor were they related to the number of PEDs deployed or the origin of ICA branches from the aneurysm. PMID- 25549191 TI - Origination of the muscular branches of the median nerve: an electrophysiological study. AB - BACKGROUND: In lower brachial plexus injury, finger flexion after brachialis motor branch transfer is relatively weak. We sought to screen potential branches of the median nerve from the upper trunk for strengthening finger flexion in addition to the brachialis motor branch. However, the spinal origin of the muscular branches of the median nerve based on electrophysiological study was unclear. OBJECTIVE: To determine the spinal origin of the muscular branches of the median nerve. METHODS: An intraoperative electrophysiological study was carried out in 18 patients who underwent contralateral C7 nerve transfer. After exposure of the brachial plexus nerve roots on the healthy side, the amplitude of the compound muscle action potential of each median nerve-innervated muscle was recorded while the different nerve roots were stimulated. RESULTS: The pronator teres received fibers from C5, C6, and C7. It had more contribution from C5 and C6 than from C7 (P<.05). The flexor carpi radialis was innervated mainly by C6 and C7. The nerve branches of the palmaris longus and flexor digitorum superficialis stemmed primarily from C7 and the lower trunk, and no significant difference was found between them (P>.05). The flexor digitorum profundus, flexor pollicis longus, pronator quadratus, and abductor pollicis brevis were innervated predominantly by the lower trunk (P<.05). CONCLUSION: This electrophysiological study indicates that the pronator teres branch might be the most feasible alternative donor nerve to supplement the brachialis motor branch and strengthen finger flexion after lower brachial plexus injury. PMID- 25549192 TI - Randomized pilot trial of intensive management of blood pressure or volume expansion in subarachnoid hemorrhage (IMPROVES). AB - BACKGROUND: Volume expansion and hypertension are widely used for the hemodynamic management of patients with subarachnoid hemorrhage. OBJECTIVE: To investigate the feasibility, adherence, and retention in a trial of volume expansion and blood pressure manipulation to prevent delayed cerebral ischemia. METHODS: A randomized pilot trial using a 2-way factorial design allocating patients within 72 hours of subarachnoid hemorrhage to either normovolemia (NV) or volume expansion (HV) and simultaneously to conventional (CBP) or augmented blood pressure (ABP) for 10 days. The study endpoints were protocol adherence and retention to follow-up. The quality of endpoints for a larger trial were 6-month modified Rankin Scale score, comprehensive neurobehavioral assessment, delayed cerebral ischemia, new stroke, and discharge disposition. RESULTS: Twenty patients were randomized and completed follow-up. The overall difference in daily mean intravenous fluid intake was 2099 mL (95% confidence interval [CI]: 867, 3333), HV vs NV group. The overall mean systolic blood pressure difference was 5 mm Hg (95% CI: -4.65, 14.75), ABP vs CBP group. Adverse events included death (n=1), delayed cerebral ischemia (n=1), and pulmonary complications (n=3). There were no differences in modified Rankin Scale score between HV and NV (difference 0.1; 95% CI: -1.26, 1.46, P=.87) or between ABP and CBP groups (-0.5, 95% CI: 1.78, 0.78, P=.43). Neuropsychological scores were similar between HV vs NV, but tended to be worse in ABP (57+/-27) vs CBP group (85+/-21, P=.04). CONCLUSION: This pilot study showed adequate feasibility and excellent retention to follow up. Given the suggestion of possible worse neurobehavioral outcome with ABP, a larger trial to determine the optimal blood pressure management in this patient population is warranted. (ClinTrials.gov NCT01414894.) PMID- 25549193 TI - Contralateral peripheral neurotization for hemiplegic upper extremity after central neurologic injury. AB - BACKGROUND: Central neurological injury (CNI) is a major contributor to physical disability that affects both adults and children all over the world. The main sequelae of chronic stage CNI are spasticity, paresis of specific muscles, and poor selective motor control. Here, we apply the concept of contralateral peripheral neurotization in spasticity releasing and motor function restoration of the affected upper extremity. OBJECTIVE: A clinical investigation was performed to verify the clinical efficacy of contralateral C7 neurotization for rescuing the affected upper extremity after CNI. METHODS: In the present study, 6 adult hemiplegia patients received the nerve transfer surgery of contralateral C7 to C7 of the affected side. Another 6 patients with matched pathological and demographic status were assigned to the control group that received rehabilitation only. During the 2-year follow-up, muscle strength of bilateral upper extremities was assessed. The Modified Ashworth Scale and Fugl-Meyer Assessment Scale were used for evaluating spasticity and functional use of the affected upper extremity, respectively. RESULTS: Both flexor spasticity release and motor functional improvements were observed in the affected upper extremity in all 6 patients who had surgery. The muscle strength of the extensor muscles and the motor control of the affected upper extremity improved significantly. There was no permanent loss of sensorimotor function of the unaffected upper extremity. CONCLUSION: This contralateral C7 neurotization approach may open a door to promote functional recovery of upper extremity paralysis after CNI. PMID- 25549195 TI - The severity of basilar invagination and atlantoaxial dislocation correlates with sagittal joint inclination, coronal joint inclination, and craniocervical tilt: a description of new indices for the craniovertebral junction. PMID- 25549194 TI - Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection. AB - BACKGROUND: 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE: To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS: CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS: Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28+/ 1.08) was significantly higher (P<.01) than for CLR1501 (3.51+/-0.44 on confocal imaging; 7.23+/-1.63 on IVIS imaging) and 5-ALA (4.81+/-0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high- contrast tumor visualization compatible with surgical applications. CONCLUSION: CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of 5-ALA, whereas CLR1502 has a superior tumor to-brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery. PMID- 25549196 TI - Distraction, compression, and extension reduction of basilar invagination and atlantoaxial dislocation. PMID- 25549197 TI - In reply: distraction, compression, and extension reduction of basilar invagination and atlantoaxial dislocation. PMID- 25549198 TI - Anatomical variations of the presigmoid suprabulbar infralabyrinthine approach. PMID- 25549199 TI - In reply: the severity of basilar invagination and atlantoaxial dislocation correlates with sagittal joint inclination, coronal joint inclination, and craniocervical tilt: a description of new indices for the craniovertebral junction. PMID- 25549200 TI - Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage. AB - BACKGROUND: Although osteoarthritis (OA) is the commonest joint disorder and has a rising prevalence as the population ages, no drugs are available that prevent or delay the onset and progression of disease. Recent studies identified the DIO2 gene encoding type 2 deiodinase (D2) as a susceptibility locus for OA, and further data suggest deiodinase-regulated local availability of triiodothyronine (T3) in the joint plays an important role in cartilage maintenance and repair. To investigate the hypothesis that reduced tissue T3 availability protects joints from development of OA, the joint phenotypes of adult mice lacking D2 (D2KO) or lacking both D1 and D2 (D1D2KO), the only enzymes that catalyze conversion of the prohormone thyroxine to active T3, were determined. METHODS: Knee joints were prepared from male 16-week-old adult wild type (WT; n=9), D2KO (n=5), and D1D2KO (n=3) mice. Articular cartilage pathology was scored using the Osteoarthritis Research Society International (OARSI) histopathology scale for murine OA to determine the severity and extent of disease. Digital X-ray microradiography was used to determine the area and mineral content of subchondral bone immediately beneath the articular cartilage surface. RESULTS: There were no differences in maximum and standardized OA scores, cartilage erosion indices, or articular cartilage cellularity among WT, D2KO, and D1D2KO mice. Subchondral bone area did not differ among genotypes, but mineral content was markedly increased in both D2KO and D1D2KO mice compared to WT. CONCLUSIONS: Although adult D2KO mice have normal articular cartilage and no other features of spontaneous joint damage, they exhibit increased subchondral bone mineral content. PMID- 25549201 TI - Assessing cerebral autoregulation via oscillatory lower body negative pressure and projection pursuit regression. AB - The process by which cerebral perfusion is maintained constant over a wide range of systemic pressures is known as "cerebral autoregulation." Effective dampening of flow against pressure changes occurs over periods as short as ~15 sec and becomes progressively greater over longer time periods. Thus, slower changes in blood pressure are effectively blunted and faster changes or fluctuations pass through to cerebral blood flow relatively unaffected. The primary difficulty in characterizing the frequency dependence of cerebral autoregulation is the lack of prominent spontaneous fluctuations in arterial pressure around the frequencies of interest (less than ~0.07 Hz or ~15 sec). Oscillatory lower body negative pressure (OLBNP) can be employed to generate oscillations in central venous return that result in arterial pressure fluctuations at the frequency of OLBNP. Moreover, Projection Pursuit Regression (PPR) provides a nonparametric method to characterize nonlinear relations inherent in the system without a priori assumptions and reveals the characteristic non-linearity of cerebral autoregulation. OLBNP generates larger fluctuations in arterial pressure as the frequency of negative pressure oscillations become slower; however, fluctuations in cerebral blood flow become progressively lesser. Hence, the PPR shows an increasingly more prominent autoregulatory region at OLBNP frequencies of 0.05 Hz and below (20 sec cycles). The goal of this approach it to allow laboratory-based determination of the characteristic nonlinear relationship between pressure and cerebral flow and could provide unique insight to integrated cerebrovascular control as well as to physiological alterations underlying impaired cerebral autoregulation (e.g., after traumatic brain injury, stroke, etc.). PMID- 25549202 TI - Effects of Bolus and Continuous Nasogastric Feeding on Gastric Emptying, Small Bowel Water Content, Superior Mesenteric Artery Blood Flow, and Plasma Hormone Concentrations in Healthy Adults: A Randomized Crossover Study. AB - OBJECTIVE: We aimed to demonstrate the effect of continuous or bolus nasogastric feeding on gastric emptying, small bowel water content, and splanchnic blood flow measured by magnetic resonance imaging (MRI) in the context of changes in plasma gastrointestinal hormone secretion. BACKGROUND: Nasogastric/nasoenteral tube feeding is often complicated by diarrhea but the contribution of feeding strategy to the etiology is unclear. METHODS: Twelve healthy adult male participants who underwent nasogastric intubation before a baseline MRI scan, received 400 mL of Resource Energy (Nestle) as a bolus over 5 minutes or continuously over 4 hours via pump in this randomized crossover study. Changes in gastric volume, small bowel water content, and superior mesenteric artery blood flow and velocity were measured over 4 hours using MRI and blood glucose and plasma concentrations of insulin, peptide YY, and ghrelin were assayed every 30 minutes. RESULTS: Bolus nasogastric feeding led to significant elevations in gastric volume (P < 0.0001), superior mesenteric artery blood flow (P < 0.0001), and velocity (P = 0.0011) compared with continuous feeding. Both types of feeding reduced small bowel water content, although there was an increase in small bowel water content with bolus feeding after 90 minutes (P < 0.0068). Similarly, both types of feeding led to a fall in plasma ghrelin concentration although this fall was greater with bolus feeding (P < 0.0001). Bolus feeding also led to an increase in concentrations of insulin (P = 0.0024) and peptide YY (P < 0.0001), not seen with continuous feeding. CONCLUSION: Continuous nasogastric feeding does not increase small bowel water content, thus fluid flux within the small bowel is not a major contributor to the etiology of tube feeding-related diarrhea. PMID- 25549203 TI - Macrophage cholesterol depletion and its effect on the phagocytosis of Cryptococcus neoformans. AB - Cryptococcosis is a life-threatening infection caused by pathogenic fungi of the genus Cryptococcus. Infection occurs upon inhalation of spores, which are able to replicate in the deep lung. Phagocytosis of Cryptococcus by macrophages is one of the ways that the disease is able to spread into the central nervous system to cause lethal meningoencephalitis. Therefore, study of the association between Cryptococcus and macrophages is important to understanding the progression of the infection. The present study describes a step-by-step protocol to study macrophage infectivity by C. neoformansin vitro. Using this protocol, the role of host sterols on host-pathogen interactions is studied. Different concentrations of methyl--cyclodextrin (MCD) were used to deplete cholesterol from murine reticulum sarcoma macrophage-like cell line J774A.1. Cholesterol depletion was confirmed and quantified using both a commercially available cholesterol quantification kit and thin layer chromatography. Cholesterol depleted cells were activated using Lipopolysacharide (LPS) and Interferon gamma (IFNgamma) and infected with antibody-opsonized Cryptococcus neoformans wild-type H99 cells at an effector-to-target ratio of 1:1. Infected cells were monitored after 2 hr of incubation with C. neoformans and their phagocytic index was calculated. Cholesterol depletion resulted in a significant reduction in the phagocytic index. The presented protocols offer a convenient method to mimic the initiation of the infection process in a laboratory environment and study the role of host lipid composition on infectivity. PMID- 25549204 TI - Intra-fraction motion of the prostate is a random walk. AB - A random walk model for intra-fraction motion has been proposed, where at each step the prostate moves a small amount from its current position in a random direction. Online tracking data from perineal ultrasound is used to validate or reject this model against alternatives. Intra-fraction motion of a prostate was recorded by 4D ultrasound (Elekta Clarity system) during 84 fractions of external beam radiotherapy of six patients. In total, the center of the prostate was tracked for 8 h in intervals of 4 s. Maximum likelihood model parameters were fitted to the data. The null hypothesis of a random walk was tested with the Dickey-Fuller test. The null hypothesis of stationarity was tested by the Kwiatkowski-Phillips-Schmidt-Shin test. The increase of variance in prostate position over time and the variability in motility between fractions were analyzed. Intra-fraction motion of the prostate was best described as a stochastic process with an auto-correlation coefficient of rho = 0.92 +/- 0.13. The random walk hypothesis (rho = 1) could not be rejected (p = 0.27). The static noise hypothesis (rho = 0) was rejected (p < 0.001). The Dickey-Fuller test rejected the null hypothesis rho = 1 in 25% to 32% of cases. On average, the Kwiatkowski-Phillips-Schmidt-Shin test rejected the null hypothesis rho = 0 with a probability of 93% to 96%. The variance in prostate position increased linearly over time (r(2) = 0.9 +/- 0.1). Variance kept increasing and did not settle at a maximum as would be expected from a stationary process. There was substantial variability in motility between fractions and patients with maximum aberrations from isocenter ranging from 0.5 mm to over 10 mm in one patient alone. In conclusion, evidence strongly suggests that intra-fraction motion of the prostate is a random walk and neither static (like inter-fraction setup errors) nor stationary (like a cyclic motion such as breathing, for example). The prostate tends to drift away from the isocenter during a fraction, and this variance increases with time, such that shorter fractions are beneficial to the problem of intra-fraction motion. As a consequence, fixed safety margins (which would over compensate at the beginning and under-compensate at the end of a fraction) cannot optimally account for intra-fraction motion. Instead, online tracking and position correction on-the-fly should be considered as the preferred approach to counter intra-fraction motion. PMID- 25549205 TI - Therapeutic Drug Monitoring and Dose Adjustment of Posaconazole Oral Suspension in Adults With Acute Myeloid Leukemia. AB - BACKGROUND: Prophylaxis with posaconazole, an extended-spectrum triazole antifungal, has been shown to increase overall survival in adults with acute myeloid leukemia receiving intensive remission induction chemotherapy. A paucity of data exists evaluating therapeutic drug monitoring and subsequent dose adjustment based on serum concentrations in humans. METHODS: An observational study was performed in 29 adult patients with acute myeloid leukemia who initially received posaconazole oral suspension 200 mg 3 times daily and required >=1 dose adjustment because of steady-state posaconazole serum concentration <0.7 mcg/mL. Four dosing schemas were compared simultaneously. Patient records were reviewed to collect patient-related and medication-related factors that may affect serum concentrations. RESULTS: Thirty-five percent of patients experienced subtherapeutic posaconazole serum concentrations with prophylactic dosing of posaconazole oral suspension. Increasing the dose and/or schedule of posaconazole oral suspension led to attainment of goal posaconazole serum concentrations in all groups. However, patients who received 400 mg orally 3 times daily experienced the least significant increase in serum concentration and remained subtherapeutic, despite doubling the posaconazole daily dose. Toxicities were similar to baseline within all groups. Increasing the dose and/or frequency of posaconazole oral suspension led to an increase in systemic exposure and did not appreciably increase incidence of toxicities. CONCLUSIONS: Patients receiving posaconazole oral suspension that experience subtherapeutic posaconazole serum concentrations may benefit from increasing the frequency to 200 mg orally 4 times daily or dose to 300 mg orally 3 times daily. PMID- 25549206 TI - Colistin: Revival of an Old Polymyxin Antibiotic. AB - Colistin (polymyxin E) is a positively charged deca-peptide antibiotic that disrupts the integrity of the outer membrane of the cell wall of gram-negative bacteria by binding to the lipid A moiety of lipopolysaccharides, resulting in cell death. The endotoxic activity of lipopolysaccharides is simultaneously inhibited. Colistin is increasingly being prescribed as rescue treatment for infections with multidrug-resistant bacilli. Nephrotoxicity and, to a lesser degree, neurotoxicity occur often during systemic colistin therapy, and have severely limited its application in the past. However, these side effects are largely reversible and can be managed through close monitoring. The prodrug colistimethate sodium (CMS) is less toxic and is, therefore, the preferred formulation for parenteral administration. Importantly, resistance to colistin seems to emerge often unless it is combined with another antibiotic, but further studies into this phenomenon are necessary. Pharmacokinetic and pharmacodynamic properties have received little attention, partly because of the physicochemical peculiarities of polymyxin antibiotics, especially their propensity to stick to other molecules and surfaces. The ratio between the area under the curve of free colistin and the pathogen's Minimal Inhibitory Concentration (MIC) best predicts microbiological and clinical responses, but more studies are needed in this area. Likewise, further standardization is needed in production and labeling of colistin formulations, and in the way the susceptibility of bacteria to colistin is determined. PMID- 25549207 TI - Detection Times of Diazepam, Clonazepam, and Alprazolam in Oral Fluid Collected From Patients Admitted to Detoxification, After High and Repeated Drug Intake. AB - BACKGROUND: Clonazepam, diazepam, and alprazolam are benzodiazepines with sedative, anticonvulsant, and anxiolytic effects, but their prevalence in drug abuse and drug overdoses has long been recognized. When detection times for psychoactive drugs in oral fluid are reported, they are most often based on therapeutic doses administered in clinical studies. Repeated ingestions of high doses, as seen after drug abuse, are however likely to cause positive samples for extended time periods. Findings of drugs of abuse in oral fluid collected from imprisoned persons might lead to negative sanctions, and the knowledge of detection times of these drugs is thus important to ensure correct interpretation. The aim of this study was to investigate the time window of detection for diazepam, clonazepam, and alprazolam in oral fluid from drug addicts admitted to detoxification. METHODS: Twenty-five patients with a history of heavy drug abuse admitted to a detoxification ward were included. Oral fluid was collected daily in the morning and the evening and urine samples every morning for 10 days, using the Intercept device. Whole blood samples were collected if the patient accepted. The cutoff levels in oral fluid were 1.3 ng/mL for diazepam, N-desmethyldiazepam, and 7-aminoclonazepam and 1 ng/mL for clonazepam and alprazolam. In urine, the cutoff levels for quantifications were 30 ng/mL for alprazolam, alpha-OH-alprazolam, and 7-aminoclonazepam, 135 ng/mL for N-desmethyldizepam, and 150 ng/mL for 3-OH-diazepam and for all the compounds, the cutoff for the screening analyses were 200 ng/mL. RESULTS: The maximum detection times for diazepam and N-desmethyldiazepam in oral fluid were 7 and 9 days, respectively. For clonazepam and 7-aminoclonazepam, the maximum detection times in oral fluid were 5 and 6 days, respectively. The maximum detection time for alprazolam in oral fluid was 2.5 days. New ingestions were not suspected in any of the cases, because the corresponding concentrations in urine were decreasing. Results from blood samples revealed that high doses of benzodiazepines had been ingested before admission, and explains the longer detection times in oral fluids than reported previously after intake of therapeutic doses of these drugs. CONCLUSIONS: This study has shown that oral fluid might be a viable alternative medium to urine when the abuse of benzodiazepines is suspected. PMID- 25549208 TI - Methods for Predicting Warfarin Dose Requirements. AB - BACKGROUND: The aim of this study was to compare the predictive performance of different warfarin dosing methods. METHODS: Data from 46 patients who were initiating warfarin therapy were available for analysis. Nine recently published dosing tools including 8 dose prediction algorithms and a Bayesian forecasting method were compared with each other in terms of their ability to predict the actual maintenance dose. The dosing tools included 4 algorithms that were based on patient characteristics (2 clinical and 2 genotype-driven algorithms), 4 algorithms based on international normalized ratio (INR) response feedback and patient characteristics (2 clinical and 2 genotype-driven algorithms), and a Bayesian forecasting method. Comparisons were conducted using measures of bias (mean prediction error) and imprecision [root mean square error (RMSE)]. RESULTS: The 2 genotype-driven INR feedback algorithms by Horne et al and Lenzini et al produced more precise maintenance dose predictions (RMSE, 1.16 and 1.19 mg/d, respectively; P < 0.05) than the genotype-driven algorithms by Gage et al and Klein et al and the Bayesian method (RMSE, 1.60, 1.62, and 1.81 mg/d respectively). The dose predictions from clinical and genotype-driven algorithms by Gage et al, Klein et al, and Horne et al were all negatively biased. Only the INR feedback algorithms (clinical and genotype) by Lenzini et al produced unbiased dose predictions. The Bayesian method produced unbiased dose predictions overall (mean prediction error, +0.37 mg/d; 95% confidence interval, 0.89 to 0.15) but overpredicted doses in patients requiring >8 mg/d. CONCLUSIONS: Overall, warfarin dosing methods that included some measure of INR response (INR feedback algorithms and Bayesian methods) produced unbiased and more precise dose predictions. The Bayesian forecasting method produced positively biased dose predictions in patients who required doses >8 mg/d. Further research to assess differences in clinical endpoints when warfarin doses are predicted using Bayesian or INR-driven algorithms is warranted. PMID- 25549209 TI - Tracking the mammary architectural features and detecting breast cancer with magnetic resonance diffusion tensor imaging. AB - Breast cancer is the most common cause of cancer among women worldwide. Early detection of breast cancer has a critical role in improving the quality of life and survival of breast cancer patients. In this paper a new approach for the detection of breast cancer is described, based on tracking the mammary architectural elements using diffusion tensor imaging (DTI). The paper focuses on the scanning protocols and image processing algorithms and software that were designed to fit the diffusion properties of the mammary fibroglandular tissue and its changes during malignant transformation. The final output yields pixel by pixel vector maps that track the architecture of the entire mammary ductal glandular trees and parametric maps of the diffusion tensor coefficients and anisotropy indices. The efficiency of the method to detect breast cancer was tested by scanning women volunteers including 68 patients with breast cancer confirmed by histopathology findings. Regions with cancer cells exhibited a marked reduction in the diffusion coefficients and in the maximal anisotropy index as compared to the normal breast tissue, providing an intrinsic contrast for delineating the boundaries of malignant growth. Overall, the sensitivity of the DTI parameters to detect breast cancer was found to be high, particularly in dense breasts, and comparable to the current standard breast MRI method that requires injection of a contrast agent. Thus, this method offers a completely non invasive, safe and sensitive tool for breast cancer detection. PMID- 25549211 TI - Functionalized thermo-responsive microgels for high performance forward osmosis desalination. AB - Stimuli-responsive hydrogels were recently proposed for energy-saving forward osmosis (FO) process. However, their low water flux and dewatering ability for reuse make them less attractive for industrial desalination process. In this work, the co-polymer microgels of N-isopropylacrylamide and acrylic acid with different mixing ratios were synthesized using surfactant-free emulsion polymerization to produce submicron-size hydrogels with high surface area and fast swelling-deswelling response. The microgels were employed as draw agents in a laboratory scale FO desalination system. The microgel-based FO process performed a high water flux up to 23.8 LMH and high water recovery ability of 72.4%. In addition, we explored a new conductivity measurement method to online analyze water flux of the FO system. This on-line conductivity analysis approach appeared to be an accurate and efficient method for evaluating microgel-based FO desalination performance. Our experimental data revealed that the stimuli responsive microgel was an efficient draw agent for FO desalination. PMID- 25549210 TI - Changes in dyadic communication during and after integrative and traditional behavioral couple therapy. AB - To examine changes in dyadic communication, as well as links between communication and long-term relationship outcomes, 134 distressed couples randomly assigned to either Traditional Behavioral Couple Therapy (TBCT; Jacobson & Margolin, 1979) or Integrative Behavioral Couple Therapy (IBCT; Jacobson & Christensen, 1998) were observed in video-recorded interactions. Observers rated discussions of relationship problems at 3 time points (pre-therapy, post-therapy, 2-year follow-up) and relationship outcomes (i.e., treatment response and relationship stability) were measured at a 5-year follow-up. Consistent with previous examinations of individual partner communication (K.J.W. Baucom et al., 2011; Sevier et al., 2008), TBCT produced greater improvements from pre-therapy to post-therapy (d = 0.27-0.43) and superior communication at post-therapy (d = 0.30-0.37). However, IBCT produced greater improvements from post-therapy to 2 year follow-up (d = 0.32-0.39). Both levels of, and changes in, dyadic communication were associated with relationship outcomes, even when controlling for individual communication. Our findings lend additional support for theoretical and practical differences between these two therapies and the utility of assessment at the level of the couple. Furthermore, they contribute to a broader pattern of findings in which relationship outcomes are more consistently linked with constructive communication than with destructive communication. PMID- 25549212 TI - Tarantula cubensis extract alters the degree of apoptosis and mitosis in canine mammary adenocarcinomas. AB - In the present study, 13 clinical cases of canine mammary adenocarcinoma were evaluated in order to understand the effect of Tarantula cubensis extract (TCE) on tumor tissue. Punch biopsies were taken from the tumors before treatment with TCE. Subcutaneous injections of TCE were administered three times at weekly intervals (3 mL per dog). Between days 7 and 10 after the third injection, the tumor masses were extirpated by complete unilateral mastectomy. Pre- and post treatment tumor tissues were immunohistochemically assessed. The expression of B cell lymphoma 2 (Bcl-2) was found to be higher in pre-treatment compared to post treatment tissues (p < 0.01) whereas Ki-67 expression was lower in post-treatment tissues (p < 0.01). No significant differences in fibroblast growth factor or vascular endothelial growth factor expression were observed between pre- and post treatment tissues (p > 0.05). The apoptotic index was determined to be low before treatment and increased during treatment. These results suggest that TCE may be effective for controlling the local growth of canine mammary adenocarcinoma by regulating apoptosis. PMID- 25549213 TI - Involvement of the Ca2+ signaling pathway in osteoprotegerin inhibition of osteoclast differentiation and maturation. AB - The purpose of this study was to determine whether the Ca(2+) signaling pathway is involved in the ability of osteoprotegerin (OPG) to inhibit osteoclast differentiation and maturation. RAW264.7 cells were incubated with macrophage colony-stimulating factor (M-CSF) + receptor activator of nuclear factor-kappaB ligand (RANKL) to stimulate osteoclastogenesis and then treated with different concentrations of OPG, an inhibitor of osteoclast differentiation. The intracellular Ca(2+) concentration [Ca(2+)]i and phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the different treatment groups were measured by flow cytometry and Western blotting, respectively. The results confirmed that M-CSF + RANKL significantly increased [Ca(2+)]i and CaMKII phosphorylation in osteoclasts (p < 0.01), and that these effects were subsequently decreased by OPG treatment. Exposure to specific inhibitors of the Ca(2+) signaling pathway revealed that these changes varied between the different OPG treatment groups. Findings from the present study indicated that the Ca(2+) signaling pathway is involved in both the regulation of osteoclastogenesis as well as inhibition of osteoclast differentiation and activation by OPG. PMID- 25549214 TI - Comparison of pharmacological and genetic inhibition of cyclooxygenase-2: effects on adult neurogenesis in the hippocampal dentate gyrus. AB - Inducible cyclooxygenase-2 (COX-2) has received much attention because of its role in neuro-inflammation and synaptic plasticity. Even though COX-2 levels are high in healthy animals, the function of this factor in adult neurogenesis has not been clearly demonstrated. Therefore, we performed the present study to compare the effects of pharmacological and genetic inhibition of COX-2 on adult hippocampal neurogenesis. Physiological saline or the same volume containing celecoxib was administered perorally every day for 5 weeks using a feeding needle. Compared to the control, pharmacological and genetic inhibition of COX-2 reduced the appearance of nestin-immunoreactive neural stem cells, Ki67-positive nuclei, and doublecortin-immunoreactive neuroblasts in the dentate gyrus. In addition, a decrease in phosphorylated cAMP response element binding protein (pCREB) at Ser133 was observed. Compared to pharmacological inhibition, genetic inhibition of COX-2 resulted in significant reduction of neural stem cells, cell proliferation, and neuroblast differentiation as well as pCREB levels. These results suggest that COX-2 is part of the molecular machinery that regulates neural stem cells, cell proliferation, and neuroblast differentiation during adult hippocampal neurogenesis via pCREB. Additionally, genetic inhibition of COX 2 strongly reduced neural stem cell populations, cell proliferation, and neuroblast differentiation in the dentate gyrus compared to pharmacological inhibition. PMID- 25549216 TI - In vitro development of canine somatic cell nuclear transfer embryos in different culture media. AB - The objective of the present study was to investigate the effects of three different culture media on the development of canine somatic cell nuclear transfer (SCNT) embryos. Canine cloned embryos were cultured in modified synthetic oviductal fluid (mSOF), porcine zygote medium-3 (PZM-3), or G1/G2 sequential media. Our results showed that the G1/G2 media yielded significantly higher morula and blastocyst development in canine SCNT embryos (26.1% and 7.8%, respectively) compared to PZM-3 (8.5% and 0%or mSOF (2.3% and 0%) media. In conclusion, this study suggests that blastocysts can be produced more efficiently using G1/G2 media to culture canine SCNT embryos. PMID- 25549217 TI - The role of rpoS, hmp, and ssrAB in Salmonella enterica Gallinarum and evaluation of a triple-deletion mutant as a live vaccine candidate in Lohmann layer chickens. AB - Salmonella enterica Gallinarum (SG) causes fowl typhoid (FT), a septicemic disease in avian species. We constructed deletion mutants lacking the stress sigma factor RpoS, the nitric oxide (NO)-detoxifying flavohemoglobin Hmp, and the SsrA/SsrB regulator to confirm the functions of these factors in SG. All gene products were fully functional in wild-type (WT) SG whereas mutants harboring single mutations or a combination of rpoS, hmp, and ssrAB mutations showed hypersusceptibility to H2O2, loss of NO metabolism, and absence of Salmonella pathogenicity island (SPI)-2 expression, respectively. A triple-deletion mutant, SGDelta3 (SGDeltarpoSDeltahmpDeltassrAB), was evaluated for attenuated virulence and protection efficacy in two-week-old Lohmann layer chickens. The SGDelta3 mutant did not cause any mortality after inoculation with either 1 * 10(6) or 1 * 10(8) colony-forming units (CFUs) of bacteria. Significantly lower numbers of salmonellae were recovered from the liver and spleen of chickens inoculated with the SGDelta3 mutant compared to chickens inoculated with WT SG. Vaccination with the SGDelta3 mutant conferred complete protection against challenge with virulent SG on the chickens comparable to the group vaccinated with a conventional vaccine strain, SG9R. Overall, these results indicate that SGDelta3 could be a promising candidate for a live Salmonella vaccine against FT. PMID- 25549218 TI - Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy. AB - Fucoidan is a sulfated polysaccharide derived from brown seaweed, including Fucus vesiculosus. This compound is known to have immunostimulatory effects on various types of immune cells including macrophages and dendritic cells. A recent study described the application of fucoidan as a vaccine adjuvant. Vaccination is regarded as the most efficient prophylactic method for preventing harmful or epidemic diseases. To increase vaccine efficacy, effective adjuvants are needed. In the present study, we determined whether fucoidan can function as an adjuvant using vaccine antigens. Flow cytometric analysis revealed that fucoidan increases the expression of the activation markers major histocompatibility complex class II, cluster of differentiation (CD)25, and CD69 in spleen cells. In combination with Bordetella bronchiseptica antigen, fucoidan increased the viability and tumor necrosis factor-alpha production of spleen cells. Furthermore, fucoidan increased the in vivo production of antigen-specific antibodies in mice inoculated with Mycoplasma hyopneumoniae antigen. Overall, this study has provided valuable information about the use of fucoidan as a vaccine adjuvant. PMID- 25549219 TI - Pathogenicity of H5N8 virus in chickens from Korea in 2014. AB - In 2014, two genetically distinct H5N8 highly pathogenic avian influenza (HPAI) viruses were isolated from poultry and wild birds in Korea. The intravenous pathogenicity indices for the two representative viruses were both 3.0. Mortality of chickens intranasally inoculated with the two H5N8 viruses was 100% with a mean death times of 2.5 and 4.5 days. Mortality rates of the contact groups for the two H5N8 viruses were 33.3% and 66.6%. Our study showed that transmissibility of the novel H5N8 viruses was different from that of previously identified H5N1 HPAI viruses, possibly due to genetic changes. PMID- 25549220 TI - Comparative proteomic analysis of proteins expression changes in the mammary tissue of cows infected with Escherichia coli mastitis. AB - Cows infected with Escherichia (E.) coli usually experience severe clinical symptoms, including damage to mammary tissues, reduced milk yield, and altered milk composition. In order to investigate the host response to E. coli infection and discover novel markers for mastitis treatment, mammary tissue samples were collected from healthy cows and bovines with naturally occurring severe E. coli mastitis. Changes of mammary tissue proteins were examined using two-dimensional gel electrophoresis and label-free proteomic approaches. A total of 95 differentially expressed proteins were identified. Of these, 56 proteins were categorized according to molecular function, cellular component, and biological processes. The most frequent biological processes influenced by the proteins were response to stress, transport, and establishment of localization. Furthermore, a network analysis of the proteins with altered expression in mammary tissues demonstrated that these factors are predominantly involved with binding and structural molecule activities. Vimentin and a-enolase were central "functional hubs" in the network. Based on results from the present study, disease-induced alterations of protein expression in mammary glands and potential markers for the effective treatment of E. coli mastitis were identified. These data have also helped elucidate defense mechanisms that protect the mammary glands and promote the pathogenesis of E. coli mastitis. PMID- 25549221 TI - Classical natural ovine scrapie prions detected in practical volumes of blood by lamb and transgenic mouse bioassays. AB - Scrapie is diagnosed antemortem in sheep by detecting misfolded isoforms of prion protein (PrP(Sc)) in lymphoid follicles of the rectal mucosa and nictitating membranes. Assay sensitivity is limited if (a) the biopsy is collected early during disease development, (b) an insufficient number of follicles is collected, or (c) peripheral accumulation of PrP(Sc) is reduced or delayed. A blood test would be convenient for mass live animal scrapie testing. Currently approved techniques, however, have their own detection limits. Novel detection methods may soon offer a non-animal-based, rapid platform with detection sensitivities that rival the prion bioassay. In anticipation, we sought to determine if diseased animals could be routinely identified with a bioassay using B lymphocytes isolated from blood sample volumes commonly collected for diagnostic purposes in small ruminants. Scrapie transmission was detected in five of six recipient lambs intravenously transfused with B lymphocytes isolated from 5~10 mL of blood from a naturally scrapie-infected sheep. Additionally, scrapie transmission was observed in 18 ovinized transgenic Tg338 mice intracerebrally inoculated with B lymphocytes isolated from 5~10 mL of blood from two naturally scrapie-infected sheep. Based on our findings, we anticipate that these blood sample volumes should be of diagnostic value. PMID- 25549222 TI - Relationship between chicken cellular immunity and endotoxin levels in dust from chicken housing environments. AB - Hazardous biochemical agents in animal husbandry indoor environments are known to promote the occurrence of various illnesses among workers and animals. The relationship between endotoxin levels in dust collected from chicken farms and various immunological markers was investigated. Peripheral blood was obtained from 20 broiler chickens and 20 laying hens from four different chicken farms in Korea. Concentrations of total or respirable dust in the inside the chicken farm buildings were measured using a polyvinyl chloride membrane filter and mini volume sampler. Endotoxin levels in the dust were determined by the Limulus Amebocyte Lysate Kinetic method. Interferon-gamma production by peripheral blood mononuclear cells stimulated with concanavalin A was significantly lower in broilers or layers from the farms with higher endotoxin concentrations than the chickens from the farms with lower endotoxin levels. An opposite pattern was observed for plasma cortisol concentrations with higher cortisol levels found in chickens from the farms with higher endotoxin levels. When peripheral lymphocytes were examined, the percentage of CD3(-)Ia(+) B cells was lower in layers from farms with higher endotoxin levels than those from locations with lower endotoxin levels. Overall, these results suggest a probable negative association between dust endotoxin levels and cell-mediated immunity in chickens. PMID- 25549225 TI - Molecular Medicine commemorates the career and science of Anthony Cerami. PMID- 25549223 TI - Acquisition of anoikis resistance up-regulates syndecan-4 expression in endothelial cells. AB - Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix, behaving as a critical mechanism in preventing adherent independent cell growth and attachment to an inappropriate matrix, thus avoiding colonization of distant organs. Cell adhesion plays an important role in neoplastic transformation. Tumors produce several molecules that facilitate their proliferation, invasion and maintenance, especially proteoglycans. The syndecan 4, a heparan sulfate proteoglycan, can act as a co-receptor of growth factors and proteins of the extracellular matrix by increasing the affinity of adhesion molecules to their specific receptors. It participates together with integrins in cell adhesion at focal contacts connecting the extracellular matrix to the cytoskeleton. Changes in the expression of syndecan-4 have been observed in tumor cells, indicating its involvement in cancer. This study investigates the role of syndecan-4 in the process of anoikis and cell transformation. Endothelial cells were submitted to sequential cycles of forced anchorage impediment and distinct lineages were obtained. Anoikis-resistant endothelial cells display morphological alterations, high rate of proliferation, poor adhesion to fibronectin, laminin and collagen IV and deregulation of the cell cycle, becoming less serum dependent. Furthermore, anoikis-resistant cell lines display a high invasive potential and a low rate of apoptosis. This is accompanied by an increase in the levels of heparan sulfate and chondroitin sulfate as well as by changes in the expression of syndecan-4 and heparanase. These results indicate that syndecan-4 plays a important role in acquisition of anoikis resistance and that the conferral of anoikis resistance may suffice to transform endothelial cells. PMID- 25549226 TI - Discovery of a master regulator of injury and healing: tipping the outcome from damage toward repair. AB - Disease processes provoke a balancing act between tissue damage and repair. In the 1980s, the discovery that tumor necrosis factor (TNF)-alpha is a general mediator of disease-related injury led to the development of novel therapeutics to neutralize its activity. In contrast, identification of potential mediator(s) of tissue repair remained elusive. Studies performed over the last 15 years have documented that the type 1 cytokine erythropoietin (EPO), produced by cells within surrounding regions subjected to injury, acts as a master regulator, controlling both damage and repair. The transducer of these activities is the previously unrecognized innate repair receptor (IRR), which is comprised of the EPO receptor and beta common receptor subunits. Notably, although proinflammatory cytokines upregulate the IRR, EPO and proinflammatory cytokines inhibit each other's production, resulting in a relative underproduction of EPO. Although exogenous EPO attenuates disease activity in many preclinical models, its clinical utility is limited by serious hematopoietic and thrombotic adverse effects. To circumvent this problem, novel compounds engineered from the structure of EPO have been developed as selective ligands of the IRR. These compounds possess no hematopoietic activity, yet are fully tissue-protective and reparative. The lead molecule of this development effort (the 11-amino acid peptide ARA290) tips the balance toward healing in diverse preclinical models of disease and is currently under evaluation in advanced clinical trials as a disease-modifying agent in painful neuropathy and diabetes. PMID- 25549227 TI - Discovery of tumor necrosis factor (TNF) and identification of the potential of anti-TNF antibodies in Dr. Cerami's laboratory. PMID- 25549228 TI - A surprising journey in translational medicine. PMID- 25549230 TI - Ken Warren and the Rockefeller Foundation's great neglected diseases network, 1978-1988: the transformation of tropical and global medicine. PMID- 25549229 TI - Statins: definitive translational research. PMID- 25549231 TI - The medical biochemistry of poverty and neglect. PMID- 25549224 TI - Incidence of hepatitis C virus (HCV) in a multicenter cohort of HIV-positive patients in Spain 2004-2011: increasing rates of HCV diagnosis but not of HCV seroconversions. AB - OBJECTIVES: We aim to describe rates and risk factors of Hepatitis C Virus (HCV) diagnoses, follow-up HCV testing and HCV seroconversion from 2004-2011 in a cohort of HIV-positive persons in Spain. METHODS: CoRIS is a multicentre, open and prospective cohort recruiting adult HIV-positive patients naive to antiretroviral therapy. We analysed patients with at least one negative and one follow-up HCV serology. Incidence Rates (IR) were calculated and multivariate Poisson regression was used to estimate adjusted Rates Ratios (aIRR). RESULTS: Of 2112 subjects, 53 HCV diagnoses were observed, IR = 0.93/100 py (95%CI: 0.7-1.2). IR increased from 0.88 in 2004-05 to 1.36 in 2010-11 (aIRR = 1.55; 95%CI: 0.37 6.55). In men who have sex with men (MSM) from 0.76 to 1.10 (aIRR = 1.45; 95%CI: 0.31-6.82); in heterosexual (HTX) subjects from 1.19 to 1.28 (aIRR = 1.08; 95%CI: 0.11-10.24). HCV seroconversion rates decreased from 1.77 to 0.65 (aIRR = 0.37; 95%CI: 0.12-1.11); in MSM from 1.06 to 0.49 (aIRR = 0.46; 95%CI: 0.09-2.31); in HTX from 2.55 to 0.59 (aIRR = 0.23; 95%CI: 0.06-0.98). HCV infection risk was higher for injecting drug users (IDU) compared to HTX (aIRR = 9.63;95%CI: 2.9 32.2); among MSM, for subjects aged 40-50 compared to 30 or less (IRR = 3.21; 95%CI: 1.7-6.2); and among HTX, for female sex (aIRR = 2.35; 95%CI: 1.03-5.34) and <200 CD4-count (aIRR = 2.39; 95%CI: 0.83-6.89). CONCLUSION: We report increases in HCV diagnoses rates which seem secondary to intensification of HCV follow-up testing but not to rises in HCV infection rates. HCV IR is higher in IDU. In MSM, HCV IR increases with age. Among HTX, HCV IR is higher in women and in subjects with impaired immunological situation. PMID- 25549232 TI - Advances in sickle cell therapies in the hydroxyurea era. AB - In the hydroxyurea era, insights into mechanisms downstream of erythrocyte sickling have led to new therapeutic approaches for patients with sickle cell disease (SCD). Therapies have been developed that target vascular adhesion, inflammation and hemolysis, including innovative biologics directed against P selectin and invariant natural killer T cells. Advances in hematopoietic stem cell transplant and gene therapy may also provide more opportunities for cures in the near future. Several clinical studies are underway to determine the safety and efficacy of these new treatments. Novel approaches to treat SCD are desperately needed, since current therapies are limited and rates of morbidity and mortality remain high. PMID- 25549234 TI - TNF antagonists opened the way to personalized medicine in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease resulting from a largely unknown interaction between genetically determined and environmental factors. Progress in the understanding of this chronic inflammation in the synovial lining of joints has led to the insight that one cytokine, tumor necrosis factor (TNF), has an important role. This insight started the development of a series of targeted and highly effective therapeutics for RA and a range of other autoinflammatory diseases. RA has changed from a severely debilitating disease into a disease where progression can be stopped in most of the patients. PMID- 25549235 TI - Whole-mount imaging of mouse embryo sensory axon projections. AB - The visualization of full-length neuronal projections in embryos is essential to gain an understanding of how mammalian neuronal networks develop. Here we describe a method to label in situ a subset of dorsal root ganglion (DRG) axon projections to assess their phenotypic characteristics using several genetically manipulated mouse lines. The TrkA-positive neurons are nociceptor neurons, dedicated to the transmission of pain signals. We utilize a TrkA(taulacZ) mouse line to label the trajectories of all TrkA-positive peripheral axons in the intact mouse embryo. We further breed the TrkA(taulacZ) line onto a Bax null background, which essentially abolishes neuronal apoptosis, in order to assess growth-related questions independently of possible effects of genetic manipulations on neuronal survival. Subsequently, genetically modified mice of interest are bred with the TrkA(taulacZ)/Bax null line and are then ready for study using the techniques described herein. This presentation includes detailed information on mouse breeding plans, genotyping at the time of dissection, tissue preparation, staining and clearing to allow for visualization of full-length axonal trajectories in whole-mount preparation. PMID- 25549237 TI - Effective electric fields along realistic DTI-based neural trajectories for modelling the stimulation mechanisms of TMS. AB - In transcranial magnetic stimulation (TMS), an applied alternating magnetic field induces an electric field in the brain that can interact with the neural system. It is generally assumed that this induced electric field is the crucial effect exciting a certain region of the brain. More specifically, it is the component of this field parallel to the neuron's local orientation, the so-called effective electric field, that can initiate neuronal stimulation. Deeper insights on the stimulation mechanisms can be acquired through extensive TMS modelling. Most models study simple representations of neurons with assumed geometries, whereas we embed realistic neural trajectories computed using tractography based on diffusion tensor images. This way of modelling ensures a more accurate spatial distribution of the effective electric field that is in addition patient and case specific. The case study of this paper focuses on the single pulse stimulation of the left primary motor cortex with a standard figure-of-eight coil. Including realistic neural geometry in the model demonstrates the strong and localized variations of the effective electric field between the tracts themselves and along them due to the interplay of factors such as the tract's position and orientation in relation to the TMS coil, the neural trajectory and its course along the white and grey matter interface. Furthermore, the influence of changes in the coil orientation is studied. Investigating the impact of tissue anisotropy confirms that its contribution is not negligible. Moreover, assuming isotropic tissues lead to errors of the same size as rotating or tilting the coil with 10 degrees. In contrast, the model proves to be less sensitive towards the not well known tissue conductivity values. PMID- 25549236 TI - Flow cytometry protocols for surface and intracellular antigen analyses of neural cell types. AB - Flow cytometry has been extensively used to define cell populations in immunology, hematology and oncology. Here, we provide a detailed description of protocols for flow cytometric analysis of the cluster of differentiation (CD) surface antigens and intracellular antigens in neural cell types. Our step-by step description of the methodological procedures include: the harvesting of neural in vitro cultures, an optional carboxyfluorescein succinimidyl ester (CFSE)-labeling step, followed by surface antigen staining with conjugated CD antibodies (e.g., CD24, CD54), and subsequent intracellar antigen detection via primary/secondary antibodies or fluorescently labeled Fab fragments (Zenon labeling). The video demonstrates the most critical steps. Moreover, principles of experimental planning, the inclusion of critical controls, and fundamentals of flow cytometric analysis (identification of target population and exclusion of debris; gating strategy; compensation for spectral overlap) are briefly explained in order to enable neurobiologists with limited prior knowledge or specific training in flow cytometry to assess its utility and to better exploit this powerful methodology. PMID- 25549239 TI - Fecal microbiota transplantation via colonoscopy for recurrent C. difficile Infection. AB - Fecal Microbiota Transplantation (FMT) is a safe and highly effective treatment for recurrent and refractory C. difficile infection (CDI). Various methods of FMT administration have been reported in the literature including nasogastric tube, upper endoscopy, enema and colonoscopy. FMT via colonoscopy yields excellent cure rates and is also well tolerated. We have found that patients find this an acceptable and tolerable mode of delivery. At our Center, we have initiated a fecal transplant program for patients with recurrent or refractory CDI. We have developed a protocol using an iterative process of revision and have performed 24 fecal transplants on 22 patients with success rates comparable to the current published literature. A systematic approach to patient and donor screening, preparation of stool, and delivery of the stool maximizes therapeutic success. Here we detail each step of the FMT protocol that can be carried out at any endoscopy center with a high degree of safety and success. PMID- 25549233 TI - An expanding role for interleukin-1 blockade from gout to cancer. AB - There is an expanding role for interleukin (IL)-1 in diseases from gout to cancer. More than any other cytokine family, the IL-1 family is closely linked to innate inflammatory and immune responses. This linkage is because the cytoplasmic segment of all members of the IL-1 family of receptors contains a domain, which is highly homologous to the cytoplasmic domains of all toll-like receptors (TLRs). This domain, termed "toll IL-1 receptor (TIR) domain," signals as does the IL-1 receptors; therefore, inflammation due to the TLR and the IL-1 families is nearly the same. Fundamental responses such as the induction of cyclo oxygenase type 2, increased surface expression of cellular adhesion molecules and increased gene expression of a broad number of inflammatory molecules characterizes IL-1 signal transduction as it does for TLR agonists. IL-1beta is the most studied member of the IL-1 family because of its role in mediating autoinflammatory disease. However, a role for IL-1alpha in disease is being validated because of the availability of a neutralizing monoclonal antibody to human IL-1alpha. There are presently three approved therapies for blocking IL-1 activity. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist, which binds to the IL-1 receptor and prevents the binding of IL-1beta as well as IL-1alpha. Rilonacept is a soluble decoy receptor that neutralizes primarily IL-1beta but also IL-1alpha. Canakinumab is a human monoclonal antibody that neutralizes only IL-1beta. Thus, a causal or significant contributing role can be established for IL-1beta and IL-1alpha in human disease. PMID- 25549241 TI - Gastrointestinal perforation. PMID- 25549240 TI - Enhancement of glucose uptake in mouse skeletal muscle cells and adipocytes by P2Y6 receptor agonists. AB - Glucose uptake by peripheral tissues such as skeletal muscles and adipocytes is important in the maintenance of glucose homeostasis. We previously demonstrated that P2Y6 receptor (P2Y6R) agonists protect pancreatic islet cells from apoptosis and stimulate glucose-dependent insulin release. Here, we investigated the effects of P2Y6R activation on glucose uptake in insulin target tissues. An agonist of the P2Y6R, P1-(5'-uridine)-P3-(5'-N4-methoxycytidine)-triphosphate (MRS2957), significantly increased the uptake of [3H]2-deoxyglucose in mouse C2C12 myotubes and 3T3-L1 adipocytes, and this stimulation was significantly decreased by a selective P2Y6R antagonist N,N"-1,4-butanediyl-bis[N'-(3 isothiocyanatophenyl)thiourea] (MRS2578). Pre-incubation with Compound C (an inhibitor of 5'-AMP-activated protein kinase, AMPK), or AMPK siRNA abolished the stimulatory effect of MRS2957 on glucose uptake. Also, MRS2957 (60 min incubation) increased recruitment of the facilitated glucose transporter-4 (GLUT4) to the cell membrane, which was blocked by MRS2578. Treatment of C2C12 myotubes with MRS2957 induced significant phosphorylation of AMPK, which increase GLUT4 expression through histone deacetylase (HDAC)5 signaling. Glucose uptake in primary mouse adipocytes from wild-type mice was stimulated upon P2Y6R activation by either MRS2957 or native agonist UDP, and the P2Y6R effect was antagonized by MRS2578. However, in adipocytes from P2Y6R-knockout mice P2Y6R agonists had no effect on glucose uptake, and there was no change in the glucose uptake by insulin. Our results indicate that the P2Y6R promotes glucose metabolism in peripheral tissues, which may be mediated through AMPK signaling. PMID- 25549238 TI - Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial. AB - BACKGROUND: Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined. METHODS AND FINDINGS: The Qidong Hepatitis B Intervention Study, a population based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10-14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996-2000 and 2008-2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%-97%), 70% (95% CI 15%-89%), and 69% (95% CI 34%-85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%-30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%-75%). Receiving a booster at age 10-14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47-0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up. CONCLUSIONS: Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg positive mothers and who have completed the HBV neonatal vaccination series. Please see later in the article for the Editors' Summary. PMID- 25549242 TI - Sample preparation strategies for mass spectrometry imaging of 3D cell culture models. AB - Three dimensional cell cultures are attractive models for biological research. They combine the flexibility and cost-effectiveness of cell culture with some of the spatial and molecular complexity of tissue. For example, many cell lines form 3D structures given appropriate in vitro conditions. Colon cancer cell lines form 3D cell culture spheroids, in vitro mimics of avascular tumor nodules. While immunohistochemistry and other classical imaging methods are popular for monitoring the distribution of specific analytes, mass spectrometric imaging examines the distribution of classes of molecules in an unbiased fashion. While MALDI mass spectrometric imaging was originally developed to interrogate samples obtained from humans or animal models, this report describes the analysis of in vitro three dimensional cell cultures, including improvements in sample preparation strategies. Herein is described methods for growth, harvesting, sectioning, washing, and analysis of 3D cell cultures via matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) imaging. Using colon carcinoma 3D cell cultures as a model system, this protocol demonstrates the ability to monitor analytes in an unbiased fashion across the 3D cell culture system with MALDI-MSI. PMID- 25549243 TI - Floral-dip transformation of flax (Linum usitatissimum) to generate transgenic progenies with a high transformation rate. AB - Agrobacterium-mediated plant transformation via floral-dip is a widely used technique in the field of plant transformation and has been reported to be successful for many plant species. However, flax (Linum usitatissimum) transformation by floral-dip has not been reported. The goal of this protocol is to establish that Agrobacterium and the floral-dip method can be used to generate transgenic flax. We show that this technique is simple, inexpensive, efficient, and more importantly, gives a higher transformation rate than the current available methods of flax transformation. In summary, inflorescences of flax were dipped in a solution of Agrobacterium carrying a binary vector plasmid (T-DNA fragment plus the Linum Insertion Sequence, LIS-1) for 1 - 2 min. The plants were laid flat on their side for 24 hr. Then, plants were maintained under normal growth conditions until the next treatment. The process of dipping was repeated 2 - 3 times, with approximately 10 - 14 day intervals between dipping. The T1 seeds were collected and germinated on soil. After approximately two weeks, treated progenies were tested by direct PCR; 2 - 3 leaves were used per plant plus the appropriate T-DNA primers. Positive transformants were selected and grown to maturity. The transformation rate was unexpectedly high, with 50 - 60% of the seeds from treated plants being positive transformants. This is a higher transformation rate than those reported for Arabidopsis thaliana and other plant species, using floral-dip transformation. It is also the highest, which has been reported so far, for flax transformation using other methods for transformation. PMID- 25549245 TI - Electrical properties of polypropylene-based composites controlled by multilayered distribution of conductive particles. AB - Materials consisting of alternating layers of pure polypropylene (PP) and carbon black filled polypropylene (PPCB) were fabricated in this work. The electrical behaviors of the multilayered composites were investigated from two directions: (1) Parallel to interfaces. The confined layer space allowed for a more compact connection between CB particles, while the conductive pathways tended to be broken up with increasing number of layers leading to a distinct enhancement of the electrical resistivity due to the separation of insulated PP layers. (2) Vertical to interfaces. The alternating assemblies of insulated and conductive layers like a parallel-plate capacitor made the electrical conductivity become frequency dependent. Following the layer multiplication process, the dielectric permittivity was significantly enhanced due to the accumulation of electrical charges at interfaces. Thus, as a microwave was incident on the dielectric medium, the interfacial polarization made the main contribution to inherent dissipation of microwave energy, so that the absorbing peak became strengthened when the material had more layers. Furthermore, the layer interfaces in the multilayered system were also effective to inhibit the propagation of cracks in the stretching process, leading to a larger elongation at the break than that of the PP/CB conventional system, which provided a potential route to fabricate electrical materials with optimal mechanical properties. PMID- 25549244 TI - Loss of FADS2 function severely impairs the use of HeLa cells as an in vitro model for host response studies involving fatty acid effects. AB - SCOPE: Established epithelial cell lines equipped with pattern recognition receptors such as the Toll-like receptor (TLR)-2 are common tools for immune response studies on invading pathogens, e.g. the obligate intracellular species of Chlamydia. Moreover, such models are widely used to elucidate fatty acid mediated immune effects. In several transformed cell lines, however, unusual loss of metabolic functions was described. The cell lines A549 and HeLa are poorly characterized in this respect. Therefore, we comparatively assessed the metabolic capacity of A549 and HeLa prior to proposed application as in vitro model for fatty acid effects on chlamydial infection. METHODOLOGY/PRINCIPAL FINDINGS: We incubated both cell lines either with substrates (C18:2n-6 or C18:3n-3) or products (C18:3n-6, C18:4n-3) of fatty acid desaturase-2 (FADS2), and analysed the fatty acid profiles after 24 h and 72 h by gas chromatography. Based on these data, we suspected that the complete discontinuation of normal biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA) in HeLa was due to loss of FADS2 function. Consequently, prostaglandin E2 (PGE2) formation was less inducible by TLR2 stimulation in HeLa, likely as a result of not only insufficient supply of precursors but also weak cyclooxygenase-2 (COX-2) response. In accordance, Chlamydia infection rates were consistently lower in HeLa than in A549. Sequence analysis revealed no alteration within the FADS2 gene in HeLa. The FADS2 expression level, however, was significantly lower and, in contrast to A549, not regulated by C18:2n-6. A549 exhibited regular fatty acid metabolism and enzyme functionality. CONCLUSIONS/SIGNIFICANCE: Our data show that HeLa cells considerably differ from A549 at several stages of fatty acid metabolism. The poor metabolic potential of HeLa, mainly concerning FADS2 upstream of COX-2 function, calls into question whether these cells represent a good model to unveil fatty acid or downstream eicosanoid effects in the course of intracellular bacterial infection. PMID- 25549246 TI - Parallel near-field photolithography with metal-coated elastomeric masks. AB - Developing a cost-effective nanolithography strategy that enables the production of subwavelength features with various shapes over large areas is a long-standing goal in the nanotechnology community. Herein, an inexpensive nanolithographic technique that combines the wafer-scale production capability of photolithography with the subwavelength feature size controllability of near-field photolithography was developed to fabricate centimeter-scale up to wafer-scale sub-100-nm variously shaped nanopatterns on surfaces. The wafer-scale elastomeric trench-based photomasks with subwavelength apertures created at the apexes were compatible with mask aligners, allowing for the production of wafer-scale subwavelength nanopatterns with adjustable feature sizes, shapes, and periodicities. The smallest feature sizes of 50 and 80 nm were achieved on positive tone and negative tone photoresist surfaces, respectively, which could be ascribed to a near-field optical effect. The fabricated centimeter-scale nanopatterns were functionalized to study cell-matrix adhesion and migration. Compared to currently developed nanolithographic methods that approach similar functionalities, this facile nanolithographic strategy combines the merits of low cost, subwavelength feature size, high throughput, and varied feature shapes, making it an affordable approach to be used in academic research for researchers at most institutions. PMID- 25549247 TI - Nonresonant energy transfers independent on the phonon densities in polyatomic liquids. AB - Energy-gap-dependent vibrational-energy transfers among the nitrile stretches of KSCN/KS(13)CN/KS(13)C(15)N in D2O, DMF, and formamide liquid solutions at room temperature were measured by the vibrational-energy-exchange method. The energy transfers are slower with a larger energy donor/acceptor gap, independent of the calculated instantaneous normal mode ("phonons" in liquids) densities or the terahertz absorption spectra. The energy-gap dependences of the nonresonant energy transfers cannot be described by phonon compensation mechanisms with the assumption that phonons are the instantaneous normal modes of the liquids. Instead, the experimental energy-gap dependences can be quantitatively reproduced by the dephasing mechanism. A simple theoretical derivation shows that the fast molecular motions in liquids randomize the modulations on the energy donor and acceptor by phonons and diminish the phonon compensation efficiency on energy transfer. Estimations based on the theoretical derivations suggest that, for most nonresonant intermolecular vibrational-energy transfers in liquids with energy gaps smaller than the thermal energy, the dephasing mechanism dominates the energy-transfer process. PMID- 25549248 TI - Polar localization of a tripartite complex of the two-component system DcuS/DcuR and the transporter DctA in Escherichia coli depends on the sensor kinase DcuS. AB - The C4-dicarboxylate responsive sensor kinase DcuS of the DcuS/DcuR two-component system of E. coli is membrane-bound and reveals a polar localization. DcuS uses the C4-dicarboxylate transporter DctA as a co-regulator forming DctA/DcuS sensor units. Here it is shown by fluorescence microscopy with fusion proteins that DcuS has a dynamic and preferential polar localization, even at very low expression levels. Single assemblies of DcuS had high mobility in fast time lapse acquisitions, and fast recovery in FRAP experiments, excluding polar accumulation due to aggregation. DctA and DcuR fused to derivatives of the YFP protein are dispersed in the membrane or in the cytosol, respectively, when expressed without DcuS, but co-localize with DcuS when co-expressed at appropriate levels. Thus, DcuS is required for location of DctA and DcuR at the poles and formation of tripartite DctA/DcuS/DcuR sensor/regulator complexes. Vice versa, DctA, DcuR and the alternative succinate transporter DauA were not essential for polar localization of DcuS, suggesting that the polar trapping occurs by DcuS. Cardiolipin, the high curvature at the cell poles, and the cytoskeletal protein MreB were not required for polar localization. In contrast, polar localization of DcuS required the presence of the cytoplasmic PAS(C) and the kinase domains of DcuS. PMID- 25549249 TI - Identification of protein network alterations upon retinal ischemia-reperfusion injury by quantitative proteomics using a Rattus norvegicus model. AB - Retinal ischemia is a common feature associated with several ocular diseases, including diabetic retinopathy. In this study, we investigated the effect of a retinal ischemia and reperfusion (I/R) injury on protein levels via a quantitative shotgun strategy using stable isotope dimethyl labeling combined with LC-MS/MS analysis. Based on the relative quantitation data of 1088 proteins, 234 proteins showed a greater than 1.5-fold change following I/R injury, 194 of which were up-regulated and 40 were down-regulated. Gene ontology analysis revealed that after I/R injury, there was an increase in the metabolic-process related proteins but a decline in cell communication, system process and transport-related proteins. A ribosome protein network and a secreted protein network consisting of many protease inhibitors were identified among the up regulated proteins, despite a suppression of the mammalian target of rapamycin (mTOR) pathway following the I/R injury. A synaptic-related protein network was found to be significantly down-regulated, implicating a functional reduction of neurons following a retinal I/R injury. Our results provide new systems-biology clues for the study of retinal ischemia. PMID- 25549251 TI - Layer-by-layer dielectric breakdown of hexagonal boron nitride. AB - Hexagonal boron nitride (BN) is widely used as a substrate and gate insulator for two-dimensional (2D) electronic devices. The studies on insulating properties and electrical reliability of BN itself, however, are quite limited. Here, we report a systematic investigation of the dielectric breakdown characteristics of BN using conductive atomic force microscopy. The electric field strength was found to be ~ 12 MV/cm, which is comparable to that of conventional SiO2 oxides because of the covalent bonding nature of BN. After the hard dielectric breakdown, the BN fractured like a flower into equilateral triangle fragments. However, when the applied voltage was terminated precisely in the middle of the dielectric breakdown, the formation of a hole that did not penetrate to the bottom metal electrode was clearly observed. Subsequent I-V measurements of the hole indicated that the BN layer remaining in the hole was still electrically inactive. On the basis of these observations, layer-by-layer breakdown was confirmed for BN with regard to both physical fracture and electrical breakdown. Moreover, statistical analysis of the breakdown voltages using a Weibull plot suggested the anisotropic formation of defects. These results are unique to layered materials and unlike the behavior observed for conventional 3D amorphous oxides. PMID- 25549250 TI - Structure based annotation of Helicobacter pylori strain 26695 proteome. AB - The availability of complete genome sequences of H. pylori 26695 has provided a wealth of information enabling us to carry out in silico studies to identify new molecular targets for pharmaceutical treatment. In order to construe the structural and functional information of complete proteome, use of computational methods are more relevant since these methods are reliable and provide a solution to the time consuming and expensive experimental methods. Out of 1590 predicted protein coding genes in H. pylori, experimentally determined structures are available for only 145 proteins in the PDB. In the absence of experimental structures, computational studies on the three dimensional (3D) structural organization would help in deciphering the protein fold, structure and active site. Functional annotation of each protein was carried out based on structural fold and binding site based ligand association. Most of these proteins are uncharacterized in this proteome and through our annotation pipeline we were able to annotate most of them. We could assign structural folds to 464 uncharacterized proteins from an initial list of 557 sequences. Of the 1195 known structural folds present in the SCOP database, 411 (34% of all known folds) are observed in the whole H. pylori 26695 proteome, with greater inclination for domains belonging to alpha/beta class (36.63%). Top folds include P-loop containing nucleoside triphosphate hydrolases (22.6%), TIM barrel (16.7%), transmembrane helix hairpin (16.05%), alpha-alpha superhelix (11.1%) and S-adenosyl-L methionine-dependent methyltransferases (10.7%). PMID- 25549252 TI - Novel PDE4 inhibitors derived from Chinese medicine forsythia. AB - Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response. PMID- 25549253 TI - Arsenic efflux from Microcystis aeruginosa under different phosphate regimes. AB - Phytoplankton plays an important role in arsenic speciation, distribution, and cycling in freshwater environments. Little information, however, is available on arsenic efflux from the cyanobacteria Microcystis aeruginosa under different phosphate regimes. This study investigated M. aeruginosa arsenic efflux and speciation by pre-exposing it to 10 uM arsenate or arsenite for 24 h during limited (12 h) and extended (13 d) depuration periods under phosphate enriched (+P) and phosphate depleted (-P) treatments. Arsenate was the predominant species detected in algal cells throughout the depuration period while arsenite only accounted for no greater than 45% of intracellular arsenic. During the limited depuration period, arsenic efflux occurred rapidly and only arsenate was detected in solutions. During the extended depuration period, however, arsenate and dimethylarsinic acid (DMA) were found to be the two predominant arsenic species detected in solutions under -P treatments, but arsenate was the only species detected under +P treatments. Experimental results also suggest that phosphorus has a significant effect in accelerating arsenic efflux and promoting arsenite bio-oxidation in M. aeruginosa. Furthermore, phosphorus depletion can reduce arsenic efflux from algal cells as well as accelerate arsenic reduction and methylation. These findings can contribute to our understanding of arsenic biogeochemistry in aquatic environments and its potential environmental risks under different phosphorus levels. PMID- 25549254 TI - Relationship between the Peripheral Lymphocyte Response to Mycophenolic Acid in vitro and the Level of ATP in Peripheral CD4+ Lymphocytes before and after Renal Transplantation. AB - OBJECTIVE: The lymphocyte immunosuppressant sensitivity test has been used to predict the pharmacodynamics of immunosuppressive drugs for the purpose of preventing acute rejection and infection after renal transplantation. On the other hand, measuring the ATP levels in peripheral CD4+ lymphocytes is also able to monitor the risks of rejection and infection in transplant recipients. In the present study, we examined the relationship between the mycophenolic acid pharmacodynamics and the ATP levels in peripheral lymphocytes before and after renal transplantation. METHODS: We examined both the pharmacological efficacy of mycophenolic acid and the lymphocyte ATP levels before and 2, 4 and 6 weeks after the operation in 20 renal transplant recipients. The drug's pharmacological efficacy was evaluated by the 50% inhibitory concentration of the drug against the in vitro proliferation of peripheral blood lymphocytes activated by T cell mitogen. The ATP levels in peripheral CD4+ lymphocytes were measured by the Immuknow assay kit. The relationships between the mycophenolic acid pharmacodynamics and ATP levels in peripheral lymphocytes were examined in these recipients. RESULTS: The immunosuppressive effects of mycophenolic acid against mitogen-activated lymphocyte proliferation were significantly and positively correlated with the lymphocyte ATP levels, but only at 6 weeks after transplantation. The relationship was not significant before or at 2 or 4 weeks after the operation. CONCLUSION: Our present data raised the possibility that evaluating the pharmacological efficacy of mycophenolic acid pre-transplantation and monitoring the ATP level 6 weeks after transplantation can predict the risk of rejection and/or infection in renal transplant recipients. PMID- 25549255 TI - Lack of association between human plasma oxytocin and interpersonal trust in a Prisoner's Dilemma paradigm. AB - Expanding interest in oxytocin, particularly the role of endogenous oxytocin in human social behavior, has created a pressing need for replication of results and verification of assay methods. In this study, we sought to replicate and extend previous results correlating plasma oxytocin with trust and trustworthy behavior. As a necessary first step, the two most commonly used commercial assays were compared in human plasma via the addition of a known quantity of exogenous oxytocin, with and without sample extraction. Plasma sample extraction was found to be critical in obtaining repeatable concentrations of oxytocin. In the subsequent trust experiment, twelve samples in duplicate, from each of 82 participants, were collected over approximately six hours during the performance of a Prisoner's Dilemma task paradigm that stressed human interpersonal trust. We found no significant relationship between plasma oxytocin concentrations and trusting or trustworthy behavior. In light of these findings, previous published work that used oxytocin immunoassays without sample extraction should be reexamined and future research exploring links between endogenous human oxytocin and trust or social behavior should proceed with careful consideration of methods and appropriate biofluids for analysis. PMID- 25549256 TI - On the effects of scale for ecosystem services mapping. AB - Ecosystems provide life-sustaining services upon which human civilization depends, but their degradation largely continues unabated. Spatially explicit information on ecosystem services (ES) provision is required to better guide decision making, particularly for mountain systems, which are characterized by vertical gradients and isolation with high topographic complexity, making them particularly sensitive to global change. But while spatially explicit ES quantification and valuation allows the identification of areas of abundant or limited supply of and demand for ES, the accuracy and usefulness of the information varies considerably depending on the scale and methods used. Using four case studies from mountainous regions in Europe and the U.S., we quantify information gains and losses when mapping five ES - carbon sequestration, flood regulation, agricultural production, timber harvest, and scenic beauty - at coarse and fine resolution (250 m vs. 25 m in Europe and 300 m vs. 30 m in the U.S.). We analyze the effects of scale on ES estimates and their spatial pattern and show how these effects are related to different ES, terrain structure and model properties. ES estimates differ substantially between the fine and coarse resolution analyses in all case studies and across all services. This scale effect is not equally strong for all ES. We show that spatially explicit information about non-clustered, isolated ES tends to be lost at coarse resolution and against expectation, mainly in less rugged terrain, which calls for finer resolution assessments in such contexts. The effect of terrain ruggedness is also related to model properties such as dependency on land use land cover data. We close with recommendations for mapping ES to make the resulting maps more comparable, and suggest a four-step approach to address the issue of scale when mapping ES that can deliver information to support ES-based decision making with greater accuracy and reliability. PMID- 25549257 TI - Attribute-based proxy re-encryption with keyword search. AB - Keyword search on encrypted data allows one to issue the search token and conduct search operations on encrypted data while still preserving keyword privacy. In the present paper, we consider the keyword search problem further and introduce a novel notion called attribute-based proxy re-encryption with keyword search (ABRKS), which introduces a promising feature: In addition to supporting keyword search on encrypted data, it enables data owners to delegate the keyword search capability to some other data users complying with the specific access control policy. To be specific, ABRKS allows (i) the data owner to outsource his encrypted data to the cloud and then ask the cloud to conduct keyword search on outsourced encrypted data with the given search token, and (ii) the data owner to delegate other data users keyword search capability in the fine-grained access control manner through allowing the cloud to re-encrypted stored encrypted data with a re-encrypted data (embedding with some form of access control policy). We formalize the syntax and security definitions for ABRKS, and propose two concrete constructions for ABRKS: key-policy ABRKS and ciphertext-policy ABRKS. In the nutshell, our constructions can be treated as the integration of technologies in the fields of attribute-based cryptography and proxy re-encryption cryptography. PMID- 25549258 TI - Intrinsically radioactive [64Cu]CuInS/ZnS quantum dots for PET and optical imaging: improved radiochemical stability and controllable Cerenkov luminescence. AB - Functionalized quantum dots (QDs) have been widely explored for multimodality bioimaging and proven to be versatile agents. Attaching positron-emitting radioisotopes onto QDs not only endows their positron emission tomography (PET) functionality, but also results in self-illuminating QDs, with no need for an external light source, by Cerenkov resonance energy transfer (CRET). Traditional chelation methods have been used to incorporate the radionuclide, but these methods are compromised by the potential for loss of radionuclide due to cleavage of the linker between particle and chelator, decomplexation of the metal, and possible altered pharmacokinetics of nanomaterials. Herein, we described a straightforward synthesis of intrinsically radioactive [(64)Cu]CuInS/ZnS QDs by directly incorporating (64)Cu into CuInS/ZnS nanostructure with (64)CuCl2 as synthesis precursor. The [(64)Cu]CuInS/ZnS QDs demonstrated excellent radiochemical stability with less than 3% free (64)Cu detected even after exposure to serum containing EDTA (5 mM) for 24 h. PEGylation can be achieved in situ during synthesis, and the PEGylated radioactive QDs showed high tumor uptake (10.8% ID/g) in a U87MG mouse xenograft model. CRET efficiency was studied as a function of concentration and (64)Cu radioactivity concentration. These [(64)Cu]CuInS/ZnS QDs were successfully applied as an efficient PET/self illuminating luminescence in vivo imaging agents. PMID- 25549260 TI - Image derived input function for [18F]-FEPPA: application to quantify translocator protein (18 kDa) in the human brain. AB - In [18F]-FEPPA positron emission topography (PET) imaging, automatic blood sampling system (ABSS) is currently the gold standard to obtain the blood time activity curve (TAC) required to extract the input function (IF). Here, we compare the performance of two image-based methods of IF extraction to the ABSS gold standard method for the quantification of translocator protein (TSPO) in the human brain. The IFs were obtained from a direct delineation of the internal carotid signal (CS) and a new concept of independent component analysis (ICA). PET scans were obtained from 18 healthy volunteers. The estimated total distribution volume (V(T)) by CS-IF and ICA-IF were compared to the reference V(T) obtained by ABSS-IF in the frontal and temporal cortex, cerebellum, striatum and thalamus regions. The V(T) values estimated using ICA-IF were more reliable than CS-IF for all brain regions. Specifically, the slope regression in the frontal cortex with ICA-IF was r2 = 0.91 (p<0.05), and r2 = 0.71 (p<0.05) using CS-IF. PMID- 25549259 TI - Genome-wide identification and comprehensive analyses of the kinomes in four pathogenic microsporidia species. AB - Microsporidia have attracted considerable attention because they infect a wide range of hosts, from invertebrates to vertebrates, and cause serious human diseases and major economic losses in the livestock industry. There are no prospective drugs to counteract this pathogen. Eukaryotic protein kinases (ePKs) play a central role in regulating many essential cellular processes and are therefore potential drug targets. In this study, a comprehensive summary and comparative analysis of the protein kinases in four microsporidia-Enterocytozoon bieneusi, Encephalitozoon cuniculi, Nosema bombycis and Nosema ceranae-was performed. The results show that there are 34 ePKs and 4 atypical protein kinases (aPKs) in E. bieneusi, 29 ePKs and 6 aPKs in E. cuniculi, 41 ePKs and 5 aPKs in N. bombycis, and 27 ePKs and 4 aPKs in N. ceranae. These data support the previous conclusion that the microsporidian kinome is the smallest eukaryotic kinome. Microsporidian kinomes contain only serine-threonine kinases and do not contain receptor-like and tyrosine kinases. Many of the kinases related to nutrient and energy signaling and the stress response have been lost in microsporidian kinomes. However, cell cycle-, development- and growth-related kinases, which are important to parasites, are well conserved. This reduction of the microsporidian kinome is in good agreement with genome compaction, but kinome density is negatively correlated with proteome size. Furthermore, the protein kinases in each microsporidian genome are under strong purifying selection pressure. No remarkable differences in kinase family classification, domain features, gain and/or loss, and selective pressure were observed in these four species. Although microsporidia adapt to different host types, the coevolution of microsporidia and their hosts was not clearly reflected in the protein kinases. Overall, this study enriches and updates the microsporidian protein kinase database and may provide valuable information and candidate targets for the design of treatments for pathogenic diseases. PMID- 25549262 TI - Validation of the bipolar disorder etiology scale based on psychological behaviorism theory and factors related to the onset of bipolar disorder. AB - OBJECTIVES: The aim of this study was to identify psychosocial factors related to the onset of bipolar I disorder (BD). To do so, the Bipolar Disorder Etiology Scale (BDES), based on psychological behaviorism, was developed and validated. Using the BDES, common factors related to both major depressive disorder (MDD) and BD and specific factors related only to BD were investigated. METHOD: The BDES, which measures 17 factors based on psychological behaviorism hypotheses, was developed and validated. This scale was administered to 113 non-clinical control subjects, 30 subjects with MDD, and 32 people with BD. ANOVA and post hoc analyses were conducted. Subscales on which MDD and BD groups scored higher than controls were classified as common factors, while those on which the BD group scored higher than MDD and control groups were classified as specific factors. RESULTS: The BDES has acceptable reliability and validity. Twelve common factors influence both MDD and BD and one specific factor influences only BD. Common factors include the following: learning grandiose self-labeling, learning dangerous behavior, reinforcing impulsive behavior, exposure to irritability, punishment of negative emotional expression, lack of support, sleep problems, antidepressant problems, positive arousal to threat, lack of social skills, and pursuit of short-term pleasure. The specific factor is manic emotional response. CONCLUSIONS: Manic emotional response was identified as a specific factor related to the onset of BD, while parents' grandiose labeling is a candidate for a specific factor. Many factors are related to the onset of both MDD and BD. PMID- 25549261 TI - On the modularity of the intrinsic flexibility of the u opioid receptor: a computational study. AB - The u opioid receptor (uOR), the principal target to control pain, belongs to the G protein-coupled receptors (GPCRs) family, one of the most highlighted protein families due to their importance as therapeutic targets. The conformational flexibility of GPCRs is one of their essential characteristics as they take part in ligand recognition and subsequent activation or inactivation mechanisms. It is assessed that the intrinsic mechanical properties of the uOR, more specifically its particular flexibility behavior, would facilitate the accomplishment of specific biological functions, at least in their first steps, even in the absence of a ligand or any chemical species usually present in its biological environment. The study of the mechanical properties of the uOR would thus bring some indications regarding the highly efficient ability of the uOR to transduce cellular message. We therefore investigate the intrinsic flexibility of the uOR in its apo-form using all-atom Molecular Dynamics simulations at the sub microsecond time scale. We particularly consider the uOR embedded in a simplified membrane model without specific ions, particular lipids, such as cholesterol moieties, or any other chemical species that could affect the flexibility of the uOR. Our analyses highlighted an important local effect due to the various bendability of the helices resulting in a diversity of shape and volume sizes adopted by the uOR binding site. Such property explains why the uOR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the uOR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra- and intracellular parts of uOR on one hand, along with a clear rigidity of the central uOR domain on the other hand. Our results show how the modularity of the uOR flexibility is related to its pre-ability to activate and to present a basal activity. PMID- 25549263 TI - Plagioclase dissolution during CO2-SO2 cosequestration: effects of sulfate. AB - Geologic CO2 sequestration (GCS) is one of the most promising methods to mitigate the adverse impacts of global climate change. The performance of GCS can be affected by mineral dissolution and precipitation induced by injected CO2. Cosequestration with acidic gas such as SO2 can reduce the high cost of GCS, but it will increase the sulfate's concentration in GCS sites, where sulfate can potentially affect plagioclase dissolution/precipitation. This work investigated the effects of 0.05 M sulfate on plagioclase (anorthite) dissolution and subsequent mineral precipitation at 90 degrees C, 100 atm CO2, and 1 M NaCl, conditions relevant to GCS sites. The adsorption of sulfate on anorthite, a Ca rich plagioclase, was examined using attenuated total reflectance Fourier transform infrared spectroscopy and then simulated using density functional theory calculations. We found that the dissolution rate of anorthite was enhanced by a factor of 1.36 by the formation of inner-sphere monodentate complexes between sulfate and the aluminum sites on anorthite surfaces. However, this effect was almost completely suppressed in the presence of 0.01 M oxalate, an organic ligand that can exist in GCS sites. Interestingly, sulfate also inhibited the formation of secondary mineral precipitation through the formation of aluminum-sulfate complexes in the aqueous phase. This work, for the first time, reports the surface complexation between sulfate and plagioclase that can occur in GCS sites. The results provide new insights for obtaining scientific guidelines for the proper amount of SO2 coinjection and finally for evaluating the economic efficiency and environmental safety of GCS operations. PMID- 25549265 TI - The I-TASSER Suite: protein structure and function prediction. PMID- 25549264 TI - Selective modulation of interhemispheric functional connectivity by HD-tACS shapes perception. AB - Oscillatory neuronal synchronization between cortical areas has been suggested to constitute a flexible mechanism to coordinate information flow in the human cerebral cortex. However, it remains unclear whether synchronized neuronal activity merely represents an epiphenomenon or whether it is causally involved in the selective gating of information. Here, we combined bilateral high-density transcranial alternating current stimulation (HD-tACS) at 40 Hz with simultaneous electroencephalographic (EEG) recordings to study immediate electrophysiological effects during the selective entrainment of oscillatory gamma-band signatures. We found that interhemispheric functional connectivity was modulated in a predictable, phase-specific way: In-phase stimulation enhanced synchronization, anti-phase stimulation impaired functional coupling. Perceptual correlates of these connectivity changes were found in an ambiguous motion task, which strongly support the functional relevance of long-range neuronal coupling. Additionally, our results revealed a decrease in oscillatory alpha power in response to the entrainment of gamma band signatures. This finding provides causal evidence for the antagonistic role of alpha and gamma oscillations in the parieto-occipital cortex and confirms that the observed gamma band modulations were physiological in nature. Our results demonstrate that synchronized cortical network activity across several spatiotemporal scales is essential for conscious perception and cognition. PMID- 25549266 TI - Light-sheet fluorescence microscopy for quantitative biology. PMID- 25549267 TI - Light-sheet imaging for systems neuroscience. PMID- 25549268 TI - Guide to light-sheet microscopy for adventurous biologists. PMID- 25549269 TI - Biophysics: using sound to move cells. PMID- 25549270 TI - Toward high-throughput biomechanical phenotyping of single molecules. PMID- 25549272 TI - Dry transfer of chemical-vapor-deposition-grown graphene onto liquid-sensitive surfaces for tunnel junction applications. AB - We report a dry transfer method that can tranfer chemical vapor deposition (CVD) grown graphene onto liquid-sensitive surfaces. The graphene grown on copper (Cu) foil substrate was first transferred onto a freestanding 4 MUm thick sputtered Cu film using the conventional wet transfer process, followed by a dry transfer process onto the target surface using a polydimethylsiloxane stamp. The dry transferred graphene has similar properties to traditional wet-transferred graphene, characterized by scanning electron microscopy, atomic force microscopy, Raman spectroscopy, and electrical transport measurements. It has a sheet resistance of 1.6 ~ 3.4 kOmega/?, hole density of (4.1 ~ 5.3) * 10(12) cm(-2), and hole mobility of 460 ~ 760 cm(2) V(-1) s(-1) without doping at room temperature. The results suggest that large-scale CVD-grown graphene can be transferred with good quality and without contaminating the target surface by any liquid. Mg/MgO/graphene tunnel junctions were fabricated using this transfer method. The junctions show good tunneling characteristics, which demonstrates the transfer technique can also be used to fabricate graphene devices on liquid sensitive surfaces. PMID- 25549271 TI - Interleaved EPI based fMRI improved by multiplexed sensitivity encoding (MUSE) and simultaneous multi-band imaging. AB - Functional magnetic resonance imaging (fMRI) is a non-invasive and powerful imaging tool for detecting brain activities. The majority of fMRI studies are performed with single-shot echo-planar imaging (EPI) due to its high temporal resolution. Recent studies have demonstrated that, by increasing the spatial resolution of fMRI, previously unidentified neuronal networks can be measured. However, it is challenging to improve the spatial resolution of conventional single-shot EPI based fMRI. Although multi-shot interleaved EPI is superior to single-shot EPI in terms of the improved spatial-resolution, reduced geometric distortions, and sharper point spread function (PSF), interleaved EPI based fMRI has two main limitations: 1) the imaging throughput is lower in interleaved EPI; 2) the magnitude and phase signal variations among EPI segments (due to physiological noise, subject motion, and B0 drift) are translated to significant in-plane aliasing artifact across the field of view (FOV). Here we report a method that integrates multiple approaches to address the technical limitations of interleaved EPI-based fMRI. Firstly, the multiplexed sensitivity-encoding (MUSE) post-processing algorithm is used to suppress in-plane aliasing artifacts resulting from time-domain signal instabilities during dynamic scans. Secondly, a simultaneous multi-band interleaved EPI pulse sequence, with a controlled aliasing scheme incorporated, is implemented to increase the imaging throughput. Thirdly, the MUSE algorithm is then generalized to accommodate fMRI data obtained with our multi-band interleaved EPI pulse sequence, suppressing both in-plane and through-plane aliasing artifacts. The blood-oxygenation-level-dependent (BOLD) signal detectability and the scan throughput can be significantly improved for interleaved EPI-based fMRI. Our human fMRI data obtained from 3 Tesla systems demonstrate the effectiveness of the developed methods. It is expected that future fMRI studies requiring high spatial-resolvability and fidelity will largely benefit from the reported techniques. PMID- 25549274 TI - Unraveling the behavior of the individual ionic activity coefficients on the basis of the balance of ion-ion and ion-water interactions. AB - We investigate the individual activity coefficients of pure 1:1 and 2:1 electrolytes using our theory that is based on the competition of ion-ion (II) and ion-water (IW) interactions (Vincze et al. J. Chem. Phys. 2010, 133, 154507). The II term is computed from grand canonical Monte Carlo simulations on the basis of the implicit solvent model of electrolytes using hard sphere ions with Pauling radii. The IW term is computed on the basis of Born's treatment of solvation using experimental hydration free energies. The two terms are coupled through the concentration-dependent dielectric constant of the electrolyte. We show that the theory can provide valuable insight into the nonmonotonic concentration dependence of individual activity coefficients. We compare our theoretical predictions against experimental data measured by electrochemical cells containing ion-specific electrodes. We find good agreement for 2:1 electrolytes, while the accuracy is worse for 1:1 systems. This deviation in accuracy is explained by the fact that the two competing terms (II and IW) are much larger in the 2:1 case, resulting in smaller relative errors. The difference of the excess chemical potentials of cations and anions is determined by asymmetries in the properties of the two ions: charge, radius, and hydration free energies. PMID- 25549273 TI - A murine model of irreversible and reversible unilateral ureteric obstruction. AB - Obstruction of the kidney may affect native or transplanted kidneys and results in kidney injury and scarring. Presented here is a model of obstructive nephropathy induced by unilateral ureteric obstruction (UUO), which can either be irreversible (UUO) or reversible (R-UUO). In the irreversible UUO model, the ureter may be obstructed for variable periods of time in order to induce increasingly severe renal inflammation and interstitial fibrotic scarring. In the reversible R-UUO model the ureter is obstructed to induce hydronephrosis, tubular dilation and inflammation. After a suitable period of time the ureteric obstruction is then surgically reversed by anastomosis of the severed previously obstructed ureter to the bladder in order to allow complete decompression of the kidney and restoration of urinary flow to the bladder. The irreversible UUO model has been used to investigate various aspects of renal inflammation and scarring including the pathogenesis of disease and the testing of potential anti inflammatory or anti-fibrotic therapies. The more challenging model of R-UUO has been used by some investigators and does offer significant research potential as it allows the study of inflammatory and immune processes and tissue remodeling in an injured and scarred kidney following the removal of the injurious stimulus. As a result, the R-UUO model offers investigators the opportunity to explore the resolution of kidney inflammation together with key aspects of tissue repair. These experimental models are of relevance to human disease as patients often present with obstruction of the renal tract that requires decompression and are commonly left with significant residual kidney impairment that has no current treatment options and may lead to eventual end stage kidney failure. PMID- 25549276 TI - A critical size for emergence of nonbulk electronic and geometric structures in dodecanethiolate-protected Au clusters. AB - We report on how the transition from the bulk structure to the cluster-specific structure occurs in n-dodecanethiolate-protected gold clusters, Au(n)(SC12)m. To elucidate this transition, we isolated a series of Au(n)(SC12)m in the n range from 38 to ~520, containing five newly identified or newly isolated clusters, Au104(SC12)45, Au(~226)(SC12)(~76), Au(~253)(SC12)(~90), Au(~356)(SC12)(~112), and Au(~520)(SC12)(~130), using reverse-phase high-performance liquid chromatography. Low-temperature optical absorption spectroscopy, powder X-ray diffractometry, and density functional theory (DFT) calculations revealed that the Au cores of Au144(SC12)60 and smaller clusters have molecular-like electronic structures and non-fcc geometric structures, whereas the structures of the Au cores of larger clusters resemble those of the bulk gold. A new structure model is proposed for Au104(SC12)45 based on combined approach between experiments and DFT calculations. PMID- 25549275 TI - Straightforward assay for quantification of social avoidance in Drosophila melanogaster. AB - Drosophila melanogaster is an emerging model to study different aspects of social interactions. For example, flies avoid areas previously occupied by stressed conspecifics due to an odorant released during stress known as the Drosophila stress odorant (dSO). Through the use of the T-maze apparatus, one can quantify the avoidance of the dSO by responder flies in a very affordable and robust assay. Conditions necessary to obtain a strong performance are presented here. A stressful experience is necessary for the flies to emit dSO, as well as enough emitter flies to cause a robust avoidance response to the presence of dSO. Genetic background, but not their group size, strongly altered the avoidance of the dSO by the responder flies. Canton-S and Elwood display a higher performance in avoiding the dSO than Oregon and Samarkand strains. This behavioral assay will allow identification of mechanisms underlying this social behavior, and the assessment of the influence of genes and environmental conditions on both emission and avoidance of the dSO. Such an assay can be included in batteries of simple diagnostic tests used to identify social deficiencies of mutants or environmental conditions of interest. PMID- 25549277 TI - Particle stabilized aqueous foams at different length scales: synergy between silica particles and alkylamines. AB - Nanoparticles can be efficient foaming agents. Yet, the detailed mechanisms of foam stabilization by these particles remain unclear. In most cases, the foamability and foam stability of a system have to be determined empirically. We used a multiscale approach to reveal how the microscopic properties of the nanoparticle dispersion are translated into their foaming behavior at the macroscopic scale. As a model system we used silica nanoparticles that were hydrophobized by the in situ adsorption of short-chain alkylamines of chain length C5 to C8. We used fluorescence spectroscopy and electrophoretic mobility measurements to characterize the bulk behavior of the nanoparticles with adsorbed amines. The interfacial behavior was probed by compressing particle monolayers while monitoring the surface tension. The macroscopic foamability and foam stability were evaluated. There are strong correlations between the system properties at all length scales. The most prominent effects are observed at a critical bulk concentration of amines at which the nanoparticles start to aggregate due to hydrophobic interactions. Our study shows how the foam properties are related to the features of the bulk dispersions and to the ordering of particles at the air/water interface. The present results help to understand the surfactant concentration dependent stages of foaming behavior of in situ hydrophobized nanoparticles. PMID- 25549278 TI - Atomic force microscopy studies on molybdenum disulfide flakes as sodium-ion anodes. AB - A microscale battery comprised of mechanically exfoliated molybdenum disulfide (MoS2) flakes with copper connections and a sodium metal reference was created and investigated as an intercalation model using in situ atomic force microscopy in a dry room environment. While an ethylene carbonate-based electrolyte with a low vapor pressure allowed topographical observations in an open cell configuration, the planar microbattery was used to conduct in situ measurements to understand the structural changes and the concomitant solid electrolyte interphase (SEI) formation at the nanoscale. Topographical observations demonstrated permanent wrinkling behavior of MoS2 electrodes upon sodiation at 0.4 V. SEI formation occurred quickly on both flake edges and planes at voltages before sodium intercalation. Force spectroscopy measurements provided quantitative data on the SEI thickness for MoS2 electrodes in sodium-ion batteries for the first time. PMID- 25549280 TI - Small molecule inhibitors of bromodomain-acetyl-lysine interactions. AB - Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain-acetyl-lysine protein-protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design. PMID- 25549281 TI - Thermoelectric energy harvesting with quantum dots. AB - We review recent theoretical work on thermoelectric energy harvesting in multi terminal quantum-dot setups. We first discuss several examples of nanoscale heat engines based on Coulomb-coupled conductors. In particular, we focus on quantum dots in the Coulomb-blockade regime, chaotic cavities and resonant tunneling through quantum dots and wells. We then turn toward quantum-dot heat engines that are driven by bosonic degrees of freedom such as phonons, magnons and microwave photons. These systems provide interesting connections to spin caloritronics and circuit quantum electrodynamics. PMID- 25549282 TI - Expression and function of the ID1 gene during transforming growth factor-beta1 induced differentiation of human embryonic stem cells to endothelial cells. AB - ID1 can mediate transforming growth factor-beta (TGF-beta)/activin receptor-like kinase-1 (ALK1)-induced (and Smad-dependent) migration in endothelial cells (ECs). However, the role that ID1 plays during differentiation of human embryonic stem cells (hESCs) into ECs induced by TGF-beta1 remains unclear. In this study, a hESC differentiation model that recapitulates the developmental steps of vasculogenesis during the early stages of embryonic development was used to explore this question. We found that TGF-beta1 increases endothelial cell differentiation and inhibits endothelial tube formation. Furthermore, at an early stage of differentiation, TGF-beta1 may induce in vitro differentiation of hESCs into ECs by inhibiting expression of ID1, while at a later stage of differentiation, TGF-beta1 may stimulate the proliferation and migration of ECs via the ALK1/Smad1/5/ID1 pathway. Downregulation of ID1 by gene silencing can lead to acceleration of TGF-beta1-induced hESC differentiation into ECs and inhibition of proliferation and migration of ECs. This study may reveal some mechanisms of in vivo vasculogenesis in the early stages of embryonic development. PMID- 25549283 TI - Accuracy of blood glucose meters for self-monitoring affects glucose control and hypoglycemia rate in children and adolescents with type 1 diabetes. AB - AIMS/HYPOTHESIS: This study investigated the accuracy of blood glucose meters for self-monitoring and its influence on glycated hemoglobin (HbA1c) levels and the frequency of hypoglycemic coma. MATERIALS AND METHODS: Self-measured and simultaneously obtained laboratory blood glucose values from 9,163 patients with type 1 diabetes <18 years of age in the German/Austrian Diabetes Prospective Documentation Initiative registry were analyzed by investigating their compliance with the International Organization for Standardization (ISO) criteria (versions 2003 and 2013) and by error grid analyses. Regression models elucidated effects on glucose control and hypoglycemia rates. RESULTS: Depending on the respective subgroup (defined by sex, age, duration of diabetes, mode of insulin therapy), 78.7-94.7% of the self-monitoring of blood glucose (SMBG) values met the old and 79.7-88.6% met the new ISO criteria. In Clarke and Parkes error grid analyses, the percentages of SMBG values in Zone A ranged between 92.8% and 94.6% (Clarke) and between 92.2% and 95.0% (Parkes). The patient group with SMBG devices measuring "far too low" (compared with the laboratory-obtained glucose levels) presented with a higher HbA1c level than those measuring "far too high," "too high," "identical/almost identical," or "too low" (based on quintiles of deviation). Performing "far too high" was associated with the highest rate of hypoglycemic coma in comparison with the other deviation quintiles. CONCLUSIONS: This study showed that current SMBG devices fulfilled neither the previous nor the new ISO criteria. Large deviations of the SMBG values from the "true" glucose levels resulted in higher HbA1c levels and markedly increased rates of hypoglycemic events. PMID- 25549284 TI - Associations between lower limb strength and gait velocity following stroke: a systematic review. AB - OBJECTIVE: The aim of this systematic review was to identify literature examining associations between isometric strength and gait velocity following stroke. METHODS: An electronic search was performed using six online databases. Targeted searching of reference lists of included articles and three relevant journals was also performed. Two independent reviewers identified relevant articles, extracted data and assessed the methodological quality of included articles. Inclusion criteria involved studies that assessed univariate correlations between gait velocity and isometric strength of individual lower limb muscle groups in a stroke population. RESULTS: Twenty-one studies were included for review. The majority of included studies had a relatively small sample size. After accounting for sample size and methodological quality, the knee extensors showed poor-to moderate correlations with gait velocity while the ankle dorsiflexors showed the strongest association with gait velocity. CONCLUSIONS: Current evidence suggests that the strength of the ankle dorsiflexors has a stronger correlation to gait velocity compared with other lower limb muscle groups. Consequently, a focus on increasing ankle dorsiflexor strength to improve gait velocity following stroke may be beneficial. However, due to limitations of the research identified, further research is needed to determine the associations between lower limb strength and gait velocity following stroke. PMID- 25549285 TI - Assessment of Multiplate platelet aggregometry using citrate, heparin or hirudin in Rhesus macaques. AB - Electrical impedance aggregometry (EIA) has gained popularity in clinical and research applications. Nonhuman primates are used to study disease and drug related mechanisms that affect hemostasis, therefore establishing normal EIA parameters are necessary. The anticoagulants sodium heparin, hirudin and sodium citrate and three agonists, ADP, ASPI, and collagen were evaluated. Whole blood from 12 adult male rhesus macaques was collected to evaluate anticoagulants, sodium heparin, hirudin and sodium citrate using three agonists (ADP, ASPI and collagen), on the Multiplate(r) 5.0 Analyzer. Platelet function was reported for three parameters: Area under the curve (AUC), aggregation, and aggregation velocity. There was a significant difference in mean AUC between citrate and heparin samples, and citrate and hirudin samples regardless of the agonist used. There was no difference in AUC between heparin and hirudin. ADP-activated samples showed an increase in impedance with hirudin samples compared to citrate. Furthermore, heparin and hirudin out-perform citrate as the anticoagulant for EIA in the macaque. Finally, this study demonstrates the utility of the Multiplate(r) system in this model and provides important insight into anticoagulant choice when using EIA. PMID- 25549286 TI - Workflow for high-content, individual cell quantification of fluorescent markers from universal microscope data, supported by open source software. AB - Advances in understanding the control mechanisms governing the behavior of cells in adherent mammalian tissue culture models are becoming increasingly dependent on modes of single-cell analysis. Methods which deliver composite data reflecting the mean values of biomarkers from cell populations risk losing subpopulation dynamics that reflect the heterogeneity of the studied biological system. In keeping with this, traditional approaches are being replaced by, or supported with, more sophisticated forms of cellular assay developed to allow assessment by high-content microscopy. These assays potentially generate large numbers of images of fluorescent biomarkers, which enabled by accompanying proprietary software packages, allows for multi-parametric measurements per cell. However, the relatively high capital costs and overspecialization of many of these devices have prevented their accessibility to many investigators. Described here is a universally applicable workflow for the quantification of multiple fluorescent marker intensities from specific subcellular regions of individual cells suitable for use with images from most fluorescent microscopes. Key to this workflow is the implementation of the freely available Cell Profiler software(1) to distinguish individual cells in these images, segment them into defined subcellular regions and deliver fluorescence marker intensity values specific to these regions. The extraction of individual cell intensity values from image data is the central purpose of this workflow and will be illustrated with the analysis of control data from a siRNA screen for G1 checkpoint regulators in adherent human cells. However, the workflow presented here can be applied to analysis of data from other means of cell perturbation (e.g., compound screens) and other forms of fluorescence based cellular markers and thus should be useful for a wide range of laboratories. PMID- 25549287 TI - The platelet-lymphocyte ratio: A simple, inexpensive and rapid prognostic marker for cardiovascular events. AB - A full blood count is a routine, inexpensive and easy test that provides information about formed blood contents. The platelet-lymphocyte ratio (PLR) is a novel inflammatory marker, which may be used in many diseases for predicting inflammation and mortality. The PLR can be easily calculated and is widely available but it may be affected by several inflammatory conditions. Recent studies show that a high PLR reflects inflammation, atherosclerosis and platelet activation. More research is needed to determine how the PLR may be used in clinical practice. PMID- 25549288 TI - PASTA: Ultra-Large Multiple Sequence Alignment for Nucleotide and Amino-Acid Sequences. AB - We introduce PASTA, a new multiple sequence alignment algorithm. PASTA uses a new technique to produce an alignment given a guide tree that enables it to be both highly scalable and very accurate. We present a study on biological and simulated data with up to 200,000 sequences, showing that PASTA produces highly accurate alignments, improving on the accuracy and scalability of the leading alignment methods (including SATe). We also show that trees estimated on PASTA alignments are highly accurate--slightly better than SATe trees, but with substantial improvements relative to other methods. Finally, PASTA is faster than SATe, highly parallelizable, and requires relatively little memory. PMID- 25549289 TI - Ischemia-induced model of diastolic dysfunction in sheep. AB - BACKGROUND: Ischemic heart failure with normal ejection fraction (HFNEF) is an increasingly recognized entity that carries similar morbidity and mortality than low ejection fraction heart failure. Animal models of diastolic dysfunction mimicking this condition are lacking and are essential for the development of therapeutic strategies. METHODS AND RESULTS: Eight Corriedale sheep, 18 +/- 5 months old, were included in the study. Basal echocardiography and myocardial perfusion evaluation (SPECT) was performed. Acute myocardial infarction (AMI) was made by occlusion (90 min) and reperfusion of the second diagonal branch of the anterior descending coronary artery. Two months after AMI, echocardiography and SPECT evaluation were performed prior to sacrifice. Basal and 2 months echocardiography showed similar fractional shortening and ventricular dimensions in each animal except for an increase in left atrial diameter. No mitral regurgitation was evidenced. SPECT imaging and pathology confirmed infarction in the apical, apico-anterior, and apico-septal segments. CONCLUSION: A novel model of ischemia-induced diastolic dysfunction with preserved ventricular thickness and ejection fraction is described. This model opens the possibility of testing therapeutic options for patients with this condition. PMID- 25549290 TI - In Vivo Retinal Vein Bypass Surgery in a Porcine Model. AB - PURPOSE: To evaluate the feasibility of retinal vein bypass surgery for induced branch retinal-vein occlusion (BRVO) in the living porcine eye. METHODS: Fifteen minipigs were used in the study. Seven days before vascular surgery, hyaluronidase and plasmin were intravitreally injected for induction of posterior vitreous detachment. Aspirin and warfarin were oral administered daily starting 5 d prior to vascular surgery for anti-coagulation. The minipigs were anethetized with an intraperitoneal injection of 300 mg/kg chloral hydrate for intravitreal injection procedure and vascular surgery. Temporary keratoprosthesis vitrectomy was performed, and intraoperative video fluorescein angiography (VFA) was possible. The central and posterior vitreous was removed together with the posterior hyaloid membrane to facilitate vascular maneuvers. BRVO was induced by bipolar diathermy on the vein at the main vein's first branching. Polyimide tubes (50.8-MUm internal diameter and 7.6-MUm wall thickness) were used as artificial vessels. Vascular manipulation was performed in a bimanual manner. Both end of a prepared tubing was inserted into venous lumen by puncturing and catheterization, and the vein bypass bridging the occlusion was created. Then, the patency of the bypass graft was assessed by intraoperative VFA. RESULTS: The retinal vein bypass surgery was surgically accomplished in 33% (5/15) of the eyes, and the immediate graft patency was confirmed by intraoperative VFA only in one eye. We observed and recorded fluorescein flow from the branch vein to the main vein through the bypass graft which bridging the occlusive vein segment. CONCLUSIONS: We demonstrated the feasibility of retinal vein bypass for induced BRVO in the living porcine eye, and the immediate graft patency was successfully evaluated by intraoperative VFA. Despite the potential, there are still some significant hurdles in vivo retinal vein bypass surgery, and modification of both surgical instruments and maneuvers is needed for further study. PMID- 25549292 TI - Glutathione S-transferase M1 and T1 gene polymorphisms and risk of endometriosis in Tunisian population. AB - OBJECTIVE: An association between endometriosis and the glutathione S-transferase M1 (GSTM1)- and GSTT1-related genes has been proposed on account of the detoxification properties of the GST enzymes. The aim of the present study was to investigate whether the polymorphisms and null mutations are associated with the susceptibility to endometriosis. METHODS: The study included 105 women with endometriosis and 150 healthy women with no laparoscopic evidence of disease. Genotyping of the GSTM1 and GSTT1 gene polymorphisms was performed by Multiplex PCR. RESULTS: There was a significant association of GSTM1 null and GSTT1 null genotypes with endometriosis both when studied alone (P = 0.001 and P = 0.03, respectively) and in combination (P = 0.00002). CONCLUSION: The findings suggest that the GSTM1 and GSTT1 gene deficiency predisposes to endometriosis in a Tunisian population and can confer a significant increased risk when the GST null genotypes are combined. PMID- 25549293 TI - Satisfaction of users with assistive technology service delivery: An exploratory analysis of experiences of parents of children with physical and multiple disabilities. AB - OBJECTIVE: To describe experience of assistive technology service delivery (ATSD) by parents of children with physical or multiple disabilities (aged 3-18 years). METHOD: Forty-seven of 115 parents participated in a postal survey assessing satisfaction with the ATSD process, employing the QUEST 2.0 and the KWAZO scales. Six of these participated in two focus groups. Descriptive statistics were used for satisfaction scores. The focus group transcripts were coded and combined with survey results by two independent researchers. RESULTS: Low satisfaction scores were reported for follow-up, AT delivery, maintenance services, access to services, coordination, and efficiency of ATSD. Several barriers to and facilitators of ATSD were mentioned and solutions to improve ATSD quality were identified. CONCLUSION: Evaluation of parents' service experience is central for identifying shortcomings in ATSD. Health professionals are advised to utilize validated instruments and strategies to assess effectiveness of technological interventions and to assure ATSD quality. PMID- 25549295 TI - Quantitative Assessment of Optic Nerve With Diffusion Tensor Imaging in Patients With Thyroid Orbitopathy. AB - PURPOSE: To detect abnormalities of the optic nerve in patients with thyroid orbitopathy using diffusion tensor MRI. METHODS: Twenty-eight patients with Graves orbitopathy prospectively underwent diffusion tensor imaging scanning. A full ophthalmic examination including visual acuity, intraocular pressure, fundoscopy, and visual field analysis was performed. Clinical activity scores were also calculated. Fractional anisotropy (FA) and mean diffusivity values of the patients were compared with age and sex-matched healthy control subjects. RESULTS: The mean FA values were decreased and mean diffusivity values were increased significantly in patients with Graves orbitopathy compared with the control subjects (p < 0.001). There was a strong reverse correlation between the FA levels and the visual fields in 4 quadrants of the optic nerve. In addition, there was a strong correlation between the degree of proptosis and the FA values in both eyes. The mean diffusivity levels were also correlated with changes in the visual field and the degree of proptosis. CONCLUSION: FA and mean diffusivity levels measured with the diffusion tensor imaging of the thyroid orbitopathy patients were affected. The changes in diffusion tensor imaging were also correlated with the ophthalmologic tests of the patients. PMID- 25549296 TI - Linking personal health data to genomic research. PMID- 25549291 TI - Origins of the endogenous and infectious laboratory mouse gammaretroviruses. AB - The mouse gammaretroviruses associated with leukemogenesis are found in the classical inbred mouse strains and in house mouse subspecies as infectious exogenous viruses (XRVs) and as endogenous retroviruses (ERVs) inserted into their host genomes. There are three major mouse leukemia virus (MuLV) subgroups in laboratory mice: ecotropic, xenotropic, and polytropic. These MuLV subgroups differ in host range, pathogenicity, receptor usage and subspecies of origin. The MuLV ERVs are recent acquisitions in the mouse genome as demonstrated by the presence of many full-length nondefective MuLV ERVs that produce XRVs, the segregation of these MuLV subgroups into different house mouse subspecies, and by the positional polymorphism of these loci among inbred strains and individual wild mice. While some ecotropic and xenotropic ERVs can produce XRVs directly, others, especially the pathogenic polytropic ERVs, do so only after recombinations that can involve all three ERV subgroups. Here, I describe individual MuLV ERVs found in the laboratory mice, their origins and geographic distribution in wild mouse subspecies, their varying ability to produce infectious virus and the biological consequences of this expression. PMID- 25549297 TI - Cell death machinery makes life more robust. AB - CED-3, a protein that is essential for programmed cell death, also has an unexpected role in the regulation of non-apoptotic genes during normal development. PMID- 25549298 TI - Treating type-1 diabetes with an epigenetic drug. AB - A single drug treats type-1 diabetes in mice by dampening inflammation and enhancing insulin production. PMID- 25549300 TI - Novel 3D/VR interactive environment for MD simulations, visualization and analysis. AB - The increasing development of computing (hardware and software) in the last decades has impacted scientific research in many fields including materials science, biology, chemistry and physics among many others. A new computational system for the accurate and fast simulation and 3D/VR visualization of nanostructures is presented here, using the open-source molecular dynamics (MD) computer program LAMMPS. This alternative computational method uses modern graphics processors, NVIDIA CUDA technology and specialized scientific codes to overcome processing speed barriers common to traditional computing methods. In conjunction with a virtual reality system used to model materials, this enhancement allows the addition of accelerated MD simulation capability. The motivation is to provide a novel research environment which simultaneously allows visualization, simulation, modeling and analysis. The research goal is to investigate the structure and properties of inorganic nanostructures (e.g., silica glass nanosprings) under different conditions using this innovative computational system. The work presented outlines a description of the 3D/VR Visualization System and basic components, an overview of important considerations such as the physical environment, details on the setup and use of the novel system, a general procedure for the accelerated MD enhancement, technical information, and relevant remarks. The impact of this work is the creation of a unique computational system combining nanoscale materials simulation, visualization and interactivity in a virtual environment, which is both a research and teaching instrument at UC Merced. PMID- 25549299 TI - Specificity in endoplasmic reticulum-stress signaling in yeast entails a step wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1. AB - Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling. PMID- 25549302 TI - Context for practice: selecting a support surface for pressure ulcer prevention and treatment, friction lesions, WOC nursing practice, and colostomy irrigation. PMID- 25549301 TI - Short-term exposure of zebrafish embryos to arecoline leads to retarded growth, motor impairment, and somite muscle fiber changes. AB - The areca nut-chewing habit is common in Southeast Asia, India, and Taiwan, and arecoline is the most abundant and potent component in the areca nut. The effects of arecoline on birth defects have been explored in many species, including chicken, mice, and zebrafish. The effects of arecoline on embryos after long-term exposure are well established; however, the effects of short-term embryo exposure to arecoline are not understood. Using zebrafish, we study the effects of short term exposure of arecoline on embryos to model the human habit of areca nut chewing during early pregnancy. Arecoline, at concentrations from 0.001% to 0.04%, was administered to zebrafish embryos from 4 to 24 hours post fertilization. The morphological changes, survival rates, body length, and skeletal muscle fiber structure were then investigated by immunohistochemistry, confocal microscopy, and conventional electron microscopy. With exposure of embryos to increasing arecoline concentrations, we observed a significant decline in the hatching and survival rates, general growth retardation, lower locomotor activity, and swimming ability impairment. Immunofluorescent staining demonstrated a loose arrangement of myosin heavy chains, and ultrastructural observations revealed altered myofibril arrangement and swelling of the mitochondria. In addition, the results of flow-cytometry and JC-1 staining to assay mitochondria activity, as well as reverse transcription-polymerase chain reaction analyses of functional gene expression, revealed mitochondrial dysfunctions after exposure to arecoline. We confirmed that short-term arecoline exposure resulted in retarded embryonic development and decreased locomotor activity due to defective somitic skeletal muscle development and mitochondrial dysfunction. PMID- 25549303 TI - Hyperbaric oxygen for the management of challenging wounds. PMID- 25549304 TI - Canadian Association for Enterostomal Therapy Governance: transitioning to the new Canada Not-for-Profit Corporations Act. PMID- 25549305 TI - Methods, levels of evidence, strength of recommendations for treatment statements for evidence-based report cards: a new beginning. AB - In 2001, the Journal began publishing a special feature the Evidence-Based Report Card. These articles were designed to systematically identify and review evidence pertaining to wound, ostomy and continence specialty practice and summarize recommendations for clinical practice. Based on feedback from WOCN members and Society leadership, the Journal will relaunch this popular and valuable special feature. This article describes methods used to generate Evidence-Based Report Cards, a taxonomy of levels of evidence, and criteria for ranking the strength of recommendations for treatment. PMID- 25549307 TI - Psychological distress and its impact on wound healing: an integrative review. AB - Wound healing is typically divided into 4 stages; disruption of any one of these stages can impair this process. This integrative review summarizes findings from key studies suggesting that psychological distress may exert a clinically relevant impact on wound healing. For example, stress has been shown to decrease levels of inflammatory mediators, prolonging the inflammatory stage of healing, and increasing overall healing time. Depression has also been linked with impeding wound healing. Hostility has also been correlated with decreased inflammatory mediators, conversely, effective communication has shown faster healing time. Compounding factors such as unhealthy behaviors are also linked to poor wound healing, such as decreased sleep, poor nutrition, reduced exercise, and increased alcohol use. Clinical evidence suggests that alcohol exposure can reduce angiogenesis. Limited sleep decreases growth hormone secretion, resulting in decreased monocyte migration and activation of macrophages. protein deficiency can decrease capillary formation, collagen synthesis, and wound remodeling. Such evidence challenges clinicians to consider psychological factors when treating wound care patients. PMID- 25549306 TI - Identifying the right surface for the right patient at the right time: generation and content validation of an algorithm for support surface selection. AB - Support surfaces are an integral component of pressure ulcer prevention and treatment, but there is insufficient evidence to guide clinical decision making in this area. In an effort to provide clinical guidance for selecting support surfaces based on individual patient needs, the Wound, Ostomy and Continence Nurses Society (WOCN(r)) set out to develop an evidence- and consensus-based algorithm. A Task Force of clinical experts was identified who: 1) reviewed the literature and identified evidence for support surface use in the prevention and treatment of pressure ulcers; 2) developed supporting statements for essential components for the algorithm, 3) developed a draft algorithm for support surface selection; and 4) determined its face validity. A consensus panel of 20 key opinion leaders was then convened that: 1.) reviewed the draft algorithm and supporting statements, 2.) reached consensus on statements lacking robust supporting evidence, 3.) modified the draft algorithm and evaluated its content validity. The Content Validity Index (CVI) for the algorithm was strong (0.95 out of 1.0) with an overall mean score of 3.72 (out of 1 to 4), suggesting that the steps were appropriate to the purpose of the algorithm. To our knowledge, this is the first evidence and consensus based algorithm for support surface selection that has undergone content validation. PMID- 25549308 TI - Comparison of outcomes in patients with venous leg ulcers treated with compression therapy alone versus combination of surgery and compression therapy: a systematic review. AB - BACKGROUND: Venous leg ulcers (VLUs) are the most prevalent type of lower extremity ulcers and can be difficult to manage. Clinicians are challenged to provide care and recommendations that promote timely healing, minimize the risk of recurrence, and are cost-effective. Compression therapy is generally considered the primary intervention for both ulcer management and prevention of recurrence. However, recent studies suggest that surgical correction of venous insufficiency may enhance healing of venous ulcers or help prevent recurrence. PURPOSE: The objective of this systematic review was to compare wound healing and recurrence rates in patients managed with compression therapy alone versus compression therapy plus surgery. SEARCH STRATEGY: The author conducted a literature review selecting primary studies published between 2002 and 2012, using the electronic databases MEDLINE/PubMed and CINAHL/EBSCOhost. The following key words were applied: leg ulcer; varicose ulcer; bandage; "stockings, compression," venous ulceration; venous ulcer; compressive therapy; compression therapy; stocking; venous surgery. Inclusion criteria included randomized controlled trials that compared VLU healing rates and recurrence rates among patients receiving compression therapy alone, and patients receiving both compression therapy and surgical intervention to correct venous incompetence. Studies published in English, Spanish, or Portuguese were included. RESULTS: Sixty-seven studies were retrieved and 4 were identified that met inclusion criteria. In 3 of the studies, researchers reported no differences in healing rates for patients managed with compression plus surgery when compared to patients managed with compression alone. One study reported higher healing rates in the surgical group. Most studies revealed lower recurrence rates in patients who were managed with surgery plus compression, but these differences were not statistically significant. CONCLUSIONS: Existing evidence supports compression therapy as the most critical element in the management of venous leg ulcers. However, evidence also suggests that surgical obliteration of incompetent perforator veins may promote longer ulcerfree periods and lower rates of recurrence. PMID- 25549309 TI - Pathology and clinical presentation of friction injuries: case series and literature review. AB - BACKGROUND: Effective wound management is dependent, in part, on identification and correction of causative factors. Trunk wounds can be caused by pressure, shear, moisture, friction, or some combination of these factors. Wounds caused by moisture and/or friction are frequently mislabeled as pressure ulcers. CASE SERIES: This article presents a series of 45 patients who developed skin injuries on the medial buttocks and/or posterior thighs that the author believes were caused primarily by friction damage to the skin. The lesions were not located over palpable bony prominences and are therefore unlikely to be pressure ulcers. They were not located in skin folds and are unlikely to represent intertriginous dermatitis. Clinical data related to these 45 patients are presented, as are the location and characteristics of the lesions. These characteristics are discussed in relation to current literature regarding the pathology and clinical presentation of wounds caused by pressure, moisture, and friction. CONCLUSION: It is critical for wound clinicians and staff nurses to accurately identify the etiology of any wound. Wounds located on fleshy prominences exposed to repetitive friction should be labeled as friction injuries. PMID- 25549310 TI - Friction-induced skin injuries-are they pressure ulcers? An updated NPUAP white paper. AB - Friction injuries are often misdiagnosed as pressure ulcers. The reason for the misdiagnosis may be a misinterpretation of classic pressure ulcer literature that reported friction increased the susceptibility of the skin to pressure damage. This analysis assesses the classic literature that led to the inclusion of friction as a causative factor in the development of pressure ulcers in light of more recent research on the effects of shear. The analysis in this article suggests that friction can contribute to pressure ulcers by creating shear strain in deeper tissues, but friction does not appear to contribute to pressure ulcers in the superficial layers of the skin. Injuries to the superficial layers of the skin caused by friction are not pressure ulcers and should not be classified or treated as such. PMID- 25549311 TI - Quality of life in US residents with ostomies as assessed using the SF36v2. AB - PURPOSE: The purpose of this study was to assess the quality of life of the adult US ostomy population (18 years of age or older). DESIGN: Cross-sectional descriptive study. SUBJECTS AND SETTING: Potential participants were randomly selected from an electronic database of 15,591 persons with ostomies. Potential respondents were contacted by e-mail and provided with an electronic nontransferable secured link to the survey. Two thousand three hundred twenty nine participants completed the survey for a response rate of 14.9% and a margin of error of 2.03%. Study respondents were geographically distributed throughout the United States, representing all 50 states. Males comprised 53% of the study respondents; the median age of participants was 65 years, with 67% of the study respondents between the ages of 50 and 74 years. Forty percent had a colostomy, 44% had an ileostomy, 13% had a urostomy, 1% had multiple stomas, and 1% were unsure of their stoma type. INSTRUMENT: Health-related quality of life was evaluated using the SF36v2 survey instrument. This instrument was selected because of its ability to measure health-related quality of life in a sample of community-dwelling people with stomas and reference the data against a general population. RESULTS: The data presented a broad profile of the adult ostomy population in the United States. The average physical component summary score for the ostomy sample fell below the average for the US general population, while the average mental component summary (MCS) score fell within the average range of the US population. Analysis revealed that physical component summary scores decrease as age categories increase; however, MCS scores increased proportionally with age, suggesting that the health burden is primarily associated with physical health status, and not mental health status. CONCLUSION: Study findings suggest that the ostomy population demonstrates successful aging similar to the US general population. This is most noticeable at age categories greater than 55 years where increasing MCS scores for males and females fell in the range equivalent to the average of the US general population. PMID- 25549312 TI - A novel use for botulinum toxin A in the management of ileostomy and urostomy leaks. AB - PURPOSE: To assess the efficacy of Botulinum toxin A (BoNT-A) in the treatment of patients with hypercontractile stomas resulting in repeated pouching system failures and leaks. DESIGN: Prospective case series. SUBJECTS AND SETTING: Ten consecutive patients who presented to the outpatient stoma clinic with actively contractile stomas that shortened spasmodically resulting in leaks were offered treatment with BoNT-A if treatment with other measures had been unsuccessful. METHODS: Following an observed reduction in the peristalsic shortening of a stoma after intradermal injection of BoNT-A for hyperhidrosis, we conducted a prospective case series of 10 patients with pouch adhesive failures attributed to spasmodic shortening of the stoma. Ten patients, 3 with urostomies and 7 with ileostomies, were offered BoNT-A injection. The first was treated cautiously with 15 units of BoNT-A injected into the muscularis layer, followed by an additional 25 units injected 1 month later. Subsequent patients received doses varying from 50 to 100 units. Ongoing treatments ranged 50 to 100 units every 3 to 6 months. RESULTS: Seventy percent (n = 7) of patients reported a useful reduction in leakage and pouching system seal failures. In these 7 patients, the frequency of pouch changes changed from an average of 2.18 to 0.44 per day (over all 10 patients this was a change from an average of 2.35 per day to 1.16 per day). No adverse side effects were reported. CONCLUSION: Findings from this clinical case series suggest that BoNT-A may be a promising treatment in the management of patients with leaks caused by actively contracting stomas. PMID- 25549313 TI - Prevalence of fecal and double fecal and urinary incontinence in hospitalized patients. AB - PURPOSE: The purpose of this study was to assess the period prevalence of fecal and double incontinence in patients with and without indwelling urinary catheters in Austrian hospitals and to identify factors associated with incontinence in this group. SUBJECTS AND SETTINGS: Austrian hospital patients from 227 Austrian hospitals with more than 50 beds were invited to participate in the study from 2009 to 2012 by means of leaflets and information sessions. The study sample comprised 9861 patients who agreed to participate in the study. METHODS: An internal coordinator was responsible for the measurement within each participating hospital. Researchers trained these coordinators and they, in turn, trained the teams of ward nurses to correctly conduct the survey and collect data on 1 day in April. The instrument used in this study was the Dutch National Prevalence Measurement of Care Problems (Landelijke Prevalentiemeting Zorgproblemen), which includes not only demographic data, questions regarding incontinence occurrence, duration, and nursing interventions, but also questions about nutritional status, level of care dependency, and pressure ulcers. RESULTS: The period prevalence of fecal incontinence was 6.5%, while the period prevalence of double incontinence among patients with an indwelling urinary catheter was 5.2% and 2.8% in patients without a urinary catheter, respectively. A variety of factors, including age, primary diagnosis, pressure ulcers excluding grade (stage) 1, low body mass index, malnutrition, and level of care dependency, were associated with fecal incontinence (P < .000). CONCLUSION: Study findings indicate that the prevalence of fecal and double continence is higher in patients with an indwelling urinary catheter as compared with patients with no urinary catheter. A longitudinal study might yield a more accurate picture regarding fecal/double incontinence. PMID- 25549314 TI - Transcutaneous tibial nerve stimulation in the treatment of lower urinary tract symptoms and its impact on health-related quality of life in patients with Parkinson disease: a randomized controlled trial. AB - PURPOSE: A randomized controlled trial study was performed to evaluate the efficacy of transcutaneous tibial nerve stimulation (TTNS) and sham TTNS, in patients with Parkinson disease (PD) with lower urinary tract symptoms (LUTS). DESIGN: Randomized controlled trial. SUBJECTS AND SETTINGS: Thirteen patients with a diagnosis of PD and bothersome LUTS were randomly allocated to one of the following groups: Group I: TTNS group (n = 8) and group II: Sham group (n = 5). Both groups attended twice a week during 5 weeks; each session lasted 30 minutes. METHODS: Eight patients received TTNS treatment and 5 subjects allocated to group II were managed with sham surface electrodes that delivered no electrical stimulation. Assessments were performed before and after the treatment; they included a 3-day bladder diary, Overactive Bladder Questionnaire (OAB-V8), and the International Consultation on Incontinence Quality of Life Questionnaire Short Form (ICIQ-SF), and urodynamic evaluation. RESULTS: Following 5 weeks of treatment, patients allocated to TTNS demonstrated statistically significant reductions in the number of urgency episodes (P = .004) and reductions in nocturia episodes (P < .01). Participants allocated to active treatment also showed better results after treatment in the OAB-V8 and ICIQ-SF scores (P < .01, respectively). Urodynamic testing revealed that patients in the active treatment group showed improvements in intravesical volume at strong desire to void (P < .05) and volume at urgency (P < .01) when compared to subjects in the sham treatment group. CONCLUSION: These findings suggest that TTNS is effective in the treatment of LUTS in patients with PD, reducing urgency and nocturia episodes and improving urodynamic parameters as well as symptom scores measured by the OAB-V8 and health-related quality-of-life scores measured by the ICIQ-SF. PMID- 25549315 TI - Understanding neuropathic wounds. PMID- 25549316 TI - Surgical management of extensive peristomal pyoderma gangrenosum associated with colon cancer. AB - BACKGROUND: Extensive peristomal skin ulcer due to pyoderma gangrenosum is difficult to manage and causes significant morbidity. CASE: A 69-year-old man presented with a 10*7-cm painful peristomal skin necrosis during cancer chemotherapy for metastatic colon adenocarcinoma. The diagnosis of peristomal pyoderma gangrenosum was made on the basis of the presence of the skin necrosis with a well-defined, undermined, violaceous border. One month after the presentation along with daily cleansing and minimal debridement without immunosuppressive treatments, wound bed preparation was deemed sufficient for a split-thickness skin graft using negative pressure wound therapy for graft fixation. One month after the operation, the ulcer was completely healed and the patient could manage ostomy pouching independently. He died of cancer 5 months later; no recurrence of the ulcer was observed during this period. CONCLUSION: Peristomal pyoderma gangrenosum was successfully treated with skin grafting after local wound management. Negative pressure wound therapy was useful for skin graft fixation in the peristomal region. PMID- 25549318 TI - Comparison of outcomes in patients with venous leg ulcers treated with compression therapy alone versus combination of surgery and compression therapy: a systematic review. PMID- 25549320 TI - Spectroscopic investigation of the interaction of water-soluble azocalix[4]arenes with bovine serum albumin. AB - In this work, three hydrosoluble azocalix[4]arene derivatives, 5-(o methylphenylazo)-25,26,27-tris(carboxymethoxy)-28-hydroxycalix[4]arene (o-MAC Calix), 5-(m-methylphenylazo)-25,26,27-tris(carboxymethoxy)-28 hydroxycalix[4]arene (m-MAC-Calix) and 5-(p-methylphenylazo)-25,26,27 tris(carboxymethoxy)-28-hydroxycalix[4]arene (p-MAC-Calix) were synthesized. Their structures were characterized by infrared spectrum (IR), nuclear magnetic resonance spectrum (1H NMR and 13C NMR) and mass spectrum (MS). The interactions between these compounds and bovine serum albumin (BSA) were studied by fluorescence spectroscopy, UV-vis spectrophotometry and circular dichroic spectroscopy. According to experimental results, three azocalix[4]arene derivatives can efficiently bind to BSA molecules and the o-MAC-Calix displays more efficient interactions with BSA molecules than m-MAC-Calix and p-MAC-Calix. Molecular docking showed that the o-MAC-Calix was embedded in the hydrophobic cavity of helical structure of BSA molecular and the tryptophan (Trp) residue of BSA molecular had strong interaction with o-MAC-Calix. The fluorescence quenching of BSA caused by azocalix[4]arene derivatives is attributed to the static quenching process. In addition, the synchronous fluorescence spectroscopy indicates that these azocalix[4]arene derivatives are more accessible to Trp residues of BSA molecules than the tyrosine (Tyr) residues. The circular dichroic spectroscopy further verified the binding of azocalix[4]arene derivatives and BSA. PMID- 25549319 TI - Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase. AB - OBJECTIVE: We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe(-/-) mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation. APPROACH AND RESULTS: We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe(-/-) mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX. CONCLUSIONS: Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1. PMID- 25549321 TI - Trait dominance promotes reflexive staring at masked angry body postures. AB - It has been shown that dominant individuals sustain eye-contact when non consciously confronted with angry faces, suggesting reflexive mechanisms underlying dominance behaviors. However, dominance and submission can be conveyed and provoked by means of not only facial but also bodily features. So far few studies have investigated the interplay of body postures with personality traits and behavior, despite the biological relevance and ecological validity of these postures. Here we investigate whether non-conscious exposure to bodily expressions of anger evokes reflex-like dominance behavior. In an interactive eye tracking experiment thirty-two participants completed three social dominance tasks with angry, happy and neutral facial, bodily and face and body compound expressions that were masked from consciousness. We confirmed our predictions of slower gaze-aversion from both non-conscious bodily and compound expressions of anger compared to happiness in high dominant individuals. Results from a follow up experiment suggest that the dominance behavior triggered by exposure to bodily anger occurs with basic detection of the category, but not recognition of the emotional content. Together these results suggest that dominant staring behavior is reflexively driven by non-conscious perception of the emotional content and triggered by not only facial but also bodily expression of anger. PMID- 25549322 TI - Evolutionary genomics and adaptive evolution of the Hedgehog gene family (Shh, Ihh and Dhh) in vertebrates. AB - The Hedgehog (Hh) gene family codes for a class of secreted proteins composed of two active domains that act as signalling molecules during embryo development, namely for the development of the nervous and skeletal systems and the formation of the testis cord. While only one Hh gene is found typically in invertebrate genomes, most vertebrates species have three (Sonic hedgehog--Shh; Indian hedgehog--Ihh; and Desert hedgehog--Dhh), each with different expression patterns and functions, which likely helped promote the increasing complexity of vertebrates and their successful diversification. In this study, we used comparative genomic and adaptive evolutionary analyses to characterize the evolution of the Hh genes in vertebrates following the two major whole genome duplication (WGD) events. To overcome the lack of Hh-coding sequences on avian publicly available databases, we used an extensive dataset of 45 avian and three non-avian reptilian genomes to show that birds have all three Hh paralogs. We find suggestions that following the WGD events, vertebrate Hh paralogous genes evolved independently within similar linkage groups and under different evolutionary rates, especially within the catalytic domain. The structural regions around the ion-binding site were identified to be under positive selection in the signaling domain. These findings contrast with those observed in invertebrates, where different lineages that experienced gene duplication retained similar selective constraints in the Hh orthologs. Our results provide new insights on the evolutionary history of the Hh gene family, the functional roles of these paralogs in vertebrate species, and on the location of mutational hotspots. PMID- 25549323 TI - Proteomic screening for amyloid proteins. AB - Despite extensive study, progress in elucidation of biological functions of amyloids and their role in pathology is largely restrained due to the lack of universal and reliable biochemical methods for their discovery. All biochemical methods developed so far allowed only identification of glutamine/asparagine-rich amyloid-forming proteins or proteins comprising amyloids that form large deposits. In this article we present a proteomic approach which may enable identification of a broad range of amyloid-forming proteins independently of specific features of their sequences or levels of expression. This approach is based on the isolation of protein fractions enriched with amyloid aggregates via sedimentation by ultracentrifugation in the presence of strong ionic detergents, such as sarkosyl or SDS. Sedimented proteins are then separated either by 2D difference gel electrophoresis or by SDS-PAGE, if they are insoluble in the buffer used for 2D difference gel electrophoresis, after which they are identified by mass-spectrometry. We validated this approach by detection of known yeast prions and mammalian proteins with established capacity for amyloid formation and also revealed yeast proteins forming detergent-insoluble aggregates in the presence of human huntingtin with expanded polyglutamine domain. Notably, with one exception, all these proteins contained glutamine/asparagine-rich stretches suggesting that their aggregates arose due to polymerization cross seeding by human huntingtin. Importantly, though the approach was developed in a yeast model, it can easily be applied to any organism thus representing an efficient and universal tool for screening for amyloid proteins. PMID- 25549325 TI - What dermatology still needs to create meaningful patient outcome measurements. PMID- 25549324 TI - MRI-monitored intra-tumoral injection of iron-oxide labeled Clostridium novyi-NT anaerobes in pancreatic carcinoma mouse model. AB - OBJECTIVES: To validate the feasibility of labeling Clostridium novyi-NT (C.novyi NT) anaerobes with iron-oxide nanoparticles for magnetic resonance imaging (MRI) and demonstrate the potential to use MRI to visualize intra-tumoral delivery of these iron-oxide labeled C.novyi-NT during percutaneous injection procedures. MATERIALS AND METHODS: All studies were approved by IACUC. C.novyi-NT were labeled with hybrid iron-oxide Texas red nanoparticles. Growth of labeled and control samples were evaluated with optical density. Labeling was confirmed with confocal fluorescence and transmission electron microscopy (TEM). MRI were performed using a 7 Tesla scanner with T2*-weighted (T2*W) sequence. Contrast-to noise ratio (CNR) measurements were performed for phantoms and signal-to-noise ratio (SNR) measurements performed in C57BL/6 mice (n = 12) with Panc02 xenografts before and after percutaneous injection of iron-oxide labeled C.novyi NT. MRI was repeated 3 and 7 days post-injection. Hematoxylin-eosin (HE), Prussian blue and Gram staining of tumor specimens were performed for confirmation of intra-tumoral delivery. RESULTS: Iron-oxide labeling had no influence upon C.novyi-NT growth. The signal intensity (SI) within T2*W images was significantly decreased for iron-oxide labeled C.novyi-NT phantoms compared to unlabeled controls. Under confocal fluorescence microscopy, the iron-oxide labeled C.novyi-NT exhibited a uniform red fluorescence consistent with observed regions of DAPI staining and overall labeling efficiency was 100% (all DAPI stained C.novyi-NT exhibited red fluorescence). Within TEM images, a large number iron granules were observed within the iron-oxide labeled C.novyi-NT; these were not observed within unlabeled controls. Intra-procedural MRI measurements permitted in vivo visualization of the intra-tumoral distribution of iron-oxide labeled C.novyi-NT following percutaneous injection (depicted as punctate regions of SI reductions within T2*-weighted images); tumor SNR decreased significantly following intra-tumoral injection of C.novyi-NT (p<0.05); these SNR reductions were maintained at 3 and 7 day follow-up intervals. Prussian blue and Gram staining confirmed presence of the iron-oxide labeled anaerobes. CONCLUSIONS: C.novyi-NT can be labeled with iron-oxide nanoparticles for MRI visualization of intra-tumoral deposition following percutaneous injection during bacteriolytic therapy. PMID- 25549326 TI - Patient-centered operating room briefings to improve surgical quality. PMID- 25549327 TI - Low cognitive load and reduced arousal impede practice effects on executive functioning, metacognitive confidence and decision making. AB - The present study investigated the effects of low cognitive workload and the absence of arousal induced via external physical stimulation (motion) on practice related improvements in executive (inhibitory) control, short-term memory, metacognitive monitoring and decision making. A total of 70 office workers performed low and moderately engaging passenger tasks in two successive 20-minute simulated drives and repeated a battery of decision making and inhibitory control tests three times-before, between and after these drives. For half the participants, visual simulation was synchronised with (moderately arousing) motion generated through LAnd Motion Platform, with vibration levels corresponding to a well-maintained unsealed road. The other half performed the same simulated drive without motion. Participants' performance significantly improved over the three test blocks, which is indicative of typical practice effects. The magnitude of these improvements was the highest when both motion and moderate cognitive load were present. The same effects declined either in the absence of motion (low arousal) or following a low cognitive workload task, thus suggesting two distinct pathways through which practice-related improvements in cognitive performance may be hampered. Practice, however, degraded certain aspects of metacognitive performance, as participants became less likely to detect incorrect decisions in the decision-making test with each subsequent test block. Implications include consideration of low cognitive load and arousal as factors responsible for performance decline and targets for the development of interventions/strategies in low load/arousal conditions such as autonomous vehicle operations and highway driving. PMID- 25549328 TI - National surveillance on vancomycin-resistant Enterococcus faecium in Taiwan: emergence and widespread of ST414 and a Tn1546-like element with simultaneous insertion of IS1251-like and IS1678. AB - Cases of bacteremia caused by vancomycin-resistant E. faecium (VRE-fm) increased significantly in Taiwan. The present multicenter surveillance study was performed to reveal the associated epidemiological characteristics. In 2012, 134 non repetitive VRE-fm isolates were prospectively collected from 12 hospitals in Taiwan. Antimicrobial susceptibility, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and analysis of van genes and Tn1546 structures were investigated. Two isolates carried vanB genes, while all the remaining isolates carried vanA genes. Three isolates demonstrated a specific vanA genotype - vanB phenotype. Nine (6.7%) isolates demonstrated tigecycline resistance, and all were susceptible to daptomycin and linezolid. Molecular typing revealed 58 pulsotypes and 13 sequence types (STs), all belonged to three major lineages 17, 18, and 78. The most frequent STs were ST17 (n = 48, 35.8%), ST414 (n = 22, 16.4%), and ST78 (n = 16, 11.9%). Among the vanA harboring isolates, eight structure types of the Tn1546-like element were demonstrated. Type I (a partial deletion in the orf1 and insertion of IS1251-like between the vanS - vanH genes) and Type II (Type I with an additional insertion of IS1678 between orf2 - vanS genes) were the most predominant, consisted of 60 (45.5%) and 62 (47.0%) isolates, respectively. The increase of VRE-fm bacteremia in Taiwan may be associated with the inter- and intra-hospital spread of some major STs and horizontal transfer of vanA genes mostly carried on two efficient Tn1546-like elements. The prevailing ST414 and widespread of the Type II Tn1546-like elements are an emerging problem that requires continuous monitoring. PMID- 25549330 TI - Spatial niche facilitates clonal reproduction in seed plants under temporal disturbance. AB - The evolutionary origins and advantages of clonal reproduction relative to sexual reproduction have been discussed for several taxonomic groups. In particular, organisms with a sessile lifestyle are often exposed to spatial and temporal environmental fluctuations. Thus, clonal propagation may be advantageous in such fluctuating environments, for sessile species that can reproduce both sexually and clonally. Here we introduce the concept of niche to a lattice space that changes spatially and temporally, by incorporating the compatibility between the characteristics of a sessile clonal plant with its habitat into a spatially explicit individual-based model. We evaluate the impact of spatially and temporally heterogeneous environments on the evolution of reproductive strategies: the optimal balance between seed and clonal reproduction of a clonal plant. The spatial niche case with local habitats led to avoidance of specialization in reproductive strategy, whereas stable environments or intensive environmental change tended to result in specialization in either clonal or seed reproduction under neutral conditions. Furthermore, an increase in spatial niches made clonal reproduction advantageous, as a consequence of competition among several genets under disturbed conditions, because a ramet reached a favorable habitat through a rare long-distance dispersal event via seed production. Thus, the existence of spatial niches could explain the advantages of clonal propagation. PMID- 25549329 TI - Antibacterial responses by peritoneal macrophages are enhanced following vitamin D supplementation. AB - Patients with chronic kidney disease (CKD), who usually display low serum 25 hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), are at high risk of infection, notably those undergoing peritoneal dialysis (PD). We hypothesized that peritoneal macrophages from PD patients are an important target for vitamin D-induced antibacterial activity. Dialysate effluent fluid was obtained from 27 non-infected PD patients. Flow cytometry indicated that PD cells were mainly monocytic (37.9+/-17.7% cells CD14+/CD45+). Ex vivo analyses showed that PD cells treated with 25D (100 nM, 6 hrs) or 1,25D (5 nM, 6 hrs) induced mRNA for antibacterial cathelicidin (CAMP) but conversely suppressed mRNA for hepcidin (HAMP). PD cells from patients with peritonitis (n = 3) showed higher baseline expression of CAMP (18-fold+/-9, p<0.05) and HAMP (64-fold+/-7) relative to cells from non-infected patients. In 12 non-infected PD patients, oral supplementation with a single dose of vitamin D2 (100,000 IU) increased serum levels of 25D from 18+/-8 to 41+/-15 ng/ml (p = 0.002). This had no significant effect on PD cell CD14/CD45 expression, but mRNA for HAMP was suppressed significantly (0.5-fold, p = 0.04). Adjustment for PD cell CD14/CD45 expression using a mixed linear statistical model also revealed increased expression of CAMP (mRNA in PD cells and protein in effluent) in vitamin D-supplemented patients. These data show for the first time that vitamin D supplementation in vitro and in vivo promotes innate immune responses that may enhance macrophage antibacterial responses in patients undergoing PD. This highlights a potentially important function for vitamin D in preventing infection-related complications in CKD. PMID- 25549332 TI - Metacommunity versus biogeography: a case study of two groups of neotropical vegetation-dwelling arthropods. AB - Biogeography and metacommunity ecology provide two different perspectives on species diversity. Both are spatial in nature but their spatial scales do not necessarily match. With recent boom of metacommunity studies, we see an increasing need for clear discrimination of spatial scales relevant for both perspectives. This discrimination is a necessary prerequisite for improved understanding of ecological phenomena across scales. Here we provide a case study to illustrate some spatial scale-dependent concepts in recent metacommunity studies and identify potential pitfalls. We presented here the diversity patterns of Neotropical lepidopterans and spiders viewed both from metacommunity and biogeographical perspectives. Specifically, we investigated how the relative importance of niche- and dispersal-based processes for community assembly change at two spatial scales: metacommunity scale, i.e. within a locality, and biogeographical scale, i.e. among localities widely scattered along a macroclimatic gradient. As expected, niche-based processes dominated the community assembly at metacommunity scale, while dispersal-based processes played a major role at biogeographical scale for both taxonomical groups. However, we also observed small but significant spatial effects at metacommunity scale and environmental effects at biogeographical scale. We also observed differences in diversity patterns between the two taxonomical groups corresponding to differences in their dispersal modes. Our results thus support the idea of continuity of processes interactively shaping diversity patterns across scales and emphasize the necessity of integration of metacommunity and biogeographical perspectives. PMID- 25549331 TI - Glaucoma screening in the Haitian Afro-Caribbean population of South Florida. AB - OBJECTIVE: To evaluate the presence of clinical signs consistent with suspected glaucoma in Haitian Afro-Caribbean individuals residing in South Florida who do not receive regular eye examinations. DESIGN: Retrospective, cross-sectional study. METHODS: SETTING: Community health center in the Little Haiti district of Miami, Florida. PATIENT POPULATION: We reviewed medical records and screening forms from five health screenings between October 2011 to October 2013 of 939 Afro-Caribbean individuals older than 18 years, who were never diagnosed with glaucoma or had an eye examination within the last ten years. PROCEDURES: Measurements of distance visual acuity (VA), intraocular eye pressure (IOP), central corneal thickness (CCT), cup-to-disc ratio (CDR), frequency doubling technology (FDT) perimeter visual field (VF). MAIN OUTCOME MEASURES: Proportion of glaucoma suspects, based on IOP greater than or equal to 24 mm Hg or CDR greater than or equal to 0.7 in either eye, and determinants of CDR and IOP. RESULTS: One hundred ninety-one (25.5%) of 750 patients were identified as glaucoma suspects. Glaucoma suspects were common in both the youngest and oldest age groups (<40 years, 20.9%; 95% confidence interval [CI], 17.9-23.9; >70 years, 25.0%; 95% CI, 21.8-28.2) and higher in men than women less than 70 years; the reverse was true after 70 years. Among all patients, mean IOP was 19.2+/-4.5 mmHg, mean CDR was 0.37+/-0.17, and mean CCT was 532+/-37.1 um. In multiple linear stepwise regression analysis, determinates of increased CDR included increasing age (P = 0.004), lack of insurance (P = 0.019), and higher IOP (P<0.001), while increasing CDR (P<0.001) and thicker CCT (P<0.001) were associated with higher IOP. CONCLUSIONS: This first glaucoma survey in a U.S. Haitian Afro-Caribbean population indicates glaucoma suspect status is high across all age groups, and suggests glaucoma monitoring in people less than 40 years of age is indicated in this population. PMID- 25549333 TI - Human cytomegalovirus gene expression in long-term infected glioma stem cells. AB - The most common adult primary brain tumor, glioblastoma (GBM), is characterized by fifteen months median patient survival and has no clear etiology. We and others have identified the presence of human cytomegalovirus (HCMV) gene products endogenously expressed in GBM tissue and primary cells, with a subset of viral genes being consistently expressed in most samples. Among these viral genes, several have important oncomodulatory properties, regulating tumor stemness, proliferation, immune evasion, invasion and angiogenesis. These findings lead us to hypothesize that a specific HCMV gene signature may be associated with GBM pathogenesis. To investigate this hypothesis, we used glioma cell lines and primary glioma stem-like cells (GSC) infected with clinical and laboratory HCMV strains and measured relative viral gene expression levels along several time points up to 15 weeks post-infection. While HCMV gene expression was detected in several infected glioma lines through week 5 post-infection, only HCMV-infected GSC expressed viral gene products 15 weeks post-infection. Efficiency of infection across time was higher in GSC compared to cell lines. Importantly, HCMV infected GSC outlived their uninfected counterparts, and this extended survival was paralleled by increased tumorsphere frequency and upregulation of stemness regulators, such as SOX2, p-STAT3, and BMX (a novel HCMV target identified in this study). Interleukin 6 (IL-6) treatment significantly upregulated HCMV gene expression in long-term infected glioma cultures, suggesting that pro inflammatory signaling in the tumor milieu may further augment HCMV gene expression and subsequent tumor progression driven by viral-induced cellular signaling. Together, our data support a critical role for long-term, low-level HCMV infection in promoting survival, stemness, and proliferation of GSC that could significantly contribute to GBM pathogenesis. PMID- 25549334 TI - Association of antenatal depression with adverse consequences for the mother and newborn in rural Ghana: findings from the DON population-based cohort study. AB - BACKGROUND: Whilst there is compelling evidence of an almost 2-fold increased risk of still births, and suggestive evidence of increased mortality among offspring of mothers with psychotic disorders, only three studies have addressed the role of antenatal depression (AND) on survival of the baby. We examined these associations in a large cohort of pregnant women in Ghana. METHODS: A Cohort study nested within 4-weekly surveillance of all women of reproductive age to identify pregnancies and collect data on births and deaths in the Kintampo Health Research Centre study area of Ghana. Women were screened for AND using the Patient Health Questionnaire (PHQ-9) to ascertain DSM-IV major or minor depression. Outcomes were adverse birth outcomes, maternal/infant morbidity, and uptake of key newborn care practices, examined using logistic regression; effect sizes reported as relative risks with 95% confidence intervals. RESULTS: 20679 (89.6%) pregnant women completed the PHQ-9. The prevalence of AND was 9.9% (n = 2032) (95% confidence interval 9.4%-10.2%). AND was associated with: prolonged labour (RR 1.25, 95% CI 1.02-1.53); peripartum complications (RR 1.11, 95% CI 1.07-1.15); postpartum complications (RR 1.27, 96% CI 1.21-1.34); non-vaginal delivery (RR 1.19, 95% CI 1.02-1.40); newborn illness (RR 1.52, 95% CI 1.16 1.99); and bed net use during pregnancy (RR 0.93, 95% CI 0.89-0.98), but not neonatal deaths, still births, low birth weight, immediate breast feeding initiation, or exclusive breastfeeding. AND was marginally associated with preterm births (RR 1.32, 95% CI 0.98-1.76). CONCLUSION: This paper has contributed important evidence on the role of antenatal depression as a potential contributor to maternal and infant morbidity. Non-pharmacological treatments anchored on primary care delivery structures are recommended as an immediate step. We further recommend that trials are designed to assess if treating antenatal depression in conjunction with improving the quality of obstetric care results in improved maternal and newborn outcomes. PMID- 25549335 TI - Crowdsourcing the unknown: the satellite search for Genghis Khan. AB - Massively parallel collaboration and emergent knowledge generation is described through a large scale survey for archaeological anomalies within ultra-high resolution earth-sensing satellite imagery. Over 10K online volunteers contributed 30K hours (3.4 years), examined 6,000 km2, and generated 2.3 million feature categorizations. Motivated by the search for Genghis Khan's tomb, participants were tasked with finding an archaeological enigma that lacks any historical description of its potential visual appearance. Without a pre-existing reference for validation we turn towards consensus, defined by kernel density estimation, to pool human perception for "out of the ordinary" features across a vast landscape. This consensus served as the training mechanism within a self evolving feedback loop between a participant and the crowd, essential driving a collective reasoning engine for anomaly detection. The resulting map led a National Geographic expedition to confirm 55 archaeological sites across a vast landscape. A increased ground-truthed accuracy was observed in those participants exposed to the peer feedback loop over those whom worked in isolation, suggesting collective reasoning can emerge within networked groups to outperform the aggregate independent ability of individuals to define the unknown. PMID- 25549336 TI - Carotenoids, birdsong and oxidative status: administration of dietary lutein is associated with an increase in song rate and circulating antioxidants (albumin and cholesterol) and a decrease in oxidative damage. AB - Despite the appealing hypothesis that carotenoid-based colouration signals oxidative status, evidence supporting the antioxidant function of these pigments is scarce. Recent studies have shown that lutein, the most common carotenoid used by birds, can enhance the expression of non-visual traits, such as birdsong. Nevertheless, the underlying physiological mechanisms remain unclear. In this study we hypothesized that male European starlings (Sturnus vulgaris) fed extra lutein increase their song rate as a consequence of an improved oxidative status. Although birdsong may be especially sensitive to the redox status, this has, to the best of our knowledge, never been tested. Together with the determination of circulating oxidative damage (ROMs, reactive oxygen metabolites), we quantified uric acid, albumin, total proteins, cholesterol, and testosterone, which are physiological parameters potentially sensitive to oxidation and/or related to both carotenoid functions and birdsong expression. We found that the birds fed extra lutein sang more frequently than control birds and showed an increase of albumin and cholesterol together with a decrease of oxidative damage. Moreover, we could show that song rate was associated with high levels of albumin and cholesterol and low levels of oxidative damage, independently from testosterone levels. Our study shows for the first time that song rate honestly signals the oxidative status of males and that dietary lutein is associated with the circulation of albumin and cholesterol in birds, providing a novel insight to the theoretical framework related to the honest signalling of carotenoid-based traits. PMID- 25549337 TI - Rapid and sensitive detection of Listeria ivanovii by loop-mediated isothermal amplification of the smcL gene. AB - A loop-mediated isothermal amplification (LAMP) assay for rapid and sensitive detection of the L. ivanovii strains had been developed and evaluated in this study. Oligonucleotide primers specific for L. ivanovii species were designed corresponding to smcL gene sequences. The primers set comprise six primers targeting eight regions on the species-specific gene smcL. The LAMP assay could be completed within 1 h at 64 degrees C in a water bath. Amplification products were directly observed by the Loopamp Fluorescent Detection Reagent (FD) or detected by agarose gel electrophoresis. Moreover, the LAMP reactions were also detected by real-time measurement of turbidity. The exclusivity of 77 non-L. ivanovii and the inclusivity of 17 L. ivanovii were both 100% in the assay. Sensitivity of the LAMP assay was 250 fg DNA and 16 CFU per reaction for detection of L. ivanovii in pure cultures and simulated human stool. The LAMP assay was 10 and 100-fold more sensitive than quantitative PCR (qPCR) and conventional PCR assays,respectively. When applied to human stool samples spiked with low level (8 CFU/0.5 g) of L. ivanovii strains, the new LAMP assay described here achieved positive detection after 6 hours enrichment. In conclusion, the new LAMP assay in this study can be used as a valuable, rapid and sensitive detection tool for the detection of L. ivanovii in field, medical and veterinary laboratories. PMID- 25549338 TI - Broad adaptive immune responses to M. tuberculosis antigens precede TST conversion in tuberculosis exposed household contacts in a TB-endemic setting. AB - BACKGROUND: The identification of Mycobacterium-tuberculosis (Mtb) infected individuals remains a challenge due to an insufficient understanding of immune responses detected with the current diagnostic tests for latent tuberculosis i.e. the tuberculin skin test (TST) or IFN-gamma release assays (IGRAs) and an inability to distinguish infection stages with current immunologic assays. Further classification based on markers other than IFN-gamma may help to define markers of early Mtb infection. METHODS: We assessed the TST status of Mtb exposed household contacts at baseline and at 6 months. Contacts were classified into those with initial positive TST (TST+); those with baseline negative TST but TST conversion at 6 months (TST converters, TSTC) and those with persistently negative TST (PTST-). We assessed their short- and long-term immune responses to PPD and ESAT-6/CFP-10 (EC) via IFN-gamma ELISPOT and a multiplex cytokine array in relation to TST status and compared them to those of TB cases to identify immune profiles associated with a spectrum of infection stages. RESULTS: After 1 and 6 days stimulation with EC, 12 cytokines (IFN-gamma, IL-2, IP-10, TNF-alpha, IL-13, IL-17, IL-10, GMCSF, MIP-1beta, MCP-3, IL-2RA and IL-1A) were not different in TSTC compared to TST+ suggesting that robust adaptive Mtb-specific immune responses precede TST conversion. Stratifying contacts by baseline IFN gamma ELISPOT to EC in combination with TST results revealed that IP-10 and IL-17 were highest in the group of TST converters with positive baseline ELISPOT, suggesting they might be markers for recent infection. CONCLUSION: We describe a detailed analysis of Mtb-specific biomarker profiles in exposed household contacts in a TB endemic area that provides insights into the dynamic immune responses to Mtb infection and may help to identify biomarkers for 'at-risk' populations beyond TST and IGRA. PMID- 25549339 TI - Prognostic value of tumor size in patients with remnant gastric cancer: is the seventh UICC stage sufficient for predicting prognosis? AB - BACKGROUND: The 7th UICC N stage may be unsuitable for remnant gastric cancer (RGC) because the original disease and previous operation usually cause abnormal lymphatic drainage. However, the prognostic significance of the current TNM staging system in RGC has not been studied. METHODS: Prospective data from 153 RGC patients who underwent curative gastrectomy from Jan 1995 to Aug 2009 were reviewed. All patients were classified according to tumor size (<3 cm as N0;>3&<=5 cm as N1;>5&<=7 cm as N2; and>7 cm as N3). The overall survival was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using the Cox proportional hazard model. RESULTS: Tumor sizes ranged from 1.0 to 15.0 cm (median 5.0 cm). Tumor size, depth of invasion and lymph node (LN) metastasis were significant prognostic factors based on both the univariate and multivariate analyses (P<0.05). In the survival analysis, the seventh edition UICC-TNM classification provided a detailed classification; however, some subgroups of the UICC-TNM classification did not have significantly different survival rates. The combination of the seventh edition T classification and the suggested N classification, with ideal relative risk (RR) results and P value, was distinctive for subgrouping the survival rates except for the IA versus IB and II A versus IIB. A modified staging system based on tumor size, predicted survival more accurately than the conventional TNM staging system. CONCLUSIONS: In RGCs, tumor size is an independent prognostic factor and a modified TNM system based on tumor size accurately predicts survival. PMID- 25549340 TI - Modulating brain oscillations to drive brain function. AB - Do neuronal oscillations play a causal role in brain function? In a study in this issue of PLOS Biology, Helfrich and colleagues address this long-standing question by attempting to drive brain oscillations using transcranial electrical current stimulation. Remarkably, they were able to manipulate visual perception by forcing brain oscillations of the left and right visual hemispheres into synchrony using oscillatory currents over both hemispheres. Under this condition, human observers more often perceived an inherently ambiguous visual stimulus in one of its perceptual instantiations. These findings shed light on the mechanisms underlying neuronal computation. They show that it is the neuronal oscillations that drive the visual experience, not the experience driving the oscillations. And they indicate that synchronized oscillatory activity groups brain areas into functional networks. This points to new ways for controlled experimental and possibly also clinical interventions for the study and modulation of brain oscillations and associated functions. PMID- 25549341 TI - We are pleased to present you with this Special Issue of the Journal of Women's Health highlighting the main topics covered at the meeting. Introduction. PMID- 25549343 TI - The transformative nature of transparency in research funding. AB - Central to research funding are grant proposals that researchers send in to potential funders for review, in the hope of approval. A survey of policies at major research funders found that there is room for more transparency in the process of grant review, which would strengthen the case for the efficiency of public spending on research. On that basis, debate was invited on which transparency measures should be implemented and how, with some concrete suggestions at hand. The present article adds to this discussion by providing further context from the literature, along with considerations on the effect size of the proposed measures. The article then explores the option of opening to the public key components of the process, makes the case for pilot projects in this area, and sketches out the potential that such measures might have to transform the research landscape in those areas in which they are implemented. PMID- 25549342 TI - Kinomic profiling of electromagnetic navigational bronchoscopy specimens: a new approach for personalized medicine. AB - PURPOSE: Researchers are currently seeking relevant lung cancer biomarkers in order to make informed decisions regarding therapeutic selection for patients in so-called "precision medicine." However, there are challenges to obtaining adequate lung cancer tissue for molecular analyses. Furthermore, current molecular testing of tumors at the genomic or transcriptomic level are very indirect measures of biological response to a drug, particularly for small molecule inhibitors that target kinases. Kinase activity profiling is therefore theorized to be more reflective of in vivo biology than many current molecular analysis techniques. As a result, this study seeks to prove the feasibility of combining a novel minimally invasive biopsy technique that expands the number of lesions amenable for biopsy with subsequent ex vivo kinase activity analysis. METHODS: Eight patients with lung lesions of varying location and size were biopsied using the novel electromagnetic navigational bronchoscopy (ENB) technique. Basal kinase activity (kinomic) profiles and ex vivo interrogation of samples in combination with tyrosine kinase inhibitors erlotinib, crizotinib, and lapatinib were performed by PamStation 12 microarray analysis. RESULTS: Kinomic profiling qualitatively identified patient specific kinase activity profiles as well as patient and drug specific changes in kinase activity profiles following exposure to inhibitor. Thus, the study has verified the feasibility of ENB as a method for obtaining tissue in adequate quantities for kinomic analysis and has demonstrated the possible use of this tissue acquisition and analysis technique as a method for future study of lung cancer biomarkers. CONCLUSIONS: We demonstrate the feasibility of using ENB-derived biopsies to perform kinase activity assessment in lung cancer patients. PMID- 25549344 TI - Lymphoscintigraphy for the assessment of autologous stem cell implantation in chronic lymphedema. AB - Lymphoscintigraphy is the criterion standard technique for the diagnosis of lymphedema. The authors present the images acquired before and 6 months after implantation of autologous stem cells in 2 patients with chronic lymphedema of the lower limbs. The stem cells implantations were carried out by multiple superficial and deep injections in the trajectory of the lymphatic vessels and also in the inguinal region. A volume of 0.75 to 1.00 mL of cell suspension (1.0 2.2 * 10(9) stem cells) was administered in each injection site. The anatomy and function of the lymphatic system were evaluated. PMID- 25549345 TI - 18F-FDG and 18F-florbetapir PET in clinical practice: regional analysis in mild cognitive impairment and Alzheimer disease. AB - OBJECTIVE: The aim of this study is to compare regional cerebral metabolic rate of glucose metabolism and amyloid-beta density in patients with Alzheimer disease (AD), mild cognitive impairment (MCI), and healthy elderly subjects. METHODS: Eighteen patients (including 6 AD, 5 amnestic MCI, and 7 controls) were enrolled at the University Hospital of Tours, France, and submitted to clinical, neuropsychological, and MRI examinations. PET images using F-florbetapir (266 MBq) and F-FDG (185 MBq) were acquired. SUV ratios in specific regions were defined using PMOD3.2 software. RESULTS: The mean values of F-FDG SUV ratio were significantly lower in frontal, anterior cingulate, and temporal regions in MCI patients than in normal elderly (-15%, -22%, and -11%, respectively). Alzheimer disease patients showed global cerebral metabolic rate of glucose metabolism decrease, especially in parietal and precuneus regions (-15% and -13% compared with healthy control subjects). Only precuneus cortex showed an increased F florbetapir uptake in AD. There was no other significant regional difference in the amyloid-beta density. CONCLUSIONS: In this study, we observed regional brain metabolic changes between MCI, AD, and controls, whereas only precuneus showed an increased amyloid-beta density in AD. F-florbetapir PET analysis needs to be visual and global, whereas F-FDG analysis can be regional. PMID- 25549346 TI - High 18F-FDG uptake in a systemic right ventricle after atrial switch. AB - A 21-year-old patient with a D-transposition of the great arteries and a single coronary ostium underwent an atrial switch operation as newborn (Senning correction at 6 days of life in 1992). For an unrelated oncological evaluation, she underwent a recent F-FDG PET/CT. The myocardial uptake was clearly more intense in the morphological right ventricle, as this ventricle has become the systemic ventricle. On the contrary, the morphological left ventricle showed a very faint FDG uptake. This case illustrates the physiological changes related to a previous cardiac surgery. PMID- 25549347 TI - Dynamic 18F-FDOPA PET Findings After Carbidopa Premedication in 2 Adult Patients With Insulinoma-Related Hyperinsulinemic Hypoglycemia. AB - (18)F-fluorodihydroxyphenylalanine (FDOPA) PET seems to be of limited value to localize pancreatic insulin-secreting tumors in adult with hyperinsulinemic hypoglycemia. Carbidopa is an efficient inhibitor of the peripheral aromatic amino acid decarboxylase, significantly reducing the physiological pancreatic FDOPA uptake. Nevertheless, carbidopa effect on FDOPA uptake in insulinomas is not fully elucidated. No final consensus has been reached about the usefulness of carbidopa in patients with insulinoma-related hyperinsulinemic hypoglycemia. Moreover, the ideal timing for PET/CT acquisitions is a matter of discussion. We report the results of dynamic FDOPA PET performed after carbidopa premedication in 2 adult patients with insulinoma. PMID- 25549348 TI - Disability adjusted life year (DALY): a useful tool for quantitative assessment of environmental pollution. AB - Disability adjusted life year (DALY) has been widely used since 1990s for evaluating global and/or regional burden of diseases. As many environmental pollutants are hazardous to human health, DALY is also recognized as an indicator to quantify the health impact of environmental pollution related to disease burden. Based on literature reviews, this article aims to give an overview of the applicable methodologies and research directions for using DALY as a tool for quantitative assessment of environmental pollution. With an introduction of the methodological framework of DALY, the requirements on data collection and manipulation for quantifying disease burdens are summarized. Regarding environmental pollutants hazardous to human beings, health effect/risk evaluation is indispensable for transforming pollution data into disease data through exposure and dose-response analyses which need careful selection of models and determination of parameters. Following the methodological discussions, real cases are analyzed with attention paid to chemical pollutants and pathogens usually encountered in environmental pollution. It can be seen from existing studies that DALY is advantageous over conventional environmental impact assessment for quantification and comparison of the risks resulted from environmental pollution. However, further studies are still required to standardize the methods of health effect evaluation regarding varied pollutants under varied circumstances before DALY calculation. PMID- 25549349 TI - Painful purpura on bilateral helices. PMID- 25549351 TI - Voting behavior, coalitions and government strength through a complex network analysis. AB - We analyze the network of relations between parliament members according to their voting behavior. In particular, we examine the emergent community structure with respect to political coalitions and government alliances. We rely on tools developed in the Complex Network literature to explore the core of these communities and use their topological features to develop new metrics for party polarization, internal coalition cohesiveness and government strength. As a case study, we focus on the Chamber of Deputies of the Italian Parliament, for which we are able to characterize the heterogeneity of the ruling coalition as well as parties specific contributions to the stability of the government over time. We find sharp contrast in the political debate which surprisingly does not imply a relevant structure based on established parties. We take a closer look to changes in the community structure after parties split up and their effect on the position of single deputies within communities. Finally, we introduce a way to track the stability of the government coalition over time that is able to discern the contribution of each member along with the impact of its possible defection. While our case study relies on the Italian parliament, whose relevance has come into the international spotlight in the present economic downturn, the methods developed here are entirely general and can therefore be applied to a multitude of other scenarios. PMID- 25549350 TI - HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice. AB - A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors. HET0016 effects were analyzed on MDA-MB-231 derived breast cancer in mouse and in vitro cell line. MDA-MB-231 tumor cells were implanted in animals' right flank and randomly assigned to early (1 and 2), starting treatments on day 0, or delayed groups (3 and 4) on day 8 after implantation of tumor. Animals received HET0016 (10 mg/kg) treatment via intraperitoneal injection for 5 days/week for either 3 or 4 weeks. Control group received vehicle treatment. Tumor sizes were measured on days 7, 14, 21, and 28 and the animals were euthanized on day 22 and 29. Proteins were extracted from the whole tumor and from cells treated with 10 uM HET0016 for 4 and 24 hrs. Protein array kits of 20 different cytokines/factors were used. ELISA was performed to observe the HIF-1alpha and MMP-2 protein expression. Other markers were confirmed by IHC. HET0016 significantly inhibited tumor growth in all treatment groups at all-time points compared to control (p<0.05). Tumor growth was completely inhibited on three of ten animals on early treatment group. Treatment groups showed significantly lower expression of pro-angiogenic factors compared to control at 21 days; however, there was no significant difference in HIF-1alpha expression after treatments. Similar results were found in vitro at 24 hrs of HET0016 treatment. After 28 days, significant increase of angiogenin, angiopoietin-1/2, EGF-R and IGF-1 pro-angiogenic factors were found (p<0.05) compared to control, as well as an higher intensity of all factors were found when compared to that of 21 day's data, suggesting a treatment resistance. HET0016 inhibited tumor growth by reducing expression of different set of pro angiogenic factors; however, a resistance to treatment seemed to happen after 21 days. PMID- 25549352 TI - Heat stress induces apoptosis through a Ca2+-mediated mitochondrial apoptotic pathway in human umbilical vein endothelial cells. AB - BACKGROUND: Heat stress can be acutely cytotoxic, and heat stress-induced apoptosis is a prominent pathological feature of heat-related illnesses, although the precise mechanisms by which heat stress triggers apoptosis are poorly defined. METHODS: The percentages of viability and cell death were assessed by WST-1 and LDH release assays. Apoptosis was assayed by DNA fragmentation and caspase activity. Expression of cleaved PARP, Apaf-1, phospho-PERK, Phospho eIF2a, ATF4, XBP-1s, ATF6, GRP78, phospho-IP3R, RYR and SERCA was estimated by Western blot. The effect of calcium overload was determined using flow cytometric analysis with the fluorescent probe Fluo-3/AM. The generation of ROS (O2-, H2O2, NO) was labeled by confocal laser scanning microscopy images of fluorescently and flow cytometry. RESULTS: In this study, we found that heat stress in HUVEC cells activated initiators of three major unfolded protein response (UPR) signaling transduction pathways: PERK-eIF2a-ATF4, IRE1-XBP-1S and ATF6 to protect against ER stress, although activation declined over time following cessation of heat stress. Furthermore, we show that intense heat stress may induce apoptosis in HUVEC cells through the calcium-mediated mitochondrial apoptotic pathway, as indicated by elevation of cytoplasmic Ca2+, expression of Apaf-1, activation of caspase-9 and caspase-3, PARP cleavage, and ultimately nucleosomal DNA fragmentation; Reactive oxygen species (ROS) appear to act upstream in this process. In addition, we provide evidence that IP3R upregulation may promote influx of Ca2+ into the cytoplasm after heat stress. CONCLUSION: Our findings describe a novel mechanism for heat stress-induced apoptosis in HUVEC cells: following elevation of cytoplasm Ca2+, activation of the mitochondrial apoptotic pathway via the IP3R upregulation, with ROS acting as an upstream regulator of the process. PMID- 25549353 TI - Hyperspectral imaging for mapping of total nitrogen spatial distribution in pepper plant. AB - Visible/near-infrared (Vis/NIR) hyperspectral imaging was employed to determine the spatial distribution of total nitrogen in pepper plant. Hyperspectral images of samples (leaves, stems, and roots of pepper plants) were acquired and their total nitrogen contents (TNCs) were measured using Dumas combustion method. Mean spectra of all samples were extracted from regions of interest (ROIs) in hyperspectral images. Random frog (RF) algorithm was implemented to select important wavelengths which carried effective information for predicting the TNCs in leaf, stem, root, and whole-plant (leaf-stem-root), respectively. Based on full spectra and the selected important wavelengths, the quantitative relationships between spectral data and the corresponding TNCs in organs (leaf, stem, and root) and whole-plant (leaf-stem-root) were separately developed using partial least-squares regression (PLSR). As a result, the PLSR model built by the important wavelengths for predicting TNCs in whole-plant (leaf-stem-root) offered a promising result of correlation coefficient (R) for prediction (RP = 0.876) and root mean square error (RMSE) for prediction (RMSEP = 0.426%). Finally, the TNC of each pixel within ROI of the sample was estimated to generate the spatial distribution map of TNC in pepper plant. The achievements of the research indicated that hyperspectral imaging is promising and presents a powerful potential to determine nitrogen contents spatial distribution in pepper plant. PMID- 25549354 TI - CCR7 expressing mesenchymal stem cells potently inhibit graft-versus-host disease by spoiling the fourth supplemental Billingham's tenet. AB - The clinical acute graft-versus-host disease (GvHD)-therapy of mesenchymal stem cells (MSCs) is not as satisfactory as expected. Secondary lymphoid organs (SLOs) are the major niches serve to initiate immune responses or induce tolerance. Our previous study showed that CCR7 guide murine MSC line C3H10T1/2 migrating to SLOs. In this study, CCR7 gene was engineered into murine MSCs by lentivirus transfection system (MSCs/CCR7). The immunomodulatory mechanism of MSCs/CCR7 was further investigated. Provoked by inflammatory cytokines, MSCs/CCR7 increased the secretion of nitric oxide and calmed down the T cell immune response in vitro. Immunofluorescent staining results showed that transfused MSCs/CCR7 can migrate to and relocate at the appropriate T cell-rich zones within SLOs in vivo. MSCs/CCR7 displayed enhanced effect in prolonging the survival and alleviating the clinical scores of the GvHD mice than normal MSCs. Owing to the critical relocation sites, MSCs/CCR7 co-infusion potently made the T cells in SLOs more naive like, thus control T cells trafficking from SLOs to the target organs. Through spoiling the fourth supplemental Billingham's tenet, MSCs/CCR7 potently inhibited the development of GvHD. The study here provides a novel therapeutic strategy of MSCs/CCR7 infusion at a low dosage to give potent immunomodulatory effect for clinical immune disease therapy. PMID- 25549355 TI - miR-150-5p inhibits hepatoma cell migration and invasion by targeting MMP14. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor because the molecular mechanisms underlying hepatocarcinogenesis are not well understood. In the study, we focused on identifying the role of miRNAs in HCC progression. miRNA microarray was used to analyze the differentially expressed miRNAs, and the results were validated by qPCR. We found that the miR-150-5p expression is down-regulated in HCC tissues compared with pair non-tumor tissues. miR-150-5p expression is also decreased in metastatic cancer tissues compared with pair primary tissues, indicating that miR 150-5p may be involved in HCC metastasis. Functionally, miR-150-5p inhibition significantly promotes hepatoma cell migration and invasion, whereas miR-150-5p overexpression suppresses cancer cell migration and invasion in vitro. The matrix metalloproteinase 14 (MMP14) is identified as a new target gene of miR-150-5p. miR-150-5p markedly inhibits MMP14 expression in hepatoma cells, and miR-150-5p expression is negative correlation with MMP14 expression in vivo. More important, re-expression of MMP14 in hepatoma cells partially reverses the effect of miR-150 5p in inhibiting cell invasion. PMID- 25549356 TI - Evaluation of scaling invariance embedded in short time series. AB - Scaling invariance of time series has been making great contributions in diverse research fields. But how to evaluate scaling exponent from a real-world series is still an open problem. Finite length of time series may induce unacceptable fluctuation and bias to statistical quantities and consequent invalidation of currently used standard methods. In this paper a new concept called correlation dependent balanced estimation of diffusion entropy is developed to evaluate scale invariance in very short time series with length ~10(2). Calculations with specified Hurst exponent values of 0.2,0.3,...,0.9 show that by using the standard central moving average de-trending procedure this method can evaluate the scaling exponents for short time series with ignorable bias (<=0.03) and sharp confidential interval (standard deviation <=0.05). Considering the stride series from ten volunteers along an approximate oval path of a specified length, we observe that though the averages and deviations of scaling exponents are close, their evolutionary behaviors display rich patterns. It has potential use in analyzing physiological signals, detecting early warning signals, and so on. As an emphasis, the our core contribution is that by means of the proposed method one can estimate precisely shannon entropy from limited records. PMID- 25549357 TI - EZH2 regulates cofilin activity and colon cancer cell migration by targeting ITGA2 gene. AB - Reorganization of cytoskeleton via actin remodeling is a basic step of cell locomotion. Although cell migration of normal and cancer cells can be stimulated by a variety of intra- and extra-cellular factors, all paths ultimate on the regulation of cofilin activity. Cofilin is a small actin-binding protein able to bind both forms of actin, globular and filament, and is regulated by phosphorylation at Serine 3. Following phosphorylation at serine 3 cofilin is inactive, therefore cannot bind actin molecules and cytoskeleton remodeling is impaired. The histone methyltransferase EZH2 is frequently over expressed in many tumour types including colorectal cancer (CRC). EZH2 over activity, which results in epigenetic gene-silencing, has been associated with many tumour properties including invasion, angiogenesis and metastasis but little is known about the underneath molecular mechanisms. Herein, we report that EZH2 is able to control cofilin activity and consequently cell locomotion of CRC cell lines through a non conventional novel axis that involves integrin signaling. Indeed, we show how genetic and pharmacological inhibition (DZNep and GSK343) of EZH2 function produces hyper phosphorylation of cofilin and reduces cell migration. We previously demonstrated by chromatin immuno-precipitation that Integrin alpha 2 (ITGalpha2) expression is regulated by EZH2. In the present study we provide evidence that in EZH2-silenced cells the signaling activity of the de-repressed ITGalpha2 is able to increase cofilin phosphorylation, which in turn reduces cell migration. This study also proposes novel mechanisms that might provide new anti metastatic strategies for CRC treatment based on the inhibition of the epigenetic factor EZH2 and/or its target gene. PMID- 25549358 TI - Olfactory attraction of the hornet Vespa velutina to honeybee colony odors and pheromones. AB - Since the beginning of the last century, the number of biological invasions has continuously increased worldwide. Due to their environmental and economical consequences, invasive species are now a major concern. Social wasps are particularly efficient invaders because of their distinctive biology and behavior. Among them, the yellow-legged hornet, Vespa velutina, is a keen hunter of domestic honeybees. Its recent introduction to Europe may induce important beekeeping, pollination, and biodiversity problems. Hornets use olfactory cues for the long-range detection of food sources, in this case the location of honeybee colonies, but the exact nature of these cues remains unknown. Here, we studied the orientation behavior of V. velutina workers towards a range of hive products and protein sources, as well as towards prominent chemical substances emitted by these food sources. In a multiple choice test performed under controlled laboratory conditions, we found that hornets are strongly attracted to the odor of some hive products, especially pollen and honey. When testing specific compounds, the honeybee aggregation pheromone, geraniol, proved highly attractive. Pheromones produced by honeybee larvae or by the queen were also of interest to hornet workers, albeit to a lesser extent. Our results indicate that V. velutina workers are selectively attracted towards olfactory cues from hives (stored food, brood, and queen), which may signal a high prey density. This study opens new perspectives for understanding hornets' hunting behavior and paves the way for developing efficient trapping strategies against this invasive species. PMID- 25549359 TI - Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver. AB - Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis. PMID- 25549360 TI - Placental genome and maternal-placental genetic interactions: a genome-wide and candidate gene association study of placental abruption. AB - While available evidence supports the role of genetics in the pathogenesis of placental abruption (PA), PA-related placental genome variations and maternal placental genetic interactions have not been investigated. Maternal blood and placental samples collected from participants in the Peruvian Abruptio Placentae Epidemiology study were genotyped using Illumina's Cardio-Metabochip platform. We examined 118,782 genome-wide SNPs and 333 SNPs in 32 candidate genes from mitochondrial biogenesis and oxidative phosphorylation pathways in placental DNA from 280 PA cases and 244 controls. We assessed maternal-placental interactions in the candidate gene SNPS and two imprinted regions (IGF2/H19 and C19MC). Univariate and penalized logistic regression models were fit to estimate odds ratios. We examined the combined effect of multiple SNPs on PA risk using weighted genetic risk scores (WGRS) with repeated ten-fold cross-validations. A multinomial model was used to investigate maternal-placental genetic interactions. In placental genome-wide and candidate gene analyses, no SNP was significant after false discovery rate correction. The top genome-wide association study (GWAS) hits were rs544201, rs1484464 (CTNNA2), rs4149570 (TNFRSF1A) and rs13055470 (ZNRF3) (p-values: 1.11e-05 to 3.54e-05). The top 200 SNPs of the GWAS overrepresented genes involved in cell cycle, growth and proliferation. The top candidate gene hits were rs16949118 (COX10) and rs7609948 (THRB) (p-values: 6.00e-03 and 8.19e-03). Participants in the highest quartile of WGRS based on cross-validations using SNPs selected from the GWAS and candidate gene analyses had a 8.40-fold (95% CI: 5.8-12.56) and a 4.46-fold (95% CI: 2.94 6.72) higher odds of PA compared to participants in the lowest quartile. We found maternal-placental genetic interactions on PA risk for two SNPs in PPARG (chr3:12313450 and chr3:12412978) and maternal imprinting effects for multiple SNPs in the C19MC and IGF2/H19 regions. Variations in the placental genome and interactions between maternal-placental genetic variations may contribute to PA risk. Larger studies may help advance our understanding of PA pathogenesis. PMID- 25549362 TI - Population biology of Schistosoma mating, aggregation, and transmission breakpoints: more reliable model analysis for the end-game in communities at risk. AB - Mathematical modeling is widely used for predictive analysis of control options for infectious agents. Challenging problems arise for modeling host-parasite systems having complex life-cycles and transmission environments. Macroparasites, like Schistosoma, inhabit highly fragmented habitats that shape their reproductive success and distribution. Overdispersion and mating success are important factors to consider in modeling control options for such systems. Simpler models based on mean worm burden (MWB) formulations do not take these into account and overestimate transmission. Proposed MWB revisions have employed prescribed distributions and mating factor corrections to derive modified MWB models that have qualitatively different equilibria, including 'breakpoints' below which the parasite goes to extinction, suggesting the possibility of elimination via long-term mass-treatment control. Despite common use, no one has attempted to validate the scope and hypotheses underlying such MWB approaches. We conducted a systematic analysis of both the classical MWB and more recent "stratified worm burden" (SWB) modeling that accounts for mating and reproductive hurdles (Allee effect). Our analysis reveals some similarities, including breakpoints, between MWB and SWB, but also significant differences between the two types of model. We show the classic MWB has inherent inconsistencies, and propose SWB as a reliable alternative for projection of long-term control outcomes. PMID- 25549361 TI - The influence of promoter architectures and regulatory motifs on gene expression in Escherichia coli. AB - The ability to regulate gene expression is of central importance for the adaptability of living organisms to changes in their external and internal environment. At the transcriptional level, binding of transcription factors (TFs) in the promoter region can modulate the transcription rate, hence making TFs central players in gene regulation. For some model organisms, information about the locations and identities of discovered TF binding sites have been collected in continually updated databases, such as RegulonDB for the well-studied case of E. coli. In order to reveal the general principles behind the binding-site arrangement and function of these regulatory architectures we propose a random promoter architecture model that preserves the overall abundance of binding sites to identify overrepresented binding site configurations. This model is analogous to the random network model used in the study of genetic network motifs, where regulatory motifs are identified through their overrepresentation with respect to a "randomly connected" genetic network. Using our model we identify TF pairs which coregulate operons in an overrepresented fashion, or individual TFs which act at multiple binding sites per promoter by, for example, cooperative binding, DNA looping, or through multiple binding domains. We furthermore explore the relationship between promoter architecture and gene expression, using three different genome-wide protein copy number censuses. Perhaps surprisingly, we find no systematic correlation between the number of activator and repressor binding sites regulating a gene and the level of gene expression. A position-weight matrix model used to estimate the binding affinity of RNA polymerase (RNAP) to the promoters of activated and repressed genes suggests that this lack of correlation might in part be due to differences in basal transcription levels, with repressed genes having a higher basal activity level. This quantitative catalogue relating promoter architecture and function provides a first step towards genome-wide predictive models of regulatory function. PMID- 25549363 TI - The membrane-associated form of alpha(s1)-casein interacts with cholesterol-rich detergent-resistant microdomains. AB - Caseins, the main milk proteins, interact with colloidal calcium phosphate to form the casein micelle. The mesostructure of this supramolecular assembly markedly influences its nutritional and technological functionalities. However, its detailed molecular organization and the cellular mechanisms involved in its biogenesis have been only partially established. There is a growing body of evidence to support the concept that alpha(s1)-casein takes center stage in casein micelle building and transport in the secretory pathway of mammary epithelial cells. Here we have investigated the membrane-associated form of alpha(s1)-casein in rat mammary epithelial cells. Using metabolic labelling we show that alpha(s1)-casein becomes associated with membranes at the level of the endoplasmic reticulum, with no subsequent increase at the level of the Golgi apparatus. From morphological and biochemical data, it appears that caseins are in a tight relationship with membranes throughout the secretory pathway. On the other hand, we have observed that the membrane-associated form of alpha(s1) casein co-purified with detergent-resistant membranes. It was poorly solubilised by Tween 20, partially insoluble in Lubrol WX, and substantially insoluble in Triton X-100. Finally, we found that cholesterol depletion results in the release of the membrane-associated form of alpha(s1)-casein. These experiments reveal that the insolubility of alpha(s1)-casein reflects its partial association with a cholesterol-rich detergent-resistant microdomain. We propose that the membrane associated form of alpha(s1)-casein interacts with the lipid microdomain, or lipid raft, that forms within the membranes of the endoplasmic reticulum, for efficient forward transport and sorting in the secretory pathway of mammary epithelial cells. PMID- 25549364 TI - Cotinine and polycyclic aromatic hydrocarbons levels in the amniotic fluid and fetal cord at birth and in the urine from pregnant smokers. AB - Cigarette smoking during pregnancy has several impacts on fetal development, including teratogenic effects. The objective of this study was to assess whether the toxic substances (cotinine and polycyclic aromatic hydrocarbons) found in pregnant smokers are transmitted to their fetuses. The outcomes were analyzed measuring cotinine and 1-hydroxypyrene in the amniotic fluid and maternal urine, benzopyrene and cotinine in the umbilical cord blood. Through a controlled cross sectional design, 125 pregnant women were selected and classified according to their smoking status: 37 current smokers, 25 passive smokers and 63 non-smokers (controls). We performed high-performance liquid chromatography to measure substances' concentrations. A post-hoc Tukey's test was used to analyze the differences between the groups. All variables were significantly different between controls and smokers. The mean ratios between the concentration of cotinine in smokers compared to controls were as follows: 5.9 [2.5-13.5], p<0.001 in the urine; 25 [11.9-52.9], p<0.001 in the amniotic fluid; and 2.6 [1.0-6.8], p = 0.044 in the umbilical cord blood. The mean ratios of 1-hydroxypyrene concentration between smokers and controls were 7.3 [1.6-29.6], p = 0.003 in the urine and 1.3 [1.0-1.7], p = 0.012 in the amniotic fluid, and of benzopyrene in umbilical cord blood was 2.9 [1.7-4.7], p<0.001. There were no significant differences between controls and passive smokers. When comparing the three groups together, there were statistical differences between all variables. Thus, the fetuses of pregnant smokers are exposed to toxic and carcinogens substances. To our knowledge, this is the first study to measure 1-hydroxypyrene in the amniotic fluid and benzopyrene in umbilical cord blood by high-performance liquid chromatography when considering pregnant women in relation to smoking exposure only. PMID- 25549365 TI - Molecular characterization of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae in Ontario, Canada, 2008-2011. AB - Due to the lack of detailed reports of Klebsiella pneumoniae carbapenemase (KPC) producing enterobacteria in Ontario, Canada, we perform a molecular characterization of KPC-producing Enterobacteriaceae submitted to the provincial reference laboratory from 2008 to 2011. Susceptibility profiles were accessed by E-test. Molecular types of isolates were determined by pulse-field gel electrophoresis (PFGE) and multilocus sequence typing. Screening of beta lactamase genes was performed by multiplex PCR and alleles were identified by DNA sequencing. The genetic platform of blaKPC gene was analyzed by PCR. Plasmid replicons were typed using PCR-based typing approach. KPC-plasmids were also evaluated by S1 nuclease-PFGE and Southern blot. Thirty unique clinical isolates (26 Klebsiella pneumoniae, 2 Enterobacter cloacae, 1 Citrobacter freundii and 1 Raoultella ornithinolytica) were identified as blaKPC positive: 4 in 2008, 3 in 2009, 10 in 2010 and 13 in 2011. The majority exhibited resistance to carbapenems, cephalosporins and fluoroquinolones and two isolates were also resistant to colistin. The isolates harbored blaKPC-2 (n = 23) or blaKPC-3 (n = 7). blaTEM-1 (n = 27) was commonly detected and occasionally blaOXA-1 (n = 3) and blaCTX-M-15 (n = 1). As expected, all K. pneumoniae isolates carried blaSHV-11. blaKPC genes were identified on Tn4401a (n = 20) or b (n = 10) isoforms, on plasmids of different sizes belonging to the incompatibility groups IncFIIA (n = 19), IncN (n = 3), IncI2 (n = 3), IncFrep (n = 2) and IncA/C (n = 1). The occurrence of KPC beta-lactamase in Ontario was mainly associated with the spread of the K. pneumoniae clone ST258. PMID- 25549366 TI - Diffusion tensor magnetic resonance imaging of the pancreas. AB - PURPOSE: To develop a diffusion-tensor-imaging (DTI) protocol that is sensitive to the complex diffusion and perfusion properties of the healthy and malignant pancreas tissues. MATERIALS AND METHODS: Twenty-eight healthy volunteers and nine patients with pancreatic-ductal-adenocacinoma (PDAC), were scanned at 3T with T2 weighted and DTI sequences. Healthy volunteers were also scanned with multi-b diffusion-weighted-imaging (DWI), whereas a standard clinical protocol complemented the PDAC patients' scans. Image processing at pixel resolution yielded parametric maps of three directional diffusion coefficients lambda1, lambda2, lambda3, apparent diffusion coefficient (ADC), and fractional anisotropy (FA), as well as a lambda1-vector map, and a main diffusion-direction map. RESULTS: DTI measurements of healthy pancreatic tissue at b-values 0,500 s/mm2 yielded: lambda1 = (2.65+/-0.35)*10-3, lambda2 = (1.87+/-0.22)*10-3, lambda3 = (1.20+/-0.18)*10-3, ADC = (1.91+/-0.22)*10-3 (all in mm2/s units) and FA = 0.38+/ 0.06. Using b-values of 100,500 s/mm2 led to a significant reduction in lambda1, lambda2, lambda3 and ADC (p<.0001) and a significant increase (p<0.0001) in FA. The reduction in the diffusion coefficients suggested a contribution of a fast intra-voxel-incoherent-motion (IVIM) component at b<=100 s/mm2, which was confirmed by the multi-b DWI results. In PDACs, lambda1, lambda2, lambda3 and ADC in both 0,500 s/mm2 and 100,500 s/mm2 b-values sets, as well as the reduction in these diffusion coefficients between the two sets, were significantly lower in comparison to the distal normal pancreatic tissue, suggesting higher cellularity and diminution of the fast-IVIM component in the cancer tissue. CONCLUSION: DTI using two reference b-values 0 and 100 s/mm2 enabled characterization of the water diffusion and anisotropy of the healthy pancreas, taking into account a contribution of IVIM. The reduction in the diffusion coefficients of PDAC, as compared to normal pancreatic tissue, and the smaller change in these coefficients in PDAC when the reference b-value was modified from 0 to 100 s/mm2, helped identifying the presence of malignancy. PMID- 25549367 TI - Using the Physician Global Assessment in a clinical setting to measure and track patient outcomes. AB - IMPORTANCE: In dermatology, the development of objective, standardized quality measures that can be used in a clinical setting is important to be able to respond to the needs of payers and credentialing and licensure bodies and to demonstrate dermatologic value. OBJECTIVE: To examine the feasibility of using Physician Global Assessment (PGA) scores to collect and track patient acne and psoriasis outcomes over time. DESIGN, SETTING, AND PARTICIPANTS: The PGA severity scores were included on physicians' billing sheets for patients with acne and psoriasis seen at a tertiary care center outpatient dermatology clinic from June 2011 through October 2012. A subset of patients from 5 clinics completed Patient Global Assessments (PtGAs) between November 2011 and May 2012. Thirty dermatology clinicians saw a total of 2770 patients with acne and 1516 patients with psoriasis in clinic, recording PGA scores for each patient. The PtGA scores were collected from 52 and 103 patients with acne and psoriasis, respectively, within the larger sample. MAIN OUTCOMES AND MEASURES: Longitudinal PGA severity scores were collected for acne and psoriasis. The PGA severity scores were analyzed over time, with the hypothesis that patient scores for both acne and psoriasis would improve between the initial and follow-up visits. The PtGA scores from a subset of clinics and dates were compared with PGA scores to assess within-clinic reliability, with the hypothesis that there would be good agreement between clinician and patient assessments. RESULTS: New patient PGA outcomes showed considerable improvement over time. At 3-month follow-up, 14.6% of the acne cohort was graded as effectively clear, compared with 2.1% at baseline (P < .001). Similarly, at 3-month follow-up, 22.3% of the psoriasis cohort was graded as effectively clear, compared with 3.1% at baseline (P < .001). Additionally, interobserver agreement between PGA and PtGA scores was good (acne, kappa = 0.68; psoriasis, kappa = 0.70). CONCLUSIONS AND RELEVANCE: The PGA can be readily incorporated into practice to track patient acne and psoriasis outcomes over time, representing an opportunity for dermatologists to evaluate performance and validate practice guidelines. PMID- 25549368 TI - [New non-pharmacological treatment methods in heart failure]. AB - The incidence of chronic heart failure (CHF) increases with the aging of the population and with the improvement in survival of patients with hypertension, coronary heart disease and diabetes, diseases which constitute the most common causes for the development of CHF. Despite the significant improvement in the treatment of patients with CHF, mortality in recent years has improved slightly. The primary treatment method for chronic heart failure is pharmacotherapy, but it has limitations. The existing data encourages to look for new treatment methods for CHF, replacing or enhancing traditional ones while constituting a low nuisance for patients. New non-pharmacological methods, including therapies based on the use of stem cells, molecular therapy, modern devices supporting the heart such as cardiac contractility modulation, spinal cord stimulation, carotid sinus nerve stimulation, cervical and intracardiac atrioventricular nodal vagal stimulation, implantable monitoring devices and wearable cardioverter defibrillator or the treatment of comorbid diseases such as hypertension and sleep dis- orders could be of particular importance. PMID- 25549369 TI - Oral health: Risk definition in halitosis. PMID- 25549370 TI - Caregiving provided to elderly people. PMID- 25549371 TI - [The new face of diagnostic microbiology]. PMID- 25549372 TI - [Microbiological diagnosis of pneumonia]. AB - Pneumonia is an importance cause of mortality and morbidity in adults. Two types of pneumonia are defined: community-acquired and nosocomial pneumonia with their corresponding etiology such as pneumococci or Haemophilus influenzae and Pseudomonas or enterobacteriaceae, respectively. However, the reality is more complex with aspiration pneumonia, pneumonia in immunocompromised patient, and pneumonia in ventilated patients. Culture in the case of nosocomial pneumonia is especially important to obtain the antibiotic susceptibility of the infectious agent and to adjust therapy. Moreover for immunocompromised patients, the differential diagnosis is much wider looking for viruses, filamentous fungi and Pneumocystis can be very informative, using new molecular assays. PMID- 25549373 TI - [Diagnostic approach of intracellular bacteria and fastidious microorganisms]. AB - Obligate or facultative intracellular bacteria are fastidious organisms that do not or poorly grow on conventional culture media. Some of them may be the cause of frequent and potentially severe infections, such as tuberculosis (Myco- bacterium tuberculosis), community-acquired respiratory infections (Legionella spp., Mycoplasma pneumoniae, Chlamydia pneumoniae) or blood culture-negative endocarditis (Coxiella burnetii, Bartonella spp., Tropheryma whipplei). The objective of this paper is to provide a comprehensive summary of the available and recommended diagnostic tests for the detection of these fastidious organisms in clinical practice. PMID- 25549374 TI - [Rapid tests during respiratory infection: an aid to non-prescription of antibiotics? ]. AB - Due to overuse, we are about to reach the end of the antibiotic era. Each of us is responsible to limit their usage to a minimum. Respiratory infections are the first cause of antibiotic prescriptions. The use of new simple tests available at the bedside can be very useful in this context. The development of sophisticated molecular diagnostic tools, such as "multiorganism" panels, may revolutionize our approach to respiratory infections. The key will be to interpret the results correctly, with due consideration of the statement, "Treat patients, not lab results". PMID- 25549375 TI - [ESBL and carbapenemases in Enterobacteriaceae]. AB - Carbapenemase-producing enterobacteria (CPE) spread all over the world during the last years, causing serious infections with increasing frequency. Very few new drugs active against CPE are expected to be clinically available. Studies summarized in this review show that there is yet room to improve our therapeutic approaches, in the treatment of infections due to CPE. PMID- 25549376 TI - [Which benefits for the clinician to implement MALDI-TOF/MS in the bacteriology laboratory?]. AB - Mass spectrometry (MALDI-TOF/MS) is a recent technology especially adapted to identify microbial pathogens. It has rapidly established itself as a must for most medical bacteriology laboratories. Its ease of use and speed of execution typically permit providing pathogen identification one day earlier to the clinicians. MALDI-TOF/MS facilitates identification of filamentous fungi and mycobacteria that require particular lab expertise when using conventional methods. This paper highlights the multiple advantages that MALDI-TOF/MS can bring to the physicians in their practice. PMID- 25549377 TI - [Bacterial genomics and metagenomics: clinical applications and medical relevance]. AB - New sequencing technologies provide in a short time and at low cost high amount of genomic sequences useful for applications such as: a) development of diagnostic PCRs and/or serological tests; b) detection of virulence factors (virulome) or genes/SNPs associated with resistance to antibiotics (resistome) and c) investigation of transmission and dissemination of bacterial pathogens. Thus, bacterial genomics of medical importance is useful to clinical microbiologists, to infectious diseases specialists as well as to epidemiologists. Determining the microbial composition of a sample by metagenomics is another application of new sequencing technologies, useful to understand the impact of bacteria on various non-infectious diseases such as obesity, asthma, or diabetes. Genomics and metagenomics will likely become a specialized diagnostic analysis. PMID- 25549378 TI - [Prosthetic hip infection due to Listeria monocytogenes: review of the literature and case report]. AB - With the ageing of the population, articular prosthetic replacements are becoming more and more frequent. One of the most feared complications is prosthetic infection, mostly due to bacteria of the cutaneous flora. Listeria monocytogenes is rarely the cause. This paper describes the management of a hip prosthetic infection due to Listeria monocytogenes. The patient was cured with antimicrobial therapy and a two-stage exchange. This case report creates an opportunity to review the literature in the aim of determining the risk factors and the optimal care. PMID- 25549379 TI - [Polycythemia, standardized disease?]. PMID- 25549380 TI - [In medicine: facts and what is conviction or empathy]. PMID- 25549382 TI - [Towards a blood screening for bronchopulmonary cancer?]. PMID- 25549381 TI - [October 2014, distant echoes of the Ebola epidemic]. PMID- 25549383 TI - [Severe community-acquired pneumonia hospitalized--recent data confirm the interest of combined therapy]. PMID- 25549384 TI - [Medical confidentiality in prison: reactions to the bill]. PMID- 25549385 TI - [Vaud tries to control the acquisition of expensive medical equipment]. PMID- 25549386 TI - [Ebola or the paradoxical memory of colonial medicine]. PMID- 25549387 TI - [ORALMEDIC(r) for treatment of aphthous stomatitis--possible side effects with repeated applications]. AB - ORALMEDIC(r) (HybenX, Epien Medical Inc., Minneapolis, MN, USA) is a relatively recent commercial agent designated for the treatment of recurrent aphthous stomatitis (RAS). It has the potential to safely and effectively reduce pain associated with RAS. We present two patients who used ORALMEDIC(r) to reduce pain caused by RAS lesions. Both patients developed side effects presenting as deep ulcerations with a necrotic base at the location where ORALMEDIC(r) has been repeatedly applied as pain did not diminish after the first application. One patient used ORALMEDIC(r) several times on the same lesion. However the other patient followed the manufacturer instructions when he successively used ORALMEDIC(r) stick twice over the same lesion. Patients were treated with systemic antibiotics and local antiseptic agents. The healing process of the ulcers was slow and has completed its course within six weeks. It is suggested that when dental surgeons recommend ORALMEDIC(r), they should emphasize the importance of using this agent according to the manufacturer's instructions in order to minimize the risk for side effects. PMID- 25549388 TI - [Pseudo-color filter in two-dimensional imaging in dentistry]. AB - Most digital systems that are currently used in two-dimensional imaging in dentistry provide opportunities for different image processing filters. One possible means of enhancing digital radiographic image is pseudocoloring (i.e., color conversion of gray-scale images). Recently, this method has become widely used in digital radiology. The human eye is more sensitive to differences in color than to differences in shades of gray. Theoretically, converting a gray scale intensity level of a digital image into colors could enhance the radiographic information. There have been some studies that applied pseudocoloring of digital radiographic images for the detection of caries and periodontal defects. However, thus far, this method failed to show a significantly improved ability for the detection of these lesions. Further investigations are necessary in order to develop specific algorithms that will increase the validity of pseudocoloring in two-dimensional imaging in dentistry. PMID- 25549389 TI - The Minamata convention on mercury and dental amalgam. PMID- 25549390 TI - Looking forward. The accomplishments of the American College of Surgeons for 2014. PMID- 25549391 TI - Presidential address: Achieving our personal best--Back to the future of the American College of Surgeons. PMID- 25549392 TI - Executive director's annual report. PMID- 25549393 TI - Georgia coalition develops bariatric surgery pilot project. PMID- 25549394 TI - Liability reform, scope of practice, trauma topped state legislative agenda in 2014. PMID- 25549395 TI - Hugh Agnew Gamble, MD, FACS: a legacy to the college. PMID- 25549396 TI - Updated compendium offers strategies to prevent health care-associated infections. PMID- 25549397 TI - NTDBA data points: Go before you go: bladder injuries. PMID- 25549398 TI - Dr. Adolph Bushell: a New England treasure & a Renaissance man for all seasons. AB - The landscape of New England lost a treasure on July 26, 2013 in the person of Dr. Adolph Bushell. He was a man for all seasons who dedicated his life to helping people around the world in meaningful ways. Dr. Bushell was 90 years old at the time of his passing, having spent over 60 of those years in the service of others; primarily through his dental expertise and leadership, but also through his amazing humanitarian efforts and lifetime of volunteerism for which he received numerous awards and recognition. PMID- 25549399 TI - The nitrous oxide "dream" of Cora Gray: a dental anesthesia story of 1884. AB - In the September 1884 issue of Frank Leslie's Popular Monthly magazine, a fictional dramatic short story was published concerning the dental use of nitrous oxide. Entitled, "Cora Gray," it was written by the well-known American journalist and poet John Whittaker Watson (1815-1848), who authored hundreds of sentimental, tragic and dramatic poems, serials and stories concerning the destitute lives and deaths of downtrodden young women of that time. His greatest poetic effort, "Beautiful Snow," (1869) tells of a young prostitute who freezes to death in a snow bank. Watson, born in New York City, was educated at the University of New York, where he studied medicine. He also developed and used his skills as an engraver, journalist and writer. Watson obviously based his imaginative narrative on his medical knowledge of nitrous oxide and its physical and psychological side effects when inhaled. The story centers around the dreamlike romantic experiences of a 19-year-old female dental patient while she is under the effects of this gas. It explicitly depicts the administration of nitrous oxide and the resulting erotic visions and hallucinations that the young patient experiences. We make reference to other cautionary scientific writings from the late 1800s, in order to point out and clarify the potentially negative repercussions of nitrous oxide when administered to female dental patients without the presence of a third party. The ethics and propriety of anesthesia administration remain as perennial questions in dentistry to this day. PMID- 25549400 TI - On the management of root canals in teeth that exhibit a draining "fistulous" tract. AB - The clinical management of teeth with necrotic pulps, with and without draining fistulous tracts, has been the subject of a wide range of personal opinions and techniques for well over a century. Fortunately, prior to the advent of the focal infection theory in the early 1900s, dental clinicians made every attempt to treat and maintain these teeth as opposed to wholesale extraction. While the treatment approaches by some may have been questionable, others claimed great success. The success claimed was empirically-based, but those that achieved this goal used methods and techniques not dissimilar to present-day practices. However, the proponents of the focal infection theory failed to consider these achievements prior to their advocacy of extracting all teeth with necrotic pulps or those that demonstrated an active infection. This paper highlights some of the prevailing concepts from opposing treatment regimens in the late 1800s in which extensive efforts were made to retain teeth. PMID- 25549401 TI - "They'll Do it Every Time"--four early dental Comic strips by Jimmy Hatlo. PMID- 25549402 TI - John G.C. Adams: father of Dental Public Health in Canada. AB - John Gennings Curtis Adams (1839-1922), Canada's first resident dental missionary, was the father of Dental Public Health in Canada. He established, personally funded and operated the first free dental hospital in North America for poor children and their mothers in Toronto from 1872, three years before the founding of The Hospital for Sick Children; he later became their first dentist of record. He was a visionary zealot for prevention of decay, dental education, and treatment over extraction. Dr. Adams understood that neither parents (rich or poor) nor physicians were aware of the extent of pathosis present in children's mouths. He petitioned individuals, lobbied politicians and unions and pressured dental organizations on the importance of twice-annual school inspections to demonstrate disease so that parents would seek care for their children. He wanted government-funded dental hospitals like his own to treat those who could not afford care. He realized his objectives and his reforms to prevent suffering, as Toronto school inspections began in 1911 and Toronto's first publicly-funded free dental clinic opened in 1913. He was Canada's first dental philanthropist and a visionary for preventive dentistry. PMID- 25549403 TI - Dental Trade Cards XLI. Henri Gerbault. PMID- 25549404 TI - Dental Postcards LVI. A bad quarter-hour. PMID- 25549406 TI - Dengue pathogenesis: a disease driven by the host response. AB - Dengue viruses cause mild disease in the majority of infected individuals. In most cases, the disease is characterised by fever, headache, pain behind the eyes, muscle ache, joint pains, vomiting and diarrhoea. In a low percentage of patients, bleeding and loss of plasma (haemorrhage and plasma leakage) may occur. The hyper-permeability syndrome results in plasma leakage and, if the compensatory mechanisms of the body fail to control the plasma leakage or if medical intervention is late, shock may set in. Profound shock will subsequently lead to acidic blood (metabolic acidosis) and development of disseminated intravascular coagulation (DIC). During DIC multiple micro thromboses occur, leading to organ failure. The mechanisms governing pathogenesis of these forms of severe disease are not clear. High amounts of virus in the blood are believed to cause vascular fragility which, together with infection of endothelial cells and high levels of cytokines and other soluble mediators, may result in bleeding. In the absence of a correlation between the amount of virus in the blood and disease severity, it is likely that response to infection is an important cause of disease. The aberrant immune response to infection is believed to result in a cytokine storm, defined as an imbalance between cytokines driving an inflammation (pro-inflammatory) and those silencing an inflammation (anti-inflammatory). Several lines of evidence indicate that displacement of viral genotype and host genetic background are key factors driving the production of a cytokine storm. Several cytokines are known to induce apoptosis, a form of cell suicide (cause of haemorrhage), and/or affect adherens junctions (cause permeability) in vitro. Whether these cytokines may have such effects in vivo remains to be established. PMID- 25549405 TI - [Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2010 and March 2011]. AB - Bacteria isolated from surgical infections during the period from April 2010 to March 2011 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 631 strains including 25 strains of Candida spp. were isolated from 170 (81.7%) of 208 patients with surgical infections. Four hundred and twenty two strains were isolated from primary infections, and 184 strains were isolated from surgical site infection. From primary infections, anaerobic Gram-negative bacteria were predominant, followed by aerobic Gram-negative bacteria, while from surgical site infection aerobic Gram-positive bacteria were predominant, followed by anaerobic Gram-negative bacteria. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus spp. such as Enterococcus faecalis, Enterococcus faecium, and Enterococcus avium was highest, followed by Streptococcus spp. such as Streptococcus anginosus and Staphylococcus spp. such as Staphylococcus aureus, in this order, from primary infections, while Enterococcus spp. such as E. faecalis and E. faecium was highest, followed by Staphylococcus spp. such as S. aureus from surgical site infection. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Pseudomonas aeruginosa in this order, and from surgical site infection, E. coli and R aeruginosa were most predominantly isolated, followed by E. cloacae and K. pneumoniae. Among anaerobic Gram-positive bacteria, the isolation rates of Parvimonas micra, Eggerthella lenta, Streptococcus constellatus, Gemella morbillorum, and Collinsella aerofaciens were the highest from primary infections, and the isolation rate from surgical site infection was generally low. Among anaerobic Gram-negative bacteria, the isolation rate of Bilophila wadsworthia was the highest from primary infections, followed by, Bacteroides fragilis and Bacteroides ovatus, and from surgical site infection, B. fragilis was most predominantly isolated, followed by Bacteroides thetaiotaomnicron, in this order. In this series, vancomycin-resistant MRSA (methicillin-resistant S. aureus), vancomycin-resistant Enterococcus spp. and multidrug-resistant P. aeruginosa were not observed. PMID- 25549407 TI - Antibodies as an unlimited source of anti-infective, anti-tumour and immunomodulatory peptides. AB - Antibodies (Abs) are emerging as an important class of therapeutic agents for the treatment of various human diseases, often conjugated to drugs or toxic substances. In recent years, the incidence of cancer and infectious diseases has increased dramatically making it imperative to discover new effective therapeutic molecules. Among these, small peptides are arousing great interest. Synthetic peptides, representative of variable and constant region fragments of Abs, were proved to exert in vitro, ex vivo and/or in vivo anti-microbial, anti-viral, anti tumour and/or immunomodulatory activities, mediated by different mechanisms of action and regardless of the specificity and isotype of the Ab. Some of these synthetic peptides possess the ability to spontaneously and reversibly self assemble in an organised network of fibril-like structure. Ab fragments may represent a novel model of targeted anti-infective and anti-tumour auto delivering drugs. PMID- 25549408 TI - Overcoming "the Valley of Death". AB - On a global level there are major challenges arising from climate change, resource use and changing age demographics. These issues have created a global marketplace for novel innovative products and solutions which can help to combat and overcome these challenges which have created significant commercial opportunities for companies, particularly for small and medium size enterprises or SMEs. Companies most likely to take advantage of these opportunities will be those which can innovate in a timely manner. Innovation significantly contributes to higher productivity and economic growth, and is core to a company's competitiveness within often challenging marketplaces. However, many factors can stifle innovation. Companies can struggle to identify finance for early-stage development, the returns can be difficult to predict, and the innovation 'landscape' is often complex and unclear. This brief review describes some of the main issues with commercialising innovative ideas and provides guidance with respect to the often complicated funding landscape both on a National and European level. PMID- 25549409 TI - Carbon dioxide as a polymer feedstock. AB - This review describes the progress made over the last 45 years since the seminal paper by Inoue's group in Tokyo on the utilisation of CO2 as a component of a polymerising system. This approach, rapidly taken up by others, focused initially on the copolymerisation of CO2 with an epoxide to yield a polycarbonate of high molecular weight. The initial catalysts for this process were based on organozinc compounds; these were extended to zinc phenoxides and then a series of metal centred compounds, particularly metal porphyrins where the central metal was aluminium, cobalt, chromium, copper, manganese and various lanthanides. Later work developed in the direction of producing stereoregular polymers. The most recent advance has concerned the copolymerisation of CO2 with butadiene via a lactone intermediate; the butadiene and CO2 are initially combined with a Pd centred catalyst to give the lactone which is then subjected to radical polymerisation. The significance of this work is that it offers a way of utilising what is normally a waste and environmentally hazardous product of many processes to synthesise a useful product. PMID- 25549410 TI - Remembrances of a UK scientist in Russia. 1966-67. AB - David Phillips was a post-doctoral fellow on a Fulbright Scholarship at the University of Texas, Austin, where he acted as host and chauffeur to one of the IUPAC representatives, the Soviet delegate, Professor Nikolai N. Kondratiev, then Deputy Director of the Institute of Chemical Physics in Moscow. During the course of ferrying him around, Nikolai asked .David about his plans after his two-year stay in Texas, David replied that he had intended to return to Europe, but was looking for one more year as a post-doctoral fellow before seeking an academic position probably back in the UK Nikolai invited him to spend time in his Institute, and eventually, through the Royal Society/Academy of Sciences Exchange programme, this came to pass. Professor Phillips now describes his experiences, both cultural and scientific, in Russia during 1966-67 where he learned much about the Russian people, and also about himself. He returned with a taste for good music, Russian literature and language, and travel generally, and for taking chances in life. PMID- 25549411 TI - Cafe Scientifique. AB - Every month, in 700 or so bars, cafes, pubs, teahouses, shopping centres, community halls, art galleries, libraries, theatres, museums, bookshops ... and a blood donation centre, 40 or so people meet to have a conversation. A conversation that happens to be about science and technology, rather than soap operas or football; this is Cafe Scientifique. PMID- 25549412 TI - Rosetta arrives at comet destination. PMID- 25549413 TI - Blood is sweet for vampire bats. PMID- 25549415 TI - Tornado strength and frequency linked to climate change. PMID- 25549414 TI - Mercury in the global ocean. PMID- 25549417 TI - The incredible shrinking dinosaurs. . . PMID- 25549416 TI - Growing GI cells may lead to personalised treatments. PMID- 25549418 TI - I am TNA. PMID- 25549419 TI - From the President. PMID- 25549420 TI - From the executive director. PMID- 25549421 TI - Stepping outside ourselves to stand on common ground. PMID- 25549422 TI - Is there a limit? Becoming/being an APRN. PMID- 25549423 TI - Nurse-midwifery history, practice and education. PMID- 25549424 TI - Where we were 27 years ago and where we are today. PMID- 25549425 TI - From the bedside to the boardroom: preparing Tennessee's next generation of nurse leaders. PMID- 25549426 TI - Nursing's golden ages. PMID- 25549428 TI - [Most influential and overlooked "conflict of interest" for all clinicians is practice of medicine itself]. PMID- 25549427 TI - The role of the APRN in addressing prescription drug abuse in Tennessee. PMID- 25549429 TI - [Presidential address 2014]. PMID- 25549430 TI - [Resent status of informed consent in cardiovascular surgery]. PMID- 25549431 TI - [Informed consent: coronary artery bypass grafting]. AB - Coronary artery bypass graft surgery (CABG) is well-documented procedure. Despite the increased prevalence of percutaneous coronary intervention (PCI), surgical revascularization will continue to have a major role in patients with coronary artery disease. As shown in previous clinical studies, physicians can provide important information about risk-adjusted outcomes to patients. A number of databases have been used to develop risk models for predicting morbidity and mortality in patients undergoing CABG. Patients must make a choice between CABG and PCI based on physicians' explanations. Major trials demonstrated a marked survival benefit from CABG among those patients at high risk of death from the disease itself as defined by the severity of angina, number of diseased vessels, and left ventricular function. However, it is not clear that patients always receive the correct information on whether CABG or PCI is the more appropriate procedure. The initial informed consent should be obtained using the relevant guidelines by an independent adviser. PMID- 25549432 TI - [Informed consent for patients undergoing surgery for ischemic cardiomyopathy]. AB - The prognosis of patients with ischemic cardiomyopathy after medical treatment remains poor, despite advances in various therapeutic strategies. In addition to the poorer prognosis, they face higher operative risk, and complex, unestablished operative procedures should be addressed when obtaining preoperative informed consent from patients with ischemic cardiomyopathy. Although the established indications for revascularization in patients with ischemic heart failure pertain to those with angina and significant coronary artery disease, the management of patients with ischemic heart failure without angina is a challenge because of the lack of evidence in this population. The possibility of combining myocardial revascularization with surgical ventricular reconstruction (SVR) to reverse left ventricular remodeling or with mitral valve plasty to repair the incompetence of mitral valve coaptation has been examined in many trials, although little difference in the long-term outcomes between the simple revascularization and the combined procedure groups have been observed. The therapeutic guidelines for patients with ischemic cardiomyopathy state that choosing to add SVR and/or mitral surgery to revascularization should be based on a precise, careful evaluation and should be performed only by surgeons with a high level of surgical expertise. PMID- 25549433 TI - [Informed consent in valvular diseases]. AB - Informed consent has two aspects. First, we must give patients sufficient, precise information on the nature of their disease, natural history, possible choices of treatment, and risks of the treatment to help them make their own decisions. The estimated risks should be based on a database, not on personal impressions or limited experience. In choosing the type of prosthetic valve in young or middle-aged patients, unbiased information based on guidelines should be presented. The second aspect of informed consent is its role as a contract for providing medical service. Estimated in-hospital mortality and major morbidities should be clarified in percentages on the consent form as confirmation of understanding. PMID- 25549434 TI - [Informed consent for aortic pathology]. AB - Obtaining informed consent from patients and their families before surgery, particularly for aortic pathology, is a necessary, and very important, step. This is because, although the risk of death from asymptomatic disease is underestimated in many cases, surgery for aortic pathology is generally associated with higher risks of mortality and morbidity than that in other fields. The importance of informed consent is the same in principle even in emergency cases. The surgeon must faithfully provide accurate medical information to the patient and family members, including a summary of the patient's condition, the purposes and necessity of treatment, alternatives, details of the procedure, risks, and possible postoperative complications. Extra consideration should be given to offering explanations at a level appropriate for the individual patient, according to factors such as age-group, philosophy, and comprehension ability, to ensure that patients fully understand and are in a position to make a decision of their own volition. The process of giving information and obtaining informed consent offers a prime opportunity to build a strong surgeon-patient relationship. PMID- 25549435 TI - [Informed consent for the Maze Procedure for atrial fibrillation]. AB - It is important to explain the benefits and risks of surgery thoroughly to patients and their families. This paper describes the benefits and risks of the Maze procedure for atrial fibrillation (AF). The purpose of the Maze procedure is the restoration of sinus rhythm from AF, recovery of cardiac function by atrial contraction, and prevention of stroke. The AF cure ratio is 70-90% after the Maze procedure. It was reported that atrial function improves due to atrial contraction after surgery, and the risk of a stroke is reduced to about 2-4 events per 1,000 patients per year after surgery. On the other hand, bleeding is the most common complication after the Maze procedure. The use of alternative surgical ablation devices instead of the cut-and-sew technique decreases the risk of bleeding. Pacemakers are implanted in 5-10% of patients after the Maze procedure due to sick sinus syndrome. In approximately 40% of patients, transient AF occurs during the first month after surgery. However, the addition of the Maze procedure to cardiac surgery for structural heart disease does not increase the surgical risk. PMID- 25549437 TI - [Importance of perioperative nutritional management]. PMID- 25549436 TI - [Informed consent in congenital defect heart surgery]. AB - In pediatric cardiac surgery, informed consent is often obtained from the patient's parents. The parents are commonly under great stress due to being in a situation where they have to make the important decision of whether their child will undergo cardiac surgery. Cardiac surgery does not necessarily determine the patient's prognosis if he or she has other organ anomalies or systemic diseases. In such cases, communication among the cardiac surgeon, pediatrician, and family becomes even more crucial. In pediatric cardiac surgery, it is important to obtain informed consent with adequate explanations, an understanding of the parents' stressful situation, and knowledge of the patient's background. In this article, we introduce two examples of obtaining informed consent for two common pediatric cardiac operations, atrial septal defect closure and ventricular septal defect closure. PMID- 25549438 TI - [Nutritional therapy for early recovery after surgery]. PMID- 25549439 TI - [What we can learn from a case of medical malpractice--a patient hospitalized to improve overall condition attempted suicide by jumping off a 4-story building in the middle of the night, but the defendant hospital was denied negligence of inpatient management]. PMID- 25549440 TI - [Tip and pitfalls in the operation of the surgery for pediatric ulcerative colitis]. PMID- 25549442 TI - [Role of nurse practitioners in the subacute and geriatric care]. PMID- 25549443 TI - [An opinion for a gender-equal society of surgeons]. AB - The number of female surgeon is continuously increasing, while the total number of surgeon is decreasing. The author has faced many difficulties while working as a pediatric surgeon and a mother of three children. Those difficulties were caused by the traditional sexual role in our society and by a fixed idea that the priority for a surgeon should be his or her profession. Here, the author addressed some suggestions which could lead the society of surgeons to a gender equal one, and could make surgery a great appeal to female surgeons and to the young generations which consider private life as important as their professions as well. Suggestions include a change the relationship between a female surgeon and her partner, a supplement of surgeons so that hospitals could change the traditional system of surgery. The author proposed to increase female managers intentionally, so that the sense of sexual difference would be diminished and proper evolution of the society would be achieved. PMID- 25549444 TI - Models at work--models in decision making. PMID- 25549445 TI - Virtually expert: modes of environmental computer simulation modeling. AB - This paper challenges three assumptions common in the literature on expertise: that expertise is linearly derived from scientific knowledge; that experts always align with the established institutional order; and that expertise is a property acquired by individuals. We criticize these ideas by juxtaposing three distinct expert practices involved with flood risk management in England. Virtual engineering is associated with commercial consultancy and relies on standardized software packages to assess local flood inundation. Mathematical experimentation refers to academic scientists creating new digital renderings of the physical dynamics of flooding. Participatory modeling denotes research projects that aim to transform the relationships between experts and local communities. Focusing on different modes of modeling we contribute an analysis of how particular models articulate with specific politics of knowledge as experts form relationships with flood risk management actors. Our empirical study also shows how models can contribute to re-distribution of expertise in local flood risk management. PMID- 25549446 TI - Dissolving decision making? Models and their roles in decision-making processes and policy at large. AB - This article studies the roles three science-based models play in Dutch policy and decision making processes. Key is the interaction between model construction and environment. Their political and scientific environments form contexts that shape the roles of models in policy decision making. Attention is paid to three aspects of the wider context of the models: a) the history of the construction process; b) (changes in) the political and scientific environments; and c) the use in policy processes over longer periods of time. Models are more successfully used when they are constructed in a stable political and scientific environment. Stability and certainty within a scientific field seems to be a key predictor for the usefulness of models for policy making. The economic model is more disputed than the ecology-based model and the model that has its theoretical foundation in physics and chemistry. The roles models play in policy processes are too complex to be considered as straightforward technocratic powers. PMID- 25549447 TI - Nicolaus Taurellus on forms and elements. AB - This article examines the conception of elements in the natural philosophy of Nicolaus Taurellus (1547-1606) and explores the theological motivation that stands behind this conception. By some of his early modern readers, Taurellus may have been understood as a proponent of material atoms. By contrast, I argue that considerations concerning the substantiality of the ultimate constituents of composites led Taurellus to an immaterialist ontology, according to which elements are immaterial forms that possess active and passive potencies as well as motion and extension. In Taurellus's view, immaterialism about elements provides support for the theological doctrine of creation ex nihilo. As he argues, the ontology of immaterial forms helps to explicate a sense in which creatures are substances, not accidents of the divine substance. In particular, he maintains that immaterial forms stand in suitable relations of ontological dependence to God: creation dependence (since forms would not exist without the divine act of creation), but neither subsistence dependence (since forms continue to exist without continued divine agency) nor activity dependence (since forms are active without requiring divine concurrence). PMID- 25549448 TI - A dictionary without definitions: romanticist science in the production and presentation of the Grimm brothers' German dictionary, 1838-1863. AB - Between 1838 and 1863 the Grimm brothers led a collaborative research project to create a new kind of dictionary documenting the history of the German language. They imagined the work would present a scientific account of linguistic cohesiveness and strengthen German unity. However, their dictionary volumes (most of which were arranged and written by Jacob Grimm) would be variously criticized for their idiosyncratic character and ultimately seen as a poor, and even prejudicial, piece of scholarship. This paper argues that such criticisms may reflect a misunderstanding of the dictionary. I claim it can be best understood as an artifact of romanticist science and its epistemological privileging of subjective perception coupled with a deeply-held faith in inter-subjective congruence. Thus situated, it is a rare and detailed case of Romantic ideas and ideals applied to the scientific study of social artifacts. Moreover, the dictionary's organization, reception, and legacy provide insights into the changing landscape of scientific practice in Germany, showcasing the difficulties of implementing a romanticist vision of science amidst widening gaps between the public and professionals, generalists and specialists. PMID- 25549449 TI - Hermann von Helmholtz's empirico-transcendentalism reconsidered: construction and constitution in Helmholtz's psychology of the object. AB - This paper aims at contributing to the ongoing efforts to get a firmer grasp of the systematic significance of the entanglement of idealism and empiricism in Helmholtz's work. Contrary to existing analyses, however, the focal point of the present exposition is Helmholtz's attempt to articulate a psychological account of objectification. Helmholtz's motive, as well as his solution to the problem of the object are outlined, and interpreted against the background of his scientific practice on the one hand, and that of empiricist and (transcendental) idealist analyses of experience on the other. The specifically psychological angle taken, not only prompts us to consider figures who have hitherto been treated as having only minor import for Helmholtz interpretation (most importantly J.S. Mill and J.G. Fichte), it furthermore sheds new light on some central tenets of the latter's psychological stance that have hitherto remained underappreciated. For one thing, this analysis reveals an explicit voluntarist tendency in Helmholtz's psychological theory. In conclusion, it is argued that the systematic significance of Helmholtz's empirico-transcendentalism with respect to questions of the mind is best understood as an attempt to found his empirical theory of perception in a second order, normative account of epistemic subjectivity. PMID- 25549450 TI - [[On evaluation of public health state in Aral Sea area]. AB - Inefficient and excessive use of water of Aral Sea Basin for the period of 40 years for agricultural land irrigation caused a significant deterioration of living conditions, changed the economic situation of the local population, its income, employment, working conditions, infrastructure of livelihood. All these components manifested in a sudden change of health status of population in Aral Sea area. Research project will help to develop a methodology for risk assessment and management, identify patterns of damage to various body systems and the rationale of diagnostic criteria for ecologically dependent diseases at the early stage, and to implement preventive and corrective actions to determine the conditions for the preservation of public health in environmental deviations of the habitat of the population living in the Aral Sea area. PMID- 25549451 TI - [Occupational morbidity in Kazakhstan]. AB - The main principle of the whole health care system in Kazakhstan is joint responsibility of state, employer and employee for the health state. Coordination of occupational therapeutic service is maintained by National Center of Industrial hygiene and occupational diseases. The country appears to have registered 6919 patients with "occupational disease" diagnosis, with new 500-600 cases register annually. Occupational diseases should be revealed at early stages, when the patients remain at their workplaces, and rehabilitation measures should be performed. PMID- 25549452 TI - [Problems of soils pollution with solid industrial waste in Kazakhstan]. AB - The problem of recycling and disposal of solid waste from metallurgical, energy and petrochemical industries is becoming more acute problem for Kazakhstan. Violations of hygiene requirements concerning the placement and operation of landfills increase the area of contaminated soil and can become a threat to environmental safety of the population in industrial centers. The research was aimed to evaluate soil contamination in the cities and towns of Kazakhstan Republic and to mark out health risk areas. Five localities with especially high levels of soil contamination were revealed. Visualization of ecological contamination on individual urban areas gives to ecologists a tool to analyze and solve medical ecology problems. The results of soil contamination mapping can contribute earmarking of funds by local authorities to carry out measures for optimizing the environment. PMID- 25549453 TI - [Main results of research concerning asbestos-related diseases in Kazakhstan Republic]. AB - Problem of safety in asbestos usage attracts close attention of specialists and agencies responsible for public health preservation nowadays. According to European researchers, studies of uncontrolled usage of amphibole asbestos demonstrate high risk of asbestosis, lung cander and pleural mesothelioma among the workers and population exposed. The article covers results of research concerning influence of chrysotile asbestos on the workers, problems of asbestos related diseases formation. The authors defined suggestions on a concept of controlled usage of chrysotile asbestos in Kazakhstan Republic. PMID- 25549454 TI - [Evaluation of induced mutagenesis in workers engaged into chrysotile asbestos production]. AB - The authors present data of cytogenetic study of workers engaged into chrysotile asbestos industry. Evaluation of chromosomal aberrations in peripheral lymphocytes of workers in main workshops of "Kustanaiskie mineral" JSC revealed reliable increase in chromosomal aberrations level. Structural chromosomal abnormalities in main groups were presented by chromosome and chromatide type aberrations with latter prevelent--that can prove chemical mutagenesis. Chromosome type aberrations were presented by paired fragments and centromere rupture, those of chromatide type--by deletions, single fragments and chromatide ruptures. Higher values of induced mutagenesis were revealed in workers of chrysotile asbestos ore concentration workshop, in workers of ore-preparation workshop, and in individuals with over 25 years of work at chrysotile asbestos production. PMID- 25549455 TI - [Vegetative nervous system state in vibration disease and chronic lumbosacral radiculopathy in miners]. AB - Clinical and functional studies helped to assess influence of vegetative nervous system on course of vibration disease and chronic lumbosacral radiculopathy in miners. Vegetative dysfunction syndrome varying in intensity was associated with simultaneous overstrain in segmentary and supersegmentary units of vegetative nervous system. The authors defined dependence between vegetative dysfunction intensity and neuromuscular disorders severity. With this, increased threshold of N-reflex with lower amplitude accompanied decrease in M-response amplitude and shorter latent period, in accordance with peripheral nerve impulse speed. The dependence between vegetative nervous system strain and neuromuscular disorders intensity underlies pain syndrome degree in vibration disease and chronic lumbosacral radiculopathy in miners. PMID- 25549456 TI - [Influence of vibration on changes in S100B protein content of peripheral blood in miners]. AB - The authors studied influence of vibration on serum neurotropic protein S100B level in miners. Vibration appeared to cause significant effect on increase of this protein level. With that, there is a moderate correlation between the protein level and intensity of the vibration effect. PMID- 25549457 TI - [Methodic approaches to evaluation of visual performance in professional computer users]. AB - Occupation-related and physiologic studies in workers using personal computers revealed variable degrees of changed visual performance in accordance with work conditions class and integral parameter of work intensity. Findings are that the performance change is caused by lower accomodation volume and decrease in temporary characteristics of clear vision stability. Correlation was established between work conditions class and percentage of the performance decrease during the working shift in videodisplay users. PMID- 25549458 TI - [Nonconventional risk factors in some psychosomatic diseases in police officers]. AB - The article deals with topical problems of improving methods of medical and psychological diagnosis and prevention of health state in police officers, in accordance with prophylactic medicine concept. The authors describe topical aspects of occupational medicine and influence of nonconventional risk factors on occurrence and course of some psychosomatic diseases. PMID- 25549459 TI - [Influence of ecologic environmental factors on diseases formation in population (review of literature)]. AB - The paper presents the analytical review concerning influence of environmental ecological factors on development of ecologically dependent diseases in adults and children. The authors necessitate to improve monitoring system of environment and public health. PMID- 25549460 TI - [Life quality parameters in prenosologic evaluation of health state in residents of protective measures area near objects of storage and destruction of chemical weapons]. AB - The article presents results of life quality assessment and subjective evaluation data on health state, used for prenosologic evaluation of health state in residents of protective measures area near objects of storage and destruction of chemical weapons. Considering specific features of residence near potentially dangerous objects, the authors conducted qualitative evaluation of satisfaction with various life facets, with taking into account the objects specificity, established correlation between life quality and self-evaluation of health with factors influencing public health state. PMID- 25549461 TI - [A problem of the HIV drug resistance]. AB - The wide use of the highly active antiretroviral therapy (HAART) of HIV infection leads to the HIV drug resistance. The simultaneous formation of the resistance to different groups of antiviral drugs compromises the efficacy of HAART. Thus, the problem of the drug resistance becomes of an enormous significance. In this review, a definition of the resistance is given; the problem of the drug resistant strains transmission is discussed; the assays used for resistance testing are described; recommendations for the antiviral drug-resistance testing are given. PMID- 25549462 TI - [Taxonomic status of the Burana virus (BURV) (Bunyaviridae, Nairovirus, Tamdy group) isolated from the ticks Haemaphysalis punctata Canestrini et Fanzago, 1877 and Haem. concinna Koch, 1844 (Ixodidae, Haemaphysalinae) in Kyrgyzstan]. AB - Complete genome sequence of the Burana virus (BURV) was determined using the next generation sequencing approach (ID GenBank KF801651). The prototype strain of BURV LEIV-Krg760 was originally isolated from the ticks Haemaphysalis punctata Canestrini et Fanzago, 1877 (Ixodidae, Haemaphysalinae), collected from cows in Tokmak wildlife sanctuary, eastern part of the Chu valley (43 degrees 10' N, 74 degrees 40' E) near Burana village, Kirgizia, in April 1971. Molecular genetics and phylogenetic analyses showed that the BURV belonged to the Nairovirus genus, Bunyaviridae and is related to Tamdy virus (TAMV) that is also associated with the ixodidae ticks of pasture biocenosis in Central Asia. Previous studies showed that TAMV is the prototypic virus of new phylogenetic Tamdy group in the Nairovirus genus. Thus, BURV was classified as a new virus of the Tamdy group, Nairovirus, Bunyaviridae. PMID- 25549464 TI - [Genetic characterization of the Wad Medani virus (WMV) (Reoviridae, Orbivirus), isolated from the ticks Hyalomma asiaticum Schulze et Schlottke, 1930 (Ixodidae: Hyalomminae) in Turkmenistan, Kazakhstan, and Armenia and from the ticks H. anatolicum Koch, 1844 in Tajikistan]. AB - Near full-genome sequence of the Wad Medani Virus (WMV) (strain LEIV-8066Tur) (Orbivirus, Reoviridae) isolated from the ticks Hyalomma asiaticum Schulze et Schlottke, 1929, collected from sheep in Baharly district in Turkmenistan, was determined using next generation sequencing approach. The similarity of the RNA dependent RNA-polymerase (Pol, VP1) amino acid sequence between WMV and the Kemerovo group orbiviruses (KEMV), as well as of the Baku virus (BAKV), was 64%. The similarity of the conserved structural protein VP3 (T2) of WMV with mosquito borne and tick-borne orbiviruses reaches 46% and 67%, respectively. For the surface proteins VP2, VP5, and VP7 (T13), which have major antigenic determinants of orbiviruses, the similarity of WMV with tickborne orbiviruses (KEMV and BAKV) is 26-30%, 45% and, 57%, respectively (ID GenBank: KJ425426-35). PMID- 25549463 TI - [Genetic characterization of the Syr-Darya valley fever virus (SDVFV) (Picornaviridae, Cardiovirus) isolated from the blood of the patients and ticks Hyalomma as. asiaticum (Hyalomminae), Dermacentor daghestanicus (Rhipicephalinae) (Ixodidae) and Ornithodoros coniceps (Argasidae) in Kazakhstan and Turkmenistan]. AB - The Syr-Darya valley fever virus (SDVFV) was originally isolated from the blood of the patient with fever in the Kyzylorda province, Kazakhstan, in July 1973 and was classified to the Cardiovirus genus (fam. Picornaviridae). Later, SDVFV was isolated from the ticks Hyalomma as. asiaticum Schulze et Schlottke, 1929 (Hyalomminae) (1 strain) and Dermacentor daghestanicus Olenev, 1929 (Rhipicephalinae) (7 strains), collected in the floodplains of the Syr-Darya river and the Ili river. In this paper, complet genome of the SDVFV (strain LEIV Tur2833) was sequenced using the next-generation sequencing approach (GenBank ID: KJ191558). It was demonstrated that, phylogenetically, the SDVFV is closely related closest to the Theiler's murine encephalomyelitis virus (TMEV) and Vilyuisk human encephalomyelitis virus (VMEV). The similarity of the SDVFV with VHEV and TMEV based on P1 region of the polyprotein-precursor (structural proteins VP1-VP4), reaches 75% and 91% for nucleotide sequences and 80% and 93% for putative amino acid sequences, respectively. For nonstructural proteins regions P2 (2A-2C) and P3 (3A-3D) similarity of SDVFV with TMEV and VHEV is 96% 98%. PMID- 25549465 TI - [Molecular epidemiological analysis of the HIV infection in the Blagoveshchensk and Khabarovsk Area (Russian Far East)]. AB - The results of the molecular-epidemiological analysis of the HIV-1 variants circulating in Blagoveshchensk and Khabarovsk (Russian Far East) were presented. In Blagoveshchensk HIV-1 IDU-A variants were dominated (92.5%), similar to the regions of the European part of Russia. In Khabarovsk the heterogeneity of circulating HIV-1 variants was noted. In addition to IDU-A variants (66.0%), the strains of subtype B (12.6%), C (4.4%) and recombinant strain form CRF02_AG (17.0%) were identified. Using the phylogenetic analysis method the version of the penetration of HIV-1 variants from China and Japan was not supported. PMID- 25549466 TI - [The suppression of a herpes simplex virus reproduction with drug resistance by combination 15lys-bis-nt and phosphate of acycloguanosine with some antiherpetic drugs]. AB - Antiherpetic activity of the double and triple combinations, including original connections 15Lys-bis-Nt and phosphate of acycloguanosine (P-ACG), was studied in vitro. For the first time, it was demonstrated that in case of their combined use with known antiherpetic agents, whose activity does not depend on TK of HSV (PFA, AraA, CDV, Rib, GLN, alphaa-IFN), synergistic or additive effects of interaction was observed. The antiviral effect of the tested combinations was studied on the model of ACG-resistant viral strain. The tested combinations could be of interest for practical medicine. PMID- 25549467 TI - [Variants of the immunoreactivity and infectious process in bank vole (Myodes glareolus) experimentally infected with the hantavirus Puumala (PUUV)]. AB - As a result of a longitudinal study of the Puumala hantavirus (PUUV) in the experimentally infected bank voles (Myodes glareolus), we revealed three groups of the voles differing in the immunoreactivity and viral antigen concentration in the organs. The close correlation between these parameters suggested the existence of various mechanisms of the hantavirus persistence in the host. PMID- 25549468 TI - [Pathogenicity of noncytophatic isolates of bovine viral diarrhea virus in experimentally infected seronegative calves]. AB - The results of experimental infection of seronegative calves with three non cytopathogenic (NCP) isolates of BVDV isolated from cattle with different clinical manifestations of the disease belonging to genotype 1 (subgenotype 1a, 1b and 1d) are presented. All tested isolates showed the virulence for seronegative calves 4 to 6 months of age. Belonging to biotype did not correlate with the ability of the virus to infect the lymphoid tissues and to induce leukopenia. All isolates of the virus led to "transiting" leukopenia (up to 2880 3800 kl/mm3) for 8-10 days after infection. Isolate cluster 1d was more virulent and caused the development of a mild respiratory syndrome and short-term diarrhea. The virulence was "strain-dependent". PMID- 25549469 TI - [Probiotics as functional food products: manufacture and approaches to evaluating of the effectiveness]. AB - This review concerns the issues of foodfortifications and the creation of functional foods (FF) and food supplements based on probiotics and covers an issue of approaches to the regulation of probiotic food products in various countries. The status of functional foods, optimizing GIT functions, as a separate category of FF is emphasized. Considering the strain-specificity effect of probiotics, the minimum criteria used for probiotics in food products are: 1) the need to identify a probiotics at genus, species, and strain levels, using the high-resolution techniques, 2) the viability and the presence of a sufficient amount of the probiotic in product at the end of shelf life, 3) the proof of functional characteristics inherent to probiotic strains, in the controlled experiments. The recommended by FA O/WHO three-stage evaluation procedure offunctional efficiency of FF includes: Phase I--safety assessment in in vitro and in vivo experiments, Phase II--Evaluation in the Double-Blind, Randomized, Placebo-Controlled trial (DBRPC) and Phase III--Post-approval monitoring. It is noted that along with the ability to obtain statistically significant results of the evaluation, there are practical difficulties of conducting DBRPC (duration, costs, difficulties in selection of target biomarkers and populations). The promising approach for assessing the functional efficacy of FF is the concept of nutrigenomics. It examines the link between the human diet and the characteristics of his genome to determine the influence of food on the expression of genes and, ultimately, to human health. Nutrigenomic approaches are promising to assess the impact of probiotics in healthy people. The focusing on the nutrigenomic response of intestinal microbial community and its individual populations (in this regard the lactobacilli can be very informative) was proposed. PMID- 25549470 TI - [L-arginine metabolism enzyme activities in rat liver subcellular fractions under condition of protein deprivation]. AB - The features of arginase and NO-synthase pathways of arginine's metabolism have been studied in rat liver subcellular fractions under condition of protein deprivation. During the experimental period (28 days) albino male rats were kept on semi synthetic casein diet AIN-93. The protein deprivation conditions were designed as total absence of protein in the diet and consumption of the diet partially deprived with 1/2 of the casein amount compared to in the regular diet. Daily diet consumption was regulated according to the pair feeding approach. It has been shown that the changes of enzyme activities, involved in L-arginine metabolism, were characterized by 1.4-1.7 fold decrease in arginase activity, accompanied with unchanged NO-synthase activity in cytosol. In mitochondrial fraction the unchanged arginase activity was accompanied by 3-5 fold increase of NO-synthase activity. At the terminal stages of the experiment the monodirectional dynamics in the studied activities have been observed in the mitochondrial and cytosolfractions in both experimental groups. In the studied subcellular fractions arginase activity decreased (2.4-2.7 fold with no protein in the diet and 1.5 fold with partly supplied protein) and was accompanied by NO synthase activity increase by 3.8 fold in cytosole fraction, by 7.2 fold in mitochondrial fraction in the group with no protein in the diet and by 2.2 and 3.5 fold in the group partialy supplied with protein respectively. The observed tendency is presumably caused by the switch of L-arginine metabolism from arginase into oxidizing NO-synthase parthway. PMID- 25549471 TI - [Influence of enzymatic hydrolyzate of mussel meat on growth and some indicators of general adaptation syndrome in rats]. AB - The impact of the 15-day consumption of enzymatic hydrolyzate of the mussels meat as a part of semi-synthetic diet on some stress biomarkers and apoptosis activity in various organs of growing male Wistar rats have been studied. Enzymatic hydrolyzate of the mussels meat (EMM) was obtained in pilot conditions using the enzyme preparation "Protozim". The animals of control group 1 (n = 8 with initial body weight of 179.4 +/- 5.9 g) and experimental group 2 (n = 8, 176.3 +/- 4.5 g) received a semi synthetic diet; the animals of the experimental group 3 (n = 8, 177.6 +/- 4.0 g) received the same semi synthetic diet in which 50% of the casein was replaced by the peptides of EMM. On the penult day of the experiment animals of groups 2 and 3 were subjected to stress exposure by electric current on their paws (current 0.4 mA for 8 seconds) and were placed in metabolic cages for the collection of daily urine. At the 15th day of the study, all control and test animals were killed by decapitation under ether anesthesia and necropsied. The content of prostaglandin E2 and beta-endorphin in blood plasma was determined by ELISA test. The concentration of urine corticosterone was measured by HPLC. DNA damage and percentage of apoptotic cells (apoptotic index) were calculated in thymus by single-cell gel electrophoresis assay (Comet assay). The relative body weight increase of animals treated with EMM was significantly (p < 0.05) higher (68.2 +/- 3.0%) than those in animals of groups 1 and 2 (57.2 +/- 4.0 and 59.7 +/ 2.8%, respectively). The apoptotic index in thymus cells of tested groups of animals (2 and 3) was significantly (p < 0.05) higher (1.13 +/- 0.09 and 1.09 +/- 0.01%) compared to intact animals of control group (1.04 +/- 0.01%). Determination of beta-endorphin and prostaglandin E2 levels did not shown any significant differences between the groups. Significantly (p < 0.05) lower concentrations of corticosterone was found in the daily urine of stressed animals from group 3 (452 +/- 78 ng/ml), treated with EMM, compared to stressed animals of group 2 that received a casein diet (834 +/- 167 ng/ml). It has been shown that consumption of EMM with a high content of short and medium peptides has an impact on effectiveness of body weight gain of growing laboratory animals, and restrict the increase of corticosterone level in rats blood, which is typical for general adaptation syndrome. PMID- 25549472 TI - [Correction of the combined vitamin deficiency in growing rats fed fiber enriched diets with different doses of vitamins]. AB - The effect of 5% dietary wheat bran (WB) on the correction of combined vitamin deficiency by two doses of vitamins (physiological and enhanced) has been analyzed using a rat model (8 groups, n = 8/group). Vitamin deficiency in male weanling Wistar rats (58.1 +/- 0.5 g) was induced by 5-fold reduction of vitamin mixture amount in the feed and complete vitamin E, B1 and B2 exclusion from the mixture for 30 days, then deficit was corrected within 5 days. Rats from control group were fed a complete semisynthetic diet containing microcrystalline cellulose 2%. Vitamin deficient diet for 35 days resulted in reduced (p < 0.05) levels of vitamin A in the liver by 25 fold, vitamin E and B1--2.0-2.3 fold, vitamin B2--by 40%, 25(OH)D blood plasma concentration--by 21% compared with the control. Feed consumption of the animals treated with vitamin deficient diet and WB was higher by 43% than in rats with vitamin deficit. Their rate of weight occupied the intermediate position between the rates of weight in deficit and in control animals, and they could not serve a full control to evaluate the WB impact on vitamin sufficiency. After filling the vitamin diet content to an adequate level vitamin E liver content was fully restored. To restore vitamins B1 and B2 liver level higher doses of vitamins (120-160% of adequate content) were required, and to restore the reduced levels of vitamin A in rat liver even 2-fold increased dose of vitamin A was insufficient. The diet enrichment with WB had no effect on vitamin B1 and B2 liver content, regardless of the amount of vitamins in the diet. Adding fiber to the diet of animals adequately provided with vitamins resulted in significantly 1,3-fold increase of 25(OH)D blood plasma concentration and a slight but significant decrease of alpha-tocopherol liver level by 16% as compared to rats not receiving WB. The enrichment of rat diet with dietary fibers worsened restoration of the reduced vitamin E status not only by filling vitamin content in the diet to an adequate level, but also by using 2 fold enhanced dose of vitamin. Within 5 days deficiency of vitamins A, B1, B2 was not eliminated with increasing vitamin diet content to an adequate level. Higher doses of vitamins are needed for the complete correction of vitamin status. The addition of vitamins to an adequate level was sufficient to normalize the elevated liver levels of MDA in rats with combined vitamin deficiency that may be associated with vitamin E status improvement. The diet enrichment with fiber did not affect on the intensity of lipid peroxidation in rat liver regardless of their provision with vitamins. PMID- 25549473 TI - [Age-dependent characteristics of nutritional status and resting metabolism in overweight and obese children]. AB - The age-dependent nutritional status and resting metabolism in overweight and obese children have been examined. The study included 625 children of 2.5-17 years old. Patients were divided into three groups: 1st--2.5-7 years old (n = 49), 2nd--8-12 years old (n = 204), 3rd--13-17 years old (n = 372). The diagnosis of overweight and obesity was based on CDC criteria: children with 85-94 BMI percentile according to age and gender had overweight, BMI 295 percentile- obesity. Anthropometry, bioelectric impedance analysis and indirect respiratory calorimetry were performed; lipid and carbohydrate parameters were measured. The fat mass percentages in children of studed groups were 41.3 +/- 1.9, 39.8 +/- 0.7 and 42.3 +/- 0.4%, the mean percent of fat mass excess--163.6 +/- 26.2, 113.7 +/- 8.3 and 134.9 +/- 8.2% respectively, p > 0.05. Prevalence of dyslipidemia in children increased with age: lipid metabolism disorders were revealed in 28.6, 49.0 u 53.2% children of the 1st, 2nd and 3rd groups respectively. The mean HDL level in the 1st and 2nd groups was significantly higher, and triglycerides- lower than in the 3rd group. The correlation of HDL level and breastfeeding duration (r1 = 0.94, p < 0.05) was found in the 1st group of children. Increased insulin level was revealed in 38.8% children in the 1st group (mean 12.8 +/- 1.4 MUIU/ml), 62.2% children in the 2nd group (21.1 +/- 0.7 MUIU/ml) and 64.8% children in the 3rd group (25.1 +/- 0.9 MUIU/ml); increased HOMA--in 36.7% (4.32 +/- 0.6), 62.2% (4.65 +/- 0.17) and 59.1% (5.56 +/- 0.21) respectively. The negative correlation of insulin and HOMA level with breastfeeding duration (r1 = 0.38 and -0.37, respectively, p < 0.05) was found in the 1st group of children. Prevalence of hyperuricemia increased from 13% in the 1st group to 21.1% in the 2nd and 44.1% in the 3rd group. Prevalence and degree of resting metabolism changes increased with age and had tendency to the shift of proportion of energy intensive substrates (fats and carbohydrates) to deceleration of carbohydrate oxidation (in 32, 50, 55.1% of children) and compensatory fat oxidation acceleration (8, 28.4 and 34.7% respectively). Mean fat oxidation rate levels significantly differed between groups and increased with age (48.38 +/- 7.14, 54.29 +/- 3.06 and 78.43 +/- 2.89 g/day in children of the 1st, 2nd and 3rd groups respectively, p < 0.001). The mean level of carbohydrate oxidation rate in the 3rd group of children was lower than normal value (p < 0.01). Resting energy expenditure was lower in the 2nd and 3rd groups of children. PMID- 25549474 TI - [Regulation of food supplements in the European Union and its member states. Part 2]. AB - The article discusses various aspects of the regional (the European Union) and national (European countries) regulation related to food supplements. The use of botanicals and minor bioactive substances in food supplements, and their labelling are studied. The EU principle of mutual recognition is described in the context of current challenges that exist in the regulatory harmonisation between the EU member states. The concept of novel foods and novel ingredients is also presented, and the procedure of their pre-market approval is described in detail. Basic principles of using claims for food supplements are also outlined. PMID- 25549475 TI - [Toxicological assessment of nanostructured silica. II. Enzymatic, biochemical indices, state of antioxidative defence]. AB - Nanostructured silica (SiO2) "Aerosil" with the size of the primary nanoparticles (NPs) of 5-30 nm, in the form of ultrasound treated water suspension was administered to rats of 80 +/- 4 g initial body weight for the first 30 days by intragastric gavage and then for 62 days with diets consumed in doses of 0.1; 1.0; 10 and 100 mg/kg body weight per day. The control group received vehicle of nanomaterial (NM)--deionized water. There were measured in liver of ani- mals the content of total cytochromes P450 and b5 in the microsomal fraction of liver, activity (Vmax) of microsomal monooxygenases with the mixed func- tion of isoforms CYP1A1, 1A2 and 2B1 on their specific substrates, the activity of conjugating liver enzymes glutathione-S-transferase and UDP-glucuronosyl transferase in microsomal fraction and cytosol, the total and non sedimentable activity of lysosomal hydrolases (beta-glucuronidase, beta-galactozydase, arylsulphatase A, B). The content of PUFA's diene conjugates and TBA-reactive substances in the blood plasma and the activity of antioxidative enzymes (glutathionperoxidase, superoxidedismutase, glutathionreductase, katalase) in erytrocytes were estimated. A set of standard biochemical parameters of blood serum was also examined (total protein, albumin, glucose, creatinine, urea, uric acid, activities of hepatic transaminases). The studies revealed changes of a number of molecu lar markers that could be interpreted as unfavorable. These include isoforms of CYP2B1 activity decrease at a dose HM 1-10 mg/kg of body weight, decrease in the serum content of total protein, albumin and glucose levels in a dose range of 0.1-10 mg/kg. These changes were absent at the maximum dose of NM, which did not allow to clearly establish the dose-response. The remaining studied fig ures resided in the normal range or experienced changes that could not be interpreted as toxic. PMID- 25549476 TI - [The specificity of children and adolescent eating habits (data for schoolchildren in Moscow and Murmansk)]. AB - Objective of the study is to evaluate the specificity of schoolchildren's eating behavior in the cities of Moscow and Murmansk. Dietary habits of 785 children 10 17 years old residing in two cities--Moscow (222 boys and 221 girls, 14.1 +/- 1.9 years old) and Murmansk (183 and 159 correspondingly, 14.1 +/- 1.8 years old)- were analyzed. The questionnaire included data on the meals ratio per day, frequency of vegetables and fruit intake, fast-food intake, hot meals, soft drinks, meat, fish and milk intake, usage of school cafeteria, regularity of breakfasts. Parents responded to questions concerning the materialsupport of family and education. It was found that more than half of schoolchildren (64.4%) had meals irregularly (3 times per day or less), only 50.9% received hot meals several times a day. Every third child (31.6%) has insufficient intake of vegetables and fruit, 11.8%--insufficient intake of meat dishes. Only 51.4% of schoolchildren consumed dairy products daily (one or several times a day). At the same time 19.5% of children used fast-food products several times a week or more often, 42.2%--carbonated drinks, and 22.7%--smoked food. Only 45.7% of schoolchildren regularly ate at school caf- eteria; 21.9% did it irregularly and 32.5%--did not attend school canteen at all. There were no significant differences between Moscow and Murmansk children as well as gender differences in the usage of school cafeteria. At the same time only 23.4% of children [26.3% in Moscow and 19.3% in Murmansk (significantly less, p = 0.032)] liked cafeteria food, 38.7% did not like and 37.9% had no certain answer. Less obese children (54.0%) have breakfast everyday than children with normal weight (75.4%, p = 0.019). Children of mothers with high and incomplete high education (89.4%) have more regular meat intake (3-4 times per week or more often) than the children of mothers with secondary, incomplete secondary and secondary special education (81.9%, p = 0.034). Schoolchildren feeding is often irregular, irrational and poorly balanced. Some of examined schoolchildren already had excessive body mass (20.7%), that may lead to metabolic and cardiovascular disturbances in young adult and mature age. PMID- 25549477 TI - [Comparative evaluation of antioxidant activity and content of prooxidant factors in different classes of foods]. AB - By using the biophysical methods (chemiluminescence, amperometry) in laboratory in vitro experiments it was demonstrated that the study of antioxidant and pro oxidant activities of different food groups allows to perform a preliminary assessment of their pro-oxidant-antioxidant capacity. It have been shown that some food prevails ability to exert pro-oxidant effects (in vitro) due to the short-term induction of free radical oxidation. Thus, among the fresh juices the increase of the maximum of flash chemiluminescence has been detected in avocado (1080, 89%) and pearjuices (136,33%), whereas the lowest ability to enhance the intensity of free radical processes has been marked for pomegranate (1,63%), orange (9, 68%) and apples juices (12, 84%). Among milk products it has been marked for sour milk (9, 06%) and yogurt (15, 11-16,02%), that allows the use of the past to correct pro-oxidant-antioxidant balance diet for people with potential danger gain peroxide processes, such as special physiological states, sport endurance, mental and emotional overload. The ability to increase the intensity of free radical oxidation have been also identified for snacks, especially buns, biscuits, bread sticks, showing the risk of formation of oxidative stress in the body during their prolonged use, particularly under the above described conditions. In some cases, foods (processed cheese and cheese curds) showed dominance factors sustained oxidative effect (in 2,1-20,7%), that indicates the possibility of an imbalance in the pro-oxidant-antioxidant system after its prolonged use in the diet, even in small quantities, especially in individuals with a reduced level of antioxidant potential of the nonspecific defense system. Investigation of antioxidant activity of foods revealed significant predominance of reducing equivalents in all freshly squeezed and some packaged fruit juices, as well as dairy products, indicating their possibility to increase the capacity of reducing components of nonspecific protection system. The presence in a number of products used for snacking (chips, puffed rice) of sufficiently high levels of antioxidant activity demonstrates the content of substances that act as proton donator having significant reducing ability. It is sufficient for high energy value of such products, indicating on the possibility of involvement of their recovery factors in plastic processes with subsequent enhancement, such as lipogenesis, that may be a prerequisite for the development of obesity, atherosclerosis and otherpathological processes. Using an integrated approach will enable a timely and appropriate to correct the ratio of pro- and antioxidant indicators of diet in order to improve the adaptive capacity of the organism in a particular physiological or pathological conditions involving oxidative metabolism disorders. PMID- 25549478 TI - [Intensity of lipid peroxidation and protein oxidative modification of goat and cow milk]. AB - Indices of free-radical peroxidation have been estimated: intensity of lipid per- oxidation and protein oxidative modification of goat and cow milk of specific breeds of forest-steppe zone of Omsk region. The obtained results indicate that processes of lipid peroxidation and protein oxidative destruction in goat and cow milk of different breeds occur with different gradation. The content of carbonile derivatives in goat milk of Saan breed 1.4 (0.95; 1.5) u/ml was lower than in cow's milk of black-and-white breed 4.6 (1.1; 6.0) u/ml (p = 0.005) what could be caused by large content of protein thiol groups of this kind of milk and lower quantity of amino acid residues that are available for carbonylation. This kind of milk is characterized by higher SH-group content than cow milk for 31% and Switzerland goat milk for 20% (p = 0.005). The content of cetodiens and attached triens in isopropanol phase of the lipid extract of goat milk of Swiss breed is lower by 30% than in cow milk. In isopropanol phase of the milk lipid extracts contain- ing phospholipids the level of Schiff grounding did not differ. The results obtained prove that goat milk contain less protein subjected to oxidative modification. PMID- 25549479 TI - [Perioperative management of patients receiving long-term antithrombotic therapy. Clinical practice guidelines]. PMID- 25549481 TI - [Intracranial and cerebral perfusion pressure in neurosurgical patients during anaesthesia with xenon]. AB - Despite difficulties in providing xenon anaesthesia, xenon still seems to be attractive for neurosurgical procedures. But data upon its effect on intracranial (ICP) and cerebral perfusion pressure (CPP) remains controversial. We monitored ICP and CPP in patients with or without intracranial hypertension during xenon inhalation in different concentrations. Our results suggest that caution should be used while inhaling xenon in high anaesthetic concentration in patients wiith known intracranial hypertension. We also address new possibilities of xenon use, e.g., for sedation in neurosurgery. The study was supported by Russian Fund for Fundamental Research, grant number 13-04-01640. PMID- 25549480 TI - [Comparative characteristics of using isoflurane, sevoflurane and target concentration of propofol during reconstructive operations on the carotid arteries]. AB - GOAL OF THE STUDY: To compare effects of isoflurane, sevoflurane and target concentration of propofol on the systemic hemodynamics, cerebral blood flow and cerebral oximetry of the brain during the carotid endarterectomy. MATERIALS AND METHODS: We studied 95 patients. The patients were divided into 3 groups. Group I included 26 patients who received isoflurane (under I MAC), Group II--40 patients who received sevoflurane (under I MAC), Group III--29 patients who received target concentration of propofol (under 4 mkg/ml) according to the method of Schneider Studied parameters were defined at the stages: before the operation (I), after the induction (II), after the intubation (III), during the separation of the carotid artery (IV), after the crossclamping of the carotid artery (V), before starting the bloodstream (VI), after starting of the bloodstream (VII), after the end of the operation (VIII). RESULTS: At the first stages of the operation, the using of isoflurane, sevoflurane and propofol was accompanied with moderate dose-dependent lowering of indicators ofcirculatory dynamics. The linear blood flow velocity (LBFV) in the middle cerebral artery on the affected side in the groups of isoflurane and propofol did not depend on the indicators ofcirculatory dynamics; in the sevoflurane group the correlation was traced During the breakoff of the blood circulation in the reconstructed carotid arteries while using the anesthesia of isoflurane, sevoflurane and propofol hemodynamics was stable. LBFV and cerebral oximetry (CO) in the groups of isoflurane and propofol did not depend on the systemic hemodynamics; in the sevoflurane group--they depended After the reinitiating of the bloodstream in the conditions of the isoflurane andpropofol anesthesia the reperfusion of the brain was moderate; in the conditions of the sevoflurane anesthesia the risk of reperfusion damage of the brain during the uncontrolled hypertension remained. At the stage of finishing the operation LBFV and CO did not depend on the systemic hemodynamics in the isoflurane and propofol groups, in the sevoflurane group the dependence was indicated. Consequently, at all the stages of the operation we indicated the disorder of the mechanisms of the brain blood supply autoregulation in the sevoflurane group. PMID- 25549482 TI - [Effect of intra-abdominal pressure in pregnant women on level of spina block and frequency of hypotension during cesarean section]. AB - INTRODUCTION: It is common knowledge that an increase of intra-abdomninal pressure (lAP) causes a decrease in the volume of cerebrospinal fluid in the lumbar and lower thoracic region, which may contribute to the development of more high spinal block. There is currently no research devoted to studying the impact of intra-abdominal pressure in pregnancy on the development of high spinal blockade. GOAL OF THE STUDY: To investigate effects of intra-abdominal pressure in pregnancy on the development of spinal blockade and incidence of hypotension during cesarean section. MATERIAL AND METHODS: 170 pregnant women with gestational age 38-40 weeks were included in the randomized, blinded, controlled study. All the women received elective cesarean section under spinal anesthesia (SA). Pregnant women w|,ere divided into two groups of 85 females each. In the first group, the anesthesiologist did not know the value of lAP and used the dose of local anesthetic focusing on height, weight, and according to his own experience. In the second group, an anesthesiologist corrected dose of local anesthetic depending on the lAP and also considered the height and weight of a woman. RESULTS: In 9.2% of women, lAP was less than 11 mmHg (physiologically normal), in 49%--from 12 to 15 mmHg (degree I of intra-abdominal hypertension (IAH)), in 40.3%--from 16 to 20 mmHg (degree II of IAH), in 1.5%--from 21 to 25 mmHg (degree III of IAH). In the first group, the incidence of high spinal block (above Th4) and incidence of arterial hypotension (systolic blood pressure under 90 mm.Hg) was two times higher than in the second group (p<0.01). CONCLUSIONS: Intra-abdominal hypertension in pregnant women contributed to the development of high spinal block and hypotension. To prevent these complications, we recommend decreasing the dose of local anesthetic with use of the Scale of the Risk of developing high spinal block in pregnant. PMID- 25549483 TI - [Metabolic and organ protective properties of various infusion solutions and the choice of starting therapy in the pre-admission stage of acetic acid poisoning]. AB - MATERIALS AND METHODS: We conducted an open prospective study in 60 patients (30 men and 30 women) with acetic acid poisoning. A randomization was performed on the groups, taking into account the tactics of infusion therapy: group I--15 patients who did not receive an infusion therapy at a pre-admission stage; group II--15 patients who received the infiusion therapy with solution of sodium chloride 0.9%; group III--15 patients who received the infusion therapy with modified gelatin (Gelofusinwn), group IV-15 patients who received the infusion therapy with reamberinum. RESULTS: We found that the most favorable results were noted in patients of group IV in the early posttraumatic period. PMID- 25549484 TI - [Prophylaxis of hepatic insufficiency after major hepatic resections]. AB - The article deals with a problem of prophylaxis of hepatic insufficiency in oncological patients after liver resections. MATERIALS AND METHODS: We analyzed data of effectiveness and safety of the use of Remaxol in oncological patients with hepatic metastasis of colorectal cancer--dynamics of indicators of cytolysis and cholestasis, hepatic protein synthesis, exchange of pigments, pro- and antioxidant system and the level of endogen intoxication in postoperative period. RESULTS: Use of Remaxol allows decreasing the duration of postoperative rehabilitation and intensive care unit staying. PMID- 25549485 TI - [Therapy with high-doses of antithrombin III in patients with septic shock and agranulocytosis]. AB - OBJECTIVE: The aim of the study was to assess efficacy of high-doses ofantithrombin 111 (AT) for treatment of septic shock in patients with an agranulocytosis. DESIGN: Prospective, controlled study. PATIENTS: 29 patients from 18 to 74 years old, with blood diseases complicated with septic shock Dates of study: from 2006 to 2012. METHODS: The patients were randomized into two groups. Group-1 included 14 patients, who did not receive AT and group-2 included 15 patients who received AT. RESULTS: Demographic indicators, condition severity according to APACHE II, level of thrombocytopenia, levels ofplasma procalcitonin, interleukin-6 (IL-6) and C-reactive protein (CRP) were the same in both groups. Level of AT was decreased in both groups; however it was higher in the group-1 (50% vs. 60%, p < 0.05). In the group-1, microorganisms were found in the blood of 9 patients. In the group-2, the microorganisms were found in the blood of 11 patients. Inflammation markers were decreased after the treatment of septic shock in both groups (p<0.05). The decreasing of procalcitonin in group-1 was from 43.8 to 1 ng/ml in 14 days and from 12.8 to 1.6 ng/ml in 7 days in group-2. The decreasing of CRP in group-1 was from 224 to 114 mg/l in 7 days and from 146 to 60 mg/l in 14 days in group-2. The decreasing of IL-6 in group-1 was from 1617 to 100 pg/ml in 3 days and from 5895 to 77 pg/ml in 7 days in group-2. A level of AT was increased only in group-2 (under 12% per day). 28-day survival was higher in group-2 (60 +/- 13% vs. 45 +/- 13%, p<0.05). We did not find any complications of the treatment with AT concentrate. CONCLUSION: Treatment of septic shock with high-doses of antithrombin III was effective and safe in patients with an agranulocytosis. PMID- 25549486 TI - [Pathogenesis and target therapy of acute respiratory distress syndrome]. AB - The paper summarizes results of experimental studies and clinical observations of the pathogenesis and effectiveness of respiratory, non-respiratory and pharmacological treatment methods for acute respiratory distress syndrome caused by direct and indirect damaging factors. The article deals with differences and peculiarities of morphological changes and lung functional disorders, clinical, laboratory and instrumental signs of various origins in ARDS and justifies necessity of differential diagnosis and differential treatment of ARDS, depending on the reasons for its development. Furthermore the article discusses an algorithm for differential diagnosis and differential treatment for ARDS caused by direct and indirect damaging factors. PMID- 25549487 TI - [Positive end-expiratory pressure adjustment in parenchimal respiratory failure: static pressure-volume loop or transpulmonary pressure?]. AB - OBJECTIVE: The aim of the study was compare the prognostic value, efficacy and safety ofpositive end-expiratory pressure (PEEP) adjustment in conformity with lower inflection point of static "pressure-volume" loop (LIP) or end-expiratory esophageal pressure (EEEP) in parenchymal respiratory failure. METHODS: We included in the study 56 patients (39 males) at age 47 +/- 17.8 years with parenchymal respiratory failure (PaO2/FiO2 < 250 mmHg, bilateral infiltrates on chest X-ray or lung CT scan, no signs of left ventricular failure), who were mecAanically ventilated for less than 48 hours. All patients were sedated and paralyzed. We measured intra- Sabdominal pressure, PaO2/FiO2, PaCO2, alveolar dead space (Vdalv), plotted static "pressure-volume" loop by low flow technique in range of 0 to 40 mbar, recording LIP Then we placed nasogastric tube with balloon for esophageal pressure measurement and measured esophageal pressure at PEEP range from 8 to 20 mbar (with 2 mbar steps) and recorded plateau pressure (Pplat), transpulmonary plateau pressure (Ptp plat), transpulmonary pressure at PEEP level (Ptp PEEP), static compliance of respiratory system (Cstat), lung compliance (Clung), chest wall compliance (Ccw) at every step. Also by volumetric capnography technique we measured end-tidal carbon dioxide concentration (EtCO2), minute volume of exhaled carbon dioxide (VCO2) volume of exhaled carbon dioxide by single breath (VtCO2) and calculate VC2/EtCO2 as a surrogate marker of pulmnonary perfusion. After that we set PEEP at EEEP level (at zero end-expirato- my ranspulmonary pressure) and recorded changes of PaO2/FiO2 and Vdalv. RESULTS: LIP value was 5 (6-10) mbar and it was less than empirically set PEEP in most of patients before enrollment and had no prognostic value for PEEP setting. EEEP level was 14 (12-18.25) mbar and it was higher than LIP in 96.4% patients. Distribution of EEEP values was close to normal unlike LIP Chest wall compliance was less than normal (100 ml/mbar) in 46% of patients. EEEP has correlation with body mass index (rho 0.554, p=0.002). We did not find any correlation between intra-abdominal pres- sure (IAP) and EEEP (p=0.376) or IAP and LIP (p=0.464). PEEP levels higher than 14 mbar led to significant decrease in Cstat and Clung (p<0.001). We observed significant decrease in VCO at PEEP levels more than 16 mbar, i.e., more than EEEP median. PEEP levels more than 16 mbar decreased VCO2/EtCO2, (decreased pulmonary perfusion) from 7.47 (6.54-8.7) at PEEP 14 mbar to 7.32 (6.35-8.76) at PEEP 20 mbar (p=0.004). PEEP setting at EEEP level increased PaO/FiO2 from 205 (154-235) to 280 (208-358) mmHg (p<0.001), did hot change Vdalv (p=0.093) and decreased Cstat and Clung in the most of patients (64.3%). CONCLUSION: L1P was lower than empirically set PEEP in most patients and did not help to optimize gas exchange. PEEP setting at EEEP level in patients with parenchimal respiratory failure increases PaO/FiO, (reflects opening of collapsed alveoli), decreases volume of expired carbon dioxide and decreases lung compliance (reflects overdistenion of opened alveoli). VCO2/EtCO2 ratio decreases (decreased pulmonary perfusion) at PEEP levels more than 16 mbar, which was more than EEEP. PMID- 25549488 TI - [Fat embolism syndrome in skeletal trauma: particularities of the diagnosis, economic aspects and the role of non-invasive ventilation in intensive care]. AB - The article deals with a multicenter study that demonstrates the possibility and feasibility of noninvasive ventilation in patients with skeletal trauma complicated wiith fat embolism syndrome. The authors found additional criteria for the severity of the condition of patients with trauma. Important criteria for the choose a type of ventilation (non-invasive and invasive) is the lack of consciousness, desynchronization of a patient with ventilator and the need for a specialized regimes or miorelaxation to synchronize with the respirator. PMID- 25549489 TI - [Modern diagnostic approaches to malignant hyperthermia susceptibility]. AB - Malignant hyperthermia is a well-known rare life-threatening autosomal-dominant pharmacogenetic disease, The arti- cle deals with a halothane-caffeine contracture test. The test is a model of muscle reaction to triggers in-vitro and it is the "golden standard" for malignant hyperthermia susceptibility (MHS) diagnosis. Genetic analysis is less invasive, but its sensitivity is significantly lower. The review discusses both the methods which are essential to be completely reproduced in Russia, and their role in modern approach to MHS diagnosis. PMID- 25549490 TI - [Diagnostics of pneumothorax with ultrasound]. AB - The article deals with a method of pneumothorax diagnostics based on verification of four ultrasound sings--lung sliding absence, B-lines absence, lung pulse absence and lung point presence. Use of ultrasound allows to quickly diagnose a pneumothorax and to monitor the condition of pleural space. Introduction of the ultrasound methods into routine work ICU specialists can increase safety of patients. PMID- 25549491 TI - [Independent lung ventilation for asymmetric injury: case report as a demonstration of common challenge]. AB - The article deals with a case of conventional mechanical ventilation in 75 y.o. woman with the background of uncompensated diabetes mellitus, suffering from bilateral pneumonia with predominantly left-sided lesion and severe sepsis. The conventional mechanical ventilation with high pressure levels led to arterial hypoxemia with P/F ratio 52. Independent lung ventilation immediately increased oxygenation up to P/F ratio 225 and evidently improved left lung aeration. The case demonstrates that while applying high pressures to open alveoli, we could not only provoke ventilator-induced lung injury and low cardiac output, but also "squeeze out" pulmonary perfusion from ventilated areas to non-ventilated ones with less intraalveolar pressure levels. PMID- 25549492 TI - [Transesophageal tracheal intubation in patient with tracheoesophageal fistula and double level cicatricial tracheal stenosis]. AB - The article deals with a case of successful anaesthesia management during the surgery due to tracheoesophageal fistula and double level cicatricial tracheal stenosis. Such surgeries are accompanied with technical and organizational difficulties both for an anaesthesiologists and endoscopist. The article discusses tactics of anaesthesia management during transesophageal balloon dilatation of tracheal stenosis, transesophageal tracheal intubation and respiratory techniques during the separation of tracheoesophageal fistula and tracheal resection. PMID- 25549493 TI - [Vladimir L'vovich Kassil' (to the 80th anniversary of birthday)]. PMID- 25549494 TI - [Alexandr Anatol'evich Eremenko (to the 60th anniversary of birthday)]. PMID- 25549495 TI - Genetic diversity and effect of natural selection at apical membrane antigen-1 (AMA-1) among Iranian Plasmodium vivax isolates. AB - Apical membrane antigen-1 (AMA-1) of Plasmodium vivax Grassi et Feletti, 1890 is a promising malaria vaccine candidate. However, antigenic variation is a major problem to design a universal malaria vaccine. Hence, detailed understanding of the pvama-1 gene polymorphism can provide conductive information on this potential vaccine component. Therefore, this study investigated the extent of genetic polymorphisms at domain I (DI), DII and partial DIII of AMA-1 among Iranian P. vivax isolates. Out of 107 blood samples, 92 were analysed based on the quality of the sequencing data. The sequences were classified into 53 haplotypes. Amino acid changes were observed at 31 positions that 17 were located at DI, 11 were at DII and the rest of them (3 positions) were at DIII. Thus, codon polymorphisms at DI were found to be higher than DII. Also, five of these polymorphic codons (D242E, T374P, S389R, Y391F, I395F) were novel and have not been reported yet. Neutrality analysis by using the dN-dS difference (the difference between the rate of non-synonymous and synonymous mutations) showed a negative diversifying selection at DI, DII and across the length of both domains. The potential B-cell epitopes were found in 5 regions of the PvAMA-1 with 10 mutation sites (E145A, K188N, E189N/K/D, K190Q/E, P210S, E227V, D242E, R249H, G253E, K352E), whereas only one mutation (G288E) has been detected in intrinsically unstructured/disordered regions. Fixation index (Fst) estimation between Iranian and Indian isolates (0.0131) indicated a significant low genetic differentiation. Distribution of the polymorphic sites and IURs mapped on a three dimensional structure of PvAMA-1 showed that these regions were located at two opposite faces of the molecule. In conclusion, the results have significant value in the design and development of a malaria vaccine based on this antigen. PMID- 25549496 TI - Quill mites of the subfamily Picobiinae (Acari: Syringophilidae) parasitising African birds, with description of two new species. AB - Two new species of the subfamily Picobiinae (Acari: Prostigmata: Syringophilidae) are described: Picobia ploceus sp. n. from Ploceus ocularis Smith (Passeriformes: Ploceidae) and Picobia lamprotornis sp. n. from Lamprotornis superbus (Ruppell) (Passeriformes: Sturnidae), both from Kenya. Additionally, new hosts are recorded: Turdoides jardineii (Smith) (Passeriformes: Leiothrichidae) from Kenya and Tanzania, T. rubiginosa (Ruppell) from Kenya, T. leucopygia (Ruppell) from Zambia and Namibia, for Picobia dziabaszewskii Glowska, Dragun-Damian et Dabert, 2012; Pycnonotus barbatus (Desfontaines) (Passeriformes: Pycnonotidae) from Kenya, for Picobia pycnonoti Glowska, Skoracki et Khourly, 2007; Dendropicos griseocephalus (Boddaert) (Piciformes: Picidae) from Tanzania and D. goertae (St. Muller) from Kenya, for Neopicobiafreya Skoracki et Unsoeld, 2014; Dendropicos fuscescens (Vieillot) from Zambia and Campethera nubica (Boddaert) from Kenya, for Picobia dryobatis (Fritsch, 1958). PMID- 25549497 TI - Modelling potential presence of metazoan endoparasites of bobcats (Lynx rufus) using verified records. AB - Helminth parasites of wild and domestic felines pose a direct or potential threat to human health. Since helminths depend on multiple environmental factors that make their transmission possible, it is imperative to predict the areas where these parasites may complete the transmission to potential hosts. Bobcats, Lynx rufus (Schreberer), are the most abundant and widely-distributed wild felid species in North America. The increase of population densities of bobcats raises concerns about their importance as reservoirs of pathogens and parasites that may affect wildlife, domestic animals and humans. Our objective was to predict the potential presence of the tapeworm Taenia rileyi Loewen, 1929, the fluke Alaria marcianae (La Rue, 1917) and the roundworm Toxocara cati (Schrank, 1788) in southern Illinois. The empirical presence of these parasites in localities across the region was analysed in combination with a sampling bias layer (i.e. bobcat presence) and with environmental data: layers of water, soil, land cover, human density and climate variables in MAXENT to create maps of potential presence for these three species in an area of 46436 km2. All climatic variables were low contributors (0.0-2.0% contribution to model creation) whereas land cover surfaced as an important variable for the presence of A. marcianae (7.6%) and T. cati (6.3%); human density (4.8%) was of secondary importance for T. rileyi. Variables of importance likely represent habitat requirements necessary for the completion of parasite life cycles. Larger areas of potential presence were found for the feline specialist T. rileyi (85%) while potential presence was less likely for A. marcianae (73%), a parasite that requires multiple aquatic intermediate hosts. This study provides information to wildlife biologists and health officials regarding the potential impacts of growing bobcat populations in combination with complex and changing environmental factors. PMID- 25549498 TI - Eutetrarhynchid trypanorhynchs (Cestoda) from elasmobranchs off Argentina, including the description of Dollfusiella taminii sp. n. and Parachristianella damiani sp. n., and amended description of Dollfusiella vooremi (Sao Clemente et Gomes, 1989). AB - During a parasitological survey of teleosts and elasmobranchs in the Argentine Sea, 3 species of eutetrarhynchids were collected from the batoids Myliobatis goodei Garman and Psammobatis bergi Marini, and the shark Mustelus schmitti Springer. The specimens collected from Mu. schmitti were identified as Dollfusiela vooremi (Spio Clemente et Gomes, 1989), whereas the specimens from My. goodei and Ps. bergi resulted in new species of Dollfusiella Campbell et Beveridge, 1994 and Parachristianella Dollfus, 1946, respectively. Dollfusiella taminii sp. n. from Ps. bergi is characterised by a distinct basal armature with basal swelling and a heteroacanthous homeomorphous metabasal armature with 7-9 falcate hooks per principal row. Parachristianella damiani sp. n. from My. goodei lacks a distinct basal armature, having 2-3 initial rows of uncinate hooks, a heteroacanthous heteromorphous metabasal armature with the first principal row of small hooks, followed by rows with 10-14 large hooks. This is the first record of Parachristianella in the southwestern Atlantic. The amended description of D. vooremi includes the detailed description of the tentacular armature, including SEM micrographs of all tentacular surfaces. This species is characterised by a basal armature consisting of rows of uncinate and falcate hooks, a basal swelling and a metabasal armature with billhooks on the antibothrial surface and uncinate hooks on the bothrial surface. The scolex peduncle of D. vooremi is covered with enlarged spinitriches. This species is restricted to carcharhiniform sharks, since the report of D. vooremi in Sympterygia bonapartii Muller et Henle off Bahia Blanca (Argentina) is dubious. PMID- 25549499 TI - A new genus and two new species of lecanicephalidean tapeworms from the striped panray, Zanobatus schoenleinii (Rhinopristiformes: Zanobatidae), off Senegal. AB - Recognised for their diversity in apical structure morphology, members of the cestode order Lecanicephalidea Wardle et McLeod, 1952 known to date exhibit relatively mundane and uniform acetabular morphology. A new lecanicephalidean genus, Zanobatocestus gen. n., is proposed for two new species found parasitising the spiral intestine of the striped panray, Zanobatus schoenleinii (Muller et Henle), off Senegal that are highly unusual in acetabular morphology. Unlike the members of the 21 recognised lecanicephalidean genera, which possess simple, uniloculate suckers or bothridia, Zanobatocestus minor sp. n. and Z. major sp. n. possess biloculate bothridia. The form of their apical structures and cocoons readily distinguish the two new species from one another. Zanobatocestus minor sp. n. exhibits an apical modification of the scolex proper that is narrow and elongated, an apical organ that is small and internal, and eggs in cocoons forming linear strands, whereas Z. major sp. n. exhibits an apical modification of the scolex proper that is wide and short, an apical organ that is extensive and primarily external, and eggs in cocoons primarily as doublets with bipolar filaments. Given the typically high host specificity of lecanicephalidean cestodes, as parasites of the only genus and species currently considered valid in the family Zanobatidae, Zanobatocestus gen. n. is likely to remain one of the less specious lecanicephalidean genera. PMID- 25549500 TI - Two new and two redescribed species of Anonchotaenia (Cestoda: Paruterinidae) from South American birds. AB - Morphological examination of novel specimens of paruterinid cestodes from passerine birds from Brazil and Chile and of museum specimens from Paraguay revealed two new species: Anonchotaenia prolixa sp. n. from Elaenia albiceps chilensis Hellmayr from Chile, and Anonchotaenia vaslata sp. n. from Tyrannus melancholicus (Vieillot) (type host) and Myiodynastes maculatus (Statius Muller) from Paraguay. The generic diagnosis of Anonchotaenia Conn, 1900 is amended, prompted by the presence of the armed cirrus and the elongated cirrus sac of A. prolixa. Two species were redescribed: Anonchotaenia brasiliensis Fuhrmann, 1908 from Tachyphonus coronatus (Vieillot) and Thraupis cyanoptera (Vieillot) (new host records) from Brazil, and Thraupis sayaca (Linnaeus) and Volatinia jacarina (Linnaeus) from Paraguay (new host and geographic records); and Anonchotaenia macrocephala Fuhrmann, 1908 from Tachycineta leucorrhoa (Vieillot) (new host record) from Brazil, Tachycineta meyeni (Cabanis) from Chile (new host and geographic record) and Stelgidopteryx ruficollis (Vieillot) from Paraguay (new host and geographic record). Scanning electron microscopy of A. brasiliensis and A. macrocephala revealed less microthrix variation than has been reported for other cyclophyllidean taxa. Sequence data were generated for nuclear ssr- and lsr DNA and mitochondrial rrnL and cox1 for A. prolixa, A. brasiliensis, and A. macrocephala. Maximum likelihood and Bayesian inference analyses supported each species as distinct, but revealed cryptic diversity among A. brasiliensis specimens from different host families. New host records of A. brasiliensis and A. macrocephala prompted a formal assessment of host specificity. Anonchotaenia prolixa was found to be oioxenous (HS(S) = 0), A. vaslata and A. macrocephala were found to be metastenoxenous (HS(S) = 3.000 and 3.302, respectively), whereas A. brasiliensis was found to be euryxenous (HS(S) = 5.876). Anonchotaenia brasiliensis has been found parasitising several species of different passerine families that participate in mixed-species foraging flocks in the Atlantic Forest. A diversity of species of other families join these flocks and are among the substantial number of South American passerine species yet to be examined for cestodes. PMID- 25549501 TI - A new species of Pseudocrepidobothrium (Cestoda: Proteocephalidea) from Pseudoplatystoma reticulatum (Pisces: Siluriformes) in the Parana River basin (Argentina). AB - This study describes the proteocephalidean tapeworm Pseudocrepidobothrium chanaorum sp. n. (Proteocephalidae: Proteocephalinae), which was found in the intestine of Pseudoplatystoma reticulatum (Eigenmann et Eigenmann) from the Colastine River, a tributary of the Parana River. The new species differs from the two other species of the genus, P. eirasi (Rego et de Chambrier, 1995) and P. ludovici Ruedi et de Chambrier, 2012, parasites of Phractocephalus hemioliopterus (Bloch et Schneider) from the Amazon River in Brazil, in having fewer proglottides (4-8 without ventral appendages vs 7-12 with ventral appendages and 20-36 without ventral appendages, respectively), a smaller scolex (350-450 MUm wide vs 495-990 MUm and 515-1020 MUm wide, respectively), in the total number of testes (21-25 vs 21-51 and 37-79, respectively), a cirrus-sac usually directed anteriorly if the vagina is posterior to the cirrus-sac vs transversely situated in the known species. The study of the tegumental surface of Pseudocrepidobothrium spp. revealed the presence of four types of microtriches: papilliform, acicular and capilliform filitriches, and gladiate spinitriches. The three species have a similar microthrix pattern, with minor differences on the immature proglottis surface. Pseudocrepidobothrium chanaorum sp. n. is the ninth proteocephalid reported from P. reticulatum. PMID- 25549502 TI - A new genus and species of Heligmonellidae (Nematoda: Trichostrongylina) parasitic in Delomys dorsalis (Rodentia: Sigmodontinae) from Misiones, Argentina. AB - Alippistrongylus bicaudatus gen. et sp. n. (Nematoda: Heligmonellidae) is described from the striped Atlantic forest rat, Delomys dorsalis (Hensel) (Rodentia: Sigmodontinae), from the province of Misiones in Argentina. The new genus and species is characterised by a synlophe of 21 unequal ridges in both sexes without a gradient in size, with two ridges weakly sclerotised and oriented perpendicularly in the dorsal left quadrant; males with a highly dissymmetrical bursa with a hypertrophied right lobe, and females with a dorsal conical appendage just posterior to the vulva, conferring a two-tailed appearance to the female worms. PMID- 25549503 TI - A new species of Anchistrotos (Copepoda: Taeniacanthidae) from hilsa shad, Tenualosa ilisha (Actinopterygii: Clupeidae), off Iraq. AB - A new species of parasitic copepod Anchistrotos tangi sp. n. (Cyclopoida: Taeniacanthidae) is described based on adult female specimens collected from the gills of hilsa shad, Tenualosa ilisha (Hamilton, 1822) (Actinopterygii: Clupeidae) captured off Iraq. The new species differs from its congeners by having the following combination of characters in the adult female: 1) the rostral area sclerotised; 2) the presence of row of spinules on the proximal and distal margins of the anal somite; 3) the maxilliped claw with 2 long whip-like setae just crossing the distal edge of claw with serrated terminal margin; and 4) the leg 5 ornamented with patched spinules distally. This is the ninth nominal species of Anchistrotos Brian, 1906. PMID- 25549504 TI - Inversion improves the recognition of facial expression in thatcherized images. AB - The Thatcher illusion provides a compelling example of the face inversion effect. However, the marked effect of inversion in the Thatcher illusion contrasts to other studies that report only a small effect of inversion on the recognition of facial expressions. To address this discrepancy, we compared the effects of inversion and thatcherization on the recognition of facial expressions. We found that inversion of normal faces caused only a small reduction in the recognition of facial expressions. In contrast, local inversion of facial features in upright thatcherized faces resulted in a much larger reduction in the recognition of facial expressions. Paradoxically, inversion of thatcherized faces caused a relative increase in the recognition of facial expressions. Together, these results suggest that different processes explain the effects of inversion on the recognition of facial expressions and on the perception of the Thatcher illusion. The grotesque perception of thatcherized images is based on a more orientation sensitive representation of the face. In contrast, the recognition of facial expression is dependent on a more orientation-insensitive representation. A similar pattern of results was evident when only the mouth or eye region was visible. These findings demonstrate that a key component of the Thatcher illusion is to be found in orientation-specific encoding of the features of the face. PMID- 25549505 TI - Objects influence the shape of remembered views: examining global and local aspects of boundary extension. AB - Boundary extension is a constructive memory error for views of scenes in which viewx tendto be remembered as more spatially expansive than they appeared. In seven experiments xwe examinedwhether local differences in boundary extension within views might exist by presenting par ticipants ith overhead views of single, elongated objects or object pairs on textured ground surfaces i:n whichobjects were oriented either vertically or horizontally. Memory for views' spatial expanse xwas testedwith either a view-recognition test or a border adjustment test in which participants could ad just thespatial expanse of a test view using the computer's mouse. The border-adjustment test was uused tossess local boundary extension (primarily); the view-recognition test was used to assess paparticipants'emories for the overall spatial expanse of views (ie global boundary extension). Across exexperiments,n the border-adjustment tests specifically, participants showed more spatial expanse along the obobject'songer axis, in some cases restricting the view along the object's shorter axis. In addition, the rerecognition-t data revealed greater boundary extension for views with vertically oriented objects than for x.iviewsth horizontally oriented objects. Taken together, the results suggest that objects in scene x iviews canfect both local and global aspects of memory for spatial expanse of scene views. PMID- 25549506 TI - An effect of contrast and luminance on visual representational momentum for location. AB - Effects of the contrast of target luminance and background luminance, and of the absolute level of target luminance, on representational momentum for the remembered final location of a previously viewed moving target were examined. Targets were high in contrast or luminance, decreasing in contrast or luminance, increasing in contrast or luminance, or low in contrast or luminance; the background was black or white. Representational momentum for target location was larger if targets were high or increasing in contrast or luminance and smaller if targets were low or decreasing in contrast or luminance. Representational momentum for target location was larger if targets were presented on a white background than on a black background. Implications for theories of localization and for theories of representational momentum are discussed. PMID- 25549507 TI - Basis for motion capture in terms of illusory motion signal obtained from oblique lines. AB - As in the Pinna illusion, when an observer moves their head backwards and forwards while fixating on the center of concentric circles that consist of oblique lines, the observer sees illusory rotation of those circles. When several dots are superimposed on the concentric circles, an observer sees the illusory rotation not only for the circles, but also for those dots (Ichikawa, Masakura, & Munechika, 2006, Perception, 35, 933-946). This illusory rotation of the dots, which have no means of generating illusory motion themselves, is based on motion capture. We examined how the number of dots affects the illusory rotation for such circles and superimposed dots. Results showed that the illusory rotation for the inner circle was most salient when the superimposed dots were extremely numerous or few, although the illusory motion for the dots increased with the increment of the dots. These results suggest that motion capture depends upon a locally obtained motion signal from the oblique lines, and upon the accumulation of the motion signal within the groups of superimposed dots. PMID- 25549508 TI - Superadditivity of the Ebbinghaus and Muller-Lyer illusions depends on the method of comparison used. AB - Illusions are useful tools for understanding fundamental visual processing. The method used to measure illusion strength is important but often neglected. We identified two methods of comparing bipart illusion elements (eg of the Muller Lyer or Ebbinghaus illusions). For simultaneous adjustment an increase in size of one figure causes a decrease in the other. For independent adjustment one figure remains fixed while the other is adjusted to match it. These direct comparison illusion effects are contrasted to separate comparison illusion effects, where a neutral stimulus is matched to each illusory figure. If the illusion is stronger for direct comparisons, it is superadditive. The superadditivity of the Ebbinghaus illusion has been investigated using only simultaneous adjustment (Franz, Gegenfurtner, Bulthoff, & Fahle, 2000, Psychological Science 11 20-25), and the Muller-Lyer illusion using only independent adjustment (Gilster & Kuhtz Buschbeck, 2010, Journal of Vision 10 (1):11, 1-13). Superadditivity was found for the Ebbinghaus but not the Muller-Lyer illusion, but this may have been due to the comparison method or differences between the illusions. Here we test both illusions with both methods of adjustment. Our results suggest that both illusions are superadditive for simultaneous adjustment, but for independent adjustment only under limited circumstances. Implications for research on illusions and perception and action are discussed. PMID- 25549509 TI - The perception of natural and modulated movement sounds. AB - The motor system is engaged when we perceive movement in the environment, even when we have no sensorimotor experience of that movement. It has been suggested that this ability relies on internal models that comprise specific exteroceptive representations, such as audition and vision. It has been shown that, for human movements, the quality of perception depends on the closeness between the perceived movement and the perceiver's own capability of reproducing it. Thus, if we are able to reproduce a movement, we also have the interoceptive motor memories that enable us to run internal models and perceive the same movements more accurately when merely observed. In a behavioral study we investigated if participants would be able to distinguish between self-produced and other produced movement sounds from a previously recorded hurdling performance. We also analyzed if participants' discriminative ability would vary as a function of specific sound features, examining rhythmic step structure and amplitude range. The results reveal that participants were able to distinguish between their own and others' movement sounds. However, changing either rhythmic step structure or amplitude range of the sounds did not influence this self-other discrimination. We suggest that identification of one's own movement sounds is holistically achieved as an auditory gestalt. PMID- 25549510 TI - Effects of radial direction and eccentricity on acceleration perception. AB - Radial optic flow can elicit impressions of self-motion--vection--or of objects moving relative to the observer, but there is disagreement as to whether humans have greater sensitivity to expanding or to contracting optic flow. Although most studies agree there is an anisotropy in sensitivity to radial optic flow, it is unclear whether this asymmetry is a function of eccentricity. The issue is further complicated by the fact that few studies have examined how acceleration sensitivity is affected, even though observers and objects in the environment seldom move at a constant speed. To address these issues, we investigated the effects of direction and eccentricity on the ability to detect acceleration in radial optic flow. Our results indicate that observers are better at detecting acceleration when viewing contraction compared with expansion and that eccentricity has no effect on the ability to detect accelerating radial optic flow. Ecological interpretations are discussed. PMID- 25549511 TI - From the wrong point of view! Athletes' ability to identify structured playing patterns suffers from the misalignment of tactic boards during time-outs in professional basketball. AB - In professional basketball, coaches commonly use time-outs to instruct players on the upcoming playing pattern. In an explorative study a total of 154 time-outs in professional basketball were analyzed and the data revealed that coaches usually present these playing patterns from their own viewing perspective on the tactic board. This habit leads to a misalignment of the instructed playing pattern with the viewing perspective of players, so that they have to mentally rotate the pattern's spatial-temporal information before they can execute the action on the court. In an experimental study thirty-two basketball experts and forty-eight novices watched video clips of different playing patterns, which were presented from their own or from a coaches' viewing perspective. Identification performance suffered significantly for experts and novices when the upcoming pattern was presented upside down. It is suggested that basketball coaches should align their tactic boards with the viewing perspective of their athletes during time-outs. PMID- 25549512 TI - The Butcher's Tongue Illusion. AB - We report two experiments, based on a novel variant of the Rubber Hand Illusion (RHI), in which tactile stimulation is referred to an artificial (out-of-body) tongue. In the experiments reported here the participant's tongue was stimulated while they looked at a mirrored dummy tongue. On average, the participants agreed with the statement that they felt as if they had been touched in the location where they saw the rubber tongue being touched (experiment 1), thus demonstrating visual capture. When the external tongue was illuminated with a laser pointer (experiment 2), a significant proportion of the participants reported feeling either tactile or thermal stimulation on their own tongue. These results therefore demonstrate that the multisensory integration of visual, tactile, and proprioceptive information that gives rise to the RHI can be extended to the tongue (a body part that is rarely seen directly). PMID- 25549513 TI - Is he playing solo or within an ensemble? How the context, visual information, and expertise may impact upon the perception of musical expressivity. AB - Visual information is imperative when developing a concrete and context-sensitive understanding of how music performance is perceived. Recent studies highlight natural, automatic, and nonconscious dependence on visual cues that ultimately refer to body expressions observed in the musician. The current study investigated how the social context of a performing musician (eg playing alone or within an ensemble) and the musical expertise of the perceivers influence the strategies used to understand and decode the visual features of music performance. Results revealed that both perceiver groups, nonmusicians and musicians, have a higher sensitivity towards gaze information; therefore, an impoverished stimulus such as a point-light display is insufficient to understand the social context in which the musician is performing. Implications for these findings are discussed. PMID- 25549514 TI - Stand up and be counted. PMID- 25549515 TI - The reliability of using postero-anterior cephalometry and cone-beam CT to determine transverse dimensions in clinical practice. AB - AIM: This study primarily aimed to assess the accuracy of classically-advocated reference points for the measurement of transverse jaw-base and dental relationships using conventional Postero-Anterior Cephalometry (PAC) and Cone Beam Computed Tomography (CBCT). METHOD: PAC and CBCT images were collected from 31 randomly selected orthodontic patients (12 males, 19 females), all of whom had a full permanent dentition. The transverse widths of the maxilla, mandible and the dentition were measured using reference points on both image modalities. Confidence intervals, intra-class coefficients and Bland Altman plots were used to assess the measurement differences derived from the two acquirement methods. RESULTS: Measurements on PAC and CBCT images demonstrated statistically significant differences in the majority of the assessed variables. The interjugal (J-J) width was one of only two variables which did not demonstrate a statistically significant difference on image comparison. The mean differences of the antegonial width (Ag-Ag) (-4.44mm, 95% CI -5.38 to -3.51) represented the greatest difference between the imaging techniques. The application of these points to a transverse skeletal analysis (J-J/Ag-Ag ratio) revealed that five of the 31 subjects (16%) recorded 'false positive' readings according to the derived data. CONCLUSION: It is recommended that clinicians are cautious when interpreting and making decisions related to transverse dimensions derived from a PAC. The PAC has a higher tendency to falsely identify individuals who require maxillary expansion procedures based on conventional clinical criteria. The errors primarily associated with identifying structures which represent the width of the mandible are significant in both PAC and CBCT techniques and require further investigation. It is postulated that the confounding effects of overlying soft tissues have a sianificant impact on a clinician's ability to identify relevant landmarks. PMID- 25549516 TI - A qualitative investigation of RANKL, RANK and OPG in a rat model of transient ankylosis. AB - INTRODUCTION: Previous studies have found ankylosis occurs as a part of the inflammatory process of aseptic root resorption initiated in a rat model. The physiologic mechanisms behind the development of dentoalveolar ankylosis and healing response are still unclear. While receptor activator of nuclear factor kappabeta ligand (RANKL), receptor activator of nuclear factor-kappabeta (RANK) and osteoprotegerin (OPG) have gained momentum in the understanding of resorption, no study to date has investigated their role in dentoalveolar ankylosis. AIMS: The aims of this study were to investigate if, and when, ankylosis occurred in the rat PDL, whether the resolution of ankylosis occurred with time and, finally, to observe the expression of RANKL, RANK and OPG during the ankylotic process. MATERIALS AND METHODS: Dry ice was applied for 20 minutes to the upper right first molar crown of 15 eight-week-old, male Sprague-Dawley rats. An additional three rats served as untreated external controls. Groups of three rats were sacrificed after the thermal insult on day 0, 4, 7, 14 and 28 respectively. Each maxilla was dissected out and processed for histological examination and RANKL, OPG and RANK immunohistochemistry. RESULTS: By the use of light microscopy and H&E staining, no ankylosis was detected in the external control group and the experimental groups at days 0 and 4. On day 7, disruption within the periodontal ligament was observed in the interradicular region and the initial signs of ankylosis were seen in the form of finger-like projections extending from the alveolar bone towards the cementum. Fourteen days after the thermal insult, all animals exhibited extensive ankylosis that spanned the entire interradicular periodontal space. At 28 days, the development of ankylosis appeared to have ceased and repair was observed, together with an intact periodontal ligament in all but one rat. Positive staining results were obtained with RANKL, RANK and OPG antibodies. The expressions of RANKL, RANK and OPG were similar in the external control group, 0-, 4-, and 28-day experimental groups. In the 7- and 14-day experimental groups, RANKL, RANK and OPG were expressed in the blood vessels within the ankylotic regions. CONCLUSIONS: During the development of ankylosis and its resolution, it was concluded from their simultaneous presence that there is a complex interaction between RANKL, RANK and OPG that requires further investigation. PMID- 25549517 TI - Changes in maxillary molar pulp blood flow during orthodontic intrusion. AB - INTRODUCTION/OBJECTIVE: The aim of this prospective study was to evaluate the effects of maxillary first molar intrusion on pulpal blood flow (PBF) in humans as recorded by laser Doppler flowmetry (LDF). MATERIALS AND METHODS: Maxillary first molars of 16 participants were divided into two groups. In the study group, 20 teeth in 10 participants were subjected to an intrusive force of 100 g delivered from mini-implants for 6 months. A control group of 6 subjects (12 teeth) received no orthodontic treatment. LDF measurements were recorded at baseline and at 3 days, 3 weeks, 3 months and 6 months during intrusion. Data was analysed using the Wilcoxon Signed Rank and Mann-Whitney U tests, with a level of p < 0.05 considered statistically significant. RESULTS: No significant changes in PBF perfusion units (PU) were observed in the control group over the course of the study. However, PBF in the study group was significantly higher at TO (8.7 +/ 0.9 PU) when compared with T1 (6.1 +/- 0.6 PU, p < 0.001) and T2 (6.0 +/- 0.6 PU, p < 0.001). PBF did not vary significantly between T1 and T2 (p = 0.073) or between T3 and T4 (p = 0.262). Moreover, PBF at the end of the study (T4) was similar to baseline PBF values for both groups (study group: p = 0.687; control group: p = 0.525). CONCLUSIONS: Despite significant short-term regressive changes in pulpal tissue during continuous molar intrusion with mini-implants and an applied force of 100 g, blood vessel function was maintained throughout intrusion, as indicated by LDF measurements of PBF, which tended to return to baseline values by the end of the observation period. These results highlight the changes that can occur in molar vascularity, especially during six months of intrusion. PMID- 25549518 TI - The effects of denervation and formoterol administration on facial growth. AB - OBJECTIVE: To identify and demonstrate possible alterations of skeletal structures which might follow either unilateral surgical denervation of the masseter muscle, unilateral intramuscular injection of formoterol directly into the masseter muscle, or intramuscular formoterol injection after surgical denervation. MATERIALS AND METHODS: Male Sprague Dawley rats (N = 16; four weeks of age) were prepared as four groups: 1. surgical sham + saline injection into the masseter muscle (sham); 2. surgical denervation of the masseter muscle only (den.); 3. surgical denervation of the masseter muscle plus intramuscular formoterol injection into the affected muscle (den.+form.); 4. intramuscular formoterol injection into the masseter muscle only (form.). The specimens were submitted for CT examination, the skulls and hemimandibles were photographed and measurements of craniofacial bones were made. RESULTS: In this relatively small sample, comparisons between non-experimental and experimental sides revealed differences, both within the groups and for the same measurements between groups, with the den. and den.+form. groups showing the most change. Relative increases in the gonial angle shown in these groups occurred bilaterally, with the change on the experimental side always greater in magnitude than the change on the contralateral side. CONCLUSIONS: Surgical denervation of the masseter muscle leads to an alteration in the size and shape of the skeletal structures close to the zygoma and the mandible. The intramuscular injection of formoterol into denervated masseter muscle seems to limit this skeletal alteration after surgical denervation. PMID- 25549519 TI - A three-dimensional evaluation of Maori and New Zealand European faces. AB - OBJECTIVE: Maori patients are often inappropriately treated using Caucasian norms, despite obvious differences in facial morphology. There is currently very little data concerning the nature and/or magnitude of these differences in facial features. The objective of the present study was therefore to evaluate the facial features of Maori and New Zealand (NZ) Europeans. METHODS: Two convenience samples of 30 Maori and 30 NZ Europeans, evenly matched for age and gender, were recruited from amongst students of the University of Otago, New Zealand. Using a 3D white-light scanner, 12 facial scans were taken of each participant, which were then merged to form a single 3D image of the face. Prior to scanning, round markers were fixed to the skin in order to facilitate the localisation of facial anthropometric points and from which vertical, sagittal, and transverse measurements were assessed from the 3D facial image. Univariate and multivariate analyses of variance were used to test for differences between the two groups before and after adjusting for body mass index (BMI). RESULTS: Significant differences were found in vertical, sagittal, and transverse facial dimensions, before and after adjusting for BMI. The overall face of Maori was significantly larger than that of NZ Europeans, although the facial proportions were generally similar. However, Maori had a broader face, more anterior position of the chin and reduced facial convexity in comparison with NZ Europeans (p < 0.01). CONCLUSION: Maori have markedly different sagittal facial features compared with NZ Europeans. These distinctive features may reflect important differences in environmental and genetic influences between the two populations. The findings from the present study may assist the clinician in the treatment planning and assessment of facial dysmorphology in these ethnic groups. PMID- 25549520 TI - Effects of low-intensity pulsed ultrasound on bone formation after the expansion of the inter-premaxillary suture in rats: a histologic and immunohistochemical study. AB - BACKGROUND: Orthodontic maxillary expansion is a commonly-performed treatment approach to correct transverse maxillary deficiencies by separating the mid palatal suture. To obtain a successful treatment result and prevent relapse, the expanded maxillary sutures require maintenance by means of qualified bone reorganisation. AIM: To assess the effects of low-intensity pulsed ultrasound (LIPUS) on sutural bone formation after the expansion of the interpremaxillary suture in rats. METHODS: Sixteen male Wistar rats, 6 to 8-week old, were used. The expansion appliance comprised a helical spring fabricated from 0.014 inch stainless steel wire (Dentaurum, Ispringen, Germany). The rats were divided into two equal groups and randomly assigned to the LIPUS treatment group or a sham operation group. LIPUS was delivered via a 2.5 cm diameter ultrasound transducer (Exogen, Smith and Nephews, Inc., Memphis, TN, USA) for 20 minutes per day during 7 days of post-expansion retention. Following retention, the rats' maxillae were surgically removed and histologic and immunohistochemical specimens were prepared and examined. RESULTS: The number of osteoblasts and blood vessel dimensions in the ultrasound group increased but was not significant, compared with the control group. A statistically significant difference in osteocalcin, VEGF and TGF-beta immunoreactivities (p < 0.01) was found in the area of the mineralising tissue. Only VEGF immunoreactivity was significant between two groups (p < 0.01) in the fibrous tissue area. CONCLUSIONS: The area of mineralising tissue in the LIPUS applied group expressed activity markers for osteocalcin, VEGF and TGF-beta compared with a surrounding area of fibrous tissue. Cellular activation in the LIPUS group was greater than that of controls. Therefore, LIPUS may be accepted as a useful approach to enhance sutural bone formation. PMID- 25549521 TI - Severity and outcome assessments of patients undertaking surgical orthodontic treatment. AB - BACKGROUND: Combined orthognathic-orthodontic treatment can be lengthy and expensive. It is therefore important to evaluate the effectiveness of proposed treatment and the likely outcomes. OBJECTIVES: To determine the demographic and surgical details of patients who received orthognathic-orthodontic treatment at Christchurch Hospital, New Zealand, and to assess treatment using the Severity and Outcome Index (SOI). METHODS: An observational and retrospective study was conducted of patients who received surgical orthodontic treatment between 2005 and 2012 at Christchurch Hospital. Pre- and post-treatment lateral cephalometric radiographs of 93 patients were evaluated. Seven cephalometric parameters were assessed using the Severity and Outcome Index. A severity score ranged from 0 for the most severe to 7 for the least severe, while the outcome score ranged from 0 for the worst to 7 for the best outcome. RESULTS: Class II patients had a severity score of 3.4 and the best outcome score of 6.2. Class III patients had a severity score of 3.3 and an outcome score of 6.1. Patients with an anterior open bite (AOB) had the worst severity score of 3.0, and the worst outcome score of 5.9. The overall treatment outcome scores for all groups were statistically significantly greater than the severity scores, which increased from 3.4 to 6.1 (p < 0.05). CONCLUSIONS: Favourable outcomes were achieved for a group of patients with a high need for treatment. Christchurch Hospital appeared to be treating cases of increased severity and gained better treatment outcomes when compared with a United Kingdom (UK) national audit. PMID- 25549522 TI - In vitro spectrophotometric evaluation of Vivera clear thermoplastic retainer discolouration. AB - AIMS: To investigate the in vitro effect of different staining solutions on the colour stability of Vivera retainers. METHODS: Thirty flat specimens fabricated using the Vivera material (Align Technology Inc., CA, USA) were assigned into five Groups (A, B, C, D and E) and immersed at 37 degrees C in solutions of distilled water (control), coffee, tea, red wine, and Coca-Cola. The CIE colour parameters (L*, a*, b*) of each specimen were measured before immersion (T0) and after 12 hours (T1), three days (T2) and seven days (T3) of solution exposure. Colour differences (AE) between the interval groups were calculated. Results: Significant differences were observed concerning (i) L* between T, and T0, Ti and T2 for Group B; (ii) a* between To and T,, T, and T3 for Groups B, C, D and E, as well as between T1 and T2 for Group C; and (iii) b* between To and T,, T2 and T3 for Group B and between T0 and T2 and T1 for Group C. The differences between deltaE(T1-T0), deltaE(T2-T0) and deltaE(T3-T0) were statistically significant for Groups B and C, as well as the difference between deltaE(T1-T0) and deltaE(T2-T0) for Group D. CONCLUSIONS: Coffee, tea and red wine caused visible changes in the retainers' colour. PMID- 25549523 TI - Accelerating orthodontic tooth movement with the aid of periodontal surgery--the practitioner viewpoint. AB - INTRODUCTION: There has been a revival of interest in the acceleration of orthodontic tooth movement (OTM) by inducing injury to dentoalveolar cortical bone. Termed corticotomy, the procedure offers an advantage to adult patients whose bone metabolism is such that any reduction in treatment time would be welcomed. The procedure has been refined for over 100 years and recent research indicates treatment duration may be reduced often by as much as a third, but it is not clear how widely the method is applied in practice. For the procedure to be successful, careful interdisciplinary management by orthodontists and periodontists is required. However, information regarding the attitude and knowledge of practitioners and the frequency of the procedure performed in Australia and New Zealand is lacking. METHODS: A questionnaire was formulated and tested in a pilot study on postgraduate orthodontic and periodontic students at The University of Adelaide. As a consequence of the responses, the wording of several questions was clarified and the sequence modified to produce the final format. Separate questionnaires were developed for specialist orthodontists and periodontists in keeping with their different backgrounds and were distributed at two relevant conferences. RESULTS AND CONCLUSIONS: The number of practitioners who had been involved with at least one corticotomy per annum was low for orthodontists (12%) and periodontists (18%). The majority of those surveyed believed that more research was required on corticotomy-facilitated OTM and would not recommend the procedure to patients without greater investigation of the technique. More than half of the sampled orthodontists indicated that they would never recommend corticotomy-facilitated orthodontics to their patients. The minority who were willing to recommend the procedure would limit involvement to adult patients, the management of ankylosed teeth, impacted canines and patients susceptible to root resorption. Over 90% of the sampled periodontists believed that there were adverse side effects. PMID- 25549524 TI - Body dysmorphic disorder and orthodontics--an overview for clinicians. AB - INTRODUCTION: Patients with body dysmorphic disorder (BDD) often seek aesthetic medical treatment including orthodontics to correct their perceived physical defects. When the disorder pertains to the dentofacial region, it is important for orthodontists to be familiar with this condition. OBJECTIVE: The purpose of this article is to provide an overview of the current knowledge on BDD and its relationship to orthodontics. METHOD: PubMed, Scopus, Science Direct, and Google Scholar databases were searched for publications relating to BDD and orthodontics. Further articles were sourced from the reference lists of the articles identified through the search. RESULTS: The literature recommends that orthodontic patients suspected of having BDD should be referred to a psychiatrist for a definitive diagnosis and subsequent management. However, this may be difficult to implement in clinical practice. Management by a psychiatrist could include pharmacotherapy and cognitive behavioural therapy. There is still debate as to whether orthodontic treatment should be provided for these patients. CONCLUSION: As health care workers providing aesthetic treatment to patients, orthodontists should be aware of BDD and its implications. Risks include repeated requests for unnecessary treatment, dissatisfaction with the result and thus potential for litigation. BDD still remains a challenge to diagnose, and further research is needed to determine the appropriate management of orthodontic patients suffering from the disorder. PMID- 25549525 TI - Orthodontic treatment in cherubism: an overview and a case report. AB - INTRODUCTION: Cherubism is a rare hereditary disease that frequently manifests as a painless enlargement of the mandible and/or maxilla. The disease usually progresses rapidly during the first and second decades of life but it is self limiting and often regresses. Although few orthodontic case reports describing cherubic patients exist, the timing and extent of surgical intervention is controversial. AIM: This present paper aims to review the treatment literature and provide a case report of a patient who underwent orthodontic/surgical management. METHODS: The patient presented with severe cherubism in her late teenage years; her main complaint was poor facial and dental appearance. Multiple teeth were missing and those present demonstrated significant preoperative root resorption. Treatment consisted of orthodontic alignment of the upper anterior teeth and a recontouring osteotomy. RESULTS: Confirmed by the patient, the combination approach led to a significant improvement in facial aesthetics and better self-esteem. Tooth movement through the osseous lesions was uneventful and no further root resoption was observed. CONCLUSION: Orthodontic treatment may be undertaken in those affected by Cherubism even with pre-existing idiopathic root resorption, but patients need to be appropriately informed and consented. PMID- 25549526 TI - Clinical problems with a double tooth and a macrodont in the maxillary anterior area: a case report. AB - BACKGROUND: Fusion is defined as the union between dentine and/or enamel of two normally separated teeth. Gemination is the cleavage of the forming dental germ to produce two partial teeth. The distinction between the conditions is often determined by the number of teeth present. However, this can be confused if supernumerary teeth are considered. AIM: The present case report describes the treatment of a patient who presented with dental fusion and macrodontia involving both upper central incisors. Besides the central incisors displaying characteristics of macrodonts, tooth 21 also showed aspects of fusion. METHODS: Management consisted of the extraction of 11 and 21 and orthodontic mesialisation of the maxillary dentition. Treatment was planned in two phases and at the end of the orthodontic phase, the upper anterior teeth were to be reshaped using composite resin. RESULTS: Orthodontic space closure is a treatment option in the clinical management of an extracted maxillary central double and/or macrodontic tooth. As no permanent teeth were absent, it was presumed that the fusion of 21 occurred with a supernumerary tooth. CONCLUSIONS: Multidisciplinary treatment following the extraction of maxillary central incisors is reported with special attention to the orthodontic and restorative considerations required to improve the aesthetic outcome. PMID- 25549527 TI - Mini-implant-borne Pendulum B appliance for maxillary molar distalisation: design and clinical procedure. AB - A treatment objective of upper molar distalisation may often be required during the correction of a malocclusion. Distalisation is not only indicated for the management of Class II patients, but also for Class III surgery patients who require decompensation in the upper arch if upper incisor retrusion is needed. Unfortunately, most conventional intra-oral devices for non-compliance maxillary molar distalisation experience anchorage loss. A Pendulum type of appliance and a mini-implant-borne distalisation mechanism have been designed which can be inserted at chair-side, without a prior laboratory procedure and immediately after mini-implant placement. For re-activation purposes, a distal screw may be added to the Pendulum B appliance. PMID- 25549528 TI - A simple technique for the direct bonding of a lingual retainer: a clinical hint. AB - The direct bonding of a fixed wire retainer often poses clinical difficulties. While there are several possible techniques, the present paper describes a simple method employing a ball clasp (S handle) to assist in the stabilisation of the wire to be attached. The advantages and disadvantages are indicated. PMID- 25549529 TI - Sterically controlled functionalization of carbon surfaces with -C6H4CH2X (X = OSO2Me or N3) groups for surface attachment of redox-active molecules. AB - Glassy carbon electrodes were modified by electrochemical reduction of a diazonium molecule ((i)Pr3SiOCH2C6H4N2(+)BF4(-)) featuring a triisopropylsilyl protected benzylic hydroxyl group. This electrochemical process introduced a monolayer of (i)Pr3SiOCH2C6H4- groups onto the surface of the electrode. The bulky -Si(i)Pr3 protecting group not only prevents the uncontrolled growth of structurally ill-defined and electronically blocking polyphenylene multilayers, but also separates the phenyl groups in the monolayer. Thus, the void spaces between these aryl units should allow a better accommodation of sizable molecules. Removal of the -Si(i)Pr3 protecting groups by (n)Bu4NF exposed the reactive benzylic hydroxyl functionalities that can undergo further transformations to anchor functional molecules. As an example, redox-active ferrocene molecules were grafted onto the modified electrode via a sequence of mesylation, azidation, and copper-catalyzed [3 + 2] cycloaddition reactions. The presence of ferrocenyl groups on the surface was confirmed by X-ray photoelectron spectroscopic and electrochemical studies. The resulting ferrocene-modified glassy carbon electrode exhibits cyclic voltammograms typical of surface-bound redox active species and remarkable electrochemical stability in an acidic aqueous environment. PMID- 25549530 TI - Overall survival in patients with a re-excision following breast conserving surgery compared to those without in a large population-based cohort. AB - AIM: To investigate the overall survival of invasive breast cancer patients with primary breast conserving surgery (BCS) followed by re-excision compared to those with primary BCS only. The Dutch re-excision indications are less stringent compared to other European and Northern American countries (Society of Surgical Oncology-American Society for Radiation Oncology (SSO/ASTRO) guideline). METHODS: Retrospective analyses in women <75years with breast cancer stage pT1-T3 treated by BCS and radiotherapy between 1999 and 2012 from a population-based database. The national guideline recommends to reserve re-excision for invasive tumours showing 'more than focally positive' margin since 2002. Patients were divided into 'primary BCS only', 're-excision by BCS', and 're-excision by mastectomy'. Multivariable Cox regression analysis was adjusted for patient and systemic treatment characteristics. RESULTS: A total of 11,695 patients were included of which 2156 (18.4%) underwent re-excision. Median time of follow-up was 61months (interquartile range (IQR) 26-101). The 5-year overall survival rates in the 'primary BCS only', 're-excision by BCS' and 're-excision by mastectomy' group were 92%, 95% and 91%, respectively. The 10-year overall survival rates were 81%, 82% and 79%, respectively (P=0.20). After multivariable analyses no significant association was observed between use of and type of re-excision and overall survival. CONCLUSIONS: The overall survival of breast cancer patients with a re excision did not significantly differ from the survival of women who underwent primary BCS only. Advising re-excision only for those tumours showing 'more than focally positive' resection margin appears safe, supposing the long-term safety of the recent SSO/ASTRO guideline that more cautiously recommended re-excision for tumours showing 'ink on tumour'. PMID- 25549531 TI - Evaluating iatrogenic prescribing: development of an oncology-focused trigger tool. AB - BACKGROUND: Drug-related iatrogenic effects are common in oncology because chemotherapy is toxic. The evaluation of the application of the guidelines may be a way to understand the occurrence of adverse drug-related event (ADE). There is no specific method for identifying ADEs and measuring harm to patients in oncology. OBJECTIVE: Our objective was to develop and test an Oncology Trigger Tool (OTT) for ADEs and to describe ADE characteristics and incidence. METHODS: A clinical advisory panel identified situations at high risk of ADE occurrence and built 22 triggers with, in each case, an analysis flowchart to confirm or refute occurrence. The OTT was used to review 288 random admissions (Oct. 2010-Sept. 2011) and measure ADE incidence and severity (CTCAE 4.03 - Common Terminology Criteria for Adverse Events). Tool feasibility (time required), inter-rater (IR) reproducibility and positive predictive value (PPV) were measured. RESULTS: Overall, 884 triggers were detected and 122 ADEs, with 42.4 ADEs/100 admissions or 46.0 ADEs/1000 patient-days, and a 31.1% rate of severe ADEs. The most common ADEs were hyperglycaemia (14.5%), unplanned drug-related admission within 30 days (13.7%) and opiate-induced constipation (12.1%). Unplanned drug-related admission was the most serious (82.4% incidence of severe harm). Mean time for OTT implementation was 21.8 min; IR reproducibility was high (kappa=0.965 (trigger); kappa=0.935 (ADE); kappa=0.853 (harm)); PPV 22-trigger version was 20.7%. CONCLUSIONS: ADE analysis flowcharts coupled with standardised grading of harm considerably reduced IR variability, thus providing a robust oncology-focused trigger tool for use in ADE audits and hospital comparisons. The involvement of a clinical advisory panel in tool development should help drive changes for improving practice. Further research on the OTT is warranted. PMID- 25549532 TI - Copper-catalyzed domino synthesis of nitrogen heterocycle-fused benzoimidazole and 1,2,4-benzothiadiazine 1,1-dioxide derivatives. AB - A convenient copper-catalyzed domino method for the synthesis of nitrogen heterocycle-fused benzoimidazole and 1,2,4-benzothiadiazine 1,1-dioxides has been developed using readily available 2-bromo-N-phenylbenzenesulfonamides and benzimidazole derivatives as the starting materials. The domino process comprises an Ullmann-type N-arylation and intramolecular C-H amination. The inexpensive and efficient copper-catalyzed method should provide a new and useful strategy for for constructing novel, biologically interesting heterocycles containing benzoimidazole and 1,2,4-benzothiadiazine 1,1-dioxide motifs. PMID- 25549533 TI - Editorial overview: Omics: Methods to monitor and manipulate biological systems: recent advances in 'omics'. PMID- 25549534 TI - A case of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome presenting with hypertrophic pachymeningitis. AB - A 43-year-old woman with a 3-year history of headache, fever, and swelling of the forehead, presented to our hospital. A general examination revealed palmar and plantar pustules. Blood analyses showed an elevated white blood cell count, C reactive protein level, and erythrocyte sedimentation rate. Brain MRI revealed a partially thickened cranial bone with gadolinium enhancement, and also abnormally enhanced dura mater. Bone scintigraphy showed involvement of the cranial bone and bilateral sternoclavicular joints. Palmar skin biopsy indicated palmoplantar pustulosis. From these results, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome with associated hypertrophic pachymeningitis was diagnosed. After corticosteroid therapy and tonsillectomy, the clinical symptoms and radiological abnormalities were improved. Clinicians should be aware of SAPHO as a potential unusual cause of hypertrophic pachymeningitis. PMID- 25549535 TI - Pulmonary function tests - an easy selection method for respiratory-gated radiotherapy in patients with left-sided breast cancer. AB - PURPOSE: The purpose of this study was to establish a feasible and convenient method for selection of the subset of patients with left-sided breast cancer for whom respiratory-gated radiotherapy (RT) would be necessary to meet the national recommendation regarding radiation dose to the heart. MATERIAL AND METHODS: The volume of heart receiving a dose equal to or higher than 25 Gy (V25Gy), the mean heart dose (Dmean) and total lung volume (TLV-CT) were obtained from treatment plans based on computer tomography (CT) series recorded during free breathing (FB), and the correlation between dose to the heart and TLV-CT was studied. Second, the correlation between TLV-CT and TLV defined from three pulmonary function tests (PFTs); spirometry, gas diffusion and plethysmograhy, was evaluated. RESULTS: Dose to the heart (V25Gy and Dmean) decreased with increasing TLV-CT. Pearson's correlation coefficient (r) for TLV-CT versus V25Gy and Dmean was equal (r = -0.809, p < 0.01) for patients planned for tangential breast RT only, and r = -0.853 and -0.861 (p < 0.01) for patients planned for loco-regional RT. Regression analysis showed good correlation between TLV-CT and TLV calculated from pulmonary function tests (R(2) >= 0.717, p < 0.01). CONCLUSION: TLV defined by routine pulmonary function tests can be used to identify the subset of left sided breast cancer patients who require respiratory-gated RT. PMID- 25549536 TI - RWDD3 and TECTA variants not linked to paclitaxel induced peripheral neuropathy in North American trial Alliance N08C1. PMID- 25549538 TI - Regional and longitudinal estimation of product lifespan distribution: a case study for automobiles and a simplified estimation method. AB - Product lifespan estimates are important information for understanding progress toward sustainable consumption and estimating the stocks and end-of-life flows of products. Publications reported actual lifespan of products; however, quantitative data are still limited for many countries and years. This study presents regional and longitudinal estimation of lifespan distribution of consumer durables, taking passenger cars as an example, and proposes a simplified method for estimating product lifespan distribution. We estimated lifespan distribution parameters for 17 countries based on the age profile of in-use cars. Sensitivity analysis demonstrated that the shape parameter of the lifespan distribution can be replaced by a constant value for all the countries and years. This enabled a simplified estimation that does not require detailed data on the age profile. Applying the simplified method, we estimated the trend in average lifespans of passenger cars from 2000 to 2009 for 20 countries. Average lifespan differed greatly between countries (9-23 years) and was increasing in many countries. This suggests consumer behavior differs greatly among countries and has changed over time, even in developed countries. The results suggest that inappropriate assumptions of average lifespan may cause significant inaccuracy in estimating the stocks and end-of-life flows of products. PMID- 25549537 TI - Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation. AB - BACKGROUND: Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA mutated CRC. PATIENTS AND METHODS: Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression. RESULTS: From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34-92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant. CONCLUSIONS: Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA mutated CRC patients. Prospective evaluation of this relationship is warranted. PMID- 25549539 TI - Effects of dietary fat saturation on fatty acid composition and gene transcription in different tissues of Iberian pigs. AB - The effect of two diets, respectively enriched with SFA (S) and PUFA (P), on FA tissue composition and gene expression was studied in fattened Iberian pigs. The FA composition of adipose, muscular and liver tissues was affected by dietary treatment. S group showed higher MUFA and MUFA/SFA ratio and lower PUFA and n-6/n 3 ratio than P group in all analyzed tissues. In muscle and liver the extracted lipids were separated into neutral lipids and polar lipid fractions which showed significantly different responses to the dietary treatment, especially in liver where no significant effect of diet was observed in NL fraction. The expression of six candidate genes related to lipogenesis and FA oxidation was analyzed by qPCR. In liver, stearoyl CoA desaturase (SCD), acetyl CoA carboxylase alpha (ACACA) and malic enzyme 1 (ME1) genes showed higher expression in S group. SCD, ACACA, ME1, and fatty acid synthase (FASN) gene expression levels showed a wide variation across the tested tissues, with much higher expression levels observed in adipose tissue than other tissues. Tissue FA profile and gene expression results support the deposition of dietary FA, the lipogenic effect of dietary saturated fat in liver and the employment of saturated dietary fat for endogenous synthesis of MUFA in all the analyzed tissues. PMID- 25549540 TI - Dual restoring effects of gastrodin on dopamine in rat models of Tourette's syndrome. AB - Tourette's syndrome (TS) occurs commonly in children, and dysfunction of dopaminergic system has long been postulated to underlie the disorder. Here, we used two TS rat models induced by 3,3'-iminodipropionitrile (IDPN) and Apomorphine (Apo) to assess an unique dopamine (DA) modulating property of gastrodin (GAS), the main bioactive component isolated from Gastrodia elata Blume, which has been widely used for treating various neurological disorders. By using high-performance liquid chromatography (HPLC), the dual restoring effects of gastrodin, at least partially, has been observed: on the one hand, gastrodin increased the down-regulated striatal DA content in IDPN-induced rats; on the other hand, gastrodin decreased the up-regulated striatal DA content in Apo induced rats. Taken together, our data corroborated that gastrodin could restore the abnormal striatal DA dually, and this therapeutic potential might be meaningful for the anti-tic treatment. PMID- 25549541 TI - In vitro transdifferentiation of human cultured CD34+ stem cells into oligodendrocyte precursors using thyroid hormones. AB - The extent of myelination on the axon promotes transmission of impulses in the neural network, any disturbances in this process results in the neurodegenerative condition. Transplantation of oligodendrocyte precursors that supports in the regeneration of axons through myelination is an important step in the restoration of damaged neurons. Therefore, in the present study, the differentiation of human CD34+ stem cells into oligodendrocytes was carried out. The pure human CD34+ culture developed from the stem cells obtained from a peripheral blood of a donor were subjected to oligodendrocyte differentiation medium (ODM). The ODM at a concentration of 40ng/ml thyroxine, 40ng/ml 3,3',5-tri-iodo-thyronine showed distinct morphological changes from day 6 to 9 with cells exhibiting conspicuous stellate morphology and extensive foot processes. The real-time PCR analysis showed prominent expression of Olig2, CNPase, PDGFRalpha and PLP1/DM20 in the differentiated cells confirming the formed cells are oligodendrocyte precursors. The expression of these genes increased from days 6 to 9 corresponding to the morphological changes observed with almost no expression of GFAP+ cells. The distinct CNPase activity was observed in these differentiated cells compared to normal CD34+ stem cells correlating with results of real-time PCR conclusively explains the development of oligodendrocytes from human CD34+ stem cells. PMID- 25549543 TI - Group I metabotropic glutamate receptor agonist DHPG modulates Kir4.1 protein and mRNA in cultured rat retinal Muller cells. AB - Muller cell gliosis is a general response in a variety of pathological alternations of the retina, which is characterized by the upregulated expression of glial fibrillary acidic protein (GFAP) and the downregulation of membrane K(+) conductance. We have demonstrated that downregulation of Kir K(+) currents in Muller cells in an experimental glaucoma model is due to activation of group I metabotropic glutamate receptor (mGluR I) by glutamate, which contributes to Muller cell gliosis. Here, whether and how activation of mGluR I modulate membrane Kir4.1 protein internalization and Kir4.1 mRNA expression were investigated in purified cultured rat retinal Muller cells using immunocytochemistry, Western blot and real-time PCR techniques. DHPG (10MUM, a selective mGluR I agonist) treatment induced Muller cell gliosis, as evidenced by enhanced GFAP expression. Although total Kir4.1 proteins extracted from the DHPG treated cells kept unchanged, Kir4.1 proteins in the cell membrane compartment were significantly decreased, which was prior to the change of GFAP in time course. In addition, DHPG (10 and 100MUM) treatment induced a transient decrease in Kir4.1 mRNA expression in the cells. All these results suggest that activation of mGluR I by DHPG may decrease the number of functional Kir4.1 channels in purified cultured rat retinal Muller cells through modulating Kir4.1 protein and mRNA, thus contributing to Muller cell gliosis. PMID- 25549542 TI - Possible involvement of iron-induced oxidative insults in neurodegeneration. AB - Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4 hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. PMID- 25549544 TI - Structural dynamics of single molecules studied with high-speed atomic force microscopy. AB - INTRODUCTION: Atomic force microscopy (AFM) is a scanning probe technique that has been in use in biology to generate sub-nanometre resolution images in near physiological environments for over 20 years. Most AFM work uses instruments that take several minutes to generate each image but instruments that can produce real time images have recently become available and there is now a reasonable body of work published on this technique. The importance of this high-speed AFM is that dynamic events of individual macromolecules can be studied. AREAS COVERED: This review focuses on specific examples that demonstrate the potential of the technique. It covers four areas in which high-speed AFM has been used to elucidate mechanisms that are either unstudied or not clearly understood. These areas are: protein-protein interactions; DNA-protein interactions; quantification of biological processes; the use of DNA origami scaffolds as nanostructures to build and study dynamic molecular events. EXPERT OPINION: High-speed AFM shares advantages and disadvantages with conventional AFM, but it compares well in quality of data generated and in ease of use with other currently available techniques of high-resolution biological imaging. As the instruments become more widespread, the value of high-speed AFM and its potential to complement other techniques in molecular and cell biology should become more appreciated. PMID- 25549545 TI - Is grandparenting a form of social engagement that benefits cognition in ageing? AB - Social engagement is a lifestyle factor that has received much attention in preventative research. Numerous studies in the current literature have argued the importance of social engagement in ageing, particularly for cognitive health. One key example of social engagement in later life is the role of a grandparent. This role promotes a socially active lifestyle that may be beneficial to cognitive ageing. Recent research has found that spending some time with grandchildren is beneficial; however, the pressures and responsibilities characteristic of this role should also be taken into consideration, as they may have opposing effects on cognitive health. Given the current popularity of grandparenting as a form of childcare, the interests of the grandparents and the impact on ageing health need to be carefully considered. PMID- 25549546 TI - Effectiveness and efficiency of cervical screening in older women. PMID- 25549547 TI - The food born mycotoxin deoxynivalenol induces low-grade inflammation in mice in the absence of observed-adverse effects. AB - SCOPE: Deoxynivalenol (DON) is the most common fungi toxin contaminating cereals and cereal-derived products. High consumption of DON is implicated in mycotoxicoses and causes a set of symptoms including diarrhea, vomiting, reduced weight gain or immunologic effects. However, such clinical intoxications are rare in humans, who are most frequently, exposed to low DON doses without developing acute symptoms. The adverse effect of chronically consumed low DON doses can not be totally excluded. Using a mouse model, we evaluated the impact on inflammatory status of subchronic administration of DON given at doses comparable to the daily human consumption. METHODS AND RESULTS: The inflammatory status was evaluated in mice receiving 1, 2.5 or 25MUg/kg bw/day DON during a 10 or 30 days period. The systemic interleukin-1 beta (IL-1beta) concentrations were evaluated by Elisa and inflammatory biomarker mRNA expressions were quantified by qPCR within brain structures and peripheral organs. While DON intake failed to modify physiological markers, we observed a systemic IL-1beta increase and a modulation of pro inflammatory gene expression in brain structures, liver, duodenum and adipose tissue. CONCLUSION: We bring here the first evidence that subchronic DON intake, at doses that match daily human intake, induces, in a murine model, a central and peripheral low grade inflammation. PMID- 25549548 TI - Moderate ethanol administration accentuates cardiomyocyte contractile dysfunction and mitochondrial injury in high fat diet-induced obesity. AB - Light to moderate drinking confers cardioprotection although it remains unclear with regards to the role of moderate drinking on cardiac function in obesity. This study was designed to examine the impact of moderate ethanol intake on myocardial function in high fat diet intake-induced obesity and the mechanism(s) involved with a focus on mitochondrial integrity. C57BL/6 mice were fed low or high fat diet for 16 weeks prior to ethanol challenge (1g/kg/d for 3 days). Cardiac contractile function, intracellular Ca(2+) homeostasis, myocardial histology, and mitochondrial integrity [aconitase activity and the mitochondrial proteins SOD1, UCP-2 and PPARgamma coactivator 1alpha (PGC-1alpha)] were assessed 24h after the final ethanol challenge. Fat diet intake compromised cardiomyocyte contractile and intracellular Ca(2+) properties (depressed peak shortening and maximal velocities of shortening/relengthening, prolonged duration of relengthening, dampened intracellular Ca(2+) rise and clearance without affecting duration of shortening). Although moderate ethanol challenge failed to alter cardiomyocyte mechanical property under low fat diet intake, it accentuated high fat diet intake-induced changes in cardiomyocyte contractile function and intracellular Ca(2+) handling. Moderate ethanol challenge failed to affect fat diet intake-induced cardiac hypertrophy as evidenced by H&E staining. High fat diet intake reduced myocardial aconitase activity, downregulated levels of mitochondrial protein UCP-2, PGC-1alpha, SOD1 and interrupted intracellular Ca(2+) regulatory proteins, the effect of which was augmented by moderate ethanol challenge. Neither high fat diet intake nor moderate ethanol challenge affected protein or mRNA levels as well as phosphorylation of Akt and GSK3beta in mouse hearts. Taken together, our data revealed that moderate ethanol challenge accentuated high fat diet-induced cardiac contractile and intracellular Ca(2+) anomalies as well as mitochondrial injury. PMID- 25549549 TI - Consumption patterns and biomarkers of exposure in cigarette smokers switched to Snus, various dissolvable tobacco products, Dual use, or tobacco abstinence. AB - The objectives of this clinical study were to evaluate changes in tobacco product use behavior and levels of selected biomarkers of exposure (BOEs) for smokers who switched to one of six conditions during clinical confinement: exclusive use of; Camel Snus, Sticks, Strips or Orbs, controlled Dual use of cigarettes and Camel Snus, or tobacco abstinence. The controlled Dual use (DU) condition mandated a 60% reduction in cigarettes smoked per day (CPD). 167 healthy U.S. male and female smokers were randomized to the six groups (n=25-30/group). Subjects smoked their usual brand of cigarette for 1 day prior to switching to their designated intervention condition. Levels of thirty-two BOEs in plasma, whole blood, urine and feces were determined before and after switching. Questionnaires that scored nicotine dependence and withdrawal discomfort were also administered. After 5 days, exclusive Snus, Sticks, Strips, or Orbs use averaged 6.1, 5.9, 13.5, and 8.5 units/day, respectively. DU subjects smoked 7.6 CPD and used 3.2 Snus pouches/day, on average. After 5 days, substantial reductions of most biomarkers, including nicotine, were observed in all groups. Toxicant exposures were similar to being tobacco abstinent after switching exclusively to Camel Snus, Sticks, Strips or Orbs. DU reductions were more modest. PMID- 25549551 TI - Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: anti-inflammatory and analgesic activities. AB - A group of 30 cyclic imides (1-10a-c) was designed for evaluation as a selective COX-2 inhibitor and investigated in vivo for anti-inflammatory and analgesic activities. Compounds 6a, 6b, 7a and 7b exhibit optimal COX-2 inhibitory potency (IC50 = 0.18, 0.24, 0.28 and 0.36 MUM; respectively) and selectivity index (SI) range of 363-668. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 6a as a highly potent (IC50 = 0.18 MUM), and an extremely selective [COX-2 (SI) = 668] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50 = 54.0 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). Molecular Docking study of the synthesized compound 6a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. Docking study showed that the methoxy moeities of 6a inserted deep inside the 2 degrees -pocket of the COX-2 active site, where the O-atoms of such groups underwent an H-bonding interaction with His(90) (3.02 A), Arg(513) (1.94, 2.83 A), and Gln(192) (3.25 A). PMID- 25549550 TI - SWDreader: a wavelet-based algorithm using spectral phase to characterize spike wave morphological variation in genetic models of absence epilepsy. AB - BACKGROUND: Spike-wave discharges (SWD) found in neuroelectrical recordings are pathognomonic to absence epilepsy. The characteristic spike-wave morphology of the spike-wave complex (SWC) constituents of SWDs can be mathematically described by a subset of possible spectral power and phase values. Morlet wavelet transform (MWT) generates time-frequency representations well-suited to identifying this SWC-associated subset. NEW METHOD: MWT decompositions of SWDs reveal spectral power concentrated at harmonic frequencies. The phase relationships underlying SWC morphology were identified by calculating the differences between phase values at SWD fundamental frequency from the 2nd, 3rd, and 4th harmonics, then using the three phase differences as coordinates to generate a density distribution in a {360 degrees *360 degrees *360 degrees } phase difference space. Strain-specific density distributions were generated from SWDs of mice carrying the Gria4, Gabrg2, or Scn8a mutations to determine whether SWC morphological variants reliably mapped to the same regions of the distribution, and if distribution values could be used to detect SWD. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, this algorithm is the first to employ spectral phase to quantify SWC morphology, making it possible to computationally distinguish SWC morphological subtypes and detect SWDs. RESULTS/CONCLUSIONS: Proof-of-concept testing of the SWDfinder algorithm shows: (1) a major pattern of variation in SWC morphology maps to one axis of the phase difference distribution, (2) variability between the strain-specific distributions reflects differences in the proportions of SWC subtypes generated during SWD, and (3) regularities in the spectral power and phase profiles of SWCs can be used to detect waveforms possessing SWC-like morphology. PMID- 25549552 TI - Synthesis and molecular modelling studies of 8-arylpyrido[3',2':4,5]thieno[3,2 d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors. AB - This paper reports the design and synthesis of a novel series of 8 arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines via microwave-assisted multi step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3 b]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N' (5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8 arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1delta/epsilon, GSK3alpha/beta, DYRK1A and CLK1) and revealed that 8-(2,4 dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1delta/epsilon and CLK1 (220 and 88 nM, respectively) while its 7-(2,4 dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1delta/epsilon and CLK1 showed that functionalization at position 7 of pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1delta/epsilon P-loop and thus a complete loss of inhibitory activity. PMID- 25549553 TI - Photodynamic effects induced by meso-tris(pentafluorophenyl)corrole and its cyclodextrin conjugates on cytoskeletal components of HeLa cells. AB - The aim of this work was to synthesize new corrole beta-cyclodextrin conjugates betaCD1 (with one beta-cyclodextrin moiety) and betaCD2 (with two beta cyclodextrin moieties) from 5,10,15-tris(pentafluorophenyl)corrole (TPFC) and to test in vitro the efficacy of these compounds towards tumoral HeLa cells. No dark cytotoxicity was observed for TPFC and betaCD1 at the concentration used for PDT cell treatment, even during long incubation periods (24 h). Fluorescence microscopy showed that TPFC and betaCD1 accumulate in HeLa cells at lysosomes and in the Golgi apparatus, respectively. The cell survival after the PDT treatment with visible light was dependent on light exposure level and compound concentration. betaCD1 was able to penetrate efficiently in the cytoplasm of the HeLa cells. In particular, we have analyzed the photodynamic effect of the corrole derivatives on the microtubules of HeLa cells and the morphological alterations on the mitotic spindle. TPFC and betaCD1 caused photocytotoxicity in tumoral HeLa cells and induced a rapid metaphase blockage of cells that also showed clearly altered configurations of the mitotic spindle. The results showed that TPFC has the highest photosensitizing efficiency on tumoral cells. PMID- 25549554 TI - Functionalized tetrahydro-1H-pyrido[4,3-b]indoles: a novel chemotype with Sirtuin 2 inhibitory activity. AB - Sirtuins are protein deacylases with regulatory roles in metabolism and stress response. Functionalized tetrahydro-1H-pyrido[4,3-b]indoles were identified as preferential sirtuin 2 inhibitors, with in vitro inhibitory potencies in the low micromolar concentrations (IC50 3-4 MUM) for the more promising candidates. The functional relevance of sirtuin inhibition was corroborated in western blots that showed hyperacetylation of p53 and alpha-tubulin in treated HepG2 and MDA-MB-231 cells. Molecular docking showed that the tetrahydropyridoindole scaffold was positioned in the NAD + pocket and the acetylated substrate channel of the sirtuin 2 protein by van der Waals/hydrophobic, H bonding and stacking interactions. Functionalized tetrahydropyridoindoles represent a novel class of sirtuin 2 inhibitors that could be further explored for its therapeutic potential. PMID- 25549556 TI - Challenge winner sees promise in daily App check. PMID- 25549555 TI - A novel pharmaceutical-ACO collaboration: the Merck/Heritage Provider Network open innovation challenge. PMID- 25549557 TI - Pharma-payer partnerships seek to prove effectiveness of care. PMID- 25549558 TI - Can gastric bypass surgery be a cure for diabetes mellitus? PMID- 25549559 TI - Environmental pollutants: a risk factor for obesity and diabetes. PMID- 25549560 TI - Early cellular aging: salt and the telomeres. PMID- 25549561 TI - [Chinese subgroup analysis of the global anticoagulant registry in the FIELD (GARFIELD) registry in the patients with non-valvular atrial fibrillation]. AB - OBJECTIVE: To describe the baseline characteristics and antithrombotic treatment of patients with non-valvular atrial fibrillation in the Chinese subgroup of GRAFIELD. METHODS: GARFIELD is an observational registry study for patients with newly diagnosed non-valvular atrial fibrillation. A total of 805 adult ( >=18 years old) patients (mean age: (66.6 +/- 11.4) years old, 39.4% female (n = 317)) diagnosed with non-valvular atrial fibrillation within the previous 6 weeks were recruited between December 2009 and October 2011 at 29 hospitals from China. Baseline data included demographics, medical history, nature of atrial fibrillation, CHA(2)DS(2) score, CHA(2)DS(2)-VASc score, and treatment at the time of diagnosis. RESULTS: There were 216 patients (26.8%) with age above 75 years old, 116 patients (14.4%) had history of stroke or TIA, 261 patients (32.4%) had coronary artery disease. Mean CHADS(2) score was 1.7 +/- 1.1, and 391 patients (48.5%) had a CHADS(2) score >= 2. Mean CHA(2)DS(2)-VASc score was 2.9 +/- 1.7, and 630 patients (78.3%) had a CHA(2)DS(2)-VASc score >= 2.Overall, 159 patients (19.8%) received no anticoagulant treatment, 51.6% (n = 415) patients received aspirin and only 28.7% (n = 231) patients received either warfarin (n = 179, 22.2%) or new oral anticoagulants (NOAC) (n = 52, 6.5%). Among patients with CHADS2 score >= 2 (n = 391), 68.3% patients (n = 267) did not receive anticoagulant therapy. Among patients with CHA(2)DS(2)-VASc >= 2 (n = 630), 71.7% (n = 452) did not receive anticoagulant therapy. For the patients with very high risk of stroke, i.e. CHA(2)DS(2)-VASc >= 6, the proportion of the patients received NOAC and warfarin were identical (14.9%, 7/47). CONCLUSIONS: This contemporary observational registry study shows that the anticoagulant therapy is somehow improved but still underused in Chinese NVAF patients. Stroke prevention according to risk scores and current guidelines in these patients remains an important task in China. PMID- 25549568 TI - Editorial comment. PMID- 25549569 TI - Comments on Zhuo et al.: prolonged treatment with macrolides in adult patients with non-cystic fibrosis bronchiectasis: meta-analysis of randomized controlled trials. PMID- 25549570 TI - Assessment of the internal structure of GOLD 2011 system. AB - BACKGROUND: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 introduced a new multidimensional system (symptom/risk) for assessment chronic obstructive pulmonary disease (COPD). The aim of this study was to explore the construct validity of the GOLD 2011 classification strategy; specifically, we evaluated its internal structure in terms of reliability and exploratory factor analysis (EFA). METHODS: Reliability (Cronbach alpha coefficient), correlations between variables and two successive EFA were performed to assess the internal structure of GOLD 2011. Symptoms (mMRC dyspnea score) and risk (number of previous year exacerbations and forced expiratory volume in the first second % of predicted) were selected as variables. RESULTS: The analysis included 679 COPD patients from two Spanish cohorts (71.4 +/- 11.7 years). Alpha coefficient of the 3 items was 0.52 for the whole sample. Variables presented statistically significant correlations, but of low to moderate magnitude. A first EFA extracted only one factor accounting 52% of the total variance. A second EFA including four items (the three GOLD 2011 variables plus comorbidities as Charlson index score), extracted two-factors accounting for 65% of the total variance. The first factor included the three items of GOLD 2011, and the second contained only one variable (comorbidities). This solution was stable in patients with different levels of COPD severity. CONCLUSIONS: The available evidence suggests that GOLD 2011 strategy presented a low reliability, and its theorized multidimensionality was not confirm by EFA. Comorbidities appears as a separate and independent domain. PMID- 25549562 TI - Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1beta, BDNF and synaptic plasticity. AB - Older individuals often experience declines in cognitive function after events (e.g. infection, or injury) that trigger activation of the immune system. This occurs at least in part because aging sensitizes the response of microglia (the brain's resident immune cells) to signals triggered by an immune challenge. In the aging brain, microglia respond to these signals by producing more pro inflammatory cytokines (e.g. interleukin-1beta or IL-1beta) and producing them for longer than microglia in younger brains. This exaggerated inflammatory response can compromise processes critical for optimal cognitive functioning. Interleukin-1beta is central to the inflammatory response and is a key mediator and modulator of an array of associated biological functions; thus its production and release is usually very tightly regulated. This review will focus on the impact of dysregulated production of IL-1beta on hippocampus dependent-memory systems and associated synaptic plasticity processes. The neurotrophin brain derived neurotrophic factor (BNDF) helps to protect neurons from damage caused by infection or injury, and it plays a critical role in many of the same memory and hippocampal plasticity processes compromised by dysregulated production of IL 1beta. This suggests that an exaggerated brain inflammatory response, arising from aging and a secondary immune challenge, may erode the capacity to provide the BDNF needed for memory-related plasticity processes at hippocampal synapses. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. PMID- 25549571 TI - Quantitative mass spectrometric immunoassay for the chemokine RANTES and its variants. AB - The chemokine RANTES plays a key role in inflammation, cell recruitment and T cell activation. RANTES is heterogenic and exists as multiple variants in vivo. Herein we describe the development and characterization of a fully quantitative mass spectrometric immunoassay (MSIA) for analysis of intact RANTES and its proteoforms in human serum and plasma samples. The assay exhibits linearity over a wide concentration range (1.56-200ng/mL), intra- and inter-assay precision with CVs <10%, and good linearity and recovery correlations. The assay was tested in different biological matrices, and it was benchmarked against an existing RANTES ELISA. The new RANTES MSIA was used to analyze RANTES and its proteoforms in a small clinical cohort, revealing the quantitative distribution and frequency of the native and truncated RANTES proteoforms. BIOLOGICAL SIGNIFICANCE: In the last two decades, RANTES has been studied extensively due to its association with numerous clinical conditions, including kidney-related, autoimmune, cardiovascular, viral and metabolic pathologies. Although a single gene product, RANTES is expressed in a range of cells and tissues presenting with different endogenously produced variants and PTMs. The structural variety and population diversity that has been identified for RANTES necessitate developing advanced methodologies that can provide insight into the protein heterogeneity and its function and regulation in disease. In this work we present a simple, efficient and high-throughput mass spectrometric immunoassay (MSIA) method for analysis of RANTES proteoforms. RANTES MSIA can detect and analyze RANTES proteoforms and provide an insight into the endogenous protein modifications. PMID- 25549572 TI - Comparison of barbed suture versus traditional suture in laparoendoscopic single site myomectomy. AB - OBJECTIVE: To compare the surgical outcomes between uterine wall repairs using barbed suture versus traditional suture during laparoendoscopic single-site myomectomy (LESS-M). STUDY DESIGN: Data were prospectively collected from 60 consecutive patients with uterine myomas at three institutions. Patients were managed by LESS-M with either traditional suture (the first 30 patients) or barbed suture (the next 30 patients). Operative time, blood loss, and technical difficulty were assessed for each patient. RESULTS: Patient characteristics (age, body mass index, other demographic data, number of myomas, and location and size of the largest myoma) were similar between the two study groups. No significant differences in operative complications, failure rate of the intended surgeries, degree of postoperative pain, or hospital stay duration were observed between the two groups. The use of barbed suture significantly reduced the suturing time for treating the uterine wall defects (P=0.014), as well as the total operative time (P=0.027). The use of barbed suture was also associated with less operative blood loss (P=0.040) and less technical difficulty (P=0.001) compared with traditional suture. CONCLUSION: The use of barbed suture in LESS-M effectively reduces the time required for suturing, thereby decreasing the total operative time, the operative blood loss, and the surgical difficulty. PMID- 25549573 TI - Stearate organogel-gelatin hydrogel based bigels: physicochemical, thermal, mechanical characterizations and in vitro drug delivery applications. AB - Over the past decade, researchers have been trying to develop alternative gel based formulations in comparison to the traditional hydrogels and emulgels. In this perspective, bigels were synthesized by mixing gelatin hydrogel and stearic acid based organogel by hot emulsification method. Two types of bigels were synthesized using sesame oil and soy bean oil based stearate organogels. Gelatin based emulgels prepared using sesame oil and soy bean oil were used as the controls. Microscopic studies revealed that the bigels contained aggregates of droplets, whereas, emulgels showed dispersed droplets within the continuum phase. The emulgels showed higher amount of leaching of oils, whereas, the leaching of the internal phase was negligible from the bigels. Presence of organogel matrix within the bigels was confirmed by XRD, FTIR and DSC methods. Bigels showed higher mucoadhesive and mechanical properties compared to emulgels. Cyclic creep recovery and stress relaxation studies confirmed the viscoelastic nature of the formulations. Four elemental Burger's model was employed to analyze the cyclic creep-recovery data. Cyclic creep-recovery studies suggested that the deformation of the bigels were lower due to the presence of the organogels within its structure. The formulations showed almost 100% recovery after the creep stage and can be explained by the higher elastic nature of the formulations. Stress relaxation study showed that the relaxation time was higher in the emulgels as compared to the bigels. Also, the % relaxation was higher in emulgels suggesting its fluid dominant nature. The in vitro biocompatibility of the bigels was checked using human epidermal keratinocyte cell line (HaCaT). Both emulgels and bigels were biocompatible in nature. The in vitro drug (ciprofloxacin) release behavior indicated non-Fickian diffusion of the drug from the matrices. The drug release showed good antimicrobial effect against Escherichia coli. Based on the results, it was concluded that the developed bigels may have huge potential to be used as alternatives to emulgels. PMID- 25549574 TI - Unilateral spectral and temporal compression reduces binaural fusion for normal hearing listeners with cochlear implant simulations. AB - Patients with single sided deafness have recently begun receiving cochlear implants in their deaf ear. These patients gain a significant benefit from having a cochlear implant. However, despite this benefit, they are considerably slower to develop binaural abilities such as summation compared to bilateral cochlear implant patients. This suggests that these patients have difficulty fusing electric and acoustic signals. Although this may reflect inherent differences between electric and acoustic stimulation, it may also reflect properties of the processor and fitting system, which result in spectral and temporal compression. To examine the possibility that unilateral spectral and temporal compression can adversely affect binaural fusion, this study tested normal hearing listeners' binaural fusion through the use of vocoded speech with unilateral spectral and temporal compression. The results indicate that unilateral spectral and temporal compression can each hinder binaural fusion and thus may adversely affect binaural abilities in patients with single sided deafness who use a cochlear implant in their deaf ear. PMID- 25549575 TI - Detection of archaeological forgeries of Iberian lead plates using nanoelectrochemical techniques. The lot of fake plates from Bugarra (Spain). AB - Identification of forgeries is of considerable interest in studies of archaeological signariums and written Iberian artifacts, elements of capital importance for the knowledge of that culture, because there are many Iberian inscribed lead plate counterfeits circulating in the market and among many museum funds. A case study of identification of forgeries of archaeological lead using voltammetry of microparticles (VMP) and scanning electrochemical microscopy (SECM), aided by conventional optical microscopy and scanning electron microscopy (SEM/EDX) is described. The electrochemical methods are essentially non-invasive so can be applied to samples of nanoscopic size. Application to the authentication of five lead plates found in the archaeological site of Los Villaricos-Torralba (Bugarra, Spain) is described. PMID- 25549578 TI - FDA reversal sends mixed message to multiple sclerosis community. PMID- 25549576 TI - Aldehyde dehydrogenase homologous folate enzymes: Evolutionary switch between cytoplasmic and mitochondrial localization. AB - Cytosolic and mitochondrial 10-formyltetrahydrofolate dehydrogenases are products of separate genes in vertebrates but only one such gene is present in invertebrates. There is a significant degree of sequence similarity between the two enzymes due to an apparent origin of the gene for the mitochondrial enzyme (ALDH1L2) from the duplication of the gene for the cytosolic enzyme (ALDH1L1). The primordial ALDH1L gene originated from a natural fusion of three unrelated genes, one of which was an aldehyde dehydrogenase. Such structural organization defined the catalytic mechanism of these enzymes, which is similar to that of aldehyde dehydrogenases. Here we report the analysis of ALDH1L1 and ALDH1L2 genes from different species and their phylogeny and evolution. We also performed sequence and structure comparison of ALDH1L enzymes possessing aldehyde dehydrogenase catalysis to those lacking this feature in an attempt to explain mechanistic differences between cytoplasmic ALDH1L1 and mitochondrial ALDH1L2 enzymes and to better understand their functional roles. PMID- 25549577 TI - Editor's choice. A randomized controlled trial of the fascia suture technique compared with a suture-mediated closure device for femoral arterial closure after endovascular aortic repair. AB - OBJECTIVES: The aim was to investigate whether the fascia suture technique (FST) can reduce access closure time and procedural costs compared with the Prostar technique (Prostar) in patients undergoing endovascular aortic repair and to evaluate the short- and mid-term outcomes of both techniques. METHODS: In this two center trial, 100 patients were randomized to access closure by either FST or Prostar between June 2006 and December 2009. The primary endpoint was access closure time. Secondary outcome measures included access related costs and evaluation of the short- and mid-term complications. Evaluation was performed peri- and post-operatively, at discharge, at 30 days and at 6 months follow up. RESULTS: The median access closure time was 12.4 minutes for FST and 19.9 minutes for Prostar (p < .001). Prostar required a 54% greater procedure time than FST, mean ratio 1.54 (95% CI 1.25-1.90, p < .001) according to regression analysis. Adjusted for operator experience the mean ratio was 1.30 (95% CI 1.09-1.55, p = .005) and for patient body mass index 1.59 (95% CI 1.28-1.96, p < .001). The technical failure rate for operators at proficiency level was 5% (2/40) compared with 28% (17/59) for those at the basic level (p = .003). The proficiency level group had a technical failure rate of 4% (1/26) for FST and 7% (1/14) for Prostar, p = 1.00, while corresponding rates for the basic level group were 27% (6/22) for FST and 30% (11/37) for Prostar (p = .84). There was a significant difference in cost in favor of FST, with a median difference of ?800 (95% CI 710 927, p < .001). CONCLUSIONS: In aortic endovascular repair FST is a faster and cheaper technique than the Prostar technique. PMID- 25549579 TI - Anticoagulant antidotes start yielding Phase III promise. PMID- 25549583 TI - Wayne Koff. PMID- 25549584 TI - Targeting the IL-17-T(H)17 pathway. PMID- 25549585 TI - Anticancer drugs: Finding the perfect combination. PMID- 25549586 TI - Cancer: mTOR inhibition curbs colorectal cancer. PMID- 25549587 TI - Infectious diseases: Two-hit antibody tackles bacteria. PMID- 25549590 TI - Reference values of lymphocyte sub-populations in healthy human immunodeficiency virus-negative Iranian adults. AB - BACKGROUND: Lymphocyte subsets enumeration is considered prominent in the management of primary and acquired immunodeficiency disorders. Because of local variations due to race, age, gender, and environmental conditions on lymphocyte subsets, and to improve the accuracy of interpretation of laboratory findings, reference intervals must be determined in every population. OBJECTIVE: To establish a normal reference range for CD3+, CD4+, CD8+, CD19+ and CD56+ lymphocytes in a healthy Iranian adult population using flowcytometry. METHOD: Blood samples were collected from 221 HIV seronegative individuals, including 112 females and 109 males, with ages ranging from 20 to 40 years old. The percentage of lymphocytes expressing either of CD3, CD4, CD8, CD19 and CD56 surface markers were determined by flowcytometry assay. RESULT: Total mean percentage and absolute count of lymphocyte subsets were as follows: CD3+: 70.90 +/- 7.54%, 1800.87 +/- 471.09 cells/ul; CD4+: 41.04 +/- 7.86%, 1039.99 +/- 338.02 cells/ul; CD8+: 31.11 +/- 6.60%, 783.95 +/- 234.87 cells/ul; CD19+: 12.77 +/- 4.56%, 328.37 +/- 153.17 cells/ul; CD56+: 15.53 +/- 6.34%, 388.62 +/- 176.17 cells/ul, respectively. The ratio of CD4+/CD8+ lymphocytes for the studied population was 1.39 +/- 0.48. Significant differences were observed between male and female subjects indicating that the average percentage of CD3+ cells (p=0.017) and CD4+ T cells (p=0.003) were higher in the female population, whereas the average percentage of CD19+ cells (p=0.02) tended to be higher among males. However, investigations on the CD56+ NK cell and CD8+ T cell sub-populations did not show any statistical differences between the two genders. In comparison with reports of other populations, we were confronted with different results. CONCLUSION: Establishing reference values of lymphocyte subsets for each population is helpful in achieving standard criteria for the prognosis of HIV infection. Therefore, normal ranges established by this survey can be used as a reference for decisions made in clinical practice. PMID- 25549591 TI - Differences in the expression of TLRs and inflammatory cytokines in pre-eclamptic compared with healthy pregnant women. AB - BACKGROUND: Preeclampsia (PE) is one of the most complex and life-threatening pregnancy disorders and is considered as a major cause of mortality among mothers and fetuses worldwide. Although the exact etiology of PE is not well known several lines of evidence support an immunological etiology for PE. OBJECTIVE: To investigate the differences in the expression of TLRs 2, 4, 5, and 6 and a group of inflammatory cytokines including IL-1, IL-6, TNF-alpha and IFN-gamma in placentas from PE and healthy pregnant women in their third trimester of pregnancy. METHODS: This case-control study was performed on fifteen PE and fifteen age and gestational matched healthy pregnant women in the third trimester of pregnancy. Real time PCR (RT-PCR) technique was used to determine the expression of TLRs 2, 4, 5, and 6 in the maternal and fetal parts of the placenta. Moreover, the expressions of IL-1, IL-6, TNF-alpha and IFN-gamma at RNA level in placental samples, peripheral, and cord blood were investigated. RESULTS: The results of the present study indicated that the expressions of TLRs 4, 5 and 6 were significantly increased in both maternal part (p<0.001 and p<0.003 for TLRs 4, 6 and TLR 5, respectively) and fetal part (p<0.001), while TLR2 showed significant increase only in the fetal part of PE placentas (p<0.002). The levels of all studied cytokines showed over-expression within peripheral and cord blood samples from PE patients (p<0.001 for IL-1, IL-6, and IFN-gamma and p<0.004 for TNF-alpha in both cord and peripheral blood samples). CONCLUSION: The finding of the present study indicated that the expression of the studied TLRs and inflammatory cytokines are generally suppressed in normal pregnancy, but are up regulated in preeclamptic women. Moreover, it seems that the maternal and fetal parts of the placenta may play different roles in the induction of the inflammatory status within the placenta. PMID- 25549589 TI - Hyaluronan Controls the Deposition of Fibronectin and Collagen and Modulates TGF beta1 Induction of Lung Myofibroblasts. AB - The contribution of hyaluronan-dependent pericellular matrix to TGF-beta1-driven induction and maintenance of myofibroblasts is not understood. Hyaluronan is an extracellular matrix (ECM) glycosaminoglycan important in cell adhesion, proliferation and migration, and is implicated in myofibroblast formation and maintenance. Reduced turnover of hyaluronan has been linked to differentiation of myofibroblasts and potentiation of lung fibrosis. Fibronectin is a fibril forming adhesive glycoprotein that is also upregulated following induction with TGF beta1. Although they are known to bind each other, the interplay between hyaluronan and fibronectin in the pericellular matrix during myofibroblast induction and matrix assembly is not clear. This study addresses the role of hyaluronan and its interaction with fibrillar matrix components during myofibroblast formation. Hyaluronan and fibronectin were increased and co localized in the ECM following myofibroblast induction by TGF-beta1. Inhibition of hyaluronan synthesis in TGF-beta1-induced lung myofibroblasts over a 4day period with 4-methyl umbelliferone (4-MU) further enhanced myofibroblast morphology, caused increased deposition of fibronectin and type I collagen in the ECM, and increased expression of alpha-smooth muscle actin and hyaluronan synthase 2 (HAS2) mRNA. Hyaluronan oligosaccharides or hyaluronidase treatment, which more effectively disrupted the pericellular matrix, had similar effects. CD44 and beta1 integrins co-localized in the cell membrane and along some stress fibers. However, CD44 and hyaluronan were specifically excluded from focal adhesions, and associated primarily with cortical actin. Time-lapse imaging of the immediate effects of hyaluronidase digestion showed that hyaluronan matrix primarily mediates attachment of membrane and cortical actin between focal contacts, suggesting that surface adhesion through hyaluronan and CD44 is distinct from focal adhesion through beta1 integrins and fibronectin. Fluorescein labeled hyaluronan bound regularly along fibronectin fibers and co-localized more with beta1 integrin and less with CD44. Therefore, the hyaluronan matrix can interfere with the assembly of fibrillar ECM components, and this interplay regulates the degree of myofibroblast formation. These data also suggest that adhesion through hyaluronan matrix impacts cytoskeletal organization, and is potentially part of a clutch mechanism that regulates stick and slip of myofibroblasts by affecting the adhesion to and organization of fibronectin and collagen. PMID- 25549592 TI - Increased IL-17A in atrial fibrillation correlates with neutrophil to lymphocyte ratio. AB - BACKGROUND: Atrial Fibrillation (AF) is the most common cardiac arrhythmia and an independent risk factor for stroke among the elderly. A role for inflammation in the atrial remodeling as well as development and recurrence of AF is known. OBJECTIVE: To compare IL-17A between patients with different types of AF and healthy individuals. METHODS: IL-17A was measured in sera of 112 patients and 107 healthy age/sex-matched controls using ELISA assay. In sera of 26 patients with elevated IL-17A (>1 Pg/ml), CCL5 and CCL18 levels were also measured. RESULTS: IL 17A was significantly increased in patients with AF compared to controls (1.28 +/ 3.5 vs. 0.19 +/- 0.64 Pg/ml, p=0.001). There was no significant difference in the level of IL-17A between different types of AF. IL-17A was significantly higher in patients with a history of coronary artery bypass graft compared to other patients (p=0.01). A significant positive correlation between IL-17A and CCL18 concentration was found (p=0.001). An increase in the Neutrophil/Lymphocyte ratio (NLR) was observed in patients with elevated serum IL-17A compared to other patients (p=0.006). Male patients showed higher increase in NLR (p=0.007) which was accompanied by a decrease in CCL5 (p=0.000) and a marginal increase in CCL18 (p=0.085) compared to females. There was an increase in CCL5 levels in patients receiving Acetylsalicylic Acid (ASA) therapy (p=0.046). CONCLUSIONS: The increase in IL-17A levels is related to the AF pathology mediated by neutrophils and monocytes. The current study signifies the role of immune cells and cytokines in the pathology of AF. PMID- 25549593 TI - Analysis of serum cytokine levels in larynx squamous cell carcinoma and dysplasia patients. AB - BACKGROUND: Although the imbalance of cytokines in Head and Neck Squamous Cell Carcinoma (HNSCC) is well known, there is scarce data regarding its occurrence during dysplasia, before the malignant transformation. OBJECTIVE: To determine whether laryngeal dysplasia patients show a different cytokine profile than patients with cancer and healthy controls. METHODS: Seventeen newly diagnosed, untreated larynx squamous cell carcinoma (SCC) and six laryngeal dysplasia patients as well as 22 healthy controls were analyzed for circulating cytokines. A flowcytometry Th1/Th2 cytokine array kit was used to quantitatively measure Interleukin-2 (IL-2), IL-4, IL-6, IL-10, Tumor Necrosis Factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) levels. Additionally, IL-8 levels were determined through ELISA. RESULTS: IL-6, IL-8 and IL-10 were determined to be statistically increased in SCC patients (p<0.05). IL-8 and IL-10 levels were also higher in SCC patients than dysplasia patients (p<0.05). Additionally, IL-6 and IL-10 were all found to be markedly increased in dysplasia patients compared with controls (p<0.05). CONCLUSION: Our results demonstrate an imbalance of IL-6 and IL-10 not only in HNSCC but also in laryngeal dysplasia. PMID- 25549588 TI - Muscle wasting in disease: molecular mechanisms and promising therapies. AB - Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting. PMID- 25549595 TI - Aqueous humor and serum concentrations of soluble MICA and MICB in glaucoma patients. AB - BACKGROUND: Immune reactions have been reported to be involved in the destruction of retinal ganglion cells (RGCs) in glaucoma. OBJECTIVE: To investigate the role of major histocompatibility complex class I-related chain A and B (MICA and MICB) molecules in the pathogenesis of glaucoma. METHODS: Aqueous humor and serum samples from 15 glaucoma patients and 45 patients with cataract, undergoing ocular surgery, were obtained. The concentrations of MICA and MICB molecules in all samples were measured using ELISA. RESULTS: Both MICA and MICB concentrations were higher in the aqueous humor of patients with glaucoma compared to those with cataract (p=0.013 and p=0.004, respectively); however, in the serum samples, no significant differences were observed. CONCLUSIONS: Increased intraocular pressure may be associated with increased expression of the MICA and MICB molecules, which could initiate the destruction of RGCs and consequent development of glaucoma. PMID- 25549594 TI - HLA-A*26 and susceptility of iranian patients with non-Hodgkin lymphoma. AB - BACKGROUND: Non-Hodgkin lymphoma (NHL) includes a wide range of diseases with different clinical and biological features. NHL is usually presented as localized or generalized lymphadenopathy. It has been suggested that the HLA class I and II are associated with susceptibility to NHL. Different ethnic groups have been found to have different HLA class I and II alleles which affect NHL. OBJECTIVE: To evaluate the association of HLA class I and class II with Non-Hodgkin's lymphoma in Iranian patients. METHODS: We performed a case-control genotyping study on 75 Iranian NHL patients who were selected from among the patients referred to the Bone Marrow Transplantation Department of Taleghani Hospital and 120 apparently healthy control subjects using the SSP-PCR by a commercial kit. RESULTS: Our results demonstrated that the HLA-A*26 (p: 0.026; OR: 8.5) and HLA B*35 (p: 0.022; OR: 0.375) alleles had positive and negative associations with NHL disease, respectively. HLA-DRB1*13 allele showed decrease of frequency in patients in comparison with the controls, but it did not remain significant after correction. CONCLUSIONS: Our results conclude that HLA-A*26 may represent as a genetic susceptibility factors in Iranian patients with Non-Hodgkin's lymphoma, a finding which generally supports contribution of genetic factors in the etiology of this disorder. In addition, these results may be useful in designing a peptide based vaccine for the Iranian NHL patients with HLA-A*26. PMID- 25549596 TI - Distribution of primary immunodeficiency disorders diagnosed in a tertiary referral center,Tehran, Iran (2006-2013). AB - BACKGROUND: Primary immunodeficiency disorders (PID) are a group of hereditary disorders characterized by an increased susceptibility to severe and recurrent infections, autoimmunity, lymphoproliferative disorders, and malignancy. OBJECTIVE: To evaluate the demographic and clinical data of PID patients diagnosed in a referral pediatric hospital. METHOD: All PID cases with a confirmed diagnosis, according to the criteria of International Union of Immunological Societies, who were referred to the Children's Medical Center in Tehran, Iran, between March 2006 and March 2013 were enrolled in this retrospective cohort study. RESULTS: Three-hundred and seven PID patients were investigated. Predominantly antibody deficiencies were the most common group of PID observed in 118 cases (38.4%), followed by the well-defined syndromes with immunodeficiency in 52 (16.9%), congenital defects of phagocyte in 45 (14.7%), combined immunodeficiencies in 36 (11.7%), autoinflammatory disorders in 34 (11.4%), immune dysregulation in 11 (3.6%), complement deficiencies in 7 (2.3%), and defects in innate immunity in 3 (1%). Selective IgA deficiency was the most prevalent disorder which affected 46 individuals (14.9%). The median diagnostic delay was 15 months. CONCLUSION: Increased awareness and availability of diagnostic tests could result in the better recognition of more undiagnosed PID cases and a decrease in diagnostic delay. PMID- 25549597 TI - Overexpression of host plant urease in transgenic silkworms. AB - Bombyx mori and mulberry constitute a model of insect-host plant interactions. Urease hydrolyzes urea to ammonia and is important for the nitrogen metabolism of silkworms because ammonia is assimilated into silk protein. Silkworms do not synthesize urease and acquire it from mulberry leaves. We synthesized the artificial DNA sequence ureas using the codon bias of B. mori to encode the signal peptide and mulberry urease protein. A transgenic vector that overexpresses ure-as under control of the silkworm midgut-specific P2 promoter was constructed. Transgenic silkworms were created via embryo microinjection. RT PCR results showed that urease was expressed during the larval stage and qPCR revealed the expression only in the midgut of transgenic lines. Urea concentration in the midgut and hemolymph of transgenic silkworms was significantly lower than in a nontransgenic line when silkworms were fed an artificial diet. Analysis of the daily body weight and food conversion efficiency of the fourth and fifth instar larvae and economic characteristics indicated no differences between transgenic silkworms and the nontransgenic line. These results suggested that overexpression of host plant urease promoted nitrogen metabolism in silkworms. PMID- 25549598 TI - Molecular phylogeny of Urosomoida agilis, and new combinations: Hemiurosomoida longa gen. nov., comb. nov., and Heterourosomoida lanceolata gen. nov., comb. nov. (Ciliophora, Hypotricha). AB - For years, systematics of three species, Urosomoida agilis (Engelmann, 1862) Hemberger in Foissner, 1982, Urosomoida longa (Gelei and Szabados, 1950) Foissner et al., 1991 and Oxytricha lanceolata Shibuya, 1930, has remained unresolved due to lack of adequate molecular data. Though, it is known since several years that the three species are not very closely related. In the present paper, 18S rRNA gene sequences for two key species, U. agilis and U. longa, and their morphology and morphometry have been analyzed. Molecular phylogeny inferred from maximum likelihood, neighbour joining and maximum parsimony methods has adequately removed ambiguity over their systematics. In phylogenetic trees, U. agilis clustered consistently with non-stylonychine oxytrichids. Both Urosomoida longa and Oxytricha lanceolata clustered consistently away from U. agilis and O. granulifera, the type species of the genera Urosomoida and Oxytricha, respectively. As a result of the current molecular phylogenetic investigation and based on previously inferred morphological and morphogenetic data it is proposed to remove Urosomoida longa and Oxytricha lanceolata from Urosomoida and incertae sedis in Oxytricha, respectively, and establish two new generic combinations, Hemiurosomoida longa gen. nov., comb. nov. and Heterourosomoida lanceolata gen. nov., comb. nov. for them. PMID- 25549600 TI - Psychometric properties of the Mayo Elbow Performance Score. AB - To translate and culturally adapt the Mayo Elbow Performance Score (MEPS), a widely used instrument for evaluating disability associated with elbow injuries, into Turkish (MEPS-T) and to determine psychometric properties of the translated version. The MEPS was translated into Turkish using published methodological guidelines. The measurement properties of the MEPS-T (construct validity and floor and ceiling effects) were tested in 91 patients with elbow pathology. The reproducibility of the MEPS-T was tested in 59 patients over 7-14 days. The responsiveness of the MEPS-T was tested in a subgroup of 46 patients diagnosed with lateral epicondylitis and who received conservative treatment for 6 weeks. The interclass correlation coefficient (ICC) was used to estimate the test-retest reliability. The construct validity was analyzed with the disabilities of the arm, shoulder and hand (DASH), Visual Analog Scale (VAS) and the Short Form 36 (SF-36). Effect size (ES) was used to assess the responsiveness. The distribution of floor and ceiling effects was determined. The MEPS-T showed very good test retest reliability (ICC 0.89). The correlation coefficients between the MEPS-T and DASH and VAS were -0.61 and -0.53, respectively (p < 0.001). The highest correlations were between the MEPS-T and the mental component summary (r = 0.47, p = 0.001) and role emotional (r = 0.45, p = 0.001). The MEPS-T ES, 0.50, was moderate (95% CI 0.33-0.62). We observed no ceiling or floor effects. The MEPS-T represents a valid, reliable and moderately responsive instrument for evaluating patients with elbow disease. PMID- 25549599 TI - Treatment of rheumatic diseases and hepatitis B virus coinfection. AB - We often encounter rheumatological patients coinfected with hepatitis B in daily practice. In this paper, we will discuss the basic characteristics of the virus of hepatitis B, course of infection, the safety of rituximab, tocilizumab, abatacept treatment and therapeutic recommendations in management of patients with rheumatic diseases. PMID- 25549601 TI - Association of cardiorespiratory fitness with pressure pain sensitivity and clinical pain in women with fibromyalgia. AB - The aim of the present study was to assess the association of cardiorespiratory fitness (CRF) with pressure pain sensitivity and clinical pain in women with fibromyalgia (FM). Thirty-one women with FM were included in the study. Pressure pain sensitivity was assessed with an electronic pressure dolorimeter. The average pressure pain threshold (PPT) from the 18 FM-related tender points and the tender points count (TPC) were recorded. Clinical pain was assessed on a 10 cm visual analog scale (VAS; from the FM impact questionnaire). The patients performed an incremental treadmill test, which consisted in six increasing workloads. Gas exchange was continuously monitored, and peak oxygen uptake (as measure of CRF) was recorded. Pairwise correlation and multiple linear regression were used to examine the association of CRF with PPT and VAS, and binary logistic regression assessed the odds of having <18 positive tender points as a function of CRF. The correlations of CRF with the average PPT and VAS were 0.355, (P < 0.001) and 0.058 (P > 0.05), respectively. Regression analyses revealed that CRF was associated with the PPT (B = 0.093; 95 % CI 0.064-0.122; P < 0.001; R (2) = 0.306) and TPC (OR 1.51; 95 % CI 1.30-1.75; P < 0.001) but not with VAS (B = 0.068; 95 % CI -0.061-0.197; P > 0.05). The findings of this study suggest that CRF is associated with pressure pain sensitivity but not with clinical pain in women with FM. Further longitudinal and intervention studies are needed to determine whether CRF could be involved in some mechanisms of pain processing. PMID- 25549602 TI - A new page to the Anatolian Journal of Cardiology. PMID- 25549603 TI - How will 2014 European Society of Cardiology Congress influence our daily practice? AB - European Cardiology Congress which was held in Barcelona in this year; was a meeting with striking results of the presented scientific studies. Herein, a brief overview of congress highlights is presented. PMID- 25549606 TI - Treatment goals in psoriasis routine care. AB - The treatment goal algorithm for psoriasis, first originated in 2007, has ever since been adopted into treatment guidelines. It remained unclear how many patients have experienced the use of treatment goals in routine care and how these are perceived. The aim of the pilot study was to get first insight in the use and impact of therapeutic goals in a large cohort of patients with psoriasis in routine care. This study is a multicenter, non-interventional, cross-sectional health care study in n = 213 dermatology centers across Germany. A standardized physician and patient questionnaire was used, including demographics, disease and treatment characteristics. To evaluate patient treatment perception and satisfaction, a questionnaire (PsoSat) addressing 8 specific items was designed. Consistency and validity of the questionnaire were controlled by factor analyses and reliability tests. In total n = 1,883 patients were included for analysis (54.2% male). Mean age was 52 years, mean disease duration 19 years. In total 45.5% (n = 856) stated an improvement of psoriatic symptoms in the last 4 weeks. In patients including treatment goals, the course of psoriasis in the last 4 weeks was rated significantly better and predicted significantly higher patient satisfaction. Patients reporting periodic outcomes measurement of psoriasis treatment, also had significantly better course of disease, higher satisfaction and a lower psoriasis severity. A majority of patients experienced the use of treatment goals in practice. The association of using treatment goals with clinical outcomes and treatment satisfaction was markedly positive. These findings indicate that the use of treatment goals and outcome measurements in fact improve psoriasis management. PMID- 25549604 TI - The discovery of Mo(III) in FeMoco: reuniting enzyme and model chemistry. AB - Biological nitrogen fixation is enabled by molybdenum-dependent nitrogenase enzymes, which effect the reduction of dinitrogen to ammonia using an Fe7MoS9C active site, referred to as the iron molybdenum cofactor or FeMoco. In this mini review, we summarize the current understanding of the molecular and electronic structure of FeMoco. The advances in our understanding of the active site structure are placed in context with the parallel evolution of synthetic model studies. The recent discovery of Mo(III) in the FeMoco active site is highlighted with an emphasis placed on the important role that model studies have played in this finding. In addition, the reactivities of synthetic models are discussed in terms of their relevance to the enzymatic system. PMID- 25549607 TI - The wheat NHX antiporter gene TaNHX2 confers salt tolerance in transgenic alfalfa by increasing the retention capacity of intracellular potassium. AB - Previous studies have shown that TaNHX2 transgenic alfalfa (Medicago sativa L.) accumulated more K(+) and less Na(+) in leaves than did the wild-type plants. To investigate whether the increased K(+) accumulation in transgenic plants is attributed to TaNHX2 gene expression and whether the compartmentalization of Na(+) into vacuoles or the intracellular compartmentalization of potassium is the critical mechanism for TaNHX2-dependent salt tolerance in transgenic alfalfa, aerated hydroponic culture was performed under three different stress conditions: control condition (0.1 mM Na(+) and 6 mM K(+) inside culture solution), K(+) sufficient salt stress (100 mM NaCl and 6 mM K(+)) and K(+)-insufficient salt stress (100 mM NaCl and 0.1 mM K(+)). The transgenic alfalfa plants had lower K(+) efflux through specific K(+) channels and higher K(+) absorption through high-affinity K(+) transporters than did the wild-type plants. Therefore, the transgenic plants had greater K(+) contents and [K(+)]/[Na(+)] ratios in leaf tissue and cell sap. The intracellular compartmentalization of potassium is critical for TaNHX2-induced salt tolerance in transgenic alfalfa. PMID- 25549608 TI - An infant with hypomotor seizures and cutaneous lesions. PMID- 25549609 TI - Performances of a portable electrospinning apparatus. AB - To demonstrate that portable electrospinning devices can spin a wide range of polymers into submicron fibres and provide a mesh quality comparable to those produced with benchtop machines. We have designed a small, battery-operated electrospinning apparatus which enables control over the voltage and the flow rate of the polymer solution via a microcontroller. It can be used to electrospin a range of commonly used polymers including poly(epsilon-caprolactone), poly(p dioxanone), poly(lactic-co-glycolic acid), poly(3-hydroxybutyrate), poly(ethylene oxide), poly(vinyl acohol) and poly(vinyl butyral). Moreover, electrospun meshes are produced with a quality comparable to a benchtop machine. We also show that the portable apparatus is able to electrospray beads and microparticles. Finally, we highlight the potential of the device for wound healing applications by demonstrating the possibility of electrospinning onto pig and human skins. Portable electrospinning devices are still at an early stage of development but they could soon become an attractive alternative to benchtop machines, in particular for uses that require mobility and a higher degree of flexibility, such as for wound healing applications. PMID- 25549610 TI - In vitro cytotoxicity of metallic ions released from dental alloys. AB - The cytotoxicity of a dental alloy depends on, but is not limited to, the extent of its corrosion behavior. Individual ions may have effects on cell viability that are different from metals interacting within the alloy structure. We aimed to investigate the cytotoxicity of individual metal ions in concentrations similar to those reported to be released from Pd-based dental alloys on mouse fibroblast cells. Metal salts were used to prepare seven solutions (concentration range 100 ppm-1 ppb) of the transition metals, such as Ni(II), Pd(II), Cu(II), and Ag(I), and the metals, such as Ga(III), In(III), and Sn(II). Cytotoxicity on mouse fibroblasts L929 was evaluated using the MTT assay. Ni, Cu, and Ag are cytotoxic at 10 ppm, Pd and Ga at 100 ppm. Sn and In were not able to induce cytotoxicity at the tested concentrations. Transition metals were able to induce cytotoxic effects in concentrations similar to those reported to be released from Pd-based dental alloys. Ni, Cu, and Ag were the most cytotoxic followed by Pd and Ga; Sn and In were not cytotoxic. Cytotoxic reactions might be considered in the etiopathogenesis of clinically observed local adverse reactions. PMID- 25549611 TI - Supportive communication with parents moderates the negative effects of electronic media use on life satisfaction during adolescence. AB - OBJECTIVES: To examine the impact of electronic media (EM) use on teenagers' life satisfaction (LS) and to assess the potential moderating effect of supportive communication with parents (SCP). METHODS: Data were drawn from the cross national Health Behaviour in School-aged Children (HBSC) study (2009/2010) in Canada, England, Germany, Hungary, Italy, Israel, The Netherlands, Poland and Scotland. Sample size: 53,973 students aged 11-15 years. RESULTS: More hours per day spent on the computer were associated with lower LS; more EM communication with friends with higher LS. This relationship became negative if EM use reached and exceeded a certain threshold. SCP moderated the effect of EM communication with friends, but not computer use for the total sample. SCP seems to be more important than computer use or EM communication with friends for LS and it seems to buffer negative effects of EM use. CONCLUSIONS: Communication with parents seems to buffer the negative effects of EM use on LS during adolescence. Higher computer use was related to lower LS, but "optimal" frequency of EM communication with friends was country specific. PMID- 25549612 TI - Health literacy and disability: differences between generations of Canadian immigrants. AB - OBJECTIVES: To determine whether there are differences in disability by immigrant generation and region of origin and recency of arrival in Canada, and the role of health literacy in this relationship. METHODS: A secondary analysis of the Canadian component of the 2003 International Adult Literacy and Skills Survey (IALSS) was undertaken. RESULTS: Compared to the third-plus generation, first generation immigrants were less likely to report disability; these differences remained even after adjustment for sociodemographic and socioeconomic factors. No differences in disability were observed between the second- and third-plus generations. Among first-generation immigrants, those not from Europe or USA were less likely to report disability regardless of their duration in Canada. Health literacy was negatively associated with disability only in the analysis comparing generations of Canadians. However, its effect was largely accounted for by education, employment status and income. CONCLUSIONS: First-generation immigrants were less likely to be disabled than the other generations. Education, employment and income provide important avenues through which individuals develop health literacy. Health literacy was not associated with disability among first generation immigrants perhaps because health literacy is low in this group. PMID- 25549613 TI - Online gaming and risks predict cyberbullying perpetration and victimization in adolescents. AB - OBJECTIVES: The present study examined factors associated with the emergence and cessation of youth cyberbullying and victimization in Taiwan. METHODS: A total of 2,315 students from 26 high schools were assessed in the 10th grade, with follow up performed in the 11th grade. Self-administered questionnaires were collected in 2010 and 2011. Multiple logistic regression was conducted to examine the factors. RESULTS: Multivariate analysis results indicated that higher levels of risk factors (online game use, exposure to violence in media, internet risk behaviors, cyber/school bullying experiences) in the 10th grade coupled with an increase in risk factors from grades 10 to 11 could be used to predict the emergence of cyberbullying perpetration/victimization. In contrast, lower levels of risk factors in the 10th grade and higher levels of protective factors coupled with a decrease in risk factors predicted the cessation of cyberbullying perpetration/victimization. CONCLUSION: Online game use, exposure to violence in media, Internet risk behaviors, and cyber/school bullying experiences can be used to predict the emergence and cessation of youth cyberbullying perpetration and victimization. PMID- 25549614 TI - Workshop report: Crystal City V--quantitative bioanalytical method validation and implementation: the 2013 revised FDA guidance. AB - In September 2013, the FDA released a draft revision of the Bioanalytical Method Validation (BMV) Guidance, which included a number of changes to the expectations for bioanalysis, most notably the inclusion of biomarker assays and data. To provide a forum for an open, inclusive discussion of the revised draft BMV Guidance, the AAPS and FDA once again collaborated to convene a two-and-a-half day workshop during early December 2013 in Baltimore, MD, USA. The resulting format embodied extensive open discussion and each thematic session included only brief, concise descriptions by Agency and industry representatives prior to opening the floor discussion. The Workshop was built around four thematic sessions (Common Topics, Chromatographic, Ligand-Binding Assays, and Biomarkers) and a final session with international regulators, concluding with a review of the outcomes and recommendations from the thematic sessions. This Workshop report summarizes the outcomes and includes topics of agreement, those where the FDA will consider the Industry's perspective, and those where the workshop provided a first open dialogue. This article will be available to the bioanalytical community at http://www.aaps.org/BMV13 . PMID- 25549615 TI - Structure of precursor microRNA's terminal loop regulates human Dicer's dicing activity by switching DExH/D domain. AB - Almost all pre-miRNAs in eukaryotic cytoplasm are recognized and processed into double-stranded microRNAs by the endonuclease Dicer protein comprising of multiple domains. As a key player in the small RNA induced gene silencing pathway, the major domains of Dicer are conserved among different species with the exception of the N-terminal components. Human Dicer's N-terminal domain has been shown to play an auto-inhibitory function of the protein's dicing activity. Such an auto-inhibition can be released when the human Dicer protein dimerizes with its partner protein, such as TRBP, PACT through the N-terminal DExH/D (ATPase-helicase) domain. The typical feature of a pre-miRNA contains a terminal loop and a stem duplex, which bind to human Dicer's DExH/D (ATPase-helicase) domain and PAZ domain respectively during the dicing reaction. Here, we show that pre-miRNA's terminal loop can regulate human Dicer's enzymatic activity by interacting with the DExH/D (ATPase-helicase) domain. We found that various editing products of pre-miR-151 by the ADAR1P110 protein, an A-to-I editing enzyme that modifies pre-miRNAs sequence, have different terminal loop structures and different activity regulatory effects on human Dicer. Single particle electron microscopy reconstruction revealed that pre-miRNAs with different terminal loop structures induce human Dicer's DExH/D (ATPase-helicase) domain into different conformational states, in correlation with their activity regulatory effects. PMID- 25549616 TI - Capturing the target genes of BldD in Saccharopolyspora erythraea using improved genomic SELEX method. AB - BldD (SACE_2077), a key developmental regulator in actinomycetes, is the first identified transcriptional factor in Saccharopolyspora erythraea positively regulating erythromycin production and morphological differentiation. Although the BldD of S. erythraea binds to the promoters of erythromycin biosynthetic genes, the interaction affinities are relatively low, implying the existence of its other target genes in S. erythraea. Through the genomic systematic evolution of ligands by exponential enrichment (SELEX) method that we herein improved, four DNA sequences of S. erythraea A226, corresponding to the promoter regions of SACE_0306 (beta-galactosidase), SACE_0811 (50S ribosomal protein L25), SACE_3410 (fumarylacetoacetate hydrolase), and SACE_6014 (aldehyde dehydrogenase), were captured with all three BldD concentrations of 0.5, 1, and 2 MUM, while the previously identified intergenic regions of eryBIV-eryAI and ermE-eryCI plus the promoter region of SACE_7115, the amfC homolog for aerial mycelium formation, could be captured only when the BldD's concentration reached 2 MUM. Electrophoretic mobility shift assay (EMSA) analysis indicated that BldD specifically bound to above seven DNA sequences, and quantitative real-time PCR (qRT-PCR) assay showed that the transcriptional levels of the abovementioned target genes decreased when bldD was disrupted in A226. Furthermore, SACE_7115 and SACE_0306 in A226 were individually inactivated, showing that SACE_7115 was predominantly involved in aerial mycelium formation, while SACE_0306 mainly controlled erythromycin production. This study provides valuable information for better understanding of the pleiotropic regulator BldD in S. erythraea, and the improved method may be useful for uncovering regulatory networks of other transcriptional factors. PMID- 25549617 TI - Simultaneous oral immunization of mice with live attenuated Escherichia coli expressing LT192-STa 13 and LT 192-STb fusion immunogen, respectively, for polyvalent vaccine candidate. AB - Previous epidemiological study showed that most of the porcine enterotoxin Escherichia coli (ETEC) strains harbor multiple enterotoxins but lack any of the fimbriae or non-fimbrial adhesion genes. Therefore, effective ETEC vaccines need to aim directly at all the enterotoxin antigens. The objective of this study was to evaluate the simultaneous immune effect of two live attenuated E. coli strains expressing LTR192G-STaA13Q and LTR192G-STb fusion immunogen, respectively. The results showed that both local mucosal and systemic immune responses against LT, STa, STb, and F41 were induced in BALB/c mice immunized orally with the recombinant E. coli strains ER-A and ER-B simultaneously. In addition, results of cellular immune responses showed that stimulation index (SI) values of immunized mice were significantly higher than control mice (P < 0.05) and a marked shift toward type-2 helper T lymphocyte (Th 2) immunity. Moreover, the induced antibodies demonstrated neutralizing effects on LT, STa, and STb producing E. coli infection. These data indicated that the use of recombinant E. coli ER-A and ER-B could be a valuable strategy for future polyvalent vaccine development of ETEC. PMID- 25549619 TI - A third glucose uptake bypass in Corynebacterium glutamicum ATCC 31833. AB - In Corynebacterium glutamicum, the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) has long been the only known glucose uptake system, but we recently found suppressor mutants emerging from a PTS-negative strain of C. glutamicum ATCC 31833 on glucose agar plates, and identified two alternative potential glucose uptake systems, the myo-inositol transporters encoded by iolT1 and iolT2. The expression of either gene renders the PTS negative strain WTDeltaptsH capable of growing on glucose. In the present study, we found a suppressor strain that still grew on glucose even after the iolT1 and iolT2 genes were both disrupted under the PTS-negative background. Whole-genome sequencing of the suppressor strain SPH1 identified a G-to-T exchange at 134 bp upstream of the bglF gene encoding an EII component of the beta-glucoside-PTS, which is found in limited wild-type strains of C. glutamicum. Introduction of the mutation into strain WTDeltaptsH allowed the PTS-negative strain to grow on glucose. Reverse transcription-quantitative PCR analysis revealed that the mutation upregulates the bglF gene by approximately 11-fold. Overexpression of bglF under the gapA promoter in strain WTDeltaptsH rendered the strain capable of growing on glucose, and deletion of bglF in strain SPH1 abolished the growth again, proving that bglF is responsible for glucose uptake in the suppressor strain. Simultaneous disruption of three glucokinase genes, glk (Cgl2185, NCgl2105), ppgK (Cgl1910, NCgl1835), and Cgl2647 (NCgl2558), in strain SPH1 resulted in no growth on glucose. Plasmid-mediated expression of any of the three genes in the triple-knockout mutant restored the growth on glucose. These results indicate that C. glutamicum ATCC 31833 has an additional non-PTS glucose uptake route consisting of the bglF-specified EII permease and native glucokinases. PMID- 25549618 TI - Asymmetric reduction of ketones and beta-keto esters by (S)-1-phenylethanol dehydrogenase from denitrifying bacterium Aromatoleum aromaticum. AB - Enzyme-catalyzed enantioselective reductions of ketones and keto esters have become popular for the production of homochiral building blocks which are valuable synthons for the preparation of biologically active compounds at industrial scale. Among many kinds of biocatalysts, dehydrogenases/reductases from various microorganisms have been used to prepare optically pure enantiomers from carbonyl compounds. (S)-1-phenylethanol dehydrogenase (PEDH) was found in the denitrifying bacterium Aromatoleum aromaticum (strain EbN1) and belongs to the short-chain dehydrogenase/reductase family. It catalyzes the stereospecific oxidation of (S)-1-phenylethanol to acetophenone during anaerobic ethylbenzene mineralization, but also the reverse reaction, i.e., NADH-dependent enantioselective reduction of acetophenone to (S)-1-phenylethanol. In this work, we present the application of PEDH for asymmetric reduction of 42 prochiral ketones and 11 beta-keto esters to enantiopure secondary alcohols. The high enantioselectivity of the reaction is explained by docking experiments and analysis of the interaction and binding energies of the theoretical enzyme substrate complexes leading to the respective (S)- or (R)-alcohols. The conversions were carried out in a batch reactor using Escherichia coli cells with heterologously produced PEDH as whole-cell catalysts and isopropanol as reaction solvent and cosubstrate for NADH recovery. Ketones were converted to the respective secondary alcohols with excellent enantiomeric excesses and high productivities. Moreover, the progress of product formation was studied for nine para-substituted acetophenone derivatives and described by neural network models, which allow to predict reactor behavior and provides insight on enzyme reactivity. Finally, equilibrium constants for conversion of these substrates were derived from the progress curves of the reactions. The obtained values matched very well with theoretical predictions. PMID- 25549620 TI - Involvement of the NADH oxidase-encoding noxA gene in oxidative stress responses in Corynebacterium glutamicum. AB - Corynebacterium glutamicum ORF NCgl0328, designated noxA, encodes an NADH oxidase enzyme. The noxA gene, which was preferentially expressed in the log growth phase, was found to be under the control of the whcA, whcB, and whcE genes, which play regulatory roles in cells under oxidative stress. While noxA transcription was minimal in whcE-deleted mutant cells (DeltawhcE) during growth, its transcription was maximal even in the stationary phase in DeltawhcA cells. The transcription levels of noxA in DeltawhcB and whcB-overexpressing cells were comparable to the levels only in the log growth phase in DeltawhcA and whcA overexpressing cells, respectively. Direct binding of purified WhcA to the promoter region of noxA was observed in vitro. The DNA-protein interaction was only possible in the presence of the reducing agent dithiothreitol. A noxA deleted mutant strain and a strain overexpressing the noxA gene (P180-noxA) were established, and these strains were found to exhibit defective cell growth. The DeltanoxA and P180-noxA strains were sensitive to the redox-cycling oxidant menadione, suggesting a role of noxA in redox balancing. Accordingly, the purified NoxA enzyme exhibited NADH-oxidizing activity. Taken together, these data show that noxA plays a role in oxidative stress responses and also that the gene is under direct control of the WhcA protein, which was shown to be a regulatory DNA-binding protein. Furthermore, the involvement and roles of the whcA, whcB, and whcE genes in regulating the expression of noxA were demonstrated. PMID- 25549621 TI - Antimicrobial compounds from seaweeds-associated bacteria and fungi. AB - In recent decade, seaweeds-associated microbial communities have been significantly evaluated for functional and chemical analyses. Such analyses let to conclude that seaweeds-associated microbial communities are highly diverse and rich sources of bioactive compounds of exceptional molecular structure. Extracting bioactive compounds from seaweed-associated microbial communities have been recently increased due to their broad-spectrum antimicrobial activities including antibacterial, antifungal, antiviral, anti-settlement, antiprotozoan, antiparasitic, and antitumor. These allelochemicals not only provide protection to host from other surrounding pelagic microorganisms, but also ensure their association with the host. Antimicrobial compounds from marine sources are promising and priority targets of biotechnological and pharmaceutical applications. This review describes the bioactive metabolites reported from seaweed-associated bacterial and fungal communities and illustrates their bioactivities. Biotechnological application of metagenomic approach for identifying novel bioactive metabolites is also dealt, in view of their future development as a strong tool to discover novel drug targets from seaweed associated microbial communities. PMID- 25549622 TI - Probing C-terminal interactions of the Pseudomonas stutzeri cyanide-degrading CynD protein. AB - The cyanide dihydratases from Bacillus pumilus and Pseudomonas stutzeri share high amino acid sequence similarity throughout except for their highly divergent C-termini. However, deletion or exchange of the C-termini had different effects upon each enzyme. Here we extended previous studies and investigated how the C terminus affects the activity and stability of three nitrilases, the cyanide dihydratases from B. pumilus (CynDpum) and P. stutzeri (CynDstut) and the cyanide hydratase from Neurospora crassa. Enzymes in which the C-terminal residues were deleted decreased in both activity and thermostability with increasing deletion lengths. However, CynDstut was more sensitive to such truncation than the other two enzymes. A domain of the P. stutzeri CynDstut C-terminus not found in the other enzymes, 306GERDST311, was shown to be necessary for functionality and explains the inactivity of the previously described CynDstut-pum hybrid. This suggests that the B. pumilus C-terminus, which lacks this motif, may have specific interactions elsewhere in the protein, preventing it from acting in trans on a heterologous CynD protein. We identify the dimerization interface A surface region 195-206 (A2) from CynDpum as this interaction site. However, this A2 region did not rescue activity in C-terminally truncated CynDstutDelta302 or enhance the activity of full-length CynDstut and therefore does not act as a general stability motif. PMID- 25549623 TI - Choosing an Appropriate Modelling Framework for Analysing Multispecies Co-culture Cell Biology Experiments. AB - In vitro cell biology assays play a crucial role in informing our understanding of the migratory, proliferative and invasive properties of many cell types in different biological contexts. While mono-culture assays involve the study of a population of cells composed of a single cell type, co-culture assays study a population of cells composed of multiple cell types (or subpopulations of cells). Such co-culture assays can provide more realistic insights into many biological processes including tissue repair, tissue regeneration and malignant spreading. Typically, system parameters, such as motility and proliferation rates, are estimated by calibrating a mathematical or computational model to the observed experimental data. However, parameter estimates can be highly sensitive to the choice of model and modelling framework. This observation motivates us to consider the fundamental question of how we can best choose a model to facilitate accurate parameter estimation for a particular assay. In this work we describe three mathematical models of mono-culture and co-culture assays that include different levels of spatial detail. We study various spatial summary statistics to explore if they can be used to distinguish between the suitability of each model over a range of parameter space. Our results for mono-culture experiments are promising, in that we suggest two spatial statistics that can be used to direct model choice. However, co-culture experiments are far more challenging: we show that these same spatial statistics which provide useful insight into mono culture systems are insufficient for co-culture systems. Therefore, we conclude that great care ought to be exercised when estimating the parameters of co culture assays. PMID- 25549624 TI - A global convergence result for processive multisite phosphorylation systems. AB - Multisite phosphorylation plays an important role in intracellular signaling. There has been much recent work aimed at understanding the dynamics of such systems when the phosphorylation/dephosphorylation mechanism is distributive, that is, when the binding of a substrate and an enzyme molecule results in the addition or removal of a single phosphate group and repeated binding therefore is required for multisite phosphorylation. In particular, such systems admit bistability. Here, we analyze a different class of multisite systems, in which the binding of a substrate and an enzyme molecule results in the addition or removal of phosphate groups at all phosphorylation sites, that is, we consider systems in which the mechanism is processive, rather than distributive. We show that in contrast to distributive systems, processive systems modeled with mass action kinetics do not admit bistability and, moreover, exhibit rigid dynamics: each invariant set contains a unique equilibrium, which is a global attractor. Additionally, we obtain a monomial parametrization of the steady states. Our proofs rely on a technique of Johnston for using "translated" networks to study systems with "toric steady states," recently given sign conditions for the injectivity of polynomial maps, and a result from monotone systems theory due to Angeli and Sontag. PMID- 25549625 TI - Exposure to heavy metals due to pesticide use by vineyard farmers. AB - OBJECTIVES: To statistically analyze serum heavy metal levels in biological samples obtained from vineyard workers from southern Brazil and check for heavy metal exposure due to pesticide use. METHODS: Serum samples were obtained from 54 farmers and 108 healthy unexposed individuals. Samples from the same farmers were obtained at three different time points over a 1-year period. Levels of lead, arsenic, nickel, zinc, manganese and copper were determined for each sample using dynamic reaction cell inductively coupled plasma mass spectrometry (DRC-ICP-MS). All results were statistically analyzed using the nonparametric Kruskal-Wallis test (followed by Dunn's post hoc test). RESULTS: Results showed that serum heavy metal levels in farmers were twofold to fourfold higher than in controls. This difference was found for all heavy metals tested and was significant (p < 0.05). Serum metal levels among the farmers also correlated with the frequency of use of pesticides at a specific time of year, which varied according to seasonal conditions influencing the need for pesticide application. CONCLUSIONS: It can be concluded that in the vineyard region assessed, farmers were more susceptible to heavy metal exposure due to pesticide use. PMID- 25549626 TI - beta-Alanine does not act through branched-chain amino acid catabolism in carp, a species with low muscular carnosine storage. AB - This study was executed to investigate the effect of dietary beta-alanine (BA) on amino acid (AA) metabolism and voluntary feed intake in carp (Cyprinus carpio) at mildly elevated temperature to exert AA catabolism. Twenty-four fish in 12 aquaria were randomly assigned to either a control diet or the same diet with 500 mg BA/kg. A 14-day period at an ideal temperature (23 degrees C) was followed by 15 days at chronic mildly elevated temperature (27 degrees C). After the 15 days, all fish were euthanised for muscle analysis on histidine-containing dipeptides (HCD), whole blood on free AA and carnitine esters. The carnosine and anserine analysis indicated that all analyses were below the detection limit of 5 umol/L, confirming that carp belongs to a species that does not store HCD. The increases in free AA concentrations due to BA supplementation failed to reach the level of significance. The effects of dietary BA on selected whole blood carnitine esters and their ratios were also not significant. The supplementation of BA tended to increase body weight gain (P = 0.081) and feed intake (P = 0.092). The lack of differences in the selected nutrient metabolites in combination with tendencies of improved growth performance warrants further investigation to unravel the mechanism of BA affecting feed intake. This first trial on the effect of BA supplementation on AA catabolism showed that its metabolic effect in carp at chronic mildly elevated temperature was very limited. Further studies need to evaluate which conditions are able to exert an effect of BA on AA metabolism. PMID- 25549627 TI - Prescriber continuity and medication adherence for complex patients. AB - BACKGROUND: Medication adherence is a critical aspect of managing cardiometabolic conditions, including diabetes, hypertension, dyslipidemia, and heart failure. Patients who have multiple cardiometabolic conditions and multiple prescribers may be at increased risk for nonadherence. OBJECTIVE: The purpose of this study was to examine the relationship between number of prescribers, number of conditions, and refill adherence to oral medications to treat cardiometabolic conditions. METHODS: In this retrospective cohort study, 7933 veterans were identified with 1 to 4 cardiometabolic conditions. Refill adherence to oral medications for diabetes, hypertension, and dyslipidemia was measured using an administrative claims-based continuous multiple-interval gap (CMG) that estimates the percentage of days a patient did not possess medication. We dichotomized refill adherence for each condition as a CMG <=20% for each year of analysis. Condition-specific logistic regression models estimated the relationship between refill adherence and number of cardiometabolic conditions and number of prescribers, controlling for demographic characteristics, other comorbidities, and a count of cardiometabolic drug classes used. RESULTS: Compared with patients with 1 prescriber, antihypertensive refill adherence was lower in patients seeing >=4 prescribers (odds ratio [OR] = 0.69; 95% CI = 0.59-0.80), but the number of cardiometabolic conditions was not a significant predictor. Antidyslipidemia refill adherence was lower in patients seeing 3 prescribers (OR = 0.80; 95% CI = 0.70-0.92) or >=4 prescribers (OR = 0.77; 95% CI = 0.64-0.91). Conversely, antidyslipidemia refill adherence improved with the number of cardiometabolic conditions, but differences were only statistically significant for >=3 conditions (OR = 1.31; 95% CI = 1.09-1.57). In multivariate regression models, the number of conditions and number of prescribers were not significant predictors of refill adherence in the group of patients with diabetes. CONCLUSIONS: Effective management of care and medication regimens for complex patients remains an unresolved challenge, but these results suggest that medication refill adherence might be improved by minimizing the number of prescribers involved in a patient's care, at least for hypertension and dyslipidemia. PMID- 25549628 TI - Publication rate of abstracts presented at the emergency medicine congresses held by the European Society for Emergency Medicine (EUSEM) in 2011 and 2012. AB - PURPOSE: The purpose of this study was to assess the publication rate of the abstracts presented at the 6th Mediterranean Emergency Medicine Congress, 2011 and the 7th European Congress on Emergency Medicine, 2012. MATERIALS AND METHODS: All abstracts, both posters and oral presentations, from the international emergency medicine congresses held by the European Society for Emergency Medicine (EUSEM) in 2011 and 2012 were identified. To establish whether these abstracts were subsequently published in peer-reviewed medical journals, the names of all the authors and the title of the abstracts were searched for in the databases of Clinical Key/Elsevier, EBSCO Discovery Service, MD Consult, Science Direct, Scopus, EMBASE, Medscape, Google Scholar and local ULAKBIM. The year of publication, consistency of author names and titles, the type of study, the journals in which papers were published and countries from which reports were submitted were all recorded. RESULTS: A total of 1721 abstracts were examined; 626 from 2011 (307 oral presentations and 319 posters) and 1095 from 2012 (154 oral presentations and 941 posters). Of all abstracts in 2011, 172 (27.5%) and of all abstracts in 2012, 265 (24.2%) were subsequently published as full-text reports in peer-reviewed journals. Of the 172 papers published in 2011, 152 (88.4%) were accepted by Science Citation Index (SCI) and/or SCI Expanded (SCI-E) journals and 155 (58.5%) of 265 papers were accepted by SCI and/or SCI-E journals in 2012 (p=0.0001). CONCLUSIONS: The publication rate of abstracts submitted to international emergency medicine congresses held by EUSEM over those 2 years was low compared with that of abstracts presented in other emergency medicine congresses. Presenters should be encouraged to send their studies to peer reviewed journals. During the selection process by the scientific panel, constructive critics should be notified to the presenters instead of simply accepting or rejecting the studies that submitted to the congress, which may increase the subsequent publication rate. PMID- 25549629 TI - MS patients are in sustained remission after stem cell transplantation, small study finds. PMID- 25549631 TI - Evolution from double to triple-antimalarial drug combinations. AB - Drug combinations are used to treat multiple-drug resistant malaria parasites and to attempt to further delay the evolution of drug resistance. Most current antimalarial combinations are binary but it is likely that new triple drug combinations will be required in the future. A review of previous triple combinations of antimalarial drugs was done to focus attention on past problems and possible future combinations. The advantages of such triple drug combinations include greater efficacy against multiple-drug resistant strains, synergistic action between the different medications and simplification of the regimen so that it could be administered under direct observation and possibly as single dose therapy. The disadvantages of poly-pharmacy include increased cost of medication, difficulty preparing robust regulatory packages and problems constructing combined formulations due to drug-drug interactions. Given the arrival of artemisinin tolerance/resistance in Southeast Asia, it is likely that new drugs introduced for malaria treatment will be in triple drug combinations. PMID- 25549632 TI - Outcomes of a school-based intervention on rabies prevention among school children in rural Sri Lanka. AB - BACKGROUND: In Sri Lanka, one of the major challenges in rabies control is to manage the dog population and subsequently to protect people, especially young children, from dog bites. METHODS: In 2009, an educational-entertainment campaign called 'Rabies Edutainment 4 Kids' was introduced in the school curricula in rural Sri Lanka to improve practices on rabies prevention and pet care among school children, and to evaluate its effectiveness through pre- and post-tests. RESULTS: The level of rabies knowledge, attitude and practice among the pupils was dependent on their responses to a survey, and scores were significantly improved both among the study and control groups after the intervention. A lecture accompanied by a rabies awareness leaflet was much more effective in improving knowledge than the leaflet alone. The type of intervention and language used was significantly associated with the score increment (p<0.001). CONCLUSIONS: The threat of rabies to pupils in Sri Lanka would be reduced if they are given appropriate information on rabies prevention as a part of the school curricula. Close collaboration with local education offices is key to successful implementation of school-based rabies control programmes, which is, in turn, crucial to the eradication of rabies from Sri Lanka. PMID- 25549630 TI - Molecular proxies for climate maladaptation in a long-lived tree (Pinus pinaster Aiton, Pinaceae). AB - Understanding adaptive genetic responses to climate change is a main challenge for preserving biological diversity. Successful predictive models for climate driven range shifts of species depend on the integration of information on adaptation, including that derived from genomic studies. Long-lived forest trees can experience substantial environmental change across generations, which results in a much more prominent adaptation lag than in annual species. Here, we show that candidate-gene SNPs (single nucleotide polymorphisms) can be used as predictors of maladaptation to climate in maritime pine (Pinus pinaster Aiton), an outcrossing long-lived keystone tree. A set of 18 SNPs potentially associated with climate, 5 of them involving amino acid-changing variants, were retained after performing logistic regression, latent factor mixed models, and Bayesian analyses of SNP-climate correlations. These relationships identified temperature as an important adaptive driver in maritime pine and highlighted that selective forces are operating differentially in geographically discrete gene pools. The frequency of the locally advantageous alleles at these selected loci was strongly correlated with survival in a common garden under extreme (hot and dry) climate conditions, which suggests that candidate-gene SNPs can be used to forecast the likely destiny of natural forest ecosystems under climate change scenarios. Differential levels of forest decline are anticipated for distinct maritime pine gene pools. Geographically defined molecular proxies for climate adaptation will thus critically enhance the predictive power of range-shift models and help establish mitigation measures for long-lived keystone forest trees in the face of impending climate change. PMID- 25549634 TI - Financial insecurity is associated with poor diabetes control, study finds. PMID- 25549633 TI - Addition of autologous mesenchymal stem cells to whole blood for bioenhanced ACL repair has no benefit in the porcine model. AB - BACKGROUND: Coculture of mesenchymal stem cells (MSCs) from the retropatellar fat pad and peripheral blood has been shown to stimulate anterior cruciate ligament (ACL) fibroblast proliferation and collagen production in vitro. Current techniques of bioenhanced ACL repair in animal studies involve adding a biologic scaffold, in this case an extracellular matrix-based scaffold saturated with autologous whole blood, to a simple suture repair of the ligament. Whether the enrichment of whole blood with MSCs would further improve the in vivo results of bioenhanced ACL repair was investigated. HYPOTHESIS: The addition of MSCs derived from adipose tissue or peripheral blood to the blood-extracellular matrix composite, which is used in bioenhanced ACL repair to stimulate healing, would improve the biomechanical properties of a bioenhanced ACL repair after 15 weeks of healing. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-four adolescent Yucatan mini-pigs underwent ACL transection followed by (1) bioenhanced ACL repair, (2) bioenhanced ACL repair with the addition of autologous adipose-derived MSCs, and (3) bioenhanced ACL repair with the addition of autologous peripheral blood derived MSCs. After 15 weeks of healing, the structural properties of the ACL (yield load, failure load, and linear stiffness) were measured. Cell and vascular density were measured in the repaired ACL via histology, and its tissue structure was qualitatively evaluated using the advanced Ligament Maturity Index. RESULTS: After 15 weeks of healing, there were no significant improvements in the biomechanical or histological properties with the addition of adipose-derived MSCs. The only significant change with the addition of peripheral blood MSCs was an increase in knee anteroposterior laxity when measured at 30 degrees of flexion. CONCLUSION: These findings suggest that the addition of adipose or peripheral blood MSCs to whole blood before saturation of an extracellular matrix carrier with the blood did not improve the functional results of bioenhanced ACL repair after 15 weeks of healing in the pig model. CLINICAL RELEVANCE: Whole blood represents a practical biologic additive to ligament repair, and any other additive (including stem cells) should be demonstrated to be superior to this baseline before clinical use is considered. PMID- 25549635 TI - Elevated transaortic valvular gradients after combined aortic valve and mitral valve replacement: an intraoperative dilemma. AB - High transaortic valvular gradients, after combined aortic valve and mitral valve replacement, require prompt intraoperative diagnosis and appropriate management. The presence of high transaortic valvular gradients after cardiopulmonary bypass, in this setting, can be secondary to the following conditions: prosthesis dysfunction, left ventricular outflow tract obstruction, supravalvular obstruction, prosthesis-patient mismatch, hyperkinetic left ventricle from administration of inotropes, left ventricular intracavitary gradients, pressure recovery phenomenon, and increased transvalvular blood flow resulting from hyperdynamic circulation or anemia. Transesophageal echocardiography is an extremely useful tool for timely diagnosis and treatment of this complication. We describe a case of a critically ill patient with endocarditis and acute lung injury, who presented for combined aortic valve and mitral valve replacement. Transesophageal echocardiographic assessment, post-cardiopulmonary bypass, revealed high transaortic valvular gradients due to encroachment of the mitral prosthesis strut on the left ventricular outflow tract, which was compounded by a small, hypertrophied, and hyperkinetic left ventricle. Discontinuation of inotropic support, administration of fluids, phenylephrine, and esmolol led to resolution of the high gradients and prevented further surgery. PMID- 25549637 TI - [New opinion on treat to target in systemic lupus erythematosus]. PMID- 25549638 TI - [Function of primary hospital into full play in treatment of traumatic brain injury]. PMID- 25549636 TI - Evaluation of hematocrit interference with MyStar extra and seven competitive devices. AB - In previous studies, meters employing dynamic electrochemistry (DE), have been shown to correct for hematocrit (HCT) interference. This laboratory investigation assessed the HCT stability of MyStar Extra (Sanofi) in comparison to 7 competitive devices (Accu-Chek Aviva Nano & Accu-Chek Performa, Roche Diagnostics; Contour XT and Contour Link, Bayer; FreeStyle Freedom Lite, Abbott; MyLife Pura, Ypsomed; OneTouch Verio Pro, LifeScan). Venous heparinized blood was freshly drawn, immediately aliquoted, and manipulated to contain 3 different blood glucose concentrations (50-80 mg/dL, 150-180 mg/dL, and 350-400 mg/dL) and 5 different HCT levels (20-25%, 30-35%, 40-45%, 50-55%, and 60-65%). After careful oxygenation to normal blood oxygen pressure, each of the 15 different samples was measured 8 times with 2 devices and 2 strip lots of each meter (32 measurements/meter/sample). YSI Stat 2300 served as laboratory reference method. Next to determination of the mean absolute relative deviation (MARD), stability to HCT influence was assumed, when less than 10% difference occurred between the highest and lowest mean glucose deviations in relation to HCT over all tested glucose ranges (HIF: hematocrit interference factor). Four of the devices showed stable performance: Contour XT (MARD: 1.3%/HIF: 6.1%), MyStar Extra (4.7%/7.1%), OneTouch Verio Pro (4.5%/7.3%), and Contour Link (6.3%/9.3%). The 4 other meters were influenced by HCT (Accu-Chek Performa: 4.7%/20.9%, Accu-Chek Aviva Nano: 4.5%/22.4%, FreeStyle Freedom Lite: 4.8%/24.5%; MyLife Pura: 6.4%/28.7%). In this study, all meters showed a good accuracy, but only 50% of them, including MyStar Extra, were shown to reliably correct for potential hematocrit influence on the meter results. PMID- 25549639 TI - [Functional electrical stimulation based on a working pattern influences function of lower extremity in subjects with early stroke and effects on diffusion tensor imaging: a randomized controlled trial]. AB - OBJECTIVE: To explore the possible mechanisms for improving lower extremity motor function in patients with early stroke through combining magnetic resonance diffusion tensor imaging (DTI) technology and functional electrical stimulation (FES) based on human walking patterns. METHODS: From August 2012 to September 2013, a total of 48 eligible patients were stratified according to age, gender, disease course, Brunnstrom staging and types of stroke. And the Minimize software was used to divided them randomly into four-channel FES group (n = 18), dual channel FES group (n = 15) and comfort stimulation group (n = 15). For all three groups, general medication and standard rehabilitation were provided. Based on normal walking pattern design of FES treatment, four-channel FES groups received the stimulations of quadriceps, hamstring, anterior tibialis and medial gastrocnemius. For the dual-channel FES group, the stimulations of tibialis anterior, peroneus longus and peroneus brevis muscles were applied. In comfort electrical stimulation group, the electrode positions were identical to the stimulation group, but there was no current output during stimulation. Before and after 3-week treatment, three groups received weekly rehabilitation evaluations of Fugl-Meyer assessment (FMA), posture assessment of stroke scale (PASS), Brunel balance assessment (BBA), Berg balance scale (BBS) and modified Barthel index (MBI). Before and after treatment, DTI examination was performed for some patients. RESULTS: Among three groups, general patient profiles and pre-treatment evaluations showed no significant difference. For intra-group comparisons versus pre-treatment, at week 1, 2 and 3, the scores of PASS, BBA, BBS, FMA and MBI had statistically significant differences (P < 0.05); At week 3 post-treatment, when four-channel and double-channel FES groups were compared versus pre-treatment, the scores of ipsilateral FA had statistically significant differences (P < 0.05). At week 1 post-treatment, MBI had statistically significant difference among 3 groups (P = 0.037). As compared with placebo, four-channel group had statistically significant difference [(52 +/- 12) vs (38 +/- 18), P < 0.05]; At week 2 post-treatment, the scores of PASS and MBI were (29 +/- 3, 73 +/- 13) in four-channel FES group versus (24 +/- 8, 60 +/- 17) in dual-channel FES group. And the scores of PASS, BBA, BBS, FMA and MBI were (9 +/- 3, 8.3 +/- 2.4, 37 +/- 7, 22 +/- 5, 73 +/- 13) in four-channel FES group versus (21 +/- 7, 6.2 +/- 3.1, 24 +/- 16, 15 +/- 8, 47 +/- 20) in comfort electrical stimulation group. When dual-channel FES and comfort stimulation groups were compared, MBI had significant statistical difference [(60 +/- 17) vs (47 +/- 20), P < 0.05]. At week 3 post-treatment, four-channel and dual-channel FES groups were compared, there was also statistical significance in FMA [(25 +/- 5) vs (20 +/- 7), P = 0.055]. The scores of PASS, BBS, FMA and MBI were (31 +/- 3, 43 +/- 8, 25 +/- 5, 81 +/- 13) in four-channel FES group versus (25 +/- 8, 29 +/- 17, 17 +/- 9, 54 +/ 25) in comfort stimulation group respectively. When dual-channel FES and comfort stimulation groups were compared, the scores of MBI were (71 +/- 15) and (54 +/- 25) respectively. And the difference was statistically significant (P < 0.05). At week 3 post-treatment, the scores of FA significantly increased [four-channel FES group (0.321 +/- 0.172) vs comfort stimulation group (0.217 +/- 0.135) (P = 0.020)]. When dual-channel FES group (0.333 +/- 0.164) and comfort stimulation group (0.217 +/- 0.135) (P = 0.049) were compared, the differences were statistically significant. DTI showed that four-channel FES group increased significantly, but contralateral fiber bundle was not obvious. And the improvements of dual-channel FES and comfort stimulation groups were insignificant. CONCLUSION: Compared with traditional dual-channel FES, functional electrical stimulation based on human walking patterns is more efficacious. And it helps to restore brain structure and function and promote motor function recovery in patients with early stroke. PMID- 25549640 TI - [Arterial remodeling in middle cerebral artery atherosclerotic stenosis:a high resolution MRI study]. AB - OBJECTIVE: To investigate remodeling mode of moderate or severe atherosclerotic stenosis of the middle cerebral artery (MCA) using high resolution MRI. METHODS: Thirty-seven consecutive symptomatic patients with atherosclerotic MCA stenosis were imaged with a 3.0-T magnetic resonance scanner. The HR-MRI protocol included four different scans: T1-weighted black blood imaging, T2-weighted MR, proton density (PD)-weighted MR, and 3D-SPACE. The wall area (VA), lumen area (LA) and plaque area (PA) were calculated. The characterization of the plaque on HR-MRI was analysed. And the difference between positive remodeling (PR) and non-postive remodeling (non-PR) was explored. RESULTS: Thirty-four patients imaging was appropriate for analyse. Positive remodeling was found in 19 lesions. Compared with the non-PR group, the PR group had greater WA [(10.9 +/- 2.5) mm2 and (9.2 +/- 1.9) mm2, P = 0.039)] and greater PA [(6.4 +/- 1.9) mm2 and (3.9 +/- 1.1) mm2, P = 0]. High intensity on DWI and irregularity of plaque surface were more frequently observed in PR than non-PR. CONCLUSION: In patients with MCA atherosclerosis, PR lesions contain larger plaques than non-PR lesions and are probably with high risk for plaque rupture and subsequent stroke. PMID- 25549641 TI - [Association of serum folic acid and homocysteine levels and 5, 10 methylenetetrahydrofolate reductase gene polymorphism with schizophrenia]. AB - OBJECTIVE: To explore the association between serum concentrations of folic acid and homocysteine (HCY), 5, 10-methylenetetrahydrofolate reductase (MTHFR) C667T polymorphism and schizophrenia. METHODS: A total of 130 schizophrenics (schizophrenia group) from our hospital and 80 healthy individuals (control group) were enrolled. The serum concentration of homocysteine was measured by the electrochemical luminescence method, the concentration of serum folic acid by enzymatic cycling assay and MTHFR C667T genotype by PCR-DNA microarray. And positive and negative syndrome scale (PANSS) was used to evaluate the mental symptoms. RESULTS: (1) Serum HCY level in schizophrenia group was higher than that in control group [(20 +/- 10) vs (11 +/- 3) umol/L; P < 0.001] while serum folate level in schizophrenia group was lower than that in control group [(6 +/- 4) vs (9 +/- 3) ng/ml; P < 0.001]; (2) the frequencies of CC, CT and TT in MTHFR C677T alleles were 13.1%, 50.0% and 36.9% in schizophrenia group versus 30.0%, 47.5% and 22.5% in control group respectively. Statistical significant inter group difference existed in the frequencies of genotypes (chi2 = 36.806, P < 0.05) . The frequencies of T and C alleles were 61.9%, 38.1% in schizophrenia group versus 46.25%, 53.75% in control group respectively. Statistical significant inter-group difference existed in the frequency of T allele (chi2 = 9.872, P < 0.05). The frequency of TT genotype in schizophrenia group was 61.9% versus 22.5% in control group. Statistically significant inter-group difference existed in the frequency of TT homozygous mutation (chi2 = 4.780, P < 0.05); (3) correlation analysis showed that serum folate level in schizophrenia group had a negative correlation with HCY level (r = -0.418, P < 0.001) . Serum HCY level had a positive correlation with negative symptoms scores (r = 0.345, P < 0.001) and serum folate level was negatively correlated with negative symptoms scores (r = 0.386, P < 0.001); (4) the serum HCY level in schizophrenia group with TT genotype was significantly higher than those with CC and CT genotypes (P < 0.05). CONCLUSION: There is a certain correlation between the serum levels of folate and HCY and the symptoms of schizophrenia. And MTHFR C677T polymorphism is a possible risk factor for schizophrenia. PMID- 25549642 TI - [Cyberknife radiosurgery for cerebral arteriovenous malformations: outlining of the radiosurgical target and obliteration]. AB - OBJECTIVE: To explore the therapeutic outcomes of cyberknife for patients with arteriovenous malformations (AVM) and outline the content of AVM targets. METHODS: Between January 2008 and October 2011, 51 patients underwent cyberknife radiosurgery for cerebral AVMs. The mean age was 27 (8-47) years. The procedures included prior embolization (n = 24), gamma knife before cyberknife (n = 2) and cyberknife initially (n = 25). The delineation of AVM targets was as follows: AVM with prior embolization, radiosurgical targets included AVM nidus, embolization areas and some small draining veins. However, low radiation dose was delivered to embolization parts and draining veins. For 25 patients without embolization, the radiosurgical target was AVM nidus. The mean target volume was 7.8 (1.2-22.0) cm3 and 15 of them were larger than 10.0 cm3. In patients harboring AVM with target volumes < 4 cm3, cyberknife radiation was delivered in a single session. And the remainder had 2 (n = 25) or 3 (n = 19) sessions. The mean marginal dose was 23(18 28) Gy. RESULTS: AVM obliteration was confirmed by magnetic resonance imaging (MRI) or angiography in 40 (78%) patients during a mean follow-up of 46 (36-70) months. Marked size reduction of AVM was obtained in 11 incompletely obliterated patients. Among them, there were second cyberknife treatment (n = 3), third embolization for complex AVM (n = 1), gamma knife (n = 1) and further follow-ups (n = 6). The higher obliteration rate of AVM was correlated with small volume of AVM in noncritical areas, prior embolization and radiation target of embolization areas. Three patients had hemorrhage during the follow-up period and recovered. Brain edema was found in patients with basal ganglion or parietal AVMs. A permanent neurological deficit (paralysis) due to adverse radiation effects developed in 1 patient. CONCLUSION: Cyberknife radiosurgery is particularly effective for patients with smaller AVMs in noncritical areas of brain. In patients with prior embolization, delineation of AVM targets including embolization areas is essential for a higher rate of obliteration. PMID- 25549643 TI - [Effect of benazepril on cardiac function in Chinese patients with chronic heart failure: a meta-analysis of randomized controlled trials]. AB - OBJECTIVE: To evaluate the efficacy and tolerability of benazepril in Chinese patients with chronic systolic heart failure. METHODS: We searched the databases of Cochrane, PubMed, EMbase, CBM and CNKI from January 1989 to November 2010 for the relevant studies. Two investigators identified randomized controlled trials (RCTs) independently according to the predefined inclusion and exclusion criteria. Statistical data analysis was performed with the Stata 11 software. RESULTS: A total of 15 studies with 1 355 Chinese patients of chronic systolic heart failure fulfilled the inclusion criteria. Among them, 546 received benazepril monotherapy. The dose range of benazepril was 5 to 40 mg daily. And it was similar to angiotensin II receptor blockers (ARBs) in improving left ventricular ejection fraction (LVEF)(P = 0.674), reducing LVEDD (P = 0.511) and improving cardiac output (P = 0.363). The combination therapy of benazepril and ARB was superior to ARB monotherapy in reducing left ventricular end-diastolic diameter (LVEDD) (P = 0.001). However, LVEF was comparable between patients with ACEI/ARB combination therapy and those with ARB monotherapy (P = 0.105). Compared with blank control, benazepril treatment was associated with a significant improvement in LVEF from baseline to follow-up (WMD = 6.5%; 95% CI: 0.9%, 12.0%; P = 0.022). Compared with baseline, benazepril treatment significantly increased LVEF (WMD = 10.4%; 95% confidence interval [CI]:7.1%, 13.8%; P < 0.001) and cardiac output (WMD = 1.5 L; CI:0.3, 2.6 L, P = 0.016). A significant reduction in LVEDD (WMD = 5.3 mm; CI: 2.7, 7.8 mm, P < 0.001) was also observed in benazepril group. As the most common side effect after benazepril treatment, cough had a prevalence of 11.6%. Other side effects were rare. CONCLUSION: Benazepril is both efficacious and safe in the management of Chinese patients with chronic heart failure. PMID- 25549644 TI - [Effects of ischemic postconditioning in patients with acute myocardial infarction undergoing primary PCI: a review and meta-analysis]. AB - OBJECTIVE: To evaluate the cardiac protective effects of ischemic postconditioning (IPC) in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: Both foreign and Chinese databases including PubMed, EMbase, Cochrane library, and CNKI were searched to identify randomized controlled trials (RCTs) that reported the effects of IPC on the myocardial infarction size, myocardial blush grade (MBG), left ventricular ejection fraction (LVEF) and major adverse cardiac events (MACE). Two reviews assessed the quality of each trial and extracted data independently. The Cochrane Collaboration's RevMan 4.2.8 software was used for statistical analysis. RESULTS: Twelve studies were identified and the Meta analysis included a total of 937 patients with AMI undergoing primary PCI with or without IPC. Pooled analysis of all studies demonstrated no significant reductions of peak CK and CK-MB with IPC relative to standard care. A secondary analysis of the studies didn't show improvements of left ventricular ejection fraction during hospitalization with IPC. However, the incidence of MACE within 3 month after primary PCI in IPC group was less than that in the control group (P = 0.04). CONCLUSION: No significant benefit of IPC for reduction of myocardial infarct size as determined by peak creatine kinase and CK-MB release, as well as LVEF. The incidence of MACE was improved in patients who received IPC. PMID- 25549645 TI - [Establishment and validation of normal human L1-L5 lumbar three-dimensional finite element model]. AB - OBJECTIVE: To create and validate a L1-L5 lumbar three-dimensional finite element model. METHODS: The L1-L5 lumbar spines of a male healthy volunteer were scanned with computed tomography (CT). And a L1-L5 lumbar three-dimensional finite element model was created with the aid of software packages of Mimics, Geomagic and Ansys. Then border conditions were set, unit type was determined, finite element mesh was divided and a model was established for loading and calculating. Average model stiffness under the conditions of flexion, extension, lateral bending and axial rotation was calculated and compared with the outcomes of former articles for validation. RESULTS: A normal human L1-L5 lumbar three dimensional finite element model was established to include 459 340 elements and 661 938 nodes. After constraining the inferior endplate of L5 vertebral body, 500 kg * m * s-2 compressive loading was imposed averagely on the superior endplate of L1 vertebral body. Then 10 kg * m2 * s-2 moment simulating flexion, extension, lateral bending and axial rotation were imposed on the superior endplate of L1 vertebral body. Eventually the average stiffness of all directions was calculated and it was similar to the outcomes of former articles. CONCLUSION: The L1-L5 lumbar three-dimensional finite element model is validated so that it may used with biomechanical simulation and analysis of normal or surgical models. PMID- 25549646 TI - [Effects of non-physical factors on neck and shoulder pain and low back pain of adolescents]. AB - OBJECTIVE: To explore the incidence of self-reported neck/shoulder pain (NSP) and lower back pain (LBP) among Chinese adolescents in Shanghai and identify the influencing factors for the incidences of these musculoskeletal disorders. METHODS: A total of 3 600 students were selected from 30 high schools randomly chosen from 237 regular full-time high schools registered in Shanghai. From each school, 40 students were selected from each of the tenth, eleventh and twelfth grades for a total of 120 students per school. The questionnaire involved questions pertaining to demographic information, learning environment and exercise habits of each student. The questionnaire also contained questions regarding the amount of weight carried by each student while commuting to and from school. And it was also used to collect specific information related with the occurrence of NSP and LBP. Logistic regression was performed to analyze the potential risk factors for NSP and LBP. RESULTS: Among 3 600 distributed questionnaires, a total of 2 842 valid questionnaires were returned. The results revealed that the incidences of NSP and LBP in the Chinese adolescent population were 41.1% and 32.8%, respectively. Both NSP and LBP were more common in girls than in boys. And 6.3% students reported at least one NSP- or LBP-induced absence from school. Chinese adolescents generally experienced a heavy academic burden (32.7% failing to achieve daily academic goals) and mental stress (16.3% suffering from insomnia); the problem of insufficient sleep was even more pronounced (52.0% falling asleep after midnight and 64.3% suffering insufficient sleep while only 31.9% feeling physically relaxed after awaking). The multivariate Logistic regression analysis suggested that gender, grade, academic burden, stress and sleep situation had a significant correlation with NSP and LBP in adolescents. CONCLUSION: The incidences of NSP and LBP are relatively high among adolescents in Shanghai. And several factors, including sedentary behaviors, personal exercise habits and backpack weight, influences the occurrences of NSP and LBP in youth. PMID- 25549647 TI - [Clinical outcomes of mini-invasive transforaminal lumbar interbody fusion under Quadrant system for upper lumbar disc herniation]. AB - OBJECTIVE: To evaluate the treatment outcomes of mini-invasive transforaminal lumbar interbody fusion by Quadrant system for upper lumbar disc herniation. METHODS: Between February 2008 and June 2011, 21 patients with upper lumbar disc herniation underwent mini-invasive transforaminal lumbar interbody fusion under Quadrant system at our institution. The relevant patient data included visual analogue scale (VAS) and Oswestry disability index (ODI) scores before and after operation 1 week, 3 months and last follow-up. And all data were collected retrospectively. RESULTS: No operation-related complications occurred. The mean operative duration was 2.8 (2.5-3) hours. The average blood loss volume was 430 (350-500) ml. Preoperative VAS was 7.3 +/- 0.8 and 2.1 +/- 0.9, 1.3 +/- 0.6, 0.6 +/- 0.5 after operation 1 week, 3 months and last follow-up respectively. Statistically significant differences were demonstrated between each group. Preoperative ODI was 43.7 +/- 12.9 and 22.5 +/- 10.4, 16.2 +/- 8.5, 11.3 +/- 7.2 after operation 1 week, 3 months and last follow up. Significant differences existed in preoperative and postoperative ODI scores respectively. CONCLUSION: Mini-invasive transforaminal lumbar interbody fusion using Quadrant system and special osteotome is safe and efficacious for upper lumbar disc herniation. PMID- 25549648 TI - [Validation of standardized uptake values for 18F-FDG in normal organs: comparison of whole-body PET/CT and PET/MRI]. AB - OBJECTIVE: To validate whether PET/MR could provide a semi-quantitative measurement (SUV(max)) comparable to that produced by PET/CT in normal organs. METHODS: 277 subjects underwent an ordinary 18F-FDG PET/CT followed by a PET/MR scan with a 25-45 min interval. Region of interest (ROIs) were drawn in 4 reference normal organs/tissues in both MRAC-PET and CTAC-PET images and the liver and erector spinae in the dual-time point PET/CT images. RESULTS: 259 malignant and 21 benign lesions, pathologically confirmed, were detected in the 220 subjects. SUV(max) derived from PET/CT (SUV(max)-CT) and PET/MR (SUV(max) MRI) was highly correlated over the reference organ ROIs (r = 0.62-0.73), except lung (r = 0.44). The SUV(max)-MRI was significantly lower than the respective SUV(max)-CT in all 4 organs and after delay-correction in liver and muscle. CONCLUSION: The results indicate that PET/MR can provide reliable measurement in physiological organs. PMID- 25549649 TI - [Typical and non-typical magnetic resonance imaging findings of neonatal hypoglycemic encephalopathy]. AB - OBJECTIVE: To analyze the typical and non-typical magnetic resonance imaging (MRI) findings of neonatal hypoglycemia encephalopathy (NHE). METHODS: The clinical data and MRI findings of 20 cases with NHE were retrospectively evaluated. RESULTS: Among them, blood glucose values were <= 1.4 mmol/L (n = 18) and 2.1 mmol/L (n = 2). And 13 cases had recurrent hypoglycemia. The major clinical symptoms included convulsion, poor response, cyanosis and apnea. The typical MRI findings of abnormal signal in occipital or parietal cortex were found in 9 cases. And the involvement sites were corpus callosum (n = 4) and posterior limb of internal capsule (n = 1). Another 11 cases revealed non-typical MRI findings of damaged brain regions, involving splenium of corpus callosum (n = 8), white matte along lateral ventricle (n = 6), extensive cortical or subcortical white matter (n = 5), internal capsule (n = 3), centrum semiovale (n = 2), globus pallidus (n = 1), local cortex (frontal lobe) (n = 1), pons (n = 1), unilateral hippocampus (n = 1) and bilateral thalamus and midbrain, brain stem and medulla oblongata (n = 1). CONCLUSION: The typical MRI findings of NHE show abnormal signal in occipital or parietal cortex. And non-typical manifestations involving multiple brain areas may be observed in cases of severe NHE. PMID- 25549650 TI - [Effect of different laparoscopic procedures for hydrosalpinx on pregnancy outcome of embryo transfer]. AB - OBJECTIVE: To explore the effects of different laparoscopic procedures before embryo transfer (ET) for hydrosalpinx on pregnancy outcomes. METHODS: Group A (n = 269) underwent laparoscopic bilateral salpingectomy before ET while group B (n = 178) had laparoscopic bilateral tubal salpingostomy for hydrosalpinx. And the pregnancy outcomes of ET were evaluated. RESULTS: The implantation, pregnancy, abortion, ectopic pregnancy and live birth rates were similar in 2 groups (P > 0.05). The interstitial pregnancy rate was 10.27% after bilateral salpingectomy. The clinical pregnancy rate increased while the interstitial pregnancy rate decreased when the intervals between salpingectomy and ET were prolonged. But there was no statistical significance (P > 0.05). CONCLUSION: Laparoscopic tubal salpingostomy is as effective as salpingectomy for hydrosalpinx before ET. The interstitial pregnancy rate increases after laparoscopic salpingectomy. The interval between salpingectomy and ET should be appropriately scheduled. PMID- 25549651 TI - [Clinical analysis of 126 cases of severe precocious preeclampsia complicated with fetal growth retardation]. AB - OBJECTIVE: To explore the clinical characteristics and maternal and infant prognosis of severe precocious preeclampsia complicated with fetal growth retardation. METHODS: A study was conducted for 126 patients with early onset severe preeclampsia. According to the gestational week (GW) of morbility, they were divided into group A (GW<28, n = 36), group B (28 <= GW<32, n = 40) and group C (32 <= GW<34, n = 50). And then compare the respective clinical characteristics and the result of mother and infant. RESULTS: At admission, no statistical difference existed among 3 groups in blood pressure, blood platelets, 24 h urine protein quantity, urea nitrogen, D-2 polymer or serum creatinine (P > 0.05).the rate of complication declined with advancing gestational weeks of morbility in all three groups. And the composition of complication indicated no statistical difference (P > 0.05); there existed statistical difference in asphyxia neonatorum and perinatal mortality rates between any two of three groups (P < 0.05 for all). Comparing expectant treatment time and delivery method of three groups, the expectant time of Group B was obviously longer than those of the other two, both indicated statistical difference (P < 0.05). However, the difference had no statistical significance between groups A and C (P > 0.05). And uterine-incision delivery was the major delivery mode among all three groups. CONCLUSION: The rates of asphyxia neonatorum and perinatal mortality decline with advancing gestational weeks of morbility in cases of severe precocious preeclampsia complicated with fetal growth retardation. Therefore, for reducing the perinatal mortality rate, proper measures include early diagnosis, active treatment, close supervision of mother and fetal conditions and termination of gestation when necessary. PMID- 25549652 TI - [Evaluation of the inadequate diagnostic rate of ultrasound guided fine needle aspiration cytology inthyroid calcified nodules]. AB - OBJECTIVE: To evaluate the inadequate diagnostic rate of ultrasound guided fine needle aspiration cytology (USFNAC) in thyroid calcified nodules. METHODS: 208 thyroid calcified nodules in 202 patients were retrospective analyzed, and all of the nodules were acquired cytological diagnosis. RESULTS: There was no significant complication in the all 208 thyroid calcified nodules. The inadequate diagnostic rate was 25.5% in thyroid calcified nodules. The inadequate diagnostic rates in micro calcifications , macro calcifications and circumjacent arc calcifications were 16.0%, 26.4% and 76.5%. The inadequate diagnostic rate in circumjacent arc calcifications were higher than those in micro calcifications and macro calcifications (P < 0.01) , and the rates were no significance in micro calcifications and macro calcifications. There was no statistical significance in different size of thyroid calcified nodules. CONCLUSIONS: The inadequate diagnostic rate in circumjacent arc calcifications was higher, and should to avoid USFNAC in these nodules. PMID- 25549653 TI - Oncologists' experiences with drug shortages. AB - PURPOSE: There have been numerous reports of shortages of injectable drugs for cancer in the last decade. We assessed physician experiences with drug shortages in a population-based cohort of medical oncologists caring for patients with lung or colorectal cancer. METHODS: We surveyed medical oncologists caring for patients with lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance Consortium from 2012 to 2013 (participation rate, 53%). Oncologists reported experiences with shortages of leucovorin, fluorouracil, dexamethasone, cyanocobalamin, paclitaxel, cisplatin, and etoposide in the prior year and whether they had used a less-effective alternative because of a shortage. We used multivariable logistic regression to assess for associations between physician or practice characteristics and encountering shortages. RESULTS: Among 330 respondents, 74% reported experiences with a shortage of at least one drug in our survey, and 28% reported using a less-effective alternative because of a shortage. Although physician demographic characteristics did not predict reports of drug shortages, practice characteristics did. Veterans Affairs (VA) oncologists were less likely to report experiencing any shortage than oncologists in single-specialty group practice (odds ratio [OR], 0.4; 95% CI, 0.2 to 0.9). The reported use of a less effective alternative to any drug was also less common among VA oncologists (OR, 0.3; 95% CI, 0.1 to 0.9) and oncologists affiliated with health maintenance organizations (OR, 0.4; 95% CI, 0.2 to 0.9) compared with physicians in single-specialty groups. CONCLUSION: Most oncologists encountered drug shortages in the year before our survey, but experiences with shortages varied with practice structure. Further research is needed to quantitatively assess the impact of drug shortages on patients and evaluate various strategies for managing them. PMID- 25549655 TI - Method to Reduce Muscle Fatigue During Transcutaneous Neuromuscular Electrical Stimulation in Major Knee and Ankle Muscle Groups. AB - BACKGROUND: A critical limitation with transcutaneous neuromuscular electrical stimulation as a rehabilitative approach is the rapid onset of muscle fatigue during repeated contractions. We have developed a method called spatially distributed sequential stimulation (SDSS) to reduce muscle fatigue by distributing the center of electrical field over a wide area within a single stimulation site, using an array of surface electrodes. OBJECTIVE: To extend the previous findings and to prove feasibility of the method by exploring the fatigue reducing ability of SDSS for lower limb muscle groups in the able-bodied population, as well as in individuals with spinal cord injury (SCI). METHODS: SDSS was delivered through 4 active electrodes applied to the knee extensors and flexors, plantarflexors, and dorsiflexors, sending a stimulation pulse to each electrode one after another with 90 degrees phase shift between successive electrodes. Isometric ankle torque was measured during fatiguing stimulations using SDSS and conventional single active electrode stimulation lasting 2 minutes. RESULTS: We demonstrated greater fatigue-reducing ability of SDSS compared with the conventional protocol, as revealed by larger values of fatigue index and/or torque peak mean in all muscles except knee flexors of able-bodied individuals, and in all muscles tested in individuals with SCI. CONCLUSIONS: Our study has revealed improvements in fatigue tolerance during transcutaneous neuromuscular electrical stimulation using SDSS, a stimulation strategy that alternates activation of subcompartments of muscles. The SDSS protocol can provide greater stimulation times with less decrement in mechanical output compared with the conventional protocol. PMID- 25549654 TI - If you did not document it, it did not happen: rates of documentation of discussion of infertility risk in adolescent and young adult oncology patients' medical records. AB - PURPOSE: The adolescent and young adult (AYA) population is underserved because of unique late-effect issues, particularly future fertility. This study sought to establish rates of documentation of discussion of risk of infertility, fertility preservation (FP) options, and referrals to fertility specialists in AYA patients' medical records at four cancer centers. METHODS: All centers reviewed randomized records within the top four AYA disease sites (breast, leukemia/lymphoma, sarcoma, and testicular). Eligible records included those of patients: diagnosed in 2011, with no prior receipt of gonadotoxic therapy; age 18 to 45 years; with no multiple primary cancers; and for whom record was not second opinion. Quality Oncology Practice Initiative methods were used to evaluate documentation of discussion of risk of infertility, discussion of FP options, and referral to a fertility specialist. RESULTS: Of 231 records, 26% documented infertility risk discussion, 24% documented FP option discussion, and 13% documented referral to a fertility specialist. Records were less likely to contain evidence of infertility risk and FP option discussions for female patients (P = .030 and .004, respectively) and those with breast cancer (P = .021 and < .001, respectively). Records for Hispanic/Latino patients were less likely to contain evidence of infertility risk discussion (P = .037). Records were less likely to document infertility risk discussion, FP option discussion, and fertility specialist referral for patients age >= 40 years (P < .001, < .001, and .002, respectively) and those who already had children (all P < .001). CONCLUSION: The overall rate of documentation of discussion of FP is low, and results show disparities among specific groups. Although greater numbers of discussions may be occurring, there is a need to create interventions to improve documentation. PMID- 25549656 TI - Wrist Rehabilitation Assisted by an Electromyography-Driven Neuromuscular Electrical Stimulation Robot After Stroke. AB - BACKGROUND: Augmented physical training with assistance from robot and neuromuscular electrical stimulation (NMES) may introduce intensive motor improvement in chronic stroke. OBJECTIVE: To compare the rehabilitation effectiveness achieved by NMES robot-assisted wrist training and that by robot assisted training. METHODS: This study was a single-blinded randomized controlled trial with a 3-month follow-up. Twenty-six hemiplegic subjects with chronic stroke were randomly assigned to receive 20-session wrist training with an electromyography (EMG)-driven NMES robot (NMES robot group, n = 11) and with an EMG-driven robot (robot group, n = 15), completed within 7 consecutive weeks. Clinical scores, Fugl-Meyer Assessment (FMA), Modified Ashworth Score (MAS), and Action Research Arm Test (ARAT) were used to evaluate the training effects before and after the training, as well as 3 months later. An EMG parameter, muscle co contraction index, was also applied to investigate the session-by-session variation in muscular coordination patterns during the training. RESULTS: The improvement in FMA (shoulder/elbow, wrist/hand) obtained in the NMES robot group was more significant than the robot group (P < .05). Significant improvement in ARAT was achieved in the NMES robot group (P < .05) but absent in the robot group. NMES robot-assisted training showed better performance in releasing muscle co-contraction than the robot-assisted across the training sessions (P < .05). CONCLUSIONS: The NMES robot-assisted wrist training was more effective than the pure robot. The additional NMES application in the treatment could bring more improvements in the distal motor functions and faster rehabilitation progress. PMID- 25549658 TI - Predicting the sun-protective decisions of young female Australian beachgoers. AB - We tested the theory of planned behaviour with additional norms to predict the sun-protective decisions of young female beachgoers in Australia. Participants (N = 336) completed standard theory of planned behaviour measures and additional normative factors (group, image and personal norms). Attitude, subjective norm, and both personal and group norms predicted intention. Intention and group norm predicted follow-up behaviour. These findings provide further evidence that it is the more proximal sources of norms reflecting one's personal and referent group influences, rather than perceptions of broader societal norms about the attractiveness of tanned images, that are important in determining young women's sun-protective decisions. PMID- 25549657 TI - Epigallocatechin-3-gallate attenuates unilateral ureteral obstruction-induced renal interstitial fibrosis in mice. AB - The severity of tubulointerstitial fibrosis is regarded as an important determinant of renal prognosis. Therapeutic strategies targeting tubulointerstitial fibrosis have been considered to have potential in the treatment of chronic kidney disease. This study aims to evaluate the protective effects of (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, against renal interstitial fibrosis in mice. EGCG was administrated intraperitoneally for 14 days in a mouse model of unilateral ureteral obstruction (UUO). The results of our histological examination showed that EGCG alleviated glomerular and tubular injury and attenuated renal interstitial fibrosis in UUO mice. Furthermore, the inflammatory responses induced by UUO were inhibited, as represented by decreased macrophage infiltration and inflammatory cytokine production. Additionally, the expression of type I and III collagen in the kidney were reduced by EGCG, which indicated an inhibition of extracellular matrix accumulation. EGCG also caused an up-regulation in alpha-smooth muscle actin expression and a down-regulation in E cadherin expression, indicating the inhibition of epithelial-to-mesenchymal transition. These changes were found to be in parallel with the decreased level of TGF-beta1 and phosphorylated Smad. In conclusion, the present study demonstrates that EGCG could attenuate renal interstitial fibrosis in UUO mice, and this renoprotective effect might be associated with its effects of inflammatory responses alleviation and TGF-beta/Smad signaling pathway inhibition. PMID- 25549660 TI - Nitrogen microplasma generated in chip-based ingroove glow discharge device for detection of organic fragments by optical emission spectrometry. AB - In this study, nitrogen was successfully used to maintain the microplasma discharge to excite and detect organic compounds for the first time. A new nitrogen glow discharge microplasma-generated in-chip-based ingroove device was developed and applied as the excitation source for optical emission spectrometry. The unique ingroove design of the discharge chamber can provide good stability and sensitivity for nitrogen microplasma to detect trace organic samples. Unlike argon/helium microplasmas, the nitrogen microplasma has a strict demand on the material of electrodes, especially cathodes. We tested the effects of four common electrode materials from various aspects and obtained the most appropriate material for nitrogen glow discharge, namely, platinum. We also studied the excitation and detection mechanism of organic compounds in nitrogen microplasma and confirmed that the main means of excitation in nitrogen plasma was through energy transfer rather than penning ionization. Several organic compounds were directly injected and detected in the optimized working conditions with the limits of detection at the hundreds of picograms level. Because of the portable nitrogen generators handily and commercially available, this detection system with nitrogen as the discharge gas can overcome the limitation of noble gas supply. In addition, the advantages of small size, low energy consumption, good stability, and reproducibility demonstrate that the nitrogen ingroove microplasma source can be applied in a portable detector for on-site and real-time spectrometry detection. PMID- 25549659 TI - Influence of a screening navigation program on social inequalities in health beliefs about colorectal cancer screening. AB - The aim of the study was to test whether a screening navigation program leads to more favorable health beliefs and decreases social inequalities in them. The selected 261 noncompliant participants in a screening navigation versus a usual screening program arm had to respond to health belief measures inspired by the Protection Motivation Theory. Regression analyses showed that social inequalities in perceived efficacy of screening, favorable attitude, and perceived facility were reduced in the screening navigation compared to the usual screening program. These results highlight the importance of health beliefs to understand the mechanism of screening navigation programs in reducing social inequalities. PMID- 25549661 TI - On the reaction of diaminocarbenes with aroylimines. AB - Several possible reaction pathways are analyzed for the recently studied experimental reaction of diaminocarbenes with aroylimines, where the carbene acted as an oxygen-abstracting agent. A number of structures corresponding to local minima and transition states are located by geometry optimization. In contrast to the more recent interpretation of the mechanism of this process, the reaction does not proceed via the direct formation of the corresponding carbonyl ylide resulted from the electrophilic addition of diaminocarbene to the carbonyl oxygen atom. Two other, more favorable pathways were predicted instead: the nucleophilic attack of the carbene lone pair on the imino nitrogen (pathway "a") or on the carbon atom in the C?N moiety of aroylimine (pathway "b"), in agreement with predictions of the frontier molecular orbital (FMO) theory. Both intermediate adducts undergo a subsequent decomposition onto nitrile ylide and urea. Which of the two pathways becomes preferential depends on the nature of the substituents: pathway "a" is more favored for the experimentally studied species, whereas pathway "b" is thermodynamically preferable for the small-sized model structures. PMID- 25549662 TI - Anisotropic microparticles created by phase separation of polymer blends confined in monodisperse emulsion drops. AB - Anisotropic microparticles are promising as a new class of colloidal or granular materials due to their advanced functionalities which are difficult to achieve with isotropic particles. However, synthesis of the anisotropic microparticles with a highly controlled size and shape still remains challenging, despite their intense demands. Here, we report a microfluidic approach to create uniform anisotropic microparticles using phase separation of polymer blends confined in emulsion drops. Two different polymers are homogeneously dissolved in organic solvent at low concentration, which is microfluidically emulsified to produce oil in-water emulsion drops. As the organic solvent diffuses out, small domains are formed in the emulsion drops, which are then merged, forming only two distinct domains. After the drops are fully consolidated, uniform anisotropic microparticles with two compartments are created. The shape of the resulting microparticles is determined by combination of a pair of polymers and type of surfactant. Spherical microparticles with eccentric core and incomplete shell are prepared by consolidation of polystyrene (PS) and poly(lactic acid) (PLA), and microparticles with single crater are formed by consolidation of PS and poly(methyl methacrylate) (PMMA); both emulsions are stabilized with poly(vinyl alcohol) (PVA). With surfactants of triblock copolymer, acorn-shaped Janus microparticles are obtained by consolidating emulsion drops containing PS and PLA. This microfluidic production of anisotropic particles can be further extended to any combination of polymers and colloids to provide a variety of structural and chemical anisotropy. PMID- 25549663 TI - Hydricity of an Fe-H Species and Catalytic CO2 Hydrogenation. AB - Despite renewed interest in carbon dioxide (CO2) reduction chemistry, examples of homogeneous iron catalysts that hydrogenate CO2 are limited compared to their noble-metal counterparts. Knowledge of the thermodynamic properties of iron hydride complexes, including M-H hydricities (DeltaGH(-)), could aid in the development of new iron-based catalysts. Here we present the experimentally determined hydricity of an iron hydride complex: (SiP(iPr)3)Fe(H2)(H), DeltaGH(-) = 54.3 +/- 0.9 kcal/mol [SiP(iPr)3 = [Si(o-C6H4PiPr2)3](-)]. We also explore the CO2 hydrogenation chemistry of a series of triphosphinoiron complexes, each with a distinct apical unit on the ligand chelate (Si(-), C(-), PhB(-), N, B). The silyliron (SiP(R)3)Fe (R = iPr and Ph) and boratoiron (PhBP(iPr)3)Fe (PhBP(iPr)3 = [PhB(CH2PiPr2)3](-)) systems, as well as the recently reported (CP(iPr)3)Fe (CP(iPr)3 = [C(o-C6H4PiPr2)3](-)), are also catalysts for CO2 hydrogenation in methanol and in the presence of triethylamine, generating methylformate and triethylammonium formate at up to 200 TON using (SiP(Ph)3)FeCl as the precatalyst. Under stoichiometric conditions, the iron hydride complexes of this series react with CO2 to give formate complexes. Finally, the proposed mechanism of the (SiP(iPr)3)-Fe system proceeds through a monohydride intermediate (SiP(iPr)3)Fe(H2)(H), in contrast to that of the known and highly active tetraphosphinoiron, (tetraphos)Fe (tetraphos = P(o-C6H4PPh2)3), CO2 hydrogenation catalyst. PMID- 25549664 TI - Virtual support for paediatric HIV treatment decision making. AB - OBJECTIVE: The objective of this study is to review clinical outcomes of recommendations made by a multidisciplinary paediatric virtual clinic (PVC) for complex case management of paediatric HIV as a model of care within a tertiary network. DESIGN: A retrospective review of the clinical outcomes of paediatric and adolescent (0-21 years) referrals to the PVC at St. Mary's Hospital, Imperial College Healthcare NHS Trust, London was performed between October 2009 and November 2013. RESULTS: 234 referrals were made for 182 children from 37 centres, discussed in 42 meetings (median age 13 years, IQR 10-15 years). Reasons for referral included virological failure (44%), simplification of the current regimen (24%) and antiretroviral drug complications (24%). At latest follow-up, PVC advice had been instituted in 80% of referrals. Suppression following virological failure was achieved in 48% following first referral and 57% following subsequent discussions and was maintained in 95% of children referred for regimen simplification. Following advice, dyslipidaemia resolved in 42% and liver function normalised in 73% with biochemical hepatitis. Adherence support aided resolution of viraemia in nine children and 12% of referrals resulted in additional support, including psychology, social services and mental health input. CONCLUSIONS: Combined multidisciplinary virtual input with adult expertise in resistance and newer agents, paediatric knowledge of pill swallowing, childhood formulations/weight banding and parental support, assists complex treatment decision making in paediatric HIV infection. The Virtual Clinic model could be applied to the management of other rare complex diseases of childhood within a clinical network. PMID- 25549665 TI - Has the first-line management of paediatric OCD improved following the introduction of NICE guidelines? PMID- 25549666 TI - Sock-line hyperpigmentation in infancy. PMID- 25549667 TI - 25 years of small molecular weight kinase inhibitors: potentials and limitations. AB - Deregulation of protein and lipid kinase activities leads to a variety of pathologies, ranging from cancer inflammatory diseases, diabetes, infectious diseases, and cardiovascular disorders. Protein kinases and lipid kinases represent, therefore, an important target for the pharmaceutical industry. In fact, approximately one-third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases. To date, 30 kinase inhibitors have been approved, which, with few exceptions, are mainly for oncological indications and directed against only a handful of protein and lipid kinases, leaving 70% of the kinome untapped. Despite these successes in kinase drug discovery, the development of kinase inhibitors with outstanding selectivity, identification and validation of driver kinase(s) in diseases, and the emerging problem of resistance to the inhibition of key target kinases remain major challenges. This minireview provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers. PMID- 25549668 TI - Interleukin-6 attenuates serotonin 2a receptor signaling by activating the JAK STAT pathway. AB - The serotonin 2A (5-HT2A) receptor and the proinflammatory cytokine, interleukin 6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior. We first demonstrated that 5-HT2A receptors and IL-6-mediated STAT3 phosphorylation colocalize in cells of the prefrontal cortex, providing the neuroanatomical substrate for a potential interaction. In the neuronally derived A1A1 cell line, which expresses both IL-6 and 5-HT2A receptors, we found that IL 6 attenuates inositol phosphate (IP) accumulation in response to the 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), suggesting that IL-6 can regulate 5-HT2A receptor function. To identify the signaling pathway(s) that mediate this effect, we measured DOI-mediated IP accumulation in the presence of IL-6 and either the JAK-STAT inhibitor 124 [(9beta,10alpha,16alpha,23E)-2,16,20,25 tetrahydroxy-9-methyl-19-norlanosta-1,5,23-triene-3,11,22-trione], JSI-124, or the extracellular signal-regulated kinase inhibitor, 2-(2-amino-3-methoxyphenyl) 4H-1-benzopyran-4-one (PD-98059). The IL-6 effect was blocked by JSI-124 but not PD-98059. Furthermore, silencing RNA knockdown of either JAK or STAT blocked the IL-6 effect, suggesting that IL-6-induced JAK-STAT activation can regulate 5-HT2A receptor signaling. Finally, to determine if IL-6 specifically regulates the 5 HT2A receptor system, we measured IP production mediated by another Gq-coupled receptor, bradykinin B2. IL-6 had no effect on bradykinin-mediated IP accumulation, suggesting that regulation may occur at the 5-HT2A receptor. These results may provide clues to the pathologic mechanisms underlying certain psychiatric disorders and may suggest novel therapeutic strategies for their treatment. PMID- 25549669 TI - G protein regulation of neuronal calcium channels: back to the future. AB - Neuronal voltage-gated calcium channels have evolved as one of the most important players for calcium entry into presynaptic endings responsible for the release of neurotransmitters. In turn, and to fine-tune synaptic activity and neuronal communication, numerous neurotransmitters exert a potent negative feedback over the calcium signal provided by G protein-coupled receptors. This regulation pathway of physiologic importance is also extensively exploited for therapeutic purposes, for instance in the treatment of neuropathic pain by morphine and other MU-opioid receptor agonists. However, despite more than three decades of intensive research, important questions remain unsolved regarding the molecular and cellular mechanisms of direct G protein inhibition of voltage-gated calcium channels. In this study, we revisit this particular regulation and explore new considerations. PMID- 25549670 TI - Cell differentiation and development in Arabidopsis are associated with changes in histone dynamics at the single-cell level. AB - The mechanism whereby the same genome can give rise to different cell types with different gene expression profiles is a fundamental problem in biology. Chromatin organization and dynamics have been shown to vary with altered gene expression in different cultured animal cell types, but there is little evidence yet from whole organisms linking chromatin dynamics with development. Here, we used both fluorescence recovery after photobleaching and two-photon photoactivation to show that in stem cells from Arabidopsis thaliana roots the mobility of the core histone H2B, as judged by exchange dynamics, is lower than in the surrounding cells of the meristem. However, as cells progress from meristematic to fully differentiated, core histones again become less mobile and more strongly bound to chromatin. We show that these transitions are largely mediated by changes in histone acetylation. We further show that altering histone acetylation levels, either in a mutant or by drug treatment, alters both the histone mobility and markers of development and differentiation. We propose that plant stem cells have relatively inactive chromatin, but they keep the potential to divide and differentiate into more dynamic states, and that these states are at least in part determined by histone acetylation levels. PMID- 25549673 TI - [Pay attention to the differences and similarities in the pathogenesis and management of multiple sclerosis and neuromyelitis optica]. PMID- 25549674 TI - [Thoughts on hot issues of neuromyelitis optica]. PMID- 25549675 TI - [Comparison of tumefactive demyelinating lesions and glioma by clinical presentations and neuroimaging studies]. AB - OBJECTIVE: To explore the clinical and imaging features of tumefactive demyelinating lesions (TDL) and glioma. METHODS: The brain computed tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H-MRS) features of 60 pathologically confirmed TDL patients and 65 glioma ones, hospitalized at Navy General Hospital from 2005 to 2013, were reviewed and analyzed. RESULTS: The mean onset age of glioma was significantly older than that of TDL. The onset symptom was headache for TDL and headache and epilepsy for glioma. The features of lesions on brain CT scan: no hyperdensity in TDL group and 39 with hyperdense lesions in glioma group. Tissue necrosis was more frequently found in lesions of glioma than TDL, especially for higher grade glioma. And increased beta and gamma-Glx on (1)H-MRS was most frequently found in TDL. CONCLUSION: The onset age of glioma is older than TDL. The headache is the top onset symptoms of TDL and epiplesy occurs frequently only in glioma. The hyperdense lesions on CT scan support more the diagnosis of glioma. The lesions with tissue necrosis may be a diagnostic clue for high grade glioma. On (1)H-MRS, increased beta and gamma-Glx are most frequently found in TDL. Dynamic observation of imaging changes may be more important for facilitating the diagnosis of TDL, especially in conjunctions with imaging characteristics and clinical features. PMID- 25549671 TI - Arabidopsis ensemble reverse-engineered gene regulatory network discloses interconnected transcription factors in oxidative stress. AB - The abiotic stress response in plants is complex and tightly controlled by gene regulation. We present an abiotic stress gene regulatory network of 200,014 interactions for 11,938 target genes by integrating four complementary reverse engineering solutions through average rank aggregation on an Arabidopsis thaliana microarray expression compendium. This ensemble performed the most robustly in benchmarking and greatly expands upon the availability of interactions currently reported. Besides recovering 1182 known regulatory interactions, cis-regulatory motifs and coherent functionalities of target genes corresponded with the predicted transcription factors. We provide a valuable resource of 572 abiotic stress modules of coregulated genes with functional and regulatory information, from which we deduced functional relationships for 1966 uncharacterized genes and many regulators. Using gain- and loss-of-function mutants of seven transcription factors grown under control and salt stress conditions, we experimentally validated 141 out of 271 predictions (52% precision) for 102 selected genes and mapped 148 additional transcription factor-gene regulatory interactions (49% recall). We identified an intricate core oxidative stress regulatory network where NAC13, NAC053, ERF6, WRKY6, and NAC032 transcription factors interconnect and function in detoxification. Our work shows that ensemble reverse-engineering can generate robust biological hypotheses of gene regulation in a multicellular eukaryote that can be tested by medium-throughput experimental validation. PMID- 25549676 TI - [Levels of Beclin 1 and LC3 in peripheral blood mononuclear cells of patients with multiple sclerosis and neuromyelitis optica and its significance]. AB - OBJECTIVE: To explore the expression and significance of Beclin 1 and LC3 in peripheral blood mononuclear cells (PBMCs) of patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) before and after treatment during acute and recurrent acute phases. METHODS: All outpatients, inpatients and healthy controls were recruited from our hospital from October 2012 to April 2014. During acute phase, PBMCs from patients with multiple sclerosis (MS) and neuromyelitis optica (NMO)(pre and post-treatment) were immediately isolated by Ficoll-Hypaque density gradient centrifugation. And the expressions of Beclin 1 and LC3 were detected by Western blot. And relapsing-remitting MS (RRMS) and relapsing NMO (RNMO) patients were followed up and the expressions of Beclin 1 and LC3 proteins compared during two acute phases. RESULTS: Compared with normal controls, the expression of Beclin 1 in PBMCs from acute phase of MS and NMO patients decreased while the expression of LC3 increased. During acute phase, the expression of Beclin 1 significantly increased after treatment in MS and NMO patients compared with pre treatment, but the expression of LC3 significantly decreased. The expression of Beclin1 obviously decreased in RRMS and recurrent RNMO compared with the previous period, but the expression of LC3 significantly increased. CONCLUSION: The autophagy level increases in PBMC from MS and NMO patients during acute phase. However it decreases after treatment. However, the autophagy levels significantly increase in RRMS and RNMO. And enhanced autophagy may play its role in the pathogenesis of MS and NMO. PMID- 25549677 TI - [Retrospective study of clinical features of neuromyelitis optica spectrum disease with connective tissue disease]. AB - OBJECTIVE: To explore the clinical features of neuromyelitis optica (NMO) spectrum disease (NMOSD) with connective tissue disease (CTD). METHODS: The clinical features of 184 NMO/NMOSD patients (NMO/NMOSD: 119/184, 64.7%; NMO/NMOSD CTD: 65/184, 35.3%) from May 2013 to May 2014 were analyzed retrospectively. And the effectiveness of long-term treatment of immunosuppressive drugs in NMOSD was evaluated. RESULTS: NMO/NMOSD-CTD patients had significantly higher female percentage (93.8% vs 83.2%, P < 0.05) and significantly higher percentage of patients with cerebral spinal fluid (CSF)-restricted oligoclonal band (OB)(41.5% vs 21.9%, P < 0.05). As compared with NMO/NMOSD-CTD counterparts, NMO/NMOSD patients had significantly higher percentage of non-specific lesions on brain MRI (62.5% vs 35.9%, P < 0.01). After >6 months consecutive long-term treatment of immunosuppressive drugs, the relapse rate post-treatment (0.36 +/- 0.85) was significantly lower than that pre-treatment (2.91 +/- 4.10, P < 0.01). And no significant difference existed in expanded disability status scale (EDSS) score between pre-and post-treatment. When using azathioprine (AZA), the percentage of relapse was significantly higher in NMO/NMOSD-CTD patients (50.0%) versus NMO/NMOSD ones (18.5%, P = 0.064); When using cyclophosphamide (CTX), there was no such significant difference. CONCLUSION: Female patients are more susceptible to have NMO/NMOSD with CTD. NMO/NMOSD-CTD patients tend to have higher percentage of CSF-restricted OB and fewer non-specific lesions on brain MRI. AZA and CTX may effectively reduce relapses in both NMO/NMOSD and NMO/NMOSD-CTD patients. However CTX is superior to AZA for reducing relapses in NMO/NMOSD-CTD patients. PMID- 25549672 TI - Soybean miR172c targets the repressive AP2 transcription factor NNC1 to activate ENOD40 expression and regulate nodule initiation. AB - MicroRNAs are noncoding RNAs that act as master regulators to modulate various biological processes by posttranscriptionally repressing their target genes. Repression of their target mRNA(s) can modulate signaling cascades and subsequent cellular events. Recently, a role for miR172 in soybean (Glycine max) nodulation has been described; however, the molecular mechanism through which miR172 acts to regulate nodulation has yet to be explored. Here, we demonstrate that soybean miR172c modulates both rhizobium infection and nodule organogenesis. miR172c was induced in soybean roots inoculated with either compatible Bradyrhizobium japonicum or lipooligosaccharide Nod factor and was highly upregulated during nodule development. Reduced activity and overexpression of miR172c caused dramatic changes in nodule initiation and nodule number. We show that soybean miR172c regulates nodule formation by repressing its target gene, Nodule Number Control1, which encodes a protein that directly targets the promoter of the early nodulin gene, ENOD40. Interestingly, transcriptional levels of miR172c were regulated by both Nod Factor Receptor1alpha/5alpha-mediated activation and by autoregulation of nodulation-mediated inhibition. Thus, we established a direct link between miR172c and the Nod factor signaling pathway in addition to adding a new layer to the precise nodulation regulation mechanism of soybean. PMID- 25549678 TI - [Clinical, magnetic resonance imaging and neuroelectrophysiological characteristics of 14 patients with lumbosacralradiculitis]. AB - OBJECTIVE: To improve the understanding of lumbosacralradiculitis by analyzing the clinical, magnetic resonance imaging (MRI) and neuroeletrophysiological characteristics of disease. METHODS: The clinical, MRI and neuroeletrophysiological data of 14 patients diagnosed as lumbosacralradiculitis were retrospectively analyzed. RESULTS: The predominant age of onset was in the forth decade. Each patient had bilateral or unilateral lower extremity numbness and weakness of variable severity, including muscle atrophy (n = 5) and decreased sensation in L4-S1 nerve root territory (n = 9). Lower extremity tendon reflexes decreased or became absent in all patients. Urinary and defecation disorders were seen in 3 patients. Lumbosacral MRI showed lumbosacral meninges and nerve root enhancement in 4 patients. Cerebrospinal fluid analysis revealed elevated white blood cell (30*10(6)/L) (n = 1) and increased protein content (n = 12) (450-1 000 mg/L, n = 7; 1 000-2 000 mg/L, n = 3; 2 000-3 000 mg/L, n = 2). Needle electromyography (EMG) demonstrated neurogenic damage in 13 patients. Motor nerve conduction study showed decreased motor never conduction velocity (MCV) (n = 5), decreased compound muscle action potential (CMAP) amplitude (n = 12), CMAP absent at right side (n = 2) and left side (n = 1) among 22 peroneal nerves; decreased MCV (n = 6), decreased CMAP amplitude (n = 6), CMAP absent at right side (n = 2) and left side (n = 1) among 23 tibial nerves. F-wave was performed for 11 patients and abnormal in 6 patients, with prolonged latency and reduced occurrence rate in right common peroneal nerve (n = 2), left prolonged latency (n = 3) and right tibial nerve (n = 1) respectively. Bilateral sural nerve conduction study revealed no abnormality. CONCLUSION: Diagnosing lumbosacralradiculitis is not easy based on lumbosacral MRI. And neuroelectrophysiological study may provide more valuable information in verifying the location of lesions and judging the damage extent of lumbosacralradiculitis. PMID- 25549679 TI - [Risk factors and prognosis of hypotension in postoperative sedation patients]. AB - OBJECTIVE: To explore the risk factors and prognosis of hypotension in postoperative sedation patients. METHODS: A total of 175 patients with postoperative sedation at our department from May 2013 to March 2014 were retrospectively reviewed. Patients with age <18 years, cardiac surgery, pheochromocytoma surgery, hemorrhagic shock, septic shock or cardiogenic shock were excluded. APACHE II, dosage and duration of sedative drug, mean arterial pressure at baseline and after sedation, central venous pressure, fluid balance, dosage and duration of norepinephrine, endotracheal intubation time and length of intensive care unit (ICU) stay were recorded. RESULTS: Blood pressures decreased significantly after administration of sedation (77.2 +/- 11.2 vs 82.6 +/- 9.3 mmHg, P = 0.000). Compared to those with lower disease severity (APACHEII <= 10), the patients with APACHEII.>10 required higher norepinephrine dosage and longer time of infusion. A longer time of norepinephrine infusion was needed for patients with coronary heart disease. Patients undergoing thoracic, abdominal or pelvic surgery, or those with hepatic dysfunction had a higher norepinephrine dosage. Decrement of blood pressure and norepinephrine duration were independent risk factors of endotracheal intubation time. And dosage and duration of norepinephrine were independent risk factors of ICU time. CONCLUSION: Disease severity, past history of heart disease, surgical site and liver function are risk factors of hypotension in postoperative sedation patients. It is important to pay attention to dosage and administrative route of sedative drug. Norepinephrine duration after sedation is an independent risk factor of endotracheal intubation time and ICU time. PMID- 25549680 TI - [Qualitative and quantitative diagnostic performance of 320-slice computed tomography for detecting coronary artery disease with respect to atherosclerotic plaque characteristics]. AB - OBJECTIVE: To investigate qualitatively and quantitatively the diagnostic performance of 320-slice CT for detection of coronary artery disease with respect to different atherosclerotic plaque characteristics. METHODS: A retrospective search was performed for inpatients underwent both coronary CT and further coronary angiography (CAG) from December 1, 2008 to December 31, 2012. The diagnostic performance of 320-slice CTA for detecting significant stenosis ( >= 50% diameter) with respect to atherosclerotic plaque characteristics were analyzed by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, kappa index (kappa), and area under the receiver operating characteristic curve (AUC). Chi-square test was used to evaluate whether there were significant differences of the true-case frequency (true positive + true negative) and false-case frequency (false positive + false negative) among groups. Bland-Altman analysis was used to determine limits of agreement between CTA and CAG. RESULTS: A total of 454 patients and 6 779 segments were analyzed. Diagnostic accuracy was higher in non-calcified segments; whereas they decreased in the presence of both mild-moderately and heavily calcified plaques. Excellent agreement (kappa = 0.810) between CT and CAG was observed for non-calcified segments, while good agreement was observed for both mild-moderately (kappa = 0.701) and heavily calcified segments (kappa = 0.750). Both mild-moderate (P = 0.000) and heavy (P = 0.000) calcification decreased the true-case frequency and increased the false-case frequency when compared to non calcification. There were no significant underestimation or overestimation for non-calcified (P = 0.087) and mild-moderately calcified (P = 0.704) segments, while there was significant overestimation for heavily calcified segments (P = 0.001). CONCLUSIONS: Great qualitative and quantitative diagnostic performances of 320-slice CT were observed in non-calcified coronary segments. However, qualitative diagnostic performance decreased in both mild-moderately and heavily calcified segments, and quantitative overestimation were observed in heavily calcified segments. PMID- 25549681 TI - [Effects of dioscorea modified pill on cognitive impairment of patients with VCIND: an preliminary study of proton magnetic resonance spectroscopy]. AB - OBJECTIVE: To explore the therapeutic effect evaluation of proton magnetic resonance spectroscopy ((1)H-MRS) in patients with vascular cognitive impairment no dementia (VCIND) with dioscorea modified pill. METHODS: A total of 100 patients with VCIND were randomly assigned into the dioscorea modified pill group (n = 50) and the aricept group (n = 50). And 50 healthy volunteers were recruited as normal group. Each patient was examined with (1)H-MRS and scored with mini mental state examination (MMSE) and clinical dementia rating (CDR) scale pre- and post-treatment. RESULTS: After therapy, the NAA/Cr ratios and the itemized scores of cognitive scale compared with that of pre-therapy had significantly difference (P < 0.05) in the dioscorea modified pill group (MMSE (26.5 +/- 2.0), CDR(0.14 +/ 0.23))vs(MMSE(25.1 +/- 2.3), CDR(0.5)). But no difference existed in the aricept group (P > 0.05). CONCLUSION: (1)H-MRS may objectively reflect cognitive dysfunction in VCIND patients. And it has important values in the therapeutic effect evaluation of VCIND with dioscorea modified pill. PMID- 25549682 TI - [Clinical characteristics of IgG4-related retroperitoneal fibrosis]. AB - OBJECTIVE: To explore the clinical characteristics of IgG4-related retroperitoneal fibrosis (RPF) in China. METHODS: From December 2010 to September 2013, a total of 107 IgG4-related disease (IgG4-RD) patients were reviewed prospectively. Their clinical, laboratory and histopathological features were summarized. And the treatment responses were analyzed. RESULTS: Among them, 22 RPF cases were identified. The male-to-female ratio and age were 4.5: 1 and 63 +/ 11 years respectively. The follow-up period was 3-28 months. The most common onset symptom was low back pain (55%). Multiple organ involvements were documented in 20 patients (91%), including lymphadenopathy (n = 9), aortitis (n = 8), sialadenitis (n = 7), dacryoadenitis (n = 5) and autoimmune pancreatitis (n = 4). Allergic histories were reported by10 subjects (46%). Eosinophilia was present in 6 subjects (27%). Serum IgG4 levels were significantly elevated in all subjects. Serum total IgE level was elevated in 12/13 tested subjects. Tissue biopsies of 12 subjects revealed massive lymphocytic infiltration and obvious tissue fibrosis. Immunohistochemical staining showed a massive infiltration of IgG4-positive plasma cell. Glucocorticoid was administrated in all subjects. Most subjects received combined therapy with immunosuppressive agents or tamoxifen. CONCLUSION: IgG4-related RPF is a systemic autoimmune disease with favorable responses to the treatments of glucocorticoid and immunosuppressive agents. PMID- 25549683 TI - [Reorganization of brain cortex after spinal cord injury based on functional magnetic resonance imaging techniques]. AB - OBJECTIVE: To explore the reorganization of brain cortex on spinal cord injury (SCI) patients with functional magnetic resonance imaging (fMRI) techniques and elucidate its recurring patterns so as to provide theoretic rationales for SCI treatment. METHODS: We designed different tasks for 9 SCI patients and 10 normal subjects. The tasks were named block design and it was divided into rest period (R) and stimulating period (S). All subjects underwent fMRI scan while they were performing the tasks. RESULTS: A significant reorganization occurred on brain cortex of SCI patients after spinal cord injury. This phenomenon changed with elapsing time after spinal cord injury. CONCLUSION: Brain cortex undergoes reorganization after spinal cord injury, especially primary sensory and motor cortex. PMID- 25549684 TI - [Imaging characteristics of basilar artery hypoplasia]. AB - OBJECTIVE: To determine the imaging characteristics of basilar artery hypoplasia (BAH). METHODS: From October 2009 to August 2013, 10 193 magnetic resonance angiogram (MRA) and 31 716 magnetic resonance imaging (MRI) consecutive cases were retrospectively retrieved from our institutional Picture Archiving and Communication System (PACS) database. BAH was defined as a continuous diameter reduction all over artery and a basilar artery diameter <= 2 mm. The same cut-off value was applied for vertebral artery hypoplasia (VAH). We measured the diameters of basilar and vertebral arteries with PACS in all patients according to source imaging and IMP construction of MRA. The carotid arterial computed tomography angiogram (CTA) profiles were reviewed in 50 patients. The fetal-type posterior circle of Willis (FTP) was assessed. The diagnosis of acute cerebral infarction was based on clinical symptoms, signs and a high signal on diffusion weighted imaging (DWI). Acute cerebral infarction was divided into anterior circulation stroke (ACS) and posterior circulation stroke (PCS). RESULTS: A total of 210 BAH were identified among 10 193 consecutive patients. BAH was more common in females (56.7%) than males (43.3%) in the patient group. They had a fetal-type of posterior cerebral artery (FTP) (175 bilateral (83.3%), 35 unilateral (16.7%)). 99.5% patients had V4 VAH and 56.0% (28/50) V1-V3 VAH. Among 210 BAH, there are 74 patients (mean age 64 years, average 25-91 years, 44 males) with a diagnosis of acute cerebral infarction (ACI). The males were predominant in ACI (59.5% in males vs 40.5% in females, P = 0.021). The frequency of BAH was detected in 74 (2.2%) among 3 294 ACI patients. CONCLUSION: As a relatively rare vascular abnormality, BAH has always unilateral or bilateral FTP and V4 VAH. PMID- 25549685 TI - [A preliminary study of dual-source computed tomography dual energy imaging in the diagnosis of acute traumatic bone marrow lesions in spine]. AB - OBJECTIVE: To explore the feasibility of virtual noncalcium technique from dual source computed tomography (DSCT) for the diagnosis of vertebral bone marrow lesions. METHODS: A total of 13 patients with acute vertebral bone marrow lesions underwent both DSCT and MRI within 3 days. And the DSCT dual-energy CT data were postprocessed for generating virtual noncalcium images and color-coded maps. Two radiologists analyzed the lesions of bone marrow by magnetic resonance (MR) imaging and virtual noncalcium images on a three-level. MR imaging interpretation served as the reference standard. Consistency check was conducted by using kappa statistics. And then the sensitivity of DSCT dual energy imaging was examined in the diagnosis of acute traumatic bone marrow lesions in spine. RESULTS: Among them, 13 vertebral body with bone marrow lesions were detected by MRI. The T2WI fat-suppression irregular high signal and slightly high density shadow under the background in noncalcium images corresponded to corresponding high signal areas on MRI. Interreader agreement was substantial for qualitative grading of DE CT images (kappa = 0.629). The sensitivity of DSCT dual energy virtual noncalcium images in the diagnosis of acute traumatic bone marrow lesions in spine were 92.3% and 84.6% for observers 1 and 2. CONCLUSION: Distinct traumatic bone marrow lesions of spine may be diagnosed with a high sensitivity on virtual noncalcium images reconstructed from DSCT and color-coded maps. And it is worth further explorations. PMID- 25549686 TI - [Arthroscopic double strand wire fixation anteriorly and posteriorly to anterior cruciate ligament for tibial intercondylar eminence fracture]. AB - OBJECTIVE: To explore the clinical outcomes of arthroscopic double strand wire fixation anteriorly and posteriorly to anterior cruciate ligament (ACL) for tibial intercondylar eminence fracture. METHODS: From January 2009 to February 2012, 12 patients with tibial intercondylar eminence fracture were selected. There were 4 males and 8 females with an average age of 19.5 +/- 10 (10-50) years. Time from injury to operation was 4 days to 2 years. All cases belonged to Meyers-Mekeever type II and type III. Arthroscopic double strand wire compressive fixation was performed anteriorly and posteriorly to ACL. Other measures included postoperative rehabilitation and supports with brace in knee extension when weight-bearing for 4-6 weeks. RESULTS: The average follow-up period was 15.6 (6 30) months. Final clinical results showed good range of motion and good knee stability. On postoperative radiology, there were good reduction of intercondylar eminence fracture and excellent healing. There was no occurrence of wire rupture. Postoperative IKDC and Lysholm scores were excellent (n = 10) and good (n = 2). There was no such complication as fragmentation of intercondylar eminence fracture bone, neurovascular injury or infection. CONCLUSION: Arthroscopic double strand compressive fixation for tibial intercondylar eminence fracture may be easily performed without injury to ACL substance. The reduction is both stable and reliable. And the clinical outcome is excellent. PMID- 25549687 TI - [Safety and acceptability of intrauterine balloon stent used in uterine after hysteroscopic adhesiolysis to prevent adhesion reformation]. AB - OBJECTIVE: To evaluate the safety and acceptability of COOK intrauterine balloon stent in uterine for one week after hysteroscopic adhesiolysis. METHODS: A total of 79 females with moderate-severe Asherman syndrome undergoing hysteroscopic division of intrauterine adhesion were enrolled from June 2012 to December 2013. They were divided into two groups of intrauterine balloon stent (n = 51) and tailed intrauterine contraceptive device (n = 28). The sterile swabs were taken from cervical canals for bacterial culture by the same microbiologist. Each patient in balloon group was requested to answer a questionnaire survey on the acceptability of balloon stent. RESULTS: 82.3% of them could tolerate discomforts during balloon placement and 86.3% desired re-ballooning if necessary. Positive microorganism cultures were seen in 17 patients (33.3%) in balloon group versus 8 (28.6%) in intrauterine contraceptive device group. And the positive rate was not different between two groups. CONCLUSION: It is relatively safe to maintain the intrauterine balloon stent in uterine for one week. And most patients accept readily the intrauterine balloon stent. PMID- 25549688 TI - [Effects of bore diameter of porous hydroxyapatite scaffolds on three-dimensional dynamic cultivation of osteoblasts]. AB - OBJECTIVE: To explore the relationship between bore diameter of porous hydroxyapatite (HA) scaffolds and the adhesion, proliferation and metabolism of osteoblasts by 3D cultivation. METHODS: MC3T3-E1 cell suspension was separately dropped axially through different bore diameter scaffolds (Group A:150 um, Group B:300 um) to confirm initial seeding. Then scaffolds were transferred into a perfusion bioreactor of 5% CO2 at 37 degrees C for 5 days with an average flow of 3.4 ml/min. After perfusion cultivation, cell proliferation between different groups of scaffolds was determined by methyl thiazolyl tetrazolium (MTT) assay and cell metabolic activities were determined by glucose consumption. Lastly cell adhesion and proliferation were observed directly by scanning electronic microscope (SEM). RESULTS: The results of MTT assay showed that the optical density/mass ratios were 1.31 +/- 0.26 in group A and 1.51 +/- 0.43 in group B. There was no significant difference (t test, P = 0.36). Glucose consumption in group A was significantly lower than that in group B [(162.38 +/- 33.09) vs (217.97 +/- 27.91) umol/L, P = 0.01]. The adhesion, proliferation, pseudopodia and extracellular matrix of osteoblasts in internal part of scaffolds after perfusion cultivation were observed by SEM. CONCLUSION: With excellent biocompatibility, porous HA scaffolds are available for fabricating tissue engineering bones. There is no effect of bore diameter on the proliferation of osteoblasts. But it affects the metabolic activity of osteoblasts. So bore diameter may be increased within a feasible range on the premise of mechanical properties. PMID- 25549689 TI - [Long-term use of mobile phone and its association with glioma: a systematic review and meta-analysis]. AB - OBJECTIVE: The hypothesis that "cell phone induces brain tumor" has become a target of much controversy for several decades and is still a matter of debate even now. We aim to make a systematic review and meta-analysis based on published studies on glioma to identify current evidences for evaluating mobile phones and glioma risk, especially on long-term use of mobile phones. METHODS: The study was conducted according to the Cochrane systematic review methods and reported according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement according to a prospective research protocol accessed via http://www.crd.york.ac.uk/prospero. The software RevMan 5 was used for statistic analysis. Latency and lateralization were used for the examining the dose-response relationship. RESULTS: Overall evidence suggested the increased risk of glioma among long-term ipsilateral users of mobile phone with an odds ratio (OR) of 1.46[1.12, 1.92] based on meta-analysis. Especially, for low-grade glioma, long-term use yielded an OR value of 2.27 [1.81, 2.85]. CONCLUSION: The evidence is currently insufficient on this issue, especially on long-term use of mobile phone. Neither a definite answer nor a clear explanation may be offered for the relationship. And larger prospective trials are warranted. PMID- 25549690 TI - Computer-based auditory phoneme discrimination training improves speech recognition in noise in experienced adult cochlear implant listeners. AB - OBJECTIVE: Specific computer-based auditory training may be a useful completion in the rehabilitation process for cochlear implant (CI) listeners to achieve sufficient speech intelligibility. This study evaluated the effectiveness of a computerized, phoneme-discrimination training programme. DESIGN: The study employed a pretest-post-test design; participants were randomly assigned to the training or control group. Over a period of three weeks, the training group was instructed to train in phoneme discrimination via computer, twice a week. Sentence recognition in different noise conditions (moderate to difficult) was tested pre- and post-training, and six months after the training was completed. The control group was tested and retested within one month. STUDY SAMPLE: Twenty seven adult CI listeners who had been using cochlear implants for more than two years participated in the programme; 15 adults in the training group, 12 adults in the control group. RESULTS: Besides significant improvements for the trained phoneme-identification task, a generalized training effect was noted via significantly improved sentence recognition in moderate noise. No significant changes were noted in the difficult noise conditions. Improved performance was maintained over an extended period. CONCLUSIONS: Phoneme-discrimination training improves experienced CI listeners' speech perception in noise. Additional research is needed to optimize auditory training for individual benefit. PMID- 25549691 TI - United States comparative costs and absenteeism of diabetic ophthalmic conditions. AB - OBJECTIVE: This retrospective cohort study examined the impact of diabetic macular edema (DME), diabetic retinopathy (DR), or diabetes on annual health benefit costs and absenteeism in US employees. METHODS: Claims data from 2001 to 2012 was extracted from the Human Capital Management Services Group Research Reference Database on annual direct/indirect health benefit costs and absences for employees aged >= 18 years. Employees with DME, DR, or diabetes were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Employees were divided into two groups, drivers or nondrivers, and examined in separate analyses. For drivers and nondrivers, the DME, DR, and diabetes cohorts were compared with their respective control groups (without diabetes). Two-part regression models controlled for demographics and job-related characteristics. RESULTS: A total of 39,702 driver and 426,549 nondriver employees were identified as having >= 1 year's continuous health plan enrollment. Direct medical costs for drivers with DME, DR, or diabetes were $6470, $8021, and $5102, respectively (>2.8 times higher and statistically significant compared with driver controls). Nondrivers with DME and DR incurred significantly higher sick leave and short-term disability costs compared with the nondrivers with diabetes and nondriver controls. In drivers with DME, the majority of days of absence were for short- and long-term disability (12.41 and 11.43 days, respectively). In drivers with DR, the majority of days of absence were for short-term disability (10.70 days). In nondrivers with DME and nondrivers with DR, the majority of days of absence were for sick leave (5.74 and 4.93 days, respectively) and short-term disability (5.08 and 4.93 days, respectively). CONCLUSION: DME and DR are associated with substantial direct medical cost and absenteeism in this real-world sample of medically insured employees. This research highlights the negative impact of DME and DR on annual costs and absenteeism and may assist employers in assessing the impact of these conditions on employees. PMID- 25549692 TI - Fibroblast growth factor-21 concentration in serum and synovial fluid is associated with radiographic bone loss of knee osteoarthritis. AB - We aimed to evaluate whether FGF-21 concentration in serum and synovial fluid (SF) is associated with radiographic bone loss of knee osteoarthritis (OA). A total of 186 OA patients and 108 controls were recruited. The radiographic bone loss of knee OA was assessed by the Ahlback grading scale. FGF-21 concentration in serum and SF was measured by enzyme-linked immunosorbent assay (ELISA). We demonstrated that OA patients had significantly higher serum FGF-21 concentration compared with controls (204.30 [range 158.25-279.16] ng/L vs. 130.72 [range 94.93 218.03] ng/L, p < 0.01). FGF-21 concentration in serum was well correlated with that in paired SF samples (r = 0.668, p < 0.001). In OA patients, those with a higher Ahlback grade had significantly higher serum and SF FGF-21 concentration (p < 0.001 for both). FGF-21 concentration in serum and SF was significantly and independently associated with the Ahlback grade (r = 0.403, p < 0.001 and r = 0.410, p < 0.001; respectively). These findings indicated that FGF-21 might be a potential biomarker for predicting bone loss of OA. Therapeutic interventions by blocking FGF-21 signaling pathways to delay the degenerative process of OA warrants further investigations. PMID- 25549693 TI - A retrospective radiographic evaluation of the anterior loop of the mental nerve: comparison between panoramic radiography and cone beam computerized tomography. AB - OBJECTIVES: To compare the prevalence and the length of mental loop, measured with panoramic radiography (PR) and cone beam computerized tomography (CBCT). MATERIAL AND METHODS: PG and CBCT images where analyzed by a single calibrated examiner to determine the presence and the position of the mental foramen (MF), its distance to the lower mandible border, the anterior length of the mental loop (ML) and the bone quality in 82 PR and 82 CBCT. RESULTS: ML was identified in 36.6 % of PR and 48.8 % of CBCT. PR showed a magnification of 1.87 when compared to CBCT. The mean of anterior extension of the inferior alveolar nerve and the distance to the inferior border of the mandible was higher for PR (2.8 mm, sd 0.91 mm on the PR , range 1.5 to 4.7 mm and 1.59, sd 0.9 on the CBCT ,range 0.4 to 4.0 mm) CONCLUSIONS: There is a magnification in PR images with respect to those of CBCT. The differences between CBCT and PR with regards to the identification and length of the ML are not statistically significant. Identification and accuracy measurements of ML did not depend on the bone quality. Considering that two dimensional imaging provides less accurate and reliable information regarding the anterior loop, a CBCT scan could be recommended when planning implant placement in the anterior region. PMID- 25549694 TI - Optical sensors for the detection of trace chloroform. AB - Optical thin film sensors have been developed to detect chloroform in aqueous and nonaqueous solutions. These sensors utilize a modified Fujiwara reaction, one of the only known methods for detecting halogenated hydrocarbons in the visible spectrum. The modified Fujiwara reagents, 2,2'-dipyridyl and tetra-n-butyl ammonium hydroxide (n-Bu4NOH or TBAH), are encapsulated in an ethyl cellulose (EC) or sol-gel film. Upon exposure of the EC sensor film to HCCl3 in petroleum ether, a colored product is produced within the film, which is analyzed spectroscopically, yielding a detection limit of 0.830 ppm (parts per million v/v or MUL/L hereinafter) and a quantification limit of 2.77 ppm. When the chloroform concentration in pentane is >=5 ppm, the color change of the EC sensor is visible to the naked eye. In aqueous chloroform solution, reaction in the sol-gel sensor film turns the sensor from colorless to dark yellow/brown, also visible to the naked eye, with a detection limit of 500 ppm. This is well below the solubility of chloroform in water (ca. 5,800 ppm). To our knowledge, these are the first optical quality thin film sensors using Fujiwara reactions for halogenated hydrocarbon detection. PMID- 25549695 TI - Volatility of atmospherically relevant alkylaminium carboxylate salts. AB - Heterogeneous neutralization reactions of ammonia and alkylamines with sulfuric acid play an important role in aerosol formation and particle growth. However, little is known about the physical and chemical properties of alkylaminium salts of organic acids. In this work we studied the thermal stability and volatility of alkylaminium carboxylate salts of short aliphatic alkylamines with monocarboxylic and dicarboxylic acids. The enthalpy of vaporization and saturation vapor pressure at 298 K were derived using the kinetic model of evaporation and the Clausius-Clapeyron relation. The vapor pressure of alkylaminium dicarboxylate salts is ~10(-6) Pa, and the vaporization enthalpy ranges from 73 to 134 kJ mol( 1). Alkylaminium monocarboxylate salts show high thermal stability, and their thermograms do not follow our evaporation model. Hence, we inferred their vapor pressure from their thermograms as comparable to that of ammonium sulfate (~10( 9) Pa). Further characterization showed that alkylaminium monocarboxylates are room temperature protic ionic liquids (RTPILs) that are more hygroscopic than ammonium sulfate (AS). We suggest that the irregular thermograms result from an incomplete neutralization reaction leading to a mixture of ionic and nonionic compounds. We conclude that these salts are expected to contribute to new particle formation and particle growth under ambient conditions and can significantly enhance the CCN activity of mixed particles in areas where SO2 emissions are regulated. PMID- 25549697 TI - Effects of paliperidone extended release on functioning level and symptoms of patients with recent onset schizophrenia: An open-label, single-arm, flexible dose, 12-months follow-up study. AB - BACKGROUND: Response to antipsychotic treatment is better in the early stages of schizophrenia. AIMS: The primary objective of this non-randomized, single-arm, multicenter clinical trial was to explore the response to treatment and safety of a flexible dose of paliperidone (mean = 6.42 mg/day) in patients with recent onset schizophrenia (< 3 years after the first episode/hospitalization). METHODS: Severity of clinical symptoms was evaluated by the Positive and Negative Syndrome Scale (PANSS), functioning was assessed using the Global Assessment of Functioning (GAF) scale and the Personal and Social Performance Scale (PSP). RESULTS: In a total of 85 patients enrolled, 80 patients were eligible. Total PSP score at baseline (50.2 +/- 11.6) increased at all visits. Total PSP score was 65.4 +/- 12.1 at month 12 (P < 0.001). GAF scores were significantly higher at all visits compared with baseline (P = 0.001). It was 62.4 +/- 12.5 with an increase of 42.9% at month 12 (P < 0.001). PANSS Positive and Negative subscales and General psychopathology subscale scores showed significant reductions beginning with month 3 and were 11.9 +/- 3.8 (29.3%; P < 0.001), 13.7 +/- 5.6 (27.3% P < 0.001) and 27.8 +/- 7.1 (23.2%; P < 0.001) at month 12, respectively. Twelve patients (14.3%) had a serious adverse event. The most common adverse events were insomnia (17.9%), nausea (8.3%), akathisia (4.8%), anxiety (4.8%) and depression (4.8%). Body weight values at the end of the study were significantly higher compared with baseline. CONCLUSION: The present study demonstrates that flexible dose of paliperidone resulted in a significant improvement in functioning and reduction in symptoms in patients with recent onset schizophrenia. PMID- 25549698 TI - Bank voles show high seropositivity rates in a natural TBEV focus in Hungary. AB - Rodents captured in a known tick-borne encephalitis virus (TBEV) focus were serologically surveyed for 4 years, with 28 visits. The collected sera were analysed by virus neutralization test. Bank vole (Myodes glareolus) had a significantly higher incidence rate of antibodies to TBEV (20.5%) than Apodemus flavicollis (3.7%) and Apodemus agrarius (4.6%). In all species, rates were higher in adults (6.8%) than in juveniles (1.7%). A higher incidence rate was observed in female A. flavicollis individuals (6.7%) than in males (1.5%). Smaller bank vole population coincided with lower (1.2-4.8%) seropositivity in all small rodents, while more abundant bank vole population meant higher (17.9%) total seropositivity. The TBEV focus originally had only Apodemus mice, bank voles appeared later, reached 20.5% positivity and raised the positivity in small rodents from 4% to 10.2% in 3 years. The results highlight the role of M. glareolus and of adult rodents in maintaining the TBEV in nature. PMID- 25549696 TI - Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine. AB - The severity and longevity of the current Ebola outbreak highlight the need for a fast-acting yet long-lasting vaccine for at-risk populations (medical personnel and rural villagers) where repeated prime-boost regimens are not feasible. While recombinant adenovirus (rAd)-based vaccines have conferred full protection against multiple strains of Ebola after a single immunization, their efficacy is impaired by pre-existing immunity (PEI) to adenovirus. To address this important issue, a panel of formulations was evaluated by an in vitro assay for their ability to protect rAd from neutralization. An amphiphilic polymer (F16, FW ~39,000) significantly improved transgene expression in the presence of anti-Ad neutralizing antibodies (NAB) at concentrations of 5 times the 50% neutralizing dose (ND50). In vivo performance of rAd in F16 was compared with unformulated virus, virus modified with poly(ethylene) glycol (PEG), and virus incorporated into poly(lactic-co-glycolic) acid (PLGA) polymeric beads. Histochemical analysis of lung tissue revealed that F16 promoted strong levels of transgene expression in naive mice and those that were exposed to adenovirus in the nasal cavity 28 days prior to immunization. Multiparameter flow cytometry revealed that F16 induced significantly more polyfunctional antigen-specific CD8+ T cells simultaneously producing IFN-gamma, IL-2, and TNF-alpha than other test formulations. These effects were not compromised by PEI. Data from formulations that provided partial protection from challenge consistently identified specific immunological requirements necessary for protection. This approach may be useful for development of formulations for other vaccine platforms that also employ ubiquitous pathogens as carriers like the influenza virus. PMID- 25549699 TI - Are soluble IL-2 receptor and IL-12p40 levels useful markers for diagnosis of tuberculous pleurisy? AB - BACKGROUND: The differential diagnostic utilities of the levels of soluble interleukin (IL)-12p40 and the IL-2 receptor in sera and pleural effusions were evaluated in patients with exudative pleural effusions. METHODS: We enrolled a total of 120 patients with exudative pleural effusions. The clinical, radiological, and histopathological diagnoses were tuberculous pleurisy in 52, malignant pleurisy in 39, and parapneumonic effusions in 29 patients. RESULTS: We measured serum IL-12p40 and adenosine deaminase (ADA) levels in patients with tuberculous pleurisy and in a control group treated for pleural effusion to determine if such levels were useful in the diagnosis of pleural effusion (p < 0.005). Definite microbiological or histopathological diagnoses of tuberculous pleurisy or pleural effusion were recorded, and we found that ADA and serum soluble IL-2 receptor levels aided in diagnosis (p < 0.001). The levels of ADA and soluble IL-2 in pleural effusions afforded sensitivities and specificities of 84.62% and 82.69% and of 70.59% and 80.88%, respectively. The soluble IL-2 receptor level afforded a sensitivity and specificity of 82.69% and 52.9%. IL 12p40 levels in pleural effusions and sera afforded sensitivities and specificities of 80.77% and 80.77% and of 60.29% and 39.71%, respectively. CONCLUSION: Soluble IL-2 receptor levels in patients with tuberculous pleurisy serve as markers of disease in non-endemic countries, similarly to ADA levels. PMID- 25549700 TI - Involvement of pituitary tumor transforming gene 1 in psoriasis, seborrheic keratosis, and skin tumors. AB - Accumulating evidence suggests that pituitary tumor transforming gene 1 (PTTG1) is a potential biomarker for cancer malignancy and a cell-cycle regulatory protein. This investigation was performed to address the subcellular localization of PTTG1 and its possible involvement in proliferative skin diseases. In vitro primary-cultured keratinocytes and skin samples from psoriasis, seborrheic keratosis (SK), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) were investigated by immunofluorescence and real-time PCR. In normal skin, PTTG1 is localized predominantly in 10% of basal keratinocytes, while 30-40% in basal and suprabasal psoriatic keratinocytes. PTTG1 mRNA in psoriatic epidermis is about 5-fold more than that in normal one (P<0.01). PTTG1 is localized in cytoplasm in primary-cultured normal and psoriatic keratinocytes, and PTTG1 in HaCaT cells is distributed throughout the cytoplasm of metaphase cells. PTTG1 is seen at both G2 and M phases, and highest PTTG1 expression correlates with highest cyclin B1 expression and highest degree of nuclear pleomorphism at M phase. The positive rate of PTTG1 in SK, BCC, and SCC is about 10%, 20%, and more than 80%, respectively. PTTG1 siRNA, which knocks down the expression of PTTG1, reduced the invasive capacity of A431 cells. In conclusion, PTTG1 is a marker for proliferative skin diseases associated with cell cycle regulation and may aid in detection of aggressive cancers. PMID- 25549701 TI - Exome sequencing on malignant meningiomas identified mutations in neurofibromatosis type 2 (NF2) and meningioma 1 (MN1) genes. AB - BACKGROUND: Meningiomas are tumors originating from the membranous layers surrounding the central nervous system, and are generally regarded as "benign" tumors of the brain. Malignant meningiomas are rare and are typically associated with a higher risk of local tumor recurrence and a poorer prognosis (median survival time <2 years). Previous genome-wide association studies and exome sequencing studies have identified genes that play a role in susceptibility to meningiomas, but these studies did not focus specifically on malignant tumors. METHODS: We performed exome sequencing on five malignant meningiomas on the Illumina HiSeq2000 platform using Agilent SureSelect Human All Exon kits. We used wANNOVAR web server to annotate and prioritize variants, identified candidate genes with recurrent mutations, and validated selected mutations by Sanger sequencing. We next designed custom NimbleGen targeted region arrays on five candidate genes, and sequenced four additional malignant meningiomas. RESULTS: From exome sequencing data, we identified several frequently mutated genes including NF2, MN1, ARID1B, SEMA4D, and MUC2, with private mutations in tumors. We sequenced these genes in four additional samples and identified potential driver mutations in NF2 (neurofibromatosis type 2) and MN1 (meningioma 1). CONCLUSIONS: We confirmed that mutations in NF2 may play a role in progression of meningiomas, and nominated MN1 as a candidate gene for malignant transformation of meningiomas. Our sample size is limited by the extreme rarity of malignant meningiomas, but our study represents one of the first sequencing studies focusing on the malignant subtype. PMID- 25549703 TI - Targeted therapy for hereditary cancer syndromes: neurofibromatosis type 1, neurofibromatosis type 2, and Gorlin syndrome. AB - Hereditary cancer syndromes are well known in the oncology community, typically affecting children, adolescents, and young adults and thereby resulting in great cumulative morbidity and mortality. These syndromes often lag behind their de novo counterparts in the development of approved novel treatment options due to their rarity in the general population. Recent work has allowed the identification of molecular aberrations and associated targeted therapies that may effectively treat these conditions. In this review, we seek to characterize some of the involved aberrations and associated targeted therapies for several germline malignancies, including neurofibromatosis types 1 and 2, and Gorlin syndrome. Though patients with hereditary cancer syndromes may be too rare to effectively include in large clinical trials, by understanding the pathophysiology of these diseases, clinicians can attain insights into the use of targeted therapies in their own practice when treating affected individuals. PMID- 25549702 TI - The contribution of non-human primate models to the development of human vaccines. AB - The non-human primates (NHPs) model in biomedical research has contributed to the study of human infectious, autoimmune, oncogenic, and neurological diseases. This review focuses on the importance of NHP models in vaccine development for tuberculosis, pertussis, Dengue, group A streptococcus (Streptococcus pyogenes) infection, HIV infection, and certain diseases in the elderly (influenza, for example). From understanding disease pathogenesis and mechanisms of protection, to assessing vaccine safety and efficacy, we discuss selected cases where the importance of the use of NHP models is highlighted. PMID- 25549704 TI - Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome. AB - Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53). PMID- 25549705 TI - Immune checkpoint blockade as a novel immunotherapeutic strategy for renal cell carcinoma: a review of clinical trials. AB - Renal cell carcinoma (RCC) is a common genitourinary malignancy; when metastatic, it is almost uniformly fatal. For many years non-specific immunotherapy was the mainstay of treatment for metastatic RCC, but led to only modest success and significant side-effects. More recently, seven targeted therapy drugs have been approved to treat metastatic RCC; these drugs impede RCC cell growth, proliferation, and angiogenesis and have had a significant impact on patient outcomes, but with infrequent long term responders. Thus, a renewed emphasis on immunotherapy has emerged over the last several years with the development and testing of a novel class of immunotherapeutic agents called checkpoint inhibitors. These drugs have targeted the programmed cell death 1 (PD-1) and cytotoxic leukocyte antigen 4 (CTLA-4) pathways on regulatory T cells, leading to immune response enhancement and immune-mediated anti-tumor effects in multiple malignancies, including RCC. A number of studies recently reported utilizing checkpoint inhibitors, either alone or in combination with other checkpoint inhibitors or vascular endothelial growth factor targeting agents, and these studies have shown significant and at times durable responses in RCC patients. This has led to the development of further phase I, II, and III trials and this review will discuss the history and currently available data for immune checkpoint blockade in RCC. PMID- 25549706 TI - Editorial: Nursing innovation and reform in health care. AB - Abstract PMID- 25549707 TI - Opinion piece: Don't come late to the party: Step up and lead. AB - Abstract PMID- 25549708 TI - Leadership style and culturally competent care: Nurse leaders' views of their practice in the multicultural care settings of the United Arab Emirates. AB - Abstract It is well recognized that nurse-leader-managers play an important role in facilitating the quality and nature of hospital care, the improvement of work performance and work satisfaction. In the United Arab Emirates they face the additional challenge of working within a context of significant linguistic and cultural diversity where leadership in the provision of culturally competent care is a major requirement. With this goal at the fore, a sample of 153 nurse-leader managers, including matrons, nursing directors, supervisors, nurses-in-charge and in-service education staff from 4 private and 6 government hospitals completed the multifactor leadership questionnaire (Bass & Avolio, 2004). The survey also explored participants' perceptions of the characteristics of good leaders and what they needed to do in their particular work place to enhance culturally competent care. The results showed nurse-leader-managers used both transformational and transactional leadership attributes but in different combinations across the two hospital types. PMID- 25549709 TI - Leadership styles of nurse managers in ethical dilemmas: Reasons and consequences. AB - Abstract Background: Understanding the reasons and consequences of leadership styles in ethical dilemmas is fundamental to exploring nurse managers' abilities to influence outcomes for patients and nursing personnel. PURPOSE: To explain the associations between different leadership styles, reasons for their application and its consequences when nurse managers make decisions in ethical dilemmas. METHODS: The data were collected between 15 October 2011 and 30 April 2012 by statistically validated questionnaire. The respondents (N = 278) were nurse managers. The data were analysed using SPSS 20.0, calculating Spearman's correlations, the Stepwise Regression and ANOVA. RESULTS: The reasons for applying different leadership styles in ethical dilemmas include personal characteristics, years in work position, institutional factors, and the professional authority of nurse managers. The applied leadership styles in ethical dilemmas are associated with the consequences regarding the satisfaction of patients,' relatives' and nurse managers' needs. CONCLUSIONS: Nurse managers exhibited leadership styles oriented to maintenance, focussing more on the 'doing the job' than on managing the decision-making in ethical dilemmas. PMID- 25549710 TI - Financial austerity measures and their effects as perceived in daily practice by Italian nurses from 2010 to 2011: A longitudinal study. AB - Abstract Most western economies have in recent years been experiencing one of the longest and deepest economic recessions since the Great Depression. During a recession health-care expenditures are often among the first to be cut. However, what is occurring in daily practice from the point of view of care has not been documented to date. Describing the cost containment interventions undertaken and their effects as perceived in daily practice by Italian nurses was the aim of the study. A longitudinal study design was adopted from 2010 to 2011 involving 1,001 nurses each year. In the 2-year period taken into consideration, participants reported a significant increase in the number of cost containment measures adopted by their health-care organisations. The effects of these cost containment measures have been perceived by nurses especially in terms of (1) increased stress levels, (2) increased number of patients with social problems, and (3) increased nursing workloads. In addition, greater difficulties in finding clinical placement for nursing students and fewer resources devoted to nursing professional development were reported, indicating that some cost containment measures will have long-term effects. The economic crisis seems to affect mainly the most vulnerable groups of society. Innovative solutions for the need to reduce the costs of National Health Services do not seem to emerge from the findings. PMID- 25549711 TI - High patient satisfaction with nurse practitioner delivered services at two health centres in urban Jamaica. AB - Abstract Objective: To explore the level of patient satisfaction with nurse practitioner delivered services at two health centres in urban Jamaica. METHOD: A cross sectional survey of 120 adult clients (age >=18 years old) seen by Nurse Practitioner at a Type 3 or Type 5 health centre in Kingston, Jamaica was conducted using a modified self-administered Nurse Practitioner Satisfaction Survey questionnaire. Data were analysed using SPSS(r) version 18 for Windows(r). RESULTS: The study achieved response rate of 91.6% (N = 120). The majority were females (77%) with an average age of 40 +/- 16 years. Most (63%) were from the Type 5 health centre and the rest (37%) were from a Type 3 facility. The mean general satisfaction score was 81 out of a possible 90 and 83% of the respondents reported they were very satisfied with another 17% expressing that they were satisfied with the nurse practitioner services at both facilities. No respondent was dissatisfied. The mean satisfaction score was significantly higher among respondents 40 years and older than that of their younger counterparts. Socio demographic and organisation characteristics were not associated with the mean satisfaction score. CONCLUSIONS: A high level of satisfaction exists among patients seen by nurse practitioners at two facilities in Kingston, Jamaica. This may represent an opportunity for expanded role of Nurse practitioners in the delivery of primary in Jamaica. PMID- 25549712 TI - Confronting the cultural challenge of the whiteness of nursing: Aboriginal registered nurses' perspectives. AB - Abstract This paper presents the findings of a study that interviewed Aboriginal nurses to explore their experiences of the whiteness of nursing. Despite concerted efforts to improve the health of Aboriginal Australians, it still remains equivalent to third world countries. One strategy identified to address this is to increase the participation rates of Aboriginal registered nurses within the Australian healthcare workforce. Presently Aboriginal nurses account for only a small percentage of the nursing workforce. While there has been research into the recruitment and retention strategies dedicated to improving the numbers of Aboriginal registered nurses, this paper focus on the experiences of Aboriginal registered nurses within Australia's mainstream healthcare system, where they are exposed and subjected on a daily basis to the 'whiteness of nursing.' PMID- 25549713 TI - Opinion piece: Regulation of nursing assistants: A critical international issue? AB - Abstract Health care or nursing assistants are valuable members of health care teams who undertake a wide range of tasks, contribute to meeting the increasingly complex healthcare needs of patients and have various levels of training. However, they are not subject to regulation in many countries. If training and regulation are pre-requisites for ensuring the standards of care delivered by registered nurses, then this must also apply to nursing assistants. Regulation ensures the need for on-going education and development which is critical to maintaining and refreshing the values underpinning compassionate care for both nursing assistants and registered nurses. PMID- 25549714 TI - Similarities and differences in educational preparation of registered and enrolled nurses in Australia: An examination of curricula content. AB - Abstract Background: Variations exist internationally in the types and numbers of nurses registered to practice. Whilst the United Kingdom has phased out second level nurses, countries such as Australia, New Zealand, Singapore and the United States have maintained a two level system. In Australia, the two levels of nurse authorised to practice are the registered nurse whom complete an undergraduate nursing degree, and enrolled nurse (EN) whom complete either a certificate or diploma programme. Recent changes to educational preparation and resulting scope of practice for ENs have resulted in increased confusion between roles and expectations of the different levels. AIM: This paper reports on findings of a study aimed at identifying differences in educational preparation of the different levels of nurse in Australia. METHOD: Course coordinators from nine organisations offering pre-registration nursing programmes completed self reporting questionnaires designed to obtain information on types and lengths of courses, and details of curricula including course objectives, teaching and assessment methods and content areas. RESULTS: Comparative analysis of survey responses identified similarities and differences between registered and EN programmes. Common areas included teaching and assessment methods, core theoretical units and general nursing skills. The diploma and degree programmes appear aligned in most theory and clinical skills. The main difference identified existed between skills taught in the two EN programmes. CONCLUSIONS: Findings further add to confusion regarding registered and ENs in Australia. Further research is required to determine expectations of employers and other major stakeholders with regard to the differences. PMID- 25549715 TI - Senior nurse role expectations of graduate registered and enrolled nurses in Australia: Content analysis of open-ended survey questions. AB - Abstract Changes to educational preparation and scope of practice for enrolled nurses (ENs) in Australia have impacted on role expectations. This paper reports results of a survey of senior nurses in Victoria, Australia, regarding opinions of the differences in role expectation and scope of practice for graduate registered and ENs. Content analysis of open-ended survey questions was used to identify themes in the written data. Results identified education, skill level and responsibility as differences between the levels of graduate nurses despite many respondents perceiving there to be no or little difference in graduate roles. PMID- 25549716 TI - New graduate nurse transition programs: Relationships with bullying and access to support. AB - Abstract New graduate nurses are often targets of bullying and horizontal violence. The support offered by new graduate nurse transition programs may moderate the effects of bullying and limit its negative impact on new graduate nurse transition. This study examined the relationships between access to support, workplace bullying and new graduate nurse transition within the context of new graduate transition programs. As part of a mixed methods study, an online survey was administered to new graduates (N = 245) approximately a year from starting employment. Bullied new graduate nurses were less able to access support when needed and had poorer transition experiences than their non-bullied peers. Participation in a formal transition program improved access to support and transition for bullied new graduate nurses. People supports within transition programs positively influenced the new graduate nurse transition experience. Formal transition programs provide support that attenuates the impact of bullying on new graduate nurses and improves transition. PMID- 25549717 TI - An exploratory study of the relationship between learning styles and academic performance among students in different nursing programs. AB - Abstract Background: Learning style is a major consideration in planning for effective and efficient instruction and learning. Learning style has been shown to influence academic performance in the previous research. Little is known about Taiwanese students' learning styles, particularly in the field of nursing education. AIM: This purpose of this study was to identify the relationship between learning styles and academic performance among nursing students in a 5 year associate degree of nursing (ADN) program and a 2-year bachelor of science in nursing (BSN) program in Taiwan. METHODS/DESIGN: This study employed a descriptive and exploratory design. The Chinese version of the Myers-Briggs type indicator Form M was an instrument. Data such as grade point average were obtained from the Office of Academic Affairs and the Registrar computerized records. Descriptive statistics, one-way analysis of variance and chi-square statistical analysis were used to explore the relationship between academic performance and learning style in Taiwanese nursing students. RESULTS/FINDINGS: The study sample included 285 nursing students: 96 students in a 2-year BSN program, and 189 students in a 5-year ADN program. Two common learning styles were found: Introversion, sensing, thinking, and judging; and introversion, sensing, feeling, and judging. A sensing-judging pair was identified in 43.3% of the participants. Academic performance was significantly related to learning style (p < 0.05, df = 15). CONCLUSION: The results of this study can help educators devise classroom and clinical instructional strategies that respond to individual needs in order to maximize academic performance and enhance student success. A large sample is recommended for further research. Understanding the learning style preferences of students can enhance learning for those who are under performing in their academic studies, thereby enhancing nursing education. PMID- 25549718 TI - Whistleblowing: An integrative literature review of data-based studies involving nurses. AB - Abstract Aim: To summarise and critique the research literature about whistleblowing and nurses. BACKGROUND: Whistleblowing is identified as a crucial issue in maintenance of healthcare standards and nurses are frequently involved in whistleblowing events. Despite the importance of this issue, to our knowledge an evaluation of this body of the data-based literature has not been undertaken. METHOD: An integrative literature review approach was used to summarise and critique the research literature. A comprehensive search of five databases including Medline, CINAHL, PubMed and Health Science: Nursing/Academic Edition, and Google, were searched using terms including: 'Whistleblow*,' 'nurs*.' In addition, relevant journals were examined, as well as reference lists of retrieved papers. Papers published during the years 2007-2013 were selected for inclusion. FINDINGS: Fifteen papers were identified, capturing data from nurses in seven countries. The findings in this review demonstrate a growing body of research for the nursing profession at large to engage and respond appropriately to issues involving suboptimal patient care or organisational wrongdoing. CONCLUSIONS: Nursing plays a key role in maintaining practice standards and in reporting care that is unacceptable although the repercussions to nurses who raise concerns are insupportable. Overall, whistleblowing and how it influences the individual, their family, work colleagues, nursing practice and policy overall, requires further national and international research attention. PMID- 25549719 TI - Adult-onset acral peeling skin syndrome in a non-identical twin: a case report in South Africa. AB - BACKGROUND: Acral peeling skin syndrome is a rare autosomal recessive disorder in which skin exfoliation is limited to the hands and feet. While it typically manifests from early childhood, in this first reported case from South Africa, the patient did not manifest clinically until the fourth decade of life. CASE REPORT: A 44-year-old woman of African descent, 1 of a set of non-identical twins, presented with recurrent episodes of skin peeling of the upper and lower limbs. The first episode occurred 4 years prior, followed by perennial skin peeling during the spring seasons. She was not on treatment for any chronic disease and reported no exposure to chemicals or other irritants. The family, including the non-identical twin sister, has no history of skin disorders and the patient's HIV antibody test was negative. At presentation, physical examination revealed ongoing exfoliation with new skin formation on the palms and soles. The mucous membranes and nails were spared. Other systems were normal. Skin biopsy taken from the palms confirmed peeling skin syndrome. The patient was managed with topical aqueous cream and analgesics. She was briefly counseled on the nature and prognosis of the disease, and referred for genetic testing and counseling. On follow-up, she continues to have skin peeling once or twice a year. CONCLUSIONS: This first reported case of this rare disease in South Africa contributes to the growing body of literature on the disease and highlights the need for clinicians to be aware of its variable clinical onset. PMID- 25549720 TI - Toll-like receptor 4 mediates the antitumor host response induced by Ganoderma atrum polysaccharide. AB - The aim of this study is to investigate the role of Toll-like receptor (TLR) 4 in Ganoderma atrum polysaccharide (PSG-1)-induced antitumor activity. In vitro, the apoptosis rate of S-180 cells was increased in PSG-1-induced peritoneal macrophage derived from C3H/HeN (wild-type) mice, but not from C3H/HeJ (TLR4 deficient) mice. In the S-180 tumor model, phagocytosis, NO and ROS release, phosphorylation of MAPKs and Akt, and expression of NF-kappaB were increased by PSG-1 in peritoneal macrophage derived from C3H/HeN mice. Furthermore, PSG-1 elevated Th1 cytokine production and enhanced the cytotoxic activity of CTL and NK cells in C3H/HeN mice. In addition, PSG-1 decreased the tumor weight and increased the apoptosis rate and caspase-3 and caspase-9 activities of tumor derived from the C3H/HeN mice. However, none of these activities were observed in C3H/HeJ mice. In summary, these findings demonstrated that the antitumor activity of PSG-1 is mediated by TLR4. PMID- 25549721 TI - Integrinbeta6-targeted immunoliposomes mediate tumor-specific drug delivery and enhance therapeutic efficacy in colon carcinoma. AB - PURPOSE: Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinbeta6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer. EXPERIMENTAL DESIGN: PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5 fluorouracil (5-FU)-induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo. RESULTS: ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC50 more than 90% in HT-29 and SW480beta6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6 targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU-induced cellular apoptosis rate than liposomes. In vivo, the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU. CONCLUSIONS: ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy. PMID- 25549722 TI - Patient-derived xenografts from non-small cell lung cancer brain metastases are valuable translational platforms for the development of personalized targeted therapy. AB - PURPOSE: The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the strategies. EXPERIMENTAL DESIGN: We established patient-derived xenografts (PDX) using NSCLC brain metastasis surgical samples and elucidated their possible preclinical and clinical implications for personalized treatment. RESULTS: NSCLC brain metastases (n = 34) showed a significantly higher successful PDX establishment rate than primary specimens (n = 64; 74% vs. 23%). PDXs derived from NSCLC brain metastases recapitulated the pathologic, genetic, and functional properties of corresponding parental tumors. Furthermore, tumor spheres established in vitro from the xenografts under serum-free conditions maintained their in vivo brain metastatic potential. Differential phenotypic and molecular responses to 20 targeted agents could subsequently be screened in vitro using these NSCLC PDXs derived from brain metastases. Although PDX establishment from primary NSCLCs was significantly influenced by histologic subtype, clinical aggressiveness, and genetic alteration status, the brain metastases exhibited consistently adequate in vivo tumor take rate and in vitro tumor sphere formation capacity, regardless of clinical and molecular conditions. CONCLUSIONS: Therefore, PDXs from NSCLC brain metastases may better represent the heterogeneous advanced NSCLC population and could be utilized as preclinical models to meet unmet clinical needs such as drug screening for personalized treatments. PMID- 25549723 TI - Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. AB - PURPOSE: To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC). EXPERIMENTAL DESIGN: Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin alpha-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. RESULTS: Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib. CONCLUSIONS: Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients. PMID- 25549725 TI - A study of implanted cardiac rhythm recorders in advanced cardiac AL amyloidosis. AB - AIMS: AL amyloidosis may respond to chemotherapy but two-thirds of patients with severe cardiac involvement die within a year of diagnosis, purportedly from tachyarrhythmias or electromechanical dissociation. We sought to characterize the nature of cardiac arrhythmias in severe cardiac AL amyloidosis using implanted cardiac rhythm recorders. METHODS AND RESULTS: Implantable loop recorders (ILRs) were inserted within 24 h of baseline evaluation at the UK National Amyloidosis Centre, into 20 consecutive patients with newly diagnosed severe cardiac AL amyloidosis and symptoms of syncope or pre-syncope. Weekly ILR recordings and additional recordings at the time of symptoms were obtained. Median (range) follow-up from baseline was 308 (10-399) days. Thirteen patients died, and median survival in the whole cohort was 61 days from device insertion. In each of eight evaluable cases, death was heralded by bradycardia, usually associated with complete atrioventricular block (CAVB), followed shortly thereafter by pulseless electrical activity. Four patients received pacemakers, a median (range) of 7 (3 38) h after development of symptomatic CAVB, but these did not prevent rapid cardiac decompensation and death in three cases. Despite 272 loop recordings, there was only one episode of non-sustained ventricular tachycardia, which was preceded by severe bradycardia. Patients who died had significantly worse global left ventricular strain on echocardiography (P = 0.029) and reduced 6 min walk distance (P = 0.048) at baseline compared with survivors. CONCLUSIONS: The discovery that bradyarrhythmias heralded terminal cardiac decompensation in most patients with severe cardiac AL amyloidosis supports a study of prophylactic pacemaker insertion in this patient population. PMID- 25549726 TI - Rare case of isolated single coronary artery causing ischaemia. PMID- 25549724 TI - Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein. AB - PURPOSE: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors. EXPERIMENTAL DESIGN: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors. RESULTS: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2. CONCLUSIONS: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy. PMID- 25549727 TI - LCZ696: too good to be true? PMID- 25549729 TI - Statement of Retraction: Dan Bi Lee, Ho Seok Suh & Yu Sung Choi. "A comparative study of low-fluence 1,064nm Q-Switched Nd:YAG laser with or without chemical peeling using Jessner's solution in melasma patients". PMID- 25549738 TI - Editorial: Is postgraduate education a luxury or necessity for professional nurses: A trans-Tasman perspective. AB - Abstract PMID- 25549728 TI - Single coronary artery anomaly with interarterial left main: caught inbetween. PMID- 25549739 TI - A psychometric evaluation of the Korean version of the evidence-based practice questionnaire for nurses. AB - BACKGROUND: Measurement of evidence-based practice (EBP) competence is a challenge in the health care setting. AIM: The purpose of this study was to evaluate the psychometric properties of the Korean version of the Evidence-Based Practice Questionnaire (EBPQ). METHODS/DESIGN: Data were collected from Korean clinical nurses (N = 801) who worked in acute care settings. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed to assess its construct validity. Concurrent validity and internal consistence were also assessed. RESULTS: Findings identified that EFA revealed a three-factor solution with 64.4% of total variance explained. The factor loadings ranged from 0.431 to 0.900 for the 24 items. The instrument showed good reliability and concurrent validity with the Critical Thinking Disposition scale. CFA revealed that the Korean version of the EBPQ was acceptable. CONCLUSION: The Korean version of the EBPQ is a valid and reliable evaluation measure of EBP competencies of nurses in South Korea. PMID- 25549740 TI - Diversity characteristics and the experiences of nursing students during clinical placements: A qualitative study of student, faculty and supervisors' views. AB - Abstract Background: Little is known about which diversity characteristics if any, impact on nursing students' clinical placements or how these may affect the quality of their learning experiences. There is therefore a need to better understand these effects not only from the student's perspective but also from the perspective of the staff who supervise them, in order to ensure students obtain maximal benefit from their placements. AIM: To describe the clinical experiences of nursing students and the diversity characteristics that affect this learning experience. METHODS: Data were collected from a series of open ended questions embedded within a larger anonymous web-based survey, from August 2011 to March 2012. Participants included first, second and third year undergraduate Bachelor of Nursing students (N = 704) and faculty members involved in the clinical learning environment (N = 165) from seven Australian universities. FINDINGS: Qualitative findings were clustered into three main themes: differences, difficulty and discrimination, each with three sub-themes. CONCLUSION: FINDINGS suggest a need to offer appropriate support for nursing students who feel different because of diversity characteristics. Whilst some of the participant perceptions are confronting they provide valuable insights for universities developing curricula and the clinical placement facilities where students obtain their experience. PMID- 25549741 TI - A regional approach to the education of nurse practitioner candidates to meet the health needs of rural Australians. AB - BACKGROUND: Local health services expressed interest in supporting a nurse practitioner (NP) program specifically designed for rural practice environments. AIM: To develop and deliver a generalist NP program that prepares candidates for practice in rural contexts. METHODS: The Master of Clinical Nursing (Nurse Practitioner) program was designed with an understanding of the burden of disease impacting on rural Australians, application of the national health priorities, the Australian Government's refocus on preventative health care and rural health workforce shortages. RESULTS: This program offers nurses who work in rural and remote settings an opportunity to advance their careers. Increasing the numbers of rural NPs will improve rural populations access to healthcare and potentially improve health outcomes. CONCLUSION: This program will equip those seeking endorsement as a NP to effectively work in rural contexts. PMID- 25549742 TI - Childhood fever management program for Korean pediatric nurses: A comparison between blended and face-to-face learning method. AB - BACKGROUND: A blended learning can be a useful learning strategy to improve the quality of fever and fever management education for pediatric nurses. AIM: This study compared the effects of a blended and face-to-face learning program on pediatric nurses' childhood fever management, using theory of planned behavior. METHODS/DESIGN: A nonequivalent control group pretest-posttest design was used. A fever management education program using blended learning (combining face-to-face and online learning components) was offered to 30 pediatric nurses, and 29 pediatric nurses received face-to-face education. RESULTS/FINDINGS: Learning outcomes did not significantly differ between the two groups. However, learners' satisfaction was higher for the blended learning program than the face-to-face learning program. CONCLUSION: A blended learning pediatric fever management program was as effective as a traditional face-to-face learning program. Therefore, a blended learning pediatric fever management-learning program could be a useful and flexible learning method for pediatric nurses. PMID- 25549743 TI - Editorial: Nurse education: Meeting the needs of people with intellectual disabilities? AB - Abstract PMID- 25549744 TI - Nursing clinical handover in neonatal care. AB - BACKGROUND: Clinical handover ensures continuity of care, providing the opportunity to transfer responsibility and accountability for the care of a patient from nurse to nurse. AIM: The aim of this study was to examine afternoon nursing clinical handover from the perspective of nurses, exploring the quality of information, the interactions and support, the efficiency and the involvement of parents in a private neonatal unit. METHODS/DESIGN: An exploratory, descriptive, prospective quantitative survey with qualitative elements was undertaken using The Handover Evaluation Scale (O'Connell, MacDonald, & Kelly, 2008). All nurses working in the Neonatal unit who attend afternoon handover, were invited to participate in the study (N = 22), with N = 16 responses received. RESULTS/FINDINGS: The quantitative and qualitative results indicate that the quality of the information handed over in neonatal care units can be maintained despite intrinsic limitations. Additionally, high levels of support and interaction between nursing staff in this stressful practice environment occur during the handover period. CONCLUSION: Given the vulnerability of neonates it is important that accurate information is efficiently handed over. In order to do this distractions should be minimised. Finally, parental involvement in handover should be actively encouraged whenever feasible. PMID- 25549745 TI - Psychological determinants of exercise behavior of nursing students. AB - BACKGROUND: Though expected to be role models in health promotion, research has shown that nursing students often have suboptimal exercise behavior. AIM: This study explored the psychological factors associated with the exercise behavior of nursing students. METHODS/DESIGN: A total of 195 first-year undergraduate nursing students completed a cross-sectional quantitative survey questionnaire, which included measures of their exercise behavior, the Physical Exercise Self-efficacy Scale, and the Exercise Barriers/Benefits Scale. RESULTS/FINDINGS: The results showed that male students spent more time exercising and had higher exercise self efficacy compared with female students, but there were no gender differences in the perceived barriers to or benefits of exercise. Fatigue brought on by exercising was the greatest perceived barrier to exercise, whereas increasing physical fitness and mental health were the greatest perceived benefits of exercise. Multiple linear regression showed that gender, exercise self-efficacy, perceived barriers to exercise, and perceived benefits of exercise were independent predictors of exercise behavior. CONCLUSION: Nurse educators can endeavor to promote exercise behavior among nursing students by highlighting the specific benefits of exercise, empowering students to overcome their perceived barriers to exercise, and enhancing students' exercise self-efficacy. PMID- 25549746 TI - Preparing nursing students for the future: Development and implementation of an Australian Bachelor of Nursing programme with a community health focus. AB - This paper focuses on changes in the educational preparation of undergraduate nurses in line with contemporary primary and preventative healthcare models. We evaluated a new Australian nursing and community care degree programme using focus groups with 38 students in their first years of study, and quantitative performance data (regarding entry, performance and course attrition). Four main themes were identified related to students' course experience: 'I think community health should be an elective'; 'Focus on relevance to practice'; 'Teaching by non nursing academics' and 'Access to support during transition to university.' Overall pass rates were 94% (first year) and 97% (second year) with a low 11% attrition rate. We conclude that based on prior experiences and stereotypical views, students may be ambivalent about the inclusion of primary and preventative care models which nevertheless are essential to enhance practice and to prepare the future nursing workforce. PMID- 25549747 TI - Pressure injury prevention success in a regional hospital. AB - BACKGROUND: This paper describes quality improvement strategies implemented following the identification of a significantly high prevalence rate and severity of pressure injuries in a regional health care facility in a large health district in Queensland, Australia. AIM: The aim of this paper is to inform health professionals of processes employed to reduce the incidence and financial burden of pressure injuries following the detection of rates that were significantly above the State average. METHOD: An audit of pressure injury prevalence data was conducted on a single day throughout a regional hospital. Prevalence data was compared to State averages and hospital strategies used to prevent injuries were examined. FINDINGS: Audit reports for this acute setting revealed that despite best practice guidelines, prevalence was a major concern. Lack of accountability, poor documentation, limited education and knowledge of risk assessment and prevention were central to the need to implement quality improvement processes. CONCLUSION: This paper outlines the results associated with implementing quality measures to reduce the prevalence of pressure injuries. Following an audit of pressure injury prevalence data, strategies were implemented to reduce noteworthy rates. Employing specific techniques can result in significantly decreasing hospital acquired pressure injuries in health care settings throughout the world. PMID- 25549748 TI - Putting it into practice: Infection control professionals' perspectives on early career nursing graduates' microbiology and infection control knowledge and practice. AB - BACKGROUND: The microbiology component of Australian undergraduate nursing programmes varies considerably. Any actual or potential impact of this variation on infection control practice, as a nursing graduate, is relatively unknown. AIMS: The aim of this study was to explore infection control professionals' perceptions of the importance of microbiology and infection control training in undergraduate nursing curricula and the perceived retention of that knowledge and its transferability to practice. METHOD: Semi-structured interviews were conducted with eight infection control professionals from a range of hospital settings in Australia. FINDINGS: Four main themes emerged: Theory versus practice, importance of role modelling, disjunction between university curricula and 'the real world,' and learning in context. CONCLUSION: As the underpinning element of infection control practice, the role of microbiology education and training in nursing education will benefit from review. Further discussions about the nature and timing of theoretical microbiology content and assessment of undergraduate students' microbiology knowledge to ensure retention and appropriate application of that knowledge in practice are urgently needed. PMID- 25549749 TI - Editorial: Above all, 'do no harm': Key considerations when including students as research participants in higher education settings. AB - Abstract PMID- 25549750 TI - A study of nursing competency, career self-efficacy and professional commitment among nurses in Taiwan. AB - BACKGROUND: Professional commitment, maintaining nursing competency, and improving self-efficacy could be necessary to enhance the quality of care service in Taiwan. AIM: The purpose of this study was to investigate the relationships among nursing competency, career self-efficacy, and professional commitment in hospital nurses. METHODS/DESIGN: We used a stratified cluster random sampling method for the selection. To take 762 nurses with work experience of more than 6 months were selected from 2 regional hospitals and 3 district hospitals in Taiwan. The nurses answered a self-report questionnaire, which was categorized into four sections: Personal background data, nursing competency, career self efficacy, and professional commitment. RESULTS/FINDINGS: The results indicate that nursing competency and career self-efficacy of nurses were at a high level, whereas professional commitment was at a medium level. Nursing competency, career self-efficacy, and professional commitment were significantly positively correlated. CONCLUSION: The career self-efficacy and professional commitment of medical and nursing personnel can help to increase nursing competency and to improve the quality of medical and nursing care. PMID- 25549751 TI - Constructing a nursing identity within the clinical environment: The student nurse experience. AB - BACKGROUND: Nursing identity is an important element of being a nurse. Student nurses begin the construction of their nursing identity during their clinical placements. AIM: The aim of this research was to examine how the student nurses of a regional Australian university construct their identity when on off-campus clinical placement. METHODS/DESIGN: Using a constructivist approach an online survey was used to elicit data in response to the question 'What elements are needed during the work integrated learning experience to enable undergraduate nursing students to construct their nursing identity?' RESULTS/FINDINGS: Findings reveal five key elements to the construction of students' nursing identity; positive role models, belonging, peer support, critical thinking abilities and confidence. CONCLUSION: Such findings are important as they provide information for student nurses, preceptors and educators in guiding clinical placement experiences that are able to facilitate the development of the nursing identity. PMID- 25549752 TI - Prevalence and characteristics of aggression and violence experienced by Western Australian nursing students during clinical practice. AB - AIM: To identify the prevalence and characteristics of aggression and violence experienced by undergraduate nursing students in the clinical setting. METHOD: A cross sectional survey of second (N = 97) and third (N = 56) year nursing students in a Western Australian University was conducted. Data were analysed using frequencies, percentages and means (standard deviation) and independent samples t-test for between group differences. RESULTS: Over 58% (N = 55) of second year and 57% (N = 32) of third year nursing students experienced some kind of non-physical violence. Various forms of physical violence were also reported by over a third (N = 33) of the second year and 25% (N = 18) of the third year nursing students. CONCLUSION: This study has identified nursing students are exposed to, and feel at significant risk of, aggression and violence in the clinical setting. Providing them with an appropriate level of knowledge and self confidence to assist in the management of the threat and actuality of such incidents is essential. PMID- 25549753 TI - What really matters? A multi-view perspective of one patient's hospital experience. AB - BACKGROUND: 'Patient experience' is both recognised and solicited as a means of assessing healthcare delivery and a method for gauging patient centredness. Research comparing healthcare recipient and provider perceptions regarding the same episode of care is lacking. AIM: To identify what mattered to a patient and family member (healthcare recipients) during the patient's hospital experience and to examine the healthcare provider's awareness of what mattered. METHODS: A qualitative descriptive investigation was undertaken using semi-structured interviews designed to compare multiple perceptions of one patient's hospital experience. Interviews were undertaken with the patient, family member, and healthcare providers. A definition of hospital experience was sought from each participant. Additional phrases as presented by the patient and family member were coded and grouped into categories and then salient themes. Phrases as presented by the healthcare providers were coded, and then allocated to the previously identified themes. FINDINGS: One patient, his wife and seven healthcare providers (doctors (2), registered nurses (4) and a patient care orderly (1)) were interviewed. Definitions of 'hospital experience' differ between participants. Recipients include pre and post hospital admission periods, whereas providers limit hospital experience to admission. Three salient themes emerged from recipient data suggesting; medication management, physical comfort and emotional security are what mattered to the recipients. Awareness was dependent upon theme and differed between the providers. CONCLUSION: Hospital experience as a term is poorly defined, and definitions differ between recipients and providers of care. Healthcare providers are not always aware of what matters to the patient and family during their hospital admission. PMID- 25549754 TI - Dexamethasone reduces nausea and vomiting but not pain after thyroid surgery: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after thyroidectomy. The aim of this article was to evaluate the efficacy of dexamethasone for prevention of PONV and pain in patients undergoing thyroidectomy. MATERIAL AND METHODS: We performed this meta-analysis based on the QUORUM (Quality of Reporting of Meta-analyses) guidelines. Our study included randomized controlled trials (RCTs) that compared preoperative single-dose administration of dexamethasone with no dexamethasone in patients undergoing thyroidectomy. The primary outcome was occurrence and severity of PONV, and the secondary outcomes included pain, use of analgesics, and steroid-related complications. RESULTS: Seven RCTs were included, with a total of 611 patients. A statistically and clinically significant difference in the incidence and severity of PONV was found in favor of dexamethasone (SMD, 0.23; 95% CI, 0.13-0.41; P<0.00001; SMD, 0.53; 95% CI, -1.03 to -0.03; P=0.04). However, there was no significant difference in reduction of pain severity and analgesic consumption in using dexamethasone (SMD, -0.83; 95% CI, -1.85 to 0.18; P=0.14; SMD, -0.19; 95% CI, -0.43 to 0.04; P=0.10). No steroid-related complications were noted. CONCLUSIONS: A single preoperative administration of dexamethasone reduced the incidence and severity of PONV but not pain severity and analgesic consumption in patients undergoing thyroidectomy. Further studies with a larger sample size are needed to further explore the efficacy of dexamethasone on postoperative pain severity and analgesic consumption. PMID- 25549755 TI - Comparison of Pipelle sampler with conventional dilatation and curettage (D&C) for Chinese endometrial biopsy. AB - The aim of this study is to investigate the accuracy and adequacy of the Pipelle endometrial sampler for endometrial biopsy as compared with those of conventional dilatation and curettage (D&C). A total of 245 patients subject to endometrial biopsy were included in this study. We have shown that the failure rates with D&C and Pipelle were 7.75% and 8.98%, respectively, without statistical difference. Additionally, the obtained specimen quality and accurate diagnosis of various diseases using the two methods had no significant statistical differences. Furthermore, patients experienced less pain when Pipelle sampler was used than D&C. Therefore, Pipelle sampler is effective in obtaining adequate endometrial tissue for histodiagnosis, and is applicable in most of the cases for Chinese endometrial biopsy. PMID- 25549756 TI - Ruthenium-catalyzed reductive amination without an external hydrogen source. AB - A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008-2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten. PMID- 25549757 TI - Comparative lipidomic profiling of two Dunaliella tertiolecta strains with different growth temperatures under nitrate-deficient conditions. AB - The metabolic changes that occur in Dunaliella tertiolecta upon exposure to low temperatures and nitrate deficiency were analyzed by exploring the fatty acid composition and lipid profile of two strains that were acclimated to different temperatures. The results indicate that the levels of linolenic acid (C18:3) and diacylglyceryl-N,N,N-trimethylhomoserine (DGTS) were significantly higher in the low-temperature (15 degrees C) strain (SCCAP K-0591) than in a strain grown at 21 degrees C (UTEX LB999). In addition, DGTS accumulated in LB999 under nitrate deficient conditions, while the levels of most lipids, including DGTS, remained almost consistent in K-0591. The higher levels of DGTS in K-0591 suggest that DGTS could play a role in adaptation to low temperatures and nitrate deficiency in this organism. The results of this research could be applied to the development of new microalgal strains with tolerance of low temperature and nitrate deficiency by metabolic engineering targeted to DGTS species. PMID- 25549758 TI - Development of a two-step indirect method for modeling Ecom50. AB - A novel approach is developed for modeling situations in which the modeled property is an algebraically transformed version of the original experimental data. In many cases such a transformation results in a data set with a significantly smaller data range. Here we explore the effects of range-of-data on modeling statistics. We illustrate a twostep method using data on the mass spectrometry collision energy (CE) that is required to decompose 50% of precursor ions to fragments (CE50). Earlier we showed that a nonlinear center-of-mass transformation, yielding Ecom50, produces values less dependent on the specific mass spectrometric experimental conditions. For this data set the Ecom50 range is 13.5% of the CE50 range. We propose a two-step modeling method. First, the original experimental data, CE50, (larger range-of-data) is modeled by a standard modeling method (PLS). Second, the calculated dependent variable resulting from the modeling is algebraically transformed (not modeled) according to the center of-mass transformation, providing the generally more useful data, Ecom50. As shown here, use of this two-step method for predicting Ecom50 (from previously published data) produces a standard error 21% smaller and correspondingly reduces the confidence interval for prediction. Some specific implications for prediction are given for a published data set. This work is part of the ongoing development of a system of models to assist in the development of human metabolites. PMID- 25549759 TI - Physical regulation of stem cells differentiation into teno-lineage: current strategies and future direction. AB - Tendon injuries are commonly encountered in the clinic, disrupting the patient's normal work/life routine and damaging the career life of athletes. Currently, there is still no effective treatment for tendon injury. Tendon tissue engineering appears to be a promising route for tendon repair and regeneration. However, current strategies utilized in research are still far away from clinical applications due to unsuccessful cellular differentiation to tendon/tenocytes. In this review, we focus on the current physical strategies (mechanical stimulation and extracellular matrix topography) and evaluate their roles in precise and stepwise tendon differentiation. A systematic comprehension of normal tendon development process by structure, gene profile and physical microenvironment analysis is likely suggestive for stepwise tenocyte differentiation. PMID- 25549760 TI - Urothelial carcinoma in bladder diverticula: outcomes after radical cystectomy. AB - PURPOSE: To characterize the clinical and pathologic staging of patients with urothelial carcinoma (UC) in bladder diverticula (BD) after undergoing radical cystectomy (RC) and determine the impact of UCBD on recurrence and survival. METHODS: We reviewed our institutional database of patients who underwent RC for UC (1971-2009). Outcomes were compared between patients with and without UCBD. Kaplan-Meier curves estimated recurrence-free survival (RFS) and overall survival (OS). Multivariable Cox regression evaluated associations between UCBD and survival. RESULTS: Inclusion criteria were met in 1991 patients. UCBD was seen in 77 (4 %) patients and occurred exclusively in men (mean age 68 +/- 8.5 years). The highest pathologic stage tumor was found in the BD in 44 (57 %) of these patients. Pathologic upstaging was more common with UCBD compared with UC not in BD (48 vs. 39 %, p = 0.031). On univariate analysis, no differences in RFS or OS were observed comparing patients with or without UCBD stratified by clinically organ-confined (<=T2) and extravesical (>T2) disease. On multivariable analysis, the presence of UCBD was not associated with differences in RFS (HR 0.92, 95 % CI 0.59-1.42, p = 0.69) or OS (HR 0.98, 95 % CI 0.74-1.31, p = 0.92). CONCLUSION: Upstaging was common in patients with UCBD, observed in almost half of the patients. There were no differences in RFS or OS after RC when comparing patients with or without UC in a diverticulum stratified by stage. PMID- 25549761 TI - The interaction between medical burden and anticholinergic cognitive burden on neuropsychological function in a geriatric primary care sample. AB - Poorer neuropsychological function is associated with increased medical burden (MB) and the use of more anticholinergic medications. However, the interaction between MB and anticholinergic cognitive burden (AB) on neuropsychological performance is unknown. In a sample of 290 elderly primary care patients, those with a greater level of AB demonstrated poorer Total Index performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Further, an interaction effect was noted such that there was a greater anticholinergic effect on RBANS Total, Attention, and Delayed Memory Index scores for participants with fewer MB. Participants with more MB demonstrated poorer performance irrespective of their level of AB. These results indicate that MB effects may be overshadowed by anticholinergic effects in older patients. PMID- 25549763 TI - Intermittent hypoxia: a low-risk research tool with therapeutic value in humans. AB - Intermittent hypoxia has generally been perceived as a high-risk stimulus, particularly in the field of sleep medicine, because it is thought to initiate detrimental cardiovascular, respiratory, cognitive, and metabolic outcomes. In contrast, the link between intermittent hypoxia and beneficial outcomes has received less attention, perhaps because it is not universally understood that outcome measures following exposure to intermittent hypoxia may be linked to the administered dose. The present review is designed to emphasize the less recognized beneficial outcomes associated with intermittent hypoxia. The review will consider the role intermittent hypoxia has in cardiovascular and autonomic adaptations, respiratory motor plasticity, and cognitive function. Each section will highlight the literature that contributed to the belief that intermittent hypoxia leads primarily to detrimental outcomes. The second segment of each section will consider the possible risks associated with experimentally rather than naturally induced intermittent hypoxia. Finally, the body of literature indicating that intermittent hypoxia initiates primarily beneficial outcomes will be considered. The overarching theme of the review is that the use of intermittent hypoxia in research investigations, coupled with reasonable safeguards, should be encouraged because of the potential benefits linked to the administration of a variety of low-risk intermittent hypoxia protocols. PMID- 25549762 TI - Very long apnea events in preterm infants. AB - Apnea is nearly universal among very low birth weight (VLBW) infants, and the associated bradycardia and desaturation may have detrimental consequences. We describe here very long (>60 s) central apnea events (VLAs) with bradycardia and desaturation, discovered using a computerized detection system applied to our database of over 100 infant years of electronic signals. Eighty-six VLAs occurred in 29 out of 335 VLBW infants. Eighteen of the 29 infants had a clinical event or condition possibly related to the VLA. Most VLAs occurred while infants were on nasal continuous positive airway pressure, supplemental oxygen, and caffeine. Apnea alarms on the bedside monitor activated in 66% of events, on average 28 s after cessation of breathing. Bradycardia alarms activated late, on average 64 s after cessation of breathing. Before VLAs oxygen saturation was unusually high, and during VLAs oxygen saturation and heart rate fell unusually slowly. We give measures of the relative severity of VLAs and theoretical calculations that describe the rate of decrease of oxygen saturation. A clinical conclusion is that very long apnea (VLA) events with bradycardia and desaturation are not rare. Apnea alarms failed to activate for about one-third of VLAs. It appears that neonatal intensive care unit (NICU) personnel respond quickly to bradycardia alarms but not consistently to apnea alarms. We speculate that more reliable apnea detection systems would improve patient safety in the NICU. A physiological conclusion is that the slow decrease of oxygen saturation is consistent with a physiological model based on assumed high values of initial oxygen saturation. PMID- 25549764 TI - No redistribution of lung blood flow by inhaled nitric oxide in endotoxemic piglets pretreated with an endothelin receptor antagonist. AB - Inhaled nitric oxide (INO) improves ventilation-perfusion matching and alleviates pulmonary hypertension in patients with acute respiratory distress syndrome. However, outcome has not yet been shown to improve, and nonresponse is common. A better understanding of the mechanisms by which INO acts may guide in improving treatment with INO in patients with severe respiratory failure. We hypothesized that INO may act not only by vasodilation in ventilated lung regions, but also by causing vasoconstriction via endothelin (ET-1) in atelectatic, nonventilated lung regions. This was studied in 30 anesthetized, mechanically ventilated piglets. The fall in oxygenation and rise in pulmonary artery pressure during a sepsislike condition (infusion of endotoxin) were blunted by INO 40 ppm. Endotoxin infusion increased serum ET-1, and INO almost doubled the ratio between mRNA expression of endothelin receptor A (mediating vasoconstriction) and B (mediating vasodilation and clearance of ET-1) (ET-A/ET-B) in atelectatic lung regions. INO caused a shift in blood flow away from atelectatic lung regions in the endotoxemic piglets, but not during ET receptor antagonism. We conclude that INO in short term experiments, in addition to causing selective pulmonary vasodilation in ventilated lung regions, increases the ET-A/ET-B mRNA expression ratio in lung tissue. This might augment the vasoconstriction in atelectatic lung regions, enhancing the redistribution of pulmonary blood flow to ventilated lung regions which are reached by INO. Such vasoconstriction may be an important additional factor explaining the effect of INO. PMID- 25549765 TI - Impact of training status on LPS-induced acute inflammation in humans. AB - The aim of the present study was to examine the impact of training status on the ability to induce a lipopolysaccharide (LPS)-induced inflammatory response systemically as well as in skeletal muscle (SkM) and adipose tissue (AT) in human subjects. Seventeen young (23.8 +/- 2.5 yr of age) healthy male subjects were included in the study with eight subjects assigned to a trained (T) group and nine subjects assigned to an untrained (UT) group. On the experimental day, catheters were inserted in the femoral artery and vein of one leg for blood sampling and a bolus of 0.3 ng LPS/kg body wt was injected into an antecubital vein in the forearm. Femoral arterial blood flow was measured by ultrasound Doppler, and arterial and venous blood samples were drawn before (Pre) LPS injection and 30, 60, 90, and 120 min after the LPS injection. Vastus lateralis muscle and abdominal subcutaneous AT biopsies were obtained Pre and 60 and 120 min after the LPS injection. LPS increased the systemic plasma TNFalpha and IL-6 level as well as the TNFalpha and IL-6 mRNA content in SkM and AT of both UT and T. However, whereas the LPS-induced inflammatory response in SkM was enhanced in T subjects relative to UT, the inflammatory response systemically and in AT was somewhat delayed in T subjects relative to UT. The present findings highlight that training status affects the ability to induce a LPS-induced acute inflammatory response in a tissue-specific manner. PMID- 25549766 TI - Is FEV1 determined in a plethysmograph a better indication of obstructive lung disease than FEV1 determined by a spirometer? PMID- 25549767 TI - Two novel CBTs for adolescents with ADHD: the value of planning skills. AB - Adolescents with ADHD have planning problems, often affecting school- and social functioning. Evidence-based treatments for adolescents with ADHD are scarce and treatment drop-out rates are substantial. The effectiveness of two new, individual, short-term cognitive behavioral therapies (CBT) was investigated: One with an aim on improving planning skills and one solution-focused treatment (SFT) without such an aim. Motivational Interviewing elements were added to both treatments to enhance treatment compliance. In a multi-center randomized clinical trial, 159 adolescents (12-17 years) with ADHD were randomly assigned to one of both treatments. Pre-, post- and 3-month follow-up data were gathered on five domains: Parent-rated ADHD, planning problems and executive functioning (primary outcomes), neuropsychological measures of planning, comorbid symptoms, general functioning, and teacher measures. Attrition was low in both treatments (5%). Adolescents improved significantly between pre- and post-test with large effect sizes on all domains. Improvements remained stable or continued to improve from post-test to follow-up, also when controlling for medication use. Marginally significant differences were found in favor of the planning-focused treatment: parents and therapists evaluated this treatment more positively than SFT and the planning-focused treatment showed more reduction of parent-rated planning problems. Two new CBTs with integrated motivational components were feasible and attrition was low. ADHD symptoms and co-existing problems of the adolescents improved from pre-test to 3 months after treatment. As the planning-focused treatment was evaluated more positive and had marginal additional beneficial effects to SFT, especially planning-focused CBT seems promising to fill the gap in available treatments for adolescents with ADHD. PMID- 25549768 TI - Less postoperative pain after laparoscopic hysterectomy than after vaginal hysterectomy. AB - PURPOSE: To find out whether the severity of acute postoperative pain differs between laparoscopic (LH) or laparoscopically assisted vaginal hysterectomy (LAVH) and vaginal hysterectomy. METHODS: In a prospective, powered, non randomized trial, the consumption of oxycodone and pain scores were evaluated in 164 women up to 20 h after VH or LH/LAVH. All hysterectomies were performed under standardized general anesthesia and the pain medication was similar in both groups. The primary endpoint was the cumulative oxycodone consumed. Main secondary endpoints were pain scores (numeric rating scale NRS), operative time and hospital stay. RESULTS: The patients in LH/LAHV group consumed less opioid than the patients in the vaginal group during the 20 h period after surgery. The difference was significant at time point 4 and 6 h. The oxycodone consumed at time point 4 h was 19.9 (95 % CI 18.1-21.7) mg in laparoscopic group and 22.8 (20.7-25.0) mg in vaginal group (p = 0.040) and at time point 6 h was 23.5 (21.5 25.6) mg in laparoscopic group and 27.4 (24.7-30.0) mg in vaginal group (p = 0.026). Pain scores were lower after laparoscopic approach and the difference was significant at time point 60 min after surgery (p = 0.026). CONCLUSION: In this study, LH was associated with reduced need of analgesics and lower acute postoperative pain scores than VH. PMID- 25549769 TI - Tumor size is an independent predictor of lymph node metastasis and survival in early stage endometrioid endometrial cancer. AB - OBJECTIVE(S): To analyze the impact of tumor size (TS) on risk of lymph node metastasis (PLN) and prognosis in endometrioid endometrial cancer grossly confined to the uterus (EEC). METHOD(S): Patients with EEC grossly confined to the uterus were identified from Surveillance, Epidemiology, and End Results dataset from 1988 to 2007. Only surgically treated patients were included. TS was analyzed as a continuous and categorical variable (TS <= 2 cm, >2-5 cm and >5 cm). Multivariable logistic regression and Cox proportional hazards models were used. RESULT(S): 19,692 patients met the inclusion criteria. In patients with TS <= 2 cm, only 2.7 % (88/3,244) had PLN; this increased to 5.8 % (372/6,355) with TS > 2-5 cm and 11.1 % (195/1,745) with TS > 5 cm. The odds of PLN increased by 14 % for each 1 cm increase in TS after controlling for age, race, depth of myometrial invasion and grade (HR 1.14, 95 % CI 1.10-1.19, p < 0.001). Further, TS was an independent predictor of disease-specific survival (DSS) even after adjusting for age, race, grade, depth of myometrial invasion, lymph node status and adjuvant radiation therapy (HR 1.13 for each 1 cm increment in TS, 95 % 1.08 1.18, p < 0.001). In multivariable analysis, larger TS (>5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31-3.35, p = 0.002); however, there was no significant difference between TS > 2-5 cm versus <=2 cm (HR 1.25, 95 % 0.85-1.83, p = 0.25). The impact of TS remained significant on DSS in subset of patients who underwent lymphadenectomy with negative lymph nodes. CONCLUSION(S): TS was an independent predictor of lymph node metastasis and disease-specific survival in patients with EEC grossly confined to the uterus. Tumor >5 cm was a predictor of disease-specific survival but no difference in outcome was noted between tumor >2-5 cm and tumor <=2 cm. PMID- 25549770 TI - Perceptions of QOL among caregivers of Mexican ancestry of adults with advanced cancer. AB - PURPOSE: There is a substantial gap in the literature about the perceptions of QOL of caregivers of Mexican ancestry. This qualitative study explores the role of culture on the perceptions of QOL of this understudied population. METHODS: Twenty caregivers providing care to adults with advanced cancer were interviewed. Thematic analysis identified several themes for each domain of QOL, including physical, psychological, social, and spiritual domains and the role of culture. RESULTS: Cultural background influenced all of the QOL domains. There was a tremendous synergy across domains of physical, psychological, social, and spiritual well-being. Extended family and religious beliefs, life experiences, and culture were important components of QOL for these caregivers. Cultural expectations influenced role functioning and caregiver burden. CONCLUSION: This study informs our understanding of the role of culture on perceptions of QOL. Future investigations should be conducted with other Latino subgroups to describe QOL and to determine the role of culture on perceived QOL. Interventions should be specifically designed to improve caregivers' QOL and to reduce the burden of cancer in this underserved population. PMID- 25549771 TI - Modeling Cerebral Blood Flow Velocity During Orthostatic Stress. AB - Cerebral autoregulation refers to the physiological process that maintains stable cerebral blood flow (CBF) during changes in arterial blood pressure (ABP). In this study, we propose a simple, nonlinear quantitative model with only four parameters that can predict CBF velocity as a function of ABP. The model was motivated by the viscoelastic-like behavior observed in the data collected during postural change from sitting to standing. Qualitative testing of the model involved analysis of dynamic responses to step-changes in pressure both within and outside the autoregulatory range, while quantitative testing was used to show that the model can fit dynamics observed in data measured from a healthy young and a healthy elderly subject. The latter involved analysis of structural and practical identifiability, sensitivity analysis, and parameter estimation. Results showed that the model is able to reproduce observed overshoot and adaptation and predict the different responses in the healthy young and the healthy elderly subject. For the healthy young subject, the overshoot was significantly more pronounced than for the elderly subject, but the recovery time was longer for the young subject. These differences resulted in different parameter values estimated using the two datasets. PMID- 25549772 TI - Repairing Fetal Membranes with a Self-adhesive Ultrathin Polymeric Film: Evaluation in Mid-gestational Rabbit Model. AB - Preterm premature rupture of membranes causes 40% of all preterm births, affecting 150000 women each year in the United States. Prenatal diagnostic procedures and surgical interventions increase incidence of adverse events, leading to iatrogenic membrane rupture after a fetoscopic procedure in 45% of cases. We propose an ultrathin, self-adherent, poly-L-lactic acid patch ("nanofilm") as a reparative wound closure after endoscopic/fetoscopic procedures. These nanofilms are compatible with application in wet conditions and with minimally invasive instrumentation. Ex vivo studies to evaluate the nanofilm were conducted using human chorion-amnion (CA) membranes. A custom-built inflation device was used for mechanical characterization of CA membranes and for assessment of nanofilm adhesion and sealing of membrane defects up to 3 mm in size. These ex vivo tests demonstrated the ability of the nanofilm to seal human CA defects ranging in size from 1 to 3 mm in diameter. In vivo survival studies were conducted in 25 mid-gestational rabbits, defects were created by perforating the uterus and the CA membranes and subsequently using the nanofilm to seal these wounds. These in vivo studies confirmed the successful sealing of defects smaller than 3 mm observed ex vivo. Histological analysis of whole harvested uteri 7 days after surgery showed intact uterine walls in 59% of the nanofilm repaired fetuses, along with increased uterine size and intrauterine development in 63% of the cases. In summary, we have developed an ultrathin, self-adhesive nanofilm for repair of uterine membrane defects. PMID- 25549773 TI - Biocompatible Optically Transparent MEMS for Micromechanical Stimulation and Multimodal Imaging of Living Cells. AB - Cells and tissues in our body are continuously subjected to mechanical stress. Mechanical stimuli, such as tensile and contractile forces, and shear stress, elicit cellular responses, including gene and protein alterations that determine key behaviors, including proliferation, differentiation, migration, and adhesion. Several tools and techniques have been developed to study these mechanobiological phenomena, including micro-electro-mechanical systems (MEMS). MEMS provide a platform for nano-to-microscale mechanical stimulation of biological samples and quantitative analysis of their biomechanical responses. However, current devices are limited in their capability to perform single cell micromechanical stimulations as well as correlating their structural phenotype by imaging techniques simultaneously. In this study, a biocompatible and optically transparent MEMS for single cell mechanobiological studies is reported. A silicon nitride microfabricated device is designed to perform uniaxial tensile deformation of single cells and tissue. Optical transparency and open architecture of the device allows coupling of the MEMS to structural and biophysical assays, including optical microscopy techniques and atomic force microscopy (AFM). We demonstrate the design, fabrication, testing, biocompatibility and multimodal imaging with optical and AFM techniques, providing a proof-of-concept for a multimodal MEMS. The integrated multimodal system would allow simultaneous controlled mechanical stimulation of single cells and correlate cellular response. PMID- 25549774 TI - Validity and Reliability of Gait and Postural Control Analysis Using the Tri axial Accelerometer of the iPod Touch. AB - Accelerometer-based assessments can identify elderly with an increased fall risk and monitor interventions. Smart devices, like the iPod Touch, with built-in accelerometers are promising for clinical gait and posture assessments due to easy use and cost-effectiveness. The aim of the present study was to establish the validity and reliability of the iPod Touch for gait and posture assessment. Sixty healthy participants (aged 18-75 years) were measured with an iPod Touch and stand-alone accelerometer while they walked under single- and dual-task conditions, and while standing in parallel and semi-tandem stance with eyes open, eyes closed and when performing a dual task. Cross-correlation values (CCV) showed high correspondence of anterior-posterior and medio-lateral signal patterns (CCV's >= 0.88). Validity of gait parameters (foot contacts, index of harmonicity, and amplitude variability) and standing posture parameters [root mean square of accelerations, median power frequency (MPF) and sway area] as indicated by intra-class correlation (ICC) was high (ICC = 0.85-0.99) and test retest reliability was good (ICC = 0.81-0.97), except for MPF (ICC = 0.59-0.87). Overall, the iPod Touch obtained valid and reliable measures of gait and postural control in healthy adults of all ages under different conditions. Additionally, smart devices have the potential to be used for clinical gait and posture assessments. PMID- 25549775 TI - pyNS: an open-source framework for 0D haemodynamic modelling. AB - A number of computational approaches have been proposed for the simulation of haemodynamics and vascular wall dynamics in complex vascular networks. Among them, 0D pulse wave propagation methods allow to efficiently model flow and pressure distributions and wall displacements throughout vascular networks at low computational costs. Although several techniques are documented in literature, the availability of open-source computational tools is still limited. We here present python Network Solver, a modular solver framework for 0D problems released under a BSD license as part of the archToolkit ( http://archtk.github.com ). As an application, we describe patient-specific models of the systemic circulation and detailed upper extremity for use in the prediction of maturation after surgical creation of vascular access for haemodialysis. PMID- 25549776 TI - Effects of Polypropylene Carbonate/Poly(D,L-lactic) Acid/Tricalcium Phosphate Elastic Composites on Improving Osteoblast Maturation. AB - Bone tissue engineering utilizing biomaterials to improve osteoblast growth has provided de novo consideration for therapy of bone diseases. Polypropylene carbonate (PPC) is a polymer with a low glass transition temperature but high elasticity. In this study, we developed a new PPC-derived composite by mixing poly-lactic acid (PLA) and tricalcium phosphate (TCP), called PPC/PLA/TCP elastic (PPTE) scaffolds. We also evaluated the beneficial effects of PPTE composites on osteoblast growth and maturation and the possible mechanisms. Compared to PPC polymers, PPTE composites had similar pore sizes and porosities but possessed better hydrophilic surface structures. Biological evaluations further revealed that PPTE composites attracted adhesion of mouse osteoblasts, and these bone cells extended along the porous scaffolds to produce accurate fibroblast-like morphologies. In parallel, seeding mouse osteoblasts onto PPTE composites time dependently increased cell growth. Sequentially, PPTE composites augmented DNA replication and cell proliferation. Consequently, PPTE composites significantly improved osteoblast mineralization. As to the mechanism, treatment with PPTE composites induced osteopontin (OPN) mRNA and protein expression and alkaline phosphatase activity. Taken together, this study showed that PPTE composites with porous and hydrophilic surfaces can stimulate osteoblast adhesion, proliferation, and maturation through an OPN-dependent mechanism. Therefore, the de novo PPTE scaffolds may have biomaterial potential for bone regeneration. PMID- 25549777 TI - Automatic Classification and Quantification of Cell Adhesion Locations on the Endothelium. AB - To target tumor hematogenous metastasis and to understand how leukocytes cross the microvessel wall to perform immune functions, it is necessary to elucidate the adhesion location and transmigration pathway of tumor cells and leukocytes on/across the endothelial cells forming the microvessel wall. We developed an algorithm to classify and quantify cell adhesion locations from photomicrographs taken from the experiments of tumor cell/leukocyte adhesion in individual microvessels. The first step is to identify the microvessel by a novel gravity field dynamic programming (DP) procedure. Next, an anisotropic image smoothing suppresses noises without unduly mitigating crucial visual features. After an adaptive thresholding process further tackles uneven lighting conditions during the imaging process, a series of local mathematical morphological operators and eigenanalysis identify tumor cells or leukocytes. Finally, a novel double component labeling procedure categorizes the cell adhesion locations. This algorithm has generated consistently encouraging performances on photomicrographs obtained from in vivo experiments for tumor cell and leukocyte adhesion locations on the endothelium forming the microvessel wall. Compared with human experts, this algorithm used 1/500-1/200 of the time without having the errors due to human subjectivity. Our automatic classification and quantification method provides a reliable and cost effective approach for biomedical image processing. PMID- 25549778 TI - Meet the Editorial Board: Alfredo Budillon. PMID- 25549779 TI - Functional Anatomy of the Thalamus as a Model of Integrated Structural and Functional Connectivity of the Human Brain In Vivo. AB - While methods of measuring non-invasively both, functional and structural brain connectivity are available, the degree of overlap between them is still unknown. In this paper this issue is addressed by investigating the connectivity pattern of a brain structure with many, well characterized structural connections, namely the thalamus. Diffusion-weighted and resting state (RS) functional MRI (fMRI) data were collected in a group of 38 healthy participants. Probabilistic tractography was performed to parcellate the thalamus into regions structurally connected to different cortical areas. The resulting regions were used as seeds for seed-based analysis of RS fMRI data. The tractographic parcellation was thus cross-validated against functional connectivity data by evaluating the overlap between the functional and structural thalamo-cortical connections originating from the parcellated regions. Our data show only a partial overall correspondence between structural and functional connections, in the same group of healthy individuals, thus suggesting that the two approaches provide complementary and not overlapping information. Future studies are warranted to extend the results we obtained in the thalamus to other structures, and to confirm that the mechanisms behind functional connectivity are more complex than just expressing structural connectivity. PMID- 25549781 TI - Enabling technologies to advance microbial isoprenoid production. AB - Microbial production of isoprenoids provides an attractive alternative to biomass extraction and chemical synthesis. Although widespread research aims for isoprenoid biosynthesis, it is still in its infancy in terms of delivering commercial products. Large barriers remain in realizing a cost-competitive process, for example, developing an optimal microbial cell factory. Here, we summarize the many tools and methods that have been developed in the metabolic engineering of isoprenoid production, with the advent of systems biology and synthetic biology, and discuss how these technologies advance to accelerate the design-build-test engineering cycle to obtain optimum microbial systems. It is anticipated that innovative combinations of new and existing technologies will continue to emerge, which will enable further development of microbial cell factories for commercial isoprenoid production. PMID- 25549780 TI - The science of badminton: game characteristics, anthropometry, physiology, visual fitness and biomechanics. AB - Badminton is a racket sport for two or four people, with a temporal structure characterized by actions of short duration and high intensity. This sport has five events: men's and women's singles, men's and women's doubles, and mixed doubles, each requiring specific preparation in terms of technique, control and physical fitness. Badminton is one of the most popular sports in the world, with 200 million adherents. The decision to include badminton in the 1992 Olympics Game increased participation in the game. This review focuses on the game characteristics, anthropometry, physiology, visual attributes and biomechanics of badminton. Players are generally tall and lean, with an ectomesomorphic body type suited to the high physiological demands of a match. Indeed, a typical match characteristic is a rally time of 7 s and a resting time of 15 s, with an effective playing time of 31%. This sport is highly demanding, with an average heart rate (HR) of over 90% of the player's maximal HR. The intermittent actions during a game are demanding on both the aerobic and anaerobic systems: 60-70% on the aerobic system and approximately 30% on the anaerobic system, with greater demand on the alactic metabolism with respect to the lactic anaerobic metabolism. The shuttlecock has an atypical trajectory, and the players perform specific movements such as lunging and jumping, and powerful strokes using a specific pattern of movement. Lastly, badminton players are visually fit, picking up accurate visual information in a short time. Knowledge of badminton can help to improve coaching and badminton skills. PMID- 25549782 TI - Preoperative CT-based nomogram for predicting overall survival in women with non endometrioid carcinomas of the uterine corpus. AB - PURPOSE: To develop a preoperative CT-based nomogram for predicting overall survival (OS) in patients with non-endometrioid carcinomas of the uterine corpus. METHODS: Waiving informed consent, the institutional review board approved this HIPAA-compliant, retrospective study of 193 women with histopathologically proven uterine papillary serous carcinomas (UPSC), uterine clear cell carcinomas (UCCC), and uterine carcinosarcomas (UCS) who underwent primary surgical resection between May 1998 and December 2011, and had a preoperative CT <= 6 weeks before surgery. All CT scans were reviewed for local or/and regional tumor extent, presence of pelvic or/and para-aortic adenopathy, and presence of distant metastases. Univariate survival analysis was performed using log-rank test and Cox regression. Variables shown significant by the univariate analysis were evaluated with the multivariable Cox regression analysis and the results were used to create a nomogram for predicting OS. The predictive accuracy of the nomogram was assessed with the concordance probability index (c-index) and a 3 year calibration plot. RESULTS: Mean patient age was 67.2 years (range 49.0 85.9); histologies included UPSC (n = 116), UCCC (n = 27), and UCS (n = 50). Median follow-up was 38.1 months (0.9-168.5 months). At multivariate analysis, patient age, ascites, and omental implants on CT were significant adverse predictors of OS and were used to build the nomogram. Concordance index for the nomogram was 0.640 +/- 0.028. CONCLUSION: We developed a nomogram with a good concordance probability at predicting OS based on readily available pretreatment clinical and imaging characteristics. This preoperative nomogram has the potential to improve initial treatment planning and patient counseling. PMID- 25549783 TI - Radiologic features of pancreatic and biliary complications following composite visceral transplantation. AB - Small bowel transplantation is a surgical technique reserved for patients with end-stage intestinal failure. Despite its inherent technical difficulties, it has emerged as the standard of care for these patients. This article reviews the background and different surgical techniques for this procedure and then fully describes the spectrum of imaging findings of pancreatic and biliary complications, which have a prevalence of up to 17%, after this procedure based on 23-year single-center experience. The pancreaticobiliary complications encountered in our experience and discussed in this article include: ampullary stenosis, biliary cast, choledocholithiasis, bile leak, recurrent cholangitis, acute pancreatitis, chronic pancreatitis, and pancreatic duct fistula. Familiarity with the broad spectrum of PB complications and their variable manifestations will help radiologists to accurately diagnose these complications which have relatively high morbidity and mortality in these immune-compromised patients. PMID- 25549784 TI - Histotype differentiation of hypo-echoic renal tumors on CEUS: usefulness of enhancement homogeneity and intensity. AB - PURPOSE: The purpose of this study is to evaluate qualitative and quantitative analysis of contrast-enhanced ultrasound (CEUS) in differential diagnoses of hypo echoic renal tumor histotypes. METHODS: Our study cohort comprised 103 clear cell renal cell carcinomas (ccRCCs), 24 papillary renal cell carcinomas (pRCCs), 28 chromophobe renal cell carcinomas (cRCCs), and 34 angiomyolipomas (AMLs), hypo echoic on ultrasound, and imaged between January 2011 and December 2013. Enhancement homogeneity and tumor-to-cortex intensity ratio (TOC ratio) were retrospectively analyzed. RESULTS: Overall, heterogeneous enhancement was more common in ccRCCs than AMLs, pRCCs, and cRCCs. TOC ratio showed the trend ccRCC > AML > pRCC = cRCC. Similar trends were seen in tumors <4 cm. Using heterogeneous enhancement or TOC ratio >107.5% to differentiate ccRCC from other histotypes, the sensitivity, specificity, positive and negative predictive values were 93.1%, 74.5%, 84.8%, and 87.5%, respectively. Tumors >4 cm exhibited considerable overlap in enhancement homogeneity among different histotypes. TOC ratios were similar between homo- and heterogeneously enhancing tumors for ccRCCs and for pRCCs and cRCCs, but higher in homogeneously enhancing than heterogeneously enhancing AMLs. In homo- and heterogeneously enhancing tumors, TOC ratios followed the trends ccRCCs > AMLs > pRCCs = cRCCs and ccRCCs > AMLs = pRCCs = cRCCs, respectively. With TOC ratio >105.81% and >72.37% to differentiate homo- and heterogeneously enhancing ccRCCs from other histotypes in tumors >4 cm with same enhancement homogeneity, the sensitivity, specificity, positive and negative predictive values were 70.0%, 85.7%, 70.0%, 85.7%, and 91.7%, 94.4%, 95.7%, 89.5%, respectively. CONCLUSION: CEUS homogeneity and TOC ratio are helpful in differential diagnosis of hypo-echoic renal tumor histotypes. Diameter and enhancement homogeneity should be considered when deciding the diagnostic TOC ratio cutoff. PMID- 25549786 TI - The energy cost of sprint running and the role of metabolic power in setting top performances. AB - PURPOSE: To estimate the energetics and biomechanics of accelerated/decelerated running on flat terrain based on its biomechanical similarity to constant speed running up/down an 'equivalent slope' dictated by the forward acceleration (a f). METHODS: Time course of a f allows one to estimate: (1) energy cost of sprint running (C sr), from the known energy cost of uphill/downhill running, and (2) instantaneous (specific) mechanical accelerating power (P sp = a f * speed). RESULTS: In medium-level sprinters (MLS), C sr and metabolic power requirement (P met = C sr * speed) at the onset of a 100-m dash attain ~50 J kg(-1) m(-1), as compared to ~4 for running at constant speed, and ~90 W kg(-1). For Bolt's current 100-m world record (9.58 s) the corresponding values attain ~105 J kg(-1) m(-1) and ~200 W kg(-1). This approach, as applied by Osgnach et al. (Med Sci Sports Exerc 42:170-178, 2010) to data obtained by video-analysis during soccer games, has been implemented in portable GPS devices (GPEXE), thus yielding P met throughout the match. Actual O2 consumed, estimated from P met assuming a monoexponential VO2 response (Patent Pending, TV2014A000074), was close to that determined by portable metabolic carts. Peak P sp (W kg(-1)) was 17.5 and 19.6 for MLS and elite soccer players, and 30 for Bolt. The ratio of horizontal to overall ground reaction force (per kg body mass) was ~20 % larger, and its angle of application in respect to the horizontal ~10 degrees smaller, for Bolt, as compared to MLS. Finally, we estimated that, on a 10 % down-sloping track Bolt could cover 100 m in 8.2 s. CONCLUSIONS: The above approach can yield useful information on the bioenergetics and biomechanics of accelerated/decelerated running. PMID- 25549785 TI - Voluntary apnea evokes diving responses in obstructive sleep apnea patients. AB - PURPOSE: Two potentially protective responses to apnea were studied in obstructive sleep apnea (OSA) patients; the diving response and the increase in Hb concentration [Hb] via spleen contraction. METHODS: Eight OSA patients and ten healthy controls performed apneas in air (A) and apneas with facial immersion in 15 degrees C water (FIA) after inspiration and without prior hyperventilation. In each condition, subjects performed three apneas of maximal voluntary duration spaced by 2 min of rest. Cardiorespiratory parameters were measured non invasively, and venous blood samples for [Hb] analysis were drawn before and after apneas. RESULT: Mean (SD) apnea durations were similar between groups (NS). In controls, the heart rate (HR) reduction was 10 +/- 10 % at apnea and 19 +/- 10 % in FIA (P < 0.05). In OSA patients, however, the fall in HR was the same in both conditions, 13 +/- 10 and 14 +/- 8 % for A and FIA, respectively (NS). In controls, the [Hb] increase was the same in A and FIA (2.2 +/- 2.9 and 2.1 +/- 2.2 %), while in OSA the [Hb] increase was greater during FIA compared to A (3.3 +/- 2.2 and 1.4 +/- 0.9 %; P < 0.05). CONCLUSION: Apnea induces a diving response and [Hb] increase in both groups. OSA patients did not show the typical training effect of the diving response seen in apnea divers despite their frequent nocturnal apneas. However, they also deviated from normal controls in response pattern; face immersion enhanced the cardiovascular diving response in controls but not in OSA, while the hematological response was enhanced by face immersion only in OSA patients. PMID- 25549787 TI - Optimal loads for a 30-s maximal power cycle ergometer test using a stationary start. AB - INTRODUCTION: A stationary start modification to the Wingate Anaerobic Test (WAnT) has become increasingly common. The aim of the present study was to determine whether the traditional 85 g kg(-1) body weight (BW) load (TRAD), or an individualized optimal load (OPT), is more suitable for obtaining peak and mean power outputs (PPO and MPO, respectively) for a stationary start. METHODS: Twelve recreationally active males and 10 females (mean age 30 +/- 9.1 and 25 +/- 5.5 years, respectively) completed three trials. The first determined the OPT load and included a familiarization of the 30-s stationary start test, followed by two randomized sessions testing the OPT and TRAD loads during the 30-s stationary start test on separate days. For each test, measures of power (watts), time, and cadence were collected to determine PPO, MPO, rate of power decline (rPD) and time to peak power (TtPP). All power data were corrected for flywheel moment of inertia. RESULTS: Results revealed significant differences between OPT and TRAD load settings for males (95.1 +/- 10.7 and 85.06 +/- 0.40 g kg(-1) BW; p = 0.008) but not for females (84.71 +/- 8.72 and 85.2 +/- 0.61 g kg(-1) BW; p = 0.813). Relative PPO was not different for OPT or TRAD loads for males (p = 0.485) or females (p = 0.488). CONCLUSION: It is not necessary to use an OPT load setting to acquire maximal PO for a 30-s cycle test using a stationary start. Instead, the traditional 85 g kg(-1) BW loading is suitable for both males and females. PMID- 25549788 TI - Differential modulation of motor cortex plasticity in skill- and endurance trained athletes. AB - PURPOSE: Extensive evidence exists that regular physical exercise offers neuroplastic benefits to the brain. In this study, exercise-specific effects on motor cortex plasticity were compared between 15 skilled and 15 endurance trained athletes and 8 controls. METHODS: Plasticity was tested with a paired associative stimulation (PAS) protocol. PAS is a non-invasive stimulation method developed to induce bidirectional changes in the excitability of the cortical projections to the target muscles. Motor cortex excitability was assessed by motor-evoked potentials (MEPs) in the task-relevant soleus muscle, elicited with transcranial magnetic stimulation, before and following PAS. To test for changes at the spinal level, soleus short latency stretch reflexes (SLSR) were elicited before and after PAS. RESULTS: PAS induced a significant (76 +/- 83 %) increase in MEP amplitude in the skill group, without significant changes in the endurance (-7 +/ 35 %) or control groups (21 +/- 30 %). Baseline MEP/post MEP ratio was significantly different between the skill and endurance groups. SLSR remained unchanged after the PAS intervention. CONCLUSION: The possible reason for differential motor cortex plasticity in skill and endurance groups is likely related to the different training-induced adaptations. The findings of the current study suggest that long-term skill training by skill group induced preferable adaptations in the task-related areas of the motor cortex because increased plasticity is known to enhance motor learning. PMID- 25549789 TI - The effect of streptozotocin and alloxan on the mRNA expression of rat hepatic transporters in vivo. AB - The effect of streptozotocin (STZ) and alloxan (ALX) on the hepatic messenger RNA (mRNA) expression of four transporters (Mrp2, Mdr1, Oct1, and Oatp1) was studied in the present work. After the healthy male Wistar rats were individually treated by a single intraperitoneal injection of ALX monohydrate (150 mg/kg) or STZ (50 mg/kg), the hepatic mRNA expression levels of Mrp2, Mdr1, Oct1, and Oatp1 were detected by real-time quantitative PCR. The results indicated that the mRNA expression levels of the Mrp2, Mdr1, Oct1, and Oatp1 in ALX-induced diabetic rats, as well as the hepatic mRNA expression of Mdr1 and Oatp1 in STZ-induced diabetic rats, were significantly decreased as compared with the control. The inhibition of ALX and STZ on hepatic transporter expression suggested that alterations of drug transporters under diabetic condition can be responsible for reduced drug clearance. PMID- 25549790 TI - Ultra rapidly dissolving repaglinide nanosized crystals prepared via bottom-up and top-down approach: influence of food on pharmacokinetics behavior. AB - The present work was undertaken with the objectives of improving the dissolution velocity, related oral bioavailability, and minimizing the fasted/fed state variability of repaglinide, a poorly water-soluble anti-diabetic active by exploring the principles of nanotechnology. Nanocrystal formulations were prepared by both top-down and bottom-up approaches. These approaches were compared in light of their ability to provide the formulation stability in terms of particle size. Soluplus(r) was used as a stabilizer and KolliphorTM E-TPGS was used as an oral absorption enhancer. In vitro dissolution profiles were investigated in distilled water, fasted and fed state simulated gastric fluid, and compared with the pure repaglinide. In vivo pharmacokinetics was performed in both the fasted and fed state using Wistar rats. Oral hypoglycemic activity was also assessed in streptozotocin-induced diabetic rats. Nanocrystals TD-A and TD-B showed 19.86 and 25.67-fold increase in saturation solubility, respectively, when compared with pure repaglinide. Almost 10 (TD-A) and 15 (TD-B)-fold enhancement in the oral bioavailability of nanocrystals was observed regardless of the fasted/fed state compared to pure repaglinide. Nanocrystal formulations also demonstrated significant (p < 0.001) hypoglycemic activity with faster onset (less than 30 min) and prolonged duration (up to 8 h) compared to pure repaglinide (after 60 min; up to 4 h, respectively). PMID- 25549791 TI - Translational application of nano delivery systems: emerging cancer therapy. PMID- 25549792 TI - A menthol-based solid dispersion technique for enhanced solubility and dissolution of sulfamethoxazole from an oral tablet matrix. AB - A menthol-based solid dispersion was designed to improve the intrinsic solubility of the poorly soluble sulfamethoxazole- a class II drug molecule of Biopharmaceutics Classification System (BCS) displaying widespread antibacterial activity. Solid dispersions of menthol and sulfamethoxazole were compressed with hydroxypropyl methylcellulose (HPMC) into suitable sulfamethoxazole-loaded matrix tablets for oral drug delivery. The sulfamethoxazole-loaded solid dispersions and compressed tablets were characterized for their physicochemical and physicomechanical properties such as changes in crystallinity, melting point, molecular transitions, and textural analysis for critical analysis of their effects on the solubility and dissolution of sulfamethoxazole. The formulations were further evaluated for swelling, degradation, solubility, and in vitro drug release behavior. In vitro drug release from the sulfamethoxazole-loaded matrix tablets displayed a minimum and maximum fractional release of 0.714 and 0.970, respectively. The tablets further displayed different release rate profiles over the study periods of 12, 16, 48, and 56 h which were attributed to the varying concentrations of menthol within each formulation. Menthol was determined as a suitable hydrophilic carrier for sulfamethoxazole since it functioned as a solubilizing and release-retarding agent for improving the solubility and dissolution of sulfamethoxazole as well as controlling the rate at which it was released. PMID- 25549793 TI - Expression of serum let-7c, let-7i, and let-7f microRNA with its target gene, pepsinogen C, in gastric cancer and precancerous disease. AB - This study examined the expression patterns of serum let-7 microRNA (miRNA) and its target gene, pepsinogen C (PGC), in gastric cancer (GC) and precancerous disease patients to evaluate their diagnostic efficiency for GC and its precursor and to investigate any correlation between the two. Serum samples were taken from 638 patients, including 214 GC patients, 222 atrophic gastritis (AG) patients, and 202 controls (CON). The expression of serum let-7 miRNA was detected in control-AG (precancerous disease) through to GC patients using quantitative reverse-transcription polymerase chain reaction. Serum PGC was determined by enzyme-linked immuno-sorbent assay. PGC expression in situ was detected by immunohistochemistry staining. The luciferase reporter gene system was used to verify correlation between let-7 miRNA and its predicted target gene. The results showed that serum let-7c, let-7i, and let-7f demonstrated significant differences in the CON-AG-GC sequence (P = 0.017, P < 0.001, P = 0.003, respectively); let-7c was significantly lower in the AG group, and let-7i and let-7f were significantly higher in the GC group. Significantly different expressions of serum PGC were found among the three diseases, and also between AG vs. CON, and GC vs. CON (P = 0.027, P = 0.001, respectively). Linear-regression analysis suggested that serum let-7c was negatively correlated to the expression of PGC (r = -0.096, P = 0.047), and serum let-7c, let-7i, and let-7f showed no association with PGC expression in tissue. In addition, serum let-7c, let-7f, and let-7i showed significant correlations with environment factors. Serum let-7c, let-7i, and let 7f demonstrated significant differences in the CON-AG-GC disease sequence indicating that let-7 miRNA might have value by serving as potential biomarker in the diagnosis of GC or its precancerous diseases. There were significant negative correlations between serum let-7c and its target gene PGC expression. PMID- 25549794 TI - HOXA5 indicates poor prognosis and suppresses cell proliferation by regulating p21 expression in non small cell lung cancer. AB - Homeobox genes, a superfamily of evolutionarily conserved developmental genes, function as critical master regulatory factors in controlling body plan specification and cell fate determination. Recently, a substantial body of evidence indicates that the aberrant Homeobox (HOX) genes also play key roles in the development of cancers. Many reports have shown not only that HOX gene expression is upregulated or downregulated in many cancers but also that the expression of specific HOX genes tends to differ based on tissue type. Homeobox A5 (HOXA5) is a master regulator of the morphogenesis and cell differentiation, and its expression is also downregulated in many cancers mediated by DNA methylation. However, its biological role and clinical significance in nonsmall cell lung cancer (NSCLC) development and progression are not well documented. In this study, we found that expression levels of HOXA5 were significantly decreased in NSCLC tissues compared with adjacent normal tissues. Its expression level was significantly correlated with tumor-node-metastasis (TNM) stages, tumor size, and lymph node metastasis. Moreover, patients with lower levels of HOXA5 expression had a relatively poor prognosis. Furthermore, ectopic overexpression of HOXA5 could inhibit cell proliferation and invasion, while knockdown HOXA5 by siRNA promoted cell proliferation in NSCLC cells partly via regulating p21 expression. Our findings present that decreased HOXA5 could be identified as a poor prognostic biomarker in NSCLC and regulate cell proliferation and invasion. PMID- 25549795 TI - The matrix metalloproteinase-7 and pro-enzyme of metalloproteinase-1 as a potential marker for patients with rectal cancer without distant metastasis. AB - The aim of this study was the evaluation of clinical usage of metalloproteinase (MMP): proMMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in serum of patients with rectal cancer, as well as the selection of parameters of the greatest diagnostic sensitivity and the determination of their relation with clinicopathological features, what is more, the demonstration whether their concentrations may have a prognostic value in the assessment of disease-free survival (DFS) and overall survival (OS). The study comprised 100 patients with rectal cancer including 29 women and 71 men. The tested group was comprised of qualified patients without distant metastasis (M0). It was demonstrated that in patients with rectal cancer, the concentrations of MMP-9, MMP-7, and proMMP-1 as well as TIMP-1 were significantly higher in comparison to the reference group. On the basis of ROC curves, the greatest diagnostic sensitivity of MMP-9 was demonstrated. When evaluating the correlation of tested parameters with the size of the tumor (T1-T2 vs T3-T4), essential differences were shown for proMMP-1 concentrations. The highest percentage of patients with progression had an increased concentration of MMP-7 and TIMP-1. During a 5-year follow-up, univariate log-rank analysis had shown an essential dependence between the concentration of MMP-7 in men and DSF which was confirmed in Cox multivariate analysis. It was demonstrated that the pretreatment concentration of proMMP-1 may be clinically useful when evaluating the mass of the tumor, whereas MMP-7 may be a prognostic factor for DFS in men with rectal cancer without distant metastasis. PMID- 25549796 TI - Establishment of an animal model of vascular restenosis with bilateral carotid artery grafting. AB - BACKGROUND: Vascular restenosis occurring after CABG is a major clinical problem that needs to be addressed. Vein grafts are associated with a higher degree of stenosis than artery grafts. However, the mechanism responsible for this effect has not been elucidated. We aimed to establish a rabbit model of vascular restenosis after bilateral carotid artery grafting, and to investigate the associated spatiotemporal changes of intimal hyperplasia in carotid artery and jugular vein grafts after surgery. MATERIAL AND METHODS: Twenty adult New Zealand white rabbits (10 males; 10 females), weighing 2.0-2.5 kg, were obtained from the Experimental Animal Center of Southern Medical University, Guangzhou, China (License No.: scxk-Guangdong-2006-0015). We quantitatively analyzed intimal thickness, area, and degree of stenosis in carotid artery and jugular vein bridges. RESULTS: After 8 weeks of a high-fat diet, rabbit carotid arteries showed early atherosclerotic lesions. With increasing time after surgery, carotid artery and jugular vein grafts showed histopathological and morphological changes, including smooth muscle cell migration, lipid deposition, intimal hyperplasia, and vascular stenosis. The degree of vascular stenosis was significantly higher in vein grafts than in artery grafts at all time points - 35.1+/-6.7% vs. 16.1+/-2.6% at Week 12, 56.2+/-8.5% vs. 23.4+/-3.4% at Week 16, and 71.2+/-1.3% vs. 25.2+/-5.3% at Week 20. CONCLUSIONS: Rabbit bilateral carotid arteries were grafted with carotid artery and jugular vein bridges to simulate pathophysiological processes that occur in people after CABG surgery. PMID- 25549797 TI - Regional effects of orthopedic manual physical therapy in the successful management of chronic jaw pain. AB - OBJECTIVE AND IMPORTANCE: Temporomandibular disorders (TMD) encompass a variety of dysfunction of the maxillofacial region. A strong relationship between TMD and cervical spine pain exists, and widespread hyperalgesia is common in TMD. This case describes the management and reduction in regional hyperalgesia in a patient with chronic TMD. CLINICAL PRESENTATION: A 23-year-old female with a 10-year history of tinnitus and bilateral (B) jaw pain, and 5-year history of intermittent neck pain, presented with pain, which could reach 10/10 on the numeric pain rating scale, locking, tightness and restricted eating habits. Cervical motion testing did not reproduce her jaw pain. Her mouth opening (MO) and B temporomandibular joint (TMJ) accessory glides were limited and painful. Accessory glides at the upper cervical facet joints reproduced her jaw pain. Pressure pain thresholds (PPT) at her B masseters and thenar eminences at the hand were diminished, indicating hyperalgesia. INTERVENTION: Treatment included passive mobilizations at her TMJs and cervical spine. Home exercises included self-mobilization of her TMJs and neck. In six sessions, her MO improved from 30 to 45 mm and average pain improved from 4/10 to 0/10. The jaw pain and function questionnaire improved from 16/52 to 5/52. PPTs at her right/left masseter and thenar eminence improved from 140/106 and 221/230 kPa to 381/389 and 562/519 kPa, respectively. CONCLUSION: This case described the treatment and reduction of upper extremity hyperalgesia of a patient with chronic jaw and neck pain. Manual therapy may be a valuable intervention in the treatment of chronic TMD with distal hyperalgesia. PMID- 25549798 TI - High-resolution small field-of-view magnetic resonance image acquisition system using a small planar coil and a pneumatic manipulator in an open MRI scanner. AB - BACKGROUND: Low-field open magnetic resonance imaging (MRI) is frequently used for performing image-guided neurosurgical procedures. Intraoperative magnetic resonance (MR) images are useful for tracking brain shifts and verifying residual tumors. However, it is difficult to precisely determine the boundary of the brain tumors and normal brain tissues because the MR image resolution is low, especially when using a low-field open MRI scanner. To overcome this problem, a high-resolution MR image acquisition system was developed and tested. METHODS: An MR-compatible manipulator with pneumatic actuators containing an MR signal receiver with a small radiofrequency (RF) coil was developed. The manipulator had five degrees of freedom for position and orientation control of the RF coil. An 8 mm planar RF coil with resistance and inductance of 2.04 [Formula: see text] and 1.00 [Formula: see text] was attached to the MR signal receiver at the distal end of the probe. MR images of phantom test devices were acquired using the MR signal receiver and normal head coil for signal-to-noise ratio (SNR) testing. RESULTS: The SNR of MR images acquired using the MR signal receiver was 8.0 times greater than that of MR images acquired using the normal head coil. The RF coil was moved by the manipulator, and local MR images of a phantom with a 2-mm grid were acquired using the MR signal receiver. A wide field-of-view MR image was generated from a montage of local MR images. CONCLUSION: A small field-of-view RF system with a pneumatic manipulator was integrated in a low-field MRI scanner to allow acquisition of both wide field-of-view and high-resolution MR images. This system is promising for image-guided neurosurgery as it may allow brain tumors to be observed more clearly and removed precisely. PMID- 25549799 TI - Automatic extraction of bone surfaces from 3D ultrasound images in orthopaedic trauma cases. AB - PURPOSE: 3D ultrasound (US) imaging has the potential to become a powerful alternative imaging modality in orthopaedic surgery as it is radiation-free and can produce 3D images (in contrast to fluoroscopy) in near-real time. Conventional B-mode US images, however, are characterized by high levels of noise and reverberation artifacts, image quality is user-dependent, and bone surfaces are blurred, which makes it difficult to both interpret images and to use them as a basis for navigated interventions. 3D US has great potential to assist orthopaedic care, possibly assisting during surgery if the anatomical structures of interest could be localized and visualized with sufficient accuracy and clarity and in a highly automated rapid manner. METHODS: In this paper, we present clinical results for a novel 3D US segmentation technique we have recently developed based on multi-resolution analysis to localize bone surfaces in 3D US volumes. Our method is validated on scans obtained from 29 trauma patients with distal radius and pelvic ring fractures. RESULTS: Qualitative and quantitative results demonstrate remarkably clear segmentations of bone surfaces with an average surface fitting error of 0.62 mm (standard deviation (SD) of 0.42 mm) for pelvic patients and 0.21 mm (SD 0.14 mm) for distal radius patients. CONCLUSIONS: These results suggest that our technique is sufficiently accurate for potential use in orthopaedic trauma applications. PMID- 25549800 TI - Identification and chromosome mapping of repetitive elements in the Astyanax scabripinnis (Teleostei: Characidae) species complex. AB - Most part of the eukaryotic genome is composed of repeated sequences or multiple copies of DNA, which were considered as "junk DNA", and may be associated to the heterochromatin. In this study, three populations of Astyanax aff. scabripinnis from Brazilian rivers of Guaratingueta and Pindamonhangaba (Sao Paulo) and a population from Maringa (Parana) were analyzed concerning the localization of the nucleolar organizer regions (Ag-NORs), the As51 satellite DNA, the 18S ribosomal DNA (rDNA), and the 5S rDNA. Repeated sequences were also isolated and identified by the Cot - 1 method, which indicated similarity (90%) with the LINE UnaL2 retrotransposon. The fluorescence in situ hybridization (FISH) showed the retrotransposon dispersed and more concentrated markers in centromeric and telomeric chromosomal regions. These sequences were co-localized and interspaced with 18S and 5S rDNA and As51, confirmed by fiber-FISH essay. The B chromosome found in these populations pointed to a conspicuous hybridization with LINE probe, which is also co-located in As51 sequences. The NORs were active at unique sites of a homologous pair in the three populations. There were no evidences that transposable elements and repetitive DNA had influence in the transcriptional regulation of ribosomal genes in our analyses. PMID- 25549801 TI - Phase separation behavior of mixed lipid systems at neutral and low pH: coarse grained simulations with DMD/LIME. AB - We extend LIME, an intermediate resolution, implicit solvent model for phospholipids previously used in discontinuous molecular dynamics simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer formation at 325 K, to the description of the geometry and energetics of 1,2-distearoyl-sn-glycero-3 phospho-L-serine (DSPS) and 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (21PC) and mixtures thereof at both neutral and low pH at 310 K. A multiscale modeling approach is used to calculate the LIME parameters from atomistic simulation data on a mixed DPPC/DSPS system at different pH values. In the model, 17 coarse-grained sites represent DSPS and 18 coarse-grained sites represent 21PC. Each of these coarse-grained sites is classified as 1 of 9 types. LIME/DMD simulations of equimolar bilayers show the following: (1) 21PC/DSPS bilayers with and without surface area restrictions separate faster at low pH than at neutral pH, (2) 21PC/DSPS systems separate at approximately the same rate regardless of whether they are subjected to surface area restrictions, and (3) bilayers with a molar ratio of 9:1 (21PC:DSPS) phase separate to form heterogeneous domains faster at low pH than at neutral pH. Our results are consistent with experimental findings of Sofou and co-workers (Bandekar et al. Mol. Pharmaceutics, 2013, 10, 152-160; Karve et al. Biomaterials, 2010, 31, 4409-4416) that more doxorubicin is released from 21PC/DSPS liposomes at low pH than at neutral pH, presumably because greater phase separation is achieved at low pH than at neutral pH. These are the first molecular-level simulations of the phase separation in mixed lipid bilayers induced by a change in pH. PMID- 25549802 TI - Unusual Zn(II) Affinities of Zinc Fingers of Poly(ADP-ribose)Polymerase 1 (PARP 1) Nuclear Protein. AB - Poly(ADP-ribose) polymerase 1 (PARP-1) is a key eukaryotic enzyme,catalyzing the NAD+ dependent poly(ADP-ribosyl)ation of protein substrates, crucial for major DNA repair pathways, and involved in other fundamental cellular processes, such as transcription, cell cycle control, and apoptosis. Its ability to bind DNA depends on two CCHC zinc finger domains, in short, PARPzf1 and PARPzf2. Using spectroscopic methods and competitive titrations with Zn(II), Co(II), and Ni(II) ions, we determined conditional dissociation constants for Zn(II) complexes of PARPzf1 and PARPzf2 at pH 7.4 (HEPESbuffer) as 26 +/- 4 nM and 4 +/- 1 pM, respectively. The former value indicates an extremely low affinity of PARPzf1 toward metal ions, meaning that under cellular conditions PARP1zf might be largely present in a "metal-free" state. This finding provides a clue to the high susceptibility of PARP-1 to oxidative stress but also raises questions regarding the activation of PARPzf1 under cellular conditions. We also determined conditional dissociation constants for Ni(II) complexes of PARPzf1 and PARPzf2 under the same conditions as 0.78 +/- 0.04 MUM and 0.26 +/- 0.05 nM, respectively. PMID- 25549803 TI - Prognostic value of inhibitor of apoptosis protein family expression in patients with acute myeloid leukemia. AB - The inhibitor of apoptosis protein (IAP) family acts as an inhibitor of apoptosis pathways. The potential prognostic value of the expression of selected IAP family members, XIAP, cIAP-1, cIAP-2 and survivin protein, was evaluated with regard to treatment response and survival of 56 newly diagnosed adult patients with acute myeloid leukemia (AML). The presence of these IAP members influenced the achievement of a complete response (CR). In addition, overall survival (OS) was influenced by low survivin expression in univariate and multivariate analysis (p = 0.014 and p = 0.013, respectively). A strong correlation was observed between members of the IAP family (XIAP and cIAP-1, XIAP and cIAP-2, cIAP-1 and cIAP-2, p < 0.001 for all comparisons), while Smac/DIABLO demonstrated an inverse correlation with XIAP, cIAP-1 and cIAP-2 (p < 0.001 for all comparisons). Further studies should be undertaken to better demonstrate the mode of action of IAP members, as well as their prognostic and therapeutic potentials. PMID- 25549804 TI - Correlation between Charlson comorbidity index and outcome in patients with chronic phase chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors upfront. PMID- 25549805 TI - Clinical usefulness of fluorescence in situ hybridization for detection of MLL rearrangements in acute myeloid leukemia. PMID- 25549806 TI - Risk of follicular lymphoma associated with BCL2 translocations in peripheral blood. AB - Many adults have circulating lymphocytes with the BCL2 gene translocation characteristic of follicular lymphoma. We therefore conducted a nested case control study of incident lymphomas with peripheral blood obtained a median 4.9 years pre-diagnosis from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Overall, 13 of 26 cases of lymphoma and 14 of 47 controls had BCL2 major breakpoint region (MBR) translocations in pre-diagnosis blood (odds ratio [OR] = 2.8). Nine cases had BCL2-MBR-positive tumors; eight of these nine had BCL2-MBR translocations in paired blood versus five of the 17 with BCL2-MBR negative tumors (p = 0.01). Comparing both tumor types to controls, blood BCL2 MBR translocations had a strong, statistically significant association with BCL2 MBR-positive tumors (OR = 26), but not with BCL2-MBR-negative tumors (OR = 0.9). All eight BCL2-MBR-positive tumors with pre-diagnosis BCL2 translocations were clonally related to these circulating cells, based on similarity of recombination sequences. These data indicate that blood BCL2-MBR translocations represent lymphoma precursor clones with malignant potential. PMID- 25549807 TI - Treatment-refractory hypereosinophilic syndrome responding to fludarabine in a 12 year-old boy. PMID- 25549808 TI - Increased prevalence of early repolarization in electrocardiograms of psoriatic patients. AB - Psoriasis (Ps) is a chronic-relapsing, inflammatory, and proliferative condition of the skin: prior studies hypothesized a link between Ps and anomalies in beta adrenergic tone. We therefore aimed to ascertain the prevalence of early repolarization pattern (ERP) in resting electrocardiograms (ECGs) of psoriatic patients compared with an appropriate control group. We performed a retrospective study of resting ECGs of 100 consecutive psoriatic patients and 100 healthy controls. The presence of ERP in at least two contiguous leads at rest ECG was recorded, and findings were also categorized according to the lead group where ERP was detected (anterior, lateral, inferior). An ERP in >= 2 contiguous leads occurred in 40 % of psoriatic patients, compared with 14 % of control subjects (p < 0.001). (36 vs 10 % in anterior leads, p < 0.001; 6 vs 3 % in inferior leads, p n.s.; 10 vs 2 % in lateral leads). After adjustment for sex, age, heart rate, and level of physical activity, the odds ratios for the presence of ERP were 8.6 (95 % CI, 2.1-35.2, p < 0.01), and 7.1 (95 % CI, 1.6-31.8, p < 0.05) in anterior leads. In a small case/control study, increased rates of ECGs showing ERP have been observed among psoriatic patients. Clinical significance of such finding needs to be assessed in further observational studies. PMID- 25549809 TI - Comparing the ecological impacts of native and invasive crayfish: could native species' translocation do more harm than good? AB - Biological invasions are a principal threat to global biodiversity. Omnivores, such as crayfish, are among the most important groups of invaders. Their introduction often results in biodiversity loss, particularly of their native counterparts. Managed relocations of native crayfish from areas under threat from invasive crayfish into isolated 'ark sites' are sometimes suggested as a conservation strategy for native crayfish; however, such relocations may have unintended detrimental consequences for the recipient ecosystem. Despite this, there have been few attempts to quantify the relative impacts of native and invasive crayfish on aquatic ecosystems. To address this deficiency we conducted a meta-analysis on the effects of native and invasive crayfish on nine ecosystem components: decomposition rate, primary productivity, plant biomass, invertebrate density, biomass and diversity, fish biomass and refuge use, and amphibian larval survival. Native and invasive crayfish significantly reduced invertebrate density and biomass, fish biomass and amphibian survival rate and significantly increased decomposition rates. Invasive crayfish also significantly reduced plant biomass and invertebrate diversity and increased primary productivity. These results show that native and invasive crayfish have wide-ranging impacts on aquatic ecosystems that may be exacerbated for invasive species. Subsequent analysis showed that the impacts of invasive crayfish were significantly greater, in comparison to native crayfish, for decomposition and primary productivity but not invertebrate density, biomass and diversity. Overall, our findings reconfirm the ecosystem altering abilities of both native and invasive crayfish, enforcing the need to carefully regulate managed relocations of native species as well as to develop control programs for invasives. PMID- 25549810 TI - Around and around the merry-go-round: multiple implantations of short- and long term ventricular assist devices in a patient with severe heart failure. AB - Multiple implantations of left ventricular assist devices over a period of three years were performed in a 17-year-old gentleman with non-ischaemic dilated cardiomyopathy and congestive cardiac failure. The first device (HeartMate II) was implanted as a bridge to transplantation. However, after few months of support the patient showed signs of myocardial recovery and the device was successfully explanted. After 2 years of uneventful follow-up, the patient's condition deteriorated requiring further mechanical support. Due to the elevated risk associated with a redo full-support LVAD implantation, we decided to implant a partial support device (Synergy CircuLite). Because of recurrent pump thrombosis requiring device exchange, the final weeks to transplantation were bridged with CentriMag short-term LVAD. After successful cardiac transplantation the patient required further temporary extracorporeal membrane oxygenation support which was weaned off and explanted on the fourth postoperative day. After further uncomplicated postoperative recovery the patient was discharged and has been doing well for 1 year of follow-up. PMID- 25549811 TI - Deep round window insertion versus standard approach in cochlear implant surgery. AB - The aim of this study was to compare the outcomes of vestibular tests and the residual hearing of patients who have undergone full insertion cochlear implant surgery using the round window approach with a hearing preservation protocol (RW HP) or the standard cochleostomy approach (SCA) without hearing preservation. A prospective study of 34 adults who underwent unilateral cochlear implantation was carried out. One group was operated using the RW-HP (n = 17) approach with Med-El +Flex(SOFT) electrode array with full insertion, while the control group underwent a more conventional SCA surgery (n = 17) with shorter perimodiolar electrodes. Assessments of residual hearing, cervical vestibular-evoked myogenic potentials (cVEMP), videonystagmography, subjective visual vertical/horizontal (SVH/SVV) were performed before and after surgery. There was a significantly (p < 0.05) greater number of subjects who exhibited complete or partial hearing preservation in the deep insertion RW-HP group (9/17) compared to the SCA group (2/15). A higher degree of vestibular loss but a lower degree of vertigo symptoms could be seen in the RW-HP group, but the differences were not statistically significant. It is possible to preserve residual hearing to a certain extent also with deep insertion. Full insertion with hearing preservation was less harmful to residual hearing particularly at 125 Hz (p < 0.05), than was the standard cochleostomy approach. PMID- 25549812 TI - Combined intense pulsed light and Er:YAG laser treatment of congenital melanocytic nevus. AB - Congenital melanocytic nevi (CMN) are benign nevomelanocytic proliferations that are present at birth. CMN are commonly classified according to their size and the management of CMN is diverse, including excision, dermabrasion and laser treatment. Several studies have shown the effectiveness of laser therapy for CMN in cosmetically sensitive and anatomically critical areas. In the present case, combination treatment with intense pulsed light (IPL) and erbium:yttrium-aluminum garnet (Er:YAG) laser was used, and its effectiveness was evaluated. A 56-year old man with a CMN on the left malar area was treated with combined IPL and Er:YAG laser treatment once monthly. After ten sessions of treatment, the lesion showed improvement leaving only a grayish hue. Thus, we report a case of CMN on face that was successfully treated with combined IPL and Er:YAG laser treatment. PMID- 25549813 TI - Efficacy of 595nm pulsed dye laser therapy for Mibelli angiokeratoma. AB - OBJECTIVE: To retrospectively study the clinical efficacy of 595nm pulsed dye laser therapy for Mibelli angiokeratoma. METHODS: 50 cases of Mibelli angiokeratoma, from 10 to 41 year-old,were treated with the 595nm pulsed dye laser. The parameters were as follows: a wavelength of 595 nm, pulse duration of 10ms, spot size of 7 mm and energy fluency of 12.0-13.5 J/cm(2). The treatments were repeated at intervals of 4-6 weeks until the lesion was cleared, or the parents discontinued the treatment. Detailed demographics and the assessment of the degree of lesion clearance were statistically analyzed through SASS18.0. RESULTS: All the 50 patients were treated 1-4 times. The total rate of significant improvement was 80%, and the rate of full recovery was 30%. We failed to find statistical significance between genders, or the size and color of lesions, which might be due to limited sample size. The most common adverse effects after treatment were purpura and edema, which usually lasted for 12 h to several days. Temporary pigment alterations were not common. Other side effects such as scar or skin texture change were not observed. CONCLUSION: Our experience confirmed the clinical efficacy and safety of the 595 nm pulse dye laser in the treatment of Mibelli angiokeratoma. PMID- 25549814 TI - Striae after topical corticosteroid: Treatment with nonablative fractional laser 1540nm. AB - Striae distensae are atrophic dermal scars associated with psychosocial stress. Several treatments have been used but there is no gold standard until now. Fractional photothermolysis has been described as a successful and safe method to treat scars. In this description, we report 4 patients (Fitzpatrick phototype IV) who developed striae distensae after long-term use of topical corticosteroids and were successfully treated with fractional nonablative 1540 nm Erbium: glass laser. PMID- 25549815 TI - Case report: Treatment failure in a case of aquagenic syringeal acrokeratoderma. AB - Aquagenic syringeal acrokeratoderma (ASA) is a rare, acquired, recurrent, and transient type of keratoderma that may occur after a few minutes of exposure to water. Herein, an 18-year-old male patient who had bilateral swelling and whitish plaques on his palms and soles is presented. The lesions on soles and heels developed within short time of immersion in water and resolved after 30 min with drying. In this case, all treatment methods, previously described in the literature in similar cases (i.e., aluminum salts, urea-salicylic acid including ointments, iontophoresis, and botulinum toxin) were ineffective. ASA is a condition that has an adverse effect on life quality. Alternative treatments are needed in ASA cases who are resistant to treatment modalities mentioned in the literature. PMID- 25549816 TI - Carbon dioxide laser plus topical 5-fluorouracil: a new combination therapeutic modality for acral vitiligo. AB - BACKGROUND: Acral vitiligo (AV) is resistant to treatment. AIM: To evaluate efficacy and safety of combining carbon dioxide (CO2) laser and 5-fluorouracil (5FU) in treating AV. METHODS: This study included 68 adult patients with AV. After randomly assigning patients into 3 groups, patients in group I were treated using 5FU, group II were treated using CO2 laser, and group III were treated using CO2 laser followed by 5FU for a maximum period of 5 months. The lesions were then evaluated both qualitatively and quantitatively. RESULTS: Almost half (49.8%) of the lesions in group III achieved G4, and 6.1% of lesions achieved G3 re-pigmentation. This response was statistically significantly higher than that in the other two groups. This was not achieved in periungual areas in the hands and feet. The pain was tolerable during sessions or at sites of 5FU application. Transient hyperpigmentation, brownish spot on nail plates, itching, and infection were temporary side effects; however, Koebnerization was not detected. CONCLUSION: We concluded that prior use of CO2 laser skin ablation, followed by 5FU application for AV is a safe and tolerable technique that improves the outcome and increases patient compliance. PMID- 25549817 TI - Treatment of early-stage erythematotelangiectatic rosacea with a Q-switched 595 nm Nd:YAG laser. AB - Erythematotelangiectatic rosacea presents as persistent erythema and telangiectasia with frequent flushing and blushing on the facial and extrafacial skin. Additionally, papulopustular rosacea shows acneiform papules, pustules, and nodules with persistent plaque-form edema. Despite garnering only grade-C or -D level recommendations, a 585-nm or 595-nm flashlamp-pumped pulsed-dye laser can be considered as an effective therapeutic modality for the treatment of rosacea in patients who are refractory to topical and/or systemic treatments. In this report, treatment with a Q-switched 595-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser with low non-purpuragenic fluence proved to be safe and effective in treating early-stage erythematotelangiectatic rosacea in two female Korean patients. Laser treatment for rosacea was delivered with the settings of pulse energy of 0.4-0.5 J/cm(2), pulse duration of 5-10 ns, 5-mm spot size, 5 Hz, and 500 shots. Additionally, we found that remarkable therapeutic effects were achieved for both rosacea and melasma by combining Q-switched quick pulse-to pulse 1,064-nm Nd:YAG and Q-switched 595-nm Nd:YAG laser treatments, which required only the changing of handpieces equipped with solid dye. In conclusion, we suggest that treatment with a Q-switched 595-nm Nd:YAG laser with low fluence may provide an additional therapeutic option for treating early-stage erythematotelangiectatic rosacea. PMID- 25549818 TI - Comparison of the effects of carboxytherapy and radiofrequency on skin rejuvenation. AB - BACKGROUND: Carboxytherapy (CA) refers to the cutaneous and subcutaneous administration of CO(2) for therapeutic purposes. Radiofrequency (RF) is a method that uses electric current for heating layers of the skin. Both techniques are indicated for the treatment of skin laxity. OBJECTIVE: The aim of this study was to compare the effects of CA and RF on human skin. METHODS: After eight patients underwent abdominoplasty, each of them received a single treatment of CA and a single treatment of RF on the right and left infra-umbilical regions, respectively. In the infra-umbilical region, CA was performed on the right and RF was performed on the left side. Untreated skin was used as a control. The sample collection period lasted 120 days. CA was administered at a velocity of 40 mL/min, and the total quantity of CO(2) infused was approximately 20 mL. RF was carried out at a temperature higher than 40 degrees C on the epidermis for 5 min. RESULTS: CA and RF led to collagen remodeling; however, this result was more evident and lasted longer with RF. With CA an increase in elastic fibers was observed, whereas with RF no alteration was observed. CONCLUSION: Our results suggest that RF is more efficient than CA in stimulating collagen synthesis. PMID- 25549819 TI - Platelet collection efficiencies of three different platelet-rich plasma preparation systems. AB - BACKGROUND: Different systems have been used for the preparation of platelet-rich plasma (PRP), but platelet collection efficiencies of these systems are not clear. OBJECTIVE: To evaluate the platelet collection efficiencies of three different PRP preparation systems. MATERIALS AND METHODS: Blood samples were obtained from the same 16 volunteers for each system. The samples were centrifuged and PRP was prepared by three systems. The ratio of the total number of platelets in PRP to the total number of platelets of the venous blood sample of the patient expressed in percentage was named as platelet collection efficiency and calculated for each system. RESULTS: Mean platelet collection efficiencies were 66.6 (min: 56.9, max: 76.9), 58.3 (min: 27.3, max: 102.8), 50.8 (min: 27.2, max: 73) for top and bottom bag system, system using citrated tube, and the system using tube with Ficoll and cell extraction kit, respectively. Statistically significant difference was found only between the platelet collection efficiencies of systems using the tube with ficoll and cell extraction kit and the top and bottom bag system (p = 0.002). CONCLUSIONS: All three systems could be used for PRP preparation, but top and bottom bag system offers a slight advantage over the system using Ficoll and cell extraction kit regarding the platelet collection efficiency. PMID- 25549820 TI - Enhancing the bioremediation by harvesting electricity from the heavily contaminated sediments. AB - To test the long-term applicability of scaled-up sediment microbial fuel cells (SMFCs) in simultaneous bioremediation of toxic-contaminated sediments and power supply for electronic devices, a 100 L SMFC inoculate with heavily contaminated sediments has been assembled and operated for over 2 years without external electron donor addition. The total organic chemical (TOC) degradation efficiency was 22.1% in the electricity generating SMFCs, which is significantly higher than that in the open-circuited SMFC (3.8%). The organic matters including contaminants in the contaminated sediments were sufficient for the electricity generation of SMFCs, even up to 8.5 years by the present SMFC theoretically. By using a power management system (PMS), the SMFC electricity could be harvested into batteries and used by commercial electronic devices. The results indicated that the SMFC-PMS system could be applied as a long-term and effective tool to simultaneously stimulate the bioremediation of the contaminated sediments and supply power for commercial devices. PMID- 25549821 TI - Anatomical considerations in adult femoral neck fractures: how anatomy influences the treatment issues? AB - Femoral neck fractures in physiologically young adults are relatively uncommon. The reported incidence of avascular necrosis and nonunion rates remain relatively high despite the advancement in understanding and surgical management. Understanding the normal femoral neck anatomy and its relationship to presenting fracture pathology in young adults could help to lessen reported high complication rates to provide better clinical outcomes. PMID- 25549822 TI - Research efforts to control highly pathogenic arenaviruses: a summary of the progress and gaps. AB - Significant progress has been made in the past 10 years in unraveling the molecular biology of highly pathogenic arenaviruses that are endemic in several West African countries (Lassa fever virus) and in some regions of South America (Argentine and Bolivian hemorrhagic fever viruses). While this has resulted in proof-of-concept studies of novel vaccine candidates in non-human primates and in the discovery of several novel antiviral small molecule drug candidates, none of them has been tested in the clinic to date. The recent Ebola outbreak in West Africa has demonstrated very clearly that there is an urgent need to develop the prophylactic and therapeutic armamentarium against viral hemorrhagic fever viruses as part of a global preparedness for future epidemics. As it pertains to this goal, the present article summarizes the current knowledge of highly pathogenic arenaviruses and identifies opportunities for translational research. PMID- 25549823 TI - Management of anticoagulation and antiplatelet therapy in patients with left ventricular assist devices. AB - Left ventricular assist devices (LVADs) have increased the survival of patients with advanced heart failure fourfold. Despite these advances, significant bleeding and thrombotic complications occur. Hemorrhage requiring surgery has been reported in up to 30% of adults and 50% of children after LVAD placement. LVAD thrombosis and embolic stroke lead to significant long-term morbidity. Adults are treated with antithrombotic therapy to prevent thrombotic complications, but the amount and intensity of treatment differs between institutions. The goal international normalized ratio for warfarin therapy varies from 1.5 to 3.0. Some physicians manage adult LVAD patients without antiplatelet medication, whereas other adults are treated with aspirin as a single agent or combined with dipyridamole. In contrast, physicians typically manage children with LVADs using the Edmonton Anticoagulation and Platelet Inhibition Protocol, a detailed algorithm for anticoagulation and antiplatelet treatment modified based on thromboelastography results. LVAD implantation causes consumption of coagulation proteins, activation of fibrinolysis, and loss of high molecular weight von Willebrand protein multimers. How these changes in the coagulation system influence the risk of hemorrhage and initiation of thrombosis is unknown. Prospective, controlled studies are needed to determine the antithrombotic regimen that most effectively balances bleeding and thrombosis in LVAD patients. PMID- 25549824 TI - A three-dimensional water quality model to evaluate the environmental capacity of nitrogen and phosphorus in Jiaozhou Bay, China. AB - Jiaozhou Bay has recently suffered from serious problems with pollution and eutrophication. Thus, land-based pollutant load must be reduced through a national control program. In this study, we developed a 3D water quality model to determine the environmental capacity of nitrogen and phosphorus in Jiaozhou Bay. A 3D hydrodynamic model (the estuarine, coastal, and ocean modeling system with sediments) was coupled with a water quality model, which was adapted from the dynamic model of nitrogen and phosphorus for a mesocosm near Jiaozhou Bay. The water quality model is divided into seven components: dissolved inorganic nitrogen, phosphate, phytoplankton, zooplankton, detritus, dissolved organic nitrogen, and dissolved organic phosphorus. Furthermore, it was calibrated based on data collected from Jiaozhou Bay in 2003. The proposed model effectively reproduced the spatiotemporal variability in nutrient concentration, thus suggesting that a reasonable numerical representation of the prototype system must be developed for further evaluation of environmental capacity. PMID- 25549825 TI - Comparison of organochlorine pesticides and PCB residues among hawksbill (Eretmochelys imbricata) and green (Chelonia mydas) turtles in the Yucatan Peninsula and their maternal transfer. AB - Organochlorine pesticides and PCB (POPs) concentrations were determined in the blood and eggs of green and hawksbill turtles. We compared concentrations between species, analyzed the relationship between turtle size and the POPs concentrations and the relationship between the concentrations in the blood of the nesting turtles and their eggs. We expected higher concentrations in the hawksbill turtle because of its higher trophic level, but concentrations were not higher in all the cases. Significant differences were found in delta-HCH blood concentrations. Lindane, heptachlor epoxide and PCB 101 concentrations were significantly higher in the hawksbill eggs. The relationship between the size of the turtles and the POP concentrations in the eggs of the hawksbills showed a negative correlation. No correlation was found between the size of the female and concentrations in the blood. In eggs, only the hawksbill turtles exhibited negative correlation in the concentration of mirex and PCB 44 and size. PMID- 25549827 TI - Effect of cleaning and disinfection of toys on infectious diseases and micro organisms in daycare nurseries. AB - BACKGROUND: The rising number of children in daycare nurseries increases opportunities for the transmission of infectious diseases. Pathogens may be transmitted directly from child to child via sneezing, coughing and touching, or indirectly via the environment. Toys are among the fomites with the highest pathogen load, but their role in disease transmission is unknown. AIM: To determine if washing and disinfection of toys can reduce sickness absence and microbial pathogen load in the nursery environment. METHODS: Twelve nurseries (caring for 587 children) were randomized to intervention and control groups. The intervention consisted of washing and disinfection of toys and linen every two weeks for three months by a commercial cleaning company. The extent and causes of sickness absence among the children were recorded in both groups before and after introduction of the intervention. Ten sampling points in each nursery were examined for bacteria and respiratory viruses. RESULTS: The presence of respiratory virus DNA/RNA was widespread, but very few pathogenic bacteria were found in the environment. The intervention reduced the presence of adenovirus [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.1-5.0], rhinovirus (OR 5.3, 95% CI 2.3-12.4) and respiratory syncytial virus (OR 4.1, 95% CI 1.5-11.2) compared with the control group, but the intervention had no effect on sickness absence or disease patterns in the nurseries. CONCLUSION: Although cleaning and disinfection of toys every two weeks can decrease the microbial load in nurseries, it does not appear to reduce sickness absence among nursery children. PMID- 25549826 TI - Rationale and design of the dual-energy computed tomography for ischemia determination compared to "gold standard" non-invasive and invasive techniques (DECIDE-Gold): A multicenter international efficacy diagnostic study of rest stress dual-energy computed tomography angiography with perfusion. AB - BACKGROUND: Dual-energy CT (DECT) has potential to improve myocardial perfusion for physiologic assessment of coronary artery disease (CAD). Diagnostic performance of rest-stress DECT perfusion (DECTP) is unknown. OBJECTIVE: DECIDE Gold is a prospective multicenter study to evaluate the accuracy of DECT to detect hemodynamic (HD) significant CAD, as compared to fractional flow reserve (FFR) as a reference standard. METHODS: Eligible participants are subjects with symptoms of CAD referred for invasive coronary angiography (ICA). Participants will undergo DECTP, which will be performed by pharmacological stress, and participants will subsequently proceed to ICA and FFR. HD-significant CAD will be defined as FFR <= 0.80. In those undergoing myocardial stress imaging (MPI) by positron emission tomography (PET), single photon emission computed tomography (SPECT) or cardiac magnetic resonance (CMR) imaging, ischemia will be graded by % ischemic myocardium. Blinded core laboratory interpretation will be performed for CCTA, DECTP, MPI, ICA, and FFR. RESULTS: Primary endpoint is accuracy of DECTP to detect >=1 HD-significant stenosis at the subject level when compared to FFR. Secondary and tertiary endpoints are accuracies of combinations of DECTP at the subject and vessel levels compared to FFR and MPI. CONCLUSION: DECIDE-Gold will determine the performance of DECTP for diagnosing ischemia. PMID- 25549828 TI - Working practices and success of infection prevention and control teams: a scoping study. AB - Little research has been undertaken on how infection prevention and control (IPC) teams operate and how their effectiveness is assessed. This review aimed to explore how IPC teams embed IPC throughout hospitals, balance outbreak management with strategic aspects of IPC work (e.g. education), and how IPC team performance is measured. A scoping exercise was performed combining literature searches, evidence synthesis, and intelligence from expert advisers. Eleven publications were identified. One paper quantified how IPC nurses spend their time, two described daily activities of IPC teams, five described initiatives to embed IPC across organizations following legislation since 1999 in the UK or changes in the delivery of healthcare, and three explored the contribution of IPC intermediaries (link nurses and champions). Eight publications reported research findings. The others reported how IPC teams are embedding IPC practice in UK hospitals. In conclusion, there is scope for research to explore different models of IPC team working and effectiveness, and cost-effectiveness. Other topics that need addressing are the willingness and ability of ward staff to assume increased responsibility for IPC and the effectiveness of intermediaries. PMID- 25549829 TI - Subjective experiences of illness recovery in individuals treated for first episode psychosis. AB - PURPOSE: Individuals with psychotic disorders identify several parallel dimensions of recovery as being important, including illness related, personal and social domains. Learning how patients deal with the experience of psychosis and recovery early in the course of illness may provide insights for improvement of early intervention services. The primary aim of the present research is to explore experiences related to recovery for individuals receiving services following a first episode of psychosis (FEP) in a specialized early intervention (SEI) program and to examine key turning points that shape such recovery. METHODS: Semi-structured interviews were carried out with 30 individuals in early recovery following an FEP. Interpretative phenomenological analysis (IPA) was used to examine the subjectively identified important processes and turning points in relation to the illness domain of recovery. RESULTS: Participants described several early recovery processes including symptom recovery; reconciling the meaning of the illness experience; regaining control over the experience; and negotiation and acceptance of treatment. Of particular relevance were the various turning points associated with the recovery processes that were described. CONCLUSIONS: Differences in illness acceptance trajectories and the turning points within such trajectories have important implications for understanding psychological adjustment to the experience of psychosis, its diagnosis and treatment. These findings underline the importance of assisting individuals with the construction of meaning following the initial illness experience. PMID- 25549830 TI - In Vivo Visualization of (Auto)Immune Processes in the Central Nervous System of Rodents. AB - The CNS is effectively shielded from the periphery by the blood-brain barrier (BBB) which limits the entry of cells and solutes. However, in autoimmune disorders such as multiple sclerosis, immune cells can overcome this barrier and induce the formation of CNS inflammatory lesions. Recently, two-photon laser scanning microscopy (TPLSM) has made it possible to visualize autoimmune processes in the living CNS in real time. However, along with a high microscopy standard, this technique requires an advanced surgical procedure to access the region of interest. Here, we describe in detail the necessary methodological steps to visualize (auto)immune processes in living rodent tissue. We focus on the procedures to image the leptomeningeal vessels of the thoracic spinal cord during transfer experimental autoimmune encephalomyelitis in LEW rats (AT EAE) and in active EAE in C57BL/6 mice (aEAE). PMID- 25549831 TI - Using Human Induced Pluripotent Stem Cells to Model Skeletal Diseases. AB - Musculoskeletal disorders affecting the bones and joints are major health problems among children and adults. Major challenges such as the genetic origins or poor diagnostics of severe skeletal disease hinder our understanding of human skeletal diseases. The recent advent of human induced pluripotent stem cells (human iPS cells) provides an unparalleled opportunity to create human-specific models of human skeletal diseases. iPS cells have the ability to self-renew, allowing us to obtain large amounts of starting material, and have the potential to differentiate into any cell types in the body. In addition, they can carry one or more mutations responsible for the disease of interest or be genetically corrected to create isogenic controls. Our work has focused on modeling rare musculoskeletal disorders including fibrodysplasia ossificans progressive (FOP), a congenital disease of increased heterotopic ossification. In this review, we will discuss our experiences and protocols differentiating human iPS cells toward the osteogenic lineage and their application to model skeletal diseases. A number of critical challenges and exciting new approaches are also discussed, which will allow the skeletal biology field to harness the potential of human iPS cells as a critical model system for understanding diseases of abnormal skeletal formation and bone regeneration. PMID- 25549832 TI - (1)H-magnetic resonance spectroscopy in social anxiety disorder. AB - BACKGROUND: Social anxiety disorder (SAD) is characterized by excessive anxiety about social interaction or performance situations, leading to avoidance and clinically significant distress. A growing literature on the neurobiology of SAD has suggested that the reward/avoidance basal ganglia circuitry in general and the glutamatergic system in particular may play a role. In the current study, we investigated (1)H-magnetic resonance spectroscopy ((1)H-MRS) concentrations in cortical, striatal, and thalamic circuitry, as well as their associations with measures of social anxiety and related symptoms, in patients with primary SAD. METHODOLOGY: Eighteen adult individuals with SAD and 19 age- and sex- matched controls participated in this study. (1)H-MRS was used to determine relative metabolite concentrations in the anterior cingulate cortex (ACC) using single voxel spectroscopy (reporting relative N-acetyl-aspartate (NAA), N-acetyl aspartate with N-acetyl-aspartyl-glutamate (NAA+NAAG), glycerophosphocholine with phosphocholine (GPC+PCh), myo-inositol, glutamate (Glu), and glutamate with its precursor glutamine (Glu+Gln)), and the caudate, putamen and thalami bilaterally using two dimensional chemical shift imaging (reporting relative NAA+NAAG and GPC+PCh). Relationships between metabolite concentrations and measures of social anxiety and related symptoms were also determined. Measures of social anxiety included symptom severity, blushing propensity, and gaze anxiety/avoidance. RESULTS: We found, first, decreased relative glutamate concentration in the ACC of SAD and changes in myo-inositol with measures of social anxiety. Second, NAA metabolite concentration was increased in thalamus of SAD, and choline metabolite concentrations were related to measures of social anxiety. Lastly, choline metabolite concentration in the caudate and putamen showed changes in relation to measures of social anxiety. CONCLUSION: These findings are consistent with evidence that the reward/avoidance basal ganglia circuitry, as well as the glutamatergic system, play a role in mediating SAD symptoms. PMID- 25549834 TI - Novel spinal pathways identified by neuronal c-Fos expression after urethrogenital reflex activation in female guinea pigs. AB - Pudendal nerve-spinal pathways are involved in urethrogenital sensation, pain and sexual activity. However, details of these pathways and their modulation are unclear. We examined spinal pathways activated by the urethrogenital reflex (UGR) and visualized by c-Fos immunoreactivity in reflexly activated neurons within spinal cord. In anesthetized female guinea pigs, a balloon was inserted into the urethra and inflated with short-repeat or long-continuous distension to activate the UGR. A second balloon recorded reflex contractions of the vagina and uterus. Two control groups had either no balloon or a vaginal balloon (VB) only. Ninety minutes after UGR activation, c-Fos immunoreactivity in L3 and S2 spinal segments was examined. Reflex activated c-Fos immunoreactivity also was investigated in some animals with acute spinal transections at either L4 or T12 levels. There was no significant difference in spinal c-Fos expression between the control groups. Short-repeat distension reliably induced a UGR and a two- to threefold increase in c-Fos-expressing neurons throughout dorsal, intermediate and lateral spinal gray matter at S2 and about twofold increase in superficial dorsal horn at L3. T12 transection had little effect on c-Fos expression at either spinal level. However, after L4 transection, UGR generation was associated with a four- to sixfold increase in c-Fos-expressing neurons in lateral horn (LH) and central canal areas at S2, and but only 20-30% increase at L3. Thus, UGR activates preganglionic neurons projecting to pelvic viscera in both sacral and lumbar spinal cord. The reflex also must activate ascending and descending spinal inhibitory circuits that suppress c-Fos-expression in neurons at both sacral and lumbar spinal levels. PMID- 25549833 TI - The association between dietary inflammatory index and risk of colorectal cancer among postmenopausal women: results from the Women's Health Initiative. AB - PURPOSE: Inflammation is a process central to carcinogenesis and in particular to colorectal cancer (CRC). Previously, we developed a dietary inflammatory index (DII) from extensive literature review to assess the inflammatory potential of diet. In the current study, we utilized this novel index in the Women's Health Initiative to prospectively evaluate its association with risk of CRC in postmenopausal women. METHODS: The DII was calculated from baseline food frequency questionnaires administered to 152,536 women aged 50-79 years without CRC at baseline between 1993 and 1998 and followed through 30 September 2010. Incident CRC cases were ascertained through a central physician adjudication process. Multiple covariate-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95 % confidence intervals (95 % CI) for colorectal, colon (proximal/distal locations), and rectal cancer risk, by DII quintiles (Q). RESULTS: During an average 11.3 years of follow-up, a total of 1,920 cases of CRC (1,559 colon and 361 rectal) were identified. Higher DII scores (representing a more pro-inflammatory diet) were associated with an increased incidence of CRC (HRQ5-Q1 1.22; 95 % CI 1.05, 1.43; p trend = 0.02) and colon cancer, specifically proximal colon cancer (HRQ5-Q1 1.35; 95 % CI 1.05, 1.67; p trend = 0.01) but not distal colon cancer (HRQ5-Q1 0.84; 95 % CI 0.61, 1.18; p trend = 0.63) or rectal cancer (HRQ5-Q1 1.20; 95 % CI 0.84, 1.72; p trend = 0.65). CONCLUSION: Consumption of pro-inflammatory diets is associated with an increased risk of CRC, especially cancers located in the proximal colon. The absence of a significant association for distal colon cancer and rectal cancer may be due to the small number of incident cases for these sites. Interventions that may reduce the inflammatory potential of the diet are warranted to test our findings, thus providing more information for colon cancer prevention. PMID- 25549836 TI - Editorial (thematic issue: all roads of renal hypertension lead to or come from CKD). PMID- 25549837 TI - Children with chronic kidney disease and hypertension: could hypertension footprints be early biomarkers? AB - Hypertension (HT) is one of the major problems in chronic kidney disease (CKD), not only for adults, but also for children. It is one of the main factors in the progression of CKD, increased rate of cardiovascular disease, and impairment in quality of life. The most important devastating effect of HT is on the cardiovascular system. It may leave significant footprints in developing children that can be carried over to adulthood. Existing data clearly show that in CKD children with proteinuria the blood pressure goal should be 50th centile, while it is 75th centile in those without proteinuria. Renin-angiotensin system inhibitors are considered the first choice pharmacological option in hypertensive CKD stage 2 to 4 patients. However, in clinical practice, pediatric nephrologists may experience significant problems in treatment and follow-up of these patients, especially in compliance. Due to multiple drug use, physician-patient and family cooperation would be essential to improve the compliance. Remembering the fact that prevention is always cheaper than treatment, we need early detection of CKD and its devastating complications, like HT. Therefore, active screening programs should be encouraged in children, as well as trying to find new biomarkers, inspired from the footprints of HT. Although the researches on new urinary biomarkers for early detection of CKD and HT are promising, more studies are needed in this area. This review aims to give an overview of HT in CKD children, mainly focusing on importance of HT, basic principles of treatment, problems in follow up, and possible markers for early detection of CKD and HT. PMID- 25549835 TI - LAG3 expression in active Mycobacterium tuberculosis infections. AB - Mycobacterium tuberculosis (MTB) is a highly successful pathogen because of its ability to persist in human lungs for long periods of time. MTB modulates several aspects of the host immune response. Lymphocyte-activation gene 3 (LAG3) is a protein with a high affinity for the CD4 receptor and is expressed mainly by regulatory T cells with immunomodulatory functions. To understand the function of LAG3 during MTB infection, a nonhuman primate model of tuberculosis, which recapitulates key aspects of natural human infection in rhesus macaques (Macaca mulatta), was used. We show that the expression of LAG3 is highly induced in the lungs and particularly in the granulomatous lesions of macaques experimentally infected with MTB. Furthermore, we show that LAG3 expression is not induced in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection. However, simian immunodeficiency virus-induced reactivation of latent tuberculosis infection results in an increased expression of LAG3 in the lungs. This response is not observed in nonhuman primates infected with non-MTB bacterial pathogens, nor with simian immunodeficiency virus alone. Our data show that LAG3 was expressed primarily on CD4(+) T cells, presumably by regulatory T cells but also by natural killer cells. The expression of LAG3 coincides with high bacterial burdens and changes in the host type 1 helper T-cell response. PMID- 25549838 TI - The use of thiazides in chronic kidney disease. AB - Hypertension is often difficult to control in patients with chronic kidney disease. Clinicians often view thiazide and thiazide-like diuretics as being ineffective in reducing blood pressure in patients with chronic kidney disease, and prefer to use loop diuretics, especially if the estimated glomerular filtration rate (eGFR) is below 50 ml/min/1.73m(2). Recent clinical trial data indicate that thiazide and thiazide-like diuretics possess important and clinically significant antihypertension properties, that are likely independent of volume reduction, even in patients with eGFR in the 15-45 ml/min range. Thiazide and thiazide-like diuretics should be given consideration for use in the treatment of hypertension in patients with chronic kidney disease, especially if there is no clinical evidence of volume overload. PMID- 25549839 TI - Central blood pressure in chronic kidney disease: latest evidence and clinical relevance. AB - Chronic kidney disease (CKD) has been consistently associated with cardiovascular disease; there is an inverse graded relationship between glomerular filtration rate and cardiovascular risk. Early-moderate CKD receives increasing recognition for its role as an independent risk factor as evidenced by its recent inclusion in the Joint British Societies' consensus recommendations for the prevention of cardiovascular disease. Data from both imaging and epidemiological studies suggest arterial stiffening and structural left ventricular disease (hypertrophy and fibrosis) are the key pathogenic mediators of cardiovascular disease in CKD. This review discusses the rationale for measuring central blood pressure in patients with CKD and whether it could provide incremental prognostic value beyond that of peripheral blood pressure. PMID- 25549840 TI - Vascular calcification and subendocardial ischemia in hemodialysis patients: a new morpho-functional score to assess cardiovascular risk: the Solofra score. AB - BACKGROUND: ESRD (end-stage renal disease) patients have a high cardiovascular mortality risk. A morphofunctional approach of vascular calcifications and myocardial perfusion is needed for the management of ESRD patients. We used SEVR (sub-endocardial viability ratio) and Kauppila score from the dialysis population of the Independent study to create a new morpho-functional score to assess cardiovascular risk in this population (the Solofra score). MATERIALS AND METHODS: 184 patients were followed-up for 36 months. A side lumbar X-ray was performed to assess vascular calcifications of lumbar aorta using the Kauppila score. Central aortic pressure and pulse velocity wave (PWV) were assessed at the carotid artery site. Myocardial perfusion was estimated with SEVR. Independent risk mortality factors were identified with univariate regression analysis (p<0.01); significance was defined as p<0.05. RESULTS: Kauppila score was 13+/ 10(range 0-24); PWV was 9.5+/-4 m/sec; basal SEVR was 1.3+/-0.9. We observed an improvement of ROC curves for SEVR and Kauppila score together compared to the ones for SEVR or Kauppila score alone. CONCLUSION: A quantitative analysis of vascular calcifications should be associated to a qualitative evaluation of arterial damage to better estimate cardiovascular mortality risk of ESRD patients. Further studies are needed to verify our hypothesis. PMID- 25549841 TI - RAAS inhibition and cardiorenal syndrome. AB - The consensus conference on cardio-renal syndromes (2008) defined 'cardio-renal syndromes' as 'disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other' and identified five subtypes of the syndromes. Various pathophysiologic mechanisms underlie cardiorenal syndrome including hemodynamic derangements, reduced cardiac output leading to impaired renal perfusion, reduced stroke volume, raised atrial filling pressures, elevated atrial pressures, sodium and water retention, venous congestion, right ventricular dysfunction and venous hypertension causing increased renal venous pressure, intra-abdominal hypertension, various neurohormonal adaptations including activation of the renin angiotensin-aldosterone system, adaptive activation of the sympathetic nervous system, cytokine release and oxidative stress. Although there are standardized clinical guidelines for the management of heart failure, and chronic kidney disease, respectively, there are no similar consensus clinical guidelines for the management of the cardiorenal syndromes. RAAS inhibition is advocated in treating systolic heart failure. There is evidence that RAAS inhibition is also useful in cardiorenal syndrome. However, RAAS inhibition, while potentially useful in the management of cardiorenal syndrome, is not the 'magic bullet', is sometimes limited by adverse renal events, is not applicable to all patients, and must be applied by physicians with due diligence and caution. Nevertheless, a more comprehensive multidisciplinary multipronged approach to managing patients with cardiorenal syndrome is even more pragmatic and commonsense given the multiple mechanisms and pathogenetic pathways implicated in the causation and perpetuation of cardiorenal syndrome. PMID- 25549842 TI - Reduction of sodium intake is a prerequisite for preventing and curing high blood pressure in hypertensive patients - second part: guidelines. AB - In the last decade many guidelines and report have been published about the optimal restriction of sodium intake for blood pressure control which deserve to be discussed in the medical community at large. The list includes i. the 2005 Dietary Guidelines of the Department of Health and Human Services and US Department of Agriculture; ii. The 2010 Dietary Guidelines for Americans; iii. The 2011 Presidential Statement of American Heart Association; iiii. The 2012 WHO guidelines on sodium intake in adults and children, v. The 2013 Report of the Institute of Medicine of the National Academies of the United States. All of them support the efficacy and feasibility of sodium restriction for blood pressure control. PMID- 25549843 TI - Effect of oral alkali supplementation on progression of chronic kidney disease. AB - Metabolic acidosis is a frequent but asymptomatic complication in chronic kidney disease (CKD). In early stages of CKD acidosis is limited to the renal tissue and progresses to reduced serum bicarbonate levels. Reduced renal tissue pH and increased ammoniagenesis are the key mechanisms of the kidney to enhance acid excretion to the urine. The expressed protein patterns in the proximal tubular epithelial cells change remarkably, the proximal convoluted tubule develops hypertrophy, and an intra-renal enhanced renin-angiotensin-system leads to interstitial fibrosis. Since nephrons are numerically reduced in CKD each remaining functional unit has to progressively increase these mechanisms to keep up the equilibrium. The adverse effects of chronic metabolic acidosis include aside from acceleration of progression of kidney disease, the development or exacerbation of bone disease, increased degradation of muscle with muscle wasting, enhanced protein degradation and inflammation. Genome wide association studies demonstrated that tubular acid-base transporters are involved in the development of arterial hypertension. Several retrospective analyses have indicated that low serum bicarbonate predicts death in cohorts with CKD and cardiovascular disease. All studies confirmed a U-shaped association of mortality and serum bicarbonate, indicating that both, acidosis and alkalosis are associated with increased mortality. Randomized controlled trials showed that base substitution, either by modification of the diet or by simply adding alkalizing agents, might halt the decline of kidney function in subjects with CKD. In 2012 a meta-analysis concluded that alkali therapy might provide a long term favorable effect on renal function in patients with CKD. PMID- 25549844 TI - Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma. AB - Since 2011, the approval of four different classes of novel drugs (the anti-CTLA 4 agent, ipilimumab; BRAF inhibitors [BRAFi]; MEK inhibitors [MEKi]; and the anti PD-1 drug, pembrolizumab) has revolutionized the care of advanced melanoma, with the disease becoming a model for the development of new treatments for other types of cancer. Further advances in the treatment of melanoma represented some of the key highlights of the European Society of Medical Oncology (ESMO) 2014 congress. The first phase III trial of an anti-PD-1 agent to report the CA209-037 study included 405 patients with metastatic melanoma previously treated with ipilimumab who were randomized 2:1 to receive nivolumab 3 mg/kg every 2 weeks or investigator's choice chemotherapy. Nivolumab was associated with a higher response rate than chemotherapy and was well tolerated, with adverse events mostly low grade and manageable using recommended treatment algorithms. New data on other immunotherapies, namely ipilimumab and pembrolizumab, were also reported. In addition, outside of immunotherapy, combination approaches involving targeted agents were also a major focus of ESMO this year, with two major phase III studies of combined BRAF inhibition and MEK inhibition being reported. Overall, new clinical trial findings reported at ESMO further endorse the view that melanoma, given the continued development of novel, effective compounds, can accurately be described as the most "dynamic" field of oncology at present. PMID- 25549845 TI - DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma. AB - Chimeric antigen receptor (CAR) T cell therapies hold great potential for treating cancers, and new CARs that can target multiple tumor types and have the potential to target non-hematological malignancies are needed. In this study, the tumor recognition ability of a natural killer cell-activating receptor, DNAM-1 was harnessed to design CARs that target multiple tumor types. DNAM-1 ligands, PVR and nectin-2, are expressed on primary human leukemia, myeloma, ovarian cancer, melanoma, neuroblastoma, and Ewing sarcoma. DNAM-1 CARs exhibit high tumor cell cytotoxicity but low IFN-gamma secretion in vitro. In contrast to other CAR designs, co-stimulatory domains did not improve the expression and function of DNAM-1 CARs. A DNAM-1/CD3zeta CAR reduced tumor burden in a murine melanoma model in vivo. In conclusion, DNAM-1-based CARs may have the potential to treat PVR and nectin-2 expressing hematological and solid tumors. PMID- 25549847 TI - Fatal traumatic aneurysm of the posterior inferior cerebellar artery with delayed rupture. AB - Traumatic aneurysms of intracranial arteries are rare, forming less than 1% of all intracranial arteries. They may be associated with penetrating and non penetrating trauma. Most cases are associated with fracturing of the skull. Rupture of traumatic aneurysms occur in up to 50% of cases and are typically delayed from days to weeks following the initiating trauma. We report a case of a 22-year-old man who was punched to the head. He was rendered unconscious but recovered and had a GCS of 14 on admission. CT scans showed subarachnoid hemorrhage. An initial angiogram was negative but on day 7 following the incident he was noted to have a 1 mm aneurysm of the posterior inferior cerebellar artery on CT angiogram. On day 9 he collapsed and was found to have new subarachnoid hemorrhage and to have a 4.0 mm * 3.7 mm. He did not recover and was declared brain dead on day 12. At autopsy, there was a 4.0 mm aneurysm of the left PICA just after the origin of the artery. Histological examination confirmed the presence of a traumatic false aneurysm in the left PICA. This case study shows sequential radiological imaging with pathologiocal correlation. PMID- 25549846 TI - Changing trends in biotechnology of secondary metabolism in medicinal and aromatic plants. AB - MAIN CONCLUSION: Medicinal and aromatic plants are known to produce secondary metabolites that find uses as flavoring agents, fragrances, insecticides, dyes and drugs. Biotechnology offers several choices through which secondary metabolism in medicinal plants can be altered in innovative ways, to overproduce phytochemicals of interest, to reduce the content of toxic compounds or even to produce novel chemicals. Detailed investigation of chromatin organization and microRNAs affecting biosynthesis of secondary metabolites as well as exploring cryptic biosynthetic clusters and synthetic biology options, may provide additional ways to harness this resource. Plant secondary metabolites are a fascinating class of phytochemicals exhibiting immense chemical diversity. Considerable enigma regarding their natural biological functions and the vast array of pharmacological activities, amongst other uses, make secondary metabolites interesting and important candidates for research. Here, we present an update on changing trends in the biotechnological approaches that are used to understand and exploit the secondary metabolism in medicinal and aromatic plants. Bioprocessing in the form of suspension culture, organ culture or transformed hairy roots has been successful in scaling up secondary metabolite production in many cases. Pathway elucidation and metabolic engineering have been useful to get enhanced yield of the metabolite of interest; or, for producing novel metabolites. Heterologous expression of putative plant secondary metabolite biosynthesis genes in a microbe is useful to validate their functions, and in some cases, also, to produce plant metabolites in microbes. Endophytes, the microbes that normally colonize plant tissues, may also produce the phytochemicals produced by the host plant. The review also provides perspectives on future research in the field. PMID- 25549848 TI - Up-regulated 14-3-3beta and 14-3-3zeta proteins in prefrontal cortex of subjects with schizophrenia: effect of psychotropic treatment. AB - 14-3-3 is a family of conserved regulatory proteins that bind to a multitude of functionally diverse signalling proteins. Various genetic studies and gene expression and proteomic analyses have involved 14-3-3 proteins in schizophrenia (SZ). On the other hand, studies about the status of these proteins in major depressive disorder (MD) are still missing. Immunoreactivity values of cytosolic 14-3-3beta and 14-3-3zeta proteins were evaluated by Western blot in prefrontal cortex (PFC) of subjects with schizophrenia (SZ; n=22), subjects with major depressive disorder (MD; n=21) and age-, gender- and postmortem delay-matched control subjects (n=52). The modulation of 14-3-3beta and 14-3-3zeta proteins by psychotropic medication was also assessed. The analysis of both proteins in SZ subjects with respect to matched control subjects showed increased 14-3-3beta (Delta=33+/-10%, p<0.05) and 14-3-3zeta (Delta=29+/-6%, p<0.05) immunoreactivity in antipsychotic-free but not in antipsychotic-treated SZ subjects. Immunoreactivity values of 14-3-3beta and 14-3-3zeta were not altered in MD subjects. These results show the specific up-regulation of 14-3-3beta and 14-3 3zeta proteins in PFC of SZ subjects and suggest a possible down-regulation of both proteins by antipsychotic treatment. PMID- 25549849 TI - Drug repositioning approaches for the discovery of new therapeutics for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD. PMID- 25549851 TI - Centrally administered isoproterenol induces sympathetic outflow via brain prostaglandin E2-mediated mechanisms in rats. AB - Brain beta-adrenoceptor stimulation can induce elevations of plasma levels of noradrenaline. However, there have been no detailed studies related to signaling pathways downstream of beta-adrenoceptors responsible for central sympathetic outflow. In the present study, we pharmacologically examined the possibility that centrally administered isoproterenol can induce elevations of plasma noradrenaline levels in a brain prostaglandin-dependent manner. In addition, we also examined whether or not intracerebroventricular administration of isoproterenol could release endogenously synthesized prostaglandin (PG) E2 in the hypothalamic paraventricular nucleus (PVN) by using the brain microdialysis technique combined with liquid chromatography-ion trap tandem mass spectrometry (LC-ITMS(n)). Under urethane anesthesia, a femoral venous line was inserted for infusion of saline and a femoral arterial line was inserted for collecting blood samples. Next, animals were placed in a stereotaxic apparatus for application of test agents. Catecholamines in the plasma were extracted by alumina absorption and were assayed by high-performance liquid chromatography with electrochemical detection. Quantification of PGE2 in rat PVN microdialysates was performed by the LC-ITMS(n) method. We demonstrated that centrally administered isoproterenol induced elevations of plasma noradrenaline could be mediated via activation of beta-adrenoceptors and the downstream phospholipase A2-cyclooxygenase pathway. Furthermore, PGE2 in the PVN and the PGE2 receptor EP3 subtype appear to play an important role in the process. Our results suggest that central isoproterenol induced sympathetic outflow is mediated via brain PGE2 in a PGE2 receptor EP3 subtype-dependent manner. PMID- 25549850 TI - Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset. AB - The neuroprotective efficacy of adaptive epigenetics, wherein beneficial gene expression changes are induced by nonharmful "conditioning" stimuli, is now well established in several acute, preclinical central nervous system injury models. Recently, in a mouse model of glaucoma, we demonstrated retinal ganglion cell (RGC) protection by repetitively "preconditioning" with hypoxia prior to disease onset, indicating an epigenetic approach may also yield benefits in chronic neurodegenerative disease. Herein, we determined whether presenting the repetitive hypoxic stimulus after disease initiation [repetitive hypoxic "postconditioning" (RH-Post)] could afford similar functional and morphologic protection against glaucomatous RGC injury. Chronic elevations in intraocular pressure (IOP) were induced unilaterally in adult male C57BL/6 mice by episcleral vein ligation. Mice were randomized to an RH-Post [1 h of systemic hypoxia (11% oxygen) every other day, starting 4 days after IOP elevation] or an untreated control group. After 3 weeks of experimental glaucoma, the 21-27% reduction and 5 25% prolongation in flash visual-evoked potential amplitudes and latencies, respectively, and the 30% impairment in visual acuity were robustly improved in RH-Post-treated mice, as was the 17% loss in RGC soma number and 20% reduction in axon integrity. These protective effects were observed without RH-Post affecting IOP. The present findings demonstrate that functional and morphologic protection of RGCs can be realized by stimulating epigenetic responses during the early stages of disease, and thus constitute a new conceptual approach to glaucoma therapeutics. PMID- 25549852 TI - Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs. AB - Electrospinning was introduced as a novel technique for preparing controlled release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR-SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR-SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6-8 degrees C/0% RH) and ambient room temperature (22 degrees C/0% RH). At higher temperature and humidity (30 degrees C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR-SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR-SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX. PMID- 25549853 TI - In-vitro evaluation of the effect of polymer structure on uptake of novel polymer insulin polyelectrolyte complexes by human epithelial cells. AB - The biocompatibility and cellular uptake of polymer, insulin polyelectrolyte complexes (PECs) prepared using polyallylamine-based polymers was evaluated in vitro using Caco-2 cell monolayers as a predictive model for human small intestinal epithelial cells. Poly(allyl amine) (PAA) and Quaternised PAA (QPAA) were thiolated using either carbodiimide mediated conjugation to N-acetylcysteine (NAC) or reaction with 2-iminothiolane hydrochloride yielding their NAC and 4 thiobutylamidine (TBA) conjugates, respectively. The effect of polymer quaternisation and/or thiolation on the IC50 of PAA was determined by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay carried out on Caco-2 cells (with and without a 24 h recovery period after samples were removed). Uptake of PECs by Caco-2 cells was monitored by microscopy using fluorescein isothiocyanate (FITC) labelled insulin and rhodamine-labelled polymers at polymer:insulin ratios (4:5) after 0.5, 1, 2 and 4 h incubation in growth media (+/-calcium) and following pre-incubation with insulin. MTT results indicated that quaternisation of PAA was associated with an improvement in IC50 values; cells treated with QPAA (0.001-4 mg mL(-1)) showed no signs of toxicity following a 24 h cell recovery period, while thiolation of QPAA resulted in a decrease in the IC50. Cellular uptake studies showed that within 2-4 h, QPAA and QPAA-TBA insulin PECs were taken up intracellularly, with PECs being localised within the perinuclear area of cells. Further investigation showed that uptake of PECs was unaffected when calcium-free media was used, while presaturating insulin receptors affected the uptake of QPAA, insulin PECs, but not QPAA-TBA PECs. The biocompatibility of PAA and uptake of insulin was improved by both thiol and quaternary substitution. PMID- 25549854 TI - Change in hippocampal theta activity during behavioral inhibition for a stimulus having an overlapping element. AB - It is believed that a decline in hippocampal theta power is induced by response inhibition for a conflict stimulus having an overlapping element. This study used a simultaneous feature positive (simul FP: A-, AX+) task and a serial FP (A-, X >A+) task. In these tasks, the compound and single stimuli have an overlapping element, and rats are required to exhibit response inhibition for the single stimulus A. We examined hippocampal theta activity during simul FP (A-, AX+), serial FP (A-, X->A+), and simple discrimination (SD; A-, X+) tasks and revealed that the transient decrease in hippocampal theta power occurred during response inhibition for the single stimulus A in simul FP tasks, which provides evidence that a transient decline in hippocampal theta power is induced by behavioral inhibition of conflict stimuli having an overlapping element. Thus, we concluded that the transient decline in hippocampal theta power was induced by behavioral inhibition for the conflict stimulus having an overlapping element. PMID- 25549856 TI - Acute aerobic exercise enhances attentional modulation of somatosensory event related potentials during a tactile discrimination task. AB - Neuroimaging research has shown that acute bouts of moderate intensity aerobic exercise can enhance attention-based neuronal activity in frontal brain regions, namely in the prefrontal cortex (PFC), as well as improve cognitive performance. The circuitry of the PFC is complex with extensive reciprocal corticocortical and thalamocortical connections, yet it remains unclear if aerobic exercise can also assist attentional control over modality-specific sensory cortices. To test this, we used a tactile discrimination task to compare tactile event-related potentials (ERPs) prior to and following an acute bout of moderate intensity aerobic exercise. We hypothesized that exercise preceding performance of the task would result in more efficient sensory gating of irrelevant/non-attended and enhancement of relevant/attended sensory information, respectively. Participants received vibrotactile stimulation to the second and fifth digit on the left hand and reported target stimuli on one digit only. ERP amplitudes for the P50, P100, N140 and long latency positivity (LLP) were quantified for attended and non attended trials at FC4, C4, CP4 and P4 while P300 amplitudes were quantified in response to attended target stimuli at electrodes FCZ, CZ and CPZ. Results showed no effect of attention on the P50, however, both P100 and LLP amplitudes were significantly greater during attended, task-relevant trials, while the N140 was enhanced for non-attended, task-irrelevant stimuli. Moreover, unattended N140 amplitudes over parietal sites contralateral to stimulation were significantly greater post-exercise versus pre-exercise, while LLP modulation varied with greater unattended amplitudes post-exercise over frontal sites and greater attended amplitudes post-exercise over parietal sites. These results suggest that a single session of moderate intensity aerobic exercise facilitated the sensory gating of task-irrelevant tactile stimuli so that relevant sensory signals could be enhanced at later stages of somatosensory processing in healthy young adults. PMID- 25549857 TI - Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour. AB - The transcription factor neuronal PAS domain-containing protein 4 (Npas4), which regulates the formation of inhibitory synapses on excitatory neurons, has been suggested as a candidate gene for neurological and psychiatric conditions such as bipolar depression, autism spectrum and cognitive disorders. A mouse model of Npas4 deficiency has been developed to investigate any role in these disorders. Behavioural characterisation of Npas4(-/-), Npas4(+/-) and Npas4(+/+) mice has been conducted using the open field, elevated zero maze (EZM), Y-maze, sociability test and forced swim test (FST) to investigate a range of behaviours. Npas4(-/-) mice spent more time in the open arm of the EZM than other genotypes, suggesting decreased anxiety-like behaviour. Npas4(+/-) mice, however, were more immobile in the FST than other genotypes, suggesting increased depression-like behaviour, and also showed impaired spatial recognition memory in the Y-maze. There were no differences between genotype in social behaviour. These results suggest that differential levels of Npas4 expression in the brain may regulate anxiety, depression and cognition related disorders. PMID- 25549855 TI - A systems approach to stress, stressors and resilience in humans. AB - The paper focuses on the biology of stress and resilience and their biomarkers in humans from the system science perspective. A stressor pushes the physiological system away from its baseline state toward a lower utility state. The physiological system may return toward the original state in one attractor basin but may be shifted to a state in another, lower utility attractor basin. While some physiological changes induced by stressors may benefit health, there is often a chronic wear and tear cost due to implementing changes to enable the return of the system to its baseline state and maintain itself in the high utility baseline attractor basin following repeated perturbations. This cost, also called allostatic load, is the utility reduction associated with both a change in state and with alterations in the attractor basin that affect system responses following future perturbations. This added cost can increase the time course of the return to baseline or the likelihood of moving into a different attractor basin following a perturbation. Opposite to this is the system's resilience which influences its ability to return to the high utility attractor basin following a perturbation by increasing the likelihood and/or speed of returning to the baseline state following a stressor. This review paper is a qualitative systematic review; it covers areas most relevant for moving the stress and resilience field forward from a more quantitative and neuroscientific perspective. PMID- 25549858 TI - Dawn simulation light impacts on different cognitive domains under sleep restriction. AB - Chronic sleep restriction (SR) has deleterious effects on cognitive performance that can be counteracted by light exposure. However, it is still unknown if naturalistic light settings (dawn simulating light) can enhance daytime cognitive performance in a sustainable matter. Seventeen participants were enrolled in a 24 h balanced cross-over study, subsequent to SR (6-h of sleep). Two different light settings were administered each morning: a) dawn simulating light (DsL; polychromatic light gradually increasing from 0 to 250 lx during 30 min before wake-up time, with light around 250 lx for 20 min after wake-up time) and b) control dim light (DL; <8 lx). Cognitive tests were performed every 2 h during scheduled wakefulness and questionnaires were completed hourly to assess subjective mood. The analyses yielded a main effect of "light condition" for the motor tracking task, sustained attention to response task and a working memory task (visual 1 and 3-back task), as well as for the Simple Reaction Time Task, such that participants showed better task performance throughout the day after morning DsL exposure compared to DL. Furthermore, low performers benefited more from the light effects compared to high performers. Conversely, no significant influences from the DsL were found for the Psychomotor Vigilance Task and a contrary effect was observed for the digit symbol substitution test. No light effects were observed for subjective perception of sleepiness, mental effort, concentration and motivation. Our data indicate that short exposure to artificial morning light may significantly enhance cognitive performance in a domain specific manner under conditions of mild SR. PMID- 25549859 TI - Morphometric changes in subcortical structures of the central auditory pathway in mice with bilateral nodular heterotopia. AB - Malformations of cortical development (MCD) have been observed in human reading and language impaired populations. Injury-induced MCD in rodent models of reading disability show morphological changes in the auditory thalamic nucleus (medial geniculate nucleus; MGN) and auditory processing impairments, thus suggesting a link between MCD, MGN, and auditory processing behavior. Previous neuroanatomical examination of a BXD29 recombinant inbred strain (BXD29-Tlr4(lps-2J)/J) revealed MCD consisting of bilateral subcortical nodular heterotopia with partial callosal agenesis. Subsequent behavioral characterization showed a severe impairment in auditory processing-a deficient behavioral phenotype seen across both male and female BXD29-Tlr4(lps-2J)/J mice. In the present study we expanded upon the neuroanatomical findings in the BXD29-Tlr4(lps-2J)/J mutant mouse by investigating whether subcortical changes in cellular morphology are present in neural structures critical to central auditory processing (MGN, and the ventral and dorsal subdivisions of the cochlear nucleus; VCN and DCN, respectively). Stereological assessment of brain tissue of male and female BXD29-Tlr4(lps-2J)/J mice previously tested on an auditory processing battery revealed overall smaller neurons in the MGN of BXD29-Tlr4(lps-2J)/J mutant mice in comparison to BXD29/Ty coisogenic controls, regardless of sex. Interestingly, examination of the VCN and DCN revealed sexually dimorphic changes in neuronal size, with a distribution shift toward larger neurons in female BXD29-Tlr4(lps-2J)/J brains. These effects were not seen in males. Together, the combined data set supports and further expands the observed co-occurrence of MCD, auditory processing impairments, and changes in subcortical anatomy of the central auditory pathway. The current stereological findings also highlight sex differences in neuroanatomical presentation in the presence of a common auditory behavioral phenotype. PMID- 25549860 TI - A clinical prediction model to assess surgical outcome in patients with cervical spondylotic myelopathy: internal and external validations using the prospective multicenter AOSpine North American and international datasets of 743 patients. AB - BACKGROUND CONTEXT: Clinical prediction rules are valuable tools in a surgical setting but should not be used to guide clinical practice until validated in other populations. PURPOSE: The objective of this study was to validate a clinical prediction rule developed to determine surgical outcome in patients with cervical spondylotic myelopathy (CSM). The study will also identify key clinical predictors of outcome at a global level. STUDY DESIGN/SETTING: This is a prospective multicenter cohort study. PATIENT SAMPLE: Two-hundred seventy-eight and 479 surgical CSM patients enrolled in the AOSpine CSM-North American (CSM-NA) and CSM-International (CSM-I) studies, respectively. OUTCOME MEASURES: The outcome measure was a Modified Japanese Orthopedic Association (mJOA) Scale. METHODS: A clinical prediction model was built using data from 272 patients enrolled in the CSM-NA study. Bootstrapping was used for internal validation. The original model was externally validated using data on 471 patients participating in the CSM-I study. The predictive performance of the model was evaluated, including its discrimination, measured by area under the receiver-operating curve (AUC), and calibration, assessed by calibration slope, observed:expected ratios, and Hosmer-Lemeshow goodness-of-fit test. RESULTS: The modified original model consisted of six covariates: age (odds ratio [OR], 0.96), duration of symptoms (0.76), baseline severity score (1.21), psychiatric comorbidities (0.44), impairment of gait (2.48), and smoking status (0.50). The AUC for the original model was 0.77 (95% confidence interval [CI]: 0.71, 0.82) and across the bootstrap replicates was 0.77 (95% CI: 0.76, 0.77), reflecting good discrimination and internal validity. The model tested on the CSM-I dataset yielded an AUC of 0.74 (95% CI: 0.69, 0.79), a calibration slope of 0.75, and an insignificant Hosmer-Lemeshow test. The ORs generated for baseline mJOA (OR, 1.26), impairment of gait (2.67), age (0.97), and smoking (0.55) were very similar to the original values of 1.28, 2.39, and 0.97, respectively. Duration of symptoms (OR, 0.94) had a significantly different odds ratio than in the original model, but the direction of its relationship with outcome was the same. Psychiatric comorbidities was not a significant predictor at an international level, likely because of underreporting: only six patients outside of North American centers were diagnosed with depression or bipolar. CONCLUSIONS: The parameter estimates generated from the original analysis were internally valid. The original model was also externally valid. The most significant global predictors of surgical outcome were baseline myelopathy severity, age, smoking status and impaired gait. PMID- 25549861 TI - Concentrations of polycyclic aromatic hydrocarbons in resuspendable fraction of settled bus dust and its implications for human exposure. AB - This preliminary study measured Polycyclic Aromatic Hydrocarbons (PAHs) concentrations in the resuspendable fraction of settled dust on 39 bus lines, to evaluate the impact of engine type (gasoline and compressed natural gas) on exposure for commuters and drivers. Benzo(b)fluoranthene(BbF) was the predominant PAH in resuspendable fraction of settled bus dust. The concentration of total PAHs was 92.90 +/- 116.00 MUg/g (range: 0.57-410) in gasoline buses and 3.97 +/- 1.81 (range: 2.01-9.47) in compressed natural gas (CNG) buses. Based on Benzo[a]pyrene (BaP) equivalent concentrations for the sum of 16 PAHs, the average daily dose (ADD) via dust ingestion and dermal contact was calculated. The ADD of PAHs was higher for commuters and drivers in gasoline-powered buses than in buses using CNG buses. For both short and long duration journeys, young commuters were exposed to higher levels of PAHs via dust ingestion and dermal contact than adult commuters. PMID- 25549862 TI - Transformation of ceria nanoparticles in cucumber plants is influenced by phosphate. AB - Transformation is a critical factor that affects the fate and toxicity of manufactured nanoparticles (NPs) in the environment and living organisms. This paper aims to investigate the effect of phosphate on the transformation of CeO2 NPs in hydroponic plants. Cucumber seedlings were treated with 2000 mg/L CeO2 NPs in nutrient solutions with or without adding phosphate (+P or -P) for 3 weeks. Large quantities of needle-like CePO4 was found outside the epidermis in the +P group. While in the -P group, CePO4 only existed in the intercellular spaces and vacuole of root cells. X-ray absorption near edge spectroscopy (XANES) indicates that content and percentage of Ce-carboxylates in the shoots of -P group (418 mg/kg, 67.5%) were much higher than those in the +P group (30.1 mg/kg, 21%). The results suggest that phosphate might influence the transformation process of CeO2 NPs in plants and subsequently their ultimate fate in the ecosystem. PMID- 25549863 TI - Tissue-specific bioaccumulation of human and veterinary antibiotics in bile, plasma, liver and muscle tissues of wild fish from a highly urbanized region. AB - We investigated the bioaccumulation of antibiotics in bile, plasma, liver and muscle tissues of wild fish from four rivers in the Pearl River Delta region. In total, 12 antibiotics were present in at least one type of fish tissues from nine wild fish species in the four rivers. The mean values of log bioaccumulation factors (log BAFs) for the detected antibiotics in fish bile, plasma, liver, and muscle tissues were at the range of 2.06-4.08, 1.85-3.47, 1.41-3.51, and 0.48 2.70, respectively. As the digestion tissues, fish bile, plasma, and liver showed strong bioaccumulation ability for some antibiotics, indicating a different bioaccumulation pattern from hydrophobic organic contaminants. Human health risk assessment based on potential fish consumption indicates that these antibiotics do not appear to pose an appreciable risk to human health. To the best of our knowledge, this is first report of bioaccumulation patterns of antibiotics in wild fish bile and plasma. PMID- 25549864 TI - Characterizing distribution, sources, and potential health risk of polybrominated diphenyl ethers (PBDEs) in office environment. AB - This study evaluated the levels and spatial distribution of PBDEs in 9 typical offices in Shanghai, China through the sample analysis of air and settled dust (floor dust, desktop dust and dust in computer case). PBDEs in air ranged from 93 to 322 pg/m(3), while the PBDEs levels in dust varied from 247 to 3.3 * 10(4) ng/g. Spatial variability of PBDEs in office dust was evident and likely influenced by air exchange and the use of electronic devices. A significant positive linear correlation was observed between the power usage rate and PBDE levels in both office air (R(2) = 0.81) and settled dust (R(2) = 0.94). The PBDEs exposure via inhalation and dust ingestion were both analyzed to estimate the life-time cancer risk, which is 1.34 * 10(-22) to 7.16 * 10(-22), significantly lower than the threshold level (10(-6)). Non-cancer risk indicated by the hazard index (<1) is also low in current exposure conditions. PMID- 25549865 TI - Bioaccumulation and oxidative stress responses measured in the estuarine ragworm (Nereis diversicolor) exposed to dissolved, nano- and bulk-sized silver. AB - The impact of Ag NPs on sediment-dwelling organisms has received relatively little attention, particularly in linking bioaccumulation to oxidative injury. The polychaete Nereis diversicolor was exposed to sediments spiked with dissolved Ag (added as AgNO3), Ag NPs (63 +/- 27 nm) and larger bulk Ag particles (202 +/- 56 MUm), for up to 11 days at sublethal concentrations (nominally 2.5, 5, 10 MUg Ag g(-1) sediment (dw)). There were concentration- and time-dependent differences in the accumulation of the three Ag forms, but all three forms elicited an oxidative stress response. In the cases of Ag NPs and bulk Ag particles, changes in antioxidant markers (glutathione, SOD, CAT, GPx, SeGPx, GST and GR) occurred without significant Ag accumulation. Differences in biomarker profiles between the three Ag forms suggest that the mechanism of oxidative stress caused by particulate Ag is distinct from that of dissolved Ag. PMID- 25549866 TI - Modeling the impacts of wildfire on runoff and pollutant transport from coastal watersheds to the nearshore environment. AB - Wildfire is a common disturbance that can significantly alter vegetation in watersheds and affect the rate of sediment and nutrient transport to adjacent nearshore oceanic environments. Changes in runoff resulting from heterogeneous wildfire effects are not well-understood due to both limitations in the field measurement of runoff and temporally-limited spatial data available to parameterize runoff models. We apply replicable, scalable methods for modeling wildfire impacts on sediment and nonpoint source pollutant export into the nearshore environment, and assess relationships between wildfire severity and runoff. Nonpoint source pollutants were modeled using a GIS-based empirical deterministic model parameterized with multi-year land cover data to quantify fire-induced increases in transport to the nearshore environment. Results indicate post-fire concentration increases in phosphorus by 161 percent, sediments by 350 percent and total suspended solids (TSS) by 53 percent above pre fire years. Higher wildfire severity was associated with the greater increase in exports of pollutants and sediment to the nearshore environment, primarily resulting from the conversion of forest and shrubland to grassland. This suggests that increasing wildfire severity with climate change will increase potential negative impacts to adjacent marine ecosystems. The approach used is replicable and can be utilized to assess the effects of other types of land cover change at landscape scales. It also provides a planning and prioritization framework for management activities associated with wildfire, including suppression, thinning, and post-fire rehabilitation, allowing for quantification of potential negative impacts to the nearshore environment in coastal basins. PMID- 25549867 TI - Increased hip fracture and mortality in chronic kidney disease individuals: the importance of competing risks. AB - BACKGROUND: Many studies have shown a correlation between chronic kidney disease (CKD) and fracture. However, increased mortality in CKD patients is a competing risk scenario not accounted for in previous studies. Our aim was to investigate the true impact of CKD on hip fracture after accounting for a competing risk with death. METHODS: We conducted a population-based cohort study to determine the impact of CKD on hip fractures in individuals aged >=50years old registered in the SIDIAP(Q) database (representative of 1.9 million people in Catalonia, Spain). Cox regression was used to estimate hazard ratio (HR) for death and hip fracture according to CKD status. A competing risk (Fine and Gray) model was fitted to estimate sub-HR for hip fracture in CKD or CKD-free patients accounting for differential mortality. RESULTS: A total of 873,073 (32,934 (3.8%) CKD) patients were observed for 3 years. During follow-up, 4,823 (14.6%) CKD and 36,328 (4.3%) CKD-free participants died (HR, 1.83 [95% CI, 1.78-1.89]), whilst 522 (1.59%) and 6,292 (0.75%) sustained hip fractures, respectively. Adjusted Cox models showed a significantly increased risk of hip fractures for the CKD group (HR, 1.16 [1.06-1.27]), but this association was attenuated in competing risk models accounting for mortality (SHR, 1.14 [1.03-1.27]). CONCLUSIONS: Both death and hip fracture rates are increased (by 83% and 16%, respectively) in CKD patients. However, the association between CKD and hip fractures is attenuated when an excess of mortality is taken into account. A competing risk with death must be considered in future analyses of association between CKD and any health outcomes. PMID- 25549868 TI - Inhibition of FSS-induced actin cytoskeleton reorganization by silencing LIMK2 gene increases the mechanosensitivity of primary osteoblasts. AB - Mechanical stimulation plays an important role in bone cell metabolic activity. However, bone cells lose their mechanosensitivity upon continuous mechanical stimulation (desensitization) and they can recover the sensitivity with insertion of appropriate rest period into the mechanical loading profiles. The concrete molecular mechanism behind the regulation of cell mechanosensitivity still remains unclear. As one kind of mechanosensitive cell to react to the mechanical stimulation, osteoblasts respond to fluid shear stress (FSS) with actin cytoskeleton reorganization, and the remodeling of actin cytoskeleton is closely associated with the alteration of cell mechanosensitivity. In order to find out whether inhibiting the actin cytoskeleton reorganization by silencing LIM-kinase 2 (LIMK2) gene would increase the mechanosensitivity of primary osteoblasts, we attenuated the formation of actin stress fiber under FSS in a more specific way: inhibiting the LIMK2 expression by RNA interference. We found that inhibition of LIMK2 expression by RNA interference attenuated the formation of FSS-induced actin stress fiber, and simultaneously maintained the integrity of actin cytoskeleton in primary osteoblasts. We confirmed that the decreased actin cytoskeleton reorganization in response to LIMK2 inhibition during FSS increased the mechanosensitivity of the osteoblasts, based on the increased c-Fos and COX-2 expression as well as the enhanced proliferative activity in response to FSS. These data suggest that osteoblasts can increase their mechanosensitivity under continuous mechanical stimulation by reducing the actin stress fiber formation through inhibiting the LIMK2 expression. This study provides us with a new and more specific method to regulate the osteoblast mechanosensitivity, and also a new therapeutic target to cure bone related diseases, which is of importance in maintaining bone mass and promoting osteogenesis. PMID- 25549869 TI - Successful treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ. AB - BRONJ has become a well-known, occasionally severe side effect of bisphosphonate therapy, as well as a clinical problem. Although treatment recommendations exist, no standard therapy has yet been established for BRONJ. Also, these recommendations identify several limitations that prevent clinicians from confidently diagnosing BRONJ. The aim of the present study was to establish a treatment approach in which all patients with exposed, infected bone or intraoral/extraoral fistulas were treated with sitafloxacin (STFX). We examined 20 BRONJ patients, fourteen with cancer and six with osteoporosis. We used the current updated definition of BRONJ (12), except that we included patients who had shown symptoms for a minimum of only one month, rather than two months. Thus half of our patients had infection with no exposed, necrotic bone in the oral cavity. We purposely excluded all patients exhibiting no signs of infection (current Stages 0 and 1). In addition, each potentially causative organism was isolated from pus collected from an intraoral or extraoral fistula in ten patients on their first visit to our department. 90% of the patients had received a course of treatment with common antibiotics. STFX was administered to all patients. We then re-evaluated the lesion every other week, to determine whether epithelialization was present. We recommended surgical treatment for cases without epithelialization within 4 weeks after the onset of administration of STFX even if bone was not exposed at the lesion. 19 of our 20 cases of Stages 2-3 BRONJ responded to 2-10 weeks of STFX treatment by entering either a remission or healed phase. While surgery was done on thirteen cases, seven others reached such phases without surgery. Every patient had at least one bacterial species that showed resistance to common antibiotics. All species in all patients were susceptible to STFX. Our results indicate that STFX, with or without minor surgery, gives a high probability of controlling infection in BRONJ patients with persistent infection after use of common antibiotics, leading to remission and/or complete healing in 95% of patients. PMID- 25549870 TI - Evaluation of the interindividual human variation in bioactivation of methyleugenol using physiologically based kinetic modeling and Monte Carlo simulations. AB - The present study aims at predicting the level of formation of the ultimate carcinogenic metabolite of methyleugenol, 1'-sulfooxymethyleugenol, in the human population by taking variability in key bioactivation and detoxification reactions into account using Monte Carlo simulations. Depending on the metabolic route, variation was simulated based on kinetic constants obtained from incubations with a range of individual human liver fractions or by combining kinetic constants obtained for specific isoenzymes with literature reported human variation in the activity of these enzymes. The results of the study indicate that formation of 1'-sulfooxymethyleugenol is predominantly affected by variation in i) P450 1A2-catalyzed bioactivation of methyleugenol to 1' hydroxymethyleugenol, ii) P450 2B6-catalyzed epoxidation of methyleugenol, iii) the apparent kinetic constants for oxidation of 1'-hydroxymethyleugenol, and iv) the apparent kinetic constants for sulfation of 1'-hydroxymethyleugenol. Based on the Monte Carlo simulations a so-called chemical-specific adjustment factor (CSAF) for intraspecies variation could be derived by dividing different percentiles by the 50th percentile of the predicted population distribution for 1'-sulfooxymethyleugenol formation. The obtained CSAF value at the 90th percentile was 3.2, indicating that the default uncertainty factor of 3.16 for human variability in kinetics may adequately cover the variation within 90% of the population. Covering 99% of the population requires a larger uncertainty factor of 6.4. In conclusion, the results showed that adequate predictions on interindividual human variation can be made with Monte Carlo-based PBK modeling. For methyleugenol this variation was observed to be in line with the default variation generally assumed in risk assessment. PMID- 25549871 TI - Metal chaperones prevent zinc-mediated cognitive decline. AB - Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD 95; AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippocampus. While we demonstrated a small regional increase in hippocampal zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippocampal formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease. PMID- 25549873 TI - Effective termination of status epilepticus by rational polypharmacy in the lithium-pilocarpine model in rats: Window of opportunity to prevent epilepsy and prediction of epilepsy by biomarkers. AB - The pilocarpine rat model, in which status epilepticus (SE) leads to epilepsy with spontaneous recurrent seizures (SRS), is widely used to study the mechanisms of epileptogenesis and develop strategies for epilepsy prevention. SE is commonly interrupted after 30-90min by high-dose diazepam or other anticonvulsants to reduce mortality. It is widely believed that SE duration of 30-60min is sufficient to induce hippocampal damage and epilepsy. However, resistance to diazepam develops during SE, so that an SE that is longer than 30min is difficult to terminate, and SE typically recurs several hours after diazepam, thus forming a bias for studies on epileptogenesis or antiepileptogenesis. We developed a drug cocktail, consisting of diazepam, phenobarbital, and scopolamine that allows complete and persistent SE termination in the lithium-pilocarpine model. A number of novel findings were obtained with this cocktail. (a) In contrast to previous reports with incomplete SE suppression, a SE of 60min duration did not induce epilepsy, whereas epilepsy with SRS developed after 90 or 120min SE; (b) by comparing groups of rats with 60 and 90min of SE, development of epilepsy could be predicted by behavioral hyperexcitability and decrease in seizure threshold, indicating that these read-outs are suited as biomarkers of epileptogenesis; (c) CA1 damage was prevented by the cocktail, but rats exhibited cell loss in the dentate hilus, which was related to development of epilepsy. These data demonstrate that the duration of SE needed for induction of epileptogenesis in this model is longer than previously thought. PMID- 25549878 TI - Using a community-based participatory research approach to evaluate resident predictors of involuntary exit from permanent supportive housing. AB - OBJECTIVE: The aim of this study was to determine an association between resident characteristics at time of entry to permanent supportive housing and exit status. METHODS: A community-based participatory research (CBPR) approach was the guiding framework for the design, implementation and evaluation of this project. This retrospective observational study used an administrative data source from a local permanent supportive housing provider to compare resident characteristics among those who left housing voluntarily or involuntarily. RESULTS: The population based sample (n=407) was comprised of 51% males and 47% African-Americans with a mean age of 40 years (SD=11.8). Involuntary exits (IEs) occurred in 40% of the sample (n=166). IE was less likely with receipt of mainstream benefits, compared to employment income (O.R.=.546, p=.032). IE was more likely for residents self identifying as African-American (O.R.=1.56, p=.037) and when children resided in the household (O.R.=2.03, p=.013). CONCLUSIONS: Despite limitations of community derived data, findings suggest that supportive housing providers consider income source and family status when designing interventions to decrease IEs. A CBPR approach is a promising framework to guide evaluation efforts for supportive housing programs. PMID- 25549872 TI - Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells. AB - Friedreich ataxia is an inherited neurodegenerative disease that leads to progressive disability. There is currently no effective treatment and patients die prematurely. The underlying genetic defect leads to reduced expression of the mitochondrial protein frataxin. Frataxin insufficiency causes mitochondrial dysfunction and ultimately cell death, particularly in peripheral sensory ganglia. There is an inverse correlation between the amount of residual frataxin and the severity of disease progression; therefore, therapeutic approaches aiming at increasing frataxin levels are expected to improve patients' conditions. We previously discovered that a significant amount of frataxin precursor is degraded by the ubiquitin/proteasome system before its functional mitochondrial maturation. We also provided evidence for the therapeutic potential of small molecules that increase frataxin levels by docking on the frataxin ubiquitination site, thus preventing frataxin ubiquitination and degradation. We called these compounds ubiquitin-competing molecules (UCM). By extending our search for effective UCM, we identified a set of new and more potent compounds that more efficiently promote frataxin accumulation. Here we show that these compounds directly interact with frataxin and prevent its ubiquitination. Interestingly, these UCM are not effective on the ubiquitin-resistant frataxin mutant, indicating their specific action on preventing frataxin ubiquitination. Most importantly, these compounds are able to promote frataxin accumulation and aconitase rescue in cells derived from patients, strongly supporting their therapeutic potential. PMID- 25549879 TI - Different sensitivity levels to norspermidine on biofilm formation in clinical and commensal Staphylococcus epidermidis strains. AB - Biofilm formation on medical and surgical devices is the main virulence factor of Staphylococcus epidermidis. A recent study has shown that norspermidine inhibits and disassembles the biofilm in the wild-type Bacillus subtilis NCBI3610 strain. In this study, the effect of norspermidine on S. epidermidis biofilm formation of clinical or commensal strains was tested. Biofilm producing strains of S. epidermidis were isolated from healthy skin (HS; n = 3), healthy conjunctiva (HC; n = 9) and ocular infection (OI; n = 19). All strains were treated with different concentrations of norspermidine, spermidine, putrescine, and cadaverine (1, 10, 25, 50 and 100 MUM), and the biofilm formation was tested on microtiter plate. Besides, cell-free supernatants of S. epidermidis growth at 4 h and 40 h were analyzed by gas chromatography coupled to mass spectrometry (GC-MS) to detect norspermidine. Results showed that norspermidine at 25 MUM and 100 MUM prevented the biofilm formation in 45.16% (14/31) and 16.13% (5/31), respectively; only in one isolate from OI, norspermidine did not have effect. Other polyamines as spermidine, putrescine and cadaverine did not have effect on the biofilm formation of the strains tested. Norspermidine was also capable to disassemble a biofilm already formed. Norspermidine was detected in the 40 h cell-free supernatant of S. epidermidis by GC-MS. Norspermidine inhibited the biofilm development of S. epidermidis on the surface of contact lens. In this work, it was demonstrated that S. epidermidis produces and releases norspermidine causing an inhibitory effect on biofilm formation. Moreover, this is the first time showing that clinical S. epidermidis strains have different sensitivity to norspermidine, which suggest that the composition and structure of the biofilms is varied. We propose that norspermidine could potentially be used in the pre treating of medical and surgical devices to inhibit the biofilm formation. PMID- 25549880 TI - Effect on outcomes and exercise performance of anemia in patients with aortic stenosis who underwent transcatheter aortic valve replacement. AB - The objectives of this study were to determine the causes and impact of anemia and hemoglobin level on functional status, physical performance, and quality of life in the preprocedural evaluation and follow-up of transcatheter aortic valve replacement (TAVR) candidates. A total of 438 patients who underwent TAVR were included. Anemia was defined as a hemoglobin level <12 g/dl in women and <13 g/dl in men. Before TAVR, anemia was encountered in 282 patients (64.4%). A potential treatable cause of anemia was detected in 90.4% of patients and was attributed to iron deficiency in 53% of them. The occurrence of anemia was an independent predictor of poorer performance in the 6-minute walk test (6MWT), a lower Duke Activity Status Index score, and Kansas City Cardiomyopathy Questionnaires overall, clinical, and social limitation scores (p <0.05 for all). A lower hemoglobin level was associated with a higher prevalence of New York Heart Association class III to IV (p <0.001) and correlated negatively with the results of all functional tests (p <0.02 for all). At follow-up, anemia was found in 62% of patients and was associated with poorer performance in the 6MWT (p = 0.023). A lower hemoglobin level after TAVR was a predictor of poorer New York Heart Association class (p = 0.020) and correlated negatively with the distance walked in the 6MWT (r = -0.191, p = 0.004) and Duke Activity Status Index score (r = 0.158, p = 0.011) at 6-month follow-up. In conclusion, anemia was very common in TAVR candidates and was attributed to iron deficiency in more than half of them. The presence of anemia and lower hemoglobin levels determined poorer functional status before and after the TAVR procedure. These results highlight the importance of implementing appropriate measures for the diagnosis and treatment of this frequent co-morbidity to improve both the accuracy of preprocedural evaluation and outcomes of TAVR candidates. PMID- 25549881 TI - Differential diagnosis between early repolarization of athlete's heart and coved type Brugada electrocardiogram. AB - Early repolarization (ER) is typically observed in highly trained athletes as a physiologic consequence of increased vagal tone. The variant of anterior (V1 to V3) ER characterized by "domed" ST-segment elevation and negative T wave raises problems of differential diagnosis with the "coved-type" electrocardiographic pattern seen in Brugada syndrome (BS). This study was designed to identify electrocardiographic criteria for distinguishing athlete's ER from BS. The study compared the electrocardiographic tracings of 61 healthy athletes (80% men, median age 23 +/- 8 years), showing "domed" ST-segment elevation and negative T wave in leads V1 to V3, with those of 92 consecutive age- and sex-matched BS patients with a "coved-type" electrocardiographic pattern. The electrocardiographic analysis focused on the ST-segment elevation at J point (STJ) and at 80 milliseconds after J point (ST80). Athletes had a lower maximum amplitude of STJ (1.46 +/- 0.7 vs 3.25 +/- 0.6 mm, p <0.001) and lower STJ/ST80 (0.8 +/- 0.3 vs 1.6 +/- 0.3, p <0.001). All patients (100%) with BS showed a downsloping ST-segment configuration (STJ/ST80 >1) versus only 2 (3%) athletes (p <0.001). An upsloping ST-segment configuration (STJ/ST80 <1) showed a sensitivity of 97%, a specificity of 100%, and a diagnostic accuracy of 98.7% for the diagnosis of ER. At multivariate analysis, STJ/ST80 ratio remained the only independent predictor for ER (odds ratio 87, 95% confidence interval 19 to 357, p <0.001). In conclusion, the STJ/ST80 ratio is a highly accurate electrocardiographic parameter for differential diagnosis between anterior ER of the athlete and BS. Our results may help in reducing the number of athletes who undergo expensive diagnostic workup or are unnecessarily disqualified from competition for changes that fall within the normal range of athlete's heart. PMID- 25549882 TI - Predictors of ventricular fibrillation at reperfusion in patients with acute ST elevation myocardial infarction treated by primary percutaneous coronary intervention. AB - Ventricular fibrillation (VF) during reperfusion (rVF) in ST-segment elevation myocardial infarction (STEMI) is an infrequent but serious event that complicates coronary interventions. The aim of this study was to analyze clinical predictors of rVF in an unselected population of patients with STEMI treated with percutaneous coronary intervention (PCI). Consecutive patients with STEMI admitted to a tertiary care hospital for primary PCI from 2007 to 2012 were retrospectively assessed for the presence of rVF. Admission electrocardiograms, stored in a digital format, were analyzed for a maximal ST-segment elevation in a single lead and the sum of ST-segment deviations in all leads. Clinical, electrocardiographic, and angiographic characteristics were tested for associations with rVF using logistic regression analysis. Among 3,724 patients with STEMI admitted from 2007 to 2012, 71 (1.9%) had rVF. In univariate analysis, history of myocardial infarction, aspirin and beta-blocker use, VF before PCI, left main coronary artery disease, inferior myocardial infarction localization, symptom-to-balloon time <360 minutes, maximal ST-segment elevation in a single lead >300 MUV, and sum of ST-segment deviations in all leads >1,500 MUV were associated with increased risk for rVF. In a multivariate analysis, sum of ST segment deviations in all leads >1500 MUV (odds ratio 3.7, 95% confidence interval 1.45 to 9.41, p = 0.006) before PCI remained an independent predictor of rVF. In-hospital mortality was 18.3% in the rVF group and 3.3% in the group without VF (p <0.001), but rVF was not an independent predictor of in-hospital death. In conclusion, the magnitude of ST-segment elevation before PCI for STEMI independently predicts rVF and should be considered in periprocedural arrhythmic risk assessment. Despite higher in-hospital mortality in patients with rVF, rVF itself has no independent prognostic value for prognosis. PMID- 25549885 TI - Cardiovascular magnetic resonance for amyloidosis. AB - Cardiac involvement drives the prognosis and treatment in systemic amyloid. Echocardiography, the mainstay of current cardiac imaging, defines cardiac structure and function. Echocardiography, in conjunction with clinical phenotype, electrocardiogram and biomarkers (brain natriuretic peptide and troponin), provides an assessment of the likelihood and extent of cardiac involvement. Two tests are transforming our understanding of cardiac amyloidosis, bone tracer scanning and cardiovascular magnetic resonance (CMR). CMR provides a "second opinion" on the heart's structure and systolic function with better accuracy and more precision than echocardiography but is unable to assess diastolic function and is not as widely available. Where CMR adds unique advantages is in evaluating myocardial tissue characterisation. With administration of contrast, the latest type of late gadolinium enhancement imaging (phase-sensitive inversion recovery sequence) is highly sensitive and specific with images virtually pathognomonic for amyloidosis. CMR is also demonstrating that the range of structural and functional changes in cardiac amyloid is broader than traditionally thought. CMR with T1 mapping, a relatively new CMR technique, can measure the amyloid burden and the myocyte response to infiltration (hypertrophy/cell loss) with advantages for tracking change (e.g. the wall thickness can stay the same but the composition can change) over time or during therapy. Such techniques hold great promise for advancing drug development in this arena and providing new prognostic insights. CMR with tissue characterisation is rewriting our understanding of cardiac amyloidosis and may lead to the development of new classification, therapies and prognostic systems. PMID- 25549887 TI - Curative resection of esophageal cancer with a double aortic arch. AB - Thoracic esophageal cancer with a double aortic arch is extremely rare. We herein report the case of a 63-year-old man with a double aortic arch who underwent an esophagectomy with a three-field lymphadenectomy for cancer in the lower thoracic esophagus. In such cases, it is important to recognize the relationship between the right and left aortic arches and the bilateral recurrent laryngeal nerves (RLNs). We were able to accurately understand the anatomical position of the RLNs using a precedent cervical procedure with partial resection of the manubrium to remove the nodes along the bilateral RLNs. PMID- 25549886 TI - Identification of the third/extra allele for forensic application in cases with TPOX tri-allelic pattern. AB - Genotyping of polymorphic short tandem repeats (STRs) loci is widely used in forensic DNA analysis. STR loci eventually present tri-allelic pattern as a genotyping irregularity and, in that situation, the doubt about the tri-allele locus frequency calculation can reduce the analysis strength. In the TPOX human STR locus, tri-allelic genotypes have been reported with a widely varied frequency among human populations. We investigate whether there is a single extra allele (the third allele) in the TPOX tri-allelic pattern, what it is, and where it is, aiming to understand its genomic anatomy and to propose the knowledge of this TPOX extra allele from genetic profile, thus preserving the two standard TPOX alleles in forensic analyses. We looked for TPOX tri-allelic subjects in 75,113 Brazilian families. Considering only the parental generation (mother+father) we had 150,226 unrelated subjects evaluated. From this total, we found 88 unrelated subjects with tri-allelic pattern in the TPOX locus (0.06%; 88/150,226). Seventy three of these 88 subjects (73/88; 83%) had the Clayton's original Type 2 tri-allelic pattern (three peaks of even intensity). The remaining 17% (15/88) show a new Type 2 derived category with heterozygote peak imbalance (one double dose peak plus one regular sized peak). In this paper we present detailed data from 66 trios (mother+father+child) with true biological relationships. In 39 of these families (39/66; 59%) the extra TPOX allele was transmitted either from the mother or from the father to the child. Evidences indicated the allele 10 as the extra TPOX allele, and it is on the X chromosome. The present data, which support the previous Lane hypothesis, improve the knowledge about tri-allelic pattern of TPOX CODIS' locus allowing the use of TPOX profile in forensic analyses even when with tri-allelic pattern. This evaluation is now available for different forensic applications. PMID- 25549888 TI - Effect of the analyzed hair length on fatty acid ethyl ester (FAEE) concentrations in hair--is there congruence of cut-offs for 0-3 and 0-6 cm hair segments? AB - BACKGROUND: According to the current SoHT consensus for the use of alcohol markers in hair FAEEs can be analyzed in the proximal 0-3 or 0-6 cm segment with the cut-offs 0.2 and 0.4 ng/mg for abstinence assessment and 0.5 and 1.0 ng/mg for chronic excessive alcohol consumption. Both sets of cut-offs should be congruent for uniform interpretation. METHODS: FAEEs were determined in parallel for the 0-3 and the 0-6 cm segment of 157 hair samples and the concentration ratio between both segments (0-3 cm)/(0-6 cm) was calculated. For comparison, EtG was measured in the 0-3 cm segment of 135 of these samples and the FAEE concentration ratio was calculated by re-evaluation of segmental concentrations from further 42 samples of a previous study. RESULTS: The concentration ratio ranged from 0.3 to 1.5 (mean 0.83, median 0.82) and showed that the current cut offs (ratio 0.50) are not congruent and that the cut-offs of the 0-3 cm are more restrictive against alcohol use or abuse. There was no correlation between the ratio and the concentration of FAEEs or EtG showing that the ratio does not depend on the drinking amount. Furthermore, no significant difference of the ratio was found between cosmetically untreated, bleached, dyed or spayed hair samples. Adaptation of the 0-3 cm cut-offs by increasing to 0.3 and 0.8 ng/mg respectively improved the congruence of both segment lengths but did not lead to a better agreement between FAEE and EtG interpretation. CONCLUSIONS: It follows from the results and further literature data that the variable length of the proximal hair segment between 3 and 6 cm which is possible according to the present SoHT consensus additionally contributes to the uncertainty of interpretation caused by biological variability and hair cosmetics. Furthermore, it is improbable from the present state of knowledge that a proximal segment length above 3 cm unambiguously enables the detection of alcohol consumption or abuse occurring more than 3 months before sampling. Therefore, it should be considered in a future consensus to redefine the hair length for both markers on 0-3 cm. PMID- 25549884 TI - Exosome and its roles in cardiovascular diseases. AB - Exosomes are nanosized vesicles secreted by cells, which are capable of carrying signaling molecules in the forms of protein, mRNA and miRNA to serve as the platforms for complex intercellular communications. During the past few years, increasing efforts have been devoted to exosome research, and tremendous progress has been made in terms of identifying the molecular composition, elucidating the mechanisms and regulations of biogenesis and characterizing the functions in a variety of physiological and pathological settings including cardiovascular diseases, a leading cause of morbidity and mortality in modern society. This review provides an update on exosome research and summarizes the roles of exosomes in cardiovascular diseases. PMID- 25549889 TI - Erratum to: Validation of the Italian version of Parkinson's Disease-Cognitive Rating Scale (PD-CRS). PMID- 25549892 TI - Predictors of slow colonic transit in children. AB - PURPOSE: Slow transit constipation (STC) and functional fecal retention (FFR) are two forms of severe intractable constipation in childhood diagnosed by nuclear transit studies (NTS). This retrospective study aims to identify the predicting factors for STC and FFR by looking at the association with neuropsychiatric disorders (NPD), obesity, family history of constipation and atopic disease. PATIENTS AND METHODS: A retrospective chart review was conducted on children with intractable constipation referred for NTS between 1st April 2003 and 1st April 2014. Comparisons were made between STC, FFR and normal transit patients with regards to NPD, obesity (BMI z score >95th percentile), family history of constipation in first and second-degree relatives and atopic disease which included food allergy, asthma and eczema. RESULTS: Between 2003 and 2014, 97 patients were referred for a NTS. Out of 36 patients with NPD, 21 (58.3 %) had STC and 13 (36.1 %) had FFR (p < 0.05). 15.8 % of patients with constipation were obese, compared to 6.4 % in the general Australian paediatric population (p < 0.05). There was no significant association between constipation and atopic disease or family history. CONCLUSION: Neuropsychiatric disorders, in particular autism, are useful predictors of STC and FFR in children. Obesity may be associated with a higher risk of developing chronic constipation. PMID- 25549891 TI - 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. AB - In 1964, Vincent Allfrey and colleagues reported the identification of histone acetylation and with deep insight proposed a regulatory role for this protein modification in transcription regulation. Subsequently, histone acetyltransferases (HATs), histone deacetylases (HDACs) and acetyl-Lys-binding proteins were identified as transcription regulators, thereby providing compelling evidence for his daring hypothesis. During the past 15 years, reversible protein acetylation and its modifying enzymes have been implicated in many cellular functions beyond transcription regulation. Here, we review the progress accomplished during the past 50 years and discuss the future of protein acetylation. PMID- 25549893 TI - Acute phase proteins and stress hormone responses in patients with newly diagnosed active pulmonary tuberculosis. AB - INTRODUCTION: Despite the high burden of disease, there have been surprisingly few studies of the acute phase and plasma catecholamine/cortisol stress hormone responses in patients with active pulmonary tuberculosis. We wished to document acute phase reactant and stress hormone responses in patients with newly diagnosed, active pulmonary tuberculosis and to compare these responses to those of a group of surgical/medical cases with conditions other than tuberculosis. METHODS: This was a prospective study of consecutive patients with newly diagnosed pulmonary tuberculosis, admitted to a tertiary hospital in Johannesburg, South Africa, documenting demographic, clinical, routine laboratory, acute phase protein and stress hormone responses relative to those of the control group. RESULTS: TB patients had a higher body temperature and pulse rate, as well as a platelet counts, ferritin, CRP and dopamine levels, with a tendency to higher cortisol levels compared to the control group. Conversely, they had a lower BMI, haemoglobin, leucocyte count, MCV and epinephrine levels than the control group. CONCLUSIONS: Patients with active pulmonary tuberculosis were documented to mount an acute stress response which was more intense than that of a control group of patients with surgical/medical conditions other than tuberculosis. PMID- 25549890 TI - In the right place at the right time: visualizing and understanding mRNA localization. AB - The spatial regulation of protein translation is an efficient way to create functional and structural asymmetries in cells. Recent research has furthered our understanding of how individual cells spatially organize protein synthesis, by applying innovative technology to characterize the relationship between mRNAs and their regulatory proteins, single-mRNA trafficking dynamics, physiological effects of abrogating mRNA localization in vivo and for endogenous mRNA labelling. The implementation of new imaging technologies has yielded valuable information on mRNA localization, for example, by observing single molecules in tissues. The emerging movements and localization patterns of mRNAs in morphologically distinct unicellular organisms and in neurons have illuminated shared and specialized mechanisms of mRNA localization, and this information is complemented by transgenic and biochemical techniques that reveal the biological consequences of mRNA mislocalization. PMID- 25549894 TI - Thoracic manifestation of Eisenmenger's syndrome in adult patients: a MDCT review. AB - Eisenmenger's syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) associated with congenital heart diseases (CHD). It is caused by simple or complex CHD with a large systemic-to-pulmonary shunt. When the pulmonary pressure exceeds the systemic pressure, the shunt reverses and central cyanosis appears. ES is a progressive and fatal condition, and it is accompanied by an increased risk of a range of potentially life-threatening complications. Patients with ES are both at risk for bleeding, due to damaged capillaries and high pressure, and for in situ pulmonary thrombosis, related to hyper-viscosity and slow blood flow in dilated pulmonary arteries. Moreover, the enlarged main pulmonary arteries and cardiac chambers may determine displacement or extrinsic compression on airways, pulmonary veins, coronary arteries, and other mediastinal structures. The clinical effects may be diverse, such as respiratory difficulties, localized pulmonary edema, cardiac dysfunction, or sudden death. Multidetector computed tomography (MDCT) allows to accurately assess in a single examination, pulmonary parenchyma and vessels, coronary artery origin, and heart chambers. The aim of this review was to illustrate the thoracic MDCT angiography findings and complications of adult patients with PAH-CHD and in particular of those with ES. PMID- 25549895 TI - Trends in self-rated health status and health services use in COPD patients (2006 2012). A Spanish population-based survey. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients often have a significant impairment in their health status, which is an independent predictor of health services use. OBJECTIVES: To describe the self-rated health status and the prevalence of health services use among COPD Spanish patients; to identify which factors are independently associated with a worse health status and a higher use of health services; and to study the time trends in the health status and prevalence of use of health services (2006-2012). METHODS: Observational study: We analyzed data from the Spanish National Health Surveys conducted in 2006 and 2012. We included responses from adults aged 40 years or over. Subjects described their health status as very good, good, fair, poor, or very poor, which was dichotomized into very good/good or fair/poor/very poor self-perceived health status. RESULTS: We identified 2,321 COPD patients. The percentage of patients with health status fair, poor, or very poor was 76.8 % in 2006 and 74.8 % in 2012 (p > 0.05). Regarding the health resources use, we observed a significant decrease in the number of visits to primary care over time in women (67.8 vs. 57.2 %, p < 0.05) and men (62.2 vs. 54.0 %, p < 0.05). However, we did not find improvement in the prevalence of emergency department visits or hospitalizations. Associated factors with a worse self-rated health status and a higher use of health services in women and men included: having three or more chronic diseases, presence of mental disorders, and absence of leisure time physical activity. CONCLUSIONS: The current study revealed a decrease in the general practitioner visits, without changes in use of other health care services in the COPD Spanish population from 2006 to 2012. The self-rated health status did not changed significantly during this period. PMID- 25549896 TI - Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome. AB - BACKGROUND: PTEN gene (MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan-Riley Ruvalcaba syndrome, and Proteus-like syndrome. Bannayan-Riley-Ruvalcaba syndrome is considered as the pediatric form of PHTS. More recently, children presenting autism spectrum disorders with macrocephaly (ASD-M) have been reported. METHODS: We report clinical data from seven patients diagnosed in childhood with a PTEN germline mutation, excluding cases of familial Cowden syndrome. RESULTS: This study underlines the variability of phenotype associated with PTEN mutations diagnosed at pediatric age. Most of the patients did not fulfill usual criteria of Bannayan-Riley-Ruvalcaba syndrome or ASD-M. CONCLUSION: PTEN testing should be considered in any child presenting with severe macrocephaly (>+4SD) and another feature of PHTS. PMID- 25549897 TI - Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2. AB - N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist (S) 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N-[[1-(5-methoxy-2 pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Several of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds. PMID- 25549898 TI - Non-transpeptidase binding arylthioether beta-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis. AB - The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, beta-lactamase resistant monocyclic beta-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine beta-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) beta-lactamase producing Moraxella catarrhalis clinical isolates. PMID- 25549899 TI - Design, synthesis, and evaluation of hybrid vitamin D3 side chain analogues as hedgehog pathway inhibitors. AB - Vitamin D3 (VD3) is a moderately potent and non-selective inhibitor of the Hedgehog (Hh) signaling cascade. Previous studies have established that the CD ring region of VD3 serves as the Hh inhibitory pharmacophore. Subsequently, compound 3, an ester linked aromatic A-ring and CD-ring derivative was identified as an improved and selective Hh inhibitor. Herein, we report modifications of the CD-ring side chain that afford enhancement of selectivity for Hh modulation thereby diminishing the detrimental effects of concomitant vitamin D receptor activation. In general, linear or moderately branched alkyl chains of five or six carbons were optimal for potent and selective inhibition of Hh signaling. Moreover, hybrid VD3 side chain derivative 20 demonstrated 4-fold improvement in Hh antagonistic activity over VD3(IC50=1.1-1.6 MUM) while gaining greater than a 1000-fold selectivity for Hh signaling over canonical activation of the vitamin D receptor pathway. PMID- 25549900 TI - uGPA: unified Gene Pathway Analyzer package for high-throughput genome-wide screening data provides mechanistic overview on human diseases. AB - BACKGROUND: Gene set or pathway analysis (GPA) can provide a comprehensive mechanistic overview in delineating molecular pathoetiology of human diseases. Existing tools that can handle for GPA on both mutational and gene expressional aspects are limited. This leads to the development of uGPA (unified Gene Pathway Analyzer). METHODS: uGPA package provides a unified solution to knowledge base driven competitive GPA that can analyze genome-wide screening data derived from multiple platforms (next generation sequencing or microarray) and sample sources (genomic or transcriptomic) on both mutational and gene expressional perspectives. It allows for a quick assessment of perspective outline of gene sets on the studied disease through enrichment test modeled by cumulative hypergeometric distribution and reports the gene components detected with events (mutation or differential gene expression) in the gene sets. RESULTS: uGPA package has been successfully verified to be applicable on input data generated from NGS-based platforms (transcriptome sequencing and whole-exome sequencing). Genome-wide screening data from other platforms should also apply. CONCLUSIONS: uGPA package delivers a simple, flexible and platform-independent functionality to multiple aspects of GPA. It equips clinicians and scientists with a useful tool in studying molecular mechanism of human diseases using modern high throughput genome-wide screening strategy, which assists personalized therapy. PMID- 25549901 TI - Lipoprotein subfractions partly mediate the association between serum uric acid and coronary artery disease. AB - BACKGROUND: Serum uric acid (SUA) has been established to be highly associated with coronary artery disease (CAD) susceptibility and lipid metabolism, but the underlying mechanisms are unclear. Recently, lipoprotein subfractions have been proposed to be more valuable in CAD risk evaluation. Hence, we sought to investigate whether the relationship between SUA and CAD is partly mediated by lipoprotein subfractions. METHODS: A total of 401 consecutive subjects undergoing coronary angiography were enrolled. The baseline clinical data including the SUA level and lipid profiles were collected. The lipoprotein subfractions were determined using the Lipoprint system. RESULTS: In the overall population, the upper SUA quintiles had significantly higher atherogenic lipid parameters and unbalanced lipoprotein subfractions especially higher small dense low-density lipoprotein-cholesterol (sdLDL-C) and lower large high-density lipoprotein cholesterol (HDL-C) (p<0.05). The levels of SUA and lipoprotein subfractions were dramatically different between male and female. After adjusting for traditional risk factors including gender, multivariate linear regression analysis suggested that SUA was positively associated with sdLDL-C (beta=0.113, p=0.013) but negatively related to large HDL-C level (beta=-0.152, p=0.002). Given the significant association of the SUA level with lipoprotein subfractions and incident CAD (adjusted OR=1.312, 95% CI 1.069-1.609, p=0.009), we performed the mediation analyses and found that 8.7-10.5% of the effect of SUA on CAD susceptibility was mediated by the increased sdLDL-C or decreased large HDL-C level (p<0.05). CONCLUSIONS: The SUA level was proved to be associated with lipoprotein subfractions including sdLDL-C (positive) and large HDL-C (negative), which partly mediated the association between SUA and CAD susceptibility. PMID- 25549902 TI - Fluidized-bed denitrification of mining water tolerates high nickel concentrations. AB - This study revealed that fluidized-bed denitrifying cultures tolerated soluble Ni concentrations up to 500 mg/L at 7-8 and 22 degrees C. From 10 to 40 mg/L of feed Ni, denitrification resulted in complete nitrate and nitrite removal. The concomitant reduction of 30 mg/L of sulfate produced 10 mg/L of sulfide that precipitated nickel, resulting in soluble effluent Ni below 22 mg/L. At this stage, Dechloromonas species were the dominant denitrifying bacteria. From 60 to 500 mg/L of feed Ni, nickel remained in solution due to the inhibition of sulfate reduction. At soluble 60 mg/L of Ni, denitrification was partially inhibited prior to recover after 34 days of enrichment by other Ni-tolerant species (including Delftia, Zoogloea and Azospira) that supported Dechloromonas. Subsequently, the FBR cultures completely removed nitrate even at 500 mg/L of Ni. Visual Minteq speciation model predicted the formation of NiS, NiCO3 and Ni3(PO4)2, whilst only Ni3(PO4)2 was detected by XRD. PMID- 25549903 TI - Steam explosion pretreatment of wheat straw to improve methane yields: investigation of the degradation kinetics of structural compounds during anaerobic digestion. AB - Wheat straw can serve as a low-cost substrate for energy production without competing with food or feed production. This study investigated the effect of steam explosion pretreatment on the biological methane potential and the degradation kinetics of wheat straw during anaerobic digestion. It was observed that the biological methane potential of the non steam exploded, ground wheat straw (276 l(N) kg VS(-1)) did not significantly differ from the best steam explosion treated sample (286 l(N) kg VS(-1)) which was achieved at a pretreatment temperature of 140 degrees C and a retention time of 60 min. Nevertheless degradation speed was improved by the pretreatment. Furthermore it was observed that compounds resulting from chemical reactions during the pretreatment and classified as pseudo-lignin were also degraded during the anaerobic batch experiments. Based on the rumen simulation technique, a model was developed to characterise the degradation process. PMID- 25549904 TI - Bioaugmentation with an acetate-type fermentation bacterium Acetobacteroides hydrogenigenes improves methane production from corn straw. AB - The effect of bioaugmentation with an acetate-type fermentation bacterium in the phylum Bacteroidetes on the anaerobic digestion of corn straw was evaluated by batch experiments. Acetobacteroides hydrogenigenes is a promising strain for bioaugmentation with relatively high growth rate, hydrogen yields and acetate tolerance, which ferments a broad spectrum of pentoses, hexoses and polyoses mainly into acetate and hydrogen. During corn straw digestion, bioaugmentation with A. hydrogenigenes led to 19-23% increase of the methane yield, with maximum of 258.1 mL/g-corn straw achieved by 10% inoculation (control, 209.3 mL/g-corn straw). Analysis of lignocellulosic composition indicated that A. hydrogenigenes could increase removal rates of cellulose and hemicelluloses in corn straw residue by 12% and 5%, respectively. Further experiment verified that the addition of A. hydrogenigenes could improve the methane yields of methyl cellulose and xylan (models for cellulose and hemicelluloses, respectively) by 16.8% and 7.0%. PMID- 25549905 TI - Logistic analysis of algae cultivation. AB - Energy requirements for resource transport of algae cultivation are unknown. This work describes the quantitative analysis of energy requirements for water and CO2 transport. Algae cultivation models were combined with the quantitative logistic decision model 'BeWhere' for the regions Benelux (Northwest Europe), southern France and Sahara. For photobioreactors, the energy consumed for transport of water and CO2 turns out to be a small percentage of the energy contained in the algae biomass (0.1-3.6%). For raceway ponds the share for transport is higher (0.7-38.5%). The energy consumption for transport is the lowest in the Benelux due to good availability of both water and CO2. Analysing transport logistics is still important, despite the low energy consumption for transport. The results demonstrate that resource requirements, resource distribution and availability and transport networks have a profound effect on the location choices for algae cultivation. PMID- 25549906 TI - Antimicrobial activity of prodigiosin isolated from Serratia marcescens UFPEDA 398. AB - Prodigiosin is an alkaloid and natural red pigment produced by Serratia marcescens. Prodigiosin has antimicrobial, antimalarial and antitumor properties and induces apoptosis in T and B lymphocytes. These properties have piqued the interest of researchers in the fields of medicine, pharmaceutics and different industries. The aim of the present study was to evaluate the antimicrobial activity of prodigiosin against pathogenic micro-organisms. The red pigments produced by S. marcescens exhibited absorption at 534 nm, Rf of 0.59 and molecular weight of 323 m/z. Antimicrobial activity was tested against oxacillin resistant Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Acinetobacter sp. and oxacillin resistant S. aureus. The standard antibiotics employed were ampicillin, chloramphenicol, gentamicin and oxacillin. The disc-diffusion tests demonstrated significant inhibition zones for S. aureus (35 +/- 0.6), E. faecalis (22 +/- 1.0) and S. pyogenes (14 +/- 0.6). However, prodigiosin showed resistance to E. coli, P. aeruginosa and acinetobacter, where no significant formation of inhibitory halos were observed. We determined the inhibitory minimum concentrations and bactericidal for 20 strains of oxacillin-resistant S. aureus (ORSA). The pattern was the antibiotic oxacillin. The minimum inhibitory concentrations observed ranged from 1, 2 and 4.0 MUg/mL, respectively, while the minimum bactericidal concentrations ranged from 2, 4, 8 and 16 MUg/mL. The S. marcescens prodigiosin produced by showed bactericidal and bacteriostatic effect showing promising antimicrobial activity and suggesting future studies regarding its applicability in antibiotics therapies directed ORSA. PMID- 25549907 TI - MMN and P300 are both modulated by the featured/featureless nature of deviant stimuli. AB - OBJECTIVE: This study was designed to test the effect of the featured/featureless nature of deviant stimuli on mismatch negativity (MMN), P300 (P3a and P3b) and on behavioral discrimination performances. METHODS: Ten healthy adults were submitted to stimuli contrasted by the presence or absence of a frequency sweep. Discrimination performances were collected during the neurophysiological sessions. RESULTS: MMN, P3a and P3b were much larger for featured deviants than for featureless ones. Behavioral data (d', at ceiling level, and reaction times) were not affected by the featured/featureless nature of the deviant stimulus. CONCLUSION: Behavioral results and MMN amplitudes are in accordance with our previous study, using the same design albeit in an ignore condition and with collection of the behavioral data deferred until after the neurophysiological sessions. The present study strengthens previous evidence suggesting that two mechanisms contribute to the MMN evoked by featured deviants: the memory comparison process and the adaptation/fresh-afferent phenomenons. SIGNIFICANCE: We here demonstrate that the neurophysiological processes underlying P300 generation are also impacted by the featured/featureless nature of the deviant stimulus and that the dissociation from behavioral data, which are not impacted, is also observed when both types of data are recorded simultaneously. PMID- 25549909 TI - Total and monomethyl mercury in terrestrial arthropods from the central California coast. AB - The aim of this project was to obtain a baseline understanding and investigate the concentration of mercury (Hg) in the tissue of terrestrial arthropods. The 4 month sampling campaign took place around Monterey Bay, California. Total mercury (HgT) concentrations (x +/- SD, dry weight) for the captured specimens ranged from 22 to 188 ng g(-1) in the Jerusalem crickets (Orthoptera: Stenopelmatidae); 65-233 ng g(-1) in the camel crickets (Orthoptera: Rhaphidophoridae); 25-227 ng g(-1) in the pill bugs (Isopoda: Armadillidiidae); 19-563 ng g(-1) in the ground beetles (Coleoptera: Carabidae); 140-441 ng g(-1) in the variegated meadowhawk dragonflies (Odonata: Libellulidae); 607-657 ng g(-1) in the pacific spiketail dragonflies (Odonata: Cordulegastridae); and 81-1,249 ng g(-1) in the wolf spiders (Araneae: Lycosidae). A subset of samples analyzed for monomethyl mercury (MMHg) suggest detrital pill bugs have a higher MMHg/HgT ratio than predatory ground beetles. PMID- 25549908 TI - New research developments and insights from Metabolism. PMID- 25549910 TI - A Brief Self-Regulatory Intervention Increases Dental Flossing in Adolescent Girls. AB - BACKGROUND: Oral diseases such as dental caries, periodontal disease, and tooth loss are a considerable public health problem. A review of the epidemiological data from many countries indicates that a global increase in dental caries prevalence affects children as well as adults. Despite the improvement in oral health of children in the last few decades, tooth decay remains one of the most common childhood diseases in both industrialized and developing countries. PURPOSE: The study evaluates the effects of a self-regulatory intervention to increase dental flossing among adolescents and examines the mediating mechanisms underlying behavioral changes. METHODS: A cluster randomized controlled trial compared a brief intervention arm with a control arm in 166 girls aged 11-15 years. Planning, self-efficacy, and behavioral intention were specified as mediators between treatment conditions and follow-up dental flossing frequency. At baseline, the intervention group received theory-guided materials on oral hygiene. Four weeks later, changes in behavior and social-cognitive variables were assessed. RESULTS: The brief self-regulatory intervention led to an increase in dental flossing and social-cognitive constructs. A sequential mediator model was identified in which first changes in intention and afterwards changes in self efficacy mediated between treatment conditions and behavioral outcomes. CONCLUSION: Intention formation and self-efficacy seem to play an instrumental role in the mechanism that facilitates dental flossing among adolescent girls. Oral self-care interventions should consider the application of intention formation strategies combined with building confidence in one's ability to adhere to the regimen. PMID- 25549911 TI - Recent advanced in bioactive systems containing pyrazole fused with a five membered heterocycle. AB - In this review we report the recent advances in bioactive system containing pyrazole fused with a five membered heterocycle, covering the time span of the last decade. All of them are represented around the common structure of the pyrazole ring fused with another five membered heterocycle containing the nitrogen, sulfur and oxygen atoms in all their possible combinations. The classification we have used is based in terms of the therapeutic area providing, when possible, some general conclusions on the targets and mechanisms of action as well as the structure-activity relationships of the molecules. PMID- 25549912 TI - Effects of tootling on classwide disruptive and appropriate behavior of upper elementary students. AB - The current study assessed the effects of a positive peer reporting procedure known as Tootling on classwide disruptive as well as appropriate behavior with fourth- and fifth-grade students and their teachers in two regular education classrooms. Tootling is a technique that teaches students to recognize and report peers' prosocial behavior rather than inappropriate behavior (i.e., as in tattling), and is also a variation on the expression, "tooting your own horn." Tootling combined with an interdependent group contingency and publicly posted feedback were assessed using an ABAB withdrawal design with a multiple baseline element across classrooms. Results demonstrated decreases in classwide disruptive behavior as well as increases in appropriate behavior compared with baseline and withdrawal phases across both classrooms, with results maintained at follow-up. Tootling was also rated highly acceptable by both teachers. Effect size calculations reflected moderate to strong effects across all comparisons. Limitations of the present study, directions for future research, and implications for practice are discussed. PMID- 25549913 TI - Sleep deprivation therapy for depression. AB - Sleep deprivation (SD) is the most widely documented rapid-onset antidepressant therapy, targeting the broadly defined depressive syndrome. Although SD responses are transient, its effects can be sustained by concomitant medications (e.g., selective serotonin reuptake inhibitors and lithium) and circadian-related interventions (e.g., bright light and sleep phase advance). Thus, considering its safety, this technique can now be considered among the first-line antidepressant treatment strategies for patients affected by mood disorders. SD is a complex intervention and it should be considered multi-target in nature. Thus, the mechanisms explaining its antidepressant effect can be looked for on many levels, involving not only monoaminergic mechanisms but also sleep homeostatic and circadian mechanisms, glutamatergic mechanisms and synaptic plasticity. PMID- 25549914 TI - Irish judges rule that brain dead pregnant woman should be allowed to die. PMID- 25549915 TI - Effects of Sustained Lung Inflation, a lung recruitment maneuver in primary acute respiratory distress syndrome, in respiratory and cerebral outcomes in preterm infants. AB - BACKGROUND: Sustained Lung Inflation (SLI) is a maneuver of lung recruitment in preterm newborns at birth that can facilitate the achieving of larger inflation volumes, leading to the clearance of lung fluid and formation of functional residual capacity (FRC). AIM: To investigate if Sustained Lung Inflation (SLI) reduces the need of invasive procedures and iatrogenic risks. STUDY DESIGN: 78 newborns (gestational age<=34 weeks, weighing<=2000 g) who didn't breathe adequately at birth and needed to receive SLI in addition to other resuscitation maneuvers (2010 guidelines). SUBJECTS: 78 preterm infants born one after the other in our department of Neonatology of Catania University from 2010 to 2012. OUTCOME MEASURES: The need of intubation and surfactant, the ventilation required, radiological signs, the incidence of intraventricular hemorrhage (IVH), periventricular leukomalacia, retinopathy in prematurity from III to IV plus grades, bronchopulmonary dysplasia, patent ductus arteriosus, pneumothorax and necrotizing enterocolitis. RESULTS: In the SLI group infants needed less intubation in the delivery room (6% vs 21%; p<0.01), less invasive mechanical ventilation (14% vs 55%; p<=0.001) and shorter duration of ventilation (9.1 days vs 13.8 days; p<=0.001). There wasn't any difference for nasal continuous positive airway pressure (82% vs 77%; p=0.43); but there was less surfactant administration (54% vs 85%; p<=0.001) and more infants received INSURE (40% vs 29%; p=0.17). We didn't found any differences in the outcomes, except for more mild intraventricular hemorrhage in the SLI group (23% vs 14%; p=0.15; OR=1.83). CONCLUSION: SLI is easier to perform even with a single operator, it reduces the necessity of more complicated maneuvers and surfactant without statistically evident adverse effects. PMID- 25549916 TI - Efficacy of treatment of cattle for liver fluke at housing: influence of differences in flukicidal activity against juvenile Fasciola hepatica. AB - Flukicides are commonly administered at housing to cattle that have grazed fluke infected pastures or that have been purchased from endemic areas. The choice of product is determined by numerous factors, one of which is the stages of Fasciola hepatica that are killed. Flukicides can be categorised into three main groups: (A) those that kill all juvenile stages and adults; (B) those that kill juveniles from six to eight weeks of age and adults and (C) those that kill adults only. This study was conducted on a commercial beef farm in Scotland and was designed to compare the efficacy of flukicides from each of these three classes in terms of their effects on faecal egg output, coproantigen and liveweight gain. The majority of animals in the untreated control group were positive for coproantigen, fluke eggs or both throughout the study duration of 16 weeks. Egg reappearance interval following housing treatment was eight weeks for clorsulon and 13 weeks for nitroxynil, though patent infections in both groups developed in only a small minority of animals; no fluke eggs were recovered from cattle treated with triclabendazole. Coproantigen was detected four weeks before the reappearance of fluke eggs in the dung. Animals treated with flukicides had significantly fewer faecal samples positive for eggs (P<0.006) and coproantigen (P<0.05) following treatment compared with the controls. Despite differences in the efficacy profiles among the flukicide-treated groups, there were no significant differences (P>0.05) in growth rates among any of the four treatment groups. There was, however, a significant negative association (P<0.001) between fluke positivity at housing and subsequent growth performance, irrespective of treatment group. PMID- 25549918 TI - Death rate is lower in high risk heart patients at US teaching hospitals during cardiology conferences. PMID- 25549917 TI - Gait knee kinematics after ACL reconstruction: 3D assessment. AB - PURPOSE: While many studies about anterior-cruciate-ligament-deficient (ACLD) patients have demonstrated functional adaptations to protect the knee joint, an increasing number of patients undergo ACL reconstruction (ACLR) surgery in order to return to their desired level of activity. The purpose of this study was to compare 3D kinematic patterns between individuals having undergone ACLR with their healthy contralateral knee and a control group. METHODS: Three-dimensional kinematic data were obtained from 15 patients pre- and post-ACLR, 15 contralateral knees and 15 healthy controls. Data were recorded during treadmill walking at self-selected speed. Flexion/extension, external/internal tibial rotation, adduction/abduction and anterior/posterior tibial translation were compared between groups. RESULTS: ACLR knees showed a significantly higher knee joint extension during the entire stance phase compared with ACLD knees. However, ACLR knees still showed a deficit of extension compared with healthy control knees. In the axial plane, there was no significant difference in pre- and postoperative kinematic data. Significant difference was achieved between ACLR knees and healthy control knees, specifically between 28 and 34 % and 44 and 54 % of the gait cycle. There was no significant difference in anterior-posterior translation or coronal plane between groups. CONLUSION: Following ACL reconstruction, patients have better clinical and kinematic parameters. Despite improvements, knee kinematics during gait in the ACLR group differed from the control group. These kinematic changes could lead to abnormal loading in the knee joint and initiate the process for future chondral degeneration. PMID- 25549919 TI - Media-fill simulation tests in manual and robotic aseptic preparation of injection solutions in syringes. AB - OBJECTIVE: The purpose of this study was to evaluate the contamination rate of media-fill products either prepared automated with a robotic system (APOTECAchemoTM) or prepared manually at cytotoxic workbenches in the same cleanroom environment and by experienced operators. Media fills were completed by microbiological environmental control in the critical zones and used to validate the cleaning and disinfection procedures of the robotic system. METHODS: The aseptic preparation of patient individual ready-to-use injection solutions was simulated by using double concentrated tryptic soy broth as growth medium, water for injection and plastic syringes as primary packaging materials. Media fills were either prepared automated (500 units) in the robot or manually (500 units) in cytotoxic workbenches in the same cleanroom over a period of 18 working days. The test solutions were incubated at room temperature (22C) over 4 weeks. Products were visually inspected for turbidity after a 2-week and 4-week period. Following incubation, growth promotion tests were performed with Staphylococcus epidermidis. During the media-fill procedures, passive air monitoring was performed with settle plates and surface monitoring with contact plates on predefined locations as well as fingerprints. The plates got incubated for 5-7 days at room temperature, followed by 2-3 days at 30-35C and the colony forming units (cfu) counted after both periods. The robot was cleaned and disinfected according to the established standard operating procedure on two working days prior to the media-fill session, while on six other working days only six critical components were sanitized at the end of the media-fill sessions. Every day UV irradiation was operated for 4 h after finishing work. RESULTS: None of the 1000 media-fill products prepared in the two different settings showed turbidity after the incubation period thereby indicating no contamination with microorganisms. All products remained uniform, clear, and light-amber solutions. In addition, the reliability of the nutrient medium and the process was demonstrated by positive growth promotion tests with S. epidermidis. During automated preparation the recommended limits < 1 cfu per settle/contact plate set for cleanroom Grade A zones were not succeeded in the carousel and working area, but in the loading area of the robot. During manual preparation, the number of cfus detected on settle/contact plates inside the workbenches lay far below the limits. The number of cfus detected on fingertips succeeded several times the limit during manual preparation but not during automated preparation. There was no difference in the microbial contamination rate depending on the extent of cleaning and disinfection of the robot. CONCLUSION: Extensive media-fill tests simulating manual and automated preparation of ready-to-use cytotoxic injection solutions revealed the same level of sterility for both procedures. The results of supplemental environmental controls confirmed that the aseptic procedures are well controlled. As there was no difference in the microbial contamination rates of the media preparations depending on the extent of cleaning and disinfection of the robot, the results were used to adapt the respective standard operating procedures. PMID- 25549920 TI - Attention enhances contrast appearance via increased input baseline of neural responses. AB - Covert spatial attention increases the perceived contrast of stimuli at attended locations, presumably via enhancement of visual neural responses. However, the relation between perceived contrast and the underlying neural responses has not been characterized. In this study, we systematically varied stimulus contrast, using a two-alternative, forced-choice comparison task to probe the effect of attention on appearance across the contrast range. We modeled performance in the task as a function of underlying neural contrast-response functions. Fitting this model to the observed data revealed that an increased input baseline in the neural responses accounted for the enhancement of apparent contrast with spatial attention. PMID- 25549922 TI - Effects of Withania somnifera and Tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells: toward targeting multidrug resistance in cancer. AB - Recent reports suggest the existence of a subpopulation of stem-like cancer cells, termed as cancer stem cells (CSCs), which bear functional and phenotypic resemblance with the adult, tissue-resident stem cells. Side population (SP) assay based on differential efflux of Hoechst 33342 has been effectively used for the isolation of CSCs. The drug resistance properties of SP cells are typically due to the increased expression of ABC transporters leading to drug efflux. Conventionally used chemotherapeutic drugs may often leads to an enrichment of SP, revealing their inability to target the drug-resistant SP and CSCs. Thus, identification of agents that can reduce the SP phenotype is currently in vogue in cancer therapeutics. Withania somnifera (WS) and Tinospora cordifolia (TC) have been used in Ayurveda for treating various diseases, including cancer. In the current study, we have investigated the effects of ethanolic (ET) extracts of WS and TC on the cancer SP phenotype. Interestingly, we found significant decrease in SP on treatment with TC-ET, but not with WS-ET. The SP-inhibitory TC ET was further fractionated into petroleum ether (TC-PET), dichloromethane (TC DCM), and n-butyl alcohol (TC-nBT) fractions using bioactivity-guided fractionation. Our data revealed that TC-PET and TC-DCM, but not TC-nBT, significantly inhibited SP in a dose-dependent manner. Furthermore, flow cytometry-based functional assays revealed that TC-PET and TC-DCM significantly inhibited ABC-B1 and ABC-G2 transporters and sensitized cancer cells toward chemotherapeutic drug-mediated cytotoxicity. Thus, the TC-PET and TC-DCM may harbor phytochemicals with the potential to reverse the drug-resistant phenotype, thus improving the efficacy of cancer chemotherapy. PMID- 25549921 TI - Modifying welding process parameters can reduce the neurotoxic potential of manganese-containing welding fumes. AB - Welding fumes (WF) are a complex mixture of toxic metals and gases, inhalation of which can lead to adverse health effects among welders. The presence of manganese (Mn) in welding electrodes is cause for concern about the potential development of Parkinson's disease (PD)-like neurological disorder. Consequently, from an occupational safety perspective, there is a critical need to prevent adverse exposures to WF. As the fume generation rate and physicochemical characteristics of welding aerosols are influenced by welding process parameters like voltage, current or shielding gas, we sought to determine if changing such parameters can alter the fume profile and consequently its neurotoxic potential. Specifically, we evaluated the influence of voltage on fume composition and neurotoxic outcome. Rats were exposed by whole-body inhalation (40 mg/m(3); 3h/day * 5 d/week * 2 weeks) to fumes generated by gas-metal arc welding using stainless steel electrodes (GMA-SS) at standard/regular voltage (25 V; RVSS) or high voltage (30 V; HVSS). Fumes generated under these conditions exhibited similar particulate morphology, appearing as chain-like aggregates; however, HVSS fumes comprised of a larger fraction of ultrafine particulates that are generally considered to be more toxic than their fine counterparts. Paradoxically, exposure to HVSS fumes did not elicit dopaminergic neurotoxicity, as monitored by the expression of dopaminergic and PD-related markers. We show that the lack of neurotoxicity is due to reduced solubility of Mn in HVSS fumes. Our findings show promise for process control procedures in developing prevention strategies for Mn-related neurotoxicity during welding; however, it warrants additional investigations to determine if such modifications can be suitably adapted at the workplace to avert or reduce adverse neurological risks. PMID- 25549923 TI - Impact of Community-Based Programs on Incarceration Outcomes Among Gay and Bisexual Stimulant-Using Homeless Adults. AB - This study was part of a randomized controlled trial designed to improve hepatitis knowledge and health promoting behaviors and subsequently decrease stimulant use and incarceration with 422 (G/B) homeless men between 18 and 46 years of age. Findings revealed that no significant program differences on incarceration in the 4 months following the intervention. However, younger participants (p = .010), and those with prior incarceration (p = .001) were at greater risk for incarceration at 4 months. An additional factor associated with incarceration at 4 months included living on the street for at least 1 week (p = .049). PMID- 25549924 TI - The influence of attention toward facial expressions on size perception. AB - According to the New Look theory, size perception is affected by emotional factors. Although previous studies have attempted to explain the effects of both emotion and motivation on size perception, they have failed to identify the underlying mechanisms. This study aimed to investigate the underlying mechanisms of size perception by applying attention toward facial expressions using the Ebbinghaus illusion as a measurement tool. The participants, female university students, were asked to judge the size of a target stimulus relative to the size of facial expressions (i.e., happy, angry, and neutral) surrounding the target. The results revealed that the participants perceived angry and neutral faces to be larger than happy faces. This finding indicates that individuals pay closer attention to neutral and angry faces than happy ones. These results suggest that the mechanisms underlying size perception involve cognitive processes that focus attention toward relevant stimuli and block out irrelevant stimuli. PMID- 25549925 TI - Structure-activity relationship of flavonoids as potent inhibitors of carbonyl reductase 1 (CBR1). AB - Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces a variety of carbonyl compounds including therapeutic drugs. CBR1 is involved in the reduction of the anthracycline anticancer drugs to their less anticancer C-13 hydroxy metabolites, which are cardiotoxic. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity, a side effect of the drugs. In this study, we evaluated 27 flavonoids for their inhibitory activities of CBR1 in order to explore the structure-activity relationship (SAR). Among them, luteolin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4 one) showed the most potent inhibition (IC5095nM), which is also more potent compared to all known classes of CBR1 inhibitors. The inhibition of luteolin was noncompetitive with respect to the substrate in the NADPH-dependent reduction direction, but CBR1 exhibited moderate NADP(+)-dependent dehydrogenase activity for some alicyclic alcohols, in which the luteolin inhibition was competitive with respect to the alcohol substrate (Ki59nM). The SAR of the flavonoids indicated that the 7-hydroxy group of luteolin was responsible for the potent inhibition of CBR1. The molecular docking of luteolin in CBR1-NADPH complex showed that theflavonoid binds to the substrate-binding cleft, in which its 7 hydroxy group formed a H-bond with main-chain oxygen of Met234, in addition to H bond interactions (of its 5-hydroxy and 4-carbonyl groups with catalytically important residues Tyr193 and/or Ser139) and a pi-stacking interaction (between its phenyl ring and Trp229). PMID- 25549926 TI - Pharmacokinetic and tissue distribution profile of curculigoside after oral and intravenously injection administration in rats by liquid chromatography-mass spectrometry. AB - Curculigoside has an extensive pharmacological activity, including estrogen-like, improving sexual behavior, antiosteoporotic, antioxidant, immunomodulatory and neuroprotective effects. However, few investigations have been conducted about the pharmacokinetics and tissue distribution of curculigoside to better understand its behavior and action mechanism in vivo. Thus, a sensitive and reliable liquid chromatography with mass spectrometry (HPLC-MS) method was established and validated for the quantification of curculigoside in rat plasma and tissue samples. Biological samples were processed with methanol precipitation, and naringin was used as the internal standard. Chromatographic separation was performed on an Agilent XDB-C18 chromatography column (3.0mm*50mm, 1.8MUm) with a mobile phase consisting of acetonitrile and 0.1% formic acid. Quantification was performed by selected ion monitoring with m/z 511.1 [M+HCO2]( ) for curculigoside and m/z 579.1 [M-H](-) for the internal standard. The validated method was successfully applied to the pharmacokinetic and tissue distribution study of curculigoside in rats. Non-compartmental pharmacokinetic parameters indicated that curculigoside had rapid distribution, extensive tissue uptake, and poor absorption into systemic circulation. The values of absolute bioavailability were 0.38%, 0.22% and 0.27% for oral doses of 100, 200 and 400mg/kg, respectively. The results of the tissue distribution study suggested that curculigoside was distributed into the heart, lung, spleen, intestine, stomach, kidney, thymus, liver, brain, testis, and bone marrow after oral administration of 150mg/kg. In conclusion, the present study may provide a material basis for study of the pharmacological action of curculigoside, and meaningful insights into further study on clinical application. PMID- 25549927 TI - Two new lignans from Saururus chinensis and their DGAT inhibitory activity. AB - Two new lignans were isolated from Saururus chinensis, along with eight known compounds. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1 and DGAT2. Among them, compounds 2, 3, 5 and 7 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 44.3+/-1.5 to 87.5+/-1.3MUM. PMID- 25549929 TI - Exploring the possibilities of capacitively coupled contactless conductivity detection in combination with liquid chromatography for the analysis of polar compounds using aminoglycosides as test case. AB - The analysis of highly polar (often charged) compounds which lack a strong UV absorbing chromophore is really challenging. Despite the numerous analytical methods published, the demand for a simple, robust and cheap technique for their analysis still persists. Here, reversed phase (RP) liquid chromatography (LC) with capacitively coupled contactless conductivity detection (C(4)D) was explored for the first time as a possible method for separation and detection of various aminoglycoside (AMG) antibiotics which were taken as typical test compounds: tobramycin (TOB), spectinomycin, streptomycin, amikacin, kanamycin A and kanamycin B. C(4)D was performed using a commercially available as well as a laboratory made cell. As ion-pairing reagents (IPR) four perfluorinated carboxylic acids were used: pentafluoropropionic acid, heptafluorobutyric acid, nonafluoropentanoic acid (NFPA) and pentadecafluorooctanoic acid (PDFOA). 0.125 mM NFPA-acetonitrile (ACN) (90:10) or 0.125 mM PDFOA-ACN (70:30) as mobile phases were suitable to detect TOB with reasonable retention times. However, NFPA was preferred for practical reasons. Its applicable concentration range in the mobile phase was strongly restricted by loss of chromatographic performance at lower levels and excessive background conductivity at higher levels. Overall repeatability and robustness of the method were rather poor which was explained by the relatively low IPR levels. Selectivity between the tested AMGs was mainly influenced by the number of protonated amino groups per molecule making it impossible to separate compounds of equal net charges. Problems encountered with gradient elution, hydrophilic interaction liquid chromatography (HILIC) and separation at high pH without IPRs are also discussed. PMID- 25549928 TI - Effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. AB - The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0 mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concentration-dependent manner. Inhibitory concentration (IC50) was 12.1 MUM. In addition, pioglitazone significantly increased the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-infinity) and the peak plasma concentration (C max) of nifedipine were significantly increased by 52.1 and 59.1 %, respectively, in the presence of pioglitazone (1.0 mg/kg) compared with control group. The total body clearance (CL/F) of nifedipine was significantly (1.0 mg/kg) decreased by pioglitazone (35.8 %). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of pioglitazone (1.0 mg/kg) was significantly higher (25.3 %) than that of the control. The metabolite-parent AUC ratio (MR) in the presence of pioglitazone (1.0 mg/kg) significantly decreased (23.9 %) compared to that of the control group. The increased bioavailability of nifedipine in the presence of pioglitazone may be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and to the inhibition of the metabolism by inhibition of CYP3A4 in the small intestine and/or the liver, and/or to a reduction of CL/F of nifedipine by pioglitazone. PMID- 25549930 TI - Survival outcomes in elderly patients with glioblastoma. AB - AIMS: Many elderly glioblastoma patients are excluded from randomised trials due to age, comorbidity or poor functional status. The purpose of this study was to describe the survival outcomes in all elderly patients with glioblastoma managed at a tertiary cancer centre. MATERIALS AND METHODS: A retrospective chart review identified 235 elderly patients (age 65 years or over) with a histological diagnosis of glioblastoma between 1 December 2006 and 31 December 2013. The primary outcome of this study was overall survival by treatment type. Univariate and multivariate Cox proportional hazard models were used to explore significant prognostic variables associated with overall survival. RESULTS: The median survival for all patients was 6.5 months (95% confidence interval 5.3-7.7), with 1 year overall survival of 23.7% (95% confidence interval 18.8-30.0). The median survival for patients treated with radiation and chemotherapy was 11.1 months (95% confidence interval 8.1-13.7). Patients treated with radiation alone had a median survival of 6.8 months (95% confidence interval 5.6-7.9). For patients managed with comfort measures only, the median survival was 1.9 months (95% confidence interval 1.6-2.6). Univariate analysis revealed age, performance status, surgery type (biopsy, subtotal resection, gross total resection) and type of treatment received (comfort measures only, radiotherapy alone, radiotherapy and chemotherapy) to be statistically associated with overall survival. In the multivariate analysis, only two predictive factors (treatment received and surgery type) were significant. CONCLUSIONS: Elderly patients with glioblastoma selected for treatment (surgery followed by radiation alone or radiation and chemotherapy) survive longer than patients managed with comfort measures. Prospective randomised trials will help guide management for patients eligible for therapy. Elderly patients with glioblastoma who are deemed not eligible for active therapy have very short survival. PMID- 25549931 TI - Predictors of respiratory-induced lung tumour motion measured on four-dimensional computed tomography. AB - AIMS: The delivery of radical radiotherapy in lung cancer is complicated by respiratory-induced tumour motion. The aim of the study was to correlate tumour motion characteristics with tumour and patient factors, particularly the anatomical lobe and pulmonary zone. MATERIALS AND METHODS: Lung tumour volumes on four-dimensional computed tomography were delineated by a single observer at maximal expiration and propagated through all 10 phases of the breathing cycle. Movements were tracked in the superior-inferior (SI), anterior-posterior (AP) and medio-lateral (ML) directions by changes in the tumour centroid coordinates. Tumour motion characteristics were correlated with anatomical lobe, pulmonary zone, tumour volume, T-stage, smoking status and spirometry. RESULTS: In 101 consecutive patients, the median magnitude of tumour motion in the SI direction was significantly larger in tumours located in lower lobes compared with upper lobes and middle/lingular lobes (0.70 cm versus 0.09 cm versus 0.26 cm, P < 0.01). No significant difference was found in median tumour motion between lower, upper and middle/lingular lobes in the AP (0.16 cm versus 0.13 cm versus 0.16 cm, P = 0.45) and ML (0.08 cm versus 0.08 cm versus 0.13 cm, P = 0.32) directions, respectively. When assessed by zone, the median tumour displacement in the SI direction was significantly larger in the lower zones (0.81 cm) as compared with the middle zones (0.30 cm) and upper zones (0.11 cm), P < 0.01. No difference was observed in the AP (P = 0.45) and ML (P = 0.73) directions. Tumour volume, T stage and forced expiratory ratio were not statistically significant predictors of respiratory-induced tumour motion. CONCLUSION: Respiratory-induced tumour motion in the SI direction was significantly greater in lower lobe and lower pulmonary zone tumours compared with apical tumours. Tumour volume, T-stage and spirometry did not correlate with the magnitude or direction of respiratory induced tumour motion. During curative radiotherapy in lung cancer, attention should be paid to motion management, especially for lower lobe tumours. PMID- 25549932 TI - Standing out and moving up: performance appraisal of cultural minority physicians. AB - Despite a growing diversity within society and health care, there seems to be a discrepancy between the number of cultural minority physicians graduating and those in training for specialization (residents) or working as a specialist in Dutch academic hospitals. The purpose of this article is to explore how performance appraisal in daily medical practice is experienced and might affect the influx of cultural minority physicians into specialty training. A critical diversity study was completed in one academic hospital using interviews (N = 27) and focus groups (15 participants) with cultural minority physicians and residents, instructing specialists and executives of medical wards. Data were digitally recorded and transcribed verbatim. A thematic and integral content analysis was performed. In addition to explicit norms on high motivation and excellent performance, implicit norms on professionalism are considered crucial in qualifying for specialty training. Stereotyped imaging on the culture and identity of cultural minority physicians and categorical thinking on diversity seem to underlie daily processes of evaluation and performance appraisal. These are experienced as inhibiting the possibilities to successfully profile for selection into residency and specialist positions. Implicit criteria appear to affect selection processes on medical wards and possibly hinder the influx of cultural minority physicians into residency and making academic hospitals more diverse. Minority and majority physicians, together with the hospital management and medical education should target inclusive norms and practices within clinical practice. PMID- 25549933 TI - Association of pre- and post-treatment expectations with improvements after acupuncture in patients with migraine. AB - OBJECTIVE: To study whether a higher expectation of acupuncture measured at baseline and after acupuncture is associated with better outcome improvements in patients with migraine. METHODS: We performed a secondary analysis of a previous published trial in which 476 patients with migraine were randomly allocated to three real acupuncture groups and one sham acupuncture control group. All the participants received 20 sessions of acupuncture over a 4-week period. The primary outcome was the number of days with a migraine attack (NDMA) assessed at 5-8 weeks after randomisation. The secondary outcomes were visual analogue scale, headache intensity and quality of life assessed at 4, 8 and 16 weeks after randomisation. Expectations of the acupuncture effect were assessed at baseline and at the end of treatment and categorised into five levels, with 0% the lowest and 100% the highest. Outcome improvement was first compared among the participants with different expectation levels using an analysis of variance model. The association between expectations of treatment and outcome improvement was then calculated using a logistic regression model. RESULTS: Patients with 100% baseline expectations did not report significantly fewer NDMA than those with 0% baseline expectations after adjusting for the covariates (at 5-8 weeks, 1.7 vs 3.9 days, p=0.987). High baseline expectations had no significant impact on improvement of the primary outcome (100% vs 0%: OR 8.50, 95% CI 0.89 to 191.65, p=0.682). However, patients with 100% post-treatment expectations reported fewer NDMA than those with 0% expectations (primary outcome: 1.3 vs 5.0 days, p<0.001) and were more likely to have a favourable response (100% vs 0%: OR 68.87, 95% CI 6.26 to 1449.73, p=0.002). Similar results were found when analysing the impact of expectation on the secondary outcomes. CONCLUSIONS: A high level of expectation after acupuncture treatment rather than at baseline was associated with better long-term outcome improvements in patients with migraine. CLINICAL TRIAL NUMBER: NCT00599586. PMID- 25549934 TI - Effects of curcumin on antioxidative activities and cytokine production in Jian carp (Cyprinus carpio var. Jian) with CCl4-induced liver damage. AB - We investigated the protective effects of curcumin on liver-damaged Cyprinus carpio var. Jian (Jian carp). The carp were fed 0.1%, 0.5%, or 1.0% curcumin for 60 days, then injected intraperitoneally with 30% carbon tetrachloride solution. Liver and blood samples were collected to measure the liver index, serum- and liver-associated enzymes, liver histology, nuclear factor-kappaB (NF-kappaB)/c Rel, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-12 mRNA expression, and the level of NF-kappaB/c-Rel protein in the liver, and for a comet assay. We found that 0.5% and 1.0% curcumin significantly reduced the CCl(4)-induced increase in the liver index. The comet assay showed that the tail moment, olive tail moment, tail length, and tail DNA% improved in fish pretreated with 0.5 or 1.0% curcumin. CCl(4)-induced histological changes, including extensive hepatocyte degeneration, indistinct cell borders, nuclear condensation, and karyolysis were clearly reduced after treatment with 0.5% and 1.0% curcumin. Moreover, 0.5% and 1.0% curcumin significantly inhibited the CCl(4)-induced increase in serum glutamic oxaloacetic transaminase and promoted the restoration of superoxide dismutase in the liver; 1.0% curcumin significantly reduced serum glutamic pyruvic transaminase and lactate dehydrogenase and hepatic malondialdehyde, but significantly increased the total antioxidant capacity and glutathione levels in the liver. The CCl(4)-induced upregulation of NF-kappaB/c Rel, IL-1beta, and TNF-alpha mRNAs and NF-kappaB/c-Rel protein levels was inhibited by 0.5% and 1.0% curcumin, and IL-12 mRNA was reduced by all three doses of curcumin. The effects of curcumin on the liver index, enzymes, histological changes, and cytokines were dose-dependent. Our results indicate that curcumin reduces CCl(4)-induced liver damage in Jian carp by upregulating antioxidative activities and inhibiting NF-kappaB, IL-1beta, TNF-alpha, and IL-12 expression. PMID- 25549935 TI - Cloning and characterization of the proximal promoter region of rainbow trout (Oncorhynchus mykiss) interleukin-6 gene. AB - Interleukin-6 (IL6) is a pleiotropic cytokine with important immunoregulatory functions. Its expression is inducible in immune cells and tissues of several fish species. We also found that IL6 mRNA abundance was significantly increased in spleen, liver, and gill of rainbow trout after experimental infection with Aeromonas salmonicida. Genomic DNA sequences of IL6 orthologs from three salmonid species revealed a conserved exon/intron structure and a high overall nucleotide identity of >88%. To uncover key mechanisms regulating IL6 expression in salmonid fish, we amplified a fragment of the proximal IL6 promoter from rainbow trout and identified in-silico conserved binding sites for NF-kappaB and CEBP. The activity of this IL6 promoter fragment was analyzed in the established human embryonic kidney line HEK-293. Luciferase- and GFP-based reporter systems revealed that the proximal IL6 promoter is activated by Escherichia coli. Essentially, both reporter systems proved that NF-kappaB p50, but not NF-kappaB p65 or CEBP, activates the IL6 promoter fragment. Truncation of this fragment caused a significant decrease in IL6 promoter activation. This characterization of the proximal promoter of the IL6-encoding gene provides basic knowledge about the IL6 gene expression in rainbow trout. PMID- 25549936 TI - Chinese zodiac results in distortion of sex ratio. PMID- 25549937 TI - A multi-label approach using binary relevance and decision trees applied to functional genomics. AB - Many classification problems, especially in the field of bioinformatics, are associated with more than one class, known as multi-label classification problems. In this study, we propose a new adaptation for the Binary Relevance algorithm taking into account possible relations among labels, focusing on the interpretability of the model, not only on its performance. Experiments were conducted to compare the performance of our approach against others commonly found in the literature and applied to functional genomic datasets. The experimental results show that our proposal has a performance comparable to that of other methods and that, at the same time, it provides an interpretable model from the multi-label problem. PMID- 25549938 TI - A fast gene selection method for multi-cancer classification using multiple support vector data description. AB - For cancer classification problems based on gene expression, the data usually has only a few dozen sizes but has thousands to tens of thousands of genes which could contain a large number of irrelevant genes. A robust feature selection algorithm is required to remove irrelevant genes and choose the informative ones. Support vector data description (SVDD) has been applied to gene selection for many years. However, SVDD cannot address the problems with multiple classes since it only considers the target class. In addition, it is time-consuming when applying SVDD to gene selection. This paper proposes a novel fast feature selection method based on multiple SVDD and applies it to multi-class microarray data. A recursive feature elimination (RFE) scheme is introduced to iteratively remove irrelevant features, so the proposed method is called multiple SVDD-RFE (MSVDD-RFE). To make full use of all classes for a given task, MSVDD-RFE independently selects a relevant gene subset for each class. The final selected gene subset is the union of these relevant gene subsets. The effectiveness and accuracy of MSVDD-RFE are validated by experiments on five publicly available microarray datasets. Our proposed method is faster and more effective than other methods. PMID- 25549939 TI - Cystamine induces AIF-mediated apoptosis through glutathione depletion. AB - Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting gamma-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death. PMID- 25549940 TI - Acute cerebellar dysfunction with neuromuscular manifestations after scorpionism presumably caused by Tityus obscurus in Santarem, Para / Brazil. AB - Scorpionism is a public health problem in many tropical countries, especially in North Africa, South India, Latin America and the Middle East. In Brazil, patients with severe scorpion envenoming have mainly cardiovascular events, including acute heart failure, acute respiratory distress syndrome and shock, death is rare. We described 58 accidents presumably caused by Tityus obscurus in Brazilian Amazonia. Patients reported a sensation of "electric shocks" which could last hours. The vast majority of patients presented a clinical picture compatible with acute cerebellar dysfunction, beginning minutes and lasting up to 2 days after the accident. They presented cerebellar ataxia, dysdiadochokinesia, dysmetry, dysarthria, dyslalia, nausea and vomiting. Besides, some patients presented myoclonus and fasciculation which can also be attributed to cerebellar dysfunction or maybe the result of direct action on skeletal muscle. Two patients had evidence of intense rhabdomyolysis and acute kidney injury. The clinical picture in this scorpion envenoming is mainly characterized by an acute dysfunction of cerebellar activities and abnormal neuromuscular manifestations and in some cases muscle injury which are not described in any other region of the world. This work presents clinical, epidemiologic, laboratory and treatment aspects of this unmatched scorpion envenoming in the state of Para, northern Brazil. PMID- 25549941 TI - Individual and combined cytotoxic effects of aflatoxin B1, zearalenone, deoxynivalenol and fumonisin B1 on BRL 3A rat liver cells. AB - This study was performed to determine the individual and combined cytotoxic effects of Aflatoxin B1 (AFB1), zearalenone (ZEA), deoxynivalenol (DON) and fumonisin B1 (FB1) on BRL 3A rat liver cells. After the mycotoxins treated the BRL 3A cells for 12, 24 and 48 h, cell viability was determined using the MTT assay. The cytotoxicity of individual mycotoxins on BRL 3A cell viability in decreasing order were DON > AFB1 > ZEA > FB1. The central composite design (CCD) was used to assess the toxicity of binary and ternary mixtures of these mycotoxins. The mixtures of AFB1+ZEA and AFB1+DON showed the synergetic toxic effects on BRL 3A cells. These toxins decreased the viability of cells by inducing intracellular reactive oxygen species (ROS) production and promoting apoptosis in the BRL 3A cells. This effect was mediated by an upregulation of the stress and apoptotic genes Hsp70, p53, Bax, Caspase-3 and Caspase-8, along with a downregulation of the antiapoptotic gene Bcl-2. In conclusion, our results suggested that the coexistence of AFB1 and ZEA or DON in agricultural products could be more hepatotoxic than individually, suggests that the toxicological interactions of these toxins need to be better understood to assess health risks. PMID- 25549942 TI - Detection of marine microalgal biotoxins using bioassays based on functional expression of tunicate xenobiotic receptors in yeast. AB - Marine microalgae can produce biotoxins that cause widespread poisoning in marine ecosystems and may also affect human health. While established microalgal biotoxins are detectable using chemical methods, a need remains for robust, inexpensive bioassays. Ligand-binding domains (LBDs) from a tunicate nuclear receptor, VDR/PXRalpha, which is orthologous to both the vertebrate pregnane X receptor (PXR) and the vitamin D receptor (VDR), can be activated by microalgal biotoxins when expressed in mammalian cell lines. Building on this observation, we developed a generic recombinant yeast bioassay platform that expresses chimeric proteins containing tunicate VDR/PXRalpha LBDs which mediate ligand dependent transcription of a reporter gene (lacZ) encoding an easily assayed enzyme (beta-galactosidase). Recombinant yeast strains expressing VDR/PXRalpha LBDs from two tunicate species, Ciona intestinalis and Botryllus schlosseri, were exposed to both synthetic and natural toxins. Structurally simple synthetic chemicals (n-butyl-p-aminobenzoate, carbamazepine, p-aminobenzoic acid, and bisphenol-A) generated EC50 values in the MUM range, while more structurally complex marine biotoxins (okadaic acid, pectenotoxin-11, and portimine) activated the assays in the nM range. Given the large number of tunicate species, we propose that tunicate VDR/PXR LBDs may be used as 'sensor elements' in similar yeast-based high-throughput bioassays for detection of established microalgal biotoxins and uncharacterised marine bioactive compounds. PMID- 25549943 TI - Stereotactic radiosurgery for pediatric patients with intracranial arteriovenous malformations: variables that may affect obliteration time and probability. AB - INTRODUCTION: It is debatable whether pediatric patients diagnosed with arteriovenous malformations (AVMs) should be treated as adults. Several indexes to classify AVMs have been proposed in the literature, and most try to predict the outcome for each specific treatment. The indexes differ in the variables considered, but they are all based in adult populations. In this study, we analyzed the variables that influence the obliteration time and probability of occurrence in a Mexican pediatric population diagnosed with an AVM and treated with stereotactic radiosurgery (SRS). METHODS: We analyzed 45 pediatric patients (<18 years) with a minimum follow-up of 10 months and a maximum of 112 months. We used logistic regression analysis and Kaplan-Meier curves to evaluate the influence of age, AVM volume, prescribed dose, minimum dose, maximum dose, time of follow-up, sex, previous hemorrhage, venous drainage, treatment technique, previous treatment and location. We also evaluated the predictive power of the following indexes: Spetzler-Martin, RBAS, or K index dose deviation. RESULTS: We found that the radiation technique used may influence the obliteration occurrence (p=0.057). The data suggests that circular arcs are a more efficient treatment technique than dynamic arcs. However, no relationship of dose or volume with treatment technique could be found. Obliteration was also dependent on follow-up time and after three years of follow-up, the obliteration probability decreases (p=0.024). According to Kaplan-Meier analysis, the nidus obliteration time was related with the location according to the Spetzler-Martin index. If the nidus was located in a non-eloquent region, there was a tendency of a shorter obliteration time (p=0.071). CONCLUSION: None of the previously proposed indexes for adults predict obliteration in this pediatric population. Treatment technique, eloquence and follow up time were the only variables that showed influence in obliteration. Since the highest probability of obliteration occurs during the first three years, if the nidus has not been obliterated after this time then another treatment option could be considered. PMID- 25549944 TI - Effects of kisspeptin-10 on in vitro proliferation and kisspeptin receptor expression in primary epithelial cell cultures isolated from bovine placental cotyledons of fetuses at the first trimester of pregnancy. AB - Kisspeptin (Kp) and Kiss-1 receptor (Kiss-1R) expressions have been reported to be in the placenta, and a possible involvement of the Kiss-1R/Kps system in regulating trophoblast invasion and proliferation has been hypothesized. The aim of the present study was to investigate whether Kiss-1R activation by kisspeptin 10 (Kp-10) could modulate in vitro proliferation and progesterone (P4) secretion of bovine primary placental cell lines isolated from cotyledons of fetuses in the first trimester of pregnancy. The involvement of Kiss-1R in the cell responses observed was also analyzed. Uteri from cows at the first trimester of pregnancy were obtained from local abattoirs. Fetal cotyledon fragments were digested with collagenase in low glucose Dulbecco's Modified Eagle's Medium and cell lines were isolated. After being characterized for epithelial polygonal morphology, the presence of binucleate cells, male gender, and the expression of cytokeratin and zona occludens 2, cell lines were cultured in a low glucose Dulbecco's Modified Eagle's Medium-based expansion medium in the presence of 0.01, 0.1, 1, and 10 MUM Kp-10. Control cells were cultured in the absence of Kp-10. Cell population doubling time was evaluated for each culture passage (P) from P1 to P10. Cells were tested for Kiss-1R mRNA expression analysis by real-time reverse transcription-polymerase chain reaction, and culture media were analyzed for P4 concentration by radioimmunoassay. Kisspeptin-10 modulated in vitro proliferation of epithelial cell lines isolated from cotyledons recovered from bovine fetuses in the first trimester of pregnancy. Inhibitory (line A) or stimulatory (line B) effects of Kp-10 on cell proliferation were found in different cell lines and observed cell responses were found to be related to Kiss-1R mRNA levels. Inhibition of cell proliferation matched with not significant variation of Kiss 1R expression, whereas stimulation of cell proliferation was found to be related to Kiss-1R upregulation. In both cell lines, no effect of Kp-10 on P4 secretion was found at any tested concentration. These results lead to the conclusion that the Kiss-1R/Kps system is involved in the regulation of cell proliferation of bovine placental cotyledon cell lines isolated at the first trimester of pregnancy but, at this gestational stage, it may not be involved in modulating placental P4 secretion. PMID- 25549945 TI - The crosstalk between TLR2 and NOD2 in Aspergillus fumigatus keratitis. AB - Innate immunity is considered to be critical in the pathogenesis of fungal keratitis. Pattern recognition receptors (PRRs) recognize conserved microbial structures called pathogen-associated molecular patterns (PAMPS), thereby initiating the innate immunity. Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (leucine-rich repeat-containing receptors, NLRs) are two major PRR families. The crosstalk between TLR2 and NOD2 is not completely understood, and their interrelationship in Aspergillus fumigates keratitis is still unclear. To our surprise, we found herein that NOD2 and TLR2 were increased by A. fumigatus conidia in immortalized human corneal epithelial cells (HCECs). In addition, NOD2 expression was up-regulated by its agonist muramyl dipeptide (MDP), along with receptor interacting protein 2 (RIP2), nuclear factor kappaB (NFkappaB)-p65, inhibitor of NFkappaB (IkappaB) alpha, and multiple inflammatory cytokines, including interleukin-6 (IL-6), IL-8 and tumor necrosis factor alpha (TNF-alpha). Interestingly, zymosan, a TLR2 agonist, promoted the expression of NOD2 and RIP2 in a TLR2-dependent manner. Furthermore, we demonstrated that the increased expression of NOD2 and RIP2 caused by A. fumigatus conidia occurred in part through a TLR2-dependent pathway. However, zymosan pretreatment decreased NOD2 and RIP2 expression along with the MDP induced secretion of inflammatory cytokines in HCECs. In agreement, NOD2 knockdown by small interfering RNA (siRNA) reduced the release of IL-6, IL-8 and TNF-alpha induced by A. fumigatus conidia. These findings suggest the existence of complex interactions between TLR2 and NOD2 in HCECs inflammatory response against A. fumigatus infection. PMID- 25549946 TI - TMEM126A, a CD137 ligand binding protein, couples with the TLR4 signal transduction pathway in macrophages. AB - We showed previously that a novel protein, transmembrane protein 126A (TMEM126A), binds to CD137 ligand (CD137L, 4-1BBL) and couples with its reverse signals in macrophages. Here, we present data showing that TMEM126A relays TLR4 signaling. Thus, up-regulation of CD54 (ICAM-1), MHC II, CD86 and CD40 expression in response to TLR4 activation was diminished in TMEM126A-deficient macrophages. Moreover in TMEM126A-deficient RAW264.7 cells, LPS/TLR4-induced late-phase JNK/SAPK and IRF-3 phosphorylation was abolished. These findings indicate that TMEM126A contributes to the TLR4 signal up-regulating the expression of genes whose products are involved in antigen presentation. PMID- 25549947 TI - Advancing research on endocrine disrupting chemicals in breast cancer: Expert panel recommendations. AB - Breast cancer incidence continues to increase in the US and Europe, a reflection of the growing influence of environment factors that interact with personal genetics. The US Environmental Protection Agency estimates that there are approximately 10,000 endocrine disrupting chemicals among the common daily exposures that could affect the risk of disease. The daunting tasks of identifying, characterizing, and elucidating the mechanisms of endocrine disrupting chemicals in breast cancer need to be addressed to produce a comprehensive model that will facilitate preventive strategies and public policy. An expert panel met to describe and bring attention to needs linking common environmental exposures, critical windows of exposure, and optimal times of assessment in investigating breast cancer risk. The group included investigators with extensive experience in the use of rodent models and in leading population studies and produced a set of recommendations for effective approaches to gaining insights into the environmental origins of breast cancer across the lifespan. PMID- 25549948 TI - Effects of 2,5-hexanedione on angiogenesis and vasculogenesis in chick embryos. AB - n-Hexane is widely used in industry and its metabolite, 2,5-hexanedione (2,5-HD), has been implicated as a neural toxin in the developing fetus. Using the chick embryo model, we have previously revealed the neurotoxicity of 2,5-HD during development and established that high dose of 2,5-HD was embryo lethal. In view of the close linkage in biology for neurogenesis and angiogenesis, we speculated that it was most likely caused by cardiovascular dysplasia, therefore in this study, we investigated the effects of 2,5-HD on the development of the vasculature, which involves vasculogenesis and angiogenesis. Using gastrulating chick embryos as a model, we demonstrated that the hemangioblasts (precursor of hematopoietic and endothelial cells) migrated to the area opaca where they form the blood islands. However, this process was impaired when the embryos were treated with 2,5-HD, suggesting that 2,5-HD is capable of impairing vasculogenesis. To study the effect of 2,5-HD exposure on angiogenesis, we used the chick yolk-sac membrane (YSM) and chorioallantoic membrane (CAM) models. We found that, at low (0.02M) concentration, 2,5-HD stimulated angiogenesis while at higher concentrations (>0.1M) it inhibited this process. This biphasic response of angiogenesis to 2,5-HD exposure was found to be associated with altered expression of the VEGF-R, FGF-2 and angiogenin. Moreover, we also determined that 2,5-HD exposure increased the reactive oxygen species (ROS) production. In conclusion, 2,5-HD could induce dysplasia in the developing vasculature, which in turn could cause extravascular hemolysis and the embryos to die. PMID- 25549950 TI - The role of tumour budding in predicting survival in patients with primary operable colorectal cancer: a systematic review. AB - Tumour budding reflects a detachment of tumour cells at the invasive front of carcinomas and is presumed to be an early step in the metastatic process. Tumour budding has received some attention in colorectal cancer as it has been proposed as an additional prognostic factor in colorectal cancer that may stratify patients into risk categories. The purpose of the review was to examine (1): The different methods of detection using either routine stains (H&E) or immunohistochemistry; (2): to compare studies that examined the different methods used to identify tumour budding; and (3) to examine the impact of tumour budding on survival in primary operable colorectal cancer. Results from the present review suggest that tumour budding can be considered a promising and strong prognostic factor in colorectal cancer. However, the implementation of the assessment of tumour budding in routine pathological work will depend on a selected, internationally accepted scoring system and validation against other established prognostic factors in patients with colorectal cancer. PMID- 25549951 TI - An instrument to assess patient satisfaction with epilepsy treatment. AB - AIMS: Patient satisfaction with antiepileptic drugs is an important component in the management of epilepsy. This study aimed to develop a visual analog scale (VAS) to evaluate patient satisfaction with the effectiveness and tolerability of the current antiepileptic treatment and to identify the most appropriate threshold scores of patient dissatisfaction predictive of a decision to change the antiepileptic drugs. METHODS: This observational study was conducted among patients with epilepsy consulting a neurologist in France. Two anonymous questionnaires were used, one for patients and one for neurologists. The patients' questionnaire assessed satisfaction using a four-point Likert scale and a 10-centimeter VAS. The neurologists' questionnaire evaluated whether the neurologist decided to change the current treatment or not. The determination of the threshold scores predictive of patient dissatisfaction correlated with a change of the medication was performed using analyses of receiver operating characteristic curves. Visual analogue scale scores collected from the patient questionnaire were tested against the responses collected from the neurologist questionnaire. RESULTS: Five hundred eighteen patient questionnaires and five hundred seven neurologist questionnaires were completed. For the satisfaction with effectiveness and tolerability, the mean VAS scores were 6.7+/-2.8 and 7.0+/ 2.8, respectively and were, respectively, 6.9+/-1.7 and 7.0+/-1.6 for patients who declared to be satisfied with their current antiepileptic drugs and were, respectively, 3.4+/-1.7 and 3.3+/-1.9 for those who declared to be dissatisfied. The neurologist decided to change the current antiepileptic drugs in 41.1% (n=208) of the cases principally because of inadequate effectiveness. With respect to the receiver operating characteristic curves, a VAS threshold of 6 would correctly predict the decision to change the current antiepileptic drugs with sensitivity and specificity values over 73% for both effectiveness and tolerability. CONCLUSIONS: The VAS developed in this study can help patients to evaluate their antiepileptic drugs and to facilitate timely treatment modification when the current treatment is unsatisfactory. PMID- 25549952 TI - Seizure detection method based on fractal dimension and gradient boosting. AB - Automatic seizure detection technology is necessary and crucial for the long-term electroencephalography (EEG) monitoring of patients with epilepsy. This article presents a patient-specific method for the detection of epileptic seizures. The fractal dimensions of preprocessed multichannel EEG were firstly estimated using a k-nearest neighbor algorithm. Then, the feature vector constructed for each epoch was fed into a trained gradient boosting classifier. After a series of postprocessing, including smoothing, threshold processing, collar operation, and union of seizure detections in a short time interval, a binary decision was made to determine whether the epoch belonged to seizure status or not. Both the epoch based and event-based assessments were used for the performance evaluation of this method on the EEG data of 21 patients from the Freiburg dataset. An average epoch-based sensitivity of 91.01% and a specificity of 95.77% were achieved. For the event-based assessment, this method obtained an average sensitivity of 94.05%, with a false detection rate of 0.27/h. PMID- 25549949 TI - Methoxychlor and its metabolite HPTE inhibit cAMP production and expression of estrogen receptors alpha and beta in the rat granulosa cell in vitro. AB - The major metabolite of the estrogenic pesticide methoxychlor (MXC) HPTE is a stronger ESR1 agonist than MXC and acts also as an ESR2 antagonist. In granulosa cells (GCs), FSH stimulates estradiol via the second messenger cAMP. HPTE inhibits estradiol biosynthesis, and this effect is greater in FSH-treated GCs than in cAMP-treated GCs. Therefore; we examined the effect of MXC/HPTE on FSH stimulated cAMP production in cultured GCs. To test involvement of ESR-signaling, we used the ESR1 and ESR2 antagonist ICI 182,780, ESR2 selective antagonist PHTPP, and ESR2 selective agonist DPN. ESR1 and ESR2 mRNA and protein levels were quantified. Both HPTE and MXC inhibited the FSH-induced cAMP production. ICI 182,780 and PHTPP mimicked the inhibitory action of HPTE. MXC/HPTE reduced FSH stimulated Esr2 mRNA and protein to basal levels. MXC/HPTE also inhibited FSH stimulated Esr1. The greater inhibition on FSH-stimulated GCs is likely due to reduced cAMP level that involves ESR-signaling, through ESR2. PMID- 25549953 TI - Religiosity, Meaning in Life and Suicidal Tendency Among Jews. AB - The study examines the impact that meaning in life, or lack thereof, has on suicidal tendencies among youth, as well as the nexus between level of religiosity, meaning in life and suicidal tendencies. Subjects were 450 students from both Jewish religious and Jewish secular schools aged 15-18. FINDINGS: a significant and negative correlation was found between a sense of meaning in life and suicidal tendencies, beyond gender or level of religiosity. In addition, no difference was found in level of suicidal tendency between Jewish religious and Jewish secular youth; however, among Jewish religious teens, a lower level of depression was reported in comparison with their secular peers. The study therefore concludes that meaning in life is the dominant variable in minimizing suicidal tendencies among youth. The results of this study may promote the establishment of prevention, intervention and therapy plans, especially in the age range that is crucial for suicide. Such programs should be based upon finding meaning in life. PMID- 25549954 TI - Depressed skull fracture by a mass of 3kg in shot putt an adolescent of 13 years. A rare sports injury. A rare fracture of the skull-deflection shot putt. AB - INTRODUCTION: More and more teenagers indulge in sports at school or in recreational settings. Some of these sports are considered to be purveyors of accidents and should be practiced by putting in place safety rules and regulations. This report is unusual case of a school child of age 13 who suffered from depressed skull fracture due to accidental fall of a mass of 3kg during an athletics meeting. PRESENTATION OF CASE: He was a 13-year-old boy who accidentally received on his head a throwing mass of 3kg thrown by a young athlete at a school athletics meeting. He became unconsciousness for a moment. The radio clinical evaluation showed a parietal depressed fracture without mass effect on the brain parenchyma to the CT scan. Depression was surgically removed in quite favorable manner. DISCUSSION: Karting is known as a particular sporting accident that causes head injuries affecting mostly children. Other sports such as boxing and skiing are also known to cause trauma but wearing helmets has significantly reduced these sports injuries. Throwing sports can also lead to accidents in the absence of strict security as demonstrated by this case. It was a skull depressed fracture that was operated upon because it entailed a risk leading to a compressive callus. CONCLUSION: This accident could have been avoided if basic safety precautions were put in place. PMID- 25549955 TI - Squamous carcinoma arising from a true tracheal bronchus: Management and case report. AB - A case of a squamous carcinoma arising in a "True" tracheal bronchus is described. The presentation and management of this case is discussed. PMID- 25549956 TI - Repair of a coccygeal hernia with a biological mesh. AB - Coccygeal herniation after coccygectomy is rare. Little is known about the management of this complication. We present a case of a 44 year old women with a coccygeal herniation 7 years after coccygectomy. She was treated two times for an infected pilonidal sinus with incision and drainage. After the last incision and drainage she had complaints of a painful swelling in the sacral area and difficulty with evacuation of her stools. A defaecography showed a coccygeal herniation. An additional MRI of the pelvic region showed a defect with a diameter of approximately 38mm. We performed a hernia repair with a biological mesh (StratticeTM surgical mesh, LifeCell Corporation USA) via a sacral approach. Her recovery was complicated by a small wound dehiscence without clinical signs of infection. The sacral wound healed per secundam. Her complaints had completely disappeared. A defaecography 2 months after surgery showed no residual herniation. To our knowledge, it is the first reported case of a coccygeal hernia repair with a biological StratticeTM surgical mesh. PMID- 25549957 TI - Sudden death due to biventricular non-compaction cardiomyopathy in a 14-year-old. AB - A 14-year-old African-American female with a long-standing medically and ablation treated history of tachycardia with associated seizures died suddenly. Upon autopsy, evidence of gross non-compaction involving the left ventricle, as well as possible subtle non-compaction of the right ventricle was discovered. Microscopically, there was focal myocyte hypertrophy as well as myxoid connective tissue and subendocardial fibroelastosis in the areas affected by the non compaction. Arrhythmia, precipitated by the underlying cardiomyopathy, led to this young girl's death. Non-compaction cardiomyopathy is a rare cardiac disorder which commonly goes undiagnosed until post-mortem, although diagnosis through echocardiogram, CT, or MRI is possible and there is criterion for diagnosis with each of these. PMID- 25549958 TI - TASER(r) conducted electrical weapons: misconceptions in the scientific/medical and other literature. AB - TASER((r)) conducted electrical weapons (CEWs) have become an important law enforcement tool. Controversial questions are often raised during discussion of some incidents in which the devices have been used. The main purpose of this paper is to point out some misconceptions about CEWs that have been published in the scientific/medical and other literature. This is a narrative review, using a multidisciplinary approach of analyzing reports from scientific/medical and other literature sources. In previous reports, durations of incapacitating effects and possible associations of CEWs with deaths-in-custody have often been overstated or exaggerated. Comparisons of CEW effects with "electrocution" are misleading. Clarification of these misconceptions may be important during policymaker decisions, practitioner operations, expert witness testimonies, and court proceedings. Despite misconceptions in the literature, CEWs can still be a valuable tool for law enforcement activities. Scientists, medical professionals, legal advisors, and investigators of police tactics should be aware of these misconceptions. PMID- 25549959 TI - Plakoglobin: a diagnostic marker of arrhythmogenic right ventricular cardiomyopathy in forensic pathology? AB - PURPOSE: The histopathological diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging in forensic medicine. Immunohistochemical myocardial analysis for plakoglobin has been suggested as a new diagnostic test for ARVC. We examined this in the setting of forensic pathology, applying this method to forensic autopsy samples. METHODS: We performed immunohistochemical staining for plakoglobin on 40 myocardial samples with an autopsy diagnosis of ARVC. In addition, histopathological reevaluation was performed applying the revised 2010 task force criteria including morphometric analysis. Myocardial samples from 15 subjects without heart disease were used as controls. RESULTS: Based on the histopathological reevaluation, 38 out of 40 cases were categorized as ARVC. A marked reduction in the plakoglobin staining was seen in 26 out of 38 myocardial samples in the ARVC-group. Of the two samples categorized as not ARVC, one showed reduced plakoglobin staining and one sample had normal staining. No control samples showed reduced plakoglobin staining. CONCLUSIONS: In conclusion, our study displayed reduced plakoglobin staining in approximately 2/3 of myocardial samples with ARVC. Our data suggests that immunostaining for plakoglobin might serve as an additional diagnostic marker of ARVC in forensic pathology, but additional validation is required. PMID- 25549960 TI - Assessment of a new infrared laser transillumination technology (808 nm) for the detection of occlusal caries-an in vitro study. AB - This study aimed to evaluate in vitro performance of near-infrared laser transillumination (NIR-LTI) for detecting early occlusal caries in permanent teeth and compare it with quantitative light-induced fluorescence (QLF), DIAGNOdent Pen (DDPen), and conventional radiography (CR). Ninety-four occlusal surfaces presenting International Caries Detection and Assessment System (ICDAS) scores ranging from 0 to 3 were selected. For the NIR-LTI examination, images were captured using a prototype, which consists of a laser beam (808 nm) and an infrared CCD camera. One occlusal site on each tooth was assessed twice by two examiners. The teeth were prepared histologically and assessed for the presence of early caries. The intraexaminer correlation showed no difference between the NIR-LTI, DDPen, and QLF analytical methods, but all these methods differed from CR. Interexaminer reproducibility was moderate for NIR-LTI, which showed sensitivity (0.68), specificity (0.85), accuracy (0.73), and area under the receiver-operating characteristic (ROC) curve (0.76) similar to those of the fluorescence method and different from those of the CR. In conclusion, the performance of NIR-LTI was comparable to that of DDPen and QLF and may therefore be considered a valid and reliable alternative for the diagnosis of incipient lesions on the occlusal surface of permanent teeth. PMID- 25549961 TI - Continuity and Change in Life Engagement Among People With Dementia. AB - The purpose of this study was to explore the change and continuity in the engagement in life of people with advanced dementia. The idea of meaningful activities is commonly used in nursing research, but few studies have been performed on what makes activities meaningful. This study aims to shed light on the meaning of activities in a life course context, changes in activity patterns due to dementia disease, and the significance of narratives told by close relatives. The 11 stories of activities were analyzed using thematic narrative analysis with Leontyev's activity theory as a theoretical framework. The findings revealed several types of changes: slow and abrupt changes in everyday and physical activities, changes in the person's level of awareness, and changes in habits in new care settings and environments. The meaningfulness of activities was connected to a person's background, his/her motives, lifestyle and identity, and the contextuality of activities. Through the narratives, nursing care personnel could acquire a nuanced picture of the person and his/her engagement in life. These narratives are vital to helping people who have dementia to keep up with meaningful activities and enhance their quality of life, especially when the person has deficiencies in communication. PMID- 25549962 TI - Support for At-Risk Girls: A School-Based Mental Health Nursing Initiative. AB - Mental health problems often go undiagnosed or unaddressed until a crisis or extreme event brings the problem to the forefront. Youth are particularly at risk for lack of identification and treatment in regard to mental health issues. This article describes an advanced nursing practice mental health initiative for at risk teenage girls based on Hildegard Peplau's nursing theory, group process, and healing through holistic health approaches. A support group, RICHES, was developed with focus on core components of relationships, identity, communication, health, esteem, and support. The acronym RICHES was chosen as the name of the support group. Selected themes and issues addressed in this school based support group are illustrated in case vignettes. Through a collaborative approach with the community and school, this practice initiative presents a unique healing process that extends knowledge in the realm of intervention with at-risk teenage girls. Further research is needed on the efficacy of support groups to modify risk factors and to address goals for primary prevention in at risk teenage girls. PMID- 25549963 TI - Keeping an eye on P. aeruginosa. PMID- 25549964 TI - Parasite physiology: Propelling artemisinin resistance. PMID- 25549965 TI - Hyperphenylalaninemia and the genomic revolution. PMID- 25549966 TI - Likelihood-based methods for evaluating principal surrogacy in augmented vaccine trials. AB - There is growing interest in assessing immune biomarkers, which are quick to measure and potentially predictive of long-term efficacy, as surrogate endpoints in randomized, placebo-controlled vaccine trials. This can be done under a principal stratification approach, with principal strata defined using a subject's potential immune responses to vaccine and placebo (the latter may be assumed to be zero). In this context, principal surrogacy refers to the extent to which vaccine efficacy varies across principal strata. Because a placebo recipient's potential immune response to vaccine is unobserved in a standard vaccine trial, augmented vaccine trials have been proposed to produce the information needed to evaluate principal surrogacy. This article reviews existing methods based on an estimated likelihood and a pseudo-score (PS) and proposes two new methods based on a semiparametric likelihood (SL) and a pseudo-likelihood (PL), for analyzing augmented vaccine trials. Unlike the PS method, the SL method does not require a model for missingness, which can be advantageous when immune response data are missing by happenstance. The SL method is shown to be asymptotically efficient, and it performs similarly to the PS and PL methods in simulation experiments. The PL method appears to have a computational advantage over the PS and SL methods. PMID- 25549969 TI - Autism cornered: network analyses reveal mechanisms of autism spectrum disorders. AB - Despite a wealth of behavioral, cognitive,biological, and genetic studies, the causes of autism have remained largely unknown.In their recent work, Snyder and colleagues(Li et al, 2014) use a systems biology approach and shed light on the molecular and cellular mechanisms underlying autism, thus opening novel avenues forunderstanding the disease and developing potential treatments. PMID- 25549968 TI - Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. AB - Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology. PMID- 25549970 TI - Autophagy induction halts axonal degeneration in a mouse model of X adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1 (-) /Abcd2 ( /-) mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients. PMID- 25549973 TI - Analytical aspects of achiral and cyclodextrin-mediated capillary electrophoresis of warfarin and its two main derivatives assisted by theoretical modeling. AB - Several distinct analytical issues have been addressed by performing capillary electrophoresis-based separations of the warfarin, 7-hydroxywarfarin and 10 hydroxywarfarin in an achiral and cyclodextrin-containing media. The measurements were conducted across a range of pH in order to find optimum conditions for achiral and chiral separations. The values of acid dissociation constant (pKa) have been determined and compared. Subsequently, after performing a series of mobility shift assays at different pH and cyclodextrin concentration, the pKa values ascribed to diastereomeric complexes with methyl-beta-cyclodextrin have been estimated. The significant pKa shifts upon complexation have been noticed for warfarin - up to 1.5 pH units, and only subtle for 10-hydroxywarfarin. A new approach that allows the estimation of association percentage based on the electrophoretic mobility curves has been also demonstrated. The complex mechanism of chiral separation has been found to be responsible for the observed migration profile, relying on a combined equilibrium between complexation/partition and protonation/deprotonation phenomena. The occurrence of the pKa-related migration order reversal has been demonstrated in achiral medium between warfarin and 7 hydroxywarfarin, and in chiral medium between enantiomers, causing a drop in enantioselectivity at specific pH. In parallel, the density functional theory based calculations have been performed in order to obtain the structures of warfarin and its derivatives as well as to rationalize the shifts in pKa values. PMID- 25549972 TI - Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study. AB - Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN. PMID- 25549974 TI - Editorial on "Present state of microchip electrophoresis: state of the art and routine applications" by Eric R. Castro and Andreas Manz. PMID- 25549976 TI - Changing the paradigm of laboratory quality control through implementation of real-time test results monitoring: For patients by patients. AB - OBJECTIVES: To develop and implement a quality control protocol using real-time patient data with immediate failure analysis and prevention of releasing results that exceed the allowable total error. DESIGN AND METHODS: Patient data are analyzed in real time using algorithms that incorporate moving medians and moving means for selected chemistry analytes. Simulation software was developed to determine optimal algorithms, establish error limits, and number of patient results for calculation of a single cumulative datum point. Algorithms for moving median (MovMed) and mean (MovMen) were chosen and validated for each analyte. Error limits (TEa) were established using biological and analytical variation with a goal of greater than 90% error detection rate during simulation runs. Middleware software was developed to prohibit the release of patient results upon error detection. RESULTS: A block size of 50 was determined to be the optimal number of patient results used in cumulative calculations. The application of MovMed and MovMen algorithms achieved 0% false rejection for 24 out of 28 tests (85.7%) during the simulation phase. Four tests had a false rejection rate ranging from 0.2 to 1.0%. Error detection rates of 100% were achieved for 16 out of 28 tests (57.1%). Twelve tests had error detection rates ranging from 94.5 to 99.8%. Traditional QC material utilization was reduced by approximately 75-85% and repeat analysis was reduced by approximately 50%. CONCLUSIONS: We successfully developed and implemented a real-time quality control protocol using patient results with true error detection and without release of erroneous results. PMID- 25549975 TI - Relationship between serum IgA/C3 ratio and severity of histological lesions using the Oxford classification in children with IgA nephropathy. AB - BACKGROUND: The aim of this study was to evaluate the usefulness of serum immunoglobulin A/complement factor 3 (IgA/C3) ratio for predicting histological severity of kidney lesions in children with IgA nephropathy (IgAN) based on World Health Organization (WHO) and the Oxford classification (OC). METHODS: We studied 89 children with IgAN with a mean age of 11.38 +/- 4.1 years (range 2-18 years). Based on available medical records, we retrospectively evaluated clinical data, IgA/C3 ratio, and kidney biopsy findings using the five-grade WHO classification and the OC The mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) (MEST) score (absent = 0, present = 1) calculated as the sum of M+E+S+T ranging from 0 to 4. RESULTS: Mean IgA/C3 ratio values were significantly higher (P < 0.05) in patients with M1, S1, and T1 compared with M0, S0, and T0, respectively (P < 0.05); there were no differences in the WHO classification. We found a significant positive correlation between the IgA/C3 ratio and proteinuria (r = 0.24) and determined optimal cutoff values of the IgA/C3 ratio, with a corresponding confidence interval for specific MEST scores. CONCLUSIONS: The IgA/C3 ratio in children with IgAN may be a useful marker of the severity of lesions found in kidney biopsy as evaluated using the OC. PMID- 25549971 TI - Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. AB - Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP 43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD. PMID- 25549977 TI - Analytical sensitivity of four commonly used hCG point of care devices. AB - BACKGROUND: Point of care (POC) hCG assays are often used to rule-out pregnancy and therefore diagnostic sensitivity, especially at low concentrations of hCG, is important. There are very few studies in the literature that seek to verify the claimed analytical sensitivity of hCG POC devices. METHODS: The analytical sensitivity of four commonly used hCG POC devices (Alere hCG Combo Cassette, ICON 20 hCG, OSOM hCG Combo Test, and Sure-Vue Serum/Urine hCG-STAT) was challenged using urine samples (n=50) selected based on quantitative hCG concentrations. The majority of these specimens (n=40) had an hCG concentration between 20 and 200 U/L. Each specimen/device combination was reviewed by three individuals. Statistical calculations were performed using Stata 12. RESULTS: The analytical sensitivity of the OSOM was significantly lower inferior than that of the other POC devices. There was no significant difference in the sensitivity of the Alere, ICON 20 and Sure-Vue devices. There was no significant difference in the individual interpretation of the hCG POC results. CONCLUSIONS: All hCG POC devices evaluated in this study were susceptible to false negative results at low concentrations of urine hCG. Laboratorians and clinicians should be aware that there are limitations when using urine hCG POC devices to rule out early pregnancy. PMID- 25549978 TI - The clinical and diagnostic performance characteristics of the high sensitivity Abbott cardiac troponin I assay. AB - OBJECTIVES: The aim of this study is to determine the imprecision profile, 99th percentile and diagnostic efficiency of a new high sensitivity cardiac troponin I (cTnI) assay. METHODS: Total imprecision was assessed by following CLSI protocol EP15-A.14. Serum pools prepared from sera of known high cardiac troponin concentrations were adjusted by dilution with serum considered to be troponin free. Determination of the 99th-percentile reference value examined a fully characterized population that had undergone non-invasive cardiac imaging. Diagnostic accuracy utilised samples from the point of care arm of the RATPAC trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers), set in the emergency departments of six hospitals. Blood samples were taken on admission and 90min from admission. Diagnosis was based on the universal definition of myocardial infarction utilising laboratory measurements of cardiac troponin performed at the participating sites together with measurements performed in a core laboratory and compared by construction of receiver operator characteristic curves. RESULTS: Total imprecision was 4%-12.1% with 10% CV of 7ng/L. cTnI was measureable in 99.5% of the samples. Troponin values were influenced by gender but not by age. The 99th percentile was 14.8ng/L (18.1 males, 8.6 females). Progressive filtering of the population reduced the 99th percentile. For the diagnosis of MI on admission the area under the curve was 0.92, statistically indistinguishable from four other assays studied (0.90-0.94). CONCLUSION: The analytical performance of the new assay meets the criteria for a high sensitivity troponin assay. PMID- 25549979 TI - Di-4-ANEPPDHQ, a fluorescent probe for the visualisation of membrane microdomains in living Arabidopsis thaliana cells. AB - Cholesterol-enriched microdomains, also called lipid rafts, are nanoscale membrane structures with a high degree of structural order. Since these microdomains play important roles in dynamic cytological events, such as cell signalling and membrane trafficking, the detection and tracking of microdomain behaviours are crucial to studies on modern membrane physiology. Currently, observation of microdomains is mostly based on the detection of specific raft resident constituents using artificial cross-link fluorescent probes. However, only a few microdomain-specific fluorescent dyes are available for plant cell biology studies. In this study, the photophysical properties of di-4-ANEPPDHQ were analysed. The use of confocal laser scanning microscope (CLSM)-based methods in the visualisation of microdomains in living cells of Arabidopsis thaliana was assessed. The results confirmed that the generalised polarisation (GP) method can be used to quantitatively visualise the membrane orders in live plant cells. This dye was found to have low cytotoxicity in plant root epidermal cells and root hairs. These findings suggest that di-4-ANEPPDHQ is an appropriate tool for the visualisation of microdomains in living plant cells. PMID- 25549980 TI - On the formation of lignin polysaccharide networks in Norway spruce. AB - In this study we were mirroring suggested in vivo phenomena of lignin hemicellulose complex formation in vitro, by cross-linking Norway spruce (Picea abies) galactoglucomannans, xylans and lignin moieties to high molecular weight complexes by laccase treatment. We were able to observe the oxidation and cross linking of non-condensed guaiacyl-type phenolic moieties attached to both of the hemicelluloses by (31)P NMR and size-exclusion chromatography. We suggest that hemicelluloses-lignin complexes form covalently linked structural units during the early stages of lignification via radical enzymatic cross-linking catalyzed by laccase. This work shows that the hemicellulose molecules in wood are covalently linked to two or more lignin units thereby making them suited for forming network structures. PMID- 25549981 TI - Evaluation of conditioning time and temperature on gelatinized starch and vitamin retention in a pelleted swine diet. AB - Two key feed processing parameters, conditioning temperature and time, were altered to determine their effects on concentration of gelatinized starch and vitamin retention in a pelleted finishing swine diet. Diet formulation (corn soybean meal based with 30% distillers dried grains with solubles) was held constant. Treatments were arranged in a 2 * 3 factorial design plus a control with 2 conditioning temperatures (77 vs. 88 degrees C) and 3 conditioner retention times (15, 30, and 60 s). In addition, a mash diet not subjected to conditioning served as a control for a total of 7 treatments. Samples were collected after conditioning but before pelleting (hot mash), after pelleting but before cooling (hot pellet), and after pelleting and cooling (cold pellet) and analyzed for percentage total starch, percentage gelatinized starch, and riboflavin, niacin, and vitamin D3 concentrations. Total percentage starch was increased by greater conditioning temperature (P = 0.041) but not time (P > 0.10), whereas higher temperature and longer time both increased (P < 0.05) percentage gelatinized starch, with increasing time resulting in a linear increase in percentage starch gelatinization (P = 0.013). The interaction between conditioning temperature and time increased percentage gelatinized starch (P = 0.003) but not percentage total starch (P > 0.10). Sample location also affected both percentage total starch and gelatinized starch (P < 0.05), with the greatest increase in percentage gelatinized starch occurring between hot mash and hot pellet samples. As expected, the pelleting process increased percentage gelatinized starch (P = 0.035; 7.3 vs. 11.7% gelatinized starch for hot mash vs. hot pellet samples, respectively), but there was no difference in total starch concentrations (P > 0.10). Finally, neither conditioning temperature nor time affected riboflavin, niacin, or vitamin D3 concentrations (P > 0.10). In summary, both increasing conditioningtemperature and time effect percentage gelatinized starch, but not to the extent of forcing the diet through a pelleting die. PMID- 25549982 TI - Accuracy of Igenity genomically estimated breeding values for predicting Australian Angus BREEDPLAN traits. AB - Genomically estimated breeding values (GEBV) for Angus beef cattle are available from at least 2 commercial suppliers (Igenity [http://www.igenity.com] and Zoetis [http://www.zoetis.com]). The utility of these GEBV for improving genetic evaluation depends on their accuracies, which can be estimated by the genetic correlation with phenotypic target traits. Genomically estimated breeding values of 1,032 Angus bulls calculated from prediction equations (PE) derived by 2 different procedures in the U.S. Angus population were supplied by Igenity. Both procedures were based on Illuminia BovineSNP50 BeadChip genotypes. In procedure sg, GEBV were calculated from PE that used subsets of only 392 SNP, where these subsets were individually selected for each trait by BayesCpi. In procedure rg GEBV were calculated from PE derived in a ridge regression approach using all available SNP. Because the total set of 1,032 bulls with GEBV contained 732 individuals used in the Igenity training population, GEBV subsets were formed characterized by a decreasing average relationship between individuals in the subsets and individuals in the training population. Accuracies of GEBV were estimated as genetic correlations between GEBV and their phenotypic target traits modeling GEBV as trait observations in a bivariate REML approach, in which phenotypic observations were those recorded in the commercial Australian Angus seed stock sector. Using results from the GEBV subset excluding all training individuals as a reference, estimated accuracies were generally in agreement with those already published, with both types of GEBV (sg and rg) yielding similar results. Accuracies for growth traits ranged from 0.29 to 0.45, for reproductive traits from 0.11 to 0.53, and for carcass traits from 0.3 to 0.75. Accuracies generally decreased with an increasing genetic distance between the training and the validation population. However, for some carcass traits characterized by a low number of phenotypic records (weight, intramuscular fat, and eye muscle area), accuracies were observed to increase but had large SE. Therefore, Igenity GEBV can be useful to Australian Angus breeders, either for blending EBV or as the sole basis for selection decisions if no other information is available. However, for carcass traits, additional phenotypic data are required. PMID- 25549983 TI - Improving genetic evaluation of litter size and piglet mortality for both genotyped and nongenotyped individuals using a single-step method. AB - A single-step method allows genetic evaluation using information of phenotypes, pedigree, and markers from genotyped and nongenotyped individuals simultaneously. This paper compared genomic predictions obtained from a single-step BLUP (SSBLUP) method, a genomic BLUP (GBLUP) method, a selection index blending (SELIND) method, and a traditional pedigree-based method (BLUP) for total number of piglets born (TNB), litter size at d 5 after birth (LS5), and mortality rate before d 5 (Mort; including stillbirth) in Danish Landrace and Yorkshire pigs. Data sets of 778,095 litters from 309,362 Landrace sows and 472,001 litters from 190,760 Yorkshire sows were used for the analysis. There were 332,795 Landrace and 207,255 Yorkshire animals in the pedigree data, among which 3,445 Landrace pigs (1,366 boars and 2,079 sows) and 3,372 Yorkshire pigs (1,241 boars and 2,131 sows) were genotyped with the Illumina PorcineSNP60 BeadChip. The results showed that the 3 methods with marker information (SSBLUP, GBLUP, and SELIND) produced more accurate predictions for genotyped animals than the pedigree-based method. For genotyped animals, the average of reliabilities for all traits in both breeds using traditional BLUP was 0.091, which increased to 0.171 w+hen using GBLUP and to 0.179 when using SELIND and further increased to 0.209 when using SSBLUP. Furthermore, the average reliability of EBV for nongenotyped animals was increased from 0.091 for traditional BLUP to 0.105 for the SSBLUP. The results indicate that the SSBLUP is a good approach to practical genomic prediction of litter size and piglet mortality in Danish Landrace and Yorkshire populations. PMID- 25549984 TI - Potential aquaculture probiont Lactococcus lactis TW34 produces nisin Z and inhibits the fish pathogen Lactococcus garvieae. AB - Bacteriocin-producing Lactococcus lactis TW34 was isolated from marine fish. TW34 bacteriocin inhibited the growth of the fish pathogen Lactococcus garvieae at 5 AU/ml (minimum inhibitory concentration), whereas the minimum bactericidal concentration was 10 AU/ml. Addition of TW34 bacteriocin to L. garvieae cultures resulted in a decrease of six orders of magnitude of viable cells counts demonstrating a bactericidal mode of action. The direct detection of the bacteriocin activity by Tricine-SDS-PAGE showed an active peptide with a molecular mass ca. 4.5 kDa. The analysis by MALDI-TOF-MS detected a strong signal at m/z 2,351.2 that corresponded to the nisin leader peptide mass without the initiating methionine, whose sequence STKDFNLDLVSVSKKDSGASPR was confirmed by MS/MS. Sequence analysis of nisin structural gene confirmed that L. lactis TW34 was a nisin Z producer. This nisin Z-producing strain with probiotic properties might be considered as an alternative in the prevention of lactococcosis, a global disease in aquaculture systems. PMID- 25549985 TI - The effect of simulation courseware on critical thinking in undergraduate nursing students: multi-site pre-post study. AB - BACKGROUND: The use of simulations has been considered as opportunities for students to enhance their critical thinking (CT), but previous studies were limited because they did not provide in-depth information on the working dynamics of simulation or on the effects of the number of simulation exposures on CT. OBJECTIVES: This study examined the effect of an integrated pediatric nursing simulation used in a nursing practicum on students' CT abilities and identified the effects of differing numbers of simulation exposures on CT in a multi-site environment. DESIGN: The study used a multi-site, pre-test, post-test design. PARTICIPANTS AND SETTINGS: A total of 237 nursing students at three universities enrolled in a pediatric practicum participated in this study from February to December 2013. METHODS: All three schools used the same simulation courseware, including the same simulation scenarios, evaluation tools, and simulation equipment. The courseware incorporated high-fidelity simulators and standardized patients. Students at school A completed one simulation session, whereas students at schools B and C completed two and three simulation sessions, respectively. Yoon's Critical Thinking Disposition tool (2008) was used to measure students' CT abilities. RESULTS: The gains in students' CT scores varied according to their numbers of exposures to the simulation courseware. With a single exposure, there were no statistically significant gains in CT, whereas three exposures to the courseware produced significant gains in CT. In seven subcategories of critical thinking, three exposures to the simulation courseware produced CT gains in the prudence and intellectual eagerness subcategories, and the overall simulation experience produced CT gains in the prudence, systematicity, healthy skepticism, and intellectual eagerness subcategories. CONCLUSIONS: Simulation courseware may produce positive learning outcomes for prudence in nursing education. In addition, the findings from the multi-site comparative study may contribute to greater understanding of how patient simulation experiences impact students' CT abilities. PMID- 25549986 TI - Absent bystanders and cognitive dissonance: a comment on Timmins & de Vries. AB - Timmins & de Vries are more sympathetic to my editorial than other critics, but they take issue with the details. They doubt whether the bystander phenomenon applies to Mid Staffs nurses; they believe that cognitive dissonance is a better explanation of why nurses fail to behave compassionately; and they think that I am 'perhaps a bit rash' to conclude that 'teaching compassion may be fruitless'. In this comment, I discuss all three points. I suggest that the bystander phenomenon is irrelevant; that Timmins & de Vries give an incomplete account of cognitive dissonance; and that it isn't rash to propose that educating nurses 'for compassion' is a red herring. Additionally, I comment on the idea that I wish to mount a 'defence of healthcare staff'. PMID- 25549987 TI - Occupational health: additional support for the aging anesthesiologist. PMID- 25549988 TI - The impact of advanced maternal age on peripartum thromboelastographic coagulation profiles: a prospective observational exploratory study. AB - PURPOSE: Advanced maternal age (AMA) is a known risk factor for pregnancy-related venous thromboembolism. However, it is unclear if underlying differences exist in the maternal coagulation profiles of AMA vs non-AMA women. The aim of this prospective observational study was to compare peripartum thromboelastography parameters of AMA and non-AMA women undergoing elective Cesarean delivery (CD). METHODS: We compared the peripartum thromboelastographic profiles of healthy AMA women (age > 35 yr) and non-AMA women (age <= 35 yr) undergoing elective CD under neuraxial anesthesia. Blood samples were drawn prior to CD and at 24 hr and 72 hr post-CD. At each time point, we assessed thromboelastographic and other standard laboratory coagulation indices. We used a linear mixed-effects regression model (SAS((r)) PROC MIXED) to assess between-group differences for individual thromboelastographic and laboratory coagulation parameters. RESULTS: The median [interquartile range] ages of women were 38 [37-41] yr and 29 [25-34] yr in the AMA and non-AMA groups, respectively (P < 0.001). We observed no statistically significant effect of study group on any thromboelastographic or laboratory coagulation parameters. No statistically significant correlations were found between any thromboelastographic parameter and maternal age. Peripartum thromboelastography and coagulation profiles of healthy AMA and healthy non-AMA women up to 72 hr post-CD were also similar. CONCLUSION: These data suggest that maternal thromboelastographic profiles of healthy AMA and non-AMA women undergoing elective CD are similar. The study was registered at ClinicalTrials.gov (identifier: NCT01416454). PMID- 25549989 TI - Erythropoiesis-stimulating agents for anaemia in chronic kidney disease: Are they all the same? PMID- 25549990 TI - The emerging epidemic of endometrial cancer: Time to take action. PMID- 25549991 TI - Obstructive carotid and/or intracranial artery disease rarely affects the incidence of haemodynamic ischaemic stroke during cardiac surgery: a study on brain perfusion single-photon emission computed tomography with acetazolamide. AB - OBJECTIVES: Ischaemic stroke is a major complication of cardiac surgery. The optimal strategies for operating on patients with obstructive carotid and/or intracranial artery disease (CIAD) are controversial. We aimed to clarify whether single-photon emission computed tomography (SPECT) with acetazolamide, to quantify the cerebral perfusion reserve, could predict the risk of haemodynamic ischaemic stroke during cardiac surgery. METHODS: The incidence of stroke related to obstructive CIAD and the corresponding autoregulatory reserve were prospectively assessed in 514 consecutive patients who underwent elective cardiac surgery with cardiopulmonary bypass (n = 484) and off-pump coronary artery bypass grafting (n = 30) between 2009 and 2013. Preoperative cerebral blood flow and its reactivity to acetazolamide were quantitatively determined in patients (n = 88) with obstructive CIAD, diagnosed by carotid ultrasonography and/or magnetic resonance angiography. RESULTS: An impaired cerebral perfusion reserve was identified in 1 (1.1%) of the 88 patients. This patient underwent prophylactic superficial temporal artery to middle cerebral artery anastomosis 1 month before coronary artery bypass surgery. Subsequently, the patient underwent conventional coronary artery bypass surgery, without experiencing perioperative stroke. Seven (1.4%) patients died in-hospital mortality and 5 (1.0%) experienced perioperative stroke. However, no patients experienced perioperative haemodynamic ischaemic stroke. CONCLUSIONS: It is unusual for CIAD to affect the incidence of haemodynamic ischaemic stroke during cardiac surgery. Brain perfusion SPECT with acetazolamide is effective for narrowing down patients at high risk of ischaemic stroke during cardiac surgery. Meanwhile, the application of brain perfusion single-photon emission tomography should be confined only to patients with obstructive CIAD because it is an expensive examination tool. PMID- 25549992 TI - Aortic root geometry in bicuspid aortic insufficiency versus stenosis: implications for valve repair. AB - OBJECTIVES: The contribution of aortic annular and root disease in bicuspid aortic valve (BAV) insufficiency remains unclear. We compared aortic root geometry between BAV stenosis and aortic insufficiency (AI), before and after repair. METHODS: Patients presenting for surgery for BAV insufficiency (n = 58) were compared with patients with BAV stenosis (n = 58). Clinical and transoesophageal echocardiographic data were collected, including end-diastolic diameters of the ventriculo-aortic junction (VAJ), aortic root, sinotubular junction (STJ) and ascending aorta (AA). RESULTS: AI patients were younger and more likely to be male compared with aortic stenosis (AS) patients. VAJ, aortic root and STJ diameters were significantly larger in AI compared with AS patients (30 +/- 0.5 vs 25 +/- 0.4 mm, P < 0.001; 41 +/- 0.8 vs 34 +/- 0.6 mm, P < 0.001; 36 +/- 0.9 vs 30 +/- 0.6 mm, P < 0.001, respectively). Following multivariable adjustment for age, sex, body surface area and ascending aortic diameter, these diameters remained larger in AI patients with a mean difference of 3, 6 and 4 mm, respectively (all P < 0.001). Mean AA diameter in the AI group was similar to the AS group (37 +/- 1.0 vs 34 +/- 0.8 mm, P = 0.06). Forty (69%) AI patients had BAV repair with a mean reduction in VAJ and STJ diameters of 5 and 9 mm compared with prerepair (P < 0.0001). CONCLUSIONS: Despite the absence of aortic aneurysms, aortic annulus and root dimensions are significantly larger in patients with BAV insufficiency compared with stenosis. Alterations in aortic root geometry contribute to the pathophysiology of BAV insufficiency and require correction for a successful repair. PMID- 25549993 TI - Differences in xenoreactive immune response and patterns of calcification of porcine and bovine tissues in alpha-Gal knock-out and wild-type mouse implantation models. AB - OBJECTIVES: Although bioprostheses are widely used in cardiovascular surgery, their durability is limited due to degeneration. Degeneration of bioprostheses limiting its clinical use results from multiple factors, and immune reaction has been considered to be one of the most important factors. The study objectives were to compare the mechanical characteristic differences of porcine and bovine prostheses, assess the differences in immune reaction among different species and tissues as well as elucidate bioprosthetic failure patterns in alpha-Gal knock out (KO) and wild-type mouse implantation models. METHODS: Six groups of different xenogeneic tissues (porcine pericardium, aortic valve, aortic wall; bovine pericardium, aortic valve and aortic wall) were implanted into the subcutaneous tissue of the wild-type mouse (n = 4) and the KO mouse (n = 4) (four xenogeneic tissue segments per each mouse). Mechanical and chemical tests, including tensile strength measurement and thermal stability test for pericardial tissues and pronase test for different xenogeneic tissues, were performed before implantation. Anti-alpha-Gal antibody titres (IgM and IgG antibodies) were measured using serum enzyme-linked immunosorbent assay analyses before implantation and 30, 60 and 90 days after implantation. Implanted tissues were harvested after 90 days and studied for histopathology and quantification of calcification. RESULTS: There were no significant differences in tensile strength and shrinkage temperature between the porcine and bovine pericardia, although the bovine pericardia showed a greater elasticity than the porcine pericardia (elongation at tensile strength, 74.8 +/- 4.5% vs 50.0 +/- 8.7%, P < 0.001). Resistance towards pronase degradation was not different among the groups of tissues (Groups 1-6, 89.1 +/- 7.6, 95.1 +/- 1.8, 90.3 +/- 5.3, 93.7 +/- 3.3, 89.1 +/- 2.4 and 89.1 +/- 3.0%, respectively; P = 0.061). The IgM titres of the alpha Gal KO mice were significantly higher at 30 days after implantation (0.71 +/- 0.27 vs 1.07 +/- 0.48, P = 0.004), whereas the IgG titres of the alpha-Gal KO mice remained higher until 60 days after implantation (at 30 days, 0.81 +/- 0.07 vs 1.28 +/- 0.79, P = 0.017; at 60 days, 0.54 +/- 0.16 vs 1.43 +/- 1.10, P = 0.045) than those of the wild-type mice. Calcium levels of tissues implanted into the alpha-Gal KO mice were significantly higher than those implanted into the wild-type mice regardless of tissue type (from Groups 1-6, 4.72 +/- 1.75 vs 27.76 +/- 22.73 MUg/mg; 3.05 +/- 1.04 vs 15.90 +/- 6.98 MUg/mg; 2.13 +/- 1.48 vs 29.76 +/- 30.71 MUg/mg; 1.02 +/- 0.53 vs 5.97 +/- 1.40 MUg/mg; 3.18 +/- 3.41 vs 30.55 +/- 66.69 MUg/mg; 6.21 +/- 5.56 vs 21.65 +/- 17.77 MUg/mg, all P <= 0.002). CONCLUSIONS: Chronic immune response to the alpha-Gal antigen may cause more severe tissue calcification in alpha-Gal KO mice. Removal of alpha-Gal antigenicity is strongly advised in xenogeneic bioprosthetic tissue implantation. PMID- 25549994 TI - Networks regulating ubiquitin and ubiquitin-like proteins promise new therapeutic targets. PMID- 25549995 TI - Potential effects of climate change on Florida's Everglades. AB - Restoration efforts in Florida's Everglades focus on preserving and restoring this unique wetland's natural landscape. Because most of the Everglades is a freshwater peatland, it requires surplus rainfall to remain a peatland. Restoration plans generally assume a stable climate, yet projections of altered climate over a 50-year time horizon suggest that this assumption may be inappropriate. Using a legacy regional hydrological model, we simulated combinations of a temperature rise of 1.5 degrees C, a +/- 10% change in rainfall, and a 0.46 m sea level rise relative to base conditions. The scenario of increased evapotranspiration and increased rainfall produced a slight increase in available water. In contrast, the more likely scenario of increased evapotranspiration and decreased rainfall lowered median water depths by 5-114 cm and shortened inundation duration periods by 5-45%. Sea level rise increased stages and inundation duration in southern Everglades National Park. These ecologically significant decreases in water depths and inundation duration periods would greatly alter current ecosystems through severe droughts, peat loss and carbon emissions, wildfires, loss of the unique ridge and slough patterns, large shifts in plant and animal communities, and increased exotic species invasions. These results suggest using adaptive restoration planning, a method that explicitly incorporates large climatic and environmental uncertainties into long-term ecosystem restoration plans, structural design, and management. Anticipated water constraints necessitate alternative approaches to restoration, including maintaining critical landscapes and facilitating transitions in others. Accommodating these uncertainties may improve the likelihood of restoration success. PMID- 25549996 TI - Collaborative implementation for ecological restoration on US Public Lands: implications for legal context, accountability, and adaptive management. AB - The Collaborative Forest Landscape Restoration Program (CFLRP), established in 2009, encourages collaborative landscape scale ecosystem restoration efforts on United States Forest Service (USFS) lands. Although the USFS employees have experience engaging in collaborative planning, CFLRP requires collaboration in implementation, a domain where little prior experience can be drawn on for guidance. The purpose of this research is to identify the ways in which CFLRP's collaborative participants and agency personnel conceptualize how stakeholders can contribute to implementation on landscape scale restoration projects, and to build theory on dynamics of collaborative implementation in environmental management. This research uses a grounded theory methodology to explore collaborative implementation from the perspectives and experiences of participants in landscapes selected as part of the CFLRP in 2010. Interviewees characterized collaborative implementation as encompassing three different types of activities: prioritization, enhancing treatments, and multiparty monitoring. The paper describes examples of activities in each of these categories and then identifies ways in which collaborative implementation in the context of CFLRP (1) is both hindered and enabled by overlapping legal mandates about agency collaboration, (2) creates opportunities for expanded accountability through informal and relational means, and, (3) creates feedback loops at multiple temporal and spatial scales through which monitoring information, prioritization, and implementation actions shape restoration work both within and across projects throughout the landscape creating more robust opportunities for adaptive management. PMID- 25549997 TI - Affinity and efficacy of copper following an algicide exposure: application of the critical burden concept for Lyngbya wollei control in Lay Lake, AL. AB - Accurate predictions of nuisance algae responses to algicide exposures are needed to guide management decisions. Copper sorption and responses of Lyngbya wollei (Farlow ex Gomont) Speziale and Dyck were measured in the laboratory and two areas in Lay Lake (AL, USA) to treatments of Captain((r)) XTR (SePRO Corporation; chelated copper algicide) and a sequential treatment of GreenClean((r)) Liquid (BioSafe Systems, LLC; peroxygen algicide) combined with Hydrothol((r)) 191 (United Phosphorus, Inc.; endothall algicide) followed by Captain XTR. Measured filament viability in laboratory exposures predicted Captain XTR alone could control L. wollei in Lay Lake, with 2 mg Cu/g algae EC75. This produced a targeted field treatment of 9.7 kg Cu/ha which was divided into three applications of 0.3 mg Cu/L as Captain XTR in the treatment areas. Laboratory and field experiments indicated treatments of Captain XTR alone and the combination treatment resulted in comparable copper sorption and responses of L. wollei. Copper adsorbed greater to L. wollei in laboratory experiments than in the treated areas of Lay Lake with comparable exposures (2 mg Cu/g L. wollei). However, responses and infused copper were similar and correlated in laboratory experiments and treated areas of Lay Lake indicating infused copper is critical for governing toxicity. Laboratory exposures as mg Cu/g algae accurately predicted the necessary algicide exposure required to attain the critical burden of infused copper and elicit desired responses of L. wollei in treated areas of Lay Lake. PMID- 25549998 TI - Accounting for results: how conservation organizations report performance information. AB - Environmental program performance information is in high demand, but little research suggests why conservation organizations differ in reporting performance information. We compared performance measurement and reporting by four private land conservation organizations: Partners for Fish and Wildlife in the US Fish and Wildlife Service (national government), Forest Stewardship Council-US (national nonprofit organization), Land and Water Conservation Departments (local government), and land trusts (local nonprofit organization). We asked: (1) How did the pattern of performance reporting relationships vary across organizations? (2) Was political conflict among organizations' principals associated with greater performance information? and (3) Did performance information provide evidence of program effectiveness? Based on our typology of performance information, we found that most organizations reported output measures such as land area or number of contracts, some reported outcome indicators such as adherence to performance standards, but few modeled or measured environmental effects. Local government Land and Water Conservation Departments reported the most types of performance information, while local land trusts reported the fewest. The case studies suggest that governance networks influence the pattern and type of performance reporting, that goal conflict among principles is associated with greater performance information, and that performance information provides unreliable causal evidence of program effectiveness. Challenging simple prescriptions to generate more data as evidence, this analysis suggests (1) complex institutional and political contexts for environmental program performance and (2) the need to supplement performance measures with in-depth evaluations that can provide causal inferences about program effectiveness. PMID- 25549999 TI - Structural and biochemical characterisation of VaF1, a P-IIIa fibrinogenolytic metalloproteinase from Vipera ammodytes ammodytes venom. AB - A high molecular mass metalloproteinase with alpha-fibrinogenolytic activity, termed VaF1, was purified from nose-horned viper (Vipera ammodytes ammodytes) venom. Subcutaneous injection of 9 MUg of VaF1 did not induce bleeding in rats. Nevertheless, in vitro it degraded collagen IV, nidogen and fibronectin, components of the extracellular matrix, although with low efficacy and narrow specificity. VaF1 would be expected to exert anti-coagulant action, due to its hydrolysis of fibrinogen, factor X, prothrombin and plasminogen, plasma proteins involved in blood coagulation. The enzyme is a single-chain glycoprotein with a molecular mass of 49.7 kDa, as determined by mass spectrometry, and multiple isoelectric points centred at pH 5.8. The complete amino acid sequence of the precursor of VaF1 was deduced by cloning and sequencing its cDNA. Composed of metalloproteinase, disintegrin-like and cysteine-rich domains, VaF1 is a typical P-IIIa subclass snake venom metalloproteinase. Although it possesses a collagen binding sequence in its disintegrin-like domain, VaF1 displayed no effect on collagen-induced platelet aggregation in vitro. Two consensus N-glycosylation sites are present in the sequence of VaF1, however, the extent of its glycosylation is low, only 5.2% of the total molecular mass. Interestingly, in standard experimental conditions VaF1 is not recognised by antiserum against the whole venom, so it can contribute to post-serotherapy complications, such as ineffective blood coagulation, in the envenomed patient. PMID- 25550000 TI - The hippocampus and exercise: histological correlates of MR-detected volume changes. AB - Growing evidence indicates that physical exercise increases hippocampal volume. This has consistently been shown in mice and men using magnetic resonance imaging. On the other hand, histological studies have reported profound alterations on a cellular level including increased adult hippocampal neurogenesis after exercise. A combined investigation of both phenomena has not been documented so far although a causal role of adult neurogenesis for increased hippocampal volume has been suggested before. We investigated 20 voluntary wheel running and 20 sedentary mice after a period of 2 month voluntary wheel running. Half of each group received focalized hippocampal irradiation to inhibit neurogenesis prior to wheel running. Structural MRI and histological investigations concerning newborn neurons (DCX), glial cells (GFAP), microglia, proliferating and pyknotic cells, neuronal activation, as well as blood vessel density and arborisation were performed. In a regression model, neurogenesis was the marker best explaining hippocampal gray matter volume. Individual analyses showed a positive correlation of gray matter volume with DCX-positive newborn neurons in the subgroups, too. GFAP-positive cells significantly interacted with gray matter volume with a positive correlation in sham-irradiated mice and no correlation in irradiated mice. Although neurogenesis appears to be an important marker of higher hippocampal gray matter volume, a monocausal relationship was not indicated, requesting further investigations. PMID- 25550002 TI - Hospital mortality after arthroplasty using a cemented stem for displaced femoral neck fractures. AB - PURPOSE: To review hospital mortality after hemiarthroplasty or total hip arthroplasty (THA) using a cemented stem for displaced femoral neck fractures. METHODS: Medical records of 284 hips in 70 men and 209 women aged 45 to 106 (mean, 81.3) years who underwent hemiarthroplasty (n=232) or THA (n=52) with a cemented stem using third-generation cementing techniques (including use of a plug, lavage, and cement pressurisation) for displaced femoral neck fractures were retrospectively reviewed. According to the American Society of Anesthesiologists (ASA) grading, 6 patients were classified preoperatively as grade 1, 77 as grade 2, 148 as grade 3, 47 as grade 4, and one as grade 5. Patients were operated on within 48 hours. Patients were rehabilitated in the hospital until discharge. The primary outcome measure was hospital mortality, including the cause of death. RESULTS: The mean length of hospital stay was 9.2 (standard deviation, 4.1) days. The hospital mortality was 5.7% (n=16). Of the 16 patients who died, 3 were classified preoperatively as ASA grade 2, 6 as grade 3, and 7 as grade 4. One patient died during the operation. One patient died in the recovery room within 6 hours. Both died from a cardiac arrest and were classified as ASA grade 4. Six patients died within the first 5 days. The causes of death were aspiration pneumonia (n=5), cardiac arrest (n=3), bowel perforation (n=2), multiple organ failure (n=3), type 2 respiratory failure (n=1), heart failure (n=1), and subarachnoid bleeding after a hospital fall (n=1). CONCLUSION: Hemiarthroplasty or THA using a cemented stem resulted in low hospital mortality in our hospital dedicated to the treatment of geriatric hip fractures. Hospital mortality was higher in patients with ASA grade 3 or higher. PMID- 25550003 TI - Cancellous screw fixation for undisplaced femoral neck fractures in the elderly. AB - PURPOSE: To review the outcomes of cancellous screw fixation for undisplaced femoral neck fractures in elderly patients and to identify the risk factors associated with poor outcomes. METHODS: Medical records of 100 patients aged 61 to 94 (mean, 78) years who underwent internal fixation with cancellous screws for undisplaced femoral neck fractures were reviewed. According to the Garden classification, 85 fractures were type 1 (impacted fractures) and 15 were type 2 (complete, undisplaced fractures). Postoperative mobility and pain were assessed through a telephone survey. Outcome measures included the length of surgery, length of hospital stay, perioperative complications, postoperative pain, pre- and post-operative mobility status, and rates and causes of implant revision and mortality. RESULTS: Of the 96 patients followed up for a mean of 39 (range, 25 76) months, 8 underwent revision surgery for avascular necrosis of the femoral head (n = 5) or non-union/implant failure (n = 3). Of the 68 patients assessed for postoperative pain and mobility, 15 had pain on movement, whereas 55 could ambulate independently with or without walking aids (out of 61 that could do so preoperatively). Overall, 30 patients had a decrease in their mobility status. Patients aged > 75 years (compared with those aged <= 75 years) were associated with longer length of hospital stay (12.7 vs. 10.2 days, p = 0.047) and higher mortality rate (23% vs. 7%, p = 0.044). The length of hospital stay was also associated with presence of ischaemic heart disease/ cerebrovascular accident (14.4 vs. 11.04 days, p = 0.002). Pain, mobility, and rates of complication and revision were not associated with any of the variables. CONCLUSION: Cancellous screw fixation for undisplaced femoral neck fractures in elderly patients was associated with relatively low complication and revision rates. PMID- 25550004 TI - Proximal femoral locking compression plate for proximal femoral fractures. AB - PURPOSE: To review short-term outcomes of proximal femoral locking compression plate (PF-LCP) fixation for proximal femoral fractures in terms of postoperative complications and failure rates. METHODS: Medical records of 21 men and 5 women aged 22 to 85 (mean, 49.7) years who underwent internal fixation with the PF-LCP for proximal femoral fractures were reviewed. Younger patients (mean age, 38.7 years) were more commonly involved in high-energy trauma with multiple musculoskeletal injuries, whereas older patients (mean age, 67.7 years) were more commonly involved in low-energy trauma. Fractures were classified into: multi fragmentary pertrochanteric fractures (n=13), transtrochanteric fractures (n=6), and subtrochanteric/proximal diaphyseal fractures (n=7). RESULTS: Patients were followed up for a mean of 14.7 months. Seven patients developed complications including loosening of locking screws (n=4), delayed union (n=2), and infection (n=1); 4 of them required additional surgeries. CONCLUSION: The PF-LCP is appropriate for complex proximal femoral fractures with poor bone quality, revision surgeries, and multi-fragmentary subtrochanteric/proximal diaphyseal fractures. For intertrochanteric fractures, the sliding hip screw system should be used to avoid failure. PMID- 25550005 TI - Early versus late flap coverage for open tibial fractures. AB - PURPOSE: To compare early versus late flap coverage for open tibial fractures. METHODS: Medical records of 83 men and 6 women (mean age, 38 years) who underwent fixation for open tibial fractures (Gustilo grades IIIB and IIIC) followed by flap coverage within (n=30) or after (n=59) 72 hours were reviewed. All fractures were treated within 24 hours. Outcome measures included bone union, infection, flap failure, the need for secondary procedures to achieve union, and eventual amputation. The early and late flap coverage groups were compared. RESULTS: Early flap coverage was associated with shorter length of hospitalisation (31.4 vs. 55.8 days, p<0.01), lower deep infection rates (23% vs. 54%, p<0.01), and smaller number of surgical procedures (6.4 vs. 9.2, p=0.01). The 2 groups did not differ significantly in terms of the time to bone union, flap failure, amputation, and the need of secondary procedures to facilitate bone union. CONCLUSION: In severe open tibial fractures, early soft-tissue coverage (within 72 hours) was associated with more favourable outcomes in terms of length of hospitalisation and infection. PMID- 25550006 TI - Minimally invasive plate osteosynthesis for distal tibial fractures. AB - PURPOSE: To review the outcomes of 53 patients who underwent minimally invasive plate osteosynthesis (MIPO) for distal tibial fractures. METHODS: Medical records of 31 men and 22 women aged 22 to 78 (mean, 51) years who underwent MIPO using a locking compression plate for distal tibial fractures of the left (n=28) and right (n=25) legs with or without intra-articular extension were reviewed. RESULTS: Patients were followed up for a mean of 26 (range, 24-38) months. The mean time from injury to surgery was 9 (range, 3-12) days. The mean operating time was 105 (range, 75-180) minutes. The mean hospital stay was 16 (range, 8-25) days. Non-weight bearing walking with a crutch was started after a mean of 5.7 (range, 3-9) days. The mean time to callus formation was 12 (range, 8-15) weeks. The mean time to full weight bearing was 15 (range, 8-22) weeks. The mean time to bone union was 25 (range, 20-30) weeks. All except 2 fractures united anatomically. At 10 months, the range of motion of the ankle joint in all patients was similar to the contralateral side. Two patients had malunion but this was not clinically significant. Five patients had superficial infection, and 2 patients had persistent pain. CONCLUSION: MIPO is effective for closed, unstable fractures of the distal tibia. It reduces surgical trauma and preserves fracture haematoma. PMID- 25550007 TI - Early reimplantation for open total talar extrusion. AB - PURPOSE: To review outcome of early reimplantation for open total talar extrusion in 7 patients. METHODS: Medical records of 5 men and 2 women aged 19 to 53 years who underwent reimplantation for open total talar extrusion within 6 hours after road traffic accident (n= 6) or industrial injury (n=1) were reviewed. The talus was first irrigated with 9 to 10 litres of saline solution, followed by 10% povidone iodine. It was then reduced after thorough debridement and fixed with tension band wiring or external fixation. Ankle mobilisation exercises were started at week 6 and full weight bearing at week 14. Outcome was assessed using the American Foot And Ankle Society score. RESULTS: After a mean follow-up of 31.9 (range, 24-46) months, the mean American Foot and Ankle Society score was 81, and the mean dorsiflexion-plantar flexion arc was 36.9o (range, 25o-45o). All patients were able to walk with a balanced, unaided gait with mild-to-moderate pain (n=3) or pain-free (n=4). No patient developed deep infection or instability. Three patients developed avascular necrosis of the talus; restriction of motion was moderate at the ankle joint and severe at the subtalar joint. None of these 3 patients opted for revision surgery, as the pain was tolerable and did not limit their daily activities, but their condition was expected to deteriorate with time. CONCLUSION: Early reimplantation is recommended for open total talar extrusion, as it restores (to some extent) hind foot mechanics, heel height, and bone stock for activities of daily living and future reconstructive options. PMID- 25550008 TI - Outcome of fixation for nonunion of extremities. AB - PURPOSE: To review the outcomes of 102 consecutive patients who underwent fixation for nonunion of extremities. METHODS: Medical records of 71 men and 31 women aged 16 to 82 (mean, 45; standard deviation [SD], 19) years who underwent fixation for nonunion of the upper (n=31) and lower (n=71) extremities were reviewed. The nonunion types included oligotrophic (n=47), hypertrophic (n=22), atrophic (n=17), defect (n=12), and comminuted (n=4). 13 of the nonunions were infected. 10 patients had concomitant injuries of the brain (n=2), abdomen (n=5), chest (n=1), and spine (n=2). 43 patients were smokers, and 19 had diabetes mellitus. 80 patients had had previous surgery, and 3 had undergone previous radiotherapy. The mean time from injury to nonunion surgery was 19 (SD, 25.6; range, 6-180) months. Outcome measures included bone union, ability to return to original work, pain, gait, and loss of range of motion. RESULTS: The mean follow up period was 26.6 (SD, 19.9; range, 8-121) months. 100 patients achieved bone union. 83 of them achieved bone union after a single surgery in a mean of 5.6 (SD, 2.9) months. The remaining 17 patients underwent multiple surgeries, 13 of whom had infected nonunions. Two patients did not achieve bone union. Of 64 patients who had work, 47 returned to their original work and 17 did not. Outcome was unsatisfactory in 5 patients who had persistent pain and/or no improvement in gait. CONCLUSION: Bone union is not necessarily associated with adequate recovery of function. PMID- 25550009 TI - Sports-related fractures in South East Scotland: an analysis of 990 fractures. AB - PURPOSE: To describe the characteristics of all sports related fractures in patients aged >= 15 years in South East Scotland in one year. METHODS: Medical records of 990 consecutive patients aged >= 15 years who presented to the Orthopaedic Trauma Unit of the Royal Infirmary of Edinburgh with sports-related fractures between 1 July 2007 and 30 June 2008 were reviewed. Acute fractures of the upper limbs, lower limbs, pelvis, and cervical spine were included, but those of the skull, facial bones, and thorax were excluded, as were stress and chronic fractures. RESULTS: The incidence of sports-related fractures was 1.8/1000/year (82% involving men). The median age of patients was 25 (interquartile range, 19 35) years. Sports-related fractures accounted for 24.6% and 5.1% of all fractures in men and women, respectively. Men aged 15 to 19 years were 9 times more likely to have sports-related fractures than women of the same age. The sports-related fractures involved the upper limbs (52.4%), lower limbs (45.4%), and axial skeleton (2.2%). 12 of 49 sports (football, rugby, skiing, snowboarding, 3 cycling disciplines, horse riding, motocross, basketball, martial arts, and ice skating) accounted for 82.8% of all sports-related fractures. Upper limb fractures outnumbered lower limb fractures in all sports, except for horse riding and motocross that the proportions were similar. CONCLUSION: In South East Scotland, most sports related fractures involved the upper limbs. PMID- 25550010 TI - Femoral and tibial tunnel positioning on graft isometry in anterior cruciate ligament reconstruction: a cadaveric study. AB - PURPOSE: To assess distance changes between the femoral and tibial attachment points of 3 different anterior cruciate ligament (ACL) tunnel entry positions throughout the range of knee motion in cadaveric knees. METHODS: The ACLs of 11 fresh-frozen cadaveric knees (from 6 men and 5 women) were removed using radiofrequency. Three tibial tunnel placements were made using a cannulated awl, and three 2.4-mm pilot tunnels were drilled on the lateral femoral condyle. One end of an inelastic suture was inserted from each of the 3 femoral holes and fixed on the femoral cortex using a suture button in turn, whereas the other end of the suture was passed through the cannulated awl and fixed on each of the 3 tibial placements in turn, with constant tension. Distance changes of the suture throughout the range of knee movement (0o, 90o, and 135o of knee flexion) were measured for each combination of tibial and femoral positions. RESULTS: The distance was minimum when the knee was in full extension (p < 0.0001). Most of the distance changes occurred during initial flexion (0o-90o). The most isometric position (mean +/- standard deviation [SD] distance change, 2.78 +/- 0.93 mm; p < 0.0001) was noted when the suture was at the anteromedial bundle placement in the femur and anterior in the tibia. The least isometric position (mean +/- SD distance change, 10.37 +/- 2.08 mm; p < 0.0001) was noted when the suture was at the mid-bundle position in the femur and at the posterolateral bundle insertion in the tibia. The anatomic position resulted in a mean +/- SD distance change of 7.63 +/- 2.01 mm (p < 0.0001). The femoral position had a greater influence on distance change than the tibial position. CONCLUSION: None of the ACL graft positions was isometric. Anatomic ACL positioning resulted in comparable anisometry to the native ACL. The minimum distance for all graft positions was noted in full extension, in which position the graft should be fixed during anatomic ACL reconstruction. PMID- 25550011 TI - Reconstruction for chronic grade-II posterior cruciate ligament deficiency in Malaysian military personnel. AB - PURPOSE: To evaluate the outcome of reconstruction for chronic grade-II posterior cruciate ligament (PCL) deficiency in Malaysian military personnel. METHODS: Medical records of 16 male military personnel aged 25 to 41 years who underwent reconstruction for chronic grade-II PCL deficiency using the quadruple hamstrings tendon by a single surgeon were reviewed. The mean time from injury to surgery was 43.6 (range, 3-104) months. 10 patients had grade-I (n=4), grade-III (n=2), and grade-IV (n=4) lesions of the medial femoral condyles. Seven patients had medial (n=6) and lateral (n=1) meniscus tears. At the 2-year follow-up, patients were asked to complete a questionnaire consisting of the Lysholm score, Tegner activity level, and International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form. Posterior drawer test, KT-2000 arthrometer test for posterior translation of the tibia, and military health grade (MHG) were assessed by an independent assessor. RESULTS: At the 2-year follow-up, the mean Lysholm score was 83; the score was excellent in 2 patients, good in 9, fair in 4, and poor in one. The mean IKDC subjective score was 74. The median Tegner activity level increased from 5.5 to 6. The posterior drawer test of 11 patients improved to grade I and the remaining 5 remained at grade II. The mean posterior translation of the tibia was 2.4 mm postoperatively; the posterior translation was normal in 8 patients, nearly normal in 7, and abnormal (>= 6 mm) in one. The MHG improved in 14 patients and remained unchanged in 2. The latter 2 patients had no chondral lesion or meniscus injury. The first one was 40 years old with a postoperative IKDC score of 55 and a Tegner activity level of 2. The second one was 34 years old with a postoperative IKDC score of 65 and posterior translation of the tibia of 6 mm. CONCLUSION: Surgical reconstruction for chronic grade-II PCL injury achieved satisfactory outcome and may be appropriate for military personnel. PMID- 25550012 TI - Clavicular hook plate for grade-III acromioclavicular dislocation. AB - PURPOSE: To review the outcomes of clavicular hook plate fixation for grade-III acromioclavicular (AC) dislocation in young athletes. METHODS: Medical records of 14 male and 5 female athletes aged 18 to 49 (mean, 29) years who underwent fixation with a 3.5-mm-thick, 15-mm-long clavicular hook plate for acute grade III AC dislocation were reviewed. The visual analogue score for pain and the Constant shoulder score were assessed. RESULTS: The mean follow-up was 4.2 years. The mean visual analogue score for pain was 1.8 (range, 1-3). The Constant shoulder score was excellent (>= 90) in 14 patients and good (83-89) in 5 patients. All patients achieved range of motion equal to that of the contralateral side at week 5. Sports activities were resumed by month 6 at the latest. CONCLUSION: The clavicular hook plate for grade- III AC dislocation enables quick return to sports activities and achieves good-to-excellent functional outcome. PMID- 25550013 TI - Injection of autologous blood versus corticosteroid for lateral epicondylitis: a randomised controlled study. AB - PURPOSE: To compare the efficacy of autologous blood injection versus corticosteroid injection for lateral epicondylitis. METHODS: 21 men and 59 women (mean age, 45.2 years) presenting with lateral epicondylitis were randomised to receive either autologous blood injection (2 ml of autologous venous blood mixed with 1 ml of 2% prilocaine hydrochloride) or corticosteroid injection (1 ml of 40 mg methylprednisolone acetate mixed with 1 ml of 2% prilocaine hydrochloride) given by a single physician. Patients were assessed before (day 0) and after (days 15, 30, and 90) treatment for elbow pain (using a visual analogue scale [VAS]), function (using the patient-rated tennis elbow evaluation [PRTEE] questionnaire), and grip strength (using a hydraulic hand dynamometer). Patients were followed up at 6 months by telephone to assess elbow pain using the VAS. RESULTS: No complications (infection, skin atrophy, neurovascular damage, or tendon rupture) were noted. 10 patients reported increased pain for up to 2 days after autologous blood injection. In both groups, the VAS score for elbow pain, PRTEE score, and grip strength improved significantly after treatment (p=0.0001), but the pattern of improvement differed. Compared with autologous blood injection, corticosteroid injection improved all 3 scores at a faster rate over the first 15 days (p=0.0001), and then started to decline slightly until day 90. After autologous blood injection, all 3 scores improved steadily and were eventually better (p=0.0001). If a 37% decrease in PRTEE is defined as complete recovery, 38 (95%) of patients with autologous blood injection and 25 (62.5%) of patients with corticosteroid injection achieved complete recovery (p=0.0001). CONCLUSION: Autologous blood injection was more effective over the follow-up period than corticosteroid injection in improving pain, function, and grip strength. It is recommended as a first-line injection treatment because it is simple, cheap, and effective. PMID- 25550014 TI - Ceramic-on-ceramic total hip arthroplasty in patients younger than 55 years. AB - PURPOSE: To review the outcomes of 65 patients younger than 55 years who underwent uncemented total hip arthroplasty (THA) using third-generation ceramic on-ceramic prostheses. METHODS: Medical records of 30 men and 35 women (80 hips) aged 18 to 55 (mean, 39) years who underwent uncemented THA using third generation ceramic-onceramic prostheses by a single surgeon were reviewed. 61 THAs used the Reflection cup with the Synergy stem (n=49), Spectron stem (n=7), or Anthology stem (n=5), and 19 THAs used the Trident cup with the Secur-Fit stem. Outcomes were assessed based on the UCLA Activity Score and Harris Hip Score, as well as radiolucency around the implants, malposition, and subsidence on radiographs. Patients were asked about their satisfaction with current activity level (yes/no), activity limitation (no limitation, musculoskeletal limitation, psychological impediments and lack of motivation, and pain or disability of the operative hip), and change in occupational activity level (same or similar, more active, and less active or disability). RESULTS: The mean follow up period was 54 (range, 24-110) months. Six patients were excluded from the analysis owing to prosthetic failure secondary to ceramic liner fracture after falling (n=2), acetabular component loosening (n=1), intolerable squeak (n=1), periprosthetic fracture (n=1), and instability (n=1). The mean UCLA Activity Score improved from 4.0 (range, 1-10) to 7.7 (range, 2-10) [p<0.001], and the mean Harris Hip Score improved from 52.8 (range, 25-69) to 91.0 (range, 38-100) [p<0.001]. No hip had evidence of subsidence, loosening, or osteolysis. 52 (80%) patients were satisfied with their activity level; 28 (43%) patients reported no activity limitation; and 57 (88%) patients kept the same or similar occupation. CONCLUSION: Ceramic-on-ceramic THA achieved acceptable clinical and radiographic outcomes. PMID- 25550015 TI - Total hip replacement using a highly crosslinked polyethylene liner in Asians with small acetabulum. AB - PURPOSE: To evaluate the medium-term outcomes of total hip replacement (THR) using a thin highly cross-linked polyethylene (HXLPE) liner in an Asian population. METHODS: Medical records of 20 men and 44 women aged 26 to 80 (mean, 59) years who underwent 80 THRs using a thin HXLPE liner by a single surgeon were reviewed. Indications for THR included dysplasia (n = 26), avascular necrosis (n=26), osteoarthritis (n = 22), rheumatoid arthritis (n = 4), and ankylosing spondylitis (n = 2). The surgical technique, implant used, and rehabilitation protocol were standardised. Radiographs were evaluated for cup migration and peri implant radiolucency. Femoral head penetration was assessed at day 1 and last follow-up using the Kang modification of the Dorr and Wan method and the PowerPoint method. RESULTS: After a mean follow-up of 7.5 (range, 5.0-11.9) years, no patient had undergone acetabular revision. Two hips were revised for the femoral stem. Femoral head penetration did not correlate with sex, age at surgery, hip pathology, acetabular inclination angle, cup size, or liner thickness. The maximum femoral head penetration was 0.09 mm/year, which was below the osteolysis threshold of 0.1 mm/year. The mean +/- standard deviation femoral head penetration was 0.29 +/- 0.12 mm (or 0.04 +/- 0.02 mm/year) by the PowerPoint method and 0.17 +/- 0.22 mm (or 0.02 +/- 0.03 mm/year) by the Kang modification of the Dorr and Wan method. Femoral head penetration correlated with the number of years of follow-up (p = 0.012). CONCLUSION: The use of a thin HXLPE liner in primary THR for patients with small acetabulum achieved good outcomes after a mean of 7.5 years. PMID- 25550016 TI - Fixation strength at the interface between Kerboull-type plate and bone cement. AB - PURPOSE: To evaluate the fixation strength at the interface between the Kerboull type plate and bone cement in 6 experimental conditions. METHODS: Experimental materials comprised a simulated acetabular block, a simulated Kerboulltype plate, a pressuriser cover, a pressuriser arm, and bone cement. The simulated Kerboull type plate was placed on the simulated acetabular block, with the pressuriser cover. Bone cement was added and the pressuriser arm was inserted. After 6 days of curing, pulling tests were performed to measure the fixation strength at the interface between the plate and the bone cement. Six experimental conditions were evaluated. In condition 1, a 1-mm plate was used with no gap between the plate and the acetabular block. In condition 2, a 2.5-mm plate was used with no gap. In condition 3, a 2.5-mm plate was used with a 2-mm gap. In condition 4, the plate was not used. In condition 5, condition 2 was tested with the model rotated 45o. In condition 6, condition 3 was tested with the model rotated 45o. RESULTS: The maximum fixation strengths in conditions 1, 2, 3, 5, and 6 were 44.4 N, 59.1 N, 122.5 N, 86.9 N, and 185.2 N, respectively. The most important factor affecting the maximum fixation strength was bone cement at the interface between the plate and the acetabular block, followed by 45o rotation during testing, and then thickness of the plate. CONCLUSION: To enhance fixation of the Kerboull-type plate with cemented acetabular cup, penetration of cement into the outer side of the Kerboull-type plate should be minimised. PMID- 25550017 TI - Curettage and reconstruction by the sandwich technique for giant cell tumours around the knee. AB - PURPOSE: To evaluate outcomes of 36 patients who underwent curettage, use of phenol, and reconstruction using the sandwich technique for giant cell tumour (GCT) of bone around the knee. METHODS: 22 women and 14 men aged 19 to 46 (mean, 29.6) years underwent intralesional curettage, use of phenol, and reconstruction using the sandwich technique for GCT of the proximal tibia (n=23) or distal femur (n=13). Two of the cases were recurrences. Two, 18, and 16 tumours were classified as grade I, grade II, and grade III, respectively. Five of the grade III tumours were associated with an extra-articular pathological fracture. Patients underwent intralesional curettage, use of phenol, and reconstruction with allograft, gel foam, and cement (the sandwich technique). Pathological fractures were fixed with plates. Functional outcome was evaluated using the Musculoskeletal Tumor Society (MSTS) score. RESULTS: The mean follow-up period was 5 (2.5-11) years. The mean MSTS score was 27.7 out of 30 (standard deviation, 3; range, 16-30). One patient with a grade III tumour in the proximal tibia had a recurrence detected elsewhere after 3 years. Her MSTS score at 2 years was 26. No patient had malignant transformation. CONCLUSION: Intralesional curettage, use of phenol, and reconstruction with allograft, gel foam, and cement (the sandwich technique) for GCT of bone achieved good functional outcome and a low recurrence rate. PMID- 25550018 TI - Reconstruction of the distal radius with non-vascularised fibular graft after resection of giant cell tumour of bone. AB - PURPOSE: To evaluate outcomes of wide resection and reconstruction of the distal radius with non-vascularised autogenous fibular grafts for giant cell tumour (GCT) of bone. METHODS: Medical records of 7 men and 5 women aged 22 to 47 (mean, 31) years who underwent wide resection of the distal radius and reconstruction with non-vascularised autogenous fibular grafts for GCT of bone were reviewed. The mean length of the resected radius was 9 (range, 7-11) cm. The ipsilateral proximal fibula with a small portion of attached ligament was harvested. The articular surface of the graft was fixed to the scapholunate articular surface by Kirschner wires, and the ligament of the fibular head was sutured to the carpal ligaments. The graft was fixed to the proximal radius with a small dynamic compression plate. Iliac cancellous bone graft was added. Pain, instability, and functional status were assessed. Wrist joint movements were measured using a goniometer. The grip strength was measured. The operated and contralateral sides were compared. RESULTS: The mean follow-up was 24 (range, 20-27) months. All patients achieved radiological union after a mean of 16 (range, 14-20) weeks. The mean active range of movement in the operated wrists was 32o dorsiflexion, 38o palmar flexion, 15o radial deviations, 12o ulnar deviations, 50o supination, and 60o pronation. Compared with the contralateral wrists, the operated wrists regained 60% of the function, with satisfactory grip strength, and normal finger and thumb movements and hand sensation. No patient had recurrence after 2 years. Two patients had minor dorsal subluxation, which was resolved with a wrist brace. Three patients had superficial infection, which was resolved with intravenous antibiotics and dressings. Two patients had peroneal nerve palsy, which recovered completely in 12 weeks. CONCLUSION: Non-vascularised fibular grafts for reconstruction of the distal radius after resection of a GCT of bone achieved good cosmetic and functional outcomes. PMID- 25550019 TI - Anthropometric estimation of body height after surgical correction of scoliosis. AB - PURPOSE: To estimate the height loss in 28 patients who had undergone surgery for scoliosis before skeletal maturity. METHODS: 28 women patients aged 11 to 18 (mean, 15) years underwent Harrington instrumentation, segmental sublaminar wiring, and posterior spinal fusion for idiopathic scoliosis. The patients' mean age at menarche was 13 (range, 10-16) years. Pre- and post-operative radiographs of the spine were taken to determine curve types, the Cobb angle, and the degree of correction. The standing and sitting heights were measured using a flexible steel tape, and the expected standing and sitting heights were derived using formulae. RESULTS: At the final follow up, the mean patient age was 20 (16-32) years. The mean standing height was 155.2 cm and the mean sitting height was 77.4 cm. Using the formulae, the mean expected standing height was 158.4 cm, indicating height loss of 3.2 cm (t=4.6, p=0.0001), and the mean expected sitting height was 79.9 cm, indicating height loss of 2.6 cm (t=3.84, p=0.001). The curve types of the 28 patients were sub-divided as thoracic (n=7), thoracolumbar (n=18), and double major (n=3). Patients with thoracolumbar curves achieved better correction and less loss of standing and sitting heights. Percentage loss of standing and sitting heights were not correlated with the apex of the curve or the degree of correction. CONCLUSION: Height loss after surgery was acceptable in comparison with height loss associated with progression of scoliosis without surgery. PMID- 25550020 TI - Anterior cervical disc replacement for degenerative disc disease. AB - PURPOSE: To review the outcomes of anterior cervical disc replacement using the Prestige LP system for degenerative disc disease. METHODS: Medical records of 12 men and 23 women aged 26 to 66 (mean, 46) years who underwent 48 anterior cervical disc replacements using the Prestige LP system by a single spine surgeon were reviewed. 22 patients underwent one-level disc replacement at C5-C6 (n=13) and C6-C7 (n=9), and 13 patients underwent 2-level disc replacement at C5-C6 and C6-C7 (n=11), C4-C5 and C5-C6 (n=1), and C6-C7 and C7-T1 (n=1). Neck Disability Index (NDI) score, visual analogue scale (VAS) for pain in the neck and arm, and physical and mental component scores of the Short Form 36 were evaluated at week 6 and months 6, 12, 24, 36, and 48. RESULTS: The NDI score, VAS score for neck and arm pain, and physical and mental component scores of the Short Form 36 improved significantly after surgery (p<0.001). 80% of patients were satisfied with the treatment. One patient developed a neck haematoma on day 1 and underwent surgical evacuation. Another patient developed Horner's syndrome and achieved partial recovery at 6 weeks and complete recovery at 6 months. No patient had implant-related complications or reoperation. CONCLUSION: The Prestige LP cervical disc implant was safe for one- and 2-level cervical disc replacement. PMID- 25550021 TI - Radiographic changes in nutritional ricket hips in children in response to treatment. AB - PURPOSE: To review radiographic changes in the proximal femurs of children of different ages during the course of treatment for nutritional rickets. METHODS: Pelvic radiographs of 161 children aged <= 13 years with nutritional rickets were retrospectively reviewed. Patients were treated with dietary counselling and vitamin D and calcium supplementation. Patients were followed up at week 3 and thereafter at a 2-month interval until ulnar convexity was achieved. Sequential radiographs of the hips in children of different ages were reviewed for each growth plate in terms of (1) the direction of growth, (2) active areas, (3) contribution of growth, and (4) the structure of the epiphysis. Radiographs were superimposed for comparison by matching the triradiate cartilage and the ischial portion of the obturator foramen. RESULTS: The direction of growth of the growth plates was from the physeal plate that is the longitudinal growth plate of the neck (LGP), the femoral neck isthmus (FNI), and the trochanteric growth plate (TGP) to the diaphyseal region, and from the perichondrium to the ossification centre in the proximal femoral epiphysis. Before the age of one year, the growth zone of the proximal femur was homogenous, with no differentiation between the LGP, FNI, and TGP. By the age of 2 years, the differentiation was more clearly established; the FNI was usually smaller than the TGP and LGP. By the age of 3 years, the FNI became prominent and the TGP remained small. By the age of 4 years, the ossification centre of the greater trochanter appeared, and the LGP extended medially as a medial overhang (MOH). During the children's growth, the LGP, FNI, or TGP remained active to a variable extent and were distinct until the age of 6 years. Gradually, the periphery of the LGP became less active than the centre of the LGP and gave rise to the 'eye sign'. The MOH generally ceased to be active beyond the age 9 years. By the age of 12 years, the TGP and FNI were minimally active and only the centre of the LGP remained active. CONCLUSION: The mineralisation process of healing rickets provides a useful biological marker for patterns of growth. Knowledge of the quantitative contribution of various growth plates of the proximal femur in childhood may increase the understanding of the pathomechanism of hip deformations. PMID- 25550022 TI - Prevalence and factors of burnout among Australian orthopaedic trainees: a cross sectional study. AB - PURPOSE: To assess the prevalence and factors of burnout among Australian orthopaedic trainees. METHODS: 236 orthopaedic registrars of the Australian Orthopaedic Association were invited to participate in a 32-item survey by email. The questionnaire assessed potential factors associated with burnout, satisfaction with the choice of orthopaedics as a career and work-life balance, and subjective overall health, as well as 3 subscales of the Maslach Burnout Inventory - Human Services Survey for assessing burnout: emotional exhaustion, depersonalisation, and personal accomplishment. Participants with high levels of either emotional exhaustion or depersonalisation were defined as having burnout. Those with and without burnout were compared. RESULTS: 51 (22%) of the 236 trainees completed the questionnaire. Of whom, 88% were satisfied with their choice of orthopaedics as a career, whereas 27% were satisfied with their work life balance. 27 (53%) respondents were considered burned out. Compared with those who did not burn out, those who burned out were less satisfied with their careers (p=0.004) and work-life balance (p=0.021). CONCLUSION: 53% of Australian orthopaedic trainees were burned out. Burnout trainees were more likely to be dissatisfied with their career choice and worklife balance. Active interventions to combat burnout and improve work-life balance are needed. PMID- 25550023 TI - Association of surgeon factors with outcome scores after total knee arthroplasty. AB - PURPOSE: To identify preoperative factors (including surgeon factors) associated with outcome scores after total knee arthroplasty (TKA). METHODS: Medical records of 2848 patients (3458 knees) who underwent primary TKA by 27 orthopaedic specialists were retrieved. Three specialty knee surgeons who had one-year fellowship in TKA performed 1930 TKAs, and 24 general orthopaedic surgeons performed 1528 TKAs. Four of them (including all 3 specialty knee surgeons) were ultrahigh- volume (>= 100 TKAs a year), and 21 of them were senior consultants (>= 5 years post residency). At 2 years, 2922 (85%) of knees had complete followup data. Oxford Knee Score, Knee Society knee and function scores, and SF 36 quality-of-life score were assessed by independent physiotherapists before and after surgery. Outcomes were compared in terms of dichotomised specialty, seniority, and surgical volume of surgeons. RESULTS: Comparing ultra-high-volume (>= 100 TKAs per year) specialty knee surgeons with general orthopaedic surgeons, the former achieved better outcomes in terms of the Oxford Knee Score at 6 months, Knee Society knee and function scores at 2 years, and SF-36 scores at 6 months and 2 years. Comparing lower-volume (<100 TKAs per year) specialty knee surgeons with general orthopaedic surgeons, the former still achieved better outcome and quality-of-life scores, except for SF-36 Mental Component Score at 2 years. CONCLUSION: Specialty training and clinical research in TKA improved outcome and quality-of-life scores. PMID- 25550024 TI - Review article: Perioperative care in enhanced recovery for total hip and knee arthroplasty. AB - Enhanced recovery pathways for total hip and knee arthroplasty can reduce length of hospital stay and perioperative morbidity. 22 studies were reviewed for identification of perioperative care interventions, including preoperative (n=4), intra-operative (n=8), and postoperative (n=4) care interventions. Factors that improve outcomes included use of pre-emptive and multimodal analgesia regimens to reduce opioid consumption, identification of patients with poor nutritional status and provision of supplements preoperatively to improve wound healing and reduce length of hospital stay, use of warming systems and tranexamic acid, avoidance of drains to reduce operative blood loss and subsequent transfusion, and early ambulation with pharmacological and mechanical prophylaxis to reduce venous thromboembolism and to speed recovery. PMID- 25550025 TI - Review article: Total hip replacement in haemodialysis or renal transplant patients. AB - 25 studies involving 755 hips in 534 patients were reviewed to determine the complication rates of total hip replacement in haemodialysis or renal transplant patients. In comparison of both groups, renal transplant patients were generally younger and more likely to receive an uncemented implant, whereas haemodialysis patients had approximately twice the infection rate and higher rates of mortality, revision, aseptic loosening, and hip dislocation. Both groups had increased complication rates, compared with patients without renal failure. PMID- 25550026 TI - Review article: Total wrist arthroplasty. AB - 18 English-language studies published between January 2003 and April 2013 were retrieved from the MEDLINE database using the key word 'total wrist arthroplasty'. In most studies, total wrist arthroplasty achieved improvement in pain and function over time. In a meta-analysis, the revision rate was 17% for third-generation implants. The survival rate was 92% for fourth-generation implants at 4 years. Complication rates ranged from 0% to 100% for third generation implants and from 6% to 47% for fourth-generation implants. Results of total wrist arthroplasty vary greatly; longer-term studies are needed to determine its cost-effectiveness. PMID- 25550027 TI - Review article: Open versus arthroscopic synovectomy for pigmented villonodular synovitis of the knee. AB - Studies published in MEDLINE between January 2010 and October 2013 were reviewed to compare open with arthroscopic synovectomy for pigmented villonodular synovitis of the knee in terms of rates of recurrence, complication, and osteoarthritis. 10 studies specifically on this topic were analysed; all were retrospective case reports, and thus level of evidence was low. Respectively after open and arthroscopic synovectomy, the overall recurrence rates were 26.7% and 24.6%, the overall complication rates were 5.7% and 3.2%, and the overall osteoarthritis rates were 20% and 17.1%. Arthroscopic and open synovectomy did not differ significantly in terms of rates of recurrence, complication, and osteoarthritis. Prospective randomised studies are needed to confirm the findings. PMID- 25550028 TI - Total sacrectomy for low-grade malignant peripheral nerve sheath tumour: a case report. AB - We report on a 58-year-old woman who underwent total sacrectomy and spinopelvic reconstruction for a low-grade malignant peripheral nerve sheath tumour involving the sacrum. One week later, she developed deep wound infection, and the entire spinopelvic reconstruction was removed. At the 36-month followup, the patient had no pain and was able to walk with a walking frame. There was no sign of recurrence or metastasis. PMID- 25550029 TI - Late recurrence of osteosarcoma: a report of two cases. AB - We report 2 cases of late recurrence of osteosarcoma after 6 and 7 years. One patient had pulmonary metastasis, and the other had soft tissue recurrence. Both patients underwent complete resection and chemotherapy. The first patient achieved complete remission and remained disease-free 47 months later and had no limitation in his daily life. The second patient had a re-recurrence and underwent further resection and chemotherapy. He remained disease-free 35 months later and could walk using a T-handled walking cane. PMID- 25550030 TI - Multiple recurrences and late metastasis of adamantinoma in the tibia: a case report. AB - Adamantinoma is a rare, low-grade, malignant bone tumour. We report on a 46-year old woman who had early multiple recurrences of adamantinoma of the right tibia and late metastasis to the lung and ribs 13 years after the first surgical treatment. She underwent multiple complete tumour excisions and eventually below knee amputation and removal of the left lung and sixth to eighth ribs. PMID- 25550031 TI - Extraskeletal myxoid chondrosarcoma of the thigh in a child: a case report. AB - Extraskeletal myxoid chondrosarcoma (EMC) is aggressive in children. The condition in children differs to that in adults and to skeletal myxoid chondrosarcoma. We report on a 9-year-old girl with EMC in her left thigh. She underwent above-knee amputation. Five months later, a small mass was noted at the right lower lobe of the lung. The patient underwent one course of ifosfamide, carboplatin, and etoposide chemotherapy, followed by resection of the mass and 8 more courses of chemotherapy. At the 2-year follow-up, she was in remission radiologically. PMID- 25550032 TI - Giant cell tumour of the distal humerus: a case report. AB - Giant cell tumour of the distal humerus is rare. We report one such case in a 30 year-old man who underwent wide resection of the tumour followed by total elbow arthroplasty using a cemented 'sloppy-hinged' total elbow prosthesis. At the 18 month follow-up, the patient had pain-free range of motion of 15o to 120o and no evidence of recurrence. PMID- 25550033 TI - Trauma-induced myelopathy in patients with retro-odontoid pseudotumour and ossification of the anterior longitudinal ligament: a report of two cases. AB - We report 2 cases of acute, progressive myelopathy after a fall in elderly patients who had a retroodontoid pseudotumour and extensive ossification of the anterior longitudinal ligament. PMID- 25550034 TI - Bony ankylosis of the knee secondary to heterotopic ossification after total knee arthroplasty: a case report. AB - We report a case of bony ankylosis of the knee secondary to severe and extensive heterotopic ossification over 9 years after primary total knee arthroplasty in a 71-year-old woman. PMID- 25550035 TI - Gentamycin-impregnated calcium phosphate cement for calcaneal osteomyelitis: a case report. AB - We report a case of chronic calcaneal osteomyelitis in a diabetic patient who was successfully treated with radical debridement and gentamycin-impregnated calcium phosphate cement. At 1.5-year follow-up, the patient could walk without any assistance. Calcium phosphate cement is an effective local antibiotic delivery system and a biocompatible material for filling the debrided space to facilitate bone formation. PMID- 25550036 TI - Use of sutures as Kirschner wire and tension-band wire for olecranon fractures: a technical note. AB - Open reduction and internal fixation using tension-band wires for displaced olecranon fractures enables restoration of extensor function. We report on 3 elderly patients with a displaced olecranon fracture who underwent open reduction and internal fixation using sutures as the Kirschner wire and tension-band wire and achieved good outcome. PMID- 25550037 TI - Letter to the Editor: Intra-articular injection of tranexamic acid to reduce blood loss after total knee arthroplasty. PMID- 25550038 TI - Audit of operation notes in an orthopaedic unit. PMID- 25550039 TI - Fixation with cancellous screws and fibular strut grafts for neglected femoral neck fractures. PMID- 25550040 TI - Genotoxicity of Thermopsis turcica on Allium cepa L. roots revealed by alkaline comet and random amplified polymorphic DNA assays. AB - This study was undertaken to evaluate genotoxic potential of Thermopsis turcica aqueous extracts on the roots of onion bulb (Allium cepa L.) by comet assay and random amplified polymorphic DNA technique. The Allium root growth inhibition test indicated that the EC50 and 2*EC50 values were 8 and 16 mg/ml concentrations of T. turcica aqueous extracts, respectively. The negative control (distilled water), positive control (methyl methane sulfonate, 10 mg/l) and 8 and 16 mg/ml concentrations of T. turcica extracts were introduced to the roots of onion bulbs for 24 and 96 h. The root growth, DNA damage in root cells and randomly amplified polymorphic DNA (RAPD) profiles of root tissue were used as endpoints of the genotoxicity. The comet assay clearly indicated that dose-dependent single strand DNA breaks in the root nuclei of onions were determined for the treatment concentrations of T. turcica extracts. In comparison to RAPD profile of negative control group, RAPD polymorphisms became evident as disappearance and/or appearance of RAPD bands in treated roots. The diagnostic and phenetic numerical analyses of RAPD profiles obviously indicated dose-dependent genotoxicity induced by Thermopsis extracts. In conclusion, the results clearly indicated that water extract of T. turcica has genotoxic potential on the roots of onion bulbs as shown by comet assay and RAPD technique. PMID- 25550041 TI - Klf2 contributes to the stemness and self-renewal of human bone marrow stromal cells. AB - Mesenchymal stem cells (MSCs) have shown great therapeutic potential in clinical trials; however, loss of pluripotency due to culture senescence is a major factor limiting their application. Understanding the physiology of stem cell self renewal and stemness, and identifying the molecules that regulate these processes, are critical to future advances in tissue and organ regeneration. The Kruppel-like factor (Klf) family are key transcription factors implicated in self renewal of embryonic stem cells. Here we identify Klf2 as a crucial transcription factor in undifferentiated human bone marrow stromal cells (hBMSCs), as indicated by gene expression in three culture media. To investigate the role of Klf2 in detail, an overexpression study using a lentiviral system in hBMSCs was performed. After Klf2 overexpression, cell proliferation was increased. The expression of pluripotency-associated genes, including Oct4, Nanog, and Rex1, was also upregulated by Klf2 overexpression. In addition, quantitative RT-PCR indicated a lower level of expression of differentiation related genes in Klf2 overexpressing cells as compared to control cells. Our results identify a functionally conserved role for Klf2 in hBMSCs, in which its expression is biologically important for stemness and self-renewal. These results are the first to show a role for Klf2 in the proliferation and pluripotency of hBMSCs. PMID- 25550042 TI - Semantic similarity measurement between gene ontology terms based on exclusively inherited shared information. AB - Quantifying the semantic similarities between pairs of terms in the Gene Ontology (GO) structure can help to explore the functional relationships between biological entities. A common approach to this problem is to measure the information they have in common based on the information content of their common ancestors. However, many studies have their limitations in measuring the information two GO terms share. This study presented a new measurement, exclusively inherited shared information (EISI) that captured the information shared by two terms based on an intuitive observation on the multiple inheritance relationships among the terms in the GO graph. EISI was derived from the information content of the exclusively inherited common ancestors (EICAs), which were screened from the common ancestors according to the attribute of their direct children. The effectiveness of EISI was evaluated against some state-of the-art measurements on both artificial and real datasets, it produced more relevant results with experts' scores on the artificial dataset, and supported the prior knowledge of gene function in pathways on the Saccharomyces genome database (SGD). The promising features of EISI are the following: (1) it provides a more effective way to characterize the semantic relationship between two GO terms by taking into account multiple common ancestors related, and (2) can quickly detect all EICAs with time complexity of O(n), which is much more efficient than other methods based on disjunctive common ancestors. It is a promising alternative to multiple inheritance based methods for practical applications on large-scale dataset. The algorithm EISI was implemented in Matlab and is freely available from http://treaton.evai.pl/EISI/. PMID- 25550043 TI - Identification of a germ cell marker gene, the dead end homologue, in Chinese sturgeon Acipenser sinensis. AB - Dead end (dnd) encodes an RNA-binding protein that is essential for primordial germ cell (PGC) migration and gametogenesis in vertebrates. In this study, a Chinese sturgeon Acipenser sinensis dead end homologue, designated Asdnd, was identified and characterized. The full-length cDNA of Asdnd was 1630base pairs (bp) and encoded a peptide of 396 amino acid residues. Multiple sequence alignment showed that AsDnd shared six conserved regions of Dnd orthologs, including the RNA recognition motif. Phylogenetic analysis revealed that AsDnd was grouped with teleosts. By quantitative real-time PCR analysis, the Asdnd transcripts were found to originate from the maternal parent and be specifically expressed in gonads of immature Chinese sturgeons of both sexes. Fluorescent in situ hybridization indicated that Asdnd transcripts were restricted to germ cells. In the testis, Asdnd was abundant in spermatogonia and tended to gradually diminish in late spermatogenic stages, while strong signals were found in primary oocytes, as opposed to oogonia, in the ovary. Zebrafish PGCs were clearly visualized at 24h post-fertilization by co-injecting RFP-Asdnd 3' UTR and GFP nos3 3' UTR mRNA, indicating that dnd 3' UTR has a conserved function among teleosts. Therefore, dnd could serve as a germ cell marker in Chinese sturgeon. PMID- 25550044 TI - Molecular cloning and functional characterization of an antifungal PR-5 protein from Ocimum basilicum. AB - Pathogenesis-related (PR) proteins are involved in biotic and abiotic stress responses of plants and are grouped into 17 families (PR-1 to PR-17). PR-5 family includes proteins related to thaumatin and osmotin, with several members possessing antimicrobial properties. In this study, a PR-5 gene showing a high degree of homology with osmotin-like protein was isolated from sweet basil (Ocimum basilicum L.). A complete open reading frame consisting of 675 nucleotides, coding for a precursor protein, was obtained by PCR amplification. Based on sequence comparisons with tobacco osmotin and other osmotin-like proteins (OLPs), this protein was named ObOLP. The predicted mature protein is 225 amino acids in length and contains 16 cysteine residues that may potentially form eight disulfide bonds, a signature common to most PR-5 proteins. Among the various abiotic stress treatments tested, including high salt, mechanical wounding and exogenous phytohormone/elicitor treatments; methyl jasmonate (MeJA) and mechanical wounding significantly induced the expression of ObOLP gene. The coding sequence of ObOLP was cloned and expressed in a bacterial host resulting in a 25kDa recombinant-HIS tagged protein, displaying antifungal activity. The ObOLP protein sequence appears to contain an N-terminal signal peptide with signatures of secretory pathway. Further, our experimental data shows that ObOLP expression is regulated transcriptionally and in silico analysis suggests that it may be post-transcriptionally and post-translationally regulated through microRNAs and post-translational protein modifications, respectively. This study appears to be the first report of isolation and characterization of osmotin-like protein gene from O. basilicum. PMID- 25550045 TI - Selection of appropriate reference genes for RT-qPCR analysis in Berkshire, Duroc, Landrace, and Yorkshire pigs. AB - Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is the most reliable molecular biology technique for assessment of mRNA expression levels. However, to obtain the accurate RT-qPCR results, the expression levels of genes of interest should be normalized with appropriate reference genes and optimal numbers of reference genes. In this study, we assessed the expression stability of 15 well-known candidate reference genes (ACTB, ALDOA, B2M, GAPDH, HPAR1, HSPCB, PGK1, POLR2G, PPIA, RPL4, RPS18, SDHA, TBP, TOP2B, and YWHAZ) in seven body tissues (liver, lung, kidney, spleen, stomach, small intestine, and large intestine) of Berkshire, Landrace, Duroc, and Yorkshire pigs using three excel-based programs, geNorm, NormFinder, and BestKeeper. Combination analysis of these three programs showed that the stable and appropriate reference genes are PPIA, TBP, and HSPCB in Berkshire pigs; PPIA, TBP, RPL4, and RPS18 in Landrace pigs; PPIA and TBP in Duroc pigs; and PPIA, TOP2B, RPL4, and RPS18 in Yorkshire pigs. Because the four pig breeds had different suitable reference genes, the selection of appropriate reference genes is essential in RT-qPCR analyses. Taken together, our data could help to select reliable reference genes for the normalization of expression levels of various target genes in pigs. PMID- 25550046 TI - Genome-wide transcriptomic profiling of ramie (Boehmeria nivea L. Gaud) in response to cadmium stress. AB - Cadmium (Cd) contamination in agricultural soils has become a major environmental problem in China. Ramie, a fiber crop, has frequently been proposed for use as a phytoremediation crop for the restoration of Cd-contaminated farmlands. However, high levels of Cd can greatly inhibit stem growth in ramie, which reduces its economic value as a crop. To understand the potential mechanisms behind this phenomenon, the ramie genes involved in the Cd stress response were identified using Illumina pair-end sequencing on two Cd-stressed plants (CdS1 and CdS2) and two control plants (CO1 and CO2). Approximately 48.7, 51.6, 41.2, and 47.1 million clean sequence reads were generated from the libraries of CO1, CO2, CdS1, and CdS2, respectively, and de novo assembled to yield 56,932 non-redundant unigenes. A total of 26,686 (46.9%) genes were annotated for their function. Comparison of gene expression levels in CO and CdS ramie revealed 155 differentially expressed genes (DEGs) between treatment and control conditions. Sixteen DEGs were further analyzed for expression differences by using real-time quantitative PCR (qRT-PCR). Among these 16 DEGs, 2 genes encoding GA2-oxidase (a major enzyme for deactivating bioactive gibberellins [GAs]) showed markedly up regulated expression in Cd stressed ramie. This might be responsible for the growth inhibition of Cd-stressed ramie. Pathway enrichment analysis revealed that the cutin, suberine and wax biosynthesis pathway was markedly enriched by DEGs. The discovery of these Cd stress-responsive genes and pathways will be helpful in further understanding the mechanism of Cd-stress response and improving Cd stress tolerance in ramie. PMID- 25550047 TI - Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5. AB - Atoh1, Hes1 and Hes5 are crucial for normal inner ear hair cell development. They regulate the expression of each other in a complex network, while they also interact with many other genes and pathways, such as Notch, FGF, SHH, WNT, BMP and RA. This paper summarized molecular pathways that involve Atoh1, Hes1, and Hes5. Some of the pathways and gene regulation mechanisms discussed here were studied in other tissues, yet they might inspire studies in inner ear hair cell development. Thereby, we presented a complex regulatory network involving these three genes, which might be crucial for proliferation and differentiation of inner ear hair cells. PMID- 25550048 TI - Characterization and gonadal expression of FOXL2 relative to Cyp19a genes in spotted scat Scatophagus argus. AB - In the present study, we cloned the full-length cDNAs of FOXL2, Cyp19a1a and Cyp19a1b and analyzed their expression patterns during gonadal development in spotted scat, Scatophagus argus. All three genes were expressed in ovaries and testes but showed sexual dimorphism. At early stages of gonadal development, the expression of FOXL2 in ovaries was higher than testes. FOXL2 expression deceased gradually as gonadal development continued, and reached the lowest level at the mature stage. Cyp19a1a and Cyp19a1b were expressed coordinately with FOXL2, except at the early vitellogenic stage in the ovary. The expression of FOXL2, Cyp19a1a and Cyp19a1b was mainly localized in granulosa cells of ovaries. In S. argus testes, strong expression of FOXL2 gene was observed in the interstitial cells including tubules and Leydig cells, while Cyp19a1a and Cyp19a1b were mainly expressed in Sertoli cells throughout gametogenesis. These results show that FOXL2 plays an essential role in sexual development, and imply that it may regulate Cyp19a1a and Cyp19a1b expression in S. argus. PMID- 25550049 TI - Association analysis between variants in KITLG gene and litter size in goats. AB - Xinong Saanen (SN) and Guanzhong (GZ) goat breeds were used to detect single nucleotide polymorphisms (SNPs) in the coding regions with their intron-exon boundaries and the proximal flanking regions of KITLG gene by DNA sequencing and genotyped by PCR-restriction fragment (PCR-RFLP). Four novel SNPs (g.12654G>A, g.12772G>A, g.12829T>C and g.23683C>T) were identified (GenBank accession No. KM609289). It was shown that Xinong Saanen and Guanzhong goat breeds were in Hardy-Weinberg disequilibrium at g.12654G>A, g.12772G>A and g.12829T>C loci (P<0.05). The g.12654G>A, g.12772G>A and g.12829T>C loci were closely linked in both goat breeds (r(2)>0.33). Results of an association analysis indicated that SNPs g.12654G>A, g.12772G>A and g.12829T>C had significant effects on litter size (P<0.05). The combined genotypes of four SNP loci also affected litter size with the C7(GG/GG/CC/CC) genotype in the SN goat breed and C1(AA/GG/CC/CC) and C7(GG/GG/CC/CC) genotypes in the GZ goat breed having the highest litter size. The biochemical and physiological functions, together with the results obtained in our investigation, suggest that C7(GG/GG/CC/CC) could be used in marker assisted selection to select the individuals with higher litter size in both goat breeds. The results extend the spectrum of genetic variation of the caprine KITLG gene, which might contribute to goat genetic resources and breeding. PMID- 25550050 TI - Whole-exome sequencing identify a new mutation of MYH7 in a Chinese family with left ventricular noncompaction. AB - BACKGROUND: Left ventricular noncompaction (LVNC) is a genetic cardiomyopathy results from the failure of myocardial development during embryogenesis. Previous reports show that defects in TAZ, SCN5A, TPM1, YWHAE, MYH7, ACTC1 and TNNT2 are associated with LVNC. Sequencing of individuals using family-based design is a powerful approach for hereditary disease. In this study, we used whole-exome sequencing to screen potentially novel causal mutations in a Chinese Han family with LVNC. METHODS: DNA from 3 individuals belonging to the same family was extracted and sequenced based on standard whole-exome sequencing protocol. The exome sequence data was analyzed using BWA, PICARD and Genome Analysis Toolkit (GATK v2.8). Non-silent single nucleotide variants (SNVs) were further selected if they exist in both LVNC patients and not in the health control. A web-based software Snv Prioritization via the INtegration of Genomic data (SPRING), was used to prioritize the causal SNV by calculating a q-value which indicates the statistical significance that a variant is causative for a query disease. RESULTS: From the LVNC family in which the mother and son were affected, a novel single nucleotide variant c.C1492G in exon 15 of MYH7 was identified probably to be the causal SNV of the family with P-value of 3.45E-05 and q-value of 4.65E-03 by SPRING. The SNV was predicted as deleterious in SIFT, PolyPhe2 and MutatioTaster database. Another 12 SNVs were also identified with P-value less than 0.05 by SPRING. CONCLUSIONS: A novel genetic variant in the coding regions of MYH7 gene was identified in a Chinese LVNC-family. The results support the previous evidence that MYH7 is a pathogenic gene for LVNC. PMID- 25550051 TI - A novel siRNA validation system for functional screening of effective RNAi targets in mammalian cells and development of a derivative lentivirus delivery system. AB - RNA interference technology is a widely used tool for the regulation of gene expression at the post-transcriptional level. One major challenge is to find the effective short interfering (si)RNA for target gene rapidly and easily, and then to deliver the siRNA into cells or tissues with high efficiency. Here, we designed a novel siRNA validation vector using a dual luciferase reporter system for the functional screening of effective RNAi targets in mammalian cells. Then, based on a siRNA expression cassette, we developed a derivative lentivirus delivery system to infect the appropriate cells or tissues for the efficient knockdown of target gene expression. Based on this system, we used human IRF7 gene, a key regulatory factor for the differentiation of monocytes to macrophages, as an example. We screened for the optimal siRNA, then packaged it into a lentiviral siRNA expression system. Then, monocytes were infected and we confirmed the knockdown of IRF7 expression could inhibit the differentiation of monocytes to macrophages. To validate our method further, we also screened and identified optimal siRNA for human TLR4 gene. In summary, we developed a novel siRNA validation system to identify optimal siRNA to target genes rapidly. In addition, the lentivirus system is an efficient tool for siRNA delivery for the further study of target gene function. Taken together, this represents an efficient and user-friendly strategy to validate and deliver siRNAs. PMID- 25550052 TI - Identification and characterization of NADPH-dependent cytochrome P450 reductase gene and cytochrome b5 gene from Plutella xylostella: possible involvement in resistance to beta-cypermethrin. AB - NADPH-cytochrome P450 reductase (CPR) and cytochrome b5 (b5) are essential for cytochrome P450 mediated biological reactions. CPR and b5 in several insects have been found to be associated with insecticide resistance. However, CPR and b5 in the diamondback moth (DBM), Plutella xylostella, are not characterized and their roles remain undefined. A full-length cDNA of CPR encoding 678 amino acids and a full-length cDNA of b5 encoding 127 amino acids were cloned from DBM. Their deduced amino acid sequences shared high identities with those of other insects and showed characteristics of classical CPRs and b5s, respectively. The mRNAs of both genes were detectable in all developmental stages with the highest expression levels occurring in the 4th instar larvae. Tissue-specific expression analysis showed that their transcripts were most abundant in gut. Transcripts of CPR and b5 in the beta-cypermethrin resistant DBM strain were 13.2- and 2.84-fold higher than those in the beta-cypermethrin susceptible strain, respectively. The expression levels of CPR and b5 were enhanced by beta-cypermethrin at the concentration of 12 mg L(-1) (~LC10). The results indicate that CPR and b5 may play essential roles in the P450 mediated resistance of DBM to beta-cypermethrin or even other insecticides. PMID- 25550053 TI - Welcome message from the Chairman of the Formosan Diabetes Care Foundation. PMID- 25550054 TI - Diabetes burden and prevention in Korea and the Western Pacific Region. AB - Diabetes burden in the Western Pacific Region (WPR) is more problematic than in any other part of the world. In 2013, the International Diabetes Federation reported >382 million people are living with diabetes around the world. About 36%, approximately 138 million people with diabetes, are living in the WPR. In addition, in the WPR, from 2012 to 2013, 6 million diabetes mellitus cases were newly diagnosed, accounting for 54.5% of all type 2 diabetes mellitus (T2DM) cases diagnosed in the world during the same period. South Korea is no exception, and the prevalence of diabetes is estimated to be as high as 5 million people. The prevalence of T2DM in Korea increased from <1% in 1960 to >10% by early 2000. According to the Ansung-Ansan Cohort study, from 2001 to 2011, T2DM increased 54% and 60% in the 50(th) and 60(th) age groups, respectively. The main reason for the rapid increase in the prevalence of diabetes in Korea was the sudden growth in the economy, resulting in rapid urbanization. Moreover, scientific evidence suggests the dramatic increase in T2DM incidence and prevalence in Korea is related to the influence of economic development, health policy, urbanization, westernized diet, decreased physical activity, as well as an individual's health behavior changes. However, diabetes management response rate was low in the newly onset groups with <20%, but gradually increased up to around 90%, then declined to <80% after 16-20 year of developing T2DM, showing an "M" management pattern. The study results revealed that despite the successful implementation of the universal health insurance system in Korea beginning in 1987, people diagnosed with T2DM were not properly managing T2DM. Most developing countries in the WPR are emulating the Korean experiences. There is clear evidence that utilization of BED (Behavioral change, Exercise, and proper Diet) could be the best vector to fight against the diabetes tsunami in the WPR. From the Korean experiences the WPR, at high risk for T2DM, could learn to prevent, intervene, and properly manage T2DM in order to reduce diabetes-related morbidity and mortality. PMID- 25550055 TI - Screening and diagnosis of diabetes in children and pregnant women. AB - The incidence and prevalence of diabetes in children has increased in recent decades. The findings of a nationwide screening program in Taiwan show that type 2 diabetes has replaced type 1 diabetes as the leading cause of diabetes in children and adolescents. Important risk factors for diabetes in children are high or low birth weights, obesity, and a family history of diabetes. The incidence of diabetes reaches plateaus during puberty. Therefore, we have developed a strategy to screen seventh-grade children with diabetes based on urinalysis and a risk score. Gestational diabetes is associated with various adverse perinatal outcomes, particularly macrosomia and birth injury, and a higher rate of Cesarean section. The 100 g oral glucose tolerance test (OGTT) for gestational diabetes was initially designed to predict maternal diabetes after delivery, and was revised by Carpenter and Coustan to predict adverse fetal outcomes. In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) proposed a 75 g OGTT to define gestational diabetes, resulting in a significant increase in the prevalence of gestational diabetes. Our data suggest that adopting the new IADPSG criteria is reasonable, since they reduce adverse perinatal outcomes and are cost-efficient. PMID- 25550056 TI - Diabetes care--improvement through measurement. AB - The National Diabetes Register (NDR) of Sweden was initiated in response to The Saint Vincent Declaration (published 1990), to provide a tool for continuous quality assurance in diabetes care. The original purpose, to monitor the results of health centres from year to year and to compare these with national and regional means, is still the most important one, while continuous follow-up of guidelines, treatments and complications are as important on a national level. The data reported contain basal clinical characteristics of the patients, as well as measures of risk-factor control and the presence of diabetes complications. Many clinics use templates within the medical record systems to verify that all information relevant to good quality assurance in diabetes care is complete, and thereafter export data to NDR. In order to create extra value, the NDR web interface, online at ndr.nu, offers functions to use when interacting with the individual patient, such as reports of all information reported to NDR, including medications and risk-factor control. The clinical results are thus reported back to the health centres (printed and instantaneously online), but are also used for scientific analyses. Such are required by the funding bodies to develop the analytical methods by quality registers, and to widely spread information, including publishing in scientific journals. Ongoing studies address, e.g., the effects of different glucose-lowering therapies, the role of ethnicity and migration, patient-reported outcomes and risks of morbidity and mortality in diabetes mellitus. PMID- 25550057 TI - Delivery of integrated diabetes care using logistics and information technology- the Joint Asia Diabetes Evaluation (JADE) program. AB - Diabetes is a global epidemic, and many affected individuals are undiagnosed, untreated, or uncontrolled. The silent and multi-system nature of diabetes and its complications, with complex care protocols, are often associated with omission of periodic assessments, clinical inertia, poor treatment compliance, and care fragmentation. These barriers at the system, patient, and care-provider levels have resulted in poor control of risk factors and under-usage of potentially life-saving medications such as statins and renin-angiotensin system inhibitors. However, in the clinical trial setting, use of nurses and protocol with frequent contact and regular monitoring have resulted in marked differences in event rates compared to epidemiological data collected in the real-world setting. The phenotypic heterogeneity and cognitive-psychological-behavioral needs of people with diabetes call for regular risk stratification to personalize care. Quality improvement initiatives targeted at patient education, task delegation, case management, and self-care promotion had the largest effect size in improving cardio-metabolic risk factors. The Joint Asia Diabetes Evaluation (JADE) program is an innovative care prototype that advocates a change in clinic setting and workflow, coordinated by a doctor-nurse team and augmented by a web based portal, which incorporates care protocols and a validated risk engine to provide decision support and regular feedback. By using logistics and information technology, supported by a network of health-care professionals to provide integrated, holistic, and evidence-based care, the JADE Program aims to establish a high-quality regional diabetes database to reflect the status of diabetes care in real-world practice, confirm efficacy data, and identify unmet needs. Through collaborative efforts, we shall evaluate the feasibility, acceptability, and cost effectiveness of this "high tech, soft touch" model to make diabetes and chronic disease care more accessible, affordable, and sustainable. PMID- 25550058 TI - A decade of diabetes care in Taiwan. AB - INTRODUCTION: Diabetes is a major non-communicable chronic disease with a great impact on health, socio-economic burden, and premature mortality around the world. It has been recognized as an important public health issue for more than two decades in Taiwan, and concerted efforts to improve diabetes care started there in 1990. In facing the challenge of the diabetes burden, the progress and outcomes of diabetes health-care delivery can be studied by reviewing all related statistical data of the past decade. METHODS: Data from annual national vital statistics, periodic surveys and audit reports collected from 2002-2012 in Taiwan were analyzed. RESULTS: The population growth rate was 0.35%/year, with negative growth in age <40. The highest rate was 6.98%/year in age >=80 y/o (p <0.001). The number of diabetics receiving any glucose-lowering agent during this period increased from 813,400 to 1,565,300, with an average growth rate of 6.76%/year (p <0.001). The age-specific prevalence rate divided by age group <20 y/o, 20-40 y/o, 40-60 y/o, 60-80 y/o and >=80 y/o in 2008 was 0.08%, 0.52%, 7.64%, 20.04% and 18.67%, respectively, for men, and 0.08%, 0.80%, 5.70%, 22.44% and 23.63% for women. Accountability measures by age group, including HbA1c (A1C), lipid profile, urine albumin and eye fundus examination, showed a trend towards improvement in 2012 (89.0%, 75.6%, 41.5% and 32.1%, respectively in 2012 (p <0.001). ABC control data from 2002, 2006 and 2011 survey results indicated a trend toward an increased proportion with A1C below 7%, with 22.1%, 34.7% and 40.9%, respectively, in the oral agents group, and 13.7%, 15.4% and 15.8% in the insulin-treated group. BP below 130/80 mmHg was 24.3%, 31.1% and 37.4%, and LDL-C below 100 mg/dl was 29.4%, 33.1% and 51.2%. The premature mortality rate < age 70 y/o decreased from 15.37 to 12.97 per 100,000 from 2002 to 2012 (p = 0.005), and the proportion of premature mortality in diabetes decreased from 36.88% to 29.99% (p <0.001). CONCLUSION: Diabetes remains the second highest cause in premature mortality, after cancer, among major non-communicable diseases in Taiwan. PMID- 25550059 TI - Team care of type 2 diabetes mellitus in Taiwan. AB - Type 2 diabetes mellitus (T2DM) is a global health-care and national policy issue. As fluctuating glycemic control in diabetes often results in serious complications, we must encourage the diabetes educators' efforts at long-term follow-up among patients with T2DM. Therefore, certified diabetes educators (CDEs) play the most pivotal roles as life-long protectors for patients with T2DM. In the past 15 years, more than 4,000 CDEs have been trained and qualified, including health professionals such as physicians, nurses, dieticians, and pharmacists. The most important initiation of diabetes share care in Taiwan was originated in I-Lan County. Initiated to provide regional diabetes care, the name of this program is the Lan-Yang Diabetes Shared Care System. In 2006, the Taiwanese Association of Diabetes Educators (TADE) carried out a nationwide survey to evaluate the status of diabetes control in Taiwan, focusing on the "ABC" goal (A: HbA1c <7.0%, B: blood pressure <130/80 mmHg, C: LDL-cholesterol <100 mg/dl/total cholesterol <160 mg/dl). The results revealed that the percentage of patients with diabetes who fulfilled all ABC goals was only 4.1%. Five years later, in 2011, TADE compared two nationwide surveys and found total ABC attainment rates of 4.1% and 8.6%, respectively. The team-care approach to T2DM has been underway for over 20 years in Taiwan. Future interventions and treatment algorithms with team-based education should aim at preventing acute and chronic complications, which remains a long-term challenge in Taiwan. PMID- 25550060 TI - Overcoming disparities in diabetes care: eight years' experience changing the diabetes care system in Changhua, Taiwan. AB - AIMS: To enhance the universal coverage of quality diabetes care and overcome disparities in care among different care-provider levels by changing the diabetes care system in Changhua, Taiwan. METHODS: The Changhua Diabetes Shared Care program's second stage commenced in 2004. Two levels of diabetes care were proposed to facilitate physician participation via advocating the more attainable goals of diabetes care. The empowerment processes were differentiated into hospital-level and primary-care-clinic-level. The community multidisciplinary care teams took the scale of the practices into consideration, and several measures were applied to ameliorate the shared care network. The implementation support team from the health authority initiated in-person, one-on-one contacts with physicians to tailor collaboration activities to the individual primary care settings. The program's performance (2004-2012) was evaluated according to the RE AIM model's five dimensions. RESULTS: There was substantial improvement in diabetes care quality across all dimensions and the proportion of attaining all goals significantly grew. CONCLUSIONS: The program achieved its primary goal of enhancing the universal coverage of quality diabetes care and overcoming disparities among different levels of care providers. PMID- 25550061 TI - Hospital-based integrated diabetes care management: an overview. AB - To provide continuous, accessible, and quality care, a diabetes share-care program has been in place in Taiwan for several years. Lukang Christian Hospital, a member of the diabetes share-care network, endeavors to provide "patient centered" care aimed at increasing care quality and reducing diabetic complications. Information technology has been employed by the hospital for monitoring care quality and analyzing cost-effectiveness. Structured health-care programs have also been developed to ensure the completeness of diabetes care and to encourage self-management of individuals at high risk for diabetes. The implementation of these strategies has led to progressive improvement in quality measures and spawned novel and creative ways to deliver care services. PMID- 25550062 TI - Long-term glycemic control by a diabetes case-management program and the challenges of diabetes care in Taiwan. AB - AIMS: This study aimed to evaluate the long-term effects on glycemic control of a diabetes care program focusing on case management and to discuss challenges in the quality of diabetes care in Taiwan. METHODS: We randomized 1,060 study subjects recruited from the Diabetes Management through an Integrated Delivery System project in 2003-2005 into intervention (n = 789 from 27 clinics) and control (n = 271 from 7 clinics) groups. The quarterly self-care and nutrition education program in the intervention group was delivered by case managers, and standard care was provided to the control group. The intervention program was conducted during 2003-2007. A multivariate mixed model analysis was used to assess the 3.5-year intervention effects on glycemic control. RESULTS: Glycated hemoglobin (HbA1c) level in the intervention group (especially for those with a baseline HbA1c level of 7-9% and >9%) was significantly lower than that in the control group 6 months after recruitment and remained lower through the subsequent three intervention years. CONCLUSIONS: The current findings provide evidence that case management provided in the pay-for-performance (P4P) diabetes care program in Taiwan was effective at improving glycemic control for at least 3 years. However, previous research indicated poverty is associated with not only higher diabetes incidence but also inequality of diabetes care in Taiwan despite universal health coverage. Those with a more severe condition were less likely to be enrolled in the P4P diabetes care program. Additional cost-effectiveness studies and more health policy reforms are needed to optimize diabetes care in Taiwan. PMID- 25550064 TI - How might 3D printing affect clinical practice? PMID- 25550063 TI - Lexical enhancement during prime-target integration: ERP evidence from matched case identity priming. AB - A number of experiments have revealed that matched-case identity PRIME-TARGET pairs are responded to faster than mismatched-case identity prime-TARGET pairs for pseudowords (e.g., JUDPE-JUDPE < judpe-JUDPE), but not for words (JUDGE-JUDGE = judge-JUDGE). These findings suggest that prime-target integration processes are enhanced when the stimuli tap onto lexical representations, overriding physical differences between the stimuli (e.g., case). To track the time course of this phenomenon, we conducted an event-related potential (ERP) masked-priming lexical decision experiment that manipulated matched versus mismatched case identity in words and pseudowords. The behavioral results replicated previous research. The ERP waves revealed that matched-case identity-priming effects were found at a very early time epoch (N/P150 effects) for words and pseudowords. Importantly, around 200 ms after target onset (N250), these differences disappeared for words but not for pseudowords. These findings suggest that different-case word forms (lower- and uppercase) tap into the same abstract representation, leading to prime-target integration very early in processing. In contrast, different-case pseudoword forms are processed as two different representations. This word-pseudoword dissociation has important implications for neural accounts of visual-word recognition. PMID- 25550065 TI - The bubble study: ultrasound confirmation of central venous catheter placement. AB - STUDY OBJECTIVE: The objective was to determine if ultrasound (US) can more rapidly confirm central venous catheter (CVC) position in comparison to chest radiography (CXR) in the emergency department. METHODS: The study included a convenience sample of emergency department patients with supradiaphragmatic CVCs and a CXR for confirmation. Ultrasound was used for CVC confirmation by visualizing microbubble artifact in the right atrium after injection of saline through the distal port. To evaluate for pneumothorax (PTX), "sliding sign" of the pleura was noted on US of the anterior chest. Blinded chart review was performed to assess CXR timing, catheter position and CVC complications. Student's t test was used to compare US time to CXR performance time and radiologist reading time. RESULTS: Fifty patients were enrolled; 4 were excluded because of inadequate views. Forty-six patients were included in the final analysis. Mean total US time was 5.0 minutes (95% confidence interval [CI], 4.2 5.9) compared to 28.2 minutes (95% CI, 16.8-39.4) for CXR performance with a mean difference of 23.1 minutes (95% CI, -34.5 to -11.8; P < .0002). When comparing only US CVC confirmation time to CXR time, US was an average of 24.0 minutes (95% CI, -35.4 to -12.7; P < .0001) faster. Comparing total US time to radiologist CXR reading time, US was an average of 294 minutes faster (95% CI, -384.5 to -203.5; P < .0000). There were a total of 3 misplaced lines and 2 patients with PTX, all of which were identified correctly on US. CONCLUSION: Ultrasound can confirm CVC placement and rule out PTX significantly faster than CXR, expediting the use of CVCs in the critically ill. PMID- 25550066 TI - A nerve-stimulating needle coated with hard microscopic glass beads can enhance the visibility of ultrasonic images. PMID- 25550067 TI - Pseudomonas songnenensis sp. nov., isolated from saline and alkaline soils in Songnen Plain, China. AB - The strain NEAU-ST5-5(T) was isolated from the saline and alkaline soil in Songnen Plain, North East of China. The bacterium was found to be aerobic, Gram stain negative, rod-shaped and motile by means of several polar flagella. It forms yellow-orange colonies with a radial wrinkled surface. Phylogenetic analyses based on the separate 16S rRNA gene sequences and concatenated 16S rRNA, gyrB and rpoD gene sequences indicated that it belongs to the genus Pseudomonas in the class Gammaproteobacteria. Strain NEAU-ST5-5(T) shows gene sequence similarities of 98.8-97.1 % for 16S rRNA, 90.5-78.4 % for gyrB and 90.4-71.1 % for rpoD with type strains of the closely related species of the genus Pseudomonas, respectively. DNA-DNA hybridization relatedness between strain NEAU ST5-5(T) and type strains of the most closely related species, Pseudomonas stutzeri DSM 5190(T), P. xanthomarina DSM 18231(T), P. kunmingensis CGMCC 1.12273(T), P. alcaliphila DSM 17744(T) and P. oleovorans subsp. lubricantis DSM 21016(T) were 43 +/- 1 to 25 +/- 2 %. The major fatty acids (>10 %) were determined to be C18:1 omega7c/C18:1 omega6c, C16:1 omega7c/C16:1 omega6c and C16:0, the predominant respiratory quinone was identified as ubiquinone 9 and polar lipids were found to consist of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unknown phospholipid, one unidentified aminophospholipid and one unknown lipid. The genotypic, chemotaxonomic and phenotypic analysis indicated that strain NEAU-ST5-5(T) represents a novel species of the genus Pseudomonas, for which the name Pseudomonas songnenensis sp. nov. is proposed. The type strain is NEAU-ST5-5(T) (=ACCC 06361(T) = DSM 27560(T)). PMID- 25550069 TI - Orientation decoding: Sense in spirals? AB - The orientation of a visual stimulus can be successfully decoded from the multivariate pattern of fMRI activity in human visual cortex. Whether this capacity requires coarse-scale orientation biases is controversial. We and others have advocated the use of spiral stimuli to eliminate a potential coarse-scale bias-the radial bias toward local orientations that are collinear with the centre of gaze-and hence narrow down the potential coarse-scale biases that could contribute to orientation decoding. The usefulness of this strategy is challenged by the computational simulations of Carlson (2014), who reported the ability to successfully decode spirals of opposite sense (opening clockwise or counter clockwise) from the pooled output of purportedly unbiased orientation filters. Here, we elaborate the mathematical relationship between spirals of opposite sense to confirm that they cannot be discriminated on the basis of the pooled output of unbiased or radially biased orientation filters. We then demonstrate that Carlson's (2014) reported decoding ability is consistent with the presence of inadvertent biases in the set of orientation filters; biases introduced by their digital implementation and unrelated to the brain's processing of orientation. These analyses demonstrate that spirals must be processed with an orientation bias other than the radial bias for successful decoding of spiral sense. PMID- 25550070 TI - Shortening of retrograde conduction time over slow pathway after atrial stimulation. PMID- 25550071 TI - Large crowding zones in peripheral vision for briefly presented stimuli. AB - When a target is flanked by distractors, it becomes more difficult to identify. In the periphery, this crowding effect extends over a wide range of target flanker separations, called the spatial extent of interaction (EoI). A recent study showed that the EoI dramatically increases in size for short presentation durations (Chung & Mansfield, 2009). Here we investigate this duration-EoI relation in greater detail and show that (a) it holds even when visibility of the unflanked target is equated for different durations, (b) the function saturates for durations shorter than 30 to 80 ms, and (c) the largest EoIs represent a critical spacing greater than 50% of eccentricity. We also investigated the effect of same or different polarity for targets and flankers across different presentation durations. We found that EoIs for target and flankers having opposite polarity (one white, the other black) show the same temporal pattern as for same polarity stimuli, but are smaller at all durations by 29% to 44%. The observed saturation of the EoI for short-duration stimuli suggests that crowding follows the locus of temporal integration. Overall, the results constrain theories that map crowding zones to fixed spatial extents or to lateral connections of fixed length in the cortex. PMID- 25550068 TI - Neural activation during anticipated peer evaluation and laboratory meal intake in overweight girls with and without loss of control eating. AB - The interpersonal model of loss of control (LOC) eating proposes that socially distressing situations lead to anxious states that trigger excessive food consumption. Self-reports support these links, but the neurobiological underpinnings of these relationships remain unclear. We therefore examined brain regions associated with anxiety in relation to LOC eating and energy intake in the laboratory. Twenty-two overweight and obese (BMIz: 1.9+/-0.4) adolescent (15.8+/-1.6y) girls with LOC eating (LOC+, n=10) and without LOC eating (LOC-, n=12) underwent functional magnetic resonance imaging (fMRI) during a simulated peer interaction chatroom paradigm. Immediately after the fMRI scan, girls consumed lunch ad libitum from a 10,934-kcal laboratory buffet meal with the instruction to "let yourself go and eat as much as you want." Pre-specified hypotheses regarding activation of five regions of interest were tested. Analysis of fMRI data revealed a significant group by peer feedback interaction in the ventromedial prefrontal cortex (vmPFC), such that LOC+ had less activity following peer rejection (vs. acceptance), while LOC- had increased activity (p<.005). Moreover, functional coupling between vmPFC and striatum for peer rejection (vs. acceptance) interacted with LOC status: coupling was positive for LOC+, but negative in LOC- (p<.005). Activity of fusiform face area (FFA) during negative peer feedback from high-value peers also interacted with LOC status (p<.005). A positive association between FFA activation and intake during the meal was observed among only those with LOC eating. In conclusion, overweight and obese girls with LOC eating may be distinguished by a failure to engage regions of prefrontal cortex implicated in emotion regulation in response to social distress. The relationship between FFA activation and food intake supports the notion that heightened sensitivity to incoming interpersonal cues and perturbations in socio-emotional neural circuits may lead to overeating in order to cope with negative affect elicited by social discomfort in susceptible youth. PMID- 25550072 TI - New insights on the role of paired membrane structures in coronavirus replication. AB - The replication of coronaviruses, as in other positive-strand RNA viruses, is closely tied to the formation of membrane-bound replicative organelles inside infected cells. The proteins responsible for rearranging cellular membranes to form the organelles are conserved not just among the Coronaviridae family members, but across the order Nidovirales. Taken together, these observations suggest that the coronavirus replicative organelle plays an important role in viral replication, perhaps facilitating the production or protection of viral RNA. However, the exact nature of this role, and the specific contexts under which it is important have not been fully elucidated. Here, we collect and interpret the recent experimental evidence about the role and importance of membrane-bound organelles in coronavirus replication. PMID- 25550073 TI - Development of transgenic mouse model expressing porcine aminopeptidase N and its susceptibility to porcine epidemic diarrhea virus. AB - Porcine coronavirus infections have known as they are specific to pigs with predominantly enteric or respiratory diseases. No laboratory animal model is yet been developed in porcine coronaviruses study. Here, we report that development of a transgenic mouse model expressing porcine APN which is susceptible to porcine coronavirus infection. The porcine APN transgene was constructed by fusing with mouse proximal APN promoter at 5' terminus and bovine growth hormone polyadenylation site at its 3' terminus. After screen on pubs from the microinjected mice, we confirmed two transgenic lines expressing porcine APN in various organs. We confirmed the susceptibility to porcine epidemic diarrhea virus, one of the porcine coronaviruses. These transgenic mice will be an important tool for research into the porcine coronaviruses. PMID- 25550074 TI - Supercritical fluid extraction of heather (Calluna vulgaris) and evaluation of anti-hepatitis C virus activity of the extracts. AB - Previous studies using lipid extracts of heather (Calluna vulgaris) leaves showed the presence of high concentrations of ursolic and oleanolic acid. These two compounds have been reported to present antiviral activity against hepatitis C virus (HCV). In this work, the supercritical fluid extraction of heather was studied with the aim of assessing a potential anti-HCV activity of the extracts owing to their triterpenic acid content. Supercritical extraction assays were carried out exploring the pressure range of 20-50 MPa, temperatures of 40-70 degrees C and 0-15% of ethanol cosolvent. The content of oleanolic and ursolic acid in the extracts were determined, and different samples were screened for cellular cytotoxicity and virus inhibition using a HCV cell culture infection system. Antiviral activity was observed in most extracts. In general, superior anti-HCV activity was observed for higher contents of oleanolic and ursolic acids in the extracts. PMID- 25550075 TI - A mitovirus related to plant mitochondrial gene confers hypovirulence on the phytopathogenic fungus Sclerotinia sclerotiorum. AB - A double-stranded RNA (dsRNA) segment was isolated from a hypovirulent strain, HC025, of Sclerotinia sclerotiorum. The complete nucleotide sequence of the dsRNA was determined to be 2530 bp in length. Using the fungal mitochondrial genetic code, the positive strand of the dsRNA was found to contain a single large open reading frame (ORF) with the characteristic conserved motifs of the RNA-dependent RNA polymerase (RdRp). BLAST analysis revealed that RdRp shares 74% sequence identity with Sclerotinia sclerotiorum mitovirus 1 (SsMV1/KL-1). The positive strand of the dsRNA could be folded into potentially stable stem-loop structures at both the 5' and 3' terminal sequences. Moreover, the 5' and 3' terminal sequences were inverted complementary sequences and formed a panhandle structure. These results reveal that this dsRNA segment represents the replicative form of a mitovirus that is a strain of SsMV1 from the genus Mitovirus in the family Narnaviridae and was tentatively designated as Sclerotinia sclerotiorum mitovirus 1 (SsMV1/HC025). Sequence comparison and phylogenetic analysis suggest that mitovirus RdRp gene was evolutionarily related to plant mitochondrial genome. Our results demonstrate that SsMV1/HC025 infection exerted obvious effects on host biological properties. Hypovirulence feature and SsMV1/HC025 could be co transmitted from hypovirulent strains to other virulent strains via hyphal contact. Thus, SsMV1/HC025 related to plant mitochondrial gene confers hypovirulence on S. sclerotiorum. PMID- 25550076 TI - Public views on principles for health care priority setting: findings of a European cross-country study using Q methodology. AB - Resources available to the health care sector are finite and typically insufficient to fulfil all the demands for health care in the population. Decisions must be made about which treatments to provide. Relatively little is known about the views of the general public regarding the principles that should guide such decisions. We present the findings of a Q methodology study designed to elicit the shared views in the general public across ten countries regarding the appropriate principles for prioritising health care resources. In 2010, 294 respondents rank ordered a set of cards and the results of these were subject to by-person factor analysis to identify common patterns in sorting. Five distinct viewpoints were identified, (I) "Egalitarianism, entitlement and equality of access"; (II) "Severity and the magnitude of health gains"; (III) "Fair innings, young people and maximising health benefits"; (IV) "The intrinsic value of life and healthy living"; (V) "Quality of life is more important than simply staying alive". Given the plurality of views on the principles for health care priority setting, no single equity principle can be used to underpin health care priority setting. Hence, the process of decision making becomes more important, in which, arguably, these multiple perspectives in society should be somehow reflected. PMID- 25550077 TI - Do time-invariant confounders explain away the association between job stress and workers' mental health? Evidence from Japanese occupational panel data. AB - It is well known that job stress is negatively related to workers' mental health, but most recent studies have not controlled for unobserved time-invariant confounders. In the current study, we attempted to validate previous observations on the association between job stress and workers' mental health, by removing the effects of unobserved time-invariant confounders. We used data from three to four waves of an occupational Japanese cohort survey, focusing on 31,382 observations of 9741 individuals who participated in at least two consecutive waves. We estimated mean-centered fixed effects models to explain psychological distress in terms of the Kessler 6 (K6) scores (range: 0-24) by eight job stress indicators related to the job demands-control, effort-reward imbalance, and organizational injustice models. Mean-centered fixed effects models reduced the magnitude of the association between jobs stress and K6 scores to 44.8-54.2% of those observed from pooled ordinary least squares. However, the association remained highly significant even after controlling for unobserved time-invariant confounders for all job stress indicators. In addition, alternatively specified models showed the robustness of the results. In all, we concluded that the validity of major job stress models, which link job stress and workers' mental health, was robust, although unobserved time-invariant confounders led to an overestimation of the association. PMID- 25550078 TI - Factor VIII Antigen, Activity, and Mutations in Hemophilia A. AB - Factor VIII (FVIII) activity, antigen, and its gene mutation in patients may give us some insight into structure-activity relationship and probable reason for its low level in a particular patient. A total of 53 cases with hemophilia A and 17 normal individuals were analyzed for FVIII: C and FVIII: Ag levels along with their blood groups to determine their cross-reacting material (CRM) status. In all, 37 cases (18 moderate and 19 mild) were found to have discordant CRM status. Missense mutations (Ala723ThrandLys439Ser) and protein truncating changes (Trp1854*andArg2326*) were observed in 2 each of these cases. Although 37 (70%) of the 53 had discordant antigen-activity ratio, majority of those mutations produced FVIII with low FVIII-specific activity. However, 4 (7.5%) of the 53 mutations produced higher specific activity of FVIII. It is possible that these mutations either produce a secretory defect or an increased metabolic turnover to account for the low levels of FVIII with these mutations. PMID- 25550079 TI - Can Plateletcrit be a Marker for Recurrent Pregnancy Loss? AB - AIM: To determine the utility of platelet (PLT) indices for the prediction of recurrent pregnancy loss (RPL). METHODS: In all, 208 patients who experienced 2 or more first trimester spontaneous abortions and 95 controls who had no abortions were studied. The hematological markers, including plateletcrit (PCT) and neutrophil (Neu) to lymphocyte (Lym) ratio (NLR), were measured. Thrombophilia genetic tests for factor V Leiden mutation, prothrombin G202I0A mutation, and methylenetetrahydrofolate reductase C677 T and A1298C mutations were performed. RESULTS: The PLT count, PCT, white blood cell count, red cell distribution width (RDW), Lym and Neu count, and NLR were significantly higher in patients with RPL than in controls. The RDW, PLT, and PCT values were higher in the low-risk group, whereas mean PLT volume values were lower than the high-risk group values. CONCLUSION: Plateletcrit is a low-cost, widely available marker for prediction of RPL in patients with a history of at least 1 abortus. PMID- 25550080 TI - Toxicity measurement in biological wastewater treatment processes: a review. AB - Biological wastewater treatment processes (WWTPs), by nature of their reliance on biological entities to degrade organics and sometimes remove nutrients, are vulnerable to toxicants present in their influent. Various toxicity measurement methods have been adopted for biological WWTPs, but most are performed off-line, and cannot be adapted to on-line monitoring tools to provide an early warning for WWTP operators. However, the past decade has seen a rapid expansion in the research and development of biosensors that can be used for toxicity assessment of aquatic environments. Some of these biosensors have also been shown to be effective for use in biological WWTPs. Nevertheless, more research is needed to: examine the sensitivity of assays and sensors based on single organisms to various toxicants and develop a matrix of biosensors or a biosensor incorporating multiple organisms that can protect WWTPs; test the micro fuel cell (MFC)-based biosensors with real wastewaters and correlate the results with the well established oxygen uptake rate (OUR)-based or CH4-based toxicity assay; and, develop advanced data processing methods for interpreting the results of on-line toxicity sensors in real WWTPs to reduce the noise due to the normal fluctuation in influent quality and quantity. PMID- 25550081 TI - A critical evaluation of magnetic activated carbon's potential for the remediation of sediment impacted by polycyclic aromatic hydrocarbons. AB - Addition of activated carbon (AC) or biochar (BC) to sediment to reduce the chemical and biological availability of organic contaminants is a promising in situ remediation technology. But concerns about leaving the adsorbed pollutants in place motivate research into sorbent recovery methods. This study explores the use of magnetic sorbents. A coal-based magnetic activated carbon (MAC) was identified as the strongest of four AC and BC derived magnetic sorbents for polycyclic aromatic hydrocarbons (PAHs) remediation. An 8.1% MAC amendment (w/w, equal to 5% AC content) was found to be as effective as 5% (w/w) pristine AC in reducing aqueous PAHs within three months by 98%. MAC recovery from sediment after three months was 77%, and incomplete MAC recovery had both, positive and negative effects. A slight rebound of aqueous PAH concentrations was observed following the MAC recovery, but aqueous PAH concentrations then dropped again after six months, likely due to the presence of the 23% unrecovered MAC. On the other hand, the 77% recovery of the 8.1% MAC dose was insufficient to reduce ecotoxic effects of fine grained AC or MAC amendment on the egestion rate, growth and reproduction of the AC sensitive species Lumbriculus variegatus. PMID- 25550083 TI - Structural and sequential context of p53: A review of experimental and theoretical evidence. AB - Approximately 27 million people are suffering from cancer that contains either an inactivating missense mutation of TP53 gene or partially abrogated p53 signaling pathway. Concerted action of folded and intrinsically disordered domains accounts for multi-faceted role of p53. The intricacy of dynamic p53 structure is believed to shed light on its cellular activity for developing new cancer therapies. In this review, insights into structural details of p53, diverse single point mutations affecting its core domain, thermodynamic understanding and therapeutic strategies for pharmacological rescue of p53 function has been illustrated. An effort has been made here to bridge the structural and sequential evidence of p53 from experimental to computational studies. First, we focused on the individual domains and the crucial protein-protein or DNA-protein contacts that determine conformation and dynamic behavior of p53. Next, the oncogenic mutations associated with cancer and its contribution to thermodynamic fluctuation has been discussed. Thus the emerging anti-cancer strategies include targeting of destabilized cancer mutants with selective inhibition of its negative regulators. Recent advances in development of small molecule inhibitors and peptides exploiting p53-MDM2 interaction has been included. In a nutshell, this review attempts to describe structural biology of p53 which provide new openings for structure-guided rescue. PMID- 25550085 TI - RETRACTED ARTICLE: Short hairpin RNA gene silencing of NLRP3 confers protection against sepsis-induced hyperbilirubinemia in a rat model. PMID- 25550084 TI - Diagnostics and environmental factors. PMID- 25550082 TI - The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis. AB - The DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase composed of a large catalytic subunit (DNA-PKcs) and the Ku70/80 heterodimer. Over the past two decades, significant progress has been made in elucidating the role of DNA-PK in non-homologous end joining (NHEJ), the major pathway for repair of ionizing radiation-induced DNA double strand breaks in human cells and recently, additional roles for DNA-PK have been reported. In this review, we will describe the biochemistry, structure and function of DNA-PK, its roles in DNA double strand break repair and its newly described roles in mitosis and other cellular processes. PMID- 25550086 TI - Intravenous immunoglobulins (IVIG) in systemic sclerosis: a challenging yet promising future. AB - The etiology and pathogenesis of systemic sclerosis are still largely unknown, but a variety of humoral and cellular autoimmune phenomena have been documented. In addition, the rarity of the disease, the broad spectrum of clinical manifestations, and the relevant risk of severe complications as well as the highly variable disease course render its management a major challenge. Some immunomodulatory agents have been used, but no single agent has given a convincing proof of effectiveness, and treatment has remained largely symptomatic through recent years. Novel therapies are currently being tested and may have the potential of modifying the disease process and overall clinical outcome. Efficacy of intravenous immunoglobulins (IVIG) in different regimens (1-2 g/kg of body weight, administered over 2-5 consecutive days) has been described in a limited number of trials and small case series, showing benefits in skin, articular, and lung interstitial disease symptoms. However, studies on IVIG in systemic sclerosis still remain few, and further randomized controlled trials should be undertaken to assess their clinical effectiveness or define the optimal dosage and times of administration. PMID- 25550087 TI - Roles of retinoic acid-inducible gene-I-like receptors (RLRs), Toll-like receptor (TLR) 3 and 2'-5' oligoadenylate synthetase as viral recognition receptors on human mast cells in response to viral infection. AB - To investigate the anti-viral responses of human mast cells, we performed PCR array analysis of these cells after infection with vesicular stomatitis virus (VSV). PCR array analysis revealed that human mast cells up-regulated several anti-viral genes, including melanoma differentiation-associated gene 5, retinoic acid-inducible gene-I, and Toll-like receptor 3, together with type I interferons and chemokines, upon VSV infection. Additionally, we found that 2'-5' oligoadenylate synthetase, which also works as a virus recognition receptor by activating the latent form of RNase L, leading to viral RNA degradation, was up regulated in human mast cells upon VSV infection. Moreover, small interfering RNA analysis to identify the receptors responsible for mast cell activation by VSV revealed that these receptors reciprocally cooperate to produce anti-viral cytokines and chemokines, inhibiting VSV replication. Our findings suggest that human mast cells produce cytokines and chemokines using several viral recognition receptors, leading to the inhibition of viral replication. These data provide novel information that improves our understanding of the roles of human mast cells in immune responses against viruses. PMID- 25550088 TI - The roles of IL-2 and IL-10 enhance anti-CD45RBmAb immune inhibition in allograft skin. AB - As a new type of immune tolerance inducer, anti-CD45RB monoclonal antibodies (anti-CD45RBmAb) can prolong the graft survival time of animal organs or cell transplantation as well as induce stable immune tolerance. Both interleukin (IL) 2 and IL-10 have important roles in the induction and maintenance of immunological tolerance. However, whether these cytokines combined with anti CD45RBmAb can promote immune tolerance is poorly understood. Therefore, we investigated the effect of IL-2 and IL-10 in vitro and in vivo on the tolerance induction by anti-CD45RBmAb. The changes of Treg and Th17 cells and Th1/Th2 cytokines in anti-CD45RBmAb induced prolongation of skin allograft survival in mice. The finding of a role for IL-2 is novel, of interest, IL-2 promoted anti CD45RBmAb-induced CD4(+) T cell differentiation into Treg and Th2 cells and suppressed Th17 and Th1 cells. IL-2 enhanced the induction of immune tolerance by anti-CD45RBmAb and significantly prolonged skin graft survival time in vivo. In contrast, this effect should be demonstrated experimentally by neutralizing IL-2 and inhibition of the effect of anti-CD45RBmAb, and neutralizing IL-10 showed no effect for anti-CD45RBmAb-induced tolerance. These data reveal that IL-2 significantly enhances anti-CD45RBmAb-induced immune tolerance via up-regulated T regulatory (Treg) cells and the balance of Th1/Th2 shifts. Conversely, IL-10 showed no effect on anti-CD45RBmAb-induced tolerance. PMID- 25550089 TI - Insufficient secretion of IL-10 by Tregs compromised its control on over activated CD4+ T effector cells in newly diagnosed adult immune thrombocytopenia patients. AB - Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder. Excessive activated CD4(+) T effector cells (Teffs) and compromised regulatory T cells (Tregs) were reported in ITP patients, yet little is known about the mechanisms. Interleukin-10 (IL-10) is an important regulatory cytokine of Tregs in inflammatory condition. It has been recently highlighted that IL-10-producing Tregs contribute to the effective controls of several autoimmune diseases. Hence this study was aimed to examine the role of IL-10 produced by Tregs in newly diagnosed ITP patients. Newly diagnosed ITP patients and healthy volunteers were enrolled to assess the numbers of peripheral Th1, Th17 cells and Tregs. CD4(+)CD25(-)Teffs and CD4(+)CD25(+)Tregs were purified. CD4(+)CD25(-)Teffs, labeled with CFSE, were cultured alone or with Tregs for 5 days, and the supernatants were then collected for IL-10 concentration test. The role of IL-10 in Tregs' inhibitory function was also determined. In ITP patients, Teffs were excessively activated, while the Tregs were numerically and functionally impaired. The percentages of IL-10(+) Tregs in Tregs' population were found elevated dramatically in ITP patients but decreased in the remitted patients. The IL-10 concentrations in the cultured supernatant were decreased in ITP patients but elevated in the remitted patients. Furthermore, the IL-10 secretion by Tregs was dramatically decreased in ITP patients. IL-10 treatment enhanced the suppression effect of Tregs toward Teffs, whereas anti-IL-10 treatment boosted the proliferation of Teffs and Th17 cells. Excessive activated Teffs and impaired Tregs play major roles in the exuberant CD4(+) T cells immune responses of ITP. The inhibitory effect of Tregs toward Teffs is largely exerted by IL-10. Insufficient secretion of IL-10 compromises the inhibitory capability of Tregs against Teffs in newly diagnosed ITP patients. PMID- 25550090 TI - Interdisciplinary exchange of ideas: progestagens for autoimmunity, biologics for pregnancy complications. AB - In recent years, there has been a growing interest in the role of immune, alloimmune and autoimmune processes in the pathogenesis of spontaneous preterm birth and recurrent pregnancy loss. The association between an inflammatory response and preterm labor has been established. Indeed, many women suffering from preterm labor have elevated inflammatory markers such as tumor necrosis factor alpha, interleukin 6 and matrix metaloproeinase 8. The role of immune processes in the pathogenesis of recurrent pregnancy loss has also been widely researched. Progesterone induces many physiologic effects necessary for healthy pregnancy, and progestagens supplementation has been used as an approach to prevent preterm labor and recurrent pregnancy loss. Progestagens also have potent anti-inflammatory and immunomodulatory actions. Because preterm labor and recurrent pregnancy loss are associated with abnormal inflammation, progestagens may maintain healthy pregnancy through both endocrine and immunologic actions. These immunologic actions, such as suppression of Th1- and Th17-related responses, enhancement of regulatory T cell (Tregs) activity and suppression of inflammation, may also be involved in pregnancy-induced remission of certain autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Accordingly, there is growing interest in the potential therapeutic role of progestagens in the treatment of MS and RA. In this review, we suggest that biologic autoimmune modulators, especially those which affect immune pathways similar to progestagens, may provide more potent and specific effects, and hence better results than progestagens, in preventing preterm labor and recurrent pregnancy loss. PMID- 25550091 TI - Invited address: "The times they are a-changin'" gene expression, neuroplasticity, and developmental research. AB - For good reason, social scientists have a long history of being suspicious of biological explanations of human behavior. Importantly, however, recent paradigmatic shifts in the life sciences have largely obviated these longstanding concerns. We highlight the changes that have occurred in genetics with its movement away from genetic determinism to an emphasis on epigenetics and in neuroscience with its switch from a fixed to a neuroplastic view of the brain. We describe these new developments noting the way they recognize, indeed place a premium upon, the role of the environment. The remainder of the paper focuses upon the challenges and opportunities for social scientists, especially those involved in developmental work, proffered by these paradigmatic shifts. The evidence clearly shows that nature and nurture are inextricably interlinked. Importantly, however, it also indicates that they are connected in a manner that honors the priority that the social sciences place upon the environment. We contend that incorporating biological processes into our developmental work will sharpen our theories and enhance their significance. We argue that such biologically integrated models will provide a clearer and more comprehensive understanding of how nurture influences behavior across the life course. PMID- 25550092 TI - In vitro biomechanical evaluation of fixation methods of sagittal split ramus osteotomy in mandibular setback. AB - The purpose of this study was to compare different internal fixation techniques with resorbable or titanium fixation system used in sagittal split ramus osteotomy (SSRO) for mandibular setback. Synthetic polyurethane hemimandible replicas were used. The distal segment was repositioned in a 5-mm setback position. The hemimandibles were divided into the following eight groups: resorbable miniplate (A), titanium miniplate (B), resorbable hybrid; resorbable miniplate and bicortical screw (C), titanium hybrid; titanium miniplate and bicortical screw (D), resorbable mixed hybrid; resorbable bicortical screw and titanium miniplate (E), titanium mixed hybrid; titanium bicortical screw and resorbable miniplate (F), three resorbable bicortical screws (G) and three titanium bicortical screws (H). The compression loads were applied on the incisal edge. The compression loads (N) at 5- and 10-mm displacement were analyzed (P < 0.05). Miniplate groups (A and B) were significantly weaker than the other groups (C ~ H). Group (H) had greatest biomechanical stability. There was no significant difference between group (D) and group (H) at 10-mm displacement. Group (G) showed a lower load than group (H) and group (D). There was no significant difference between the hybrid and mixed hybrid groups. It was concluded that additional placement of a bicortical screw, either titanium or resorbable with a miniplate may provide significantly better stabilization. PMID- 25550094 TI - Factors predicting secondary displacement after non-operative treatment of undisplaced femoral neck fractures. AB - INTRODUCTION: We quantified the risk and the time of occurrence of secondary fracture displacement in non-operatively treated femoral neck fractures in our clinic, as well as investigated potential predicting patient- and fracture related factors. METHODS: The records of 593 patients with femoral neck fractures from January 2000 to December 2009 were reviewed. Sixty-one patients [mean age 83.0 years (SD 9.9)] with undisplaced femoral neck fractures initially received non-operative treatment. The occurrence and the time of secondary fracture displacement were documented, as well as demographics and radiological parameters. Radiographs were evaluated independently by two surgeons. Multivariable regression and Kaplan-Meier survival analyses were used. RESULTS: Thirty-four (55.7 %) fractures showed secondary displacement occurring within the first 12 weeks after initiation of non-operative treatment. Twenty (38 %) fractures originally classified as Garden I were found to be Garden II. The risk of secondary displacement was three times higher (RR = 2.8; 95 % CI 1.7-4.8, p < 0.001) for these fractures in comparison with those confirmed as Garden I. Patients with a history of previously diagnosed osteoporosis were at a higher risk of secondary displacement as well (RR = 1.3; 95 % CI 1.0-1.5). CONCLUSIONS: Non-operative treatment of femoral neck fractures is a treatment option, but only in well-selected cases. The majority of secondary displacements were associated with initial misdiagnosis using the Garden classification. For Garden II, primary surgical treatment is likely a better option, and therefore careful application of the Garden classification in this context is essential. PMID- 25550093 TI - Acute Wnt pathway activation positively regulates leptin gene expression in mature adipocytes. AB - Genome-wide association studies (GWAS) have revealed the implication of several Wnt signaling pathway components, including its effector transcription factor 7 like 2 (TCF7L2) in diabetes and other metabolic disorders. As TCF7L2 is expressed in adipocytes, we investigated its expression and function in rodent fat tissue and mature adipocytes. We found that TCF7L2 mRNA expression in C57BL/6 mouse epididymal fat tissue was up-regulated by feeding but down-regulated by intraperitoneal insulin injection. In high-fat diet (HFD) fed mice, db/db mice and Zucker (fa/fa) rats, epididymal fat TCF7L2 mRNA levels were lower than the corresponding controls. Treating rat adipocytes with 100nM insulin repressed TCF7L2 mRNA and protein levels, associated with the repression of leptin mRNA level. The treatment with 1nM insulin, however, stimulated TCF7L2 and leptin mRNA levels. This stimulation could be attenuated by iCRT14, an inhibitor of beta catenin/TCF-responsive transcription. Wnt3a stimulated leptin mRNA level, which was also blocked by iCRT14 co-treatment. Utilizing the leptin-expressing cell line HTR8 as a tool, we defined an evolutionarily conserved CREB binding motif that mediated Wnt3a activation. Although Wnt activation is known to repress the differentiation of 3T3-L1 cells towards mature adipocytes, short-term Wnt3a treatment of differentiated 3T3-L1 cells stimulated leptin mRNA levels. Thus, wnt pathway plays a dual function in adipocytes, including the well-known repressive effect on adipogenesis and the stimulation of leptin production in mature adipocytes in response to nutritional status. PMID- 25550095 TI - Hospital readmission after hip fracture. AB - INTRODUCTION: Readmission to the hospital following a hip fracture is common, often involves an adverse event, and strains an already overburdened health care system. OBJECTIVES: To assess the rate of 30-day readmission to the hospital after discharge for care of hip fracture. A secondary objective was measurement of the 30-day mortality rate for those patients readmitted versus those patients not readmitted to the hospital after discharge. MATERIALS AND METHODS: Study design was a retrospective review of registry data comparing readmitted patients to those not readmitted after hip fracture. Setting was a university affiliated level 3 trauma center. PARTICIPANTS: 1,081 patients aged 65 and older. MEASUREMENTS: rate of readmission, rate of mortality, predictors of readmission. RESULTS: 129 patients (11.9 %) were readmitted to the hospital within 30 days of their initial discharge date. The primary causes of readmission were surgical in nature for 24/129 (18.6 %) patients and 105/129 (81.4 %) were readmitted for medical or other reasons. Twenty-four (18.6 %) patients who were readmitted died during readmission. The one-year mortality rate for patients readmitted within 30 days was 56.2 vs. a 21.8 % 1-year mortality rate for those patients not readmitted (p < 0.0001). Independent predictors of readmission were age >85 (OR = 1.52; p = 0.03), time to surgery >24 h (OR = 1.50; p = 0.05), Charlson score >=4 (OR = 1.70; p = 0.04), delirium (OR = 1.65; p = 0.01), dementia (OR = 1.61; p = 0.01), history of arrhythmia with pacemaker placement (OR = 1.75; p = 0.02), and presence of a pre-op arrhythmia (OR = 1.62; p = 0.02). CONCLUSION: Readmission after hip fracture is harmful and undesirable-18.6 % of readmitted patients died during their readmission and the average length of stay was 8.7 days. Approximately one of every six readmissions was identified as potentially preventable with interventions. PMID- 25550096 TI - Neuro-ophthalmological findings in patients with acquired prosopagnosia. PMID- 25550097 TI - Thalidomide reduces choroidal thickness and optic disc edema in a patient with POEMS syndrome. PMID- 25550098 TI - Relationships among serum lipoprotein lipase mass, visceral fat, and retinal nerve fiber layer thickness. AB - PURPOSE: The purpose of the study was to determine whether there were significant correlations among the serum lipoprotein lipase mass, visceral fat, and the retinal nerve fiber layer (RNFL) thickness. METHODS: We studied 118 consecutive subjects. Optical coherence tomography (OCT) was used to measure the RNFL thickness. The Pearson correlation coefficient was used to determine the relationships among lipoprotein lipase (LPL) mass, visceral fat area by computed tomography, OCT, and other parameters. We performed a multiple regression analysis to identify independent factors for the RNFL sectors that were the most strongly correlated with the LPL mass and visceral fat area. RESULTS: The LPL mass was significantly correlated with the nasal RNFL thickness in both eyes (right eye: r = 0.24, p = 0.008, left eye: 0.32, 0.0008) and inferior RNFL thickness in the left eye ( r = 0.23, p = 0.01). The visceral fat area was significantly correlated with the nasal RNFL thickness in both eyes (right eye: r = -0.19, p = 0.04, left eye: -0.30, 0.0008) and the inferior RNFL thickness in the left eye ( r = -0.23, p = 0.01). The subcutaneous fat area was not significantly correlated with any OCT parameters. The multiple regression analysis revealed that age, LPL mass, and visceral fat area were independent contributors to the nasal RNFL thickness in the left eye (age, standard regression coefficient = -0.34 , p = 0.0004; LPL mass, 0.26, 2.49, 0.01; visceral fat area, -0.21, 0.03). CONCLUSION: A reduction of lipoprotein lipase and accumulation of visceral fat might produce retinal neurodegenerative disorders that decrease the RNFL thickness, especially on the nasal side. PMID- 25550099 TI - Inhibition of cell proliferation and migration after HTRA1 knockdown in retinal pigment epithelial cells. AB - PURPOSE: The purpose of this study was to investigate the role of HtrA serine peptidase 1 (HTRA1) in the proliferation and migration of cells of the human retinal pigment epithelial cell line ARPE-19, and the possible mechanisms involved. METHODS: ARPE-19 cells were transduced by a recombinant lentiviral vector carrying HTRA1-shRNA to knockdown HTRA1 expression. Subsequent HTRA1 gene and HTRA1 protein levels in these cells and control cells were detected by quantitative real-time PCR and Western blot, respectively. Changes in cell proliferation and migration associated with the inhibition of HTRA1 expression were assessed, as well as changes in the mRNA levels of transforming growth factor beta 1 (TGFB1), bone morphogenetic protein 4 (BMP4), and bone morphogenetic protein 2 (BMP2). RESULTS: The recombinant lentivirus carrying HTRA1-shRNA was successfully generated, as evidenced by reduced levels of HTRA1 mRNA and HTRA1 protein in ARPE-19 cells. The knockdown of HTRA1 in ARPE-19 cells was associated with reduced cellular proliferation and migration, and increased mRNA levels of TGF-beta1, BMP4, and BMP2. CONCLUSIONS: Silence of the HTRA1 gene was associated with significantly higher levels of TGF-beta1, BMP4, and BMP2 mRNA and reduction in the proliferation and migration of ARPE-19 cells. PMID- 25550100 TI - Child protection decisions to substantiate hospital child protection teams' reports of suspected maltreatment. AB - The present study focuses on the way child protection officers (CPOs) in Israel assess suspected abuse and neglect (SCAN) reports made by hospital child protection teams (CPTs), to determine whether the alleged maltreatment is substantiated. The study was conducted in six medical centers and included 358 reports investigated by CPOs for SCAN. A structured questionnaire was completed by hospital CPTs to capture all relevant information on each child referred to the CPTs. Structured phone interviews were conducted with each of the CPOs who received a CPT report. Bivariate associations and multivariate logistic regressions were conducted to estimate the substantiation rate of cases reported by CPTs and the types of maltreatment substantiated, as well as to identify case characteristics of the child and the family that were associated with the CPOs' substantiation decision. CPO follow-up investigations revealed a substantiation rate of 53.5%. The maltreatment type most commonly substantiated was neglect. The case characteristics associated with substantiation included socio-demographic background, parents' health and functioning, previous contact with social services, characteristics of the hospital referral, medical findings and an assessment of the parents' behaviors. The findings of the study highlighted the importance of cooperation between the health and welfare services and the policy makers. This cooperation is essential for identifying early signs of maltreatment. Enhanced cooperation and effective information transfer between various professionals would help prevent or at least reduce the recurrence of maltreatment and would ensure that the children and their families are treated appropriately. PMID- 25550101 TI - Osterix-Cre transgene causes craniofacial bone development defect. AB - The Cre/loxP system has been widely used to generate tissue-specific gene knockout mice. Inducible (Tet-off) Osx-GFP::Cre (Osx-Cre) mouse line that targets osteoblasts is widely used in the bone research field. In this study, we investigated the effect of Osx-Cre on craniofacial bone development. We found that newborn Osx-Cre mice showed severe hypomineralization in parietal, frontal, and nasal bones as well as the coronal sutural area when compared to control mice. As the mice matured, the intramembranous bone hypomineralization phenotype became less severe. The major hypomineralization defect in parietal, frontal, and nasal bones had mostly disappeared by postnatal day 21, but the defect in sutural areas persisted. Importantly, Doxycycline treatment eliminated cranial bone defects at birth which indicates that Cre expression may be responsible for the phenotype. In addition, we showed that the primary calvarial osteoblasts isolated from neonatal Osx-Cre mice had comparable differentiation ability compared to their littermate controls. This study reinforces the idea that Cre-positive litter mates are indispensable controls in studies using conditional gene deletion. PMID- 25550102 TI - Heritability and genetics of serum dickkopf 1 levels in African ancestry families. AB - The aim of the study was to determine the heritability of serum dickkopf-1 (DKK1) and its association with DKK1 polymorphisms in African ancestry subjects. Serum DKK1 was measured in 422 Afro-Caribbean men and women aged 18+ from 7 large, multi-generational families (mean family size: 60; 3,215 relative pairs). Twenty four common single nucleotide polymorphisms (SNPs) were genotyped within an 80 kilobase-pair region encompassing the DKK1 gene. Heritability was estimated and SNPs were tested for association with serum DKK1 using variance components analysis. DKK1 mRNA expression was tested in peripheral blood of 16 individuals from each of the rs7069912 genotypes. Mean serum DKK1 was 1724.1 pg/mL and was significantly lower in women than men (P = 0.043). Residual genetic heritability of serum DKK1 was 0.4460 (P < 0.0001). Six SNPs reached nominal significance with DKK1, with rs7069912 being significant after adjustment for multiple comparisons. Two of these six SNPs represented independent association signals (rs7069912 and rs16928725), which accounted for 4.6% of the phenotypic variation in DKK1. Additionally, carriers of the rs7069912 variant had significantly greater DKK1 expression than non-carriers (P = 0.036). Serum DKK1 levels are highly heritable in the African ancestry families. Two SNPs within the DKK1 region accounted for nearly 5% of the variation in serum DKK1. PMID- 25550103 TI - Recurrence of rib prominence following surgery for adolescent idiopathic scoliosis with pedicle screws and direct vertebral body derotation. AB - PURPOSE: Pedicle screw constructs combined with direct vertebral body derotation (DVBD) provide a powerful corrective force of the rib prominence associated with adolescent idiopathic scoliosis (AIS). We wished to evaluate the incidence and correlative factors associated with recurrence of rib prominence (RRP) developing postoperatively despite adequate initial correction. METHODS: 103 patients with AIS underwent pedicle screw fixation with DVBD without thoracoplasty and had postoperative scoliometer readings at 6, 12, and 24 months. Patients with RRP, defined as a postoperative scoliometer increase >=5 degrees , were compared to those without recurrence. RESULTS: The mean rib prominence measured 14.0 +/- 4.3 degrees preoperatively, with a correction of 50.3 +/- 26.7 % at 6 months, 49.0 +/- 39.0 % at 1 year, and 49.1 +/- 26.7 % at 2 years. RRP was identified in 15.5 % of the patients with a correction of 57.5 +/- 25.5 % at 6 months, 47.2 +/- 42.5 % at 1 year, and 40.4 +/- 21.6 % at 2 years. At 2 years, the RRP group demonstrated a significantly larger major coronal Cobb (p < 0.05) and a trend towards less curve correction (p = 0.09). Patients with open triradiates had a significantly higher rate of RRP compared to those with closed (p = 0.01). Worsening apical vertebral rotation at 2 years post-operation occurred in 43.8 % (7/16) of the patients with RRP. CONCLUSION: RRP after posterior fusion for AIS with all pedicle screw constructs and DVBD occurred in 15.5 % of patients in our study. Patients with open triradiate cartilage had a significantly higher rate of RRP, although most with RRP were skeletally mature. There was a trend towards loss of coronal correction and increased apical vertebral rotation at 2 years in patients with RRP. The potential for RRP after adequate initial correction should be discussed with patients. LEVEL OF EVIDENCE: 2. PMID- 25550104 TI - Pelvic incidence and pelvic tilt measurements using femoral heads or acetabular domes to identify centers of the hips: comparison of two methods. AB - PURPOSE: The aim of the study was to compare pelvic incidence (PI) and pelvic tilt (PT) measurements using the bicoxofemoral axis obtained from either femoral heads or acetabular domes on lateral digital radiographs of the spine. METHODS: Standing lateral radiographs of the spine of patients without hip pathologies were analyzed. PI and PT were measured on 50 radiographs using the femoral heads first followed by measurements performed with the acetabular domes to define the bicoxofemoral axis. Agreement between the methods was quantified by intraclass correlation coefficient (ICC) and median error for a single measurement (SEM). Intraobserver reproducibility and interobserver reliability of both methods of identification of bicoxofemoral axis and its impact on PI and PT measurements were tested on 31 radiographs and quantified by ICC and SEM. RESULTS: There was an excellent agreement in PI as well as in PT between measurements performed using whether the femoral heads or the acetabular domes (ICC: 0.99; SEM: 0.56 degrees for PI and ICC: 0.99; SEM: 0.2 degrees for PT). Excellent intraobserver reproducibility was revealed for both methods (ICC: 0.99 and SEM: <=0.17 degrees for PI and ICC: 0.99; SEM: <=0.18 degrees for PT). Both methods presented excellent interobserver reliability (ICC: 0.99 and SEM: <=0.54 degrees for PI and ICC: >=0.98; SEM: <=0.9 degrees for PT). CONCLUSIONS: We suggest that either the femoral heads or the acetabular domes may be used for reliable PI and PT measurements on the lateral standing long-cassette digital radiographs of the spine. PMID- 25550105 TI - Polychlorinated dibenzo-p-dioxins and dibenzofurans in Niagara River suspended sediments. AB - Niagara River archived suspended sediments were analyzed for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs/Fs) to investigate temporal trends and to assess congener profiles as source indicators. In general, concentrations ranged from 6 to 35 pg g(-1) toxic equivalents (TEQs) and 1000 6000 pg g(-1) total PCDDs/Fs and reflected a slight decline in the 1980s, but with little apparent change since that time. This temporal trend was consistent with those observed in Lake Ontario environmental compartments. The observed levels generally reflected ambient background levels in the Niagara River; however, three samples were substantially above ambient levels and a fourth sample, while not elevated, had a profile that was distinctly different from those typically observed at Niagara-on-the-Lake at the mouth of the Niagara River. Event-based concentrations ranged from approximately 160-620 pg g(-1) TEQs; congener profiles for these samples were consistent with known source areas in the Niagara River watershed, including Pettit Flume and Bloody Run Creek. These qualitative and quantitative results indicated loadings of dioxins and furans from hazardous waste sites in the Niagara River are occurring episodically, and can be measured in suspended sediments downstream at the river mouth at Niagara-on-the-Lake. PMID- 25550106 TI - Multixenobiotic resistance efflux activity in Daphnia magna and Lumbriculus variegatus. AB - Multixenobiotic resistance is a phenomenon in which ATP-binding cassette (ABC) family proteins transfer harmful compounds out of cells. Daphnia magna and Lumbriculus variegatus are model species in aquatic ecotoxicology, but the presence and activity of ABC proteins have not been well described in these species. The aim of this work was to study the presence, activity, and inhibition of ABC transport proteins in D. magna and L. variegatus. The presence of abcb1 and abcc transcripts in 8-9-day-old D. magna was investigated by qRT-PCR. The activity of MXR in D. magna and L. variegatus was explored by influx of the fluorescent ABC protein substrates rhodamine B and calcein-AM, with and without the model inhibitors verapamil (unspecific ABC inhibitor), reversin 205 (ABCB1 inhibitor) and MK571 (ABCC inhibitor). Juvenile D. magna possessed all examined abcb and abcc transcripts, but only reversin 205 inhibited MXR activity. The MXR activity in L. variegatus was inhibited by MK571, and to a lesser extent by verapamil, whereas reversin 205 seemed to stimulate the transport activity. Whereas calcein-AM worked better as an MXR substrate in D. magna, rhodamine B was a better substrate for L. variegatus MXR activity measurements. This is the first report on MXR activity in the order Lumbriculida, subclass Oligochaeta, and class Clitellata. PMID- 25550107 TI - Interactions between suspension characteristics and physicochemical properties of silver and copper oxide nanoparticles: a case study for optimizing nanoparticle stock suspensions using a central composite design. AB - The preparation of a stable nanoparticle stock suspension is the first step in nanotoxicological studies, but how different preparation methods influence the physicochemical properties of nanoparticles in a solution, even in Milli-Q water, is often under-appreciated. In this study, a systematic approach using a central composite design (CCD) was employed to investigate the effects of sonication time and suspension concentration on the physicochemical properties (i.e. hydrodynamic diameter, zeta potential and ion dissolution) of silver (Ag) and copper oxide (CuO) nanoparticles (NPs) and to identify optimal conditions for suspension preparation in Milli-Q water; defined as giving the smallest particle sizes, highest suspension stability and lowest ion dissolution. Indeed, all the physicochemical properties of AgNPs and CuONPs varied dramatically depending on how the stock suspensions were prepared and differed profoundly between nanoparticle types, indicating the importance of suspension preparation. Moreover, the physicochemical properties of AgNPs and CuONPs, at least in simple media (Milli-Q water), behaved in predictable ways as a function of sonication time and suspension concentration, confirming the validity of our models. Overall, the approach allows systematic assessment of the influence of various factors on key properties of nanoparticle suspensions, which will facilitate optimization of the preparation of nanoparticle stock suspensions and improve the reproducibility of nanotoxicological results. We recommend that further attention be given to details of stock suspension preparation before conducting nanotoxicological studies as these can have an important influence on the behavior and subsequent toxicity of nanoparticles. PMID- 25550108 TI - Transformation kinetics of trenbolone acetate metabolites and estrogens in urine and feces of implanted steers. AB - Biotransformation of trenbolone acetate metabolites and estrogens derived from animal feeding operations in soils, waste storage systems, and in land applied manure has been well characterized. Yet recent data demonstrate potential for steroid transport into the environment directly from feedyard pens via runoff or airborne particulate matter. Therefore, the objective of this study was to determine steroid transformation rates in beef cattle excreta. Feces and urine were collected from steers recently treated with steroidal implants. Excreta were stored and periodically extracted over 112 d then analyzed for trenbolone acetate metabolites and estrogens by liquid chromatography mass spectrometry. Conjugated steroids were present primarily in urine, and conjugates quickly degraded to free steroid with a half-life of 0.6-1.0 d. The primary trenbolone acetate metabolite, 17alpha-trenbolone, had a half-life of 5.1-9.5 d. Likewise, 17alpha-estradiol was the predominant estrogen, with a half-life of 8.6-53 d. Secondary trenbolone metabolites formed from 17alpha-trenbolone biotransformation were observed at low concentrations less than 10% initial 17alpha-trenbolone concentrations. Estrone was the primary metabolite of 17alpha-estradiol and concentrations of estrone exceeded initial 17alpha-estradiol concentration in all sample types. These results suggest manure-borne steroids are more stable in excreta than in soil microcosms. PMID- 25550109 TI - Year-round record of dissolved and particulate metals in surface snow at Dome Concordia (East Antarctica). AB - From January to December 2010, surface snow samples were collected with monthly resolution at the Concordia station (75 degrees 06'S, 123 degrees 20'E), on the Antarctic plateau, and analysed for major and trace elements in both dissolved and particulate (i.e. insoluble particles, >0.45 MUm) phase. Additional surface snow samples were collected with daily resolution, for the determination of sea salt sodium and not-sea-salt calcium, in order to support the discussion on the seasonal variations of trace elements. Concentrations of alkaline and alkaline earth elements were higher in winter (April-October) than in summer (November March) by a factor of 1.2-3.3, in agreement with the higher concentration of sea salt atmospheric particles reaching the Antarctic plateau during the winter. Similarly, trace elements were generally higher in winter by a factor of 1.2-1.5, whereas Al and Fe did not show any significant seasonal trend. Partitioning between dissolved and particulate phases did not change with the sampling period, but it depended only on the element: alkaline and alkaline-earth elements, as well as Co, Cu, Mn, Pb and Zn were for the most part (>80%) in the dissolved phase, whereas Al and Fe were mainly associated with the particulate phase (>80%) and Cd, Cr, V were nearly equally distributed between the phases. Finally, the estimated marine and crustal enrichment factors indicated that Cd, Cr, Cu, Pb and Zn have a dominant anthropogenic origin, with a possible contribution from the Concordia station activities. PMID- 25550111 TI - Field methods for rapidly characterizing paint waste during bridge rehabilitation. AB - For Department of Transportation (DOT) agencies, bridge rehabilitation involving paint removal results in waste that is often managed as hazardous. Hence, an approach that provides field characterization of the waste classification would be beneficial. In this study, an analysis of variables critical to the leaching process was conducted to develop a predictive tool for waste classification. This approach first involved identifying mechanistic processes that control leaching. Because steel grit is used to remove paint, elevated iron concentrations remain in the paint waste. As such, iron oxide coatings provide an important surface for metal adsorption. The diffuse layer model was invoked (logKMe=4.65 for Pb and logKMe=2.11 for Cr), where 90% of the data were captured within the 95% confidence level. Based on an understanding of mechanistic processes along with principal component analysis (PCA) of data obtained from field-portable X-ray fluorescence (FP-XRF), statistically-based models for leaching from paint waste were developed. Modeling resulted in 96% of the data falling within the 95% confidence level for Pb (R(2) 0.6-0.9, p ? 0.04), Ba (R(2) 0.5-0.7, p ? 0.1), and Zn (R(2) 0.6-0.7, p ? 0.08). However, the regression model obtained for Cr leaching was not significant (R(2) 0.3-0.5, p ? 0.75). The results of this work may assist DOT agencies with applying a predictive tool in the field that addresses the mobility of trace metals as well as disposal and management of paint waste during bridge rehabilitation. PMID- 25550110 TI - Emissions of PBDD/Fs, PCDD/Fs and PBDEs from flame-retarded high-impact polystyrene under thermal stress. AB - The emissions of polybrominated diphenyl ethers (PBDEs), polybrominated dibenzo-p dioxins and dibenzofurans (PBDD/Fs) and their chlorinated analogues (PCDD/Fs) during the thermal treatment of a high impact polystyrene (HIPS) TV casing were investigated. The halogenated compounds were analyzed in the original material and in the gases emitted during its treatment at temperatures between 50 degrees C and 250 degrees C. DecaBDE was the primary PBDE in the TV casing, which also contained high levels of PBDFs (ppm range). At the lower treatment temperatures, non-modified PBDEs evaporated from the samples. Conversely, at 200 degrees C or above, debromination reactions led to the formation of additional tri- through nonaBDE. The formation of new PBDD/Fs was also detected in the gas phase when the plastic was heated to 200 degrees C or 250 degrees C, with higher yields of furans than dioxins. This appreciably increased the toxic equivalent (TEQ) levels of the gas phase relative to those seen in the untreated sample. In all cases, the levels and TEQ contributions from PCDD/Fs were negligible compared to those for brominated analogues. PMID- 25550112 TI - Transformation of bisphenol A in water distribution systems: a pilot-scale study. AB - Halogenations of bisphenol A (BPA) in a pilot-scale water distribution system (WDS) of a cement-lined ductile cast iron pipe were investigated. The water in the pilot-scale WDS was chlorinated with a free chlorine concentration of 0.7 mg L(-1) using sodium hypochlorite, and with an initial BPA concentration of 100 MUg L(-1) was spiked in the WDS. Halogenated compounds in the BPA experiments were identified using EI/GC/MS and GC. Several BPA congeners, including 2 chlorobisphenol A (MCBPA), dichlorobisphenol A (D2-CBPA), 2,2',6 trichlorobisphenol A (T3CBPA), 2,2',6,6'-tetrachlorobisphenol A (T4CBPA), 2 bromobisphenol A (MBBPA), and bromochlorobisphenol A (MBMCBPA) were found. Moreover, further halogenation yielded other reaction intermediates, including 2,4,6-trichlorophenol (T3CP), dichlorobisphenol A, bromodichlorophenol, and dibromochlorophenol. After halogenation for 120min, most of the abovementioned reaction intermediates disappeared and were replaced by trihalomethanes (THMs). Based on these experimental findings, the halogenation process of BPA oxidation in a WDS includes three stages: (1) halogenation on the aromatic ring; (2) chlorine or bromine substitution followed by cleavage of the alpha-C bond on the isopropyl moiety with a positive partial charge and a beta'-C bond on the benzene moiety with a negative partial charge; and (3) THMs and a minor HAA formation from phenolic intermediates through the benzene ring opening with a chlorine and bromine substitution of the hydrogen on the carbon atoms. The oxidation mechanisms of the entire transformation from BPA to THM/HAA in the WDS were proposed. PMID- 25550113 TI - Does modulation of spinal N-methyl-D-aspartic acid receptor by pre-activation accelerate the development of morphine tolerance? AB - Repeated morphine administration usually leads to a number of neuroadaptive processes, including tolerance and sensitization. However, research has shown that the induction and maintenance of central sensitization is dependent on N methyl-d-aspartic acid receptor (NMDAR) activation. Chronic morphine exposure has been shown to result in spinal sensitization and activation of spinal NMDARs. Chronic morphine treatment and the activation of spinal NMDARs may be synergistic and form a closed loop that may worsen the development of morphine analgesic tolerance and spinal sensitization. Inhibition of NMDARs with an antagonist could effectively alleviate the development of morphine analgesic tolerance. So, what is the effect of modulating spinal NMDAR activation with exogenous agonists or neuropathic input on the development of morphine-induced analgesic tolerance? Our hypothesis is that chronic morphine treatment may worsen the already activation of spinal NMDARs and spinal sensitization after agonist application or neuropathic input to shorten the process of morphine-induced analgesic tolerance. PMID- 25550114 TI - Therapeutic vaccination in chronic hepatitis B--approaches, problems, and new perspectives. Preface. PMID- 25550115 TI - Toll-like receptor (TLR)-mediated innate immune responses in the control of hepatitis B virus (HBV) infection. AB - The role of adaptive immune responses in the control of hepatitis B virus (HBV) infection is well accepted. The contribution of innate immune responses to the viral control is recognized but yet not fully understood. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms including the intracellular antiviral pathways and the production of antiviral effectors like interferons (IFNs) and pro-inflammatory cytokines. Activation of the TLR3 pathway and the production of IFN-beta represent one of the major mechanisms leading to the suppression of HBV replication in the liver, as shown in different in vitro and in vivo models. TLR4 signaling and TLR2 signaling result in the activation of intracellular pathways including MAPK and PI-3 K/Akt in hepatocytes and reduce HBV replication in an IFN-independent manner. HBV is able to counteract the actions of TLR3 and TLR2/4 through downregulation of TLR expression and attenuation of the cellular signaling pathways. Thus, TLR ligands are promising candidates as immunomodulators and therapeutics for the treatment of chronic HBV infection. Specific antiviral treatment against HBV could recover the TLR functions in chronic HBV infection and increase the effectiveness of therapeutic approaches based on TLR activation. PMID- 25550116 TI - Laparoscopic peritoneal lavage for perforated colonic diverticulitis: a definitive treatment? Retrospective analysis of 63 cases. AB - BACKGROUND: The ideal treatment of perforated diverticulitis and the indications for elective colon resection remain controversial. Considering the significant morbidity and mortality rates related to traditional resection, efforts have been made to reduce the invasiveness of surgery in recent decades. Laparoscopic peritoneal lavage has emerged as an effective alternative option. We retrospectively investigated the effectiveness of laparoscopic peritoneal lavage for perforated diverticulitis and the possibility that it could be a definitive treatment. METHODS: We included patients treated with laparoscopic peritoneal lavage for perforated diverticulitis. The inclusion criteria were all emergency patients with generalized peritonitis due to Hinchey III perforated diverticulitis and some cases of Hinchey II and IV. RESULTS: Sixty-three patients were treated with laparoscopic peritoneal lavage. Six patients (9.5 %) had Hinchey II diverticulitis; 54 patients (85.7 %) had Hinchey III; and three patients (4.8 %) had Hinchey IV. The mean operative time was 87.3 min (+/-25.4 min), and the overall morbidity rate was 14.3 %. One patient died because of pulmonary embolism, and there were six early reinterventions because of treatment failure. Delayed colon resection was performed in four of the remaining 57 patients (7 %) because of recurrent diverticulitis. In the other 53 patients (93 %), we saw no recurrence of diverticulitis and no intervention was performed after a median follow-up period of 54 months (interquartile range 27-98 months). CONCLUSIONS: Laparoscopic peritoneal lavage for perforated diverticulitis can be considered a safe and effective alternative to traditional surgical resection, and using this approach, most elective colon resection might be avoided. PMID- 25550117 TI - Laparoscopic en bloc excision of gastrointestinal stromal tumors of the rectum after neoadjuvant imatinib therapy: anteriorly extended intersphincteric resection combined with partial resection of the prostate. AB - We herein present a novel technique for laparoscopic en bloc excision involving anteriorly extended intersphincteric resection with partial resection of the posterior lobe of the prostate for large rectal gastrointestinal stromal tumors (GISTs). The sequence of neoadjuvant imatinib therapy and this less invasive surgery for marginally resectable rectal GISTs has the potential to obviate the need for urinary reconstruction and permanent stomas without jeopardizing the tumor margin status. PMID- 25550119 TI - Effect of blue light emitting diodes on melanoma cells: involvement of apoptotic signaling. AB - The present study was undertaken to examine whether blue LED irradiation induces cellular apoptosis in B16-F10 cells and whether it blocks the early growth of melanoma cells in mice. Irradiation with blue LED was observed to reduce cell viability and to induce apoptotic cell death, as accompanied by exposure of phosphatidylserine on the plasma outside membrane and an accumulation of a sub-G1 population. Furthermore, the mitochondrial membrane potential increased, and mitochondria-related apoptotic proteins (cytochrome c, caspase 3, and PARP) were observed. In addition, the level of intracellular superoxide anion (O2(-)) gradually increased. Interestingly the phosphorylation of p53 increased at earlier times under blue LED irradiation, but reduced after exposure for a longer time. Additionally, the thickness of the mice footpad injected with B16-F10 cells decreased significantly until the 9th day of blue LED irradiation, indicating the inhibition of the early growth rate of the melanoma cells. Our data demonstrate that blue LED irradiation induces apoptotic cell death by activating the mitochondria-mediated pathway and reduces the early growth rate of melanoma cells. Further studies are needed to elucidate the precise mechanism of blue LED in melanoma cells. PMID- 25550118 TI - Non-human primate and rat cardiac fibroblasts show similar extracellular matrix related and cellular adhesion gene responses to substance P. AB - BACKGROUND: The sensory nerve neuropeptide substance P (SP) regulates cardiac fibrosis in rodents under pressure overload conditions. Interestingly, SP induces transient increased expression of specific genes in isolated rat cardiac fibroblasts, without resultant changes in cell function. This suggests that SP 'primes' fibroblasts, but does not directly activate them. We investigated whether these unusual findings are specific to rodent fibroblasts or are translatable to a larger animal model more closely related to humans. METHODS: We compared the effects of SP on genes associated with extracellular matrix (ECM) regulation, cell-cell adhesion, cell-matrix adhesion and ECM in cardiac fibroblasts isolated from a non-human primate and Sprague-Dawley rats. RESULTS: We found that rodent and non-human primate cardiac fibroblasts showed similar responses in genes that relate to ECM regulation and cell adhesion in response to SP. There were large discrepancies in ECM component genes, however, this did not result in collagen or laminin synthesis in rat or non-human primate fibroblasts in response to SP. CONCLUSIONS: This study further supports the notion that SP serves as a 'primer' for fibroblasts rather than initiating direct effects and suggests that rodent fibroblasts are a suitable model for studying gene and functional responses to SP in the absence of human or non-human primate fibroblasts. PMID- 25550120 TI - Photoelectrocatalytic degradation of benzoic acid using Au doped TiO2 thin films. AB - Highly transparent pure and Au doped TiO2 thin films are successfully deposited by using simple chemical spray pyrolysis technique. The effect of Au doping onto the structural and physicochemical properties has been investigated. The PEC study shows that, both short circuit current (Isc) and open circuit voltage (Voc) are (Isc=1.81mA and Voc=890mV) relatively higher at 3at.% Au doping percentage. XRD study shows that the films are nanocrystalline in nature with tetragonal crystal structure. FESEM images show that the film surface covered with a smooth, uniform, compact and rice shaped nanoparticles. The Au doped thin films exhibit indirect band gap, decreases from 3.23 to 3.09eV with increase in Au doping. The chemical composition and valence states of pure and Au doped TiO2 films are studied by using X-ray photoelectron spectroscopy. The photocatalytic degradation effect is 49% higher in case 3at.% Au doped TiO2 than the pure TiO2 thin film photoelectrodes in the degradation of benzoic acid. It is revealed that Au doped TiO2 can be reused for five cycles of experiments without a requirement of post treatment while the degradation efficiency was retained. PMID- 25550121 TI - Photosensitizer-encapsulated amphiphilic chitosan derivative micelles: photoactivity and enhancement of phototoxicity against human pancreatic cancer cells. AB - Photosensitizer-encapsulated amphiphilic chitosan derivative (Photosan-DA-Chit) micelles with controlled photoactivity have been prepared using a simple self assembly method in phosphate-buffered saline (pH 6.2). The fluorescence quantum yield and fluorescence lifetime of the Photosan-DA-Chit micelles were lower than those of free Photosan, which indicated that the micelles were suppressing the photoactivity of Photosan. However, upon incubation with human pancreatic cancer cells (i.e., Panc-1 cells), the Photosan-DA-Chit micelles showed higher fluorescence activity than free Photosan and generated higher levels of reactive oxygen species under laser illumination. The Photosan-DA-Chit micelles therefore exhibited strong phototoxicity, which led to significant levels of apoptosis in the Panc-1 cells. In the absence of light, however, the Photosan-DA-Chit micelles showed no cytotoxicity. These results indicated that they could be used as a potential photodynamic therapy in pancreatic cancer. PMID- 25550122 TI - Synthesis, molecular structure, theoretical calculation, DNA/protein interaction and cytotoxic activity of manganese(III) complex with 8-hydroxyquinoline. AB - Manganese(III) complex (1) [Mn(8-hq)3] (where 8-hq=8-hydroxyquinoline) has been synthesized and characterized by elemental, spectral (UV-vis, FT-IR) and thermal analysis. The structure of complex (1) has been determined by single crystal X ray diffraction studies and the configuration around manganese(III) ion was elongated octahedral coordination geometry. Density functional theory calculations were performed for ligand and its complex. Binding studies of ligand and complex 1 with calf thymus DNA (CT-DNA) was investigated by absorption, fluorescence, circular dichroic (CD) spectroscopy and viscosity measurements. Absorption spectral studies revealed that ligand and complex 1 binds to DNA groove and its intrinsic binding strength has been found to be 2.57*10(4) and 2.91*10(4)M(-1). A molecular docking study confirm that the complex 1 is a minor groove binder and was stabilized through hydrogen bonding interactions. Complex 1 exhibits a good binding propensity to bovine serum albumin (BSA) protein. The in vitro cytotoxicity study of complex 1 on breast cancer cell line (MCF-7) indicate that it has the potential to act as effective anticancer drug, with IC50 values of 3.25MUM. The ligand and its complex have been screened for antimicrobial activities and the complex showed better antimicrobial activity than the free ligand. PMID- 25550123 TI - Validity of the body adiposity index in adults with Down syndrome. AB - The purpose of this investigation was to determine the agreement between the body adiposity index (BAI) and dual energy X-ray absorptiometry (DXA) for measuring BF% in adults with Down syndrome (DS). Twenty adults (male: n=10; female: n=10) with Down syndrome volunteered to participate in this study. Criterion BF% was determined by DXA and predicted BF% was estimated by the BAI method. There was a significant mean difference (p<0.001) between DXA BF% (39.94+/-10.80%) and the BAI BF% (42.60+/-8.19%). The correlation between the two BF% variables was large and significant (r=0.73, p<0.001). However, the standard error of the estimate and total error was 7.79% and 7.86%, respectively. Additionally, the 95% limits of agreement ranged from 12.21% below to 17.52% above the constant error of 2.65%. Our findings suggest that on average, the BAI significantly overestimated BF% when compared to DXA values. Though there was a strong correlation between both methods, the wide limits of agreement suggest there is large amount of individual error when estimating BF% via the BAI. Therefore, the use of the BAI for individuals with DS does not appear to be accurate for estimating BF%. PMID- 25550124 TI - Focus on the brain of the cardiac arrest survivor. PMID- 25550125 TI - Social and Demographic Factors Influencing Inferior Vena Cava Filter Retrieval at a Single Institution in the United States. AB - PURPOSE: Retrievable inferior vena cava filters (IVCFs) are associated with long term adverse events that have increased interest in improving filter retrieval rates. Determining the influential patient social and demographic factors affecting IVCF retrieval is important to personalize patient management strategies and attain optimal patient care. MATERIALS AND METHODS: Seven-hundred and sixty-two patients were retrospectively studied who had a filter placed at our institution between January 2011 and November 2013. Age, gender, race, cancer history, distance to residence from retrieval institution, and insurance status were identified for each patient, and those receiving retrievable IVCFs were further evaluated for retrieval rate and time to retrieval. RESULTS: Of the 762 filters placed, 133 were permanent filters. Of the 629 retrievable filters placed, 406 met the inclusion criteria and were eligible for retrieval. Results revealed patients with Medicare were less likely to have their filters retrieved (p = 0.031). Older age was also associated with a lower likelihood of retrieval (p < 0.001) as was living further from the medical center (p = 0.027). Patients who were white and had Medicare were more likely than similarly insured black patients to have their filters retrieved (p = 0.024). CONCLUSIONS: The retrieval rate of IVCFs was most influenced by insurance status, distance from the medical center, and age. Race was statistically significant only when combined with insurance status. The results of this study suggest that these patient groups may need closer follow-up in order to obtain optimal IVCF retrieval rates. PMID- 25550128 TI - Blinatumomab approved for rare leukemia. PMID- 25550126 TI - Buprenorphine maintenance treatment retention improves nationally recommended preventive primary care screenings when integrated into urban federally qualified health centers. AB - Buprenorphine maintenance therapy (BMT) expands treatment access for opioid dependence and can be integrated into primary health-care settings. Treating opioid dependence, however, should ideally improve other aspects of overall health, including preventive services. Therefore, we examined how BMT affects preventive health-care outcomes, specifically nine nationally recommended primary care quality health-care indicators (QHIs), within federally qualified health centers (FQHCs) from an observational cohort study of 266 opioid-dependent patients initiating BMT between 07/01/07 and 11/30/08 within Connecticut's largest FQHC network. Nine nationally recommended preventive QHIs were collected longitudinally from electronic health records, including screening for chronic infections, metabolic conditions, and cancer. A composite QHI score (QHI-S), based on the percentage of eligible QHIs achieved, was categorized as QHI-S >=80% (recommended) and >=90% (optimal). The proportion of subjects achieving a composite QHI-S >=80 and >=90 % was 57.1 and 28.6%, respectively. Screening was highest for hypertension (91.0%), hepatitis C (80.1%), hepatitis B (76.3%), human immunodeficiency virus (71.4%), and hyperlipidemia (72.9%) and lower for syphilis (49.3%) and cervical (58.5%), breast (44.4%), and colorectal (48.7%) cancer. Achieving QHI-S >=80% was positively and independently associated with >=3-month BMT retention (adjusted odds ratio (AOR) = 2.19; 95% confidence interval (CI) = 1.18-4.04) and BMT prescription by primary care providers (PCPs) rather than addiction psychiatric specialists (AOR = 3.38; 95% CI = 1.78-6.37), and negatively with being female (AOR = 0.30; 95% CI = 0.16-0.55). Within primary health-care settings, achieving greater nationally recommended health-care screenings or QHIs was associated with being able to successfully retain patients on buprenorphine longer (3 months or more) and when buprenorphine was prescribed simultaneously by PCPs rather than psychiatric specialists. Decreased preventive screening for opioid-dependent women, however, may require gender-based strategies for achieving health-care parity. When patients can be retained, integrating BMT into urban FQHCs is associated with improved health outcomes including increased multiple preventive health-care screenings. PMID- 25550127 TI - Hepatic lipase (LIPC) C-514T gene polymorphism is associated with cardiometabolic parameters and cardiovascular risk factors but not with fatty liver in Mexican population. AB - The aim of the present study was to evaluate the role of the C-514T (rs1800588) gene polymorphism of the hepatic lipase (LIPC) as susceptibility marker for fatty liver in the Mexican population. The polymorphism was genotyped by 5' exonuclease TaqMan assays in a group of 1468 subjects (980 with and 488 without fatty liver) belonging to the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Anthropometric and biochemical measurements were performed on all individuals. The polymorphism was not associated with fatty liver, however, under dominant model, the TT genotype was associated with increased levels of triglycerides (P=0.0002), apolipoprotein A1 (P=0.015), triglycerides/HDL-cholesterol index (P=0.046) and increased frequency of type 2 diabetes mellitus (P=0.045). On the other hand, the same genotype was associated with the presence of small LDLs (P=0.003). The risk analysis showed that under a dominant model, the LIPC C-514T polymorphism was associated with increased risk of type 2 diabetes (OR=1.42, P=0.029), hypertriglyceridemia (OR=1.36, P=0.006), and coronary artery calcification (CAC)>=1 (OR=1.44, P=0.015) and decreased risk of hypoalphalipoproteinemia (OR=0.78, P=0.036). The results suggest that the LIPC C 154T polymorphism is associated with cardiometabolic parameters and cardiovascular risk factors but not with fatty liver in Mexican population. The association detected with CAC indicates that this polymorphism could be a marker for subclinical atherosclerosis. PMID- 25550129 TI - Pharmacists praise new Medicare billing opportunities: provider status still critical, they say. PMID- 25550130 TI - Pharmacists integrate into geriatric emergency department. PMID- 25550131 TI - Writing meeting minutes for a pharmacy and therapeutics committee and its subcommittees. PMID- 25550132 TI - Trametinib: a novel signal transduction inhibitor for the treatment of metastatic cutaneous melanoma. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, administration, cost, and place in therapy of trametinib for the treatment of metastatic melanoma are reviewed. SUMMARY: Approximately 40-60% of malignant melanomas have gene mutations at codon 600 of the BRAF gene that result in the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is the first-in-class mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that targets a kinase in the MAPK pathway that plays a key role in oncogenic cell proliferation, survival, invasion, tumor angiogenesis, and escape from apoptosis. It is approved by the Food and Drug Administration for use in patients whose tumors express the BRAF V600E or V600K gene mutations. Moreover, trametinib is also indicated for use in combination with dabrafenib (a BRAF inhibitor). Trametinib is not indicated in patients who have received prior BRAF inhibitor therapy due to poor response and possible cross-resistance. The most common adverse effects associated with the use of trametinib for both monotherapy and combination therapy are rash, diarrhea, peripheral edema, fatigue, and dermatitis. The recommended dosage of trametinib monotherapy is 2 mg orally once daily until disease progression or unacceptable toxicity occurs. With a daily dose of 2 mg, an estimated 30-day course of treatment would cost approximately $9135. CONCLUSION: Trametinib, a novel MEK inhibitor, provides an alternative therapy for patients with BRAF V600 E/K metastatic melanoma as a single agent or in combination therapy for patients not previously treated with a BRAF inhibitor. More studies are needed to determine the safe and effective combination or sequencing of trametinib with other therapies. PMID- 25550133 TI - Influenza treatment with oseltamivir outside of labeled recommendations. AB - PURPOSE: Published evidence regarding the use of the antiinfluenza agent oseltamivir outside of the standard dosing recommendations is reviewed. SUMMARY: Oseltamivir is a neuraminidase inhibitor indicated for the treatment of uncomplicated influenza in patients two weeks of age or older who have been symptomatic for no more than two days; the recommended dosage is 75 mg twice daily by mouth for five days. A literature search identified six studies evaluating the effects of administering oseltamivir 48 hours or more after the onset of influenza symptoms, administering the drug at double the standard dose, or continuing therapy for more than five days. Two randomized controlled trials found that double-dose oseltamivir therapy conferred no significant survival benefit. The results of one retrospective study of intensive care unit (ICU) patients infected with the influenza H1N1 strain suggested improved survival among those who received oseltamivir no later than five days after symptom onset. CONCLUSION: Oseltamivir may increase survival when used within five days of symptom onset in influenza H1N1-infected patients who require ICU admission. There appears to be no benefit in starting treatment more than 48 hours after symptom onset in hospitalized general medicine patients or outpatients infected with either H1N1 or other influenza strains or in doubling the dose of oseltamivir in hospitalized patients or outpatients. There are scant data supporting the use of oseltamivir for longer than five days in any patient population, with the possible exception of critically ill H1N1-infected ICU patients, who may benefit from extended treatment in some cases. PMID- 25550134 TI - Safe and effective use of eculizumab in the treatment of severe Shiga toxin Escherichia coli-associated hemolytic uremic syndrome. AB - PURPOSE: A severe case of Shiga toxin Escherichia coli (STEC)-associated hemolytic uremic syndrome (HUS) successfully treated with eculizumab is reported. SUMMARY: An 18-year-old man was admitted to the intensive care unit with HUS due to laboratory-confirmed STEC O121. He was initially treated with plasmapheresis and required hemodialysis for anuric acute kidney injury. Plasmapheresis was stopped due to complications. He continued to show evidence of ongoing hemolysis and kidney injury. Due to the lack of clinical improvement in renal function and hematologic status as well as the severity of the patient's symptoms, the decision was made to initiate eculizumab. The patient was given i.v. eculizumab 900 mg infused over 35 minutes weekly for four weeks, followed by 1200 mg infused over 35 minutes one week later as the fifth dose and then every two weeks thereafter. The patient also received i.v. ciprofloxacin 400 mg infused over 60 minutes once every 24 hours for meningococcal prophylaxis and bacterial eradication. After initiation of eculizumab, the patient's platelet count rapidly improved. After three doses of eculizumab, the patient's renal function improved, and further hemodialysis was no longer required. The patient continued to receive twice-monthly eculizumab infusions to complete a two-month treatment course (seven doses), at which point his renal function returned to baseline. The initial two infusions were administered as an inpatient, and the remainder was infused in the outpatient setting. CONCLUSION: An 18-year-old man who developed severe HUS due to STEC O121 and was unresponsive to traditional supportive therapies was successfully treated with eculizumab. PMID- 25550135 TI - Comparison of free fraction serum valproic acid concentrations between inpatients and outpatients. AB - PURPOSE: The differences in free fraction serum valproic acid concentrations between inpatients and outpatients were compared, and factors associated with therapeutic discordance were evaluated. METHODS: This retrospective, single center, cross-sectional study included patients with both a free and a total valproic acid concentration drawn within 30 minutes of each other between January 7, 2003, and June 1, 2011. Serum valproic acid concentrations were stratified by admission status (inpatient versus outpatient). In the primary analysis, for patients who had multiple paired concentrations drawn, one free valproic acid level and one total valproic acid level (i.e., one pair) were chosen at random for each inpatient. Information regarding patient demographics, laboratory data, and concomitant medication therapy was collected. Single and multivariable logistic regressions were performed to determine the odds of therapeutic discordance. RESULTS: During the study period, inpatient concentrations were measured in 220 patients, and outpatient concentrations were measured in 41 patients. The median total valproic acid concentration in the inpatient group was significantly lower than that in the outpatient group (54 MUg/mL versus 83 MUg/mL, p < 0.001). The median free fraction of inpatient levels was nearly twice as high as that of outpatient levels (28.8% versus 15.5%, p < 0.001). Levels drawn in inpatients were therapeutically discordant 63% of the time compared to only 19% in outpatients (p < 0.001). Multivariable logistic regression identified low albumin as an independent risk factor for therapeutic discordance. CONCLUSION: The median free fraction of valproic acid was significantly higher in inpatients than in outpatients. Low albumin concentration was a predictor of discordance between free and total valproic acid concentrations. PMID- 25550136 TI - Building an outpatient cancer center pharmacy program across a tristate region. AB - PURPOSE: The transition to a hybrid model of oncology pharmacy services including remote order verification across a regional network of cancer centers is described. SUMMARY: Five years ago the University of Pittsburgh Medical Center (UPMC) began a major expansion of its cancer care services, gradually integrating 19 community-based physician practice sites into its tristate oncology network as affiliated hospital-based clinics (HBCs). The network expansion was achieved through a stepwise process including (1) development of oncology medication protocols, (2) interdisciplinary efforts to modify oncology care workflows, (3) implementation of a hybrid practice model to optimize the use of clinical pharmacy resources, and (4) focused staff training programs. Under the hybrid practice model, first checks of antineoplastic medication orders, premedication orders, and laboratory values are performed by either onsite or remote pharmacists, with all second checks performed remotely. In 2013, network pharmacists implemented large numbers of medication therapy interventions to improve chemotherapy and biological response modifier dosing (n = 641) and nonchemotherapy medication use (n = 1082); other documented interventions included patient counseling to help optimize the use of erythropoietin stimulating agents and other medications (n = 441) and anticoagulation-related dosing adjustments and patient education (n = 102). CONCLUSION: Nineteen ambulatory care centers were successfully integrated into the UPMC oncology network as affiliated HBCs through a stepwise process that included workflow modifications, staff training, and a hybrid pharmacy services model that ensures a two-pharmacist check of antineoplastic orders in accordance with regulatory and quality standards. PMID- 25550137 TI - Effect of computerized prescriber order entry on pharmacy: experience of one health system. AB - PURPOSE: Pharmacists' satisfaction with a computerized prescriber order-entry (CPOE) system and the impact of CPOE on pharmacy workflows and order verification were investigated. SUMMARY: A mixed-method study was conducted to evaluate the implementation of a CPOE system in three hospitals of a large Michigan-based health system and early user experience with the system. Surveys of pharmacists before (n = 54) and after (n = 42) CPOE implementation indicated that they held generally positive expectations about CPOE prior to and during system implementation and continued to hold positive views about CPOE after several months of system use. In interviews and focus group discussions, pharmacists reported a number of important CPOE benefits, but they also cited challenges related to CPOE provider alerts, uncertainty about medication timing, and the need to support providers by serving as informal CPOE system trainers. Direct observation of pharmacists before and after CPOE implementation indicated decreases in both the rate of order clarification events (from 0.89 to 0.35 per hour, p < 0.001) and the average time spent per hour clarifying orders (from 4.75 to 2.11 minutes, p = 0.008). CONCLUSION: Several months after CPOE implementation, pharmacists indicated that several aspects of their workload had improved, including the process of medication order clarification, their ability to prioritize work, and their ability to move around within the hospital to respond to demand. However, pharmacists also noted that order ambiguity still existed and that the system needed to be optimized to gain efficiencies and increase clarity. PMID- 25550138 TI - Reduction of clinical support warnings through recategorization of severity levels. AB - PURPOSE: Study results indicating that non-clinically significant alerts generated by clinical support systems can be reduced by recategorizing alert severity levels, thereby decreasing alert fatigue, are presented. METHODS: In a single-site retrospective pre-post study, all drug-drug interaction alerts displayed by a medical center's clinical support system over a three-month baseline period were evaluated by a multidisciplinary expert panel. Based on a review of pharmaceutical package inserts and other evidence, the panel reduced the severity ranking of 99 of the 201 most frequently triggered alerts with the aim of reducing nonactionable alerts (i.e., alerts viewed but not resulting in a clinical intervention such as the discontinuation of a medication, a dose reduction, or the ordering of a laboratory test). Alert frequencies and types during the baseline period and a one-month period after adjustment of the alert severity rankings were compared to characterize the distribution of alert override responses. RESULTS: Comparison of drug-drug interaction alerts before (n = 8023) and after (n = 7270) alert recategorization indicated significant differences in pharmacists' documentation of override responses in four evaluated categories (p < 0.001 for all comparisons); notably, alerts overrides in the "not clinically significant" category declined 22%. No significant difference was detected in the numbers of reported medication errors related to clinically significant drug-drug interaction alerts before and after alert recategorization. CONCLUSION: Reducing the number of nonactionable drug-drug interaction alerts by recategorizing alert severity levels decreased alert overrides by 6%. PMID- 25550139 TI - Assessing the self-development potential of a pharmacy management practitioner through self-assessment survey. AB - PURPOSE: The self-development potential of pharmacy management practitioners related to self-management, team development, and network management was assessed. METHODS: A survey instrument consisting of 12 self-assessment questions and 11 questions about demographics was distributed to pharmacy management practitioners to assess their abilities to manage themselves, their teams, and their networks. The tool was distributed by e-mail hyperlink to 190 potential respondents. Only surveys from respondents who had a pharmacy degree and direct supervisory capacity were analyzed. Respondents rated their progress toward meeting the three imperatives on a scale of 1-5. Responses to the questions were analyzed as ordinal data, with median responses used for assessment. RESULTS: A total of 160 responses were received via e-mail, 149 (93%) of which met the inclusion criteria. About half of all respondents were practicing at institutions of 600 beds or more and supervised at least five employees. The majority of respondents identified their abilities to manage themselves, their teams, and their networks as areas of strength but also acknowledged that using all three of these skills on a daily basis was an area of opportunity. Respondents generally identified management of their network as an area needing work. CONCLUSION: The majority of survey respondents identified their skills in self-, team, and network management as areas of strength. Respondents generally identified management of their network as an area needing work. Respondents also identified the use of all three imperatives on a daily basis as an area of opportunity for improvement. PMID- 25550140 TI - Implementation of a comprehensive medication prior-authorization service. AB - PURPOSE: The development and successful implementation of a comprehensive medication prior-authorization service are described. SUMMARY: At our 550-bed academic medical center, we found an increasing number of Medicare write-offs as a result of the off-label use of specialty medications. Furthermore, more insurers were requiring that prior authorization be attained before patients began treatment with a high-cost specialty medication. After investigating who was pursuing these prior authorizations and where they were documented, it became clear that no department within the hospital owned this responsibility. Our pharmacy department initiated a specialty medication prior-authorization and medication assistance program to review all medication orders written for high cost specialty medications administered or infused in any of the health system's outpatient clinics, including chemotherapy infusions. A full-time specialty pharmacy coordinator was hired in fall 2010. This pharmacist was responsible for spearheading the overall specialty medication strategy for the health system. Our prior-authorization work across our health system has not only helped to reduce Medicare write-offs and commercial insurance denials but also has resulted in closer working relationships with individuals in other departments of the hospital. Several million dollars in additional write-offs were avoided because our prior-authorization staff identified prescribed therapies that would not be covered by Medicare or commercial insurers before they were started. In total, we decreased write-offs or increased revenues by over $6.2 million during this time frame, a return on investment exceeding 20:1. CONCLUSION: A comprehensive medication prior-authorization service generated additional revenue due to a decrease in lost charges and an increase in net reimbursement. PMID- 25550141 TI - Impact of BRCA1/2 mutation on young women's 5-year parenthood rates: a prospective comparative study (GENEPSO-PS cohort). AB - Previous qualitative and intentions surveys have shown that the disclosure of a BRCA1/2 mutation might deter young women from becoming pregnant. However, to our knowledge, no comparative studies have ever documented the possibility that positive genetic test results might affect these women's future reproductive rates. Our aim was therefore to quantify the impact of BRCA1/2 mutation disclosure on long-term relationships between partners and childbearing rates. Participants were cancer-free women belonging to families in which a deleterious BRCA1/2 mutation had been identified, who had attended one of the 29 participating cancer genetic clinics for BRCA1/2 testing between 2000 and 2006. Logistic regression models were used to determine predictors of the 5-year self reported parenthood rate. The sample consisted of 271 women aged 18-45 years (126 BRCA1/2 mutation carriers and 145 non-carriers). Couples had separated more frequently among BRCA1/2 carriers than non-carriers (10 vs. 3%, p = .040), especially among nulliparous carriers (13%). Among the 104 women who were childless at disclosure, disclosure of a BRCA1/2 mutation was not significantly associated with childbearing during the 5-year follow-up period [adjusted odds ratio .64, 95% confidence interval (CI) (.26, 1.57), p = .334]. Among the 167 women with at least one child at disclosure of a BRCA1/2 mutation had no conspicuous effect on the childbearing trends [adjOR .88, 95% CI (.35, 2.21), p = .787]. The disclosure of a BRCA1/2 mutation might impact couples' relationships and future mothering rates, particularly among nulliparous women. Studies on larger populations are now required to confirm these findings. PMID- 25550142 TI - Hispanic older adult mortality in the United States: new estimates and an assessment of factors shaping the Hispanic paradox. AB - Hispanics make up a rapidly growing proportion of the U.S. older adult population, so a firm grasp of their mortality patterns is paramount for identifying racial/ethnic differences in life chances in the population as a whole. Documentation of Hispanic mortality is also essential for assessing whether the Hispanic paradox--the similarity in death rates between Hispanics and non-Hispanic whites despite Hispanics' socioeconomic disadvantage--characterizes all adult Hispanics or just some age, gender, nativity, or national-origin subgroups. We estimate age-/sex- and cause-specific mortality rate ratios and life expectancy for foreign-born and U.S.-born Hispanics, foreign-born and U.S. born Mexican Americans, non-Hispanic blacks, and non-Hispanic whites ages 65 and older using the 1989-2006 National Health Interview Survey Linked Mortality Files. Results affirm that Hispanic mortality estimates are favorable relative to those of blacks and whites, but particularly so for foreign-born Hispanics and smoking-related causes. However, if not for Hispanics' socioeconomic disadvantage, their mortality levels would be even more favorable. PMID- 25550143 TI - The Non-uniqueness Property of the Intrinsic Estimator in APC Models. AB - This article explores an important property of the intrinsic estimator that has received no attention in literature: the age, period, and cohort estimates of the intrinsic estimator are not unique but vary with the parameterization and reference categories chosen for these variables. We give a formal proof of the non-uniqueness property for effect coding and dummy variable coding. Using data on female mortality in the United States over the years 1960-1999, we show that the variation in the results obtained for different parameterizations and reference categories is substantial and leads to contradictory conclusions. We conclude that the non-uniqueness property is a new argument for not routinely applying the intrinsic estimator. PMID- 25550146 TI - Facial Structure Predicts Sexual Orientation in Both Men and Women. AB - Biological models have typically framed sexual orientation in terms of effects of variation in fetal androgen signaling on sexual differentiation, although other biological models exist. Despite marked sex differences in facial structure, the relationship between sexual orientation and facial structure is understudied. A total of 52 lesbian women, 134 heterosexual women, 77 gay men, and 127 heterosexual men were recruited at a Canadian campus and various Canadian Pride and sexuality events. We found that facial structure differed depending on sexual orientation; substantial variation in sexual orientation was predicted using facial metrics computed by a facial modelling program from photographs of White faces. At the univariate level, lesbian and heterosexual women differed in 17 facial features (out of 63) and four were unique multivariate predictors in logistic regression. Gay and heterosexual men differed in 11 facial features at the univariate level, of which three were unique multivariate predictors. Some, but not all, of the facial metrics differed between the sexes. Lesbian women had noses that were more turned up (also more turned up in heterosexual men), mouths that were more puckered, smaller foreheads, and marginally more masculine face shapes (also in heterosexual men) than heterosexual women. Gay men had more convex cheeks, shorter noses (also in heterosexual women), and foreheads that were more tilted back relative to heterosexual men. Principal components analysis and discriminant functions analysis generally corroborated these results. The mechanisms underlying variation in craniofacial structure--both related and unrelated to sexual differentiation--may thus be important in understanding the development of sexual orientation. PMID- 25550145 TI - Motivations to test for HIV among partners in concordant HIV-negative and HIV discordant gay male couples. AB - Previous studies of HIV testing among gay men describe the motivations, facilitators and barriers, behaviors, and demographic characteristics of individuals who test. What little research focuses on HIV testing among gay men in relationships shows that they do not test regularly or, in some cases, at all their motivations to test have not been investigated. With so little data on HIV testing for this population, and the continued privileging of individually focused approaches, gay men in relationships fall into a blind spot of research and prevention efforts. This study examined motivations to test for HIV using qualitative data from both partners in 20 gay male couples. Analysis revealed that the partners' motivations were either event-related (e.g., participants testing at the beginning of their relationship or HIV-negative participants in an HIV-discordant relationship testing after risky episode with their discordant primary partner) or partner-related (e.g., participants testing in response to a request or suggestion to test from their primary partner or participants testing out of concern for their primary partner's health and well-being). These data provide insight into relationship-oriented motivations to test for HIV for gay men in relationships and, in doing so, evidence their commitment to their primary partner and relationship. These motivations can be leveraged to increase HIV testing among gay men in relationships, a population that tests less often than single gay men, yet, until recently, has been underserved by prevention efforts. PMID- 25550147 TI - Transcranial direct current stimulation based metaplasticity protocols in working memory. AB - BACKGROUND: It has been already shown that delivering tDCS that are spaced by an interval alters its impact on motor plasticity. These effects can be explained, based on metaplasticity in which a previous modification of activity in a neuronal network can change the effects of subsequent interventions in the same network. But to date there is limited data assessing metaplasticity effects in cognitive functioning. OBJECTIVES: The aim of this study was to test several tDCS based metaplasticity protocols in working memory (WM), by studying the impact of various interstimulation intervals in the performance of a 3-back task. METHODS: Fifteen healthy volunteers per experiment participated in this study. Experiments 1 and 2 tested an anodal tDCS-induced metaplasticity protocol (1 mA, 10 + 10') with 3 interstimulation intervals (10, 30, and 60 min). Experiment 3 determined the effects of a similar protocol-with a 10-min interval between two sessions of cathodal tDCS or anodal plus cathodal tDCS (1 mA, 10 + 10'). RESULTS: Two consecutive sessions of anodal tDCS delivered with a 10 min interval between them did not improve WM performance (P = .095). This effect remained the same if the interval was increased to 30 or 60 min. In contrast, when a 10 min interval was given between two consecutive cathodal tDCS sessions, performance in the 3 back task increased (P = .042). CONCLUSIONS: These results suggest that the polarity effects of tDCS on working memory are dependent on the previous level of activity of the recruited neural population. PMID- 25550144 TI - Phylogeny and biogeography of wild roses with specific attention to polyploids. AB - BACKGROUND AND AIMS: The genus Rosa (150-200 species) is widely distributed throughout temperate and sub-tropical habitats from the northern hemisphere to tropical Asia, with only one tropical African species. In order to better understand the evolution of roses, this study examines infrageneric relationships with respect to conventional taxonomy, considers the extent of allopolyploidization and infers macroevolutionary processes that have led to the current distribution of the genus. METHODS: Phylogenetic relationships among 101 species of the genus Rosa were reconstructed using sequences from the plastid psbA-trnH spacer, trnL intron, trnL-F spacer, trnS-G spacer and trnG intron, as well as from nuclear glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which was used to identify putative allopolyploids and infer their possible origins. Chloroplast phylogeny was used to estimate divergence times and reconstruct ancestral areas. KEY RESULTS: Most subgenera and sections defined by traditional taxonomy are not monophyletic. However, several clades are partly consistent with currently recognized sections. Allopolyploidy seems to have played an important role in stabilizing intersectional hybrids. Biogeographic analyses suggest that Asia played a central role as a genetic reservoir in the evolution of the genus Rosa. CONCLUSIONS: The ancestral area reconstruction suggests that despite an early presence on the American continent, most extant American species are the results of a later re-colonization from Asia, probably through the Bering Land Bridge. The results suggest more recent exchanges between Asia and western North America than with eastern North America. The current distribution of roses from the Synstylae lineage in Europe is probably the result of a migration from Asia approx. 30 million years ago, after the closure of the Turgai strait. Directions for a new sectional classification of the genus Rosa are proposed, and the analyses provide an evolutionary framework for future studies on this notoriously difficult genus. PMID- 25550148 TI - Abstract-to-publication ratio and predictors for publication success for papers presented at the Italian Emergency Medicine Meeting: a cross-sectional study. PMID- 25550149 TI - Building the avian tree of life using a large-scale, sparse supermatrix. AB - Birds are the most diverse tetrapod class, with about 10,000 extant species that represent a remarkable evolutionary radiation in which most taxa arose during a short period of time. There has been a tremendous increase in the amount of molecular data available from birds, and more than two-thirds of these species have some sequence data available. Here we assembled these available sequence data from birds to estimate a large-scale avian phylogeny. We performed an unconstrained maximum likelihood analysis of a sparse supermatrix comprising 22 nuclear loci and seven mitochondrial regions from 6714 species. We inferred a phylogeny with a backbone remarkably similar to that obtained by detailed analyses of multigene datasets, yet with the addition of thousands of more taxa. All orders were monophyletic with generally high support. While most families and genera were well supported, a number of them, especially within the oscine passerines, had little or no support. This likely reflects problems with the circumscription of these genera and families. Our results indicate that the amount of sequence data currently available is sufficient to produce a robust estimate of the avian tree of life using current methods of inference. The availability of a tree that is unconstrained by prior information, with branch lengths that have a direct connection to the underlying data, should be useful for comparative methods, taxonomic revisions, and prioritizing taxa that should be targeted for additional data collection. PMID- 25550150 TI - Development of a multilocus sequence typing scheme for the study of Anaplasma marginale population structure over space and time. AB - Bovine Anaplasmosis caused by Anaplasma marginale is a worldwide disease prevalent in tropical and subtropical regions where Rhipicephalus microplus is considered the most significant biological vector. Molecular markers previously applied for A. marginale typing are efficient for isolate discrimination but they are not a suitable tool for studying population structure and dynamics. Here we report the development of an MLST scheme based on the study of seven genes: dnaA, ftsZ, groEl, lipA, recA, secY and sucB. Five annotated genomes (Saint Maries, Florida, Mississippi, Puerto Rico and Virginia) and 53 bovine blood samples from different world regions were analyzed. High nucleotide diversity and a large proportion of synonymous substitutions, indicative of negative selection resulted from DnaSP 5.00.02 package application. Recombination events were detected in almost all genes, this evidence together with the coexistence of more than one A. marginale strain in the same sample might suggest the superinfection phenomena as a potential source of variation. The allelic profile analysis performed through GoeBURST shown two main CC that did not support geography. In addition, the AMOVA test confirmed the occurrence of at least two main genetically divergent groups. The composition of the emergent groups reflected the impact of both historical and environmental traits on A. marginale population structure. Finally, a web based platform "Galaxy MLST-Pipeline" was developed to automate DNA sequence editing and data analysis that together with the Data Base are freely available to users. The A. marginale MLST scheme developed here is a valuable tool with a high discrimination power, besides PCR based strategies are still the better choice for epidemiological intracellular pathogens studies. Finally, the allelic profile describe herein would contribute to uncover the mechanisms in how intracellular pathogens challenge virulence paradigm. PMID- 25550152 TI - Cognitive behaviorism: a tribute to the contributions of Thomas Zentall. PMID- 25550151 TI - Identification of the source of A (H10N8) virus causing human infection. AB - A novel H10N8 influenza A virus has been detected in three humans in China since December 2013. Although this virus was hypothesized to be a novel reassortant among influenza viruses from wild birds and domestic poultry, its evolutionary path leading to human infection is unknown. Sporadic surveillance at the live poultry market (LPM) suspected to be the source of infection for the first H10N8 patient has shown a gradual increase in influenza virus prevalence culminating with a predominance of H10N8 viruses. Influenza viruses detected in the LPM up to 8 months prior to human infection contributed genetic components to the zoonotic virus. These H10N8 viruses have continued to evolve within this LPM subsequent to the human infection, and continuous assessments of these H10N8 viruses will be necessary. Serological surveillance showed that the virus appears to have been present throughout the LPM system in Nanchang, China. Reduction of the influenza virus burden in LPMs is essential in preventing future emergence of novel influenza viruses with zoonotic and pandemic potential. PMID- 25550153 TI - Bioreducible core-crosslinked hyaluronic acid micelle for targeted cancer therapy. AB - For drug delivery nanocarriers to be a safe and effective therapeutic option, blood stability, tumor-targetability, and intracellular drug release features should be considered. In this study, to develop a potent drug delivery carrier that can meet the multiple requirements, we engineered a bioreducible core crosslinked polymeric micelle based on hyaluronic acid (CC-HAM) by a facile method using d,l-dithiothreitol in aqueous conditions. The CC-HAM exhibited enhanced structural stability under diluted conditions with PBS containing FBS or sodium dodecyl sulfates. We also successfully encapsulated doxorubicin (DOX), chosen as a hydrophobic anti-cancer drug, in CC-HAMs with high loading efficiency (>80%). The drug release rate of CC-HAMs was rapidly accelerated in the presence of glutathione, whereas the drug release was significantly retarded in physiological buffer (pH7.4). An in vivo biodistribution study demonstrated the superior tumor targetability of CC-HAMs to that of non-crosslinked HAMs, primarily ascribed to robust stability of CC-HAMs in the bloodstream. Notably, these results correspond with the improved pharmacokinetics and tumor accumulation of DOX-loaded CC-HAMs as well as their excellent therapeutic efficacy. Overall, these results suggest that the robust, bioreducible CC-HAM can be applied as a potent doxorubicin delivery carrier for targeted cancer therapy. PMID- 25550154 TI - A novel collagen-nanohydroxyapatite microRNA-activated scaffold for tissue engineering applications capable of efficient delivery of both miR-mimics and antagomiRs to human mesenchymal stem cells. AB - Manipulation of gene expression through the use of microRNAs (miRNAs) offers tremendous potential for the field of tissue engineering. However, the lack of sufficient site-specific and bioactive delivery systems has severely hampered the clinical translation of miRNA-based therapies. In this study, we developed a novel non-viral bioactive delivery platform for miRNA mimics and antagomiRs to allow for a vast range of therapeutic applications. By combining nanohydroxyapatite (nHA) particles with reporter miRNAs (nanomiRs) and collagen nanohydroxyapatite scaffolds, this work introduces the first non-viral, non-lipid platform to date, capable of efficient delivery of mature miRNA molecules to human mesenchymal stem cells (hMSCs), a particularly difficult cell type to transfect effectively, with minimal treatment-associated cytotoxicity. Firstly, miRNAs were successfully delivered to hMSCs in monolayer, with internalisation efficiencies of 17.4 and 39.6% for nanomiR-mimics and nanoantagomiRs respectively, and both nanomiR-mimics and nanoantagomiRs yielded sustained interfering activity of greater than 90% in monolayer over 7 days. When applied to 3D scaffolds, significant RNA interference of 20% for nanomiR-mimics and 88.4% for nanoantagomiRs was achieved with no cytotoxicity issues over a 7 day period. In summary, in-house synthesised non-viral nHA particles efficiently delivered reporter miRNAs both in monolayer and on scaffolds demonstrating the immense potential of this innovative miRNA-activated scaffold system for tissue engineering applications. PMID- 25550155 TI - Quantitative 3D molecular cutaneous absorption in human skin using label free nonlinear microscopy. AB - Understanding the penetration mechanisms of drugs into human skin is a key issue in pharmaceutical and cosmetics research. To date, the techniques available for percutaneous penetration of compounds fail to provide a quantitative 3D map of molecular concentration distribution in complex tissues as the detected microscopy images are an intricate combination of concentration distribution and laser beam attenuation upon deep penetration. Here we introduce and validate a novel framework for imaging and reconstructing molecular concentration within the depth of artificial and human skin samples. Our approach combines the use of deuterated molecular compounds together with coherent anti-Stokes Raman scattering spectroscopy and microscopy that permits targeted molecules to be unambiguously discriminated within skin layers. We demonstrate both intercellular and transcellular pathways for different active compounds, together with in-depth concentration profiles reflecting the detailed skin barrier architecture. This method provides an enabling platform for establishing functional activity of topically applied products. PMID- 25550156 TI - Late pregnancy progesterone treatment as a modulatory signal for postpartum behavior. AB - Changes in plasma progesterone levels during late pregnancy are a determining factor in the expression of maternal behavior during lactation. Previous studies showed that mild opioidergic stimulation during late pregnancy makes lactating females more sensitive to opioidergic-induced inhibition of maternal behavior and more willing to display hunting behavior. Such previous behaviorally meaningful opioidergic stimulation also selectively increased serum progesterone levels. The present study tested whether progesterone treatment during late pregnancy interferes with the display of maternal behavior and behavioral selection during lactation. In Experiment 1, rats were treated with progesterone (400 and 500 MUg per day) from the 17th day to the 22nd day of pregnancy. The lowest progesterone dose did not interfere with pregnancy or parturition, and this dose was used in Experiments 2 and 3, in which the rats were treated with subcutaneous progesterone or peanut oil for 5 days beginning on pregnancy day 17. On day 5 of lactation, dams were challenged with subcutaneous morphine (1.5 mg/kg), or saline. The rats were then tested for maternal care (Experiment 2) or behavioral selection with pups and cockroaches (Experiment 3). Animals treated with progesterone during late pregnancy and challenged with morphine during lactation exhibited a significant decrease in maternal behavior in both Experiments 2 and 3. Predatory hunting was not modified by progesterone treatment. These results indicate that sensitivity to opioidergic-mediated inhibition of maternal behavior is enhanced by prepartum progesterone administration. Thus progesterone might be part of the opioid-triggered prepartum signaling leading to behavioral changes during lactation. PMID- 25550157 TI - SHARPIN overexpression induces tumorigenesis in human prostate cancer LNCaP, DU145 and PC-3 cells via NF-kappaB/ERK/Akt signaling pathway. AB - SHARPIN emerges higher expression in prostate cancerous tissues than in benign prostate hyperplasia by means of immunohistochemistry in our previous study. In this work, we performed the gain of function assay and find that overexpression of SHARPIN in LNCaP, DU145 and PC-3 cells promoted cell proliferation, invasiveness and reduced apoptosis. Furthermore, SHARPIN overexpression displayed elevated Bcl-2 and Survivin expression and reduced levels of Bax, cleaved caspase 3. Meanwhile, entropic expression of SHARPIN increased the levels of phosphorylated p65, IkBalpha, ERK and Akt, were selectively increased in these cells. Collectively, our study unraveled the ability of SHARPIN overexpression to induce tumorigenesis of prostate cancer cells through the NF-kB/ERK/Akt pathway and transformation of apoptosis-associated proteins. PMID- 25550158 TI - Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression. AB - Sodium taurocholate cotransporting polypeptide (NTCP) is an entry receptor for hepatitis B virus (HBV) and is regarded as one of the determinants that confer HBV permissiveness to host cells. However, how host factors regulate the ability of NTCP to support HBV infection is largely unknown. We aimed to identify the host signaling that regulated NTCP expression and thereby permissiveness to HBV. Here, a cell-based chemical screening method identified that Ro41-5253 decreased host susceptibility to HBV infection. Pretreatment with Ro41-5253 inhibited the viral entry process without affecting HBV replication. Intriguingly, Ro41-5253 reduced expression of both NTCP mRNA and protein. We found that retinoic acid receptor (RAR) regulated the promoter activity of the human NTCP (hNTCP) gene and that Ro41-5253 repressed the hNTCP promoter by antagonizing RAR. RAR recruited to the hNTCP promoter region, and nucleotides -112 to -96 of the hNTCP was suggested to be critical for RAR-mediated transcriptional activation. HBV susceptibility was decreased in pharmacologically RAR-inactivated cells. CD2665 showed a stronger anti-HBV potential and disrupted the spread of HBV infection that was achieved by continuous reproduction of the whole HBV life cycle. In addition, this mechanism was significant for drug development, as antagonization of RAR blocked infection of multiple HBV genotypes and also a clinically relevant HBV mutant that was resistant to nucleoside analogs. Thus, RAR is crucial for regulating NTCP expression that determines permissiveness to HBV infection. This is the first demonstration showing host regulation of NTCP to support HBV infection. PMID- 25550159 TI - Crystal structure of the human primase. AB - DNA replication in bacteria and eukaryotes requires the activity of DNA primase, a DNA-dependent RNA polymerase that lays short RNA primers for DNA polymerases. Eukaryotic and archaeal primases are heterodimers consisting of small catalytic and large accessory subunits, both of which are necessary for RNA primer synthesis. Understanding of RNA synthesis priming in eukaryotes is currently limited due to the lack of crystal structures of the full-length primase and its complexes with substrates in initiation and elongation states. Here we report the crystal structure of the full-length human primase, revealing the precise overall organization of the enzyme, the relative positions of its functional domains, and the mode of its interaction with modeled DNA and RNA. The structure indicates that the dramatic conformational changes in primase are necessary to accomplish the initiation and then elongation of RNA synthesis. The presence of a long linker between the N- and C-terminal domains of p58 provides the structural basis for the bulk of enzyme's conformational flexibility. Deletion of most of this linker affected the initiation and elongation steps of the primer synthesis. PMID- 25550160 TI - F-ATPase of Drosophila melanogaster forms 53-picosiemen (53-pS) channels responsible for mitochondrial Ca2+-induced Ca2+ release. AB - Mitochondria of Drosophila melanogaster undergo Ca(2+)-induced Ca(2+) release through a putative channel (mCrC) that has several regulatory features of the permeability transition pore (PTP). The PTP is an inner membrane channel that forms from F-ATPase, possessing a conductance of 500 picosiemens (pS) in mammals and of 300 pS in yeast. In contrast to the PTP, the mCrC of Drosophila is not permeable to sucrose and appears to be selective for Ca(2+) and H(+). We show (i) that like the PTP, the mCrC is affected by the sense of rotation of F-ATPase, by Bz-423, and by Mg(2+)/ADP; (ii) that expression of human cyclophilin D in mitochondria of Drosophila S2R(+) cells sensitizes the mCrC to Ca(2+) but does not increase its apparent size; and (iii) that purified dimers of D. melanogaster F-ATPase reconstituted into lipid bilayers form 53-pS channels activated by Ca(2+) and thiol oxidants and inhibited by Mg(2+)/gamma-imino ATP. These findings indicate that the mCrC is the PTP of D. melanogaster and that the signature conductance of F-ATPase channels depends on unique structural features that may underscore specific roles in different species. PMID- 25550161 TI - Transmission of atherosclerosis susceptibility with gut microbial transplantation. AB - Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility. PMID- 25550163 TI - Structure-guided mutational analysis of gene regulation by the Bacillus subtilis pbuE adenine-responsive riboswitch in a cellular context. AB - Riboswitches are a broadly distributed form of RNA-based gene regulation in Bacteria and, more rarely, Archaea and Eukarya. Most often found in the 5'-leader sequence of bacterial mRNAs, they are generally composed of two functional domains: a receptor (aptamer) domain that binds an effector molecule and a regulatory domain (or expression platform) that instructs the expression machinery. One of the most studied riboswitches is the Bacillus subtilis adenine responsive pbuE riboswitch, which regulates gene expression at the transcriptional level, up-regulating expression in response to increased intracellular effector concentrations. In this work, we analyzed sequence and structural elements that contribute to efficient ligand-dependent regulatory activity in a co-transcriptional and cellular context. Unexpectedly, we found that the P1 helix, which acts as the antitermination element of the switch in this RNA, supported ligand-dependent activation of a reporter gene over a broad spectrum of lengths from 3 to 10 bp. This same trend was also observed using a minimal in vitro single-turnover transcription assay, revealing that this behavior is intrinsic to the RNA sequence. We also found that the sequences at the distal tip of the terminator not directly involved in alternative secondary structure formation are highly important for efficient regulation. These data strongly support a model in which the switch is highly localized to the P1 helix adjacent to the ligand-binding pocket that likely presents a local kinetic block to invasion of the aptamer by the terminator. PMID- 25550162 TI - Low intracellular iron increases the stability of matriptase-2. AB - Matriptase-2 (MT2) is a type II transmembrane serine protease that is predominantly expressed in hepatocytes. It suppresses the expression of hepatic hepcidin, an iron regulatory hormone, by cleaving membrane hemojuvelin into an inactive form. Hemojuvelin is a bone morphogenetic protein (BMP) co-receptor. Here, we report that MT2 is up-regulated under iron deprivation. In HepG2 cells stably expressing the coding sequence of the MT2 gene, TMPRSS6, incubation with apo-transferrin or the membrane-impermeable iron chelator, deferoxamine mesylate salt, was able to increase MT2 levels. This increase did not result from the inhibition of MT2 shedding from the cells. Rather, studies using a membrane permeable iron chelator, salicylaldehyde isonicotinoyl hydrazone, revealed that depletion of cellular iron was able to decrease the degradation of MT2 independently of internalization. We found that lack of the putative endocytosis motif in its cytoplasmic domain largely abolished the sensitivity of MT2 to iron depletion. Neither acute nor chronic iron deficiency was able to alter the association of Tmprss6 mRNA with polyribosomes in the liver of rats indicating a lack of translational regulation by low iron levels. Studies in mice showed that Tmprss6 mRNA was not regulated by iron nor the BMP-mediated signaling with no evident correlation with either Bmp6 mRNA or Id1 mRNA, a target of BMP signaling. These results suggest that regulation of MT2 occurs at the level of protein degradation rather than by changes in the rate of internalization and translational or transcriptional mechanisms and that the cytoplasmic domain of MT2 is necessary for its regulation. PMID- 25550164 TI - Dynamics of nucleosome assembly and effects of DNA methylation. AB - The nucleosome is the fundamental packing unit of the eukaryotic genome, and CpG methylation is an epigenetic modification associated with gene repression and silencing. We investigated nucleosome assembly mediated by histone chaperone Nap1 and the effects of CpG methylation based on three-color single molecule FRET measurements, which enabled direct monitoring of histone binding in the context of DNA wrapping. According to our observation, (H3-H4)2 tetramer incorporation must precede H2A-H2B dimer binding, which is independent of DNA termini wrapping. Upon CpG methylation, (H3-H4)2 tetramer incorporation and DNA termini wrapping are facilitated, whereas proper incorporation of H2A-H2B dimers is inhibited. We suggest that these changes are due to rigidified DNA and increased random binding of histones to DNA. According to the results, CpG methylation expedites nucleosome assembly in the presence of abundant DNA and histones, which may help facilitate gene packaging in chromatin. The results also indicate that the slowest steps in nucleosome assembly are DNA termini wrapping and tetramer positioning, both of which are affected heavily by changes in the physical properties of DNA. PMID- 25550166 TI - Toxic effect of palladium on embryonic development of zebrafish. AB - Since palladium (Pd) is now increasingly used in modern industry, it progressively accumulates in the environment, especially in aquatic ecosystem. The potential toxicity of Pd has therefore caused extensive concern worldwidely. In the present study, we investigated the toxic effect of Pd on zebrafish development. Acute Pd exposure significantly decreased both the survival rate (LC50: 292.6 MUg/L, viz. 2.75 MUM) and hatching rate (IC50: 181.5 MUg/L, viz. 1.71 MUM) of zebrafish during embryonic development. The most common developmental defect observed in Pd treated embryos is pericardiac edema, which occurs in a dose-dependent manner. Whole mount immunostaining and histological studies revealed that Pd exposure would produce the elongated, string-like heart. The heartbeat rate of zebrafish embryos was also decreased after Pd exposure. Consistently, mRNA expression levels of several cardiac-related genes were affected by Pd, suggesting a potential molecular mechanism of Pd-induced cardiac malformation of zebrafish embryo. Moreover, similar to other metals, Pd exposure resulted in the elevated expression of general metal-inducible genes. It was also found that the expression of several antioxidant enzymes was significantly down regulated in the presence of Pd. Taken together, our study investigated the effects of Pd on zebrafish embryonic development and its potential molecular mechanisms, paving the way for the full understanding of Pd toxicity. PMID- 25550165 TI - Cloning of multiple ERalpha mRNA variants in killifish (Fundulus heteroclitus), and differential expression by tissue type, stage of reproduction, and estrogen exposure in fish from polluted and unpolluted environments. AB - To test the hypothesis that alternative splicing could be an adaptive mechanism for populations subject to multi-generational estrogenic exposures, we compared estrogen receptor alpha (ERalpha) splicing variants in two populations of killifish (Fundulus heteroclitus): one resident in an estrogenic polluted environment (New Bedford Harbor, NBH, MA, USA) and one from a relatively uncontaminated reference site (Scorton Creek, SC, MA, USA). In total we identified 19 ERalpha variants, each with deletions of one or more coding exons. Four of the variants with potential functional relevance were analyzed by qPCR to test for population differences in expression by tissue type, site, sex, seasonal reproductive status and estrogen treatment. Significantly, a 5'-truncated short form variant (ERalphaS) was highly expressed in liver and ovary, and was associated with seasonal reproductive activity in SC but not NBH fish. Both ERalphaS and the full-length long variant (ERalphaL) were estrogen-inducible (ERalphaS>ERalphaL) but the induction response was lower in NBH than in SC fish. In contrast, NBH killifish were hyper-responsive to estrogen as measured by expression of two other estrogen responsive genes: vitellogenin (Vtg) and aromatase B (AroB). Most strikingly, two ERalpha deletion variants (Delta6 and Delta6-8), lacking ligand binding and activation function domains, were identified in a subset of NBH fish, where they were associated with reduced responsiveness to estrogen treatment. Together, these results support the hypothesis that alternative splicing of the esr1 gene of killifish could be an autoregulatory mechanism by which estrogen modulates the differential expression of ERalpha, and suggests a novel and adaptive mechanistic response to xenoestrogenic exposure. PMID- 25550167 TI - Abuse Characteristics and Individual Differences Related to Disclosing Childhood Sexual, Physical, and Emotional Abuse and Witnessed Domestic Violence. AB - Many adult survivors of childhood abuse hide their victimization, avoiding disclosure that could identify perpetrators, end the abuse, and bring help to the victim. We surveyed 1,679 women undergraduates to understand disclosure of childhood sexual, physical, and emotional abuse, and, for the first time, witnessed domestic violence, which many consider to be emotionally abusive. A substantial minority of victims failed to ever disclose their sexual abuse (23%), physical abuse (34%), emotional abuse (20%), and witnessed domestic violence (29%). Overall, abuse-specific factors were better predictors of disclosure than individual-level characteristics. Disclosure of sexual abuse was related to experiencing more frequent abuse (by the same and by multiple perpetrators), being more worried about injury and more upset at the time of the abuse, and self labeling as a victim of abuse. Disclosure of physical abuse was related to experiencing more frequent abuse (by the same and multiple perpetrators), being less emotionally close to the perpetrator, being older when the abuse ended, being more worried and upset, and self-labeling as a victim. Disclosure of emotional abuse was associated with being older when the abuse ended, and being more worried and upset. Disclosure was unrelated to victim demographic characteristics or defensive reactions (dissociative proneness, fantasy proneness, repressive coping style, and temporary forgetting), except that among physical and emotional abuse victims, repressors were less likely to disclose than non-repressors. Disclosure of witnessing domestic violence was not significantly related to any factors measured. PMID- 25550168 TI - Violence and Abuse Against Women Who Have Attempted Suicide by Deliberate Self Poisoning: A 2-Year Follow-Up Study in Iran. AB - Sources of data about the occurrence of domestic violence are scarce in Iran. The aim of this study was to evaluate the behavioral effects of different types of domestic violence on women who had attempted suicide by deliberate self-poisoning (DSP). A total of 195 women who had attempted suicide by DSP in response to "violence and abuse" were followed up for 2 years. The most common type of violence, as mentioned by the women themselves as the motive of self-poisoning, was physical abuse (92%) followed by verbal abuse (2.1%), multi-abuses (2.1%), emotional abuse (1.6%), and sexual abuse (1.1%). Suicidal ideation and attempt were more common in those who were consulted sometime after they had initially presented to the hospital with DSP or those who had suffered repeated domestic abuse. It was concluded that invention of methods other than the current consultation system is necessary to prevent repeated suicide attempts among abused women in Iran. PMID- 25550169 TI - Acute painless hepatitis in pregnancy--a cause for concern? PMID- 25550170 TI - Changing phenotypic expression in a patient with a mitochondrial encephalopathy due to 13042G>A de novo mutation--a 5 year follow up. AB - Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam. PMID- 25550172 TI - Postoperative cognitive dysfunction after liver transplantation. AB - OBJECTIVE: Postoperative cognitive dysfunction (POCD) in liver transplant (LT) recipients is defined as a "more than expected" postoperative deterioration in cognitive domains, including short-term and long-term memory, mood, consciousness and circadian rhythm. It is diagnosed, after exclusion of other neurological complications, by using specific neuropsychological tests that need preoperative baseline. The aim of this systematic review was to assess the prevalence of POCD after LT and to analyze patients' symptoms, type and timing of assessment used. METHODS: PubMed, MEDLINE and The Cochrane Li-brary were searched up from January 1986 to August 2014. Study eligibility criteria are as follows: prospective and retrospective studies on human adult subjects describing prevalence of POCD and/or its sequelae after LT episodes were included. RESULTS: Eighteen studies were identified. The timing of testing for POCD may vary between different studies and within the single study, ranging from 0.5 to 32 weeks. POCD occurs in up to 50% of LT recipient. CONCLUSION: Future studies should be focused on detecting preoperative and intraoperative factors associated to POCD in order to carry out appropriate strategies aimed at reducing this disabling health condition. Relationship between POCD and long-term outcome needs to be investigated. PMID- 25550171 TI - Curcumin boosts DHA in the brain: Implications for the prevention of anxiety disorders. AB - Dietary deficiency of docosahexaenoic acid (C22:6 n-3; DHA) is linked to the neuropathology of several cognitive disorders, including anxiety. DHA, which is essential for brain development and protection, is primarily obtained through the diet or synthesized from dietary precursors, however the conversion efficiency is low. Curcumin (diferuloylmethane), which is a principal component of the spice turmeric, complements the action of DHA in the brain, and this study was performed to determine molecular mechanisms involved. We report that curcumin enhances the synthesis of DHA from its precursor, alpha-linolenic acid (C18:3 n 3; ALA) and elevates levels of enzymes involved in the synthesis of DHA such as FADS2 and elongase 2 in both liver and brain tissues. Furthermore, in vivo treatment with curcumin and ALA reduced anxiety-like behavior in rodents. Taken together, these data suggest that curcumin enhances DHA synthesis, resulting in elevated brain DHA content. These findings have important implications for human health and the prevention of cognitive disease, particularly for populations eating a plant-based diet or who do not consume fish, a primary source of DHA, since DHA is essential for brain function and its deficiency is implicated in many types of neurological disorders. PMID- 25550173 TI - The association between platelet/lymphocyte ratio and coronary artery disease severity. AB - OBJECTIVE: In this study, we aimed to explore the association between platelet-to lymphocyte ratio (PLR) and the severity of atherosclerosis in coronary artery disease (CAD). METHODS: Clinical and laboratory data of 388 patients who underwent coronary angiography were evaluated retrospectively. Gensini score, which indicates the severity of atherosclerosis, was calculated for all of the patients. Patients with CAD were categorized as mild and severe atherosclerosis, according to their Gensini score. Eighty patients with normal coronary arteries formed the control group. Mean PLR values of the three study groups were compared. Also, PLR value was tested for whether it showed a positive correlation with Gensini score. RESULTS: The mean PLR of the severe atherosclerosis group was significantly higher than that of the mild atherosclerosis and controls groups (p<0.001). Also, PLR was positively correlated with Gensini score in CAD patients. A cut-off value of 111 for PLR predicted severe atherosclerosis with 61% sensitivity and 59% specificity. Pre-procedural PLR level was found to be independently associated with Gensini score, together with WBC, age, and low HDL level, in the multivariate analysis. CONCLUSION: Our study suggests that high PLR appears to be additive to conventional risk factors and commonly used biomarkers in predicting severe atherosclerosis. PMID- 25550174 TI - Novel predictors of infarct-related artery patency for ST-segment elevation myocardial infarction: Platelet-to-lymphocyte ratio, uric acid, and neutrophil-to lymphocyte ratio. AB - OBJECTIVE: The neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), and uric acid (UA) are inflammatory markers in cardiovascular disease. However, there are not enough data on infarct-related artery (IRA) patency in ST segment elevation myocardial infarction (STEMI). We aimed to investigate the association of NLR, PLR, and UA with IRA patency before percutaneous coronary intervention (PCI) in STEMI. METHODS: The study was designed as a retrospective study. Three hundred and twenty-four consecutive patients with STEMI were divided into two groups according to pre-PCI Thrombolysis in Myocardial Infarction flow grade (TIMI). Patients with a TIMI flow grade of into the spontaneous reperfusion (SR) group, while patients with TIMI flow grade of 0, 1 and 2 were placed into the non-SR group. The chi2 and independent-samples t-test, Mann-Whitney U test, multivariate logistic regression analysis, and receiver-operator characteristic (ROC) curve analysis were used for the statistical analysis. RESULTS: PLR, NLR, and UA values in the SR group were lower than in the non-SR group (p<0.004, p<0.001, p<0.001, respectively). In the multivariate analysis, serum UA level and PLR were found to be independent predictors of pre-PCI IRA patency. In the ROC curve analysis, PLR >190, UA>5.75 mg/dL, and NLR>4.2 predicted non-SR. The sensitivity and specificity of the association between low IRA TIMI flow grade and PLR were 88% and 84%, 72% and 66% for UA, and 74% and 44% for NLR, respectively. CONCLUSION: We determined that PLR and UA are novel predictors of IRA patency before PCI. We suggest that PLR and UA may be used in risk stratifying STEMI. PMID- 25550175 TI - Plasma urotensin II and neurokinin B levels in acute myocardial infarction and stable coronary artery disease. AB - OBJECTIVE: This aim of the study is to investigate whether there are possible plasma urotensin-II (U-II) and neurokinin B (NKB) level changes in patients with acute myocardial infarction (AMI) or not and plasma urotensin-II (U-II) and neurokinin B (NKB) level changes in patients with acute myocardial infarction (AMI) and stable coronary artery disease (CAD) and to evaluate whether there is any relationship between these changes and the pathogenesis of these diseases. METHODS: This is a prospective case-control study. Three groups were formed from randomly admitted patients with AMI, stable CAD, and controls. Biochemical parameters and U-II and NKB levels were measured. Patients with congestive heart failure, chronic hepatic and renal failure, severe cardiac valve disease, and severe pulmonary hypertension were excluded from the study. The normality of the data was evaluated using the Kolmogorov-Smirnov test. We compared the three groups with one-way ANOVA and Tukey test (Kruskal-Wallis test and Mann-Whitney U test). RESULTS: Compared with controls (n=31) and CAD patients (n=32), AMI patients (n=32) had lower U-II and NKB levels. In cases of stable CAD, U-II and NKB levels were similar. A positive correlation was found between U-II and NKB (r=0.720; p=0.000). U-II and NKB were poorly correlated with left ventricle ejection fraction but not with C-reactive protein. CONCLUSION: We found that U-II and NKB levels were lower in patients with AMI in than those with CAD or the control group. According to our findings, the decreased U-II and NKB levels were related to complicated atherosclerotic events. PMID- 25550176 TI - Apical transverse motion is associated with speckle-tracking radial dyssynchrony in patients with non-ischemic dilated cardiomyopathy. AB - OBJECTIVE: Apical transverse motion (ATM) is a new parameter for assessing left ventricular (LV) dyssynchrony. Speckle-tracking radial strain analysis seems to be the best method to identify potential responders to cardiac resynchronization therapy. The aim of our study was to investigate the association between ATM and radial dyssynchrony assessed by speckle-tracking echocardiography in patients with non-ischemic dilated cardiomyopathy (NDC). METHODS: We examined 35 NDC patients (mean age 49.2 +/- 28.1 years; 21 males). Cardiac dimension and ejection fraction (EF) were measured. Speckle-tracking analysis was performed on two dimensional greyscale images in the mid-LV short axis view and apical views to calculate global radial, circumferential, and longitudinal strain (GRS, GCS, GLS), as well as rotational indexes (LV twist and torsion). Radial dyssynchrony was defined as a difference in time to peak systolic radial strain between the anteroseptal and posterior segments with a cut-off value of 130 ms. ATM was estimated using motion traces of 2 opposite apical segments. RESULTS: Radial dyssynchrony was significantly correlated with ATMloop (r = 0.78, p < 0.001), ATM4CV (r = 0.71, p = 0.001), ATM3CV (r = 0.67, p = 0.003), GRS (r = -0.51, p = 0.04), GCS (r = -0.55, p = 0.03), LV twist (r = -0.58, p = 0.02), and LV torsion (r = -0.56, p = 0.03). The receiver operating characteristics analysis for ATMloop to distinguish between patients with and without radial dyssynchrony revealed an area under the curve value of 0.88 (CI: 0.73-1.04, p = 0.005). The best cut-off value was 2.5 mm for ATMloop (85% sensitivity and 86% specificity). CONCLUSION: Apical transverse motion is closely associated with radial dyssynchrony assessed by speckle-tracking echocardiography. Quantitative measure of apical rocking has the potential for clinical applications. PMID- 25550177 TI - Altered heart rate variability depend on the characteristics of coronary lesions in stable angina pectoris. AB - OBJECTIVE: Dysfunction of cardiac autonomic nerve system is considered as one of risk factors for coronary atherosclerotic heart disease. Heart rate variability (HRV) has been used to study the correlation between damage of coronary artery and dysfunction of autonomic nervous system. We hypothesize the correlation between damage of coronary artery and dysfunction of autonomic nervous system by HRV among subjects with stable angina. METHODS: A 236 subjects who diagnosed as stable angina pectoris by elective coronary angiography, were divided into two groups by Gensini score system (GS):GS<=32 (GS1) and GS2>32 (GS2). Subgroups were divided based on location of stenosis lesions and the number of coronary artery disease. 86 subjects suspicious with stable angina pectoris with normal coronary angiography were selected as the control group. All subjects were received 24 hour ambulatory electrocardiogram and the result of time-domain HRV was analyzed (SDNN, SDANN, SDNNind, RMSSD, PNN50). RESULTS: Compared with control group, SDNN, SDNNind and RMSSD lower in GS1, and SDNN, SDANN, SDNNind, RMSSD, PNN50 lower in GS2; ccompared with GS1, SDNN was lower in GS2. Compared with control group, SDNN in one-vessel, SDNN, SDANN in two-vessel diseased and in three-vessel diseased were lower, and compared with two-vessel diseased, SDNN, SDANN lower in three vessel diseased. Compared with right-coronary artery diseased, SDNN and SDANN in left-coronary artery diseased group were lower, while compared with lesions in left circumflex, SDNN in lesions in left anterior descending artery lower. CONCLUSION: HRV may be play a crucial role in estimating the correlation between damage of coronary artery and dysfunction of autonomic nerve system. PMID- 25550178 TI - Relationship between red cell distribution width and long-term mortality in patients with non-ST elevation acute coronary syndrome. AB - OBJECTIVE: Red cell distribution width (RDW) has been reported to be a predictor of cardiac events in coronary artery disease (CAD). Here, we hypothesized that RDW level on admission would be predictive of adverse outcomes in non-ST elevation acute coronary syndrome (NST-ACS). METHODS: In total, 202 patients with NST-ACS (159 males and 43 females) were retrospectively analyzed. The patients were divided into two groups based on the 50th percentile of admission RDW levels. A high RDW group (n=100) was defined as those patients having RDW levels of >14.0. The relationship between RDW and primary endpoint (cardiovascular death), secondary endpoints [(reinfarction, repeat target vessel revascularization-percutaneous/surgical)], and major adverse cardiac events (MACE) were assessed. The median follow-up time was 18 (13-24) months. RESULTS: The patients in the high RDW group were older (62.9 vs. 57.5, p = 0.001). Multivessel disease, low-density lipoprotein, creatinine, platelet, CK-MB, troponin I, and RDW were higher (p = 0.047, p = 0.003, p = 0.012, p = 0.012, p = 0.017, p < 0.001, respectively), and gender (male/female), ejection fraction, and hemoglobin levels were lower (p = 0.021, p = 0.04, p = 0.016, respectively) in the high RDW group. Cardiovascular death and MACE were higher in the high RDW group (16% vs. 4.9%, p = 0.01, 52% vs. 31.4%, p = 0.003, respectively). By multiple regression analysis in 202 patients, age >= 65 and RDW >14.0% on admission were found to be powerful independent predictors of cardiovascular mortality (OR: 4.5, 95% CI: 1.5-13.1, p = 0.005, OR: 3.0, 95% CI: 1.0-8.9, p = 0.039, respectively). CONCLUSION: A high RDW level on admission is associated with increased long-term mortality in patients with NST-ACS. PMID- 25550179 TI - Assessment of left ventricular functions with tissue Doppler, strain, and strain rate echocardiography in patients with familial Mediterranean fever. AB - OBJECTIVE: This study assessed the early changes in regional and global systolic and diastolic myocardial functions in patients with familial Mediterranean fever without any cardiovascular symptoms using tissue Doppler and strain and strain rate echocardiography and compared them to the results of a control group. METHODS: This study has a cross-sectional and observational design. FMF patients with normal left ventricular function were included in the study. We excluded patients who had arrhythmia, acquired/congenital heart disease, pericarditis, or acute attack. We compared 45 children with familial Mediterranean fever on colchicine therapy and 45 age- and sex-matched healthy children. RESULTS: The 45 patients with familial Mediterranean fever included 24 (55.3%) girls and 21 (46.7%) boys with a mean age of 11.3 +/- 3.7 (range 2-18) years. The mean disease duration was 4.6 +/- 2.4 (range 0.5-10) years. In the patient group, the homozygous M694V mutation was the most common (64.4%) mutation. The patients with familial Mediterranean fever had statistically lower longitudinal global strain, radial global strain, and strain rates (-14.44 +/- 4.77%, 14.80 +/- 6.29%, and 0.59 +/- 0.24 s, respectively) than the controls (-17.40 +/- 1.79%, 17.53 +/- 4.63%, and 0.83 +/- 0.51 s) (p < 0.05). The circumferential global strain did not differ significantly between the groups. CONCLUSION: Patients with familial Mediterranean fever who are subclinical from a cardiac aspect might have normal left ventricular function as measured by conventional echocardiography. However, the disease affects their myocardial tissue, and these patients should be followed with conventional, strain, and strain rate echocardiography techniques regularly. PMID- 25550180 TI - Unmasking of atrial repolarization waves using a simple modified limb lead system. AB - OBJECTIVE: In the present study, a modified limb lead (MLL) system was used to record the Ta wave in sinus rhythm and with AV block in male patients. METHODS: Eighty male subjects (mean age 36 +/- 7 years) in sinus rhythm and 20 male patients with AV block (mean age 72 +/- 5 years) were included in this study. Standard limb lead (SLL) ECGs and MLL ECGs were recorded for 60 seconds each with an EDAN SE-1010 PC ECG system. RESULTS: In sinus rhythm subjects, the observable Ta wave duration was 109 +/- 4.7 ms, the P-Ta duration was 196 +/- 5.1 ms, and the corrected P-Ta duration was 238 +/- 7.2 ms. The Ta wave peak amplitude was 42 +/- 8 uV. In AV block patients, the Ta wave duration was 314 +/- 28 ms the P Ta duration was 418 +/- 29 ms and the corrected P-Ta duration was 46 +/- 31 ms, while the Ta wave peak amplitude was -37 +/- 9 uV. A correlation was found between the P and Ta wave amplitude, and no correlation was found between the P and Ta wave duration or the Ta amplitude and Ta duration in sinus rhythm and AV block subjects. CONCLUSION: The end of the Ta wave is not observable in sinus rhythm subjects, as it extends into the QRS complex and ST segment. In AV block patients, the Ta wave duration was generally three times longer than the observable Ta duration in sinus rhythm subjects. PMID- 25550181 TI - Looking beyond the scope: recurrent rectal bleeding in a young woman. PMID- 25550182 TI - An endoscopic Mayo score of 0 is associated with a lower risk of colectomy than a score of 1 in ulcerative colitis. PMID- 25550183 TI - Elevation in Total Homocysteine Levels in Chinese Patients With Essential Hypertension Treated With Antihypertensive Benazepril. AB - OBJECTIVE: To investigate the effect of benazepril on plasma homocysteine (Hcy) levels and to analyze the correlation between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and changes in Hcy levels in response to benazepril. METHODS: A total of 231 patients with mild to moderate essential hypertension were enrolled, and benazepril was orally administered at a dose of 10 mg/d for 2 weeks. Plasma Hcy levels were measured by high-performance liquid chromatography at baseline and after 2 weeks of treatment. Genotyping of the MTHFR C677T polymorphism was performed by TaqMan probe technique. RESULTS: There was no significant change in Hcy level after benazepril treatment for 2 weeks (P = .97). However, stratified by baseline Hcy levels, the patients with baseline Hcy <10 MUmol/L had a significant increase in plasma Hcy levels (P = .003). The results from the multivariable linear regression analysis demonstrated a significant correlation between baseline Hcy levels and the changes in Hcy levels found in both the unadjusted (P = .002) and the adjusted model (P = .004). Strikingly, we found no significant effect modification by the MTHFR C677T polymorphism on the Hcy changes after benazepril treatment. There were also no statistically significant interactions of gene and environment factors (ie, gene smoking and drinking) on the changes in Hcy levels after benazepril treatment. CONCLUSION: Benazepril may cause an increase in plasma Hcy levels among patients with hypertension with low baseline Hcy levels, while effect modification by MTHFR C677T genotypes on the changes in Hcy levels in response to benazepril was not significant among patients with essential hypertension. PMID- 25550184 TI - Decorin in human oral cancer: a promising predictive biomarker of S-1 neoadjuvant chemosensitivity. AB - We reported previously that decorin (DCN) is significantly up-regulated in chemoresistant cancer cell lines. DCN is a small leucine-rich proteoglycan that exists and functions in stromal and epithelial cells. Accumulating evidence suggests that DCN affects the biology of several types of cancer by directly/indirectly targeting the signaling molecules involved in cell growth, survival, metastasis, and angiogenesis, however, the molecular mechanisms of DCN in chemoresistance and its clinical relevance are still unknown. Here we assumed that DCN silencing cells increase chemosusceptibility to S-1, consisted of tegafur, prodrug of 5-fluorouracil. We first established DCN knockdown transfectants derived from oral cancer cells for following experiments including chemosusceptibility assay to S-1. In addition to the in vitro data, DCN knockdown zenografting tumors in nude mice demonstrate decreasing cell proliferation and increasing apoptosis with dephosphorylation of AKT after S-1 chemotherapy. We also investigated whether DCN expression predicts the clinical responses of neoadjuvant chemotherapy (NAC) using S-1 (S-1 NAC) for oral cancer patients. Immunohistochemistry data in the preoperative biopsy samples was analyzed to determine the cut-off point for status of DCN expression by receiver operating curve analysis. Interestingly, low DCN expression was observed in five (83%) of six cases with complete responses to S-1 NAC, and in one (10%) case of 10 cases with stable/progressive disease, indicating that S-1 chemosensitivity is dramatically effective in oral cancer patients with low DCN expression compared with high DCN expression. Our findings suggest that DCN is a key regulator for chemoresistant mechanisms, and is a predictive immunomarker of the response to S 1 NAC and patient prognosis. PMID- 25550185 TI - Double-stranded RNA transcribed from vector-based oligodeoxynucleotide acts as transcription factor decoy. AB - In this study, we designed a short hairpin RNA vector-based oligodeoxynucleotide (VB-ODN) carrying transcription factor (TF) consensus sequence which could function as a decoy to block TF activity. Specifically, VB-ODN for Nuclear factor kappaB (NF-kappaB) could inhibit cell viability and decrease downstream gene expression in HEK293 cells without affecting expression of NF-kappaB itself. The specific binding between VB-ODN produced double-stranded RNA and NF-kappaB was evidenced by electrophoretic mobility shift assay. Moreover, similar VB-ODNs designed for three other TFs also inhibit their downstream gene expression but not that of themselves. Our study provides a new design of decoy for blocking TF activity. PMID- 25550186 TI - Reliability and differentiation capability of dynamic and static kinematic measurements of rearfoot eversion in patellofemoral pain. AB - BACKGROUND: Excessive rearfoot eversion is thought to be a risk factor for patellofemoral pain development, due to the kinesiological relationship with ascendant adaptations. Individuals with patellofemoral pain are often diagnosed through static clinical tests, in scientific studies and clinical practice. However, the adaptations seem to appear in dynamic conditions. Performing static vs. dynamic evaluations of widely used measures would add to the knowledge in this area. Thus, the aim of this study was to determine the reliability and differentiation capability of three rearfoot eversion measures: rearfoot range of motion, static clinical test and static measurement using a three-dimensional system. METHOD: A total of 29 individuals with patellofemoral pain and 25 control individuals (18-30 years) participated in this study. Each subject underwent three-dimensional motion analysis during stair climbing and static clinical tests. Intraclass correlation coefficient and standard error measurements were performed to verify the reliability of the variables and receiver operating characteristic curves to show the diagnostic accuracy of each variable. In addition, analyses of variance were performed to identify differences between groups. FINDINGS: Rearfoot range of motion demonstrated higher diagnostic accuracy (an area under the curve score of 0.72) than static measures and was able to differentiate the groups. Only the static clinical test presented poor and moderate reliability. Other variables presented high to very high values. INTERPRETATION: Rearfoot range of motion was the variable that presented the best results in terms of reliability and differentiation capability. Static variables do not seem to be related to patellofemoral pain and have low accuracy values. PMID- 25550187 TI - Spatial aspects of blood coagulation: two decades of research on the self sustained traveling wave of thrombin. AB - In a number of experimental studies, it has been demonstrated that the forefront of blood coagulation can propagate in the manner of a signal relay. These data strongly support the concept that the formation of a blood clot is governed by a self-sustained traveling wave of thrombin. The present review critically appraises the experimental data obtained in recent decades concerning the self sustained spatial propagation of thrombin. Open questions regarding the experimental detection of the self-sustained propagation of thrombin are discussed. PMID- 25550188 TI - Orange juice intake during a fatty meal consumption reduces the postprandial low grade inflammatory response in healthy subjects. AB - BACKGROUND AND AIMS: Evidence associates polyphenol-rich foods to reduction of low-grade inflammation and mortality for cardiovascular disease, the mechanisms underlying such effects being still unclear. Consumption of a fatty meal by healthy volunteers induces rapid and reversible low-grade inflammation. The aim of the present study was to evaluate the effect of orange juice on cellular modifications induced by a fatty meal. METHODS AND RESULTS: 18 apparently healthy subjects consumed a fatty meal, during which they drunk orange juice, either blond or red, or water, according to a randomized cross-over design. Two hours after the end of the fatty meal, both white blood cell (WBC) and platelet counts significantly increased (12.5 and 5%, respectively), while mean platelet volume decreased and a 25% release of myeloperoxidase (MPO) from polymorphonuclear leukocyte occurred. Both juices significantly prevented WBC increase and MPO degranulation, in respect to control. Triglycerides significantly increased (42%) after the fatty meal, but at a lower extent when red orange juice was consumed with the meal (20%), in respect to blond orange juice or control. This effect was statistically significant in the subgroup of 8 subjects with hypertriglyceridemia. Vascular stiffness (augmentation index), measured by Endo PAT2000, significantly decreased after the meal only in conjunction with red orange juice. CONCLUSION: In healthy subjects the concomitant intake of orange juice may prevent the low-grade inflammatory reaction induced by a fatty meal, at cellular and possibly at vascular function levels. The relative role of different polyphenols on the observed effects of orange juices remains to be established. PMID- 25550189 TI - High prophylactic LMWH dose successfully suppressed hemostatic activation in pregnant woman with a new prothrombin c.1787G>A mutation. PMID- 25550190 TI - Iron therapy in anaemic adults without chronic kidney disease. AB - BACKGROUND: Anaemia affects about a quarter of the world's population. An estimated 50% of anaemic people have anaemia due to iron deficiency. OBJECTIVES: To assess the safety and efficacy of iron therapies for the treatment of adults with anaemia who are not pregnant or lactating and do not have chronic kidney disease. SEARCH METHODS: We ran the search on 11 July 2013. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE (Ovid SP), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus (EBSCO Host), the Institute for Scientific Information Web of Science (ISI WOS) Scientific Citation Index (SCI)-EXPANDED (1970) and Conference Proceedings Citation Index (CPCI)-Science (1990) and Clinicaltrials.gov; we also screened reference lists. An updated search was run on 24 November 2014 but the results have not yet been incorporated into the review. SELECTION CRITERIA: Two review authors independently selected references for further assessment by going through all titles and abstracts. Further selection was based on review of full-text articles for selected references. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence interval (CI) for binary outcomes and the mean difference (MD) or the standardised mean difference (SMD) with 95% CI for continuous outcomes. We performed meta-analysis when possible, when I(2) was less than or equal to 80% using a fixed-effect or random-effects model, using Review Manager software. The range of point estimates for individual studies is presented when I(2) > 80%. MAIN RESULTS: We included in this systematic review 4745 participants who were randomly assigned in 21 trials. Trials were conducted in a wide variety of clinical settings. Most trials included participants with mild to moderate anaemia and excluded participants who were allergic to iron therapy. All trials were at high risk of bias for one or more domains. We compared both oral iron and parenteral iron versus inactive controls and compared different iron preparations.The comparison between oral iron and inactive control revealed no evidence of clinical benefit in terms of mortality (RR 1.05, 95% CI 0.68 to 1.61; four studies, N = 659; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged from 0.3 to 3.1 g/dL higher in the oral iron group than in the inactive control group. The proportion of participants who required blood transfusion was lower with oral iron than with inactive control (RR 0.74, 95% CI 0.55 to 0.99; three studies, N = 546; very low-quality evidence). Evidence was inadequate for determination of the effect of parenteral iron on mortality versus oral iron (RR 1.49, 95% CI 0.56 to 3.94; 10 studies, N = 2141; very low-quality evidence) or inactive control (RR 1.04, 95% CI 0.63 to 1.69; six studies, N = 1009; very low-quality evidence). Haemoglobin levels were higher with parenteral iron than with oral iron (MD -0.50 g/dL, 95% CI -0.73 to -0.27; six studies, N = 769; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged between 0.3 and 3.0 g/dL higher in the parenteral iron group than in the inactive control group. Differences in the proportion of participants requiring blood transfusion between parenteral iron and oral iron groups (RR 0.61, 95% CI 0.24 to 1.58; two studies, N = 371; very low-quality evidence) or between parenteral iron groups and inactive controls (RR 0.84, 95% CI 0.66 to 1.06; eight studies, N = 1315; very low-quality evidence) were imprecise. Average blood volume transfused was less in the parenteral iron group than in the oral iron group (MD -0.54 units, 95% CI -0.96 to -0.12; very low-quality evidence) based on one study involving 44 people. Differences between therapies in quality of life or in the proportion of participants with serious adverse events were imprecise (very low-quality evidence). No trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare. Adverse effects related to oral iron treatment included nausea, diarrhoea and constipation; most were mild.Comparisons of one iron preparation over another for mortality, haemoglobin or serious adverse events were imprecise. No information was available on quality of life. Thus, little evidence was found to support the use of one preparation or regimen over another.Subgroup analyses did not reveal consistent results; therefore we were unable to determine whether iron is useful in specific clinical situations, or whether iron therapy might be useful for people who are receiving erythropoietin. AUTHORS' CONCLUSIONS: * Very low-quality evidence suggests that oral iron might decrease the proportion of people who require blood transfusion, and no evidence indicates that it decreases mortality. Oral iron might be useful in adults who can tolerate the adverse events, which are usually mild.* Very low-quality evidence suggests that intravenous iron results in a modest increase in haemoglobin levels compared with oral iron or inactive control without clinical benefit.* No evidence can be found to show any advantage of one iron preparation or regimen over another.* Additional randomised controlled trials with low risk of bias and powered to measure clinically useful outcomes such as mortality, quality of life and blood transfusion requirements are needed. PMID- 25550191 TI - Simultaneous quantification of naproxcinod and its active metabolite naproxen in rat plasma using LC-MS/MS: application to a pharmacokinetic study. AB - In this study, a liquid chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine naproxcinod and naproxen concentrations in rat plasma for the first time. Plasma samples were prepared by simple one-step extraction with methanol for protein precipitation using only 50 MUL plasma. Separation was performed on a Synergi Fusion-RP C18 column with a run time of 4 min. Naproxcinod, naproxen and internal standard concentrations were detected in the positive ion mode using multiple reaction monitoring (MRM) of the transitions at m/z 348.2->302.2, 231.1->185.1 and 271.2->203.1, respectively. The calibration curves were linear, with all correlation coefficients being >=0.9952, in the range of 1.00-400 ng/mL for naproxcinod and 20.0-8000 ng/mL for naproxen. Their accuracy was in the range of -8.1% to 8.7%, and the intra- and inter-day variations were <=4.53%. The mean extraction recovery of all analytes was more than 93.1% efficient. Stability testing showed that naproxcinod and naproxen remained stable during the whole analytical procedure. After validation, the method was successfully applied to a pharmacokinetic study of naproxcinod and naproxen in rats. The AUC0-infinity of naproxen was 74.6 times larger than that of naproxcinod, which indicated that naproxcinod was rapidly metabolized into naproxen in rats. PMID- 25550192 TI - Simultaneous determination of tazarotene and its active metabolite tazarotenic acid in minipig plasma by LC-MS/MS and its application in pharmacokinetic study after topical administration of tazarotene gel. AB - To study the systemic exposure of tazarotene formulation after topical administration, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of tazarotene and tazarotenic acid in minipig plasma. Similar extraction recoveries for both analytes were obtained after the plasma samples were acidified by glacial acetic acid (5%) and extracted by ethyl ether-cyclohexane (4:1, v/v). Separation of the analytes was achieved within a short time by the addition of 0.1% formic acid to the mobile phase. Gradient elution was used to avoid the matrix effect. The method was linear over the concentration range of 10-600 pg/mL for both analytes. The data of intra- and inter-run precision and accuracy were lower than 5.2%, 7.3% and 7.3% for both analytes. The developed method can be applied to investigate the transdermal pharmacokinetics and the systemic exposure of tazarotene formulation after topical administration. PMID- 25550193 TI - Validation of 3D surface reconstruction of vertebrae and spinal column using 3D ultrasound data--a pilot study. AB - Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of spine associated with vertebra rotation. The Cobb angle and axial vertebral rotation are important parameters to assess the severity of scoliosis. However, the vertebral rotation is seldom measured from radiographs due to time consuming. Different techniques have been developed to extract 3D spinal information. Among many techniques, ultrasound imaging is a promising method. This pilot study reported an image processing method to reconstruct the posterior surface of vertebrae from 3D ultrasound data. Three cadaver vertebrae, a Sawbones spine phantom, and a spine from a child with AIS were used to validate the development. The in-vitro result showed the surface of the reconstructed image was visually similar to the original objects. The dimension measurement error was <5 mm and the Pearson correlation was >0.99. The results also showed a high accuracy in vertebral rotation with errors of 0.8 +/- 0.3 degrees , 2.8 +/- 0.3 degrees and 3.6 +/- 0.5 degrees for the rotation values of 0 degrees , 15 degrees and 30 degrees , respectively. Meanwhile, the difference in the Cobb angle between the phantom and the image was 4 degrees and the vertebral rotation at the apex was 2 degrees . The Cobb angle measured from the in-vivo ultrasound image was 4 degrees different from the radiograph. PMID- 25550194 TI - Interstitial lung disease arising from erlotinib treatment in a Caucasian patient. PMID- 25550195 TI - Active learning for semi-supervised clustering based on locally linear propagation reconstruction. AB - The success of semi-supervised clustering relies on the effectiveness of side information. To get effective side information, a new active learner learning pairwise constraints known as must-link and cannot-link constraints is proposed in this paper. Three novel techniques are developed for learning effective pairwise constraints. The first technique is used to identify samples less important to cluster structures. This technique makes use of a kernel version of locally linear embedding for manifold learning. Samples neither important to locally linear propagation reconstructions of other samples nor on flat patches in the learned manifold are regarded as unimportant samples. The second is a novel criterion for query selection. This criterion considers not only the importance of a sample to expanding the space coverage of the learned samples but also the expected number of queries needed to learn the sample. To facilitate semi-supervised clustering, the third technique yields inferred must-links for passing information about flat patches in the learned manifold to semi-supervised clustering algorithms. Experimental results have shown that the learned pairwise constraints can capture the underlying cluster structures and proven the feasibility of the proposed approach. PMID- 25550196 TI - Social dominance and the Affective Neuroscience Personality Scales. AB - The tendency for cohabiting mammals to organise themselves into dominance hierarchies is a well-documented phenomenon and has consistently been linked to the activity of testosterone and cortisol. However, a systematic account of it within the "basic emotion" taxonomy proposed by Panksepp remains uncharted. The Affective Neuroscience Personality Scales (ANPS), developed to measure the influence of basic affective systems on human temperamental variability, were used as a tool through which to dissociate incentives that promote social dominance from other personality stereotypes. 36 Males were assayed for baseline testosterone and cortisol. Dominance, conceptualised as an egocentric incentive for gaining social influence, was found to positively correlate with the testosterone: cortisol ratio but not with any existing subscales of the ANPS. While these findings suggest that trait dominance can be monitored as an independent personality variable according to a distinct bodily hormone pattern, whether this reflects a distinguishable synaptic-neuronal chemical profile remains unresolved. PMID- 25550197 TI - Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells. AB - HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndrome (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. Although homozygous knockout of Hspa9 is embryonically lethal, mice with heterozygous deletion of Hspa9 (Hspa9(+/-)) are viable and have a 50% reduction in Hspa9 expression. Hspa9(+/-) mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9(+/-) mice have a cell-intrinsic reduction in bone marrow colony-forming unit-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9(+/-) B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNA interference and observed reduced B-cell progenitors in vivo, indicating that appropriate levels (>=50%) of Hspa9 are required for normal B lymphopoiesis in vivo. Knockdown of Hspa9 in an interleukin 7 (IL-7)-dependent mouse B-cell line reduced signal transducer and activator of transcription 5 (Stat5) phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B cells. Collectively, these data imply a role for Hspa9 in B lymphopoiesis and Stat5 activation downstream of IL-7 signaling. PMID- 25550198 TI - Conformational preferences underlying reduced activity of a thermophilic ribonuclease H. AB - The conformational basis for reduced activity of the thermophilic ribonuclease HI enzyme from Thermus thermophilus, compared to its mesophilic homolog from Escherichia coli, is elucidated using a combination of NMR spectroscopy and molecular dynamics (MD) simulations. Explicit-solvent all-atom MD simulations of the two wild-type proteins and an E. coli mutant in which a glycine residue is inserted after position 80 to mimic the T. thermophilus protein reproduce the differences in conformational dynamics determined from (15)N spin-relaxation NMR spectroscopy of three loop regions that surround the active site and contain functionally important residues: the glycine-rich region, the handle region, and the beta5/alphaE loop. Examination of the MD trajectories indicates that the thermophilic protein samples conformations productive for substrate binding and activity less frequently than the mesophilic enzyme, although these differences may manifest as either increased or decreased relative flexibility of the different regions. Additional MD simulations indicate that mutations increasing activity of the T. thermophilus enzyme at mesophilic temperatures do so by reconfiguring the local environments of the mutated sites to more closely resemble active conformations. Taken together, the results show that both locally increased and decreased flexibility contribute to an overall reduction in activity of T. thermophilus ribonuclease H compared to its mesophilic E. coli homolog. PMID- 25550199 TI - Cytokine-induced S-nitrosylation of soluble guanylyl cyclase and expression of phosphodiesterase 1A contribute to dysfunction of longitudinal smooth muscle relaxation. AB - The effect of proinflammatory cytokines on the expression and activity of soluble guanylyl cyclase (sGC) and cGMP-phosphodiesterases (PDEs) was determined in intestinal longitudinal smooth muscle. In control muscle cells, cGMP levels are regulated via activation of sGC and PDE5; the activity of the latter is regulated via feedback phosphorylation by cGMP-dependent protein kinase. In muscle cells isolated from muscle strips cultured with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNF-alpha) or obtained from the colon of TNBS (2,4,6 trinitrobenzene sulfonic acid)-treated mice, expression of inducible nitric oxide synthase (iNOS) was induced and sGC was S-nitrosylated, resulting in attenuation of nitric oxide (NO)-induced sGC activity and cGMP formation. The effect of cytokines on sGC S-nitrosylation and activity was blocked by the iNOS inhibitor 1400W [N-([3-(aminomethyl)phenyl]methyl)ethanimidamide dihydrochloride]. The effect of cytokines on cGMP levels measured in the absence of IBMX (3-isobutyl-1 methylxanthine), however, was partly reversed by 1400W or PDE1 inhibitor vinpocetine and completely reversed by a combination of 1400W and vinpocetine. Expression of PDE1A was induced and was accompanied by an increase in PDE1A activity in muscle cells isolated from muscle strips cultured with IL-1beta or TNF-alpha or obtained from the colon of TNBS-treated mice; the effect of cytokines on PDE1 expression and activity was blocked by MG132 (benzyl N-[(2S)-4 methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2 yl]amino]-1-oxopentan-2-yl]carbamate), an inhibitor of nuclear factor kappaB activity. NO-induced muscle relaxation was inhibited in longitudinal muscle cells isolated from muscle strips cultured with IL-1beta or TNF-alpha or obtained from the colon of TNBS-treated mice, and this inhibition was completely reversed by the combination of both 1400W and vinpocetine. Inhibition of smooth muscle relaxation during inflammation reflects the combined effects of decreased sGC activity via S-nitrosylation and increased cGMP hydrolysis via PDE1 expression. PMID- 25550200 TI - Sulfa drugs inhibit sepiapterin reduction and chemical redox cycling by sepiapterin reductase. AB - Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism. SPR also mediates chemical redox cycling, catalyzing one-electron reduction of redox-active chemicals, including quinones and bipyridinium herbicides (e.g., menadione, 9,10-phenanthrenequinone, and diquat); rapid reaction of the reduced radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide- and sulfonylurea-based sulfa drugs were found to be potent noncompetitive inhibitors of both sepiapterin reduction and redox cycling. The most potent inhibitors of sepiapterin reduction (IC50s = 31-180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole, and chlorpropamide. Higher concentrations of the sulfa drugs (IC50s = 0.37-19.4 MUM) were required to inhibit redox cycling, presumably because of distinct mechanisms of sepiapterin reduction and redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4 dependent amino acid hydroxylases, sulfa drugs inhibited both BH2/BH4 biosynthesis and redox cycling mediated by SPR. Inhibition of BH2/BH4 resulted in decreased production of dopamine and dopamine metabolites, 3,4 dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxytryptamine. Sulfathiazole (200 MUM) markedly suppressed neurotransmitter production, an effect reversed by BH4. These data suggest that SPR and BH4-dependent enzymes, are "off-targets" of sulfa drugs, which may underlie their untoward effects. The ability of the sulfa drugs to inhibit redox cycling may ameliorate ROS-mediated toxicity generated by redox active drugs and chemicals, contributing to their anti-inflammatory activity. PMID- 25550201 TI - AT1 receptor antagonism to reduce aortic expansion in Marfan syndrome: lost in translation or in need of different interpretation? PMID- 25550202 TI - Critical role of platelet glycoprotein ibalpha in arterial remodeling. AB - OBJECTIVE: Arteriogenesis is strongly dependent on the recruitment of leukocytes, especially monocytes, into the perivascular space of growing collateral vessels. On the basis of previous findings that platelets are central players in inflammatory processes and mediate the recruitment of leukocytes, the aim of this study was to assess the role of platelets in a model of arterial remodeling. APPROACH AND RESULTS: C57Bl6 wild-type mice, IL4-R/Iba mice lacking the extracellular domain of the glycoprotein Ibalpha (GPIbalpha) receptor, and mice treated with antibodies to block GPIbalpha or deplete circulating platelets were studied in peripheral arteriogenesis. Using a novel model of intravital 2-photon and epifluorescence imaging, we visualized and quantified the interaction of platelets with leukocytes and the vascular endothelium in vivo. We found that transient platelet adhesion to the endothelium of collateral vessels was a major event during arteriogenesis and depended on GPIbalpha. Furthermore, leukocyte recruitment was obviously affected in animals with defective platelet GPIbalpha function. In IL4-R/Iba mice, transient and firm leukocyte adhesion to the endothelium of collateral vessels, as well as leukocyte accumulation in the perivascular space, were significantly reduced. Furthermore, we detected platelet leukocyte aggregates within the circulation, which were significantly reduced in IL4-R/Iba animals. Finally, platelet depletion and loss of GPIbalpha function resulted in poor reperfusion recovery as determined by laser Doppler imaging. CONCLUSIONS: Thus, GPIbalpha-mediated interactions between platelets and endothelial cells, as well as leukocytes, support innate immune cell recruitment and promote arteriogenesis-establishing platelets as critical players in this process. PMID- 25550203 TI - Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women. AB - OBJECTIVE: Sex hormones may be critical determinants of ischemic heart disease and death in women, but results from previous studies are conflicting. To clarify this, we tested the hypothesis that extreme plasma concentrations of endogenous estradiol and testosterone are associated with risk of ischemic heart disease and death in women. APPROACH AND RESULTS: In a nested prospective cohort study, we measured plasma estradiol in 4600 and total testosterone in 4716 women not receiving oral contraceptives or hormonal replacement therapy from the 1981 to 1983 examination of the Copenhagen City Heart Study. During <=30 years of follow up, 1013 women developed ischemic heart disease and 2716 died. In women with a plasma estradiol below the fifth percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk of ischemic heart disease was 44% (95% confidence interval, 14%-81%) higher; however, plasma estradiol concentrations did not associate with death. Also, in women with a plasma testosterone concentration at or above the 95th percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk was 68% (34%-210%) higher for ischemic heart disease, 36% (18%-58%) higher for any death, and 38% (15%-65%) higher for death from other causes than cardiovascular disease and cancer. These results were similar for postmenopausal women alone. CONCLUSIONS: In women, extreme low concentrations of endogenous estradiol were associated with high risk of ischemic heart disease, and extreme high concentrations of endogenous testosterone were associated with high risk of ischemic heart disease and death. PMID- 25550205 TI - Re-evaluation of the anticoagulant properties of high-density lipoprotein-brief report. AB - OBJECTIVE: This study was conducted to resolve the striking controversy between our previous report that high-density lipoprotein (HDL) enhances activated protein C (APC)/protein S anticoagulant actions and a subsequent, contradicting report that HDL lacks this activity. APPROACH AND RESULTS: When fresh HDL preparations from 2 laboratories were subjected to Superose 6 column chromatography, fractions containing HDL-enhanced APC:protein S anticoagulant actions in clotting assays, thereby validating our previous report. Moreover, the ability of HDL to enhance the anticoagulant actions of APC:protein S was neutralized by anti-apoAI antibodies, further indicating that the activity is because of HDL particles and not because of contaminating phospholipid vesicles. Density gradient subfractionation studies of HDL showed that large HDL subfractions (densities between 1.063 and 1.125 g/mL) contained the APC:protein S enhancing activity. Fresh HDL stored at 4 degrees C gradually lost its anticoagulant enhancing activity for 14 days, indicating moderate instability in this activity of purified HDL. CONCLUSIONS: These studies conclusively demonstrate that freshly prepared HDL fractions possess anticoagulant activity. Fractions from Superose 6 columns that contain HDL reproducibly enhance APC:protein S anticoagulant activity, consistent with the hypothesis that HDL has antithrombotic activity and with the observation that low HDL levels are found in male venous thrombosis patients. Understanding the basis for this activity could lead to novel therapeutic approaches to regulate venous thrombosis. PMID- 25550204 TI - MEF2B-Nox1 signaling is critical for stretch-induced phenotypic modulation of vascular smooth muscle cells. AB - OBJECTIVE: Blood vessel hemodynamics have profound influences on function and structure of vascular cells. One of the main mechanical forces influencing vascular smooth muscle cells (VSMC) is cyclic stretch (CS). Increased CS stimulates reactive oxygen species (ROS) production in VSMC, leading to their dedifferentiation, yet the mechanisms involved are poorly understood. This study was designed to test the hypothesis that pathological CS stimulates NADPH oxidase isoform 1 (Nox1)-derived ROS via MEF2B, leading to VSMC dysfunction via a switch from a contractile to a synthetic phenotype. APPROACH AND RESULTS: Using a newly developed isoform-specific Nox1 inhibitor and gene silencing technology, we demonstrate that a novel pathway, including MEF2B-Nox1-ROS, is upregulated under pathological stretch conditions, and this pathway promotes a VSMC phenotypic switch from a contractile to a synthetic phenotype. We observed that CS (10% at 1 Hz) mimicking systemic hypertension in humans increased Nox1 mRNA, protein levels, and enzymatic activity in a time-dependent manner, and this upregulation was mediated by MEF2B. Furthermore, we show that stretch-induced Nox1-derived ROS upregulated a specific marker for synthetic phenotype (osteopontin), whereas it downregulated classical markers for contractile phenotype (calponin1 and smoothelin B). In addition, our data demonstrated that stretch-induced Nox1 activation decreases actin fiber density and augments matrix metalloproteinase 9 activity, VSMC migration, and vectorial alignment. CONCLUSIONS: These results suggest that CS initiates a signal through MEF2B that potentiates Nox1-mediated ROS production and causes VSMC to switch to a synthetic phenotype. The data also characterize a new Nox1 inhibitor as a potential therapy for treatment of vascular dysfunction in hypertension. PMID- 25550208 TI - Extracellular cyclophilin A activates platelets via EMMPRIN (CD147) and PI3K/Akt signaling, which promotes platelet adhesion and thrombus formation in vitro and in vivo. AB - OBJECTIVE: Cyclophilin A (CyPA) is secreted under inflammatory conditions by various cell types. Whereas the important role of intracellular CyPA for platelet function has been reported, the effect of extracellular CyPA on platelet function has not been investigated yet. APPROACH AND RESULTS: Inhibition of extracellular CyPA through a novel specific inhibitor MM284 reduced thrombus after ferric chloride-induced injury in vivo. In vitro extracellular CyPA enhanced thrombus formation even in CyPA(-/-) platelets. Treatment of isolated platelets with recombinant CyPA resulted in platelet degranulation in a time- and dose-dependent manner. Inhibition of the platelet surface receptor extracellular matrix metalloproteinase inducer (cluster of differentiation 147) by an anticluster of differentiation 147 monoclonal antibody significantly reduced CyPA-dependent platelet degranulation. Pretreatment of platelets with CyPA enhanced their recruitment to mouse carotid arteries after arterial injury, which could be inhibited by an anticluster of differentiation 147 monoclonal antibody (intravital microscopy). The role of extracellular CyPA in adhesion could be confirmed by infusing CyPA(-/-) platelets in CyPA(+/+) mice and by infusing CyPA(+/+) platelets in CyPA(-/-) mice. Stimulation of platelets with CyPA induced phosphorylation of Akt, which could in turn be inhibited in the presence of phosphoinositid-3-kinase inhibitors. Akt-1(-/-) platelets revealed a markedly decreased degranulation on CyPA stimulation. Finally, ADP-induced platelet aggregation was attenuated by MM284, as well as by inhibiting paracrine-secreted CyPA without directly affecting Ca(2+)-signaling. CONCLUSIONS: Extracellular CyPA activates platelets via cluster of differentiation 147-mediated phosphoinositid-3 kinase/Akt-signaling, leading to enhanced adhesion and thrombus formation independently of intracellular CyPA. Targeting extracellular CyPA via a specific inhibitor may be a promising strategy for platelet inhibition without affecting critical functions of intracellular CyPA. PMID- 25550209 TI - Ezetimibe: rescued by randomization (clinical and mendelian). PMID- 25550206 TI - Human experimental endotoxemia in modeling the pathophysiology, genomics, and therapeutics of innate immunity in complex cardiometabolic diseases. AB - Inflammation is a fundamental feature of several complex cardiometabolic diseases. Indeed, obesity, insulin resistance, metabolic dyslipidemia, and atherosclerosis are all closely linked inflammatory states. Increasing evidence suggests that the infectious, biome-related, or endogenous activation of the innate immune system may contribute to the development of metabolic syndrome and cardiovascular disease. Here, we describe the human experimental endotoxemia model for the specific study of innate immunity in understanding further the pathogenesis of cardiometabolic disease. In a controlled, experimental setting, administration of an intravenous bolus of purified Escherichia coli endotoxin activates innate immunity in healthy human volunteers. During endotoxemia, changes emerge in glucose metabolism, lipoprotein composition, and lipoprotein functions that closely resemble those observed chronically in inflammatory cardiovascular disease risk states. In this review, we describe the transient systemic inflammation and specific metabolic consequences that develop during human endotoxemia. Such a model provides a controlled induction of systemic inflammation, eliminates confounding, undermines reverse causation, and possesses unique potential as a starting point for genomic screening and testing of novel therapeutics for treatment of the inflammatory underpinning of cardiometabolic disease. PMID- 25550207 TI - Syndecan-1 modulates the motility and resolution responses of macrophages. AB - OBJECTIVE: Syndecan-1 (Sdc-1) is a member of a family of cell surface proteoglycans, which has been reported to participate in the regulation of events relevant to tissue repair and chronic injury responses, including cell-substrate interactions, matrix remodeling, and cell migration. In this study, we report the functional significance of Sdc-1 in polarized macrophage populations and its role in adhesion and motility events relevant to resolution of the inflammatory program. APPROACH AND RESULTS: Macrophage Sdc-1 expression is associated with differentiated M2 macrophages with high intrinsic motility, and Sdc-1 deficiency is characterized by impaired migration and enhanced adhesion. Leukocyte infiltration and emigration were examined in a thioglycollate-induced model of peritonitis in Sdc-1(+/+) and Sdc-1(-/-) mice. Although the infiltration of inflammatory cells was similar in both cohorts, a significant delay in the lymphatic clearance of Sdc-1(-/-) macrophages was observed. Moreover, we observed enhanced inflammation and greater burden of atherosclerotic plaques in ApoE(-/ )Sdc-1(-/-) mice maintained on a Western diet. CONCLUSIONS: These results demonstrate that defective motility in Sdc-1(-/-) macrophages promotes a persistent inflammatory state with relevance to the pathogenesis of atherosclerosis. PMID- 25550210 TI - Cinnamate of inulin as a vehicle for delivery of colonic drugs. AB - Colon diseases are difficult to treat because oral administrated drugs are absorbed at the stomach and intestine levels and they do not reach colon; in addition, intravenous administrated drugs are eliminated from the body before reaching colon. Inulin is a naturally occurring polysaccharide found in many plants. It consists of beta 2-1 linked D-fructose molecules having a glucosyl unit at the reducing end. Various inulin and dextran hydrogels have been developed that serve as potential carrier for introduction of drugs into the colon. Because inulin is not absorbed in the stomach or in the small intestine, and inulin is degraded by colonic bacteria, drugs encapsulated in inulin-coated vesicles could be specifically liberated in the colon. Therefore, the use of inulin-coated vesicles could represent an advance for the treatment of colon diseases. Here, we study the use of a cinnamoylated derivative of chicory inulin as a vehicle for the controlled delivery of colonic drugs. The encapsulation of methotrexate in inulin vesicles and its release and activity was studied in colon cancer cells in cultures. PMID- 25550211 TI - Delivery of an adenovirus vector plasmid by ultrapure oligochitosan based polyplexes. AB - Ultrapure oligochitosans have been recently reported as efficient non-viral vectors for the delivery of pCMS-EGFP plasmid (5.5kbp) to the cornea and retina. However, the delivery of oncolytic adenoviral plasmids (40kbp) represents a unique challenge. In this work, we elaborated self assembled O15 and O25 UOC/pAdTLRGD polyplexes, and we studied the influence of the N/P ratio, the pH of the transfection medium and the salt concentration on the particle size and zeta potential by an orthogonal experimental design. All polyplexes showed a particle size lower than 200nm and a positive zeta potential. These parameters were influenced by the N/P ratio, salt concentration, and pH of the transfection medium. The selected polyplexes were able to bind, release, and protect the plasmid from DNase degradation. Transfection experiments in HEK293 and A549 cell lines demonstrated that UOC/pAdTLRGD polyplexes were able to deliver the plasmid and transfect both cell lines. These results suggest that O15 and O25 UOC based polyplexes are suitable for future in vivo applications. PMID- 25550212 TI - Do patients really gain outcome benefits when using the high-flex knee prostheses in total knee arthroplasty? A meta-analysis of randomized controlled trials. AB - The purpose of this study was to undertake a meta-analysis to evaluate whether patients really gain outcome benefits when using the high-flex (HF) prostheses in total knee arthroplasty (TKA) compared with standard (STD) implants. Only randomized controlled trials were included in this meta-analysis. After searching PubMed, Embase, Wed of Science and Cochrane Library, 1042 papers were identified and 18 trials were finally eligible for meta-analysis including 2069 knees (1906 patients). We found no statistically significant difference between the two designs in terms of ROM, knee scores (KSS, HSS, WOMAC, and SF-36), patients' satisfaction and complications. Hence there is currently no evidence to confirm that the use of high-flex prostheses in short-term is superior to the standard prostheses after total knee arthroplasty. PMID- 25550213 TI - Two-Day Length of Stay is Not Inferior to 3 Days in Total Knee Arthroplasty with Regards to 30-Day Readmissions. AB - The impact of a shortened length of stay (LOS) following total knee arthroplasty (TKA) on the risk of readmission is not well documented despite recent trends towards shorter hospitalization. We retrospectively compared the adjusted risk of 30-day readmission following TKA between patients with 2-, 3- and 4-day LOS using current postoperative care protocols. A total of 23,655 consecutive primary, unilateral TKAs operated between 01/01/2009 and 12/31/2011 were studied retrospectively using non-inferiority testing. The main outcome was 30-day readmission. Two-day LOS decreased the odds of readmission by a factor of 0.96, with an upper bound one-sided 95% confidence interval of 1.10. After adjusting for other variables, LOS of 2 days is not inferior to 3 days with respect to the risk of 30-day readmission. PMID- 25550214 TI - Sorafenib Maintenance Appears Safe and Improves Clinical Outcomes in FLT3-ITD Acute Myeloid Leukemia After Allogeneic Hematopoietic Cell Transplantation. AB - BACKGROUND: The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) gene is one of the most frequently observed genetic alterations in acute myeloid leukemia (AML), with an incidence of about 20% to 30%. FLT3-ITD is significantly associated with a poor outcome, and offering an allogeneic hematopoietic cell transplantation (allo-HCT) is recommended for patients harboring this mutation. Sorafenib is a tyrosine kinase inhibitor active against RAF, VEGF, and FLT3-ITD. It has been used in an off-label fashion in FLT3-ITD AML. PATIENTS AND METHODS: We retrospectively assessed the successful use of sorafenib after allo-HCT in patients with FLT3-ITD AML. Six FLT3-ITD AML patients received sorafenib as posttransplantation maintenance therapy (n = 5) or as salvage therapy after a post-allo-HCT relapse (n = 1) and continued afterward. RESULTS: One patient developed myocardial infarction 100 days after initiation of sorafenib. Interestingly, skin graft versus host disease (grade II) was observed in 5 of 6 patients and generally occurred within few days after initiation of sorafenib, but it responded promptly to corticosteroid therapy in all patients. All 6 patients were alive and in complete remission at a median follow-up of 16 months (range, 10-29 months) since first induction and at a median follow-up of 12 months (range, 4-20 months) since initiation of sorafenib. Remarkably, the disease of all patients was in molecular remission. CONCLUSION: Sorafenib appears to be an effective maintenance therapy after allo-HCT in FLT3-ITD AML, with achievement of durable complete responses. This suggests an immunomodulatory effect of sorafenib in the posttransplantation setting and warrants a broader clinical evaluation of the use of maintenance sorafenib in FLT3-ITD AML. PMID- 25550215 TI - The use of air separation in recycling CRT TV sets. AB - The aim of this paper is to examine the possibility of use of air separation in recycling CRT TV sets and determine the effect of operating variables of separators. Eight CRT TV sets were collected and after manual disassembly, parts of CRT TV sets were sorted into four fractions taking into account their properties. The subject of this research was the fraction consisting of yokes of a cathode tube, cables, connectors and wires. Testing samples were obtained by manual disassembly, shredding and sieving, after which the separation on the model of a cross-flow gravity air separator with horizontal flow was carried out. Four grain sizes, 4/2mm, 2/1mm, 1/0.5mm and -0.5mm, were tested on the separator. Testing was carried out according to the central composite design for three factors: splitter height, air velocity and feed position. The evaluation of results was carried out by the analysis of two parameters: concentrate grade and recovery. The obtained values of the concentrate grade varied from 45.9% for the smallest grain size of -0.5mm to 89.4% for the grain size of 1/0.5mm while recovery was very high, mostly over 99%. The highest increase of metal content in the concentrate of 21.1% was recorded for the smallest grain size of -0.5%. The Analysis of Variance showed that the splitter height and feed position have the strongest effect on the concentrate grade. PMID- 25550216 TI - Abrupt changes in pentobarbital sensitivity in preBotzinger complex region, hypoglossal motor nucleus, nucleus tractus solitarius, and cortex during rat transitional period (P10-P15). AB - On postnatal days P10-P15 in rat medulla, neurotransmitter receptor subunit composition shifts toward a more mature phenotype. Since medullary GABAARs regulate cardiorespiratory function, abrupt alterations in GABAergic synaptic inhibition could disrupt homeostasis. We hypothesized that GABAARs on medullary neurons become more resistant to positive allosteric modulation during P10-P15. Medullary and cortical slices from P10 to P20 rats were used to record spontaneous action potentials in pre-Botzinger Complex (preBotC-region), hypoglossal (XII) motor nucleus, nucleus tractus solitarius (NTS), and cortex during exposure to pentobarbital (positive allosteric modulator of GABAARs). On P14, pentobarbital resistance abruptly increased in preBotC-region and decreased in NTS, but these changes in pentobarbital resistance were not present on P15. Pentobarbital resistance decreased in XII motor nucleus during P11-P15 with a nadir at P14. Abrupt changes in pentobarbital resistance indicate changes in GABAergic receptor composition and function that may compensate for potential increased GABAergic inhibition and respiratory depression that occurs during this key developmental transitional period. PMID- 25550217 TI - Polymer-based nanocarriers for vaginal drug delivery. AB - The vaginal delivery of various drugs is well described and its relevance established in current medical practice. Alongside recent advances and achievements in the fields of pharmaceutical nanotechnology and nanomedicine, there is an increasing interest in the potential use of different nanocarriers for the delivery of old and new pharmacologically active molecules with either therapeutic or prophylactic purposes. Nanosystems of polymeric nature in particular have been investigated over the last years and their interactions with mucosal fluids and tissues, as well as genital tract biodistribution upon vaginal administration, are now better understood. While different applications have been envisioned, most of the current research is focusing in the development of nano formulations with the potential to inhibit the vaginal transmission of HIV upon sexual intercourse. The present work focuses its discussion on the potential and perils of polymer-based nanocarriers for the vaginal administration of different pharmacologically active molecules. PMID- 25550218 TI - The molecular, cellular, and morphological components of blood-brain barrier development during embryogenesis. AB - The blood brain barrier (BBB) is a hallmark of blood vessels in the brain and functions to protect the brain from unwanted blood born materials, support the unique metabolic needs of the brain, and define a stable environment crucial for brain homeostasis. The temporal profile of BBB development was long debated until recent studies produced convincing evidence demonstrating that the BBB is established and functional during embryogenesis. Here we review research focused on the molecular, cellular and morphological characteristics of BBB development. Our review discusses the precise temporal profile of BBB formation, the development of endothelial cell ultrastructure and the molecular components that provide sealing and transporting properties, the molecular pathways involved in the induction of BBB specific endothelial cell differentiation, the signaling pathways driving developmental angiogenesis versus barrier-genesis, and finally the contribution of other cell types to BBB formation. We examine aspects of BBB development that are still unresolved while highlighting research tools that could provide new insight to answer these open questions. PMID- 25550219 TI - Smac mimetics as IAP antagonists. AB - As the Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in human cancers, they represent promising targets for therapeutic intervention. Small-molecule inhibitors of IAP proteins mimicking the endogenous IAP antagonist Smac, called Smac mimetics, neutralize IAP proteins and thereby promote the induction of cell death. Smac mimetics have been shown in preclinical models of human cancer to directly trigger cancer cell death or to sensitize for cancer cell death induced by a variety of cytotoxic stimuli. Smac mimetics are currently undergoing clinical evaluation in phase I/II trials, demonstrating that therapeutic targeting of IAP proteins has reached the clinical stage. PMID- 25550221 TI - Characteristics and intraoperative treatments associated with head and neck free tissue transfer complications and failures. AB - OBJECTIVE: To investigate the association between perioperative patient characteristics and treatment modalities (eg, vasopressor use and volume of fluid administration) with complications and failure rates in patients undergoing head and neck free tissue transfer (FTT). STUDY DESIGN: A retrospective review of medical records. SETTING: Perioperative hospitalization for head and neck FTT at 1 tertiary care medical center between January 1, 2009, and October 31, 2011. SUBJECTS AND METHODS: Consecutive patients (N=235) who underwent head and neck FTT. Demographic, patient characteristic, and intraoperative data were extracted from medical records. Complication and failure rates within the first 30 days were collected RESULTS: In a multivariate analysis controlling for age, sex, ethnicity, reason for receiving flap, and type and volume of fluid given, perioperative complication was significantly associated with surgical blood loss (P=.019; 95% confidence interval [CI], 1.01-1.16), while the rate of intraoperative fluid administration did not reach statistical significance (P=.06; 95% CI, 0.99-1.28). In a univariate analysis, FTT failure was significantly associated with reason for surgery (odds ratio, 5.40; P=.03; 95% CI, 1.69-17.3) and preoperative diagnosis of coronary artery disease (odds ratio, 3.60; P=.03; 95% CI, 1.16-11.2). Intraoperative vasopressor administration was not associated with either FTT complication or failure rate. CONCLUSIONS: FTT complications were associated with surgical blood loss but not the use of vasoactive drugs. For patients undergoing FTT, judicious monitoring of blood loss may help stratify the risk of complication and failure. PMID- 25550222 TI - Assessment of mitochondrial membrane potential in HEI-OC1 and LLC-PK1 cells treated with gentamicin and mitoquinone. AB - OBJECTIVE: To determine the effects of concurrent treatment with gentamicin and the mitochondria-targeted antioxidant mitoquinone (MitoQ; which may prevent gentamicin ototoxicity) on change in the mitochondrial membrane potential (Deltapsi(m)), a precursor of apoptosis. STUDY DESIGN: Prospective and controlled. SETTING: Academic research laboratory. SUBJECTS AND METHODS: LLC-PK1 (Lilly Laboratories Culture-Pig Kidney Type 1) and HEI-OC1 (House Ear Institute Organ of Corti 1) cells-renal and auditory cell lines, respectively-were used in this study. Deltapsi(m) was assessed by flow cytometry through the MitoProbe JC-1 Kit for Flow Cytometry in untreated LLC-PK1 and HEI-OC1 cells and cells exposed to low- (100uM) or high- (2000uM) dose gentamicin for 24 hours, with and without 0.5uM each of MitoQ or idebenone (IDB; an untargeted ubiquinone). RESULTS: Deltapsi(m) was not different in untreated LLC-PK1 cells and cells coincubated with low-dose gentamicin and MitoQ or IDB (P > .05). In HEI-OC1 cells, coincubation with low-dose gentamicin and MitoQ decreased Deltapsi(m) (P = .002). Coincubation of LLC-PK1 cells with high-dose gentamicin and DMSO, MitoQ, or IDB depolarized Deltapsi(m) (P < .0001), with MitoQ depolarizing the Deltapsi(m) to a greater extent than that of IDB (P = .03). In contrast, HEI-OC1 cells demonstrated a hyperpolarized Deltapsi(m) when coincubated with high-dose gentamicin and DMSO, MitoQ, or IDB (P < .001). CONCLUSION: The combination of gentamicin and MitoQ holds the potential to disrupt Deltapsi(m). This suggests a heightened need to monitor for toxicity in patients receiving both agents. PMID- 25550223 TI - Analysis of an online match discussion board: improving the otolaryngology-head and neck surgery match. AB - OBJECTIVE: "The Match" has become the accepted selection process for graduate medical education. Otomatch.com has provided an online forum for Otolaryngology Head and Neck Surgery (OHNS) Match-related questions for over a decade. Herein, we aim to delineate the type of posts on Otomatch to better understand the perspective of medical students applying for OHNS residency. STUDY DESIGN: Retrospective review of an OHNS Match-related online forum. SUBJECTS AND METHODS: Subjects were contributors to an OHNS Match-related online forum. Posts on Otomatch between December 2001 and April 2014 were reviewed. The title of each thread and number of views were recorded for quantitative analysis. Each thread was organized into 1 of 6 major categories and 1 of 18 subcategories. National Resident Matching Program (NRMP) data were utilized for comparison. RESULTS: We identified 1921 threads corresponding to over 2 million page views. Over 40% of threads were related to questions about specific programs, and 27% were discussions about interviews. Views, a surrogate measure for popularity, reflected different trends. The majority of individuals viewed posts on interviews (42%), program-specific questions (20%), and how to rank programs (11%). There was an increase in viewership tracked with a rise in applicant numbers based on NRMP data. CONCLUSION: Our study provides an in-depth analysis of a popular discussion forum for medical students interested in the OHNS Match process. The most viewed posts are about interview dates and questions regarding specific programs. We provide suggestions to address unmet needs for medical students and potentially improve the Match process. PMID- 25550224 TI - An anatomically based analysis of objectively measured pediatric snoring: a pilot study. AB - OBJECTIVE: To assess pediatric habitual snoring (PS) using home sleep test (HST) technology and attempt to correlate the objective components of PS to specific upper airway anatomy. In addition, the effects of adenotonsillectomy (+/ turbinoplasty) on objective measures of PS were evaluated. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Pediatric patients with a chief complaint of snoring and probable obstructive sleep apnea underwent an HST (SNAP Diagnostics, Wheeling, Illinois) with a detailed acoustical snoring analysis prior to adenotonsillectomy (+/ turbinoplasty). During surgery, detailed anatomical measurements were performed and correlated to snoring analysis results. After surgery, patients were offered another HST with snoring analysis. Data analysis was performed using descriptive statistics and statistical correlation with attention to the multiple-comparisons paradox. RESULTS: Twenty-two patients (45% male; mean age, 5.4 years [range, 2.4 8.4 years]) completed the preoperative HST and operative measurements. Unlike typical adult snoring, only a minority of PS was from palatal flutter (mean palatal component, 24%; median, 10%). The resistance occurrence percentage (ROP, percentage of breathing events with snoring noise) was associated with body mass index (BMI; Spearman rho=0.55; P=.017), subjective turbinate size (0.54; P=.032), palatal obstruction (0.63; P=.008), and mean oxygen saturation (-0.729; P=.0003) but not adenotonsillar hypertrophy. Twelve patients (54%) completed a postoperative HST. The ROP was significantly reduced (median, 20.5% vs 6.5%; P=.006, sign rank test) postoperatively. The magnitude of the ROP reduction was proportional to the volume of the removed tonsils (0.74; P=.022). CONCLUSION: Pediatric snoring has different acoustical characteristics than adult snoring. Objective PS is associated with BMI, turbinate size, and palatal obstruction. Adenotonsillectomy (+/-turbinoplasty) may significantly reduce objective PS. PMID- 25550225 TI - TORP ossiculoplasty outcomes with and without a stapes footplate prosthesis. AB - OBJECTIVE: The titanium stapes footplate prosthesis (FPP) was designed to ensure a stable connection of a total ossicular replacement prosthesis (TORP) to the stapes footplate and maximize acoustic coupling by centering the footplate on the oval window. Our goal was to assess the impact of the FPP on TORP ossiculoplasty outcomes. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS: Adult patients undergoing TORP ossiculoplasty with (n=53) or without (n=108) a stapes FPP. METHODS: Rate of prosthesis displacement and audiologic outcomes were tabulated for statistical analysis. RESULTS: A lower rate of prosthesis displacement and statistically better audiologic outcomes were seen in FPP patients. The pure-tone average air-bone gap (PTA-ABG) was closed to <20 dB in 69.8% (37/53) of patients in the study arm and 44.4% (48/108) of patients in the control arm (P=.003). The PTA-ABG was decreased by a mean+/-SD of 19.3+/-11.7 dB and 12.6+/-11.0 dB in the study and control groups, respectively (P=.0012). CONCLUSIONS: Use of the titanium stapes FPP during TORP ossiculoplasty provides a statistically significant advantage in short-term PTA-ABG closure and a higher rate of successful rehabilitation of conductive hearing loss. Further studies are necessary to assess any long-term advantages a FPP may offer. PMID- 25550226 TI - Recent randomized controlled trials in otolaryngology. AB - OBJECTIVE: To assess recent trends in the prevalence and quality of reporting of randomized controlled trials (RCTs) in 4 otolaryngology journals. STUDY DESIGN: Methodology and reporting analysis. SETTING: Randomized controlled trials in 4 otolaryngology journals. SUBJECTS AND METHODS: All RCTs published from 2011 to 2013 in 4 major otolaryngology journals were examined for characteristics of study design, quality of design and reporting, and funding. RESULTS: Of 5279 articles published in 4 leading otolaryngology journals from 2011 to 2013, 189 (3.3%) were RCTs. The majority of RCTs were clinical studies (86%), with the largest proportion consisting of sinonasal topics (31%). Most interventions were medical (46%), followed by surgical (38%) and mixed (16%). In terms of quality, randomization method was reported in 54% of RCTs, blinding in 33%, and adverse events in 65%. Intention-to-treat analysis was used in 32%; P values were reported in 87% and confidence intervals in 10%. Research funding was most often absent or not reported (55%), followed by not-for-profit (25%). CONCLUSIONS: Based on review of 4 otolaryngology journals, RCTs are still a small proportion of all published studies in the field of otolaryngology. There seem to be trends toward improvement in quality of design and reporting of RCTs, although many quality features remain suboptimal. Practitioners both designing and interpreting RCTs should critically evaluate RCTs for quality. PMID- 25550227 TI - "The Memory of Beauty" Survives Alzheimer's Disease (but Cannot Help Memory). AB - The aesthetic experience, in particular the experience of beauty in the visual arts, should have neural correlates in the human brain. Neuroesthetics is principally implemented by functional studies in normal subjects, but the neuropsychology of the aesthetic experience, that is, the impact of brain damage on the appreciation of works of art, is a neglected field. Here, 16 mild to moderate Alzheimer's disease patients and 15 caregivers expressed their preference on 16 works of art (eight representational and eight abstract) during programmed visits to an art gallery. A week later, all subjects expressed a preference rate on reproductions of the same works presented in the gallery. Both patients and caregivers were consistent in assigning preference ratings, and in patients consistency was independent of the ability to recognize the works on which the preference rate had been given in an explicit memory task. Caregivers performed at ceiling in the memory task. Both patients and caregivers assigned higher preference ratings for representational than for abstract works and preference consistency was comparable in representational and abstract works. Furthermore, in the memory task, patients did not recognize better artworks they had assigned higher preference ratings to, suggesting that emotional stimuli (as presumably visual works of art are) cannot enhance declarative memory in this pathology. Our data, which were gathered in an ecological context and with real world stimuli, confirm previous findings on the stability of aesthetic preference in patients with Alzheimer's disease and on the independence of aesthetic preference from cognitive abilities such as memory. PMID- 25550229 TI - Co-targeting BRAF and cyclin dependent kinases 4/6 for BRAF mutant cancers. AB - Selective BRAF inhibitors have demonstrated significant clinical benefit in melanoma patients harboring oncogenic BRAF mutations. However, the majority of such patients either exhibit de novo resistance from the beginning of the treatment or acquire resistance and eventually relapse. Despite tremendous progress in understanding the underlying mechanisms of resistance, overcoming resistance to BRAF inhibitors remains an unmet medical need. Constitutive activation of cyclin-dependent kinases (CDK) 4/6 as a result of genetic aberrations including CDKN2A inactivation and CCND1 amplification is common across many cancer types and frequently co-occurs with oncogenic BRAF mutations. Also, cyclin D1 overexpression is a common feature of resistance to BRAF inhibitors. Here we review CDK4/6 as a therapeutic target in BRAF mutant cancers and discuss emerging evidence supporting a critical role of cyclin D1/CDK4/6 axis in de novo and acquired resistance to BRAF inhibitors. Co-targeting CDK4/6 and BRAF could be a more effective therapy to augment clinical response of BRAF inhibitors and overcome resistance in BRAF mutant cancers. PMID- 25550228 TI - Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. AB - BACKGROUND: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. OBJECTIVE: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. METHODS: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). RESULTS: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: -5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose dependent dissolution and absorption limitations. CONCLUSION: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD. PMID- 25550230 TI - Virus-induced modulation of lower airway diseases: pathogenesis and pharmacologic approaches to treatment. AB - Uncomplicated upper respiratory viral infections are the most common cause of days lost from work and school and exert a major economic burden. In susceptible individuals, however, common respiratory viruses, particularly human rhinoviruses, also can have a major impact on diseases that involve the lower airways, including asthma, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis (CF). Respiratory virus-induced wheezing illnesses in early life are a significant risk factor for the subsequent development of asthma, and virus infections may also play a role in the development and progression of airway remodeling in asthma. It is clear that upper respiratory tract virus infections can spread to the lower airway and trigger acute attacks of asthma, COPD or CF. These exacerbations can be life-threatening, and exert an enormous burden on health care systems. In recent years we have gained new insights into the mechanisms by which respiratory viruses may induce acute exacerbations of lower airway diseases, as well as into host defense pathways that may regulate the outcomes to viral infections. In the current article we review the role of viruses in lower airway diseases, including our current understanding on pathways by which they may cause remodeling and trigger acute exacerbations. We also review the efficacy of current and emerging therapies used to treat these lower airway diseases on the outcomes due to viral infection, and discuss alternative therapeutic approaches for the management of virus-induced airway inflammation. PMID- 25550232 TI - [Comorbidities and affective disorders]. PMID- 25550233 TI - [Affective disorders and personality disorders]. AB - Coexistence in an individual of an affective disorder and a personality disorder is very common and there is an abundant literature on it. Articles are numerous and heterogeneous ; the results are sometimes imprecise or discordant. Some data are, despite these reserves, shared by the scientific community. The main consensus is first on a bad prognosis, with a high rate of all DSM axes comorbidities, secondly on the trap of a same phenomenology for different underlying mechanisms. A review is presented. PMID- 25550234 TI - [Affective disorders and anxiety comorbidities]. AB - Anxiety disorders are frequently associated with affective disorders and represent one of the most important comorbidity in patients with bipolar disorder. Their prevalence is high, whatever the anxiety disorder, with nevertheless higher rates for generalized anxiety disorder (18.4 to 19.9% for lifetime prevalence). Such high frequencies raise essential questions about the link between these groups of disorders, and if it is necessary to distinguish them or to consider their phenomenological overlap as resulting of common disease processes. The existence of comorbid anxiety disorder in bipolar disorder significantly worsens its evolution, inducing more severe episodes, shortening remission periods, favoring relapses and suicide as well as substance use, and reducing quality of life in comparison to bipolar patients without anxiety. The mechanisms that link the anxious symptomatology to mood dysregulation are still poorly understood, although it is likely that genetic factors play a key role, combined with other factors of vulnerability, including those involved in coping strategy to address ongoing distress. Despite the high impact of anxiety on the severity of bipolar disorder course, few randomized controlled trials examined treatments of comorbid anxiety disorders and only recent recommendations offer useful therapeutic perspectives. In this context, it seems necessary to better understand the features associated with the occurence of anxiety disorders in affective disorders, in order to better identify the mechanisms underlying such comorbidity, together with working to develop therapeutics that efficiently target them. PMID- 25550235 TI - [Attention deficit hyperactivity disorder and/or bipolar disorder?]. AB - The attention deficit disorder and the bipolar disorder maintain a complex relation. Indeed, these two syndromes share numerous symptoms that engender numerous diagnostic difficulties. According to several studies, it seems that these two disorders are really different with significant differences at the functional and anatomical level. However, there are common cognitive deficits as well as relatively frequent co-morbidity which is necessary to know in order to adjust the treatment. PMID- 25550236 TI - [Affective disorders and impulsivity]. AB - Impulsivity is a complex and important phenomenon in mood disorders. Impulse control disorders, as defined in DSM, are more frequent in mood disorders especially in Bipolar Disorder type I, and are associated with a more severe course of illness. Dimensional studies demonstrate that impulsivity is a core manifestation of bipolar disorder both as state- and trait-dependent markers in patients. Comorbid substance use disorders are often associated with a higher level of impulsivity whereas the relation between suicidal behaviors and higher impulsivity remains uncertain. Moreover, neuropsychological tests were used to study correlation between clinical impulsivity and laboratory measurements of impulsivity. Level of correlation remains weak and several explanations are proposed in the literature. PMID- 25550237 TI - [Comorbidity of affective disorders and alcohol use disorder]. AB - The comorbidity of affective disorders with alcohol use disorder remains insufficiently taken into account. In spite of the well-known frequency of the addict comorbidity in most psychiatric disorders, the level of association between affective disorders and alcohol is still underestimated and poorly understood. The label of "double diagnosis" relates to a simple addition of two independent pathologies. It is suggested to consider a "dual psychopathology" combining the effects of one disorder on the other. Interactions between the two disorders commit a complex state calling a new clinical reading, an adapted therapeutic strategy through a necessary integration of care. Association of alcohol use disorder and affective disorder, particularly in bipolar disorders, is correlated with severity, unstable course, treatment resistance and a greater risk of suicide. Alcohol aggravates depression and hampers therapeutics. Alcohol and mania remain a dreaded danger. The mechanism of the comorbid association does not only refer to a behavioral strategy of compensation but seems strongly based on a shared and crossed vulnerability, related to the genetics of the 5HT carrier and gene Clock. Therapeutic limitations do suggest the implementation of an "integrated" device which supposes a new organization of care and facilitation of collaborations between Addiction and Psychiatry. PMID- 25550238 TI - [Affective disorders: endocrine and metabolic comorbidities]. AB - Links between affective and endocrine-metabolic disorders are numerous and complex. In this review, we explore most frequent endocrine-metabolic comorbidities. On the one hand, these comorbidities imply numerous iatrogenic effects from antipsychotics (metabolic side-effects) or from lithium (endocrine side-effects). On the other hand, these comorbidities are also associated with affective disorders independently from medication. We will successively examine metabolic syndrome, glycemic disturbances, obesity and thyroid disorders among patients with affective disorders. Endocrinemetabolic comorbidities can be individually encountered, but can also be associated. Therefore, they substantially impact morbidity and mortality by increasing cardiovascular risk factors. Two distinct approaches give an account of processes involved in these comorbidities: common environmental factors (iatrogenic effects, lifestyle), and/or shared physiological vulnerabilities. In conclusion, we provide a synthesis of important results and recommendations related to endocrine-metabolic comorbidities in affective disorders : heavy influence on morbidity and mortality, undertreatment of somatic diseases, importance of endocrine and metabolic side effects from main mood stabilizers, impact from sex and age on the prevalence of comorbidities, influence from previous depressive episodes in bipolar disorders, and relevance of systematic screening for subclinical (biological) disturbances. PMID- 25550239 TI - [Do sleep abnormalities contribute to cardiovascular risk in bipolar disorders?]. AB - OBJECTIVES: The aim of this review is to summarize the state of knowledge concerning the relationship between cardiovascular risk, sleep abnormalities, and emotional reactivity in patients with bipolar disorder (BD). METHOD: A scientific literature search of international articles was performed during August and September 2014 using the PubMed electronic database. We used the following MeSH terms : "Bipolar Disorders", "Cardiovascular risk", "Emotional reactivity", "Sleep apnea", and "Sleep disorder". RESULTS: Obstructive sleep apnea (OSA) is a sleep disorder strongly associated with BD, which tends to fragment sleep. OSA is associated with an increased cardiovascular risk. Furthermore, emotional hyper reactivity is favored by "hostility" temperaments, BD and sleep deprivation. The combination of these factors interacts and also results in an increased cardiovascular risk. Taken as a whole, both sleep disorders and emotional hyper reactivity seem to increase the risk of cardiovascular diseases in BD. CONCLUSION: These data emphasize the central role of sleep abnormalities and emotional reactivity in the vulnerability of BD to express cardiovascular diseases. From a clinical point of view, these data also emphasize the importance of identifying and care for sleep abnormalities in BD in order to improve BD outcome. PMID- 25550240 TI - [Affective disorders and eating disorders]. AB - Epidemiologic studies show a frequent co-occurence of affective and eating disorders. The incidence of one disorder in patients suffering from the other disorder is well over the incidence in the general population. Several causes could explain this increased comorbidity. First, the iatrogenic origin is detailed. Indeed, psychotropic drugs, and particularly mood stabilizers, often lead to modification in eating behaviors, generally inducing weight gain. These drugs can increase desire for food, reduce baseline metabolism or decrease motor activity. Also, affective and eating disorders share several characteristics in semiology. These similarities can not only obscure the differential diagnosis but may also attest of conjoint pathophysiological bases in the two conditions. However, genetic and biological findings so far are too sparse to corroborate this last hypothesis. Nonetheless, it is noteworthy that comorbidity of affective and eating disorders worsens patients'prognosis and is associated with more severe forms of affective disorders characterized by an earlier age of onset in the disease, higher number of mood episodes and a higher suicidality. Lastly, psychotropic drugs used in affective disorders (lithium, antiepileptic mood stabilizers, atypical antipsychotics, antidepressants) are reviewed in order to weigh their efficacy in eating disorders. This could help establish the best therapeutic option when confronted to comorbidity. PMID- 25550241 TI - [Affective disorders and neurological comorbidities]. AB - Mood disorders occupy a vast area in the field of psychiatry. Advances in the study of the brain, but also epidemiology and genetics allow us to make more solid connections between these disorders and neurological disorders, resuming a process of reconciliation between both specialties. The purpose of this short review is to draw the attention of the psychiatrist to these links, especially with a brief presentation of the psychiatric manifestations of a number of neurodegenerative diseases and more particularly frontotemporal dementia. PMID- 25550242 TI - [Dissociative disorders and affective disorders]. AB - The phenomenology of dissociative disorders may be complex and sometimes confusing. We describe here two cases who were initially misdiagnosed. The first case concerned a 61 year-old woman, who was initially diagnosed as an isolated dissociative fugue and was actually suffering from severe major depressive episode. The second case concerned a 55 year-old man, who was suffering from type I bipolar disorder and polyvascular disease, and was initially diagnosed as dissociative fugue in a mooddestabilization context, while it was finally a stroke. Yet dissociative disorders as affective disorder comorbidity are relatively unknown. We made a review on this topic. Dissociative disorders are often studied through psycho-trauma issues. Litterature is rare on affective illness comorbid with dissociative disorders, but highlight the link between bipolar and dissociative disorders. The later comorbidity often refers to an early onset subtype with also comorbid panic and depersonalization-derealization disorder. Besides, unipolar patients suffering from dissociative symptoms have more often cyclothymic affective temperament. Despite the limits of such studies dissociative symptoms-BD association seems to correspond to a clinical reality and further works on this topic may be warranted. PMID- 25550243 TI - [Co-occuring mood and substance use disorders]. AB - Mood and substance use disorders commonly co-occur, yet there is little evidence based research to guide the pharmacologic management of these comorbid disorders. The authors review the existing empirical findings including current clinical pharmacotherapy practices for treating co-occurring mood and substance use disorders and call into question current clinical practices. The specific mood disorders reviewed are bipolar and major depressive disorders (either one co occurring with a substance use disorder). The authors also highlight knowledge gaps that may serve as a basis for future research. Findings from the relatively small amount of available data indicate that pharmacotherapy for managing mood symptoms might be effective in patients with substance dependence, although results have not been consistent across all studies. In most studies, medications for managing mood symptoms did not appear to have an impact on the substance use disorder. Research has only begun to address optimal pharmacologic management of co-occurring disorders. In addition, current clinical treatment for drug dependence often exclude new pharmacotherapies approved by the French Haute Autorite de Sante for treating certain types of addiction. With new data becoming available, it appears that we need to revisit current practice in the pharmacological management of co-occurring mood and substance use disorders. PMID- 25550244 TI - Transcriptome changes upon in vitro challenge with Mycobacterium bovis in monocyte-derived macrophages from bovine tuberculosis-infected and healthy cows. AB - As innate immune cells, macrophages are expected to respond to mycobacterial infection equally in both Mycobacterium bovis-infected cows and healthy cows. We previously found that monocyte-derived macrophages (MDMs) from M. bovis-infected cows respond differently than MDMs from healthy cows when exposed to in vitro M. bovis challenge. We have now used the AgilentTM Bovine Gene Expression Microarray to examine transcriptional differences between these MDMs. At a high multiplicity of infection (10), in vitro challenge led to changes in several thousands of genes, with dysregulation at multiple orders of magnitude. For example, significant changes were seen for colony stimulating factor 3 (granulocyte) (CSF3), colony stimulating factor 2 (granulocyte-macrophage) (CSF2), and chemokine (C-C motif) ligand 20 (CCL20). Classical macrophage activation was also observed, although to a lesser degree in interleukin 12 (IL12) expression. For macrophages, kallikrein-related peptidase 12 (KLK12) and protease, serine, 2 (trypsin 2) (PRSS2), as well as a secreted protein, acidic, cysteine-rich (osteonectin) (SPARC)-centered matricellular gene network, were differentially expressed in infected animals. Finally, global transcriptome fold-changes caused by in vitro challenge were higher in healthy cows than in tuberculosis-positive cows, suggesting that healthy macrophages responded marginally better to in vitro infection. Macrophages from healthy and already infected animals can both be fully activated during M. bovis infection, yet there are differences between these macrophages: distinct expression pattern in matricellular proteins, and their different responses to in vitro infection. PMID- 25550245 TI - Application of chemometrics in determination of the acid dissociation constants (pKa) of several benzodiazepine derivatives as poorly soluble drugs in the presence of ionic surfactants. AB - In this study, the acid dissociation constants (pKa) of some benzodiazepine derivatives including chlordiazepoxide, clonazepam, lorazepam, and oxazepam in aqueous micellar solution were determined spectrophotometrically at an ionic strength of 0.1M at 25 degrees C. The effect of cetyl trimethylammonium bromide (CTAB) as a cationic and sodium n-dodecyl sulfate(SDS) as an anionic surfactant on the absorption spectra of benzodiazepine drugs at different pH values were studied. The acidity constants of all related species are estimated by considering the surfactant concept and the application of chemometric methods using the whole spectral fitting of the collected data to an established factor analysis model. DATAN(r) software (Ver. 5.0, Multid Analyses AB, and Goteborg, Sweden) was applied to determine the acidity constants. In this study, a simple and fast method to determine the ionization constant (pKa) of poorly soluble drugs was developed using surfactants. The acidity constant (i.e. pKa) for chlordiazepoxide, clonazepam, lorazepam, and oxazepam were reported as 4.62, pKa1 value of 1.52 and pKa2 value of 10.51, pKa1 value of 1.53 and pKa2 value of 10.92 and pKa1 value 1.63 and pKa2 value of 11.21 respectively. The results showed that the peak values in the spectrophotometric absorption spectra of drugs are influenced by the presence of anionic and cationic surfactants. According to the results, by changing the SDS concentration from 0 to 0.05M, the pKa of chlordiazepoxide was increased to 5.9, the pKa1 of lorazepam was decreased to 0.1 while the pKa2 was increased to 11.5. Increase in SDS concentration has not shown significant alteration in pKa of clonazepam and oxazepam. Results indicate that by Changing the CTAB concentration from 0 to 0.05M, the pKa of chlordiazepoxide was reduced to 4.4, the pKa1 of clonazepam was decreased to 0.1 and the pKa2 was decreased to 9.1, the pKa1 of lorazepam was decreased to 0.4 and the pKa2 was decreased to 9.4, the pKa1 of oxazepam was decreased to 0.3 and the pKa2 was decreased to 9.7. Based on the results obtained from the study, charge of anionic and cationic surfactants leads to an electrostatic interaction between surfactant and the protonated form of the drug molecule. The electrostatic interactions can be attractive or repulsive forces and influence of separation of protons and consequently increase or decrease the acidity constants. PMID- 25550246 TI - Normal limits of ECG measurements related to atrial activity using a modified limb lead system. PMID- 25550231 TI - Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. AB - Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery. PMID- 25550247 TI - Prognostic value of mean platelet volume in patients after acute coronary syndrome. PMID- 25550248 TI - Influence of left ventricular type on QT interval in hypertensive patients. PMID- 25550249 TI - Cardiotoxicity due to chemotherapy for breast cancer: the dark side of the moon. PMID- 25550250 TI - Mortality in heart failure patients. AB - Heart failure (HF) is a clinical syndrome, which is becoming a major public health problem in recent decades, due to its increasing prevalence, especially in the developed countries, mostly due to prolonged lifespan of the general population as well as the increased of HF patients. The HF treatment, particularly, new pharmacological and non-pharmacological agents, has markedly improved clinical outcomes of patients with HF including increased life expectancy and improved quality of life. However, despite the facts that mortality in HF patients has decreased, it still remains unacceptably high. This review of summarizes the evidence to date about the mortality of HF patients. Despite the impressive achievements in the pharmacological and non pharmacological treatment of HF patients which has undeniably improved the survival of these patients, the mortality still remains high particularly among elderly, male and African-American patients. Patients with HF and reduced ejection fraction have higher mortality rates, most commonly due to cardiovascular causes, compared with patients HF and preserved ejection fraction. PMID- 25550251 TI - A new cause of silent myocardial infarction: Bonsai. PMID- 25550252 TI - Case of fatal heart failure with biventricular noncompaction, genital skeletal abnormalities and mental retardation. PMID- 25550253 TI - Combined catheter thrombus fragmentation and percutaneous thrombectomy in a patient with massive pulmonary emboli and acute cerebral infarct. PMID- 25550254 TI - The usefulness of cardiac magnetic resonance in prevention of sudden cardiac death after myocardial infarction. PMID- 25550255 TI - P-wave dispersion and left ventricular diastolic dysfunction in hypertension. PMID- 25550256 TI - Breast arterial calcifications and carotid intima-media thickness and hemodynamics: is there any association? PMID- 25550257 TI - ADMA is a useful marker, but many confounding factors should be considered! PMID- 25550258 TI - Should systemic thrombolytic therapy be considered a first-line treatment in acute pulmonary embolism? PMID- 25550259 TI - Association of mitral annular calcification with fetuin-A levels. PMID- 25550260 TI - Cholesterol: is accused for the atherosclerosis proximal to myocardial bridging? PMID- 25550261 TI - Homocysteine and masked hypertension. PMID- 25550262 TI - Peripartum cardiomyopathy and triplet pregnancy. PMID- 25550263 TI - Heart rate recovery and methodological issues. PMID- 25550264 TI - The first experiences with the lotus valve system in Turkey as an alternative valve system in TAVI. PMID- 25550265 TI - Dizygotic twin with congenital AV block. PMID- 25550266 TI - Primum non nocere. PMID- 25550267 TI - Coronary-pulmonary artery fistula: heart-on-a-heart appearance. PMID- 25550268 TI - Ventricular tachycardia and syncope: a complication of an echinococcal cyst caused by left ventricular outflow tract obstruction. PMID- 25550269 TI - Asymptomatic giant pseudoaneurysm in the ascending aorta after Bentall procedure. PMID- 25550270 TI - A challenging image during pacemaker implantation: venous spasm. PMID- 25550271 TI - Temporary pacemaker with left bundle branch block image in ECG: left ventricle via right common carotid artery. PMID- 25550272 TI - Medicare and private spending trends from 2008 to 2012 diverge in Texas. AB - The recent relatively slow growth in health care spending masks significant differences among payers, clinical settings, and geographic areas. To better understand the spending slowdown, we focus on 2008-2012 trends in Texas among Medicare fee-for-service beneficiaries and enrollees in Blue Cross Blue Shield of Texas (BCBSTX). Spending per person for Medicare grew only 1.5% per year on average, compared with 5.2% for BCBSTX. In Medicare, utilization rates were relatively flat, while prices grew more slowly than input prices. In BCBSTX, spending growth was driven by increases in negotiated prices, in particular hospital prices. We find that geographic variation declined sharply in Medicare, due to drops in spending on post-acute care in two notoriously high-spending regions but rose slightly in BCBSTX. The aggregate spending trends mask two divergent stories: spending growth in Medicare is very slow, but price increases continue to drive unsustainable spending growth among the privately insured. PMID- 25550273 TI - Cellular mechanisms of the cytotoxicity of the anticancer drug elesclomol and its complex with Cu(II). AB - The potent anticancer drug elesclomol, which forms an extremely strong complex with copper, is currently undergoing clinical trials. However, its mechanism of action is not well understood. Treatment of human erythroleukemic K562 cells with either elesclomol or Cu(II)-elesclomol caused an immediate halt in cell growth which was followed by a loss of cell viability after several hours. Treatment of K562 cells also resulted in induction of apoptosis as measured by annexin V binding. Elesclomol or Cu(II)-elesclomol treatment caused a G1 cell cycle block in synchronized Chinese hamster ovary cells. Elesclomol and Cu(II)-elesclomol induced DNA double strand breaks in K562 cells, suggesting that they may also have exerted their cytotoxicity by damaging DNA. Cu(II)-elesclomol also weakly inhibited DNA topoisomerase I (5.99.1.2) but was not active against DNA topoisomerase IIalpha (5.99.1.3). Elesclomol or Cu(II)-elesclomol treatment had little effect on the mitochondrial membrane potential of viable K562 cells. NCI COMPARE analysis showed that Cu(II)-elesclomol exerted its cytotoxicity by mechanisms similar to other cytotoxic copper chelating compounds. Experiments with cross-resistant cell lines overexpressing several ATP-binding cassette (ABC) type efflux transporters showed that neither elesclomol nor Cu(II)-elesclomol were cross-resistant to cells overexpressing either ABCB1 (Pgp) or ABCG2 (BCRP), but that cells overexpressing ABCC1 (MRP1) were slightly cross-resistant. In conclusion, these results showed that elesclomol caused a rapid halt in cell growth, induced apoptosis, and may also have inhibited cell growth, in part, through its ability to damage DNA. PMID- 25550274 TI - Facial emotion recognition deficits in abstinent cannabis dependent patients. AB - BACKGROUND: Cannabis is clearly the most popular illicit drug in North America, Europe and in other parts of the world. Evidence is accumulating for the involvement of the endocannabinoid system in emotional processing. However, only few studies examined emotional processing in chronic, heavy cannabis users and these studies were performed in cannabis dependent patients who were abstinent for 12-48 hours. The aim of this study was to investigate facial emotion identification and discrimination abilities in patients with cannabis dependence who were abstinent for at least 1 month. METHODS: The study included 30 males with cannabis dependency according to DSM-IV criteria and who had been abstinent for at least 1 month and 30 healthy controls. All the subjects were evaluated with Facial Emotion Identification Test (FEIT) and Facial Emotion Discrimination Test (FEDT). RESULTS: The main finding of this study was the presence of deficits in both identification and discrimination of facial emotions in cannabis dependent patients during abstinence. In addition, when we examined negative and positive emotions separately, we found out that abstinent cannabis dependent patients performed significantly worse than controls in the identification of negative emotions but not positive emotions. CONCLUSIONS: Our findings indicate that facial emotion recognition deficits which have previously been observed in current cannabis users are still detectable in abstinent cannabis dependent patients and do not improve quickly with abstinence (an average of 3.2 months). PMID- 25550275 TI - Exploring determinants of progression in Parkinson's disease. Is there a difference among Jewish ethnic groups? AB - INTRODUCTION: Parkinson's disease (PD) displays an individually variable rate of progression, of which the underlying mechanisms are largely unknown, but may involve genetic factors. In this study, we aimed to explore the effect of ethnic origin on PD progression rate in Israeli Jews, as expressed by time from onset until reaching Hoehn and Yahr stage 3 (HY3). METHODS: Consecutive patients with PD followed bi-annually at the Movement Disorders Institute at Sheba Medical Center, were included. Demographic data and clinical information, including age at PD onset (AO), H&Y staging, and family history of PD, were collected. Ethnicity was determined based on the parents' origin and was categorized as Ashkenazi Jews (AJ), Yemenite Jews (YJ), North African Jews (NAJ) and Oriental Jews (OJ) excluding YJ. Associations between the above variables and the time to HY3 were determined using Cox proportional hazards model. Survival curves were derived from the model. RESULTS: Of 707 patients [430 males, AJ: 458, YJ: 37, NAJ: 75 and OJ: 137] included in the analysis, 343 had reached HY3. In a multivariate analysis, a longer time to HY3 was significantly associated with a younger AO (HR = 1.07, p < 0.001). YJ showed a significantly shorter time to HY3 compared to AJ and OJ, but not compared to NAJ. Time to HY3 was significantly shorter for NAJ than for OJ. CONCLUSION: Jewish PD patients of Yemenite and North African origin may have a more rapid progression of PD, compared to those of Ashkenazi and Oriental origin, suggesting distinctive genetic influences. PMID- 25550276 TI - "Human guinea pig" asks for animal studies. PMID- 25550277 TI - Introduction: Antibody-targeted therapy special issue. PMID- 25550282 TI - Maternal perinatal undernutrition modifies lactose and serotranferrin in milk: relevance to the programming of metabolic diseases? AB - A close link between intrauterine growth restriction and development of chronic adult diseases such as obesity, diabetes, and hypertension has been established both in humans and animals. Modification of growth velocity during the early postnatal period (i.e., lactation) may also sensitize to the development of metabolic syndrome in adulthood. This suggests that milk composition may have long-lasting programming/deprogramming metabolic effects in the offspring. We therefore assess the effects of maternal perinatal denutrition on breast milk composition in a food-restricted 50% (FR50) rat model. Monosaccharides and fatty acids were characterized by gas chromatography, and proteins were profiled by surface-enhanced laser desorption/ionization-time-of-flight analysis in milk samples from FR50 and control rat dams. Milk analysis of FR50 rats demonstrated that maternal undernutrition decreases lactose concentration and modulates lipid profile at postnatal day 10 by increasing the unsaturated fatty acids/saturated fatty acids and diminishes serotransferrin levels at postnatal day 21. Our data indicate that maternal perinatal undernutrition modifies milk composition both quantitatively and qualitatively. These modifications by maternal nutrition open new perspectives to identify molecules that could be used in artificial milk to protect from the subsequent development of metabolic diseases. PMID- 25550281 TI - The role of AMP-activated protein kinase in the androgenic potentiation of cannabinoid-induced changes in energy homeostasis. AB - Orexigenic mediators can impact the hypothalamic feeding circuitry via the activation of AMP-dependent protein kinase (AMPK). Given that testosterone is an orexigenic hormone, we hypothesized that androgenic changes in energy balance are due to enhanced cannabinoid-induced inhibition of anorexigenic proopiomelanocortin (POMC) neurons via activation of AMPK. To this end, whole animal experiments were carried out in gonadectomized male guinea pigs treated subcutaneously with either testosterone propionate (TP; 400 MUg) or its sesame oil vehicle (0.1 ml). TP-treated animals displayed increases in energy intake associated with increases in meal size. TP also increased several indices of energy expenditure as well as the p-AMPK/AMPK ratio in the arcuate nucleus (ARC) measured 2 and 24 h posttreatment. Subcutaneous administration of the CB1 receptor antagonist AM251 (3 mg/kg) rapidly blocked the hyperphagic effect of TP. This was mimicked largely upon third ventricular administration of AM251 (10 MUg). Electrophysiological studies revealed that TP potentiated the ability of the cannabinoid receptor agonist WIN 55,212-2 to decrease the frequency of miniature excitatory postsynaptic currents in ARC neurons. TP also increased the basal frequency of miniature inhibitory postsynaptic currents. In addition, depolarization-induced suppression (DSE) is potentiated in cells from TP-treated animals and blocked by AM251. The AMPK inhibitor compound C attenuated DSE from TP-treated animals, whereas the AMPK activator metformin enhanced DSE from vehicle-treated animals. These effects occurred in a sizable number of identified POMC neurons. Collectively, these results indicate that the androgen-induced increases in energy intake are mediated via an AMPK-dependent augmentation in endocannabinoid tone onto POMC neurons. PMID- 25550284 TI - Evidence for the vertical transmission of Sunshine virus. AB - Sunshine virus is a paramyxovirus of pythons associated with neurorespiratory disease and mortalities. This report provides evidence for its vertical transmission. In a collection of over 200 Australian pythons, a dam and a sire, both carpet pythons (Morelia spilota), were PCR-positive for Sunshine virus at a time when the dam was likely to have been gravid. A clutch of 21 eggs was laid and three non-viable eggs were tested for the presence of Sunshine virus by PCR. One egg had been incubating for 34 days while the other two had been incubating for 49 days. The surface of all three eggs was negative for Sunshine virus but swabs of the allantois and amnion were positive in all three eggs. Embryo tissue samples were tested from the two 49 day old eggs. From one embryo, a sample of brain and a pooled sample of lung, liver, kidney and intestine were positive, while for the other embryo, a pooled sample of lung, liver, kidney, intestine and brain was positive. Fourteen of the 21 eggs hatched and all hatchlings were tested by PCR at least once between the ages of 53 and 229 days old. All hatchlings were PCR-negative for Sunshine virus. PMID- 25550283 TI - Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus. AB - Leptin receptors (ObRs) in the forebrain and hindbrain have been independently recognized as important mediators of leptin responses. We recently used low-dose leptin infusions to show that chronic activation of both hypothalamic and hindbrain ObRs is required to reduce body fat. The objective of the present study was to identify the brain nuclei that are selectively activated in rats that received chronic infusion of leptin in both the forebrain and hindbrain. Either saline or leptin was infused into third and fourth ventricles (0.1 MUg/24 h in the third ventricle and 0.6 MUg/24 h in the fourth ventricle) of male Sprague Dawley rats for 6 days using Alzet pumps. Rats infused with leptin into both ventricles (LL rats) showed a significant increase in phosphorylated (p)STAT3 immunoreactivity in the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and posterior hypothalamus compared with other groups. No differences in pSTAT3 immunoreactivity were observed in midbrain or hindbrain nuclei despite a sixfold higher infusion of leptin into the fourth ventricle than the third ventricle. DeltaFosB immunoreactivity, a marker of chronic neuronal activation, showed that multiple brain nuclei were chronically activated due to the process of infusion, but only the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and ventral tuberomamillary nucleus showed a significant increase in LL rats compared with other groups. These data demonstrate that low-dose leptin in the hindbrain increases pSTAT3 in areas of the hypothalamus known to respond to leptin, supporting the hypothesis that leptin-induced weight loss requires an integrated response from both the hindbrain and forebrain. PMID- 25550285 TI - Revisiting bovine pyometra--new insights into the disease using a culture independent deep sequencing approach. AB - The bacteria present in the uterus during pyometra have previously been studied using bacteriological culturing. These studies identified Fusobacterium necrophorum and Trueperella pyogenes as the major contributors to the pathogenesis of pyometra. However, an increasing number of culture-independent studies have demonstrated that the bacterial diversity in most environments is underestimated in culture-based studies. Consequently, fastidious pyometra associated pathogens may have been overlooked. Therefore, the primary purpose of this study was to investigate the diversity of bacteria in the uterus of cows with pyometra by using culture-independent 16S rRNA PCR combined with next generation sequencing. We investigated the microbial composition in the uterus of 21 cows with pyometra, which were obtained from a Danish slaughterhouse. Similar to the observations from the culture studies, Fusobacteriaceae, the family that F. necrophorum belongs to, was the operational taxonomic unit (OTU) observed in the largest quantities. By contrast, the Actinomycetaceae family, which includes T. pyogenes, constituted only 1% of the total number of reads. Thus we cannot confirm the previously reported role of species from this family in the pathogenesis of pyometra. Finally, we identified a large number of sequences representing three families of Gram-negative bacteria in the pyometra samples: Porphyromonadaceae, Mycoplasmataceae, and Pasteurellaceae. It is likely that these families comprise potential pathogenic species of a fastidious nature, which have been overlooked in previous studies. Our results increase the knowledge of the complexity of the pyometra microbiota and suggest that pathogens in addition to F. necrophorum may be involved in the pathogenesis of pyometra. PMID- 25550286 TI - Discrete stochastic metapopulation model with arbitrarily distributed infectious period. AB - In this study, a stochastic discrete-time model is developed to study the spread of an infectious disease in an n-patch environment. The model includes an arbitrary distribution of the (random) infectious period T, and the results are used to investigate how the distribution of T may influence the model outcomes. General results are applied to specific distributions including Geometric, Negative Binomial, Poisson and Uniform. The model outcomes are contrasted both numerically and analytically by comparing the corresponding basic reproduction numbers R0 and probability of a minor epidemic (or probability of disease extinction) P0. It is shown analytically that for n = 2 the reproduction numbers corresponding to different distributions of T can be ordered based on the probability generating function phiT of T. In addition, numerical simulations are carried out to examine the final epidemic size F and duration of the epidemic D of a two-patch model. PMID- 25550287 TI - Effects of additional food in a delayed predator-prey model. AB - We examine the effects of supplying additional food to predator in a gestation delay induced predator-prey system with habitat complexity. Additional food works in favor of predator growth in our model. Presence of additional food reduces the predatory attack rate to prey in the model. Supplying additional food we can control predator population. Taking time delay as bifurcation parameter the stability of the coexisting equilibrium point is analyzed. Hopf bifurcation analysis is done with respect to time delay in presence of additional food. The direction of Hopf bifurcations and the stability of bifurcated periodic solutions are determined by applying the normal form theory and the center manifold theorem. The qualitative dynamical behavior of the model is simulated using experimental parameter values. It is observed that fluctuations of the population size can be controlled either by supplying additional food suitably or by increasing the degree of habitat complexity. It is pointed out that Hopf bifurcation occurs in the system when the delay crosses some critical value. This critical value of delay strongly depends on quality and quantity of supplied additional food. Therefore, the variation of predator population significantly effects the dynamics of the model. Model results are compared with experimental results and biological implications of the analytical findings are discussed in the conclusion section. PMID- 25550288 TI - A process evaluation of an adolescent weight management intervention: findings and recommendations. AB - Process evaluation is valuable in guiding development of effective intervention programmes but rare in adolescent weight management. This paper presents a process evaluation of the Loozit((r)) randomized controlled trial, a community based behavioural lifestyle intervention for obese 13-16 year olds. Adolescents were randomized to receive the two-phase Loozit((r)) group programme, with (n = 73) or without (n = 78), additional therapeutic contact (telephone coaching, short message service and/or emails) in Phase 2. Quantitative and qualitative process data were collected. Facilitators used a standardized evaluation form to document participant attendance, and comment on lesson adherence and process delivery. Adolescents and parents completed satisfaction questionnaires at 2-, 12 and 24-month follow-ups. Following the intervention, 14 adolescents who provided informed written consent were interviewed about their experience with additional therapeutic contact. Data were analysed using descriptive statistics, parametric and non-parametric tests to compare group means, and thematic analyses. Group attendance rates averaged 85 and 47% during Phases 1 (0-2 months) and 2 (3-24 months), respectively. Facilitators frequently noted that participants reported making healthy lifestyle changes. Elements enjoyed in the sessions included practical activities, fun active games, resistance training and forming new friendships. Adolescents struggled with setting specific, measurable, achievable, realistic and timely (SMART) goals. Overall, participants were satisfied with the help received including the telephone and electronic contact. More than 80% of participants found the programme changed adolescents' eating and physical activity habits, and 89% of parents reported changing parenting strategies. Future adolescent group-based programmes may enhance participant engagement and programme effectiveness by including more interactive and frequent telephone and electronic contact. PMID- 25550289 TI - Protocol compliance of administering parenteral medication in Dutch hospitals: an evaluation and cost estimation of the implementation. AB - OBJECTIVES: Preventable adverse drug events (ADEs) are closely related to administration processes of parenteral medication. The Dutch Patient Safety Program provided a protocol for administering parenteral medication to reduce the amount of ADEs. The execution of the protocol was evaluated and a cost estimation was performed to provide insight in the associated costs of protocol compliance. METHODS: A longitudinal evaluation study was performed in secondary care. A total of 2154 observations of the administration process of parenteral medication were carried out within 10 measurements in 19 hospitals between November 2011 and December 2012. The total time needed for the process was measured in a sample of five hospitals. Multilevel linear and logistic regression analyses were used to analyse the trend over time of the implementation and to assess the association between hospital and administration characteristics, and compliance of the protocol. A cost estimation provided insight into the costs of performing a complete administration process and the costs at department level for 1 year. RESULTS: The complete protocol was performed in 19% of the observations. The proceeding 'check by a second nurse' was least performed. Large differences were found between individual hospitals in performing the administration protocol. The compliance of the protocol was negatively influenced in case of disturbance of the administrator. The overall trend over time of completion of the protocol fluctuated during the study period. On average, 3 min 26 s were needed to perform the complete protocol, which costs ?2.42. Extrapolating the costs to department level, including cost for clinical lessons, the difference in costs in performing the complete protocol and an incomplete protocol was ?7.891 for 1 year. CONCLUSIONS: The protocol for administering parenteral medication is still not implemented completely, therefore an investment in time and Euros is needed. PMID- 25550290 TI - Ethnic minority patients not at increased risk of adverse events during hospitalisation in urban hospitals in the Netherlands: results of a prospective observational study. AB - OBJECTIVES: We analysed potential differences in incidence, type, nature, impact and preventability of adverse events (AEs) during hospitalisation between ethnic Dutch and ethnic minority patients, and the role of patient-related determinants. We hypothesised an increased AE incidence for ethnic minority patients. SETTING: We conducted a prospective cohort study in four urban hospitals. PARTICIPANTS: 763 Dutch patients and 576 ethnic minority patients aged between 45 and 75, admitted for at least one night, were included in the study. All patients completed a questionnaire on patient-related determinants (eg, language proficiency). OUTCOME MEASURES: Incidence, type (eg, diagnostic AEs), impact and nature of AEs were assessed with a two-stage medical record review. Logistic regression analysis was used to adjust for patient and admission characteristics, and to investigate the contribution of patient-related determinants to AE risk. RESULTS: There was no significant difference in the incidence of AEs: 11% (95% CI 9% to 14%) in Dutch patients and 10% (95% CI 7% to 12%) in ethnic minority patients. Also, there was no significant difference in the incidence of preventable AEs: 3% (95% CI 1% to 4%) in Dutch patients and 1% (95% CI 0% to 2%) in ethnic minority patients. Low language proficiency, inadequate health literacy and low educational level did not increase the risk of an AE. CONCLUSIONS: Compared with Dutch patients, ethnic minority patients were not at increased risk of AEs while receiving care in Dutch hospitals. Healthcare providers seem to have responded effectively to specific patient care needs, but we do not know whether this occurred in an ad hoc or in a systematic way. PMID- 25550291 TI - Do smoking habits differ between women and men in contemporary Western populations? Evidence from half a million people in the UK Biobank study. AB - OBJECTIVES: Several studies have shown that smoking may confer a greater excess risk for chronic diseases in women compared with men. The reasons for this excess risk of smoking in women are unclear, yet sex differences in smoking habits may play a role. We, thus, characterised sex differences in smoking habits in a contemporary Western population. DESIGN: Cross-sectional population-based study. SETTING: UK Biobank Resource. PARTICIPANTS: 499,797 (54% women) individuals with data on smoking habits. MAIN OUTCOME MEASURES: Women-to-men prevalence ratios in smoking status, and the women-minus-men mean difference in age at smoking initiation, number of cigarettes smoked daily and age at smoking cessation in 5 year birth cohort bands. RESULTS: The women-to-men ever-smoking ratio ranged from 0.57 in the oldest to 0.87 in the youngest birth cohort. In the oldest cohort, born 1935-1939, women started smoking 1.9 years (95% CI 1.7 to 2.1) later than did men, but in those born after 1959 there was no difference in the age at initiation. The oldest women smoked 5.3 (95% CI 4.7 to 5.9) cigarettes per day fewer than did the oldest men, compared with 2.0 (95% CI 1.7 to 2.3) fewer cigarettes smoked per day in the youngest, born 1965-1969. Among quitters, women born before 1945 were, on average, 1.5 years older than their male contemporaries, but this differential was 1 year or less among people born after 1949. CONCLUSIONS: Differences in smoking behaviour between women and men have decreased over time. Even past differentials are unlikely to explain the increased susceptibility to smoking-related chronic disease in women compared with men that has previously been observed. Future studies are required to determine whether sex differences in the physiological and biological effects of smoking are responsible for the differential impact of smoking on health in women and men. PMID- 25550292 TI - Does a healthy lifestyle behaviour influence the prognosis of low back pain among men and women in a general population? A population-based cohort study. AB - OBJECTIVES: To study the influence of healthy lifestyle behaviour on the prognosis of occasional low back pain among men and women in a general population. DESIGN: Cohort study with a 4-year follow-up. SETTINGS: General population in Stockholm County, Sweden. PARTICIPANTS: The study sample comprised 3938 men and 5056 women aged 18-84 from the Stockholm Public Health Cohort reporting occasional low back pain in the baseline questionnaire 2006. MEASURES: Lifestyle factors and potential confounders were assessed at baseline. The lifestyle factors smoking habits, alcohol consumption, leisure physical activity and consumption of fruit and vegetables were dichotomised using recommendations for a health-enhancing lifestyle and combined to form the exposure variable 'healthy lifestyle behaviour'. The exposure was categorised into five levels according to the number of healthy lifestyle factors met. The follow-up questionnaire in 2010 gave information about the outcome, long duration troublesome low back pain. Crude and adjusted binomial regression models were applied to estimate the association between the exposure and the outcome analysing men and women separately. RESULTS: The risk of developing long duration troublesome low back pain among women with occasional low back pain decreased with increasing healthy lifestyle behaviour (trend test: p=0.006). 21% (28/131) among women with no healthy lifestyle factor (reference) experienced the outcome compared to 9% (36/420) among women with all four factors. Compared to the reference group, the risk was reduced by 35% (RR 0.65, 95% CI 0.44 to 0.96) for women with one healthy lifestyle factor and 52% (RR 0.48, 95% CI 0.31 to 0.77) for women with all four healthy lifestyle factors. There were no clear associations found among men. CONCLUSIONS: Healthy lifestyle behaviour seems to decrease the risk of developing long duration troublesome low back pain among women with occasional low back pain and may be recommended to improve the prognosis. PMID- 25550293 TI - Prevalence and determinants of caesarean section in private and public health facilities in underserved South Asian communities: cross-sectional analysis of data from Bangladesh, India and Nepal. AB - OBJECTIVES: To describe the prevalence and determinants of births by caesarean section in private and public health facilities in underserved communities in South Asia. DESIGN: Cross-sectional study. SETTING: 81 community-based geographical clusters in four locations in Bangladesh, India and Nepal (three rural, one urban). PARTICIPANTS: 45,327 births occurring in the study areas between 2005 and 2012. OUTCOME MEASURES: Proportion of caesarean section deliveries by location and type of facility; determinants of caesarean section delivery by location. RESULTS: Institutional delivery rates varied widely between settings, from 21% in rural India to 90% in urban India. The proportion of private and charitable facility births delivered by caesarean section was 73% in Bangladesh, 30% in rural Nepal, 18% in urban India and 5% in rural India. The odds of caesarean section were greater in private and charitable health facilities than in public facilities in three of four study locations, even when adjusted for pregnancy and delivery characteristics, maternal characteristics and year of delivery (Bangladesh: adjusted OR (AOR) 5.91, 95% CI 5.15 to 6.78; Nepal: AOR 2.37, 95% CI 1.62 to 3.44; urban India: AOR 1.22, 95% CI 1.09 to 1.38). We found that highly educated women were particularly likely to deliver by caesarean in private facilities in urban India (AOR 2.10; 95% CI 1.61 to 2.75) and also in rural Bangladesh (AOR 11.09, 95% CI 6.28 to 19.57). CONCLUSIONS: Our results lend support to the hypothesis that increased caesarean section rates in these South Asian countries may be driven in part by the private sector. They also suggest that preferences for caesarean delivery may be higher among highly educated women, and that individual-level and provider-level factors interact in driving caesarean rates higher. Rates of caesarean section in the private sector, and their maternal and neonatal health outcomes, require close monitoring. PMID- 25550294 TI - The relationship between the number of cardiologists and clinical practice patterns in acute heart failure: a cross-sectional observational study. AB - OBJECTIVES: Despite the increasing burden of acute heart failure (AHF) on healthcare systems, the association between centralised cardiovascular specialist care and the quality of AHF care remains unknown. We examine the relationship between the number of cardiologists per hospital and hospital practice variations. DESIGN, SETTING AND PARTICIPANTS: In a retrospective observational study, we analysed 38,668 patients with AHF admitted to 546 Japanese acute care hospitals between 2010 and 2011 using the Diagnosis Procedure Combination administrative claims database. Sample hospitals were categorised into four groups according to the number of cardiologists per facility (none, 1-4, 5-9 and >=10). To confirm the capability of administrative data to identify patients with AHF, the >=10 cardiologists group was compared with two recent clinical registries in Japan. MAIN OUTCOME MEASURES: Using multivariable logistic regression models, patient risk-adjusted in-hospital mortality rates and age-sex adjusted ORs of various AHF therapies were calculated and compared among four hospital groups. RESULTS: The >=10 cardiologists group of hospitals from the administrative database had similar major underlying disease incidence and therapeutic practices to those of the clinical registry hospitals. Age-adjusted and sex-adjusted ORs of various AHF therapies in the four hospital groups revealed wide practice variations associated with the number of cardiologists. Adjusted in-hospital mortality demonstrated a negative association with the number of cardiologists. In addition, the different hospital-level distribution patterns of specific therapeutic practices illustrated the diffusion process of therapies across facilities. CONCLUSIONS: Wide practice variations in AHF care were associated with the number of cardiologists per facility, indicating a possible relationship between the quality of AHF care and manpower resources. The provision of recommended therapies increased together with the number of cardiologists. PMID- 25550295 TI - Relationship between social cognitive theory constructs and self-reported condom use: assessment of behaviour in a subgroup of the Safe in the City trial. AB - OBJECTIVES: Previous studies have found social cognitive theory (SCT)-framed interventions are successful for improving condom use and reducing sexually transmitted infections (STIs). We conducted a secondary analysis of behavioural data from the Safe in the City intervention trial (2003-2005) to investigate the influence of SCT constructs on study participants' self-reported use of condoms at last intercourse. METHODS: The main trial was conducted from 2003 to 2005 at three public US STI clinics. Patients (n=38,635) were either shown a 'safer sex' video in the waiting room, or received the standard waiting room experience, based on their visit date. A nested behavioural assessment was administered to a subsample of study participants following their index clinic visit and again at 3 months follow-up. We used multivariable modified Poisson regression models to examine the relationships among SCT constructs (sexual self-efficacy, self control self-efficacy, self-efficacy with most recent partner, hedonistic outcome expectancies and partner expected outcomes) and self-reported condom use at last sex act at the 3-month follow-up study visit. RESULTS: Of 1252 participants included in analysis, 39% reported using a condom at last sex act. Male gender, homosexual orientation and single status were significant correlates of condom use. Both unadjusted and adjusted models indicate that sexual self-efficacy (adjusted relative risk (RRa)=1.50, 95% CI 1.23 to 1.84), self-control self efficacy (RRa=1.67, 95% CI 1.37 to 2.04), self-efficacy with most recent partner (RRa=2.56, 95% CI 2.01 to 3.27), more favourable hedonistic outcome expectancies (RRa=1.83, 95% CI 1.54 to 2.17) and more favourable partner expected outcomes (RRa=9.74, 95% CI 3.21 to 29.57) were significantly associated with condom use at last sex act. CONCLUSIONS: Social cognitive skills, such as self-efficacy and partner expected outcomes, are an important aspect of condom use behaviour. TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT00137370). PMID- 25550296 TI - Moxibustion for the treatment of pressure ulcers: study protocol for a pilot, multicentre, randomised controlled trial. AB - INTRODUCTION: Pressure ulcers are common in the elderly and immobile. Currently, there are few proven effective treatments for pressure ulcers. This trial aims to evaluate the feasibility, efficacy and safety of moxibustion for pressure ulcers. METHODS/ANALYSIS: This is a multicentre, two-armed, parallel-design randomised controlled trial (RCT). 30 eligible patients with pressure ulcers will be randomised in a ratio of 1:1 to the treatment group and control group. The participants in the treatment group will undergo indirect moxibustion for 30 min before application of a dressing, one session daily, five sessions weekly for 4 weeks. The patients in the control group will only receive a dressing, applied in the same way as in the treatment group. Both groups will be followed up for 3 months. The primary outcome measures will be wound surface area (WSA) and proportion of ulcers healed within trial period (PUHTP). The secondary outcomes will be the Pressure Ulcer Scale for Healing (PUSH Tool), visual analogue scale (VAS) and adverse events. All outcomes will be evaluated at the beginning of the study, at the end of the second week, at 4 weeks after randomisation and at 1 and 3 months after treatment cessation. ETHICS/DISSEMINATION: This trial has undergone ethical scrutiny and been approved by the ethics review boards of First Affiliated Hospital of Heilongjiang University of Chinese Medicine and Second Affiliated Hospital of Heilongjiang University of Chinese Medicine (Permission number: HZYEYLP2014). The results of this study will provide clinical evidence for the feasibility, efficacy and safety of moxibustion for pressure ulcers. TRIAL REGISTRATION NUMBER: ChiCTR-TRC-13003959. PMID- 25550297 TI - Standardised method for reporting exercise programmes: protocol for a modified Delphi study. AB - INTRODUCTION: Exercise is integral to health across the lifespan and important for people with chronic health conditions. A systematic review of exercise trials for chronic conditions reported suboptimal descriptions of the evaluated interventions and concluded that this hinders interpretation and replication. The aim of this project is to develop a standardised method for reporting essential exercise programme details being evaluated in clinical trials. METHODS AND ANALYSIS: A modified Delphi technique will be used to gain consensus among international exercise experts. We will use three sequential rounds of anonymous online questionnaires to refine a standardised checklist. A draft checklist of potentially relevant items was developed based on the results of a systematic review of exercise systematic reviews. An international panel of experts was identified by exercise systematic review authorship, established international profile in exercise research and practice and by peer referral. In round 1, the international panel of experts will be asked to rate the importance of each draft item and provide additional suggestions for revisions or new items. Consensus will be considered reached if at least 70% of the panel strongly agree/disagree that an item should be included or excluded. Where agreement is not reached or there are suggestions for altered or new items, these will be taken to round 2 together with an aggregated summary of round 1 responses. Following the second round, a ranking of item importance will be made to rationalise the number of items. The final template will be distributed to panel members for approval. ETHICS AND DISSEMINATION: Ethics approval was received from The Cabrini Institute Ethics Committee, Melbourne, Australia (HREC 02-07-04-14). We plan to use a stepwise process to develop and refine a standardised and internationally agreed template for explicit reporting of exercise programmes. The template will be generalisable across all types of exercise interventions. The findings will be disseminated through peer-reviewed publications and conference presentations. PMID- 25550298 TI - Mycothermus thermophilus gen. et comb. nov., a new home for the itinerant thermophile Scytalidium thermophilum (Torula thermophila). AB - Thermophilic fungi have received substantial attention in industry for their potential to produce thermostable enzymes and as production platforms tolerant of high temperature. Studies exploring the ecology and biosystematics of thermophilic fungi have lagged behind studies in applied biology. The species commonly known as Scytalidium thermophilum (Chaetomiaceae) is one of the most frequently encountered organisms in surveys of thermophilic fungi. There is evidence that it is ecologically and economically important, for example in the context of commercial mushroom growing. As described here, this species should not be placed in the genus Scytalidium or any other existing genus. We propose a new genus and combination, Mycothermus thermophilus. PMID- 25550299 TI - Neurospora crassa ASM-1 complements the conidiation defect in a stuA mutant of Aspergillus nidulans. AB - Aspergillus nidulans StuA and Neurospora crassa ASM-1 are orthologous APSES (ASM 1, PHD1, SOK2, Efg1, StuA) transcription factors conserved across a diverse group of fungi. StuA and ASM-1 have roles in asexual (conidiation) and sexual (ascospore formation) development in both organisms. To address the hypothesis that the last common ancestor of these diverse fungi regulated conidiation with similar genes, asm-1 was introduced into the stuA1 mutant of A. nidulans. Expression of asm-1 complemented defective conidiophore morphology and restored conidia production to wild type levels in stuA1. Expression of asm-1 in the stuA1 strain did not rescue the defect in sexual development. When the conidiation regulator AbaA was tagged at its C-terminus with GFP in A. nidulans, it localized to nuclei in phialides. When expressed in the stuA1 mutant, AbaA::GFP localized to nuclei in conidiophores but no longer was confined to phialides, suggesting that expression of AbaA in specific cell types of the conidiophore was conditioned by StuA. Our data suggest that the function in conidiation of StuA and ASM-1 is conserved and support the view that, despite the great morphological and ontogenic diversity of their condiphores, the last common ancestor of A. nidulans and N. crassa produced an ortholog of StuA that was involved in conidiophore development. PMID- 25550300 TI - Fusarium dactylidis sp. nov., a novel nivalenol toxin-producing species sister to F. pseudograminearum isolated from orchard grass (Dactylis glomerata) in Oregon and New Zealand. AB - The B trichothecene toxin-producing clade (B clade) of Fusarium includes the etiological agents of Fusarium head blight, crown rot of wheat and barley and stem and ear rot of maize. B clade isolates also have been recovered from several wild and cultivated grasses, including Dactylis glomerata (orchard grass or cock's foot), one of the world's most important forage grasses. Two isolates from the latter host are formally described here as F. dactylidis. Phenotypically F. dactylidis most closely resembles F. ussurianum from the Russian Far East. Both species produce symmetrical sporodochial conidia that are similar in size and curved toward both ends. However, conidia of F. ussurianum typically end in a narrow apical beak while the apical cell of F. dactylidis is acute. Fusarium dactylidis produced nivalenol mycotoxin in planta as well as low but detectable amounts of the estrogenic mycotoxin zearalenone in vitro. Results of a pathogenicity test revealed that F. dactylidis induced mild head blight on wheat. PMID- 25550301 TI - A specific type of cyclin-like F-box domain gene is involved in the cryogenic autolysis of Volvariella volvacea. AB - Cryogenic autolysis is a typical phenomenon of abnormal metabolism in Volvariella volvacea. Recent studies have identified 20 significantly up-regulated genes via high-throughput sequencing of the mRNAs expressed in the mycelia of V. volvacea after cold exposure. Among these significantly up-regulated genes, 15 annotated genes were used for functional annotation cluster analysis. Our results showed that the cyclin-like F-box domain (FBDC) formed the functional cluster with the lowest P-value. We also observed a significant expansion of FBDC families in V. volvacea. Among these, the FBDC3 family displayed the maximal gene expansion in V. volvacea. Gene expression profiling analysis revealed only one FBDC gene in V. volvacea (FBDV1) that was significantly up-regulated, which is located in the FBDC3 family. Comparative genomics analysis revealed the homologous sequences of FBDV1 with high similarity were clustered on the same scaffold. However, FBDV1 was located far from these clusters, indicating the divergence of duplicated genes. Relative time estimation and rate test provided evidence for the divergence of FBDV1 after recent duplications. Real-time RT-PCR analysis confirmed that the expression of the FBDV1 was significantly up-regulated (P < 0.001) after cold-treatment of V. volvacea for 4 h. These observations suggest that the FBDV1 is involved in the cryogenic autolysis of V. volvacea. PMID- 25550302 TI - Nivicolous Stemonitales from the Austral Andes: analysis of morphological variability, distribution and phenology as a first step toward testing the large scale coherence of species and biogeographical properties. AB - Nivicolous myxomycetes occur at the edge of spring-melting snow in mountainous areas. They are mostly considered cosmopolitan species morphologically and ecologically uniform across their entire distribution ranges. Thus, long-distance dispersal has been suggested to be the main mechanism shaping their ranges and geographical variability patterns. To test this hypothesis we conducted the first detailed analysis of morphological variability, occurrence frequency and phenology of nivicolous myxomycetes collected in the hitherto unexplored Austral Andes of South America (southern hemisphere = SH) in the comparative context of data from the northern hemisphere (NH). We used Stemonitales, the most representative and numerous taxonomic order in nivicolous myxomycetes, as a model. A total of 131 South American collections represented 13 species or morphotypes. One of them, Lamproderma andinum, is new to science and described here. Several others, L. aeneum, L. album, L. pulveratum, "Meriderma aff. aggregatum ad. int.", M. carestiae and "M. spinulosporum ad. int.", were previously unknown from the SH. Lamproderma ovoideum is reported for the first time from South America and Collaria nigricapillitia is new for Argentina. The fine-scale morphological analysis of all species from the study area and reference NH material demonstrated a high intraspecific variability in most of them. This suggests isolation and independent evolutionary processes among remote populations. On the other hand, the uniform morphology of a few species indicates that long-distance dispersal is also an effective mechanism, although not as universal as usually assumed, in some nivicolous myxomycetes. Analysis of nivicolous species assemblages also showed significant differences among major geographic regions in that the Stemonitales were significantly less common in the SH than in the NH. Furthermore, the occurrence of nivicolous species in summer and autumn, out of the typical phenological season, is recognized as a possible distinctive phenomenon for the SH populations. PMID- 25550303 TI - True morels (Morchella, Pezizales) of Europe and North America: evolutionary relationships inferred from multilocus data and a unified taxonomy. AB - Applying early names, with or without original material, to genealogical species is challenging. For morels this task is especially difficult because of high morphological stasis and high plasticity of apothecium color and shape. Here we propose a nomenclatural revision of true morels (Morchella, Pezizales) from Europe and North America, based on molecular phylogenetic analyses of portions of the genes for RNA polymerase II largest subunit (RPB1) and second largest subunit (RPB2), translation elongation factor-1alpha (TEF1), the nuc rDNA region encompassing the internal transcribed spacers 1 and 2, along with the 5.8S rDNA (ITS), and partial nuc 28S rDNA D1-D2 domains (28S). The 107 newly sequenced collections were from both continents, including 48 types, together with previously published sequences. Names are applied to 30 of the 65 currently recognized genealogical species. Results of the present study revealed that the number of Morchella species in Europe (n = 21) is nearly identical to that in North America (n = 22). Only seven species were found on both continents, consistent with previous reports of high continental endemism within the genus. Presently it is not possible to tell whether the transoceanic disjunctions were due to human activities, migration across a Bering land bridge or long-distance dispersal. In an effort to stabilize the taxonomy, due in part to the recent publication of synonyms for 11 of the species, accepted names are presented together with their corresponding later synonyms. A new subclade that includes holotypes of M. castanea and M. brunneorosea is identified in sect. Morchella (Esculenta Clade). Lectotypes for Morchella deliciosa, M. eximia and M. tridentina are designated here, as well as epitypes for M. dunalii, M. eximia, M. purpurascens and M. vulgaris. Morchella conica was determined to be illegitimate, and further research is required to determine the identity of M. elata and M. inamoena. PMID- 25550304 TI - Thelephora versatilis and Thelephora pseudoversatilis: two new cryptic species with polymorphic basidiomes inhabiting tropical deciduous and sub-perennial forests of the Mexican Pacific coast. AB - Thelephora is a genus of ectomycorrhizal basidiomycetes with basidiomes of varied shape which has been poorly studied in tropical ecosystems. In this paper, we present Thelephora versatilis and Thelephora pseudoversatilis, two new species collected in the same localities of deciduous and sub-perennial tropical forests of Jalisco, Mexico. Basidiomes of both species are brownish gray to violet brown with clavarioid-mesopodal, sub-resupinate or completely resupinate growth forms. In turn, phylogenetic analyses using nrDNA ITS sequences showed that these species are not closed related, nevertheless they are part of a well-supported clade conformed by several species of Thelephora, Tomentella and some undescribed Thelephorales. Morphological segregation of these species was attained by analyzing spore and hyphae characters using a wide sample. Significant statistical differences between the new species were observed regarding spore size, spine size and context hyphae width. This work exemplifies the relevance of integrating both morphological and molecular data, as well of the use of an appropriate sample size in order to discriminate among morphological cryptic species. PMID- 25550305 TI - Prevalence of Symptoms and Quality of Life Among Jordanian Cancer Patients. AB - In Jordan, little is known about cancer-related symptoms prevalence, severity, and its impacts on patients' quality of life. Therefore, this study was conducted to estimate cancer-related symptoms prevalence, severity, and predictors of quality of life of cancer patients in Jordan. A descriptive cross-sectional survey design was used. The sample consisted of 498 Jordanian cancer patients. There were slightly more males (51.6%) and a mean age of 44.3 (SD = 15.3) years. The mean of the number of symptoms reported by patients was 11 (SD = 3.3). The most prevalent symptoms were fatigue (92.5%), feeling drowsy (87.1%), lack of appetite (86.3%), being distressed (86.1%), and pain (85.5%). Furthermore, Jordanian cancer patients had low mean total scores for quality of life at a level of 18.5 (SD = 4.9). A comprehensive palliative care program is recommended, led by a representative from the Ministry of Health, to integrate palliative care within the current health care system in Jordan. PMID- 25550306 TI - Experiences With Family Health Conversations at Residential Homes for Older People. AB - The aim of this study was to highlight family members' experiences of participating in Family Health Conversation (FamHC), based on families in which a family member was living in a residential home for older people. A total of 10 families and 22 family members participated in evaluating family interviews 1 month after participating in FamHC. The interviews were analyzed by qualitative content analysis. The main finding was being a part of FamHC increased family members' insights, understanding, and communication within the family. Getting confirmation from nurses was essential to cope with the new life situation, which also meant that they felt comfortable to partly hand over the responsibility for the older person who moved to the residential home. By being open and expressing their feelings, a bad conscience could be relieved. These findings showed that FamHC could be helpful for family members in adapting to this novel situation. PMID- 25550307 TI - Test-retest reliability and validity of the Sniffin' TOM odor memory test. AB - Few attempts have been made to develop an olfactory test that captures episodic retention of olfactory information. Assessment of episodic odor memory is of particular interest in aging and in the cognitively impaired as both episodic memory deficits and olfactory loss have been targeted as reliable hallmarks of cognitive decline and impending dementia. Here, 96 healthy participants (18-92 years) and an additional 19 older people with mild cognitive impairment were tested (73-82 years). Participants were presented with 8 common odors with intentional encoding instructions that were followed by a yes-no recognition test. After recognition completion, participants were asked to identify all odors by means of free or cued identification. A retest of the odor memory test (Sniffin' TOM = test of odor memory) took place 17 days later. The results revealed satisfactory test-retest reliability (0.70) of odor recognition memory. Both recognition and identification performance were negatively affected by age and more pronounced among the cognitively impaired. In conclusion, the present work presents a reliable, valid, and simple test of episodic odor recognition memory that may be used in clinical groups where both episodic memory deficits and olfactory loss are prevalent preclinically such as Alzheimer's disease. PMID- 25550310 TI - Development of a computational biomechanical infant model for the investigation of infant head injury by shaking. AB - The inertial loading thresholds for infant head injury are of profound medico legal and safety-engineering significance. Injurious experimentation with infants is impossible, and physical and computational biomechanical modelling has been frustrated by a paucity of paediatric biomechanical data. This study describes the development of a computational infant model (MD Adams(r)) by combining radiological, kinematic, mechanical modelling and literature-based data. Previous studies have suggested the neck as critical in determining inertial head loading. The biomechanical effects of varying neck stiffness parameters during simulated shakes were investigated, measuring peak translational and rotational accelerations and rotational velocities at the vertex. A neck quasi-static stiffness of 0.6 Nm/deg and lowest rate-dependent stiffness predisposed the model infant head to the highest accelerations. Plotted against scaled infant injury tolerance curves, simulations produced head accelerations commensurate with those produced during simulated physical model shaking reported in the literature. The model provides a computational platform for the exploitation of improvements in head biofidelity for investigating a wider range of injurious scenarios. PMID- 25550311 TI - Drug industry "freebies" and sponsorship will be banned in India from January 2015. PMID- 25550312 TI - Exploring the relationship between disease-related knowledge and health risk behaviours in young people with congenital heart disease. AB - BACKGROUND: In order to prevent cardiac complications, young people with congenital heart disease (CHD) should conduct heart-healthy behaviours. Therefore, they are assumed to have a good understanding of their disease. However, empirical data on the relationship between disease-related knowledge and health behaviours in this population is lacking. AIMS: This study aimed (a) to describe the health risk behaviours of young people with CHD; (b) to describe their level of disease-related knowledge; and (c) to explore the relationship between the level of disease-related knowledge and health risk behaviours. METHODS: Data were collected in 429 young people with CHD. Health risk behaviours were assessed using the Health Behaviour Scale for CHD and the Baecke questionnaire. Disease-related knowledge was evaluated using the Leuven Knowledge Questionnaire for CHD. An overall health behaviour risk score, a total knowledge score and eight thematic knowledge subscale scores were calculated. Eight relationships between knowledge and health risk behaviours were tested. RESULTS: Patients presented moderate to good overall health behaviour. Disease-related knowledge was found to be relatively poor. Furthermore, better understanding of endocarditis was significantly associated with the performance of annual dental visits. CONCLUSIONS: This study was the first to explore the relationship between disease-related knowledge and health risk behaviours in young people with CHD. Little evidence, however, was found to support this relationship. Additional studies are needed to evaluate the effectiveness of other strategies altering the health-compromising behaviours of these patients. PMID- 25550313 TI - Cecal ligation and puncture accelerates development of ventilator-induced lung injury. AB - Sepsis is a leading cause of respiratory failure requiring mechanical ventilation, but the interaction between sepsis and ventilation is unclear. While prior studies demonstrated a priming role with endotoxin, actual septic animal models have yielded conflicting results regarding the role of preceding sepsis on development of subsequent ventilator-induced lung injury (VILI). Using a rat cecal ligation and puncture (CLP) model of sepsis and subsequent injurious ventilation, we sought to determine if sepsis affects development of VILI. Adult male Sprague-Dawley rats were subject to CLP or sham operation and, after 12 h, underwent injurious mechanical ventilation (tidal volume 30 ml/kg, positive end expiratory pressure 0 cmH2O) for either 0, 60, or 120 min. Biochemical and physiological measurements, as well as computed tomography, were used to assess injury at 0, 60, and 120 min of ventilation. Before ventilation, CLP rats had higher levels of alveolar neutrophils and interleukin-1beta. After 60 min of ventilation, CLP rats had worse injury as evidenced by increased alveolar inflammation, permeability, respiratory static compliance, edema, oxygenation, and computed tomography. By 120 min, CLP and sham rats had comparable levels of lung injury as assessed by many, but not all, of these metrics. CLP rats had an accelerated and worse loss of end-expiratory lung volume relative to sham, and consistently higher levels of alveolar interleukin-1beta. Loss of aeration and progression of edema was more pronounced in dependent lung regions. We conclude that CLP initiated pulmonary inflammation in rats, and accelerated the development of subsequent VILI. PMID- 25550317 TI - New ESC guidelines: aortic disease. PMID- 25550315 TI - Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer. AB - Human studies and clues from animal models have provided important links between gastrointestinal (GI) tract bacteria and colon cancer. Gut microbiota antigenic stimuli play an important role in shaping the intestinal immune responses. Therefore, especially in the case of inflammation-associated colon cancer, gut bacteria antigens may affect tumorigenesis. The present study aimed to investigate the effects of the oral administration of a bacterial product with known immunomodulatory properties on inflammation-driven colorectal neoplasmatogenesis. For that, we used cholera-toxin and a well-established mouse model of colon cancer in which neoplasia is initiated by a single dose of the genotoxic agent azoxymethane (AOM) and subsequently promoted by inflammation caused by the colitogenic substance dextran sodium sulfate (DSS). We found that a single, low, non-pathogenic dose of CT, given orally at the beginning of each DSS treatment cycle downregulated neutrophils and upregulated regulatory T-cells and IL-10 in the colonic mucosa. The CT-induced disruption of the tumor-promoting character of DSS-induced inflammation led to the reduction of the AOM-initiated colonic polypoidogenesis. This result adds value to the emerging notion that certain GI tract bacteria or their products affect the immune system and render the microenvironment of preneoplastic lesions less favorable for promoting their evolution to cancer. PMID- 25550318 TI - Guidelines for the diagnosis, management and prevention of implantable cardiac electronic device infection. PMID- 25550319 TI - Exercise pulmonary hypertension in primary mitral regurgitation: what does it predict? PMID- 25550314 TI - Working with nitric oxide and hydrogen sulfide in biological systems. AB - Nitric oxide (NO) and hydrogen sulfide (H2S) are gasotransmitter molecules important in numerous physiological and pathological processes. Although these molecules were first known as environmental toxicants, it is now evident that that they are intricately involved in diverse cellular functions with impact on numerous physiological and pathogenic processes. NO and H2S share some common characteristics but also have unique chemical properties that suggest potential complementary interactions between the two in affecting cellular biochemistry and metabolism. Central among these is the interactions between NO, H2S, and thiols that constitute new ways to regulate protein function, signaling, and cellular responses. In this review, we discuss fundamental biochemical principals, molecular functions, measurement methods, and the pathophysiological relevance of NO and H2S. PMID- 25550320 TI - Morg1 heterozygous deficiency ameliorates hypoxia-induced acute renal injury. AB - Acute kidney injury is a common complication of critically ill patients and may occur as a result of various factors and coexisting previous illnesses. Some pathophysiological responses seen in critical illness can be similar to the human physiological response to extreme environmental challenges, such as hypoxia from reduced oxygen availability at high altitudes (systemic hypoxia). Due to oxygen deficiency, mammalian cells activate the transcriptional factor hypoxia-inducible factor (HIF); its degradation is regulated by prolyl hydroxylase 3 (PHD3) in interaction with the scaffold protein MAPK organizer 1 (Morg1). While homozygous Morg1(-/-) mice are embryonically lethal, the kidneys of heterozygous Morg1(+/-) mice reveal elevated HIF protein levels and increased serum erythropoietin compared with wild-type Morg1(+/+) mice. In this study, we exposed wild-type and Morg1(+/-) mice to 10% oxygen in a hypoxic chamber for 3 days. This reduced oxygen concentration leads to a deterioration of renal function, an increase in renal inflammation, and significantly more tubular damage and apoptosis in the kidneys of wild-type (Morg1(+/+)) mice. In sharp contrast, Morg1(+/-) kidneys were protected against systemic hypoxia. They show significantly less renal lesions, reduced or no inflammation, and less tubular damage and apoptosis. Thus short-term systemic and subsequently renal hypoxia which may occur in many patients in the intensive care unit induces in wild-type mice renal injury, which is ameliorated by Morg1 deficiency. Our findings suggest that therapeutical manipulation of Morg1 may be an interesting novel target to prevent hypoxia associated renal damage. PMID- 25550322 TI - CRISPR-Cas9-mediated single-gene and gene family disruption in Trypanosoma cruzi. AB - Trypanosoma cruzi is a protozoan parasite of humans and animals, affecting 10 to 20 million people and innumerable animals, primarily in the Americas. Despite being the largest cause of infection-induced heart disease worldwide, even among the neglected tropical diseases (NTDs) T. cruzi is considered one of the least well understood and understudied. The genetic complexity of T. cruzi as well as the limited set of efficient techniques for genome engineering contribute significantly to the relative lack of progress in and understanding of this pathogen. Here, we adapted the CRISPR-Cas9 system for the genetic engineering of T. cruzi, demonstrating rapid and efficient knockout of multiple endogenous genes, including essential genes. We observed that in the absence of a template, repair of the Cas9-induced double-stranded breaks (DSBs) in T. cruzi occurs exclusively by microhomology-mediated end joining (MMEJ) with various-sized deletions. When a template for DNA repair is provided, DSB repair by homologous recombination is achieved at an efficiency several orders of magnitude higher than that in the absence of CRISPR-Cas9-induced DSBs. We also demonstrate the high multiplexing capacity of CRISPR-Cas9 in T. cruzi by knocking down expression of an enzyme gene family consisting of 65 members, resulting in a significant reduction of enzymatic product with no apparent off-target mutations. Lastly, we show that Cas9 can mediate disruption of its own coding sequence, rescuing a growth defect in stable Cas9-expressing parasites. These results establish a powerful new tool for the analysis of gene functions in T. cruzi, enabling the study of essential genes and their functions and analysis of the many large families of related genes that occupy a substantial portion of the T. cruzi genome. IMPORTANCE: Trypanosoma cruzi, the causative agent of human Chagas disease, is the leading worldwide cause of infectious myocarditis. Diagnostics for the infection are relatively poor, treatment options are limited and of variable effectiveness, and suitable vaccines are nonexistent. The T. cruzi genome is replete with genes of unknown function and greatly expanded gene families with hundreds of members. The absence of facile genetic engineering tools, including RNA interference, for T. cruzi has prevented elucidation of gene and gene family function and the development of better infection prevention and control measures. In this study, we demonstrate that the CRISPR-Cas9 system is a versatile and powerful tool for genome manipulations in T. cruzi, bringing new opportunities for unraveling the functions of previously uncharacterized genes and how this human pathogen engages its large families of genes encoding surface proteins to interact with human and animal hosts. PMID- 25550321 TI - LocZ is a new cell division protein involved in proper septum placement in Streptococcus pneumoniae. AB - How bacteria control proper septum placement at midcell, to guarantee the generation of identical daughter cells, is still largely unknown. Although different systems involved in the selection of the division site have been described in selected species, these do not appear to be widely conserved. Here, we report that LocZ (Spr0334), a newly identified cell division protein, is involved in proper septum placement in Streptococcus pneumoniae. We show that locZ is not essential but that its deletion results in cell division defects and shape deformation, causing cells to divide asymmetrically and generate unequally sized, occasionally anucleated, daughter cells. LocZ has a unique localization profile. It arrives early at midcell, before FtsZ and FtsA, and leaves the septum early, apparently moving along with the equatorial rings that mark the future division sites. Consistently, cells lacking LocZ also show misplacement of the Z ring, suggesting that it could act as a positive regulator to determine septum placement. LocZ was identified as a substrate of the Ser/Thr protein kinase StkP, which regulates cell division in S. pneumoniae. Interestingly, homologues of LocZ are found only in streptococci, lactococci, and enterococci, indicating that this close phylogenetically related group of bacteria evolved a specific solution to spatially regulate cell division. IMPORTANCE: Bacterial cell division is a highly ordered process regulated in time and space. Recently, we reported that the Ser/Thr protein kinase StkP regulates cell division in Streptococcus pneumoniae, through phosphorylation of several key proteins. Here, we characterized one of the StkP substrates, Spr0334, which we named LocZ. We show that LocZ is a new cell division protein important for proper septum placement and likely functions as a marker of the cell division site. Consistently, LocZ supports proper Z-ring positioning at midcell. LocZ is conserved only among streptococci, lactococci, and enterococci, which lack homologues of the Min and nucleoid occlusion effectors, indicating that these bacteria adapted a unique mechanism to find their middle, reflecting their specific shape and symmetry. PMID- 25550326 TI - PRSice: Polygenic Risk Score software. AB - SUMMARY: A polygenic risk score (PRS) is a sum of trait-associated alleles across many genetic loci, typically weighted by effect sizes estimated from a genome wide association study. The application of PRS has grown in recent years as their utility for detecting shared genetic aetiology among traits has become appreciated; PRS can also be used to establish the presence of a genetic signal in underpowered studies, to infer the genetic architecture of a trait, for screening in clinical trials, and can act as a biomarker for a phenotype. Here we present the first dedicated PRS software, PRSice ('precise'), for calculating, applying, evaluating and plotting the results of PRS. PRSice can calculate PRS at a large number of thresholds ("high resolution") to provide the best-fit PRS, as well as provide results calculated at broad P-value thresholds, can thin Single Nucleotide Polymorphisms (SNPs) according to linkage disequilibrium and P-value or use all SNPs, handles genotyped and imputed data, can calculate and incorporate ancestry-informative variables, and can apply PRS across multiple traits in a single run. We exemplify the use of PRSice via application to data on schizophrenia, major depressive disorder and smoking, illustrate the importance of identifying the best-fit PRS and estimate a P-value significance threshold for high-resolution PRS studies. AVAILABILITY AND IMPLEMENTATION: PRSice is written in R, including wrappers for bash data management scripts and PLINK-1.9 to minimize computational time. PRSice runs as a command-line program with a variety of user-options, and is freely available for download from http://PRSice.info CONTACT: jack.euesden@kcl.ac.uk or paul.oreilly@kcl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25550323 TI - A 2-pyridone-amide inhibitor targets the glucose metabolism pathway of Chlamydia trachomatis. AB - In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. IMPORTANCE: Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections. PMID- 25550327 TI - Self-esteem and fear of negative evaluation as mediators between family socioeconomic status and social anxiety in Chinese emerging adults. AB - AIMS: The social causation hypothesis suggests that the stress in connection with a depressing social position results in the development of mental disorders. This study examines the psychological mechanisms underlying the link between family socioeconomic status (SES) and social anxiety in Chinese emerging adults. METHODS: A self-administered questionnaire was given to a representative sample (N = 717) of undergraduate students (17-23 years old) at three universities in China. Correlational and structural equation modeling analyses were employed to test the hypothesized three-path effect of self-esteem and fear of negative evaluation (FNE) as mediators between family SES and social anxiety. RESULTS: Findings suggest the following: (1) the emerging adults belonging to families with low SES are at an increased risk of social anxiety, and (2) lower family SES caused lower self-esteem, which, in turn, serves to enhance the levels of FNE, thereby increasing social anxiety. CONCLUSION: In addressing the prevention and treatment of social anxiety, we conclude that preventive efforts toward improving self-esteem may help reduce social anxiety in individuals with low family SES. PMID- 25550328 TI - Phosphorus and calcium: a review for the adult nutrition support clinician. AB - Phosphorus (P) and calcium (Ca) serve vital roles in the human body and are essential components of nutrition support therapy. Regulation of P and regulation of Ca in the body are closely interrelated, and P and Ca homeostasis can be affected by several factors, including disease states, clinical condition, severity of illness, and medications. Nutrition support clinicians must understand these factors to prevent and treat P and Ca disorders in patients receiving nutrition support therapy. This review provides an overview of P and Ca for the adult nutrition support clinician, with some emphasis on the hospitalized inpatient. PMID- 25550329 TI - Prevalence of inadequate vitamin d status and associated factors in children with cystic fibrosis. AB - BACKGROUND: This study aimed to determine the prevalence of inadequate serum 25 hydroxyvitamin D (25(OH)D) levels in a pediatric Canadian cystic fibrosis (CF) population and to assess the effectiveness of a vitamin D supplementation protocol on improving vitamin D status. A secondary objective was to analyze factors that may be associated with inadequate 25(OH)D levels. METHODS: Vitamin D supplementation, 25(OH)D levels, and factors hypothesized to be associated with 25(OH)D levels were collected through a retrospective chart review (2010 and 2011) of 96 patients (1-18 years) at one CF clinic in Canada. Adequacy of 25(OH)D was set at >=75 nmol/L. Patients with inadequate 25(OH)D levels in 2010 were prescribed an additional 1000 IU/d for levels <60 nmol/L or 400 IU/d for levels 60-75 nmol/L. RESULTS: Inadequate 25(OH)D levels were observed in 26% of patients in 2010 and 23% in 2011. After supplementation was increased for those with inadequate 25(OH)D levels in 2010 (n = 20), a significant increase in 25(OH)D levels was observed in 2011 (P = .03). Adequate status was achieved in 50% of these patients (n = 10). Age was significantly negatively associated with 25(OH)D levels in both years (P = .002). Percentage of forced expiratory volume in 1 second was significantly positively associated with 25(OH)D levels in 2011 (P = .03). CONCLUSION: While vitamin D supplementation was effective at increasing serum 25(OH)D, this protocol did not achieve optimal serum 25(OH)D levels in 25% of the population. Increasing age had the strongest association with 25(OH)D. Current supplementation protocols may require reevaluation based on emerging evidence and revised Cystic Fibrosis Foundation guidelines. PMID- 25550332 TI - Calcium phosphate cement - gelatin powder composite testing in canine models: Clinical implications for treatment of bone defects. AB - Previous studies have reported the excellent biocompatibility of calcium phosphate cement. However, calcium phosphate cement needs further improvement in order for it to promote bone replacement and eventual bone substitution, as it exhibits slow biodegradability and thus remains in the body over an extended period of time. In this study, we mixed calcium phosphate cement with gelatin powder in order to create a composite containing macropores with interconnectivity, and we then implanted it into canine femurs from the diaphysis to the distal metaphysis. Eight dogs were divided into the sham group, the control (C0) group with 100 wt% calcium phosphate cement, the C10 group with 90 wt% calcium phosphate cement and 10 wt% gelatin powder, and the C15 group with 85 wt% calcium phosphate cement and 15 wt% gelatin powder. Bone replaceability in C10 and C15 at 3 and 6 months was evaluated by radiography, micro-CT, histomorphometry, and mineral apposition rate. New bone formation was seen in C10 and C15 although that was not seen in C0 at six months. The mineral apposition rate was significantly higher in C15 than in C10 in both the diaphysis and metaphysis, and the composite was found to have excellent biodegradability and bone replaceability in canine subjects. As the composite is easily and rapidly prepared, it is likely to become a new bone substitute for use in clinical settings. PMID- 25550331 TI - Neural correlates of suicidal ideation and its reduction in depression. AB - BACKGROUND: The neural correlates of suicidal ideation and its reduction after treatment are unknown. We hypothesized that increased regional cerebral glucose metabolism in the infralimbic cortex (Brodmann area 25), amygdala, and subgenual anterior cingulate cortex would be associated with suicidal ideation and its reduction after ketamine infusion. METHODS: Medication-free patients (n=19) with treatment-resistant major depressive disorder underwent positron emission tomography imaging at baseline and 230 minutes after an open-label ketamine infusion (0.5 mg/kg for 40 minutes). RESULTS: Baseline suicidal ideation and regional cerebral glucose metabolism in the infralimbic cortex were significantly correlated (r=.59, P=.007); but not overall mood scores (r=-.07, P=.79). Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex (r=.54, P=.02). Metabolism in other areas of interest was not significantly correlated with suicidal ideation or depression. CONCLUSION: The infralimbic cortex may be implicated in suicidal ideation. PMID- 25550330 TI - Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential. AB - BACKGROUND: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. METHODS: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. RESULTS: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. CONCLUSIONS: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2 related antioxidant potential. PMID- 25550336 TI - Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study. AB - OBJECTIVE: To describe the cross-sectional and longitudinal associations between knee regional effusion-synovitis and structural changes in older adults. METHODS: A total of 977 subjects were randomly selected from the local community (mean 62 years, 50% female) at baseline and 404 were followed up 2.6 years later. T2 weighted MRI was used to assess knee effusion-synovitis in four subregions: suprapatellar pouch, central portion, posterior femoral recess and subpopliteal recess. Knee cartilage defects, cartilage volume and bone marrow lesions (BMLs) were measured using MRI at baseline and follow-up. RESULTS: Cross-sectionally, effusion-synovitis in most subregions was significantly associated with a higher risk of cartilage defects, BMLs and reduced cartilage volume. Longitudinally, suprapatellar pouch effusion-synovitis at baseline predicted an increase in cartilage defects (p<0.01), loss of cartilage volume (p=0.04) and an increase in BMLs (p=0.02) in multivariable analyses. The significant associations of effusion synovitis with cartilage volume and BMLs disappeared after adjustment for cartilage defects. Effusion-synovitis in whole knee joint (p<0.01) and subpopliteal recess (p<0.05) was consistently associated with longitudinal changes in cartilage defects but not in cartilage volume and BMLs. CONCLUSIONS: There are independent associations between knee joint effusion-synovitis and knee cartilage defects in both cross-sectional and longitudinal analyses, suggesting a potential causal relationship. The associations of effusion-synovitis with BMLs and cartilage volume were largely dependent on cartilage defects, suggesting potential causal pathways. PMID- 25550337 TI - Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis. AB - OBJECTIVES: To evaluate maintenance of response while reducing intravenous abatacept dose from ~10 mg/kg to ~5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6. METHODS: This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ~10 mg/kg and ~5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, >=2 courses high-dose steroids, return to open-label abatacept ~10 mg/kg, or DAS28 (C reactive protein) >=3.2 at two consecutive visits). RESULTS: 108 patients were randomised (~10 mg/kg, n=58; ~5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (~10 mg/kg) vs 34% (~5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ~10 mg/kg group was 20.3-24.1 ug/mL, compared with 8.8-12.0 ug/mL for the ~5 mg/kg group. CONCLUSIONS: This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after >=1 year on abatacept (~10 mg/kg). TRIAL REGISTRATION NUMBER: NCT00989235. PMID- 25550338 TI - Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial. AB - OBJECTIVE: To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA). METHODS: Baseline and 3 month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and alpha-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression. RESULTS: During the 2-year follow-up, the proportion of patients testing positive declined significantly regarding antibodies to cVim, cFib and CEP-1, while anti-CCP antibody occurrence remained stable over time. Turning anti-cVim antibody negative was most common, and anti-cVim antibody seroreversion during the first three months associated with significantly less 2-year radiographic progression compared with patients who remained positive. Median antibody levels of all tested ACPAs declined uniformly during initial methotrexate therapy and following response to add-on therapy, with no significant relation to treatment regimen or radiographic progression. CONCLUSIONS: The influence of early antirheumatic therapy on ACPA seroreversions was markedly different across specificities, and early disappearance of anti-cVim antibodies associated with better radiological outcome. Thus, these data suggest that the disappearance of particular ACPA reactivities may be beneficial in early RA. TRIAL REGISTRATION NUMBER: WHO database at the Karolinska institute: CT20080004; and clinicaltrials.gov: NCT00764725. PMID- 25550339 TI - Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. AB - OBJECTIVE: To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN). STUDY DESIGN: This is an open randomised controlled parallel group study. METHODS: Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time. RESULTS: 150 patients (92% women; aged 35.5+/-12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8+/-26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by >=30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35). CONCLUSIONS: TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen. TRIAL REGISTRATION NUMBER: Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319). PMID- 25550340 TI - The effect of forced exercise on knee joints in Dio2(-/-) mice: type II iodothyronine deiodinase-deficient mice are less prone to develop OA-like cartilage damage upon excessive mechanical stress. AB - OBJECTIVE: To further explore deiodinase iodothyronine type 2 (DIO2) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of Dio2 deficiency. METHODS: Wild-type and C57BL/6-Dio2( /-) -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein-protein interactions. RESULTS: In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change >=1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1), supporting the use of forced running as an OA model in mice. Dio2-deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes. CONCLUSIONS: Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of Dio2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the Dio2 knockout (eg, Gnas) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr). These data further support DIO2 activity as a therapeutic target in OA. PMID- 25550341 TI - Enhanced mesenteric arterial responsiveness to angiotensin II is androgen receptor-dependent in prenatally protein-restricted adult female rat offspring. AB - Gestational protein restriction results in intrauterine growth restriction and hypertension in adult female growth-restricted rats. Enhanced vascular responsiveness to angiotensin II is observed, and blockade of the renin angiotensin system abolishes hypertension in adult growth-restricted rats, suggesting that the renin-angiotensin system contributes to intrauterine growth restriction-induced hypertension. Moreover, growth-restricted adult rats have higher plasma testosterone levels, and antiandrogen treatment abolishes hypertension, indicating an important role for testosterone. We hypothesized that androgens may play a pivotal role in the enhanced responsiveness to Ang II and hypertension. Female offspring of pregnant rats fed 20% protein (control) or 6% protein diet (protein restricted), at 6 mo of age, were studied. Plasma testosterone and mean arterial pressure in protein-restricted offspring were significantly higher compared to controls. Flutamide treatment (10 mg/kg/day subcutaneously for 10 days) reduced mean arterial pressure in protein-restricted offspring but was without significant effect in controls. Vascular Agtr1/Agtr2 ratio was significantly higher in protein-restricted offspring, an effect that was reversed by flutamide. Flutamide treatment did not have any effect on Agtr1/Agtr2 ratio in controls. Enhanced contractile response to angiotensin II in mesenteric arteries was observed in protein-restricted offspring compared with control. Flutamide treatment reversed the enhanced contractile response to angiotensin II in protein-restricted offspring without significant effect in controls. Vascular reactivity to phenylephrine was similar between the control and protein-restricted offspring with and without flutamide treatment, suggesting that enhanced contractile response and flutamide's reversal effect is specific to angiotensin II. These results suggest that prenatally protein-restricted rats exhibit an enhanced responsiveness to angiotensin II that is testosterone dependent. PMID- 25550342 TI - Uterine histotroph and conceptus development. I. cooperative effects of arginine and secreted phosphoprotein 1 on proliferation of ovine trophectoderm cells via activation of the PDK1-Akt/PKB-TSC2-MTORC1 signaling cascade. AB - The greatest limitation to reproductive performance in most mammals, including humans, is embryonic mortality, which, in general, claims 20%-40% of the embryos during the peri-implantation period of pregnancy. Both arginine and secreted phosphoprotein 1 (SPP1) are multifunctional molecules that increase significantly in ovine uterine histotroph during early pregnancy. However, little is known about the relationship and underlying mechanisms for synergistic effects of arginine and SPP1, if any, on conceptus (embryo/fetus and associated extraembryonic membranes) development. Therefore, we conducted in vitro experiments using our established ovine trophectoderm cell line (oTr1) isolated from Day 15 ovine conceptuses to determine their proliferative response to individual and synergistic effects of arginine and recombinant SPP1 (rSPP1) that contains an RGD binding sequence. At physiological concentrations, arginine (0.2 mM) stimulated oTr1 cell proliferation 1.7-fold (P < 0.05) at 48 h, whereas rSPP1 (10 ng/ml) had no such effect. However, an additive effect on oTr1 cell proliferation was induced by combination of arginine and SPP1 as compared to the control (2.1-fold increase; P < 0.01), arginine alone (1.3-fold increase; P < 0.05), and rSPP1 alone (1.5-fold increase; P < 0.01). This additive effect was mediated through cooperative activation of the PDK1-Akt/PKB-TSC2-MTORC1 cell signaling cascade. Collectively, results suggest that arginine and SPP1 in histotroph act cooperatively to enhance survival, growth, and development of ovine conceptuses. PMID- 25550345 TI - Correction for Bakkaiova et al., The strictly aerobic yeast Yarrowia lipolytica tolerates loss of a mitochondrial DNA-packaging protein. PMID- 25550343 TI - Inhibitory SMADs: potential regulators of ovarian function. AB - Transforming growth factor beta (TGFB) superfamily signaling regulates essential reproductive functions. Dysregulation of TGFB signaling results in cellular and molecular deficiencies in the ovary, leading to reproductive diseases and cancer development. SMAD proteins are canonical TGFB signaling components consisting of receptor-regulated SMADs (SMAD1/2/3/5/9), a common SMAD (SMAD4), and inhibitory SMADs (SMAD6/7). Inhibitory SMADs are negative regulators of TGFB and bone morphogenetic protein signaling, and their reproductive functions are poorly defined. Emerging evidence supports that inhibitory SMADs are potential regulators of ovarian function. Further efforts and new genetic models are needed to unveil the role of inhibitory SMADs in the ovary. PMID- 25550347 TI - Editorial commentary: emerging problems impeding the elimination of the last polioviruses: silent circulation of wild strains in a well-immunized population. PMID- 25550348 TI - Editorial commentary: ambulatory management of chest-indrawing pneumonia. PMID- 25550349 TI - Oral amoxicillin versus benzyl penicillin for severe pneumonia among kenyan children: a pragmatic randomized controlled noninferiority trial. AB - BACKGROUND: There are concerns that the evidence from studies showing noninferiority of oral amoxicillin to benzyl penicillin for severe pneumonia may not be generalizable to high-mortality settings. METHODS: An open-label, multicenter, randomized controlled noninferiority trial was conducted at 6 Kenyan hospitals. Eligible children aged 2-59 months were randomized to receive amoxicillin or benzyl penicillin and followed up for the primary outcome of treatment failure at 48 hours. A noninferiority margin of risk difference between amoxicillin and benzyl penicillin groups was prespecified at 7%. RESULTS: We recruited 527 children, including 302 (57.3%) with comorbidity. Treatment failure was observed in 20 of 260 (7.7%) and 21 of 261 (8.0%) of patients in the amoxicillin and benzyl penicillin arms, respectively (risk difference, -0.3% [95% confidence interval, -5.0% to 4.3%]) in per-protocol analyses. These findings were supported by the results of intention-to-treat analyses. Treatment failure by day 5 postenrollment was 11.4% and 11.0% and rising to 13.5% and 16.8% by day 14 in the amoxicillin vs benzyl penicillin groups, respectively. The most frequent cause of cumulative treatment failure at day 14 was clinical deterioration within 48 hours of enrollment (33/59 [55.9%]). Four patients died (overall mortality 0.8%) during the study, 3 of whom were allocated to the benzyl penicillin group. The presence of wheeze was independently associated with less frequent treatment failure. CONCLUSIONS: Our findings confirm noninferiority of amoxicillin to benzyl penicillin, provide estimates of risk of treatment failure in Kenya, and offer important additional evidence for policy making in sub Saharan Africa. CLINICAL TRIAL REGISTRATION: NCT01399723. PMID- 25550351 TI - Prostatic hyperplasia in acromegaly, a myth or reality: a case-control study. AB - CONTEXT: Disorders of the prostate gland are more prevalent in patients with acromegaly. GH-insulin-like growth factor 1 (IGF1) axis plays an additive role in prostatic growth and development. OBJECTIVE: To correlate the structural and histopathological changes of the prostate and prostatic symptoms with GH/IGF1 in patients with acromegaly. DESIGN: Case-control study, from January 2012 to November 2013. SETTING: Tertiary referral centre university hospital in Northern India. PATIENTS: Fifty-three men with acromegaly and 50 healthy men matched for age and BMI. MAIN OUTCOME MEASURES: International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) levels, dimensions of the prostate on trans rectal ultrasonography, parameters on uroflowmetry, and immunopositivity with anti-IGF1 antibody in prostatic tissue biopsies. RESULTS: Despite low serum testosterone levels (8.9 nmol/l vs 14.3 nmol/l, acromegaly vs control), patients with acromegaly had marginally higher IPSS, PSA levels, and grades of enlarged prostate and obstructive features on uroflowmetry compared with controls. Dimensions of the prostate on ultrasonography were also significantly higher in patients. These changes were present irrespective of age, current gonadal status, and disease activity. Evidence of prostatic hyperplasia on biopsy was seen in six of 14 patients (42.8%) who underwent prostatic biopsy while it was absent in the controls. Immunohistochemistry with anti-IGF1 antibody showed moderate positivity in all the 14 patients who underwent biopsy with benign prostatic hyperplasia, compared with mild positivity in 21% of controls. Similarly, 14 control patients with prostatic malignancies showed variable positivity, four patients had strong, two each had mild and moderate positivity, while six were negative. CONCLUSIONS: In patients with acromegaly, there is a higher frequency of structural changes in the prostate, along with greater prostatic volume and obstructive features, compared with healthy controls, irrespective of age, gonadal status, and disease activity. PMID- 25550350 TI - Genetic analysis and characterization of wild poliovirus type 1 during sustained transmission in a population with >95% vaccine coverage, Israel 2013. AB - BACKGROUND: Israel has >95% polio vaccine coverage with the last 9 birth cohorts immunized exclusively with inactivated polio vaccine (IPV). Using acute flaccid paralysis and routine, monthly countrywide environmental surveillance, no wild poliovirus circulation was detected between 1989 and February 2013, after which wild type 1 polioviruses South Asia genotype (WPV1-SOAS) have persistently circulated in southern Israel and intermittently in other areas without any paralytic cases as determined by intensified surveillance of environmental and human samples. We aimed to characterize antigenic and neurovirulence properties of WPV1-SOAS silently circulating in a highly vaccinated population. METHODS: WPV1-SOAS capsid genes from environmental and stool surveillance isolates were sequenced, their neurovirulence was determined using transgenic mouse expressing the human poliovirus receptor (Tg21-PVR) mice, and their antigenicity was characterized by in vitro neutralization using human sera, epitope-specific monoclonal murine anti-oral poliovirus vaccine (OPV) antibodies, and sera from IPV-immunized rats and mice. RESULTS: WPV1 amino acid sequences in neutralizing epitopes varied from Sabin 1 and Mahoney, with little variation among WPV1 isolates. Neutralization by monoclonal antibodies against 3 of 4 OPV epitopes was lost. Three-fold lower geometric mean titers (Z = -4.018; P < .001, Wilcoxon signed-rank test) against WPV1 than against Mahoney in human serum correlated with 4- to 6-fold lower neutralization titers in serum from IPV-immunized rats and mice. WPV1-SOAS isolates were neurovirulent (50% intramuscular paralytic dose in Tg21-PVR mice: log10(7.0)). IPV-immunized mice were protected against WPV1 induced paralysis. CONCLUSIONS: Phenotypic and antigenic profile changes of WPV1 SOAS may have contributed to the intense silent transmission, whereas the reduced neurovirulence may have contributed to the absence of paralytic cases in the background of high population immunity. PMID- 25550352 TI - Body composition, bone turnover, and bone mass in trans men during testosterone treatment: 1-year follow-up data from a prospective case-controlled study (ENIGI). AB - PURPOSE: To assess the evolution of body composition and bone metabolism in trans men during the first year of cross-sex hormonal therapy. METHODS: In a prospective controlled study, we included 23 trans men (female-to-male trans persons) and 23 age-matched control women. In both groups, we examined grip strength (hand dynamometer), biochemical markers of bone turnover (C-terminal telopeptides of type 1 collagen (CTX) and procollagen 1 aminoterminal propeptide (P1NP)), total body fat and lean mass, and areal bone mineral density (aBMD) by dual-X-ray absorptiometry (DXA) and fat and muscle area at the forearm and calf, bone geometry, and volumetric bone mineral density (vBMD) by peripheral quantitative computed tomography (pQCT), before treatment and after 1 year of treatment with undecanoate (1000 mg i.m./12 weeks). RESULTS: Before hormonal treatment, trans men had similar bone and body composition compared with control women. Testosterone treatment induced in trans men a gain in muscle mass (+10.4%) and strength and loss of fat mass (-9.7%) (all P<0.001) and increased the levels of P1NP and CTX (both P<0.01). Areal and volumetric bone parameters remained largely unchanged apart from a small increase in trabecular vBMD at the distal radius and in BMD at the total hip in trans men (P=0.036 and P=0.001 respectively). None of these changes were observed in the control group. CONCLUSIONS: Short-term testosterone treatment in trans men increased muscle mass and bone turnover. The latter may rather reflect an anabolic effect of testosterone treatment rather than bone loss. PMID- 25550353 TI - Rapid assessment of avoidable blindness and diabetic retinopathy in Republic of Moldova. AB - OBJECTIVE: To evaluate the prevalence and causes of blindness and visual impairment, the prevalence of diabetes mellitus and diabetic retinopathy among people aged >=50 years in the Republic of Moldova using Rapid Assessment of Avoidable Blindness plus Diabetic Retinopathy ('RAAB+DR') techniques. MATERIALS AND METHODS: 111 communities of people aged >=50 years were randomly selected. In addition to standard RAAB procedures in all people with diabetes (previous history of the disease or with a random blood glucose level >11.1 mm/L (200 mg/dL)), a dilated fundus examination was performed to assess the presence and the degree of diabetic retinopathy using the Scottish DR grading system. RESULTS: 3877 (98%) people out of the 3885 eligible people were examined. The prevalence of blindness was 1.4% (95% CI 1.0% to 1.8%). The major causes of blindness and severe visual impairment were untreated cataract (58.2%), glaucoma (10.9%), and other posterior segment causes (10.9%). The estimated prevalence of diabetes was 11.4%. Among all people with diabetes, 55.9% had some form of retinopathy, and sight threatening diabetic retinopathy affected 14.6%. CONCLUSIONS: The RAAB+DR survey in the Republic of Moldova established that untreated cataract is the major cause of avoidable blindness in rural areas. This needs to be tackled by expanding the geographical coverage of cataract surgical services. PMID- 25550354 TI - The combined use of alphavirus replicons and pseudoinfectious particles for the discovery of antivirals derived from natural products. AB - Alphaviruses are a prominent class of reemergent pathogens due to their globally expanding ranges, potential for lethality, and possible use as bioweapons. The absence of effective treatments for alphaviruses highlights the need for innovative strategies to identify antiviral agents. Primary screens that use noninfectious self-replicating RNAs, termed replicons, have been used to identify potential antiviral compounds for alphaviruses. Only inhibitors of viral genome replication, however, will be identified using replicons, which excludes many other druggable steps in the viral life cycle. To address this limitation, we developed a western equine encephalitis virus pseudoinfectious particle system that reproduces several crucial viral life cycle steps in addition to genome replication. We used this system to screen a library containing ~26,000 extracts derived from marine microbes, and we identified multiple bacterial strains that produce compounds with potential antiviral activity. We subsequently used pseudoinfectious particle and replicon assays in parallel to counterscreen candidate extracts, and followed antiviral activity during biochemical fractionation and purification to differentiate between inhibitors of viral entry and genome replication. This novel process led to the isolation of a known alphavirus entry inhibitor, bafilomycin, thereby validating the approach for the screening and identification of potential antiviral compounds. PMID- 25550355 TI - Large scale meta-analysis of fragment-based screening campaigns: privileged fragments and complementary technologies. AB - A first step in fragment-based drug discovery (FBDD) often entails a fragment based screen (FBS) to identify fragment "hits." However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we sought to investigate three questions: (1) What makes a fragment amenable for FBS? (2) How do hits from different fragment screening technologies and target classes compare with each other? (3) What is the best way to pair FBS assay technologies? In doing so, we identified substructures that were privileged for specific target classes, as well as fragments that were privileged for authentic activity against many targets. We also revealed some of the discrepancies between technologies. Finally, we uncovered a simple rule of thumb in screening strategy: when choosing two technologies for a campaign, pairing a biochemical and biophysical screen tends to yield the greatest coverage of authentic hits. PMID- 25550356 TI - The effect of dietary fat levels on the size and development of Chrysomya megacephala (Diptera: Calliphoridae). AB - Variation in the type of tissue that larvae feed on can produce marked differences in developmental rate and body size, which can compromise predictions of minimum postmortem interval. A series of experiments were conducted to investigate the effect of fat content in the diet on larval growth in Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae), an important forensic blowfly species in China. Bionomical parameters such as body size, development time, mortality, and sex ratio were observed. The results indicated that fat content in the diet has a dramatic effect on the body size and larval development. More dietary fat content was beneficial for development of larvae in first and early second instar. But it was adverse in the later third instar. Significantly, a high-fat diet resulted in increased development rates and the production of undersized larvae and adults. Overall mortality of larvae and pupa was higher when more fat was added to the diet, but sex ratio of adults was not negatively affected. This study highlights that the fat content in the diet should be considered in the entomological research and forensic application when estimating minimum postmortem interval on the basis of larval body size and developmental stage. PMID- 25550357 TI - Culiseta subochrea as a bioindicator of metal contamination in Shadegan International Wetland, Iran (Diptera: Culicidae). AB - The quantity of some trace metals of mosquito larvae in Shadegan International Wetland from Iran was evaluated. Water, waterbed sediment, and mosquito larvae samplings were carried out from an urban site in the east of the wetland, using standard methods in December 2011. The identified Culiseta subochrea (Edwards) and Aedes caspius s.l. (Pallas) larvae, water, and waterbed sediment samples were analyzed for As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Pb, and Zn trace metals using standard preparation and isolation procedure. Result showed that the waterbed sediment and Cu. subochrea larvae are polluted with all trace metals investigated except As and Hg. The trace metals bioaccumulated in the Cu. subochrea larvae range from 31.78 at the lowest level for Cr to 3822.7 at the highest level for Cd. In a conclusion, this is the first report confirmed that Cu. subochrea likely used as a bioindicator to trace metal pollution in marine ecosystems in the world, especially wetlands. PMID- 25550358 TI - One-year routine opportunistic screening for hypertension in formal medical settings and potential improvements in hypertension awareness among older persons in developing countries: evidence from the Study on Global Ageing and Adult Health (SAGE). AB - Hypertension is a leading risk factor in the global disease burden. Limited hypertension awareness is a major determinant of widespread gaps in hypertension treatment and control, especially in developing countries. We analyzed data on persons aged 50 years or older from 6 low- and middle-income countries participating in the first wave (2007-2010) of the World Health Organization's Survey of Global Ageing and Adult Health (SAGE). Our estimates suggest that just 1 year of routine opportunistic hypertension screening during formal visits to medical-care providers could yield significant increases in hypertension awareness among seniors in the developing world. We also show that eliminating missed opportunities for hypertension screening in medical settings would not necessarily exacerbate existing socioeconomic differences in hypertension awareness, despite requiring at least occasional contact with a formal health care provider for obtaining a hypertension diagnosis. Thus, routine opportunistic screening for hypertension in formal medical settings may provide a simple but reliable way to increase hypertension awareness. Moreover, the proposed approach has the added advantage of leveraging existing resources and infrastructures, as well as facilitating a direct transition from the point of diagnosis to subsequent expert counseling and clinical care for newly identified hypertension patients. PMID- 25550359 TI - Validation of secondary data sources to identify Parkinson disease against clinical diagnostic criteria. AB - Parkinson disease (PD) is the second most common neurodegenerative disorder. Its diagnosis relies solely on a clinical examination and is not straightforward because no diagnostic test exists. Large, population-based, prospective cohort studies designed to examine other outcomes that are more common than PD might provide cost-efficient alternatives for studying the disease. However, most cohort studies have not implemented rigorous systematic screening for PD. A majority of epidemiologic studies that utilize population-based prospective designs rely on secondary data sources to identify PD cases. Direct validation of these secondary sources against clinical diagnostic criteria is lacking. The Framingham Heart Study has prospectively screened and evaluated participants for PD based on clinical diagnostic criteria. We assessed the predictive value of secondary sources for PD identification relative to clinical diagnostic criteria in the Framingham Heart Study (2001-2012). We found positive predictive values of 1.0 (95% confidence interval: 0.868, 1.0), 1.0 (95% confidence interval: 0.839, 1.0), and 0.50 (95% confidence interval: 0.307, 0.694) for PD identified from self-report, use of antiparkinsonian medications, and Medicare claims, respectively. The negative predictive values were all higher than 0.99. Our results highlight the limitations of using only Medicare claims data and suggest that population-based cohorts may be utilized for the study of PD determined via self-report or medication inventories while preserving a high degree of confidence in the validity of PD case identification. PMID- 25550360 TI - Antioxidant vitamin intake and mortality: the Leisure World Cohort Study. AB - To assess the relationship between antioxidant vitamin intake and all-cause mortality in older adults, we examined these associations using data from the Leisure World Cohort Study, a prospective study of residents of the Leisure World retirement community in Laguna Hills, California. In the early 1980s, participants (who were aged 44-101 years) completed a postal survey, which included details on use of vitamin supplements and dietary intake of foods containing vitamins A and C. Age-adjusted and multivariate-adjusted (for factors related to mortality in this cohort-smoking, alcohol intake, caffeine consumption, exercise, body mass index, and histories of hypertension, angina, heart attack, stroke, diabetes, rheumatoid arthritis, and cancer) hazard ratios for death were calculated using Cox regression for 8,640 women and 4,983 men (median age at entry, 74 years). During follow-up (1981-2013), 13,104 participants died (median age at death, 88 years). Neither dietary nor supplemental intake of vitamin A or vitamin C nor supplemental intake of vitamin E was significantly associated with mortality after multivariate adjustment. A compendium that summarizes previous findings of cohort studies evaluating vitamin intake and mortality is provided. Attenuation in the observed associations between mortality and antioxidant vitamin use after adjustment for confounders in our study and in previous studies suggests that such consumption identifies persons with other mortality-associated lifestyle and health risk factors. PMID- 25550362 TI - Thoracic aortic calcification is associated with incident stroke in the general population in addition to established risk factors. AB - AIMS: The aorta is a major source of cerebral thromboembolism, but its role in stroke pathogenesis is not well understood due to its poor accessibility for non invasive imaging. We examined whether thoracic aortic calcification (TAC), a marker of aortic plaque load, is associated with stroke in addition to established risk factors. METHODS AND RESULTS: A total of 3930 subjects from the population-based Heinz Nixdorf Recall study (45-75 years; 47.1% men) without previous stroke, coronary heart disease, or myocardial infarction were evaluated for incident stroke events over 109.0 +/- 23.3 months. Cox proportional hazards regressions were used to examine associations with stroke of TAC in addition to established risk factors (age, sex, systolic blood pressure, LDL, HDL, diabetes, and smoking) and coronary artery calcification (CAC). 101 incident strokes occurred during the follow-up period. Subjects suffering a stroke had significantly higher TAC values at baseline than the remaining subjects (median = 83.1 [Q1;Q3 = 4.7;472.9] vs. 15.7 [0.0;117.1]; P < 0.001). In a multivariable Cox proportional hazards regression, log(TAC + 1) (hazards ratio [HR] = 1.09 [95% confidence interval = 1.00-1.19]; P = 0.044) was associated with stroke in addition to established risk factors. Further analyses revealed that log(DTAC + 1), i.e. calcification of the descending aorta (1.11 [1.02-1.20]; P = 0.016), but not log(ATAC + 1), i.e. calcification of the ascending aorta (1.02 [0.93-1.11]; P = 0.713), was associated with stroke. The HR for log(TAC + 1) decreased to 1.06 (0.97-1.16; P = 0.202), when log(CAC + 1) was also inserted into multivariable analyses. CONCLUSION: Calcification of the thoracic aorta, more specifically its descending segment, is associated with incident stroke in addition to established risk factors. CAC outperforms aortic calcification as a stroke predictor. PMID- 25550363 TI - Appropriateness criteria for cardiovascular imaging use in heart failure: report of literature review. AB - The Imaging Task Force appointed by the European Society of Cardiology (ESC) and the European Association of Cardiovascular Imaging (EACVI) identified the need to develop appropriateness criteria for the use of cardiovascular imaging in heart failure as a result of continuously increasing demand for imaging in diagnosis, definition of aetiology, follow-up, and treatment planning. This article presents the report of literature review performed in order to inform the process of definition of clinical indications and to aid the decisions of the appropriateness criteria voting panel. The report is structured according to identified common heart failure clinical scenarios. PMID- 25550361 TI - Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. AB - Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637. PMID- 25550364 TI - Three-dimensional volume imaging with electron microscopy toward connectome. AB - Ultrastructural analyses with electron microscopy have provided indispensable information to understand physiology and pathology of the nervous system. Recent advancement in imaging methodology paved the way for complete reconstruction of the neuronal connection map in the central nervous system, which is termed 'connectome' and would provide key insights to understand the functions of the brain. The critical advancement includes serial ultrastructural observation with scanning electron microscopy (SEM) instead of conventional serial sectioning transmission electron microscopy along with specific tissue preparation methods to increase heavy metal deposition for efficient SEM imaging. The advanced imaging methods using SEM have distinct advantages and disadvantages in multiple aspects, such as resolution and imaging speed, and should be selected depending on the observation conditions, such as target tissue sizes, required spatial resolution and necessity for re-observation. Dealing with the huge dataset remained to be a major obstacle, and automation in segmentation and 3D reconstruction would be critical to understand neuronal circuits in a larger volume of the brain. Future improvement in acquisition and analyses of the morphological data obtained with the advanced SEM imaging is awaited to elucidate the significance of whole connectome as the structural basis of the consciousness, intelligence and memory of a subject. PMID- 25550367 TI - Letter by Freeman et Al regarding article, "evidence-based nursing review of craniectomy care". PMID- 25550366 TI - Limited reliability of computed tomographic perfusion acute infarct volume measurements compared with diffusion-weighted imaging in anterior circulation stroke. AB - BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) can reliably identify critically ischemic tissue shortly after stroke onset. We tested whether thresholded computed tomographic cerebral blood flow (CT-CBF) and CT-cerebral blood volume (CT-CBV) maps are sufficiently accurate to substitute for DWI for estimating the critically ischemic tissue volume. METHODS: Ischemic volumes of 55 patients with acute anterior circulation stroke were assessed on DWI by visual segmentation and on CT-CBF and CT-CBV with segmentation using 15% and 30% thresholds, respectively. The contrast:noise ratios of ischemic regions on the DWI and CT perfusion (CTP) images were measured. Correlation and Bland-Altman analyses were used to assess the reliability of CTP. RESULTS: Mean contrast:noise ratios for DWI, CT-CBF, and CT-CBV were 4.3, 0.9, and 0.4, respectively. CTP and DWI lesion volumes were highly correlated (R(2)=0.87 for CT-CBF; R(2)=0.83 for CT CBV; P<0.001). Bland-Altman analyses revealed little systemic bias (-2.6 mL) but high measurement variability (95% confidence interval, +/-56.7 mL) between mean CT-CBF and DWI lesion volumes, and systemic bias (-26 mL) and high measurement variability (95% confidence interval, +/-64.0 mL) between mean CT-CBV and DWI lesion volumes. A simulated treatment study demonstrated that using CTP-CBF instead of DWI for detecting a statistically significant effect would require at least twice as many patients. CONCLUSIONS: The poor contrast:noise ratios of CT CBV and CT-CBF compared with those of DWI result in large measurement error, making it problematic to substitute CTP for DWI in selecting individual acute stroke patients for treatment. CTP could be used for treatment studies of patient groups, but the number of patients needed to identify a significant effect is much higher than the number needed if DWI is used. PMID- 25550365 TI - Norrin protected blood-brain barrier via frizzled-4/beta-catenin pathway after subarachnoid hemorrhage in rats. AB - BACKGROUND AND PURPOSE: Norrin and its receptor Frizzled-4 have important roles in the blood-brain barrier development. This study is to investigate a potential role and mechanism of Norrin/Frizzled-4 on protecting blood-brain barrier integrity after subarachnoid hemorrhage (SAH). METHODS: One hundred and seventy eight male Sprague-Dawley rats were used. SAH model was induced by endovascular perforation. Frizzled-4 small interfering RNA was injected intracerebroventricularly 48 hours before SAH. Norrin was administrated intracerebroventricularly 3 hours after SAH. SAH grade, neurological scores, brain water content, Evans blue extravasation, western blots, and immunofluorescence were used to study the mechanisms of Norrin and its receptor regulation protein TSPAN12, as well as neurological outcome. RESULTS: Endogenous Norrin and TSPAN12 expression were increased after SAH, and Norrin was colocalized with astrocytes marker glial fibrillary acidic protein in cortex. Exogenous Norrin treatment significantly alleviated neurobehavioral dysfunction, reduced brain water content and Evans blue extravasation, promoted beta-catenin nuclear translocation, and increased Occludin, VE-Cadherin, and ZO-1 expressions. These effects were abolished by Frizzled-4 small interfering RNA pretreated before SAH. CONCLUSIONS: Norrin protected blood-brain barrier integrity and improved neurological outcome after SAH, and the action of Norrin appeared mediated by Frizzled-4 receptor activation, which promoted beta-catenin nuclear translocation, which then enhanced Occludin, VE-Cadherin, and ZO-1 expression. Norrin might have potential to protect blood-brain barrier after SAH. PMID- 25550369 TI - Variations in acute hospital stroke care and factors influencing adherence to quality indicators in 6 European audits. AB - BACKGROUND AND PURPOSE: We compared compliance with standards of acute stroke care between 6 European audits and identified factors associated with delivery of appropriate care. METHODS: Data were derived from stroke audits in Germany, Poland, Scotland, Catalonia, Sweden, and England/Wales/Northern-Ireland participating within the European Implementation Score (EIS) collaboration. Associations between demographic and clinical characteristics with adherence to predefined quality indicators were investigated by hierarchical logistic regression analyses. RESULTS: In 2007/2008 data from 329 122 patients with stroke were documented. Substantial variations in adherence to quality indicators were found; older age was associated with a lower probability of receiving thrombolytic therapy, anticoagulant therapy, or stroke unit treatment and a higher probability of being tested for dysphagia. Women were less likely to receive anticoagulant or antiplatelet therapy or stroke unit treatment. No major weekend effect was found. CONCLUSIONS: Detected variations in performance of acute stroke services were found. Differences in adherence to quality indicators might indicate population subgroups with specific needs for improving care delivery. PMID- 25550370 TI - Response to letter regarding article, "evidence-based nursing review of craniectomy care". PMID- 25550368 TI - Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke. AB - BACKGROUND AND PURPOSE: Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. METHODS: WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. RESULTS: A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99*10(-5)); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). CONCLUSIONS: A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction. PMID- 25550371 TI - Delayed pituitary adenylate cyclase-activating polypeptide delivery after brain stroke improves functional recovery by inducing m2 microglia/macrophage polarization. AB - BACKGROUND AND PURPOSE: Until now, except thrombolysis, the therapeutical strategies targeting the acute phase of cerebral ischemia have been proven ineffective, and no approach is available to attenuate the delayed cell death mechanisms and the resulting functional deficits in the late phase. Then, we investigated whether a targeted and delayed delivery of pituitary adenylate cyclase-activating polypeptide (PACAP), a peptide known to exert neuroprotective activities, may dampen delayed pathophysiological processes improving functional recovery. METHODS: Three days after permanent focal ischemia, PACAP-producing stem cells were transplanted intracerebro ventricularly in nonimmunosuppressed mice. At 7 and 14 days post ischemia, the effects of this stem cell-based targeted delivery of PACAP on functional recovery, volume lesions, and inflammatory processes were analyzed. RESULTS: The delivery of PACAP in the vicinity of the infarct zone 3 days post stroke promotes fast, stable, and efficient functional recovery. This was correlated with a modulation of the postischemic inflammatory response. Transcriptomic and Ingenuity Pathway Analysis based bioinformatic analyses identified several gene networks, functions, and key transcriptional factors, such as nuclear factor-kappaB, C/EBP-beta, and Notch/RBP J as PACAP's potential targets. Such PACAP-dependent immunomodulation was further confirmed by morphometric and phenotypic analyses of microglial cells showing increased number of Arginase-1(+) cells in mice treated with PACAP-expressing cells specifically, demonstrating the redirection of the microglial response toward a neuroprotective M2 phenotype. CONCLUSIONS: Our results demonstrated that immunomodulatory strategies capable of redirecting the microglial response toward a neuroprotective M2 phenotype in the late phase of brain ischemia could represent attractive options for stroke treatment in a new and unexploited therapeutical window. PMID- 25550372 TI - Sex differences in short-term outcomes after acute ischemic stroke: the fukuoka stroke registry. AB - BACKGROUND AND PURPOSE: Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke. METHODS: Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3-6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes. RESULTS: Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, >=8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08 1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged >=70 years, but no clear sex difference was found in patients aged <70 years. CONCLUSIONS: Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke. PMID- 25550373 TI - New grading system based on magnetic resonance imaging in a mouse model of subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: A grading system for experimental subarachnoid hemorrhage (SAH) that does not require animal euthanasia is currently unavailable. We proposed a new grading system based on MRI and evaluated the feasibility of this method in a mouse model of SAH. METHODS: SAH was induced by endovascular perforation in adult male C57BL/6 mice. Mice underwent MRI 24 hours after SAH and were categorized into the following 5 grades based on T2*-weighted imaging: Grade 0, no visible SAH or intraventricular hemorrhage (IVH); Grade 1, minimal/localized SAH without IVH; Grade 2, minimal/localized SAH with IVH; Grade 3, thick/diffuse SAH without IVH; and Grade 4, thick/diffuse SAH with IVH. Neurological deficits were then assessed and the mice euthanized for conventional SAH grading. RESULTS: Among a total of 47 mice, 4% were scored as grade 0, 30% as grade 1, 11% as grade 2, 30% as grade 3, and 26% as grade 4. This MRI grading had excellent interobserver reliability (weighted kappa value =0.94), and there were strong correlations between the MRI grading and the conventional grading (r=0.85; P<0.001) or between MRI grade and neurological scores (r=-0.46; P<0.01). CONCLUSIONS: The new MRI grading correlated well with conventional grading and enabled in vivo evaluation of SAH severity. This grading system may offer advantages in future studies of experimental SAH. PMID- 25550375 TI - Telestroke assessment on the move: prehospital streamlining of patient pathways. PMID- 25550374 TI - Hypertension treatment intensification among stroke survivors with uncontrolled blood pressure. AB - BACKGROUND AND PURPOSE: We examined blood pressure 1 year after stroke discharge and its association with treatment intensification. METHODS: We examined the systolic blood pressure (SBP) stratified by discharge SBP (<=140, 141-160, or >160 mm Hg) among a national cohort of Veterans discharged after acute ischemic stroke. Hypertension treatment opportunities were defined as outpatient SBP >160 mm Hg or repeated SBPs >140 mm Hg. Treatment intensification was defined as the proportion of treatment opportunities with antihypertensive changes (range, 0% 100%, where 100% indicates that each elevated SBP always resulted in medication change). RESULTS: Among 3153 patients with ischemic stroke, 38% had >=1 elevated outpatient SBP eligible for treatment intensification in the 1 year after stroke. Thirty percent of patients had a discharge SBP <=140 mm Hg, and an average 1.93 treatment opportunities and treatment intensification occurred in 58% of eligible visits. Forty-seven percent of patients discharged with SBP 141 to160 mm Hg had an average of 2.1 opportunities for intensification and treatment intensification occurred in 60% of visits. Sixty-three percent of the patients discharged with an SBP >160 mm Hg had an average of 2.4 intensification opportunities, and treatment intensification occurred in 65% of visits. CONCLUSIONS: Patients with discharge SBP >160 mm Hg had numerous opportunities to improve hypertension control. Secondary stroke prevention efforts should focus on initiation and review of antihypertensives before acute stroke discharge; management of antihypertensives and titration; and patient medication adherence counseling. PMID- 25550376 TI - Response to letter regarding article, "comparative effectiveness of carotid revascularization therapies: evidence from a national hospital discharge database". PMID- 25550377 TI - Letter by Giri regarding article, "comparative effectiveness of carotid revascularization therapies: evidence from a national hospital discharge database". PMID- 25550378 TI - Is there an easy, effective, efficient, and inexpensive technique to reduce pain of arterial punctures? PMID- 25550379 TI - The where-to-do-it of noninvasive ventilation revisited. PMID- 25550380 TI - The complexity of interpreting plateau pressure in ARDS. PMID- 25550382 TI - Introducing Wolfgang Baehr, the 2014 recipient of the Proctor Award. PMID- 25550384 TI - Precision medicine meets public health: population screening for BRCA1 and BRCA2. PMID- 25550385 TI - Non-coding RNA as lung disease biomarkers. AB - Biomarkers are quantifiable indicators of disease. These surrogates should be specific, sensitive, predictive, robust and easily accessible. A major class of RNA described as non-coding RNA fulfils many of these criteria, and recent studies have demonstrated that the two major subclasses of non-coding RNA, long non-coding RNA and, in particular, microRNA are promising potential biomarkers. The ability to detect non-coding RNAs in biofluids has highlighted their usefulness as non-invasive markers of lung disease. Because expression of specific non-coding RNAs is altered in many lung diseases and their levels in the circulation often reflect the changes in expression of their lung-specific counterparts, exploiting these biomolecules as diagnostic tools seems an obvious goal. New technology is driving developments in this area and there has been significant recent progress with respect to lung cancer diagnostics. The non coding RNA biomarker field represents a clear example of modern-day bench-to bedside research. PMID- 25550386 TI - Molecular identification of fungal pathogens in nodular skin lesions of cats. AB - In a retrospective study, we investigated 52 formalin-fixed, paraffin-embedded (FFPE) samples from cats with histologically confirmed cutaneous and subcutaneous mycoses to determine if the pathogens could be identified by molecular methods. Aim of the study was to obtain a deep understanding of the spectrum of infectious agents, which, as we hypothesized, was not available by histopathology alone. Detection of feline and fungal DNA was achieved in 92.3% and 94.2% of the samples, respectively. Most of the subcutaneous infections in cats were caused by Alternaria spp. (63.5%), followed by Cryptococcus neoformans (7.7%), Histoplasma capsulatum (5.8%), Sporothrix spp. (3.8%), Aspergillus vitricola, Aureobasidium pullulans, Exophiala attenuata, Fusarium oxysporum, Lecythophora cateniformis, Microsporum canis, and Phialophora sp. (1.9% each). The results from molecular identification indicate that correct identifications of the fungal pathogens by histology alone were rarely possible. The spectrum of fungal pathogens identified after DNA extraction from FFPE samples was much broader than that expected by classical histopathology. This was especially noted in alternariosis in that the micromorphological pattern in tissue was misleading and could be confused with that of cryptococcosis. Due to different susceptibilities to antifungal agents, it is important to arrive at a definitive diagnosis, which might be possible by examination of the fungus recovered in culture and/or molecular methods, in addition to the histopathologic techniques. PMID- 25550383 TI - Membrane protein transport in photoreceptors: the function of PDEdelta: the Proctor lecture. AB - This lecture details the elucidation of cGMP phosphodiesterase (PDEdelta), discovered 25 years ago by Joe Beavo at the University of Washington. PDEdelta, once identified as a fourth PDE6 subunit, is now regarded as a promiscuous prenyl binding protein and important chaperone of prenylated small G proteins of the Ras superfamily and prenylated proteins of phototransduction. Alfred Wittinghofer's group in Germany showed that PDEdelta forms an immunoglobulin-like beta-sandwich fold that is closely related in structure to other lipid-binding proteins, for example, Uncoordinated 119 (UNC119) and RhoGDI. His group cocrystallized PDEdelta with ARL (Arf-like) 2(GTP), and later with farnesylated Rheb (ras homolog expressed in brain). PDEdelta specifically accommodates farnesyl and geranylgeranyl moieties in the absence of bound protein. Germline deletion of the Pde6d gene encoding PDEdelta impeded transport of rhodopsin kinase (GRK1) and PDE6 to outer segments, causing slowly progressing, recessive retinitis pigmentosa. A rare PDE6D null allele in human patients, discovered by Tania Attie Bitach in France, specifically impeded trafficking of farnesylated phosphatidylinositol 3,4,5-trisphosphate (PIP3) 5-phosphatase (INPP5E) to cilia, causing severe syndromic ciliopathy (Joubert syndrome). Binding of cargo to PDEdelta is controlled by Arf-like proteins, ARL2 and ARL3, charged with guanosine-5'-triphosphate (GTP). Arf-like proteins 2 and 3 are unprenylated small GTPases that serve as cargo displacement factors. The lifetime of ARL3(GTP) is controlled by its GTPase-activating protein, retinitis pigmentosa protein 2 (RP2), which accelerates GTPase activity up to 90,000-fold. RP2 null alleles in human patients are associated with severe X-linked retinitis pigmentosa (XLRP). Germline deletion of RP2 in mouse, however, causes only a mild form of XLRP. Absence of RP2 prolongs the activity of ARL3(GTP) that, in turn, impedes PDE6delta-cargo interactions and trafficking of prenylated protein to the outer segments. Hyperactive ARL3(GTP), acting as a hyperactive cargo displacement factor, is predicted to be key in the pathobiology of RP2-XLRP. PMID- 25550387 TI - Peroxide sensing and signaling in the Sporothrix schenckii complex: an in silico analysis to uncover putative mechanisms regulating the Hog1 and AP-1 like signaling pathways. AB - In order to understand how fungal pathogens can survive inside the host, we must analyze how they evade the fungicidal mechanisms mounted by the host's immune system, such as generation of toxic reactive oxygen species. Studies have shown that infections caused by Sporothrix brasiliensis can be more aggressive than those due to Sporothrix schenckii. Therefore, we propose to analyze and compare the ability of these two pathogenic species to counteract oxidative stress, which, as noted, can be relevant in the host response to infection. We have shown that S. brasiliensis is more resistant to different oxidants, such as H2O2 and menadione, when compared with S. schenckii. Furthermore, our results suggest that the molecular mechanisms by which Sporothrix spp. AP-1 like transcription factors are regulated probably differs from the one seen in other fungal pathogens. Interestingly, comparison between sequences of SbHog1 and SsHog1 stress activated protein kinases suggest that S. brasiliensis Hog1 display mutations that could account for the differences seen in stress sensitivities of these two species. In summary, this is the first study to our knowledge to investigate oxidative stress responses of Sporothrix spp. and provided a model that can be employed in vivo to address how these fungal pathogens can surmount the oxidative stress generated by the host. PMID- 25550388 TI - Toxicity and efficacy differences between liposomal amphotericin B formulations in uninfected and Aspergillus fumigatus infected mice. AB - Because of the reduced toxicity associated with liposomal amphotericin B preparations, different amphotericin B liposome products have been made. In the present study, we compared the amphotericin B liposomal formulations, AmBisome((r)) (AmBi) and Lambin((r)) (Lbn), in uninfected and Aspergillus fumigatus infected mice, using several in vitro and in vivo toxicity and efficacy assays. The results showed that the formulations were significantly different, with Lbn 1.6-fold larger than AmBi. Lbn was also more toxic than AmBi based on the RBC potassium release assay and intravenous dosing in uninfected mice given a single 50 mg/kg dose (80% mortality for Lbn vs. 0% for AmBi). Renal tubular changes after intravenous daily dosing for 14 days were seen in uninfected mice given 5 mg/kg Lbn but not with AmBi. Survival following A. fumigatus challenge was 30% for 10 mg/kg Lbn and 60% for 10 mg/kg AmBi. When the BAL and lungs were collected 24 h after the second treatment, AmBi at 10 or 15 mg/kg or 15 mg/kg Lbn lowered the BAL fungal burden significantly vs. the controls (P <= 0.05), while there was no difference in lung fungal burden amongst the groups. In contrast, lung histopathology at this same early timepoint showed that AmBi was associated with markedly fewer fungal elements and less lung tissue damage than Lbn. In conclusion, given the differences in size, toxicity, and efficacy, AmBi and Lbn were not physically or functionally comparable, and these differences underscore the need for adequate testing when comparing amphotericin B liposome formulations. PMID- 25550389 TI - The serum glucan level and pathological changes of antifungal treatment for lower respiratory tract infection of Candida albicans. AB - Due to the fact that Candida albicans colonizes in the upper respiratory tracts of healthy people, whether or not its isolation from airway secretions is sufficient to warrant treatment remains controversial. The animal models of immunosuppressive rats with pulmonary candidiasis were established by the intratracheal inoculating suspensions of C. albicans, and the animals were divided into the following three groups: (1) antifungal treatment group, (2) saline control group, and (3) blank control group. We noted the following in our studies: (1) The fungal load of the saline control group gradually increased such that it was higher than those of the antifungal treated group and was significant from the fourth day of treatment (P < 0.01). (2) The serum (1,3)-beta-D-glucan (BG) in the saline control group also gradually increased so that it was significantly higher than found with the treated group by the sixth day of treatment (P < 0.05), and in fact, the rank of pulmonary colony count and BG in the two groups at different time points showed an almost perfect linear correlation. (3) The median survival period of the rats in the antifungal treated group and saline control group was 15 and 8 days respectively, no rats died in the blank control group. (4) The lung lesions from the saline control group gradually became more aggravated than those in the antifungal treated group; no significant pathological changes were found in the blank control group. Antifungal treatment (micafungin) is capable of efficaciously decreasing the lung fungal burden, and continuous monitoring of BG is useful for the evaluation of therapeutic effect of antifungals. Infection of C. albicans with associated pathological damage implies the need for antifungal therapy. PMID- 25550390 TI - Translation elongation factor 1-alpha gene as a potential taxonomic and identification marker in dermatophytes. AB - Intra- and interspecies variations of the translation elongation factor 1-alpha (Tef-1alpha) gene were evaluated as a new identification marker in a wide range of dermatophytes, which included 167 strains of 30 species. An optimized pan dermatophyte primer pair was designed, and the target was sequenced. Consensus sequences were used for multiple alignment and phylogenetic tree analysis and the levels of intra- and interspecific nucleotide polymorphism were assessed. Between species, the analyzed part of the Tef-1alpha gene varied in length from 709 to 769 nucleotides. Significant numbers of species including Trichophyton rubrum, T. tonsurans, T. schoenleinii, T. concentricum, T. violaceum, Epidermophyton floccosum, Microsporum ferrugineum, M. canis, M. audouinii, T. equinum, T. eriotrephon, and T. erinacei were invariant in Tef-1alpha and had sufficient barcoding distance with neighboring species. Although overall consistency was found between ITS phylogeny as the current molecular marker of dermatophytes and Tef-1alpha, a higher discriminatory power of Tef-1alpha appeared particularly useful in some clades of closely related species such as the A. vanbreuseghemii, T. rubrum, A. benhamiae, and A. otae complexes. Nevertheless, we stress that a single gene can not specify species borderlines among dermatophytes and multiple lines of evidence based on a multilocus inquiry may ascertain an incontrovertible evaluation of kinship. PMID- 25550392 TI - Candida tropicalis isolates obtained from veterinary sources show resistance to azoles and produce virulence factors. AB - Candida tropicalis has been associated with invasive candidiasis, being the first or second most common non-Candida albicans Candida species isolated in humans with candidemia and candiduria, as well as being frequently isolated from healthy animals. This study aimed to characterize C. tropicalis isolates (n = 64) obtained from several animal species regarding antifungal susceptibility and production of virulence factors. The isolates were obtained from the microbiota of healthy animals (goats, n = 25; sheep, n = 6; psittacines, n = 14; rheas, n = 6; horses, n = 2; sirenians, n = 5; shrimp, n = 1), as well as from aquatic mammals found dead in the environment (cetaceans, n = 5). The isolates were subjected to in vitro susceptibility testing by broth microdilution according to the CLSI M27-A3 protocol against amphotericin B, caspofungin, itraconazole, and fluconazole. We also evaluated the virulence attributes, such as proteases and phospholipases, as well as biofilm formation. Resistance to itraconazole (n = 29) and fluconazole (n = 30) was detected among isolates from every source; resistance to both azoles was detected in 24 isolates, but none of them were resistant to amphotericin B and caspofungin. Protease production was detected in the majority of the isolates (n = 59), but phospholipase was produced by only a few of them (n = 6). The isolates showed different patterns in biofilm production, being considered strong producers (n = 41), moderate producers (n = 11), weak producers (n = 9) or non-producers (n = 3). In summary, C. tropicalis isolated from animals showed high rate of resistance to azoles, expressed virulence factors and therefore may represent a potential threat to human and animal health. PMID- 25550391 TI - Utility of adding Pneumocystis jirovecii DNA detection in nasopharyngeal aspirates in immunocompromised adult patients with febrile pneumonia. AB - Detection of viral and bacterial DNA in nasopharyngeal aspirates (NPAs) is now a routine practice in emergency cases of febrile pneumonia. We investigated whether Pneumocystis jirovecii DNA could also be detected in these cases by conducting retrospective screening of 324 consecutive NPAs from 324 adult patients (198 or 61% were immunocompromised) admitted with suspected pulmonary infections during the 2012 influenza epidemic season, using a real-time quantitative polymerase chain reaction (PCR) assay (PjqPCR), which targets the P. jirovecii mitochondrial large subunit ribosomal RNA gene. These NPAs had already been tested for 22 respiratory pathogens (18 viruses and 4 bacteria), but we found that 16 NPAs (4.9%) were PjqPCR-positive, making P. jirovecii the fourth most prevalent of the 23 microorganisms in the screen. Eleven of the 16 PjqPCR-positive patients were immunocompromised, and five had underlying pulmonary conditions. Nine NPAs were also positive for another respiratory pathogen. Six had PjqPCR-positive induced sputa less than 3 days after the NPA procedure, and five were diagnosed with pneumocystis pneumonia (four with chronic lymphoproliferative disorders and one AIDS patient). In all six available pairs quantification of P. jirovecii DNA showed fewer copies in NPA than in induced sputum and three PjqPCR-negative NPAs corresponded to PjqPCR-positive bronchoalveolar lavage fluids, underscoring the fact that a negative PjqPCR screen does not exclude a diagnosis of pneumocystosis. Including P. jirovecii DNA detection to the panel of microorganisms included in screening tests used for febrile pneumonia may encourage additional investigations or support use of anti-pneumocystis pneumonia prophylaxis in immunocompromised patients. PMID- 25550393 TI - The man-in-the-moon face: a qualitative study of body image, self-image and medication use in systemic lupus erythematosus. AB - OBJECTIVE: Little is yet known about the interactions between body image, self image, medication use and adherence to medication in people with SLE. Using a qualitative mode of enquiry, we sought to understand these experiences within a group of patients diagnosed with SLE. METHODS: Fifteen participants (14 female, 1 male) with SLE took part in semi-structured interviews. Their ages ranged from 22 to 57 years and disease duration ranged from 3 to 20 years. Interviews were audio recorded and transcribed verbatim. Data were analysed using interpretative phenomenological analysis. RESULTS: Analysis revealed four themes that are presented set within the overarching concept of body and self-image: the road to diagnosis, communication and treatment concordance, living with the medication and self-image-faking it. Narratives revealed significant dissatisfaction with body image, an externally located concept. Worries about appearance and weight were most commonly mentioned and were often related to steroid use. Creative non compliance with medication was frequently described and greater concordant relationships with physicians desired. Overall, participants sought increased investment in self-image, an internally located concept. CONCLUSION: Body and self-image are important issues for individuals with SLE. Yet participants in our study generally felt that their health care providers did not give enough consideration to their concerns over the outward appearance effects of both the disease and its treatment. PMID- 25550394 TI - Emergence of multiple resistance profiles involving azoles, echinocandins and amphotericin B in Candida glabrata isolates from a neutropenia patient with prolonged fungaemia. PMID- 25550395 TI - Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial mesenchymal transition and fibrosis during peritoneal dialysis. AB - Peritoneal dialysis (PD) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial-mesenchymal transition (EMT) and fibrosis, eventually leading to PD discontinuation. The peritoneum from Cav1-/- mice showed increased EMT, thickness, and fibrosis. Exposure of Cav1-/- mice to PD fluids further increased peritoneal membrane thickness, altered permeability, and increased the number of FSP-1/cytokeratin positive cells invading the sub-mesothelial stroma. High-throughput quantitative proteomics revealed increased abundance of collagens, FN, and laminin, as well as proteins related to TGF-beta activity in matrices derived from Cav1-/- cells. Lack of Cav1 was associated with hyperactivation of a MEK-ERK1/2-Snail-1 pathway that regulated the Smad2-3/Smad1-5-8 balance. Pharmacological blockade of MEK rescued E-cadherin and ZO-1 inter-cellular junction localization, reduced fibrosis, and restored peritoneal function in Cav1-/- mice. Moreover, treatment of human PD-patient-derived MCs with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced re-acquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD. PMID- 25550397 TI - Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease has emerged as a novel cardiovascular risk factor. The aim of the study was to assess the effect of different ectopic fat depots on left ventricular (LV) function in subjects with nonalcoholic fatty liver disease. METHODS AND RESULTS: Myocardial and hepatic triglyceride contents were measured with 1.5 T magnetic resonance spectroscopy and LV function, visceral adipose tissue (VAT) and subcutaneous adipose tissue, epicardial and pericardial fat by MRI in 75 nondiabetic men. Subjects were stratified by hepatic triglyceride content into low, moderate, and high liver fat groups. Myocardial triglyceride, epicardial and pericardial fat, VAT, and subcutaneous adipose tissue increased stepwise from low to high liver fat group. Parameters of LV diastolic function showed a stepwise decrease over tertiles of liver fat and VAT, and they were inversely correlated with hepatic triglyceride, VAT, and VAT/subcutaneous adipose tissue ratio. In multivariable analyses, hepatic triglyceride and VAT were independent predictors of LV diastolic function, whereas myocardial triglyceride was not associated with measures of diastolic function. CONCLUSIONS: Myocardial triglyceride, epicardial and pericardial fat increased with increasing amount of liver fat and VAT. Hepatic steatosis and VAT associated with significant changes in LV structure and function. The association of LV diastolic function with hepatic triglyceride and VAT may be because of toxic systemic effects. The effects of myocardial triglyceride on LV structure and function seem to be more complex than previously thought and merit further study. PMID- 25550396 TI - Investigating the zoonotic origin of the West African Ebola epidemic. AB - The severe Ebola virus disease epidemic occurring in West Africa stems from a single zoonotic transmission event to a 2-year-old boy in Meliandou, Guinea. We investigated the zoonotic origins of the epidemic using wildlife surveys, interviews, and molecular analyses of bat and environmental samples. We found no evidence for a concurrent outbreak in larger wildlife. Exposure to fruit bats is common in the region, but the index case may have been infected by playing in a hollow tree housing a colony of insectivorous free-tailed bats (Mops condylurus). Bats in this family have previously been discussed as potential sources for Ebola virus outbreaks, and experimental data have shown that this species can survive experimental infection. These analyses expand the range of possible Ebola virus sources to include insectivorous bats and reiterate the importance of broader sampling efforts for understanding Ebola virus ecology. PMID- 25550398 TI - Effect of physical activity on age-related changes in cardiac function and performance in women. AB - BACKGROUND: Higher levels of physical activity are associated with reduced cardiovascular mortality but its effect on age-related changes in cardiac structure and function is unknown. The present study defines the effect of daily physical activity on age-related changes in cardiac structure, function, metabolism, and performance in healthy women. METHODS AND RESULTS: Sixty-three healthy women were grouped according to age (young, 20-30 years, n=21; middle, 40 50 years, n=22; and older, 65-81 years, n=20) and daily physical activity level (low active<7500 and high active>12,500 steps/d). Participants underwent cardiac MRI including tissue tagging and 31P spectroscopy and exercise testing with noninvasive central hemodynamic measurements. Aging was associated with increased concentric remodeling (P<0.01) and left ventricular torsion (P<0.01), and a decline in diastolic function (P<0.01), cardiac phosphocreatine:ATP ratio (P<0.01), peak exercise cardiac power output (P<0.01), and O2 consumption (P<0.01). Older high-active women demonstrated a phosphocreatine:ATP ratio and relative peak O2 consumption similar to young low-active women, and 23% and 26% higher than older low-active women (phosphocreatine:ATP ratio, 1.9+/-0.2 versus 1.4+/-0.1; P<0.05 and O2 consumption, 24.1+/-3.8 versus 17.8+/-2.0 mL/[kg.min]; P<0.01). In older women, physical activity had no effect on eccentricity ratio (0.9+/-0.2 versus 0.8+/-0.1 g/mL; P=0.19), E/A ratio (1.3+/-0.5 versus 1.4+/-0.5; P=0.66), torsion (7.6+/-1.7 versus 8.0 degrees +/-2.1 degrees ; P=0.20), and peak cardiac power output (3.4+/-0.7 versus 3.4+/-0.8 W; P=0.91). CONCLUSIONS: A higher level of daily physical activity preserves cardiac metabolism and exercise capacity with aging but has limited effect on age-related changes in concentric remodeling, diastolic function, and cardiac performance. PMID- 25550399 TI - Cardio-chemical exchange saturation transfer magnetic resonance imaging reveals molecular signatures of endogenous fibrosis and exogenous contrast media. AB - BACKGROUND: Application of emerging molecular MRI techniques, including chemical exchange saturation transfer (CEST)-MRI, to cardiac imaging is desirable; however, conventional methods are poorly suited for cardiac imaging, particularly in small animals with rapid heart rates. We developed a CEST-encoded steady state and retrospectively gated cardiac cine imaging sequence in which the presence of fibrosis or paraCEST contrast agents was directly encoded into the steady-state myocardial signal intensity (cardioCEST). METHODS AND RESULTS: Development of cardioCEST: A CEST-encoded cardiac cine MRI sequence was implemented on a 9.4T small animal scanner. CardioCEST of fibrosis was serially performed by acquisition of a series of CEST-encoded cine images at multiple offset frequencies in mice (n=7) after surgically induced myocardial infarction. Scar formation was quantified using a spectral modeling approach and confirmed with histological staining. Separately, circulatory redistribution kinetics of the paramagnetic CEST agent Eu-HPDO3A were probed in mice using cardioCEST imaging, revealing rapid myocardial redistribution, and washout within 30 minutes (n=6). Manipulation of vascular tone resulted in heightened peak CEST contrast in the heart, but did not alter redistribution kinetics (n=6). At 28 days after myocardial infarction (n=3), CEST contrast kinetics in infarct zone tissue were altered, demonstrating gradual accumulation of Eu-HPDO3A in the increased extracellular space. CONCLUSIONS: cardioCEST MRI enables in vivo imaging of myocardial fibrosis using endogenous contrast mechanisms, and of exogenously delivered paraCEST agents, and can enable multiplexed imaging of multiple molecular targets at high-resolution coupled with conventional cardiac MRI scans. PMID- 25550401 TI - Trimming the fat, do we know where to begin? PMID- 25550402 TI - Using metaphor to translate the science of resilience and developmental outcomes. AB - Developmental scientists have used a variety of linguistic devices to communicate the science of resilience, but their effectiveness at improving understanding and expanding support for evidence-based social policies has not been empirically tested. We describe the process of developing, testing, and refining an Explanatory Metaphor to communicate the science of resilience to the public and policymakers. We argue that public understanding is key to bridging the research to-practice divide and that communications is a social science endeavor in its own right that requires careful empirical research. PMID- 25550400 TI - Imaging vessel wall biology to predict outcome in abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) rupture risk is currently determined based on size and symptoms. This approach does not address the rupture risk associated with small aneurysms. Given the role of matrix metalloproteinases (MMPs) in AAA weakening and rupture, we investigated the potential of MMP targeted imaging for detection of aneurysm biology and prediction of outcome in a mouse model of AAA with spontaneous rupture. METHODS AND RESULTS: Fifteen-week old mice (n=66) were infused with angiotensin II for 4 weeks to induce AAA. Saline-infused mice (n=16) served as control. The surviving animals underwent in vivo MMP-targeted micro-single photon emission computed tomographic/computed tomographic imaging, using RP805, a technetium-99m-labeled MMP-specific tracer, followed by ex vivo planar imaging, morphometry, and gene expression analysis. RP805 uptake in suprarenal aorta on micro-single photon emission computed tomographic images was significantly higher in animals with AAA when compared with angiotensin II-infused animals without AAA or control animals. CD68 expression and MMP activity were increased in AAA, and significant correlations were noted between RP805 uptake and CD68 expression or MMP activity but not aortic diameter. A group of angiotensin II-infused animals (n=24) were imaged at 1 week and were followed up for additional 3 weeks. RP805 uptake in suprarenal aorta at 1 week was significantly higher in mice that later developed rupture or AAA. Furthermore, tracer uptake at 1 week correlated with aortic diameter at 4 weeks. CONCLUSIONS: MMP-targeted imaging reflects vessel wall inflammation and can predict future aortic expansion or rupture in murine AAA. If confirmed in humans, this may provide a new paradigm for AAA risk stratification. PMID- 25550403 TI - In-group rationalizations of risk and indoor tanning: A textual analysis of an online forum. AB - Unlike other health behaviors, there does not appear to be a strong relationship between perceived skin cancer risk and reduction or cessation of indoor tanning bed use. This study seeks to address this inconsistency by determining how indoor tanning bed users rationalize skin cancer risk with their tanning behavior. Qualitative textual analysis of indoor tanning message board posts (N = 330) revealed varied perceptions of risk, including acknowledging the risk of indoor tanning; denying or downplaying risk, often citing perceived health benefits associated with tanning; blaming outside forces for cancer, such as lotion or genetics; and fatalistic beliefs about cancer. These results highlight the nuanced relationship between perceived skin cancer risk and indoor tanning bed use. PMID- 25550405 TI - Do we understand the personalized medicine paradigm? Personalized medicine marks the beginning of a new attitude in medicine. PMID- 25550404 TI - Actomyosin bundles serve as a tension sensor and a platform for ERK activation. AB - Tensile forces generated by stress fibers drive signal transduction events at focal adhesions. Here, we report that stress fibers per se act as a platform for tension-induced activation of biochemical signals. The MAP kinase, ERK is activated on stress fibers in a myosin II-dependent manner. In myosin II inhibited cells, uniaxial stretching of cell adhesion substrates restores ERK activation on stress fibers. By quantifying myosin II- or mechanical stretch mediated tensile forces in individual stress fibers, we show that ERK activation on stress fibers correlates positively with tensile forces acting on the fibers, indicating stress fibers as a tension sensor in ERK activation. Myosin II dependent ERK activation is also observed on actomyosin bundles connecting E cadherin clusters, thus suggesting that actomyosin bundles, in general, work as a platform for tension-dependent ERK activation. PMID- 25550406 TI - End-of-Life Care for People With Cancer From Ethnic Minority Groups: A Systematic Review. AB - BACKGROUND: Ethnic/racial minorities encounter disparities in healthcare, which may carry into end-of-life (EOL) care. Advanced cancer, highly prevalent and morbid, presents with worsening symptoms, heightening the need for supportive and EOL care. PURPOSE: To conduct a systematic review examining ethnic/racial disparities in EOL care for cancer patients. DESIGN: We searched four electronic databases for all original research examining EOL care use, preferences, and beliefs for cancer patients from ethnic/racial minority groups. RESULTS: Twenty five studies were included: 20 quantitative and five qualitative. All had a full text English language article and focused on the ethnic/racial minority groups of African Americans, Hispanics Americans, or Asian Americans. Key themes included EOL decision making processes, family involvement, provider communication, religion and spirituality, and patient preferences. Hospice was the most studied EOL care, and was most used among Whites, followed by use among Hispanics, and least used by African and Asian Americans. African Americans perceived a greater need for hospice, yet more frequently had inadequate knowledge. African Americans preferred aggressive treatment, yet EOL care provided was often inconsistent with preferences. Hispanics and African Americans less often documented advance care plans, citing religious coping and spirituality as factors. CONCLUSION: EOL care differences among ethnic/racial minority cancer patients were found in the processes, preferences, and beliefs regarding their care. Further steps are needed to explore the exact causes of differences, yet possible explanations include religious or cultural differences, caregiver respect for patient autonomy, access barriers, and knowledge of EOL care options. PMID- 25550407 TI - Developing Organizational Guidelines for the Prevention and Management of Suicide in Clients and Carers Receiving Palliative Care in Australia. AB - This article describes the process of developing a suicide guideline in palliative care. Little literature was available, but utilizing the partnership model, a working party consulted with each discipline regarding specific requirements. The working party experienced significant challenges in creating policy that would adequately cover the diverse needs of all members of the palliative care team, as it was recognized that all staff needed guidance. The final guideline incorporated specific action plans for each discipline; mandatory training for all staff was endorsed through a recognized suicide alertness training program; advanced training in suicide intervention skills for key clinical staff will be required; and a "Rapid Plan Team" was recommended. This policy development has required significant work and the combined expertise of many disciplines. PMID- 25550408 TI - Nonpain Symptom Prevalence and Intensity of Inpatients With Moderate to Severe Cancer Pain in China. AB - OBJECTIVES: To identify prevalence and severity of nonpain symptoms and to clarify possible influences on each nonpain symptom. METHODS: The study used a descriptive survey design. Chinese version of the Edmonton Symptom Assessment System was used. Patients' demographic and pain characteristics were collected. RESULTS: The most common symptoms reported were loss of appetite (94.3%) followed by insomnia (93.3%), and tiredness (91.6%). Prevalence rates of nonpain symptom were all above 70% except "thinking clearly." Prevalence and severity of nonpain symptoms varied by gender, age, primary cancer, and pain characteristics, especially intensity, number of breakthrough pain episodes per day, and number of pain sites. CONCLUSIONS: Most inpatients with cancer pain experienced concurrent nonpain symptoms. Comprehensive symptom assessment and intervention managing multiple symptoms are essential for these inpatients. PMID- 25550409 TI - Precision medicine for managing diabetes. PMID- 25550410 TI - Development of a highly stable, nonaqueous glucagon formulation for delivery via infusion pump systems. AB - Despite a vigorous research effort, to date, the development of systems that achieve glucagon stability in aqueous formulations (without reconstitution) has failed to produce any clinical candidates. We have developed a novel, nonaqueous glucagon formulation based on a biocompatible pharmaceutical solvent, dimethyl sulfoxide, which demonstrates excellent physical and chemical stability at relatively high concentrations and at high temperatures. This article reports the development of a novel, biocompatible, nonaqueous native human glucagon formulation for potential use in subcutaneous infusion pump systems. Data are presented that demonstrate physical and chemical stability under presumed storage conditions (>2 years at room temperature) as well as "in use" stability and compatibility in an Insulet's OmniPod((r)) infusion pump. Also presented are results of a skin irritation study in a rabbit model and pharmacokinetics/pharmacodynamics data following pump administration of glucagon in a diabetic swine model. This nonaqueous glucagon formulation is suitable for further clinical development in pump systems. PMID- 25550411 TI - Obtaining reimbursement in France and Italy for new diabetes products. AB - Manufacturers launching next-generation or innovative medical devices in Europe face a very heterogeneous reimbursement landscape, with each country having its own pathways, timing, requirements and success factors. We selected 2 markets for a deeper look into the reimbursement landscape: France, representing a country with central decision making with defined processes, and Italy, which delegates reimbursement decisions to the regional level, resulting in a less transparent approach to reimbursement. Based on our experience in working on various new product launches and analyzing recent reimbursement decisions, we found that payers in both countries do not reward improved next-generation products with incremental reimbursement. Looking at innovations, we observe that manufacturers face a challenging and lengthy process to obtain reimbursement. In addition, requirements and key success factors differ by country: In France, comparative clinical evidence and budget impact very much drive reimbursement decisions in terms of pricing and restrictions, whereas in Italy, regional key opinion leader (KOL) support and additional local observational data are key. PMID- 25550412 TI - The standard of care in amyotrophic lateral sclerosis: a centralised multidisciplinary clinic encounter sets a new benchmark for a uniquely challenging neurodegenerative disorder. PMID- 25550413 TI - Interictal cerebral and systemic endothelial dysfunction in patients with migraine: a case-control study. AB - BACKGROUND: Although systemic endothelial function is unimpaired in migraine, it is unknown whether cerebral endothelial function impairment exists in migraineurs. MATERIALS AND METHODS: We conducted a prospective study to assess endothelial function in migraineurs (n=45) and healthy volunteers (n=44). Cerebral endothelial function was assessed by Breath Holding Index (BHI) on transcranial Doppler in bilateral middle cerebral artery (MCA at 30-60 mm), posterior cerebral artery (PCA at 60-80 mm) and basilar artery (BA at 80-120 mm) using bilateral monitoring probes fixed on headband. Brachial artery flow mediated dilation (FMD) was used as measure of systemic endothelial function. RESULTS: There was no difference in baseline mean velocities of MCA, PCA, BA among migraineurs and controls. Mean BHI was significantly lower in PCA (p<0.001) and BA (p<0.001) in patients with migraine with no difference in MCA (p=0.909, 0.450). Cerebral endothelial dysfunction (BHI<1.15) was present in 62.2% of migraineurs in the right PCA (p<0.001), 57.8% in left PCA (p<0.001) and 77.8% in BA (BHI <0.83, p<0.001). There was no difference in BHI among migraineurs without and with aura (n=15). Cerebral and systemic endothelial function had no correlation in migraineurs. Increasing BMI was identified as a predictor of impaired BHI in the BA in migraineurs (p=0.020). Age, sex, presence of aura, lateralisation of headache, headache frequency, time to last attack and impaired FMD were not associated with impaired PCA and BA BHI in migraineurs. CONCLUSIONS: Migraineurs may have isolated cerebral endothelial dysfunction restricted to the posterior circulation in the absence of systemic endothelial dysfunction. PMID- 25550415 TI - Autonomic dysregulation in frontotemporal dementia. PMID- 25550414 TI - Comparative efficacy of interferon beta versus glatiramer acetate for relapsing remitting multiple sclerosis. AB - Interferon beta (INFbeta) and glatiramer acetate (GA) are widely used in patients with relapsing-remitting multiple sclerosis (RRMS). However, it is still unclear whether they have different efficacy. We performed a systematic search of head-to head trials for gaining objective reliable data to compare the two drugs, using the Cochrane Collaboration methodology. We identified five randomised-controlled trials (RCTs) (2858 participants) comparing directly INFbeta versus GA in RRMS. All studies were at high risk for attrition bias. Both therapies showed similar efficacy at 24 months, considering clinical (patients with relapse or progression) and one MRI activity (enhancing lesions) measure. At 3 years, evidence from a single study showed that the relapse rate was higher in the INFbeta group than in the GA group (risk ratio 1.40, 95% CI 1.13 to 1.74, p 0.002). However, the average reduction in T2-weighted and T1-weighted lesion volume was significantly greater in the INFbeta group than in the GA group (mean difference (MD) -0.58, 95% CI -0.99 to -0.18, p 0.004, and MD -0.20, 95% CI -0.33 to -0.07, p 0.003, respectively). The number of participants who dropped out of the studies because of adverse events was similar in the two groups. These data support clinicians in the use of these therapies, based on their similar safety and efficacy in the prevention of disease activity, although the different effect on MRI measures and the different tolerability might have a role in the therapeutic choice at the individual level. PMID- 25550416 TI - A multidisciplinary clinic approach improves survival in ALS: a comparative study of ALS in Ireland and Northern Ireland. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive debilitating neurodegenerative disease, with a life expectancy of 3-5 years from first symptom. There is compelling evidence that those who attend a multidisciplinary clinic experience improved survival. The purpose of the study was to explore the survival of patients with ALS ascertained through population-based Registers in the Republic of Ireland (RoI) and Northern Ireland (NI), and to determine whether centralisation of services confers advantage compared with community-based care supported by a specialist care worker. METHODS: The island of Ireland is divided into two countries, RoI and NI, each with an independent healthcare system. Both countries have population-based ALS Registers with full ascertainment. Data from all 719 incident ALS cases from Ireland and NI, diagnosed between 1 January 2005 and 31 December 2010, were used in the analysis. RESULTS: A survival benefit was identified for patients who attended the multidisciplinary ALS clinic in the RoI. (HR 0.59, 95% CI 0.49 to 0.71, p<0.001). This difference was preserved following multivariate analysis. A trend towards improved survival was noted for patients with ALS from NI when compared with RoI patients who did not attend a multidisciplinary clinic. CONCLUSIONS: Centralised multidisciplinary care confers a survival advantage for patients with ALS and is superior to devolved community based care. We propose that multiple decision-making processes within a multidisciplinary setting lead to an enriched set of clinical encounters for the patient and carer that enhances clinical outcome. PMID- 25550417 TI - Trends in smoking among adults with serious psychological distress during comprehensive tobacco control in New York City, 2003-2012. PMID- 25550418 TI - Waterpipe tobacco smoking legislation and policy enactment: a global analysis. AB - OBJECTIVE: (1) To review how current global tobacco control policies address regulation of waterpipe tobacco smoking (WTS). (2) To identify features associated with enactment and enforcement of WTS legislation. DATA SOURCES: (1) Legislations compiled by Tobacco Control Laws (www.tobaccocontrollaws.org). (2) Weekly news articles by 'Google Alerts' (www.google.com/alerts) from July 2013 to August 2014. STUDY SELECTION: (1) Countries containing legislative reviews, written by legal experts, were included. Countries prohibiting tobacco sales were excluded. (2) News articles discussing aspects of the WHO FCTC were included. News articles related to electronic-waterpipe, crime, smuggling, opinion pieces or brief mentions of WTS were excluded. DATA ABSTRACTION: (1) Two reviewers independently abstracted the definition of "tobacco product" and/or "smoking". Four tobacco control domains (smokefree law, misleading descriptors, health warning labels and advertising/promotion/sponsorship) were assigned one of four categories based on the degree to which WTS had specific legislation. (2) Two investigators independently assigned at least one theme and associated subtheme to each news article. DATA SYNTHESIS: (1) Reviewed legislations of 62 countries showed that most do not address WTS regulation but instead rely on generic tobacco/smoking definitions to cover all tobacco products. Where WTS was specifically addressed, no additional legislative guidance accounted for the unique way it is smoked, except for in one country specifying health warnings on waterpipe apparatuses (2) News articles mainly reported on noncompliance with public smoking bans, especially in India, Pakistan and the UK. CONCLUSIONS: A regulatory framework evaluated for effectiveness and tailored for the specificities of WTS needs to be developed. PMID- 25550419 TI - An evaluation of the FDA's analysis of the costs and benefits of the graphic warning label regulation. AB - The Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food and Drug Administration (FDA) regulatory authority over cigarettes and smokeless tobacco products and authorised it to assert jurisdiction over other tobacco products. As with other Federal agencies, FDA is required to assess the costs and benefits of its significant regulatory actions. To date, FDA has issued economic impact analyses of one proposed and one final rule requiring graphic warning labels (GWLs) on cigarette packaging and, most recently, of a proposed rule that would assert FDA's authority over tobacco products other than cigarettes and smokeless tobacco. Given the controversy over the FDA's approach to assessing net economic benefits in its proposed and final rules on GWLs and the importance of having economic impact analyses prepared in accordance with sound economic analysis, a group of prominent economists met in early 2014 to review that approach and, where indicated, to offer suggestions for an improved analysis. We concluded that the analysis of the impact of GWLs on smoking substantially underestimated the benefits and overestimated the costs, leading the FDA to substantially underestimate the net benefits of the GWLs. We hope that the FDA will find our evaluation useful in subsequent analyses, not only of GWLs but also of other regulations regarding tobacco products. Most of what we discuss applies to all instances of evaluating the costs and benefits of tobacco product regulation and, we believe, should be considered in FDA's future analyses of proposed rules. PMID- 25550420 TI - Variations in state use of antitobacco message themes predict youth smoking prevalence in the USA, 1999-2005. AB - OBJECTIVE: This study tests relationships between the volume of advertisements (ads; public service announcements (PSAs)) employed in state antismoking campaigns, use of different themes and stylistic features in these PSAs, and state youth smoking prevalence between 1999 and 2005. METHODS: We merged commercially available data on televised antismoking PSAs that aired between 1998 and 2004 with data on state tobacco control activity to test the relationship between the volume and content of youth-targeted and general-targeted/adult targeted antismoking PSAs on youth smoking prevalence, controlling for other tobacco control efforts. We use content analysis and ordinary least squares (OLS) regression to assess which thematic and stylistic features employed in state antismoking PSAs are associated with reduced smoking prevalence. RESULTS: A 100 ad increase in the yearly volume of youth-targeted state antismoking PSAs was associated with a 0.1 percentage point decrease in state youth smoking rates in the following year. This relationship was driven by variation in state use of PSAs emphasising health consequences to self or others and anti-industry appeals. Controlling for appearances of these themes, use of graphic imagery and personal testimonials did not predict reduced smoking prevalence. Adult-targeted/general targeted PSAs were not associated with youth smoking prevalence. CONCLUSIONS: Youth-targeted state antitobacco PSAs that emphasise the health consequences of smoking (to oneself and others) and contain anti-industry appeals are associated with reduced youth smoking rates. Future work should avoid typologies that do not account for the co-occurrence of thematic and stylistic content in antitobacco PSAs. PMID- 25550421 TI - Methods of the International Tobacco Control (ITC) China Survey: Waves 1, 2 and 3. AB - This paper describes the methods of sampling design and data collection of Wave 1, 2 and 3 of the International Tobacco Control (ITC) China Survey, with major focus on longitudinal features of the study. Key measures of quality of the survey data, such as retention rates and final sample sizes, are presented. Sample replenishment procedures are outlined, including the addition of a new city, Kunming, at Wave 3. Methods for constructing the longitudinal and cross sectional survey weights are briefly described. PMID- 25550422 TI - RNA structure generates natural cooperativity between single-stranded RNA binding proteins targeting 5' and 3'UTRs. AB - In post-transcriptional regulation, an mRNA molecule is bound by many proteins and/or miRNAs to modulate its function. To enable combinatorial gene regulation, these binding partners of an RNA must communicate with each other, exhibiting cooperativity. Even in the absence of direct physical interactions between the binding partners, such cooperativity can be mediated through RNA secondary structures, since they affect the accessibility of the binding sites. Here we propose a quantitative measure of this structure-mediated cooperativity that can be numerically calculated for an arbitrary RNA sequence. Focusing on an RNA with two binding sites, we derive a characteristic difference of free energy differences, i.e. DeltaDeltaG, as a measure of the effect of the occupancy of one binding site on the binding strength of another. We apply this measure to a large number of human and Caenorhabditis elegans mRNAs, and find that structure mediated cooperativity is a generic feature. Interestingly, this cooperativity not only affects binding sites in close proximity along the sequence but also configurations in which one binding site is located in the 5'UTR and the other is located in the 3'UTR of the mRNA. Furthermore, we find that this end-to-end cooperativity is determined by the UTR sequences while the sequences of the coding regions are irrelevant. PMID- 25550423 TI - Human PrimPol is a highly error-prone polymerase regulated by single-stranded DNA binding proteins. AB - PrimPol is a recently identified polymerase involved in eukaryotic DNA damage tolerance, employed in both re-priming and translesion synthesis mechanisms to bypass nuclear and mitochondrial DNA lesions. In this report, we investigate how the enzymatic activities of human PrimPol are regulated. We show that, unlike other TLS polymerases, PrimPol is not stimulated by PCNA and does not interact with it in vivo. We identify that PrimPol interacts with both of the major single strand binding proteins, RPA and mtSSB in vivo. Using NMR spectroscopy, we characterize the domains responsible for the PrimPol-RPA interaction, revealing that PrimPol binds directly to the N-terminal domain of RPA70. In contrast to the established role of SSBs in stimulating replicative polymerases, we find that SSBs significantly limit the primase and polymerase activities of PrimPol. To identify the requirement for this regulation, we employed two forward mutation assays to characterize PrimPol's replication fidelity. We find that PrimPol is a mutagenic polymerase, with a unique error specificity that is highly biased towards insertion-deletion errors. Given the error-prone disposition of PrimPol, we propose a mechanism whereby SSBs greatly restrict the contribution of this enzyme to DNA replication at stalled forks, thus reducing the mutagenic potential of PrimPol during genome replication. PMID- 25550424 TI - Modified ribosome profiling reveals high abundance of ribosome protected mRNA fragments derived from 3' untranslated regions. AB - Ribosome profiling identifies ribosome positions on translated mRNAs. A prominent feature of published datasets is the near complete absence of ribosomes in 3' untranslated regions (3'UTR) although substantial ribosome density can be observed on non-coding RNAs. Here we perform ribosome profiling in cultured Drosophila and human cells and show that different features of translation are revealed depending on the nuclease and the digestion conditions used. Most importantly, we observe high abundance of ribosome protected fragments in 3'UTRs of thousands of genes without manipulation of translation termination. Affinity purification of ribosomes indicates that the 3'UTR reads originate from ribosome protected fragments. Association of ribosomes with the 3'UTR may be due to ribosome migration through the stop codon or 3'UTR mRNA binding to ribosomes on the coding sequence. This association depends primarily on the relative length of the 3'UTR and may be related to translational regulation or ribosome recycling, for which the efficiency is known to inversely correlate with 3'UTR length. Together our results indicate that ribosome profiling is highly dependent on digestion conditions and that ribosomes commonly associate with the 3'UTR, which may have a role in translational regulation. PMID- 25550425 TI - Structural basis of DNA recognition by PCG2 reveals a novel DNA binding mode for winged helix-turn-helix domains. AB - The MBP1 family proteins are the DNA binding subunits of MBF cell-cycle transcription factor complexes and contain an N terminal winged helix-turn-helix (wHTH) DNA binding domain (DBD). Although the DNA binding mechanism of MBP1 from Saccharomyces cerevisiae has been extensively studied, the structural framework and the DNA binding mode of other MBP1 family proteins remains to be disclosed. Here, we determined the crystal structure of the DBD of PCG2, the Magnaporthe oryzae orthologue of MBP1, bound to MCB-DNA. The structure revealed that the wing, the 20-loop, helix A and helix B in PCG2-DBD are important elements for DNA binding. Unlike previously characterized wHTH proteins, PCG2-DBD utilizes the wing and helix-B to bind the minor groove and the major groove of the MCB-DNA whilst the 20-loop and helix A interact non-specifically with DNA. Notably, two glutamines Q89 and Q82 within the wing were found to recognize the MCB core CGCG sequence through making hydrogen bond interactions. Further in vitro assays confirmed essential roles of Q89 and Q82 in the DNA binding. These data together indicate that the MBP1 homologue PCG2 employs an unusual mode of binding to target DNA and demonstrate the versatility of wHTH domains. PMID- 25550426 TI - The architecture of the 12RSS in V(D)J recombination signal and synaptic complexes. AB - V(D)J recombination is initiated by RAG1 and RAG2, which together with HMGB1 bind to a recombination signal sequence (12RSS or 23RSS) to form the signal complex (SC) and then capture a complementary partner RSS, yielding the paired complex (PC). Little is known regarding the structural changes that accompany the SC to PC transition or the structural features that allow RAG to distinguish its two asymmetric substrates. To address these issues, we analyzed the structure of the 12RSS in the SC and PC using fluorescence resonance energy transfer (FRET) and molecular dynamics modeling. The resulting models indicate that the 12RSS adopts a strongly bent V-shaped structure upon RAG/HMGB1 binding and reveal structural differences, particularly near the heptamer, between the 12RSS in the SC and PC. Comparison of models of the 12RSS and 23RSS in the PC reveals broadly similar shapes but a distinct number and location of DNA bends as well as a smaller central cavity for the 12RSS. These findings provide the most detailed view yet of the 12RSS in RAG-DNA complexes and highlight structural features of the RSS that might underlie activation of RAG-mediated cleavage and substrate asymmetry important for the 12/23 rule of V(D)J recombination. PMID- 25550427 TI - A naturally occurring 4-bp deletion in the intron 4 of p53 creates a spectrum of novel p53 isoforms with anti-apoptosis function. AB - p53 functions as a tumor suppressor by transcriptionally regulating the expression of genes involved in controlling cell proliferation or apoptosis. p53 and its isoform Delta133p53/Delta113p53 form a negative regulation loop in that p53 activates the expression of Delta133p53/Delta113p53 while Delta133p53/Delta113p53 specifically antagonizes p53 apoptotic activity. This pathway is especially important to safeguard the process of embryogenesis because sudden activation of p53 by DNA damage signals or developmental stress is detrimental to a developing embryo. Here we report the identification of five novel p53 isoforms. p53beta is generated due to alternative splicing of the intron 8 of p53 while the other four, namely, TA2p53, TA3p53, TA4p53 and TA5p53, result from the combination of alternative splicing of intron 1 (within intron 4 of the p53 gene) of the Delta113p53 gene and a naturally occurring CATT 4 bp deletion within the alternative splicing product in zebrafish. The CATT 4 bp deletion creates four translation start codons which are in-frame to the open reading frame of Delta113p53. We also show that TAp53 shares the same promoter with Delta113p53 and functions to antagonize p53 apoptotic activity. The identification of Delta113p53/TA2/3/4/5p53 reveals a pro-survival mechanism which operates robustly during embryogenesis in response to the DNA-damage condition. PMID- 25550428 TI - EvoTol: a protein-sequence based evolutionary intolerance framework for disease gene prioritization. AB - Methods to interpret personal genome sequences are increasingly required. Here, we report a novel framework (EvoTol) to identify disease-causing genes using patient sequence data from within protein coding-regions. EvoTol quantifies a gene's intolerance to mutation using evolutionary conservation of protein sequences and can incorporate tissue-specific gene expression data. We apply this framework to the analysis of whole-exome sequence data in epilepsy and congenital heart disease, and demonstrate EvoTol's ability to identify known disease-causing genes is unmatched by competing methods. Application of EvoTol to the human interactome revealed networks enriched for genes intolerant to protein sequence variation, informing novel polygenic contributions to human disease. PMID- 25550429 TI - Identification of RNA polymerase III-transcribed Alu loci by computational screening of RNA-Seq data. AB - Of the ~ 1.3 million Alu elements in the human genome, only a tiny number are estimated to be active in transcription by RNA polymerase (Pol) III. Tracing the individual loci from which Alu transcripts originate is complicated by their highly repetitive nature. By exploiting RNA-Seq data sets and unique Alu DNA sequences, we devised a bioinformatic pipeline allowing us to identify Pol III dependent transcripts of individual Alu elements. When applied to ENCODE transcriptomes of seven human cell lines, this search strategy identified ~ 1300 Alu loci corresponding to detectable transcripts, with ~ 120 of them expressed in at least three cell lines. In vitro transcription of selected Alus did not reflect their in vivo expression properties, and required the native 5'-flanking region in addition to internal promoter. We also identified a cluster of expressed AluYa5-derived transcription units, juxtaposed to snaR genes on chromosome 19, formed by a promoter-containing left monomer fused to an Alu unrelated downstream moiety. Autonomous Pol III transcription was also revealed for Alus nested within Pol II-transcribed genes. The ability to investigate Alu transcriptomes at single-locus resolution will facilitate both the identification of novel biologically relevant Alu RNAs and the assessment of Alu expression alteration under pathological conditions. PMID- 25550431 TI - Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB-siRNA conjugates. AB - Delivery of siRNA is a key hurdle to realizing the therapeutic promise of RNAi. By targeting internalizing cell surface antigens, antibody-siRNA complexes provide a possible solution. However, initial reports of antibody-siRNA complexes relied on non-specific charged interactions and have not been broadly applicable. To assess and improve this delivery method, we built on an industrial platform of therapeutic antibodies called THIOMABs, engineered to enable precise covalent coupling of siRNAs. We report that such coupling generates monomeric antibody siRNA conjugates (ARCs) that retain antibody and siRNA activities. To broadly assess this technology, we generated a battery of THIOMABs against seven targets that use multiple internalization routes, enabling systematic manipulation of multiple parameters that impact delivery. We identify ARCs that induce targeted silencing in vitro and extend tests to target prostate carcinoma cells following systemic administration in mouse models. However, optimal silencing was restricted to specific conditions and only observed using a subset of ARCs. Trafficking studies point to ARC entrapment in endocytic compartments as a limiting factor, independent of the route of antigen internalization. Our broad characterization of multiple parameters using therapeutic-grade conjugate technology provides a thorough assessment of this delivery technology, highlighting both examples of success as well as remaining challenges. PMID- 25550430 TI - Chromatin-dependent regulation of RNA polymerases II and III activity throughout the transcription cycle. AB - The particular behaviour of eukaryotic RNA polymerases along different gene regions and amongst distinct gene functional groups is not totally understood. To cast light onto the alternative active or backtracking states of RNA polymerase II, we have quantitatively mapped active RNA polymerases at a high resolution following a new biotin-based genomic run-on (BioGRO) technique. Compared with conventional profiling with chromatin immunoprecipitation, the analysis of the BioGRO profiles in Saccharomyces cerevisiae shows that RNA polymerase II has unique activity profiles at both gene ends, which are highly dependent on positioned nucleosomes. This is the first demonstration of the in vivo influence of positioned nucleosomes on transcription elongation. The particular features at the 5' end and around the polyadenylation site indicate that this polymerase undergoes extensive specific-activity regulation in the initial and final transcription elongation phases. The genes encoding for ribosomal proteins show distinctive features at both ends. BioGRO also provides the first nascentome analysis for RNA polymerase III, which indicates that transcription of tRNA genes is poorly regulated at the individual copy level. The present study provides a novel perspective of the transcription cycle that incorporates inactivation/reactivation as an important aspect of RNA polymerase dynamics. PMID- 25550432 TI - Five checkpoints maintaining the fidelity of transcription by RNA polymerases in structural and energetic details. AB - Transcriptional fidelity, which prevents the misincorporation of incorrect nucleoside monophosphates in RNA, is essential for life. Results from molecular dynamics (MD) simulations of eukaryotic RNA polymerase (RNAP) II and bacterial RNAP with experimental data suggest that fidelity may involve as many as five checkpoints. Using MD simulations, the effects of different active site NTPs in both open and closed trigger loop (TL) structures of RNAPs are compared. Unfavorable initial binding of mismatched substrates in the active site with an open TL is proposed to be the first fidelity checkpoint. The leaving of an incorrect substrate is much easier than a correct one energetically from the umbrella sampling simulations. Then, the closing motion of the TL, required for catalysis, is hindered by the presence of mismatched NTPs. Mismatched NTPs also lead to conformational changes in the active site, which perturb the coordination of magnesium ions and likely affect the ability to proceed with catalysis. This step appears to be the most important checkpoint for deoxy-NTP discrimination. Finally, structural perturbations in the template DNA and the nascent RNA in the presence of mismatches likely hinder nucleotide addition and provide the structural foundation for backtracking followed by removing erroneously incorporated nucleotides during proofreading. PMID- 25550433 TI - A structural determinant in the uracil DNA glycosylase superfamily for the removal of uracil from adenine/uracil base pairs. AB - The uracil DNA glycosylase superfamily consists of several distinct families. Family 2 mismatch-specific uracil DNA glycosylase (MUG) from Escherichia coli is known to exhibit glycosylase activity on three mismatched base pairs, T/U, G/U and C/U. Family 1 uracil N-glycosylase (UNG) from E. coli is an extremely efficient enzyme that can remove uracil from any uracil-containing base pairs including the A/U base pair. Here, we report the identification of an important structural determinant that underlies the functional difference between MUG and UNG. Substitution of a Lys residue at position 68 with Asn in MUG not only accelerates the removal of uracil from mismatched base pairs but also enables the enzyme to gain catalytic activity on A/U base pairs. Binding and kinetic analysis demonstrate that the MUG-K68N substitution results in enhanced ground state binding and transition state interactions. Molecular modeling reveals that MUG K68N, UNG-N123 and family 5 Thermus thermophiles UDGb-A111N can form bidentate hydrogen bonds with the N3 and O4 moieties of the uracil base. Genetic analysis indicates the gain of function for A/U base pairs allows the MUG-K68N mutant to remove uracil incorporated into the genome during DNA replication. The implications of this study in the origin of life are discussed. PMID- 25550434 TI - Identification of the endosomal sorting complex required for transport-I (ESCRT I) as an important modulator of anti-miR uptake by cancer cells. AB - Mechanisms of unassisted delivery of RNA therapeutics, including inhibitors of microRNAs, remain poorly understood. We observed that the hepatocellular carcinoma cell line SKHEP1 retains productive free uptake of a miR-21 inhibitor (anti-miR-21). Uptake of anti-miR-21, but not a mismatch (MM) control, induces expression of known miR-21 targets (DDAH1, ANKRD46) and leads to dose-dependent inhibition of cell growth. To elucidate mechanisms of SKHEP1 sensitivity to anti miR-21, we conducted an unbiased shRNA screen that revealed tumor susceptibility gene 101 (TSG101), a component of the endosomal sorting complex required for transport (ESCRT-I), as an important determinant of anti-proliferative effects of anti-miR-21. RNA interference-mediated knockdown of TSG101 and another ESCRT-I protein, VPS28, improved uptake of anti-miR-21 in parental SKHEP1 cells and restored productive uptake to SKHEP1 clones with acquired resistance to anti-miR 21. Depletion of ESCRT-I in several additional cancer cell lines with inherently poor uptake resulted in improved activity of anti-miR-21. Finally, knockdown of TSG101 increased uptake of anti-miR-21 by cancer cells in vivo following systemic delivery. Collectively, these data support an important role for the ESCRT-I complex in the regulation of productive free uptake of anti-miRs and reveal potential avenues for improving oligonucleotide free uptake by cancer cells. PMID- 25550435 TI - Absolute binding-free energies between standard RNA/DNA nucleobases and amino acid sidechain analogs in different environments. AB - Despite the great importance of nucleic acid-protein interactions in the cell, our understanding of their physico-chemical basis remains incomplete. In order to address this challenge, we have for the first time determined potentials of mean force and the associated absolute binding free energies between all standard RNA/DNA nucleobases and amino-acid sidechain analogs in high- and low-dielectric environments using molecular dynamics simulations and umbrella sampling. A comparison against a limited set of available experimental values for analogous systems attests to the quality of the computational approach and the force field used. Overall, our analysis provides a microscopic picture behind nucleobase/sidechain interaction preferences and creates a unified framework for understanding and sculpting nucleic acid-protein interactions in different contexts. Here, we use this framework to demonstrate a strong relationship between nucleobase density profiles of mRNAs and nucleobase affinity profiles of their cognate proteins and critically analyze a recent hypothesis that the two may be capable of direct, complementary interactions. PMID- 25550436 TI - Switching between polymerase and exonuclease sites in DNA polymerase epsilon. AB - The balance between exonuclease and polymerase activities promotes DNA synthesis over degradation when nucleotides are correctly added to the new strand by replicative B-family polymerases. Misincorporations shift the balance toward the exonuclease site, and the balance tips back in favor of DNA synthesis when the incorrect nucleotides have been removed. Most B-family DNA polymerases have an extended beta-hairpin loop that appears to be important for switching from the exonuclease site to the polymerase site, a process that affects fidelity of the DNA polymerase. Here, we show that DNA polymerase epsilon can switch between the polymerase site and exonuclease site in a processive manner despite the absence of an extended beta-hairpin loop. K967 and R988 are two conserved amino acids in the palm and thumb domain that interact with bases on the primer strand in the minor groove at positions n-2 and n-4/n-5, respectively. DNA polymerase epsilon depends on both K967 and R988 to stabilize the 3'-terminus of the DNA within the polymerase site and on R988 to processively switch between the exonuclease and polymerase sites. Based on a structural alignment with DNA polymerase delta, we propose that arginines corresponding to R988 might have a similar function in other B-family polymerases. PMID- 25550437 TI - NFATc2 mediates epigenetic modification of dendritic cell cytokine and chemokine responses to dectin-1 stimulation. AB - The transcription factor NFATc2 regulates dendritic cell (DC) responses to microbial stimulation through the C-type lectin receptor dectin-1. But the genetic targets of NFATc2 and their effects on DC function remain largely unknown. Therefore we used ChIP-seq to conduct genome-wide mapping of NFATc2 target sites in dectin-1-activated DCs. By combining binding-site data with a comprehensive gene expression profile, we found that NFATc2 occupancy regulates the expression of a subset of dectin-1-activated genes. Surprisingly, NFATc2 targeted an extensive range of DC-derived cytokines and chemokines, including regulatory cytokines such as IL2, IL23a and IL12b. Furthermore, we demonstrated that NFATc2 binding is required to induce the histone 3 lysine 4 trimethylation (H3K4me3) epigenetic mark, which is associated with enhanced gene expression. Together, these data show that the transcription factor NFATc2 mediates epigenetic modification of DC cytokine and chemokine genes leading to activation of their expression. PMID- 25550438 TI - Central cardiac limit to aerobic capacity in patients with exertional pulmonary venous hypertension: implications for heart failure with preserved ejection fraction. AB - BACKGROUND: The mechanism of functional limitation in heart failure with preserved ejection fraction remains controversial. We examined the contributions of central cardiac and peripheral mechanisms and hypothesized that the pulmonary vascular response to exercise is an important determinant of aerobic capacity among patients with exertional pulmonary venous hypertension (ePVH). METHODS AND RESULTS: We compared 31 ePVH patients (peak VO2<80% of predicted and peak pulmonary arterial wedge pressure>=20 mm Hg) with 31 age- and sex-matched controls (peak VO2>80% predicted) who underwent invasive cardiopulmonary exercise testing for unexplained exertional intolerance. ePVH patients had lower peak cardiac output (73+/-14% versus 103+/-18% predicted; P<0.001) compared with controls, related both to impaired chronotropic response (peak heart rate 111+/ 25 beats per minute versus 136+/-24 beats per minute; P<0.001) and to reduced peak stroke volume index (47+/-10 mL/min per m(2) versus 54+/-15 mL/min per m(2); P=0.03). Peak systemic O2 extraction was not different between groups (arterial mixed venous oxygen content difference: 13.0+/-2.1 mL/dL versus 13.4+/-2.4 mL/dL; P=0.46). ePVH patients had higher resting (150+/-74 versus 106+/-50 dyne/s per cm(-5); P=0.009), peak (124+/-74 dyne/s per cm(-5) versus 70+/-41 dyne/s per cm( 5); P<0.001), and isoflow pulmonary vascular resistance (124+/-74 dyne/s per cm( 5) versus 91+/-33 dyne/s per cm(-5) at cardiac output~10.6 L/min; P=0.04). Pulmonary vascular resistance decreased with exercise in all control subjects but increased in 36% (n=11) of ePVH patients. Abnormal pulmonary vascular response was not associated with peak VO2. CONCLUSIONS: Reduced cardiac output response, rather than impaired peripheral O2 extraction, constrains oxygen delivery and aerobic capacity in ePVH. Pulmonary vascular dysfunction is common in patients with ePVH at rest and during exercise. PMID- 25550439 TI - Ventricular conduction and long-term heart failure outcomes and mortality in African Americans: insights from the Jackson Heart Study. AB - BACKGROUND: QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. METHODS AND RESULTS: We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12 lead ECG. We defined QRS prolongation as QRS>=100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0-14.4) versus 7.1% (95% CI, 6.3-8.0) and 8.2% (95% CI, 6.9-9.7) versus 4.4% (95% CI, 3.7-5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03-1.56; P=0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01 1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. CONCLUSIONS: QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities. PMID- 25550440 TI - Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis. AB - BACKGROUND: Continuous angiotensin-II infusion induced the uptake of monocytic fibroblast precursors that initiated the development of cardiac fibrosis; these cells and concurrent fibrosis were absent in mice lacking tumor necrosis factor receptor 1 (TNFR1). We now investigated their cellular origin and temporal uptake and the involvement of TNFR1 in monocyte-to-fibroblast differentiation. METHODS AND RESULTS: Within a day, angiotensin-II induced a proinflammatory environment characterized by production of inflammatory chemokines, cytokines, and TH1 interleukins and uptake of bone marrow-derived M1 cells. After a week, the cardiac environment changed to profibrotic with growth factor and TH2-interleukin synthesis, uptake of bone marrow-derived M2 cells, and the presence of M2-related fibroblasts. TNFR1 signaling was not necessary for early M1 uptake, but its absence diminished the amount of M2 cells. TNFR1-knockout hearts also showed reduced levels of cytokine expression, but not of TH-related lymphokines. Reconstitution of wild-type bone marrow into TNFR1-knockout mice was sufficient to restore M2 uptake, upregulation of proinflammatory and profibrotic genes, and development of fibrosis in response to angiotensin-II. We also developed an in vitro mouse monocyte-to-fibroblast maturation assay that confirmed the essential role of TNFR1 in the sequential progression of monocyte activation and fibroblast formation. CONCLUSIONS: Development of cardiac fibrosis in response to angiotensin-II was mediated by myeloid precursors and consisted of 2 stages. A primary M1 inflammatory response was followed by a subsequent M2 fibrotic response. Although the first phase seemed to be independent of TNFR1 signaling, the later phase (and development of fibrosis) was abrogated by deletion of TNFR1. PMID- 25550441 TI - Exercise oscillatory ventilation in patients with Fontan physiology. AB - BACKGROUND: Exercise oscillatory ventilation (EOV) refers to regular oscillations in minute ventilation (VE) during exercise. Its presence correlates with heart failure severity and worse prognosis in adults with acquired heart failure. We evaluated the prevalence and predictive value of EOV in patients with single ventricle Fontan physiology. METHODS AND RESULTS: We performed a cross-sectional analysis and prospective survival analysis of patients who had undergone a Fontan procedure and subsequent cardiopulmonary exercise test. Data were reviewed for baseline characteristics and incident mortality, heart transplant, or nonelective cardiovascular hospitalization. EOV was defined as regular oscillations for >60% of exercise duration with amplitude >15% of average VE. Survival analysis was performed using Cox regression. Among 253 subjects, EOV was present in 37.5%. Patients with EOV were younger (18.8+/-9.0 versus 21.7+/-10.1 years; P=0.02). EOV was associated with higher New York Heart Association functional class (P=0.02) and VE/VCO2 slope (36.8+/-6.9 versus 33.7+/-5.7; P=0.0002), but not with peak VO2 (59.7+/-14.3 versus 61.0+/-16.0% predicted; P=0.52) or noninvasive measures of cardiac function. The presence of EOV was associated with slightly lower mean cardiac index but other invasive hemodynamic variables were similar. During a median follow-up of 5.5 years, 22 patients underwent transplant or died (n=19 primary deaths, 3 transplants with 2 subsequent deaths). EOV was associated with increased risk of death or transplant (hazard ratio, 3.9; 95% confidence interval, 1.5-10.0; P=0.002) and also predicted the combined outcome of death, transplant, or nonelective cardiovascular hospitalization after adjusting for New York Heart Association functional class, peak VO2, and other covariates (multivariable hazard ratio, 2.0; 95% confidence interval, 1.2-3.6; P=0.01). CONCLUSIONS: EOV is common in the Fontan population and strongly predicts lower transplant-free survival. PMID- 25550442 TI - Novel Therapeutic Strategies for Delirium in Patients With Cancer: A Preliminary Study. AB - To compare the efficacy of antipsychotics (APs) for delirium treatment in patients with cancer, 27 patients treated with 1 of the 4 APs, haloperidol (HPD), risperidone (RIS), olanzapine (OLZ), and quetiapine (QTP), were divided into 2 groups: long half-life (T1/2; HPD, RIS, and OLZ) versus short T1/2 (QTP) or the multiacting receptor-targeted APs (MARTAs; OLZ and QTP) versus the non-MARTA (HPD and RIS). The symptom severity was evaluated by the memorial delirium rating scale (MDAS) on days 0, 3, and 7 following intervention. Significant improvements in total MDAS scores were found in all groups on day 3. However, on day 7, only the short T1/2 group and MARTA group showed significant improvement. Consideration of an AP's pharmacological properties may be helpful for improving the outcomes of pharmacological delirium intervention in patients with cancer. PMID- 25550443 TI - Managing Advanced Progressive Supranuclear Palsy and Corticobasal Degeneration in a Palliative Care Unit: Admission Triggers and Outcomes. AB - BACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized by rapid deterioration and a fatal outcome. OBJECTIVES: Admission triggers, treatment efficacy, and care patterns. METHODS: Retrospective analysis of patients with PSP/CBD admitted to an inpatient specialized palliative care service. RESULTS: In 38 patients, there were 63 admissions for swallowing difficulties, falls, pain, impaired communication, cognitive/mood disturbances, respiratory symptoms, and infection. Mean length of stay was 11.6 days. Treatment response was variable. In 68%, of admission episodes there was stabilization or improvement, 75% were discharged home. In case of readmission, the mean interval has been 9.7 months. Time since diagnosis and admission triggers were not associated with outcome or death. CONCLUSION: Patients showed high symptom load contrasting with discharge rates and subsequent health care utilization. Brief multidisciplinary interventions might be helpful to preserve autonomy. PMID- 25550444 TI - Enhancing Cognitive Function Using Perceptual-Cognitive Training. AB - Three-dimensional multiple object tracking (3D-MOT) is a perceptual-cognitive training system based on a 3D virtual environment. This is the first study to examine the effects of 3D-MOT training on attention, working memory, and visual information processing speed as well as using functional brain imaging on a normative population. Twenty university-aged students were recruited and divided into a training (NT) and nonactive control (CON) group. Cognitive functions were assessed using neuropsychological tests, and correlates of brain functions were assessed using quantitative electroencephalography (qEEG). Results indicate that 10 sessions of 3D-MOT training can enhance attention, visual information processing speed, and working memory, and also leads to quantifiable changes in resting-state neuroelectric brain function. PMID- 25550445 TI - Alanyl-glutamine improves pancreatic beta-cell function following ex vivo inflammatory challenge. AB - Obesity-associated diabetes and concomitant inflammation may compromise pancreatic beta-cell integrity and function. l-glutamine and l-alanine are potent insulin secretagogues, with antioxidant and cytoprotective properties. Herein, we studied whether the dipeptide l-alanyl-l-glutamine (Ala-Gln) could exert protective effects via sirtuin 1/HUR (SIRT1/HUR) signalling in beta-cells, against detrimental responses following ex vivo stimulation with inflammatory mediators derived from macrophages (IMMs). The macrophages were derived from blood obtained from obese subjects. Macrophages were exposed (or not) to lipopolysaccharide (LPS) to generate a pro-inflammatory cytokine cocktail. The cytokine profile was determined following analysis by flow cytometry. Insulin secreting BRIN-BD11 beta-cells were exposed to IMMs and then cultured with or without Ala-Gln for 24 h. Chronic insulin secretion, the l-glutamine-glutathione (GSH) axis, and the level of insulin receptor beta (IR-beta), heat shock protein 70 (HSP70), SIRT1/HUR, CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome c oxidase IV (COX IV) were evaluated. Concentrations of cytokines, including interleukin 1beta (IL1beta), IL6, IL10 and tumour necrosis factor alpha (TNFalpha) in the IMMs, were higher following exposure to LPS. Subsequently, when beta-cells were exposed to IMMs, chronic insulin secretion, and IR-beta and COX IV levels were decreased, but these effects were partially or fully attenuated by the addition of Ala-Gln. The glutamine-GSH axis and HSP70 levels, which were compromised by IMMs, were also restored by Ala-Gln, possibly due to protection of SIRT1/HUR levels, and a reduction of CHOP expression. Using an ex vivo inflammatory approach, we have demonstrated Ala-Gln-dependent beta-cell protection mediated by coordinated effects on the glutamine-GSH axis, and the HSP pathway, maintenance of mitochondrial metabolism and stimulus-secretion coupling essential for insulin release. PMID- 25550446 TI - A Successful Model for a Comprehensive Patient Flow Management Center at an Academic Health System. AB - This article reports on an innovative approach to managing patient flow at a multicampus academic health system, integrating multiple services into a single, centralized Patient Flow Management Center that manages supply and demand for inpatient services across the system. Control of bed management was centralized across 3 campuses and key services were integrated, including bed management, case management, environmental services, patient transport, ambulance and helicopter dispatch, and transfer center. A single technology platform was introduced, as was providing round-the-clock patient placement by critical care nurses, and adding medical directors. Daily bed meetings with nurse managers and charge nurses drive action plans. This article reports immediate improvements in the first year of operations in emergency department walkouts, emergency department boarding, ambulance diversion, growth in transfer volume, reduction in lost transfers, reduction in time to bed assignment, and bed turnover time. The authors believe theirs is the first institution to integrate services and centralize bed management so comprehensively. PMID- 25550447 TI - Vasculitis in children. AB - Primary systemic vasculitides of the young are relatively rare diseases, but are associated with significant morbidity and mortality, particularly if there is diagnostic delay. We provide an overview of paediatric vasculitides with emphasis on key differences in vasculitis presentation and management between children and adults. Significant advances in the field of paediatric vasculitis research include the development of classification criteria and disease outcome tools for paediatric disease; inclusion of paediatric patients in international multicentre randomized controlled trials of therapies in vasculitis; and development of rare disease trial designs for therapeutic trials of paediatric vasculitis. The continuation of unmet needs as well as the exploration of potential therapeutic avenues and considerations in the design of future trials are also discussed. PMID- 25550448 TI - Diabetes mellitus, a complex and heterogeneous disease, and the role of insulin resistance as a determinant of diabetic kidney disease. AB - Diabetes mellitus (DM) is increasingly recognized as a heterogeneous condition. The individualization of care and treatment necessitates an understanding of the individual patient's pathophysiology of DM that underpins their DM classification and clinical presentation. Classical type-2 diabetes mellitus is due to a combination of insulin resistance and an insulin secretory defect. Type-1 diabetes is characterized by a near-absolute deficiency of insulin secretion. More recently, advances in genetics and a better appreciation of the atypical features of DM has resulted in more categories of diabetes. In the context of kidney disease, patients with DM and microalbuminuria are more insulin resistant, and insulin resistance may be a pathway that results in accelerated progression of diabetic kidney disease. This review summarizes the updated classification of DM, including more rarer categories and their associated renal manifestations that need to be considered in patients who present with atypical features. The benefits and limitations of the tests utilized to make a diagnosis of DM are discussed. We also review the putative pathways and mechanisms by which insulin resistance drives the progression of diabetic kidney disease. PMID- 25550449 TI - Role for telomerase in pulmonary hypertension. AB - BACKGROUND: Cells exhibiting dysregulated growth may express telomerase reverse transcriptase (TERT), the dual function of which consists of maintaining telomere length, in association with the RNA template molecule TERC, and controlling cell growth. Here, we investigated lung TERT in human and experimental pulmonary hypertension (PH) and its role in controlling pulmonary artery smooth muscle cell (PA-SMC) proliferation. METHODS AND RESULTS: Marked TERT expression or activity was found in lungs from patients with idiopathic PH and from mice with PH induced by hypoxia or serotonin-transporter overexpression (SM22-5HTT(+) mice), chiefly within PA-SMCs. In cultured mouse PA-SMCs, TERT was expressed on growth stimulation by serum. The TERT inhibitor imetelstat and the TERT activator TA65 abrogated and stimulated PA-SMC growth, respectively. PA-SMCs from PH mice showed a heightened proliferative phenotype associated with increased TERT expression, which was suppressed by imetelstat treatment. TERC(-/-) mice at generation 2 and TERT(-/-) mice at generations 2, 3, and 4 developed less severe PH than did wild type mice exposed to chronic hypoxia, with less distal pulmonary artery muscularization and fewer Ki67-stained proliferating PA-SMCs. Telomere length differed between TERC(-/-) and TERT(-/-) mice, whereas PH severity was similar in the 2 strains and across generations. Chronic imetelstat treatment reduced hypoxia-induced PH in wild-type mice or partially reversed established PH in SM22 5HTT(+) mice while simultaneously decreasing TERT expression. Opposite effects occurred in mice treated with TA65. CONCLUSIONS: Telomerase exerts telomere independent effects on PA-SMC growth in PH and may constitute a treatment target for PH. PMID- 25550451 TI - Evaluation of platelet distribution width and mean platelet volume in patients with carotid artery stenosis: author's reply. PMID- 25550452 TI - The effect of peroneus brevis tendon anatomy on the stability of fractures at the fifth metatarsal base. AB - BACKGROUND: Nonunion of classic Jones fractures has typically been attributed to the precarious vascular anatomy of the proximal fifth metatarsal. Despite this theory, the operative treatment of these fractures utilizes biomechanical solutions. The purpose of the present study was to evaluate the influence of the peroneus brevis (PB) tendon on the stability of fractures of the proximal fifth metatarsal. METHODS: We utilized 5 matched pairs (10 specimens) of fresh-frozen cadaveric specimens. We used 2 loading conditions: (1) a simulated fracture distal to the PB insertion (Jones equivalent) and (2) a simulated fracture within the footprint of the PB insertion (avulsion equivalent). Following the creation of the fracture, each lower extremity was statically loaded through the Achilles and PB tendons. Our primary outcome measure was the degree of fracture diastasis with loading of the PB. Anteroposterior images with and without loading were obtained to evaluate fracture separation. We utilized a paired Student t test and the intraclass correlation coefficient (ICC) for all statistical analyses. RESULTS: The average length of the PB footprint was 15.2 mm. The simulated Jones fractures demonstrated greater fracture widening following loading of the PB tendon compared to the simulated avulsion fractures. The simulated avulsion fractures widened 0.4 mm on loading compared to 1.1 mm of widening in the simulated Jones fractures (P = .02). Intraobserver reliability for all radiographic measurements showed substantial agreement (ICC = 0.91). CONCLUSION: The PB exerted a deforming force on the proximal fragment of simulated Jones fractures. This deforming force was less pronounced in the simulated avulsion fractures. The principal findings of this study were that proximal fifth metatarsal fractures distal to the PB insertion were significantly more unstable than more proximal fractures. CLINICAL RELEVANCE: Our findings help support the notion that a mechanical component may contribute to the poor healing potential of Jones fractures secondary to deformation exerted by the PB tendon. PMID- 25550450 TI - Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a. AB - BACKGROUND: Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. METHODS AND RESULTS: Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Kruppel-like factor 2, and Kruppel-like factor 4, leading to NOD-like receptor family pyrin domain containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1beta. CONCLUSIONS: Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction. PMID- 25550453 TI - Risk factors for wound complications in patients after elective orthopedic foot and ankle surgery. AB - BACKGROUND: The aim of this study was to quantify the incidence of postoperative wound complications in elective foot and ankle surgery as well as the risk factors for postoperative wound complications. METHODS: Two hundred ninety-five elective orthopaedic foot and ankle operative procedures were performed in 290 patients between January 2006 and June 2010. A logistic multiple regression model was used to identify independent risk factors for postoperative wound healing complications/infection. RESULTS: The overall prevalence of postoperative wound complications within our cohort was 16.9%. In 4 patients (1.4%) deep infection was diagnosed requiring operative irrigation and debridement. Using a logistic multiple regression model we identified the following statistically independent risk factors: age >= 60 years (OR = 8.98, 95% CI = 3.55 to 25.02), tobacco use (OR = 48.77, 95% CI = 15.55 to 139.71), and tourniquet time >= 90 minutes (OR = 7.02, 95% CI = 2.77 to 19.32). CONCLUSION: Patients at risk for postoperative wound healing complications following elective orthopaedic foot and ankle surgery include those with higher age, tobacco use, and prolonged use of tourniquet. LEVEL OF EVIDENCE: Prognostic Level III, comparative study. PMID- 25550454 TI - Are estimates of socioeconomic inequalities in chronic disease artefactually narrowed by self-reported measures of prevalence in low-income and middle-income countries? Findings from the WHO-SAGE survey. AB - BACKGROUND: The use of self-reported measures of chronic disease may substantially underestimate prevalence in low-income and middle-income country settings, especially in groups with lower socioeconomic status (SES). We sought to determine whether socioeconomic inequalities in the prevalence of non communicable chronic diseases (NCDs) differ if estimated by using symptom-based or criterion-based measures compared with self-reported physician diagnoses. METHODS: Using population-representative data sets of the WHO Study of Global Ageing and Adult Health (SAGE), 2007-2010 (n=42 464), we calculated wealth related and education-related concentration indices of self-reported diagnoses and symptom-based measures of angina, hypertension, asthma/chronic lung disease, visual impairment and depression in three 'low-income and lower middle-income countries'-China, Ghana and India-and three 'upper-middle-income countries' Mexico, Russia and South Africa. RESULTS: SES gradients in NCD prevalence tended to be positive for self-reported diagnoses compared with symptom-based/criterion based measures. In China, Ghana and India, SES gradients were positive for hypertension, angina, visual impairment and depression when using self-reported diagnoses, but were attenuated or became negative when using symptom based/criterion-based measures. In Mexico, Russia and South Africa, this distinction was not observed consistently. For example, concentration index of self-reported versus symptom-based angina were: in China: 0.07 vs. -0.11, Ghana: 0.04 vs. -0.21, India: 0.02 vs. -0.16, Mexico: 0.19 vs. -0.22, Russia: -0.01 vs. 0.02 and South Africa: 0.37 vs. 0.02. CONCLUSIONS: Socioeconomic inequalities in NCD prevalence tend to be artefactually positive when using self-report compared with symptom-based or criterion-based diagnostic criteria, with greater bias occurring in low-income countries. Using standardised, symptom-based measures would provide more valid estimates of NCD inequalities. PMID- 25550455 TI - Protective role of the dynamin inhibitor Dynasore against the cholesterol dependent cytolysin of Trueperella pyogenes. AB - The virulence of many Gram-positive bacteria depends on cholesterol-dependent cytolysins (CDCs), which form pores in eukaryotic cell plasma membranes. Pyolysin (PLO) from Trueperella pyogenes provided a unique opportunity to explore cellular responses to CDCs because it does not require thiol activation. Sublytic concentrations of PLO stimulated phosphorylation of MAPK ERK and p38 in primary stromal cells, and induced autophagy as determined by protein light-chain 3B cleavage. Although, inhibitors of MAPK or autophagy did not affect PLO-induced cytolysis. However, 10 MUM 3-hydroxynaphthalene-2-carboxylic acid-(3,4 dihydroxybenzylidene)-hydrazide (Dynasore), a dynamin guanosine 5'-triphosphatase inhibitor, protected stromal cells against PLO-induced cytolysis as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (85 +/- 17% versus 50 +/- 9% cell viability), measuring extracellular ATP, and kinetic assays. This was a generalized mechanism because Dynasore also protected HeLa cells against streptolysin O. Furthermore, the effect was reversible, with stromal cell sensitivity to PLO restored within 30 minutes of Dynasore removal. The protective effect of Dynasore was not conferred by dynamin inhibition, induction of ERK phosphorylation, or Dynasore binding to PLO. Rather, Dynasore reduced cellular cholesterol and disrupted plasma membrane lipid rafts, similar to positive control methyl-beta-cyclodextrin. Dynasore is a tractable tool to explore the complexity of cholesterol homeostasis in eukaryotic cells and to develop strategies to counter CDCs. PMID- 25550456 TI - Gut microbes promote colonic serotonin production through an effect of short chain fatty acids on enterochromaffin cells. AB - Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5 HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 +/- 3 ng/mg; HM, 25 +/- 2 ng/mg; and CR, 35 +/- 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis. PMID- 25550457 TI - PI-PLCbeta1b affects Akt activation, cyclin E expression, and caspase cleavage, promoting cell survival in pro-B-lymphoblastic cells exposed to oxidative stress. AB - The phosphoinositide-dependent signal transduction pathway has been implicated in the control of a variety of biologic processes, such as the regulation of cellular metabolism and homeostasis, cell proliferation and differentiation, and apoptosis. One of the key players in the regulation of inositol lipid signaling is the phospholipase Cbeta1 (PI-PLCbeta1), that hydrolyzes phosphatidylinositol 4,5-bisphosphate [PtIns(4,5)P2], giving rise to the second messengers inositol triphosphate and diacylglicerol. PI-PLCbeta1 has been associated with the regulation of several cellular functions, some of which have not yet been fully understood. In particular, it has been reported that PI-PLCbeta1 protects murine fibroblasts from oxidative stress-induced cell death. The mediators of oxidative stress, reactive oxygen species (ROS), have been shown to regulate major epigenetic processes, causing the silencing of tumor suppressors and enhancing the proliferation of leukemic cells under oxidative stress. Investigation of the interplay between ROS, PI-PLCbeta1, and their signaling mediators in leukemia might therefore reveal innovative targets of pharmacological therapy in the treatment for leukemia. In this work, we demonstrate that in pro-B-lymphoblastic cells (Ba/F3), treated with H2O2, PI-PLCbeta1b conferred resistance to cell death, promoting cell cycle progression and cell proliferation and influencing the expression of cyclin A and E. Interestingly, we found that, expression of PI PLCbeta1b affects the activity of caspase-3, caspase-7, and of several protein kinases induced by oxidative stress. In particular, PI-PLCbeta1b expression completely abolished the phosphorylation of Erk1/2 MAP kinases, down-regulated phosphatase and tensin homolog (PTEN), and up-regulated the phosphorylation of Akt, thereby sustaining cellular proliferation. PMID- 25550458 TI - Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly. AB - Mutations in PIK3CA, the gene encoding the p110alpha catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 +/- 5%; wild-type 117 +/- 3%, mean +/- sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 +/- 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion of Akt2 increased median survival by 44%, neither organ overgrowth, nor hypoglycemia were rescued, indicating that both the growth and metabolic functions of constitutive PI3K activity can be Akt2 independent. This mouse model demonstrates the critical role of PI3K in the regulation of both organ size and glucose metabolism at the whole animal level. PMID- 25550460 TI - Optimized dietary strategies to protect skeletal muscle mass during periods of unavoidable energy deficit. AB - Interactions between dietary protein and energy balance on the regulation of human skeletal muscle protein turnover are not well described. A dietary protein intake above the recommended dietary allowance during energy balance typically enhances nitrogen retention and up-regulates muscle protein synthesis, which in turn may promote positive protein balance and skeletal muscle accretion. Recent studies show that during energy deficit, muscle protein synthesis is down regulated with concomitant increases in ubiquitin proteasome-mediated muscle proteolysis and nitrogen excretion, reflecting the loss of skeletal muscle mass. However, consuming high-protein diets (1.6-2.4 g/kg per day), or high-quality, protein-based meals (15-30 g whey) during energy deficit attenuates intracellular proteolysis, restores muscle protein synthesis, and mitigates skeletal muscle loss. These findings are particularly important for physically active, normal weight individuals because attenuating the extent to which skeletal muscle mass is lost during energy deficit could prevent decrements in performance, reduce injury risk, and facilitate recovery. This article reviews the relationship between energy status, protein intake, and muscle protein turnover, and explores future research directives designed to protect skeletal muscle mass in physically active, normal-weight adults. PMID- 25550459 TI - Matrix metalloproteinase 8 degrades apolipoprotein A-I and reduces its cholesterol efflux capacity. AB - Various cell types in atherosclerotic lesions express matrix metalloproteinase (MMP)-8. We investigated whether MMP-8 affects the structure and antiatherogenic function of apolipoprotein (apo) A-I, the main protein component of HDL particles. Furthermore, we studied serum lipid profiles and cholesterol efflux capacity in MMP-8-deficient mouse model. Incubation of apoA-I (28 kDa) with activated MMP-8 yielded 22 kDa and 25 kDa apoA-I fragments. Mass spectrometric analyses revealed that apoA-I was cleaved at its carboxyl-terminal part. Treatment of apoA-I and HDL with MMP-8 resulted in significant reduction (up to 84%, P < 0.001) in their ability to facilitate cholesterol efflux from cholesterol-loaded THP-1 macrophages. The cleavage of apoA-I by MMP-8 and the reduction in its cholesterol efflux capacity was inhibited by doxycycline. MMP-8 deficient mice had significantly lower serum triglyceride (TG) levels (P = 0.003) and larger HDL particles compared with wild-type (WT) mice. However, no differences were observed in the apoA-I levels or serum cholesterol efflux capacities between the mouse groups. Proteolytic modification of apoA-I by MMP-8 may impair the first steps of reverse cholesterol transport, leading to increased accumulation of cholesterol in the vessel walls. Eventually, inhibition of MMPs by doxycycline may reduce the risk for atherosclerotic vascular diseases. PMID- 25550461 TI - Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation. AB - Clusterin/apolipoprotein J (apoJ) is an extracellular chaperone involved in the quality control system against protein aggregation. A minor part of apoJ is transported in blood bound to LDLs, but its function is unknown. Our aim was to determine the role of apoJ bound to LDLs. Total LDL from human plasma was fractionated into native LDL [LDL(+)] and electronegative LDL [LDL(-)]. The latter was separated into nonaggregated [nagLDL(-)] and aggregated LDL(-) [agLDL( )]. The content of apoJ was 6-fold higher in LDL(-) than in LDL(+) and 7-fold higher in agLDL(-) than in nagLDL(-). The proportion of LDL particles containing apoJ (LDL/J+) was 3-fold lower in LDL(+) than in LDL(-). LDL/J+ particles shared several characteristics with agLDL(-), including increased negative charge and aggregation. apoJ-depleted particles (LDL/J-) showed increased susceptibility to aggregation, whether spontaneous or induced by proteolysis or lipolysis, as was revealed by turbidimetric analysis, gel filtration chromatography, lipoprotein precipitation, native gradient gel electrophoresis, circular dichroism, and transmission electronic microscopy. The addition of purified apoJ to total LDL also prevented its aggregation induced by proteolysis or lipolysis. These findings point to apoJ as a key modulator of LDL aggregation and reveal a putative new therapeutic strategy against atherosclerosis. PMID- 25550462 TI - p38alpha function in osteoblasts influences adipose tissue homeostasis. AB - The skeleton acts as an endocrine organ that regulates energy metabolism and calcium and phosphorous homeostasis through the secretion of osteocalcin (Oc) and fibroblast growth factor 23 (FGF23). However, evidence suggests that osteoblasts secrete additional unknown factors that contribute to the endocrine function of bone. To search for these additional factors, we generated mice with a conditional osteoblast-specific deletion of p38alpha MAPK known to display profound defects in bone homeostasis. Herein, we show that impaired osteoblast function is associated with a strong decrease in body weight and adiposity (P < 0.01). The differences in adiposity were not associated with diminished caloric intake, but rather reflected 20% increased energy expenditure and the up regulation of uncoupling protein-1 (Ucp1) in white adipose tissue (WAT) and brown adipose tissue (BAT) (P < 0.05). These alterations in lipid metabolism and energy expenditure were correlated with a decrease in the blood levels of neuropeptide Y (NPY) (40% lower) rather than changes in the serum levels of insulin, Oc, or FGF23. Among all Npy-expressing tissues, only bone and primary osteoblasts showed a decline in Npy expression (P < 0.01). Moreover, the intraperitoneal administration of recombinant NPY partially restored the WAT weight and adipocyte size of p38alpha-deficient mice (P < 0.05). Altogether, these results further suggest that, in addition to Oc, other bone-derived signals affect WAT and energy expenditure contributing to the regulation of energy metabolism. PMID- 25550464 TI - A novel role of low molecular weight hyaluronan in breast cancer metastasis. AB - Low molecular weight hyaluronan (LMW-HA), a degradation fragment of the extracellular matrix component hyaluronan (HA), has been proven to play a crucial role in cancer progression. However, no systematic clinical study of breast cancer has been performed to correlate LMW-HA levels with metastasis. In the present study, we analyzed 176 serum specimens and found for the first time that the serum LMW-HA (but not total HA) level significantly correlated with lymph node metastasis, suggesting that serum LMW-HA represents a better prognostic indicator of breast cancer progression than HA. Similarly, we found that breast cancer cell lines displaying higher invasive potential had a higher LMW-HA concentration than less-invasive cell lines. This higher LMW-HA level was accompanied by the overexpression of hyaluronan synthase (HAS2) and hyaluronidase (both HYAL1 and HYAL2). Of great importance, decreasing LMW-HA production significantly inhibited breast cancer cell migration and invasion. Overall, our results suggest that during cancer progression, cancer cells may actively remodel their microenvironment via an autocrine/paracrine-like process, resulting in elevated LMW-HA levels, which in turn may facilitate cancer progression by promoting the migration and invasion of cancer cells. Therefore, cancer associated LMW-HA may be a more promising molecular biomarker than total HA for detecting metastasis and may have further applications in breast cancer treatment. PMID- 25550463 TI - The hypoxia-inducible miR-429 regulates hypoxia-inducible factor-1alpha expression in human endothelial cells through a negative feedback loop. AB - Hypoxia-inducible factors (HIFs) 1 and 2 are dimeric alpha/beta transcription factors that regulate cellular responses to low oxygen. HIF-1 is induced first, whereas HIF-2 is associated with chronic hypoxia. To determine how HIF1A mRNA, the inducible subunit of HIF-1, is regulated during hypoxia, we followed HIF1A mRNA levels in primary HUVECs over 24 hours using quantitative PCR. HIF1A and VEGF A (VEGFA) mRNA, a transcriptional target of HIF-1, increased ~ 2.5- and 8 fold at 2-4 hours, respectively. To determine how the mRNAs were regulated, we identified a microRNA (miRNA), miR-429, that destabilized HIF1A message and decreased VEGFA mRNA by inhibiting HIF1A. Target protector analysis, which interferes with miRNA-mRNA complex formation, confirmed that miR-429 targeted HIF1A message. Desferoxamine treatment, which inhibits the hydroxylases that promote HIF-1alpha protein degradation, stabilized HIF-1 activity during normoxic conditions and elevated miR-429 levels, demonstrating that HIF-1 promotes miR-429 expression. RNA-sequencing-based transcriptome analysis indicated that inhibition of miRNA-429 in HUVECs up-regulated 209 mRNAs, a number of which regulate angiogenesis. The results demonstrate that HIF-1 is in a negative regulatory loop with miR-429, that miR-429 attenuates HIF-1 activity by decreasing HIF1A message during the early stages of hypoxia before HIF-2 is activated, and this regulatory network helps explain the HIF-1 transition to HIF-2 during chronic hypoxia in endothelial cells. PMID- 25550466 TI - A potential role for cannabinoid receptors in the therapeutic action of fenofibrate. AB - Cannabinoids are reported to have actions through peroxisome proliferator activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-alpha agonist fenofibrate exhibited submicromolar affinity for both receptors (pKi CB1, 6.3 +/- 0.1; CB2, 7.7 +/- 0.1). Functionally, fenofibrate acted as an agonist at the CB2 receptor (pEC50, 7.7 +/- 0.1) and a partial agonist at the CB1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [(3)H]-CP55940 at the CB1 receptor, (kfast without: 1.2 +/- 0.2/min; with: 3.8 +/- 0.1 * 10(-2)/min) and decrease the maximal response to CP55940 (Rmax, 86 +/- 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB1 receptors (pEC50, 6.0 +/- 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target. PMID- 25550465 TI - Increased Akt signaling in the mosquito fat body increases adult survivorship. AB - Akt signaling regulates diverse physiologies in a wide range of organisms. We examine the impact of increased Akt signaling in the fat body of 2 mosquito species, the Asian malaria mosquito Anopheles stephensi and the yellow fever mosquito Aedes aegypti. Overexpression of a myristoylated and active form of A. stephensi and Ae. aegypti Akt in the fat body of transgenic mosquitoes led to activation of the downstream signaling molecules forkhead box O (FOXO) and p70 S6 kinase in a tissue and blood meal-specific manner. In both species, increased Akt signaling in the fat body after blood feeding significantly increased adult survivorship relative to nontransgenic sibling controls. In A. stephensi, survivorship was increased by 15% to 45%, while in Ae. aegypti, it increased 14% to 47%. Transgenic mosquitoes fed only sugar, and thus not expressing active Akt, had no significant difference in survivorship relative to nontransgenic siblings. Expression of active Akt also increased expression of fat body vitellogenin, but the number of viable eggs did not differ significantly between transgenic and nontransgenic controls. This work demonstrates a novel mechanism of enhanced survivorship through increased Akt signaling in the fat bodies of multiple mosquito genera and provides new tools to unlock the molecular underpinnings of aging in eukaryotic organisms. PMID- 25550467 TI - Cytosolic aconitase activity sustains adipogenic capacity of adipose tissue connecting iron metabolism and adipogenesis. AB - To gain insight into the regulation of intracellular iron homeostasis in adipose tissue, we investigated the role of iron regulatory protein 1/cytosolic aconitase 1 (ACO1). ACO1 gene expression and activity increased in parallel to expression of adipogenic genes during differentiation of both murine 3T3-L1 cells and human preadipocytes. Lentiviral knockdown (KD) of Aco1 in 3T3-L1 preadipocytes led to diminished cytosolic aconitase activity and isocitrate dehydrogenase 1 (NADP(+)), soluble (Idh1) mRNA levels, decreased intracellular NADPH:NADP ratio, and impaired adipogenesis during adipocyte differentiation. In addition, Aco1 KD in fully differentiated 3T3-L1 adipocytes decreased lipogenic, Idh1, Adipoq, and Glut4 gene expression. A bidirectional cross-talk was found between intracellular iron levels and ACO1 gene expression and protein activity. Although iron in excess, known to increase reactive oxygen species production, and iron depletion both resulted in decreased ACO1 mRNA levels and activity, Aco1 KD led to reduced gene expression of transferrin receptor (Tfrc) and transferrin, disrupting intracellular iron uptake. In agreement with these findings, in 2 human independent cohorts (n = 85 and n = 38), ACO1 gene expression was positively associated with adipogenic markers in subcutaneous and visceral adipose tissue. ACO1 gene expression was also positively associated with the gene expression of TFRC while negatively linked to ferroportin (solute carrier family 40 (iron regulated transporter), member 1) mRNA levels. Altogether, these results suggest that ACO1 activity is required for the normal adipogenic capacity of adipose tissue by connecting iron, energy metabolism, and adipogenesis. PMID- 25550468 TI - The endogenous zinc finger transcription factor, ZNF24, modulates the angiogenic potential of human microvascular endothelial cells. AB - We have previously identified a zinc finger transcription factor, ZNF24 (zinc finger protein 24), as a novel inhibitor of tumor angiogenesis and have demonstrated that ZNF24 exerts this effect by repressing the transcription of VEGF in breast cancer cells. Here we focused on the role of ZNF24 in modulating the angiogenic potential of the endothelial compartment. Knockdown of ZNF24 by siRNA in human primary microvascular endothelial cells (ECs) led to significantly decreased cell migration and invasion compared with control siRNA. ZNF24 knockdown consistently led to significantly impaired VEGF receptor 2 (VEGFR2) signaling and decreased levels of matrix metalloproteinase-2 (MMP-2), with no effect on levels of major regulators of MMP-2 activity such as the tissue inhibitors of metalloproteinases and MMP-14. Moreover, silencing ZNF24 in these cells led to significantly decreased EC proliferation. Quantitative PCR array analyses identified multiple cell cycle regulators as potential ZNF24 downstream targets which may be responsible for the decreased proliferation in ECs. In vivo, knockdown of ZNF24 specifically in microvascular ECs led to significantly decreased formation of functional vascular networks. Taken together, these results demonstrate that ZNF24 plays an essential role in modulating the angiogenic potential of microvascular ECs by regulating the proliferation, migration, and invasion of these cells. PMID- 25550470 TI - Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1alpha. AB - During a course of colitis, production of the gaseous mediator hydrogen sulfide (H2S) is markedly up-regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H2S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H2S in experimental colitis are mediated via stabilization of hypoxia-inducible factor (HIF)-1alpha. The hapten dinitrobenzene sulfonic acid was used to induce colitis in rats and mice. This resulted in an elevated expression of the H2S-producing enzyme, cystathionine gamma-lyase (CSE), and HIF-1alpha at sites of mucosal ulceration, and the expression of these 2 enzymes followed a similar pattern throughout the course of colitis. This represented a functionally important relationship because the loss of CSE-derived H2S production led to decreased HIF-1alpha stabilization and exacerbation of colitis. Furthermore, application of an H2S-releasing molecule, diallyl disulfide (DADS), stabilized colonic HIF-1alpha expression, up-regulated hypoxia-responsive genes, and reduced the severity of disease during peak inflammation. Importantly, the ability of DADS to promote the resolution of colitis was abolished when coadministered with an inhibitor of HIF-1alpha in vivo (PX-478). DADS was also able to maintain HIF-1alpha expression at a later point in colitis, when HIF 1alpha levels would have normally returned to control levels, and to enhance resolution. Finally, we found that HIF-1alpha stabilization inhibited colonic H2S production and may represent a negative feedback mechanism to prevent prolonged HIF-1alpha stabilization. Our findings demonstrate an important link between H2S and HIF-1alpha in the resolution of inflammation and injury during colitis and provide mechanistic insights into the therapeutic value of H2S donors. PMID- 25550469 TI - The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice. AB - Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR) dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism. PMID- 25550473 TI - Molecular diagnostics: a revolution in progress. PMID- 25550472 TI - Sustained inflation versus positive pressure ventilation at birth: a systematic review and meta-analysis. AB - CONTEXT: Sustained inflation (SI) has been advocated as an alternative to intermittent positive pressure ventilation (IPPV) during the resuscitation of neonates at birth, to facilitate the early development of an effective functional residual capacity, reduce atelectotrauma and improve oxygenation after the birth of preterm infants. OBJECTIVE: The primary aim was to review the available literature on the use of SI compared with IPPV at birth in preterm infants for major neonatal outcomes, including bronchopulmonary dysplasia (BPD) and death. DATA SOURCE: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials, until 6 October 2014. STUDY SELECTION: Randomised clinical trials comparing the effects of SI with IPPV at birth in preterm infants for neonatal outcomes. DATA EXTRACTION AND SYNTHESIS: Descriptive and quantitative information was extracted; data were pooled using a random effects model. Heterogeneity was assessed using the Q statistic and I(2). RESULTS: Pooled analysis showed significant reduction in the need for mechanical ventilation within 72 h after birth (relative risk (RR) 0.87 (0.77 to 0.97), absolute risk reduction (ARR) 0.10 (-0.17 to -0.03), number needed to treat 10) in preterm infants treated with an initial SI compared with IPPV. However, significantly more infants treated with SI received treatment for patent ductus arteriosus (RR 1.27 (1.05 to 1.54), ARR 0.10 (0.03 to 0.16), number needed to harm 10). There were no differences in BPD, death at the latest follow-up and the combined outcome of death or BPD among survivors between the groups. CONCLUSIONS: Compared with IPPV, preterm infants initially treated with SI at birth required less mechanical ventilation with no improvement in the rate of BPD and/or death. The use of SI should be restricted to randomised trials until future studies demonstrate the efficacy and safety of this lung aeration manoeuvre. PMID- 25550471 TI - Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement. AB - SETD1A is a member of trithorax-related histone methyltransferases that methylate lysine 4 at histone H3 (H3K4). We showed previously that Setd1a is required for mesoderm specification and hematopoietic lineage differentiation in vitro. However, it remains unknown whether or not Setd1a controls specific hematopoietic lineage commitment and differentiation during animal development. Here, we reported that homozygous Setd1a knockout (KO) mice are embryonic lethal. Loss of the Setd1a gene in the hematopoietic compartment resulted in a blockage of the progenitor B-cell-to-precursor B-cell development in bone marrow (BM) and B-cell maturation in spleen. The Setd1a-cKO (conditional knockout) mice exhibited an enlarged spleen with disrupted spleen architecture and leukocytopenia. Mechanistically, Setd1a deficiency in BM reduced the levels of H3K4me3 at critical B-cell gene loci, including Pax5 and Rag1/2, which are critical for the IgH (Ig heavy-chain) locus contractions and rearrangement. Subsequently, the differential long-range looped interactions of the enhancer EMU with proximal 5' DH region and 3' regulatory regions as well as with Pax5-activated intergenic repeat elements and 5' distal VH genes were compromised by the Setd1a-cKO. Together, our findings revealed a critical role of Setd1a and its mediated epigenetic modifications in regulating the IgH rearrangement and B-cell development. PMID- 25550474 TI - An interview with Bert Vogelstein and Kenneth Kinzler. PMID- 25550475 TI - A 5-month-old boy with delay in growth and development and decreased muscle tone. PMID- 25550476 TI - Commentary. PMID- 25550477 TI - Commentary. PMID- 25550479 TI - Linear perspective: a visual revolution. PMID- 25550480 TI - Conversions of tricyclic antidepressants and antipsychotics with selected P450s from Sorangium cellulosum So ce56. AB - Human cytochromes P450 (P450s) play a major role in the biotransformation of drugs. The generated metabolites are important for pharmaceutical, medical, and biotechnological applications and can be used for derivatization or toxicological studies. The availability of human drug metabolites is restricted and alternative ways of production are requested. For this, microbial P450s turned out to be a useful tool for the conversion of drugs and related derivatives. Here, we used 10 P450s from the myxobacterium Sorangium cellulosum So ce56, which have been cloned, expressed, and purified. The P450s were investigated concerning the conversion of the antidepressant drugs amitriptyline, clomipramine, imipramine, and promethazine; the antipsychotic drugs carbamazepine, chlorpromazine, and thioridazine, as well as their precursors, iminodibenzyl and phenothiazine. Amitriptyline, chlorpromazine, clomipramine, imipramine, and thioridazine are efficiently converted during the in vitro reaction and were chosen to upscale the production by an Escherichia coli-based whole-cell bioconversion system. Two different approaches, a whole-cell system using M9CA medium and a system using resting cells in buffer, were used for the production of sufficient amounts of metabolites for NMR analysis. Amitriptyline, clomipramine, and imipramine are converted to the corresponding 10-hydroxylated products, whereas the conversion of chlorpromazine and thioridazine leads to a sulfoxidation in position 5. It is shown for the first time that myxobacterial P450s are efficient to produce known human drug metabolites in a milligram scale, revealing their ability to synthesize pharmaceutically important compounds. PMID- 25550481 TI - Long-term follow-up after removal of colorectal adenomas provides evidence for risk stratification of patients at colonoscopic polypectomy. PMID- 25550482 TI - Pulse oximetry may lead to unnecessary hospital admissions for infants with bronchiolitis and mild hypoxaemia. PMID- 25550483 TI - Treatment of hepatitis C, then, now and tomorrow. PMID- 25550484 TI - Accounting for baseline differences in meta-analysis. PMID- 25550485 TI - Improving osteopathic medical training in providing health care to lesbian, gay, bisexual, and transgender patients. PMID- 25550487 TI - Correction. PMID- 25550486 TI - Gray zone: why a delayed acceptance of osteopathic medicine persists in the international community. PMID- 25550488 TI - Identification of musculoskeletal disorders in medically underserved regions of South America and Vietnam. AB - CONTEXT: Musculoskeletal disorders have been implicated as the leading cause of disability throughout the world, representing a high percentage of the disease burden in many nations. Anecdotal evidence suggests that musculoskeletal pain has become increasingly pervasive, especially among rural populations of developing countries. OBJECTIVE: To characterize specific musculoskeletal disorders in medically underserved regions where these issues have not yet been thoroughly examined. METHODS: The sample comprised adult residents receiving care during brief medical outreach trips to South America (Peru, Ecuador, and Argentina) and Vietnam from December 2010 to March 2013. Patients completed an anonymous questionnaire on musculoskeletal pain, self-reported health status, and health care-seeking behavior. Demographic information was also obtained. RESULTS: In Vietnam, 295 patients aged 20 to 88 years (mean [SD], 59 [14.7] years) completed the survey, 204 (69%) of whom were women. In South America, 552 patients aged 18 to 86 years (mean [SD], 44 [17.24] years) completed the survey, 398 (72.1%) of whom were women. Among the Vietnamese patients, acute pain was most frequently felt in the knees (132 [44.7%]), which were also the most frequent site of chronic pain (122 [41.4%]). Among the South American patients, acute pain was felt most frequently in the lower back (225 [47%]), and the upper back (253 [46.6%]) was the most frequent site of chronic pain. Associations were found between sex and chronic pain, with women reporting more chronic pain than men in the shoulder (17 [53%] vs 15 [47%], respectively), upper back (85 [79%] vs 22 [21%]), hand/wrist (153 [85%] vs 52 [15%]), and knee (40 [80%] vs 7 [20%]). Men reported more acute knee pain than women (73 [48%] vs 148 [38%], respectively). For patients in both samples, acute pain was associated with chronic pain in the same location for all body parts (P<.01). CONCLUSION: This study characterized specific musculoskeletal disorders in selected poor and underserved regions in Vietnam and South America. Owing to reported regional differences, the authors recommend that global treatment protocols be developed with a population-specific approach after conducting a needs assessment for musculoskeletal disorders. PMID- 25550489 TI - The emerging use of platelet-rich plasma in musculoskeletal medicine. AB - Platelet-rich plasma (PRP) is one of many new developments within the expanding field of regenerative medicine. Specialists in areas such as orthopedics, physical medicine and rehabilitation, and rheumatology have been exploring the benefits of this novel therapy. Although PRP therapy remains controversial and has minimal clinical trial support, the use of orthobiologics such as PRP continues to advance as patients seek nonsurgical approaches to acute and chronic musculoskeletal injury and disease. However, academic acceptance as well as insurance reimbursement remain reliant on solid and repeatable positive results from large clinical trials. The authors summarize the evolution of PRP therapy and report on its status. PMID- 25550491 TI - Mastering the art of abstracts. PMID- 25550490 TI - Use of a novel assay to measure pre- to posttraining palpatory skills of first year osteopathic medical students. AB - CONTEXT: Although palpation is a central skill in the practice of osteopathic medicine, few data are available on factors affecting the development of palpatory skills. OBJECTIVE: To use a novel palpatory skills assay to assess the role of training and practice in the development of palpatory skills in an osteopathic medical student population. METHODS: The palpatory skills of first year osteopathic medical students were assessed using a simple, objective palpation assay that consisted of locating a dime placed under sheets of copy paper at depths of 50, 100, 150, 200, 300, and 400 sheets. Two trials were performed at each depth. The assay was performed at the beginning and at the end of the students' first term. To determine whether practice with the assay impacted participant performance, a third assay was conducted to compare the performance of students who completed the assays at the beginning and at the end of the term with that of students who had never completed the assay. RESULTS: Sixty-three participants completed the assays at the beginning and end of the term. Fifty-seven of those 63 participants and 192 participants who had not previously completed the assay completed the third assay. A wide variability in number of correct responses per participant was observed at both the beginning (range, 0-11 correct) and the end (range, 2-12 correct) of the term. The mean (SD) number of correct responses per participant increased from the beginning (5.49 [2.78]) to the end (7.17 [2.27]) of the term. Analysis using the generalized estimating equation model demonstrated that both paper depth and experience (ie, beginning vs end of the term) were statistically significant determinants of the number of correct responses (P<.001). The Kaplan-Meier method indicated that the median paper depth at which participants first scored no correct responses increased from 200 sheets (95% CI, 171-229) at the beginning of the term to 300 sheets (95% CI, 232-367) at the end of the term (P<.001). In the third assay, no significant differences were noted in the performance of students who had completed the 2 previous assays vs participants who had not completed the previous assays (P=.136). CONCLUSION: Participants' palpatory skills improved from the beginning to the end of the term. The range of participants' palpatory skills at the beginning of the term suggests that other factors in addition to training influenced participants' palpatory skill level. Additional research is needed to identify and investigate factors that influence the development of palpatory skills. PMID- 25550492 TI - Resolution of hypothyroidism after correction of somatovisceral reflex dysfunction by refusion of the cervical spine. AB - Psychosis is a rare initial presentation of new-onset hypothyroidism. The author describes the case of a 29-year-old woman who presented with psychosis caused by hypothyroidism, or myxedema madness. Although the patient's psychosis resolved after standard monotherapy using levothyroxine sodium, her hypothyroidism persisted. Imaging of the patient's cervical spine showed that previous C5-C6 and C6-C7 fusions had failed. The failed fusions were corrected, and the patient's hypothyroidism resolved, suggesting that the somatovisceral reflex was the cause of the patient's hypothyroidism. Although somatovisceral reflex dysfunctions are rare, physicians should consider them as potential underlying causes of their patients' presenting medical conditions. PMID- 25550493 TI - Massive subgaleal hematoma and clinical suspicion of child abuse. PMID- 25550495 TI - Hallux metatarsophalangeal (MTP) joint arthroscopy for hallux rigidus. AB - Arthroscopy of the hallux metatarsophalangeal (MTP) joint is an evolving technique for hallux rigidus and other disorders of the hallux MTP joint. Purported advantages of this minimally invasive procedure include rapid rehabilitation and the ability to identify and address other intra-articular and sesamoid pathologies without additional dissection. Larger, prospective, and comparative outcomes studies are needed to optimize the treatment algorithm. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 25550496 TI - Quality and patient safety. PMID- 25550498 TI - Dorsal plating of low-energy Lisfranc injuries: a case report. AB - Surgically repairing acute Lisfranc injuries remains a difficult task, and the injury remains a challenging one for the treating surgeon. Although there are many proponents of acute arthrodesis for Lisfranc injuries, there remain a proportion of patients with low-energy trauma who may be best treated with open reduction internal fixation and joint salvaging procedures. Here, the authors present a case report and technique to anatomically fix Lisfranc injuries while preventing any concomitant articular damage in the process. They have found this to be a reliable and safe procedure in this demanding patient population. LEVELS: Level IV-Case Report. PMID- 25550499 TI - Septic ankle with purulence tracking up the flexor hallucis longus tendon sheath leading to deep venous thrombosis/pulmonary embolism and compartment syndrome. AB - The differential diagnosis for lower extremity swelling and ankle pain is broad and can have overlapping and related diagnoses. If there is concern for more than one diagnosis, the practitioner should perform a thorough physical examination, order the appropriate studies, and perform the correct procedures to completely diagnose and treat the patient. This article presents the case of a 19-year-old male who presented with 5 days of left ankle pain, fevers, and swelling without any known trauma to the area. Physical examination was concerning for a septic ankle joint, cellulitis, deep venous thrombosis, and compartment syndrome. Duplex venous ultrasound confirmed a deep venous thrombosis in the popliteal vein. Joint aspiration of the ankle had gross purulence with the presence of methicillin resistant Staphylococcus aureus. The patient was taken emergently to the operating room where he was found to have gross purulence in the deep posterior compartment, medial and lateral soft tissues of the ankle, and gross purulence in the ankle joint. The deep posterior compartment also had significant muscle necrosis and evidence of compartment syndrome. This case presents the possibility of a septic ankle leading to compartment syndrome and deep venous thrombosis/pulmonary embolism due to the intra-articular nature of the flexor hallucis longus tendon sheath. LEVEL OF EVIDENCE: Case report, Level IV. PMID- 25550500 TI - Science and culture: Q&A with Roger Malina. PMID- 25550503 TI - beta-Helical architecture of cytoskeletal bactofilin filaments revealed by solid state NMR. AB - Bactofilins are a widespread class of bacterial filament-forming proteins, which serve as cytoskeletal scaffolds in various cellular pathways. They are characterized by a conserved architecture, featuring a central conserved domain (DUF583) that is flanked by variable terminal regions. Here, we present a detailed investigation of bactofilin filaments from Caulobacter crescentus by high-resolution solid-state NMR spectroscopy. De novo sequential resonance assignments were obtained for residues Ala39 to Phe137, spanning the conserved DUF583 domain. Analysis of the secondary chemical shifts shows that this core region adopts predominantly beta-sheet secondary structure. Mutational studies of conserved hydrophobic residues located in the identified beta-strand segments suggest that bactofilin folding and polymerization is mediated by an extensive and redundant network of hydrophobic interactions, consistent with the high intrinsic stability of bactofilin polymers. Transmission electron microscopy revealed a propensity of bactofilin to form filament bundles as well as sheet like, 2D crystalline assemblies, which may represent the supramolecular arrangement of bactofilin in the native context. Based on the diffraction pattern of these 2D crystalline assemblies, scanning transmission electron microscopy measurements of the mass per length of BacA filaments, and the distribution of beta-strand segments identified by solid-state NMR, we propose that the DUF583 domain adopts a beta-helical architecture, in which 18 beta-strand segments are arranged in six consecutive windings of a beta-helix. PMID- 25550504 TI - Activated CD4+CCR5+ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques. AB - An effective T-cell-based AIDS vaccine should induce strong HIV-specific CD8(+) T cells in mucosal tissues without increasing the availability of target cells for the virus. Here, we evaluated five immunization strategies that include Human adenovirus-5 (AdHu5), Chimpanzee adenovirus-6 (AdC6) or -7 (AdC7), Vaccinia virus (VV), and DNA given by electroporation (DNA/EP), all expressing Simian immunodeficiency virus group specific antigen/transactivator of transcription (SIV(mac239Gag/Tat)). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EP-VV-AdC6, DNA/EP-VV-AdC7, or AdHu5-AdHu5-AdHu5 and were challenged repeatedly with low-dose intrarectal SIVmac239. Upon challenge, there were no significant differences among study groups in terms of virus acquisition or viral load after infection. When taken together, the immunization regimens did not protect against SIV acquisition compared with controls but did result in an ~ 1.6-log decline in set-point viremia. Although all immunized RMs had detectable SIV-specific CD8(+) T cells in blood and rectal mucosa, we found no correlation between the number or function of these SIV-specific CD8(+) T cells and protection against SIV acquisition. Interestingly, RMs experiencing breakthrough infection showed significantly higher prechallenge levels of CD4(+)C-C chemokine receptor type 5 (CCR5)(+)HLA DR(+) T cells in the rectal biopsies (RB) than animals that remained uninfected. In addition, among the infected RMs, the percentage of CD4(+)CCR5(+)Ki-67(+) T cells in RBs prechallenge correlated with higher early viremia. Overall, these data suggest that the levels of activated CD4(+)CCR5(+) target T cells in the rectal mucosa may predict the risk of SIV acquisition in RMs vaccinated with vectors that express SIVGag/Tat. PMID- 25550506 TI - Parasitism alters three power laws of scaling in a metazoan community: Taylor's law, density-mass allometry, and variance-mass allometry. AB - How do the lifestyles (free-living unparasitized, free-living parasitized, and parasitic) of animal species affect major ecological power-law relationships? We investigated this question in metazoan communities in lakes of Otago, New Zealand. In 13,752 samples comprising 1,037,058 organisms, we found that species of different lifestyles differed in taxonomic distribution and body mass and were well described by three power laws: a spatial Taylor's law (the spatial variance in population density was a power-law function of the spatial mean population density); density-mass allometry (the spatial mean population density was a power law function of mean body mass); and variance-mass allometry (the spatial variance in population density was a power-law function of mean body mass). To our knowledge, this constitutes the first empirical confirmation of variance-mass allometry for any animal community. We found that the parameter values of all three relationships differed for species with different lifestyles in the same communities. Taylor's law and density-mass allometry accurately predicted the form and parameter values of variance-mass allometry. We conclude that species of different lifestyles in these metazoan communities obeyed the same major ecological power-law relationships but did so with parameters specific to each lifestyle, probably reflecting differences among lifestyles in population dynamics and spatial distribution. PMID- 25550505 TI - INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. AB - The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15(INK4b), p16(INK4a), and ARF (alternate reading frame). Although p15(INK4b) has its own ORF, p16(INK4a) and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15(INK4b) exon 1 joined to p16(INK4a) exons 2 and 3. We have named this isoform pALT(INK4a/b) (for alternative splicing). We show that pALT(INK4a/b) is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALT(INK4a/b) expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substrate attachment, and expression of oncogenes. When overexpressed in naked mole rat or human cells, pALT(INK4a/b) has stronger ability to induce cell-cycle arrest than either p15(INK4b) or p16(INK4a). We hypothesize that the presence of the fourth product, pALT(INK4a/b) of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species. PMID- 25550507 TI - Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval. AB - In the present study we test the hypothesis that extinction is not a consequence of retrieval in unreinforced conditioned stimulus (CS) presentation but the mere perception of the CS in the absence of a conditioned response. Animals with cannulae implanted in the CA1 region of hippocampus were subjected to extinction of contextual fear conditioning. Muscimol infused intra-CA1 before an extinction training session of contextual fear conditioning (CFC) blocks retrieval but not consolidation of extinction measured 24 h later. Additionally, this inhibition of retrieval does not affect early persistence of extinction when tested 7 d later or its spontaneous recovery after 2 wk. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of extraribosomal protein synthesis, given into the CA1, impair extinction of CFC regardless of whether its retrieval was blocked by muscimol. Therefore, retrieval performance in the first unreinforced session is not necessary for the installation, maintenance, or spontaneous recovery of extinction of CFC. PMID- 25550508 TI - Nitric oxide negatively regulates abscisic acid signaling in guard cells by S nitrosylation of OST1. AB - The phytohormone abscisic acid (ABA) plays important roles in plant development and adaptation to environmental stress. ABA induces the production of nitric oxide (NO) in guard cells, but how NO regulates ABA signaling is not understood. Here, we show that NO negatively regulates ABA signaling in guard cells by inhibiting open stomata 1 (OST1)/sucrose nonfermenting 1 (SNF1)-related protein kinase 2.6 (SnRK2.6) through S-nitrosylation. We found that SnRK2.6 is S nitrosylated at cysteine 137, a residue adjacent to the kinase catalytic site. Dysfunction in the S-nitrosoglutathione (GSNO) reductase (GSNOR) gene in the gsnor1-3 mutant causes NO overaccumulation in guard cells, constitutive S nitrosylation of SnRK2.6, and impairment of ABA-induced stomatal closure. Introduction of the Cys137 to Ser mutated SnRK2.6 into the gsnor1-3/ost1-3 double mutant partially suppressed the effect of gsnor1-3 on ABA-induced stomatal closure. A cysteine residue corresponding to Cys137 of SnRK2.6 is present in several yeast and human protein kinases and can be S-nitrosylated, suggesting that the S-nitrosylation may be an evolutionarily conserved mechanism for protein kinase regulation. PMID- 25550509 TI - The chemistry of negotiation: rhythmic, glycan-driven acidification in a symbiotic conversation. AB - Glycans have emerged as critical determinants of immune maturation, microbial nutrition, and host health in diverse symbioses. In this study, we asked how cyclic delivery of a single host-derived glycan contributes to the dynamic stability of the mutualism between the squid Euprymna scolopes and its specific, bioluminescent symbiont, Vibrio fischeri. V. fischeri colonizes the crypts of a host organ that is used for behavioral light production. E. scolopes synthesizes the polymeric glycan chitin in macrophage-like immune cells called hemocytes. We show here that, just before dusk, hemocytes migrate from the vasculature into the symbiotic crypts, where they lyse and release particulate chitin, a behavior that is established only in the mature symbiosis. Diel transcriptional rhythms in both partners further indicate that the chitin is provided and metabolized only at night. A V. fischeri mutant defective in chitin catabolism was able to maintain a normal symbiont population level, but only until the symbiotic organ reached maturity (~ 4 wk after colonization); this result provided a direct link between chitin utilization and symbiont persistence. Finally, catabolism of chitin by the symbionts was also specifically required for a periodic acidification of the adult crypts each night. This acidification, which increases the level of oxygen available to the symbionts, enhances their capacity to produce bioluminescence at night. We propose that other animal hosts may similarly regulate the activities of epithelium-associated microbial communities through the strategic provision of specific nutrients, whose catabolism modulates conditions like pH or anoxia in their symbionts' habitat. PMID- 25550510 TI - Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. AB - Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1alpha and eIF2alpha phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases. PMID- 25550511 TI - Subunit determination of the conductance of hair-cell mechanotransducer channels. AB - Cochlear hair cells convert sound stimuli into electrical signals by gating of mechanically sensitive ion channels in their stereociliary (hair) bundle. The molecular identity of this ion channel is still unclear, but its properties are modulated by accessory proteins. Two such proteins are transmembrane channel-like protein isoform 1 (TMC1) and tetraspan membrane protein of hair cell stereocilia (TMHS, also known as lipoma HMGIC fusion partner-like 5, LHFPL5), both thought to be integral components of the mechanotransduction machinery. Here we show that, in mice harboring an Lhfpl5 null mutation, the unitary conductance of outer hair cell mechanotransducer (MT) channels was reduced relative to wild type, and the tonotopic gradient in conductance, where channels from the cochlear base are nearly twice as conducting as those at the apex, was almost absent. The macroscopic MT current in these mutants was attenuated and the tonotopic gradient in amplitude was also lost, although the current was not completely extinguished. The consequences of Lhfpl5 mutation mirror those due to Tmc1 mutation, suggesting a part of the MT-channel conferring a large and tonotopically variable conductance is similarly disrupted in the absence of Lhfpl5 or Tmc1. Immunolabelling demonstrated TMC1 throughout the stereociliary bundles in wild type but not in Lhfpl5 mutants, implying the channel effect of Lhfpl5 mutations stems from down-regulation of TMC1. Both LHFPL5 and TMC1 were shown to interact with protocadherin-15, a component of the tip link, which applies force to the MT channel. We propose that titration of the TMC1 content of the MT channel sets the gradient in unitary conductance along the cochlea. PMID- 25550512 TI - Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus. AB - NMDA receptors (NMDARs) require the coagonists D-serine or glycine for their activation, but whether the identity of the coagonist could be synapse specific and developmentally regulated remains elusive. We therefore investigated the contribution of D-serine and glycine by recording NMDAR-mediated responses at hippocampal Schaffer collaterals (SC)-CA1 and medial perforant path-dentate gyrus (mPP-DG) synapses in juvenile and adult rats. Selective depletion of endogenous coagonists with enzymatic scavengers as well as pharmacological inhibition of endogenous D-amino acid oxidase activity revealed that D-serine is the preferred coagonist at SC-CA1 mature synapses, whereas, unexpectedly, glycine is mainly involved at mPP-DG synapses. Nevertheless, both coagonist functions are driven by the levels of synaptic activity as inferred by recording long-term potentiation generated at both connections. This regional compartmentalization in the coagonist identity is associated to different GluN1/GluN2A to GluN1/GluN2B subunit composition of synaptic NMDARs. During postnatal development, the replacement of GluN2B- by GluN2A-containing NMDARs at SC-CA1 synapses parallels a change in the identity of the coagonist from glycine to D-serine. In contrast, NMDARs subunit composition at mPP-DG synapses is not altered and glycine remains the main coagonist throughout postnatal development. Altogether, our observations disclose an unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of D-serine And Glycine In Modulating Nmdars During The Maturation Of Tripartite Glutamatergic Synapses. PMID- 25550514 TI - A promising approach to molecular counting problem in superresolution microscopy. PMID- 25550513 TI - Sensory determinants of behavioral dynamics in Drosophila thermotaxis. AB - Complex animal behaviors are built from dynamical relationships between sensory inputs, neuronal activity, and motor outputs in patterns with strategic value. Connecting these patterns illuminates how nervous systems compute behavior. Here, we study Drosophila larva navigation up temperature gradients toward preferred temperatures (positive thermotaxis). By tracking the movements of animals responding to fixed spatial temperature gradients or random temperature fluctuations, we calculate the sensitivity and dynamics of the conversion of thermosensory inputs into motor responses. We discover three thermosensory neurons in each dorsal organ ganglion (DOG) that are required for positive thermotaxis. Random optogenetic stimulation of the DOG thermosensory neurons evokes behavioral patterns that mimic the response to temperature variations. In vivo calcium and voltage imaging reveals that the DOG thermosensory neurons exhibit activity patterns with sensitivity and dynamics matched to the behavioral response. Temporal processing of temperature variations carried out by the DOG thermosensory neurons emerges in distinct motor responses during thermotaxis. PMID- 25550515 TI - Intracellular osteopontin regulates homeostasis and function of natural killer cells. AB - Natural killer (NK) cells play an essential role in the immune response to infection and cancer. After infection or during homeostatic expansion NK cells express a developmental program that includes a contraction phase followed by the formation of long-lived mature memory-like cells. Although this NK cell response pattern is well established, the underlying mechanisms that ensure efficient transition to long-lived NK cells remain largely undefined. Here we report that deficient expression of intracellular osteopontin (OPN-i) by NK cells results in defective responses to IL-15 associated with a substantial increase in the NK cell contraction phase of homeostatic expansion, defective expression of the Eomes transcription factor, and diminished responses to metastatic tumors. The OPN-i-deficient phenotype is accompanied by increased NK cell apoptosis, impaired transition from immature to mature NK cells, and diminished ability to develop memory-like NK cells that respond to mouse cytomegalovirus. Gene pathway analysis of OPN-i-deficient NK cells suggests that the mechanistic target of rapamycin pathway may connect OPN-i to Eomes and T-bet expression by mature NK cells following up-regulation of OPN-i after IL-15 stimulation. Identification of OPN-i as an essential molecular component for maintenance of functional NK cell expansion provides insight into the NK cell response and may provide the basis for improved approaches to immunotherapy for infectious disease and cancer. PMID- 25550516 TI - Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARgamma effects. AB - A unique population of Foxp3(+)CD4(+) regulatory T (Treg) cells resides in visceral adipose tissue (VAT) of lean mice, especially in the epididymal fat depot. VAT Tregs are unusual in their very high representation within the CD4(+) T-cell compartment, their transcriptome, and their repertoire of antigen-specific T-cell receptors. They are important regulators of local and systemic inflammation and metabolism. The overall goal of this study was to learn how the VAT Treg transcriptome adapts to different stimuli; in particular, its response to aging in lean mice, to metabolic perturbations associated with obesity, and to certain signaling events routed through PPARgamma, the "master-regulator" of adipocyte differentiation. We show that the VAT Treg signature is imposed early in life, well before age-dependent expansion of the adipose-tissue Treg population. VAT Tregs in obese mice lose the signature typical of lean individuals but gain an additional set of over- and underrepresented transcripts. This obese mouse VAT Treg signature depends on phosphorylation of the serine residue at position 273 of PPARgamma, in striking parallel to a pathway recently elucidated in adipocytes. These findings are important to consider in designing drugs to target type 2 diabetes and other features of the "metabolic syndrome." PMID- 25550517 TI - G protein-coupled odorant receptors underlie mechanosensitivity in mammalian olfactory sensory neurons. AB - Mechanosensitive cells are essential for organisms to sense the external and internal environments, and a variety of molecules have been implicated as mechanical sensors. Here we report that odorant receptors (ORs), a large family of G protein-coupled receptors, underlie the responses to both chemical and mechanical stimuli in mouse olfactory sensory neurons (OSNs). Genetic ablation of key signaling proteins in odor transduction or disruption of OR-G protein coupling eliminates mechanical responses. Curiously, OSNs expressing different OR types display significantly different responses to mechanical stimuli. Genetic swap of putatively mechanosensitive ORs abolishes or reduces mechanical responses of OSNs. Furthermore, ectopic expression of an OR restores mechanosensitivity in loss-of-function OSNs. Lastly, heterologous expression of an OR confers mechanosensitivity to its host cells. These results indicate that certain ORs are both necessary and sufficient to cause mechanical responses, revealing a previously unidentified mechanism for mechanotransduction. PMID- 25550520 TI - Should we "reef" obsolete oil platforms? PMID- 25550519 TI - Dialkylresorcinols as bacterial signaling molecules. AB - It is well recognized that bacteria communicate via small diffusible molecules, a process termed quorum sensing. The best understood quorum sensing systems are those that use acylated homoserine lactones (AHLs) for communication. The prototype of those systems consists of a LuxI-like AHL synthase and a cognate LuxR receptor that detects the signal. However, many proteobacteria possess LuxR receptors, yet lack any LuxI-type synthase, and thus these receptors are referred to as LuxR orphans or solos. In addition to the well-known AHLs, little is known about the signaling molecules that are sensed by LuxR solos. Here, we describe a novel cell-cell communication system in the insect and human pathogen Photorhabdus asymbiotica. We identified the LuxR homolog PauR to sense dialkylresorcinols (DARs) and cyclohexanediones (CHDs) instead of AHLs as signals. The DarABC synthesis pathway produces the molecules, and the entire system emerged as important for virulence. Moreover, we have analyzed more than 90 different Photorhabdus strains by HPLC/MS and showed that these DARs and CHDs are specific to the human pathogen P. asymbiotica. On the basis of genomic evidence, 116 other bacterial species are putative DAR producers, among them many human pathogens. Therefore, we discuss the possibility of DARs as novel and widespread bacterial signaling molecules and show that bacterial cell-cell communication goes far beyond AHL signaling in nature. PMID- 25550518 TI - Tracking heavy water (D2O) incorporation for identifying and sorting active microbial cells. AB - Microbial communities are essential to the function of virtually all ecosystems and eukaryotes, including humans. However, it is still a major challenge to identify microbial cells active under natural conditions in complex systems. In this study, we developed a new method to identify and sort active microbes on the single-cell level in complex samples using stable isotope probing with heavy water (D2O) combined with Raman microspectroscopy. Incorporation of D2O-derived D into the biomass of autotrophic and heterotrophic bacteria and archaea could be unambiguously detected via C-D signature peaks in single-cell Raman spectra, and the obtained labeling pattern was confirmed by nanoscale-resolution secondary ion MS. In fast-growing Escherichia coli cells, label detection was already possible after 20 min. For functional analyses of microbial communities, the detection of D incorporation from D2O in individual microbial cells via Raman microspectroscopy can be directly combined with FISH for the identification of active microbes. Applying this approach to mouse cecal microbiota revealed that the host-compound foragers Akkermansia muciniphila and Bacteroides acidifaciens exhibited distinctive response patterns to amendments of mucin and sugars. By Raman-based cell sorting of active (deuterated) cells with optical tweezers and subsequent multiple displacement amplification and DNA sequencing, novel cecal microbes stimulated by mucin and/or glucosamine were identified, demonstrating the potential of the nondestructive D2O-Raman approach for targeted sorting of microbial cells with defined functional properties for single-cell genomics. PMID- 25550521 TI - The polarity of myxobacterial gliding is regulated by direct interactions between the gliding motors and the Ras homolog MglA. AB - Gliding motility in Myxococcus xanthus is powered by flagella stator homologs that move in helical trajectories using proton motive force. The Frz chemosensory pathway regulates the cell polarity axis through MglA, a Ras family GTPase; however, little is known about how MglA establishes the polarity of gliding, because the gliding motors move simultaneously in opposite directions. Here we examined the localization and dynamics of MglA and gliding motors in high spatial and time resolution. We determined that MglA localizes not only at the cell poles, but also along the cell bodies, forming a decreasing concentration gradient toward the lagging cell pole. MglA directly interacts with the motor protein AglR, and the spatial distribution of AglR reversals is positively correlated with the MglA gradient. Thus, the motors moving toward lagging cell poles are less likely to reverse, generating stronger forward propulsion. MglB, the GTPase-activating protein of MglA, regulates motor reversal by maintaining the MglA gradient. Our results suggest a mechanism whereby bacteria use Ras family proteins to modulate cellular polarity. PMID- 25550522 TI - Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome. PMID- 25550523 TI - Hip fractures sustained in hospital: comorbidities and outcome. AB - BACKGROUND: Guidelines on the management of hip fracture in the elderly focus on fractures suffered in the community. Between 4% and 7% of hip fractures occur in hospital. Mortality is higher in those who sustain hip fracture in hospital than those who sustain a fracture in the community. However, it is not known if sustaining a nosocomial fracture is an independent risk factor for a poor outcome. OBJECTIVE: To compare outcomes of hip fracture sustained in the community and sustained while in hospital for another reason. After adjusting for confounders, we sought to determine if sustaining a fracture in hospital was an independent risk factor for a poor outcome. METHODS: Using the National Hip Fracture Database, we identified all patients admitted to Leicester Royal Infirmary with hip fracture between July 2009 and February 2013. We extracted demographic data, details of comorbidity, and 30-day and long-term mortality. Age, gender, American Society of Anaesthesiologists (ASA) grade, time to surgery, and survival were compared between patients with hospital-acquired and those with community-acquired hip fracture. RESULTS: During the study period, 2987 patients were treated for hip fracture; 2984 were included in the study. Of these, 261 (8.7%) sustained the fracture while in hospital. Those who sustained the fracture in hospital were more commonly men (106/261 (41%)) than those with a community acquired fracture (738/2723 (27%)) and had a worse ASA grade (III or IV, 215/230 (93%) vs 1647/2573 (64%)). Thirty-day mortality was higher in those with a hospital-acquired fracture (48/261 (18%)) than in those with a community-acquired fracture (212/2723 (7.8%)) (p<0.001). However, after adjustment for confounding variables, the association between hip fracture, in-hospital and 30-day mortality was not significant: OR 1.2 (95% CI 0.8 to 2.0), p=0.40. Longer-term mortality was associated with hip fracture in hospital after adjustment for confounding variables in multivariate proportional hazards regression: HR 1.5 (95% CI 1.2 to 1.8), p<0.001. CONCLUSIONS: Patients who sustain hip fractures in hospital are unsurprisingly sicker than those who sustain hip fractures in the community. Although being in hospital is not an independent risk factor, this easily identifiable group of patients are at particular risk of a poor outcome. We suggest that it might be appropriate to consider modifying the guidelines for treatment of hip fracture for this group in an attempt to improve outcome. PMID- 25550524 TI - Spatial and temporal action of chicken primordial germ cells during initial migration. AB - In most animals, primordial germ cells (PGCs) originate from an extragonadal region and migrate across the embryo to the gonads, where they differentiate and function. During their migration, PGCs move passively by morphogenetic movement of the embryo or move actively through signaling molecules. To uncover the underlying mechanism of first-phase PGC migration toward the germinal crescent in chickens, we investigated the spatial and temporal action of PGCs during primitive streak formation. Exogenously transplanted PGCs migrated toward the anterior region of the embryo and the embryonic gonads when they were transplanted into the subgerminal cavity, but not into the posterior marginal zone, in Eyal-Giladi and Kochav stage X embryos. These results indicate that for passive migration toward the anterior region the initial location of PGCs should be the central region. Notably, although PGCs and DF-1 cells migrated passively toward the anterior region, only PGCs migrated to the germinal crescent, where endogenous PGCs mainly reside, by active movement. In a live-imaging experiment with green fluorescence protein-expressing transgenic embryos, exogenous PGCs demonstrated markedly faster migration when they reached the anterior one-third of the embryo, while somatic cells showed epiblast movement with constant speed. Also, migrating PGCs exhibited successive contraction and expansion indicating their active migration. Our results suggest that chicken PGCs use sequential passive and active forces to migrate toward the germinal crescent. PMID- 25550525 TI - A novel role for GSK3 in the regulation of the processes of human labour. AB - Preterm birth remains the largest single cause of neonatal death and morbidity. Infection and/or inflammation are strongly associated with preterm delivery. Glycogen synthase kinase 3 (GSK3) is known to be a crucial mediator of inflammation homeostasis. The aims of this study were to determine the effect of spontaneous human labour in foetal membranes and myometrium on GSK3alpha/beta expression, and the effect of inhibition of GSK3alpha/beta on pro-labour mediators in foetal membranes and myometrium stimulated with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. Term and preterm labour in foetal membranes was associated with significantly decreased serine phosphorylated GSK3alpha and beta expression, and thus increased GSK3 activity. There was no effect of term labour on serine phosphorylated GSK3beta expression in myometrium. The specific GSK3alpha/beta inhibitor CHIR99021 significantly decreased lipopolysaccharide (ligand to TLR4)-stimulated pro-inflammatory cytokine gene expression and release; COX2 gene expression and prostaglandin release; and MMP9 gene expression and pro MMP9 release in foetal membranes and/or myometrium. CHIR99021 also decreased FSL1 (TLR2 ligand) and flagellin (TLR5 ligand)-induced pro-inflammatory cytokine gene expression and release and COX2 mRNA expression and prostaglandin release. GSK3beta siRNA knockdown in primary myometrial cells was associated with a significant decrease in IL1beta and TNFalpha-induced pro inflammatory cytokine and prostaglandin release. In conclusion, GSK3alpha/beta activity is increased in foetal membranes after term and preterm labour. Pharmacological blockade of the kinase GSK3 markedly reduced pro-inflammatory and pro-labour mediators in human foetal membranes and myometrium, providing a possible therapeutics for the management of preterm labour. PMID- 25550526 TI - Carbon dioxide elimination and oxygen consumption in mechanically ventilated children. AB - BACKGROUND: Accurate measurement of carbon dioxide elimination (VCO2 ) and oxygen consumption (VO2 ) at the bedside may help titrate nutritional and respiratory support in mechanically ventilated patients. Continuous VCO2 monitoring is now available with many ventilators. However, because normative data are sparsely available in the literature, we aimed to describe the range of VCO2 and VO2 values observed in mechanically ventilated children. We also aimed to examine the characteristics of VCO2 values that are associated with standard steady state (5 min period when VCO2 and VO2 variability are < 10%). METHODS: Mechanically ventilated patients who underwent indirect calorimetry testing were eligible for inclusion, and subjects who achieved standard steady state were included. Normalized VCO2 and VO2 values (mL/kg/min) were modeled against subject height, and correlation coefficients were computed to quantify the goodness of fit. A steady-state definition using only VCO2 was developed (VCO2 variability of < 5% for a 5-min period) and tested against standard steady state using sensitivity and specificity. RESULTS: Steady-state data from 87 indirect calorimetry tests (in 70 subjects) were included. For age groups < 0.5, 0.5-8, and > 8 y, the mean VCO2 values were 7.6, 5.8, and 3.5 mL/kg/min. Normalized VCO2 and VO2 values were inversely related to subject height and age. The relationships between normalized gas exchange values and height were demonstrated by the models: VCO2 = 115 * (height in cm)(-0.71) (R = 0.61, P < .001) and VO2 = 130 * (height in cm)(-0.72) (R = 0.61, P < .001). Steady-state VCO2 predicted standard steady state (sensitivity of 0.84, specificity of 1.0, P < .01). CONCLUSIONS: VCO2 and VO2 measurements correlated with subject height and age. Smaller and younger subjects produced larger amounts of CO2 and consumed more O2 per unit of body weight. The use of a 5-min period when VCO2 varied by < 5% predicted standard steady state. Our observations may facilitate greater utility of VCO2 at the bedside in the pediatric ICU and thereby extend the benefits of metabolic monitoring to a larger group of patients. PMID- 25550527 TI - Relapsing polychondritis with initial presentations of recurrent negative pressure pulmonary edema and acute respiratory failure. AB - Relapsing polychondritis is a rare autoimmune disease causing inflammation in cartilaginous structures and other tissues throughout the body. Negative-pressure pulmonary edema (NPPE) due to laryngeal swelling from relapsing polychondritis is rare and has not been reported. Here, we report a case of relapsing polychondritis in an 18-y-old female who presented with recurrent NPPE and acute respiratory failure, which was diagnosed initially as ARDS during the influenza season. She underwent an emergent tracheotomy to relieve the upper airway obstruction resulting from severe laryngeal edema. A chest radiograph showed diffuse infiltrations, pneumothorax, and pneumomediastinum. The pulmonary infiltrations resolved rapidly in 2 d, and NPPE was diagnosed. Left ear swelling with erythematous change and saddle nose developed during the course of hospitalization, and an ear biopsy demonstrated severe cartilage necrosis. Relapsing polychondritis was diagnosed based on clinical images and pathological findings. PMID- 25550528 TI - Management of chronic myelogenous leukemia in pregnancy. AB - Discovery of tyrosine kinase inhibitors has led to improvement in survival of chronic myelogenous leukemia (CML) patients. Many young CML patients encounter pregnancy during their lifetime. Tyrosine kinase inhibitors inhibit several proteins that are known to have important functions in gonadal development, implantation and fetal development, thus increasing the risk of embryo toxicities. Studies have shown imatinib to be embryotoxic in animals with varying effects in fertility. Since pregnancy is rare in CML, there are no randomized controlled trials to address the optimal management of this condition. However, there are several case reports and case series on CML in pregnancy. At the present time, there is no consensus on how to manage different pregnancy situations in CML. In this article, we review current literature on CML in pregnancy, discuss the effects of several tyrosine kinase inhibitors on fertility and pregnancy and suggest an evidence-based treatment of CML in pregnancy. PMID- 25550529 TI - Female genital tract chronic graft-versus-host disease: review of the literature. AB - BACKGROUND: Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the involvement of skin, oral cavity, eyes, liver and gut is well described, gynaecological manifestations are rare, often undiagnosed and untreated. MATERIALS AND METHODS: A selective literature search of articles in English language, published from 1982 to 2014 (indexed in PubMed) was performed. DISCUSSION: Genital cGVHD is characterised by polymorphic clinical manifestations with sclerotic changes of the vulva and vagina. Introital stenosis or complete vaginal closure were reported in severe cases. Thus, cGVHD can seriously affect female sexual function and the overall quality of life. A prompt diagnosis and an appropriate therapy may prevent the development of severe forms and the need for surgery. Thus, a systematic specialized gynaecological consultation should be performed early in every allo-HSCT recipient as part of the routine post transplantation management, even in asymptomatic women. PMID- 25550530 TI - Cytokine networks in animal models of colitis-associated cancer. AB - BACKGROUND/AIM: It is well-known that inflammatory bowel disease (IBD) poses an increased, yet not definitely estimated, risk of colitis-associated colon cancer (CAC), which is considered a more aggressive and distinct in both genetic and molecular levels clinical entity compared to sporadic colorectal cancer (CRC). The present review discusses the cytokine networks involved in CAC-based translational findings from suitable animal models of the disease. Moreover, we summarize the most prominent data concerning the role of Th1, Th2, Th17 and anti inflammatory cytokines in the pathogenesis of CAC. Last, we briefly address the controversies between basic science findings in IBD and CAC and suggest further directions regarding research on cytokines. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of cytokines in the context of CAC. MATERIALS AND METHODS: The MEDLINE database was thoroughly searched using the keywords: cytokines, colitis-associated cancer, animal models, carcinogenesis. Additional articles were gathered and evaluated. PMID- 25550531 TI - Class II transactivator expression in melanoma cells facilitates T-cell engulfment. AB - BACKGROUND/AIM: Melanoma cells express high levels of HLA class II, cell surface antigen-presenting proteins, which is an anomalous phenotype among solid tumors. There has never been a satisfying explanation for how this HLA class II-positive phenotype is related to tumor development. Lugini and colleagues demonstrated that melanoma cells have the capacity to engulf T-cells. We considered the possibility that this capacity could be dependent on HLA class II expression. MATERIALS AND METHODS: We co-cultured melanoma and CD4-positive, labeled, Jurkat C T-cells. The melanoma cells were transformed with an expression vector for CIITA, the obligate HLA class II gene transactivator. We then assayed for the transfer of label to the melanoma cells. RESULTS: CIITA expression facilitated engulfment of the T-cell material but not material from B-cells. CONCLUSION: The results suggest a possible mechanism for HLA class II-positive melanoma cells in blunting an anti-tumor response and suggest a possible target for melanoma therapy. PMID- 25550532 TI - The anti-hypertensive drug prazosin induces apoptosis in the medullary thyroid carcinoma cell line TT. AB - BACKGROUND/AIM: Medullary thyroid carcinoma (MTC) is a tumor associated with poor prognosis since it exhibits high resistance against conventional cancer therapy. Recent studies have shown that quinazolines exhibit a pro-apoptotic effect on malignant cells. The aim of the present study was to elucidate whether MTC cells are affected by quinazolines, in particular prazosin. MATERIALS AND METHODS: Proliferation, apoptosis and cell morphology of the MTC cell line TT were analyzed by WST-1 assay, caspase 3/7 activation tests and microscopy. Fibroblasts were used as control for non-malignant cells. RESULTS: Prazosin potently inhibited the growth of TT cells, induced apoptosis and caused vacuolization, as well as needle-like filopodia. Fibroblasts were affected by prazosin in the same way as MTC cells. CONCLUSION: MTC cells are responsive to prazosin treatment similar to other malignancies. The fact that fibroblasts also respond to prazosin further highlights the importance to identify the unknown pro-apoptotic target of quinazolines. PMID- 25550534 TI - Oncolytic potential of a novel KGFR tyrosine kinase inhibitor using a KGFR selective breast cancer xenograft model. AB - BACKGROUND: Keratinocyte growth factor (KGF)/KGF receptor (KGFR) signaling produces a rapid increase in the progression of breast cancer. Molecular modeling was used to create a group of KGFR-selective kinase inhibitors (TKI). Compound L 27 is a potent and selective KGFR TKI. The present study examined the oncolytic potential of L-27 using a breast cancer xenograft model. MATERIALS AND METHODS: An orthotopic xenograft model was developed with KGF-transfected MCF-7 cells to examine the influence of L-27 upon KGFR-mediated tumor progression. RESULTS: L-27 was found to produce a dose-related reduction in the growth and metastasis of mouse xenograft tumors. Furthermore, L-27 treatment did not produce any signs of gross toxicity. CONCLUSION: L-27 was found to reduce the growth and metastasis of MCF-7 tumor xenografts with elevated expression of KGF. Thus, KGFR TKI may provide a new therapeutic approach for the treatment of breast and other types of cancer. PMID- 25550533 TI - Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down-regulation of STAT3-NFkappaB signaling. AB - BACKGROUND/AIM: The cancer stem cell (CSC) model postulates the existence of a small proportion of cancer cells capable of sustaining tumor formation, self renewal and differentiation. Signal Transducer and Activator of Transcription 3 (STAT3) signaling is known to be selectively activated in breast CSC populations. However, it is yet to be determined which molecular mechanisms regulate STAT3 signaling in CSCs and what chemopreventive agents are effective for suppressing CSC growth. The aim of this study was to examine the potential efficacy of curcumin and epigallocatechin gallate (EGCG) against CSC and to uncover the molecular mechanisms of their anticancer effects. MATERIALS AND METHODS: To suppress the CSC phenotype, two breast cancer cell lines (MDA-MB-231 cells and MCF7 cells transfected with HER2) were treated with curcumin (10 MUM) with or without EGCG (10 MUM) for 48 h. We used tumor-sphere formation and wound-healing assays to determine CSC phenotype. To quantify CSC populations, Fluorescence activated cell sorting profiling was monitored. STAT3 phosphorylation and interaction with Nuclear Factor-kB (NFkB) were analyzed by performing western blot and immunoprecipitation assays. RESULTS: Combined curcumin and EGCG treatment reduced the cancer stem-like Cluster of differentiation 44 (CD44) positive cell population. Western blot and immunoprecipitation analyses revealed that curcumin and EGCG specifically inhibited STAT3 phosphorylation and STAT3 NFkB interaction was retained. CONCLUSION: This study suggests that curcumin and EGCG function as antitumor agents for suppressing breast CSCs. STAT3 and NFkappaB signaling pathways could serve as targets for reducing CSCs leading to novel targeted-therapy for treating breast cancer. PMID- 25550535 TI - Targeting chemokine receptor CXCR7 inhibits glioma cell proliferation and mobility. AB - BACKGROUND: The functional contribution of chemokine receptor CXCR7 to malignant brain tumor biology remains controversial. MATERIALS AND METHODS: Complementary methods were used to confirm CXCR7 expression in clinical glioblastoma multiforme (GBM) specimens and multiple GBM cell lines. Loss-of-function studies were performed using small interfering RNA (siRNA) technology. RESULTS: Elevated CXCR7 levels correlated with reduced survival in glioma patients. CXCR7 was expressed by GBM cell lines and stem-like progenitor cells. Knockdown of CXCR7 by siRNA attenuated phosphorylation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway in response to CXCL12 and resulted in significantly reduced cell proliferation, invasion and migration. Similarly, treatment of glioma cells with a small molecule antagonist of CXCR7, CCX771, significantly inhibited cell proliferation and invasion. CONCLUSION: CXCR7 actively promotes the proliferation and invasive behavior of glioma tumor cells and stem-like progenitor cells and may be a potential target for glioma therapy. PMID- 25550536 TI - Enlargement and multinucleation of u937 leukemia and MCF7 breast carcinoma cells by antineoplastic agents to enhance sensitivity to low frequency ultrasound and to DNA-directed anticancer agents. AB - BACKGROUND/AIM: Cytochalasin B is a mycogenic toxin that preferentially damages malignant cells through multiple mechanisms. The microfilament-disrupting agent inhibits cytokinesis, producing enlarged and multinucleated neoplastic cells without enlarging or producing multinucleated normal cells. In addition, cytochalasin B has been shown to induce apoptosis and to increase the mitochondrial activity of malignant cells. In spite of these pharmacological properties potentially exploitable in cancer chemotherapy, no cytochalasin congener or derivative and indeed no microfilament-directed agent has yet been examined in the clinic. Nevertheless, it will likely be necessary to combine microfilament-directed agents with other chemotherapeutic agents, and potentially with other anti-neoplastic modalities to amplify the mechanisms by which microfilament-directed agents inflict damage. These combinations could increase the likelihood of obtaining clinically useful activities with microfilament directed agents and decrease the often inevitable emergence of drug resistance. Therefore, this study intends to determine appropriate chemotherapeutic agents to use concurrently with cytochalasin B and with other microfilament-directed agents. MATERIALS AND METHODS: Since cytochalasin B has shown in vitro efficacy against anchorage-independent growth, as well as against attached malignancies, both U937 human monocytic leukemia and MCF7 human breast carcinoma cells were evaluated. These cell lines were assessed for their sensitivity to a comprehensive array of chemotherapeutic agents that could amplify the cytoskeletal effects of microfilament-directed agents or that could themselves be potentiated by the cellular effects of such agents. In addition, clinically approved microtubule-directed agents, as well as clinically-active anti neoplastic agents not specifically cytoskeletal-directed, were examined for their ability to potentiate cell enlargement, one of the hallmark features of microfilament-directed agents. Conditions for inducing optimal enlargement and multinucleation of neoplastic cells with cytochalasin B were also defined. RESULTS: U937 and MCF7 cells have differing sensitivities to chemotherapeutic agents indicating that different regimens will likely be needed for various cell types in concomitant cytochalasin B-mediated chemotherapy. It was noted that microtubule-directed agents (paclitaxel and vincristine) would likely have a synergistic effect with cytochalasin B as they produced a substantial enlargement in viable cells at their 50% inhibitory (IC50) values. Interestingly, doxorubicin and mitomycin C also produced considerable cell enlargement, suggesting that nucleic acid-directed agents may be used to further enhance the cell-enlargement and multinucleation effects of microfilament-directed agents if appropriate sequences and concentrations can be found for the combination of agents. A subsequent publication in this series will examine the optimal combinations of chemotherapeutic agents with microfilament-directed agents in regards to drug concentrations and sequential timing. U937 cells exposed to cytochalasin B exhibited substantial cell enlargement and multinucleation that was still prevalent 8 days post-administration depending on the concentration used. CONCLUSION: Taken together, it appears that cytochalasin B has substantial synergistic potential with microtubule- and nucleic acid-directed agents. PMID- 25550537 TI - Dual targeting NG2 and GD3A using Mab-Zap immunotoxin results in reduced glioma cell viability in vitro. AB - BACKGROUND: Effective treatments for glioblastoma multiforme (GBM) are lacking due, in part, to cellular heterogeneity. Consequently, single-target therapeutic strategies are unlikely to succeed. Simultaneous targeting of different neoplastic cell populations within the same tumour may, therefore, prove of value. Neuron-glia 2 (NG2), a transmembrane chondroitin sulphate proteoglycan, present on developing glial cells, and GD3(A), a ganglioside expressed on developing migratory glia, are re-expressed in GBM. MATERIALS AND METHODS: The aims of this study were to conduct 'proof of concept' experiments in human GBM cell lines to show that proliferative high NG2-expressing cells and high GD3(A) expressing migratory cells could be effectively ablated using a Mab-Zap saporin immunotoxin system. RESULTS: The combinatorial ablation of both NG2 and GD3(A) expressing cells resulted in significant reduction in GBM cell viability compared to single epitope targeting and controls (p<0.0001); non-neoplastic astrocytes were not affected. CONCLUSION: Multiple targeting of GBM sub-populations may, therefore, help inform novel therapeutic approaches. PMID- 25550538 TI - Differential contribution of ROS to resveratrol-induced cell death and loss of self-renewal capacity of ovarian cancer stem cells. AB - BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to contribute to the poor prognosis of ovarian cancer as a major cause of fatal recurrence. Identification of effective measures to eliminate ovarian CSCs through induction of cell death and/or loss of self-renewal capacity would, therefore, be key to successful management of ovarian cancer. MATERIALS AND METHODS: The effects of resveratrol on the viability and self-renewal capacity of CSCs derived from A2780 human ovarian cancer cells were examined. The involvement of reactive oxygen species (ROS) was also investigated. RESULTS: At a non-toxic to normal human fibroblasts concentration, resveratrol effectively killed ovarian CSCs independently of ROS, while ROS-dependently impaired the self-renewal capacity of ovarian CSCs that survived resveratrol treatment. CONCLUSION: Our findings not only shed light on a novel mechanism of action for resveratrol but also suggest that resveratrol, or its analogs, may be useful for CSC-directed therapy against ovarian cancer. PMID- 25550539 TI - Oil palm phenolics (OPP) inhibit pancreatic cancer cell proliferation via suppression of NF-kappaB pathway. AB - BACKGROUND: Oil palm phenolics (OPP) or Palm Juice (PJ), a water soluble extract from the palm fruit (Elaies guineensis) has been documented to have anti carcinogenic activities in various cancer types. MATERIALS AND METHODS: To investigate OPP effects in pancreatic cancer (PaCa) cells, two PaCa cell lines (PANC-1 and BxPC-3) were treated with different OPP doses. The anti proliferative, apoptotic and anti-invasive properties of OPP were evaluated using MTS, cytoplasmic histone-DNA fragmentation and matrigel invasive assays, respectively. RESULTS: OPP suppressed PaCa proliferation in a dose-dependent manner. Its anti-invasive effects were validated by decreased expressions of MMP 9 and VEGF. Cell-cycle analysis demonstrated that cells were arrested in the S phase. OPP-induced apoptosis was associated with decrease in survivin and Bcl-XL expressions and increased expression of cleaved caspase-3, caspase-9 and PARP. CONCLUSION: Overall, our results demonstrate the anti-tumor effects of OPP on PaCa cells, providing initial evidence towards its potential therapeutic use. PMID- 25550540 TI - Pattern of IGF-1 variants' expression in human cancer cell lines using a novel q RT-PCR approach. AB - BACKGROUND/AIM: Although insulin-like growth factor-1 (IGF-1) is well-implicated in cancer biology, the potential roles of IGF-1 variants in different types of cancer are largely unknown. The aim of the present study was to in vitro characterize several human cancers for their IGF-1 variant expression patterns. MATERIALS AND METHODS: Using a novel quantitative real-time polymerase chain reaction (qRT-PCR) assay, twelve human cancer cell lines were investigated for their endogenous expression levels of IGF-1 variants, including classes. Additionally, the hormonal regulation of IGF-1 transcripts was investigated in PC3 cells. RESULTS: IGF-1Ea and Eb were found at higher levels in KLE and MEL28 cells, respectively. MCF7 had the lowest expression of Ec peptide and, along with MB231, lacked IGF-1Eb. In most cases, class 1 proved as the predominant origin. Estradiol (E2) or dexamethasone (Dexa) significantly modulated IGF-1Ea and IGF 1Eb and down-regulated the Ec peptide in PC3. CONCLUSION: Our results contribute to the notion of distinct roles of IGF-1 isoforms in human cancer depending on the type of malignancy. PMID- 25550541 TI - Is relative quantification dispensable for the measurement of microRNAs as serum biomarkers in germ cell tumors? AB - BACKGROUND: Classical biomarkers alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase (AFP, bHCG and LDH) are elevated in only 60% of all testicular germ cell tumor (TGCT) patients. microRNAs (miRNAs) are a novel class of useful biomarkers in cancer and miRNAs of the miR-371-3 cluster were proven to be valuable markers for TGCT patients. MATERIALS AND METHODS: We compared the Ct and DeltaCt values of miR-371-3 by real time PCR (qPCR) with and without 18S rRNA for normalization. Expression of miR-371a-3p, miR-372 and miR 373-3p was measured in 25 TGCTs, 4 non-TGCTs and 17 age-matched male controls. RESULTS: A highly positive correlation between Ct and DeltaCt values was found in all samples. The highest correlation was found for miR-371a-3p (R2: 0.956). CONCLUSION: RESULTS show that qPCR can be used without endogenous control for analyzing miR-371-3 in the serum of patients with testicular cancer and male controls if the technical procedure is performed under controlled conditions. PMID- 25550542 TI - Diminished expression of MiR-15a is an independent prognostic marker for breast cancer cases. AB - BACKGROUND/AIM: MiR-15a targets Cyclin E1 (CCNE1), which regulates the cell cycle and promotes cell proliferation and progression. Herein, we investigated the clinicopathological significance of miR-15a as a prognostic marker in breast cancer (BC) cases. MATERIALS AND METHODS: We collected primary tumor samples of 230 BC cases, including 68 triple-negative cases. The expression levels of miR 15a in primary tumors were measured by qRT-PCR assay. RESULTS: Low expression of miR-15a in primary tumors was significantly correlated with shorter disease-free survival (p=0.0012) and overall survival (p=0.005) compared to the high miR-15a expression in triple-negative BC cases. Multivariate analysis indicated that low miR-15a expression was an independent prognostic factor for overall survival [RR=2.56(1.03-7.18), p=0.04]. CONCLUSION: MiR-15a expression levels could be a promising biological and prognostic marker for overall survival especially in triple-negative BC cases. PMID- 25550543 TI - Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. AB - BACKGROUND/AIM: The purpose of the present study was to establish an effective immunotherapy by skewing the cosignal balance to be on the positive side by using the combination of monoclonal antibody (mAb) against 4-1BB also known as Cluster of Differentiation (CD) 137 as a co-stimulatory effector and to programmed death 1 (PD-1) to blockade the immune checkpoint. MATERIALS AND METHODS: Mice implanted with 1*10(5) CT26 cells were treated with anti 4-1BB mAb alone, anti PD-1 mAb alone, or both anti 4-1BB mAb and anti PD-1 mAb. Immune cell populations were analyzed by flow cytometry. Tumor-infiltrating T-cells were evaluated by immunohistochemistry. RESULTS: Mice treated with the combination therapy had the best antitumor response that resulted in complete tumor rejection. The numbers of CD4(+) interferon (IFN)-gamma(+) and CD8(+) IFN-gamma(+) T-cells were significantly higher in the combination group. The number of tumor-infiltrating T cells was significantly increased in the combination therapy. CONCLUSION: The therapeutic strategy of targeting co-signal molecules has promising clinical applications in the future. PMID- 25550544 TI - Vascular endothelial growth factor, basic fibroblast growth factor and epithelial growth factor receptor in peripheral nerve sheath tumors of neurofibromatosis type 1. AB - BACKGROUND/AIM: Neurofibromas, benign tumors of the nerve sheaths, are the hallmark of neurofibromatosis type 1 (NF1), an autosomal-dominant inherited tumor predisposition syndrome. Malignant tumors arising from nerve sheath cells are an important factor influencing the life expectancy of NF1 patients. Expression of growth factors and growth factor receptors play a key role in the development of tumors. Therapy of peripheral nerve sheath (PNS) tumors is predominantly surgical. The outcome in malignant entities of NF1-affected patients remains poor, despite many efforts to implement pharmacological therapy into the treatment modalities. Growth of peripheral nerve sheath tumors is finely-adjusted by growth factors and PNS tumors express growth factor receptors. However, quantification of receptor expression and comparison to the expression of other related factors are not available. The aim of the present study was to determine growth factor expression relevant for growth control in neurofibromas of NF1. MATERIALS AND METHODS: Fifty-eight dermal, dermal/diffuse and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) of NF1 affected patients were analyzed immunohistochemically for the expression of growth factors relevant for angiogenesis: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epithelial growth factor receptor (EGFR). The vessel density was also determined quantitatively by light microscopy. RESULTS: Plexiform neurofibroma revealed a higher expression level for VEGF compared to dermal/diffuse neurofibroma. However, statistical significant differences for VEGF expression and of all other proteins investigated were found in comparison to MPNST only. EGFR expression was remarkably high in NF1 patients in their first decade of life. However, this result has to be interpreted with caution in view of the high number of young patients with MPNST in this age group. Vessel density correlated with tumor type. Vessel density increased significantly comparing benign nerve sheath tumors and MPNST (p<0.05). DISCUSSION/CONCLUSION: This study revealed the presence of factors and receptors involved in angiogenesis as a prerequisite for tumor development and maintenance of PNS in NF1. These factors are highly expressed in all tumors of this study. This study reveals these relevant factors in nerve sheath tumors and also described the significant increase of vessel density in MPNST compared to benign counterparts. Anti-angiogenic drugs are presently investigated for application in NF1 tumor treatment, in particular for patients with a surgically-intractable high tumor burden. Drugs capable of blocking the EGFR receptor-mediated pathway are promising tools within the pharmacological repertoires to treat these patients. PMID- 25550545 TI - Verification of a canine PSMA (FolH1) antibody. AB - BACKGROUND: Canine prostate cancer (PC) is a highly aggressive malignancy. However, in contrast to man, neither standard screening strategies nor curative therapeutic options exist for the companion animal. A prostate-specific membrane antigen (PSMA) screening as molecular marker akin to human PC is currently not available for dogs as data on specific canine PSMA detection are contradictory. MATERIALS AND METHODS: To evaluate an antibody for specific canine PSMA detection by western blotting (WB), lysates of three canine prostatic cell lines (CT1258, DT08/40, DT08/46) were comparatively analyzed by WB and mass spectrometry (MS) to the human cell lines VCaP, LnCaP and PC-3. RESULTS: MS analyses of the detected canine proteins confirmed cross reactivity of the antibody clone YPSMA-1 with canine PSMA. CONCLUSION: The MS analyses of the extracted canine protein bands proved that the YPSMA-1 clone is as well specific for canine PSMA in WB and, thus, represents a reliable tool for comparative PSMA studies. PMID- 25550546 TI - CD47 activation-induced UHRF1 over-expression is associated with silencing of tumor suppressor gene p16INK4A in glioblastoma cells. AB - CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-kappaB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis. PMID- 25550547 TI - Human adipose tissue-derived mesenchymal stem cells inhibit melanoma growth in vitro and in vivo. AB - BACKGROUND/AIM: The effects of adipose tissue-derived mesenchymal stem cells (AT MSCs) on the growth of human malignancies, including melanoma, are controversial and the underlying mechanisms are not yet-well understood. The aim of the present study was to investigate the in vitro and in vivo anti-tumor effects of human AT MSCs on human melanoma. MATERIALS AND METHODS: The inhibitory effect of AT-MSC conditioned medium (AT-MSC-CM) on the growth of A375SM and A375P (human melanoma) cells was evaluated using a cell viability assay. Cell-cycle arrest and apoptosis in melanoma cells were investigated by flow cytometry and western blot analysis. To evaluate the in vivo anti-tumor effect of AT-MSCs, CM-DiI-labeled AT-MSCs were circumtumorally injected in tumor-bearing athymic mice and tumor size was measured. RESULTS: AT-MSC-CM inhibited melanoma growth by altering cell-cycle distribution and inducing apoptosis in vitro. AT-MSCs suppressed tumor growth in tumor-bearing athymic mice and fluorescence analysis showed that AT-MSCs migrated efficiently to tumor tissues. CONCLUSION: AT-MSCs inhibit the growth of melanoma suggesting promise as a novel therapeutic agent for melanoma. PMID- 25550548 TI - Influence of p53 status on the effects of boron neutron capture therapy in glioblastoma. AB - BACKGROUND/AIM: The tumor suppressor gene p53 is mutated in glioblastoma. We studied the relationship between the p53 gene and the biological effects of boron neutron capture therapy (BNCT). MATERIALS AND METHODS: The human glioblastoma cells; A172, expressing wild-type p53, and T98G, with mutant p53, were irradiated by the Kyoto University Research Reactor (KUR). The biological effects after neutron irradiation were evaluated by the cell killing effect, 53BP1 foci assay and apoptosis induction. RESULTS: The survival-fraction data revealed that A172 was more radiosensitive than T98G, but the difference was reduced when boronophenylalanine (BPA) was present. Both cell lines exhibited similar numbers of foci, suggesting that the initial levels of DNA damage did not depend on p53 function. Detection of apoptosis revealed a lower rate of apoptosis in the T98G. CONCLUSION: BNCT causes cell death in glioblastoma cells, regardless of p53 mutation status. In T98G cells, cell killing and apoptosis occurred effectively following BNCT. PMID- 25550549 TI - In vitro anticancer activity of PI3K alpha selective inhibitor BYL719 in head and neck cancer. AB - BACKGROUND/AIM: The purpose of the present study was to explore the antiproliferative effect of BYL719, a specific inhibitor for phosphatidylinositol 3-kinase (PI3K) p110alpha, in human head and neck cancer cell lines, as a single agent or in combination with the irreversible EGFR tyrosine kinase inhibitor, dacomitinib. MATERIALS AND METHODS: Six head and neck cancer cell lines consisting of two PIK3CA mutant cell lines, SNU-1076 and Detroit562, and four PIK3CA wild-type cell lines, SNU-1066, SNU-1041, FaDu and SCC25, were analyzed. RESULTS: The PIK3CA-mutant cell lines were more sensitive to BYL719 than the PIK3CA wild-type cell lines. Following BYL719 treatment, all PIK3CA wild-type cell lines, except for the SNU-1066 cell line, exhibited higher IC50 values compared to the PIK3CA mutant cell lines. Administration of BYL719 induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependant manner. Furthermore, the administration of BYL719 reduced the level of p-mTOR, p AKT and p-S6 expression indicating the down-regulation of downstream signaling. CONCLUSION: BYL719, a PI3K alpha selective blocker, could be a promising factor in the treatment of head and neck cancer either as a single agent or in combination with dacomitinib. PMID- 25550550 TI - KML001 enhances anticancer activity of gemcitabine against pancreatic cancer cells. AB - BACKGROUND/AIM: Gemcitabine is a drug commonly used to treat pancreatic cancer but chemoresistance to it is a common clinical issue. KML001 (sodium meta arsenite) has demonstrated certain antitumor activity. The objective of the study was to evaluate the influence of KML001 on the anticancer activity of gemcitabine against pancreatic cancer cells. MATERIALS AND METHODS: Cell proliferation, migration, and invasion were assessed, as well as the expression of nuclear factor-kappa B (NF-kappaB) p65, epidermal growth factor receptor (EGFR), matrix metalloproteinase-2 (MMP2), and vascular endothelial growth factor-C (VEGFC) in pancreatic cancer cells. RESULTS: Treatment with a combination of KML001 and gemcitabine resulted in significant inhibition of cell proliferation, migration, and invasion, and significantly reduced EGFR and MMP2 expression compared to gemcitabine treatment-alone. CONCLUSION: Combination treatment of gemcitabine and KML001 could be an effective chemotherapeutic treatment for pancreatic cancer. PMID- 25550551 TI - Cytotoxic effect of s-petasin and iso-s-petasin on the proliferation of human prostate cancer cells. AB - BACKGROUND: Petasin (Petasides hybridus) is a perennial shrub that is found in Europe as well as parts of Asia and North America and is being used to treat hypertension, tumors and asthma. In a previous study, we reported that petasin possesses biological effects including inhibition of testosterone production and the release of corticosterone from rat zona fasciculata-reticularis cells, and anti-proliferative effect on human T24 bladder carcinoma cells. MATERIALS AND METHODS: In the present study, we assessed the effects of S-petasin and iso-S petasin on the growth and proliferation of two hormone-independent DU145 and PC3 and one hormone-dependent LNCaP prostate cancer cell line at concentrations of 10(-7)-10(-5) mol/l. The cell proliferation index, cell number index, expression of caspases and apoptosis-associated proteins and cell morphology were measured. RESULTS: S-Petasin and iso-S-petasin reduced the viable cell number and increased the numbers of apoptotic cells in the tested cell lines in a dose-dependent manner. Western blot analysis revealed that S-petasin and iso-S-petasin reduced the protein levels of procaspase 3, 8, and 9 and cleaved poly(ADP-ribose) polymerase (PARP) in all tested prostate cancer cell lines, and reduced that of procaspase 7 in LNCaP and PC3 cells. At the same time, S-petasin and iso-S petasin increased mitochondrial membrane permeability and cytochrome c release from mitochondria to the cytosol via reducing the ratio of BCL2/BAX in DU145 and PC3 cells, and up-regulating the levels of p53 in DU145 cells but down-regulating it in PC3 cells. CONCLUSION: These results indicate that S-petasin and iso-S petasin induce apoptosis via the activation of mitochondria-related pathways in prostate cancer cells, suggesting S-petasin and iso-S-petasin could be potential anticancer agents. PMID- 25550552 TI - Dendrofalconerol A suppresses migrating cancer cells via EMT and integrin proteins. AB - BACKGROUND/AIM: Enhanced cell motility is a hallmark of highly metastatic cancer cells. The anti-migratory activity of Dendrofalconerol A (DF-A), a pure bis(bibenzyls) isolated from the stem of Dendrobium falconeri (Orchidaceae) is reported in the present study. MATERIALS AND METHODS: Cytotoxicity effects of DF A on H460 lung cancer cells was determined by the MTT assay. We also investigated the mechanism of DF-A-mediated EMT and integrin proteins level by western blotting. RESULTS: DF-A at concentrations of 0.5-5 MUM significantly reduced the protein level of migrating cells in a dose-dependent manner. The expression of migration-related integrins, including integrin beta1 and integrin alpha4 was significantly reduced in response to DF-A treatment. Also, DF-A was shown to suppress epithelial to mesenchymal transition (EMT), as indicated by cadherin switch from N- to E-cadherin and decrease of Snail, Slug and vimentin. CONCLUSION: This study revealed the potential of DF-A, an anti-metastasis agent and the underlying mechanism in this in vitro assay with H460 cells, which leads to the development of a novel anti-metastatic agent. PMID- 25550553 TI - Comparative effects between fucoxanthinol and its precursor fucoxanthin on viability and apoptosis of breast cancer cell lines MCF-7 and MDA-MB-231. AB - BACKGROUND/AIM: We evaluated whether low doses of the natural carotenoid fucoxanthin and/or of its metabolite fucoxanthinol are effective against proliferation of estrogen-sensitive MCF-7 and estrogen-resistant MDA-MB-231 breast cancer cell lines. MATERIALS AND METHODS: These cell lines were stimulated with 10 to 20 MUM fucoxanthin and/or fucoxanthinol, followed by cell viability assays, Annexin V immunofluorescence to evaluate apoptosis, as well as mRNA and protein extractions for changes in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) members' expressions and nuclear translocations. RESULTS: Fucoxanthin and fucoxanthinol reduced the viability of MCF-7 and MDA-MB 231 cells in a time-dependent manner as a result of increased apoptosis. In both cell lines, modulatory actions of fucoxanthinol on members of the NF-kappaB pathway were more pronounced than that of fucoxanthin. CONCLUSION: In MDA-MB-231 cells, fucoxanthinol reduced nuclear levels of NF-kappaB members' p65, p52 and RelB. Fucoxanthinol and fucoxanthin could be effective for the treatment and/or prevention of breast cancer. PMID- 25550554 TI - Active estrogen synthesis and its function in prostate cancer-derived stromal cells. AB - BACKGROUND: It remains unclear whether estrogen is produced in prostate cancer (PCa) and how it functions in PCa. MATERIALS AND METHODS: To examine the production of estrogen in PCa cells, the concentration of estrogen in the medium in which LNCaP cells and PCa-derived stromal cells (PCaSC) were co-cultured, was measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), while aromatase (CYP19) mRNA expression was confirmed by real-time polymerase chain reaction (RT-PCR) methods. To verify whether estrogen is synthesized from testosterone in PCaSC functions, PCaSC were co-cultured with breast cancer MCF-7 E10 cells, which were stably-transfected with ERE-GFP, in the presence of testosterone. GFP expression was detected when PCaSCs could synthesize estrogen. The proliferation of PC-3 cells in the presence of PCaSC was determined by cell count. RESULTS: PCaSC metabolized excessive testosterone to estrogen, which activated estrogen receptor in breast cancer cells. Moreover, estrogen synthesized from testosterone in PCaSC regulated the proliferation of PC-3 cell via repression of some unknown growth factors that were secreted from PCaSC. CONCLUSION: A chimeric co-culture method between breast cancer cells and PCaSC revealed the production of active estrogen in PCaSC. High-dose testosterone therapy might introduce a new potential strategy to treat CRPC. PMID- 25550555 TI - Discovery of PAT-1102, a novel, potent and orally active histone deacetylase inhibitor with antitumor activity in cancer mouse models. AB - AIM: Histone deacetylase (HDAC) inhibitors are a class of drugs that modulate transcriptional activity in cells and are known to induce cell-cycle arrest and angiogenesis, the major components of tumor cell proliferation. The aim of the present study was to characterize a novel hydroxamic acid-based HDAC inhibitor, PAT-1102, and determine its efficacy and tolerability in pre-clinical models. MATERIALS AND METHODS: HDAC enzyme inhibition was measured using HeLa cell nuclear extracts, and recombinant HDAC enzymes. Antiproliferative activity was assessed in a panel of cancer cell lines. Histone hyper-acetylation status and p21 induction were assessed in HeLa cells by immunoblotting. The effect on apoptosis was tested by caspase-3 activation and detection of cleaved poly-ADP ribose polymerase (PARP). Single-dose pharmacokinetics of the compound were assessed in BALB/c mice following oral and intravenous administration. Antitumor efficacy was evaluated in tumor-bearing mice established from lung and colorectal cancer cells (A549 and HCT116, respectively). RESULTS: PAT-1102 demonstrated potent HDAC-inhibitory activity and growth-inhibitory properties against a panel of cancer cell lines. The optimized compound PAT-1102 exhibits good aqueous solubility, metabolic stability and a favorable pharmacokinetic profile. Once daily oral administration of PAT-1102 resulted in significant antitumor activity and was well-tolerated in mice. CONCLUSION: Our results indicate that PAT-1102 is a novel, potent, orally available HDAC inhibitor with antiproliferative activity against several human cancer cell lines and antitumor activity in mouse xenograft models. Based on the pre-clinical efficacy and safety profile of PAT-1102, the compound demonstrates significant potential for evaluation as a novel drug candidate for cancer therapy. PMID- 25550556 TI - Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer. AB - BACKGROUND/AIM: The expression of the CD44 variant exon 9 (CD44v9) was investigated in order to elucidate its significance for cancer stem cells in circulating human colorectal cancer cells (CTCs). MATERIALS AND METHODS: After peripheral blood was drawn from patients with colorectal cancer, CTCs were collected. Using the reverse transcription-polymerase chain reaction method, we examined the relationship between expression of CD44v9 mRNA and prognosis. RESULTS: In 60 out of 150 patients with colorectal cancer, expression of CD44v9 mRNA was positive in CTCs. In patients with stage III disease, the 5-year survival rate was 89% for patients with negative CD44v9 expression, whereas it was 52.4% in patients with positive expression (p<0.05). In patients with stage IV unresectable cancer, the 2-year survival rate was 70.1% in cases with CD44v9 negative expression and 33.3% in cases of positive expression (p<0.05). CONCLUSION: CD44v9 mRNA in the CTCs of colorectal cancer is useful as a factor predicting recurrence, prognosis, and treatment efficacy. PMID- 25550557 TI - Epidermal growth factor-induced cell death and radiosensitization in epidermal growth factor receptor-overexpressing cancer cell lines. AB - BACKGROUND/AIM: The aim of the present study was to suggest potential mechanisms of epidermal growth factor (EGF)-induced cell death and radiosensitization in EGF receptor (EGFR)-overexpressing cancer cell lines. MATERIALS AND METHODS: Two EGFR overexpressing cancer cell lines (AMC-HN3, and A431), one EGFR-null cancer cell line (H520) and normal fibroblasts were cultured with 0.01-1000 nM of recombinant human EGF (rhEGF), and a clonogenic assay was performed. After culturing serum starved cells with 10 nM rhEGF, the expression patterns of two apoptosis associated proteins (cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP)) and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway were measured using immunoblotting. The radiosensitizing effect of EGF was also evaluated with a clonogenic assay and phosphorylated H2AX (gammaH2AX) immunofluorescence. RESULTS: In the clonogenic assay, the number of colonies was decreased in a dose-dependent manner in EGFR overexpressing cancer cell lines. The expression of cleaved caspase-3 and cleaved PARP was significantly induced in EGFR-overexpressing cancer cell lines. As for the PI3K/AKT/mTOR signaling pathway, EGF paradoxically suppressed the expression of PI3K, AKT and mTOR in a time-dependent manner. As for the radiosensitizing effect, EGF enhanced the radiosensitivity of AMC-HN3 and A431 cells. CONCLUSION: rhEGF treatment induced cell death in the two EGFR-overexpressing cancer cell lines, and the mode of cell death was apoptosis. Moreover, cell death might be associated with the paradoxical suppression of PI3K/AKT/mTOR signaling pathway. rhEGF in combination with radiation augmented the radiation effect in EGFR overexpressing cancer cell lines via inhibition of DNA damage repair. PMID- 25550558 TI - Determination of gene expression and serum levels of MnSOD and GPX1 in colorectal cancer. AB - BACKGROUND/AIM: Oxidative stress plays a role on the development of colorectal cancer. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPX1) are crucial in regulating oxidative balance and its stabilization. Possible mechanisms of action of these enzymes in various types of cancers require further investigation. We aimed to determine expression levels of these genes and their effects on protein levels in serum of patients with colorectal cancer. MATERIALS AND METHODS: Expression levels of genes were determined using Real Time-Polymerase chain reaction in 35 patients with colorectal cancer. We used enzyme-linked immunosorbent assay to determine MnSOD and GPX1 levels. RESULTS: We found significant differences in GPX1 expression between tumor and normal tissues, with a 2-fold decrease in tumor tissues (p<0.05). However, although no significant difference was found between the expression of MnSOD gene in tumor and that in normal tissues, there was a 1.13-fold change in expression. We observed no relationship between expressions of either gene and their levels in serum. CONCLUSION: The GPX1 gene may play a critical role in the development of colorectal cancer. PMID- 25550559 TI - FOXD1 expression is associated with poor prognosis in non-small cell lung cancer. AB - AIM: Clinical microarray datasets were analyzed to search for new therapeutic targets and prognostic markers of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Microarray datasets from 90 lung cancer specimens, were analyzed with focus on the FOXD1 gene. Levels of FOXD1 mRNA were assessed in lung cancer cell lines and these levels were correlated with survival. RESULTS: FOXD1 knockdown led to suppression of cell proliferation. Moreover, patients with high FOXD1 expression survived for a significantly shorter time than those with low FOXD1 expression. CONCLUSION: The expression status of FOXD1 is a novel prognostic factor and may lead to new treatment strategies for NSCLC. PMID- 25550560 TI - Akt1 rs2498801 is related to survival in head and neck squamous cell cancer treated with radiotherapy. AB - BACKGROUND: Radiotherapy (RT) with or without chemotherapy (CT) plays an important role as exclusive treatment in patients with head and neck squamous cell cancer (HNSCC). Unfortunately, in some cases, benefit for patients is not recorded and only treatment-related complications are registered. MATERIALS AND METHODS: Data relating to Akt1 single nucleotide polymorphism (SNP) and response to treatment of 46 patients treated with exclusive RT or RT-CT for HNSCC were evaluated. RESULTS: For heterozygous patients median overall survival was 28.5 months, while for the wild-type group median overall survival was 10.9 (p=0.019). Three-year survival was 85% for mutated Akt1 homozygosis and 40% for patients with a heterozygous status (p=0.019, hazard ratio (HR)=7.960). CONCLUSION: SNP of rs2498804 can recognize patients resistant to RT-CT. Further studies are needed to confirm our data and to investigate the role of Akt SNPs in HNSCC patients. PMID- 25550561 TI - Resveratrol at anti-angiogenesis/anticancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs. AB - BACKGROUND: Resveratrol increases nitric oxide (NO) production via increased expression and activation of endothelial-form-NO-synthase (eNOS) in endothelial cells. However, the role of downstream cGMP/protein kinase G (PKG) signaling, a pathway activated by NO/eNOS, in pro- and anti-angiogenic effects of resveratrol is still unclear. MATERIALS AND METHODS: Endogenous NO/cGMP/PKG pathway and downstream cell-survival proteins (Inhibitor of Apoptosis Proteins, IAPs) were studied in relation to pro- and anti-angiogenic effects of resveratrol in human umbilical vein endothelial cells (HUVECs). RESULTS: Resveratrol at higher/anti angiogenic concentrations inhibits HUVEC tube formation and cell migration/invasion (indices of angiogenesis). Resveratrol at lower concentrations stimulates proliferation and protects HUVECs against spontaneous apoptosis. 8-Br cGMP, a direct activator of PKG, protects against pro-apoptotic effects of high concentration resveratrol. Western blot analyses showed that anti-angiogenic concentrations of resveratrol suppress endogenous PKG kinase activity and decrease the expression of four cell-survival proteins, c-IAP1, c-IAP2, livin and XIAP. CONCLUSION: Resveratrol-induced anti-angiogenesis/pro-apoptosis induced suppression of PKG signaling and decreased expression of the cell-survival proteins c-IAP1, c-IAP2, livin and XIAP. PMID- 25550562 TI - Anticancer effects of brominated indole alkaloid Eudistomin H from marine ascidian Eudistoma viride against cervical cancer cells (HeLa). AB - Marine invertebrates called ascidians are prolific producers of bioactive substances. The ascidian Eudistoma viride, distributed along the Southeast coast of India, was investigated for its in vitro cytotoxic activity against human cervical carcinoma (HeLa) cells by the MTT assay. The crude methanolic extract of E. viride, with an IC50 of 53 MUg/ml, was dose-dependently cytotoxic. It was more potent at 100 MUg/ml than cyclohexamide (1 MUg/ml), reducing cell viability to 9.2%. Among nine fractions separated by chromatography, ECF-8 exhibited prominent cytoxic activity at 10 MUg/ml. The HPLC fraction EHF-21 of ECF-8 was remarkably dose- and time-dependently cytotoxic, with 39.8% viable cells at 1 MUg/ml compared to 51% in cyclohexamide-treated cells at the same concentration; the IC50 was 0.49 MUg/ml. Hoechst staining of HeLa cells treated with EHF-21 at 0.5 MUg/ml revealed apoptotic events such an cell shrinkage, membrane blebbing, chromatin condensation and formation of apoptotic bodies. Cell size and granularity study showed changes in light scatter, indicating the characteristic feature of cells dying by apoptosis. The cell-cycle analysis of HeLa cells treated with fraction EHF-21 at 1 MUg/ml showed the marked arrest of cells in G0/G1, S and G2/M phases and an increase in the sub G0/G1 population indicated an increase in the apoptotic cell population. The statistical analysis of the sub-G1 region showed a dose-dependent induction of apoptosis. DNA fragmentation was also observed in HeLa cells treated with EHF-21. The active EHF-21 fraction, a brominated indole alkaloid Eudistomin H, led to apoptotic death of HeLa cells. PMID- 25550563 TI - Urological procedures in patients with peritoneal carcinomatosis of colorectal cancer treated with HIPEC: morbidity and survival analysis. AB - AIM: To investigate whether cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is a feasible and effective option for patients with urological involvement of peritoneal carcinomatosis from colorectal cancer (CRC-PC). PATIENTS AND METHODS: The characteristics of patients with CRC PC treated with CRS+HIPEC, with or without a urological procedure, between April 2005 and June 2013 in two tertiary Centres were analyzed. RESULTS: Thirty-eight patients (14%) out of 267 CRC-PC patients treated with CRS+HIPEC had a urological procedure during cytoreduction. The median survival was not significantly different between patients with or without a urological procedure (26.9 versus 32.1 months, p=0.29). Severe complications occurred more in patients with a urological procedure (47% versus 20%, p<0.001). In patients with a urological procedure, the most frequent complications were gastrointestinal leakage (n=9) and intra-abdominal abscess formation (n=5). CONCLUSION: Urological resections as a part of CRS+HIPEC in patients with peritoneal carcinomatosis of colorectal origin are feasible and effective. Severe complications are prevalent in these patients but survival is comparable to patients without involvement of the urinary system. PMID- 25550564 TI - Prognostic significance of microscopic tumor burden in sentinel lymph node in patients with cutaneous melanoma. AB - BACKGROUND/AIM: Sentinel lymph node (SLN) biopsy provides useful prognostic information for patients with melanoma. The present study sought to determine the prognostic value of SLN tumor burden on overall survival (OS) and disease-free survival (DFS). We also assessed its association with non-sentinel lympth node (NSLN) involvement. PATIENTS AND METHODS: We conducted a retrospective review of 138 patients with cutaneous melanoma, who were found to have positive SLNs from 2000 to 2011. SLN tumor burden was measured in the maximum diameter of the largest tumor focus. OS and DFS were assessed by the Kaplan-Meier method and Cox proportional hazard regression model. A logistic regression model was used to evaluate the association between SLN tumor burden and NSLN positivity. RESULTS: On multivariable analysis, SLN tumor burden was significantly associated with OS (hazard ratio (HR)>1 vs. <= 1 mm=5.15; 95% confidence interval (CI)=2.32-11.44; p<0.0001) and DFS rate (HR>1 vs. <= 1 mm=3.02; 95% CI=1.37-6.67; p=0.0064). On univariate analysis, SLN tumor burden was significantly associated with NSLN positivity (OR>1 vs. <= 1 mm=3.41; 95% CI=1.03-11.27; p=0.04). CONCLUSION: SLN tumor burden, by measuring the maximum diameter of the largest tumor focus, is significantly associated with OS, DFS and NSLN involvement. PMID- 25550565 TI - Presence of CD3-positive T-cells in oral premalignant leukoplakia indicates prevention of cancer transformation. AB - AIM: Leukoplakias (LPLs) are lesions in the oral mucosa that have a potential to transform into oral squamous cell carcinoma (OSCC). As the degree of immunosurveillance may be important for this transformation to occur, the aim of this study was to determine the presence of immune cells in LPLs with dysplasia in relation to later development of OSCC. MATERIALS AND METHODS: Biopsies from 16 patients with clinical diagnosis of LPL and histopathological diagnosis of hyperkeratosis with dysplasia were immunostained with antibodies to detect CD3(+) T cells, CD1a(+) LCs, Ki-67(+) and p53-expressing cells. Patients were divided into two groups: LPL with dysplasia that transformed into OSCC (LPL-dys) and that which did not (LPL-ca). RESULTS: Quantitative analyses showed significantly lower numbers of CD3(+) T-cells in LPL-ca than in LPL-dys. No significant differences were detected when comparing LPL-dys and LPL-ca regarding CD1a(+), p53(+) and Ki 67(+) cells. CONCLUSION: The number of CD3-expressing T-cells may be important for preventing malignant transformation of LPL. PMID- 25550566 TI - CT-guided brachytherapy as salvage therapy for intrahepatic recurrence of HCC after surgical resection. AB - AIM: Prevalence of patients with unresectable recurrence of hepatocellular carcinoma (HCC) after previous resection is rising. The purpose of this study was to determine survival of patients undergoing computed tomography-guided brachytherapy (CT-HDRBT). PATIENTS AND METHODS: Altogether 19 patients with unresectable HCC recurrence were treated with CT-HDRBT at our Institution. Patients underwent single-fraction high-dose irradiation by an iridium-192 source after CT fluoroscopy-guided catheter placement. The median tumor-enclosing target dose was 20 Gy. RESULTS: The median follow-up was 33 months. According to the Kaplan-Meier method, median overall survival after CT-HDRBT was 50 months, and median survival after first hepatic resection was 87 months. The median duration of local tumor control was 32 months and time to disease progression was 20 months. There were no serious complications after CT-HDRBT and no treatment related deaths. CONCLUSION: CT-HDRBT is a safe, potentially life prolonging technique in patients with recurrence of HCC who have few therapeutic options. PMID- 25550567 TI - Single hepatocellular carcinoma smaller than 2 cm: are ethanol injection and radiofrequency ablation equally effective? AB - BACKGROUND/AIM: The impact of radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) on survival in patients with small hepatocellular carcinoma (HCC) is unclear. We compared their efficacy in cirrhotics with single HCC <=2 cm. PATIENTS AND METHODS: Two hundred forty-four cirrhotics with single HCC <=2 cm treated with PEI (108 cases) or RFA (136 cases) were enrolled in the study. Eighty-one patients in each group were selected for propensity score matching analysis. RESULTS: The five-year survival was not significantly different (64.7% in PEI and 72.9% in RFA group) but the 5-year recurrence (73.3% in PEI and 49% in RFA group, p=0.023) and local tumor progression (49% in PEI and 30.1% in RFA group, p=0.018) were higher in the PEI group. CONCLUSION: PEI and RFA are equally effective in treating HCCs smaller than 2 cm in terms of 5-year survival, despite higher cumulative and local recurrence rates, in patients treated with PEI. PMID- 25550569 TI - Pre-treatment neutrophil to lymphocyte ratio is a predictor of prognosis in endometrial cancer. AB - BACKGROUND/AIM: Inflammation and tumor immunology are important in the prognosis of various cancers. We herein investigated whether pre-treatment neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and serum cancer antigen 125 (CA125) predict recurrence and survival in patients with endometrial cancer (EC). PATIENTS AND METHODS: We collected complete blood counts and clinicopathological data from medical records of 320 patients with EC; their pre treatment NLR, PLR and CA125 were analyzed for correlations with recurrence and survival, retrospectively. RESULTS: Disease-free survival (DFS) and overall survival (OS) rates of patients with high NLR and CA125 were significantly shorter than those for patients with low NLR and CA125 (DFS: p=0.002 and p<0.001; OS: p<0.001 and p<0.001, respectively). Furthermore, NLR was also an independent predictive factor for mortality in multivariate analysis (hazard ratio (HR)=3.318; 95% confidence interval (CI)=1.154-9.538; p=0.026). CONCLUSION: Pre treatment NLR is a predictor of poor prognosis in EC. PMID- 25550568 TI - Radiosurgery with 20 Gy provides better local contol of 1-3 brain metastases from breast cancer than with lower doses. AB - AIM: To determine the optimal dose of radiosurgery-alone for patients with 1-3 cerebral metastases from breast cancer. PATIENTS AND METHODS: Patients receiving 20 Gy (n=20) were compared to those receiving 16-18.5 Gy (n=10) for local control, distant brain control and overall survival. Seven other variables were also evaluated. RESULTS: Radiosurgery dose achieved significance on univariate (p=0.002; log-rank and Wilcoxon test) and multivariate analysis (p=0.004) of local control. Twelve-month local control rates were 94% after 20 Gy and 48% after 16-18.5 Gy. On univariate analysis of distant brain control, radiosurgery dose was not a significant factor, with 12-month rates of 73% and 60%, respectively. Regarding overall survival, radiosurgery dose was of borderline significance (p=0.059; Wilcoxon test). Twelve-month overall survival rates were 75% and 40%, respectively. On Cox regression analysis, radiosurgery dose exhibited a trend for improving survival (p=0.10). CONCLUSION: Radiosurgery with 20 Gy resulted in significantly better local control and led to a trend towards improved overall survival compared to treatment with 16-18.5 Gy. PMID- 25550570 TI - Immunohistochemical, cytogenetic, and molecular cytogenetic characterization of both components of a dedifferentiated liposarcoma: implications for histogenesis. AB - Dedifferentiated liposarcoma (DDLS) is a malignant adipocytic tumor showing transition from an atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLS) to a non-lipogenic sarcoma of variable histological grades. We present the immunohistochemical, cytogenetic, and molecular cytogenetic findings of DDLS arising in the right chest wall of a 76-year-old man. Magnetic resonance imaging exhibited a large mass composed of two components with heterogeneous signal intensities, suggesting the coexistence of a fatty area and another soft tissue component. The grossly heterogeneous mass was histologically composed of an ALT/WDLS component transitioning abruptly into a dedifferentiated component. Immunohistochemistry was positive for murine double-minute 2 (MDM2), cyclin dependent kinase 4 (CDK4), and p16 in both components, although a more strong and diffuse staining was found in the dedifferentiated area. The MIB-1 labeling index was extremely higher in the dedifferentiated area compared to the ALT/WDLS area. Cytogenetic analysis of the ALT/WDLS component revealed the following karyotype: 46,X,-Y,+r. Notably, cytogenetic analysis of the dedifferentiated component revealed a similar but more complex karyotype. Spectral karyotyping demonstrated that the ring chromosome was entirely composed of material from chromosome 12. Interphase fluorescence in situ hybridization analysis revealed amplification of MDM2 and CDK4 in both components. These findings suggest that multiple abnormal clones derived from a single precursor cell would be present in DDLS, with one or more containing supernumerary rings or giant marker chromosomes. PMID- 25550571 TI - Paucity of tumor-infiltrating lymphocytes is an unfavorable prognosticator and predicts lymph node metastases in cutaneous melanoma patients. AB - BACKGROUND/AIM: Tumor infiltrating lymphocytes (TILs) have been a subject of growing scientific interest; however, a full picture of their role in cancer pathogenesis is still unclear. The present study aimed to reveal correlations between TIL grade and clinicopathological features, especially 5-year survival parameters in cutaneous malignant melanoma (CMM) patients. MATERIALS AND METHODS: Presence of TILs was assessed by hematoxylin and eosin staining in routine diagnostic histopathological specimens from 104 patients with cutaneous melanoma. RESULTS: In the entire group of 104 patients, decreasing TIL intensity was a highly negative prognostic factor and indicated considerably shorter overall survival (OS), cancer-specific overall survival (CSOS) and disease-free survival (DFS). We also report on a significant association between decreased TIL intensity and worse prognosis in lymph node-negative patients. Shorter survival (p=0.002 for OS, p=0.038 for CSOS and p=0.011 for DFS) was observed in patients with negative sentinel lymph node biopsies (SLNB), as well as in patients with lack of metastases in regional lymph nodes (p=0.034 for OS, p<0.001 for CSOS and DFS). CONCLUSION: Our results indicate that TIL grade is a valuable diagnostic parameter that may be helpful in risk stratification in CMM. PMID- 25550572 TI - Usefulness of duloxetine for Paclitaxel-induced peripheral neuropathy treatment in gynecological cancer patients. AB - AIM: The present study aimed at evaluating the usefulness and adverse effects of duloxetine treatment for paclitaxel-induced peripheral neuropathy in gynecological cancer patients. PATIENTS AND METHODS: Medical records of gynecological cancer patients treated with duloxetine were retrospectively studied to evaluate the drug's efficacy for paclitaxel-induced peripheral neuropathy. RESULTS: RESULTS from 25 patients showed that an improved response was observed in 14 (56%). By univariate and multivariate analysis, the patient's age, tumor origin, regimen of chemotherapy, accumulated doses of paclitaxel or carboplatin, previous medication, maintenance dosage and timing of treatment with duloxetine were found not to be associated with the effectiveness of duloxetine treatment. Adverse effects with duloxetine were mild and well-tolerated. CONCLUSION: As an option, duloxetine can be effectively used for paclitaxel induced peripheral neuropathy in patients with gynecological cancers, irrespective of patients' age, origin of the tumor, regimen of chemotherapy, or previous medication. PMID- 25550573 TI - Impact of adjuvant pelvic radiotherapy in stage I uterine sarcoma. AB - BACKGROUND/AIM: The optimal adjuvant therapy for stage I uterine sarcoma remains unresolved and may consist of radiotherapy (RT), chemotherapy, hormonal therapy or observation. We analyzed the impact of adjuvant pelvic RT on overall survival (OS), cause-specific survival (CSS), disease-free survival (DFS), pelvic control (PC) and patterns of failure. PATIENTS AND METHODS: A retrospective analysis of 157 patients with International Federation of Gynecology and Obstetrics FIGO stage I uterine sarcoma was performed. RT was given postoperatively to a dose of 45-51 Gy in 28-30 fractions. RESULTS: The 5-year OS, CSS, DFS and PC was 58%, 62%, 47% and 72%, respectively. Adjuvant RT significantly improved PC (85% for RT group vs. 64% for non-RT group; p=0.02) but did not impact OS, CSS or DFS. CONCLUSION: The addition of adjuvant pelvic RT significantly improved PC for patients with stage I uterine sarcoma. As systemic therapies continue to improve, optimal locoregional control may result in improved patient outcomes. PMID- 25550574 TI - Reduced dose of salvage-line regorafenib monotherapy for metastatic colorectal cancer in Japan. AB - BACKGROUND: Salvage-line regorafenib monotherapy exhibited a marked survival benefit for metastatic colorectal cancer (mCRC). However, the toxicity of this regimen has resulted in the clinical use of a reduced dose of regorafenib. PATIENTS AND METHODS: Thirty-two Japanese mCRC patients (median age=61 years) who had been treated with regorafenib were retrospectively examined. RESULTS: Best objective response rate was 0% and stable disease (SD) was 31%. Median progression-free survival was 81 days and median overall survival was 233 days. Adverse events of any grade were observed in all patients: 17 (53%) patients suffered grade 3 or 4 adverse events including fatigue (13%), anorexia (13%), hand-foot skin reaction (22%) and elevations of alanine aminotransferase/aspartate aminotransferase (19%/16%). One patient with grade 5 liver dysfunction was identified (3%). Twenty-nine (91%) patients required treatment dose reduction or a delay in treatment. The relative dose intensity was 59%. Regorafenib treatments were terminated because of disease progression (59%) or adverse events (34%). CONCLUSION: Despite a decrease in the intensity of regorafenib treatment, because of severe adverse events, a fairly favorable efficacy was achieved in Japanese patients. PMID- 25550575 TI - Differential impact of fosaprepitant on infusion site adverse events between cisplatin- and anthracycline-based chemotherapy regimens. AB - BACKGROUND: Fosaprepitant may be associated with infusion site adverse events (AEs), and these adverse events possibly vary according to chemotherapy regimen. PATIENTS AND METHODS: 267 oncology patients who were administered anthracycline- or cisplatin-based regimens were retrospectively studied. Multivariate logistic regression was performed in stratified analyses to evaluate potential regimen specific effects of fosaprepitant. RESULTS: 41.7% of patients administered fosaprepitant experienced infusion site AEs. On the other hand, only 10.9% of patients administered aprepitant experienced AEs. Multivariate analysis showed a statistically significant overall increased risk of infusion site reaction associated with fosaprepitant (p<0.001), but when evaluated separately according to chemotherapy regimen, this relationship appeared to be largely confined to patients receiving an anthracycline-based regimen (OR=12.95, 95%CI=5.74-29.20). No association was observed among patients on cisplatin-based regimens. A test for interaction was statistically significant (p=0.001). CONCLUSION: Fosaprepitant is associated with an elevated risk of infusion site reaction in patients receiving anthracyclines. PMID- 25550576 TI - Predicting survival of patients with metastatic epidural spinal cord compression from cancer of the head-and-neck. AB - AIM: To develop an instrument for estimating survival after irradiation for metastatic epidural spinal cord compression (MESCC) from head and neck cancer. PATIENTS AND METHODS: In 58 patients, eleven factors were evaluated for influence on survival: age, gender, performance status, tumor site, time from cancer diagnosis until MESCC, affected vertebrae, walking ability, further osseous lesions, organ metastases, time developing motor deficits and radiation regimen. Factors with significant association with survival or a trend (multivariate analysis) were used for scoring. RESULTS: Walking ability, visceral metastases and time to developing motor deficits were included in the score. Scoring points were calculated by dividing 6-month survival rates by 10. Patients' scores were obtained from adding the points of the three factors. Four groups were created, 7 10, 12-15, 16-18 and 21 points. Six-month survival rates were 0%, 27%, 71% and 100% (p<0.001). CONCLUSION: With this new instrument, one can estimate 6-month survival probabilities of patients with MESCC from head-and-neck cancer. PMID- 25550577 TI - Comparative analysis of tumor angiogenesis and clinical features of 55 cases of pleomorphic carcinoma and adenocarcinoma of the lung. AB - BACKGROUND/AIM: Pleomorphic carcinoma (PC) of the lung is a rare tumor that usually has an aggressive clinical course and a poor prognosis. Clinical and pathological features remain unclear. The aim of this study was to determine whether tumor angiogenesis of PC is up-regulated compared to that in adenocarcinoma (AD). MATERIALS AND METHODS: We collected 55 cases of PC and AD in which the patients had undergone either lung resection or autopsy and immunohistochemically examined the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1alpha and microvessel density (MVD) in tissue specimens. RESULTS: VEGF was expressed in many cases of both PC and AD with no significant differences between the groups. In contrast, the expression of HIF-1alpha and MVD were significantly greater in PC than AD. Median survival time of the PC group was 14.7 months and significantly shorter than that of the AD group. CONCLUSION: MVD and expression of HIF-1alpha are associated with angiogenesis in PC and confer a poorer prognosis. Tumor angiogenesis provides significant prognostic information regarding clinical outcome in patients with PC. PMID- 25550578 TI - Multiparametric pelvic MRI accuracy in diagnosing clinically significant prostate cancer in the reevaluation of biopsy microfocal tumor. AB - AIM: To evaluate the accuracy of multi-parametric pelvic magnetic resonance imaging (mpMRI) in diagnosing prostate cancer (PCa) in men with initial biopsy microfocal cancer. PATIENTS AND METHODS: From January 2012 to July 2014, 40 patients before undergoing repeat transperineal saturation prostate biopsy (SPBx; median, 28 cores) for the presence of a microfocal PCa were submitted to 3.0 Tesla mpMRI. RESULTS: A T1c clinical stage PCa was found in 23 (57.5%) patients submitted to SPBx; mpMRI was positive in 16/40 (40%) cases and in 11 of them a clinically significant PCa was found. On the contrary, the 12 men with negative mpMRI had a quantitative histology suitable for clinically insignificant cancer. Diagnostic accuracy of mpMRI in diagnosing significant PCa was equal to 100%. CONCLUSION: Multi-parametric pMRI should be suggested in the re-evaluation of microfocal cancer as a selection approach of patients at risk for clinically significant PCa. PMID- 25550579 TI - Clinical significance of adjuvant surgery following chemotherapy for patients with initially unresectable stage IV gastric cancer. AB - BACKGROUND: More effective treatment is necessary to improve the poor prognosis for patients with unresectable gastric cancer. We investigated the efficacy and feasibility of adjuvant surgery following chemotherapy. PATIENTS AND METHODS: Records of 70 patients with unresectable stage IV gastric cancer who underwent induction chemotherapy were reviewed retrospectively. Patients who developed an absence of non-curative clinical factors during chemotherapy underwent gastrectomy [adjuvant surgery (AS) group]; the others continued chemotherapy [non AS group]. RESULTS: Non-AS and AS groups contained 56 (80%) and 14 (20%) patients, respectively. In the AS group, 92.9% of patients had one non-curative clinical factor, while 48.2% of patients in the non-AS group had two or more non curative clinical factors (p=0.0386). In the AS group, operative outcomes, including the postoperative complication rate (21.4%), were acceptable. The 3 year overall survival rate in the AS group was 65.6% versus 7.7% in the non-AS group (p<0.0001). In patients with one non-curative clinical factor of peritoneal dissemination, the median survival of the AS group was 29.5 months versus 11.4 months in the non-AS group (p=0.0230). CONCLUSION: Adjuvant surgery for initially unresectable stage IV gastric cancer was safe and feasible, and may improve the prognosis for patients with one non-curative clinical factor, such as peritoneal dissemination. PMID- 25550580 TI - Cardiac tamponade due to bleeding as a potential lethal complication after surgery for esophageal cancer. AB - BACKGROUND: Cardiac tamponade, due to bleeding in the pericardial space after esophagectomy for esophageal cancer, is an extremely rare complication and may be associated with sudden hemodynamic instability that can lead to death unless there is prompt diagnosis and appropriate treatment. CASE REPORT: A 76-year-old man underwent sub-total esophagectomy via a cervico-right thoracoabdominal approach and reconstruction with a gastric tube through the retrosternal route. On postoperative day 4, the patient developed hypotension due to cardiac tamponade caused by bleeding into the pericardial space and he had a decreased level of consciousness. Pericardial resection and open drainage via a minimal left anterior thoracotomy was performed that resulted in hemodynamic improvement followed by an uneventful recovery. CONCLUSION: Cardiac tamponade due to postoperative bleeding, which is a rare but life-threatening complication, should be considered as a cause of hemodynamic instability in the early postoperative period after esophagectomy. PMID- 25550581 TI - Expression of hepatocyte growth factor in prostate cancer may indicate a biochemical recurrence after radical prostatectomy. AB - We previously found that prostate cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) express hepatocyte growth factor (HGF) and that the HGF/c-MET proto oncogene product (c-MET) signal has a role in the maintenance of prostate CSCs/CICs in an autocrine fashion. HGF is, thus, a novel marker for prostate CSCs/CICs. We hypothesized that high expression of HGF might be related to early recurrence of prostate cancer after radical prostatectomy, and the purpose of the present study was to evaluate the relationship between expression of HGF in prostate tissues and biochemical recurrence after radical prostatectomy. One hundred-one patients with prostate cancer who underwent open or laparoscopic radical prostatectomy from November 2008 to October 2011 with an adequate prostate-specific antigen (PSA) follow-up period, were investigated. Immunohistochemical staining of HGF was compared to biochemical recurrence after radical prostatectomy. Patients with tumors exhibiting HGF positivity of 5% or more had a significantly shorter biochemical recurrence-free period than that of patients whose tumor HGF positivity was less than 5% (p=0.001). In multivariate Cox regression, preoperative PSA and HGF positivity were independent predictors of biochemical recurrence following prostatectomy. Our finding suggests a direct link between expression of HGF, a novel prostate marker of CSCs/CICs, and biochemical recurrence after radical prostatectomy in patients with prostate cancer. PMID- 25550582 TI - Benefit of neoadjuvant chemotherapy for Siewert type II esophagogastric junction adenocarcinoma. AB - AIM: Our objective was to clarify if preoperative chemotherapy was associated with improved survival in Japanese patients with Siewert type II adenocarcinoma of the esophagogastric junction. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 86 patients with Siewert type II adenocarcinoma who underwent R0 resection at the Kitasato University between 1997 and 2013. Cox regression analysis using a backward stepwise selection method was performed to identify independent prognostic factors for relapse-free survival (RFS). RESULTS: The median age was 67 years. The male:female ratio was 74:12. Right thoracic, left thoracic and transhiatal approaches were performed in 10, 10 and 66 patients, respectively, and perioperative transfusion in 16 patients. Preoperative chemotherapy was administered to 19 patients; out of these, 13 received chemotherapy using the DCS regimen (docetaxel 40 mg/m(2), day 1; cisplatin 60 mg/m(2), day 1; S-1 80-120 mg/body, days 1-14; every 28 days). A median of three cycles of preoperative DCS chemotherapy were used. Histological responses of 1b, 2, 3 and unknown grades were obtained in three, three, four and three patients, respectively. The 5-year RFS rate was 55%, and the median follow up period was 36 months. Cox regression analysis regarding RFS identified (y)pN1 3 [hazard ratio (HR)=4.44; 95% confidence interval (CI)=1.98-11.27], performance of perioperative transfusion (HR=4.71; 95% CI=1.69-11.88) and no preoperative chemotherapy (HR=3.75; 95% CI=1.22-14.26) as significant and independent indicators of poor prognosis. CONCLUSION: Preoperative chemotherapy using DCS is potentially beneficial for Japanese patients with Siewert type II adenocarcinoma. Further prospective clinical studies are required to confirm our findings. PMID- 25550583 TI - Surgical treatment of metastatic femoral fractures: achieving an improved quality of life for cancer patients. AB - BACKGROUND: The femur is the most common long bone affected by metastatic carcinoma. We report our experience regarding treatment of metastatic femoral fracture using femoral head prosthesis (FHP) or intramedullary nailing (IM nail) with augmentation by polymethylmethacrylate (PMMA). PATIENTS AND METHODS: Thirty five complete fractures in 33 patients were treated surgically. Metastatic lesions were present in the femoral head to neck region (n=9), trochanteric to shaft region (n=23) and supracondular region (n=3). RESULTS: Eight out of 9 patients with proximal femoral metastasis reconstructed by FHP were later able to walk outdoors. For the 11 patients with trochanteric metastasis, the short type of gamma nail was used for bony fixation. In two patients the inserted IM nails were broken. All other cases showed excellent clinical outcomes. For the 12 patients with femoral shaft metastasis, the long type of gamma nail was inserted. Nine cases showed excellent clinical outcomes without any serious complications. CONCLUSION: FHP is indicated for metastases in the femoral head to neck region. IM nailing is best indicated when the lesion is located in the proximal to mid shaft and the patient's life expectancy is <6 month. PMID- 25550584 TI - Survival in patients with clear cell renal cell carcinoma is predicted by HIF 1alpha expression. AB - AIM: To investigate hypoxia inducible factor-1alpha's (HIF-1alpha) immunohistochemical expression in clear cell renal cell carcinoma (ccRCC) treated with radical nephrectomy. PATIENTS AND METHODS: One hundred and forty-eight patients were considered from those who underwent radical nephrectomy between 1983 and 1993. Archived materials were retrieved from the Institute of Pathological Anatomy for immunostaining. The features considered on the histological specimens were tumor stage, grade, as well as cellular and vascular HIF-1alpha expression. All considered parameters were correlated with time to recurrence (TTR) and overall survival (OS). RESULTS: TTR was significantly longer in patients with low cellular HIF-1alpha expression; patients' survival was higher in those with low HIF-1alpha expression. Regarding vascular HIF-1alpha expression, the differences were not statistically significant when considering TTR and OS. On univariate analysis, age, clinical stage and HIF-1alpha cellular expression showed a significant association with OS. CONCLUSION: Cellular HIF 1alpha is an important indicator of prognosis in patients with ccRCC; high HIF 1alpha expression predicts poor survival. PMID- 25550585 TI - Deregulation of glyceraldehyde-3-phosphate dehydrogenase expression during tumor progression of human cutaneous melanoma. AB - BACKGROUND/AIM: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a highly abundant housekeeping gene. GAPDH overexpression has been reported in diverse types of human cancers including cutaneous melanoma. Our goal was to quantify GAPDH mRNA and protein expression in the whole spectrum of primary and metastatic melanomas in the search for a specific role for this ubiquitous molecule during tumor progression. MATERIALS AND METHODS: Intratumoral GAPDH mRNA expression was quantified by real-time PCR in 71 cases, including 29 primary melanomas and 42 metastatic cases. Relative expression levels in thin (<=1 mm) and thick (>1 mm) primary tumors and 'in-transit', lymph node and distant metastases were compared. Similarly, protein expression was investigated by means of immunohistochemistry. Specific exons of GAPDH were analyzed by DNA sequencing. RESULTS: GAPDH mRNA expression was significantly up-regulated in thick melanomas when compared to primary thin melanomas. Similar differences were also encountered between metastatic melanomas when compared to lymph-node metastatic melanomas. Interestingly, GAPDH protein immunoexpression was higher in thick melanomas and distant metastases than in thin tumors and lymph node metastases, respectively. However, no specific point-mutations in GAPDH-specific exons were found in any patient. CONCLUSION: Deregulation of GAPDH during melanoma progression was demonstrated in our series by mRNA and protein expression studies. PMID- 25550586 TI - Impact of lower mediastinal lymphadenectomy for the treatment of esophagogastric junction carcinoma. AB - AIM: To define the optimal extent of resection for esophagogastric junction (EGJ) carcinoma. PATIENTS AND METHODS: We retrospectively reviewed medical records of 193 patients with EGJ adenocarcinoma or squamous cell carcinoma who underwent surgery at the Kitasato University. An index was calculated to evaluate the therapeutic value of lymphadenectomy. RESULTS: The following factors were identified as independent predictors of poor survival: (y)pT3-4, (y)pN3, ly2-3, no performance of splenectomy and R1-2. Although metastases were found in mediastinal lymph-nodes in patients with esophageal invasion of <=30 mm, the index was 0 for all mediastinal lymph-nodes. By contrast, in patients with esophageal invasion of >30 mm, the index was 13.9 for the No. 110 nodes, which was the second highest after the index for the No. 1 nodes. CONCLUSION: In EGJ cancer patients with esophageal invasion of >30 mm, aggressive lower mediastinal lymphadenectomy with R0 resection is required to obtain the best result. PMID- 25550587 TI - Impact of clinical pharmacy services in a hematology/oncology inpatient setting. AB - BACKGROUND/AIM: Clinical pharmacists are contributing to safe medication use by providing comprehensive management to patients and medical staff. However, little is known regarding their impact in oncology. The aim of this study was to document and evaluate the role of clinical pharmacy services in a hematology/oncology department. PATIENTS AND METHODS: A prospective, descriptive, observational study was carried out from May 2012 to May 2013. Medication reviews concerning hospitalized adult cancer patients were performed twice a week. Medication problems, pharmaceutical interventions and acceptance rate by the oncologists were recorded by a clinical pharmacist. RESULTS: A total of 4,393 prescriptions (including chemotherapy and support) of 489 adult cancer patients (mean age=63 years) were analyzed. The pharmacist identified 552 drug-related problems (12.6% of the prescriptions) primarily related to anti-infective agents (59.5%). Medication problems included inappropriate medications (20.6%), untreated indications (14.8%), inappropriate administrations (14.1%), underdosing (11.7%), drug-drug interactions (14.3%), lack of monitoring (9.6%), overdosing (8.9%), administration omissions (3.5%) and side-effects (2.5%). Interventions (n=552) led to treatment discontinuation (26.2%), drug dosing adjustments (21.5%), drug additions (16.9%), alternate routes of administration (11.7%), replacement of a drug by another one (10.7%), therapeutic drug monitoring (10.3%) and optimizing administration (2.6%). Most (96%) of the interventions were accepted and implemented by the medical staff. CONCLUSION: The integration of clinical pharmacy services resulted in drug-specific interventions in 12.6 % of the prescriptions of hospitalized adult patients with cancer. Medication problems mostly concerned anti-infective agents. The intervention acceptance rate by oncologists was high. The outcome of care in the hematology/oncology inpatient setting remains to be measured. PMID- 25550588 TI - Azacitidine in the front-line treatment of therapy-related myeloid neoplasms: a multicenter case series. AB - BACKGROUND/AIM: A continued increase in the incidence of therapy-related myeloid neoplasms (t-MN) is expected due to the improvement of chemotherapeutic treatments for solid and haematological malignancies. The use of 5-azacytidine (AZA) is emerging in these patients. We, therefore, analyzed the outcome of patients with t-MN ineligible for intensive chemotherapy treated in the front line with AZA. PATIENTS AND METHODS: We retrospectively collected clinical data from consecutive patients with t-MN treated in the front-line with AZA at five Haematology Centers. Response to therapy, overall survival (OS) and safety were considered. RESULTS: The overall response rate was of 35.7% with a median OS of 9.6 months. Patients who were heavily pre-treated for their primary malignancy (more than 3 lines of chemotherapy) presented a significant inferior OS (4.9 months). The principal reported toxicity was haematological with severe infections occurring in a minority of patients. Fatigue was the most common extra haematological toxicity. CONCLUSION: New aspects emerged on the management of t MN. AZA may represent a reasonable choice for patients ineligible for intensive treatment, with the exception of heavily pre-treated patients who presented anyway- a worse outcome. PMID- 25550589 TI - Phase I study of S-1 plus fractional cisplatin as adjuvant chemotherapy for advanced gastric cancer in an outpatient setting (KOGC-03). AB - AIM: The aim of this phase I study was to adjust the dose of cisplatin as adjuvant combination chemotherapy with S-1 in an outpatient setting for gastric cancer. PATIENTS AND METHODS: The first course was initiated with S-1 monotherapy on days 1-28. From the second to the sixth course, S-1 was administered on days 1 28 and cisplatin was added on days 1, 15, and 29. The dose level of cisplatin was escalated as follows: 20 mg/m(2) (level 1); 25 mg/m(2) (level 2); 30 mg/m(2) (level 3). Dose-limiting toxicity was a delay factor of the start of the next course due to incomplete recovery. RESULTS: The maximum tolerated and recommended doses were confirmed as level 3 and level 2, respectively. CONCLUSION: Although further clinical trials are recommended to evaluate efficacy, this combination of S-1 plus cisplatin regimen is expected to become a standard adjuvant treatment for gastric cancer in the outpatient setting. PMID- 25550590 TI - Systemic treatment options for epithelioid haemangioendothelioma: the Royal Marsden Hospital experience. AB - BACKGROUND: Epithelioid haemangioendothelioma (EHE) is a rare vascular tumour, which can arise at any site. There is little published data about the management of these tumours. PATIENTS AND METHODS: A retrospective review of patients with histologically-proven EHE presenting to the Royal Marsden Hospital from January 1999 to January 2012. RESULTS: Thirty-two patients (23 females) were identified with a median age of 44 (range=17-78). Twenty patients presented with diffuse disease. Median overall survival (OS) was 9.8 years in 10 patients with operable disease. Amongst those with inoperable disease (n=22), patients with liver disease had the longest median OS (9.8 years), while those with lung and mediastinal disease had the shortest OS (3.6 years). A variety of treatments were used for inoperable disease with infrequent radiological responses. CONCLUSION: The clinical behaviour can vary depending on the site of disease. Surgery, if feasible, has the best outcome. In those with inoperable disease, a period of observation to assess the tumour behaviour is recommended. The role of medical therapy remains unclear. PMID- 25550591 TI - Sunitinib-induced thyrotoxicosis - a not so rare entity. AB - BACKGROUND/AIM: The tyrosine kinase inhibitor (TKI) sunitinib malate is nowadays a standard first-line treatment option for patients with metastatic clear-cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the incidence and clinical course of thyrotoxicosis in our cohort of patients treated with sunitinib. PATIENTS AND METHODS: Medical records of all patients treated with first-line sunitinib for mRCC at our Institution between November 2008 and March 2014 were retrospectively reviewed. Thyroid function was assessed after every 2 cycles of therapy, during the 2 weeks off period. RESULTS: Out of the 62 included patients, hypothyroidism has developed during therapy in 12 patients (19%) and it was preceded by thyrotoxicosis in 2 (3.2%). CONCLUSION: Sunitinib-induced thyrotoxicosis (SIT), a not so rare entity, was followed by hypothyroidism. The patterns of occurrence and possible significance of SIT, as predictive marker of better treatment response to sunitinib, need to be validated in further studies. PMID- 25550592 TI - Neutrophil-rich gastric carcinoma in the integrated cancer registry of eastern Sicily, Italy. AB - BACKGROUND/AIM: Neutrophil-rich carcinoma is a variant of gastric carcinoma that has not been well-studied or characterized. The purpose of the present study was to reveal the incidence and clinicopathological findings compared to ordinary gastric carcinoma. PATIENTS AND METHODS: A population-based series of 430 gastric cancers, identified between 2003 and 2006 from the province of Messina (insular Italy; population, 662,450), was used. The number of tumor-infiltrating neutrophils was assessed in a semi-quantitative manner using the mean value of 20 non-overlapping high-power fields (magnification, 400; 0.08 mm(2)). Tumors with >10 neutrophils per 20 high-power fields were arbitrarily considered as neutrophil-rich gastric carcinomas. Moreover, MUC1 immunohistochemical expression was investigated to show possible correlation with neutrophil infiltration in gastric carcinomas. RESULTS: Among 193 gastric cancers resected for curative purposes, 30 (15.54%) were represented by neutrophil-rich gastric carcinomas. These tumors occurred more frequently in patients aged more than 72 years (p<0.05), showing an inverse correlation with mucinous subtype according to the WHO classification (p<0.001) and expressed MUC1. However, intensity and distribution of MUC1 was heterogeneous, and independent of neutrophil infiltration within the tumor stroma. CONCLUSION: Neutrophil-rich carcinoma seems to represent a distinctive morphological variant of gastric carcinoma, although the true mechanism for the infiltration of neutrophils is still unclear. PMID- 25550593 TI - Salvage method for unplanned excision of soft tissue sarcoma: long-term results of second-look surgery following radio-hyperthermo-chemotherapy. AB - We have established a "second-look operation" protocol that consists of whole biopsy of surgical scar tissue following radio-hyperthermo-chemotherapy (RHC) after unplanned excision of soft tissue sarcoma. Out of 30 patients who underwent RHC for soft tissue sarcoma at our Institution, 6 were enrolled into this study to undergo a second-look operation for unplanned excision. Radiotherapy was given to a total dose of 32 Gy. Hyperthermia was conducted once a week, for a total of five sessions. Chemotherapy was performed at weekly intervals. Surgery was performed to excise the scar tissue that was enhanced on preoperative MRI. In all six cases, no residual tumors were identified in resected scar tissue; thus, no additional wide excision was performed. The average follow-up period was 10.9 years. There were no local recurrences, and all patients were alive at their final follow-up. Long-term follow-up confirmed that RHC can replace additional wide excision for unplanned excision of soft tissue sarcoma. PMID- 25550594 TI - Perioperative serum albumin correlates with postoperative pancreatic fistula after pancreaticoduodenectomy. AB - OBJECTIVES: Despite improvements in surgical techniques, instruments and perioperative management, postoperative pancreatic fistula (POPF) remains a serious complication after pancreaticoduodenectomy. The aim of the present study was to characterize a high-risk group for POPF after pancreaticoduodenectomy using perioperative clinical variables of patients. PATIENTS AND METHODS: This retrospective study comprised of 247 patients who had undergone pancreaticoduodenectomy between May 2000 and May 2013. Perioperative risk factors pertinent to development of POPF were investigated using univariate and multivariate analyses. RESULTS: POPF developed in 43 out of 247 patients (17.4 %). In univariate analysis, male gender (p=0.005), higher postoperative serum amylase (p=0.025) and lower postoperative serum albumin (p=0.041) were significant risk factors for POPF. In multivariate analysis, male gender (p=0.008) and lower postoperative serum albumin (p=0.010) were found to be independent risk factors. CONCLUSION: Male gender and postoperative lower serum albumin were associated with the development of POPF after pancreaticoduodenectomy. PMID- 25550595 TI - Factors predicting recurrence in patients with Siewert type II carcinoma treated with curative resection. AB - AIM: To evaluate the recurrence risk for Siewert type II esophagogastric junction carcinoma treated with curative resection. PATIENTS AND METHODS: We retrospectively analyzed clinicopathological and recurrence-free survival (RFS) data of 52 patients after curative resection for Siewert type II carcinoma focusing on the role of lymph node metastasis around the greater curvature or parapyloric area. RESULTS: Recurrence was observed in 21 (40%) patients; the median time-to-recurrence was 11 months (range=3-33 months). According to multivariate Cox proportional hazard regression analysis, involvement of nodes no. 4sa, 4sb, 4d, 5 and/or 6 (odds ratio (OR)=6.62; 95% confidence interval (CI)=1.27-41.1; p=0.04) and younger age (OR=2.10; 95% CI=1.25-3.82; p<0.01) were significant independent risk factors affecting RFS. CONCLUSION: Involvement of no. 4-6 nodes appears to predict recurrence of Siewert type II carcinoma treated with curative resection. Patients with this risk factor may benefit from effective use of perioperative chemotherapy. PMID- 25550596 TI - Assessment of surgical treatment and postoperative nutrition in gastric cancer patients older than 80 years. AB - BACKGROUND: A gastrectomy for gastric cancer is sometimes required in patients older than 80 years due to the continuously increasing age of society. However, if a gastrectomy worsens the postoperative quality of life and daily activity in elderly patients because of poor nutrition, the procedure may not always be a useful treatment strategy. PATIENTS AND METHODS: Clinicopathological data of patients with gastric cancer who underwent a gastrectomy at our Department between 1998 and 2008 (N=471) were collected and analyzed. The results of treatment for patients older than 80 years (N=41) were analyzed and compared against those of patients younger than 80 years (N=430). RESULTS: Patients older than 80 years had a higher frequency of preoperative co-morbidities than patients younger than 80 years. However, there was no statistical difference in postoperative complications regarding nutrition between the two groups. CONCLUSION: Older age is not a determinant of poor nutrition following gastrectomy. Gastrectomy for gastric cancer is, therefore, a useful treatment strategy, regardless of ageing. PMID- 25550597 TI - Lapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trial. AB - BACKGROUND: Trastuzumab, one important treatment option for HER2-positive metastatic breast cancer (MBC) is limited by its cardiotoxic potential. Lapatinib and pegylated liposomal doxorubicin (PLD) represent a cardiosparing alternative that can cross the blood brain barrier. This is important, because one third of breast cancer patients develop brain metastases. PATIENTS AND METHODS: We included 24 patients with HER2-positive MBC progressing under trastuzumab. They received 1,250 mg lapatinib daily until progression plus PLD (40 mg/m(2)) every 4 weeks for maximal 6 cycles. The primary end-point was the overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), 1-year PFS and 1-year OS rates. RESULTS: ORR was 54%. Median PFS was 5.8 and median OS 23.3 months. The one-year PFS rate was 27% and 1-year OS rate 76%. CONCLUSION: Lapatinib-plus-PLD is active and safe in HER2-positive MBC, especially suitable for patients with cardiological risk or brain metastases. PMID- 25550598 TI - MicroRNA expressions in HPV-induced cervical dysplasia and cancer. AB - BACKGROUND/AIM: The role of oncogenic or high-risk human papillomavirus (HPV) in cervical carcinogenesis is inevitable, yet not fully understood. Detailed analysis of microRNA (miRNA) alterations occurring during high-risk HPV transformation will increase our current understanding over cervical carcinogenesis. The two main aims of the study were: (i) finding association between HPV infection characteristics and socio-demographic variables, (ii) finding an predictors of clinical outcome. MATERIALS AND METHODS: The expression levels of different microRNAs (miR-21, miR-27a, miR-34a, miR-155, miR-196a, miR 203) were determined in formalin-fixed paraffin-embedded (FFPE) human HPV positive cervical dysplastic and tumorous tissue samples using quantitative real time PCR (qPCR). Sociodemographic and life-style factors were also analyzed. RESULTS: The expression of miR-27a was significantly higher in cervical intraepithelial neoplasia (CIN)2-3 compared to CIN1 (p=0.023) and in squamous cell carcinoma (SCC) compared to CIN2-3 (p=0.033). Moreover, significantly lower levels of miR-34a were detected in CIN2-3 than in CIN1 (p=0.041) and in SCC than in CIN2-3 (p=0.021). Furthermore, we found significant differences in subjects with multiple HPV in miR-27a (p=0.015) and miR-203 (p=0.025) in CIN2-3 compared to CIN1 and miR-21 (p=0.002), mir-27a (p=0.001) and miR-34a (p=0.001) in SCC/CIN2 3. Expression of miR-27a, showing up-regulation in CIN2-3 compared to CIN1 (p=0.028) and miR-34a (down-regulated), correlated with HPV 16 positivity (CIN2 3/CIN1: p=0.027 and SCC/CIN2-3: p=0.036). MiR-34a expression was also significantly altered in connection to smoking status and presence of HPV 16. CONCLUSION: The demand for additional, alternative molecular biomarkers with prognostic potential is strong. Evaluation of miRNA expression might be helpful to distinguish different cervical lesions and might be able to help in the prediction of HPV infection outcome. PMID- 25550599 TI - Inhibition of placental growth factor in renal cell carcinoma. AB - BACKGROUND/AIM: Placental growth factor (PlGF) is up-regulated in major malignant diseases or following antiangiogenic therapy, although it is present in low levels under normal physiological conditions. TB403, a monoclonal antibody against PlGF, was investigated in clear cell renal cell carcinoma (ccRCC) xenografts since it has been proposed as a potential target in oncology. MATERIALS AND METHODS: Human ccRCCs were implanted in athymic nude mice to evaluate the efficacy of TB403 and to excise xenograft tumors for molecular experiments. RESULTS: TB403 did not significantly inhibit tumor growth in treatment-naive or sunitinib-resistant ccRCC xenografts. Gene expression profiling resulted in over-expression of the C1orf38 gene, which induced immunoreactivity in macrophages. Angiogenesis PCR arrays showed that VEGFR-1 was not expressed in ccRCC xenografts. CONCLUSION: PlGF blockade did not have a broad antiangiogenic efficacy; however, it might be effective on-target in VEGFR1 expressing tumors. The inhibition of VEGF pathway may induce the activity of tumor-associated-macrophages for angiogenesis escape. PMID- 25550600 TI - Non-pegylated liposomal doxorubicin plus ifosfamide in metastatic soft tissue sarcoma: results from a phase-II trial. AB - BACKGROUND/AIM: Non-pegylated liposomal doxorubicin (NPLD) has demonstrated antitumour activity equivalent to conventional doxorubicin and a significantly lower risk of cardiotoxicity. This phase II trial was performed to evaluate the activity and the safety of NPLD and ifosfamide combination in patients with metastatic soft tissue sarcoma. PATIENTS AND METHODS: Thirty-four patients received NPLD 40 mg/m(2) (d1) and ifosfamide 3 g/m(2)/day (d1-3) every three weeks as first-line therapy of metastatic soft tissue sarcoma. The treatment was planned for a maximum of six cycles. RESULTS: The objective response (OR) rate among response-assessable patients was 55.9%. The median progression-free survival (PFS) was 4.2 months and the median overall survival (OS) was 11.2 months. Symptomatic grade 3 cardiotoxicity occurred in one patient (3%). CONCLUSION: The combination of NPLD and ifosfamide reported in a population of metastatic soft tissue sarcoma patients at risk for developing heart failure encourage antitumour activity, similar to that of classical doxorubicin. PMID- 25550601 TI - Transarterial chemoembolization with miriplatin plus epirubicin in patients with hepatocellular carcinoma. AB - AIM: We aimed to evaluate the therapeutic efficacy of transcatheter arterial chemoembolization (TACE) using miriplatin plus epirubicin in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The efficacy of TACE was evaluated by dynamic computed tomography (CT) or magnetic resonance imaging (MRI) three months after the procedure according to the Response Evaluation Criteria in Cancer Study Group of Japan. Adverse events (AEs), including clinical symptoms, hematological toxicities and blood chemistry toxicities, were assessed using Common Terminology Criteria Version 4.0. RESULTS: Thirty patients with HCC received TACE with miriplatin (miriplatin group) and 29 patients received TACE with miriplatin plus epirubicin (miriplatin-plus-epirubicin group). AEs, such as anorexia and neutropenia, were observed more frequently in the miriplatin-plus epirubicin group than in the miriplatin group (p=0.028 and 0.014, respectively). However, there was no significant difference in the incidence of these AEs (grade 3/4) between groups. The objective response rate (ORR), including the complete response (CR) and partial response (PR), was 76.7% in the miriplatin group and 58.6% in the miriplatin-plus-epirubicin group (p=0.224). The median time to progression (TTP) in the miriplatin group and the miriplatin-plus-epirubicin group was 8.2 and 6.1 months, respectively (p=0.123). CONCLUSION: Although TACE with miriplatin plus epirubicin was safe and tolerable, no additional anti-tumor effects were observed compared to TACE with miriplatin. Further analysis is required to refine the efficacy of TACE using miriplatin plus epirubicin. PMID- 25550602 TI - Prognostic markers for patient outcome following vaccination with multiple MHC Class I/II-restricted WT1 peptide-pulsed dendritic cells plus chemotherapy for pancreatic cancer. AB - BACKGROUND/AIM: Treatment combining dendritic cells (DCs) pulsed with three types of major histocompatibility complex (MHC) class I and II (DC/WT1-I/II)-restricted Wilms' tumor 1 (WT1) peptides with chemotherapy may stabilize disease in pancreatic cancer patients. MATERIALS AND METHODS: Laboratory data from seven patients with pancreatic cancer who underwent combined DC/WT1-I/II vaccination and chemotherapy were analyzed. The DC phenotypes and plasma cytokine profiles were analyzed via flow cytometry. RESULTS: The post-treatment neutrophil to lymphocyte (N/L) ratio was a treatment-related prognostic factor for better survival. Moreover, the mean fluorescence intensities (MFIs) of human leukocyte antigen (HLA)-DR and cluster of differentiation (CD)83 on DCs were significantly increased after chemoimmunotherapy. Interestingly, interleukin (IL)-6 level in plasma was significantly increased after chemoimmunotherapy in non-super responders. CONCLUSION: An increased N/L ratio, as well as HLA-DR and CD83 MFI levels may be prognostic markers of longer survival in patients with advanced pancreatic cancer who undergo chemoimmunotherapy. PMID- 25550603 TI - Primary gastric small cell carcinoma: a series of seven cases. AB - AIM: To present a series of seven cases of gastric small cell carcinoma (GSCC) treated surgically and to illustrate the clinicopathological features and clinical course. PATIENTS AND METHODS: Among 1,832 patients with gastric cancer who underwent gastric resection between 1997 and 2012, we reviewed the clinical records of 7 patients with histopathological diagnoses of GSCC. RESULTS: No patients had preoperative confirmation of GSCC from endoscopic biopsy. Curative resection (R0) was achieved in 5 patients (71.4%). Two out of the 5 patients with curative resection survived more than four years. Two out of 3 patients who received weekly paclitaxel had progression-free survival of more than 10 months. The median survival time for the whole patient group was 14 months and the 3-year survival rate was 25.0%. CONCLUSION: Curative surgery with adjuvant chemotherapy may be essential to improve the prognosis of GSCC, and weekly paclitaxel chemotherapy may represent a promising chemotherapy for GSCC. PMID- 25550604 TI - Histological grade (HG) in invasive ductal carcinomas of the breast of less than 1 cm: clinical and biological associations during progression from HG1 to HG3. AB - AIM: To study the clinical and biological (cellular proliferation and hormone dependence) associations during the progression of histological grade (HG), from HG1 to HG3, in invasive ductal carcinomas of the breast (IDC) <1 cm. PATIENTS AND METHODS: The study group included 119 women with IDCs <=1 cm, aged between 27 and 88 years (median=61 years). The parameters analyzed were: histological grade (HG1: 52; HG2: 45; HG3: 22); axillary lymph node involvement (N); distant metastasis (M); and immunohistochemical expression of estrogen (ER), progesterone (PR) and androgen (AR) receptors, and Ki67, p53 and B-cell lymphoma 2 (BCL2). RESULTS: Compared to HG3 tumors, HG1s exhibited an increased expression of ER, AR and BCL2, as well as lower expression of p53 and Ki67. In HG1 tumors, significant (p<0.05) associations were found between ER and PR (positive), ER and p53 (negative), ER and Ki67 (negative), PR and AR (positive), PR and p53 (negative), AR and p53 (negative), p53 and BCL2 (negative), and between BCL2 and Ki67 (negative). HG3s only showed significant (p<0.05) associations between ER and Ki 67 (negative) and between BCL2 or Ki-67 (negative). Only two significant relationships (ER-Ki67 and BCL2-Ki67) persisted in all three grades. CONCLUSION: Our results lead us to the following conclusions: i) compared HG1, HG3 ductal carcinomas exhibited decreased expression of ER, AR and BCL2 and increased expression of p53 and Ki67; and ii) only two significant and negative relations (ER-Ki67 and BCL2-Ki67) persisted in all three grades. PMID- 25550605 TI - Cancer of unknown primary during pregnancy: an exceptionally rare coexistence. AB - BACKGROUND: Cancer in pregnancy is a rare disease with breast cancer, cervical cancer, melanoma and Hodgkin's disease to be the most commonly diagnosed malignancies during gestation. Cancer of unknown primary (CUP) is a well recognized clinical disorder where the primary site can not be identified after a standard diagnostic approach. CUP in pregnancy has rarely been described. MATERIALS AND METHODS: We searched MEDLINE and contacted cancer Centers in Europe, United States and Australia where patients with CUP or pregnant patients with cancer were diagnosed and treated. RESULTS: Since 1976 we identified 18 pregnant women with CUP in a median gestational age of 34 weeks. Most of these patients were diagnosed with poorly-differentiated histology, had poor response to systemic treatment and a median maternal survival of 8 months. Seventy-two percent of mothers have died, while 80% of the newborns were alive and healthy. Almost one fourth of placentas examined showed metastatic disease. CONCLUSION: CUP during pregnancy is a very rare coexistence, usually has an aggressive disease with poor response to chemotherapy and a dismal prognosis. Both obstetricians and oncologists should be aware of this rare condition. PMID- 25550655 TI - The Launch of the Institute of Musculoskeletal Health and Arthritis 2014-2018 Strategic Plan: Positive Implications for Canadian Chiropractors and their Patients. PMID- 25550606 TI - MRI evaluation of residual breast cancer after neoadjuvant chemotherapy: influence of patient, tumor and chemotherapy characteristics on the correlation with pathological response. AB - AIM: The aim of this study was to evaluate the correlation between the residual tumor measured on magnetic resonance imaging and pathological results and to assess whether this correlation varies according to patient, tumor or chemotherapy characteristics. PATIENTS AND METHODS: The study population included women treated for breast cancer with indication of neoadjuvant chemotherapy in our tertiary breast cancer Unit between January 2008 and December 2011. Factors related to patients, tumor and chemotherapy were studied. Pearson's correlation coefficient between the size of the tumor on MRI and pathological response was calculated for the entire population. It was also calculated according to patient, tumor and chemotherapy characteristics. RESULTS: During the study period, 107 consecutive women were included. The size of residual tumor on the MRI significantly correlated with the size on pathological result with a Pearson correlation coefficient of 0.52 (p<0.001). The correlation was stronger for women aged 50 years and older (r=0.64, p<0.001) and for post-menopausal women (r=0.61, p<0.001). The correlation was stronger for those with triple-negative tumors (r=0.69, p=0.002) but weaker for those with tumors with a ductal carcinoma in situ component (r =0.18, p=0.42). CONCLUSION: The size of breast cancer obtained by MRI is significantly correlated to the pathological size of the tumor. This correlation was stronger among women aged 50 years and more, among post menopausal women, and among women who had triple-negative tumors. PMID- 25550656 TI - JCCA Sports Chiropractic 6th Issue. PMID- 25550657 TI - Chiropractors tackling the inactivity epidemic. PMID- 25550658 TI - Concussions in the NHL: A narrative review of the literature. AB - Ice hockey has been identified as a sport with a high risk for concussions. Given the health sequelae associated with the injury, a great deal of attention has been placed on its diagnosis, management and return-to-play protocols. The highest level of ice hockey in North America is played in the National Hockey League (NHL), and concussions pose a serious threat to the health of the players and the game itself. Unfortunately, the scientific literature on concussions in ice hockey is derived mostly from research conducted on youth and amateur levels of play, leaving a gap in our knowledge at the professional level. This narrative review attempts to summarize what is known about concussion incidence, mechanisms of injury and risk factors in the NHL. PMID- 25550659 TI - Treatment of Myositis Ossificans with acetic acid phonophoresis: a case series. AB - OBJECTIVE: To create awareness of myositis ossificans (MO) as a potential complication of muscle contusion by presenting its clinical presentation and diagnostic features. An effective method of treatment is offered for those patients who develop traumatic MO. MANAGEMENT: Patients in this case series developed traumatic MO, confirmed on diagnostic ultrasound. Patients participated in a treatment regimen consisting of phonophoresis of acetic acid with ultrasound. OUTCOME: In all cases, a trial of phonophoresis therapy significantly decreased patient signs, symptoms and the size of the calcification on diagnostic ultrasound in most at a 4-week post diagnosis mark. DISCUSSION: Due to the potential damage to the muscle and its function, that surgical excision carries; safe effective methods of conservative treatment for MO are crucial. MO deserves more attention in the literature due to its common presentation in athletes. PMID- 25550660 TI - A pilot study of postural stability testing using controls: the modified BESS protocol integrated with an H-pattern visual screen and fixed gaze coupled with cervical range of motion. AB - OBJECTIVE: The purpose of this study was to investigate baseline postural stability of a normal healthy population using the modified balance error scoring system (M-BESS) integrated with H-pattern testing (HP) and cervical range of motion with fixed ocular gaze (CROM). METHODS: Postural error scores for twelve participants were scored during each twenty second trial of the M-BESS protocol stances (double-leg [DL], tandem [TL] and single-leg [SL]). Participants also completed the same M-BESS protocol with the inclusion of HP and CROM conditions for a total of nine trials. RESULTS: The total mean +/- standard deviation and median of errors within each condition were not different (M-BESS 2.6 +/- 2.1, 2.0; HP 1.3 +/- 1.1, 2.0; CROM 2.0 +/- 2.0, 2.0; p>0.05). CONCLUSION: Although a small sample size, our findings suggest that with normal, healthy, subjects challenging their visual input and cervical range of motion while balancing gives you a similar number of errors as the standard M-BESS protocol. PMID- 25550661 TI - A four year prospective study of injuries in elite Ontario youth provincial and national soccer players during training and matchplay. AB - INTRODUCTION: With over 200 million amateur players worldwide, soccer is one of the most popular and internationally recognized sports today. By understanding how and why soccer injuries occur we hope to reduce prevalent injuries amongst elite soccer athletes. METHODS: Via a prospective cohort, we examined both male and female soccer players eligible to train with the Ontario Soccer Association provincial program between the ages of 13 to 17 during the period of October 10, 2008 and April 20, 2012. Data collection occurred during all player exposures to potential injury. Exposures occurred at the Soccer Centre, Ontario Training grounds and various other venues on multiple playing surfaces. RESULTS: A total number of 733 injuries were recorded. Muscle strain, pull or tightness was responsible for 45.6% of all injuries and ranked as the most prevalent injury. DISCUSSION: As anticipated, the highest injury reported was muscular strain, which warrants more suitable preventive programs aimed at strengthening and properly warming up the players' muscles. PMID- 25550662 TI - A case of early sports specialization in an adolescent athlete. AB - Early sport specialization (ESS) refers to intense year round training in a specific sport with the exclusion of other sports at a young age. This approach to training is heavily debated and there are claims both in support and against ESS. ESS is considered to be more common in the modern day youth athlete and could be a source of overuse injuries and burnout. This case describes a 16 year old elite level baseball pitcher who engaged in high volume, intense training at a young age which lead to several significant throwing related injuries. The case highlights the historical context of ESS, the potential risk and benefits as well as the evidence for its effectiveness. It is important for health care professionals to be informed on the topic of ESS in order to educate athletes, parents, coaches and organizations of the potential risks and benefits. PMID- 25550663 TI - Juvenile Osteochondritis Dissecans in a 13-year-old male athlete: A case report. AB - OBJECTIVE: To present the clinical management of juvenile osteochondritis dissecans (OCD) of the knee and highlight the importance of a timely diagnosis to optimize the time needed for less invasive, non-operative therapy. CLINICAL FEATURES: A 13-year-old provincial level male soccer player presenting with recurrent anterior knee pain despite ongoing manual therapy. INTERVENTION AND OUTCOME: A multidisciplinary, non-operative treatment approach was utilized to promote natural healing of the osteochondral lesion. The plan of management consisted of patient education, activity modification, manual therapy, passive modalities and rehabilitation, while being overseen by an orthopaedic surgeon. CONCLUSIONS: Considering the serious consequences of misdiagnosing osteochondritis dissecans, such as the potential for future joint instability and accelerated joint degeneration, a high degree of suspicion should be considered with young individuals presenting with nonspecific, recurrent knee pain. A narrative review of the literature is provided to allow practitioners to apply current best practices to appropriately manage juvenile OCD and become more cognizant of the common knee differential diagnoses in the young athletic population. PMID- 25550664 TI - Influence of MRI field strength on clinical decision making in knee cartilage injury - A case study. AB - OBJECTIVE: To increase clinicians' awareness of the differences in image resolution and potential diagnostic accuracy between small and large-field MR Scanners. To present an example of a clinical decision making challenge in how to proceed when knee MRI and clinical findings don't agree. CLINICAL FEATURES: A 38 year old female mountain biker presented with knee pain and clinical features strongly suggestive of a torn meniscus or loose bodies. An initial MRI using a small field strength (0.18T) scanner was reported as normal. Her clinical presentation was suspicious enough that a repeat MRI on a high-field (1.5T) scanner was ordered. The second MRI included high resolution 3D volumetric imaging which revealed cartilage damage and loose bodies. INTERVENTION AND OUTCOME: The patient was treated with arthroscopic surgery which confirmed the presence of meniscal and chondral injury and resulted in notable improvement in the patient's symptoms. CONCLUSION: Clinicians should consider scanner quality and diagnostic accuracy before discounting strongly suggestive clinical history and examination findings when MRIs are reported as normal. PMID- 25550665 TI - Ulnar Impaction Syndrome: A case series investigating the appropriate diagnosis, management, and post-operative considerations. AB - Ulnar sided wrist pain is a common site for upper extremity disability. Ulnar impaction syndrome results in a spectrum of triangular fibrocartilage complex (TFCC) injuries and associated lunate, triquetrum, and ligamentous damage. Patients commonly present with insidious ulnar sided wrist pain and clicking, and a history of trauma or repetitive axial loading and rotation. In this case series, three patients presented to a sports chiropractor for evaluation and were subsequently diagnosed with ulnar impaction syndrome. Treatment strategies consist of conservative management, arthroscopic debridement or repair, arthroscopic wafer procedure, or ulnar shortening osteotomy. For the athlete, intervention should be individualized and sport-specific, considering athletic priorities, healing potential, return to play, and long-term health concerns. PMID- 25550666 TI - Guyon Canal Syndrome: lack of management in a case of unresolved handlebar palsy. AB - OBJECTIVE: To present the clinical diagnostic features including management of Guyon canal syndrome in a case with unresolved sensory deficits in a young female cyclist. CLINICAL PRESENTATION: After 14 days of cycling across Canada, a 23-year old female experienced sensory loss, followed by atrophy and a "claw" hand appearance of her left hand. INTERVENTION AND OUTCOME: Treatment included cervical chiropractic manipulation, soft tissue therapy and the use of cycling gloves. Seven years after the initial injury a lack of sensation in the ulnar nerve distribution of her left hand has persisted. DISCUSSION: This case demonstrates that a lack of proper management can lead to permanent sensory loss and is worth highlighting. Various therapists evaluated the patient's symptoms and provided minimal care. No diagnosis was given, nor were appropriate measures taken for her to understand the risks of continuing to ride. SUMMARY: Although treatment for Guyon Canal Syndrome can be as easy as cessation from cycling until symptoms subside, other treatment options could be utilized to help manage ulnar nerve compression injuries in cyclists. PMID- 25550667 TI - Can injury in major junior hockey players be predicted by a pre-season functional movement screen - a prospective cohort study. AB - BACKGROUND: The Functional Movement Screen (FMS) is a tool that is commonly used to predict the occurrence of injury. Previous studies have shown that a score of 14 or less (with a maximum possible score of 21) successfully predicted future injury occurrence in athletes. No studies have looked at the use of the FMS to predict injuries in hockey players. OBJECTIVE: To see if injury in major junior hockey players can be predicted by a preseason FMS. METHODS: A convenience sample of 20 hockey players was scored on the FMS prior to the start of the hockey season. Injuries and number of man-games lost for each injury were documented over the course of the season. RESULTS: The mean FMS score was 14.7+/-2.58. Those with an FMS score of <=14 were not more likely to sustain an injury as determined by the Fisher's exact test (one-tailed, P = 0.32). CONCLUSION: This study did not support the notion that lower FMS scores predict injury in major junior hockey players. PMID- 25550668 TI - A survey of Canadian Alpine ski racing coaches regarding spinal protective devices for their athletes. AB - INTRODUCTION: Spinal protective devices are a recent addition to the protective equipment worn by competitive and recreational alpine skiers and snowboarders. Their rate of use is not documented at the time of publication. The objective of this study was to examine the current attitudes and recommendations of Canadian alpine ski racing coaches towards spinal protective devices. METHODS: A convenience sample of alpine ski racing coaches across Canada were contacted in each provincial sport governing body in the ski racing community. A ten question online survey was attached to the initial email. Descriptive statistical analysis was utilized. RESULTS: A total of 29 Canadian alpine ski racing coaches completed the study survey. All participants were familiar with spinal protective devices and 51.7% of respondents reported that they do not actively enforce spinal protective device use with their ski racing athletes. 80% of respondents reported that their Canadian ski racing club did not have guidelines or policies regarding spinal protective device use. 86.2% of respondents were unaware if their provincial sport organization had a policy regarding their use. DISCUSSION: The majority of coaches reporting training athletes aged 10-15, which may help to explain why only half of those surveyed enforce the use of spinal protective devices. This group of athletes may not participate in speed events as frequently as older athletes, where the use of spinal protective devices is more common. CONCLUSION: The majority of Canadian Alpine ski coaches report a belief that spinal protective device use is important, however, far fewer enforce their use, or work in an environment with a policy requiring it. Further research is required to determine the differences in beliefs and practice. PMID- 25550669 TI - Meniscal allograft transplant in a 16-year-old male soccer player: A case report. AB - Meniscal allograft transplantation (MAT) is a relatively new procedure that has gained popularity in the last couple of decades as a possible alternative to a meniscectomy to provide significant pain relief, improve function, and prevent the early onset of degenerative joint disease (DJD). As of present, evidence is limited and conflicting on the success of such procedures. In this case, a 16 year old male athlete underwent numerous surgical procedures to correct a left anterior cruciate ligament (ACL) rupture with associated medial and lateral meniscal damage that occurred as a result of a non-contact mechanism of injury. Following multiple procedures, including repair of both menisci and follow-up partial meniscectomy of the lateral meniscus, the patient continued to experience symptoms on the left lateral knee, making him a candidate for MAT. This case is used to highlight what a MAT is, what makes someone a candidate for this type of procedure, the current evidence surrounding the success of this intervention, and some rehabilitation considerations following surgery. The role of chiropractors and primary clinicians is to ensure that young athletes undergo early intervention to offset any degenerative changes that would be associated with sustained meniscal lesions. PMID- 25550670 TI - The clinical and biomechanical effects of fascial-muscular lengthening therapy on tight hip flexor patients with and without low back pain. AB - BACKGROUND: Many patients have tight hip flexors with or without low back pain. Manual fascial-muscular lengthening therapy (FMLT) is one commonly used treatment for this population. OBJECTIVE: Investigate the clinical and biomechanical effects of manual FMLT on tight hip flexor patients with and without low back pain. METHODS: A nonrandomized trial, before-and-after experiment with multiple baselines conducted on two different patient populations: 1) Mechanical low back pain patients with tight hip flexors (n = 10) and 2) Asymptomatic group with tight hip flexors (n = 8). Four treatments of manual FMLT were performed on the hip flexor of the two groups of patients over a two-week period. Primary outcome measures over the two-week period were 1) Maximum voluntary trunk flexor and extensor moments, 2) Disability (Roland Morris Disability Questionnaire) and pain (10-cm Visual Analogue Scale), 3) Passive hip extension mobility. RESULTS: Primary outcome analysis involved within-groups comparisons. Maximum voluntary trunk extension demonstrated increases for the low back pain patients. The low back pain patients demonstrated a small, but significant, reduction in disability and pain. Both groups demonstrated an increase in passive hip extension measurements. CONCLUSION: This preliminary study demonstrated interesting results from manual FMLT on two tight hip flexor patient populations with and without low back pain. However, there were several significant limitations from this study, which restrict the ability to generalize the results. PMID- 25550671 TI - Effects of spinal manipulation versus therapeutic exercise on adults with chronic low back pain: a literature review. AB - BACKGROUND CONTEXT: Chronic low back pain (CLBP) is a prevalent disorder that has a significant burden to society in terms of loss of work time and increased economic cost. Two common treatment choices of intervention for CLBP are spinal manipulation and prescribed exercise. PURPOSE: The purpose of this systematic review was to examine the effectiveness of spinal manipulation vs prescribed exercise for patients diagnosed with CLBP. Studies that compared head-to-head spinal manipulation to an exercise group were included in this review. METHODS: A search of the current literature was conducted using a keyword process in CINAHL, Cochrane Register of Controlled Trials Database, Medline, and Embase. The search was conducted on, and included studies available up to August 29(th) 2014. Studies were included based on PICOS criteria 1) individuals with CLBP defined as lasting 12 weeks or longer; 2) spinal manipulation performed by a health care practitioner; 3) prescribed exercise for the treatment of CLBP and monitored by a health care practitioner; 4) measurable clinical outcomes for reducing pain, disability or improving function; 5) randomized controlled trials. The quality of included articles was determined by the author using the criteria developed and used by the Physiotherapy Evidence Database (PEDro). RESULTS: Three randomized controlled trials met the inclusion criteria of this systematic review and were included in this review. The outcomes used in these studies included Disability Indexes, Pain Scales and function improvement scales. The results included a mix of effects with one study finding spinal manipulation as more effective and another finding the exercises more so. The third study found both interventions offering equal effects in the long term. CONCLUSION: Based on the findings of this systematic review there is no conclusive evidence that clearly favours spinal manipulation or exercise as more effective in treatment of CLBP. More studies are needed to further explore which intervention is more effective. PMID- 25550673 TI - RCCSS(C) Research Funding Awards. PMID- 25550672 TI - Immediate changes in temporomandibular joint opening and pain following vibration therapy: a feasibility pilot study. AB - OBJECTIVE: The purpose of this pilot study was to determine the scientific and process feasibility in an effort to direct future larger trials. METHODS: Scientific Feasibility: Twelve subjects were randomly allocated to an intervention and a control group. The intervention protocol consisted of intraoral vibration therapy on the muscles of mastication bilaterally for a period of 1 minute per muscle. Process Feasibility: Several feasibility outcomes were examined including recruitment and retention rates and consent. RESULTS: Scientific Feasibility: Large effect sizes were generated for both mouth opening and VAS in favour of the intervention group. Process Feasibility: a recruitment ratio of 2.3 respondents to 1 participant was determined, along with a retention to loss ratio of 13:1 and a consent to loss ratio of 12:0. CONCLUSION: Scientific Feasibility: The scientific results should be interpreted with caution due to the small sample sizes employed. The study seems to support the scientific feasibility of a future larger single treatment trial. Process Feasibility: Recruitment and retention rates and ratios seem to support future studies. Utilizing the feasibility results of the current study to direct a future larger multiple treatment trial consistent with other comparable TMD studies however is limited. PMID- 25550674 TI - Market frictions: A unified model of search costs and switching costs. AB - It is well known that search costs and switching costs can create market power by constraining the ability of consumers to change suppliers. While previous research has examined each cost in isolation, this paper demonstrates the benefits of examining the two types of friction in unison. The paper shows how subtle distinctions between the two costs can provide important differences in their effects upon consumer behaviour, competition and welfare. In addition, the paper also illustrates a simple empirical methodology for estimating separate measures of both costs, while demonstrating a potential bias that can arise if only one cost is considered. PMID- 25550675 TI - Thermodynamic properties of liquid Au-Bi-Sn alloys. AB - The thermodynamic properties of the liquid ternary Au-Bi-Sn alloys were determined using an electromotive force (EMF) method with an eutectic mixture of (KCl + LiCl) as liquid electrolyte. The cell arrangement was: [Formula: see text] The measurements were carried out over the temperature range from 723 K to 973 K. The compositions investigated were situated on three different cross-sections with a constant ratio of Au:Bi = 2:1, 1:1, and 1:2. The partial Gibbs free energies of Sn in liquid Au-Bi-Sn alloys were determined as a function of concentration and temperature. The integral Gibbs free energy and the integral enthalpy at T = 800 K were calculated by the Gibbs-Duhem integration. The ternary interaction parameters were evaluated using the Redlich-Kister-Muggianu polynomial. PMID- 25550676 TI - A numerical study of adaptive space and time discretisations for Gross-Pitaevskii equations. AB - As a basic principle, benefits of adaptive discretisations are an improved balance between required accuracy and efficiency as well as an enhancement of the reliability of numerical computations. In this work, the capacity of locally adaptive space and time discretisations for the numerical solution of low dimensional nonlinear Schrodinger equations is investigated. The considered model equation is related to the time-dependent Gross-Pitaevskii equation arising in the description of Bose-Einstein condensates in dilute gases. The performance of the Fourier-pseudo spectral method constrained to uniform meshes versus the locally adaptive finite element method and of higher-order exponential operator splitting methods with variable time stepsizes is studied. Numerical experiments confirm that a local time stepsize control based on a posteriori local error estimators or embedded splitting pairs, respectively, is effective in different situations with an enhancement either in efficiency or reliability. As expected, adaptive time-splitting schemes combined with fast Fourier transform techniques are favourable regarding accuracy and efficiency when applied to Gross-Pitaevskii equations with a defocusing nonlinearity and a mildly varying regular solution. However, the numerical solution of nonlinear Schrodinger equations in the semi classical regime becomes a demanding task. Due to the highly oscillatory and nonlinear nature of the problem, the spatial mesh size and the time increments need to be of the size of the decisive parameter [Formula: see text], especially when it is desired to capture correctly the quantitative behaviour of the wave function itself. The required high resolution in space constricts the feasibility of numerical computations for both, the Fourier pseudo-spectral and the finite element method. Nevertheless, for smaller parameter values locally adaptive time discretisations facilitate to determine the time stepsizes sufficiently small in order that the numerical approximation captures correctly the behaviour of the analytical solution. Further illustrations for Gross-Pitaevskii equations with a focusing nonlinearity or a sharp Gaussian as initial condition, respectively, complement the numerical study. PMID- 25550677 TI - Belowground eco-restoration of a suburban waste-storage landscape: Earthworm dynamics in grassland and in a succession of woody vegetation covers. AB - Restoration of belowground ecology is seldom a priority in designing revegetation strategies for disturbed landscapes. We determined earthworm abundance and diversity in a 16-year old grass sward (grassland), a 6-year old (Plantation-04) and a 4-year old (Plantation-06) plantation, both of mixed woody species, on a reclaimed waste disposal site, and in nearby remnant woodland, in suburban Sydney, Australia. While no catches were made in autumn, more earthworms were found in spring (21 +/- 8.6 m-2) than in winter (10.2 +/- 5.9 m-2) or summer (14.4 +/- 5.5 m-2). Earthworm abundance in spring was in the order grassland ~ Plantation-04 (35.2 m-2) > woodland (12.8 m-2) > Plantation-06 (0.8 m-2). None of the revegetated covers had restored earthworm diversity to levels found in the woodland. Exotic species, mostly Microscolex dubius, dominated in the four vegetation covers at any time; the only two native species (Heteroporodrilus sp. and Megascoleceides sp.) found were in the woodland. We also assessed how quality of the evolving soils from the three revegetated covers, compared with that from the woodland, impacted viability of common exotic earthworm species. Both weight gain and cocoon production by the exotic earthworms were higher in the soil from Plantation-04 than in soils from the other vegetation covers, including the woodland; the two variables were positively correlated with the pH and mineral nutrient content (as indicated by electrical conductivity that was in turn correlated with clay content) of the soil. Age of vegetation rather than its composition explained differences in the level of earthworm recovery observed. PMID- 25550678 TI - Coordination Chemistry of Cyclic Disilylated Germylenes and Stannylenes with Group 11 Metals. AB - Reactions of Et3P adducts of bissilylated germylenes and stannylenes with gold, silver, and copper cyanides led to cyanogermyl or -stannyl complexes of the respective metals. In the course of the reaction the phosphine moved to the metal, while the cyanide migrated to the low-coordinate group 14 element. The respective gold complexes were found to be monomeric, whereas the silver and copper complexes exhibited a tendency to dimerize in the solid state. Attempts to abstract the phosphine ligand with B(C6F5)3 led only to the formation of adducts with the borane coordinating to the cyanide nitrogen atom. PMID- 25550679 TI - Silanetriols as Powerful Starting Materials for Selective Condensation to Bulky POSS Cages. AB - Controlled condensation reactions of tertiary silanetriols CH3(CH2) n (CH3)2CSi(OH)3 (1b-f; n = 1-5) in the presence of trifluoroacetic acid and the hydrolysis of CH3(CH2)6(CH3)2CSiCl3 (3) lead to the selective formation of the corresponding disiloxane tetrols [CH3(CH2) n (CH3)2CSi(OH)2]2O (2b-g; n = 1-6) in good yields. The TBAF-driven condensation reactions of the silanetriols CH3(CH2) n (CH3)2CSi(OH)3 (1a-c; n = 0-2) as well as of the disiloxane-1,1,3,3-tetrol 2d (n = 3) yield in the selective formation of the first T8 cages bearing tertiary carbon substituents, CH3(CH2) n (CH3)2C (4a-d; n = 0-3), which was not possible via the condensation of their alkoxysilane counterparts so far. The resulting compounds 2b-g and 4a-d have been characterized by multinuclear NMR, MS, and single-crystal X-ray diffraction. PMID- 25550680 TI - Does premedication with dexmedetomidine provide perioperative hemodynamic stability in hypertensive patients? AB - BACKGROUND: Perioperative hemodynamic fluctuations are seen more often in hypertensive patients than in normotensive patients. The purpose of our study was to investigate the perioperative hemodynamic effects of dexmedetomidine and midazolam used for premedication in hypertensive patients relative to each other and in comparison to normotensive patients. METHODS: One-hundred-forty female, normotensive or hypertensive patients undergoing myomectomies or hysterectomies. They were randomly enrolled into the subgroups: Group ND (normotensive dexmedetomidine); Group HD (hypertensive-dexmedetomine); Group NM (normotensive midazolam); Group HM (hypertensive- midazolam). Dexmedetomidine was administered at a concentration of 0.5 MUg.kg(-1), and midazolam was administered at a concentration of 0.025 MUg.kg(-1) via intravenous (IV) infusion before the induction of anaesthesia. Haemodynamic parameters were recorded at several times (T(beginning), T(preop5 min), T(preop 10 min), T(induction), T(intubation), T(intubation 5 min), T(initial surgery), T(surgery 15 min), T(surgery 30 min), T(extubation), T(extubation 5 min)). Propofol amount for induction, time between induction and initial surgery, demand of antihypertensive therapy, rescue atropine were recorded. Quantitative clinical and demographic characteristics were compared using One Way ANOVA. The values were compared using One-way Analysis of Variance. Additionally periodic variations were examined by One way Repeated Measures Analysis of Variance for groups separately. RESULTS: SBP was significantly different between normotensive and hypertensive groups at the following time points: T(preop 5 min), T(preop 10 min), T(induction), T(intubation), T(intubation 5 min) and T(initial surgery). MBP was significantly different in the hypertensive groups at T(induction), T(intubation), T(intubation 5 min), T(initial surgery), T(surgery 15 min), T(surgery 30 min), T(extubation) and T(extubation 5 min). The perioperative requirements for antihypertensive drugs were significantly higher in Group HM. CONCLUSION: In the hypertensive patients, dexmedetomidine premedication provides better hemodynamic stability compared with midazolam, and because it decreases the antihypertensive requirements, its use might be beneficial. TRIAL REGISTRATION: TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02058485. PMID- 25550682 TI - Care planning needs of palliative home care clients: Development of the interRAI palliative care assessment clinical assessment protocols (CAPs). AB - BACKGROUND: The interRAI Palliative Care (interRAI PC) assessment instrument provides a standardized, comprehensive means to identify person-specific need and supports clinicians to address important factors such as aspects of function, health, and social support. The interRAI Clinical Assessment Protocols (CAPs) inform clinicians of priority issues requiring further investigation where specific intervention may be warranted and equip clinicians with evidence to better inform development of a person-specific plan of care. This is the first study to describe the interRAI PC CAP development process and provide an overview of distributional properties of the eight interRAI PC CAPs among community dwelling adults receiving palliative home care services. METHODS: Secondary data analysis used interRAI PC assessments (N = 6,769) collected as part of regular clinical practice at baseline (N = 6,769) and follow-up (N = 1,000). Clients across six regional jurisdictions in Ontario, Canada, assessed to receive palliative homecare services between 2006 and 2011 were included (mean age 70.0 years; +/-13.4 years). Descriptive analyses focused on the eight interRAI PC CAPs: Fatigue, Sleep Disturbance, Nutrition, Pressure Ulcers, Pain, Dyspnea, Mood Disturbance and Delirium. RESULTS: The majority of clients triggered at least one CAP while two thirds triggered two or more. Triggering rates ranged from 74% for the Fatigue CAP to less than 15% for the Delirium and Pressure Ulcers CAPs. The hierarchical CAP triggering structure suggested Fatigue and Dyspnea CAPs were persistent issues prevalent among the majority of clients while Delirium and Pressure Ulcers CAPs rarely trigger in isolation and most often trigger later in the illness trajectory. CONCLUSION: When any of the eight interRAI PC CAPs are triggered, clinicians should take notice. CAPs triggered at high rates such as fatigue, dyspnea, and pain warrant increased attention for the majority of clients. Consideration of triggered CAPs provide evidence to inform a collaborative decision making process on whether or not issues raised by the CAPs should be addressed in the plan of care. Integrating evidence from the interRAI PC CAPs into the clinical decision making process support care planning to address client strengths, preferences and needs with greater acuity. PMID- 25550681 TI - In vivo study of the effects of exogenous hydrogen sulfide on lung mitochondria in acute lung injury in rats. AB - BACKGROUND: Acute lung injury (ALI) is a serious disease with high incidence in ICU, and impaired mitochondria function plays a significant role in ALI. In this study, we examined the possible roles of exogenous hydrogen sulfide (H2S) in lung mitochondria regulation in ALI rats. METHODS: The rat ALI model was induced by an intra-tongue vein Lipopolysaccharide (LPS) injection. We used sodium hydrosulphide (NaHS) as the H2S donor. We randomly divided 40 Sprague-Dawley rats into five groups: control, LPS injury, LPS + low-dose NaHS (0.78 mg * kg(-1)), LPS + middle-dose NaHS (1.56 mg * kg(-1)), and LPS + high-dose NaHS (3.12 mg * kg(-1)). Rats were killed 3 h after NaHS administration. We calculated a semi quantitative histological index of lung injury assessments and measured the lung wet-to-dry weight ratio. We further analyzed serum for interleukin-1beta levels using enzyme-linked immunosorbent assays. We observed lung mitochondria ultrastructures with an electron microscope. We examined oxidative stress markers in lung mitochondria and the mitochondrial swelling and activity. We analyzed lung mitochondria and cytosol Cyt-c protein expression using Western blotting. RESULTS: Compared to the control group, the quantitative assessment score index, wet-to-dry weight ratios, and interleukin-1beta content in the LPS injury group were significantly increased and the mitochondrial ultrastructure damaged. Furthermore, mitochondrial activity, adenosine triphosphatease, superoxide dismutase, glutathione peroxidase, and mitochondrial Cyt-c protein expression were significantly decreased, and malondialdehyde content, mitochondrial swelling, and cytosol Cyt-c protein expression were significantly increased in the LPS injury group compared to the control group. These effects were lessened by NaHS. CONCLUSION: Exogenous H2S provided a protective effect against ALI by decreasing the mitochondrial lipid peroxidation level and protecting the cell structure in the LPS-induced rat models. Its regulatory effect on lung mitochondria is positively correlated with the dosage. PMID- 25550683 TI - Attitudes and referral patterns of lung cancer specialists in Europe to Specialized Palliative Care (SPC) and the practice of Early Palliative Care (EPC). AB - PURPOSE: To examine availability of Palliative Care (PC) services and referral patterns of European Lung cancer specialists to PC. METHODS: All members of the EORTC Lung Cancer Group (LCG) were asked via email to participate in an on-line survey. RESULTS: 50 out of 170 (29.4%) replied: 24 medical oncologists, 14 radiation/clinical oncologists, 11 pulmonologists and 1 thoracic surgeon. All but two of respondents (96%) had access to at least one component of PC services. In terms of referral of patients to PC almost 75% of respondents would refer most of their patients when there were no treatment options or at the end of life, while only 22% would refer patients at earlier stages of disease. Barriers for referral to PC were negative attitudes of patients to PC (26%), lack of availability of PC services (20%), lack of expertise of PC physicians(18%), the belief that referral to PC signifies abandoning patients (8%), and that PC specialists discourage active oncological therapy (8%). Whilst most of the respondents expressed positive attitudes, 12-22% had overtly negative attitudes towards PC. Seventy eight (78%) of respondents expressed an interest to participate in a trial of early PC (EPC). CONCLUSION: Despite good availability of SPC services at institutions of members of the EORTC LCG, and most respondents expressing positive attitudes towards PC, their practice involved referral of patients to PC late in the disease trajectory, hence Lung Cancer specialists in Europe have not adopted the practice of EPC concurrent with active oncological care. PMID- 25550684 TI - A transition program to primary health care for new graduate nurses: a strategy towards building a sustainable primary health care nurse workforce? AB - BACKGROUND: This debate discusses the potential merits of a New Graduate Nurse Transition to Primary Health Care Program as an untested but potential nursing workforce development and sustainability strategy. Increasingly in Australia, health policy is focusing on the role of general practice and multidisciplinary teams in meeting the service needs of ageing populations in the community. Primary health care nurses who work in general practice are integral members of the multidisciplinary team - but this workforce is ageing and predicted to face increasing shortages in the future. At the same time, Australia is currently experiencing a surplus of and a corresponding lack of employment opportunities for new graduate nurses. This situation is likely to compound workforce shortages in the future. A national nursing workforce plan that addresses supply and demand issues of primary health care nurses is required. Innovative solutions are required to support and retain the current primary health care nursing workforce, whilst building a skilled and sustainable workforce for the future. DISCUSSION: This debate article discusses the primary health care nursing workforce dilemma currently facing policy makers in Australia and presents an argument for the potential value of a New Graduate Transition to Primary Health Care Program as a workforce development and sustainability strategy. An exploration of factors that may contribute or hinder transition program for new graduates in primary health care implementation is considered. SUMMARY: A graduate transition program to primary health care may play an important role in addressing primary health care workforce shortages in the future. There are, however, a number of factors that need to be simultaneously addressed if a skilled and sustainable workforce for the future is to be realised. The development of a transition program to primary health care should be based on a number of core principles and be subjected to both a summative and cost-effectiveness evaluation involving all key stakeholders. PMID- 25550685 TI - Unmet support needs of early-onset dementia family caregivers: a mixed-design study. AB - BACKGROUND: Though advances in knowledge and diagnostics make it possible today to identify persons with early-onset dementia or a related cognitive disorder much sooner, little is known about the support needs of the family caregivers of these persons. The aim of this study was to document the unmet support needs of this specific group of caregivers. This knowledge is essential to open avenues for the development of innovative interventions and professional services tailored to their specific needs. METHODS: This study was conducted using a mixed research design. Participants were 32 family caregivers in their 50s recruited through memory clinics and Alzheimer Societies in Quebec (Canada). The Family Caregivers Support Agreement (FCSA) tool, based on a partnership approach between caregiver and assessor, was used to collect data in the course of a semi structured interview, combined with open-ended questions. RESULTS: The unmet support needs reported by nearly 70% of the caregivers were primarily of a psycho educational nature. Caregivers wished primarily: (1) to receive more information on available help and financial resources; (2) to have their relatives feel valued as persons and to offer them stimulating activities adjusted to their residual abilities; (3) to reduce stress stemming from their caregiver role assumed at an early age and to have the chance to enjoy more time for themselves; and (4) to receive help at the right time and for the help to be tailored to their situation of caregiver of a young person. CONCLUSIONS: Results show numerous unmet support needs, including some specific to this group of family caregivers. Use of the FCSA tool allowed accurately assessing the needs that emerged from mutual exchanges. Avenues for professional innovative interventions are proposed. PMID- 25550686 TI - The critical elements of effective academic-practice partnerships: a framework derived from the Department of Veterans Affairs Nursing Academy. AB - BACKGROUND: The nursing profession is exploring how academic-practice partnerships should be structured to maximize the potential benefits for each partner. As part of an evaluation of the U.S. Department of Veterans Affairs Nursing Academy (VANA) program, we sought to identify indicators of successful partnerships during the crucial first year. METHODS: We conducted a qualitative analysis of 142 individual interviews and 23 focus groups with stakeholders from 15 partnerships across the nation. Interview respondents typically included the nursing school Dean, the VA chief nurse, both VANA Program Directors (VA-based and nursing school-based), and select VANA faculty members. The focus groups included a total of 222 VANA students and the nursing unit managers and staff from units where VANA students were placed. An ethnographic approach was utilized to identify emergent themes from these data that underscored indicators of and influences on Launch Year achievement. RESULTS: We emphasize five key themes: the criticality of inter-organizational collaboration; challenges arising from blending different cultures; challenges associated with recruiting nurses to take on faculty roles; the importance of structuring the partnership to promote evidence-based practice and simulation-based learning in the clinical setting; and recognizing that stable relationships must be based on long-term commitments rather than short-term changes in the demand for nursing care. CONCLUSIONS: Developing an academic-clinical partnership requires identifying how organizations with different leadership and management structures, different responsibilities, goals and priorities, different cultures, and different financial models and accountability systems can bridge these differences to develop joint programs integrating activities across the organizations. The experience of the VANA sites in implementing academic-clinical partnerships provides a broad set of experiences from which to learn about how such partnerships can be effectively implemented, the barriers and challenges that will be encountered, and strategies and factors to overcome challenges and build an effective, sustainable partnership. This framework provides actionable guidelines for structuring and implementing effective academic-practice partnerships that support undergraduate nursing education. PMID- 25550687 TI - CDK2-AP1 inhibits growth of breast cancer cells by regulating cell cycle and increasing docetaxel sensitivity in vivo and in vitro. AB - BACKGROUND: Cell cycle regulatory pathway is a well-established pathway mainly dependent on cyclin-dependent kinases (CDKs), which are regulated positively by cyclins and negatively by cyclin-dependent kinase inhibitors(CKIs). Cyclin dependent kinase 2 associate protein 1(CDK2-AP1) is a specific negative regulatory protein for CDK2, is important in the cancer cell cycle. However, the function of CDK2-AP1 in breast cancer remains unclear. We designed therefore explored the effects of CDK2-AP1 on breast cancer growth and its chemo sensitivity. METHODS: Expression of CDK2-AP1, CDK2 and CyclinD1 in 209 cases of pathological specimens using IHC staining was measured. Lost-of-function and Gain of-function assays were used in vivo and in vitro relating to the specific role of CDK2-AP1 in breast cancer. We analyzed in vivo and in vitro the impact of CDK2 AP1 on chemotherapy sensitivity in breast cancer. RESULTS: The positive ratio of CDK2-AP1 expression was reduced successively in normal breast tissue, DCIS, invasive breast cancer and relapsed breast cancer, however, with CDK2 and CyclinD1 it was suggested that CDK2-AP1 was correlated closely with the tumorigenesis and progress, and might work as a tumor suppressor. After down regulating CDK2-AP1 in breast cancer cells, the cell cycle was accelerated and cell proliferation enhanced. The cell cycle was arrested in G0/G1 phase and G2/M phase after up-regulating CDK2-AP1 in breast cancer cells, inhibiting cell proliferation. The expression of CDK2 and CyclinD1 changed accordingly after downregulation or upregulation of CDK2-AP1 by western blot, suggesting a role of the CDK2-AP1/CDK2/CyclinD1 cell cycle pathway in the initiation and progression of breast cancer. Similar results were obtained in animal assays. The data indicates that CDK2-AP1 can induce sensitivity to docetaxel treatment in breast cancer cells. CONCLUSIONS: CDK2-AP1 affects tumorigenesis, tumor growth and chemo sensitivity by cell cycle regulation, which can potentially to be a therapeutical agent in breast cancer. PMID- 25550688 TI - Differential drug resistance acquisition to doxorubicin and paclitaxel in breast cancer cells. AB - BACKGROUND: Several signal transduction pathways have been reported being involved in the acquisition of P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) upon exposure to anti-cancer drugs, whereas there is evidence indicating that the expression and activity of P-gp were not equally or even reversely modulated by different drugs. METHODS: To further illustrate this drug specific effect, possible mechanisms that enable breast cancer cells MCF-7 to acquire MDR to either paclitaxel (PTX) or doxorubicin (DOX) were investigated in a time-dependent manner. RESULTS: The results suggested that at least two pathways participated in this process. One was the short and transient activation of NF-kappaB, the second one was the relatively prolonged induction of PXR. Both PXR and NF-kappaB pathways took part in the PTX drug resistance acquisition, whereas DOX did not exert a significant effect on the PXR-mediated induction of P gp. Furthermore, the property of NF-kappaB activation shared by DOX and PTX was not identical. An attempt made in the present study demonstrated that the acquired resistance to DOX was via or partially via NF-kappaB activation but not its upstream receptor TLR4, while PTX can induce the drug resistance via TLR4-NF kappaB pathway. CONCLUSIONS: To our knowledge, this report is among the first to directly compare the time dependence of NF-kappaB and PXR pathways. The current study provides useful insight into the distinct ability of DOX and PTX to induce P-gp mediated MDR in breast cancer. Different strategies may be required to circumvent MDR in the presence of different anti-cancer drugs. PMID- 25550689 TI - Implementation of integrated care for type 2 diabetes: a protocol for mixed methods research. AB - INTRODUCTION: While integrated care for diabetes mellitus type 2 has achieved good results in terms of intermediate clinical and process outcomes, the evidence based knowledge on its implementation is scarce, and insights generalisable to other settings therefore remain limited. OBJECTIVE: This study protocol provides a description of the design and methodology of a mixed methods study on the implementation of integrated care for type 2 diabetes. The aim of the proposed research is to investigate the mechanisms by which and the context in which integrated care for type 2 diabetes has been implemented, which outcomes have been achieved and how the context and mechanisms have affected the outcomes. METHODS: This article describes a convergent parallel mixed methods research design, including a systematic literature review on the implementation of integrated care for type 2 diabetes as well as a case study on two Dutch best practices on integrated care for type 2 diabetes. DISCUSSION: The implementation of integrated care for diabetes type 2 is an under-researched area. Insights from this study could be applied to other settings as well as other chronic conditions to strengthen the evidence on the implementation of integrated care. PMID- 25550690 TI - Project INTEGRATE - a common methodological approach to understand integrated health care in Europe. AB - BACKGROUND: The use of case studies in health services research has proven to be an excellent methodology for gaining in-depth understanding of the organisation and delivery of health care. This is particularly relevant when looking at the complexity of integrated healthcare programmes, where multifaceted interactions occur at the different levels of care and often without a clear link between the interventions (new and/or existing) and their impact on outcomes (in terms of patients health, both patient and professional satisfaction and cost effectiveness). Still, integrated care is seen as a core strategy in the sustainability of health and care provision in most societies in Europe and beyond. More specifically, at present, there is neither clear evidence on transferable factors of integrated care success nor a method for determining how to establish these specific success factors. The drawback of case methodology in this case, however, is that the in-depth results or lessons generated are usually highly context-specific and thus brings the challenge of transferability of findings to other settings, as different health care systems and different indications are often not comparable. Project INTEGRATE, a European Commission funded project, has been designed to overcome these problems; it looks into four chronic conditions in different European settings, under a common methodology framework (taking a mixed-methods approach) to try to overcome the issue of context specificity and limited transferability. The common methodological framework described in this paper seeks to bring together the different case study findings in a way that key lessons may be derived and transferred between countries, contexts and patient-groups, where integrated care is delivered in order to provide insight into generalisability and build on existing evidence in this field. METHODOLOGY: To compare the different integrated care experiences, a mixed-methods approach has been adopted with the creation of a common methodological framework (including data collection tools and case study template report) to be used by the case studies for their analyses. METHODS OF ANALYSIS: The four case studies attempt to compare health care services before and after the 'integration' of care, while triangulating the findings using quantitative and qualitative data, and provide an in-depth description of the organisation and delivery of care, and the impact on outcomes. The common framework aims to allow for the extraction of key transferable learning from the cases, taking into account context-dependency. CONCLUSION: The application and evaluation of the common methodological approach aim to distill and identify important elements for successful integrated care, in order to strengthen the evidence base for integrated care (by facilitating cross-context comparisons), increase the transferability of findings from highly context-specific to other settings and lead to concrete and practical policy and operational recommendations. PMID- 25550691 TI - Health care agreements as a tool for coordinating health and social services. AB - INTRODUCTION: In 2007, a substantial reform changed the administrative boundaries of the Danish health care system and introduced health care agreements to be signed between municipal and regional authorities. To assess the health care agreements as a tool for coordinating health and social services, a survey was conducted before (2005-2006) and after the reform (2011). THEORY AND METHODS: The study was designed on the basis of a modified version of Alter and Hage's framework for conceptualising coordination. Both surveys addressed all municipal level units (n = 271/98) and a random sample of general practitioners (n = 700/853). RESULTS: The health care agreements were considered more useful for coordinating care than the previous health plans. The power relationship between the regional and municipal authorities in drawing up the agreements was described as more equal. Familiarity with the agreements among general practitioners was higher, as was the perceived influence of the health care agreements on their work. DISCUSSION: Health care agreements with specific content and with regular follow-up and systematic mechanisms for organising feedback between collaborative partners exemplify a useful tool for the coordination of health and social services. CONCLUSION: There are substantial improvements with the new health agreements in terms of formalising a better coordination of the health care system. PMID- 25550692 TI - The use of outcome and process indicators to incentivize integrated care for frail older people: a case study of primary care services in Sweden. AB - BACKGROUND: A number of reforms have been implemented in Swedish health care to support integrated care for frail older people and to reduce utilization of hospital care by this group. Outcomes and process indicators have been used in pay-for-performance (P4P) schemes by both national and local governments to support developments. OBJECTIVE: To analyse limitations in the use of outcome and process indicators to incentivize integrated care for elderly patients with significant health care needs in the context of primary care. METHOD: Data were collected from the Region Skane county council. Eight primary care providers and associated community services were compared in a ranking exercise based on information from interviews and registered data. Registered data from 150 primary care providers were analysed in regression models. RESULTS AND CONCLUSION: Both the ranking exercise and regression models revealed important problems related to risk-adjustment, attribution, randomness and measurement fixation when using indicators in P4P schemes and for external accountability purposes. Instead of using indicators in incentive schemes targeting individual providers, indicators may be used for diagnostic purposes and to support development of new knowledge, targeting local systems that move beyond organizational boundaries. PMID- 25550693 TI - The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy. AB - The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy. PMID- 25550695 TI - Reference values for peripheral blood lymphocyte subsets in a healthy korean population. AB - Flow cytometric immunophenotyping of peripheral blood lymphocyte subsets is a powerful tool for evaluating cellular immunity and monitoring immune-mediated diseases. The numbers and proportions of blood lymphocyte subsets are influenced by factors such as gender, age, ethnicity, and lifestyle. This study aimed to establish reference ranges for peripheral blood lymphocyte subsets in a healthy Korean population. Blood samples from 294 healthy adults were collected. Lymphocyte subsets were analyzed using a single-platform method with a flow cytometer; white blood cells and lymphocytes were analyzed using an automated hematology analyzer. The mean value of the white blood cell count was 5,665 cells/ul, and the mean values of the subtype counts (percentages) were as follows: lymphocytes, 1,928 cells/ul (35.08%); CD3(+) cells, 1,305 cells/ul (67.53%); CD3(+)CD4(+) cells, 787 cells/ul (40.55%); CD3(+)CD8(+) cells, 479 cells/ul (25.23%); CD3(-)CD19(+) cells, 203 cells/ul (10.43%); and CD3(-)CD56(+) cells, 300 cells/ul (15.63%). Additionally, the CD4(+)/CD8(+) ratio was 1.81. In this study, gender and age significantly influenced blood lymphocyte subsets. Our results demonstrate that, as with other populations, a healthy Korean population has its own, region-specific, lymphocyte subset reference ranges. PMID- 25550696 TI - Simultaneous Inhibition of CXCR4 and VLA-4 Exhibits Combinatorial Effect in Overcoming Stroma-Mediated Chemotherapy Resistance in Mantle Cell Lymphoma Cells. AB - There is growing evidence that crosstalk between mantle cell lymphoma (MCL) cells and stromal microenvironments, such as bone marrow and secondary lymphoid tissues, promotes tumor progression by enhancing survival and growth as well as drug resistance of MCL cells. Recent advances in the understanding of lymphoma microenvironment have led to the identification of crucial factors involved in the crosstalk and subsequent generation of their targeted agents. In the present study, we evaluated the combinatory effect of blocking antibodies (Ab) targeting CXCR4 and VLA-4, both of which were known to play significant roles in the induction of environment-mediated drug resistance (EMDR) in MCL cell line, Jeko 1. Simultaneous treatment with anti-CXCR4 and anti-VLA-4 Ab not only reduced the migration of Jeko-1 cells into the protective stromal cells, but also enhanced sensitivity of Jeko-1 to a chemotherapeutic agent to a greater degree than with either Ab alone. These combinatorial effects were associated with decreased phosphorylation of ERK1/2, AKT and NF-kappaB. Importantly, drug resistance could not be overcome once the adhesion of Jeko-1 to the stromal occurred despite the combined use of Abs, suggesting that the efforts to mitigate migration of MCLs should be attempted as much as possible. Our results provide a basis for a future development of therapeutic strategies targeting both CXCR4 and VLA-4, such as Ab combinations or bispecific antibodies, to improve treatment outcomes of MCL with grave prognosis. PMID- 25550694 TI - Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. AB - T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation. PMID- 25550697 TI - Characterization of Proinflammatory Responses and Innate Signaling Activation in Macrophages Infected with Mycobacterium scrofulaceum. AB - Mycobacterium scrofulaceum is an environmental and slow-growing atypical mycobacterium. Emerging evidence suggests that M. scrofulaceum infection is associated with cervical lymphadenitis in children and pulmonary or systemic infections in immunocompromised adults. However, the nature of host innate immune responses to M. scrofulaceum remains unclear. In this study, we examined the innate immune responses in murine bone marrow-derived macrophages (BMDMs) infected with different M. scrofulaceum strains including ATCC type strains and two clinically isolated strains (rough and smooth types). All three strains resulted in the production of proinflammatory cytokines in BMDMs mediated through toll-like receptor-2 and the adaptor MyD88. Activation of MAPKs (extracellular signal-regulated kinase 1/2, and p38, and c-Jun N-terminal kinase) and nuclear receptor (NF)-kappaB together with intracellular reactive oxygen species generation were required for the expression of proinflammatory cytokines in BMDMs. In addition, the rough morphotypes of M. scrofulaceum clinical strains induced higher levels of proinflammatory cytokines, MAPK and NF-kappaB activation, and ROS production than other strains. When mice were infected with different M. scrofulaceum strains, those infected with the rough strain showed the greatest hepatosplenomegaly, granulomatous lesions, and immune cell infiltration in the lungs. Notably, the bacterial load was higher in mice infected with rough colonies than in mice infected with ATCC or smooth strains. Collectively, these data indicate that rough M. scrofulaceum induces higher inflammatory responses and virulence than ATCC or smooth strains. PMID- 25550698 TI - SUMO Proteins are not Involved in TGF-beta1-induced, Smad3/4-mediated Germline alpha Transcription, but PIASy Suppresses it in CH12F3-2A B Cells. AB - TGF-beta induces IgA class switching by B cells. We previously reported that Smad3 and Smad4, pivotal TGF-beta signal-transducing transcription factors, mediate germline (GL) alpha transcription induced by TGF-beta1, resulting in IgA switching by mouse B cells. Post-translational sumoylation of Smad3 and Smad4 regulates TGF-beta-induced transcriptional activation in certain cell types. In the present study, we investigated the effect of sumoylation on TGF-beta1 induced, Smad3/4-mediated GLalpha transcription and IgA switching by mouse B cell line, CH12F3-2A. Overexpression of small ubiquitin-like modifier (SUMO)-1, SUMO-2 or SUMO-3 did not affect TGF-beta1-induced, Smad3/4-mediated GLalpha promoter activity, expression of endogenous GLalpha transcripts, surface IgA expression, and IgA production. Next, we tested the effect of the E3 ligase PIASy on TGF beta1-induced, Smad3/4-mediated GLalpha promoter activity. We found that PIASy overexpression suppresses the GLalpha promoter activity in cooperation with histone deacetylase 1. Taken together, these results suggest that SUMO itself does not affect regulation of GLalpha transcription and IgA switching induced by TGF-beta1/Smad3/4, while PIASy acts as a repressor. PMID- 25550699 TI - Evidence for Direct Inhibition of MHC-Restricted Antigen Processing by Dexamethasone. AB - Dexamethasone (Dex) was shown to inhibit the differentiation, maturation, and antigen-presenting function of dendritic cells (DC) when added during DC generation or maturation stages. Here, we examined the direct effects of Dex on MHC-restricted antigen processing. Macrophages were incubated with microencapsulated ovalbumin (OVA) in the presence of different concentrations of Dex for 2 h, and the efficacy of OVA peptide presentation was evaluated using OVA specific CD8 and CD4 T cells. Dex inhibited both class I- and class II-restricted presentation of OVA to T cells; this inhibitory effect on antigen presentation was much more potent in immature macrophages than in mature macrophages. The presentation of the exogenously added OVA peptide SIINFEKL was not blocked by Dex. In addition, short-term treatment of macrophages with Dex had no discernible effects on the phagocytic activity, total expression levels of MHC molecules or co-stimulatory molecules. These results demonstrate that Dex inhibits intracellular processing events of phagocytosed antigens in macrophages. PMID- 25550700 TI - Current issues of pediatric inflammatory bowel disease in Korea. AB - Inflammatory bowel disease (IBD) is a chronic relapsing disorder of unknown etiology, which is believed to be multifactorial. Recently, the incidence of pediatric IBD has steeply increased in Korea since 2000. Poorly controlled disease activity can result in complications such as intestinal fistulae, abscess, and stricture, as well as growth retardation and delayed puberty in children. Because of a lack of confirmative tests, various diagnostic modalities must be used to diagnose IBD. Onset age, location, behavior, and activity are important in selecting treatments. Monogenic IBD must be excluded among infantile and refractory very-early-onset IBD. Early aggressive therapy using biologics has recently been proposed for peripubertal children to prevent growth failure and malnutrition. PMID- 25550702 TI - A comparison of the efficacy of amoxicillin and nasal irrigation in treatment of acute sinusitis in children. AB - PURPOSE: The efficacy of antibiotic therapy for acute sinusitis is controversial. This study aimed to compare the efficacies of amoxicillin with nasal irrigation and nasal irrigation alone for acute sinusitis in children. METHODS: This randomized, double-blind, controlled study included 80 children aged 4-15 years with a clinical presentation of acute sinusitis. Patients were randomly assigned to receive either amoxicillin (80 mg/kg/day) in 3 divided doses orally for 14 days with saline nasal irrigation (for 5 days) and 0.25% phenylephrine (for 2 days) or the same treatment without amoxicillin. Clinical improvements in their initial symptoms were assessed on days 3, 14, 21, and 28. RESULTS: On day 3, patients in the amoxicillin with nasal irrigation group showed significant clinical improvement (P=0.001), but there was no significant difference in the degree of improvement between the amoxicillin with nasal irrigation and nasal irrigation alone groups during follow-up (P>0.05). In addition, no significant differences were seen in age, sex, and degree of improvement between groups (P>0.05). CONCLUSION: High-dose amoxicillin with saline nasal irrigation relieved acute sinusitis symptoms faster and more often than saline nasal irrigation alone. However, antibiotic treatment for acute sinusitis confers only a small therapeutic benefit over nasal irrigation. PMID- 25550701 TI - Vascular health late after Kawasaki disease: implications for accelerated atherosclerosis. AB - Kawasaki disease (KD), an acute vasculitis that primarily affects young children, is the most common acquired paediatric cardiovascular disease in developed countries. While sequelae of arterial inflammation in the acute phase of KD are well documented, its late effects on vascular health are increasingly unveiled. Late vascular dysfunction is characterized by structural alterations and functional impairment in term of arterial stiffening and endothelial dysfunction and shown to involve both coronary and systemic arteries. Further evidence suggests that continuous low grade inflammation and ongoing active remodeling of coronary arterial lesions occur late after acute illness and may play a role in structural and functional alterations of the arteries. Potential importance of genetic modulation on vascular health late after KD is implicated by associations between mannose binding lectin and inflammatory gene polymorphisms with severity of peripheral arterial stiffening and carotid intima-media thickening. The changes in cholesterol and lipoproteins levels late after KD further appear similar to those proposed to be atherogenic. While data on adverse vascular health are less controversial in patients with persistent or regressed coronary arterial aneurysms, data appear conflicting in individuals with no coronary arterial involvements or only transient coronary ectasia. Notwithstanding, concerns have been raised with regard to predisposition of KD in childhood to accelerated atherosclerosis in adulthood. Until further evidence-based data are available, however, it remains important to assess and monitor cardiovascular risk factors and to promote cardiovascular health in children with a history of KD in the long term. PMID- 25550703 TI - Effect of adenotonsillar hypertrophy on right ventricle function in children. AB - PURPOSE: Chronic upper airway obstruction causes hypoxemic pulmonary vasoconstriction, which may lead to right ventricle (RV) dysfunction. Adenotonsillar hypertrophy (ATH) is the most common cause of upper airway obstruction in children. Therefore, we aimed to evaluate RV function in children with ATH. METHODS: Twenty-one children (male/female, 15/6; mean age, 92.3!3/439.0 months; age range, 4-15 years) with ATH and 21 healthy age- and gender-matched controls were included in this study. Tricuspid annular plane systolic excursion and RV myocardial performance index were measured by transthoracic echocardiography. Further, the plasma level of N-terminal of probrain natriuretic peptide (NT-proBNP), an indicator of RV function, was determined. RESULTS: The snoring-tiredness during daytime-observed apnea-high blood pressure (STOP) questionnaire was completed by the patients' parents, and loud snoring was noted in the ATH group. The plasma NT-proBNP level was significantly higher in the ATH group than that in the controls (66.44+/-37.63 pg/mL vs. 27.85+/-8.89 pg/mL, P=0.001). The echocardiographic parameters were not significantly different between the groups. CONCLUSION: We were unable to confirm the significance of echocardiographic evidence of RV dysfunction in the management of children with ATH. However, the plasma NT-proBNP level was significantly higher in the ATH group than that in the control, suggesting that chronic airway obstruction in children may carry a risk for cardiac dysfunction. Therefore, more patients should be examined using transthoracic echocardiography. In addition, pediatricians and otolaryngologists should consider cardiologic aspects during the management of children with severe ATH. PMID- 25550704 TI - Clinical features and short-term outcomes of pediatric acute fulminant myocarditis in a single center. AB - PURPOSE: The aims of this study were to document our single-center experience with pediatric acute fulminant myocarditis (AFM) and to investigate its clinical features and short-term outcomes. METHODS: We performed a retrospective chart review of all children <18 years old who were diagnosed with AFM between October 2008 and February 2013. Data about patient demographics, initial symptoms, investigation results, management, and outcomes between survivors and nonsurvivors were collected. RESULTS: Seventeen of 21 patients (80.9%) with myocarditis were diagnosed with AFM. Eleven patients (64.7%) survived to discharge, and 6 (35.3%) died. Electrocardiography on admission revealed dysrhythmia in 10 patients (58.8%); of these, all 7 patients with a complete atrioventricular block survived. Fractional shortening upon admission was significantly different between the survivors (16%) and nonsurvivors (8.5%) (P=0.01). Of the serial biochemical markers, only the initial brain natriuretic peptide (P=0.03) and peak blood urea nitrogen levels (P=0.02) were significantly different. Of 17 patients, 4 (23.5%) required medical treatment only. Extracorporeal membrane oxygenation (ECMO) was performed in 13 patients (76.5%); the survival rate in these patients was 53.8%. ECMO support was initiated >24 hours after admission in 4 of the 13 patients (30.7%), and 3 of those 4 patients (75%) died. CONCLUSION: AFM outcomes may be associated with complete atrioventricular block upon hospital admission, left ventricular fractional shortening at admission, time from admission to the initiation of ECMO support, initial brain natriuretic peptide level, and peak blood urea nitrogen level. PMID- 25550705 TI - Wernicke's encephalopathy in a child with high dose thiamine therapy. AB - Wernicke's encephalopathy is an acute neurological disorder characterized by mental confusion, oculomotor dysfunction, and ataxia. It has been reported in individuals with alcohol dependence, hyperemesis gravidarum, and prolonged parenteral nutrition without vitamin supplementation. Here we present the case of a 13-year-old male patient with neuroblastoma and a history of poor oral intake and nausea for 3 months. After admission, he showed gait disturbances, nystagmus, and excessive dizziness; his mental state, however, indicated he was alert, which did not fit the classical triad of Wernicke's encephalopathy. A diagnosis of Wernicke's encephalopathy was made only after brain magnetic resonance imaging and serum thiamine level analyses were performed. The patient's symptoms remained after 5 days of treatment with 100-mg thiamine once daily; thus, we increased the dosage to 500 mg 3 times daily, 1,500 mg per day. His symptoms then improved after 20 days of replacement therapy. This case report describes a pediatric patient who was promptly diagnosed with Wernicke's encephalopathy, despite only 2 suspicious symptoms, and who completely recovered after high doses of thiamine were given intravenously. PMID- 25550706 TI - Multifocal kaposiform hemangioendothelioma of soft tissue with bilateral pulmonary involvement in an adolescent. AB - Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor of intermediate malignancy with resemblance to Kaposi sarcoma. It occurs predominantly in pediatric age groups as a cutaneous lesion with focal infiltration into the adjacent soft tissue and bone. Although visceral involvement is very uncommon, several cases with bone, retroperitoneal, or mediastinal involvement have been described. KHE has been reported to occasionally occur in unusual sites such as the thymus, tonsils, larynx, paranasal sinuses, deltoid muscle, spleen, uterine cervix, thoracic spine, and even the breast. Multifocal KHE is an extremely rare entity with few reports available in the literature, none of which describes pulmonary involvement. Herein, we report a unique case of multifocal KHE in a 13-year-old boy presenting with a huge soft tissue mass in the upper extremity complicated by bilateral pulmonary nodules that developed into large, necrotic tumor masses. PMID- 25550707 TI - Sinonasal adenoid cystic carcinoma following formaldehyde exposure in the operating theatre. AB - We present a case report of an auxiliary nurse who developed an adenoid cystic carcinoma in her left maxillary sinus following occupational exposure to formaldehyde in the operating theatre. Currently, the epidemiological evidence that formaldehyde can cause cancer in humans is considered to be limited. Previous case-control-studies of formaldehyde and sinonasal cancer have mainly investigated subjects who were concomitantly exposed to wood dust, a known risk factor to the development of sinonasal adenocarcinoma of intestinal type. Our case report presents a patient who has developed an adenoid cystic carcinoma following exposure to formaldehyde. We suggest that the occupational physician remains alert to formaldehyde as an occupational hazard among health care workers. PMID- 25550708 TI - Outcome-volume relationships and transhiatal esophagectomy: minimizing "failure to rescue". AB - BACKGROUND: The objective of this study is to describe the system and technical factors that enabled our moderate size transhiatal esophagectomy program to achieve low mortality rates. METHODS: A retrospective chart review was conducted on 200 consecutive patients who underwent transhiatal esophagectomy at Robert Wood Johnson University Hospital. Primary outcomes included operative times, estimated blood loss, frequency and nature of complications, and lengths of stay in the hospital and the intensive care unit. RESULTS: In general, surgical outcomes tended to improve over the course of this study. We identified decreased operative time, intra-operative blood loss, frequency of complications, and lengths of intensive care unit and hospital stay as the program matured. Through coordinated actions of the surgical and anesthesia teams, all intraoperative injuries were responded to in an effective, emergent fashion and all but one patient was saved. This resulted in an inhospital and 30-day mortality rate of only 0.5%. CONCLUSIONS: Our study suggests that a dual attending approach, focus on avoiding "failure to rescue", increased volume, and a surgeon driven commitment to quality improvement may lead to low mortality rates after transhiatal esophagectomy. PMID- 25550709 TI - HeatmapGenerator: high performance RNAseq and microarray visualization software suite to examine differential gene expression levels using an R and C++ hybrid computational pipeline. AB - BACKGROUND: The graphical visualization of gene expression data using heatmaps has become an integral component of modern-day medical research. Heatmaps are used extensively to plot quantitative differences in gene expression levels, such as those measured with RNAseq and microarray experiments, to provide qualitative large-scale views of the transcriptonomic landscape. Creating high-quality heatmaps is a computationally intensive task, often requiring considerable programming experience, particularly for customizing features to a specific dataset at hand. METHODS: Software to create publication-quality heatmaps is developed with the R programming language, C++ programming language, and OpenGL application programming interface (API) to create industry-grade high performance graphics. RESULTS: We create a graphical user interface (GUI) software package called HeatmapGenerator for Windows OS and Mac OS X as an intuitive, user friendly alternative to researchers with minimal prior coding experience to allow them to create publication-quality heatmaps using R graphics without sacrificing their desired level of customization. The simplicity of HeatmapGenerator is that it only requires the user to upload a preformatted input file and download the publicly available R software language, among a few other operating system specific requirements. Advanced features such as color, text labels, scaling, legend construction, and even database storage can be easily customized with no prior programming knowledge. CONCLUSION: We provide an intuitive and user friendly software package, HeatmapGenerator, to create high-quality, customizable heatmaps generated using the high-resolution color graphics capabilities of R. The software is available for Microsoft Windows and Apple Mac OS X. HeatmapGenerator is released under the GNU General Public License and publicly available at: http://sourceforge.net/projects/heatmapgenerator/. The Mac OS X direct download is available at: http://sourceforge.net/projects/heatmapgenerator/files/HeatmapGenerator_MAC_OSX.t r.gz/download. The Windows OS direct download is available at: http://sourceforge.net/projects/heatmapgenerator/files/HeatmapGenerator_WINDOWS.z p/download. PMID- 25550710 TI - LC-MS/MS determination and pharmacokinetic study of columbianadin in rat plasma after intravenous administration of pure columbianadin. AB - BACKGROUND: Columbianadin, one of the active coumarins, is isolated from Radix Angelicae pubescentis which has been used as a traditional Chinese medicine for the treatment of rheumatic diseases for thousands of years. A fast and sensitive method is required for the determination of columbianadin for pharmacokinetic studies. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is a preeminent analytical tool for rapid biomedical analysis. RESULTS: A sensitive LC MS/MS method has been validated to determine the concentration of columbianadin in rat plasma after intravenous administration of columbianadin (1, 2.5 and 5 mg kg(-1)). Liquid-liquid extraction was used to extract columbianadin from the rat plasma. Bergapten was selected as an internal standard (IS). The separations were performed on an Eclipse plus C18 column (4.6 * 100 mm, 1.8 MUm) with ammonium acetate aqueous solution (1 mmol L(-1)) and acetonitrile as the mobile phase. The flow rate was set at 0.300 mL min(-1). Quantification was performed using multiple reaction monitoring (MRM) mode to monitor transitions of m/z 329.3 -> 229.3 for columbianadin and m/z 217.2 -> 202.2 for IS at positive ionization mode. The calibration curve was linear over the concentration range of 4-20000 ng mL(-1) with a correlation coefficient (r) of 0.996 or better. The precision of intra- and inter-batch assays ranged from 4.02 to 7.33% and accuracies determined at three concentrations ranged between 91.9% and 106%. The lower limit of quantification was about 4 ng mL(-1). CONCLUSION: The proposed LC-MS/MS method is simple, rapid and highly sensitive so that it could be used to evaluate pharmacokinetic properties of columbianadin in rat plasma after intravenous administration. PMID- 25550712 TI - An acidic, thermostable exochitinase with beta-N-acetylglucosaminidase activity from Paenibacillus barengoltzii converting chitin to N-acetyl glucosamine. AB - BACKGROUND: N-acetyl-beta-D-glucosamine (GlcNAc) is widely used as a valuable pharmacological agent and a functional food additive. The traditional chemical process for GlcNAc production has some problems such as high production cost, low yield, and acidic pollution. Hence, to identify a novel chitinase that is suitable for bioconversion of chitin to GlcNAc is of great value. RESULTS: A novel chitinase gene (PbChi74) from Paenibacillus barengoltzii was cloned and heterologously expressed in Escherichia coli as an intracellular soluble protein. The gene has an open reading frame (ORF) of 2,163 bp encoding 720 amino acids. The recombinant chitinase (PbChi74) was purified to apparent homogeneity with a purification fold of 2.2 and a recovery yield of 57.9%. The molecular mass of the purified enzyme was estimated to be 74.6 kDa and 74.3 kDa by SDS-PAGE and gel filtration, respectively. PbChi74 displayed an acidic pH optimum of 4.5 and a temperature optimum of 65 degrees C. The enzyme showed high activity toward colloidal chitin, glycol chitin, N-acetyl chitooligosaccharides, and p nitrophenyl N-acetyl beta-glucosaminide. PbChi74 hydrolyzed colloidal chitin to yield N-acetyl chitobiose [(GlcNAc)2] at the initial stage, which was further converted to its monomer N-acetyl glucosamine (GlcNAc), suggesting that it is an exochitinase with beta-N-acetylglucosaminidase activity. The purified PbChi74 coupled with RmNAG (beta-N-acetylglucosaminidase from Rhizomucor miehei) was used to convert colloidal chitin to GlcNAc, and GlcNAc was the sole end product at a concentration of 27.8 mg mL(-1) with a conversion yield of 92.6%. These results suggest that PbChi74 may have great potential in chitin conversion. CONCLUSIONS: The excellent thermostability and hydrolytic properties may give the exochitinase great potential in GlcNAc production from chitin. This is the first report on an exochitinase with N-acetyl-beta-D-glucosaminidase activity from Paenibacillus species. PMID- 25550713 TI - Congenital middle mesocolic hernia: A case report. AB - Internal hernia is herniation of a viscus, usually in the small bowel, through a normal or abnormal aperture within the peritoneal cavity. Its incidence has been reported to be one to two per cent. Internal hernias are classified based on location, and the hernial orifice can be either congenital or acquired. Paraduodenal hernias are the most common type (53 per cent). Paraduodenal hernia is often a misnomer and is referred to as a mesocolic hernia. Left and right mesocolic hernias are common, while middle and transverse types are rare. We are reporting a rare congenital middle mesocolic hernia presenting as a complete transection of the small intestine due to blunt injury to the abdomen. PMID- 25550711 TI - Kinetic transcriptome analysis reveals an essentially intact induction system in a cellulase hyper-producer Trichoderma reesei strain. AB - BACKGROUND: The filamentous fungus Trichoderma reesei is the main industrial cellulolytic enzyme producer. Several strains have been developed in the past using random mutagenesis, and despite impressive performance enhancements, the pressure for low-cost cellulases has stimulated continuous research in the field. In this context, comparative study of the lower and higher producer strains obtained through random mutagenesis using systems biology tools (genome and transcriptome sequencing) can shed light on the mechanisms of cellulase production and help identify genes linked to performance. Previously, our group published comparative genome sequencing of the lower and higher producer strains NG 14 and RUT C30. In this follow-up work, we examine how these mutations affect phenotype as regards the transcriptome and cultivation behaviour. RESULTS: We performed kinetic transcriptome analysis of the NG 14 and RUT C30 strains of early enzyme production induced by lactose using bioreactor cultivations close to an industrial cultivation regime. RUT C30 exhibited both earlier onset of protein production (3 h) and higher steady-state productivity. A rather small number of genes compared to previous studies were regulated (568), most of them being specific to the NG 14 strain (319). Clustering analysis highlighted similar behaviour for some functional categories and allowed us to distinguish between induction-related genes and productivity-related genes. Cross-comparison of our transcriptome data with previously identified mutations revealed that most genes from our dataset have not been mutated. Interestingly, the few mutated genes belong to the same clusters, suggesting that these clusters contain genes playing a role in strain performance. CONCLUSIONS: This is the first kinetic analysis of a transcriptomic study carried out under conditions approaching industrial ones with two related strains of T. reesei showing distinctive cultivation behaviour. Our study sheds some light on some of the events occurring in these strains following induction by lactose. The fact that few regulated genes have been affected by mutagenesis suggests that the induction mechanism is essentially intact compared to that for the wild-type isolate QM6a and might be engineered for further improvement of T. reesei. Genes from two specific clusters might be potential targets for such genetic engineering. PMID- 25550714 TI - Cryptogenic invasive Klebsiella pneumoniae liver abscess syndrome (CIKPLA) in Western Australia? AB - Virulent serotypes of Klebsiella pneumoniae are recognised to cause metastatic infections at various sites. Prevalence of this invasive syndrome has been observed worldwide with predominance in Asian series. However, reports in an Australian setting have been limited. We report two cases of fulminating community-acquired invasive Klebsiella pneumoniae liver abscess syndrome occurring in two Caucasian patients, from two different, distant suburbs in Western Australia with no known clinical comorbidities prior to the hospital presentation and no history of recent travel overseas. The interval between both admissions was 18 days, where only one patient survived. PMID- 25550715 TI - Dengue co-infection in a blood stream infection caused by Stenotrophomonas maltophilia: A case report. AB - Stenotrophomonas maltophilia (S. maltophilia) is an emerging opportunistic bacterial pathogen with resistance to several commonly used antibiotics. Owing to its multidrug resistance (MDR), management of S. maltophilia blood stream infection (BSI) is challenging and requires the selection of appropriate antibiotic therapy. The presence of thrombocytopenia and shock are independent risk factors associated with increased mortality in patients with S. maltophilia BSI. We describe an unusual case of S. maltophilia BSI in a middle-age female complicated by dengue fever. We highlight the importance of early recognition of both dengue and S. maltophilia infection in management of such cases. PMID- 25550716 TI - The effectiveness of self-directed learning (SDL) for teaching physiology to first-year medical students. AB - BACKGROUND: Self-directed learning (SDL) has become popular in medical curricula and has been advocated as an effective learning strategy for medical students to develop competence in knowledge acquisition. AIMS: The primary aim was to find out if there was any benefit of supplementing self-directed learning activity with a traditional lecture on two different topics in physiology for first-year medical students. METHOD: Two batches of first-year Bachelor of Medicine and Bachelor of Surgery (MBBS) (Batch A and Batch B) comprising 125 students each, received an SDL session on Morphological classification of anaemia. The students belonging to Batch A received a one-hour lecture on the same topic three days prior to the SDL session. The students were given a 10 multiple choice questions (MCQ) test for a maximum of 10 marks immediately following the SDL session. The next topic, Conducting system of the heart, disorders and conduction blocks was taught to both batches in traditional lecture format. This was followed by an SDL session on the same topic for Batch A only. The students were evaluated with a MCQ test for a maximum of 10 marks. RESULTS: The mean test scores on the first topic were 4.38+/-2.06 (n=119) and 4.17+/-1.71 (n=118) for Batch A and Batch B, respectively. The mean test scores on the second topic were 5.4+/- 1.54 (n=112) and 5.15+/-1.37 (n=107) for Batch A and Batch B, respectively. There was no significant difference between the groups. CONCLUSION: For first-year medical students, SDL is an effective teaching strategy for learning physiology. However, no additional benefit is gained by supplementing SDL with a lecture to facilitate learning physiology. PMID- 25550717 TI - Young Australian adults' reactions to viewing personalised UV photoaged photographs. AB - BACKGROUND: Despite two nationwide sun-protection awareness campaigns, young Australian adults continue to sunbathe. Since their primary motivation for tanning is appearance enhancement, it may well be that campaigns that highlight the negative effects of tanning on appearance are more effective than campaigns that emphasise the health risks associated with sun exposure. AIMS: This study aims to explore young adults' reactions to viewing a photoaged photograph of the sun damage already visible in their facial image. METHOD: Semi-structured interviews were conducted with seven females and three males aged 20-30 years. The interview transcripts were transcribed verbatim and were then subjected to Interpretive Phenomenological Analysis (IPA). RESULTS: Three themes and eight sub themes emerged from the analysis. Collectively they revealed that participants' fear-based reaction to their photoaged photographs triggered in them feelings of unattractiveness, which in turn motivated them to change to their existing sun tanning behaviours. CONCLUSION: Although media-popularised representations of suntanned skin being the desired norm were identified as a barrier to skin protective behavioural change, personalised ultraviolet (UV) photoaged photographs, when accompanied by an explanation of the skin damage that unprotected ultraviolet radiation (UVR) exposure causes, were effective in changing young adults' sun-tanning intentions. Hence, a need exists for positive non-tanning appearance-related messages to be incorporated into sun exposure education campaigns. PMID- 25550718 TI - Did the American Medical Association make the correct decision classifying obesity as a disease? PMID- 25550719 TI - Proton pump inhibitors: Are we still prescribing them without valid indications? AB - BACKGROUND: Evidence from several Western studies has shown an alarmingly high and inappropriate rate of prescription of proton pump inhibitors (PPIs), which may be associated with increased healthcare costs and adverse outcomes. PPI prescribing patterns remain largely unknown in well-developed healthcare systems in Southeast Asia. AIMS: We aimed to determine the prevalence of inappropriate prescription of PPI among elderly patients without documentation of valid indications, in a tertiary teaching hospital in Singapore. METHOD: We carried out a retrospective clinical records review of 150 elderly patients aged >=65 years that had been admitted to two internal medicine wards between 25 May 2011 and 28 June 2011 to determine the appropriateness of indications for PPIs prescribed at hospital discharge. PPI indications were categorised as "valid", "likely invalid", and "probable" based on current clinical literature. Pre-admission and discharge prescriptions were reviewed to determine continuation of pre-admission and new PPI prescriptions at discharge. Data on clinical characteristics and concurrent use of ulcerogenic medications were collected. RESULTS: From a total of 150 patients, 80 (53 per cent) received prescriptions for PPIs. Of these, 65 (81.2 per cent) had no valid documented indications (i.e., the indication was classed as "likely invalid"); 10 (12.5 per cent) had valid indications; and in five cases (6.2 per cent) the indication was "probable". The most common "likely invalid" indication was primary gastrointestinal bleeding prophylaxis (GIP) among low-dose aspirin users in 28 patients (43 per cent) of invalid PPI prescriptions. CONCLUSION: Inappropriate prescribing of PPIs without documented valid indications was prevalent among elderly patients at our tertiary teaching hospital in Singapore, providing evidence that shows a similar trend to PPI prescribing to data from Western countries. PMID- 25550720 TI - Synthesis and characterization of a hyper-branched water-soluble beta cyclodextrin polymer. AB - A new hyper-branched water-soluble polymer was synthesized by reacting beta cyclodextrin with pyromellitic dianhydride beyond the critical conditions that allow the phenomenon of gelation to occur. The molar ratio between the monomers is a crucial parameter that rules the gelation process. Nevertheless, the concentration of monomers in the solvent phase plays a key role as well. Hyper branched beta-cyclodextrin-based polymers were obtained performing the syntheses with excess of solvent and cross-linking agent, and the conditions for critical dilution were determined experimentally. A hyper-branched polymer with very high water solubility was obtained and fully characterized both as for its chemical structure and for its capability to encapsulate substances. Fluorescein was used as probe molecule to test the complexation properties of the new material. PMID- 25550721 TI - Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction. AB - Condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties were prepared by a regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction of a 4-aryl-2-phenyl 1,4-benzoxazepine derivative obtained from flavanone. The relative configuration of products were determined by the correlation of (3) J H,H coupling data with the geometry of major conformers accessed by DFT conformational analysis. Separated enantiomers of the products were characterized by HPLC-ECD data, which allowed their configurational assignment on the basis of TDDFT-ECD calculation of the solution conformers. Two compounds showed neuroprotective activities against hydrogen peroxide (H2O2) or beta-amyloid25-35 (Abeta25-35)-induced cellular injuries in human neuroblastoma SH-SY5Y cells in the range of those of positive controls. PMID- 25550723 TI - Synthesis of a resin monomer-soluble polyrotaxane crosslinker containing cleavable end groups. AB - A resin monomer-soluble polyrotaxane (PRX) crosslinker with cleavable end groups was synthesized to develop degradable photosetting composite resins. The PRX containing 50 alpha-cyclodextrins (alpha-CDs) with disulfide end groups was initially modified with n-butylamine to obtain a resin monomer-soluble PRX. The PRX containing 13 n-butyl groups per alpha-CD molecule was completely soluble in conventional resin monomers such as 2-hydroxyethyl methacrylate (HEMA) and urethane dimethacrylate (UDMA). The synthesized n-butyl-containing PRX was further modified with 2-aminoethyl methacrylate to provide crosslinkable acrylic groups onto PRX. The prepared resin monomer-soluble PRX crosslinker was successfully polymerized with a mixture of HEMA and UDMA to provide photosetting plastic. It was confirmed that the Vickers hardness of the prepared plastic was greatly decreased after treatment with dithiothreitol. This indicates that the resin monomer-soluble PRX crosslinker can be applied to design degradable photosetting plastics potentially used in the industrial or biomedical field. PMID- 25550724 TI - Improving ITC studies of cyclodextrin inclusion compounds by global analysis of conventional and non-conventional experiments. AB - The study of 1:1 cyclodextrin inclusion compounds by isothermal titration calorimetry was explored in a theoretical and experimental point of view to compare the efficiency of conventional and non-conventional experiments. All direct and competitive protocols were described and evaluated in terms of accuracy on both binding constant and inclusion enthalpy. Significant improvement in the calorimetric characterization may be obtained by means of the global analysis of non-conventional experiments coupled to the standard titration protocol. While the titration-release approach proved to be the most accurate strategy for classical complexations, the valuable contribution of other non conventional experiments was demonstrated for issues concerning weak stability, enthalpy, or solubility. PMID- 25550722 TI - Encapsulation of biocides by cyclodextrins: toward synergistic effects against pathogens. AB - Host-guest chemistry is useful for the construction of nanosized objects. Some of the widely used hosts are probably the cyclodextrins (CDs). CDs can form water soluble complexes with numerous hydrophobic compounds. They have been widespread used in medicine, drug delivery and are of interest for the biocides encapsulation. Indeed, this enables the development of more or less complex systems that release antimicrobial agents with time. In this paper, the general features of CDs and their applications in the field of biocides have been reviewed. As the key point is the formation of biocide-CD inclusion complexes, this review deals with this in depth and the advantages of biocide encapsulation are highlighted throughout several examples from the literature. Finally, some future directions of investigation have been proposed. We hope that scientists studying biocide applications receive inspiration from this review to exploit the opportunities offered by CDs in their respective research areas. PMID- 25550725 TI - Cyclodextrin-grafted polymers functionalized with phosphanes: a new tool for aqueous organometallic catalysis. AB - New cyclodextrin (CD)-grafted polymers functionalized with water-soluble phosphanes were synthesized in three steps starting from polyNAS. Once characterized by NMR spectroscopy and size-exclusion chromatography, they were used as additives in Rh-catalyzed hydroformylation of 1-hexadecene. The combined supramolecular and coordinating properties of these polymers allowed increasing the catalytic activity of the reaction without affecting the selectivities. PMID- 25550726 TI - A general metal-free approach for the stereoselective synthesis of C-glycals from unactivated alkynes. AB - A novel metal-free strategy for a rapid and alpha-selctive C-alkynylation of glycals was developed. The reaction utilizes TMSOTf as a promoter to generate in situ trimethylsilylacetylene for C-alkynylation. Thanks to this methodology, we can access C-glycosides in a single step from a variety of acetylenes , i.e., arylacetylenes and most importantly aliphatic alkynes. PMID- 25550727 TI - A green approach to the synthesis of novel phytosphingolipidyl beta-cyclodextrin designed to interact with membranes. AB - This work reports the synthesis of a new family of mono-substituted amphiphilic cyclodextrins using a green methodology. Reactions using greener and safer catalysts with more environmentally friendly purification solvents were performed. Four unreported mono-substituted cyclodextrins bearing a phytosphingolipidyl chain and a fatty acid chain (C10, C12, C14 and C18) were successfully obtained with a promising yield. PMID- 25550728 TI - Galactan synthesis in a single step via oligomerization of monosaccharides. AB - Galactans ranging in length from one to five residues were prepared in a single step by treatment of the glycosyl donor 2,3,4-tri-O-benzoyl-beta-D galactopyranosyl fluoride with lanthanum perchlorate in the presence of an initiator alcohol. The product oligosaccharides were readily chromatographically separable. This oligomerization was used to synthesize a pentagalactan in a single step from monosaccharide building blocks in reasonable overall yields. PMID- 25550729 TI - Design and synthesis of novel bis-annulated caged polycycles via ring-closing metathesis: pushpakenediol. AB - Intricate caged molecular frameworks are assembled by an atom economical process via a Diels-Alder (DA) reaction, a Claisen rearrangement, a ring-closing metathesis (RCM) and an alkenyl Grignard addition. The introduction of olefinic moieties in the pentacycloundecane (PCUD) framework at appropriate positions followed by RCM led to the formation of novel heptacyclic cage systems. PMID- 25550730 TI - One-pot four-component reaction for convenient synthesis of functionalized 1 benzamidospiro[indoline-3,4'-pyridines]. AB - The one-pot four-component reaction of benzohydrazide (2-picolinohydrazide), acetylenedicarboxylate, isatins and malononitrile (ethyl cyanoacetate) with triethylamine as base catalyst afforded functionalized 1-benzamidospiro[indoline 3,4'-pyridines] in good yields. (1)H NMR spectra indicated that an equilibrium of cis/trans-conformations exist in the obtained products. PMID- 25550731 TI - Aspergiloid I, an unprecedented spirolactone norditerpenoid from the plant derived endophytic fungus Aspergillus sp. YXf3. AB - An unusual C18 norditerpenoid, aspergiloid I (1), was isolated from the culture broth of Aspergillus sp. YXf3, an endophytic fungus derived from Ginkgo biloba. Its structure was unambiguously established by analysis of HRMS-ESI and spectroscopic data, and the absolute configuration was determined by low temperature (100 K) single crystal X-ray diffraction with Cu Kalpha radiation. This compound is structurally characterized by a new carbon skeleton with an unprecedented 6/5/6 tricyclic ring system bearing an alpha,beta-unsaturated spirolactone moiety in ring B, and represents a new subclass of norditerpenoid, the skeleton of which is named aspergilane. The hypothetical biosynthetic pathway for 1 was also proposed. The cytotoxic, antimicrobial, anti-oxidant and enzyme inhibitory activities of 1 were evaluated. PMID- 25550732 TI - Solution processable diketopyrrolopyrrole (DPP) cored small molecules with BODIPY end groups as novel donors for organic solar cells. AB - Two novel triads based on a diketopyrrolopyrrole (DPP) central core and two 4,4 difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) units attached by thiophene rings have been synthesised having high molar extinction coefficients. These triads were characterised and used as donor materials in small molecule, solution processable organic solar cells. Both triads were blended with PC71BM as an acceptor in different ratios by wt % and their photovoltaic properties were studied. For both the triads a modest photovoltaic performance was observed, having an efficiency of 0.65%. Moreover, in order to understand the ground and excited state properties and vertical absorption profile of DPP and BODIPY units within the triads, theoretical DFT and TDDFT calculations were performed. PMID- 25550733 TI - Linear-g-hyperbranched and cyclodextrin-based amphiphilic block copolymer as a multifunctional nanocarrier. AB - In this paper, a novel, multifunctional polymer nanocarrier was designed to provide adequate volume for high drug loading, to afford a multiregion encapsulation ability, and to achieve controlled drug release. An amphiphilic, triblock polymer (ABC) with hyperbranched polycarbonsilane (HBPCSi) and beta cyclodextrin (beta-CD) moieties were first synthesized by the combination of a two-step reversible addition-fragmentation transfer polymerization into a pseudo one-step hydrosilylation and quaternization reaction. The ABC then self-assembled into stable micelles with a core-shell structure in aqueous solution. These resulting micelles are multifunctional nanocarriers which possess higher drug loading capability due to the introduction of HBPCSi segments and beta-CD moieties, and exhibit controlled drug release based on the diffusion release mechanism. The novel multifunctional nanocarrier may be applicable to produce highly efficient and specialized delivery systems for drugs, genes, and diagnostic agents. PMID- 25550734 TI - Synthesis and properties of novel star-shaped oligofluorene conjugated systems with BODIPY cores. AB - Star-shaped conjugated systems with varying oligofluorene arm length and substitution patterns of the central BODIPY core have been synthesised, leading to two families of compounds, T-B1-T-B4 and Y-B1-Y-B4, with T- and Y-shaped motifs, respectively. Thermal stability, cyclic voltammetry, absorption and photoluminescence spectroscopy of each member of these two families were studied in order to determine their suitability as emissive materials in photonic applications. PMID- 25550735 TI - Anomalous diffusion of Ibuprofen in cyclodextrin nanosponge hydrogels: an HRMAS NMR study. AB - Ibuprofen sodium salt (IP) was encapsulated in cyclodextrin nanosponges (CDNS) obtained by cross-linking of beta-cyclodextrin with ethylenediaminetetraacetic acid dianhydride (EDTAn) in two different preparations: CDNSEDTA 1:4 and 1:8, where the 1:n notation indicates the CD to EDTAn molar ratio. The entrapment of IP was achieved by swelling the two polymers with a 0.27 M solution of IP in D2O, leading to colourless, homogeneous hydrogels loaded with IP. The molecular environment and the transport properties of IP in the hydrogels were studied by high resolution magic angle spinning (HRMAS) NMR spectroscopy. The mean square displacement (MSD) of IP in the gels was obtained by a pulsed field gradient spin echo (PGSE) NMR pulse sequence at different observation times t d. The MSD is proportional to the observation time elevated to a scaling factor alpha. The alpha values define the normal Gaussian random motion (alpha = 1), or the anomalous diffusion (alpha < 1, subdiffusion, alpha > 1 superdiffusion). The experimental data here reported point out that IP undergoes subdiffusive regime in CDNSEDTA 1:4, while a slightly superdiffusive behaviour is observed in CDNSEDTA 1:8. The transition between the two dynamic regimes is triggered by the polymer structure. CDNSEDTA 1:4 is characterized by a nanoporous structure able to induce confinement effects on IP, thus causing subdiffusive random motion. CDNSEDTA 1:8 is characterized not only by nanopores, but also by dangling EDTA groups ending with ionized COO(-) groups. The negative potential provided by such groups to the polymer backbone is responsible for the acceleration effects on the IP anion thus leading to the superdiffusive behaviour observed. These results point out that HRMAS NMR spectroscopy is a powerful direct method for the assessment of the transport properties of a drug encapsulated in polymeric scaffolds. The diffusion properties of IP in CDNS can be modulated by suitable polymer synthesis; this finding opens the possibility to design suitable systems for drug delivery with predictable and desired drug release properties. PMID- 25550736 TI - Synthesis of the pentasaccharide repeating unit of the O-antigen of E. coli O117:K98:H4. AB - The pentasaccharide repeating unit of the O-antigen of E. coli O117:K98:H4 strain has been synthesized using a combination of sequential glycosylations and [3 + 2] block synthetic strategy from the suitably protected monosaccharide intermediates. Thioglycosides and glycosyl trichloroacetimidate derivatives have been used as glycosyl donors in the glycosylations. PMID- 25550737 TI - Synthesis of nanodiamond derivatives carrying amino functions and quantification by a modified Kaiser test. AB - Nanodiamonds functionalized with different organic moieties carrying terminal amino groups have been synthesized. These include conjugates generated by Diels Alder reactions of ortho-quinodimethanes formed in situ from pyrazine and 5,6 dihydrocyclobuta[d]pyrimidine derivatives. For the quantification of primary amino groups a modified photometric assay based on the Kaiser test has been developed and validated for different types of aminated nanodiamond. The results correspond well to values obtained by thermogravimetry. The method represents an alternative wet-chemical quantification method in cases where other techniques like elemental analysis fail due to unfavourable combustion behaviour of the analyte or other impediments. PMID- 25550738 TI - Stereoselective synthesis of perillaldehyde-based chiral beta-amino acid derivatives through conjugate addition of lithium amides. AB - The Michael addition of dibenzylamine to (+)-tert-butyl perillate (3) and to (+) tert-butyl phellandrate (6), derived from (S)-(-)-perillaldehyde (1), resulted in diastereomeric beta-amino esters 7A-D in a moderately stereospecific reaction in a ratio of 76:17:6:1. After separation of the diastereoisomers, the major product, cis isomer 7A, was quantitatively isomerized to the minor component, trans-amino ester 7D. All four isomers were transformed to the corresponding beta amino acids 10A-D, which are promising building blocks for the synthesis of beta peptides and 1,3-heterocycles in three steps. The steric effects of the isopropyl group at position 4 and of the alpha-methyl substituent of (R)-N-benzyl-N-alpha methylbenzylamine on the reactivity were also studied and, upon application of a chiral amine, excellent stereoselectivity of the conjugate addition was observed. Amino ester 11 was obtained as a single product and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale. PMID- 25550739 TI - Removal of volatile organic compounds using amphiphilic cyclodextrin-coated polypropylene. AB - Polypropylene nonwovens were functionalised using a self-assembled, amphiphilic cyclodextrin coating and the potential for water purification by removal of pollutants was studied. As benzene is one of the problematic compounds in the Water Framework Directive, six volatile organic compounds (benzene and five benzene-based substances) were chosen as model compounds. The compounds were tested as a mixture in order to provide a more realistic situation since the wastewater will be a complex mixture containing multiple pollutants. The volatile organic compounds are known to form stable inclusion complexes with cyclodextrins. Six different amphiphilic cyclodextrin derivatives were synthesised in order to elucidate whether or not the uptake abilities of the coating depend on the structure of the derivative. Headspace gas chromatography was used for quantification of the uptake exploiting the volatile nature of benzene and its derivatives. The capacity was shown to increase beyond the expected stoichiometries of guest-host complexes with ratios of up to 16:1. PMID- 25550740 TI - Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space. AB - The diastereoselective oxazoline-directed lithiation of calix[4]arenes is reported with diastereoselective ratios of greater than 100:1 in some instances. Notably, it has been found that the opposite diastereomer can be accessed via this approach merely through the choice of an alkyllithium reagent. The inherently chiral oxazoline calix[4]arenes have also been preliminarily examined as ligands in the palladium-catalyzed Tsuji-Trost allylation reaction, returning results comparable to their planar chiral ferrocene counterparts pointing towards future application of these types of compounds. PMID- 25550741 TI - Preparation and evaluation of cyclodextrin polypseudorotaxane with PEGylated liposome as a sustained release drug carrier. AB - Cyclodextrins (CDs) can form polypseudorotaxanes (PPRXs) with drugs or drug carriers possessing linear polymers such as polyethylene glycol (PEG). On the other hand, PEGylated liposomes have been utilized as a representative anticancer drug carrier. However, little is known about the formation of CD PPRX with PEGylated liposome. In the present study, we first report the formation of CD PPRX with PEGylated liposome and evaluate it as a sustained release drug carrier. PEGylated liposome encapsulating doxorubicin was disrupted by the addition of alpha-CD. Meanwhile, gamma-CD included two PEG chains and/or one bending PEG chain of PEGylated liposome and formed PPRX without the disruption of the membrane integrity of the PEGylated liposome. Moreover, the release of doxorubicin and/or PEGylated liposome encapsulating doxorubicin from the PPRX was prolonged in accordance with the matrix type release mechanism. These findings suggest the potential of gamma-CD PPRX as sustained release carriers for PEGylated liposome products. PMID- 25550742 TI - Detonation nanodiamonds biofunctionalization and immobilization to titanium alloy surfaces as first steps towards medical application. AB - Due to their outstanding properties nanodiamonds are a promising nanoscale material in various applications such as microelectronics, polishing, optical monitoring, medicine and biotechnology. Beyond the typical diamond characteristics like extreme hardness or high thermal conductivity, they have additional benefits as intrinsic fluorescence due to lattice defects without photobleaching, obtained during the high pressure high temperature process. Further the carbon surface and its various functional groups in consequence of the synthesis, facilitate additional chemical and biological modification. In this work we present our recent results on chemical modification of the nanodiamond surface with phosphate groups and their electrochemically assisted immobilization on titanium-based materials to increase adhesion at biomaterial surfaces. The starting material is detonation nanodiamond, which exhibits a heterogeneous surface due to the functional groups resulting from the nitrogen rich explosives and the subsequent purification steps after detonation synthesis. Nanodiamond surfaces are chemically homogenized before proceeding with further functionalization. Suspensions of resulting surface-modified nanodiamonds are applied to the titanium alloy surfaces and the nanodiamonds subsequently fixed by electrochemical immobilization. Titanium and its alloys have been widely used in bone and dental implants for being a metal that is biocompatible with body tissues and able to bind with adjacent bone during healing. In order to improve titanium material properties towards biomedical applications the authors aim to increase adhesion to bone material by incorporating nanodiamonds into the implant surface, namely the anodically grown titanium dioxide layer. Differently functionalized nanodiamonds are characterized by infrared spectroscopy and the modified titanium alloys surfaces by scanning and transmission electron microscopy. The process described shows an adsorption and immobilization of modified nanodiamonds on titanium; where aminosilanized nanodiamonds coupled with O-phosphorylethanolamine show a homogeneous interaction with the titanium substrate. PMID- 25550743 TI - Self-assembled monolayers of shape-persistent macrocycles on graphite: interior design and conformational polymorphism. AB - Three shape-persistent naphthylene-phenylene-acetylene macrocycles of identical backbone structures and extraannular substitution patterns but different (empty, apolar, polar) nanopore fillings are self-assembled at the solid/liquid interface of highly oriented pyrolytic graphite and 1,2,4-trichlorobenzene. Submolecularly resolved images of the resulting two-dimensional (2D) crystalline monolayer patterns are obtained by in situ scanning tunneling microscopy. A concentration dependent conformational polymorphism is found, and open and more dense packing motifs are observed. For all three compounds alike lattice parameters are found, therefore the intermolecular macrocycle distances are mainly determined by their size and symmetry. This is an excellent example that the graphite acts as a template for the macrocycle organization independent from their specific interior. PMID- 25550744 TI - Mono- and multilayers of molecular spoked carbazole wheels on graphite. AB - Self-assembled monolayers of a molecular spoked wheel (a shape-persistent macrocycle with an intraannular spoke/hub system) and its synthetic precursor are investigated by scanning tunneling microscopy (STM) at the liquid/solid interface of 1-octanoic acid and highly oriented pyrolytic graphite. The submolecularly resolved STM images reveal that the molecules indeed behave as more or less rigid objects of certain sizes and shapes - depending on their chemical structures. In addition, the images provide insight into the multilayer growth of the molecular spoked wheels (MSWs), where the first adlayer acts as a template for the commensurate adsorption of molecules in the second layer. PMID- 25550745 TI - Binding mode and free energy prediction of fisetin/beta-cyclodextrin inclusion complexes. AB - In the present study, our aim is to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of beta-cyclodextrin (beta-CD) at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The molecular docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the beta-CD cavity, whilst less binding or even unbinding preference was observed in the complexes where the larger chromone ring is located in the cavity. All MM- and QM PBSA/GBSA free energy predictions supported the more stable fisetin/beta-CD complex of the bound phenyl ring. Van der Waals interaction is the key force in forming the complexes. In addition, the quantum mechanics calculations with M06 2X/6-31G(d,p) clearly showed that both solvation effect and BSSE correction cannot be neglected for the energy determination of the chosen system. PMID- 25550746 TI - Synthesis of an organic-soluble pi-conjugated [3]rotaxane via rotation of glucopyranose units in permethylated beta-cyclodextrin. AB - We synthesized symmetrically insulated oligo(para-phenylene) and oligothiophene with a pseudo-linked [3]rotaxane structure by full rotation of glucopyranose units via a flipping (tumbling) mechanism in the pi-conjugated guest having two permethylated beta-cyclodextrin units at both ends. We also succeeded in the synthesis of an organic-soluble fixed [3]rotaxane by a cross-coupling or complexation reaction of thus formed pseudo linked [3]rotaxane. Oligo(para phenylene), oligothiophene, and porphyrin derivatives were used as pi-conjugated guests with stopper groups. PMID- 25550747 TI - Thermal and oxidative stability of the Ocimum basilicum L. essential oil/beta cyclodextrin supramolecular system. AB - Ocimum basilicum L. essential oil and its beta-cyclodextrin (beta-CD) complex have been investigated with respect to their stability against the degradative action of air/oxygen and temperature. This supramolecular system was obtained by a crystallization method in order to achieve the equilibrium of complexed uncomplexed volatile compounds in an ethanol/water solution at 50 degrees C. Both the raw essential oil and its beta-CD complex have been subjected to thermal and oxidative degradation conditions in order to evaluate the protective capacity of beta-CD. The relative concentration of the O. basilicum L. essential oil compounds, as determined by GC-MS, varies accordingly with their sensitivity to the thermal and/or oxidative degradation conditions imposed. Furthermore, the relative concentration of the volatile O. basilicum L. compounds found in the beta-CD complex is quite different in comparison with the raw material. An increase of the relative concentration of linalool oxide from 0.3% to 1.1%, in addition to many sesquiterpene oxides, has been observed. beta-CD complexation of the O. basilicum essential oil modifies the relative concentration of the encapsulated volatile compounds. Thus, linalool was better encapsulated in beta CD, while methylchavicol (estragole) was encapsulated in beta-CD at a concentration close to that of the raw essential oil. Higher relative concentrations from the degradation of the oxygenated compounds such as linalool oxide and aromadendren oxide were determined in the raw O. basilicum L. essential oil in comparison with the corresponding beta-CD complex. For the first time, the protective capability of natural beta-CD for labile basil essential oil compounds has been demonstrated. PMID- 25550748 TI - A novel 4-aminoantipyrine-Pd(II) complex catalyzes Suzuki-Miyaura cross-coupling reactions of aryl halides. AB - A simple and efficient catalytic system based on a Pd complex of 4 aminoantipyrine, 4-AAP-Pd(II), was found to be highly active for Suzuki-Miyaura cross-coupling of aryl iodides and bromides with phenylboronic acids under mild reaction conditions. Good to excellent product yields from the cross-coupling reaction can be achieved when the reaction is carried out in ethanol, in the open air, using low loading of 4-AAP-Pd(II) as a precatalyst, and in the presence of aqueous K2CO3 as the base. A variety of functional groups are tolerated. PMID- 25550749 TI - A study on the inhibitory mechanism for cholesterol absorption by alpha cyclodextrin administration. AB - BACKGROUND: Micelle formation of cholesterol with lecithin and bile salts is a key process for intestinal absorption of lipids. Some dietary fibers commonly used to reduce the lipid content in the body are thought to inhibit lipid absorption by binding to bile salts and decreasing the lipid solubility. Amongst these, alpha-cyclodextrin (alpha-CD) is reportedly one of the most powerful dietary fibers for decreasing blood cholesterol. However, it is difficult to believe that alpha-CD directly removes cholesterol because it has a very low affinity for cholesterol and its mechanism of action is less well understood than those of other dietary fibers. To identify this mechanism, we investigated the interaction of alpha-CD with lecithin and bile salts, which are essential components for the dissolution of cholesterol in the small intestine, and the effect of alpha-CD on micellar solubility of cholesterol. RESULTS: alpha-CD was added to Fed-State Simulated Intestinal Fluid (FeSSIF), and precipitation of a white solid was observed. Analytical data showed that the precipitate was a lecithin and alpha-CD complex with a molar ratio of 1:4 or 1:5. The micellar solubility of cholesterol in the mixture of FeSSIF and alpha-CD was investigated, and found to decrease through lecithin precipitation caused by the addition of alpha-CD, in a dose-dependent manner. Furthermore, each of several other water soluble dietary fibers was added to the FeSSIF, and no precipitate was generated. CONCLUSION: This study suggests that alpha-CD decreases the micellar solubility of cholesterol in the lumen of the small intestine via the precipitation of lecithin from bile salt micelles by complex formation with alpha-CD. It further indicates that the lecithin precipitation effect on the bile salt micelles by alpha-CD addition clearly differs from addition of other water-soluble dietary fibers. The decrease in micellar cholesterol solubility in the FeSSIF was the strongest with alpha-CD addition. PMID- 25550750 TI - Synthesis of modified cyclic and acyclic dextrins and comparison of their complexation ability. AB - We compared the complex forming ability of alpha-, beta- and gamma-cyclodextrins (alpha-CD, beta-CD and gamma-CD) with their open ring analogs. In addition to the native cyclodextrins also modified cyclodextrins and the corresponding maltooligomers, functionalized with neutral 2-hydroxypropyl moieties, were synthesized. A new synthetic route was worked out via bromination, benzylation, deacetylation and debenzylation to obtain the 2-hydroxypropyl maltooligomer counterparts. The complexation properties of non-modified and modified cyclic and acyclic dextrins were studied and compared by photon correlation spectroscopy (PCS) and capillary electrophoresis (CE) using model guest compounds. In some cases cyclodextrins and their open-ring analogs (acyclodextrins) show similar complexation abilities, while with other guests considerably different behavior was observed depending on the molecular dimensions and chemical characteristics of the guests. This was explained by the enhanced flexibility of the non-closed rings. Even the signs of enantiorecognition were observed for the chloropheniramine/hydroxypropyl maltohexaose system. Further studies are planned to help the deeper understanding of the interactions. PMID- 25550751 TI - (2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues. AB - Efficient and scalable syntheses of enantiomerically pure (2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-mono(di,tri)fluoromethylcyclopropyl]alanines 9a-c, as well as allo-D-threonine (4) and (2S,3R)-beta-methylphenylalanine (3), using the Belokon' approach with (S)- and (R)-2-[(N-benzylprolyl)amino]benzophenone [(S)- and (R) 10] as reusable chiral auxiliaries have been developed. Three new fluoromethyl analogues of the naturally occurring octadepsipeptide hormaomycin (1) with (fluoromethylcyclopropyl)alanine moieties have been synthesized and subjected to preliminary tests of their antibiotic activity. PMID- 25550752 TI - Recent advances in the electrochemical construction of heterocycles. AB - Due to the fact that the major portion of pharmaceuticals and agrochemicals contains heterocyclic units and since the overall number of commercially used heterocyclic compounds is steadily growing, heterocyclic chemistry remains in the focus of the synthetic community. Enormous efforts have been made in the last decades in order to render the production of such compounds more selective and efficient. However, most of the conventional methods for the construction of heterocyclic cores still involve the use of strong acids or bases, the operation at elevated temperatures and/or the use of expensive catalysts and reagents. In this regard, electrosynthesis can provide a milder and more environmentally benign alternative. In fact, numerous examples for the electrochemical construction of heterocycles have been reported in recent years. These cases demonstrate that ring formation can be achieved efficiently under ambient conditions without the use of additional reagents. In order to account for the recent developments in this field, a selection of representative reactions is presented and discussed in this review. PMID- 25550753 TI - Synthesis and characterization of a new photoinduced switchable beta-cyclodextrin dimer. AB - This paper reports an efficient preparation of bridged bis-beta-CD AZO-CDim 1 bearing azobenzene as a linker and exhibiting high solubility in water. The photoisomerization properties were studied by UV-vis and HPLC and supported by ab initio calculations. The cis/trans ratio of AZO-CDim 1 is 7:93 without irradiation and 37:63 after 120 min of irradiation at 365 nm; the reaction is reversible after irradiation at 254 nm. The photoinduced, switchable binding behavior of AZO-CDim 1 was evaluated by ITC, NMR and molecular modeling in the presence of a ditopic adamantyl guest. The results indicate that AZO-CDim 1 can form two different inclusion complexes with an adamantyl dimer depending on its photoinduced isomers. Both cavities of cis-AZO-CDim 1 are complexed simultaneously by two adamantyl units of the guest forming a 1:1 complex while trans-AZO-CDim 1 seems to lead to the formation of supramolecular polymers with an n:n stoichiometry. PMID- 25550754 TI - Copper-promoted hydration and annulation of 2-fluorophenylacetylene derivatives: from alkynes to benzo[b]furans and benzo[b]thiophenes. AB - An efficient copper-promoted hydration reaction and its application in the synthesis of benzo[b]furan and benzo[b]thiophene derivatives is presented starting from readily available 2-fluorophenylacetylene derivatives. The key annulation step involves the hydration of the C-F bond of 2-fluorophenylacetylene derivatives followed by an intramolecular annulation to afford benzo[b]furan and benzo[b]thiophene derivatives. Moreover, structurally important 2,2' bisbenzofuran scaffolds are provided in good yields. PMID- 25550755 TI - Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolecular [1,5]-hydride shift/isomerization reaction. AB - Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]-hydride shift/isomerization reaction has been realized, using the inherent reducing power of 3-pyrrolines. A series of N-arylpyrrole containing amines are obtained in high yields. PMID- 25550756 TI - Organic chemistry on surfaces: Direct cyclopropanation by dihalocarbene addition to vinyl terminated self-assembled monolayers (SAMs). AB - C11-Vinyl-terminated self-assembled monolayers (SAMs) on silica surfaces are successfully modified in C-C bond forming reactions with dihalocarbenes to generate SAMs, terminated with dihalo- (fluoro, chloro, bromo) cyclopropane motifs with about 30% surface coverage. PMID- 25550757 TI - Cyclodextrin-polysaccharide-based, in situ-gelled system for ocular antifungal delivery. AB - Fluconazole was studied with two different hydrophilic cyclodextrins (hydroxypropyl-beta-cyclodextrin (HPBCD) and sulfobutyl ether-beta-cyclodextrin (SBECD)) for the formation of inclusion complexes. HPBCD and SBECD showed low cell cytotoxicity in human keratocytes as assessed by the label-free xCELLigence system for real-time monitoring. The fluconazole-HPBCD complex was incorporated into an ion-sensitive ophthalmic gel composed of the natural polysaccharides gellan gum and kappa-carrageenan. This system showed good bioadhesive properties and effective control of fluconazole release. PMID- 25550758 TI - Palladium-catalyzed 2,5-diheteroarylation of 2,5-dibromothiophene derivatives. AB - Conditions allowing the one pot 2,5-diheteroarylation of 2,5-dibromothiophene derivatives in the presence of palladium catalysts are reported. Using KOAc as the base, DMA as the solvent and only 0.5-2 mol % palladium catalysts, the target 2,5-diheteroarylated thiophenes were obtained in moderate to good yields and with a wide variety of heteroarenes such as thiazoles, thiophenes, furans, pyrroles, pyrazoles or isoxazoles. Moreover, sequential heteroarylation reactions allow the access to 2,5-diheteroarylated thiophenes bearing two different heteroaryl units. PMID- 25550759 TI - Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs. AB - Methyl and ethyl thioether groups were introduced at all primary positions of alpha-, beta-, and gamma-cyclodextrin by nucleophilic displacement reactions starting from the corresponding per-(6-deoxy-6-bromo)cyclodextrins. Further modification of all 2-OH positions by etherification with iodo terminated triethylene glycol monomethyl ether (and tetraethylene glycol monomethyl ether, respectively) furnished water-soluble hosts. Especially the beta-cyclodextrin derivatives exhibit very high binding potentials towards the anaesthetic drugs sevoflurane and halothane. Since the resulting inclusion compounds are highly soluble in water at temperatures <=37 degrees C they are good candidates for new aqueous dosage forms which would avoid inhalation anaesthesia. PMID- 25550760 TI - Nucleic acid chemistry. PMID- 25550762 TI - Trogopterins A-C: Three new neolignans from feces of Trogopterus xanthipes. AB - Seven compounds, including three neolignans 1-3, a norlignan 4, and three diterpenoids 5-7, were isolated from the feces of Trogopterus xanthipes. Structures of these compounds were identified by 1D and 2D NMR as well as MS. The absolute configurations of compounds 1, 2, and 4 were determined by comparing CD spectra and optical rotations. Among the isolated compounds, 1-3 were novel and subsequently named trogopterins A, B, and C, respectively. Likewise, compound 4 was isolated from nature for the first time. Cytotoxic activities of compounds 1 4 were evaluated. Compounds 1-3 exhibited moderate cytotoxic activities against HL-60 cells with IC50 values of 34.77-45.68 MUM. PMID- 25550761 TI - Come-back of phenanthridine and phenanthridinium derivatives in the 21st century. AB - Phenanthridine derivatives are one of the most intensively studied families of biologically active compounds with efficient DNA binding capability. Attracting attention since DNA structure discovery (1960s), they were early recognized as a symbol of DNA intercalative binding, for many decades applied as gold-standard DNA- and RNA-fluorescent markers (ethidium bromide), probes for cell viability (propidium iodide), but also "ill-famed" for various toxic (genotoxic) and mutagenic effects. After two decades of low interest, the discovery of phenanthridine alkaloids and new studies of antiparasitic/antitumor properties of phenanthridine derivatives resulted in the strong increase of the scientific interest about the turn of this century. Here are summarized phenanthridine related advances in the 21st century (2000-present period) with emphasis on the supramolecular interactions and bioorganic chemistry, as well as novel or improved synthetic approaches. PMID- 25550763 TI - A comparative study of the interactions of cationic hetarenes with quadruplex-DNA forming oligonucleotide sequences of the insulin-linked polymorphic region (ILPR). AB - The interactions of the ILPR sequence (ILPR = "insulin-linked polymorphic region") a2 [d(ACAG4TGTG4ACAG4TGTG4)] with [2.2.2]heptamethinecyanine derivatives 1a-e and with the already established quadruplex ligands coralyne (2), 3,3'-[2,6 pyridinediylbis(carbonylimino)]bis[1-methylquinolinium] (3), 4,4',4'',4''' (21H,23H-porphine-5,10,15,20-tetrayl)tetrakis[1-methylpyridinium] (4), naphtho[2,1-b:3,4-b':6,5-b'':7,8-b''']tetraquinolizinium (5) and thiazole orange (6) were studied. It is demonstrated with absorption, fluorescence and CD spectroscopy that all investigated ligands bind with relatively high affinity to the ILPR-quadruplex DNA a2 (0.2-5.5 * 10(6) M(-1)) and that in most cases the binding parameters of ligand-ILPR complexes are different from the ones observed with other native quadruplex-forming DNA sequences. PMID- 25550764 TI - Morita-Baylis-Hillman reaction of acrylamide with isatin derivatives. AB - The Morita-Baylis-Hillman reaction of acrylamide, as an activated alkene, has seen little development due to its low reactivity. We have developed the reaction using isatin derivatives with acrylamide, DABCO as a promoter and phenol as an additive in acetonitrile. The corresponding aza version with acrylate and acrylonitrile has also been developed resulting in high product yields. PMID- 25550765 TI - One-pot functionalisation of N-substituted tetrahydroisoquinolines by photooxidation and tunable organometallic trapping of iminium intermediates. AB - Nucleophilic trapping of iminium salts generated via oxidative functionalisation of tertiary amines is well established with stabilised carbon nucleophiles. The few reports of organometallic additions have limited scope of substrate and organometallic nucleophile. We report a novel, one-pot methodology that functionalises N-substituted tetrahydroisoquinolines by visible light-assisted photooxidation, followed by trapping of the resultant iminium ions with organometallic nucleophiles. This affords 1,2-disubstituted tetrahydroisoquinolines in moderate to excellent yields. PMID- 25550766 TI - Our Experience with MR Imaging of Perianal Fistulas. AB - Magnetic resonance imaging (MRI) depicts infectious foci in the perianal region better than any other imaging modality. MRI allows definition of the fistula, associated abscess formation and its secondary extensions. Accurate information is necessary for surgical treatment and to obtain a decrease in the incidence of recurrence and complications. Radiologists should be familiar with anatomical and pathological findings of perianal fistulas and classify them using the MRI - based grading system. The purpose of this article was to provide an overview for evaluation of perianal fistulas, examples of various fistula types and their classification. PMID- 25550767 TI - Clear cell papillary renal cell carcinoma: a review. AB - The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type. PMID- 25550768 TI - BRAF mutation as a potential marker to identify the proximal colon serrated polyps with malignant potential. AB - A large number of serrated polyps with malignant potential in the proximal colon were underestimated using currently available criteria mostly based on architectural and cytological features, contributing to proximal interval colorectal cancers. Recently, increasing evidences indicate that BRAF((V600E)) mutation is a specific molecular feature and driver of the serrated pathway, and proximal serrated polyps with BRAF((V600E)) mutation have a high risk of progression to malignancy. We proposed that immunohistochemical detection of BRAF((V600E)) using a BRAF((V600E)) mutation-specific antibody is a feasible technique for reproducibly identifying proximal serrated polyps with malignant potential in clinical practice, which may need more aggressive treatment and vigilant clinical monitoring. PMID- 25550769 TI - Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: histological, immunohistochemical and biochemical study. AB - This study was designed to demonstrate the histopathological and biochemical changes in rat cerebral cortex and testicles due to chronic usage of tramadol and the effect of withdrawal. Thirty adult male rats weighing 180-200 gm were classified into three groups; group I (control group) group II (10 rats received 50 mg/kg/day of tramadol intraperitoneally for 4 weeks) and group III (10 rats received the same dose as group II then kept 4 weeks later to study the effect of withdrawal). Histological and immunohistochemical examination of cerebral cortex and testicular specimens for Bax (apoptotic marker) were carried out. Testicular specimens were examined by electron microscopy. RT-PCR after RNA extraction from both specimens was done for the genes of some antioxidant enzymes .Also, malondialdehyde (MDA) was measured colourimetrically in tissues homogenizate. The results of this study demonstrated histological changes in testicular and brain tissues in group II compared to group I with increased apoptotic index proved by increased Bax expression. Moreover in this group increased MDA level with decreased gene expression of the antioxidant enzymes revealed oxidative stress. Group III showed signs of improvement but not returned completely normal. It could be concluded that administration of tramadol have histological abnormalities on both cerebral cortex and testicular tissues associated with oxidative stress in these organs. Also, there is increased apoptosis in both organs which regresses with withdrawal. These findings may provide a possible explanation for delayed fertility and psychological changes associated with tramadol abuse. PMID- 25550770 TI - Ulinastatin inhibits oxidant-induced endothelial hyperpermeability and apoptotic signaling. AB - Oxidants are important signaling molecules known to increase endothelial permeability. Studies implicate reactive oxygen species (ROS) and the intrinsic apoptotic signaling cascades as mediators of vascular hyperpermeability. Here we report the protective effects of ulinastatin, a serine protease inhibitor with antiapoptotic properties, against oxidant-induced endothelial monolayer hyperpermeability. HUVECs were respectively pretreated with 10,000 and 50,000 u/l ulinastatin, followed by stimulation of 0.6 mM H2O2. Monolayer permeability was determined by transendothelial electrical resistance (TER); Mitochondrial release of cytochrome c was determined by enzyme-linked immunosorbent assay; Caspase-3 activity was measured by fluorometric assay; Adherens junction protein beta catenin was detected by immunofluorescense staining; Ratio of cell apoptosis was evaluated by Annexin-V/PI double stain assay; Mitochondrial membrane potential (Deltapsim) was determined with JC-1; Intracellular ATP content was assayed by a commercial kit; Bax and Bcl-2 expression were estimated by western blotting; Intracellular reactive oxygen species (ROS) level was measured by DCFH-DA. H2O2 exposure resulted in endothelial hyperpermeability and ROS formation (P < 0.05). The activation of mitochondrial intrinsic apoptotic signaling pathway was evidenced from BAX up-regulation, Bcl-2 down-regulation, mitochondrial depolarization, an increase in cytochrome c release, and activation of caspase-3 (P < 0.05). UTI (50,000 u/l) attenuated endothelial hyperpermeability, ROS formation, mitochondrial dysfunction, cytochrome c release, activation of caspase 3, and disruption of cell adherens junctions (P < 0.05). Together, these results demonstrate that UTI provides protection against vascular hyperpermeability by modulating the intrinsic apoptotic signaling. PMID- 25550771 TI - Down-regulation of PTEN by HCV core protein through activating nuclear factor kappaB. AB - The hepatitis C virus (HCV) core protein is an important causative agent in HCV related hepatocellular carcinoma (HCC). Tumor suppressor gene PTEN appears to act in the liver at the crossroad of processes controlling cell proliferation. In this study we investigated the effect of the HCV core protein on the PTEN pathway in hepatocarcinogenesis. The HCV core was transfected stably into HepG2 cell. The effect of HCV core on cell proliferation and viability were detected by 3-(4, 5) dimethylthiahiazo-(-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) assay, clonogenic survival assay and Fluorescence Activating Cell Sorter (FACS) analysis. The expressions of PTEN were detected by real time RT-PCR and/or Western blot analysis, also the mechanism of down-regulation of PTEN was explored by western blot, luciferase assay and RNA interference. We found the HCV core promoted cell proliferation, survival and G2/M phase accumulation. It downregulated PTEN at mRNA and protein level and activated PTEN downstream gene Akt accompanied with NF kappaB activation. Furthermore, the inhibition of HCV core by its specific shRNAs decreased the effect of growth promotion and G2/M phase arrest, inhibited the expression of nuclear p65 and increased PTEN expression. The activity of PTEN was restored when treated with NF-kappaB inhibitor PDTC. By luciferase assay we found that NF-kappaB inhibited PTEN promoter transcription activity directly in HCV core cells, while PDTC was contrary. Our study suggests that HCV proteins could modulate PTEN by activating NF-kappaB. Furthermore strategies designed to restore the expression of PTEN may be promising therapies for preventing HCV dependent hepatocarcinogenesis. PMID- 25550772 TI - Bcl-xL overexpression and its association with the progress of tongue carcinoma. AB - Apoptosis-related protein B-cell lymphoma-extra large (Bcl-xL) has a crucial role in the control of cell death through its inhibition of apoptosis. This study was designed to investigate the expression of Bcl-xL in relation to the development of tongue carcinoma and whether it has potential as a marker for the clinical diagnosis of tongue carcinoma and as a therapeutic target to evaluate the dynamic of tongue carcinoma progression. A statistical analysis of 100 cases oral tongue carcinoma tissue specimens were performed using pathological grading and clinical TNM staging, and 14 cases corresponding non-tumor tissues as control. The changes in Bcl-xL mRNA expression between different pathological grades and clinical TNM stages of tissue were analyzed by RT-PCR. Additionally, immunohistochemical SP method and Western blot assays were employed to detect changes in Bcl-xL protein expression in different tongue carcinoma tissues. The results showed the expression of Bcl-xL was significantly higher in tongue carcinoma tissues than in normal tongue tissues and was positively associated with the degree of differentiation and the clinical TNM staging, but negatively correlated with the degree of malignancy of the tumor. There was higher expression of Bcl-xL in oral tongue squamous cell carcinoma (OTSCC) tissues compared with oral tongue adenocarcinoma (OTA) tissues, but Bcl-xL expression in tissue with lymph node metastasis was significantly higher than that without lymph node metastasis. Thus, Bcl-xL overexpression may be closely related to the dynamic of the pathogenesis and development of tongue carcinoma. It may be a useful marker for clinical diagnosis and an aid to evaluating the efficacy of therapeutics in tongue carcinoma. PMID- 25550773 TI - Hypoxic preconditioning protects cardiomyocytes against hypoxia/reoxygenation injury through AMPK/eNOS/PGC-1alpha signaling pathway. AB - OBJECTIVE: AMP-activated protein kinase (AMPK) is an important regulator of multiple cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in hypoxic preconditioning (HPC), protecting cardiomyocytes against hypoxia reoxygenation (H/R) injury remains uncertain. METHODS: H9c2 cells were preconditioned by exposing to 10 min of hypoxia and 30 min of reoxygenation. Then, the preconditioned and non-preconditioned cardiomyocytes were exposed to 90 min of hypoxia followed by 120 min of reoxygenation. RESULTS: HPC protected H9c2 cells against H/R injury, the AMPK inhibitor or eNOS inhibitor abolished the effect of HPC. Compared with H/R group, HPC significantly increased the expression of p-AMPK (Thr172). HPC also markedly increased p-eNOS (Ser1177) expression, which was abolished by AMPK inhibition. HPC significantly increased PGC-1alpha expression, which were nullified by AMPK inhibition or eNOS inhibition. HPC attenuated the oxidative stress by increasing the SOD activity and decreasing the MDA and ROS level, which were abolished by AMPK inhibition or eNOS inhibition. Interestingly, the AMPK activator metformin mimicked the effects of HPC in part. CONCLUSIONS: These results indicated that HPC protects H9c2 cells against H/R injury by reducing oxidative stress partly via AMPK/eNOS/PGC-1alpha signaling pathway. PMID- 25550774 TI - Antibacterial activity and mechanism of action of Monarda punctata essential oil and its main components against common bacterial pathogens in respiratory tract. AB - The aim of the current research work was to study the chemical composition of the essential oil of Monarda punctata along with evaluating the essential oil and its major components for their antibacterial effects against some frequently encountered respiratory infection causing pathogens. Gas chromatographic mass spectrometric analysis revealed the presence of 13 chemical constituents with thymol (75.2%), p-cymene (6.7%), limonene (5.4), and carvacrol (3.5%) as the major constituents. The oil composition was dominated by the oxygenated monoterpenes. Antibacterial activity of the essential oil and its major constituents (thymol, p-cymene, limonene) was evaluated against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae and Escherichia coli. The study revealed that the essential oil and its constituents exhibited a broad spectrum and variable degree of antibacterial activity against different strains. Among the tested strains, Streptococcus pyogenes, Escherichia coli and Streptococcus pneumoniae were the most susceptible bacterial strain showing lowest MIC and MBC values. Methicillin-resistant Staphylococcus aureus was the most resistant bacterial strain to the essential oil treatment showing relatively higher MIC and MBC values. Scanning electron microscopy revealed that the essential oil induced potent and dose-dependent membrane damage in S. pyogenes and MRSA bacterial strains. The reactive oxygen species generated by the Monarda punctata essential oil were identified using 2', 7'-dichlorofluorescein diacetate (DCFDA).This study indicated that the Monarda punctata essential oil to a great extent and thymol to a lower extent triggered a substantial increase in the ROS levels in S. pyogenes bacterial cultures which ultimately cause membrane damage as revealed by SEM results. PMID- 25550775 TI - LPS pretreatment ameliorates D-galactosamine/lipopolysaccharide-induced acute liver failure in rat. AB - Acute liver failure (ALF) remains an extremely poor prognosis and high mortality; with no effective treatments. The endotoxin tolerance (ET) phenotype has been reported to exhibit protective activities in several sepsis models. We now investigated the effects and underlying intraperitoneal injection of the same volume of pyrogen-free 0.9% sodium chloride instead of LPS for five consecutive days before D-GalN/LPS injection in rats. The serum levels of TNF-alpha, IL-6, ALT, AST and TBiL from ET + ALF group and ALF group were measured at different time points. Our results showed that ET + ALF group markedly reduced the serum levels of TNF-alpha, IL-6, ALT, AST and TBiL and histological features in the ET + ALF group were improved significantly. Furthermore, LPS pre-treatment inhibited D-GalN/LPS-induced NF-kappaB activation, Bax activation, signal transducer and activator of transcription-1 (STAT1) and signal transducer and activator of transcription-3 (STAT3) activities. LPS pre-treatment also significantly enhance the expression of suppressors of cytokine signaling 1 (SOCS1) and suppressors of cytokine signaling 3 (SOCS3). Our experimental data indicated that ET might alleviate D-GalN/LPS-induced ALF by inhibiting the inflammatory response, inactivation of STAT1 and STAT3 and up-regulation of SOCS1 and SOCS3. PMID- 25550776 TI - Expression of transcription factor grainyhead-like 2 is diminished in cervical cancer. AB - The transcription factor grainyhead-like 2 (GRHL2) is evolutionarily conserved in many different species, and is involved in morphogenesis, epithelial differentiation, and the control of the epithelial-mesenchymal transition. It has also recently been implicated in carcinogenesis, but its role in this remains controversial. Expression of GRHL2 has not previously been reported in cervical cancer, so the present study aimed to characterize GRHL2 expression in cervical cancer-derived cell lines (CCCLs) and cervical tissues with different grades of lesions. Microarray analysis found that the expression of 58 genes was down regulated in CCCLs compared to HaCaT cells (non-tumorigenic human epithelial cell line). The expression of eight of these genes was validated by quantitative real time PCR (qPCR), and GRHL2 was found to be the most down-regulated. Western blot assays corroborated that GRHL2 protein levels were strongly down-regulated in CCCLs. Cervical cells from women without cervical lesions were shown to express GRHL2, while immunohistochemistry found that positivity to GRHL2 decreased in cervical cancer tissues. In conclusion, a loss or strong reduction in GRHL2 expression appears to be a characteristic of cervical cancer, suggesting that GRHL2 down-regulation is a necessary step during cervical carcinogenesis. However, further studies are needed to delineate the role of GRHL2 in cervical cancer and during malignant progression. PMID- 25550777 TI - Long term follow up of through-the-scope balloon dilation as compared to strictureplasty and bowel resection of intestinal strictures in crohn's disease. AB - BACKGROUND & AIMS: Ileo-colonic strictures are common complication of Crohn's disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital. METHODS: In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations. RESULTS: 53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon. CONCLUSIONS: Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment. PMID- 25550778 TI - Upregulation of CD147 promotes cell invasion, epithelial-to-mesenchymal transition and activates MAPK/ERK signaling pathway in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common cancers in the world. CD147, a transmembrane protein, has been reported to be correlated with various cancers. In this study, we aimed to investigate the mechanism of CD147 in regulating drug resistance, cell invasion and epithelial-to-mesenchymal transition (EMT) in CRC cells. qRT-PCR and western blotting were used to evaluated the expression of CD147 in 40 CRC cases and 4 cell lines. Increased expression of CD147 at both mRNA and protein levels was found in CRC samples, and the level of CD147 was correlated with lymph node metastasis. CD147 overexpression increased the 5 Fluorouracil (5-FU) resistance, enhanced the invasion and EMT of CRC cells by regulating EMT markers and MMPs. Adverse results were obtained in CD147 knockdown CRC cell line. Further investigation revealed that CD147 activated MAPK/ERK pathway, ERK inhibitor U0126 suppressed the CD147-induced cell invasion, migration and MMP-2, MMP-9 expression. Taken together, our study indicates that CD147 promotes the 5-FU resistance, and MAPK/ERK signaling pathway is involved in CD147-promoted invasion and EMT of CRC cells. PMID- 25550779 TI - microRNA-137 modulates pancreatic cancer cells tumor growth, invasion and sensitivity to chemotherapy. AB - BACKGROUND: We intended to investigate the role of microRNA 137 (miR-137) in regulating pancreatic cancer cells' growth in vitro and tumor development in vivo. METHODS: QTR-PCR was used to examine the expression of miR-137 in pancreatic cancer cell lines and tumor cells from human patients. Lentivirual vector containing miR-137 mimic was used to overexpress miR-137 in PANC-1 and MIA PaCa-2 cells. The effects of overexpressing miR-137 on pancreatic cancer cell invasion and chemo-sensitivity to 5-fluorouracil (5-FU) were examined by cell migration and survival essays in vitro. The molecular target of miR-137, pleiotropic growth factor (PTN), was down-regulated by siRNA to examine its effects on cancer cell invasion. MIA PaCa-2 cells with endogenously overexpressed miR-137 were transplanted into null mice to examine tumor growth in vivo. RESULTS: We found miR-137 was markedly underexpressed in both pancreatic cancer cell lines and tumor cells from patients. In cancer cells, transfection of lentivirus containing miR-137 mimic was able to markedly upregulate endogenous expression of miR-137, inhibited cancer cell invasion and increased sensitivities to chemotherapy reagent 5-FU. PTN was significantly down-regulated by overexpressing miR-137 in pancreatic cancer cells, and knocking down PTN was effective to rescue the reduced cancer cell invasion ability caused by miR-137 overexpression. More importantly, overexpressing miR-137 led to significant inhibition on tumor formation, including reductions in tumor weight and tumor size in vivo. CONCLUSION: Our study demonstrated that miR-137 played an important role in pancreatic cancer development. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer. PMID- 25550780 TI - The role of integrin-beta/FAK in cyclic mechanical stimulation in MG-63 cells. AB - OBJECTIVE: This study aims to explore the function of Integrin-beta/FAK in the mechanical signal transduction and the connection with downstream ERK signal pathways. METHODS: Human osteosarcoma MG63 cell lines were used in this study. The effects of mechanical strain on the Integrin-beta1 expression, FAK and ERK signal pathway in Human osteosarcoma MG63 cells were detected using RT-PCR and Western-blotting methods. The localization of FAK in Human osteosarcoma MG63 cells were determined using immunofluorescent method. The interaction between Integrin-beta1 and FAK were detected by using co-immunoprecipitation method. RESULTS: The expression of Integrin-beta1 shows a notable bimodel distribution, mechanical strain stimulation can promote Integrin-beta1 expression and the phosphorylation of FAK and ERK, mechanical strain activated FAK and ERK mediated by Integrin-beta1. CONCLUSION: Integrin-beta1 may play an important role in osteoblast proliferation differentiation process, it might feel external strain stimulation through ECM composition and makes FAK phosphated through the interaction with FAK, thus causing a series of activation of signal molecules. Finally it reduces MAPK (ERK) activation and cellular responses to finish mechanical signal transduction. PMID- 25550781 TI - Doxycycline attenuates acute lung injury following cardiopulmonary bypass: involvement of matrix metalloproteinases. AB - Acute lung injury (ALI) was one of the major complications after cardiopulmonary bypass (CPB). Matrix metalloproteinases (MMPs) play an important role in ALI following CPB. In this study, we investigated the effects of doxycycline (DOX), a potent MMP inhibitor, on MMP-9 and ALI in the rat model of CPB. 48 adult male Sprague-Dawley rats were randomized into four groups: group I (Control group, underwent cannulation + heparinization only); group II (CPB group, underwent 60 minutes of normothermic CPB); group III (Low-dose treatment group, underwent 60 minutes of normothermic CPB with DOX gavage 30 mg/kg *1 week ahead of CPB); and group IV (High-dose treatment group, underwent 60-minutes of normothermic CPB with DOX gavage 60 mg/kg *1 week ahead of CPB). The effects of doxycycline on ALI were determined by measuring the lung Wet/Dry ratio, the inflammation of bronchoalveolar lavage fluid (BALF) and the ultrastructural changes of the lungs. The role of doxycycline on MMP-9 was assessed by the plasma concentration, the activity and the expression in lung tissue. Our results demonstrated that the lung Wet/Dry weight ratio and the inflammatory mediators (TNF-alpha, IL-1beta) in BALF were decreased significantly with doxycycline treatment. The lung damages were attenuated by doxycycline. The levels of plasma concentration, the activity and the expression of MMP-9 in lung tissue were suppressed with doxycycline and the effects were dose dependent. Doxycycline could suppress the expression of MMP 9 and cytokines, and improve the ALI following CPB. PMID- 25550782 TI - Acoustic radiation force impulse elastography in differentiating renal solid masses: a preliminary experience. AB - New diagnostic methods are required to diagnose renal mass. Thus, we assessed virtual tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) elastography in differentiation of renal solid masses. Forty-two patients with renal masses were assessed by VTQ in terms of measurement of the shear wave velocity (SWV). The masses were divided into three groups. They were clear cell carcinoma (CCC) angiomyolipoma (AML), and pseudotumor. The differences among the three groups in SWV, as well as between masses and its surrounding parenchyma, were investigated. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance. We found that the SWV among the three groups were significant different (F = 6.976, P = 0.003) and the SWV of pseudotumor (3.14 +/- 0.75 m/s) was significantly higher than CCC (2.46 +/- 0.45 m/s) and AML (2.49 +/- 0.63 m/s) (P = 0.007 and 0.001 respectively). There were no significant difference between CCC and AML in SWV (P = 0.719). For each group, there was no significant difference between the mass and its surrounding parenchyma (P = 0.693, 0.892, and 0.714, respectively). Between pseudotumor and CCC, the optimal cut-off value of SWV for differential diagnoses was 3.07 m/s; and the area under the ROC curve (AUC) was 0.78 (95% CI: 0.560 to 0.924) (P = 0.004), the sensitivity and specificity were 100% and 58.3%, respectively. Between pseudotumor and AML, the optimal cut-off value of SWV for differential diagnoses was 3.03 m/s, thus AUC curve was 0.786 (95% CI: 0.591 to 0.918) (P = 0.002), the sensitivity and specificity were 100% and 58.3%, respectively. No significant difference was found between AML and CCC (P = 0.587) and the AUC was 0.562. To conclude, our results support that ARFI has potential value in differentiation between CCC and pseudotumor, or between AML and pseudotumor, however, it fails to make a distinction between CCC and AML. PMID- 25550783 TI - Solitary fibrous tumor of the thymus with variegated epithelial components. AB - Solitary fibrous tumor is a rare mesenchymal neoplasm, characterized by peculiar histological features composed by the proliferation of spindle cells in "patternless pattern". Although it has been known to sometimes be accompanied by epithelioid cells, the presence of a well-formed epithelial structure is far more rare. We describe herein the case of a 60-year-old female with the radiological finding of a single nodular lesion in the anterior mediastinum. Histopathological examination of the surgically resected specimen led to the diagnosis of solitary fibrous tumor of the thymus with a spectrum of well-formed epithelial components: i) glandular structure, reminiscent of breast or eccrine gland, ii) neural tube like structure, and iii) clusters of endocrine-like cells. Immunohistochemical analysis revealed that the spindle cells expressed CD34, vimentin, bcl-2 and Stat 6, but not keratin (cytokeratin-AE1/AE3) or epithelial membrane antigen. In contrast, the epithelial components lost expression of most of these marker proteins, including Stat-6, but continued to express vimentin and strongly expressed keratin. Since no relevant past literature was found, the current case could be interpreted as a unique and previously undescribed variant of solitary fibrous tumor comprising conventional spindle cells with a spectrum of well formed epithelial components. Pathogenesis that may have given rise to these variegated mixtures of spindle cells and epithelial components in a single tumor is also discussed. PMID- 25550784 TI - Expression of prorenin receptor in renal biopsies from patients with IgA nephropathy. AB - Prorenin receptor (PRR) has been implicated in the onset and progression of various renal diseases, though its possible association with immunoglobulin A (IgA) nephropathy remains unclear. In the present study, we tried to clarify expression and pathophysiological significance of PRR in IgA nephropathy. We immunohistochemically assessed PRR levels in renal biopsy specimens from 48 patients with IgA nephropathy and evaluated its relevance to the clinical and pathological features of the disease. PRR was detected mainly in renal tubular cells, which was confirmed at the subcellular level using immunoelectron microscopy. The PRR-positive area (%PRR area) correlated with daily urinary protein, which is known to reflect disease severity (r=0.286, P=0.049). PRR levels were weaker in tubular cells bordering areas of severe interstitial fibrosis, where alpha-smooth muscle actin-positive myofibroblasts were present. We also used immunohistochemical detection of microtubule-associated protein-1 light chain 3 (LC3) and electron microscopy to assess autophagy, a cytoprotective mechanism downstream of PRR. We noted an apparent coincidence between autophagy activation in tubular cells and PRR expression in the same cells. Taken together, our findings suggest that renal expression of PRR in IgA nephropathy may be a compensatory response slowing disease progression by preventing tubular cell death and subsequent fibrosis through activation of cytoprotective autophagic machinery. Further studies using different type of kidney diseases could draw conclusion if the present finding is a generalized observation beyond IgA nephropathy. PMID- 25550785 TI - Overexpression of GRIM-19, a mitochondrial respiratory chain complex I protein, suppresses hepatocellular carcinoma growth. AB - GRIM-19 has been demonstrated as an important regulator for the normal tissue development. Recently, more evidences regarded GRIM-19 as the new tumor suppressor. However, the possible mechanisms underlying GRIM-19 suppressing cancer growth are unclear. In the present study, Paired hepatocellular carcinoma (HCC) and adjacent non-tumor liver tissues were obtained from 54 patients who underwent primary surgical HCC tissue resection. GRIM-19 protein expression in HCC tissues was performed by immunohistochemistry. Cells were transfected by lentiviruses plasmid expressing GRIM-19. RT-PCR and Western blot analyses were performed to confirm the expression of GRIM-19 mRNA or protein. Cell proliferation was assessed by MTT and FCM analyses. Mitochondrial membrane potential and apoptosis were respectively determined by using fluorescence microscopy and FCM analyses. AKT1, pAKT1, cyclinD1, CDK4, PCNA, Bax, Bcl-2, cleaved caspase-9, cleaved caspase-3, and cytochrome C were detected by Western blot and immunofluorescence. GRIM-19 protein expression was markedly lower in HCC than in paired adjacent non-tumor liver tissues. GRIM-19 overexpression in HCC cells significantly induced cell cycle arrest and enhanced apoptosis. We also found that AKT1 expression and phosphorylation were regulated by the expression of GRIM-19. Collectively, our study demonstrated that GRIM-19 overexpression suppressed HCC growth and downregulated AKT1 expression, suggesting that GRIM-19 might play a crucial role in hepatocarcinogenesis through negatively regulating the PI3K/AKT signaling pathway. PMID- 25550786 TI - Epstein-Barr virus infection is inversely correlated with the expression of retinoblastoma protein in Reed-Sternberg cells in classic Hodgkin lymphoma. AB - Classic Hodgkin lymphoma (cHL) is characterized by few neoplastic Hodgkin/Reed Sternberg (H/RS) cells in a background of intense inflammatory infiltrate. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 82 cases of cHL were studied. Five- micrometer sections were prepared and stained with haematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, pRb, ki-67 and cleaved caspase-3. In situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS cells. There were 45 nodular sclerosis, 28 mixed cellularity, 4 lymphocyte-rich, and 5 lymphocyte depletion subtypes in this series of cases. EBV and pRb were detected in 55% (46/82) and 64% (50/82) of the cases respectively. EBV was detected in 78% (25/32) of pRb-negative cases and 81% (29/36) of EBV negative cases are pRb-positive. A statistically significant inverse relationship was observed between the presence of EBV and expression of pRb (P = 0.001). In conclusion, EBV infection is inversely correlated with pRb in H/RS cells in cHL. PMID- 25550787 TI - miRNA-124 down-regulates SOX8 expression and suppresses cell proliferation in non small cell lung cancer. AB - Non-small lung cell carcinoma (NSCLC) is a leading lethal disease and a global health burden. The function of the Sex determining region Y (SRY)-related high mobility group box (SOX) family gene in cancer has attracted the attention of more and more scientists recently, yet there are few reports regarding the role of SOX in NSCLC. Our study aimed to investigate the expression of SOX8, a protein belonging to the E group of the SOX family, as well as SOX9, in non-small cell lung cancer (NSCLC) and the relationship of gene expression to clinicopathological factors and prognosis in patients. Immunohistochemical analysis was used to measure the expression of SOX8 in 80 NSCLC and 7 adjacent normal tissues. SOX8 expression was detected as elevated in tumor samples and correlated to tumor size (P < 0.001), lymph node metastasis (P = 0.001), differentiation classification (P = 0.015), and clinical stage (P = 0.013) significantly. Moreover, Kaplan-Meier survival analysis demonstrated that shorter survival time for patients who had higher SOX8 expression (P < 0.001). In addition, our experiments indicate that miRNA-124 functions as a tumor suppressor in NSCLC. We also demonstrate miRNA-124 directly targeted and decreased SOX8 in NSCLC cell lines, suggesting smiRNA-124 may regulate NSCLC cell proliferation via decreasing SOX8 (oncogenicity of biomarker in NSCLC). PMID- 25550788 TI - Adenoid cystic carcinoma of the tracheobronchial tree: clinicopathologic and immunohistochemical studies of 21 cases. AB - AIMS: To review retrospectively 21 cases adenoid cystic carcinoma of the tracheobronchial tree (TACC) with emphasis on their clinical and pathologic features, treatment and the possible prognostic factors. METHODS AND RESULTS: 21 cases TACC diagnosed by surgical biopsy or resection at the Peking Union Medical College Hospital (PUMCH) over 10 years. Patients aged 24-69 years (median, 49 years), 6 men/15 women. Cough (18/21), dyspnea (14/21) and hemoptysis (10/21) were the most frequent manifestations. 15 patients had tumors in trachea. Ten patients had pathologically positive margin (n = 11). Immunohistochemically, BCL 2, CD117, P16, type IV collagen, SMA and P63 were positive (20/20); GFAP was focally positive (4/20); TTF-1 and P53 were negative (0/20). Ki-67 index ranged from 2% to 35%. Fifteen patients had followed up, 13 of which received postoperative radiotherapy. The median relapse-free survival (RFS) was 56.9 months and the 5-year RFS was 48.6%. By univariate analysis, postoperative radiotherapy had favorable prognostic significance (P < 0.05). CONCLUSIONS: TACC, which is mainly located in primary trachea or bronchus, is difficult to be detected at early stage. The tumors are not likely to be completely removed by surgery, and postoperative radiotherapy is helpful for reducing the likelihood of recurrence and metastasis. PMID- 25550789 TI - Effect of DAPK1 gene on proliferation, migration, and invasion of carcinoma of pancreas BxPC-3 cell line. AB - DAPK1 can induce apoptosis in several cells; to determine the effect of DAPK1 would provide a new potential therapeutic strategy for treating pancreatic cancer. The aim of the present study was to investigate the effect of DAPK1 gene on proliferation, migration, and invasion of carcinoma of pancreas BxPC-3 cell line and explore the possible mechanisms. In our study, DAPK1 over-expressed cells were established by using the lentiviral transfection method, and DAPK1 obviously increased in BxPC-3 cells after transient transfection. Cell Counting Kit-8 (CCK-8) assay was used to determine the BxPC-3 cells proliferation after transfection. Apoptosis of the BxPC-3 cells was determined by using flow cytometry analysis. In addition, cell adhesion assay and in vitro invasion assay were performed. Western blotting was used to determine the protein expressions of caspase-3, DAPK1, VEGF, PEDF, MMP2, AKT, P-AKT, P-ERK, Bcl2, and Bax. Our results demonstrated that DAPK1 gene over-expression can suppress the proliferation, migration, and invasion of carcinoma of pancreas BxPC-3 cell line, and the possible mechanisms may be correlated to induction of mitochondria-mediated apoptosis, down-regulations of MMP-2 and VEGF, up-regulations of PEDF, through the PI3K/Akt and ERK pathways. PMID- 25550790 TI - Isolation of myeloid-derived suppressor cells subsets from spleens of orthotopic liver cancer-bearing mice by fluorescent-activated and magnetic-activated cell sorting: similarities and differences. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that commonly expand during tumor development and that play a critical role in suppression of immune responses. MDSCs can be classified into two groups: Mo-MDSCs and G-MDSCs. These cells differ in their morphology, phenotype, differentiation ability, and immunosuppressive activity, and inhibit immune responses via different mechanisms. Therefore, identifying an effective method for isolating viable Mo-MDSCs and G-MDSCs is important. Here, we demonstrated the differences and similarities between fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) in sorting G-MDSCs and Mo-MDSCs. Both MACS and FACS could obtain G-MDSCs and Mo-MDSCs with high viability and purity. A high yield and purity of G-MDSCs could be obtained both by using FACS and MACS, because G-MDSCs are highly expressed in the spleen of tumor-bearing mice. However, Mo-MDSCs, which comprise a small population among leukocytes, when sorted by MACS, could be obtained at much greater cell number, although with a slightly lower purity, than when sorted by FACS. In conclusion, we recommended using both FACS and MACS for isolating G-MDSCs, and using MACS for isolation of Mo-MDSCs. PMID- 25550791 TI - Increased frequencies of nuocytes in peripheral blood from patients with Graves' hyperthyroidism. AB - Newly identified nuocytes play an important role in Th2 cell mediated immunity such as protective immune responses to helminth parasites, allergic asthma and chronic rhinosinusitis. However, the contributions of nuocytes in the occurrence and development of Graves' hyperthyroidism remains unknown. Previous studies found that there was a predominant Th2 phenotype in patients with Graves' hyperthyroidism, it might relate to polarization of nuocytes. Nuocytes were defined by transcription factor RORalpha, various cell surface markers (T1/ST2, IL-17RB, ICOS, CD45) and associated cytokines. In this study, these cells related genes or molecules in PBMC from patients with Graves' hyperthyroidism were measured, and the potential correlation between them was analyzed. The expression levels of T1/ST2, IL-17RB, ICOS, IL-5 and IL-13, which represented nuocytes associated molecules were significantly increased in patients, meanwhile, the RORalpha mRNA also had a tendency to increase. In addition, IFN-gamma and T-bet (Th1 related cytokine and transcription factor) were obviously decreased, and there was a positive correlation between IL-17RB and IL-13. These results suggested that there were polarized nuocytes in Graves' hyperthyroidism patients, and which closely related to the down-regulation of Th1 cells or relatively advantage of Th2 differentiation. PMID- 25550792 TI - Tumor suppressive microRNA-193b promotes breast cancer progression via targeting DNAJC13 and RAB22A. AB - Breast cancer is still a leading cause of cancer deaths in women. Despite improvements in therapeutic approaches in local control, metastatic relapse is almost always incurable, underlining the importance to better understand the biological bases that contribute to disease progression. In this study, we demonstrated that miR-193b was significantly down-regulated in two primary human breast cancer cell lines (MDA-MB-231 and MCF-7). Reconstitution of miR-193b expression resulted in decreasing cell proliferation, clonogenicity, migration and invasion. By using in silico prediction algorithms approach for target identification, we identified DNAJC13 (HPS40) and RAB22A to be direct targets of miR-193b. Concordantly, Re-expression of miR-193b decreased DNAJC13 (HPS40) and RAB22A expression. Luciferase reporter assays confirmed the direct interaction of miR-193b with both DNAJC13 (HPS40) and RAB22A. Our findings have demonstrated that miR-193b as a novel tumor suppressor plays an important role in breast cancer progression, understanding the mechanisms could account for the aggressive behaviour of breast cancer. PMID- 25550793 TI - MicroRNA-29 mediates TGFbeta1-induced extracellular matrix synthesis by targeting wnt/beta-catenin pathway in human orbital fibroblasts. AB - PURPOSE: Transforming growth factor beta1 (TGFbeta1) is very important in the synthesis and degradation of extracellular matrix (ECM) and also in the mediation of human orbital fibroblasts (OFs) proliferation. MicroRNA-29 (MiR-29) plays an important role in this process. In the present study, the effects of TGFbeta1 on the expression of miR-29 and whether miR-29 is involved in pro-survival signaling pathways mediated by TGFbeta1 were examined in human OFs. METHODS: Detecting the influence of TGFbeta1 on the expression of miR-29a/b/c by real-time PCR analysis. Using 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) to detecting the influence of miR-29 on the increased proliferation caused by TGF beta1 on the human orbital fibroblasts. Using soft agar assay to detecting the influence of miR-29 on the increased colony formation caused by TGF-beta1 on the human orbital fibroblasts. Western blot was used to detect the specific mechanisin. RESULTS: TGFbeta1 treatment decreases the expression of miR-29 in OFs. In the cultured OFs, the value of optical density (OD) in the group treated with miR-29 is lower than that in the group treated without miR-29 (P < 0.05). In the cultured OFs, the ratio of colony formation in the group treated with miR-29 is lower than that in the group treated without miR-29 (P < 0.05). In OFs, miR-29 decreases the secretion of Wnt3a and activation of beta-catenin whether the treatment of TGFbeta1 was used or not. MiR-29 decreases expression of Collagen, type I, alpha 1 (COL1A1) through down-regulation of wnt/beta-catenin pathway. CONCLUSIONS: In OFs TGFbeta1 treatment decreases expression of miR-29 which can cause the inhibition of normal ability of TGFbeta1. MiR-29 inhibits TGFbeta1 induced proliferation of OFS cell and decreases colony formation of OFS cell after TGFbeta1 treatment. MiR-29 Mediates TGFbeta1-induced Extracellular matrix synthesis through activation of Wnt/beta-catenin pathway in human OFs. PMID- 25550794 TI - Mitotically active cellular fibroma of ovary should be differentiated from fibrosarcoma: a case report and review of literature. AB - The clinicopathologic characteristic of mitotically active cellular fibroma is significantly different from the malignant behavior of ovarian fibrosarcoma. Therefore, it's very important to differentiate mitotically active cellular fibroma from ovarian fibrosarcoma. We report a case in which a 39-year-old woman was found with an ovarian tumor measuring 105 * 71 * 47 mm. The tumor ruptured and adhered to the peritoneum. Microscopic examination showed densely cellular spindle-shaped tumor cells. The cellular atypia was mild. The Ki-67 proliferation index was approximately 10%. The patient remained free of tumor for more than 66 months without any adjuvant chemotherapy after operation. After reviewing the literature, we diagnosed this case as mitotically active cellular fibroma rather than ovarian fibrosarcoma. It is very important to differentiate these two tumors because of the marked differences in treatment modalities and prognosis between them. The ovarian fibrous tumors with mitotic figures >= 4 per 10 high-power fields but no severe nuclear atypia should be mostly diagnosed as mitotically active cellular fibroma of ovary. The correct diagnosis is the key to avoid excessive treatments. PMID- 25550795 TI - Significance of nonmucinous lepidic component with mild nuclear atypia in the discrimination of multiple primary lung cancers from intrapulmonary metastases. AB - The distinguishing of intrapulmonary metastases from multiple primaries is of great clinical importance. Although comprehensive histological assessment (CHA) was recommended for addressing this problem, the limitations of CHA have been addressed. We hypothesized that a nonmucinous lepidic component with mild nuclear atypia (NLCMA) may be one of the important sign suggesting primary lesions. In this study, we measured the value of NLCMA in distinguishing multiple primaries from intrapulmonary metastases. We retrospectively analyzed a cohort of 54 patients with 116 lesions (70 comparisons). Intrapulmonary metastases and multiple primaries were differentiated on the basis of CHA (Method I) and CHA combined with the assessment of NLCMA (Method II), respectively. Then, the results of two methods were compared with survival analysis. 33 cases were defined as multiple primaries and 21 cases as metastases by Method I, while 41 cases as multiple primaries and 13 cases as metastases by Method II. On univariate analysis, there was a better DFS in patients with a tumor <= 3 cm (P=0.012), female gender (P=0.011), highest N0 (P=0.002), absent micropapillary (P=0.013), multiple primaries (P=0.008 by method I, P < 0.001 by method II). A multivariate analysis adjusting for gender, tumor size, micropapillary and multiple primaries/metastases (by methodI and method II, respectively) indicated that multiple primaries (by method II) was an independent predictors for DFS. The presence of NLCMA may indicate that a lesion should be defined as primary in multifocal adenocarcinoma. PMID- 25550796 TI - Expression profiling and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in sporadic human renal cell carcinoma. AB - PURPOSE: This study aimed to evaluate the expression of DNA methyltransferase (DNMT) family proteins in renal cell carcinoma (RCC) and to assess the clinical significance and prognostic value of their expression patterns. METHODS: A total of 97 renal cell carcinoma and 52 no-tumor tissues were recruited for immunohistochemical analysis of their expression. RESULTS: DNMT1, DNMT3A and DNMT3B proteins were highly expressed in clear cell RCC, papillary RCC and chromophobe RCC tissues than that of no-tumor tissues (all P < 0.05). DNMT1, DNMT3A and DNMT3B expression was significantly associated with tumor size (P=0.003, 0.001 and 0.003, respectively), tumor pathology stage (P=0.039, 0.034 and 0.037, respectively), histopathological grading (P=0.042, 0.026 and 0.031, respectively), lymph node metastasis (P=0.022, 0.030 and 0.020, respectively) and vascular invasion (P=0.042, 0.031 and 0.044, respectively). The Kaplan-Meier survival analysis demonstrated that expression of DNMTs protein in RCC was significantly associated with shorter over all survival and disease-free survival (all P < 0.05). Furthermore, multivariate analysis showed that the expression of DNMT1 was an independent prognostic factor for overall survival (OS) (P=0.036), and the expression of DNMT3A or DNMT3B was an independent prognostic factor for disease-free survival (DFS) in the patients (P=0.031 and P=0.023, respectively). CONCLUSIONS: DNMTs were higher expressed in RCC than no-tumor tissues, and the expression of DNMTs were strongly associated with RCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence, and prognosis. DNMTs may thus serve as prognostic markers and novel therapeutic targets for RCC patients. PMID- 25550797 TI - Prognostic value of immune cell infiltration, tertiary lymphoid structures and PD L1 expression in Merkel cell carcinomas. AB - Merkel cell carcinoma (MCC) is an aggressive, virus-associated, neuroendocrine tumor of the skin mainly affecting immunocompromised patients. Higher intratumoral infiltration with CD3 and CD8 positive T-cells is associated with a better prognosis, highlighting the relevance of the immune system for MCC development and progression. In this study 21 primary MCCs were stained with immune cell markers including CD3, CD4, CD8, CD68, CD20, and S100. Furthermore, tumor-infiltrating neutrophils, tertiary lymphoid structures and PD-L1 expression were analyzed and correlated with overall and recurrence free survival. All MCCs were Merkel Cell Polyomavirus positive. Overall and recurrence-free survival did not correlate with intra- and peritumoral CD3 and CD8 T-cell infiltration. In addition, no significant association regarding prognosis was found for tumor associated neutrophils, tumor-associated macrophages or PD-L1 positivity in MCCs. Interestingly, the presence of tertiary lymphoid structures (TLS) in the tumor microenvironment significantly correlated with recurrence-free survival (P=0.025). In addition, TLS were significantly associated with a higher CD8/CD4 ratio in the tumor periphery (P=0.032), but not in the center of the tumor (P > 0.999). These results demonstrate for the first time that TLS, easily assessed in paraffin-embedded tissue in the tumor periphery of MCCs, may be a valuable prognostic factor indicating prolonged recurrence free survival. PMID- 25550798 TI - Effect of celecoxib combined with chemotherapy drug on malignant biological behaviors of gastric cancer. AB - Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has been reported to have antitumor effects. In some tumor models, the combination of celecoxib with chemotherapy agents has shown synergistic antitumor effect; however, the effect of celecoxib combination with tegafur/gimeracil/oteracil potassium on the malignant biological behaviors of gastric cancer in nude mice is unclear. In this study, female nude mice were subcutaneously transplanted with SGC-7901 gastric cancer cells. When the tumor model formed, the mice were divided into control group, celecoxib group, tegafur/gimeracil/oteracil potassium group, and the combination of both drug regimens group. Mice were treated for 3 weeks. Following treatment, the proliferating index was calculated, apoptosis related proteins, COX-2, vascular endothelial growth factor-C (VEGF-C) and lymphatic vessel density were quantified in tumor tissues by immunohistochemistry. Apoptosis was evaluated by TUNEL staining. The results revealed that celecoxib and tegafur/gimeracil/oteracil potassium alone significantly inhibited tumor growth. The combination of these two drugs showed a synergistic antitumor effect. Both celecoxib and tegafur/gimeracil/oteracil potassium alone inhibited proliferation and promoted apoptosis. The combination of these two drugs further enhanced this anticancer effect. Both celecoxib and the combination treatment inhibited lymphangiogenesis and the expression of COX-2 and VEGF-C. However, tegafur/gimeracil/oteracil potassium treatment had no obvious effect on lymphangiogenesis. These results suggested that the combination of celecoxib and tegafur/gimeracil/oteracil potassium produced a synergistic antitumor effect, possibly by inhibiting the proliferation of tumor cells and promoting apoptosis. Celecoxib and celecoxib in combination with tegafur/gimeracil/oteracil potassium possibly by reducing the expression of COX-2, in turn down-regulating the expression of VEGF-C, resulted in the inhibition of lymphangiogenesis. PMID- 25550799 TI - Favorable proliferation and differentiation capabilities of neural precursor cells derived from rat cochlear nucleus. AB - NSCs/NPCs could be used for Sensorineural hearing loss treatment, because of the extensive capacity for self-renewal and pluripotency. In order to isolate and identify neural precursor cells (NPCs), we established a strategy to isolate and cultivate NPCs. Immunohistochemistry, immunofluorescence, Western blotting, and electron microscopy were used to characterize the cells and compare their differentiation patterns with those of olfactory bulb and olfactory epithelium NPCs. Furthermore, NPCs from the cochlear nucleus were sustained good cell viability and cloning efficiency after cryopreservation and thawing. Finally, high capacity to differentiate into astrocytes, oligodendrocytes, and neurons of NPCs was found. In conclusion, NPCs isolated from the cochlear nucleus can proliferate and differentiate into functional neurons, which offers a potential strategy for sensorineural hearing loss treatment. In addition, the storage method developed here will benefit further exploration of NPCs. PMID- 25550800 TI - Regulation of apoptosis by long non-coding RNA HIF1A-AS1 in VSMCs: implications for TAA pathogenesis. AB - OBJECTIVE: Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as transcriptional regulation, cell growth and tumorigenesis. However, little was known about whether lncRNA HIF 1 alpha antisense RNA 1 (HIF1a-AS1) in regulating the proliferation and apoptosis of VSMCs in vitro and the expression of HIF1a-AS1 in serum of TAA patients. METHODS: The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining. Expression of genes and proteins were analyzed by real-time PCR and western blotting respectively. Cells were transfected with siRNAs as a gene silencing methods. RESULTS: In serum of TAA patients, the expression of HIF1a-AS1 was significantly increased (superior to 6 folds) compared to the normal control. Moreover, PA induced cell apoptosis in VSMCs in a time- and dose-dependent manner, and the proportion of the apoptotic cells had gained as compared to untreatment group. PA also induced upregulation expression of HIF1a-AS1. We also found that transfection of cells with HIF1a-AS1 siRNA decreased the expression of caspase3 and caspase8 and increased the expression of Bcl2, and protected PA-induced cell apoptosis in VSMCs. CONCLUSIONS: HIF1a-AS1 was overexpressed in the thoracoabdominal aorta aneurysm and the interaction between HIF1a-AS1 and apoptotic proteins plays a key role in the proliferation and apoptosis of VSMCs in vitro, which may contribute to the pathogenesis of thoracoabdominal aorta aneurysm. PMID- 25550801 TI - miR-451 inhibits invasion and proliferation of bladder cancer by regulating EMT. AB - MicroRNAs (miRNAs) have recently been reported play a crucial role in some tumors. In order to investigate the association of miR-451 with bladder cancer, we investigate the expression of miR-451 in bladder cancer tissues and its role in biological behavior of T24, 5637 and J28 bladder cancer cell lines. Quantitative RT-PCR results showed miR-451 was significantly down-regulated in bladder cancer tissues and paracancerous tissues compared with normal bladder tissues. miR-451 expression was significantly associated with histological differentiation degree and TNM stage. Over-expression of miR-451 was established by transfecting miR-451 mimics into T24, 5637 and J28 cells, and its effects on the biological behavior of bladder cancer were studied using transwell assay, migration assay, adhesion assay, MTT and flow cytometry. Results indicated over expression of miR-451 significantly inhibited cell proliferation, migration, invasion and induced apoptosis of the bladder cancer cells. Furthermore, we investigated the expression level of EMT related proteins in transfected 5637 cells by western blot. Results shown E-cadherin was up-regulated more significantly than N-cadherin, vimentin and Snail. N-cadherin and vimentin were up-regulated significantly when miR-451 was inhibited in miR-451 inhibitor group, however, no significant changes in mimics group. In conclusion, miR451 should be a tumor-suppressing gene in bladder cancer. miR-451 could maintain the bladder tumor cells in epithelial phenotype, inhibit EMT process, thereby reducing the invasion and migration of tumor cells. PMID- 25550802 TI - Aquaporin-8 mediates human esophageal cancer Eca-109 cell migration via the EGFR Erk1/2 pathway. AB - Abnormal expression of aquaporins (AQPs) has been reported in several human cancers. Epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinases1/2 (ERK1/2) are associated with tumorigenesis and cancer progression and may upregulate AQPs expression. In this study, we investigated acquaporin-8 expression and signaling via epidermal growth factor receptor-extracellular signal-regulated kinases1/2 in human esophageal cancer Eca-109 cells by western blot, immunofluorescence and wound healing (scratch) assays. Our results showed that epidermal growth factor (EGF) induced both Eca-109 migration and AQP8 expression. Wound healing results showed that cell migration was increased by 1.23-1.10-fold at 24 h and 48 h after EGF treatment. AQP8 expression was significantly increased (1.19-fold) at 48 h after EGF treatment in Eca-109. The EGFR kinase inhibitor, PD153035, blocked EGF-induced AQP8 expression and cell migration. AQP8 expression was decreased from 3.65-fold (EGF-treated) to 0.55 fold (PD153035-treated) in Eca-109. Furthermore, the MEK [MAPK (mitogen-activated protein kinase)/Erk1/2]/Erk1/2 inhibitor U0126 also inhibited EGF-induced AQP8 expression and cell migration. AQP8 expression was decreased from 3.92-fold (EGF treated) to 1.38-fold (U0126-treated) in Eca-109. In conclusions, EGF induces AQP8 expression and cell migration in Eca-109 cells via the EGFR/Erk1/2 signal transduction pathway. PMID- 25550803 TI - Down-regulation of miR-181b promotes apoptosis by targeting CYLD in thyroid papillary cancer. AB - MicroRNAs (miRNAs) are a small class of non-coding RNAs that are widely deregulated in various cancers. They act as either oncogenes or tumor suppressor genes in human cancer. The purpose of this study was to examine the potential role of miR-181b in human thyroid papillary cancer. The expression levels of different miRNAs were measured by micro array analysis in 10 thyroid papillary cancer specimens and adjacent normal thyroid cancer tissues. MTT assays, colony formation assays, apoptosis assays were used to explore the potential function of miR-181b inhibitor in TPC1 human thyroid papillary cancer cells. Luciferase reporter assays were performed to validate the regulation of a putative target of miR-181b, in corroboration with qPCR and western blot assays. We found that the expression of miR-181b was higher in thyroid papillary cancer specimens compared with adjacent normal tissues (P < 0.05). Downregulation of miR-181b inhibited cellular growth and promoted cellular apoptosis. Luciferase assays indicated that miR-181b can bind with its putative target site in the 3'-untranslated region (3' UTR) of CYLD, suggesting that CYLD is a direct target of miR-181b. Western blot analysis indicated that downregulation of miR-181b results in the upregulation of CYLD at protein levels. Taken together, downregulation of miR-181b expression causes cellular growth inhibition, promoting cellular apoptosis by targeting CYLD. These findings suggest that downregulation of the expression of miR-181b may be a therapeutic target for the treatment of human thyroid papillary cancer. PMID- 25550804 TI - VEGF/VEGFR2 and PDGF-B/PDGFR-beta expression in non-metastatic renal cell carcinoma: a retrospective study in 1,091 consecutive patients. AB - PURPOSE: We aimed to investigate the correlations between the expression of VEGF, PDGF-B, and their receptors (VEGFR2 and PDGFR-beta) with pathologic stage or cell type in non-metastatic renal cell carcinoma. MATERIALS AND METHODS: VEGF, VEGFR2, PDGF-B, and PDGFR-beta protein expression were evaluated immunohistochemically in prospectively collected 1,423 tumour samples obtained during radical or partial nephrectomy at a tertiary referral center. Intensity of expression was quantified on a scale of 0 to 3, and was compared among renal cell carcinoma cell types. RESULTS: The study cohort consisted of 1,091 patients, of mean age 54 years, including 968 (88.7%) with clear cell, 82 (7.5%) with papillary, 31 (2.8%) with chromophobe, 4 (0.4%) with unclassified, and 6 (0.5%) with other types of renal cell carcinoma. VEGF expression increased with higher T and N stage and Fuhrman nuclear grade. PDGFR-beta expression was highest in clear cell renal cell carcinoma, whereas VEGF and PDGF-B expression were highest in papillary renal cell carcinoma. After adjusting for T stage and Fuhrman nuclear grade using multivariate logistic regression analysis, VEGF (OR = 3.57, P < 0.001), VEGFR2 (OR = 1.82, P = 0.017), and PDGF-B (OR = 2.46, P = 0.019) expression were significantly greater in papillary than in clear cell type. CONCLUSIONS: Our results indicate that the cytoplasmic expression of VEGF, VEGFR2, PDGF-B, and PDGFR-beta in RCC tumour cells is different in various pathologic stage and cell type. Notably, VEGF and PDGF-B expression are higher in papillary than in clear cell renal cell carcinoma. Further studies using quantitative measurement of proangiogenic factors in tumour cell are needed. PMID- 25550805 TI - Inhibitory effects of intrathecal p38beta antisense oligonucleotide on bone cancer pain in rats. AB - OBJECTIVE: To evaluate the effects of intrathecal administration p38beta antisense oligonucleotide on the development of bone cancer pain rats. METHODS: Forty female SD rats weighing 180~220 g were randomly divided into 4 groups (n = 10 each): Group A (control group): intra-tibial injection of 3 MUl Hank's solution; group B (model group): intra-tibial injection of 3 MUl MADB-106 mammary gland carcinoma cells of rats (4.8 * 10(3)/MUl); group C (p38beta-SODN 20 MUg); group D (p38beta-ASODN 20 MUg). The model procedures in group C and D were same to those in the group B. From the 14th day after operation, p38beta-SODN 20 MUg and p38beta-ASODN 20 MUg were respectively intrathecally administrated in group C and D once daily for 6 days whereas normal saline was for group A and B. Mechanical withdrawal threshold and radiant heat threshold of rat hind paws were measured before operation and every other day until 22 d of post-operation. The lumbar 4-6 spinal cord was removed on the 22(nd) day. The expression of spinal p38beta protein was determined by Western blot. RESULTS: No significant differences in mechanical withdrawal threshold and radiant heat threshold were found at all time points in control group. During the first 6 days after operation there were obvious differences in radiant heat stimulus between control group between the other groups (P < 0.05); During 14-22 days after operation, mechanical pain threshold and radiant heat threshold between p38beta-SODN group and Model group were significantly changed compared with that in control group (P < 0.05). However, the differences were not remarkable between control group and p38beta-ASODN group (P > 0.05). The expression of p38beta protein in lumbar spinal cord was significantly higher between p38beta-SODN group and Model group than that in control group (P < 0.05). There was no significant difference in p38beta protein expression between p38beta-ASODN group and control group (P > 0.05). CONCLUSIONS: Hyperalgesia induced by bone cancer can be inhibited by intrathecal administration of p38beta antisense oligonucleotide, which is achieved by reducing expression of p38beta protein. PMID- 25550806 TI - A key mediator, PTX3, of IKK/IkappaB/NF-kappaB exacerbates human umbilical vein endothelial cell injury and dysfunction. AB - OBJECTIVE: This study was performed to investigate PTX3-mediated iNOS expression and IKK/IkappaB/NF-kappaB activation in PA-induced atherosclerotic HUVECs injury model. METHODS: The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining. Expression of genes and proteins were analyzed by real-time PCR and western blotting respectively. Cells were transfected with siRNAs as a gene silencing methods. RESULTS: PA induced cell apoptosis in human umbilical vein endothelial cells in a time and dose-dependent manner. PA also induced upregulation expression of PTX3. TPCA-1, an inhibitor of IKK-2, could suppress the expression of PTX3 and phospho IkappaB-alpha in PA-induced endothelial dysfunction cell model. We also found that transfection of cells with PTX3 siRNA reduced the expression of iNOS and NO, and protected PA-induced cell apoptosis in HUVECs. CONCLUSIONS: PTX3 could exacerbate endothelial dysfunction, at least partially, through IKK/IkappaB/NF kappaB activation and overexpression of iNOS and NO, and advance the development of atherosclerosis. PMID- 25550807 TI - Effects of fentanyl anesthesia and sufentanil anesthesia on regulatory T cells frequencies. AB - BACKGROUND: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) can inhibit anti tumor immune responses and opioids were also immunosuppressive. We set out to compare the effects of sufentanil and fentanyl on Tregs frequencies both in vitro and in breast cancer (BC) patients undergoing eradicative operation. METHODS: PBMCs from 12 BC patients were activated in vitro in the presence of fentanyl or sufentanil. The percentage of Tregs was detected by flow cytometry after seven days culture. Other 38 patients who underwent eradicative operation were prospectively randomized to sufentanil anesthesia and fentanyl anesthesia. Blood samples were collected for Tregs quantification by flow cytometry analysis and for Foxp3 mRNA expression by RT-PCR, at 10 min before anesthesia (D0), 24h (D1), and 168 h (D7) after the operation respectively. RESULTS: Activation of PBMCs in the presence of either fentanyl or sufentanil increased the Tregs number, and the effect of sufentanil was more significant under the same analgesic effect with fentanyl. In the 38 operated cases, both the Tregs frequencies and Foxp3 mRNA expression on D1 decreased in comparison to those on D0, but then recovered on D7. By comparing SF and F group, there ware no significant differences in Tregs frequencies and Foxp3 mRNA expression on D0, D1 and D7. CONCLUSION: With the same analgesic potency, sufentanil is more powerful in increasing the Tregs quantity than fentanyl in vitro. But there are no significant differences as to Tregs frequencies between sufentanil anesthesia and fentanyl anesthesia perioperatively. Further studies are needed to determine the differences in the Tregs function and long-term outcome of these patients. PMID- 25550808 TI - Value of fine needle aspiration cell blocks in the diagnosis and classification of lymphoma. AB - Fine needle aspiration biopsy (FNAB) is a simple yet accurate diagnostic procedure. However, the role of FNAB in lymphoma diagnosis and classification remains controversial. This study aimed to evaluate the value of FNAB cell blocks in the diagnosis and classification of lymphoma using our patented aspirator in a pencil-grip operation manner and a simplified cell block preparation method. We retrospectively reviewed 177 cases of lymph node and extranodal lymphoproliferative disorders that were diagnosed with cytomorphology, morphology, and immunohistochemistry of cell blocks. Of these, 83 were primary lymphoma; 14 were recurrent lymphoma; 8 were suspected as lymphoma, and 72 were benign reactive hyperplasia (BRH). Our analysis indicated 99.0% sensitivity, 95.9% specificity, 97.1% positive predictive value, and 98.6% negative predictive value in discriminating among primary/recurrent lymphoma and BRH. The diagnostic accuracy for sub-classification of lymphoma was 86.6% (84/97), with 77.8% (7/9) for classical Hodgkin's lymphoma and 87.5% (77/88) for non-Hodgkin's lymphoma. Our results implicated cell blocks as a reliable and useful adjunct to FNAB for the diagnosis and classification of lymphoma. Cytomorphology, morphology, and immunohistochemical studies of cell blocks offered very high accuracy in the diagnosis of lymphoma and allowed further sub-classification in many cases. Thus, patients with a definitive diagnosis and classification might avoid invasive and expensive surgical biopsy procedures. PMID- 25550809 TI - MicroRNA-25 regulates small cell lung cancer cell development and cell cycle through cyclin E2. AB - PURPOSE: We intended to examine the underlying mechanism of microRNA-25 (miR-25) in regulating small cell lung cancer (SCLC). METHODS: The miR-25 expression was measured by quantitative RT-PCR (qRT-PCR) in 5 SCLC cell lines and 9 human SCLC tissues. In SCLC cell line H510A cells, endogenous miR-25 was downregulated by stable transfection of antisense oligonucleotide of miR-25 (miR-25-as). Then the effects of miR-25 downregulation on SCLC growth, invasion and chemoresistance were assessed by MTT, migration and cisplatin assays, respectively. Furthermore, the effects of miR-25 downregulation on cancer cell cycle arrest, production of cell cycle proteins cyclin E2 and CDK2 were examined by cell cycle assay, western blot and luciferase assays, respectively. Finally, cyclin E2 was over-expressed in H510A cells to investigate its effect on miR-25 mediated SCLC regulation. RESULTS: In both SCLC cells and human SCLC tumor tissues, miR-25 was overexpressed. Down-regulation of miR-25 in H510A cells significantly reduced cancer cell growth, invasive capability and resistance to cisplatin. Also, it induced G1 cell cycle arrest and downregulated cell cycle related proteins cyclin E2 and CDK2. Luciferase assay demonstrated cyclin E2 was directly targeted by miR 25. Overexpression of cyclin E2 in H510A cells reversed the cell cycle arrest and restored invasive capability impaired by miR-25 downregulation. CONCLUSIONS: Our study shows miR-25 is overexpressed in SCLC and acting as oncogenic regulator by regulating cyclin E2. PMID- 25550810 TI - Chromosome aberrations and spermatogenic disorders in mice with Robertsonian translocation (11; 13). AB - OBJECTIVE: To determine the diagnostic features of Robertsonian (Rob) translocation (11; 13) in mice and the mechanisms underlying the effect on spermatogenesis and reproductive decline. METHODS: A Rob translocation (11; 13) mouse model was established by cross-breeding, and confirmed by chromosome analysis. Chromosome aberrations and translocation patterns were identified in mice with Rob translocation (11; 13) by fluorescence in situ hybridization (FISH). Spermatogenic disorders were investigated at different stages of spermatogenesis. Immunofluorescent analysis was performed on sections of testis and epididymis specimens during spermatogenic meiosis. The weight of the testes and reproductive decline were recorded. RESULTS: The crossed Rob translocation (11; 13) mouse has 39 chromosomes, including a fusion chromosome (included chromosomes 11 and 13) using dual color FISH. There was no difference in the distribution pattern of SYCP3 and gammaH2AX in spermatocytes between Rob translocation and wild-type mice; however, round haploid spermatids presented characteristic morphologic changes of apoptosis and the number of haploid spermatids was decreased. Furthermore, the immature germ cells were released into the epididymis and the number of mature sperm was reduced. CONCLUSIONS: Chromosome aberrations and spermatogenic disorders may result from apoptosis of round haploid spermatids and a reduced number of mature sperm in Rob translocation (11; 13) mice. Abnormal sperm and reduced number of sperm may be one of the main reasons for reproductive decline and male infertility in Rob translocation (11; 13) mice. PMID- 25550811 TI - TET3 mediates the activation of human hepatic stellate cells via modulating the expression of long non-coding RNA HIF1A-AS1. AB - Activated Hepatic stellate cells (HSCs) play a critical role in liver fibrosis and a lot of efforts have been made to dissect the underlying mechanism involved in activation of HSCs. However, the underlying mechanism remains douteux up to now. In the present study, we found that TET3, one member of ten-eleven translocation (TET) protein family, reduced significantly in HSCs LX-2 activated by TGF-beta1. To study the function of TET3 in activation of HSCs, knockdown was performed by RNA interference. Results showed that cell proliferation rise significantly and cell apoptosis reduce obviously after knockdown of TET3. Meanwhile, IHC showed that the expression of alpha-SMA rise significantly compared to control. These results indicated that TET3 is closely associated with the activation of HSCs. Further studies found that long non-coding RNA HIF1A-AS1 was reduced significantly in LX-2 cell after treatment with siRNA for TET3. The result hinted that TET3 activate HSCs through modulating the expression of HIF1A AS1. To confirm this hypothesis, RNA interference was performed to silence the HIF1A-AS1. Results showed that HIF1A-AS1 silencing lead to enhancing in cell proliferation and declining apoptosis. Taken together, TET3 can mediate the activation of HSCs via modulating the expression of the long non-coding RNA HIF1A AS1. PMID- 25550812 TI - Expression of vascular endothelial growth factor C and anti-angiogenesis therapy in endometriosis. AB - Angiogenesis is an important pathogenesis of Endometriosis. Vascular endothelial growth factor C (VEGF-C) is one of the most important factor in the regulation of both normal and abnormal angiogenesis. Anti-angiogenic treatment of endometriosis is still in the exploratory stage. In this study, we investigate the relationship between VEGF-C and endometriosis, the therapeutic effects of Endostar in the rat endometriosis model. We then demonstrated that Immunohistochemical expression of VEGF-C was higher in endometriotic tissues than in control normal ovary tissues (P < 0.01) and higher in the endomertriosis grade III-IV than in endomertriosis grade I-II (P=0.013). In rat endometriosis model, we observed a significant reduction in the mean volume and weight of the endometriotic implants per rat in the treatment group as compared with the control group. By immunohistochemical evaluation, there was a significant reduction in VEGF-C expression after treatment in all areas examined. VEGF-C may be involved in the pathogenesis of endomertriosis by regulating the angiogenesis. Endostar has therapeutic effects of endometriosis lesions in the rat endometriosis model. PMID- 25550813 TI - Thymic epithelial tumors: a clinicopathologic study of 249 cases from a single institution. AB - The WHO histological classification for thymic epithelial tumors of 2004 edition is widely used, but its prognostic value is still controversial. In the present study we collected 249 Chinese patients with thymic epithelial tumors from West China Hospital of Sichuan University since 1999-2009 to assess the prognosis relating to tumor stages, histological classifications, MG and adjuvant therapy. There were 18 cases of type A (7.2%), 97 of type AB (39.0%), 22 of type B1 (8.8%), 63 of type B2 (25.3%), 16 of type B3 (6.5%) thymomas and 33 of thymic carcinomas (13.3%). According to the Massaoka staging, there were 107 patients in stage I (43%), 73 patients in stage II (29.3%), 50 patients in stage III (20.1%) and 19 in stage IV (7.6%). 101 patients (40.6%) complicated with MG, the incidence of MG was highest in type B3 thymomas, then in B2, none of thymic carcinomas complicated with MG. Cox regression analysis showed the Masaoka stage was the most important prognostic factor. Besides of staging, WHO histological classification was also an independent prognostic factor. The age, gender, MG and adjuvant therapy have no significant influence to the prognosis of the patients. PMID- 25550814 TI - alpha-Naphthoflavone modulates inflammatory response in adipocytes-macrophages interaction through NFkappaB signaling. AB - OBJECTIVE: Our previous study demonstrated that alpha-naphthoflavone (alpha-NF) inhibits mouse 3T3-L1 pre-adipocytes differentiation via PPARgamma, a key transcription factor in adipogenesis. Due to the critical role of inflammation in adipogenesis, we speculated that the suppression role of alpha-NF in adipogenesis might involve in modulation of cytokines secretion raised by adipocyte differentiation cocktail. Therefore, the present study aims to investigate the role of alpha-NF in modulating of inflammatory response during adipocytes differentiation and adipocyte-macrophage interaction. METHODS: Conditioned medium from different doses of alpha-NF treated 10-day differentiated 3T3-L1 adipocytes were collected to culture RAW264.7 macrophages. Conditioned medium from activated macrophages and alpha-NF pre-treated macrophage were used to investigate the effects of alpha-NF in adipocytes differentiation. Cultured cells and medium were harvested for RT-PCR, Western blot and ELISA. RESULTS: alpha-NF dose-dependently decreased TNF-alpha and IL-6 and increased IL-10 expression induced by IDM (Insulin, dexamethasone, isobutylmethylxanthine) in 3T3-L1 pre-adipocytes. Conditioned medium from alpha-NF treated 3T3-L1 differentiated cells inhibited inflammatory response in mouse macrophage cell line RAW264.7 in contrast to IDM control medium. NFKB activation elicited by IDM was suppressed by alpha-NF in a dose-response manner. Consequently, decreased TNF-alpha and increased IL-10 secretion, downstream targets of NFKB signaling pathway, were observed with alpha NF in macrophages. Finally, Conditioned medium from alpha-NF pre-treated, LPS activated macrophages ameliorated the suppression of 3T3-L1 adipogenesis by LPS activated macrophages. CONCLUSION: Our results suggest that alpha-NF regulates inflammation response in both adipocytes and macrophages and adipocyte-macrophage interaction which contributes to pre-adipocyte differentiation. PMID- 25550815 TI - Hepatic arterial administration of sorafenib and iodized oil effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX2 hepatocellular carcinoma model. AB - AIM: To investigate the therapeutic effect of the hepatic arterial administration of sorafenib in rabbit VX-2 hepatocellular carcinoma (HCC) model. METHODS: Rabbit VX-2 HCC models were established via implanting VX-2 tumors into the livers, and randomly divided into four groups, respectively treated with (1) The hepatic arterial administration of iodized oil alone (TACE-i), (2) The hepatic arterial administration of iodized oil and pharmorubicin (TACE-ip), (3) The hepatic arterial administration of iodized and cis-DDP (TACE-ic), (4) The hepatic arterial administration of iodized and sorafenib (TACE-is). The growth rate and intrahepatic metastasis of implanted VX-2 tumor in each rabbit were measured. Microvessel density (MVD) in the adjacent tissues of implanted VX-2 tumor were estimated by detecting the expression of CD34 and VEGF level in tumor adjacent tissues were also examined by Immunohistochemistry. RESULTS: Compared with other groups, TACE-is treatment group presented a better effect on inhibiting tumor growth rate and intrahepatic metastasis in rabbit VX-2 HCC model. The angiogenesis (assessed by MVD) in the adjacent tissues were suppressed more dramatically in TACE-is treated group. Moreover, TACE-is treatment did not significantly increase the levels of alanine transaminase and creatinine compared to the group with TACE-i treatment. CONCLUSION: The hepatic arterial administration of sorafenib and iodized oil (TACE-is) effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX-2 HCC model without obvious hepatic and renal toxicity. One of the related mechanisms may be due to the inhibition of angiogenesis in the adjacent tissues. Our data indicated that TACE is may be a secure and effective treatment for HCC. PMID- 25550816 TI - Cell transplantation into ischemic myocardium using mesenchymal stem cells transfected by vascular endothelial growth factor. AB - AIMS: To investigate the effects of mesenchymal stem cells (MSCs) transplantation combining with vascular endothelial growth factor (VEGF) gene therapy on myocardium rebuilding, angiogenesis, and heart function improvement in rats with myocardial infarction. METHODS: SD rat MSCs were isolated, cultured in vitro, labeled with BrdU and transfected by Ad.VEGF gene. Four weeks after left anterior descending artery was ligated to create rat myocardial infarction, cardiac function was examined with echocardiography. Rats were randomly divided into four groups (n = 10 in each group): Group I: MSCs/Ad.VEGF implantation; Group II: MSCs implantation; Group III: Ad.VEGF injection; Group IV: Control. MSCs differentiation was observed 4 weeks after transplantation. Immunohistochemistry and angiogenesis were observed. Echocardiography was performed to detect the effects on heart function. RESULTS: MSCs labeled with BrdU could be identified in host hearts in group I and II, most of them positively stained with cTnT antibody. Echocardiography indicated that the improvement of the LVEF value in group I was more significant than that in the other three groups (P < 0.01, respectively). Some cells were incorporated into the coronary capillaries in the infarcted region. The capillary density in group I was higher than that in the other three groups (P < 0.01, respectively). CONCLUSION: MSCs implantation combining with VEGF gene therapy can obviously repair damaged myocardium and enhance the angiogenesis in ischemic heart tissue. PMID- 25550817 TI - Tanycytic ependymoma in a 76-year-old Puerto Rican male. AB - Ependymoma is a slowly growing tumor in children and young adults originating from the wall of the ventricles or from the spinal canal that is composed of neoplastic ependymal cells. Tanycytic ependymoma is a rare variant of ependymoma usually arising in the intra medullary spine. The World Health Organization classifies the tanycytic ependymoma as a grade II tumor. The diagnosis of tanycytic ependymoma is challenging since the morphology of the lesions resemble those found in schwannoma and astrocytomas. In the present study, we show a case of a 76 years old male with a progressive paraparesis for 8 years, due to a spinal tumor. Radiological and histological studies were used to classify the tumor as tanycytic ependymoma. Therefore, it is important to be aware of tanycytic ependymoma and its immunohistochemistry profile in older patients, especially within the Caribbean Hispanic population. To our knowledge this is the oldest patient known to have this rare tumor and the first case reported in Puerto Rico. PMID- 25550818 TI - Evidence of the presence of amyloid substance in the blood of familial amyloidotic polyneuropathy patients with ATTR Val30Met mutation. AB - Transthyretin (TTR) is a major amyloid fibril protein found in patients with familial amyloidotic polynuropathy (FAP) and senile systemic amyloidosis (SSA). Mainly synthesized in the live, TTR is transferred in the form of tetramer bound with thyroxine, retinol-binding protein (RBP) and lipoprotein in the blood. The aim of this study was to demonstrate the presence of amyloid substances in the blood by investigated the hemocoelom amyloid in different tissue sections from autopsies such as brain, kidney, heart and aorta arch tissue. Congo red staining was employed following by application of polarized light examination, to verify the presence of amyloid deposition in the tissues. Immunohistochemical staining was then performed to identify the specific type of amyloid deposition. Matrix assisted laser desorption-ionization/time of flight mass spectrometry (MALDI TOF/MS) was also used to analyze TTR mutation in FAP patients. All subjects were FAP ATTR Val30Met patients. In FAP patients, TTR amyloid deposition was found mainly in the tunica intima of the aortic arch. Interestingly, amyloid substance was found in the blood of FAP patient. Our results suggest that amyloid substance was present in the blood of FAP ATTR Val30Met patients. PMID- 25550819 TI - Optimal freezing and thawing for the survival of peripheral nerves in severed rabbit limbs. AB - This study aimed to investigate the optimal freezing and thawing procedures for the survival of peripheral nerves in severed rabbit limbs. Twenty New Zealand White rabbits were randomized into four groups: normal control, slow-freezing fast-thawing, slow-freezing slow-thawing, fast-freezing fast-thawing, with five animals in each group. The hind limbs of the rabbits were severed at 1 cm above the knee joint. The severed limbs were cryopreserved with various freezing and thawing procedures. The sciatic nerves were harvested and trypsinized into single nerve fibers for morphological evaluation. The cell viability of the nerve fibers was examined by staining with Calcein-AM and propidium iodide. The fluorescent intensity of the nerve fibers was measured with a laser scanning confocal microscope. The morphology of the nerve fibers in the slow-freezing fast-thawing group was very similar with that of the normal control group, with only mild demyelination. The slow-freezing fast-thawing group and slow-freezing slow thawing group showed severely damaged nerve fibers. The fluorescent intensities of the nerve fibers was significantly different among the four groups, with a decreasing order of normal control, slow-freezing fast-thawing, slow-freezing slow-thawing, and fast-freezing fast-thawing (P < 0.05). Of the various cryopreservative procedures, slow-freezing fast thawing has the minimal effects on the survival of nerve fibers in severed rabbit limbs. PMID- 25550820 TI - Neutrophil CD64 expression is a predictor of mortality for patients in the intensive care unit. AB - BACKGROUND: Neutrophil CD64 has been shown to be a promising biomarker for bacterial infection and sepsis identification. However, the prognostic value of CD64 in predicting the likelihood of survival for patients in intensive care unit (ICU) is unclear. METHODS: A total of 797 patients in the ICU of Xin-Hua Hospital, Shanghai, China were enrolled. We determined the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores from these patients and collected blood samples to measure the levels of neutrophil CD64, thyroid hormone and C reactive protein (CRP). We assessed the association between APACHE II scores or these biomarkers and mortality of patients in the ICU. Receiver operating characteristic (ROC) curves were generated and the Area Under the Curve (AUC) for each indicator was determined. RESULTS: The AUC for CD64 was 0.752 +/- 0.026, which was higher than that of FT3 (0.696 +/- 0.028) and CRP (0.672 +/- 0.026). APACHE II scores had the highest AUC (0.872 +/- 0.018). The level of neutrophil CD64 expression positively associated with CRP and APACHE II, and negatively correlated with FT3. Multiple regression analysis revealed that APACHE II scores (Standard beta value = 0.183, P < 0.001), CD64 (Standard beta value = 0.518, P < 0.001) or log (CRP) (Standard beta value = 1.203, P < 0.001) independently predicted ICU mortality. CONCLUSION: CD64 had the greatest power for predicting ICU mortality other than APACHE II scores. This result indicates that CD64 may be used as a biomarker to in combination with the use of APACHE II scores to improve the accuracy of predicting mortality outcome for patients in the ICU. PMID- 25550821 TI - Inhibition of neutral sphingomyelinase decreases arachidonic acid mediated inflammation in liver ischemia-reperfusion injury. AB - This study aimed to determine the role of selective neutral sphingomyelinase (N SMase) inhibition on arachidonic acid (AA) mediated inflammation following liver ischemia-reperfusion (IR) injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Levels of AA in liver tissue were determined by multiple reaction monitoring (MRM) using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin E2 (PGE2) were measured in liver tissue. Arachidonic acid levels, activity of PLA2, COX and PGE2 levels were significantly increased in postischemic liver tissue compared to nonischemic controls. N-SMase inhibition significantly decreased COX activity and PGE2 levels in postischemic liver. Future studies evaluating agents blocking N-SMase activity can facilitate the development of treatment strategies to alleviate inflammation in liver I/R injury. PMID- 25550822 TI - Expression of sarcosine metabolism-related proteins according to metastatic site in breast cancer. AB - We aimed to evaluate the expression of sarcosine metabolism-related proteins according to site of metastatic breast cancer, and the clinical implications. Immunohistochemical staining for glycine N-methyltransferase (GNMT), sarcosine dehydrogenase (SARDH), and l-pipecolic acid oxidase (PIPOX) was performed on tissue microarrays from 162 metastatic breast cancer (bone metastases = 47, brain metastases = 39, liver metastases = 24, and lung metastases = 52). Sarcosine metabolism-related proteins showed variable expression with regard to metastatic sites. GNMT was expressed in brain and lung metastases, but not in bone and liver metastases (P = 0.016). In view of the sarcosine metabolic phenotype, high sarcosine and intermediate type were only found in the brain and lung metastases, and low sarcosine type was observed more frequently in bone and lung metastases (P = 0.047). By univariate analysis, PIPOX positivity was correlated with shorter overall survival (OS) (P = 0.031). In lung metastases, PIPOX positivity (P = 0.019) and stromal PIPOX positivity (P = 0.001) were associated with shorter OS. In conclusion, in metastatic breast cancer, sarcosine metabolism-related proteins are differently expressed according to the metastatic site. Expression of GNMT and high sarcosine type are predominantly observed in brain and lung metastases. PMID- 25550823 TI - High expression of REGgamma is associated with metastasis and poor prognosis of patients with breast cancer. AB - REGgamma (REGgamma) has been recently found in several types of human cancer, however, its clinical significance in metastasis and prognosis of breast cancer remains unknown. In this study, immunohistochemical staining and western blot analysis were performed to evaluate REGgamma expression in both mouse and human breast cancer specimens. We found that in MMTV-PyMT mice, 14 out of 20 (70%) mouse mammary carcinomas were REGgamma positive, which was significantly higher than control (0/20, 0%, P < 0.001) and lower than metastatic lung tumour (20/20, 100%, P = 0.027). Further investigation for REGgamma expression in 136 human breast cancer tissues with the paired peritumoural normal breast tissues and 140 breast benign disease tissue samples showed that REGgamma was undetectable in normal breast tissues and nonmetastatic axillary lymph nodes (ALNs), whereas 111 out of 136 (81.6%) breast cancer tissue samples were REGgamma positive, which was significantly higher than breast benign disease tissues (9/140, 6.4%, P < 0.001) and lower than metastatic ALNs (116/116, 100%, P < 0.001). The 5-year disease free and overall survivals of patients with negative/low level of REGgamma were significantly higher than those of patients with high level of REGgamma (P < 0.05). Cox regression analyses further indicated that REGgamma could serve as a novel independent prognostic factor for breast cancer (OR = 4.369, P = 0.008). Our results suggest that the high expression of REGgamma might predict metastasis and poor prognosis in breast cancer. PMID- 25550824 TI - Increased activity of Rho kinase contributes to hemoglobin-induced early disruption of the blood-brain barrier in vivo after the occurrence of intracerebral hemorrhage. AB - This study is to examine whether the activation of Rho kinase (ROCK) accounts for hemoglobin (Hb)-induced disruption of blood-brain barrier (BBB) after the occurrence of intracerebral hemorrhage. A model of intracerebral injection of Hb was established in rats. Changes in the levels of mRNA of RhoA, ROCK2 and matrix metalloproteinase-9 (MMP-9) were measured using quantitative real-time polymerase chain reaction. Protein expression of RhoA, ROCK2, claudin-5 and MMP-9, as well as ROCK activity, were determined using Western blotting. Immunohistochemical assay was performed to visualize the expression of RhoA, ROCK2, claudin-5 and MMP 9 in endothelial cells. Hb injection produced a significant increase in BBB permeability and water content in the brain. Significant reduction of claudin-5 expression was detected by Western blotting and immunofluorescence in Hb group. The levels of RhoA and ROCK2 were significantly up-regulated from 6 h to 12 h after Hb injection and were concomitant with the increase in ROCK activity. Immunofluorescence double staining showed enhanced p-myosin light chain immunoreactivity but diminished claudin-5 staining in endothelial cells. Significant up-regulation of MMP-9 expression was detected after Hb injection, and statistical analyses further confirmed a positive correlation of MMP-9 expression with ROCK activity. The results showed that ROCK was activated in endothelial cells by Hb. This may account for the early disruption of the BBB via up-regulation of p-myosin light chain expression and aggravation of injuries to TJ proteins. The activation of ROCK may also increase MMP-9 expression, thereby leading to further BBB disruption. PMID- 25550825 TI - Effects of zedoary turmeric oil on P450 activities in rats with liver cirrhosis induced by thioacetamide. AB - The aim of this study was to elucidate the effects of zedoary turmeric oil (ZTO) on P450 activities (CYP1A2, CYP2C9, CYP2C19, CYP2B6, CYP2D6 and CYP3A4) in rats with liver cirrhosis induced by thioacetamide (TAA). For the induction of liver cirrhosis, rats were given TAA in their drinking water at a concentration of 0.03% for consecutive 5 weeks and then 0.04% for the next consecutive 5 weeks throughout the establishment of cirrhosis. Then the cirrhotic rats were ip given saline, ZTO 100, 200 and 400 mg/kg, respectively, once daily for 2 weeks. When cirrhosis model was established at week 10, all rats of five groups were administered intragastrically with 15 mg/kg phenacetin, 0.6 mg/kg tolbutamide, 15 mg/kg omeprazole, 15 mg/kg bupropion, 15 mg/kg metoprolol, and 10 mg/kg midazolam. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The degree of liver cirrhosis was assessed by HE staining. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from the model group increased by approximately 4-fold, and a decreased level of albumin (Alb) was also observed, as compared to the control group (P < 0.05). However, ZTO was found to reverse those changes of serum levels observed in the model group, and the 200 mg/kg ZTO treatment group showed the most obvious reverse tendency with significantly decreased ALT, AST and increased Alb levels (P < 0.05). The results indicated that ZTO with the dose of 100 mg/kg could inhibit the activities of CYP450 isoforms CYP2C9 and CYP2D6 in vivo in cirrhotic rats induced by TAA, while ZTO with the dose of 400 mg/kg could induce the activity of CYP2C19 in vivo in cirrhotic rats induced by TAA. However, ZTO showed no influence on cirrhotic rat hepatic CYP1A2, CYP2B6 and CYP3A4 activity in vivo. This has certain guiding significance to clinical treatment. PMID- 25550826 TI - Aberrant expression of Per1, Per2 and Per3 and their prognostic relevance in non small cell lung cancer. AB - The objective of the current study was to investigate the expression pattern and clinicopathological significance of Period1 (Per1), Period2 (Per2) and Period3 (Per3) in patients with non-small cell lung cancer (NSCLC). In 130 archived NSCLC tissues, the positive rate of Per1 (86/130, 66.2%), Per2 (77/130, 59.2%) and Per3 (82/130, 63.1%) were reduced in human lung cancer samples compared with adjacent normal lung tissues (Per1, 119/130, 91.5%; Per2, 115/130, 88.5%; Per3, 121/130, 93.1%), as measured by immunohistochemical staining. Loss of Per1 was correlated with poor differentiation (P < 0.001), tumor status (P=0.04), high p-TNM stage (P < 0.001) and lymph node metastasis (P=0.045). The similar tendencies were also found in the correlation of the expression of Per2 and Per3 with clinicopathological factors. In addition, a significant correlation was found between Per1 and Per2 (P < 0.001) in 130 cases of NSCLC. Similarly, a significant correlation was found between Per2 and Per3 (P=0.045). Patients with lower expression of Per1, Per2 and Per3 had a shorter survival time than those with higher expression. These results indicate that loss of Per may promote tumor progression in NSCLC, and may serve as a novel prognostic biomarker of NSCLC. PMID- 25550827 TI - Cyclic tension promotes osteogenic differentiation in human periodontal ligament stem cells. AB - Orthodontic forces result in alveolar bone resorption and formation predominantly on the pressure and tension sides of the tooth roots, respectively. Human periodontal ligament stem cells (PDLSCs) have demonstrated the capacity to differentiate into osteoblasts, and they play important roles in maintaining homeostasis and regenerating periodontal tissues. However, little is known about how PDLSCs contribute to osteoblastogenesis during orthodontic tooth movement on the tension side. In this study, we applied a 12% cyclic tension force to PDLSCs cultured in osteoinductive medium. The osteogenic markers Runx2, ALP, and OCN were detected at the mRNA and protein levels at different time points using real time PCR and western blot analyses. We discovered that the mRNA and protein levels of Runx2, ALP and OCN were significantly up-regulated after 6, 12 and 24 hours of mechanical loading on PDLSCs compared to levels in unstimulated PDLSCs (P < 0.05). This study demonstrates, for the first time, the effects of mechanical tensile strain on the osteogenic differentiation of PDLSCs, as examined with a Flexcell FX-4000T Tension Plus System. Our findings suggested that cyclic tension could promote the osteogenic differentiation of PDLSCs. Furthermore, the effects of orthodontic force on alveolar bone remodeling might be achieved by PDLSCs. PMID- 25550828 TI - PTK7 protein is decreased in epithelial ovarian carcinomas with poor prognosis. AB - Epithelial ovarian cancer is the most common tumor of ovary. PTK7 plays an important role in tumors. Till now, there is no report about the role of PTK7 in ovarian epithelial neoplasms. This study aims to investigate the expression of PTK7 protein in epithelial ovarian tumors, and its relationship with clinical pathological characteristics. In this study, immunohistochemical staining was used to detect the expression of PTK7 protein in 14 samples of normal fallopian tube epithelium and 204 cases of epithelial ovarian tumor. The relationship between the expression of PTK7 and pathological indicators was statistically analyzed. Kaplan-Meier survival function was used to analyze the prognosis. The expression of PTK7 was found in 92.86% (13/14) of normal fallopian tube epithelium and 45.10% (92/204) of epithelial ovarian tumor tissues. The expression level of PTK7 was significantly decreased from the benign, the intermediate type, to malignant ovarian epithelial tumors (P < 0.001), and decreased from the normal control group to serous carcinomas (P < 0.001). The expression of PTK7 was significantly different in type I and type II epithelial ovarian carcinomas (P < 0.001). PTK7 protein expression was associated with clinical stages (P = 0.038) and metastases (P = 0.038) in ovarian borderline serous tumors. PTK7 protein expression was associated with clinical stages (P = 0.011), WHO grading (P = 0.004), and MDACC grading (P < 0.001) in ovarian serous carcinomas. The survival analysis showed that patients with negative expression of PTK7 protein had a poorer outcome than those with positive expression (P = 0.017). These results indicate that PTK7 protein may be a tumor suppressor and a potential prognostic marker in ovarian serous carcinomas. PMID- 25550829 TI - Preoperative serum CA19-9 levels is an independent prognostic factor in patients with resected hilar cholangiocarcinoma. AB - To investigate the appropriate cutoff point of CA19-9 for prognosis and other potential prognostic factors that may affect survival of patients with hilar cholangiocarcinoma (HC) after radical surgery. 168 patients who had undergone radical surgery for hilar cholangiocarcinoma and resultant macroscopic curative resection (R0 and R1) were discreetly selected for analyses. Categorized versions were used in univariate model to determine the appropriate cutoff point of CA19 9. CA19-9 and other clinicopathologic factors were analyzed for influence on survival by univariate and multivariate methods. The strongest univariate predictor among the categorized preoperative CA19-9 measures was CA19-9 less than 150 IU/L (P = 0.000). In univariate analysis, tumor size, Bismuth-Corlette classification, portal vein invasion, Lymph node metastasis, resection margin and preoperative CA19-9 levels were identified as significant prognostic factors. In multivariable analysis, lymph node metastasis, resection margin and preoperative CA19-9 levels were independent prognostic factors. our results demonstrated that preoperative CA19-9 levels was also an independent prognostic factor for hilar cholangiocarcinoma, and the most discriminative cutoff point of CA19-9 for prognosis proved to be at 150 U/ml. PMID- 25550830 TI - Cardioprotective effect of resveratrol on atherogenic diet-fed rats. AB - Atherogenic or high fat diets were known to induce cardiovascular diseases, and several active compounds were tested to protect/prevent the risk of cardiovascular diseases. We aimed to investigate the cardio protective effect of resveratrol against atherogenic diet fed rats. Male Wistar rats were administered atherogenic diet for 30 days and further continued for 15 days with or with resveratrol in the diet. The serum lipid profile, antioxidant enzyme activity, lipid peroxidation, lipid metabolic proteins and cardiac tissue markers were examined. The histopathology of myocardium and aorta were also examined. The abnormal serum lipid profile found in atherogenic rats was reversed by the administration of resveratrol. Similarly, the enzymatic (catalase, superoxide dismutase, glutathione-peroxidase), non-enzymatic (reduced-glutathione, Vitamin C, E) antioxidants were improved by the resveratrol fed against atherogenic diet. Interestingly, resveratrol activated the lipid metabolic proteins (SIRT1, eNOS and AMPKa), suggesting its protective effect on lipid metabolism. Further analysis on tissue damage revealed that resveratrol had significantly protected the tissue damage and maintains the morphology of cardiac tissue. Altogether, our results suggest that resveratrol played a significant role in the prevention of cardiovascular system against the high fat diet. Emphasising the anti-atherogenic property of resveratrol, we propose resveratrol as a potential compound to be consumed for the healthy life-style. PMID- 25550831 TI - Overexpression of EpCAM and Trop2 in pituitary adenomas. AB - We sought to investigate the expression of EpCAM and Trop2 in Pituitary adenomas (PAs) and study the correlation of protein expression with invasiveness, proliferation, clinical functioning, recurrence/progression, and some other factors. We investigated the expression of EpCAM and Trop2 in 74 samples of PAs by immunohistochemistry and made correlative analysis of protein overexpression with clinicopathological parameters. Follow-up data was analyzed for recurrence/progression with Kaplan-Meier method and Multivariate Cox regression analysis. Immunohistochemistry results showed that overexpression rates of EpCAM and Trop2 were 51/74 (68.9%) and 43/74 (58.1%), respectively. For both EpCAM and Trop2, PAs with invasiveness showed a higher overexpression rate than PAs without invasiveness (PEpCAM = 0.001; PTrop2 = 0.006). Nonfunctional Pituitary adenomas (NFPAs) demonstrated a higher EpCAM overexpression than functional Pituitary adenomas (FPAs) (P = 0.026). Both EpCAM and Trop2 overexpression correlated significantly with expression of proliferation factor Ki-67 (PEpCAM = 0.011; PTrop2 = 0.000), but not with gender and age. Follow-up analysis revealed that Trop2 overexpression was a significantly predictive factor for recurrence/progression by means of Kaplan-Meier method d (P = 0.028) and Multivariate Cox regression analysis (P = 0.025). This study reveals that both EpCAM and Trop2 overexpression in PAs correlate significantly with invasiveness and proliferation. EpCAM presents a potential target for differential diagnosis and immunotherapy for NFPAs. Follow-up analysis shows that Trop2 is a predictive factor for recurrence/progression for PAs. PMID- 25550832 TI - Decreased HCRP1 expression is associated with poor prognosis in breast cancer patients. AB - BACKGROUND: Downregulation of hepatocellular carcinoma related protein 1 (HCRP1) has been reported to be associated with a poor prognosis in a variety of malignant tumors. The purpose of this study was to assess HCRP1 expression in breast cancer and to examine its possible correlation with commonly used prognostic factors, particularly epidermal growth factor receptor (EGFR). METHODS: Immunohistochemical analysis was performed on tumors from 194 patients with primary breast cancer. HCRP1 expression was analyzed along with major clinicopathological variables. RESULTS: HCRP1 protein expression was shown to be correlated with age (P = 0.001), histological grade (P = 0.005), tumor progression (P = 0.013), and death (P = 0.001), but not with tumor size, lymph node metastasis, or Ki67 status. Kaplan-Meier survival curves showed that lower HCRP1 expression was significantly correlated with increased short-term survival (P < 0.001), and both univariate and multivariate analyses revealed that HCRP1, tumor size, lymph-node metastasis, and human epidermal growth factor receptor-2 (HER-2) were independent prognostic factors (all P < 0.05). In addition, low HCRP1 expression was much more frequent in triple negative breast cancer (TNBC; 63.89%) than in luminal (16.95%) and HER-2 overexpression phenotypes (7.5%; P < 0.001), and significant correlations between HCRP1 and survival time were observed for the TNBC group (P < 0.004). Furthermore, an inverse relationship between HCRP1 and EGFR expression was found both for the complete set of all cases (P < 0.001), and for each phenotype analyzed individually (P < 0.05). CONCLUSION: Our results suggest that HCRP1 may play an important role in EGFR regulation and that its decreased expression is an independent predictor of breast cancer, especially in TNBC patients. PMID- 25550833 TI - Role of TGF-beta1/p38 MAPK pathway in hepatitis B virus-induced tubular epithelial-myofibroblast transdifferentiation. AB - OBJECTIVE: This study is to investigate the hepatitis B virus (HBV)-induced tubular epithelial-myofibroblast transdifferentiation (TEMT) in human renal tubular epithelial HK-2 cells. METHODS: Human proximal tubular epithelial HK-2 cells were cultured. These HK-2 cells were divided into 4 groups: the blank control group, the vector control group, the HBV-transfected group, and the inhibitor-treated group. Transfection was performed with lipofectamine. Measurements of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in culture supernatant were determined by electrochemiluminescence immunoassay. Immunocytochemical staining, reverse transcription PCR (RT-PCR), and Western blot analysis were performed to detect the mRNA and protein expression levels, respectively. RESULTS: The immunocytochemical staining showed that, the expression level of E-cadherin was dramatically decreased, while the alpha-SMA expression level was significantly elevated, in HBV-transfected HK-2 cells. The mRNA level of TGF-beta1 and the protein level of p-p38 mitogen-activated protein kinase (MAPK) were elevated in HK-2 cells transfected with HBV. When treated with the p38 MAPK-specific inhibitor, the activation of p38 MAPK was eliminated in HBV transfected HK-2 cells. In addition, the altered expression levels of E-cadherin and alpha-SMA, the increased contents of HBeAg and HBsAg in the culture supernatant, as well as the morphological changes of TEMT in HBV-transfected HK-2 cells, were all reversed by the inhibiter treatment. CONCLUSION: HBV transfection could induce TEMT in HK-2 cells, which was mediated by the TGF-beta1/p38 MAPK pathway. These findings provide new insights into the prevention and treatment of HBV-associated glomerulonephritis. PMID- 25550834 TI - Expression of aryl hydrocarbon receptor in relation to p53 status and clinicopathological parameters in breast cancer. AB - The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor implicated in multiple cellular processes and its expression has been shown to play a critical role in tumorigenesis. However, the role of AhR in tumorigenesis of breast cancer remains unclear. In the current study, we investigated the expression levels of AhR in breast lesions and assessing the correlation between AhR expression and clinicopathological variables using breast cancer tissue microarray. Meanwhile, 10 paired of fresh breast cancer and corresponding non cancer samples were detected for AhR and p53 expression by Western blot, respectively. Results showed that AhR expression levels in breast cancer tissues were significantly higher than that in the non-cancer tissues. AhR expression was associated with the pathological type and P53 status, but not patients age, tumor grade and TNM, as well as ER, PR, C-erbB2, Ki-67, AR, EGFR status. Moreover, Western blot data suggested a negative correlation between p53 protein and AhR protein expression levels. The results suggest that high levels of AhR were expressed in the majority of breast cancer tissues and closely associated with P53 status and histological types of breast cancer. AHR and its abnormal expression may play an important role in multiple stages of breast cancer progression. PMID- 25550835 TI - Overexpression of long non-coding RNA UCA1 predicts a poor prognosis in patients with esophageal squamous cell carcinoma. AB - INTRODUCTION: Long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology, and the lncRNA UCA1 is upregulated in several cancers such as bladder cancer, breast cancer and colorectal cancer, however, the contributions of UCA1 to esophageal cancer remain largely unknown. METHODS: Expression levels of lncRNA UCA1 in esophageal squamous cell carcinoma (ESCC) patients and esophageal cancer cell lines were evaluated by quantitative real time PCR (qRT-PCR), and its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA was used to suppress UCA1 expression in esophageal cancer cell line. In vitro assays were conducted to further explore its underlying roles in tumor progression. RESULTS: The relative level of UCA1 was significantly higher in ESCC tissues compared to the adjacent non-tumor tissues, and remarkably higher expression of UCA1 was found in esophageal cancer cell lines compared with the immortalized esophageal epithelial cell line NE1. The ESCC patients with higher UCA1 expression had an advanced clinical stage and a poorer prognosis than those with lower expression. In vitro assays, our data indicated that downregulation of UCA1 decrease cell proliferation, migration, and invasion ability. CONCLUSIONS: lncRNA UCA1 might be considered as a novel molecule involved in ESCC progression, which provides a potential prognostic biomarker and therapeutic target. PMID- 25550836 TI - Significance of multidrug resistance gene-related proteins in the postoperative chemotherapy of gastric cancer. AB - BACKGROUND: Multidrug resistance (MDR) is a serious problem in chemotherapy and is one of the main reasons for a poor outcome of gastric cancer. Study on the key proteins in multidrug resistance is necessary for the treatment of gastric cancer. METHODS: The expression of ToPo II, MRP and GST-pi in 119 gastric cancers was retrospectively examined, and the results were analyzed in correlation with clinicopathological data. ToPo II negative, MRP positive and GST-pi positive were regarded as three risk factors which may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: high-risk group (>=2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patients' survival time of the two groups were also analyzed. RESULTS: The positive rates of ToPo II, MRP and GST-pi were 73.9%, 42.9% and 51.3%, respectively. The positively correlation between the expression of MRP and GST-pi had been found. A significant correlation was shown between ToPo II expression and the level of differentiation. Significant differences with GST-pi expression were also found in relation to the sex and differentiation. In the high-risk group, the 3-year survival rate of patients with/without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, but the difference was not statistically significant (P>0.05). In the low-risk group, the 3-year survival rate of patients with/without chemotherapy were 81.2% and 51.5%, 5-year survival rates were 71.9% and 45.5%, and the difference was statistically significant (P<0.05). CONCLUSIONS: Combined detection of MDR-related proteins ToPo II, MRP and GST-pi may be prospectively valuable for postoperative individualized chemotherapy, and further predict the outcomes of gastric cancer patients. PMID- 25550837 TI - Primary lymphoepithelioma-like carcinoma of salivary glands: a clinicopathological study of 21 cases. AB - Lymphoepithelioma-like carcinoma (LELC) of salivary glands is a rare kind tumor. In this study, the authors evaluated 21 patients with LELC of salivary glands who had long-term follow-up. Clinical characteristics, Epstein-Barr virus (EBV) infection, immunohistochemical features, oncoprotein expression, treatments, and outcomes were analyzed. All patients were Chinese. Their ages ranged from 20 to 73 years. All tumors showed the typical syncytial growth pattern of undifferentiated epithelial cells with a significant lymphocyte reaction. All of patients were found by in situ hybridization to have the EBV genome. All tumors showed positive immunostaining of AE1/AE3, CK5/6 and p63. Nearly all cases had bcl-2 oncoprotein expression, but the detection rate of p53, and c-erb B-2 expression was extremely low. LELC of salivary glands is a distinct entity of salivary cancer. LELC of salivary glands can receive multimodality treatment and has a better prognosis similar to that of nasopharyngeal carcinoma. PMID- 25550838 TI - Squamous cell carcinoma in a duplicated renal pelvis. AB - We report an extremely rare case of squamous cell carcinoma (SCC) of the renal pelvis associated with an incompletely duplicated renal pelvis and ureter. A 71 year-old woman presented with left lower back pain and gross hematuria. Urinary cytology showed atypical squamous cells. Computed tomography, magnetic resonance imaging and retrograde pyelography revealed left incompletely duplicated renal pelvis and ureter and a mass in the left upper renal pelvis. A clinical diagnosis of left renal pelvic cancer was made and the patient underwent total nephroureterectomy. Histological examination of the resected specimen revealed SCC with marked keratinization in the upper renal pelvis. The tumor had invaded the renal parenchyma and perinephric fat. There was no urothelial carcinoma component. The pathological stage was pT4 N0. There was no evidence of recurrence 6 months postoperatively. Because the prognosis of SCC of the upper urinary tract is poor, urologists and pathologists should be aware that SCC may develop in duplicated urinary systems. PMID- 25550839 TI - RVLM-IML pathway may implicate controlling peripheral airways by melanocortinergic-sympathetic signaling: a transneuronal labeling study using pseudorabies virus. AB - Pseudorabies virus (PRV)-614 was injected into the tracheal wall of male MC4R-GFP transgenic mice, resulting in retrograde infections in spinal cord and autonomic premotor areas of the brain including the rostroventrolateral medulla (RVLM). This polysynaptic pathway to the airway may form the substrate underlying the impact of IML and RVLM on airway function. The neurochemical phenotype of MC4R GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML and the rostral ventrolateral medulla (RVLM). These data demonstrate the RVLM-IML pathway of synaptically connected neurons extending to the airway through melanocortinergic-sympathetic signaling. PMID- 25550841 TI - Uterine superficial serous carcinomas and extensive serous endometrial intraepithelial carcinomas: clinicopathological analysis of 6 patients. AB - Uterine superficial serous carcinoma (SSC) and serous endometrial intraepithelial carcinoma (SEIC) are unique malignancies found primarily in postmenopausal women. SSC and SEIC lesions measuring 1 cm or less are categorized as minimal uterine serous carcinoma (MUSC). Less well understood, however, the clinical behavior of SSC and SEIC lesions measuring more than 1 cm. We investigated 6 postmenopausal patients, aged 69-83 years, with SSC or SEIC and without hyperestrogenism. All but 1 patient had tumors originating from the surface of polyps, including 3 patients who each had an enormous polyp occupying the entire uterine cavity. Two patients had extensive SEICs measuring more than 1 cm; the others had SSCs, including 1 MUSC. The mesenchymal cells of the cancer-bearing polyps lacked the morphologic characteristics of endometrial stroma, and the cancer glands often immunostained negatively for estrogen receptors and progesterone receptors. Diffuse immunostaining for human epidermal growth factor receptor 2 was detected in 3 patients, and p53 was detected in all. Cyclin E, a downstream molecule of the F-box and WD repeat domain-containing 7 (FBXW7), was detected in all patients. Microdissected cancer glands showed p53 mutations in 2 patients and a FBXW7 mutation in 1 patient. These findings suggest that mutations of FBXW7 and p53 may contribute to the carcinogenesis of less invasive tumor subtypes. Pathologists and physicians should carefully evaluate SSC and SEIC lesions involving large polyps but lacking myometrial invasion. PMID- 25550840 TI - Blood vessel invasion and other variables as predictors of long-term survival in Japanese and British patients with primary invasive breast cancer. AB - This study was undertaken to investigate the associations of blood vessel invasion (BVI), lymphatic vessel invasion (LVI) or other variables and long-term survival in 173 Japanese and 184 British patients with primary invasive breast cancer, and whether they are associated with survival differences between Japanese and British patients. BVI was detected by objective methods, using both factor VIII-related antigen (F-VIII) staining and elastica van Gieson (E v G) staining. BVI was classified into three subtypes. 1) BVI e, BVI detected by E v G staining alone, 2) BVI f, BVI detected by F-VIII staining alone, 3) BVIef, BVI evaluated by combining BVIf and BVIe. LVI was also detected by objective methods, using lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) staining alone. There was a borderline significance between the frequencies for BVIef of British patients and those of Japanese patients (8.2% vs 3.5%; P = 0.06) but not for LVI (P = 0.36). British patients had a significantly worse relapse-free survival (RFS) and overall survival (OS) than Japanese patients (P < 0.01, P < 0.01, respectively) even though their tumors were smaller and more ER-positive with a similar prevalence of lymph-node involvement. LVI was not significantly associated with RFS and OS, however, BVIef positive tumors had a significantly worse RFS and OS compared with BVIef negative patients, after statistical adjustment for the other variables (P = 0.02, P = 0.01, respectively). The present study shows that BVIef variability might contribute to the Japanese and British disparities in breast cancer outcomes. PMID- 25550842 TI - Dual high expression of STAT3 and cyclinD1 is associated with poor prognosis after curative resection of esophageal squamous cell carcinoma. AB - BACKGROUND: Signal transducer of activator of transcription 3 (STAT3) and cyclinD1 are overexpressed in various human cancers, and their overexpression positively correlates to tumor progression and poor prognosis. However, the clinical significance of dual high expression of these two proteins in esophageal squamous cell carcinoma (ESCC) has yet to be determined. METHODS: The expression of STAT3 and cyclinD1 was analyzed in tissue microarrays containing tumor and adjacent tissue samples from 82 patients who had undergone curative resection for histologically proven ESCC. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the prognostic value of STAT3 and cyclinD1 expression. RESULTS: We discovered that expressions of STAT3 and cyclinD1 in cancer tissues were significantly higher than that in adjacent tissues. High expression of STAT3 and cyclinD1 was associated with malignant behaviors. Moreover, the expression of STAT3 was positively associated with the expression of cyclinD1. High STAT3 or cyclinD1 expression alone was associated with lower overall survival (OS) rates. Furthermore, dual high expression of STAT3 and cyclinD1 expression predict even worse survival outcome in both univariate and multivariate analysis. CONCLUSION: STAT3 and cyclinD1 correlate with more aggressive tumor behavior in ESCC. When STAT3 and cyclinD1 are considered together, they serve as effective prognostic markers in patients with surgically resected ESCC. PMID- 25550843 TI - Expression of papillary thyroid carcinoma-associated molecular markers and their significance in follicular epithelial dysplasia with papillary thyroid carcinoma like nuclear alterations in Hashimoto's thyroiditis. AB - The aim of this study was to evaluate the expression of papillary thyroid carcinoma (PTC)-associated tumor markers in follicular epithelial dysplasia showing PTC-like nuclear alterations (FED) in Hashimoto's thyroiditis (HT) and to explore the relationship between HT and PTC. In this study, 43 PTC, 18 HT with FED and 16 peritumoral benign thyroid tissues were immunohistochemically analyzed for CK19, galectin-3, HBME-1, CD56, claudin-1 and NGAL expression. Our research revealed that in HT, the expression of CK19, galectin-3, HBME-1, claudin-1 and NGAL was focal and limited to FED, while CD56 was strongly positive in FED and most Hurthle cells. The stain intensity of CK19, claudin-1 and NGAL in FED decreased compared with PTC, but were significantly higher than that in peritumoral benign thyroid tissues (all P < 0.0125). For galectin-3, HBME-1 and CD56, no statistically significant difference was detected between HT and peritumoral benign thyroid tissues (all P > 0.05). In conclusion, In HT, FED might be a precancerous condition closely associated with PTC development as they have overlaps in cytological and immunomarker profiles, indicating that in patients with HT, under prolonged stimuli from chronic inflammation, part of follicular epithelia may show regeneration, hyperplasia, Hurthle cell metaplasia and dysplasia, eventually malignant transformation. Hence, long term follow-up and regular inspection would be necessary for Hashimoto's thyroiditis with FED. PMID- 25550844 TI - Increased IL-12 and decreased IL-33 serum levels are associated with increased Th1 and suppressed Th2 cytokine profile in patients with diabetic nephropathy (CURES-134). AB - The role played by recently discovered novel cytokine IL-33 in controlling T helper (Th)1 and Th2 cytokines under conditions of diabetic nephropathy (DN) is less well studied. In the present study, we estimated the levels of IL-33 along with both Th1 and Th2 cytokines in the serum of normal glucose tolerant (NGT), diabetic subjects with (DN) or without nephropathy (DM) and correlated it with the clinical risk factors of diabetes and nephropathy. 222 study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES): 61 NGT, 79 DM and 82 DN. IL-33 level was estimated by ELISA while other Th1 (IL-12, IFN-gamma and IL-2) and Th2 (IL-4, IL-5 and IL-13) cytokines were measured using a Bio-plex bead assay. DM subjects showed a mixed Th1-Th2 profile (increased IFN-g, IL-12, IL-4 and IL-13 and decreased IL-33) while DN subjects showed enhanced Th1 profile (increased IFN-g, IL-2 and IL-12) with suppression of Th2 cytokine (decreased IL 33 and IL-13). The IL-33 levels showed a serial decline with increasing severity of insulin resistance and microalbuminuria. DN was associated with enhanced Th1 response and suppression of Th2 responses which might be due to inreased levels of IL-12 and decreased levels of IL-33 cytokines respectively. PMID- 25550845 TI - Comparison of the gene expression profiles between gallstones and gallbladder polyps. AB - BACKGROUND: Gallstones and gallbladder polyps (GPs) are two major types of gallbladder diseases that share multiple common symptoms. However, their pathological mechanism remains largely unknown. The aim of our study is to identify gallstones and GPs related-genes and gain an insight into the underlying genetic basis of these diseases. METHODS: We enrolled 7 patients with gallstones and 2 patients with GP for RNA-Seq and we conducted functional enrichment analysis and protein-protein interaction (PPI) networks analysis for identified differentially expressed genes (DEGs). RESULTS: RNA-Seq produced 41.7 million in gallstones and 32.1 million pairs in GPs. A total of 147 DEGs was identified between gallstones and GPs. We found GO terms for molecular functions significantly enriched in antigen binding (GO:0003823, P=5.9E-11), while for biological processes, the enriched GO terms were immune response (GO:0006955, P=2.6E-15), and for cellular component, the enriched GO terms were extracellular region (GO:0005576, P=2.7E-15). To further evaluate the biological significance for the DEGs, we also performed the KEGG pathway enrichment analysis. The most significant pathway in our KEGG analysis was Cytokine-cytokine receptor interaction (P=7.5E-06). PPI network analysis indicated that the significant hub proteins containing S100A9 (S100 calcium binding protein A9, Degree=94) and CR2 (complement component receptor 2, Degree=8). CONCLUSION: This present study suggests some promising genes and may provide a clue to the role of these genes playing in the development of gallstones and GPs. PMID- 25550846 TI - Gastrointestinal stromal tumors with exon 8 c-kit gene mutation might occur at extragastric sites and have metastasis-prone nature. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the human gut. Most sporadic GISTs have somatic gain-of-function mutations of the c-kit gene. The mutations are frequently found at exon 11, sometimes at exon 9 and rarely at exon 13 or 17. Recently, exon 8 c-kit gene mutations were reported in very minor proportion of sporadic GISTs. We also found 3 GISTs with exon 8 c kit gene mutations in approximately 1,000 sporadic GISTs examined. In the present report, we showed the clinicopathological data of those GISTs. One case had a deletion of codon 419 of aspartate, and 2 cases had a substitution of 3 amino acids of codon 417 to codon 419 to tyrosine. The former was the same mutation recently reported in 2 GIST cases, but the latter has not been reported in any GISTs. All three cases occurred at extragastric sites and two of three showed distant metastasis. Since the remaining case was regarded as high risk for recurrence, imatinib adjuvant treatment has been done without evidence of metastasis. Our results confirmed the idea that exon 8 mutations are minor but actually existing abnormalities in sporadic GISTs, and suggested that such GISTs have a feature of extragastric development and a metastasis-prone nature. Since the exon 8 mutations appeared to be really sensitive to imatinib as shown in the present case study, accurate genotyping including exon 8 of the c-kit gene is necessary in GISTs to predict response to imatinib in both the unresectable/metastatic and adjuvant settings. PMID- 25550847 TI - Increased expression of miR-24 is associated with acute myeloid leukemia with t(8;21). AB - This study was designed to learn the expression status of miR-24 and its clinical relevance in patients with acute myeloid leukemia (AML). We detected the miR-24 expression levels using real-time quantitative PCR in 84 AML patients and investigated the clinical significance of miR-24 expression in AML. There was no difference in clinical parameters between cases with miR-24 high expression and with miR-24 low expression. The frequency of miR-24 high expression was higher in patients with t(8;21) than in others (82% (9/11) versus 44% (32/72), P=0.026). The levels of miR-24 expression had no correlation with the mutations of nine genes (FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, N/K-RAS and C/EBPA). Meanwhile, among the group who obtained CR, the cases with miR-24 high expression had no difference in overall survival (OS) and relapse-free survival (RFS) than those with miR-24 low expression (P=0.612 and 0.665, respectively). These findings implicated that miR-24 high regulation is a common event in AML with t(8;21), and it might serve as a novel and selective therapeutic target for the treatment of AML with t(8;21). PMID- 25550848 TI - Correlation of EGFR mutation and histological subtype according to the IASLC/ATS/ERS classification of lung adenocarcinoma. AB - OBJECTIVE: To evaluate the correlation of EGFR mutation and histological subtypes of lung adenocarcinoma based on the IASLC/ATS/ERS classification. METHODS: EGFR exons 18-21 of 206 resected lung adenocarcinoma specimens were analyzed with pyrosequecing, then the differences between histological subtypes and EGFR mutation were compared. RESULTS: EGFR mutation was detected in 123 specmens, most of which were papillary and acinar predominant adenocarcinoma. EGFR mutation rate of the specimens with papillary, acinar or lepidic component was higher than without these components (P < 0.05), and with solid or mucinous component was lower than that without the component (P < 0.05). EGFR mutation in solid predominant mixed other subtypes was more commonly found than that of pure solid component (P=0.018). CONCLUSIONS: The presence of well-differentiated components in lung adenocarcinoma, such as lepidic, papillary and acinar, indicates a higher EGFR mutation rate, while the solid and mucinous component indicate a lower EGFR mutation rate. There is heterogeneity of EGFR mutation in lung adenocarcinoma. PMID- 25550849 TI - MicroRNA-139-3p indicates a poor prognosis of colon cancer. AB - MicroRNAs (miRNAs) play an important role in the regulation of gene expression and are involved in almost biological procession. Recently, miR-139-5p has been reported to be downregulated in some types of cancer, and inhibits cancer cell invasion and metastasis. However, there are few reports on the role of miR-139-3p in cancer. In this study, we examined the expression level of miR-139-3p in 63 pairs of colon cancer and adjacent paracancerous tissues using quantitative reverse transcription PCR. The levels of miR-139-3p in colon cancer tissues were significantly lower than those in adjacent noncancerous tissues. There was an inverse correlation between the level of miR-139-3p and patient's age. Lower level of miR-139-3p was significantly associated with poor overall survival, especially in patients with TNM stages I and II. In conclusion, miR-139-3p has potential as a prognostic biomarker for colon cancer. Further prospective studies are required to validate this result. PMID- 25550850 TI - Clinical significance of TMPRSS4 in prostate cancer. AB - Transmembrane protease serine 4 (TMPRSS4) is a type-II transmembrane serine protease that plays an important role in the migration of cancer cells. This study aimed to investigate both the expression of TMPRSS4 and its clinical significance in prostate cancer. The expression of TMPRSS4 was evaluated in 73 pairs of prostate cancer and adjacent non-cancerous tissues by immunohistochemistry. The level of TMPRSS4 in prostate cancer tissues was significantly higher than that in adjacent non-cancerous tissues. High TMPRSS4 expression was significantly associated with advanced TNM stage and LNM. No association between TMPRSS4 expression and progression-free survival was observed in all patients. Stratified analyses according to clinical features revealed that patients with low TMPRSS4 expression had poor prognosis compared with those with high TMPRSS4 expression in subjects not receiving neoadjuvant chemotherapy. In conclusion, TMPRSS4 showed abnormal expression in prostate cancer tissues. TMPRSS4 may be a potential prognostic biomarker for prostate cancer patients who did not undergo neoadjuvant chemotherapy. PMID- 25550851 TI - Expression of PBK/TOPK in cervical cancer and cervical intraepithelial neoplasia. AB - objectives: To evaluate the expression of PBK/TOPK (PDZ-binding kinase/T-LAK cell originated protein kinase) and its clinical significance in cervical cancer and cervical intraepithelial neoplasia. METHODS: PBK/TOPK expression was detected in 28 cases of low-grade cervical intraepithelial neoplasia (CINI), 62 cases of high grade intraepithelial neoplasia and 80 cases of cervical cancer by immunohistochemistry (IHC). Then, the correlation between PBK/TOPK expression and clinicopathological features was quantitatively analyzed by measuring the positive unit (PU). RESULTS: PBK/TOPK expression was significantly greater in cervical cancer than that in high-grade intraepithelial neoplasia and CINI (P < 0.05). Meanwhile, PBK/TOPK expression in high-grade intraepithelial neoplasia was significantly higher compared with that in CINI (P < 0.05). In addition, PBK/TOPK expression in cervical cancer significantly correlated with histological type, differentiation, lymph node metastasis, vaginal and cervical invasion, TNM stage and tumor size (P < 0.05). CONCLUSION: PBK/TOPK expression is closely associated with cervical cancer and cervical intraepithelial neoplasia, which may be served as a useful target for tumor diagnosis and immunotherapy. PMID- 25550852 TI - Expression of long non-coding RNA LOC285194 and its prognostic significance in human pancreatic ductal adenocarcinoma. AB - INTRODUCTION: Dysregulation of long non-coding RNAs (lncRNAs) plays critical roles in tumor progression. lncRNA LOC285194 was previously shown to be correlated with aggressive clinicopathological features and poor prognosis in several cancers. The aim of this study was to investigate relationship between LOC285194 expression and clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). METHODS: Quantitative real-time PCR (qRT-PCR) assay was performed to detect the expression of lncRNA LOC285194 in human PDAC cells and tissue samples. The association of LOC285194 expression with clinicopathologic features was analyzed. Kaplan-Meier analyses were used to assess survival of patients. Univariate and multivariate analyses were performed using the Cox proportional hazards model to analyze the prognostic significance of LOC285194 expression. RESULTS: Our data showed that the relative level of LOC285194 in PDAC cells was significantly lower than that in normal human pancreatic duct epithelial cell line. Also, the expression of LOC285194 in PDAC tissues was significantly lower than that in adjacent non-tumor tissues. By statistical analyses, low LOC285194 expression was observed to be closely correlated with clinical stage, lymphnode metastasis and liver metastasis. Kaplan-Meier survival analysis revealed that patients with low LOC285194 expression had a poor overall survival compared with the high LOC285194 group (P < 0.05). Univariate and multivariate analyses showed that low LOC285194 expression was an independent poor prognostic factor for PDAC patients. CONCLUSIONS: Our data provided the first evidence that reduced LOC285194 in PDAC tissues was correlated with tumor progression, and lncRNA LOC285194 might be a potential molecular biomarker for predicting the prognosis of patients. PMID- 25550853 TI - Down-expression of F box only protein 8 correlates with tumor grade and poor prognosis in human glioma. AB - F box only protein 8 (FBX8) is a novel component of F-box proteins which involved in the ubiquitin-dependent proteolytic pathway. Recent studies have revealed that FBX8 was unregulated in tumor cells and was closely associated with tumor progression and metastasis of other cancer, but little research has been done yet to test its usefulness as a prognostic marker in human glioma. In the present study, we investigated the expression of FBX8 in glioma tissues using immunohistochemical analysis and evaluated its prognostic significance in glioma. We found that 44/77 (57.14%) gilomas had positive expression of FBX8, while 65/77 (84.42%) normal brain tissue had positive expression of FBX8. The expression level of FBX8 was remarkably down-regulated in glioma tissues compared with normal brain tissues (P < 0.001). The down-expression of FBX8 in tumor cells was strongly correlated with tumor grade of patients with glioma (P < 0.05). Patients with lower expression of FBX8 protein had shorter overall survival time than those with higher level expression of FBX8 (P < 0.05). Multivariate analysis showed that FBX8 down-expression was an independent prognostic indicator for glioma patient's survival. Our results suggest that a potential application of FBX8 in prognosis prediction and therapeutic application in glioma. PMID- 25550854 TI - Decreased expression of interleukin-36alpha predicts poor prognosis in colorectal cancer patients. AB - Interleukin-36alpha (IL-36alpha), previously designated as IL-1F6, has been found to have a pathogenic role in psoriasis. However, possible functions of IL-36alpha in cancer remain unclear. In present study, we investigate the possible role of interleukin-36alpha involved in the pathogenesis of colorectal cancer. IL-36alpha expression was detected in 345 colorectal cancer tissue samples by immunohistochemical staining, and its relation with clinicopathologic parameters and prognosis of colorectal cancer patients were analyzed. IL-36alpha was highly expressed in nearly half of all tested colorectal cancer patients. However, low expression level of IL-36alpha significantly correlated with larger tumor size and advanced TNM stage. Kaplan-Meier survival analysis showed that low expression level of IL-36alpha resulted in a remarkably poor prognosis of colorectal cancer patients. Multivariate Cox's analysis revealed that the IL-36alpha expression level was a significant and independent prognostic factor for overall survival rate of colorectal cancer patients. Thus, our study may provide insight into the application of IL-36alpha as a novel predictor of prognosis and a potential therapeutic drug for colorectal cancer. PMID- 25550855 TI - Mesenteric and splenic contributions to portal venous CT perfusion in hepatic diffuse disease. AB - AIM: To investigate the changes and contributions of superior mesenteric venous perfusion (SMVP) and splenic venous perfusion (SpVP) to portal venous CT perfusion in canine model of hepatic diffuse disease. MATERIALS AND METHODS: By selective catheterization in superior mesenteric and splenic arteries respectively after CT perfusion scanning, SMVP and SpVP became available. Sixteen dogs were adopted and induced by carbon tetrachloride after data under normal conditions were collected. After 3, 6, 9 and 12 months from carbon tetrachloride intervention, liver biopsies by puncture or operation were performed after CT perfusion scanning. SMVP and SpVP under different pathologic conditions were compared and analyzed. RESULTS: Three stages of hepatic diffuse lesions were defined according to pathologic changes, namely hepatitis, hepatic fibrosis, and cirrhosis. The number of dogs which survived from each stage was: 16 from normal, 12 from hepatitis, 10 from hepatic fibrosis and 4 from cirrhosis. During this progressive period, SpVP ml/(min.100 ml) declined slightly, but there were no significant differences between different stages (P > 0.05). SMVP ml/(min.100 ml) in stage of normal (64.1 +/- 8.1) and hepatic fibrosis (44.4 +/- 4.5), normal and cirrhosis (42.6 +/- 5.4), hepatitis (61.3 +/- 6.4) and hepatic fibrosis, hepatitis and cirrhosis was significantly different, but there was no significant difference of SMVP between normal and hepatitis (P = 0.326) or hepatic fibrosis and cirrhosis (P = 0.668). CONCLUSIONS: With our evidence of interventional CT perfusion, it is mesenteric, not splenic, perfusion that might coincide with hepatic portal venous perfusion during the progressive period of hepatic diffuse disease. PMID- 25550856 TI - Serum toll-like receptors are potential biomarkers of radiation pneumonia in locally advanced NSCLC. AB - OBJECTIVE: Toll-like receptors (TLRs) are highly or lowly expressed in a wide variety of tumors and exhibit either pro-tumor or anti-tumor activities. In the present study, we investigate whether there are relationships between the expressions of TLRs and the occurrence of radiation pneumonia in advanced NSCLC patients treated with radiotherapy. MATERIALS AND METHODS: 76 patients diagnosed with NSCLC and 50 healthy controls were recruited from Oct 2012 to Jan 2014. The expressions of serum TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and TLR9 were detected by ELISA techniques. Fisher exact test, chi(2) test, ROC working curve and Cox regression model were applied to analyze all data. RESULTS: serum TLR1, TLR2, TLR4, and TLR9 exhibited a relative high expression level in NSCLC patients compared with healthy controls. Importantly, pre-neutrophil granulocyte ratio was associated with the expression of TLR1, TLR2, and TLR4. Moreover, the patients with high ratio of neutrophil granulocyte significantly increased the occurrence of fever in comparison to normal neutrophil ratio in NSCLC patients during the course of radiotherapy. We further evaluated the containing of TLRs when patients had temperatures and found serum TLR1, TLR2 and TLR4 were over expressed. Finally, 26 of 76 patients were diagnosed with different stages of radiation induced pneumonia; as a result, the contents of TLR1 and TLR4 before radiotherapy were identified as independent significances with pneumonia occurrence. CONCLUSIONS: The pretreatment levels of TLR1 and TLR4 have the predictive value to be clinically potential biomarkers of pneumonia risk in locally advanced NSCLC. PMID- 25550857 TI - Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study. AB - The interleukin-1 receptor associated kinases 1 (IRAK1) is a down stream effector molecule of the toll like receptor (TLR) signaling pathway, which is involved in inflammation, autoimmunity and cancer. However, the role of IRAK1 in lung cancer remains unclarified. Herein, we investigated the protein expression and the clinicopathological significance of IRAK1 in 3 formalin-fixed paraffin-embedded lung cancer tissue microarrays by using immunohistochemistry, which included 365 tumor and 30 normal lung tissues. We found that the expression of IRAK1 in lung cancer was significantly higher compared with that in normal lung tissues (P=0.002). Receiver operating characteristic (ROC) curves were generated to evaluate the power of IRAK1 to distinguish lung cancer from non-cancerous lung tissue. The area under curve (AUC) of ROC of IRAK1 was 0.643 (95% CI 0.550~0.735, P=0.009). Additionally, IRAK1 expression was related to clinical TNM stage (r=0.241, P < 0.001), lymph node metastasis (r=0.279, P < 0.001) and tumor size (r=0.299, P < 0.001) in lung cancer. In the subgroup of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the positive rates of IRAK1 were both higher than that in the normal lung tissues (P=0.003, P=0.002, respectively). Further spearman analysis showed that IRAK1 protein in NSCLC was positive correlated with clinical TNM stage (r=0.222, P < 0.001), lymph node metastasis (r=0.277, P < 0.001), tumor size (r=0.292, P < 0.001) and distal metastasis (r=0.110, P=0.043). In conclusion, the expression of IRAK1 protein might be valuable in identifying patients with increased risks of lung cancer and might act as a target for diagnosis and gene therapy for lung cancer. PMID- 25550858 TI - Differential expression of MST4, STK25 and PDCD10 between benign prostatic hyperplasia and prostate cancer. AB - Both benign prostatic hyperplasia (BPH) and prostate cancer (PC) are common diseases for men around the world. Both serine/threonine protein kinase MST4 (MST4) and serine/threonine kinase 25 (STK25) belong to the Ste20-like kinases and interact with programmed cell death 10 (PDCD10) which is closely linked to cancer diseases. To clarify the roles of MST4, STK25 and PDCD10 in prostate carcinogenesis, we examined MST4, STK25 and PDCD10 expression in tissue microarray blocks containing 110 cores of BPH and 160 cores of PC immunohistochemically and evaluated their correlation with clinicopathological findings. MST4 was not expressed in all the BPH cases and expressed in 38.7% of PC cases (P < 0.0001). STK25 expression was found in 77.3% of BPH cases and 93.1% of PC cases (P < 0.0001). PDCD10 staining was considered weak in 82 (74.5%) and strong in 28 (25.5%) of BPH cases. However, in prostate cancer cases, PDCD10 staining was weak in 95 (59.4%) and strong in 65 (40.6%) (P < 0.05). PDCD10 and STK25 immunostaining were associated with age in prostatic hyperplasia cases (P < 0.05). The staining intensity for STK25 was significantly greater in Gleason grades 3-5 (47.1% of such cases staining strongly) compared with other grades of prostate cancer (only 26.5% of these cases staining strongly; P < 0.05). Our results suggest that MST4, STK25 and PDCD10 are unregulated in prostate cancer and may play roles in prostate tumorigenesis. MST4 may be a helpful marker for identifying prostate cancer. PMID- 25550859 TI - PI3K/AKT signaling pathway plays a role in enhancement of eNOS activity by recombinant human angiotensin converting enzyme 2 in human umbilical vein endothelial cells. AB - The aim of this study was to investigate the effect of PI3K/AKT signaling pathway in the activity of recombinant human angiotensin converting enzyme 2 (rhACE2) promoted the activity of endothelial nitric oxide synthase (eNOS). The human umbilical vein endothelial cells (HUVEC) were cultured in vitro. Then treated with Ang II (1*10(-6) mol/L) for 24 h. The rhACE2 (100 MUmol/L) was added and incubated for 5, 10, 15, 30, 60 min respectively which was based on Ang II intervention. The effect of rhACE2 on phosphorylation eNOS level was also observed in the presence of LY294002 (10 MUmol/L) (PI3K/AKT inhibitors). Griess reagent method was applied to measure NO contents in cell culture supernatant, RT PCR to detect the expression of eNOSmRNA in HUVEC, and Western blot to detect the expression of eNOS and phosphorylated eNOS. In Ang II intervention group, NO contents were significantly lower than control group (P < 0.05). Through rhACE2 treatment, the NO contents in cell culture medium and the expression level of phosphorylated eNOS were significantly higher than in Ang II intervention group (P < 0.05), but eNOSmRNA and non-phosphorylated eNOS protein expression level showed no significant difference (P > 0.05). After HUVEC was intervened by PI3K/AKT pathway inhibitor LY294002, the expression level of phosphorylated eNOS was significantly lower than that in the rhACE2 30 min treatment group (P < 0.05). rhACE2 may reduce the activity of Ang II inhibited endothelial cell eNOS, which can be blocked by PI3K/AKT pathway inhibitor LY294002, suggesting PI3K/AKT signaling pathway plays an important role in rhACE2's promotion of the activity of endothelial cell eNOS. PMID- 25550860 TI - Association detection between genetic variants in the microRNA binding sites of toll-like receptors signaling pathway genes and bladder cancer susceptibility. AB - Bladder cancer (BCa) is the second most common urological malignancy, and the incidence of BCa has dramatically increased recently. Various toll-like receptors (TLRs) signaling pathway proteins were proven to be associated with BCa susceptibility. However, the effect of genetic variants in TLRs signaling pathway genes on risk of BCa has not been elucidated clearly. Previous studies mainly focused on the coding region of target genes, while in this study, polymorphisms in the non-coding region, microRNA (miRNA) binding sites were investigated as potential targets. We used bioinformatics approach to screen 100 BCa related TLRs signaling pathway genes. Candidate polymorphisms were select in this region and 8 polymorphisms were confirmed. Rs72552316, located at the 3'UTR of the TLR7 gene, exhibited significant association with risk of BCa, indicating a strong relationship with decreased risk of BCa (P <= 0.0001). Furthermore, no association was detected between all the polymorphisms and recurrence-free survival time of overall study population or non-muscle invasive BCa subgroups. In conclusion, rs72552316 in the miRNA binding sites of TLR7 might contribute to BCa susceptibility, and this finding provided new targets for high BCa risk population screening. PMID- 25550861 TI - Downregulation of PI3Kcb utilizing adenovirus-mediated transfer of siRNA attenuates bone cancer pain. AB - Phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in intracellular signal transduction pathways involved in chronic pain states. PI3K is implicated in pathomechanisms of enhanced synaptic strength, such as wind-up and central sensitization in the spinal dorsal horn. The PI3Kcb gene encoding the class 1A PI3K catalytic subunit p110beta is one of the most important molecular of the P13K signaling pathway. Here, we used small interfering RNA (siRNA) targeted to PI3Kcb by adenovirus-mediated transfer, to determine whether inhibition of PI3Kcb was a potential therapeutic target for bone cancer pain (BCP). In this study, treatment of BCP model in rats with PI3Kcb-specific siRNA resulted in inhibited pain-related behavior. Depletion of PI3Kcb decreased the protein levels of spinal PI3Kcb and phospho-Akt (P-Akt)-downstream targets of PI3K. Knockdown of PI3Kcb by siRNA also induced decreased expression of GFAP and OX42, suggesting that the upregulation of spinal PI3Kcb may increase glia excitability, at least in part by regulating glia message. Our findings suggest that siRNA-mediated gene silencing of PI3Kcb may be a useful therapeutic strategy for BCP. PMID- 25550862 TI - Uterine smooth muscle tumors of uncertain malignant potential (STUMP): pathology, follow-up and recurrence. AB - The term smooth uterine muscle of uncertain malignant potential (STUMPs) indicates a group of uterine smooth muscle tumors (SMTs) that cannot be diagnosed unequivocally as benign or malignant. Diagnosis, surgical management, and follow up of this neoplasm remain controversial, especially in pre-menopausal women with fertility desire, due to the non aggressive behaviour and prolonged survival rate when compared to leiomyosarcomas. However, recurrence is estimated between 8.7% and 11% and may include delayed-recurrences. We reported five cases of uterine masses treated by surgical procedure diagnosed as STUMP on final pathology. Four patients underwent a total abdominal hysterectomy with or without salpingo oophorectomy. One patient underwent excision of uterine mass and subsequent total abdominal hysterectomy plus bilateral salpingo-oophorectomy after the diagnosis of STUMP. All patients in our study remained recurrence-free to date (with a follow up period ranging from 6 to 81 months). Based on our experience and in consideration of the lack of consensus regarding the malignant potential, diagnostic criteria, gold-standard treatment and follow-up, we believe that close multidisciplinary management is mandatory in the event of STUMP. We suggest that gynaecologist, dedicated pathologist (with high level of expertize in gynaecological pathology) and oncologist should work as a team in the counselling and management of this neoplasm from detection till completion of follow up. Furthermore, we recommend immunohistochemistry to investigate the overexpression of p16 and p53 in order to identify the cohort of patients at increased risk of recurrence who may benefit from more aggressive surgical-oncological strategies. PMID- 25550863 TI - Single nucleotide polymorphisms in VEGF gene are associated with an increased risk of osteosarcoma. AB - We aimed to assess whether the five common SNPs can affect the risk of osteosarcoma, and its association with demographic characteristics of osteosarcoma. 165 osteosarcoma patients and 330 cancer-free controls were enrolled into our study. Five common SNPs in VEGF gene, -2578C/A (rs699947), 1156G/A (rs1570360), +1612G/A (rs10434), +936C/T (rs3025039) and -634G/C (rs2010963), were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Conditional logistic regression analyses found that individuals with AA genotype and A allele of rs699947 were associated with an increased risk of osteosarcoma. Individuals with GG genotype and G allele of rs2010963 were associated with an increased risk of osteosarcoma. By stratified analysis, AA genotype of rs699947 was associated with an increased risk of osteosarcoma in those with shorter age, males and a family history of cancer, and GG genotype of rs2010963 was correlated with an increased risk of osteosarcoma in those with shorter age, females and a family history of cancer. Our study suggests that rs699947 and rs2010963 polymorphisms may play a role in the pathogenesis of osteosarcoma. PMID- 25550864 TI - HBV serum and renal biopsy markers are associated with the clinicopathological characteristics of HBV-associated nephropathy. AB - BACKGROUND: Accumulated evidence has shown that hepatitis B virus infection is associated with numerous types of nephropathy but it remains to clarify the different role of HBV markers, either in serum or deposit in kidney, in the pathogenesis of HBV-associated nephropathy. In this study, we investigated the relationship between HBV markers and HBV-associated nephropathy by using multi linear regression in Chinese patients with HBV-associated membranous nephropathy (MN). METHODS: A total of 196 cases of HBV-associated MN, which were diagnosed based on renal biopsy, were collected during the period of January 2000 to December 2009 from our hospital. Serum and renal biopsy HBV markers included HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBC. HBV-associated nephropathy was characterized by a panel of clinical manifestations and pathological parameters, which included proteinuria, hematuria, serum creatinine, hypertension, and renal damage in glomeruli, tubules, interstitium, and blood vessels. Multilinear regression was used to analyze the relationship between the HBV markers in serum and renal biopsy and the clinicopathological characteristics of HBV-associated nephropathy. RESULTS: After analysis of the clinical and pathological data in 196 cases of HBV-associated membranous nephropathy, this study revealed that glomerular lesion was marginally associated with serum HBsAg (P = 0.0528), Anti HBs (P = 0.0978), but significantly associated with the presence of IgA (P = 0.0242), IgG (P < 0.0001) and C3 (P = 0.0064) in renal biopsy. There was no significant association between glomerular lesion and HBV markers in kidney. The presence of crescent and renal tube impairment was not related to HBV markers. The renal fibrosis was significantly related to gender (P = 0.023), age (P = 0.0211), HBsAg (P = 0.0001) and HBcAg (P = 0.0083) and C3 (P = 0.0299) in renal biopsy. Notably, the renal blood vessel impairment was significantly related to systolic Blood Pressure (SBP) (P < 0.0001), diastolic blood pressure (DBP) (P = 0.0002), serum HBsAg (P = 0.0428), serum HBeAg (P = 0.0766), FRA (P = 0.0002), and HBsAg (P = 0.0241) and HBcAg (P = 0.0599) in renal tissues. Also, the renal interstitial infiltration was related to patient age (P = 0.015, SBP (P < 0.0001), DBP (P = 0.0001), C3 (P = 0.0028), FRA (P = 0.0165), HBsAg (P = 0.0016) and HBcAg (P = 0.0203) in kidney biopsy. These results suggest that the major pathological changes in kidneys in HBV patients are related to one or more HBV markers, such as HBsAg, HBeAg, or anti-HBs antibody. Besides, most of the pathological changes in kidneys are related to C3 and FRA in kidney tissues. The clinical markers of nephropathy, such as proteinuria, hematuria and creatine serum levels, were also evaluated for their relationship with HBV markers in serum and kidney tissues. We found proteinuria was marginally related to HBV DNA (P = 0.0537), significantly related to IgA (0.0223). Hematouria was significantly related to IgA (P = 0.0434), IgG (P < 0.0001), and C1q (P = 0.0282). The serum creatine level was related to patient gender (P = 0.0077), SBP (P < 0.0001), DBP (0.0049), IgG (P-0.0006), and C3 (P = 0.0113). These clinical manifestations were not related to HBV markers in either serum or kidney. These results indicate that some of clinical manifestations of nephropathy are related to HBV markers, but the relationship is limited. PMID- 25550865 TI - Association of HLA-DQA1 (rs9272219) with susceptibility to rheumatoid arthritis in a Han Chinese population. AB - HLA-DQA1 (rs9272219) has been previously reported that it is a susceptibility locus in rheumatoid arthritis (RA) of UK Caucasian population and North American; however, it has not reported in RA of Chinese population. Our study was to identify whether or not this relationship is reside between rs9272219 and RA in a Han Chinese population. 207 patients with RA and 199 control subjects were recruited. The single nucleotide polymorphism (SNP) of rs9272219 was tested in alleles and genotype frequencies and the data was analyzed by doing the statistic analysis of odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses after pairwise linkage disequilibrium (LD) was estimated. Finally, the Alleles and genotype frequencies distribution of rs9272219 locus among RA patients and control subjects were in accordance with Hardy-Weinberg equilibrium. We found significant association between rs9272219 and RA of Chinese population (OR 0.494, 95% confidence interval [95% CI] 0.354 0.688, P = 0 and OR 2.541, 95% CI 1.695-3.808, P = 0, respectively). In this study, we found that the SNP of rs9272219 in HLA-DQA1 is a potential susceptibility locus in RA of Han Chinese population; the results suggest that HLA-DQA1 may be related to the development of RA. PMID- 25550866 TI - Colon composited B cell lymphoma involving intestinal mesenteric lymph nodes combined with adenocarcinoma and schistosome infection: a case report. AB - Here we reported one rare case of colon composited B cell lymphoma associated with adenocarcinoma. The composited B cell lymphoma composed of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and large B-cell lymphoma. Additionally, adjacent intestinal mesenteric lymph modes were involved. And interestingly, schistosome infection was also found in lymphoma and adjacent tissues. The patient was given a usual local intestinal resection for colon adenocarcinoma. But in the site of one surgical margin, 10 cm away from intestinal carcinoma, we found another mass. Beneath the neoplasm, several swollen intestinal mesenteric lymph nodes were detected. By H&E staining and immunohistochemistry, it was eventually demonstrated the patient suffered complicated neoplasms. So far, there were just several references about colon lymphoma combined with adenocarcinoma. But the present case is the first to report that colon composited B cell lymphoma associated with adenocarcinoma and schistosome infection. PMID- 25550867 TI - Secondary glaucoma as initial manifestation of ring melanoma: a case report and review of literature. AB - Melanomas account for over 70% of adult malignancies in the eye and occur primarily in the choroid. Melanomas rarely originate in the ciliary body, with an annual incidence of approximately 1.6 cases per million. While the incidence rate of these tumors is low, malignant melanomas metastasize at early stages of disease development and show poor prognoses. Malignant melanomas of the ciliary body are often deeply hidden and have complex clinical manifestations, which are easily misdiagnosed and affect the prognosis. Here, we report a case of monocular ciliary body melanoma in an elderly Asian woman. Using this case as an example, we perform a systematic review of the disease's clinical symptoms, signs, diagnoses, differential diagnoses, treatment and prognosis. PMID- 25550868 TI - Premelanosome-negative inflammatory angiomyolipoma of liver with expression of cathepsin K and TFE3. AB - We report the first case of inflammatory variant of hepatic angiomyolipoma (AML) with expression of transcription factor E3 (TFE3) protein but negativity for HMB45 and melan A in a 62-year-old female. Imaging studies revealed a tumor in the left lobe of liver, sized 5.8 cm in maximum diameter. Microscopically, the lesion was composed of large polygonal or epithelioid cells with copious eosinophilic granular cytoplasm. There was a very prominent stromal lymphoplasmacytic infiltrate. Immunohistochemically, the tumor cells showed very strong and diffuse positivity for smooth muscle actin, and cathepsin K, while S 100 protein, keratin, desmin, HMB45 and Melan-A are negative. However, there was multifocal and very convincing nuclear positivity for TFE3, thus confirms the diagnosis. PMID- 25550869 TI - Primary malignant melanoma of esophagus: a case report and review of literature. AB - Primary malignant melanoma of esophagus is a rare but highly aggressive neoplasm, with an incidence less than 0.2% of all primary esophagus neoplasms. There are no clinical differences from other forms of esophagus cancer. Because initial symptoms are nonspecific, the patients are usually diagnosed at a late stage. The prognosis is poor, and curative effect seems disappointed. Several reports suggest that most of patients die from distant metastases, and the 5-year survival rate is approximately 4.2%. This case report includes a review of the surgical pathology, clinical features and treatment of primary malignant melanoma of esophagus. This case report presents a 56-year-old female with primary malignant melanoma of esophagus, treated by surgical resection. Till now, the patient is still alive for 5 months without any chemotherapy, radiotherapy and immunomodulatory therapy. PMID- 25550870 TI - Intravascular large B-cell lymphoma manifesting as cholecystitis: report of an Asian variant showing gain of chromosome 18 with concurrent deletion of chromosome 6q. AB - Intravascular large B-cell lymphoma (IVLBCL), which involves the lumen of small vessels, is a rare variant of extranodal diffuse large B-cell lymphomas. Herein, we present a case of IVLBCL manifesting as cholecystitis in a 77-year-old Japanese man. He presented with fever, fatigue, and weight loss. Physical examination revealed tenderness of the right upper quadrant. The white blood cell count and C-reactive protein levels were elevated. Computed tomography revealed gallbladder thickening and pericholecystic fluid collection; these observations were consistent with the diagnosis of cholecystitis. Serum soluble interleukin-2 receptor levels were highly elevated, and gallium scintigraphy revealed an abnormal accumulation in the spleen, implying lymphoma. Consequently, G-banding analysis of the patient's bone marrow aspirates revealed the presence of different abnormal clones, including those with gain of chromosome 18 and deletion of chromosome 6q. As cholecystectomy was necessary, a concurrent splenectomy was performed to diagnose the disease definitively. Histopathologically, atypical large lymphoid cells were observed to be localized in the vasculature in both the spleen and gallbladder; the atypical cells expressed high levels of CD20, CD5, and CD10, immunohistochemically. These findings were consistent with IVLBCL. The patient underwent post-operative treatment with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone. However, a pancreatic fistula developed during chemotherapy, causing left pleural effusion and peritoneal effusion; the patient developed sepsis from multidrug-resistant microorganisms, and subsequently died of multi organ failure 6 months after the diagnosis. No obvious recurrence of the tumor was found during autopsy. We discuss the characteristic karyotype and immunohistochemical status observed in this case. PMID- 25550871 TI - Diffuse large B-cell lymphoma solely involving bilateral adrenal glands and stomach: report of an extremely rare case with review of the literature. AB - A 60-year-old man complained of nausea, vomiting, decreased appetite, and a feeling of abdominal fullness in August 2013. Based on biopsy findings from an upper gastrointestinal endoscopy examination, a diagnosis of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), non-GC type, was made. F18 fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed abnormal accumulations solely in the gastric wall (SUVmax = 14.5), the left adrenal gland (SUVmax = 14.3), and the right adrenal gland (SUVmax = 8.5). The clinical stage (Ann Arbor) was IVA, the serum LDH level was within the reference range, and the International Prognostic Index (IPI) was low intermediate. The serum soluble IL-2 receptor level was within the reference range, and there was no evidence of HIV, EB virus, or autoimmune disease. After the completion of 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and 2 parallel cycles of prophylactic intrathecal (I.T.), an upper gastrointestinal endoscopy and a FDG-PET/CT examination showed complete remission (CR). The patient received 8 cycles of ritsuximab therapy, 6 cycles of CHOP, and 3 cycles of I.T. The patient has maintained a CR for about 14 months. A literature search revealed that malignant lymphoma with involvement confined to the adrenal gland and gastrointestinal tract is exceedingly rare, and only 3 cases of malignant lymphoma have been reported, with involvement of the stomach in 2 cases and the duodenum in 1 case. All of the cases were diagnosed as DLBCL. The case described herein represents the third case with involvement of the stomach. PMID- 25550872 TI - Congenital neuroblastoma with placental involvement. AB - We describe an extremely rare case of congenital neuroblastoma with placental involvement. A fetus with a left abdominal mass detected during ultrasonography at 23 weeks' gestation developed hydrops fetalis by 26 weeks' gestation. The mother developed hypertension at 26 5/7 weeks' gestation. Based on a clinical diagnosis of pregnancy-induced hypertension, labor was induced at 26 6/7 weeks. However, intrauterine fetal death was diagnosed during delivery. Postmortern examination revealed a solid tumor at the site of the left adrenal gland. Histological examination of the tumor revealed dense proliferation of small round tumor cells with sparse cytoplasm and hyperchromatic nuclei. Some tumor-cell complexes contained abundant neurofibrils and Hormer-Wright rosettes were observed. A diagnosis of neuroblastoma of the left adrenal gland was made. The liver was markedly enlarged and was extensively replaced by neuroblastoma cells. In addition, small nests of tumor cells were detected in the blood vessels of various organs including the heart, lung, spleen, kidneys, stomach, small and large intestine, thyroid gland, testis, spinal cord, and bone marrow. Histological examination of the enlarged placenta revealed numerous neuroblastoma cells in the villous fetal capillary spaces. The present case was unusual in that the tumor cells were found not only in the chorionic villi, but also in the intervillous space of the maternal vascular system. However, there was no clinical evidence of maternal metastasis. PMID- 25550873 TI - Multifocal canalicular adenoma of the minor labial salivary glands. AB - Canalicular adenoma (CA) is an uncommon benign neoplasia of salivary glands which is clinically difficult to recognise. Despite having an excellent prognosis, the histological diagnosis and clinical management of this entity can be troublesome. While the main differential diagnosis to consider is basal cell adenoma (BCA), similar histological patterns and multifocality have been observed in adenoid cystic carcinoma (ACC) and polymorphous low-grade adenocarcinoma (PLGA), both locally-aggressive malignancies which require radically different treatment to CA. An emphasis has been placed on the value of immunohistochemistry in avoiding diagnostic and surgical errors. CA is positive for AE1/AE3, CD117 and S-100 protein, and negative for p63, alpha-SMA, Ki 67 and vimentin. Here we discuss the case of a 61-year-old female with CA in her right upper lip, showing multifocal growth histologically. The differential diagnosis with other adenomas is discussed in addition to the role of immunohistochemical studies that can confirm the clinical and surgical findings. PMID- 25550874 TI - Sacrococcygeal teratoma with nephroblastic elements: a case report and review of literature. AB - Sacrococcygeal teratoma with nephroblastic elements is very rare. Only 8 cases have been reported up to date. 3 cases were misdiagnosed as extrarenal nephroblastomas and were administered excessive treatments such as chemotherapy and radiation therapy. It has a great significance to distinguish sacrococcygeal teratoma with nephroblastic elements from extrarenal nephroblastoma for their different biological behaviors, therapies and prognoses. Here we report one case of sacrococcygeal teratoma with nephroblastic elements in a newborn with review of the literature. This is the first case of sacrococcygeal teratoma with nephroblastic elements in Chinese to our knowledge. PMID- 25550875 TI - Neuroendocrine carcinoma of the larynx with subcutaneous and intramuscular metastases: a case report. AB - Neuroendocrine carcinomas have become increasingly recognized as more reports are emerging to describe these rare tumors. Primary sites include the lung, liver, throat, and other organs. Laryngeal neuroendocrine carcinomas are relatively rare, and the subtypes as well as the prognoses are quite different in most cases. Metastases to the liver, lungs and other parts are common. However, metastases to subcutaneous tissues or muscles have been rarely reported. We report a case of a neuroendocrine carcinoma of the larynx with subcutaneous and muscle metastases. PMID- 25550876 TI - Primary alveolar soft part sarcoma of the uterine cervix: a case report and literature review. AB - Alveolar soft part sarcoma (ASPS) is a tumor of unknown histogenesis, composed of large, epithelioid cells with eosinophilic cytoplasm, having an alveolar pattern. Primary ASPS of uterine cervix is very rare. In this report, we present a 21-aged old female with primary ASPS in the uterine cervix and discuss the clinicopathological characteristics, immunophenotype, molecular genetic feature and differential diagnosis of ASPS of cervix. PMID- 25550877 TI - Evaluation of 18F-fluorodeoxyglucose uptake in enlarged mediastinal lymph nodes in patients with lung cancer. AB - Accurate lymph nodal staging of lung cancer is critical for determining the treatment options. With the help of (18)F-fluorodeoxyglucose positron emission tomography/computer tomography ((18)F-FDG-PET/CT), the clinician can rule out/in the regional lymph nodes positive for metastasis in the patients with lung cancer in a majority of cases. However, a small proportion of cases with false positivity of metastasis have been reported. Transbronchial needle aspirations and mediastinoscopic biopsies are still necessary to determine whether enlarged hypermetabolic mediastinal lymph nodes are positive for lung cancer metastasis. Here we report three intricate cases showing hypermetabolic activity in the mediastinal lymph nodes in the patients with pathologically diagnosed lung cancer on PET/CT. The first patient had squamous cell carcinoma in the left upper lobe of the lung with surrounding necrotizing granulomas and concurrent with silicosis and granulomatous inflammation in the lymph nodes; the second presented with symptoms of viral pneumonia, which was pathologically diagnosed as a lung adenocarcinoma, stage IA, concurrent with sarcoidosis involving the lymph nodes; the last case was diagnosed as squamous cell carcinoma in the right upper lobe of the lung, but lymph nodes showed reactive hyperplasia. These cases suggest that some cases are so complex that avid (18)F-FDG uptake in the mediastinal lymph nodes in the patients with pathologically diagnosed lung cancer should be carefully analyzed based on individual patients' clinical background. PMID- 25550878 TI - Ovarian angioleiomyoma: a case report. AB - Angioleiomyoma (ALM) is a rare and painful, benign neoplasm that is referred to an uncommon type of leiomyoma originating from smooth muscle cells of arterial and venous walls. ALM is very rarely found in the female genital organs such as uterus or ovary. Herein, we present the case of a huge primary ovarian ALM in a 35 year-old woman, clinically and radiologically mimicking an ovarian fibroma, which histologically has diffuse myxoid degeneration. This is the third case of ovarian ALM and the first case of ovarian ALM with diffuse degeneration reported in English literatures, to the best of our knowledge. PMID- 25550879 TI - A case of multiple macronodular hepatic tuberculosis difficult to differentiate from hepatocellular carcinoma with intrahepatic metastasis: CT-guided fine needle aspiration biopsy confirmed the diagnosis. AB - Multiple macronodular hepatic tuberculosis is difficult to be differentiated from hepatocellular carcinoma with intrahepatic metastasis in clinical practice, especially when hepatitis B with or without liver cirrhosis coexists with it. Herein, we report a 30-year-old man with a 10-year history of hepatitis B and a family medical history of hepatocellular carcinoma related with hepatitis B that was finally diagnosed as multiple macronodular hepatic tuberculosis. Abdominal B mode ultrasonography (US) and plain computed tomography (CT) revealed multiple unequal-sized nodules in the liver. CT-guided fine needle aspiration biopsy (FNAB) of the liver demonstrated a caseating granuloma with lymphocytes, multinucleate giant cells and epithelioid cells compatible with the diagnosis of tuberculosis and no hepatoma cells were detected. Thus, the diagnosis of hepatic tuberculosis was confirmed and hepatocellular carcinoma with intrahepatic metastasis was excluded. PMID- 25550880 TI - Epithelioid trophoblastic tumor after induced abortion with previous broad choriocarcinoma: a case report and review of literature. AB - Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a prior gestational event. We present a 44-year-old woman who had unusual pregnancy related history. The patient received her second spontaneous abortion at the age of 25 years and had suffered from choriocarcinoma in left board ligament at the age of 29 years. She admitted no more treatment after 3 courses of multiagent chemotherapy when serum beta-hCG returned to normal. Then she had Full-term delivery, induced abortion at the ages of 32, 33 years. The patient had high serum levels of beta-human chorionic gonadotropin (6587 IU/L). Microscopically, the tumor was composed of mainly mononuclear tumor cells, grew in cords, nests, and sheets within which were aggregates of hyaline material. Most were with distinct cell borders, eosinophilic cytoplasm. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CK18), P63, focal reactivity for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The Ki-67 index was 77%. The histological and immunohistochemical features were characteristic of epithelioid trophoblastic tumor. This is the first reported case of these two gestational trophoblastic tumor happened on one person with the intervening normal pregnancy. PMID- 25550881 TI - Amebic lung abscess with coexisting lung adenocarcinoma: a unusual case of amebiasis. AB - Amebic lung abscess with concurrent lung cancer, but without either a liver abscess or amebic colitis, is extremely uncommon. Here, we report a 70-year-old man presenting with pulmonary amebiasis and coexisting lung adenocarcinoma. During his first-time hospitalization, the diagnosis of lung amebiasis was confirmed by morphological observation and PCR in formalin-fixed and paraffin embedded sediments of pleural effusion. Almost four months later, the patient was readmitted to hospital for similar complaints. On readmission, lung adenocarcinoma was diagnosed by liquid-based sputum cytology and thought to be delayed because coexisting amebic lung abscess. This case demonstrated that sediments of pleural effusion may be used for further pathological examination after routine cytology has shown negative results. At the same time, we concluded that lung cancer may easily go undetected in the patients with pulmonary amebiasis and repetitive evaluation by cytology and imaging follow-up are useful to find potential cancer. PMID- 25550882 TI - Xanthogranulomatous cystitis imitating bladder neoplasm: a case report and review of literature. AB - Xanthogranulomatous cystitis is a rare, benign chronic inflammatory disorder with unclear etiology. Since its similar features to bladder neoplasm, it is extremely easy to be mistaken for malignant tumor. We herein reported a case of xanthogranulomatous cystitis in a 54-year-old male who presented with low abdominal pain and painless, total macrohematuria. Microscopy showed proliferation of large foam histiocytes which expressed CD68 and vimentin. Ki-67 showed a lower proliferation index (< 10%). Histopathology and immunohistochemical findings confirmed the diagnosis. This case highlighted the significance of recognizing this unusual lesion and differentiating it from its histological mimics by immunohistochemical staining. PMID- 25550883 TI - Bilateral ovarian mixed epithelial adenocarcinoma in a postmenopausal woman with unilateral ovarian yolk sac tumor component. AB - Ovarian yolk sac tumors (YSTs) usually occur in the young women and have been rarely documented in perimenopausal and postmenopausal women. The different age distribution supposes their complex nomenclature and histogenesis. We report a case of bilateral ovarian epithelial carcinoma with right ovarian YST component in a postmenopausal woman. The patient was treated by surgery and adjuvant combination chemotherapy of taxol and carboplatin for 6 courses and has been clinically free of tumor for 6 months. The correlation between the YST and the epithelial components always confuse us. Ovarian yolk sac tumors are not a discrete entity and represent a multifaceted group of neoplasms. The conjunction of multi antibodies help in differential diagnoses. In addition to a thorough case description, the literature concerning this entity is reviewed and discussed. PMID- 25550884 TI - Cutaneous apocrine carcinoma in groin with bilateral lymph node metastasis: a case report and review of the literature. AB - Cutaneous apocrine carcinoma (CAC) is a rare type of malignant adnexal tumour with only scattered reports. We report a 52-year-old male patient of CAC in groin with bilateral lymph node metastasis. The patient had a left inguinal subcutaneous mass 3 cm * 2 cm in size for 4 years, and received a wide local excision of the tumour. Pathological sectioning suggested CAC. The immunohistochemical staining revealed GCDFP15 (+), 34BE12 (+), ER (+), PR (+), CK7 (+), Ki67 (5%-10%), HER2/Neu (-), P53 (-), P63 (-), and CK20 (-). Two subcutaneous masses of 2 cm * 1 cm were found below the original incision 10 months after the operation, and regional lymphadenectomy was performed. During the outpatient follow-up, B-ultrasound examination showed abnormal enlargement of the right inguinal lymph nodes 17 months later, and right inguinal lymphadenectomy was performed. No evidence of recurrent or metastasis disease has been seen after a follow-up period of 16 months till now. We review the literature on pathological and immunohistochemical study of CAC and discuss its diagnostic dilemma. PMID- 25550885 TI - Effect of umbilical cord mesenchymal stem cell in peri-implant bone defect after immediate implant: an experiment study in beagle dogs. AB - BACKGROUND: For the sake of reducing post extraction resorption, getting optimal positioning of the implant and shortening treatment time, immediate implant placement following tooth extraction has been proposed as a treatment option. However, the large bone defect peri-implant has a negative influence on the process of bone healing. In this study, umbilical cord mesenchymal stem cells (UCMSCs) were transplanted into the bone defect peri-implant inbeagle dogs and the effect of UCMSCs on bone regeneration in peri-implant were assessed. METHODS: The mandibular second, third and fourth premolars of 8 beagle dogs were extracted bilaterally. The defects in one side were filled with platelet-rich fibrin (PRF) and then UCMSCs were injected into the defect area, while the defects in the other side were filled with PRF only as control group. The titanium implant was placed into the distal root socket of each extracted tooth. The animals were sacrificed at week 2, 4 and 8 post operative. The bone defects adjacent to the implant which are 4 mm in height, 4 mm in the mesio-distal direction and 3.5 mm in the bucco-lingual direction were made after immediate implant. Histomorphometric analysis was performed using methylene blue-fuchsin acid staining and hematoxylin and eosin (HE) staining to evaluate bone regeneration. RESULTS: The direct bone-to-implant contact (BIC) in the experiment after 4 and 8 weeks was 56.47+/-1.18% and 76.23+/-2.08%; and in the control group was40.79+/ 0.65% and 61.17+/-2.79%, respectively. The percentage of newly formed bone after 2, 4 and 8 weeks was 17.60+/-1.5%, 49.82+/-4.02% and 67.16+/-2.1% in experiment group; and in control group 14.30+/-1.25%, 37.04+/-2.29% and 58.83+/-3.36%, respectively. These results represented significant differences statistically. CONCLUSION: Intra-bone marrow injection of UCMSCs can promote new bone formation. UCMSCs can be used to as excellent seed cells to repair the large defect peri implant after immediate implant. PMID- 25550886 TI - Knockdown of S100A7 reduces lung squamous cell carcinoma cell growth in vitro and in vivo. AB - OBJECTIVE: S100A7 plays a role in the malignant potential of several epithelial cancers, and could candidate diagnostic marker or therapeutic target. Nuclear factor kappa B (NF-kappaB) regulates cancer cell growth and is modulated by phospholipase activity in many cancer cells. In the present study, we first evaluate the involvement of S100A7 in lung squamous cell carcinoma and its clinical usefulness for diagnosis. We then study whether knockdown of S100A7 in lung squamous cell carcinoma cells would reduce cell proliferation and NF-kappaB activity in vitro and attenuate tumor growth in vivo. METHODS: We examined S100A7 expression in lung squamous cell carcinoma tissues by immunohistology .The human lung squamous cell carcinoma cell line NCI-H520 were transduced with short hairpin RNA targeting S100A7. Quantitative reverse transcriptase-polymerase chain reaction and immunoblotting confirmed knockdown of S100A7 messenger RNA and protein, respectively. Cell proliferation was evaluated by the MTT assay. NF kappaB phosphorylation was assayed by western blot. 1*10(6) of NCI-H520/S100A7 knockdown cells were injected into the left flanks of nude mice (aged 6 to 8 weeks). Tumors were followed for 35 days, then removed and stained with hematoxylin and eosin, stained with Ki-67, and analyzed for S100A7 protein expression. RESULTS: S100A7 protein levels were significantly higher in carcinoma specimens than in nonneoplastic tissues. S100A7 might be a useful marker for diagnosis of lung squamous cell carcinoma. In vitro data showed that inhibition of S100A7 decreased proliferation of NCI-H520 cells. S100A7 knockdown reduced NF kappaB phosphorylation and tumor growth in vivo and vivo. Explanted knockdown tumors maintained lower S100A7 levels compared with wild-type, confirmed by immunohistology. Ki-67 staining was more prominent throughout the wild-type tumors compared with knockdown tumors. CONCLUSIONS: Our present results suggest that S100A7 level is a promising tool for diagnosis of lung squamous cell carcinoma. Knockdown of S100A7 suppresses lung cancer growth in part by attenuating NF-kappaB activity. S100A7 may be a promising therapeutic target for lung squamous cell carcinoma. PMID- 25550887 TI - Sarcomatoid combined hepatocellular-cholangiocarcinoma: a case report and review of literature. AB - Sarcomatoid combined hepatocellular-cholangiocarcinoma is an extremely rare primary hepatic malignancy and only a few cases have been reported. Herein, we report a case of combined hepatocellular-cholangiocarcinoma with sarcomatoid changes in a 52-year-old man, who had a history of liver cirrhosis and transarterial chemoembolization. The resected liver revealed a mass of 4.5*3.5 cm. Microscopically, the tumor was composed of adenocarcinoma intermingled with poorly differentiated hepatocellular carcinoma, which contained atypical spindle cells. We also present a short review of reported cases of sarcomatoid combined hepatocellular-cholangiocarcinoma. PMID- 25550888 TI - PIK3CA and PIK3CB expression and relationship with multidrug resistance in colorectal carcinoma. AB - The phosphoinositide 3-kinases (PI3Ks) are a critical family of signaling enzymes that participate in many cellular processes that promote the transformation of a normal cell into a cancer cell. These processes include cancer cell proliferation, migration, and invasion. However, the correlation between PI3Ks and multidrug resistance (MDR) remains unclear. The prognostic value of PI3Ks has not been previously evaluated. Thus, this study aims to evaluate the association between PIK3CA and PIK3CB expression and the MDR gene in colorectal cancer (CRC) patients. Immunohistochemistry was employed to detect the expressions of PIK3CA, PIK3CB, MDR-1, LRP, GST-pi, and Topo II in 316 CRC specimens. Patients were followed-up annually by telephone or at an outpatient clinic. Results revealed that PIK3CA and PIK3CB expression was correlated with the degree of tumor differentiation and lymph node metastasis (P < 0.05). The overexpression of MDR 1, LRP, Topo II, and GST-pi was found to be 72.78%, 70.89%, 77.53%, and 76.58% of CRC, respectively. Correlation analysis showed that PIK3CA and PIK3CB expression exhibits a positive correlation with MDR-1, LRP, and GST-pi with correlation coefficients of 0.288, 0.128, and 0.197, respectively (P < 0.05). Kaplan-Meier analysis revealed that the five-year survival rate of patients without lymph node metastasis, positive expression of PIK3CA and PIK3CB, and negative expression of GST-pi and MDR-1 was higher than those with these characteristics. Multivariate analysis revealed that GST-pi, MDR-1 expression, and lymph node metastasis could serve as independent predictive factors of overall survival. The expression of both PIK3CA and PIK3CB is increased and related to the development and progress of colorectal carcinoma and MDR. The combined detection of PIK3CA andPIK3CB is important for patients with colorectal carcinoma in prognosis and optimal therapy. PMID- 25550889 TI - Function and subsets of dendritic cells and natural killer cells were decreased in gastric cancer. AB - Dendritic cells (DCs) and natural killer (NK) cells initiate specific immune responses against tumor cells. The aim of the present study was to determine the cytotoxicity and the subsets of the DC and NK cells and the cytokines level of DC and NK cells from cancer tissue and peripheral blood in the gastric cancer patients. Cytotoxicity of DC and NK was determined using the Cytotox non radioactive assay. The cytotoxic activity of DC or NK isolated from cancer tissue and peripheral blood was attenuated in gastric cancer patients. CD11c, CD80, CD83, CD16, CD57 and CD69 were decreased in the cancer tissue and peripheral blood in the gastric cancer patients. CD86, CCR7 and CD59 were no significance in the cancer tissue and peripheral blood from gastric cancer patients. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, T-bet and IL-15Rbeta levels were decreased in DC and NK from the gastric cancer tissue and peripheral blood in the gastric cancer patients. IL-15 and IL-15Ralpha level were no significance in DC and NK in the gastric cancer tissue and peripheral blood in the gastric cancer patients. These results indicate that the cytotoxic activity and subsets and cytokines of DC and NK cells in the cancer tissue and peripheral blood in the gastric cancer patients were decreased. The decrease of subsets content and cytokines of DC and NK may contribute to a decrease in the function of DC and NK in the tissue and peripheral blood in the gastric cancer patients. PMID- 25550891 TI - Selection of chemotherapy for non-small cell lung cancer is facilitated by new therapeutic strategies. AB - Nowadays, advanced non-small cell lung cancer is still an incurable disease. Recent researches have led to considerable progress in the treatment of non-small cell lung cancer. This article reviews the main studies on chemotherapy on non small cell lung cancer and discusses the new therapeutic strategies available to date. Stable disease (SD) is necessary in chemotherapy for tumor. The proportion of population with responders or SD basically maintained similar regardless of regimens. The overall survival after chemotherapy for patients with SD was lower than patients with responders, and higher than patients with progressive disease. Greater benefits could be achieved in patients with effective induction chemotherapy using chemotherapeutic agents for maintenance therapy, whereas the benefits were relatively small for patients with SD. It has been found that epidermal growth factor receptor (EGFR) mutation status had certain correlation with the efficacy of chemotherapy. First-line chemotherapy has shown advantages in effective rate and progression free survival on EGFR mutant. EGFR mutation produced significant effects on the efficacy of postoperative adjuvant chemotherapy. Patients with EGFR mutation had a higher effective rate than wild type EGFR patients, and patients with responders had a greater benefit in progression free survival from maintenance therapy. However, it is still necessary to carry out more careful and deeper studies and analyses on traditional cytotoxic chemotherapy, to further optimize cytotoxic chemotherapy and to use molecular targeted agents with different mechanisms. PMID- 25550890 TI - Role of microRNAs on therapy resistance in Non-Hodgkin's lymphoma. AB - Non-Hodgkin's lymphoma (NHL) is a heterogeneous group of malignancies that originate in lymphatic hematopoietic tissue. Chemotherapy has been used as the main therapy for NHL all the time, and local radiotherapy is also a necessary approach to supplementary treatment. However, resistance of tumor cells to chemo- and radiotherapy often prevent a successful long-term treatment of NHL. MicroRNAs (miRNAs) are a class of approximately 22-nucleotide endogenous non-coding RNAs that play an important regulatory role in gene expression, involving in the process of cell proliferation and differentiation. Alterations of miRNAs have been reported in a variety of human cancers, such as lymphomas, and will critically influence the tumor development and progression. Recently, there is increasing evidence that miRNAs could also influence sensitivity of tumor cells to chemo- and radiotherapy, revealing a crucial role of microRNAs in resistance to anticancer treatment. Therefore, understanding the role of miRNAs in chemo- and radio-resistance of tumor and targeting specific miRNAs will open novel avenues for lymphoma treatment and improve the prognosis of NHL patients. This review outlines the role of miRNAs associated with chemo-and radiotherapy resistance in NHL. PMID- 25550892 TI - Stem cell-based therapies for age-related macular degeneration: current status and prospects. AB - Age-related macular degeneration (AMD) is one of the major causes of irreversible blindness both in developed and developing countries. During the past decades, the managements of neovascular AMD (wet AMD) have dramatically progressed. However, still no effective treatment for non-neovascular AMD (dry AMD) which was characterized by geographic macular atrophy. Recent advances in stem cell sciences have demonstrated that retinal pigment epithelium (RPE) cells can be generated from several types of stem cells (including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, et al) by cell co culturing or defined factors. Additionally, studies also showed that visual function could be recovered by transplantation of these cells into subretinal space in vivo. Moreover, the United States Food and Drug Administration already approved several clinical trials to evaluate the efficiencies of stem cell based cell transplantation for dry AMD patients. Till now, a few patients enrolled in these studies achieved promising outcomes. This review will summarize recent advances in stem cell based RPE differentiation, transplantation, and the preliminary results of clinical trials. The obstacles and prospects in this field will also be discussed. PMID- 25550893 TI - Stem cell and endometriosis: new knowledge may be producing novel therapies. AB - The human endometrium is a dynamic tissue, which undergoes cycles of growth and regression with each menstrual cycle. Adult progenitor stem cells are likely responsible for this remarkable regenerative capacity; these same progenitor stem cells may also have an enhanced capacity to generate endometriosis if shed in a retrograde fashion. The progenitor stem cells reside in the uterus, and, however, may also travel from other tissues such as bone marrow to repopulate the progenitor population. Mesenchymal stem cells are also involved in the pathogenesis of endometriosis and may be the principle source of endometriosis outside of the peritoneal cavity when they differentiate into endometriosis in ectopic locations. The present short review mainly summarizes the latest observations contributing to the current knowledge regarding the presence and the potential contribution of stem cells in the etiology of endometriosis. All these data can have clinical implications and provide a basis for new potential therapeutic applications. PMID- 25550894 TI - Fructopyrano-(1->4)-glucopyranose inhibits the proliferation of liver cancer cells and angiogenesis in a VEGF/VEGFR dependent manner. AB - PURPOSE: To investigate whether fructopyrano-(1->4)-glucopyranose (FG) inhibits the proliferation of liver cancer cells and angiogenesis in a vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) dependent manner. METHODS: Bel-7402, HepG2 and SMMC-7721 cells with high expression of VEGF and VEGFR were screened. Bel-7402 cells and human microvascular endothelial cells (HMEC) were treated with FG for 48 h. CCK-8 assay was used to detect cell proliferation. Wound healing assay was used to investigate effect of FG on the migration of HMECs. Tube formation assay was done to test influence of FG on the angiogenesis of HMECs, and qRT-PCR and western blot assay were performed to detect mRNA and protein expression of VEGF, Fit-1 and KDR. Nude mice were inoculated with Bel-7402 cells, and influence of FG on tumor growth, microvessel density (MVD) and VEGF expression in tumor was investigated. RESULTS: Bel-7402 cells had a significantly higher expression of VEGF and VEGFR when compared with HepG2 cells and SMMC-7721 cells. FG could markedly reduce the mRNA and protein expressions of VEGF, Fit-1 and KDR in Bel 7402 cells and inhibit the proliferation of Bel-7402 cells in a concentration dependent manner. In addition, FG was able to remarkably inhibit the proliferation, migration and angiogenesis of HMECs, exerting anti-angiogenetic effect. In cancer-bearing nude mice, FG was found to inhibit the tumor growth, reduce MVD in tumors and decrease the VEGF in tumors. CONCLUSIONS: FG can inhibit proliferation of liver cancer cells and suppression angiogenesis in liver cancer in a VEGF/VEGFR dependent manner. PMID- 25550895 TI - The efficacy and safety of certolizumab pegol (CZP) in the treatment of active rheumatoid arthritis (RA): a meta-analysis from nine randomized controlled trials. AB - OBJECTIVE: Certolizumab pegol (CZP) is a novel anti-TNF agent that is used for patients with moderate to severe active rheumatoid arthritis (RA). However, the efficacy of CZP in RA remains controversial. Thus, we performed this meta analysis to assess the efficacy and safety of CZP in the treatment of RA patients. METHODS: Eligible studies were randomized controlled trials (RCTs) that evaluated the efficacy and safe of CZP in the patients with active RA. The primary outcome was American College of Rheumatology 20% (ACR20), and secondary outcome were ACR50, ACR70, disease activity, patient-reported outcomes (PROs), and adverse events. A fixed-effect model or random-effect model was used to pool the estimates, depending on the absence or presence of heterogeneity among the included studies. RESULTS: Nine RCTs with a total of 5228 patients were included in this meta-analysis, and all of the patients were administered CZP or placebo. The pooled results showed that CZP significantly improved the ACR20, ACR50, ACR70 response rates, and physical function. CZP was associated with a statistically significant reduction in Disease Activity Score in 28 joints-Erythrocyte sedimentation rate, arthritis pain, and fatigue. Patients who received CZP treatment did not have a higher incidence of treatment-related adverse events, no matter in any intensity. CONCLUSIONS: CZP 200 or 400mg in the treatment of active RA significantly reduced the RA signs and symptoms, and improved physical function as compared with the placebo. More large-scale RCTs are needed to evaluate the long-term efficacy and safety of CZP in the treatment of active RA. PMID- 25550896 TI - The association of tea consumption and the risk and progression of prostate cancer: a meta-analysis. AB - Many studies have focused on the association of tea consumption and the risk and progression of prostate cancer (PCa). However, the evidence is inadequate to draw robust conclusions. To shed light on these inconclusive findings, we conducted a meta-analysis. We searched the database of PubMed and Web of Science for eligible articles. The relevant data were abstracted by two independent reviewers and performed with Stata 11.0. 21 studies were included. The pooled outcomes showed that there was a significant association between tea consumption and PCa risk (OR=0.84, 95% CI (0.71-0.98)); tea consumption could reduce PCa risk in China and India (OR=0.40 and 0.48, 95% CI (0.25-0.66) and (0.24-0.97), respectively); both green and black tea consumption showed no significant effect on PCa risk (OR=0.73 and 0.95, 95% CI (0.52-1.02) and (0.82-1.11), respectively); the highest level tea consumption showed significant protective effect on the low-grade PCa (OR=0.66, 95% CI (0.46-0.93)); no significant effect was found in both localized and advanced PCa in stage subgroup analyses (OR=1.12 and 0.85, 95% CI (0.82-1.54) and (0.62-1.16), respectively). The results show that regardless of tea type, tea consumption might be a potential protective factor for the PCa, especially in China and India. Tea consumption might be the protective factor for low-grade PCa. However, more relevant studies are needed to further explore this association. PMID- 25550897 TI - Doxorubicin-eluting beads versus conventional transarterialchemoembolization for the treatment of hepatocellular carcinoma: a meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis to evaluate the efficacy and toxicity of DEB-TACE in the treatment of patients with intermediate-stage HCC. METHODS: Studies published in PubMed, Embase and Web of Science, were systematically reviewed to identify those that assessed the efficacy and toxicity of DEB-TACE in the treatment of patients with HCC. Hazard ratio, risk ratioand 95% confidence intervalswere calculated, using a fixed-effects model or a random-effects model. RESULTS: Nine studies with a total of 830 patients met the inclusion criteria were included in this study. DEB-TACE significantly improved overall survivaland progression free survival, and also increased objective response rateand disease control rate. However, in subgroup analyses, pooled results showed that, the survival benefits of DEB-TACE were not found in the randomized controlled trials, but were observed in Non-RCTs. The incidence of most common adverse events, including nausea, pain, fever, and fatigue, was not significant difference between the DEB-TACE group and conventional TACEgroup. CONCLUSIONS: Despite DEB TACE significantly prolonged the survival and response rate in the patients with HCC, the conclusion about the survival benefits should be interpreted with caution, since these findings were only found in retrospective Non-RCTs, and not in prospective RCTs. PMID- 25550898 TI - Risk association of meningiomas with MTHFR C677T and GSTs polymorphisms: a meta analysis. AB - Previous studies have shown that the single nucleotide polymorphisms (SNPs) in Methylenetetrahydrofolate reductase (MTHFR) and Glutathione S-transferases (GSTs, including GSTM1, GSTT1) genes play an important role in determining the response of an individual to environmental pathogenesis and significantly relate to incidences of various human tumors, including brain tumors. However, these genes' polymorphisms on meningioma risk remains poorly understood. The relevant inferences from previous studies are hindered by their limited statistical power and conflicting results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association between these polymorphisms and human meningioma risk. A literature search for eligible studies published before January 1, 2014 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. Pooled odds ratios (OR) with their corresponding 95% confidence intervals (95% CI) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. Heterogeneity and publication bias were evaluated. All statistical analyses were conducted by using the software of STATA 12.0 (STATA Corporation, College Station, TX, USA). For MTHFR C677T (dbSNP: rs1801133) (C T) polymorphism, 9 individual case-control studies from six publications with 1,615 cases and 1,909 controls were obtained. For GSTM1 null polymorphism, there were 4 studies with 417 cases and 1,735 controls. For GSTT1 null polymorphism, there were 4 studies with 405 cases and 1,622 controls. The combined results for the MTHFR C677T show that carriers of the CT genotype may be associated with a higher meningioma risk (OR = 1.20, 95% CI 1.05-1.38, P = 0.009). Stratified analyses show that Caucasians have significantly higher risk if they carry the CT genotype of MTHFR (OR = 1.31, 95% CI 1.05-1.63, P = 0.02). Risk of Caucasians carrying TT + CT genotype is also significantly higher (OR = 1.27, 95% CI 1.02-1.58, P = 0.03). Risk of Caucasians carrying TT genotype is not significantly different compared to control population (OR = 0.96, 95% CI 0.69-1.34, P = 0.82). All of the enrolled studies about GSTM1/GSTT1 are on Caucasians. The pooled ORGSTM1 and ORGSTT1 were not significant in Caucasian population. These results indicate SNPs of MTHFR C677T are related to meningioma risk with ethnic differences. Caucasians carrying CT genotype of MTHFR C677T have significantly higher meningioma susceptibility. SNPs of GSTM1/GSTT1 are not related to meningioma risk. PMID- 25550899 TI - Molecular and clinical analysis in a series of patients with Pyknodysostosis reveals some uncommon phenotypic findings. AB - Pyknodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, deformity of the skull, osteosclerosis, hypoplasia of the clavicle, and bone fragility. Radiographs show increased bone density, osteosclerosis, and acroosteolysis of the terminal phalanges. The pycnodysostosis gene is located on chromosome 1q21 and encodes an enzyme called Cathepsin K. Cathepsin K is a cysteine protease lysosomal protein associated with the degradation of bone and cartilage. In the current study, the authors described the clinical, radiological and molecular features of a group of six Mexican patients, including two familial and two sporadic cases, with Pyknodysostosis. One of the patients presented hypoacusia, an unusual finding in this disease. PMID- 25550900 TI - Associations between the C3435T polymorphism of the ABCB1 gene and drug resistance in epilepsy: a meta-analysis. AB - OBJECTIVE: A meta-analysis was performed to comprehensively evaluate the correlations between the C3435T polymorphism of ABCB1 (the ATP-binding cassette, subfamily B, member 1 transporter gene) and drug resistance in epilepsy. METHODS: Inclusion and exclusion criteria and a strategy for searching original literature were developed and utilized to search Chinese and non-Chinese databases. Research reports discussing correlations between the ABCB1 C3435T polymorphism and patient responses to anti-epileptic drug (AED) therapy were collected. Comparisons and comprehensive quantitative analyses were conducted using an allele model (C vs. T), and a genotype model (CC vs. CT+TT). In addition, subgroup analyses were performed that divided the included studies according to the race of the study subjects (Asian or Caucasian), based on the geographical region in which each study was conducted. RESULTS: The meta-analysis included a total of 23 publications that examined a total of 3,912 drug-resistant epileptic patients and 4,419 epileptic patients for whom drug treatment was effective. The included studies did not exhibit publication bias. Statistical analyses revealed that the C3435T polymorphism was not significantly correlated with drug resistance in epilepsy. The random-effects model comparing the C and T alleles produced an odds ratio (OR) of 1.10 with a 95% confidence interval (CI) of 0.98-1.25 and P = 0.46. Subgroup analyses suggested that in Caucasian population there are significant differences between resistance group (RN) and control group (N) in both allele model (C vsT: OR = 1.13; 95% CI: 1.03-1.25) and genotype model (CC vsCT+TT: OR = 1.27; 95% CI: 1.08-1.50). CONCLUSION: The ABCB1 C3435T polymorphism is associated with drug resistance in epilepsy in Caucasian population. PMID- 25550901 TI - Down-regulation of hypoxia-inducible factor-1 suppresses malignant biological behavior of triple-negative breast cancer cells. AB - This study is to investigate the effect and mechanism of reduced hypoxia inducible factor (HIF)-1a expression on malignant behavior of MDA-MB-231 cells. HIF-1alpha expression was interfered by siRNA. Western blot was used to detect protein expression of HIF-1alpha, active fragments of caspase 3 and vimentin. Cell count, flow cytometry and Hoechst staining were used to evaluate cell growth and apoptosis. Matrigel invasion and wound scratch assay were performed to measure the ability of cell invasion and migration. After MDA-MB-231 cells were transfected with HIF-1alpha-targeted siRNA, HIF-1alpha protein expression was successfully interrupted and cell growth was retarded. Compared with random siRNA group, reduced HIF-1alpha protein expression in HIF-1alpha-targeted siRNA group facilitated cell apoptosis but had no effect on cell cycle. In addition, cells treated with HIF-1alpha-targeted siRNA expressed active fragments of caspase 3 (17 and 12 kD) after serum starvation for 0 to 60 h. Caspase 3 activity assay further confirmed the above finding. Reduced HIF-1alpha expression impaired the migration and invasiveness with a reduction in the expression of vimentin and CK18 protein. Inhibition of HIF-1alpha protein synthesis or enhancement of its degradation reversed its malignant phenotypes and could probably be a potential means for the treatment of triple-negative breast cancer. PMID- 25550902 TI - In vitro effect of progesterone on human melanoma (BLM) cell growth. AB - Epidemiological data suggest there is a female sex advantage in melanoma skin cancer. Female sex hormones have been attributed to this protection. There has been no experimental evidence to link female sex hormones directly with melanoma protection until our recently published work on mouse melanoma (B16F10) cells. Our recently published work showed that progesterone significantly inhibited mouse melanoma cell growth in vitro. This study was extended to human melanoma (BLM) cells. Research work revealed that progesterone inhibited human melanoma cell growth also in vitro. The mechanism of inhibition was due to autophagy and this effect of progesterone was not mediated through progesterone receptor. PMID- 25550903 TI - Oral contraceptive use and kidney cancer risk among women: evidence from a meta analysis. AB - Previous studies have investigated the relationship between oral contraceptives (OCs) use and kidney cancer risk. However, they yielded inconsistent results. To our knowledge, a comprehensive assessment of the association between OC and kidney cancer risk has not been reported. Hence, we conducted a meta-analysis to quantify the association. We identified all relevant studies up to July 2014 through a literature search of using PubMed and EMBASE, and by reviewing the references from the retrieved articles. Fixed-effect and random-effect models were used to estimate summary relative risks (SRRs) and the corresponding 95% confidence intervals (CIs). A total of 12 studies were eligible and included in this meta-analysis, involving 4,206 kidney cancer cases and 638,677 participants. The SRR of kidney cancer for ever versus never OC use was 0.89 (95% CI: 0.82 0.98). The protection became stronger when compared the longest duration of OC use with never use (RR = 0.80; 95% CI: 0.68-0.94). In dose-response analysis, we found that the kidney cancer risk decreased by 2% for per 1 year increment in OC use (RR = 0.98; 95% CI: 0.96-0.99). No apparent heterogeneity was observed across studies included in this analysis. Egger's and Begg's test also indicated no publication bias. The present study suggested that OC may reduce the risk of kidney cancer, especially for long-term users. More well-conducted and large scale prospective studies are warranted to confirm the effects of OC use on kidney cancer. PMID- 25550904 TI - A minimally invasive posterior lumbar interbody fusion using percutaneous long arm pedicle screw system for degenerative lumbar disease. AB - The aim of this study is to evaluate the therapeutic efficacy of patients with lumbar degeneration and instability treated with percutaneous pedicle screw fixation and minimally invasive lumbar interbody fusion. Twenty-one patients were selected in our hospital from November, 2012 to March, 2013. The patients with an average age 55.62 years, including 8 vertebral spondylolisthesis, 4 lumbar intervertebral disc herniation, and 9 lumbar spinal canal stenosis cases. All the patients were managed to take the lumbar MRI and radiographs. The comparison of preoperative and postoperative (3 days, 2 weeks, 3 months) VAS and ODI score were analyzed. The results indicated that VAS scores were 7.14 +/- 0.79 before operation, and 5.19 +/- 0.81 in 3 days after operation, 4 +/- 0.84 after 2 weeks, and 2.67 +/- 0.66 after 3 months. The pain was relieved, and the postoperative VAS score was lower than that before treatment (P < 0.05). ODI score was 55.8 +/- 11.4 before operation, 47.38 +/- 9.38 after 3 days, 41.38 +/- 8.09 after 2 weeks, 35.76 +/- 4.50 after 3 months. ODI score was obviously decreased (P < 0.05). In conclusion, percutaneous pedicle screw fixation combined with minimally invasive interbody fusion is a safe, effective, feasible minimally invasive spine operation, with worthy for spreading. PMID- 25550905 TI - Minimal invasive trans-eyelid approach to anterior and middle skull base meningioma: a preliminary study of Shanghai Huashan hospital. AB - Transpalpebral or trans-eyelid approach is a modified trans-orbital access to lesions of anterior cranial fossa and sellar region. But whether this approach is also suitable for tumors extending laterally to the temporal lobe or middle cranial fossa is not clarified. We would like to share our experiences from the cadaveric anatomy study to clinical operations. We used 5 cadavers to study trans eyelid approaches in a step-by-step fashion. And then assisted by an experienced ophthalmologist for incisions, we treated 3 female patients via this approach: One with spheno-orbital meningioma, one with sellar tuberculum meningioma, and the other with medial sphenoidal wing meningioma. After studying the cadavers, we made several revisions to the previously reported approach: 1) move the incision close to the edge of the eyelid, which resembled the double-eyelid incision. 2) A vascularized periosteum flap was dissected for repairing the opened frontal sinus and reconstruction of the skull base. 3) The dura was sutured up with a slice of temporalis muscle. Then we treated 3 patients by this approach. All tumors were totally resected as Simpson Grade I. Complications included orbital apex syndrome and transient oculomotor paralysis because of tumor invasion into orbit and cavernous sinus. No cerebrospinal fluid leakage. We find that trans-eyelid approach is suitable for lesions not only at anterior cranial base or sellar region, but also extending to middle cranial base, especially around sphenoidal wings within 2 cm range or spheno-orbital region. Thus, we propose whether it appropriate to nominate this approach as 'trans-eyelid pterional approach', since it may treat some anterior and middle cranial fossa lesions with a mini craniotomy around pterion. PMID- 25550906 TI - New steroid derivative with hypoglycemic activity. AB - Data indicates that some steroid derivatives may induce changes on glucose levels; nevertheless, data are very confusing. Therefore, more pharmacological data are needed to characterize the activity induced by the steroid derivatives on glucose levels. The aim of this study was to synthesize a new steroid derivative for evaluate its hypoglycemic activity. The effects of steroid derivative on glucose concentration were evaluated in a diabetic animal model using glibenclamide and metformin as controls. In addition, the pregnenolone dihydrotestosterone conjugate was bound to Tc-99m using radioimmunoassay methods, to evaluate the pharmacokinetics of the steroid derivative over time. The results showed that the pregnenolone-dihydrotestosterone conjugate induces changes on the glucose levels in similar form than glibenclamide. Other data showed that the biodistribution of Tc-99m-steroid derivativein brain was higher in comparison with spleen, stomach, intestine liver and kidney. In conclusion, the pregnenolone dihydrotestosterone conjugate exerts hypoglycemic activity and this phenomenon could depend of its physicochemical properties which could be related to the degree of lipophilicity of the steroidderivative. PMID- 25550907 TI - Polymorphisms in the PTX1 may not be associated with ischemic stroke susceptibility. AB - OBJECTIVE: Ischemic stroke is a global health burden due to the increasingly higher incidence rate and mortality rate. Etiological research into the role of genetics in this heterogeneous disease may have diagnostic and prognostic implications. The present study was designed to assess the association between PTX1 SNPs: -717A>G and -286C>T>A, and ischemic stroke risk. METHODS: Risk of ischemic stroke was estimated using summary ORs. The fixed effects model was performed in calculating the pooled ORs. All statistical data were analyzed with STATA software. RESULTS: We combined 4,604 subjects for SNP -717A>G and 3,093 subjects for SNP -286C>T>A. SNP -717A>G was not found to be significantly associated with ischemic stroke risk (GG vs. AA, OR = 1.12, 95% CI = 0.83-1.50, PHet = 0.207; GG + GA vs. AA, OR = 1.04, 95% CI = 0.93-1.17, PHet = 0.533; GG vs. GA + AA, OR = 1.10, 95% CI = 0.82-1.47, PHet = 0.220). Meta-analysis of SNP 286C>T>A also demonstrated no statistical evidence of a significant association with ischemic stroke (AA vs. CC, OR = 0.86, 95% CI = 0.59-1.25, PHet = 0.348; AA vs. CC, OR = 0.92, 95% CI = 0.80-1.06, PHet = 0.609; AA vs. CC, OR = 0.89, 95% CI = 0.62-1.30, PHet = 0.374). CONCLUSIONS: These results suggest that the PTX1 gene polymorphisms may not be associated with a predisposition to ischemic stroke. PMID- 25550908 TI - Diagnostic value of mesothelinin pancreatic cancer: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: An increasing number of studies have examined the ability of mesothelin to be a marker for the diagnosis of pancreatic cancer (PCa). The exact role of mesothelin needs to be elucidated. The aim of this study is to determine the overall accuracy of mesothelinin PCa through a meta-analysis of published studies. MATERIALS AND METHODS: Publications addressing the accuracy of mesothelin in the diagnosis of PCa were selected from Pubmed, Embase, Cochrane Library, Web of Science, and The Chinese Journals Full-text Database (CNKI). The following indexes of test accuracy were computed for eachstudy: sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). The diagnostic threshold identified for each study wasused to plot a summary receiver operating characteristic (SROC) curve. Statistical analysis was performed by Meta-Disc1.4 and STATA 12.0 software. RESULTS: 12 studies met the inclusion criteria. The summary estimates for mesothelin in the diagnosis of PCa were: sensitivity 0.71 (95% CI, 0.67-0.75), specificity 0.88 (95% CI, 0.85-0.91), positive likelihood ratio (PLR) 8.53 (95% CI, 3.42-21.27), negative likelihood ratio (NLR) 0.36 (95% CI, 0.28-0.46)and diagnostic odds ratio 33.93 (95% CI, 10.71-107.5). The SROC curveindicated that the maximum joint sensitivity and specificity (Q-value) was 0.81; the area under the curve was 0.88. CONCLUSION: Our findings suggest that mesothelin may be a useful diagnostic adjunctive tool for confirming PCa. However, further large scale studies are needed to confirm these findings. PMID- 25550909 TI - EphB4 expression in pterygium is associated with microvessel density. AB - OBJECTIVE: Angiogenesis is a key component of the pathogenesis process of pterygium, which is the growth of fibrovascular tissue on the cornea. It has been reported that EphB4, a receptor tyrosine kinase of the ephrin-Eph system, plays important role in vascular development during embryogenesis and tumor angiogenesis and is potentially involved in ocular angiogenesis. The aim of this study is to investigate the role of EphB4 in pterygia. METHODS: Fifteen pterygium samples and their paired upper bulbar conjunctiva were evaluated for expression of EphB4 and CD31 by using immunohistochemical staining. The expression level of the mRNA of EphB4 gene in 7 pterygia and matched upper bulbar conjunctiva was evaluated by using a quantitative real-time RT-PCR analysis. Microvessel density (MVD) was assessed with antibody that targets CD31. RESULTS: EphB4 protein was high expressed in the epithelium and stroma of pterygia compared to those in upper bulbar conjunctiva. Immunohistochemical staining showed that pterygia presented with statistically significant higher average count of microvessel compared to normal conjunctivae (28.24 +/- 6.79 vs 11.09 +/- 2.96 per high power field, P < 0.001). MVD values in stroma of the pterygium and normal conjunctiva presented a significant correlation with EphB4 staining (P < 0.001). Compared with autologous upper bulbar conjunctiva grafts, the expression of the EphB4 mRNA was increased in pterygia in 4 paired samples, including those 3 recurrent ones. CONCLUSION: The expression of EphB4 in pterygium was significantly related with the increased MVD and may be involved in angiogenesis. EphB4 protein is a potential target for treatment of pterygium. PMID- 25550910 TI - Etiologic and clinical analysis of chronic complex anal and rectal inflammation in children less than 3 years old. AB - OBJECTIVE: To analyze the etiology and clinical diagnostic method for chronic complex anal and rectal inflammation in children less than 3 years old. METHOD: Seven children (5 males and 2 females; 1 year 8 months to 3 years of age at the time of physician evaluation) with chronic complex anal and rectal inflammation were enrolled between May 2008 and May 2013 at our hospital. Clinical history, results of auxiliary examinations, and empirical treatment of the children were analyzed retrospectively combined with the etiologic diagnosis. RESULTS: Four patients were confirmed to have Crohn's disease and one patient was confirmed to have intestinal tuberculosis; two patients were suspected to have Crohn's disease. Anemia and low pre-albumin level were common (seven patients); serologic testing revealed four patients with elevated IgG levels and seven patients with elevated IgA levels; there were no patients with positive tuberculosis antibody titers and two patients were weakly positive for C-ANCA (one patient with Crohn's disease and one patient intestinal tuberculosis). Colonoscopies revealed that the entire colon was affected in one patient, the left hemicolon was affected in four patients, and the sigmoid colon and rectum were affected in two patients. Two patients with Crohn's disease and one patient with intestinal tuberculosis were diagnosed by colonoscopies in combination with histopathologic examinations. Two patients with Crohn's disease were confirmed after empirical drug treatment, and two other patients were not definitely diagnosed. CONCLUSION: The possibility of Crohn's disease or intestinal tuberculosis should be considered in the clinical diagnosis of complex chronic anal and rectal inflammation in younger children. Local surgery is sometimes unnecessary. Empirical drug treatment should be used if necessary. PMID- 25550911 TI - Changes of serum neurohormone after renal sympathetic denervation in dogs with pacing-induced heart failure. AB - BACKGROUND: Neurohormonal activation is a commonly cited array of phenomena in the body's physiologic response to heart failure (HF). The aim of the present study was to determine the change law of serum neurohormones after renal sympathetic denervation (RSD) in dogs with pacing-induced HF. METHODS: Twenty eight beagles were randomly divided into control group, RSD group, HF group and HF + RSD group. The control group was implanted pacemakers without pacing; the RSD group underwent renal artery ablation without pacing; the HF group was implanted pacemakers with ventricular pacing at 240 bpm for 3 weeks; and HF + RSD group underwent renal artery ablation and with ventricular pacing at 240 bpm for 3 weeks. Blood samples were taken at baseline, and 3, 6, 9, 12, 15, 18, 21 days in all the dogs for neurohormones measurement. RESULTS: After 3 weeks, the systolic femoral artery pressures in the HF and HF + RSD groups were reduced after pacing 3 weeks. There was an increase significantly in BNP, angiotensin II, aldosterone, endothelin-1 and decrease in renalase after 3 weeks when compared with baseline in HF group. RSD significantly suppressed the changes of plasma neurohormones concentration in experimental HF, but RSD had not obviously impact on the levels of plasma neurohormones during 3 weeks in RSD group. CONCLUSIONS: RSD attenuates the changes of levels of plasma neurohormones in the activated renin-angiotensin-aldosterone system (RAAS) but had not obviously effect in the normal physiology of RAAS. PMID- 25550912 TI - Effects of lentivirus mediated STAT3 silencing on human chronic myeloid leukemia cells and leukemia mice. AB - OBJECTIVE: To investigate the effects of lentivirus mediated STAT3 silencing on human chronic myeloid leukemia cells (K562) and the growth of chronic myeloid leukemia mice as well as to explore the potential mechanisms. METHODS: Unbtreated K562 cells (CON), blank lentivirus transfected K562 cells (NC) and K562 cells expressing STAT3 siRNA (STAT3 siRNA) were injected into SCID mice to establish the chronic myeloid leukemia model in mice. The growth, peripheral white blood cell count and spleen index in these mice were determined. RESULTS: In vitro experiment showed, when compared with control group, the interference efficiency of STAT3 expression was as high as 97.5% in K562 cells. Western blot assay revealed that the expression of c-Myc, Bcl-xL and Cyclin D1 reduced by 17.01%, 7.3% and 6.82%, respectively, showing significant difference when compared with control group (P < 0.01). These findings were consistent with those from fluorescence quantitative PCR. In vivo experiment showed the body weight of mice reduced progressively and the peripheral white blood cell count increased gradually in control group, accompanied by dragging hind limbs and progressive enlargement of the spleen. The body weight remained unchanged, peripheral white blood cell count reduced gradually and the spleen did not enlarge in mice treated with STAT3 siRNA expressing cells. CONCLUSION: Lentivirus mediated STAT3 silencing may inhibit the expression of its downstream genes (c-Myc, Bcl-xL and Cyclin D1) related to cell proliferation, apoptosis and cycle to suppress the malignant biological behaviors, and STAT3 silencing also inhibit the leukemogenic potency of K562 cells in mice. PMID- 25550913 TI - Regulation of gene expression in HBV- and HCV-related hepatocellular carcinoma: integrated GWRS and GWGS analyses. AB - OBJECTIVES: To explore the molecular mechanism of hepatitis B virus-related and hepatitis C virus-related hepatocellular carcinoma, samples from hepatitis B virus and hepatitis C virus infected patients and the normal were compared, respectively. METHODS: In both experiments, genes with high value were selected based on a genome-wide relative significance and genome-wide global significance model. Co-expression network of the selected genes was constructed, and transcription factors in the network were identified. Molecular complex detection algorithm was used to obtain sub-networks. RESULTS: Based on the new model, the top 300 genes were selected. Co-expression network was constructed and transcription factors were identified. We obtained two common genes FCN2 and CXCL14, and two common transcription factors RFX5 and EZH2. In hepatitis B virus experiment, cluster 1 and 3 had the higher value. In cluster 1, ten of the 17 genes and one transcription factor were all reported associated with hepatocellular carcinoma. In cluster 3, transcription factor ESR1 was reported related with hepatocellular carcinoma. In hepatitis C virus experiment, the value of cluster 3 and 4 was higher. In cluster 3, nine genes were reported to play a key role in hepatocellular carcinoma. In cluster 4, there were 5 genes in the 34 genes. To compare the relevance of a node in holding together communicating nodes, centralities based analysis was performed and we obtained some genes with high stress value. CONCLUSION: The analysis above helped us to understand the pathogenesis of hepatitis B virus and hepatitis C virus associated hepatocellular carcinoma. PMID- 25550914 TI - Prognostic value and efficacy evaluation of novel drugs for cytogenetic aberrations in multiple myeloma: a meta-analysis. AB - Cytogenetic abnormalities have emerged as the major novel prognostic factors in multiple myeloma (MM) patients. This meta-analysis comprehensively investigates the association between the cytogenetic abnormalities and survival of MM patients. We searched the PubMed, EMBASE, SCOPUS, and Cochrane databases for articles published until February, 2014. Thirty eligible studies involving 10276 patients were included to examine the association of three chromosomal abnormalities, t (4; 14), del (17p), and Amp (1q21), with survival in MM patients. The main outcome measures were progression-free survival (PFS) and overall survival (OS). Individuals with t (4; 14), del (17p), and Amp (1q21) had low OS and PFS. In a subgroup analysis for therapy regimen, lenalidomide- and bortezomib-based therapies increased the PFS of patients with Amp (1q21) (HR=1.50, 95% CI=0.95-2.36, p=0.084) and t (4; 14) (HR=1.38, 95% CI=0.90-2.11, p=0.143). The presence of del (17p) elicited no significant influence on the prognosis of patients under different therapy regimens. Our meta-analysis provides globally quantifiable confirmation of the adverse prognostic value of t (4; 14), del (17p), and Amp (1q21) in OS and PFS for MM patients. Lenalidomide- and bortezomib-based therapies were partly conducive to improve the prognosis of individuals with t (4; 14). Bortezomib-based therapy can partly improve the PFS of patients with Amp (1q21). PMID- 25550915 TI - Baicalin down regulates the expression of TLR4 and NFkB-p65 in colon tissue in mice with colitis induced by dextran sulfate sodium. AB - BACKGROUND: Baicalin is one of flavonoid extracts from Scutellaria baicalensis, which has several functions including anti-inflammation, anti-bacteria, antitumor and et al. However, the mechanisms of anti-inflammatory of baicalin in ulcerative colitis is not clear. METHODS: Mice colitis models were established by dextran sodium sulfate, Mice administrated with baicalin (100 mg/kg) and mesalazine (100 mg/kg) twice daily by intragastric injection for 7 days after colitis induced were defined as treated group. Then the mice were sacrificed and the colon samples were collected. Toll-like receptor-2, 4, 9 were detected by immunohistochemistry. Signaling proteins such as TLR4, MyD88, and NF-kappaB p65 were analyzed by western blotting. Cytokine's mRNA include TNF-alpha, IL-6 IL-10 and IL-13 were measured by reverse transcription polymerase chain reaction. Modified disease activity index were used to analyse the severity of the disease by assessed of diarrhea, stool (occult) blood and body weight loss of the mice. RESULTS: Compared with control and model groups, modified disease activity index in baicalin and mesalazine treated, mice decreased gradually. Immunohistochemistry analysis showed the expression of TLR4, but not TLR2 and TLR9, in the mucosa of mice colon were decreased. Western blot analysis showed that in colitis model, the expression of NF-kappaB p65 and TLR4 decreased (P < 0.05), while the expression of MyD88 increased significantly compared to control group, and MyD88 expression can not be repressed by baicalin (P < 0.05). Baicalin and mesalazine treatment suppressed the expression of TNF-alpha, IL-6 and IL-13 mRNA (P < 0.05), yet up-regulated the expression of IL-10 mRNA (P < 0.05), compared to the DDS and control groups. CONCLUSIONS: Baicalin administration by intragastric injection ameliorates the severity of colon inflammation. The possible mechanism of anti-inflammatory response by baicalin may involve in the blocking of the TLR4/NF-kappaB-p65/IL-6 signaling pathway. PMID- 25550916 TI - Hyperbaric oxygen therapy reduces apoptosis after spinal cord injury in rats. AB - Hyperbaric oxygen therapy (HBOT) protects brain tissue from inflammatory injury by suppressing mitochondrial apoptotic pathways. However, its neuroprotective mechanism via anti-apoptosis in spinal cord injury (SCI) is still unclear. In our study, Male Sprague-Dawley rats were randomly divided into three groups: sham operated (SH), SCI model, and SCI + HBOT. Rats in each group were randomly divided into four sub-groups in a time-dependent manner (1 day, 3 days, 7 days and 14 days after surgery). Expression of adaptor molecule apoptosis-associated speck-like protein (ASC) and caspase-3 was evaluated at the indicated time after injury. Our data showed that HBOT downregulated expression of ASC in SCI rats at the mRNA and protein levels. HBOT mitigated caspase-3 release in injured spinal cord tissue. We conclude that HBOT prevents inflammation apoptosis after SCI, likely through suppression of ASC and caspase-3. PMID- 25550917 TI - MDA-7/IL-24 inhibits cell survival by inducing apoptosis in nasopharyngeal carcinoma. AB - AIMS: Nasopharyngeal carcinoma (NPC) is the most common primary malignancy of the nasopharynx. Due to its local recurrence and distant metastasis, conventional therapy is usually ineffective. MDA-7/IL-24 (melanoma differentiation associated gene 7), a member of the IL10 family of cytokines, inhibits growth of various human cancer cells, but the underlying mechanism is largely unknown. There is no report of mda-7 in nasopharyngeal carcinoma. We aimed to investigate the role of MDA-7/IL-24 in NPC. METHODS: Immune defective adenoviral vector carrying the gene was produced, infected NPC CNE cells and observed its growth, cell proliferation, apoptosis and the effect of combination with chemotherapy. RESULTS: The results showed that (1) MDA-7/IL-24 inhibited NPC CNE cell growth and survival; (2) mda-7 induced cell apoptosis and death; (3) MDA-7/IL-24 in collaboration with chemotherapy induced cell apoptosis significantly; (4) MDA-7/IL-24 induced cell apoptosis by down-regulation of anti-apoptosis molecules such as Bcl-2 and Bcl-xl and up-regulation of caspase 3. CONCLUSION: The results suggested that MDA-7/IL 24 had obvious therapeutic effect in NPC cells. It is verified that adenovirus mediated MDA-7/IL-24 represents a potentially important new approach to NPC therapy. PMID- 25550918 TI - Therapeutic effect of low frequency electric stimulation on the epileptogenic focus in amygdale-kindled rats. AB - This study was to examine the therapeutic effect of low-frequency electric stimulation (LFS) on the epileptogenic focus in amygdale-kindled rats, and to find out the optimal stimulus parameters. A microelectrode was implanted into the right amygdale of adult male rats. After fully kindling, LFS was delivered to the right amygdale (through the electrode) between seizures to induce stimulus trains (10 repetitive sequences). Next, we undertook controlled experiment in order to exclude the influence of seizure induction intervals on seizure. Fully kindled rats experienced trials for 4 days, the intervals of the repetitive seizure inducing stimulation was randomized for 5 min, 10 min, 15 min, and 20 min respectively. Finally, we applied an orthogonal design to test the 4 factors of parameters (frequency, pulse duration, current intensity and persistence time), in order to find out the best stimulus parameters. Results showed that compared to control group, the stage-4 seizure induction rate decreased dramatically in LFS group and animals in experiment group were more likely to be non-responsive to seizure-inducing stimuli. There were no statistical differences in the different seizure induction intervals. Significant differences were observed in different stimulus frequencies and stimulus train persistence times on the stage 4 seizure induction rate. These findings indicated that 1 Hz LFS is the best. Training for 5 min is more efficacious in controlling seizure. Thus, our results suggest that LFS applied directly to the site of seizure was effective and further studies are required to explore the most effective parameters for developing implanted stimulator. PMID- 25550919 TI - Decreased SCF/c-kit signaling pathway contributes to loss of interstitial cells of Cajal in gallstone disease. AB - Cholecystolithiasis is a common disease, and gallbladder dysmotility is considered as a pivotal pathogenesis. Interstitial cells of Cajal (ICCs) serve as pacemakers and mediators of neuromuscular transmission for gastrointestinal motility. Reduction of ICCs has been reported in gallstone diseases. However, there are no reasonable mechanisms for the cholecystolithiasis-associated loss of ICCs in humans. Stem cell factor (SCF) and its ligand c-kit are essential for normal development and survival of ICCs. To date, little is known about the SCF/c kit signaling pathway in gallstone diseases. The purpose of this study was to investigate the role of the SCF/c-kit signaling pathway in the loss of ICCs in cholecystolithiasis. Data from 18 patients with gallstones and 14 individuals without gallstones were compared. The gallbladder contractility was assessed by measuring the gallbladder ejection fraction (GEF) ultrasonographically. Tissues samples were obtained during surgery, changes of ICC quantities were analyzed by immunohistochemistry, and the mRNA and protein expression of SCF and c-kit were detected by Real-Time PCR and Western-blot analysis. Compared with the controls, the GEF was significantly reduced in the gallstone group, and decreased number of ICCs was present obviously in the gallstone group. Furthermore, the mRNA and protein expression of SCF and c-kit were significantly attenuated in the gallstone group. These data indicate that gallbladder motility may be affected by reduction of ICCs in gallstone disease. Additionally, the decreased of SCF/c-kit signaling pathway play an important role in the loss of ICCs. PMID- 25550920 TI - Rho-kinase inhibition is involved in the activation of PI3-kinase/Akt during ischemic-preconditioning-induced cardiomyocyte apoptosis. AB - We and others have reported that Rho-kinase plays an important role in the pathogenesis of heart ischemia/reperfusion (I/R) injury. Studies also have demonstrated that the activation of Rho-kinase was reversed in ischemic preconditioning (IPC). This study aimed to explain the mechanism of Rho-kinase mediated cardiomyocyte apoptosis increased in I/R and reversed in IPC. MATERIALS AND METHODS: Studies were performed with female Wistar rats. The I/R rats were created by ligating the left anterior descending branch (LAD) for 30 min and releasing the ligature for 180 min. The IPC rats underwent IPC (two cycles of 5 min ligation of the LAD and 5 min reflow) before I/R. RESULTS: Ischemia followed by reperfusion caused a significant increase in Rho-kinase and a decrease in Akt phosphorylation. Administration of fasudil, an inhibitor of Rho-kinase, decreased myocardial infarction size and cardiomyocyte apoptosis and increased Akt activation. IPC also caused the reduced Rho-kinase activity and cardiomyocyte apoptosis and a significant increase in Akt activity (P<0.05 vs I/R). CONCLUSION: Rho-kinase inhibition by IPC leads to reduced cardiomyocyte apoptosis may be mediated by activation of PI3-kinase/Akt. PMID- 25550921 TI - miR-132/212 cluster inhibits the growth of lung cancer xenografts in nude mice. AB - OBJECTIVE: Lung cancer remains the leading cause of cancer-related death worldwide and microRNAs (miRNAs) play important roles in lung cancer progression. In this study, we investigate the effects of miR-132/212 cluster on the growth of subcutaneous xenografts of human lung cancer H1299 cells in nude mice, and further explore the underlying mechanisms. METHODS: Nude mice with subcutaneous transplantation tumor of human lung cancer H1299 cells were randomly divided into three groups: the sham group, the control vector group, and the microRNA-132/212 group. The control vector and microRNA-132/212 cluster plasmid was intratumoral injected respectively. Tumor volume was measured during the intervention process, with a tumor growth curve generated. Immunohistochemistry was performed to analyze the expression level of Ki-67, P21, CyclinD1 and CD31 in each group. RESULTS: The tumor volume of miR-132/212 group was significantly smaller than that of the control group at the terminal time point (P < 0.05). The expression levels of Ki-67, CyclinD1 and CD31 in the miR-132/212 group was significantly lower than the control group (P < 0.05), while the expression levels of P21 in the miR-132/212 group were significantly higher than the control group (P < 0.05). CONCLUSION: miR-132/212 cluster significantly inhibited the growth of subcutaneous xenografts of human lung cancer H1299 cells in nude mice. The inhibitory effect of miR-132/212 cluster in tumor growth may be mediated by upregulating the expression of P21 and downregulating the expression of CyclinD1, thereby inhibiting tumor tissue proliferation and angiogenesis and resulting in the inhibition of tumor growth. PMID- 25550922 TI - Current diagnosis and management of malignant gastrocolic fistulas: a single surgical unit's experience. AB - Gastrocolic fistula (GCF) is associated with a variety of diseases, but in recent years it has most frequently been observed with gastric or colonic malignancy. The management of primary tumor lesions and optimal surgical treatment strategies remain controversial. In this study, we explore the clinical diagnosis and treatment of GCF by retrospectively analyzing the records of GCF patients treated between August 2008 and February 2014. Three female patients and one male patient with an average age of 61 years were diagnosed with GCF caused by malignancy during this period. The predominant symptoms were diarrhea, vomiting, weight loss, and abdominal pain. Gastrointestinal contrast series combined with fiber endoscopy was the most accurate method of diagnosing the GCF, while CT and MRI were helpful in identifying the extent of tumor invasion and evaluating the possibility of en-bloc resection. Pathological and immunohistochemical tests, including staining for CK-20, CK-7, and CDX-2, suggested that three cases originated in the colon and one case in the stomach. All four cases underwent single-stage en-bloc fistula resection; two severely malnourished patients received concurrent colostomies. One patient died of postoperative anastomotic leakage and cardiopulmonary failure, but the remaining three patients were discharged in improved condition. En-bloc resection followed by adjuvant chemotherapy can result in long term survival. Gastrointestinal contrast series combined with fiber endoscopy showed high sensitivity in the diagnosis of GCF. Immunohistochemical staining can be conducted for tumors with an unclear source. Single-stage radical en-bloc fistula resection is the recommended surgical treatment, and concurrent colostomy should be considered in severely malnourished patients. PMID- 25550923 TI - Effect of umbilical cord mesenchymal stem cell in peri-implant bone defect after immediate implant: an experiment study in beagle dogs. AB - BACKGROUND: For the sake of reducing post extraction resorption, getting optimal positioning of the implant and shortening treatment time, immediate implant placement following tooth extraction has been proposed as a treatment option. However, the large bone defect peri-implant has a negative influence on the process of bone healing. In this study, umbilical cord mesenchymal stem cells (UCMSCs) were transplanted into the bone defect peri-implant in beagle dogs and the effect of UCMSCs on bone regeneration in peri-implant were assessed. METHODS: The mandibular second, third and fourth premolars of 8 beagle dogs were extracted bilaterally. The defects in one side were filled with platelet-rich fibrin (PRF) and then UCMSCs were injected into the defect area, while the defects in the other side were filled with PRF only as control group. The titanium implant was placed into the distal root socket of each extracted tooth. The animals were sacrificed at week 2, 4 and 8 post operation. The bone defects adjacent to the implant which are 4 mm in height, 4 mm in the mesio-distal direction and 3.5 mm in the bucco-lingual direction were made after immediate implant. Histomorphometric analysis was performed using methylene blue-fuchsin acid staining and hematoxylin and eosin (HE) staining to evaluate bone regeneration. RESULTS: The direct bone-to-implant contact (BIC) in the experiment after 4 and 8 weeks was 56.47 +/- 1.18% and 76.23 +/- 2.08%; and in the control group was40.79 +/- 0.65% and 61.17 +/- 2.79%, respectively. The percentage of newly formed bone after 2, 4 and 8 weeks was 17.60 +/- 1.5%, 49.82 +/- 4.02% and 67.16 +/- 2.1% in experiment group; and in control group 14.30 +/- 1.25%, 37.04 +/- 2.29% and 58.83 +/- 3.36%, respectively. These results represented significant differences statistically. CONCLUSION: Intra-bone marrow injection of UCMSCs can promote new bone formation. UCMSCs can be used to as excellent seed cells to repair the large defect peri-implant after immediate implant. PMID- 25550924 TI - Clinical in vestigation of misdiagnosis of invasive pulmonary aspergillosis in 26 immunocompetent patients. AB - The clinical features of invasive pulmonary aspergillosis (IPA) in immunocompromised patients is well studied in the past decades. While the manifestations of IPA in immunocompetent patients remain unclear.The purpose of this study was to determine the clinical and radiological manifestations of invasive pulmonary aspergillosis (IPA) in patients without immunosuppression, as well as the reasons for the misdiagnosis of IPA. We retrieved and retrospectively reviewed the records of 102 patients from whom surgical lung specimens of chronic inflammatory granulomas were harvested. 26 patients were eventually diagnosed with pulmonary aspergillosis on Grocott methenamine silver staining. We investigated these patients in detail. We found that the rate of misdiagnosis before the lung surgery was as high as 73%. The most common symptom was hemoptysis, and the main feature in radiology was nodule or mass lesion. Air crescent sign or Halo sign were not common in our study. The atypical radiological manifestations and non-specific clinical findings make the diagnosis of IPA difficult and lead to a high misdiagnosis rate. PMID- 25550925 TI - Inhibition of 15-lipoxygenase (15-LOX) reverses hypoxia-induced down-regulation of potassium channels Kv1.5 and Kv2.1Inhibition of 15-lipoxygenase (15-LOX) reverses hypoxia-induced down-regulation of potassium channels Kv1.5 and Kv2.1. AB - The inhibition of voltage-gated potassium channels (Kv) plays an important role in the cerebral hypoxia-induced cell death. The activity of Kv can be inhibited by 15-hydroxyeicosatetrienoic acid (15-HETE). Therefore, as the key enzyme which catalyzed the formation of 15-HETE, 15-LOX may be involved in Kv inhibition induced by cerebral hypoxia. In our study, Wistar rats cerebral arterial smooth muscle cells (CASMCs) were placed under the condition of hypoxia and control, 15 LOX was proved involved in hypoxia-induced vasoconstriction. Furthermore, 15-LOX gene over expression under normoxic condition, as well as 15-LOX gene knockout or inhibition under hypoxic condition was performed to investigate the expression and activity of Kv1.5 and Kv2.1 in CASMCs. Results showed that both hypoxia and 15-LOX over expression could cause Kv1.5 and Kv2.1 suppression, but no suppression was observed under hypoxic condition when 15-LOX gene was knockout or inhibited, which made 15-LOX a new target for the treatment of cerebral hypoxia. In conclusion, AA/15-LOX/15-HETE induces vasoconstriction by down-regulating Kv channels, and Kv2.1/1.5 channels are the targets. Our study also suggests a therapeutic strategy to improve ischemic vascular occlusion by lowering 15-HETE level and preventing Kv channel down-regulation, which makes 15-LOX as a new target for the treatment of cerebral hypoxia. PMID- 25550926 TI - Vitamin C and E intake and risk of bladder cancer: a meta-analysis of observational studies. AB - Epidemiologic studies that investigate whether vitamin C and E intake protects against bladder cancer have yielded inconsistent results. We conducted a systematic review and meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence investigating vitamin C and E intake and bladder cancer. Studies were identified through a search of PubMed and Embase databases and of references from relevant publications. Meta-analyses were conducted to estimate summary risk estimates (REs) and 95% confidence intervals (CIs) for vitamin C and E intake using fixed- or random-effects model depending on the heterogeneity of the studies. Subgroup analyses were performed according to study design, sex, geographical regions and source of vitamins intake. The summary REs of bladder cancer for all published studies was 0.90 (95% CI, 0.79 1.00) and 0.82 (95% CI, 0.72-0.90) for vitamin C and E intake, respectively, with no evidence of between-study heterogeneity for vitamin E, but some heterogeneity for vitamin C intake. Although some of the summary effects were non-significant, subgroup analyses showed that these inverse relationships were not modified by study design, sex, geographical regions and source of vitamins intake for vitamin E intake. Our results indicated that high intake of vitamin E could reduce bladder cancer risk. However, the inverse association between vitamin C and bladder cancer seemed to be limited. Further studies using larger samples and a rigorous methodology are warranted. PMID- 25550927 TI - Trends in age-specific cerebrovascular disease in the European Union. AB - Although the mortality of cerebrovascular disease (CVD) has been steadily declined in the European Union (EU), CVD remains among the major causes of death in EU. As risk factors such asobesity and diabetes mellitus are increasing, the trends of European CVD mortality remains unknown. To understand the variation in CVD mortality of different EU countries, we studied the trends in CVD mortality in EU countries over the last three decades between males and females. Age- and sex-specific mortality rates between 1980 and 2011 were calculated by data from the WHO mortality database. Joinpoint software was used to calculate annual percentage changes and to characterize trends in mortality rates over time. Our study showed that between 1980 and 2011, CVD mortality significantly decreased in both men and women across all age groups. The specific mortality trends varied largely between EU countries. The plateau trend was observed in little regions at different age groups, however, the EU as a whole displayed declined trend CVD mortality. During the last three decades, CVD mortality decreased substantially in the entire population of EU. However, despite this overall decline in CVD mortality, several areas were identified as having no change in their CVD mortality rates at different period. The whole EU needs to establish strict prevention measures toreduce the incidence of CVD risk factors. PMID- 25550928 TI - XPG Asp1104His polymorphism and gastrointestinal cancers risk: a meta-analysis. AB - Several studies have reported the association between the Asp1104His polymorphism in xeroderma pigmentosum group G (XPG) gene and risk of gastrointestinal cancers. However, the results are inconsistent. This meta-analysis was performed to assess the association between XPG Asp1104His polymorphism and gastrointestinal cancers risk. Relevant studies were identified using PubMed, Web of Science, CNKI, WanFang and VIP databases up to July 22, 2014. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed- or random effects model. 13 case-control studies from twelve publications with 4275 patients and 5735 controls were included. Overall, a significant association was found between the XPG Asp1104His polymorphism and the risk of gastrointestinal cancers (dominant model: OR = 1.15, 95% CI: 1.05-1.26; His/His vs. Asp/Asp: OR = 1.15, 95% CI: 1.01-1.32). When the analysis was stratified by ethnicity, similar results were observed in Asians under homozygote model; in stratification analysis by cancer type, increased cancer risk was detected in colorectal and hepatocellular carcinoma, but not for other gastrointestinal cancers. Furthermore, in subgroup analysis by source of control, we failed to detect any association among population, hospital and family-based populations. This meta analysis indicated that the XPG Asp1104His polymorphism may be a risk factor for gastrointestinal cancers, especially of colorectal cancer. PMID- 25550929 TI - Effect of (-)-epigallocatechin-3-gallate in preventing bone loss in ovariectomized rats and possible mechanisms. AB - Despite recent developments reported in studies of (-)-epigallocatechin-3-gallate (EGCG), its early preventive effect of mitigating bone loss is not well understood. We investigated the effect of EGCG in preventing bone loss in ovariectomized (OVX) female rats, and explored the possible underlying mechanisms. Twelve-week-old female Sprague-Dawley rats, were divided into 3 groups: group A received intraperitoneal EGCG for 12 consecutive weeks, begun 3 days after ovariectomy; group B received ovariectomy alone; group C, received a sham operation. At the end of the experiment, tibias and femurs were harvested for: (1) micro-CT scanning and measurement of bone mineral density (BMD) and bone morphological parameters; (2) a 3-point bending test; (3) HE staining and an immunohistological study investigating Sema4D expression. RESULTS: The BMD and BV/TV of group A were significantly higher than for the OVX group. The trabecular separation (Tb.Sp) of group A was significantly lower than for group B. RESULTS from the 3-point bending test showed no statistical significance among all the groups. Bone histological studies indicated that trabecular bone was denser in group C, while group B had less dense trabecular bone, and the bone morphological status of group A was intermediate between groups A and C. The immunohistological study demonstrated that Sema4D was more highly expressed as a percentage of the brown-stained area in group B than in the other 2 groups. CONCLUSION: EGCG had a positive effect on mitigating bone loss in ovariectomized rats, and it inhibited Sema4D expression in bone tissue. Early stage supplementation of EGCG at a dose of 10 mg/kg/day after the onset of ovariectomy did not entirely eliminate bone loss. PMID- 25550930 TI - Serum cytokeratin 18 fragment level as a noninvasive biomarker for non-alcoholic fatty liver disease. AB - BACKGROUND AND AIM: We evaluated the usefulness of serum cytokeratin 18 fragment (CK18-F) as a noninvasive biomarker in differentiating nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver (NAFL) since the prognosis of the 2 diseases differ. METHODS: 116 Japanese patients with nonalcoholic fatty liver disease (NAFLD) proven by liver biopsy were studied. Histological findings were classified according to the NAFLD activity score (NAS) proposed by the Nonalcoholic Steatohepatitis Clinical Research Network. The correlation between histological findings and serum CK18-F levels was investigated. RESULTS: Serum CK18-F levels showed a positive correlation with histologic steatosis (rho = 0.271, P = 0.0033), inflammation (rho = 0.353, P = 0.0005), ballooning (rho = 0.372, P = 0.0001), and the total NAS (rho = 0.474, P = 2.68 * 10-7). The serum CK18-F level was significantly lower for NAFL (NAS <= 2) than for borderline NASH (NAS of 3-4) or definite NASH (NAS >= 5) (P = 0.0294, P = 1.163 * 10-5, respectively). The serum CK18-F level was significantly higher for definite NASH than for borderline NASH (P = 0.0002). The area under the receiver operating characteristic curve of serum CK18-F to predict the presence of NAFL and definite NASH was 0.762 and 0.757, respectively. The optimal cut-off point of serum CK18-F for NAFL and definite NASH was 230 and 270 U/L, respectively. The sensitivity, specificity, positive predict value, and negative predict value of serum CK18-F for NAFL were 0.89, 0.65, 0.34, and 0.97, and those for definite NASH were 0.64, 0.76, 0.72, and 0.67, respectively. Accuracies of diagnosis for both NAFL and definite NASH were 0.70. CONCLUSIONS: Serum CK18-F could be a clinically useful biomarker to discriminate between NAFL and NASH. PMID- 25550931 TI - Association of Interleukin-10 promotor polymorphisms with atrial fibrillation in Han Chinese. AB - There is an accumulating body of evidence indicating strong association between inflammation and the pathogenesis of atrial fibrillation (AF). IL-10 is a multifunctional anti-inflammatory cytokine that down-regulates cell-mediated immune responses and cytotoxic inflammatory responses. The aim of the present study is to investigate the association of IL-10 gene -592A/C polymorphism with AF in Han Chinese. 117 AF patients and 100 healthy volunteers were eligible for this study. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-10 -592A/C genotypes (AA, AC, and CC) was 55.00%, 35.00%, and 10.00% in the controls, and 71.79%, 23.08%, and 5.13% in AF subjects, respectively (p = 0.0335). The frequency of the A allele in the AF group was significantly higher than that in the control group (83.33% vs 72.50%, p = 0.0063). Compared with the CC genotype, the AA genotype had increased risk of AF in both unadjusted and adjusted analyses. The average serum IL-10 levels in AA genotype were statistically lower than in AC + CC genotype (p = 0.0000). These findings suggest that IL-10 -592A/C polymorphism is associated with AF and the A allele has increased risk for AF in Han Chinese. PMID- 25550932 TI - Evaluation of mean platelet volume in patients with hepatitis B virus infection. AB - OBJECTIVE: Mean platelet volume (MPV), which is determined by a routine complete blood count, is a parameter that is usually overlooked by clinicians. The present study was designed to investigate the association between MPV and different disease states in patients with hepatitis B virus (HBV) infection. METHODS: A total of 120 patients, including 17 with acute hepatitis B (AHB), 62 with chronic hepatitis B (CHB), and 41 with chronic severe hepatitis B (CSHB), as well as 58 healthy controls (HCs) were enrolled in the study. At study entry, blood samples were collected from all subjects to examine liver function and renal function, determine the international normalized ratio and perform routine hematological tests. RESULTS: We demonstrated that MPV was significantly increased in CSHB and CHB patients compared with HCs and AHB patients (all P<0.05). Among the patient groups, the CSHB patients had the highest MPV. Increased MPV was clinically associated with severe liver disease. CONCLUSIONS: MPV is significantly increased in chronic HBV-infected patients and is associated with disease severity; thus, it may serve as an important biomarker. PMID- 25550933 TI - Folic acid attenuates cognitive dysfunction in streptozotocin-induced diabetic rats. AB - Diabetic cognitive dysfunction is common in patients with diabetes but its pathogenesis is not clear. The aim of the present study is to investigate the role of 5', 10' methylene tetrahydrofolate reductase (MTHFR) in the development of diabetic cognitive impairment and test whether folic acid (FA) supplementation prevents cognitive dysfunction in diabetic rats. In the current study, three months after streptozotocin-induced diabetes onset, rats showed cognitive dysfunction including the prolonged escape latency, the decreased time spent in the target quadrant and the declined number of crossing the platform in Morris water maze test. Diabetic rats also presented elevated plasma homocysteine level and downregulation of MTHFR in hippocampus revealed by Western blotting. The diabetic cognitive dysfunction was attenuated by 30-day dietary FA treatment with a significantly decreased homocysteine level. In conclusion, these results suggest that MTHFR plays a crucial role in diabetic cognitive dysfunction and folate fortification might become a potent therapeutic strategy against diabetic cognitive impairment. PMID- 25550934 TI - Andrographolide inhibits proliferation of human lung cancer cells and the related mechanisms. AB - This study is to determine effect of Andrographolide (AD) on the growth of the non-small cell lung cancer cell line H3255. Expression of vascular endothelial growth factor (VEGF), transforming growth factor beta1 (TGF-beta1), and the activity of protein kinase C (PKC) were also detected. The H3255 cells were treated with 1.0, 2.5, or 5.0 MUM AD for 24 h. MTT assay was performed to examine cell viability. Levels of VEGF and TGF-beta1 were detected by ELISA. The ATPase activity and PKC activity were tested. AD treatments decreased cell viability via a concentration-dependent manner, leading to decreases in the Na(+)-K(+)-ATPase activities (P < 0.05). AD also increased levels of the DNA fragmentation and releasing of lactate dehydrogenase. AD also reduced VEGF and TGF-beta1 levels, and inhibited protein kinase C activities in H3255 cells (P < 0.05). AD inhibits proliferation of lung cancer cells via a concentration-dependent manner by a mechanism related to reducing levels of VEGF and TGF-beta1. Thus, AD might be a potent anti-lung cancer agent. PMID- 25550935 TI - The effect of epidermal growth factor applied locally for pelviureteral anastomoses. AB - OBJECTIVE: To investigate the effect of epidermal growth factor (EGF) on fibrous tissue formation and wound healing in experimental pelviureteral anastomosis (PUA). MATERIALS AND METHODS: Twelve rabbits were divided equally into 2 groups: control (C) and epidermal growth factor (EGF). A 1-cm length of the ureteropelvic segment was resected through a laparotomy incision and then anastomosis was performed. The rabbits were administered locally with 100 MUg/kg EGF (EGF group) all around the anastomosis lines after the surgical procedure. The C group did not receive any medication during their procedure. Intravenous pyelography was carried out on postoperative day 21. The rabbits were sacrificed and dissected under a dissecting microscope and examined for acute inflammation (AI), chronic inflammation (CI), granulation tissue amount (GTA), granulation tissue fibroblast maturation (GTFM), collagen deposition (CD), neovascularization (N), re epithelization (R), and peripheral tissue reaction (PTR) in the anastomosis lines 3 weeks later. RESULTS: There were no significant differences in the GTA, N, or R scores in the C group compared with those in the EGF group. In the EGF group, AI and CI scores were lower than they were in the C group. CD, GTFM, and PTR in the EGF group were higher than they were in the C group. CONCLUSION: EGF did not decrease CD, GTFM, or PTR, but did decrease important parameters in wound healing such as acute inflammation and chronic inflammation in an experimental model of PUA in rabbits. PMID- 25550936 TI - Effect of cold adaptation on activities of relevant enzymes and antioxidant system in rats. AB - Exercise in cold environments can cause significant metabolic regulation and antioxidant behavior. For discussing enzymatic responses towards cold adaptation, we investigated enzyme activities of adenylate cyclase (AC) and phosphodiesterase (PDE) in liver, skeletal muscle, and brown adipose tissue (BAT), as well as Na(+).K(+) ATPase and Na(+)/K(+) ratio in blood. Malondialdehyde (MDA) and superoxide dismutase (SOD) activity in blood were also studied to address the effect of cold adaptation on oxidative damage and antioxidant system. Experimental results indicated that enzyme activities in liver, skeletal muscle and BAT maintained relatively constant for the control group. For the cold adaptation group, enzyme activities in liver and skeletal muscle were in high levels at the beginning, and then gradually decreased to similar values with the control group. However, enzyme activities in BAT performed an increasing trend and significantly higher than the control at the end. In addition, decreased oxidative damage and activated antioxidant system was observed along with the cold adaptation process. PMID- 25550937 TI - Development of a novel anti ESAT-6 monoclonal antibody for screening of Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a major global public health problem with an estimated one third of the world's population infected with Mycobacterium tuberculosis, thus necessitating fast and accurate diagnosis of TB. However, the diagnosis of latent infection remains difficult due to the lack of a simple, reliable test for M. tuberculosis infection. The objective of the current study was to generate and characterize a novel monoclonal antibody (mAb) that specifically target the early secretory antigenic target 6 (ESAT-6) protein for tuberculosis (TB) immunological diagnosis. The BALB/c mice were immunized by a peptide with 13 amino acids (amino acid residues 24 to 36) of ESAT-6 protein. Stable hybridomas cell lines were established and mAb was identified by Western Blot, immunoprecipitation (IP) and Enzyme linked immunosorbent assay (ELISA). In addition, this mouse mAb was used to coat plates, and biotin-labelled polyclonal antibodies were used to detect the antigens. Finally, the antibody was verified in 280 patient sputum culture supernatants and pleural effusion aspirates. The positive detection rate of the generated ESAT-6 mAb was 91% in the clinical diagnosis of tuberculosis pleural effusion, and this mAb had a sensitivity of 92.4% and a specificity of 100% in all M. tuberculosis cases. Our data indicated that the mAb generated in this study can potentially serve as a tool in the laboratory diagnosis of TB. PMID- 25550938 TI - Interfering effect of bilirubin on the determination of alkaline phosphatase. AB - OBJECTIVE: This study was designed to evaluate whether the high concentration of bilirubin is able to interfere the determination of alkaline phosphatase (ALP). METHODS: Clinical tests evaluating the interfering substance of bilirubin of various concentrations on the determination of ALP were conducted based upon the Clinical and Laboratory Standards Institute (CLSI) document EP7-A2, the most recent guideline on interference testing approved in 2005. RESULTS: Paired t-test comparing different doses of bilirubin revealed that the concentration of 1 000 MUmmol/L bilirubin negatively interfered the determination of ALP levels. The experiment designed with five different concentrations of bilirubin showed that bilirubin can exert negative interference on the measurement of ALP in a linear pattern. CONCLUSION: High concentration of bilirubin can cause false measurement of ALP levels, probably interfering with the clinical prognosis of liver diseases. PMID- 25550939 TI - Spontaneous type B aortic dissection in antepartum gemellary pregnancy and endovascular repair. AB - BACKGROUND: It has been found that 50% of all aortic dissections can be attributable to pregnancy in women younger than 45 years of age. An estimated 30% of cases are type B, with half occurring in the antepartum period. To date type B aortic dissection has rarely been reported in gemellary pregnancies. CASE: A 24 year-old primigravida at 36 weeks of gemellary gestation presented symptoms of severe and persistent chest pain for 1 day, before suffering the acute type B aortic dissection. The primigravida was treated with immediate cesarean section and endovacular stent graft placement. CONCLUSION: Aortic dissection is a rare complication of pregnancy, especially in gemellary pregnancies. Pregnancy is considered an independent risk factor for aortic dissection and endovascular repair may be an ideal option for the treatment of complicated type B aortic dissection during pregnancy, with reduced maternal and fetal mortality. PMID- 25550940 TI - Genome-wide ChIP-seq analysis of TCF4 binding regions in colorectal cancer cells. AB - OBJECTIVE: TCF4 (transcriptional factor 4) forms a complex with its transcriptional coactivator beta-catenin and the coactivator carries the final signal output from the canonical Wnt signaling pathway, which is essential for the growth of normal epithelium and also plays important roles in carcinogenesis of colon epithelium. We aimed to gain a better understanding of the genes bound by TCF4 in colorectal cancer cells. METHODS: SW620 human colorectal cancer cells were cultured. The TCF4 antibody of this study was confirmed in SW620 cells by Western Blot. A ChIP-seq based genome-wide analysis of TCF4 chromatin occupancy in colorectal cancer cells was conducted and 1506 high confidence TCF4 binding sites wereidentified. RESULTS: Sequence analysis revealed that the binding sites harbor a consensus sequence of C-G/C-A-G-C-T/C-C-T-T-C. Gene ontology and pathway analysis showed that TCF4 regulated 18 genes in Wnt signaling pathway and 97 other transcription factors. CONCLUSION: Our results suggest TCF4 binding regions were enriched with a motif of C-G/C-A-G-C-T/C-C-T-T-C. The gene regulation of TCF4 may be conserved in colorectal cancer and glioma cells. TCF4 may be involved in a series of important biological processes such as regulation of metabolic and biosynthetic (GO: 0010604, GO: 0031328, GO: 0009891, GO: 0051173, GO: 0010557, GO: 0045935), adhesion (GO: 0007155, GO: 0022610), apoptosis (GO: 0042981, GO: 0043067, GO: 0010941), and important signaling pathways (Wnt, Chemokine, Calciu, GnRH). PMID- 25550941 TI - A systematic assessment of genotoxicity on pivaloylacylation-7ADCA-a wide existing antibiotic impurity. AB - The safety of antibiotics has been becoming an important worldwide concern. As an inevitable and widespread existing impurity of beta-lactam antibiotics, pivaloylacylation-7ADCA may has potential impact on drug safety. However, due to the restriction on traditional drug production technique, purified pivaloylacylation-7ADCA cannot be acquired and thus the toxicity of pivaloylacylation-7ADCA remains completely unknown. In this study, we firstly assessed the genotoxicity of newly purified pivaloylacylation-7ADCA. A series of well-designed experiments, including bacterial reverse mutation assay (Ames assay), mouse lymphoma assay (TK gene mutation test), chromosomal aberration assay, in vivo mouse micronucleus test and single cell gel electrophoresis assay (comet assay), were performed in genotoxicity assessment of pivaloylacylation 7ADCA at three different genetic endpoints, i.e. gene mutation, chromosome aberration or breakage, and DNA strand breaks. No genotoxicity were observed at all tested genetic endpoints, suggesting that pivaloylacylation-7ADCA has no mutagenic effect. To our knowledge, this is the first systematic assessment on the toxicity of newly synthesized pivaloylacylation-7ADCA, which should be an important part of the drug safety evaluation of beta-lactam antibiotics. Moreover, our study is expected to serve as a reference for the genotoxicity assessment of other antibiotic impurities, by using purified impurity as test sample and by combining a group of well-designed genotoxic assays with different species, major genetic endpoints and in vivo/vitro tests. PMID- 25550943 TI - Correlation analysis of peripheral blood T cell subgroups, immunoglobulin and prognosis of early hepatocellular carcinoma after hepatectomy. AB - To investigate the prediction value of preoperative changes in the immunological function for the prognosis of hepatocellular carcinoma (HCC) after hepatectomy, 158 cases of HCC patients who received liver resection in our hospital from 2009 to 2010 were enrolled in this study. Immune indices [CD3(+), CD4(+), CD8(+), CD19(+) and natural killer (NK), IgA, IgM, IgG], AFP level were calculated. The differences between preoperation and postoperation group, exclude were not both statistically significant (both P > 0.05), whereas IgA group was not (P < 0.05),The follow-up data showed that the 3-year recurrence rates of high level group on HBsAg, CD3, CD4, CD8, CD19 and IgGwerelarger than that of low level group,while the 3-year recurrence rates of high level group on AFP, NK, IgA and IgM smaller than that of low level group, and we found that CD3(+), CD4(+), CD8(+) and NK(+), CD19(+), HBsAg, IgA and IgG above were statistically different (P < 0.05), AFP and IgM were no difference with prognosis of HCC (P > 0.05).The markers level were not both statistically significant with age, gender, grade, tumor size (P > 0.05). Multiple logistic regression analysis indicated that CD4(+), CD8(+) and NK(+) were closely correlated with HCC postoperative survival rate (P < 0.05) (Y = 1.262*CD4(+)+1.448*CD8(+)-0.646*NK(+)). Construction of Cox's proportional hazards regression model showed IgA and IgG were correlated with HCC postoperative survival rate at a trend (P = 0.079) (Y = 127.9*IgG 28.7*IgM). Preoperative Immune indices (CD4(+), CD8(+), NK(+), IgA, IgG) were closely correlated with HCC survival rate and these were considerable predictive value for the malignantfeature and prognosis of HCC. PMID- 25550942 TI - The clinical effects of dendritic cell vaccines combined with cytokine-induced killer cells intraperitoneal injected on patients with malignant ascites. AB - Malignant ascites (MA) is a pathological condition due to a variety of primary abdominal and extra-abdominal neoplasms. It is a primary cause of morbidity and presents many difficulties in evaluation and treatment. In this study we used dendritic cell vaccines combined with cytokine-induced killer (CIK) cells intraperitoneal injected in patients with MA, and evaluated the safety and efficacy of this treatment. The results showed that the percentage of CD3(+) CD56(+) CIK cells after treatment increased significantly while the percentage of CD4(+) CD25(+) Treg cells decreased (P < 0.05). The clinical response rate (RR) was 40.9% and disease control rate (DCR) was 77.3%. We then studied and identified the mechanisms of the anti-tumor effects of the vaccines by analyzing a series of cytokines that are commonly involved in tumor progression and ascitic development including granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TGF-alpha), tumor necrosis factor-beta (TGF-beta), Vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1). These data demonstrated that intraperitoneal injection with DC vaccines combined with CIK cells in patients with malignant peritoneal effusion is safe and feasible. This therapy modality can achieve a certain clinical benefit even in patients resistant to conventional treatments. PMID- 25550944 TI - Effect of anterior cervical discectomy and fusion on adjacent segments in rabbits. AB - This study is to investigate the effect of anterior cervical discectomy with internal fixation and fusion at different levels on adjacent segments in rabbits. Sixty New Zealand rabbits were randomly divided into four groups, one control group and three model groups, with 15 in each group. Each group underwent anterior cervical internal fixation and fusion at C3-4, C4-5, and C5-6 levels respectively. X-ray film was examined three, six and nine months after fusion to observe the changes in intervertebral space and endplate of adjacent segment. Immunohistochemistry was utilized to evaluate the effects of different fusion methods on adjacent segments of spine. As time went by, in model groups, the majority of cartilage endplates were calcified, as examined by X-ray. Immunohistochemical results of the intervertebral disc showed that the expression levels of collagen type II in nucleus pulposus were decreased significantly, while the expression levels collagen type I in annular fibrosus were increased. And collagen type I tends to replace collagen type II gradually in nucleus pulposus as time goes by. The change in collagen between upper and lower adjacent segments at C3-4 and C4-5 showed no statistical significance after fixation and fusion (p > 0.05). But for C5-6, the change showed statistical significance (p < 0.05). Cervical internal fixation and fusion can induce intervertebral disc degeneration of adjacent segment in rabbits, and cervical internal fixation and fusion operated at different levels may result in different effects on adjacent segments of cervical intervertebral disc. PMID- 25550945 TI - Causes and managements of postoperative complications after degenerative scoliosis treatments with internal fixation. AB - OBJECTIVE: To investigate the causes and managements of early postoperative complications of degenerative scoliosis (DS) treated with internal pedicle screw fixation. METHODS: From Jan 2000 to Apr 2013, 325 DS patients treated with internal pedicle screw fixation in our hospital were retrospectively involved. The categories, causes, managements and outcomes of early postoperative complications were statistically analyzed. RESULTS: Early postoperative complications occurred in 10.76% of the patients including 16 cases of lower limb numb or pain, 6 cases of decreased lower limb sensitivity and motor functions, which accounted for 62.86% of all complications, followed by incision infections (4/35, 11.43%) and rare cases of cerebrospinal fluid leakage, cardiac and renal inadequacy, urinary system and pulmonary infections. The incidence of overall complications (19.79%, p = 0.001) and nerve injuries (11.46%, p = 0.000) were significantly higher in long-segment than in short-segment fixations. Improper screw implanting, over correction of scoliosis and insufficient blood supply of the spinal cord during operation were risk factors for early postoperative complications and most of them were cured by anti-infection medication, incision dressing change, nerve nourishment, adjusting the screws and anti-osteoporosis treatments within 6 months after surgery. Only three cases with severe nerve injury did not improve until the 6 months postoperative follow-up. CONCLUSIONS: Most of the postoperative complications in our DS patients disappeared within 6 months after surgery and more than half of complications were nerve injuries. PMID- 25550946 TI - Effect of continuous positive airway pressure on blood pressure in hypertensive patients with coronary artery bypass grafting and obstructive sleep apnea. AB - BACKGROUND: Previous studies have documented that obstructive sleep apnea (OSA) increases the incidence of hypertension, respiratory failure and unexpected post operative deaths during night in coronary artery bypass grafting (CABG) patients. We hypothesized that continuous positive airway pressure (CPAP) reduces blood pressure in these patients. METHODS: We conducted a prospective, controlled study in 51 patients. The subjects received CPAP treatment were defined as CPAP group, whereas those refused to use CPAP were served as controls. Blood pressure was measured by 24 h ambulatory blood pressure at baseline and at six months. RESULTS: Fifty-one patients completed the study. CPAP group and controls had similar characteristics. Compared with the control group, the 24-h SBP and 24-h DBP in the CPAP group had a tendency towards lower levels, but the differences were not statistically significant. But the change of SBP in CPAP treatment was significantly higher than controls (CPAP: 10.0 +/- 13.5 mm Hg vs. CONTROL: 2.9 +/ 10.5 mm Hg, P = 0.040). The rate of hypertension control was improved in the CPAP treatment, but had no statistical difference compared to the controls (CPAP, 76.0% vs. CONTROL, 61.5%; P = 0.260). Compared with controls, the proportion of non-dipping hypertension had a markedly improvement in the CPAP group (CONTROL, 46.2% vs. CPAP, 16.0%; P = 0.034). CONCLUSIONS: CPAP therapy decreased SBP and improved the status of non-dipping hypertension and alleviated daytime somnolence in hypertensive patients with CABG and OSA on standardized antihypertensive treatment. But DBP and hypertension control did not significantly change compared with the control group. PMID- 25550947 TI - Chronic compression of the posterior longitudinal ligament of the cervical spine is associated with abnormal discharge of middle cervical ganglion. AB - There are abundant sympathetic nerve fibers in cervical posterior longitudinal ligament (PLL). The aim of this study was to investigate the role of PLL in the occurrence of sympathetic symptoms. Ten healthy adult beagles were selected and anesthetized to establish a PLL compression model by C4/5 discectomy, nucleus pulposus tissue replantation, and plate internal fixation. The middle cervical ganglia (MCG) activities were recorded before modeling, shortly after modeling, and two months after modeling. The waveform parameters and spectral densities of autonomic discharge of MCG among the three periods were compared. There was significant difference only in terms of the area of waveform per unit time between before and shortly after modeling. Abnormal discharge waveforms of MCG were detected in two months after modeling. The wave amplitude and waveform area per unit time in two months after modeling were increased significantly compared with those in shortly after modeling. Functional spectral decomposition found a significant increase in 100-250 Hz in two months after modeling. In conclusion, abnormal discharge of MCG caused by chronic compression of PLL may be one of the pathological basis of sympathetic nervous symptoms. PMID- 25550948 TI - Adiponectin and visfatin may serve as diagnosis markers for metabolic syndrome in Uygur population. AB - OBJECTIVES: This study is to determine if two adipocytokines, adiponectin and visfatin, can be used as diagnosis markers for metabolic syndrome (MS) in Uygur population. METHODS: Sixty-two MS patients and 41 control individuals with normal body weights were enrolled in this study. Abdominal subcutaneous and omental adipose tissues were collected for determination of biochemical indices. The adipokines serum levels were determined by enzyme-linked immunosorbent assay (ELISA). Blood were collected from the MS patients and the control individuals and extracted proteins and RNAs subjected to western blot analysis and real-time PCR to determine adiponectin and visfatin expression, respectively. RESULTS: ELISA indicated that the serum adiponectin in the MS group was decreased (0.59 +/ 0.21 versus 0.49 +/- 0.18) in comparison with the control group (P < 0.05). But the serum visfatin in the MS group were increased (1.07 +/- 0.41 versus 1.25 +/- 0.32) when compared with the control group (P < 0.05). The western blot revealed decreased adiponectin and increased visfatin expression in the MS patients when compared with the normal controls. Further real-time RT-PCR analysis showed that the adiponectin and visfatin expression are altered via a transcriptional mechanism. CONCLUSIONS: Adiponectin and visfatin might be used as diagnosis markers of MS in Uygur population. PMID- 25550949 TI - The association between multiple sclerosis and fracture risk. AB - Sever studies were performed to assess the association between multiple sclerosis (MS) and fracture risk. However, the results were inconsistent and inconclusive. In the present study, the possible association was investigated by a meta analysis. Eligible articles were identified for the period up to August 2014. Pooled risk ratios (RR) with 95% confidence intervals (CI) were appropriately derived from random-effects models. Nine studies with more than 9,000,000 subjects were eligible. We found that MS was significant associated with fracture risk in overall population (OR = 1.58, 95% CI 1.36-1.84, P < 0.01). In terms of subgroup analyses by fracture sites, the associations were significant in femur (RR = 4.57, 95% CI 3.01-6.69, P < 0.01), hip (RR = 3.01, 95% CI 2.72-3.41, P < 0.01), tibia (RR = 2.72, 95% CI 2.22-3.32, P < 0.01), humerus (RR = 1.78, 95% CI 1.12-2.40, P = 0.02), pelvis (RR = 1.34, 95% CI 1.12-1.67, P < 0.01), and vertebrae (RR = 1.30, 95% CI 1.13-1.69, P < 0.01). This meta-analysis suggested that MS may be associated with fracture development. PMID- 25550950 TI - Three-dimensional image navigation system-assisted anterior cervical screw fixation for treatment of acute odontoid fracture. AB - This study is to investigate the role of three-dimensional image navigation system for surgical treatment of odontoid fracture. A total of 21 patients were enrolled in this study. The anterior cervical hollow screw fixation was performed for treatment of acute odontoid fracture under monitoring of isocentric C-arm three-dimensional navigation system (Iso-C 3D) navigation system. The postoperative follow-up investigation duration was 13.8 +/- 4.4 months. Twenty patients with odontoid fracture had bone union without intraoperative and postoperative complications. No loosening, dislocation or fracture of screw occurred. The average healing time was from 3 to 4 months. The cervical postoperative organ function evaluation of patients was scored by Smiley-Webster scoring methods. Eighteen cases were scored as excellent; 2 cases were scored as fine; 1 case was scored as good; and no case was scored as poor. Iso-C 3D image navigation system-assisted anterior cervical screw fixation is an effective approach for treatment of odontoid fracture. PMID- 25550951 TI - CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma. AB - Cutaneous malignant melanoma represents the major cause of mortality among skin cancers. Metastasis-associated protein CD24 is a small, heavily glycosylated cell surface protein that is overexpressed in various human malignancies. The present study was designed to determine the roles of CD24 in cutaneous malignant melanoma. The levels of CD24 mRNA and protein in cutaneous malignant melanoma tissues were detected by RT-PCR, Western blot and IHC. In patient samples, the levels of CD24 mRNA and protein were higher in cancer tissues than that in normal tissues. CD24 expression decreased the survival time of the patients with melanoma. Taken together, these results suggest that CD24 may be used as a new drug target for cutaneous malignant melanoma. PMID- 25550952 TI - Assessment of hepatic steatosis on contrast enhanced computed tomography in patients with colorectal cancer. AB - AIMS: Non-alcoholic fatty liver disease is often seen in patients with colorectal cancer. Insulin resistance and metabolic syndrome are related to increased risk of colorectal cancer. The aim of this study was to quantitatively determine the relationship between non-alcoholic fatty liver disease and colorectal cancer with the examination of routine abdominopelvic computed tomography images taken for staging. METHODS: A retrospective evaluation was made of the colonoscopy and histopathology reports of 1630 patients who presented for a scanning or diagnostic colonoscopy examination. Colorectal cancer was determined histopathologically in 129 cases. Colorectal cancer patients with distant metastasis or additional malignancies were excluded from the study. A total of 105 patients met the criteria and were included in the study. A control group was formed of 94 patients with no history of cancer. The liver density on abdominopelvic computed tomography and serum transaminase values were recorded for the patients and compared with those of the control group. RESULTS: The groups were similar in respect of age, gender and aspartate aminotransferase levels. Although not statistically significant, the alanine aminotransferase levels of the patient group were high compared to the control group. The liver density on computed tomography was statistically significantly lower in the patient group than in the control group. CONCLUSION: The liver density measurement on contrast abdominopelvic computed tomography of colorectal cancer patients was low, which is consistent with non-alcoholic fatty liver disease. PMID- 25550953 TI - The application of reverse tubular medial upper arm flap in the reconstruction of ripped facial defects. AB - Reverse medial upper arm flap is usually utilized in the reconstruction of defects in soft tissues of head and facial skin and is with good clinical efficacy. However, it has not been used in the reconstruction of ripped defects. In this study, we used the reverse tubular medial upper arm flap to repair the ripped facial defects. The reverse tubular skin flap from the medial upper arm was longitudinally cut into two parts. One part was used for the reconstruction of ripped facial defects. The other part was used as inner lining to repair the defects of mucosa. Using this method, 3 patients with ripped facial defects were successfully repaired. Thus the reverse tubular medial upper arm flap was successfully used in the reconstruction of ripped facial defects with little surgical trauma, simple manipulation of the operation, increased success rate of the operation and reduced incidence of complications. PMID- 25550954 TI - Reduced E-Cadherin expression is a prognostic biomarker of non-small cell lung cancer: a meta-analysis based on 2395 subjects. AB - OBJECTIVE: Previous studies related to the prognostic value of E-Cadherin expression on non-small cell lung cancer (NSCLC) were inconsistent. The present study aimed to evaluate the relation between E-Cadherin expression and the prognosis of NSCLC. METHODS: We performed a meta-analysis based on 14 studies including 2395 NSCLC patients. Literature retrieval, data extraction, and meta analyses were performed according to the Revman 5.0 guidelines. We utilized the fixed-effect model to pool the HR according to the test of heterogeneity in the meta-analysis. RESULTS: A total of 14 eligible studies including 2395 NSCLC patients were analyzed. In total, 51.2% of the patients were considered as having reduced expression of E-Cadherin according to the authors' cutoff. The pooled hazard ratio (HR) of reduced expression of E-Cadherin for overall survival (OS) was 1.19 (95% CI: 1.01 to 1.40, P=0.04), showing a worse survival when E-Cadherin expression is decreased. CONCLUSION: Patients with reduced expression of E cadherin have a poorer OS compared with those with normal or high expression of E cadherin. PMID- 25550956 TI - Development and evaluation of a nurse-led hypertension management model in a community: a pilot randomized controlled trial. AB - This study aims to develop a nurse-led hypertension management model in the community setting and pilot it to an experimental trial. A total of 73 recruited participants were randomly allocated into two groups. The study group received a home visit and 2-4 telephone follow-ups from the trained community nurses assisted by nursing student volunteers. The control group received doctor-led hypertension management. Data was collected at recruitment and immediately after the 8-week program. Outcome measures included blood pressure readings, self-care adherence, self-efficacy, quality of life, and patient satisfaction. Participants from the study group led by nurses had significant improvement in self-care adherence, patient satisfaction post-intervention than those from the control group led by doctors. However, there were no statistical significant differences in blood pressure readings, quality of life and self-efficacy between the two groups. The findings show that the nurse-led hypertension management appears to be a promising way to manage hypertensive patients at the community level, particularly when the healthcare system is better integrated. PMID- 25550955 TI - Reduced-intensity and myeloablative conditioning allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome: a meta-analysis and systematic review. AB - BACKGROUND: We performed a systematic review and meta-analysis to compare the clinical outcomes and toxicity of reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). EVIDENCE ACQUISITION: A comprehensive PubMed and Embase search was performed using the following keywords: "reduced-intensity", "myeloablative", "AML", and "MDS". The primary endpoints were overall survival (OS) and event-free survival (EFS), and the secondary endpoints were relapse incidence (RI), non-relapse mortality (NRM), grade II-IV acute graft-versus-host disease (aGVHD), and chronic GVHD (cGVHD). RESULTS: Eight studies (2 prospective and 6 retrospective) involving 6464 patients who received RIC (n = 1571) or MAC (n = 4893) alloHSCT were included in the analysis. Median age and the number of patients with low hematopoietic cell transplantation-specific comorbidity index scores and who received ex vivo or in vivo T cell depletion were higher in the RIC arm than in the MAC arm. Significant heterogeneity was not found among the studies for any of the endpoints except for grade II-IV aGVHD. OS (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.84-1.08; p = 0.47) and EFS (OR, 0.88; 95% CI, 0.77-1.00; p = 0.05) were similar in the RIC and MAC arms, whereas RI (OR, 1.41; 95% CI, 1.24-1.59; p < 0.00001) was higher in the RIC arm than in the MAC arm. The incidence of grade II-IV aGVHD (OR, 0.59; 95% CI, 0.36-0.96; p = 0.03) was lower in the RIC arm than in the MAC arm; however, NRM (OR, 0.99; 95% CI, 0.87-1.13; p = 0.85), total cGVHD (OR, 1.10; 95% CI, 0.88-1.38; p = 0.38), and extensive cGVHD (OR, 1.01; 95% CI, 0.75-1.37; p = 0.95) were not significantly different between the two arms. CONCLUSION: RIC alloHSCT may be an effective treatment strategy for AML/MDS patients who are not suitable candidates for MAC alloHSCT. However, heterogeneity in baseline patient characteristics and treatment protocols may have influenced the outcomes of RIC alloHSCT in our analysis. Future randomized controlled trials are needed to confirm our findings. PMID- 25550957 TI - Acetazolamide pre-treatment before ascending to high altitudes: when to start? AB - Hypoxia is the main responsible factor initiating the symptoms of acute mountain sickness (AMS) in susceptible individuals. Measures that improve oxygenation and/or hasten acclimatization like pre-treatment with acetazolamide will prevent the development of AMS. We hypothesized that pre-treatment with acetazolamide the day before arrival at high altitude would elicit improved oxygenation compared to placebo not until the second day of high-altitude exposure. Fifteen study participants were randomly assigned in a double blind fashion to receive placebo or acetazolamide (2 * 125 mg) before (10 hours and 1 hour) exposure to high altitude (Monte Rosa plateau, 3480 m). Beside AMS scoring, heart rate, minute ventilation, and blood gas analyses were performed during rest and submaximal exercise at low altitude and on day 1, 2 and 3 at high altitude. From low altitude to day 1 at high altitude changes of pH (7.41 +/- 0.01 vs. 7.48 +/- 0.04) and HCO3 (24.0 +/- 0.46 vs. 24.6 +/- 2.6 mmol/L) within the placebo group differed significantly from those within the acetazolamide group (7.41 +/- 0.01 vs. 7.41 +/- 0.02; 23.6 +/- 0.38 vs. 20.7 +/- 1.8 mmol/L) (P < 0.05). AMS incidence tended to be lower with acetazolamide (P < 0.1). From low altitude to day 2 at high altitude changes of paO2 within the placebo group (75.3 +/- 5.4 vs. 40.5 +/- 3.4 mmHg) differed significantly from those within the acetazolamide group (76.5 +/- 4.5 vs. 48.2 +/- 4.9 mmHg) (P < 0.05). In conclusion, pre treatment with low-dose acetazolamide on the day before ascending to high altitude tended to reduce AMS incidence on the first day at high altitude but improved oxygen availability to tissues not until the second day of exposure. Therefore, it is suggested that the beginning of pre-treatment with low-dose acetazolamide at least two days before arrival at high altitude, in contrast to usual recommendations, would be of greater beneficial effect on AMS development. PMID- 25550958 TI - Effects of electroacupuncture preconditioning on jugular vein glucose level and cerebral edema in rats undergoing cerebral ischemia reperfusion that induced injury. AB - OBJECTIVE: To determine the effects of electroacupuncture (EA) preconditioning on the blood glucose level in jugular vein and water content in brain tissues in rats undergoing cerebral ischemia reperfusion that induced injury. METHODS: 90 healthy male Wister rats were randomly assigned to 3 groups: sham-operation (SH) group, cerebral ischemia reperfusion (IR) group and electroacupuncture (EA) preconditioning plus IR group. EA group was pretreated with EA delivered to acupoints of "Baihui" (Du 20) and "Shuigou" (Du 26) 30 min before cerebral ischemia. RESULTS: No marked difference was observed in brain water content 2 h after procedure in IR group, SH group and EA group. Compared with SH group, the brain water contents in IR group and EA group were significantly higher 6 h after reperfusion and peaked at 48 h (P < 0.01). The blood glucose levels in EA and IR groups were significantly higher than that of SH group 2 h after reperfusion, which peaked at 6 h and tended to decline up to 24 h after reperfusion (P < 0.01). 2 h, 6 h, and 24 h after reperfusion, EA group had significantly lower blood glucose levels than IR group (P < 0.01). CONCLUSION: Electroacupuncture preconditioning can significantly inhibit the augmentation of the blood glucose level and attenuate cerebral edema induced by reperfusion, which leads to alleviation of injury caused by ischemia reperfusion. PMID- 25550960 TI - Association between polymorphisms in the integrin gene predicted microRNA binding sites and bladder cancer risk. AB - Bladder cancer (BC) is the ninth most frequent malignancies in the world and the occurrence of this disease has dramatically increased in recent years. Integrins have been demonstrated to play an important role in the development and progression of BC. However, the association between polymorphisms in integrin genes and BC susceptibility was still unclear. A number of studies mainly focused on polymorphisms in the coding regions of integrin genes previously, while in this study, polymorphisms in the 3' untranslated regions (3'UTR) were investigated in Chinese Han population. According to previous study, seven single nucleotide polymorphisms (SNPs) in predicted microRNA (miRNA) target sites were chosen as potential targets. And four SNPs including rs11902171, rs2675, rs17664, and rs1062484, were finally examined for their effect on BC risk and clinical prognosis. These four polymorphisms were genotyped by using the high-resolution melting method (HRM) in 317 BC patients with long-time follow-up together with 317 age-matched healthy controls. AC carriers of rs2675 in ITGB5 were associated with an increased risk of BC (OR 1.44, 95% CI 1.02-2.03). No significant relationship was detected between these SNPs and the recurrence-free survival time of overall study population or non-muscle invasive BC subgroups in univariable analysis. In conclusion, rs2675 in miRNA binding sites of ITGB5 might be a potential target for BC susceptibility prediction. PMID- 25550959 TI - Replication of association of nine susceptibility loci with Graves' disease in the Chinese Han population. AB - This study is to evaluate the association of 9 single nucleotide polymorphisms (SNPs) with Graves' disease (GD) in different homogenous samples of the Chinese Han population. A total of 2,865 unrelated individuals were enrolled from Linyi City, Shandong Province, China, including 1,139 patients of GD and 1,726 controls. All 9 SNPs showed significant associations with GD (P < 1.3*10(-4), Bonferroni corrected Pc < 0.001). The most significant association was detected at rs2281388 at the HLA-DPB1 locus (P=1.3*10(-21); OR=1.62, 95% CI: 1.47-1.79). After adjusting for gender and age, 7 SNPs remained significantly associated with GD (P < 3.4*10(-4), Pc < 0.003). The risk of GD caused by any of these SNPs was not significantly different between female and male participants (Phet > 0.15). Four SNPs located in MHC regions were significantly associated with GD in different ages (P < 8.4*10(-4), Pc < 0.04). The risks of any SNP leading to the development of GD did not differ significantly in different ages (P_trend > 0.02, Pc > 0.18). The rs6457617 at the HLA-DR-DQ locus was significantly correlated with gender in GD patients (P=0.004, Pc =0.04). No significant correlation was found between any SNP and age of diagnosis in GD patients (P > 0.02, Pc > 0.17). The 9 previously identified SNPs are associated with GD in the Chinese Han population. And, gender and age may not influence the associations between the 9 SNPs and GD. PMID- 25550961 TI - Characterization of phenylalanine hydroxylase gene mutations in phenylketonuria in Xinjiang of China. AB - To investigate the spectrum and frequency of phenylalanine hydroxylase (PAH) gene mutations in phenylketonuria (PKU) patients in Xinjiang, China. Polymerase chain reaction (PCR), in combination with single-strand conformation polymorphism (SSCP) and DNA sequencing analyses were performed, to screen potential mutations in the PAH gene in 46 individual PKU patients. Direct DNA sequencing was used to analyze the all of the exons in the PAH gene, including the promoter and flanking intron regions, in another 15 PKU patients. Our results indicated that, 30 different mutation types were identified in all 122 PAH alleles, with the mutation detection rate of 78.7% (96/122). Four novel mutations, i.e., 5' Flanking -626G>A, 5'-Flanking -480DelACT, S196fsX4, and IVS8+1G>C, were identified for the first time. Similar to other regions in North China, R243Q, EX6-96A>G, IVS4-1A>G, R111X, and Y356X were the most prevalent PAH mutations in PKU patients from Xinjiang. Additionally, common mutations showed different frequencies in Xinjiang, when compared to other areas. Furthermore, sixteen different PAH gene mutation types were identified for the first time in the minorities in Xinjiang. Distinctive mutation spectrum of PAH gene in PKU patients from Xinjiang were characterized, which may promote the construction of PAH gene mutation database and serve as valuable tools for genetic diagnosis and counseling, and prognostic evaluation for PKU cases in the local area. PMID- 25550962 TI - Comparison of tomographic and colonoscopic diagnoses in the presence of colonic wall thickening. AB - INTRODUCTION AND OBJECTIVE: Colonic wall thickening is a common condition in a number of benignant and malignant diseases. This study investigated the accuracy of radiological diagnoses in patients diagnosed with colonic wall thickening using multislice CT (MDCT). MATERIALS AND METHOD: Files of patients with colonic wall thickening diagnosed with 64-slice MDCT were reviewed retrospectively. The colonoscopy results of these patients were grouped under neoplastic process (cancer and adenomatous polyp), inflammatory bowel disease (IBD), diverticulitis and other etiology (nonspecific events, ischemic colitis, solitary rectal ulcer, external compression, secondary to volvulus and radiotherapy), and the results were statistically evaluated. p values < 0.05 were considered statistically significant. RESULTS: The study was performed on 505 files (290 males [57.4%], 215 females [42.6%], mean age: 49.15 +/- 18.4 years). CT and colonoscopic diagnoses were reviewed and the following CT to colonoscopy ratios was observed: neoplastic process: 44.4% vs. 40.2%; IBD: 42.4% vs. 42.4%; diverticulitis: 4% vs. 4.2%; other etiology: 9.3% vs. 3.2%. Colonoscopy failed to identify pathology in 9.9% of the patients. The sensitivity, specificity, PPV, NPV and accuracy of CT were 95.6%, 90.4%, 87.1%, 96.8% and 92.4%, respectively, in detecting neoplastic processes; 97.2%, 97.9%, 97.2%, 97.9% and 97.6%, respectively, in detecting IBD; 90.5%, 99.8%, 95%, 99.6% and 99.4%, respectively, in detecting diverticulitis, and 50%, 96,7%, 62.5%, 94.6% and 92%, respectively, in detecting other etiology. CONCLUSION: While, accuracy of 64 slice-CT in diagnosing colonic wall thickenings secondary especially to neoplastic processes, IBD and diverticulitis was significantly higher, but differential diagnosis is challenging in pathologies due to other etiologies. PMID- 25550963 TI - Prevalence and risk factors of anxiety status among students aged 13-26 years. AB - Previous study revealed that 8%-12% adolescents suffered from various types of anxiety disorders, and which had interfered with adolescent daily life function and affected adolescent social function. The aim of this study was to evaluate anxiety status and its related factors among students aged 13-26 years from Wuhu, China. This was a cross-sectional observational study. A sample of school students who come from a university, four high schools and four middle schools in Wuhu city were recruited, Self-Rating Anxiety Scale (SAS) was used to measure the anxiety status among students aged 13-26 years, and some demographic characteristics of students also was determined. A total of 5249 students were included in our study. The overall rate of anxiety status among students was 14.1%. A significant difference was observed between anxiety status and sex, mothers education level, dietary and siesta habit (P < 0.05), only-child family, gentle temper, regular breakfast habit, friend support was associated with lower scores on anxiety status. The findings indicated that anxiety status is common among school students. Preventive and treatment strategies are highly recommended. PMID- 25550964 TI - Association of endothelial lipase genetic polymorphism with lacunar infarction in a Chinese population. AB - INTRODUCTION: This study sought to investigate the correlation between the single nucleotide polymorphism (SNP) rs9958947C>T in the endothelial lipase (LIPG) gene promoter and lacunar infarction in the Han population in China. MATERIALS AND METHODS: A case-control method was applied in this study, which included 378 patients with lacunar infarction in the patient group and 404 healthy individuals who received a routine physical examination in the control group. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to detect the SNP (rs9958947) in the LIPG promoter for the two groups. RESULTS: The T allele frequency (51.32%) and CT+TT genotype frequency (77.78%) in the patient group were significantly higher than those in the control group (43.32% and 66.34%, respectively). Comparison of the T allele frequency and CT+TT genotype frequency between the two groups showed statistically significant differences. Logistic regression analysis showed that the T allele, male, smoking, hypertension, hyperlipidemia and diabetes were independent risk factors for lacunar infarction in the Han population in China. CONCLUSION: Therefore, we concluded that SNP rs9958947 in the LIPG gene promoter is associated with the incidence of lacunar infarction. PMID- 25550965 TI - A functional single-nucleotide polymorphism in interleukin-6 promoter is associated with p wave dispersion in hypertensive subjects with atrial fibrillation. AB - Inflammation has been shown to be implicated in the pathophysiology of atrial fibrillation (AF). Interleukin-6 (IL-6) is a pleiotropic cytokine, functions as a mediator of inflammatory response and has both pro-inflammatory and anti inflammatory properties. Little is known about genetic factors of inflammation in the accompanying atrial electrical remodeling expressed by P wave dispersion (Pdisp). The aim of the present study is to evaluate the association of -634C/G polymorphism of IL-6 gene with Pdisp in Han Chinese hypertensive patients with AF. A total of 100 patients with essential hypertension (EH) were eligible for this study. Patients with paroxysmal AF (n=50) were allocated to the AF group, and 50 subjects without AF to the control group. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-6 -634C/G genotypes (CC, CG, and GG) was 68.00%, 28.00%, and 4.00% in the controls, and 44.00%, 40.00%, and 16.00% in AF subjects, respectively (P=0.0269). The frequency of the G allele in the AF group was significantly higher than that in the control group (36.00% vs 18.00%, P=0.0041). Compared to the wild type CC, the G allele carriers (CG + GG genotypes) had a 2.7045-fold increased risk of AF (odds ratio =2.7045, 95% confidence interval =1.1966-6.1126, P=0.0156). AF patients with the CG + GG genotype had longer Pdisp (P=0.0032) than did patients with the CC genotype. The longer Pdisp in the subjects with the CG + GG genotype was also found in the control group (P=0.0016). These findings support that IL-6 -634C/G polymorphism is associated with Pdisp and AF, suggesting an active implication of inflammation in the atrial electrophysiological remodeling predisposing to AF. PMID- 25550966 TI - Long-term impact of earthquake stress on fasting glucose control and diabetes prevalence among Chinese adults of Tangshan. AB - OBJECTIVE: To investigate the long-term influence of stresses from the 1976 Tangshan earthquake on blood glucose control and the incidence of diabetes mellitus in Chinese people of Tangshan. METHODS: 1,551 adults >= 37 years of age were recruited for this investigation in Tangshan city of China, where one of the deadliest earthquakes occurred in 1796. All subjects finished a questionnaire. 1,030 of them who experienced that earthquake were selected into the exposure group, while 521 were gathered as the control group who have not exposed to any earthquake. The numbers of subjects who were first identified with diabetes or had normal FBG but with diabetic history were added for the calculation of diabetes prevalence. Statistic-analysis was applied on the baseline data, and incidences of IFG as well as diabetes among all groups. RESULTS: Statistic comparisons indicate there is no significant difference on average fasting glucose levels between the control group and the exposure group. However, the prevalence of IFG and diabetes among the exposure group displays significant variance with the control group. The prevalence of diabetes among exposure groups is significantly higher than the control group. Women are more likely to have diabetes after experiencing earthquake stresses compared to men. The earthquake stress was linked to higher diabetes incidence as an independent factor. CONCLUSIONS: The earthquake stress has long-term impacts on diabetes incidence as an independent risk factor. Emerging and long-term managements regarding the care of IFG and diabetes in populations exposed to earthquake stress should be concerned. PMID- 25550967 TI - Association between the dietary factors and metabolic syndrome with chronic kidney disease in Chinese adults. AB - OBJECTIVE: The aim of study was to examine the relationship between the dietary nutrition and the prevalence and risk of renal damage in patients with metabolic syndrome. METHODS: 260 patients with metabolic syndrome and chronic renal disease meeting criterion were recruited in this cross-sectional study. Metabolic syndrome was defined according to NCEP-ATPIII guidelines. Food-frequency questionnaire was performed to collect the information on dietary nutrition. Anthropometric measurements, including body weight, height and waist circumference were collected. Blood pressure, triglyceride, cholesterol, high density lipoprotein-cholesterol and fasting plasma glucose, renal function and 24 hour urine protein were measured. The correlations between GFR and actual nutrient intakes of participants were examined. RESULTS: The actual intakes of energy, carbohydrates, protein, fat and cholesterol in participate were all significantly higher than recommended nutrient intakes/adequate intakes of Chinese Dietary Reference Intakes. GFR was significantly inversely correlated with energy, protein intake, cholesterol intake, carbohydrates intake, sodium intake, calcium intake and actual protein/energy ratio. Logistic regression analyses showed that actual protein intakes/recommended protein intakes (APIs/RPIs) were significant independent predictors of GFR < 60 ml/min*1.73 m(2). CONCLUSIONS: Dietary nutrition is closely correlated with kidney damage in patients with metabolic syndrome. High protein intakes may be one of the risk factors of renal damage. PMID- 25550968 TI - Correlation research on ADMA plasma levels and left ventricular function of peritoneal dialysis patients. AB - Asymmetric dimethylarginine (ADMA) has been involved in the development mechanism of cardiovascular disease (CVD) in patients with chronic kidney disease. The aim of this study is to investigate the relationship between the plasma ADMA levels and echocardiography, and understand the relationship between ADMA and left ventricular function. All of the patients were divided into three groups, including End-stage renal disease patients on CAPD, Conservative treatment in patients with ESRD and Control group. All the cases in the outpatient clinic or hospital at the next morning were collected fasting venous blood 2 ml. All cases were detected by American GE company Vivid7 Colour Doppler Ultrasonic Echocardiograph to detected left ventricular end-diastolic dimension (LVEDD), Left atrial diameter (LAD), Left ventricular posterior wall thickness in diastole (LVPWT), Interventricular septum thickness in diastole (IVST), left ventricular ejection fraction (LVEF). There were significant differences among all of the three groups for the GFR, urine albumin, SGA, Hb, iPTH and ALB levels. There was statistically significant difference for serum ADMA levels among three groups (F = 34.047, P = 0.000). CAPD patient plasma ADMA levels were negatively correlated with LVEF, and positively correlated with LVMI, LVM, LVEDD, LAD. Conservative treatment group had higher proportion of average artery, left ventricular hypertrophy and left ventricular mass index. The peritoneal dialysis fluid ADMA levels of CAPD patients with peritoneal were positively correlated with LVEF (r = 0.367, P = 0.046), negatively correlated with LVMI. In conclusion, ADMA may be involved in change of left ventricular structure, function, and remodeling process through a complex network. PMID- 25550969 TI - Effects of cigarette smoke on aerobic capacity and serum MDA content and SOD activity of animal. AB - OBJECTIVE: Study the effects of cigarette smoke on aerobic capacity, serum MDA content and SOD activity of animal. METHODS: 60 male mice are randomly divided into mild smoking group, heavy smoking group, and control group, and the exhausted swimming time, serum SOD activity and MDA content of the three groups of mice are respectively measured before and after the experiment. RESULTS: After the experiment, the exhausted swimming time for the control group, mild smoking and heavy smoking groups is respectively 276.57 min, 215.57 min and 176.54 min, and the serum SOD activities for the three objects are 216.46 U/mL, 169.16 U/mL and 154.91 U/mL, and the MDA contents are respectively 16.41 mol/mL, 22.31 mol/mL and 23.55 mol/mL. According to the comparison, it is found that compared with the control group and pre-intervention, the exhausted swimming time and serum SOD activity of the smoking group decreases obviously, and its MDA content rises sharply, and the difference has significance (P < 0.05), moreover, the heavy smoking group has more obvious changes than the mild group. CONCLUSION: Cigarette smoke can significantly weaken the aerobic capacity and fatigue resistance of mice, and the more the smoking time is longer, the more the harmful effect is more serious, this is related to the SOD activity drops and MDA content rises due to smoking. PMID- 25550970 TI - Association study of polymorphism of FXIIIVal34Leu gene and polycystic ovary syndrome. AB - OBJECTIVE: To study the distribution of polymorphism of FXIIIVal34Leu gene in patients with polycystic ovary syndrome and to explore its relationship with polycystic ovary syndrome. METHODS: FXIIIVal34Leu genotype of 120 patients with polycystic ovary syndrome (PCOS) and 90 controls was detected, and the endocrine and metabolic conditions of PCOS patients and the control group were analyzed. RESULTS: Body mass index (BMI) of PCOS patients (26.45+/-5.81) kg/m(2) was higher than the control group (22.33+/-5.58) kg/m(2), (p=0.00); the androgen level of PCOS group was (0.67+/-0.85) ng/mL higher than the control group (0.42+/-0.22) ng/mL, (p=0.02), and the luteinizing hormone (LH) (16.8+/-3.61 IU/L) level is higher than the control group (9.23+/-4.67) IU/L, (p=0.01). Frequency of Val34Leu allele in PCOS group was 1.25%, which was not statistically significant compared to the control group (P=0.56). BMI of patients with the genotype of FXIIIVal34Leu was relatively higher (with the average 34+/-1 kg/m(2)), and serum HDL level was significantly lower (0.23+/-0.11 mmol/L). Polymorphism of FXIIIVal34Leu gene had no correlation with susceptibility of PCOS. CONCLUSION: Polymorphism of FXIIIA1 gene may be related to metabolism of PCOS patients; the mutation of FXIIIAVal34Leu is not at the common site for PCOS; polymorphism of FXIIIVal34Leu gene may not have correlation with PCOS. PMID- 25550971 TI - Day surgery management model in china: practical experience and initial evaluation. AB - OBJECTIVES: Day surgery has been increasingly performed in some major teaching hospitals in China. We aimed to evaluate the current day surgery management model (DSMM) and compare the clinical outcome and health service utility of day surgery with inpatient surgery. METHODS: We reviewed 14482 day surgery cases under the DSMM and 2591 inpatient surgery cases under the non-DSMM between September 2006 and September 2012 in Shanghai East Hospital. The endpoints of interest were hospitalization days, incision infection rate and hospital cost. RESULTS: Among 14482 day surgery cases, only 52 (0.4%) were converted to hospitalization. The average hospitalization time of the patients was 2-10 hours. None of them had incision infection. Hospital cost of DSMM was less than 50% of non-DSMM (inpatient surgery). The most common postoperative complications were nausea, vomiting and dizziness. Nearly half of patients had mild to moderate pain after surgery. CONCLUSIONS: DSMM optimizes the utilization of healthcare resources by reducing hospital admission, hospital cost and incision infection in China. PMID- 25550972 TI - Patch clamp apply in cardiomyocytes derived from patient's iPS cells for individual anticancer therapy. AB - Cardiac side-effects of chemotherapy are old dogs for cancer patient at the beginning of cancer treatment. The deleterious side-effects of chemotherapy on the cardiovascular system have been deemed as a serious clinical issue for a long term, especially sudden cardiac death (SCD) due to QT prolongation. Since induced pluripotent stem cells has been firstly reported by Takahashi and Yamanaka in 2006, iPS has become a valuable research tool. Especially, cardiomyocytes have been successfully derived from human iPS cells which carry on corresponding genetic information of disease, and therefore show a great promise in drug screen on the diseasing model. In this study, we hypothesized that iPS cells created from patient with cancer and carried corresponding genetic alteration will provide a genetic background for sensitivity screening of anticancer drug, as well as side-effects of cardiovascular system. PMID- 25550973 TI - Comparison of open reduction internal fixation and conservative treatment plus open reduction internal fixation for calcaneal fractures. AB - To compare the effect of open reduction internal fixation and conservative treatment combined with open reduction internal fixation for subjects with calcaneal fractures, 130 patients with calcaneal fractures were divided into observation group and control group. Observation group were treated with open reduction internal fixation and conservative treatment, control group treated as open reduction internal fixation. The healing related indicators, daily life activities ability score of observation group after treatment 6 months were significantly higher than that of the control group, there was no significant difference for the healing rate of excellent and good rate, the daily life activities ability score after one and three year between two groups. Open reduction internal fixation combined with conservative treatment in treatment of calcaneal fractures can clear anatomic structure and have fast function recovery. Thus, it should be as the preferred method for the treatment of calcaneal fractures. PMID- 25550974 TI - Role of PET/CT in the diagnosis, staging, and follow-up of a nasal-type natural killer T-cell lymphoma in the larynx: a case report and literature review. AB - BACKGROUND: Nasal-type natural killer T-cell lymphoma involving the larynx is uncommon. Our search revealed only 12 cases reported previously in the English language literature. CASE REPORT: We report a case of laryngeal NKTCL. In December 2011, the patient was diagnosed with nasal-type NKTCL and FDG PET/CT showed the lesions were confined to the nasal cavity (stage I). At 1 year after radiotherapy, the patient presented with hoarseness and FDG PET/CT revealed high FDG uptake in the subglottic region and left cervical lymph nodes. A biopsy of the subglottis confirmed NKTCL (stage II). He then received chemotherapy and 14 months after the completion of chemotherapy, FDG PET/CT showed no evidence of recurrence or metastasis. CONCLUSIONS: PET/CT has better sensitivity than other conventional methods and may play an important role in the diagnosis, staging, and follow-up of nasal-type natural killer T-cell lymphoma. PMID- 25550975 TI - Diffuse alveolar hemorrhage after erlotinib combined with concurrent chemoradiotherapy in a patient with esophageal carcinoma. AB - Diffuse alveolar hemorrhage (DAH) is a life-threatening clinical pathologic syndrome caused by a variety of diseases. We report a case of DAH related to combination therapy of chemoradiotherapy and erlotinib. As to know, DAH following chemoradiotherapy was only reported among hematopoietic stem cell transplant recipients with hematologic malignancies till now. DAH associated with chemoradiotherapy for oesophageal carcinoma has not been reported. This is the first DAH report on erlotinib-combined chemoradiotherapy for esophageal cancer. The authors believe epidermal growth factor receptor tyrosine kinase inhibitor erlotinib increased the lung injury. Molecular targeted drugs are gradually applied to be combined with chemoradiation, whether this combination will cause the increase of serious adverse reactions need further study. This case can provide certain reference for erlotinib in the treatment. Meanwhile, after long term hormone therapy for DAH, the patient was diagnosed with pneumocystis carinii pneumonia. It reminds us to attach importance to the immunosuppressive diseases after long-term hormone treatment. PMID- 25550976 TI - Jejunogastric intussusception: a rare complication of gastric cancer surgery. AB - Jejunogastric intussusception (JGI) is a rare condition and less than 200 cases have been published since its first description in 1914. In addition, JGI is potentially lethal complication of gastrectomy or gastrojejunostomy. We report the case of a 73-year-old man with a history of a Billroth II procedure who presented to the emergency department after 6 hours of epigastric pain and hematemesis. Endoscopy and computed tomography showed intussuscepted jejunum through a gastrojejunostomy that required emergency operation. At laparotomy a retrograde type II, JGI was confirmed and managed by resection of involved intestine. Postoperative recovery was uneventful. This case presents the rare complication of acute jejunogastric intussusception more than 25 years after a Billroth II procedure. PMID- 25550977 TI - Two-staged stent-assisted angioplasty treatment strategy for severe left main coronary distal bifurcation stenosis associated with the right coronary chronic total occlusion. AB - A 63-year-old female patient, with history of 8-year hypertension and 10-year hyperlipidemia, presented with severe left main coronary bifurcation stenosis (LMCS) associated with the right coronary artery chronic total occlusion (CTO RCA). On the day of admission, she received drug treatment with aspirin, clopidogrel, heparin, statins, angiotensin converting enzyme inhibitors and beta blocker. On the next day, she underwent CTO recanalization with 6F guiding catheter and two rapamycin-eluting stents, and showed no postoperative discomfort after interventional treatment. Considering having hypertensive nephropathy and chronic renal insufficiency, the patient then received intravenous saline full hydration therapy. Two weeks after successful completion of the RCA revascularization, the original collateral circulation in the blood flow from the LMC to RCA became two-way flow. Under the safe and reliable protective condition, staged percutaneous coronary intervention (PCI) with 6F XB3.0 guiding catheter and rapamycin-eluting stents was applied to treat the LMCL. 9-month postoperative follow-up with coronary computed tomographic imaging showed no restenosis inside the original stent, without any myocardial ischemic event. Our successful approach to turn the original unprotected LMCS combined with CTO-RCA into a protective one reduces the interventional risk and provides additional option besides coronary artery bypass graft surgery to treat such complex coronary artery disease (CAD). PMID- 25550978 TI - Three cases giant panda attack on human at Beijing Zoo. AB - Panda is regarded as Chinese national treasure. Most people always thought they were cute and just ate bamboo and had never imagined a panda could be vicious. Giant panda attacks on human are rare. There, we present three cases of giant panda attacks on humans at the Panda House at Beijing Zoo from September 2006 to June 2009 to warn people of the giant panda's potentially dangerous behavior. PMID- 25550979 TI - Primary malignant melanoma of the esophagus with subtotal esophagectomy: a case report. AB - Primary malignant melanoma of the esophagus (PMME) is a rare disease, comprising 0.1-0.2% of all malignant esophageal neoplasms. The most common symptoms include progressive dysphagia, chest and back pain, choking feeling and weight loss. PMME cannot be definitely diagnosed from clinical symptoms or CT examination, but can be confirmed by histological examination or a pathological examination. Immunohistochemical examination with positive results of S-100 protein and human melanoma black 45 (HMB45) makes a definitive diagnosis. Esophagectomy is the standard treatment for localized PMME. But the prognosis is poor. Inoperableness, metastases and insensitiveness of radiotherapy and chemotherapy in advanced tumors have led to poor prognosis. Here, we report a case of a 61-year-old male with progressive dysphagia for 1 month. After barium X-ray test, chest and abdomen computed tomography examination, upper gastrointestinal endoscopy and biopsy, the patient accepted esophagectomy, then the pathologic and immunohistochemical examination conformed the diagnosis of PMME. PMID- 25550980 TI - Recurrent abdominal pain and fever as clinical manifestations: epiploic appendagitis. AB - Epiploic appendagitis is a relatively rare disease which includes primary and secondary types. Typical manifestations of Primary Epiploic Appendagitis (PEA) are similar to appendicitis except that it is not usually accompanied with fever or leucocytosis, thus misdiagnosis of diverticulitis or appendicitis in clinical settings is common. In this study, we presented a case study of a patient diagnosed with PEA and recurrent abdominal pain and fever for four months The patient experienced persistent dull abdominal pain since four months age and after tolerating a recent episode of pain for two days, and developed a fewer of up to 39 degrees C accompanied with chills. Clinical analysis and computed tomography (CT) were conducted to better understand PEA. PMID- 25550981 TI - A case report of huge perirenal liposarcoma associated with renal cell carcinoma and reviews of three previous cases. AB - Retroperitoneal liposarcoma (RPLS) is a rare malignant tumor yet with a high recurrence rate. It is mostly observed in limbs and during retroperitoneal clearance, and accounts for nearly 40% of all adult retroperitoneal soft tissue sarcomas [1]. Renal cell carcinoma (RCC) is a common cancer developed in urinary system and its occurrence rate accounts for 3% of whole body malignant tumors [2]. In this report, we present a case of large perirenal liposarcoma associated with RCC, which is to date the fourth identified case. We analyzed the clinical pathologic data of this patient and reviewed the other three cases. Compared to the other cases, this patient is diagnosed at the youngest age and the liposarcoma tumor is with the largest diameter. Moreover, we have been following up the patient after operation for the longest time. All of these made this report rare and important. PMID- 25550982 TI - Gallstone ectopia in the lungs: case report and literature review. AB - Gallstone ectopia in the lungs is relatively rare, which accounts for its frequent misdiagnosis. This paper reports a case found in a suspicious lung cancer surgery. The patient received intrahepatic duct stone removal surgery and partial hepatectomy five months prior to the report. He started showing symptoms of cough and hemoptysis without any apparent cause one month before this report. Enhanced computed tomography showed a solid mass in the lower lobe of the right lung, which was considered as hamartoma or lung cancer. A wedge-shaped excision was then performed in the lower lobe of the right lung. After the surgery, postoperative findings and pathological examination results showed gallstone ectopia in the lung. This case reminds us that gallstones that overflow into the intraperitoneal section can enter the thoracic cavity through diaphragmatic weakness and travel to the lung, thus forming an inflammatory mass. The case also reminds us of the following points in clinical diagnosis: 1) remove gallstones to the greatest extent during cholelithiasis surgery to prevent the stones from migrating from the intraperitoneal area, which causes intraperitoneal and thoracic cavity complications; 2) conduct routine chest imaging examination after cholelithiasis surgery during the clinical follow-up period to facilitate early detection and timely treatment of intrathoracic complications; 3) inquire whether the patients suffering from a solid mass of the lower lobe of right lung, have cholelithiasis history to facilitate clinical diagnosis and avoid misdiagnosis, mistreatment, and treatment delay. PMID- 25550983 TI - Emergency treatment of esophageal varix incarceration in the endoscope and ligation device during endoscopic variceal rubber band ligation. AB - Sclerotherapy and endoscopic esophageal variceal ligation (EVL) are commonly used to treat and prevent variceal bleeding. As of today, there has been no report on an unexpected incarceration of a varix hooked on with the bands from the endoscopic EVL device. We recently experienced this emergency while using the 7 band ring endoscopic EVL device (Boston Scientific Corp., Boston, MA) for prophylaxis of variceal bleeding. In this case, the varix body itself was accidently incarcerated in the crevice of the esophageal endoscope after highly negative pressure of absorption was applied on the endoscope. In this situation, using force to take out the gastroscope was not an option as it would tear the vein and cause massive hemorrhage. We were managed to ligate the varix with rubber bands while releasing the incarceration. We observed that ligation of the varix at the same position using all seven ligation bands resulted in disappearance of the targeted varix. The surrounding esophageal mucosa became smooth after the treatment. PMID- 25550984 TI - Small bowel volvulus in mid and late pregnancy: can early diagnosis be established to avoid catastrophic outcomes? AB - Volvulus in pregnancy is rare and difficult to diagnose. Delayed diagnosis would result in high maternal and fetal mortality. Here we present an unusual case of small bowel volvulus in late pregnancy timely managed by emergency Cesarean section and derotation with excellent maternal and fetal outcomes. Volvulus should be considered in patients complaining ongoing abdominal pain, nausea, vomiting, constipation even diarrhea. Imaging is essential for early and precise diagnosis, including plain abdominal film, MRI and/or ultrasound. Once highly suspected or diagnosed of volvulus or ileus, emergency laparotomy should be performed immediately to avoid catastrophic outcomes, because the maternal and fetal prognosis is dependent on the interval from volvulus to operation apart from the degree of volvulus. PMID- 25550985 TI - Association between plasma homocysteine status and hypothyroidism: a meta analysis. AB - PURPOSE: To figure out plasma homocysteine (Hcy) status in patients with subclinical hypothyroidism (SH) and overt hypothyroidism (OH) compared with healthy subjects, and the effect of levothyroxine (L-T4) on plasma homocysteine status in patients with hypothyroidism. METHODS: PubMed Web of Science, and The Cochrane Library were used to identify eligible studies. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of selected studies. All analyses were performed using the STATA, version 12 software. RESULTS: Our meta analysis indicated that plasma Hcy concentrations elevated in OH patients without L-T4 treatment compared with healthy subjects. However, this elevation was not observed in the comparison between patients withSH without L-T4 treatment and healthy subjects. Moreover, plasma Hcy levels were found to be higher in patients with OH without L-T4 treatment than in patients with SH without L-T4 treatment. Finally, plasma Hcy concentrations decreased after L-T4 treatment in patients with SH or OH. CONCLUSIONS: Plasma Hcy status is associated with the severity of hypothyroidism and L-T4 treatment is helpful for patients with hypothyroidism to reduce the plasma Hcy levels. PMID- 25550986 TI - Application of 4G wireless network-based system for remote diagnosis and nursing of stomal complications. AB - BACKGROUND: This study aims to apply 4G wireless network in the remote diagnosis of stoma complications for the first time. BACKGROUND: Remote diagnosis and nursing care for a variety of illnesses are urgently needed in clinical settings. OBJECTIVES: Combining with relevant clinical manifestations, an Android phone based intelligent diagnosis system was designed to construct a universe, easy access to exploitation and human-computer interaction database and exploitation environment for applications and programs. METHODS: "Production rule" and forward reasoning method were utilized to design arborescence structures and logic reasoner associated with stoma complications. Stoma physicians were responsible for delivering evaluation scores on patients' health status using analytic hierarchy process. The emphasis of this study is to exploit an "Android phone based system for remote diagnosis of stoma", which is of certain universe usage. RESULTS: Such system was tested in the Medicine Information Center of Qilu Hospital of Shandong University and initially applied in the city of De Zhou, Shandong province, China. CONCLUSIONS: These results collectively demonstrated that the system is easy to carry, of high utility and free from the limitations of wire network environment, etc. It provides clinical evidence for establishing a novel type model for the exchange between patients and physicians. PMID- 25550987 TI - Selective antegrade cerebral perfusion reduces brain injury following deep hypothermic circulatory arrest in the piglets' model by decreasing the levels of protein SUMO2/3-ylation. AB - Selective antegrade cerebral perfusion (SACP), which was adopted by many surgical groups for complex neonatal cardiac surgery, especially aortic arch repair, is a proven adjunct for neuroprotection during deep hypothermic circulatory arrest (DHCA). Several recent studies suggest that SUMO2/3 modification of proteins is markedly activated during deep hypothermia and believed to be an endogenous neuroprotective stress response. Here, we report that SACP reduces the increasing degree of SUMO2/3 conjugation following DHCA. Piglets were subjected to 1 h SACP and/or 1 h DHCA. DHCA was sufficient to markedly increase in protein SUMOylation by SUMO2/3 both in the hippocampus and cerebral cortex. SACP, especially at flow rate of 50 ml/kg/min, reduces the increasing degree of SUMO2/3 conjugation and also reduces levels of pro-apoptotic factors, Bax and Caspase 3, and increases levels of antiapoptotic factors, Bcl-2, following DHCA both in the hippocampus and cerebral cortex. This suggests that SACP at flow rate of 50 ml/kg/min is more appropriate for neuroprotection during DHCA in the pig model and level of protein SUMO2/3-ylation maybe an indicator of the degree of brain injury. PMID- 25550988 TI - mir-155 regulates cardiac allograft rejection by targing the expression of suppressor of cytokine signaling-1 (DOCS1) in dendritic cells. AB - Previously, we observed that mir-155 is induced during dendritic cell (DC) differentiation. We now demon-strated convincing evidence indicating that mir-155 promotes DC maturation and regulates its capacity for antigen presentation and induction of alloreactive T cell activation. Interestingly, the induction of miR 155 expression in DCs is dependent on the TLR4/Myd88/NF-kappaB signaling. Our mechanistic studies further revealed that SOCS1 is a direct target for mir-155, and by binding to its 3'UTR, mir-155 is likely to affect SOCS1 translation. Suppression of mir-155 expression in DCs significantly attenuated LPS-induced DC maturation along with reduced capability to stimulate allogeneic T cell proliferation. As a result, administration of antagomiR-155 provided protection for cardiac allografts from rejection. Together, our data support that suppression of miR-155 in DCs could be a viable therapeutic strategy for prevention and treatment of allograft rejection in clinical setting of transplantation. PMID- 25550989 TI - Effects of nerve growth factor on nerve regeneration after corneal nerve damage. AB - The study aims to determine the relation between the effects of mouse nerve growth factor (mNGF) and nerve regeneration after corneal surgery nerve damage. Mechanical nerve injury animal model was established by LASIK (the excimer laser keratomileusis) surgery in 12 Belgian rabbits. mNGF and the balanced salt solution (BBS) were alternatively administered in the left and right eye two times every day for 8 weeks. The morphous and growth of the sub-basal nerve plexus and superficial stroma were observed by in vivo confocal microscopy at the end of weeks 1, 2, 4 and 8 after the surgery. The animal model is successfully established. The morphology and density of corneal nerve have been observed and demonstrated by confocal microscopy. A systematic administration of mNGF can significantly promote the nerve regeneration at the end of weeks 1, 2, 4 and 8, which comparing to the administration of balanced salt solution (P < 0.05). mNGF has effect on sub-basal nerve plexus and superficial stroma after corneal nerve damage which is caused by LASIK. The experimental results suggested that the mNGF may solve the problem of dry eye after LASIK. PMID- 25550990 TI - Expression of brain adiponectin in a murine model of transient cerebral ischemia. AB - OBJECTIVE: Adiponectin is a hormone that is mainly secreted by fat cells. Adiponectin has anti-inflammatory and anti-atherosclerotic effects, and a protective effect against ischemic brain injury, but the level of expression of adiponectin in brain tissue is unknown. In the current study, a mouse model of transient cerebral ischemia was used to determine the level of expression of adiponectin in ischemic brain tissue. METHODS: Sixty CD-1 mice underwent transient middle cerebral artery occlusion. The level of expression of adiponectin in mouse brain tissues 1 hour, 4 hours, 1 day, 3 days, and 7 days, after cerebral ischemia/reperfusion injury were determined using a real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: The level of expression of adiponectin in mouse ischemic brain tissues increased after cerebral ischemia/reperfusion injury and was higher in the central area of ischemia than in the peripheral area. The level of expression of adiponectin occurred only in vascular endothelial cells. There was no significant change in the level of expression of adiponectin mRNA in brain tissue pre- and post-ischemia/reperfusion injury. CONCLUSION: After cerebral ischemia/reperfusion injury, adiponectin accumulated in the vascular endothelial cells of ischemic brain tissues, and non-endogenous adiponectin was generated. Circulating adiponectin accumulated in ischemic brain tissues through its role in adhering to damaged vascular endothelial cells. PMID- 25550991 TI - A security evaluation of the Rigid-fix crosses pin system used for anterior cruciate ligament reconstruction in tibial fixation site. AB - Our study aims to evaluate the safeness and feasibility that Rigid-fix cross pin system was used for hamstring graft anterior cruciate ligament (ACL) reconstruction in the tibial fixation site. In this study, eleven adult conservative cadaver knees were performed using the Rigid-fix Cross Pin device in the tibial fixation site for modeling the ACL reconstruction. The guide rod top was put through the tibial tunnel at the three horizontal positions: equal pace to articular facet (group A), the plane 5 mm below articular facet (group B), and the plane 10 mm below articular facet (group C). We gave four rotation positions to the cross-pin guide: 0 degrees , 30 degrees , 45 degrees , 60 degrees slope, referring to the parallel line of the posterior border of tibial plateau. We recorded the iatrogenic damages incidence, in the four different slope angle in the three groups, and then compare the incidence using Chi-Square test. Our results suggested that the incidence of chondral injury of tibial plateau in group B and group C was significantly lower compared to group A (chi (2) A-B = 27.077, chi (2) A-C 45.517, P = 0.000); However, there was no significant difference for the incidence penetrating the medial condyle of tibial plateau among the three groups (chi (2) = 5.733, P = 0.057); The highest incidence of injuring ligamentum transversum is in group A with 72.7%, especially at the 60 degrees slope angle. In summary, our study suggested that in order to achieve the satisfactory clinical effect for the Rigid-fix system used in the tibia end fixation of ACL reconstruction surgery, the guide rod top should be put at the 5 mm below articular facet with a slope that parallel to the tibial medial plane at 30 degrees -60 degrees slope angle. PMID- 25550992 TI - Ordered Carboxylates on TiO2(110) Formed at Aqueous Interfaces. AB - As models for probing the interactions between TiO2 surfaces and the dye molecules employed in dye-sensitized solar cells, carboxylic acids are an important class of molecules. In this work, we present a scanning tunneling microscopy (STM) and low-energy electron diffraction (LEED) study of three small carboxylic acids (formic, acetic, and benzoic) that were reacted with the TiO2(110) surface via a dipping procedure. The three molecules display quite different adsorption behavior, illustrating the different interadsorbate interactions that can occur. After exposure to a 10 mM solution, formic acid forms a rather disordered formate overlayer with two distinct binding geometries. Acetic acid forms a well-ordered (2 * 1) acetate overlayer similar to that observed following deposition from vapor. Benzoic acid forms a (2 * 2) overlayer, which is stabilized by intermolecular interactions between the phenyl groups. PMID- 25550993 TI - Postoperative reactive lymphadenitis: A potential cause of false-positive FDG PET/CT. AB - A wide variety of surgical related uptake has been reported on F18-fluoro-2-deoxy D-glucose positron emission tomography/computed tomography (FDG PET/CT) scan, most of which can be differentiated from neoplastic process based on the pattern of FDG uptake and/or anatomic appearance on the integrated CT in image interpretation. A more potential problem we may be aware is postoperative reactive lymphadenitis, which may mimic regional nodal metastases on FDG PET/CT. This review presents five case examples demonstrating that postoperative reactive lymphadenitis could be a false-positive source for regional nodal metastasis on FDG PET/CT. Surgical oncologists and radiologists should be aware of reactive lymphadenitis in interpreting postoperative restaging FDG PET/CT scan when FDG avid lymphadenopathy is only seen in the lymphatic draining location from surgical site. PMID- 25550995 TI - Improvement of distension and mural visualization of bowel loops using neutral oral contrasts in abdominal computed tomography. AB - AIM: To assess and compare the image quality of 4% sorbitol and diluted iodine 2% (positive oral contrast agent) in abdomino-pelvic multi-detector computed tomography. METHODS: Two-hundred patients, referred to the Radiology Department of a central educational hospital for multi-detector row abdominal-pelvic computed tomography, were randomly divided into two groups: the first group received 1500 mL of 4% sorbitol solution as a neutral contrast agent, while in the second group 1500 mL of meglumin solution as a positive contrast agent was administered in a one-way randomized prospective study. The results were independently reviewed by two radiologists. Luminal distension and mural thickness and mucosal enhancement were compared between the two groups. Statistical analysis of the results was performed by Statistical Package for the Social Sciences software version 16 and the Mann-Whitney test at a confidence level of 95%. RESULTS: Use of neutral oral contrast agent significantly improved visualization of the small bowel wall thickness and mural appearance in comparison with administration of positive contrast agent (P < 0.01). In patients who received sorbitol, the small bowel showed better distention compared with those who received iodine solution as a positive contrast agent (P < 0.05). CONCLUSION: The results of the study demonstrated that oral administration of sorbitol solution allows better luminal distention and visualization of mural features than iodine solution as a positive contrast agent. PMID- 25550996 TI - Can outer-to-outer diameter be used alone in diagnosing appendicitis on 128-slice MDCT? AB - AIM: To assess the frequency of visualization, position and diameter of normal appendix on 128-slice multidetector computed tomography (MDCT) in adult population. METHODS: Retrospective cross sectional study conducted at Radiology Department, Dallah Hospital, Riyadh, Saudi Arabia from March 2013 to October 2013. Non-enhanced computed tomography scans of abdomen and pelvis of 98 patients presenting with hematuria (not associated with abdominal pain, fever or colonic disease) were reviewed by two radiologists, blinded to patient history. The study group included 55 females and 43 males with overall mean age of 54.7 years (range 21 to 94 years). The coronal reformatted images were reviewed in addition to the axial images. The frequency of visualization of appendix was recorded with assessment of position, diameter and luminal contents. RESULTS: The appendix was recorded as definitely visualized in 99% of patients and mean outer-to-outer diameter of the appendix was 5.6 +/- 1.3 mm (range 3.0-11.0 mm). CONCLUSION: MDCT with its multiplanar reformation display is extremely useful for visualization of normal appendix. The normal appendix is very variable in its position and diameter. In the absence of other signs, the diagnosis of acute appendix should not be made solely on outer-to-outer appendiceal diameter. PMID- 25550994 TI - Functional topography of the corpus callosum investigated by DTI and fMRI. AB - This short review examines the most recent functional studies of the topographic organization of the human corpus callosum, the main interhemispheric commissure. After a brief description of its anatomy, development, microstructure, and function, it examines and discusses the latest findings obtained using diffusion tensor imaging (DTI) and tractography (DTT) and functional magnetic resonance imaging (fMRI), three recently developed imaging techniques that have significantly expanded and refined our knowledge of the commissure. While DTI and DTT have been providing insights into its microstructure, integrity and level of myelination, fMRI has been the key technique in documenting the activation of white matter fibers, particularly in the corpus callosum. By combining DTT and fMRI it has been possible to describe the trajectory of the callosal fibers interconnecting the primary olfactory, gustatory, motor, somatic sensory, auditory and visual cortices at sites where the activation elicited by peripheral stimulation was detected by fMRI. These studies have demonstrated the presence of callosal fiber tracts that cross the commissure at the level of the genu, body, and splenium, at sites showing fMRI activation. Altogether such findings lend further support to the notion that the corpus callosum displays a functional topographic organization that can be explored with fMRI. PMID- 25550997 TI - Ovarian thecal metaplasia of the adrenal gland in association with Beckwith Wiedemann syndrome. AB - Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with increased risk to develop malignancies including adrenocortical carcinoma. Ovarian thecal metaplasia of the adrenal gland is a rare tumor-like mesenchymal lesion in BWS patients that lacks detailed radiological description. We report a 17-year-old female patient with BWS, associated with bilateral Wilms tumor, hepatic hemangiomatosis, pancreatic neuroendocrine tumor, and a phyllodes tumor of the right breast. Surveillance abdominal ultrasound identified a right adrenal mass that was further characterized by computed tomography and magnetic resonance imaging. Radiologically, this mass displayed features that overlap with adrenocortical carcinoma and pheochromocytoma but after pathological examination this proved to be an ovarian thecal metaplasia of the adrenal gland. Adrenal masses in BWS should raise the suspicion for adrenocortical carcinoma though other adrenal tumors including ovarian thecal metaplasia can be seen in these patients. PMID- 25550998 TI - Traumatic carotid-rosenthal fistula treated with Jostent Graftmaster. AB - Traumatic injuries of the carotid artery may result in severe morbidity and mortality. The most common location of carotid artery injury is the cavernous segment, which may result in fistulous connection to the cavernous sinus and ophthalmic veins, which in turn lead to pressure symptoms in the ipsilateral orbit. Unlike the commonly reported direct traumatic carotid-cavernous fistula, we describe an unusual case of a 38-year-old man presented with a traumatic brain injury led to a fistula connection between the cavernous carotid artery and the ipsilateral basal vein of Rosenthal, with eventual drainage to the straight and transverse sinuses. The basal vein of Rosenthal is usually formed from confluence of anterior and middle cerebral veins deep in the Sylvian fissure and drain the insular cortex and the cerebral peduncles to the vein of Galen. Immediate endovascular deployment of a covered stent in the cavernous carotid artery allowed sealing the laceration site. Three months follow up showed a non-focal neurological examination and healed carotid laceration over the covered stent. PMID- 25550999 TI - Tuberculous osteomyelitis/arthritis of the first costo-clavicular joint and sternum. AB - A young Somali immigrant presents with a two-year history of a large, firm, painful right anterolateral chest wall sternal mass. The patient denied any history of trauma or infection at the site and did not have a fever, erythematous lesion at the site, clubbing, or lymphadenopathy. A lateral chest radiograph demonstrated a low density mass isolated to the subcutaneous soft tissue overlying the sternum, ribs and clavicle. Computed tomography (CT) with contrast demonstrated a cystic lesion in the right anterolateral chest wall deep to the pectoralis muscle. Enhanced CT of the chest demonstrated sclerosis and destruction of the rib and costochondral joint and manubrio-sternal joint narrowing. Ultrasound-guided biopsy and aspiration returned 500 cc of purulent, cloudy yellow, foul-smelling fluid. Acid-fact bacilli stain and the nucleic acid amplification test identified and confirmed Mycobacterium tuberculosis. A diagnosis of tuberculous osteomyelitis/septic arthritis was made and antibiotic coverage for tuberculosis was initiated. PMID- 25551000 TI - Focal fatty change in the liver that developed after cholecystectomy. AB - Focal fatty change of the segment IV of the liver has been attributed to local systemic venous inflow replacing the portal venous supply, which could develop or be accentuated after gastrectomy. However, focal fatty change due to aberrant pancreaticoduodenal vein that developed after cholecystectomy has never been reported. We report a 30-year-old man with such a rare lesion, which was initially misdiagnosed as a hepatocellular carcinoma, but was confirmed on computed tomography during selective gastroduodenal arteriography. The lesion disappeared 12 mo later without any intervention. PMID- 25551001 TI - The effect of repeated firings on the color change of dental ceramics using different glazing methods. AB - PURPOSE: Surface color is one of the main criteria to obtain an ideal esthetic. Many factors such as the type of the material, surface specifications, number of firings, firing temperature and thickness of the porcelain are all important to provide an unchanged surface color in dental ceramics. The aim of this study was to evaluate the color changes in dental ceramics according to the material type and glazing methods, during the multiple firings. MATERIALS AND METHODS: Three different types of dental ceramics (IPS Classical metal ceramic, Empress Esthetic and Empress 2 ceramics) were used in the study. Porcelains were evaluated under five main groups according to glaze and natural glaze methods. Color changes (DeltaE) and changes in color parameters (DeltaL, Deltaa, Deltab) were determined using colorimeter during the control, the first, third, fifth, and seventh firings. The statistical analysis of the results was performed using ANOVA and Tukey test. RESULTS: The color changes which occurred upon material-method-firing interaction were statistically significant (P<.05). DeltaE, DeltaL, Deltaa and Deltab values also demonstrated a negative trend. The MC-G group was less affected in terms of color changes compared to other groups. In all-ceramic specimens, the surface color was significantly affected by multiple firings. CONCLUSION: Firing detrimentally affected the structure of the porcelain surface and hence caused fading of the color and prominence of yellow and red characters. Compressible all-ceramics were remarkably affected by repeated firings due to their crystalline structure. PMID- 25551002 TI - Shear bond strength of a new self-adhering flowable composite resin for lithium disilicate-reinforced CAD/CAM ceramic material. AB - PURPOSE: The purpose of this study was to evaluate and compare the effects of different surface pretreatment techniques on the surface roughness and shear bond strength of a new self-adhering flowable composite resin for use with lithium disilicate-reinforced CAD/CAM ceramic material. MATERIALS AND METHODS: A total of one hundred thirty lithium disilicate CAD/CAM ceramic plates with dimensions of 6 mm * 4 mm and 3 mm thick were prepared. Specimens were then assigned into five groups (n=26) as follows: untreated control, coating with 30 um silica oxide particles (CojetTM Sand), 9.6% hydrofluoric acid etching, Er:YAG laser irradiation, and grinding with a high-speed fine diamond bur. A self-adhering flowable composite resin (Vertise Flow) was applied onto the pre-treated ceramic plates using the Ultradent shear bond Teflon mold system. Surface roughness was measured by atomic force microscopy. Shear bond strength test were performed using a universal testing machine at a crosshead speed of 1 mm/min. Surface roughness data were analyzed by one-way ANOVA and the Tukey HSD tests. Shear bond strength test values were analyzed by Kruskal-Wallis and Mann-Whitney U tests at alpha=.05. RESULTS: Hydrofluoric acid etching and grinding with high-speed fine diamond bur produced significantly higher surface roughness than the other pretreatment groups (P<.05). Hydrofluoric acid etching and silica coating yielded the highest shear bond strength values (P<.001). CONCLUSION: Self-adhering flowable composite resin used as repair composite resin exhibited very low bond strength irrespective of the surface pretreatments used. PMID- 25551003 TI - Effect of anatomic, semi-anatomic and non-anatomic occlusal surface tooth preparations on the adaptation of zirconia copings. AB - PURPOSE: To compare the accuracy of marginal and internal adaptation of zirconia (Zr) copings fabricated on anatomic (A), semi-anatomic (SA) and non-anatomic (NA) occlusal surface preparations. MATERIALS AND METHODS: 45 extracted bicuspid teeth were prepared for receiving zirconia crowns, with different occlusal preparation designs A=15, SA=15 & NA=15. The Zr copings were fabricated by using CAD4DENT, CAD/CAM. The copings were adjusted, cemented and were cross sectioned centrally from buccal cusp tip to lingual cusp tip into mesial and distal halves. The copings were examined under electron microscope at *200 magnification and the measurements were recorded at 9 predetermined areas in micrometers. RESULTS: Overall mean gap values for the three groups was found to be 155.93+/-33.98 um with Anatomical Occlusal preparation design having the least gap value of 139.23+/-30.85 um showing the best adaptation among the groups. Post Hoc Tukey's test showed a statistically significant difference (P=.007) between the means of gap for A & NA preparation designs. Measurements recorded at 9 predetermined points showed variations for the three groups. CONCLUSION: Anatomical occlusal preparation designs resulted in better marginal and internal adaptation of Zr copings. There is a considerable variation between the measured marginal and internal gap values for the Zr copings fabricated by the (CAD4DENT-CAD/CAM). This variation may be associated with the lack of standardization of the preparation of teeth, computerized designing of the coping for each tooth, cement used, uniform pressure application during the cementation of the copings, sectioning of the copings and the microscopic measurements. PMID- 25551004 TI - Effects of coloring procedures on zirconia/veneer ceramics bond strength. AB - PURPOSE: The most common failure seen in restorations with a zirconia core is total or layered delamination of the ceramic veneer. In the present study, the shear bond strengths between veneering ceramics and colored zirconia oxide core materials were evaluated. MATERIALS AND METHODS: Zirconia discs (15 * 12 * 1.6 mm) were divided into 11 groups of 12 discs each. Groups were colored according to the Vita Classic scale: A3, B1, C4, D2, and D4. Each group was treated with the recommended shading time for 3 s, or with prolonged shading for 60 s, except for the control group. Samples were veneered with 3 mm thick and 3.5 mm in diameter translucent ceramic and subjected to shear test in a universal testing machine with a crosshead speed of 1 mm/min. One-way analysis of variance (ANOVA) and Tukey's HSD tests were used for comparisons of the groups having the same shading times. A paired t-test was used for groups of the same color (3 s/60 s). RESULTS: Among the 11 groups investigated C4 (3 s) had the highest bond strength with a value of 36.40 MPa, while A3 (3 s) showed the lowest bond strength with a value of 29.47 MPa. CONCLUSION: Coloring procedures can affect zirconia/ceramic bond strength. However, the results also showed that bond strengths of all the investigated groups were clinically acceptable. PMID- 25551005 TI - Comparative analysis of transmittance for different types of commercially available zirconia and lithium disilicate materials. AB - PURPOSE: Translucency and colour stability are two most important aspects for an aesthetic dental restoration. Glass ceramic restorations are popular amongst clinicians because of their superior aesthetic properties. In the last decade, zirconia has generated tremendous interest due to its favorable mechanical and biological properties. However, zirconia lacks the translucency that lithium disilicate materials possess and therefore has limitations in its use, especially in esthetically demanding situations. There has been a great thrust in research towards developing translucent zirconia materials for dental restorations. The objective of the study was to evaluate and compare the transmittance of a translucent variant of zirconia to lithium disilicate. MATERIALS AND METHODS: Two commercially available zirconia materials (conventional and high translucency) and 2 lithium disilicate materials (conventional and high translucency) with standardized dimensions were fabricated. Transmittance values were measured for all samples followed by a microstructural analysis using a finite element scanning electron microscope. One way analysis of variance combined with a Tukey post hoc test was used to analyze the data obtained (P=.05). RESULTS: High translucency lithium disilicate showed highest transmittance of all materials studied, followed by conventional lithium disilicate, high translucency zirconia and conventional zirconia. The difference between all groups of materials was statistically significant. The transmittance of the different materials correlated to their microstructure analysis. CONCLUSION: Despite manufacturers' efforts to make zirconia significantly more translucent, the transmittance values of these materials still do not match conventional lithium disilicate. More research is required on zirconia towards making the material more translucent for its potential use as esthetic monolithic restoration. PMID- 25551006 TI - Mechanical properties of zirconia after different surface treatments and repeated firings. AB - PURPOSE: This study investigated the influence of surface conditioning procedures and repeated firings on monoclinic content and strength of zirconia before cementation. MATERIALS AND METHODS: Sintered bar-shaped zirconia specimens were subjected to no surface treatment (control), air abrasion, or grinding (n=21). Their roughness was evaluated using a profilometer, and microscope analysis was performed on one specimen of each group. Then, 2 or 10 repeated firings (n=10) were executed, the monoclinic content of specimens was analyzed by X-ray diffraction, and a three-point flexural strength test was performed. Surface roughness values were compared using one-way analysis of variance (ANOVA) and Tukey honestly significant difference (HSD) tests, the monoclinic content values were tested using Kruskal-Wallis and Mann-Whitney U tests, and the flexural strength values were tested using two-way ANOVA and Tukey HSD tests (P=.05). Spearman's correlation test was performed to define relationships among measured parameters. RESULTS: Surface-treated specimens were rougher than untreated specimens and had a higher monoclinic content (P<.005), and the relationship between roughness and monoclinic content was significant (P<.000). Neither surface treatment nor firing significantly affected the flexural strength, but Weibull analysis showed that for the air-abraded samples the characteristic strength was significantly lower after the 10(th) firing than after the 2(nd) firing. CONCLUSION: After firing, a negligible amount of monoclinic content remained on the zirconia surfaces, and rougher surfaces had higher monoclinic contents than untreated surfaces. Multiple firings could be performed if necessary, but the fracture probability could increase after multiple firings for rougher surfaces. PMID- 25551007 TI - Accuracy of 3D white light scanning of abutment teeth impressions: evaluation of trueness and precision. AB - PURPOSE: This study aimed to evaluate the accuracy of digitizing dental impressions of abutment teeth using a white light scanner and to compare the findings among teeth types. MATERIALS AND METHODS: To assess precision, impressions of the canine, premolar, and molar prepared to receive all-ceramic crowns were repeatedly scanned to obtain five sets of 3-D data (STL files). Point clouds were compared and error sizes were measured (n=10 per type). Next, to evaluate trueness, impressions of teeth were rotated by 10 degrees -20 degrees and scanned. The obtained data were compared with the first set of data for precision assessment, and the error sizes were measured (n=5 per type). The Kruskal-Wallis test was performed to evaluate precision and trueness among three teeth types, and post-hoc comparisons were performed using the Mann-Whitney U test with Bonferroni correction (alpha=.05). RESULTS: Precision discrepancies for the canine, premolar, and molar were 3.7 um, 3.2 um, and 7.3 um, respectively, indicating the poorest precision for the molar (P<.001). Trueness discrepancies for teeth types were 6.2 um, 11.2 um, and 21.8 um, respectively, indicating the poorest trueness for the molar (P=.007). CONCLUSION: In respect to accuracy the molar showed the largest discrepancies compared with the canine and premolar. Digitizing of dental impressions of abutment teeth using a white light scanner was assessed to be a highly accurate method and provided discrepancy values in a clinically acceptable range. Further study is needed to improve digitizing performance of white light scanning in axial wall. PMID- 25551008 TI - Influence of gag reflex on removable prosthetic restoration tolerance according to the patient section of the short form of the Gagging Problem Assessment Questionnaire. AB - PURPOSE: To assess removable prosthetic restoration tolerance according to the patient section of the short form of the Gagging Problem Assessment Questionnaire (GPA-pa SF) and the influence of gender, education level and prosthesis type and denture-related mucosal irritation on the GPA-pa SF scores before treatment and over a period of two months after prosthesis insertion. MATERIALS AND METHODS: 130 participants who required removable prosthesis were surveyed with a standard form that included questions regarding age, gender, education level, dental attendance, and prosthetic restoration type. Participants answered the GPA-pa SF before restoration (T0) and 1 day (T1), 2 days (T2), 15 days (T3), 1 month (T4), and 2 months (T5) after prosthesis insertion. RESULTS: Of the 130 participants, 110 participants completed the prosthetic restoration procedure, but only 93 of these were able to use the prosthesis over the two-month period. The mean GPA-pa SF score obtained at T0 was higher than the scores obtained at the other periods in the total of the sample. Significant difference was present between mean scores obtained at T0-T1 and T2-T3 than scores obtained at other periods (P<.05). Female participants and participants with denture-related mucosal irritation had higher GPA-pa SF scores at all time points analysed. Significant difference was present between mean GPA-pa SF scores obtained at T2-T3 than scores obtained at other periods for females and participants with denture-related mucosal irritation (P<.05). Education level and prosthesis type did not significantly influence the GPA-pa SF score at any time point analysed (P>.05). CONCLUSION: GPA pa SF scores were higher before the restoration procedure began, and decreased over time with the use of prosthesis. Gender and denture-related mucosal irritation affected the GPA-pa SF scores. PMID- 25551009 TI - Faculty-supervised measurements of the face and of mandibular movements on young adults. AB - PURPOSE: The purpose of this study was to determine the average facial proportions and mandibular movement capacity of 316 first-year dental students who carefully recorded them on each other. MATERIALS AND METHODS: This early exacting clinical experience was closely supervised by the authors in Columbus, Ohio during 1969-70. Five vertical and six horizontal distances were measured on each subject's face. An ala-tragus line and an occlusal line were drawn on the left side of the face to determine if these two lines were parallel. Measurements of mandibular movements involved maximum normal and hinge opening at the incisors and maximum amounts of right, left lateral and protrusive excursions of the mandible. RESULTS: The ala width and distance between the tips of upper right and left canine cusps averaged (35.2 mm and 34.8 mm) but with very large individual variations. The distance between ala to occlusal plane lines was 29.9 mm at the tragus and 31.3 mm near the ala. The angle between orbitale and ala-tragus averaged 13.6 degrees. CONCLUSION: The upper lip length was the most variable and the distance between the pupils was the most stable of the eleven facial measurements. The ala-tragus line and the occlusal plane lines were for all practical purposes parallel. Maximum jaw opening averaged 51.2 mm which was 3.0 times larger than maximal hinge opening of 17.2 mm. The maximum right plus left side jaw excursions (9.2 and 9.4 mm) totaled 18.6 mm, 2.3 times more than the 8.0 mm mean maximum forward protrusion. PMID- 25551010 TI - Influence of abutment materials on the implant-abutment joint stability in internal conical connection type implant systems. AB - PURPOSE: This study evaluated the influence of abutment materials on the stability of the implant-abutment joint in internal conical connection type implant systems. MATERIALS AND METHODS: Internal conical connection type implants, cement-retained abutments, and tungsten carbide-coated abutment screws were used. The abutments were fabricated with commercially pure grade 3 titanium (group T3), commercially pure grade 4 titanium (group T4), or Ti-6Al-4V (group TA) (n=5, each). In order to assess the amount of settlement after abutment fixation, a 30-Ncm tightening torque was applied, then the change in length before and after tightening the abutment screw was measured, and the preload exerted was recorded. The compressive bending strength was measured under the ISO14801 conditions. In order to determine whether there were significant changes in settlement, preload, and compressive bending strength before and after abutment fixation depending on abutment materials, one-way ANOVA and Tukey's HSD post-hoc test was performed. RESULTS: Group TA exhibited the smallest mean change in the combined length of the implant and abutment before and after fixation, and no difference was observed between groups T3 and T4 (P>.05). Group TA exhibited the highest preload and compressive bending strength values, followed by T4, then T3 (P<.001). CONCLUSION: The abutment material can influence the stability of the interface in internal conical connection type implant systems. The strength of the abutment material was inversely correlated with settlement, and positively correlated with compressive bending strength. Preload was inversely proportional to the frictional coefficient of the abutment material. PMID- 25551011 TI - The influence of systemically administered oxytocin on the implant-bone interface area: an experimental study in the rabbit. AB - PURPOSE: The purpose of this study was to assess the effect of systemically administered oxytocin (OT) on the implant-bone interface by using histomorphometric analysis and the removal torque test. MATERIALS AND METHODS: A total of 10 adult, New Zealand white, female rabbits were used in this experiment. We placed 2 implants (CSM; CSM Implant, Daegu, South Korea) in each distal femoral metaphysis on both the right and left sides; the implants on both sides were placed 10 mm apart. In each rabbit, 1 implant was prepared for histomorphometric analysis and the other 3 were prepared for the removal torque test (RT). The animals received intramuscular injections of either saline (control group; 0.15 M NaCl) or OT (experimental group; 200 ug/rabbit). The injections were initiated on Day 3 following the implant surgery and were continued for 4 subsequent weeks; the injections were administered twice per day (at a 12-h interval), for 2 days per week. RESULTS: While no statistically significant difference was observed between the two groups (P=.787), the control group had stronger removal torque values. The serum OT concentration (ELISA value) was higher in the OT-treated group, although no statistically significant difference was found. Further, the histomorphometric parameter (bone-toimplant contact [BIC], inter-thread bone, and peri-implant bone) values were higher in the experimental group, but the differences were not significant. CONCLUSION: We postulate that OT supplementation via intramuscular injection weakly contributes to the bone response at the implant-bone interface in rabbits. Therefore, higher concentrations or more frequent administration of OT may be required for a greater bone response to the implant. Further studies analyzing these aspects are needed. PMID- 25551012 TI - Osteoblastic behavior to zirconium coating on Ti-6Al-4V alloy. AB - PURPOSE: The purpose of this study was to assess the surface characteristics and the biocompatibility of zirconium (Zr) coating on Ti-6Al-4V alloy surface by radio frequency (RF) magnetron sputtering method. MATERIALS AND METHODS: The zirconium films were developed on Ti-6Al-4V discs using RF magnetron sputtering method. Surface profile, surface composition, surface roughness and surface energy were evaluated. Electrochemical test was performed to evaluate the corrosion behavior. Cell proliferation, alkaline phosphatase (ALP) activity and gene expression of mineralized matrix markers were measured. RESULTS: SEM and EDS analysis showed that zirconium deposition was performed successfully on Ti-6Al-4V alloy substrate. Ti-6Al-4V group and Zr-coating group showed no significant difference in surface roughness (P>.05). Surface energy was significantly higher in Zr-coating group than in Ti-6Al-4V group (P<.05). No difference in cell morphology was observed between Ti-6Al-4V group and Zr-coating group. Cell proliferation was higher in Zr-coating group than Ti-6Al-4V group at 1, 3 and 5 days (P<.05). Zr-coating group showed higher ALP activity level than Ti-6Al-4V group (P<.05). The mRNA expressions of bone sialoprotein (BSP) and osteocalcin (OCN) on Zr-coating group increased approximately 1.2-fold and 2.1-fold respectively, compared to that of Ti-6Al-4V group. CONCLUSION: These results suggest that zirconium coating on Ti-6Al-4V alloy could enhance the early osteoblast responses. This property could make non-toxic metal coatings on Ti-6Al 4V alloy suitable for orthopedic and dental implants. PMID- 25551013 TI - Alveolar ridge preservation of an extraction socket using autogenous tooth bone graft material for implant site development: prospective case series. AB - This case series evaluated the clinical efficacy of autogenous tooth bone graft material (AutoBT) in alveolar ridge preservation of an extraction socket. Thirteen patients who received extraction socket graft using AutoBT followed by delayed implant placements from Nov. 2008 to Aug. 2010 were evaluated. A total of fifteen implants were placed. The primary and secondary stability of the placed implants were an average of 58 ISQ and 77.9 ISQ, respectively. The average amount of crestal bone loss around the implant was 0.05 mm during an average of 22.5 months (from 12 to 34 months) of functional loading. Newly formed tissues were evident from the 3-month specimen. Within the limitations of this case, autogenous tooth bone graft material can be a favorable bone substitute for extraction socket graft due to its good bone remodeling and osteoconductivity. PMID- 25551014 TI - A prospective study on the effectiveness of newly developed autogenous tooth bone graft material for sinus bone graft procedure. AB - PURPOSE: The purpose of this prospective study was to evaluate the effectiveness of newly developed autogenous tooth bone graft material (AutoBT)application for sinus bone graft procedure. MATERIALS AND METHODS: The patients with less than 5.0 mm of residual bone height in maxillary posterior area were enrolled. For the sinus bone graft procedure, Bio-Oss was grafted in control group and AutoBT powder was grafted in experimental group. Clinical and radiographic examination were done for the comparison of grafted materials in sinus cavity between groups. At 4 months after sinus bone graft procedure, biopsy specimens were analyzed by microcomputed tomography and histomorphometric examination for the evaluation of healing state of bone graft site. RESULTS: In CT evaluation, there was no difference in bone density, bone height and sinus membrane thickness between groups. In microCT analysis, there was no difference in total bone volume, new bone volume, bone mineral density of new bone between groups. There was significant difference trabecular thickness (0.07 um in Bio-Oss group Vs. 0.08 um in AutoBT group) (P=.006). In histomorphometric analysis, there was no difference in new bone formation, residual graft material, bone marrow space between groups. There was significant difference osteoid thickness (8.35 um in Bio-Oss group Vs. 13.12 um in AutoBT group) (P=.025). CONCLUSION: AutoBT could be considered a viable alternative to the autogenous bone or other bone graft materials in sinus bone graft procedure. PMID- 25551015 TI - Comparable efficacy of silk fibroin with the collagen membranes for guided bone regeneration in rat calvarial defects. AB - PURPOSE: Silk fibroin (SF) is a new degradable barrier membrane for guided bone regeneration (GBR) that can reduce the risk of pathogen transmission and the high costs associated with the use of collagen membranes. This study compared the efficacy of SF membranes on GBR with collagen membranes (Bio-Gide(r)) using a rat calvarial defect model. MATERIALS AND METHODS: Thirty-six male Sprague Dawley rats with two 5 mm-sized circular defects in the calvarial bone were prepared (n=72). The study groups were divided into a control group (no membrane) and two experimental groups (SF membrane and Bio-Gide(r)). Each group of 24 samples was subdivided at 2, 4, and 8 weeks after implantation. New bone formation was evaluated using microcomputerized tomography and histological examination. RESULTS: Bone regeneration was observed in the SF and Bio-Gide(r)-treated groups to a greater extent than in the control group (mean volume of new bone was 5.49 +/- 1.48 mm(3) at 8 weeks). There were different patterns of bone regeneration between the SF membrane and the Bio-Gide(r) samples. However, the absolute volume of new bone in the SF membrane-treated group was not significantly different from that in the collagen membrane-treated group at 8 weeks (8.75 +/- 0.80 vs. 8.47 +/ 0.75 mm(3), respectively, P=.592). CONCLUSION: SF membranes successfully enhanced comparable volumes of bone regeneration in calvarial bone defects compared with collagen membranes. Considering the lower cost and lesser risk of infectious transmission from animal tissue, SF membranes are a viable alternative to collagen membranes for GBR. PMID- 25551017 TI - Editors' Pick: Contamination has always been the issue! PMID- 25551016 TI - The influence of thread geometry on implant osseointegration under immediate loading: a literature review. AB - Implant success is achieved by the synergistic combination of numerous biomechanical factors. This report examines the mechanical aspect of implants. In particular, it is focused on macrodesign such as thread shape, pitch, width and depth, and crestal module of implants. This study reviews the literature regarding the effect of implant thread geometry on primary stability and osseointegration under immediate loading. The search strategy included both in vitro and in vivo studies published in the MEDLINE database from January 2000 to June 2014. Various geometrical parameters are analyzed to evaluate their significance for optimal stress distribution, implant surface area, and bone remodeling responses during the process of osseointegration. PMID- 25551018 TI - A case of multiple myeloma in a poultry worker. AB - BACKGROUND: Livestock breeders including poultry workers are exposed to various agricultural chemicals including pesticides and/or organic solvents. Multiple myeloma is a rare disease in Korea, and few reports have investigated the influence of occupational exposures on multiple myeloma occurrence. CASE PRESENTATION: A 61-year-old male poultry farm worker presented with bone pain and generalized weakness. A bone marrow biopsy was performed, and he was diagnosed with multiple myeloma. The patient had worked in a poultry farm for 16 years and was exposed to various pesticides and organic solvents such as formaldehyde without any proper personal protective equipment. Results of the work reenactment revealed that the concentration of formaldehyde (17.53 ppm) greatly exceeded the time-weighted average (0.5 ppm) and short-term exposure limit (1.0 ppm) suggested in the Korean Industrial Safety and Health Act. CONCLUSIONS: This case report suggests that poultry workers may be exposed to high levels of various hazardous chemicals including pesticides and/or organic solvents. Numerous previous studies have suggested an association between multiple myeloma and exposure to agricultural chemicals; thus, multiple myeloma in this patient might have resulted from the prolonged, high exposure to these chemicals. PMID- 25551019 TI - The association between shift work and hyperuricemia in steelmaking male workers. AB - OBJECTIVES: The aim of this study was to examine the association between shift work and hyperuricemia among steel company workers. METHODS: We examined 1,029 male workers at a Korean steel company between June 6 and June 28, 2013. We conducted anthropometric measurements, questionnaire surveys, and blood tests. Hyperuricemia was defined as a serum uric acid concentration of >=7.0 mg/dL. Logistic regression analyses were performed. In the full model, analysis was adjusted for covariates including age, body mass index, lifestyle factors, and comorbidities. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all models. RESULTS: The participants included 276 daytime workers and 753 shift workers. Among daytime workers, 72 (26.1%) individuals had hyperuricemia, as did 282 (37.5%) individuals among shift workers (p <0.001). There was a statistically significant association between shift work and hyperuricemia. In the unadjusted model, the OR of shift work was 1.70 (95% CI 1.25-2.31) for hyperuricemia. In the full model, the OR of shift work was also statistically significant after adjustment for covariates (OR 1.41, 95% CI 1.02 1.96). CONCLUSIONS: Among male steel workers, a significant association between shift work and hyperuricemia was observed. PMID- 25551020 TI - Work-relatedness of lung cancer by smoking and histologic type in Korea. AB - OBJECTIVES: This study investigated the distribution of causative agents related to occupational lung cancer, their relationships with work, and associations between work-relatedness and the histologic type of lung cancer. METHODS: We used data from the occupational surveillance system in Korea in 2013. In addition, data from 1,404 participants diagnosed with lung cancer were collected through interviews. We included the patients' longest-held job in the analysis. Work relatedness was categorized as "definite," "probable," "possible," "suspicious," "none," or "undetermined." RESULTS: Among the subjects, 69.3% were men and 30.7% were women. Regarding smoking status, current smokers were the most prevalent (35.5%), followed by non-smokers (32.3%), ex-smokers (32.2%). Regarding the causative agents of lung cancer, asbestos (1.0%) and crystalline silica (0.9%) were the most common in definite work-related cases, while non-arsenical insecticide (2.8%) was the most common in probable cases followed by diesel engine exhaust (1.9%) and asbestos (1.0%). Regarding histologic type, adenocarcinoma was the most common (41.7%), followed by squamous cell carcinoma (21.2%). Among current smokers, squamous cell carcinoma was the most common among definite and probable cases (13.4%), while non-small cell lung cancer was the least common (7.1%). Among non-smokers, squamous cell carcinoma was the most common (21.4%), while the least common was adenocarcinoma (1.6%). CONCLUSIONS: Approximately, 9.5% of all lung cancer cases in Korea are occupational-related lung cancer. Well-known substances associated with lung cancer, such as crystalline silica, asbestos, and diesel engine exhaust, are of particular concern. However, the histologic types of lung cancer related to smoking were inconsistent with previous studies when work-relatedness was taken into account. Future studies are required to clarify the incidence of occupational lung cancer in agricultural workers exposed to non-arsenical insecticides and the associations between work-relatedness and the histologic type of lung cancer. PMID- 25551021 TI - Serum prostate-specific antigen levels and type of work in tire manufacturing workers. AB - OBJECTIVES: This study measures serum prostate-specific antigen (PSA) levels in tire-manufacturing workers, and attempts to find occupational or non-occupational factors that related to their PSA levels. METHODS: A total of 1,958 healthy male workers (1,699 were production workers and 259 were office workers) took PSA measurement for analysis. RESULTS: After adjusting for age, body mass index, hypertension, regular exercise, alcohol drinking and smoking, which were significantly related to serum PSA levels or known related factors of serum PSA levels, the geometric mean PSA levels were significantly high in the office workers (p = 0.017), the older age group (p < 0.001), the group with hypertension (p = 0.046) and the group of individuals that do not exercise regularly (p = 0.015) and the office workers were more likely to have a serum PSA level of >=4.0 (OR 7.73, 95% CI: 2.78-21.46) or 2.5 ng/mL (OR 2.74, 95% CI: 1.49-5.08). After stratifying by age and adjusting aforementioned covariates, office workers 50 years of age and older had the significantly higher geometric mean PSA levels (p = 0.017) and were more likely to have a serum PSA level of >=4.0 ng/mL (OR 12.90, 95% CI: 3.65-45.64) or 2.5 ng/mL (OR 3.90, 95% CI: 1.64-9.25) than production workers 50 years of age and older. CONCLUSIONS: This study showed that serum PSA levels were significantly higher among the group with hypertension or the group of individuals that did not exercise regularly or group of office workers who were considered to have lesser physical activities. PMID- 25551022 TI - Endothelial cell-initiated extravasation of cancer cells visualized in zebrafish. AB - The extravasation of cancer cells, a key step for distant metastasis, is thought to be initiated by disruption of the endothelial barrier by malignant cancer cells. An endothelial covering-type extravasation of cancer cells in addition to conventional cancer cell invasion-type extravasation was dynamically visualized in a zebrafish hematogenous metastasis model. The inhibition of VEGF-signaling impaired the invasion-type extravasation via inhibition of cancer cell polarization and motility. Paradoxically, the anti-angiogenic treatment showed the promotion, rather than the inhibition, of the endothelial covering-type extravasation of cancer cells, with structural changes in the endothelial walls. These findings may be a set of clues to the full understanding of the metastatic process as well as the metastatic acceleration by anti-angiogenic reagents observed in preclinical studies. PMID- 25551025 TI - Confirmation bias leads to overestimation of losses of woody plant foliage to insect herbivores in tropical regions. AB - Confirmation bias, i.e., the tendency of humans to seek out evidence in a manner that confirms their hypotheses, is almost overlooked in ecological studies. For decades, insect herbivory was commonly accepted to be highest in tropical regions. By comparing the data collected blindly (when the observer was not aware of the research hypothesis being tested) with the results of non-blind studies (when the observer knew what results could be expected), we tested the hypothesis that the records made in the tropics could have overestimated community-wide losses of plant foliage to insects due to the confirmation bias. The average loss of leaf area of woody plants to defoliating insects in Brazil, when measured by a blind method (1.11%), was significantly lower than the loss measured in non-blind studies, both original (5.14%) and published (6.37%). We attribute the overestimation of the community-wide losses of plant foliage to insects in non blind studies to the unconsciously preconceived selection of study species with higher-than-average levels of herbivory. Based on our findings, we urge for caution in obtaining community-wide characteristics from the results of multiple single-species studies. Our data suggest that we may need to revise the paradigm of the highest level of background insect herbivory in the tropical regions. More generally, we argue that more attention should be paid by ecologists to the problem of biases occurring at the pre-publication phases of the scientific research and, consequently, to the development and the wide application of methods that avoid biases occurring due to unconscious psychological processes. PMID- 25551024 TI - Three-dimensional anatomy of the ostrich (Struthio camelus) knee joint. AB - The three-dimensional anatomy of the ostrich (Struthio camelus) knee (femorotibial, femorofibular, and femoropatellar) joint has scarcely been studied, and could elucidate certain mechanobiological properties of sesamoid bones. The adult ostrich is unique in that it has double patellae, while another similar ratite bird, the emu, has none. Understanding why these patellae form and what purpose they may serve is dually important for future studies on ratites as well as for understanding the mechanobiological characteristics of sesamoid bone development. For this purpose, we present a three-dimensional anatomical study of the ostrich knee joint, detailing osteology, ligaments and menisci, and myology. We have identified seven muscles which connect to the two patellae and compare our findings to past descriptions. These descriptions can be used to further study the biomechanical loading and implications of the double patella in the ostrich. PMID- 25551023 TI - Mobile gene silencing in Arabidopsis is regulated by hydrogen peroxide. AB - In plants and nematodes, RNAi can spread from cells from which it is initiated to other cells in the organism. The underlying mechanism controlling the mobility of RNAi signals is not known, especially in the case of plants. A genetic screen designed to recover plants impaired in the movement but not the production or effectiveness of the RNAi signal identified RCI3, which encodes a hydrogen peroxide (H2O2)-producing type III peroxidase, as a key regulator of silencing mobility in Arabidopsis thaliana. Silencing initiated in the roots of rci3 plants failed to spread into leaf tissue or floral tissue. Application of exogenous H2O2 reinstated the spread in rci3 plants and accelerated it in wild-type plants. The addition of catalase or MnO2, which breaks down H2O2, slowed the spread of silencing in wild-type plants. We propose that endogenous H2O2, under the control of peroxidases, regulates the spread of gene silencing by altering plasmodesmata permeability through remodelling of local cell wall structure, and may play a role in regulating systemic viral defence. PMID- 25551027 TI - Quantifying the effect of intervertebral cartilage on neutral posture in the necks of sauropod dinosaurs. AB - Attempts to reconstruct the neutral neck posture of sauropod dinosaurs, or indeed any tetrapod, are doomed to failure when based only on the geometry of the bony cervical vertebrae. The thickness of the articular cartilage between the centra of adjacent vertebrae affects posture. It extends (raises) the neck by an amount roughly proportional to the thickness of the cartilage. It is possible to quantify the angle of extension at an intervertebral joint: it is roughly equal, in radians, to the cartilage thickness divided by the height of the zygapophyseal facets over the centre of rotation. Applying this formula to published measurements of well-known sauropod specimens suggests that if the thickness of cartilage were equal to 4.5%, 10% or 18% of centrum length, the neutral pose of the Apatosaurus louisae holotype CM 3018 would be extended by an average of 5.5, 11.8 or 21.2 degrees, respectively, at each intervertebral joint. For the Diplodocus carnegii holotype CM 84, the corresponding angles of additional extension are even greater: 8.4, 18.6 or 33.3 degrees. The cartilaginous neutral postures (CNPs) calculated for 10% cartilage-the most reasonable estimate-appear outlandish. But it must be remembered that these would not have been the habitual life postures, because tetrapods habitually extend the base of their neck and flex the anterior part, yielding the distinctive S-curve most easily seen in birds. PMID- 25551026 TI - Structure, ontogeny and evolution of the patellar tendon in emus (Dromaius novaehollandiae) and other palaeognath birds. AB - The patella (kneecap) exhibits multiple evolutionary origins in birds, mammals, and lizards, and is thought to increase the mechanical advantage of the knee extensor muscles. Despite appreciable interest in the specialized anatomy and locomotion of palaeognathous birds (ratites and relatives), the structure, ontogeny and evolution of the patella in these species remains poorly characterized. Within Palaeognathae, the patella has been reported to be either present, absent, or fused with other bones, but it is unclear how much of this variation is real, erroneous or ontogenetic. Clarification of the patella's form in palaeognaths would provide insight into the early evolution of the patella in birds, in addition to the specialized locomotion of these species. Findings would also provide new character data of use in resolving the controversial evolutionary relationships of palaeognaths. In this study, we examined the gross and histological anatomy of the emu patellar tendon across several age groups from five weeks to 18 months. We combined these results with our observations and those of others regarding the patella in palaeognaths and their outgroups (both extant and extinct), to reconstruct the evolution of the patella in birds. We found no evidence of an ossified patella in emus, but noted its tendon to have a highly unusual morphology comprising large volumes of adipose tissue contained within a collagenous meshwork. The emu patellar tendon also included increasing amounts of a cartilage-like tissue throughout ontogeny. We speculate that the unusual morphology of the patellar tendon in emus results from assimilation of a peri-articular fat pad, and metaplastic formation of cartilage, both potentially as adaptations to increasing tendon load. We corroborate previous observations of a 'double patella' in ostriches, but in contrast to some assertions, we find independent (i.e., unfused) ossified patellae in kiwis and tinamous. Our reconstructions suggest a single evolutionary origin of the patella in birds and that the ancestral patella is likely to have been a composite structure comprising a small ossified portion, lost by some species (e.g., emus, moa) but expanded in others (e.g., ostriches). PMID- 25551028 TI - Ontogenetic scaling patterns and functional anatomy of the pelvic limb musculature in emus (Dromaius novaehollandiae). AB - Emus (Dromaius novaehollandiae) are exclusively terrestrial, bipedal and cursorial ratites with some similar biomechanical characteristics to humans. Their growth rates are impressive, as their body mass increases eighty-fold from hatching to adulthood whilst maintaining the same mode of locomotion throughout life. These ontogenetic characteristics stimulate biomechanical questions about the strategies that allow emus to cope with their rapid growth and locomotion, which can be partly addressed via scaling (allometric) analysis of morphology. In this study we have collected pelvic limb anatomical data (muscle architecture, tendon length, tendon mass and bone lengths) and calculated muscle physiological cross sectional area (PCSA) and average tendon cross sectional area from emus across three ontogenetic stages (n = 17, body masses from 3.6 to 42 kg). The data were analysed by reduced major axis regression to determine how these biomechanically relevant aspects of morphology scaled with body mass. Muscle mass and PCSA showed a marked trend towards positive allometry (26 and 27 out of 34 muscles respectively) and fascicle length showed a more mixed scaling pattern. The long tendons of the main digital flexors scaled with positive allometry for all characteristics whilst other tendons demonstrated a less clear scaling pattern. Finally, the two longer bones of the limb (tibiotarsus and tarsometatarsus) also exhibited positive allometry for length, and two others (femur and first phalanx of digit III) had trends towards isometry. These results indicate that emus experience a relative increase in their muscle force generating capacities, as well as potentially increasing the force-sustaining capacities of their tendons, as they grow. Furthermore, we have clarified anatomical descriptions and provided illustrations of the pelvic limb muscle tendon units in emus. PMID- 25551029 TI - Data-adaptive image-denoising for detecting and quantifying nanoparticle entry in mucosal tissues through intravital 2-photon microscopy. AB - Intravital 2-photon microscopy of mucosal membranes across which nanoparticles enter the organism typically generates noisy images. Because the noise results from the random statistics of only very few photons detected per pixel, it cannot be avoided by technical means. Fluorescent nanoparticles contained in the tissue may be represented by a few bright pixels which closely resemble the noise structure. We here present a data-adaptive method for digital denoising of datasets obtained by 2-photon microscopy. The algorithm exploits both local and non-local redundancy of the underlying ground-truth signal to reduce noise. Our approach automatically adapts the strength of noise suppression in a data adaptive way by using a Bayesian network. The results show that the specific adaption to both signal and noise characteristics improves the preservation of fine structures such as nanoparticles while less artefacts were produced as compared to reference algorithms. Our method is applicable to other imaging modalities as well, provided the specific noise characteristics are known and taken into account. PMID- 25551030 TI - Electrostatic interplay: The interaction triangle of polyamines, silicic acid, and phosphate studied through turbidity measurements, silicomolybdic acid test, and (29)Si NMR spectroscopy. AB - The discovery of long-chain polyamines as biomolecules that are tightly associated to biosilica in diatom cell walls has inspired numerous in vitro studies aiming to characterize polyamine-silica interactions. The determination of these interactions at the molecular level is of fundamental interest on one hand for the understanding of cell wall biogenesis in diatoms and on the other hand for designing bioinspired materials synthesis approaches. The present contribution deals with the influence of amines and polyamines upon the initial self-assembly processes taking place during polyamine-mediated silica formation in solution. The influence of phosphate upon these processes is studied. For this purpose, sodium metasilicate solutions containing additives such as polyallylamine, allylamine and others in the presence/absence of phosphate were investigated. The analyses are based mainly on turbidity measurements yielding information about the early aggregation steps which finally give rise to the formation and precipitation of silica. PMID- 25551031 TI - Effects of surface functionalization on the adsorption of human serum albumin onto nanoparticles - a fluorescence correlation spectroscopy study. AB - By using fluorescence correlation spectroscopy (FCS), we have studied the adsorption of human serum albumin (HSA) onto Fe-Pt nanoparticles (NPs, 6 nm radius), CdSe/ZnS quantum dots (QDs, 5 nm radius) and Au and Ag nanoclusters (1-4 nm radius), which are enshrouded by various water-solubilizing surface layers exposing different chemical functional groups (carboxyl, amino and both), thereby endowing the NPs with different surface charges. We have also measured the effects of modified surface functionalizations on the protein via succinylation and amination. A step-wise increase in hydrodynamic radius with protein concentration was always observed, revealing formation of protein monolayers coating the NPs, independent of their surface charge. The differences in the thickness of the protein corona were rationalized in terms of the different orientations in which HSA adsorbs onto the NPs. The midpoints of the binding transition, which quantifies the affinity of HSA toward the NP, were observed to differ by almost four orders of magnitude. These variations can be understood in terms of specific Coulombic interactions between the proteins and the NP surfaces. PMID- 25551032 TI - Dissipation signals due to lateral tip oscillations in FM-AFM. AB - We study the coupling of lateral and normal tip oscillations and its effect on the imaging process of frequency-modulated dynamic atomic force microscopy. The coupling is induced by the interaction between tip and surface. Energy is transferred from the normal to the lateral excitation, which can be detected as damping of the cantilever oscillation. However, energy can be transferred back into the normal oscillation, if not dissipated by the usually uncontrolled mechanical damping of the lateral excitation. For certain cantilevers, this dissipation mechanism can lead to dissipation rates larger than 0.01 eV per period. The mechanism produces an atomic contrast for ionic crystals with two maxima per unit cell in a line scan. PMID- 25551034 TI - Optical properties and electrical transport of thin films of terbium(III) bis(phthalocyanine) on cobalt. AB - The optical and electrical properties of terbium(III) bis(phthalocyanine) (TbPc2) films on cobalt substrates were studied using variable angle spectroscopic ellipsometry (VASE) and current sensing atomic force microscopy (cs-AFM). Thin films of TbPc2 with a thickness between 18 nm and 87 nm were prepared by organic molecular beam deposition onto a cobalt layer grown by electron beam evaporation. The molecular orientation of the molecules on the metallic film was estimated from the analysis of the spectroscopic ellipsometry data. A detailed analysis of the AFM topography shows that the TbPc2 films consist of islands which increase in size with the thickness of the organic film. Furthermore, the cs-AFM technique allows local variations of the organic film topography to be correlated with electrical transport properties. Local current mapping as well as local I-V spectroscopy shows that despite the granular structure of the films, the electrical transport is uniform through the organic films on the microscale. The AFM-based electrical measurements allow the local charge carrier mobility of the TbPc2 thin films to be quantified with nanoscale resolution. PMID- 25551033 TI - Effect of silver nanoparticles on human mesenchymal stem cell differentiation. AB - BACKGROUND: Silver nanoparticles (Ag-NP) are one of the fastest growing products in nano-medicine due to their enhanced antibacterial activity at the nanoscale level. In biomedicine, hundreds of products have been coated with Ag-NP. For example, various medical devices include silver, such as surgical instruments, bone implants and wound dressings. After the degradation of these materials, or depending on the coating technique, silver in nanoparticle or ion form can be released and may come into close contact with tissues and cells. Despite incorporation of Ag-NP as an antibacterial agent in different products, the toxicological and biological effects of silver in the human body after long-term and low-concentration exposure are not well understood. In the current study, we investigated the effects of both ionic and nanoparticulate silver on the differentiation of human mesenchymal stem cells (hMSCs) into adipogenic, osteogenic and chondrogenic lineages and on the secretion of the respective differentiation markers adiponectin, osteocalcin and aggrecan. RESULTS: As shown through laser scanning microscopy, Ag-NP with a size of 80 nm (hydrodynamic diameter) were taken up into hMSCs as nanoparticulate material. After 24 h of incubation, these Ag-NP were mainly found in the endo-lysosomal cell compartment as agglomerated material. Cytotoxicity was observed for differentiated or undifferentiated hMSCs treated with high silver concentrations (>=20 ug.mL(-1) Ag NP; >=1.5 ug.mL(-1) Ag(+) ions) but not with low-concentration treatments (<=10 ug.mL(-1) Ag-NP; <=1.0 ug.mL(-1) Ag(+) ions). Subtoxic concentrations of Ag-NP and Ag(+) ions impaired the adipogenic and osteogenic differentiation of hMSCs in a concentration-dependent manner, whereas chondrogenic differentiation was unaffected after 21 d of incubation. In contrast to aggrecan, the inhibitory effect of adipogenic and osteogenic differentiation was confirmed by a decrease in the secretion of specific biomarkers, including adiponectin (adipocytes) and osteocalcin (osteoblasts). CONCLUSION: Aside from the well-studied antibacterial effect of silver, little is known about the influence of nano-silver on cell differentiation processes. Our results demonstrate that ionic or nanoparticulate silver attenuates the adipogenic and osteogenic differentiation of hMSCs even at non-toxic concentrations. Therefore, more studies are needed to investigate the effects of silver species on cells at low concentrations during long-term treatment. PMID- 25551035 TI - Nanomanipulation and environmental nanotechnology. PMID- 25551036 TI - Effect of channel length on the electrical response of carbon nanotube field effect transistors to deoxyribonucleic acid hybridization. AB - A single-walled carbon nanotube (SWCNT) in a field-effect transistor (FET) configuration provides an ideal electronic path for label-free detection of nucleic acid hybridization. The simultaneous influence of more than one response mechanism in hybridization detection causes a variation in electrical parameters such as conductance, transconductance, threshold voltage and hysteresis gap. The channel length (L) dependence of each of these parameters necessitates the need to include them when interpreting the effect of L on the response to hybridization. Using the definitions of intrinsic effective mobility (ue) and device field-effect mobility (uf), two new parameters were defined to interpret the effect of L on the FET response to hybridization. Our results indicate that FETs with ~300 um long SWCNT exhibited the most appreciable response to hybridization, which complied with the variation trend in response to the newly defined parameters. PMID- 25551037 TI - The gut wall provides an effective barrier against nanoparticle uptake. AB - BACKGROUND: The omnipresence of nanoparticles (NPs) in numerous goods has led to a constant risk of exposure and inadvertent uptake for humans. This situation calls for thorough investigation of the consequences of NP intake. As the vast mucosa of the human gastrointestinal tract represents an attractive site of entry, we wanted to take a look on the fate that ingested NPs suffer in the gut. As a model to investigate NP uptake we used the isolated perfused rat small intestine. Differently sized fluorescent latex particles were used as exemplary anthropogenic NPs. RESULTS: The particles were administered as bolus into the isolated intestine, and samples from the luminal, vascular and lymphatic compartments were collected over time. NP amounts in the different fluids were determined by fluorescence measurements. No particles could be detected in the vascular and lymphatic system. By contrast a major amount of NPs was found in luminal samples. Yet, a substantial share of particles could not be recovered in the fluid fractions, indicating a sink function of the intestinal tissue for NPs. A histological examination of the gut revealed that virtually no particles adhered to the epithelium or resided in the tissue, the bulk of particles seemed to be trapped in the mucus lining the gut tube. When this mucus was dissolved and removed from the gut almost the entire amount of particles missing could be recovered: over 95% of the given NPs were present in the two fractions, the luminal samples and the dissolved mucus. To foster NP uptake via an extended interaction time with the epithelium, the intestinal peristalsis was decelerated and the duration of the experiment was prolonged. Even under those conditions, no particle fluorescence was detected in the vascular and lymphatic samples. CONCLUSION: We could show that after intestinal exposure with a large dose of NPs the vast majority of NPs did obviously not come into contact with the epithelium but was either directly discarded from the gut or trapped in mucus. The healthy small intestinal tract evidently provides an effective barrier against NP uptake whereby the mucus film seems to play an important role. PMID- 25551038 TI - Properties of plasmonic arrays produced by pulsed-laser nanostructuring of thin Au films. AB - A brief description of research advances in the area of short-pulse-laser nanostructuring of thin Au films is followed by examples of experimental data and a discussion of our results on the characterization of structural and optical properties of gold nanostructures. These consist of partially spherical or spheroidal nanoparticles (NPs) which have a size distribution (80 +/- 42 nm) and self-organization characterized by a short-distance order (length scale ~140 nm). For the NP shapes produced, an observably broader tuning range (of about 150 nm) of the surface plasmon resonance (SPR) band is obtained by renewal thin film deposition and laser annealing of the NP array. Despite the broadened SPR bands, which indicate damping confirmed by short dephasing times not exceeding 4 fs, the self-organized Au NP structures reveal quite a strong enhancement of the optical signal. This was consistent with the near-field modeling and micro-Raman measurements as well as a test of the electrochemical sensing capability. PMID- 25551040 TI - Modification of a single-molecule AFM probe with highly defined surface functionality. AB - Single-molecule force spectroscopy with an atomic force microscope has been widely used to study inter- and intramolecular interactions. To obtain data consistent with single molecular events, a well-defined method is critical to limit the number of molecules at the apex of an AFM probe to one or to a few. In this paper, we demonstrate an easy method for single-molecule probe modification by using the Cu-catalyzed alkyne-azide cycloaddition reaction. Excess terminal alkynes were covalently attached to the probe, and a bi-functional molecule containing an azide at one end and a carboxylic acid at the other was dissolved in the reaction solution. By simply contacting the probe and the Cu substrate, controlled carboxylation on the probe apex could be achieved, since the 'click' reaction requires the co-exist of alkyne, azide and Cu(I). The finite contact area would result in a highly defined surface functionality of the probe down to single molecule level with high reproducibility. PMID- 25551039 TI - Sequence-dependent electrical response of ssDNA-decorated carbon nanotube, field effect transistors to dopamine. AB - Single-walled carbon nanotube (SWCNT)-based field-effect transistors (FETs) have been explored for use as biological/chemical sensors. Dopamine (DA) is a biomolecule with great clinical significance for disease diagnosis, however, SWCNT FETs lack responsivity and selectivity for its detection due to the presence of interfering compounds such as uric acid (UA). Surface modification of CNTs using single-stranded deoxyribonucleic acid (ssDNA) renders the surface responsive to DA and screens the interferent. Due to the presence of different bases in ssDNA, it is necessary to investigate the effect of sequence on the FET based molecular recognition of DA. SWCNT FETs were decorated with homo- and repeated-base ssDNA sequences, and the electrical response induced by DA in the presence and absence of UA was gauged in terms of the variation in transistor electrical parameters including conductance, transconductance, threshold voltage and hysteresis gap. Our results showed that the response of ssDNA-decorated devices to DA, irrespective of the presence or absence of UA, was DNA sequence dependent and exhibited the trend: G > A > C and GA > GT > AC > CT, for homo- and repeated-base sequences, respectively. The different response of various SWCNT ssDNA systems to DA underlines the sequence selectivity, whereas the detection of DA in the presence of UA highlights the molecular selectivity of the ssDNA decorated devices. PMID- 25551041 TI - Biopolymer colloids for controlling and templating inorganic synthesis. AB - Biopolymers and biopolymer colloids can act as controlling agents and templates not only in many processes in nature, but also in a wide range of synthetic approaches. Inorganic materials can be either synthesized ex situ and later incorporated into a biopolymer structuring matrix or grown in situ in the presence of biopolymers. In this review, we focus mainly on the latter case and distinguish between the following possibilities: (i) biopolymers as controlling agents of nucleation and growth of inorganic materials; (ii) biopolymers as supports, either as molecular supports or as carrier particles acting as cores of core-shell structures; and (iii) so-called "soft templates", which include on one hand stabilized droplets, micelles, and vesicles, and on the other hand continuous scaffolds generated by gelling biopolymers. PMID- 25551042 TI - UHV deposition and characterization of a mononuclear iron(III) beta-diketonate complex on Au(111). AB - The adsorption of the sterically hindered beta-diketonate complex Fe(dpm)3, where Hdpm = dipivaloylmethane, on Au(111) was investigated by ultraviolet photoelectron spectroscopy (UPS) and scanning tunnelling microscopy (STM). The high volatility of the molecule limited the growth of the film to a few monolayers. While UPS evidenced the presence of the beta-diketonate ligands on the surface, the integrity of the molecule on the surface could not be assessed. The low temperature STM images were more informative and at submonolayer coverage they showed the presence of regular domains characterized by a flat morphology and height of ~0.3 nm. Along with these domains, tetra-lobed features adsorbed on the kinks of the herringbone were also observed. DFT-simulated images of the pristine molecule and its possible decomposition products allowed to assess the partial fragmentation of Fe(dpm)3 upon adsorption on the Au(111) surface. Structural features with intact molecules were only observed for the saturation coverage. An ex situ prepared thick film of the complex was also investigated by X-ray magnetic circular dichroism (XMCD) and features typical of high-spin iron(III) in octahedral environment were observed. PMID- 25551043 TI - Modeling viscoelasticity through spring-dashpot models in intermittent-contact atomic force microscopy. AB - We examine different approaches to model viscoelasticity within atomic force microscopy (AFM) simulation. Our study ranges from very simple linear spring dashpot models to more sophisticated nonlinear systems that are able to reproduce fundamental properties of viscoelastic surfaces, including creep, stress relaxation and the presence of multiple relaxation times. Some of the models examined have been previously used in AFM simulation, but their applicability to different situations has not yet been examined in detail. The behavior of each model is analyzed here in terms of force-distance curves, dissipated energy and any inherent unphysical artifacts. We focus in this paper on single-eigenmode tip sample impacts, but the models and results can also be useful in the context of multifrequency AFM, in which the tip trajectories are very complex and there is a wider range of sample deformation frequencies (descriptions of tip-sample model behaviors in the context of multifrequency AFM require detailed studies and are beyond the scope of this work). PMID- 25551045 TI - Two-dimensional and tubular structures of misfit compounds: Structural and electronic properties. AB - Misfit layer compounds are structures that consist of two sublattices differing in at least one of their lattice constants. The two different layers are stacked either an alternating or in a more complex series resulting in mono- or multi layer misfit compounds. To date, planar and bent misfit structures, such as tubes, scrolls or nanoparticles, have been synthesized and interesting magnetic and physical properties have been observed as a result of their special structures. Based on these observations, we present an overview of such misfit systems and summarize and discuss their electronic structure as well as the interlayer bonding behaviour, which is not completely understood yet. Furthermore, a more detailed insight into the SnS-SnS2 system is given, which was the first tubular misfit compound that has been synthesized and extensively investigated. PMID- 25551044 TI - Nanometer-resolved mechanical properties around GaN crystal surface steps. AB - The mechanical properties of surfaces and nanostructures deviate from their bulk counterparts due to surface stress and reduced dimensionality. Experimental indentation-based techniques present the challenge of measuring these effects, while avoiding artifacts caused by the measurement technique itself. We performed a molecular dynamics study to investigate the mechanical properties of a GaN step of only a few lattice constants step height and scrutinized its applicability to indentation experiments using a finite element approach (FEM). We show that the breakdown of half-space symmetry leads to an "artificial" reduction of the elastic properties of comparable lateral dimensions which overlays the effect of surface stress. Contact resonance atomic force microscopy (CR-AFM) was used to compare the simulation results with experiments. PMID- 25551046 TI - Advances in NO2 sensing with individual single-walled carbon nanotube transistors. AB - The charge carrier transport in carbon nanotubes is highly sensitive to certain molecules attached to their surface. This property has generated interest for their application in sensing gases, chemicals and biomolecules. With over a decade of research, a clearer picture of the interactions between the carbon nanotube and its surroundings has been achieved. In this review, we intend to summarize the current knowledge on this topic, focusing not only on the effect of adsorbates but also the effect of dielectric charge traps on the electrical transport in single-walled carbon nanotube transistors that are to be used in sensing applications. Recently, contact-passivated, open-channel individual single-walled carbon nanotube field-effect transistors have been shown to be operational at room temperature with ultra-low power consumption. Sensor recovery within minutes through UV illumination or self-heating has been shown. Improvements in fabrication processes aimed at reducing the impact of charge traps have reduced the hysteresis, drift and low-frequency noise in carbon nanotube transistors. While open challenges such as large-scale fabrication, selectivity tuning and noise reduction still remain, these results demonstrate considerable progress in transforming the promise of carbon nanotube properties into functional ultra-low power, highly sensitive gas sensors. PMID- 25551047 TI - Influence of stabilising agents and pH on the size of SnO2 nanoparticles. AB - According to recent research, the use of nanoparticles as a gas-sensitive material increases the selectivity and sensitivity and shortens the response time of a sensor. However, the synthesis of SnO2 nanoparticles presents many difficulties. The following article presents a simple and inexpensive method for the synthesis of SnO2 nanoparticles. The influence of the surfactant and polymer choice on the size of the resulting nanoparticles was investigated and a mechanism describing their interaction was proposed. It was found that stable colloids of SnO2 nanoparticles are formed in the presence of both PEI and Triton X-100 surfactants as stabilising agents. However, an additional factor essential for good stabilisation of the nanoparticles was an appropriate acidity level of the solution. Under optimal conditions, nanoparticles having an average diameter of about 10 nm are reproducibly formed. PMID- 25551048 TI - Electrical contacts to individual SWCNTs: A review. AB - Owing to their superior electrical characteristics, nanometer dimensions and definable lengths, single-walled carbon nanotubes (SWCNTs) are considered as one of the most promising materials for various types of nanodevices. Additionally, they can be used as either passive or active elements. To be integrated into circuitry or devices, they are typically connected with metal leads to provide electrical contacts. The properties and quality of these electrical contacts are important for the function and performance of SWCNT-based devices. Since carbon nanotubes are quasi-one-dimensional structures, contacts to them are different from those for bulk semiconductors. Additionally, some techniques used in Si based technology are not compatible with SWCNT-based device fabrication, such as the contact area cleaning technique. In this review, an overview of the investigations of metal-SWCNT contacts is presented, including the principle of charge carrier injection through the metal-SWCNT contacts and experimental achievements. The methods for characterizing the electrical contacts are discussed as well. The parameters which influence the contact properties are summarized, mainly focusing on the contact geometry, metal type and the cleanliness of the SWCNT surface affected by the fabrication processes. Moreover, the challenges for widespread application of CNFETs are additionally discussed. PMID- 25551049 TI - Low cost, p-ZnO/n-Si, rectifying, nano heterojunction diode: Fabrication and electrical characterization. AB - A low cost, highly rectifying, nano heterojunction (p-ZnO/n-Si) diode was fabricated using solution-processed, p-type, ZnO nanoparticles and an n-type Si substrate. p-type ZnO nanoparticles were synthesized using a chemical synthesis route and characterized by XRD and a Hall effect measurement system. The device was fabricated by forming thin film of synthesized p-ZnO nanoparticles on an n-Si substrate using a dip coating technique. The device was then characterized by current-voltage (I-V) and capacitance-voltage (C-V) measurements. The effect of UV illumination on the I-V characteristics was also explored and indicated the formation of a highly rectifying, nano heterojunction with a rectification ratio of 101 at 3 V, which increased nearly 2.5 times (232 at 3 V) under UV illumination. However, the cut-in voltage decreases from 1.5 V to 0.9 V under UV illumination. The fabricated device could be used in switches, rectifiers, clipper and clamper circuits, BJTs, MOSFETs and other electronic circuitry. PMID- 25551050 TI - In situ metalation of free base phthalocyanine covalently bonded to silicon surfaces. AB - Free 4-undecenoxyphthalocyanine molecules were covalently bonded to Si(100) and porous silicon through thermic hydrosilylation of the terminal double bonds of the undecenyl chains. The success of the anchoring strategy on both surfaces was demonstrated by the combination of X-ray photoelectron spectroscopy with control experiments performed adopting the commercially available 2,3,9,10,16,17,23,24 octakis(octyloxy)-29H,31H-phthalocyanine, which is not suited for silicon anchoring. Moreover, the study of the shape of the XPS N 1s band gave relevant information on the interactions occurring between the anchored molecules and the substrates. The spectra suggest that the phthalocyanine ring interacts significantly with the flat Si surface, whilst ring-surface interactions are less relevant on porous Si. The surface-bonded molecules were then metalated in situ with Co by using wet chemistry. The efficiency of the metalation process was evaluated by XPS measurements and, in particular, on porous silicon, the complexation of cobalt was confirmed by the disappearance in the FTIR spectra of the band at 3290 cm(-1) due to -NH stretches. Finally, XPS results revealed that the different surface-phthalocyanine interactions observed for flat and porous substrates affect the efficiency of the in situ metalation process. PMID- 25551051 TI - Hybrid spin-crossover nanostructures. AB - This review reports on the recent progress in the synthesis, modelling and application of hybrid spin-crossover materials, including core-shell nanoparticles and multilayer thin films or nanopatterns. These systems combine, often in synergy, different physical properties (optical, magnetic, mechanical and electrical) of their constituents with the switching properties of spin crossover complexes, providing access to materials with unprecedented capabilities. PMID- 25551052 TI - Characterization of 10,12-pentacosadiynoic acid Langmuir-Blodgett monolayers and their use in metal-insulator-metal tunnel devices. AB - The characterization of Langmuir-Blodgett thin films of 10,12-pentacosadiynoic acid (PDA) and their use in metal-insulator-metal (MIM) devices were studied. The Langmuir monolayer behavior of the PDA film was studied at the air/water interface using surface tension-area isotherms of polymeric and monomeric PDA. Langmuir-Blodgett (LB, vertical deposition) and Langmuir-Schaefer (LS, horizontal deposition) techniques were used to deposit the PDA film on various substrates (glass, quartz, silicon, and nickel-coated film on glass). The electrochemical, electrical and optical properties of the LB and LS PDA films were studied using cyclic voltammetry, current-voltage characteristics (I-V), and UV-vis and FTIR spectroscopies. Atomic force microscopy measurements were performed in order to analyze the surface morphology and roughness of the films. A MIM tunnel diode was fabricated using a PDA monolayer assembly as the insulating barrier, which was sandwiched between two nickel layers. The precise control of the thickness of the insulating monolayers proved critical for electron tunneling to take place in the MIM structure. The current-voltage characteristics of the MIM diode revealed tunneling behavior in the fabricated Ni-PDA LB film-Ni structures. PMID- 25551053 TI - Spectroscopic mapping and selective electronic tuning of molecular orbitals in phosphorescent organometallic complexes - a new strategy for OLED materials. AB - The improvement of molecular electronic devices such as organic light-emitting diodes requires fundamental knowledge about the structural and electronic properties of the employed molecules as well as their interactions with neighboring molecules or interfaces. We show that highly resolved scanning tunneling microscopy (STM) and spectroscopy (STS) are powerful tools to correlate the electronic properties of phosphorescent complexes (i.e., triplet emitters) with their molecular structure as well as the local environment around a single molecule. We used spectroscopic mapping to visualize several occupied and unoccupied molecular frontier orbitals of Pt(II) complexes adsorbed on Au(111). The analysis showed that the molecules exhibit a peculiar localized strong hybridization that leads to partial depopulation of a dz2 orbital, while the ligand orbitals are almost unchanged. We further found that substitution of functional groups at well-defined positions can alter specific molecular orbitals without influencing the others. The results open a path toward the tailored design of electronic and optical properties of triplet emitters by smart ligand substitution, which may improve the performance of future OLED devices. PMID- 25551054 TI - Nanoencapsulation of ultra-small superparamagnetic particles of iron oxide into human serum albumin nanoparticles. AB - Human serum albumin nanoparticles have been utilized as drug delivery systems for a variety of medical applications. Since ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents in magnetic resonance imaging, their encapsulation into the protein matrix enables the synthesis of diagnostic and theranostic agents by surface modification and co-encapsulation of active pharmaceutical ingredients. The present investigation deals with the surface modification and nanoencapsulation of USPIO into an albumin matrix by using ethanolic desolvation. Particles of narrow size distribution and with a defined particle structure have been achieved. PMID- 25551055 TI - Influence of the supramolecular architecture on the magnetic properties of a Dy(III) single-molecule magnet: an ab initio investigation. AB - Single-crystal angular-resolved magnetometry and wavefunction-based calculations have been used to reconsider the magnetic properties of a recently reported Dy(III)-based single-molecule magnet, namely [Dy(hfac)3(L(1))] with hfac(-) = 1,1,1,5,5,5-hexafluoroacetylacetonate and L(1) = 2-(4,5-bis(propylthio)-1,3 dithiol-2-ylidene)-6-(pyridin-2-yl)-5H-[1,3]dithiolo[4',5':4,5]benzo[1,2 d]imidazole. The magnetic susceptibility and magnetization at low temperature are found to be strongly influenced by supramolecular interactions. Moreover, taking into account the hydrogen-bond networks in the calculations allows to explain the orientation of the magnetic axes. This strongly suggests that hydrogen bonds play an important role in the modulation of the electrostatic environment around the Dy(III) center that governs the nature of its magnetic ground-state and the orientation of its anisotropy axes. We thus show here that SMM properties that rely on supramolecular organization may not be transferable into single-molecule devices. PMID- 25551056 TI - Localized surface plasmon resonances in nanostructures to enhance nonlinear vibrational spectroscopies: towards an astonishing molecular sensitivity. AB - Vibrational transitions contain some of the richest fingerprints of molecules and materials, providing considerable physicochemical information. Vibrational transitions can be characterized by different spectroscopies, and alternatively by several imaging techniques enabling to reach sub-microscopic spatial resolution. In a quest to always push forward the detection limit and to lower the number of needed vibrational oscillators to get a reliable signal or imaging contrast, surface plasmon resonances (SPR) are extensively used to increase the local field close to the oscillators. Another approach is based on maximizing the collective response of the excited vibrational oscillators through molecular coherence. Both features are often naturally combined in vibrational nonlinear optical techniques. In this frame, this paper reviews the main achievements of the two most common vibrational nonlinear optical spectroscopies, namely surface enhanced sum-frequency generation (SE-SFG) and surface-enhanced coherent anti Stokes Raman scattering (SE-CARS). They can be considered as the nonlinear counterpart and/or combination of the linear surface-enhanced infrared absorption (SEIRA) and surface-enhanced Raman scattering (SERS) techniques, respectively, which are themselves a branching of the conventional IR and spontaneous Raman spectroscopies. Compared to their linear equivalent, those nonlinear vibrational spectroscopies have proved to reach higher sensitivity down to the single molecule level, opening the way to astonishing perspectives for molecular analysis. PMID- 25551057 TI - Anticancer efficacy of a supramolecular complex of a 2-diethylaminoethyl-dextran MMA graft copolymer and paclitaxel used as an artificial enzyme. AB - The anticancer efficacy of a supramolecular complex that was used as an artificial enzyme against multi-drug-resistant cancer cells was confirmed. A complex of diethylaminoethyl-dextran-methacrylic acid methylester copolymer (DDMC)/paclitaxel (PTX), obtained with PTX as the guest and DDMC as the host, formed a nanoparticle 50-300 nm in size. This complex is considered to be useful as a drug delivery system (DDS) for anticancer compounds since it formed a stable polymeric micelle in water. The resistance of B16F10 melanoma cells to PTX was shown clearly through a maximum survival curve. Conversely, the DDMC/PTX complex showed a superior anticancer efficacy and cell killing rate, as determined through a Michaelis-Menten-type equation, which may promote an allosteric supramolecular reaction to tubulin, in the same manner as an enzymatic reaction. The DDMC/PTX complex showed significantly higher anticancer activity compared to PTX alone in mouse skin in vivo. The median survival times of the saline, PTX, DDMC/PTX4 (particle size 50 nm), and DDMC/PTX5 (particle size 290 nm) groups were 120 h (treatment (T)/control (C), 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed twice the effectiveness of PTX alone (p < 0.036). Above all, the DDMC/PTX complex is not degraded in cells and acts as an intact supramolecular assembly, which adds a new species to the range of DDS. PMID- 25551058 TI - Coating with luminal gut-constituents alters adherence of nanoparticles to intestinal epithelial cells. AB - BACKGROUND: Anthropogenic nanoparticles (NPs) have found their way into many goods of everyday life. Inhalation, ingestion and skin contact are potential routes for NPs to enter the body. In particular the digestive tract with its huge absorptive surface area provides a prime gateway for NP uptake. Considering that NPs are covered by luminal gut-constituents en route through the gastrointestinal tract, we wanted to know if such modifications have an influence on the interaction between NPs and enterocytes. RESULTS: We investigated the consequences of a treatment with various luminal gut-constituents on the adherence of nanoparticles to intestinal epithelial cells. Carboxylated polystyrene particles 20, 100 and 200 nm in size represented our anthropogenic NPs, and differentiated Caco-2 cells served as model for mature enterocytes of the small intestine. Pretreatment with the proteins BSA and casein consistently reduced the adherence of all NPs to the cultured enterocytes, while incubation of NPs with meat extract had no obvious effect on particle adherence. In contrast, contact with intestinal fluid appeared to increase the particle-cell interaction of 20 and 100 nm NPs. CONCLUSION: Luminal gut-constituents may both attenuate and augment the adherence of NPs to cell surfaces. These effects appear to be dependent on the particle size as well as on the type of interacting protein. While some proteins will rather passivate particles towards cell attachment, possibly by increasing colloid stability or camouflaging attachment sites, certain components of intestinal fluid are capable to modify particle surfaces in such a way that interactions with cellular surface structures result in an increased binding. PMID- 25551059 TI - Nanobioarchitectures based on chlorophyll photopigment, artificial lipid bilayers and carbon nanotubes. AB - In the last decade, building biohybrid materials has gained considerable interest in the field of nanotechnology. This paper describes an original design for bionanoarchitectures with interesting properties and potential bioapplications. Multilamellar lipid vesicles (obtained by hydration of a dipalmitoyl phosphatidylcholine thin film) with and without cholesterol were labelled with a natural photopigment (chlorophyll a), which functioned as a sensor to detect modifications in the artificial lipid bilayers. These biomimetic membranes were used to build non-covalent structures with single-walled carbon nanotubes. Different biophysical methods were employed to characterize these biohybrids such as: UV-vis absorption and emission spectroscopy, zeta potential measurements, AFM and chemiluminescence techniques. The designed, carbon-based biohybrids exhibited good physical stability, good antioxidant and antimicrobial properties, and could be used as biocoating materials. As compared to the cholesterol-free samples, the cholesterol-containing hybrid structures demonstrated better stability (i.e., their zeta potential reached the value of -36.4 mV), more pronounced oxygen radical scavenging ability (affording an antioxidant activity of 73.25%) and enhanced biocidal ability, offering inhibition zones of 12.4, 11.3 and 10.2 mm in diameter, against Escherichia coli, Staphylococcus aureus and Enterococcus faecalis, respectively. PMID- 25551060 TI - Advanced atomic force microscopy techniques II. PMID- 25551061 TI - Liquid-phase exfoliated graphene: functionalization, characterization, and applications. AB - The development of chemical strategies to render graphene viable for incorporation into devices is a great challenge. A promising approach is the production of stable graphene dispersions from the exfoliation of graphite in water and organic solvents. The challenges involve the production of a large quantity of graphene sheets with tailored distribution in thickness, size, and shape. In this review, we present some of the recent efforts towards the controlled production of graphene in dispersions. We also describe some of the chemical protocols that have provided insight into the vast organic chemistry of the single atomic plane of graphite. Controlled chemical reactions applied to graphene are expected to significantly improve the design of hierarchical, functional platforms, driving the inclusion of graphene into advanced functional materials forward. PMID- 25551062 TI - Gas sensing properties of nanocrystalline diamond at room temperature. AB - This study describes an integrated NH3 sensor based on a hydrogenated nanocrystalline diamond (NCD)-sensitive layer coated on an interdigitated electrode structure. The gas sensing properties of the sensor structure were examined using a reducing gas (NH3) at room temperature and were found to be dependent on the electrode arrangement. A pronounced response of the sensor, which was comprised of dense electrode arrays (of 50 um separation distance), was observed. The sensor functionality was explained by the surface transfer doping effect. Moreover, the three-dimensional model of the current density distribution of the hydrogenated NCD describes the transient flow of electrons between interdigitated electrodes and the hydrogenated NCD surface, that is, the formation of a closed current loop. PMID- 25551063 TI - Inorganic Janus particles for biomedical applications. AB - Based on recent developments regarding the synthesis and design of Janus nanoparticles, they have attracted increased scientific interest due to their outstanding properties. There are several combinations of multicomponent hetero nanostructures including either purely organic or inorganic, as well as composite organic-inorganic compounds. Janus particles are interconnected by solid state interfaces and, therefore, are distinguished by two physically or chemically distinct surfaces. They may be, for instance, hydrophilic on one side and hydrophobic on the other, thus, creating giant amphiphiles revealing the endeavor of self-assembly. Novel optical, electronic, magnetic, and superficial properties emerge in inorganic Janus particles from their dimensions and unique morphology at the nanoscale. As a result, inorganic Janus nanoparticles are highly versatile nanomaterials with great potential in different scientific and technological fields. In this paper, we highlight some advances in the synthesis of inorganic Janus nanoparticles, focusing on the heterogeneous nucleation technique and characteristics of the resulting high quality nanoparticles. The properties emphasized in this review range from the monodispersity and size-tunability and, therefore, precise control over size-dependent features, to the biomedical application as theranostic agents. Hence, we show their optical properties based on plasmonic resonance, the two-photon activity, the magnetic properties, as well as their biocompatibility and interaction with human blood serum. PMID- 25551065 TI - Si/Ge intermixing during Ge Stranski-Krastanov growth. AB - The Stranski-Krastanov growth of Ge islands on Si(001) has been widely studied. The morphology changes of Ge islands during growth, from nucleation to hut/island formation and growth, followed by hut-to-dome island transformation and dislocation nucleation of domes, have been well described, even at the atomic scale, using techniques such as scanning tunneling microscopy and transmission electron microscopy. Although it is known that these islands do not consist of pure Ge (due to Si/Ge intermixing), the composition of the Ge islands is not precisely known. In the present work, atom probe tomography was used to study the composition of buried dome islands at the atomic scale, in the three-dimensional space. The core of the island was shown to contain about 55 atom % Ge, while the Ge composition surrounding this core decreases rapidly in all directions in the islands to reach a Ge concentration of about 15 atom %. The Ge distribution in the islands follows a cylindrical symmetry and Ge segregation is observed only in the {113} facets of the islands. The Ge composition of the wetting layer is not homogeneous, varying from 5 to 30 atom %. PMID- 25551064 TI - Interaction of dermatologically relevant nanoparticles with skin cells and skin. AB - The investigation of nanoparticle interactions with tissues is complex. High levels of standardization, ideally testing of different material types in the same biological model, and combinations of sensitive imaging and detection methods are required. Here, we present our studies on nanoparticle interactions with skin, skin cells, and biological media. Silica, titanium dioxide and silver particles were chosen as representative examples for different types of skin exposure to nanomaterials, e.g., unintended environmental exposure (silica) versus intended exposure through application of sunscreen (titanium dioxide) or antiseptics (silver). Because each particle type exhibits specific physicochemical properties, we were able to apply different combinations of methods to examine skin penetration and cellular uptake, including optical microscopy, electron microscopy, X-ray microscopy on cells and tissue sections, flow cytometry of isolated skin cells as well as Raman microscopy on whole tissue blocks. In order to assess the biological relevance of such findings, cell viability and free radical production were monitored on cells and in whole tissue samples. The combination of technologies and the joint discussion of results enabled us to look at nanoparticle-skin interactions and the biological relevance of our findings from different angles. PMID- 25551066 TI - Synthesis of radioactively labelled CdSe/CdS/ZnS quantum dots for in vivo experiments. AB - During the last decades of nanoparticles research, many nanomaterials have been developed for applications in the field of bio-labelling. For the visualization of transport processes in the body, organs and cells, luminescent quantum dots (QDs) make for highly useful diagnostic tools. However, intercellular routes, bio distribution, metabolism during degradation or quantification of the excretion of nanoparticles, and the study of the biological response to the QDs themselves are areas which to date have not been fully investigated. In order to aid in addressing those issues, CdSe/CdS/ZnS QDs were radioactively labelled, which allows quantification of the QD concentration in the whole body or in ex vivo samples by gamma-counting. However, the synthesis of radioactively labelled QDs is not trivial since the coating process must be completely adapted, and material availability, security and avoidance of radioactive waste must be considered. In this contribution, the coating of CdSe/CdS QDs with a radioactive (65)ZnS shell using a modified, operator-safe, SILAR procedure is presented. Under UV illumination, no difference in the photoluminescence of the radioactive and non radioactive CdSe/CdS/ZnS colloidal solutions was observed. Furthermore, a down scaled synthesis for the production of very small batches of 5 nmol QDs without loss in the fluorescence quality was developed. Subsequently, the radio-labelled QDs were phase transferred by encapsulation into an amphiphilic polymer. gamma counting of the radioactivity provided confirmation of the successful labelling and phase transfer of the QDs. PMID- 25551068 TI - Low-cost plasmonic solar cells prepared by chemical spray pyrolysis. AB - Solar cells consisting of an extremely thin In2S3/CuInS2 buffer/absorber layer uniformly covering planar ZnO were prepared entirely by chemical spray pyrolysis. Au nanoparticles (Au-NPs) were formed via thermal decomposition of a gold(III) chloride trihydrate (HAuCl4.3H2O) precursor by spraying 2 mmol/L of the aqueous precursor solution onto a substrate held at 260 degrees C. Current-voltage scans and external quantum efficiency spectra were used to evaluate the solar cell performance. This work investigates the effect of the location of the Au-NP layer deposition (front side vs rear side) in the solar cell and the effect of varying the volume (2.5-10 mL) of the sprayed Au precursor solution. A 63% increase (from 4.6 to 7.5 mA/cm(2)) of the short-circuit current density was observed when 2.5 mL of the precursor solution was deposited onto the rear side of the solar cell. PMID- 25551067 TI - Nanoparticle interactions with live cells: Quantitative fluorescence microscopy of nanoparticle size effects. AB - Engineered nanomaterials are known to enter human cells, often via active endocytosis. Mechanistic details of the interactions between nanoparticles (NPs) with cells are still not well enough understood. NP size is a key parameter that controls the endocytic mechanism and affects the cellular uptake yield. Therefore, we have systematically analyzed the cellular uptake of fluorescent NPs in the size range of 3.3-100 nm (diameter) by live cells. By using spinning disk confocal microscopy in combination with quantitative image analysis, we studied the time courses of NP association with the cell membrane and subsequent internalization. NPs with diameters of less than 10 nm were observed to accumulate at the plasma membrane before being internalized by the cells. In contrast, larger NPs (100 nm) were directly internalized without prior accumulation at the plasma membrane, regardless of their surface charges. We attribute this distinct size dependence to the requirement of a sufficiently strong local interaction of the NPs with the endocytic machinery in order to trigger the subsequent internalization. PMID- 25551069 TI - Modern treatment of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common type of arrhythmia and has a large global burden. In general, treatment of AF is based on medication and consists of rate and rhythm control together with anticoagulation. However, surgical treatment may be required in patients with AF combined with organic valvular heart diseases or who experience recurrence despite medication. In addition, surgical treatment plays a role in the treatment of lone AF. This article reviews the various surgical treatment options for AF. PMID- 25551070 TI - Outcomes of nonpledgeted horizontal mattress suture technique for mitral valve replacement. AB - BACKGROUND: Most surgeons favor the pledgeted suture technique for heart valve replacements because they believe it decreases the risk of paravalvular leak (PVL). We hypothesized that the use of nonpledgeted rather than pledgeted sutures during mitral valve replacement (MVR) may decrease the incidence of prosthetic valve endocarditis (PVE) and risk of a major PVL. METHODS: We analyzed 263 patients, divided into 175 patients who underwent MVR with nonpledgeted sutures from January 2003 to December 2013 and 88 patients who underwent MVR with pledgeted sutures from January 1995 to December 2001. We compared the occurrence of PVL and PVE between these groups. RESULTS: In patients who underwent MVR with or without tricuspid valve surgery and/or a Maze operation, PVL occurred in 1.1% of the pledgeted group and 2.9% of the nonpledgeted group. The incidence of PVE was 2.9% in the nonpledgeted group and 1.1% in the pledgeted group. No differences were statistically significant. CONCLUSION: We suggest that a nonpledgeted suture technique can be an alternative to the traditional use of pledgeted sutures in most patients who undergo MVR, with no significant difference in the incidence of PVL. PMID- 25551071 TI - Neurologic outcomes of preoperative acute silent cerebral infarction in patients with cardiac surgery. AB - BACKGROUND: Acute cerebral infarction is a major risk factor for postoperative neurologic complications in cardiac surgery. However, the outcomes associated with acute silent cerebral infarction (ASCI) have not been not well established. Few studies have reported the postoperative outcomes of these patients in light of preoperative Diffusion-weighted magnetic resonance imaging (DWI). We studied the postoperative neurologic outcomes of patients with preoperative ASCI detected by DWI. METHODS: We retrospectively studied 32 patients with preoperative ASCI detected by DWI. None of the patients had preoperative neurologic symptoms. The mean age at operation was 68.8+/-9.5 years. Five patients had previous histories of stroke. Four patients had been diagnosed with infective endocarditis. Single cerebral infarct lesions were detected in 16 patients, double lesions in 13, and multiple lesions (>5) in three. The median size of the infarct lesions was 4 mm (range, 2 to 25 mm). The operations of three of the 32 patients were delayed pending follow-up DWI studies. RESULTS: There were two in-hospital mortalities. Neurologic complications also occurred in two patients. One patient developed extensive cerebral infarction unrelated to preoperative infarct lesions. One patient showed sustained delirium over one week but recovered completely without any neurologic deficits. In two patients, postoperative DWI confirmed that no significant changes had occurred in the lesions. CONCLUSION: Patients with preoperative ASCI showed excellent postoperative neurologic outcomes. Preoperative ASCI was not a risk factor for postoperative neurologic deterioration. PMID- 25551072 TI - The factors affecting recurrence of symptoms after infrainguinal arterial endovascular angioplasty. AB - BACKGROUND: This study reports the result of endovascular treatment for arterial occlusive disease limited to femoropopliteal lesions, focusing on the recurrence of symptoms instead of patency. METHODS: This was a retrospective, single-center study. From April 2007 to November 2011, 48 limbs in 38 patients underwent endovascular stenting or balloon angioplasty to treat femoropopliteal arterial occlusive disease. The factors affecting the recurrence of symptoms were analyzed. RESULTS: The mean age of the patients was 69.60+/-7.62 years. Among the baseline characteristics of the patients, initial hyperlipidemia was the most important factor affecting the recurrence of symptoms (relative risk=5.810, p=0.031). The presence of a dorsal arch was also a significant factor (relative risk=0.675, p=0.047). CONCLUSION: The major factors that affect the recurrence of symptoms after endovascular treatment for femoropopliteal arterial occlusive lesions are hyperlipidemia and the presence of a dorsal arch. Therefore, the usage of lipid-lowering agents after endovascular treatment and taking the presence of a dorsal arch into consideration are important elements of managing the recurrence of symptoms. PMID- 25551073 TI - Systemic inflammation response syndrome score predicts the mortality in multiple trauma patients. AB - BACKGROUND: Numerous statistical models have been developed to accurately predict outcomes in multiple trauma patients. However, such trauma scoring systems reflect the patient's physiological condition, which can only be determined to a limited extent, and are difficult to use when performing a rapid initial assessment. We studied the predictive ability of the systemic inflammatory response syndrome (SIRS) score compared to other scoring systems. METHODS: We retrospectively reviewed 229 patients with multiple trauma combined with chest injury from January 2006 to June 2011. A SIRS score was calculated for patients based on their presentation to the emergency room. The patients were divided into two groups: those with an SIRS score of two points or above and those with an SIRS score of one or zero. Then, the outcomes between the two groups were compared. Furthermore, the ability of the SIRS score and other injury severity scoring systems to predict mortality was compared. RESULTS: Hospital death occurred in 12 patients (5.2%). There were no significant differences in the general characteristics of patients, but the trauma severity scores were significantly different between the two groups. The SIRS scores, number of complications, and mortality rate were significantly higher in those with a SIRS score of two or above (p<0.001). In the multivariant analysis, the SIRS score was the only independent factor related to mortality. CONCLUSION: The SIRS score is easily calculated on admission and may accurately predict mortality in patients with multiple traumas. PMID- 25551074 TI - Technique of Coronary Transfer for TGA with Single Coronary Artery. AB - An eight-day-old neonate was diagnosed with dextro-transposition of the great arteries, atrial septal defect, patent ductus arteriosus, and a single sinus origin of the coronary arteries. The single coronary artery originated from the left sinus (sinus 2), had a proximal left circumflex arterial branch, and passed anteriorly to the right side of the aorta, further branching into the right coronary and left anterior descending arteries. We successfully performed an arterial switch operation and coronary transfer by tube graft reconstruction with autologous aortic tissue to treat the dextro-transposition of the great arteries and atrial septal defect with a single-sinus origin of the coronary arteries. PMID- 25551075 TI - Heart transplantation in a patient with persistent left superior vena cava. AB - A 56-year-old male presented with severe exertional dyspnea and pitting edema in the lower extremities. The pre-operative evaluation demonstrated biventricular dysfunction associated with severe tricuspid valve regurgitation and a persistent left superior vena cava. He was registered as a transplantation candidate, and orthotopic heart transplantation was performed using the standard bicaval technique. The left superior vena cava was connected to the right atrial appendage after the construction of a conduit using the recipient's autologous coronary sinus tissue. One-month postoperatively, computed tomography imagery demonstrated a patent conduit between the left superior vena cava and right atrial appendage. PMID- 25551076 TI - Multiple aortic operations in loeys-dietz syndrome: report of 2 cases. AB - Due to its low prevalence and because there is lack of awareness about it, Loeys Dietz syndrome is often mis-diagnosed as Marfan syndrome, which has similar skeletal abnormalities and aortic pathology. However, the differential diagnosis between these two connective tissue diseases is critical because they correspond to different surgical indications and surgical decision-making. We report two cases of successful thoracoabdominal aortic replacement in patients with previously undiagnosed Loeys-Dietz syndrome. PMID- 25551077 TI - Pseudoaneurysm of surgically reconstructed right ventricular outflow tract complicated by superior vena cava syndrome. AB - Pseudoaneurysm of the right ventricular outflow tract (RVOT) has been reported as a rare complication of RVOT reconstruction performed using conduit replacement or patch repair. Rarely, it may present alongside symptoms secondary to the compression of adjoining mediastinal structures. We report the case of a patient who developed a symptomatic RVOT pseudoaneurysm one month after a total correction of tetralogy of Fallot. In the present case, superior vena cava syndrome was caused by compression of the superior vena cava, which was a very unusual presentation. PMID- 25551078 TI - Minimal invasive coronary artery fistula ligation. AB - A coronary artery fistula was surgically ligated in a 38-year-old woman via a left anterior mini-thoracotomy without the use of cardiopulmonary bypass. In selected cases, this surgical approach can provide an excellent surgical exposure for coronary artery fistula ligation. It also offers an excellent cosmetic result and shorter hospital stay. PMID- 25551079 TI - Visceral debranching thoracic endovascular aneurysm repair for chronic dissecting thoracoabdominal aortic aneurysm. AB - Type II chronic dissecting thoracoabdominal aortic aneurysms are a surgically challenging disease. The conventional thoracoabdominal aortic aneurysm repair technique using cardiopulmonary bypass is a high-risk procedure. However, a recently developed endovascular technique may be an alternative treatment for the disease, but faces the obstacle of lesional restriction. This new technique uses a hybrid strategy to overcome the limits of endovascular thoracoabdominal aortic aneurysm repair. Herein, we report on a successful outcome after performing the hybrid visceral debranching procedure. PMID- 25551080 TI - Acute thrombotic occlusion of left internal jugular vein compressed by bypass graft for thoracic endovascular aortic repair debranching procedure. AB - Thoracic endovascular aortic repair has become a widespread alternative treatment option for thoracic aortic aneurysm. The debranching of arch vessels may be required to provide an acceptable landing zone for an endovascular stent graft. We report a case where the bypass graft used in the thoracic endovascular aortic repair procedure compressed the left internal jugular vein, causing acute thrombotic occlusion. PMID- 25551081 TI - Endovascular Rescue of a Narrowed Aorto-Aortic Bypass Graft in a Patient with Takayasu's Arteritis. AB - We report a case of successful endovascular treatment of a pseudoaneurysm and the obstruction of an aorto-aortic bypass graft, which had been performed to treat Takayasu's arteritis fifteen years prior, at the thoracic aorta. Along with the immediate relief of proximal hypertension that had caused severe heart failure, the successful exclusion of the pseudoaneurysm and the patency of the stem graft were maintained three years after the procedure. PMID- 25551082 TI - Pulmonary vein to esophageal fistula after staged hybrid totally thoracoscopic surgical and percutaneous radiofrequency catheter ablation: a case report. AB - A case of a fistula running from the pulmonary vein to the esophagus after a staged hybrid procedure combining total thoracoscopic ablation and percutaneous radiofrequency catheter ablation has not been reported previously. We describe such a case in a 37-year-old man who was successfully treated by surgery. PMID- 25551083 TI - Outpatient Drainage Therapy with a Thoracic Vent for Traumatic Pneumothorax due to Bull Attack. AB - Outpatient drainage therapy is generally indicated for spontaneous pneumothoraces. A 63-year-old man, who had been attacked by a bull sustaining injuries on the right side of his chest, was referred to the emergency room with dyspnea. His chest X-ray showed a small pneumothorax. The next day, a chest X-ray demonstrated that his pneumothorax had worsened, although no hemothorax was identified. Outpatient drainage therapy with a thoracic vent was initiated. The air leak stopped on the third day and the thoracic vent was removed on the sixth day. Thoracic vents can be a useful modality for treating traumatic pneumothorax without hemothorax. PMID- 25551084 TI - Pulmonary actinomycosis associated with endobronchial vegetable foreign body. AB - A 51-year-old woman visited our hospital with massive hemoptysis. She had suffered from recurrent hemoptysis for five years and had undergone bronchial artery embolization many times. The patient had a history of pulmonary tuberculosis and bronchiectasis. Chest radiography showed consolidation around the nodule in the lateral basal segment of the right lower lobe. We successfully performed a right lower lobectomy. The histological study of the resected specimen showed a vegetable foreign body and clumps of Actinomyces, indicating actinomycosis, which was suggested to be the cause of the hemoptysis. This was a very rare case of hemoptysis caused by a vegetable foreign body and actinomycosis. PMID- 25551085 TI - Spontaneous pneumomediastinum with concurrent pneumorrhachis. AB - Spontaneous pneumomediastinum is a very uncommon entity that is defined as the presence of free air in the mediastinum without an obvious etiology. The presence of air in the spinal canal, known as concurrent pneumorrhachis, is an extremely rare epiphenomenon of spontaneous pneumomediastinum. We report a rare case of spontaneous pneumomediastinum with pneumorrhachis associated with influenza. The patient was diagnosed without invasive procedures, was managed with supportive treatment, and recovered without any complications. PMID- 25551086 TI - Pneumothorax induced by pulmonary paragonimiasis: two cases report. PMID- 25551087 TI - Author's Reply to Comments on "Pneumothorax Induced by Pulmonary Paragonimiasis: Two Cases Report". PMID- 25551088 TI - Complications and medicolegal problems. PMID- 25551089 TI - The effectiveness of decompression for patients with dentigerous cysts, keratocystic odontogenic tumors, and unicystic ameloblastoma. AB - OBJECTIVES: The aim of this study was to verify the clinical effectiveness of decompression in decreasing the size of a cyst. In addition to the different types of cysts, we tried to reveal what effect host factors, such as the initial size of the lesion and the age of the patient, have on the velocity of cyst shrinkage. MATERIALS AND METHODS: With the aid of a panoramic view, we measured the size of the cysts before and after decompression in 13 dentigerous cysts (DCs), 14 keratocystic odontogenic tumors (KTOCs), and 5 unicystic ameloblastoma (UA) cases. The velocity of shrinkage in the three cystic groups was calculated. Relationships between the age of the patient, the initial size of the cyst, and the shrinkage velocity were investigated. RESULTS: The three types of cysts showed no inter-type differences in their velocity of shrinkage. However, there was a statistically meaningful relationship between the initial size of the lesion and the absolute velocity of shrinkage in the DC group (P=0.02, R=0.65) and the KTOC group (P=0.02, R=0.56). There was also a significant relationship between the age of the patient and the absolute velocity of shrinkage in the KTOC group (P=0.04, R=0.45) and the UA group (P=0.04, R=0.46). CONCLUSION: There was no difference in the decrease in size due to decompression among the different types of cysts. However, the age of the patient and the initial size of the lesion showed a significant relationship with the velocity of shrinkage. PMID- 25551090 TI - Reconstruction plates used in the surgery for mandibular discontinuity defect. AB - OBJECTIVES: The purpose of this study was to analyze the survival rate of reconstruction plates that were used to correct mandibular discontinuity defects. MATERIALS AND METHODS: We analyzed clinical and radiological data of 36 patients. Only discontinuous mandibular defect cases were included in the study. Reconstruction plate survival rate was analyzed according to age, gender, location of defect, defect size, and whether the patient underwent a bone graft procedure, coronoidectomy, and/or postoperative radiation therapy (RT). RESULTS: Plate-related complications developed in 8 patients, 7 of which underwent plate removal. No significant differences were found in plate survival rate according to age, gender, location of defect, defect size, or whether a bone graft procedure was performed. However, there were differences in the plate survival rate that depended on whether the patient underwent coronoidectomy or postoperative RT. In the early stages (9.25+/-5.10 months), plate fracture was the most common complication, but in the later stages (35.75+/-17.00 months), screw loosening was the most common complication. CONCLUSION: It is important to establish the time-related risk of complications such as plate fracture or screw loosening. Coronoidectomy should be considered in most cases to prevent complications. Postoperative RT can affect the survival rate and hazard rate after a reconstruction plate is fitted. PMID- 25551091 TI - A two-year audit of non-vascularized iliac crest bone graft for mandibular reconstruction: technique, experience and challenges. AB - OBJECTIVES: Non-vascularized iliac crest bone graft (NVIBG) is a known treatment option in mandibular reconstruction following jaw resection, but no documented review of patients treated with NVIBG exists for northern Nigeria. The experience and technique from a Nigerian tertiary hospital may serve as baseline data for comparison and improvement of practice for other institutions. MATERIALS AND METHODS: A retrospective review of medical records and patient case files from January 2012 to December 2013 was undertaken. All case files and other medical records of patients who had reconstruction with NVIBG for benign or malignant lesions with immediate or delayed reconstruction were selected for review. RESULTS: Twenty patients had mandibular reconstruction with NVIBG during the study period. Two patients were excluded because of incomplete medical records. Eighteen patients' (male=14, female=4) records were reviewed. Their ages ranged from 13 to 62 years (mean 26.0+/-10.6 years). Indications for NVIBG included jaw tumors (n=16; 88.3%), jaw cyst (n=1; 5.6%) and gunshot injury (n=1; 5.6%). Jaw tumors seen were ameloblastoma (n=15; 83.3%) and osteosarcoma (n=1; 5.6%). Treatments done were mandibular resection with condylar resection (n=7; 38.9%), mandibular segmental resection (n=10; 55.6%) and subtotal mandibulectomy (n=1; 5.6%). Patients' postoperative reviews and radiographs revealed good facial profile and continued bone stability up to 1 year following NVIBG. CONCLUSION: NVIBGs provide an acceptable alternative to vascularized bone grafts, genetically engineered bone, and distraction osteogenesis for mandibular reconstruction in resource-limited centers. PMID- 25551092 TI - Analysis and evaluation of relative positions of mandibular third molar and mandibular canal impacts. AB - OBJECTIVES: This study used cone-beam computed tomography (CBCT) images to categorize the relationships between the mandibular canal and the roots and investigated the prevalence of nerve damage. MATERIALS AND METHODS: Through CBCT images, contact and three-dimensional positional relationships between the roots of the mandibular third molar and the mandibular canal were investigated. With this data, prevalence of nerve damage according to the presence of contact and three-dimensional positional relationships was studied. Other factors that affected the prevalence of nerve damage were also investigated. RESULTS: When the mandibular third molar and the mandibular canal were shown to have direct contact in CBCT images, the prevalence of nerve damage was higher than in other cases. Also, in cases where the mandibular canal was horizontally lingual to the mandibular third molar and the mandibular canal was vertically at the cervical level of the mandibular third molar, the prevalence of nerve damage was higher than in opposite cases. The percentage of mandibular canal contact with the roots of the mandibular third molar was higher when the mandibular canal was horizontally lingual to the mandibular third molar. Finally, the prevalence of nerve damage was higher when the diameter of the mandibular canal lumen suddenly decreased at the contact area between the mandibular canal and the roots, as shown in CBCT images. CONCLUSION: The three-dimensional relationship of the mandibular third molar and the mandibular canal can help predict nerve damage and can guide patient expectations of the possibility and extent of nerve damage. PMID- 25551093 TI - Comparison of resorbable plates and titanium plates for fixation stability of combined mandibular symphysis and angle fractures. AB - OBJECTIVES: We compared resorbable plates with titanium plates for treatment of combined mandibular angle and symphyseal fractures. MATERIALS AND METHODS: Patients with mandibular angle and symphysis fractures were divided into two groups. The control (T) group received titanium plates while the experimental (R) group received resorbable plates. All procedures were carried out under general anesthesia using standard surgical techniques. We compared the frequency of wound dehiscence, development of infection, malocclusion, malunion, screw breakage, and any other technical difficulties between the two groups. RESULTS: Thirteen patients were included in the R group, where 39 resorbable plates were applied. The T group consisted of 16 patients who received 48 titanium plates. The mean age in the R and T groups was 28.29 and 24.23 years, respectively. Primary healing of the fractured mandible was obtained in all patients in both groups. Postoperative complications were minor and transient. Moreover, there were no significant differences in the rates of various complications between the two groups. Breakage of 3 screws during the perioperative period was seen in the R group, while no screws or plates were broken in the T group. CONCLUSION: Resorbable plates can be used to stabilize combined mandibular angle and symphysis fractures. PMID- 25551094 TI - Effect of recombinant human bone morphogenetic protein-2 on bisphosphonate treated osteoblasts. AB - OBJECTIVES: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphophonate therapy that has been reported in recent years. Osteoclastic inactivity by bisphosphonate is the known cause of BRONJ. Bone morphogenetic protein-2 (BMP-2) plays an important role in the development of bone. Recombinant human BMP-2 (rhBMP-2) is potentially useful as an activation factor for bone repair. We hypothesized that rhBMP-2 would enhance the osteoclast osteoblast interaction related to bone remodeling. MATERIALS AND METHODS: Human fetal osteoblast cells (hFOB 1.19) were treated with 100 uM alendronate, and 100 ng/mL rhBMP-2 was added. Cells were incubated for a further 48 hours, and cell viability was measured using an MTT assay. Expression of the three cytokines from osteoblasts, receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF), were analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Cell viability was decreased to 82.75%+/-1.00% by alendronate and then increased to 110.43%+/-1.35% after treatment with rhBMP-2 (P<0.05, respectively). OPG, RANKL, and M-CSF expression were all decreased by alendronate treatment. RANKL and M-CSF expression were increased, but OPG was not significantly affected by rhBMP-2. CONCLUSION: rhBMP2 does not affect OPG gene expression in hFOB, but it may increase RANKL and M-CSF gene expression. PMID- 25551095 TI - Outcomes of open versus closed treatment in the management of mandibular subcondylar fractures. AB - OBJECTIVES: To compare the clinical and radiological outcomes after closed reduction (CR) and open reduction and internal fixation (ORIF) in the management of subcondylar fractures. MATERIALS AND METHODS: Forty-eight patients presenting with subcondylar fracture between January 2010 and March 2013 were evaluated retrospectively. Fifteen patients were treated with CR and 33 patients with ORIF. The clinical and radiologic parameters were evaluated during follow-up (mean, 7.06 months; range, 3 to 36 months). RESULTS: In the CR group, no patients had any problems with regard to the clinical parameters. The average period of maxillomandibular fixation (MMF) was 5.47 days. The preoperative average tangential angulation of the fractured fragment was 3.67 degrees , and loss of ramus height was 2.44 mm. In the ORIF group, no clinical problems were observed, and the average period of MMF was 6.33 days. The preoperative average tangential angulation of the subcondylar fragment was 8.66 degrees , and loss of ramus height was 3.61 mm. CONCLUSION: CR provided satisfactory clinical results, though ORIF provided more accurate reduction of the fractured fragment. So there is no distinct displacement of fractured fragment, CR should be selected than ORIF because of no need for surgery. PMID- 25551096 TI - Mouth opening limitation caused by coronoid hyperplasia: a report of four cases. AB - Coronoid process hyperplasia is a rare condition that causes mouth opening limitation, otherwise known as trismus. The elongated coronoid processes impinge on the medial surfaces of the zygomatic arches when opening the mouth, which limits movement of the mandible and leads to trismus. Patients with trismus due to coronoid process hyperplasia do not have any definite symptoms such as temporomandibular joint pain or sounds upon clinical examination, and no significant abnormal signs are observed on panoramic radiographs or magnetic resonance images of the temporomandibular joint. Thus, the diagnosis of trismus is usually very difficult. However, computed tomography can help with the diagnosis, and the condition can be treated by surgery and postoperative physical therapy. This paper describes four cases of patients who visited our clinic for trismus and were subsequently diagnosed with coronoid process hyperplasia. Three were successfully treated with a coronoidectomy and postoperative physical therapy. PMID- 25551097 TI - A swelling of the maxilla: a case report and differential diagnosis. AB - Ossifying fibromas are benign fibro-osseous tumors of mesenchymal origin. Although ossifying fibromas have principally been found in the jaw, they have also been reported in the frontal, ethmoid, sphenoid, and temporal bones, as well as the orbit and anterior cranial fossa. Ossifying fibromas affecting the jaw exhibit variable behaviors ranging from slow growth to occasionally aggressive local destruction. In the present article, we discuss a differential diagnosis considered for maxillary swellings and report a rare case of ossifying fibroma occurring in the maxilla. PMID- 25551098 TI - Oral foregut cyst in the ventral tongue: a case report. AB - An oral foregut cyst is a rare congenital choristoma lined by the respiratory and/or gastrointestinal epithelium. The exact etiology has not been fully identified, but it is thought to arise from misplaced primitive foregut. This lesion develops asymptomatically but sometimes causes difficulty in swallowing and pronunciation depending on its size. Thus, the first choice of treatment is surgical excision. Surgeons associated with head and neck pathology should include the oral foregut cyst in the differential diagnosis for ranula, dermoid cyst, thyroglossal duct cyst and lymphangioma in cases of pediatric head and neck lesions. PMID- 25551099 TI - Knowledge, attitude and practice of urban and rural households towards principles of nutrition in Iran: results of NUTRIKAP survey. AB - BACKGROUND: The aim of this study was to assess knowledge, attitude and practice of urban and rural households toward principles of nutrition in Iran. METHODS: The study population was Iranian households who live in rural and urban areas in all provinces of the country. The sampling method at households' level in each province was single stage cluster sampling with equal size clusters. The incumbent data was collected by a structured questionnaire and through the interview with the eligible subject in each household. RESULTS: A total of 14,136 Iranian households were selected as total sample size, 9,149 urban households, and 4,987 rural households. Around 57.2% of urban and 49.5% of rural households was aware of food groups. Respectively in urban and rural households, about 35.1% and 39.7% had correct knowledge toward roles of food groups. Approximately 41.5% and 39.9% of households had accurate knowledge about reason of food eating in urban and rural areas, respectively. The results showed that 79.6% of them had favorable attitudes. The most of the households consumed red meat and poultry weekly whereas fish was eaten rarely. Fruits, vegetables and dairy were consumed daily in the most of households. Sugar intake was daily in the most of households and cream and butter intake was weekly. CONCLUSION: The most of households had moderate knowledge and good attitudes. Practice of families about food consumption was good. The results of this study can be used for proper intervention for improving of health society. PMID- 25551101 TI - Amelioration of lipid peroxidation in vivo and in vitro by Satureja khozestanica essential oil in alloxan-induced diabetic rats. AB - BACKGROUND: We examined possible protective effect of Satureja khozestanica essential oil (SKE) on in vivo and in vitro lipid peroxidation in alloxan-induced Type 1 diabetic rats. METHODS: Thirty Sprage-dawley male rats were divided into three groups randomly; group one as control, group two diabetic untreatment, and group three treatments with SKE by 500 ppm in drinking water, respectively. Diabetes was induced in the second and third groups by alloxan injection subcutaneously. After 8 weeks, animals were anaesthetized, livers and kidneys were then removed immediately and used fresh or kept frozen until their lipid peroxidation analysis. Lipid peroxidation was determined by measurement of thiobarbituric acid reactive substances (TBARS). Blood samples were also collected before killing to measure the levels of fasting blood suger (FBS) and lipid peroxidation. RESULTS: SKE significantly inhibited the levels of FBS, TBARS serum and kidney content in treated group compared with the diabetic untreated group. Also the levels of malonedialdehyde liver content unaltered in treated group. SKE significantly inhibited LDL oxidation in vitro. CONCLUSIONS: The findings showed that SKE exerts beneficial effects on the lipid peroxidation in alloxan-induced Type 1 diabetic rats. PMID- 25551100 TI - Bisphosphonate therapy in pediatric patients. AB - Although for many decades bisphosphonates were used for adult bone loss, bisphosphonate administration in pediatric patients is new and was initiated in the past 15-year. The indications for pediatric bisphosphonates was extended to childhood malignancies with bone involvement, after additional effects were unveiled for bisphosphonates with recent research. In this article we review childhood bone loss and conditions with bone involvement in which bisphosphonate therapy have been used. We also review mechanisms of action of bisphosphonates, and present indications of bisphosphonate therapy in pediatric patients based on results of clinical trials. PMID- 25551103 TI - Changes in glycosylated haemoglobin and treatment outcomes in patients with tuberculosis in Iran: a cohort study. AB - BACKGROUND: Diabetes mellitus (DM) affects tuberculosis (TB) treatment outcomes, mostly by increasing recurrence, mortality and treatment failure. The objectives were to determine the pattern of change in glycosylated haemoglobin (HbA1c) level in new TB patients admitted to hospital at the start and 3-months after TB treatment, and to relate the measurements at these two time intervals to whether patients successfully completed treatment. METHODS: A prospective cohort study was conducted on hospitalized new TB patients at Masih Daneshvari Hospital from 2012 to 2013. All patients were tested for HbA1c at the beginning and 3 months after initiation of TB treatment. Changes in HbA1c were compared to TB treatment outcome. RESULTS: There were 317 new TB cases admitted to hospital of which 158 had HbA1c at baseline and 3-months. Of these, 67 (42%) had normal values, 54 had an elevated HbA1c at either base-line or 3-months (uncertain diabetes status) and 37 (24%) had elevated HbA1c (>=6.5%) at both time points (DM). There were differences between the groups: those with DM were older, had a known history of DM and a higher prevalence of cavities on chest x-ray. There were 150 (95%) patients who successfully completed treatment with no significant differences between the groups. CONCLUSION: There were changes in HbA1c during the first three-months of anti-TB treatment, but these were not associated with differences in TB treatment outcomes. Transient hyperglycemia should be considered in TB patients and needs to be taken into account in planning care and management. PMID- 25551105 TI - Editorial message. PMID- 25551102 TI - Lifestyle advice follow-up improve glycemic control, redox and inflammatory status in patients with type 2 diabetes. AB - BACKGROUND: The dietary composition associated to physical activity could play a significant role in improving insulin sensitivity and reducing risk of diabetes and its complications. This study was designed to investigate whether glycemic control, redox and inflammatory status impairments in patients with type 2 diabetes (T2D), were improved after 90 (d90) and 180 (d180) days follow-up of nutritional advices. METHODS: Patients with T2D (n = 85) aged of 50 +/- 8 years (Female/Male, 45/40), treated with oral antidiabetics (OAD) alone, with a body mass index (BMI) of 26 +/- 2, were recruited. At the beginning of the study (d0), patients were instructed to follow-up nutritional advices adapted to T2D, and 30 to 45 min of walking per day. Assays were realized at d90 and d180 of follow-up. Data were compared by student 't' test and Pearson's correlation coefficients were determined between biochemical parameters and nutritional advices follow-up. RESULTS: Reduced glycated haemoglobin (HbA1c), glucose and total cholesterol (TC) were noted in patients with T2D, at d90 and d180 compared to d0. Thiobarbituric acid reactive substances (TBARS) and hydroperoxyde levels were lower at d90 and d180 than d0. Serum nitric oxide (NO) was decreased at d180 compared to d0 and d90. In erythrocytes, superoxide dismutase (SOD) activity increased by 7% at d180 vs d0. Moreover, activity of glutathione peroxidase (GPx) enhanced (P < 0.05), whereas that of glutathione reductase (GRed) decreased (P < 0.001) at d90 vs d0. Resistin values were lower at d180 than d0 and d90 (P < 0.001). A progressive decrease in tumor necrosis factor-alpha (TNF-alpha) was observed at d90 and d180 vs d0. CONCLUSION: Nutritional advices associated to physical activity improve glycemic control, serum TC, redox and inflammatory status in T2D, in particular after 3 months of counseling. However, these results need to be supported with a longer dietary treatment and more rigorous control during the follow-up. PMID- 25551104 TI - Paraoxonase-1 gene Q192R and L55M polymorphisms and risk of cardiovascular disease in Egyptian patients with type 2 diabetes mellitus. AB - BACKGROUND: Increased oxidative stress or an impaired antioxidant defense mechanism may play a crucial role in the onset and progression of atherosclerosis. Recently, Paraoxonase -1 (PON1) which accounts for most of the antioxidant effect of high density lipoprotein (HDL) cholesterol has been presented as a potential therapeutic agent against atherosclerosis development. Allele frequencies for PON1 gene that influence enzyme concentration as well as activity differ greatly among ethnic groups and data from several studies showed ethnic variations in the interpretation of cardiovascular disease (CVD) associated with PON1 polymorphisms. In this work, we investigated PON1 Q192R and L55M polymorphisms in Egyptian patients with type 2 diabetes mellitus (T2DM) and its association with CVD. METHODS: The study included 184 subjects classified into 3 groups; T2DM, T2DM + CVD, and healthy controls. PON1 polymorphisms were genotyped by real-time PCR and PON1 concentration was assayed in serum by ELISA (enzyme linked immunesorbent assay). RESULTS: Genotype and allele frequencies of Q192R were significantly different between controls and diabetic patients. Frequency of QQ genotype was significantly higher in healthy controls, while QR and RR genotypes were significantly higher in diabetic patients (p = 0.02). Frequency of 55LL and LM genotypes were significantly higher in patients than in controls (p = 0.009). Q192R polymorphism associated with CVD in our diabetic patients (p = 0.01) and with low serum PON1 concentration (p = 0.04). Multiple logistic regression analysis revealed significant correlations between 192R and other independent CVD risk factors. CONCLUSION: PON1 192R and 55 L alleles are associated with T2DM. Q192R polymorphism is associated with CVD and lower serum enzyme concentration and might represents a novel risk factor for CVD in Egyptian patients with T2DM. PMID- 25551107 TI - Message from the guest editor. PMID- 25551108 TI - Epidemiology of neural tube defects. AB - OBJECTIVE: To find the prevalence of neural tube defects (NTDs), and compare the findings with local and international data, and highlight the important role of folic acid supplementation and flour fortification with folic acid in preventing NTDs. METHODS: This is a retrospective study of data retrieved from the medical records of live newborn infants admitted to the Neonatal Intensive Care Unit (NICU), Security Forces Hospital (SFH), Riyadh, Saudi Arabia with NTDs spanning 14 years (1996-2009). All pregnant women on their first antenatal visit to the primary care clinic were prescribed folic acid 0.5 mg daily, or 5 mg if there is a family history of NTD. The pre-fortification prevalence is compared to post fortification, before and after excluding syndromic, genetic, and chromosomal causes. The results were compared with reports from other parts of Saudi Arabia and internationally, through a literature search using MEDLINE. RESULTS: The prevalence of NTDs during the period was 1.2 per 1000 live births. The pre fortification of flour with folic acid prevalence was 1.46 per 1000 live births. The post-fortification prevalence was 1.05 (p=0.103). After excluding syndromic, genetic, and chromosomal causes from calculation of the prevalence, there was a significant reduction in the prevalence, from 1.46 to 0.81 per 1000 live births (p=0.0088). Syndromic, genetic, and chromosomal causes were identified in 20 cases (19.4%). Only 2% of mothers received preconception folic acid, and only 10% of them received it during the first 4 weeks of gestation. CONCLUSION: Despite the implementation of fortification of flour with folic acid since 2001, the prevalence of NTDs in the Kingdom of Saudi Arabia is still high. This is due to the impact of genetic, syndromic, and chromosomal causes of NTD not preventable by folic acid. Other factors like unplanned pregnancy and lack of awareness of the role of folic acid in preventing nonsyndromic causes, play a significant role. PMID- 25551109 TI - Neural tube defects. Challenging, yet preventable. PMID- 25551106 TI - Epidemiology, prenatal management, and prevention of neural tube defects. AB - This review article discusses the epidemiology, risk factors, prenatal screening, diagnosis, prevention potentials, and epidemiologic impact of neural tube defects (NTDs). The average incidence of NTDs is 1/1000 births, with a marked geographic variation. In the developed countries, the incidence of NTDs has fallen over recent decades. However, it still remains high in the less-developed countries in Latin America, Africa, the Middle East, Asia, and the Far East (>1 to 11/1000 births). Recognized NTDs risks include maternal diabetes, obesity, lower socioeconomic status, hyperthermia, and exposure to certain teratogens during the periconceptional period. Periconceptional folic acid supplementation decreased the prevalence of NTDs by 50-70%, and an obligatory folic acid fortification of food was adopted in several countries to reach women with unplanned pregnancies and those facing social deprivation. Prevention of NTDs can be accelerated if more, especially low income countries, adopted fortification of the staple food in their communities. PMID- 25551110 TI - Sirenomelia and severe caudal regression syndrome. AB - OBJECTIVE: To describe cases of sirenomelia and severe caudal regression syndrome (CRS), to report the prevalence of sirenomelia, and compare our findings with the literature. METHODS: Retrospective data was retrieved from the medical records of infants with the diagnosis of sirenomelia and CRS and their mothers from 1989 to 2010 (22 years) at the Security Forces Hospital, Riyadh, Saudi Arabia. A perinatologist, neonatologist, pediatric neurologist, and radiologist ascertained the diagnoses. The cases were identified as part of a study of neural tube defects during that period. A literature search was conducted using MEDLINE. RESULTS: During the 22-year study period, the total number of deliveries was 124,933 out of whom, 4 patients with sirenomelia, and 2 patients with severe forms of CRS were identified. All the patients with sirenomelia had single umbilical artery, and none were the infant of a diabetic mother. One patient was a twin, and another was one of triplets. The 2 patients with CRS were sisters, their mother suffered from type II diabetes mellitus and morbid obesity on insulin, and neither of them had a single umbilical artery. Other associated anomalies with sirenomelia included an absent radius, thumb, and index finger in one patient, Potter's syndrome, abnormal ribs, microphthalmia, congenital heart disease, hypoplastic lungs, and diaphragmatic hernia. CONCLUSION: The prevalence of sirenomelia (3.2 per 100,000) is high compared with the international prevalence of one per 100,000. Both cases of CRS were infants of type II diabetic mother with poor control, supporting the strong correlation of CRS and maternal diabetes. PMID- 25551111 TI - Split cord malformation associated with spinal open neural tube defect. AB - OBJECTIVE: To illustrate the clinical and radiological findings of split cord malformation (SCM) in patients with spinal open neural tube defect (SONTD), and report the outcome of their treatment. METHODS: A retrospective study of the clinical and radiological findings of 11 patients diagnosed with SCM, identified among 83 patients with SONTD at King Khalid University Hospital, in Riyadh, Saudi Arabia between 1995 and 2010. RESULTS: There were 6 girls and 5 boys; their age ranged from less than a year to 9 years (mean 4.2 years). Six patients had type I SCM, and 5 patients type II SCM. The CT and MRI imaging showed characteristic bony, cartilaginous, or fibrous septum, and other SONTD-associated anomalies. Seven patients were graded A & B according to the Frankel grading score, and none of them required surgery, while worsening neurology led to surgical intervention in 3 patients, with clinical improvement after surgery, and one patient that underwent cord untethering remained stable. CONCLUSION: Split cord malformation is not uncommon among patients with SONTD. It tends to involve mainly the lumbar spine, and female predominance is more remarkable in type I. Neurological manifestations of SCM may be superimposed with SONTD. Surgery is effective for symptomatic patients, and not indicated in the severely disabled. PMID- 25551112 TI - Genetic, chromosomal, and syndromic causes of neural tube defects. AB - OBJECTIVE: To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. METHODS: We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. RESULTS: Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. CONCLUSION: There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions. PMID- 25551114 TI - Agenesis of the corpus callosum associated with spinal open neural tube defect. AB - OBJECTIVE: To ascertain the incidence and clinical implications of agenesis of the corpus callosum (ACC) in spinal open neural tube defects (SONTD). METHODS: All cases of SONTD registered at the Spina Bifida Clinic in King Khalid University Hospital, Riyadh, Saudi Arabia between 1995 and 2010 were retrospectively reviewed, and mid-sagittal MRI of the corpus callosum (CC) area was analyzed in each case. Neurodevelopmental outcome was classified as poor in children with seizures, severe neurodevelopmental impairment, or death. RESULTS: Thirty-eight patients (45.8%) with ACC were identified among 83 cases with SONTD. Patients' age ranged between one and 16 years. Total ACC was found in 10 patients, partial ACC in 25, and in 3 patients, the CC was hypoplastic. Active hydrocephalus was an associated finding in 9 out of 10 patients with total ACC, 22 out of 25 with partial ACC, and in all patients with hypoplasia of the CC. Thirteen patients (34.2%) had normal intellectual function, whereas 24 patients presented with learning disability, epilepsy, or poor intellectual function; and one patient died of respiratory failure. CONCLUSION: Agenesis of the corpus callosum is found in a significant portion of patients with SONTD. When associated with hydrocephalus, its presence affects neuro-developmental outcome. PMID- 25551113 TI - Classification, clinical features, and genetics of neural tube defects. AB - Neural tube defects (NTDs) constitute a major health burden (0.5-2/1000 pregnancies worldwide), and remain a preventable cause of still birth, neonatal, and infant death, or significant lifelong handicaps. The malformations result from failure of the neural folds to fuse in the midline, and form the neural tube between the third and the fourth week of embryonic development. This review article discusses their classification, clinical features, and genetics. Most NTDs are sporadic and both genetic, and non-genetic environmental factors are involved in its etiology. Consanguinity was suggested to contribute to the high incidence of NTDs in several countries, including Saudi Arabia. Syndromes, often associated with chromosomal anomalies, account for <10% of all NTDs; but a higher proportion (20%) has been documented in Saudi Arabia. Genetic predisposition constitutes the major underlying risk factor, with a strong implication of genes that regulate folate one-carbon metabolism and planar cell polarity. PMID- 25551115 TI - Uronephrological outcomes of patients with neural tube defects. Does a spina bifida clinic make a difference? AB - OBJECTIVE: To review the uronephrological outcomes of myelomeningocele (MMC) patients attending a Spina Bifida Clinic. METHODS: We retrospectively reviewed the medical records of all patients from the combined Spina Bifida Clinic, at King Khalid University Hospital, Riyadh, Saudi Arabia between 1999 and 2009 who had at least one year of follow-up with us. We examined their demographic data, uronephrological status at presentation, most recent follow-up, and the rate of surgical intervention. RESULTS: During the 10-year period, 188 patients were actively followed-up. The mean age at presentation was 5.3 years +/- 3.6 SD. At their last follow-up, 109 patients (58%) were using clean intermittent catheterization, 44 (23%) had received Botox injections, and 26 (14%) had undergone bladder reconstruction. Most (66%) patients were older than 3 years when they presented to us; this group had a significantly higher rate of surgical intervention (Botox or reconstruction) compared with those who came to us earlier (p=0.003 for patients receiving Botox injections, and p=0.025 for patients undergoing bladder reconstruction). CONCLUSION: Our multidisciplinary Spina Bifida Clinic is an integral part of MCC management to reach a safe urological outcome. Early presentations to our clinic resulted in a lesser need for surgical intercession compared with those who presented at more than 3 years old. PMID- 25551116 TI - Epidemiology of neural tube defects in Saudi Arabia. AB - OBJECTIVE: To evaluate the distribution and pattern of neural tube defects in Saudi Arabia by creating a hospital based registry. METHODS: All cases registered in the King Faisal Specialist Hospital and Research Center (KFSH&RC) neural tube defect (NTD) registry since it was established in October 2000 until December 2012 were studied through active surveillance comprising a registrar who collects NTD information by reviewing the patient's medical records, and interviewing patient's families. RESULTS: The total number of patients registered from October 2000 to December 2012 was 718 patients. There were more females (417, 58%) than males (301, 42%). Of 620 mothers who underwent antenatal ultrasonography; 392 (63%) were diagnosed at birth, and 204 (33%) were diagnosed with antenatal hydrocephalus. In our registry sample, most mothers (95%) did not take folic acid 3 months prior to pregnancy, and 76% did not take folic acid during the 3 months after conception with the affected child. Only 5% received folic acid prior to conception. CONCLUSION: The KFSH&RC-NTD registry has met its objectives as a source of data that may significantly contribute to the prevention of NTDs, and improving quality of care for NTD patients through active publication of registry findings and management approaches. PMID- 25551117 TI - Split cord malformation type I distal to segmental myelomeningocele. AB - The coexistence of myelomeningocele (MMC) and split cord malformation (SCM) is a well-known phenomenon. The SCM is usually above or at the level of the MMC. Split cord malformation distal to the MMC is considered to be the rarest form of such a combination. We report a case of SCM (type I) distal to the MMC diagnosed pre operatively. Repair of the MMC and the SCM were carried out in the same setting. PMID- 25551118 TI - An overview of the Prince Salman Center for Disability Research scientific outcomes. PMID- 25551119 TI - No money, no research. PMID- 25551120 TI - The author file: Alexei Vyssotski. PMID- 25551121 TI - Cell biology: Versatile clusters formed by light. PMID- 25551122 TI - Sensors and probes: Voltage sensors revisited. PMID- 25551123 TI - Proteomics: Probing the protein structure-ome. PMID- 25551124 TI - Genetics: Cleaving RNA with Cas9. PMID- 25551125 TI - Biochemistry: Protein interactions in situ. PMID- 25551126 TI - Sequencing: Rereading familiar messages. PMID- 25551127 TI - Cell biology: Prostate cancer in 3D. PMID- 25551128 TI - Author's reply: To PMID 24953576. PMID- 25551129 TI - Henoch-Schonlein purpura in children: limited benefit of corticosteroids. AB - QUESTION: A child recently presented to my office with lower limb petechiae, arthralgia, and abdominal pain characteristic of Henoch-Schonlein purpura (HSP). Will systemic corticosteroids help relieve these symptoms and prevent potential HSP complications such as intussusception and nephritis? ANSWER: Henoch-Schonlein purpura is a common and self-limiting disease in children. Current evidence does not support universal treatment of HSP with corticosteroids. Recent trials and meta-analyses found that corticosteroids do not prevent the onset of renal disease or abdominal complications. However, corticosteroids are effective as treatment of abdominal pain, arthralgia, and purpura. Clinicians are advised to use their discretion in choosing which patients might benefit most from oral corticosteroid treatment. PMID- 25551130 TI - Roles of nurse practitioners and family physicians in community health centres. AB - OBJECTIVE: To describe the models of practice used by nurse practitioners (NPs) and FPs in community health centres (CHCs), and to examine the roles of NPs and FPs in these models. DESIGN: Cross-sectional study using an organizational survey completed by managers of the CHC sites, as well as administrative data on patient sociodemographic characteristics and encounter activities. SETTING: A total of 21 CHCs (13 main sites and 8 satellite sites) operating in eastern Ontario during the period from December 1, 2006, to November 30, 2008. PARTICIPANTS: A total of 44 849 patients, 53 full-time equivalent FPs, and 41 full-time equivalent NPs. MAIN OUTCOME MEASURES: Family physicians' and NPs' models of practice, the sociodemographic characteristics and medical profiles of patients who were treated in each model of practice, and FPs' and NPs' use of time. RESULTS: Patients were attributed to 1 of 3 models of practice in CHCs based on the proportion of visits to FPs and NPs: FP care (53% of patients), NP care (29%), and shared care (18%). Patients who received care in the NP model of practice were younger and more likely to be female, be homeless, and not have postsecondary education.Patients who received care in the FP model of practice had more complex medical conditions (cardiovascular disease, mental illness, lung disease, and diabetes) and more annual visits. Patients who received care in the shared care model had intermediate profiles. Nurse practitioners performed more off-site care and walk-in visits. Family physicians and NPs spent a similar proportion of time performing various duties such as direct clinical care and administration tasks. CONCLUSION: Although NPs mainly cared for their own patient panels (in the NP care model), they did share some patients with FPs and provide some care to patients under the FP model of practice. Patients who were cared for by FPs and NPs had quite different characteristics. PMID- 25551131 TI - Efficacy and tolerability of benzodiazepines for the treatment of behavioral and psychological symptoms of dementia: a systematic review of randomized controlled trials. AB - The objective of this review is to summarize the available data on the use of benzodiazepines for the treatment of behavioral and psychological symptoms of dementia (BPSD) from randomized controlled trials (RCTs). A systematic search of 5 major databases, PubMed, MEDLINE, PsychINFO, EMBASE, and Cochrane Collaboration, yielded a total of 5 RCTs. One study compared diazepam to thioridazine, 1 trial compared oxazepam to haloperidol and diphenhydramine, 1 trial compared alprazolam to lorazepam, 1 trial compared lorazepam to haloperidol, and 1 trial compared intramuscular (IM) lorazepam to IM olanzapine and placebo. The data indicates that in 4 of the 5 studies, there was no significant difference in efficacy between the active drugs to treat the symptoms of BPSD. One study indicated that thioridazine may have better efficacy than diazepam for treating symptoms of BPSD. In 1 study, the active drugs had greater efficacy in treating BPSD when compared to placebo. There was no significant difference between the active drugs in terms of tolerability. However, in 2 of the 5 studies, about a third of the patients were noted to have dropped out of the studies. Available data, although limited, do not support the routine use of benzodiazepines for the treatment of BPSD. But these drugs may be used in certain circumstances where other psychotropic medications are unsafe for use in individuals with BPSD or when there are significant medication allergies or tolerability issues with certain classes of psychotropic medications. PMID- 25551132 TI - Association of apolipoprotein E genetic variation in Alzheimer's disease in Indian population: a meta-analysis. AB - BACKGROUND: Dementia is an age-related disorder associated with elderly population, resulting from interaction of lifestyle risk factors with genetic, vascular, and other risk factors to affect risk of disease. Alzheimer's disease (AD) is the most common form of dementia, estimated to be affecting 4.4% of the population older than 65 years of age. Apolipoprotein E (ApoE) epsilon4 allele is a known genetic risk factor for AD, which not only predisposes and influences the severity of pathological changes in the brain, thereby modifying the age at onset, but also promotes cognitive decline early in nondemented older people. OBJECTIVES: To review the published evidence on ApoE polymorphism with the susceptibility to AD and frequency of ApoE epsilon4 genotype (epsilon4/-) and homozygotes (epsilon4/4) among patients diagnosed with AD as compared to controls in Indian Population. MATERIALS AND METHODS: In the present study, MEDLINE was reviewed for articles published till June 2013 supplemented by citation analysis from retrieved articles to select case-control studies. A meta-analysis was performed to demonstrate the association of ApoE gene with vascular dementia by random effects to demonstrate models. The association was assessed by odds ratio (OR) with 95% confidence intervals (CIs). STUDY SELECTION: Case-control studies, using clinical criteria for AD with ApoE polymorphism determined for allele and genotype in both cases and controls. STATISTICAL ANALYSIS: A meta-analysis was performed to demonstrate the association of ApoE gene with AD by random effects to demonstrate models. The association was assessed by OR with 95% CIs. We also looked for publication bias and performed sensitivity analysis to investigate the influence of each individual study. RESULTS: A total of 7 studies representing data from 417 patients with AD and 651 controls in the Indian population were eligible. The ApoE epsilon2/4, epsilon3/4, and epsilon4/4 genotypes (OR = 3.93, 95% CI: 1.60-9.68; OR = 4.18, 95% CI: 2.54-6.87; OR = 4.81, 95% CI: 1.95-11.86, respectively) as well as ApoE epsilon4 allele (OR = 5.90, 95% CI: 3.44-10.13) were associated with an increased risk of AD, whereas ApoE epsilon2/3, epsilon3/3 genotypes (OR = 0.52, 95% CI: 0.32-0.83; OR = 0.28, 95% CI: 0.19-0.42), and ApoE epsilon3 allele (OR = 0.29, 95% CI: 0.17-0.50) were found to be marginally significant protective factors for AD. There was no significant difference in ApoE epsilon2/2 genotype and ApoE epsilon2 allele frequency (OR = 0.42; 95% CI: 0.11-1.68; OR = 0.69, 95% CI: 0.37-1.31, respectively) in patients with AD and controls. CONCLUSIONS: These results indicate that all genotypes of ApoE epsilon4 allele, that is, epsilon2/4, epsilon3/4, and epsilon4/4, are associated with an increased risk of AD, whereas ApoE epsilon2/2, epsilon2/3, and epsilon3/3 are protective for AD. PMID- 25551133 TI - Learning behaviour and preferences of family medicine residents under a flexible academic curriculum. AB - OBJECTIVE: To determine family medicine residents' learning behaviour and preferences outside of clinical settings in order to help guide the development of an effective academic program that can maximize their learning. DESIGN: Retrospective descriptive analysis of academic learning logs submitted by residents as part of their academic training requirements between 2008 and 2011. SETTING: London, Ont. PARTICIPANTS: All family medicine residents at Western University who had completed their academic program requirements (N = 72) by submitting 300 or more credits (1 credit = 1 hour). MAIN OUTCOME MEASURES: Amount of time spent on various learning modalities, location where the learning took place, resources used for self-study, and the objective of the learning activity. RESULTS: A total of 72 residents completed their academic requirements during the study period and logged a total of 25 068 hours of academic learning. Residents chose to spend most of their academic time engaging in self-study (44%), attending staff physicians' teaching sessions (20%),and participating in conferences, courses, or workshops (12%) and in postgraduate medical education sessions (12%). Textbooks (26%), medical journals (20%), and point-of-care resources (12%) were the 3 most common resources used for self-study. The hospital (32%), residents' homes (32%),and family medicine clinics (14%) were the most frequently cited locations where academic learning occurred. While all physicians used a variety of educational activities, most residents (67%) chose self-study as their primary method of learning. The topic for academic learning appeared to have some influence on the learning modalities used by residents. CONCLUSION: Residents used a variety of learning modalities and chose self-study over other more traditional modalities (eg, lectures) for most of their academic learning. A successful academic program must take into account residents' various learning preferences and habits while providing guidance and training in the use of more effective learning methods and resources to maximize educational outcomes. PMID- 25551135 TI - Evaluation of an initiation protocol of 4 mg of warfarin for atrial fibrillation in the outpatient setting. AB - OBJECTIVE: To describe the efficacy and safety of an initiation algorithm for 4 mg of warfarin in ambulatory patients with atrial fibrillation. DESIGN: Prospectively planned retrospective chart review. SETTING: Centre for Family Medicine Family Health Team in Kitchener, Ont. PARTICIPANTS: Ambulatory patients requiring anticoagulation for atrial fibrillation. INTERVENTIONS: Patients were prescribed 4 mg of warfarin to be taken once daily for 3 days. An international normalized ratio (INR) measured on the morning of the fourth day was used to predict the maintenance dose of warfarin. Subsequent INR measurements were obtained biweekly until patients reached their actual maintenance dose. MAIN OUTCOME MEASURES: Number of INR values greater than or equal to 4.0 before the warfarin maintenance dose was achieved. Secondary outcome measures included thromboembolic and bleeding events, number of days required to reach therapeutic INR, and correlation between predicted and actual warfarin maintenance dose. RESULTS: Twenty-five patients were included in the study. The average age was 76.0 years (range 56.0 to 89.0), and 17 patients were women. The average CHADS2 (congestive heart failure, hypertension, age >= 75 years,diabetes mellitus, and stroke or transient ischemic attack) score was 2.0.Only 1 patient had an INR greater than 4.0 during the study period. The mean time to achieve a therapeutic INR was 11.0 days. The day 4 INR was moderately predictive of the maintenance dose (r2 = 0.47). There were no adverse events that required medical attention during the study period. CONCLUSION: In this pilot study, an initiation algorithm for 4 mg of warfarin was safe and achieved a therapeutic INR within a reasonable time frame in outpatients with atrial fibrillation. PMID- 25551134 TI - Preventing Alzheimer's disease by means of natural selection. AB - The amyloid cascade model for the origin of sporadic forms of Alzheimer's disease (AD) posits that the imbalance in the production and clearance of beta-amyloid is a necessary condition for the disease. A competing theory called the entropic selection hypothesis asserts that the primary cause of sporadic AD is age-induced mitochondrial dysregulation and the following cascade of events: (i) metabolic reprogramming-the upregulation of oxidative phosphorylation in compensation for insufficient energy production in neurons, (ii) natural selection-competition between intact and reprogrammed neurons for energy substrates and (iii) propagation-the spread of the disease due to the selective advantage of neurons with upregulated metabolism. Experimental studies to evaluate the predictions of the amyloid cascade model are being continually retuned to accommodate conflicts of the predictions with empirical data. Clinical trials of treatments for AD based on anti-amyloid therapy have been unsuccessful. We contend that these anomalies and failures stem from a fundamental deficit of the amyloid hypothesis: the model derives from a nuclear-genomic perspective of sporadic AD and discounts the bioenergetic processes that characterize the progression of most age-related disorders. In this article, we review the anomalies of the amyloid model and the theoretical and empirical support for the entropic selection theory. We also discuss the new therapeutic strategies based on natural selection which the model proposes. PMID- 25551136 TI - Computational investigation of cicada aerodynamics in forward flight. AB - Free forward flight of cicadas is investigated through high-speed photogrammetry, three-dimensional surface reconstruction and computational fluid dynamics simulations. We report two new vortices generated by the cicada's wide body. One is the thorax-generated vortex, which helps the downwash flow, indicating a new phenomenon of lift enhancement. Another is the cicada posterior body vortex, which entangles with the vortex ring composed of wing tip, trailing edge and wing root vortices. Some other vortex features include: independently developed left- and right-hand side leading edge vortex (LEV), dual-core LEV structure at the mid wing region and near-wake two-vortex-ring structure. In the cicada forward flight, approximately 79% of the total lift is generated during the downstroke. Cicada wings experience drag in the downstroke, and generate thrust during the upstroke. Energetics study shows that the cicada in free forward flight consumes much more power in the downstroke than in the upstroke, to provide enough lift to support the weight and to overcome drag to move forward. PMID- 25551137 TI - Screening for lifestyle and mental health risk factors in the waiting room: feasibility study of the Case-finding Health Assessment Tool. AB - OBJECTIVE: To assess the feasibility and acceptability of administering the validated Case-finding Health Assessment Tool (CHAT) in Canadian family practice waiting rooms to identify risk factors for depression, anxiety, anger control,smoking, drinking, other drug use, gambling, exposure to abuse, and physical inactivity. DESIGN: Cross-sectional survey. SETTING: One urban academic family practice and one inner-city community health centre in British Columbia. PARTICIPANTS: Convenience sample of consecutive adult patients (19 years of age or older) and their attending family physicians. MAIN OUTCOME MEASURES: Rates of completion; positive responses to and wanting help with identified lifestyle and mental health risk factors; rates of objections to any questions; and positive and negative comments about the CHAT by participating physicians and patients. RESULTS: A total of 265 eligible adults presented in the waiting rooms over 5 full days and 3 half-days, 176 (66%) of whom enrolled in the study; 161(91%) completed the CHAT, and 107 (66%) completed acceptability feedback forms. The prevalence of risk factors among patients in the academic and inner-city practice samples was different, with 20% and 63%, respectively,recording positive responses to both depression screening questions,34% and 60% positive for anxiety, 11% and 71% currently smoking, 6%and 22% feeling they needed to cut down on alcohol, 1% and 48% having used recreational drugs in the past year, and 11% and 65% with problems controlling anger. While many requested help with reducing risk factors,such as smoking (20%) and mental health symptoms (25% to 27%), a total of 35% (57 of 161) wanted help with an identified issue that day. Patients and physicians found the CHAT acceptable, with no patients objecting to any question except the alcohol question (2 objected). Most comments were positive. CONCLUSION: The CHAT allowed efficient identification of 9 risk factors, as well as identification of those wanting help. It could be used to screen all or targeted adult Canadian primary care patients in waiting rooms. PMID- 25551138 TI - First carrot, then stick: how the adaptive hybridization of incentives promotes cooperation. AB - Social institutions often use rewards and penalties to promote cooperation. Providing incentives tends to be costly, so it is important to find effective and efficient policies for the combined use of rewards and penalties. Most studies of cooperation, however, have addressed rewarding and punishing in isolation and have focused on peer-to-peer sanctioning as opposed to institutional sanctioning. Here, we demonstrate that an institutional sanctioning policy we call 'first carrot, then stick' is unexpectedly successful in promoting cooperation. The policy switches the incentive from rewarding to punishing when the frequency of cooperators exceeds a threshold. We find that this policy establishes and recovers full cooperation at lower cost and under a wider range of conditions than either rewards or penalties alone, in both well-mixed and spatial populations. In particular, the spatial dynamics of cooperation make it evident how punishment acts as a 'booster stage' that capitalizes on and amplifies the pro-social effects of rewarding. Together, our results show that the adaptive hybridization of incentives offers the 'best of both worlds' by combining the effectiveness of rewarding in establishing cooperation with the effectiveness of punishing in recovering it, thereby providing a surprisingly inexpensive and widely applicable method of promoting cooperation. PMID- 25551139 TI - Memory-endowed US cities and their demographic interactions. AB - A quantitative understanding of cities' demographic dynamics is becoming a potentially useful tool for planning sustainable growth. The concomitant theory should reveal details of the cities' past and also of its interaction with nearby urban conglomerates for providing a reasonably complete picture. Using the exhaustive database of the Census Bureau in a time window of 170 years, we exhibit here empirical evidence for time and space correlations in the demographic dynamics of US counties, with a characteristic memory time of 25 years and typical distances of interaction of 200 km. These correlations are much larger than those observed in a European country (Spain), indicating more coherent evolution in US cities. We also measure the resilience of US cities to historical events, finding a demographical post-traumatic amnesia after wars (such as the American Civil War) or economic crisis (such as the 1929 Stock Market Crash). PMID- 25551140 TI - A continuum model of docking of synaptic vesicle to plasma membrane. AB - Neurotransmitter release from neuronal terminals is governed by synaptic vesicle fusion. Vesicles filled with transmitters are docked at the neuronal membrane by means of the SNARE machinery. After a series of events leading up to the fusion pore formation, neurotransmitters are released into the synaptic cleft. In this paper, we study the mechanics of the docking process. A continuum model is used to determine the deformation of a spherical vesicle and a plasma membrane, under the influence of SNARE-machinery forces and electrostatic repulsion. Our analysis provides information on the variation of in-plane stress in the membranes, which is known to affect fusion. Also, a simple model is proposed to study hemifusion. PMID- 25551141 TI - Classification of the pre-settlement behaviour of barnacle cyprids. AB - Barnacle cyprids exhibit a complex swimming and exploratory behaviour on surfaces and settlement is a consequence of extensive surface probing and selection of suitable settlement sites. In this work, the behaviour of cyprids in their pre settlement phase was studied by three-dimensional video stereoscopy. With this technique, three-dimensional trajectories were obtained that were quantitatively analysed. The velocity during vertical sinking of cyprids of Balanus amphitrite was used with a modified form of Stokes' law to calculate their mean body density. Furthermore, a classification of the swimming patterns allowed the extension of existing models describing cyprid locomotion and swimming behaviour. The patterns were characterized with respect to their occurrence, transition between patterns and their velocity distribution, and motions were identified that led to surface contacts. This analysis provides a classification framework, which can assist future attempts to identify behavioural responses of cyprids to specific settlement cues. PMID- 25551142 TI - Quantifying long-term evolution of intra-urban spatial interactions. AB - Understanding the long-term impact that changes in a city's transportation infrastructure have on its spatial interactions remains a challenge. The difficulty arises from the fact that the real impact may not be revealed in static or aggregated mobility measures, as these are remarkably robust to perturbations. More generally, the lack of longitudinal, cross-sectional data demonstrating the evolution of spatial interactions at a meaningful urban scale also hinders us from evaluating the sensitivity of movement indicators, limiting our capacity to understand the evolution of urban mobility in depth. Using very large mobility records distributed over 3 years, we quantify the impact of the completion of a metro line extension: the Circle Line (CCL) in Singapore. We find that the commonly used movement indicators are almost identical before and after the project was completed. However, in comparing the temporal community structure across years, we do observe significant differences in the spatial reorganization of the affected geographical areas. The completion of CCL enables travellers to re-identify their desired destinations collectively with lower transport cost, making the community structure more consistent. These changes in locality are dynamic and characterized over short timescales, offering us a different approach to identify and analyse the long-term impact of new infrastructures on cities and their evolution dynamics. PMID- 25551143 TI - Care of the elderly program at the University of Alberta: meeting the challenges of treating the aging population. AB - PROBLEM ADDRESSED: The population is aging rapidly and there are implications for health care delivery in the face of few physicians specializing in care of the elderly (COE). OBJECTIVE OF PROGRAM: To train physicians wishing to provide COE services. PROGRAM DESCRIPTION: The COE program at the University of Alberta in Edmonton is an enhanced skills diploma program lasting 6 months to 1 year, with core program requirements including geriatric inpatient care,geriatric psychiatry, ambulatory care, continuing care, and outreach. There is a longitudinal clinic component and a research project requirement. The program is designed to cover the 85 core competencies in the Can MEDS-Family Medicine roles. CONCLUSION: There is a need for COE physicians to provide clinical care as well as fill educational, administrative, and research roles to meet the health care needs of medically complex seniors. These physicians require alternative funding and a departmental home within a university if they are to provide an academic service. PMID- 25551144 TI - Adhesion-dependent rupturing of Saccharomyces cerevisiae on biological antimicrobial nanostructured surfaces. AB - Recent studies have shown that some nanostructured surfaces (NSS), many of which are derived from surfaces found on insect cuticles, rupture and kill adhered prokaryotic microbes. Most important, the nanoscale topography is directly responsible for this effect. Although parameters such as cell adhesion and cell wall rigidity have been suggested to play significant roles in this process, there is little experimental evidence regarding the underlying mechanisms involving NSS-induced microbial rupture. In this work, we report the NSS-induced rupturing of a eukaryotic microorganism, Saccharomyces cerevisiae. We show that the amount of NSS-induced rupture of S. cerevisiae is dependent on both the adhesive qualities of the yeast cell and the nanostructure geometry of the NSS. Thus, we are providing the first empirical evidence that these parameters play a direct role in the rupturing of microbes on NSS. Our observations of this phenomenon with S. cerevisiae, particularly the morphological changes, are strikingly similar to that reported for bacteria despite the differences in the yeast cell wall structure. Consequently, NSS provide a novel approach for the control of microbial growth and development of broad-spectrum microbicidal surfaces. PMID- 25551145 TI - How receptor diffusion influences gradient sensing. AB - Chemotaxis, or directed motion in chemical gradients, is critical for various biological processes. Many eukaryotic cells perform spatial sensing, i.e. they detect gradients by comparing spatial differences in binding occupancy of chemosensory receptors across their membrane. In many theoretical models of spatial sensing, it is assumed, for the sake of simplicity, that the receptors concerned do not move. However, in reality, receptors undergo diverse modes of diffusion, and can traverse considerable distances in the time it takes such cells to turn in an external gradient. This sets a physical limit on the accuracy of spatial sensing, which we explore using a model in which receptors diffuse freely over the membrane. We find that the Fisher information carried in binding and unbinding events decreases monotonically with the diffusion constant of the receptors. PMID- 25551146 TI - Revealing the dependence of cell spreading kinetics on its spreading morphology using microcontact printed fibronectin patterns. AB - Since the dawn of in vitro cell cultures, how cells interact and proliferate within a given external environment has always been an important issue in the study of cell biology. It is now well known that mammalian cells typically exhibit a three-phase sigmoid spreading on encountering a substrate. To further this understanding, we examined the influence of cell shape towards the second rapid expansion phase of spreading. Specifically, 3T3 fibroblasts were seeded onto silicon elastomer films made from polydimethylsiloxane (PDMS), and micro contact printed with fibronectin stripes of various dimensions. PDMS is adopted in our study for its biocompatibility, its ease in producing very smooth surfaces, and in the fabrication of micro-contact printing stamps. The substrate patterns are compared with respect to their influence on cell spreading over time. Our studies reveal, during the early rapid expansion phase, 3T3 fibroblasts are found to spread radially following a t?1.8 law; meanwhile, they proliferated in a lengthwise fashion on the striped patterns, following a t?1 law. We account for the observed differences in kinetics through a simple geometric analysis which predicted similar trends. In particular, a t2 law for radial spreading cells, and a t1 law for lengthwise spreading cells. PMID- 25551147 TI - Dynamics of airflow in a short inhalation. AB - During a rapid inhalation, such as a sniff, the flow in the airways accelerates and decays quickly. The consequences for flow development and convective transport of an inhaled gas were investigated in a subject geometry extending from the nose to the bronchi. The progress of flow transition and the advance of an inhaled non-absorbed gas were determined using highly resolved simulations of a sniff 0.5 s long, 1 l s-1 peak flow, 364 ml inhaled volume. In the nose, the distribution of airflow evolved through three phases: (i) an initial transient of about 50 ms, roughly the filling time for a nasal volume, (ii) quasi-equilibrium over the majority of the inhalation, and (iii) a terminating phase. Flow transition commenced in the supraglottic region within 20 ms, resulting in large amplitude fluctuations persisting throughout the inhalation; in the nose, fluctuations that arose nearer peak flow were of much reduced intensity and diminished in the flow decay phase. Measures of gas concentration showed non uniform build-up and wash-out of the inhaled gas in the nose. At the carina, the form of the temporal concentration profile reflected both shear dispersion and airway filling defects owing to recirculation regions. PMID- 25551148 TI - Magnetically induced behaviour of ferritin corpuscles in avian ears: can cuticulosomes function as magnetosomes? AB - Magnetoreception is an enigmatic, poorly understood sensory ability, described mainly on the basis of behavioural studies in animals of diverse taxa. Recently, corpuscles containing superparamagnetic iron-storage protein ferritin were found in the inner ear hair cells of birds, a predominantly single ferritin corpuscle per cell. It was suggested that these corpuscles might represent magnetosomes and function as magnetosensors. Here we determine ferritin low-field paramagnetic susceptibility to estimate its magnetically induced intracellular behaviour. Physical simulations show that ferritin corpuscles cannot be deformed or rotate in weak geomagnetic fields, and thus cannot provide magnetoreception via deformation of the cuticular plate. Furthermore, we reached an alternative hypothesis that ferritin corpuscle in avian ears may function as an intracellular electromagnetic oscillator. Such an oscillator would generate additional cellular electric potential related to normal cell conditions. Though the phenomenon seems to be weak, this effect deserves further analyses. PMID- 25551149 TI - Collective action and the collaborative brain. AB - Humans are unique both in their cognitive abilities and in the extent of cooperation in large groups of unrelated individuals. How our species evolved high intelligence in spite of various costs of having a large brain is perplexing. Equally puzzling is how our ancestors managed to overcome the collective action problem and evolve strong innate preferences for cooperative behaviour. Here, I theoretically study the evolution of social-cognitive competencies as driven by selection emerging from the need to produce public goods in games against nature or in direct competition with other groups. I use collaborative ability in collective actions as a proxy for social-cognitive competencies. My results suggest that collaborative ability is more likely to evolve first by between-group conflicts and then later be utilized and improved in games against nature. If collaborative abilities remain low, the species is predicted to become genetically dimorphic with a small proportion of individuals contributing to public goods and the rest free-riding. Evolution of collaborative ability creates conditions for the subsequent evolution of collaborative communication and cultural learning. PMID- 25551150 TI - Toughening mechanisms in bioinspired multilayered materials. AB - Outstanding mechanical properties of biological multilayered materials are strongly influenced by nanoscale features in their structure. In this study, mechanical behaviour and toughening mechanisms of abalone nacre-inspired multilayered materials are explored. In nacre's structure, the organic matrix, pillars and the roughness of the aragonite platelets play important roles in its overall mechanical performance. A micromechanical model for multilayered biological materials is proposed to simulate their mechanical deformation and toughening mechanisms. The fundamental hypothesis of the model is the inclusion of nanoscale pillars with near theoretical strength (sigmath ~ E/30). It is also assumed that pillars and asperities confine the organic matrix to the proximity of the platelets, and, hence, increase their stiffness, since it has been previously shown that the organic matrix behaves more stiffly in the proximity of mineral platelets. The modelling results are in excellent agreement with the available experimental data for abalone nacre. The results demonstrate that the aragonite platelets, pillars and organic matrix synergistically affect the stiffness of nacre, and the pillars significantly contribute to the mechanical performance of nacre. It is also shown that the roughness induced interactions between the organic matrix and aragonite platelet, represented in the model by asperity elements, play a key role in strength and toughness of abalone nacre. The highly nonlinear behaviour of the proposed multilayered material is the result of distributed deformation in the nacre-like structure due to the existence of nano-asperities and nanopillars with near theoretical strength. Finally, tensile toughness is studied as a function of the components in the microstructure of nacre. PMID- 25551151 TI - Active regulation of longitudinal arch compression and recoil during walking and running. AB - The longitudinal arch (LA) of the human foot compresses and recoils in response to being cyclically loaded. This has typically been considered a passive process, however, it has recently been shown that the plantar intrinsic foot muscles have the capacity to actively assist in controlling LA motion. Here we tested the hypothesis that intrinsic foot muscles, abductor hallucis (AH), flexor digitorum brevis (FDB) and quadratus plantae (QP), actively lengthen and shorten during the stance phase of gait in response to loading of the foot. Nine participants walked at 1.25 m s-1 and ran at 2.78 and 3.89 m s-1 on a force-instrumented treadmill while foot and ankle kinematics were recorded according to a multisegment foot model. Muscle-tendon unit (MTU) lengths, determined from the foot kinematics, and intramuscular electromyography (EMG) signals were recorded from AH, FDB and QP. Peak EMG amplitude was determined during the stance phase for each participant at each gait velocity. All muscles underwent a process of slow active lengthening during LA compression, followed by a rapid shortening as the arch recoiled during the propulsive phase. Changes in MTU length and peak EMG increased significantly with increasing gait velocity for all muscles. This is the first in vivo evidence that the plantar intrinsic foot muscles function in parallel to the plantar aponeurosis, actively regulating the stiffness of the foot in response to the magnitude of forces encountered during locomotion. These muscles may therefore contribute to power absorption and generation at the foot, limit strain on the plantar aponeurosis and facilitate efficient foot ground force transmission. PMID- 25551152 TI - Emergence of multicellularity in a model of cell growth, death and aggregation under size-dependent selection. AB - How multicellular life forms evolved from unicellular ones constitutes a major problem in our understanding of the evolution of our biosphere. A recent set of experiments involving yeast cell populations have shown that selection for faster sedimenting cells leads to the appearance of stable aggregates of cells that are able to split into smaller clusters. It was suggested that the observed evolutionary patterns could be the result of evolved programmes affecting cell death. Here, we show, using a simple model of cell-cell interactions and evolving adhesion rates, that the observed patterns in cluster size and localized mortality can be easily interpreted in terms of waste accumulation and toxicity driven apoptosis. This simple mechanism would have played a key role in the early evolution of multicellular life forms based on both aggregative and clonal development. The potential extensions of this work and its implications for natural and synthetic multicellularity are discussed. PMID- 25551153 TI - beta-Catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring (InSpiRe), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe, we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified beta-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-alpha and TNF-alpha clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/beta-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development. PMID- 25551154 TI - Robust and precise morphogen-mediated patterning: trade-offs, constraints and mechanisms. AB - The patterning of many developing tissues is organized by morphogens. Genetic and environmental perturbations of gene expression, protein synthesis and ligand binding are among the sources of unreliability that limit the accuracy and precision of morphogen-mediated patterning. While it has been found that the robustness of morphogen gradients to the perturbation of morphogen synthesis can be enhanced by particular mechanisms, how such mechanisms affect robustness to other perturbations, such as to receptor synthesis for the same morphogen, has been little explored. Here, we investigate the interplay between the robustness of patterning to the changes in receptor synthesis and morphogen synthesis and to the effects of cell-to-cell variability. Our analysis elucidates the trade-offs and constraints that arise as a result of achieving these three performance objectives simultaneously in the context of simple, steady-state morphogen gradients formed by diffusion and receptor-mediated uptake. Analysis of the interdependence between length scales of patterning and these performance objectives reveals several potential mechanisms for mitigating such trade-offs and constraints. One involves downregulation of receptor synthesis in the morphogen source, while another involves the presence of non-signalling cell surface morphogen-binding molecules. Both of these mechanisms occur in Drosophila wing discs during their patterning. We computationally elucidate how these mechanisms improve the robustness and precision of morphogen-mediated patterning. PMID- 25551155 TI - A consistent muscle activation strategy underlies crawling and swimming in Caenorhabditis elegans. AB - Although undulatory swimming is observed in many organisms, the neuromuscular basis for undulatory movement patterns is not well understood. To better understand the basis for the generation of these movement patterns, we studied muscle activity in the nematode Caenorhabditis elegans. Caenorhabditis elegans exhibits a range of locomotion patterns: in low viscosity fluids the undulation has a wavelength longer than the body and propagates rapidly, while in high viscosity fluids or on agar media the undulatory waves are shorter and slower. Theoretical treatment of observed behaviour has suggested a large change in force posture relationships at different viscosities, but analysis of bend propagation suggests that short-range proprioceptive feedback is used to control and generate body bends. How muscles could be activated in a way consistent with both these results is unclear. We therefore combined automated worm tracking with calcium imaging to determine muscle activation strategy in a variety of external substrates. Remarkably, we observed that across locomotion patterns spanning a threefold change in wavelength, peak muscle activation occurs approximately 45 degrees (1/8th of a cycle) ahead of peak midline curvature. Although the location of peak force is predicted to vary widely, the activation pattern is consistent with required force in a model incorporating putative length- and velocity-dependence of muscle strength. Furthermore, a linear combination of local curvature and velocity can match the pattern of activation. This suggests that proprioception can enable the worm to swim effectively while working within the limitations of muscle biomechanics and neural control. PMID- 25551157 TI - Physician's role in diagnosing and managing asthma. PMID- 25551158 TI - The driving role of consortia on the critical path to innovative therapies. PMID- 25551156 TI - A novel dysregulated pathway-identification analysis based on global influence of within-pathway effects and crosstalk between pathways. AB - Identifying dysregulated pathways from high-throughput experimental data in order to infer underlying biological insights is an important task. Current pathway identification methods focus on single pathways in isolation; however, consideration of crosstalk between pathways could improve our understanding of alterations in biological states. We propose a novel method of pathway analysis based on global influence (PAGI) to identify dysregulated pathways, by considering both within-pathway effects and crosstalk between pathways. We constructed a global gene-gene network based on the relationships among genes extracted from a pathway database. We then evaluated the extent of differential expression for each gene, and mapped them to the global network. The random walk with restart algorithm was used to calculate the extent of genes affected by global influence. Finally, we used cumulative distribution functions to determine the significance values of the dysregulated pathways. We applied the PAGI method to five cancer microarray datasets, and compared our results with gene set enrichment analysis and five other methods. Based on these analyses, we demonstrated that PAGI can effectively identify dysregulated pathways associated with cancer, with strong reproducibility and robustness. We implemented PAGI using the freely available R-based and Web-based tools (http://bioinfo.hrbmu.edu.cn/PAGI). PMID- 25551159 TI - [The medicine in al Andalus]. PMID- 25551160 TI - [Misleading acronyms]. PMID- 25551161 TI - Small-cell variant of ALK+ anaplastic large-cell lymphoma with a leukemic phase. PMID- 25551162 TI - Granular lymphoid cells are not always part of T-cell lineage: an atypical case of mantle cell lymphoma. PMID- 25551163 TI - Reporting acuity outcomes and refractive accuracy after LASIK. PMID- 25551164 TI - Epithelial remodeling following myopic LASIK. PMID- 25551165 TI - Seeing the world more clearly. PMID- 25551167 TI - Perovskites and their potential use in solar energy applications. PMID- 25551166 TI - Implementation of Community Health Fund in Tanzania: why do some districts perform better than others? AB - In early 1990s, Tanzania, like other African countries, introduced user fees in public health systems. Although user fees were considered important in promoting health, they appear to reduce people's access to health services. To counteract the detrimental effects of the user fees, various types of health insurances were introduced, including the Community Health Fund (CHF). Drawing from the review of minutes, health facility visits and key informant interviews, this study explored why implementation of the CHF in Tanzania has been more successful in some districts than in others. The findings indicate that in Lindi district, the enrolment rate for the CHF was very low. This was attributed to high premium rates, frequent drug stock-out, lack of trust by the community members to the health providers, low incentives and local politics. In contrast, in Iramba district, the performance was better. Availability of drugs in the health facilities, effective supervision, commitment of the top district-level officials and incentives to the health facility committees were the main factors that facilitated good performance of the fund in Iramba district. The focus of the implementation needs to be placed on the active engagement of the local-level leaders and politicians who are responsible for the implementation of the policy. Equally important is the availability of quality health services in the health facilities. PMID- 25551168 TI - Chiral primary amine catalyzed asymmetric Michael addition of malononitrile to alpha-substituted vinyl ketone. AB - The first efficient and highly enantioselective Michael addition-protonation reaction of malononitriles to alpha-substituted vinyl ketones has been developed by using a chiral primary amine as the organocatalyst. With a Hantzsch ester as the hydride source, an enantioselective tandem reduction, Michael addition protonation reaction of benzylidenemalononitrile has also been achieved with good yields and high enantioselectivities. PMID- 25551169 TI - Estimating the value of volunteer-assisted community-based aging services: a case example. AB - This study demonstrates the use of a social return on investment (SROI) approach in estimating the financial and social value created by volunteer-assisted community-based aging services. An expanded value added statement (EVAS) analysis found that the total value of outputs produced by the Concierge Club of San Diego substantially exceeded the cost of the program, after considering likely secondary and tertiary benefits for a range of affected stakeholders-including elderly service recipients, family members, volunteers, and societal institutions. Additional research is needed regarding the direct and indirect costs and benefits of volunteer support services for vulnerable older adults and their families. PMID- 25551171 TI - Tandem catalysis of amines using porous graphene oxide. AB - Porous graphene oxide can be used as a metal-free catalyst in the presence of air for oxidative coupling of primary amines. Herein, we explore a GO-catalyzed carbon-carbon or/and carbon-heteroatom bond formation strategy to functionalize primary amines in tandem to produce a series of valuable products, i.e., alpha aminophosphonates, alpha-aminonitriles, and polycyclic heterocompounds. Furthermore, when decorated with nano-Pd, the Pd-coated porous graphene oxide can be used as a bifunctional catalyst for tandem oxidation and hydrogenation reactions in the N-alkylation of primary amines, achieving good to excellent yields under mild conditions. PMID- 25551172 TI - Long-lived population inversion in isovalently doped quantum dots. AB - Optical gain from colloidal quantum dots has been desired for several decades since their discovery. While gain from multiexcitations is by now well established, nonradiative Auger recombination limits the lifetime of such population inversion in quantum dots. CdSe cores isovalently doped by one to few Te atoms capped with rod-shaped CdS are examined as a candidate system for enhanced stimulated emission properties. Emission depletion spectroscopy shows a behavior characteristic of 3-level gain systems in these quantum dots. This implies complete removal of the 2-fold degeneracy of the lowest energy electronic excitation due to the large repulsive exciton-exciton interaction in the doubly excited state. Using emission depletion measurements of the trap-associated emission from poorly passivated CdS quantum dots, we show that 3-level characteristics are typical of emission resulting from a band edge to trap state transition, but reveal subtle differences between the two systems. These results allow for unprecedented observation of long-lived population inversion from singly excited quantum dots. PMID- 25551170 TI - Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging. AB - Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5 MUM) or cisplatinum (CDDP) (5 MUM) for 3 h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72 h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G2/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G2/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G2/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells. PMID- 25551173 TI - Determination of the formylglycinamide ribonucleotide amidotransferase ammonia pathway by combining 3D-RISM theory with experiment. AB - Molecular tunnels in enzyme systems possess variable architecture and are therefore difficult to predict. In this work, we design and apply an algorithm to resolve the pathway followed by ammonia using the bifunctional enzyme formylglycinamide ribonucleotide amidotransferase (FGAR-AT) as a model system. Though its crystal structure has been determined, an ammonia pathway connecting the glutaminase domain to the 30 A distal FGAR/ATP binding site remains elusive. Crystallography suggested two purported paths: an N-terminal-adjacent path (path 1) and an auxiliary ADP-adjacent path (path 2). The algorithm presented here, RismPath, which enables fast and accurate determination of solvent distribution inside a protein channel, predicted path 2 as the preferred mode of ammonia transfer. Supporting experimental studies validate the identity of the path, and results lead to the conclusion that the residues in the middle of the channel do not partake in catalytic coupling and serve only as channel walls facilitating ammonia transfer. PMID- 25551174 TI - Attachment, continuing bonds, and complicated grief following violent loss: testing a moderated model. AB - There is increasing consensus that mourners' general attachment security and ongoing sense of connectedness to the deceased figure prominently in adjustment to bereavement. However, the interplay between these variables has not been investigated thoroughly. We therefore studied 195 young adults who were bereaved by violent causes (homicide, suicide, and fatal accidents) in the previous 2 years, measuring their attachment-related insecurities (anxiety and avoidance), their specific ongoing attachment or "continuing bond" (CB) to the deceased, and their complicated grief (CG) symptomatology over the loss of this relationship. Analyses indicated that CBs were concurrently linked with greater CG symptomatology. However, other results also suggested that attachment could moderate the adaptiveness of maintaining a sense of connection to the deceased loved one. Specifically, CBs were less predictive of CG symptomatology for individuals with high anxiety and low avoidance, and most predictive of intense grieving for bereaved people whose attachment styles were more highly avoidant and minimally anxious. These findings suggest the relevance of evaluating the appropriateness of clinical techniques that emphasize or deemphasize the CB for mourners who differ in their styles of attachment. Such studies could potentially promote a better match of interventions to clients whose styles of coping are congruent with these procedures. PMID- 25551176 TI - Developmental Trajectory of Information-Processing Skills in Children: Computer Based Assessment. AB - There are significant merits to a comprehensive cognitive assessment, but they are also time-consuming, costly, and susceptible to practice effects and may not detect change in the context of medical interventions or minor brain disruptions. Brief computer-based assessments focused on "fluid" cognitive domains (e.g., information-processing skills), which are vulnerable to disruption as a result of a brain injury, may provide an alternative assessment option. This study sought to: (a) examine the utility of a well-established, adult-based computerized tool, CogSport for Kids (CogState), for evaluating information-processing skills in children and adolescents; and (b) to report normative data for healthy children and adolescents. The study was a cross-sectional, community-based observational study of typically developing children aged 9 to 17 years old (N = 832). Participants completed the CogSport for Kids test battery, which includes six brief computerized tasks that assess cognitive functions including processing speed, attention, and working memory. Results showed an improvement with age for response speed and accuracy. The greatest change occurred between 9 and 12 years with performance stabilizing at 15 years. This brief screening tool is appropriate for clinical and research use in children aged 9 years and older and may be used to track cognitive development from childhood into adulthood and to identify children who deviate from normal expectations. PMID- 25551175 TI - A text messaging intervention to improve retention in care and virologic suppression in a U.S. urban safety-net HIV clinic: study protocol for the Connect4Care (C4C) randomized controlled trial. AB - BACKGROUND: Few data exist on the use of text messaging as a tool to promote retention in HIV care and virologic suppression at the clinic level in the United States. We describe the protocol for a study designed to investigate whether a text messaging intervention that supports healthy behaviors, encourages consistent engagement with care, and promotes antiretroviral persistence can improve retention in care and virologic suppression among patients in an urban safety-net HIV clinic in San Francisco. METHODS/DESIGN: Connect4Care (C4C) is a single-site, randomized year-long study of text message appointment reminders vs. text message appointment reminders plus thrice-weekly supportive, informational, and motivational text messages. Eligible consenting patients are allocated 1:1 to the two arms within strata defined by HIV diagnosis within the past 12 months (i.e. "newly diagnosed") vs. earlier. Study participants must receive primary care at the San Francisco General Hospital HIV clinic, speak English, possess a cell phone and be willing to send/receive up to 25 text messages per month, a have viral load >200 copies/MUL, and be either new to the clinic or have a history of poor retention. The primary efficacy outcome is virologic suppression at 12 months and the key secondary outcome, which will also be examined as a mediator of the primary outcome, is retention in HIV care, as operationalized by kept and missed primary care visits. Process outcomes include text message response rate and percent of time in study without cell phone service. Generalized estimating equation log-binomial models will be used for intent to treat, per protocol, and mediation analyses. An assessment of the cost and cost effectiveness of the intervention is planned along with a qualitative evaluation of the intervention. DISCUSSION: Findings from this study will provide valuable information about the use of behavioral-theory based text messaging to promote retention in HIV care and virologic suppression, further elucidate the challenges of using texting technology with marginalized urban populations, and help guide the development of new mobile health strategies to improve HIV care cascade outcomes. TRIAL REGISTRATION: NCT01917994. PMID- 25551177 TI - Plant pathogenic bacteria target the actin microfilament network involved in the trafficking of disease defense components. AB - Cells of infected organisms transport disease defense-related molecules along actin filaments to deliver them to their sites of action to combat the pathogen. To accommodate higher demand for intracellular traffic, plant F-actin density increases transiently during infection or treatment of Arabidopsis with pathogen associated molecules. Many animal and plant pathogens interfere with actin polymerization and depolymerization to avoid immune responses. Pseudomonas syringae, a plant extracellular pathogen, injects HopW1 effector into host cells to disrupt the actin cytoskeleton and reduce vesicle movement in order to elude defense responses. In some Arabidopsis accessions, however, HopW1 is recognized and causes resistance via an actin-independent mechanism. HopW1 targets isoform 7 of vegetative actin (ACT7) that is regulated by phytohormones and environmental factors. We hypothesize that dynamic changes of ACT7 filaments are involved in plant immunity. PMID- 25551179 TI - Oxidation half-reaction of aqueous nucleosides and nucleotides via photoelectron spectroscopy augmented by ab initio calculations. AB - Oxidative damage to DNA and hole transport between nucleobases in oxidized DNA are important processes in lesion formation for which surprisingly poor thermodynamic data exist, the relative ease of oxidizing the four nucleobases being one such example. Theoretical simulations of radiation damage and charge transport in DNA depend on accurate values for vertical ionization energies (VIEs), reorganization energies, and standard reduction potentials. Liquid-jet photoelectron spectroscopy can be used to directly study the oxidation half reaction. The VIEs of nucleic acid building blocks are measured in their native buffered aqueous environment. The experimental investigation of purine and pyrimidine nucleotides, nucleosides, pentose sugars, and inorganic phosphate demonstrates that photoelectron spectra of nucleotides arise as a spectral sum over their individual chemical components; that is, the electronic interactions between each component are effectively screened from one another by water. Electronic structure theory affords the assignment of the lowest energy photoelectron band in all investigated nucleosides and nucleotides to a single ionizing transition centered solely on the nucleobase. Thus, combining the measured VIEs with theoretically determined reorganization energies allows for the spectroscopic determination of the one-electron redox potentials that have been difficult to establish via electrochemistry. PMID- 25551178 TI - The microbiology of impetigo in indigenous children: associations between Streptococcus pyogenes, Staphylococcus aureus, scabies, and nasal carriage. AB - BACKGROUND: Impetigo is caused by both Streptococcus pyogenes and Staphylococcus aureus; the relative contributions of each have been reported to fluctuate with time and region. While S. aureus is reportedly on the increase in most industrialised settings, S. pyogenes is still thought to drive impetigo in endemic, tropical regions. However, few studies have utilised high quality microbiological culture methods to confirm this assumption. We report the prevalence and antimicrobial resistance of impetigo pathogens recovered in a randomised, controlled trial of impetigo treatment conducted in remote Indigenous communities of northern Australia. METHODS: Each child had one or two sores, and the anterior nares, swabbed. All swabs were transported in skim milk tryptone glucose glycogen broth and frozen at -70 degrees C, until plated on horse blood agar. S. aureus and S. pyogenes were confirmed with latex agglutination. RESULTS: From 508 children, we collected 872 swabs of sores and 504 swabs from the anterior nares prior to commencement of antibiotic therapy. S. pyogenes and S. aureus were identified together in 503/872 (58%) of sores; with an additional 207/872 (24%) sores having S. pyogenes and 81/872 (9%) S. aureus, in isolation. Skin sore swabs taken during episodes with a concurrent diagnosis of scabies were more likely to culture S. pyogenes (OR 2.2, 95% CI 1.1 - 4.4, p = 0.03). Eighteen percent of children had nasal carriage of skin pathogens. There was no association between the presence of S. aureus in the nose and skin. Methicillin resistance was detected in 15% of children who cultured S. aureus from either a sore or their nose. There was no association found between the severity of impetigo and the detection of a skin pathogen. CONCLUSIONS: S. pyogenes remains the principal pathogen in tropical impetigo; the relatively high contribution of S. aureus as a co-pathogen has also been confirmed. Children with scabies were more likely to have S. pyogenes detected. While clearance of S. pyogenes is the key determinant of treatment efficacy, co-infection with S. aureus warrants consideration of treatment options that are effective against both pathogens where impetigo is severe and prevalent. TRIAL REGISTRATION: This trial is registered; ACTRN12609000858291 . PMID- 25551180 TI - Synthesis and evaluation of series of diazine-bridged dinuclear platinum(II) complexes through in vitro toxicity and molecular modeling: correlation between structure and activity of Pt(II) complexes. AB - Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(MU-pz)}(2+) (L, ethylenediamine, en; (+/-)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(+/-)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2 dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd) and one pyridazine (pydz) bridged {[Pt(en)Cl]2(MU-pydz)}(2+) complex were prepared. The anticancer potential of these complexes were determined through in vitro cytotoxicity assay in human fibroblasts (MRC5) and two carcinoma cell lines (A375 and HCT116), interaction with double stranded DNA through in vitro assay, and molecular docking study. All complexes inhibited cell proliferation with inhibitory concentrations in the 0.5 120 MUM range. While {[Pt(1,3-pd)Cl]2(MU-pz)}(2+) showed improved activity and {[Pt(en)Cl]2(MU-pydz)}(2+) showed comparable activity to that of clinically relevant cisplatin, {[Pt(en)Cl]2(MU-pydz)}(2+) was less toxic in an assay with zebrafish (Danio rerio) embryos, causing no adverse developmental effects. The in vitro cytotoxicity of all diazine-bridged dinuclear Pt(II) complexes is discussed in correlation to their structural characteristics. PMID- 25551182 TI - Healthy kids out of school: using mixed methods to develop principles for promoting healthy eating and physical activity in out-of-school settings in the United States. AB - INTRODUCTION: Widespread practices supporting availability of healthful foods, beverages, and physical activity in out-of-school-time (OST) settings would further obesity prevention efforts. The objective of this article was to describe principles to guide policy development in support of healthy eating and physical activity practices in out-of-school settings to promote obesity prevention. METHODS: The Institute of Medicine's L.E.A.D. framework (Locate Evidence, Evaluate it, Assemble it, and Inform Decisions) was used to identify practices relevant to children's healthful eating in most OST settings: 1) locate and evaluate information from a national survey of children's perceptions of healthful-food access; published research, reports, policies and guidelines; and roundtables with OST organizations' administrators; 2) assemble information to prioritize actionable practices; and 3) inform programmatic direction. RESULTS: Three evidence-informed guiding principles for short-duration OST resulted: 1) drink right: choose water instead of sugar-sweetened beverages; 2) move more: boost movement and physical activity in all programs; and 3) snack smart: fuel up on fruits and vegetables. CONCLUSION: Healthy Kids Out of School was launched to support the dissemination and implementation of these guiding principles in short duration OST settings, complementing efforts in other OST settings to shift norms around eating and physical activity. PMID- 25551181 TI - Somatostatin is essential for the sexual dimorphism of GH secretion, corticosteroid-binding globulin production, and corticosterone levels in mice. AB - Distinct male and female patterns of pituitary GH secretion produce sexually differentiated hepatic gene expression profiles, thereby influencing steroid and xenobiotic metabolism. We used a fully automated system to obtain serial nocturnal blood samples every 15 minutes from cannulated wild-type (WT) and somatostatin knockout (Sst-KO) mice to determine the role of SST, the principal inhibitor of GH release, in the generation of sexually dimorphic GH pulsatility. WT males had lower mean and median GH values, less random GH secretory bursts, and longer trough periods between GH pulses than WT females. Each of these parameters was feminized in male Sst-KO mice, whereas female Sst-KO mice had higher GH levels than all other groups, but GH pulsatility was unaffected. We next performed hepatic mRNA profiling with high-density microarrays. Male Sst-KO mice exhibited a globally feminized pattern of GH-dependent mRNA levels, but female Sst-KO mice were largely unaffected. Among the differentially expressed female-predominant genes was Serpina6, which encodes corticosteroid-binding globulin (CBG). Increased CBG was associated with elevated diurnal peak plasma corticosterone in unstressed WT females and both sexes of Sst-KO mice compared with WT males. Sst-KO mice also had exaggerated ACTH and corticosterone responses to acute restraint stress. However, consistent with their lack of phenotypic signs of excess glucocorticoids, cerebrospinal fluid concentrations of free corticosterone in Sst-KO mice were not elevated. In summary, SST is necessary for the prolonged interpulse troughs that define masculinized pituitary GH secretion. SST also contributes to sexual dimorphism of the hypothalamic-pituitary-adrenal axis via GH-dependent regulation of hepatic CBG production. PMID- 25551183 TI - Sodium, saturated fat, and trans fat content per 1,000 kilocalories: temporal trends in fast-food restaurants, United States, 2000-2013. AB - INTRODUCTION: Intakes of sodium, saturated fat, and trans fat remain high despite recommendations to limit these nutrients for cardiometabolic risk reduction. A major contributor to intake of these nutrients is foods prepared outside the home, particularly from fast-food restaurants. METHODS: We analyzed the nutrient content of frequently ordered items from 3 US national fast-food chains: fried potatoes (large French fries), cheeseburgers (2-oz and 4-oz), and a grilled chicken sandwich. We used an archival website to obtain data on sodium, saturated fat, and trans fat content for these items from 2000 through 2013. The amount of each nutrient per 1,000 kcal was calculated to determine whether there were trends in product reformulation. RESULTS: Sodium content per 1,000 kcal differed widely among the 3 chains by food item, precluding generalizations across chains. During the 14-year period, sodium content per 1,000 kcal for large French fries remained high for all 3 chains, although the range narrowed from 316-2,000 mg per 1,000 kcal in 2000 to 700-1,420 mg per 1,000 kcal in 2013. Among the items assessed, cheeseburgers were the main contributor of saturated fat, and there was little change in content per 1,000 kcal for this item during the 14-year period. In contrast, there was a sharp decline in saturated and trans fat content of large French fries per 1,000 kcal. Post-2009, the major contributor of trans fat per 1,000 kcal was cheeseburgers; trans fat content of this item remained stable during the 14-year period. CONCLUSION: With the exception of French fries, little evidence was found during the 14-year period of product reformulation by restaurants to become more consistent with dietary guidance to reduce intakes of sodium and saturated fat. PMID- 25551184 TI - Temporal trends in fast-food restaurant energy, sodium, saturated fat, and trans fat content, United States, 1996-2013. AB - INTRODUCTION: Excess intakes of energy, sodium, saturated fat, and trans fat are associated with increased risk for cardiometabolic syndrome. Trends in fast-food restaurant portion sizes can inform policy decisions. We examined the variability of popular food items in 3 fast-food restaurants in the United States by portion size during the past 18 years. METHODS: Items from 3 national fast-food chains were selected: French fries, cheeseburgers, grilled chicken sandwich, and regular cola. Data on energy, sodium, saturated fat, and trans fat content were collated from 1996 through 2013 using an archival website. Time trends were assessed using simple linear regression models, using energy or a nutrient component as the dependent variable and the year as the independent variable. RESULTS: For most items, energy content per serving differed among chain restaurants for all menu items (P <= .04); energy content of 56% of items decreased (beta range, -0.1 to 5.8 kcal) and the content of 44% increased (beta range, 0.6-10.6 kcal). For sodium, the content of 18% of the items significantly decreased (beta range, -4.1 to -24.0 mg) and the content for 33% increased (beta range, 1.9-29.6 mg). Absolute differences were modest. The saturated and trans fat content, post-2009, was modest for French fries. In 2013, the energy content of a large-sized bundled meal (cheeseburger, French fries, and regular cola) represented 65% to 80% of a 2,000-calorie-per-day diet, and sodium content represented 63% to 91% of the 2,300-mg-per-day recommendation and 97% to 139% of the 1,500-mg-per-day recommendation. CONCLUSION: Findings suggest that efforts to promote reductions in energy, sodium, saturated fat, and trans fat intakes need to be shifted from emphasizing portion-size labels to additional factors such as total calories, frequency of eating, number of items ordered, menu choices, and energy-containing beverages. PMID- 25551185 TI - Considering trends in sodium, trans fat, and saturated fat as key metrics of cardiometobolic risk reduction. PMID- 25551186 TI - Developing a measure of muscular power during a functional task for older adults. AB - BACKGROUND: Muscular power is an important aspect of many activities of daily living and declines at a faster rate than other fitness parameters (i.e. muscular strength and endurance). Assessing muscular power among older adults is problematic as many of the popular tests are contraindicated among older adults and field tests to assess muscular power among older adults have not been validated among older adults. Therefore, the aim of the present investigation was to determine the validity and reliability of a field test to measure of muscular power during a functional movement among community-dwelling older adults (>= 65 years). METHODS: Twenty community-dwelling older adults (71.6 +/- 5.6) volunteered to have their muscular power assessed during repeated sit-to-stand (STS) tasks. Each participant performed 10 STS with 60 s rest between trials. Muscular power was assessed during this functional movement with the Tendo as well as change in center of mass (COM) over time using cinematography. RESULTS: Relative power measured by Tendo was 5.34 +/- 1.67 W/kg and values for COM were 5.39 +/- 1.73 W/kg (p = .86). Cronbach's alpha for Tendo muscular power for repeated trials was .98. CONCLUSIONS: Tendo is a simple field method of determining muscular power among older adults and validation is essential. Results from this investigation support Tendo as a valid and reliable method for determining muscular power during a STS task among older adults. Clinicians may use this tool to evaluate and assess progress in older adults' power and physical functioning. PMID- 25551187 TI - New coumarin derivative as an eco-friendly inhibitor of corrosion of mild steel in Acid medium. AB - The anticorrosion ability of a synthesized coumarin, namely 2-(coumarin-4 yloxy)acetohydrazide (EFCI), for mild steel (MS) in 1 M hydrochloric acid solution has been studied using a weight loss method. The effect of temperature on the corrosion rate was investigated, and some thermodynamic parameters were calculated. The results indicated that inhibition efficiencies were enhanced with an increase in concentration of inhibitor and decreased with a rise in temperature. The IE value reaches 94.7% at the highest used concentration of the new eco-friendly inhibitor. The adsorption of inhibitor on MS surface was found to obey a Langmuir adsorption isotherm. Scanning electron microscopy (SEM) was performed on inhibited and uninhibited mild steel samples to characterize the surface. The Density Function theory (DFT) was employed for quantum-chemical calculations such as EHOMO (highest occupied molecular orbital energy), ELUMO (lowest unoccupied molecular orbital energy) and MU (dipole moment), and the obtained results were found to be consistent with the experimental findings. The synthesized inhibitor was characterized by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopic studies. PMID- 25551188 TI - Characterization of ambrette seed oil and its mode of action in bacteria. AB - In the present study, chemical composition and the antibacterial mechanism of ambrette seed oil are investigated. Chemical composition of the oil was analysed by gas chromatography-mass spectrometry (GC-MS). Thirty-five compounds were identified and the major compounds were found to be farnesol acetate (51.45%) and ambrettolide (12.96%). The antibacterial activity was performed by well diffusion assay and the mechanisms were studied by measuring the alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and protein leakage assays. The antibacterial effect of the ambrette seed oil showed inhibitory effect against Bacillus subtilis, Staphylococcus aureus and Enterococcus faecalis. The LDH activity was high in all tested bacteria compared with control, whereas the ALP and protein concentrations were also increased in E. faecalis. Molecular docking revealed the ligands farnesol acetate and ambrettolide had satisfactory binding energy towards the beta lactamase TEM-72 and dihydrofolate reductase (DHFR) protein. Due to its better antibacterial properties, the ambrette seed oil could be used as a source of antibacterial agents. PMID- 25551189 TI - One-step (18)F labeling of non-peptidic bivalent integrin alphavbeta3 antagonist for cancer imaging. AB - A rapid one-step (18)F labeling reaction with fluoridealuminum complex, which is based on chelation chemistry, has received a surge of interest for (18)F radiolabeling of peptides. In this study, a non-peptidic bivalent integrin alphavbeta3 antagonist (bivalent-IA) was conjugated with 1,4,7-triazacyclononane 1,4-diiacetic acid (NODA). A novel (18)F labeled radiotracer, (18)F-bivalent-IA, was developed via one step (18)F-AlF/NODA chelation reaction in aqueous phase with high radiochemical yield (65-75%, decay corrected) and good specific activity (750-850 mCi/MUmol). The tumor integrin targeting efficiency and in vivo pharmacokinetic profile of (18)F-bivalent-IA were evaluated in U-87 MG (integrin positive) and MDA-MB-231 (integrin negative) models by small-animal PET/CT scan followed by a biodistribution study. The PET/CT and ROI results showed high tumor uptake of (18)F-bivalent-IA in U-87 MG tumor-bearing mice from 5 to 120 min p.i. with good contrast, and the U-87 MG tumor uptake values (6.35 +/- 0.67%ID/g, at 1 h p.i.) were 6 times higher than those of MDA-MB-231 tumor (1.05 +/- 0.12%ID/g, at 1 h p.i.) (P < 0.0001) which correlated with the integrin alphavbeta3 expression in tumor tissues confirmed by immunohistochemistry. Co-injection of the (18)F-bivalent-IA with 6 nmol (6 MUg) of nonradioactive bivalent-IA effectively blocked tumor uptake demonstrating the integrin alphavbeta3 specificity. In conclusion, the first (18)F labeled non-peptidic bivalent integrin alphavbeta3 targeting radiotracer, (18)F-bivalent-IA, was developed and proved to be a highly potent and specific PET radiopharmaceutical for noninvasive imaging of integrin alphavbeta3, which plays a critical role in tumor angiogenesis and metastasis. PMID- 25551190 TI - A three dimensional visualisation approach to protein heavy-atom structure reconstruction. AB - BACKGROUND: A commonly recurring problem in structural protein studies, is the determination of all heavy atom positions from the knowledge of the central alpha carbon coordinates. RESULTS: We employ advances in virtual reality to address the problem. The outcome is a 3D visualisation based technique where all the heavy backbone and side chain atoms are treated on equal footing, in terms of the Calpha coordinates. Each heavy atom is visualised on the surfaces of a different two-sphere, that is centered at another heavy backbone and side chain atoms. In particular, the rotamers are visible as clusters, that display a clear and strong dependence on the underlying backbone secondary structure. CONCLUSIONS: We demonstrate that there is a clear interdependence between rotameric states and secondary structure. Our method easily detects those atoms in a crystallographic protein structure which are either outliers or have been likely misplaced, possibly due to radiation damage. Our approach forms a basis for the development of a new generation, visualization based side chain construction, validation and refinement tools. The heavy atom positions are identified in a manner which accounts for the secondary structure environment, leading to improved accuracy. PMID- 25551192 TI - Statistical considerations in the development of injury risk functions. AB - OBJECTIVE: We address 4 frequently misunderstood and important statistical ideas in the construction of injury risk functions. These include the similarities of survival analysis and logistic regression, the correct scale on which to construct pointwise confidence intervals for injury risk, the ability to discern which form of injury risk function is optimal, and the handling of repeated tests on the same subject. METHODS: The statistical models are explored through simulation and examination of the underlying mathematics. RESULTS: We provide recommendations for the statistically valid construction and correct interpretation of single-predictor injury risk functions. CONCLUSIONS: This article aims to provide useful and understandable statistical guidance to improve the practice in constructing injury risk functions. PMID- 25551191 TI - The Dutch Parelsnoer Institute--Neurodegenerative diseases; methods, design and baseline results. AB - BACKGROUND: The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile. METHODS: The Pearl Neurodegenerative Diseases is a 3 year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). DISCUSSION: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset. PMID- 25551193 TI - Biomass pyrolysis liquid to citric acid via 2-step bioconversion. AB - BACKGROUND: The use of fossil carbon sources for fuels and petrochemicals has serious impacts on our environment and is unable to meet the demand in the future. A promising and sustainable alternative is to substitute fossil carbon sources with microbial cell factories converting lignocellulosic biomass into desirable value added products. However, such bioprocesses require tolerance to inhibitory compounds generated during pretreatment of biomass. In this study, the process of sequential two-step bio-conversion of biomass pyrolysis liquid containing levoglucosan (LG) to citric acid without chemical detoxification has been explored, which can greatly improve the utilization efficiency of lignocellulosic biomass. RESULTS: The sequential two-step bio-conversion of corn stover pyrolysis liquid to citric acid has been established. The first step conversion by Phanerochaete chrysosporium (P. chrysosporium) is desirable to decrease the content of other compounds except levoglucosan as a pretreatment for the second conversion. The remaining levoglucosan in solution was further converted into citric acid by Aspergillus niger (A. niger) CBX-209. Thus the conversion of cellulose to citric acid is completed by both pyrolysis and bio conversion technology. Under experimental conditions, levoglucosan yield is 12% based on the feedstock and the citric acid yield can reach 82.1% based on the levoglucosan content in the pyrolysis liquid (namely 82.1 g of citric acid per 100 g of levoglucosan). CONCLUSION: The study shows that P. chrysosporium and A. niger have the potential to be used as production platforms for value-added products from pyrolyzed lignocellulosic biomass. Selected P. chrysosporium is able to decrease the content of other compounds except levoglucosan and levoglucosan can be further converted into citric acid in the residual liquids by A. niger. Thus the conversion of cellulose to citric acid is completed by both pyrolysis and bio-conversion technology. PMID- 25551194 TI - Twelve-month incidence and clearance of oral HPV infection in HIV-negative and HIV-infected men who have sex with men: the H2M cohort study. AB - BACKGROUND: Our aim was to compare the 12-month incidence and clearance of oral high-risk HPV infection between HIV-infected men who have sex with men (MSM) and HIV-negative MSM. METHODS: MSM aged 18 years or older were recruited in Amsterdam, the Netherlands. Questionnaire data and oral-rinse and gargle samples were collected at baseline, and after 6 and 12 months. HPV DNA was genotyped using the SPF10-PCR & DEIA-LiPA25 system (version 1). Determinants of oral HPV incidence and clearance were explored using Cox and logistic regression analyses respectively. RESULTS: 433 HIV-negative and 290 HIV-infected MSM were included in these analyses. The median follow-up time per participant was 12 months (range 3 15). During follow-up, 114 incident oral high-risk HPV infections were observed. The incidence rate of HPV-16 was 3.5/1000 person-months (PM) in HIV-infected and 0.9/1000 PM in HIV-negative MSM (IRR 4.1; 95% CI 1.3-13.2). The incidence rates of other high-risk HPV types ranged between 1.3-3.5/1000 PM in HIV-infected and 0.0-1.1/1000 PM in HIV-negative MSM. In multivariable analyses, HIV infection (adjusted hazard ratio [aHR] 3.8; 95% CI 2.3-6.2) and a higher number of recent oral sex partners (aHR 2.4 for >=8 partners compared to <=2; 95% CI 1.4-4.2) were associated with HPV incidence. Of the 111 baseline oral high-risk infections, 59 (53.2%) were cleared. In multivariable analyses, only a higher number of recent oral sex partners was associated with HPV clearance (adjusted odds ratio 3.4 for >=8 compared to <=2 partners; 95% CI 1.3-9.0). CONCLUSIONS: The incidence rate of oral high-risk HPV infection was higher in HIV-infected MSM and in those with a higher number of recent oral sex partners. Just over half of the oral high-risk HPV infections at baseline were cleared after 12 months, with a higher likelihood of clearance among MSM reporting higher numbers of recent oral sex partners, but no difference by HIV status. PMID- 25551195 TI - Pim-1 acts as an oncogene in human salivary gland adenoid cystic carcinoma. AB - BACKGROUND: Pim-1 (Provirus integration site for Moloney murine leukemia virus 1) belongs to the Ser/Thr kinase family and plays a pivotal role in occurrence and development of oncogenesis. Recent studies have demonstrated that Pim-1 phosphorylates RUNX3 and alters its subcellular localization. However, few studies have concerned the implications of Pim-1 in the salivary gland adenoid cystic carcinoma (ACC). In this study, we aimed to clarify the function of Pim-1 in ACC in vitro. Meanwhile, we measured the levels of Pim-1 and RUNX3 in the ACC tissues. The correlations between Pim-1/RUNX3 levels and clinical parameters were also analyzed. METHODS: SACC-83 and SACC-LM cells were transfected with the Pim-1 siRNA. Pim-1 mRNA and protein expression were measured using real-time PCR and immnuoblot, respectively. Cell proliferation was analyzed by CCK-8 assay. Cell cycle, apoptosis, and mitochondrial membrane potential were detected by flow cytometry. Effects of Pim-1 on cells' invasion were evaluated by transwell migration assay. Pim-1 and RUNX3 levels in ACC tissues were examined by immunohistochemistry. RESULTS: Pim-1 siRNA reduces cell proliferation, induces apoptosis, causes cell cycle arrest through cell cycle related proteins (Cyclin D1 and CDK4), mitochondrial depolarization, and decreases invasive ability in SACC-83 and SACC-LM cells. Pim-1 and RUNX3 levels are significantly relevant and associated with T-stage and nerve invasion in the ACC tissues. CONCLUSIONS: This study demonstrates the oncogenic role of Pim-1 in ACC. The findings also suggest that Pim-1 may serve as a neoteric therapeutic target and potential prognostic marker for ACC cancer. PMID- 25551196 TI - Potentials of interferon therapy in the treatment of pancreatic cancer. AB - Pancreatic cancer is a highly aggressive malignancy with limited treatment options. To improve survival for patients with pancreatic cancer, research has focused on other treatment modalities like adding biological modulators such as type-I interferons (IFNs). Type I IFNs (ie, IFN-alpha/IFN-beta) have antiproliferative, antiviral, and immunoregulatory activities. Furthermore, they are able to induce apoptosis, exert cell cycle blocking, and sensitize tumor cells for chemo- and radiotherapy. A few years ago in vitro, in vivo, and several clinical trials have been described regarding adjuvant IFN-alpha therapy in the treatment of pancreatic cancer. Some studies reported a remarkable increase in the 2- and 5-year survival. Unfortunately, the only randomized clinical trial did not show a significant increase in overall survival, although the increased median survival implicated that some patients in the experimental group benefited from the adjuvant IFN-alpha therapy. Furthermore, encouraging in vitro and in vivo data points to a possible role for adjuvant IFN therapy. However, up till now, the use of IFNs in the treatment of pancreatic cancer remains controversial. This review, therefore, aims to describe, based on the available data, whether there is a distinct role for IFN therapy in the treatment of pancreatic cancer. PMID- 25551198 TI - Effects of socio-economic household characteristics on traditional knowledge and usage of wild yams and medicinal plants in the Mahafaly region of south-western Madagascar. AB - BACKGROUND: Rural households in the Mahafaly region of semi-arid SW-Madagascar strongly depend on the exploitation of natural resources for their basic needs and income regeneration. An overuse of such resources threatens the natural environment and people's livelihood. Our study focuses on the diversity and use of wild yams and medicinal plants. METHODS: We hypothesized that knowledge on the use of these resources highly depends on farmers' socio-economic household characteristics. To test this hypothesis, an ethnobotanical survey was conducted based on semi-structured interviews recording socio-economic base data and information on local knowledge of medicinal and wild yam species. This was followed by field inventories compiling plant material for botanical identification. RESULTS: Six species of wild yam and a total of 214 medicinal plants from 68 families and 163 genera were identified. Cluster and discriminant analysis yielded two groups of households with different wealth status characterized by differences in livestock numbers, off-farm activities, agricultural land and harvests. A generalized linear model highlighted that economic factors significantly affect the collection of wild yams, whereas the use of medicinal plants depends to a higher degree on socio-cultural factors. CONCLUSIONS: Wild yams play an important role in local food security in the Mahafaly region, especially for poor farmers, and medicinal plants are a primary source of health care for the majority of local people. Our results indicate the influence of socio-economic household characteristics on the use of forest products and its intensity, which should be considered in future management plans for local and regional forest conservation. PMID- 25551199 TI - Seeking a second opinion in pediatric oncology. AB - OBJECTIVES: The goal of this study was to identify second opinion consultations by physicians and to determine patient and family factors that appeared to contribute to a second opinion being sought. METHODS: One hundred and fifty consecutive parents of children with cancer recently treated in our Department of Pediatric Hematology Oncology were interviewed by telephone. The questionnaire included epidemiological data, details about the disease, timing of the second opinion consultation, reasons for seeking a second opinion, and the outcome of the consultation. RESULTS: Thirty-seven (24.7%) parents sought a second opinion. Advice was sought from other physicians in the hospital or at other clinics. There was a correlation to a higher socioeconomic status (P = .003) and to the number of educational years (P = .001). Most of the parents sought a second opinion because they wanted confirmation about the treatment protocol and the professional level of the hematologist oncologist/surgeon and the institution. CONCLUSIONS: Second opinion consultations were not uncommon and were mainly secondary to the desire for reassurance. Pediatric oncologists should ensure that patients and their families feel comfortable requesting a second opinion consultation. PMID- 25551197 TI - Signaling function of Na,K-ATPase induced by ouabain against LPS as an inflammation model in hippocampus. AB - BACKGROUND: Ouabain (OUA) is a newly recognized hormone that is synthesized in the adrenal cortex and hypothalamus. Low doses of OUA can activate a signaling pathway by interaction with Na,K-ATPase, which is protective against a number of insults. OUA has central and peripheral anti-inflammatory effects. Lipopolysaccharide (LPS), via toll-like receptor 4 activation, is a widely used model to induce systemic inflammation. This study used a low OUA dose to evaluate its effects on inflammation induced by LPS injection in rats. METHODS: Adult male Wistar rats received acute intraperitoneal (ip) OUA (1.8 MUg/kg) or saline 20 minutes before LPS (200 MUg/kg, ip) or saline injection. Some of the animals had their femoral artery catheterized in order to assess arterial blood pressure values before and after OUA administration. Na,K-ATPase activity, cytokine mRNA levels, apoptosis-related proteins, NF-kappaB activation brain-derived neurotrophic factor BDNF, corticosterone and TNF-alpha levels were measured. RESULTS: OUA pretreatment decreased mRNA levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and IL-1beta, which are activated by LPS in the hippocampus, but with no effect on serum measures of these factors. None of these OUA effects were linked to Na,K-ATPase activity. The involvement of the inflammatory transcription factor NF-kappaB in the OUA effect was indicated by its prevention of LPS-induced nuclear translocation of the NF kappaB subunit, RELA (p65), as well as the decreased cytosol levels of the NF kappaB inhibitor, IKB, in the hippocampus. OUA pretreatment reversed the LPS induced glial fibrillary acidic protein (GFAP) activation and associated inflammation in the dentate gyrus. OUA also prevented LPS-induced increases in the hippocampal Bax/Bcl2 ratio suggesting an anti-apoptotic action in the brain. CONCLUSION: Our results suggest that a low dose of OUA has an important anti inflammatory effect in the rat hippocampus. This effect was associated with decreased GFAP induction by LPS in the dentate gyrus, a brain area linked to adult neurogenesis. PMID- 25551200 TI - Influence of repeated anaesthesia on physiological parameters in male Wistar rats: a telemetric study about isoflurane, ketamine-xylazine and a combination of medetomidine, midazolam and fentanyl. AB - BACKGROUND: This study evaluated the influence of repeated anaesthesia using isoflurane (ISO, 2-3 Vol%), ketamine-xylazine (KX, 100 mg.kg(-1) + 5 mg.kg(-1), i.m.) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg.kg(-1) + 2.0 mg.kg(-1) + 0.005 mg.kg(-1), i.m.) on heart rate (HR), arterial blood pressure (BP), body temperature (BT), duration of anaesthetic intervals and body weight (BW) in Wistar rats. Rats were instrumented with a telemetric system for the measurement of systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), pulse pressure (PP), HR and BT during induction, maintenance and recovery of anaesthesia. Each anaesthesia was performed six times within three weeks. KX was not antagonized, but ISO delivery was terminated 40 minutes after induction and MMF was reversed with atipamezole-flumazenil-naloxone (AFN, 0.75 mg.kg(-1) + 0.2 mg.kg(-1) + 0.12 mg.kg(-1), s.c.). RESULTS: With repeated anaesthesia, ISO showed a decrease of HR and BP. A significant decrease of PP could be observed with repeated anaesthesia using MMF. HR and BP were not affected by repeated KX anaesthesia, but we noted a reduction of sleeping time and BW. Neither MMF nor ISO showed significant differences in the duration of anaesthetic intervals and BW. With KX we observed tissue necrosis at the injection site and surgical tolerance was not achieved in 25% of the anaesthesias performed. CONCLUSION: HR, BP values, BT, duration of anaesthetic intervals and BW were affected differently by repeated anaesthesia performed with ISO, KX or MMF. ISO produced a reproducible anaesthesia, thereby being suitable for repeated use, but with a decrease of HR and BP throughout the six anaesthesias. The use of ISO in cases where these parameters should be unaffected is therefore not advised. The inability to produce a surgical tolerance, the reduction of sleeping time and BW, as well as the tissue necrosis are significant contraindications for a repeated use of KX. Only mild changes of BP were found with repeated MMF anaesthesia, so it seems suitable for serial use, unless the high BP and the low HR during the surgical plane of anaesthesia are undesirable for a special procedure. PMID- 25551202 TI - Racial and ethnic disparities in health: examining the contexts that shape resilience and risk. AB - Race, ethnicity, and social class differences in the prevalence and effects of cardiovascular risk factors have been observed in many studies. Understanding the drivers of these differences is critical to efforts aimed at reducing racial disparities in health. Two articles in this volume of Psychosomatic Medicine contribute to our understanding of the underlying mechanisms driving racial disparities in health. The first article confirms the deleterious effects of psychosocial stressors on neuroendocrine function and suggests that the effects of stress on cortisol patterning are worse for Black and Latino individuals than for White individuals. The second meta-analysis article indicates that, in comparison to Whites, Black individuals display higher levels of high frequency heart rate variability, a measure of parasympathetic activity that may be an indicator of potential resilience to stress. To interpret these effects, it can be useful to move beyond assessments of phenotype and to consider the psychosocial context in which people live and assessments of risk are made. The psychosocial context includes variables and processes that influence the type, timing, and frequency of stress exposure, and the levels of background stress. Ultimately, these variables may create race and class differences in the underlying mechanisms that contribute to the development of different risk factors for adverse health outcomes such as cardiovascular disease, diabetes, and cancer. This editorial describes the relevance of incorporating the variables associated with psychosocial context when building new models in the next generation of research on health disparities. PMID- 25551201 TI - Ethnic differences in resting heart rate variability: a systematic review and meta-analysis. AB - BACKGROUND: Ethnic disparities in cardiovascular morbidity and mortality are widely documented in the literature. Recently, research has shown that decreased parasympathetic cardiac modulation is associated with the established and emerging risk factors for cardiovascular disease (CVD) and stroke. In consideration of the disproportionate CVD risk and disease profile of African Americans (AAs), it is plausible that decreased cardiac parasympathetic functioning may partially explain these disparities. In the present systematic review and meta-analysis, we assess the available evidence for a reliable ethnic difference in tonic vagally mediated heart rate variability (HRV), an indicator of parasympathetic cardiac modulation. METHODS: A systematic literature search was conducted yielding studies comparing tonic HRV in AAs and European Americans. Adjusted standardized effect sizes (Hedges g) were calculated using a mixed effects model, with restricted maximum likelihood estimation for 17 studies containing appropriate measures of vagally mediated HRV. RESULTS: Meta-analysis results suggest that AAs have greater HRV than do European Americans (Hedges g = 0.93, 95% confidence interval = 0.25-1.62), even after consideration of several covariates including health status, medication use, and subgroup stratification by sex and age. CONCLUSIONS: These findings suggest that decreased vagally mediated HRV is not likely to account for the persistent health disparities experienced by AAs with respect to CVD risk and burden. These disparities underscore the need for continued research addressing socioethnic cardiovascular differences and the biobehavioral mechanisms involved. PMID- 25551203 TI - Comparison of nested, multiplex, qPCR; FISH; SeptiFast and blood culture methods in detection and identification of bacteria and fungi in blood of patients with sepsis. AB - BACKGROUND: Microbiological diagnosis of sepsis relies primarily on blood culture data. This study compares four diagnostic methods, i.e. those developed by us: nested, multiplex, qPCR (qPCR) and FISH with commercial methods: SeptiFast (Roche) (SF) and BacT/ALERT(r) 3D blood culture system (bioMerieux). Blood samples were derived from adult patients with clinical symptoms of sepsis, according to SIRS criteria, hospitalized in the Intensive Care Unit. RESULTS: Using qPCR, FISH, SF, and culture, microbial presence was found in 71.8%, 29.6%, 25.3%, and 36.6% of samples, respectively. It was demonstrated that qPCR was significantly more likely to detect microorganisms than the remaining methods; qPCR confirmed the results obtained with the SF kit in all cases wherein bacteria were detected with simultaneous confirmation of Gram-typing. All data collected through the FISH method were corroborated by qPCR. CONCLUSIONS: The qPCR and FISH methods described in this study may constitute alternatives to blood culture and to the few existing commercial molecular assays since they enable the detection of the majority of microbial species, and the qPCR method allows their identification in a higher number of samples than the SF test. FISH made it possible to show the presence of microbes in a blood sample even before its culture. PMID- 25551205 TI - Treatment Outcomes of Patients with Tuberculosis in New York City. AB - CONTEXT: Treatment completion for tuberculosis (TB) is one of the essential components of TB prevention and control. Delays in treatment completion and incomplete treatment can result in increased transmission, development of drug resistance, and increased morbidity and mortality. Understanding the reasons for poor treatment outcomes may help improve TB control efforts. OBJECTIVE: To identify those at highest risk and determine the reasons for poor treatment outcomes among TB cases (January 2009-June 2010). DESIGN: Retrospective analysis. SETTING/PARTICIPANTS: New York City TB patients eligible to complete treatment within 12 months. MAIN OUTCOME MEASURES: Poisson regression models were used to identify risk factors associated with delayed completion and incomplete treatment compared with completion within 12 months of initiating treatment (timely completion). Reasons for delayed completion and incomplete treatment were summarized. RESULTS: Of 1008 cases eligible to complete treatment within 12 months, 921 (91%) had timely completion, 48 (5%) had delayed completion, and 39 (4%) had incomplete treatment. Cases with delayed completion and incomplete treatment were more likely to have extrapulmonary TB (adjusted risk ratio = 3.31; 95% confidence interval, 1.79-6.14; and adjusted risk ratio = 3.34; 95% confidence interval, 1.73-6.44, respectively). Primary reasons for delayed completion were a physician's decision to extend treatment (35%) and interrupted treatment (31%), whereas those for incomplete treatment included lost to care (38%), moved (28%), and refusal to continue treatment (26%). CONCLUSION: Overall, treatment completion in New York City was high. Patients with delayed completion and incomplete treatment had extrapulmonary disease in common. However, specific reasons suggest that delayed completion may be clinically motivated whereas incomplete treatment may result from social conditions. PMID- 25551206 TI - MRI, CT scan, and ultrasound in the diagnosis of nonalcoholic fatty liver disease. PMID- 25551207 TI - Evaluation of metabolic syndrome and nonalcoholic steatohepatitis. PMID- 25551204 TI - Developmentally distinct activities of the exocyst enable rapid cell elongation and determine meristem size during primary root growth in Arabidopsis. AB - BACKGROUND: Exocytosis is integral to root growth: trafficking components of systems that control growth (e.g., PIN auxin transport proteins) to the plasma membrane, and secreting materials that expand the cell wall to the apoplast. Spatiotemporal regulation of exocytosis in eukaryotes often involves the exocyst, an octameric complex that tethers selected secretory vesicles to specific sites on the plasma membrane and facilitates their exocytosis. We evaluated Arabidopsis lines with mutations in four exocyst components (SEC5, SEC8, EXO70A1 and EXO84B) to explore exocyst function in primary root growth. RESULTS: The mutants have root growth rates that are 82% to 11% of wild-type. Even in lines with the most severe defects, the organization of the quiescent center and tissue layers at the root tips appears similar to wild-type, although meristematic, transition, and elongation zones are shorter. Reduced cell production rates in the mutants are due to the shorter meristems, but not to lengthened cell cycles. Additionally, mutants demonstrate reduced anisotropic cell expansion in the elongation zone, but not the meristematic zone, resulting in shorter mature cells that are similar in shape to wild-type. As expected, hypersensitivity to brefeldin A links the mutant root growth defect to altered vesicular trafficking. Several experimental approaches (e.g., dose-response measurements, localization of signaling components) failed to identify aberrant auxin or brassinosteroid signaling as a primary driver for reduced root growth in exocyst mutants. CONCLUSIONS: The exocyst participates in two spatially distinct developmental processes, apparently by mechanisms not directly linked to auxin or brassinosteroid signaling pathways, to help establish root meristem size, and to facilitate rapid cell expansion in the elongation zone. PMID- 25551208 TI - Prophylactic arterial embolization as the possible new gold standard for high risk peptic ulcer bleeding after achieved endoscopic hemostasis. PMID- 25551209 TI - Gender in probiotic use. PMID- 25551210 TI - Endoscopic ultrasound-guided endotherapy. AB - Over the last 2 decades, endoscopic ultrasound (EUS) has evolved from a noninvasive diagnostic tool to a combined diagnostic and therapeutic modality. The use of EUS complementary to endoscopic retrograde cholangiopancreatography (ERCP) has made possible biliary and pancreatic drainage in situations where conventional ERCP is unsuccessful or unlikely to be feasible. The degree of proximity to the pancreas achieved during the procedure has enabled therapeutic interventions such as drainage of peripancreatic fluid collections, pancreatic cyst ablation, and pancreatic cancer therapy. Real-time visualization of flow in adjacent blood vessels using Doppler ultrasound has allowed endovascular therapy for ablation of gastric varices and feeding vessels. Furthermore, the role of EUS is evolving in a multitude of applications such as bilioenteric and enteroenteric anastomosis in a minimally invasive manner, potentially reducing the need for surgery. This article reviews the role of EUS as an alternative to surgery in selective situations and provides an overview of future directions and evolving uses of EUS. PMID- 25551211 TI - Acute Liver Failure Due to Acetaminophen Poisoning in Patients With Prior Weight Loss Surgery: A Case Series. AB - GOALS: To identify an association between prior weight loss surgery (WLS) and acetaminophen-induced acute liver failure (ALF). BACKGROUND: WLS, which has increased in proportion to the global rise of obesity, alters the absorption and metabolism of many drugs including acetaminophen (APAP) and may predispose to toxicity. No study has identified an association between prior WLS and APAP-ALF. STUDY: We retrospectively reviewed a cohort of patients who presented to our center with ALF. We identified 101 patients who presented to our center with ALF between January 2009 and December 2011. All patients were prospectively enrolled into a database using consensus criteria. A history of WLS was obtained through a retrospective chart review. RESULTS: Fifty-four patients (53.5%) had APAP-ALF and 47 (46.5%) had ALF caused by other etiologies. A prior history of WLS was present in 9 of the 54 patients with APAP-ALF versus 0 of the 47 with non-APAP-ALF (P=0.003). Patients with APAP-ALF and prior WLS did not have higher rates of factors commonly associated with APAP overdose, including depression, alcohol abuse, intent to cause self-harm, or use of APAP-narcotic combination drugs. CONCLUSIONS: A history of WLS may predispose to hepatotoxicity and ALF caused by acetaminophen. PMID- 25551212 TI - Disentangling migratory routes and wintering grounds of Iberian near-threatened European Rollers Coracias garrulus. AB - Long-distance migrants are suffering drastic declines in the last decades. Causes beneath this problem are complex due to the wide spatial and temporal scale involved. We aim to reveal migratory routes, stopover areas, wintering grounds, and migratory strategies for the most southwestern populations of the near threatened European Roller Coracias garrulus in order to identify conservation key areas for the non-breeding stage of this species. To this end, we used tracking data from seven satellite transmitters fitted to birds breeding in different populations throughout the Iberian Peninsula and four geolocators fitted to individuals in a southeastern Iberian population. Precise satellite data were used to describe daily activity patterns and speed in relation to the main regions crossed during the migration. Individuals from the most southwestern Iberian populations made a detour towards the Atlantic African coast whereas those from northeastern populations followed a straight north-to-south route. We identified important stopover areas in the Sahel belt, mainly in the surroundings of the Lake Chad, and wintering grounds on southwestern Africa farther west than previously reported for the species. Concerning the migratory strategy, satellite data revealed: 1) a mainly nocturnal flying activity, 2) that migration speed depended on the type of crossed habitat, with higher average speed while crossing the desert; and 3) that the migration was slower and lasted longer in autumn than in spring. The studied populations showed weak migratory connectivity, suggesting the confluence of birds from a wide range of breeding grounds in a restricted wintering area. Therefore, we suggest to target on defining precisely key areas for this species and identifying specific threats in them in order to develop an appropriate global conservation programme for the European Roller. PMID- 25551213 TI - Algorithm for automatic forced spirometry quality assessment: technological developments. AB - We hypothesized that the implementation of automatic real-time assessment of quality of forced spirometry (FS) may significantly enhance the potential for extensive deployment of a FS program in the community. Recent studies have demonstrated that the application of quality criteria defined by the ATS/ERS (American Thoracic Society/European Respiratory Society) in commercially available equipment with automatic quality assessment can be markedly improved. To this end, an algorithm for assessing quality of FS automatically was reported. The current research describes the mathematical developments of the algorithm. An innovative analysis of the shape of the spirometric curve, adding 23 new metrics to the traditional 4 recommended by ATS/ERS, was done. The algorithm was created through a two-step iterative process including: (1) an initial version using the standard FS curves recommended by the ATS; and, (2) a refined version using curves from patients. In each of these steps the results were assessed against one expert's opinion. Finally, an independent set of FS curves from 291 patients was used for validation purposes. The novel mathematical approach to characterize the FS curves led to appropriate FS classification with high specificity (95%) and sensitivity (96%). The results constitute the basis for a successful transfer of FS testing to non-specialized professionals in the community. PMID- 25551214 TI - Exercise training reduces cardiac dysfunction and remodeling in ovariectomized rats submitted to myocardial infarction. AB - The aim of this study was to evaluate whether exercise training (ET) prevents or minimizes cardiac dysfunction and pathological ventricular remodeling in ovariectomized rats subjected to myocardial infarction (MI) and to examine the possible mechanisms involved in this process. Ovariectomized Wistar rats were subjected to either MI or fictitious surgery (Sham) and randomly divided into the following groups: Control, OVX+SHAMSED, OVX+SHAMET, OVX+MISED and OVX+MIET. ET was performed on a motorized treadmill (5x/wk, 60 min/day, 8 weeks). Cardiac function was assessed by ventricular catheterization and Dihydroethidium fluorescence (DHE) was evaluated to analyze cardiac oxidative stress. Histological analyses were made to assess collagen deposition, myocyte hypertrophy and infarct size. Western Blotting was performed to analyze the protein expression of catalase and SOD-2, as well as Gp91phox and AT1 receptor (AT1R). MI-trained rats had significantly increased in +dP/dt and decreased left ventricular end-diastolic pressure compared with MI-sedentary rats. Moreover, oxidative stress and collagen deposition was reduced, as was myocyte hypertrophy. These effects occurred in parallel with a reduction in both AT1R and Gp91phox expression and an increase in catalase expression. SOD-2 expression was not altered. These results indicate that ET improves the functional cardiac parameters associated with attenuation of cardiac remodeling in ovariectomized rats subjected to MI. The mechanism seems to be related to a reduction in the expression of both the AT1 receptor and Gp91phox as well as an increase in the antioxidant enzyme catalase, which contributes to a reduction in oxidative stress. Therefore, ET may be an important therapeutic target for the prevention of heart failure in postmenopausal women affected by MI. PMID- 25551215 TI - An ephemeral sexual population of Phytophthora infestans in the Northeastern United States and Canada. AB - Phytophthora infestans, the causal agent of late blight disease, has been reported in North America since the mid-nineteenth century. In the United States the lack of or very limited sexual reproduction has resulted in largely clonal populations of P. infestans. In 2010 and 2011, but not in 2012 or 2013, 20 rare and diverse genotypes of P. infestans were detected in a region that centered around central New York State. The ratio of A1 to A2 mating types among these genotypes was close to the 50?50 ratio expected for sexual recombination. These genotypes were diverse at the glucose-6-phosphate isomerase locus, differed in their microsatellite profiles, showed different banding patterns in a restriction fragment length polymorphism assay using a moderately repetitive and highly polymorphic probe (RG57), were polymorphic for four different nuclear genes and differed in their sensitivity to the systemic fungicide mefenoxam. The null hypothesis of linkage equilibrium was not rejected, which suggests the population could be sexual. These new genotypes were monomorphic in their mitochondrial haplotype that was the same as US-22. Through parentage exclusion testing using microsatellite data and sequences of four nuclear genes, recent dominant lineages US-8, US-11, US-23, and US-24 were excluded as possible parents for these genotypes. Further analyses indicated that US-22 could not be eliminated as a possible parent for 14 of the 20 genotypes. We conclude that US-22 could be a parent of some, but not all, of the new genotypes found in 2010 and 2011. There were at least two other parents for this population and the genotypic characteristics of the other parents were identified. PMID- 25551217 TI - When small words foretell academic success: the case of college admissions essays. AB - The smallest and most commonly used words in English are pronouns, articles, and other function words. Almost invisible to the reader or writer, function words can reveal ways people think and approach topics. A computerized text analysis of over 50,000 college admissions essays from more than 25,000 entering students found a coherent dimension of language use based on eight standard function word categories. The dimension, which reflected the degree students used categorical versus dynamic language, was analyzed to track college grades over students' four years of college. Higher grades were associated with greater article and preposition use, indicating categorical language (i.e., references to complexly organized objects and concepts). Lower grades were associated with greater use of auxiliary verbs, pronouns, adverbs, conjunctions, and negations, indicating more dynamic language (i.e., personal narratives). The links between the categorical dynamic index (CDI) and academic performance hint at the cognitive styles rewarded by higher education institutions. PMID- 25551216 TI - Long-range gene flow and the effects of climatic and ecological factors on genetic structuring in a large, solitary carnivore: the Eurasian lynx. AB - Due to their high mobility, large terrestrial predators are potentially capable of maintaining high connectivity, and therefore low genetic differentiation among populations. However, previous molecular studies have provided contradictory findings in relation to this. To elucidate patterns of genetic structure in large carnivores, we studied the genetic variability of the Eurasian lynx, Lynx lynx throughout north-eastern Europe using microsatellite, mitochondrial DNA control region and Y chromosome-linked markers. Using SAMOVA we found analogous patterns of genetic structure based on both mtDNA and microsatellites, which coincided with a relatively little evidence for male-biased dispersal. No polymorphism for the cytochrome b and ATP6 mtDNA genes and Y chromosome-linked markers were found. Lynx inhabiting a large area encompassing Finland, the Baltic countries and western Russia formed a single genetic unit, while some marginal populations were clearly divergent from others. The existence of a migration corridor was suggested to correspond with distribution of continuous forest cover. The lowest variability (in both markers) was found in lynx from Norway and Bialowieza Primeval Forest (BPF), which coincided with a recent demographic bottleneck (Norway) or high habitat fragmentation (BPF). The Carpathian population, being monomorphic for the control region, showed relatively high microsatellite diversity, suggesting the effect of a past bottleneck (e.g. during Last Glacial Maximum) on its present genetic composition. Genetic structuring for the mtDNA control region was best explained by latitude and snow cover depth. Microsatellite structuring correlated with the lynx's main prey, especially the proportion of red deer (Cervus elaphus) in its diet. Eurasian lynx are capable of maintaining panmictic populations across eastern Europe unless they are severely limited by habitat continuity or a reduction in numbers. Different correlations of mtDNA and microsatellite population divergence patterns with climatic and ecological factors may suggest separate selective pressures acting on males and females in this solitary carnivore. PMID- 25551218 TI - Emotion attribution to a non-humanoid robot in different social situations. AB - In the last few years there was an increasing interest in building companion robots that interact in a socially acceptable way with humans. In order to interact in a meaningful way a robot has to convey intentionality and emotions of some sort in order to increase believability. We suggest that human-robot interaction should be considered as a specific form of inter-specific interaction and that human-animal interaction can provide a useful biological model for designing social robots. Dogs can provide a promising biological model since during the domestication process dogs were able to adapt to the human environment and to participate in complex social interactions. In this observational study we propose to design emotionally expressive behaviour of robots using the behaviour of dogs as inspiration and to test these dog-inspired robots with humans in inter specific context. In two experiments (wizard-of-oz scenarios) we examined humans' ability to recognize two basic and a secondary emotion expressed by a robot. In Experiment 1 we provided our companion robot with two kinds of emotional behaviour ("happiness" and "fear"), and studied whether people attribute the appropriate emotion to the robot, and interact with it accordingly. In Experiment 2 we investigated whether participants tend to attribute guilty behaviour to a robot in a relevant context by examining whether relying on the robot's greeting behaviour human participants can detect if the robot transgressed a predetermined rule. Results of Experiment 1 showed that people readily attribute emotions to a social robot and interact with it in accordance with the expressed emotional behaviour. Results of Experiment 2 showed that people are able to recognize if the robot transgressed on the basis of its greeting behaviour. In summary, our findings showed that dog-inspired behaviour is a suitable medium for making people attribute emotional states to a non-humanoid robot. PMID- 25551219 TI - In vivo effect of pneumonia on surfactant disaturated-phosphatidylcholine kinetics in newborn infants. AB - BACKGROUND: Bacterial pneumonia in newborns often leads to surfactant deficiency or dysfunction, as surfactant is inactivated or its production/turnover impaired. No data are available in vivo in humans on the mechanism of surfactant depletion in neonatal pneumonia. We studied the kinetics of surfactant's major component, disaturated-phosphatidylcholine (DSPC), in neonatal pneumonia, and we compared our findings with those obtained from control newborn lungs. METHODS: We studied thirty-one term or near-term newborns (gestational age 39.7+/-1.7 weeks, birth weight 3185+/-529 g) requiring mechanical ventilation. Fifteen newborns had pneumonia, while 16 newborns were on mechanical ventilation but had no lung disease. Infants received an intratracheal dose of 13C labeled dipalmitoyl phosphatidylcholine at the study start. We measured the amount and the isotopic enrichment of DSPC-palmitate from serial tracheal aspirates by gas chromatography and gas chromatography-mass spectrometry, respectively, and we calculated the DSPC half-life (HL) and pool size (PS) from the isotopic enrichment curves of surfactant DSPC-palmitate. RESULTS: The mean DSPC amount obtained from all tracheal aspirates did not differ between the two groups. DSPC HL was 12.7 (6.5 20.2) h and 25.6 (17.9-60.6) h in infants with pneumonia compared with control infants (p = 0.003). DSPC PS was 14.1 (6.6-30.9) mg/kg in infants with pneumonia and 34.1 (25.6-65.0) mg/kg in controls, p = 0.042. Myeloperoxidase (MPO) activity, as a marker of lung inflammation, was 1322 (531-2821) mU/ml of Epithelial Lining Fluid (ELF) and 371(174-1080) mU/ml ELF in infants with pneumonia and in controls, p = 0.047. In infants with pneumonia, DSPC PS and HL significantly and inversely correlated with mean Oxygenation Index (OI) during the study (DSPC PS vs. OI R = -0.710, p = 0.004 and HL vs. OI R = -0.525, p = 0.044, respectively). CONCLUSIONS: We demonstrated for the first time in vivo in humans that DSPC HL and PS were markedly impaired in neonatal pneumonia and that they inversely correlated with the degree of respiratory failure. PMID- 25551220 TI - Predicting in vitro rumen VFA production using CNCPS carbohydrate fractions with multiple linear models and artificial neural networks. AB - The objectives of this trial were to develop multiple linear regression (MLR) models and three-layer Levenberg-Marquardt back propagation (BP3) neural network models using the Cornell Net Carbohydrate and Protein System (CNCPS) carbohydrate fractions as dietary variables for predicting in vitro rumen volatile fatty acid (VFA) production and further compare MLR and BP3 models. Two datasets were established for the trial, of which the first dataset containing 45 feed mixtures with concentrate/roughage ratios of 10?90, 20?80, 30?70, 40?60, and 50?50 were used for establishing the models and the second dataset containing 10 feed mixtures with the same concentrate/roughage ratios with the first dataset were used for testing the models. The VFA production of feed samples was determined using an in vitro incubation technique. The CNCPS carbohydrate fractions (g), i.e. CA (sugars), CB1 (starch and pectin), CB2 (available cell wall) of feed samples were calculated based on chemical analysis. The performance of MLR models and BP3 models were compared using a paired t-test, the determination coefficient (R2) and the root mean square prediction error (RMSPE) between observed and predicted values. Statistical analysis indicated that VFA production (mmol) was significantly correlated with CNCPS carbohydrate fractions (g) CA, CB1, and CB2 in a multiple linear pattern. Compared with MLR models, BP3 models were more accurate in predicting acetate, propionate, and total VFA production while similar in predicting butyrate production. The trial indicated that both MLR and BP3 models were suitable for predicting in vitro rumen VFA production of feed mixtures using CNCPS carbohydrate fractions CA, CB1, and CB2 as input dietary variables while BP3 models showed greater accuracy for prediction. PMID- 25551222 TI - Movement behaviour of the carabid beetle Pterostichus melanarius in crops and at a habitat interface explains patterns of population redistribution in the field. AB - Animals may respond to habitat quality and habitat edges and these responses may affect their distribution between habitats. We studied the movement behaviour of a ground-dwelling generalist predator, the carabid beetle Pterostichus melanarius (Illiger). We performed a mark-recapture experiment in two adjacent habitats; a large plot with oilseed radish (Raphanus sativus) and a plot with rye (Secale cereale). We used model selection to identify a minimal model representing the mark-recapture data, and determine whether habitat-specific motility and boundary behaviour affected population redistribution. We determined movement characteristics of P. melanarius in laboratory arenas with the same plant species using video recording. Both the field and arena results showed preference behaviour of P. melanarius at the habitat interface. In the field, significantly more beetles moved from rye to oilseed radish than from radish to rye. In the arena, habitat entry was more frequent into oilseed radish than into rye. In the field, movement was best described by a Fokker-Planck diffusion model that contained preference behaviour at the interface and did not account for habitat specific motility. Likewise, motility calculated from movement data using the Patlak model was not different between habitats in the arena studies. Motility (m2 d-1) calculated from behavioural data resulted in estimates that were similar to those determined in the field. Thus individual behaviour explained population redistribution in the field qualitatively as well as quantitatively. The findings provide a basis for evaluating movement within and across habitats in complex agricultural landscapes with multiple habitats and habitat interfaces. PMID- 25551221 TI - Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance. AB - A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2 week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor alpha, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results indicate that irbesartan improves stress-induced adipose tissue inflammation and insulin resistance. Our results suggests that irbesartan treatment exerts additive benefits for glucose metabolism in hypertensive patients with mental stress. PMID- 25551223 TI - Dispersal pathways and genetic differentiation among worldwide populations of the invasive weed Centaurea solstitialis L. (Asteraceae). AB - The natural history of introduced species is often unclear due to a lack of historical records. Even when historical information is readily available, important factors of the invasions such as genetic bottlenecks, hybridization, historical relationships among populations and adaptive changes are left unknown. In this study, we developed a set of nuclear, simple sequence repeat markers and used these to characterize the genetic diversity and population structure among native (Eurasian) and non-native (North and South American) populations of Centaurea solstitialis L., (yellow starthistle). We used these data to test hypotheses about the invasion pathways of the species that were based on historical and geographical records, and we make inferences about historical relationships among populations and demographic processes following invasion. We confirm that the center of diversity and the native range of the species is likely the eastern Mediterranean region in the vicinity of Turkey. From this region, the species likely proceeded to colonize other parts of Europe and Asia via a slow, stepwise range expansion. Spanish populations were the primary source of seed to invade South America via human-mediated events, as was evident from historical records, but populations from the eastern Mediterranean region were also important. North American populations were largely derived from South America, but had secondary contributors. We suggest that the introduction history of non-native populations from disparate parts of the native range have allowed not just one, but multiple opportunities first in South America then again in North America for the creation of novel genotypes via intraspecific hybridization. We propose that multiple intraspecific hybridization events may have created especially potent conditions for the selection of a noxious invader, and may explain differences in genetic patterns among North and South America populations, inferred differences in demographic processes, as well as morphological differences previously reported from common garden experiments. PMID- 25551226 TI - Ranging in human sonar: effects of additional early reflections and exploratory head movements. AB - Many blind people rely on echoes from self-produced sounds to assess their environment. It has been shown that human subjects can use echolocation for directional localization and orientation in a room, but echo-acoustic distance perception--e.g. to determine one's position in a room--has received little scientific attention, and systematic studies on the influence of additional early reflections and exploratory head movements are lacking. This study investigates echo-acoustic distance discrimination in virtual echo-acoustic space, using the impulse responses of a real corridor. Six blindfolded sighted subjects and a blind echolocation expert had to discriminate between two positions in the virtual corridor, which differed by their distance to the front wall, but not to the lateral walls. To solve this task, participants evaluated echoes that were generated in real time from self-produced vocalizations. Across experimental conditions, we systematically varied the restrictions for head rotations, the subjects' orientation in virtual space and the reference position. Three key results were observed. First, all participants successfully solved the task with discrimination thresholds below 1 m for all reference distances (0.75-4 m). Performance was best for the smallest reference distance of 0.75 m, with thresholds around 20 cm. Second, distance discrimination performance was relatively robust against additional early reflections, compared to other echolocation tasks like directional localization. Third, free head rotations during echolocation can improve distance discrimination performance in complex environmental settings. However, head movements do not necessarily provide a benefit over static echolocation from an optimal single orientation. These results show that accurate distance discrimination through echolocation is possible over a wide range of reference distances and environmental conditions. This is an important functional benefit of human echolocation, which may also play a major role in the calibration of auditory space representations. PMID- 25551224 TI - Molecular diagnostic tools for detection and differentiation of phytoplasmas based on chaperonin-60 reveal differences in host plant infection patterns. AB - Phytoplasmas ('Candidatus Phytoplasma' spp.) are insect-vectored bacteria that infect a wide variety of plants, including many agriculturally important species. The infections can cause devastating yield losses by inducing morphological changes that dramatically alter inflorescence development. Detection of phytoplasma infection typically utilizes sequences located within the 16S-23S rRNA-encoding locus, and these sequences are necessary for strain identification by currently accepted standards for phytoplasma classification. However, these methods can generate PCR products >1400 bp that are less divergent in sequence than protein-encoding genes, limiting strain resolution in certain cases. We describe a method for accessing the chaperonin-60 (cpn60) gene sequence from a diverse array of 'Ca.Phytoplasma' spp. Two degenerate primer sets were designed based on the known sequence diversity of cpn60 from 'Ca.Phytoplasma' spp. and used to amplify cpn60 gene fragments from various reference samples and infected plant tissues. Forty three cpn60 sequences were thereby determined. The cpn60 PCR gel electrophoresis method was highly sensitive compared to 16S-23S-targeted PCR gel electrophoresis. The topology of a phylogenetic tree generated using cpn60 sequences was congruent with that reported for 16S rRNA-encoding genes. The cpn60 sequences were used to design a hybridization array using oligonucleotide-coupled fluorescent microspheres, providing rapid diagnosis and typing of phytoplasma infections. The oligonucleotide-coupled fluorescent microsphere assay revealed samples that were infected simultaneously with two subtypes of phytoplasma. These tools were applied to show that two host plants, Brassica napus and Camelina sativa, displayed different phytoplasma infection patterns. PMID- 25551225 TI - Environmentally selected aphid variants in clonality context display differential patterns of methylation in the genome. AB - Heritability of acquired phenotypic traits is an adaptive evolutionary process that appears more complex than the basic allele selection guided by environmental pressure. In insects, the trans-generational transmission of epigenetic marks in clonal and/or sexual species is poorly documented. Aphids were used as a model to explore this feature because their asexual phase generates a stochastic and/or environment-oriented repertoire of variants. The a priori unchanged genome in clonal individuals prompts us to hypothesize whether covalent methyl DNA marks might be associated to the phenotypic variability and fitness selection. The full differential transcriptome between two environmentally selected clonal variants that originated from the same founder mother was mapped on the entire genomic scaffolds, in parallel with the methyl cytosine distribution. Data suggest that the assortments of heavily methylated DNA sites are distinct in these two clonal phenotypes. This might constitute an epigenetic mechanism that confers the robust adaptation of insect species to various environments involving clonal reproduction. PMID- 25551227 TI - Expanding the knowledge of the geographic distribution of Trypanosoma cruzi TcII and TcV/TcVI genotypes in the Brazilian Amazon. AB - Trypanosoma cruzi infection is a complex sylvatic enzooty involving a wide range of animal species. Six discrete typing units (DTUs) of T. cruzi, named TcI to TcVI, are currently recognized. One unanswered question concerning the epidemiology of T. cruzi is the distribution pattern of TcII and hybrid DTUs in nature, including their virtual absence in the Brazilian Amazon, the current endemic area of Chagas disease in Brazil. Herein, we characterized biological samples that were collected in previous epizootiological studies carried out in the Amazon Basin in Brazil. We performed T. cruzi genotyping using four polymorphic genes to identify T. cruzi DTUs: mini-exon, 1f8, histone 3 and gp72. This analysis was conducted in the following biological samples: (i) two T. cruzi isolates obtained by culturing of stools from the triatomine species Rhodnius picttipes and (ii) five serum samples from dogs in which trypomastigotes were observed during fresh blood examination. We report for the first time the presence of TcII and hybrid DTUs (TcV/TcVI) in the Amazon region in mixed infections with TcI. Furthermore, sequencing of the constitutive gene, gp72, demonstrated diversity in TcII even within the same forest fragment. These data show that TcII is distributed in the five main Brazilian biomes and is likely more prevalent than currently described. It is very probable that there is no biological or ecological barrier to the transmission and establishment of any DTU in any biome in Brazil. PMID- 25551228 TI - Flatfoot diagnosis by a unique bimodal distribution of footprint index in children. AB - BACKGROUND: More than 1000 scientific papers have been devoted to flatfoot issue. However, a bimodal distribution of flatfoot indices in school-aged children has never been discovered. The purposes of this study were to establish a new classification of flatfoot by characteristic in frequency distribution of footprint index and to endue the classification with discrepancy in physical fitness. METHODS/PRINCIPAL FINDINGS: In a longitudinal survey of physical fitness and body structure, weight bearing footprints and 3 physical fitness related tests were measured in 1228 school-aged children. Frequency distribution of initial data was tested by Kolmogorov-Smirnov test for normality and a unique bimodal distribution of footprint index was identified. The frequency distribution of footprint index manifests two distinct modes, flatfoot and non flatfoot, by deconvolution and bootstrapping procedures. A constant intersection value of 1.0 in Staheli's arch index and 0.6 in Chippaux-Smirak index could distinguish the two modes of children, and the value was constant in different age, sex, and weight status. The performance of the one leg balance was inferior in flatfoot girls (median, 4.0 seconds in flatfoot girls vs. 4.3 seconds in non flatfoot girls, p = 0.04, 95% CI 0.404-0.484). DISCUSSION: The natural bimodality lends itself to a flatfoot classification. Bimodality suggests development of the child's foot arch would be a leap from one state to another, rather than a continuous growth as body height and weight. The underlying dynamics of the human foot arch and motor development will trigger research prospects. PMID- 25551229 TI - Dr-FtsA, an actin homologue in Deinococcus radiodurans differentially affects Dr FtsZ and Ec-FtsZ functions in vitro. AB - The Deinococcus radiodurans genome encodes homologues of divisome proteins including FtsZ and FtsA. FtsZ of this bacterium (Dr-FtsZ) has been recently characterized. In this paper, we study FtsA of D. radiodurans (Dr-FtsA) and its involvement in regulation of FtsZ function. Recombinant Dr-FtsA showed neither ATPase nor GTPase activity and its polymerization was ATP dependent. Interestingly, we observed that Dr-FtsA, when compared with E. coli FtsA (Ec FtsA), has lower affinity for both Dr-FtsZ and Ec-FtsZ. Also, Dr-FtsA showed differential effects on GTPase activity and sedimentation characteristics of Dr FtsZ and Ec-FtsZ. For instance, Dr-FtsA stimulated GTPase activity of Dr-FtsZ while GTPase activity of Ec-FtsZ was reduced in the presence of Dr-FtsA. Stimulation of GTPase activity of Dr-FtsZ by Dr-FtsA resulted in depolymerization of Dr-FtsZ. Dr-FtsA effects on GTPase activity and polymerization/depolymerisation characteristics of Dr-FtsZ did not change significantly in the presence of ATP. Recombinant E. coli expressing Dr-FtsA showed cell division inhibition in spite of in trans expression of Dr-FtsZ in these cells. These results suggested that Dr-FtsA, although it lacks ATPase activity, is still functional and differentially affects Dr-FtsZ and Ec-FtsZ function in vitro. PMID- 25551230 TI - Comparison of human induced pluripotent stem-cell derived cardiomyocytes with human mesenchymal stem cells following acute myocardial infarction. AB - INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC CMs) have recently been shown to express key cardiac proteins and improve in vivo cardiac function when administered following myocardial infarction. However, the efficacy of hiPSC-derived cell therapies, in direct comparison to current, well established stem cell-based therapies, is yet to be elucidated. The goal of the current study was to compare the therapeutic efficacy of human mesenchymal stem cells (hMSCs) with hiPSC-CMs in mitigating myocardial infarction (MI). METHODS: Male athymic nude hyrats were subjected to permanent ligation of the left anterior-descending (LAD) coronary artery to induce acute MI. Four experimental groups were studied: 1) control (non-MI), 2) MI, 3) hMSCs (MI+MSC), and 4) hiPSC CMs (MI+hiPSC-derived cardiomyocytes). The hiPSC-CMs and hMSCs were labeled with superparamagnetic iron oxide (SPIO) in vitro to track the transplanted cells in the ischemic heart by high-field cardiac MRI. These cells were injected into the ischemic heart 30-min after LAD ligation. Four-weeks after MI, cardiac MRI was performed to track the transplanted cells in the infarct heart. Additionally, echocardiography (M-mode) was performed to evaluate the cardiac function. Immunohistological and western blot studies were performed to assess the cell tracking, engraftment and cardiac fibrosis in the infarct heart tissues. RESULTS: Echocardiography data showed a significantly improved cardiac function in the hiPSC-CMs and hMSCs groups, when compared to MI. Immunohistological studies showed expression of connexin-43, alpha-actinin and myosin heavy chain in engrafted hiPSC-CMs. Cardiac fibrosis was significantly decreased in hiPSC-CMs group when compared to hMSCs or MI groups. Overall, this study demonstrated improved cardiac function with decreased fibrosis with both hiPSC-CMs and hMSCs groups when compared with MI group. PMID- 25551231 TI - The study of fingerprint characteristics of Dayi Pu-Erh tea using a fully automatic HS-SPME/GC-MS and combined chemometrics method. AB - The quality of tea is presently evaluated by the sensory assessment of professional tea tasters, however, this approach is both inconsistent and inaccurate. A more standardized and efficient method is urgently needed to objectively evaluate tea quality. In this study, the chemical fingerprint of 7 different Dayi Pu-erh tea brands and 3 different Ya'an tea brands on the market were analyzed using fully automatic headspace solid-phase microextraction (HS SPME) combined with gas chromatography-mass spectrometry (GC-MS). A total of 78 volatiles were separated, among 75 volatiles were identified by GC-MS in seven Dayi Pu-erh teas, and the major chemical components included methoxyphenolic compounds, hydrocarbons, and alcohol compounds, such as 1,2,3-trimethoxybenzene, 1,2,4-trimethoxybenzene, 2,6,10,14-tetramethyl-pentadecane, linalool and its oxides, alpha-terpineol, and phytol. The overlapping ratio of peaks (ORP) of the chromatogram in the seven Dayi Pu-erh tea samples was greater than 89.55%, whereas the ORP of Ya'an tea samples was less than 79.10%. The similarity and differences of the Dayi Pu-erh tea samples were also characterized using correlation coefficient similarity and principal component analysis (PCA). The results showed that the correlation coefficient of similarity of the seven Dayi Pu-erh tea samples was greater than 0.820 and was gathered in a specific area, which showed that samples from different brands were basically the same, despite have some slightly differences of chemical indexes was found. These results showed that the GC-MS fingerprint combined with the PCA approach can be used as an effective tool for the quality assessment and control of Pu-erh tea. PMID- 25551234 TI - Posttraumatic stress disorder in the US veteran population: results from the National Health and Resilience in Veterans Study. AB - OBJECTIVE: To describe the prevalence of posttraumatic stress disorder (PTSD) and comorbid psychiatric disorders and identify correlates of PTSD in a contemporary, nationally representative sample of US veterans. METHOD: Data were analyzed from Wave 1 of the National Health and Resilience in Veterans Study, a cross sectional, retrospective, web-based survey of a population-based sample of 3,157 US veterans conducted between October and December 2011. The main outcome measure was probable lifetime PTSD, which was assessed by using a DSM-IV version of the PTSD Checklist (PCL), the PCL-Specific Stressor version. RESULTS: The weighted lifetime and current prevalence of probable PTSD was 8.0% (standard error [SE] = 0.48) and 4.8% (SE = 0.40), respectively. 87.0% of veterans reported exposure to at least 1 potentially traumatic event (PTE); veterans reported a mean of 3.4 (SD = 2.8) different PTE types in their lifetime. Sudden death of a loved one was the most frequently endorsed PTE (61.3%), and sexual abuse in adulthood had the highest conditional probability of PTSD (37.3%). PTSD was associated with increased odds of mood, anxiety, and substance use disorders (odds ratios [ORs] = 2.2-19.1, P values < .001); suicidal ideation (OR = 9.7, P < .001); and suicide attempts (OR = 11.8, P < .001). Psychosocial factors, including resilience, community integration, and secure attachment, were associated with decreased odds of PTSD (ORs = 0.5-0.7, P values < .05). CONCLUSIONS: In a nationally representative sample of US veterans, the prevalence of lifetime and current PTSD was 8.0% and 4.8%, respectively, and PTSD was associated with elevated risk for several psychiatric conditions and suicidality. Veterans reported exposure to many PTE types in addition to combat, and conditional risk for PTSD was high for noncombat-related trauma. Prevention and treatment efforts designed to bolster protective psychosocial factors may help mitigate PTSD risk in this population. PMID- 25551233 TI - Camouflage and individual variation in shore crabs (Carcinus maenas) from different habitats. AB - Camouflage is widespread throughout the natural world and conceals animals from predators in a vast range of habitats. Because successful camouflage usually involves matching aspects of the background environment, species and populations should evolve appearances tuned to their local habitat, termed phenotype environment associations. However, although this has been studied in various species, little work has objectively quantified the appearances of camouflaged animals from different habitats, or related this to factors such as ontogeny and individual variation. Here, we tested for phenotype-environment associations in the common shore crab (Carcinus maenas), a species highly variable in appearance and found in a wide range of habitats. We used field surveys and digital image analysis of the colors and patterns of crabs found in four locations around Cornwall in the UK to quantify how individuals vary with habitat (predominantly rockpool, mussel bed, and mudflat). We find that individuals from sites comprising different backgrounds show substantial differences in several aspects of color and pattern, and that this is also dependent on life stage (adult or juvenile). Furthermore, the level of individual variation is dependent on site and life stage, with juvenile crabs often more variable than adults, and individuals from more homogenous habitats less diverse. Ours is the most comprehensive study to date exploring phenotype-environment associations for camouflage and individual variation in a species, and we discuss the implications of our results in terms of the mechanisms and selection pressures that may drive this. PMID- 25551235 TI - The relationship between neurocognitive and psychosocial functioning in major depressive disorder: a systematic review. AB - OBJECTIVE: Neurocognitive deficits are demonstrated in major depressive disorder (MDD) and most likely contribute to the functional impairment experienced by affected individuals. We systematically reviewed the evidence on neurocognitive deficits and their relationship(s) to psychosocial functioning in MDD. DATA SOURCES: English-language literature was searched in MEDLINE, EMBASE, Science Direct, and PsycInfo databases for the years 1980-October 15, 2013, with the following terms: (depressive disorder or depressive disorder, major) and permutations of (cognitive, neurocognitive, neuropsych*) with (impairment, deficit, performance, test) and (quality of life; functional outcomes; outcome assessment, health care) or (assessment, outcomes; assessment, patient outcomes; outcomes assessment; outcomes assessments, patient). STUDY SELECTION: Inclusion criteria were (1) nongeriatric adults (< 60 years) with a primary diagnosis of MDD by DSM-IV, ICD-9, or ICD-10 criteria; (2) use of neuropsychological tests; and (3) use of a specific measure of social, occupational, or daily functioning. Of 488 articles identified in the initial search, 10 met the inclusion criteria. DATA EXTRACTION: Two independent appraisers assessed eligibility of the studies. Substantial heterogeneity in the samples and methods precluded a quantitative meta-analysis, so we performed a narrative descriptive review. RESULTS: The included studies employed a variety of neurocognitive tests and assessments of psychosocial functioning. Overall, depressed samples had neurocognitive deficits in various domains that were associated with different measures of psychosocial functioning. However, these findings were constrained by methodological limitations of studies. CONCLUSIONS: The limited evidence base suggests that neurocognitive functioning appears to be broadly associated with functional impairment in individuals with MDD, but the quality of evidence is weak. Further studies to clarify the relationship(s) between neurocognitive and psychosocial functioning in MDD will benefit from larger and more homogeneous samples, prospective designs with multivariate analyses, and use of comprehensive assessments of psychosocial functioning that are validated in depressed populations. PMID- 25551236 TI - An overview of vortioxetine. AB - Six clinicians provide an overview of the serotonergic antidepressant vortioxetine, which was recently approved for the treatment of major depressive disorder in adults. They discuss the pharmacologic profile and receptor-mediated effects of vortioxetine in relation to potential outcomes. Additionally, they summarize the clinical trials, which demonstrate vortioxetine's efficacy, and discuss findings related to safety and tolerability that have high relevance to patient compliance. PMID- 25551237 TI - Updates and trends in the treatment of major depressive disorder. AB - Mental illness accounts for 7.4% of the total disease burden worldwide-more than HIV/AIDS, tuberculosis, or diabetes-making it the leading cause of years lost to disability. Depressive disorders make up 40.5% of that disability, the most of all mental illnesses. Despite the devastating global effects of depression, a report on approval trends by the US Food and Drug Administration (FDA) found that new molecular entities (NMEs) approved for targeting psychiatric illness peaked in the 1960s and have been declining since. PMID- 25551238 TI - The safety of duloxetine during pregnancy and lactation. AB - Depression is common in women, especially during pregnancy and the postpartum period. Untreated depression is associated with many adverse gestational outcomes. It is therefore important to know about the safety of different antidepressant drugs during pregnancy and lactation so that informed decisions can be made regarding treatment. This article summarizes published literature on the subject with regard to duloxetine, an antidepressant with serotonin norepinephrine reuptake inhibition properties. In general, it appears that the use of duloxetine during pregnancy is associated with an increase in the risk of spontaneous abortion, but no increase in other adverse outcomes, such as major fetal malformations. Late-pregnancy exposure to duloxetine may be associated with poor neonatal adaptation syndrome, but the magnitude of this risk is not known. Infant exposure to duloxetine in breast milk is less than 1% of the maternal weight-adjusted dose, suggesting that duloxetine can be safely administered to a woman who is breastfeeding her infant. In general, the very limited data available on the subject do not uncover a signal that the use of duloxetine during pregnancy or lactation increases the risk of adverse outcomes. PMID- 25551239 TI - Inflammation, obesity, and metabolic syndrome in depression: analysis of the 2009 2010 National Health and Nutrition Examination Survey (NHANES). AB - OBJECTIVE: To describe the rates of elevated inflammation, obesity, and metabolic syndrome (MetS) within a large cohort of individuals with depression and to examine the interrelationships of inflammation and MetS in depressed individuals. METHOD: Analyses were conducted on study participants from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) with Patient Health Questionnaire (PHQ-9) depression scores >= 10 to (1) examine the relationship of inflammation (C-reactive protein; CRP) with demographic and clinical characteristics and (2) examine the prevalence of MetS criteria within CRP groups. RESULTS: 5,579 participants provided PHQ-9 data; of those, 606 had PHQ-9 scores >= 10 and were included in further analysis. Of the 606 depressed participants, 585 participants had valid CRP data; 275 participants (47.01%) had CRP levels >= 3.0 mg/L, while 170 (29.06%) had CRP levels >= 5.0 mg/L. Elevated inflammation was significantly correlated with body weight, waist circumference, body mass index, insulin, 2-hour glucose tolerance, and self-report general health (P values < .05). 112 subjects (41.18%) met American Heart Association/National Heart, Lung, and Blood Institute criteria for MetS. Those with elevated CRP were more likely to meet criteria for MetS (odds ratios of 2.81 for those with CRP levels >= 3.0 mg/L and 1.94 for those with CRP levels >= 5.0 mg/L). CONCLUSIONS: Over 29% of depressed individuals had elevated levels of CRP, and 41% met criteria for MetS. Individuals with elevated inflammation are more likely to be obese and meet criteria for MetS. These results highlight the significant inflammatory and metabolic burden of individuals with depression. PMID- 25551241 TI - Estimating PTSD prevalence in US veterans: considering combat exposure, PTSD checklist cutpoints, and DSM-5. PMID- 25551240 TI - A naturalistic study of the association between antidepressant treatment and outcome of smoking cessation treatment. AB - OBJECTIVE: Psychiatric, medical, and substance use comorbidities are highly prevalent among smokers, and many of these comorbidities have been found to be associated with reduced rate of success in clinical trials for smoking cessation. While much has been established about the best available treatments from these clinical trials, little is known about the effect of concomitant psychiatric medications on quit rates in smoking cessation programs. On the basis of results in populations with tobacco dependence and other substance use disorders, we hypothesized that smokers taking antidepressants would have a lower rate of quitting in an outpatient smoking cessation program. METHOD: We performed a naturalistic chart review of veterans (N = 144) enrolled in the Veterans Affairs Greater Los Angeles Mental Health Clinic Smoking Cessation Program from March 2011 through July 2013, who met DSM-IV-TR criteria for nicotine dependence. The primary outcome was smoking cessation with treatment, as evidenced by a patient report of at least 1 week of abstinence and an exhaled carbon monoxide level of <= 6 ppm (if available) at the end of acute treatment, with comparators including concomitant psychotropic medication treatment, psychiatric and medical comorbidities, and the presence of a substance use disorder history. We utilized stepwise binary logistic regression as the main statistical technique. RESULTS: We found that current antidepressant treatment (P = .003) and history of substance use disorder (P = .01) (particularly cocaine [P = .02]) were associated with a lower rate of quitting smoking. Furthermore, the association between antidepressant treatment and reduced rate of smoking cessation was primarily seen in patients with a history of substance use disorder (P = .003). CONCLUSIONS: While preliminary, these results suggest an important clinical interaction meriting future study. If these findings are confirmed, clinicians may want to consider the risk of reduced ability to quit smoking in patients with a history of substance use disorder who are taking antidepressants. PMID- 25551242 TI - Physicians at veterans administration hospitals need to be knowledgeable about military sexual trauma in women. PMID- 25551243 TI - Risks in discontinuation trials with antidepressants. PMID- 25551244 TI - Health care systems issues and disparities in ADHD care for African American adults. AB - The diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) may be overlooked among African Americans. Barriers within the medical profession pose challenges, including biases among health care professionals and a lack of specialty services. Educating medical professionals in cultural competence, as well as educating community gateway contacts (such as clergy and educators) about ADHD, should improve the diagnosis and treatment of African American adults who have ADHD. More specialists are needed in underserved areas. PMID- 25551245 TI - Attitudinal barriers to prescribing LAI antipsychotics in the outpatient setting: communicating with patients, families, and caregivers. AB - Patients with schizophrenia who are nonadherent to medication are at risk for repeated relapse and rehospitalization from this chronic and lifelong mental illness. Effective, oral medications can be difficult for patients to maintain on a daily basis, and long-acting injectable (LAI) antipsychotics can help to alleviate this challenge. However, some physicians' attitudinal barriers that need to be overcome include the belief that patients do not have adherence problems, concerns about LAI antipsychotic efficacy over traditional oral agents, the perception that the time and cost to administer this formulation outweighs its benefit, and the perception that injectable medications undermine patients' autonomy. A better understanding of LAIs and their potential benefits may help physicians to implement a long-term treatment plan that provides the best outcome for patients. PMID- 25551246 TI - Developing a therapeutic plan for treating MS: evidence for new treatments. AB - Patients with multiple sclerosis (MS) require an individualized treatment plan that will help slow disability progression and reduce the number and duration of relapses. The available disease-modifying therapies are approved for relapsing forms of MS, with one agent also approved for secondary progressive MS. Clinicians must know the benefits and adverse effects associated with these treatments and guide patients to the most appropriate medication tailored to their disease course and presentation, as well as to their preferred administration method. To treat relapses that have not spontaneously remitted, clinicians may use short-term steroids (IV or oral formulations) or, for acute relapses in patients who cannot tolerate steroids, plasma exchange or IV immunoglobulin (IVIG). Patients may also have questions regarding complementary and alternative medicines, so clinicians should know which options are most promising for patients with MS. PMID- 25551247 TI - Prevalence of hyperhomocysteinemia in China: a systematic review and meta analysis. AB - Hyperhomocysteinemia (HHcy, total homocysteine concentrations > 15 MUmol/L) has been associated with increased risk of many diseases. A systematic review was performed to summarize the prevalence of HHcy in China. We searched multiple international and Chinese scientific databases for relevant literature, and further manually screened reference lists and corresponded with original authors. Pooled prevalence of HHcy was calculated using random effects model. Subgroup analysis, meta-regression and sensitivity analysis were also performed. A total of 36 studies consisting 60,754 subjects (57.3% male; age range, 3-97 years) were finally included. The overall pooled prevalence of HHcy was 27.5%. Geographically, the prevalence was high in north areas, intermediate in central areas, and low in south areas, and was higher in inland versus coastal areas. The prevalence increased with age and was significantly higher in men than in women. Rural residents had a slightly higher HHcy prevalence than urban residents, and the studies conducted during 2006 to 2012 presented a higher HHcy prevalence than those during 1990 to 2005. In summary, the prevalence of HHcy in China is high, particularly in northern populations, the inlanders, males, and the elderly. Homocysteine-lowering strategies are necessary to reduce this highly preventable disorder. PMID- 25551248 TI - The relationship between serum 25-hydroxyvitamin D concentration, cardiorespiratory fitness, and insulin resistance in Japanese men. AB - Here, we aim to investigate the independent and combined associations of serum 25 hydroxyvitamin D (25(OH)D) and cardiorespiratory fitness (CRF) with glucose metabolism. Fasting blood samples of 107 men aged 40-79 years were analyzed for 25(OH)D, glucose, insulin, glycated hemoglobin, and lipid profile. Homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated from the fasting concentrations of glucose and insulin. Visceral fat area (VFA) was determined by magnetic resonance imaging and CRF by measuring maximal oxygen uptake. Median 25(OH)D concentration was 36.3 nmol/L, while the prevalence of 25(OH)D deficiency was 74.8%. Participants with high CRF had significantly lower HOMA-IR, glycated hemoglobin, and insulin values than participants with low CRF (p < 0.05). Higher 25(OH)D concentration was strongly correlated with lower HOMA IR and insulin values independent of VFA (p < 0.01) but significantly affected by CRF. In the high CRF group, participants with higher 25(OH)D concentration had lower HOMA-IR values than participants with low 25(OH)D concentration (p < 0.05). Higher 25(OH)D and CRF are crucial for reducing insulin resistance regardless of abdominal fat. In addition, higher 25(OH)D concentration may strengthen the effect of CRF on reducing insulin resistance in middle-aged and elderly Japanese men with high CRF. PMID- 25551249 TI - Hepcidin-25, mean corpuscular volume, and ferritin as predictors of response to oral iron supplementation in hemodialysis patients. AB - The benefit of oral iron therapy (OIT) and factors predictive of OIT response are not established in hemodialysis (HD) patients with iron deficiency anemia (IDA). We examined the values of hepcidin-25, mean corpuscular volume (MCV), and ferritin as predictors of OIT response. Oral ferrous fumarate (50 mg/day, 8 weeks) was given to 51 HD patients with IDA (hemoglobin (Hb) < 12 g/dL, ferritin < 100 ng/mL) treated with an erythropoietin activator. Sixteen patients were responders (improvement of Hb (DeltaHb) >= 2 g/dL) and 35 were non-responders (DeltaHb < 2g/dL). Baseline Hb, MCV, serum hepcidin-25, ferritin, iron parameters, and C-reactive protein (CRP) before and DeltaHb after OIT were compared between groups. Hepcidin-25, MCV, ferritin, and transferrin saturation were lower in the responders than in the non-responders. Hepcidin-25 positively correlated with ferritin. Hepcidin-25, MCV, and ferritin positively correlated with baseline Hb and negatively correlated with DeltaHb. Despite normal CRP levels in all patients, CRP correlated positively with hepcidin-25 and ferritin. Stepwise multiple linear regression analysis and receiver operating characteristics curve analysis revealed that hepcidin-25, MCV, and ferritin could predict OIT response. We conclude that hepcidin-25, MCV, and ferritin could be useful markers of iron storage status and may help predict OIT response in HD patients. PMID- 25551252 TI - Funnel-metadynamics and solution NMR to estimate protein-ligand affinities. AB - One of the intrinsic properties of proteins is their capacity to interact selectively with other molecules in their environment, inducing many chemical equilibria each differentiated by the mutual affinities of the components. A comprehensive understanding of these molecular binding processes at atomistic resolution requires formally the complete description of the system dynamics and statistics at the relevant time scales. While solution NMR observables are averaged over different time scales, from picosecond to second, recent new molecular dynamics protocols accelerated considerably the simulation time of realistic model systems. Based on known ligands recently discovered either by crystallography or NMR for the human peroxiredoxin 5, their affinities were for the first time accurately evaluated at atomistic resolution comparing absolute binding free-energy estimated by funnel-metadynamics simulations and solution NMR experiments. In particular, free-energy calculations are demonstrated to discriminate two closely related ligands as pyrocatechol and 4-methylpyrocathecol separated just by 1 kcal/mol in aqueous solution. The results provide a new experimental and theoretical basis for the estimation of ligand-protein affinities. PMID- 25551253 TI - Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors. AB - Autophagy is a conserved cellular process that involves the degradation of cellular components for energy maintenance and cytoplasmic quality control that has recently gained interest as a novel target for a variety of human diseases, including cancer. A prime candidate to determine the potential therapeutic benefit of targeting autophagy is the kinase ULK1, whose activation initiates autophagy. Here, we report the first structures of ULK1, in complex with multiple potent inhibitors. These structures show features unique to the enzyme and will provide a path for the rational design of selective compounds as cellular probes and potential therapeutics. PMID- 25551254 TI - Quantifying the benefit of wellbore leakage potential estimates for prioritizing long-term MVA well sampling at a CO2 storage site. AB - This work uses probabilistic methods to simulate a hypothetical geologic CO2 storage site in a depleted oil and gas field, where the large number of legacy wells would make it cost-prohibitive to sample all wells for all measurements as part of the postinjection site care. Deep well leakage potential scores were assigned to the wells using a random subsample of 100 wells from a detailed study of 826 legacy wells that penetrate the basal Cambrian formation on the U.S. side of the U.S./Canadian border. Analytical solutions and Monte Carlo simulations were used to quantify the statistical power of selecting a leaking well. Power curves were developed as a function of (1) the number of leaking wells within the Area of Review; (2) the sampling design (random or judgmental, choosing first the wells with the highest deep leakage potential scores); (3) the number of wells included in the monitoring sampling plan; and (4) the relationship between a well's leakage potential score and its relative probability of leakage. Cases where the deep well leakage potential scores are fully or partially informative of the relative leakage probability are compared to a noninformative base case in which leakage is equiprobable across all wells in the Area of Review. The results show that accurate prior knowledge about the probability of well leakage adds measurable value to the ability to detect a leaking well during the monitoring program, and that the loss in detection ability due to imperfect knowledge of the leakage probability can be quantified. This work underscores the importance of a data-driven, risk-based monitoring program that incorporates uncertainty quantification into long-term monitoring sampling plans at geologic CO2 storage sites. PMID- 25551250 TI - Developmental programming of cardiovascular disease following intrauterine growth restriction: findings utilising a rat model of maternal protein restriction. AB - Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of "programming". The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype. PMID- 25551251 TI - A review of the impact of dietary intakes in human pregnancy on infant birthweight. AB - Studies assessing maternal dietary intakes and the relationship with birthweight are inconsistent, thus attempting to draw inferences on the role of maternal nutrition in determining the fetal growth trajectory is difficult. The aim of this review is to provide updated evidence from epidemiological and randomized controlled trials on the impact of dietary and supplemental intakes of omega-3 long-chain polyunsaturated fatty acids, zinc, folate, iron, calcium, and vitamin D, as well as dietary patterns, on infant birthweight. A comprehensive review of the literature was undertaken via the electronic databases Pubmed, Cochrane Library, and Medline. Included articles were those published in English, in scholarly journals, and which provided information about diet and nutrition during pregnancy and infant birthweight. There is insufficient evidence for omega 3 fatty acid supplements' ability to reduce risk of low birthweight (LBW), and more robust evidence from studies supplementing with zinc, calcium, and/or vitamin D needs to be established. Iron supplementation appears to increase birthweight, particularly when there are increases in maternal hemoglobin concentrations in the third trimester. There is limited evidence supporting the use of folic acid supplements to reduce the risk for LBW; however, supplementation may increase birthweight by ~130 g. Consumption of whole foods such as fruit, vegetables, low-fat dairy, and lean meats throughout pregnancy appears beneficial for appropriate birthweight. Intervention studies with an understanding of optimal dietary patterns may provide promising results for both maternal and perinatal health. Outcomes from these studies will help determine what sort of dietary advice could be promoted to women during pregnancy in order to promote the best health for themselves and their baby. PMID- 25551255 TI - From Binary Cu2S to ternary Cu-In-S and quaternary Cu-In-Zn-S nanocrystals with tunable composition via partial cation exchange. AB - We present an approach for the synthesis of ternary copper indium sulfide (CIS) and quaternary copper indium zinc sulfide (CIZS) nanocrystals (NCs) by means of partial cation exchange with In(3+) and Zn(2+). The approach consists of a sequential three-step synthesis: first, binary Cu2S NCs were synthesized, followed by the homogeneous incorporation of In(3+) by an in situ partial cation exchange reaction, leading to CIS NCs. In the last step, a second partial exchange was performed where Zn(2+) partially replaced the Cu(+) and In(3+) cations at the surface, creating a ZnS-rich shell with the preservation of the size and shape. By careful tuning reaction parameters (growth and exchange times as well as the initial Cu(+):In(3+):Zn(2+) ratios), control over both the size and composition was achieved. This led to a broad tuning of photoluminescence of the final CIZS NCs, ranging from 880 to 1030 nm without altering the NCs size. Cytotoxicity tests confirmed the biocompatibility of the synthesized CIZS NCs, which opens up opportunities for their application as near-infrared fluorescent markers in the biomedical field. PMID- 25551256 TI - Correction to p-Toluenesulfonic Acid Mediated 1,3-Dipolar Cycloaddition of Nitroolefins with NaN3 for Synthesis of 4-Aryl-NH-1,2,3-triazoles. PMID- 25551257 TI - Rotation during lifting tasks: effects of rotation frequency and task order on localized muscle fatigue and performance. AB - Though widely considered to reduce the risk of work-related musculoskeletal disorders, there is limited evidence suggesting that rotating between tasks is effective in doing so. The purpose of the current study was to quantify the effects of rotation and parameters of rotation (frequency and task order) on muscle fatigue and performance. This was done using a simulated lifting task, with rotation between two levels of loading of the same muscle groups. Twelve participants completed six experimental sessions during which repetitive box lifting was performed for one hour either with or without rotation. When rotation was present, it occurred every 15 minutes or every 30 minutes and was between two load levels (box weights). Rotation reduced fatigue and cardiovascular demand compared to the heavier load without rotation, with a mean reduction of ~33% in perceived discomfort and a ~17% reduction in percentage of heart rate reserve. Further, rotation increased fatigue and cardiovascular demand compared to the lighter load without rotation, with a mean increase of ~34% perceived discomfort and a ~19% increase in percentage of heart rate reserve. Neither rotation frequency nor task order had definitive effects, though maximum discomfort ratings were nearly 20% higher when starting with the lighter load task. These parameters of rotation should be further evaluated under more realistic task conditions. PMID- 25551260 TI - The relationship between body mass index and cancer screening utilization among older women in Latin American and Caribbean cities. AB - To examine the relationship between body mass index and cancer screening utilization, we analyzed data from six cities of the Health, Well-Being and Aging in Latin America and the Caribbean Study on 5,230 women aged 60 and older, from 1999 to 2000. We found that underweight women were less likely to have had a mammogram, a breast self-exam, and a Pap smear, relative to normal-weight women. However, overweight or obese women were more likely to have a breast self-exam and a Pap smear. Thus, being underweight had a role for decreased cancer screening utilization among older women in Latin American cities, but not being overweight or obese, which was associated with decreased cancer screening in most previous studies. PMID- 25551258 TI - Nasal carriage of mecA-positive methicillin-resistant Staphylococcus aureus in pigs exhibits dose-response to zinc supplementation. AB - Zinc (Zn) is often supplemented at elevated concentrations in swine diets, particularly in piglets, to prevent enteric infections and promote growth. Previous studies from Denmark have suggested a genetic linkage and a phenotypic association between Zn resistance, encoded by czrC, and methicillin-resistance conferred by mecA in Staphylococcus aureus. Such an association has not been reported in the U.S. swine population. We conducted an analysis of the effects of Zn, supplemented as zinc oxide (ZnO), on the nasal carriage of methicillin resistant Staphylococcus aureus (MRSA) in nursery (n=40) and finisher pigs (n=40) enrolled in a nutritional study. Nasal swabs, collected from nursery and finisher pigs, were inoculated onto MRSA CHROMagar and presumptive MRSA colonies were tested for the presence of mecA and czrC genes by polymerase chain reaction. Zinc susceptibility was determined by the agar dilution method. The prevalence of mecA positive MRSA was 10% (4/40) and 20% (8/40) among nursery and finisher pigs, respectively. Of the 12 mecA-positive S. aureus isolates, 7 had the czrC gene (58.3%) compared to none among the 68 mecA-negative isolates. The presence of both mecA (p=0.002) and czrC (p=0.006) genes were positively associated with higher levels of Zn supplementation. The median minimum inhibitory concentrations of Zn for czrC-positive and czrC-negative isolates were 12 and 2 mM, respectively (p<0.0001). The link between czrC and mecA genes suggests the importance of elevated Zn supplementation in the co-selection and propagation of methicillin resistance among S. aureus in pigs. PMID- 25551259 TI - Suicidal ideation and distress in family members bereaved by suicide in Portugal. AB - The present study assessed the impact of suicide and distress on suicidal ideation in a sample of 93 Portuguese family members bereaved by suicide. A control community sample of 102 adults also participated. After controlling for educational level, those bereaved by the suicide of a family member were found to have higher levels of suicidal ideation. Forty-two percent of family members had Suicide Ideation Questionnaire scores at or above the cutoff point. General distress, depression, anxiety, and hostility related to suicidal ideation, whereas time since suicide also interacted with general distress and depression in predicting suicidal ideation. PMID- 25551261 TI - Sample size calculation based on efficient unconditional tests for clinical trials with historical controls. AB - In historical clinical trials, the sample size and the number of success in the control group are often considered as given. The traditional method for sample size calculation is based on an asymptotic approach developed by Makuch and Simon (1980). Exact unconditional approaches may be considered as alternative to control for the type I error rate where the asymptotic approach may fail to do so. We provide the sample size calculation using an efficient exact unconditional testing procedure based on estimation and maximization. The sample size using the exact unconditional approach based on estimation and maximization is generally smaller than those based on the other approaches. PMID- 25551262 TI - Building on the legacy of AJIDD: new challenges and opportunities. PMID- 25551263 TI - Variability of the aging process in dementia-free adults with Down syndrome. AB - The aim of this cross-sectional study was to analyze the typical aging process in adults with Down syndrome, focusing on its variability. The sample comprised 120 adults with Down syndrome who were free of dementia. Ages ranged from 20 to 69 years. Each participant was assessed on cognitive functioning and social adaptation, and was checked for the presence of psychopathological disorders. Results revealed an age-related deterioration in both cognitive and social adaptation skills, the extent of this decline depending on the dimension under scrutiny, and interindividual variability in aging profiles. PMID- 25551264 TI - Support and self-efficacy among Latino and White parents of children with ID. AB - Research indicates that mothers of children with ID who receive familial support experience less stress than those who receive less support. Less is known about the relation of support to mothers' evaluation of parenting self-efficacy, particularly in Latino families. We examined the relationship of different types of family support to life satisfaction and parenting self-efficacy (PSE), and explored whether income and ethnicity moderated these relationships. Interviews with 84 Latino and 37 White participants revealed that partner emotional support predicted life satisfaction and PSE in both ethnic groups, with a stronger relationship evident for the PSE of Latino mothers. Income was not a significant moderator. These findings provide guidance for more effective family interventions targeted toward Latinos. PMID- 25551265 TI - Caregiver strain and sensory features in children with autism spectrum disorder and other developmental disabilities. AB - Caring for children with disabilities contributes to increased levels of parent stress or caregiver strain. However, the potential relationship of sensory features to strain among caregivers of children with autism spectrum disorder (ASD) and other developmental disabilities (DD) is unknown. Sensory features include overreactions, underreactions, and unusual interests in sensations, which may negatively impact family functioning. This descriptive study confirmed three caregiver strain types (i.e., objective, subjective internalized, subjective externalized) and explored differences among ASD (n = 71) and DD (n = 36) groups, with the ASD group reporting higher levels. Furthermore, this study explored the contribution of sensory features to caregiver strain, finding differential contributions to strain in the ASD group and covariate contributions (i.e., child cognition, mother's education) in the DD group. PMID- 25551266 TI - Predictors of specialized inpatient admissions for adults with intellectual disability. AB - Individuals with intellectual disability (ID) have complex mental health needs and may seek specialized ID psychiatric services. This study reports on predictors of specialized inpatient admissions for 234 individuals with ID who received outpatient services at a psychiatric hospital. Overall, from 2007-2012, 55 of the 234 outpatients were triaged into the specialized inpatient unit. Aggression towards others and psychotropic polypharmacy significantly predicted these admissions. Unlike previous research, schizophrenia and level of ID did not predict admissions, suggesting that these factors may have a differential impact in specialized versus mainstream inpatient services. Findings are discussed in relation to how specialized inpatient units can be most responsive to these vulnerable patients and the factors that may impact clinical decision making. PMID- 25551267 TI - Symptoms of attention-deficit/hyperactivity disorder in Down syndrome: effects of the dopamine receptor D4 gene. AB - This study examined individual differences in ADHD symptoms and executive function (EF) in children with Down syndrome (DS) in relation to the dopamine receptor D4 (DRD4) gene, a gene often linked to ADHD in people without DS. Participants included 68 individuals with DS (7-21 years), assessed through laboratory tasks, caregiver reports, and experimenter ratings. Saliva samples were collected from the DS group and 66 children without DS to compare DRD4 allele distribution, showing no difference between the groups. When the sample with DS was stratified for ethnicity (n = 32), the DRD4 7-repeat allele significantly related to parent and experimenter ratings, but not to laboratory assessments. These results suggest that nontrisomy genetic factors may contribute to individual differences in ADHD symptoms in persons with DS. PMID- 25551268 TI - Parent and teacher perspectives about problem behavior in children with Williams syndrome. AB - Problem behavior of 52 children with Williams syndrome ages 6 to 17 years old was examined based on both parent and teacher report. Generally good inter-rater agreement was found. Common areas of problem behavior based both on parent and teacher report included attention problems, anxiety difficulties, repetitive behaviors (e.g., obsessions, compulsions, picking nose or skin), and social problems, reflecting a robust behavioral phenotype in Williams syndrome present across contexts. Some rater differences were observed; most notably, parents reported more attention and mood difficulties than did teachers, while teachers reported more oppositionality and aggression than did parents. Relations to intellectual functioning, age, and gender were examined. The implications of the findings for understanding the behavioral phenotype associated with Williams syndrome are discussed. PMID- 25551271 TI - Clinical features and prognostic significance of TCF3-PBX1 fusion gene in Chinese children with acute lymphoblastic leukemia by using a modified ALL-BFM-95 protocol. AB - For children with precursor B (pre-B) acute lymphoblastic leukemia (ALL) with TCF3-PBX1 fusion gene, their prognosis has been a controversial topic. From January 2008 to December 2012 in our hospital, 450 patients were diagnosed as ALL. Clinical characteristics of 20 patients with TCF3-PBX1 fusion gene were analyzed retrospectively, which were classified to the intermediate-risk (IR) group according to Chinese Children Leukemia Group-2008 (CCLG-2008) risk stratification criteria and protocol based on the backbone of BFM 95 trails. Eighty five cases without TCF3-PBX1 in the same IR group were regarded as the comparison group. There were no differences in age, gender, initial white blood cell (WBC) count, status of central nerves system (CNS) at diagnosis and complete remission (CR) rates of bone marrow (BM) between the two groups (P > .05). The 5 year probability of event-free survival (EFS) rates were 84.4 +/- 15.6% and 73.5 +/- 15.6% in the TCF3-PBX1 group and the comparison group (P = .35), respectively. The 5-year probability of overall survival (OS) rates were 86.0 +/- 17.6% and 81.8 +/- 17.6% (P = .46), respectively. Relapse rates were 10.5% and 12.9% (P = 1.00), respectively. There were not cases with CNS relapse in the TCF3 PBX1 group. When intensive chemotherapy was used, the TCF3-PBX1 was associated with a favorable outcome in childhood pre-B ALL. PMID- 25551272 TI - Thoracoabdominal organ volumes for small women. AB - OBJECTIVE: Thoracoabdominal injuries commonly occur as a result of motor vehicle crashes. In order to design occupant protection systems that reduce risk of injury, researchers are using a variety of tools, including computational human body models. Though research has been conducted to provide morphological and volumetric data for the thoracoabdominal cavity of the average male, there is currently an interest in developing models for a wider range of occupants. One particular cohort of interest is the small female by stature and weight because of their use in restraint system development. Geometric data on thoracoabdominal organs are needed to construct accurate representations of female occupants. This study aimed to gather information on organ volumes from clinical medical imaging studies of small females. METHODS: Anonymized clinical computed tomography (CT) and magnetic resonance images were used to segment organs relevant to crash induced injuries: namely, the liver, spleen, left kidney, right kidney, pancreas, gallbladder, lungs, and heart. Segmentations were conducted using semi-automatic techniques. Additionally, diametric measurements of the vena cava, aorta, trachea, and colon were obtained from the medical images at discrete locations using linear measurement tools. RESULTS: A total of 14 adult scans were selected with stature and weight ranges of 145.0 to 162.6 cm and 43.7 to 65.5 kg, respectively. The following are the average thoracoabdominal organ volumes: liver (1,224.5 +/- 220.7 mL), spleen (151.6 +/- 42.1 mL), left kidney (123.7 +/- 20.1 mL), right kidney (115.4 +/- 20.9 mL), heart (417.8 +/- 36.6 mL), pancreas (54.1 +/- 11.8 mL), and gallbladder (20.6 +/- 13.4 mL). The average diameters were 19.7 +/- 3.2 mm and 17.7 +/- 5.1 mm for the vena cava and aorta, respectively. The colon had an average diameter of 37.9 +/- 7.1 mm. CONCLUSION: Data characterizing the small female are important to validate the geometries used in computational models, including models derived from scaling techniques and those developed using subject-specific medical imaging. The goal of this study was to use a sample of subjects anthropometrically representative of small females to evaluate the average volume for organs commonly injured in motor vehicle crashes. Based on these data, the right and left lungs were strongly correlated with stature and the heart was strongly correlated with weight. Ultimately, these measurements will be useful for the validation of computational models of the small female. PMID- 25551273 TI - Prostaglandin signaling in ciliogenesis during development. PMID- 25551274 TI - The Children's Memory Questionnaire-Revised. AB - The aim of the current study was to conduct a factor analysis of the Children's Memory Questionnaire-Revised (CMQ-R) and evaluate it as a reliable and effective measurement of memory functioning in children. The CMQ-R is a 36-item questionnaire designed to assess parents' perceptions of their children's memory. Three hundred and seventy-one children aged 5 to 12 years old participated in this study. Three hundred and forty-two children were recruited from schools and 29 were recruited from Kaleidoscope outpatient medical and allied health clinics. Parents of all 371 children completed the CMQ-R, and the parents of 6-, 8-, 10-, and 12-year-olds in the school group completed a 2nd CMQ-R approximately 1 month later. In the school group, children at these ages also participated in a formal assessment of memory. In the clinical group, all 29 children were tested. The results indicated that correlations between the CMQ-R and formal memory testing were low; however, these results improved slightly when age groups were separated with the highest correlation occurring for the 12-year-olds. The school and clinical groups were compared on measures of the CMQ-R, and results indicated that there was a significant difference in the CMQ-R total between the school and clinical groups. A factor analysis of the CMQ-R revealed three factors with moderate to strong loadings, and these reflected, although were not limited to, episodic memory, visual memory, and working memory/attention. The possibility is discussed that the CMQ-R was assessing different aspects of memory than formal testing and that these are likely to be everyday memory abilities. PMID- 25551275 TI - The conversation. PMID- 25551276 TI - Folding and self-association of atTic20 in lipid membranes: implications for understanding protein transport across the inner envelope membrane of chloroplasts. AB - BACKGROUND: The Arabidopsis thaliana protein atTic20 is a key component of the protein import machinery at the inner envelope membrane of chloroplasts. As a component of the TIC complex, it is believed to form a preprotein-conducting channel across the inner membrane. RESULTS: We report a method for producing large amounts of recombinant atTic20 using a codon-optimized strain of E. coli coupled with an autoinduction method of protein expression. This method resulted in the recombinant protein being directed to the bacterial membrane without the addition of a bacterial targeting sequence. Using biochemical and biophysical approaches, we were able to demonstrate that atTic20 homo-oligomerizes in vitro when solubilized in detergents or reconstituted into liposomes. Furthermore, we present evidence that the extramembranous N-terminus of the mature protein displays characteristics that are consistent with it being an intrinsically disordered protein domain. CONCLUSION: Our work strengthens the hypothesis that atTic20 functions similarly to other small alpha-helical integral membrane proteins, such as Tim23, that are involved in protein transport across membranes. PMID- 25551277 TI - Using internet search queries for infectious disease surveillance: screening diseases for suitability. AB - BACKGROUND: Internet-based surveillance systems provide a novel approach to monitoring infectious diseases. Surveillance systems built on internet data are economically, logistically and epidemiologically appealing and have shown significant promise. The potential for these systems has increased with increased internet availability and shifts in health-related information seeking behaviour. This approach to monitoring infectious diseases has, however, only been applied to single or small groups of select diseases. This study aims to systematically investigate the potential for developing surveillance and early warning systems using internet search data, for a wide range of infectious diseases. METHODS: Official notifications for 64 infectious diseases in Australia were downloaded and correlated with frequencies for 164 internet search terms for the period 2009 13 using Spearman's rank correlations. Time series cross correlations were performed to assess the potential for search terms to be used in construction of early warning systems. RESULTS: Notifications for 17 infectious diseases (26.6%) were found to be significantly correlated with a selected search term. The use of internet metrics as a means of surveillance has not previously been described for 12 (70.6%) of these diseases. The majority of diseases identified were vaccine preventable, vector-borne or sexually transmissible; cross correlations, however, indicated that vector-borne and vaccine preventable diseases are best suited for development of early warning systems. CONCLUSIONS: The findings of this study suggest that internet-based surveillance systems have broader applicability to monitoring infectious diseases than has previously been recognised. Furthermore, internet-based surveillance systems have a potential role in forecasting emerging infectious disease events, especially for vaccine-preventable and vector-borne diseases. PMID- 25551278 TI - Adverse effects of parental smoking during pregnancy in urban and rural areas. AB - BACKGROUND: Parental smoking during pregnancy is associated with lower birthweight and gestational age, as well as with the risks of low birthweight (LBW) and preterm birth. The present study aims to assess the association of parental smoking during pregnancy with birth outcomes in urban and rural areas. METHODS: This was a secondary analysis of data collected in the Indonesia Family Life Survey, between 1993 and 2007, the first national prospective longitudinal cohort study in Indonesia. Retrospective data of parental smoking habits, socioeconomic status, pregnancy history and birth outcomes were collected from parents with children aged 0 to 5 years (n = 3789). We assessed the relationships between the amount of parental smoking during pregnancy with birthweight (LBW) and with gestational age (preterm birth). RESULTS: We found a significant reduction in birthweight to be associated with maternal smoking. Smoking (except for paternal smoking) was associated with a decrease in the gestational age and an increased risk of preterm birth. Different associations were found in urban area, infants born to smoking fathers and both smoking parents (>20 cigarettes/day for both cases) had a significant reduction in birthweight and gestational age as well as an increased risk of LBW and preterm birth. CONCLUSIONS: Residence was found to be an effect modifier of the relation between parental smoking during pregnancy, amount of parental smoking, and birth outcomes on their children. Smoking cessation/reduction and smoking intervention program should be advised and prioritized to the area that is more prone to the adverse birth outcomes. PMID- 25551279 TI - Biopsy-proven autoimmune myocarditis in HIV-associated dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy occurring in HIV-infected patients raises both diagnostic and therapeutic challenging problems. Indeed myocardial involvement in HIV infection has been variously attributed to several causes, including viral, toxic, nutritional and autoimmune, but no specific treatment capable to substantially improve patients' prognosis has been recognized so far. CASE PRESENTATION: Hereby we describe the case of an autoimmune myocarditis manifesting with heart failure in a3 9-year-old man with HIV infection. Left ventricular endomyocardial biopsy showed a lymphocytic myocarditis characterized by over-expression of HLA-DR and negative polymerase chain reaction for cardiotropic viruses. Steroid treatment was followed by recovery of cardiac dimension and function. CONCLUSION: Presence of auto-reactive myocarditis should be considered in patients with HIV-associated dilated cardiomyopathy. Its recognition by endomyocardial biopsy followed by steroid administration may result in a complete resolution of cardiac disease. PMID- 25551280 TI - Bacteriological methods as add on tests to fine-needle aspiration cytology in diagnosis of tuberculous lymphadenitis: can they reduce the diagnostic dilemma? AB - BACKGROUND: The diagnostic accuracy of fine-needle aspiration (FNA) cytology for the diagnosis of tuberculous lymphadenitis (TBLN) is confounded by mimicking cytomorphologic disorders. The objective of this study was to determine whether supplementing FNA cytology with bacteriological methods improves the overall accuracy of TBLN diagnosis. METHODS: Two hundred presumptive TBLN cases were included in the study. FNA specimens were collected and examined for cytomorphologic changes, for acid-fast bacilli (AFB) by microscopy and for mycobacterial growth on culture. Culture was done using Lowenstein-Jensen (LJ) medium and mycobacteria growth indicator tube (BACTEC MGIT 960 TB detection system). Differentiation between M. tuberculosis complex (MTBc) and non tuberculous mycobacteria (NTM) was done by using 500 MUg/ml para-nitrobenzoic acid (PNB) susceptibility testing. RESULTS: Cytomorphology detected TBLN among 80% (160/200) of the presumptive cases. Culture results were available for 188 cases. Twelve samples were excluded due to contamination on both culture methods. Culture confirmed cases accounted for 78% (147/188) of which MTBc constituted 97.3% (143/147). Among presumptive cases, classified by FNA cytology as 'abscess', 11 were culture positive. Microscopy detected 31.3% (46/147) of culture confirmed mycobacterial lymphadenitis of which 11% (4/37) were diagnosed non-suggestive for tuberculosis (TB) by FNA cytology. Compared to culture (LJ & BACTEC MGIT 960) and AFB microscopy as composite gold standard, FNA cytology had a sensitivity of 88.4% and a specificity of 48.8%. The positive predictive value was 86.1% while the negative predictive value was 54.1%. The confirming power and the ROC curve area was 1.73 and 0.69, respectively. CONCLUSION: FNA cytology showed a relatively high sensitivity but a low specificity. Combining bacteriological methods with FNA cytology in an endemic region like Ethiopia improves the overall accuracy of the diagnosis of mycobacterial lymphadenitis, which in turn may lead to better patient management. PMID- 25551281 TI - Integrative network analysis of TCGA data for ovarian cancer. AB - BACKGROUND: Over the past years, tremendous efforts have been made to elucidate the molecular basis of the initiation and progression of ovarian cancer. However, most existing studies have been focused on individual genes or a single type of data, which may lack the power to detect the complex mechanisms of cancer formation by overlooking the interactions of different genetic and epigenetic factors. RESULTS: We propose an integrative framework to identify genetic and epigenetic features related to ovarian cancer and to quantify the causal relationships among these features using a probabilistic graphical model based on the Cancer Genome Atlas (TCGA) data. In the feature selection, we first defined a set of seed genes by including 48 candidate tumor suppressors or oncogenes and an additional 20 ovarian cancer related genes reported in the literature. The seed genes were then fed into a stepwise correlation-based selector to identify 271 additional features including 177 genes, 82 copy number variation sites, 11 methylation sites and 1 somatic mutation (at gene TP53). We built a Bayesian network model with a logit link function to quantify the causal relationships among these features and discovered a set of 13 hub genes including ARID1A, C19orf53, CSKN2A1 and COL5A2. The directed graph revealed many potential genetic pathways, some of which confirmed the existing results in the literature. Clustering analysis further suggested four gene clusters, three of which correspond to well-defined cellular processes including cell division, tumor invasion and mitochondrial system. In addition, two genes related to glycoprotein synthesis, PSG11 and GALNT10, were found highly predictive for the overall survival time of ovarian cancer patients. CONCLUSIONS: The proposed framework is effective in identifying possible important genetic and epigenetic features that are related to complex cancer diseases. The constructed Bayesian network has identified some new genetic/epigenetic pathways, which may shed new light into the molecular mechanisms of ovarian cancer. PMID- 25551282 TI - Temporal dynamics of the very premature infant gut dominant microbiota. AB - BACKGROUND: The very-preterm infant gut microbiota is increasingly explored due to its probable role in the development of life threatening diseases. Results of high-throughput studies validate and renew the interest in approaches with lower resolution such as PCR-Temporal Temperature Gel Electrophoresis (TTGE) for the follow-up of dominant microbiota dynamics. We report here an extensive longitudinal study of gut colonization in very preterm infants. We explored by 16S rDNA-based PCR-TTGE a total of 354 stool specimens sampled during routine monitoring from the 1(st) to the 8(th) week of life in 30 very pre-term infants born before 30 weeks of gestational age. RESULTS: Combining comparison with a diversity ladder and sequencing allowed affiliation of 50 Species-Level Operational Taxonomic Units (SLOTUs) as well as semi-quantitative estimation of Operational Taxonomic Units (OTUs). Coagulase-negative staphylococci, mainly the Staphylococcus epidermidis, was found in all the infants during the study period and was the most represented (75.7% of the SLOTUs) from the first days of life. Enterococci, present in 60% of the infants were early, highly represented and persistent colonizers of the premature gut. Later Enterobacteriaceae and the genus Clostridium appeared and were found in 10 (33%) and 21 infants (70%), respectively. We showed a high representation of Veillonella in more than a quarter of the infants and being able to persistently colonize premature gut. The genera Anaerococcus, Aquabacterium, Bacillus, Bifidobacterium, Corynebacterium, Micrococcus, Oceanobacillus, Propionibacterium, Pseudomonas, Rothia, Sarcina, Sneathia and Streptococcus were observed as transient or persistent colonizers, each genus being found in a minority of infants. CONCLUSIONS: Despite low resolution, PCR-TTGE remains complementary to high-throughput sequencing-based approaches because it allows the follow-up of dominant bacteria in gut microbiota in a large longitudinal cohorts of preterm neonates. We described the development of pre-term gut microbiota that should be now replaced regarding the functional role of major OTUs. PMID- 25551283 TI - Bridging the gap--planning Lifestyle Medicine fellowship curricula: A cross sectional study. AB - BACKGROUND: The emerging field, Lifestyle Medicine (LM), is the evidence-based practice of assisting individuals and families to adopt and sustain behaviors that can improve health. While competencies for LM education have been defined, and undergraduate curricula have been published, there are no published reports that address graduate level fellowship in LM. This paper describes the process of planning a LM fellowship curriculum at a major, academic teaching institution. METHODS: In September 2012 Harvard Medical School Department of Physical Medicine and Rehabilitation approved a "Research Fellowship in Lifestyle Medicine". A Likert scale questionnaire was created and disseminated to forty LM stakeholders worldwide, which measured perceived relative importance of six domains and eight educational experiences to include in a one-year LM fellowship. Statistical procedures included analysis of variance and the Wilcoxon signed-rank test. RESULTS: Thirty-five stakeholders (87.5%) completed the survey. All domains except smoking cessation were graded at 4 or 5 by at least 85% of the respondents. After excluding smoking cessation, nutrition, physical activity, behavioral change techniques, stress resiliency, and personal health behaviors were rated as equally important components of a LM fellowship curriculum (average M = 4.69, SD = 0.15, p = 0.12). All educational experiences, with the exception of completing certification programs, research experience and fund raising, were graded at 4 or 5 by at least 82% of the responders. The remaining educational experiences, i.e. clinical practice, teaching physicians and medical students, teaching other health care providers, developing lifestyle interventions and developing health promotion programs were ranked as equally important in a LM fellowship program (average M = 4.23, SD = 0.11, p = 0.07). CONCLUSIONS: Lifestyle fellowship curricula components were defined based on LM stakeholders' input. These domains and educational experiences represent the range of competencies previously noted as important in the practice of LM. As the foundation of an inaugural physician fellowship, they inform the educational objectives and future evaluation of this fellowship. PMID- 25551284 TI - MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. AB - BACKGROUND: Metastasis have considered as an important clinical obstacle in the treatment of human cancer including bladder cancer. Post-transcriptional regulation has emerged as robust effectors of metastasis. MiRNAs are involved in cancer development and progression, acting as tumor suppressors or oncogenes. In this study, we focus on it that microRNA-34a functions as an anti-metastatic microRNA and suppress angiogenesis in bladder cancer by directly targeting CD44. METHODS: The expression of mir-34a was detected by quantitative real-time PCR. Oligonucleotide and lentivirus were used to overexpress miR-34a. Tube formation assay and transwell assay were used to examine the effect on bladder cancer tube formation, migration and invasion in vitro. Animal models were used to examine the effect on metastasis and angiogenesis in vivo. Luciferase assay was carried out to verify the precise target of miR-34a. RESULTS: We not only proved that mir 34a was significantly downregulated in bladder cancer tissues and cell lines but also that circulating miR-34a levels are reduced in bladder cancer, and their levels were positively relevance. Gain-of-function experiments investigated that increased mir-34a expression suppressed tube formation and reduced cell migration and invasion. In vivo metastasis, assays also demonstrated that overexpression of mir34a markedly inhibited bladder cancer metastasis. CD31, an endothelial cell specific marker which stained in T24 tumors to evaluate for blood vessel density, the immunohistochemistry results showed that blood vessel quantification reduced dramatically in the T24 tumors over-expressing mir-34a. Combining with our previous studies and bioinformatics analysis, we expected that CD44 gene was a direct target of mir-34a, siRNA-mediated knockdown of CD44 partially phenocopied mir-34a overexpression suggesting that the pro-apoptotic role of mir-34a may be mediated primarily through CD44 regulation, whereas restoring the expression of CD44 attenuated the function of mir-34a in bladder cancer cells. Additionally, we identified that EMT (epithelial-mesenchymal transition) related proteins could be regulated by mir-34a which indicated that mir-34a could partially reserve EMT. CONCLUSION: Our study defines a major metastasis and angiogenesis suppressive role for mir-34a, a microRNA functions as a tumor suppressor in bladder cancer by directly targeting CD44, which would be helpful as a therapeutic approach to block bladder cancer metastasis. PMID- 25551285 TI - A new modified Tsuge suture for flexor tendon repairs: the biomechanical analysis and clinical application. AB - PURPOSE: This study is to develop a new suturing technique for flexor tendon repair by modifying the extant Tsuge repair techniques and to use biomechanical analysis to compare the new method with four established repair techniques and evaluate its clinical efficacy in the repair of 47 flexor tendons in 22 patients. METHODS: The biomechanical analysis relied on 50 flexor digitorum profundus tendons harvested from fresh cadavers. The tendons were randomly divided into five groups, transected, and repaired by use of a 1. double-loop suture, 2. double modified locking Kessler, 3. four-strand Savage, 4. modified six-strand Savage, and 5. the new technique. The tensile force and breaking force of all repaired tendons were measured by static loading trials. For clinical application, 22 patients with acute flexor tendon injuries were treated with the new modified Tsuge suture and follow-up for more than 12 months. RESULTS: While differences in the tensile force and breaking force in the modified Tsuge sutures and modified six-strand Savage sutures were not statistically significant, static loading trials showed the tensile force, in the form of a 2-mm gap formation, and the breaking force of the new modified Tsuge sutures were, statistically, both higher than the ones characteristic of double-loop sutures, double modified locking Kessler, and four-strand Savage sutures. After 12 months, restored functions were observed in all the patients during the postoperative 12 months. Total active motion (TAM) score demonstrated that more than 90% fingers were estimated as excellent or good. CONCLUSION: The new modified Tsuge sutures described here have evident higher tensile and breaking forces compared to other four-strand core suture techniques, suggesting, in turn, that this new technique is a good alternative for flexor tendon repairs in clinical applications. PMID- 25551286 TI - Caveolin-1 mediated uptake via langerin restricts HIV-1 infection in human Langerhans cells. AB - BACKGROUND: Human Langerhans cells (LCs) reside in foreskin and vaginal mucosa and are the first immune cells to interact with HIV-1 during sexual transmission. LCs capture HIV-1 through the C-type lectin receptor langerin, which routes the virus into Birbeck granules (BGs), thereby preventing HIV-1 infection. BGs are langerin-positive organelles exclusively present in LCs, however, their origin and function are unknown. RESULTS: Here, we not only show that langerin and caveolin-1 co-localize at the cell membrane and in vesicles but also that BGs are langerin/caveolin-1-positive vesicles are linked to the lysosomal degradation pathway in LCs. Moreover, inhibition of caveolar endocytosis in primary LCs abrogated HIV-1 sequestering into langerin(+) caveolar structures. Notably, both inhibition of caveolar uptake and silencing of caveolar structure protein caveolin-1 resulted in increased HIV-1 integration and subsequent infection. In contrast, inhibition of clathrin-mediated endocytosis did not affect HIV-1 integration, even though HIV-1 uptake was decreased, suggesting that clathrin mediated endocytosis is not involved in HIV-1 restriction in LCs. CONCLUSIONS: Thus, our data strongly indicate that BGs belong to the caveolar endocytosis pathway and that caveolin-1 mediated HIV-1 uptake is an intrinsic restriction mechanism present in human LCs that prevents HIV-1 infection. Harnessing this particular internalization pathway has the potential to facilitate strategies to combat HIV-1 transmission. PMID- 25551287 TI - Co-localisation of the blackleg resistance genes Rlm2 and LepR3 on Brassica napus chromosome A10. AB - BACKGROUND: The protection of canola (Brassica napus) crops against blackleg disease, caused by the fungal pathogen Leptosphaeria maculans, is largely mediated by race-specific resistance genes (R-genes). While many R-genes effective against blackleg disease have been identified in Brassica species, information of the precise genomic locations of the genes is limited. RESULTS: In this study, the Rlm2 gene for resistance to blackleg, located on chromosome A10 of the B. napus cultivar 'Glacier', was targeted for fine mapping. Molecular markers tightly linked to the gene were developed for use in mapping the resistance locus and defining the physical interval in B. napus. Rlm2 was localised to a 5.8 cM interval corresponding to approximately 873 kb of the B. napus chromosome A10. CONCLUSION: The recently-cloned B. napus R-gene, LepR3, occupies the same region of A10 as Rlm2 and analysis of the putative B. napus and B. rapa genes in the homologous region identified several additional candidate defense-related genes that may control Rlm2 function. PMID- 25551288 TI - Predictive factors for successful limb salvage surgery in diabetic foot patients. AB - BACKGROUND: The goal of salvage surgery in the diabetic foot is maximal preservation of the limb, but it is also important to resect unviable tissue sufficiently to avoid reamputation. This study aims to provide information on determining the optimal amputation level that allows preservation of as much limb length as possible without the risk of further reamputation by analyzing several predictive factors. METHODS: Between April 2004 and July 2013, 154 patients underwent limb salvage surgery for distal diabetic foot gangrene. According to the final level of amputation, the patients were divided into two groups: Patients with primary success of the limb salvage, and patients that failed to heal after the primary limb salvage surgery. The factors predictive of success, including comorbidity, laboratory findings, and radiologic findings were evaluated by a retrospective chart review. RESULTS: The mean age of the study population was 63.9 years, with a male-to-female ratio of approximately 2:1. The mean follow-up duration was 30 months. Statistical analysis showed that underlying renal disease, limited activity before surgery, a low hemoglobin level, a high white blood cell count, a high C-reactive protein level, and damage to two or more vessels on preoperative computed tomography (CT) angiogram were significantly associated with the success or failure of limb salvage. The five year survival rate was 81.6% for the limb salvage success group and 36.4% for the limb salvage failure group. CONCLUSION: This study evaluated the factors predictive of the success of limb salvage surgery and identified indicators for preserving as much as possible of the leg of a patient with diabetic foot. This should help surgeons to establish the appropriate amputation level for a case of diabetic foot and help prevent consecutive operations. PMID- 25551291 TI - Hierarchically porous polymers from hyper-cross-linked block polymer precursors. AB - We report synthesis of hierarchically porous polymers (HPPs) consisting of micropores and well-defined 3D continuous mesopores by combination of hyper-cross linking and block polymer self-assembly. Copolymerization of 4-vinylbenzyl chloride (VBzCl) with divinylbenzene (DVB) in the presence of polylactide (PLA) macro-chain-transfer agent produced a cross-linked block polymer precursor PLA-b P(VBzCl-co-DVB) via reversible addition-fragmentation chain transfer polymerization. A nanoscopic bicontinuous morphology containing PLA and P(VBzCl co-DVB) microdomains was obtained as a result of polymerization-induced microphase separation. While a basic treatment of the precursor selectively removed PLA to yield a reticulated mesoporous polymer, hyper-cross-linking of the precursor by FeCl3 generated micropores in the P(VBzCl-co-DVB) microdomain via Friedel-Crafts alkylation and simultaneously degraded PLA to produce the HPP containing micropores in the mesoporous framework. The mesopore size of the HPP could be precisely controlled from 6 to 15 nm by controlling the molar mass of PLA. We demonstrate acceleration in adsorption rate in the HPP compared to a hyper-cross-linked microporous polymer. PMID- 25551289 TI - Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes. AB - BACKGROUND: Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, although it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. The involvement of imprinted genes has also attracted much attention, not least because two of the earliest discovered were shown to be oppositely imprinted and antagonistic in their regulation of growth. The Igf2 gene encodes a paternally expressed ligand that promotes growth, while maternally expressed Igf2r encodes a cell surface receptor that restricts growth by sequestering Igf2 and targeting it for lysosomal degradation. There are now over 150 imprinted genes known in mammals, but no other clear examples of antagonistic gene pairs have been identified. The delta like 1 gene (Dlk1) encodes a putative ligand that promotes fetal growth and in adults restricts adipose deposition. Conversely, Grb10 encodes an intracellular signalling adaptor protein that, when expressed from the maternal allele, acts to restrict fetal growth and is permissive for adipose deposition in adulthood. RESULTS: Here, using knockout mice, we present genetic and physiological evidence that these two factors exert their opposite effects on growth and physiology through a common signalling pathway. The major effects are on body size (particularly growth during early life), lean:adipose proportions, glucose regulated metabolism and lipid storage in the liver. A biochemical pathway linking the two cell signalling factors remains to be defined. CONCLUSIONS: We propose that Dlk1 and Grb10 define a mammalian growth axis that is separate from the IGF pathway, yet also features an antagonistic imprinted gene pair. PMID- 25551290 TI - Alternatives to antibiotics in animal agriculture: an ecoimmunological view. AB - Ecological immunology (or ecoimmunology) is a new discipline in animal health and immunology that extends immunologists' views into a natural context where animals and humans have co-evolved. Antibiotic resistance and tolerance (ART) in bacteria are manifested in antibiosis-surviving subsets of resisters and persisters. ART has emerged though natural evolutionary consequences enriched by human nosocomial and agricultural practices, in particular, wide use of antibiotics that overwhelms other ecological and immunological interactions. Most previous reviews of antibiotic resistance focus on resisters but overlook persisters, although both are fundamental to bacteria survival through antibiosis. Here, we discuss resisters and persisters together to contrast the distinct ecological responses of persisters during antibiotic stress and propose different regimens to eradicate persisters. Our intention is not only to provide an ecoimmunological interpretation, but also to use an ecoimmunological system to categorize available alternatives and promote the discovery of prospective approaches to relieve ART problems within the general scope of improving animal health. Thus, we will categorize available alternatives to antibiotics and envision applications of ecoimmunological tenets to promote related studies in animal production. PMID- 25551292 TI - Recognition of the small regulatory RNA RydC by the bacterial Hfq protein. AB - Bacterial small RNAs (sRNAs) are key elements of regulatory networks that modulate gene expression. The sRNA RydC of Salmonella sp. and Escherichia coli is an example of this class of riboregulators. Like many other sRNAs, RydC bears a 'seed' region that recognises specific transcripts through base-pairing, and its activities are facilitated by the RNA chaperone Hfq. The crystal structure of RydC in complex with E. coli Hfq at a 3.48 A resolution illuminates how the protein interacts with and presents the sRNA for target recognition. Consolidating the protein-RNA complex is a host of distributed interactions mediated by the natively unstructured termini of Hfq. Based on the structure and other data, we propose a model for a dynamic effector complex comprising Hfq, small RNA, and the cognate mRNA target. PMID- 25551293 TI - A kinase-independent function of AKT promotes cancer cell survival. AB - The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer. PMID- 25551294 TI - A mutant Escherichia coli that attaches peptidoglycan to lipopolysaccharide and displays cell wall on its surface. AB - The lipopolysaccharide (LPS) forms the surface-exposed leaflet of the outer membrane (OM) of Gram-negative bacteria, an organelle that shields the underlying peptidoglycan (PG) cell wall. Both LPS and PG are essential cell envelope components that are synthesized independently and assembled by dedicated transenvelope multiprotein complexes. We have identified a point-mutation in the gene for O-antigen ligase (WaaL) in Escherichia coli that causes LPS to be modified with PG subunits, intersecting these two pathways. Synthesis of the PG modified LPS (LPS*) requires ready access to the small PG precursor pool but does not weaken cell wall integrity, challenging models of precursor sequestration at PG assembly machinery. LPS* is efficiently transported to the cell surface without impairing OM function. Because LPS* contains the canonical vancomycin binding site, these surface-exposed molecules confer increased vancomycin resistance by functioning as molecular decoys that titrate the antibiotic away from its intracellular target. This unexpected LPS glycosylation fuses two potent pathogen-associated molecular patterns (PAMPs). PMID- 25551296 TI - Frameshift mutations of TAF1C gene, a core component for transcription by RNA polymerase I, and its regional heterogeneity in gastric and colorectal cancers. AB - Initiation of transcription for ribosomal RNA (rRNA) by RNA polymerase I requires TATA-binding protein (TBP) and TBP-associated factors (TAF1A, TAF1B and TAF1C). p53 tumour suppressor inhibits rRNA transcription by blocking TAF1C-UBF interaction, but alterations of TAF1C itself in tumorigenesis remain unknown. The aim of this study was to explore whether TAF1C gene was mutated in gastric (GC) and colorectal cancers (CRC).In a public database, we found that TAF1C gene had a mononucleotide repeat (C8) in the coding sequences that might be a mutation target in the cancers with microsatellite instability (MSI). We analysed 79 GC and 124 CRC by single-strand conformation polymorphism and DNA sequencing analyses. In this study, we found TAF1C frameshift mutations (8.8% of GC and 10.1% of CRC with MSI-H), which were not found in stable MSI/low MSI (MSS/MSI-L) (0/90). In addition, we analysed intratumoural heterogeneity (ITH) of TAF1C frameshift mutations in 16 CRC and found that three CRC (18.8%) harboured regional ITH of the TAF1C frameshift mutations. Our results indicate that TAF1C gene harboured not only somatic frameshift mutations but also the mutational ITH, which together might play a role in tumourigenesis of GC and CRC. Our data also suggest that multi-regional mutation analysis is needed for a better evaluation of the mutation status in CRC. PMID- 25551295 TI - Intramolecular N-glycan/polypeptide interactions observed at multiple N-glycan remodeling steps through [(13)C,(15)N]-N-acetylglucosamine labeling of immunoglobulin G1. AB - Asparagine-linked (N) glycosylation is a common eukaryotic protein modification that affects protein folding, function, and stability through intramolecular interactions between N-glycan and polypeptide residues. Attempts to characterize the structure-activity relationship of each N-glycan are hindered by inherent properties of the glycoprotein, including glycan conformational and compositional heterogeneity. These limitations can be addressed by using a combination of nuclear magnetic resonance techniques following enzymatic glycan remodeling to simultaneously generate homogeneous glycoforms. However, widely applicable methods do not yet exist. To address this technological gap, immature glycoforms of the immunoglobulin G1 fragment crystallizable (Fc) were isolated in a homogeneous state and enzymatically remodeled with [(13)C,(15)N]-N acetylglucosamine (GlcNAc). UDP-[(13)C,(15)N]GlcNAc was synthesized enzymatically in a one-pot reaction from [(13)C]glucose and [(15)N-amido]glutamine. Modifying Fc with recombinantly expressed glycosyltransferases (Gnt1 and Gnt2) and UDP [(13)C,(15)N]GlcNAc resulted in complete glycoform conversion as judged by mass spectrometry. Two-dimensional heteronuclear single-quantum coherence spectra of the Gnt1 product, containing a single [(13)C,(15)N]GlcNAc residue on each N glycan, showed that the N-glycan is stabilized through interactions with polypeptide residues. Similar spectra of homogeneous glycoforms, halted at different points along the N-glycan remodeling pathway, revealed the presence of an increased level of interaction between the N-glycan and polypeptide at each step, including mannose trimming, as the N-glycan was converted to a complex type, biantennary form. Thus, conformational restriction increases as Fc N-glycan maturation proceeds. Gnt1 and Gnt2 catalyze fundamental reactions in the synthesis of every glycoprotein with a complex-type N-glycan; thus, the strategies presented herein can be applied to a broad range of glycoprotein studies. PMID- 25551297 TI - Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours. AB - Napsin A and alpha-methylacyl-coenzyme A racemase (AMACR, P504S) have recently been described as being frequently expressed in clear cell carcinomas (CCC) of the gynecological tract. The present study was conducted to assess the test performance of these newer markers relative to the more traditional marker, hepatocyte nuclear factor 1beta (HNF1beta), in a large and histotypically diverse dataset. A total of 279 ovarian tumours in tissue microarrays were immunohistochemically assessed for the expression of Napsin A, AMACR and HNF1beta. HNF1beta, Napsin A and AMACR were expressed in 92%, 82% and 63% of 65 CCC, 7%, 1% and 1% of 101 serous carcinomas, 37%, 5.3% and 0% of 19 endometrioid carcinomas, 60%, 0% and 0% of 45 mucinous tumours, 100%, 0% and 0% of seven yolk sac tumours, and 0%, 16.7% and 16.7% of six steroid cell tumours NOS, respectively. All other tumours, including 18 adult-type granulosa cell tumours, eight dysgerminomas and nine other miscellaneous tumour types were negative for all three markers. Using a benchmark of >=1% of tumour cells for positivity and CCC as the diagnostic end-point, the sensitivity, specificity, negative predictive value and positive predictive value of Napsin A expression were 0.82, 0.99, 0.94, and 0.98, respectively (odds ratio 439, p < 0.0001). Respective parameters were 0.92, 0.79, 0.97, and 0.58 (odds ratio 44, p < 0.0001) for HNF1beta and 0.63, 0.99, 0.89, and 0.5 (odds ratio 112, p < 0.0001) for AMACR. The combination of any two positive markers, irrespective of the staining pattern of the third, significantly predicted the CCC histotype in every analytic scenario. In summary, HNF1beta is highly sensitive but is suboptimally specific in isolation, whereas AMACR is highly specific but is suboptimally sensitive. Napsin A is specific but of intermediate sensitivity. Napsin A, AMACR and HNF1beta are all viable markers of CCC that can be deployed as components of larger panels when CCC is a diagnostic consideration. PMID- 25551298 TI - p16 immunoreactivity in endometrial stromal cells: stromal p16 expression characterises but is not specific for endometrial polyps. AB - It has been proposed recently that stromal cell p16 immunoreactivity may be useful in the diagnosis of endometrial polyps (EPs). However, the specificity of p16 staining is uncertain and it is also unclear whether sporadic and tamoxifen related polyps show similar findings. We performed p16 immunostaining on 35 normal endometrial specimens and 32 EPs, six of which were associated with tamoxifen therapy. Normal cyclical endometrium showed patchy glandular staining and there was also focal stromal p16 expression in the functional layer of most proliferative and secretory endometria. Atrophic and lower uterine segment endometrial stromal cells were negative except for localised immunoreactivity in one atrophic case. The EPs demonstrated glandular p16 expression, particularly in epithelium showing ciliated metaplasia. Stromal p16 staining was also seen in all EPs, although the proportion of positive cells varied considerably (20-90%). There was no significant difference in staining between sporadic and tamoxifen associated cases. In conclusion, stromal p16 immunoreactivity is characteristic of EPs and this may reflect the pathogenesis of polyp formation. Immunohistochemistry can help to distinguish polypoid and non-polypoid mucosa, particularly in small or disrupted biopsy specimens. However, stromal p16 expression is not completely specific since focal staining may be present in normal endometrium. PMID- 25551299 TI - NUT protein immunoreactivity in ovarian germ cell tumours. AB - The aim of this study was to investigate NUT (nuclear protein in the testis) expression in ovarian germ cell tumours (GCTs). Immunostaining for NUT protein was performed in 10 mature cystic teratomas and in 49 malignant ovarian GCTs including 15 pure dysgerminomas, six dysgerminomas associated with gonadoblastoma, nine yolk sac tumours, 12 immature teratomas, and seven mixed malignant tumours. Only nuclear staining was considered a positive finding although cytoplasmic staining was noted when present. Thirty-seven (76%) malignant GCTs were NUT positive but staining was usually of weak to moderate intensity and observed in a relatively small proportion of neoplastic cells. Staining in immature teratomas and yolk sac tumours was restricted to foci of hepatoid and intestinal/glandular differentiation, where both nuclear and cytoplasmic reactivity were observed. In dysgerminoma associated with gonadoblastoma only the in situ and invasive germ cell elements were NUT positive. Nuclear staining was not seen in benign teratomas. Most malignant ovarian GCTs express NUT protein, albeit focally, and this should be considered when evaluating immunostaining in the differential diagnosis of poorly differentiated malignancies, particularly NUT midline carcinoma. Since NUT protein appears to play a role in normal germ cell maturation it may influence intestinal or hepatoid differentiation within malignant GCTs. PMID- 25551300 TI - Diagnostic performance of CD66c in lung adenocarcinoma-associated malignant pleural effusion: comparison with CEA, CA 19-9, and CYFRA 21-1. AB - Various tumour markers have been evaluated in malignant pleural effusions, but not CD66c. This study evaluated the diagnostic ability of CD66c in lung adenocarcinoma-associated malignant pleural effusions (LA-MPEs) and compared it with other known tumour markers. Forty-seven cases of LA-MPE and 52 cases of benign pleural effusions were collected. The levels of CD66c, CEA, CA 19-9, and CYFRA 21-1 were measured by enzyme immunoassay. The expression of CD66c, CEA, and CA 19-9 in cell blocks was measured by immunocytochemistry. CEA had the best diagnostic values, with a sensitivity of 87.2% and specificity of 92.3%. Both CD66c and CA 19-9 showed the highest specificity of 98.1%, with sensitivities of 63.8% and 55.3%, respectively. CYFRA 21-1 had a sensitivity of 83.0% and specificity of 76.9%. CEA combined with CA 19-9 reached a sensitivity of 91.5% and a specificity of 98.1%. The sensitivities of immunocytochemical staining for CD66c, CEA, and CA 19-9 were 72.5%, 75%, and 40%, respectively. CD66c showed a diagnostic performance comparable to CYFRA 21-1 and CA 19-9 by enzyme immunoassay. Immunocytochemical study showed that CD66c and CEA were more sensitive than CA19-9. Both studies support CD66c as a potential tumour marker to differentiate LA-MPE from benign effusions. PMID- 25551301 TI - CD117 and CD43 are useful adjuncts in the distinction of adenoid cystic carcinoma from adenoid basal cell carcinoma. AB - Distinction of cutaneous adenoid cystic carcinoma (ACC) from adenoid basal cell carcinoma (BCC) is an occasional diagnostic dilemma in dermatopathology.We examined the immunohistochemical staining patterns with CD117 and CD43 in ACCs and BCCs, including BCCs with an adenoid growth pattern, to determine whether a combination of these markers can assist in the differential diagnosis.Fifteen cases each of ACC and BCC, including seven BCCs with a partial or entirely adenoid growth pattern were immunohistochemically stained for CD117 and CD43. The stains were interpreted semi-quantitatively.Staining for CD43 and CD117 was significantly more common in ACC than in BCC. Forty percent of ACCs showed staining for CD43, while no cases of BCC were positive. CD117 was positive in all cases of ACC, with 93% showing moderate or strong staining. BCC were less frequently positive, with only 20% of cases showing labelling of weak or moderate intensity.Immunohistochemical positivity for CD117 and CD43 are likely to be helpful adjuncts in the separation of cutaneous ACC from adenoid BCC. PMID- 25551302 TI - Plasma cholesterol in adults with phenylketonuria. AB - Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) catabolism resulting from a deficiency of L-phenylalanine hydroxylase (PAH). An association between hyperphenylalaninaemia (HPA) and hypocholesterolaemia has been reported in children. However, controversy exists as to whether this is due to the low protein diet or to a disruption to cholesterol biosynthesis inherent to those with PKU. We investigated the relationship between blood Phe and plasma cholesterol in 41 apparently healthy adults with PKU (26 female, 15 male, age 18 57 years, median age 26 years) attending a PKU outpatient clinic at an adult tertiary care hospital. Of these patients, 33 (80%) were compliant with a Phe restricted diet with amino acid supplementation, whereas eight (20%) were not. The PKU subjects had a mean body mass index (BMI) of 30.3 +/- 1.8 kg/m; 72% were obese, 14% overweight, with only 14% having normal BMI. The mean blood Phe was 1194 +/- 522 MUmol/L with plasma total cholesterol, triglyceride, HDL cholesterol, LDL-cholesterol and apolipoprotein (apo) B concentrations of 4.3 +/- 0.8 mmol/L, 1.6 +/- 0.8 mmol/L, 1.2 +/- 0.3 mmol/L, 2.3 +/- 0.8 mmol/L, and 0.83 +/- 0.21 g/L, respectively. The mean LDL-cholesterol was 19% lower in PKU females than that of 8944 age-matched females from a community population (2.5 +/- 0.8 mmol/L vs. 3.1 +/- 0.9 mmol/L, p < 0.001). Similarly, the mean LDL-cholesterol was 32% lower in PKU males than 3786 age-matched males (2.1 +/- 0.7 mmol/L vs. 3.1 +/- 1.0 mmol/L, p < 0.0001). No correlations were observed between Phe and total cholesterol, LDL-cholesterol or apoB in the PKU cohort. Adults with PKU had low-normal cholesterol concentrations, with no correlation observed between Phe and cholesterol levels. Our findings support the concept that the HPA found in PKU, rather than an effect of a low-protein diet, leads to hypocholesterolaemia. Studies are required to determine whether this cholesterol-lowering effect confers cardioprotection. PMID- 25551303 TI - 'Aussie normals': an a priori study to develop clinical chemistry reference intervals in a healthy Australian population. AB - Development of reference intervals is difficult, time consuming, expensive and beyond the scope of most laboratories. The Aussie Normals study is a direct a priori study to determine reference intervals in healthy Australian adults. All volunteers completed a health and lifestyle questionnaire and exclusion was based on conditions such as pregnancy, diabetes, renal or cardiovascular disease. Up to 91 biochemical analyses were undertaken on a variety of analytical platforms using serum samples collected from 1856 volunteers. We report on our findings for 40 of these analytes and two calculated parameters performed on the Abbott ARCHITECTci8200/ci16200 analysers. Not all samples were analysed for all assays due to volume requirements or assay/instrument availability. Results with elevated interference indices and those deemed unsuitable after clinical evaluation were removed from the database. Reference intervals were partitioned based on the method of Harris and Boyd into three scenarios, combined gender, males and females and age and gender. We have performed a detailed reference interval study on a healthy Australian population considering the effects of sex, age and body mass. These reference intervals may be adapted to other manufacturer's analytical methods using method transference. PMID- 25551304 TI - Identification of a novel splicing mutation in the fibrinogen gamma chain gene leading to dysfibrinogenaemia in a Chinese pedigree. AB - Congenital dysfibrinogenaemia is a rare disease characterised by inherited abnormality in the fibrinogen molecule, leading to functional defects. In this study, we investigated the molecular basis of dysfibrinogenaemia in a Chinese pedigree. Functional fibrinogen of venous blood samples was measured by Clauss method, and the antigens of fibrinogen in plasma were measured by immunoturbidimetry assay. All the exons and exon-intron boundaries of the three fibrinogen genes were analysed by direct sequencing. Fibrinogen electrophoresis, fibrinogen clottability measurement, fibrin polymerisation measurement, and electron microscopy scanning were also used in this study. The proband showed prolonged thrombin time, prolonged reptilase time, reduced fibrinogen activity level and normal plasma fibrinogen antigen. The sequencing results of the proband revealed a novel heterozygous IVS9+1delG mutation of FGG gene, which could also be called FGG p.Val434Serfs29. The same results were also found in her mother, sister and daughter. Both thrombin-induced fibrin polymerisation and reptilase induced fibrin polymerisation were significantly impaired compared to normal control. Fibrinogen clottability measurement showed that only about 38.7% molecules of plasma fibrinogen of the proband were involved in the clot formation. Scanning electron microscopy revealed that the proband's average fibre diameters (159 +/- 36 nm; n = 100) were found to be significantly thicker than the control's diameter (108 +/- 21 nm; n = 100) (p<0.001). The fibrin clot of the proband showed irregular structure and highly branched fibres. We conclude that the mutation is responsible for the proband's dysfibrinogenaemia and clinical symptoms. PMID- 25551305 TI - Prevalence of maternal red cell alloimmunisation: a population study from Queensland, Australia. AB - The aim of this study was to determine the current prevalence of red cell antigen alloimmunisation in Australia. Blood group (ABO and RhD) and red cell antibody screen results of pregnant women who presented at public hospitals in Queensland between the period of January 2011 and June 2013 were evaluated retrospectively. Antibody prevalence in pregnancy was compared to other published studies. A total of 482 positive antibody screens from 66,354 samples (0.73%) were identified. The prevalence of antibodies was: anti-E 27.6%; anti-D 10.4%; anti-Kell 9.5%; anti-c 8.7%; anti-Duffy 3.1%, including Fy and Fy; anti-MNS 7.9%, including M, N, S and s; anti-Lewis 6%, including Le and Le; and multiple antibodies (16%, including anti-D). Compared to other studies, including one from Australia in 1977, the anti-D alloimmunisation rate had dropped significantly, with little change in anti-c and some increase in anti-E and anti-Kell cases. Continued vigilance is required to ensure eligible RhD negative women receive prophylaxis according to the current RhD immunoprophylaxis guidelines, especially those who have a fetomaternal haemorrhage (FMH). RhD positive women that are at risk of developing an antibody during pregnancy should have their pregnancy monitored according to published guidelines. Once antibodies are identified, consideration should be given to paternal antigen status in an attempt to identify the pregnancy that will be at risk of alloimmunisation. PMID- 25551306 TI - Molecular surveillance for carbapenemase genes in carbapenem-resistant Pseudomonas aeruginosa in Australian patients with cystic fibrosis. AB - The aim of this study was to assess the prevalence of acquired carbapenemase genes amongst carbapenem non-susceptible Pseudomonas aeruginosa isolates in Australian patients with cystic fibrosis (CF). Cross-sectional molecular surveillance for acquired carbapenemase genes was performed on CF P. aeruginosa isolates from two isolate banks comprising: (i) 662 carbapenem resistant P. aeruginosa isolates from 227 patients attending 10 geographically diverse Australian CF centres (2007-2009), and (ii) 519 P. aeruginosa isolates from a cohort of 173 adult patients attending one Queensland CF clinic in 2011. All 1189 P. aeruginosa isolates were tested by polymerase chain reaction (PCR) protocols targeting ten common carbapenemase genes, as well the Class 1 integron intI1 gene and the aadB aminoglycoside resistance gene. No carbapenemase genes were identified among all isolates tested. The intI1 and aadB genes were frequently detected and were significantly associated with the AUST-02 strain (OR 24.6, 95% CI 9.3-65.6; p < 0.0001) predominantly from Queensland patients. Despite the high prevalence of carbapenem resistance in P. aeruginosa in Australian patients with CF, no acquired carbapenemase genes were detected in the study, suggesting chromosomal mutations remain the key resistance mechanism in CF isolates. Systematic surveillance for carbapenemase-producing P. aeruginosa in CF by molecular surveillance is ongoing. PMID- 25551307 TI - Extended spectrum beta-lactamase testing of community Enterobacteriaceae in the west of Australia: poor performance of phenotypic methods. AB - Expanded spectrum beta-lactamase (ESBL) producing organisms have long been recognised in institutions worldwide. Recently, community isolates producing ESBL have been reported overseas and in eastern Australia. We tested 571 consecutive Enterobacteriaceae urinary isolates from Western Australia and the Northern Territory phenotypically by calibrated dichotomous sensitivity (CDS) methods in two periods (2007 and 2012). Eleven ESBL-producing isolates from 2012 and 39 banked strains were genotyped by PCR. Twenty-six (4.6%) strains produced ESBL by CDS. Only 57.7% of CDS-confirmed ESBL strains had an initial reduced cephalosporin zone. Vitek 2 identified only nine (34.6%) CDS-ESBL strains. There was no significant change in ESBL strain prevalence over the two periods by CDS, but our laboratory information system showed a steady increase from 2007-2012 in ESBL strain prevalence (identified by multiple methods) at a rate of 0.02% per month to reach 2% by 2012. Genotyping of 50 CDS-confirmed isolates demonstrated ESBL genes in 44 (88%), mainly CTX-M genes. Twenty-five ESBL strains contained more than one beta-lactamase gene, up to a maximum of three genes. There is a rising prevalence of ESBL strains in our communities. CDS and Vitek-2 testing is neither sensitive nor specific in detecting ESBL enzymes. Routine laboratories need access to genotyping to identify and monitor ESBLs in the community. PMID- 25551308 TI - Evaluation of the BD Max Cdiff assay for the detection of toxigenic Clostridium difficile in human stool specimens. AB - The Becton Dickinson (BD) PCR-based GeneOhm Cdiff assay has demonstrated a high sensitivity and specificity for detecting Clostridium difficile. Recently, the BD Max platform, using the same principles as BD GeneOhm, has become available in Australia. This study aimed to investigate the sensitivity and specificity of BD Max Cdiff assay for the detection of toxigenic C. difficile in an Australian setting. Between December 2013 and January 2014, 406 stool specimens from 349 patients were analysed with the BD Max Cdiff assay. Direct and enrichment toxigenic culture were performed on bioMerieux ChromID C. difficile agar as a reference method. isolates from specimens with discrepant results were further analysed with an in-house PCR to detect the presence of toxin genes. The overall prevalence of toxigenic C. difficile was 7.2%. Concordance between the BD Max assay and enrichment culture was 98.5%. The sensitivity, specificity, positive predictive value and negative predictive value for the BD Max Cdiff assay were 95.5%, 99.0%, 87.5% and 99.7%, respectively, when compared to direct culture, and 91.7%, 99.0%, 88.0% and 99.4%, respectively, when compared to enrichment culture. The new BD Max Cdiff assay appeared to be an excellent platform for rapid and accurate detection of toxigenic C. difficile. PMID- 25551310 TI - Purpuric exanthem caused by Ross River virus infection. PMID- 25551309 TI - Intraductal tubulopapillary neoplasm of pancreas with associated invasive carcinoma, lymph node, rectal and hepatic metastases. PMID- 25551311 TI - Use of immunohistochemistry for SSTR2A to support a diagnosis of phosphaturic mesenchymal tumour. PMID- 25551312 TI - Do primary nasopharyngeal atypical carcinoid tumours really exist? PMID- 25551313 TI - A concurrent primary hepatic MALT lymphoma and hepatocellular carcinoma. PMID- 25551314 TI - Metastatic colon adenocarcinoma to the placenta. PMID- 25551315 TI - Oxyntic gland polyposis. PMID- 25551316 TI - Hazards of a floating separator gel: a case study. PMID- 25551317 TI - Anesthetic Implications of Ebola Patient Management: A Review of the Literature and Policies. AB - As of mid-October 2014, the ongoing Ebola epidemic in Western Africa has affected approximately 10,000 patients, approached a 50% mortality rate, and crossed political and geographic borders without precedent. The disease has spread throughout Liberia, Guinea, and Sierra Leone. Isolated cases have arrived in urban centers in Europe and North America. The exponential growth, currently unabated, highlights the urgent need for effective and immediate management protocols for the various health care subspecialties that may care for Ebola virus disease patients. We conducted a comprehensive review of the literature to identify key areas of anesthetic care affected by this disease. The serious potential for "high-risk exposure" and "direct contact" (as defined by the Centers for Disease Control and Prevention) of anesthesiologists caring for Ebola patients prompted this urgent investigation. A search was conducted using MEDLINE/PubMed, MeSH, Cochrane Review, and Google Scholar. Key words included "anesthesia" and/or "ebola" combined with "surgery," "intubation," "laryngoscopy," "bronchoscopy," "stethoscope," "ventilation," "ventilator," "phlebotomy," "venous cannulation," "operating room," "personal protection," "equipment," "aerosol," "respiratory failure," or "needle stick." No language or date limits were applied. We also included secondary-source data from government organizations and scientific societies such as the Centers for Disease Control and Prevention, World Health Organization, American Society of Anesthesiologists, and American College of Surgeons. Articles were reviewed for primary-source data related to inpatient management of Ebola cases as well as evidence-based management guidelines and protocols for the care of Ebola patients in the operative room, infection control, and health care worker personal protection. Two hundred thirty-six articles were identified using the aforementioned terminology in the scientific database search engines. Twenty articles met search criteria for information related to inpatient Ebola virus disease management or animal virology studies as primary or secondary sources. In addition, 9 articles met search criteria as tertiary sources, representing published guidelines. The recommendations developed in this article are based on these 29 source documents. Anesthesia-specific literature regarding the care of Ebola patients is very limited. Secondary-source guidelines and policies represent the majority of available information. Data from controlled animal experiments and tuberculosis patient research provide some evidence for the existing recommendations and identify future guideline considerations. PMID- 25551318 TI - Size does matter: importance of large bubbles and small-scale hot spots for methane transport. AB - Ebullition (bubbling) is an important mechanism for the transfer of methane (CH4) from shallow waters to the atmosphere. Because of their stochastic nature, however, ebullition fluxes are difficult to accurately resolve. Hydroacoustic surveys have the potential to significantly improve the spatiotemporal observation of emission fluxes, but knowledge of bubble size distribution is also necessary to accurately assess local, regional, and global water body CH4 emission estimates. Therefore, we explore the importance of bubble size and small scale flux variability on CH4 transport in and emissions from a reservoir with a bubble-size-calibrated echosounder that can efficiently and economically survey greater areas while still resolving individual bubbles. Using a postprocessing method that resolves bubble density, we found that the largest 10% of the >6700 observed bubbles were responsible for more than 65% of the total CH4 transport. Furthermore, the asymmetry of CH4 ebullition flux distribution and the high spatial heterogeneity of those fluxes suggests that inadvertently omitting emission hot spots (i.e., areas of high flux) could lead to significant underestimations of CH4 emissions from localized areas and potentially from entire water bodies. While the bubble sizes resolved by the hydroacoustic method may provide insight into the factors controlling ebullition (e.g., sediment type, carbon sedimentation), the better resolution of small-scale CH4 emission hot spots afforded by hydroacoustics will bring us closer to the true CH4 emission estimates from all shallow waters, be them lakes, reservoirs, or coastal oceans and seas. PMID- 25551319 TI - Organocatalytic enantioselective formal C(sp(2))-H alkylation. AB - An organocatalytic enantioselective formal C(sp(2))-H alkylation is reported. This alkylative desymmetrization of prochiral 2,2-disubstituted cyclopentene-1,3 dione is catalyzed by a bifunctional tertiary aminourea derivative, utilizes air stable and inexpensive nitroalkanes as the alkylating agents, and delivers synthetically versatile five-membered carbocycles containing an all-carbon quaternary stereogenic center remote from the reaction site in excellent enantioselectivity. PMID- 25551321 TI - Salusin-beta induces smooth muscle cell proliferation by regulating cyclins D1 and E expression through MAPKs signaling pathways. AB - Despite the clear mitogenic effect of salusin-beta on vascular smooth muscle cells (VSMCs), which contributes to its proatherosclerotic effects, additional studies are needed to explore its underlying mechanisms. The aim of this study was to investigate the mechanism of salusin-beta's effects on VSMCs cell cycle regulation and the possible signal pathways. Salusin-beta accelerated the G1/S phase transition in VSMCs and increased the expression levels of cyclins D1 and E. Silencing either cyclin D1 or cyclin E gene inhibited salusin-beta-induced VSMCs proliferation, cell cycle progression, phosphorylation of the Rb protein, and dissociation of the E2F-Rb complex. Importantly, expression of cyclin E was also induced by cyclin D1. Next, we found that salusin-beta increased the protein expressions of activator protein-1 (AP-1) subunits c-Jun and c-Fos, and enhanced binding of AP-1 to the promoter region of cyclin D1. In addition, inhibition of AP-1 activity could lead to significant suppression of salusin-beta-induced cyclin D1 expression. Furthermore, MPAKs pathways were found to mediate salusin beta-induced VSMCs proliferation, cyclin D1, cyclin E, c-Jun, and c-Fos expression. These results suggest that salusin-beta promotes cell cycle progression of VSMCs by upregulating the cyclin D1 and cyclin E, in an AP-1 dependent manner through mitogen-activated protein kinases signaling pathways. PMID- 25551320 TI - mAKAP-a master scaffold for cardiac remodeling. AB - Cardiac remodeling is regulated by an extensive intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cellular adaptation. In the last few years, it has become apparent that multimolecular signaling complexes or "signalosomes" are important for fidelity in intracellular signaling and for mediating crosstalk between the different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPbeta serves as a scaffold for a large signalosome that is responsive to cAMP, calcium, hypoxia, and mitogen-activated protein kinase signaling. The main function of mAKAPbeta signalosomes is to modulate stress-related gene expression regulated by the transcription factors NFATc, MEF2, and HIF-1alpha and type II histone deacetylases that control pathological cardiac hypertrophy. PMID- 25551322 TI - Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials. AB - Warfarin is yet the most widely used oral anticoagulant for thromboembolic diseases, despite the recently emerged novel anticoagulants. However, difficulty in maintaining stable dose within the therapeutic range and subsequent serious adverse effects markedly limited its use in clinical practice. Pharmacogenetics based warfarin dosing algorithm is a recently emerged strategy to predict the initial and maintaining dose of warfarin. However, whether this algorithm is superior over conventional clinically guided dosing algorithm remains controversial. We made a comparison of pharmacogenetics-based versus clinically guided dosing algorithm by an updated meta-analysis. We searched OVID MEDLINE, EMBASE, and the Cochrane Library for relevant citations. The primary outcome was the percentage of time in therapeutic range. The secondary outcomes were time to stable therapeutic dose and the risks of adverse events including all-cause mortality, thromboembolic events, total bleedings, and major bleedings. Eleven randomized controlled trials with 2639 participants were included. Our pooled estimates indicated that pharmacogenetics-based dosing algorithm did not improve percentage of time in therapeutic range [weighted mean difference, 4.26; 95% confidence interval (CI), -0.50 to 9.01; P = 0.08], but it significantly shortened the time to stable therapeutic dose (weighted mean difference, -8.67; 95% CI, -11.86 to -5.49; P < 0.00001). Additionally, pharmacogenetics-based algorithm significantly reduced the risk of major bleedings (odds ratio, 0.48; 95% CI, 0.23 to 0.98; P = 0.04), but it did not reduce the risks of all-cause mortality, total bleedings, or thromboembolic events. Our results suggest that pharmacogenetics-based warfarin dosing algorithm significantly improves the efficiency of International Normalized Ratio correction and reduces the risk of major hemorrhage. PMID- 25551323 TI - A nuclear option? G-protein coupled receptors at the nucleus in cardiac myocytes. PMID- 25551326 TI - Complete earlobe keloid resection with fistulectomy. AB - BACKGROUND: The earlobe is a location with a high risk of keloid scar formation. Keloid scars pose a surgical challenge from recidivation. The objective of this study was to investigate a new surgical approach for the treatment of auricular keloids. METHODS AND RESULTS: In the past 4 years, 11 earlobe keloids of 9 patients have been excised by fistulectomy (perforation operation). All of the patients were followed up for at least 12 months without recurrence. CONCLUSIONS: As a new surgical approach, a perforation operation together with fistulectomy is suitable for lobular keloids. PMID- 25551327 TI - Effect of an epidermal growth factor-containing cream on postinflammatory hyperpigmentation after Q-switched 532-nm neodymium-doped yttrium aluminum garnet laser treatment. AB - BACKGROUND: Topical application of epidermal growth factor (EGF) promotes wound healing and may reduce the risk of laser-induced postinflammatory hyperpigmentation (PIH). OBJECTIVE: To investigate the effect of an EGF containing cream on the incidence of laser-induced PIH. METHODS: Twenty-five Korean patients with senile lentigines were recruited and underwent 532-nm Q switched Nd:YAG laser treatment. Postoperatively, patients applied either an EGF containing cream or a control cream to the laser-treated area. Skin color and transepidermal water loss (TEWL) were measured on Days 0, 3, 7, and 35 using a Mexameter and Tewameter, respectively. RESULTS: The EGF-containing cream resulted in a nonsignificant reduction in the laser-induced increase in TEWL (p = .052 on Day 7) but significantly decreased the melanin index and incidence of PIH on Day 35 (p = .031 and p = .027, respectively). CONCLUSION: Epidermal growth factor containing creams may be an effective measure to prevent laser treatment-induced PIH in Asian patients. PMID- 25551328 TI - Myxoid neurofibroma treated with Mohs micrographic surgery. PMID- 25551329 TI - Treatment of invasive squamous cell carcinomas in an open Clagett window. PMID- 25551330 TI - Comparative study on the localized surface plasmon resonance of boron- and phosphorus-doped silicon nanocrystals. AB - Localized surface plasmon resonance (LSPR) of doped Si nanocrystals (NCs) is critical to the development of Si-based plasmonics. We now experimentally show that LSPR can be obtained from both B- and P-doped Si NCs in the mid-infrared region. Both experiments and calculations demonstrate that the Drude model can be used to describe the LSPR of Si NCs if the dielectric screening and carrier effective mass of Si NCs are considered. When the doping levels of B and P are similar, the LSPR energy of B-doped Si NCs is higher than that of P-doped Si NCs because B is more efficiently activated to produce free carriers than P in Si NCs. We find that the plasmonic coupling between Si NCs is effectively blocked by oxide at the NC surface. The LSPR quality factors of B- and P-doped Si NCs approach those of traditional noble metal NCs. We demonstrate that LSPR is an effective means to gain physical insights on the electronic properties of doped Si NCs. The current work on the model semiconductor NCs, i.e., Si NCs has important implication for the physical understanding and practical use of semiconductor NC plasmonics. PMID- 25551331 TI - Diversity-oriented facile access to highly fluorescent membrane-permeable benz[c,d]indole N-heteroarene BF2 dyes. AB - A diversity-oriented one-pot synthesis of a series of membrane-permeable BF2 rigidified benz[c,d]indole N-heteroarene BBN and BBC dyes has been achieved from the condensation of two commercial components (benz[c,d]indol-2-one and a set of N-heteroarene derivatives that can be selected from thousands of commercially available sources) and the subsequent in situ BF2 complexation reaction. These dyes enjoy a set of excellent photophysical properties including the large Stokes shift, high solution and solid-state fluorescence, and excellent photostabilities. PMID- 25551332 TI - Occurrence and antimicrobial resistance of Escherichia coli in oysters and mussels from Atlantic Canada. AB - Acquiring antimicrobial-resistant (AMR) bacteria through consuming contaminated animal food products is an emerging public health concern, though the sources of contamination are not always clear. This study characterized the occurrence of AMR in Escherichia coli from bivalve molluscs and assessed for the possible sources in the Hillsborough river complex of Prince Edward Island, Canada in areas overlapping with an oyster fishery. Multivariable statistical analysis indicated that the probability of detecting E. coli increased as the estimated dosage of animal effluent contamination decreased. Isolates with AMR were only found from sampling sites closest to untreated human effluent sources. Twenty seven percent (n=6 of 22) of the isolates were pathogenic, with virulence factors consistent with extraintestinal E. coli of human origin. Though there is more evidence of contamination arising from human effluent, more research is needed to identify driving sources. PMID- 25551333 TI - Rescue volunteers' posttraumatic symptoms, distress, and fear of death: attachment insecurity moderates. AB - This study addresses the contribution of attachment orientations of ultra orthodox volunteer rescuers involved in terror events to their posttraumatic symptoms, distress, and fear of death. The authors compared 53 ultra-orthodox rescuers operating in a terror-stricken area in Israel to 36 ultra-orthodox men unexposed to terror. Rescuers displayed lower distress than controls but were not significantly different in fear of death or posttraumatic symptoms. Attachment anxiety was found to be a risk factor by contributing uniquely to posttraumatic symptoms, distress, and fear of death, and as a debilitating factor among rescuers. PMID- 25551334 TI - Kiwi fruit (Actinidia chinensis) quality determination based on surface acoustic wave resonator combined with electronic nose. AB - In this study, electronic nose (EN) combined with a 433 MHz surface acoustic wave resonator (SAWR) was used to determine Kiwi fruit quality under 12-day storage. EN responses to Kiwi samples were measured and analyzed by principal component analysis (PCA) and stochastic resonance (SR) methods. SAWR frequency eigen values were also measured to predict freshness. Kiwi fruit sample's weight loss index and human sensory evaluation were examined to characteristic its quality and freshness. Kiwi fruit's quality predictive models based on EN, SAWR, and EN combined with SAWR were developed, respectively. Weight loss and human sensory evaluation results demonstrated that Kiwi fruit's quality decline and overall acceptance decrease during the storage. Experiment result indicated that the PCA method could qualitatively discriminate all Kiwi fruit samples with different storage time. Both SR and SAWR frequency analysis methods could successfully discriminate samples with high regression coefficients (R = 0.98093 and R = 0.99014, respectively). The validation experiment results showed that the mixed predictive model developed using EN combined with SAWR present higher quality prediction accuracy than the model developed either by EN or by SAWR. This method exhibits some advantages including high accuracy, non-destructive, low cost, etc. It provides an effective way for fruit quality rapid analysis. PMID- 25551335 TI - Application of voltammetric techniques at microelectrodes to the study of the chemical stability of highly reactive species. AB - The application of voltammetric techniques to the study of chemical speciation and stability is addressed both theoretically and experimentally in this work. In such systems, electrode reactions are coupled to homogeneous chemical equilibria (complexations, protonations, ion associations, ...) that can be studied in a simple, economical, and accurate way by means of electrochemical methods. These are of particular interest when some of the participating species are unstable given that the generation and characterization of the species are performed in situ and on a short time scale. With the above aim, simple explicit solutions are presented in this article for quantitative characterization with any voltammetric technique and with the most common electrode geometries. From the theoretical results obtained, it is pointed out that the use of square-wave voltammetry in combination with microelectrodes is very suitable. Finally, the theory is applied to the investigation of the ion association between the anthraquinone radical monoanion and the tetrabutylammonium cation in acetonitrile medium. PMID- 25551336 TI - Synergistic growth of Bacillus and Pseudomonas and its degradation potential on pretreated polypropylene. AB - This study investigated biodegradation of physically pretreated polypropylene (PP) by using two different combinations of microorganisms, namely, Bacillus flexus + Pseudomonas azotoformans(B1) and B. flexus + B. subtilis(B2), for a period of 12 months. The growth rate of (B1) was found to be high throughout the study period, and reached a maximum of 1 * 10(14) colony-forming units (CFU)/mL. At the end of the experiment, the polymers become hydrophilic. Carbonyl indices showed that ultraviolet (UV)-treated polymers started degrading faster than the thermally treated PP. The thermogravimetric analysis also revealed that UV treated PP exposed to the B. flexus + P. azotoformans combination for 1 year exhibited maximum degradation (22.7%). The gravimetric weight loss method showed 1.95% weight loss followed by 1.45% with B. flexus + B. subtilis. The changes in the carbonyl indices of the polymer through Fourier-transform infrared (FTIR) analysis also support the degradation. PMID- 25551337 TI - Development and Outcomes of a Text Messaging Tobacco Cessation Intervention With Urban Adolescents. AB - BACKGROUND: This paper describes the development of an urban adolescent text messaging tobacco cessation intervention and preliminary findings from a randomized, controlled trial. The authors successfully adapted a face-to-face intervention into a personalized, automated, and interactive 5-day texting protocol. METHODS: Respondent-driven sampling was used beginning at a community substance abuse facility. Seventy-two tobacco-dependent adolescents were randomized into an automated computer texting program that delivered either the experimental condition of 30 motivational interviewing- and social network counseling-based personalized messages or the attention control condition consisting of a texting program covering general (non-smoking-related) health habits. All teens were provided smartphones for the study and were assessed at baseline and at 1, 3, and 6 months post intervention. Analyses examined condition*time interactions. RESULTS: At 6 months, the experimental condition decreased the number of cigarettes smoked in the past 30 days, increased intentions not to smoke in the future, and increased peer social support compared with controls. Effect sizes were moderate to large. CONCLUSIONS: These findings are unique, as they target urban adolescents with a mobile health format and add to the growing literature on the efficacy of text-delivered interventions. PMID- 25551339 TI - Gaining insights into pediatric pulmonary hypertensive disorders through patient registries. PMID- 25551340 TI - Adult-onset asthma prevention. Should we be investing in antioxidant defense? PMID- 25551341 TI - What about targeting smooth muscle remodeling in severe asthma? PMID- 25551342 TI - Uncovering the bronchovascular links in patients with chronic obstructive pulmonary disease with pulmonary hypertension. PMID- 25551343 TI - Willie Sutton and the future of acute respiratory distress syndrome research. PMID- 25551344 TI - Nature, nurture, and lung volumes. PMID- 25551345 TI - Pulmonary hypertension in premature infants. Sharpening the tools of detection. PMID- 25551346 TI - Therapy for Mycobacterium avium complex lung disease. It ain't perfect, but it's progress. PMID- 25551347 TI - New European regulation for clinical trials of medicinal products. PMID- 25551348 TI - A case of amiodarone-induced acute fibrinous and organizing pneumonia mimicking mesothelioma. PMID- 25551349 TI - Temporal assessment of airway remodeling in severe asthma using quantitative computed tomography. PMID- 25551350 TI - Intraindividual response to treatment with pirfenidone in idiopathic pulmonary fibrosis. PMID- 25551351 TI - Ultra-low-dose chest computer tomography screening of an asbestos-exposed population in Western Australia. PMID- 25551352 TI - Humidifier disinfectant-associated interstitial lung disease and the Ardystil syndrome. PMID- 25551353 TI - Reply: Is every inhalant safe? PMID- 25551354 TI - Lymphadenopathy and upper airway obstruction. PMID- 25551355 TI - Oxaliplatin and Doxorubicin for relapsed or refractory high-risk neuroblastoma. AB - Patients with relapsed or refractory neuroblastoma have poor long-term survival. New therapeutic regimens are needed. Doxorubicin and cisplatin are commonly used in the treatment of high-risk neuroblastoma. Oxaliplatin, a platinum compound with a 1,2-diaminocyclohexan carrier ligand, is more potent than cisplatin with less nephrotoxicity and ototoxicity. We treated seven relapsed/refractory neuroblastoma patients using oxaliplatin (105-130 mg/m(2)) and doxorubicin (60-75 mg/m(2)) together with dexrazoxane (10 mg/mg of doxorubicin) administered intravenously every three weeks. Prolonged thrombocytopenia causing treatment delay was observed when oxaliplatin was administered at 130 mg/m(2). A reduced dose of oxaliplatin 105 mg/m(2) on day 1 with doxorubicin at 20 mg/m(2)/dose on days 1-3 was well tolerated. Sensory neuropathies were mild and transient. No cardiotoxicity was noted despite all patients having a history of prior anthracycline exposure. Best responses included 1 complete response, 1 partial response, 1 mixed response, 3 stable diseases. In our cohort of heavily pretreated relapsed and refractory neuroblastoma patients, the combination of oxaliplatin and doxorubicin demonstrated anti-tumor activity and merits further investigation. PMID- 25551356 TI - Spatiotemporal approaches to analyzing pedestrian fatalities: the case of Cali, Colombia. AB - OBJECTIVE: Injuries among pedestrians are a major public health concern in Colombian cities such as Cali. This is one of the first studies in Latin America to apply Bayesian maximum entropy (BME) methods to visualize and produce fine scale, highly accurate estimates of citywide pedestrian fatalities. The purpose of this study is to determine the BME method that best estimates pedestrian mortality rates and reduces statistical noise. We further utilized BME methods to identify and differentiate spatial patterns and persistent versus transient pedestrian mortality hotspots. METHODS: In this multiyear study, geocoded pedestrian mortality data from the Cali Injury Surveillance System (2008 to 2010) and census data were utilized to accurately visualize and estimate pedestrian fatalities. We investigated the effects of temporal and spatial scales, addressing issues arising from the rarity of pedestrian fatality events using 3 BME methods (simple kriging, Poisson kriging, and uniform model Bayesian maximum entropy). To reduce statistical noise while retaining a fine spatial and temporal scale, data were aggregated over 9-month incidence periods and censal sectors. Based on a cross-validation of BME methods, Poisson kriging was selected as the best BME method. Finally, the spatiotemporal and urban built environment characteristics of Cali pedestrian mortality hotspots were linked to intervention measures provided in Mead et al.'s (2014) pedestrian mortality review. RESULTS: The BME space-time analysis in Cali resulted in maps displaying hotspots of high pedestrian fatalities extending over small areas with radii of 0.25 to 1.1 km and temporal durations of 1 month to 3 years. Mapping the spatiotemporal distribution of pedestrian mortality rates identified high-priority areas for prevention strategies. The BME results allow us to identify possible intervention strategies according to the persistence and built environment of the hotspot; for example, through enforcement or long-term environmental modifications. CONCLUSIONS: BME methods provide useful information on the time and place of injuries and can inform policy strategies by isolating priority areas for interventions, contributing to intervention evaluation, and helping to generate hypotheses and identify the preventative strategies that may be suitable to those areas (e.g., street-level methods: pedestrian crossings, enforcement interventions; or citywide approaches: limiting vehicle speeds). This specific information is highly relevant for public health interventions because it provides the ability to target precise locations. PMID- 25551357 TI - A Quick Assessment of Visuospatial Abilities in Adolescents Using the Design Organization Test (DOT). AB - Tests measuring visuospatial abilities have shown that these abilities increase during adolescence. Unfortunately, the Block Design test and other such tests are complicated and time-consuming to administer, making them unsuitable for use with large groups of restless adolescents. The results of the Design Organization Test (DOT), a quick pen-and-paper test, have been shown to correlate with those of the Block Design test. A group of 198 healthy adolescents (110 male and 88 female) aged 12 to 19 years old participated in this study. A slightly modified version of the DOT has been used in which we shortened the administration time to avoid a ceiling effect in the score. Scores show a linear increase with age (on average 2.0 points per year, r = .61) independent of sex. Scores did not differ between individual setting and group setting. Thus, the DOT is a simple and effective way to assess visuospatial ability in large groups, such as in schools, and it can be easily administered year after year to follow the development of students. PMID- 25551358 TI - Regulating Pol III transcription to change Pol II transcriptome. PMID- 25551359 TI - A LARGe surprise links ATR and Rho. PMID- 25551361 TI - Turn of phrase. PMID- 25551360 TI - The role of Cullin3-mediated ubiquitination of the catalytic subunit of PP2A in TRAIL signaling. AB - Protein phosphatase 2A (PP2A) is the major serine-threonine phosphatase that regulates a number of cell signaling pathways. PP2A activity is controlled partially through protein degradation; however, the underlying mechanism is not fully understood. Here we show that PP2A/C, a catalytic subunit of PP2A, is degraded by the Cullin3 (Cul3) ligase-mediated ubiquitin-proteasome pathway. In response to death receptor signaling by tumor-necrosis factor-related apoptosis inducing ligand (TRAIL), PP2A/C, caspase-8 and Cul3, a subunit of the cullin family of E3 ligases, are recruited into the death-inducing signaling complex (DISC) where the Cul3 ligase targets PP2A/C for ubiquitination and subsequent degradation. Functionally, knockdown of PP2A/C expression by siRNA or pharmacological inhibition of PP2A activity increases TRAIL-induced apoptosis. In cancer cells that have developed acquired TRAIL resistance, PP2A phosphatase activity is increased, and PP2A/C protein is resistant to TRAIL-induced degradation. Thus, this work identifies a new mechanism by which PP2A/C is regulated by Cul3 ligase-mediated degradation in response to death receptor signaling and suggests that inhibition of PP2A/C degradation may contribute to resistance of cancer cells to death receptor-induced apoptosis. PMID- 25551364 TI - How "proficient" is proficient? Bilingual listeners' recognition of English words in noise. AB - PURPOSE: Shi (2011, 2013) obtained sensitivity/specificity measures of bilingual listeners' English and relative proficiency ratings as the predictor of English word recognition in quiet. The current study investigated how relative proficiency predicted word recognition in noise. METHOD: Forty-two monolingual and 168 bilingual normal-hearing listeners were included. Bilingual listeners rated their proficiency in listening, speaking, and reading in English and in the other language using an 11-point scale. Listeners were presented with 50 English monosyllabic words in quiet at 45 dB HL and in multitalker babble with a signal to-noise ratio of +6 and 0 dB. RESULTS: Data in quiet confirmed Shi's (2013) finding that relative proficiency with or without dominance predicted well whether bilinguals performed on par with the monolingual norm. Predicting the outcome was difficult for the 2 noise conditions. To identify bilinguals whose performance fell below the normative range, dominance per se or a combination of dominance and average relative proficiency rating yielded the best sensitivity/specificity and summary measures, including Youden's index. CONCLUSION: Bilinguals' word recognition is more difficult to predict in noise than in quiet; however, proficiency and dominance variables can predict reasonably well whether bilinguals may perform at a monolingual normative level. PMID- 25551362 TI - ExpaRNA-P: simultaneous exact pattern matching and folding of RNAs. AB - BACKGROUND: Identifying sequence-structure motifs common to two RNAs can speed up the comparison of structural RNAs substantially. The core algorithm of the existent approach ExpaRNA solves this problem for a priori known input structures. However, such structures are rarely known; moreover, predicting them computationally is no rescue, since single sequence structure prediction is highly unreliable. RESULTS: The novel algorithm ExpaRNA-P computes exactly matching sequence-structure motifs in entire Boltzmann-distributed structure ensembles of two RNAs; thereby we match and fold RNAs simultaneously, analogous to the well-known "simultaneous alignment and folding" of RNAs. While this implies much higher flexibility compared to ExpaRNA, ExpaRNA-P has the same very low complexity (quadratic in time and space), which is enabled by its novel structure ensemble-based sparsification. Furthermore, we devise a generalized chaining algorithm to compute compatible subsets of ExpaRNA-P's sequence structure motifs. Resulting in the very fast RNA alignment approach ExpLoc-P, we utilize the best chain as anchor constraints for the sequence-structure alignment tool LocARNA. ExpLoc-P is benchmarked in several variants and versus state-of-the art approaches. In particular, we formally introduce and evaluate strict and relaxed variants of the problem; the latter makes the approach sensitive to compensatory mutations. Across a benchmark set of typical non-coding RNAs, ExpLoc P has similar accuracy to LocARNA but is four times faster (in both variants), while it achieves a speed-up over 30-fold for the longest benchmark sequences (~400nt). Finally, different ExpLoc-P variants enable tailoring of the method to specific application scenarios. ExpaRNA-P and ExpLoc-P are distributed as part of the LocARNA package. The source code is freely available at http://www.bioinf.uni freiburg.de/Software/ExpaRNA-P . CONCLUSIONS: ExpaRNA-P's novel ensemble-based sparsification reduces its complexity to quadratic time and space. Thereby, ExpaRNA-P significantly speeds up sequence-structure alignment while maintaining the alignment quality. Different ExpaRNA-P variants support a wide range of applications. PMID- 25551365 TI - The feasibility of a randomised controlled trial of Dyadic Developmental Psychotherapy. AB - BACKGROUND: Maltreated children have significant and complex problems which clinicians find difficult to diagnose and treat. Previous US pilot work suggests that Dyadic Developmental Psychotherapy (DDP) may be effective; however, rigorous evidence from a randomised controlled trial (RCT) is lacking. The purpose of this study is to establish the feasibility of an RCT of DDP by exploring the ways that DDP is operating across different UK sites and the impacts of current practice on the potential set-up of an RCT. METHODS: Qualitative methods (interviews, focus groups and teleconferences) were used to explore trial feasibility with therapists and service managers from teams implementing both DDP and possible control interventions. Data were analysed thematically and related to various aspects of trial design. RESULTS: DDP was commonly regarded as having a particular congruence with the complexity of maltreatment-associated problems and a common operating model of DDP was evident across sites. A single control therapy was harder to establish, however, and it is likely to be a non-specific and context-dependent intervention/s offered within mainstream Child and Adolescent Mental Health Services (CAMHS). Because a 'gold standard' Treatment as Usual (TAU) does not currently exist, randomisation between DDP and TAU (CAMHS) therefore looks feasible and ethical. The nature of family change during DDP was regarded as multi-faceted, non-linear and relationship-based. Assessment tools need to be carefully considered in terms of their ability to capture change that covers both individual child and family-based functioning. CONCLUSIONS: An RCT of DDP is feasible and timely. This study has demonstrated widespread interest, support and engagement regarding an RCT and permissions have been gained from sites that have shown readiness to participate. As maltreated children are among the most vulnerable in society, and as there are currently no treatments with RCT evidence, such a trial would be a major advance in the field. PMID- 25551366 TI - The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease: a population based cohort study. AB - BACKGROUND: Chromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fruits, alcohol, or wine, and if rs4977574 interacts with environmental factors on known CVD risk markers. METHODS: Multivariable Cox regression analyses were performed in 23,949 individuals from the population-based prospective Malmo Diet and Cancer Study (MDCS), of whom 3,164 developed CVD during 15 years of follow up. The rs4977574 variant (major allele: A; minor allele: G) was genotyped using TaqMan(r) Assay Design probes. Dietary data were collected at baseline using a modified diet history method. Cross-sectional analyses were performed in 4,828 MDCS participants with fasting blood levels of circulating risk factors measured at baseline. RESULTS: Each rs4977574 G allele was associated with a 16% increased incidence of CVD (95% confidence interval (CI), 1.10-1.22). Higher vegetable intake (hazard ratio (HR), 0.95 [CI: 0.91-0.996]), wine intake (HR, 0.91 [CI: 0.86-0.96]), and total alcohol consumption (HR, 0.92 [CI: 0.86-0.98]) were associated with lower CVD incidence. The increased CVD incidence by the G allele was restricted to individuals with medium or high vegetable intake (Pinteraction = 0.043), and to non- and low consumers of wine (Pinteraction = 0.029). Although rs4977574 did not associate with any known risk markers, stratification by vegetable intake and smoking suggested an interaction with rs4977574 on glycated hemoglobin and high-density lipoprotein cholesterol (Pinteraction = 0.015 and 0.049, respectively). CONCLUSIONS: Our results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD. PMID- 25551367 TI - Spatial pattern of severe acute respiratory syndrome in-out flow in 2003 in Mainland China. AB - BACKGROUND: Severe acute respiratory syndrome (SARS) spread to 32 countries and regions within a few months in 2003. There were 5327 SARS cases from November 2002 to May 2003 in Mainland China, which involved 29 provinces, resulted in 349 deaths, and directly caused economic losses of $18.3 billion. METHODS: This study used an in-out flow model and flow mapping to visualize and explore the spatial pattern of SARS transmission in different regions. In-out flow is measured by the in-out degree and clustering coefficient of SARS. Flow mapping is an exploratory method of spatial visualization for interaction data. RESULTS: The findings were as follows. (1) SARS in-out flow had a clear hierarchy. It formed two main centers, Guangdong in South China and Beijing in North China, and two secondary centers, Shanxi and Inner Mongolia, both connected to Beijing. (2) "Spring Festival travel" strengthened external flow, but "SARS panic effect" played a more significant role and pushed the external flow to the peak. (3) External flow and its three typical kinds showed obvious spatial heterogeneity, such as self spreading flow (spatial displacement of SARS cases only within the province or municipality of onset and medical locations); hospitalized flow (spatial displacement of SARS cases that had been seen by a hospital doctor); and migrant flow (spatial displacement of SARS cases among migrant workers). (4) Internal and external flow tended to occur in younger groups, and occupational differentiation was particularly evident. Low-income groups of male migrants aged 19-35 years were the main routes of external flow. CONCLUSIONS: During 2002-2003, SARS in-out flow played an important role in countrywide transmission of the disease in Mainland China. The flow had obvious spatial heterogeneity, which was influenced by migrants' behavior characteristics. In addition, the Chinese holiday effect led to irregular spread of SARS, but the panic effect was more apparent in the middle and late stages of the epidemic. These findings constitute valuable input to prevent and control future serious infectious diseases like SARS. PMID- 25551368 TI - PD_NGSAtlas: a reference database combining next-generation sequencing epigenomic and transcriptomic data for psychiatric disorders. AB - BACKGROUND: Psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) are projected to lead the global disease burden within the next decade. Several lines of evidence suggest that epigenetic- or genetic-mediated dysfunction is frequently present in these disorders. To date, the inheritance patterns have been complicated by the problem of integrating epigenomic and transcriptomic factors that have yet to be elucidated. Therefore, there is a need to build a comprehensive database for storing epigenomic and transcriptomic data relating to psychiatric disorders. DESCRIPTION: We have developed the PD_NGSAtlas, which focuses on the efficient storage of epigenomic and transcriptomic data based on next-generation sequencing and on the quantitative analyses of epigenetic and transcriptional alterations involved in psychiatric disorders. The current release of the PD_NGSAtlas contains 43 DNA methylation profiles and 37 transcription profiles detected by MeDIP-Seq and RNA-Seq, respectively, in two distinct brain regions and peripheral blood of SZ, BP and non-psychiatric controls. In addition to these data that were generated in-house, we have included, and will continue to include, published DNA methylation and gene expression data from other research groups, with a focus on psychiatric disorders. A flexible query engine has been developed for the acquisition of methylation profiles and transcription profiles for special genes or genomic regions of interest of the selected samples. Furthermore, the PD_NGSAtlas offers online tools for identifying aberrantly methylated and expressed events involved in psychiatric disorders. A genome browser has been developed to provide integrative and detailed views of multidimensional data in a given genomic context, which can help researchers understand molecular mechanisms from epigenetic and transcriptional perspectives. Moreover, users can download the methylation and transcription data for further analyses. CONCLUSIONS: The PD_NGSAtlas aims to provide storage of epigenomic and transcriptomic data as well as quantitative analyses of epigenetic and transcriptional alterations involved in psychiatric disorders. The PD_NGSAtlas will be a valuable data resource and will enable researchers to investigate the pathophysiology and aetiology of disease in detail. The database is available at http://bioinfo.hrbmu.edu.cn/pd_ngsatlas/. PMID- 25551369 TI - Molecular signatures of lymph node status by intrinsic subtype: gene expression analysis of primary breast tumors from patients with and without metastatic lymph nodes. AB - BACKGROUND: Identification of a gene expression signature in primary breast tumors that could classify patients by lymph node status would allow patients to avoid the morbidities of surgical disruption of the lymph nodes. Attempts to identify such a signature have, to date, been unsuccessful. Because breast tumor subtypes have unique molecular characteristics and different sites of metastasis, molecular signatures for lymph node involvement may vary by subtype. METHODS: Gene expression data was generated from HG U133A 2.0 arrays for 135 node positive and 210 node negative primary breast tumors. Intrinsic subtype was assigned using the BreastPRS. Differential gene expression analysis was performed using one-way ANOVA using lymph node status as the variable with a False-discovery rate <0.05, to define significance. RESULTS: Luminal A tumors were most common (51%) followed by basal-like (27%), HER2-enriched (14%) luminal B (7%) and normal-like (1%). Basal-like and luminal A tumors were less likely to have metastatic lymph nodes (35% and 37%, respectively) compared to luminal B or HER2-enriched (52% and 51%, respectively). No differentially expressed genes associated with lymph node status were detected when all tumors were considered together or within each subtype. CONCLUSIONS: Gene expression patterns from the primary tumor are not able to stratify patients by lymph node status. Although the primary breast tumor may influence tumor cell dissemination, once metastatic cells enter the lymphatics, it is likely that characteristics of the lymph node microenvironment, such as establishment of a pre-metastatic niche and release of pro-survival factors, determine which cells are able to colonize. The inability to utilize molecular profiles from the primary tumor to determine lymph node status suggest that other avenues of investigation, such as how systemic factors including diminished immune response or genetic susceptibility contribute to metastasis, may be critical in the development of tools for non-surgical assessment of lymph node status with a corresponding reduction in downstream sequelae associated with disruption of the lymphatics. PMID- 25551370 TI - Medical residents reflect on their prejudices toward poverty: a photovoice training project. AB - BACKGROUND: Clinicians face challenges in delivering care to socioeconomically disadvantaged patients. While both the public and academic sectors recognize the importance of addressing social inequities in healthcare, there is room for improvement in the training of family physicians, who report being ill-equipped to provide care that is responsive to the living conditions of these patients. This study explored: (i) residents' perceptions and experience in relation to providing care for socioeconomically disadvantaged patients, and (ii) how participating in a photovoice study helped them uncover and examine some of their prejudices and assumptions about poverty. METHODS: We conducted a participatory photovoice study. Participants were four family medicine residents, two medical supervisors, and two researchers. Residents attended six photovoice meetings at which they discussed photos they had taken. In collaboration with the researchers, the participants defined the research questions, took photos, and participated in data analysis and results dissemination. Meetings were recorded and transcribed for analysis, which consisted of coding, peer debriefing, thematic analysis, and interpretation. RESULTS: The medical residents uncovered and examined their own prejudices and misconceptions about poverty. They reported feeling unprepared to provide care to socioeconomically disadvantaged patients. Supported by medical supervisors and researchers, the residents underwent a three phase reflexive process of: (1) engaging reflexively, (2) break(ing) through, and (3) taking action. The results indicated that medical residents subsequently felt encouraged to adopt a care approach that helped them overcome the social distance between themselves and their socioeconomically disadvantaged patients. CONCLUSIONS: This study highlights the importance of providing medical training on issues related to poverty and increasing awareness about social inequalities in medical education to counteract prejudices toward socioeconomically disadvantaged patients. Future studies should examine which elective courses and training could provide suitable tools to clinicians to improve their competence in delivering care to socioeconomically disadvantaged patients. PMID- 25551371 TI - The near-quantitative sampling of genomic DNA from various food-borne Eubacteria. AB - BACKGROUND: The disruption of the bacterial cell wall plays an important part in achieving quantitative extraction of DNA from Eubacteria essential for accurate analyses of genetic material recovered from environmental samples. RESULTS: In this work we have tested a dozen commercial bacterial genomic DNA extraction methodologies on an average of 7.70 * 10(6) (+/-9.05%), 4.77 * 10(8) (+/-31.0%), and 5.93 * 10(8) (+/-4.69%) colony forming units (CFU) associated with 3 cultures (n = 3) each of Brochothrix thermosphacta (Bt; Gram-positive), Shigella sonnei (Ss; Gram-negative), and Escherichia coli O79 (Ec; Gram-negative). We have utilized real-time PCR (qPCR) quantification with two specific sets of primers associated with the 16S rRNA "gene" to determine the number of copies CFU(-1) by comparing the unknown target DNA qPCR results with standards for each primer set. Based upon statistical analyses of our results, we determined that the Agencourt Genfind v2, High Pure PCR Template Prep Kit, and Omnilyse methods consistently provided the best yield of genomic DNA ranging from 141 to 934, 8 to 21, and 16 to 27 16S rDNA copies CFU(-1) for Bt, Ss, and Ec. If one assumes 6-7 copies of the 16S rRNA gene per genome, between 1 and 3 genomes per actively dividing cell and >= 100 cells CFU(-1) for Bt (found to be a reasonable assumption using an optical method expounded upon herein) or between 1 and 2 cells CFU(-1) for either Ss or Ec, then the Omnilyse procedure provided nearly quantitative extraction of genomic DNA from these isolates (934 +/- 19.9 copies CFU(-1) for Bt; 20.8 +/- 2.68 copies CFU(-1) for Ss; 26.9 +/- 3.39 copies CFU(-1) for Ec). The Agencourt, High Pure, and Omnilyse technologies were subsequently assessed using 5 additional Gram-positive and 10 Gram-negative foodborne isolates (n = 3) using a set of "universal" 16S rDNA primers. CONCLUSION: Overall, the most notable DNA extraction method was found to be the Omnilyse procedure which is a "bead blender" technology involving high frequency agitation in the presence of zirconium silicate beads. PMID- 25551372 TI - Removal of well-fixed components in femoral revision arthroplasty with controlled segmentation of the proximal femur. AB - BACKGROUND: The transfemoral and the extended trochanteric osteotomies are the most common osteotomies used in femoral revision, both when proximal or diaphyseal fixation of the new component has been decided. We present an alternative approach to the trochanteric osteotomies, most frequently used with distally fixated stems, to overcome their shortcomings of osteotomy migration and nonunion, but, most of all, the uncontrollable fragmentation of the femur. METHODS: The procedure includes a complete circular femoral osteotomy just below the stem tip to prevent distal fracture propagation and a subsequent preplanned segmentation of the proximal femur for better exposure and fast removal of the old prosthesis. The bone fragments are reattached with cerclage wires to the revision prosthesis, which is safely anchored distally. A modified posterolateral approach is used, as the preservation of the continuity of the abductors, the greater trochanter, and the vastus lateralis is a prerequisite. RESULTS: Between 2006 and 2012, 47 stems (33 women, 14 men, mean age 68 years, range 39-88 years) were revised using this technique. They were 12 (26%) stable and 35 (74%) loose prostheses and were all revised to tapered, fluted, grit-blasted stems. No fracture of the trochanters or the distal femur occurred intraoperatively. Mean follow-up was 28 months (range 6-70 months). No case of trochanteric migration or nonunion of the osteotomies was recorded. Restoration of the preexisting bone defects occurred in 83% of the patients. Three patients required repeat revision due to dislocation and one due to a postoperative periprosthetic fracture. None of the failures was attributed to the procedure itself. CONCLUSIONS: This new osteotomy technique may seem aggressive at first, but, at least in our hands, has effectively increased the speed of the femoral revision, particularly for the most difficult well-fixed components, but not at the expense of safety. PMID- 25551373 TI - Sampling time and performance in rat whisker sensory system. AB - We designed a behavioural paradigm for vibro-tactile detection to characterise the sampling time and performance in the rat whisker sensory system. Rats initiated a trial by nose-poking into an aperture where their whiskers came into contact with two meshes. A continuous nose-poke for a random duration triggered stimulus presentation. Stimuli were a sequence of discrete Gaussian deflections of the mesh that increased in amplitude over time - across 5 conditions, time to maximum amplitude varied from 0.5 to 8 seconds. Rats indicated the detected stimulus by choosing between two reward spouts. Two rats completed more than 500 trials per condition. Rats' stimulus sampling duration increased and performance dropped with increasing task difficulty. For all conditions the median reaction time was longer for correct trials than incorrect trials. Higher rates of increment in stimulus amplitude resulted in faster rise in performance as a function of stimulus sampling duration. Rats' behaviour indicated a dynamic stimulus sampling whereby nose-poke was maintained until a stimulus was correctly identified or the rat experienced a false alarm. The perception was then manifested in behaviour after a motor delay. We thus modelled the results with 3 parameters: signal detection, false alarm, and motor delay. The model captured the main features of the data and produced parameter estimates that were biologically plausible and highly similar across the two rats. PMID- 25551374 TI - Olive oil and vitamin D synergistically prevent bone loss in mice. AB - As the Mediterranean diet (and particularly olive oil) has been associated with bone health, we investigated the impact of extra virgin oil as a source of polyphenols on bone metabolism. In that purpose sham-operated (SH) or ovariectomized (OVX) mice were subjected to refined or virgin olive oil. Two supplementary OVX groups were given either refined or virgin olive oil fortified with vitamin D3, to assess the possible synergistic effects with another liposoluble nutrient. After 30 days of exposure, bone mineral density and gene expression were evaluated. Consistent with previous data, ovariectomy was associated with increased bone turnover and led to impaired bone mass and micro architecture. The expression of oxidative stress markers were enhanced as well. Virgin olive oil fortified with vitamin D3 prevented such changes in terms of both bone remodeling and bone mineral density. The expression of inflammation and oxidative stress mRNA was also lower in this group. Overall, our data suggest a protective impact of virgin olive oil as a source of polyphenols in addition to vitamin D3 on bone metabolism through improvement of oxidative stress and inflammation. PMID- 25551375 TI - Application and evaluation of interactive 3D PDF for presenting and sharing planning results for liver surgery in clinical routine. AB - BACKGROUND & OBJECTIVES: The Portable Document Format (PDF) is the de-facto standard for the exchange of electronic documents. It is platform-independent, suitable for the exchange of medical data, and allows for the embedding of three dimensional (3D) surface mesh models. In this article, we present the first clinical routine application of interactive 3D surface mesh models which have been integrated into PDF files for the presentation and the exchange of Computer Assisted Surgery Planning (CASP) results in liver surgery. We aimed to prove the feasibility of applying 3D PDF in medical reporting and investigated the user experience with this new technology. METHODS: We developed an interactive 3D PDF report document format and implemented a software tool to create these reports automatically. After more than 1000 liver CASP cases that have been reported in clinical routine using our 3D PDF report, an international user survey was carried out online to evaluate the user experience. RESULTS: Our solution enables the user to interactively explore the anatomical configuration and to have different analyses and various resection proposals displayed within a 3D PDF document covering only a single page that acts more like a software application than like a typical PDF file ("PDF App"). The new 3D PDF report offers many advantages over the previous solutions. According to the results of the online survey, the users have assessed the pragmatic quality (functionality, usability, perspicuity, efficiency) as well as the hedonic quality (attractiveness, novelty) very positively. CONCLUSION: The usage of 3D PDF for reporting and sharing CASP results is feasible and well accepted by the target audience. Using interactive PDF with embedded 3D models is an enabler for presenting and exchanging complex medical information in an easy and platform-independent way. Medical staff as well as patients can benefit from the possibilities provided by 3D PDF. Our results open the door for a wider use of this new technology, since the basic idea can and should be applied for many medical disciplines and use cases. PMID- 25551376 TI - Comparing Leishman and Giemsa staining for the assessment of peripheral blood smear preparations in a malaria-endemic region in India. AB - BACKGROUND: Microscopy of peripheral blood thin and thick films remains the reference for malaria diagnosis. Although Giemsa staining is most commonly used, the Leishman staining method provides better visualization of the nuclear chromatin pattern of cells. It is less well known whether accuracy of parasitaemia assessment is equally accurate with the latter method. METHODS: Peripheral blood thin and thick smears from consecutive febrile patients admitted to Ispat General hospital, Rourkela, Odhisa, India, were stained with Giemsa and Leishman stain. Methods were compared for species identification, parasite quantification, and ability for identification of alternative diagnoses. RESULTS: Blood films from 1,180 fever patients were compared according to staining method, of which 111 were identified as parasitaemic using Giemsa and 110 with Leishman staining. The Kappa value as a measure of agreement between methods was 0.995 (p < 0.001), and the log10parasitaemia between methods were strongly correlated (r2 = 0.9981). In parasite negative patients, thin smear assessment contributed to making a diagnosis in 276/1,180 (23%) of cases. These assessments were better made in Leishman-stained preparations, especially for the assessment of morphological changes in red and white cells. CONCLUSION: Leishman's staining method for thin and thick smears is a good alternative to Giemsa's stain for identifying Plasmodium parasites. The Leishman method is superior for visualization of red and white blood cell morphology. PMID- 25551377 TI - A case study of discordant overlapping meta-analyses: vitamin d supplements and fracture. AB - BACKGROUND: Overlapping meta-analyses on the same topic are now very common, and discordant results often occur. To explore why discordant results arise, we examined a common topic for overlapping meta-analyses- vitamin D supplements and fracture. METHODS AND FINDINGS: We identified 24 meta-analyses of vitamin D (with or without calcium) and fracture in a PubMed search in October 2013, and analysed a sample of 7 meta-analyses in the highest ranking general medicine journals. We used the AMSTAR tool to assess the quality of the meta-analyses, and compared their methodologies, analytic techniques and results. Applying the AMSTAR tool suggested the meta-analyses were generally of high quality. Despite this, there were important differences in trial selection, data extraction, and analytical methods that were only apparent after detailed assessment. 25 trials were included in at least one meta-analysis. Four meta-analyses included all eligible trials according to the stated inclusion and exclusion criteria, but the other 3 meta-analyses "missed" between 3 and 8 trials, and 2 meta-analyses included apparently ineligible trials. The relative risks used for individual trials differed between meta-analyses for total fracture in 10 of 15 trials, and for hip fracture in 6 of 12 trials, because of different outcome definitions and analytic approaches. The majority of differences (11/16) led to more favourable estimates of vitamin D efficacy compared to estimates derived from unadjusted intention-to treat analyses using all randomised participants. The conclusions of the meta analyses were discordant, ranging from strong statements that vitamin D prevents fractures to equally strong statements that vitamin D without calcium does not prevent fractures. CONCLUSIONS: Substantial differences in trial selection, outcome definition and analytic methods between overlapping meta-analyses led to discordant estimates of the efficacy of vitamin D for fracture prevention. Strategies for conducting and reporting overlapping meta-analyses are required, to improve their accuracy and transparency. PMID- 25551378 TI - Does predation risk affect mating behavior? An experimental test in dumpling squid (Euprymna tasmanica). AB - INTRODUCTION: One of the most important trade-offs for many animals is that between survival and reproduction. This is particularly apparent when mating increases the risk of predation, either by increasing conspicuousness, reducing mobility or inhibiting an individual's ability to detect predators. Individuals may mitigate the risk of predation by altering their reproductive behavior (e.g. increasing anti-predator responses to reduce conspicuousness). The degree to which individuals modulate their reproductive behavior in relation to predation risk is difficult to predict because both the optimal investment in current and future reproduction (due to life-history strategies) and level of predation risk may differ between the sexes and among species. Here, we investigate the effect of increased predation risk on the reproductive behavior of dumpling squid (Euprymna tasmanica). RESULTS: Females, but not males, showed a substantial increase in the number of inks (an anti-predator behavior) before mating commenced in the presence of a predator (sand flathead Platycephalus bassensis). However, predation risk did not affect copulation duration, the likelihood of mating, female anti-predator behavior during or after mating or male anti predator behavior at any time. CONCLUSIONS: Inking is a common anti-predator defense in cephalopods, thought to act like a smokescreen, decoy or distraction. Female dumpling squid are probably using this form of defense in response to the increase in predation risk prior to mating. Conversely, males were undeterred by the increase in predation risk. A lack of change in these variables may occur if the benefit of completing mating outweighs the risk of predation. Prioritizing current reproduction, even under predation risk, can occur when the chance of future reproduction is low, there is substantial energetic investment into mating, or the potential fitness payoffs of mating are high. PMID- 25551379 TI - Natural hybridization and introgression between Ligularia cymbulifera and L. tongolensis (Asteraceae, Senecioneae) in four different locations. AB - Natural hybridization has been considered to represent an important factor influencing the high diversity of the genus Ligularia Cass. in the Hengduan Mountains, China. Natural hybridization has been confirmed to occur frequently in Ligularia. To date, however, it has been demonstrated only within a single population. In this paper, we present evidence of natural hybridization in Ligularia from four different locations. The internal transcribed spacer (ITS) region of the nuclear ribosomal DNA and three chloroplast intergenic spacers (trnK-rps16, trnL-rpl32 and trnQ-5'rps16) of 149 accessions of putative hybrids and their putative parents (L. cymbulifera and L. tongolensis) were analyzed for evidence of hybridization. The ITS data clearly distinguished two putative parental species and sympatric L. vellerea and supported the hypothesis that those morphological intermediates were products of natural hybridization between L. cymbulifera and L. tongolensis. Moreover, several identified morphological parents were actual introgressed products. Because of hybridization and introgression, chloroplast DNA sequences generated a poorly resolved network. The present results indicate that varying degrees of hybridization and introgression occur differently depending on the habitat context. We conclude that gene flow caused by natural hybridization in Ligularia indeed plays an important role in the species diversity. PMID- 25551380 TI - Effects of diets high in unsaturated Fatty acids on socially induced stress responses in Guinea pigs. AB - Unsaturated fatty acids (UFAs), such as omega-3 and omega-6 poly- and omega-9 monounsaturated fatty acids are important nutrients and major components of neuronal cell membranes. They play a major role in modulating brain functions and physiology and may therefore diminish behavioral and physiological stress reactions in corroboration with decreased cortisol concentrations. Functionally, cortisol itself can modulate several behaviors and also the fatty acid metabolism in the long term. But only little is known about the behavioral and physiological influences of dietary UFAs in a social group, where individuals are regularly exposed to stressful situations. Therefore, the aim of this study was to determine the effects of dietary UFAs on saliva cortisol concentrations and behavioral responses in socially confronted guinea pigs. Three groups of animals were additionally supplemented with 500 mg chia seeds (high in omega-3), walnuts (high in omega-6), or peanuts (high in omega-9) per kg bodyweight each day and compared to a control group. During social confrontation saliva cortisol concentrations significantly increased in all groups, which was accompanied by a loss in bodyweight. However, cortisol levels remained lower in the chia and walnut groups compared to controls. Additionally, the walnut group displayed significantly increased locomotion, while no differences between groups were detected in socio-positive, sexual, or aggressive behaviors. Total plasma omega 3, omega-6, and omega-9 fatty acids were significantly increased in the corresponding groups, due to the dietary supplementations. However, a significant decrease in plasma omega-3 and an increase in plasma n-6 fatty acids were detected in the chia group when comparing the measurements before and after social confrontation. We conclude that both omega-3 and omega-6 polyunsaturated fatty acids can diminish behavioral and physiological stress responses to the social environment, enabling individuals to cope with social stressors, but at the expense of plasma derived omega-3 fatty acids. PMID- 25551381 TI - Midkine-deficiency delays chondrogenesis during the early phase of fracture healing in mice. AB - The growth and differentiation factor midkine (Mdk) plays an important role in bone development and remodeling. Mdk-deficient mice display a high bone mass phenotype when aged 12 and 18 months. Furthermore, Mdk has been identified as a negative regulator of mechanically induced bone formation and it induces pro chondrogenic, pro-angiogenic and pro-inflammatory effects. Together with the finding that Mdk is expressed in chondrocytes during fracture healing, we hypothesized that Mdk could play a complex role in endochondral ossification during the bone healing process. Femoral osteotomies stabilized using an external fixator were created in wildtype and Mdk-deficient mice. Fracture healing was evaluated 4, 10, 21 and 28 days after surgery using 3-point-bending, micro computed tomography, histology and immunohistology. We demonstrated that Mdk deficient mice displayed delayed chondrogenesis during the early phase of fracture healing as well as significantly decreased flexural rigidity and moment of inertia of the fracture callus 21 days after fracture. Mdk-deficiency diminished beta-catenin expression in chondrocytes and delayed presence of macrophages during early fracture healing. We also investigated the impact of Mdk knockdown using siRNA on ATDC5 chondroprogenitor cells in vitro. Knockdown of Mdk expression resulted in a decrease of beta-catenin and chondrogenic differentiation-related matrix proteins, suggesting that delayed chondrogenesis during fracture healing in Mdk-deficient mice may be due to a cell-autonomous mechanism involving reduced beta-catenin signaling. Our results demonstrated that Mdk plays a crucial role in the early inflammation phase and during the development of cartilaginous callus in the fracture healing process. PMID- 25551382 TI - Birth weight and risk of adiposity among adult Inuit in Greenland. AB - OBJECTIVE: The Inuit population in Greenland has undergone rapid socioeconomic and nutritional changes simultaneously with an increasing prevalence of obesity. Therefore, the objective was to examine fetal programming as part of the aetiology of obesity among Inuit in Greenland by investigating the association between birth weight and measures of body composition and fat distribution in adulthood. METHODS: The study was based on cross-sectional data from a total of 1,473 adults aged 18-61 years in two population-based surveys conducted in Greenland between 1999-2001 and 2005-2010. Information on birth weight was collected from birth records. Adiposity was assessed by anthropometry, fat mass index (FMI), fat-free mass index (FFMI), and visceral (VAT) and subcutaneous adipose tissue (SAT) estimated by ultrasound. The associations to birth weight were analyzed using linear regression models and quadratic splines. Analyses were stratified by sex, and adjusted for age, birthplace, ancestry and family history of obesity. RESULTS: Spline analyses showed linear relations between birth weight and adult adiposity. In multiple regression analyses, birth weight was positively associated with BMI, waist circumference, FMI, FFMI and SAT with generally weaker associations among women compared to men. Birth weight was only associated with VAT after additional adjustment for waist circumference and appeared to be specific and inverse for men only. CONCLUSIONS: Higher birth weight among Inuit was associated with adiposity in adulthood. More studies are needed to explore a potential inverse association between birth size and VAT. PMID- 25551384 TI - An accurate, flexible and small optical fiber sensor: a novel technological breakthrough for real-time analysis of dynamic blood flow data in vivo. AB - Because of the limitations of existing methods and techniques for directly obtaining real-time blood data, no accurate microflow in vivo real-time analysis method exists. To establish a novel technical platform for real-time in vivo detection and to analyze average blood pressure and other blood flow parameters, a small, accurate, flexible, and nontoxic Fabry-Perot fiber sensor was designed. The carotid sheath was implanted through intubation of the rabbit carotid artery (n = 8), and the blood pressure and other detection data were determined directly through the veins. The fiber detection results were compared with test results obtained using color Doppler ultrasound and a physiological pressure sensor recorder. Pairwise comparisons among the blood pressure results obtained using the three methods indicated that real-time blood pressure information obtained through the fiber sensor technique exhibited better correlation than the data obtained with the other techniques. The highest correlation (correlation coefficient of 0.86) was obtained between the fiber sensor and pressure sensor. The blood pressure values were positively related to the total cholesterol level, low-density lipoprotein level, number of red blood cells, and hemoglobin level, with correlation coefficients of 0.033, 0.129, 0.358, and 0.373, respectively. The blood pressure values had no obvious relationship with the number of white blood cells and high-density lipoprotein and had a negative relationship with triglyceride levels, with a correlation coefficient of -0.031. The average ambulatory blood pressure measured by the fiber sensor exhibited a negative correlation with the quantity of blood platelets (correlation coefficient of 0.839, P<0.05). The novel fiber sensor can thus obtain in vivo blood pressure data accurately, stably, and in real time; the sensor can also determine the content and status of the blood flow to some extent. Therefore, the fiber sensor can obtain partially real-time vascular rheology information and may thus enable the early diagnosis of blood rheology disorders and diseases. PMID- 25551383 TI - Middle Pleistocene hominin teeth from Longtan Cave, Hexian, China. AB - Excavations at the Longtan Cave, Hexian, Anhui Province of Eastern China, have yielded several hominin fossils including crania, mandibular fragments, and teeth currently dated to 412 +/- 25 ka. While previous studies have focused on the cranial remains, there are no detailed analyses of the dental evidence. In this study, we provide metric and morphological descriptions and comparisons of ten teeth recovered from Hexian, including microcomputed tomography analyses. Our results indicate that the Hexian teeth are metrically and morphologically primitive and overlap with H. ergaster and East Asian Early and mid-Middle Pleistocene hominins in their large dimensions and occlusal complexities. However, the Hexian teeth differ from H. ergaster in features such as conspicuous vertical grooves on the labial/buccal surfaces of the central incisor and the upper premolar, the crown outline shapes of upper and lower molars and the numbers, shapes, and divergences of the roots. Despite their close geological ages, the Hexian teeth are also more primitive than Zhoukoudian specimens, and resemble Sangiran Early Pleistocene teeth. In addition, no typical Neanderthal features have been identified in the Hexian sample. Our study highlights the metrical and morphological primitive status of the Hexian sample in comparison to contemporaneous or even earlier populations of Asia. Based on this finding, we suggest that the primitive-derived gradients of the Asian hominins cannot be satisfactorily fitted along a chronological sequence, suggesting complex evolutionary scenarios with the coexistence and/or survival of different lineages in Eurasia. Hexian could represent the persistence in time of a H. erectus group that would have retained primitive features that were lost in other Asian populations such as Zhoukoudian or Panxian Dadong. Our study expands the metrical and morphological variations known for the East Asian hominins before the mid Middle Pleistocene and warns about the possibility that the Asian hominin variability may have been taxonomically oversimplified. PMID- 25551385 TI - Potassium channel antagonists 4-aminopyridine and the T-butyl carbamate derivative of 4-aminopyridine improve hind limb function in chronically non ambulatory dogs; a blinded, placebo-controlled trial. AB - 4-Aminopyridine (4-AP) blocks voltage gated potassium channels, restoring conduction to demyelinated axons and improving function in demyelinating conditions, but its use is associated with adverse effects and benefit in spinal cord injury is limited. Derivatives of 4-AP have been developed to improve clinical efficacy while reducing toxicity. We compared the therapeutic effects of orally administered 4-AP and its t-butyl carbamate derivative (t-butyl) with placebo in dogs that had suffered an acute spinal cord injury that left them chronically paralyzed. Nineteen dogs were entered into the trial, conducted in two-week treatment blocks starting with placebo, followed by random assignment to 4-AP or t-butyl, a washout and then the opposite medication followed by placebo. Investigators and owners were blinded to treatment group. Primary outcome measures included open field gait score (OFS), and treadmill based stepping score and regularity index, with additional secondary measures also considered. Thirteen of 19 dogs completed the protocol. Two were euthanized due to unrelated heath problems, two developed side effects and two were unable to complete for unrelated reasons. Dogs showed significant improvement in supported stepping score (from 17.39 to 37.24% with 4-AP; 16.85 to 29.18% with t-butyl p<0.0001) and OFS (from 3.63 to 4.73 with 4-AP; 3.78 to 4.45 with t-butyl, p = 0.005). Response was individually variable and most dramatic in three dogs that were able to walk without support with treatment. No significant difference was found between 4-AP and t-butyl. No adverse effects were reported with t-butyl but gastrointestinal upset and seizures were observed in two dogs with 4-AP. In conclusion, both 4-AP and t-butyl significantly improved supported stepping ability in dogs with chronic spinal cord injury with no adverse effects noted with t-butyl. Drug response varied widely between individuals, highlighting the need to understand the factors that influence canine and human patients' response to therapy. PMID- 25551386 TI - Time pressure increases cooperation in competitively framed social dilemmas. AB - What makes people willing to pay costs to benefit others? Does such cooperation require effortful self-control, or do automatic, intuitive processes favor cooperation? Time pressure has been shown to increase cooperative behavior in Public Goods Games, implying a predisposition towards cooperation. Consistent with the hypothesis that this predisposition results from the fact that cooperation is typically advantageous outside the lab, it has further been shown that the time pressure effect is undermined by prior experience playing lab games (where selfishness is the more advantageous strategy). Furthermore, a recent study found that time pressure increases cooperation even in a game framed as a competition, suggesting that the time pressure effect is not the result of social norm compliance. Here, we successfully replicate these findings, again observing a positive effect of time pressure on cooperation in a competitively framed game, but not when using the standard cooperative framing. These results suggest that participants' intuitions favor cooperation rather than norm compliance, and also that simply changing the framing of the Public Goods Game is enough to make it appear novel to participants and thus to restore the time pressure effect. PMID- 25551387 TI - Ecological changes in Coyotes (Canis latrans) in response to the ice age megafaunal extinctions. AB - Coyotes (Canis latrans) are an important species in human-inhabited areas. They control pests and are the apex predators in many ecosystems. Because of their importance it is imperative to understand how environmental change will affect this species. The end of the Pleistocene Ice Age brought with it many ecological changes for coyotes and here we statistically determine the changes that occurred in coyotes, when these changes occurred, and what the ecological consequences were of these changes. We examined the mandibles of three coyote populations: Pleistocene Rancho La Brean (13-29 Ka), earliest Holocene Rancho La Brean (8-10 Ka), and Recent from North America, using 2D geometric morphometrics to determine the morphological differences among them. Our results show that these three populations were morphologically distinct. The Pleistocene coyotes had an overall robust mandible with an increased shearing arcade and a decreased grinding arcade, adapted for carnivory and killing larger prey; whereas the modern populations show a gracile morphology with a tendency toward omnivory or grinding. The earliest Holocene populations are intermediate in morphology and smallest in size. These findings indicate that a niche shift occurred in coyotes at the Pleistocene/Holocene boundary - from a hunter of large prey to a small prey/more omnivorous animal. Species interactions between Canis were the most likely cause of this transition. This study shows that the Pleistocene extinction event affected species that did not go extinct as well as those that did. PMID- 25551388 TI - Assessment of genetic diversity of sweet potato in Puerto Rico. AB - Sweet potato (Ipomoea batatas L.) is the seventh most important food crop due to its distinct advantages, such as adaptability to different environmental conditions and high nutritional value. Assessing the genetic diversity of this important crop is necessary due to the constant increase of demand for food and the need for conservation of agricultural and genetic resources. In Puerto Rico (PR), the genetic diversity of sweet potato has been poorly understood, although it has been part of the diet since Pre-Columbus time. Thus, 137 landraces from different localities around PR were collected and subjected to a genetic diversity analysis using 23 SSR-markers. In addition, 8 accessions from a collection grown in Gurabo, PR at the Agricultural Experimental Station (GAES), 10 US commercial cultivars and 12 Puerto Rican accessions from the USDA repository collection were included in this assessment. The results of the analysis of the 23 loci showed 255 alleles in the 167 samples. Observed heterozygosity was high across populations (0.71) while measurements of total heterozygosity revealed a large genetic diversity throughout the population and within populations. UPGMA clustering method revealed two main clusters. Cluster 1 contained 12 PR accessions from the USDA repository collection, while cluster 2 consisted of PR landraces, US commercial cultivars and the PR accessions from GAES. Population structure analysis grouped PR landraces in five groups including four US commercial cultivars. Our study shows the presence of a high level of genetic diversity of sweet potato across PR which can be related to the genetic makeup of sweet potato, human intervention and out-crossing nature of the plant. The history of domestication and dispersal of sweet potato in the Caribbean and the high levels of genetic diversity found through this study makes sweet potato an invaluable resource that needs to be protected and further studied. PMID- 25551389 TI - Poor clinical outcomes among pneumonia patients with depressive disorder. AB - BACKGROUND: Some studies suggested that psychological stress may be associated with the severity and duration of infectious diseases. In this population-based study, we investigated associations between depressive disorder (DD) and pneumonia outcomes in Taiwan with a large-scale database from the National Health Insurance. METHODS: Our study defined 112,198 patients who were hospitalized with a principal diagnosis of pneumonia. We defined their admission date for treatment of pneumonia as the index date. Subsequently, we selected 2,394 patients with DD within 3 years prior to their index date and 11,970 matched patients without DD. We carried out separate conditional logistic regressions to explore the association of clinical pneumonia treatment outcome (ICU admission, use of mechanical ventilation, acute respiratory failure and in-hospital death) with previously diagnosed DD. RESULTS: Patients with DD had a significantly higher probability of an intensive care unit admission (18.1% vs. 12.9%; p<0.001), need for mechanical ventilation (21.9% vs. 18.1%; p<0.001) and in-hospital death (10.4% vs. 9.0%; p = 0.025) than patients without DD. The study showed that pneumonia patients with DD were respectively 1.41- (95% CI: 1.25~1.59, p<0.001), 1.28- (95% CI: 1.14~1.43, p<0.001), and 1.17- times (95% CI: 1.01~1.36, p = 0.039) greater odds of being admitted to the ICU, need for mechanical ventilation, and in-hospital death than patients without DD after adjusting for monthly income, urbanization level, geographic region and Charlson Comorbidity Index score. CONCLUSIONS: In conclusion, we found that pneumonia patients with DD were associated with poor treatment outcomes compared to patients without DD. PMID- 25551390 TI - Impairment of myocardial mitochondria in viral myocardial disease and its reflective window in peripheral cells. AB - BACKGROUND: Viral myocardial disease (VMD) is a common disease inducing heart failure. It has not been clear the roles of mitochondrial damage in the pathological changes of cardiomyocytes in VMD. METHODS: Myocardial tissues and lymphocytes were collected from 83 VMD patients. Control groups included 12 cases of healthy accidental death with myocardial autopsy and 23 healthy blood donors. The mouse model of viral myocarditis (VMC) was established by Coxsackie virus B3 infection and myocardial tissues and skeletal muscle were collected. Mitochondrial DNA (mtDNA) deletion rate was quantitatively determined using polymerase chain reaction. RESULTS: There was significantly difference of myocardial mitochondrial DNA deletion rate between VMD or VMC group and control group (P<0.05). Moreover, the loss of mitochondrial membrane phospholipids was significantly different between VMD or VMC group and control group. In VMC mice, there were negative correlations between myocardial mtDNA3867 deletion rate and left ventricular peak systolic pressure (LVPSP) (r = -0.66, P<0.05), and between myocardial mtDNA3867 deletion rate and +dp/dtmax (r = -0.79, P<0.05), while there was positive correlation between myocardial mtDNA3867 deletion rate and -dp/dtmax (r = 0.80, P<0.05). CONCLUSION: Mitochondrial damage is an important pathophysiological mechanism leading to myocardial injury and cardiac dysfunction. The mitochondrial damage in the skeletal muscle and lymphocytes reflect a "window" of myocardial mitochondrial damage. PMID- 25551391 TI - Improving Google Flu Trends estimates for the United States through transformation. AB - Google Flu Trends (GFT) uses Internet search queries in an effort to provide early warning of increases in influenza-like illness (ILI). In the United States, GFT estimates the percentage of physician visits related to ILI (%ILINet) reported by the Centers for Disease Control and Prevention (CDC). However, during the 2012-13 influenza season, GFT overestimated %ILINet by an appreciable amount and estimated the peak in incidence three weeks late. Using data from 2010-14, we investigated the relationship between GFT estimates (%GFT) and %ILINet. Based on the relationship between the relative change in %GFT and the relative change in %ILINet, we transformed %GFT estimates to better correspond with %ILINet values. In 2010-13, our transformed %GFT estimates were within +/- 10% of %ILINet values for 17 of the 29 weeks that %ILINet was above the seasonal baseline value determined by the CDC; in contrast, the original %GFT estimates were within +/- 10% of %ILINet values for only two of these 29 weeks. Relative to the %ILINet peak in 2012-13, the peak in our transformed %GFT estimates was 2% lower and one week later, whereas the peak in the original %GFT estimates was 74% higher and three weeks later. The same transformation improved %GFT estimates using the recalibrated 2013 GFT model in early 2013-14. Our transformed %GFT estimates can be calculated approximately one week before %ILINet values are reported by the CDC and the transformation equation was stable over the time period investigated (2010-13). We anticipate our results will facilitate future use of GFT. PMID- 25551392 TI - The production and perception of emotionally expressive walking sounds: similarities between musical performance and everyday motor activity. AB - Several studies have investigated the encoding and perception of emotional expressivity in music performance. A relevant question concerns how the ability to communicate emotions in music performance is acquired. In accordance with recent theories on the embodiment of emotion, we suggest here that both the expression and recognition of emotion in music might at least in part rely on knowledge about the sounds of expressive body movements. We test this hypothesis by drawing parallels between musical expression of emotions and expression of emotions in sounds associated with a non-musical motor activity: walking. In a combined production-perception design, two experiments were conducted, and expressive acoustical features were compared across modalities. An initial performance experiment tested for similar feature use in walking sounds and music performance, and revealed that strong similarities exist. Features related to sound intensity, tempo and tempo regularity were identified as been used similarly in both domains. Participants in a subsequent perception experiment were able to recognize both non-emotional and emotional properties of the sound generating walkers. An analysis of the acoustical correlates of behavioral data revealed that variations in sound intensity, tempo, and tempo regularity were likely used to recognize expressed emotions. Taken together, these results lend support the motor origin hypothesis for the musical expression of emotions. PMID- 25551395 TI - Frugal fat or munificent muscle: genomic imprinting and metabolism. AB - Variation in body composition is a popular obsession. The culturally 'ideal' body type is light on fat and heavy on muscle but the human population is collectively laying on fat. A new study finds antagonistic effects of two imprinted genes, Grb10 and Dlk1, on body composition in mice. These findings pose the question whether there is an evolutionary conflict between genes of maternal and paternal origin over the optimal proportions of body fat and lean muscle mass. PMID- 25551393 TI - Transcriptome analysis and transient transformation suggest an ancient duplicated MYB transcription factor as a candidate gene for leaf red coloration in peach. AB - BACKGROUND: Leaf red coloration is an important characteristic in many plant species, including cultivars of ornamental peach (Prunus persica). Peach leaf color is controlled by a single Gr gene on linkage group 6, with a red allele dominant over the green allele. Here, we report the identification of a candidate gene of Gr in peach. RESULTS: The red coloration of peach leaves is due to accumulation of anthocyanin pigments, which is regulated at the transcriptional level. Based on transcriptome comparison between red- and green-colored leaves, an MYB transcription regulator PpMYB10.4 in the Gr interval was identified to regulate anthocyanin pigmentation in peach leaf. Transient expression of PpMYB10.4 in tobacco and peach leaves can induce anthocyain accumulation. Moreover, a functional MYB gene PpMYB10.2 on linkage group 3, which is homologous to PpMYB10.4, is also expressed in both red- and green-colored leaves, but plays no role in leaf red coloration. This suggests a complex mechanism underlying anthocyanin accumulation in peach leaf. In addition, PpMYB10.4 and other anthocyanin-activating MYB genes in Rosaceae responsible for anthocyanin accumulation in fruit are dated to a common ancestor about 70 million years ago (MYA). However, PpMYB10.4 has diverged from these anthocyanin-activating MYBs to generate a new gene family, which regulates anthocyanin accumulation in vegetative organs such as leaves. CONCLUSIONS: Activation of an ancient duplicated MYB gene PpMYB10.4 in the Gr interval on LG 6, which represents a novel branch of anthocyanin-activating MYB genes in Rosaceae, is able to activate leaf red coloration in peach. PMID- 25551396 TI - Molecular evidence that only two opsin subfamilies, the blue light- (SWS2) and green light-sensitive (RH2), drive color vision in Atlantic cod (Gadus morhua). AB - Teleosts show a great variety in visual opsin complement, due to both gene duplication and gene loss. The repertoire ranges from one subfamily of visual opsins (scotopic vision) including rod opsin only retinas seen in many deep-sea species to multiple subfamilies of visual opsins in some pelagic species. We have investigated the opsin repertoire of Atlantic cod (Gadus morhua) using information in the recently sequenced cod genome and found that despite cod not being a deep sea species it lacks visual subfamilies sensitive towards the most extreme parts of the light spectra representing UV and red light. Furthermore, we find that Atlantic cod has duplicated paralogs of both blue-sensitive SWS2 and green-sensitive RH2 subfamilies, with members belonging to each subfamily linked in tandem within the genome (two SWS2-, and three RH2A genes, respectively). The presence of multiple cone opsin genes indicates that there have been duplication events in the cod ancestor SWS2 and RH2 opsins producing paralogs that have been retained in Atlantic. Our results are supported by expressional analysis of cone opsins, which further revealed an ontogenetic change in the array of cone opsins expressed. These findings suggest life stage specific programs for opsin regulation which could be linked to habitat changes and available light as the larvae is transformed into an early juvenile. Altogether we provide the first molecular evidence for color vision driven by only two families of cone opsins due to gene loss in a teleost. PMID- 25551397 TI - Influence of genetic variants in TPMT and COMT associated with cisplatin induced hearing loss in patients with cancer: two new cohorts and a meta-analysis reveal significant heterogeneity between cohorts. AB - Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested. PMID- 25551399 TI - Visualizing the molecular recognition trajectory of an intrinsically disordered protein using multinuclear relaxation dispersion NMR. AB - Despite playing important roles throughout biology, molecular recognition mechanisms in intrinsically disordered proteins remain poorly understood. We present a combination of (1)H(N), (13)C', and (15)N relaxation dispersion NMR, measured at multiple titration points, to map the interaction between the disordered domain of Sendai virus nucleoprotein (NT) and the C-terminal domain of the phosphoprotein (PX). Interaction with PX funnels the free-state equilibrium of NT by stabilizing one of the previously identified helical substates present in the prerecognition ensemble in a nonspecific and dynamic encounter complex on the surface of PX. This helix then locates into the binding site at a rate coincident with intrinsic breathing motions of the helical groove on the surface of PX. The binding kinetics of complex formation are thus regulated by the intrinsic free-state conformational dynamics of both proteins. This approach, providing high-resolution structural and kinetic information about a complex folding and binding interaction trajectory, can be applied to a number of experimental systems to provide a general framework for understanding conformational disorder in biomolecular function. PMID- 25551398 TI - Etomidate and Ketamine: Residual Motor and Adrenal Dysfunction that Persist beyond Recovery from Loss of Righting Reflex in Rats. AB - We tested the hypothesis that etomidate and ketamine produce residual effects that modify functional mobility (measured by the balance beam test) and adrenal function (adrenocorticotropic hormone (ACTH) stimulation) immediately following recovery from loss of righting reflex in rats. Intravenous etomidate or ketamine was administered in a randomized, crossover fashion (2 or 4 mg/kg and 20 or 40 mg/kg, respectively) on eight consecutive days. Following recovery of righting reflex, animals were assessed for residual effects on functional mobility on the balance beam, motor behavior in the open field and adrenal function through ACTH stimulation. We evaluated the consequences of the effects of the anesthetic agent induced motor behavior on functional mobility. On the balance beam, etomidate treated rats maintained their grip longer than ketamine-treated rats, indicating greater balance abilities (mean +/- SD, 21.5 +/- 25.1 s vs. 3.0 +/- 4.3 s respectively, p < 0.021). In the open field test, both dosages of etomidate and ketamine had opposite effects on travel behavior, showing ketamine-induced hyperlocomotion and etomidate-induced hypolocomotion. There was a significant interaction between anesthetic agent and motor behavior effects for functional mobility effects (p < 0.001). Corticosterone levels were lower after both 40 mg/kg ketamine and 4 mg/kg etomidate anesthesia compared to placebo, an effect stronger with etomidate than ketamine (p < 0.001). Following recovery from anesthesia, etomidate and ketamine have substantial side effects. Ketamine induced hyperlocomotion with 20 and 40 mg/kg has stronger effects on functional mobility than etomidate-induced hypolocomotion with 2 and 4 mg/kg. Etomidate (4 mg/kg) has stronger adrenal suppression effects than ketamine (40 mg/kg). PMID- 25551400 TI - Calcifying species sensitivity distributions for ocean acidification. AB - Increasing CO2 atmospheric levels lead to increasing ocean acidification, thereby enhancing calcium carbonate dissolution of calcifying species. We gathered peer reviewed experimental data on the effects of acidified seawater on calcifying species growth, reproduction, and survival. The data were used to derive species specific median effective concentrations, i.e., pH50, and pH10, via logistic regression. Subsequently, we developed species sensitivity distributions (SSDs) to assess the potentially affected fraction (PAF) of species exposed to pH declines. Effects on species growth were observed at higher pH than those on species reproduction (mean pH10 was 7.73 vs 7.63 and mean pH50 was 7.28 vs 7.11 for the two life processes, respectively) and the variability in the sensitivity of species increased with increasing number of species available for the PAF (pH10 standard deviation was 0.20, 0.21, and 0.33 for survival, reproduction, and growth, respectively). The SSDs were then applied to two climate change scenarios to estimate the increase in PAF (DeltaPAF) by future ocean acidification. In a high CO2 emission scenario, DeltaPAF was 3 to 10% (for pH50) and 21 to 32% (for pH10). In a low emission scenario, DeltaPAF was 1 to 4% (for pH50) and 7 to 12% (for pH10). Our SSDs developed for the effect of decreasing ocean pH on calcifying marine species assemblages can also be used for comparison with other environmental stressors. PMID- 25551401 TI - Is There a Gradient of Mortality Risk among Men with Low Cardiorespiratory Fitness? AB - PURPOSE: A low level of cardiorespiratory fitness (CRF) is a strong and independent predictor of all-cause mortality in men; however, it is unknown whether a gradient of mortality risk exists within the lowest CRF category. METHODS: A total of 6251 apparently healthy men (mean age, 48.7 +/- 6.3 yr) completed a comprehensive baseline clinical examination, including a maximal treadmill exercise test at Cooper Clinic between 1971 and 2006. In accord with previous studies using this cohort, low CRF was defined as a treadmill time in the first quintile within each age category of 40-49, 50-59, and 60-69 yr. The low CRF cohort was then grouped by tertiles (low/low, LL; mid/low, ML; and high/low, HL) using the same age categories. RESULTS: After a mean follow-up period of 19.1 +/- 10.4 yr, 1259 deaths occurred. Adjusted all-cause mortality rates were 57.0, 31.1, and 34.4 deaths per 10,000 man-years across LL, ML, and HL CRF categories for the 40- to 49-yr-old age group (P trend = 0.007). Similar trends were seen across low CRF categories for the 50- to 59-yr-old and 60- to 69 yr-old age groups (P trend = 0.02 and 0.09, respectively). When using treadmill time as a continuous variable, each 1-min increment in treadmill time was associated with a 9%, 11%, and 15% reduction in risk of all-cause mortality among low-CRF men in the 40-49, 50-59, and 60-69 age groups, respectively. CONCLUSIONS: An inverse trend in all-cause mortality exists among men across LL, ML, and HL CRF groups. Although all low-fit men should be targeted for physical activity intervention, it is especially important to target the LL CRF group. PMID- 25551402 TI - Muscle Activity during Walking Measured Using 3D MRI Segmentations and [18F] Fluorodeoxyglucose in Combination with Positron Emission Tomography. AB - PURPOSE: This study aimed to determine the contribution of each muscle of the lower limb to walking using positron emission tomography (PET) with [F] fluorodeoxyglucose (FDG). Furthermore, we compared our results obtained using volumetric analysis of entire muscles with those obtained using a more traditional approach considering the uptake in only one slice in each segment. METHODS: Ten healthy subjects walked on a treadmill at self-selected comfortable walking speed for 90 min, 60 min before and 30 min after intravenous injection of 50-MBq FDG. A PET/computerized tomography scan of the lower limb was made subsequently. The three-dimensional contours of 39 muscles in the left lower limb were semiautomatically determined from magnetic resonance imaging scans. After nonrigidly registering the magnetic resonance imaging to the computerized tomography scans, we superimposed the muscle contours on the PET scans. RESULTS: The muscles with the highest median FDG uptake among all subjects were the soleus, gluteus maximus, vastus lateralis, gastrocnemius medialis, and adductor magnus. We found a wide range of FDG uptake values among subjects, including in some of the most important muscles involved in walking (e.g., soleus, gluteus medius, gastrocnemius medialis). Compared with the volumetric analysis, the single slice analysis did not yield an accurate estimate of the FDG uptake in many of the most active muscles, including the gluteus medius and minimus (overestimated) as well as all the thigh muscles (underestimated). CONCLUSIONS: The distribution of FDG among the muscles varied between subjects, suggesting that each subject had a unique activation pattern. The FDG uptake as estimated from single slices did not correspond well to the uptake obtained from volumetric analysis, which illustrates the added value of our novel three-dimensional image analysis techniques. PMID- 25551403 TI - Aerobic Function and Muscle Deoxygenation Dynamics during Ramp Exercise in Children. AB - PURPOSE: This study aimed to characterize changes in deoxyhemoglobin ([HHb]) response dynamics in boys and girls during ramp incremental exercise to investigate whether the reduced peak oxygen uptake (peak VO2) in girls is associated with poorer matching of muscle O2 delivery to muscle O2 utilization, as evidenced by a more rapid increase in [HHb]. METHODS: Fifty-two children (31 boys, 9.9 +/- 0.6 yr, 1.38 +/- 0.07 m, 31.70 +/- 5.78 kg) completed ramp incremental exercise on a cycle ergometer during which pulmonary gas exchange and muscle oxygenation parameters were measured. RESULTS: When muscle [HHb] was expressed against absolute work rate and VO2, girls had an earlier change in [HHb], as evidenced by the lower c/d parameter (girls, 54 +/- 20 W, vs boys, 67 +/- 19 W, P = 0.023; girls, 0.82 +/- 0.28 L.min(-1), vs boys, 0.95 +/- 0.19 L.min(-1), P = 0.055) and plateau (girls, 85 +/- 12 W, vs boys, 99 +/- 18 W, P = 0.031; girls, 1.02 +/- 0.25 L.min(-1), vs boys, 1.22 +/- 0.28 L.min(-1), P = 0.014). However, when expressed against relative work rate or VO2, there were no sex differences in ([HHb]) response dynamics (all P > 0.20). Significant correlations were observed between absolute and fat-free mass normalized peak VO2 and the HHb c/d and plateau parameters when expressed against absolute work rate or VO2. Furthermore, when entered into a multiple regression model, the [HHb] plateau against absolute VO2 contributed 12% of the variance in peak VO2 after adjusting for fat-free mass, gas exchange threshold, and body fatness (model R2 = 0.81, P < 0.001). CONCLUSIONS: The sex difference in peak VO2 in 9- to 10-yr-old children is, in part, related to sex-specific changes in muscle O2 extraction dynamics during incremental exercise. PMID- 25551404 TI - Sodium Supplementation and Exercise-Associated Hyponatremia during Prolonged Exercise. AB - PURPOSE: This work examines whether sodium supplementation is important in prevention of hyponatremia during continuous exercise up to 30 h and whether any distinguishing characteristics of those developing hyponatremia could be identified. METHODS: Participants of the 161-km Western States Endurance Run underwent body weight measurements before, during, and after the race, completed a postrace questionnaire about drinking strategies and use of sodium supplementation during four race segments, and underwent analysis of postrace serum sodium concentration. RESULTS: The postrace questionnaire was completed by 74.5% of the 376 starters, a postrace blood sample was provided by 61.1% of the 296 finishers, and 53.0% of finishers completed the postrace survey and also provided a postrace blood sample. Among this population, the incidence of hyponatremia among finishers was 6.6% and sodium supplements were used by 93.9% of the runners. Postrace serum sodium concentration was found to be directly related to the rate of sodium intake in supplements (r = 0.24, P = 0.0027) and indirectly related to the percentage change in body weight from immediately before the race start (r = -0.19, P = 0.010). There was no difference in rate of sodium intake in supplements between the hyponatremic and normonatremic finishers, and none of the hyponatremic finishers lost >4.3% body weight. Hyponatremic finishers were not distinguished from normonatremic or hypernatremic finishers by other runner characteristics considered, drinking strategies, or gastrointestinal symptoms of nausea and vomiting. CONCLUSIONS: We conclude that a low sodium intake in supplements has minimal responsibility for development of hyponatremia during continuous exercise up to 30 h, whereas overhydration is the primary characteristic of those developing hyponatremia. Therefore, avoiding overhydration seems to be the most important means for preventing hyponatremia under these conditions. PMID- 25551405 TI - Anodal Transcranial Direct Current Stimulation Prolongs the Cross-education of Strength and Corticomotor Plasticity. AB - PURPOSE: This study aimed to assess the efficacy of applying anodal transcranial direct-current stimulation (a-tDCS) to the ipsilateral motor cortex (iM1) during unilateral strength training to enhance the neurophysiological and functional effects of cross-education. METHODS: Twenty-four healthy volunteers were randomly allocated to perform either of the following: strength training during a-tDCS (ST + a-tDCS), strength training during sham tDCS (ST + sham), or a-tDCS during rest (a-tDCS) across 2 wk. Strength training of the right biceps brachii involved four sets of six repetitions at 80% of one-repetition maximum three times per week. Anodal tDCS was applied to the iM1 at 1.5 mA for 15 min during each strength training session. Outcome measures included one-repetition maximum strength of the untrained biceps brachii, corticomotoneuronal excitability, cross-activation, and short-interval intracortical inhibition (SICI) of the iM1 determined by transcranial magnetic stimulation. RESULTS: Immediately after the final training session, there was an increase in strength for both the ST + a-tDCS (12.5%, P < 0.001) and the ST + sham group (9.4%, P = 0.007), which was accompanied by significant increases in corticomotoneuronal excitability and decreases in SICI for both groups. After a 48-h retention period, strength increase was maintained in the ST + a-tDCS (13.0%, P = 0.001) group, which was significantly greater than the ST + sham group (7.6%, P = 0.039). Similarly, increases in corticomotoneuronal excitability and decreases in SICI were maintained in the ST + a-tDCS group but not in the ST + sham group. No main effects were reported for the a-tDCS group (all P > 0.05). CONCLUSIONS: The addition of a-tDCS to the iM1 during unilateral strength training prolongs the benefits of cross-education, which may have significant implications to enhancement of rehabilitation outcomes after a single-limb injury or impairment. PMID- 25551406 TI - Therapeutic Drug Monitoring of Belatacept in Kidney Transplantation. AB - Belatacept is a novel immunosuppressive drug that inhibits the co-stimulatory signal required for T-cell activation and has been approved for the prevention of acute rejection after kidney transplantation. In this article, the need for and possibility of therapeutic drug monitoring (TDM) of belatacept is reviewed. Clinical studies have defined the upper limit of the therapeutic window, but the lower limit is unknown. The pharmacokinetics and pharmacodynamics of belatacept display only limited interpatient variability but no data are available on the intrapatient variability of these parameters. Several assays to measure serum belatacept concentrations and its in vitro immunologic effects have been developed, but these are not commercially available and require validation. Importantly, pharmacodynamic assays have not been correlated with clinical outcomes (both efficacy and safety) and have only used surrogate laboratory readouts. TDM is likely to become feasible in the near future if these assays are developed further. However, because its pharmacokinetics and pharmacodynamics seem to vary little between individual patients, it may not be necessary to perform TDM for this drug. There could be a role for such an approach if one seeks to lower the belatacept doses further in an attempt to minimize adverse events. A future, prospective concentration-ranging study that defines the lower end of the belatacept therapeutic window should, however, be conducted first to provide the rationale for performing TDM of this novel immunosuppressant. PMID- 25551407 TI - An Automated Homogeneous Immunoassay for Quantitating Imatinib Concentrations in Plasma. AB - BACKGROUND: Imatinib pharmacokinetic variability and the relationship of trough concentrations with clinical outcomes have been extensively reported. Although physical methods to quantitate imatinib exist, they are not widely available for routine use. An automated homogenous immunoassay for imatinib has been developed, facilitating routine imatinib testing. METHODS: Imatinib-selective monoclonal antibodies, without substantial cross-reactivity to the N-desmethyl metabolite or N-desmethyl conjugates, were produced. The antibodies were conjugated to 200 nm particles to develop immunoassay reagents on the Beckman Coulter AU480 analyzer. These reagents were analytically validated using Clinical Laboratory Standards Institute protocols. Method comparison to liquid chromatography tandem mass spectrometry (LC-MS/MS) was conducted using 77 plasma samples collected from subjects receiving imatinib. RESULTS: The assay requires 4 uL of sample without pretreatment. The nonlinear calibration curve ranges from 0 to 3000 ng/mL. With automated sample dilution, concentrations of up to 9000 ng/mL can be quantitated. The AU480 produces the first result in 10 minutes and up to 400 tests per hour. Repeatability ranged from 2.0% to 6.0% coefficient of variation, and within laboratory reproducibility ranged from 2.9% to 7.4% coefficient of variation. Standard curve stability was 2 weeks and on-board reagent stability was 6 weeks. For clinical samples with imatinib concentrations from 438 to 2691 ng/mL, method comparison with LC-MS/MS gave a slope of 0.995 with a y-intercept of 24.3 and a correlation coefficient of 0.978. CONCLUSIONS: The immunoassay is suitable for quantitating imatinib in human plasma, demonstrating good correlation with a physical method. Testing for optimal imatinib exposure can now be performed on routine clinical analyzers. PMID- 25551408 TI - Associations of Leg Length, Trunk Length, and Total Adult Height With Meniere's: Cross-Sectional Analysis in the UK Biobank. AB - OBJECTIVES: To investigate whether adverse intrauterine and/or childhood exposures, using established anthropometric measures (e.g., components of adult height, including total height, leg length, and trunk length) as a proxy for childhood exposures, are associated with self-reported Meniere's disease. DESIGN: Cross-sectional data from the UK Biobank were used to compare 1,327 self-reported Meniere's cases with 479,500 controls. The authors used logistic regression models to investigate the relation of Meniere's disease with the components of adult height. Models were adjusted for a range of potential confounders including age, sex, body mass index, ethnicity, type 2 diabetes, coronary heart disease, and socioeconomic status. RESULTS: In the UK Biobank, Meniere's was inversely associated with overall stature (odds ratio [OR] per standard deviation increase in height, 0.87; 95% confidence interval [CI], 0.80-0.94) and leg length (OR, 0.88; 95% CI, 0.82-0.94) in fully adjusted models. No association was noted in adjusted models with trunk length (OR, 0.94; 95% CI, 0.88-1.01). CONCLUSIONS: The specific association between leg length, a potential marker of adverse childhood environments, and Meniere's may suggest that early-life environmental exposures that influence skeletal growth may also influence the risk of developing Meniere's in later life. PMID- 25551409 TI - Examining the impact of cochlear implantation on the early gross motor development of children with a hearing loss. AB - OBJECTIVE: As deaf children are now implanted at a very early age, the influence of a cochlear implant (CI) on the early motor development of children with a hearing loss becomes relevant. DESIGN: Forty-eight children with a hearing loss were included in this controlled prospective follow-up study and were subdivided into a CI group (n = 23) receiving a CI during the follow-up period and a control group (n = 25) receiving no CI during the follow-up period. All children were assessed around the ages of 6 (T1), 12 (T2), 18 (T3), and 24 (T4) months with a motor test battery consisting of the Peabody Developmental Motor Scales-2 (PDMS 2), Alberta Infant Motor Scales (AIMS) (only at T1 and T2), and Ghent Developmental Balance Test (GDBT) (only at T3 and T4). In addition, collic vestibular-evoked myogenic potential testing was performed in all children. Group differences in PDMS-2 Gross Motor Quotient (GMQ), Fine Motor Quotient, AIMS z score, and GDBT z score were analyzed using Linear Mixed Model (LMM) analysis for repeated measures. RESULTS: For PDMS-2 GMQ, the LMM revealed significant effects for group (p = 0.04), test moment (p < 0.001), and for the interaction between these two factors (p = 0.035). Contrasts indicated that the CI group showed a greater deterioration in PDMS-2 GMQ between T2 and T3 compared with that showed by the control group (p = 0.002). The LMM for PDMS-2 Fine Motor Quotient and AIMS z score showed no significant effects. For GDBT z score, the LMM pointed out significant effects for group (p = 0.013) and test moment (p < 0.001), but no significant interaction between these two factors. Contrasts indicated that the CI group performed significantly weaker than the control group at both test moments (T3 and T4; all p < 0.012) and that both groups showed a significant recovery in GDBTz scores between T3 and T4 (all p < 0.012). CONCLUSIONS: This study shows that the trajectory of gross motor development can be changed in children with a hearing loss after a cochlear implantation. Implanted children show a drop in their gross motor performance within the age range of 6 to 18 months, at which period the majority of the implantations took place, with a tendency of recovery toward the age of 2 years. However, longer follow-up will be necessary to trace whether the implanted children catch up their motor delay in comparison with nonimplanted children with a hearing loss at later age. PMID- 25551410 TI - Deterioration of Speech Recognition Ability Over a Period of 5 Years in Adults Ages 18 to 70 Years: Results of the Dutch Online Speech-in-Noise Test. AB - OBJECTIVES: The first aim of the present study was to determine the change in speech recognition in noise over a period of 5 years in participants ages 18 to 70 years at baseline. The second aim was to investigate whether age, gender, educational level, the level of initial speech recognition in noise, and reported chronic conditions were associated with a change in speech recognition in noise. DESIGN: The baseline and 5-year follow-up data of 427 participants with and without hearing impairment participating in the National Longitudinal Study on Hearing (NL-SH) were analyzed. The ability to recognize speech in noise was measured twice with the online National Hearing Test, a digit-triplet speech-in noise test. Speech-reception-threshold in noise (SRTn) scores were calculated, corresponding to 50% speech intelligibility. Unaided SRTn scores obtained with the same transducer (headphones or loudspeakers) at both test moments were included. Changes in SRTn were calculated as a raw shift (T1 - T0) and an adjusted shift for regression towards the mean. Paired t tests and multivariable linear regression analyses were applied. RESULTS: The mean increase (i.e., deterioration) in SRTn was 0.38-dB signal-to-noise ratio (SNR) over 5 years (p < 0.001). Results of the multivariable regression analyses showed that the age group of 50 to 59 years had a significantly larger deterioration in SRTn compared with the age group of 18 to 39 years (raw shift: beta: 0.64-dB SNR; 95% confidence interval: 0.07-1.22; p = 0.028, adjusted for initial speech recognition level - adjusted shift: beta: 0.82-dB SNR; 95% confidence interval: 0.27-1.34; p = 0.004). Gender, educational level, and the number of chronic conditions were not associated with a change in SRTn over time. No significant differences in increase of SRTn were found between the initial levels of speech recognition (i.e., good, insufficient, or poor) when taking into account the phenomenon regression towards the mean. CONCLUSIONS: The study results indicate that hearing deterioration of speech recognition in noise over 5 years can also be detected in adults ages 18 to 70 years. This rather small numeric change might represent a relevant impact on an individual's ability to understand speech in everyday life. PMID- 25551411 TI - Nasal nitric oxide in patients with inherited retinal dystrophies. AB - BACKGROUND: Ciliopathies refer to a wide variety of diseases in which mutations in the genes encoding proteins involved in ciliogenesis or protein transport to the primary cilia play pathogenetic roles, and in such diseases, retinal involvement may be present. Nitric oxide (NO) plays an important role in airway physiology, including regulation of ciliary motility and host defense. In primary ciliary dyskinesia, a syndromic ciliopathy, nasal NO (nNO) levels were reported to be extremely low compared with controls, possibly reflecting molecular defects leading to structural and functional ciliary abnormalities. We investigated whether decreased nitric levels were also present in patients with retinal inherited dystrophies. METHODS: Nasal NO was measured in a group of patients with syndromic and nonsyndromic inherited retinal dystrophies. RESULTS: Patients with inherited retinal dystrophies, both syndromic and nonsyndromic, had mean nNO levels that were lower than healthy controls. Seven patients had particularly low levels of nNO: 3 patients with retinitis pigmentosa and 4 individual patients with Mainzer-Saldino syndrome, Bardet-Biedl syndrome, Usher syndrome, and cone rod disease. CONCLUSIONS: These findings provide evidence that there is an underlying abnormal ciliary function involving the nasal epithelium in some patients with inherited retinal dystrophies. PMID- 25551414 TI - Ruthenium-catalyzed alkene-alkyne coupling of disubstituted olefins: application to the stereoselective synthesis of trisubstituted enecarbamates. AB - The Ru-catalyzed alkene-alkyne coupling reaction has been demonstrated to be an enabling methodology for the synthesis of complex molecules. However, to date, it has been limited to monosubstituted olefins. Herein we report the first general utilization of disubstituted olefins in the Ru-catalyzed alkene-alkyne coupling reaction by employing carbamate directing groups. The products are stereodefined trisusbstituted enecarbamates. The elaboration of these structures toward the asymmetric synthesis of complex aminocyclopentitols and 1,2-amino alcohols is discussed. PMID- 25551412 TI - Characteristics of dynamic magnetic resonance image enhancement in prolactinomas resistant to dopamine agonist therapy. AB - OBJECTIVE: The objective of this study was to determine whether dynamic magnetic resonance imaging (dMRI) enhancement parameters could predict dopamine agonist (DA) resistance in prolactinomas. METHODS: We retrospectively identified patients with prolactinomas who were treated with DA and underwent dMRI from 2001 through 2012 at Mayo Clinic (Rochester, MN). Intensities of the adenoma and pituitary gland were measured by drawing regions of interest on the images. Enhancement ratio, enhancement peak, prepeak slope (PPS), and enhancement time were compared between DA-resistant and DA-responsive groups, between DA-treated and DA-naive groups, and between the first and follow-up dMRIs. RESULTS: We identified 49 patients with prolactinomas, with 6 (12.2%) showing DA resistance. Thirty-seven patients (75.5%) underwent dMRI while receiving treatment, 12 (25.5%) underwent dMRI before starting therapy, and 10 (20.4%) had follow-up dMRI after DA therapy. The PPS of the tumor was higher in the treatment-resistant group versus the responsive group (mean [SD], 4.42 [3.19] vs 2.65 [1.59]; P = 0.03), whereas no difference was noted in the pituitary gland (5.79 [2.21] vs 4.06 [2.48]; P = 0.11). Logistic regression analysis indicated that tumor PPS was associated with DA resistance (odds ratio, 1.71; 95% confidence interval, 1.07-3.27; P = 0.02). CONCLUSIONS: Dynamic MRI with PPS analysis potentially can be used early in the treatment course to evaluate DA resistance in pituitary prolactinomas. PMID- 25551415 TI - Outcomes of patients with right ventricular failure on milrinone after left ventricular assist device implantation. AB - Previous studies have grouped together both patients requiring right ventricular assist devices (RVADs) with patients requiring prolonged milrinone therapy after left ventricular assist device (LVAD) implantation. We retrospectively identified 149 patients receiving LVADs and 18 (12.1%) of which developed right ventricular (RV) failure. We then separated these patients into those requiring RVADs versus prolonged milrinone therapy. This included 10 patients who were treated with prolonged milrinone and eight patients who underwent RVAD placement. Overall, the RV failure group had worse survival compared with the non-RV failure cohort (p = 0.038). However, this was only for the subgroup of patients who required RVADs, who had a 1, 6, 12, and 24 month survival of 62.5%, 37.5%, 37.5%, and 37.5%, respectively, versus 96.8%, 92.1%, 86.7%, and 84.4% for patients without RV failure (p < 0.001). Patients treated with prolonged milrinone therapy for RV failure had similar survivals compared with patients without RV failure. In the RV failure group, age, preoperative renal failure, and previous cardiac surgery were predictors of the need for prolonged postoperative milrinone. As LVADs become a more widely used therapy for patients with refractory, end-stage heart failure, it will be important to reduce the incidence of RV failure, as it yields significant morbidity and increases cost. PMID- 25551417 TI - Exposure of the hidden anti-ferromagnetism in paramagnetic CdSe:Mn nanocrystals. AB - We present theoretical and experimental investigations of the magnetism of paramagnetic semiconductor CdSe:Mn nanocrystals and propose an efficient approach to the exposure and analysis of the underlying anti-ferromagnetic interactions between magnetic ions therein. A key advance made here is the development of an analysis method with the exploitation of group theory technique that allows us to distinguish the anti-ferromagnetic interactions between aggregative Mn(2+) ions from the overall pronounced paramagnetism of magnetic-ion-doped semiconductor nanocrystals. By using the method, we clearly reveal and identify the signatures of anti-ferromagnetism from the measured temperature-dependent magnetisms and furthermore determine the average number of Mn(2+) ions and the fraction of aggregative ones in the measured CdSe:Mn nanocrystals. PMID- 25551416 TI - Physiological characterization of the SynCardia total artificial heart in a mock circulation system. AB - The SynCardia total artificial heart (TAH) has emerged as an effective, life saving biventricular replacement system for a wide variety of patients with end stage heart failure. Although the clinical performance of the TAH is established, modern physiological characterization, in terms of elastance behavior and pressure-volume (PV) characterization has not been defined. Herein, we examine the TAH in terms of elastance using a nonejecting left ventricle, and then characterize the PV relation of the TAH by varying preload and afterload parameters using a Donovan Mock Circulatory System. We demonstrate that the TAH does not operate with time-varying elastance, differing from the human heart. Furthermore, we show that the TAH has a PV relation behavior that also differs from that of the human heart. The TAH does exhibit Starling-like behavior, with output increasing via preload-dependent mechanisms, without reliance on an alteration of inotropic state within the operating window of the TAH. Within our testing range, the TAH is insensitive to variations in afterload; however, this insensitivity has a limit, the limit being the maximum driving pressure of the pneumatic driver. Understanding the physiology of the TAH affords insight into the functional parameters that govern artificial heart behavior providing perspective on differences compared with the human heart. PMID- 25551418 TI - Preparation of conformationally restricted beta(2,2)- and beta(2,2,3)-amino esters and derivatives containing an all-carbon quaternary center. AB - beta-Amino acids are routinely incorporated into peptidic drugs to increase their stability and to incur conformational biases. However, the synthesis of highly substituted beta-amino acids still represents a great challenge. A new approach to their preparation is reported involving a Vilsmeier-Haack reaction with nonaromatic carbon nucleophiles. The highly challenging preparation of contiguous tertiary and all-carbon quaternary centers was successfully used to generate several beta(2,2,3)-amino esters, such as derivatives of homoproline, homoalanine, and homopipecolinic esters. PMID- 25551419 TI - Measurements of the absorption cross section of (13)CHO(13)CHO at visible wavelengths and application to DOAS retrievals. AB - The trace gas glyoxal (CHOCHO) forms from the atmospheric oxidation of hydrocarbons and is a precursor to secondary organic aerosol. We have measured the absorption cross section of disubstituted (13)CHO(13)CHO ((13)C glyoxal) at moderately high (1 cm(-1)) optical resolution between 21 280 and 23 260 cm(-1) (430-470 nm). The isotopic shifts in the position of absorption features were found to be largest near 455 nm (Deltanu = 14 cm(-1); Deltalambda = 0.29 nm), whereas no significant shifts were observed near 440 nm (Deltanu < 0.5 cm(-1); Deltalambda < 0.01 nm). These shifts are used to investigate the selective detection of (12)C glyoxal (natural isotope abundance) and (13)C glyoxal by in situ cavity enhanced differential optical absorption spectroscopy (CE-DOAS) in a series of sensitivity tests using synthetic spectra, and laboratory measurements of mixtures containing (12)C and (13)C glyoxal, nitrogen dioxide, and other interfering absorbers. We find the changes in apparent spectral band shapes remain significant at the moderately high optical resolution typical of CE-DOAS (0.55 nm fwhm). CE-DOAS allows for the selective online detection of both isotopes with detection limits of ~200 pptv (1 pptv = 10(-12) volume mixing ratio), and sensitivity toward total glyoxal of few pptv. The (13)C absorption cross section is available for download from the Supporting Information. PMID- 25551420 TI - Cloning, soluble expression, and purification of the RNA polymerase II subunit RPB5 from Saccharomyces cerevisiae. AB - We report the molecular cloning, expression, and single-step homogeneous purification of RNA polymerase II subunit RPB5 from Saccharomyces cerevisiae. RPB5 is a 210 amino acid nuclear protein that functions as the fifth largest subunit of polymerase II and plays a central role in transcription. The gene that codes for RPB5 was generated by amplification by polymerase chain reaction. It was then inserted in the expression vector pET28a(+) under the transcriptional control of the bacteriophage T7 promoter and lac operator. BL21(DE3) Escherichia coli strain transformed with the rpb5 expression vector pET28a(+)-rpb5 accumulates large amounts of a soluble protein of about 30 kDa (25 kDa plus 5 kDa double His6-Tag at N and C-terminal). The protein was purified to homogeneity using immobilized metal affinity chromatography. RPB5 recombinant protein was further confirmed by immunoblotting with anti-His antibody. In this study, the expression and purification procedures have provided a simple and efficient method to obtain pure RPB5 in large quantities. This will provide an opportunity to study the role of S. cerevisiae RPB5 in gene expression and transcription regulation. Furthermore, it can provide additional knowledge of the interaction partners of RPB5 during various steps of transcription and gene expression. PMID- 25551421 TI - Always with me: understanding experiences of bereaved children whose baby sibling died. AB - An arts-based qualitative method was used to explore the experiences of children's bereavement after a baby sibling's death, in the context of their family and school life. Data were collected during in-depth interviews with 9 bereaved children and 5 parents from 4 Canadian families and analyzed. A central process, evolving sibling relationship over the years, and a pattern of vulnerability/resilience, ran through all four themes, which reflected ideas of connection, impact of parental grief, disenfranchisement and growth. Findings indicated that home and school are critical to children in creating safe spaces for expressing the evolving nature of infant sibling bereavement. PMID- 25551422 TI - Survival of Brucella abortus aqpX mutant in fresh and ripened cheeses. AB - The objective of this work was to evaluate the survival of a Brucella abortus aqpX mutant during the elaboration and conservation of fresh and ripened cheeses at 4 degrees C and 24 degrees C. The pH values and water activity were monitored for each type of cheese. The fresh cheese was elaborated with raw milk inoculated with 6*108 colony-forming units (CFU)/mL each of parental and mutant strain. Ripening cheeses were elaborated with both raw and pasteurized milk and inoculated with 12*108 CFU/mL each of parental and mutant strains. In fresh cheese, survival was observed during elaboration and conservation for 7 days at 4 degrees C in mutant and parental strains. The number of survivors of the mutant strain was 10 times lower compared with the parental strain at pH 5 and a(w) of 0.930. In the cheese elaborated with raw milk and ripened at 24 degrees C, both strains survived until day 17 at pH 4.0 and a(w) of 0.89. However, when the cheese was elaborated with pasteurized milk, the parental strain survived until day 31 of ripening, and the mutant strain survived 24 days at pH 4 and a(w) of 0.886. The survival of the mutant strain showed a diminution of one logarithm during elaboration and ripening of cheese as compared with the parental strain. When the cheese was elaborated with raw milk and ripened at 4 degrees C, survival of the parental strain was 24 days, whereas the mutant strain survived only 17 days (pH 5 and a(w) 0.90). Regarding the cheese elaborated with pasteurized milk and maturated at 4 degrees C, both strains survived 31 days (pH 5 and a(w) 0.90), with the same survival diminution during elaboration and ripening. Our results show that in both types of cheese, the mutated aqpX strain survived 10 times less than the parental strain, which shows that the aqpX gene can be related to the survival of Brucella abortus in this type of cheese. PMID- 25551423 TI - Label-free optical biosensors based on aptamer-functionalized porous silicon scaffolds. AB - A proof-of-concept for a label-free and reagentless optical biosensing platform based on nanostructured porous silicon (PSi) and aptamers is presented in this work. Aptamers are oligonucleotides (single-stranded DNA or RNA) that can bind their targets with high affinity and specificity, making them excellent recognition elements for biosensor design. Here we describe the fabrication and characterization of aptamer-conjugated PSi biosensors, where a previously characterized his-tag binding aptamer (6H7) is used as model system. Exposure of the aptamer-functionalized PSi to the target proteins as well as to complex fluids (i.e., bacteria lysates containing target proteins) results in robust and well-defined changes in the PSi optical interference spectrum, ascribed to specific aptamer-protein binding events occurring within the nanoscale pores, monitored in real time. The biosensors show exceptional stability and can be easily regenerated by a short rinsing step for multiple biosensing analyses. This proof-of-concept study demonstrates the possibility of designing highly stable and specific label-free optical PSi biosensors, employing aptamers as capture probes, holding immense potential for application in detection of a broad range of targets, in a simple yet reliable manner. PMID- 25551425 TI - An evaluation of self-esteem and quality of life in orthodontic patients: Effects of crowding and protrusion. AB - Objective: To evaluate the effect of dental crowding and lip protrusion on self esteem and quality of life (QOL) in female orthodontic patients with Class I malocclusion. Materials and Methods: The study sample consisted of 201 patients (mean age 22.6 +/- 3.0 years) who sought orthodontic treatment. All the patients were evaluated before treatment in terms of their degree of dental crowding and lip protrusion. Rosenberg's Self-Esteem Scale and the Orthognathic Quality of Life Questionnaire (OQLQ) were used to determine self-esteem and QOL and to evaluate whether these values were related to malocclusion severity. Results: The results indicated that severe crowding and severe protrusion can result in lower self-esteem and poorer QOL (P < .05) than mild crowding and protrusion in Class I malocclusion. In the oral function component of the OQLQ, the severity of protrusion did not have significant effect. Conclusions: In Class I malocclusion, patients with mild crowding or protrusion had significantly better self-esteem and QOL scores than severe crowding or protrusion patients. PMID- 25551424 TI - Examining Potential Substance Use Disorders Among Former Interscholastic Athletes. AB - BACKGROUND: Despite numerous studies examining the association between competitive sports participation and substance use behaviors among adolescents and young adults, the use of standardized measures to assess potential substance use disorders has been largely neglected. The objective of this study was to examine if past involvement in interscholastic sports (competitive school sponsored sports) was associated with potential substance use disorders in young adulthood. METHODS: Data for this study were taken from the Student Life Survey (SLS). A total of 3442 young adults participated in the SLS during the spring semester in 2013, with 74% of males and 71% of females indicating participation in interscholastic sport during high school. RESULTS: Respondents who participated in interscholastic sports during high school had higher odds of positive screens for potential alcohol use disorders when compared with their peers who did not participate in interscholastic sports. No association was detected between interscholastic sports participation and potential drug abuse disorders. Moreover, previous involvement in certain types of sports was found to be associated with positive screens for potential alcohol use disorders (i.e., crew and football) and positive screens for potential drug abuse disorders (i.e., lacrosse) among the sample of young adults. CONCLUSIONS: School and community sport organizations should be aware of the potential link between sports participation and potential substance use disorders, and may consider brief substance use screeners during yearly physicals to monitor potential substance use problems among athletes. PMID- 25551426 TI - Signs and symptoms of TMJ disorders in adults after adolescent Herbst therapy: a 6-year and 32-year radiographic and clinical follow-up study. AB - OBJECTIVE: To analyze radiographic signs of temperomandibular joint (TMJ) osteoarthritis and clinical TMJ symptoms in patients 6 years and 32 years after treatment with a Herbst appliance. MATERIALS AND METHODS: Fourteen patients were derived from a sample of 22 with Class II division 1 malocclusions consecutively treated with a banded Herbst appliance at the age of 12-14 years old (T1-T2). The subjects were reexamined after therapy at the ages of 20 years (T3) and 46 years (T4). The TMJs of the 14 patients were analyzed radiographically (conventional lateral tomography at T3 and cone-beam computed tomography at T4) and clinically/anamnestically at T3 and T4. RESULTS: Six years after Herbst therapy, signs of osteoarthritis were seen in one patient. At the 32-year follow-up, two additional patients had developed signs of osteoarthritis. At the 6-year follow up, TMJ clicking was present in two patients, though none of the patients reported TMJ pain. At the 32-year follow-up, six patients had TMJ clicking and one patient had TMJ pain. CONCLUSIONS: This longitudinal very-long-term follow-up study after Herbst therapy revealed only minor problems from the TMJ. The TMJ findings 6 years and 32 years after Herbst treatment corresponded to those in the general population. Thus, in the very long term, the Herbst appliance does not appear to be harmful to the TMJ. PMID- 25551427 TI - Short-term effects produced by rapid maxillary expansion and facemask therapy in Class III patients with different vertical skeletal relationships. AB - OBJECTIVE: To evaluate the dentoskeletal short-term effects of rapid maxillary expansion and facemask therapy (RME/FM) in a sample of Class III patients showing different vertical skeletal relationships. MATERIALS AND METHODS: Seventy-nine patients (35 females and 44 males) having Class III malocclusion were consecutively treated using RME/FM therapy with application of the protraction force in a downward and forward direction and inclination of about 30 degrees to the occlusal plane. All patients were evaluated at the beginning (T1; mean age, 7.7 years) and at the end (T2; mean age, 9.2 years) of orthopedic therapy and divided into three groups according to their vertical skeletal relationships: normal group (NG), hypodivergent group (HypoG), and hyperdivergent group (HyperG). Statistical comparisons between the three groups were performed on the starting forms (T1), the final forms (T2), and the treatment changes (T1-T2) using the ANOVA with Tukey's post hoc tests. RESULTS: Favorable modification in terms of maxillary advancement (changes in SNA ranging from 1.4 degrees to 1.8 degrees ) and intermaxillary sagittal skeletal relationships (changes in Wits appraisal ranging from 2.5 mm to 3.5 mm) were recorded in all groups. The three groups showed no statistically significant differences in changes in either sagittal or vertical skeletal variables. CONCLUSIONS: The various vertical skeletal features do not influence the short-term outcomes of RME/FM therapy. PMID- 25551428 TI - Emergence of New Sequence Type OXA-48 Carbapenemase-Producing Enterobacteriaceae in Kuwait. AB - The aim of this study was to investigate the infections due to OXA-48 carbapenemase-producing bacteria in tertiary hospitals in Kuwait (September 2011 to April 2013) and to determine the sequence types (STs) of the corresponding isolates. Eleven OXA-48 carbapenemase-producing Enterobacteriaceae isolates were recovered from patients treated in nine different hospitals in Kuwait. Susceptibility testing to eighteen antibiotics was done using the E-test. PCR assays were performed for the detection of genes encoding extended-spectrum beta lactamases (ESBLs) (blaCTX-M, blaSHV, and blaTEM) and carbapenemases (blaOXA-48, blaVIM, blaNDM, blaIMP, blaGIM, and blaKPC). STs were determined by Multilocus Sequence Typing. Seven Klebsiella pneumoniae, two Escherichia coli, one Enterobacter cloacae, and one Morganella morganii harbored the blaOXA-48 gene. The K. pneumoniae and E. coli belonged to seven and two different STs, respectively, which were not related to those reported from this region. The majority of the isolates carried either blaCTX-M or blaSHV genes and showed a multidrug-resistant phenotype, including resistance to tigecycline. Multidrug resistant Enterobacteriaceae harboring the blaOXA-48 gene are emerging in Kuwait with different STs compared to those identified in other countries of the region. Detection of OXA-48-producing Enterobacteriaceae in Kuwait is important to prevent its rapid spread. PMID- 25551429 TI - What changes upon resettlement: understanding difference in pre- and post resettlement dietary habits among South-Asian refugees. AB - This study was conducted with the Montagnard refugee women (n = 42) to understand their pre-resettlement living conditions and estimate pre- and post-resettlement differences in their intake of major food groups. In-depth interviews were conducted with the participants in their homes by multilingual Montagnard women fluent in English and their tribal languages. Most of the participants did not receive education and 39% reported household incomes of $500 or less per month. Participants had a very limited or no experience in weekly food shopping and budgeting before moving to the United States. In comparison of food habits, intake of different types of meat increased upon resettlement (P < .05). Pre resettlement food shortage experience and receiving >= $500 in SNAP increased the odds of high meat intake. Due to a significant shift in food choices and environment, refugees are at a higher risk of experiencing poor health after moving to the United States. PMID- 25551430 TI - Low vitamin D levels are associated with both iron deficiency and anemia in children and adolescents. AB - BACKGROUND: We aimed to examine the association between vitamin D deficiency and anemia in a nationally representative sample of Korean children and adolescents. METHODS: Cross-sectional data on 2526 children and adolescents aged 10-20 years from the Korea National Health and Nutrition Examination Survey-V (2010-2012) were used. Anemia was defined according to specifications of the World Health Organization. Iron deficiency was defined as serum ferritin level of <12 ng/mL and transferrin saturation (TSAT) <16%. RESULTS: The prevalence of vitamin D deficiency in Korean children and adolescents was high especially in female (35.7% vs. 50.9%, P < 0.001). The prevalence of anemia was also higher in female (1.1% vs. 6.8%; P < 0.001). In logistic regression, risk factors for anemia were female sex, old age, post-menarche, low household income, vitamin D deficiency, and iron deficiency. The Odds Ratio for anemia, iron deficiency and iron deficiency anemia (IDA) in subjects with vitamin D deficiency (<15 ng/mL) were 1.81(95% CI, 1.13-2.88), 1.94(95% CI, 1.27-2.97), and 2.26 (95% CI, 1.20-4.24) after controlling for other risk factors. However, after examining the sexes separately, only female subjects showed statistical significance. After further controlling for iron deficiency, the risk of anemia was not significant (P = 0.261). CONCLUSIONS: Vitamin D deficiency is associated with increased risk of anemia, especially iron deficiency anemia, in healthy female children and adolescents. However, the association is attenuated after adjustment for iron deficiency. Further studies are needed to determine whether vitamin D deficiency is the cause of anemia, or bystander of nutritional deficiency which cause iron deficiency. PMID- 25551431 TI - Treatment patterns and outcomes among patients with high-intermediate/high-risk diffuse large B-cell lymphoma in the USA. AB - Objective Clinical trials have demonstrated improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL) treated with regimens containing rituximab, but variations in real-world treatment patterns and outcomes have not been studied. The objective of this study was to characterize real-world treatment patterns and outcomes in higher risk DLBCL patients. Methods Patients with an International Prognostic Index score (IPI) >=3 who received initial rituximab based therapy from 2005 to 2012 were identified via electronic medical record data from the International Oncology Network. Initial therapy, rates of complete response (CR), post-CR treatments, and outcomes were evaluated. Results Among 257 eligible patients, 75% achieved a CR: 77% (158/206) of patients receiving R-CHOP compared to 71% (36/51) of patients receiving initial therapies other than R CHOP. Post-CR, 78% of the 158 patients receiving R-CHOP underwent active surveillance; 13% received maintenance rituximab-based treatment; and 6% received radiation therapy. Relapse rates among patients receiving maintenance rituximab, active surveillance, and radiation therapy were 28% (6/21), 19% (24/124), and 0%, (0/10), respectively (P = 0.08). Discussion This study found that active surveillance continues to be the most commonly utilized treatment regimen among DLBCL patients with an IPI score >=3 achieving a CR on first-line R-CHOP. Other approaches aimed at increasing the time to relapse are being utilized as well, but the clinical benefit of these modalities is unclear. Conclusion Results of this study are consistent with the results from clinical trials and suggest the need for further evaluation of maintenance therapy options for patients at higher risk of relapse. PMID- 25551433 TI - Predicting breast cancer using an expression values weighted clinical classifier. AB - BACKGROUND: Clinical data, such as patient history, laboratory analysis, ultrasound parameters-which are the basis of day-to-day clinical decision support are often used to guide the clinical management of cancer in the presence of microarray data. Several data fusion techniques are available to integrate genomics or proteomics data, but only a few studies have created a single prediction model using both gene expression and clinical data. These studies often remain inconclusive regarding an obtained improvement in prediction performance. To improve clinical management, these data should be fully exploited. This requires efficient algorithms to integrate these data sets and design a final classifier. LS-SVM classifiers and generalized eigenvalue/singular value decompositions are successfully used in many bioinformatics applications for prediction tasks. While bringing up the benefits of these two techniques, we propose a machine learning approach, a weighted LS-SVM classifier to integrate two data sources: microarray and clinical parameters. RESULTS: We compared and evaluated the proposed methods on five breast cancer case studies. Compared to LS SVM classifier on individual data sets, generalized eigenvalue decomposition (GEVD) and kernel GEVD, the proposed weighted LS-SVM classifier offers good prediction performance, in terms of test area under ROC Curve (AUC), on all breast cancer case studies. CONCLUSIONS: Thus a clinical classifier weighted with microarray data set results in significantly improved diagnosis, prognosis and prediction responses to therapy. The proposed model has been shown as a promising mathematical framework in both data fusion and non-linear classification problems. PMID- 25551432 TI - Intimate Partner Violence and its Health Impact on Ethnic Minority Women [corrected]. AB - In the United States, intimate partner violence (IPV) against women disproportionately affects ethnic minorities. Further, disparities related to socioeconomic and foreign-born status impact the adverse physical and mental health outcomes as a result of IPV, further exacerbating these health consequences. This article reviews 36 U.S. studies on the physical (e.g., multiple injuries, disordered eating patterns), mental (e.g., depression, post traumatic stress disorder), and sexual and reproductive health conditions (e.g., HIV/STIs, unintended pregnancy) resulting from IPV victimization among ethnic minority (i.e., Black/African American, Hispanic/Latina, Native American/Alaska Native, Asian American) women, some of whom are immigrants. Most studies either did not have a sufficient sample size of ethnic minority women or did not use adequate statistical techniques to examine differences among different racial/ethnic groups. Few studies focused on Native American/Alaska Native and immigrant ethnic minority women and many of the intra-ethnic group studies have confounded race/ethnicity with income and other social determinants of health. Nonetheless, of the available data, there is evidence of health inequities associated with both minority ethnicity and IPV. To appropriately respond to the health needs of these groups of women, it is necessary to consider social, cultural, structural, and political barriers (e.g., medical mistrust, historical racism and trauma, perceived discrimination, immigration status) to patient provider communication and help-seeking behaviors related to IPV, which can influence health outcomes. This comprehensive approach will mitigate the racial/ethnic and socioeconomic disparities related to IPV and associated health outcomes and behaviors. PMID- 25551434 TI - Interleukin-17A promotes functional activation of systemic sclerosis patient derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway. AB - INTRODUCTION: Dermal vascular smooth muscle cells (DVSMCs) are important for vascular wall fibrosis in microangiopathy of systemic sclerosis (SSc). T helper 17 cell-associated cytokines, particularly interleukin-17A (IL-17A), have been demonstrated to play a role in the pathogenesis of SSc. However, the effect of IL 17A on the DVSMCs in microangiopathy of SSc has not been established. In the present study, we investigated the effect of IL-17A on the SSc patient-derived DVSMCs. METHODS: DVSMCs from patients with SSc and healthy subjects were incubated using IL-17A or serum derived from patients with SSc. Subsequently, the proliferation, collagen synthesis and secretion, and migration of DVSMCs were analysed using a cell counting kit-8 (CCK-8), dual-luciferase reporter assay, real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and transwell assay. The protein phosphorylation of signalling pathways in the process of IL-17A-mediated DVSMC activation was investigated and validated by specific signalling pathway inhibitor. RESULTS: IL-17A and serum from patients with SSc could promote the proliferation, collagen synthesis and secretion, and migration of DVSMCs. IL-17A neutralising antibody could inhibit the IL-17A-induced activation of DVSMCs. Additionally, IL-17A induced the activation of extracellular-regulated protein kinases 1/2 (ERK1/2) in DVSMCs, and ERK1/2 inhibitor could block the IL-17A elicited activation of DVSMCs. CONCLUSIONS: Our results suggested that IL-17A derived from patients with SSc might induce the proliferation, collagen synthesis and secretion, and migration of DVSMCs via ERK1/2 signalling pathway, raising the likelihood that IL-17A and ERK1/2 might be promising therapeutic targets for the treatment of SSc-related vasculopathy. PMID- 25551435 TI - A family cluster of three confirmed cases infected with avian influenza A (H7N9) virus in Zhejiang Province of China. AB - BACKGROUND: A total of 453 laboratory-confirmed cases infected with avian influenza A (H7N9) virus (including 175 deaths) have been reported till October 2,2014, of which 30.68% (139/453) of the cases were identified from Zhejiang Province. We describe the largest reported cluster of virologically confirmed H7N9 cases, comprised by a fatal Index case and two mild secondary cases. METHODS: A retrospective investigation was conducted in January of 2014. Three confirmed cases, their close contacts, and relevant environments samples were tested by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), viral culture, and sequencing. Serum samples were tested by haemagglutination inhibition (HI) assay. RESULTS: The Index case, a 49-year-old farmer with type II diabetes, who lived with his daughter (Case 2, aged 24) and wife (Case 3, aged 43) and his son-in-law (H7N9 negative). The Index case and Case 3 worked daily in a live bird market. Onset of illness in Index case occurred in January 13, 2014 and subsequently, he died of multi-organ failure on January 20. Case 2 presented with mild symptoms on January 20 following frequent unprotected bed-side care of the Index case between January 14 to 19, and exposed to live bird market on January 17. Case 3 became unwell on January 23 after providing bedside care to the Index case on January 17 to 18, and following the contact with Case 2 during January 21 to 22 at the funeral of the Index case. The two secondary cases were discharged on February 2 and 5 separately after early treatment with antiviral medication. Four virus strains were isolated and genome analyses showed 99.6 ~100% genetic homology, with two amino mutations (V192I in NS and V280A in NP). 42% (11/26) of environmental samples collected in January were H7N9 positive. Twenty-five close contacts remained well and were negative for H7N9 infection by RT-PCR and HI assay. CONCLUSIONS: In the present study, the Index case was infected from a live bird market while the two secondary cases were infected by the Index case during unprotected exposure. This family cluster is, therefore, compatible with non-sustained person-to-person transmission of avian influenza A/H7N9. PMID- 25551437 TI - Recovering the raw data behind a non-parametric survival curve. AB - BACKGROUND: Researchers often wish to carry out additional calculations or analyses using the survival data from one or more studies of other authors. When it is not possible to obtain the raw data directly, reconstruction techniques provide a valuable alternative. Several authors have proposed methods/tools for extracting data from such curves using a digitizing software. Instead of using a digitizer to read in the coordinates from a raster image, we propose directly reading in the lines of the PostScript file of a vector image. METHODS: Using examples, and a formal error analysis, we illustrate the extent to which, with what accuracy and precision, and in what circumstances, this information can be recovered from the various electronic formats in which such curves are published. We focus on the additional precision, and elimination of observer variation, achieved by using vector-based formats rendered by PostScript, rather than the lower resolution image-based formats that have been analyzed up to now. We provide some R code to process these. RESULTS: If the raster-based images are available, one can reliably recover much of the original information that seems to be 'hidden' beneath published survival curves. If the original images can be obtained as a PostScript file, the data recovered from it can then be either input into these tools or processed directly. We found that the PostScript used by Stata discloses considerably more of the data hidden behind survival curves than that generated by other statistical packages. CONCLUSIONS: When it is not possible to obtain the raw data from the authors, reconstruction techniques are a valuable alternative. Compared with previous approaches, one advantage of ours is that there is no observer variation: there is no need to repeat the digitization process, since the extraction is completely replicable. PMID- 25551436 TI - A randomized controlled trial of mental health interventions for survivors of systematic violence in Kurdistan, Northern Iraq. AB - BACKGROUND: Experiencing systematic violence and trauma increases the risk of poor mental health outcomes; few interventions for these types of exposures have been evaluated in low resource contexts. The objective of this randomized controlled trial was to assess the effectiveness of two psychotherapeutic interventions, Behavioral Activation Treatment for Depression (BATD) and Cognitive Processing Therapy (CPT), in reducing depression symptoms using a locally adapted and validated version of the Hopkins Symptom Checklist and dysfunction measured with a locally developed scale. Secondary outcomes included posttraumatic stress, anxiety, and traumatic grief symptoms. METHODS: Twenty community mental health workers, working in rural health clinics, were randomly assigned to training in one of the two interventions. The community mental health workers conducted baseline assessments, enrolled survivors of systematic violence based on severity of depression symptoms, and randomly assigned them to treatment or waitlist-control. Blinded community mental health workers conducted post intervention assessments on average five months later. RESULTS: Adult survivors of systematic violence were screened (N = 732) with 281 enrolled in the trial; 215 randomized to an intervention (114 to BATD; 101 to CPT) and 66 to waitlist control (33 to BATD; 33 to CPT). Nearly 70% (n = 149) of the intervention participants completed treatment and post-intervention assessments; 53 (80%) waitlist-controls completed post-intervention assessments. Estimated effect sizes for depression and dysfunction were 0.60 and 0.55 respectively, comparing BATD participants to all controls and 0.84 and 0.79 respectively, compared to BATD controls only. Estimated effect sizes for depression and dysfunction were 0.70 and 0.90 respectively comparing CPT participants to all controls and 0.44 and 0.63 respectively compared to CPT controls only. Using a permutation-based hypothesis test that is robust to the model assumptions implicit in regression models, BATD had significant effects on depression (p = .003) and dysfunction (p = .007), while CPT had a significant effect on dysfunction only (p = .004). CONCLUSIONS: Both interventions showed moderate to strong effects on most outcomes. This study demonstrates effectiveness of these interventions in low resource environments by mental health workers with limited prior experience. TRIAL REGISTRATION: ClinicalTrials.Gov NCT00925262 . Registered June 3, 2009. PMID- 25551438 TI - Heat exposure and bicycling trigger recurrent aseptic meningitis: a case report. AB - BACKGROUND: Aseptic meningitis associated with herpes simplex virus type 2 often has a relapsing-remitting clinical phenotype. Factors that lead to disease activation and reactivation are currently incompletely understood. CASE PRESENTATION: We describe the case of a 49-year-old Caucasian man who developed recurrent episodes of herpes simplex virus type 2-associated aseptic meningitis in the setting of heat exposure and bicycling. This case is compelling in that substantial data were available to the examining physicians on the amount of physical exercise and heat exposure. Strenuous physical activities or heat exposure in isolation did not cause re-occurrence of clinical signs and symptoms. CONCLUSIONS: This case illustrates that the dual activation of mechanical and temperature receptors in dorsal root ganglia may lead to the recurrent reactivation and afferent dissemination of latent herpes simplex virus type 2 in some patients. PMID- 25551439 TI - Comparative analyses of proteins from Haemophilus influenzae biofilm and planktonic populations using metabolic labeling and mass spectrometry. AB - BACKGROUND: Non-typeable H. influenzae (NTHi) is a nasopharyngeal commensal that can become an opportunistic pathogen causing infections such as otitis media, pneumonia, and bronchitis. NTHi is known to form biofilms. Resistance of bacterial biofilms to clearance by host defense mechanisms and antibiotic treatments is well-established. In the current study, we used stable isotope labeling by amino acids in cell culture (SILAC) to compare the proteomic profiles of NTHi biofilm and planktonic organisms. Duplicate continuous-flow growth chambers containing defined media with either "light" (L) isoleucine or "heavy" (H) (13)C6-labeled isoleucine were used to grow planktonic (L) and biofilm (H) samples, respectively. Bacteria were removed from the chambers, mixed based on weight, and protein extracts were generated. Liquid chromatography-mass spectrometry (LC-MS) was performed on the tryptic peptides and 814 unique proteins were identified with 99% confidence. RESULTS: Comparisons of the NTHi biofilm to planktonic samples demonstrated that 127 proteins showed differential expression with p-values <=0.05. Pathway analysis demonstrated that proteins involved in energy metabolism, protein synthesis, and purine, pyrimidine, nucleoside, and nucleotide processes showed a general trend of downregulation in the biofilm compared to planktonic organisms. Conversely, proteins involved in transcription, DNA metabolism, and fatty acid and phospholipid metabolism showed a general trend of upregulation under biofilm conditions. Selected reaction monitoring (SRM)-MS was used to validate a subset of these proteins; among these were aerobic respiration control protein ArcA, NAD nucleotidase and heme-binding protein A. CONCLUSIONS: The present proteomic study indicates that the NTHi biofilm exists in a semi-dormant state with decreased energy metabolism and protein synthesis yet is still capable of managing oxidative stress and in acquiring necessary cofactors important for biofilm survival. PMID- 25551440 TI - New insight into secreted ribonuclease structure: binase is a natural dimer. AB - The biological effects of ribonucleases (RNases), such as the control of the blood vessels growth, the toxicity towards tumour cells and antiviral activity, require a detailed explanation. One of the most intriguing properties of RNases which can contribute to their biological effects is the ability to form dimers, which facilitates efficient RNA hydrolysis and the evasion of ribonuclease inhibitor. Dimeric forms of microbial RNase binase secreted by Bacillus pumilus (former B. intermedius) have only been found in crystals to date. Our study is the first report directly confirming the existence of binase dimers in solution and under natural conditions of enzyme biosynthesis and secretion by bacilli. Using different variants of gel electrophoresis, immunoblotting, size-exclusion chromatography and mass-spectrometry, we revealed that binase is a stable natural dimer with high catalytic activity. PMID- 25551441 TI - Seasonal photochemical transformations of nitrogen species in a forest stream and lake. AB - The photochemical release of inorganic nitrogen from dissolved organic matter is an important source of bio-available nitrogen (N) in N-limited aquatic ecosystems. We conducted photochemical experiments and used mathematical models based on pseudo-first-order reaction kinetics to quantify the photochemical transformations of individual N species and their seasonal effects on N cycling in a mountain forest stream and lake (Plesne Lake, Czech Republic). Results from laboratory experiments on photochemical changes in N speciation were compared to measured lake N budgets. Concentrations of organic nitrogen (Norg; 40-58 umol L 1) decreased from 3 to 26% during 48-hour laboratory irradiation (an equivalent of 4-5 days of natural solar insolation) due to photochemical mineralization to ammonium (NH4+) and other N forms (Nx; possibly N oxides and N2). In addition to Norg mineralization, Nx also originated from photochemical nitrate (NO3-) reduction. Laboratory exposure of a first-order forest stream water samples showed a high amount of seasonality, with the maximum rates of Norg mineralization and NH4+ production in winter and spring, and the maximum NO3- reduction occurring in summer. These photochemical changes could have an ecologically significant effect on NH4+ concentrations in streams (doubling their terrestrial fluxes from soils) and on concentrations of dissolved Norg in the lake. In contrast, photochemical reactions reduced NO3- fluxes by a negligible (<1%) amount and had a negligible effect on the aquatic cycle of this N form. PMID- 25551442 TI - pH-dependent conformational changes in the HCV NS3 protein modulate its ATPase and helicase activities. AB - The hepatitis C virus (HCV) infects 170 to 200 million people worldwide and is, therefore, a major health problem. The lack of efficient treatments that specifically target the viral proteins or RNA and its high chronicity rate make hepatitis C the cause of many deaths and hepatic transplants annually. The NS3 protein is considered an important target for the development of anti-HCV drugs because it is composed of two domains (a serine protease in the N-terminal portion and an RNA helicase/NTPase in the C-terminal portion), which are essential for viral replication and proliferation. We expressed and purified both the NS3 helicase domain (NS3hel) and the full-length NS3 protein (NS3FL) and characterized pH-dependent structural changes associated with the increase in their ATPase and helicase activities at acidic pH. Using intrinsic fluorescence experiments, we have observed that NS3hel was less stable at pH 6.4 than at pH 7.2. Moreover, binding curves using an extrinsic fluorescent probe (bis-ANS) and ATPase assays performed under different pH conditions demonstrated that the hydrophobic clefts of NS3 are significantly more exposed to the aqueous medium at acidic pH. Using fluorescence spectroscopy and anisotropy assays, we have also observed more protein interaction with DNA upon pH acidification, which suggests that the hydrophobic clefts exposure on NS3 might be related to a loss of stability that could lead it to adopt a more open conformation. This conformational change at acidic pH would stimulate both its ATPase and helicase activities, as well as its ability to bind DNA. Taken together, our results indicate that the NS3 protein adopts a more open conformation due to acidification from pH 7.2 to 6.4, resulting in a more active form at a pH that is found near Golgi-derived membranes. This increased activity could better allow NS3 to carry out its functions during HCV replication. PMID- 25551443 TI - Physiological and metabolic effects of 5-aminolevulinic acid for mitigating salinity stress in creeping bentgrass. AB - The objectives of this study were to determine whether foliar application of a chlorophyll precursor, 5-aminolevulinic acid (ALA), could mitigate salinity stress damages in perennial grass species by regulating photosynthetic activities, ion content, antioxidant metabolism, or metabolite accumulation. A salinity-sensitive perennial grass species, creeping bentgrass (Agrostis stolonifera), was irrigated daily with 200 mM NaCl for 28 d, which were foliar sprayed with water or ALA (0.5 mg L-1) weekly during the experiment in growth chamber. Foliar application of ALA was effective in mitigating physiological damage resulting from salinity stress, as manifested by increased turf quality, shoot growth rate, leaf relative water content, chlorophyll content, net photosynthetic rate, stomatal conductance and transpiration rate. Foliar application of ALA also alleviated membrane damages, as shown by lower membrane electrolyte leakage and lipid peroxidation, which was associated with increases in the activities of antioxidant enzymes. Leaf content of Na+ was reduced and the ratio of K+/Na+ was increased with ALA application under salinity stress. The positive effects of ALA for salinity tolerance were also associated with the accumulation of organic acids (alpha-ketoglutaric acid, succinic acid, and malic acid), amino acids (alanine, 5-oxoproline, aspartic acid, and gamma -aminobutyric acid), and sugars (glucose, fructose, galactose, lyxose, allose, xylose, sucrose, and maltose). ALA-mitigation of physiological damages by salinity could be due to suppression of Na+ accumulation and enhanced physiological and metabolic activities related to photosynthesis, respiration, osmotic regulation, and antioxidant defense. PMID- 25551444 TI - NSK-01105, a novel sorafenib derivative, inhibits human prostate tumor growth via suppression of VEGFR2/EGFR-mediated angiogenesis. AB - The purpose of this study is to investigate the anti-angiogenic activities of NSK 01105, a novel sorafenib derivative, in in vitro, ex vivo and in vivo models, and explore the potential mechanisms. NSK-01105 significantly inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human umbilical vein endothelial cells at non-cytotoxic concentrations as shown by wound-healing, transwell migration and endothelial cell tube formation assays, respectively. Cell viability and invasion of LNCaP and PC-3 cells were significantly inhibited by cytotoxicity assay and matrigel invasion assay. Furthermore, NSK-01105 also inhibited ex vivo angiogenesis in matrigel plug assay. Western blot analysis showed that NSK-01105 down-regulated VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) and the activation of epidermal growth factor receptor (EGFR). Tumor volumes were significantly reduced by NSK 01105 at 60 mg/kg/day in both xenograft models. Immunohistochemical staining demonstrated a close association between inhibition of tumor growth and neovascularization. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors, and one of the potential mechanisms may be attributed to anti-angiogenic activities. PMID- 25551445 TI - Magnetic Cross-Linked Enzyme Aggregates (mCLEAs) of Candida antarctica lipase: an efficient and stable biocatalyst for biodiesel synthesis. AB - Enzyme-catalyzed production of biodiesel is the object of extensive research due to the global shortage of fossil fuels and increased environmental concerns. Herein we report the preparation and main characteristics of a novel biocatalyst consisting of Cross-Linked Enzyme Aggregates (CLEAs) of Candida antarctica lipase B (CALB) which are covalently bound to magnetic nanoparticles, and tackle its use for the synthesis of biodiesel from non-edible vegetable and waste frying oils. For this purpose, insolubilized CALB was covalently cross-linked to magnetic nanoparticles of magnetite which the surface was functionalized with -NH2 groups. The resulting biocatalyst combines the relevant catalytic properties of CLEAs (as great stability and feasibility for their reutilization) and the magnetic character, and thus the final product (mCLEAs) are superparamagnetic particles of a robust catalyst which is more stable than the free enzyme, easily recoverable from the reaction medium and reusable for new catalytic cycles. We have studied the main properties of this biocatalyst and we have assessed its utility to catalyze transesterification reactions to obtain biodiesel from non-edible vegetable oils including unrefined soybean, jatropha and cameline, as well as waste frying oil. Using 1% mCLEAs (w/w of oil) conversions near 80% were routinely obtained at 30 degrees C after 24 h of reaction, this value rising to 92% after 72 h. Moreover, the magnetic biocatalyst can be easily recovered from the reaction mixture and reused for at least ten consecutive cycles of 24 h without apparent loss of activity. The obtained results suggest that mCLEAs prepared from CALB can become a powerful biocatalyst for application at industrial scale with better performance than those currently available. PMID- 25551446 TI - Genomic, proteomic, morphological, and phylogenetic analyses of vB_EcoP_SU10, a podoviridae phage with C3 morphology. AB - A recently isolated phage, vB_EcoP_SU10 (SU10), with the unusual elongated C3 morphotype, can infect a wide range of Escherichia coli strains. We have sequenced the genome of this phage and characterized it further by mass spectrometry based proteomics, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and ultra-thin section electron microscopy. The genome size is 77,327 base pairs and its genes, and genome architecture, show high similarity to the phiEco32 phage genes and genome. The TEM images reveal that SU10 have a quite long tail for being a Podoviridae phage, and that the tail also changes conformation upon infection. The ultra-thin section electron microscopy images of phages at the stage of replication within the host cell show that the phages form a honeycomb-like structure under packaging of genomes and assembly of mature capsids. This implies a tight link between the replication and cutting of the concatemeric genome, genome packaging, and capsid assembly. We have also performed a phylogenetic analysis of the structural genes common between Podoviridae phages of the C1 and C3 morphotypes. The result shows that the structural genes have coevolved, and that they form two distinct groups linked to their morphotypes. The structural genes of C1 and C3 phages appear to have diverged around 280 million years ago applying a molecular clock calibrated according to the presumed split between the Escherichia - Salmonella genera. PMID- 25551447 TI - Meta-analysis of prostate cancer gene expression data identifies a novel discriminatory signature enriched for glycosylating enzymes. AB - BACKGROUND: Tumorigenesis is characterised by changes in transcriptional control. Extensive transcript expression data have been acquired over the last decade and used to classify prostate cancers. Prostate cancer is, however, a heterogeneous multifocal cancer and this poses challenges in identifying robust transcript biomarkers. METHODS: In this study, we have undertaken a meta-analysis of publicly available transcriptomic data spanning datasets and technologies from the last decade and encompassing laser capture microdissected and macrodissected sample sets. RESULTS: We identified a 33 gene signature that can discriminate between benign tissue controls and localised prostate cancers irrespective of detection platform or dissection status. These genes were significantly overexpressed in localised prostate cancer versus benign tissue in at least three datasets within the Oncomine Compendium of Expression Array Data. In addition, they were also overexpressed in a recent exon-array dataset as well a prostate cancer RNA-seq dataset generated as part of the The Cancer Genomics Atlas (TCGA) initiative. Biologically, glycosylation was the single enriched process associated with this 33 gene signature, encompassing four glycosylating enzymes. We went on to evaluate the performance of this signature against three individual markers of prostate cancer, v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) expression, prostate specific antigen (PSA) expression and androgen receptor (AR) expression in an additional independent dataset. Our signature had greater discriminatory power than these markers both for localised cancer and metastatic disease relative to benign tissue, or in the case of metastasis, also localised prostate cancer. CONCLUSION: In conclusion, robust transcript biomarkers are present within datasets assembled over many years and cohorts and our study provides both examples and a strategy for refining and comparing datasets to obtain additional markers as more data are generated. PMID- 25551449 TI - Health workforce equity in urban community health service of China. AB - OBJECTIVES: To reveal the equity of health workforce distribution in urban community health service (CHS), and to provide evidence for further development of community health service in China. METHODS: A community-based, cross-sectional study was conducted in China from September to December 2011. In the study, 190 CHS centers were selected from 10 provinces of China via stratified multistage cluster sampling. Human resources profiles and basic characteristics of each CHS centers were collected. Lorenz curves and Gini Coefficient were used to measure the inequality in the distribution of health workforce in community health service centers by population size and geographical area. Wilcoxon rank test for paired samples was used to analyze the differences in equity between different health indicators. RESULTS: On average, there were 7.37 health workers, including 3.25 doctors and 2.32 nurses per 10,000 population ratio. Significant differences were found in all indicators across the samples, while Beijing, Shandong and Zhejiang ranked the highest among these provinces. The Gini coefficients for health workers, doctors and nurses per 10,000 population ratio were 0.39, 0.44, and 0.48, respectively. The equity of doctors per 10,000 population ratio (G = 0.39) was better than that of doctors per square kilometer (G = 0.44) (P = 0.005). Among the total 6,573 health workers, 1,755(26.7%) had undergraduate degree or above, 2,722(41.4%)had junior college degree and 215(3.3%) had high school education. Significant inequity was found in the distribution of workers with undergraduate degree or above (G = 0.52), which was worse than that of health works per 10000 population (P<0.001). CONCLUSIONS: Health workforce inequity was found in this study, especially in quality and geographic distribution. These findings suggest a need for more innovative policies to improve health equity in Chinese urban CHS centers. PMID- 25551448 TI - A meta-analysis to derive literature-based benchmarks for readmission and hospital mortality after patient discharge from intensive care. AB - INTRODUCTION: We sought to derive literature-based summary estimates of readmission to the ICU and hospital mortality among patients discharged alive from the ICU. METHODS: We searched MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials from inception to March 2013, as well as the reference lists in the publications of the included studies. We selected cohort studies of ICU discharge prognostic factors that in which readmission to the ICU or hospital mortality among patients discharged alive from the ICU was reported. Two reviewers independently abstracted the number of patients readmitted to the ICU and hospital deaths among patients discharged alive from the ICU. Fixed effects and random effects models were used to estimate the pooled cumulative incidence of ICU readmission and the pooled cumulative incidence of hospital mortality. RESULTS: The analysis included 58 studies (n = 2,073,170 patients). The majority of studies followed patients until hospital discharge (n = 46 studies) and reported readmission to the ICU (n = 46 studies) or hospital mortality (n = 49 studies). The cumulative incidence of ICU readmission was 4.0 readmissions (95% confidence interval (CI), 3.9 to 4.0) per 100 patient discharges using fixed effects pooling and 6.3 readmissions (95% CI, 5.6 to 6.9) per 100 patient discharges using random effects pooling. The cumulative incidence of hospital mortality was 3.3 deaths (95% CI, 3.3 to 3.3) per 100 patient discharges using fixed effects pooling and 6.8 deaths (95% CI, 6.1 to 7.6) per 100 patient discharges using random effects pooling. There was significant heterogeneity for the pooled estimates, which was partially explained by patient, institution and study methodological characteristics. CONCLUSIONS: Using current literature estimates, for every 100 patients discharged alive from the ICU, between 4 and 6 patients on average will be readmitted to the ICU and between 3 and 7 patients on average will die prior to hospital discharge. These estimates can inform the selection of benchmarks for quality metrics of transitions of patient care between the ICU and the hospital ward. PMID- 25551450 TI - Binpairs: utilization of Illumina paired-end information for improving efficiency of taxonomic binning of metagenomic sequences. AB - MOTIVATION: Paired-end sequencing protocols, offered by next generation sequencing (NGS) platforms like Illumia, generate a pair of reads for every DNA fragment in a sample. Although this protocol has been utilized for several metagenomics studies, most taxonomic binning approaches classify each of the reads (forming a pair), independently. The present work explores some simple but effective strategies of utilizing pairing-information of Illumina short reads for improving the accuracy of taxonomic binning of metagenomic datasets. The strategies proposed can be used in conjunction with all genres of existing binning methods. RESULTS: Validation results suggest that employment of these "Binpairs" strategies can provide significant improvements in the binning outcome. The quality of the taxonomic assignments thus obtained are often comparable to those that can only be achieved with relatively longer reads obtained using other NGS platforms (such as Roche). AVAILABILITY: An implementation of the proposed strategies of utilizing pairing information is freely available for academic users at https://metagenomics.atc.tcs.com/binning/binpairs. PMID- 25551451 TI - Oncostatin M maintains the hematopoietic microenvironment in the bone marrow by modulating adipogenesis and osteogenesis. AB - The bone marrow (BM) is an essential organ for hematopoiesis in adult, in which proliferation and differentiation of hematopoietic stem/progenitor cells (HSPC) is orchestrated by various stromal cells. Alterations of BM hematopoietic environment lead to various hematopoietic disorders as exemplified by the linking of fatty marrow with increased adipogenesis to anemia or pancytopenia. Therefore, the composition of mesenchymal stromal cell (MSC)-derived cells in the BM could be crucial for proper hematopoiesis, but the mechanisms underlying the MSC differentiation for hematopoiesis remain poorly understood. In this study, we show that Oncostatin M (OSM) knock out mice exhibited pancytopenia advancing fatty marrow with age. OSM strongly inhibited adipogenesis from BM MSC in vitro, whereas it enhanced their osteogenesis but suppressed the terminal differentiation. Intriguingly, OSM allowed the MSC-derived cells to support the ex vivo expansion of HSPC effectively as feeder cells. Furthermore, the administration of OSM in lethally irradiated wild-type mice blocked fatty marrow and enhanced the recovery of HSPC number in the BM and peripheral blood cells after engraftment of HSPC. Collectively, OSM plays multiple critical roles in the maintenance and development of the hematopoietic microenvironment in the BM at a steady state as well as after injury. PMID- 25551452 TI - Tau reduction diminishes spatial learning and memory deficits after mild repetitive traumatic brain injury in mice. AB - OBJECTIVE: Because reduction of the microtubule-associated protein Tau has beneficial effects in mouse models of Alzheimer's disease and epilepsy, we wanted to determine whether this strategy can also improve the outcome of mild traumatic brain injury (TBI). METHODS: We adapted a mild frontal impact model of TBI for wildtype C57Bl/6J mice and characterized the behavioral deficits it causes in these animals. The Barnes maze, Y maze, contextual and cued fear conditioning, elevated plus maze, open field, balance beam, and forced swim test were used to assess different behavioral functions. Magnetic resonance imaging (MRI, 7 Tesla) and histological analysis of brain sections were used to look for neuropathological alterations. We also compared the functional effects of this TBI model and of controlled cortical impact in mice with two, one or no Tau alleles. RESULTS: Repeated (2-hit), but not single (1-hit), mild frontal impact impaired spatial learning and memory in wildtype mice as determined by testing of mice in the Barnes maze one month after the injury. Locomotor activity, anxiety, depression and fear related behaviors did not differ between injured and sham injured mice. MRI imaging did not reveal focal injury or mass lesions shortly after the injury. Complete ablation or partial reduction of tau prevented deficits in spatial learning and memory after repeated mild frontal impact. Complete tau ablation also showed a trend towards protection after a single controlled cortical impact. Complete or partial reduction of tau also reduced the level of axonopathy in the corpus callosum after repeated mild frontal impact. INTERPRETATION: Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects. PMID- 25551453 TI - Isolation and characterization of Faecalibacterium prausnitzii from calves and piglets. AB - The goal of our study was to isolate and characterize Faecalibacterium prausnitzii from fecal samples of healthy calves and piglets, in order to develop a novel probiotic for livestock animals. We identified 203 isolates of Faecalibacterium sp., which were clustered in 40 genetically distinct groups. One representative isolate from each cluster was selected for further characterization. The concentrations of the short chain fatty acids (SCFA) acetate, butyrate, propionate and isobutyrate in the culture media were measured by gas chromatography. We observed reduction in the concentration of acetate followed by concomitant increase in the concentration of butyrate, suggesting that the isolates were consuming acetate present in the media and producing butyrate. Butyrate production correlated positively with bacterial growth. Since butyrate has many benefits to the colonic epithelial cells, the selection of strains that produce higher amounts of butyrate is extremely important for the development of this potential probiotic. The effect of pH and concentration of bile salts on bacterial growth was also evaluated in order to mimic the conditions encountered by F. prausnitzii in vivo. The optimal pH for growth ranged between 5.5 and 6.7, while most isolates were inhibited by of the lowest concentration of bile salts tested (0.1%). Antimicrobial resistance profile showed that most isolates of Faecalibacterium sp. were resistant against ciprofloxacin and sulfamethoxazole-trimethoprim. More than 50% of the isolates were resistant to tetracycline, amikacin, cefepime and cefoxitin. A total of 19 different combinations of multidrug resistance were observed among the isolates. Our results provide new insights into the cultural and physiological characteristics of Faecalibacterium prausnitzii illustrating large variability in short chain fatty acid production, in vitro growth, sensitivity to bile salts, and antibiotic resistance and suggesting that future probiotic candidates should be carefully studied before elected for in vivo studies. PMID- 25551454 TI - Costs of eliminating malaria and the impact of the global fund in 34 countries. AB - BACKGROUND: International financing for malaria increased more than 18-fold between 2000 and 2011; the largest source came from The Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund). Countries have made substantial progress, but achieving elimination requires sustained finances to interrupt transmission and prevent reintroduction. Since 2011, global financing for malaria has declined, fueling concerns that further progress will be impeded, especially for current malaria-eliminating countries that may face resurgent malaria if programs are disrupted. OBJECTIVES: This study aims to 1) assess past total and Global Fund funding to the 34 current malaria-eliminating countries, and 2) estimate their future funding needs to achieve malaria elimination and prevent reintroduction through 2030. METHODS: Historical funding is assessed against trends in country-level malaria annual parasite incidences (APIs) and income per capita. Following Kizewski et al. (2007), program costs to eliminate malaria and prevent reintroduction through 2030 are estimated using a deterministic model. The cost parameters are tailored to a package of interventions aimed at malaria elimination and prevention of reintroduction. RESULTS: The majority of Global Fund-supported countries experiencing increases in total funding from 2005 to 2010 coincided with reductions in malaria APIs and also overall GNI per capita average annual growth. The total amount of projected funding needed for the current malaria-eliminating countries to achieve elimination and prevent reintroduction through 2030 is approximately US$8.5 billion, or about $1.84 per person at risk per year (PPY) (ranging from $2.51 PPY in 2014 to $1.43 PPY in 2030). CONCLUSIONS: Although external donor funding, particularly from the Global Fund, has been key for many malaria-eliminating countries, sustained and sufficient financing is critical for furthering global malaria elimination. Projected cost estimates for elimination provide policymakers with an indication of the level of financial resources that should be mobilized to achieve malaria elimination goals. PMID- 25551455 TI - Identification of an unclassified paramyxovirus in Coleura afra: a potential case of host specificity. AB - Bats are known to harbor multiple paramyxoviruses. Despite the creation of two new genera, Aquaparamyxovirus and Ferlavirus, to accommodate this increasing diversity, several recently isolated or characterized viruses remain unclassified beyond the subfamily level. In the present study, among 985 bats belonging to 6 species sampled in the Belinga caves of Gabon, RNA of an unclassified paramyxovirus (Belinga bat virus, BelPV) was discovered in 14 African sheath tailed bats (Coleura afra), one of which exhibited several hemorrhagic lesions at necropsy, and viral sequence was obtained in two animals. Phylogenetically, BelPV is related to J virus and Beilong virus (BeiPV), two other unclassified paramyxoviruses isolated from rodents. In the diseased BelPV-infected C. afra individual, high viral load was detected in the heart, and the lesions were consistent with those reported in wild rodents and mice experimentally infected by J virus. BelPV was not detected in other tested bat species sharing the same roosting sites and living in very close proximity with C. afra in the two caves sampled, suggesting that this virus may be host-specific for C. afra. The mode of transmission of this paramyxovirus in bat populations remains to be discovered. PMID- 25551456 TI - Subfamily-specific adaptations in the structures of two penicillin-binding proteins from Mycobacterium tuberculosis. AB - Beta-lactam antibiotics target penicillin-binding proteins including several enzyme classes essential for bacterial cell-wall homeostasis. To better understand the functional and inhibitor-binding specificities of penicillin binding proteins from the pathogen, Mycobacterium tuberculosis, we carried out structural and phylogenetic analysis of two predicted D,D-carboxypeptidases, Rv2911 and Rv3330. Optimization of Rv2911 for crystallization using directed evolution and the GFP folding reporter method yielded a soluble quadruple mutant. Structures of optimized Rv2911 bound to phenylmethylsulfonyl fluoride and Rv3330 bound to meropenem show that, in contrast to the nonspecific inhibitor, meropenem forms an extended interaction with the enzyme along a conserved surface. Phylogenetic analysis shows that Rv2911 and Rv3330 belong to different clades that emerged in Actinobacteria and are not represented in model organisms such as Escherichia coli and Bacillus subtilis. Clade-specific adaptations allow these enzymes to fulfill distinct physiological roles despite strict conservation of core catalytic residues. The characteristic differences include potential protein protein interaction surfaces and specificity-determining residues surrounding the catalytic site. Overall, these structural insights lay the groundwork to develop improved beta-lactam therapeutics for tuberculosis. PMID- 25551458 TI - Tinnitus and hearing survey: a screening tool to differentiate bothersome tinnitus from hearing difficulties. AB - PURPOSE: Individuals complaining of tinnitus often attribute hearing problems to the tinnitus. In such cases some (or all) of their reported "tinnitus distress" may in fact be caused by trouble communicating due to hearing problems. We developed the Tinnitus and Hearing Survey (THS) as a tool to rapidly differentiate hearing problems from tinnitus problems. METHOD: For 2 of our research studies, we administered the THS twice (mean of 16.5 days between tests) to 67 participants who did not receive intervention. These data allow for measures of statistical validation of the THS. RESULTS: Reliability of the THS was good to excellent regarding internal consistency (alpha=.86-.94), test-retest reliability (r=.76-.83), and convergent validity between the Tinnitus Handicap Inventory (Newman, Jacobson, & Spitzer, 1996; Newman, Sandridge, & Jacobson, 1998) and the A (Tinnitus) subscale of the THS (r=.78). Factor analysis confirmed that the 2 subscales, A (Tinnitus) and B (Hearing), have strong internal structure, explaining 71.7% of the total variance, and low correlation with each other (r=.46), resulting in a small amount of shared variance (21%). CONCLUSION: These results provide evidence that the THS is statistically validated and reliable for use in assisting patients and clinicians in quickly (and collaboratively) determining whether intervention for tinnitus is appropriate. PMID- 25551459 TI - Infection and colonization by Stenotrophomonas maltophilia: antimicrobial susceptibility and clinical background of strains isolated at a tertiary care centre in Hungary. AB - BACKGROUND: Stenotrophomonas maltophilia is an important opportunistic, mainly nosocomial pathogen that emerged in the last decades worldwide. Due to its inherent extended antibiotic resistance, therapeutic options are strongly limited. New resistance mechanisms in S. maltophilia make antibiotic therapy even more difficult. The aim of our study was to investigate the antimicrobial resistance of S. maltophilia isolates collected in our laboratory and to reveal related clinical background. METHOD: Consecutive non-duplicate S. maltophilia isolates (n = 160) were collected in a three-year period. Conventional methods, automated identification system and MALDI-TOF MS was used for identification, ERIC-PCR for genetic relationship analysis and broth microdilution method to determine the susceptibility for trimethoprim/sulfamethoxazole (SXT), ciprofloxacin, levofloxacin, moxifloxacin, colistin, doxycycline and tigecycline. Clinical final reports were used retrospectively to collect clinical information. RESULTS: ERIC-PCR revealed large heterogeneity. Trimethoprim/sulfamethoxazole, moxifloxacin and levofloxacin were found to be the most effective agents with MIC50/MIC90 0.5/1, 0.25/1, 1/2 mg/l, respectively. Seventy percent of patients with S. maltophilia infection were treated in intensive care units. All-cause mortality rate was 45%. Nearly 70% of the isolates were collected from polymicrobial infections/colonizations. CONCLUSIONS: Trimethoprim/sulfamethoxazole is the most potent antibiotic agent against S. maltophilia. In case of SXT hypersensitivity, intolerance or resistance, fluoroquinolones are alternative therapeutic options. Missing clinical breakpoints, consensus antibiotic susceptibility testing guidelines and clinical trials make the interpretation of antibiotic susceptibility testing results difficult. The indirect pathogenicity of S. maltophilia in polymicrobial infections or colonizations has to be taken into consideration. PMID- 25551460 TI - In-kennel behavior predicts length of stay in shelter dogs. AB - Previous empirical evaluations of training programs aimed at improving dog adoption rates assume that dogs exhibiting certain behaviors are more adoptable. However, no systematic data are available to indicate that the spontaneous behavior of shelter dogs has an effect on adopter preference. The aim of the present study was to determine whether any behaviors that dogs exhibit spontaneously in the presence of potential adopters were associated with the dogs' length of stay in the shelter. A sample of 289 dogs was videotaped for 1 min daily throughout their stay at a county shelter. To account for differences in adopter behavior, experimenters varied from solitary passive observers to pairs of interactive observers. Dogs behaved more attentively to active observers. To account for adopter preference for morphology, dogs were divided into "morphologically preferred" and "non-preferred" groups. Morphologically preferred dogs were small, long coated, ratters, herders, and lap dogs. No theoretically significant differences in behavior were observed between the two different dog morphologies. When accounting for morphological preference, three behaviors were found to have a significant effect on length of stay in all dogs: leaning or rubbing on the enclosure wall (increased median length of stay by 30 days), facing away from the front of the enclosure (increased by 15 days), and standing (increased by 7 days). When combinations of behaviors were assessed, back and forth motion was found to predict a longer stay (increased by 24 days). No consistent behavioral changes were observed due to time spent at the shelter. These findings will allow shelters to focus behavioral modification efforts only on behaviors likely to influence adopters' choices. PMID- 25551461 TI - Biosynthesis of versipelostatin: identification of an enzyme-catalyzed [4+2] cycloaddition required for macrocyclization of spirotetronate-containing polyketides. AB - Versipelostatin (VST) is an unusual 17-membered macrocyclic polyketide product that contains a spirotetronate skeleton. In this study, the entire VST biosynthetic gene cluster (vst) spanning 108 kb from Streptomyces versipellis 4083-SVS6 was identified by heterologous expression using a bacterial artificial chromosome vector. Here, we demonstrate that an enzyme, VstJ, catalyzes the stereoselective [4+2]-cycloaddition between the conjugated diene and the exocyclic olefin of a newly identified tetronate-containing intermediate to form the spirotetronate skeleton during VST biosynthesis. PMID- 25551457 TI - No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. AB - Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 * 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations. PMID- 25551462 TI - Genome wide identification, phylogeny and expression of zinc transporter genes in common carp. AB - BACKGROUND: Zinc is an essential trace element in organisms, which serves as a cofactor for hundreds of enzymes that are involved in many pivotal biological processes including growth, development, reproduction and immunity. Therefore, the homeostasis of zinc in the cell is fundamental. The zinc transporter gene family is a large gene family that encodes proteins which regulate the movement of zinc across cellular and intracellular membranes. However, studies on teleost zinc transporters are mainly limited to model species. METHODOLOGY/PRINCIPAL FINDINGS: We identified a set of 37 zinc transporters in common carp genome, including 17 from SLC30 family (ZnT), and 20 from SLC39 family (ZIP). Phylogenetic and syntenic analysis revealed that most of the zinc transporters are highly conserved, though recent gene duplication and gene losses do exist. Through examining the copy number of zinc transporter genes across several vertebrate genomes, thirteen zinc transporters in common carp are found to have undergone the gene duplications, including SLC30A1, SLC30A2, SLC30A5, SLC30A7, SLC30A9, SLC30A10, SLC39A1, SLC39A3, SLC39A4, SLC39A5, SLC39A6, SLC39A7 and SLC39A9. The expression patterns of all zinc transporters were established in various tissues, including blood, brain, gill, heart, intestine, liver, muscle, skin, spleen and kidney, and showed that most of the zinc transporters were ubiquitously expressed, indicating the critical role of zinc transporters in common carp. CONCLUSIONS: To some extent, examination of gene families with detailed phylogenetic or orthology analysis could verify the authenticity and accuracy of assembly and annotation of the recently published common carp whole genome sequences. The gene families are also considered as a unique source for evolutionary studies. Moreover, the whole set of common carp zinc transporters provides an important genomic resource for future biochemical, toxicological and physiological studies of zinc in teleost. PMID- 25551463 TI - Generation of eosinophils from cryopreserved murine bone marrow cells. AB - Eosinophils are produced in the bone marrow from CD34+ eosinophil lineage committed progenitors, whose levels in the bone marrow are elevated in a variety of human diseases. These findings suggest that increased eosinophil lineage committed progenitor production is an important process in disease-associated eosinophilia. The pathways central to the biology of the eosinophil lineage committed progenitor remain largely unknown. Thus, developing new methods to investigate the regulators of eosinophil lineage-committed progenitor differentiation is needed to identify potential therapeutic targets to specifically inhibit eosinophil production. We tested cytokine regimens to optimize liquid cultures for the study of eosinophil lineage-committed progenitor and eosinophil precursor differentiation into mature eosinophils. Stem cell factor (but not fms-related tyrosine kinase 3 ligand) was required for optimal yield of eosinophils. Furthermore, we evaluated the effects of cell preservation and scale on the culture, successfully culturing functional eosinophils from fresh and frozen murine bone marrow cells and in a standard-sized and 96-well culture format. In summary, we have developed an adaptable culture system that yields functionally competent eosinophils from murine low-density bone marrow cells and whose cytokine regime includes expansion of progenitors with stem cell factor alone with subsequent differentiation with interleukin 5. PMID- 25551464 TI - Oropharyngeal and nasal Staphylococcus aureus carriage by healthy children. AB - BACKGROUND: As healthy children are the main reservoir of respiratory pathogens and the main cause of bacterial diffusion in the community, it could be interesting to investigate the type of screening that should be used during the early years of life in order to obtain a more precise estimate of Staphylococcus aureus circulation. The aim of this study was to evaluate oropharyngeal and nasal S. aureus carriage in otherwise healthy children and adolescents aged 6-17 years. METHODS: The oropharyngeal and nasal samples were collected in December 2013 from 497 healthy students attending five randomly selected schools in Milan, Italy, using an ESwab kit, and S. aureus was identified using the RIDA(r)GENE methicillin-resistant S. aureus (MRSA) system. RESULTS: Two hundred and sixty four subjects (53.1%) were identified as S. aureus carriers: 129 (25.9%) oropharyngeal carriers and 195 (39.2%) nasal carriers, of whom 60 (12.1%) were both oropharyngeal and nasal carriers. Oropharyngeal carriage increased with age (p < 0.001), whereas nasal carriage decreased. There was little or no agreement between oropharyngeal and nasal carriage in any of the age groups. MRSA was identified in only three cases (0.6%), always in nasal samples. There were no differences between the carriers and non-carriers in terms of the distribution of age, gender, ethnicity, the number of siblings in the household, exposure to passive smoking, previous clinical history, allergic sensitisation, or previous influenza, pneumococcal and meningococcal vaccinations. The frequency of male children was higher among the subjects with positive nasal and oropharyngeal swabs (66.7%) than among those with positive oropharyngeal swabs alone (46.4%; p = 0.02). CONCLUSIONS: The oropharyngeal carriage of mainly methicillin-sensitive S. aureus is frequent in otherwise healthy children, including a relatively high proportion of those without nasal colonisation. These findings highlight the importance of adding throat to nasal screening when monitoring the circulation of S. aureus in the community. PMID- 25551466 TI - A novel reproductive mode in frogs: a new species of fanged frog with internal fertilization and birth of tadpoles. AB - We describe a new species of fanged frog (Limnonectes larvaepartus) that is unique among anurans in having both internal fertilization and birth of tadpoles. The new species is endemic to Sulawesi Island, Indonesia. This is the fourth valid species of Limnonectes described from Sulawesi despite that the radiation includes at least 15 species and possibly many more. Fewer than a dozen of the 6455 species of frogs in the world are known to have internal fertilization, and of these, all but the new species either deposit fertilized eggs or give birth to froglets. PMID- 25551465 TI - Residents in difficulty--just slower learners? A case-control study. AB - BACKGROUND: Recent meta-analyses have found small-moderate positive associations between general performance in medical school and postgraduate medical education. In addition, a couple of studies have found an association between poor performance in medical school and disciplinary action against practicing doctors. The aim of this study was to examine if a sample of Danish residents in difficulty tended to struggle already in medical school, and to determine whether administratively observable performance indicators in medical school could predict difficulties in residency. METHODS: The study design was a cumulative incidence matched case-control study. The source population was all active specialist trainees, who were medical school graduates from Aarhus University, in 2010 to June 2013 in two Danish regions. Cases were doctors who decelerated, transferred, or dropped out of residency. Cases and controls were matched for graduation year. Medical school exam failures, grades, completion time, and academic dispensations as predictors of case status were examined with conditional logistic regression. RESULTS: In total 89 cases and 343 controls were identified. The total number of medical school re-examinations and the time it took to complete medical school were significant individual predictors of subsequent difficulties (deceleration, transferral or dropout) in residency whereas average medical school grades were not. CONCLUSIONS: Residents in difficulty eventually reached similar competence levels as controls during medical school; however, they needed more exam attempts and longer time to complete their studies, and so seemed to be slower learners. A change from "fixed length variable-outcome programmes" to "fixed-outcome variable-length programmes" has been proposed as a way of dealing with the fact that not all learners reach the same level of competence for all activities at exactly the same time. This study seems to support the logic of such an approach to these residents in difficulty. PMID- 25551467 TI - Section curve reconstruction and mean-camber curve extraction of a point-sampled blade surface. AB - The blade is one of the most critical parts of an aviation engine, and a small change in the blade geometry may significantly affect the dynamics performance of the aviation engine. Rapid advancements in 3D scanning techniques have enabled the inspection of the blade shape using a dense and accurate point cloud. This paper proposes a new method to achieving two common tasks in blade inspection: section curve reconstruction and mean-camber curve extraction with the representation of a point cloud. The mathematical morphology is expanded and applied to restrain the effect of the measuring defects and generate an ordered sequence of 2D measured points in the section plane. Then, the energy and distance are minimized to iteratively smoothen the measured points, approximate the section curve and extract the mean-camber curve. In addition, a turbine blade is machined and scanned to observe the curvature variation, energy variation and approximation error, which demonstrates the availability of the proposed method. The proposed method is simple to implement and can be applied in aviation casting blade finish inspection, large forging-blade allowance inspection and visual guided robot grinding localization. PMID- 25551468 TI - Rearrangement of a Krebs-type polyoxometalate upon coordination of N,O bis(bidentate) ligands. AB - Selective coordination of 2,3-pyzdc to the Krebs-type [{Ni(H2O)3}2(WO2)2(SbW9O33)2](10-) anion promotes a skeletal rearrangement that results in the [(2,3-pyzdc)2{NaNi2(H2O)4Sb2W20O70}2](22-) (Ni4) hybrid dimer showing a novel dinickel containing a 20-tungsto-2-antimonate(III) framework stabilized by N,O-bis(bidentate) bridging ligands. The solution stability and magnetism of Ni4 is discussed. PMID- 25551469 TI - Anti-Outer membrane protein C and anti-glycoprotein 2 antibodies in inflammatory bowel disease and their association with complicated forms of Crohn's disease. AB - BACKGROUND: Precise diagnostics of inflammatory bowel disease (IBD) and identification of potentially more aggressive phenotypes of Crohn's disease (CD) is urgently needed. The aim of our prospective study was to assess the relationship between serum anti-OmpC IgA (Outer membrane protein C), anti-GP2 (anti-glycoprotein 2) IgG and anti-GP2 IgA antibodies with IBD and their association with complicated forms of CD. METHODS: The study included 86 patients with CD, 25 patients with UC and 45 controls, blood donors. In CD group, 24/86 (28%) had B1 phenotype, 20/86 (23%) B2, 13/86 (15%) B3 and 29/86 (34%) B2 + B3. L1 involvement was present in 13/86 (15%), L2 in 13/86 (15%), L3 in 60/86 (70%). Serum anti-OmpC IgA, anti-GP2 IgG and IgA antibodies were investigated by means of ELISA. The data obtained were tested statistically by means of descriptive statistics, non-paired t-test, Mann-Whitney rank sum test, Spearman rank order correlation and Pearson product moment correlation using SigmaStat software. RESULTS: Anti-OmpC IgA were noted to be significantly higher in CD (median 32.6, inter-quartile range (IQR) 18.9-60.7) compared to the controls (median 18.3, IQR 11.1-23.1), p < 0.001. Anti-GP2 IgG were significantly higher in CD (median 13.9, IQR 8.6-25.6) compared to the controls (median 8.0, IQR 4.7-10.8), p < 0.001. Anti-GP2 IgA were significantly higher in CD (median 20.1, IQR 9.1-40.4) compared to the controls (median 9.8, IQR 5.6-16.9), p < 0.001. Significant difference was found in anti-OmpC IgA between UC (median 26.2, IQR 20.2-36.4) and the controls (median 18.3, IQR 11.1-23.1), p < 0.001. In CD anti-OmpC IgA were significantly higher in B2 compared to B1: p = 0.041 and in B2 + B3 compared to B1: p = 0.036. Anti-GP2 IgA were significantly higher in B2 + B3 compared to B1: p = 0.009 and in B3 compared to B1: p = 0.029. In CD there was a significant difference in anti OmpC IgA between patients with surgery and without surgery, p = 0.005. CONCLUSIONS: We have confirmed association between anti-OmpC IgA and IBD (CD and UC) and an association between anti-GP2 (IgG and IgA) and CD. Patients with complicated forms of CD have significantly higher levels of anti-OmpC IgA and anti-GP2 IgA. PMID- 25551470 TI - Prospective study of superior cluneal nerve disorder as a potential cause of low back pain and leg symptoms. AB - BACKGROUND: Entrapment of the superior cluneal nerve (SCN) in an osteofibrous tunnel has been reported as a cause of low back pain (LBP). However, there are few reports on the prevalence of SCN disorder and there are several reports only on favorable outcomes of treatment of SCN disorder on LBP. The purposes of this prospective study were to investigate the prevalence of SCN disorder and to characterize clinical manifestations of this clinical entity. METHODS: A total of 834 patients suffering from LBP and/or leg symptoms were enrolled in this study. Diagnostic criteria for suspected SCN disorder were that the maximally tender point was on the posterior iliac crest 70 mm from the midline and that palpation of the tender point reproduced the chief complaint. When patients met both criteria, a nerve block injection was performed. At the initial evaluation, LBP and leg symptoms were assessed by visual analog scale (VAS) score. At 15 min and 1 week after the injection, VAS pain levels were recorded. If insufficient pain decrease or recurrence of pain was observed, injections were repeated weekly up to three times. Surgery was done under microscopy. Operative findings of the SCN and outcomes were recorded. RESULTS: Of the 834 patients, 113 (14%) met the criteria and were given nerve block injections. Of these, 54 (49%) had leg symptoms. Before injection, the mean VAS score was 68.6 +/- 19.2 mm. At 1 week after injection, the mean VAS score significantly decreased to 45.2 +/- 28.8 mm (p < 0.05). Ninety-six of the 113 patients (85%) experienced more than a 20 mm decrease of the VAS score following three injections and 77 patients (68%) experienced more than a 50% decrease in the VAS score. Surgery was performed in 19 patients who had intractable symptoms. Complete and almost complete relief of leg symptoms were obtained in five of these surgical patients. CONCLUSIONS: SCN disorder is not a rare clinical entity and should be considered as a cause of chronic LBP or leg pain. Approximately 50% of SCN disorder patients had leg symptoms. PMID- 25551471 TI - A general design strategy for block copolymer directed self-assembly patterning of integrated circuits contact holes using an alphabet approach. AB - Directed self-assembly (DSA) is a promising lithography candidate for technology nodes beyond 14 nm. Researchers have shown contact hole patterning for random logic circuits using DSA with small physical templates. This paper introduces an alphabet approach that uses a minimal set of small physical templates to pattern all contacts configurations on integrated circuits. We illustrate, through experiments, a general and scalable template design strategy that links the DSA material properties to the technology node requirements. PMID- 25551473 TI - JAFC over the years 1999-2014. PMID- 25551472 TI - Latexin inhibits the proliferation of CD133+ miapaca-2 pancreatic cancer stem like cells. AB - BACKGROUND: An increasing number of evidence suggests that pancreatic cancer contains cancer stem cells (CSCs), which may be relevant to the resistance of chemotherapy. Latexin (Lxn) is a negative regulator of stem cell proliferation and we investigate the effects of Lxn on CD133+ pancreatic cancer stem-like cells. METHODS: CD133+ miapaca-2 cells, a human pancreatic carcinoma cell line, were isolated and sorted by magnetic activated cell sorting and flow cytometry. The capacity for self-renewal, proliferation, and tumorigenicity of CD133+ miapaca-2 cells was determined by the floating spheres test and tumor xenograft assays. Protein and mRNA expression of Lxn in CD133+ and CD133- miapaca-2 cells were detected by Western blotting and qRT-PCR, respectively. After CD133+ miapaca 2 cells were treated with Lxn in serum-free medium (SFM), cell proliferation was assayed with a Cell Counting Kit 8 (CCK-8) and apoptosis was analyzed by flow cytometry. The protein and mRNA expression levels of Bcl-2, bax, and c-myc were also analyzed. RESULTS: We successfully isolated CD133+ miapaca-2 cells that exhibited the capacity for self-renewal in SFM, a proliferation potential in DMEM supplemented with FBS, and high tumorigenicity in nude mice. Lxn protein and mRNA expression levels in CD133+ miapaca-2 cells were significantly lower than those in CD133- cells. Lxn-treated CD133+ miapaca-2 cells exhibited increased apoptosis and low proliferation activity, down-regulation of Bcl-2 and c-myc expression, and up-regulation of Bax expression in a dose-dependent manner. CONCLUSIONS: Lxn induces apoptosis and inhibits the proliferation of CD133+ miapaca-2 cells. These changes are associated with down-regulation of Bcl-2 and c-myc and up-regulation of Bax. PMID- 25551474 TI - Bioinspired design of nanostructured elastomers with cross-linked soft matrix grafting on the oriented rigid nanofibers to mimic mechanical properties of human skin. AB - Human skin exhibits highly nonlinear elastic properties that are essential to its physiological functions. It is soft at low strain but stiff at high strain, thereby protecting internal organs and tissues from mechanical trauma. However, to date, the development of materials to mimic the unique mechanical properties of human skin is still a great challenge. Here we report a bioinspired design of nanostructured elastomers combining two abundant plant-based biopolymers, stiff cellulose and elastic polyisoprene (natural rubber), to mimic the mechanical properties of human skin. The nanostructured elastomers show highly nonlinear mechanical properties closely mimicking that of human skin. Importantly, the mechanical properties of these nanostructured elastomers can be tuned by adjusting cellulose content, providing the opportunity to synthesize materials that mimic the mechanical properties of different types of skins. Given the simplicity, efficiency, and tunability, this design may provide a promising strategy for creating artificial skin for both general mechanical and biomedical applications. PMID- 25551475 TI - Integrating virtual reality with activity management for the treatment of fibromyalgia: acceptability and preliminary efficacy. AB - OBJECTIVES: Cognitive-behavioral therapies (CBT) for fibromyalgia syndrome (FMS) are important interventions in the management of this condition. Empirical evidence reports that although the results are promising, further research is needed to respond more appropriately to these patients. This study focuses on exploring the use of Virtual Reality (VR) as an adjunct to the activity management component. The aim of this study is to present the results of a small sized randomized controlled trial to test the preliminary efficacy and acceptability of this component. MATERIALS AND METHODS: The final sample was composed of 61 women diagnosed with FMS according to the American College of Rheumatology. The sample was randomly allocated to 2 conditions: VR treatment and treatment as usual. RESULTS: Participants in the VR condition achieved significant improvements in the primary outcome: disability measured with the FIQ. The improvement was also significant in secondary outcomes, such as perceived quality of life and some of the coping strategies included in the Chronic Pain Coping Inventory: task persistence and exercise. There were no differences in other secondary outcome measures like pain intensity and interference and depression. Participants reported high satisfaction with the VR component. DISCUSSION: The effects were related to the psychological aspects targeted in the treatment. The component was well accepted by FMS patients referred from a public hospital. These findings show that the VR component could be useful in the CBT treatment of FMS and encourage us to continue exploring the use of integrating VR with CBT interventions for the treatment of FMS. PMID- 25551476 TI - Publicly available online educational videos regarding pediatric needle pain: a scoping review. AB - OBJECTIVES: The objectives of this scoping review were to: (1) identify publicly available educational videos on needle pain management; and (2) evaluate the content of these videos. METHODS: Reviewers screened publicly available educational videos on pediatric needle pain management available on YouTube and Google using a broad-based search strategy. Videos were categorized using the CRAAP Test: Current, Relevant, from a trustworthy source (Authority), Accurate and evidence-based, and for what Purpose does the source exist. RESULTS: Twenty five relevant, educational videos were identified. The intended audience for most videos was parents (n=16, 64%), followed by clinicians (n=6, 24%) and children (n=3, 12%). Common examples of needle pain included immunizations or IV insertion, with interventions appropriate for infants through school-aged children. The most frequently described techniques were parent-guided distraction and behavioral factors such as comfort holds and parent demeanor. Most videos were Current (96%), Relevant (100%), created by a trustworthy source: Authority (76%), and all were Accurate, with Purpose relating to needle pain management. None of the videos addressed the unique needs of children with a preexisting diagnosis of needle phobia. DISCUSSION: Publicly available educational videos offer clinicians, parents, and children evidence-based techniques to manage pediatric needle pain. Further evaluation is needed to determine whether this form of education meets the needs of target audiences and whether this type of content can lead to improved management of pediatric needle pain. PMID- 25551477 TI - Clinical Value of Serum Neuroplasticity Mediators in Identifying the Central Sensitivity Syndrome in Patients With Chronic Pain With and Without Structural Pathology. AB - BACKGROUND AND OBJECTIVES: Central sensitivity syndrome (CSS) encompasses disorders with overlapping symptoms in a spectrum of structural pathology from persistent somatic nociception (eg, osteoarthritis) to absence of tissue injury such as in fibromyalgia, chronic tension-type headache, and myofascial pain syndrome. Likewise, the spectrum of the neuroplasticity mediators associated with CSS might present a pattern of clinical utility. METHODS: We studied the brain derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-alpha), and interleukins 6 (IL-6) and IL-10 in female patients with CSS absent of structural pathology (chronic tension-type headache [n=30], myofascial pain syndrome [n=29], fibromyalgia [n=22]); with CSS due to persistent somatic/visceral nociception (osteoarthritis [n=27] and endometriosis [n=32]); and in pain-free controls (n=37). RESULTS: Patients with CSS absent of structural pathology presented higher serum TNF-alpha (28.61+/-12.74 pg/mL) and BDNF (49.87+/-31.86 ng/mL) than those with persistent somatic/visceral nociception (TNF-alpha=17.35+/-7.38 pg/mL; BDNF=20.44+/-8.30 ng/mL) and controls (TNF-alpha=21.41+/-5.74 pg/mL, BDNF=14.09+/ 11.80 ng/mL). Moreover, CSS patients absent of structural pathology presented lower IL levels. Receiver operator characteristics analysis showed the ability of BDNF to screen CSS (irrespective of the presence of structural pathology) from controls (cutoff=13.31 ng/mL, area under the curve [AUC]=0.86, sensitivity=95.06%, specificity=56.76%); and its ability to identify persistent nociception in CSS patients when experiencing moderate-severe depressive symptoms (AUC=0.81; cutoff=42.83 ng/mL, sensitivity=56.80%, specificity=100%). When the level of pain measured on the visual analog scale was <5 and moderate-severe depressive symptoms were observed TNF-alpha discriminated structural pathology in the chronic pain conditions (AUC=0.97; cutoff=22.11 pg/mL, sensitivity=90%, specificity=91.3%). CONCLUSION: Neuroplasticity mediators could play a role as screening tools for pain clinicians, and as validation of the complex and diffuse symptoms of these patients. PMID- 25551478 TI - Testing the Feasibility of DARWeb: An Online Intervention for Children With Functional Abdominal Pain and Their Parents. AB - OBJECTIVES: To test the feasibility of an online intervention (DARWeb) for children with functional abdominal pain and their families. METHODS: An online intervention (with 7 units for children and 7 for parents) was developed from a cognitive-behavioral perspective. A total of 15 families were given access to the intervention and asked to rate their satisfaction with each unit and the overall program (using scales from 0 to 10). Moreover, they were interviewed at the end of the program to obtain more information about their impressions of the program. RESULTS: Nine families (60%) completed the entire program. Parents rated each unit above a median of 8; children also rated all of the units except the first 2 above a median of 8. Global ratings were also very positive. Qualitative data reinforce the idea that the participants were quite satisfied with the intervention, they appreciated the fact that it was online, and they learned coping strategies (they were especially happy with relaxation) and to give less importance to pain. Although they appreciated the available resources, they would like to have more multimedia and interactive resources, and some form of professional contact. Parents also suggest that it was a burden (in terms of time) to supervise their children's progress in the program. DISCUSSION: DARWeb has been shown to be a feasible intervention, and it seems to be well designed. However, some improvements need to be considered based on the experiences of these participating families, and further research should be conducted to test its efficacy. PMID- 25551480 TI - Managing pain in obese patients: meeting weighty challenges. PMID- 25551481 TI - Lithium for post-electroconvulsive therapy depressive relapse prevention: a consideration of the evidence. AB - Lithium has been used for several decades as a prophylactic against depressive relapse after successful index electroconvulsive therapy (ECT). The literature on this topic is reviewed, and it is concluded that, in the main, there is strong evidence that lithium can help prevent relapses in the first 6 months after index ECT. However, there are several unanswered questions about its use post-ECT, including optimal target blood level, duration of use, and concomitant antidepressant choice. In this report, the author provides a review of the evidence for using lithium in this setting, outlines the pertinent unanswered questions, and proposes future research directions and guidelines for current clinical care. PMID- 25551479 TI - The toxoplasma-host cell junction is anchored to the cell cortex to sustain parasite invasive force. AB - BACKGROUND: The public health threats imposed by toxoplasmosis worldwide and by malaria in sub-Saharan countries are directly associated with the capacity of their related causative agents Toxoplasma and Plasmodium, respectively, to colonize and expand inside host cells. Therefore, deciphering how these two Apicomplexan protozoan parasites access their host cells has been highlighted as a priority research with the perspective of designing anti-invasive molecules to prevent diseases. Central to the mechanism of invasion for both genera is mechanical force, which is thought to be applied by the parasite at the interface between the two cells following assembly of a unique cell-cell junction but this model lacks direct evidence and has been challenged by recent genetic studies. In this work, using parasites expressing the fluorescent core component of this junction, we analyze characteristic features of the kinematics of penetration of more than 1,000 invasion events. RESULTS: The majority of invasion events occur with a typical forward rotational progression of the parasite through a static junction into an invaginating host cell plasma membrane. However, if parasites encounter resistance and if the junction is not strongly anchored to the host cell cortex, as when parasites do not secrete the toxofilin protein and, therefore, are unable to locally remodel the cortical actin cytoskeleton, the junction travels retrogradely with the host cell membrane along the parasite surface allowing the formation of a functional vacuole. Kinetic measurements of the invasive trajectories strongly support a similar parasite driven force in both static and capped junctions, both of which lead to successful invasion. However, about 20% of toxofilin mutants fail to enter and eventually disengage from the host cell membrane while the secreted RhOptry Neck (RON2) molecules are posteriorally capped before being cleaved and released in the medium. By contrast in cells characterized by low cortex tension and high cortical actin dynamics junction capping and entry failure are drastically reduced. CONCLUSIONS: This kinematic analysis newly highlights that to invade cells parasites need to engage their motor with the junction molecular complex where force is efficiently applied only upon proper anchorage to the host cell membrane and cortex. PMID- 25551482 TI - A real-time pinch-to-zoom motion detection by means of a surface EMG-based human computer interface. AB - In this paper, we propose a system for inferring the pinch-to-zoom gesture using surface EMG (Electromyography) signals in real time. Pinch-to-zoom, which is a common gesture in smart devices such as an iPhone or an Android phone, is used to control the size of images or web pages according to the distance between the thumb and index finger. To infer the finger motion, we recorded EMG signals obtained from the first dorsal interosseous muscle, which is highly related to the pinch-to-zoom gesture, and used a support vector machine for classification between four finger motion distances. The powers which are estimated by Welch's method were used as feature vectors. In order to solve the multiclass classification problem, we applied a one-versus-one strategy, since a support vector machine is basically a binary classifier. As a result, our system yields 93.38% classification accuracy averaged over six subjects. The classification accuracy was estimated using 10-fold cross validation. Through our system, we expect to not only develop practical prosthetic devices but to also construct a novel user experience (UX) for smart devices. PMID- 25551483 TI - In-to-out body antenna-independent path loss model for multilayered tissues and heterogeneous medium. AB - In this paper, we investigate multilayered lossy and heterogeneous media for wireless body area networks (WBAN) to develop a simple, fast and efficient analytical in-to-out body path loss (PL) model at 2.45 GHz and, thus, avoid time consuming simulations. The PL model is an antenna-independent model and is validated with simulations in layered medium, as well as in a 3D human model using electromagnetic solvers. PMID- 25551484 TI - Non-cooperative target recognition by means of singular value decomposition applied to radar high resolution range profiles. AB - Radar high resolution range profiles are widely used among the target recognition community for the detection and identification of flying targets. In this paper, singular value decomposition is applied to extract the relevant information and to model each aircraft as a subspace. The identification algorithm is based on angle between subspaces and takes place in a transformed domain. In order to have a wide database of radar signatures and evaluate the performance, simulated range profiles are used as the recognition database while the test samples comprise data of actual range profiles collected in a measurement campaign. Thanks to the modeling of aircraft as subspaces only the valuable information of each target is used in the recognition process. Thus, one of the main advantages of using singular value decomposition, is that it helps to overcome the notable dissimilarities found in the shape and signal-to-noise ratio between actual and simulated profiles due to their difference in nature. Despite these differences, the recognition rates obtained with the algorithm are quite promising. PMID- 25551485 TI - QOS-aware error recovery in wireless body sensor networks using adaptive network coding. AB - Wireless body sensor networks (WBSNs) for healthcare and medical applications are real-time and life-critical infrastructures, which require a strict guarantee of quality of service (QoS), in terms of latency, error rate and reliability. Considering the criticality of healthcare and medical applications, WBSNs need to fulfill users/applications and the corresponding network's QoS requirements. For instance, for a real-time application to support on-time data delivery, a WBSN needs to guarantee a constrained delay at the network level. A network coding based error recovery mechanism is an emerging mechanism that can be used in these systems to support QoS at very low energy, memory and hardware cost. However, in dynamic network environments and user requirements, the original non-adaptive version of network coding fails to support some of the network and user QoS requirements. This work explores the QoS requirements of WBSNs in both perspectives of QoS. Based on these requirements, this paper proposes an adaptive network coding-based, QoS-aware error recovery mechanism for WBSNs. It utilizes network-level and user-/application-level information to make it adaptive in both contexts. Thus, it provides improved QoS support adaptively in terms of reliability, energy efficiency and delay. Simulation results show the potential of the proposed mechanism in terms of adaptability, reliability, real-time data delivery and network lifetime compared to its counterparts. PMID- 25551486 TI - Welcome to the 38th Lauriston S. Taylor lecture on radiation protection and measurements. PMID- 25551487 TI - Introduction of the 38th Lauriston S. Taylor lecturer in radiation protection and measurements: Fred A. Mettler, Jr. PMID- 25551488 TI - 38th Lauriston S. Taylor lecture: on the shoulders of giants - radiation protection over 50 years. AB - Most advances in science, technology, and radiation protection are not truly new ideas but rather build upon a foundation of prior work and achievements by earlier generations of scientists and researchers. This paper summarizes major achievements over the last 50-70 y in the various areas involved in radiation protection as well as giving information about some of those who were, and are, significant contributors. PMID- 25551489 TI - Welcome to the Fiftieth Annual Meeting of the NCRP: achievements of the past 50 years and addressing the needs of the future. PMID- 25551490 TI - Eleventh annual Warren K. Sinclair keynote address-science, radiation protection and NCRP: building on the past, looking to the future. AB - The many reports and other authoritative documents developed and published by the National Council on Radiation Protection and Measurements (NCRP) have been of great service to the nation and the radiation protection community since its Congressional charter was signed into law 50 y ago. There will be a continuing need for NCRP to identify the principles upon which radiation protection is to be based and to provide guidance on best practices for the practical application of those principles for the many beneficial uses of radiation in society. The unique and invaluable resource that is NCRP is in large part due to the selfless dedication and numerous contributions of its Council and scientific committee members. The multidisciplinary composition of these leading experts and their collective input on complex questions provide a unique synergy that results in a comprehensive and well-balanced approach to addressing current and future radiation protection challenges. Subsequent articles in these proceedings covering a broad range of relevant topics will review sentinel accomplishments of the past as well as current work and future challenges that are in keeping with NCRP's mission to advance the science of radiation protection in the public interest. PMID- 25551491 TI - Eleventh annual Warren K. Sinclair keynote address Q&A. PMID- 25551492 TI - Integrating basic radiobiological science and epidemiological studies: why and how. AB - There is quite an extensive set of epidemiology studies conducted for a range of different radiation exposure scenarios and in some cases at doses that can be considered to be in the low dose range (<100 mGy). In addition, there is an extensive literature on the effects of radiation at animal and cellular levels, as well as expanding knowledge of the underlying mechanisms of disease formation (both cancer and non-cancer). A significant concern is that these two areas of study have been linked rarely to support each other-to enhance low dose/low dose rate extrapolation and reduction of uncertainty in risk estimates. Research should provide specific types of data to support the epidemiology and thereby enhance the radiation risk assessment process. Such an approach is one that can be adapted from that used for chemical exposures. It is based on the concept of adverse outcome pathways for the formation of adverse health outcomes. The adverse outcome pathway conceptual framework is considered to be a logical sequence of events (so-called key events) or processes within biological systems that can be used to understand adverse effects and refine the current risk assessment practice. This approach, which has only been used currently for chemicals, shifts the risk assessment focus from traditional apical endpoints (e.g., cancer and cardiovascular disease) to the development of a mechanistic understanding of effects at a molecular and cellular level. The need is to further the knowledge of the key events in radiation-induced diseases and to provide information on the dose and dose-rate response for these. It is proposed that the key-event approach be used in conjunction with enhanced radiation epidemiology data to reduce overall uncertainty in low dose/low dose-rate cancer and non-cancer risk estimates. PMID- 25551493 TI - Review of NASA approach to space radiation risk assessments for Mars exploration. AB - Long duration space missions present unique radiation protection challenges due to the complexity of the space radiation environment, which includes high charge and energy particles and other highly ionizing radiation such as neutrons. Based on a recommendation by the National Council on Radiation Protection and Measurements, a 3% lifetime risk of exposure-induced death for cancer has been used as a basis for risk limitation by the National Aeronautics and Space Administration (NASA) for low-Earth orbit missions. NASA has developed a risk based approach to radiation exposure limits that accounts for individual factors (age, gender, and smoking history) and assesses the uncertainties in risk estimates. New radiation quality factors with associated probability distribution functions to represent the quality factor's uncertainty have been developed based on track structure models and recent radiobiology data for high charge and energy particles. The current radiation dose limits are reviewed for spaceflight and the various qualitative and quantitative uncertainties that impact the risk of exposure-induced death estimates using the NASA Space Cancer Risk (NSCR) model. NSCR estimates of the number of "safe days" in deep space to be within exposure limits and risk estimates for a Mars exploration mission are described. PMID- 25551494 TI - Biological effectiveness of photons and electrons as a function of energy. PMID- 25551495 TI - Basic criteria, epidemiology, radiobiology, and risk (program area committee 1) session Q&A. PMID- 25551497 TI - Decision making for late-phase recovery from nuclear or radiological incidents. AB - Much of the effort on radiological emergency preparedness has focused on the initial responses to an event (e.g., rescuing or triaging missions), while guidance on the more complex issues (e.g., radiological remediation or population resettlement) of long-term recovery has been lacking. The recent major nuclear accidents at Chernobyl, Ukraine, in 1986 and Fukushima, Japan, in 2011 have clearly shown that radiological effects can spread over extended areas and last for a long period of time, thus making planning for long-term recovery an essential extension to the overall response. Similar challenges may be encountered in the aftermath of malicious acts involving devices such as radiological dispersal devices or improvised nuclear devices. Given the potentially unprecedented nature of the impact, the affected communities would have to face a series of daunting tasks in attempting to return to normality. To achieve this objective, a top priority is to conduct an effective and timely remediation of the contaminated areas. In contrast to emergency responses, the late-stage recovery effort is necessarily community focused and therefore will be driven by stakeholders. However, given the nature of the contamination and the widespread impact, cleanup in the aftermath of a major incident could involve a rather complex decision-making process for which the requisite experiences may not be readily available. To this end, the National Council on Radiation Protection and Measurements (NCRP) established a scientific committee to prepare a comprehensive study that develops a framework and recommends an approach to optimizing decision making in late-phase recovery in the wake of major nuclear or radiological incidents. This study, published as NCRP Report No. 175, addresses all relevant dimensions in decision making for long-term recovery. The report describes optimization as a flexible, graded, and iterative process that consists of a series of steps, all of which involve deliberations with stakeholders as central to the success of a community-focused recovery. Above all, it also presents a new paradigm that specifically addresses a long-term approach to managing the challenging radiological conditions that could be encountered by the communities. In conclusion, the report makes a series of recommendations aimed at enhancing and strengthening the effort toward long-term recovery following a major nuclear or radiological incident. PMID- 25551496 TI - Public health and medical preparedness for a nuclear detonation: the nuclear incident medical enterprise. AB - Resilience and the ability to mitigate the consequences of a nuclear incident are enhanced by (1) effective planning, preparation and training; (2) ongoing interaction, formal exercises, and evaluation among the sectors involved; (3) effective and timely response and communication; and (4) continuous improvements based on new science, technology, experience, and ideas. Public health and medical planning require a complex, multi-faceted systematic approach involving federal, state, local, tribal, and territorial governments; private sector organizations; academia; industry; international partners; and individual experts and volunteers. The approach developed by the U.S. Department of Health and Human Services Nuclear Incident Medical Enterprise (NIME) is the result of efforts from government and nongovernment experts. It is a "bottom-up" systematic approach built on the available and emerging science that considers physical infrastructure damage, the spectrum of injuries, a scarce resources setting, the need for decision making in the face of a rapidly evolving situation with limited information early on, timely communication, and the need for tools and just-in time information for responders who will likely be unfamiliar with radiation medicine and uncertain and overwhelmed in the face of the large number of casualties and the presence of radioactivity. The components of NIME can be used to support planning for, response to, and recovery from the effects of a nuclear incident. Recognizing that it is a continuous work-in-progress, the current status of the public health and medical preparedness and response for a nuclear incident is provided. PMID- 25551498 TI - Nuclear and radiological security and safety (program area committees 3 & 5) session Q&A. PMID- 25551499 TI - Radiation safety of sealed radioactive sources. AB - Sealed radioactive sources are used in a wide variety of occupational settings and under differing regulatory/licensing structures. The definition of a sealed radioactive source varies between U.S. regulatory authorities and standard setting organizations. Potential problems with sealed sources cover a range of risks and impacts. The loss of control of high activity sealed sources can result in very high or even fatal doses to members of the public who come in contact with them. Sources that are not adequately sealed and that fail can cause spread of contamination and potential intake of radioactive material. There is also the possibility that sealed sources may be (or threaten to be) used for terrorist purposes and disruptive opportunities. Until fairly recently, generally licensed sealed sources and devices received little, if any, regulatory oversight and were often forgotten, lost or unaccounted for. Nonetheless, generally licensed devices can contain fairly significant quantities of radioactive material, and there is some potential for exposure if a device is treated in a way for which it was never designed. Industrial radiographers use and handle high activity and/or high dose-rate sealed sources in the field with a high degree of independence and minimal regulatory oversight. Failure to follow operational procedures and properly handle radiography sources can and has resulted in serious injuries and death. Industrial radiographers have experienced a disproportionately large fraction of incidents that have resulted in unintended exposure to radiation. Sources do not have to contain significant quantities of radioactive material to cause problems in the event of their failure. A loss of integrity can cause the spread of contamination and potential exposure to workers and members of the public. The National Council on Radiation Protection and Measurements has previously provided recommendations on select aspects of sealed source programs. Future efforts to provide recommendations for sealed source programs are discussed. PMID- 25551500 TI - Pennsylvania's technologically enhanced, naturally occurring radioactive material experiences and studies of the oil and gas industry. AB - This presentation provides an overview of the Commonwealth of Pennsylvania's experiences and ongoing studies related to technologically enhanced, naturally occurring radioactive material (TENORM) in the oil and gas industry. It has been known for many years that Pennsylvania's geology is unique, with several areas having relatively high levels of natural uranium and thorium. In the 1950s, a few areas of the state were evaluated for commercial uranium production. In the late 1970s, scoping studies of radon in homes prompted the Pennsylvania Department of Environmental Protection (DEP) Bureau of Radiation Protection (BRP) to begin planning for a larger state-wide radon study. The BRP and Oil and Gas Bureau also performed a TENORM study of produced water in the early 1990s for a number of conventional oil and gas wells. More recently, BRP and the Bureau of Solid Waste developed radiation monitoring regulations for all Pennsylvania solid waste disposal facilities. These were implemented in 2001, prompting another evaluation of oil and gas operations and sludge generated from the treatment of conventionally produced water and brine but mainly focused on the disposal of TENORM solid waste in the state's Resource Conservation and Recovery Act Subtitle D landfills. However, since 2008, the increase in volumes of gas well wastewater and levels of Ra observed in the unconventional shale gas well flow-back fracking water has compelled DEP to fully re-examine these oil and gas operations. Specifically, with BRP in the lead, a new TENORM study of oil and gas operations and related wastewater treatment operations has been initiated (), supported by an American National Standards Institute standard on TENORM () and a U.S. Government Accountability Office report on shale resource development and risks (). This study began in early 2013 and will examine the potential public and worker radiation exposure and environmental impact as well as re-evaluate TENORM waste disposal. This presentation summarizes conventional and unconventional oil and gas well operations, geology and respective uranium/thorium content, radium content in oil and gas wastewater, treatment solids, radon in natural gas, the scope of other TENORM issues in the state, regulatory framework, national regulations and guidance. It also provides an overview of past and the status of ongoing TENORM studies in the Commonwealth (; Rowan and Kraemer 2012; ). PMID- 25551501 TI - Application of an informatics-based decision-making framework and process to the assessment of radiation safety in nanotechnology. AB - The National Council on Radiation Protection and Measurements (NCRP) established NCRP Scientific Committee 2-6 to develop a report on the current state of knowledge and guidance for radiation safety programs involved with nanotechnology. Nanotechnology is the understanding and control of matter at the nanoscale, at dimensions between ~1 and 100 nm, where unique phenomena enable novel applications. While the full report is in preparation, this paper presents and applies an informatics-based decision-making framework and process through which the radiation protection community can anticipate that nano-enabled applications, processes, nanomaterials, and nanoparticles are likely to become present or are already present in radiation-related activities; recognize specific situations where environmental and worker safety, health, well-being, and productivity may be affected by nano-related activities; evaluate how radiation protection practices may need to be altered to improve protection; control information, interpretations, assumptions, and conclusions to implement scientifically sound decisions and actions; and confirm that desired protection outcomes have been achieved. This generally applicable framework and supporting process can be continuously applied to achieve health and safety at the convergence of nanotechnology and radiation-related activities. PMID- 25551502 TI - Operational and environmental radiation protection (program area committees 2 & 5)-session Q&A. PMID- 25551503 TI - Framework and need for dosimetry and measurements: quantitation matters. AB - It has always been recognized that radiation measurements and dosimetry (M &8; D) play a crucial role in developing radiation protection programs for workers and members of the public, particularly as they relate to mitigating potential health risks from exposure to radiation. The National Council on Radiation Protection and Measurements (NCRP) has always devoted significant resources to these scientific disciplines in terms of its published reports, and it is anticipated that this emphasis will continue. This includes focus on both external and internal radiation exposure as well as radiation and radioactivity measurement methodology. NCRP, as part of its management of scientific activities, has designated Program Area Committee 6 to focus on radiation M &8; D. This paper briefly describes how radiation M &8; D has been addressed historically in terms of NCRP activities. It reports how the emphases have changed over the years and how NCRP has worked effectively with other radiation protection organizations, such as the International Commission on Radiological Protection, to leverage its expertise in advancing the science of M &8; D. Current and prospective activities in M &8; D by NCRP are also described to frame the future in these areas of interest necessary for the optimum application of radiation protection principles and programs. PMID- 25551505 TI - Protection of patients in diagnostic and interventional medical imaging: collaboration is the key. AB - The radiology community (medical physicists, radiologic technologists, radiologists, and interventional proceduralists) has led the educational and awareness efforts in the medical arena to reduce radiation dose to patients through effective collaborations that bridge traditional medical specialty silos to reach health worker stakeholders. These successful collaborations have also included both vendors and regulators, with the overarching goal of radiation protection of patients (justification, optimization, and use of dose reference levels). This focus on patients often raises overall safety awareness and lowers occupational radiation doses as well. It is critical that the entire radiology community continue to act as leaders in these radiation safety efforts for both employees and patients. In order to be successful, it is important to understand safety culture and the growing, worldwide, multimedia resources that are available. There is little time or budget to recreate or duplicate training materials or risk communication information that may already exist. Together with the increasingly fast-paced and demanding healthcare environment and sharp focus on quality, it has never been more important to understand how to achieve better quality care for radiology departments. It is also important to measure and report quality for many customers, including patients, referring providers, and many other stakeholders. This short report will briefly define safety culture and describe methods for using collective learning tools that document radiation protection of patients in diagnostic and interventional imaging. These tools include the use of imaging modality registries, such as the Computed Tomography Does Index Registry, peer review of imaging reports, the use of clinical decision support, and guidelines. Finally, the Image Gently and Image Wisely campaigns provide examples of cross-disciplinary collaboration to improve radiation protection of patients. PMID- 25551504 TI - Dose reconstruction for the million worker study: status and guidelines. AB - The primary aim of the epidemiologic study of one million U.S. radiation workers and veterans [the Million Worker Study (MWS)] is to provide scientifically valid information on the level of radiation risk when exposures are received gradually over time and not within seconds, as was the case for Japanese atomic bomb survivors. The primary outcome of the epidemiologic study is cancer mortality, but other causes of death such as cardiovascular disease and cerebrovascular disease will be evaluated. The success of the study is tied to the validity of the dose reconstruction approaches to provide realistic estimates of organ specific radiation absorbed doses that are as accurate and precise as possible and to properly evaluate their accompanying uncertainties. The dosimetry aspects for the MWS are challenging in that they address diverse exposure scenarios for diverse occupational groups being studied over a period of up to 70 y. The dosimetric issues differ among the varied exposed populations that are considered: atomic veterans, U.S. Department of Energy workers exposed to both penetrating radiation and intakes of radionuclides, nuclear power plant workers, medical radiation workers, and industrial radiographers. While a major source of radiation exposure to the study population comes from external gamma- or x-ray sources, for some of the study groups, there is a meaningful component of radionuclide intakes that requires internal radiation dosimetry assessments. Scientific Committee 6-9 has been established by the National Council on Radiation Protection and Measurements (NCRP) to produce a report on the comprehensive organ dose assessment (including uncertainty analysis) for the MWS. The NCRP dosimetry report will cover the specifics of practical dose reconstruction for the ongoing epidemiologic studies with uncertainty analysis discussions and will be a specific application of the guidance provided in NCRP Report Nos. 158, 163, 164, and 171. The main role of the Committee is to provide guidelines to the various groups of dosimetrists involved in the MWS to ensure that certain dosimetry criteria are considered: calculation of annual absorbed doses in the organs of interest, separation of low and high linear-energy transfer components, evaluation of uncertainties, and quality assurance and quality control. It is recognized that the MWS and its approaches to dosimetry are a work in progress and that there will be flexibility and changes in direction as new information is obtained with regard to both dosimetry and the epidemiologic features of the study components. This paper focuses on the description of the various components of the MWS, the available dosimetry results, and the challenges that have been encountered. It is expected that the Committee will complete its report in 2016. PMID- 25551506 TI - Protection and measurement in radiation therapy. AB - In radiation therapy, unlike most other applications involving radiation, the intention is to deliver high doses of radiation to diseased tissue, constrained by the effects of radiation to healthy tissue. With regard to patient exposure, the radiation protection framework of justification, optimization, and limitation is a direct part of the prescription process of radiation therapy. Staff and public exposures are typically far below occupational maximum permissible exposures. However, a number of other issues arise in radiation therapy that fall into the category of radiation protection. After an historical review, this paper discusses several contemporary and emerging concerns within radiation therapy, including fetal dose, secondary malignancies, and dose to implantable devices, all of which involve accurate dose assessment outside the intended treatment volume. Other concerns include quality and safety, molecularly based disease assessment and treatment, and other novel treatment strategies. The paper ends with a discussion of the interplay between best practices and regulatory oversight. PMID- 25551508 TI - Radiation protection in medicine (program area committee 4) session Q&A. PMID- 25551507 TI - Protection of the gametes embryo/fetus from prenatal radiation exposure. AB - There is no convincing evidence of germline mutation manifest as heritable disease in the offspring of humans attributable to ionizing radiation, yet radiation clearly induces mutations in microbes and somatic cells of rodents and humans. Doses to the embryo estimated to be in the range of 0.15-0.2 Gy during the pre-implantation and pre-somite stages may increase the risk of embryonic loss. However, an increased risk of congenital malformations or growth retardation has not been observed in the surviving embryos. These results are primarily derived from mammalian animal studies and are referred to as the "all or-none phenomenon." The tissue reaction effects of ionizing radiation (previously referred to as deterministic effects) are congenital malformations, mental retardation, decreased intelligence quotient, microcephaly, neurobehavioral effects, convulsive disorders, growth retardation (height and weight), and embryonic and fetal death (miscarriage, stillbirth). All these effects are consistent with having a threshold dose below which there is no increased risk. The risk of cancer in offspring that have been exposed to diagnostic x-ray procedures while in utero has been debated for 55 y. High doses to the embryo or fetus (e.g., >0.5 Gy) increase the risk of cancer. Most pregnant women exposed to x-ray procedures and other forms of ionizing radiation today received doses to the embryo or fetus <0.1 Gy. The risk of cancer in offspring exposed in utero at exposures <0.1 Gy is controversial and has not been fully resolved. Diagnostic imaging procedures using ionizing radiation that are clinically indicated for the pregnant patient and her fetus should be performed because the clinical benefits outweigh the potential oncogenic risks. PMID- 25551509 TI - Historical trends in radiation protection, policy and communications: 1964 to the present. AB - The past 50 y have seen substantial developments in radiation epidemiology, technology, dosimetry, regulations, and protection efforts. During the last five decades, radiation communication has also evolved, growing more sophisticated as communication science and practice have advanced and matured. This talk covers the trends in radiation protection over the past 50 y, illustrated by progress in science and practice of risk communication and changes in societal expectations, and examines challenges that will confront radiation risk communication in the future. PMID- 25551510 TI - U.S. radiation protection: role of national and international recommendations and opportunities for collaboration (harmony, not dissonance). AB - For much of the 20th century, U.S. radiation protection policies were similar to those elsewhere in the world, in large part because the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP) were closely aligned. In the 1970s, several U.S. regulations were released at about the same time as the 1977 recommendations from ICRP. The regulatory development process in the United States can be lengthy with ample opportunities for public involvement. While such deliberation is essential and beneficial, the rulemaking process does not lend itself to making frequent technical updates to rules. For this reason, many of the current radiation protection regulations in the United States are out of step with current recommendations of the ICRP and NCRP. The U.S. Nuclear Regulatory Commission and the U.S. Environmental Protection Agency are considering updates to important radiation protection regulations. These regulatory development actions could present the United States with an opportunity for incorporating the latest science into the U.S. system of radiation protection and provide for consideration of the latest recommendations of ICRP and NCRP. In particular, a revision of the recommendations in NCRP Report No. 116 (Limitation of Exposure to Ionizing Radiation) could provide U.S. agencies with useful advice to be considered in these rulemakings. PMID- 25551511 TI - Radiation education, risk communication, outreach, and policy (program area committee 7)-session Q&A. PMID- 25551512 TI - Capturing opportunities and meeting challenges in radiation protection. AB - This summary of the 2014 Annual Meeting of the National Council on Radiation Protection and Measurement (NCRP) captures the opportunities presented during the Warren K. Sinclair Keynote Address, the Lauriston S. Taylor Lecture, and the six scientific sessions including the subsequent questions and answers. It captures the important issues that emerge in these opportunities and discusses the challenges that they bring to radiation protection. These opportunities arise in the basic sciences; in operational areas such as emerging technologies, preparing for the improbable but possible event, industry and medicine; and in education, communication and policy. The challenges include identifying the most important aspects of radiation protection and measurement, prioritizing them in accordance with the NCRP mission, and gaining support for the activities of the NCRP to address these issues in the fulfillment of its charter. PMID- 25551513 TI - Risks and challenges of radiation exposure at work. PMID- 25551516 TI - High anhydrous proton conductivity of imidazole-loaded mesoporous polyimides over a wide range from subzero to moderate temperature. AB - On-board fuel cell technology requires proton conducting materials with high conductivity not only at intermediate temperatures for work but also at room temperature and even at subzero temperature for startup when exposed to the colder climate. To develop such materials is still challenging because many promising candidates for the proton transport on the basis of extended microstructures of water molecules suffer from significant damage by heat at temperatures above 80 degrees C or by freeze below -5 degrees C. Here we show imidazole loaded tetrahedral polyimides with mesopores and good stability (Im@Td PNDI 1 and Im@Td-PPI 2) exhibiting a high anhydrous proton conductivity over a wide temperature range from -40 to 90 degrees C. Among all anhydrous proton conductors, the conductivity of 2 is the highest at temperatures below 40 degrees C and comparable with the best materials, His@[Al(OH)(1,4-ndc)]n and [Zn3(H2PO4)6(H2O)3](Hbim), above 40 degrees C. PMID- 25551517 TI - Dental caries and periodontal disease in Brazilian children and adolescents with cerebral palsy. AB - The aim of the present study was determine the prevalence and factors associated with dental caries and periodontal disease in Brazilian children and adolescents with cerebral palsy (CP). This is a cross-sectional study conducted with 80 patients ranging in age from 2 to 18 years old. Oral exams were conducted by an examiner with records of DMFT, dmft, Gingival Bleeding Index (GBI) and Community Periodontal Index (CPI). The statistical analysis used Poisson Regression with robust variance estimation (alpha = 0.05). The prevalence of dental caries was 59.3%, with DMFT and mean dmft of 1.71 +/- 2.42 and 2.22 +/- 3.23, respectively. The mean GBI was 22.44%, and in the CPI, the prevalence of gingival bleeding, calculus, shallow and deep pockets were 94.73%, 79.62%, 12.90% and 3.22%, respectively. The caregiver's educational level of less than eight years were associated with the dental caries experience (PR = 1.439; 95%CI = 1.09-1.89). The periodontal alterations were associated with female sex (PR = 0.82; 95%CI = 0.69 0.97), caregiver's educational level of less than eight years (PR = 1.15; 95%CI = 1.03-1.29), poor oral perception (PR = 0.89; 95%CI = 0.80-0.98), serious communication problem (PR = 0.87; 95%CI = 0.76-0.99) and athetoid type of CP (PR = 0.85; 95%CI = 0.75-0.97). The patients with CP presented high dental caries experience and periodontal alterations, which were associated with their demographic, socioeconomic, oral health perception and systemic information. PMID- 25551518 TI - Identifying environmental risk factors of cholera in a coastal area with geospatial technologies. AB - Satellites contribute significantly to environmental quality and public health. Environmental factors are important indicators for the prediction of disease outbreaks. This study reveals the environmental factors associated with cholera in Zhejiang, a coastal province of China, using both Remote Sensing (RS) and Geographic information System (GIS). The analysis validated the correlation between the indirect satellite measurements of sea surface temperature (SST), sea surface height (SSH) and ocean chlorophyll concentration (OCC) and the local cholera magnitude based on a ten-year monthly data from the year 1999 to 2008. Cholera magnitude has been strongly affected by the concurrent variables of SST and SSH, while OCC has a one-month time lag effect. A cholera prediction model has been established based on the sea environmental factors. The results of hot spot analysis showed the local cholera magnitude in counties significantly associated with the estuaries and rivers. PMID- 25551519 TI - ABM Clinical Protocol #13: Contraception During Breastfeeding, Revised 2015. AB - A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 25551520 TI - Penaeus orientolis prawn freshness rapid determination method based on electronic nose and non-linear stochastic resonance technique. AB - In this paper, Penaeus orientolis prawn freshness rapid determination method using electronic nose (e-nose) and non-linear data processing technique is studied. E-nose responses to prawns stored at 4 degrees C are measured. Meanwhile, physical/chemical indexes (firmness, pH, total volatile basic nitrogen (TVB-N), total viable count (TVC), and human sensory evaluation) are examined to provide freshness references for e-nose analysis. E-nose measurement data is analyzed by principal component analysis (PCA), stochastic resonance (SR), and double-layered cascaded serial stochastic resonance (DCSSR). PCA partially discriminates prawns under different storage time. SR and DCSSR signal-to-noise ratio (SNR) spectrum eigen values discriminate prawns successfully. Multi variables regressions (MVR) are conducted between physical/chemical indexes and SR/DCSSR output SNR minimal (SNR-Min) values. Results indicate that SNR-Min values present more significant linearity relation with physical/chemical indexes. Prawn freshness forecasting model is developed via Harris fitting regression on DCSSR SNR-Min values. Validating experiments demonstrate that forecasting accuracy of this model is 94.29%. PMID- 25551521 TI - Household food security and hunger in rural and urban communities in the Free State Province, South Africa. AB - Household food security impacts heavily on quality of life. We determined factors associated with food insecurity in 886 households in rural and urban Free State Province, South Africa. Significantly more urban than rural households reported current food shortage (81% and 47%, respectively). Predictors of food security included vegetable production in rural areas and keeping food for future use in urban households. Microwave oven ownership was negatively associated with food insecurity in urban households and using a primus or paraffin stove positively associated with food insecurity in rural households. Interventions to improve food availability and access should be emphasized. PMID- 25551522 TI - A roadside study of observable driver distractions. AB - OBJECTIVE: This study investigated the prevalence of observable distractions while driving and the effect of drivers' characteristics and time-related variables on their prevalence. METHODS: Using roadside observation, 2 independent observers collected data at 4 randomly selected locations in St. Albans, UK. RESULTS: Of the 10,984 drivers observed, 16.8% were engaged in a secondary task, with talking to passengers being the most common distraction (8.8%), followed by smoking (1.9%) and talking on a hands-free mobile phone (1.7%). An additional 1.0% were observed talking on a handheld phone, and the rest of the distractions (e.g., texting, drinking) were recorded in less than 1% of the drivers observed. Gender-related differences were found for a number of different distractions (i.e., talking to passengers, drinking, and handheld mobile phone conversations), but age emerged as a significant predictor for most secondary tasks, including talking to passengers, smoking, hands-free mobile phone use, handheld mobile phone use, texting/keying numbers, drinking, and engagement in any type of distraction (all distractions combined). The overall pattern for age was that middle-aged and older drivers were less likely to be distracted than younger drivers. CONCLUSIONS: This work provides further evidence of the relatively high rate of distracted driving in the UK. The findings clearly indicate that younger drivers are more likely to drive distracted, which probably contributes to their higher crash rates. PMID- 25551523 TI - The public-private pendulum--patient choice and equity in Sweden. PMID- 25551524 TI - The amyloidogenic V122I transthyretin variant in elderly black Americans. AB - BACKGROUND: Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS: We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS: After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS: We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.). PMID- 25551525 TI - Biologically inactive leptin and early-onset extreme obesity. AB - Mutations in the gene encoding leptin (LEP) typically lead to an absence of circulating leptin and to extreme obesity. We describe a 2-year-old boy with early-onset extreme obesity due to a novel homozygous transversion (c.298G->T) in LEP, leading to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y) and high immunoreactive levels of leptin. Overexpression studies confirmed that the mutant protein is secreted but neither binds to nor activates the leptin receptor. The mutant protein failed to reduce food intake and body weight in leptin-deficient ob/ob mice. Treatment of the patient with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss. PMID- 25551526 TI - Disorders of plasma sodium--causes, consequences, and correction. PMID- 25551527 TI - Images in clinical medicine. Wellens' syndrome. PMID- 25551528 TI - Clinical problem-solving. Diagnosing one letter at a time. PMID- 25551531 TI - Hemoglobin threshold for transfusion in septic shock. PMID- 25551532 TI - Hemoglobin threshold for transfusion in septic shock. PMID- 25551530 TI - Atypical hyperplasia of the breast--risk assessment and management options. PMID- 25551533 TI - Hemoglobin threshold for transfusion in septic shock. PMID- 25551534 TI - Hemoglobin threshold for transfusion in septic shock. PMID- 25551535 TI - Inhaled glucocorticoids and COPD exacerbations. PMID- 25551536 TI - Inhaled glucocorticoids and COPD exacerbations. PMID- 25551537 TI - Inhaled glucocorticoids and COPD exacerbations. PMID- 25551538 TI - Inhaled glucocorticoids and COPD exacerbations. PMID- 25551539 TI - Fractional flow reserve-guided PCI. PMID- 25551540 TI - Fractional flow reserve-guided PCI. PMID- 25551541 TI - Health and health care in South Africa. PMID- 25551542 TI - Health and health care in South Africa. PMID- 25551543 TI - Airway fistula closure after stem-cell infusion. PMID- 25551544 TI - International health care systems--selected measures. PMID- 25551545 TI - Images in clinical medicine. Mobile large left atrial thrombus. PMID- 25551546 TI - The molecular structure of methylfluoroisocyanato silane: a combined microwave spectral and theoretical study. AB - The structure of methylfluoroisocyanato silane (Me-SiHF-NCO) has been deduced by a combination of microwave (MW) spectra including data from (12,13)C, (14,15)N, and (28,29,30)Si isotopomers, and ab initio calculations. The rotational constants (RC) for the most abundant isotopes are A = 6301.415(45), B = 1535.078(39), and C = 1310.485(39) MHz. The symmetric quartic centrifugal distortion constants have been identified, using the I(r) representation for C1 symmetry, which includes the 3-fold rotor. The spectra of the isotopomer combinations gave a partial substitution structure where the C2Si3, Si3N4, and N4C9 bond lengths are 1.8427(70), 1.7086(77), and 1.2120(90)A; although the C2Si3N4 angle is close to tetrahedral (109.71 degrees (52)), the Si3N4C9 angle is wide (157.69 degrees (18)). The rotational constants are only consistent with a trans-orientation for each of the dihedral angles (HC2Si3N4, C2Si3N4C9, and Si3N4C9O10). The structural analysis was completed by calculations of the equilibrium structure, using MP3 in conjunction with an aug-cc-pVTZ basis set (434 Cartesian basis functions). This gave A = 6240.324, B = 1518.489, and C = 1297.819 MHz. The equilibrium structure bond lengths for C2Si3, Si3N4, and N4C9 were 1.8485, 1.7147, and 1.1947 A, with the C2Si3N4 and Si3N4C9 angles 109.55 and 156.67 degrees , respectively. Although the SiNC polynomial bending surface is complex, the data points can be fit to the simple form V(x) = 50.36(91)x(4) - 7.53(44)x(5), with comparatively little loss of accuracy. The A-rotational constant is strongly influenced by the Si3N4C9 angle, and smaller bases lead to this angle being nearly linear. The theoretical results suggest a very heavily polarized molecule, which is supported by the positions of the local electron density minima within the bonds and electron density calculations. PMID- 25551547 TI - Application of nanostructured TCNQ to potentiometric ion-selective K(+) and Na(+) electrodes. AB - A new type of potentiometric solid-state ion-selective electrode (SS-ISE) has been fabricated with an intermediate layer made of 7,7,8,8 tetracyanoquinodimethane (TCNQ) or its ion-radical salts and an ionophore-based ion-selective membrane. To show the influence of the TCNQ layer on electrode selectivity, sodium- and potassium-sensitive membranes were applied. A good Nernstian response with a slope of 59.24 mV/dec in the range from 10(-6.5) to 10( 1) M KCl and 58.68 mV/dec (10(-6) to 10(-1) M NaCl) was observed. The influence of an interfacial water film was assessed by an aqueous-layer test performed during potentiometric measurements. The stability of the electrical potential of the new solid-contact electrodes was tested by performing current-reversal chronopotentiometry, and the capacitance of the electrodes is 132 MUF or 154 MUF for K(+) and Na(+) solid-contact electrodes. These properties confirmed the analytical applicability of TCNQ-based SC-ISEs and should allow the development of a new solid-state ion sensor group. PMID- 25551548 TI - Exosome-dependent and independent mechanisms are involved in prion-like transmission of propagated Cu/Zn superoxide dismutase misfolding. AB - Amyotrophic lateral sclerosis (ALS), a fatal adult-onset degenerative neuromuscular disorder with a poorly defined etiology, progresses in an orderly spatiotemporal manner from one or more foci within the nervous system, reminiscent of prion disease pathology. We have previously shown that misfolded mutant Cu/Zn superoxide dismutase (SOD1), mutation of which is associated with a subset of ALS cases, can induce endogenous wild-type SOD1 misfolding in the intracellular environment in a templating fashion similar to that of misfolded prion protein. Our recent observations further extend the prion paradigm of pathological SOD1 to help explain the intercellular transmission of disease along the neuroaxis. It has been shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or released to the extracellular environment on the surface of exosomes secreted from living cells. Furthermore, once propagation of misfolded wild-type SOD1 has been initiated in human cell culture, it continues over multiple passages of transfer and cell growth. Propagation and transmission of misfolded wild-type SOD1 is therefore a potential mechanism in the systematic progression of ALS pathology. PMID- 25551549 TI - A conservative mutant of a proteolytic fragment produced during fibril formation enhances fibrillogenesis. AB - The fibrillogenesis of a peptide corresponding to residues 35-51 of human alpha lactalbumin (1GYDTQAIVENNESTEYG17) can be dramatically enhanced by the addition of a tetrapeptide TDYG homologous to its C-terminus (TEYG). Generation of spontaneous hydrolytic products similar to this peptide was demonstrated by mass spectrometry analysis of GYDTQAIVENNESTEYG peptide solution components during fibrillogenesis. Possible mechanisms and roles of short peptides in protein metabolism are discussed. PMID- 25551550 TI - Percutaneous transhepatic biliary drainage in an infant with obstructive jaundice caused by neuroblastoma. AB - Neuroblastoma presenting with obstructive jaundice is a rare event. Management of this condition includes surgery, chemotherapy, radiotherapy, temporary cholecystostomy tube, endoscopic retrograde cholangiopancreatography (ERCP), and internal biliary drainage (IBD). We herein describe our experience with one infant affected by neuroblastoma presenting with jaundice, who successfully underwent percutaneous transhepatic biliary drainage (PTBD). This report introduces PTBD as a viable treatment option for neuroblastoma and obstructive jaundice and provides a review of the pertinent literature. PMID- 25551551 TI - Bereavement, postdisaster trauma, and behavioral changes in tsunami survivors. AB - This study examined whether the death of family members intensifies the survivors' posttraumatic stress and behavioral changes. Data were collected by interviewing 416 adult survivors from nine habitations of the Nagapattinam district in the state of Tamil Nadu in India 14 months after the 2004 tsunami. Compared to those nonbereaved, bereaved survivors reported more posttraumatic stress disorder, depression, anxiety, negative affect, deteriorated mental health, adverse physical health symptoms, alcohol consumption, family conflicts, and fear. When a tsunami trauma includes death of a loved one, psychological, physical, and behavioral ramifications are especially severe. PMID- 25551553 TI - Whale shark (Rhincodon typus) seasonal presence, residence time and habitat use at darwin island, galapagos marine reserve. AB - The life history of the whale shark (Rhincodon typus), including its reproductive ecology, still remains largely unknown. Here, we present results from the first whale shark population study around Darwin Island, Galapagos Marine Reserve. Following a diversified approach we characterized seasonal occurrence, population structure and size, and described habitat use of whale sharks based on fine scale movements around the island. Whale shark presence at Darwin Island was negatively correlated with Sea Surface Temperature (SST), with highest abundance corresponding to a cool season between July and December over six years of monitoring. From 2011 to 2013 we photo-identified 82 whale sharks ranging from 4 to 13.1 m Total Length (TL). Size distribution was bimodal, with a great majority (91.5%) of adult female individuals averaging 11.35 m+/-0.12 m (TL+/-SE), all but one showing signs of a potential pregnancy. Population dynamics models for apparently pregnant sharks estimated the presence of 3.76+/-0.90 (mean +/- SE) sharks in the study area per day with an individual residence time of 2.09+/-0.51 (mean +/- SE) days. Movement patterns analysis of four apparently pregnant individuals tracked with acoustic tags at Darwin Island revealed an intense use of Darwin's Arch, where no feeding or specific behavior has been recorded, together with periodic excursions around the island's vicinity. Sharks showed a preference for intermediate depths (20-30 m) with occasional dives mostly to mid water, remaining the majority of their time at water temperatures between 24-25 degrees C. All of our results point to Darwin Island as an important stopover in a migration, possibly with reproductive purposes, rather than an aggregation site. Current studies carried out in this area to investigate regional scale movement patterns may provide essential information about possible pupping grounds for this enigmatic species. PMID- 25551552 TI - Distractor evoked deviations of saccade trajectory are modulated by fixation activity in the superior colliculus: computational and behavioral evidence. AB - Previous studies have shown that saccades may deviate towards or away from task irrelevant visual distractors. This observation has been attributed to active suppression (inhibition) of the distractor location unfolding over time: early in time inhibition at the distractor location is incomplete causing deviation towards the distractor, while later in time when inhibition is complete the eyes deviate away from the distractor. In a recent computational study, Wang, Kruijne and Theeuwes proposed an alternative theory that the lateral interactions in the superior colliculus (SC), which are characterized by short-distance excitation and long-distance inhibition, are sufficient for generating both deviations towards and away from distractors. In the present study, we performed a meta analysis of the literature, ran model simulations and conducted two behavioral experiments to further explore this unconventional theory. Confirming predictions generated by the model simulations, the behavioral experiments show that a) saccades deviate towards close distractors and away from remote distractors, and b) the amount of deviation depends on the strength of fixation activity in the SC, which can be manipulated by turning off the fixation stimulus before or after target onset (Experiment 1), or by varying the eccentricity of the target and distractor (Experiment 2). PMID- 25551554 TI - Plant-plant-microbe mechanisms involved in soil-borne disease suppression on a maize and pepper intercropping system. AB - BACKGROUND: Intercropping systems could increase crop diversity and avoid vulnerability to biotic stresses. Most studies have shown that intercropping can provide relief to crops against wind-dispersed pathogens. However, there was limited data on how the practice of intercropping help crops against soil-borne Phytophthora disease. PRINCIPAL FINDINGS: Compared to pepper monoculture, a large scale intercropping study of maize grown between pepper rows reduced disease levels of the soil-borne pepper Phytophthora blight. These reduced disease levels of Phytophthora in the intercropping system were correlated with the ability of maize plants to form a "root wall" that restricted the movement of Phytophthora capsici across rows. Experimentally, it was found that maize roots attracted the zoospores of P. capsici and then inhibited their growth. When maize plants were grown in close proximity to each other, the roots produced and secreted larger quantities of 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) and 6 methoxy-2-benzoxazolinone (MBOA). Furthermore, MBOA, benzothiazole (BZO), and 2 (methylthio)-benzothiazole (MBZO) were identified in root exudates of maize and showed antimicrobial activity against P. capsici. CONCLUSIONS: Maize could form a "root wall" to restrict the spread of P. capsici across rows in maize and pepper intercropping systems. Antimicrobe compounds secreted by maize root were one of the factors that resulted in the inhibition of P. capsici. These results provide new insights into plant-plant-microbe mechanisms involved in intercropping systems. PMID- 25551556 TI - Annual movement patterns of endangered ivory gulls: the importance of sea ice. AB - The ivory gull (Pagophila eburnea) is an endangered seabird that spends its entire year in the Arctic environment. In the past three decades, threats from various sources have contributed to a >70% decline in Canada. To assess the annual habitat needs of this species, we attached satellite transmitters to 12 ivory gulls on Seymour Island, Nunavut in 2010, which provided up to four breeding seasons of tracking data. Analysis of migratory behaviour revealed considerable individual variation of post-breeding migratory route selection. Ivory gulls traveled a median of 74 days during post-breeding migration, but only 18 days during pre-breeding migration. In contrast to predictions, ivory gulls did not use the Greenland coast during migratory periods. Ivory gulls overwintered near the ice edge in Davis Strait, but also used the Labrador Sea in late February and March. We suggest that the timing of formation and recession and extent of sea ice plays a large role in ivory gull distribution and migratory timing. PMID- 25551555 TI - Denervation impairs regeneration of amputated zebrafish fins. AB - BACKGROUND: Zebrafish are able to regenerate many of its tissues and organs after damage. In amphibians this process is regulated by nerve fibres present at the site of injury, which have been proposed to release factors into the amputated limbs/fins, promoting and sustaining the proliferation of blastemal cells. Although some candidate factors have been proposed to mediate the nerve dependency of regeneration, the molecular mechanisms involved in this process remain unclear. RESULTS: We have used zebrafish as a model system to address the role of nerve fibres in fin regeneration. We have developed a protocol for pectoral fin denervation followed by amputation and analysed the regenerative process under this experimental conditions. Upon denervation fins were able to close the wound and form a wound epidermis, but could not establish a functional apical epithelial cap, with a posterior failure of blastema formation and outgrowth, and the accumulation of several defects. The expression patterns of genes known to be key players during fin regeneration were altered upon denervation, suggesting that nerves can contribute to the regulation of the Fgf, Wnt and Shh pathways during zebrafish fin regeneration. CONCLUSIONS: Our results demonstrate that proper innervation of the zebrafish pectoral fin is essential for a successful regenerative process, and establish this organism as a useful model to understand the molecular and cellular mechanisms of nerve dependence, during vertebrate regeneration. PMID- 25551557 TI - Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma. AB - Osteosarcoma is an aggressive bone tumor that preferentially develops in adolescents. The tumor is characterized by an abundance of genomic aberrations, which hampers the identification of the driver genes involved in osteosarcoma tumorigenesis. Our study aims to identify these genes by the investigation of focal copy number aberrations (CNAs, <3 Mb). For this purpose, we subjected 26 primary tumors of osteosarcoma patients to high-resolution single nucleotide polymorphism array analyses and identified 139 somatic focal CNAs. Of these, 72 had at least one gene located within or overlapping the focal CNA, with a total of 94 genes. For 84 of these genes, the expression status in 31 osteosarcoma samples was determined by expression microarray analysis. This enabled us to identify the genes of which the over- or underexpression was in more than 35% of cases in accordance to their copy number status (gain or loss). These candidate genes were subsequently validated in an independent set and furthermore corroborated as driver genes by verifying their role in other tumor types. We identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. In osteosarcoma, CMTM8 has been shown to suppress EGFR signaling. In other tumor types, CMTM8 is known to suppress the activity of the oncogenic protein c-Met and GPR177 is known as an overexpressed upstream regulator of the Wnt-pathway. Further studies are needed to determine whether these proteins also exert the latter functions in osteosarcoma tumorigenesis. PMID- 25551558 TI - Epistasis as a determinant of the HIV-1 protease's robustness to mutation. AB - The robustness of phenotypes to mutation is critical to protein evolution; robustness may be an adaptive trait if it promotes evolution. We hypothesised that native proteins subjected to natural selection in vivo should be more robust than proteins generated in vitro in the absence of natural selection. We compared the mutational robustness of two human immunodeficiency virus type 1 (HIV-1) proteases with comparable catalytic efficiencies, one isolated from an infected individual and the second generated in vitro via random mutagenesis. Single mutations in the protease (82 and 60 in the wild-type and mutant backgrounds, respectively) were randomly generated in vitro and the catalytic efficiency of each mutant was determined. No differences were observed between these two protease variants when lethal, neutral, and deleterious mutations were compared (P = 0.8025, chi-squared test). Similarly, average catalytic efficiency (-72.6% and -64.5%, respectively) did not significantly differ between protease mutant libraries (P = 0.3414, Mann Whitney test). Overall, the two parental proteins displayed similar mutational robustness. Importantly, strong and widespread epistatic interactions were observed when the effect of the same mutation was compared in both proteases, suggesting that epistasis can be a key determinant of the robustness displayed by the in vitro generated protease. PMID- 25551559 TI - Predictors of the extent of carotid atherosclerosis in patients treated with radiotherapy for nasopharyngeal carcinoma. AB - OBJECTIVE: To determine the predictors of the extent of carotid atherosclerosis in patients treated with radiotherapy (RT) for nasopharyngeal carcinoma (NPC). METHODS: The present study investigated 129 post-RT NPC patients. Carotid atherosclerotic parameters, such as carotid intima-media thickness, carotid arterial stiffness and carotid plaque burden (plaque score, the presence of plaque and >=50% stenosis) were assessed using ultrasonography. The association between carotid atherosclerotic parameters and nine potential predictors, including age, gender, post-RT duration, radiation dose, chemotherapy, diabetes mellitus, hypertension, hypercholesterolemia, and smoking, were determined using multiple regression. The cutoff values of age, post-RT duration and number of cardiovascular risk factors for the presence of carotid plaque or >=50% carotid stenosis were analyzed using receiver operating characteristic (ROC) curve analysis. Multiple testing was corrected using Benjamini-Hochberg false discovery rate. RESULTS: Age, post-RT duration and number of cardiovascular risk factors were significantly associated with carotid plaque burden (corrected P value, Pcor<0.05). Age of 44.5 years (sensitivity = 99.2% and specificity = 50%, Pcor<0.01) and post-RT duration of 8.5 years (sensitivity = 75.7% and specificity = 64.3%, Pcor<0.001) were the cutoff values for detecting carotid plaque, while post-RT duration of 13.5 years (sensitivity = 66.7% and specificity = 71.6%, Pcor<0.001) and 1.5 cardiovascular risk factors (sensitivity = 40.7% and specificity = 84.3%, Pcor<0.05) were the cutoff values for screening >=50% carotid stenosis. CONCLUSIONS: Age, post-RT duration and number of cardiovascular risk factors are significant predictors of carotid atherosclerosis in post-RT NPC patients. Post-RT NPC patients, who are at least 45 years old, with post-RT duration of 9 years or above, and/or have >=2 cardiovascular risk factors, are more susceptible to carotid atherosclerosis. PMID- 25551560 TI - Granulocyte colony-stimulating factor reduces fibrosis in a mouse model of chronic pancreatitis. AB - BACKGROUND: Chronic pancreatitis (CP) is a necroinflammatory process resulting in extensive pancreatic fibrosis. Granulocyte colony-stimulating factor (G-CSF), a hematopoietic stem cell mobilizer, has been shown to exert an anti-fibrotic effect partly through the enrichment of bone marrow (BM) cells in fibrotic organ. We aimed to test the effect of G-CSF on fibrosis in a mouse model of CP. METHODS: CP was induced in C57Bl/6J mice by consecutive cerulein injection (50 ug/kg/day, 2 days a week) for 6 weeks. Mice were then treated with G-CSF (200 ug/kg/day, 5 day a week) or normal saline for 1 week, and sacrificed at week 7 or week 9 after first cerulein injection. Pancreatic histology, pancreatic matrix metallopeptidase 9 (MMP-9), MMP-13 and collagen expression were examined. Pancreatic myofibroblasts were isolated and cultured with G-CSF. Collagen, MMP-9 and MMP-13 expression by myofibroblasts was examined. The BM-mismatched mice model was used to examine the change of BM-derived myofibroblasts and non myofibroblastic BM cells by G-CSF in the pancreas. RESULTS: The pancreatic collagen expression were significantly decreased in the G-CSF-treated group sacrificed at week 9. While collagen produced from myofibroblasts was not affected by G-CSF, the increase of MMP13 expression was observed in vitro. There were no effect of G-CSF in the number of myofibroblasts and BM-derived myofibroblasts. However, the number of non-myofibroblastic BM cells and macrophages were significantly increased in the pancreata of cerulein- and G-CSF treated mice, suggesting a potential anti-fibrotic role of non-myofibroblastic BM cells and macrophages stimulated by G-CSF. CONCLUSIONS: Our data indicated that G CSF contributed to the regression of pancreatic fibrosis. The anti-fibrotic effects were possibly through the stimulation of MMP-13 from myofibroblasts, and the enhanced accumulation of non-myofibroblastic BM cells and macrophages in the pancreas. PMID- 25551561 TI - Spotting East African mammals in open savannah from space. AB - Knowledge of population dynamics is essential for managing and conserving wildlife. Traditional methods of counting wild animals such as aerial survey or ground counts not only disturb animals, but also can be labour intensive and costly. New, commercially available very high-resolution satellite images offer great potential for accurate estimates of animal abundance over large open areas. However, little research has been conducted in the area of satellite-aided wildlife census, although computer processing speeds and image analysis algorithms have vastly improved. This paper explores the possibility of detecting large animals in the open savannah of Maasai Mara National Reserve, Kenya from very high-resolution GeoEye-1 satellite images. A hybrid image classification method was employed for this specific purpose by incorporating the advantages of both pixel-based and object-based image classification approaches. This was performed in two steps: firstly, a pixel-based image classification method, i.e., artificial neural network was applied to classify potential targets with similar spectral reflectance at pixel level; and then an object-based image classification method was used to further differentiate animal targets from the surrounding landscapes through the applications of expert knowledge. As a result, the large animals in two pilot study areas were successfully detected with an average count error of 8.2%, omission error of 6.6% and commission error of 13.7%. The results of the study show for the first time that it is feasible to perform automated detection and counting of large wild animals in open savannahs from space, and therefore provide a complementary and alternative approach to the conventional wildlife survey techniques. PMID- 25551562 TI - Motivational Interviewing With and Without Normative Feedback for Adolescents With Substance Use Problems: A Preliminary Study. AB - BACKGROUND: Many adolescents in need of substance use disorder treatments never engage in treatment. Further, the most promising interventions that could be adapted to target treatment engagement often use normative feedback (NF) despite concerns about its appropriateness for adolescents. This preliminary study will inform a larger trial designed to isolate whether NF is an inert, helpful, or harmful active ingredient within pretreatment motivational interviewing (MI) interventions designed to increase treatment engagement. METHODS: Adolescents (N = 48) presenting for treatment intake assessments were randomized to receive MI (n = 22) or MI+NF (n = 26) immediately following their assessments. Three-month outcomes included the percentage of youth engaged in treatment, the percentage of youth reporting past-month binge drinking, and the percentage of days of abstinence. RESULTS: Treatments were delivered with high fidelity, and a high proportion of eligible participants were recruited and retained in this study. Participants significantly increased their percentage of days of abstinence by approximately 10% at follow-up (d = .32, P =.03), with no significant differences between groups. Fifty-five percent of youth in MI and 41.7% of youth in MI+NF engaged in treatment (odds ratio [OR] = .60, nonsignificant; 95% confidence interval, CI [0.136-2.68]). CONCLUSIONS: Larger trials should test whether NF is an active ingredient in adolescent MI interventions, and should also determine the mechanisms through which MI+NF may produce effects. PMID- 25551563 TI - MiR-145 expression accelerates esophageal adenocarcinoma progression by enhancing cell invasion and anoikis resistance. AB - BACKGROUND: Carcinoma of the esophagus has a high case fatality ratio and is now the 6th most common cause of cancer deaths in the world. We previously conducted a study to profile the expression of miRNAs in esophageal adenocarcinoma (EAC) pre and post induction therapy. Of the miRNAs differentially expressed post induction chemoradiation, miR-145, a known tumor suppressor miRNA, was upregulated 8-fold following induction therapy, however, its expression was associated with shorter disease-free survival. This unexpected result was explored in this current study. METHODS: In order to study the role of miR-145 in EAC, miRNA-145 was overexpressed in 3 EAC cell lines (OE33, FLO-1, SK-GT-4) and one ESCC cell line (KYSE-410). After validation of the expression of miR-145, hallmarks of cancer such as cell proliferation, resistance to chemotherapy drugs or anoikis, and cell invasion were analyzed. RESULTS: There were no differences in cell proliferation and 5 FU resistance between miR145 cell lines and the control cell lines. miR-145 expression also had no effect on cisplatin resistance in two of three cell lines (OE33 and FLO-1), but miR-145 appeared to protect SK GT-4 cells against cisplatin treatment. However, there was a significant difference in cell invasion, cell adhesion and resistance to anoikis. All three EAC miR-145 cell lines invaded more than their respective controls. Similarly, OE33 and SK-GT-4 miR-145 cell lines were able to survive longer in a suspension state. DISCUSSION: While expression of miR-145 in ESCC stopped proliferation and invasion, expression of miR-145 in EAC cells enhanced invasion and anoikis resistance. Although more work is required to understand how miR-145 conveys these effects, expression of miR-145 appears to promote EAC progression by enhancing invasion and protection against anoikis, which could in turn facilitate distant metastasis. PMID- 25551564 TI - Fish sound production in the presence of harmful algal blooms in the eastern Gulf of Mexico. AB - This paper presents the first known research to examine sound production by fishes during harmful algal blooms (HABs). Most fish sound production is species specific and repetitive, enabling passive acoustic monitoring to identify the distribution and behavior of soniferous species. Autonomous gliders that collect passive acoustic data and environmental data concurrently can be used to establish the oceanographic conditions surrounding sound-producing organisms. Three passive acoustic glider missions were conducted off west-central Florida in October 2011, and September and October 2012. The deployment period for two missions was dictated by the presence of red tide events with the glider path specifically set to encounter toxic Karenia brevis blooms (a.k.a red tides). Oceanographic conditions measured by the glider were significantly correlated to the variation in sounds from six known or suspected species of fish across the three missions with depth consistently being the most significant factor. At the time and space scales of this study, there was no detectable effect of red tide on sound production. Sounds were still recorded within red tide-affected waters from species with overlapping depth ranges. These results suggest that the fishes studied here did not alter their sound production nor migrate out of red tide affected areas. Although these results are preliminary because of the limited measurements, the data and methods presented here provide a proof of principle and could serve as protocol for future studies on the effects of algal blooms on the behavior of soniferous fishes. To fully capture the effects of episodic events, we suggest that stationary or vertically profiling acoustic recorders and environmental sampling be used as a complement to glider measurements. PMID- 25551565 TI - Protection against chemotaxis in the anti-inflammatory effect of bioactives from tomato ketchup. AB - The consumption of tomato products has been associated with a decreased risk for chronic inflammatory diseases. In this study, the anti-inflammatory potential of tomato ketchup was evaluated by studying the effect of tomato ketchup extracts and bioactives from tomato ketchup on human monocytes and vascular endothelial cells (HUVEC). HUVEC were pre-treated for 1 h with either individual bioactives (7.5 uM lycopene, 1.4 uM alpha-tocopherol or 55 uM ascorbic acid) or a combination of these three compounds, or with the hydrophilic or lipophilic tomato ketchup extracts or with the two extracts combined. After the pretreatment, the cells were washed and challenged with TNF-alpha (10 ng/ml) for 6 h. The medium was used for the determination of the release of cytokines and the chemotaxis of monocytes. Inflammatory protein expression and production were assayed with real-time RT-PCR and ELISA. It was found that tomato ketchup extracts significantly reduced gene expression and release of the pro inflammatory cytokines TNF-alpha and IL-8 in HUVEC after the inflammatory challenge, whereas the release of the anti-inflammatory cytokine IL-10 was increased. Chemotaxis was effectively impeded as demonstrated by a reduced monocyte migration. This effect correlated with the reduction of IL-8 production in the presence of the test compounds and extracts. The results consistently emphasize the contribution of lycopene to the anti-inflammatory effect of tomato ketchup. Other compounds in tomato ketchup such as alpha-tocopherol and ascorbic acid appeared to strengthen the anti-inflammatory effect of lycopene. The tomato ketchup extracts subtly interfered with several inflammatory phases that inhibit chemotaxis. Such a pleotropic mode of action exemplifies its potential mitigation of diseases characterized by prolonged low grade inflammation. PMID- 25551566 TI - Trigeminocardiac reflex by mandibular extension on rat pial microcirculation: role of nitric oxide. AB - In the present study we have extended our previous findings about the effects of 10 minutes of passive mandibular extension in anesthetized Wistar rats. By prolonging the observation time to 3 hours, we showed that 10 minutes mandibular extension caused a significant reduction of the mean arterial blood pressure and heart rate respect to baseline values, which persisted up to 160 minutes after mandibular extension. These effects were accompanied by a characteristic biphasic response of pial arterioles: during mandibular extension, pial arterioles constricted and after mandibular extension dilated for the whole observation period. Interestingly, the administration of the opioid receptor antagonist naloxone abolished the vasoconstriction observed during mandibular extension, while the administration of Nomega-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, abolished the vasodilation observed after mandibular extension. Either drug did not affect the reduction of mean arterial blood pressure and heart rate induced by mandibular extension. By qRT-PCR, we also showed that neuronal nitric oxide synthase gene expression was significantly increased compared with baseline conditions during and after mandibular extension and endothelial nitric oxide synthase gene expression markedly increased at 2 hours after mandibular extension. Finally, western blotting detected a significant increase in neuronal and endothelial nitric oxide synthase protein expression. In conclusion mandibular extension caused complex effects on pial microcirculation involving opioid receptor activation and nitric oxide release by both neurons and endothelial vascular cells at different times. PMID- 25551567 TI - Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine. AB - We investigated the role of autophagy, a controlled cellular self-digestion process, in regulating survival of neurons exposed to atypical antipsychotic olanzapine. Olanzapine induced autophagy in human SH-SY5Y neuronal cell line, as confirmed by the increase in autophagic flux and presence of autophagic vesicles, fusion of autophagosomes with lysosomes, and increase in the expression of autophagy-related (ATG) genes ATG4B, ATG5, and ATG7. The production of reactive oxygen species, but not modulation of the main autophagy repressor MTOR or its upstream regulators AMP-activated protein kinase and AKT1, was responsible for olanzapine-triggered autophagy. Olanzapine-mediated oxidative stress also induced mitochondrial depolarization and damage, and the autophagic clearance of dysfunctional mitochondria was confirmed by electron microscopy, colocalization of autophagosome-associated MAP1LC3B (LC3B henceforth) and mitochondria, and mitochondrial association with the autophagic cargo receptor SQSTM1/p62. While olanzapine-triggered mitochondrial damage was not overtly toxic to SH-SY5Y cells, their death was readily initiated upon the inhibition of autophagy with pharmacological inhibitors, RNA interference knockdown of BECN1 and LC3B, or biological free radical nitric oxide. The treatment of mice with olanzapine for 14 d increased the brain levels of autophagosome-associated LC3B-II and mRNA encoding Atg4b, Atg5, Atg7, Atg12, Gabarap, and Becn1. The administration of the autophagy inhibitor chloroquine significantly increased the expression of proapoptotic genes (Trp53, Bax, Bak1, Pmaip1, Bcl2l11, Cdkn1a, and Cdkn1b) and DNA fragmentation in the frontal brain region of olanzapine-exposed animals. These data indicate that olanzapine-triggered autophagy protects neurons from otherwise fatal mitochondrial damage, and that inhibition of autophagy might unmask the neurotoxic action of the drug. PMID- 25551568 TI - Comparative transcriptome analyses between a spontaneous late-ripening sweet orange mutant and its wild type suggest the functions of ABA, sucrose and JA during citrus fruit ripening. AB - A spontaneous late-ripening mutant of 'Jincheng' (C. sinensis L. Osbeck) sweet orange exhibited a delay of fruit pigmentation and harvesting. In this work, we studied the processes of orange fruit ripening through the comparative analysis between the Jincheng mutant and its wild type. This study revealed that the fruit quality began to differ on 166th days after anthesis. At this stage, fruits were subjected to transcriptome analysis by RNA sequencing. 13,412 differentially expressed unigenes (DEGs) were found. Of these unigenes, 75.8% were down regulated in the wild type, suggesting that the transcription level of wild type was lower than that of the mutant during this stage. These DEGs were mainly clustered into five pathways: metabolic pathways, plant-pathogen interaction, spliceosome, biosynthesis of plant hormones and biosynthesis of phenylpropanoids. Therefore, the expression profiles of the genes that are involved in abscisic acid, sucrose, and jasmonic acid metabolism and signal transduction pathways were analyzed during the six fruit ripening stages. The results revealed the regulation mechanism of sweet orange fruit ripening metabolism in the following four aspects: First, the more mature orange fruits were, the lower the transcription levels were. Second, the expression level of PME boosted with the maturity of the citrus fruit. Therefore, the expression level of PME might represent the degree of the orange fruit ripeness. Third, the interaction of PP2C, PYR/PYL, and SnRK2 was peculiar to the orange fruit ripening process. Fourth, abscisic acid, sucrose, and jasmonic acid all took part in orange fruit ripening process and might interact with each other. These findings provide an insight into the intricate process of sweet orange fruit ripening. PMID- 25551569 TI - Oxidative DNA damage in kidneys and heart of hypertensive mice is prevented by blocking angiotensin II and aldosterone receptors. AB - INTRODUCTION: Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied. METHODS: In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg * min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis. RESULTS: Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-kappaB were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone. CONCLUSION: Angiotensin II induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore has beneficial effects on end-organ damage independent of blood pressure normalization. PMID- 25551570 TI - Intratracheal instillation of high dose adenoviral vectors is sufficient to induce lung injury and fibrosis in mice. AB - RATIONALE: Replication deficient adenoviruses (Ad) vectors are common tools in gene therapy. Since Ad vectors are known to activate innate and adaptive immunity, we investigated whether intratracheal administration of Ad vectors alone is sufficient to induce lung injury and pulmonary fibrosis. METHODS: We instilled Ad viruses ranging from 107 to 1.625*109 ifu/mouse as well as the same volume of PBS and bleomycin. 14 and 21 days after administration, we collected bronchoalveolar lavage fluid (BALF) and mouse lung tissues. We measured the protein concentration, total and differential cell counts, and TGF-beta1 production, performed Trichrome staining and Sircol assay, determined gene and protein levels of profibrotic cytokines, MMPs, and Wnt signaling proteins, and conducted TUNEL staining and co-immunofluorescence for GFP and alpha-SMA staining. RESULTS: Instillation of high dose Ad vectors (1.625*109 ifu/mouse) into mouse lungs induced high levels of protein content, inflammatory cells, and TGF-beta1 in BALF, comparable to those in bleomycin-instilled lungs. The collagen content and mRNA levels of Col1a1, Col1a2, PCNA, and alpha-SMA were also increased in the lungs. Instillation of both bleomycin and Ad vectors increased expression levels of TNFalpha and IL-1beta but not IL-10. Instillation of bleomycin but not Ad increased the expression of IL-1alpha, IL-13 and IL-16. Treatment with bleomycin or Ad vectors increased expression levels of integrin alpha1, alpha5, and alphav, MMP9, whereas treatment with bleomycin but not Ad vectors induced MMP2 expression levels. Both bleomycin and Ad vectors induced mRNA levels of Wnt2, 2b, 5b, and Lrp6. Intratracheal instillation of Ad viruses also induced DNA damages and Ad viral infection-mediated fibrosis is not limited to the infection sites. CONCLUSIONS: Our results suggest that administration of Ad vectors induces an inflammatory response, lung injury, and pulmonary fibrosis in a dose dependent manner. PMID- 25551571 TI - Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing remitting multiple sclerosis. AB - BACKGROUND: Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1. METHODS: RRMS patients (18-65 years; Expanded Disability Status Scale score <=5) were randomized to double-blind placebo or peginterferon beta-1a 125 MUg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted. RESULTS: 1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p < 0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium enhancing plus non-enhancing new T2) lesions (all p < 0.0001), as well as the volume of T2 and T1 lesions (p < 0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p < 0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity. CONCLUSION: During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00906399. PMID- 25551572 TI - Medial frontal white and gray matter contributions to general intelligence. AB - The medial orbitofrontal cortex (mOFC) and rostral anterior cingulate cortex (rACC) are part of a wider neural network that plays an important role in general intelligence and executive function. We used structural brain imaging to quantify magnetic resonance gray matter volume and diffusion tensor white matter integrity of the mOFC-rACC network in 26 healthy participants who also completed neuropsychological tests of intellectual abilities and executive function. Stochastic tractography, the most effective Diffusion Tensor Imaging method for examining white matter connections between adjacent gray matter regions, was employed to assess the integrity of mOFC-rACC pathways. Fractional anisotropy (FA), which reflects the integrity of white matter connections, was calculated. Results indicated that higher intelligence correlated with greater gray matter volumes for both mOFC and rACC, as well as with increased FA for left posterior mOFC-rACC connectivity. Hierarchical regression analyses revealed that DTI derived FA of left posterior mOFC-rACC uniquely accounted for 29%-34% of the variance in IQ, in comparison to 11%-16% uniquely explained by gray matter volume of the left rACC. Together, left rACC gray matter volume and white matter connectivity between left posterior mOFC and rACC accounted for up to 50% of the variance in general intelligence. This study is to our knowledge the first to examine white matter connectivity between OFC and ACC, two gray matter regions of interests that are very close in physical proximity, and underscores the important independent contributions of variations in rACC gray matter volume and mOFC-rACC white matter connectivity to individual differences in general intelligence. PMID- 25551573 TI - Antibacterial activity of novel cationic peptides against clinical isolates of multi-drug resistant Staphylococcus pseudintermedius from infected dogs. AB - Staphylococcus pseudintermedius is a major cause of skin and soft tissue infections in companion animals and has zoonotic potential. Additionally, methicillin-resistant S. pseudintermedius (MRSP) has emerged with resistance to virtually all classes of antimicrobials. Thus, novel treatment options with new modes of action are required. Here, we investigated the antimicrobial activity of six synthetic short peptides against clinical isolates of methicillin-susceptible and MRSP isolated from infected dogs. All six peptides demonstrated potent anti staphylococcal activity regardless of existing resistance phenotype. The most effective peptides were RRIKA (with modified C terminus to increase amphipathicity and hydrophobicity) and WR-12 (alpha-helical peptide consisting exclusively of arginine and tryptophan) with minimum inhibitory concentration50 (MIC50) of 1 uM and MIC90 of 2 uM. RR (short anti-inflammatory peptide) and IK8 "D isoform" demonstrated good antimicrobial activity with MIC50 of 4 uM and MIC90 of 8 uM. Penetratin and (KFF)3K (two cell penetrating peptides) were the least effective with MIC50 of 8 uM and MIC90 of 16 uM. Killing kinetics revealed a major advantage of peptides over conventional antibiotics, demonstrating potent bactericidal activity within minutes. Studies with propidium iodide and transmission electron microscopy revealed that peptides damaged the bacterial membrane leading to leakage of cytoplasmic contents and consequently, cell death. A potent synergistic increase in the antibacterial effect of the cell penetrating peptide (KFF)3K was noticed when combined with other peptides and with antibiotics. In addition, all peptides displayed synergistic interactions when combined together. Furthermore, peptides demonstrated good therapeutic indices with minimal toxicity toward mammalian cells. Resistance to peptides did not evolve after 10 passages of S. pseudintermedius at sub-inhibitory concentration. However, the MICs of amikacin and ciprofloxacin increased 32 and 8 fold, respectively; under similar conditions. Taken together, these results support designing of peptide-based therapeutics for combating MRSP infections, particularly for topical application. PMID- 25551575 TI - Machine learning for biomedical literature triage. AB - This paper presents a machine learning system for supporting the first task of the biological literature manual curation process, called triage. We compare the performance of various classification models, by experimenting with dataset sampling factors and a set of features, as well as three different machine learning algorithms (Naive Bayes, Support Vector Machine and Logistic Model Trees). The results show that the most fitting model to handle the imbalanced datasets of the triage classification task is obtained by using domain relevant features, an under-sampling technique, and the Logistic Model Trees algorithm. PMID- 25551574 TI - The proteomic and genomic teratogenicity elicited by valproic acid is preventable with resveratrol and alpha-tocopherol. AB - BACKGROUND: Previously, we reported that valproic acid (VPA), a common antiepileptic drug and a potent teratogenic, dowregulates RBP4 in chicken embryo model (CEM) when induced by VPA. Whether such teratogenicity is associated with more advanced proteomic and genomic alterations, we further performed this present study. METHODOLOGY/PRINCIPAL FINDINGS: VPA (60 uM) was applied to 36 chicken embryos at HH stage 10 (day-1.5). Resveratrol (RV) and vitamin E (vit E) (each at 0.2 and 2.0 uM) were applied simultaneously to explore the alleviation effect. The proteins in the cervical muscles of the day-1 chicks were analyzed using 2D-electrophoresis and LC/MS/MS. While the genomics associated with each specific protein alteration was examined with RT-PCR and qPCR. At earlier embryonic stage, VPA downregulated PEBP1 and BHMT genes and at the same time upregulated MYL1, ALB and FLNC genes significantly (p<0.05) without affecting PKM2 gene. Alternatively, VPA directly inhibited the folate-independent (or the betaine-dependent) remethylation pathway. These features were effectively alleviated by RV and vit E. CONCLUSIONS: VPA alters the expression of PEBP1, BHMT, MYL1, ALB and FLNC that are closely related with metabolic myopathies, myogenesis, albumin gene expression, and haemolytic anemia. On the other hand, VPA directly inhibits the betaine-dependent remethylation pathway. Taken together, VPA elicits hemorrhagic myoliposis via these action mechanisms, and RV and vit E are effective for alleviation of such adverse effects. PMID- 25551576 TI - Interferon beta and vitamin D synergize to induce immunoregulatory receptors on peripheral blood monocytes of multiple sclerosis patients. AB - Immunoglobulin-like transcript (ILT) 3 and 4 are inhibitory receptors that modulate immune responses. Their expression has been reported to be affected by interferon, offering a possible mechanism by which this cytokine exerts its therapeutic effect in multiple sclerosis, a condition thought to involve excessive immune activity. To investigate this possibility, we measured expression of ILT3 and ILT4 on immune cells from multiple sclerosis patients, and in post-mortem brain tissue. We also studied the ability of interferon beta, alone or in combination with vitamin D, to induce upregulation of these receptors in vitro, and compared expression levels between interferon-treated and untreated multiple sclerosis patients. In vitro interferon beta treatment led to a robust upregulation of ILT3 and ILT4 on monocytes, and dihydroxyvitamin D3 increased expression of ILT3 but not ILT4. ILT3 was abundant in demyelinating lesions in postmortem brain, and expression on monocytes in the cerebrospinal fluid was higher than in peripheral blood, suggesting that the central nervous system milieu induces ILT3, or that ILT3 positive monocytes preferentially enter the brain. Our data are consistent with involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D. PMID- 25551578 TI - Extragenic suppressor mutations in DeltaripA disrupt stability and function of LpxA. AB - BACKGROUND: Francisella tularensis is a Gram-negative bacterium that infects hundreds of species including humans, and has evolved to grow efficiently within a plethora of cell types. RipA is a conserved membrane protein of F. tularensis, which is required for growth inside host cells. As a means to determine RipA function we isolated and mapped independent extragenic suppressor mutants in ?ripA that restored growth in host cells. Each suppressor mutation mapped to one of two essential genes, lpxA or glmU, which are involved in lipid A synthesis. We repaired the suppressor mutation in lpxA (S102, LpxA T36N) and the mutation in glmU (S103, GlmU E57D), and demonstrated that each mutation was responsible for the suppressor phenotype in their respective strains. We hypothesize that the mutation in S102 altered the stability of LpxA, which can provide a clue to RipA function. LpxA is an UDP-N-acetylglucosamine acyltransferase that catalyzes the transfer of an acyl chain from acyl carrier protein (ACP) to UDP-N acetylglucosamine (UDP-GlcNAc) to begin lipid A synthesis. RESULTS: LpxA was more abundant in the presence of RipA. Induced expression of lpxA in the DeltaripA strain stopped bacterial division. The LpxA T36N S102 protein was less stable and therefore less abundant than wild type LpxA protein. CONCLUSION: These data suggest RipA functions to modulate lipid A synthesis in F. tularensis as a way to adapt to the host cell environment by interacting with LpxA. PMID- 25551579 TI - Construct validity of the Experiences of Therapy Questionnaire (ETQ). AB - BACKGROUND: The Experiences of Therapy Questionnaire (ETQ) is a reliable measure of adverse effects associated with psychotherapy. The measure has not been subject to validity analyses. This study sought to examine the validity of the ETQ by comparison against a measure of therapist satisfaction. METHODS: Participants were recruited from the Black Dog Institute's website and completed all measures online, at two time points (two weeks apart). Correlational analyses compared scale scores on the ETQ with related constructs of the Therapist Satisfaction Scale (TSS). To exclude any impact of current depression on ratings, we examined correlations between salient ETQ and TSS scales after controlling for depression severity. RESULTS: Forty-six participants completed all the measures at both time points. Hypothesised associations between the ETQ and TSS scales were supported, irrespective of current depression severity. CONCLUSIONS: The validity of the ETQ is supported; however limitations of the study are noted, including generalizability due to sample characteristics. PMID- 25551580 TI - Comparison of three longitudinal analysis models for the health-related quality of life in oncology: a simulation study. AB - BACKGROUND: Health-Related Quality of Life (HRQoL) is an important endpoint in oncology clinical trials aiming to investigate the clinical benefit of new therapeutic strategies for the patient. However, the longitudinal analysis of HRQoL remains complex and unstandardized. There is clearly a need to propose accessible statistical methods and meaningful results for clinicians. The objective of this study was to compare three strategies for longitudinal analyses of HRQoL data in oncology clinical trials through a simulation study. METHODS: The methods proposed were: the score and mixed model (SM); a survival analysis approach based on the time to HRQoL score deterioration (TTD); and the longitudinal partial credit model (LPCM). Simulations compared the methods in terms of type I error and statistical power of the test of an interaction effect between treatment arm and time. Several simulation scenarios were explored based on the EORTC HRQoL questionnaires and varying the number of patients (100, 200 or 300), items (1, 2 or 4) and response categories per item (4 or 7). Five or 10 measurement times were considered, with correlations ranging from low to high between each measure. The impact of informative missing data on these methods was also studied to reflect the reality of most clinical trials. RESULTS: With complete data, the type I error rate was close to the expected value (5%) for all methods, while the SM method was the most powerful method, followed by LPCM. The power of TTD is low for single-item dimensions, because only four possible values exist for the score. When the number of items increases, the power of the SM approach remained stable, those of the TTD method increases while the power of LPCM remained stable. With 10 measurement times, the LPCM was less efficient. With informative missing data, the statistical power of SM and TTD tended to decrease, while that of LPCM tended to increase. CONCLUSIONS: To conclude, the SM model was the most powerful model, irrespective of the scenario considered, and the presence or not of missing data. The TTD method should be avoided for single item dimensions of the EORTC questionnaire. While the LPCM model was more adapted to this kind of data, it was less efficient than the SM model. These results warrant validation through comparisons on real data. PMID- 25551581 TI - Treatment of stage IV gastric cancer with induction chemotherapy using S-1 and cisplatin followed by curative resection in selected patients. AB - BACKGROUND: The standard treatment for stage IV gastric cancer is chemotherapy, but outcomes remain poor. The effectiveness of induction chemotherapy followed by surgery in selected patients who had a good response to chemotherapy is unclear. METHODS: A total of 59 patients with stage IV gastric cancer received induction chemotherapy with S-1 and cisplatin. In each cycle, oral S-1 (80 mg/m2) was administered for 3 weeks, followed by a 2-week drug holiday. Intravenous cisplatin (60 mg/m2) was administered on day 8 after adequate premedication and hydration. If unresectable features resolved after chemotherapy, patients underwent curative (R0) resection. The safety and outcomes of this treatment combination were evaluated, and predictive factors for survival were determined. RESULTS: Thirteen of 59 patients (22%) were eligible for R0 resection after induction chemotherapy. Kaplan-Meier analysis showed an overall median survival time of 13 months and a 3-year survival rate of 18.2%. Among patients who underwent R0 resection, the median survival time was 53 months and the 3-year survival rate was 53.8%. Multivariate analyses showed that negative para-aortic lymph nodes and undergoing R0 resection were independent predictors of survival. CONCLUSIONS: Treatment of stage IV gastric cancer with S-1 and cisplatin induction chemotherapy followed by R0 resection is safe and may improve survival compared with chemotherapy alone. Further study of this dual-modality therapy is warranted. PMID- 25551583 TI - Application of open chain tetraimidazolium salts as precursors for the synthesis of silver tetra(NHC) complexes. AB - The synthesis of 3-((1H-imidazol-1-yl)methyl)-1-methyl-1H-imidazol-3-ium iodide 1 for the synthesis of multidentate tetra-N-heterocyclic carbene (NHC) structures is described. Two acyclic open chain tetra(NHC) precursors are synthesized together with their corresponding silver complexes. On the basis of nuclear magnetic resonance (NMR) spectroscopy and single crystal X-ray diffraction (XRD) data, the coordination geometry of the silver complexes is discussed. Dependent on the length of the alkyl bridge of the tetradentate ligand either a double helix structure with four linear-coordinated silver cations or a twisted geometry with two linear-coordinated silver cations is obtained. PMID- 25551582 TI - Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence. AB - INTRODUCTION: Elafin is an endogenous serine protease inhibitor. The majority of breast cancer cell lines lack elafin expression compared to human mammary epithelial cells. In this study, we hypothesized that elafin is downregulated during breast and ovarian tumorigenesis. METHODS: We examined elafin expression by immunohistochemistry (IHC) in specimens of normal breast tissue (n = 24), ductal carcinoma in situ (DCIS) (n = 54), and invasive breast cancer (n = 793). IHC analysis of elafin expression was also performed in normal fallopian tube tissue (n = 20), ovarian cystadenomas (n = 9), borderline ovarian tumors (n = 21), and invasive ovarian carcinomas (n = 216). To understand the significance of elafin in luminal breast cancer cell lines, wild-type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells. RESULTS: Elafin expression was downregulated in 24% of DCIS and 83% of invasive breast tumors when compared to elafin expression in the normal mammary epithelium. However, the presence of elafin-positive cells in invasive breast tumors, even at low frequency, correlated with poor recurrence-free survival (RFS), reduced overall survival (OS), and clinicopathological markers of aggressive tumor behavior. Elafin-positive cells were an especially strong and independent prognostic marker of reduced RFS in IHC-defined luminal A-like tumors. Elafin was also downregulated in 33% of ovarian cystadenomas, 43% of borderline ovarian tumors, and 86% of invasive ovarian carcinomas when compared to elafin expression in the normal fallopian tube. In ovarian tumors, elafin positive cells were correlated with reduced RFS, OS and disease-specific survival (DSS) only in stage I/II patients and not in stage III/IV patients. Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain-independent manner. CONCLUSIONS: Elafin predicts poor outcome in breast and ovarian cancer patients and delineates a subset of endocrine receptor-positive breast cancer patients susceptible to recurrence who could benefit from more aggressive intervention. Our in vitro results suggest that elafin arrests luminal breast cancer cells, perhaps suggesting a role in tumor dormancy. PMID- 25551584 TI - Z-schematic water splitting into H2 and O2 using metal sulfide as a hydrogen evolving photocatalyst and reduced graphene oxide as a solid-state electron mediator. AB - Z-schematic water splitting was successfully demonstrated using metal sulfide photocatalysts that were usually unsuitable for water splitting as single particulate photocatalysts due to photocorrosion. When metal sulfide photocatalysts with a p-type semiconductor character as a H2-evolving photocatalyst were combined with reduced graphene oxide-TiO2 composite as an O2 evolving photocatalyst, water splitting into H2 and O2 in a stoichiometric amount proceeded. In this system, photogenerated electrons in the TiO2 with an n-type semiconductor character transferred to the metal sulfide through a reduced graphene oxide to achieve water splitting. Moreover, this system was active for solar water splitting. PMID- 25551585 TI - A retrospective analysis of myocardial preservation techniques during coronary artery bypass graft surgery: are we protecting the heart? AB - BACKGROUND: Retrograde perfusion into coronary sinus during coronary artery bypass graft (CABG) surgery reduces the need for cardioplegic interruptions and ensures the distribution of cardioplegia to stenosed vessel territories, therefore enhancing the delivery of cardioplegia to the subendocardium. Peri operative myocardial injury (PMI), as measured by the rise of serum level of cardiac biomarkers, has been associated with short and long-term clinical outcomes. We conducted a retrospective analysis to investigate whether the combination of antegrade and retrograde techniques of cardioplegia delivery is associated with a reduced PMI than that observed with the traditional methods of myocardial preservation. METHODS: Fifty-four consecutive patients underwent CABG surgery using either antegrade cold blood cardioplegia (group 1, n = 28) or cross clamp fibrillation (group 2, n = 16) or antegrade retrograde warm blood cardioplegia (group 3, n = 10). The study primary end-point was PMI, evaluated with total area under the curve (AUC) of high-sensitivity Troponin-T (hsTnT), measured pre-operatively and at 6, 12, 24, 48 and 72 hours post-surgery. Secondary endpoints were acute kidney injury (AKI) and inotrope scores, length of intensive care unit (ICU) and hospital stay, new onset atrial fibrillation (AF) and clinical outcomes at 6 weeks (death, non-fatal myocardial infarction, coronary artery revascularization, stroke). RESULTS: There was evidence that mean total AUC of hsTnT was different among the three groups (P = 0.050). In particular mean total AUC of hsTnT was significantly lower in group 3 compared to both group 1 (-16.55; 95% CI: -30.08, -3.01; P = 0.018) with slightly weaker evidence of a lower mean hsTnT in group 3 when compared to group 2 (-15.13; 95% CI -29.87, -0.39; P = 0.044). There was no evidence of a difference when comparing group 2 to group 1 (-1.42,; 95% CI: -12.95, 10.12, P = 0.806). CONCLUSIONS: Our retrospective analysis suggests that, compared to traditional methods of myocardial preservation, antegrade retrograde cardioplegia may reduce PMI in patients undergoing first time CABG surgery. PMID- 25551586 TI - Construct validity and factor structure of the pittsburgh sleep quality index and epworth sleepiness scale in a multi-national study of African, South East Asian and South American college students. AB - BACKGROUND: The Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) are questionnaires used to assess sleep quality and excessive daytime sleepiness in clinical and population-based studies. The present study aimed to evaluate the construct validity and factor structure of the PSQI and ESS questionnaires among young adults in four countries (Chile, Ethiopia, Peru and Thailand). METHODS: A cross-sectional study was conducted among 8,481 undergraduate students. Students were invited to complete a self-administered questionnaire that collected information about lifestyle, demographic, and sleep characteristics. In each country, the construct validity and factorial structures of PSQI and ESS questionnaires were tested through exploratory and confirmatory factor analyses (EFA and CFA). RESULTS: The largest component-total correlation coefficient for sleep quality as assessed using PSQI was noted in Chile (r = 0.71) while the smallest component-total correlation coefficient was noted for sleep medication use in Peru (r = 0.28). The largest component-total correlation coefficient for excessive daytime sleepiness as assessed using ESS was found for item 1 (sitting/reading) in Chile (r = 0.65) while the lowest item-total correlation was observed for item 6 (sitting and talking to someone) in Thailand (r = 0.35). Using both EFA and CFA a two-factor model was found for PSQI questionnaire in Chile, Ethiopia and Thailand while a three-factor model was found for Peru. For the ESS questionnaire, we noted two factors for all four countries. CONCLUSION: Overall, we documented cross-cultural comparability of sleep quality and excessive daytime sleepiness measures using the PSQI and ESS questionnaires among Asian, South American and African young adults. Although both the PSQI and ESS were originally developed as single-factor questionnaires, the results of our EFA and CFA revealed the multi- dimensionality of the scales suggesting limited usefulness of the global PSQI and ESS scores to assess sleep quality and excessive daytime sleepiness. PMID- 25551587 TI - PGC TagSNP and its interaction with H. pylori and relation with gene expression in susceptibility to gastric carcinogenesis. AB - BACKGROUND: Pepsinogen C (PGC) plays an important role in sustaining the cellular differentiation during the process of gastric carcinogenesis. This study aimed to assess the role of PGC tagSNPs and their interactions with Helicobacter pylori (H. pylori) in the development of gastric cancer and its precursor, atrophic gastritis. METHODS: Four PGC tagSNPs (rs6941539, rs6912200, rs3789210 and rs6939861) were genotyped by Sequenom MassARRAY platform in a total of 2311 subjects consisting of 642 gastric cancer, 774 atrophic gastritis, and 895 healthy control subjects. The mRNA and protein expression levels of PGC in gastric tissues and in serum were respectively measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry, and Eenzyme-linked immunoabsorbent assay (ELISA). RESULTS: We found associations between PGC rs3789210 CG/GG genotypes and reduced gastric cancer risk and between PGC rs6939861 A variant allele and increased risks of both gastric cancer and atrophic gastritis. As for the haplotypes of PGC rs6941539-rs6912200-rs3789210 rs6939861 loci, the TTCA and TTGG haplotypes were respectively associated with increased and reduced risks of both gastric cancer and atrophic gastritis; additionally, the CTCA haplotype was associated with increased atrophic gastritis risk. Very interestingly, rs6912200 CT/TT genotypes had a positive interaction with H. pylori, synergistically elevating the gastric cancer risk. Moreover, healthy subjects who carried rs6912200 CT, TT and CT/TT variant genotypes had lower histological and serum expression levels of PGC protein. CONCLUSIONS: Our findings highlight an important role of PGC rs3789210 and rs6939861 in altering susceptibility to atrophic gastritis and/or gastric cancer. Moreover, people who carry rs6912200 variant genotypes exhibit higher gastric cancer risk in case of getting H. pylori infection, which strongly suggest a necessity of preventing and/or eliminating H. pylori infection in those individuals. PMID- 25551589 TI - Continuing medical education revisited: theoretical assumptions and practical implications: a qualitative study. AB - BACKGROUND: Recent research has evidenced that although investment in Continuing Medical Education (CME), both in terms of participation as well as financial resources allocated to it, has been steadily increasing to catch up with accelerating advances in health information and technology, effectiveness of CME is reported to be rather limited. Poor and disproportional returns can be attributed to failure of CME courses to address and stimulate an adult audience. METHODS: The present study initially drew on research findings and adult learning theories, providing the basis for comprehending adult learning, while entailing practical implications on fostering effectiveness in the design and delivery of CME. On a second level, a qualitative study was conducted with the aim to elucidate parameters accounting for effectiveness in educational interventions. Qualitative data was retrieved through 12 in-depth interviews, conducted with a random sample of participants in the 26th European Workshop of Advanced Plastic Surgery (EWAPS). The data underwent a three level qualitative analysis, following the "grounded theory" methodology, comprising 'open coding', 'axial coding' and 'selective coding'. RESULTS: Findings from the EWAPS study come in line with relevant literature, entailing significant implications for the necessity to apply a more effective and efficient paradigm in the design and delivery of educational interventions, advocating for implementing learner-centered schemata in CME and benefiting from a model that draws on the learning environment and social aspects of learning. CONCLUSIONS: What emerged as a pivotal parameter in designing educational interventions is to focus on small group educational events which could provide a supportive friendly context, enhance motivation through learner-centered approaches and allow interaction, experimentation and critical reflection. It should be outlined however that further research is required as the present study is limited in scope, having dealt with a limited sample. PMID- 25551588 TI - Microrna expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms. AB - BACKGROUND: Although, substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce. Recent microRNA (miRNA)-based research reveals the involvement of miRNAs in various aspects of CNS development and proposes that they might compose key molecules underlying oncogenesis. The current study evaluated miRNA differential expression detected between pediatric embryonal brain tumors and normal controls to characterize candidate biomarkers related to diagnosis, prognosis and therapy. METHODS: Overall, 19 embryonal brain tumors; 15 Medulloblastomas (MBs) and 4 Atypical Teratoid/Rabdoid Tumors (AT/RTs) were studied. As controls, 13 samples were used; The First-Choice Human Brain Reference RNA and 12 samples from deceased children who underwent autopsy and were not present with any brain malignancy. RNA extraction was carried out using the Trizol method, whilst miRNA extraction was performed with the mirVANA miRNA isolation kit. The experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative Real-Time Polymerase Chain Reaction was performed to validate the expression profiles of miR-34a and miR-601 in all 32 samples initially screened with miRNA microarrays and in an additional independent cohort of 30 patients (21MBs and 9 AT/RTs). Moreover, meta-analyses was performed in total 27 embryonal tumor samples; 19 MBs, 8 ATRTs and 121 control samples. Twelve germinomas were also used as an independent validation cohort. All deregulated miRNAs were correlated to patients' clinical characteristics and pathological measures. RESULTS: In several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics. Based on that, miR-601 could serve as a putative tumor suppressor gene, whilst miR-34a as an oncogene. In general, miR-34a demonstrated oncogenic roles in all pediatric embryonal CNS neoplasms studied. CONCLUSIONS: Deeper understanding of the aberrant miRNA expression in pediatric embryonal brain tumors might aid in the development of tumor-specific miRNA signatures, which could potentially afford promising biomarkers related to diagnosis, prognosis and patient targeted therapy. PMID- 25551590 TI - Emphysematous vaginitis. AB - BACKGROUND: Emphysematous vaginitis is a rare condition, characterized by the presence of multiple gas-filled cysts in the vaginal and/or exocervical mucosa. Although its etiology is not completely understood, it is self-limited, with a benign clinical course. Vaginal discharge, sometimes bloody, and pruritus are the most common symptoms. Chronic and acute inflammation can be found, and diseases that impair the immune system and pregnancy have been associated with this condition. CASE REPORT: A 48-year-old postmenopausal woman, with a history of hysterectomy with several comorbidities, presented with a 4-month history of bloody discharge and vulvar pruritus. Examination showed multiple cystic lesions, 1 to 5 mm, occupying the posterior and right lateral vaginal walls. Speculum examination produced crepitus. Vaginal wet mount was normal, except for diminished lactobacilli; results of Trichomonas vaginalis DNA test and vaginal cultures were negative. Lugol's iodine applied to the vagina was taken up by the intact lesions. Biopsy result showed typical features of emphysematous vaginitis. CONCLUSIONS: This is an unusual entity, presenting with common gynecological complaints, and both physicians and pathologists should be aware to prevent misdiagnosis and overtreatment. PMID- 25551591 TI - Performance of Cervical Cancer Screening Techniques in HIV-Infected Women in Uganda. AB - OBJECTIVE: Women infected with human immunodeficiency virus (HIV) have a higher risk of HPV infections and developing cervical cancer, thus screening them is imperative. This study was aimed to evaluate and compare the performance of 3 cervical cancer screening options among HIV-infected women in Uganda. MATERIALS AND METHODS: Data from 2,337 Ugandan women who reported their HIV status were obtained from a population-based cervical cancer screening study. Women were offered 3 screening tests: vaginal and cervical careHPV and visual inspection with acetic acid (VIA), and the results were evaluated by HIV status. RESULTS: The prevalence of HIV infection was 16.5%. Women infected with HIV had a higher prevalence of cervical intraepithelial neoplasia grade 2+ (CIN2+) than uninfected women (12.9% vs 1.7%; p < .001). The sensitivity for cervical careHPV among the HIV-infected women was 94.3% compared to 81.3% among the uninfected women. Whereas the sensitivity for vaginal careHPV was also higher among the HIV infected women, the sensitivity of VIA was higher among the uninfected women. The mean vaginal and cervical careHPV signal strength was higher in the HIV-infected women than in the uninfected women (p < .001). CONCLUSIONS: CareHPV is very sensitive for detecting CIN2+ in HIV-infected women, even using a vaginal sample. The sensitivity of careHPV in HIV-infected women is higher than in HIV-uninfected women. However, additional research is needed to determine the best option for screening and triage of HPV-positive women that can be implemented in low resource settings, especially among HIV- and HPV-positive women. PMID- 25551592 TI - Comparison of Topical Lidocaine Spray With Placebo for Pain Relief in Colposcopic Procedures: A Randomized, Placebo-Controlled, Double-Blind Study. AB - OBJECTIVE: To compare the effectiveness of topical lidocaine spray compared to a placebo for relieving pain during colposcopic cervical biopsies and endocervical curettage. METHODS: This randomized, placebo-controlled, double-blind study included patients with abnormal cervical cytologic results requiring colposcopy and directed cervical punch biopsy with or without endocervical curettage (ECC). The patients were randomly assigned to either the 10% lidocaine spray or the placebo group. The patients were asked to rate the pain level immediately after the cervical biopsy and ECC, and mean pain scores of the 2 groups were compared. RESULTS: A total of 214 women were included in the study: 104 in the lidocaine group and 110 in the control group. Age, parity, and history of previous vaginal delivery and cesarean section were similar in both groups. Mean +/- SD age was 41.5 +/- 10.6 years in the lidocaine group and 43 +/- 11.3 years in the control group. Pain scores after cervical biopsy and ECC were also similar between the 2 groups. Mean +/- SD pain scores associated with cervical biopsy were 2.18 +/- 1.7 in the lidocaine group and 2.31 +/- 1.6 in the control group. DISCUSSION AND CONCLUSION: In our population, there is no evidence to recommend the use of routine locally sprayed lidocaine anesthesia before cervical punch biopsy or ECC. PMID- 25551593 TI - Tobacco cessation among users of telephone and web-based interventions--four states, 2011-2012. AB - Smoking caused an average of 480,000 deaths per year in the United States from 2005 to 2009, and three in 10 cancer deaths in the United States are tobacco related. Tobacco cessation is a high public health priority, and all states offer some form of tobacco cessation service. Quitlines provide telephone-based counseling services and are an effective intervention for tobacco cessation. In addition to telephone services, 96% of all U.S. quitlines offer Web-based cessation services. Evidence is limited on the number of tobacco users who use more than one type of service, and studies report mixed results on whether combined telephone and Web-based counseling improves long-term cessation compared with telephone alone. CDC conducted a survey of users of telephone and Web-based cessation services in four states to determine the cessation success of users of these interventions. After adjusting for multiple variables, persons who used both telephone and Web-based services were more likely to report abstinence from smoking for 30 days at follow up (odds ratio = 1.3) compared with telephone-only users and with Web-only users (odds ratio = 1.5). These findings suggest that states might consider offering both types of cessation services to increase cessation success. PMID- 25551594 TI - Tetrodotoxin poisoning outbreak from imported dried puffer fish--Minneapolis, Minnesota, 2014. AB - On June 13, 2014, two patients went to the Hennepin County Medical Center Emergency Department in Minneapolis, Minnesota, with symptoms suggestive of tetrodotoxin poisoning (i.e., oral paresthesias, weakness, and dyspnea) after consuming dried puffer fish (also known as globefish) purchased during a recent visit to New York City. The patients said two friends who consumed the same fish had similar, although less pronounced, symptoms and had not sought care. The Minnesota Department of Health conducted an investigation to determine the source of the product and samples were sent to the Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition for chemical and genetic analysis. Genetic analysis identified the product as puffer fish (Lagocephalus lunaris) and chemical analysis determined it was contaminated with high levels of tetrodotoxin. A traceback investigation was unable to determine the original source of the product. Tetrodotoxin is a deadly, potent poison; the minimum lethal dose in an adult human is estimated to be 2-3 mg. Tetrodotoxin is a heat stable and acid-stable, nonprotein, alkaloid toxin found in many species of the fish family Tetraodontidae (puffer fish) as well as in certain gobies, amphibians, invertebrates, and the blue-ringed octopus. Tetrodotoxin exerts its effects by blocking voltage-activated sodium channels, terminating nerve conduction and muscle action potentials, leading to progressive paralysis and, in extreme cases, to death from respiratory failure. Because these fish were reportedly purchased in the United States, they pose a substantial U.S. public health hazard given the potency of the toxin and the high levels of toxin found in the fish. PMID- 25551595 TI - Perceptions of the risk for Ebola and health facility use among health workers and pregnant and lactating women--Kenema District, Sierra Leone, September 2014. AB - With an estimated maternal mortality ratio of 1,100 per 100,000 live births and a neonatal mortality rate of 49 per 1,000 live births, Sierra Leone has the highest maternal mortality ratio and the fourth highest neonatal mortality rate in the world, accounting for 2,400 maternal and 11,200 newborn deaths annually. By straining the fragile health care infrastructure, the Ebola virus disease (Ebola) epidemic might put pregnant women and their newborns at even greater risk for adverse outcomes. PMID- 25551596 TI - Aseptic meningitis outbreak associated with echovirus 30 among high school football players--Los Angeles County, California, 2014. AB - On August 4, 2014, the Acute Communicable Disease Control Program of the Los Angeles County Department of Public Health received a report of three aseptic meningitis cases among football players at a county high school. An investigation was conducted to determine the extent of the outbreak, identify potential exposures, and recommend control measures. An outbreak-associated aseptic meningitis case was defined as an illness of any team or family member with onset during July 28-August 11 with 1) cerebrospinal fluid pleocytosis and negative bacterial culture or 2) an emergency department visit with headache, fever, and stiff neck. Ten cases were identified; nine in males, and one in a female; patient ages ranged from 13 to 17 years. All the patients sought care at an emergency department, and five were hospitalized, resulting in 12 total hospital days. All 10 patients have recovered. Eight patients were football players, and two were siblings of football players. The most affected subgroup was the junior varsity football team, with seven cases out of 57 players (attack rate = 12.3%); the relative risk for aseptic meningitis was higher among players who were linemen than among those who were not linemen (relative risk = 5.4 [p = 0.03]). Of the 10 patients, eight tested positive by polymerase chain reaction for enterovirus, and two were not tested. Echovirus testing was performed at the California Viral and Rickettsial Disease Laboratory. Of the eight specimens testing positive for enterovirus, seven tested positive for echovirus 30, and one specimen could not be typed because of insufficient quantity. PMID- 25551599 TI - Transcriptional responses of a bicarbonate-tolerant monocot, Puccinellia tenuiflora, and a related bicarbonate-sensitive species, Poa annua, to NaHCO3 stress. AB - Puccinellia tenuiflora is an alkaline salt-tolerant monocot found in saline alkali soil in China. To identify the genes which are determining the higher tolerance of P. tenuiflora compared to bicarbonate sensitive species, we examined the responses of P. tenuiflora and a related bicarbonate-sensitive Poeae plant, Poa annua, to two days of 20 mM NaHCO3 stress by RNA-seq analysis. We obtained 28 and 38 million reads for P. tenuiflora and P. annua, respectively. For each species, the reads of both unstressed and stressed samples were combined for de novo assembly of contigs. We obtained 77,329 contigs for P. tenuiflora and 115,335 contigs for P. annua. NaHCO3 stress resulted in greater than two-fold absolute expression value changes in 157 of the P. tenuiflora contigs and 1090 of P. annua contigs. Homologs of the genes involved in Fe acquisition, which are important for the survival of plants under alkaline stress, were up-regulated in P. tenuiflora and down-regulated in P. annua. The smaller number of the genes differentially regulated in P. tenuiflora suggests that the genes regulating bicarbonate tolerance are constitutively expressed in P. tenuiflora. PMID- 25551598 TI - The effects of endogenous non-peptide molecule isatin and hydrogen peroxide on proteomic profiling of rat brain amyloid-beta binding proteins: relevance to Alzheimer's disease? AB - The amyloid-beta peptide is considered as a key player in the development and progression of Alzheimer's disease (AD). Although good evidence exists that amyloid-beta accumulates inside cells, intracellular brain amyloid-binding proteins remain poorly characterized. Proteomic profiling of rat brain homogenates, performed in this study, resulted in identification of 89 individual intracellular amyloid-binding proteins, and approximately 25% of them were proteins that we had previously identified as specifically binding to isatin, an endogenous neuroprotector molecule. A significant proportion of the amyloid binding proteins (more than 30%) are differentially expressed or altered/oxidatively modified in AD patients. Incubation of brain homogenates with 70 uM hydrogen peroxide significantly influenced the profile of amyloid-beta binding proteins and 0.1 mM isatin decreased the number of identified amyloid beta binding proteins both in control and hydrogen peroxide treated brain homogenates. The effects of hydrogen peroxide and isatin have been confirmed in optical biosensor experiments with purified glyceraldehyde-3-phosphate dehydrogenase, one of the known crucial amyloid-beta binding proteins (also identified in this study). Data obtained suggest that isatin protects crucial intracellular protein targets against amyloid binding, and possibly favors intracellular degradation of this protein via preventing formation of amyloid beta oligomers described in the literature for some isatin derivatives. PMID- 25551600 TI - Elucidating pharmacological mechanisms of natural medicines by biclustering analysis of the gene expression profile: a case study on curcumin and Si-Wu-Tang. AB - Natural medicines have attracted wide attention in recent years. It is of great significance to clarify the pharmacological mechanisms of natural medicines. In prior studies, we established a method for elucidating pharmacological mechanisms of natural products contained in connectivity map (cMap), in terms of module profiles of gene expression in chemical treatments. In this study, we explore whether this methodology is applicable to dissecting the pharmacological mechanisms of natural medicines beyond the agents contained in cMap. First, the gene expression profiles of curcumin (a typical isolated natural medicine) and Si Wu-Tang (a classic traditional Chinese medicine formula) treatments were merged with those of cMap-derived 1309 agents, respectively. Then, a biclustering analysis was performed using FABIA method to identify gene modules. The biological functions of gene modules provide preliminary insights into pharmacological mechanisms of both natural medicines. The module profile can be characterized by a binary vector, which allowed us to compare the expression profiles of natural medicines with those of cMap-derived agents. Accordingly, we predicted a series of pharmacological effects for curcumin and Si-Wu-Tang by the indications of cMap-covered drugs. Most predictions were supported by experimental observations, suggesting the potential use of this method in natural medicine dissection. PMID- 25551597 TI - Alternative RNA structure-coupled gene regulations in tumorigenesis. AB - Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s) into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level. Meanwhile, ARS can regulate the presence/absence of upstream open reading frames and microRNA targeting sites in 5'UTRs and 3'UTRs, respectively, thus affecting translational efficiencies and protein expression levels. Furthermore, since ARS may alter exon-intron structures, it can influence the biogenesis of intronic microRNAs and indirectly affect the expression of the target genes of these microRNAs. The connections between ARS and multiple regulatory mechanisms underline the importance of ARS in determining cell fate. Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis. Here I will review our current knowledge in this field, and discuss potential future directions. PMID- 25551602 TI - Diagnostic potential of differentially expressed Homer1, IL-1beta, and TNF-alpha in coronary artery disease. AB - Increasing evidences suggest that inflammation plays an important role in the pathogenesis of coronary artery disease (CAD). Numerous inflammatory cytokines and related genes mediate adverse cardiovascular events in patients with CAD, such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and Homer in the present study. The study was carried out on 163 CAD patients at different stages and 68 controls. The gene expression of Homer1, Homer2, Homer3, IL-1beta, and TNF-alpha in the peripheral blood leukocytes were measured by real time polymerase chain reaction. The mRNA levels of Homer1, IL-1beta, and TNF alpha in CAD patients were significantly higher than those in the control group, but not Homer2 and Homer3. However, there was no considerable difference in the mRNA levels of Homer1, IL-1beta, and TNF-alpha among AMI, UAP, and SAP three subgroups of CAD. The receiver operating characteristic (ROC) curves showed that Homer1 had a better diagnostic value for UAP patients compared with IL-1beta and TNF-alpha. Like IL-1beta and TNF-alpha, Homer1 may also be an important participant of atherosclerotic plaque development and eventually rupture. The results of the present study may provide an important basis for diagnosing CAD patients, and provide new therapeutic targets for CAD. PMID- 25551601 TI - Transcriptome-wide analysis of SAMe superfamily to novelty phosphoethanolamine N methyltransferase copy in Lonicera japonica. AB - The S-adenosyl-L-methionine-dependent methyltransferase superfamily plays important roles in plant development. The buds of Lonicera japonica are used as Chinese medical material and foods; chinese people began domesticating L. japonica thousands of years ago. Compared to the wild species, L. japonica var. chinensis, L. japonica gives a higher yield of buds, a fact closely related to positive selection over the long cultivation period of the species. Genome duplications, which are always detected in the domestic species, are the source of the multifaceted roles of the functional gene. In this paper, we investigated the evolution of the SAMe genes in L. japonica and L. japonica var. chinensis and further analyzed the roles of the duplicated genes among special groups. The SAMe protein sequences were subdivided into three clusters and several subgroups. The difference in transcriptional levels of the duplicated genes showed that seven SAMe genes could be related to the differences between the wild and the domesticated varieties. The sequence diversity of seven SAMe genes was also analyzed, and the results showed that different gene expression levels between the varieties could not be related to amino acid variation. The transcriptional level of duplicated PEAMT could be regulated through the SAM-SAH cycle. PMID- 25551603 TI - Cyclodextrin-complexed Ocimum basilicum leaves essential oil increases Fos protein expression in the central nervous system and produce an antihyperalgesic effect in animal models for fibromyalgia. AB - O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. beta Cyclodextrin (beta-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in beta-CD (LEO/beta-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/beta-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-betaCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with beta-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia. PMID- 25551604 TI - Polyester-based (bio)degradable polymers as environmentally friendly materials for sustainable development. AB - This review focuses on the polyesters such as polylactide and polyhydroxyalkonoates, as well as polyamides produced from renewable resources, which are currently among the most promising (bio)degradable polymers. Synthetic pathways, favourable properties and utilisation (most important applications) of these attractive polymer families are outlined. Environmental impact and in particular (bio)degradation of aliphatic polyesters, polyamides and related copolymer structures are described in view of the potential applications in various fields. PMID- 25551606 TI - Asymmetric synthesis and evaluation of danshensu-cysteine conjugates as novel potential anti-apoptotic drug candidates. AB - We have previously reported that the danshensu-cysteine conjugate N-((R)-3 benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2) induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2 induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes. PMID- 25551605 TI - Accelerating in situ endothelialisation of cardiovascular bypass grafts. AB - The patency of synthetic cardiovascular grafts in the long run is synonymous with their ability to inhibit the processes of intimal hyperplasia, thrombosis and calcification. In the human body, the endothelium of blood vessels exhibits characteristics that inhibit such processes. As such it is not surprising that research in tissue engineering is directed towards replicating the functionality of the natural endothelium in cardiovascular grafts. This can be done either by seeding the endothelium within the lumen of the grafts prior to implantation or by designing the graft such that in situ endothelialisation takes place after implantation. Due to certain difficulties identified with in vitro endothelialisation, in situ endothelialisation, which will be the focus of this article, has garnered interest in the last years. To promote in situ endothelialisation, the following aspects can be taken into account: (1) Endothelial progenital cell mobilization, adhesion and proliferation; (2) Regulating differentiation of progenitor cells to mature endothelium; (3) Preventing thrombogenesis and inflammation during endothelialisation. This article aims to review and compile recent developments to promote the in situ endothelialisation of cardiovascular grafts and subsequently improve their patency, which can also have widespread implications in the field of tissue engineering. PMID- 25551607 TI - Comparisons of de novo transcriptome assemblers in diploid and polyploid species using peanut (Arachis spp.) RNA-Seq data. AB - The narrow genetic base and limited genetic information on Arachis species have hindered the process of marker-assisted selection of peanut cultivars. However, recent developments in sequencing technologies have expanded opportunities to exploit genetic resources, and at lower cost. To use the genetic information for Arachis species available at the transcriptome level, it is important to have a good quality reference transcriptome. The available Tifrunner 454 FLEX transcriptome sequences have an assembly with 37,000 contigs and low N50 values of 500-751 bp. Therefore, we generated de novo transcriptome assemblies, with about 38 million reads in the tetraploid cultivar OLin, and 16 million reads in each of the diploids, A. duranensis K38901 and A. ipaensis KGBSPSc30076 using three different de novo assemblers, Trinity, SOAPdenovo-Trans and TransAByss. All these assemblers can use single kmer analysis, and the latter two also permit multiple kmer analysis. Assemblies generated for all three samples had N50 values ranging from 1278-1641 bp in Arachis hypogaea (AABB), 1401-1492 bp in Arachis duranensis (AA), and 1107-1342 bp in Arachis ipaensis (BB). Comparison with legume ESTs and protein databases suggests that assemblies generated had more than 40% full length transcripts with good continuity. Also, on mapping the raw reads to each of the assemblies generated, Trinity had a high success rate in assembling sequences compared to both TransAByss and SOAPdenovo-Trans. De novo assembly of OLin had a greater number of contigs (67,098) and longer contig length (N50 = 1,641) compared to the Tifrunner TSA. Despite having shorter read length (2 * 50) than the Tifrunner 454FLEX TSA, de novo assembly of OLin proved superior in comparison. Assemblies generated to represent different genome combinations may serve as a valuable resource for the peanut research community. PMID- 25551610 TI - Proteomic analysis of kidney in rats chronically exposed to monosodium glutamate. AB - BACKGROUND: Chronic monosodium glutamate (MSG) intake causes kidney dysfunction and renal oxidative stress in the animal model. To gain insight into the renal changes induced by MSG, proteomic analysis of the kidneys was performed. METHODS: Six week old male Wistar rats were given drinking water with or without MSG (2 mg/g body weight, n = 10 per group) for 9 months. Kidneys were removed, frozen, and stored at -75 degrees C. After protein extraction, 2-D gel electrophoresis was performed and renal proteome profiles were examined with Colloidal Coomassie Brilliant Blue staining. Statistically significant protein spots (ANOVA, p<0.05) with 1.2-fold difference were excised and analyzed by LC-MS. Proteomic data were confirmed by immunohistochemistry and Western blot analyses. RESULTS: The differential image analysis showed 157 changed spots, of which 71 spots were higher and 86 spots were lower in the MSG-treated group compared with those in the control group. Eight statistically significant and differentially expressed proteins were identified: glutathione S-transferase class-pi, heat shock cognate 71 kDa, phosphoserine phosphatase, phosphoglycerate kinase, cytosolic glycerol-3 phosphate dehydrogenase, 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, alpha-ketoglutarate dehydrogenase and succinyl-CoA ligase. CONCLUSION: The identified proteins are mainly related to oxidative stress and metabolism. They provide a valuable clue to explore the mechanism of renal handling and toxicity on chronic MSG intake. PMID- 25551611 TI - Symmetry breaking on density in escaping ants: experiment and alarm pheromone model. AB - The symmetry breaking observed in nature is fascinating. This symmetry breaking is observed in both human crowds and ant colonies. In such cases, when escaping from a closed space with two symmetrically located exits, one exit is used more often than the other. Group size and density have been reported as having no significant impact on symmetry breaking, and the alignment rule has been used to model symmetry breaking. Density usually plays important roles in collective behavior. However, density is not well-studied in symmetry breaking, which forms the major basis of this paper. The experiment described in this paper on an ant colony displays an increase then decrease of symmetry breaking versus ant density. This result suggests that a Vicsek-like model with an alignment rule may not be the correct model for escaping ants. Based on biological facts that ants use pheromones to communicate, rather than seeing how other individuals move, we propose a simple yet effective alarm pheromone model. The model results agree well with the experimental outcomes. As a measure, this paper redefines symmetry breaking as the collective asymmetry by deducing the random fluctuations. This research indicates that ants deposit and respond to the alarm pheromone, and the accumulation of this biased information sharing leads to symmetry breaking, which suggests true fundamental rules of collective escape behavior in ants. PMID- 25551608 TI - A comparative analysis of genetic differentiation across six shared willow host species in leaf- and bud-galling sawflies. AB - Genetic divergence and speciation in plant-feeding insects could be driven by contrasting selection pressures imposed by different plant species and taxa. While numerous examples of host-associated differentiation (HAD) have been found, the overall importance of HAD in insect diversification remains unclear, as few studies have investigated its frequency in relation to all speciation events. One promising way to infer the prevalence and repeatability of HAD is to estimate genetic differentiation in multiple insect taxa that use the same set of hosts. To this end, we measured and compared variation in mitochondrial COI and nuclear ITS2 sequences in population samples of leaf-galling Pontania and bud-galling Euura sawflies (Hymenoptera: Tenthredinidae) collected from six Salix species in two replicate locations in northern Fennoscandia. We found evidence of frequent HAD in both species complexes, as individuals from the same willow species tended to cluster together on both mitochondrial and nuclear phylogenetic trees. Although few fixed differences among the putative species were found, hierarchical AMOVAs showed that most of the genetic variation in the samples was explained by host species rather than by sampling location. Nevertheless, the levels of HAD measured across specific pairs of host species were not correlated in the two focal galler groups. Hence, our results support the hypothesis of HAD as a central force in herbivore speciation, but also indicate that evolutionary trajectories are only weakly repeatable even in temporally overlapping radiations of related insect taxa. PMID- 25551609 TI - Interleukin-1beta enhances FasL-induced caspase-3/-7 activity without increasing apoptosis in primary mouse hepatocytes. AB - Sustained inflammation may increase the susceptibility of hepatocytes to apoptotic cell death and therefore exacerbate liver damage. Here we report that the pro-inflammatory cytokine IL-1beta sensitizes primary murine hepatocytes to Fas ligand (FasL)-induced caspase-3/-7 activity. This process was dependent on JNK1/2 and the BH3-only proteins Bim and Bid. Mathematical modeling revealed that incubation of hepatocytes with IL-1beta depleted the anti-apoptotic Bcl-2 protein pool and thus shifted hepatocytes to mitochondrial type II apoptosis following Fas activation. As a consequence, IL-1beta and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1beta pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1beta and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1beta was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF-kappaB DNA binding was increased in response to IL-1beta plus FasL and gene-expression profiling of NF kappaB regulated genes revealed a transcriptional and translational upregulation of the caspase-8 inhibitor A20. A mathematical model was developed to explain the contradictious occurrence of both increased caspase-3/-7 activity and elevated cell viability by including a heterogeneous distribution of Bcl-2 proteins and variations in Fas signaling resulting in different subpopulations of hepatocytes. PMID- 25551613 TI - Bouncing back: plant-associated soil microbes respond rapidly to prairie establishment. AB - It is well established that soil microbial communities change in response to altered land use and land cover, but less is known about the timing of these changes. Understanding temporal patterns in recovering microbial communities is an important part of improving how we assess and manage reconstructed ecosystems. We assessed patterns of community-level microbial diversity and abundance in corn and prairie plots 2 to 4 years after establishment in agricultural fields, using phospholipid fatty acid biomarkers. Principal components analysis of the lipid biomarkers revealed differing composition between corn and prairie soil microbial communities. Despite no changes to the biomass of Gram-positive bacteria and actinomycetes, total biomass, arbuscular mycorrhizal fungi biomass, and Gram negative bacteria biomass were significantly higher in restored prairie plots, approaching levels found in long-established prairies. These results indicate that plant-associated soil microbes in agricultural soils can shift in less than 2 years after establishment of perennial grasslands. PMID- 25551612 TI - Ubiquitous transgene expression of the glucosylceramide-synthesizing enzyme accelerates glucosylceramide accumulation and storage cells in a Gaucher disease mouse model. AB - Gaucher disease is a lysosomal storage disease caused by defective activity of acid beta-glucosidase (GCase), which leads to the accumulation of its major substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in many cells. To modulate cellular substrate concentration in viable mouse models of Gaucher disease (Gba1 mutants), a novel mouse model was created with enhanced glycosphingolipid biosynthesis. This was accomplished by cross-breeding Gba1 mutant mice with mice expressing a transgene (GCStg) containing the mouse glucosylceramide synthase (GCS, Ugcg) cDNA driven by the ROSA promoter, yielding GCStg/Gba1 mice. The GCStg rescued Ugcg null mice from embryonic lethality. GCStg/Gba1 mice showed 2-3 fold increases in tissue GCS activity as well as accelerated GlcCer accumulation and the appearance of lipid-laden CD68 positive macrophages in visceral organs. Although GlcCer/GlcSph concentrations were elevated in the brain, there was no neurodegenerative phenotype up to 1 yr of age conceivably due to the greater residual GCase hydrolytic activity in the brains than in the visceral tissues of 9V/null mice. These studies provide 'proof of principle' for threshold substrate flux that modifies phenotypic development in Gaucher disease and other lysosomal storage diseases. PMID- 25551614 TI - Differential range use between age classes of southern African Bearded Vultures Gypaetus barbatus. AB - Bearded Vulture Gypaetus barbatus movements were investigated in southern Africa to determine whether an individual's age, sex or breeding status influenced its ranging behaviour and to provide the information required to guide conservation activities. Data from satellite transmitters fitted to 18 individuals of four age classes were used to determine range size and use. Because of the nature of the movements of marked individuals, these data could be used to determine the overall foraging range of the entire population, which was estimated to be 51 767 km(2). Although juvenile, immature and sub-adult birds used different parts of the overall range, their combined foraging range was 65% (33 636 km(2)) of the overall range. Average adult home ranges (286 km(2)) were only around 1% the size of the average foraging ranges of non-adults (10 540 -25 985 km(2)), with those of breeding adults being even smaller (95 km(2)). Home ranges of breeding adults did not vary in size between seasons but adults utilized their home range more intensively whilst breeding, moving greater distances during the incubation and chick hatching period. Range size and use increased as non-adults aged. Immatures and sub-adults had larger range sizes during winter, but range use of non-adults did not vary seasonally. Range size and use did not differ between the sexes in any of the age classes. Information on home range size and use enables specific areas within the species' range to be targeted for management planning, education and conservation action. PMID- 25551615 TI - Bats on a budget: torpor-assisted migration saves time and energy. AB - Bats and birds must balance time and energy budgets during migration. Migrating bats face similar physiological challenges to birds, but nocturnality creates special challenges for bats, such as a conflict between travelling and refueling, which many birds avoid by feeding in daylight and flying at night. As endothermic animals, bats and birds alike must expend substantial amounts of energy to maintain high body temperatures. For migratory birds refueling at stopovers, remaining euthermic during inactive periods reduces the net refuelling rate, thereby prolonging stopover duration and delaying subsequent movement. We hypothesized that bats could mitigate similar ambient-temperature dependent costs by using a torpor-assisted migration strategy. We studied silver-haired bats Lasionycteris noctivagans during autumn migration using a combination of respirometry and temperature-sensitive radiotelemetry to estimate energy costs incurred under ambient temperature conditions, and the energy that bats saved by using torpor during daytime roosting periods. All bats, regardless of sex, age, or body condition used torpor at stopover and saved up to 91% of the energy they would have expended to remain euthermic. Furthermore, bats modulated use of torpor depending on ambient temperature. By adjusting the time spent torpid, bats achieved a rate of energy expenditure independent of the ambient temperature encountered at stopover. By lowering body temperature during inactive periods, fuel stores are spared, reducing the need for refuelling. Optimal migration models consider trade-offs between time and energy. Heterothermy provides a physiological strategy that allows bats to conserve energy without paying a time penalty as they migrate. Although uncommon, some avian lineages are known to use heterothermy, and current theoretical models of migration may not be appropriate for these groups. We propose that thermoregulatory strategies should be an important consideration of future migration studies of both bats and birds. PMID- 25551616 TI - Detection of transgenes in local maize varieties of small-scale farmers in eastern cape, South Africa. AB - Small-scale subsistence farmers in South Africa have been introduced to genetically modified (GM) crops for more than a decade. Little is known about i) the extent of transgene introgression into locally recycled seed, ii) what short and long-term ecological and socioeconomic impacts such mixing of seeds might have, iii) how the farmers perceive GM crops, and iv) to what degree approval conditions are followed and controlled. This study conducted in the Eastern Cape, South Africa, aims primarily at addressing the first of these issues. We analysed for transgenes in 796 individual maize plants (leaves) and 20 seed batches collected in a village where GM insect resistant maize was previously promoted and grown as part of an governmental agricultural development program over a seven year period (2001-2008). Additionally, we surveyed the varieties of maize grown and the farmers' practices of recycling and sharing of seed in the same community (26 farmers were interviewed). Recycling and sharing of seeds were common in the community and may contribute to spread and persistence of transgenes in maize on a local or regional level. By analysing DNA we found that the commonly used transgene promoter p35s occurred in one of the 796 leaf samples (0.0013%) and in five of the 20 seed samples (25%). Three of the 20 seed samples (15%) included herbicide tolerant maize (NK603) intentionally grown by the farmers from seed bought from local seed retailers or acquired through a currently running agricultural development program. The two remaining positive seed samples (10%) included genes for insect resistance (from MON810). In both cases the farmers were unaware of the transgenes present. In conclusion, we demonstrate that transgenes are mixed into seed storages of small-scale farming communities where recycling and sharing of seeds are common, i.e. spread beyond the control of the formal seed system. PMID- 25551617 TI - Constructal law of vascular trees for facilitation of flow. AB - Diverse tree structures such as blood vessels, branches of a tree and river basins exist in nature. The constructal law states that the evolution of flow structures in nature has a tendency to facilitate flow. This study suggests a theoretical basis for evaluation of flow facilitation within vascular structure from the perspective of evolution. A novel evolution parameter (Ev) is proposed to quantify the flow capacity of vascular structures. Ev is defined as the ratio of the flow conductance of an evolving structure (configuration with imperfection) to the flow conductance of structure with least imperfection. Attaining higher Ev enables the structure to expedite flow circulation with less energy dissipation. For both Newtonian and non-Newtonian fluids, the evolution parameter was developed as a function of geometrical shape factors in laminar and turbulent fully developed flows. It was found that the non-Newtonian or Newtonian behavior of fluid as well as flow behavior such as laminar or turbulent behavior affects the evolution parameter. Using measured vascular morphometric data of various organs and species, the evolution parameter was calculated. The evolution parameter of the tree structures in biological systems was found to be in the range of 0.95 to 1. The conclusion is that various organs in various species have high capacity to facilitate flow within their respective vascular structures. PMID- 25551618 TI - Efficacy of combined vancomycin and fosfomycin against methicillin-resistant Staphylococcus aureus in biofilms in vivo. AB - Infection by methicillin-resistant Staphylococcus aureus (MRSA) is a life threatening condition, and formation of biofilms can lead to treatment failure in a clinical setting. The aim of this study was to demonstrate the in vivo bactericidal effects of a combination of vancomycin (VAN) and fosfomycin (FOS) against MRSA in a rat carboxymethyl cellulose-pouch biofilm model. The results of the time-kill assay showed that the combination therapy was capable of killing at low minimal inhibitory concentrations (MIC) (1/2 * MIC VAN +1 * MIC FOS and 1 * MIC VAN + 1 * MIC FOS). In the in vivo study, a synergistically bactericidal effect was observed when using the combination therapy on MRSA embedded in the mature biofilm model. In comparison with the untreated control group and the groups receiving either VAN or FOS alone, the rats treated with combination therapy had lower MRSA colony counts in exudates from the pouch, lower white blood cell and neutrophil counts, and C-reactive protein (CRP) in peripheral blood. Furthermore, histological analysis of the pouch wall indicated combination therapy resulted in disappearance of biofilm-like structures, marked decrease in necrosis, and formation of granular tissue. In conclusion, the combination of VAN with FOS had a synergistic bactericidal effect on chronic MRSA infection embedded in biofilm, providing an alternative approach to treating this condition. PMID- 25551620 TI - Drivers of time-activity budget variability during breeding in a pelagic seabird. AB - During breeding, animal behaviour is particularly sensitive to environmental and food resource availability. Additionally, factors such as sex, body condition, and offspring developmental stage can influence behaviour. Amongst seabirds, behaviour is generally predictably affected by local foraging conditions and has therefore been suggested as a potentially useful proxy to indicate prey state. However, besides prey availability and distribution, a range of other variables also influence seabird behavior, and these need to be accounted for to increase the signal-to-noise ratio when assessing specific characteristics of the environment based on behavioural attributes. The aim of this study was to use continuous, fine-scale time-activity budget data from a pelagic seabird (Cape gannet, Morus capensis) to determine the influence of intrinsic (sex and body condition) and extrinsic (offspring and time) variables on parent behaviour during breeding. Foraging trip duration and chick provisioning rates were clearly sex-specific and associated with chick developmental stage. Females made fewer, longer foraging trips and spent less time at the nest during chick provisioning. These sex-specific differences became increasingly apparent with chick development. Additionally, parents in better body condition spent longer periods at their nests and those which returned later in the day had longer overall nest attendance bouts. Using recent technological advances, this study provides new insights into the foraging behaviour of breeding seabirds, particularly during the post-guarding phase. The biparental strategy of chick provisioning revealed in this study appears to be an example where the costs of egg development to the female are balanced by paternal-dominated chick provisioning particularly as the chick nears fledging. PMID- 25551619 TI - Advancing research and practice in HIV and rehabilitation: a framework of research priorities in HIV, disability and rehabilitation. AB - BACKGROUND: HIV increasingly is experienced as a complex chronic illness where individuals are living longer with a range of physical, cognitive, mental and social health-related challenges associated with HIV, comorbidities and aging, a concept that may be termed 'disability'. Rehabilitation such as physical therapy and occupational therapy can help address disability and has the potential to improve quality of life in people living with HIV. Hence, the role for rehabilitation in the context of HIV, aging and comorbidities is emerging. Our aim was to establish a framework of research priorities in HIV, disability and rehabilitation. METHODS: We convened people living with HIV, clinicians, researchers, service providers, representatives from community-based organizations and policy and funding stakeholders to participate in the first International Forum on HIV and Rehabilitation Research. We conducted a multi stakeholder consultation to identify current and emerging issues in HIV, disability and rehabilitation. Data were collated and analyzed using content analytical techniques. RESULTS: Ninety-two participants attended the Forum from Canada, United Kingdom (UK), Ireland and the United States. Situated within three overarching themes (episodic health and disability across the life course; rehabilitation; and methodological advances), the Framework of Research Priorities in HIV, Disability and Rehabilitation includes six research priorities: 1) episodic health and disability; 2) aging with HIV across the life course; 3) concurrent health conditions; 4) access to rehabilitation and models of rehabilitation service provision; 5) effectiveness of rehabilitation interventions; and 6) enhancing outcome measurement in HIV and rehabilitation research. The Framework includes methodological considerations and environmental and personal contextual factors (or lenses) through which to approach research in the field. Knowledge translation should be implemented throughout the development and application of research knowledge to inform HIV clinical practice, programming and policy. CONCLUSIONS: These priorities highlight the emerging priorities of living long-term with HIV and outline a plan for HIV and rehabilitation research in resource-rich countries such as the UK and Canada. PMID- 25551621 TI - Decreased expression of microRNA-126 is associated with poor prognosis in patients with cervical cancer. AB - BACKGROUND: MicroRNA-126(miR-126) has been shown to be frequently down-regulated in a variety of malignancies and act as a potential tumor suppressor. However, its correlations with the clinicopathological characters of cervical cancer remain unclear. METHODS: TaqMan quantitative RT-PCR was used to determine the expression level of miR-126 in tissue samples. The associations of miR-126 expression with clinicopathologic variables were analyzed. Kaplan-Meier survival analysis was performed to analyze the association of miR-126 expression with overall survival (OS) of patients. Univariate and multivariate Cox regression analyses were performed. RESULTS: miR-126 expression level in human cervical cancer tissues was significantly lower than that in adjacent nontumorous tissues (mean +/- SD: 0.59 +/- 0.44 vs. 1.00 +/- 0.51, P < 0.0001). Decreased miR-126 expression in cervical cancer was found to be significantly associated with lymphatic invasion (P = 0.002), distant metastasis (P < 0.001), FIGO stage (P = 0.009), and histological grade (P = 0.005). Kaplan-Meier analysis showed that patients with lower levels of miR-126 had significantly poorer survival than those with higher expression of this miRNA in patients, with a 5-year OS of 45.7% and 70.9%, respectively (P = 0.002). Multivariate analysis revealed that miR-126 expression (HR = 3.97, 95% CI: 2.01-20.22; P = 0.003) was independently associated with the OS. CONCLUSION: Our data suggests the potential of miR-126 as a prognostic biomarker for cervical cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_220. PMID- 25551622 TI - Renal cell carcinoma with Xp 11.2 translocation as a second tumor in a long-term survivor of advanced neuroblastoma. AB - Renal cell carcinoma (RCC) is an uncommon tumor in childhood and adolescence, and is exceptionally rare as a secondary neoplasm related to prior anti-neoplastic therapy. We report a case of RCC with Xp11.2 translocation in a 17 year old boy who is a survivor of stage 4 neuroblastoma 13 years earlier. PMID- 25551623 TI - Effect of external magnetic field on IV 99mTc-labeled aminosilane-coated iron oxide nanoparticles: demonstration in a rat model: special report. AB - Among the most interesting applications of ferromagnetic nanoparticles (NPs) in medicine is the potential for localizing pharmacologically or radioactively tagged agents directly to selected tissues selected by an adjustable external magnetic field. This concept is demonstrated by the application external magnetic field on IV Tc-labeled aminosilane-coated iron oxide NPs in a rat model. In a model comparing a rat with a 0.3-T magnet over a hind paw versus a rat without a magnet, a static acquisition at 45 minutes showed that 27% of the administered radioactivity was in the area subtended by the magnet, whereas the liver displays a percentage of binding of 14% in the presence of the magnet and of 16% in the absence of an external magnetic field. These preliminary results suggest that the application of an external magnetic field may be a viable route for the development of methods for the confinement of magnetic NPs labeled with radioactive isotopes targeted for predetermined sites of the body. PMID- 25551624 TI - Micro- and macro-geographic scale effect on the molecular imprint of selection and adaptation in Norway spruce. AB - Forest tree species of temperate and boreal regions have undergone a long history of demographic changes and evolutionary adaptations. The main objective of this study was to detect signals of selection in Norway spruce (Picea abies [L.] Karst), at different sampling-scales and to investigate, accounting for population structure, the effect of environment on species genetic diversity. A total of 384 single nucleotide polymorphisms (SNPs) representing 290 genes were genotyped at two geographic scales: across 12 populations distributed along two altitudinal-transects in the Alps (micro-geographic scale), and across 27 populations belonging to the range of Norway spruce in central and south-east Europe (macro-geographic scale). At the macrogeographic scale, principal component analysis combined with Bayesian clustering revealed three major clusters, corresponding to the main areas of southern spruce occurrence, i.e. the Alps, Carpathians, and Hercynia. The populations along the altitudinal transects were not differentiated. To assess the role of selection in structuring genetic variation, we applied a Bayesian and coalescent-based F(ST)-outlier method and tested for correlations between allele frequencies and climatic variables using regression analyses. At the macro-geographic scale, the F(ST)-outlier methods detected together 11 F(ST)-outliers. Six outliers were detected when the same analyses were carried out taking into account the genetic structure. Regression analyses with population structure correction resulted in the identification of two (micro-geographic scale) and 38 SNPs (macro-geographic scale) significantly correlated with temperature and/or precipitation. Six of these loci overlapped with F(ST)-outliers, among them two loci encoding an enzyme involved in riboflavin biosynthesis and a sucrose synthase. The results of this study indicate a strong relationship between genetic and environmental variation at both geographic scales. It also suggests that an integrative approach combining different outlier detection methods and population sampling at different geographic scales is useful to identify loci potentially involved in adaptation. PMID- 25551626 TI - Effect of hippotherapy on gross motor function in children with cerebral palsy: a randomized controlled trial. AB - OBJECTIVE: To examine whether hippotherapy has a clinically significant effect on gross motor function in children with cerebral palsy (CP). DESIGN: Randomized controlled trial. SETTING: Outpatient therapy center. PARTICIPANTS: Ninety-two children with CP, aged 4-10 years, presenting variable function (Gross Motor Function Classification System [GMFCS] levels I-IV). INTERVENTION: Hippotherapy (30 minutes twice weekly for 8 consecutive weeks). OUTCOME MEASURES: Gross Motor Function Measure (GMFM)-88, GMFM-66, and Pediatric Balance Scale. RESULTS: Pre- and post-treatment measures were completed by 91 children (45 in the intervention group and 46 in the control group). Differences in improvement on all three measures significantly differed between groups after the 8-week study period. Dimensions of GMFM-88 improved significantly after hippotherapy varied by GMFCS level: dimension E in level I, dimensions D and E in level II, dimensions C and D in level III, and dimensions B and C in level IV. CONCLUSION: Hippotherapy positively affects gross motor function and balance in children with CP of various functional levels. PMID- 25551625 TI - Mutational profiles of different macroscopic subtypes of colorectal adenoma reveal distinct pathogenetic roles for KRAS, BRAF and PIK3CA. AB - BACKGROUND: Investigations of genetic alterations and correlations with histology or morphology could provide further insights into colorectal carcinogenesis. Nevertheless, such genetic changes were less investigated in adenoma stage and a comprehensive survey of oncogenic mutations in EGFR signaling pathway according to different morphologic subtypes has not been performed. METHODS: A total of 94 neoplasms, including 34 polypoid adenoma, 16 lateral spreading tumors-granular (LST-G), 20 non-granular LST (LST-NG), and 24 depressed tumors, were subjected for mutational analysis of KRAS (exon 2), BRAF (exon 11 and 15), PIK3CA (exon 9 and 20), AKT (exon 4), EGFR (exon 18-24) and HER2 (exon18-24). RESULTS: KRAS mutation was noted more frequently in LST (13/36, 36.1%) than polypoid neoplasms (5/34, 14.7%, p = 0.041). When comparing with LST-NG, LST-G had a significantly higher frequency of KRAS mutation. (9/16, 56.3% vs. 4/20, 20.0%, p = 0.024). BRAF mutation (V600E) was found in 2 of 36 (5.6%)LSTs and 1 of 34 (2.9%) polypoid lesions. The two LST lesions with BRAF mutation were pathologically proven to be serrated adenoma. PIK3CA mutation (exon 9 E545K) was identified only in LST (5/36, 13.9%). Mutations in KRAS, BRAF or PIK3CA occurred in a mutually exclusive manner. All mutations were absent in the specimens obtained from depressed type neoplasms. CONCLUSIONS: Three different macroscopic subtypes of colorectal neoplasms display distinct carcinogenetic pathways in EGFR networking. Further molecular studies of CRCs should take macroscopic subtypes into consideration and highlight the importance of consensus and communication between endoscopic and pathologic diagnosis. PMID- 25551627 TI - Hearing care for elders: a personal reflection on participatory action learning with primary care providers. AB - PURPOSE: This report is a reflective critical narrative of the authors' experience with an interdisciplinary collaboration of primary care providers (PCPs) and hearing health care providers (HHCPs) that followed the principles of participatory action research/learning. The goal for this report is to describe the 1st author's observed barriers to PCPs' willingness to learn about hearing health care and the subsequent facilitators to learning. METHOD: A team of PCPs and HHCPs created the "Communication: Hearing Loss in Elders" educational module. The module included (a) prereading developed from a combination of literature reviews and contextual factors and (b) a case study. RESULTS: The authors present the list of topics included in the module, and they reflect on why and how these topics were deemed important by the team. In particular, 2 topics were identified for motivating PCPs' behavior regarding hearing health care: (a) the overlap in symptoms and possible causation among depression, dementia, and hearing loss and (b) how hearing can affect efficiency of care regarding other health issues. CONCLUSIONS: This personal reflective narrative gives the authors' opinions about what can make for a successful collaboration and presents some hypotheses regarding information that may motivate behavior change with regard to hearing care. PMID- 25551628 TI - 17beta-estradiol suppresses lipopolysaccharide-induced acute lung injury through PI3K/Akt/SGK1 mediated up-regulation of epithelial sodium channel (ENaC) in vivo and in vitro. AB - BACKGROUND: 17beta-estradiol can suppress acute lung injury (ALI) and regulate alveolar epithelial sodium channel (ENaC). However the relationship between these two functions remains unclear. This study is conducted to assess the role of ENaC and the PI3K/Akt/SGK1 signaling pathway in 17beta-estradiol therapy in attenuating LPS-induced ALI. METHODS: ALI was induced in C57BL/J male mice by intratracheal administration of lipopolysaccharide (LPS). Concurrent with LPS administration, 17beta-estradiol or sterile saline was administered to ALI model with or without the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin. The lung histological changes, inflammatory mediators in bronchoalveolar lavage fluid (BALF), wet/dry weight ratio (W/D) and alveolar fluid clearance (AFC) were measured 4 hours after LPS challenge in vivo. For in vitro studies, LPS challenged MLE-12 cells were pre-incubated with or without wortmannin for 30 minutes prior to 17beta-estradiol treatment. Expression of ENaC subunits was assessed by reverse transcriptase PCR, western blot, cell surface biotinylation, and immunohistochemistry. The levels of phosphorylated Akt and SGK1 in lung tissue and lung cell lines were investigated by western blot. RESULTS: 17beta estradiol suppressed LPS-mediated ALI in mice by diminishing inflammatory mediators and enhancing AFC. 17beta-estradiol promoted the expression and surface abundance of alpha-ENaC, and increased the levels of phosphorylated-Akt and phosphorylated-SGK1 following LPS challenge. This induction was abolished by the PI3K inhibitor wortmannin in vivo and in vitro. CONCLUSION: 17beta-estradiol attenuates LPS-induced ALI not only by repressing inflammation, but also by reducing pulmonary edema via elevation of alpha-ENaC expression and membrane abundance. These effects were mediated, at least partially, via activation of the PI3K/Akt/SGK1 signaling pathway. PMID- 25551630 TI - Allodaposuchus palustris sp. nov. from the upper cretaceous of Fumanya (South Eastern Pyrenees, Iberian Peninsula): systematics, palaeoecology and palaeobiogeography of the enigmatic allodaposuchian crocodylians. AB - The controversial European genus Allodaposuchus is currently composed of two species (A. precedens, A. subjuniperus) and it has been traditionally considered a basal eusuchian clade of crocodylomorphs. In the present work, the new species A. palustris is erected on the base of cranial and postcranial remains from the lower Maastrichtian of the southern Pyrenees. Phylogenetic analyses here including both cranial and postcranial data support the hypothesis that Allodaposuchus is included within Crocodylia. The studied specimen suggests little change in postcranial skeleton along the evolutionary history of crocodylians, except for some bone elements such as the axis, the first caudal vertebra and the ilium. The specimen was found in an organic mudstone corresponding to a coastal wetland environment. Thus, A. palustris from Fumanya is the first Allodaposuchus reported in lacustrine-palustrine settings that expand the ecological range for this genus. The S-DIVA palaeobiogeographic reconstruction of ancestral area suggests that early members of Crocodylia rapidly widespread for the Northern Hemisphere landmasses no later than the Campanian, leading the apparition of endemic groups. In that way "Allodaposuchia" represents an endemic European clade probably originated in the Ibero-Armorican domain in the late Campanian and dispersed by the Southern European archipelago prior to the early Maastrichtian. PMID- 25551629 TI - Helix 8 and the i3 loop of the muscarinic M3 receptor are crucial sites for its regulation by the Gbeta5-RGS7 complex. AB - The muscarinic M3 receptor (M3R) is a Gq-coupled receptor and is known to interact with many intracellular regulatory proteins. One of these molecules is Gbeta5-RGS7, the permanently associated heterodimer of G protein beta-subunit Gbeta5 and RGS7, a regulator of G protein signaling. Gbeta5-RGS7 can attenuate M3R-stimulated release of Ca(2+) from intracellular stores or enhance the influx of Ca(2+) across the plasma membrane. Here we show that deletion of amino acids 304-345 from the central portion of the i3 loop renders M3R insensitive to regulation by Gbeta5-RGS7. In addition to the i3 loop, interaction of M3R with Gbeta5-RGS7 requires helix 8. According to circular dichroism spectroscopy, the peptide corresponding to amino acids 548-567 in the C-terminus of M3R assumes an alpha-helical conformation. Substitution of Thr553 and Leu558 with Pro residues disrupts this alpha-helix and abolished binding to Gbeta5-RGS7. Introduction of the double Pro substitution into full-length M3R (M3R(TP/LP)) prevents trafficking of the receptor to the cell surface. Using atropine or other antagonists as pharmacologic chaperones, we were able to increase the level of surface expression of the TP/LP mutant to levels comparable to that of wild-type M3R. However, M3R-stimulated calcium signaling is still severely compromised. These results show that the interaction of M3R with Gbeta5-RGS7 requires helix 8 and the central portion of the i3 loop. PMID- 25551631 TI - Instrumentational complexity of music genres and why simplicity sells. AB - Listening habits are strongly influenced by two opposing aspects, the desire for variety and the demand for uniformity in music. In this work we quantify these two notions in terms of instrumentation and production technologies that are typically involved in crafting popular music. We assign an 'instrumentational complexity value' to each music style. Styles of low instrumentational complexity tend to have generic instrumentations that can also be found in many other styles. Styles of high complexity, on the other hand, are characterized by a large variety of instruments that can only be found in a small number of other styles. To model these results we propose a simple stochastic model that explicitly takes the capabilities of artists into account. We find empirical evidence that individual styles show dramatic changes in their instrumentational complexity over the last fifty years. 'New wave' or 'disco' quickly climbed towards higher complexity in the 70s and fell back to low complexity levels shortly afterwards, whereas styles like 'folk rock' remained at constant high instrumentational complexity levels. We show that changes in the instrumentational complexity of a style are related to its number of sales and to the number of artists contributing to that style. As a style attracts a growing number of artists, its instrumentational variety usually increases. At the same time the instrumentational uniformity of a style decreases, i.e. a unique stylistic and increasingly complex expression pattern emerges. In contrast, album sales of a given style typically increase with decreasing instrumentational complexity. This can be interpreted as music becoming increasingly formulaic in terms of instrumentation once commercial or mainstream success sets in. PMID- 25551632 TI - Correlation between lamina cribrosa tilt angles, myopia and glaucoma using OCT with a wide bandwidth femtosecond mode-locked laser. AB - PURPOSE: To measure horizontal and vertical lamina cribrosa (LC) tilt angles and investigate associated factors using prototype optical coherence tomography (OCT) with a broad wavelength laser light source. DESIGN: Cross sectional study. METHODS: Twenty-eight no glaucoma eyes (from 15 subjects) and 25 glaucoma eyes (from 14 patients) were enrolled. A total of 300 optic nerve head B-scans were obtained in 10 um steps and the inner edge of Bruch's membrane opening (BMO) was identified as the reference plane. The vertical and horizontal angles between BMO line and approximate the best-fitting line for the surface of the LC were measured and potential associated factors were estimated with univariate and multivariate logistic regression analyses. RESULTS: The median (interquartile range) horizontal and vertical tilt angles were 7.10 (2.43-11.45) degrees and 4.15 (2.60-6.85) degrees in eyes without glaucoma and 8.50 (4.40-14.10) degrees and 9.30 (6.90-14.15) degrees in glaucoma eyes, respectively. The refractive errors had a statistically significant association with horizontal LC tilt angles (coefficients, -1.53 per diopter) and glaucoma had a significant correlation with vertical tilt angles (coefficients, 6.56) using multiple logistic regression analysis (p<0.001). CONCLUSIONS: OCT allowed evaluation of the internal tilting of the LC compared with the BMO. The horizontal internal LC tilt angle was correlated with refractive errors, corresponding to myopic physiological changes, and vertical internal LC tilt was correlated with glaucoma, corresponding to glaucomatous pathological changes. These parameters have important implications for investigation of the correlation between myopia, glaucoma and LC morphological features. PMID- 25551633 TI - Asynchronous changes in vegetation, runoff and erosion in the nile river watershed during the holocene. AB - The termination of the African Humid Period in northeastern Africa during the early Holocene was marked by the southward migration of the rain belt and the disappearance of the Green Sahara. This interval of drastic environmental changes was also marked by the initiation of food production by North African hunter gatherer populations and thus provides critical information on human-environment relationships. However, existing records of regional climatic and environmental changes exhibit large differences in timing and modes of the wet/dry transition at the end of the African Humid Period. Here we present independent records of changes in river runoff, vegetation and erosion in the Nile River watershed during the Holocene obtained from a unique sedimentary sequence on the Nile River fan using organic and inorganic proxy data. This high-resolution reconstruction allows to examine the phase relationship between the changes of these three parameters and provides a detailed picture of the environmental conditions during the Paleolithic/Neolithic transition. The data show that river runoff decreased gradually during the wet/arid transition at the end of the AHP whereas rapid shifts of vegetation and erosion occurred earlier between 8.7 and ~6 ka BP. These asynchronous changes are compared to other regional records and provide new insights into the threshold responses of the environment to climatic changes. Our record demonstrates that the degradation of the environment in northeastern Africa was more abrupt and occurred earlier than previously thought and may have accelerated the process of domestication in order to secure sustainable food resources for the Neolithic African populations. PMID- 25551636 TI - The relationship between canopy cover and colony size of the wood ant Formica lugubris--implications for the thermal effects on a keystone ant species. AB - Climate change may affect ecosystems and biodiversity through the impacts of rising temperature on species' body size. In terms of physiology and genetics, the colony is the unit of selection for ants so colony size can be considered the body size of a colony. For polydomous ant species, a colony is spread across several nests. This study aims to clarify how climate change may influence an ecologically significant ant species group by investigating thermal effects on wood ant colony size. The strong link between canopy cover and the local temperatures of wood ant's nesting location provides a feasible approach for our study. Our results showed that nests were larger in shadier areas where the thermal environment was colder and more stable compared to open areas. Colonies (sum of nests in a polydomous colony) also tended to be larger in shadier areas than in open areas. In addition to temperature, our results supported that food resource availability may be an additional factor mediating the relationship between canopy cover and nest size. The effects of canopy cover on total colony size may act at the nest level because of the positive relationship between total colony size and mean nest size, rather than at the colony level due to lack of link between canopy cover and number of nests per colony. Causal relationships between the environment and the life-history characteristics may suggest possible future impacts of climate change on these species. PMID- 25551635 TI - Evaluating aesthetic experience through personal-appearance styles: a behavioral and electrophysiological study. AB - Consumers' aesthetic experience has often been linked with the concept of beauty, which is regarded as subjective and may vary between individuals, cultures and places, and across time. With the advent of brain-imaging techniques, there is more and more evidence to suggest that aesthetic experience lies not only in the eye of the beholder, but also in the brain of the beholder. However, there are gaps in the previous research in this area, as several significant issues have not yet been addressed. Specifically, it is unclear whether the human brain really pays more attention and generates more positive emotional responses to beautiful things. To explore the brain activity relating to consumers' aesthetic experiences, 15 participants were recruited voluntarily to view a series of personal-appearance styles. They were invited to make aesthetic judgments while their brain activity was recorded by electroencephalography. Two electroencephalographic (EEG) indicators, theta coherence and frontal alpha symmetry, were utilized. Theta coherence is a measure of linear synchronization between signals at two electrode sites. It reflects the degree of functional cooperation between the underlying neuronal substrates and was used to explore the attentional processing involved in aesthetic judgments. Frontal alpha asymmetry is derived by subtracting the log-transformed absolute alpha power of the left hemisphere from the analogous log-transformed alpha power of the right hemisphere. It was used as an indicator of emotional response. During aesthetic judgments, long-range theta coherence increased in both hemispheres and more positive frontal alpha asymmetry was found when the styles were judged to be beautiful. Therefore, participants demonstrated brain activity suggestive of central executive processing and more positive emotional responses when they considered styles to be beautiful. The study provides some insight into the brain activity associated with consumers' aesthetic experiences, and suggests new directions for exploring consumer behavior from the perspective of neuroscience. PMID- 25551634 TI - N-homocysteinylation induces different structural and functional consequences on acidic and basic proteins. AB - One of the proposed mechanisms of homocysteine toxicity in human is the modification of proteins by the metabolite of Hcy, homocysteine thilolactone (HTL). Incubation of proteins with HTL has earlier been shown to form covalent adducts with epsilon-amino group of lysine residues of protein (called N homocysteinylation). It has been believed that protein N-homocysteinylation is the pathological hallmark of cardiovascular and neurodegenerative disorders as homocysteinylation induces structural and functional alterations in proteins. In the present study, reactivity of HTL towards proteins with different physico chemical properties and hence their structural and functional alterations were studied using different spectroscopic approaches. We found that N homocysteinylation has opposite consequences on acidic and basic proteins suggesting that pI of the protein determines the extent of homocysteinylation, and the structural and functional consequences due to homocysteinylation. Mechanistically, pI of protein determines the extent of N-homocysteinylation and the associated structural and functional alterations. The study suggests the role of HTL primarily targeting acidic proteins in eliciting its toxicity that could yield mechanistic insights for the associated neurodegeneration. PMID- 25551638 TI - Evaluating the relationship of eating behaviors of university students with body mass index and self-esteem. AB - This study investigated the relationship between eating behaviors (Dutch Eating Behavior Questionnaire-DEBQ), self-esteem (Rosenberg Self-Esteem Scale-RSES), and body mass index (BMI) in university students. A total of 503 students (129 men and 374 women), 18-23 years of age were included in the study. According to BMI, 8.3% of students were underweight; 47.3% were overweight; and 74.4% were of healthy weight. The level of self-esteem of 86.5% of young people was high, 13.5% moderate. The mean score (33.3 +/- 11.8) of emotional-eating behavior was higher for women than for men (27.9 +/- 10.1) . Recommendations include assessing eating behaviors via longitudinal studies with large samples, and identifying at-risk groups, as useful approaches for informing prevention. PMID- 25551637 TI - Generation of a nanobody targeting the paraflagellar rod protein of trypanosomes. AB - Trypanosomes are protozoan parasites that cause diseases in humans and livestock for which no vaccines are available. Disease eradication requires sensitive diagnostic tools and efficient treatment strategies. Immunodiagnostics based on antigen detection are preferable to antibody detection because the latter cannot differentiate between active infection and cure. Classical monoclonal antibodies are inaccessible to cryptic epitopes (based on their size-150 kDa), costly to produce and require cold chain maintenance, a condition that is difficult to achieve in trypanosomiasis endemic regions, which are mostly rural. Nanobodies are recombinant, heat-stable, small-sized (15 kDa), antigen-specific, single domain, variable fragments derived from heavy chain-only antibodies in camelids. Because of numerous advantages over classical antibodies, we investigated the use of nanobodies for the targeting of trypanosome-specific antigens and diagnostic potential. An alpaca was immunized using lysates of Trypanosoma evansi. Using phage display and bio-panning techniques, a cross-reactive nanobody (Nb392) targeting all trypanosome species and isolates tested was selected. Imunoblotting, immunofluorescence microscopy, immunoprecipitation and mass spectrometry assays were combined to identify the target recognized. Nb392 targets paraflagellar rod protein (PFR1) of T. evansi, T. brucei, T. congolense and T. vivax. Two different RNAi mutants with defective PFR assembly (PFR2RNAi and KIF9BRNAi) were used to confirm its specificity. In conclusion, using a complex protein mixture for alpaca immunization, we generated a highly specific nanobody (Nb392) that targets a conserved trypanosome protein, i.e., PFR1 in the flagella of trypanosomes. Nb392 is an excellent marker for the PFR and can be useful in the diagnosis of trypanosomiasis. In addition, as demonstrated, Nb392 can be a useful research or PFR protein isolation tool. PMID- 25551640 TI - Charge disproportionation in tetragonal La2MoO5, a small band gap semiconductor influenced by direct Mo-Mo bonding. AB - The structure of the novel compound La2MoO5 has been solved from powder X-ray and neutron diffraction data and belongs to the tetragonal space group P4/m (no. 83) with a = 12.6847(3) A and c = 6.0568(2) A and with Z = 8. It consists of equal proportions of bioctahedral (Mo2O10) and square prismatic (Mo2O8) dimers, both of which contain direct Mo-Mo bonds and are arranged in 1D chains. The Mo-Mo bond length in the Mo2O10 dimers is 2.684(8) A, while there are two types of Mo2O8 dimers with Mo-Mo bonds lengths of 2.22(2) and 2.28(2) A. Although the average Mo oxidation state in La2MoO5 is 4+, the very different Mo-Mo distances reflect the fact that the Mo2O10 dimers contain only Mo(5+) (d(1)), while the prismatic Mo2O8 dimers only contain Mo(3+) (d(3)), a result directly confirmed by density function theory calculations. This is due to the complete disproportionation of Mo(4+), a phenomenon which has not previously been observed in solid-state compounds. La2MoO5 is diamagnetic, behavior which is not expected for a nonmetallic transition-metal oxide whose cation sites have an odd number of d electrons. The resistivity displays the Arrhenius-type activated behavior expected for a semiconductor with a band gap of 0.5 eV, exhibiting an unusually small transport gap relative to other diamagnetic oxides. Diffuse reflectance studies indicate that La2MoO5 is a rare example of a stable oxide semiconductor with strong infrared absorbance. It is shown that the d-orbital splitting associated with the Mo2O8 and Mo2O10 dimeric units can be rationalized using simple molecular orbital bonding concepts. PMID- 25551639 TI - Gene delivery to adipose tissue using transcriptionally targeted rAAV8 vectors. AB - In recent years, the increasing prevalence of obesity and obesity-related co morbidities fostered intensive research in the field of adipose tissue biology. To further unravel molecular mechanisms of adipose tissue function, genetic tools enabling functional studies in vitro and in vivo are essential. While the use of transgenic animals is well established, attempts using viral and non-viral vectors to genetically modify adipocytes in vivo are rare. Therefore, we here characterized recombinant Adeno-associated virus (rAAV) vectors regarding their potency as gene transfer vehicles for adipose tissue. Our results demonstrate that a single dose of systemically applied rAAV8-CMV-eGFP can give rise to remarkable transgene expression in murine adipose tissues. Upon transcriptional targeting of the rAAV8 vector to adipocytes using a 2.2 kb fragment of the murine adiponectin (mAP2.2) promoter, eGFP expression was significantly decreased in off target tissues while efficient transduction was maintained in subcutaneous and visceral fat depots. Moreover, rAAV8-mAP2.2-mediated expression of perilipin A - a lipid-droplet-associated protein - resulted in significant changes in metabolic parameters only three weeks post vector administration. Taken together, our findings indicate that rAAV vector technology is applicable as a flexible tool to genetically modify adipocytes for functional proof-of-concept studies and the assessment of putative therapeutic targets in vivo. PMID- 25551643 TI - Just the facts: changes in older driver attitudes after exposure to educational interventions. AB - OBJECTIVES: To examine the change in cognitive processing as measured by consciousness raising and attitudes toward driving following educational interventions for older adults. METHODS: Older adults who viewed a research-based applied theater production about older driver safety (n = 110) were compared to those who were exposed to a print-based publication available to all drivers (n = 100). RESULTS: After viewing the play developed with input from older adults and others, older adult viewers' attitudes toward driving shifted in a manner consistent with an increased openness or willingness to consider changing their driving behavior. Conversely, after reading the print-based materials, the older adults felt more empowered to continue drive. CONCLUSIONS: Demonstrating that an intervention that takes into account the views of older drivers can lead to attitudinal outcomes that differ from those achieved with typical "just the facts" programs is an important step in understanding how program content and format affect outcomes. Future interdisciplinary work such as this may enhance our capabilities to understand more about the processes involved in influencing change in attitudes and behaviors. PMID- 25551642 TI - Large-scale SNP discovery through RNA sequencing and SNP genotyping by targeted enrichment sequencing in cassava (Manihot esculenta Crantz). AB - Cassava (Manihot esculenta Crantz) is one of the most important crop species being the main source of dietary energy in several countries. Marker-assisted selection has become an essential tool in plant breeding. Single nucleotide polymorphism (SNP) discovery via transcriptome sequencing is an attractive strategy for genome complexity reduction in organisms with large genomes. We sequenced the transcriptome of 16 cassava accessions using the Illumina HiSeq platform and identified 675,559 EST-derived SNP markers. A subset of those markers was subsequently genotyped by capture-based targeted enrichment sequencing in 100 F1 progeny segregating for starch viscosity phenotypes. A total of 2,110 non-redundant SNP markers were used to construct a genetic map. This map encompasses 1,785 cM and consists of 19 linkage groups. A major quantitative trait locus (QTL) controlling starch pasting properties was identified and shown to coincide with the QTL previously reported for this trait. With a high-density SNP-based linkage map presented here, we also uncovered a novel QTL associated with starch pasting time on LG 10. PMID- 25551641 TI - Non-steroidal anti-inflammatory drugs use is associated with reduced risk of inflammation-associated cancers: NIH-AARP study. AB - BACKGROUND: Chronic inflammation has been linked to cancers, and use of non steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of several cancers. To further refine the magnitude of NSAID-related associations, in particular for cancers related to inflammation, such as alcohol , infection-, obesity-, and smoking-related cancers, as well as for less common cancers, we evaluated the use of NSAIDs and cancer risk in a very large cohort. We used propensity scores to account for potential selection bias and hypothesized that NSAID use is associated with decreased cancer incidence. METHODS: We conducted a prospective study among 314,522 participants in the NIH AARP Diet and Health Study. Individuals who completed the lifestyle questionnaire, which included NSAID use, in 1996-1997 were followed through 2006. Information on cancer incidence was ascertained by linking to cancer registries and vital status databases. FINDINGS: During 2,715,994 person-years of follow-up (median 10.1 person-years), there were 51,894 incident cancers. Compared with non users of NSAIDs, individuals who reported use in the 12 months prior to interview had a significantly lower risk of all inflammation-related cancer, alcohol related, infection-related, obesity-related, and smoking-related cancers [hazard ratio (HR) (95% CI)) 0.90 (0.87-0.93), 0.80 (0.74-0.85), 0.82 (0.78-0.87), 0.88 (0.84-0.92), and 0.88 (0.85-0.92) respectively)]. CONCLUSIONS: After accounting for potential selection bias, our data showed an inverse association between NSAID use and alcohol-related, infection-related, obesity-related, and smoking related cancers and support the hypothesis that inflammation is related to an increased risk of certain cancers. PMID- 25551644 TI - Organocatalytic enantio- and diastereoselective synthesis of 1,2 dihydronaphthalenes from isobenzopyrylium ions. AB - A highly efficient asymmetric synthesis of dihydronaphthalenes is disclosed. The process represents a new addition to the limited asymmetric reactions of isobenzopyryliums, a family of versatile 10pi-electron aromatic species. Excellent asymmetric induction is achieved for the first time without an anchoring group in the 4-position or a metal catalyst, both of which were required previously in these reactions. The success is attributed to the unusual chiral counteranion (meanwhile also the nucleophile) generated in situ from the chiral phosphate and the boronic acid as well as the leaving group. Preliminary control experiments provided important insight into the reaction mechanism. PMID- 25551645 TI - Modeling for Fidelity: virtual mentorship by scientists fosters teacher self efficacy and promotes implementation of novel high school biomedical curricula. AB - This small-scale comparison case study evaluates the impact of an innovative approach to teacher professional development designed to promote implementation of a novel cutting edge high school neurological disorders curriculum. 'Modeling for Fidelity' (MFF) centers on an extended mentor relationship between teachers and biomedical scientists carried out in a virtual format in conjunction with extensive online educative materials. Four teachers from different diverse high schools in Massachusetts and Ohio who experienced MFF contextualized to a 6-week Neurological Disorders curriculum with the same science mentor were compared to a teacher who had experienced an intensive in-person professional development contextualized to the same curriculum with the same mentor. Fidelity of implementation was measured directly using an established metric and indirectly via student performance. The results show that teachers valued MFF, particularly the mentor relationship and were able to use it effectively to ensure critical components of the learning objectives were preserved. Moreover their students performed equivalently to those whose teacher had experienced intensive in-person professional development. Participants in all school settings demonstrated large (Cohen's d>2.0) and significant (p<0.0001 per-post) changes in conceptual knowledge as well as self-efficacy towards learning about neurological disorders (Cohen's d>1.5, p<0.0001 pre-post). The data demonstrates that the virtual mentorship format in conjunction with extensive online educative materials is an effective method of developing extended interactions between biomedical scientists and teachers that are scalable and not geographically constrained, facilitating teacher implementation of novel cutting-edge curricula. PMID- 25551647 TI - RSO interview with Kendall Berry. PMID- 25551646 TI - Functional mapping of protein-protein interactions in an enzyme complex by directed evolution. AB - The shikimate pathway enzyme chorismate mutase converts chorismate into prephenate, a precursor of Tyr and Phe. The intracellular chorismate mutase (MtCM) of Mycobacterium tuberculosis is poorly active on its own, but becomes >100-fold more efficient upon formation of a complex with the first enzyme of the shikimate pathway, 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase (MtDS). The crystal structure of the enzyme complex revealed involvement of C-terminal MtCM residues with the MtDS interface. Here we employed evolutionary strategies to probe the tolerance to substitution of the C-terminal MtCM residues from positions 84-90. Variants with randomized positions were subjected to stringent selection in vivo requiring productive interactions with MtDS for survival. Sequence patterns identified in active library members coincide with residue conservation in natural chorismate mutases of the AroQdelta subclass to which MtCM belongs. An Arg-Gly dyad at positions 85 and 86, invariant in AroQdelta sequences, was intolerant to mutation, whereas Leu88 and Gly89 exhibited a preference for small and hydrophobic residues in functional MtCM-MtDS complexes. In the absence of MtDS, selection under relaxed conditions identifies positions 84-86 as MtCM integrity determinants, suggesting that the more C-terminal residues function in the activation by MtDS. Several MtCM variants, purified using a novel plasmid-based T7 RNA polymerase gene expression system, showed that a diminished ability to physically interact with MtDS correlates with reduced activatability and feedback regulatory control by Tyr and Phe. Mapping critical protein-protein interaction sites by evolutionary strategies may pinpoint promising targets for drugs that interfere with the activity of protein complexes. PMID- 25551648 TI - Radon mitigation in cold climates at Kitigan Zibi Anishinabeg. AB - Available radon mitigation results were gathered for 85 houses mainly by installing sub-slab depressurization systems (SSDS) with two types of discharge and fan locations: Above ground level discharge with the fan located in the basement (AGL) or above roof line discharge with the fan located in the attic (ARL). A comparative analysis was made of mitigation efficiency and of exhaust icing. Results show that both SSDS scenarios reduced radon levels similarly. The results of SSDS with AGL show that a sealed radon fan having proper fittings and sealed piping was able to reduce the radon to acceptable levels, and that these installations were less subject to obstructive icing of the exhaust in cold climates. PMID- 25551649 TI - ReactorHealth Physics operations at the NIST center for neutron research. AB - Performing health physics and radiation safety functions under a special nuclear material license and a research and test reactor license at a major government research and development laboratory encompasses many elements not encountered by industrial, general, or broad scope licenses. This article reviews elements of the health physics and radiation safety program at the NIST Center for Neutron Research, including the early history and discovery of the neutron, applications of neutron research, reactor overview, safety and security of radiation sources and radioactive material, and general health physics procedures. These comprise precautions and control of tritium, training program, neutron beam sample processing, laboratory audits, inventory and leak tests, meter calibration, repair and evaluation, radioactive waste management, and emergency response. In addition, the radiation monitoring systems will be reviewed including confinement building monitoring, ventilation filter radiation monitors, secondary coolant monitors, gaseous fission product monitors, gas monitors, ventilation tritium monitor, and the plant effluent monitor systems. PMID- 25551650 TI - An approach to radiation safety department benchmarking in academic and medical facilities. AB - Based on anecdotal evidence and networking with colleagues at other facilities, it has become evident that some radiation safety departments are not adequately staffed and radiation safety professionals need to increase their staffing levels. Discussions with management regarding radiation safety department staffing often lead to similar conclusions. Management acknowledges the Radiation Safety Officer (RSO) or Director of Radiation Safety's concern but asks the RSO to provide benchmarking and justification for additional full-time equivalents (FTEs). The RSO must determine a method to benchmark and justify additional staffing needs while struggling to maintain a safe and compliant radiation safety program. Benchmarking and justification are extremely important tools that are commonly used to demonstrate the need for increased staffing in other disciplines and are tools that can be used by radiation safety professionals. Parameters that most RSOs would expect to be positive predictors of radiation safety staff size generally are and can be emphasized in benchmarking and justification report summaries. Facilities with large radiation safety departments tend to have large numbers of authorized users, be broad-scope programs, be subject to increased controls regulations, have large clinical operations, have significant numbers of academic radiation-producing machines, and have laser safety responsibilities. PMID- 25551651 TI - An overview of a non-medical x-ray safety program at a large university. AB - OBJECTIVES: Compared to clinical x-ray equipment, non-medical x-ray producing equipment has been subject to limited radiation safety oversight. However, the concern of unnecessary or even hazardous personnel exposure has always been associated with the use of ionizing radiation. The goal of this paper is to review the process of developing and implementing a systematic and structured radiation safety program at a large university that aims to provide adequate oversight and education to ensure personnel safety. METHODS: At Duke University, the program currently consists of 26 active and 11 inactive x-ray authorized users and over 50 active x-ray tubes. The main foci of the non-medical x-ray program are equipment inventory, training for authorized user and operator, personnel dosimetry, and future regular inspections. The requirement for personnel dosimetry was investigated by deploying film badges on open beam equipment. Quarterly environmental badge reports were collected and served as one of the justifications for the discontinuation of personnel badges. CONCLUSION: In order to maintain adequate oversight and awareness of radiation safety, our office found success through establishing an open channel of communication, providing regular refresher training and conducting regular inspections. PMID- 25551652 TI - An update on a spreadsheet method for computing consequences to the nearest maximally exposed offsite individual in compliance with DOE-STD-3009-94. AB - Protection of the public from hazardous airborne releases at U.S. Department of Energy non-reactor nuclear facilities is the highest priority in all operations. As a result, the safety basis calculations that derive the protection of the public in the form of safety-class structures, systems, and components (SC SSCs) must accurately model the accident event and airborne plume in order to characterize the relative severity of the consequences. The simple Gaussian plume model is the most accurate and most commonly used model to describe the pollutant plume relative concentration (X/Q) downwind at receptor. As a result, the X/Q value can easily be calculated by an electronic spreadsheet as shown by this paper. PMID- 25551653 TI - Efficacy of common decontamination methods for cleaning contaminated wounds. AB - Emergency preparedness and response for work with hazardous materials, including radiological materials, necessarily have to involve injuries sustained by the workers. Removing radionuclide contamination from wounds in tissue is essential to minimizing the intake of radiological materials and the internal dose to the individual. This study compares the efficacy of common decontamination methods for removal of Co from contaminated wounds inflicted in pig tissue. The decontamination procedures investigated include a commercially available, non prescription, surfactant-based, non-ionic wound cleanser spray; a physiologic saline solution spray; and a physiologic saline solution pour. Three different types of wounds are examined: smooth incision, jagged cut, and blunt force trauma wounds. The cleanser and saline sprays are more effective at decontaminating all three wounds than the saline pour. Within the statistical limitations of the study, the difference between the cleanser spray and the saline spray is not significant. However, the cleanser spray successfully decontaminates the wound to a lower mean value. The most noticeable impact in the decontamination process appears to be due to the spray pressure employed with the cleanser and saline sprays. PMID- 25551655 TI - Make your words support your message. AB - Correct use of terms in a manuscript or policy statement is important to meet the objectives of the paper. Inappropriate terms can be counter-productive. The World Health Organization (WHO) recommends the following: 'Terminology in national drug control legislation and policies should be clear and unambiguous in order not to confuse the use of controlled medicines for medical and scientific purposes with misuse' and terminology should always be respectful. This commentary lists English language terminology that can impair access to controlled medicines for the treatment of pain and suffering (an objective of the international substance control conventions), including pain management and the treatment of opioid dependence. The commentary also suggests alternative wording. Assessment of terminology correctness is language sensitive and should therefore be conducted by native speakers. In all language communities, advocates should explore and discuss the terminology with health-care professionals and their clients/patients, and they should promote the use of correct vocabulary. PMID- 25551656 TI - HIV symptom burden and anemia among HIV-positive individuals: cross-sectional results of a community-based positive living with HIV (POLH) study in Nepal. AB - BACKGROUND: Previous research has reported high rates of anemia in people living with HIV/AIDS (PLWHA) in hospital or tertiary care settings. The objective of this community-based study was to measure the prevalence of anemia and describe the risk factors, with a specific emphasis on HIV symptom burden, in PLWHA in the Kathmandu Valley, Nepal. METHODS: We conducted a cross-sectional survey of 319 PLWHA residing in the Kathmandu Valley, Nepal. We recruited participants from five non-governmental organizations in the Kathmandu Valley. Descriptive statistics and multivariable logistic regression analyses were used. RESULTS: Our study found a 55.8% prevalence of anemia in PLWHA in the Kathmandu Valley. The prevalence of anemia among the participants with first, second, third, and fourth quartiles of HIV symptom burden was 44.8%, 49.3%, 60.3%, and 69.6%, respectively. Compared to the participants with lowest level of HIV symptom burden, the participants with highest level of HIV symptom burden were more likely to have anemia (adjusted odds ratio = 2.14; 95% confidence interval = 1.07 to 4.30). CONCLUSION: Due to a high prevalence of anemia in a community-based sample of PLWHA, HIV patients should be counseled on their risk of developing anemia and encouraged to seek timely care for HIV symptoms. PMID- 25551658 TI - mTORCing about myogenic differentiation. PMID- 25551659 TI - eCounterscreening: using QSAR predictions to prioritize testing for off-target activities and setting the balance between benefit and risk. AB - During drug development, compounds are tested against counterscreens, a panel of off-target activities that would be undesirable for a drug to have. Testing every compound against every counterscreen is generally too costly in terms of time and money, and we need to find a rational way of prioritizing counterscreen testing. Here we present the eCounterscreening paradigm, wherein predictions from QSAR models for counterscreen activity are used to generate a recommendation as to whether a specific compound in a specific project should be tested against a specific counterscreen. The rules behind the recommendations, which can be summarized in a risk-benefit plot specific for a counterscreen/project combination, are based on a previously assembled database of prospective QSAR predictions. The recommendations require two user-defined cutoffs: the level of activity in a specific counterscreen that is considered undesirable and the level of risk the chemist is willing to accept that an undesired counterscreen activity will go undetected. We demonstrate in a simulated prospective experiment that eCounterscreening can be used to postpone a large fraction of counterscreen testing and still have an acceptably low risk of undetected counterscreen activity. PMID- 25551657 TI - Autophagy activation is involved in 3,4-methylenedioxymethamphetamine ('ecstasy') -induced neurotoxicity in cultured cortical neurons. AB - Autophagic (type II) cell death, characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells, has been suggested to play pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug causing long-term neurotoxicity in the brain. Apoptotic (type I) and necrotic (type III) cell death have been implicated in MDMA-induced neurotoxicity, while the role of autophagy in MDMA-elicited neurotoxicity has not been investigated. The present study aimed to evaluate the occurrence and contribution of autophagy to neurotoxicity in cultured rat cortical neurons challenged with MDMA. Autophagy activation was monitored by expression of microtubule-associated protein 1 light chain 3 (LC3; an autophagic marker) using immunofluorescence and western blot analysis. Here, we demonstrate that MDMA exposure induced monodansylcadaverine (MDC)- and LC3B-densely stained autophagosome formation and increased conversion of LC3B-I to LC3B-II, coinciding with the neurodegenerative phase of MDMA challenge. Autophagy inhibitor 3-methyladenine (3-MA) pretreatment significantly attenuated MDMA-induced autophagosome accumulation, LC3B-II expression, and ameliorated MDMA-triggered neurite damage and neuronal death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in neurons and aggravated neurite degeneration, indicating that excessive autophagosome accumulation contributes to MDMA-induced neurotoxicity. Furthermore, MDMA induced phosphorylation of AMP-activated protein kinase (AMPK) and its downstream unc-51 like kinase 1 (ULK1), suggesting the AMPK/ULK1 signaling pathway might be involved in MDMA-induced autophagy activation. PMID- 25551660 TI - Combination of silver nanoparticles and Drosera binata extract as a possible alternative for antibiotic treatment of burn wound infections caused by resistant Staphylococcus aureus. AB - Staphylococcus aureus is the most common infectious agent involved in the development of skin infections that are associated with antibiotic resistance, such as burn wounds. As drug resistance is a growing problem it is essential to establish novel antimicrobials. Currently, antibiotic resistance in bacteria is successfully controlled by multi-drug therapies. Here we demonstrate that secondary metabolites present in the extract obtained from Drosera binata in vitro cultures are effective antibacterial agents against S. aureus grown in planktonic culture and in biofilm. Moreover, this is the first report demonstrating the synergistic interaction between the D. binata extract and silver nanoparticles (AgNPs), which results in the spectacular enhancement of the observed bactericidal activity, while having no cytotoxic effects on human keratinocytes. Simultaneous use of these two agents in significantly reduced quantities produces the same effect, i.e. by killing 99.9% of bacteria in inoculum or eradicating the staphylococcal biofilm, as higher amounts of the agents used individually. Our data indicates that combining AgNPs with either the D. binata extract or with its pure compound (3-chloroplumbagin) may provide a safe and highly effective alternative to commonly used antibiotics, which are ineffective towards the antibiotic-resistant S. aureus. PMID- 25551662 TI - Catalytic asymmetric construction of pyrroloindolines via an in situ generated magnesium catalyst. AB - An asymmetric formal [3 + 2]-cycloaddition between meso-aziridines and C3 alkylindoles mediated by an in situ generated magnesium catalyst was developed for asymmetric construction of pyrroloindolines. A variety of pyrroloindolines could be obtained by employing commercial available ligands with the assistance of an easily prepared achiral ligand. PMID- 25551661 TI - Genome-scale transcriptome analysis in response to nitric oxide in birch cells: implications of the triterpene biosynthetic pathway. AB - Evidence supporting nitric oxide (NO) as a mediator of plant biochemistry continues to grow, but its functions at the molecular level remains poorly understood and, in some cases, controversial. To study the role of NO at the transcriptional level in Betula platyphylla cells, we conducted a genome-scale transcriptome analysis of these cells. The transcriptome of untreated birch cells and those treated by sodium nitroprusside (SNP) were analyzed using the Solexa sequencing. Data were collected by sequencing cDNA libraries of birch cells, which had a long period to adapt to the suspension culture conditions before SNP treated cells and untreated cells were sampled. Among the 34,100 UniGenes detected, BLASTX search revealed that 20,631 genes showed significant (E values<=10-5) sequence similarity with proteins from the NR-database. Numerous expressed sequence tags (i.e., 1374) were identified as differentially expressed between the 12 h SNP-treated cells and control cells samples: 403 up-regulated and 971 down-regulated. From this, we specifically examined a core set of NO related transcripts. The altered expression levels of several transcripts, as determined by transcriptome analysis, was confirmed by qRT-PCR. The results of transcriptome analysis, gene expression quantification, the content of triterpenoid and activities of defensive enzymes elucidated NO has a significant effect on many processes including triterpenoid production, carbohydrate metabolism and cell wall biosynthesis. PMID- 25551663 TI - Protein reconstitution into freestanding planar lipid membranes for electrophysiological characterization. AB - The reconstitution of channel-forming proteins into planar lipid bilayers enables their functional characterization at very low (sometimes below attomolar) concentrations. We describe the three main approaches used in our laboratories (the Mueller-Rudin technique, in which the bilayers contain an organic solvent, the Montal-Mueller or solvent-free technique, and a method for membrane reconstitution via liposome formation), and we discuss their respective advantages and limitations. Despite the differences in the reconstitution procedures, subsequent protein characterization is based on the same electrophysiological technique. A transmembrane electric field is applied, inducing an ion current and allowing conclusions to be drawn on apparent pore sizes, or suggesting functional properties such as channel opening and closing upon ligand binding, pH-induced conformational changes, ion selectivity or substrate specificity. PMID- 25551664 TI - Generation of living cell arrays for atomic force microscopy studies. AB - Atomic force microscopy (AFM) is a useful tool for studying the morphology or the nanomechanical and adhesive properties of live microorganisms under physiological conditions. However, to perform AFM imaging, living cells must be immobilized firmly enough to withstand the lateral forces exerted by the scanning tip, but without denaturing them. This protocol describes how to immobilize living cells, ranging from spores of bacteria to yeast cells, into polydimethylsiloxane (PDMS) stamps, with no chemical or physical denaturation. This protocol generates arrays of living cells, allowing statistically relevant measurements to be obtained from AFM measurements, which can increase the relevance of results. The first step of the protocol is to generate a microstructured silicon master, from which many microstructured PDMS stamps can be replicated. Living cells are finally assembled into the microstructures of these PDMS stamps using a convective and capillary assembly. The complete procedure can be performed in 1 week, although the first step is done only once, and thus repeats can be completed within 1 d. PMID- 25551665 TI - A high-throughput in vivo micronucleus assay for genome instability screening in mice. AB - We describe a sensitive, robust, high-throughput method for quantifying the formation of micronuclei, markers of genome instability, in mouse erythrocytes. Micronuclei are whole chromosomes or chromosome segments that have been separated from the nucleus. Other methods of detection rely on labor-intensive, microscopy based techniques. Here we describe a 2-d, 96-well plate-based flow cytometric method of micronucleus scoring that is simple enough for a research technician experienced in flow cytometry to perform. The assay detects low levels of genome instability that cannot be readily identified by classic phenotyping, using 25 MUl of blood. By using this assay, we have screened >10,000 blood samples and discovered novel genes that contribute to vertebrate genome maintenance, as well as novel disease models and mechanisms of genome instability disorders. We discuss experimental design considerations, including statistical power calculation, we provide troubleshooting tips and we discuss factors that contribute to a false-positive increase in the number of micronucleated red blood cells and to experimental variability. PMID- 25551666 TI - Synthesis and structure of trinuclear W3S4 clusters bearing aminophosphine ligands and their reactivity toward halides and pseudohalides. AB - The aminophosphine ligand (2-aminoethyl)diphenylphosphine (edpp) has been coordinated to the W3(MU-S)(MU-S)3 cluster unit to afford trimetallic complex [W3S4Br3(edpp)3](+) (1(+)) in a one-step synthesis process with high yields. Related [W3S4X3(edpp)3](+) clusters (X = F(-), Cl(-), NCS(-); 2(+)-4(+)) have been isolated by treating 1(+) with the corresponding halide or pseudohalide salt. The structure of complexes 1(+) to 4(+) contains an incomplete W3S4 cubane type cluster unit, and only one of the possible isomers is formed: the one with the phosphorus atoms trans to the capping sulfur and the amino groups trans to the bridging sulphurs. The remaining coordination position on each metal is occupied by X. Detailed studies using stopped-flow, (31)P{(1)H} NMR, and ESI-MS have been carried out in order to understand the solution behavior and the kinetics of interconversion among species 1(+), 2(+), 3(+), and 4(+) in solution. Density functional theory (DFT) calculations have been also carried out on the reactions of cluster 1(+) with the different anions. The whole set of experimental and theoretical data indicate that the actual mechanism of substitutions in these clusters is strongly dependent on the nature of the leaving and entering anions. The interaction between an entering F(-) and the amino group coordinated to the adjacent metal have also been found to be especially relevant to the kinetics of these reactions. PMID- 25551667 TI - A rare homozygous MFSD8 single-base-pair deletion and frameshift in the whole genome sequence of a Chinese Crested dog with neuronal ceroid lipofuscinosis. AB - BACKGROUND: The neuronal ceroid lipofuscinoses are heritable lysosomal storage diseases characterized by progressive neurological impairment and the accumulation of autofluorescent storage granules in neurons and other cell types. Various forms of human neuronal ceroid lipofuscinosis have been attributed to mutations in at least 13 different genes. So far, mutations in the canine orthologs of 7 of these genes have been identified in DNA from dogs with neuronal ceroid lipofuscinosis. The identification of new causal mutations could lead to the establishment of canine models to investigate the pathogenesis of the corresponding human neuronal ceroid lipofuscinoses and to evaluate and optimize therapeutic interventions for these fatal human diseases. CASE PRESENTATION: We obtained blood and formalin-fixed paraffin-embedded brain sections from a rescue dog that was reported to be a young adult Chinese Crested. The dog was euthanized at approximately 19 months of age as a consequence of progressive neurological decline that included blindness, anxiety, and cognitive impairment. A diagnosis of neuronal ceroid lipofuscinosis was made based on neurological signs, magnetic resonance imaging of the brain, and fluorescence microscopic and electron microscopic examination of brain sections. We isolated DNA from the blood and used it to generate a whole genome sequence with 33-fold average coverage. Among the 7.2 million potential sequence variants revealed by aligning the sequence reads to the canine genome reference sequence was a homozygous single base pair deletion in the canine ortholog of one of 13 known human NCL genes: MFSD8:c.843delT. MFSD8:c.843delT is predicted to cause a frame shift and premature stop codon resulting in a truncated protein, MFSD8:p.F282Lfs13*, missing its 239 C-terminal amino acids. The MFSD8:c.843delT allele is absent from the whole genome sequences of 101 healthy canids or dogs with other diseases. The genotyping of archived DNA from 1478 Chinese Cresteds did not identify any additional MFSD8:c.843delT homozygotes and found only one heterozygote. CONCLUSION: We conclude that the neurodegenerative disease of the Chinese Crested rescue dog was neuronal ceroid lipofuscinosis and that homozygosity for the MFSD8:c.843delT sequence variant was very likely to be the molecular-genetic cause of the disease. PMID- 25551668 TI - High-dose Chemotherapy With Autologous Stem Cell Rescue in Saudi Children Less Than 3 Years of Age With Embryonal Brain Tumors. AB - High-dose chemotherapy with autologous stem cell rescue (HDC/ASCR) has been used in children under the age of 3 years with embryonal brain tumors to avoid or delay the use of radiation. We reviewed the medical records of 10 Saudi children less than 3 years of age with embryonal brain tumors who underwent HDC/ASCR. All 10 patients underwent surgical resection followed by 3 to 5 cycles of induction chemotherapy and 1 to 3 cycles of HDC/ASCR using carboplatin and thiotepa. Isotretinoin was used as a maintenance therapy in 4 patients. Five patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumors, 1 had an embryonal tumor with abundant neuropil and true rosettes, and 1 had pineoblastoma. The median age of the patients was 1.9 years. A total of 19 HDC/ASCR procedures were performed. Radiotherapy (RT) was administered to 5 patients after HDC/ASCR and as a salvage therapy in 1 patient. The progression-free survival rate was 50% at 1 year and at 2 years, with a median follow-up of 24 months. All 5 patients with medulloblastoma are still alive without evidence of disease, but the other patients died secondary to tumor progression. This experience suggests that strategies combining myeloablative chemotherapy and autologous stem cell rescue appear to be feasible for children with embryonal brain tumors in the Middle East. PMID- 25551669 TI - Infantile hemophagocytic lymphohistiocytosis in a case of chediak-higashi syndrome caused by a mutation in the LYST/CHS1 gene presenting with delayed umbilical cord detachment and diarrhea. AB - A 2-month-old female infant, born to consanguineous parents, presented with infections in skin and upper respiratory tract. She was notable for delayed umbilical cord detachment, partial albinism, and neurological irritability. Giant granules were present in white blood cells. The intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient with 82% and 8% perforin-containing CD8 T cells at active and nonactive hemophagocytic lymphohistiocytosis (HLH) disease, respectively. HLH was confirmed by hemophagocytosis in bone marrow and absent natural killer cell activity. The patient carried a homozygous G>A mutation in the 3' splice site of intron 24 of the LYST/CHS1 gene, leading to the use of an alternative YAG splice site located in exon 25, introducing a premature STOP codon (L2355fsX2370; NP_000072.2). The early-onset accelerated phase in this severe phenotype of Chediak-Higashi syndrome was probably induced by rotaviral infection. Interestingly, the intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient. Late separation of the umbilical cord in concordance with clinical symptoms should lead to evaluation of a possible neutrophil dysfunction including Chediak-Higashi syndrome before onset of HLH. PMID- 25551670 TI - Using surface-enhanced Raman spectroscopy and electrochemically driven melting to discriminate Yersinia pestis from Y. pseudotuberculosis based on single nucleotide polymorphisms within unpurified polymerase chain reaction amplicons. AB - The development of sensors for the detection of pathogen-specific DNA, including relevant species/strain level discrimination, is critical in molecular diagnostics with major impacts in areas such as bioterrorism and food safety. Herein, we use electrochemically driven denaturation assays monitored by surface enhanced Raman spectroscopy (SERS) to target single nucleotide polymorphisms (SNPs) that distinguish DNA amplicons generated from Yersinia pestis, the causative agent of plague, from the closely related species Y. pseudotuberculosis. Two assays targeting SNPs within the groEL and metH genes of these two species have been successfully designed. Polymerase chain reaction (PCR) was used to produce Texas Red labeled single-stranded DNA (ssDNA) amplicons of 262 and 251 bases for the groEL and metH targets, respectively. These amplicons were used in an unpurified form to hybridize to immobilized probes then subjected to electrochemically driven melting. In all cases electrochemically driven melting was able to discriminate between fully homologous DNA and that containing SNPs. The metH assay was particularly challenging due to the presence of only a single base mismatch in the middle of the 251 base long PCR amplicon. However, manipulation of assay conditions (conducting the electrochemical experiments at 10 degrees C) resulted in greater discrimination between the complementary and mismatched DNA. Replicate data were collected and analyzed for each duplex on different days, using different batches of PCR product and different sphere segment void (SSV) substrates. Despite the variability introduced by these differences, the assays are shown to be reliable and robust providing a new platform for strain discrimination using unpurified PCR samples. PMID- 25551671 TI - Remote ischemic preconditioning reduces perioperative cardiac and renal events in patients undergoing elective coronary intervention: a meta-analysis of 11 randomized trials. AB - BACKGROUND: Results from randomized controlled trials (RCT) concerning cardiac and renal effect of remote ischemic preconditioning(RIPC) in patients with stable coronary artery disease(CAD) are inconsistent. The aim of this study was to explore whether RIPC reduce cardiac and renal events after elective percutaneous coronary intervention (PCI). METHODS AND RESULTS: RCTs with data on cardiac or renal effect of RIPC in PCI were searched from Pubmed, EMBase, and Cochrane library (up to July 2014). Meta-regression and subgroup analysis were performed to identify the potential sources of significant heterogeneity(I(2) >= 40%). Eleven RCTs enrolling a total of 1713 study subjects with stable CAD were selected. Compared with controls, RIPC significantly reduced perioperative incidence of myocardial infarction (MI) [odds ratio(OR) = 0.68; 95% CI, 0.51 to 0.91; P = 0.01; I(2) = 41.0%] and contrast-induced acute kidney injury(AKI) (OR = 0.61; 95% CI, 0.38 to 0.98; P = 0.04; I(2) = 39.0%). Meta-regression and subgroup analyses confirmed that the major source of heterogeneity for the incidence of MI was male proportion (coefficient = -0.049; P = 0.047; adjusted R(2) = 0.988; P = 0.02 for subgroup difference). CONCLUSIONS: The present meta-analysis of RCTs suggests that RIPC may offer cardiorenal protection by reducing the incidence of MI and AKI in patients undergoing elective PCI. Moreover, this effect on MI is more pronounced in male subjects. Future high-quality, large-scale clinical trials should focus on the long-term clinical effect of RIPC. PMID- 25551672 TI - Identification of quantitative trait loci for phosphorus use efficiency traits in rice using a high density SNP map. AB - BACKGROUND: Soil phosphorus (P) deficiency is one of the major limiting factors to crop production. The development of crop varieties with improved P use efficiency (PUE) is an important strategy for sustainable agriculture. The objectives of this research were to identify quantitative trait loci (QTLs) linked to PUE traits using a high-density single nucleotide polymorphism (SNP) map and to estimate the epistatic interactions and environmental effects in rice (Oryza sativa L.). RESULTS: We conducted a two-year field experiment under low and normal P conditions using a recombinant inbred population of rice derived from Zhenshan 97 and Minghui 63 (indica). We investigated three yield traits, biomass (BIOM), harvest index (HI), and grain yield (Yield), and eight PUE traits: total P uptake (PUP), P harvest index (PHI), grain P use efficiency (gPUE) based on P accumulation in grains, straw P use efficiency (strPUE) based on P accumulation in straw, P use efficiency for biomass (PUEb) and for grain yield (PUEg) based on P accumulation in the whole plant, P translocation (PT), and P translocation efficiency (PTE). Of the 36 QTLs and 24 epistatic interactions identified, 26 QTLs and 12 interactions were detected for PUE traits. The environment affected seven QTLs and three epistatic interactions. Four QTLs (qPHI1 and qPHI2 for PHI, qPUEg2 for PUEg, and qPTE8 for PTE) with strong effects were environmentally independent. By comparing our results with similar QTLs in previous studies, three QTLs for PUE traits (qPUP1 and qPUP10 for PUP, and qPHI6 for PHI) were found across various genetic backgrounds. Seven regions were shared by QTLs for yield and PUE traits. CONCLUSION: Most QTLs linked to PUE traits were different from those linked to yield traits, suggesting different genetic controls underlying these two traits. Those chromosomal regions with large effects that are not affected by different environments are promising for improving P use efficiency. The seven regions shared by QTLs linked to yield and PUE traits imply the possibility of the simultaneous improvement of yield and PUE traits. PMID- 25551673 TI - Unmanned aircraft systems for studying spatial abundance of ungulates: relevance to spatial epidemiology. AB - Complex ecological and epidemiological systems require multidisciplinary and innovative research. Low cost unmanned aircraft systems (UAS) can provide information on the spatial pattern of hosts' distribution and abundance, which is crucial as regards modelling the determinants of disease transmission and persistence on a fine spatial scale. In this context we have studied the spatial epidemiology of tuberculosis (TB) in the ungulate community of Donana National Park (South-western Spain) by modelling species host (red deer, fallow deer and cattle) abundance at fine spatial scale. The use of UAS high-resolution images has allowed us to collect data to model the environmental determinants of host abundance, and in a further step to evaluate their relationships with the spatial risk of TB throughout the ungulate community. We discuss the ecological, epidemiological and logistic conditions under which UAS may contribute to study the wildlife/livestock sanitary interface, where the spatial aggregation of hosts becomes crucial. These findings are relevant for planning and implementing research, fundamentally when managing disease in multi-host systems, and focusing on risky areas. Therefore, managers should prioritize the implementation of control strategies to reduce disease of conservation, economic and social relevance. PMID- 25551674 TI - Two distinct classes of QTL determine rust resistance in sorghum. AB - BACKGROUND: Agriculture is facing enormous challenges to feed a growing population in the face of rapidly evolving pests and pathogens. The rusts, in particular, are a major pathogen of cereal crops with the potential to cause large reductions in yield. Improving stable disease resistance is an on-going major and challenging focus for many plant breeding programs, due to the rapidly evolving nature of the pathogen. Sorghum is a major summer cereal crop that is also a host for a rust pathogen Puccinia purpurea, which occurs in almost all sorghum growing areas of the world, causing direct and indirect yield losses in sorghum worldwide, however knowledge about its genetic control is still limited. In order to further investigate this issue, QTL and association mapping methods were implemented to study rust resistance in three bi-parental populations and an association mapping set of elite breeding lines in different environments. RESULTS: In total, 64 significant or highly significant QTL and 21 suggestive rust resistance QTL were identified representing 55 unique genomic regions. Comparisons across populations within the current study and with rust QTL identified previously in both sorghum and maize revealed a high degree of correspondence in QTL location. Negative phenotypic correlations were observed between rust, maturity and height, indicating a trend for both early maturing and shorter genotypes to be more susceptible to rust. CONCLUSIONS: The significant amount of QTL co-location across traits, in addition to the consistency in the direction of QTL allele effects, has provided evidence to support pleiotropic QTL action across rust, height, maturity and stay-green, supporting the role of carbon stress in susceptibility to rust. Classical rust resistance QTL regions that did not co-locate with height, maturity or stay-green QTL were found to be significantly enriched for the defence-related NBS-encoding gene family, in contrast to the lack of defence-related gene enrichment in multi-trait effect rust resistance QTL. The distinction of disease resistance QTL hot-spots, enriched with defence-related gene families from QTL which impact on development and partitioning, provides plant breeders with knowledge which will allow for fast-tracking varieties with both durable pathogen resistance and appropriate adaptive traits. PMID- 25551676 TI - Return of pandemic H1N1 influenza virus. AB - BACKGROUND: Influenza pandemics are usually caused by the re-assortment of several influenza viruses, results in the emergence of new influenza virus strains that can infect the entire population. These pandemic strains, as well as seasonal influenza viruses, are subjected to extensive antigenic change that has, so far, prevented the generation of a universal vaccine. METHODS: Samples of patients hospitalized due to infection with the pandemic H1N1 influenza virus (A(H1N1)pdm09) from 2009, when the virus first appeared, until 2013 were analyzed. RESULTS: While many patients were hospitalized in 2009 due to infection with the pandemic H1N1 influenza virus, only small percentages of patients were hospitalized later in 2010-2012. Surprisingly, however in 2012-2013, we noticed that the percentages of patients hospitalized due to the pandemic H1N1 influenza infection increased significantly. Moreover, the ages of hospitalized patients differed throughout this entire period (2009-2013) and pregnant women were especially vulnerable to the infection. CONCLUSIONS: High percentages of patients (especially pregnant women) were hospitalized in 2013 due to the A(H1N1)pdm09 infection, which may have been enabled by an antigenic drift from those which circulated at the onset of the pandemic. PMID- 25551675 TI - Multiple functions of the SNARE protein Snap29 in autophagy, endocytic, and exocytic trafficking during epithelial formation in Drosophila. AB - How autophagic degradation is linked to endosomal trafficking routes is little known. Here we screened a collection of uncharacterized Drosophila mutants affecting membrane transport to identify new genes that also have a role in autophagy. We isolated a loss of function mutant in Snap29 (Synaptosomal associated protein 29 kDa), the gene encoding the Drosophila homolog of the human protein SNAP29 and have characterized its function in vivo. Snap29 contains 2 soluble NSF attachment protein receptor (SNARE) domains and a asparagine-proline phenylalanine (NPF motif) at its N terminus and rescue experiments indicate that both SNARE domains are required for function, whereas the NPF motif is in part dispensable. We find that Snap29 interacts with SNARE proteins, localizes to multiple trafficking organelles, and is required for protein trafficking and for proper Golgi apparatus morphology. Developing tissue lacking Snap29 displays distinctive epithelial architecture defects and accumulates large amounts of autophagosomes, highlighting a major role of Snap29 in autophagy and secretion. Mutants for autophagy genes do not display epithelial architecture or secretion defects, suggesting that the these alterations of the Snap29 mutant are unlikely to be caused by the impairment of autophagy. In contrast, we find evidence of elevated levels of hop-Stat92E (hopscotch-signal transducer and activator of transcription protein at 92E) ligand, receptor, and associated signaling, which might underlie the epithelial defects. In summary, our findings support a role of Snap29 at key steps of membrane trafficking, and predict that signaling defects may contribute to the pathogenesis of cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma (CEDNIK), a human congenital syndrome due to loss of Snap29. PMID- 25551677 TI - Interpersonal violence, alcohol use, and acquired capability for suicide. AB - Acquired capability for suicide (ACS), defined as pain tolerance and fearlessness about death, is theorized as necessary to enact suicide. This study examined the associations of interpersonal violence and alcohol use with ACS in 502 college students. General fearlessness/pain tolerance was positively associated with male gender and alcohol use. Fearlessness about death was positively associated with male gender and general physical violence perpetration. However, these risk factors did not explain variance in ACS beyond male gender and history of suicide attempts/nonsuicidal self-injury. These findings add to the understanding of ACS correlates. PMID- 25551678 TI - Reliability of the interprofessional collaborator assessment rubric (ICAR) in multi source feedback (MSF) with post-graduate medical residents. AB - BACKGROUND: Increased attention on collaboration and teamwork competency development in medical education has raised the need for valid and reliable approaches to the assessment of collaboration competencies in post-graduate medical education. The purpose of this study was to evaluate the reliability of a modified Interprofessional Collaborator Assessment Rubric (ICAR) in a multi source feedback (MSF) process for assessing post-graduate medical residents' collaborator competencies. METHODS: Post-graduate medical residents (n = 16) received ICAR assessments from three different rater groups (physicians, nurses and allied health professionals) over a four-week rotation. Internal consistency, inter-rater reliability, inter-group differences and relationship between rater characteristics and ICAR scores were analyzed using Cronbach's alpha, one-way and two-way repeated measures ANOVA, and logistic regression. RESULTS: Missing data decreased from 13.1% using daily assessments to 8.8% utilizing an MSF process, p = .032. High internal consistency measures were demonstrated for overall ICAR scores (alpha = .981) and individual assessment domains within the ICAR (alpha = .881 to .963). There were no significant differences between scores of physician, nurse, and allied health raters on collaborator competencies (F2,5 = 1.225, p = .297, eta2 = .016). Rater gender was the only significant factor influencing scores with female raters scoring residents significantly lower than male raters (6.12 v. 6.82; F1,5 = 7.184, p = .008, eta 2 = .045). CONCLUSION: The study findings suggest that the use of the modified ICAR in a MSF assessment process could be a feasible and reliable assessment approach to providing formative feedback to post-graduate medical residents on collaborator competencies. PMID- 25551679 TI - Osteosarcoma in patients with Rothmund-Thomson syndrome. AB - BACKGROUND: Rothmund-Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited. PROCEDURE: Seven patients with osteosarcoma, treated in the Cooperative Osteosarcoma Study Group-trials, had a diagnosis of RTS. Their patient-, tumor- and treatment related variables and outcome were reviewed retrospectively. RESULTS: Median age at diagnosis of osteosarcoma was 13 years (range 7-16), five were female, two male. Tumor involved proximal tibia (n = 4), distal tibia (n = 1), distal fibula (n = 1) and proximal ulna (n = 1). Three patients had metastatic disease at diagnosis. All patients received surgery and chemotherapy. Four of seven patients required dose modifications and three of them terminated treatment prematurely. Complete resection of the primary tumor was achieved in all individuals. Two of three affected patients failed to achieve surgical clearance of their primary metastases and died. The third patient relapsed with multiple metastases and died. Two of four patients with localized disease were alive in first complete remission, a third patient in second complete remission after recurrence and a fourth patient died of acute leukemia, while still in first complete remission of osteosarcoma. CONCLUSIONS: Patients with RTS and osteosarcoma may be cured of their cancer with appropriate multimodal therapy. They should be treated like other osteosarcoma patients but preexisting disorders, needs for special support and development of toxicities have to be considered. PMID- 25551680 TI - Hypotheses, limits, models and life. AB - Life is launching a new section, called Hypotheses in the Life Sciences. The new Section will complement the other sections of Life, providing a feedstock of ideas whose tests can be published in the wider Life family, and elsewhere. We will consider hypotheses that are supported by real world, rigorous evidence, by clear arguments, and which provide a potential solution to a genuine gap in our understanding of any aspect of the life sciences. PMID- 25551681 TI - Occurrence of Far-Red Light Photoacclimation (FaRLiP) in Diverse Cyanobacteria. AB - Cyanobacteria have evolved a number of acclimation strategies to sense and respond to changing nutrient and light conditions. Leptolyngbya sp. JSC-1 was recently shown to photoacclimate to far-red light by extensively remodeling its photosystem (PS) I, PS II and phycobilisome complexes, thereby gaining the ability to grow in far-red light. A 21-gene photosynthetic gene cluster (rfpA/B/C, apcA2/B2/D2/E2/D3, psbA3/D3/C2/B2/ H2/A4, psaA2/B2/L2/I2/F2/J2) that is specifically expressed in far-red light encodes the core subunits of the three major photosynthetic complexes. The growth responses to far-red light were studied here for five additional cyanobacterial strains, each of which has a gene cluster similar to that in Leptolyngbya sp. JSC-1. After acclimation all five strains could grow continuously in far-red light. Under these growth conditions each strain synthesizes chlorophylls d, f and a after photoacclimation, and each strain produces modified forms of PS I, PS II (and phycobiliproteins) that absorb light between 700 and 800 nm. We conclude that these photosynthetic gene clusters are diagnostic of the capacity to photoacclimate to and grow in far-red light. Given the diversity of terrestrial environments from which these cyanobacteria were isolated, it is likely that FaRLiP plays an important role in optimizing photosynthesis in terrestrial environments. PMID- 25551684 TI - Direct one-pot synthesis of chemically anisotropic particles with tunable morphology, dimensions, and surface roughness. AB - Previously, synthesis of anisotropic particles by seeded polymerizations has involved multiple process steps. In conventional one-pot dispersion polymerization (Dis.P) with a cross-linker added, only spherical particles are produced due to rapid and high cross-linking. In this Article, a straightforward one-pot preparation of monodisperse anisotropic particles with tunable morphology, dimensions, surface roughness, and asymmetrically distributed functional groups is described. With a cross-linker of divinylbenzene (DVB, 8%), ethylene glycol dimethacrylate (EGDMA, 6%), or dimethacryloyloxybenzophenone (DMABP, 5%) added at 40 min, shortly after the end of nucleation stage in Dis.P of styrene (St) in methanol and water (6/4, vol), the swollen growing particles are inhomogeneously cross-linked at first. Then, at low gel contents of 59%, 49%, and 69%, corresponding to the cases using DVB, EGDMA, and DMABP, respectively, the growing particle phase separates and snowman- or dumbbell-like particles are generated. Thermodynamic and kinetic analyses reveal that moderate cross-linking and sufficient swelling of growing particles determine the formation and growth of anisotropic particles during polymerization. Morphology, surface roughness, sizes, and cross-linking degrees of each domain of final particles are tuned continuously by varying start addition time and contents of cross-linkers. The snowman-like particles fabricated with DVB have a gradient cross-linking and asymmetrical distribution of pendant vinyl groups from their body to head. The dumbbell-like particles prepared using DMABP have only one domain cross-linked; i.e., only one domain contains photosensitive benzophenone (BP) groups. With addition of glycidyl methacrylate (GMA) or propargyl methacrylate (PMA) together with DVB or EGDMA, epoxy or alkynyl groups are asymmetrically incorporated. With the aid of these functional groups, carboxyl, amino, or thiol groups and PEG (200) are attached by thiol-ene (yne) click and photocoupling reactions. PMID- 25551683 TI - Expected Problem Drinker Possible Self: Predictor of Alcohol Problems and Tobacco Use in Adolescents. AB - BACKGROUND: Alcohol and tobacco use commonly co-occur in adolescents. According to the cross-substance facilitation of information processing hypothesis, cognitive structures related to one substance increase use of another related substance through enhanced cognitive processing. In this study, the authors test this hypothesis by determining whether a problem drinker "possible self" in 8th grade predicts alcohol and tobacco use in 9th grade. METHODS: A secondary data analysis of a 12-month longitudinal dataset was conducted. The outcome variables were alcohol consumption, alcohol problems, and tobacco use in 9th grade. The main predictor of interest was presence of an expected problem drinker possible self in 8th grade. Zero-inflated gamma regression, zero-inflated negative binomial regression, and logistic regression were used. RESULTS: Among 137 adolescents, controlling for known family, parent, and peer determinants, and corresponding 8th grade behavior, having an expected problem drinker possible self in 8th grade predicted alcohol problems, but not level of alcohol consumption in 9th grade. Moreover, the expected problem drinker possible self in 8th grade predicted tobacco use in 9th grade, controlling for known determinants and concurrent alcohol problems. CONCLUSIONS: Findings provide support for the cross-substance facilitation hypothesis, suggesting that interventions designed to modify the expected problem drinker possible self may reduce not only adolescent alcohol use but also tobacco use. Further studies are needed to determine whether smoking content is embedded in a drinking cognition or 2 separate but related drinking and smoking cognitions account for the association between alcohol and tobacco use. PMID- 25551682 TI - Salt acclimation of cyanobacteria and their application in biotechnology. AB - The long evolutionary history and photo-autotrophic lifestyle of cyanobacteria has allowed them to colonize almost all photic habitats on Earth, including environments with high or fluctuating salinity. Their basal salt acclimation strategy includes two principal reactions, the active export of ions and the accumulation of compatible solutes. Cyanobacterial salt acclimation has been characterized in much detail using selected model cyanobacteria, but their salt sensing and regulatory mechanisms are less well understood. Here, we briefly review recent advances in the identification of salt acclimation processes and the essential genes/proteins involved in acclimation to high salt. This knowledge is of increasing importance because the necessary mass cultivation of cyanobacteria for future use in biotechnology will be performed in sea water. In addition, cyanobacterial salt resistance genes also can be applied to improve the salt tolerance of salt sensitive organisms, such as crop plants. PMID- 25551686 TI - Evaluation of visual function and retinal structure in adult amblyopes. AB - PURPOSE: To evaluate visual function and its relationship to structure in adult amblyopic subjects. METHODS: This observational, cross-sectional study included 24 adult amblyopes and 19 healthy subjects. The amblyopes were separated into three groups: anisometropic amblyopes (n = 15), strabismic amblyopes (n = 5), and strabismic amblyopes with anisometropia (n = 4). The relationships of the multifocal visual evoked potential (VEP) results with the clinical findings and psychophysical (Humphrey visual field) and structural (spectral domain optical coherence tomography) diagnostic test data were then investigated. RESULTS: Significant differences in the multifocal VEP amplitude responses (abnormal cluster defects), combining the interocular and monocular probability analysis, were observed between the anisometropic amblyopic (80%) and nonamblyopic eyes (13.3%) (p < 0.001), whereas in strabismic amblyopia, such defects were found in 100% of the amblyopic and nonamblyopic eyes. Delayed multifocal VEP interocular and monocular latencies were seen in 66.6 and 26.6% of the anisometropic amblyopic and nonamblyopic eyes, with no significant differences between eyes (p = 0.065). Likewise, latency delays were found in 40% of both strabismic amblyopic and nonamblyopic eyes. Multifocal VEP latency showed significant differences between anisometropic and strabismic amblyopic eyes (p = 0.036). Significant agreement was found between the Humphrey visual field and the multifocal VEP visual field defects in the central area of the visual field (p = 0.033). The average retinal nerve fiber layer thickness, foveal and macular thickness, and macular volume, as measured by spectral domain optical coherence tomography, did not show any significant differences between the amblyopic and nonamblyopic eyes and the control group. CONCLUSIONS: Multifocal VEP amplitudes and latencies were significantly affected in amblyopic eyes and, to a lesser extent, in nonamblyopic eyes. Multifocal VEP response latencies were more delayed in anisometropic eyes than in strabismic eyes, suggesting that anisometropic and strabismic amblyopia may represent different neural abnormalities. PMID- 25551687 TI - Driving self-restriction and motor vehicle collision occurrence in glaucoma. AB - PURPOSE: To confirm that subjects with primary open-angle glaucoma (POAG) who avoid driving in high-risk situations are less likely to be involved in motor vehicle collisions (MVCs) than those who do not. METHODS: This study evaluated 252 consecutive Japanese aged between 40 and 85 years with POAG. All participants were requested to answer a questionnaire on their driving habits, including self restriction in driving at night, in rain, in fog, on freeways, and lane changing, and history of MVCs. Those who reported restricting their driving in one or more ways constituted the self-restriction group, and those who reported no self restriction made up the no-restriction group. The prevalence of MVCs and the crash rate (number of MVCs/10,000 km driven) were compared between the two groups. The association between prevalence of MVCs and the number of driving self restrictions was also evaluated. RESULTS: The association between driving self restriction and MVCs was observed among the male subjects, not among the female subjects. Among the male subjects, the prevalence of MVCs was significantly higher in the no-restriction group than in the self-restriction group (no restriction group, 33/107 = 30.8%; self-restriction group, 9/66 = 13.6%, p = 0.01). The crash rate was also significantly higher in the no-restriction group (no-restriction group, 1.4 +/- 0.8; self-restriction group, 0.4 +/- 0.3, average +/- SE, p = 0.01). No restriction was significantly associated with MVCs (multivariable-adjusted odds ratios, 2.43 [95% confidence interval, 1.03 to 5.73]). The number of driving self-restrictions was also associated with MVCs (multivariable-adjusted odds ratios, 0.41 [95% confidence interval, 0.18 to 0.99], per one increment of self-restriction). CONCLUSIONS: Driving self restriction may be associated with a reduced prevalence of MVCs in men with POAG. PMID- 25551688 TI - Intraocular Scattering after Instillation of Diquafosol Ophthalmic Solution. AB - PURPOSE: To assess the changes in intraocular scattering before and after instillation of diquafosol ophthalmic solution in patients with short tear breakup time (TBUT) dry eye. METHODS: We prospectively examined 20 eyes of 20 short TBUT dry eye patients (study group) and age-matched 20 eyes of 20 healthy subjects (control group). Intraocular scattering was measured as the objective scattering index (OSI) at 0.5-second intervals over 10 seconds without blinking. Patients were instructed to start topical administration of 3% diquafosol ophthalmic solution six times daily for 4 weeks. RESULTS: The OSI significantly deteriorated after 7.0 seconds compared with the initial value of OSI after the blinking in the study group. The OSI was also significantly higher in the study group than in the control group at 4.5 to 10.0 seconds after the blinking (p < 0.05). We found significant improvements 2 weeks after treatment not only in TBUT (p < 0.001) but also in the mean OSI, the OSI change rate, and the slope of the linear regression line of the OSI within 10 seconds (p < 0.001, p = 0.003, and p = 0.002, respectively). We also found significant improvements 4 weeks after treatment in these variables. CONCLUSIONS: Intraocular scattering deteriorates significantly with time in patients with short TBUT dry eye. Diquafosol ophthalmic solution exhibits an improvement not only in TBUT but also in intraocular scattering, indicating that diquafosol is also effective for improving the optical quality of the eye. PMID- 25551685 TI - Cell surface marker profiling of human tracheal basal cells reveals distinct subpopulations, identifies MST1/MSP as a mitogenic signal, and identifies new biomarkers for lung squamous cell carcinomas. AB - BACKGROUND: The large airways of the lungs (trachea and bronchi) are lined with a pseudostratified mucociliary epithelium, which is maintained by stem cells/progenitors within the basal cell compartment. Alterations in basal cell behavior can contribute to large airway diseases including squamous cell carcinomas (SQCCs). Basal cells have traditionally been thought of as a uniform population defined by basolateral position, cuboidal cell shape, and expression of pan-basal cell lineage markers like KRT5 and TP63. While some evidence suggests that basal cells are not all functionally equivalent, few heterogeneously expressed markers have been identified to purify and study subpopulations. In addition, few signaling pathways have been identified that regulate their cell behavior. The goals of this work were to investigate tracheal basal cell diversity and to identify new signaling pathways that regulate basal cell behavior. METHODS: We used flow cytometry (FACS) to profile cell surface marker expression at a single cell level in primary human tracheal basal cell cultures that maintain stem cell/progenitor activity. FACS results were validated with tissue staining, in silico comparisons with normal basal cell and lung cancer datasets, and an in vitro proliferation assay. RESULTS: We identified 105 surface markers, with 47 markers identifying potential subpopulations. These subpopulations generally fell into more (~ > 13%) or less abundant (~ < 6%) groups. Microarray gene expression profiling supported the heterogeneous expression of these markers in the total population, and immunostaining of large airway tissue suggested that some of these markers are relevant in vivo. 24 markers were enriched in lung SQCCs relative to adenocarcinomas, with four markers having prognostic significance in SQCCs. We also identified 33 signaling receptors, including the MST1R/RON growth factor receptor, whose ligand MST1/MSP was mitogenic for basal cells. CONCLUSION: This work provides the largest description to date of molecular diversity among human large airway basal cells. Furthermore, these markers can be used to further study basal cell function in repair and disease, and may aid in the classification and study of SQCCs. PMID- 25551689 TI - The influence of astragalus polysaccharide and beta-elemene on LX-2 cell growth, apoptosis and activation. AB - BACKGROUND: Activated hepatic stellate cells are the main source of excessive collagen deposition in liver fibrosis. Here we report the inhibitory effects of the combinational treatment of two natural products, astragalus polysaccharide (APS) and beta-elemene (ELE) on the activation of human liver hepatic stellate cell line LX-2 cells. METHODS: Cultured LX-2 cells were treated with different concentrations of APS or ELE for 24 or 48 hours. Cell viability/apoptosis was measured by MTT assay and Annexin V/PI staining , activation related genes including alpha-SMA and CD44 expressions were measured by real-time PCR and western blot respectively. RESULTS: The majority of LX-2 cells showed morphological change in the presence of APS or ELE for 24 hours. Treatment with APS + ELE for 24 or 48 hours significantly inhabited the cell proliferation compared with APS or ELE treatment alone on LX-2 cells. APS + ELE may block the up-regulation of alpha-SMA and CD44 both in mRNA and protein levels through TGF beta pathway in LX-2 cells. CONCLUSION: APS or ELE treatment alone on LX-2 cells could inhibit cell proliferation and induce apoptosis. The combinational treatment using APS + ELE significantly increased the killing efficiency on LX-2 cells. alpha-SMA and CD44 expressions was inhibited upon APS + ELE treatment through TGF-beta pathway in LX-2 cells. The results indicated a novel treatment using natural products for liver diseases with anti-fibrotic effect. PMID- 25551690 TI - Synthesis, characterization, and biological interaction of glyconanoparticles with controlled branching. AB - Branched amphiphilic copolymers were synthesized through the reversible addition fragmentation chain transfer (RAFT) chain extension of a poly(methyl acrylate) macro-chain transfer agent using a protected galactose monomer and a polymerizable chain transfer agent branching unit. After galactose deprotection, the copolymers were self-assembled via nanoprecipitation. The resultant nanoparticles were analyzed for their size, shape, and biological interaction with a galactose binding lectin. Using light scattering, the nanoparticles were determined to be solid spheres. Nanoparticles containing branched glycoblocks bound significantly more lectin than those containing comparable linear blocks. By adjusting the molecular weight and branching of the copolymer, the size of the self-assembled nanoparticle and the saccharide density on its surface can be varied. PMID- 25551691 TI - Differentiating ADHD from oral language difficulties in children: role of movements and effects of stimulant medication. AB - BACKGROUND: The current study was designed to test if an objective measure of both attention and movement would differentiate children with Oral Language Disorders (OLD) from those with comorbid Attention Deficit/Hyperactivity Disorder (ADHD) and if stimulant medication improved performance when both disorders were present. METHODS: The sample consisted of thirty-three children with an identified oral language disorder (of which 22 had comorbid ADHD) ages 6 to 13 who were enrolled in a yearlong intensive learning intervention program. Those on a stimulant medication were tested at baseline and again a year later on and off medication. RESULTS: Objective measures that included an infrared motion analysis system which tracked and recorded subtle movements discriminated children with OLD from those with a comorbid ADHD disorder whereas classic attention measures did not. There were better attention scores and fewer movements in children while on-medication. CONCLUSIONS: Use of an objective measurement that includes movement detection improves objective diagnostic differential for OLD and ADHD and provides quantifiable changes in performance related to medication for both OLD and ADHD. PMID- 25551692 TI - Carcinosarcoma of native renal pelvis in recipient after a renal transplant: a case report. AB - BACKGROUND: Carcinosarcoma is a malignancy that rarely occurs in the renal pelvis. MATERIALS AND METHODS: We present a case of histologically proven, native renal pelvis carcinosarcoma in a 65-year-old woman who had accepted a renal transplant. We performed a laparoscopic ureterectomy, combined with lymph node dissection and immunosuppression with sirolimus (SRL), which was alternated with the conventional immunosuppressant--cyclosporine. RESULTS: This patient was still alive 34 months after renal transplantation. CONCLUSIONS: Operation is still the best choice, and the SRL may be beneficial for preventing the progression of a tumor. PMID- 25551695 TI - Simplifying cardiovascular magnetic resonance pulse sequence terminology. AB - We propose a set of simplified terms to describe applied Cardiovascular Magnetic Resonance (CMR) pulse sequence techniques in clinical reports, scientific articles and societal guidelines or recommendations. Rather than using various technical details in clinical reports, the description of the technical approach should be based on the purpose of the pulse sequence. In scientific papers or other technical work, this should be followed by a more detailed description of the pulse sequence and settings. The use of a unified set of widely understood terms would facilitate the communication between referring physicians and CMR readers by increasing the clarity of CMR reports and thus improve overall patient care. Applied in research articles, its use would facilitate non-expert readers' understanding of the methodology used and its clinical meaning. PMID- 25551694 TI - Sneddon's syndrome: a comprehensive review of the literature. AB - Sneddon's syndrome (SS) is a rare non-inflammatory thrombotic vasculopathy characterized by the combination of cerebrovascular disease with livedo racemosa(LR). The Orpha number for SS is ORPHA820. It has been estimated that the incidence of SS is 4 per 1 million per annum in general population and generally occurs in women between the ages of 20 and 42 years. LR may precede the onset of stroke by years and the trunk and/or buttocks are involved in nearly all patients. The cerebrovascular manifestations are mostly secondary to ischemia (transient ischemic attacks and cerebral infarct). Other neurological symptoms range from headache, cerebral hemorrhage, seizures, cognitive and psychiatric disturbances. The involved internal organs include heart, kidney, and eyes. Histological findings of skin are characteristic and the involved vessels are small to medium-sized arteries at the border of dermis to subcutis with a distinct histopathological time course. The main diagnostic criteria are general LR with typical histopathological findings on skin biopsy and focal neurological deficits. The pathogenesis is related to hypercoagulable state and intrinsic small-vessel vasculopathy. The optimal management remains an unsolved problem and long-term anticoagulation have been recommended for cerebral ischemic events based on the presumed pathogenesis. There are controversial results in treatment of SS with immunomodulatory agents. The aim of this review is to comprehensively discuss this disease. PMID- 25551696 TI - Adnexal masses in pregnancy. AB - With the advent of routine obstetrical ultrasound, the diagnosis of an adnexal mass in pregnancy has become increasingly common. Although the reported incidence and expected clinical course varies based on the gestational age at the time of diagnosis and the criteria used to define an adnexal mass, the majority of adnexal masses diagnosed in pregnancy are benign and are likely to resolve without complication or intervention. This review will discuss the epidemiology of adnexal masses in pregnancy, diagnostic tools, potential complications, and management options during pregnancy. PMID- 25551697 TI - Adnexal pathology. Foreword. PMID- 25551698 TI - Adnexal masses in children and adolescents. AB - Adnexal masses in children encompass a variety of lesions of the ovaries and fallopian tubes, including ovarian cysts and tumors (benign or malignant), fallopian tube cysts and abscesses, paratubal cysts, and endometriomas. When developing a differential diagnosis for adnexal masses in childhood, the clinician must have a broad understanding of adnexal pathology and consider the patient's age, presenting complaints, physical examination findings, and imaging results to generate a list of possible diagnoses and the appropriate treatment plan. We review the clinical presentation of these lesions and discuss the current recommendations for their management. PMID- 25551700 TI - The association of MDM2 c.346G>A genetic variant with the risk of osteosarcoma in Chinese. AB - Previous studies suggest that the MDM2 gene is one of the most important candidate genes for influencing the risk of osteosarcoma. This study aims to investigate the potential association of MDM2 c.346G>A genetic variant with the risk of osteosarcoma in Chinese. A total of 738 subjects were recruited in this study. The genotypes of MDM2 c.346G>A genetic variant were detected by the created restriction site-polymerase chain reaction. Our data suggest that the MDM2 c.346G>A genetic variant is associated with the increased risk of osteosarcoma in the homozygote comparison (AA vs. GG: odds ratio [OR]=2.36, 95% confidence interval [CI] 1.30-4.28, chi2=8.35, p=0.004), recessive model (AA vs. GA/GG: OR=2.32, 95% CI 1.30-4.13, chi2=8.50, p=0.004), and allele comparison (A vs. G: OR=1.27, 95% CI 1.01-1.60, chi2=4.34, p=0.037). Results from this study indicated that the allele-A and genotype-AA of MDM2 c.346G>A genetic variant could be an increased risk factor for the susceptibility to osteosarcoma and might be used as a potential molecular marker for evaluating the risk of osteosarcoma. PMID- 25551699 TI - Micafungin for the treatment of proven and suspected invasive candidiasis in children and adults: findings from a multicenter prospective observational study. AB - BACKGROUND: A multicenter observational study was conducted in Italy to assess the safety of micafungin in the daily clinical practice for the treatment of proven and suspected invasive candidiasis (IC), as well as to describe rates of clinical response to micafungin treatment. METHODS: From October 2010 to March 2012, data from consecutive eligible neonate, pediatric, and adult patients treated with micafungin for a proven or suspected IC were collected. Patients were deemed as eligible if they or their parents signed an informed consent. The study endpoints were to assess safety of micafungin in the treatment of both proven and suspected IC, and to describe rates of clinical response to micafungin treatment. Clinical response was assessed at the end of micafungin treatment (EOMT) and defined as favorable (complete or partial resolution of signs and symptoms) or unfavorable (stability or progression). RESULTS: During the study period, 108 patients with proven or suspected IC were enrolled. Thirty-six out of 108 patients (33%) were < 18 year-old (median 1 year), whereas 72 (67%) were >= 18 year-old (median 71 years). Neonates in NICU accounted for 36% of pediatric patients, with the majority of them (54%) being extremely low birth weight (ELBW) newborns. Fifty-eight out of 108 patients (54%) received micafungin for a proven IC, whereas 50/108 patients (46%) were treated for a suspected IC. Among proven IC, candidemia accounted for the majority of events (54/58, 93%), with Candida albicans (35/58, 60%) as the most frequently isolated species. Therapy was discontinued due to occurrence of an adverse event in 4/108 subjects (4%). No pediatric patient had treatment interruption because of adverse events. A 67% favorable response rate was observed at EOMT. No age-, species-, underlying conditions- or ward-related differences of favorable response were observed. Survival at EOMT was 90% (97/108 patients), with rates of 97% (35/36) and 86% (62/72) among children and adults, respectively. CONCLUSIONS: Micafungin was well tolerated in a heterogeneous real world population with a bimodal age distribution. A high rate of favorable response to micafungin treatment was reported in both proven and suspected IC. PMID- 25551701 TI - Get a license, buckle up, and slow down: risky driving patterns among saudis. AB - INTRODUCTION: Road traffic injuries are the largest cause of loss of disability adjusted life years for men and women of all ages in the Kingdom of Saudi Arabia, but data on driving habits there are lacking. To inform policymakers on drivers' abilities and driving habits, we analyzed data from the Saudi Health Interview Survey 2013. METHODS: We surveyed a representative sample of 5,235 Saudi males aged 15 years or older on wearing seat belts, exceeding speed limits, and using a handheld cell phone while driving. Male and female respondents were surveyed on wearing seat belts as passengers. RESULTS: Among Saudi males, 71.7% reported having had a driver's license, but more than 43% of unlicensed males drove a vehicle. Among drivers, 86.1% engaged in at least one risky behavior while driving. Older and unlicensed drivers were more likely to take risks while driving. This risk decreased among the more educated, current smokers, and those who are physically active. Up to 94.9% and 98.5% of respondents reported not wearing a seat belt in the front and the back passenger seats, respectively. DISCUSSION: The high burden of road traffic injuries in the Kingdom is not surprising given our findings. Our study calls for aggressive monitoring and enforcement of traffic laws. Awareness and proper education for drivers and their families should be developed jointly by the Ministries of Health, Interior Affairs, and Education and provided through their channels. PMID- 25551703 TI - Standardized uptake value of 18F-fluorodeoxyglucose positron emission tomography for prediction of tumor recurrence in breast cancer beyond tumor burden. AB - INTRODUCTION: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can reveal the metabolic activity of malignant tumors. Recent advances gained from molecular studies suggest that tumor biology can be a good predictor of prognosis in breast cancer. We compared the ability of maximum standardized uptake values (SUVmax) derived by FDG-PET with tumor burden in predicting tumor recurrence for patients with breast cancer. METHODS: 496 patients with breast cancer who underwent preoperative FDG-PET between April 2004 and May 2009 were retrospectively identified. SUVmax was obtained by FDG-PET, and the cutoff point was defined using a time-dependent receiver operating characteristic curve for recurrence-free survival (RFS). The primary endpoint was RFS. RESULTS: In multivariate analysis for RFS, SUVmax carried independent prognostic significance (hazard ratio, 2.39; 95% confidence interval, 1.20 to 4.76; P = 0.012). When the patients were classified into four groups according to the combined factors of tumor size (<=2 cm versus >2 cm) and SUVmax (<4 versus >=4), RFS differed significantly (P < 0.001). Similarly, SUVmax had prognostic value in combination with nodal status (negative versus positive) or stage (I versus II and III) (P < 0.001 and P = 0.001, respectively). In hormone receptor-positive disease, SUVmax remained a significant prognostic factor for RFS based on multivariate analysis. CONCLUSIONS: Our results highlight the prognostic value of FDG-PET in prediction of tumor relapse for patients with breast cancer. Particularly in patients with hormone receptor-positive disease, the tumor metabolic information provided by FDG-PET is more significantly correlated with prognosis than tumor burden. PMID- 25551705 TI - Fused 1,5-benzothiazepines from o-aminothiophenol and its derivatives as versatile synthons. AB - This review describes the reactions of o-aminothiophenol and its derivatives as building blocks for the synthesis of poly-functionalised 1,5-benzothiazepines with pharmacological interest. Annelated 1,5-benzothiazepines were prepared by acyclocondensation reaction of o-aminothiophenol and its derivatives with carbonyl and other functionalities. In case ofcarbonyl function this reaction takes place by a nucleophilic addition, followed by a cyclisation and concomitant elimi-nation of water. The objective of this survey is to provide a comprehensive account of the synthesis of various 1,5-ben-zothiazepines derivatives and their potential to develop better chemotherapeutic agents. PMID- 25551702 TI - Suppression of allelic recombination and aneuploidy by cohesin is independent of Chk1 in Saccharomyces cerevisiae. AB - Sister chromatid cohesion (SCC), which is established during DNA replication, ensures genome stability. Establishment of SCC is inhibited in G2. However, this inhibition is relived and SCC is established as a response to DNA damage, a process known as Damage Induced Cohesion (DIC). In yeast, Chk1, which is a kinase that functions in DNA damage signal transduction, is considered an activator of SCC through DIC. Nonetheless, here we show that, unlike SCC mutations, loss of CHK1 did not increase spontaneous or damage-induced allelic recombination or aneuploidy. We suggest that Chk1 has a redundant role in the control of DIC or that DIC is redundant for maintaining genome stability. PMID- 25551706 TI - The role of ionic surfactants on the solubilization of cyclohexenone compounds in aqueous media. AB - The solubilization and partitioning study of five newly synthesized organic compounds (Cyclohexenone Carboxylates) with ionic surfactants, sodium dodecylsulphate (SDS) and cetyltrimethylammonium bromide (CTAB) was studied using ultraviolet-visible absorption spectroscopy technique. The differential spectroscopic technique was employed to study the partition coefficient (K(x)) of organic molecules between bulk water phase and the miceller phase. The values of partitioning coefficient were in the range 29.714 * 10(3) to 5.46 * 10(6). The standard free energy of partitioning (DeltaG(op)) was also determined, which was found out in the range of -25 to -38 kJ /mole and shows the stability of the system. The results show that the cyclohexenone carboxylate compounds have great interactions with CTAB as compared to SDS. PMID- 25551704 TI - Aggregation of Abeta(25-35) on DOPC and DOPC/DHA bilayers: an atomic force microscopy study. AB - beta amyloid peptide plays an important role in both the manifestation and progression of Alzheimer disease. It has a tendency to aggregate, forming low molecular weight soluble oligomers, higher-molecular weight protofibrillar oligomers and insoluble fibrils. The relative importance of these single oligomeric-polymeric species, in relation to the morbidity of the disease, is currently being debated. Here we present an Atomic Force Microscopy (AFM) study of Abeta(25-35) aggregation on hydrophobic dioleoylphosphatidylcholine (DOPC) and DOPC/docosahexaenoic 22?6 acid (DHA) lipid bilayers. Abeta(25-35) is the smallest fragment retaining the biological activity of the full-length peptide, whereas DOPC and DOPC/DHA lipid bilayers were selected as models of cell-membrane environments characterized by different fluidity. Our results provide evidence that in hydrophobic DOPC and DOPC/DHA lipid bilayers, Abeta(25-35) forms layered aggregates composed of mainly annular structures. The mutual interaction between annular structures and lipid surfaces end-results into a membrane solubilization. The presence of DHA as a membrane-fluidizing agent is essential to protect the membrane from damage caused by interactions with peptide aggregates; to reduces the bilayer defects where the delipidation process starts. PMID- 25551708 TI - Chemical reactivity of quinmerac herbicide through the Fukui function. AB - In the present work we have calculated DFT reactivity descriptors for quinmerac (7-chloro-3-methylquinoline-8-carboxylic acid) at the MP2/6-311++G(d,p)//B3LYP/6 311++G(2d,2p) level of theory to analyze its reactivity. Reactivity descriptors such as ionization energy, molecular hardness, electrophilicity, condensed Fukui function and total energies were calculated to predict changes in its reactivity. The Fukui function values predict that electrophilic and free radical attacks on quinmerac might cause aromatic substitutions, while nucleophilic attacks would cause cleavage of the C=N bond. PMID- 25551707 TI - Feasibility of clinoptilolite application as a microporous carrier for pH controlled oral delivery of aspirin. AB - Clinoptilolite is a natural zeolite which due to high surface area/volume ratio has found many applications in industries and medicine. Aspirin is a non steroidal anti-inflammatory drug which is currently used as an anticoagulant, antinociceptive, antipyretic, and anti-inflammatory drug. It is an acidic drug which induces gastric irritation due to inhibition of cyclooxygenase I located in gastric mucosa. In the present work, adsorption and desorption of aspirin on Iranian clinoptilolite micronized particles were studied in acidic and relatively alkaline pHs. Effect of particle size of clinoptilolite was also investigated on adsorption and desorption of aspirin. Specific surfaces, particle sizes, and zeta potentials of clinoptilolite particles were also determined. Scanning electron micrograph was used to study the morphology and crystallinity of clinoptilolite particles. The results showed that adsorption and desorption of aspirin on clinoptilolite are particle size- and pH-dependent. The present work proposes clinoptilolite as an inexpensive, efficient, and non-toxic natural available microporous material for aspirin oral delivery. PMID- 25551709 TI - Solvent-free synthesis of dihydropyrano[3,2-c]chromene and biscoumarin derivatives using magnesium oxide nanoparticles as a recyclable catalyst. AB - In these research, an efficient one pot approach for the synthesis of dihydropyrano[3,2-c]chromenes and biscoumarins as important heterocyclic compounds with pharmacological and biological properties have been prepared using nanocrystalline magnesium oxide. Magnesium oxide nanoparticles were significantly catalyzed three-component reaction of aldehydes, ethyl cyanoacetate and 4 hydroxycoumarin in high yields and short reaction times under solvent-free conditions. Nano magnesium oxide as an efficient, available and cheap heterogeneous nanoparticles were used for several times in the synthesis of dihydropyrano [3,2-c]chromenes and biscoumarins. PMID- 25551710 TI - Human granulocyte colony stimulating factor (G-CSF) produced in the filamentous fungus Aspergillus niger. AB - For the first time, a fungal production system is described for expression and secretion of the medically important human protein G-CSF, in Aspergillus niger. A reliable strategy was chosen with in-frame fusion of G-CSF behind a KEX2 cleavage site downstream of the coding region of the highly secreted homologous glucoamylase. This provided secretion levels of 5-10 mg/l culture medium of correctly processed G-CSF, although the majority of the protein (>90%) was biologically inactive. Following denaturation/ concentration and chromatographic separation/ renaturation, the G-CSF proliferation activity increased considerably, and analytical immobilised metal affinity chromatography confirmed the monomeric and correctly folded protein. These data suggest that this human secretory protein secreted into the medium of A. niger was not correctly folded, and that it escaped the endoplasmic reticulum folding control systems. This is compared to the folding of G-CSF produced in bacteria and yeast. PMID- 25551711 TI - Synthesis, crystal structure and physico-chemical properties of 3,3'-[(4 hydroxyphenyl)methyl] bis-(4-hydroxy-2H-chromen-2-one). AB - The compound 3,3'-[(4-Hydroxyphenyl)methyl]bis-(4-hydroxy-2H-chromen-2-one) was synthesized by the Knoevenagel reaction. Crystals, suitable for X-ray data collection, were grown by slow evaporation from an ethanol solution. The product 3,3'-[(4-Hydroxyphenyl)methyl]bis-(4-hydroxy-2H-chromen-2-one) . ethanol crystallizes in the monoclinic system, space group P2(1)/n. The ultraviolet/visible absorption spectra in different solvents were recorded. Sensitivity of the compound to solvent polarity and hydrogen bonding with protic (ethanol, H(2)O) and aprotic (dimethylsulfoxide, acetonitrile) solvents was detected. Based on (1)H-NMR spectroscopy as well as on potentiometric and UV/vis titration experiments the acid dissociation constants for 3,3'-[(4 Hydroxyphenyl)methyl]bis-(4-hydroxy-2H-chromen-2-one) were estimated. PMID- 25551712 TI - The self-evaluation of Slovenian prospective chemistry teachers' progress during their practical pedagogical training in primary schools. AB - The present research deals with the self-evaluation of prospective chemistry teachers' progress during their practical pedagogical training (PPT) in primary schools. The sample consisted of 42 students from the 3rd and 4th years of the undergraduate programmes "Chemistry and Biology" or "Chemistry and Physics" at the Faculty of Education, University of Ljubljana. For the purpose of the investigation, the students completed questionnaires after each day of their practical pedagogical training, and at the end the entire training wrote reflective essays about their most significant experiences. Analysis of the results reveals that the students believe that practical pedagogical training makes a crucial contribution to their practical pedagogical education in the light of their future profession. The students also reported on their progress concerning the various skills that were developed. PMID- 25551713 TI - Syntheses, characterization, and properties of Ru(II) complexes based on pi conjugated terpyridine ligand with tetrathiafulvalene moiety. AB - Two ruthenium(II) complexes [Ru(TTF-terpy)(terpy)][PF(6)](2) (terpy = 2,2':6',2'' terpyridine) (1) and [Ru(TTF-terpy)(2)][PF6](2) (2) were synthesized by reactions of Ru(terpy)(dmso)(2)Cl(2) or cis-Ru(dmso)(4)Cl(2) with 4'-tetrathiafulvalene 2,2':6',2''-terpyridine (TTF-terpy), respectively. The crystal structure of 1 has been determined by X-ray crystallography. In the crystal of complex 1, molecules are seized together into 1D chains via pi...pi stacking interactions. The electrochemical and spectroscopic properties of these compounds have been studied. The results show that these Ru(II) complexes show stepwise redox processes in solution, and are promising building blocks for the construction of multi-functional materials. PMID- 25551714 TI - Supercritical fluid chromatography and scale up study. AB - The influence of process parameters on supercritical fluid chromatography (SFC) was investigated together with scaling-up to the preparative scale. Within this scope, separation of model compounds (caffeine and theophylline), dependencies on pressures, temperatures, types and concentrations of the modifiers, and types of stationary phases, were examined separately. Experiments were performed on analytical scale and on pilot preparative scale SFC apparatus. Bare silica and silica 2-ethylpyridine were used as stationary phases, with CO(2)/methanol or CO(2)/ethanol at elevated pressures and temperatures as mobile phase. Observations obtained on the analytical scale were used for scaling-up to preparative scale. The aim of this study is evaluating the influences of process parameters when separating model compounds using SFC, and s practical demonstration of the scaling-up method of SFC along with the operation of a pilot preparative to production scale SFC apparatus, which is one of the bigger similar apparatuses worldwide. PMID- 25551715 TI - Preparation, characterization and catalytic activity of NiOx and NiOx/ZrO2 for oxidation of phenol in aqueous solution. AB - In the present study bulk NiO(x) and supported NiO(x)/ZrO(2) catalysts have been prepared. The bulk NiO(x) was synthesized using the precipitation-oxidation method with reverse order of precipitation while deposition-precipitation technique was used for the preparation of zirconia supported catalyst. The as prepared samples were characterized by means of XRD, HRTEM, SAED, IR spectroscopy, and chemical analyses. It was found that under the applied synthesis procedure nanosized and highly dispersed oxide materials with high active oxygen content were obtained. The catalytic activity and selectivity of these oxide catalysts have been studied in reaction of low-temperature oxidation of phenol in aqueous phase. The effects of several parameters such as catalyst amount, temperature and solution pH on the degradation efficiency of the process were also investigated. Experimental results demonstrated that phenol could be completely degraded under all reaction conditions, except at pH = 12. PMID- 25551716 TI - Determination of selected protoporphyrins in parma ham with use of 5,10,15,20 tetra(4-hydroxyphenyl)porphyrin as a surrogate standard in the recovery study. AB - A high-performance liquid chromatographic method for the determination of hemin, protoporphyrin IX (PPIX), and zinc(II)protoporphyrin IX (Zn(II)PPIX) in Parma ham was developed. The detection was done by means of a universal DAD-detector, whereby quantification of the three naturally occurring protoporphyrins was carried out at lambda = 414 nm, i.e., very close to the respective maxima of their Soret bands. The extraction thereof from the meat matrix was done by a mixture of acetone and chloroacetic acid (100 mL + 0.2 g). Usage of 5,10,15,20 tetra(4-hydroxyphenyl)porphyrin (THPP) as a surrogate standard and its detection fixed at lambda = 444 nm, allowed to obtain accurate (ca. 96%) recovery results. Established concentrations of hemin, Zn(II)PPIX, and PPIX in the Parma ham samples were 15.97, 19.96 and 1.52 ug g(-1), respectively. PMID- 25551717 TI - Estimating mean crystallite size of magnetite using multivariate calibration and powder x-ray diffraction analysis. AB - Powder X-ray diffraction patterns for 29 samples of magnetite, acquired using a conventional diffractometer, were used to build PLS calibration-based methods and variable selection to estimate mean crystallite size of magnetite directly from powder X-ray diffraction patterns. The best IPLS model corresponds to the Bragg reflections at 35.4 degrees (h k l = 3 1 1), 43.0 degrees (h k l = 4 0 0), 53.6 degrees (h k l = 4 2 2), and 57.0 degrees (h k l = 5 1 1) in 2theta. The best model was a GA-PLS which produced a model with RMSEP of 0.9 nm, and a correlation coefficient of 0.9976 between mean crystallite sizes calculated using Williamson Hall approach and the ones predicted by GA-PLS method. These results indicate that magnetite mean crystallite sizes can be predicted directly from Powder X-Ray Diffraction and multivariate calibration using PLS variable selection approach. PMID- 25551718 TI - Synthesis, characterization and DFT studies of two new pi-conjugated-conjugated pyridine-based tetrathiafulvalene derivatives. AB - Two new pi-conjugated pyridine-based tetrathiafulvalene derivatives, 2-(2- (4,5 bis(methylthio)-1,3-dithiol-2-ylidene)-6-phenyl-[1,3]dithiolo[4,5-b][1,4]dithiin 5-yl)pyridine (2a) and 3-(2-(4,5-bis(methylthio)-1,3-dithiol-2-ylidene)-6 (pyridin-2-yl) -[1,3]dithiolo[4,5-b][1,4]dithiin-5-yl)quinoline (2b), have been synthesized and characterized by 1H NMR, elemental analysis and mass spectroscopies. The compound 2a has also been studied by X-ray crystallography and theoretical calculations using density functional theory (DFT) framework with B3LYP/6-311+G(d,p) level of theory. Its crystal structure is triclinic system, space group P1-. The unit cell dimensions are: a = 8.813(3) A, b = 11.082(3) A, c = 12.620(4) A, alfa = 88.805(5) degrees , beta = 80.440(5) degrees , gama = 75.680(5) degrees , V = 1177.3(6) A3, Z = 2. The molecule exhibits one classical C-H...N intermolecular hydrogen bonds, two kinds of short intermolecular S...S interactions and two types of C-H...pi supramolecular interactions. PMID- 25551719 TI - Synthesis and anti-inflammatory activity of new N-acyl-2-pyrazolines bearing homologous alkyloxy side chains. AB - A series of new pyrazoline derivatives (1a-2h) equipped with N-acyl arms and homologous alkyloxy side chains were synthesized and characterized on the basis of spectroscopic data and microanalysis. All the synthesized compounds were screened for their in-vitro anti-inflammatory activity to examine the effect of alkyloxy side chain length on activity. Compounds with odd number of carbons in alkyloxy side chain showed better activity as compared to even ones. Compound 2c (96% inhibition, IC(50) = 173.06 +/- 2.312 mM) was found to be the most active compound of the series with better activity than the standard (Indomethacine, 92% inhibition, IC(50) = 273.12 +/- 2.33 mM). Compound 1a (86%, IC(50) = 296.16 +/- 2.091 mM) was the second best with comparable activity to the standard drug. However, the other compounds of series showed moderate to low activity. Interestingly, parallel cytotoxicity studies of compounds 1a-2h against PC-3 cell line revealed either no or very low cytotoxicity. The study may contribute in developing useful alternatives to presently used NSAIDs with harmful gastric effects due to direct cytotoxicity. PMID- 25551721 TI - Ternary ion-association complexes of cobalt with 4-(2-pyridylazo)resorcinol and tetrazolium salts. AB - The formation of ternary ion-association complexes of Co(II) with 4-(2 pyridylazo)resorcinol (PAR) and tetrazolium salts (TS) - (3-(4,5-dimethylThiazol 2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and 3-(2-naphtyl)-2,5-diphenyl-2H tetrazolium chloride (TV) - were investigated with the aid of the extraction spectrophotometric method. The optimum conditions for the extraction of Co(II) were found. On the basis of the experimental data and their mathematical treatment the association process in aqueous phase and extraction process was investigated quantitatively. The molar ratios of the components in the associates were determined. The results show that the extracted species could be represented with the general formula (TS)[CoH(PAR)(2)]. The following key constants were calculated: association constant, distribution constant, extraction constant and recovery factor. The validity of Beer's law was checked and some analytical characteristics were calculated. PMID- 25551720 TI - Complexation equilibria and coordination aspects of Zn(II) complexes contain 2 aminobenzamide and some bioactive amino acid mixed ligands: pH-metric, spectroscopic and thermodynamic studies. AB - Mixed ligand complexation of 2-aminobenzamide (2AB) as ligand [L] with Zn(II) in the presence of some bio-relevant amino acid constituents like glycine (gly), L alanine (ala), L-valine (val) and L-phenylalanine (phe) as ligand [B] have been investigated using pH-metric measurements with a combined pH electrode at different temperatures (300, 310, 320 and 330 +/- 0.1 K) in 50% (v/v) ethanol water mixture containing I = 0.15 M NaClO(4) as supporting electrolyte. Computer assisted analysis of the experimental titration data showed the presence of ZnLB and ZnLB2 species as mixed ligand complexes in addition to various binary species. In ZnLB/ZnLB(2) species, both primary and secondary ligands act as bidentate to form a stable six, five membered chelate ring. The calculated stabilization parameter Deltalog K, log X, log X' and % R.S. values clearly show the mixed ligand complexes have higher stabilities than their binary. Thermodynamic parameters DeltaG, DeltaH and DeltaS have been derived from the temperature dependence of the stability constants. The complexation behavior of ZnLB species has been studied by means of electronic spectra. The percentage distribution of various binary and mixed ligand species of each type of the complexes in solution depending on pH and the ratio of Zn(II) to 2 aminobenzamide/amino acid of the systems. PMID- 25551722 TI - Carboxylic acid reduction over silica supported Cu, Ni and Cu2In, Ni2In catalysts. AB - Hydroconversion of caprylic acid as model compound was studied in a flow-through fixed-bed reactor at 21 bar total pressure and 240-360 degrees C reaction temperature over various hydrogenating active phases: pure metal (Cu, Ni) and intermetallic compound (Cu(2)In, Ni(2)In) nanoparticles. Different silicas produced by dissimilar methods and a commercial gama-alumina were compared as appropriate supports. Catalyst precursors were activated in reducing H(2) flow at 21 bar and 450 degrees C as routine pretreatment. Catalysts of high activity and selectivity for alcohol production can be obtained by varying the supports, the main metals and their indium modified bimetallic forms. Diversity of catalytic behavior reflects the complexity of the surface reactions. Caprylic alcohol formation was substantiated to proceed through caprylic aldehyde intermediates, however it can be also dehydrated to dicaprylic ether or octenes over alumina support. Silica supports, especially a less compact variant seem to be more inert for side reactions than alumina. Different morphology of studied silicas can highly influence the catalytic performances taking place over different metal particles. PMID- 25551723 TI - Physicochemical properties of lomefloxacin, levofloxacin, and moxifloxacin relevant to the biopharmaceutics classification system. AB - The aim of this investigation was to identify the impact of physicochemical properties of three fluoroquinolones (second, third, and fourth generation) on bioavailability in relation to the Biopharmaceutics Classification System (BCS) by in silico and in vitro methods. These properties were estimated by analyzing the electrostatic potential pattern and values of the free energy of solvation as well as the distribution coefficients and true partition coefficients of the studied compounds. This study was based on theoretical quantum-chemical methods and the in vitro shake-flask technique with two immiscible phases (n-octanol and phosphate buffer) as well as the experimental potentiometric method to estimate protonation macro- and micro-constants. Properties identified in the in vitro and in silico studies were similar and indicated high lipophilic properties of the studied molecules as well as their good solubility in a polar medium. It appears that both the theoretical methods and simple in vitro studies are useful tools for predicting the bioavailability of medicinal substances based on the BCS principles. PMID- 25551724 TI - New approaches for the synthesis and cytotoxicity of thiazoles derived from cyclohexanone. AB - A new class of substituted thiazole derivatives 6a-c which showed promising anticancer activity was synthesized via the reaction of cyclohexanone with phenylisothiocyanate with a good yield. The latter compounds reacted with benzendiazonium chloride to form corresponding 5-phenylazothiazole derivatives 8a and 8b, respectively. Moreover, the reaction of thiazole derivatives 6a-c with each of elemental sulfur and either of malononitrile or ethyl cyanoacetate gave the thiophene derivatives 10a-e, respectively. Compounds 10a-e were subjected to a series of heterocylclization reactions to give heterocyclic derivatives. Their cytotoxicity against four human tumor cells lines was measured and showed promising anticancer activity. PMID- 25551725 TI - Spectrophotometric determination of 4-acetamidophenyl N'-(sulphanilamide) acetate in biological fluids. AB - A simple, accurate and low cost spectrophotometric method is proposed for the determination of the synthesized paracetamol derivative; 4-acetamidophenyl N' (sulphanilamide) acetate (APSA) in biological fluids. The spectrophotometric method is based on a condensation reaction between the alcoholic solution of APSA and acidic solution of p-dimethylaminobenzaldeyde (DPMK) to generate a yellow colored product. The linear range for the determination of APSA was 1-10 ug mL( 1) with molar absorptivity of 3.6877 * 10(4) L mol(-1) cm(-1) and Sandell's sensitivity of 0.001 ug cm-2/0.001 absorbance unit. During the inter-day and intra-day analysis, the relative standard deviation for replicated determination of APSA was found to be less than 2.0% and accuracy was 99.20-101.60% and 99.10 101.30% in blood and urine samples, respectively. There was no interference with commonly used blood and urine sample. The developed spectrophotometric method was successfully applied to assess APSA in biological fluids. PMID- 25551726 TI - Facile preparation of graphene by high-temperature electrolysis and its application in supercapacitor. AB - Graphene is well known owing to its astonishing properties: stronger than diamond, more conductive than copper and more flexible than rubber. Because of its potential uses in industry, researchers have been searching for less toxicity ways to make graphene in large amount with lower cost. We demonstrated an efficient method to prepare graphene by high temperature electrolysis technique. High resolution scanning electron microscopy and raman spectroscopy were used to characterize the microstructure of graphene. Graphene was assembled into the supercapacitor and its performance of electrochemical capacitor was investigated by constant current charge and discharge, cyclic voltammetry and AC impedance. The results showed that the micro-morphology of the prepared graphene was multilayer and it was favorable when the electrolytic voltage was 1.5 V. When the current density is 1 mA/cm(2), the specific capacitance of the graphene supercapacitor can reach 78.01 F/g in 6 mol/L KOH electrolyte, which was an increase of 114% compared with 36.43 F/g of conventional KOH electrolyte. PMID- 25551727 TI - Optimization of ultrasound-assisted extraction of phenols from seeds of grape pomace. AB - The aim of this research was to optimize the extraction condition of ultrasound assisted extraction (UAE) of phenols from the red grape of Vranac variety (Vitis vinifera L.) pomace seeds. The minimum experiments needed for optimization of UAE by response surface methodology (RSM) were obtained by spectrophotometric and HPLC analyses of seed extracts. UAE greatly depends on three independent variables: extraction temperature, time and liquid/solid ratio. The RSM can be used for optimization of UAE conditions to obtain maximum responses such as extraction yield, TPC, (+)-catechin, (-)-epicatechin and proanthocyanidin content. The predicted values of the model were in accordance with experimental data under the same conditions (RSD was 0.74%). Experimental data also confirmed that UAE gives a better yield of phenolics than conventional solvent extraction (23.76% increase). The UAE under optimal extraction conditions is suitable for obtaining extracts that are rich in phenolic content, and have strong antioxidant activity which could be used as additives in food and medicaments. PMID- 25551728 TI - Synthesis, spectral and antifungal analysis of diaryldithiophosphates of mono- and dibutyltin(IV): x-ray structure of [{(3,5-CH3)2C6H3O)2PS2}2Sn(nBu)2]. AB - Diaryldithiophosphate complexes of mono- and dibutyltin(IV) corresponding to [(ArO)(2)PS(2)(n)Sn(nBu)xCl(4-x-n)] (Ar = o-CH(3)C(6)H(4), m-CH(3)C(6)H(4), p CH(3)C(6)H(4), 4-Cl-3-CH(3)C(6)H(3), (3,5-CH(3))(2)C(6)H(3); n = 1, 2 for x = 1 and n = 2 for x = 2) were successfully isolated and characterized by elemental analyses, IR, multinuclear NMR ((1)H, (13)C, (31)P and (119)Sn) spectroscopy and X-ray analysis. The thermal properties of the complex [(3,5 CH(3))(2)C(6)H(3)O(2)PS(2)](2)Sn(nBu)(2) (12) have been examined by combined DTA/ DTG thermal analyses. Single crystal X-ray analysis of [(3,5 CH(3))(2)C(6)H(3)O(2)PS(2)](2)S(n)(nBu)(2) (12) revealed that two diaryldithiophosphate ions are coordinated to tin atom in an anisobidentate fashion through the sulfur atoms of each dithiophosphate moiety leading to distorted skew-trapezoidal bipyramidal geometry. The antifungal activity depicts that these complexes are active against fungus Penicillium chrysogenium. PMID- 25551729 TI - Ageing of water or dissolution of glass: an electrical conductivity study. AB - Water and water based solutions are often stored in glass vessels. There are many studies in the literature dealing with solubility of glass-strictly speaking leaching of its components-in water. In present work the leaching process was investigated by measuring the electrical resistance/conductivity of water in a gas tight closed cell under nitrogen atmosphere during three weeks in the temperature range from 5 degrees C to 40 degrees C. From obtained results it was concluded, that the observed increase in electrical conductivity of water actually extremely diluted solution of ions released form glass - in the used time period, can be ascribed to the leaching of ions from the glass solely. PMID- 25551730 TI - Study of thermodynamic properties of solution of ampicillin sodium in methanol at T = 298.15 k. AB - Osmotic coefficients of the solution of Ampicillin sodium in methanol at T = 298.15 K were measured using the isopiestic technique and head space-gas chromatography. The experimental osmotic coefficients have been correlated using the ion interaction model of Pitzer, e-NRTL model of Chen, NRF and a fourth- order polynomial in terms of molality. In this work, reference solution is NaI CH(3)OH. The vapor pressures of the solutions and the solvent activities have been calculated from the osmotic coefficients. Reliability of the models in expression of the osmotic coefficients were compared on the basis of standard deviation of the fittings. The best fit of experimental osmotic coefficients data have been obtained by the Pitzer based ion interaction model. PMID- 25551731 TI - A novel derivatization procedure and chiral gas chromatographic method for enantiomeric purity screening of L-carnitine. AB - L-Carnitine is used extensively in functional foods and food supplements; consequently, the control of its enantiomeric purity is of paramount importance. A new derivatization procedure and chiral gas chromatographic method with flame ionization detection, using a cyclodextrin based stationary phase, enables prompt, simple, and inexpensive screening of the enantiomeric ratio of L- and D carnitine in samples with different matrices. Conversion of carnitine to beta acetoxy-gama-butyrolactone was optimized for maximum conversion (98% of the desired product lactone was formed and 2% of the side product gama crotonolactone) and minimum racemization (no changes at the chiral center were detected) and time consumption. As it is shown in this study, a fast gas chromatographic method, with total run time of 7 min, together with the new derivatization procedure enables an effective enantiomeric purity screening of L carnitine in real samples such as food supplements and L-carnitine raw ingredient. PMID- 25551732 TI - Study of the complexation of 1,3-diethyl 2-(azulen-1-ylmethylene)propanedioate with lanthanide cations. AB - This work is devoted to the electrochemical characterization of 1,3-diethyl 2 (azulen-1-ylmethylene)propanedioate by cyclic voltammetry and differential pulse voltammetry. The redox processes are established, analyzed and assessed to the particular functional groups at which they take place. The complexation behavior towards lanthanide metal ions (Sm(3+), Eu(3+), Yb(3+), Tb(3+)) was studied by electrochemical methods and UV-Vis spectroscopy. PMID- 25551733 TI - Amination of aryl halides with aqueous ammonia catalyzed by green recyclable poly(4-vinylpyridine)-supported copper iodide nanoparticles catalyst. AB - In this research efficient procedure for the amination of aryl halides with aqueous ammonia in the presence of poly(4-vinylpyridine)-supported copper iodide nanoparticles catalyst is reported. A wide range of aryl halides including aryl iodides and aryl bromides are converted into the corresponding aniline derivatives. The experimental procedure with poly(4-vinylpyridine)-supported copper iodide nanoparticles catalyst is quite straightforward and it is recycled up to 3 consecutive runs by simple filtration. PMID- 25551734 TI - Prediction of stability constants of lanthanide complexes with amino acids by model based on connectivity index 3chiv. AB - In order to model the stability of lanthanide complexes with amino acids, we used a set of 20 mono-complexes of La(3+), Ce(3+), Pr(3+), Nd(3+) and Sm(3+) with glycine, alanine, valine and leucine. The quadratic model based on the (3)chi(v) index gave r = 0.978, S.E. = 0.08. The predictive power of the model was tested by splitting the initial set of complexes on training (N = 15) and test set (N = 5). This enabled the logarithm of the stability constant, log K(1), of the leucine complex of neodymium(III) and all four complexes of samarium(III) to be predicted with S.E. = 0.11. PMID- 25551735 TI - Room-temperature negative differential resistance in graphene field effect transistors: experiments and theory. AB - In this paper we demonstrate experimentally and discuss the negative differential resistance (NDR) in dual-gated graphene field effect transistors (GFETs) at room temperature for various channel lengths, ranging from 200 nm to 5 MUm. The GFETs were fabricated using chemically vapor-deposited graphene with a top gate oxide down to 2.5 nm of equivalent oxide thickness (EOT). We originally explain and demonstrate with systematic simulations that the onset of NDR occurs in the unipolar region itself and that the main mechanism behind NDR is associated with the competition between the specific field dependence of carrier density and the drift velocity in GFET. Finally, we show experimentally that NDR behavior can still be obtained with devices of higher EOTs; however, this comes at the cost of requiring higher bias values and achieving lower NDR level. PMID- 25551736 TI - Peripheral mononuclear leukocyte DNA damage, plasma prolidase activity, and oxidative status in patients with benign prostatic hyperplasia. AB - OBJECTIVES: Prolidase plays a major role in collagen turnover, matrix remodeling, and cell growth. Benign prostatic hyperplasia (BPH) may be associated with an increased extracellular matrix deposition. Therefore, the present study was designed to investigate the plasma prolidase activity, oxidative status, and peripheral mononuclear leukocyte DNA damage in patients with BPH. PATIENTS AND METHODS: Twenty-six male patients with BPH and 24 healthy male subjects were included in this study. Blood samples were collected from antecubital vein after an overnight fasting period, and the plasma was separated. Plasma prolidase activity, total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) were determined. The peripheral lymphocyte oxidative DNA damage was determined using an alkaline single cell gel electrophoresis assay (comet assay). RESULTS: The plasma prolidase activity, TOS levels, OSI values, and peripheral mononuclear leukocyte DNA damage were significantly higher (P < 0.001), while the TAC levels were significantly lower (P < 0.001) in patients with BPH than controls. In BPH patients, the prolidase activity was significantly associated with TAC levels (r = -0.366, P < 0.05), TOS levels (r = 0.573, P < 0.001), and OSI (r = 0.618, P < 0.001) and peripheral mononuclear leukocyte DNA damage (r = 0.461, P < 0.001). CONCLUSIONS: Our results showed that BPH might be associated with an increased oxidative stress, and also an increased plasma prolidase activity. Increased prolidase activity might play an important role in the etiopathogenesis and/or progression of BPH. PMID- 25551737 TI - Current perspectives on psychological insulin resistance: primary care provider and patient views. AB - BACKGROUND: Psychological insulin resistance (PIR) refers to reluctance of providers to prescribe and patients to take insulin. Processes and tools have been developed to address PIR. The purpose of this qualitative study was to examine current understanding and opinions of insulin therapy of primary care providers (PCPs) and patients with type 2 diabetes (both naive to insulin and insulin users). SUBJECTS AND METHODS: Providers (n=23 PCPs) and patients (n=96) participated in 1:1 interviews and 12 racially/ethnically diverse focus groups, respectively, conducted by trained qualitative researchers using pilot-tested scripts. Participants examined insulin devices and needles while specific questions were asked about insulin therapy. Recorded sessions were transcribed and analyzed. RESULTS: Salient themes related to injection resistance, patient adherence, health system barriers, and education emerged during the sessions. Provider knowledge about insulin injection devices and approaches varied and was often limited, particularly regarding needle sizes, which influenced prescribing practices and patient education. Other barriers included limited time and personnel. However, PCPs placed priority on continuing education on devices, needles, insulin adjustment, educational approaches, and cost. Patient focus groups revealed a strong desire for knowledge on injection logistics, particularly by insulin users who felt that they had received inadequate education. Most patients had limited experience with tools like shorter needles but would consider injecting if presented. Those who had self-injection experience were more willing to accept insulin. Cost concerns and need for information were frequently reported. CONCLUSIONS: Findings reveal that programs and tools designed to address problems associated with PIR have yet to be fully realized. PMID- 25551738 TI - Correction to "synthesis of magnetic noble metal (nano)particles". PMID- 25551739 TI - The preoperative evaluation of the neurosurgical patient. PMID- 25551740 TI - Neurotrauma. PMID- 25551741 TI - Functional neurosurgery: anesthetic considerations. PMID- 25551742 TI - Intraoperative neuromonitoring. PMID- 25551743 TI - Anesthetic management of supratentorial tumors. PMID- 25551744 TI - Anesthesia for interventional neuroradiology. PMID- 25551746 TI - Neuroimaging for the nonradiologist. PMID- 25551745 TI - Neuromonitoring in the ICU. PMID- 25551747 TI - Surgical and endovascular management of cerebral aneurysms. PMID- 25551748 TI - Postoperative care of the surgical patient with neurological disease. PMID- 25551750 TI - Preface. International Anesthesiology Clinics. PMID- 25551751 TI - A single hot event stimulates adult performance but reduces egg survival in the oriental fruit moth, Grapholitha molesta. AB - Climate warming is expected to increase the exposure of insects to hot events (involving a few hours at extreme high temperatures). These events are unlikely to cause widespread mortality but may modify population dynamics via impacting life history traits such as adult fecundity and egg hatching. These effects and their potential impact on population predictions are still largely unknown. In this study, we simulated a single hot event (maximum of 38 degrees C lasting for 4 h) of a magnitude increasingly found under field conditions and examined its effect in the oriental fruit moth, Grapholitha molesta. This hot event had no impact on the survival of G. molesta adults, copulation periods or male longevity. However, the event increased female lifespan and the length of the oviposition period, leading to a potential increase in lifetime fecundity and suggesting hormesis. In contrast, exposure of males to this event markedly reduced the net reproductive value. Male heat treatment delayed the onset of oviposition in the females they mated with, as well as causing a decrease in the duration of oviposition period and lifetime fecundity. Both male and female stress also reduced egg hatch. Our findings of hormetic effects on female performance but concurrent detrimental effects on egg hatch suggest that hot events have unpredictable consequences on the population dynamics of this pest species with implications for likely effects associated with climate warming. PMID- 25551753 TI - Association of frequent use of food labels with weight loss behaviors among low income reproductive-age women. AB - OBJECTIVE: To examine whether frequent use of food labels is associated with weight loss behaviors among low-income reproductive-age women. METHODS: A self administered survey of 1245 women aged 16 to 40 years assessed the frequency of food label use and weight loss behaviors during the past 12 months. Multivariate logistic regression analyses were performed to examine the association between frequent use of food labels and weight loss behaviors after adjusting for confounders. RESULTS: Overall, 10.4% to 19.6% of women frequently used food labels to obtain information on different sections (ingredient list, nutrient claims, nutrition panel, serving size, or health claims), dietary components (calories, total fat, saturated fat, cholesterol, sodium/salt, fiber, sugar, vitamins, or minerals), and food products (desserts, snacks, frozen dinners, cereals, salad dressings, table spreads, or raw/processed meat). Women who used food labels frequently were more likely to engage in healthy weight loss behaviors compared to those who used them infrequently or did not use them at all. For example, the odds ratios (OR) and 95% confidence interval (CI) of "began to exercise/exercised more" for the 3 categories of food label use mentioned above were 2.24 and 1.65-3.04; 2.52 and 1.90-3.32; and 1.85 and 1.36-2.52, respectively. The odds of healthy weight loss behaviors were 2 to 4 times higher when food labels were used frequently to seek information on calories and nutrients such as total fat, saturated fat, or cholesterol. However, frequent food label users were also more likely to practice a few unhealthy weight loss behaviors, such as taking diet pills, medicines, herbs, or supplements without a prescription. CONCLUSIONS: Frequent use of food labels was associated with increased healthy weight loss behaviors among reproductive-age women, which can be incorporated into obesity preventive strategies with distinct awareness regarding unhealthy weight loss behaviors. PMID- 25551752 TI - Identifying glioblastoma gene networks based on hypergeometric test analysis. AB - Patient specific therapy is emerging as an important possibility for many cancer patients. However, to identify such therapies it is essential to determine the genomic and transcriptional alterations present in one tumor relative to control samples. This presents a challenge since use of a single sample precludes many standard statistical analysis techniques. We reasoned that one means of addressing this issue is by comparing transcriptional changes in one tumor with those observed in a large cohort of patients analyzed by The Cancer Genome Atlas (TCGA). To test this directly, we devised a bioinformatics pipeline to identify differentially expressed genes in tumors resected from patients suffering from the most common malignant adult brain tumor, glioblastoma (GBM). We performed RNA sequencing on tumors from individual GBM patients and filtered the results through the TCGA database in order to identify possible gene networks that are overrepresented in GBM samples relative to controls. Importantly, we demonstrate that hypergeometric-based analysis of gene pairs identifies gene networks that validate experimentally. These studies identify a putative workflow for uncovering differentially expressed patient specific genes and gene networks for GBM and other cancers. PMID- 25551754 TI - Mice lacking the SLAM family member CD84 display unaltered platelet function in hemostasis and thrombosis. AB - BACKGROUND: Platelets are anuclear cell fragments derived from bone marrow megakaryocytes that safeguard vascular integrity by forming thrombi at sites of vascular injury. Although the early events of thrombus formation--platelet adhesion and aggregation--have been intensively studied, less is known about the mechanisms and receptors that stabilize platelet-platelet interactions once a thrombus has formed. One receptor that has been implicated in this process is the signaling lymphocyte activation molecule (SLAM) family member CD84, which can undergo homophilic interactions and becomes phosphorylated upon platelet aggregation. OBJECTIVE: The role of CD84 in platelet physiology and thrombus formation was investigated in CD84-deficient mice. METHODS AND RESULTS: We generated CD84-deficient mice and analyzed their platelets in vitro and in vivo. Cd84(-/-) platelets exhibited normal activation and aggregation responses to classical platelet agonists. Furthermore, CD84 deficiency did not affect integrin mediated clot retraction and spreading of activated platelets on fibrinogen. Notably, also the formation of stable three-dimensional thrombi on collagen coated surfaces under flow ex vivo was unaltered in the blood of Cd84(-/-) mice. In vivo, Cd84(-/-) mice exhibited unaltered hemostatic function and arterial thrombus formation. CONCLUSION: These results show that CD84 is dispensable for thrombus formation and stabilization, indicating that its deficiency may be functionally compensated by other receptors or that it may be important for platelet functions different from platelet-platelet interactions. PMID- 25551755 TI - Compete to play: trade-off with social contact in long-tailed macaques (Macaca fascicularis). AB - Many animal species engage in various forms of solitary object play, but this activity seems to be of particular importance in primates. If playing objects constitute a valuable resource, and access to such objects is limited, a competitive context may arise. We inserted a unique toy within a mini-colony of long-tailed macaque (Macaca fascicularis) and compared their behaviors to sessions without playing object. An automatic color-based 3D video device was used to track the positions of each animal and the toy, and this data was categorized into 5 exclusive behaviors (resting, locomotion, foraging, social contact and object play). As expected, the delay to first access to the object reflected the hierarchy of the colony, indicating that a competition took place to own this unique resource of entertainment. In addition, we found that the amount of object play was not correlated with social or foraging behavior, suggesting independent motivational mechanisms. Conversely, object playing time was negatively correlated with idling time, thus indicating its relation to pastime activities. Interestingly, the amount of social contacts in the group was significantly reduced by the heightened competitive context, suggesting that competitors are more likely to be perceived as potential threat requiring caution, as shown in humans. Experimental manipulation of competitive contexts in primates reveals common mental processes involved in social judgment, and shows that access to valuable resources can be a sufficient cause for variations in group cohesion. PMID- 25551756 TI - The kidney transcriptome and proteome defined by transcriptomics and antibody based profiling. AB - To understand renal functions and disease, it is important to define the molecular constituents of the various compartments of the kidney. Here, we used comparative transcriptomic analysis of all major organs and tissues in the human body, in combination with kidney tissue micro array based immunohistochemistry, to generate a comprehensive description of the kidney-specific transcriptome and proteome. A special emphasis was placed on the identification of genes and proteins that were elevated in specific kidney subcompartments. Our analysis identified close to 400 genes that had elevated expression in the kidney, as compared to the other analysed tissues, and these were further subdivided, depending on expression levels, into tissue enriched, group enriched or tissue enhanced. Immunohistochemistry allowed us to identify proteins with distinct localisation to the glomeruli (n = 11), proximal tubules (n = 120), distal tubules (n = 9) or collecting ducts (n = 8). Among the identified kidney elevated transcripts, we found several proteins not previously characterised or identified as elevated in kidney. This description of the kidney specific transcriptome and proteome provides a resource for basic and clinical research to facilitate studies to understand kidney biology and disease. PMID- 25551757 TI - Distinct regions of the large extracellular domain of tetraspanin CD9 are involved in the control of human multinucleated giant cell formation. AB - Multinucleated giant cells, formed by the fusion of monocytes/macrophages, are features of chronic granulomatous inflammation associated with infections or the persistent presence of foreign material. The tetraspanins CD9 and CD81 regulate multinucleated giant cell formation: soluble recombinant proteins corresponding to the large extracellular domain (EC2) of human but not mouse CD9 can inhibit multinucleated giant cell formation, whereas human CD81 EC2 can antagonise this effect. Tetraspanin EC2 are all likely to have a conserved three helix sub-domain and a much less well-conserved or hypervariable sub-domain formed by short helices and interconnecting loops stabilised by two or more disulfide bridges. Using CD9/CD81 EC2 chimeras and point mutants we have mapped the specific regions of the CD9 EC2 involved in multinucleated giant cell formation. These were primarily located in two helices, one in each sub-domain. The cysteine residues involved in the formation of the disulfide bridges in CD9 EC2 were all essential for inhibitory activity but a conserved glycine residue in the tetraspanin defining 'CCG' motif was not. A tyrosine residue in one of the active regions that is not conserved between human and mouse CD9 EC2, predicted to be solvent exposed, was found to be only peripherally involved in this activity. We have defined two spatially-distinct sites on the CD9 EC2 that are required for inhibitory activity. Agents that target these sites could have therapeutic applications in diseases in which multinucleated giant cells play a pathogenic role. PMID- 25551758 TI - Can children discriminate sugar-sweetened from non-nutritively sweetened beverages and how do they like them? AB - BACKGROUND: Replacement of sugar-sweetened by non-nutritively sweetened beverages or water may reduce excess weight gain in children. However, it is unclear whether children like non-nutritively sweetened beverages as much as sugar sweetened beverages. We examined whether children could taste a difference between non-nutritively sweetened beverages and matching sugar-sweetened beverages, and which of the two types of beverage they liked best. METHODS: 89 children aged 5 to 12 tasted seven non-nutritively sweetened beverages and matching sugar-sweetened beverages, for a total of 14 beverages. We used Triangle tests to check their ability to discriminate between the matched versions, and a 5-point scale to measure how much the children liked each individual beverage. RESULTS: Overall, 24% of children appeared to be genuinely capable of distinguishing between non-nutritively sweetened and sugar-sweetened beverages. The mean +/- SD score for how much the children liked the non-nutritively sweetened beverages was 3.39 +/- 0.7 and that for the sugar-sweetened beverages 3.39 +/- 0.6 (P = 0.9) on a scale running from 1 (disgusting) to 5 (delicious). The children preferred some beverages to others irrespective of whether they were sugar-sweetened or non-nutritively sweetened (P = 0.000). Children who correctly identified which of three drinks contained the same sweetener and which one was different also showed no preference for either type. CONCLUSION: We found that about one in four children were able to discriminate between non-nutritively sweetened and sugar-sweetened beverages but children liked both varieties equally. Non-nutritively sweetened beverages may therefore be an acceptable alternative to sugar-sweetened beverages although water remains the healthiest beverage for children. PMID- 25551759 TI - Influential factors of insufficient physical activity among adolescents with asthma in Taiwan. AB - PURPOSE: Little research has been reported concerning insufficient physical activity in Taiwanese adolescents with asthma. The aims of this paper are to compare the amount of physical activity between asthmatic and non-asthmatic adolescents in Taiwan, as well as to investigate the influential factors associated with insufficient physical activity in asthmatic adolescents. METHODS: Self-reporting structured questionnaires (socio-economic status, scale of family support for physical activity, amount of physical activity) and peak expiratory flow were assessed from 286 adolescents with asthma and 588 non-asthmatic adolescents in a cross-sectional design. Insufficient amount of physical activity was based on less than 300 minutes per week of moderate and vigorous physical activity. RESULTS: Adolescents with asthma have a greater amount of physical activity and a higher level of family support than those who are non-asthmatic. In Taiwan, adolescents with asthma, girls relative to boys, obesity relative to average weight, and low family support relative to high family support were found to be associated with insufficient physical activity. CONCLUSION: Physical activity in adolescents with asthma is insufficient especially in girls, in asthmatics with obesity, and in those with low family support. We suggest that physical activity programs should be applied to Taiwan adolescents with asthma in order to match the criteria of 300 minutes per week of moderate and vigorous physical activity, especially for girls, the obese and those with a low level of family support. PMID- 25551760 TI - Comparison of drug release and pharmacokinetics after transarterial chemoembolization using diverse lipiodol emulsions and drug-eluting beads. AB - In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4?1 volume ratio Lipiodol emulsion (group A), 1?1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4?1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization. PMID- 25551761 TI - Mangrove habitat use by juvenile reef fish: meta-analysis reveals that tidal regime matters more than biogeographic region. AB - Identification of critical life-stage habitats is key to successful conservation efforts. Juveniles of some species show great flexibility in habitat use while other species rely heavily on a restricted number of juvenile habitats for protection and food. Considering the rapid degradation of coastal marine habitats worldwide, it is important to evaluate which species are more susceptible to loss of juvenile nursery habitats and how this differs across large biogeographic regions. Here we used a meta-analysis approach to investigate habitat use by juvenile reef fish species in tropical coastal ecosystems across the globe. Densities of juvenile fish species were compared among mangrove, seagrass and coral reef habitats. In the Caribbean, the majority of species showed significantly higher juvenile densities in mangroves as compared to seagrass beds and coral reefs, while for the Indo-Pacific region seagrass beds harbored the highest overall densities. Further analysis indicated that differences in tidal amplitude, irrespective of biogeographic region, appeared to be the major driver for this phenomenon. In addition, juvenile reef fish use of mangroves increased with increasing water salinity. In the Caribbean, species of specific families (e.g. Lutjanidae, Haemulidae) showed a higher reliance on mangroves or seagrass beds as juvenile habitats than other species, whereas in the Indo-Pacific family specific trends of juvenile habitat utilization were less apparent. The findings of this study highlight the importance of incorporating region-specific tidal inundation regimes into marine spatial conservation planning and ecosystem based management. Furthermore, the significant role of water salinity and tidal access as drivers of mangrove fish habitat use implies that changes in seawater level and rainfall due to climate change may have important effects on how juvenile reef fish use nearshore seascapes in the future. PMID- 25551762 TI - Multi-scale imaging and informatics pipeline for in situ pluripotent stem cell analysis. AB - Human pluripotent stem (hPS) cells are a potential source of cells for medical therapy and an ideal system to study fate decisions in early development. However, hPS cells cultured in vitro exhibit a high degree of heterogeneity, presenting an obstacle to clinical translation. hPS cells grow in spatially patterned colony structures, necessitating quantitative single-cell image analysis. We offer a tool for analyzing the spatial population context of hPS cells that integrates automated fluorescent microscopy with an analysis pipeline. It enables high-throughput detection of colonies at low resolution, with single cellular and sub-cellular analysis at high resolutions, generating seamless in situ maps of single-cellular data organized by colony. We demonstrate the tool's utility by analyzing inter- and intra-colony heterogeneity of hPS cell cycle regulation and pluripotency marker expression. We measured the heterogeneity within individual colonies by analyzing cell cycle as a function of distance. Cells loosely associated with the outside of the colony are more likely to be in G1, reflecting a less pluripotent state, while cells within the first pluripotent layer are more likely to be in G2, possibly reflecting a G2/M block. Our multi scale analysis tool groups colony regions into density classes, and cells belonging to those classes have distinct distributions of pluripotency markers and respond differently to DNA damage induction. Lastly, we demonstrate that our pipeline can robustly handle high-content, high-resolution single molecular mRNA FISH data by using novel image processing techniques. Overall, the imaging informatics pipeline presented offers a novel approach to the analysis of hPS cells that includes not only single cell features but also colony wide, and more generally, multi-scale spatial configuration. PMID- 25551763 TI - Evidence that the heterogeneity of a T4 population is the result of heritable traits. AB - Many bacteriophage populations display heterogeneity in their adsorption characteristics; a portion of the phage population remains free in solution throughout adsorption experiments (residual fraction). This residual fraction generally constitutes a minority of phages that exhibit significantly slower adsorption kinetics than the main phage stock (main fraction). While this phenomenon is likely the result of evolutionary driving forces, the present study demonstrates that the residual fraction is not always the result of phenotypic variations within a single genotype, as is generally thought. Experiments with phage T4 showed that two subgroups with distinct adsorption traits that were passed on to their progeny could be isolated from the original phage stock. Sequencing of genes involved in adsorption revealed two point mutations in gene 37 of residual fraction isolates, which resulted in modifications to the long tail-fiber, the organelle of attachment and host cell recognition. Adsorption studies consistently showed that T4 phage stocks amplified from residual fraction isolates had significantly lower adsorption efficiencies than those amplified from main fractions. The conducted experiments provide convincing evidence that the observed heterogeneity in T4 adsorption behavior is the result of conserved mutations to the phage genome and is not exclusively the result of phenotypic variations within the population. While it is believed high mutation rates exist to hasten phage adaptation, this study shows that this bet hedging strategy can also, in the short term, inadvertently handicap the phage's adsorption capabilities to a given host under normal infection conditions, resulting in the residual fraction observed in adsorption experiments. PMID- 25551764 TI - Systematic analysis of fly models with multiple drivers reveals different effects of ataxin-1 and huntingtin in neuron subtype-specific expression. AB - The fruit fly, Drosophila melanogaster, is a commonly used model organism for neurodegenerative diseases. Its major advantages include a short lifespan and its susceptibility to manipulation using sophisticated genetic techniques. Here, we report the systematic comparison of fly models of two polyglutamine (polyQ) diseases. We induced expression of the normal and mutant forms of full-length Ataxin-1 and Huntingtin exon 1 in cholinergic, dopaminergic, and motor neurons, and glial cells using cell type-specific drivers. We systematically analyzed their effects based on multiple phenotypes: eclosion rate, lifespan, motor performance, and circadian rhythms of spontaneous activity. This systematic assay system enabled us to quantitatively evaluate and compare the functional disabilities of different genotypes. The results suggest different effects of Ataxin-1 and Huntingtin on specific types of neural cells during development and in adulthood. In addition, we confirmed the therapeutic effects of LiCl and butyrate using representative models. These results support the usefulness of this assay system for screening candidate chemical compounds that modify the pathologies of polyQ diseases. PMID- 25551765 TI - Fomiroid A, a novel compound from the mushroom Fomitopsis nigra, inhibits NPC1L1 mediated cholesterol uptake via a mode of action distinct from that of ezetimibe. AB - Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe. PMID- 25551766 TI - Yokukansan, a kampo medicine, protects PC12 cells from glutamate-induced death by augmenting gene expression of cystine/glutamate antiporter system Xc-. AB - Effects of the kampo medicine yokukansan on gene expression of the cystine/glutamate antiporter system Xc-, which protects against glutamate-induced cytotoxicity, were examined in Pheochromocytoma cells (PC12 cells). Yokukansan inhibited glutamate-induced PC12 cell death. Similar cytoprotective effects were found in Uncaria hook. Experiments to clarify the active compounds revealed that geissoschizine methyl ether, hirsuteine, hirsutine, and procyanidin B1 in Uncaria hook, had cytoprotective effects. These components enhanced gene expressions of system Xc- subunits xCT and 4F2hc, and also ameliorated the glutamate-induced decrease in glutathione levels. These results suggest that the cytoprotective effect of yokukansan may be attributed to geissoschizine methyl ether, hirsuteine, hirsutine, and procyanidin B1 in Uncaria hook. PMID- 25551767 TI - Multiscale investigation of mealiness in apple: an atypical role for a pectin methylesterase during fruit maturation. AB - BACKGROUND: Apple fruit mealiness is one of the most important textural problems that results from an undesirable ripening process during storage. This phenotype is characterized by textural deterioration described as soft, grainy and dry fruit. Despite several studies, little is known about mealiness development and the associated molecular events. In this study, we integrated phenotypic, microscopic, transcriptomic and biochemical analyses to gain insights into the molecular basis of mealiness development. RESULTS: Instrumental texture characterization allowed the refinement of the definition of apple mealiness. In parallel, a new and simple quantitative test to assess this phenotype was developed. CONCLUSIONS: These data support the role of PME in cell wall remodelling during apple fruit development and ripening and suggest a local action of these enzymes. Mealiness may partially result from qualitative and spatial variations of pectin microarchitecture rather than quantitative pectin differences, and these changes may occur early in fruit development. The specific MdPME2 gene highlighted in this study could be a good early marker of texture unfavourable trait in apple. PMID- 25551768 TI - Co-circulation of dengue virus type 3 genotypes in Vientiane capital, Lao PDR. AB - During the 2012 epidemic of dengue in Vientiane capital, Lao PDR, a major serotype switch from dengue 1 to 3 was observed. A molecular epidemiology study demonstrated that dengue 3 remained the predominant serotype in 2013, but also revealed the co-circulation of two genotypes, supporting the hypothesis of multiple geographic origins of dengue 3 strains circulating in Vientiane capital. PMID- 25551769 TI - Unexpected high diversity of galling insects in the Amazonian upper canopy: the savanna out there. AB - A relatively large number of studies reassert the strong relationship between galling insect diversity and extreme hydric and thermal status in some habitats, and an overall pattern of a greater number of galling species in the understory of scleromorphic vegetation. We compared galling insect diversity in the forest canopy and its relationship with tree richness among upland terra firme, varzea, and igapo floodplains in Amazonia, Brazil. The soils of these forest types have highly different hydric and nutritional status. Overall, we examined the upper layer of 1,091 tree crowns. Galling species richness and abundance were higher in terra firme forests compared to varzea and igapo forests. GLM-ANCOVA models revealed that the number of tree species sampled in each forest type was determinant in the gall-forming insect diversity. The ratio between galling insect richness and number of tree species sampled (GIR/TSS ratio) was higher in the terra firme forest and in seasonally flooded igapo, while the varzea presented the lowest GIR/TSS ratio. In this study, we recorded unprecedented values of galling species diversity and abundance per sampling point. The GIR/TSS ratio from varzea was approximately 2.5 times higher than the highest value of this ratio ever reported in the literature. Based on this fact, we ascertained that varzea and igapo floodplain forests (with lower GIA and GIR), together with the speciose terra firme galling community emerge as the gall diversity apex landscape among all biogeographic regions already investigated. Contrary to expectation, our results also support the "harsh environment hypothesis", and unveil the Amazonian upper canopy as similar to Mediterranean vegetation habitats, hygrothermically stressed environments with leaf temperature at lethal limits and high levels of leaf sclerophylly. PMID- 25551771 TI - Detection of human urinary 5-hydroxymethylcytosine by stable isotope dilution HPLC-MS/MS analysis. AB - The sixth DNA base 5-hydroxymethylcytosine (5hmC) is the major oxidation product of the epigenetic modification 5-methylcytosine (5mC), mediating DNA demethylation in mammals. Reduced 5hmC levels are found to be linked with various tumors and neurological diseases; therefore, 5hmC is an emerging biomarker for disease diagnosis, treatment, and prognosis. Due to its advantages of being sterile, easily accessible in large volumes, and noninvasive to patients, urine is a favored diagnostic biofluid for 5hmC analysis. Here we developed an accurate, sensitive, and specific assay for quantification of 5mC, 5hmC, and other DNA demethylation intermediates in human urine. The urinary samples were desalted and enriched using off-line solid-phase extraction, followed by stable isotope dilution HPLC-MS/MS analysis for 5hmC and 5mC. By the use of ammonium bicarbonate (NH4HCO3) as an additive to the mobile phase, we improved the online coupled MS/MS detection of 5mC, 5hmC, and 5-formylcytosine (5fC) by 1.8-14.3 times. The recovery of the method is approximately 100% for 5hmC, and 70-90% for 5mC. The relative standard deviation (RSD) of the interday precision is about 2.9 10.6%, and that of the intraday precision is about 1.4-7.7%. By the analysis of 13 volunteers using the developed method, we for the first time demonstrate the presence of 5hmC in human urine. Unexpectedly, we observed that the level of 5hmC (22.6 +/- 13.7 nmol/L) is comparable to that of its precursor 5mC (52.4 +/- 50.2 nmol/L) in human urine. Since the abundance of 5hmC (as a rare DNA base) is 1 or 2 orders of magnitude lower than 5mC in genomic DNA, our finding probably implicates a much higher turnover of 5hmC than 5mC in mammalian genomic DNA and underscores the importance of DNA demethylation in daily life. PMID- 25551770 TI - Subgroup-elimination transcriptomics identifies signaling proteins that define subclasses of TRPV1-positive neurons and a novel paracrine circuit. AB - Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p<0.05, fold-change>1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination rather than enrichment of the subgroup of interest revealed proteins that define subclasses of TRPV1-positive neurons and suggests a novel paracrine circuit. PMID- 25551772 TI - Cell competition: winning out by losing notch. AB - Cell competition where 'loser' cells are eliminated by neighbors with higher fitness is a widespread phenomenon in development. However, a growing body of evidence argues cells with somatic mutations compete with their wild type counterparts in the earliest stages of cancer development. Recent studies have begun to shed light on the molecular and cellular mechanisms that alter the competitiveness of cells carrying somatic mutations in adult tissues. Cells with a 'winner' phenotype create clones which may expand into extensive fields of mutant cells within normal appearing epithelium, favoring the accumulation of further genetic alterations and the evolution of cancer. Here we focus on how mutations which disrupt the Notch signaling pathway confer a 'super competitor' status on cells in squamous epithelia and consider the broader implications for cancer evolution. PMID- 25551774 TI - Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion. AB - MYO1C, a single-headed class I myosin, associates with cholesterol-enriched lipid rafts and facilitates their recycling from intracellular compartments to the cell surface. Absence of functional MYO1C disturbs the cellular distribution of lipid rafts, causes the accumulation of cholesterol-enriched membranes in the perinuclear recycling compartment, and leads to enlargement of endolysosomal membranes. Several feeder pathways, including classical endocytosis but also the autophagy pathway, maintain the health of the cell by selective degradation of cargo through fusion with the lysosome. Here we show that loss of functional MYO1C leads to an increase in total cellular cholesterol and its disrupted subcellular distribution. We observe an accumulation of autophagic structures caused by a block in fusion with the lysosome and a defect in autophagic cargo degradation. Interestingly, the loss of MYO1C has no effect on degradation of endocytic cargo such as EGFR, illustrating that although the endolysosomal compartment is enlarged in size, it is functional, contains active hydrolases, and the correct pH. Our results highlight the importance of correct lipid composition in autophagosomes and lysosomes to enable them to fuse. Ablating MYO1C function causes abnormal cholesterol distribution, which has a major selective impact on the autophagy pathway. PMID- 25551775 TI - 2-Halogenoimidazolium salt catalyzed aza-Diels-Alder reaction through halogen bond formation. AB - 2-Halogenoimidazolium salts are found to catalyze aza-Diels-Alder reaction of aldimines with Danishefsky diene in an efficient manner. Comparative studies and titration experiments support the formation of halogen bonding between imines and catalysts. PMID- 25551773 TI - A comprehensive expression analysis of mucins in appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor. AB - BACKGROUND: Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma. METHODS: Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma. RESULTS: The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93-24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05 34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13-10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma. CONCLUSIONS: Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery. PMID- 25551777 TI - Protective effects of (1-(4-hydroxy-phenyl)-3-m-tolyl-propenone chalcone in indomethacin-induced gastric erosive damage in rats. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) can result in peptic ulcer disease (PUD) which is a common condition worldwide. The aim of this study was to evaluate the antiulcer properties of (1-(4-hydroxy-phenyl)-3-m-tolyl propenone) (HPTP) chalcone in rats using indomethacin as ulcerogenic agent. RESULTS: None of the rats showed symptoms of kidney and liver toxicity during the term of the study. Administration of HPTP had decreased the acidity, increased gastric wall mucus and flattening of gastric mucosa and reducing erosive gastric damage area. HPTP also showed dose dependent increase in SOD, GPx activity and PGE2 level and decrease MDA. H & E stain showed decreased infiltration of leucocytes with edema of submucosal layer. PAS staining showed intense uptake of magenta color of gastric wall mucus in rats fed with HPTP, and immunohistochemical staining of gastric mucosa revealed over-expression of HSP70 protein, down-expression of Bax protein and over expression of TGF-beta in rats administered with HPTP. CONCLUSION: This study has revealed that chalcone1-(4 hydroxy-phenyl)-3-m-tolyl-propenone can serve as a safe and effective antiulcer agent as it has been proved to increase pH and gastric wall mucus, increase GPx, SOD, PGE2, and decrease MDA level, ultimately, it has also contributes towards the over-expression of HSP protein andTGF-beta, and down-expression of Bax protein. PMID- 25551778 TI - Exploration of a possible relationship between examiner stringency and personality factors in clinical assessments: a pilot study. AB - BACKGROUND: The reliability of clinical examinations is known to vary considerably. Inter-examiner variability is a key source of this variability. Some examiners consistently give lower scores to some candidates compared to other examiners and vice versa - the 'hawk- dove' effect. Stable examiner characteristics, such as personality factors, may influence examiner stringency. We investigated whether examiner stringency is related to personality factors. METHODS: We recruited 12 examiners to view and score a video-recorded five station OSCE of six Year 1 undergraduate medical students at our institution. In addition examiners completed a validated personality questionnaire. Examiners' markings were tested for statistically significant differences using non parametric one way analysis of variance. The relationship between examiners' markings and examiner personality factors was investigated using Spearman correlation coefficient. RESULTS: At each station there was a statistically significant difference between examiners markings, confirming the presence of inter-examiner variability. Correlation analysis showed no association between stringency and any of the five major personality factors. When we omitted an outlier examiner we found a statistically significant negative correlation between examiner stringency and openness to experience with a correlation coefficients (rho) of - 0.66 (p = 0.03). Conversely there was a moderate positive correlation between examiner stringency and neuroticism with a correlation coefficient (rho) of 0.73 (p = 0.01). CONCLUSIONS: In this study we did not find any relationship between examiner stringency and examiner personality factors. However, following the elimination of an outlier examiner from the analysis, we found a significant relationship between examiner stringency and two of the big five personality factors (neuroticism and openness to experience). The significance of this outlier is not known. As this was a small pilot study we recommend further studies in this field to investigate if there is a relationship between examiner stringency in clinical assessments and personality factors. PMID- 25551776 TI - Topical antibiotics as a major contextual hazard toward bacteremia within selective digestive decontamination studies: a meta-analysis. AB - BACKGROUND: Among methods for preventing pneumonia and possibly also bacteremia in intensive care unit (ICU) patients, Selective Digestive Decontamination (SDD) appears most effective within randomized concurrent controlled trials (RCCT's) although more recent trials have been cluster randomized. However, of the SDD components, whether protocolized parenteral antibiotic prophylaxis (PPAP) is required, and whether the topical antibiotic actually presents a contextual hazard, remain unresolved. The objective here is to compare the bacteremia rates and patterns of isolates in SDD-RCCT's versus the broader evidence base. METHODS: Bacteremia incidence proportion data were extracted from component (control and intervention) groups decanted from studies investigating antibiotic (SDD) or non antibiotic methods of VAP prevention and summarized using random effects meta analysis of study and group level data. A reference category of groups derived from purely observational studies without any prevention method under study provided a benchmark incidence. RESULTS: Within SDD RCCTs, the mean bacteremia incidence among concurrent component groups not exposed to PPAP (27 control; 17.1%; 13.1-22.1% and 12 intervention groups; 16.2%; 9.1-27.3%) is double that of the benchmark bacteremia incidence derived from 39 benchmark groups (8.3; 6.8 10.2%) and also 20 control groups from studies of non-antibiotic methods (7.1%; 4.8 - 10.5). There is a selective increase in coagulase negative staphylococci (CNS) but not in Pseudomonas aeruginosa among bacteremia isolates within control groups of SDD-RCCT's versus benchmark groups with data available. CONCLUSIONS: The topical antibiotic component of SDD presents a major contextual hazard toward bacteremia against which the PPAP component partially mitigates. PMID- 25551779 TI - Chemical profiling (HPLC-NMR & HPLC-MS), isolation, and identification of bioactive meroditerpenoids from the southern Australian marine brown alga Sargassum paradoxum. AB - A phytochemical investigation of a southern Australian marine brown alga, Sargassum paradoxum, resulted in the isolation and identification of four new (5, 9, 10, and 15) and nine previously reported (1, 2, 6-8, and 11-14) bioactive meroditerpenoids. HPLC-NMR and HPLC-MS were central to the identification of a new unstable compound, sargahydroquinal (9), and pivotal in the deconvolution of eight (1, 2, 5-7, and 10-12) other meroditerpenoids. In particular, the complete characterization and identification of the two main constituents (1 and 2) in the crude dichloromethane extract was achieved using stop-flow HPLC-NMR and HPLC-MS. This study resulted in the first acquisition of gHMBCAD NMR spectra in the stop flow HPLC-NMR mode for a system solely equipped with a 60 MUL HPLC-NMR flow cell without the use of a cold probe, microcoil, or any pre-concentration. PMID- 25551780 TI - New ikarugamycin derivatives with antifungal and antibacterial properties from Streptomyces zhaozhouensis. AB - A bioassay guided fractionation of the ethyl acetate extract from culture broths of the strain Streptomyces zhaozhouensis CA-185989 led to the isolation of three new polycyclic tetramic acid macrolactams (1-3) and four known compounds. All the new compounds were structurally related to the known Streptomyces metabolite ikarugamycin (4). Their structural elucidation was accomplished using a combination of electrospray-time of flight mass spectrometry (ESI-TOF MS) and 1D and 2D NMR analyses. Compounds 1-3 showed antifungal activity against Aspergillus fumigatus, Candida albicans and antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA). PMID- 25551782 TI - Preliminary Results of Multiple Epiphyseal Drilling and Autologous Bone Marrow Implantation for Osteonecrosis of the Femoral Head Secondary to Sickle Cell Disease in Children. AB - BACKGROUND: Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) during childhood. The natural history of ONFH in SCD is poor with progression to femoral head collapse and deformity that ultimately may lead to hip osteoarthritis. Multiple epiphyseal drilling with autologous bone marrow implantation may enhance the mechanism of osteogenic repair. The purpose of this study was to describe early clinical and radiographic outcomes in pediatric patients with ONFH secondary to SCD after multiple epiphyseal drilling and AMBI. METHODS: Nine boys and 2 girls (14 hips) with a mean age of 12.7 years (range, 9.7-18 y) at the time of surgery were evaluated. All patients were followed for at least 1 year after surgery and the mean duration of follow-up was 25 months (range, 12-47 mo). Clinical outcome was assessed by the pain domain from the Children's Hospital Oakland Hip Evaluation Scale and by hip range of motion. The extent of femoral head involvement was assessed by measuring the arc of necrosis and the amount of collapse on anteroposterior and frog lateral radiographs. The University of Pennsylvania system was used to assess the osteonecrosis stage. Wilcoxon signed-rank tests were used to compare radiographic and clinical variables. RESULTS: Compared with preoperative measures, multiple epiphyseal drilling with AMBI resulted in significant improvement in pain (P=0.0010), internal hip rotation (P=0.0005), external hip rotation (P=0.0010), and flexion (P=0.0015). The amount of lateral collapse (P=0.4609), anterior collapse (P=0.4258), and the arc of necrosis (P=0.2251) were not significant after surgery. The majority of the hips had either improvement in the Steinberg stage of disease (4/14 hips) or no further progression (7/14 hips) at the latest follow-up. There were no surgical complications. CONCLUSIONS: Multiple epiphyseal drilling with autologous bone marrow cell implantation allows for short-term clinical improvement and limits radiographic progression of ONFH associated with SCD in children with minimal morbidity. PMID- 25551781 TI - Does the use of chitosan contribute to oxalate kidney stone formation? AB - Chitosan is widely used in the biomedical field due its chemical and pharmacological properties. However, intake of chitosan results in renal tissue accumulation of chitosan and promotes an increase in calcium excretion. On the other hand, the effect of chitosan on the formation of calcium oxalate crystals (CaOx) has not been described. In this work, we evaluated the antioxidant capacity of chitosan and its interference in the formation of CaOx crystals in vitro. Here, the chitosan obtained commercially had its identity confirmed by nuclear magnetic resonance and infrared spectroscopy. In several tests, this chitosan showed low or no antioxidant activity. However, it also showed excellent copper-chelating activity. In vitro, chitosan acted as an inducer mainly of monohydrate CaOx crystal formation, which is more prevalent in patients with urolithiasis. We also observed that chitosan modifies the morphology and size of these crystals, as well as changes the surface charge of the crystals, making them even more positive, which can facilitate the interaction of these crystals with renal cells. Chitosan greatly influences the formation of crystals in vitro, and in vivo analyses should be conducted to assess the risk of using chitosan. PMID- 25551783 TI - Hemiepiphysiodesis Implants for Late-onset Tibia Vara: A Comparison of Cost, Surgical Success, and Implant Failure. AB - BACKGROUND: The purpose of this study was to compare hemiepiphysiodesis implants for late-onset tibia vara and to evaluate patient characteristics that may predict surgical failure. METHODS: This is a retrospective review of late-onset tibia vara patients treated with temporary hemiepiphysiodesis from 1998 to 2012. Mechanical axis deviation (MAD), mechanical axis angle, mechanical lateral distal femoral angle, and medial proximal tibial angle were measured on standing bone length radiographs. Surgical failure was defined as residual deformity requiring osteotomy, revision surgery, or MAD exceeding 40 mm at the time of final follow up. Implant failure was recorded. Costs included implants and disposables required for construct placement. Staple constructs included 2 or 3 staples. Plate constructs included the plate, screws, guide wires, and drill bits. RESULTS: A total of 25 patients with 38 temporary lateral proximal tibia hemiepiphysiodeses met the inclusion criteria. The average body mass index (BMI) was 39.1 kg/m with an average follow-up of 3.0 years (minimum 1 y). Surgical failure occurred in 57.9% of patients. Greater BMI (P=0.05) and more severe deformity (MAD, mechanical axis angle, and medial proximal tibial angle; P<0.01) predicted higher rates of surgical failure. Younger age predicted higher rates of implant failure (P<0.01). There were no differences in surgical or implant failure between staple and plate systems. Hospital costs of plate constructs ($781 to $1244) were 1.5 to 3.5 times greater than the staple constructs ($332 to $498). CONCLUSIONS: Greater BMI, more severe deformity, and younger age were predictive of surgical or implant failure. There was no difference in success between implant types, whereas the cost of plate constructs was 1.5 to 3.5 times greater than staples. The rate of surgical failure was high (58%) and consideration should be given to reserving hemiepiphysiodesis for patients with lower BMI and less severe deformity. In our population, if hemiepiphysiodesis was not offered to patients with BMI>35 or MAD>80 mm varus, the surgical failure rate would diminish to 28%. The failure rate outside these parameters would be 88%. LEVEL OF EVIDENCE: Level II-Prognostic. PMID- 25551784 TI - Helping Families Make Difficult Choices: Creation and Implementation of a Decision Aid for Neuromuscular Scoliosis Surgery. AB - BACKGROUND: Decision aids serve to prepare families for a meaningful discussion with their physician during the shared decision-making (SDM) process. Although SDM processes have been used primarily in adult health care settings, we sought to develop a decision aid for use in pediatrics. The treatment of neuromuscular scoliosis was selected due to the complexity of decision making when surgery is considered. Our objective was to determine whether this tool would improve families' knowledge and satisfaction while decreasing decisional conflict. METHODS: The decision aid was created using a multistep process to provide unbiased evidence-based information about the risks and benefits of the treatment options for neuromuscular scoliosis. The initial draft was written by an orthopaedic surgeon and then formatted by a multidisciplinary group to meet international decision aid standards. The document underwent local, national, and international peer review before prospective implementation by 4 orthopaedic surgeons at a single institution. The decision aid was evaluated and revised for further use. RESULTS: Eleven children, mean age 12 years (range, 8 to 17 y), were included in the study. Nine of the 11 families opted for surgery. The mean scores on the knowledge test increased from 3.0 (range, 2 to 5) to 4.0 (range, 3 to 5) of a possible 5 points (P=0.067). The mean item score on the SDM satisfaction scale was 3.8 (range, 3.5 to 4.0). The mean score on the SURE test for decisional conflict was 3.7 (range, 3 to 4) of a maximum score of 4. The mean total score on the clinician SDM satisfaction scale was 22.5 (range, 17 to 25). CONCLUSIONS: The decision aid created for this complex decision resulted in improvements in knowledge gain, satisfaction, and decisional conflict while gaining acceptance of the physicians who utilized it. Consideration should be given to developing additional decision aids within professional societies to maximize efficiency and consensus. PMID- 25551785 TI - Psychopathy, depression, and anxiety as predictors of suicidal ideation in offenders. AB - Compared to nonoffenders, offenders are at increased risk for suicidal ideation and psychopathy. However, literature currently lacks sufficient understanding of moderating pathways linking psychopathy to suicidal ideation among offenders. This study investigated anxiety and depressive symptoms as potential moderators using a sample of 162 male offenders in the New Jersey correctional system. Results supported a significant positive correlation between secondary psychopathy and suicidal ideation. In addition, depression and physiological anxiety moderated the association between secondary psychopathy and suicidal ideation. Present findings may assist in determining relevant suicide risk factors (i.e., depression, physiological anxiety, secondary psychopathy) to assess for in offenders. PMID- 25551788 TI - Controlled fabrication of multicompartmental polymeric microparticles by sequential micromolding via surface-tension-induced droplet formation. AB - Polymeric multicompartmental microparticles have significant potential in many applications due to the capability to hold various functions in discrete domains within a single particle. Despite recent progress in microfluidic techniques, simple and scalable fabrication methods for multicompartmental particles remain challenging. This study reports a simple sequential micromolding method to produce monodisperse multicompartmental particles with precisely controllable size, shape, and compartmentalization. Specifically, our fabrication procedure involves sequential formation of primary and secondary compartments in micromolds via surface-tension-induced droplet formation coupled with simple photopolymerization. Results show that monodisperse bicompartmental particles with precisely controllable size, shape, and chemistry can be readily fabricated without sophisticated control or equipment. This technique is then extended to produce multicompartmental particles with controllable number of compartments and their size ratios through simple design of mold geometry. Also, core-shell particles with controlled number of cores for primary compartments can be readily produced by simple tuning of wettability. Finally, we demonstrate that the as prepared multicompartmental particles can exhibit controlled release of multiple payloads based on design of particle compositions. Combined, these results illustrate a simple, robust, and scalable fabrication of highly monodisperse and complex multicompartmental particles in a controlled manner based on sequential micromolding. PMID- 25551786 TI - A hyper-dynamic nature of bivalent promoter states underlies coordinated developmental gene expression modules. AB - BACKGROUND: Chromatin remodeling is crucial for proper programing of developmental gene expression. Recent work provides a dynamic view of post translational histone modifications during differentiation; however there is little insight on the evolution of combinatorial genome-wide patterns of chromatin marks, excluding an essential aspect of developmental gene regulation. RESULTS: We report here a 15-chromatin state Hidden Markov Model which describes changes in chromatin signatures in relation to transcription profiles during differentiation of human pre-adipocytes into adipocytes. We identify nineteen modules of gene expression reflecting multiple waves of transcriptional up- and down-regulation which characterize adipogenic differentiation. From our model, we developed chromatin state matrices fitting each of these transcription modules to show how the complexity and dynamic nature of chromatin signatures relate to expression patterns. Spatial relationships between chromatin states underlie a high-order chromatin organization in differentiating adipocytes. We show the importance of gene expression level in generating diversity in chromatin signatures, and show that the hyper-dynamic nature of H3K4me2/H3K27me3-marked 'bivalent' promoter states underlies many of the gene expression patterns associated with adipogenic differentiation. CONCLUSIONS: Our results reveal the highly dynamic nature of bivalent promoter states within the adipogenic lineage. The data constitute a valuable resource enabling the assessment of possibilities to alter the adipogenic program. PMID- 25551787 TI - Optimization of the recombinant production and purification of a self-assembling peptide in Escherichia coli. AB - BACKGROUND: Amphiphilic peptides are important building blocks to generate nanostructured biomaterials for drug delivery and tissue engineering applications. We have shown that the self-assembling peptide SA2 (Ac-AAVVLLLWEE) can be recombinantly produced in E. coli when fused to the small ubiquitin-like modifier (SUMO) protein. Although this system yielded peptides of high purity with no residual amino acids after cleavage of the SUMO fusion protein, the yield after purification was generally low (~1 mg/L bacterial culture) as compared to other peptides and proteins produced with the same method and under the same conditions. RESULTS: The aim of this study is to understand the underlying mechanisms causing the low yield of this recombinant peptide in E. coli and to optimize both production and purification of recombinant SA2 peptides. It was demonstrated that by simply changing the medium to a well-balanced auto-induction medium the yield of recombinant production was augmented (~4 fold). Moreover, it was demonstrated that self-assembly of SUMO-SA2 fusion proteins caused the low peptide yields after purification. By replacing the second IMAC purification step with a selective precipitation step, peptide yields could be increased approx. 3 fold. With these optimizations in place the overall yield of purified SA2 peptide increased with 12-fold. CONCLUSION: Premature self-assembly of the SUMO-SA2 fusion construct interfered with proper purification of the SA2 peptide, resulting in low yields of purified peptide and this could be prevented by changing the mode of purification. These findings are important when setting up purification schemes for other self-assembling peptides with the use of a SUMO fusion construct. PMID- 25551789 TI - Sustained improvements in students' mental health literacy with use of a mental health curriculum in Canadian schools. AB - BACKGROUND: Enhancement of mental health literacy for youth is a focus of increasing interest for mental health professionals and educators alike. Schools are an ideal site for addressing mental health literacy in young people. Currently, there is limited evidence regarding the impact of curriculum-based interventions within high school settings. We examined the effect of a high school mental health curriculum (The Guide) in enhancing mental health literacy in Canadian schools. METHODS: We conducted a secondary analysis on surveys of students who participated in a classroom mental health course taught by their usual teachers. Evaluation of students' mental health literacy (knowledge/attitudes) was completed before and after classroom implementation and at 2-month follow-up. We used paired-samples t-tests and Cohen's d value to determine the significance and impact of change. RESULTS: There were 265 students who completed all surveys. Students' knowledge significantly improved between pre and post-tests (p < 0.001; d = 0.90) and was maintained at follow-up (p < 0.001; d = 0.73). Similarly, attitude significantly improved between pre- and post-tests (p < 0.001; d = 0.25) and was significantly higher at follow-up than base-line (p < 0.007; d = 0.18) CONCLUSIONS: The Guide, applied by usual teachers in usual classroom curriculum, may help improve student knowledge and attitudes regarding mental health. This is the first study to demonstrate the positive impact of a curriculum-based mental health literacy program in a Canadian high school population. PMID- 25551790 TI - Variations in DEPDC5 gene and its association with chronic hepatitis C virus infection in Saudi Arabia. AB - BACKGROUND: Variations at DEPDC5 gene have been recently reported as genetic markers associated with hepatocellular carcinoma (HCC) progression in chronic HCV infected patients. This study was conducted to assess the association of DEPDC5 variants with advanced liver cirrhosis and HCC development among chronic HCV infected patients in Saudi Arabian population. METHODS: Six-hundred and one HCV infected patients were genotyped for DEPDC5 polymorphisms (rs1012068 and rs5998152), in comparison with 592 non-infected healthy control subjects. The allelic frequency and genotype distribution of both DEPDC5 polymorphisms were determined followed by haplotype frequency estimation and multiple logistic regression analysis. RESULTS: The frequency of the risk alleles of both rs1012068 and rs5998152 was shown to be more in healthy control subjects than in patients (p = 0.0001, OR = 0.704, CI = 0.591-0.839; p = 0.002, OR = 0.761, CI = 0. 0.639 0.907, respectively). Also, our results revealed that GT for SNP rs1012068 (OR =1.715; 95% CI 1.132-2.597; p = 0.0104) and CT for SNP rs5998152 (OR = 1.932; 95% CI 1.276-2.925; p = 0.0017) showed significant association with development of cirrhosis compared with the GG and CC genotypes, respectively. The data also revealed that subjects with the T allele of both SNPs appeared to have a lower susceptibility to HCV-related cirrhosis/HCC than those with the G allele of rs1012068 (p = 0.038, OR = 1.353, 95 % CI 1.017-1.800) and C allele of rs5998152 (p = 0.043, OR = 1.342, 95 % CI 1.010-1.784). Haplotype analysis showed that a combination of T-T alleles of rs1012068 and rs5998152 was significantly associated with liver cirrhosis (frequency = 71.3% and p = 0.027) and with cirrhosis/HCC (frequency = 71.4% and P = 0.045). Also, multiple logistic regression analysis showed that rs5998152 (OR = 2.844, 95% CI 1.333-6.069 and p = 0.007), rs1012068 (OR = 2.793, 95% CI 1.316-5.928 and p = 0.010), age (OR = 1.029, 95% CI 1.001-1.057 and p = 0.041) and HCV genotypes (OR = 0.247, 95% CI 0.097-0.630 and p = 0.003) were independently associated with chronicity of HCV infection. CONCLUSION: Genetic variations in DEPDC5 gene region may influence HCV associated liver cirrhosis and/or HCC development. PMID- 25551791 TI - Evaluating the effect of a web-based quality improvement system with feedback and outreach visits on guideline concordance in the field of cardiac rehabilitation: rationale and study protocol. AB - BACKGROUND: Implementation of clinical practice guidelines into daily care is hampered by a variety of barriers related to professional knowledge and collaboration in teams and organizations. To improve guideline concordance by changing the clinical decision-making behavior of professionals, computerized decision support (CDS) has been shown to be one of the most effective instruments. However, to address barriers at the organizational level, additional interventions are needed. Continuous monitoring and systematic improvement of quality are increasingly used to achieve change at this level in complex health care systems. The study aims to assess the effectiveness of a web-based quality improvement (QI) system with indicator-based performance feedback and educational outreach visits to overcome organizational barriers for guideline concordance in multidisciplinary teams in the field of cardiac rehabilitation (CR). METHODS: A multicenter cluster-randomized trial with a balanced incomplete block design will be conducted in 18 Dutch CR clinics using an electronic patient record with CDS at the point of care. The intervention consists of (i) periodic performance feedback on quality indicators for CR and (ii) educational outreach visits to support local multidisciplinary QI teams focussing on systematically improving the care they provide. The intervention is supported by a web-based system which provides an overview of the feedback and facilitates development and monitoring of local QI plans. The primary outcome will be concordance to national CR guidelines with respect to the CR needs assessment and therapy indication procedure. Secondary outcomes are changes in performance of CR clinics as measured by structure, process and outcome indicators, and changes in practice variation on these indicators. We will also conduct a qualitative process evaluation (concept-mapping methodology) to assess experiences from participating CR clinics and to gain insight into factors which influence the implementation of the intervention. DISCUSSION: To our knowledge, this will be the first study to evaluate the effect of providing performance feedback with a web-based system that incorporates underlying QI concepts. The results may contribute to improving CR in the Netherlands, increasing knowledge on facilitators of guideline implementation in multidisciplinary health care teams and identifying success factors of multifaceted feedback interventions. TRIAL REGISTRATION: NTR3251. PMID- 25551792 TI - Assessment of left ventricular function by two-dimensional speckle-tracking echocardiography in small breed dogs with hyperadrenocorticism. AB - BACKGROUND: Hyperadrenocorticism (HAC) is associated with an increased prevalence of hypertension. This study investigated the left ventricular function using two dimensional speckle-tracking echocardiography (2D-STE) in small breed dogs affected with spontaneous HAC. Age-matched healthy controls (n = 9), dogs with pituitary-dependent hyperadrenocorticism (PDH, n = 10), and dogs with adrenal dependent hyperadrenocorticism (ADH, n = 9) were included in this study. Conventional echocardiography, global longitudinal and circumferential strain, and strain rate were assessed. RESULTS: On group-wise comparison, left ventricular free wall (LVFWd) and interventricular septal thickness in diastole (IVSd) were thickest in the ADH group, followed by the PDH and controls (P = 0.014 and P = 0.001, respectively). Neither LVFWd nor IVSd was correlated with systemic blood pressure (P = 0.238 and P = 0.113, respectively). The values of all variables derived from the global strain and strain rate in longitudinal and circumferential directions followed the same pattern: highest in the controls, followed by PDH and then ADH (all P < 0.05, respectively). On multiple regression analyses, global longitudinal strain, global longitudinal strain rate in systole and early diastole, and global circumferential strain all decreased linearly with increased IVSd (all P < 0.05). CONCLUSIONS: Left ventricular hypertrophy (LVH) was more prevalent in the HAC group compared to the control group. Association between hypertension and development of LVH was not identified. Decreased global longitudinal and circumferential strains were associated with increased IVSd. 2D STE revealed significant decreases in systolic functions that were undetected using conventional echocardiography in the ADH and PDH groups. PMID- 25551793 TI - MicroRNA-301a promotes migration and invasion by targeting TGFBR2 in human colorectal cancer. AB - BACKGROUND: MicroRNAs (miRNAs) have been reported to play crucial roles in regulating a variety of genes pivotal for tumor metastasis. MicroRNA-301a (miR 301a) is overexpressed and displays oncogenic activity in many cancers. However, little is known about the potential roles of miR-301a in colorectal cancer (CRC). METHODS: Taqman probe stem-loop real-time PCR was used to quantitatively measure the expression level of miR-301a in 48 cases of CRC tissues and the matched adjacent non-tumor mucosa as well as in CRC cell lines. miR-301a mimics and inhibitors were used to up-regulate and down-regulate miR-301a in CRC cells, respectively; lentivirus was used to construct miR-301a stably up- and down regulated CRC cell lines. Metastasis ability was evaluated by transwell and wound healing assays while invasion was measured by transwell coated with matrix gel in vitro; in vivo metastasis was performed on nude mice model. The target of miR 301a was predicted by TargetScan software and validated by qRT-PCR, immunohistochemistry, western blot and luciferase reporter gene assay. RESULTS: The expression of miR-301a was significantly higher in lymph node metastasis positive CRC samples compared with negative ones. Downregulation of miR-301a significantly inhibited the migration and invasion both in vitro and in vivo while forced up-regulation of miR-301a promoted migration and invasion. TGFBR2 was identified to be the downstream target of miR-301a. Knockdown of TGFBR2 in cells treated by miR-301a inhibitor elevated the previously abrogated migration and invasion. CONCLUSIONS: Our data indicated that miR-301a correlated with the metastatic and invasive ability in human colorectal cancers and miR-301a exerted its role as oncogene by targeting TGFBR2. PMID- 25551796 TI - Editorial. PMID- 25551795 TI - Facilitating home-based treatment of hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients' quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient's primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility. PMID- 25551794 TI - Heterogeneous induction of microglia M2a phenotype by central administration of interleukin-4. AB - BACKGROUND: Acquisition of the M1 or M2 phenotypes by microglia has been shown to occur during the development of pathological conditions, with M1 activation being widely involved in neurotoxicity in relation with the anatomical localization and the reactivity of subtypes of microglia cells. On the contrary, little is known on the ability of microglia to undergo M2 polarization by interleukin-4 (IL4), the typical M2a polarization signal for peripheral macrophages. METHODS: Recombinant mouse IL4 was injected in the third cerebral ventricle of mice to induce brain alternative polarization. The mRNA levels of Fizz1, Arg1, and Ym1 genes, known to be up-regulated by IL4 in peripheral macrophages, together with additional polarization markers, were evaluated in the striatum and frontal cortex at different time intervals after central administration of IL4; in parallel, M2a protein expression was evaluated in tissue extracts and at the cellular level. RESULTS: Our results show that the potency and temporal profile of IL4-mediated M2a gene induction vary depending on the gene analyzed and according to the specific brain area analyzed, with the striatum showing a reduced M2a response compared with the frontal cortex, as further substantiated by assays of polarization protein levels. Of notice, Fizz1 mRNA induction reached 100-fold level, underscoring the potency of this specific IL4 signaling pathway in the brain. In addition, immunochemistry assays demonstrated the localization of the M2 response specifically to microglia cells and, more interestingly, the existence of a subpopulation of microglia cells amenable to undergoing M2a polarization in the healthy mouse brain. CONCLUSIONS: These results show that the responsiveness of brain macrophages to centrally administered IL4 may vary depending on the gene and brain area analyzed, and that M2a polarization can be ascribed to a subpopulation of IL4-responsive microglia cells. The biochemical pathways that enable microglia to undergo M2a activation represent key aspects for understanding the physiopathology of neuroinflammation and for developing novel therapeutic and diagnostic agents. PMID- 25551797 TI - The effect of bioactive compounds in tea on lipid metabolism and obesity through regulation of peroxisome proliferator-activated receptors. AB - PURPOSE OF REVIEW: The hypolipidemic and antiobesogenic effects of tea intake have been associated with bioactive compounds that regulate peroxisome proliferator-activated receptors (PPARs). This review describes the recent research on two of these compounds, (-)-epigallocatechin gallate (EGCG) and linalool. RECENT FINDINGS: Catechins (specifically EGCG) are key bioactive compounds found in tea, and a recent study has shown that linalool may also be an active tea compound. These compounds act on lipid metabolism by regulating PPAR subtypes. EGCG inhibits the key adipogenic transcription factor PPARgamma while activating PPARalpha, whereas linalool is a PPARalpha agonist activating hepatic fatty acid uptake and subsequent oxidation to reduce plasma triglyceride levels. SUMMARY: The collective activities of EGCG and linalool in tea may exert hypolipidemic and antiobesogenic effects by regulating PPARs. The research summarized in this review expands our understanding of the biological and physiological mechanisms of the bioactive compounds found in tea. PMID- 25551798 TI - Flavan-3-ols, theobromine, and the effects of cocoa and chocolate on cardiometabolic risk factors. AB - PURPOSE OF REVIEW: Although there is growing interest surrounding the potential health benefits of cocoa and chocolate, the relative contribution of bioactive constituents for these effects remains unclear. This review summarizes the recent research on the cardiometabolic effects of cocoa and chocolate with a focus on two key constituents: flavan-3-ols and theobromine. RECENT FINDINGS: Recent meta analyses suggest beneficial cardiometabolic effects of chocolate following short term intake, including improvements in flow-mediated dilatation, blood pressure, lipoprotein levels and biomarkers of insulin resistance. Flavan-3-ols may play a role, but it is currently unclear which specific compounds or metabolites are key. Theobromine has also been shown to improve lipoprotein levels in trials, although these findings need verification at habitual intake levels. Longer term dose-response randomized controlled trials are required to determine the sustainability of the short-term effects and the optimal dose. Quantifying levels of bioactives in intervention products and their metabolites in biological samples will facilitate the assessment of their relative impact and the underlying mechanisms of action. SUMMARY: Promising data support the beneficial cardiometabolic effects of cocoa and chocolate intake, with significant interest in the flavan-3-ol and theobromine content. Validated biomarkers of intake together with more relevant mechanistic insights from experimental models using physiologically relevant concentrations and metabolites will continue to inform this research field. PMID- 25551799 TI - Toward systems epidemiology of coffee and health. AB - PURPOSE OF REVIEW: Coffee is one of the most widely consumed beverages in the world and has been associated with many health conditions. This review examines the limitations of the classic epidemiological approach to studies of coffee and health, and describes the progress in systems epidemiology of coffee and its correlated constituent, caffeine. Implications and applications of this growing body of knowledge are also discussed. RECENT FINDINGS: Population-based metabolomic studies of coffee replicate coffee-metabolite correlations observed in clinical settings but have also identified novel metabolites of coffee response, such as specific sphingomyelin derivatives and acylcarnitines. Genome wide analyses of self-reported coffee and caffeine intake and serum levels of caffeine support an overwhelming role for caffeine in modulating the coffee consumption behavior. Interindividual variation in the physiological exposure or response to any of the many chemicals present in coffee may alter the persistence and magnitude of their effects. It is thus imperative that future studies of coffee and health account for this variation. SUMMARY: Systems epidemiological approaches promise to inform causality, parse the constituents of coffee responsible for health effects, and identify the subgroups most likely to benefit from increasing or decreasing coffee consumption. PMID- 25551800 TI - Metabolomics as a tool in nutritional research. AB - PURPOSE OF REVIEW: Metabolomics is emerging as a powerful tool for studying metabolic processes and in recent years, the applications in the area of nutrition have risen rapidly. The present review gives an overview of the current applications in the field of nutrition and identifies areas in need of advancement. RECENT FINDINGS: Applications in nutrition research can in general be divided into three main areas: identification of dietary biomarkers, study of diet-related diseases and identification of biomarkers of disease and application to dietary intervention studies as a tool to identify molecular mechanisms. SUMMARY: Metabolomics has made a significant impact on all the areas identified above and is set to have a major impact on the study of diet-health relationships. PMID- 25551801 TI - Dietary fatty acids, dietary patterns, and lipoprotein metabolism. AB - PURPOSE OF REVIEW: Few studies have reviewed the impact of dietary fat and dietary patterns on lipoprotein metabolism. This review intends to provide perspective on this topic, while focusing primarily on the studies that assessed intravascular lipoprotein kinetics in humans using isotope methodologies. RECENT FINDINGS: Data suggest that dietary saturated fatty acids slow the clearance of LDL apolipoprotein (apo)B-100 and of apoA-I from the circulation, whereas possibly increasing also apoA-I production. Dietary trans fats reduce the clearance of LDL apoB-100, whereas increasing the clearance of apoA-I. n-3 polyunsaturated fatty acids (PUFAs) intake reduces the production of apoB-48 containing lipoproteins as well as of VLDL apoB-100 and increases their conversion into smaller lipoproteins. Medium-chain triglycerides appear to have no significant effect on lipoprotein kinetics. Finally, Mediterranean diet in the absence of weight loss reduces LDL cholesterol, primarily by enhancing its clearance from the circulation. SUMMARY: Kinetic studies with tracers allow a better appreciation of the impact of specific dietary factors on plasma lipid risk factors. However, additional studies are required to better document the effect of monounsaturated fatty acids, n-6 PUFAs, and of whole diets on lipoprotein metabolism. PMID- 25551802 TI - Apolipoprotein M in lipid metabolism and cardiometabolic diseases. AB - PURPOSE: This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases. RECENT FINDINGS: ApoM's likely role(s) in health and disease has become more diverse after the discovery that apoM functions as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P. SUMMARY: The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also, the importance in regulating endothelial function is being investigated. Furthermore, both apoM and S1P have been linked to diabetes and glucose and insulin metabolism. Finally, genetic variations in the apoM gene are associated with lipid disturbances, diabetes and rheumatoid arthritis. These findings suggest not only diverse effects of apoM, but also the important question of whether apoM mainly acts as a S1P carrier, if apoM carries other substances with biological effects as well, or whether the apoM protein has effects on its own. PMID- 25551804 TI - Classification of reported statin intolerance. PMID- 25551805 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 25551806 TI - Therapy and clinical trials. PMID- 25551803 TI - The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. AB - PURPOSE OF REVIEW: To describe the roles of apolipoprotein C-III (apoC-III) and apoE in VLDL and LDL metabolism RECENT FINDINGS: ApoC-III can block clearance from the circulation of apolipoprotein B (apoB) lipoproteins, whereas apoE mediates their clearance. Normolipidemia is sustained by hepatic secretion of VLDL and IDL subspecies that contain both apoE and apoC-III (VLDL E+C-III+). Most of this VLDL E+C-III+ is speedily lipolyzed, reduced in apoC-III content, and cleared from the circulation as apoE containing dense VLDL, IDL, and light LDL. In contrast, in hypertriglyceridemia, most VLDL is secreted with apoC-III but without apoE, and so it is not cleared until it loses apoC-III during lipolysis to dense LDL. In normolipidemia, the liver also secretes IDL and large and medium size LDL, whereas in hypertriglyceridemia, the liver secretes more dense LDL with and without apoC-III. These pathways establish the hypertriglyceridemic phenotype and link it metabolically to dense LDL. Dietary carbohydrate compared with unsaturated fat suppresses metabolic pathways mediated by apoE that are qualitatively similar to those suppressed in hypertriglyceridemia. SUMMARY: The opposing actions of apoC-III and apoE on subspecies of VLDL and LDL, and the direct secretion of LDL in several sizes, establish much of the basic structure of human apoB lipoprotein metabolism in normal and hypertriglyceridemic humans. PMID- 25551809 TI - Influence of morphology and hemodynamic factors on rupture of multiple intracranial aneurysms: matched-pairs of ruptured-unruptured aneurysms located unilaterally on the anterior circulation. AB - BACKGROUND: The authors evaluated the impact of morphological and hemodynamic factors on the rupture of matched-pairs of ruptured-unruptured intracranial aneurysms on one patient's ipsilateral anterior circulation with 3D reconstruction model and computational fluid dynamic method simulation. METHODS: 20 patients with intracranial aneurysms pairs on the same-side of anterior circulation but with different rupture status were retrospectively collected. Each pair was divided into ruptured-unruptured group. Patient-specific models based on their 3D-DSA images were constructed and analyzed. The relative locations, morphologic and hemodynamic factors of these two groups were compared. RESULTS: There was no significant difference in the relative bleeding location. The morphological factors analysis found that the ruptured aneurysms more often had irregular shape and had significantly higher maximum height and aspect ratio. The hemodynamic factors analysis found lower minimum wall shear stress (WSSmin) and more low-wall shear stress-area (LSA) in the ruptured aneurysms than that of the unruptured ones. The ruptured aneurysms more often had WSSmin on the dome. CONCLUSIONS: Intracranial aneurysms pairs with different rupture status on unilateral side of anterior circulation may be a good disease model to investigate possible characteristics linked to rupture independent of patient characteristics. Irregular shape, larger size, higher aspect ratio, lower WSSmin and more LSA may indicate a higher risk for their rupture. PMID- 25551811 TI - The effects of sufentanil added to low-dose hyperbaric bupivacaine in unilateral spinal anaesthesia for outpatients undergoing knee arthroscopy. AB - OBJECTIVES: The aim of this study is to examine the effects of sufentanil added to low-dose hyperbaric bupivacaine in unilateral spinal anaesthesia for outpatients undergoing knee arthroscopy. METHODS: Sixty two patients (ASA I-II) aged 20 to 50 who were planning on undergoing a knee arthroscopy were enrolled in this study. Patients were randomly divided into two groups. Unilateral spinal anaesthesia with 1ml 0.5% hyperbaric bupivacaine was administered to Group B (n=33); and unilateral spinal anaesthesia with 0.5ml (2.5ug) sufentanil added to 1ml hyperbaric bupivacaine was administered to Group BS (n=29). RESULTS: There were no statistically significant differences observed between the groups in terms of demographic data, hemodynamic parameters, maximum sensorial, sympathetic and motor block levels, time to motor block resolution, and time of discharge (p>0.05). There were statistically significant differences between the groups in terms of two segments regression time (Group B=52 min., Group BS=59 min.), ambulation time (Group B=147 min., Group BS=157 min.) and urination time (Group B=136 min., Group BS=149 min.) (p<0.05). In this study, no itching was observed in Group B, whereas seven patients in Group BS were observed as having postoperative itching (p<0.05). CONCLUSION: All patients were successfully given unilateral spinal anaesthesia with sufentanil added to low-dose hyperbaric bupivacaine for an outpatient knee arthroscopy, without affecting the time of discharge. However, for one-day interventions such as arthroscopy, it was concluded that administration of only low-dose hyperbaric bupivacaine was sufficient. PMID- 25551810 TI - Comparison of the postoperative analgesic efficacy of an ultrasound-guided fascia iliaca compartment block versus 3 in 1 block in hip prosthesis surgery. AB - OBJECTIVES: In this study, we aimed to compare the postoperative analgesic efficiency of an ultrasound-guided fascia iliaca compartment block and a 3 in 1 block in patients who underwent hip prosthesis surgery as a result of hip fracture. METHODS: With approval from the local ethics committee, 70 patients, aged 20 to 80, undergoing hip prosthesis surgery under elective conditions were included in this randomized, prospective, controlled study. They were informed of the patient-controlled analgesia (PCA) device and visual analog scale (VAS). All patients were separated randomly into three groups. Anaesthesia induction was standardized for all groups. An ultrasound guidance fascia iliaca compartment block (FICB) was applied to the first group before anaesthesia induction. For the second group, a 3 in 1 block was applied, while for the control group no block was applied. After incision on all patients, 20 mg tenoxicam and 1 mg/kg tramadol were injected intravenously. Following surgery, IV tramadol PCA was begun on all patients routinely. In our study, the presence of cortisol and ACTH levels, hemodinamical parameters, nausea and sedation were determined. RESULTS: We observed a decrease in VAS values and opioid consumption, no adverse effects on nausea and sedation, and a suppression of stress hormones in both the ultrasound guided FICB and 3 in 1 block groups. CONCLUSION: We believe that the safe and efficient application of the ultrasound-guided 3 in 1 block and the FICB is necessary in multimodal analgesic treatment in order to enable postoperative analgesia in hip prosthesis surgery. PMID- 25551808 TI - Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis. AB - BACKGROUND: Approximately 7% of survivors from meningococcal meningitis (MM) suffer from neurological sequelae due to brain damage in the course of meningitis. The present study focuses on the role of matrix metalloproteinases (MMPs) in a novel mouse model of MM-induced brain damage. METHODS: The model is based on intracisternal infection of BALB/c mice with a serogroup C Neisseria meningitidis strain. Mice were infected with meningococci and randomised for treatment with the MMP inhibitor batimastat (BB-94) or vehicle. Animal survival, brain injury and host-response biomarkers were assessed 48 h after meningococcal challenge. RESULTS: Mice that received BB-94 presented significantly diminished MMP-9 levels (p < 0.01), intracerebral bleeding (p < 0.01), and blood-brain barrier (BBB) breakdown (p < 0.05) in comparison with untreated animals. In mice suffering from MM, the amount of MMP-9 measured by zymography significantly correlated with both intracerebral haemorrhage (p < 0.01) and BBB disruption (p < 0.05). CONCLUSIONS: MMPs significantly contribute to brain damage associated with experimental MM. Inhibition of MMPs reduces intracranial complications in mice suffering from MM, representing a potential adjuvant strategy in MM post infection sequelae. PMID- 25551812 TI - [Effects of triple shoulder injection accompanied by fluoroscopy on pain experienced by patients with chronic shoulder pain]. AB - OBJECTIVES: This study aimed at determining the short-, mid- and long-term effects of a triple shoulder injection accompanied by fluoroscopy on Visual Analogue Scale (VAS) values in patients with chronic shoulder pain. METHODS: The study was conducted by retrospective investigation of the files of 92 patients experiencing chronic shoulder pain, and on whom a triple shoulder injection with 40 mg methylprednisolone and 25 mg bupivacaine accompanied by fluoroscopy was applied between January 01, 2011 and August 31, 2012. RESULTS: 1st week, 1st-6th month, and 1st year VAS values were significantly lower when compared to the basal VAS values from a statistical point of view (p<0.001). However, VAS values corresponding to the 6th month and 1st year were significantly higher than the VAS values corresponding to the 1st week and 1st month when considered statistically (p<0.001). CONCLUSION: Triple shoulder injection accompanied by fluoroscopy applied on patients with chronic shoulder pain is effective in short , mid- and long-term, but its mid- and long-term effectiveness is less than its short-term effectiveness. PMID- 25551813 TI - [Comparison of hemodynamics, recovery profile and postoperative analgesia of unilateral spinal anaesthesia with combined sciatic-femoral nerve block in knee arthroscopy]. AB - OBJECTIVES: In this randomized, controlled, blind study, a combined sciatic femoral nerve block with levobupivacaine was compared with a unilateral spinal anaesthesia with respect to effectiveness, patient and surgeon satisfaction, and the effect on postoperative pain in arthroscopic knee surgery. METHODS: Patients were randomly divided into two groups. Group I (n=20) received a combined sciatic femoral nerve block with levobupivacaine 0.5% totalling 40 ml. In group II (n=20), a spinal anaesthesia in the lateral decubitus position (ULSA) with 7.5 mg levobupivacaine 0.5% was performed, and patients were kept in the same position to achieve an anaesthesia level of T12 (maximum 10 minutes). The development of motor and sensorial block on both sides and onset time to surgical anaesthesia were recorded. The time required for the postoperative recovery score to be >=12 was recorded. In the postoperative period, postoperative analgesia (VAS), motor block, side effects, and patient and surgeon satisfaction were recorded at the 1st, 3rd, 6th and 12th hours. RESULTS: Time of readiness for surgery was significantly shorter in Group II (p<0.05). All patients were satisfied with both techniques. There were no differences in judgement between the groups. VAS scores at the 6th hour were significantly lower in group I than in group II (p<0.05). CONCLUSION: Combined sciatic-femoral nerve block for outpatient arthroscopic knee surgery offers satisfactory anaesthesia, with a clinical profile similar to that of low-dose spinal anesthesia. Sciatic-femoral nerve blocks are associated with significantly lower pain scores during the first 6 postoperative hours. PMID- 25551814 TI - [Effects of a thoracic paravertebral block on postoperative analgesia in patients undergoing modified radical mastectomy]. AB - OBJECTIVES: Following mastectomy, 50% of patients have chronic postoperative pain. Studies have shown that a paravertebral block is an effective method of analgesia as well as anaesthesia. The aim of this study is to compare postoperative pain values and opioid consumption after a single dose of 150 mg levobupivacaine with a thoracic paravertebral block in patients undergoing mastectomy. METHODS: Enrolled in the study were forty patients, aged 20 to 65, diagnosed with breast cancer, and undergoing modified radical mastectomy and axillary dissection. Patients were randomized into two groups, as control group (group K, n=20) and thoracic paravertebral group (Group T, n=20). Postoperative pain values were recorded at 0, 1st, 6th, 12th and 24th hour at rest, using a 0 10 mm Visual Analogue Scale (VAS). Additional quantities of postoperative tramadol (1.5 mg/kg, iv infusion) were recorded. RESULTS: Postoperatively, at 0, 1st, 6th, 12th and 24th hour, patients in the control group had significantly higher VAS values than the group treated with a thoracic paravertebral block (p<0.01). Compared to VAS scores at postoperative 0 h, there was a statistically significant decrease in VAS scores at 1st, 6th, 12th and 24th hour in both groups (p<0.01). Additional use of tramadol was significantly lower in group T (p<0.01). CONCLUSION: A paravertebral block with a single dose of 150 mg levobupivacaine before general anaesthesia in patients undergoing modified radical mastectomy and axillary lymph node dissection decreases postoperative pain values and the need for analgesics during the postoperative 24 hours. PMID- 25551815 TI - Ultrasound-guided infraclavicular and sciatic block for a patient who had surgery simultaneously for syndactili of the right hand and polydactilia of the right foot: case report. AB - A major advantage of ultrasound (US) has been reduction in the amount of local anaesthetic (LA) needed for successful blocks. Reduced LA requirement reduces the risk of LA toxicity when multiple blocks are to be done for surgery of more than one extremity in the same patient. The 38-year-old female was scheduled for elective surgery of polydactilia in her right foot and syndactili in her right hand. A sciatic nerve block and an infraclavicular block were applied to the patient, with ultrasound guidance. The sciatic block was performed at the popliteal level in figure of four position in prone position. The lateral sagital technique was used for the infraclavicular block. Both blocks were successful, and the patient was ready for surgery 30 minutes after block performances. The patient didn't need any additional anaesthetic or analgesic during the operation. Surgery was performed uneventfully on both extremities. This is the first case report in the literature in which multiple blocks were applied to two different extremities, the leg and arm. In conclusion, our case report is a good example of multiple blocks in different extremities being performed successfully and safely according to US guidance and using low doses of local anaesthetics. PMID- 25551816 TI - [Complex regional pain syndrome type 1 after fracture of distal phalanx: case report]. AB - Complex Regional Pain Syndrome (CRPS) is a disease characterized especially by pain, swelling, limited range of motion, vasomotor instability and patchy bone demineralization in the extremities. In this case, we report a 46-year-old woman diagnosed with CRPS type 1, whose complaints, such as swelling in the left hand, pain, and limitation of movement, started 2 months after a fracture of the distal phalanx in the left 4th finger. Her complaints were reduced with treatment of calcitonin, gabapentin, calcium and vitamin D3, retrograde edema massage, contrast baths, conventional TENS, pulsed ultrasound, desensitization and exercise with range of joint motion. CRPS type 1 should be considered in the differential diagnosis of upper limb pains which start after a fracture of the distal phalanx. PMID- 25551818 TI - Alternative anaesthetic management in ankylosing spondylitis. PMID- 25551817 TI - Regional anaesthesia in a Duchenne muscular dystrophy patient for upper extremity amputation. AB - Duchenne muscular dystrophy (DMD) is the most common of the neuromuscular disorders. DMD is usually a challenge for the anaesthesiologist, with poor cardiac function, a high risk of developing rhabdomyolysis, and the probable life threatening complications of general anaesthesia. To avoid possible morbidity associated with general anaesthesia, we applied a supraclavicular blockade. In this report, we present a 17-year-old DMD patient with a massive rhabdomyosarcoma, for whom a left arm amputation was indicated. In the post operative period, a malignant hyperthermia-like reaction occurred, which resolved in a short time. We suggest a regional blockade as a safer alternative to general anaesthesia for the management of high risk DMD patients during orthopedic procedures. PMID- 25551819 TI - Odorous house ants (Tapinoma sessile) as back-seat drivers of localized ant decline in urban habitats. AB - Invasive species and habitat disturbance threaten biodiversity worldwide by modifying ecosystem performance and displacing native organisms. Similar homogenization impacts manifest locally when urbanization forces native species to relocate or reinvade perpetually altered habitat. This study investigated correlations between ant richness and abundance in response to urbanization and the nearby presence of invasive ant species, odorous house ants (Tapinoma sessile), within its native region. Surveying localized ant composition within natural, semi-natural, and urban habitat supported efforts to determine whether T. sessile appear to be primary (drivers) threats as instigators or secondary (passengers) threats as inheritors of indigenous ant decline. Sampling 180 sites, evenly split between all habitats with and without T. sessile present, yielded 45 total species. Although urbanization and T. sessile presence factors were significantly linked to ant decline, their interaction correlated to the greatest reduction of total ant richness (74%) and abundance (81%). Total richness appeared to decrease from 27 species to 18 when natural habitat is urbanized and from 18 species to 7 with T. sessile present in urban plots. Odorous house ant presence minimally influenced ant communities within natural and semi-natural habitat, highlighting the importance of habitat alteration and T. sessile presence interactions. Results suggest urbanization releases T. sessile from unknown constraints by decreasing ant richness and competition. Within urban environment, T. sessile are pre-adapted to quickly exploit new resources and grow to supercolony strength wherein T. sessile drive adjacent biodiversity loss. Odorous house ants act as passengers and drivers of ecological change throughout different phases of urban 'invasion'. This progression through surviving habitat alteration, exploiting new resources, thriving, and further reducing interspecific competition supports a "back-seat driver" role and affects pest management strategies. As demonstrated by T. sessile, this article concludes native species can become back-seat drivers of biodiversity loss and potentially thrive as "metro-invasive" species. PMID- 25551820 TI - A full bayesian approach for boolean genetic network inference. AB - Boolean networks are a simple but efficient model for describing gene regulatory systems. A number of algorithms have been proposed to infer Boolean networks. However, these methods do not take full consideration of the effects of noise and model uncertainty. In this paper, we propose a full Bayesian approach to infer Boolean genetic networks. Markov chain Monte Carlo algorithms are used to obtain the posterior samples of both the network structure and the related parameters. In addition to regular link addition and removal moves, which can guarantee the irreducibility of the Markov chain for traversing the whole network space, carefully constructed mixture proposals are used to improve the Markov chain Monte Carlo convergence. Both simulations and a real application on cell-cycle data show that our method is more powerful than existing methods for the inference of both the topology and logic relations of the Boolean network from observed data. PMID- 25551821 TI - Quantitative spectral K-edge imaging in preclinical photon-counting x-ray computed tomography. AB - OBJECTIVES: The objective of this study was to investigate the feasibility and the accuracy of spectral computed tomography (spectral CT) to determine the tissue concentrations and localization of high-attenuation, iodine-based contrast agents in mice. Iodine tissue concentrations determined with spectral CT are compared with concentrations measured with single-photon emission computed tomography (SPECT) and inductively coupled plasma mass spectrometry (ICP-MS). MATERIALS AND METHODS: All animal procedures were performed according to the US National Institutes of Health principles of laboratory animal care and were approved by the ethical review committee of Maastricht, The Netherlands. Healthy Swiss mice (n = 4) were injected with an iodinated emulsion radiolabeled with indium as multimodal contrast agent for CT and SPECT. The CT and SPECT scans were acquired using a dedicated small-animal SPECT/CT system. Subsequently, scans were performed with a preclinical spectral CT scanner equipped with a photon-counting detector and 6 energy threshold levels. Quantitative data analysis of SPECT and spectral CT scans were obtained using 3-dimensional volumes-of-interest drawing methods. The ICP-MS on dissected organs was performed to determine iodine uptake per organ and was compared with the amounts determined from spectral CT and SPECT. RESULTS: Iodine concentrations obtained with image-processed spectral CT data correlated well with data obtained either with noninvasive SPECT imaging (slope = 0.96, r = 0.75) or with ICP-MS (slope = 0.99, r = 0.89) in tissue samples. CONCLUSIONS: This preclinical proof-of-concept study shows the in vivo quantification of iodine concentrations in tissues using spectral CT. Our multimodal imaging approach with spectral CT and SPECT using radiolabeled iodinated emulsions together with ICP-based quantification allows a direct comparison of all methods. Benchmarked against ICP-MS data, spectral CT in the present implementation shows a slight underestimation of organ iodine concentrations compared with SPECT but with a more narrow distribution. This slight deviation is most likely caused by experimental rather than technical issues. PMID- 25551822 TI - Automated classification of usual interstitial pneumonia using regional volumetric texture analysis in high-resolution computed tomography. AB - OBJECTIVES: We propose a novel computational approach for the automated classification of classic versus atypical usual interstitial pneumonia (UIP). MATERIALS AND METHODS: Thirty-three patients with UIP were enrolled in this study. They were classified as classic versus atypical UIP by a consensus of 2 thoracic radiologists with more than 15 years of experience using the American Thoracic Society evidence-based guidelines for computed tomography diagnosis of UIP. Two cardiothoracic fellows with 1 year of subspecialty training provided independent readings. The system is based on regional characterization of the morphological tissue properties of lung using volumetric texture analysis of multiple-detector computed tomography images. A simple digital atlas with 36 lung subregions is used to locate texture properties, from which the responses of multidirectional Riesz wavelets are obtained. Machine learning is used to aggregate and to map the regional texture attributes to a simple score that can be used to stratify patients with UIP into classic and atypical subtypes. RESULTS: We compared the predictions on the basis of regional volumetric texture analysis with the ground truth established by expert consensus. The area under the receiver operating characteristic curve of the proposed score was estimated to be 0.81 using a leave-one-patient-out cross-validation, with high specificity for classic UIP. The performance of our automated method was found to be similar to that of the 2 fellows and to the agreement between experienced chest radiologists reported in the literature. However, the errors of our method and the fellows occurred on different cases, which suggests that combining human and computerized evaluations may be synergistic. CONCLUSIONS: Our results are encouraging and suggest that an automated system may be useful in routine clinical practice as a diagnostic aid for identifying patients with complex lung disease such as classic UIP, obviating the need for invasive surgical lung biopsy and its associated risks. PMID- 25551823 TI - Krypton for computed tomography lung ventilation imaging: preliminary animal data. AB - OBJECTIVES: The objective of this study was to assess the feasibility and safety of krypton ventilation imaging with intraindividual comparison to xenon ventilation computed tomography (CT). MATERIALS AND METHODS: In a first step, attenuation of different concentrations of xenon and krypton was analyzed in a phantom setting. Thereafter, 7 male New Zealand white rabbits (4.4-6.0 kg) were included in an animal study. After orotracheal intubation, an unenhanced CT scan was obtained in end-inspiratory breath-hold. Thereafter, xenon- (30%) and krypton enhanced (70%) ventilation CT was performed in random order. After a 2-minute wash-in of gas A, CT imaging was performed. After a 45-minute wash-out period and another 2-minute wash-in of gas B, another CT scan was performed using the same scan protocol. Heart rate and oxygen saturation were measured. Unenhanced and krypton or xenon data were registered and subtracted using a nonrigid image registration tool. Enhancement was quantified and statistically analyzed. RESULTS: One animal had to be excluded from data analysis owing to problems during intubation. The CT scans in the remaining 6 animals were completed without complications. There were no relevant differences in oxygen saturation or heart rate between the scans. Xenon resulted in a mean increase of enhancement of 35.3 +/- 5.5 HU, whereas krypton achieved a mean increase of 21.9 +/- 1.8 HU in enhancement (P = 0.0055). CONCLUSIONS: The use of krypton for lung ventilation imaging appears to be feasible and safe. Despite the use of a markedly higher concentration of krypton, enhancement is significantly worse when compared with xenon CT ventilation imaging, but sufficiently high for CT ventilation imaging studies. PMID- 25551824 TI - Fetal growth is associated with maternal fasting plasma glucose at first prenatal visit. AB - AIMS: Fasting plasma glucose (FPG) concentration measured at the first prenatal visit is a predictor of gestational diabetes mellitus (GDM); however, whether this test is indicative of fetal growth has not been clarified. Thus, the purpose of this study was to determine whether birth weight and birth length were related to FPG levels at the first prenatal visit. MATERIALS AND METHODS: Research samples were collected from pregnant women who took an FPG test at their first prenatal visit (10-24 gestational weeks), received regular prenatal care, and delivered in our center. FPG value, maternal pre-gravid BMI, weight gain before FPG test, before and after Oral Glucose Tolerance Test (OGTT), neonatal birthweight, birth length, Ponderal Index and birthing method were recorded for analysis. Data were analyzed by independent sample t test, Pearson correlation, and Chi-square test, followed by partial correlation or logistic regression to confirm differences. Statistical significance level was alpha = 0.05. RESULTS: 2284 pregnant women, including 462 GDM and 1822 with normal glucose tolerance (NGT) were recruited for the present study. FPG concentration at the first prenatal visit was associated with neonatal birth weight (partial correlation coefficient r' = 0.089, P<0.001) and birth length (partial correlation coefficient r' = 0.061, P = 0.005), but not with Ponderal Index or birthing method. Maternal pre-gravid BMI was associated with FPG value (partial correlation coefficient r' = 0.113, P<0.001). FPG concentration at the first prenatal visit (OR = 2.945, P<0.001), weight gain before OGTT test (OR = 1.039, P = 0.010), and age (OR = 1.107, P<0.001) were independent related factors of GDM. CONCLUSION: Fasting plasma glucose concentration at the first prenatal visit is associated with fetal growth. Maternal pre-gravid BMI and weight gain are related to glucose metabolism. PMID- 25551825 TI - Hot Fusion: an efficient method to clone multiple DNA fragments as well as inverted repeats without ligase. AB - Molecular cloning is utilized in nearly every facet of biological and medical research. We have developed a method, termed Hot Fusion, to efficiently clone one or multiple DNA fragments into plasmid vectors without the use of ligase. The method is directional, produces seamless junctions and is not dependent on the availability of restriction sites for inserts. Fragments are assembled based on shared homology regions of 17-30 bp at the junctions, which greatly simplifies the construct design. Hot Fusion is carried out in a one-step, single tube reaction at 50 degrees C for one hour followed by cooling to room temperature. In addition to its utility for multi-fragment assembly Hot Fusion provides a highly efficient method for cloning DNA fragments containing inverted repeats for applications such as RNAi. The overall cloning efficiency is in the order of 90 95%. PMID- 25551827 TI - Long-term regional shifts in plant community composition are largely explained by local deer impact experiments. AB - The fact that herbivores and predators exert top-down effects to alter community composition and dynamics at lower trophic levels is no longer controversial, yet we still lack evidence of the full nature, extent, and longer-term effects of these impacts. Here, we use results from a set of replicated experiments on the local impacts of white-tailed deer to evaluate the extent to which such impacts could account for half-century shifts in forest plant communities across the upper Midwest, USA. We measured species' responses to deer at four sites using 10 20 year-old deer exclosures. Among common species, eight were more abundant outside the exclosures, seven were commoner inside, and 16 had similar abundances in- and outside. Deer herbivory greatly increased the abundance of ferns and graminoids and doubled the abundance of exotic plants. In contrast, deer greatly reduced tree regeneration, shrub cover (100-200 fold in two species), plant height, plant reproduction, and the abundance of forbs. None of 36 focal species increased in reproduction or grew taller in the presence of deer, contrary to expectations. We compared these results to data on 50-year regional shifts in species abundances across 62 sites. The effects of herbivory by white-tailed deer accurately account for many of the long-term regional shifts observed in species' abundances (R2 = 0.41). These results support the conjecture that deer impacts have driven many of the regional shifts in forest understory cover and composition observed in recent decades. Our ability to link results from shorter term, local experiments to regional long-term studies of ecological change strengthens the inferences we can draw from both approaches. PMID- 25551826 TI - You turn me cold: evidence for temperature contagion. AB - INTRODUCTION: During social interactions, our own physiological responses influence those of others. Synchronization of physiological (and behavioural) responses can facilitate emotional understanding and group coherence through inter-subjectivity. Here we investigate if observing cues indicating a change in another's body temperature results in a corresponding temperature change in the observer. METHODS: Thirty-six healthy participants (age; 22.9+/-3.1 yrs) each observed, then rated, eight purpose-made videos (3 min duration) that depicted actors with either their right or left hand in visibly warm (warm videos) or cold water (cold videos). Four control videos with the actors' hand in front of the water were also shown. Temperature of participant observers' right and left hands was concurrently measured using a thermistor within a Wheatstone bridge with a theoretical temperature sensitivity of <0.0001 degrees C. Temperature data were analysed in a repeated measures ANOVA (temperature * actor's hand * observer's hand). RESULTS: Participants rated the videos showing hands immersed in cold water as being significantly cooler than hands immersed in warm water, F(1,34) = 256.67, p<0.001. Participants' own hands also showed a significant temperature dependent effect: hands were significantly colder when observing cold vs. warm videos F(1,34) = 13.83, p = 0.001 with post-hoc t-test demonstrating a significant reduction in participants' own left (t(35) = -3.54, p = 0.001) and right (t(35) = -2.33, p = 0.026) hand temperature during observation of cold videos but no change to warm videos (p>0.1). There was however no evidence of left-right mirroring of these temperature effects p>0.1). Sensitivity to temperature contagion was also predicted by inter-individual differences in self report empathy. CONCLUSIONS: We illustrate physiological contagion of temperature in healthy individuals, suggesting that empathetic understanding for primary low level physiological challenges (as well as more complex emotions) are grounded in somatic simulation. PMID- 25551828 TI - Vibrio cholerae ghosts (VCG) exert immunomodulatory effect on dendritic cells for enhanced antigen presentation and induction of protective immunity. AB - BACKGROUND: We previously showed that the Vibrio cholerae ghost platform (VCG; empty V. cholerae cell envelopes) is an effective delivery system for vaccine antigens promoting the induction of substantial immunity in the absence of external adjuvants. However, the mechanism by which these cell envelopes enhance immunity and stimulate a predominantly Th1 cellular and humoral immune response has not been elucidated. We hypothesized that the immunostimulatory ability of VCG involves dendritic cell (DC) activation. OBJECTIVE: The aims of this study were: a) to investigate the ability of DCs [using mouse bone marrow-derived DCs (BMDCs) as a model system] to take up and internalize VCGs; b) to evaluate the immunomodulatory effect of internalized VCGs on DC activation and maturation and their functional capacity to present chlamydial antigen to naive and infection sensitized CD4+ T cells and; c) to evaluate the ability of VCGs to enhance the protective immunity of a chlamydial antigen. RESULTS: VCGs were efficiently internalized by DCs without affecting their viability and modulated DC-mediated immune responses. VCG-pulsed DCs showed increased secretion of proinflammatory cytokines and expression of co-stimulatory molecules associated with DC maturation in response to stimulation with UV-irradiated chlamydial elementary bodies (UV-EBs). Furthermore, this interaction resulted in effective chlamydial antigen presentation to infection-sensitized but not naive CD4+ T cells and enhancement of protective immunity. CONCLUSIONS: The present study demonstrated that VCGs activate DCs leading to the surface expression of co-stimulatory molecules associated with DC activation and maturation and enhancement of protective immunity induced by a chlamydial antigen. The results indicate that the immunoenhancing activity of VCG for increased T-cell activation against antigens is mediated, at least in part, through DC triggering. Thus, VCGs could be harnessed as immunomodulators to target antigens to DCs for enhancement of protective immunity against microbial infections. PMID- 25551829 TI - Enhanced Wnt/beta-catenin and Notch signalling in the activated canine hepatic progenitor cell niche. AB - BACKGROUND: The liver has a large regenerative capacity. Hepatocytes can replicate and regenerate a diseased liver. However, as is the case in severe liver diseases, this replication may become insufficient or exhausted and hepatic progenitor cells (HPCs) can be activated in an attempt to restore liver function. Due to their bi-potent differentiation capacity, these HPCs have great potential for regenerative approaches yet over-activation does pose potential health risks. Therefore the mechanisms leading to activation must be elucidated prior to safe implementation in the veterinary clinic. Wnt/beta-catenin and Notch signalling have been implicated in the activation of HPCs in mouse models and in humans. Here we assessed the involvement in canine HPC activation. Gene-expression profiles were derived from laser microdissected HPC niches from lobular dissecting hepatitis (LDH) and normal liver tissue, with a focus on Wnt/beta catenin and Notch signalling. Immunohistochemical and immunofluorescent studies were combined to assess the role of the pathways in HPCs during LDH. RESULTS: Gene-expression confirmed higher expression of Wnt/beta-catenin and Notch pathway components and target genes in activated HPC niches in diseased liver compared to quiescent HPC niches from normal liver. Immunofluorescence confirmed the activation of these pathways in the HPCs during disease. Immunohistochemistry showed proliferating HPCs during LDH, and double immunofluorescence showed downregulation of Wnt/beta-catenin and Notch in differentiating HPCs. Vimentin, a mesenchymal marker, was expressed on a subset of undifferentiated HPCs. CONCLUSIONS: Together these studies clearly revealed that both Wnt/beta-catenin and Notch signalling pathways are enhanced in undifferentiated, proliferating and potentially migrating HPCs during severe progressive canine liver disease (LDH). PMID- 25551831 TI - Pharmacokinetics, Safety and Tolerability of Single Dose Dalbavancin in Children 12-17 Years of Age. AB - BACKGROUND: Dalbavancin is a lipoglycopeptide antibiotic with Gram-positive activity and novel pharmacokinetic (PK) properties that result in a prolonged terminal half-life of 15.5 days in adults. Once weekly dosing in adults in phase 3 studies of complicated skin and skin structure infections documented dalbavancin exposures associated with clinical and microbiologic efficacy. PK properties have not been examined in children. The primary objective of this open label, multicenter single-dose phase 1 study was to characterize the PK of dalbavancin in hospitalized pediatric subjects 12-17 years of age. METHODS: A single dose of 1000 mg of dalbavancin (the standard adult dose) was administered as a 30-minute intravenous infusion to subjects weighing 60 kg or greater and 15 mg/kg for subjects weighing <60 kg. A noncompartmental PK analysis was performed. RESULTS: The apparent terminal t1/2 was approximately 9 days and was similar for dalbavancin dosages of 1000 mg and 15 mg/kg. Median dalbavancin plasma exposures (Cmax and AUCinf) when administered as 1000 mg to subjects weighing 60 kg or greater were similar to those when dalbavancin was administered at 15 mg/kg to subjects weighing <60 kg and slightly lower than exposures in adults given 1000 mg in prior PK and treatment studies. Single dose dalbavancin was well tolerated. CONCLUSIONS: Given dalbavancin exposures documented in children 12-17 years of age, and recognized dose proportionality, appropriate dosing can be modeled for pediatric phase 3 trials in acute bacterial skin and skin structure infections, to achieve the same exposure that is reported to be safe and effective in adults. PMID- 25551832 TI - Case control study of rotavirus vaccine effectiveness in Portugal during 6 years of private market use. AB - BACKGROUND: Although recommended by the vaccine committee of the Portuguese Paediatric Society, rotavirus vaccines have not been included in the routine immunization schedule. They have been available privately since 2006 with estimated coverage reaching approximately 30%. However, unlike other European countries using the vaccine, sentinel surveillance has detected fluctuations but no clear trends in the rate of gastrointestinal disease presentations. In this study, we set out to establish the real world effectiveness of rotavirus immunization in this low vaccine coverage setting. METHODS: We carried out a test negative case control study on a population of children attending a regional pediatric hospital, between 2006 and 2012, with symptoms of acute gastroenteritis and producing a stool sample for routine rotavirus testing. We calculated exposure odds ratio (ratio of odds of antecedent vaccination among cases compared with controls) to derive vaccine effectiveness ([1 - adjusted odds ratio]/100) against both hospital attendance and admission. RESULTS: Vaccine effectiveness against attendance with rotavirus acute gastroenteritis was 83.7% (95% confidence interval: 73.9-89.8) and against hospital admission was 96.1% (95% confidence interval: 83.8-99.1). No significant difference between the 2 available vaccines was detected. CONCLUSION: Both rotavirus vaccines offer a high degree of individual protection in this population. PMID- 25551830 TI - Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden. AB - Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL) has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden. PMID- 25551834 TI - A patient with Fever and rash. PMID- 25551839 TI - Rotavirus enteritis in Dadaab refugee camps: implications for immunization programs in Kenya and Resettlement Countries. PMID- 25551840 TI - Physical properties of materials derived from diamondoid molecules. AB - Diamondoids are small hydrocarbon molecules which have the same rigid cage structure as bulk diamond. They can be considered the smallest nanoparticles of diamond. They exhibit a mixture of properties inherited from bulk cubic diamond as well as a number of unique properties related to their size and structure. Diamondoids with different sizes and shapes can be separated and purified, enabling detailed studies of the effects of size and structure on the diamondoids' properties and also allowing the creation of chemically functionalized diamondoids which can be used to create new materials. Most notable among these new materials are self-assembled monolayers of diamondoid thiols, which exhibit a number of unique electron emission properties. PMID- 25551841 TI - Municipal waste collectors and hepatitis B and C virus infection: a cross sectional study. AB - There is some evidence that municipal waste collectors are at risk of Hepatitis B virus infection (HBV). Published information on risk of Hepatitis C Virus (HCV) infection among waste collectors is scant. We aimed to investigate the prevalence and possible risk factors of HBV and HCV infections among waste collectors in a municipality of the broader region of Attica, Greece. A cross-sectional sero prevalence study was conducted in a municipality of the broader region of Attica, Greece. Fifty waste collectors participated in the study (response rate: 95%). The group of municipal waste collectors was compared to a convenient sample of white collar employees not exposed to waste (No 83). Waste collectors recorded a significantly higher prevalence of hepatitis B virus infection (anti-HBc positivity) in comparison to the reference group (15% vs. 2.5%, respectively; p .001). Waste collectors who reported frequent exposure to needle-stick injuries had higher risk of HBV infection (RR 8.28; 95% CI 1.076-63.79; p 0.033). Only one municipal waste collector was anti-HCV positive. Our study corroborates previous results of an increased prevalence of Hepatitis B infection among municipal waste collectors. In addition we found that needle stick injuries were associated with the risk of HBV infection. By contrast, HCV infection does not seem to represent a significant occupational hazard among waste collectors. Vaccination against HBV among municipal solid waste collectors and promotion and use of safer methods for the collection of non-hospital medical waste could represent potential measures for the prevention of Hepatitis B Virus infection among municipal waste collectors. PMID- 25551842 TI - A nightmare for haematology clinics: extensively drug-resistant (XDR) Acinetobacter baumannnii. AB - The purpose of our study was to share experience on demographic characteristics and clinical outcome of the patients infected with extensively drug-resistant Acinetobacter baumannii (XDRAB) in haematology clinics, focusing on the period with a sudden increase in the number of XDRAB cases. A regular patient-based infection control programme was set up in haematology clinics and haematopoietic stem cell transplant centre starting from 2008. An infection control nurse visited all patients daily. A form including demographic data and laboratory results were recorded for all patients. The source of infections was identified according to the criteria proposed by the Centers for Disease Control and Prevention. While haematology ward-acquired XRDAB was rare before 2012, between January 2012 and July 2013, 29 A. baumannii infection episodes were detected in 28 patients. All but one isolate were MDR and 72.4% (21 out of 29) were XDR. Blood cultures revealed A. baumannii in 26 out of 29 episodes. While the haematological malignancy was relapsing or not under remission in 15 patients, four patients were under remission, and 10 patients were newly diagnosed. The mortality rate was 81.2%. All patients with a poor outcome died in the first week after the index blood culture was performed. In 16 out of 29 episodes, the patients died before the culture results became available. Colistin was initiated for the treatment in 11 out of 29 episodes. Three patients received colistin combined with sulbactam or sulbactam containing beta-lactams; the remaining eight patients who received colistin monotherapy were already under carbapenems. In conclusion, XDRAB infections can easily become nightmares for haematology clinics without any reliable treatment option. PMID- 25551843 TI - Circulating Apo 2L levels decreased in genotype II hepatitis C with pegylated interferon-2 alpha treatment. AB - Pro-inflammatory factors regulated by TRAIL in vivo may lead to the development of novel therapeutic strategies for diseases as diverse as infection, autoimmunity and allergy. In this study we aimed to investigate the relationship between IFN treatment response, HCV viral load and sApo 2L levels. Eleven HCV treatment naive HCV-infected patients were treated with pegIFN alfa-2a. Intensive serum circulating Apo 2L levels were monitored at study visits on day 0 (pretreatment), and in weeks 4, 6 and 12. HCV-RNA and sApo 2L levels decreased gradually with PegIF-alfa 2 treatment and the differences were significant between day 0 and week 4 (p 0.001, p 0.005 and p 0.01, p 0.005 respectively); between day 0 and week 12 (p 0.001, p 0.005 and p 0.001, p 0.000 respectively); between weeks 6 and 12 (p 0.01, p 0.05 and p 0.01, p 0.05 respectively). We suggest that decreased levels of circulating Apo 2L may reflect its increased binding to its ligand expressed on hepatocytes or lymphocytes under the influence of PegIFN treatment. PMID- 25551844 TI - Raltegravir use prospectively assessed in a major HIV outpatient clinic in Italy: sample population, virological-immunological activity, and tolerability profile. AB - Raltegravir, as the first HIV integrase inhibitor, has been used and prospectively monitored since 2010 in our HIV outpatient centre, where over 1,200 patients are monitored. The aim of our report is to perform an interim assessment of the background, the safety profile and the clinical-laboratory monitoring of all patients treated with a combination antiretroviral therapy (cART) including raltegravir, for at least 12 months. In all, 109 pretreated patients started a raltegravir-containing cART when aged 44.8 plus or minus 19.2 years, with a history of HIV infection lasting 13.4 plus or minus 9.7 years. All subjects were monitored for at least 12 months (mean 17.2 plus or minus 10.3 months). In the vast majority of cases (93 of 109: 85.3%), multiple (3-16) prior cART changes prompted raltegravir introduction in advanced-salvage lines: 72 of 109 (66.1%) patients had even developed a concurrent triple-class resistance to anti-HIV compounds. The most frequent companion antiretroviral agents were: darunavir/ritonavir (75 cases), maraviroc (47 subjects), and etravirine (38 cases). The most common underlying conditions were: AIDS (46 patients), liver cirrhosis (31 cases), AIDS-related or other malignancies (23 cases), and major cardio-cerebro-vascular events (18 cases). A chronic HCV and HBV hepatitis were of concern in 48 and 23 patients, respectively. The adjunct of raltegravir favourably affected all clinical-laboratory markers of HIV disease progression, and those of the broad spectrum of comorbidities, except for two patients who failed the raltegravir-containing cART due to insufficient adherence. Despite the already compromised clinical situation, a minority of subjects experienced mild transient clinical-laboratory untoward events possibly attributable to raltegravir, such that no patients discontinued raltegravir during the observation period. Only three AIDS-defining conditions became apparent during raltegravir-based cART; chemotherapy and/or radiotherapy cycles were performed as scheduled in patients suffering from cancer; chronic hepatitis B and C progressed to liver cirrhosis and/or hepatocarcinoma in only 2 and 6 patients. Otherwise, treatment with pegylated interferon-ribavirin became feasible in 25 patients of 48 with chronic HCV. During raltegravir-containing cART, neither autoimmune disorders nor novel malignancies were diagnosed. Only mild-transient gastrointestinal disorders, fatigue, dizziness, insomnia and cutaneous rash were reported, although their relationship with the study drug was difficult to assess due to multiple comorbidities and polypharmacy. Abnormal liver function testings were observed in 57 patients (52.3%), all suffering from concurrent hepato biliary disorders. Significant increases in serum lipids and/or lipase levels versus baseline values were never registered: serum lipid levels significantly improved after raltegravir introduction. Our experience with raltegravir underlines its excellent efficacy and safety profile, which exploits a novel mechanism of action, and displays no cross-resistance with any other antiretroviral. A progressively extended prescription in naive patients and early cART lines will allow the therapeutic potential of raltegravir to be exploited. PMID- 25551845 TI - Comparison of serum IL-1beta and C reactive protein levels in early diagnosis and management of neonatal sepsis. AB - Clinical signs and symptoms of non-infectious diseases are similar to those of infectious diseases during infancy. Therefore, rapid new methods for diagnosis of infections in infants are urgently needed. To examine the utility of measuring serum IL-1 beta for immediate diagnosis of sepsis in infants, in this cross sectional epidemiological study blood samples were taken from 83 infants (41 female and 42 male) in whom infection was suspected and who were admitted to hospital. To perform serum interleukin (IL)-1 beta and quantitative C-reactive protein (CRP) tests, blood samples were placed in ice containers and delivered to the laboratory. The serum was removed from the samples at 4 degrees Celsius and stored in refrigerators at minus 30 degrees Celsius until the time of testing. The results were analysed by t tests. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of serum IL-1 beta were 27%, 71%, 25%, and 73%, respectively. Sensitivity, specificity, PPV and NPV of serum quantitative CRP were 76%, 60%, 40% and 88%, respectively. Hence quantitative serum CRP measurement for the diagnosis of infections is more efficient than measuring serum IL-1 beta levels. In general, quantitative serum CRP measurement as an alternative to other tests such as serum IL-1 beta assays might be an ideal test for diagnosing infections in infants. PMID- 25551846 TI - 2009 H1N1 flu pandemic among professional basketball players: data from 18 countries. AB - Although influenza may be propagated in innumerable occasions and daily situations involving exposure, basketball may create many chances for close contact in which influenza could spread. This study aims to quantify and assess the impact of the 2009 H1N1 influenza pandemic among professional basketball players. A multi-step strategy was followed to gather the relevant data during the 2009-10 basketball season. Possible risk factors were recorded; logistic regression was performed to assess the impact of the former. Where data were only available in the press, cases were also verified by subsequent communication with the national basketball federations. Relevant data were available for 18 countries (218 teams, 3,024 players). In all, 52 H1N1 cases in 19 teams were reported. A larger number of players presented as a risk factor for the emergence of H1N1 cases to a borderline extent (Odds Ratio, OR 1.19, 95% CI 1.00-1.41, p 0.056). A borderline association also implicated the population of the city-basis (OR 1.01, 95% CI 1.00-1.02, p 0.094). On the other hand, no significant association with risk of H1N1 emergence was demonstrated regarding latitude and longitude of the city-basis. Even in environments where the best possible preventive and other medical care is provided influenza continues to be a threat. The microenvironment (crowding index, players per team) seemed to represent the most meaningful predictor regarding H1N1 emergence in a basketball team. PMID- 25551847 TI - Unsuspected tuberculosis in COPD and use of levofloxacin: diagnostic challenges. AB - A 92-year-old female ex-smoker with chronic obstructive pulmonary disease (COPD) GOLD III, was admitted because of communitarian pneumonia in November 2013. She had been using inhaled corticosteroids and bronchodilators and presented five exacerbations of COPD due to pneumonia in the same year, with hospitalizations in March and September. The patient underwent the routine protocol for exacerbated COPD, and bacilloscopy for tuberculosis (TB) was negative. On admission, she had intense dyspnea and a productive cough that improved by administration of levofloxacin. Tests with Ziehll-Neelsen staining in bronchopulmonary secretions resulted negative. Notwithstanding, during actual admission, the culture in Lowenstein-Jensen medium seeded in September was found positive for M. tuberculosis susceptible to isoniazid, rifampin, streptomycin, and ethambutol. Therefore, the patient underwent the standard regimen for tuberculosis. Except in September, when she used piperacillin-tazobactam, all previous exacerbations of COPD were treated with levofloxacin. This effective drug against M. tuberculosis can hinder its growth in culture. The use of levofloxacin in unsuspected TB may constitute an additional diagnostic challenge, and risk of late diagnosis is increased in patients with COPD in use of inhaled corticosteroids. Case studies may contribute to increase the suspicion index about TB associated with COPD. PMID- 25551848 TI - An incidental case of biliary fascioliasis mimicking cholangiocellular carcinoma. AB - Fascioliasis is a zoonotic infestation caused by Fasciola hepatica that usually attacks mammals, such as goats, sheep and cattle. The parasites can infect humans via freshwater plants contaminated with encysted metacercariae. In the acute phase, which involves hepatic invasion, the disease may present with abdominal pain, mild fever and hepatomegaly. In the chronic phase, the parasites settle into the biliary tracts, and then cause cholangitis and cholestasis. Sometimes, the disease may mimic malignancies, creating a mass appearance. Endoscopic retrograde cholangiopancreatography (ERCP) is an important diagnostic and treatment method because it allows simultaneous diagnosis and treatment. Here, we present a 44-year-old female patient who presented to our hospital with complaints of abdominal pain, nausea, vomiting, anorexia and weight loss. After diagnostic investigations with laboratory and imaging methods, she was initially hospitalized with a preliminary diagnosis of cholangiocellular carcinoma (CCC). However, after a full work-up, the patient was diagnosed with Fasciola hepatica via ERCP and parasites were extracted with ERCP at the same time and then treated with a single dose of triclabendazole 10 mg/kg. Two months later, the clinical status of the patient had improved markedly, with resolution of all symptoms and all laboratory and imaging tests returning to within normal limits. PMID- 25551849 TI - What is hiding behind bubbles of air? An unusual Streptococcus pyogenes meningitis. AB - Streptococcus pyogenes is a rare but aggressive cause of meningitis, which often evolves in a poor outcome with fatal consequences. Although lumbar puncture and CT scan of the brain are the gold standard of diagnosis of cerebral infections, they can have some limitations. We report and describe the clinical history and neuroimaging of a 36-year-old woman admitted to the emergency department of our hospital three days after the onset of earache and otorrhoea. When the patient developed an emergent refractory status epilepticus, the CT scan of the brain showed an unusual pneumocephalus. However, the MRI study of the brain revealed a pachymeningitis with partial thrombosis of the right transverse sinus and subdural empyema due to a S. pyogenes otitis media. Prompt diagnosis and the specific findings of the MRI allowed rapid correct treatment and thus led to a good outcome for the patient. PMID- 25551850 TI - Focal epithelial hyperplasia in a Turkish family. AB - Focal epithelial hyperplasia (FEH) is a benign proliferative condition that is more frequently found in children of certain ethnic groups. Human papillomavirus (HPV) 13 and 32 genotypes has been consistently detected in these lesions. In this study a daughter, mother and father had FEH, and HPV 13 was shown by sequence analysis in the lesions of these patients. Cryotherapy was applied to the lesions and the lesions improved, but did not recover properly. In conclusion, HPV genotyping should be performed in FEH cases. PMID- 25551851 TI - Acute brucellosis associated with leukocytoclastic vasculitis and splenic infarct. AB - Brucellosis is globally the most prevalent multisystem infection of zoonotic origin, while it is still one of the most important public health problems in Turkey as non-pasteurised milk and dairy products are consumed. Early diagnosis is vital to prevent the possibly lethal complications caused by the disease. However, diagnosis might be delayed as the disease does not have a single and typical manifestation and presents with various symptoms of different systems. Brucellosis and associated splenic infarct have rarely been studied, there being few cases in the literature. One of the rare involvements in this disease is dermatological involvement, which has been found in less than 10 percent of brucellosis cases. In this study, we discuss a 17 year old male patient who was admitted to our hospital due to fever, abdominal pain, arthralgia and rash on legs, diagnosed with brucellosis through brucellosis tube agglutination test and found to have splenic infarct upon examination and leukocytoclastic vasculitis according to the skin biopsies in the light of the present literature. PMID- 25551852 TI - Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment. AB - Primary biliary cirrhosis (PBC) and multiple sclerosis (MS) are considered autoimmune diseases with a multifactorial aetiology which is thought to be due to a combination of genetic predisposition and environmental triggers. An association of both diseases has been previously described in sporadic case reports. Fingolimod, an antagonist of the sphingosine 1 phosphate receptor family (S1P1/3/4/5), is a promising and effective drug in the treatment of MS. Here we describe a case of PBC like syndrome that was unmasked, concomitantly or consequently to Epstein Barr virus (EBV) infection reactivation, in a 34 year old male patient with relapsing remitting multiple sclerosis who was receiving fingolimod treatment. PMID- 25551853 TI - Recombinant Human Erythropoietin (RHuEpo) and Granular Colony Stimulating Factor (G-CSF) in hepatitis C virus (HCV) related to mixed cryoglobulinaemia associated to membranoproliferative glomerulonephritis type I: a case report description. AB - HCV infection is related to hepatic disease and mixed cryoglobulinaemia (MC). Renal involvement is reported in one third of cryoglobulinaemic patients. The combination of HCV related MC with renal involvement has been associated with poor survival and identified as Hepatitis C Virus Risk Syndrome (HCV RS). Here we describe antiviral treatment and management of side effects (anaemia and neutropenia) with RHuEpo and G CSF in a rare case of HCV RS. PMID- 25551854 TI - Demystifying the epidemic among Achaeans during the Trojan War. AB - Although some modern scholars believe that Homer had at least a basic medical education, given that a plethora of medical terms may be found in his poems, in the case of the pestilence that killed the Achaeans (one of the Hellenic peoples believed to have inhabited the Peloponnese) at Troy, his reference was simply informative. No symptoms were mentioned and the only thing known was that mules and dogs were the first to die. While Delphic Apollo was usually on the side of Peloponnesians, during the Trojan War Apollo Smintheus (the Mouse God) sided with the Trojans. Apollo was invoked as Smintheus by his priest Chryses two times and on both occasions a pestilence ensued. In our paper we try to clarify whether this pestilence, as we believe, was caused by a member of the Alphavirus genus, which can inflict a serious epidemic both on human and animal species, especially in equines. PMID- 25551855 TI - Recording medical students' encounters with standardized patients using Google Glass: providing end-of-life clinical education. AB - PROBLEM: Medical education today frequently includes standardized patient (SP) encounters to teach history-taking, physical exam, and communication skills. However, traditional wall-mounted cameras, used to record video for faculty and student feedback and evaluation, provide a limited view of key nonverbal communication behaviors during clinical encounters. APPROACH: In 2013, 30 second year medical students participated in an end-of-life module that included SP encounters in which the SPs used Google Glass to record their first-person perspective. Students reviewed the Google Glass video and traditional videos and then completed a postencounter, self-evaluation survey and a follow-up survey about the experience. OUTCOMES: Google Glass was used successfully to record 30 student/SP encounters. One temporary Google Glass hardware failure was observed. Of the 30 students, 7 (23%) reported a "positive, nondistracting experience"; 11 (37%) a "positive, initially distracting experience"; 5 (17%) a "neutral experience"; and 3 (10%) a "negative experience." Four students (13%) opted to withhold judgment until they reviewed the videos but reported Google Glass as "distracting." According to follow-up survey responses, 16 students (of 23; 70%) found Google Glass "worth including in the [clinical skills program]," whereas 7 (30%) did not. NEXT STEPS: Google Glass can be used to video record students during SP encounters and provides a novel perspective for the analysis and evaluation of their interpersonal communication skills and nonverbal behaviors. Next steps include a larger, more rigorous comparison of Google Glass versus traditional videos and expanded use of this technology in other aspects of the clinical skills training program. PMID- 25551856 TI - Medicine as a performing art: what we can learn about empathic communication from theater arts. AB - The authors describe how they came to the realization that theater arts techniques can be useful and effective tools for teaching interpersonal communication skills (ICS) in medical education. After recognizing the outstanding interpersonal skills demonstrated by two actors-turned-doctors, in 2010 the authors began to develop a technique called Facilitated Simulation Education and Evaluation (FSEE) to teach ICS. In FSEE, actors and residents are coached in empathic, and therefore effective, ICS using a novel technique based on lessons learned from theater arts education. Competence in ICS includes the ability to listen actively, observe acutely, and communicate clearly and compassionately, with the ultimate goal of improving medical outcomes. Resident, actor, and faculty perceptions after two years of experience with FSEE have been positive. After describing the FSEE approach, the authors suggest next steps for studying and expanding the role of theater arts in ICS training. PMID- 25551857 TI - The development of professional identity and the formation of teams in the Veterans Affairs Connecticut Healthcare System's Center of Excellence in Primary Care Education Program (CoEPCE). AB - PURPOSE: The United States Department of Veterans Affairs Connecticut Healthcare System (VACHS) is one of five Centers of Excellence in Primary Care Education (CoEPCE) pilot sites. The overall goal of the CoEPCE program, which is funded by the Office of Academic Affiliations, is to develop and implement innovative approaches for training future health care providers in postgraduate education programs to function effectively in teams to provide exceptional patient care. This longitudinal study employs theoretically grounded qualitative methods to understand the effect of a combined nursing and medical training model on professional identity and team development at the VACHS CoEPCE site. METHOD: The authors used qualitative approaches to understand trainees' experiences, expectations, and impressions of the program. From September 2011 to August 2012, they conducted 28 interviews of 18 trainees (internal medicine [IM] residents and nurse practitioners [NPs]) and subjected data to three stages of open, iterative coding. RESULTS: Major themes illuminate both the evolution of individual professional identity within both types of trainees and the dynamic process of group identity development. Results suggest that initially IM residents struggled to understand NPs' roles and responsibilities, whereas NP trainees doubted their ability to work alongside physicians. At the end of one academic year, these uncertainties disappeared, and what was originally artificial had transformed into an organic interprofessional team of health providers who shared a strong sense of understanding and trust. CONCLUSIONS: This study provides early evidence of successful interprofessional collaboration among NPs and IM residents in a primary care training program. PMID- 25551858 TI - Junior doctors' views of how their undergraduate clinical electives in palliative care influenced their current practice of medicine. AB - PURPOSE: To explore how junior doctors (doctors in postgraduate training) retrospectively perceived the influence of their undergraduate palliative care attachments (clinical electives) on their current medical practice. METHOD: From 2008 to 2013, 100 students participated in palliative care attachments at the University of Adelaide School of Medicine. In 2013, the authors invited 14 of these, now junior doctors, to be in this study. Participants took part in one-on one, semistructured interviews. Interview data were analyzed for themes. RESULTS: Nine junior doctors participated. They were sent a summary of the findings to check whether the themes captured each participant's experiences. Eight replied and agreed. Two main themes were identified: (1) from apprehension to gaining a sense of control, and (2) gaining perspective on the practice of medicine. Participants perceived that the learning experiences from the attachments provided them with a sense of confidence and control over their interactions with dying patients and families. This positive influence not only was present when caring for patients at the end of life but also influenced the participants' identity as medical practitioners. CONCLUSIONS: Findings suggest that junior doctors trained earlier in palliative care have enhanced competencies of professionalism, patient-centered medicine, psychosocial and spiritual aspects of palliative care, communication, teamwork, and self-awareness. Learning a palliative approach can help them make a difference in treating dying patients, but also in general patient care. Therefore, physicians trained in palliative care may be better prepared to contribute to a health care system that is person centered, ethically conscientious, and personally fulfilling. PMID- 25551859 TI - Where population health misses the mark: breaking the 80/20 rule. AB - Conventional population management theory, predicated on prevention and keeping the healthy majority healthy, fails to address the root cause of the unsustainable health care spending trajectory in the United States. The national health care agenda has been heavily influenced by the assumptions that disease prevention and the general promotion of "population health" will be sufficient to reduce health care spending to a sustainable level. However, a very small subset of the population with chronic and complex conditions account for a disproportionate share of health care spending, and unnecessary variation in the care of those chronic and complex episodes wastes 20% to 30% of the episodic spending. Health care spending follows what is known as "the 80/20 rule," with 80% of all spending being incurred by only 20% of the population. Whether a population is defined as a company, a county, or a country, the overwhelming majority of their health care spending comes from a small minority of the individuals, and the bulk of that spending is associated with either largely unavoidable and unpredictable single events or complex episodes of care. Achieving an economically sustainable health care system will require more efficient and effective delivery of those complex episodes of care. PMID- 25551860 TI - Postgraduate nurse practitioner residency programs: supporting transition to practice. AB - The 2010 Institute of Medicine report The Future of Nursing recommended residency programs for nurses. The number of such postgraduate residencies for nurse practitioners (NPs) is increasing in community settings; still, the Institute of Medicine's recommendation departs from the tradition of direct entry into practice after the completion of a formal nursing program. Research shows that residencies support NPs' transition to practice, but very few data support their impact on patient care. Postgraduate residencies are controversial, and the authors of this Commentary discuss the naming, funding mechanisms, and possible mandating of these programs.The authors believe that residencies should not be mandated but encouraged for new NPs and for those moving to new clinical settings. Team-based residencies provide both an opportunity to improve collaboration and a model of patient-centered care. PMID- 25551861 TI - Training the next generation of doctors in palliative care is the key to the new era of value-based care. AB - There is a common misperception that palliative care is just another term for hospice care. Although it includes hospice, palliative care is also the long-term coordinated care of the chronically ill, which is delivered at a cost savings. Why does it matter that the average American understand what palliative care means? Because the evidence shows that U.S. patients near the end of life are spending exorbitant amounts of money on health care they do not want and the country cannot afford. To better understand why palliative care is an important issue in the current debate about health care reform, the authors first briefly review landmark legal cases in the area of end-of-life care. They then discuss the role of palliative care in conversations in the current health care climate and conclude by emphasizing the importance of integrating palliative care into the standard medical curriculum. The authors predict that palliative care will be accepted in the United States as a much-needed and desirable field of medicine. Getting there, however, will require a multifaceted approach including payment reform, encouraging an open conversation among the U.S. public, and training physicians to offer the best possible care and guidance until a patient's last breath. PMID- 25551864 TI - Bioabsorbable plates and screws fixation in mandible fractures: clinical retrospective research during a 10-year period. AB - We present the basic guidelines for the safe fixation of a mandible fracture using a bioabsorbable system with less strength than the metallic system based on our 10 years of experience.We conducted a retrospective review of 75 patients who had undergone fixation using a bioabsorbable system for a mandible fracture. We analyzed the method of fixation and the size and thickness of the plates and screws that were selected depending on the mandible's fracture site.Minor complications including intraoral wound disruptions and infections occurred in 12 (16%) patients, and 2 (2.7%) patients among 10 patients who presented with infections had nonunion; therefore, they underwent replacement of the absorbable system with the titanium system. Bone resorption that was caused by the absorbable plate occurred in 12 (16%) patients.The bioabsorbable system also may be able to replace the metallic system in the fixation of comminuted mandible fractures if further research on the development of the system is supported. PMID- 25551863 TI - Frequency and impact of informant replacement in Alzheimer disease research. AB - Informants serve an essential role in Alzheimer disease research. Were an informant to be replaced during a longitudinal study, this could have negative implications. We used data from the National Alzheimer's Coordinating Center Uniform Data Set to examine the frequency of informant replacement among Alzheimer disease dementia participants, whether patient and informant characteristics were associated with replacement, and how replacement affected research outcome measures. Informant replacement was common (15.5%) and typically occurred after the first or the second research visit. Adult child (24%) and other (38%) informants were more frequently replaced than spouse informants (10%). Older spouse informant age and younger adult child informant age were associated with replacement. The between-visit change in Functional Assessment Questionnaire scores was greater in patients who replaced informants than in those with stable informants. Clinical Dementia Rating-Sum of Boxes, Functional Assessment Questionnaire, and Neuropsychiatric Inventory scores showed greater variability in between-visit change in patients who replaced informants compared with those with stable informants. These findings suggest that informant replacement is relatively common, may have implications to study analyses, and warrant further examination in the setting of clinical trials. PMID- 25551865 TI - Prevention of distal flap necrosis in a rat random skin flap model by gene electro transfer delivering VEGF(165) plasmid. AB - Background Therapeutic delivery of angiogenic growth factors is a promising approach for treating ischemia observed in skin flaps and chronic wounds.Several studies have demonstrated that vascular endothelial growth factor(VEGF) helps mitigate skin flap necrosis by facilitating angiogenesis. The present study aimed to demonstrate an electrically-mediated nonviral gene delivery approach using a non-invasive multi-electrode array (MEA) for effective treatment of ischemic skin flaps.Methods We used a standard random dorsal skin flap model in rats. The study aimed to determine the optimal treatment sites on the skin flap, optimal plasmid dose and timing of the treatment for preventing distal flap necrosis.Results We determined that two treatment sites on the ischemic flap with a plasmid dose of 50-100 MUg per treatment site proved adequate to prevent 95% flap necrosis, and that this was significantly better than the no treatment or injection only group. A 2-day window was critical to deliver the VEGF to achieve flap survival and prevent necrosis. Histological examination demonstrated minimal electro transfer associated tissue damage.Conclusions Our results demonstrate that MEA can be used as a non-invasive physical gene delivery method for plasmid VEGF, resulting in a significant reduction of necrosis in ischemic wounds. We propose that this method could be translated into a potential therapeutic approach to deliver growth factors to prevent ischemia in cases of chronic wounds, burns and skin flap necrosis. PMID- 25551862 TI - Dantrolene, a treatment for Alzheimer disease? AB - Alzheimer disease (AD) is a fatal progressive disease and the most common form of dementia without effective treatments. Previous studies support that the disruption of endoplasmic reticulum Ca through overactivation of ryanodine receptors plays an important role in the pathogenesis of AD. Normalization of intracellular Ca homeostasis could be an effective strategy for AD therapies. Dantrolene, an antagonist of ryanodine receptors and an FDA-approved drug for clinical treatment of malignant hyperthermia and muscle spasms, exhibits neuroprotective effects in multiple models of neurodegenerative disorders. Recent preclinical studies consistently support the therapeutic effects of dantrolene in various types of AD animal models and were summarized in the current review. PMID- 25551866 TI - Picking up the pieces. AB - The idea of managing patients who have experienced unimaginable horror or suffering can be very daunting. As general practitioners (GPs) we are often the first port of call for people after a significant event or, alternatively, become involved when the patient emerges from the tertiary care system. Part of our role is to help 'pick up the pieces', whether the effects have been predominantly physical, psychological or a combination of both. Sometimes the person before you is fragmented, the pieces so fragile and far flung, that putting them back together seems an impossible task. PMID- 25551867 TI - Extensive lip ulcers. PMID- 25551868 TI - Genetics in general practice. PMID- 25551869 TI - Reply: To PMID 25006600. PMID- 25551870 TI - Spirometry screening. PMID- 25551871 TI - Anticoagulants. PMID- 25551872 TI - Reply: To PMID 24791763. PMID- 25551873 TI - Appropriate prescribing for viral conjunctivitis. PMID- 25551874 TI - Imaging for cardiac disease: a practical guide for general practitioners. PMID- 25551875 TI - Reply: To PMID 24791764. PMID- 25551876 TI - Problem gambling. PMID- 25551877 TI - Reply: To PMID 24897984. PMID- 25551878 TI - Flashes and floaters: a practical approach to assessment and management. PMID- 25551879 TI - Reply: To PMID 24701623. PMID- 25551880 TI - Stroke. PMID- 25551881 TI - Medication highlights: new recommendations for palivizumab (Synagis). PMID- 25551882 TI - Erythropoietin and neuroprotection in preterm infants. PMID- 25551883 TI - Author's response. PMID- 25551884 TI - The emoluments of scientific workers. PMID- 25551885 TI - Evolution and war. PMID- 25551886 TI - [Questionnaire survey regarding work environment and support for women physicians conducted on directors of main hospitals affiliated to medical schools nationwide]. PMID- 25551887 TI - How I stayed sane. PMID- 25551888 TI - Innovating professional associations. PMID- 25551889 TI - Tri-Solfen article apology and retraction. PMID- 25551890 TI - Shedding light on animal hoarding. PMID- 25551891 TI - ERADICATE pays off in PNG. PMID- 25551892 TI - Stroking your cat improves its immunity. PMID- 25551894 TI - EVA and the World Equestrian Games. PMID- 25551893 TI - Developing your managerial and people skills--new online resources. PMID- 25551895 TI - Comment on claims of misuse of Tri-Solfen. PMID- 25551896 TI - The true value of a veterinarian. PMID- 25551897 TI - The Irish Maternity Early Warning System (IMEWS). PMID- 25551898 TI - How well do performance indicators perform? PMID- 25551899 TI - Victimisation and psychosocial difficulties associated with sexual orientation concerns: a school-based study of adolescents. AB - This study examined victimisation, substance misuse, relationships, sexual activity, mental health difficulties and suicidal behaviour among adolescents with sexual orientation concerns in comparison to those without such concerns. 1112 Irish students (mean age 14 yrs) in 17 mixed-gender secondary schools completed a self-report questionnaire with standardised scales and measures of psychosocial difficulties. 58 students (5%) reported having concerns regarding their sexual orientation. Compared with their peers, they had higher levels of mental health difficulties and a markedly-increased prevalence of attempted suicide (29% vs. 2%), physical assault (40% vs. 8%), sexual assault (16%vs. 1%) and substance misuse. Almost all those (90%) with sexual orientation concerns reported having had sex compared to just 4% of their peers. These results highlight the significant difficulties associated with sexual orientation concerns in adolescents in Ireland. Early and targeted interventions are essential to address their needs. PMID- 25551900 TI - The appropriateness of a proton pump inhibitor prescription. AB - Proton pump inhibitors (PPIs) are one of the most commonly prescribed groups of drug in Ireland, at great expense to the Irish healthcare executive. This study aims to evaluate the appropriateness of PPI prescriptions on admission and discharge in a tertiary referral hospital. All non-elective admissions in the Emergency Department in one week were included in the study. 102 patients in total were included, with 36 (35.4%) treated with a PPI on admission. Of these, only 3 (8.3%) had a clear indication noted as per current NICE guidelines. 18 new in-hospital PPI prescriptions were documented. 11 (61%) of which were present on discharge prescriptions. Continuing PPI prescription on discharge into the community may be inappropriate, costly and potentially harmful. Brief interventions aimed at reducing inappropriate PPI prescriptions have been shown to be effective at reducing the cost and potential harm of unnecessary treatment. PMID- 25551901 TI - An unusual cause of acute scrotum in a child. AB - Acute non-traumatic scrotal pain in children, commonly due to a torted testicular appendage (hydatid of Morgagni) or torted epididymal appendage is well described. These vestigial embryonal duct remnants are of Mullerian and Wolffian duct origin respectively. Very rarely, the other infrequently encountered Wolffian duct remnants known as the paradidymis or organ of Giraldes and the superior and inferior aberrant ducts known as the organs of Haller can become torted. We describe the presentation, management and diagnosis of a torted embryonal remnant arising from the distal spermatic cord. PMID- 25551902 TI - Animal attack: an unusual case of multiple trauma in childhood. AB - A 21/2 year old girl attended our facility following attack by a tapir at a city zoo. She sustained multiple injuries including a forearm laceration and multiple perforating wounds to her abdominal wall. She had several procedures, including bowel resection, performed under the care of the General Paediatric Surgery and Plastic Surgery teams and was treated with a course of IV antibiotics. She recovered well and to date has suffered no long-term adverse outcome. PMID- 25551903 TI - Left atrial appendage thrombus with resulting stroke post-RF ablation for atrial fibrillation in a patient on dabigatran. AB - Dabigatran etexilate is licensed for use in prevention of deep venous thromboembolism and in prevention of stroke and systemic embolism in nonvalvular atrial fibrillation (AF). It has also been used in patients for other indications as a substitute for warfarin therapy because it requires no monitoring; one group being patients undergoing radiofrequency (RF), ablation for AF, although there have been no consensus guidelines with regards to dosage and timing of dose. We report the case of a patient with documentary evidence of left atrial appendage (LAA) thrombus formation and neurological sequelae post-RF ablation despite being on dabigatran. This case highlights the concern that periprocedural dabigatran may not provide adequate protection from development of LAA thrombus and that a standardised protocol will need to be developed and undergo large multicentre trials before dabigatran can be safely used for patients undergoing RF-ablation. PMID- 25551905 TI - Re: Follow-up arrangements for breast cancer patients; is it appropriate to transfer surveillance to general practitioners? PMID- 25551904 TI - Confronting evidence: individualised care and the case for shared decision making. AB - In many clinical scenarios there exists more than one clinically appropriate intervention strategy. When these involve subjective trade-offs between potential benefits and harms, patients' preferences should inform decision-making. Shared decision-making is a collaborative process, where clinician and patient reconcile the best available evidence with respect for patients' individualized care preferences. In practice, clinicians may be poorly equipped to participate in this process. Shared decision-making is applicable to many conditions including stable coronary artery disease, end-of-life care, and numerous small decisions in chronic disease management. There is evidence of more clinically appropriate care patterns, improved patient understanding and sense of empowerment. Many trials reported a 20% reduction in major surgery in favour of conservative treatment, although demand tends to increase for some interventions. The generalizability of international evidence to Ireland is unclear. Considering the potential benefits, there is a case for implementing and evaluating shared decision-making pilot projects in Ireland. PMID- 25551906 TI - Pseudo pseudogout. PMID- 25551907 TI - [Nursing and the new productive model]. PMID- 25551908 TI - [The rights of the person at the end of life, in light of the new legislation]. AB - In the last two years there has been a major legislative developments on the individual rights at the end of life process. The aim of this paper is to analyze the content of these new laws in order to know how are regulated the individual rights during the process of death, the duties of health workers who treat these patients and guarantees that public authorities and health institutions are required to provide to ensure the proper exercise of these rights. PMID- 25551909 TI - [Dressings for moist wound healing. Are "homogeneous groups" viable?]. PMID- 25551910 TI - [Accessibility plan: can offer a higher quality for a lower cost?]. AB - OBJECTIVES: Redirect demand pathology severity level IV-V of the hospital emergency room (ED) to the Primary Health Care (AP) reference, increase in technical consultation and assess the effectiveness of the proposed Accessibility Plan (PA). Improving the quality of care offered, lowering the cost to achieve it. DESIGN: Quality research study conducted in January-2010 data collected throughout 2009, and compare them versus those obtained in 2008. SETTING AND PARTICIPANTS: Population allocated to the ABS Sagrada Familia (23,265 users). MEASUREMENTS: Beneficiaries in HUS AP and population due to specialized care, population scheduled diagnostic and therapeutic procedures (radiology, laboratory echo-doppler, cryosurgery ...), total annual visits, attendance, repetition,... RESULTS: Increased 86.5% of emergency radiographs in AP (avoiding lead to ED), 7.4% fewer referrals to the emergency; implantation circuit urgent analytical (laboratory of HUS not collapsed) 13.6% fewer referrals to vascular surgery (the Eco-Doppler), 5.92% less analytical (thank Cardio-Check), 297 fewer referrals to dermatology (for cryotherapy), 9.65% less refe- rrals to psychiatry (through group workshops mental health), decreased frequency (1.4%) and recurrence (2.3%) over 2007, 23.9% of referrals to ED pathology avoided level IV-V served in AP; save ? 57,335 on 2007. CONCLUSIONS: Programs that includes the PA has proven its effectiveness, having offered improved quality and user satisfaction, spending economic decline, to be addressed and resolved in AP visits to level IV-V ED. PMID- 25551911 TI - [The value of vaccines in the present moment]. AB - The vaccines have decreased the frequency of infectious diseases until control or eradication. In this situation, some people forget the benefits of vaccines, they consider unscientific and false aspects and are not vaccinated. Occur "bags" of susceptible individuals and cases of disease. The current measles situation is an example. We need to "give value to vaccines", disseminate their achievements and make a permanent promotion of their great benefits and safety PMID- 25551912 TI - [The nurse in the surgical area: prevention of complications and implemention of intervention in patient care]. AB - The contribution made by the surgical nurse is essential to ensure the security of the patient who is subjected to surgery as well as accompany this specialized professional work to ensure that the patient is in the best physical and mental condition to deal with procedures of these characteristics. Nurse care in the surgical area is frequently described from a biomedical approach as it focuses on the type of surgery or the surgical technique, a perspective that might be inadequate and obsolete in identifying the areas of professional intervention and in clarifying the objectives of the nursing staff in the surgical area. In this paper nursing interventions such as emotional support, enhanced security and the prevention of infection are described as well as the identification of potential complications more prevalent in the different stages of surgical procedure, such as bleeding, hypoxia or hypothermia, among others, all these different points are developed, from a rationalistic nursing approach with emphasis on a humanistic vision of patient care. The specificity of the surgical area demands a prepared and competent professional nurse in the emotional support of the patient and his or her family, as well as the demons- tration of knowledge and skills in technical management and instruments associated with each type of surgery. It also requires competence in the diagnosis of potential com- plications and the development of activities designed to the prevention, early detection and treatment of potential health problems. PMID- 25551913 TI - [If you take a step back, it should be only to gain momentum again]. PMID- 25551914 TI - [Effectiveness of arterial puncture with fine needle]. AB - The arterial puncture is a procedure that patients and nurses are faced with suspicion by the pain it causes. We evaluate the effectiveness of a new protocol of arterial puncture with fine needle (paf) less painful and damaging. Comparative randomized design for independent samples on patients who request samples of arterial blood. Analysis of the variables of pain intensity compared pain and technical difficulty. Significant confirmation of the alternative hypothesis in favor of lower rates of pain and technical difficulty with paf. PMID- 25551915 TI - [Influence of obesity in sexual and reproductive health]. AB - INTRODUCTION: The global epidemic of overweight and obesity is becoming, as its growth into a major public health problem in many parts of the world affects about half the general population and is therefore a problem common among fertile. EXPOSURE: Obesity and overweight are common conditions that have implications not only for overall health, but also largely on reproductive health. A high prevalence of obese women in the sterile population and numerous studies have highlighted the link between obesity and infertility. Obesity increases the risks of obstetric and neonatal complications, including decreased fertility in women who ovulate and is also associated with menstrual disorders and increased risk of recurrent spontaneous abortions. CONCLUSIONS: Changes in lifestyle, the realization of a diet and exercise program, are the first line of treatment for obesity. PMID- 25551916 TI - [Intestinal stimulation in patients with colostomy]. AB - We presented/displayed our experience in the recovery of the evacuator function of the intestine in patients entered in our service with direction diagnoses of Ileo Paralitico or Adinamico (Functional), that by some cause has been taken part surgically and is carrying of a temporary or permanent colostomia. Our experience is based on more than 10 patients, but we have only gathered the data of ten clinical histories. This stimulation we have obtained it, introducing a sounding Foley type through estoma, trying not to produce to the patient the minimum annoyance to him. We have looked for justification, as much physiological as anatomical, that it entails this answer of recovery of the intestinal peristaltismo, using body solid and not liquid, with idea that thus we respected better the normal intestinal operation in these patients, that already has it altered, to the being carrying of a colostomia. PMID- 25551917 TI - [Quality of care in adult resuscitation unit]. AB - Nowadays the quality of care has become a key piece in medical assistance. Apart from doing things correctly we should have an objective knowledge of the opinion of the user That opinion could be known thanks to the analysis of the perceived quality care from the patient. From October to December of 2008 a descriptive, transversal and retrospective research has been developed in a resuscitation unit at a third level hospital of the Community of Madrid. This research has been for all the registrations to the service, through the Servqhos questionnaire. The aims of the research were to evaluate the quality perceived at the resuscitation unit; to know the profile of the patient treated and to identify the possible improvements and problems as well. The patients were anonymous and they presented themselves voluntary 19 of 42 registrations in total answered the questionnaire with a rate of reply of 45%. The average age registered were 57 years old with an average of stay of 11 days. The most prevalent pathologies were neoplasias and polytraumatisms. According to the quality perceived by the unity there has not been any relationship among gender study level, labor activity marital status and previous hospital stay. At the area of information to the patient there have been some deficiencies as well as some discrimination from the attending staff. Noise is valuated negatively by the patients. Further to the professionalism, is valuated positively at all the social classes. The global quality perceived of the unity were very good from the patient. PMID- 25551918 TI - Effects of linoleic acid on generalized convulsive and nonconvulsive epileptic seizures. AB - BACKGROUND/AIM: To comparatively investigate the effects of linoleic acid on convulsive and nonconvulsive epileptic seizures. MATERIALS AND METHODS: Rats were divided into 3 groups: convulsive epileptic rats receiving only pentylentetrazole (PTZ) injections (group 1), convulsive epileptic rats receiving PTZ and linoleic acid (group 2), and Wistar Albino Glaxo rats from Rijswijk with genetic absence epilepsy receiving linoleic acid (group 3). The duration and severity of convulsive activity were determined in groups in which convulsive seizures were induced by PTZ. In group 3, intravenous linoleic acid was administered after 1-h baseline electroencephalography (EEG) recordings. The EEG recordings were analyzed. RESULTS: When groups 1 and 2 were compared, the delay in onset of minor seizures and the decrease in the number of rats developing major seizures were found statistically significant. When the mean spike-wave discharge number and duration values for the rats in group 3 were compared to baseline values, a statistically significant increase was found in the 1st and 6th hours and there was no significant difference in the 24th hour. CONCLUSION: While our study shows that linoleic acid may be effective in the treatment of generalized convulsive epilepsy along with conventional antiepileptic drugs used in epilepsy treatment, it reports that linoleic acid is not appropriate in the treatment of nonconvulsive epilepsies. PMID- 25551919 TI - Comparison of intraarticular bupivacaine and levobupivacaine injection in rat synovial inflammation. AB - BACKGROUND/AIM: Both bupivacaine and levobupivacaine are local anesthetics with strong analgesic efficacy that can be used intraarticularly. The aim of this study was to compare the effects of intraarticular bupivacaine and levobupivacaine injection on inflammation in articular cartilage and the synovium of the rat knee joint. MATERIALS AND METHODS: Twenty Sprague-Dawley rats were injected in the right knee joint with 0.2 mL of bupivacaine, while 0.2 mL of levobupivacaine was injected into the left knee joint. Groups of 5 were sacrificed on days 1, 7, 14, and 21 after bupivacaine and levobupivacaine administration and knee joints were examined for subintimal fibrosis, synovial hyperplasia, chronic inflammation, neutrophil infiltration, edema, and synovial and periarticular congestion by microscopy. Alterations in the articular cartilage structure were evaluated using Mankin scoring. RESULTS: We found that both drugs have similar effects on synovial and articular cartilage resulting in mild to moderate congestion, edema, neutrophil infiltration, chronic inflammation, and synovial hyperplasia, which diminished gradually. However, increases in fibrosis were also seen to varying degrees. Thus, the use of these drugs intraarticularly can be recommended. CONCLUSION: Careful usage of bupivacaine and levobupivacaine is recommended in intraarticular applications since they cause inflammation shortly after injection and fibrosis at later time points. PMID- 25551920 TI - Effect of Ginkgo biloba on brain volume after carotid artery occlusion in rats: a stereological and histopathological study. AB - BACKGROUND/AIM: This study investigated the effect of Ginkgo biloba (GB) on brain volume in cerebral ischemia induced by stopping carotid artery blood flow. MATERIALS AND METHODS: Twenty-four adult male rats were divided into 4 groups of 6 rats each. No procedure was performed on the control group. Ischemia was applied to the rats in the ischemia and ischemia + GB groups by clamping the arteria carotis communis for 30 min. The rats in the ischemia + GB group were given 100 mg/kg drops (Tebokan Fort Drop, Abdi Ibrahim Ilac Sanayi A.$., Turkey) containing dry GB leaf extract orally, every day for 14 days from the day of ischemia. In the sham group, surgical stress alone was applied by performing a skin incision. On the 14th day, brain tissues were extracted and evaluated stereologically and histopathologically. RESULTS: The only statistically significant difference was observed between the sham and control groups. CONCLUSION: This result may be interpreted as surgical stress, established by cutaneous incision, having an adverse effect on brain volume. Additionally, the absence of any difference in terms of brain volume following 30 min of ischemia between the ischemia and control groups suggests that a probable postischemic rise in brain volume disappears within 14 days. PMID- 25551921 TI - Evaluation of histopathologic and histomorphometric changes of testicular tissue and gonadotropin levels following consumption of methylphenidate in male mice. AB - BACKGROUND/AIM: One of the most common psychiatric disorders in children is attention-deficit/hyperactivity disorder, which is treated extensively by methylphenidate. This study investigates the assessment of the effects of methylphenidate on histopathologic and histomorphometric changes of the testes and serum levels of gonadotropin in mice. MATERIALS AND METHODS: In this study, 36 adult male mice were used. After determining their body weights, the animals were divided randomly into 2 experimental groups and 1 control group. The experimental groups received methylphenidate (2 and 10 mg kg(-1) day(-1)) via gavage for a period of 40 days. After evaluation of body weight, general anesthesia was used for taking blood samples from the heart in order to measure testosterone and levels of gonadotropin in serum. For the purpose of weighing the bodies and measuring the thickness of the germinal epithelium, the testes were removed and the possibility of any pathological changes was considered. RESULTS: The results showed that methylphenidate could decrease the thickness of the germinal epithelium and body weight significantly, and could increase the levels of spermatogonia and serum gonadotropins and testosterone. Histopathological changes were also seen for vascular dilatation and congestion in interstitial tissue. CONCLUSION: Our findings demonstrated that administration of methylphenidate in adulthood may have an effect on spermatogenesis due to the influence of gonadotropin hormones on testis function. PMID- 25551922 TI - Comparison of hippocampal interleukin-6 immunoreactivity after exhaustive exercise in both exercise-trained and untrained rats. AB - BACKGROUND/AIM: Exhaustive exercise is a strong stress factor and can impact cytokine production in the brain. Interleukin-6 (IL-6) is produced in greater amounts than any other cytokine in response to exercise, and its effects are closely related to both exercise duration and intensity. In this study, we measured the differences between the amount of IL-6 reactivity of the hippocampus after an exhaustive session ofrunning in long-term exercise-trained and untrained rats. MATERIALS AND METHODS: The exercise-trained group ran on a treadmill for 12 weeks. Both groups were forced to run until exhaustion. Each group of rats was sacrificed immediately, 1 day, or 3 days after exhaustion and the brains were evaluated for IL-6 immunoreactivity in the hippocampus. RESULTS: Hippocampal IL-6 immunoreactivity was absent in controls, mild to severe in untrained rats, and weak to mild in long-term-trained rats. The most prominent increase in IL-6 was observed in the untrained rats sacrificed 1 day after exhaustion. CONCLUSION: Exercise to exhaustion resulted in increased IL-6 levels in brain slices in both groups of rats, but long-term exercise training protected the hippocampus from exposure to an extreme increase in IL-6. The immediate effects of these cytokine levels were observed 1 day after exhaustion. PMID- 25551923 TI - Pharmacological profile of a nitric oxide donor spermine NONOate in the mouse corpus cavernosum. AB - BACKGROUND/AIM: To investigate the effects of spermine NONOate in the cavernous tissue obtained from mice treated or untreated with sildenafil. MATERIALS AND METHODS: We studied the effects of spermine NONOate on the tone and nitrergic relaxation responses of isolated mouse corpus cavernosum and compared them with sodium nitroprusside in the absence or presence of L-nitroarginine, hydroxocobalamin, pyrogallol, diethyldithiocarbamate (DETCA), or 1H [1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The neurogenic contractions and relaxations of the tissues were induced by electrical field stimulation. Some mice received a single oral dose of sildenafil and after 1 h the effects of spermine NONOate were evaluated by in vitro studies. RESULTS: Spermine NONOate relaxed mouse corpus cavernosum in a concentration-dependent manner. Spermine NONOate-induced relaxation was relatively slow to develop and it was reversible and reproducible. These relaxations were significantly suppressed by hydroxocobalamin, diethyldithiocarbamate, or ODQ, but not by L-nitroarginine or pyrogallol. Spermine NONOate potentiated the nitrergic relaxations to electrical field stimulation (EFS), whereas it significantly reduced EFS-induced contractions. Sildenafil treatment can enhance the relaxant responses to spermine NONOate and EFS. CONCLUSION: These findings suggest that spermine NONOate has a potent relaxant action in cavernous tissue and this effect can be potentiated by oral sildenafil treatments. Spermine NONOate may be considered an attractive treatment for erectile dysfunction in pathologic disorders with a lack of endogenous NO production. PMID- 25551924 TI - The role of hepcidin and its related genes (BMP6, GDF-15, and HJV) in rats exposed to ischemia and reperfusion. AB - BACKGROUND/AIM: To determine the roles of hepcidin and its related genes in a renal ischemia/reperfusion model. MATERIALS AND METHODS: A total of 20 Wistar albino rats were equally divided into 2 groups: Group I was the control group and Group II was the ischemia and reperfusion (I/R) group (60 min of ischemia + 48 h of reperfusion). I/R was performed on the left kidneys of these rats and then the I/R-treated kidneys were removed. The levels of serum biochemical markers were evaluated after renal I/R. The expression levels of hepcidin-linked genes [growth differentiation factor 15 (GDF-15), bone morphogenetic protein 6 (BMP6), and hemojuvelin (HJV)] were also measured by RT-PCR technique. In addition, the tissues were evaluated histopathologically. RESULTS: No significant association was found between renal dysfunction and I/R when compared to biochemical parameters (P > 0.05). However, differences in platelet values were statistically significant (P < 0.05). Expression levels of GDF-15, BMP6, and HJV genes increased, but this increase was not statistically significant. In addition, histopathological evaluation was performed using hematoxylin and eosin stain. This showed a significant relationship between the control group and I/R group for ischemic and nonischemic kidney scoring. CONCLUSION: Hepcidin and BMP6, HJV, and GDF-15 should be taken into account when investigating the process of I/R. PMID- 25551925 TI - The effect of lycopene on the ototoxicity induced by cisplatin. AB - Background/aim: To determine the efficacy of lycopene, which is considered an antioxidant agent, in decreasing the cochlear damage induced by cisplatin. MATERIALS AND METHODS: A total of 38 rats were randomized into 4 groups: control, cisplatin, cisplatin + lycopene, and lycopene-treated groups. In all groups, the distortion-product otoacoustic emission measurements were performed on days 0, 1, 2, and 5. RESULTS: There were no significant differences between the control and lycopene groups at any frequencies. In the cisplatin group, the statistically significant differences were found in the measurements taken between day 0 and day 5 at all frequencies and between days 1 and 5 and days 2 and 5 at some frequencies (P < 0.05). In the cisplatin + lycopene group, a statistically significant difference was found at some frequencies between the measurements taken on days 0 and 5, days 1 and 5, and days 2 and 5 (P < 0.05). Contrary to the results found in the cisplatin group, hearing ability in the lycopene-treated group was observed as being preserved at low frequencies in the measurements taken on days 0 and 5 and days 2 and 5. CONCLUSION: The data of this study suggest that lycopene can prevent the development of ototoxicity induced by cisplatin, especially at low frequencies. Studies on this issue with longer durations and different dose ranges may contribute to the identification of potentially prophylactic effects of lycopene against cisplatin ototoxicity at higher frequencies, as well. PMID- 25551926 TI - Oxaliplatin and ototoxicity: is it really safe for hearing? AB - BACKGROUND/AIM: Oxaliplatin is an effective and widely used chemotherapeutic agent in the treatment of many solid tumors. The most common side effects are peripheral neuropathy, gastrointestinal toxicity, and neutropenia. There have been some case reports about ototoxicity with oxaliplatin, but no clinical trials. In this trial, we explored whether or not oxaliplatin has ototoxic effects. MATERIALS AND METHODS: A total of 18 patients, 14 with colorectal cancer and 4 with pancreatic cancer, were included in this study. Four patients (22%) were treated with a capecitabine and oxaliplatin (CapeOx) regimen, and 14 patients (78%) were treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX-6). Patients' pretreatment and posttreatment hearing levels were assessed with high-frequency audiometry and otoacoustic emission tests. RESULTS: The median time between the first and the last oxaliplatin doses was 3.2 months (range: 2-7 months). There was no hearing loss in tests conducted for both ears of patients at frequencies of 500, 1000, 2000, 4000, 6000, 8000, 12,000, and 16,000 Hz. There was no difference between the pretreatment and posttreatment otoacoustic emission tests. CONCLUSION: Oxaliplatin is a reliable agent in terms of ototoxicity. PMID- 25551927 TI - Is there a genetic predisposition for Turkish patients with sarcoidosis in the 329-bp region containing the BTNL2 rs2076530 polymorphism? AB - BACKGROUND/AIM: Sarcoidosis is a complex, multifactorial immune disorder with unknown etiology. A single nucleotide polymorphism (G->A, rs2076530) in the butyrophilin-like 2 (BTNL2) gene results in a truncating protein formation. It has been previously reported that this variation may be a risk factor for sarcoidosis in certain ethnic groups. This study was conducted to determine whether there is any genetic predisposition for the BTNL2 rs2076530 polymorphism in the 329-bp region in Turkish patients with sarcoidosis. MATERIALS AND METHODS: DNA samples were obtained from volunteers including 53 Turkish patients with sarcoidosis and 52 healthy controls. Analysis of the 329-bp region was carried out by polymerase chain reaction and sequencing of genomic DNA. RESULTS: We did not find any genetic variation except the rs2076530 polymorphism in the 329-bp region. The AA genotype was associated with an increased risk of sarcoidosis in a recessive model [P = 0.027, OR 2.56 (95% CI 1.02-6.49)], but it did not include a risk for sarcoidosis in a dominant model (P = 0.885). CONCLUSION: Our results emphasize the recessive characteristic of the rs2076530 polymorphism in Turkish patients with sarcoidosis. The lack of any genetic variation except rs2076530 in the 329-bp region is another significant finding for Turkish patients. PMID- 25551928 TI - Clinical and demographic findings of patients with rheumatoid arthritis and ankylosing spondylitis treated in a tertiary care center in Turkey. AB - BACKGROUND/AIM: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are 2 common rheumatic diseases that are frequent causes of disability. In this descriptive study, demographic, clinical, and laboratory findings of patients with RA and AS being followed in a tertiary care center in Turkey were reported. MATERIALS AND METHODS: The patient data of 45 RA and 45 AS cases were collected retrospectively from electronic medical records. Demographic findings, clinical and laboratory assessments of disease activity, drugs used for the treatment, and effect on quality of life of patients with RA and AS were analyzed. RESULTS: In RA patients, 27% had mild, 44% had moderate, and 29% had severe disease and 25% of the patients had satisfactory functional state. In AS patients, the mean Bath Ankylosing Spondylitis Disease Activity Index score was 4.6 +/- 2.3 and 64% had active disease. Sixteen percent of the patients with AS reported satisfactory functional state. In RA cases, the highest percentage of patients were treated with biological agents. In AS cases, 24% of patients were treated with NSAIDs and 22% received biological agents. CONCLUSION: In our tertiary care center, the majority of patients with RA and AS had active disease with unsatisfactory functional states. PMID- 25551929 TI - Comparison in clinical features and life impact between juvenile-onset and adult onset ankylosing spondylitis. AB - BACKGROUND/AIM: To compare the differences in clinical characteristics and disease impact on life between patients with juvenile-onset ankylosing spondylitis (JoAS) and patients with adult-onset AS (AoAS). MATERIALS AND METHODS: Demographic and clinical data were collected from 139 AS patients. Disease activity was defined with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional status was assessed with the Bath Ankylosing Spondylitis Functional Index (BASFI). Status of quality of life was evaluated with the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. RESULTS: There were 50 patients with JoAS (36.0%) and 89 with AoAS (64.0%). The JoAS group showed more onset with peripheral joints involvement (P < 0.001), significant diagnosis delay (P < 0.001), worse functional status (P = 0.002), and poorer quality of life (P = 0.002). Patients with JoAS also showed a significantly lower rate in college education (P = 0.037) and marriage (P = 0.013). The rate of employment in the JoAS group was lower than that in the AoAS group. Although the difference in employment did not reach a significant level, the JoAS group included more patients who had not been employed since reaching adulthood (P = 0.015). CONCLUSION: Compared to patients with AoAS, patients with JoAS may need more specific clinical interventions as well as social assistance. PMID- 25551930 TI - Asymmetric dimethyl arginine levels in chronic hemodialysis patients. AB - BACKGROUND/AIM: To investigate serum asymmetric dimethyl arginine (ADMA) levels in maintenance hemodialysis (HD) patients and to assess their potential correlations with C-reactive protein (CRP), albumin, and cholesterol levels as the established cardiovascular and nutritional parameters. MATERIALS AND METHODS: Forty-nine patients on maintenance HD treatment and 22 healthy volunteers with similar age and sex characteristics were recruited into the study. Serum albumin, CRP, creatinine, calcium, phosphate, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, hemoglobin, white blood cell counts, and serum ADMA levels were measured. RESULTS: HD patients had significantly higher ADMA levels compared with healthy controls (0.51 +/- 0.25 vs. 0.35 +/- 0.15, P = 0.002). While white blood cell counts and body mass index values were similar between the 2 groups, CRP and LDL cholesterol were significantly higher and albumin and HDL cholesterol were significantly lower in HD patients compared with healthy controls. ADMA concentrations were positively correlated with mean age (P = 0.02, r = 0.360), LDL cholesterol levels (P = 0.006, r = 0.325), and CRP levels (P = 0.02, r = 0.268) and negatively correlated with serum albumin levels (P = 0.005, r = -0.331). CONCLUSION: ADMA levels were found to be higher in HD patients and were shown to be correlated with preestablished inflammatory and nutritional biomarkers. PMID- 25551931 TI - The comparison of folate and vitamin B12 levels between depressive and nondepressive postmenopausal women. AB - BACKGROUND/AIM: To investigate if there is any association between the serum folate and vitamin B12 status and the depressive symptoms in postmenopausal women. MATERIALS AND METHODS: The study included 95 postmenopausal women. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess their depressive symptoms. The investigated women were classified into 2 groups based on the existence of depressive symptoms. These 2 groups were compared in terms of folic acid and vitamin B12 levels. RESULTS: Among 95 cases, 27 postmenopausal women scored 16 or more on the CES-D scale and were classified as the depressive group (Group 1), and 68 postmenopausal women scored 15 or less and were classified as the nondepressive group (Group 2). The serum levels of folate were 11.5 +/- 5.4 ng/mL in group 1 and 12.3 +/- 5.3 ng/mL in group 2. The concentrations of vitamin B12 were 456.2 +/- 343.4 pg/mL in group 1 and 446.5 +/- 165.1 pg/mL in group 2. The folate and vitamin B12 levels did not significantly correlate to the frequency of depressive symptoms (P = 0.52 and P = 0.24, respectively). CONCLUSION: In this study, no correlation was detected between serum folate and vitamin B12 levels and depressive symptoms in postmenopausal women. Supplementation of folic acid and vitamin B12 for postmenopausal women does not seem to be an effective intervention to reduce depressive symptoms. PMID- 25551932 TI - Incidence of maternal vitamin D deficiency in a region of Ankara, Turkey: a preliminary study. AB - BACKGROUND/AIM: To evaluate vitamin D levels and risk factors for vitamin D deficiency in healthy newborns and their mothers. MATERIALS AND METHODS: Ninety nine healthy pregnant women (>= 37 weeks of gestation) were enrolled in the study. Previous history of pregnancies and births, nutritional status, multivitamin supplementation, educational status, type of clothing, and the economic level of the family were recorded. Blood samples were drawn from the mothers and the umbilical cord of the newborns to measure serum 25(OH)D3, calcium, phosphorus, and parathormone levels. RESULTS: While vitamin D insufficiency was identified as 62.6% in mothers, it was 58.6% in newborns; on the other hand, the incidence of vitamin D deficiency was 18.2% and 15.2% in mothers and newborns, respectively. Maternal serum 25(OH)D3 concentrations were not significantly related to the number of pregnancies or births, type of clothing, or the nutritional, economical, or educational status of the family (P > 0.05). CONCLUSION: These findings suggest that despite a sunny environment, maternal vitamin D deficiency and insufficiency are still important health problems in a developed region of Turkey. Therefore, more effective vitamin D prophylaxis programs are required to prevent vitamin D deficiency in pregnant women and their offspring. PMID- 25551933 TI - Migraine prevalence, disability, and sociodemographic properties in the eastern region of Turkey: a population-based door-to-door survey. AB - BACKGROUND/AIM: To determine the frequency of migraine in the eastern part of Turkey and its sociodemographic characteristics, impact on disability, and clinical aspects. MATERIALS AND METHODS: The study was conducted door-to-door in the eastern part of Turkey. Those who suffered from headaches were diagnosed with migraine as per the 2004 diagnosis criteria of the International Headache Society and its frequency was determined. Demographic data and Migraine Disability Assessment Scale (MIDAS) scores were recorded. RESULTS: Of the individuals evaluated, 60.4% (883) suffered from headaches, of which 43.6% (637) were evaluated as nonmigraine and 16.8% (246) as migraine headaches. Migraine prevalence was detected to be 10.3% (75) in men and 23.1% (171) in women. When the MIDAS scale was considered, 7.3% of the patients were classified with mild pain, 36.9% with mild to moderate pain, 41% with moderate pain, and 14.6% with severe pain. CONCLUSION: Migraine headache has a wide and complex range of symptoms and is frequently observed in women and young adults. The prevalence of migraine among the general population of eastern Turkey was found to be similar to the averages in the rest of the country, as well to the averages of studies in Europe. PMID- 25551934 TI - Effects of osteocytes on vibration-induced reflex muscle activity in postmenopausal women. AB - BACKGROUND/AIM: To assess whether osteocytes have an effect on reflex myoelectrical activity during whole-body vibration (WBV) in postmenopausal women. MATERIALS AND METHODS: Participants were classified into 2 groups: the low bone mineral density (BMD) group (n = 37) and normal BMD group (n = 43). Hip BMD was measured using dual-energy X-ray absorptiometry. Surface electromyography data recorded from the adductor longus muscle were processed to obtain vibration induced reflex myoelectrical activity. Changes in plasma sclerostin (SOST) levels with WBV were expressed as a standardized vibration-induced SOST index. RESULTS: The standardized vibration-induced SOST index was 1.03 +/- 0.24 in the low BMD group and 0.99 +/- 0.33 in the normal BMD group. For plasma SOST levels, no group by-time interaction was found. The resting myoelectrical activities of adductor muscles increased significantly during WBV in both groups. However, there was no significant difference in the main effects of WBV on resting myoelectrical activity between the groups. The standardized vibration-induced plasma SOST index was found to be a significant independent predictor of the standardized vibration induced reflex myoelectrical activity of the adductor muscle in both groups. CONCLUSION: This study suggests that osteocytes serve as mechanoreceptors of reflex electromyography during WBV. PMID- 25551936 TI - Clonal comparison of Acinetobacter strains isolated from intensive care patients and the intensive care unit environment. AB - BACKGROUND/AIM: Acinetobacter baumannii is one of the most commonly encountered microorganisms in nosocomial infections. It is thought that strains found in the environment can be a source for contamination of patients by Acinetobacter strains that are resistant to environmental conditions. This study was carried out to compare Acinetobacter strains isolated from a variety of nonviable environments and from patients in intensive care units (ICUs), and to explore whether environmental areas may be a source for bacterial contamination. MATERIALS AND METHODS: We studied A. baumannii strains isolated from ICU patients. When A. baumannii was isolated from the clinical sample of a patient, swab samples were collected from various areas in the ICU. VITEK 2 (bioMerieux, France) was used for the identification of A. baumannii strains and for antibiotic sensitivity tests. DNA fingerprinting analysis was performed with the repetitive sequence-based polymerase chain reaction (rep-PCR) method using a DiversiLab device (bioMerieux). RESULTS: During the study, a total of 100 A. baumannii strains including 92 samples from 61 patients and 8 samples from the environment were isolated. All of the isolated strains were found to have multiresistance to antibiotics. DNA fingerprinting results showed that 7 of the 8 strains isolated from the environment were identical to many strains isolated from the patients. The greatest similarity between samples was found for 1 A. baumannii strain isolated from a computer keyboard, which was identical to the bacterium isolated from 17 other samples. CONCLUSION: A high level of similarity was found between strains isolated from the environment and patients, suggesting deficiencies in implementation of infection control measures. PMID- 25551935 TI - Determining torsion angle of humerus head using MRI method. AB - BACKGROUND/AIM: To measure the torsion angle of the humerus using images obtained via magnetic resonance imaging (MRI) in healthy volunteers and to evaluate outcomes with respect to sex and age groups. MATERIALS AND METHODS: The study consisted of 36 healthy adults (18 males and 18 females aged between 20 and 68 years). The humeral torsion angle (HTA) was calculated using axial MRI images. Differences between results in terms of sex and age groups were evaluated with the Mann-Whitney U test. RESULTS: The median HTA was 21.5 degrees (25th to 75th percentile: 7.8 degrees -28 degrees; range: -4 degrees to 36 degrees) in females, while it was 18.5 degrees (25th to 75th percentile: 7.5 degrees-32.3 degrees; range: 2 degrees to 41 degrees) in males. HTA median value was 19.5 degrees (25th to 75th percentile: 8.3 degrees-30.5 degrees; range: -4 degrees to 41 degrees) in all healthy volunteers. No significant differences were found between gender and age groups. CONCLUSION: Considering intersocietal anatomic differences, our study may shed light on torsion angle for Turkey by determining mean torsion angle value. Moreover, this study indicated that HTA can be successfully measured using MRI. We think that our outcomes can be used as a reference for prosthesis design and shoulder joint prosthesis replacement. Moreover, we also think that this study will provide benefits in examining pathologies related to the shoulder joint, such as recurrent anterior dislocation syndrome. PMID- 25551937 TI - Attitudes towards influenza vaccination in high socioeconomic status Turkish parents. AB - BACKGROUND/AIM: To better understand the knowledge, attitudes, and demographic factors that influence the rate of influenza vaccination among high socioeconomic status parents. MATERIALS AND METHODS: Questionnaire exploring the attitudes of parents to the influenza vaccine, and their knowledge about influenza and its vaccination, was given to parents of children from 1 through 16 years of age attending the Turgut Ozal University Hospital after the 2011/12 influenza season. RESULTS: In the present study, 285 mothers and their children participated and 8.8% (n = 25) of children had the influenza vaccination. Between the vaccinated and nonvaccinated groups, there were statistically significantly differences for having received the recommendation of the physician, consulting with the physician, having the influenza vaccine previously, and having a chronic disease. The most common misconceptions of the parents about the vaccine were; there being no need for it, it not being useful, it having no effect, and it being harmful. Parents' knowledge about influenza and the influenza vaccine were not satisfactory. CONCLUSION: Reliable information from both health care providers during visits and the media about influenza, its severity, and the effectiveness and side effects of its vaccine should be provided. PMID- 25551938 TI - Genotype distribution of hepatitis C virus in Khorasan Razavi Province, Iran. AB - BACKGROUND/AIM: Several types of the hepatitis C virus (HCV), with variations in different parts of the genome, have been isolated from different regions of the world. Based on heterogenic sequences in the isolated genome, HCV is classified into different genotypes and subtypes. Data on distribution of HCV genotypes in a certain region could be important to patient management. Therefore, this study was conducted to determine the distribution of HCV in Mashhad, Northeast Iran. MATERIALS AND METHODS: This cross-sectional study was conducted on 103 patients with HCV infections in Mashhad. Among the participants, at least 22 (21.4%) were intravenous drug users. HCV seropositivity was determined by an enzyme-linked immunosorbent assay and was confirmed by reverse transcriptase polymerase chain reaction. HCV-positive samples were selected for HCV genotyping using genotype specific primers. RESULTS: Of 103 subjects, 43 (41.7%) and 34 (33.0%) had genotypes 1a and 3a, respectively. Other genotypes including 1b, 2a, 2b, 3b, and 5a were found in 4 (3.9%), 1 (1.0%), 3 (2.9%), 4 (3.9%), and 1 (1.0%), respectively. Coinfections with 2 genotypes were also observed in 11 (10.7%) patients. Genotyping for 2 (1.9%) of 103 samples did not produce any results. CONCLUSION: Genotypes la and 3a were found to be the most prevalent HCV genotypes in Mashhad, Iran. PMID- 25551939 TI - Hepatitis C virus genotypes in Adana and Antakya regions of Turkey. AB - BACKGROUND/AIM: Hepatitis C virus (HCV) genotype 1 was found to be dominant in Turkey. In this study, HCV genotypes were examined in the Adana and Antakya regions of Turkey. MATERIALS AND METHODS: The study consisted of 639 HCV-RNA positive patients with chronic HCV infection in Adana (214 males and 101 females) and Antakya (139 males and 185 females) in Turkey. Real time-polymerase chain reaction was used for genotype determination. RESULTS: In Antakya, it was determined that the percentages of genotypes of type la (0.31%), 1b (86.73%), 2 (9.26%), 3 (0.93%), and 4 (2.78%) were compatible with the nationwide results seen in Turkey. In Adana, the percentages of genotypes of type 1a (3.49%), 1b (55.24%), 2 (14.60%), 3 (26.03%), and 4 (0.63%) were found to be different. This difference was mainly due to the infection rates in males: genotype 1b was significantly lower (42.5% versus 82.2%, P < 0.001) in men in Adana, but genotype 2 (17.8% versus 7.9%, P = 0.021) and genotype 3 (34.6% versus 7.9%, P < 0.001) were significantly higher in men than in women in Adana. CONCLUSION: Rates of genotypes 2 and 3 were unexpectedly high in Adana compared to other parts of Turkey. PMID- 25551940 TI - Transradial approach in the diagnosis and treatment of coronary artery disease: a 2-center experience. AB - BACKGROUND/AIM: To document the safety, success, and complications of transradial coronary procedures. MATERIALS AND METHODS: This retrospective study consisted of 427 patients who had undergone transradial coronary angiography and/or angioplasty between June 2010 and May 2012. The main outcome measures were the procedural safety, success rate, and complications associated with transradial interventions. RESULTS: Procedural success rate was 93.2% (398/427), with cannulation time of 2.1 +/- 1.4 min, diagnostic time of 5.6 +/- 2.1 min, fluoroscopy time of 9.5 +/- 6.6 min, and total procedure time of 47.1 +/- 20.2 min. The main causes for unsuccessful procedures were failed radial puncture (11 patients), serious radial artery spasm (12 patients), and distinct tortuosity (5 patients) and severe proximal stenosis (1 patient) of the right subclavian artery. Of 398 patients, 345 (86.7%) underwent both coronary angiography and angioplasty, while the remaining 53 (13.3%) had coronary angiography only. Major complication was recorded in only 1 patient (transient ischemic attack), whereas minor complications were observed in 76 patients (17 with symptomatic sinus bradycardia, 12 with venous thrombosis, 22 with hematoma, and 25 with radial artery occlusion). CONCLUSION: Our experience revealed that the transradial approach is a safe and feasible method for coronary procedures in patients with various manifestations of coronary disease. PMID- 25551941 TI - Seasonal variation and risk factors associated with surgical site infection rate in Kano, Nigeria. AB - BACKGROUND/AIM: To evaluate the seasonal variations and risk factors associated with surgical site infection (SSI) rate in Kano. MATERIALS AND METHODS: A total of 5800 patients admitted for surgery, drawn from Aminu Kano Teaching Hospital and Murtala Mohammed Specialist Hospital, underwent different types of surgical procedures between January 2010 and December 2011. Out of those patients, 1463 confirmed infected cases were screened for bacterial and fungal infection by standard microbiological procedures. Questionnaires were administered after informed consent to ascertain patients' lifestyles. Medical histories were obtained from their case files. RESULTS: Out of 5800 patients, 1463 were confirmed to be clinically infected, giving rise to a 25.2% incidence of SSI. E. coli (28.0%) and S. aureus (19.0%) were the most frequently isolated SSIs. Over the 2 years of study in the 2 hospitals, infection rates were highest in the month of March and lowest in August. Obesity, diabetes, anemia, number of personnel in the operating room, time of surgery, and position on operation list were all significantly associated with SSI. CONCLUSION: Seasonal variation in SSI rates as observed in this study is a new dimension not reported before in Kano. Further research should be carried out to evaluate this observation critically. PMID- 25551943 TI - Age-related changes in biomechanical parameters of the cornea and intraocular pressure in a healthy Turkish population. AB - BACKGROUND/AIM: To investigate age-related changes in intraocular pressure (IOP) and biomechanical parameters of the cornea in healthy subjects. MATERIALS AND METHODS: There were 404 healthy subjects included prospectively in this study. The subjects were divided into 3 groups (Group 1:93 subjects aged < 18, Group 2:189 subjects aged between 18 and 59, and Group 3:122 subjects aged >= 60). Corneal compensated IOP (IOPCC), Goldmann correlated IOP (IOPg), corneal hysteresis (CH), and corneal resistance factor (CRF) were measured by the Ocular Response Analyzer. RESULTS: When all the study groups were evaluated, a moderately significant negative correlation was found between age and CH and between age and CRF (Spearman's rho = -0.372 and -0.353, respectively; P < 0.0001 for both correlations). There were significant age-related differences among the 3 groups in terms of IOPg, CH, CRF, and central corneal thickness (P = 0.002, P = 0.000, P = 0.000, P = 0.006). There was no confirmation of any difference of IOPcc among the groups (P = 0.427). CONCLUSION: The mean values of IOPg, CH, and CRF were lower than the other parameters in Group 3 but no significant differences were determined in IOPcc values in the age groups. PMID- 25551942 TI - The relationship between lower urinary tract symptoms associated with benign prostatic hyperplasia and erectile dysfunction: the role of autonomic hyperactivity. AB - BACKGROUND/AIM: To investigate whether autonomic nervous system (ANS) hyperactivity may be a potential cause for the relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). MATERIALS AND METHODS: Twenty-four patients were recruited for this study. Complete physical examinations, urine analysis, uroflowmetry, and postvoid residual urine volume (PVRU) analysis were performed. The potential impact of some factors such as hyperglycemia, obesity, and hyperlipidemia were analyzed. These values were correlated with the various symptom scores. We performed an electromyographic and an electrocardiographic evaluation. The alterations after treatment with 2 different alpha-blockers were also analyzed. RESULTS: The electromyographic and electrocardiographic assessments revealed a minimal increase in ANS activity and it did not change significantly after treatment (P > 0.05). After treatment, maximum flow rate increased and PVRU decreased significantly (P < 0.001 and P < 0.001, respectively); total and free testosterone levels increased significantly (P = 0.0068 and P = 0.0071, respectively). There was a statistically significant difference between the 2 treatment groups regarding the outcomes of the Danish Prostate Symptom Score questionnaire (P = 0.047). CONCLUSION: This current study suggested that the effect of ANS hyperactivity is not the fundamental factor underlying the relationship between LUTS and ED. PMID- 25551944 TI - The effect of lateral internal sphincterotomy on resting anal sphincter pressures. AB - BACKGROUND/AIM: Anal fissures are one of the most common proctologic disorders. This study aimed to investigate alterations in anal sphincteric resting pressures after lateral internal sphincterotomy, which was performed for chronic anal fissure treatment. MATERIALS AND METHODS: Fifty-six (68.3%) male and 26 (31.7%) female patients were included in this study. Patients complicated with fistula-in ano, abscess, cancer, inflammatory bowel disease, dermatitis, poor general condition, allergy to any of the standard medications, previous history of anal trauma, previous anal surgery, or diagnosis of a neurological disease and patients who did not give consent to the trial were excluded from the study. Two groups were formed: a control group with 41 healthy volunteers and a study group with 41 chronic anal fissure patients. Preoperative and postoperative manometric anal measurements were compared. RESULTS: Preoperative mean resting anal sphincter pressure was 51.29 mmHg for the control group and was 59.99 mmHg for the patient group. Although resting anal sphincteric pressures of the patient group remained within the physiological range, when compared with the control group there was a statistically significant difference. Postoperative mean resting anal sphincteric pressures of the patient group was 32.43 mmHg. CONCLUSION: Lateral internal sphincterotomy decreases resting anal sphincter pressures effectively in chronic anal fissure patients. PMID- 25551945 TI - Endocrine abnormalities of patients with cleft lip and/or cleft palate during the neonatal period. AB - BACKGROUND/AIM: There are close interactions among the developing oral cavity, pituitary gland, and central nervous system (CNS) in early embryonic life. In this study we aimed to screen endocrine abnormalities in patients with orofacial clefts in the neonatal period. MATERIALS AND METHODS: Thirty-one patients with isolated orofacial median clefts wereincluded in the study. Pituitary, thyroid, and adrenal hormones were measured at the first week and remeasured in the third or fourth weeks. Imaging studies were done for detection of CNS anomalies in all patients. RESULTS: Endocrine abnormality was detected in 22 (70.9%) patients. The number of patients with single and multiple endocrine abnormalities were 13 (41.9%) and 9 (29%), respectively. Thyroid hormone-related disorders were detected in 10 (32.3%) patients. Growth hormone deficiency was detected in 4 (12.9%) patients. Adrenocorticotrophic hormone and/or glucocorticoid deficiency was detected in 5 (16.1%) patients. Neonatal hypoglycemia due to endocrinological abnormalities was detected in 6 (19.4%) patients. Defected mini-puberty was seen in 2 (15.4%) patients. There was no relationship between the types of orofacial cleft and endocrine abnormalities. CONCLUSION: Endocrinological evaluation of the patients with orofacial clefts in the neonatal period is a worthwhile endeavor to detect hormone deficiencies regardless of the type of the cleft. PMID- 25551946 TI - Anesthetic management and perioperative complications in transcatheter aortic valve implantation: the Turkish experience. AB - BACKGROUND/AIM: To describe the anesthetic management and early results of transcatheter aortic valve implantation (TAVI) in a single center in Turkey. MATERIALS AND METHODS: We evaluated 79 (54 females, 25 males; mean age: 76 +/- 9 years) consecutive symptomatic patients with severe aortic stenosis who underwent TAVI under general anesthesia between July 2011 and September 2012. We preferred a transfemoral approach as the first option. RESULTS: The duration of anesthesia was 149 +/- 49 min. Thirty-eight percent of the patients were extubated in the cardiac catheterization laboratory. Three patients required a permanent pacemaker, while 8 patients required inotropic support in the postoperative period. Mortality rate was 9% within 30 days. Fifteen patients had vascular complications, of which 53% were treated surgically. CONCLUSION: Today, as a result of developments in technology, TAVI can be considered as a beneficial alternative treatment option for inoperable aortic stenosis patients. Thus, anesthesiologists will be confronted with a number of TAVI cases, and so they should be prepared to face issues related to the patient's safety both during the administration of anesthesia and in the postoperative period in the near future. PMID- 25551948 TI - Current diagnosis and management of ovarian cysts. AB - The epidemiology of ovarian cysts is unclear due to the lack of consistent reporting and a high likelihood of spontaneous resolution. In the USA, postmenopausal women have an ovarian cyst incidence of 18% over a 15-year period. Worldwide, about 7% of women have an ovarian cyst at some point in their lives. In Europe, a large screening trial revealed a 21.2% incidence of ovarian cysts among healthy postmenopausal women. The American College of Obstetricians and Gynecologists (ACOG) stated that simple cysts found on ultrasound may be safely followed without intervention, even in postmenopausal women. These cysts are not likely cancer precursors, nor markers of increased risk, and can be managed conservatively. Simple ovarian cysts appear to be stable or resolve by the next annual examination. These findings support recent recommendations to follow unilocular simple cysts in postmenopausal women without intervention. For those patients, ovarian cancer screening and follow up include a CA-125 blood test and transvaginal ultrasonography (TVU) at baseline, an annual TVU for three additional years, and annual CA-125 tests for five years beyond baseline. The TVU screening examination is considered positive (abnormal and suspicious for ovarian cancer) when findings included: 1) ovarian volume greater than 10 cubic cm; 2) cyst volume greater than ten cubic cm; 3) any solid area or papillary projection extending into the cavity of a cystic ovarian tumor of any size; or, 4) any mixed (solid/cystic) component within a cystic ovarian tumor. Women with positive screening examinations are referred to gynecologic oncology unit for follow-up investigation. Diagnostic consideration and surgical management of ovarian cysts are discussed. PMID- 25551947 TI - Early graft dysfunction and mortality rate in marginal donor liver transplantation. AB - BACKGROUND/AIM: To determine the effect of marginal donor livers on mortality and graft survival in liver transplantation (LT) recipients. MATERIALS AND METHODS: Donors with any 1 of following were considered marginal donors: age >=65 years, sodium level >= 165 mmol/L and cold ischemia time >= 12 h. Donors were classified according to the donor risk index (DRI) < 1.7 and >= 1.7. The transplant recipients' model for end-stage liver disease (MELD) scores were considered low if < 20 and high if >= 20. Early graft dysfunction (EGD) and mortality rate were evaluated. RESULTS: During the study period 47 patients underwent cadaveric LT. The mean age of the donors and recipients was 45 years (range: 5-72 years) and 46 years (range: 4-66 years), respectively. In all, there were 15 marginal donors and 18 donors with a DRI > 1.7. In total, 4 LT patients that received livers from marginal donors and 5 that received livers from donors with a DRI >= 1.7 had EGD. Among the recipients of marginal livers, 5 died, versus 4 of the recipients of standard livers. There was no significant difference in EGD or mortality rate between the patients that received livers from marginal donors or those with a DRI >= 1.7 and patients that received standard donor livers. CONCLUSION: Marginal and DRI >= 1.7 donors negatively affected LT outcomes, but not significantly. PMID- 25551949 TI - Platelet-activating factor acetylhydrolase and premature ovarian failure. AB - Premature ovarian failure (POF) appears to be a complex disease entity with several underlying etiopathogenic contributions including the possibility of multiple distinctly different autoimmune mechanisms, in which inflammatory autoimmunity targeted to ovarian-specific germline antigens (e.g., zona pellucida proteins or Mater) or differentiation/regulatory factors (e.g. inhibin-alpha) were regarded as one of the most crucial factors. Platelet-activating factor (PAF) and PAF class oxidized phospholipids stimulate the occurrence and development of inflammation and atherosclerosis. PAF acetylhydrolase (PAF-AH) can hydrolyze PAF and PAF class oxidized phospholipids and eventually prevent the body from the damage of these inflammatory mediators. These findings indicate a potential relationship between PAF-AH and POF thus have major implications for the future health of women who suffer with premature ovarian failure. PMID- 25551950 TI - Behcet disease and pregnancy. AB - PURPOSE: Behcet disease (BD) is a multisystemic vaculitis commonly diagnosed in reproductive years. The authors aimed to investigate the relationship between BD and pregnancy outcomes. MATERIALS AND METHODS: In this multicenter retrospective survey study, the authors compared the pregnancy outcomes of BD patients with the healthy controls. RESULTS: A total of 298 pregnancies of 94 patients with BD and 219 pregnancies of 95 healthy controls were evaluated. The mean birth weight of all babies of women with BD and the control group were 3,214 grams and 3,351 grams, respectively (p = 0.028). The miscarriage rates were also higher in the BD group. The com- plication rates of pregnancy with hypertension, preeclampsia, preterm labour in the study group and the control group were 12.8% and 11.6%, respectively (p = 0.489). CONCLUSION: The current study demonstrated that BD patients delivered smaller babies and they have higher miscarriage rates when compared to the healthy controls which might be due to the vasculitis of the placenta. PMID- 25551951 TI - Proteomic investigation of the severe preeclampsia treatment by low molecular weight heparin. AB - PURPOSE: The primary goal of this study is to investigate the mechanism of severe preeclampsia (PE) treatment by low molecular weight heparin (LMWH). MATERIALS AND METHODS: Using two-dimensional difference in-gel electrophoresis (2D-DIGE) combined with matrix assisted laser desorption ionization-time-of-flight/time-of flight mass spectrometry (MALDI-TOF/TOF) approach to identify the proteins that expressed differently in the serum samples of five patients before and after subcutaneous injection of LMWH (0.4 ml/person). RESULTS: Seven protein spots were identified in 2D-DIGE that show significant change in expression level after LMWH treat- ment. Further analysis of seven protein spots with MALDI-TOF/TOF identified six different proteins. To confirm the proteomic data, two meaningful proteins of the six proteins, alpha-1-acid glycoprotein (AGP) and serotransferrin are subjected to immunoblotting. All of the proteins are obviously down-regulated after LMWH treatment. CONCLUSIONS: PE is a pregnancy-specific disease that clinically manifests as new-onset hypertension and proteinuria after 20 weeks of gestation. LMWH is an effective treatment of severe PE. The present proteomics based investigation may provide a new angle to understand the mechanism of severe PE treatment with LMWH. PMID- 25551952 TI - Effectiveness of ultrasound-guided transversus abdominis plane block and rectus sheath block in pain control and recovery after gynecological transumbilical single-incision laparoscopic surgery. AB - PURPOSE: To evaluate the effectiveness of ultrasound-guided transversus abdominis plane (TAP) and rectus sheath (RS) blocks in pain management and recovery after gynecological single-incision laparoscopic surgery (SILS). MATERIALS AND METHODS: Abilateral TAP block (Group A, n = 9), bilateral TAP and RS blocks (Group B, n = 10), and a bilateral RS block (Group C, n = 9) with 40 ml ropivacaine per patient were conducted in 28 patients undergoing SILS for ovarian tumors. A pain score and walking distance in a 6-minute walk test (6MWT) were examined. RESULTS: Pain scores were significantly lower on postoperative day (POD) 3 than on POD 1 in Groups B (p = 0.03) and C (p = 0.02). The walking distance on POD 3 was comparable with that before surgery in Group C (p = 0.75), but shorter in Groups A (p = 0.004) and B (p = 0.02). CONCLUSIONS: The RS block alone was the most effective in relieving pain and accelerating general recovery after gynecological SILS. PMID- 25551953 TI - Histologic changes caused by nonabsorbable sutures after ovarian suspension. AB - PURPOSE: To evaluate intraovarian histologic changes caused by polypropylene and silk sutures that commonly are used in ovarian suspension. MATERIALS AND METHODS: Twenty-four female rats were randomly allocated to three study groups: a sham group receiving no ovarian suspension; the other two groups that had right ovarian suspension with polypropylene and silk sutures. At 90 days after surgery, the histologic changes and ovarian weight reduction in the suspended ovaries and severity of pelvic adhesions were evaluated. RESULTS: There were no differences between study groups in focal inflammation, cystic structures, or vascularity. Adhesion severity and ovarian weight reduction in suspended ovaries and cysts around the suspended ovary were significantly greater in the silk than sham group. The frequency of hematoma within the suspended ovary was significantly greater in the polypropylene than sham group. CONCLUSIONS: Polypropylene suture caused less adhesion severity or ovarian weight reduction than silk suture. This suggests that polypropylene suture may be the better suture for ovarian suspension procedures. PMID- 25551954 TI - Exaggerated placental site/placental site trophoblastic tumor: an underestimated risk factor for emergency peripartum hysterectomy. AB - OBJECTIVE: To assess the indications and possible underlying causes of emergency peripartum hysterectomy (EPH) at the present hos- pital during the 2001-2011 period. MATERIALS AND METHODS: A revision of the charts and pathology reports corresponding to 42,728 parturients. RESULTS: During the study period, 25 peripartum hysterectomies were performed (0.61/1.000), of which 23 were EPHs (0.54/1.000) and two were planned cesarean hysterectomies. The indication for EPH was acute postpartum hemorrhage in 22 of 23 instances (95.7%). Roughly two-thirds of the operated uteri (16/25, 64%) showed placental site anomalies, half corresponding to different degrees of placental accretism and half to anomalies derived from the implantation site intermediate trophoblast. In five cases (31%), the anomaly was an exaggerated placental site and three cases corresponded to placental site trophoblastic tumors. Of the 16 cases showing placental site anomalies, ten (62.5%) were associated with one or more previous cesarean sections. CONCLUSIONS: Roughly one-third of EPHs performed at the present center during the last ten years were associated with placental site anomalies originating in the implantation site intermediate trophoblast (exaggerated placental site and placental site trophoblastic tumor). This association has not been described before, and should be taken into consideration when facing acute peripartum hemorrhage predisposing to EPH. PMID- 25551955 TI - Treatment of tubal pregnancy using comprehensive interventional methods. AB - OBJECTIVE: To investigate the efficacy of combined interventional methods in treatment of tubal pregnancy. MATERIALS AND METHODS: One hundred sixty-two patients with tubal pregnancy were enrolled in this study. In all patients, the feeding uterine artery at affected side was perfused with methotrexate (MTX), followed by occlusion using gelatin sponge. Nineteen patients were also treated by perfusion of MTX in ovarian artery at affected side which partially participated in blood supply. Seven patients received direct puncture perfusion of MTX under B ultrasound guidance. Four cases received perfusion of MTX through fallopian tube. After surgery, the serum beta-human chorionic gonadotropin (beta HCG) level was regularly detected, and B ultrasound was used to monitor the pelvic mass change. For 33 patients with fertility requirement, hysterosalpingography (HSG) was conducted after menstruation restoration. RESULTS: Tubal pregnancy was terminated in 160 patients (98.76%), with inefficacy in two patients (1.23%) who were treated by surgery. HSG showed tubal patency in 27 patients. Tubal obstruction was found in the other six patients. After recanalization, three cases were unobstructed, with obstruction in other three cases. Fifteen patients achieved intrauterine pregnancy after six to 17 months from surgery. CONCLUSIONS: Comprehensive interventional treatment can prevent internal bleeding caused by failure of many conservative treatments, improve the indication and success rate of treatment, and preserve the complete fallopian tube. PMID- 25551956 TI - Folic acid and neural tube defects: are Jordanian pregnant women aware? AB - OBJECTIVES: To assess Jordanian pregnant women's awareness of folic acid and its contribution to neural tube defects (NTDs) prevention and to their folic acid intake. MATERIALS AND METHODS: One thousand pregnant women were interviewed about their knowledge of folic acid for NTDs prevention and their folic acid intake using a questionnaire. RESULTS: Of 1,000 women surveyed, 93.4% reported hearing of folic acid and 30.3% of NTDs. Only 16.2% knew that folic acid can reduce NTDs risk; 42.0% of those aware of folic acid believed it should be taken periconceptionally but only 16.9% did so. The most common information sources on folic acid were physicians (82.8%). CONCLUSIONS: Whereas a large percentage of pregnant Jordanian women were aware of folic acid, only a small proportion are aware that it prevents NTDs and should be taken periconceptionally. Also, there was a gap between awareness, knowledge, and intake of folic acid. Awareness and knowledge of NTDs was less prevalent among Jordanian women. Despite the efforts that have been undertaken, further effort is required to educate Jordanian women about folic acid contribution to NTDs prevention. PMID- 25551957 TI - Clinical analysis of emergency peripartum hysterectomies in a tertiary center. AB - OBJECTIVE: To investigate the incidence, indications, complications, and risk factors associated with increased mortality and morbidity of emergency peripartum hysterectomy (EPH). MATERIALS AND METHODS: The authors retrospectively analyzed 48 cases of EPH performed within six-year interval at Ondokuz Mayis University Hospital. EPH was defined as the operation performed for life-threatening hemorrhage which could not be controlled with conservative treatment modalities within 24 hours of a delivery. RESULTS: The incidence of EPH was 5.03 per 1,000 deliveries. The most common indication for EPH was abnormal placental adherence (n = 22, 45.8%), followed by uter- ine atony (n = 19, 39.6%). All the patients with placenta accreta had a history of repeat cesarian section (CS) and placenta previa.Total hysterectomy was performed in almost all of the patients (n = 47, 97.9%). All women required blood transfusions. Maternal morbidity was significant, with bladder injury (31.3%) and disseminated intravascular coagulation (18.7%) among the most common complications. There were one maternal (2.1%) and five neonatal deaths (10.4%). CONCLUSION: Since most of the EPH cases are associated with prior cesarean delivery, decision of the first CS should be made for true obstetrical indications.If conservative treatments fail to control massive obstetrical bleeding, blood products and an experienced obstetrician should be ready to perform EPH to decrease the maternal mor- bidity and mortality. PMID- 25551958 TI - Premature ovarian failure: diagnosis and treatment. AB - Premature ovarian failure (POF), also known as primary ovarian insufficiency, is diagnosed in the event when primary or secondary amenorrhea and hypoestrogenism with high levels of gonadotropins occur in women before the age of 40. POF, caused by genetic, autoimmune and environmental factors, leads to a decrease in numbers of primordial follicles, accelerated atresia, and impaired follicular function. The diagnosis of POF is an indication for hormonal replacement therapy (HRT), which should be continued until the mean age of menopause in a given population. HRT reduces the intensity of vasomotor symptoms and has a beneficial effect on the central nervous, skeletal, cardiovascular, and urinary-reproductive systems. PMID- 25551959 TI - Manual versus computer-automated semen analysis. AB - OBJECTIVE: To evaluate agreement of conventional sperm analysis with computer aided semen analysis (CASA) regarding concentration, motility, and morphology using samples from infertile men. MATERIALS AND METHODS: In this study a total of 195 male partners of couples who underwent evaluation of infertility were included. All semen samples were examined by conventional method and CASA in terms of morphology, motility, and concentration. Pearson correlation analysis and the Bland-Altman method were used to assess correlation and agreement between conventional semen analysis and CASA measurements. RESULTS: When the two methods were compared in terms of concentration, motility, and morphology, there was a statistically significant correlation in all variables. The best correlation was obtained for sperm concentration. However, there was a poor correlation for sperm morphology between conventional method and CASA. Sperm concentration and morphology obtained by CASA were 14% and 87% lower, respectively; motility was 21% higher than the conventional method. CONCLUSION: Although CASA systems are objective and rapid, they should be evaluated in terms of cost-effectiveness, however they may be useful in over-loaded assisted reproductive technique (ART) clinics. PMID- 25551960 TI - Association study of vascular endothelial growth factor gene polymorphisms with ectopic pregnancy in Chinese women. AB - OBJECTIVE: The purpose of this study is to evaluate potential associations between vascular endothelial growth factor (VEGF) gene polymorphisms and ectopic pregnancy (EP) in Chinese women. MATERIALS AND METHODS: This was a case-control study wherein 192 women with a history of EP were compared to 210 post-menopausal controls with two pregnancies and no EP for the genotyping of VEGF polymorphisms. Genotyping of the VEGF gene polymorphisms at -460C/T, -1 154G/A, -2578C/A and +936C/T were performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: No significant differences were found in genotype and allele distributions of the -460C/T, +936C/T polymorphisms between cases and controls. Compared with the -1154G/G genotype, the -1154(A/A+G/A) genotype could significantly reduce the risk of developing EP. For the -2578C/A polymorphism, the A/A+C/A geno- type could significantly decrease the risk of developing EP, compared with the C/C genotype. The haplotype analysis suggested that the TAA (VEGF -460/-1154/-2578) and CAA haplotypes could significantly decrease the risk of developing EP compared with the haplotype of TGC. CONCLUSION: The -1154A or 2578A alleles of VEGF gene could significantly decrease the risk of EP and might be po- tentially protective factors for EP development in Chinese women. PMID- 25551961 TI - Risk of pelvic floor dysfunctions in young athletes. AB - PURPOSE OF INVESTIGATION: Numerous epidemiological studies have shown a correlation between sport and the development of pelvic floor dysfunction. Therefore, the aim of the present study was to evaluate the prevalence of urinary incontinence in female young athletes. MATERIALS AND METHODS: The epidemiological study was conducted on 105 female volleyball players, who were given a questionnaire, self-compiled, consisting of four main domains (personal data and medical history, urinary incontinence, urinary disorders, and judgment on the questionnaire). RESULTS: In a total of 105 athletes, the present authors observed that 65.7% had reported at least one symptom of stress urinary incontinence (SUI) and/or urgency, during sport or in daily life situations. In particular, the 49.52% reported urge urinary incontinence, 20% urine loss for urgency, and 29.52% SUI. In addition, the present authors observed that nocturia was reported in 70.48% of cases, incomplete bladder emptying in 55.24%, urinary hesitancy in the 36.19%, and pelvic pain in 52.38%. In all cases, the symptoms were occasional and low. In relation to the coexistence of symptoms, the present authors observed that 22.85% of athletes had only symptoms of urge urinary incontinence, 6.66% mixed incontinence, and 6.66% symptoms of urge urinary incontinence associated to urine loss for SUI. CONCLUSION: The present authors observed a relationship between the sport and the pelvic floor dysfunction, in particular urinary incontinence. PMID- 25551962 TI - Maternal soluble vascular cytoplasmic adhesion molecule-1 and fibronectin levels in early- and late-onset preeclamptic pregnancies. AB - OBJECTIVE: The purpose of this study was to investigate maternal plasma soluble vascular cytoplasmic adhesion molecule-1 (sVCAM-1) and fibronectin levels in the patients with early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP) and also to determine whether different mechanisms are involved in these two forms of disorders. MATERIAL AND METHODS: The authors performed a case control study consisting of randomly selected 80 healthy pregnant women (group 1 = control group) and 80 preeclamptic women (group 2 = defined study group). Study group consisted of43 patients with EOP and 37 patients with LOP. sVCAM-1 and fibronectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and the findings were compared between the groups. RESULTS: The mean levels of sVCAM-1 and fibronectin were significantly higher in the LOP group than those in the normotensive group (p = 0.043 and 0.010 respectively). Markers were significantly different between the two hypertensive groups of pregnancy. The EOP group had a higher level of sVCAM-1 and fibronectin concentration than the LOP group (p = 0.01, for both markers). There was a positive correlation both between the values of plasma fibronectin and the systolic-diastolic blood pressure measurements (r:0.43 and 0.44, respectively), and between sVCAM-1 and the systolic/diastolic blood pressure measurements (r = 0.54 and 0.64, respectively). CONCLUSION: Increased plasma levels of fibronectin and sVCAM-1 were found in the preeclamptic patients, especially in those with early-onset preeclampsia. These markers might be related to the pathogenesis of different types of preeclampsia. PMID- 25551963 TI - Can combination of Day 3 and Day 5 embryo morphology be useful to predict pregnancy in in-vitro fertilization cycles? AB - OBJECTIVE: To determine whether embryos having all top qualified both on Day 3 and Day 5 have higher pregnancy rates than the oth- ers. MATERIALS AND METHODS: The study included 143 consecutive cycles were recruited in which Day 5 embryo transfer was available. Cleavage stage embryos were graded according to 1 to 4 scoring system, based on fragmentation, cell symmetry, and blastomere num- ber. Among cleavage stage embryos, Grade 1 and Grade 2a/2b were further stratified as 'top quality' embryos to be transferred, others were defined as control group. Blastocyst stage embryos were graded from 1 to 6 according to intracellular mass (ICM) and trophec- toderm (TE). Day 5 fresh embryo transfer was performed in all cases using soft catheter. Positive pregnancy test was accepted when serum beta human chorionic gonadotrophin (1-hCG) exceeded 20 mIU/ml. RESULTS: On the cleavage stage, top quality embryo was available in 47 of 143(32.9%) cases. Of the 47 embryos, the number of cases reaching any Grade 4, 3 quality, and early blastocyst on Day 5 were 22 (46.8%), 15 (31.9%), and 10 (21.3%). The respective figures on the control group (n = 96) were 33 (34.4%), 37 (38.5%), and 26 (27.1%) (p > 0.05). The pregnancy rates were also similar. CONCLUSION: All top qualified embryos both on Day 3 and 5 did not reveal higher pregnancy rate than the others. PMID- 25551964 TI - Vaginal preparation with povidone iodine disinfection and saline douching as a safe and effective method in prevention of oocyte pickup-associated pelvic inflammation without spoiling the reproductive outcome: evidence from a large cohort study. AB - PURPOSE OF INVESTIGATION: The aim of this study was to investigate if vaginal preparation procedure affects the occurrence of oocyte pickup-associated pelvic inflammation (OPU-PI) and the reproductive outcome in an in vitro fertilization (IVF) program. MATERIALS AND METHODS: The occurrence of OPU-PI and the reproductive outcome were compared between 956 infertile patients undergoing vaginal preparation with saline douching alone versus 1,216 infertile patients undergoing a combination ofpovidone iodine disinfection and subsequent saline douching in an IVF program. RESULTS: OPU-PI occurred in four patients (0.042%) in the saline douching alone group, whereas there were no cases in the combination group (p = 0.016). There were no significant differences in the rate of fertilization, morphologically good embryo acquisition, clinical and ongoing pregnancy between the two groups (p > 0.23). CONCLUSIONS: This large cohort study demonstrated that a combination of vaginal povidone iodine disinfection and subsequent saline douching is more effective procedure than saline douching alone to prevent OPU-PI, without spoiling the oocyte quality. PMID- 25551965 TI - Elevated tissue levels of tumor necrosis factor-alpha in vulvar vestibulitis syndrome. AB - The purpose of this study was to compare levels of inflammatory cytokines, namely TNF-alpha, IL-1beta, and IL-1 receptor in women with vulvar vestibulitis syndrome (VVS) relative to levels in controls. The authors hypothesized that tissue concentrations of inflammatory cytokines would be elevated significantly in women with VVB compared to pain-free controls. The study population consisted of 15 women with strictly defined VVB in reproductive age and 13 age-matched women with no history of vulvodynia. For TNF-alpha, positive staining was observed in 40% of the samples from the study group and in 7.7% of the samples from the control group. The difference between the groups was statistically significant (p < 0.05). In conclusion, a limitation of the present study was the relatively small sam- ple size. However, the authors' intention was simply to propose that the local inflammation may be mediated by cytokines as TNF-alpha may rather than trying to single out a pathogenesis of VVS. The authors' findings of elevated TNF alpha may suggest new therapeutic alternatives for VVS, as inhibiting cytokine synthesis or antagonism of the cytokine receptor. PMID- 25551966 TI - MRI and MRI 3-D reconstruction of anatomic characteristics of the cardinal and uterosacral ligaments in uterine prolapsed women. AB - OBJECTIVE: This study aimed to evaluate the anatomical alterations of the cardinal ligaments (CL) and uterosacral ligaments (USL) in women with uterine prolapse by magnetic resonance imaging (MRI) and MRI three-dimensional reconstruction (3DR). MATERIALS AND METHODS: Forty patients with uterine prolapse and 40 volunteers with normal support underwent thin layer scan MRI. The 3D models were reconstructed with MRI data and 3D software. Origin, inserted end, geometric shape features of the CL and USL, were compared between the two groups, and the correlation in study group between the MRI and surgical dissection were reported. RESULTS: In the study group, trauma was found in the USL in the insertion or origin. The dorsal USL attached to the sacrum in four (10%) patients was quite different from 12 (30%) patients of the control group. There was no significant difference in the inserted end of the USL between the two groups, nor in the origin and inserted end of the CL. In the study group, MRI and MRI 3DR better evaluated the anatomical characteristics of the USL compared to intraoperative detection via laparoscopy. DISCUSSION: The approach using MRI and MRI 3DR can non-invasively detect the anatomic abnormality associated with the USL in uterine prolapsed women and can be a useful preoperative planning tool. PMID- 25551967 TI - Serum neutrophil gelatinase associated lipocalin and plasma nitric oxide levels in healthy and preeclamptic pregnants. AB - AIMS: The authors aimed to evaluate serum neutrophil gelatinase associated lipocalin (NGAL) and plasma nitric oxide (NO) levels in preeclamptic and healthy pregnant women above 24 gestation weeks. MATERIALS AND METHODS: Forty-nine healthy and 21 preeclamptic (total 70) pregnant women participated voluntarily in the study. Presence of 140 mmHg and above systolic and 90 mmHg and above diastolic blood pressure which emerges after 20th gestation week, proteinuria more than 300 mg/24 hour, and edema were used as diagnostic criterion for preeclamptic pregnant women. Measurements of serum NGAL and plasma NO were performed with enzyme linked immunosorbent assay (ELISA) and photometric method, respectively. RESULTS: Serum NGAL and plasma NO levels of healthy and preeclamptic groups did not show a statistical difference. In preeclamptic group, a statistically meaningful correlation was found between level of NGAL and body mass index (BMI) of sampling time, creatinine and NGAL, total protein and NO, and albumin and NO. CONCLUSIONS: Serum NGAL levels, correlated with serum creatinine levels in this study, may be the early marker of renal damage which may develop mainly due to inflammation and endothelial damage. The authors could not find a statistical difference for serum NGAL and plasma NO levels between healthy pregnant and preeclamptic groups. Varieties peculiar to humans in preeclampsia, impossibility of obtaining first trimester tissue material as an evidence of inadequate trophoblast invasion, and different appearance of maternal reaction to underlying main pathology in every case may restrict clarification of etiopathogenesis. PMID- 25551968 TI - Investigation and analysis of contraceptive measures towards different reproductive-aged women in Yangzhou. AB - OBJECTIVE: This study aims to retrospectively investigate the contraceptive methods of different reproductive-aged women in two different regions of Yangzhou, China, to understand the changes of the contraceptive methods, and to analyze the targeted improvements of future informed choices of contraception and birth control, and reduce the occurrence of the unintended pregnancies. MATERIALS AND METHODS: This study included 13,407 and 20,876 married reproductive-aged women (MCW) that were chosen from a city downtown and a county-level city, respectively, for the group-organized random sampling questionnaire survey. RESULTS: There was a significant urban-rural difference in the choice of contraceptive methods in different MCW. The female choices of contraception were single; the accessibility of contraceptive supplies, and personalized services could improve the implementation rate of long-term contraceptive measures. The cooperation of male contraceptive responsibility was related to the education levels and enhanced male-female communication. CONCLUSIONS: It was very important for urban and rural women with different ages to choose different contraceptive measures, suggesting that these choices require the development of different educational models towards women of different ages and regions. The accessibility to various aspects of counseling and contraceptive measures should be strengthened, meanwhile male participation should also be promoted to prevent unwanted pregnancies and to reduce the health hazards related to sexual activities. PMID- 25551969 TI - Does the estradiol level on the day of human chorionic gonadotropin administration predict the clinical outcome of controlled ovarian hyperstimulation? AB - OBJECTIVE: To investigate the effect of serum estradiol (E2) levels on the day of human chorionic gonadotropin (hCG) administration on the outcome of controlled ovarian hyperstimulation (COH) in both long gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist protocols. MATERIALS AND METHODS: This study included 212 in vitro fertilization-embryo transfer (IVF-ET) cycles performed with either long GnRH agonist or GnRH antagonist protocols were classified into three groups according to serum E2 levels measured on the day of hCG injection: < 2,000 pg/ml, 2,000-4,000 pg/ml, and > 4,000 pg/ml. The three groups were compared according to age, number of retrieved oocytes, number of transferred embryos, and pregnancy rates for each of the stimulation protocols. RESULTS: The long and antagonist protocols were performed in 130 and 82 cycles, respectively. The pregnancy rates were 21.5% (28/130) and 23.2% (19/82) in the long- and antagonist-protocol groups, respectively. Serum E2 levels were measured on the day of hCG administration as < 2,000 pg/ml in 65 cycles, 2,000-4,000 pg/ml in 76 cycles, and > 4,000 pg/ml in 71 cycles. The number of retrieved oocytes increased in parallel to serum E2 levels (p = 0.001). However, there was no significant difference among groups in the pregnancy rates (p = 0.116). Similarly, the number of retrieved oocytes increased in parallel to serum E2 levels in both of the protocol groups (p value was 0.001 in both long GnRH agonist and antagonist protocols), but there was no correlation between the pregnancy rates and serum E2 levels (p value of long GnRH agonist protocol was 0.254 and thep value of antagonist group was 0.349). CONCLUSION: The serum E2 level on the day of hCG administration does not predict the pregnancy outcome in IVF with either long GnRH agonist or GnRH antagonist protocols. PMID- 25551970 TI - Relation of red cell distribution width to the presence and severity of endometriosis. AB - AIM: Although the exact pathogenesis of endometriosis is not known, it is proposed to be a chronic inflammatory disease. The asso- ciation between red cell distribution width (RDW) and inflammation is well established. Therefore, in the present study, the authors aimed to investigate the association between presence and severity of endometriosis and RDW. MATERIALS AND METHODS: Fifty endometriosis patients and 48 controls were included in the study. The endometriosis group was categorized in two subgroups as mild-to-moderate (n = 35) and moderate-to-severe disease (n = 15). CA-125 and RDW values of all participants were measured. RESULTS: Both RDW (17.7 +/- 2.2 vs 14.9 +/- 1.5, p < 0.001) and CA-125 (50.6 +/- 35.1 vs 27.9 +/- 4.8) levels were significantly higher in the endometriosis patients when compared to the control group. Moreover the authors found a significant positive correlation between RDW and CA-125 levels (r: 0.495, p < 0.001). CONCLUSION: The present study results demonstrated that RDW levels were significantly increased in endometrio- sis patients and associated with the severity of endometriosis. PMID- 25551971 TI - Influence of aggressive nutritional support on growth and development of very low birth weight infants. AB - AIM: To investigate the influence of the early postnatal aggressive nutritional support on the very low birth weight infants (VLBWI) during hospitalization. MATERIALS AND METHODS: Surviving premature infants without obvious deformity, with gestational age more than 28 weeks and less than 32 weeks, birth weight 1,000 g to 1,500 g, admitted in NICU in Affiliated Children's Hospital of Suzhou University during 12 hours after birth and stay for two weeks or more from January 2008 to December 2011 were selected, including 44 cases (admitted from September 2010 to December 2011) in the observation group and 36 cases in the control group (admitted from January 2008 and September 2010). The infants in the observation group were treated by aggressive nutritional management, while traditional nutritional management for infants in the control group. The variations of nutritional intake, weight gain, jaundice index, blood biochemistry, serum electrolytes indexes, and complications were compared between the two groups. RESULTS: Compared to the control group, the average growth rate and the albumin (ALB) and prealbumin (PA) levels two week after birth and before leaving hospital of the infants in the observation group was significantly higher (p < 0.05), and the incidence of the extrauterine growth retardation was significantly decreasing (p < 0.05). However, the days of hyperbilirubinemia, highest value of the serum bilirubin, duration ofjaundice, platelets after intravenous nutrition, liver function, blood lipid levels, blood glucose, blood PH, serum creatinine, urea nitrogen, and electrolytes of the first day and the seventh day after birth and the in- cidence of parenteral nutrition-associated cholestasis (PNAC) and necrotizing enterocolitis (NEC) between the two group had no difference (p > 0.05). CONCLUSION: The implementation of aggressive nutritional management on the with VLBWI was safe and effective. PMID- 25551972 TI - Marked improvement of vulvovaginitis of unknown origin in a pediatric patient- case report. AB - PURPOSE: To present a novel therapy for pediatric vulvovaginitis. MATERIALS AND METHODS: An eight-year-old girl with persistent severe vulvovaginitis of unknown origin also complained of unexplained weight gain and sudden academic difficulties. She was treated with dextroamphetamine sulfate. RESULTS: She not only showed very quick and excellent relief from her vulvovaginitis but she also lost weight and improved her mentality. CONCLUSIONS: Sympathomimetic amine therapy may benefit pediatric vulvovaginitis when an infectious cause cannot be ascertained. PMID- 25551973 TI - Intraoperative asystole associated with fibroid uterus. AB - The authors present the case of a patient with a large retroperitoneal fibroid whose laparotomy was abandoned due to intraoperative asystole. Perioperative management and possible etiological factors are discussed in this paper. PMID- 25551974 TI - Pregnancy and delivery after vesico ileocystoplasty--a case report. AB - Neobladder is continent urinary reservoir made from a detubularized segment of bowel, with implantation of ureters and urethra. The most common indication for this operation is bladder replacement after cystectomy following bladder cancer in elderly or cervical cancer Stage IV patients. Nowadays indications are expanded to many benign diseases (interstitial cystitis (IC), neurogenic bladder, chronic pelvic pain) in reproductive age. Pregnancy in women with neobladder is a rare condition, hence published experience is limited. Most of the published cases were delivered by cesarean, due to the concern for possible complications. The authors report a case of a 36-year-old woman who underwent a vesico ileocystoplasty for IC, became pregnant six years after the operation, and delivered a healthy baby vaginally. Her obstetric and urologic outcomes were assessed, during, and after pregnancy. Careful antenatal monitoring by both an obstetrician and a urologist, awareness of potential complications, and their prompt treatment, can result in a successful pregnancy and vaginal delivery where neither fetus or mother nor neobladder are endangered. PMID- 25551975 TI - Posterior reversible encephalopathy syndrome in obstetric patients. Report of three cases with literature review. AB - Posterior reversible encephalopathy syndrome (PRES) is a serious clinico neuroradiological maternal complication in pregnancy. Although it has various etiologies such as hypertensive encephalopathy, renal failure, autoimmune disorders, sepsis, multiple organ failure, and treatment with immunosuppressant or cytotoxic agents, pregnancy and postpartum complicated by hypertensive disorders more frequently lead to this condition. PRES is clinically characterized by headache, confusion, seizures, vomiting, and visual disturbances with radiographic vasogenic edema especially affecting symmetrical parietal and occipital lobes. The underlying pathophysiology is still a matter of debate. Prompt recognition and early intervention greatly improve the prognosis, so that obstetricians should be well aware of this rare entity. Timely imaging is of crucial importance especially in patients with an uncertain diagnosis for determining the appropriate treatment and preventing the possible development of neurologic deficits. In the present report, three cases of PRES are presented with clinical and radiological findings in pregnancies complicated by severe pre eclampsia and eclampsia. The latest literature in the field is also carefully reviewed. PMID- 25551976 TI - Psychosexual and social consequences in a woman with undiagnosed Mayer-Rokitansky Kuster-Hauser syndrome. AB - PURPOSE: To report a woman with devastating psychosexual and social consequences as a result of undiagnosed Mayer-Rokitansky- Kuster-Hauser syndrome (MRKH) syndrome. MATERIALS AND METHODS: An 18-year-old woman was referred after being divorced for "absent vagina and uterus". On examination, secondary sexual characteristics were normal. Vaginal and rectal examinations revealed absent vagina and uterus. Investigations showed normal hormonal profile, 46 XX karyotype, and normal intravenous pyelography. Pelvic ultrasonography and magnetic resonance imaging (MRI) confirmed the absence of the uterus and presence bilateral ovaries. RESULTS: A diagnosis of MRKH syndrome was made and she underwent successful modified laparoscopic Vecchietti operation for creation of a new vagina. Vaginal dilators were used after the surgery. Two years of follow up confirmed that vaginal length was about ten cm. CONCLUSION: The proper diagnosis, counseling, and prompt treatment of MRKH syndrome can prevent tragic consequences. PMID- 25551977 TI - [JSN and MHLW Clinical Practice Guideline for PKD 2014]. PMID- 25551978 TI - [Regulatory mechanism of bone metabolism]. PMID- 25551979 TI - [Mechanism of calcification]. PMID- 25551980 TI - [Regulation of parathyroid hormone secretion and pathogenesis of secondary hyperparathyroidism]. PMID- 25551981 TI - [FGF23 in CKD-MBD]. PMID- 25551982 TI - [Role of vitamin D in chronic kidney disease]. PMID- 25551983 TI - [Chronic kidney disease as a fracture risk]. PMID- 25551984 TI - [CKD-MBD as a predictor of mortality]. PMID- 25551985 TI - [Conservative management and pharmacological intervention for CKD-related mineral and bone disorder]. PMID- 25551986 TI - [Clinical characteristics of patients with IgA nephropathy and long-term survival after dialysis therapy]. AB - BACKGROUND AND OBJECTIVES: Little is known about the treatment and clinical status of patients with biopsy-proven IgA nephropathy (IgAN) during long-term maintenance dialysis. METHODS: Fifty-two of 433 patients with IgAN who had favorable survival rates of 93.3% and 65.1% at 10 and 20 years, respectively, in a previous study and had reached end-stage kidney disease were followed up for 11.1 +/- 6.2 years. Forty of the 52 patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) at the final observation in February 2012 were eligible for entry in this study. Laboratory findings, treatments and complications during the long-term follow-up were analyzed. RESULTS: Mean age at starting dialysis (HD, n = 39; PD, n = 1) was 44.2 +/- 13.1 years. Vascular access was achieved through an arteriovenous fistula in 95% of the 39 patients. Prescription rates of anti-hypertensive agents (68%), anti-platelet agents (35%), and statins (15%) were relatively low. The cardiothoracic ratio was well-controlled (< 50%) in about 60% of all patients and mean values for hemoglobin (10.6 +/- 1.31 g/dL), adjusted calcium (9.56 +/- 0.81 mg/dL), phosphate(5.89 +/- 1.64 mg/dL), and intact-PTH (186 +/- 221 pg/mL) were within the treatment goals recommended by Japanese guidelines. Complications during follow-up comprised cardiovascular events (n = 11), malignancy (n = 4), diabetes (n = 2), and arterial fibrillation (n = 2). Patients who remained on dialysis for > 10 years (n = 22) had started dialysis when they were significantly younger, and had a higher rate of onset of malignancy and of intact PTH values than those who were on dialysis for < 10 years (n = 18). CONCLUSIONS: Patients with IgAN who remain on dialysis over the long-term can maintain stable and favorable clinical findings although the occurrence of malignant complications and bone mineral metabolic disorder should be monitored. PMID- 25551987 TI - [Relationship between serum uric acid levels and muscle strength/volume: a new insight from a large-scale survey]. AB - AIM: Serum uric acid (UA) concentration is regulated by its production in the liver and/or intestine and its rate of excretion from the kidneys. However, little is known about skeletal muscle involvement in determining the physiological UA level. The present trial explores whether muscle strength and/or muscle volume is associated with UA levels. MATERIAL & METHODS: Muscle strength was evaluated in terms of grasping power calculated as an average of right and left hand measurements in relation to other parameters in 14,333 subjects (median age; 41.2 years), who were recruited to the study. Skeletal muscle volume was calculated based on the bioimpedance method by subtracting estimated fat volume plus estimated bone weight from the total body weight. RESULTS: 1) Multiple regression analyses to explain the association with UA levels (dependent variable) revealed that BMI, BUN, triglyceride, muscle strength, AST, age and sex are independent variables. 2) Higher UA levels (assessed as 4 UA quartiles) are associated with higher muscle volume, muscle strength, BMI, DBP, and serum creatinine (Cr) concentration. 3) Greater DBP (assessed as 2 UA categories) was associated with higher BMI, muscle strength, muscle volume, UA levels and serum Cr concentration. 4) Regression coefficient "t" for muscle strength was the largest among the other parameters including serum Cr concentration in the UA level ranging from 5.5 to 6.5 mg/dL. CONCLUSION: There was an association between muscle strength/volume and UA levels in the near physiological UA range, suggesting that the circulating UA levels can be, at least in part, controlled by its production in the skeletal muscles. PMID- 25551988 TI - [More fractures, increased mortality. Is drinking milk not so good after all?]. PMID- 25551989 TI - [Skin disease effects the bones. Nail involvement suggests psoriatic arthritis]. PMID- 25551990 TI - [Physician consultation at the end of life. What are the patient's wishes?]. PMID- 25551991 TI - [E-cigarettes under scrutiny. "We don't want yet another new addictive substance"]. PMID- 25551992 TI - [Return of the kilos. Tempo of weight loss does not matter]. PMID- 25551993 TI - [Meta-analysis sows doubt. Vegetarians live healthier lives but is it the food?]. PMID- 25551994 TI - [Exertion-induced dyspnea and dysphagia. An unusual lump in the neck]. PMID- 25551995 TI - [In 2015 a 3.8 % increase in funds for remedies will be available throughout the country]. PMID- 25551996 TI - [Pharmacist can no longer substitute all medications]. PMID- 25551998 TI - [GOA: accounting consultation fees appropriately]. PMID- 25551997 TI - [Offer preventive services systematically!]. PMID- 25551999 TI - [Sissi therapy apparently helps with back pain]. PMID- 25552000 TI - [Physician recommends an unusual cough therapy]. PMID- 25552001 TI - [World AIDS Day. Campaign also for inclusion of HIV positive patients!]. PMID- 25552002 TI - [Unnecessary procedures again. Less is more!]. PMID- 25552003 TI - [Choosing wisely - also in Germany. Doing what is appropriate for the patient]. PMID- 25552004 TI - [Atrial fibrillation and other arrhythmias. When endurance sports induce cardiac arrhythmias]. PMID- 25552005 TI - [Diagnosis and therapy updated. In uncomplicated cystitis the symptoms count]. PMID- 25552006 TI - [Complications after goiter operation. Suddenly paresthesia appeared]. PMID- 25552007 TI - [When employment should cease, when work incapacity? Maternal protection begins in pregnancy]. PMID- 25552008 TI - [Study in the Netherlands. How safe are home deliveries?]. PMID- 25552009 TI - [Immediate ticagrelor administration useful in STEMI]. PMID- 25552010 TI - [Fat people have common cancers]. PMID- 25552011 TI - [A few months breastfeeding protects against maternal diabetes]. PMID- 25552012 TI - [Celiac disease is largely genetic]. PMID- 25552013 TI - [Furosemide bolus in acute heart failure]. PMID- 25552014 TI - [Gastric band out of place]. PMID- 25552015 TI - [Advanced liver cirrhosis: beta blockers seem harmful]. PMID- 25552016 TI - [Light exercise training goes well with aortic aneurysm]. PMID- 25552017 TI - [A black growth on the back]. PMID- 25552018 TI - [Rhinitis - causes, complications, therapy]. PMID- 25552019 TI - [COPD - non - pharmacological management and pulmonary rehabilitation]. PMID- 25552020 TI - [Non operative therapy of stable coronary artery disease]. PMID- 25552021 TI - [Deep vein thrombosis - advances in diagnosis and treatment]. PMID- 25552022 TI - [Alcoholism - risk factors, diagnosis, therapy]. PMID- 25552023 TI - [Multimodal pain therapy in chronic low back pain]. PMID- 25552024 TI - [Lower urinary tract symptoms associated with benign prostatic enlargement]. PMID- 25552025 TI - [Physician-patient communication]. PMID- 25552026 TI - [Glucocorticoid-induced hyperglycemia - mechanisms, detection and therapeutic management]. PMID- 25552027 TI - [North-Western Research Center for Hygiene and Public Health. 90th anniversary: results and prospects of scientific work]. AB - The authors represented results on major research directions followed by the Institute since its foundation, the prospects of their development in hygiene and industrial medicine. PMID- 25552028 TI - [Medical and biologic research of electromagnetic fields in radiofrequencies range. Results and prospects]. AB - The authors present research findings on the problem of technology-related electromagnetic fields as an occupational risk factor of workers health disturbances, and on the issue of prevention measures development against this adverse physical factor effects. Prospects for further research development in the field of electromagnetic safety are discussed. PMID- 25552029 TI - [Results concerning hygienic and therapeutic aspects of laser rays over recent decades]. AB - Long-term studies in hygienic, prevention and treatment aspects of laser radiation are summarized. Findings in the given field resulted in over 20 patents and in more than 200 articles, which evidences research novelty. PMID- 25552030 TI - [Justifying expedience connected with development of Federal Law "On chemical safety"]. AB - Based on analysis of present legal acts and regulations concerning chemicals handling in Russia, the authors necessitate development of Federal Law "On chemical safety". PMID- 25552031 TI - [Influence of industrial pollution of ambient air on health of workers engaged into open air activities in cold conditions]. AB - The article presents the results of a study on assessment of occupational exposure to air pollutants and related health effects in3792 outdoor workers engaged in operations performed in the vicinity of non-ferrous metallurgical facilities in Far North. Findings are that during cold season repeated climate and weather conditions are associated with higher level of chemical hazards and dust in surface air. At the air temperature below -17 degrees C, maximal single concentrations of major pollutants can exceed MAC up to 10 times. With that, transitory disablement morbidity parameters and occupational accidents frequency increase significantly. The workers with long exposure to cooling meteorological factors and air pollution demonstrate significantly increased prevalence of respiratory and circulatory diseases, despite relatively low levels of sculpture dioxide and dust in the air, not exceeding the occupational exposure limits. It has been concluded that severe cold is to be considered asa factor increasing occupational risk at air polluted outdoor worksites dueto more intense air pollution, higher traumatism risk and lower efficiency of filter antidust masks respiratory PPE and due to modification of the toxic effects. PMID- 25552032 TI - [Occupational morbidity among miners engaged into contemporary method of extracting copper-nickel ores in Kola Transpolar regions]. AB - The risks for developing occupational pathology and its specific features were studied in 358 Kola Transpolar copper-nickel miners who were diagnosed with 722 cases of occupational diseases (OD) in the years 1990-2013. The highest risk for developing OD, which are dominated by the diseases of the musculoskeletal system, has been found in tunnellers (OR = 12,8) and operators of drilling rigs (OR = 10,4). A significant increase in the risk of OD has been established in miners with length of service at 11-15 years and over 25 years. The conclusion is made about the need to improve the technical, medical and organizational measures targetted at preventing health problems in this group of workers. PMID- 25552034 TI - [Effects in eyes, caused by laser rays emitted by laser-beam projectors]. AB - Health assessment of laser radiation emitted by laser-beam projectors used for laser shows in concert and theatrical events was carried out. The effects of various laser radiation wavelengths and regimes on functional state of eye retina were studied. PMID- 25552033 TI - [Evaluating occupational risk in night shift work schedule]. AB - The authors analyzed and summarized risk values of acute and chronic health disorders in night shift workers. Average annual risk increments for various chronic diseases in night shift workers were calculated. Based on these data, the authors conclude on hazard degree of night shift work. PMID- 25552035 TI - [Contemporary aspects of clinical manifestations, diagnosis and treatment of occupational microfibrosis]. AB - Upper extremities occupational diseases resulting from physical overstrain are widely spread types of occupational pathology. The most common disease is myofibrosis. Seen nowadays, significant use of manual work in physical labour occupations cause high level of occupational morbidity due to physical overstrain. Review of previous studies showed that in spite of topicality the problem still lacks attention. Therefore the use of modern methods of occupational myofibrosis diagnosis such as contrast myography and ultrasound study, development of early diagnostic criteria, more accurate determination of severity degree and the process dynamics gets growing social and priority importance. PMID- 25552036 TI - [Legal and methodologic problems of assessing relationships between diseases and occupational activities]. AB - The article covers improvement of examination methods aimed to assess relationship between disease and occupation. The authors describe the most topical problems of this examination, not considered by operating regulatory acts, and possible ways to improve: unify the regulations determining criteria of relationships between disease and occupation, give arbitration functions to some occupational centers for resolving conflict and ambivalent examination situations about relationships between disease and occupation, presumption of employer's guilt principle to be implicated into examination concerning relationships between disease and occupation in the case of the employer's inability to justify safe working conditions for the diseased worker who has probable occupational disorder signs. PMID- 25552037 TI - [Comparative investigation of rheological characteristics of the original drug Triderm and its generics in the form of cream]. AB - Rheological properties of mild pharmaceutical formulations (creams) with glucocorticosteroids, such as Triderm (Belgium), Akriderm GK (Russia) and Kanizon plus (India) were studied. The study revealed differences in the structural strength properties of the medicines (viscosity, critical shear stress). The necessity of rheological investigations during development of generic medicines was shown. PMID- 25552038 TI - [Ergoferon liquid dosage form--efficacious and safe treatment for childhood acute respiratory infections. Interim outcomes of a multi-center, randomized, double blind, placebo-controlled clinical trial]. AB - The pediatric dosage form of Egroferon--a drug indicated for the treatment of influenza and acute respiratory infections (ARIs)--is developed taking in account the broad range of pathogens (most of which are viruses), and age-dependent features of immune system reactions (absence of specific immunity and immunological memory, relative "immaturity" of immune reactions, reduced interferon production by immunocompetent cells, etc.). Ergoferon interferes with the non-specific mechanisms of antiviral defence that ensure eliciting of an immune response, regardless of the virus type (the interferon system and CD4+cells), and influences virus-induced histamine release and histamine-mediated inflammatory reactions. Used over four years in clinical practice, the drug has shown a high efficacy and safety profile for the treatment of influenza and ARIs in adult patients. The purpose of the multi-center, randomized, double-blind, placebo-controlled study was to evaluate the clinical efficacy and safety of a new ergoferon liquid dosage form in the treatment of ARIs in children. The publication contains the results of the fist study stage completed as per the study plan and data from the interim analysis. METHODS. The screening involved a total of 162 subjects, aged 3 to 17 years (average, 8.2 +/- 3.9 years), that had presented to 13 research centers based in Russia with common signs and symptoms of ARI (body temperature >= 38.0 degrees C, as measured with a digital infrared temporal artery thermometer; symptom severity score >= 4) during seasonal morbidity. Ergoferon was administered in 82 subjects receiving the therapeutic regimen of the drug for 5 days; 80 children received placebo. The subjects were monitored for 6 days. Treatment efficacy was assessed on the basis of morning, evening and total daily ARI symptom scores, including scoring estimates of fever, general symptoms and symptoms affecting the nose, throat and chest. Along with this, calculations were performed to obtain the Total Index (TI) of ARI; illness severity was evaluated using a mathematical "area under the curve" model. RESULTS. Starting from Day 2, the percentage of convalescents was observed to increase--from 6% (morning) and 14% (evening) to 20% and 29% on Day 3, respectively, and 58% and 61% on Day 4. The results suggested a substantially higher efficacy of Ergoferon as compared to placebo treatment (the Cochran-Mantel Haenszel chi2 test: chi2 = 21.7; p < 0.0001). Ergoferon had a marked effect on fever and other signs of intoxication. In Ergoferon group, the percentage of non fever subjects, with the endpoint defined at <= 37.2 degrees C, was 43% on Day 2, as estimated in the morning and the evening (vs 25% and 19% in the placebo group, respectively; chi2 = 10.6; p = 0.012), and 83% in the morning and 84% in the evening on Day 3 (vs 60% and 54% in the placebo group, respectively; chi2 = 16.7; p = 0.001). The Generalized Linear Model (GENMOD) procedure confirmed the significance of differences between the Ergoferon and placebo groups according to the following parameters: 1) Ergoferon was significantly more effective in reducing body temperature (to lower values) than the placebo; 2) Ergoferon had an earlier effect on fever (main marker of viremia), as compared to placebo; 3) The significant Ergoferon's superiority over placebo was also evident by the morning and evening measurements throughout the five-day therapy. The TI was observed to significantly decrease starting from Day 2 of Ergoferon administration: from 13.0 +/- 4.5 to 7.9 +/- 4.8 on Day 2 and 4.5 +/- 2.9 on Day 3 (based on the patient's diary data); from 14.3 +/- 4.2 to 4.9 +/- 3.0 on Day 3 (based on the doctor's assessment). The severity of ARI-related intoxication signs was reduced most significantly, in particular as indicated by the results of doctor's objective examination on Day 3 (GENMOD: factor "Treatment"--chi2 = 147.8; p < 0.0001; factor "Day of administration"--X>=6.1; p = 0.013; Tukey-Kramer post hoc analysis: z = -3.09; p = 0.024). The average fever duration in ergoferon-treated subjects was 1.9 +/- 0.8 days (p < 0.0001). The overall duration of ARI was much shorter in Ergoferon group than in the group of placebo (p = 0.021). The "area under the curve" measure of TI in Ergoferon group was significantly lower as compared to Placebo group, both according to the patient's diary records (21.9 +/ 10.9 TI x Days vs 28.0 +/- 13.0 TI x Days; p < 0.002) and the doctor's examination (12.4 +/- 4.7 vs 14.2 +/- 5.2 TI x Days; p = 0.023). Ergoferon treatment was associated with a lower frequency of using antipyretics (chi2 = 4.1; p = 0.043), particularly on the first day of illness. The monitoring of adverse events as well as the haematology, biochemistry and urinalysis findings were indicative of Ergoferon's safety. No signs of drug incompatibility were observed as a result of ergoferon administration in combination with antipyretics, decongestants, expectorants, inhaled corticosteroids, cromoglicic acid derivatives, leukotriene receptor antagonists, short-acting beta2 agonists and topical anti-septics. There were also no cases of bacterial complications, worsening of illness severity, or acute exacerbations of coexisting allergy or chronic ENT pathology. The children demonstrated good drug tolerance and 100% treatment compliance. CONCLUSIONS. Ergoferon liquid dosage form is an efficacious and safe treatment for ARIs in children. The study results demonstrated the drug's efficacy against the major syndromes associated and caused by viremia- fever and general intoxication. The early onset of the drug's effect was shown to result in a shorter time to convalescence and reduced ARI severity, particularly during the initial days of illness. PMID- 25552039 TI - [Meglumine acridonacetate and complex therapy of patients with newly identified advanced pulmonary tuberculosis]. AB - Clinical and immunological efficacy of meglumine acridonacetate (cycloferon) tablets was evaluated in complex treatment of patients with newly diagnosed advanced pulmonary tuberculosis. It was shown that the use of cycloferon according to our scheme increased the efficacy of the therapy (earlier disappearance of the disease symptoms and bacteria isolation, shorter-terms of cavern healing, more pronounced positive radiographic dynamics vs. the patients under the etiotropic therapy). The use of cycloferon normalized the number of gamma interferon receptors, increased the gamma interferon serum levels, reduced the incidence of the side effects (liver damage) due to the use of TB drugs. Such a use of cycloferon was cost effective. The use of sycloferon is possible in the complex treatment of outpatients with advanced pulmonary tuberculosis. PMID- 25552040 TI - [Redox-dependent processes in blood plasma, neutrophils and erythrocytes of patients with ovary cancer after polychemotherapy by CAP scheme]. AB - The dynamics of the redox-dependent processes in blood plasma, neutrophils and erythrocytes of the patients with ovary cancer of the IIIrd clinical stage by FIGO after polychemotherapy according to the CAP scheme is considered. In the blood plasma and erythrocytes there were estimated the values of protein oxidative modification: carbonyl derivatives at lambda = 346 nm, 370 nm, 430 nm and 530 nm; the lipid peroxidation parameters: malonic dialdehyde, dienic conjugates, ketodiens, shiff's bases; the fermentative chain of the antioxidant system: activities of catalase, glutationtransferase and superoxide dismutase. In the peripheral blood neutrophils there were cytochemically determined the myeloperoxidase activity and the number of the active neutrophils in the spontaneous NBTR-test. After the polychemotherapy there were detected higher levels of the protein oxidative modification products and the products of the lipid peroxidation in the blood plasma and erythrocytes of the patients. Simultaneous increase of the activity of the antioxidant enzymes in the blood plasma could be evident of a high level of the lipid antioxidants peroxidation system functioning, whereas the simultaneous decrease of the activity of the antioxidant enzymes in the erythrocytes was indicative of passible development of oxidative stress in them. After the chemotherapy there was observed a significant and reliable decrease of the total number of the neutrophils. After the second course of the chemotherapy the activity of myeloperoxidase in them in the spontaneous NBTR-test as well decreased. Such a dynamics of the redox-depended processes in various components of the blood in the tumour carrier was characteristic of the tumor biological picture and required the use of differential multicomponent antioxidant therapy in patients with ovary cancer. PMID- 25552041 TI - [Biologically active compounds produced by microbial endophytes]. AB - Microbial endophytes present a rich and not fully studied source of novel natural biologically active compounds of wide interest all over the world. The research of natural compounds with various biological effects produced by endophytes are described in the review. PMID- 25552042 TI - [Molecular imprinted polymers for penicillins and tetracyclines]. AB - The molecular imprinted polymers (MIPs) for penicillins and tetracyclines described in the literature were analysed with a purpose of evaluating their possible use for the antibiotic sorption isolation. PMID- 25552043 TI - [Contribution of microbiologists of Kirov City to development of penicillin and streptomycin production processes (70 years since development of technology for submerged production of first domestic antibiotics)]. AB - The publication is concerned with development of the technological processes for submered production of the first domestic antibiotics 70 years age. The literature data on the contribution of the microbiologists of the Kirov City and mainly the workers of the Red Army Research Institute of Epidemiology and Hygiene (nowadays Central Research Institute No. 48 of the Ministry of Defense of the Russian Federation, Kirov), to development of the manufacture processes for production of penicillin and streptomycin are reviewed. PMID- 25552044 TI - [In commemoration of the 90th anniversary of S. M. Navashin]. PMID- 25552045 TI - [The perfection of biology and discrepancies of humoral regulation non-surmounted in phylogenesis. The unified algorithm of pathogenesis of metabolic "pandemics" as diseases of civilization]. AB - The striving to biological perfection became apparent under becoming of each out of seven biological functions at the consequent stages of phylogenesis: at cellular autocrine level; in paracrin regulated functional cenosis of cells, organs; at the organism level. However, regulative interaction simultaneously on all levels in vivo results in functional incoordination. There are no reasons to name them contradictions. They are targeted to development of organism; they are formed on different levels of regulation and sometimes are not comparable in full measure; incoordinations of regulation are never outdone. The striving of biology to perfection resulted in incoordinations becoming less apparent in conditions of physiological level of physical chemical parameters and concentrations of biochemical analytes staying within strict standard limits. The physiological values "are backed up" from below by realization of biological function of homeostasis. The upper level "is limited" by biological function of endoecology- leanliness of intercellular medium. The incoordinations of humoral and nervous regulation are manifested under impact of unfavorable factors of environment on organism. At that, regulatory incoordinations developed at distantly spaced degrees of phylogenesis came out as pathogenic factors of "metabolic pandemics"- civilization diseases. Ifdisease ofn oninfectious etiology is propagated in population with rate of 5 - 7% its pathogenesis is based on disorder ofb iologicalf unctions and biological reactions, meaning those impacts of environment that Homo sapiens didn't learn to match in phylogenesis. The strict normalization of biological functions and biological reactions can be the only pathogenetically and effective prevention and treatment of this pathology. The application ofp harmaceuticals is the foundation ofs ymptomatic therapy only. PMID- 25552046 TI - [The antioxidant activity of components of blood serum of donors and recipients before liver transplantation]. AB - The antioxidant activity is implemented in human blood serum by ascorbic acid, uric acid, amino acids, glucose, mono unsaturated fatty acids (in the first instance Omega-9 oleic acid), essential polyenoic fatty acids, thiol groups of albumins and proteins, tripeptide and pigment of bilirubin. The antioxidant activity of blood serum of donors and recipients before liver transplantation was determined The input of particular biochemical analytes into liver transplantation was determined too. The antioxidant parameters were detected using technique of termo-induced chemiluminescence under application of set of corresponding reagents. The analysis of antioxidant activity of blood serum in donors and recipients with hepatic pathology revealed in vivo a significant disorder in the syndrome of compensatory anti-inflammatory defense. Under hepatic pathology, absence of endogenous ascorbic acid, deficiency of exogenous ascorbic acid and disorder of antioxidant activity the uric acid and bilirubin become the major hydrophilic acceptors of active forms of oxygen and inhibitors of oxidative processes in vivo. In patients with physiological level of bilirubin the uric acid provides 40%-80% of antioxidant activity. In case of high hyperbilirubinemia in recipients only 9.6%. It is possible to consider hyperiricosuria under aphysiological processes as a nonspecific test of activation of biological reaction of inflammation, syndrome of compensatory anti-inflammatory defense and test of disorder of biological function of endoecology. To activate the syndrome of compensatory anti-inflammatory defense it is very important to decrease both hyperiricosuria and compensatory function of uric acid as an acceptor of active forms of oxygen by force of prolonged intake of optimal amount of ascorbic acid. PMID- 25552047 TI - [The indicators of immunity in patients with aseptic instability of knee joint]. AB - The examination was applied to sampling of 17 patients with stable implants after 18-36 months after endoprosthesis replacement of knee joint and to sampling of 17 patients with developed within this time-frame aseptic instability of endoprosthesis within the same time-frame. The typing of lymphocytes of peripheral blood was implemented using laser flow cytometry. The detection of immunoglobulins, cytokines, circulating immune complexes was made applying the technique of enzymoimmunoassay. In case of development of aseptic instability the signs testifying moderate activation of immune system and starting dysfunction of monocyte macrophage component of immune system. At that, IL-6, TNFalpha, CD14+HLA DR provided the most complete information on the side of diagnostic of developing aseptic instability of joint. PMID- 25552048 TI - [The reagents kit to detect Metyorchis biis, Opisthorchis viverrini and Clonorchis sinensis, Opisthorchis felineus--agents of opisthorchiasis using technique of polymerase chain reaction in real-time]. AB - The helminths Opisthorchis felineus, Opisthorchis viverrini, Clonorchis sinensis, Metorchis bilis are the agents of opisthorchiasis. The actual diagnostic of parasitic diseases based on microscope analysis of samples of human feces to detect presence of ova of parasites suffers of many shortcomings, in particular low sensitivity especially at earlier stages. The purpose of this study was to compare results of detection of parasites using both classical technique and technique of specific differentiation based on extraction of nucleic acids from samples of human feces and implementation of reaction of amplification of the chosen fragment of DNA with detection of products of polymerase chain reaction in the real time. The study detected 150 out of 165 positive samples and also 6 out of 37 negative samples both validated by coproovoscopy. PMID- 25552049 TI - [The comparative characteristic of immune status of males with bacterial inflammatory urogenital pathology of different etiology in the city of Orenburg]. AB - The article discusses presence of typical characteristics of parameters of system immunity under gonococcal and nonspecific uretroprostatitis and diagnostic value of these indicators. The reliable differences of immunologic indicators in patients with gonorrhea are established as compared to patients with nonspecific bacterial uretroprostatitis. The study established in peripheral blood the reliable decrease of level of leukocytes, relative amount of monocytes, phagocyte index, functional reserve of leukocytes at the expense of spontaneous and stimulated NBT test, IgA, sIgA. On the contrary, the study detected increasing of level of IgM and lactoferrin in patients with gonorrhea as compared to corresponding indicators in patients nonspecific infections. Under gonorrhea, the largest deviation of indicators from standard values was established for lactoferrin. The detected differences of immunologic parameters can be used as differentiating markers of nonspecific and gonococcal uretroprostatitis and criteria of effectiveness of immune correction. PMID- 25552050 TI - [The application of mass spectrometry technique MALDI-TOF for inter-specific differentiation of closely-related vibrio]. AB - The study was targeted to apply mass spectrometry analysis for inter-specific differentiation of collection strains of representatives of genus vibrio and identification of comma bacilli extracted from samples of boat ballast waters. The samples consisted of 207 museum strains of cultures and 347 microorganisms from samples of boat ballast waters. The identification of microorganisms was implemented using MALDI-TOF mass spectrometers. The application of MALDI biotyping made it possible to detect inaccuracies in specific and generic characteristics of collection strains V. alginolyticus, V. parahaemolyticus, Shewanella, V. mimicus and to enhance characteristic and quality of collections of microorganisms. The effective application of MALDI to monitor boat ballast waters is demonstrated. This technique allows detecting of complete vibrio landscape of pathogenic and non pathogenic genus. The possibility to detect strains of comma bacillus and cholera agents is demonstrated. The mode of orientation on V. albensis at the stage of selection of suspicious colonies is proposed. PMID- 25552051 TI - [The carrier protein of cholesterol ethers: the physical chemical characteristics, functions, role in pathogenesis of atherosclerosis and grounds for inhibition (a lecture)]. AB - The first function of carrier protein of cholesterol ethers in phylogenesis was passive transfer of polar diglycerides from lipoproteins of very low density to lipoproteins of very high density to proceed with hydrolysis. At the later degrees, carrier protein of cholesterol ethers initiated reverse transfer of polyenoic fatty acids from lipoproteins of very high density to lipoproteins of very low density in form of polyenoic ethers with spirit cholesterol. This occurrence became a stage of transfer and active absorption by cells polyenoic fatty acids using apoB-100 receptor endocytosis in lipoproteins of very low density. Later on, in phylogenesis under mutation of carrier protein of cholesterol ethers null cells began compensatory absorb polyenoic fatty acids in lipoproteins of very high density by force of apoE/A-I endocytosis. In certain percentage of species of animals (primates, rabbits) and humans the cells absorb polyenoicfatty acids byforce of apoB-100 endocytosis. In other species (rats and mice) the cells absorb polyenoic fatty acids through apoE/A = I receptors. In animals, under first receptor absorption of polyenoic fatty acids by cells it is easy to reproduce atherosclerosis and atheromatosis on the model of exogenous hypercholesterolemia and it is practically impossible in second case. The absence in vivo of lipoproteins of very high density and triple associate of lipoproteins of very high density + carrier protein of cholesterol ethers + lipoproteins of very low density is followed by increasing of spirit cholesterol-lipoproteins of very high density and decreasing of content of spirit cholesterol-lipoproteins of very low density as risk factors of human atherosclerosis. This occurrence served as foundation for proposal to apply blockers of action of carrier protein of cholesterol ethers in patients with atherosclerosis. The main function of lipoproteins of very high density as of all lipoproteins is to transfer fatty acids to cells and only in second instance to transfer from all cells spirit cholesterol in the form of mono-ethers cholesterol. Only results of clinical studies will demonstrate the effectiveness of compensatory apoE/A-I receptor endocytosis of lipoproteins of very low density in comparison with physiological apoB-100 endocytosis. PMID- 25552052 TI - [The approbation of technique of mass spectrometry with matrix-activated laser desorption/ionization for identification of plague agent]. AB - The study of sampling of strains of Y. pestis of main and altaic subspecies was implemented. The modern technique of identification of microorganisms was applied using MALDI-TOF mass spectrometry analysis. The evaluation of biological safety of method of sampling preparation was implemented. To supplement the identification base "BioTyper" the spectrum of typical strains of Y. pestis were obtained. The enhanced identification base was used to evaluate possibilities of application of MALDI-TOF technology for identification and taxonomic differentiation of Y. pestis from other representatives of genus of Yersinia. In the process of study a complete concordance of results of mass spectrometry identification and classic cultural method was observed. On the basis of mass spectrometry characteristic of analyzed sampling the differentiation between strains of Y. pestis of subspecies pestis and strains of subspecies altaica was implemented. The study results testify the effectiveness of application of mass spectrometry analysis for reliable interspecies and intraspecific differentiation of plague agent. The simplicity and velocity of sampling preparation and implementation of analysis and low cost of active storage allow considering the MALDI-TOF technology of mass spectrometry identification as highly perspective method for laboratory diagnostic of plague agent. PMID- 25552053 TI - [The biological kinetics of biofilms of clinical strains of Staphylococcus aureus and Pseudomonas aeruginosa separated from patients with bronchopulmonary complications under traumatic disease of spinal cord]. AB - The capacity and intensity of formation of microbial biofilms was analyzed in 24 strains of Staphylococcus aureus and Pseudomonas aeruginosa in static conditions of cultivation during 24, 48, 72 and 96 yours. The microorganisms were separated from patients with bronchopulmonary infectious complications in acute and early periods of traumatic disease of spinal cord. PMID- 25552054 TI - [The acquired overt cytomegalovirus infection (primary form and reactivation) in adult immune safety patients]. AB - The analysis was applied to clinical course of disease in 102 patients with acquired overt cytomegalovirus infection (75 patients with primary form, 27 patients with reactivation). The primary form of acquired overt cytomegalovirus infection was identified on the basis of detection in enzymoimmunoassay of CMV lgM under negative CMV-IgG or CMV-IgM and CMV-IgG with avidity less that 50%. The reactivation was diagnosed under identification of CMV-IgG with avidity 50% and more with low indicators of CMV-IgM. The acquired overt cytomegalovirus infection occurs more often in males of young age and proceeds mainly in generalized medium severe form with fever, intoxication and hepatosplenomegaly. The clinical differences are limited by higher rate of generalized forms of disease, febrile fever, weakness, hepatomegaly with increasing of activity of aminotransferase of blood serum, manifestation of signs of affection of respiratory tracts and increase of number of atypical mononuclear leukocytes of peripheral blood in patients with primary form of acquired overt cytomegalovirus infection as compared with reactivated infection. PMID- 25552055 TI - [The comparison of tests for qualitative evaluation of Ureaplasma parvum, Mycoplasma hominis: "Mycoplasma duo", "Ureaplasma microtest", "Mycoplasma microtest" and "AmpliSens-Florocenosis-mycoplasma-FL"]. AB - The genital mycoplasma is an opportunistic bacteria and its detection is to be implemented in qualitative format. The study was organized to compare reagents kits "Mycoplasma Duo", "Ureaplasma Microtest", "Mycoplasma microtest" and "AmpliSens-Florocenosis-Mycoplasma-FL". The study resulted in high indicators of diagnostic sensitivity and diagnostic specificity for all kits. At that, the lowest indicators were registered under application of "Mycoplasma Duo" kit. The study reveled correlation of qualitative values detected by using cultural analysis and polymerase chain reaction. The reproducibility of qualitative values of cultural method occurred significantly lower in comparison with "AmpliSens Florocenosis-Mycoplasma-FL " kit. PMID- 25552056 TI - [The lysate and recombinant antigens in ELISA-test-systems for diagnostic of herpes simplex]. AB - The lysate and recombinant antigens of various production included informula of ELISA-test-systems were analyzed. The ELISA-test-systems are used for detection of IgG to Herpes simplex virus type I and II. For testing the panel of serums PTH 201 (BBI Inc.) were used. The samples of this panel contain antibodies to Herpes simplex virus type I and II in mixed titers. The 69 serums of donors were used too (17 samples had IgG to Herpes simplex virus type I, 23 samples to Herpes simplex virus type II and 29 samples had no antibodies to Herpes simplex virus). The diagnostic capacity of mixture of recombinant antigens gG1 Herpes simplex virus type I and gG2 Herpes simplex virus type II (The research-and-production complex "DiaprofMed") was comparable with mixture of lysate antigen Herpes simplex virus type I and II (Membrane) EIE Antigen ("Virion Ltd."). In the test systems for differentiation of IgG to Herpes simplex virus type I the recombinant antigen gG1 Herpes simplex virus type I proved to be comparable with commercial analogue Herpes simplex virus-1 gG1M ("Viral Therapeutics Inc."'). At the same time, capacity to detect IgG to Herpes simplex virus type II in recombinant protein gG2 Herpes simplex virus type II is significantly higher than in its analogue Herpes simplex virus-2 gG2c ("Viral Therapeutics Inc."). PMID- 25552057 TI - [The procedure of phlebotomy for clinical laboratory studies: perspectives of development of pre-analytical stage of laboratory process]. AB - The study was carried out to analyze issues occurring under implementation by medical nurses the procedure of phlebotomy for laboratory studies in Russia and to compare with international experience for enhancing quality of pre-analytical stage of laboratory studies. The technique of sociological survey was applied. The sampling included 123 medical nurses of the Northern West federal okrug and the Ural federal okrug. The questionnaire referred to issues of application of phlebotomy. The results were compared to data of international survey concerning the pre-analytical stage of laboratory studies carried out by the working group of the European Federation of clinical chemistry and laboratory medicine (EFLM WG PA). In Russia, the most frequent issues under blood drawing were dubbed analyses (80.4%), out-of-the-way placement of vein (39.9%), blood sampling in newborns and children aged up to 1 year (10.5%), casual pricks of needle (28%). The study established that among causes of repeated analyses were hemolysis (79.1%), "mixed up" samples of patients (15.7%), broken test tubes (5.2%). The survey determined that 19.6% of medical nurses had no training in blood drawing from vein for clinical laboratory studies. The international survey demonstrated that not all countries had both training programs on phlebotomy and national guidelines on its implementation. This issue requires an additional study. The training and educational programs for medical personnel occupied with phlebotomy are to be developed. The national standards are to be developed harmonized with international recommendations on implementation of this procedure to enhance quality of pre-analytical stage of laboratory studies. PMID- 25552058 TI - [On the state and prospects of development of remote neutron therapy]. AB - The state and prospects of remote neutron therapy were analyzed in this review. Years of experience with fast neutrons, both positive and negative, allow evaluating the most promising ways of further development of this area of radiation therapy. These include conducting targeted research for those tumors which received some encouraging results, a use of the combination of fast neutron therapy and conformal photon therapy as well as the creation of specialized medical facilities for neutron therapy based on optimization of both parameters of spatial distribution of the dose and radiobiological characteristics. PMID- 25552059 TI - [Clinical perspectives of the study of RANK/RANKL/OPG system components in primary and metastatic bone tumor]. AB - Disbalance of bone homeostasis, associated with malfunctioning of RANK/RANKL/OPG system underlies the oncological processes such as the destruction of bone, metastasis development, tumor progression. Pathological activity of system was described in such conditions, as breast cancer, prostate cancer, multiple myeloma, squamous cell carcinoma, Hodgkin's disease, and also metastasis in bones from lung cancer and other malignant diseases. In the literature, there is evidence of involvement of RANK/RANKL/OPG system in the pathogenesis of bone tumors (osteosarcoma, giant cell tumor of bone, chondroblastoma). Experimental data show that RANKL inhibitors can play a role in reducing tumor-induced lesions of bone in multiple myeloma, breast cancer, prostate cancer and lung cancer. Also this review presents data from clinical studies of the drug efficacy targeted on RANK/RANKL/OPG system and results of authors' study of the levels of this system's components and proinflammatory cytokines in blood serum of primary bone sarcoma patients. PMID- 25552060 TI - [Basic principles and results of brachytherapy in gynecological oncology]. AB - The fundamental basics of contact radiation therapy (brachytherapy) for gynecological cancer are presented. During brachytherapy the principles of conformal radiotherapy should be implemented, the aim of which is to sum the maximum possible dose of radiation to the tumor and decrease the dose load in adjacent organs and tissues, which allows reducing the frequency of radiation damage at treatment of primary tumors. It is really feasible only on modern technological level, thanks to precision topometry preparation, optimal computer dosimetrical and radiobiological planning of each session and radiotherapy in general. Successful local and long-term results of the contact radiation therapy for cancer of cervix and endometrium are due to optimal anatomical and topometrical ratio of the tumor localization, radioactive sources, and also physical and radiobiological laws of distribution and effects of ionizing radiation, the dose load accounting rules. PMID- 25552061 TI - [Exosomal intercellular communication system and its role in the process of metastatic dissemination]. AB - Metabolism and information between cells is the basis of the existence of any multicellular organism. Malfunction of the intercellular communication play an important and sometimes decisive role in the pathogenesis of the most diseases, including cancer. According to traditional views, functional integration of individual cells in tissues, organs and organ systems is mediated by the efficient work of regulatory systems: nervous, immune, endocrine. Over the past few years the attention of scientists is attracted the ability of cells to "communicate" with the help of nanoscale vesicular formations, or so-called exosomes. There are accumulated data that the cells of the most tissues secrete exosomes into the intercellular environment, after which, by means of stream of blood or lymph, exosomes transferred to anatomically distant sites where they are accepted by the other cells. It is showed that the content of exosomes are not random and that vesicular transport may be targeted and to play a significant physiological and even "pathophysiological" role. The aim of this review is the analysis and integration of modern scientific data on the role of exosomes in the process of tumor progression and presentation of possible ways and methods of using these data in the practice of oncology. PMID- 25552062 TI - [Dynamics of prostate-specific antigen concentration--growth kinetics of prostate cancer?]. AB - Current research confirms that the prostate-specific antigen (PSA) is not just a protein required for liquefaction of the ejaculate but it plays biological role in the development of prostate cancer. Assessment of the PSA dynamics offers good opportunities for understanding the kinetics of growth of prostate tumors. The most frequently it is performed calculation of PSA doubling time (PSADT), a parameter that requires a logarithmic analysis and takes into account the exponential nature of tumor growth. The review shows modern clinical applications and evaluation of PSADT at all stages of prostate cancer development. PMID- 25552063 TI - [Alternative means of drug therapy for cancer: antineoplastons--antitumor properties and mechanisms of action]. AB - This review presents data on the antitumor properties of antineoplastons- alternative means of treatment for cancer originally isolated from human blood and urine. It was assumed that antineoplastons (derivatives of peptides and amino acids) are natural regulators of cell differentiation. In experimental studies it was showed that synthetic antineoplastons (A10-3-phenyl-acetyl-amino-2,6 piperidinedione and AS2-1--a mixture of phenylacetic acid and phenylacetylglutamine) were able to prevent the introduction of glutamine into the cell, to block the action of Bcl-2, to activate p53 and p21, to inhibit histone deacetylase, to induce apoptosis. In experiments in vitro and in vivo in several studies it was registered antitumor activity, mainly on models of hepatocellular carcinoma and glioma. Clinical data are limited by reports of individual clinical cases or series of cases and the results of several clinical trials Phase I-II, indicating a possible antitumor activity. PMID- 25552064 TI - [Epidemiology of prostate cancer (cohort study)]. AB - The paper presents an analysis of morbidity and mortality from prostate cancer ("crude" and standardized rates), taking into account regional differences. The regularities of the dynamics of analytical rates are particularly observed. PMID- 25552065 TI - [Cancer incidence in the Altai Republic]. AB - From all regions of the Siberian Federal District (SFD), the Altai Republic is the least urbanized territory, more than third of its population is Altai. The Altai Republic ranks the 11th for cancer incidence among 12 territories of SFD. Cancer incidence rate is 1.4 times less in females than in males. There is a tendency toward increased cancer incidence in the Republic. The two most common cancer sites in males are digestive and respiratory organs. In females, the most common cancer sites are reproductive and digestive organs. Prostate cancer has the highest incidence rate in males and kidney cancer in females. Increase in the cancer incidence rate was observed among male patients who are younger and older than able-bodied age and in female patients who were younger than able-bodied age. Problems related to the improvement of methods for cancer prevention, early detection and treatment are of great importance. PMID- 25552066 TI - [Prognostic value of bone marrow lesions in children with neuroblastoma detected by flow cytometry]. AB - The purpose of the study was to evaluate the prognostic value of the detection of tumor cells in the bone marrow (BM) in children with neuroblastoma (NB) by flow cytometry. The detection of tumor cells was performed in BM of 51 patients with NB (24 boys and 27 girls) aged from 6 days to 15 years (median--1 year 3 months). Flow cytometry allowed determining NB cells in BM in a much larger number of cases than cytomorphology (49.0% and 29.4% of patients, respectively). Patients, in whom NB cells were not detected in BM by flow cytometry, had significantly better event-free and overall survival rates as well as progression free survival (83.5%, 87.7% and 86,8%, respectively) compared with those in whom immunophenotyping revealed the tumor cells (28.0%, 35.87% and 34,3%, respectively). The prognostic value of the detection of BM lesion by flow cytometry was also confirmed in selected groups of patients with other criteria of stratification. Therefore the detection of tumor cells in BM by flow cytometry could potentially be considered in conjunction with other factors in choosing treatment strategy in patients with NB. PMID- 25552067 TI - [Role of single-photon emission-computed tomography and x-ray computed tomography in diagnosing lymphatic metastases in patients with non-small cell lung cancer]. AB - Single photon emission tomography (SPECT) with 99mTc-MIBI was performed after conventional staging in 83 operated non-small cell lung cancer (NSCLC) patients. Diagnostic results of SPECT and conventional computerized tomography (CT) staging were validated by histological examinations of operation material. According to histological verification 35 of 83 evaluated patients had lymph node (LN) invasion by NSCLC. SPECT detected LN involvement in 28 of these 35 patients and was false positive in additional 16 patients. Pneumonia or atelectasis were detected in 12 of 16 patients with false positive SPECT results. Sensitivity (Sen), specificity (Sp), accuracy (Ac), positive (PPV) and negative (NPV) predictive values of SPECT in diagnosis of LN invasion by NSCLC was as follows: 80%, 66%, 72%, 65%, 82%. Diagnostic accuracy of CT for detection of LN involvement was inferior to SPECT: Sen--71%, Sp--62%, Ac--66%, PPV--58%, NPV- 75%. Combination of SPECT and CT data offer promising solutions with Sen reached 94% or high Sp which in patients without atelectasis or pneumonia can reach 96%. PMID- 25552068 TI - [Hyperthermic chemoperfusion of the pleural cavity in the combined treatment for malignant pleural mesothelioma]. AB - The literature and our own experience were analyzed in multimodal approach to the treatment of patients with malignant pleural mesothelioma (MPM). Survival and quality of life of patients with MPM who underwent multimodal treatment, according to modern standards, are often limited by the occurrence of local recurrences. The value of a number of local therapy methods is still being explored in order to determine the possible side effects as well as the duration of disease-free survival. Photodynamic therapy and intraoperative hyperthermic chemoperfusion of the pleural cavity are the methods of the local treatment of this disease, applied after surgery. These approaches have been investigated separately in several studies, but their efficacy and tolerability is still not clear. The authors wanted to find the best indications for the use of these methods and to assess the immediate and long-term results. PMID- 25552069 TI - [The results of chemoradiotherapy for locally advanced laryngeal cancer with hyperfractionated radiotherapy]. AB - Single chemoradiotherapy (CRT) was performed in 27 patients with laryngeal cancer (T3-4N0-3M0). Radiotherapy (RT) was carried out in hyperfractionated mode 1+1 Gy (every 4-5 hours), 5 times a week to CFD 60 Gy with a 2-week break after CFD 30 40 Gy. Courses of polychemotherapy (PCT) were performed simultaneously with RT at each stage of treatment. Overall 5-year survival of patients in the whole by the group (T3-4N0-3) was 44.6%, for patients with T3N0--72.7%, T3N1-20--42.9%, T4N1-2 -40.0% with an average life expectancy 38.1; 50.8; 39.0 and 39.8 months respectively. During a 5-year follow-up the local control of the primary tumor at T3 was equal to 61%, T4--25% with a median remission of 40.6 and 13.5 months respectively. During this period the regional control at metastases N1 was 50%, with a median remission of 32.7 months. In 4 patients of 5 with N2 and in all 3 patients with N3 during the first year after CRT continued growth or tumor recurrence was diagnosed. Thus, conservative CRT provides relatively satisfactory 5-year outcomes in patients with tumors T3N0-1. PMID- 25552070 TI - [Mixed (photon-neutron) therapy in complex treatment for locally advanced breast cancer]. AB - Long term results of treatment of patients with locally advanced breast carcinoma with the use of mixed photon-neutron therapy (PNT) are presented. Among 201 patients with locally advanced breast cancer receiving radiation therapy, in 95 of them it was implemented as a combination of photon and neutron radiation therapy and in 106--in the form of mega-volt photon therapy (PT). Comparative evaluation of the long-term results of treatment proved the superiority of PNT. The immediate effect after PNT in the form of complete and partial response of tumor was registered in 87.4%, and after PT--in 49% of cases. Five-year and ten year survival rates without signs of disease after PNT were 58.1% and 29.5%, and after PT--36.4% and 7.4% respectively. Substantial differences in toxicity of techniques were not observed. PMID- 25552071 TI - [Immediate and long-term results of brachytherapy in complex treatment for esophageal cancer]. AB - For treatment of cancer of the thoracic esophagus, the method of neoadjuvant chemoradiotherapy (CRT) with a use of intraluminal brachytherapy (BT) was performed. The study included 51 patients (mean age 56.9 +/- 4.3 years). The length of the primary tumor up to 6 cm was determined in 18 patients, more than 6 cm--33 patients. CRT included three BT sessions (7Gy X 3; q7d) and two cycles of chemotherapy (PF; q28d). After CRT in 30 (62.4%) patients there was marked a complete or partial radiological tumor regression. In 40-45 days after CRT surgery performed. Subtotal resection of esophagus of the Lewis type was performed in 29 cases, transtracheal ex- tirpation of the esophagus--in 2, minimally invasive esopha- gectomy--in 17 cases. Postoperative complications occurred in 22 (44%) patients; one patient died (2%). In 11 (23%) patients morphological investigation revealed a complete regression of the primary tumor. Thus, a use of intraluminal BT in combination with chemotherapy in many cases promoted reducing the size of the primary tumor of the esophagus, which was an effective factor in improving surgical results. PMID- 25552072 TI - [Combined treatment of patients with locally advanced rectal cancer]. AB - The objective of this study was to improve the immediate and long-term results of combined treatment of patients with locally advanced rectal cancer. The study included 128 patients with morphologically confirmed diagnosis and clinical stage cT3/T4 and N-/N+, treated from 1998 to 2009. The comparison group had 64 patients, combined treatment included prolonged preoperative radiotherapy 4 Gy and 40 Gy, surgery was performed after 4 weeks. In the study group--also 64 patients--combined treatment consisted of preoperative chemoradiotherapy (continuous a-120 hour infusion of 5-fluorouracil at a dose of 500 mg/m2 in the first and last week of radiotherapy in 2 Gy to 50 Gy), surgery was performed through 6 weeks after chemoradiotherapy. Excision of the primary tumor was performed in 40 (62.5%) patients in the control group and in 53 (82.8%) patients in the study group. Wherein R-0 resections were performed in 32 (67%) patients and in 41 (73%), and R-1 resections--in 1 (2%) patients, and 7 (13%) patients in the control and study groups respectively. A 5-year survival rate was 43.6 +/- 7.2% control and 62.7 +/- 5.1 % in the study group. PMID- 25552073 TI - [Microviscosity of erythrocyte membranes in breast cancer patients: connection with the receptor phenotype of the tumor]. AB - The state of the viscosity of erythrocyte membranes in breast cancer patients (68 -in menopause and 32--with menstrual cycle) was studied in comparison with the content of steroid hormone receptors in the tumor tissue and the age of patients. It is showed that the less hormone dependence of the tumor the higher viscosity of erythrocyte membranes that manifested by a decrease in the coefficient of eximerization (CE) of pyrene in the protein/lipid and in particular, lipid/lipid membrane layers. Increasing CE of pyrene in lipid/lipid layer of erythrocyte membranes above 1.7 units, reflecting a decline in their microviscosity, could be considered as an additional extra-tumor criterion for identification of the tumor as of hormone dependent type. PMID- 25552074 TI - [Chemoradiotherapy in the combined treatment for laryngopharyngeal cancer]. AB - The study included 62 patients with morphologically verified squamous cell carcinoma of laryngopharynx, stages T2-4N0-2M0. As a result of the treatment complete regression was recorded in 28.1 +/- 7.9% of cases, partial regression- in 50.0 +/- 8.8% of patients, and stabilization--in 21.9 +/- 7.3% of cases. The total efficiency of therapy made up 78.1 +/- 7.3%. Chemotherapy complications and radiation injuries did not exceed I-II grade by CTC-NCIC criteria and PTOG/EORTC scale, were easily stopped, did not affect the time periods of further treatment and had no considerable influence on the postoperative period. Conservative surgery was performed in 26% of cases. The total 5-year survival rate made up 65.4 +/- 8.4%, relapse-free 5-year survival rate--60.6 +/- 8.9%. The efficiency of the vocal function rehabilitation made up 73.9 +/- 9.1%. Rehabilitation time was 21 +/- 8.2 days. PMID- 25552075 TI - [The effect of sodium fluoroacetate and metformin on the antitumor activity of cyclophosphamide on the autochthonous mice sarcoma model]. AB - Previously it was found that sodium fluoroacetate (SF) inhibited the growth of the Ehrlich cancer by means of monotherapy and enhanced the antitumor effect of cyclophosphamide (CP) in experiments with autochthonous subcutaneous tumors induced by benzo (a) pyrene. In this study a comparison of the antitumor activity of SF and metformin showed that both substances did not have significant effect in monotherapy but enhanced the effect of CP, increasing the percentage of tumors with the same or reduced volume. Besides, SF, unlike metformin increased the average duration of effect. The data obtained promoted further study of the mechanism of the antitumor effect of SF and the search effective combination with already known antitumor drugs. PMID- 25552077 TI - [Michael Lazarevich Gershanovich--one of the founders of cancer chemotherapy in Russia]. AB - Michael Lazarevich Gershanovich was born 90 years ago. He has made a significant contribution to foundation and development of chemotherapy for malignant tumors. Doctor of Medical Sciences, Professor, Laureate of the State Prize of the Russian Federation, Honored Scientist of the Russian Federation, Academician of the Russian Academy of Natural Sciences, a member of the Editorial Board of the Journal "Problems in Oncology" ("Voprosy Onkologii), member of the World Club of Petersburgians, a retired lieutenant-colonel Michael Lazarevich, until his last day (16.12.2013), was the head of the Department of Medical Oncology of the N.N.Petrov Research Institute of Oncology, St. Petersburg. PMID- 25552076 TI - [Are we ready for the growing threat of virus dependent cervical cancer and the initiation of screening in conditions of insurance medicine?]. AB - The dynamics is presented of the rates of virus dependent diseases, in particular cervical cancer (CC), which are directly connected with the level of organization of screening and subsequent treatment of cancer. It is shown that in conditions of insurance medicine a reduction of examination rooms and female enrollment in cytology screening is observed. As a result, over the past 5 years, CC incidence in the Novgorod region increased 1.2 times, and in Russia as a whole, the proportion of such cases in female population under 29 years since 2000 increased 4.5 times (from 2.0% to 9%). The urgent task of cancer control is to restore examination rooms, to overcome disagreements between government institutions and medical departments, to increase coverage of women by cytology screening by means of formation of the program of individual accounting of women. PMID- 25552078 TI - [Prof. N.E. Kushlinsky (on the occasion of his 60th birthday)]. PMID- 25552079 TI - [The distribution of GABA-ergic neurons in rat neocortex in the postnatal period after the perinatal hypoxia]. AB - The distribution of GABA-ergic neurons in different areas of the neocortex (frontal, sensorimotor, visual cortex) was studied in Wistar rats at different time periods of postnatal development after their exposure to perinatal hypoxia. To identify these neurons, the antibodies against GAD-67, the marker of GABA ergic neurons, were used. It was found that the exposure to perinatal hypoxia caused a significant reduction in the number of GAD-67-expressing neurons in both upper and deep layers of the cortex in juvenile age (day 20 of postnatal period), that persisted until the prepubertal period (day 40). In experimental animals at postnatal day 40, the numbers of neurons that synthesized GAD-67, were two times lower in each of the layers of the neocortex than those in control animals. It is suggested that a drastic reduction in the number of GABA-ergic neurons in the neocortex could be a result of the damaging effects of acute perinatal hypoxia on the processes of progenitor cell migration from the subventricular zone, or on the synthesis of the factors controlling these migration processes as well as on GABA-ergic neuron maturation, leading to a delay of GAD-67 expression. PMID- 25552080 TI - [Structural and functional organization of cart peptide-expressing neurons in brain amygdala]. AB - The aim of the study was to identify the specific features of structural and functional organization of the neurons in dorsomedial nucleus of amygdala containing immunoreactive CART peptide. The study was carried out on 15 Wistar rats using an immunocytochemical demonstration of CART peptide and Golgi method. CART peptide-expressing neurons in subependymal zone of the nucleus were shown to be neuroblastoformal, while those located in its central zones were short dendritic. These data demonstrate that CART peptide-expressing neurons are belong to a sparcely branched neuronal system. The results obtained in this work together with the analysis of the literature and the provisions of A.L. Polenov (1993) concept on the origin and evolution of the neuroendocrine cells and neurohormonal regulation in Metazoa, suggest that CART peptide appeared during the early stages of the formation of the regulatory chemical communication in the multicellular organisms. PMID- 25552081 TI - [The effect of anthropometric factors on human cerebellar mass and its age dynamics]. AB - The purpose of this work was to examine the dependence of human cerebellar mass and its age dynamics on the body length and body-build type. The study was carried out on 295 objects--the corpses of the individuals of both sexes (173 males and 122 females) who died at the age of 20-99 years. The length of the body, the transverse diameter of the chest and the cerebellar mass were measured. Somatotype was determined by the Rees-Eysenck index. It was found that human cerebellar mass ranged from 103 to 197 g (with the average of 144 +/- 1.0 g) and was significantly greater in men than in women (150.5 +/- 1.3 g vs. 133.9 +/- 1.2 g, P < 0.001). Age affected cerebellar mass in men (R = -0.46) more, than in women (R = -0.43). In men, a period of relative stability of the cerebellar mass lasted up to about 50 years and then was followed by a period of its decrease. In women, the stable period was observed until approximately 70 years. The cerebellar mass was related to the body length (R = 0.35 for men and R = 0.36 for women). The dependence of the cerebellar mass on the body length was greater in men (1.0 g/cm) greater than in women (0.5 g/cm): with the increase of the body length the difference in the values of the cerebellar mass between men and women was found to grow. The cerebellar mass in the individuals with various body-build types was not significantly different PMID- 25552082 TI - [Calbindin-containing neurons of the ventral horn of murine spinal cord gray matter]. AB - The study was performed in 4 C57black/6 mice to examine the neurons located in T(II), L(IV), L(V) and L(VI) segments of the spinal cord (SC) ventral horn, containing 28 kD calbindin (CAB) and 200 kD neurofilament (NF) proteins. To demonstrate immunoreactive neurons, the cells were labeled with antibodies against CAB and double labeled with antibodies against CAB and NF. The total cell population was demonstrated using NeuroTrace Red Fluorescent Nissl Stain. Results have shown that CAB-immunopositive neurons were identified in ventromedial area of the ventral horn at all SC levels and were represented by Renshaw cells. CAB positive interneurons located in the medial area of the ventral horn were present only in SC lumbar segments. CAB-positive motorneurons that were identified in the medial area of the ventral horn, were present in one SC segment (L(IV)) and were also found to contain a NF protein. PMID- 25552083 TI - [Morpho-functional characteristic of the lateral vaults of the epidural space of the spinal cord and their clinical significance]. AB - The study of the epidural space was performed on 362 samples of the vertebral column obtained from the fetuses aged from 16 weeks, newborns, children and adult persons aged up to 90 years, using anatomical and histological methods. Within the lateral parts of the epidural space, the lateral vaults were distinguished. A new anatomical interpretation of these structures is proposed, considering them as a complex of anatomical structures including the periosteum of the intervertebral foramen, the sleeve of dura mater, intervertebral veins, spinal arteries, adipose tissue, the system of the connective-tissue trabeculae, recurrent nerves controlling the blood flow in the vascular system of the vertebral channel and promoting the communication of the epidural space with the paravertebral areas. PMID- 25552084 TI - [Structural changes and cellular composition of the mesenterial lymph nodes in mice of first generation after parental exposure to radiation]. AB - Changes of the structure and cellular composition of mesenterial lymph nodes were studied in 93 outbred albino mice born from parents exposed to 0.3 and 3.0 Gy of the ionizing radiation, after single intraperitoneal immunization of the offspring with sheep erythrocytes. The changes (lymphoid tissue hypoplasia with the reduction of lymphocyte and plasma cell numbers, increase of apoptotic cell, macrophage and reticular cell numbers, as well as cell detritis volume) were more pronounced after an exposure to high-dose radiation. The outgrowth of node stroma, circulatory disturbances and tissue edema were observed. The processes of lymphoid tissue reduction in the cortex affected the medullary structure, finally resulting in the early lymph node involution, that reflected the changes in the general adaptation and defense reactions of the whole immune system. PMID- 25552085 TI - [The structure of the esophageal glands proper in the individuals of elderly and senile age]. AB - Esophageal submucosal glands (esophageal glands proper) were studied in 19 individuals of elderly and senile age (without subdivision according to gender), as well as in persons of I period of mature age (6 to 7 cases in each group). It was shown that the glandular acini contained thin, elongated cells and cuboidal cells between the mucocytes surrounded by the myoepithelial cells. Around the acini, the myofibroblasts were found. The number of fibroblasts and lymphocytes in glandular stroma increased with age. The number of plasma cells was increased with age in the stroma of the glands of the upper part of the esophagus. Small excretory ducts were arranged in groups, often surrounded by the clusters of lymphoid cells. The number of lymphoid cells and fibroblasts around the large excretory ducts was found to increase with age. PMID- 25552086 TI - [Echo-morphometric characteristics of human skin in patients with idiopathic scoliosis]. AB - The purpose of the work was to explore the informational value and methodological aspects of the echographic evaluation of the skin structural characteristics in patients with idiopathic thoracolumbar scoliosis (IS), grades III-IV. The study included 49 patients with grades III-IV IS aged 7-18 years and 16 healthy people. According to echomorphometric data, the age dependence of the of the skin thickness was detected in thoracic, lumbar, areas and in the lower extremity regions. In patients aged 14-16 years with, the asymmetry of skin thickness was found between the left and right areas of the thoracic area (P < 0.05). Skin of thoracic area in IS patients aged 12-16 years was significantly thinner than in healthy persons of the same age. Statistically significant correlation of an average power between the body mass index (BMI) and the skin thickness of thoracic and lumbar areas was detected in IS patients, while in the group of healthy persons there was a highly significant correlation between the skin thickness of the thoracic area and BMI. PMID- 25552087 TI - [Peculiarities of regenerative processes after the plasty of osteochondral defects with combined cell-tissue grafts on the basis of autologous and allogeneic cell cultures from costal cartilage tissue]. AB - From a position of in vivo regenerative medicine, the efficacy of plasty of osteochondral defects of the articular surface was evaluated in rabbits. The combined cell-tissue grafts were used with the demineralized spongy bone as a biomatrix and autologous or allogeneic cells from the rib cartilage tissue. Morphofunctional characteristics of the cell cultures obtained were studied using morphological, histochemical, immunohistochemical and flow cytometric methods. Cells had features typical to cartilage cell line. While the macroscopic appearance of the plasty area was similar, some differences of histogenesis were observed at the early stages after the placement of transplants containing autologous as well as allogeneic cells, into the osteochondral defect area. In both cases, the complete recovery of subchondral bone and hyaline cartilage took place. PMID- 25552088 TI - [Morphological characteristics of reparative osteogenesis under the conditions of transosseous osteosynthesis and intramedullary introduction of hydroxyapatite coated wires]. AB - In the experiments performed on 16 dogs, an open comminuted tibial fracture was modeled, then wires with hydroxyapatite coating were inserted intramedullary, and osteosynthesis was performed using the Ilizarov fixator. Bone regenerates were studied 14-360 days after the surgery using the methods of light microscopy, scanning electron microscopy, and X-ray electron probe microanalysis. It was found that a zone of active reparative osteo- and angiogenesis was formed around the wires, as well as a bone sheath with the properties of osteogenesis conductor and inductor. Fracture consolidation occured early according to the primary type without cartilaginous and connective tissue formation in bone adhesion. PMID- 25552089 TI - [Histomorphometric charactheristic of skeletal muscle regenerating after a closed partial crush injury]. AB - To evaluate the degree of skeletal muscle regeneration in 15 adult Wistar rats, the closed partial crush injury of anterior tibial muscle was modeled. The study was performed using the methods of light microscopy and computer-assisted morphometry of semithin sections. The continuity of the crushed muscle fibres (MF) was restored by day 21 after the injury. After 90 days endomysial fibrosis was substantially reduced and its vasculairity increased; the variability of MF diameters was restored, however the branched structure and myopathic changes of the regenerated tissue persisted and were presumably associated with an incomplete reinnervation of the damaged intramuscular nerves. PMID- 25552090 TI - [Foot arch shape in children aged 2-5 years according to the data of plantography and holographic interferometry]. AB - 25 children aged 2 to 5 years were examined orthopedically using the methods of plantometry and holographic interferometry of three-dimensional casts of footprints. The computer maps of the foot arch surface were obtained and the graphic reconstruction of the arch shape was performed in normal cases and in children with flatfoot. Most significant deviations of the foot arch shape, probably associated with the development delay, were detected in 4-5-year-old children under the dynamic load. Some additional advantages of holographic interferometry for the early diagnosis of flatfoot in children were demonstrated. PMID- 25552091 TI - [The anatomical basis of the formation of the pedicled bone grafts on the upper extremity]. AB - The study of the vascular bed of the upper extremities was performed by the method of anatomical preparation of 24 formalin-fixed cadaver specimens from 5 men and 7 women and by the injection of black latex into the arterial bed of 4 male and 4 female cadavers (16 specimens). The arteries, directly feeding the bones, and the arteries that provide blood supply to the muscles, attached to the bones, were studied. M. pectoralis major, m. pronator teres, m. pronator quadratus, mm. lumbricalis and interosseus were examined. These studies were followed by the experimental surgeries during which bone grafts on vascular pedicle were formed and moved. It was found that the feeding arteries of the bone grafts on musculo-vascular pedicle were: on the clavicula--the branches of a. thoracoacromialis, on the brachium--muscular branches of a. brachialis, on the proximal parts of forearm bones--muscular branches of a. radialis and ulnaris, on the distal parts of forearm bones--the branches of a. interosseous anterior, on the metacarpal bones--the branches of aa. metacarpalis palmaris and dorsalis. The size of the bone transplants is determined by the size of the defect of recipient field and varies from 3 to 8 cm. The displacement of vascularised bone graft can be made over the distance from 4 to 8 cm. PMID- 25552092 TI - [Neuroglobin distribution in the human cerebellar cortex (an immunohistochemical study)]. AB - Neuroglobin is a recently discovered heme-containing protein located predominantly in the mammalian brain. This paper for the first time presents the data on neuroglobin distribution in human cerbellum using immunohistochemistry. Neuroglobin immunoreactivity in the cerebellum was found in all the cases studied (n = 7), although its intensity varied. Distinct reaction was found in Purkinje cells and the areas of cerebellar glomeruli. PMID- 25552093 TI - [Tissue reactions to the use of implants manufactured from lactic acid polymers]. AB - Recent literature on the morphological results of the application of polymers produced from lactic acid (polylactides--PLA), contains a plethora of experimental and clinical data on the efficiency and safety of their use for the medico-biological purposes. However, the question on the actual rate of biological disintegration of PLA materials remains unanswered. There are conflicting views on the inflammatory reaction ranging from a complete negation of an inflammatory response to PLA implantation up to the reports describing the expressed aseptic inflammatory reactions caused by presence of this material in tissues. Some researchers report the total absence of the foreign-body reactions to this class of implants, while some others indicate the obligatory formation of the foreign-body giant cells. Further research is necessary to precisely predict degradation processes of and to detect all the potential risks associated with the use of PLA-based materials. PMID- 25552094 TI - [Zoya Sergeyevna Khlystova and the development of the problems of embryonic morpho- and histogenesis (to centenary of birth)]. PMID- 25552095 TI - [Yuriy Ivanovich Borodin (to 85th birthday)]. PMID- 25552096 TI - [Vadim Nikolayevich Shvalyov (to 85th birthday)]. PMID- 25552097 TI - [Academician of the Academy of Medical Sciences Anatoliy Panteleimonovich Kolesov (1924-1987)]. PMID- 25552098 TI - [Coronary microvascular obstruction phenomenon after endovascular recanalization in patients with chronic coronary occlusions]. AB - The article analyzed no-reflow phenomenon after endovascular recanalization for chronic coronary occlusion. An assessment of antegrade blood flow was made while performing the coronary angiography according to TIMI classification. The Rentrop scale was used for evaluation of retrograde blood flow. The results of investigation showed, that the frequency of occurrence of no-reflow phenomenon after endovascular recanalization in the case of chronic coronary occlusion wasn't higher than 5%. The onset of no-reflow phenomenon after endovascular recanalization in chronic coronary occlusion doesn't depend on the volume of retrograde collateral filling of distal coronary bloodstream. A postponed restoration of antegrade blood flow was possible in patients with previously manifested (Rentrop II-III) retrograde collateral filling of periphery. PMID- 25552099 TI - [Endarterectomy and reconstruction of the left anterior descending artery: immediate and long-term results]. AB - An analysis of the results of treatment of 149 patients was made. The revasculization of the myocardium and the endarterectomy using the left anterior descending artery were carried out in these patients at the period from 2003 to 2010. The middle age was 59.5 +/- 8.4 years. The exertional angina of the III-IV functional class was noted in 76% of the patients and 72% of patients had the myocardial infarction in anamneses. The follow-up study included 127 operated patients. The mean follow-up period was 43.3 +/- 23.9 months (maximal period--8.5 years). The hospital lethality consisted of 2.7%. The survival rate was 89.3% in a long-term period. The cineangiography was performed on 52 patients in mean terms 50.2 +/- 22.9 months. A patency of arterial grafts was 51(98.1%), the patency of venous grafts--77 (93.9%). The signs of involution of the venous grafts were in 3 (3.7%. PMID- 25552100 TI - [Long-term results of surgical treatment of the extracranial arteries aneurysm]. AB - Aneurysms of extracranial arteries are sufficiently rare pathology in the extracranial arteries surgery. The authors aimed to research the frequency of occurrence of the extracranial arteries aneurysm, reasons of the onset, the localization, clinical manifestations and surgical treatment strategy. A retrospective study presents 10 cases of the extracranial arteries aneurysm for the last 5 years. A presence of aneurysmatic dilatation of extra-cranial arteries was detected according to the data of ultrasonic duplex scanning (UDS) and patients were directed to the hospital. The UDS was carried out as a routine procedure because of the presence of earlier acute stroke or the transitory ischemic attack. All the patients were carefully examined. A computed tomography and the recurring UDS were performed and the neurologic status of patients was estimated. An indication to surgical treatment was an increase of the internal carotid artery diameter and the common carotid artery more than 50% or equal to it. The presence of the local saccular aneurysm was one of the reasons. Surgical treatment strategy was determined by the anatomic position and possibilities for the reconstruction. The results of given operations showed, that the surgical treatment strategy should be recommended and could be fully justified in this pathology. PMID- 25552101 TI - [Surgical treatment of multiple isolated intrapulmonary metastases]. AB - An analysis of treatment results was made in 226 patients with multiple isolated intrapulmonary metastases of solid tumors. It appears that surgical removal of metastases was possible in patients with satisfactory functional resources and accurate evaluation in order to validate the indications for surgery. The operation shouldn't result in considerable reduction of quality of life and didn't prevent using other methods of treatment such as medicamental and radiation therapy. The indications to surgical intervention have to be set as individual in consideration of the number of metastases and potential of the patient to undergo the surgery. PMID- 25552102 TI - [Percutaneous endoscopic gastrostomy for long-term artificial enteral nutrition of seriously ill and trauma patients]. AB - Percutaneous endoscopic gastrostomy was performed on 55 patients of anaesthesiology resuscitation clinic of Military Medical Academy during the last 5 years. A surgery duration was about 13.7 +/- 0.5 minutes. The following complications were observed: postoperative wound infections (3 cases), uncontrolled removals of the feeding tube (2 cases), bleeding was noted in 1 patient. The authors recommend the method of percutaneous endoscopic gastrostomy for widespread adoption in patient care institutions according to their experience. The enteral feeding could be used when patients would have the swallowing malfunction during more than 3 weeks. PMID- 25552103 TI - [Pathogenesis of visceral functions disorder in diffuse peritonitis]. AB - Clinical and laboratory signs of abdominal sepsis and endotoxicosis were noted in 194 examined patients with diffuse peritonitis. It was stated that pathogenesis of visceral functions mainly expressed as a splanchnic blood circulation disturbance, massive translocation of gut organisms in portal bloodstream and the functional liver insufficiency particularly marked as form of macrophage liver insufficiency. The complex program of liver rehabilitation should be included in standards of treatment of the patients with diffuse peritonitis. It should be based on preventive measures of the enteral detoxication and microbial decontamination of small intestine and at the same time the intraportal transsubilical infusion correcting therapy has to be applied. PMID- 25552104 TI - [Risk factors of fatal outcome in pancreatonecrosis]. AB - The article analyzed risk factors after operations for pancreatonecrosis in order to predict a course of the disease and carefully plan the treatment. It was revealed that the lethality level depended on different factors: the sex, age, a period of admission to the hospital, prevalence of necrotic suppurative process and severity of operative trauma. The authors made a conclusion of radical change to treatment approach. The open operations should be reduced at the expense of introduction of low-invasive methods of treatment in the case of pancreatonecrosis. PMID- 25552105 TI - [Is the localization of the tumor in intra-peritoneal part of the rectum contraindication to transanal endoscopic microsurgery]. AB - Transanal endoscopic microsurgery (TEM) is the method used in cases of benign tumors at the early stages of rectal cancer. The tumor localization in peritonized part of the rectum indicates a limiting level for removal of the neoplasm. TEM was performed on 137 patients. The mean age was 63.8 +/- 9.8 years and the number of women consisted of 65.7%. Neoplasms were located in the upper ampullar rectum and a potential possibility of connection with the peritoneal cavity was noted in 12 (8.7%) patients, but during TEM it was only in 5 cases. There wasn't any conversion to a peritoneal surgery. The wound closures were carried out from the side of the rectum lumen and all the operations were finished with the control laparoscopy and formation of sigmostoma. The stomas were closed in 3 patients on fifth- sixth weeks. A connection with the peritoneal cavity during TEM isn't critical event in the case of wound closure through surgical rectoscope and it doesn't lead to the conversion to radical operation. PMID- 25552106 TI - [Dynamics of local expression of connexin-43 and basic fibroblast growth factor receptors in patients with skin and soft-tissue infections against the background of diabetes mellitus type II]. AB - Clinical results of wound healing dynamics were studied in 60 patients with soft tissue infection against the background of diabetes mellitus type II. At the same time the study considered indices of intercellular contacts protein tissue expression such as connexin 43 (Cx43) and basic fibroblast growth factor receptors (bFGFR). The basic therapy of biopsy material of wound borders was applied. The reduction of bFGFR expression and the minor growth of Cx43 expression were observed. The pain syndrome proceeded for a long time and there were signs of perifocal inflammation, retard wound healing with granulation tissue. The application of combined method of ozone therapy which included autohemotherapy with ozone and an external management of wound by ozone-oxygen mixture facilitated to considerable shortening of inflammatory phase and regeneration. It was associated with increased Cx43 expression (in 1.9 times) in comparison with initial level and bFGFR was enlarged in 1.7 times to eighth day of postoperative period. PMID- 25552107 TI - [Extracorporal surgical treatment of patients with renal cell carcinoma]. AB - Municipal multidisciplinary hospital No 2, Saint-Petersburg The article presents results of 9 extracorporal renal resections for carcinoma with the following autotransplantation. The mean duration of operation was 297.8 minutes and the mean period of hypothermic ischemia consisted of 112,6 minutes. A postoperative follow-up (max 4 years) revealed that there isn't noted any dissemination of the tumor and functional condition of the transplanted kidney was satisfactory. The extracorporal renal resection with the following autotransplantation could be performed according to absolute indication of organ saving and technical impossibility of renal resection in situ. In the case, when experienced surgeons carry out the operation, the existing risk of postoperative complications is low in spite of large volume and traumatic character of surgery in interdisciplinary approach. PMID- 25552108 TI - [Small tension pneumothoraxes according to roentgenogram]. AB - The article analyzes the results of clinical observations and significance of small pneumothorax which displaces the mediastinum in polytrauma. On the basis of clinical data the author compiled a comparison table of tension and non-tension pneumothoraxes. For the first time it was stated the significance of small tension pneumothorax and validated the reason to consider small pneumothoraxes which shift the mediastinum as "tension" according to roentgenogram. PMID- 25552110 TI - [Features of diagnostics and surgical strategy of diaphragmatic rupture in patients with closed chest and abdominal polytrauma]. AB - The article presents results of diagnostics and surgical treatment of diaphragmatic rupture in 32 victims with an estimation of diagnostic value of different instrumental methods of investigation and the efficacy of surgical approach. The correct interpretation of typical clinical and instrumental signs in consideration with trauma mechanogenesis allowed diagnostics of diaphragmatic rupture before the operation in 17 (53.1%) cases. It was observed that an undiagnosed rupture of the left hemidiaphragm caused a formation of posttraumatic diaphragmatic hernia in 2 (6.2%) patients. The laparotomy was applied in 28 patients as a surgical approach and thoracotomy--in 2patients. The laparotomy and after that thoracotomy were performed on one patient. The thoracotomy and laparotomy were carried out on the second patient in turn. The authors consider the laparotomy as optimal variant of surgical approach in acute period of trauma. The postoperative lethality was 15.6%. PMID- 25552109 TI - [Surgical strategy in bullet wound of the thorax accompanied by shock]. AB - The article analyzes the experience of treatment of bullet penetrating wounds of the thorax accompanied by shock in 131 armed forces personnel of internal army and officers of the Ministry of Home Affairs of Russia during contra-terrorist operations on the North Caucasus at the period from 2000 to 2011. The postoperative lethality was reduced from 22.7% to 10.8% due to usage of the strategy which was directed to decrease of surgical aggression in 65 patients. PMID- 25552111 TI - [Features of clinical picture and diagnostic aspects of intestional rotation and fixation disorders in children]. AB - Clinical manifestations and diagnostic methods of particular anatomical variants of intestinal rotation and fixation disorders were discussed by the authors in 208 children of different age groups. There was revealed the tendency to reduce rotation abnormalities diversity with the increase of age group. At the same time the frequency of occurrence of the colon fixation anomalies characterized by chronic recurrent process and progressing colostasis was enlarged. PMID- 25552112 TI - [Acute renal failure after cardiopulmonary bypass surgery in children with congenital heart disease]. AB - The article presents the research based on data of 30 children with congenital heart disease. The mean age of the patients was 7 months. It was shown that open cardiac surgery caused an expressed but transitory expression of renal biomarkers, creatinine clearance and serum creatinine level. The frequency of occurrences of acute renal failure was 46.6%. Both biomarkers returned to normal values before discharge from the hospital. PMID- 25552113 TI - [Application of prolonged flow-aspiration drainage of laparotomy wounds in order to reduce suppurative septic complications in bowels reconstructive surgery]. AB - The article presents the follow-up study of 254 onco-proctologic patients after reconstructive abdominoperitoneal resections. Patients were divided into 4 statistically homogeneous groups (2 main and 2 control groups). A comparative analysis of middle and lateral laparotomy wounds healing was made. Laparotomy wounds were stitched up using conventional method (in layers, tightly) and using other method of prolonged flow-aspiration drainage of hypodermic tissue. Postoperative wound infections were noted in 11.4% patients in case of conventional means. The prolonged flow-aspiration drainage in laparotomy wounds causes only 1.5% of complications. PMID- 25552114 TI - [Advantages and disadvantages of warfarin and pradaxa therapy for venous thromboembolism]. AB - An analysis of complex examination of 110 patients with venous thromboembolism was made. The patients were separated into 2 groups. The first group included 60 patients, who had the start heparin therapy during 7 days with the following 6 month warfarin therapy. Warfarin was substituted by pradaxa (dabigatran) for 50 patients of the second group. The efficacy of pradaxa could be compared with warfarin. However, pradaxa had a number of advantages such as the predictable anticoagulant effect, standard dosages. This medicine is more predictable and doesn't require a control of homeostasis and an adjustment of drug dosage. PMID- 25552115 TI - [Cryptosporidiosis of the pancreas]. PMID- 25552116 TI - [Assessment of medical care quality in craniocerebral trauma on the base of data analysis]. AB - An analysis of 658 medical records of inpatient treatment from 15 hospitals of St.Petersburg was made using a computer-aided technology of the assessment of medical care quality. It was revealed that a proper quality of medical care in craniocerebral trauma was only in 52.9% cases. Different defects of medical care were noted in the rest of observations. It influenced on the condition of the patients (1.0%), the delivery and assessment of health care (40% and 38%, respectively), health resources (18%), social resources (1.0%). Defects of medical records were indicated in 38% patients. It caused a reduction of medical care. Risks of occurrence of medical care defects are low in children hospitals in the case of combined craniocerebral trauma. PMID- 25552117 TI - [Surgeons-artists, artists-surgeons]. PMID- 25552118 TI - [Features of diagnostics and surgical treatment of the thyroid "follicular carcinoma"]. PMID- 25552119 TI - [Syndrome of low anterior resection of the rectum and methods of its surgical correction]. PMID- 25552120 TI - [Floating venous thrombosis of the lower extremities--modern approaches to surgical treatment]. PMID- 25552121 TI - [Professor Valentin Aleksandrovich Neverov (to his 70th birthday) (collective of authors)]. PMID- 25552123 TI - Comparison of outcomes in patients with early-stage mucinous endometrial cancer and those with endometrioid endometrial cancer, with and without adjuvant therapy. AB - OBJECTIVE: To compare risk factors, treatment, and outcomes in patients with stage I/II mucinous endometrial cancer (MEC) relative to those of patients with endometrioid endometrial cancer (EEC). STUDY DESIGN: We conducted a case-control study of patients with MEC and EEC. Patients with stage IA, IB, or II MEC treated at the 2 institutions between 01/01/1996 and 01/01/2007 were identified. Each MEC case was matched with 2 EEC controls by age, stage, grade, and year of diagnosis. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS: A total of 34 patients with MEC were compared to 68 controls with EEC. All patients were treated by hysterectomy and bilateral salpingo-oophorectomy. Use of adjuvant radiation therapy was similar between cases and controls. The 5-year disease-free survival (DFS) rates were not significantly different in patients with MEC when compared to those with EEC (89% vs. 92%, respectively, p = 0.2). The 5-year OS rates for patients with MEC and the control group were 95% and 96%, respectively (p = 0.1). CONCLUSION: Patients with early-stage with early-stage MEC and EEC have similar DFS and overall survival. PMID- 25552124 TI - Egg donation brokers: an analysis of agency versus in vitro fertilization clinic websites. AB - OBJECTIVE: To compare websites of agencies that broker the services of women who provide human eggs for in vitro fertilization versus clinics that recruit egg providers. STUDY DESIGN: We examined 207 websites, of which 128 were egg provider agency 40%) or clinic (60%) websites that recruited providers online. We compared them regarding several variables related to adherence to American Society for Reproductive Medicine (ASRM) guidelines. RESULTS: According to their respective websites, agencies were more likely than clinics to mention ASRM guidelines, be located in the West/Pacific, indicate compensation, offer a fee range, set their minimum > $5,000, specify preferable traits, cap provider age at 31, require an education minimum, allow both parties to meet, discuss short-term risks, and not acknowledge a possible cancer risk. Only 25.5% of agencies and 19.5% of clinics mention psychological/emotional risks, and 11.8% and 5.2%, respectively, mention risk to future fertility. CONCLUSION: This research, the first to systematically compare several key aspects of egg provider agencies versus clinics, suggests it significant differences in adherence to guidelines, raising several concerns and suggesting needs for consideration of improved monitoring and regulation by ASRM or others. PMID- 25552125 TI - Combined laparoscopy and hysteroscopy for the detection of female genital system anomalies results of 3,811 infertile women. AB - OBJECTIVE: To assess the prevalence of Mullerian and gonadal anomalies in a group of infertile women using a combination of diagnostic laparoscopy and hysteroscopy. STUDY DESIGN: This was a retrospective descriptive study in the setting of a university hospital. The records of 3,811 women who underwent laparoscopy and hysteroscopy for infertility were reviewed. RESULTS: Mullerian duct anomalies (MDAs) were diagnosed in 287/3,811 (7.5%) women, gonadal anomalies in 40/3,811 (1.04%) women, MDAs and gonadal anomalies in 22/3,811 (0.57%) women, and "undefined anomalies" in 8/3,811 (0.2%) women. Among the 287 women with MDAs 54.9% were diagnosed with a septate uterus, 14.2% with an arcuate uterus, 10.2% with a bicornuate uterus, 5.8% with a unicornuate uterus, 4.7% with tubal anomalies, 3.6% with a hypoplastic uterus, 2.9% with Mullerian agenesis, 1.8% with a septate uterus and a double cervix, 1.1% with uterus didelphys, and 0.7% with a longitudinal vaginal septum. Among the 40 women with gonadal anomalies 70% were diagnosed with hypoplastic ovaries, 25% with streak gonads, and 5% with an accessory ovary. Among the 22 women with combined Mullerian and gonadal anomalies 50% were diagnosed with streak gonads and a hypoplastic uterus, 31.8% with a hypoplastic uterus and hypoplastic ovaries, and 18.2% with ovarian and tubal anomalies. CONCLUSION: Combined laparoscopy and hysteroscopy are valuable tools for the diagnosis and classification of female genital system anomalies. PMID- 25552126 TI - Endometrial stromal sarcoma: a clinicopathologic study of 29 patients. AB - OBJECTIVE: To analyze clinicopathological characteristics, treatment, and survival in patients with endometrial stromal sarcoma (ESS). STUDY DESIGN: Patients with ESS were identified from the tumor registry of the two participating institutions. Categorical variables were evaluated by chi analytis or Fisher's exact test. Survival estimates were plotted utilizing the Kaplan Meier method. The log-rank test was utilized to quantify survival differences on univariate analysis. RESULTS: A total of 29 patients with ESS were included: 14 (48%) patients with stage I, 1 (3.4%) with stage II, 5 (17%) with stage III, and 9 (31%) with stage IV disease. Median age was 44 (range, 25-62). Most patients were treated by hysterectomy and salpingooophorectomy. Sixteen patients (55%) received adjuvant therapy after surgery. The most common type of adjuvant therapy was hormonal treatment. Median follow-up was 84 months (range, 1-382 months). Four patients with stage I (36%), 2 with stage III (18%), and 5 (46%) with stage IV developed disease recurrences. In 8 cases (73%) the recurrence site was the abdomen and pelvis, and in 3 cases (27%) the recurrence site was the lung. CONCLUSION: ESS is an indolent tumor with propensity for late recurrence. Age, early tumor stage (stage I), lymph node dissection, and adjuvant therapy did not affect disease-free or overall survival. PMID- 25552127 TI - Modified natural cycle in vitro fertilization an alternative in vitro fertilization treatment with lower costs per achieved pregnancy but longer treatment time. AB - OBJECTIVE: To analyze the cost and time requirement per achieved pregnancy in optimized modified natural cycle in vitro fertilization (mNC-IVF) based on a treatment protocol with very few consultations and to compare those with conventional gonadotropin-stimulated aVF (clVF) cycles. STUDY DESIGN: Mono centric prospective trial. Eighty infertile patients each received 1 modified mNC IVF cycle using low doses of the clomiphene citrate. Based on the number of consultations and the clinical pregnancy rate per cycle, the total costs and required time to achieve a pregnancy were analyzed and compared with cIVF. Calculations for cIVF were based on standard therapy protocols and outcomes of European registries. RESULTS: Patients (21-42 years old, 35.4 +/- 4.7 years) undergoing mNC-IVF required on average 1.2 consultations before follicle aspiration. Pregnancy rate per transfer and per initiated cycle were 25% and 13.6%, respectively. Multiple pregnancies did not occur. According to the calculations, total costs per pregnancy rate were around 15% lower with mNC-IVF as compared to cIVF. In contrast, time to achieve an equal pregnancy rate was calculated to take around 30% longer with mNC-IVF as compared to cIVF. CONCLUSION: mNC-IVF using very low dosages of clomiphene citrate avoids multiple pregnancies and is less expensive but more time consuming per achieved pregnancy when compared to clVF. PMID- 25552129 TI - Clinical response to a second uterine curettage in patients with low-risk gestational trophoblastic disease: a pilot study. AB - OBJECTIVE: To determine the curative effect of a repeat uterine evacuation in patients with low-risk gestational trophoblastic neoplasia. STUDY DESIGN: Patients with low-risk gestational trophoblastic neoplasia (GTN)(N=12), diagnosed according to the International Federation of Gynecology and Obstetrics 2002 guidelines, were enrolled in a prospective cohort study. Primary outcomes were need for chemotherapy after second uterine evacuation and number of chemotherapy courses needed to achieve complete remission. RESULTS: Ten patients (83%) did not require chemotherapy and were cured bya second curettage. Two patients failed to respond to the second curettage and received single-agent chemotherapy with actinomycin-D (1.25 mg/m2 biweekly, slow intravenous administration). Both patients responded to chemotherapy as second-line therapy. A 100% remission rate was achieved, with no recurrence at the 1-year follow-up. One patient (8%) had a uterine perforation. CONCLUSION: Second curettage has a favorable response rate. It seems reasonable to perform a second curettage in patients with low-risk GTN in settings where serum beta-hCG assay follow-up is highly reliable and available. However, its potential complications and inconvenience must be discussed critically with each patient. PMID- 25552128 TI - Obstetric vulvar lacerations and postpartum dyspareunia. AB - OBJECTIVE: To report the type and prevalence of obstetric lacerations in a primigravid patient population after term spontaneous vaginal delivery without episiotomy. We examined the characteristics of lacerations in patients with postpartum dyspareunia or vulvodynia. STUDY DESIGN: This was a retrospective cohort of primiparous patients who spontaneously delivered in the residents' service at a large urban hospital under the supervision of Ob/Gyn faculty. Data was extracted from medical records using discharge diagnosis codes. Postpartum medical records and diagnostic codes of all patients with lacerations and postpartum dyspareunia were reviewed. The study was IRB approved. RESULTS: A cohort of 1617 primiparous patients with spontaneous vaginal delivery met the inclusion criteria. No tears were recorded in 836 patients (51.7%), first-degree tears in 413 cases (25.5%), second-degree tears in 271 cases (16.8%), third degree tears in 58 cases (3.6%), fourth-degree in 21 cases (1.3%), and 18 cases (1.1%) were not further classified. Only 51 patients (3.2%) with first- and second-degree lacerations had postpartum complications, and merely 6 (0.4%) had vulvar pain and 6 (0.4%) had dyspareunia. However, 4 of those patients (33.3%) required vulvoplasty for complete dyspareunia remission. CONCLUSION: Almost half of patients with spontaneous vaginal delivery without episiotomy experienced some type of vaginal laceration. A first degree was documented in >25% of cases; however, <10% of those subsequently had complaints of vulvar pain or dyspareunia. PMID- 25552130 TI - The case for in vitro maturation lower cost and more patient friendly. AB - OBJECTIVE: To compare in vitromaturation (IVM) to conventional in vitro fertilization (IVF) with a focus on what is required of patients in order to complete cycles, the differences in work required from the clinic providing the service, and the difference in the cost of cycles. STUDY DESIGN: This was a retrospective cohort-control study. RESULTS: With IVM as compared to IVF: office visits were reduced by an average of 3.2, the number of venipunctures was decreased by an average of 4.5, transvaginal ultrasound examinations were decreased by an average of 2.3, the number of injections given by the patient to herself was decreased by an average of 48.7, the interval from starting gonadotropins to receiving hCG was decreased by an average of 4.6 days, the number of endocrine tests was reduced by an average of 11.4, the number of minutes required for oocyte retrieval was increased by an average of 20.1 minutes, and the number of intracytoplasmic sperm injection procedures increased by an average of 1.7, medication costs were decreased by an average of 91%, and the total cost of a cycle was reduced by an average of 45.9%. CONCLUSION: Patient friendliness and cycle costs are clear advantages of IVM over conventional IVF. PMID- 25552131 TI - A checklist for timeout on labor and delivery: a pilot study to improve communication and safety. AB - OBJECTIVE: To assess the impact on staff communication of a standardized checklist for timeout for patients undergoing a trial of labor after cesarean section and/or elective induction at term. STUDY DESIGN: A comparison of presurvey and postsurvey questionnaire results for labor and delivery personnel assessing communication before and after checklist implementation. RESULTS: From October 2011 through March 2012, 52.9% (N=37) of 70 eligible patients had the standardized checklist for timeout performed. Prior to implementation of the checklist, 66% of respondents (48.8% of nurses, 100% of residents, 90% of attendings) slightly or strongly agreed that their opinions were heard versus 83% of respondents during the study period (73.7% of nurses, 100% of residents, 100% of attendings). Following the intervention, nurses reported that they were more likely to feel as though their opinions were heard (p = 0.05). CONCLUSION: Implementation of a formalized obstetric timeout improved the subjective perception of communication among obstetric staff. This tool has the potential to improve patient safety in labor and delivery. PMID- 25552132 TI - Promoting preconception, pregnancy, and postpartum care following bariatric surgery: a best practice planning toolkit for patients and their physicians. AB - Most bariatric procedures are performed in reproductive-aged women. Managing sequelae of postoperative anatomic and physiologic changes can be complex, particularly in women. Standardizing preconception, pregnancy, and postpartum management may limit practice variation and improve pore. We therefore provide a clinical toolkit consisting of physician checklists and corresponding written patient educational material to achieve these goals. PMID- 25552133 TI - Severe ovarian hyperstimulation syndrome in patients with autoimmune disorders: a report of two cases. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) following ovulation induction is common and varies in severity from mild to severe. Severe OHSS can be life threatening and requires hospitalization and procedures to reduce the extracellular fluid accumulation. Ovulation induction regimen and patient characteristics such as young age and low body weight have been identified as risk factors for OHSS, and follicle count >20 may be predictive of increased risk for moderate to severe OHSS. Whether any other patient factors are important in this risk equation is unknown. CASES: We report on 2 patients with type 1 diabetes mellitus (T1DM) and other autoimmune diseases who experienced a total of 4 episodes of OHSS, 2 of which were severe. CONCLUSION: T1DM, with or without other concomitant autoimmune diseases, may increase the risk for severe OHSS. Awareness of the interaction of preexisting conditions and risk for vascular leak disorders is needed for comprehensive counseling prior to embarking on ovarian stimulation. Preventive measures may be important considerations in this population. PMID- 25552134 TI - Twin anemia polycythemia sequence: a report of three cases. AB - BACKGROUND: Vascular anastomoses in monochorionic placentas are the key factor in the develop- ment of several complications, including twin anemiapolycythemia sequence (TAPS). TAPS is an uncommon form of chronic fetofetal transfusion, characterized by large intertwin hemoglobin (Hb) differences in the absence of amniotic fluid discordances. CASE: We report 3 unusual cases of spontaneous TAPS. Looking to the intertwin Hb differences, each case fits in a different stage of postnatal twin anemia-polycythemia classification. Five of the 6 twins had a good outcome despite major hemodynamic changes. CONCLUSION: Spontaneous TAPS is by far more infrequent than its postlaser counterpart. Our report is somewhat uncommon due to the fact that the 3 cases were spontaneous, consecutive, and each one fit as an example of the various degrees of severity according to the described classifications of this condition. PMID- 25552135 TI - Complete hydatidiform mole and live fetus in a singleton pregnancy with confined placental mosaicism and fetomaternal hemorrhage: a case report. AB - BACKGROUND: Coexistence of complete mole and a live fetus is uncommon (1:22,000 100,000), more so with euploidy. CASE: We present a case of a molar pregnancy with a euploid fetus who had close fetal evaluation for second trimester bleeding. The patient presented at 29 weeks' pregnancy with decreased fetal movements, a result of fetomaternal hemorrhage. She underwent cesarean section and delivered a live infant. By close follow-up and a multidisciplinary approach, the appropriate diagnosis and a favorable outcome were achieved. Both mother and the child at 5 years of age are doing well. CONCLUSION: Detailed anatomic and molecular studies demonstrated a complete mole resulting from confined placental mosaicism, with molar tissue showing a single paternal allele at 8/8 informative loci, all shared with the fetus, thus this coexistent molar pregnancy was not that of a separate conceptus. PMID- 25552136 TI - Cornual ectopic pregnancy: an example of the overdiagnosis of molar ectopic pregnancy: a case report. AB - BACKGROUND: Molar ectopic pregnancies are rare. A literature search revealed that molar ectopic pregnancies are overdiagnosed. CASE: A 25-year-old, G5P3013, African American woman presented to a com- munity hospital with sudden onset of sharp, stabbing, low abdominal pain and nausea and vomiting. Quantitative hCG was 6,644 mIU/mL and ultrasound demonstrated increased vascularity and a hypoechoic, partially tubular collection in the left adnexa concerning for ectopic pregnancy. Laparoscopy revealed a small amount of blood and a slight bulge in the left uterine cornu, which ruptured during blunt exploration. Laparotomy revealed the ruptured left uterine cornu with tissue protruding. A wedge resection of the cornu was performed. The pathologic findings from the cornual resection were consistent with a complete mole. Immunohistochemical staining was performed using p57 analysis 1.5 years later and was consistent with early ectopic pregnancy. CONCLUSION: p57 analysis is an important adjunct in the accurate diagnosis of ectopic hydatidiform molar pregnancy. PMID- 25552137 TI - Live full-term ovarian ectopic pregnancy: a case report. AB - BACKGROUND: Ovarian ectopic pregnancy is rare, with an incidence of 1/7,000 to 1/40,000. Only a few of them progress to full term and survive. Most of them rupture in the first trimester and require emergency surgical intervention. CASE: An African American woman at 38 4/7 weeks' gestation presented to labor thd delivery with decreased smaal movement. Fetal presentation was vertex by ultrasound, which failed to detect ectopic pregnancy. The patient underwent cesarean section for nonreassuring fetal status. Dense pelvic adhesions and an unexpected, live, left ovarian ectopic pregnancy were encountered during laparotomy. CONCLUSION: This case stresses the importance of starting prenatal care early and having a routine first trimester transvaginal ultrasound, which could enhance PMID- 25552138 TI - Perforated levonorgestrel-releasing intrauterine system resulting in small bowel obstruction: a case report. AB - BACKGROUND: Complications arising from use of the levonorgestrel-releasing intrauterine system (LNG-IUS) are uncommon. Perforation of the uterus by an LNG IUS leading to small bowel obstruction (SBO) has not been reported in the literature. CASE: A 29-year-old woman presented to the emergency department with abdominal pain, constipation, nausea, and vomiting. CT scan revealed dilated loops of small bowel suggestive of SBO and an IUD that did not appear within the uterine cavity. Laparoscopy revealed a dense adhesive band of tissue extending from 2 cm caudad to the umbilical port site to 1 arm of the perforated LNG-IUS at the posterior uterine wall. Two bowel loops were twisted around the adhesive band multiple times. The band was taken down at the IUD and the bowel loops were spontaneously freed. The LNG-IUS was removed. CONCLUSION: Use of the LNG-IUS is on the rise in the United States and is a recommended first-line contraceptive agent in the obese patient. Management of perforated IUD in an obese patient should take into account individual patient characteristics. Laparoscopic management of a SBO due to a perforated IUD in an obese patient is possible. PMID- 25552139 TI - Direct injection of vasopressin during hysteroscopic myomectomy: a case report. AB - BACKGROUND: Hysteroscopic myomectomy is the ideal procedure for symptomatic women with submucosalfibroids who desire to preserve their fertility. Vascular myomas can limit visualization when a mechanical morcellator is used. Injection of a dilute vasopressin solution has been shown to decrease blood loss during laparoscopic myomectomy. To date, direct injection of a dilute vasopressin during hysteroscopic myomectomy has not been described. CASE: Our first patient's hysteroscopic myomectomy of a vascular submucosal myoma had to be terminated before complete resection due to impaired visualization and maximum fluid overload. During a subsequent patient's procedure, direct injection ofa dilute vasopressin through the operative port decreased intraoperaftve bleeding and enabled complete resection. CONCLUSION: Injecting a dilute vasopressin solution directly into a vascular submucosal myoma during hysteroscopic resection can assist with hemostasis and visualization, enabling complete resection. PMID- 25552140 TI - Vitamin C as an antioxidant: evaluation of its role on pulmonary contusion experimental model. AB - BACKGROUND/AIM: To analyze the protective activity of vitamin C on the lungs by assessing biochemical and histopathological analysi after performing an experimental isolated lung contusion model. MATERIALS AND METHODS: Fifty-four male Sprague-Dawley male rats were used. The rats were randomly separated into 4 groups Vitamin C (200 mg/kg) was injected intraperitoneally 30 min after trauma. Blood samples were obtained for myeloperoxidase (MPO) glutirthione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities and malondialdehyde (MDA) levels Blood gas analysis and bronchoalveolar lavage was performed. The lung tissue was also extracted for histopathological examination. RESULTS: The lung contusion enhanced MDA, SOD, CAT, and MPO and diminished GSH Px. Vitamin C administration after th pulmonary contusion was found to diminish the level of MDA and the activities of SOD, CAT, and MPO and to enhance the level of GSH-Px (P < 0.05). Contusion-induced disrupted gas analysis and leukocyte infiltration were both resolved by the vitamin C. CONCLUSION: The present results indicate that vitamin C administration attenuated the oxidative damage and morphological change induced by pulmonary contusion in an experimental rat study. PMID- 25552141 TI - Evaluation of 4 methods for the serological diagnosis of Epstein-Barr virus infection using an immunofluorescence assay as the reference method. AB - BACKGROUND/AIM: Tests specific for VCA IgM, VCA IgG, and EBNA IgG are used to diagnose Epstein-Barr virus (EBV) infections and interpret disease status. The immunofluorescence assay (IFA) is accepted as the "gold standard" test. The purpose of this study was to evaluate the performance of 4 methods in comparison with IFA. MATERIALS AND METHODS: In total, 101 serum samples were obtained from clinically suspected cases of EBV infection between May 2010 and May 2012 and evaluated by IFA. All serum samples were analyzed by an immunoblot assay, enzyme linked fluorescent assay (ELFA), enzyme immunoassay (EIA), and immunochromatographic assay (ICA). RESULTS: ELFA and ICA results were in good agreement with IFA for the detection ofVCA IgM, VCA IgG, and EBNA IgG. The results of the immunoblot assay agreed less well with IFA for EBNA IgG, while EIA results were not in agreement with IFA for EBNA IgG or VCA IgM. CONCLUSION: Among the tests studied, ELFA and ICA appear to be suitable methods for the diagnosis and staging of EBV when considering cost-effectiveness, turnaround times, need for a specialist, and IFA concordance. PMID- 25552142 TI - Cell apoptosis and proliferation in rat brains after intracerebral hemorrhage: role of Wnt/beta-catenin signaling pathway. AB - BACKGROUND/AIM: To investigate the role of Wnt/beta-catenin signaling pathway in cell apoptosis and proliferation in intracerebral hemorrhage (ICH) in rats. MATERIALS AND METHODS: The ICH rats were established by stereotaxic infusion of 50 uL autologous arterial blood into the right striatum. Pathological characteristics of brain tissue was assessed by hematoxylin and eosin and TUNEL staining, and the expressions of proliferating cell nuclear antigen (PCNA) and Wnt3a/beta-catenin/cyclin D1 were investigated by immunohistochemistry or reverse transcription polymerase chain reaction. RESULTS: The number of apoptotic cells and PCNA-positive cells kept increasing from the day following the ICH induction and reached a peak on the 3rd and 14th days, respectively. Some of the PCNA positive cells could coexpress neurofilament protein-200 or glial fibrillary acidic protein. Wnt3a, beta-catenin, cyclin D1, and PCNA mRNAs reached maximal expression levels on the 3rd, 7th, 7th, and 14th days, respectively. Moreover, the number of apoptotic cells was significantly positively correlated with the expressions of Wnt3a and beta-catenin mRNAs, and negatively correlated with the number of PCNA-positive cells. CONCLUSION: Our results suggest that the Wnt/beta catenin signaling pathway is associated with cell apoptosis and expression of PCNA in the ICH rat brain and regulates the balance between cell apoptosis and proliferation. PMID- 25552143 TI - Evaluation of apoptotic cell death following transient maternal hypotension in fetal rat brain: temporal pattern within the first 24 h after procedure. AB - BACKGROUND/AIM: To explore the effects of maternal transient systemic hypotension on apoptotic neuronal death in an intrauterine fetal rat brain during the first 24 h after induction of hypotension. MATERIALS AND METHODS: A total of 40 pregnant Sprague-Dawley rats were subjected to either transient systemic hypotension produced for 30 min by blood withdrawal via femoral artery catheterization (hypotension group) or sham operation (control group) on day 15. Two randomly selected fetuses were taken from each rat at 0, 6, 12, and 24 h after the procedure. Apoptosis was evaluated in sections from the whole fetal brain by TUNEL and caspase-3 staining. RESULTS: TUNEL (+) and caspase (+) cells were detected only on the walls of the ventricles of both groups and more abundantly in the hypotension groups than in the control groups at all time points (P <0.05). The increase in TUNEL (+) and caspase (+) cells was highest at 12 h (P < 0.05) following hypotension compared to the other hypotension groups. CONCLUSION: Maternal transient systemic hypotension caused the hypoxia-ischemia (HI)-induced death of immature neurons by apoptosis, and this is especially prominent at 12 h after the insult. Determination of the susceptibility of a developing brain to HI at a certain time may have potential significance on the timing of neuroprotective measures. PMID- 25552144 TI - A pilot experimental study of a catheter to facilitate treatment for penetrating cardiac injury. AB - BACKGROUND/AIM: Penetrating heart injuries result in high mortality. We designed a new catheter to facilitate the treatment of penetrating cardiac injuries and provide more effective initial bleeding control and fluid replacement. MATERIALS AND METHODS: The cardiac injury model was applied to 8 female 1-year-old Sus domesticus pigs. Subjects were grouped according to whether a Foley catheter or a newly designed catheter was placed into the heart through cardiac lacerations. Changes in systolic blood pressures, mortality, and problems encountered during surgery and other intraoperative findings were recorded. RESULTS: There were higher mean blood pressure measurements in the newly designed catheter group during stages IV to VII. All subjects had tamponade and cardiac activity after completion of the repair of all lacerations in the catheter group, whereas in the other group only one subject did. Intraoperative direct fluid infusion to the heart through the catheters in the diastole was performed in all subjects of both groups. However, regurgitation from the cardiac cavity in the systole was seen only in the Foley catheter group. All of the intraoperative complications were seen in the same group. PMID- 25552145 TI - Effects of short-term hyperglycemia on the vasoconstriction of the aorta. AB - BACKGROUND/AIM: To investigate vasoconstrictor responses of healthy blood vessels to short-term hyperglycemic conditions such as postprandial hyperglycemia, gestational diabetes mellitus, and steroid-induced diabetes. MATERIALS AND METHODS: Female Wistar rat aorta rings were incubated in normal (11 mM) and high (22 mM and 44 mM) glucose concentrations for 4 h. Responses of vasoconstriction were measured in reaction to serotonin (10-5 M), phenylephrine (10-6 M), and KC1 (60 mM) compared to the ambient condition, including different glucose concentrations. RESULTS: While the responses of vasoconstriction to KC1 were increased in the presence of Krebs' solution with high glucose, no statistically significant changes were observed in the reaction to serotonin and phenylephrine. In addition, malondialdehyde levels were increased in hyperglycemic conditions. CONCLUSION: Short-term hyperglycemia may lead to augmented contractile response in aorta rings through several mechanisms, and our results showed that oxidative stress is probably one of them. PMID- 25552146 TI - Discovering missing heritability and early risk prediction for type 2 diabetes: a new perspective for genome-wide association study analysis with the Nurses' Health Study and the Health Professionals' Follow-Up Study. AB - BACKGROUND/AIM: Despite the rise in type 2 diabetes prevalence worldwide, we do not have a method for early risk prediction. The predictive ability of genetic models has been found to be little or negligible so far. In this study, we aimed to develop a better early risk prediction method for type 2 diabetes. MATERIALS AND METHODS: We used phenotypic and genotypic data from the Nurses' Health Study and Health Professionals' Follow-up Study cohorts and analyzed them by using binary logistic regression. RESULTS: Phenotypic variables yielded 70.7% overall correctness and an area under the curve (AUC) of 0.77. With regard to genotype, 798 single nucleotide polymorphisms with P-values of lower than 1.0E-3 yielded 90.0% correctness and an AUC of 0.965. This is the highest score in the literature, even including the scores obtained with phenotypic variables. The additive contributions of phenotype and genotype increased the overall correctness to 92.9% and the AUC to 0.980. CONCLUSION: Our results showed that genotype could be used to obtain a higher score, which could enable early risk prediction. These findings present new possibilities for genome-wide association study analysis in terms of discovering missing heritability. These results should be confirmed by follow-up studies. PMID- 25552147 TI - Behavioural and neurobiological consequences of 2 different chronic stressors in rats. AB - BACKGROUND/AIM: To compare the behavioural and neurobiological consequences of chronic headache and chronic mild stress (CMS) in rats. MATERIALS AND METHODS: Forty-eight male Wistar rats were divided into 4 groups: 1) control group, 2) chronic headache group, 3) CMS group, and 4) sham group. Their behaviour prior to (D0) and after (D14) chronic stress was analysed. Afterwards, they were exposed to the Elevated Plus Maze (EPM) in order to evaluate anxiety-like behaviour and the Forced Swim Test (FST) for observation of depressive-like behaviour. Ultrasonic vocalisations (USVs) were recorded by a USV detector system at DO and D14 and during the FST. The c-fos expressions in various brain regions were analysed 2 h after the EPM and FST. RESULTS: The control group showed significantly more sleeping behaviour at D14 (chi2 = 8.213, P = 0.042), emitted more negative and positive affect USVs at D14 (chi2 = 9.853, P = 0.020) and during FST (chi2 = 4.000, P = 0.046) than the chronic headache and CMS groups, and showed significantly less anxiety-like behaviour in the EPM than the CMS group (P = 0.021). CONCLUSION: These results suggest that CMS increases anxiety like behaviour but not depressive-like behaviour, while chronic headache does not have a significant effect on these behaviours in rats. PMID- 25552149 TI - Association analyses of oxidative stress, aerobic capacity, daily physical activity, and body composition parameters in patients with mild to moderate COPD. AB - BACKGROUND/AIM: To investigate total oxidant and antioxidant status, maximal aerobic capacity, daily physical activity, pulmonary functions, and body composition changes, as well as the associations among these parameters, in patients with mild to moderate chronic obstructive pulmonary disease (COPD) versus healthy controls. MATERIALS AND METHODS: The study included 30 male patients newly diagnosed with COPD and 30 body mass index-matched, nonsmoker male controls. Maximal aerobic capacity, daily physical activity, total oxidant and antioxidant status, pulmonary function tests, body composition, and anthropometric parameters were measured. RESULTS: Maximal aerobic capacity and total antioxidant values were lower in patients with COPD compared to the controls. The total oxidant value, body fat percentage, and waist/hip ratio were higher in patients with COPD than in the healthy controls. There was a moderately negative correlation between the total oxidant value and the maximal aerobic capacity, while there was a moderately positive correlation between the total antioxidant values and maximal aerobic capacity in patients with COPD. CONCLUSION: Low aerobic capacity, increased oxidative stress, and adiposity are related to impaired pulmonary functions in patients with mild to moderate COPD and might have a role in the pathogenesis of COPD. PMID- 25552148 TI - Investigation of serum macrophage migration inhibitor factor and monocyte chemotactic protein-1 levels in irritable bowel syndrome. AB - AIM: Irritable bowel syndrome (IBS), a functional disorder of the bowel, has been thought to result from immune activation. The aim of this study was to evaluate macrophage migration inhibitory factor (MMIF) and monocyte chemotactic protein-1 (MCP-1) levels in IBS patients. MATERIALS AND METHODS: We enrolled 30 IBS patients and 30 healthy controls. The MMIF and MCP-1 levels of all patients and controls were detected using commercial enzyme-linked immunosorbent assay kits. RESULTS: Serum MMIF and MCP-1 levels were markedly higher in IBS patients than in controls. White blood cell, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts did not differ significantly between groups. CONCLUSION: These results show that alterations in MMIF and MCP-1 affect the proinflammatory process. They also suggest that MMIF and MCP-1 may play a substantial role in IBS. PMID- 25552150 TI - Effects of oral hormone replacement therapy on mean platelet volume in postmenopausal women. AB - BACKGROUND/AIM: To examine the effects of hormone replacement therapy (HRT) on mean platelet volume (MPV), lipid profile, and C-reactive protein (CRP) levels in postmenopausal women who have a high risk and incidence of cardiovascular disease. MATERIALS AND METHODS: This study was performed retrospectively. Twenty seven healthy postmenopausal women received 1 mg estradiol and 2 mg drospirenone orally for 6 months. Twenty-eight healthy postmenopausal women not taking any HRT were admitted to the study as the control population. RESULTS: Time effect (independent from group effect) was statistically significant for the MPV variable (P = 0.025), but there was no significant change in MPV levels and other cardiovascular disease risk markers in women receiving HRT compared to women in the control group. CONCLUSION: Younger postmenopausal women taking HRT and women who initiated hormone therapy close to menopause are not at increased risk of cardiovascular disease. PMID- 25552151 TI - Serum fetuin-A levels in postmenopausal women with osteoporosis. AB - BACKGROUND/AIM: One of the functions of fetuin-A is the restriction of formation and expansion ofextraosseous hydroxyapatite crystals. TIhe exact correlation of fetuin-A with bone mineral density (BMD) has not been clearly elucidated yet. In this study, we aimed to assess the relationship between BMD and fetuin-A in postmenopausal women. MATERIALS AND METHODS: Fifty postmenopausal women (25 with osteoporosis, 25 healthy controls) were included in the study. All participants were comparable for age and body mass index. None of the osteoporotic patients had received any medical treatment for osteoporosis. Serum fetuin-A levels were measured by ELISA method. RESULTS: BMD scores of the groups were statistically significant (P < 0.001). Serum fetuin-A levels of the osteoporosis group were significantly lower compared to the control group (P = 0.009). Additionally, there was there was a mild to moderate positive correlation between fetuin-A and lumbar (r = 0.381, P = 0.06) and femoral (r = 0.143, P = 0.50) BMD in the osteoporotic group, though it did not reach statistical significance. CONCLUSION: Decreased fetuin-A levels in women with postmenopausal osteoporosis suggest that fetuin-A may have a role in the development of osteoporosis. Further studies are required to define the exact role of fetuin-A in bone metabolism. PMID- 25552152 TI - Endobronchial ultrasound-guided transbronchial needle biopsy for the diagnosis of mediastinal lymphadenopathy in patients with extrathoracic malignancies. AB - BACKGROUND/AIM: Mediastinal lymphadenopathy is common in extrathoracic malignancies and should not always be considered a metastatic lesion. The purpose of this study is to determine the diagnostic value of endobronchial ultrasound guided transbronchial needle biopsy (EBUS-TBNA) in patients with extrathoracic malignancies. MATERIALS AND METHODS: This study included 54 consecutive patients with extrathoracic malignancies who had suspected mediastinal metastases and had undergone EBUS-TBNA for diagnosis. RESULTS: Using EBUS-TBNA, 27 of 54 patients (50%) were diagnosed with mediastinal metastases. Among patients with mediastinal metastases, 2 (3.7%) had a sarcoid-like reaction, 5 (9.3%) had tuberculosis, and 17 (31.5%) had reactive lymph nodes. In 3 cases (5.5%), a specific diagnosis could not be determined following EBUS-TBNA. Two patients underwent surgical staging of their mediastinal lymphadenopathy, which allowed the detection of mediastinal metastases in 1 patient and that of reactive lymph nodes in the other. The sensitivity, specificity, negative predictive value, and diagnostic accuracy of EBUS-TBNA for the diagnosis of extrathoracic malignancies were calculated as 93%, 100%, 92.6%, and 96.3%, respectively. CONCLUSION: EBUS-TBNA is a safe and effective procedure. We should consider whether EBUS-TBNA should be the primary diagnostic tool for the diagnosis of mediastinal lymphadenopathy in patients with extrathoracic malignancies. PMID- 25552153 TI - The validity and reliability of the Turkish version of the University of Toronto Atrial Fibrillation Severity Scale. AB - BACKGROUND/AIM: There are various instruments to assess quality of life (QoL) in patients with atrial fibrillation (AF). The aim of this study is to determine the reliability and validity of the Turkish version of the University of Toronto Atrial Fibrillation Severity Scale (AFSS). MATERIALS AND METHODS: The AFSS and Short Form-36 (SF-36) were completed by 130 patients with documented AF. The Canadian Cardiovascular Society Severity in Atrial Fibrillation (SAF) scale and European Heart Rhythm Association (EHRA) scale were also utilized by the attending physicians. To assess test-retest reliability, the AFSS was readministered to 47 clinically stable patients at a 1-month follow-up visit. Internal consistency reliability, test-retest reproducibility, and construct validity were evaluated. RESULTS: The mean age of the patients was 63.1 + 10.9 years and 58.5% of patients were male. The outcome scores of the Turkish version of the AFSS showed good correlations with theoretically related SF-36 domains. Additionally, AFSS outcome scores showed a linear correlation with the SAF and EHRA scores. Cronbach's alpha values for internal consistency were consistent and similar with the English language version of the AFSS. Intraclass correlation coefficients for reproducibility exceeded 0.80 for every item. CONCLUSION: Convergent-divergent and known-groups validity and reliability were established for the Turkish version of the University of Toronto AFSS. PMID- 25552154 TI - Effect of nodule size on the reliability of fine-needle aspiration biopsy in thyroid nodules. AB - BACKGROUND/AIM: To investigate the reliability of fine-needle aspiration biopsy (FNAB) in thyroid nodules and benign/malignant discrimination, particularly in large nodules. MATERIALS AND METHODS: A retrospective analysis of 1466 nodules in 402 patients with thyroid nodules who underwent thyroid surgery was made. The pathologic results of the thyroid nodules from preoperative FNAB and postoperative surgical pathology results were compared. RESULTS: FNAB was found to be in accordance with the postoperative pathologic results. A concordance between the FNAB and postoperative pathologic results, particularly in nodules less than 3 cm in size, was detected. However, a similar finding was not detected in nodules larger than 3 cm in size. The rates, calculated without taking into consideration the nodule dimensions, were found to be: sensitivity, 47.65%; specificity, 93.98%; false-negative, 52.35%; and false-positive 6.02% CONCLUSION: In our experience, the false-negative rate of FNAB in nodules larger than 3 cm was high. Therefore, we have concluded that in the event of malignant FNAB, this rate is significant; however, in the event of benign FNAB, it should not be trusted too much. PMID- 25552155 TI - Possible metabolic impact of Ramadan fasting in healthy men. AB - BACKGROUND/AIM: Insulin sensitivity and beta-cell function during Ramadan fasting in healthy male subjects have not been investigated so far. We assessed the changes of these and other metabolic parameters to judge the potential metabolic benefits of Ramadan fasting. MATERIALS AND METHODS: Twenty-four healthy males of Turkish origin living in Germany, with normal glucose tolerance, participated in this study during Ramadan of 2009; 19 who completed fasting were analyzed. Blood was drawn at sunset after a period of fasting lasting approximately 15 h on days 0, 16, and 30 of Ramadan, as well as 7 and 28 days later. Insulin sensitivity (Homeostasis Model Assessment, HOMA), beta-cell function, and other parameters were assessed. RESULTS: Ramadan fasting was associated with a significant reduction (-) or increment (+) for the following variables: insulin sensitivity ( 20%; P = 0.04), beta-cell function (+10%; P = 0.049), high-density lipoprotein cholesterol (-23%; P = 0.0003), low-density lipoprotein cholesterol (+14%; P = 0.007), nonesterified fatty acids (-62%; P < 0.0001), resistin (-20%; P = 0.01), adiponectin (+16%; P = 0.003), and glucagon (-21%; P = 0.01). C-peptide, insulin, leptin, triglyceride, and very low-density lipoprotein cholesterol concentrations were not significantly changed. CONCLUSION: Ramadan fasting is associated with transiently impaired insulin sensitivity, compensated for by an increased beta cell function. However, the pattern of insulin resistance-mediating adipocytokines suggests a potentially beneficial metabolic effect of Ramadan fasting. PMID- 25552156 TI - Is the combined use of insulin resistance indices, including adipokines, more reliable in metabolic syndrome? AB - BACKGROUND/AIM: To determine the levels of adipokines (leptin, adiponectin, resistin, and visfatin) and the indices of insulin sensitivity/ resistance, and to examine the relationship among them in patients with metabolic syndrome (MetS). MATERIALS AND METHODS: The study groups included 45 subjects with MetS (31 women/14 men), and 45 sex- and age-matched non-MetS healthy volunteers (31 women/14 men). The levels of adipokines were determined by enzyme-linked immunosorbent assay. RESULTS: The levels of leptin and visfatin were significantly higher in the MetS than in the non-MetS subjects (P < 0.01). There was no difference in adiponectin levels in subjects with and without MetS (P = 0.052). Similarly, resistin did not show any statistically significant difference. A statistically significant positive correlation ofleptin with insulin levels was observed, while negative correlations of visfatin levels with age, and resistin levels with the ratio of adiponectin to leptin, were found in the MetS (P <0.05). The combination of adipokines, insulin resistance-sensitivity parameters, and MetS criteria parameters gave more significant differences than a single parameter. CONCLUSION: Since the parameters mentioned above might affect, interact with, and/or interfere with each other, the combinations of these parameters might give more reliable results to evaluate the insulin resistance/sensitivity in MetS patients. PMID- 25552157 TI - The role of FDG-PET/CT in detecting unsuspected and unknown distant metastasis in the initial staging of NSCLC. AB - BACKGROUND/AIM: Our purpose in this retrospective study was to determine the ratio of unexpected [metastases within the coverage area of thorax computed tomography (CT)] and unknown (metastases out of the coverage area of thorax CT) metastases by positron emission tomography/CT (PET/CT) in patients with newly diagnosed non-small cell lung cancer (NSCLC) who had no defined metastatic lesion, and to investigate the contribution of fludeoxyglucose (FDG)-PET/CT in metastasis staging. MATERIALS AND METHODS: A total of 567 patients (489 males and 78 females, mean age 60.9 +/- 10.7 years) were enrolled in this study. Among the 567 patients, a total of 156 patients who underwent PET/CT for metabolic characterization (group 1) and had solitary pulmonary nodules (group la, n = 39) or solitary pulmonary masses (group lb, n = 117) and the remaining 411 patients (group 2) with NSCLC who had PET/CT performed for staging formed the basis of this study RESULTS: In group 1, 5/39 (12.8%) patients with a solitary pulmonary nodule and 29/117 (24.8%) patients with a solitary pulmonary mass had distant metastases. In group 2, 129 patients of 411 (31.4%) had distant metastasis. CONCLUSION: FDG-PET/CT is proven to be an effective method in detection of unsuspected-unknown metastasis, either in patients with solitary pulmonary lesion or in the initial staging of patients with NSCLC. PMID- 25552158 TI - Detection of the frequency of PER-1 type extended-spectrum beta-lactamase producing Acinetobacter baumannii clinical isolates in Turkey: a multicenter study. AB - BACKGROUND/AIM: beta-Lactamases are an important resistance mechanism in Acinetobacter baumannii. Pseudomonas extended-resistance (PER-1) type beta lactamase-producing strains have been reported from various geographic locations; however, PER-1 type beta-lactamases from Turkish hospitals have not been investigated extensively. The aim of this study was to determine the prevalence of PER-1 type beta-lactamases in A. baumannii isolates in various regions of Turkey. MATERIALS AND METHODS: A total of 763 clinical A. baumannii isolates were collected from 9 university hospitals and 2 state hospitals between 2008 and 2011. Molecular amplification of the OXA-51 gene from the A. baumannii genome was performed in order to verify identification of the species. Real-time polymerase chain reaction was used to detect blaPER-1 genes. RESULTS: PER-1 was detected in 24.6% of the isolates. The annual frequencies of the PER-1 enzyme were detected as 52.2%, 35.9%, and 8.3% in 2008, 2009, and 2010, respectively. PER-1 prevalence decreased gradually over time. The differences observed in PER-1 prevalence among the regions of Turkey were statistically significant (chi-square test; P < 0.001). CONCLUSION: These data demonstrate that the frequency of detection of PER 1 type beta-lactamases in A. baumannii species has decreased in Turkey. However, the increased carbapenem resistance, together with multidrug resistance, has created a worrisome situation regarding this pathogen. PMID- 25552159 TI - The comparison of pandemic HIN1 IgG levels between HIN1 influenza-vaccinated healthcare workers and unvaccinated healthcare workers. AB - BACKGROUND/AIM: To compare pandemic H1N1 (pH1N1) IgG antibody levels between healthcare workers who were vaccinated with the pH1N1 influenza vaccine and the unvaccinated healthcare workers who were selected as the control group. MATERIALS AND METHODS: A total of 68 healthcare workers were included in this study. Of those, 53 were adults vaccinated with the H1N1 influenza vaccine and 15 were unvaccinated. Serum samples were parsed and stored at -40 degrees C until they were examined. RESULTS: Of the total 53 vaccinated healthcare workers, 16 (30.1%) were positive for IgG antibodies (titer > 11), 17 (32.0%) were negative for IgG antibodies (titer < 9), and 20 (37.7%) were borderline (titer: 9-11). Of the 15 unvaccinated healthcare workers, 1 (6.6%) was positive for IgG antibodies, 11 (73.3%) were negative for IgG antibodies, and the remaining 3 (20.0%) had borderline values (P = 0.014, P < 0.05). In both groups, there was no statistically significant difference between IgG-negative, IgG-positive, and borderline subjects in terms of age or sex. CONCLUSION: The IgG antibody level was higher in the vaccinated healthcare workers than among the unvaccinated healthcare workers. PMID- 25552160 TI - Investigation into the frequency of Helicobacter pylori infection with carbon 14 urea breath test in patients with vitiligo. AB - BACKGROUND/AIM: Vitiligo is a common, acquired depigmenting skin disorder. The relationship between Helicobacter pylori (HP) infection and autoimmune dermatological disease has been previously reported. However, the frequency of HP infection in patients with vitiligo has not been reported. In this study, we aimed to investigate the frequency of HP infection with the carbon 14 (C14) urea breath test (UBT) in patients with vitiligo. MATERIALS AND METHODS: This study included 34 patients (18 males and 16 females) with vitiligo and 30 age- and sex matched healthy controls. HP infection was diagnosed using the C14 UBT (Heliprobe). Statistical analysis was performed using SPSS 19. RESULTS: The frequency of HP infection was 64.7% in the patient group and 33.3% in the control group according to the C14 UBT (chi- square test, P = 0.012). HP infection frequency is statistically significantly higher in patients with vitiligo. CONCLUSION: To the best of our knowledge, this is the first investigation of the frequency of HP positivity in patients with vitiligo. To better understand the role of HP in vitiligo as an etiological or initiating factor, further experimental and clinical studies with a greater number of patients are needed. PMID- 25552161 TI - A general consideration of the importance of nutrition for critically ill patients. AB - BACKGROUND/AIM: Malnutrition is a common medical condition among intensive care unit patients. It should be monitored carefully, since early management of malnutrition can dramatically improve the medical condition of the patients. A general consideration of enteral feeding shows that it is much more useful than parenteral administration, because it is more physiological and poses a lower risk of hyperalimentation. MATERIALS AND METHODS: In this retrospective study, we scanned all files and personal information of patients hospitalized in intensive care units between 2009 and 2012 due to various medical conditions. We evaluated the nutritional status of patients with biochemical parameters that were retrieved from the files. RESULTS: In total, 198 patients were identified from hospital records. Almost every patient was given nutritional support either through enteral or parenteral feeding. The albumin levels of 56 patients did not increase, even when they were fed with calculated nutritional support (36.6%). The prealbumin levels of the patients had a tendency to increase after the provision of nutritional additives. CONCLUSION: In appropriately selected critically ill patients, the role of nutritional support in the management of nutritional deficiencies is important. In order to calculate proper feeding goals, a full nutritional assessment is necessary. PMID- 25552162 TI - The increase of mean platelet volume in patients with Alzheimer disease. AB - BACKGROUND/AIM: Vascular risk factors play an important role in the progression of Alzheimer disease (AD). Mean platelet volume (MPV) is a determinant of platelet functionality and increased MPV is associated with an increased risk of vascular inflammation. Here we aimed to examine whether MPV could be used as a marker of vascular damage in AD and to discuss the relation between MPV and other vascular risk factors. MATERIALS AND METHODS: A total of 109 outpatients with AD and 81 healthy controls were included in this study. Diagnosis of AD was made according to defined criteria. The Turkish version of the Mini Mental State Examination (MMSE) was used for cognitive assessment. According to the test results, patients were divided into 2 subgroups, mild (MMSE >= 18) and moderate (MMSE < 18), and their MPV levels were compared. RESULTS: MPV levels were higher in the AD group. There was no statistically significant difference between the moderate group and the mild group according to MPV values. CONCLUSION: Increased MPV in patients with AD may point to platelet dysfunction. MPV is an indicator of increased in vivo platelet activation. Hence, platelets could be the link between vascular risk factors and AD. The assessment of MPV in patients with AD may help identify the patients that could benefit from additional antiplatelet therapy. PMID- 25552163 TI - Comparison of motor pattern of periodic limb movements in patients with restless legs syndrome and obstructive sleep apnea syndrome. AB - BACKGROUND/AIM: Periodic limb movements (PLMs) are repetitive and stereotypical movements of the lower extremities that occur during sleep. The purpose of this study was to analyze the leg muscle activity patterns in PLMs seen in restless legs syndrome (RLS) and obstructive sleep apnea syndrome (OSAS). MATERIALS AND METHODS: In this study, 1260 PLMs from 4 patients with RLS and 4 patients with OSAS were analyzed. The spreading and frequency characteristics of the gastrocnemius, medial hamstring, and vastus muscles were examined separately for each muscle in addition to the tibialis anterior muscle already included in the standard polysomnography recording. RESULTS: A greater number of PLMs (57.34%) were observed in patients with RLS. A greater number of apnea-related PLMs (59.83%) were observed in patients with OSAS. The number of PLMs with spreading characteristics was higher in both patient groups. In both groups, the first muscle to contract was most frequently the tibialis anterior. Analysis of the subsequent contraction patterns showed no regular course in RLS and OSAS patients. CONCLUSION: PLMs may occur with a nonstereotypical muscle spreading pattern generated by different, independent, and, most frequently, unsynchronized spinal generators. PMID- 25552164 TI - Evaluation report of pediatric intensive care units in Turkey. AB - BACKGROUND/AIM: To collect data from throughout Turkey in order to facilitate the organization of pediatric intensive care units (PICUs), and to develop short-term immediate action plans and draft long-term strategic plans. MATERIALS AND METHODS: A total of 35 specialists including 17 pediatric critical care (PCC) specialists, 9 PCC fellows in training, and 9 pediatricians working in PICUs evaluated PICUs and their infrastructures, mortality rates, appropriateness of indications for PICU admissions, PICU bed numbers, and utilization of those PICU beds. RESULTS: PICU bed numbers, PCC specialist numbers, and PICU nurse numbers are insufficient in Turkey. The high percentage of inappropriate and inefficient use of current PICU beds is also another problem. CONCLUSION: In the light of this report, it is obvious that pediatric intensive care services are successful and efficient only in the presence of PCC specialists in PICUs. Studies for improving the infrastructure of PICUs and the training of PCC specialists and other health personnel should be started immediately. PMID- 25552165 TI - An examination of the symptoms of anxiety and parental attitude in children with hemophilia. AB - BACKGROUND/AIM: Hemophilia is an inherited disease with serious repercussions. Psychiatric symptoms are frequently seen in children and adolescents with hemophilia. The aim of this study was to assess symptoms of anxiety in children with hemophilia and parental attitude towards children with hemophilia. MATERIALS AND METHODS: 42 boys were assessed according to child and adolescent psychiatry. Anxiety symptoms and parental attitude were obtained by the State-Trait Anxiety Scale, the Self-Report for Childhood Anxiety Related Disorders (SCARED) and the Parent Attitude Research Instrument (PARI). RESULTS: The mean age was 11.6 +/- 2.5 (range; 7-16). State anxiety scores (44.02 +/- 6.9) were higher than trait anxiety scores (32.7 + 7.5). The most interesting results were high scores related to overprotective mothering (47.9 +/- 9.7) and the application of strict discipline (39.4 +/- 9.1). The total SCARED scores obtained were (23.25 +/- 11.3). CONCLUSION: Assuring a high quality of life is important for children and adolescents with chronic illness. Quality of life is negatively affected by psychiatric symptoms (e.g. anxiety symptoms, depression, intra-familial stress symptoms) in children with hemophilia. This study suggests that high anxiety scores and problems related to parental attitude can be seen in children and adolescents with hemophilia. These problems caused by parental attitude and anxiety symptoms should be considered in the treatment of hemophilia. PMID- 25552166 TI - A comparison of dysfunctional voiding scores between patients with nocturnal enuresis and healthy children. AB - BACKGROUND/AIM: To compare dysfunctional voiding symptom scores (DVSSs) between enuretic children and nonenuretic controls and to investigate associated factors that may affect DVSS. MATERIALS AND METHODS: A questionnaire including demographic features, educational status of parents, DVSS questions, and urinary tract infection (UTI) history was designed. A total of 269 patients were included; Group 1 comprised 161 patients with no voiding symptoms and Group 2 comprised 108 patients with nocturnal enuresis (NE). Children with DVSS of greater than 8.5 were suspected to have dysfunctional voiding. The results were evaluated using SPSS 15.0 with Kruskal-Wallis and multivariate logistic regression tests. RESULTS: The median DVSS was 2 (interquartile range [IQR]: 1-3) in Group 1 and 8 (IQR: 5-12) in Group 2. The percentage of children with DVSS greater than 8.5 was 0.6% in Group 1 and 53.1% in Group 2 (P = 0.01). The percentage of children with UTI history was significantly higher in Group 2 (34.3%) than Group 1 (15.9%) (P = 0.03). An increase in the educational level of the father decreased DVSS by 0.5-fold. Presence of UTI history increased DVSS 2.5 fold. CONCLUSION: The DVSS is a rapid, easy tool for determining abnormal voiding parameters in children. Children with NE had higher DVSSs, which was significantly affected by the father's educational status and the child's UTI history. PMID- 25552167 TI - Stress indicators during general anesthesia with opioid analgesics in children. AB - BACKGROUND/AIM: To determine which of the applied opioid analgesics brings the most powerful blockade of the stress response with the fewest side effects in children. MATERIALS AND METHODS: This was a prospective, observational clinical study. The study included 150 boys, aged 2-5 years, ASA I, who underwent herniectomy or orchidopexy in day case surgery. The introduction and maintenance of anesthesia was intravenous (propofol, rocuronium, and opioids); airway was maintained by laryngeal mask and ventilation by mixture of oxygen/air. Subjects were divided into 3 groups depending on the applied opioid analgesics (fentanyl, alfentanil, remifentanil). RESULTS: The fentanyl group had the highest blood glucose values (AS = 5.14; SD = 0.47) and the highest increase in cortisone level at the moment of incision and at awakening (AS = 536.09; SD = 198.56). The lowest increase in cortisone was recorded in the remifentanil group. A significant decrease in leptin was registered at awakening in the fentanyl group and at the moment of incision in the remifentanil group (P= 0.939). CONCLUSION: Remifentanil is the opioid analgesic with the highest suppressing effect on the stress response to surgical intervention in children. PMID- 25552168 TI - Comparison of estrogen and betamethasone in the topical treatment of labial adhesions in prepubertal girls. AB - BACKGROUND/AIM: To compare estrogen and betamethasone in the topical treatment of labial adhesions in prepubertal girls. MATERIALS AND METHODS: In this retrospective study, we evaluated 39 girls with labial adhesions covering at least 50% of the vaginal opening. Of the total patients, 20 were treated with a topical estrogen preparation, while the remaining 19 patients were treated with a combination of betamethasone cream and petroleum ointment (Vaseline) for 3 to 9 weeks. RESULTS: Sixteen of 20 (80%) patients in the estrogen treatment group were treated successfully with topical estrogen cream only, and 17 of 19 (89.4%) patients in the second group were treated successfully with a combination of betamethasone cream and petroleum ointment. Two patients (2/20) in the estrogen treatment group underwent a surgical procedure for the manual separation of the labial adhesion. One patient (1/19) treated with betamethasone cream and petroleum ointment required a manual separation procedure. We observed a side effect of labial enlargement in 2 patients (10%) who were treated with estrogen only, while the only side effect of the betamethasone treatment was local irritation, which occurred in a single patient (5.2%). In addition, the success rate of the betamethasone treatment exceeded that of the topical estrogen (89.4% and 80%, respectively). CONCLUSION: Betamethasone cream with petroleum ointment is a safe and effective primary therapy for prepubertal labial adhesions. PMID- 25552169 TI - Prohepcidin in maternal circulation: is it related to spontaneous preterm labor? AB - BACKGROUND/AIM: To investigate whether spontaneous preterm labor (PTL) with intact membranes is associated with changes in maternal serum prohepcidin concentrations. MATERIALS AND METHODS: The study consisted of patients with spontaneous PTL with intact membranes (n = 25), a control group of healthy pregnant women between the 24th and 37th gestational weeks (n = 22), and uncomplicated term pregnancies in spontaneous labor (n = 19). Blood samples were collected from patients at the time of clinical diagnosis. Levels of prohepcidin, hemoglobin, serum ferritin, serum iron, unsaturated iron binding capacity, total iron binding capacity, transferrin and transferrin saturation, C reactive protein, and interleukin-6 were measured. RESULTS: Patients with spontaneous PTL had significantly lower maternal serum prohepcidin concentrations than term delivery and control subjects. CONCLUSION: Maternal serum prohepcidin concentration is lower in patients with spontaneous PTL compared to term delivery and control subjects. This suggests that measuring maternal serum prohepcidin concentrations in PTL may be a feasible method for understanding etiologic causes of spontaneous preterm delivery, but, before suggesting this as a course of action, low levels of prohepcidin in patients with PTL need to be more fully investigated. PMID- 25552170 TI - Relationship between placental localisation, birth weight, umbilical Doppler parameters, and foetal sex. AB - BACKGROUND/AIM: The aim of this study is to examine the relationship between placental localisation, birth weight, and foetal sex. It also evaluates umbilical artery Doppler parameters and their relationship with placental localisation. MATERIALS AND METHODS: This is a retrospective study of 500 healthy pregnant women who gave birth at our university. All women had undergone a detailed ultrasound and Doppler examination at 20-23 weeks. The ultrasonography results of the patients were examined retrospectively. Foetal biometry, birth weight, and umbilical artery Doppler parameters were recorded and compared according to placental localisation. RESULTS: Birth weight was significantly higher in foetuses with anteriorly located placenta. The incidence of female foetuses was higher (62%) in relation to anteriorly located placentas, whereas male incidence was higher (51.9%) in relation to posterior placentas. A comparison of Doppler parameters betiveen groups revealed significantly higher pulsatility index (PI) and resistance index (RI) values in posteriorly located placentas. CONCLUSION: Foetal sex might affect placental localisation. Doppler parameters and birth weight might also differ according to placental side. These factors should be taken into consideration during the evaluation of obstetric patients. PMID- 25552171 TI - Evaluation of scleral-fixated intraocular lens position anomalies by anterior segment optical coherence tomography. AB - BACKGROUND/AIM: To measure the positions of scleral-fixated intraocular lenses (IOLs) using anterior segment optical coherence tomography (OCT) and to evaluate the influence of the position of scleral-fixated IOL on the quality of vision. MATERIALS AND METHODS: Twenty-six eyes of 26 patients were included in the study. The average age was 57.5 (11 to 78) years. Anterior segment images were taken using slit lamp optical coherence tomography (SL-OCT) and were used to evaluate the position of the IOL. RESULTS: The average amounts of tilt and decentration were 2.25 degrees +/- 1.93 degrees and 359.28 +/- 194.70 um, respectively. There was a positive and moderate relationship between tilt and astigmatism caused by the position of the IOL (P = 0.030). No relationship was detected between decentration and the astigmatism caused by the position of the IOL (P = 0.285). CONCLUSION: Scleral-fixated IOL position can be evaluated with SL-OCT, which is a noncontact, noninvasive, reproducible, and reliable method of evaluation. Anterior segment OCT has been shown to provide sensitive measurements but not in all cases. The present study showed that a tilted scleral-fixated IOL behaved like a toric IOL, and the astigmatism caused by the position of the scleral-fixated IOL therefore could increase or decrease total astigmatism. PMID- 25552172 TI - Optimizing individual treatment outcomes in men with lower urinary tract symptoms using storage subscale score/total International Prostate Symptom Score (IPSS) as a new IPSS ratio. AB - BACKGROUND/AIM: To evaluate the effects of the storage/total International Prostate Symptom Score (s/T) ratio on the selection and success of medical therapy in men with lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: A total of 54 men (>45 years of age) with moderate or severe LUTS were divided into 2 groups according to the s/T ratio: Group 1 at <0.43 and Group 2 at >0.43. Tamsulosin (0.4 mg to Group 1) and tolterodine ER (4 mg to Group 2) were administered. Patients were evaluated during the 1st and 3rd months of follow-up treatment. RESULTS: Thirty-seven (68.5%) and 17 (31.5%) patients were in Groups 1 and 2, respectively. The mean s/T ratios in Groups 1 and 2 increased to 0.38 +/- 0.19 from 0.33 +/- 0.08 (P = 0.03) and decreased to 0.54 +/- 0.18 from 0.59 +/- 0.1 (P = 0.17) during the 3rd month of follow-up, respectively. The treatment success rates of Groups 1 and 2 were 88.4% and 75.7%, respectively. Nine unsuccessful cases were treated with combination therapy and the treatment success was 86.6% at follow-up. CONCLUSION: The s/T ratio is effective to determine symptom dominance in men with LUTS and can guide medical treatment selection through better identification of symptoms. PMID- 25552173 TI - A new knot-supporting instrument and knot technique for laparoscopic surgery. AB - BACKGROUND/AIM: We report here an instrument designed by Dr Hasan Bdrekci that provides support to the knot to facilitate knot tying in laparoscopic procedures. We call the device the 'B6rekci knot-supporting instrument' and the technique 'B6rekci's knot technique' MATERIALS AND METHODS: To evaluate the efficacy of this instrument, 17 surgeons performing laparoscopic surgery tied 3 knots using the classical intracorporeal method and then using the intracorporeal knot supporting instrument. The times required to tie each knot were recorded and compared statistically. RESULTS: Comparing the 2 knotting methods, the time spent tying the knots was shorter with the knot-supporting instrument in all 3 trials and the difference was significant (P = 0.026) in the third trial. CONCLUSION: This alternative technique can be used for all knots in laparoscopic surgery when classical intracorporeal knotting is difficult. PMID- 25552174 TI - The diagnostic efficiency of CT and MRI in ileosigmoid knotting. PMID- 25552175 TI - Investigation of linezolid resistance in Staphylococcus epidermidis: first reported linezolid resistant coagulase negative staphylococcus in Turkey. PMID- 25552187 TI - Peroxyauraptenol Inhibits Inflammation and NLRP3 Inflammasome Activation by Inhibiting Reactive Oxygen Species Generation and Preserving Mitochondrial Integrity. AB - Peroxyauraptenol (PXT) is a peroxide-containing coumarin compound isolated from the seeds of Cnidium monnieri. PXT exerts anti-inflammatory activities, as it reduces the levels of inducible nitric oxide synthase, nitric oxide, IL-6, and NLRP3 inflammasome-derived IL-1beta in lipopolysaccharide-activated macrophages. PXT also exerts anti-inflammatory activity by reducing reactive oxygen species generation (including mitochondrial), mitogen-activated protein kinase, protein kinase C-alpha/delta phosphorylation, and the release of mitochondrial DNA into the cytosol. In addition, PXT suppresses the phagocytic activity of macrophages and IL-1beta secretion by Klebsiella pneumoniae-infected macrophages. The unique peroxide group is important for the anti-inflammatory activity of PXT, as this activity is reduced when the peroxide group is replaced by a hydroxyl group. These findings suggest that PXT may be a candidate for the development of anti inflammatory agents or a healthy supplement for preventing and ameliorating inflammation-related diseases. PMID- 25552188 TI - Risk factors and placental histopathological findings of term born low birth weight neonates. AB - INTRODUCTION: Low birth weight (LBW) is associated with increased neonatal morbidity and mortality. Hence, this condition should be well studied. The aims of this study were to identify the risk factors for term born LBW, as well as the placental histopathological lesions observed. METHODS: This case control study was carried out in the University Teaching Hospital and the Central Maternity, both of Yaounde, Cameroon, from November 1st, 2013 to April 30th, 2014. Maternal medical records and placentas of term born (>=37 completed weeks) LBW (<2500 g at birth) or normal weight (3000-3500 g) were compared. The main variables recorded included maternal age and parity, maternal height, complications that occurred during pregnancy, maternal pre-gestational body mass index, the number of antenatal visits, the sex and birth weight of the newborn, the umbilical cord length, the placental weight and placental histology. Data were analyzed using Epi info 3.5.4. Fisher exact test, t-test and logistic regression were used for comparison. P < 0.05 was considered statistically significant. RESULTS: and DISCUSSION: A total of 30 cases of LBW and the same number of controls were examined. Significant risk factors for LBW were primiparity (aOR 14.0, 95%CI 2.1 92.7), hypertensive diseases of pregnancy (aOR 18.1, 95%CI 1.02-322.5) and <4 antenatal visits (aOR 9.5, 95%CI 1.3-67.5). Significant placental lesions were placental infarction (aOR 19.5, 95%CI 2.9-130.1) and chronic villitis (aOR 35.9, 95%CI 1.2-1034.3). Our study showed that primiparous women, those with pregnancy induced hypertensive diseases and those with <4 antenatal visits were more at risk for LBW. Significant placental lesions observed among LBW were placental infarcts and chronic villitis. Since LBW has the tendency to recur, and given that some causes such as placental infarcts are preventable, we recommend that a histological examination of the placenta should always be carried out in cases of LBW. PMID- 25552189 TI - Increased glucocerebrosidase expression and activity in preeclamptic placenta. AB - INTRODUCTION: Lysosomal glucosidase beta acid (GBA) deficiency is inherent to Gaucher disease, Parkinsonism and Lewy-body dementia. Increased GBA expression has never been associated with human disease. We describe increased GBA expression and activity in placenta from preeclamptic pregnancies. METHODS: 112 placenta biopsies were available for qPCR, analysis of GBA gene expression and activity. Microanalysis was performed on 20 placenta samples. Alternatively spliced placental GBA transcripts were cloned, expressed in HEK293 cells and analyzed by Western blot and activity assay. RESULTS: GBA is expressed in the syncytiotrophoblast layer of human placenta already at 5 weeks of gestation. We identified five novel GBA transcripts in placenta that enzymatically inactive when expressed in HEK293 cells. Both GBA RNA expression and enzymatic activity are upregulated in preeclamptic placenta. Microarray analysis of 20 placenta tissues identified 158 genes co-regulating with GBA expression and gene enrichment analysis highlights lysosomal function. In our micro-array data GBA expression does not correlate with FLT1 expression, currently the most powerful marker for preeclampsia. There are 89 transcripts that are negatively correlated with GBA expression of which BMP4 and TFEB are interesting as they are essential to early placenta function. DISCUSSION: Although very speculative, we hypothesize that increased GBA expression might relate to placentation through decreased BMP4 signaling or vascularization through downregulation of TFEB. Ceramide, the product of hydrolysis of glucosylceramide by GBA and involved in the regulation of cell differentiation, survival and apoptosis, is another putative candidate linking increased GBA activity to preeclampsia. Both pathways merit further investigation. PMID- 25552190 TI - Tissue fibrocytes are a subpopulation of macrophages. PMID- 25552191 TI - Reply: tissue fibrocytes are a subpopulation of macrophages. PMID- 25552193 TI - Nanomaterial with high antimicrobial efficacy--copper/polyaniline nanocomposite. AB - This study explores different mechanisms of antimicrobial action by designing hybrid nanomaterials that provide a new approach in the fight against resistant microbes. Here, we present a cheap copper-polyaniline (Cu-PANI) nanocomposite material with enhanced antimicrobial properties, prepared by simple in situ polymerization method, when polymer and metal nanoparticles are produced simultaneously. The copper nanoparticles (CuNPs) are uniformly dispersed in the polymer and have a narrow size distribution (dav = 6 nm). We found that CuNPs and PANI act synergistically against three strains, Escherichia coli, Staphylococcus aureus, and Candida albicans, and resulting nanocomposite exhibits higher antimicrobial activity than any component acting alone. Before using the colony counting method to quantify its time and concentration antimicrobial activity, different techniques (UV-visible spectroscopy, transmission electron microscopy, scanning electron microscope, field emission scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectrophotometry, and inductively coupled plasma optical emission spectrometry) were used to identify the optical, structural, and chemical aspects of the formed Cu-PANI nanocomposite. The antimicrobial activity of this nanocomposite shows that the microbial growth has been fully inhibited; moreover, some of the tested microbes were killed. Atomic force microscopy revealed dramatic changes in morphology of tested cells due to disruption of their cell wall integrity after incubation with Cu-PANI nanocomposite. PMID- 25552194 TI - Suppression of copper thin film loss during graphene synthesis. AB - Thin metal films can be used to catalyze the growth of nanomaterials in place of the bulk metal, while greatly reducing the amount of material used. A big drawback of copper thin films (0.5-1.5 MUm thick) is that, under high temperature/vacuum synthesis, the mass loss of films severely reduces the process time due to discontinuities in the metal film, thereby limiting the time scale for controlling metal grain and film growth. In this work, we have developed a facile method, namely "covered growth" to extend the time copper thin films can be exposed to high temperature/vacuum environment for graphene synthesis. The key to preventing severe mass loss of copper film during the high temperature chemical vapor deposition (CVD) process is to have a cover piece on top of the growth substrate. This new "covered growth" method enables the high-temperature annealing of the copper film upward of 4 h with minimal mass loss, while increasing copper film grain and graphene domain size. Graphene was then successfully grown on the capped copper film with subsequent transfer for device fabrication. Device characterization indicated equivalent physical, chemical, and electrical properties to conventional CVD graphene. Our "covered growth" provides a convenient and effective solution to the mass loss issue of thin films that serve as catalysts for a variety of 2D material syntheses. PMID- 25552195 TI - Enhanced environmental stability induced by effective polarization of a polar dielectric layer in a trilayer dielectric system of organic field-effect transistors: a quantitative study. AB - We report a concept fabrication method that helps to improve the performance and stability of copper phthalocyanine (CuPc) based organic field-effect transistors (OFETs) in ambient. The devices were fabricated using a trilayer dielectric system that contains a bilayer polymer dielectrics consisting of a hydrophobic thin layer of poly(methyl methacrylate) (PMMA) on poly(vinyl alcohol) (PVA) or poly(4-vinylphenol) (PVP) or polystyrene (PS) with Al2O3 as a third layer. We have explored the peculiarities in the device performance (i.e., superior performance under ambient humidity), which are caused due to the polarization of dipoles residing in the polar dielectric material. The anomalous behavior of the bias-stress measured under vacuum has been explained successfully by a stretched exponential function modified by adding a time dependent dipole polarization term. The OFET with a dielectric layer of PVA or PVP containing hydroxyl groups has shown enhanced characteristics and remains highly stable without any degradation even after 300 days in ambient with three times enhancement in carrier mobility (0.015 cm(2).V(-1).s(-1)) compared to vacuum. This has been attributed to the enhanced polarization of hydroxyl groups in the presence of absorbed water molecules at the CuPc/PMMA interface. In addition, a model has been proposed based on the polarization of hydroxyl groups to explain the enhanced stability in these devices. We believe that this general method using a trilayer dielectric system can be extended to fabricate other OFETs with materials that are known to show high performances under vacuum but degrade under ambient conditions. PMID- 25552196 TI - Climate for evidence informed health system policymaking in Cameroon and Uganda before and after the introduction of knowledge translation platforms: a structured review of governmental policy documents. AB - BACKGROUND: There is a scarcity of empirical data on African country climates for evidence-informed health system policymaking (EIHSP) to backup the longstanding reputation that research evidence is not valued enough by health policymakers as an information input.Herein, we assess whether and how changes have occurred in the climate for EIHSP before and after the establishment of two Knowledge Translation Platforms housed in government institutions in Cameroon and Uganda since 2006. METHODS: We merged content analysis techniques and policy sciences analytical frameworks to guide this structured review of governmental policy documents geared at achieving health Millennium Development Goals. We combined i) a quantitative exploration of the usage statistics of research-related words and constructs, citations of types of evidence, and budgets allocated to research related activities; and (ii) an interpretive exploration using a deductive thematic analysis approach to uncover changes in the institutions, interests, ideas, and external factors displaying the country climate for EIHSP. Descriptive statistics compared quantitative data across countries during the periods 2001 2006 and 2007-2012. RESULTS: We reviewed 54 documents, including 33 grants approved by global health initiatives. The usage statistics of research-related words and constructs showed an increase over time across countries. Varied forms of data, information, or research were instrumentally used to describe the burden and determinants of poverty and health conditions. The use of evidence syntheses to frame poverty and health problems, select strategies, or forecast the expected outcomes has remained sparse over time and across countries. The budgets for research increased over time from 28.496 to 95.467 million Euros (335%) in Cameroon and 38.064 to 58.884 million US dollars (155%) in Uganda, with most resources allocated to health sector performance monitoring and evaluation. The consistent naming of elements pertaining to the climate for EIHSP features the greater influence of external donors through policy transfer. CONCLUSIONS: This structured review of governmental policy documents illustrates the nascent conducive climate for EIHSP in Cameroon and Uganda and the persistent undervalue of evidence syntheses. Global and national health stakeholders should raise the profile of evidence syntheses (e.g., systematic reviews) as an information input when shaping policies and programmes. PMID- 25552203 TI - Detection of pure ground-glass nodules in the lung by low-dose multi-detector computed tomography, with use of an iterative reconstruction method: a comparison with conventional image reconstruction by the filtered back-projection method. AB - PURPOSE: To evaluate the feasibility of the iterative reconstruction (IR) method with low-dose multi-detector computed tomography (MDCT) for lung cancer screening. MATERIALS AND METHODS: A chest CT phantom containing simulated ground glass nodules (GGNs) of 5 different sizes was scanned by use of 16-row and 64-row MDCT. Tube currents of 10, 20, and 30 mA were used for the low-dose CT. To assess the detectability of pure GGNs, a radiologist-performance test was conducted. Mean visual scores for simulated GGNs were compared for reconstructed images from filtered back-projection (FBP) and the IR method. RESULTS: When 64-row MDCT was used, visual scores for simulated GGNs were significantly higher for the IR method than for the FBP method under any conditions; scores were also significantly higher for 16-row MDCT under some conditions. CONCLUSIONS: The results of this experimental chest phantom study showed that use of the IR method improved the detectability of simulated pure GGNs. PMID- 25552204 TI - Up-regulation of miR-9 expression predicate advanced clinicopathological features and poor prognosis in patients with hepatocellular carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous small (19-24 nt long) noncoding RNAs that regulate gene expression in a sequence specific manner. An increasing association between miRNA and cancer has been recently reported. Hepatocellular carcinoma (HCC), as the fifth most common cancer and the most common cause of death in men, has become the third leading cause of cancer-related deaths globally. In this study, we investigated the miR-9 expression in HCC to evaluate their value in prognosis of this tumor. METHODS: The expression of miR-9 in matched normal and tumor tissues of HCC was evaluated using a quantitative real time RT-PCR. A Kaplan-Meier survival curve was generated following a log-rank test. RESULTS: It was observed that miR-9 expression was upregulated in HCC tissues compared with noncancerous liver tissues (7.26 +/- 1.30 vs. 3.14 +/- 1.08, P < 0.001). The up-regulation of miR-9 in HCC cancer tissues was also significantly correlated with aggressive clinicopathological features. We found that the patients with high miR-9 expression have a higher tumor staging (P = 0.0389) and are in higher risk of venous infiltration (P < 0.0001). Moreover, the results of Kaplan-Meier analyses showed that HCC patients with the high miR-9 expression tend to have shorter overall survival (P < 0.0001). The multivariate analysis clearly indicated that the high miR-9 expression in biopsy samples may be considered as an independent prognostic factor in HCC for decreased survival (4.28; 95%CI, 2.77-7.23, P < 0.001). CONCLUSION: Our data indicate the potential of miR-9 as a novel prognostic biomarker for HCC. Large well-designed studies with diverse populations and functional evaluations are warranted to confirm and extend our findings. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_228. PMID- 25552205 TI - Long-term bowel disorders following radial cystectomy: an underestimated issue? AB - PURPOSE: Patients after radical cystectomy (RC) frequently complain about bowel disorders (BDs). Reports addressing related long-term complications are sparse. This cross-sectional study assessed changes in bowel habits (BH) after RC. METHODS: A total of 89 patients with a minimum follow-up >=1 year after surgery were evaluated with a questionnaire. Patients with BD prior to surgery were excluded. Symptoms such as diarrhea, constipation, bloating/flatulence, incomplete defecation, uncontrolled stool loss, and impact on quality of life (QoL) were assessed. RESULTS: A total of 46.1 % of patients reported changes in BH; however, only 25.8 % reported experiencing related dissatisfaction. Primary causes of dissatisfaction were diarrhea and uncontrolled stool loss. The most common complaints were bloating/flatulence and the feeling of incomplete defecation, but these symptoms did not necessarily lead to dissatisfaction or impairment in quality of life. No difference was identified between an orthotopic neobladder and ileal conduit, and even patients without bowel surgery were affected. QoL, health status, and energy level were significantly decreased in unsatisfied patients. CONCLUSIONS: About 25 % of patients complain about BDs after RC. More prospective studies assessing symptoms, comorbidities, and dietary habits are necessary to address this issue and to identify strategies for follow up recommendations. PMID- 25552206 TI - Prognostic value of saturated prostate cryoablation for localized prostate cancer. AB - PURPOSE: To evaluate the oncological outcomes and complications of patients with saturated prostate cryoablation. METHODS: A cohort of 208 patients cumulatively treated between June 2008 and December 2012 qualified for study inclusion, each undergoing total-gland cryoablation for prostate cancer. The degree of saturated prostate cryoablation was defined as the average prostate volume per cryoprobe (APVC), and divided into four groups (groups 1-4: <3 ml, 3 to <4 ml, 4 to <5 ml, ?5 ml, respectively). Post-ablative complications were measured prospectively at weeks 1, 2, 4, 8, 12, and 24 by using the Common Terminology Criteria for Adverse Events. Biochemical failure was gauged by Phoenix criterion. The Kruskal-Wallis rank sum test and Chi-square test were used to compare clinical characteristics of therapeutic subsets. The Cox proportional hazard model was applied for comparison of recurrence risk between groups. RESULTS: APVC group 1 had the highest pre-operative PSA value and smallest prostate size among the groups. Multivariate analysis of risks of biochemical failures revealed that the larger the APVC, the higher the hazard (p for trend = 0.01). Compared to the group 1 patients, the hazard ratios of biochemical failures in groups 2-4 were 4.4 (confidence interval (CI): 0.5-37), 8.8 (CI 1.1-73), and 9.4 (CI 1.1-78), respectively. Nevertheless, the complication rate of APVC group 1 patients was similar to the other three groups. CONCLUSIONS: Saturated prostate cryoablation by reducing APVC would be beneficial for cancer control without compromising patient safety. PMID- 25552208 TI - Why study global health? PMID- 25552209 TI - Use of head circumference as a predictor of height of individual. AB - BACKGROUND: Establishing personal identity is one of the main concerns in forensic investigations. In forensic anthropology, estimation of height from head circumference has a significant role in establishing personal identity. OBJECTIVE: The objective of the present study was an attempt to understand the relationship between height and head circumference of an individual and to derive regression formulae to estimate the height from the head circumference. METHOD: The present study consisted of 440 (258 male and 182 female) students of age group 17 to 25 years studying in Kathmandu University School of Medical Sciences, Dhulikhel, Nepal during the period from November 2012 to October 2013. Height and head circumference of an individual were measured in centimeter. Data were analyzed by using statistical software SPSS-16. RESULT: The findings of the present study were significant correlation between height and head circumference (r = 0.443, p < 0.01 for male, r = 0.302, p<0.01 for female, and r = 0. 398, p < 0.01 for combined (male and female). The regression equation for height and head circumference was found to be Y = 1.734X + 70.36 (R2 = 0.196) for male, Y = 0.916X + 106.8 (R2 = 0.091) for female, and Y = 1.648 X + 71.69 (R2 = 0.158) for combined (male and female), where Y is the height of Individual and X is the Head Circumference. CONCLUSION: Head circumference showed highly significant positive correlation with individual's height. Therefore, the present study will help in medico-legal cases in establishing the identity of an individual and this would also be useful for Anatomists and Anthropologists. PMID- 25552207 TI - Sarcopenia as a predictor of complications in penile cancer patients undergoing inguinal lymph node dissection. AB - PURPOSE: Lymphadenectomy (LND) is part of the surgical management of penile cancer but causes significant perioperative morbidity. We determined whether sarcopenia, a novel marker of nutritional status, is a predictor of postoperative complications after LND. MATERIALS AND METHODS: Seventy-nine patients underwent LND for penile cancer from 1999 to 2014, and 43 had available preoperative abdominal imaging. Skeletal muscle index (SMI) was calculated on axial computed tomography images at the third lumbar vertebrae, and an SMI of 55 cm(2)/m(2) was used to classify patients as sarcopenic versus not. This classification was then correlated with postoperative complications and survival. RESULTS: Median lumbar SMI was 54.7 cm(2)/m(2) with 22 (51.2 %) patients categorized as sarcopenic versus 21 (48.8 %) who were not. Twenty-seven postoperative complications occurred in 20 patients within 30 days, of which 11 (40.7 %) were major (Clavien score >=IIIa) and 16 (59.3 %) were minor. The most common complications were wound dehiscence (25.9 %), wound infection (18.5 %), lymphocele (18.5 %), and flap necrosis (14.8 %). On univariate analysis, the presence of sarcopenia, nodal disease, and lymphovascular invasion were predictors of postoperative complications. On multivariate analysis, only sarcopenia was an independent predictor of 30-day complications [p = 0.038; 95 % confidence interval (CI) 1.1 21.1]. Although sarcopenia was not statistically associated with worse overall survival (OS), there was a trend toward poorer outcomes in these patients. CONCLUSIONS: Sarcopenia can be a useful prognostic tool to predict the likelihood of postoperative complications after LND for penile cancer. Preoperative nutritional supplementation may help reduce complication rates in the future. PMID- 25552210 TI - Comparison of ultrasound guided transversus abdominis plane block versus local wound infiltration for post operative analgesia in patients undergoing gynaecological surgery under general anaesthesia. AB - BACKGROUND: Transversus abdominis plane block has been recently developed as a part of multimodal post operative analgesic techniques. We compared the analgesic efficacy of this technique with local bupivacaine infiltration in patients undergoing gynaecological surgeries with pfannenstiel incision and lower midline incision under general anaesthesia. OBJECTIVES: To evaluate the efficacy of ultrasound guided transversus abdominis plane block for postoperative analgesia. METHODS: Patients were randomly allocated to three groups: control group (n=15), transversus abdominis plane block group (n=15), who received bilateral transversus abdominis plane blockwith 0.25% bupivacaine, and local infiltration group (n=15), who received local wound infiltration with 0.25% bupivacaine at the end of surgery. All patients received intramuscular diclofenac 12 hourly and intravenous tramadol SOS in the postoperative period. Visual analogue scores for pain were assessed at 1,2,4,8,12 and 24 hours postoperatively and these were compared between the three groups. Average tramadol consumption in 24 hours were also compared among the three groups. Data were subjected to univariate ANOVA test and chi-square test. Level of significance was set at 0.05. RESULTS: Visual analogue scores were significantly less in transversus abdominis plane block group and effect lasted up to 12 hours at rest postoperatively and 8 hours during cough and movement. CONCLUSION: Bilateral Transversus abdominis plane block was effective in reducing postoperative pain scores for 8 to 12 hours postoperatively. This block was also successful in reducing postoperative opioid requirement. PMID- 25552211 TI - Delayed graft dislocation after thoracic aortic endovascular repair. AB - BACKGROUND: Endograft dislocation in thoracic aorta has not been widely studied. OBJECTIVES: The purpose of this study is to analyze the incidence and predisposing factor in a single centre experience after 117 procedures. METHOD: Between November 2000 and December 2011, all consecutive patients undergoing endovascular repair for descending thoracic or thoraco-abdominal aortic disease were identified. Follow-up imaging protocol included triple-phase CT-angiography at 1, 4, and 12 months, and annually thereafter. Migration was defined as proximal/ distal movements >10 mm relative to anatomical landmarks or any movement leading to symptoms or reintervention. RESULT: We identified 117 patients. Mean follow-up was 32 months (range, 1-144). Overall, five (4.3%) patients with thoracic EG dislocation were identified. Dislocation was classified as collapse/infolding in 3 cases and migration in 2. Mean delay of the dislocation was 12.7 months. Only one patient developed symptoms and required an additional endograft. In the group of dislocated endografts, mean age (53 +/- 20 vs. 68 +/- 15, P = .032) and the diameter of the aortic lesion were lower (4.1 cm +/- 1.6 vs. 5.6 cm +/- 1.8, P = .069), and the proximal landing zone at "zones 2 and 3" were more frequently used (5 vs. 65, P = 0.81). All but one patient with collapse/infolding are still alive and doing well at a mean follow-up of 80 months. CONCLUSION: Dislocation is an infrequent complication, but not so rare. Young age, small aortic diameter , and proximal sealing at the distal arch were the most important data associated with this complication. PMID- 25552212 TI - Safety profile and patient satisfaction of the routine use of propofol in gastrointestinal endoscopy. AB - BACKGROUD: Routine use of sedation in upper gastrointestinal endoscopy is uncommon in Nepal. There is no study on use of propofol sedation in routine endoscopy examination in Nepal. This study was conducted in order to assess the patient satisfaction and safety profile in patient undergoing routine upper GI endoscopic examination on outpatients. OBJECTIVE: To study safety profile and patient satisfaction of use of propofol in patients undergoing upper GI endoscopy. METHOD: A prospective, observational study was conducted in the endoscopy unit of Dhulikhel hospital, Kathmandu University Hospital from July 2011 to 2012 July. Patients who were referred to upper GI endoscopy were offered to sedation under propofol. Informed consent was taken after explaining side effects, advantages and risk-benefit to the clients. The propofol was administered by the endoscopy nurse under guidance and supervision of the endoscopy performing physician. Data were collected and analyzed using SPSS version 16.0 with 0.05 level of significance. RESULT: Total of 203 patients included in the study. Among 203 patients, 21.2% were males and 78.8% were females; 83.7% were of less than of 60 years age and 16.3% above 60 years of age. The mean total dose of propofol required was 136.08 +/- 48.82 mg. Total of 29.1 % of cases required O2 administration during the procedure time due to transient drop in O2 saturation. Total of 4.4% of cases required fluid administration due to transient fall in blood pressure. Total of 68.0% of cases were completely sedated; 28.6% had minor restless and 3.4% showed agitation during induction period of propofol sedation. Total of 99.5% of patients reported pleasant experience while 0.5% reported unpleasant. Among 203 respondents, 98.5% responded they would prefer to do the procedure under propofol sedation in the future; 1.5% responded they did not want sedations in the future. CONCLUSION: Upper GI endoscopy can safely be performed under propofol sedation administered by registered trained nurse under the supervision of endoscopist. PMID- 25552213 TI - Is single dose povidone iodine sclerotherapy effective in chyluria? AB - BACKGROUND: Chyluria is a chronic debilitating condition characterized by formation of pyelo-lymphatic connections. Renal pelvic instillation sclerotherapy is a minimally invasive treatment modality in treatment of chyluria. Various sclerosant with different regimen have been described in literature but there is no single consensus on this regard. OBJECTIVE: To evaluate the effectiveness and safety of single dose 0.2% povidone iodine renal pelvic instillation sclerotherapy for the treatment of chyluria. METHODS: In a prospective study from August 2010 till July 2013, forty one patients presenting with milky urine were included. Apart from ether test, presence of lymphocytes in urine and urine triglycerides levels were also done to confirm chyluria. On a day care basis under local anesthesia 5F open ended ureteric catheter was introduced in the ureteric orifice of affected side. Freshly prepared 7-10 ml of 0.2% povidone iodine solution was instilled with the patient in Trendelenburg position. RESULTS: Total of 41 patients were enrolled ( 27 males and 14 females; mean age 40 years, SD 8.9, range 19-61) with a mean follow up of 20 months. Immediate clearance was seen in all patients and recurrence in 7 (17%). Mean disease free duration was 18 months. Two patients had moderate to severe flank pain. CONCLUSION: Single dose 0.2% povidone iodine sclerotherapy is safe and effective treatment for chyluria. As it offers treatment on a day care basis, continuous ureteral and urethral catheterizations can be avoided. PMID- 25552214 TI - Measurement of right atrial volume and diameters in healthy Nepalese with normal echocardiogram. AB - BACKGROUND: The size of right atrium is expected to be different in diverse healthy ethnic groups. It is important to know the normal size of right atrium in our healthy population. OBJECTIVE: The study aimed to find out the normal values of right atrial volume, right atrial short axis diameter and right atrial long axis diameter in healthy Nepalese population with normal echocardiographic findings. It also looked at correlations between right atrial dimensions and the right atrial volume. METHOD: Verbal consent was taken from all the participants. One hundred participants between the age of 18 and 60 years with normal echocardiographic findings and without any chronic disease were included in this study. Right atrial volume was measured by using area length method. Right atrial short axis diameter and Right atrial long axis diameter were measured in the four chamber view. RESULT: The mean right atrial volume was 23.64+/-5.36 ml (range 11.30-40.00 ml).The range of right atrial short axis diameter and right atrial long axis diameter were 1.34-3.80 cm and 2.4-4.7 cm respectively. CONCLUSION: The size of right atrium in the Nepalese population is smaller compared to western population. Male right atrial volume size is greater than female in Nepalese population similar to western population. The findings of normal value of right atrial volume and right atrial diameter in Nepalese population will help the physician to assess patients with various conditions affecting the right atrium. PMID- 25552215 TI - Incidence and risk factors of surgical site infection following cesarean section at Dhulikhel Hospital. AB - BACKGROUND: Cesarean Section (CS) is one of the most commonly performed surgical procedures in obstetrical and gynecological department. Surgical site infection (SSI) after a cesarean section increases maternal morbidity prolongs hospital stay and medical costs. OBJECTIVE: The aim of this study was to find out the incidence and associated risk factors of surgical site infection among cesarean section cases. METHOD: A prospective, descriptive study was conducted at Dhulikhel Hospital, department of Obstetrics and Gynaecology from July 2013 to June 2014. Total of 648 women who underwent surgical procedure for delivery during study period were included in the study. Data was collected from patient using structred pro forma and examination of wound till discharge was done. Data was compared in terms of presence of surgical site infection and study variables. Wound was evaluated for the development of SSI on third day, and fifth post operative day, and on the day of discharge. RESULTS: Total of 648 cases were studied. The mean age was 24+/-4.18. Among the studied cases 92% were literate and 8% were illiterate. Antenatal clinic was attended by 97.7%. The incidence rate of surgical site infection was 82 (12.6%). SSI was found to be common in women who had rupture of membrane before surgery (p=0.020), who underwent emergency surgery (p=0.0004), and the women who had vertical skin incision (p=0.0001) and interrupted skin suturing (p=0.0001) during surgery. CONCLUSION: Surgical site infection following caesarean section is common. Various modifiable risk factors were observed in this study. Development of SSI is related to multifactorial rather than one factor. Development and strict implementation of protocol by all the health care professionals could be effective to minimize and prevent the infection rate after caesarean section. PMID- 25552216 TI - Delirium in critically ill patients in a tertiary care centre in western region of Nepal. AB - BACKGROUND: Delirium affects a significant proportion of critically ill patients admitted in hospital. It is associated with various adverse outcomes. Despite its enormous prognostic significance it tends to be underdiagnosed. There is a dearth of studies on risk factors of delirium in our setting. OBJECTIVES: The main objectives of this study was to find out the prevalence, rate of non recognition and risk factors associated with delirium in hospitalized critically ill patients. METHODS: A hospital based cross-sectional study was carried out. Data was collected using a predesigned semi-structured proforma and Intensive care delirium screening checklist was used to screen for delirium in patients admitted in various wards of Manipal teaching hospital, Pokhara, Nepal. RESULTS: Ninety five cases were included in the analysis. The mean age of study group was 58.9 +/ 19.1 years. Delirium was present in 15/95 cases and it was not recognized by treating physician in about one third of cases. Odds ratio (OR) was statistically significantly increased in patients with history of stroke (OR=4.484 95% CI=1.0896;18.459), alcohol use (OR=10.792 95% CI=2.906;40.072), smoking (OR= 4.836 95% CI= 1.411;16.576), use of restraint (OR=17.143 95% CI=4.401;66.766), nasogastric tube placement (OR= 7.731 95% CI=2.348;25.452) and use of Foley's catheter (OR=12.000 95% CI= 3.072;46.877). CONCLUSION: About 16% of critically ill patients were found to be delirious. In about one third of the cases delirium was not recognized. Both patient related and iatrogenic factors may increase the risk of delirium in hospitalized critically ill patients. PMID- 25552217 TI - Study of working experience in remote rural areas after medical graduation. AB - BACKGROUND: Posting of doctors in remote rural areas has always been a priority for Government; however data are scarce in the country about experience of doctors of working in remote areas after medical graduation. OBJECTIVE: A questionnaire survey of doctors was planned to analyze their experience of working after graduation in remote rural areas in various parts of the country. METHOD: The cross-sectional survey was done by convenience sampling method. A one page questionnaire with one partially closed-end and five open-end type questions was distributed to the doctors who had worked in remote rural areas after graduation under various governments' postings. RESULT: Two-third of participants had their home in urban areas and 89.8% had stayed for 1 to 5 years. About half of the participants had difficulty in getting the posting in the remote areas of their choice. Most participants indicated provision of opportunities for Residential (postgraduate) Training as their reasons of going to remote areas as well as their suggestions to encourage young graduates to go there. Similarly most also suggested appropriate career, salary and incentives to encourage doctors to go to work in remote areas. About 85% of participants pointed out the major problem faced while posted in remote areas as difficulty in handling varied situations with no guidance or seniors available around. CONCLUSION: The notable points indicated by the participants are centered on the opportunity for Residential Training and difficulties faced without such training. Residential Training is a priority to be considered while planning the health policy for optimum health care of people. PMID- 25552218 TI - Distally based sural faciocutaneous and fascial (adipofascial) flap for reconstruction of distal leg, ankle and foot defects. AB - BACKGROUND: Any soft tissue defect in distal leg, ankle and hind foot is still a challenging problem. There are various options for coverage of such defects, but the distally based sural neurocutaneous and neurofascial flap based on the sural nerve and superficial sural artery has been an important option. OBJECTIVE: To evaluate the efficacy of distally based sural flap in reconstruction of the distal leg, ankle and hind foot soft tissue defects. METHOD: Seventeen patients with soft tissue defects over distal leg, ankle and hind foot were included in this study. All patients were treated with distally based sural flap. Most of the cases were due to trauma (16 cases) which compromised tendon and bone. One case was of malignant melanoma of sole of hind foot which required wide excision and soft tissue reconstruction with sural flap. RESULT: In all cases defects were successfully covered. Three showed venous congestion and partial necrosis. One developed secondary infection. One flap failed completely. Mean follow up of patients was 20 months (6-36 months). CONCLUSION: Sural flap is a good option for reconstruction of distal leg, ankle and foot defects. PMID- 25552219 TI - Comparison of oxidant-antioxidant status in patients with vitiligo and healthy population. AB - BACKGROUND: Vitiligo is a well-recognized pigmentary disorder of the skin and /or mucous membrane characterized by circumscribed ivory or chalky white macules devoid of identifiable melanocytes. The pathogenesis of vitiligo is complex and still not well understood. According to autocytotoxic hypothesis, oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration. The role of free radicals and oxidative damage in the pathophysiology of vitiligo has been documented in recent studies. OBJECTIVE: To evaluate the role of oxidative stress in patients with vitiligo and of healthy controls by measuring levels of the oxidant malondialdehyde (MDA) and antioxidants vitamin C and vitamin E in serum and catalase (CAT) in erythrocytes. METHOD: A total of 80 clinically diagnosed cases of vitiligo and 80 control subjects were included in the study to assess the activity of MDA, vitamin C and vitamin E in serum and CAT in erythrocytes of patients and controls by using the spectrophotometric assay. RESULT: There was statistically significant increase in the levels of MDA in patients with vitiligo compared to the control group (p<0.001). No significant difference was found in the levels of vitamin C (p=0.411) and vitamin E (p=0.771) between the patients with vitiligo and control group. The levels of CAT in the vitiligo patients were found to be significantly lower than those of controls (p<0.001). CONCLUSION: Increased oxidative stress and decreased catalase have been observed in vitiligo patients and the data suggesting that the free radicals may be involved in the destruction of melanocytes or dysregulation of melanogenesis. PMID- 25552220 TI - Association of cardiovascular risk factors and coronary artery lesion among coronary artery disease patients. AB - BACKGROUND: Coronary artery disease (CAD) is associated with the numbers of risk factors causing coronary atherosclerosis. Coronary artery stenosis is mostly caused by coronary atherosclerosis. OBJECTIVE: This study aims to analyze the association between coronary artery stenosis and cardiovascular risk factors. METHODS: An observational study was conducted among CAD patients. The diagnostic coronary angiogram was performed from femoral approach using standard catheters and techniques to find out any abnormalities. RESULT: A total 73 patients (44 male and 29 female) with coronary artery disease undergoing diagnostic coronary angiography was included with the documented cardiovascular risk factors. The coronary stenosis was found in 40 patients on the basis of stenosis grading. Among the established cardiovascular risk factors, sex, diabetes mellitus and smokers show are significantly associated with coronary stenosis among CAD patients. The present study shows the significant association of coronary stenosis among male CAD patients (OR 2.47; CI 0.94-6.48, p<0.05) and similar association has been observed in diabetes mellitus (OR 3.32; CI 1.12-9.84, p<0.05) and smoking (OR 4.10; CI 1.45-11.61, p<0.01). CONCLUSION: The prevalence of CAD is increased with numbers of presence of cardiovascular risk factors. Male gender, diabetes mellitus and smoking are significantly associated with coronary stenosis among CAD patients. However, hypertension and dyslipidemia are comparable between coronary stenosis and no significant stenosis group. PMID- 25552221 TI - Pathologies en-route of oral basaloid malignancies to basaloid squamous cell carcinoma. AB - Accurate histopathological diagnosis of any tumour is imperative because of variable prognostic and clinical implications. Basaloid squamous cell carcinoma (BSCC) is a rare distinctive histological variant of oral squamous cell carcinoma (OSCC) exhibiting an aggressive clinical course and poor prognosis. The advanced stage of presentation is speculatively responsible for this biological behaviour which is manifested by development of metastasis and subsequently poor survival. However, the non-specific clinical appearance and histopathological resemblance of BSCC with OSCC and other oral basaloid malignancies (OBM) especially in limited sample size poses diagnostic difficulties. The article emphasizes on the diagnostic criteria and pitfalls encountered in making the differential diagnosis of BSCC from OBMs along with report of a case presented at a dental college in January 2012. PMID- 25552222 TI - Fibro-epithelial hyperplasia mimicking mucocele. AB - The effects of chronic local irritation have been seen commonly in the form of fibroma or mucocele in children. We report a ten year old girl with the chief complaint of swelling in the lower right region of labial mucosa which was diagnosed clinically as mucocele and histologically as fibro-epithelial hyperplasia. Surgical excision was done under local anesthesia with no post operative complication. PMID- 25552223 TI - Difficult journey from delivery to discharge, case of congenital diaphragmatic hernia. AB - We report a case of congenital diaphragmatic hernia which was diagnosed prenatally for which surgical correction was done on second day of life. The child was discharged in 17 days and has resulted in good post repair condition of patient. PMID- 25552224 TI - Pulmonary azygous lobe--an anatomical variant. AB - Pulmonary azygous lobe is one of the common lung malformations. There is only few article about azygous lobe. Its a small accessory lobe sometimes found on the upper part of the right lung, separated from the rest of the upper lobe by a deep groove lodging the ayzygous vein. This reports decribes the presence of azygous lobe, a rare anatomical variant, encounted during chest x-ray discussion. We describe here the anatomical basis and the clinical significance of azygous lobe. PMID- 25552225 TI - Oral submucous fibrosis: a review article on etiopathogenesis. AB - Areca quid chewing related oral mucosal lesions are potential hazard to a large population worldwide. Commercially freeze dried products such as pan masala, guthka and mawa have high concentration of areca nut per chew and appear to cause OSMF more rapidly than by self prepared conventional betel quid that contain smaller amounts of areca nut. The basic constituent of areca nut is either raw or dried or boiled or baked. Diverse agents including lime, tobacco, catechu, cloves, saffron and leaf of piper betel leaves may form a part of formulation. Many of the undesirable aspects of areca nut have been attributed to arecoline. These chemical appear to interfere with the molecular processes of deposition and or degradation of extracellular matrix molecules such as collagen, causing imbalance in the normal process. The most likely events that take place with regards to the above imbalance may be reduced phagocytosis of collagen by fibroblasts, up or down regulation of copper dependent enzyme lysyl oxidase, matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases . It has been postulated that areca nut may also induce the development of the disease by increased levels of cytokines in the lamina propria. Current evidence implicates collagen related genes in susceptibility and pathogenesis of OSMF. The individual mechanisms operating at various stages of the disease--initial, intermediate and advanced--need further study in order to propose appropriate therapeutic interventions. PMID- 25552226 TI - Analysis of health sector gender equality and social inclusion strategy 2009 of Nepal. AB - The policy on gender equality and social inclusion (GESI) in health sector of Nepal is formulated in 2009 targeting toward poor, vulnerable, marginalized social and ethnic groups. Gender inequality and social discrimination are a social problem that affect on individual health finally. The main objective of this paper is to critically analysis and evaluates the Government's strategy on health sector gender equality and social inclusion in Nepal. We collected published and unpublished information assessing the public health, policy analysis and research needs from different sources. A different policy approaches for the analysis and evaluation of GESI strategies is applied in this paper. Universal education, community participation, individual, group and mass communication approaches, and social capital are the key aspects of effective implementation of policy at target levels. PMID- 25552227 TI - Molecular mechanistic origin of nanoscale contact, friction, and scratch in complex particulate systems. AB - Nanoscale contact mechanisms, such as friction, scratch, and wear, have a profound impact on physics of technologically important particulate systems. Determining the key underlying interparticle interactions that govern the properties of the particulate systems has been long an engineering challenge. Here, we focus on particulate calcium-silicate-hydrate (C-S-H) as a model system and use atomistic simulations to decode the interplay between crystallographic directions, structural defects, and atomic species on normal and frictional forces. By exhibiting high material inhomogeneity and low structural symmetry, C S-H provides an excellent system to explore various contact-induced nanoscale deformation mechanisms in complex particulate systems. Our findings provide a deep fundamental understanding of the role of inherent material features, such as van der Waals versus Coulombic interactions and the role of atomic species, in controlling the nanoscale normal contact, friction, and scratch mechanisms, thereby providing de novo insight and strategies for intelligent modulation of the physics of the particulate systems. This work is the first report on atomic scale investigation of the contact-induced nanoscale mechanisms in structurally complex C-S-H materials and can potentially open new opportunities for knowledge based engineering of several other particulate systems such as ceramics, sands, and powders and self-assembly of colloidal systems in general. PMID- 25552228 TI - Remission of type 2 diabetes after omega loop gastric bypass for morbid obesity. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is a validated technique for the treatment of morbid obesity and results in a significant rate of remission of type 2 diabetes (T2D). Omega gastric bypass (OGBP) is an effective and simpler alternative for weight loss, but its effect on T2D is unclear. METHODS: Between December 2006 and September 2012, 804 laparoscopic OGBPs were carried out in our centre. Among these, 100 (12.4%) patients had T2D at the time of the intervention. Remission of T2D was defined by a glycated haemoglobin (HbA1c) level of <6% without concomitant treatment. RESULTS: Postoperative follow-up was completed by 81 patients (mean age: 49 +/- 11 years; mean weight at surgery: 133 +/- 29 kg; mean body mass index (BMI): 47 +/- 9 kg/m(2)). Mean preoperative HbA1c was 8 +/- 2 g/dL. Before OGBP, seven patients (9%) had received no oral hypoglycaemic treatment, 30 (37%) had received monotherapy, 26 (32%) bitherapy, six (7%) tritherapy and 12 (15%) patients had used insulin. Over a mean follow-up of 26 months (range 1-75), mean weight decreased to 94 +/- 23 kg and mean BMI to 35 kg/m(2). Seventy-one (88%) patients had complete remission of T2D and the other 10 (12%) had reduced their treatment. Seven patients (58%) initially treated with insulin no longer required this treatment. Mean time to remission of T2D for patients receiving one or more oral therapies versus insulin was 6.9 versus 17.9 months. CONCLUSIONS: OMBP is effective treatment for obesity in terms of weight loss and remission of T2D. PMID- 25552229 TI - The presence of Helicobacter pylori is not associated with long-term anastomotic complications in gastric bypass patients. AB - BACKGROUND: Eradication of Helicobacter pylori prior to Roux-en-Y gastric bypass (RYGB) has been advocated as a measure to reduce the complications of anastomotic ulceration. However, evidence to support a causal relationship between preoperative H. pylori status and postoperative anastomotic ulceration is weak. METHODS: Intraoperative gastric biopsies were obtained on consecutive patients who underwent laparoscopic RYGB at our institution from December 2007 to June 2010. These samples were analyzed by Warthin-Starry stain for H. Pylori organisms. Retrospective chart review was conducted to determine the preoperative presence of acid dyspepsia and acid suppression therapy and to determine postoperative ulcer symptoms, smoking, NSAID or steroid use, and compliance with ulcer prophylaxis. The incidence of ulcer visualization, perforation, and stricture were obtained from a prospectively collected database. Fisher's exact test was used for analyzing associations between discrete groups. Multiple logistic regression was used to assess associations between anastomotic ulcer complications and potential predictors. RESULTS: Histologic evaluation for H. pylori was available in 708 of the 728 patients who underwent RYGB. Fourteen patients were lost to follow up leaving 694 patients available for review. H. pylori was positive in 66 (9.5 %) patients who did not go on to receive definitive treatment for eradication. Marginal ulcers or related late complications were seen in a total of 113 (16.3 %) patients. In the H. pylori positive group, five patients (7.6 %) developed ulcer complications compared to 108 (17.1 %) in the H. pylori negative group (p = 0.05). Groups were not different in terms of preoperative demographics, postoperative ulcer prophylaxis compliance, steroid, NSAIDs, and cigarette use. CONCLUSION: The presence of H. pylori infection at the time of RYGB was found to be associated with a significantly lower incidence of anastomotic ulcer complications postoperatively. This study brings into question efforts and expense allocated to identify and eradicate H. pylori prior to RYGB. PMID- 25552230 TI - Risk factors for urinary retention after laparoscopic inguinal hernia repairs. AB - BACKGROUND: Postoperative urinary retention (POUR) is a common entity following surgery, particularly after laparoscopic inguinal hernia repair. Here the intent is to investigate the incidence of POUR in all comers at a single institution following laparoscopic inguinal hernia repair. METHODS: A retrospective chart review of all patients who underwent laparoscopic hernia repair at our institution from January 2010 through December 2013 was performed. POUR was defined as the inability to spontaneously urinate following surgery, requiring straight catheterization or placement of a Foley catheter. Perioperative data including narcotic use, operative time, type of mesh, and intraoperative fluid use were also recorded for each patient. RESULTS: A total of 346 patients underwent laparoscopic inguinal hernia repair in the specified time period, 340 patients were included in this study. The incidence of POUR after laparoscopic inguinal hernia repair at our institution was 8.2 % (n = 28) with the most common presentation of POUR being failure to void (n = 23). Postoperative narcotic use of 6.5 mg or greater of morphine or morphine equivalent was associated with higher risk of POUR via ROC analysis (OR 2.5, 95 % CI 1.2-5.6, p = 0.025). In univariate analysis, age greater than 50 years was also a risk factor for developing POUR (OR 2.8, 95 % CI 1.2-6.4, p = 0.02). Factors not found to be significant included intraoperative IV fluids, history of BPH, unilateral versus bilateral repair, and preoperative void time in relation to surgery start. CONCLUSIONS: Minimizing postoperative narcotic medications may reduce the risk of developing POUR after laparoscopic inguinal hernia repairs. If possible surgeons should consider non-steroidal anti-inflammatory drugs, acetaminophen, or regional anesthetic blocks to minimize postoperative narcotic requirements. PMID- 25552232 TI - Incorporating patient-preference evidence into regulatory decision making. AB - BACKGROUND: Patients have a unique role in deciding what treatments should be available for them and regulatory agencies should take their preferences into account when making treatment approval decisions. This is the first study designed to obtain quantitative patient-preference evidence to inform regulatory approval decisions by the Food and Drug Administration Center for Devices and Radiological Health. METHODS: Five-hundred and forty United States adults with body mass index (BMI) >= 30 kg/m(2) evaluated tradeoffs among effectiveness, safety, and other attributes of weight-loss devices in a scientific survey. Discrete-choice experiments were used to quantify the importance of safety, effectiveness, and other attributes of weight-loss devices to obese respondents. A tool based on these measures is being used to inform benefit-risk assessments for premarket approval of medical devices. RESULTS: Respondent choices yielded preference scores indicating their relative value for attributes of weight-loss devices in this study. We developed a tool to estimate the minimum weight loss acceptable by a patient to receive a device with a given risk profile and the maximum mortality risk tolerable in exchange for a given weight loss. For example, to accept a device with 0.01 % mortality risk, a risk tolerant patient will require about 10 % total body weight loss lasting 5 years. CONCLUSIONS: Patient preference evidence was used make regulatory decision making more patient centered. In addition, we captured the heterogeneity of patient preferences allowing market approval of effective devices for risk tolerant patients. CDRH is using the study tool to define minimum clinical effectiveness to evaluate new weight-loss devices. The methods presented can be applied to a wide variety of medical products. This study supports the ongoing development of a guidance document on incorporating patient preferences into medical-device premarket approval decisions. PMID- 25552231 TI - A prospective non-randomised single-center study comparing laparoscopic and robotic distal pancreatectomy. AB - BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is increasing in popularity thanks to the benefits that have been recently demonstrated by many authors. The Da Vinci((r)) Surgical System could overcome some limits of laparoscopy, helping the surgeons to perform safer and faster difficult procedures. Nowadays, prospective clinical trials comparing LDP to robotic distal pancreatectomy (RDP) are lacking. The aim of this study is to present a prospective comparison between the two techniques. METHODS: Since November 2011, all patients suitable for minimally invasive distal pancreatectomy were assigned either to LDP or RDP, depending on the availability of the Da Vinci((r)) Surgical System for our Surgical Unit. Demographics, clinical, and intra- and postoperative data, including estimated costs of the procedure, were prospectively collected. Follow up included cross-sectional imaging ended on April 2014. RESULTS: Twenty-two patients underwent RDP and 21 LDP; patients' characteristics were similar. The median operative time was longer and procedures' cost was double in RDP group. The conversion to open rate and the median length of postoperative hospital stay were 4.5 % and 7 days, respectively, in both groups. Pancreatic fistula developed in 57.1 % (12/21) and 50 % (11/22) of LDP and RDP, respectively (p = 0.870), being grade A the most frequent. Mortality was nil and an R0 resection was achieved in all Patients. The overall number of lymph nodes harvested was similar between the two groups. CONCLUSIONS: Both RDP and LDP are valid techniques for the treatment of distal pancreatic tumors. The advantages of RDP are claimed by many but still under investigation. Some of these advantages are more subjective than objective, and it seems difficult to demonstrate a real superiority of one technique over the other in a standardized fashion. In our experience, laparoscopy has not been abandoned in favor of the robot: we continue to perform both approaches choosing upon single patient's characteristics. PMID- 25552234 TI - Erratum to: Tacks, staples, or suture: method of peritoneal closure in laparoscopic transabdominal preperitoneal inguinal hernia repair effects early quality of life. PMID- 25552233 TI - Donor safety in live donor laparoscopic liver procurement: systematic review and meta-analysis. AB - BACKGROUND: Donor safety is a major concern in live organ donation. Live donor laparoscopic liver procurement is an advanced surgical procedure that is performed in highly specialized centers. Since its first report, not much progress has been endeavored for that procedure. METHODS: We planned to include all the randomized and comparative nonrandomized studies. Patients' population: live donors who are submitted to organ procurement via laparoscopy. RESULTS: Out of 5,636 records retrieved from the literature, only seven nonrandomized studies were included in this review, which encompassed 418 patients, 151 patients of whom underwent laparoscopic procurement. The quality scores for the included studies ranged from 66 to 76 %. The operative time was significantly shorter in the conventional open group (SD = 0.863, 95 % CI 0.107-1.819). Blood loss in the laparoscopic group was comparable with the conventional open approach (SD = 0.307, 95 % CI -0.807 to 0.192). In subgroup analysis, laparoscopy was protective against blood loss in laparoscopic parenchymal dissection (SD = -1.168, 95 % CI 1.758 to -0.577). The hospital stay was equal in both groups. Patients in laparoscopic group consumed fewer analgesics compared with conventional open group (SD = -0.33, 95 % CI -0.63 to -0.03). Analgesics use was lower in the laparoscopic group compared with the conventional approach. The rate of Clavien complications was equal in both groups (OR 0.721, 95 % CI 0.303-1.716). No difference was found between subgroup analysis based on the harvested liver lobe. Funnel plot and statistical methods used revealed low probability of publication BIAS. CONCLUSIONS: Live donor laparoscopic liver procurement could be as safe as the conventional open approach. Lower blood loss and lower consumtion of analgesics might be offered in the laparoscopic approach. PMID- 25552235 TI - Modified laparoscopic hepatectomy for hepatic hemangioma. AB - BACKGROUND: Laparoscopic hepatectomy (LH) using many different surgical techniques has become increasingly popular for the management of hepatic tumors. The performance of surgical procedures involving the least possible impairment is expected increasingly more often by both surgeons and patients. We herein describe a clinical cohort of ten patients with hepatic cavernous hemangioma (HCH) who underwent modified LH (MLH) with a new technique. We herein present the advantages of the low level of impairment during performance of this modified procedure and compare the outcomes of MLH with those of traditional LH (TLH) for HCH. METHODS: We retrospectively evaluated the treatment outcomes in 24 patients with HCH who underwent MLH (n = 10) or TLH (n = 14) from February 2008 to January 2013. Their demographic, intraoperative, and postoperative variables were compared. RESULTS: MLH was successful in all patients. An electromechanical morcellator allowed for easy extraction of the entire HCH without the use of a cumbersome retrieval bag, enlarged incision, or hand-assisted incision. There was no conversion to an open operation or significant perioperative complications. The operation time (P = 0.037), time to removal of the HCH (P < 0.0001), visual analog scale pain score on the first postoperative day (P = 0.012), time to off bed activity (P = 0.036), and postoperative hospital stay (P = 0.048) were significantly lower in the MLH group than in the TLH group. CONCLUSIONS: MLH involving the use of an electromechanical morcellator provides expedient recovery and minimal postoperative pain and scarring. It is a feasible, effective, and safe surgical procedure and embodies all of the benefits of minimally invasive surgery for patients with HCH. PMID- 25552236 TI - Three-month results of the effect of Ultrapro or Prolene mesh on post-operative pain and well-being following endoscopic totally extraperitoneal hernia repair (TULP trial). AB - BACKGROUND: Recurrence rates after inguinal hernia repair have been reduced to a few per cent, since mesh repair has become standard of care. Lightweight meshes reduce post-operative pain and stiffness in open anterior repair, but for endoscopic repair, the discussion about this benefit is ongoing. This study was done to analyse the effects of lightweight mesh versus heavyweight mesh following endoscopic totally extraperitoneal (TEP) hernia repair. METHODS: In a single centre double-blindly randomized clinical trial, 950 patients with unilateral primary inguinal hernia were randomized to undergo endoscopic TEP using either an Ultrapro((r)) or a Prolene((r)) mesh. Data were collected by validated questionnaires at day 1, day 7, after 6 weeks and after 3 months, and clinical assessment was performed after 3 months. The presence of groin pain after 3 months, defined as an NRS score >3, was evaluated as the primary outcome measure. Secondary outcomes were foreign body feeling and the impact of pain and foreign body feeling on daily activities. RESULTS: At 3-month follow-up, the incidence of pain (NRS 4-10) was 2 versus 0.9 % in the lightweight and heavyweight mesh group, respectively (p = 0.17). Pain interfered with daily activities in 1.7 % of the lightweight and 1.5 % of heavyweight group. In the lightweight group, 20 % of patients reported a foreign body feeling versus 18 % in the heavyweight group (p = 0.62). No differences between the groups were observed regarding time to return to work, interference with sports and sexual activities, testicular pain and ejaculatory pain. Severe preoperative pain (OR 2.01, 95 % CI 1.21-3.35, p = 0.01) was the only independent predictor of any post-operative pain after 3 months. CONCLUSION: Three months after TEP inguinal repair, there were no significant differences between lightweight and heavyweight mesh use regarding the incidence of pain, foreign body feeling or any other endpoint. PMID- 25552237 TI - Three-dimensional study of the skin/subcutaneous complex using in vivo whole body 3T MRI: review of the literature and confirmation of a generic pattern of organization. AB - PURPOSE: With a view to developing a tool for predicting the behavior of soft tissues during plastic surgery procedures, we looked for the existence of homologies in the overall pattern of organization of the skin/subcutaneous tissue complex between various body parts, using high-resolution in vivo imaging methods and data available in the literature. METHODS: 3T MRI scanning sequences were performed using appropriate radiofrequency coils on the face, thorax, breast, abdomen and lower extremity of six healthy volunteers. The radiological findings were segmented and converted into volumetric data. RESULTS: The superficial and deep adipose tissue was found to be clearly separated by an intermediate layer called stratum membranosum or superficial fascia. This continuous layer covered all the anatomical parts of the body examined. It was found to have several components in the trunk and limbs and to form a continuous layer with the superficial muscular aponeurotic system in the face. A retaining connective network consisting of superficial and deep retinacula cutis detected in all the regions investigated sometimes formed more densely packed structures playing the role of skin ligaments. CONCLUSION: The results of a 3T MRI study on subcutaneous tissue showed the existence of a common pattern of organization of the skin subcutaneous tissue complex in the various parts of the body studied. This general model is subject to quantitative variations and tissue differentiation processes promoting the sliding or contractility of the supporting tissue. Three dimensional reconstructions were obtained by post-processing the MRI images and will be used to perform pre-surgical simulations by settings a generic model that can be adapted to the different localization of the human body in a procedural way. PMID- 25552238 TI - Sternal foramina: incidence in Greek population, anatomy and clinical considerations. AB - PURPOSE: Sternal foramina represent developmental defects in the sternum, which occur due to incomplete fusion of the sternal ossification centers. Sternal foramina have been correlated with several clinical implications and constitute a subject of interest for the forensic practice. The aim of this study is to define their incidence in Greek population. METHODS: The presence of midline foramen was studied in 60 dried, adult sterna derived from the Anatomy Department of Medical School of Aristotle University of Thessaloniki. Measurements were made with a 0.01-mm accuracy caliber and photographic documentation was obtained. Additionally, computed tomography scanning of the sterna was performed. RESULTS: Sternal foramina were found in 11 subjects, resulting in an incidence of 18.3% over the total population. In 27.3% of the subjects with sternal foramen, a single sternal foramen was observed in the body of the sternum, while in 45.5% of the sterna presenting sternal foramina, multiple xiphoidal foramina were noticed. In two specimens, association of xiphoidal foramina with sternal cleft was documented. CONCLUSION: Sternal foramina are variant quite common in the population, with distinct imaging pattern and awareness of their existence is important for the physician. PMID- 25552239 TI - Percutaneous nephrolithotomy for infection stones: what is the risk for postoperative sepsis? A retrospective cohort study. AB - The purpose of this study was to compare the postoperative course of patients with positive stone culture (SC) to patients with sterile SC, and to analyze the predictors for post percutaneous nephrolithotomy (PCNL) sepsis; and to describe the type and resistance patterns of bacteria responsible for post PCNL sepsis. From a cohort of 206 consecutive patients undergoing PCNL, we identified 45 patients with a positive SC (group A) and compared them to patients with a sterile SC (group B). Association between different groups was assessed using Chi square, two-tailed Student's t test and Mann-Whitney U test, as appropriate. Twenty-three patients had postoperative sepsis and regression analysis was performed to identify clinical variables associated with sepsis. Demographics, stone load and hospitalization time were similar in both groups. Postoperative sepsis developed in 31.1% of patients in group A compared to 5.9% in group B. In multivariate analysis, only positive SC was an independent risk factor for postoperative sepsis (OR 6.894, 95% CI 2.31-20.59, P = 0.001). All patients responded well to treatment with no septic complications. Enterococci were the prevalent organism (29.4%) in patients with a positive SC. Quinolone resistance was high in both gram negative and gram positive bacteria. Patients with an infected stone are at high risk to develop postoperative sepsis despite standard preoperative antibiotic preparation. SC is important to direct further treatment as almost half of patients with positive SC have a discordant or sterile urine culture. Determining the prevalent bacteria and resistance patterns in SC can aid the selection of empiric antibiotic therapy in high-risk patients. PMID- 25552240 TI - The Convergence of Virtual Reality and Social Networks: Threats to Privacy and Autonomy. AB - The rapid evolution of information, communication and entertainment technologies will transform the lives of citizens and ultimately transform society. This paper focuses on ethical issues associated with the likely convergence of virtual realities (VR) and social networks (SNs), hereafter VRSNs. We examine a scenario in which a significant segment of the world's population has a presence in a VRSN. Given the pace of technological development and the popularity of these new forms of social interaction, this scenario is plausible. However, it brings with it ethical problems. Two central ethical issues are addressed: those of privacy and those of autonomy. VRSNs pose threats to both privacy and autonomy. The threats to privacy can be broadly categorized as threats to informational privacy, threats to physical privacy, and threats to associational privacy. Each of these threats is further subdivided. The threats to autonomy can be broadly categorized as threats to freedom, to knowledge and to authenticity. Again, these three threats are divided into subcategories. Having categorized the main threats posed by VRSNs, a number of recommendations are provided so that policy-makers, developers, and users can make the best possible use of VRSNs. PMID- 25552241 TI - Parental Expressed Emotion and Youth Psychopathology: New Directions for an Old Construct. AB - Levels of parental expressed emotion (EE) are prospectively associated with the symptomatic course of a range of childhood psychiatric disorders. This article reviews the literature linking parental EE to youth psychopathology and proposes a novel framework for understanding its mechanisms of action. We find that, despite noteworthy methodological limitations, parental EE is linked consistently to a more deleterious course of mood, anxiety, and psychotic disorders in youth. Its mechanism of action is unknown. Models of "toxic family stress" (referring to frequent, sustained, and uncontrollable stress without protective influences) provide one framework for understanding how high EE environments interact with individual biological vulnerabilities to promote illness onset and recurrence. Research aimed at understanding biological responses (e.g., stress reactivity, arousal) to familial EE is needed. Such work may inform efforts to understand how EE affects the course of psychiatric disorders and may guide the development of novel interventions emphasizing emotion regulation strategies. PMID- 25552242 TI - The Role of Reactive Aggression in the Link Between Hyperactive-Impulsive Behaviors and Peer Rejection in Adolescents. AB - Attention-deficit/hyperactivity disorder (ADHD) symptoms and aggressive behaviors are both associated with peer rejection, but little is known the nature of this association with respect to the two symptom dimensions of hyperactivity impulsivity and inattention and different types of aggression. The present study examines the relations between dimensions of ADHD symptomatology, proactive and reactive aggression, and peer rejection in adolescence. Teacher-reported data were obtained for 200 high school students (grades 9-12; 48% female; predominately Latino). In structural equation modeling path analyses, the indirect effects of reactive aggression accounted for the link between hyperactivity-impulsivity and peer rejection. Within the same model, neither inattention nor proactive aggression were associated with peer rejection. These findings suggest that reactive aggression may be a key mechanism through which hyperactive-impulsive behavior is associated with peer rejection. Future research and intervention efforts should address the role of reactive aggression among youth with ADHD symptomatology. PMID- 25552243 TI - Relationship between hearing threshold at the affected and unaffected ear in unilateral Meniere's disease. AB - Hearing loss in Meniere's disease has been described to affect above all low frequencies (upward curve) with a tendency to become irreversible and non fluctuating at the higher frequencies (peaked curve) over time. The aim of the study was to determine the effects of MD on hearing function on the basis of differences existing between the affected and the unaffected ear in a group of patients affected by definite unilateral MD and whose contralateral ear was not affected by any disease other than age-related hearing loss (ARHL). Following this procedure we have also evaluated the possible effects of age and disease duration on hearing loss in MD. The study group consisted of 86 subjects affected by definite unilateral MD. In our sample a peaked audiometric curve characterized the affected ears; however, the result after subtracting the normal ear hearing threshold was an upward sloping curve, which highlighted the greater suffering at the lower frequencies. On the basis of differences existing between affected and unaffected ear, our data suggest that threshold evolution is more related to disease duration rather than to age. PMID- 25552246 TI - Cryptococcosis in bone marrow following treatment for Hodgkin lymphoma. PMID- 25552247 TI - Numerous Reed-Sternberg cells in bone marrow aspirate from a patient with the syncytial variant of nodular sclerosis classical Hodgkin lymphoma. PMID- 25552245 TI - A nuclear odyssey: fibroblast growth factor-2 (FGF-2) as a regulator of nuclear homeostasis in the nervous system. AB - Nuclear localization of classical growth factors is a well-known phenomenon but still remains a molecular and cellular conundrum. Fibroblast growth factor-2 (FGF 2) is an excellent example of a protein which functions as an extracellular molecule involved in canonical receptor tyrosine kinase signaling as well as displaying intracellular functions. Paracrine and nuclear functions are two important sides of the same protein. FGF-2 is expressed in isoforms with different molecular weights from one mRNA species. In rodents, all of these isoforms become imported to the nucleus. In this review, we discuss structural and functional aspects of FGF-2 isoforms in the nervous system. The nuclear odyssey of FGF-2 is reflected by nuclear dynamics, localization to nuclear bodies such as nucleoli, binding to chromatin and engagement in various protein interactions. Recently discovered molecular partnerships of the isoforms shed light on their nuclear functions, thereby greatly extending our knowledge of the multifaceted functions of FGF-2. PMID- 25552248 TI - Clinical features and treatment outcomes of primary cutaneous B-cell lymphoma: a single-center analysis in South Korea. AB - Clinical features and treatment outcomes of primary cutaneous B-cell lymphoma (PCBCL) have rarely been reviewed, due to the rarity and pathologic obscurity of this disease. We reviewed 21 patients who were pathologically diagnosed with PCBCL from Samsung Medical Center's lymphoma cohort, following the WHO-EORTC classification system: primary cutaneous follicle-center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT), and cutaneous diffuse large B-cell lymphoma, other (PCDLBCL, other). Of 2831 B-cell lymphoma cases, PCBCL comprised only 0.74 % of cases (N = 21, eight PCLBCL, LT (0.28 %), 10 PCMZL (0.35 %), two PCDLBCL, other (0.06 %), and one PCFCL (0.03 %)). Eighteen of 21 patients received treatment for PCBCL (12 chemotherapy alone, three radiotherapy alone, three chemotherapy following radiotherapy) and complete response (CR) was observed in 17 patients. The median progression-free survival was 44 months [95 % confidence interval (CI): 11-61 months]. Two patients had died at the time of analysis, with a median follow-up duration of 85 months [95 % confidence interval (CI): 55-118 months]. PCBCL cases in this study have a higher proportion of disseminated PCMZL and PCLBCL, LT, and excellent outcomes were observed with chemotherapy, including R-CHOP or R-CVP irrespective of staging and pathologic subtype. PMID- 25552244 TI - Lipid rafts: integrated platforms for vascular organization offering therapeutic opportunities. AB - Research on the nanoscale membrane structures known as lipid rafts is relevant to the fields of cancer biology, inflammation and ischaemia. Lipid rafts recruit molecules critical to signalling and regulation of the invasion process in malignant cells, the leukocytes that provide immunity in inflammation and the endothelial cells that build blood and lymphatic vessels, as well as the patterning of neural networks. As angiogenesis is a common denominator, regulation of receptors and signalling molecules critical to angiogenesis is central to the design of new approaches aimed at reducing, promoting or normalizing the angiogenic process. The goal of this review is to highlight some of the key issues that indicate the involvement of endothelial cell lipid rafts at each step of so-called 'sprouting angiogenesis', from stimulation of the vascular endothelial growth factor to the choice of tip cells, activation of migratory and invasion pathways, recruitment of molecules that guide axons in vascular patterning and maturation of blood vessels. Finally, the review addresses opportunities for future studies to define how these lipid domains (and their constituents) may be manipulated to stimulate the so-called 'normalization' of vascular networks within tumors, and be identified as the main target, enabling the development of more efficient chemotherapeutics and cancer immunotherapies. PMID- 25552249 TI - Characteristics of Wind-Infective Farms of the 2006 Bluetongue Serotype 8 Epidemic in Northern Europe. AB - Bluetongue is a Culicoides-borne viral disease of livestock. In 2006, northern Europe experienced a major outbreak of this disease with devastating effects on the livestock industry. The outbreak quickly spread over the region, primarily affecting cattle and sheep. A previous analysis of the role of vector flight and wind in the spread of this virus across northern Europe indicated that infection at 1,326 (65%) of the reported infected farms could be traced back to just 599 (29%) farms (wind-infective farms). Rather than focusing on presence or absence of vectors or difference between infected and non-infected farms, we investigate the zoological and environmental characteristics of these 599 wind-infective farms (which can be thought of as super-spreaders) in order to characterize what makes them distinct from non-infective farms. Differences in temperature, precipitation, and the density of sheep at individual farms were identified between these two groups. These environmental and zoological factors are known to affect vector abundance and may have promoted bluetongue virus transmission. Identifying such ecological differences can help in the description and quantification of relative risk in affected areas. PMID- 25552251 TI - Use of Intravenous Thrombolytic Therapy in Acute Ischemic Stroke Patients: Evaluation of Clinical Outcomes. AB - The use of intravenous thrombolytic therapy (ITT) in acute ischemic stroke (AIS) patients is still debated in China. We present the analysis of clinico demographic retrospective data of 646 AIS patients that were treated by alteplase ITT at our hospital. The data collected included age, gender, education, income, drug use before disease onset, and awareness of stroke/ITT. The risk factors studied were hypertension, diabetes, hyperlipidemia, atrial fibrillation, coronary heart disease, cerebral infarction, transient ischemic attack, valvular heart disease, thyroid disease, migraine, asymptomatic carotid stenosis, family history of stroke, hyperhomocysteinemia, smoking, drinking, and gingivitis. Pre ITT patient data included blood pressure and time from onset to hospital. Post ITT patient data included National Institutes of Health Stroke Scale (NIHSS) scores, clinical outcome, revascularization, hemorrhage, healing rate, and 90-day mortality. Hospital management information included monthly ITT cases, discharges, bed turnaround times, length of hospital stay, bed utilization, drug ratio, massive cerebral infarction decompressive craniectomy, and social impact. Prognosis evaluation was based on post-ITT NIHSS and modified Rankin Scale (mRS) scores. We found that ITT success rate was 75.85 %, with a bleeding rate of 1.55 % and a 90-day mortality rate of 2.01 %. Overall, the data suggest that the ITT therapy was highly successful in AIS patients treated at our hospital. PMID- 25552250 TI - Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance. AB - Ischemic heart disease is the leading cause of death for both men and women worldwide, accruing 7.4 million deaths in 2012. There has been a continued search for better cardioprotective modalities that would reduce myocardial ischemia reperfusion injury. Among these attempts, a more convenient model of ischemic preconditioning, known as remote ischemic preconditioning (RIPC) was first introduced in 1993 by Przyklenk and colleagues who reported that brief regional occlusion-reperfusion episodes in one vascular bed of the heart render protection to remote myocardial tissue. Subsequently, major advances in myocardial RIPC came with the use of skeletal muscle as the ischemic stimulus. To date, numerous studies have revealed that RIPC applied to the kidney, liver, mesentery, and skeletal muscle, have all exhibited cardioprotective effects. The main purpose of this review article is to summarize the new advances in understanding the molecular mechanisms of RIPC during the past 5 years, including those related to capsaicin-activated C sensory fibers, hypoxia-inducible factor 1alpha, connexin 43, extracellular vesicles, microRNA-144, microRNA-1, and nitrite. In addition, we have discussed results from several recent human clinical trials with RIPC. Taken together, the emerging clinical evidence supports the concept that the effectiveness of RIPC paired with its low-cost and non-invasive features makes it an ideal treatment before reperfusion after sustained ischemia. More carefully designed studies are warranted to fully exploit the clinical benefits of RIPC and its potential implications in patients with cardiovascular disease. PMID- 25552252 TI - The Efficacy and Safety of Endoscopic Balloon Dilation Combined with Stenting in Patients with Biliary Anastomotic Strictures After Orthotopic Liver Transplantation. AB - Endoscopic balloon dilation combined with stenting has been increasingly used in managing biliary anastomotic strictures (BAS) after orthotopic liver transplantation (OLT). However, data on the efficacy and safety vary among different studies. To obtain reliable estimates for the efficacy and safety of this endoscopic combination therapy in post-OLT BAS. A systematic search was conducted in the literature published until June 2012. The outcomes of individual study were transformed into comparable data using the Freeman-Tukey double arcsine transformation method. Fixed-effect or random-effect models were built to simulate the outcomes. Subgroup analysis and meta-regression were used to explore the sources of clinical heterogeneity. Clinical resolution and recurrence were defined as the primary outcomes and complications and mortality as secondary outcomes. Nineteen studies (15 retrospective, 4 prospective; 17 full-texts, 2 abstracts) were included, with a total of 745 patients. Fully covered self expandable metal stent was only reported in one study, achieving a resolution rate of 92.3 %, recurrence rate of 8.3 %, and complication rate of 7.7 %. For 18 studies using plastic stents, the pooled resolution rate was 86 % (95 % CI 80-91 %; I (2) = 74.7 %). Abstracts, study design, and the delay from OLT to BAS diagnosis were contributing factors for heterogeneity in resolution. The pooled recurrence rate was 9 % (95 % CI 5-13 %; I (2) = 59.6 %). Longer stenting duration predicted less recurrence (OR = 0.95, p = 0.002). The pooled complication rate was 14 % (95 % CI 8-21 %, I (2) = 71.2 %). No procedure-related mortality was reported. Endoscopic balloon dilation combined with stenting is a relatively effective and safe modality in post-OLT BAS. PMID- 25552253 TI - Functional impairment due to bereavement after the death of adolescent or young adult offspring in a national population study of 1,051,515 parents. AB - PURPOSE: This study addresses the burden of grief after the death of an adolescent or young adult offspring. Parental bereavement following the death of an adolescent or young adult offspring is associated with considerable psychiatric and somatic impairment. Our aim is to fill a research gap by examining offspring death due to suicide, accidents, or natural causes in relation to risk of parental sickness absence with psychiatric or somatic disorders. METHODS: This whole population-based prospective study included mothers and fathers of all offspring aged 16-24 years in Sweden on December 31, 2004 (n = 1,051,515). This study had no loss to follow-up and exposure, confounders, and the outcome were recorded independently of each other. Cox survival analysis was used to model time to sickness absence exceeding 30 days, adjusting for parental demographic characteristics, previous parental sickness absence and disability pension, and inpatient and outpatient psychiatric and somatic healthcare prior to offspring death in 2001-2004. This large study population provided satisfactory statistical power for stratification by parents' sex and adolescent and young adults' cause of death. RESULTS: Mothers and fathers of offspring suicide and accident decedents both had over tenfold higher risk for psychiatric sickness absence exceeding 30 days as compared to parents of live offspring. Fathers of suicide decedents were at 40 % higher risk for somatic sickness absence. CONCLUSIONS: This is the largest study to date of parents who survived their offspring's death and the first study of work-related outcomes in bereaved parents. This study uses a broad metric of work-related functional impairment, sickness absence, for capturing the burden of sudden offspring death. PMID- 25552254 TI - Association between spondylolisthesis and L5 fracture in patients with Osteogenesis Imperfecta. AB - PURPOSE: To investigate if an association between spondylolisthesis and L5 fracture occurs in patients affected by Osteogenesis Imperfecta (O.I.). METHODS: Anteroposterior and lateral radiograms were performed on the sample (38 O.I. patients, of whom 19 presenting listhesis); on imaging studies spondylolisthesis was quantified according to the Meyerding classification. Genant's semiquantitative classification was applied on lateral view to evaluate the L5 fractures; skeleton spinal morphometry (MXA) was carried out on the same images to collect quantitative data comparable and superimposable to Genant's classification. The gathered information were analyzed through statistical tests (O.R., chi 2 test, Fisher's test, Pearson's correlation coefficient). RESULTS: The prevalence of L5 fractures is 73.7 % in O.I. patients with spondylolisthesis and their risk of experiencing such a fracture is twice than O.I. patients without listhesis (OR 2.04). Pearson's chi 2 test demonstrates an association between L5 spondylolisthesis and L5 fracture, especially with moderate, posterior fractures (p = 0.017) and primarily in patients affected by type IV O.I. CONCLUSIONS: Spondylolisthesis represents a risk factor for the development of more severe and biconcave/posterior type fractures of L5 in patients suffering from O.I., especially in type IV. This fits the hypothesis that the anterior sliding of the soma of L5 alters the dynamics of action of the load forces, localizing them on the central and posterior heights that become the focus of the stress due to movement of flexion-extension and twisting of the spine. As a result, there is greater probability of developing an important subsidence of the central and posterior walls of the soma. PMID- 25552255 TI - Common genetic variant on 14q13.3 contributes to thyroid cancer susceptibility: evidence based on 12 studies. AB - Several genome-wide association studies on thyroid cancer (TC) have reported similar findings of a new susceptibility locus, 14q13.3. After that, a number of studies reported that rs944289 polymorphism at chromosome 14q13.3 has been implicated in TC risk. However, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 12 studies involving a total of 7,598 TC cases, 53,613 controls, and 239 nuclear families for 14q13.3-rs944289 polymorphism to evaluate its effect on genetic susceptibility for TC. An overall random-effect per-allele OR of 1.30 (95 % CI 1.21-1.40, P < 10(-5)) was found for the polymorphism. Significant results were also observed for under dominant and recessive genetic models. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians (T allele: OR 1.29, 95 % CI 1.17-1.42, P < 10(-5)) and East Asians (T allele: OR 1.33, 95 % CI 1.18-1.49, P < 10(-5)). Further in stratified analyses according to study design and sample size, evidence of gene-disease association was also obtained. In addition, we found that rs944289 confers its risk, for both papillary thyroid carcinoma and follicular thyroid carcinoma when stratified by histological types of TC. Furthermore, our results on stratified analysis according to radiation exposure status showed an increased sporadic TC risk, while no associations were detected among radiation-related TCs for rs944289 polymorphism. Our result demonstrated that rs944289 polymorphism on 14q13.3 is a low penetrant risk factor for developing TC. PMID- 25552256 TI - Long-term efficacy of alemtuzumab in polymyositis. PMID- 25552257 TI - Procyanidin B2 3,3"-di-O-gallate inhibits endothelial cells growth and motility by targeting VEGFR2 and integrin signaling pathways. AB - Targeting angiogenesis, one of the hallmarks of carcinogenesis, using non-toxic phytochemicals has emerged as a translational opportunity for angioprevention and to control advanced stages of malignancy. Herein, we investigated the inhibitory effects and associated mechanism/s of action of Procyanidin B2-3,3"-di- O-gallate (B2G2), a major component of grape seed extract, on human umbilical vein endothelial cells (HUVECs) and human prostate microvascular endothelial cells (HPMECs). Our results showed that B2G2 (10-40 MUM) inhibits growth and induces death in both HUVECs and HPMECs. Additional studies revealed that B2G2 causes a G1 arrest in cell cycle progression of HUVECs by down-regulating cyclins (D1 and A), CDKs (Cdk2 and Cdc2) and Cdc25c phosphatase and up-regulating CDK inhibitors (p21 and p27) expression. B2G2 also induced strong apoptotic death in HUVECs through increasing p53, Bax and Smac/Diablo expression while decreasing Bcl-2 and survivin levels. Additionally, B2G2 inhibited the growth factors-induced capillary tube formation in HUVECs and HPMECs. Interestingly, conditioned media (CCM) from prostate cancer (PCA) cells (LNCaP and PC3) grown under normoxic (~21% O2) and hypoxic (1% O2) conditions significantly enhanced the tube formation in HUVECs, which was compromised in presence of conditioned media from B2G2-treated PCA cells. B2G2 also inhibited the motility and invasiveness of both HUVECs and HPMECs. Mechanistic studies showed that B2G2 targets VEGFR2/PI3K/Akt and integrin signaling molecules which are important for endothelial cells survival, proliferation, tube formation and motility. Overall, we report that B2G2 inhibits several attributes of angiogenesis in cell culture; therefore, it warrants further investigation for efficacy for angioprevention and cancer control. PMID- 25552258 TI - Basic mechanisms for adverse cardiovascular events associated with air pollution. AB - Air pollution is a significant cause of cardiovascular morbidity and mortality worldwide. Although the epidemiologic association between air pollution exposures and exacerbation of cardiovascular disease (CVD) is well established, the mechanisms by which these exposures promote CVD are incompletely understood. This review provides an overview of the components of air pollution, an overview of the cardiovascular effects of air pollution exposure, and a review of the basic mechanisms that are activated by exposure to promote CVD. PMID- 25552260 TI - NICE guidance on place of birth falls short of neutrality. PMID- 25552259 TI - The structures of glycophorin C N-glycans, a putative component of the GPC receptor site for Plasmodium falciparum EBA-140 ligand. AB - Glycophorins C and D are highly glycosylated integral sialoglycoproteins of human red blood cell membranes carrying the Gerbich blood group antigens. The O- and N glycosidic chains of the major erythrocyte glycoprotein (Lisowska E. 2001, Antigenic properties of human glycophorins - an update. Adv Exp Med Biol, 491:155 169; Tomita M and Marchesi VT. 1975, Amino-acid sequence and oligosaccharide attachment sites of human erythrocyte glycophorin. Proc Natl Acad Sci USA, 72:2964-2968.) are well characterized but the structure of GPC N-glycans has remained unknown. This problem became important since it was reported that GPC N glycans play an essential role in the interaction with Plasmodium falciparum EBA 140 merozoite ligand. The elucidation of these structures seems essential for full characterization of the GPC binding site for the EBA-140 ligand. We have employed detailed structural analysis using sequential mass spectrometry to show that many GPC N-glycans contain H2 antigen structures and several contain polylactosamine structures capped with fucose. The results obtained indicate structural heterogeneity of the GPC N-glycans and show the existence of structural elements not found in glycophorin A N-glycans. Our results also open a possibility of new interpretation of the data concerning the binding of P. falciparum EBA-140 ligand to GPC. We hypothesize that preferable terminal fucosylation of N-glycosidic chains containing repeating lactosamine units of the GPC Gerbich variant could be an explanation for why the EBA-140 ligand does not react with GPC Gerbich and an indication that the EBA-140 interaction with GPC is distinctly dependent on the GPC N-glycan structure. PMID- 25552261 TI - Analysis of new designer drugs in post-mortem blood using high-resolution mass spectrometry. AB - An analytical method was developed and validated for the purpose of detecting and quantifying 37 new designer drugs including cathinones, hallucinogenic phenethylamines and piperazines. Using only 100 uL whole blood, a salting-out assisted liquid-liquid extraction with acetonitrile was performed to isolate target compounds followed by chromatographic separation using a Waters ACQUITY ultra performance liquid chromatograph coupled to a Waters XEVO quadrupole time of-flight mass spectrometer. Mephedrone-d3 was used as an internal standard. A gradient elution was used in combination with a Waters ACQUITY HSS C18 column (2.1 * 150 mm, 1.8 um). Samples were analyzed using the detector in positive electrospray ionization mode with MS(E) acquisition. All compounds of interest were resolved in a 15 min run time and positively identified based on accurate mass of the molecular ion, two product ions and retention time. All analyte calibration curves were linear over the range of 0.05-2 mg/L with most correlation coefficient (r(2)) values >0.98. The limits of detection were within the range of 0.007-0.07 mg/L and limits of quantification within 0.05-0.1 mg/L. All analytes were stable 48 h after extraction and most were stable in blood after 1 week stored in a refrigerator and 3 freeze-thaw cycles. No carryover was observed up to 10 mg/L and no interferences from common therapeutic drugs or endogenous compounds. Recoveries ranged from 71 to 100% and matrix effects were assessed for blank, post-mortem and decomposed blood. All bias and % coefficient of variation values were within the acceptable values of +/-15 and <=15%, respectively (+/-20 and <=20% at lower limit of quantification). The method was applied to several forensic cases where the subject exhibited behavior characteristic of designer drug intoxication and where routine screening for a panel of drugs was negative. PMID- 25552262 TI - Paediatric multiple sclerosis: a qualitative study of families' diagnosis experiences. AB - OBJECTIVE: To examine children's and parents' experiences of obtaining a diagnosis of paediatric multiple sclerosis (MS) and identify potential facilitators and barriers to early diagnosis. DESIGN: Qualitative, semi structured interviews conducted face-to-face in home settings with 31 parents and 21 children and adolescents (8-17 years old) with a clinical diagnosis of MS. Participants were recruited from 16 NHS Trusts and four MS voluntary organisations in the UK. Interviews were recorded and transcribed verbatim and analysed using the constant comparative method. RESULTS: Time to diagnosis ranged from 1 to 96 months (median 11.5, mean 23.3, SD 27.3). The findings suggest that delayed presentation to healthcare services, generalists' assumptions about the nature of reported symptoms, lack of awareness of paediatric MS and delayed referral to specialists in paediatric MS were barriers to early investigation and accurate diagnosis. Children, adolescents and parents felt that their concerns about the child's health were not always taken seriously during medical consultations and that clinicians could be reluctant to diagnose MS in childhood. This created additional uncertainty about the child's condition and long-term prognosis. CONCLUSIONS: Obtaining a diagnosis of paediatric MS can be a challenging and lengthy process with potentially adverse implications for the health of children/adolescents. Valuing families' knowledge and experience of their child's health, performing a thorough medical examination early in the disease course and organising prompt referrals may aid the early investigation and diagnosis of this disease. In view of the diagnostic challenges, children/adolescents with suspected MS would benefit from early referrals to specialists in paediatric MS. PMID- 25552263 TI - The GMC and doctors' suicides. PMID- 25552264 TI - Politicians must commit resources and not just words to NHS, says BMA chairman. PMID- 25552265 TI - Transatlantic variation in the attributed etiology of psychosis. AB - BACKGROUND: Differences in transatlantic perception of psychosis have been reported in the historical psychiatric literature. AIMS: This study aims to determine if articles in the American Journal of Psychiatry (AJP) are more likely to attribute biological factors to the etiology of psychosis than those of the British Journal of Psychiatry (BJP). METHODS: A systematic MEDLINE search for articles in the AJP and BJP from 2005 to 2007 identified 360 abstracts with psychosis and etiology-related words. Chi-square analyses were used to test differences in the proportion of attributed biological or psychosocial etiology of psychosis in each journal. RESULTS: A greater proportion of abstracts (83/87) in the AJP attributed biological etiology of psychosis (chi(2) = 12.33, df = 1, p < 0.001), while a greater proportion in the BJP (16/44 abstracts) attributed psychosocial etiology (chi(2) = 19.76, df = 1, p < 0.001). CONCLUSIONS: The AJP tends to publish biomedical explanations of psychosis, while the BJP shows a relative preference for psychosocial theories. PMID- 25552266 TI - Lessons from Medicare coverage of colonoscopy and prostate-specific antigen test. AB - Under the 1997 Balanced Budget Act, Medicare expanded coverage of colonoscopy and prostate-specific antigen tests from diagnostic and surveillance tests to preventive screenings. The preventive tests now are covered with no deductibles or copayments. Reducing out-of-pocket costs increases premiums, resulting in a subsidy to beneficiaries who use the service by nonusers, and by taxpayers who shoulder the bulk of Medicare's costs. Using Medicare fee-for-service claims and the Medicare Current Beneficiary Survey, we estimate the behavioral and financial consequences of these Balanced Budget Act coverage expansions. We find that fee for-service Medicare-covered colonoscopies increased by 3.5 percentage points after the coverage expansion, and prostate-specific antigen tests increased by 6.8 percentage points. Beneficiaries with lower incomes, less education, and those lacking a usual source of care or supplemental insurance were less likely to use these tests. Therefore, they generally received much smaller net benefits from the coverage of colonoscopies than more advantaged beneficiaries. PMID- 25552267 TI - Association between dietary fiber and lower risk of all-cause mortality: a meta analysis of cohort studies. AB - Although in vitro and in vivo experiments have suggested that dietary fiber might have beneficial effects on health, results on the association between fiber intake and all-cause mortality in epidemiologic studies have been inconsistent. Therefore, we conducted a meta-analysis of prospective cohort studies to quantitatively assess this association. Pertinent studies were identified by searching articles in PubMed and Web of Knowledge through May 2014 and reviewing the reference lists of the retrieved articles. Study-specific risk estimates were combined using random-effects models. Seventeen prospective studies (1997-2014) that had a total of 67,260 deaths and 982,411 cohort members were included. When comparing persons with dietary fiber intakes in the top tertile with persons whose intakes were in the bottom tertile, we found a statistically significant inverse association between fiber intake and all-cause mortality, with an overall relative risk of 0.84 (95% confidence interval: 0.80, 0.87; I(2) = 41.2%). There was a 10% reduction in risk for per each 10-g/day increase in fiber intake (relative risk = 0.90; 95% confidence interval: 0.86, 0.94; I(2) = 77.2%). The combined estimate was robust across subgroup and sensitivity analyses. No publication bias was detected. A higher dietary fiber intake was associated with a reduced risk of death. These findings suggest that fiber intake may offer a potential public health benefit in reducing all-cause mortality. PMID- 25552268 TI - Successful rescue of an adult with refractory anaphylactic shock and abdominal compartment syndrome with venoarterial extracorporeal membrane oxygenation and bedside laparotomy. AB - The incidence of life-threatening anaphylactic reactions related to anesthesia is approximately 1 in 6000 anesthetics administered, and is associated with mortality as high as 5%. In such cases the use of extracorporeal membrane oxygenation (ECMO) in the setting of refractory shock following anaphylaxis may be life saving. Abdominal compartment syndrome (ACS) itself and in this case complicating ECMO support, is a potentially devastating complication of high volume resuscitation. Decompressive laparotomy is the treatment of choice for ACS. We present a patient treated with venoarterial ECMO for refractory shock following anaphylaxis who developed ACS that was successfully treated with urgent decompressive laparotomy performed in the intensive care unit. This case report highlights the role of abdominal compartment syndrome as a rare but potentially fatal cause of low circuit flow in ECMO-supported patients and proposes a stepwise approach to decision making in this setting. Urgent decompressive laparotomy is potentially lifesaving in this circumstance, and should be urgently considered once other causes of low ECMO flow have been excluded. PMID- 25552269 TI - Prevalence of Epileptiform Discharges in Healthy Infants. AB - Most studies on epileptiform discharges in young children were performed using analog electroencephalographic (EEG) recording systems and a limited numbers of electrodes that might have a lower detection rate for epileptiform discharges than modern digital recording systems. Knowing the prevalence of epileptiform discharges in healthy children is critical for a valid interpretation of findings in patients with a suspected epileptic disorder. We reviewed EEG recordings of 393 otherwise healthy children aged 12 to 60 months using digital EEG recording with respect to epileptiform discharges. We found epileptiform discharges in 3 children aged 12, 34 and 55 months resulting in a prevalence of epileptiform discharges in our cohort of 0.76% (95% confidence interval 0.0% to 1.62%). The prevalence of epileptiform discharges in children younger than 5 years is by far lower than in older children, and the digital findings are in accordance with previous data of conventional EEG. PMID- 25552270 TI - Multisensory Plasticity in Superior Colliculus Neurons is Mediated by Association Cortex. AB - The ability to integrate information from different senses, and thereby facilitate detecting and localizing events, normally develops gradually in cat superior colliculus (SC) neurons as experience with cross-modal events is acquired. Here, we demonstrate that the portal for this experience-based change is association cortex. Unilaterally deactivating this cortex whenever visual auditory events were present resulted in the failure of ipsilateral SC neurons to develop the ability to integrate those cross-modal inputs, even though they retained the ability to respond to them. In contrast, their counterparts in the opposite SC developed this capacity normally. The deficits were eliminated by providing cross-modal experience when cortex was active. These observations underscore the collaborative developmental processes that take place among different levels of the neuraxis to adapt the brain's multisensory (and sensorimotor) circuits to the environment in which they will be used. PMID- 25552272 TI - Does health intervention research have real world policy and practice impacts: testing a new impact assessment tool. AB - BACKGROUND: There is a growing emphasis on the importance of research having demonstrable public benefit. Measurements of the impacts of research are therefore needed. We applied a modified impact assessment process that builds on best practice to 5 years (2003-2007) of intervention research funded by Australia's National Health and Medical Research Council to determine if these studies had post-research real-world policy and practice impacts. METHODS: We used a mixed method sequential methodology whereby chief investigators of eligible intervention studies who completed two surveys and an interview were included in our final sample (n = 50), on which we conducted post-research impact assessments. Data from the surveys and interviews were triangulated with additional information obtained from documentary analysis to develop comprehensive case studies. These case studies were then summarized and the reported impacts were scored by an expert panel using criteria for four impact dimensions: corroboration; attribution, reach, and importance. RESULTS: Nineteen (38%) of the cases in our final sample were found to have had policy and practice impacts, with an even distribution of high, medium, and low impact scores. While the tool facilitated a rigorous and explicit criterion-based assessment of post research impacts, it was not always possible to obtain evidence using documentary analysis to corroborate the impacts reported in chief investigator interviews. CONCLUSIONS: While policy and practice is ideally informed by reviews of evidence, some intervention research can and does have real world impacts that can be attributed to single studies. We recommend impact assessments apply explicit criteria to consider the corroboration, attribution, reach, and importance of reported impacts on policy and practice. Impact assessments should also allow sufficient time between impact data collection and completion of the original research and include mechanisms to obtain end-user input to corroborate claims and reduce biases that result from seeking information from researchers only. PMID- 25552271 TI - Natural RNA interference directs a heritable response to the environment. AB - RNA interference can induce heritable gene silencing, but it remains unexplored whether similar mechanisms play a general role in responses to cues that occur in the wild. We show that transient, mild heat stress in the nematode Caenorhabditis elegans results in changes in messenger RNA levels that last for more than one generation. The affected transcripts are enriched for genes targeted by germline siRNAs downstream of the piRNA pathway, and worms defective for germline RNAi are defective for these heritable effects. Our results demonstrate that a specific siRNA pathway transmits information about variable environmental conditions between generations. PMID- 25552273 TI - Diosgenin-induced protection against myocardial ischaemia-reperfusion injury is mediated by mitochondrial KATP channels in a rat model. AB - OBJECTIVE: This study was aimed to evaluate the effects of diosgenin on myocardial ischaemia-reperfusion injury and the potential involvement of mitochondrial KATP (mitoKATP) channel and nitric oxide (NO) system blockades in this field. MATERIALS AND METHODS: After isolation of hearts of male Wister rats, the study was conducted on control and diosgenin- receiving hearts in the presence or absence of 5-HD and L-NAME (as antagonists of mitoKATP channel and NO system, respectively) in an isolated buffer-perfused heart model. Global ischaemia was induced by 30-min occlusion of aortic flow followed by 90-min reperfusion. Cardiac haemodynamics were recorded throughout the experiment using a PowerLab data acquisition system. RESULTS: The levels of creatine kinase (CK MB) and lactate dehydrogenase (LDH) in the coronary effluents were estimated colourimetrically. Diosgenin pre-administration significantly decreased the release of LDH and CK-MD into the coronary effluent as compared the with the control group (P < 0.05). The left ventricular developed pressure (LVDP) and contractility (+/- dP/dt) were significantly improved and restored to pre ischaemic values in the diosgenin-receiving group (P < 0.05). There were no significant differences in left ventricular end-diastolic pressure, coronary flow and heart rate between the control and diosgenin-treated groups during the pre ischaemic and reperfusion periods. Blocking the mitoKATP channels by 5-HD completely eliminated the positive effect of the diosgenin on the LVDP and +/- dP/dt (P < 0.05). However, blocking the NO system by L-NAME slightly reduced the diosgenin effects and the inhibitory effect of L-NAME was less than 5-HD. CONCLUSION: The results showed that diosgenin may have cardioprotective effects against myocardial reperfusion injury through activating the mitoKATP channels. PMID- 25552274 TI - Prediction of reversibility of intestinal mucosal damage after ischemia reperfusion injury by plasma intestinal fatty acid-binding protein levels in pigs. AB - OBJECTIVE: The aims of this study were to elucidate the association between plasma intestinal fatty acid-binding protein (I-FABP) level and actual pathological damage of intestinal mucosa and its reversibility. METHODS: An intestinal ischemia-reperfusion model was created by temporary occlusion of the descending aorta in 9 pigs which were divided into 3 groups according to the duration of visceral ischemic insult: 15-minute ischemia (n=3), 30-minute ischemia (n=3) and 60-minute ischemia (n=3). Blood samples and short segments of the jejunum for pathological examinations, including immunohistochemical staining of I-FABP, Ki-67 and E-cadherin, were taken at the beginning of the operation (T1) and 15 minutes (T2), 30 minutes (T3), 45 minutes (T4) and 60 minutes (T5) after reperfusion. RESULTS: Plasma I-FABP after 15 minutes of ischemia reached a peak of 1859 +/- 1089 pg/ml at T3, while the level after 30 minutes of ischemia achieved a peak level of 5053 +/- 1 717 pg/ml at T5. The level after 60 minutes of ischemia demonstrated a rapid increment up to 10734 +/- 93 pg/ml at T3. There was a significant difference in the trend of plasma I-FABP levels between 30 minutes and 60 minutes of ischemia (p=0.01). The strongest immunohistochemical staining of the intestinal epithelium for I-FABP was observed at T4 after 30 minutes of ischemia, with the shedding of injured epithelium followed by re epithelialisation, with sequential up-regulation of Ki67 and E-cadherin. However, the intestinal epithelium after 60 minutes of ischemia demonstrated the lack of I FABP expression with irreversible damage. CONCLUSION: Plasma I-FABP levels may be a crucial marker to recognize the reversibility of damage of the intestinal epithelium after an ischemic insult and the level of 5000 pg/ml is considered to be the critical borderline for irreversibility, which might prevent diagnostic delay in the clinical setting. PMID- 25552275 TI - The evolution of selfing is accompanied by reduced efficacy of selection and purging of deleterious mutations. AB - The transition from outcrossing to selfing is predicted to reduce the genome-wide efficacy of selection because of the lower effective population size (Ne) that accompanies this change in mating system. However, strongly recessive deleterious mutations exposed in the homozygous backgrounds of selfers should be under strong purifying selection. Here, we examine estimates of the distribution of fitness effects (DFE) and changes in the magnitude of effective selection coefficients (Nes) acting on mutations during the transition from outcrossing to selfing. Using forward simulations, we investigated the ability of a DFE inference approach to detect the joint influence of mating system and the dominance of deleterious mutations on selection efficacy. We investigated predictions from our simulations in the annual plant Eichhornia paniculata, in which selfing has evolved from outcrossing on multiple occasions. We used range-wide sampling to generate population genomic datasets and identified nonsynonymous and synonymous polymorphisms segregating in outcrossing and selfing populations. We found that the transition to selfing was accompanied by a change in the DFE, with a larger fraction of effectively neutral sites (Nes < 1), a result consistent with the effects of reduced Ne in selfers. Moreover, an increased proportion of sites in selfers were under strong purifying selection (Nes > 100), and simulations suggest that this is due to the exposure of recessive deleterious mutations. We conclude that the transition to selfing has been accompanied by the genome-wide influences of reduced Ne and strong purifying selection against deleterious recessive mutations, an example of purging at the molecular level. PMID- 25552277 TI - Clubfoot associated with congenital constriction band: the Ponseti method perspective. AB - BACKGROUND: The clubfoot and congenital constriction band is a known association in which the clubfoot is considered as being rigid, responding poorly to casting, and requiring surgical interventions. OBJECTIVE AND METHODS: The series describes 3 cases of clubfoot with deep ipsilateral congenital constriction bands managed with Ponseti method and immediate outcomes achieved. RESULTS AND CONCLUSIONS: The feet responded favorably to casting although equinus correction required more extensive surgical interventions. The preexisting edema in distal limb often precluded a snuggly fitting cast increasing the cast numbers. Careful monitoring of vascularity is essential. Simultaneous procedures of release of constriction bands, correction of hand anomalies and equinus can be combined to the advantage of the patient. LEVELS OF EVIDENCE: Case report, Level IV. PMID- 25552276 TI - A HIF-independent mediator of transcriptional responses to oxygen deprivation in Caenorhabditis elegans. AB - The adaptive response to hypoxia is accompanied by widespread transcriptional changes that allow for prolonged survival in low oxygen. Many of these changes are directly regulated by the conserved hypoxia-inducible factor-1 (HIF-1) complex; however, even in its absence, many oxygen-sensitive transcripts in Caenorhabditis elegans are appropriately regulated in hypoxia. To identify mediators of these non-HIF-dependent responses, we established a hif-1 mutant reporter line that expresses GFP in hypoxia or when worms are treated with the hypoxia mimetic cobalt chloride (CoCl2). The reporter is selective and HIF independent, in that it remains insensitive to a number of cellular stresses, but is unaffected by mutation of the prolyl hydroxylase egl-9, suggesting that the regulators of this response pathway are different from those controlling the HIF pathway. We used the HIF-independent reporter to screen a transcription factor RNA interference (RNAi) library and identified genes that are required for hypoxia-sensitive and CoCl2-induced GFP expression. We identified the zinc finger protein BLMP-1 as a mediator of the HIF-independent response. We show that mutation of blmp-1 renders animals sensitive to hypoxic exposure and that blmp-1 is required for appropriate hypoxic-induced expression of HIF-independent transcripts. Further, we demonstrate that BLMP-1 is necessary for an increase of hypoxia-dependent histone acetylation within the promoter of a non-HIF-dependent hypoxia response gene. PMID- 25552278 TI - Gravity versus manual external rotation stress view in evaluating ankle stability: a prospective study. AB - BACKGROUND: The purpose of this prospective study was to determine whether gravity versus manual external rotation stress testing effectively detects widening of the medial clear space in isolated ankle fractures when compared with the uninjured contralateral side. METHODS: Manual external rotation stress and gravity stress tests were performed on injured and uninjured ankles of ankle fracture patients in a clinic setting. Medial clear space measurements were recorded and differences between gravity and manual stress views were determined. RESULTS: Twenty consecutive patients with ankle injury were enrolled in the study. When compared with the uninjured side, gravity stress views showed a statistically significant (P = .017) increase in medial clear space widening (1.85 +/- 1.07 mm) compared with manual stress view widening (1.35 +/- 1.04 mm). CONCLUSIONS: This study suggests that gravity stress views are as effective as manual external rotation stress views in detecting medial clear space widening in isolated fibular fractures. LEVEL OF EVIDENCE: Diagnostic, Level II: Prospective, comparative trial. PMID- 25552279 TI - Concentrated parenteral nutrition solutions and central venous catheter complications in preterm infants. AB - Standardised, concentrated neonatal parenteral nutrition (PN) regimens can overcome early nutritional deficits in very preterm infants. A PN regimen with increased macronutrient content (standardised, concentrated, added macronutrients parenteral (SCAMP)) has been shown to improve early head growth in a randomised controlled trial. Line complications including late onset sepsis were secondary outcomes of this study. Infants were started on standardised, concentrated PN at birth and randomised at 2-5 days to either switch to SCAMP or remain on control PN. Central venous catheter (CVC), blood culture (BC) and inflammatory marker data were collected for the 28-day intervention period. 150 infants were randomised with mean (SD) birth weight (g) of 900 (158) versus 884 (183) in SCAMP (n=74) and control (n=76) groups, respectively. There were no differences in CVC use/type or duration or in positive/negative BC with/without associated C reactive protein rise in SCAMP versus control groups. Increasing the macronutrient content of a standardised, concentrated neonatal PN regimen does not increase CVC complication rates. TRIAL REGISTRATION NUMBER: ISRCTN 76597892. PMID- 25552281 TI - Editorial: Neurosurgical Focus yearly summary. PMID- 25552280 TI - A randomised trial of re-feeding gastric residuals in preterm infants. AB - OBJECTIVE: To determine whether re-feeding of gastric residual volumes reduces the time needed to achieve full enteral feeding in preterm infants. DESIGN: Parallel-group randomised controlled trial with a 1:1 allocation ratio. SETTING: Regional referral neonatal intensive care unit. PATIENTS: 72 infants of gestational age 23(0/7) to 28(6/7) weeks receiving minimal enteral nutrition (<24 mL/kg/day) during the first week after birth. INTERVENTIONS: Infants were randomised to either be re-fed with gastric residual volumes (Re-feeding group) or receive fresh formula/human milk (Fresh-feeding group) whenever large gastric residual volumes were noted. MAIN OUTCOME MEASURE: The primary efficacy end point was time to achieve full enteral feeding (>=120 mL/kg/day) after randomisation. RESULTS: The mean time to full enteral feeding was 10.0 days in the Re-feeding group and 11.3 days in the Fresh-feeding group (mean difference favouring re feeding: -1.3 days; 95% CI -2.9 to 0.3; p=0.11). The composite safety end point of spontaneous intestinal perforation, surgical necrotising enterocolitis, or death occurred in 6 of 36 infants (17%) in the Re-feeding group versus 10 of 36 infants (28%) in the Fresh-feeding group (p=0.26). CONCLUSIONS: Re-feeding gastric residual volumes in extremely preterm infants does not reduce time to achieve full enteral feeding. This trial suggests that re-feeding might be as safe as fresh feeding, but further research is needed, due to lack of sufficient statistical power in this study for safety analysis. TRIAL REGISTRATION NUMBER: NCT01420263NCT01420263. PMID- 25552282 TI - Introduction: a focus on low-grade glioma. PMID- 25552283 TI - Functional preoperative and intraoperative mapping and monitoring: increasing safety and efficacy in glioma surgery. AB - Greater extent of resection (EOR) of low-grade gliomas is associated with improved survival. Proximity to eloquent cortical regions often limits resectability and elevates the risk of surgery-related deficits. Therefore, functional localization of eloquent cortex or subcortical fiber tracts can enhance the EOR and functional outcome. Imaging techniques such as functional MRI and diffusion tensor imaging fiber tracking, and neurophysiological methods like navigated transcranial magnetic stimulation and magnetoencephalography, make it possible to identify eloquent areas prior to resective surgery and to tailor indication and surgical approach but also to assess the surgical risk. Intraoperative monitoring with direct cortical stimulation and subcortical stimulation enables surgeons to preserve essential functional tissue during surgery. Through tailored pre- and intraoperative mapping and monitoring the EOR can be maximized, with reduced rates of surgery-related deficits. PMID- 25552284 TI - Introduction of a standardized multimodality image protocol for navigation-guided surgery of suspected low-grade gliomas. AB - OBJECT Surgery of suspected low-grade gliomas (LGGs) poses a special challenge for neurosurgeons due to their diffusely infiltrative growth and histopathological heterogeneity. Consequently, neuronavigation with multimodality imaging data, such as structural and metabolic data, fiber tracking, and 3D brain visualization, has been proposed to optimize surgery. However, currently no standardized protocol has been established for multimodality imaging data in modern glioma surgery. The aim of this study was therefore to define a specific protocol for multimodality imaging and navigation for suspected LGG. METHODS Fifty-one patients who underwent surgery for a diffusely infiltrating glioma with nonsignificant contrast enhancement on MRI and available multimodality imaging data were included. In the first 40 patients with glioma, the authors retrospectively reviewed the imaging data, including structural MRI (contrast enhanced T1-weighted, T2-weighted, and FLAIR sequences), metabolic images derived from PET, or MR spectroscopy chemical shift imaging, fiber tracking, and 3D brain surface/vessel visualization, to define standardized image settings and specific indications for each imaging modality. The feasibility and surgical relevance of this new protocol was subsequently prospectively investigated during surgery with the assistance of an advanced electromagnetic navigation system in the remaining 11 patients. Furthermore, specific surgical outcome parameters, including the extent of resection, histological analysis of the metabolic hotspot, presence of a new postoperative neurological deficit, and intraoperative accuracy of 3D brain visualization models, were assessed in each of these patients. RESULTS After reviewing these first 40 cases of glioma, the authors defined a specific protocol with standardized image settings and specific indications that allows for optimal and simultaneous visualization of structural and metabolic data, fiber tracking, and 3D brain visualization. This new protocol was feasible and was estimated to be surgically relevant during navigation-guided surgery in all 11 patients. According to the authors' predefined surgical outcome parameters, they observed a complete resection in all resectable gliomas (n = 5) by using contour visualization with T2-weighted or FLAIR images. Additionally, tumor tissue derived from the metabolic hotspot showed the presence of malignant tissue in all WHO Grade III or IV gliomas (n = 5). Moreover, no permanent postoperative neurological deficits occurred in any of these patients, and fiber tracking and/or intraoperative monitoring were applied during surgery in the vast majority of cases (n = 10). Furthermore, the authors found a significant intraoperative topographical correlation of 3D brain surface and vessel models with gyral anatomy and superficial vessels. Finally, real-time navigation with multimodality imaging data using the advanced electromagnetic navigation system was found to be useful for precise guidance to surgical targets, such as the tumor margin or the metabolic hotspot. CONCLUSIONS In this study, the authors defined a specific protocol for multimodality imaging data in suspected LGGs, and they propose the application of this new protocol for advanced navigation-guided procedures optimally in conjunction with continuous electromagnetic instrument tracking to optimize glioma surgery. PMID- 25552285 TI - Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation. AB - OBJECT Cerebral gangliogliomas (GGs) are highly associated with intractable epilepsy. Incomplete resection due to proximity to eloquent brain regions or misinterpretation of the resection amount is a strong negative predictor for local tumor recurrence and persisting seizures. A potential method for dealing with this obstacle could be the application of intraoperative high-field MRI (iopMRI) combined with neuronavigation. METHODS Sixty-nine patients (31 female, 38 male; median age 28.5 +/- 15.4 years) suffering from cerebral GGs were included in this retrospective study. Five patients received surgery twice in the observation period. In 48 of the 69 patients, 1.5-T iopMRI combined with neuronavigational guidance was used. Lesions close to eloquent brain areas were resected with the implementation of preoperative diffusion tensor imaging tractography and blood oxygenation level-dependent functional MRI (15 patients). RESULTS Overall, complete resection was accomplished in 60 of 69 surgical procedures (87%). Two patients underwent biopsy only, and in 7 patients, subtotal resection was accomplished because of proximity to critical brain areas. Excluding the 2 biopsies, complete resection using neuronavigation/iopMRI was documented in 33 of 46 cases (72%) by intraoperative imaging. Remnant tumor mass was identified intraoperatively in 13 of 46 patients (28%). After intraoperative second-look surgery, the authors improved the total resection rate by 9 patients (up to 91% [42 of 46]). Of 21 patients undergoing conventional surgery, 14 (67%) had complete resection without the use of iopMRI. Regarding epilepsy outcome, 42 of 60 patients with seizures (70%) became completely seizure free (Engel Class IA) after a median follow-up time of 55.5 +/- 36.2 months. Neurological deficits were found temporarily in 1 (1.4%) patient and permanently in 4 (5.8%) patients. CONCLUSIONS Using iopMRI combined with neuronavigation in cerebral GG surgery, the authors raised the rate of complete resection in this series by 19%. Given the fact that total resection is a strong predictor of long-term seizure control, this technique may contribute to improved seizure outcome and reduced neurological morbidity. PMID- 25552287 TI - Immediate effects of real-time feedback on jump-landing kinematics. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: To determine if the addition of real-time feedback (RTF) to postresponse feedback (PRF) improves jump landing kinematics compared to PRF alone and a no-feedback control group. BACKGROUND: Injury-prevention programs to reduce risk of anterior cruciate ligament injury have shown promising results in altering jump-landing biomechanics. Real-time feedback provided during the task may allow participants to more easily understand and execute new movement strategies compared to PRF provided after the task is completed. METHODS: Thirty-six healthy females were randomized to 1 of 3 groups: RTF plus PRF, PRF, or control. Sagittal plane moments and angles at the knee and hip, frontal plane angles at the knee, and vertical ground reaction forces during a jump-landing task were quantified at baseline and postintervention. The RTF plus PRF and PRF groups received a PowerPoint presentation containing the goals of correct landing technique. In addition to the PowerPoint presentation, the RTF plus PRF group was provided real time visualization of their frontal plane knee angle. Participants in the control group performed the jump-landing task without feedback. RESULTS: Posttraining, the RTF plus PRF and PRF groups demonstrated similar improvements in hip and knee flexion and decreased vertical ground reaction forces compared to the control group. There were no changes in frontal plane knee kinematics between groups posttraining. CONCLUSION: The addition of RTF to PRF did not result in significant changes in jump-landing kinematics compared to PRF alone. LEVEL OF EVIDENCE: Prevention, level 5. PMID- 25552288 TI - Cumulative loads increase at the knee joint with slow-speed running compared to faster running: a biomechanical study. AB - STUDY DESIGN: Biomechanical cross-sectional study. OBJECTIVE: To investigate the hypothesis that the cumulative load at the knee during running increases as running speed decreases. BACKGROUND: The knee joint load per stride decreases as running speed decreases. However, by decreasing running speed, the number of strides per given distance is increased. Running a given distance at a slower speed may increase the cumulative load at the knee joint compared with running the same distance at a higher speed, hence increasing the risk of running-related injuries in the knee. METHODS: Kinematic and ground reaction force data were collected from 16 recreational runners, during steady-state running with a rearfoot strike pattern at 3 different speeds (mean +/- SD): 8.02 +/- 0.17 km/h, 11.79 +/- 0.21 km/h, and 15.78 +/- 0.22 km/h. The cumulative load (cumulative impulse) over a 1000-m distance was calculated at the knee joint on the basis of a standard 3-D inverse-dynamics approach. RESULTS: Based on a 1000-m running distance, the cumulative load at the knee was significantly higher at a slow running speed than at a high running speed (relative difference, 80%). The mean load per stride at the knee increased significantly across all biomechanical parameters, except impulse, following an increase in running speed. CONCLUSION: Slow-speed running decreases knee joint loads per stride and increases the cumulative load at the knee joint for a given running distance compared to faster running. The primary reason for the increase in cumulative load at slower speeds is an increase in number of strides needed to cover the same distance. PMID- 25552286 TI - Survival and low-grade glioma: the emergence of genetic information. AB - Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low-grade (World Health Organization [WHO] Grade II) glioma. Low-grade glioma (LGG) is a uniformly fatal disease of young adults (mean age 41 years), with survival averaging approximately 7 years. Although LGG patients have better survival than patients with high-grade (WHO Grade III or IV) glioma, all LGGs eventually progress to high-grade glioma and death. Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute suggest that for the majority of LGG patients, overall survival has not significantly improved over the past 3 decades, highlighting the need for intensified study of this tumor. Recently published research suggests that historically used clinical variables are not sufficient (and are likely inferior) prognostic and predictive indicators relative to information provided by recently discovered tumor markers (e.g., 1p/19q deletion and IDH1 or IDH2 mutation status), tumor expression profiles (e.g., the proneural profile) and/or constitutive genotype (e.g., rs55705857 on 8q24.21). Discovery of such tumor and constitutive variation may identify variables needed to improve randomization in clinical trials as well as identify patients more sensitive to current treatments and targets for improved treatment in the future. This article reports on survival trends for patients diagnosed with LGG within the United States from 1973 through 2011 and reviews the emerging role of tumor and constitutive genetics in refining risk stratification, defining targeted therapy, and improving survival for this group of relatively young patients. PMID- 25552289 TI - Continuous synthesis of polymer-coated drug particles by porous hollow fiber membrane-based antisolvent crystallization. AB - Using porous hollow fiber membranes, this study illustrates a novel technique to continuously synthesize polymer-coated drug crystals by antisolvent crystallization. The synthesized polymer-coated drug crystals involve crystals of the drug Griseofulvin (GF) coated by a thin layer of the polymer Eudragit RL100. The process feed, an acetone solution of the drug GF containing the dissolved polymer, was passed through the shell side of a membrane module containing many porous hollow fibers of Nylon-6. Through the lumen of the hollow fibers, the antisolvent water was passed at a higher pressure to inject water jets through every pore in the fiber wall into the shell-side acetone feed solution, creating an extremely high level of supersaturation and immediate crystallization. It appears that the GF crystals are formed first and serve as nuclei for the precipitation of the polymer Eudragit, which forms a thin coating around the GF crystals. The polymer-coated drug crystals were collected by a filtration device at the shell-side outlet of the membrane module, and the surface morphology, particle size distribution, and the polymer coating thickness were then characterized by scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM), laser diffraction spectroscopy (LDS), and thermogravimetric analysis (TGA). To study the properties of the coated drug crystals, X-ray diffraction (XRD), Raman spectroscopy, and dissolution tests were implemented. These results indicate that a polymer-coated, free-flowing product was successfully developed under appropriate conditions in this novel porous hollow fiber antisolvent crystallization (PHFAC) method. The coated drug particles can be potentially used for controlled release. The molecular and the crystal structures of GF were not affected by the PHFAC method, which may be easily scaled up. PMID- 25552290 TI - Changes in the levels of off-flavor generation in soybean through biotic elicitor treatments. AB - The nutritional benefits of soybean remain underutilized as the off-flavor present in it limits the consumption and acceptability among people. The aim of the present study was to unveil the effect of the phytohormones methyl jasmonate (MJ: 0, 50 MUM, 1 mM, and 15 mM) and salicylic acid (SA: 0, 50 MUM, 0.1 mM, and 10 mM) as elicitors on two contrasting off-flavor soybean varieties at different growth stages (1, bloom; 2, pod development; 3, seed development). The effects of two elicitors varied widely and were found to be dose dependent and growth stage independent. SA reduces the lipoxygenase (LOX) and hydroperoxide lyase (HPL) activity, which in turn resulted in reduction in the TBA number and carbonyl value in contrast to MJ. SA 0.1 mM is the most effective dose in reduction of off flavor determining parameters and protein oxidation, and it reduces the LOX and HPL activity by 2.3- and 2.4-fold, respectively in "high off-flavor" cultivar 'Bragg' compared to "low off-flavor" cultivar 'DS 2706' which showed 1.4- and 2.1 fold, respectively. This reduction in protein oxidation is also supported by enhanced content of antioxidant enzymes. Thus, phytohormone SA can be used in reduction of off-flavor generation, more effectively than MJ treatments, in soybean. PMID- 25552292 TI - Elimination of burn-in open-circuit voltage degradation by ZnO surface modification in organic solar cells. AB - Photodegradation of inverted organic solar cells based on ZnO as an electron transport layer (ETL) was studied over short time scales of 5 min and 8 h. Devices with ZnO as ETL reproducibly exhibited a steep loss of open-circuit voltage, VOC, and shunt resistance, RSH, in a matter of minutes upon illumination. Removing the UV-content of illumination minimized VOC loss and impact on the device's shunting behavior, indicating its role in the loss. Application of an ultrathin layer of Al on ZnO led to almost negligible photoinduced VOC loss up to 8 h of exposure. By applying the fundamental Shockley diode equation, we approximated the VOC loss to be caused by dramatic increases in reverse saturation current I0. We attribute the increased rate of recombination to diminished carrier selectivity at the ZnO/organic interface. Devices with Al modified ZnO ETL demonstrated remarkable RSH (1.4 kOmega cm(2) at 1 sun), rectification ratio (10(6)) and reverse saturation current density (2.1 * 10(-7) mA/cm(2)). PMID- 25552291 TI - Data-independent MS/MS quantification of neuropeptides for determination of putative feeding-related neurohormones in microdialysate. AB - Food consumption is an important behavior that is regulated by an intricate array of neuropeptides (NPs). Although many feeding-related NPs have been identified in mammals, precise mechanisms are unclear and difficult to study in mammals, as current methods are not highly multiplexed and require extensive a priori knowledge about analytes. New advances in data-independent acquisition (DIA) MS/MS and the open-source quantification software Skyline have opened up the possibility to identify hundreds of compounds and quantify them from a single DIA MS/MS run. An untargeted DIA MS(E) quantification method using Skyline software for multiplexed, discovery-driven quantification was developed and found to produce linear calibration curves for peptides at physiologically relevant concentrations using a protein digest as internal standard. By using this method, preliminary relative quantification of the crab Cancer borealis neuropeptidome (<2 kDa, 137 peptides from 18 families) was possible in microdialysates from 8 replicate feeding experiments. Of these NPs, 55 were detected with an average mass error below 10 ppm. The time-resolved profiles of relative concentration changes for 6 are shown, and there is great potential for the use of this method in future experiments to aid in correlation of NP changes with behavior. This work presents an unbiased approach to winnowing candidate NPs related to a behavior of interest in a functionally relevant manner, and demonstrates the success of such a UPLC-MS(E) quantification method using the open source software Skyline. PMID- 25552293 TI - Facile synthesis of gold@graphitized mesoporous silica nanocomposite and its surface-assisted laser desorption/ionization for time-of-flight mass spectroscopy. AB - In this work, a novel core-shell structured gold@graphitized mesoporous silica nanocomposite (Au@GMSN) was synthesized by in situ graphitization of template within the mesochannels of mesoporous silica shell on gold core and demonstrated to be promising nanomaterials for surface-assisted laser desorption/ionization time-of-flight mass spectroscopy (SALDI-TOF MS). The integration of the graphitized mesoporous silica with the gold nanoparticles endowed Au@GMSN with large surface areas of graphitic structure, good dispersibility, and strong ultraviolet (UV) absorption. Au@GMSN exerted the synergistic effect on the efficient detection of small-molecular-weight analytes including amino acids, neutral saccharides, peptides, and traditional Chinese medicine. The Au@GMSN assisted laser desorption/ionization exhibited the following superiorities: high ionization efficiency, low fragmentation interference, favorable salt tolerance, and good reproducibility. Moreover, because of the large hydrophobic inner surface area of the graphitized mesoporous silica shell, the Au@GMSN demonstrated its promising capacity in the pre-enrichment of aromatic analytes prior to SALDI TOF MS, which favored rapid and sensitive detection. PMID- 25552294 TI - Terthiophene-containing copolymers and homopolymer blends as high-performance dielectric materials. AB - This work explores the dielectric and polarization properties of block copolymers and homopolymer blends containing a terthiophene-rich, electronically polarized block (PTTEMA) and an insulating polystyrene block (PS). PTTEMA-b-PS block copolymers were synthesized by reverse addition-fragmentation chain transfer (RAFT) polymerization, and PTTEMA/PS homopolymer blends with the same PTTEMA weight percentages were produced by solution blending. DSC and XRD characterization show that crystallinity increases with PTTEMA content, indicating the presence of terthiophene-rich crystalline domains. Under an applied electric field, these domains are electronically polarized, but the insulating PS block inhibits current leakage, resulting in enhanced dielectric properties. Impedance measurements show that relative permittivity increases with PTTEMA content. The permittivity values are higher in PTTEMA-b-PS copolymers with moderate PTTEMA content due to the ability of the PS block to inhibit PTTEMA association, resulting in a higher density of isolated, terthiophene-rich polarizable domains. Freestanding PTTEMA/PS blend films containing up to 40 wt % PTTEMA have almost 40% greater recoverable energy density compared to pure PS films polarized to the same electric field strength. PMID- 25552302 TI - Reply: No dawn yet of a new age in spinal cord rehabilitation. PMID- 25552301 TI - Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy. AB - Temporal lobe epilepsy is associated with large-scale, wide-ranging changes in gene expression in the hippocampus. Epigenetic changes to DNA are attractive mechanisms to explain the sustained hyperexcitability of chronic epilepsy. Here, through methylation analysis of all annotated C-phosphate-G islands and promoter regions in the human genome, we report a pilot study of the methylation profiles of temporal lobe epilepsy with or without hippocampal sclerosis. Furthermore, by comparative analysis of expression and promoter methylation, we identify methylation sensitive non-coding RNA in human temporal lobe epilepsy. A total of 146 protein-coding genes exhibited altered DNA methylation in temporal lobe epilepsy hippocampus (n = 9) when compared to control (n = 5), with 81.5% of the promoters of these genes displaying hypermethylation. Unique methylation profiles were evident in temporal lobe epilepsy with or without hippocampal sclerosis, in addition to a common methylation profile regardless of pathology grade. Gene ontology terms associated with development, neuron remodelling and neuron maturation were over-represented in the methylation profile of Watson Grade 1 samples (mild hippocampal sclerosis). In addition to genes associated with neuronal, neurotransmitter/synaptic transmission and cell death functions, differential hypermethylation of genes associated with transcriptional regulation was evident in temporal lobe epilepsy, but overall few genes previously associated with epilepsy were among the differentially methylated. Finally, a panel of 13, methylation-sensitive microRNA were identified in temporal lobe epilepsy including MIR27A, miR-193a-5p (MIR193A) and miR-876-3p (MIR876), and the differential methylation of long non-coding RNA documented for the first time. The present study therefore reports select, genome-wide DNA methylation changes in human temporal lobe epilepsy that may contribute to the molecular architecture of the epileptic brain. PMID- 25552304 TI - Comparison of the Treatments of Patients With Cancer in Their Last 6 Months Between ICU and Cancer Center. AB - PURPOSE: To investigate the treatments of patients with cancer in their last 6 months of life in intensive care unit (ICU) and Cancer Center. METHOD: A prospective study was conducted on patients with cancer who died between January 2010 and July 2013 in the ICU and the Cancer Center (55 and 161 cases, respectively) of Tongji Hospital, Wuhan, China. The differences were compared by Chi-square test or Fisher test. RESULTS: The differences in the treatments of patients with cancer between 2 groups were statistically significant. The proportion of patients with cancer who accepted blood transfusion (except albumin) was significantly higher in the ICU than in the Cancer Center. CONCLUSION: Patients with cancer in the ICU were more likely to receive active treatments and less palliative and hospice care at the end of life than patients in the Cancer Center. PMID- 25552305 TI - Malignant Bowel Obstruction in Patients With Recurrent Ovarian Cancer. AB - We sought to report incidence, risk factors, and survival related to bowel obstruction in 311 ovarian cancer patients with recurrent disease. A total of 68 (22%) had a documented bowel obstruction during their cancer course, and 49 (16%) developed it after cancer recurrence. Surprisingly, 142 (45%) fit into an "unknown" category (3+ months of data lacking from last contact/death). No risk factors were identified; management included surgery (n = 21), conservative measures (n = 21), and other (n = 7). Documented bowel obstruction was not associated with a statistically significant reduction in survival after cancer recurrence. In conclusion, although bowel obstruction occurs in only a subgroup of patients with ovarian cancer and does not appear to detract from survival after cancer recurrence, limited end-of-life information may be resulting in an underestimation of incidence. PMID- 25552306 TI - Sequential Assessments of the Eastern Cooperative Oncology Group Performance Scale Enhance Prognostic Value in Patients With Terminally Ill Cancer Receiving Palliative Care. AB - This study aimed to assess the utility of the Eastern Cooperative Oncology Group (ECOG) performance scale assessments on days 1 and 8 of palliative care, as well as scale change between these assessments, as prognostic tools for patients with terminally ill cancer. A total of 2392 patients with terminally ill cancer who received palliative care between January 2006 and December 2011 at a single medical center were analyzed. Our study showed that the ECOG scale is a useful prognostic tool to predict life expectancy in patients with terminally ill cancer. The ECOG scale assessments at different time points under palliative care were independent predictors for overall survival. The combined ECOG scale assessments on days 1 and 8 predicted survival more precisely than using day 1 ECOG scale assessment alone. PMID- 25552303 TI - Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus. AB - The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. PMID- 25552307 TI - Mitochondrial depolarization and asystole in the globally ischemic rabbit heart: coordinated response to interventions affecting energy balance. AB - Mitochondrial membrane potential (DeltaPsim) depolarization has been implicated in the loss of excitability (asystole) during global ischemia, which is relevant for the success of defibrillation and resuscitation after cardiac arrest. However, the relationship between DeltaPsim depolarization and asystole during no flow ischemia remains unknown. We applied spatial Fourier analysis to confocally recorded fluorescence emitted by DeltaPsim-sensitive dye tetramethylrhodamine methyl ester. The time of ischemic DeltaPsim depolarization (tmito_depol) was defined as the time of 50% decrease in the magnitude of spectral peaks reflecting DeltaPsim. The time of asystole (tasys) was determined as the time when spontaneous and induced ventricular activity ceased to exist. Interventions included tachypacing (150 ms), myosin II ATPase inhibitor blebbistatin (heart immobilizer), and the combination of blebbistatin and the inhibitor of glycolysis iodoacetate. In the absence of blebbistatin, confocal images were obtained during brief perfusion with hyperkalemic solution and after the contraction failed between 7 and 15 min of ischemia. In control, tmito_depol and tasys were 24.4 +/- 6.0 and 26.0 +/- 5.0 min, respectively. Tachypacing did not significantly affect either parameter. Blebbistatin dramatically delayed tmito_depol and tasys (51.4 +/- 8.6 and 45.7 +/- 5.3 min, respectively; both P < 0.0001 vs. control). Iodoacetate combined with blebbistatin accelerated both events (tmito_depol, 12.7 +/- 1.8 min; and tasys, 6.5 +/- 1.1 min; both P < 0.03 vs. control). In all groups pooled together, tasys was strongly correlated with tmito_depol (R(2) = 0.845; P < 0.0001). These data may indicate a causal relationship between DeltaPsim depolarization and asystole or a similar dependence of the two events on energy depletion during ischemia. Our results urge caution against the use of blebbistatin in studies addressing pathophysiology of myocardial ischemia. PMID- 25552308 TI - SOD1 overexpression prevents acute hyperglycemia-induced cerebral myogenic dysfunction: relevance to contralateral hemisphere and stroke outcomes. AB - Admission hyperglycemia (HG) amplifies vascular injury and neurological deficits in acute ischemic stroke, but the mechanisms remain controversial. We recently reported that ischemia-reperfusion (I/R) injury impairs the myogenic response in both hemispheres via increased nitration. However, whether HG amplifies contralateral myogenic dysfunction and whether loss of tone in the contralateral hemisphere contributes to stroke outcomes remain to be determined. Our hypothesis was that contralateral myogenic dysfunction worsens stroke outcomes after acute hyperglycemic stroke in an oxidative stress-dependent manner. Male wild-type or SOD1 transgenic rats were injected with saline or 40% glucose solution 10 min before surgery and then subjected to 30 min of ischemia/45 min or 24 h of reperfusion. In another set of animals (n = 5), SOD1 was overexpressed only in the contralateral hemisphere by stereotaxic adenovirus injection 2-3 wk before I/R. Myogenic tone and neurovascular outcomes were determined. HG exacerbated myogenic dysfunction in contralateral side only, which was associated with infarct size expansion, increased edema, and more pronounced neurological deficit. Global and selective SOD1 overexpression restored myogenic reactivity in ipsilateral and contralateral sides, respectively, and enhanced neurovascular outcomes. In conclusion, our results show that SOD1 overexpression nullified the detrimental effects of HG on myogenic tone and stroke outcomes and that the contralateral hemisphere may be a novel target for the management of acute hyperglycemic stroke. PMID- 25552309 TI - Radiation-induced lung injury and inflammation in mice: role of inducible nitric oxide synthase and surfactant protein D. AB - Reactive nitrogen species (RNS) generated after exposure to radiation have been implicated in lung injury. Surfactant protein D (SP-D) is a pulmonary collectin that suppresses inducible nitric oxide synthase (iNOS)-mediated RNS production. Herein, we analyzed the role of iNOS and SP-D in radiation-induced lung injury. Exposure of wild-type (WT) mice to gamma-radiation (8 Gy) caused acute lung injury and inflammation, as measured by increases in bronchoalveolar lavage (BAL) protein and cell content at 24 h. Radiation also caused alterations in SP-D structure at 24 h and 4 weeks post exposure. These responses were blunted in iNOS(-/-) mice. Conversely, loss of iNOS had no effect on radiation-induced expression of phospho-H2A.X or tumor necrosis factor (TNF)-alpha. Additionally, at 24 h post radiation, cyclooxygenase expression and BAL lipocalin-2 levels were increased in iNOS(-/-) mice, and heme oxygenase (HO)-1(+) and Ym1(+) macrophages were evident. Loss of SP-D resulted in increased numbers of enlarged HO-1(+) macrophages in the lung following radiation, along with upregulation of TNF alpha, CCL2, and CXCL2, whereas expression of phospho-H2A.X was diminished. To determine if RNS play a role in the altered sensitivity of SP-D(-/-) mice to radiation, iNOS(-/-)/SP-D(-/-) mice were used. Radiation-induced injury, oxidative stress, and tissue repair were generally similar in iNOS(-/-)/SP-D(-/-) and SP-D(-/-) mice. In contrast, TNF-alpha, CCL2, and CXCL2 expression was attenuated. These data indicate that although iNOS is involved in radiation induced injury and altered SP-D structure, in the absence of SP-D, it functions to promote proinflammatory signaling. Thus, multiple inflammatory pathways contribute to the pathogenic response to radiation. PMID- 25552312 TI - HVM: a web-based tool for alignment of EF-hand lobes relative to their local pseudo two-fold axes. AB - We have developed a method to align a pair of EF-hand domains, an EF-lobe, using the symmetry axis that is intrinsic to the EF-lobe itself. The coordinate system for the alignment is dependent only on the symmetry of the EF-lobe. The absolute positions of each component in the structure can be described in this coordinate system. Our site provides the foundation for the analyses and comparisons of structural features of EF-lobes. PMID- 25552311 TI - Molecular characterization of E2 glycoprotein of classical swine fever virus: adaptation and propagation in porcine kidney cells. AB - Classical swine fever virus (CSFV) is the causative agent of a highly contagious disease, hog cholera in pigs. The disease is endemic in many parts of the world, and vaccination is the only way to protect the animals from CSFV infection. The lapinized vaccine strains are occasionally not protective because of animal to animal passage, inadequate vaccination strategy, suboptimal vaccine dose, and emergence of new variants. The surface glycoprotein E2 of CSFV is a major antigenic determinant and can modulate the disease outcome in pigs. In the present study, we characterized the CSFV in porcine kidney cells. The CSFV vaccine strains showed enhanced replication following 15 passages in porcine kidney cells. Nucleotide sequence analysis of the E2 protein gene of the cell culture-adapted vaccine strain of CSFV showed a mutation in putative amino acid sequences that are identical to its virulent counterpart. The study suggests the possibility of exaltation in vaccine strains following its adaptation in host cells and paves the way for a further exploration of the biology of its outbreak. PMID- 25552310 TI - Effect of culture conditions on microRNA expression in primary adult control and COPD lung fibroblasts in vitro. AB - In vitro cell cultures, including lung fibroblasts, have been used to identify microRNAs (miRNAs) associated with chronic obstructive pulmonary disease (COPD) pathogenesis. However, culture conditions may affect miRNA expression. We examined whether miRNA expression in primary adult lung fibroblasts varies with cell density or passage in vitro and whether culture conditions confound the identification of altered miRNA expression in COPD lung fibroblasts. Primary adult control and COPD lung fibroblasts were cultured until passage 3 or 8, after which cells were further cultured for 3 or 7 d (low vs. high density). Then, cells at low density were cultured with serum-free media, and those at high density were cultured with serum-free media in the absence or presence of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) for 24 h. RNA was extracted to perform miRNA microarray from which 1.25-fold differential expression and 10% false discovery rate were applied to identify "invariant" and "variant" miRNA for the various culture conditions. Of the 2226 miRNAs evaluated, 39.0% for cell density, 40.7% for cell passage, and 29.4% for both conditions were identified as "invariant" miRNAs. Furthermore, 38.1% of the evaluated miRNAs were "invariant" for cell passage with IL-1beta and TNF-alpha. Differentially expressed miRNAs between control and COPD lung fibroblasts were identified with and without IL-1beta and TNF-alpha, and of these, 32 out of the 34 top-ranked miRNAs exceeded the differences due to culture conditions. Thus, culture conditions may affect miRNA expression of adult human lung fibroblasts. Nevertheless, in vitro cultures can be used to assess differential miRNA expression in COPD lung fibroblasts. PMID- 25552313 TI - A staggered decameric assembly of human C-reactive protein stabilized by zinc ions revealed by X-ray crystallography. AB - Human C-reactive protein (CRP) is an acute phase protein, which harbours both host defence and scavenging properties. In this study, we obtained two new crystal forms of CRP, where CRP forms a symmetric, staggered dimer of pentamers. In one of these structures, obtained in the presence of HIV-1 Tat protein, this dimer of pentamers is stabilized by two zinc ions trapped within a cleft of the effector face of CRP. These two decameric interfaces involve complementary surfaces of CRP pentamers and bury a large area of ~2000 A(2) per pentamer, suggesting a biological role of this interface. These two novel decameric interfaces and the involvement of zinc might have important consequences in the understanding of CRP biological functions. PMID- 25552314 TI - A Novel Monoclonal Antibody Against a Synthetic Peptide from beta-Actin can React with its Corresponding Protein. AB - Actin is one of the most widely studied structural and multifunctional housekeeping proteins in eukaryotic cells with important roles in many cell functions. Antibodies against beta-actin and other housekeeping gene-encoded proteins are used as internal loading controls in Western blot analyses. The aim of this study was to produce a monoclonal antibody (mAb) against a synthetic peptide derived from N-terminal region of beta-actin and to study its reactivity with different organisms. A synthetic peptide, derived from beta-actin, was designed and used to produce a mAb by hybridoma technology. The produced antibody (clone 4E5- A10) was purified by an affinity chromatography column followed by characterization of purified mAb using SDS-PAGE, ELISA and Western blot. Our results showed that 4E5-A10 was an IgM and had desired purity and excellent reactivity with the immunizing peptide with an affinity constant of 2.7x10(8) M( 1)>. It could detect a band of about 45 kDa, corresponding to beta-actin, in Western blot. Furthermore, it could react in a more sensitive manner and with a wider range of organisms than a known commercial anti beta-actin antibody. Our data suggest that 4E5-A10 can act as a sensitive probe for detection of beta actin as an internal loading control, for a wide range of organisms, in Western blot analyses. PMID- 25552315 TI - Structural and functional connectivity mapping of the vestibular circuitry from human brainstem to cortex. AB - Structural and functional interconnections of the bilateral central vestibular network have not yet been completely delineated. This includes both ipsilateral and contralateral pathways and crossing sites on the way from the vestibular nuclei via the thalamic relay stations to multiple "vestibular cortex" areas. This study investigated "vestibular" connectivity in the living human brain in between the vestibular nuclei and the parieto-insular vestibular cortex (PIVC) by combined structural and functional connectivity mapping using diffusion tensor imaging and functional connectivity magnetic resonance imaging in 24 healthy right-handed volunteers. We observed a congruent functional and structural link between the vestibular nuclei and the ipsilateral and contralateral PIVC. Five separate and distinct vestibular pathways were identified: three run ipsilaterally, while the two others cross either in the pons or the midbrain. Two of the ipsilateral projections run through the posterolateral or paramedian thalamic subnuclei, while the third bypasses the thalamus to reach the inferior part of the insular cortex directly. Both contralateral pathways travel through the posterolateral thalamus. At the cortical level, the PIVC regions of both hemispheres with a right hemispherical dominance are interconnected transcallosally through the antero-caudal splenium. The above-described bilateral vestibular circuitry in its entirety takes the form of a structure of a rope ladder extending from the brainstem to the cortex with three crossings in the brainstem (vestibular nuclei, pons, midbrain), none at thalamic level and a fourth cortical crossing through the splenium of the corpus callosum. PMID- 25552316 TI - Genoarchitecture of the rostral hindbrain of a shark: basis for understanding the emergence of the cerebellum at the agnathan-gnathostome transition. AB - The cerebellum is present in all extant gnathostomes or jawed vertebrates, of which cartilaginous fishes represent the most ancient radiation. Since the isthmic organizer induces the formation of the cerebellum, comparative genoarchitectonic analysis on the meso-isthmo-cerebellar region of cartilaginous fishes with respect to that of jawless vertebrates could reveal why the isthmic organizer acquires the ability to induce the formation of the cerebellum in gnathostomes. In the present work we analyzed the expression pattern of a variety of genes related to the cerebellar formation and patterning (ScOtx2, ScGbx2, ScFgf8, ScLmx1b, ScIrx1, ScIrx3, ScEn2, ScPax6 and ScLhx9) by in situ hybridization, and the distribution of Pax6 protein in the developing hindbrain of the shark Scyliorhinus canicula. The genoarchitectonic code in this species revealed high degree of conservation with respect to that of other gnathostomes. This resemblance may reveal the features of the ancestral condition of the gene network operating for specification of the rostral hindbrain patterning. Accordingly, the main subdivisions of the rostral hindbrain of S. canicula could be recognized. Our results support the existence of a rhombomere 0, identified as the ScFgf8/ScGbx2/ScEn2-positive and mainly negative ScIrx3 domain just caudal to the midbrain ScIrx1/ScOtx2/ScLmx1b-positive domain. The differential ScEn2 and Pax6 expression in the rhombomere 1 revealed anterior and posterior subdivisions. Interestingly, dissimilarities between S. canicula and lampreys (jawless vertebrates) were noted in the expression of Irx, Lhx and Pax genes, which could be part of significant gene network changes through evolution that caused the emergence of the cerebellum. PMID- 25552317 TI - How can motor systems retain performance over a wide temperature range? Lessons from the crustacean stomatogastric nervous system. AB - Marine invertebrates, such as lobsters and crabs, deal with a widely and wildly fluctuating temperature environment. Here, we describe the effects of changing temperature on the motor patterns generated by the stomatogastric nervous system of the crab, Cancer borealis. Over a broad range of "permissive" temperatures, the pyloric rhythm increases in frequency but maintains its characteristic phase relationships. Nonetheless, at more extreme high temperatures, the normal triphasic pyloric rhythm breaks down, or "crashes". We present both experimental and computational approaches to understanding the stability of both single neurons and networks to temperature perturbations, and discuss data that shows that the "crash" temperatures themselves may be environmentally regulated. These approaches provide insight into how the nervous system can be stable to a global perturbation, such as temperature, in spite of the fact that all biological processes are temperature dependent. PMID- 25552319 TI - Solution to the isotope dilution challenge. PMID- 25552318 TI - Clutter and conspecifics: a comparison of their influence on echolocation and flight behaviour in Daubenton's bat, Myotis daubentonii. AB - We compared the influence of conspecifics and clutter on echolocation and flight speed in the bat Myotis daubentonii. In a large room, actual pairs of bats exhibited greater disparity in peak frequency (PF), minimum frequency (F MIN) and call period compared to virtual pairs of bats, each flying alone. Greater inter individual disparity in PF and F MIN may reduce acoustic interference and/or increase signal self-recognition in the presence of conspecifics. Bats flying alone in a smaller flight room, to simulate a more cluttered habitat as compared to the large flight room, produced calls of shorter duration and call period, lower intensity, and flew at lower speeds. In cluttered space, shorter call duration should reduce masking, while shorter call period equals more updates to the bat's auditory scene. Lower intensity likely reflects reduced range detection requirements, reduced speed the demands of flying in clutter. Our results show that some changes (e.g. PF separation) are associated with conspecifics, others with closed habitat (e.g. reduced call intensity). However, we demonstrate that call duration, period, and flight speed appear similarly influenced by conspecifics and clutter. We suggest that some changes reduce conspecific interference and/or improve self-recognition, while others demonstrate that bats experience each other like clutter. PMID- 25552320 TI - A skyline-view imaging technique for axial projection of the patella: a clinical study. AB - Our purpose in this study was to evaluate the clinical usefulness of a new skyline-view imaging technique for axial projection of the patella with use of the anterior border of the patella and tibial tuberosity as position indicators. Our database consisted of pairs of axial images of the patella of the same patients, obtained with use of conventional and new techniques for the radiographic diagnosis of knee-joint diseases. A total of 118 pairs of knee images were obtained from 103 patients ranging in age from 16 to 86 years (mean age 49.7 years). The patellar axial positioning errors were determined in each of the images obtained with the two techniques. The relative error according to the patellar tilt was determined from each of the axial images of the patellas of the same patients obtained with the conventional and new techniques for the radiographic diagnosis of knee-joint diseases. The patellar axial positioning error was 0.40 with the conventional technique, whereas that with the new technique was significantly different at 0.30. This clinical study confirmed that the new skyline-view imaging technique, which uses the anterior border of the patella and the tibial tuberosity as position markers that can be confirmed by palpation, provides more accurate axial images than the conventional imaging technique. PMID- 25552321 TI - New serotypes of porcine teschovirus identified in Shanghai, China. AB - Teschoviruses are widely endemic and commonly found in pig fecal samples. In this study, we collected fecal specimens from various pig herds and genotyped them based on the VP1 gene. Of 322 samples, 276 were positive, giving a PTV infectivity rate of 85.7 %. PTV4 was the most common serotype found in Shanghai, followed by PTV8 and PTV10. Interestingly, Some Shanghai strains belonging to a new PTV serotype were also isolated. In phylogenetic analysis, PTV SH8 did not correspond to any known serotype. PTV4 and PTV6 showed similar levels of sequence identity to PTV SH8. These data suggest that PTV SH8 is a new serotype, distinct from the new serotype PTV wild boar/WB2C-TV/2011/HUN, which clusters with PTV SH2, SH10, and SH25. PMID- 25552322 TI - Determination of residues of fipronil and its metabolites in cauliflower by using gas chromatography-tandem mass spectrometry. AB - Fipronil is a widely used insecticide with a well-described toxicological pathway. Recently it has been widely used in India to control vegetable pests. The present study has been carried out to observe the persistence pattern of fipronil and its metabolites-fipronil sulfone, fipronil sulfide, fipronil desulfinyl in cauliflower and soil so as to know the potential risk if any to consumers and environment. Fipronil was applied @ 56 g a.i. ha(-1). Samples of cauliflower and soil were collected periodically; processed using QuEChERS method and analyzed by GCMS/MS. In cauliflower, residues of fipronil and its metabolites reached below detectable level before 30 days of application whereas in soil about 95% of total fipronil residues got degraded within same time period. Washing and washing followed by cooking or boiling was found effective in reducing residues. A safe waiting period of 15 days is therefore suggested before consuming cauliflower. PMID- 25552323 TI - Soil washing of fluorine contaminated soil using various washing solutions. AB - Bench-scale soil washing experiments were conducted to remove fluoride from contaminated soils. Five washing solutions including hydrochloric acid (HCl), nitric acid (HNO3), sodium hydroxide (NaOH), sulfuric acid (H2SO4) and tartaric acid (C4H6O6) were tested. The concentration of the washing solutions used ranged from 0.1 to 3 M with a liquid to solid ratio of 10. The soil washing results showed that the most effective washing solution for the removal of fluoride from contaminated soils was HCl. The highest fluoride removal results of approximately 97 % from the contaminated soil were obtained using 3 M HCl. The fluoride removal efficiency of the washing solution increases in the following order: C4H6O6 < NaOH < H2SO4 < HNO3 < HCl. PMID- 25552324 TI - Assessment of ozone variations and meteorological influences at a rural site in Northern Xinjiang. AB - Ozone concentrations and meteorological data were continuously monitored online from June to December 2013 at the Akedala regional atmosphere station in an arid region of Central Asia. We present daily, monthly, and seasonal variations of ozone concentrations in the atmosphere and elucidate possible emission sources. The ozone concentrations of this region varied from 14.7 to 58.6 ppb. A remarkable seasonal variation of ozone in aerosols was observed with highest level in summer, followed by autumn and winter. The daily peak value of ozone was observed at 9:00-11:00 a.m. while the lowest was at 17:00-19:00 p.m. The backward trajectories of air masses showed potential emission sources to be from the northwest and south during the measurement period. The backward trajectory also revealed that ozone concentrations during the measurement period were likely attributable to the emission from anthropogenic activities, and medium-range atmospheric transport from cities in central Asia and the northern slope of the Tian Shan Mountains. PMID- 25552325 TI - Synthesis of iron oxide rods coated with polymer brushes and control of their assembly in thin films. AB - We investigated the surface-initiated atom transfer radical polymerization (SI ATRP) of methyl methacrylate (MMA) using monodisperse rod-type particles of iron oxide, beta-FeOOH. The slow hydrolysis of iron(III) chloride yielded monodisperse beta-FeOOH rods with an average length-to-width ratio, L/W, of 6 (L = 210 nm and W = 35 nm on average). The surfaces of the beta-FeOOH rods were modified with a triethoxysilane derivative as an ATRP-initiating site, namely, (2-bromo-2 methyl)propionyloxypropyl triethoxysilane. The SI-ATRP of MMA, mediated by a copper complex, was performed using the initiator-coated beta-FeOOH rods in the presence of a "sacrificial" free initiator. Well-defined poly(methyl methacrylate) (PMMA) brushes with molecular weights of up to 700,000 could be grafted on the beta-FeOOH rods with a surface density as high as 0.3 chains/nm(2). The resultant polymer-brush-afforded hybrid rods exhibited high dispersibility in various solvents for PMMA without forming aggregates. Thin films were prepared by dip-coating from a suspension of the hybrid rods, and the rods were oriented in a specific direction in the films. The arrangement of the rods could be controlled by varying the chain length of the polymer brush and the withdrawal speed during the dip-coating process. PMID- 25552326 TI - Fine-scale chemical exposure differs in point and nonpoint source plumes. AB - Increasing influxes of anthropogenic chemicals into aquatic ecosystems has led to growing global concern surrounding human and ecosystem health. As more freshwater systems are deemed not potable or usable for agricultural purposes, more attention is being paid to remediation and mitigation efforts. Predicting and preventing the impacts of the chemical inputs first requires a thorough understanding of the spatio-temporal distribution of chemical plumes in natural habitats. Plume dispersion is intimately tied to fluid mechanics; therefore, alterations in the way that chemical plumes are introduced to habitats can have profound effects on chemical distribution. Such alterations can subsequently alter the exposure to which organisms are subjected. This study examined the influence of point versus nonpoint sources in structuring the distribution of chemicals in a simulated flowing freshwater habitat. The fine-scale (molecular) spatio-temporal distribution of chemicals was measured in situ using an electrochemical detector. Molecular concentration at varying distance and height from the source was quantified using dopamine coupled with an electrochemical detection system. The fine-scale distribution of chemical plumes from point and nonpoint sources showed significant differences in how organisms will be exposed to chemicals. Overall, this study characterized plumes from nonpoint sources as having significantly longer peak lengths and rise times as well as greater peak heights and maximum slopes than plumes from point sources, thus providing a significantly different exposure paradigm. This quantification of how chemicals move differently throughout a fluid medium when introduced from point and nonpoint sources allows a greater understanding of how chemical plumes can potentially affect aquatic ecosystems. PMID- 25552327 TI - Nanoparticulate TiO2 protection of midgut damage in the silkworm (Bombyx mori) following phoxim exposure. AB - Bombyx mori (B. mori) is often subjected to phoxim poisoning in China due to phoxim exposure, which leads to a decrease in silk production. Nanoparticulate (NP) titanium dioxide (nano-TiO2) has been shown to attenuate damages in B. mori caused by phoxim exposure. However, little is known about the molecular mechanisms of midgut injury due to organophosphorus insecticide exposure and its repair by nano-TiO2 pretreatment. In this study, phoxim exposure for 36 h led to significant decreases in body weight and survival and increased oxidative stress and midgut injury. Pretreatment with nano-TiO2 attenuated the phoxim-induced midgut injury, increased body weight and survival, and decreased oxidative stress in the midgut of B. mori. Digital gene-expression data showed that exposure to phoxim results in significant changes in the expression of 254 genes in the phoxim-exposed midgut and 303 genes in phoxim + nano-TiO2-exposed midgut. Specifically, phoxim exposure led to upregulation of Tpx, alpha-amylase, trypsin, and glycoside hydrolase genes involved in digestion and absorption. Phoxim exposure also led to the downregulation of Cyp450 and Cyp4C1 genes involved in an antioxidant capacity. In contrast, a combination of both phoxim and nano-TiO2 treatment significantly decreased the change in alpha-amylase, trypsin, and glycoside hydrolases (GHs), which are involved in digestion and absorption. These results indicated that Tpx, alpha-amylase, trypsin, GHs, Cyp450, and Cyp4C1 may be potential biomarkers of midgut toxicity caused by phoxim exposure and the attenuation of these toxic impacts by nano-TiO2. PMID- 25552328 TI - The Comparison of Infusion of Two Different Sedation Regimens with Propofol and Ketamine Combination During Plastic and Reconstructive Surgery. AB - OBJECTIVE: Anesthetic agents are often combined to enhance their therapeutic effects while minimizing adverse events. The aim of this study was to evaluate the effects of two different sedation regimens of ketamine and propofol combination via infusion on perioperative variables in patients who underwent plastic and reconstructive surgery. METHODS: This randomized double-blind clinical trial was done on 80 patients who were randomized to two groups; group 1 (n = 40) received a 2:1 mixture of 9 mg/ml propofol and 4.5 mg/ml ketamine, and group 2 (n = 40) received a 4:1 mixture of 9 mg/ml propofol and 2.25 mg/ml ketamine. After premedication and before local anesthetic injection, the infusion of mixtures was adjusted to attain the Ramsay sedation scores of 5 in both groups. We recorded induction time, sedation efficacy, cardiovascular and respiratory events, recovery time, and incidence of adverse events during and after the procedure. RESULTS: The mean of volume infusion of mixtures in the beginning of the procedure was higher in group 2 (3.2 +/- 1. 2 ml) than in group 1 (2.4 +/- 0.8 ml) (p < 0.001). The induction time for sedation was 2.8 +/- 0.8 min and 2.6 +/- 0.4 min in group 1 and group 2, respectively (p = 0. 92). The number of oversedated patients was greater in group 2 compared to group 1 but not statistically significant (p = 0. 80). The sedation efficacy was similar between the two groups. The hemodynamic changes during the procedure were greater in group 2 compared to group 1 (p = 0. 001). The recovery time was not significantly different between the two groups (p = 0.43). The mean pain score in the recovery room was lower in group 1 than group 2 (1.2 +/- 0.8 vs 2.8 +/- 1.8, p = 0. 01). Moreover, 4 (10 %) patients in group 1 and 10 (25 %) patients in group 2 needed opioid administration (p = 0. 02). Other postoperative adverse events were similar between the two groups. CONCLUSION: We recommend the use of a 2:1 combination of propofol-ketamine, because it reduced the rescue propofol requirement and consequently produced lower cardiovascular and respiratory depression effects and also less postoperative pain. PMID- 25552329 TI - A novel flap technique for repairing large lower lip defects. AB - There are many well-established methods for the reconstruction of the lower lip. The selection of a particular method generally relies on the amount of lip resected and the amount of lip remaining. In cases of large defects (>50% of the lip length) where direct closure and lip-switch techniques are inadequate, a perioral flap is used. All techniques for perioral flaps described until now result in an unwanted decrease in circumoral opening. The only available method that keeps the circumoral opening the same is a distant or regional free flap, and this technique is usually reserved for more extreme defects because it is more radical, technically demanding, and can pose a greater risk of complications. In this study, we describe a novel technique for reconstruction of the lower lip using a perioral flap in which the circumoral opening is kept the same. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 25552330 TI - Quantitative Analysis of Diffusion-Weighted Imaging for Diagnosis of Puerperal Breast Abscess After Polyacrylamide Hydrogel Augmentation Mammoplasty: Compared with Other Conventional Modalities. AB - PURPOSE: Puerperal breast abscess after polyacrylamide hydrogel (PAAG) augmentation mammoplasty can induce breast auto-inflation resulting in serious consequences. Mammography, ultrasound, and conventional MRI are poor at detecting related PAAG abnormality histologically. We evaluated the value of diffusion weighted imaging (DWI) in the quantitative analysis of puerperal PAAG abscess after augmentation mammoplasty. MATERIALS AND METHODS: This was a retrospective study, and a waiver for informed consent was granted. Sixteen puerperal women with breast discomfort underwent conventional breast non-enhanced MRI and axial DWI using a 3T MR scanner. Qualitative analysis of the signal intensity on DWI and conventional sequences was performed. The apparent diffusion coefficient (ADC) values of the affected and contralateral normal PAAG cysts were measured quantitatively. Paired t test was used to evaluate whether there was significant difference. RESULTS: Both affected and normal PAAG cysts showed equal signal intensity on conventional T1WI and fat saturation T2WI, which were not helpful in detecting puerperal PAAG abscess. However, the affected PAAG cysts had a significantly decreased ADC value of 1.477 +/- 0.332 * 10(-3)mm(2)/s and showed obvious hypo-intensity on the ADC map and increased signal intensity on DWI compared with the ADC value of 2.775 +/- 0.233 * 10(-3)mm(2)/s of the contralateral normal PAAG cysts. CONCLUSION: DWI and quantitative measurement of ADC values are of great value for the diagnosis of puerperal PAAG abscess. Standardized MRI should be suggested to these puerperal women with breast discomfort or just for the purpose of check up. DWI should be selected as the essential MRI sequence. PMID- 25552331 TI - Personalized keystroke dynamics for self-powered human--machine interfacing. AB - The computer keyboard is one of the most common, reliable, accessible, and effective tools used for human--machine interfacing and information exchange. Although keyboards have been used for hundreds of years for advancing human civilization, studying human behavior by keystroke dynamics using smart keyboards remains a great challenge. Here we report a self-powered, non-mechanical-punching keyboard enabled by contact electrification between human fingers and keys, which converts mechanical stimuli applied to the keyboard into local electronic signals without applying an external power. The intelligent keyboard (IKB) can not only sensitively trigger a wireless alarm system once gentle finger tapping occurs but also trace and record typed content by detecting both the dynamic time intervals between and during the inputting of letters and the force used for each typing action. Such features hold promise for its use as a smart security system that can realize detection, alert, recording, and identification. Moreover, the IKB is able to identify personal characteristics from different individuals, assisted by the behavioral biometric of keystroke dynamics. Furthermore, the IKB can effectively harness typing motions for electricity to charge commercial electronics at arbitrary typing speeds greater than 100 characters per min. Given the above features, the IKB can be potentially applied not only to self-powered electronics but also to artificial intelligence, cyber security, and computer or network access control. PMID- 25552332 TI - Flexibility and color monitoring of cellulose nanocrystal iridescent solid films using anionic or neutral polymers. AB - One property of sulfated cellulose nanocrystals (CNCs) is their ability to self assemble from a concentrated suspension under specific drying conditions into an iridescent film. Such colored films are very brittle, which makes them difficult to handle or integrate within an industrial process. The goal of this study is (i) to produce flexible films using neutral poly(ethylene glycol) (PEG) and (ii) to modulate their coloration using an anionic polyacrylate (PAAS). The first part is dedicated to studying the physicochemical interactions of the two polymers with CNCs using techniques such as zeta potential measurements, dynamic light scattering (DLS), quartz crystal microbalance (QCM), and atomic force microscopy (AFM). Iridescent solid films were then produced and characterized using scanning electron microscopy (SEM) and UV-visible spectroscopy. The mechanical and thermal properties of films incorporating CNC were measured to evaluate improvements in flexibility. The addition of 10 wt % of PEG makes these films much more flexible (with a doubling of the elongation), with the coloration being preserved and the temperature of degradation increasing by almost 35 degrees C. Up to 160 MUmol/gCNC PAAS can be added to tune the coloration of the CNC films by producing a more narrow, stronger coloration in the visible spectrum (higher absorption) with a well-pronounced fingerprint texture. PMID- 25552333 TI - JOSPT: plus ultra--further beyond. PMID- 25552334 TI - Heterotopic ossification in a recreational soccer player. PMID- 25552340 TI - Langerhans cell histiocytosis and pituitary function. PMID- 25552341 TI - Hormonal correlations of premature ejaculation. AB - Premature ejaculation is the most frequent male sexual dysfunction, significantly impairing quality of life of both the patient and the partner and affecting up to one-third of men of every age. In the last years, our knowledge about this topic has greatly increased, and studies on the causes and treatments related to ejaculatory disorders have shed a light on previously uncharted territory. Public interest on sexual dysfunctions has likewise increased in the general population: the time lapse between the first symptoms of sexual dysfunction and the seeking of medical advice has been significantly reduced, whereas demand for a treatment has markedly increased. A role of endocrine regulation has been established in all the aspects of male reproduction; however, the endocrine control of ejaculation is not fully understood. Sex steroid, pituitary, and thyroid hormones have all been advocated as potential candidates in the regulation of the ejaculatory process, but exact mechanisms are not clear yet and further studies are required in order to identify potential targets for treatment. PMID- 25552343 TI - Nanosheet-structured boron nitride spheres with a versatile adsorption capacity for water cleaning. AB - Here, we report the synthesis of nanosheet-structured boron nitride spheres (NSBNSs) by a catalyzing thermal evaporation method from solid B powders. The NSBNSs consist of radially oriented ultrathin nanosheets with the sheet edges oriented on the surface. Formation of this unique structure occurs only at a certain reaction temperature. The diameter from 4 MUm to 700 nm and the nanosheet thickness from 9.1 to 3.1 nm of the NSBNSs can be well-controlled by appropriately changing the mass ratio of boron powders and catalyst. The NSBNSs possess versatile adsorption capacity, exhibiting excellent adsorption performance for oil, dyes, and heavy metal ions from water. The oil uptake reaches 7.8 times its own weight. The adsorption capacities for malachite green and methylene blue are 324 and 233 mg/g, while those for Cu(2+), Pb(2+), and Cd(2+) are 678.7, 536.7, and 107.0 mg/g, respectively. The adsorption capacities of the NSBNSs for Cu(2+) and Pb(2+) are higher or much higher than those of the adsorbents reported previously. These results demonstrate the great potential of NSBNSs for water treatment and cleaning. PMID- 25552342 TI - A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. AB - BACKGROUND: Deregulated autophagy followed by cellular senescence in biliary epithelial cells (BECs) may be closely related to the abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in primary biliary cirrhosis (PBC). We examined an involvement of endoplasmic reticulum (ER) stress in the deregulated autophagy and cellular senescence in PBC. METHODS: We examined the degree of ER stress using markers; glucose-regulated protein 78 (GRP78) and protein disulfide isomerases (PDI), autophagy and cellular senescence in cultured BECs treated with an ER stress inducer, tunicamycin (TM), glycochenodeoxycholic acid (GCDC), and palmitic acid (PA), and the effect of pretreatment with tauroursodeoxycholic acid (TUDCA). We examined the expression of PDI and GRP78 in livers taken from the patients with PBC (n = 43) and 75 control livers. RESULTS: The expression of ER stress markers was significantly increased in cultured BECs treated with TM, GCDC or PA in BECs (p < 0.05), and pretreatment with TUDCA significantly suppressed the induced ER stress (p < 0.05). Autophagy, deregulated autophagy, and cellular senescence were induced in BECs treated with TM, GCDC, or PA. Pretreatment with TUDCA further increased autophagy in BECs treated with PA and suppressed cellular senescence caused by treatments with TM, GCDC, or PA (p < 0.05). A granular expression of PDI and GRP78 was significantly more extensive in small bile ducts in PBC, compared with control livers (p < 0.05). The expression of GRP78 was seen in senescent BECs in PBC. CONCLUSIONS: ER stress may play a role in the pathogenesis of deregulated autophagy and cellular senescence in biliary epithelial lesions in PBC. PMID- 25552344 TI - Lung re-inflation after one-lung ventilation for thoracic surgery: an alternative technique. PMID- 25552345 TI - Sodium cholate-templated blue light-emitting Ag subnanoclusters: in vivo toxicity and imaging in zebrafish embryos. AB - We report a novel green chemical approach for the synthesis of blue light emitting and water-soluble Ag subnanoclusters, using sodium cholate (NaC) as a template at a concentration higher than the critical micelle concentration (CMC) at room temperature. However, under photochemical irradiation, small anisotropic and spherically shaped Ag nanoparticles (3-11 nm) were obtained upon changing the concentration of NaC from below to above the CMC. The matrix-assisted laser desorption ionization time-of-flight and electrospray ionization mass spectra showed that the cluster sample was composed of Ag4 and Ag6. The optical properties of the clusters were studied by UV-visible and luminescence spectroscopy. The lifetime of the synthesized fluorescent Ag nanoclusters (AgNCs) was measured using a time-correlated single-photon counting technique. High resolution transmission electron microscopy was used to assess the size of clusters and nanoparticles. A protocol for transferring nanoclusters to organic solvents is also described. Toxicity and bioimaging studies of NaC templated AgNCs were conducted using developmental stage zebrafish embryos. From the survival and hatching experiment, no significant toxic effect was observed at AgNC concentrations of up to 200 MUL/mL, and the NC-stained embryos exhibited blue fluorescence with high intensity for a long period of time, which shows that AgNCs are more stable in living system. PMID- 25552347 TI - Dependence of fungal characteristics on seed morphology and shear stress in bioreactors. AB - The fungal morphology during submerged cultivations has a profound influence on the overall performance of bioreactors. In this research, glucoamylase production by Aspergillus niger has been taken as a model to improve more insights. The morphology engineering could be conducted effectively by changing the seed morphology, as well as specific power input. During the fed-batch cultivations, pellet formation under milder shear stress field helped to reduce the broth viscosity, thus relieving oxygen limitation and promoting the enzyme production. Furthermore, we found that the relation between the shear stress field, which was characterized by energy dissipation rate/circulation function (EDCF), and enzyme activity was consistent with quadratic parabola, which threw light on the process optimization and scale-up for industrial enzyme production. PMID- 25552348 TI - Artificial neural network associated to UV/Vis spectroscopy for monitoring bioreactions in biopharmaceutical processes. AB - Currently, mammalian cells are the most utilized hosts for biopharmaceutical production. The culture media for these cell lines include commonly in their composition a pH indicator. Spectroscopic techniques are used for biopharmaceutical process monitoring, among them, UV-Vis spectroscopy has found scarce applications. This work aimed to define artificial neural networks architecture and fit its parameters to predict some nutrients and metabolites, as well as viable cell concentration based on UV-Vis spectral data of mammalian cell bioprocess using phenol red in culture medium. The BHK-21 cell line was used as a mammalian cell model. Off-line spectra of supernatant samples taken from batches performed at different dissolved oxygen concentrations in two bioreactor configurations and with two pH control strategies were used to define two artificial neural networks. According to absolute errors, glutamine (0.13 +/- 0.14 mM), glutamate (0.02 +/- 0.02 mM), glucose (1.11 +/- 1.70 mM), lactate (0.84 +/- 0.68 mM) and viable cell concentrations (1.89 10(5) +/- 1.90 10(5) cell/mL) were suitably predicted. The prediction error averages for monitored variables were lower than those previously reported using different spectroscopic techniques in combination with partial least squares or artificial neural network. The present work allows for UV-VIS sensor development, and decreases cost related to nutrients and metabolite quantifications. PMID- 25552349 TI - Wide-field spectral domain-optical coherence tomography in central serous chorioretinopathy. AB - The aim the study was to describe wide-field spectral-domain optical coherence tomography morphologic relationships of the vitreous, retina, and choroid in central serous chorioretinopathy (CSCR) eyes. Standardized horizontal, vertical, and two oblique (supertemporal to inferonasal and supranasal to inferotemporal) SD-OCT sections were collected for 40 patient with CSCR. For extramacular imaging, images were obtained from eight locations: (1) nasal to the optic disk, (2) extreme nasal periphery, (3) superior to the superotemporal vascular arcade, (4) extreme superior periphery, (5) inferior to the inferotemporal vascular arcade, (6) extreme inferior periphery, (7) temporal to the macula, and (8) extreme temporal periphery. Wide-angle montage images of OCT from equator to equator were composed with a montaging software. Average subfoveal choroidal thickness was 478 +/- 114 um (range 232-695 um) at the macular level, 367 +/- 94 um in the superior periphery, 257 +/- 103 um in the inferior periphery, 431 +/- 121 and 280 +/- 88 um in the nasal and in the temporal periphery, respectively. Wide-field EDI-OCT revealed a relative thinning of the inner choroidal layer in the periphery, including the small and medium large vessels, which ranged from 86 um nasally to 120.1 um superiorly, with a mean of 98.8 +/- 13.6 um. Beneath the thinned inner choroidal layer, hyporeflective lumina, corresponding to the outer choroidal layer, were identified in the periphery of all eyes. The outer choroidal layer thickness ranged from 175.5 um temporally to 235.5 um superiorly, with a mean of 217.8 +/- 41.4 um. The novel approach of montaging SD-OCT images to examine relationships between the choroid, retina, and associated structures adjacent to and outside of the macula may have a number of relevant applications in the study of pathologic features of central serous chorioretinopathy. PMID- 25552350 TI - A maternal high fat diet has long-lasting effects on skeletal muscle lipid and PLIN protein content in rat offspring at young adulthood. AB - A maternal high fat diet (HFD) can have adverse effects on skeletal muscle development. Skeletal muscle PLIN proteins (PLIN2, 3 and 5) are thought to play critical roles in lipid metabolism, however effects of HFD on PLIN and lipases (HSL, ATGL, CGI-58) in mothers as well as their offspring have yet to be investigated. The primary objective of this study was to determine whether maternal HFD would influence skeletal muscle lipase and PLIN protein content in offspring at weaning (19 d) and young adulthood (3 mo). Female rats (28 d old, n = 9/group) were fed control (CON, AIN93G, 7% soybean oil) or HFD (AIN93G, 20% lard) for 10 weeks prior to mating and throughout pregnancy and lactation. All offspring were weaned to CON [n = 18/group, 1 female and 1 male pup per litter were studied at weaning (19 d) and 3 mo of age]. There was no effect of sex for the main outcomes measured in plantaris, therefore male and female data was combined. Maternal HFD resulted in higher triacylglycerol content in pups at 3 mo (p < 0.05), as well as in the dams (p = 0.015). Maternal HFD resulted in higher PLIN5 content in pups at weaning and 3 mo (p = 0.05). PLIN2 and PLIN5 content decreased at 3 mo versus weaning (p < 0.001). HFD dams had a higher PLIN3 content (p = 0.016). Diet had no effect on ATGL, CGI-58, or HSL content. In conclusion, exposure to a maternal HFD resulted in higher skeletal muscle lipid and PLIN5 content in plantaris of offspring through to young adulthood. PMID- 25552351 TI - Influence of growth hormone receptor (GHR) exon 3 and -202A/C IGFBP-3 genetic polymorphisms on clinical and biochemical features and therapeutic outcome of patients with acromegaly. AB - BACKGROUND: The association of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms with clinical presentation, biochemical measurements and response to therapies in acromegaly have been suggested. OBJECTIVE: To evaluate the presence of these polymorphisms in acromegaly and their influence on clinical and laboratorial characteristics of patients at diagnosis and after treatment in a large cohort of acromegalic patients. PATIENTS AND METHODS: This is a cross-sectional study developed in a single tertiary reference center. Clinical data were obtained from the medical records of 186 acromegalic patients (116 women, age range 21-88 years). GH and IGF1 levels and GHR-exon 3 and -202 A/C IGFBP3 polymorphisms were evaluated in the same hospital. RESULTS: At diagnosis, serum GH concentrations were lower in patients with GHR-d3 genotype than those with GHR-fl, whereas an association of lower IGFBP3 levels with d3 allele was observed only after neurosurgical or medical treatments. However, these associations were not confirmed in posterior statistical analysis. CONCLUSION: Our results suggest that GHR-exon 3 and -202 A/C IGFBP3 polymorphisms did not show any consistent association on clinical and laboratorial features of acromegalic patients even after treatment. PMID- 25552352 TI - Nerve growth factor induces neurite outgrowth of PC12 cells by promoting Gbetagamma-microtubule interaction. AB - BACKGROUND: Assembly and disassembly of microtubules (MTs) is critical for neurite outgrowth and differentiation. Evidence suggests that nerve growth factor (NGF) induces neurite outgrowth from PC12 cells by activating the receptor tyrosine kinase, TrkA. G protein-coupled receptors (GPCRs) as well as heterotrimeric G proteins are also involved in regulating neurite outgrowth. However, the possible connection between these pathways and how they might ultimately converge to regulate the assembly and organization of MTs during neurite outgrowth is not well understood. RESULTS: Here, we report that Gbetagamma, an important component of the GPCR pathway, is critical for NGF induced neuronal differentiation of PC12 cells. We have found that NGF promoted the interaction of Gbetagamma with MTs and stimulated MT assembly. While Gbetagamma-sequestering peptide GRK2i inhibited neurite formation, disrupted MTs, and induced neurite damage, the Gbetagamma activator mSIRK stimulated neurite outgrowth, which indicates the involvement of Gbetagamma in this process. Because we have shown earlier that prenylation and subsequent methylation/demethylation of gamma subunits are required for the Gbetagamma-MTs interaction in vitro, small molecule inhibitors (L-28 and L-23) targeting prenylated methylated protein methyl esterase (PMPMEase) were tested in the current study. We found that these inhibitors disrupted Gbetagamma and MUTau organization and affected cellular morphology and neurite outgrowth. In further support of a role of Gbetagamma-MT interaction in neuronal differentiation, it was observed that overexpression of Gbetagamma in PC12 cells induced neurite outgrowth in the absence of added NGF. Moreover, overexpressed Gbetagamma exhibited a pattern of association with MTs similar to that observed in NGF-differentiated cells. CONCLUSIONS: Altogether, our results demonstrate that betagamma subunit of heterotrimeric G proteins play a critical role in neurite outgrowth and differentiation by interacting with MTs and modulating MT rearrangement. PMID- 25552353 TI - How long does biomedical research take? Studying the time taken between biomedical and health research and its translation into products, policy, and practice. AB - BACKGROUND: The time taken, or 'time lags', between biomedical/health research and its translation into health improvements is receiving growing attention. Reducing time lags should increase rates of return to such research. However, ways to measure time lags are under-developed, with little attention on where time lags arise within overall timelines. The process marker model has been proposed as a better way forward than the current focus on an increasingly complex series of translation 'gaps'. Starting from that model, we aimed to develop better methods to measure and understand time lags and develop ways to identify policy options and produce recommendations for future studies. METHODS: Following reviews of the literature on time lags and of relevant policy documents, we developed a new approach to conduct case studies of time lags. We built on the process marker model, including developing a matrix with a series of overlapping tracks to allow us to present and measure elements within any overall time lag. We identified a reduced number of key markers or calibration points and tested our new approach in seven case studies of research leading to interventions in cardiovascular disease and mental health. Finally, we analysed the data to address our study's key aims. RESULTS: The literature review illustrated the lack of agreement on starting points for measuring time lags. We mapped points from policy documents onto our matrix and thus highlighted key areas of concern, for example around delays before new therapies become widely available. Our seven completed case studies demonstrate we have made considerable progress in developing methods to measure and understand time lags. The matrix of overlapping tracks of activity in the research and implementation processes facilitated analysis of time lags along each track, and at the cross-over points where the next track started. We identified some factors that speed up translation through the actions of companies, researchers, funders, policymakers, and regulators. Recommendations for further work are built on progress made, limitations identified and revised terminology. CONCLUSIONS: Our advances identify complexities, provide a firm basis for further methodological work along and between tracks, and begin to indicate potential ways of reducing lags. PMID- 25552354 TI - Doxorubicin-Mediated Cardiotoxicity: Role of Mitochondrial Connexin 43. AB - Doxorubicin is the highly effective anthracycline, but its clinical use is limited by cardiotoxicity and consequent dysfunction. It has been proposed that the etiology of this is related to mitochondrial dysfunction. Connexin 43 (Cx43), the principal protein building block of cardiac gap junctions and hemichannels, plays an important role in cardioprotection. Recent reports confirmed the presence of Cx43 in the mitochondria as well. In this study, the role of mitochondrial Cx43 was evaluated 3 or 6 h after Doxorubicin administration to the rat heart cell line H9c2. Pharmacological inhibition of Hsp90 demonstrated that the mitochondrial Cx43 conferred cardioprotection by reducing cytosolic and mitochondrial reactive oxygen species production, mitochondrial calcium overload and mitochondrial membrane depolarization and cytochrome c release. In conclusion, our study demonstrates that Cx43 plays an important role in the protection of cardiac cells from Doxorubicin-induced toxicity. PMID- 25552355 TI - What the dead can teach the living: systemic nature of heart failure with preserved ejection fraction. PMID- 25552356 TI - Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. AB - BACKGROUND: Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. METHODS AND RESULTS: We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with >=1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. CONCLUSIONS: In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF. PMID- 25552358 TI - How to repeat a success and control a bad influence. PMID- 25552357 TI - Control of the T follicular helper-germinal center B-cell axis by CD8+ regulatory T cells limits atherosclerosis and tertiary lymphoid organ development. AB - BACKGROUND: The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. METHODS AND RESULTS: Here, we analyzed the contribution of Qa-1-restricted CD8(+) regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8(+) regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. CONCLUSIONS: This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenic and that CD8(+) regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach. PMID- 25552359 TI - Four carbapenem-resistant gram-negative species carrying distinct carbapenemases in a single patient. AB - Carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, and Acinetobacter baumannii were isolated from a single patient, each producing different carbapenemases (NDM-1, KPC-2, IMP, and OXA-23, respectively). The NDM-1-producing E. coli strain was preceded by a clonally related carbapenem susceptible strain a month earlier, suggesting in vivo acquisition of blaNDM-1. PMID- 25552360 TI - Cost-effective pooling of DNA from nasopharyngeal swab samples for large-scale detection of bacteria by real-time PCR. AB - We investigated the potential of pooling DNA from nasopharyngeal specimens to reduce the cost of real-time PCR (RT-PCR) for bacterial detection. Lyophilization is required to reconcentrate DNA. This strategy yields a high specificity (86%) and a high sensitivity (96%). We estimate that compared to individual testing, 37% fewer RT-PCR tests are needed. PMID- 25552361 TI - Isolation and characterization of influenza C viruses in the Philippines and Japan. AB - From November 2009 to December 2013 in the Philippines, 15 influenza C viruses were isolated, using MDCK cells, from specimens obtained from children with severe pneumonia and influenza-like illness (ILI). This is the first report of influenza C virus isolation in the Philippines. In addition, from January 2008 to December 2013, 7 influenza C viruses were isolated from specimens that were obtained from children with acute respiratory illness (ARI) in Sendai city, Japan. Antigenic analysis with monoclonal antibodies to the hemagglutinin esterase (HE) glycoprotein showed that 19 strains (12 from the Philippines and 7 from Japan) were similar to the influenza C virus reference strain C/Sao Paulo/378/82 (SP82). Phylogenetic analysis of the HE gene showed that the strains from the Philippines and Japan formed distinct clusters within an SP82-related lineage. The clusters that included the Philippine and Japanese strains were shown to have diverged from a common ancestor around 1993. In addition, phylogenetic analysis of the internal genes showed that all strains isolated in the Philippines and Japan had emerged through reassortment events. The composition of the internal genes of the Philippine strains was different from that of the Japanese strains, although all strains were classified into an SP82 related lineage by HE gene sequence analysis. These observations suggest that the influenza C viruses analyzed here had emerged through different reassortment events; however, the time and place at which the reassortment events occurred were not determined. PMID- 25552362 TI - Sputum volume predicts sputum mycobacterial load during the first 2 weeks of antituberculosis treatment. AB - Disease severity in patients with pulmonary tuberculosis is associated with mycobacterial sputum load. To ascertain whether reduced sputum production during treatment is a useful clinical sign of improvement, we analyzed the mycobacterial loads of 5,552 sputum samples collected from 439 newly diagnosed sputum smear positive tuberculosis patients who participated in six 14-day studies of antituberculosis treatment. Sputum volumes were categorized as low (<6 ml), medium (6 to 10 ml), or large (>10 ml), and mycobacterial load was measured by the time to positivity in liquid culture and the CFU counts on solid culture. The association of sputum volume with mycobacterial load was estimated with multiple linear regression models adjusted for repeated measures. The predictor variables were sputum volume category, treatment day, specific study , and the interaction of sputum volume category and treatment day. Mycobacterial load was significantly associated only with the day on treatment and sputum volume, which tended to decrease with ongoing treatment. With the volume held constant, each day on treatment decreased the log CFU by 0.082 (P<0.001) and increased the time to positivity (TTP) by 1.04 h (P<0.001). From low to medium and from medium to large sputum volumes, the log CFU/ml increased by 0.265 (P<0.003) and 0.490 (P<0.001), respectively, and the TTP decreased by 1.17 h (P<0.001) and 1.30 h (P<0.001), respectively, for a given day of treatment. The variability of the sputum load measurements increased with the day of treatment and lower sputum volumes. The significant association of sputum volume and mycobacterial load validates decreasing sputum production as a clinical sign of improvement during early antituberculosis treatment. PMID- 25552363 TI - Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2 positive breast cancer. AB - Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p < 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p < 0.0001) and trastuzumab (62 vs. 67 %, p < 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients. PMID- 25552364 TI - Prognostic and predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial. AB - PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. NCIC CTG MA.21 randomized 2,104 patients to doxorubicin, cyclophosphamide, and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin, and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide, and paclitaxel (EC/T). Patients were <=60 years, with node positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffin-embedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Among 1094 cases completing PAM50 intrinsic subtyping, 27 % were classified as luminal A, 23 % luminal B, 18 % HER2E, and 32 % basal-like. CEF and EC/T were superior to AC/T (p = 0.01). Higher continuous ROR was multivariately associated with worse RFS (p = 0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p = 0.002). Compared with luminal A, hazard ratios were luminal B = 1.48 (95 % CI 0.92-2.37); HER2E = 2.68 (95 % CI 1.60-4.48); and basal-like = 1.97 (95 % CI 1.10-3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs. EC/T + CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) was predictive of taxane benefit (EC/T vs. CEF; p = 0.05). Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T, and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF. PMID- 25552365 TI - Clinicopathological characteristics of chinese colorectal cancer patients under 30 years of age: implication in diagnosis and therapy. AB - OBJECTIVES: The incidence of colorectal cancer (CRC) is increasing in younger populations; the characteristics and prognosis of those younger patients are not fully understood. The aim of this retrospective study was to analyze the clinicopathological features of Chinese CRC patients under 30 years of age. METHODS: We reviewed the clinical and pathological features of 83 CRC patients (33 males and 50 females) aged 13-30 years (mean, 26.1 years) selected from consecutive 5,830 patients with primary CRC referred to Shanghai Changzheng Hospital between January 1995 and December 2013. RESULTS: The duration from the onset of symptoms to diagnosis ranged from 3 days to 24.0 months (average 4.6 months). The most common symptom at the time of diagnosis was bloody stool, occurring in 66.3% of the patients. 60.2% patients had tumors located in the rectum and 72.8% of them presented advanced diseases (TNM stage III or IV). More male patients presented as M1 stage than the female patients. Patients with CRC metastasis complained of more fatigue at the time of diagnosis than their counterparts without metastasis (31.0% vs. 5.8%, p = 0.002), but had less pronounced bowel habit change (38.0% vs. 65.4%, p = 0.017). Additionally, there were differences in histologic distributions of the tumors between patients with and without metastasis (p = 0.021). CONCLUSIONS: Compared with older CRC patients, younger CRC patients (<30 yr) have a higher frequency of mucinous adenocarcinomas, more aggressive diseases and poorer prognosis. Identification of clinicopathological characteristics in younger CRC patients would help diagnose and treat the disease in this unique group of CRC patients in the clinic. PMID- 25552367 TI - Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy. AB - Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pBC). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pBC starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 mL blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to >= 40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pCR) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P = 0.08) and 30% (P = 0.02), respectively, with EpCAM/MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAM-positive CTCs at baseline achieved pCR (P = 0.13). EpCAM positive CTCs and CEC counts were not correlated to pCR. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pBC. We found no associations of CTC and CEC counts with pCR to NAC. The clinical relevance of MCAM-positive CTCs deserves further study. PMID- 25552366 TI - Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer. AB - Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance the signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen liganded (MDV3100, bicalutamide, flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors, and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the prostate-specific antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b. PMID- 25552368 TI - A novel therapeutic strategy to rescue the immune effector function of proteolytically inactivated cancer therapeutic antibodies. AB - Primary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity. PMID- 25552369 TI - Histone deacetylase 6 represents a novel drug target in the oncogenic Hedgehog signaling pathway. AB - Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6's impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened- and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma. PMID- 25552370 TI - Tumor Necrosis Factor (TNF) Receptor Superfamily Member 1b on CD8+ T Cells and TNF Receptor Superfamily Member 1a on Non-CD8+ T Cells Contribute Significantly to Upper Genital Tract Pathology Following Chlamydial Infection. AB - BACKGROUND: We demonstrated previously that tumor necrosis factor alpha (TNF alpha)-producing Chlamydia-specific CD8(+) T cells cause oviduct pathological sequelae. METHODS: In the current study, we used wild-type C57BL/6J (WT) mice with a deficiency in genes encoding TNF receptor superfamily member 1a (TNFR1; TNFR1 knockout [KO] mice), TNF receptor superfamily member 1b (TNFR2; TNFR2 KO mice), and both TNFR1 and TNFR2 (TNFR1/2 double KO [DKO] mice) and mix-match adoptive transfers of CD8(+) T cells to study chlamydial pathogenesis. RESULTS: TNFR1 KO, TNFR2 KO, and TNFR1/2 DKO mice displayed comparable clearance of primary or secondary genital Chlamydia muridarum infection but significantly reduced oviduct pathology, compared with WT animals. The Chlamydia-specific total cellular cytokine response in splenic and draining lymph nodes and the antibody response in serum were comparable between the WT and KO animals. However, CD8(+) T cells from TNFR2 KO mice displayed significantly reduced activation (CD11a expression and cytokine production), compared with TNFR1 KO or WT animals. Repletion of TNFR2 KO mice with WT CD8(+) T cells but not with TNFR2 KO CD8(+) T cells and repletion of TNFR1 KO mice with either WT or TNFR1 KO CD8(+) T cells restored oviduct pathology to WT levels in both KO groups. CONCLUSIONS: Collectively, these results demonstrate that TNFR2-bearing CD8(+) T cells and TNFR1-bearing non-CD8(+) T cells contribute significantly to oviduct pathology following genital chlamydial infection. PMID- 25552371 TI - Alveolar Macrophages Isolated Directly From Human Cytomegalovirus (HCMV) Seropositive Individuals Are Sites of HCMV Reactivation In Vivo. AB - Human cytomegalovirus (HCMV) causes significant morbidity in the immunocompromised host. Following primary infection, the virus establishes latent infection in progenitor cells of the myeloid lineage. These cells exhibit limited viral gene transcription and no evidence of de novo virion production. It is well recognized that differentiation of latently infected myeloid progenitor cells to dendritic or macrophage-like cells permits viral reactivation in vitro. This has been used to support the concept that viral reactivation in HCMV carriers routinely occurs from such terminally differentiated myeloid cells in vivo. However, to date this has not been shown for in vivo-differentiated macrophages. This study is the first to demonstrate that alveolar macrophages from HCMV carriers express immediate early lytic genes and produce infectious virus. This supports the view, until now based on in vitro data, that terminally differentiated myeloid cells in vivo are sites of HCMV reactivation and potential centers of viral dissemination in latently infected individuals with no evidence of virus disease or dissemination. PMID- 25552372 TI - The effect of glycogen reduction on cardiorespiratory and metabolic responses during downhill running. AB - PURPOSE: Exercise-induced muscle damage and lowered glycogen are common during heavy training periods, and may prolong recovery. We examined the effects of lowered glycogen on cardiorespiratory, metabolic and perceptual responses to downhill running. METHODS: Twelve men performed two downhill runs (-12 % gradient, 12.1 +/- 1.1 km h(-1)) separated by 6 weeks, under normal (NORM) and reduced glycogen (RED) conditions in a crossover design. For RED, participants performed exhaustive cycling at 60 % [Formula: see text]O2max power (95 +/- 13 min) in the evening, and the next morning completed a downhill run comprising of five stages of 8 min running, with 2 min recovery (1 % gradient, 8 km h(-1)) between each stage. Expired gas, heart rate, rating of perceived exertion (RPE) and blood lactate (bLa) and glucose were measured for each stage. RESULTS: Blood glucose (P < 0.05) and respiratory exchange ratio (P < 0.01) were lower in RED, than NORM, throughout the downhill run. RED demonstrated higher bLa until stage Four (P < 0.05), and RPE for stages Two and Five (P < 0.05).Ventilatory equivalent of carbon dioxide output ([Formula: see text]/[Formula: see text]) was higher for stages One (P < 0.01), Two and Five (P < 0.05), and oxygen uptake ([Formula: see text] E/[Formula: see text]O2) was lower for stages Three and Four (P < 0.05) for RED. CONCLUSIONS: Downhill running with reduced glycogen, elevated fat oxidation and bLa response, and, in part, increased effort perception. The alterations in [Formula: see text] E/[Formula: see text]O2 and bLa may suggest that carbon dioxide removal was somewhat impaired. PMID- 25552383 TI - Congenital rickets due to vitamin D deficiency in the mothers. AB - BACKGROUND & AIMS: We wished to review all published reports of congenital rickets to identify the causes and characteristics. METHODS: 25 cases were identified in 19 published reports in which there was radiological and/or histological evidence of rickets in the first two weeks after birth. Cases of rickets associated with maternal renal failure were excluded as were infants born at less than 32 weeks gestation. RESULTS: There was evidence of maternal deficiency in 24 of these cases. In 16 cases the diagnosis of the rickets led to the identification of symptomatic osteomalacia in the mothers. Of the 12 mothers who had assays for serum 25-hydroxyvitamin D (25OHD) 11 had values less than 10 ng/mL. Presentations in the infants included craniotabes, wide skull sutures, rachitic rosaries, enlargement of the wrists, tetany and convulsions. In two cases rickets had been suspected from antenatal X-rays. In five cases fractures were found at the time of initial presentation. Of the 16 infants with serum calcium assays 15 had values lower than 8.8 mg/dL. Of 13 infants who had serum alkaline phosphatase assays 12 had abnormally high levels. Of the seven infants in whom serum 25OHD was measured before treatment, all had values less than 10 ng/mL. CONCLUSIONS: These reports provide strong support for the view that maternal deficiency leads to overt bone disease from before birth. Maternal deficiency probably also leads to impairment of bone quality in postnatal life. The importance of ensuring adequate vitamin D nutrition in pregnancy is emphasised. PMID- 25552382 TI - Cellular localization and adaptive changes of the cardiac delta opioid receptor system in an experimental model of heart failure in rats. AB - The role of the cardiac opioid system in congestive heart failure (CHF) is not fully understood. Therefore, this project investigated the cellular localization of delta opioid receptors (DOR) in left ventricle (LV) myocardium and adaptive changes in DOR and its endogenous ligand, the precursor peptide proenkephalin (PENK), during CHF. Following IRB approval, DOR localization was determined by radioligand binding using [H(3)]Naltrindole and by double immunofluorescence confocal analysis in the LV of male Wistar rats. Additionally, 28 days following an infrarenal aortocaval fistula (ACF) the extent of CHF and adaptions in left ventricular DOR and PENK expression were examined by hemodynamic measurements, RT PCR, and Western blot. DOR specific membrane binding sites were identified in LV myocardium. DOR were colocalized with L-type Ca(2+)-channels (Cav1.2) as well as with intracellular ryanodine receptors (RyR) of the sarcoplasmatic reticulum. Following ACF severe congestive heart failure developed in all rats and was accompanied by up-regulation of DOR and PENK on mRNA as well as receptor proteins representing consecutive adaptations. These findings might suggest that the cardiac delta opioid system possesses the ability to play a regulatory role in the cardiomyocyte calcium homeostasis, especially in response to heart failure. PMID- 25552384 TI - Pretreatment screening on distant metastases and head and neck cancer patients: Validation of risk factors and influence on survival. AB - BACKGROUND AND PURPOSE: Previously identified high risk factors for development of distant metastases are: three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6cm, low jugular lymph node metastases, locoregional tumor recurrence and second primary tumors. The aims of this study were to validate these specific risk factors and to investigate the impact of time (i.e. during screening or follow-up) of detection of distant metastases on survival. MATERIAL AND METHODS: From a total of 301 HNSCC patients with high risk factors who were scheduled for extensive treatment and underwent pretreatment screening on distant metastases using chest CT and/or whole body PET(-CT) (in some patients combined with whole body MRI), the high risk factors, the development and time point of distant metastases and survival were analyzed. RESULTS: Forty-four percent developed distant metastases. Multivariate analysis revealed that bilateral lymph node metastases is the strongest predictive factor. Locoregional recurrence and second primary tumor were the risk factors associated with the lowest cumulative incidence. However, if the risk factor locoregional recurrence was split into local and regional recurrences, regional recurrence became a high risk factor. The more high risk factors a patient had the lower the 5-year distant metastases free survival was. Patients with distant metastases detected pretreatment has a significant worse survival (corrected for lead time bias) compared to patients with distant metastases diagnosed during follow-up. CONCLUSIONS: The validity of three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6cm, low jugular lymph node metastases and regional recurrence as high risk factors for the development of distant metastases was confirmed. If more high risk factors are present the cumulative incidence of distant metastases increases significantly. The detection of distant metastases by pretreatment screening worsens the overall survival as compared to distant metastases detected during follow-up. PMID- 25552385 TI - Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells. AB - BACKGROUND: Eribulin mesylate (eribulin), a non-taxane microtubule dynamic inhibitor, has been widely used in the treatment of patients with advanced or metastatic breast cancer. The combined antitumor and anticancer stem cell (CSC) activities of eribulin with endocrine therapeutic agents have not yet been examined in breast cancer cells. We herein investigated the combined effects of eribulin and antiestrogens. METHODS: A panel of eight breast cancer cell lines, including five estrogen receptor (ER)-positive and three ER-negative cell lines, was used. These cells were treated with eribulin and/or the antiestrogen, 4 hydroxytamoxifen or fulvestrant. Their growth inhibitory activities and effects on cell cycle progression, apoptosis, and the CSC population were investigated. CSCs were detected using the CD44/CD24/EpCAM, Aldefluor, and mammosphere assays. RESULTS: The 50% growth inhibitory concentrations of eribulin were 0.38-2.64 nM for the eight cell lines tested. Eribulin exhibited significant antitumor activity under estrogen-supplemented conditions in ER-positive breast cancer cells. The combined antitumor activity of eribulin with an antiestrogen was evaluated using the combination index. The combination index was 0.43-1.46 for ER positive cell lines. The additive antitumor effect of eribulin with 4-OHT was only significant in MCF-7 cells. Eribulin induced the accumulation of G2/M and apoptosis, while antiestrogens induced the retardation of G1-S cell cycle and apoptosis, respectively. Estrogen markedly increased the proportion of CSCs, whereas antiestrogens inhibited increases in ER-positive cell lines. Moreover, eribulin decreased the proportion of CSCs in either ER-positive or ER-negative cell lines. The combined treatment of eribulin with an antiestrogen did not additively decrease the proportion of CSCs in ER-positive cell lines. DISCUSSION: The results of the present study demonstrated that eribulin had potent antitumor effects on estrogen-stimulated ER-positive breast cancer cells and the combined treatment of eribulin with an antiestrogen resulted in a weakly additive antitumor effect. We herein suggested for the first time that eribulin exhibited anti-CSC effects on either ER-positive or ER-negative breast cancer cells. PMID- 25552386 TI - Advances in cardiac magnetic resonance imaging of congenital heart disease. AB - Due to advances in cardiac surgery, survival of patients with congenital heart disease has increased considerably during the past decades. Many of these patients require repeated cardiovascular magnetic resonance imaging to assess cardiac anatomy and function. In the past decade, technological advances have enabled faster and more robust cardiovascular magnetic resonance with improved image quality and spatial as well as temporal resolution. This review aims to provide an overview of advances in cardiovascular magnetic resonance hardware and acquisition techniques relevant to both pediatric and adult patients with congenital heart disease and discusses the techniques used to assess function, anatomy, flow and tissue characterization. PMID- 25552387 TI - Cardiac magnetic resonance imaging in children. AB - MRI is an important additional tool in the diagnostic work-up of children with congenital heart disease. This review aims to summarise the role MRI has in this patient population. Echocardiography remains the main diagnostic tool in congenital heart disease. In specific situations, MRI is used for anatomical imaging of congenital heart disease. This includes detailed assessment of intracardiac anatomy with 2-D and 3-D sequences. MRI is particularly useful for assessment of retrosternal structures in the heart and for imaging large vessel anatomy. Functional assessment includes assessment of ventricular function using 2-D cine techniques. Of particular interest in congenital heart disease is assessment of right and single ventricular function. Two-dimensional and newer 3 D techniques to quantify flow in these patients are or will soon become an integral part of quantification of shunt size, valve function and complex flow patterns in large vessels. More advanced uses of MRI include imaging of cardiovascular function during stress and tissue characterisation of the myocardium. Techniques used for this purpose need further validation before they can become part of the daily routine of MRI assessment of congenital heart disease. PMID- 25552388 TI - What the cardiothoracic surgeon wants to know from the radiologist: from X-ray reporting to imaging consultancy and Heart Team membership. AB - In the early days of cardiac surgery, the pretreatment multidisciplinary discussion involved a presentation of the case history and diagnostic imaging by the clinical cardiologist. At this time, most, if not all, cardiac imaging techniques were in the hands of the cardiologist. If the radiologist made a report, this was done relatively late in the clinical process and only concerned the perioperative radiographs. In recent years, multidisciplinary decision-making in the context of a Heart Team has gained an increasingly important role in the process of decision-making with regard to the available therapy options in individual patients. Nevertheless, the concept of the Heart Team is still evolving. The minimal requirements for the Heart Team include the presence of the attending cardiologist, an interventional cardiologist and a cardiac surgeon. Those members of the Heart Team should be aware of the local possibilities, should correctly make conclusions about the available data and should put this information into the clinical context and preference of the patient. In addition, in areas where expertise in cardiac imaging such as CT and MRI is relevant, this would explicitly require expertise of the Heart Team in these specific areas, most often by involving a radiologist, to provide the optimal joint treatment strategy recommendation. PMID- 25552389 TI - Measurements in radiology: the need for high reproducibility. PMID- 25552390 TI - Why measure tumours? AB - This article questions the scientific justification of ingrained radiologic practices exemplified by size measurements of childhood solid tumours. This is approached by a critical review of staging systems from a selection of paediatric oncological treatment protocols. Local staging remains size-dependent for some tumour types. The consequent stage assignment can significantly influence treatment intensity. Still, the protocols tend not to give precise guidance on how to perform scans and standardise measurements. Also, they do not estimate or account for the inevitable variability in measurements. Counts and measurements of lung nodules are, within some tumour groups, used for diagnosis of metastatic disease. There is, however, no evidence that nodule size is a useful discriminator of benign and malignant lung nodules. The efficacy of imaging depends chiefly on observations being precise, accurate and valid for the desired diagnostic purpose. Because measurements without estimates of their errors are meaningless, studies of variability dependent on tumour shape and location, imaging device and observer need to be encouraged. Reproducible observations make good candidates for staging parameters if they have prognostic validity and at the same time show little covariation with (thereby adding new information to) the existing staging system. The lack of scientific rigour has made the validity of size measurement very difficult to assess. Action is needed, the most important being radiologists' active contribution in development of oncological staging systems, attention to standardisation, knowledge about errors in measurement and protection against undue influence of such errors in the staging of the individual child. PMID- 25552392 TI - Blunt renal trauma in children with pre-existing renal abnormalities. AB - The kidneys are the most commonly injured genitourinary organ in children following blunt abdominal trauma. Though the retroperitoneal location affords the kidneys some protection from the forces experienced in blunt abdominal trauma, the kidneys are at greater risk of injury when a disease process exposes them from their normal shielded location. In such cases, the injuries may appear to be disproportionate in relation to the severity of the trauma history, confusing the imaging findings. Recognition of both the underlying disease process as well as the manifestations of acute trauma is important; therefore, we present a pictorial essay of traumatized kidneys in children with pre-existing renal abnormalities. PMID- 25552394 TI - Medial triceps brachii free flap in reconstructive surgery: a prospective study in eight patients. AB - INTRODUCTION: In this study, we present a prospective series of medial triceps free flaps for ankle and foot complex defects coverage and discuss its numerous advantages. MATERIALS AND METHODS: Between January 2011 and December 2012, eight patients, two women and six men underwent medial triceps brachii (MTB) free flap procedure to cover defects localized at the ankle and foot in our department. Patient mean age was 37.3 +/- 15.2 years at the time of surgery (range of 13-53 years). Mean defect size to be covered was 21.8 +/- 9.9 cm(2). The bone was exposed at the level of the calcaneum in six cases, at the level of the forefoot in one case, and at the level of the lateral malleolus in one case. Special attention was accorded to intra-operative findings. Flap survival and complications on both the donor and recipient site were prospectively evaluated. RESULTS: Mean MTB flap raising time was 51.3 +/- 6.0 min. All the flaps survived and there was no partial flap necrosis. A skin graft was performed after a mean time of 11.8 +/- 2.1 days post-operative. The mean follow-up was 18.1 +/- 3.8 months. Complications at the donor site level included one hematoma and a case of hypertrophic scar. Complete healing of both the donor and recipient sites was achieved in all cases. CONCLUSIONS: MTB free flap appears to be a useful option for covering small to medium defects in lower limb extremities. Due to the constant anatomy of the MTB nerve, we suggest that the flap could also be used as an innervated free flap for small or medium muscular reanimation such as sequelae of forearm and hand muscle impairment, or facial palsy. PMID- 25552395 TI - Lessons learned from treating patients with unstable multifragmentary fractures of the proximal humerus by minimal invasive plate osteosynthesis. AB - INTRODUCTION: The authors present clinical and radiographic results of minimal invasive plate osteosynthesis (MIPO) for three- or four-part fractures of the proximal humerus. PATIENTS AND METHODS: Twenty-six patients with three- or four part proximal humeral fractures treated with the MIPO technique through the deltoid splitting approach were clinically and radiographically evaluated at a minimum of 12 months with an average of 20.1 months. The valgus-impacted type of three-part fracture was excluded to verify the results of the MIPO with unstable multifragmentary fractures of the proximal humerus. RESULTS: Twenty female patients and six male patients were included (mean age 67 years; range 18-90 years). No cases of nonunion were seen. The mean forward flexion, abduction, and external rotation were 145 degrees , 119 degrees , and 48 degrees , respectively. The mean visual analog scale (VAS) for pain was 1.47 points. The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 14.5 points, and the mean UCLA score was 29.6 points. The mean neck-shaft angle was 134 degrees . Twenty-three patients had adequate medial support, and three patients did not have adequate medial support on initial postoperative radiographs. Five shoulders (19 %) developed complicated results. Two cases of proximal malposition of the plate (7.7 %) and two intra-articular screw penetrations (7.7 %) were observed. One case of osteonecrosis of the humeral head was identified at the final follow up (3.8 %). CONCLUSION: The MIPO technique provides reliable radiologic and functional outcomes for three- and four-part proximal humeral fractures. Our results might support the use of MIPO for treating unstable multi fragmentary fractures of proximal humerus such as three- or four-part fractures to decrease osteonecrosis of humeral head. PMID- 25552396 TI - Comparison of novel intramedullary nailing with mini-invasive plating in surgical fixation of displaced midshaft clavicle fractures. AB - INTRODUCTION: This prospective randomized pilot study sought to determine whether fixation with Sonoma CRx intramedullary pin is a comparable alternative to minimally invasive plating fixation in patients with displaced clavicle fractures. MATERIALS AND METHODS: A total of 45 consecutive patients (Robinson class B1 or B2) were randomly allocated into two groups; intramedullary pin (IMP) group (n = 24, mean age; 33.17 +/- 8.60 years, 14 males 58.3 %) received Sonoma CRx Collarbone pin (Sonoma, USA) whereas locking midshaft superior plating (MIPPO) group (n = 21, 32.38 +/- 8.41 years, 12 males) patients received minimally invasive locking midshaft superior plating (Acumed, USA). Patients were followed up with a mean time of 11.82 +/- 4.22 and 14.45 +/- 6.43 months, respectively. Functional status, as the primary outcome measure, was assessed using quick disability of the arm, shoulder and hand (DASH) scores. RESULTS: Mean time of operation and mean time of fluoroscopy were significantly shorter in the IMP group than those in MIPPO group (p < 0.001 and p = 0.03, respectively). Time of hospital stay was significantly shorter in IMP group (p < 0.001). Complications were rare in the early postoperative period. Time until bony union was significantly shorter in IMP group. Mean quick DASH scores were not significantly different between two groups. Implant failure occurred in one patient from each group. Cosmetic dissatisfaction was more common in MIPPO group. CONCLUSION: Given the shorter operative times and better cosmetic appearance, Sonoma CRx intramedullary pin may be an alternative to minimally invasive plating. Further safety studies are warranted. PMID- 25552397 TI - L-Leucine and NO-mediated cardiovascular function. AB - Reduced availability of nitric oxide (NO) in the vasculature is a major factor contributing to the impaired action of insulin on blood flow and, therefore, insulin resistance in obese and diabetic subjects. Available evidence shows that vascular insulin resistance plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Interestingly, increased concentrations of L-leucine in the plasma occur in obese humans and other animals with vascular dysfunction. Among branched-chain amino acids, L-leucine is unique in inhibiting NO synthesis from L-arginine in endothelial cells and may modulate cardiovascular homeostasis in insulin resistance. Results of recent studies indicate that L-leucine is an activator of glutamine:fructose-6-phosphate aminotransferase (GFAT), which is the first and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, L-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells. We propose that reducing circulating levels of L-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects. Such means may include dietary supplementation with either alpha-ketoglutarate to enhance the catabolism of L leucine in the small intestine and other tissues or with N-ethyl-L-glutamine to inhibit GFAT activity in endothelial cells. Preventing leucine-induced activation of GFAT by nutritional supplements or pharmaceutical drugs may contribute to improved cardiovascular function by enhancing vascular NO synthesis. PMID- 25552399 TI - Image-Guided Cryoablation of the Spine in a Swine Model: Clinical, Radiological, and Pathological Findings with Light and Electron Microscopy. AB - PURPOSE: This study was designed to present the feasibility of an in vivo image guided percutaneous cryoablation of the porcine vertebral body. METHODS: The institutional animal care committee approved this study. Cone-beam computed tomography (CBCT)-guided vertebral cryoablations (n = 22) were performed in eight pigs with short, 2-min, single or double-freezing protocols. Protective measures to nerves included dioxide carbon (CO2) epidural injections and spinal canal temperature monitoring. Clinical, radiological, and pathological data with light (n = 20) or transmission electron (n = 2) microscopic analyses were evaluated after 6 days of clinical follow-up and euthanasia. RESULTS: CBCT/fluoroscopic guided transpedicular vertebral body cryoprobe positioning and CO2 epidural injection were successful in all procedures. No major complications were observed in seven animals (87.5 %, n = 8). A minor complication was observed in one pig (12.5 %, n = 1). Logistic regression model analysis showed the cryoprobe-spinal canal (Cp-Sc) distance as the most efficient parameter to categorize spinal canal temperatures lower than 19 degrees C (p < 0.004), with a significant Pearson's correlation test (p < 0.041) between the Cp-Sc distance and the lowest spinal canal temperatures. Ablation zones encompassed pedicles and the posterior wall of the vertebral bodies with an inflammatory rim, although no inflammatory infiltrate was depicted in the surrounding neural structures at light microscopy. Ultrastructural analyses evidenced myelin sheath disruption in some large nerve fibers, although neurological deficits were not observed. CONCLUSIONS: CBCT guided vertebral cryoablation of the porcine spine is feasible under a combination of a short freezing protocol and protective measures to the surrounding nerves. Ultrastructural analyses may be helpful assess the early modifications of the nerve fibers. PMID- 25552398 TI - In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci. AB - Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structural variation in mammary ductal development, and determined if these QTL correlated with genomic intervals conferring BrCa susceptibility in humans. For about half of the traits, developmental variation among the complete set of strains in this study was greater (P < 0.05) than that of previously studied strains, or strains in current common use for mammary gland biology. Correlations were also detected with previously reported variation in mammary tumor latency and metastasis. In-silico genome-wide association identified 20 mammary development QTL (Mdq). Of these, five were syntenic with previously reported human BrCa loci. The most significant (P = 1 * 10(-11)) association of the study was on MMU6 and contained the genes Plxna4, Plxna4os1, and Chchd3. On MMU5, a QTL was detected (P = 8 * 10(-7)) that was syntenic to a human BrCa locus on h12q24.5 containing the genes Tbx3 and Tbx5. Intersection of linked SNP (r(2) > 0.8) with genomic and epigenomic features, and intersection of candidate genes with gene expression and survival data from human BrCa highlighted several for further study. These results support the conclusion that mammary tumorigenesis and normal ductal development are influenced by common genetic factors and that further studies of genetically diverse mice can improve our understanding of BrCa in humans. PMID- 25552400 TI - Pharmacokinetics of neamine in rats and anti-cervical cancer activity in vitro and in vivo. AB - OBJECTIVE: To study the pharmacokinetics of neamine in rats and to evaluate its anti-cervical cancer activity. METHODS: The plasma level of neamine was determined by HPLC-ELSD. Pharmacokinetic parameters were calculated using DAS 2.0 software. Tissue microarray analysis was conducted to examine angiogenin (ANG) expression in normal and cancerous cervical tissues and to determine its correlation with clinical and pathologic presentations of cervical cancers. The anti-cervical cancer activity of neamine was assessed both in vitro and in vivo. RESULTS: After intravenous (i.v.) administration of 15, 30, and 60 mg kg(-1) neamine, the pharmacokinetic parameters were as follows: AUC(0-t), 9,398.0 +/- 653.4, 19,235.2 +/- 2,939.0, and 35,437.7 +/- 3,772.2 mg L(-1) min; C max, 170.8 +/- 13.1, 353.3 +/- 15.8, and 464.0 +/- 33.1 mg L(-1); T 1/2, 34.9 +/- 4.1, 46.8 +/- 5.1, and 58.0 +/- 12.5 min, respectively. The bioavailability of neamine administered through intramuscular, subcutaneous, intraperitoneal and intragastric route was 14.0 +/- 3.0, 8.4 +/- 0.6, 6.5 +/- 3.3, and 3.1 +/- 0.2 %, respectively. Up-regulated ANG expression and increased nuclear translocation were observed in cervical cancers as compared to normal cervical tissues. Moreover, upregulation of ANG was positively correlated with primary tumor invasion. Neamine inhibited ANG-induced HUVEC and HeLa cell proliferation as well as nuclear translocation of ANG. Consistently, neamine inhibited both the establishment and progression of xenograft human cervical cancers in athymic mice. CONCLUSIONS: The bioavailability of neamine administered through extravascular routes was low. The half-life of neamine through i.v. administration was short. This suggests that a higher dosing frequency in order to maintain a therapeutic effect. Neamine holds potential against cervical cancer. The mechanisms of neamine inhibition are through blocking nuclear translocation of ANG thereby inhibiting both angiogenesis and cancer cell proliferation. PMID- 25552401 TI - Phase I/II study of gefitinib (Iressa((r))) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. AB - PURPOSE: Vorinostat has been shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated non-small cell lung cancer (NSCLC). METHODS: A 3 + 3 dose-escalation design was used to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Three dose levels were tested: 250 mg/day gefitinib on days 1-28 and 200, 300 or 400 mg/day vorinostat on days 1-7, and 15-21 out of every 28 days. The primary endpoint was median progression-free survival (PFS). RESULTS: Fifty-two patients were enrolled and treated (43 in phase II). The median age was 59 years, 28 patients were male, 44 had adenocarcinoma, 29 had never smoked, and 36 had undergone one prior treatment. Twenty-two patients exhibited sensitive EGFR mutations. Planned dose escalation was completed without reaching the MTD. The RP2D was 250 mg gefitinib and 400 mg vorinostat. In 43 assessable patients in phase II, the median PFS was 3.2 months; the overall survival (OS) was 19.0 months. There were 16 partial responses and six cases of stable disease. In EGFR mutant NSCLC, response rate was 77 %, median PFS was 9.1 months, and median OS was 24.1 months. The most common adverse events were anorexia and diarrhea. CONCLUSIONS: Treatment with 250 mg gefitinib daily with biweekly 400 mg/day vorinostat was feasible and well tolerated. In an unselected patient population, this combination dose did not improve PFS. However, this combination showed a potential for improving efficacy of gefitinib in EGFR-mutant NSCLC (NCT01027676). PMID- 25552402 TI - The effect of food on the high clearance drug asenapine after sublingual administration to healthy male volunteers. AB - PURPOSE: To determine the effects of food on the pharmacokinetics of sublingual asenapine. METHODS: Healthy male volunteers (n=26, age 19-53 years) randomly received a single sublingual dose of asenapine 5 mg after >= 10 h fasting (Treatment A, reference), after a high-fat meal (Treatment B) and after >= 10 h fasting with a high-fat meal at 4 h post-dose (Treatment C). Blood samples were drawn over 72 h to measure asenapine plasma concentrations. Effects of food intake on asenapine pharmacokinetics were assessed using bioequivalence criteria and evaluated using a compartmental modelling analysis. RESULTS: Compared with the reference, mean asenapine exposure (AUC0-last and AUC0-infinity) was approximately 20 % lower after intake of a high-fat meal prior to dosing, whereas Cmax decreased by only about 10 %. When a high-fat meal was taken 4 h post-dose in the fasting state, asenapine concentrations were similar to the reference during the first 4 h post-dose. After the meal intake, asenapine concentrations decreased quickly for several hours. Compartmental modelling indicated that a transient 2.5-fold increase in asenapine clearance after eating could explain the asenapine concentration-time profiles for both food regimens. CONCLUSIONS: To our knowledge, this is the first study investigating the effect of food upon the sublingual administration of a drug. A high-fat meal taken before or 4 h post dose of sublingual asenapine indirectly caused a transient increase in liver blood flow that resulted in a temporal increase in asenapine clearance. As the effects on asenapine exposure were small and not clinically relevant, no additional restrictions are required for the timing of food intake in relation to asenapine dosing. PMID- 25552404 TI - Isolated popliteus tendon injury does not lead to abnormal laxity in posterior stabilised total knee arthroplasty. AB - PURPOSE: The popliteus tendon is crucial to postero-lateral stability and prone to iatrogenic injury intra-operatively. Its role in the stability of the replaced knee remains contentious. The aim of this study was to use computer navigation to quantify the effect of popliteus sectioning on the 'envelope of laxity' (EoL) offered by a posterior-stabilised (PS) total knee arthroplasty (TKA) and compare with that of the native knee. METHODS: Loaded cadaveric legs were mounted on a purpose built rig. EoL was measured in 3 degrees of freedom using computer navigation. Knees were subjectively stressed in varus/valgus, internal/external rotation and anterior draw. This was performed preoperatively, during TKA and after sectioning of the popliteus tendon. Real-time data were recorded at 0 degrees , 30 degrees , 60 degrees and 90 degrees of flexion as the operating surgeon stressed the knee in 3 degrees of freedom to its subjective endpoint. Mixed-effect modelling was used to quantify the effects of intervention on degree of laxity. RESULTS: In all conditions, there was an increase in laxity with knee flexion. Insertion of a PS TKA resulted in increased constraint, particularly in rotation. Sectioning of the popliteus did not result in a significant increase in knee laxity to 90o of knee flexion. However, at deeper flexion angles, tendon sectioning overcame the constraints of the implant resulting in a significant increase in rotatory and varus/valgus laxity towards the native condition. CONCLUSION: These findings support the view that certain current designs of PS knee replacement can constrain the knee in flexion in the absence of postero lateral deficiency. For this implant, isolated sectioning of the popliteus tendon did not substantially generate abnormal knee laxity. PMID- 25552403 TI - N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction. AB - PURPOSE: N(1)-methylnicotinamide (NMN) was proposed as an in vivo probe for drug interactions involving renal cation transporters, which, for example, transport the oral antidiabetic drug metformin, based on a study with the inhibitor pyrimethamine. The role of NMN for predicting other interactions with involvement of renal cation transporters (organic cation transporter 2, OCT2; multidrug and toxin extrusion proteins 1 and 2-K, MATE1 and MATE2-K) is unclear. METHODS: We determined inhibition of metformin or NMN transport by trimethoprim using cell lines expressing OCT2, MATE1, or MATE2-K. Moreover, a randomized, open-label, two phase crossover study was performed in 12 healthy volunteers. In each phase, 850 mg metformin hydrochloride was administered p.o. in the evening of day 4 and in the morning of day 5. In phase B, 200 mg trimethoprim was administered additionally p.o. twice daily for 5 days. Metformin pharmacokinetics and effects (measured by OGTT) and NMN pharmacokinetics were determined. RESULTS: Trimethoprim inhibited metformin transport with K i values of 27.2, 6.3, and 28.9 MUM and NMN transport with IC50 values of 133.9, 29.1, and 0.61 MUM for OCT2, MATE1, and MATE2-K, respectively. In the clinical study, trimethoprim increased metformin area under the plasma concentration-time curve (AUC) by 29.5 % and decreased metformin and NMN renal clearances by 26.4 and 19.9 %, respectively (p <= 0.01). Moreover, decreases of NMN and metformin renal clearances due to trimethoprim correlated significantly (r S=0.727, p=0.010). CONCLUSIONS: These data on the metformin-trimethoprim interaction support the potential utility of N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters. PMID- 25552405 TI - Does a non-stemmed constrained condylar prosthesis predispose to early failure of primary total knee arthroplasty? AB - PURPOSE: The use of unlinked constrained condylar components (CCK) has been extended to primary total knee arthroplasty (TKA); however, there is limited literature on its outcomes. The purpose of this retrospective cohort study was to assess clinical outcomes of one particular design of primary, non-stemmed, unlinked constrained TKA and to compare them with a control group of PS-TKA utilizing the same implant design. METHODS: The clinical and radiographic outcomes of 486-cemented, non-stemmed, primary TKA's performed by two surgeons at one institution using similar surgical algorithm, technique and prosthetic design were retrospectively reviewed. Primary TKA components were used in all knees; the only difference between groups was the type of polyethylene inserts used (CCK vs PS). Pre-operative deformity, knee society scores (KSS), range-of-motion (ROM), radiographic data and revision rates were compared. RESULTS: Both groups had comparable demographics, pre-operative coronal plane alignment, ROM and KSS. At a mean follow-up of 3.5 years, no difference was found in ROM, KSS, radiographic outcomes and revision rates. CONCLUSIONS: Cemented, primary, non-stemmed CCK-TKA offered comparable clinico-radiographic results to PS-TKA at short-term follow up. Use of a semi-constrained insert without additional stems did not predispose to failure due to aseptic loosening with this implant design. Moreover, the rate of revision due to instability was lowered. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 25552407 TI - Introduction: don't forget the environment of our patients. AB - The Views and Reviews section of this issue deals with environmental consequences for gametes, embryos, the fetus, newborns, and childhood development. PMID- 25552406 TI - Individual valgus correction angle improves accuracy of postoperative limb alignment restoration after total knee arthroplasty. AB - PURPOSE: The purpose of the current study was to compare and investigate the effect of fixed and individual valgus correction angle (VCA) on postoperative alignment restoration. It is hypothesized that individual VCA would be more accurate than fixed VCA in postoperative limb alignment restoration. METHODS: Four hundred and fifty-two patients with 546 consecutive uncomplicated primary total knee arthroplasties performed by a single surgeon, with 302 knees that had individual VCA (group A) and 244 knees that had fixed 5 degrees VCA (group B), were enroled in this study. Preoperative and postoperative full-length standing hip-to-ankle radiographs were used to assess limb alignment. Postoperative hip knee-ankle angle (theta), femoral component angle (alpha) and tibial component angle (beta) were measured and compared between the two groups. RESULTS: Mean postoperative theta angle and alpha angle were 178.9 degrees (SD 1.3 degrees ) and 89.1 degrees (SD 1.1 degrees ) in the group A, whereas they were 177.8 degrees (SD 1.9 degrees ) and 87.9 degrees (SD 1.5 degrees ) in the group B. There were significant differences in both parameters between the two groups (p = 0.021 and 0.016, respectively). Mean postoperative beta was 89.8 degrees (SD 1.2 degrees ) in the group A and 89.7 degrees (SD 1.3 degrees ) in the group B, and no significant difference was detected. There were 114 (37.7 %), 221 (73.2 %) and 265 (87.7 %) knees that had restoration of mechanical axis to +/-1 degrees , +/-2 degrees , +/-3 degrees of neutral, respectively, and 37 (12.3 %) outliers (>+/-3 degrees ) in the group A, whereas there were 48 (19.7 %), 122 (50.0 %) and 170 (69.7 %) knees that had restoration of mechanical axis to +/-1 degrees , +/-2 degrees , +/-3 degrees of neutral, respectively, and 74 (30.3 %) outliers in the group B. Group A had a higher percentage of restoration of limb alignment and fewer outliers than those in the group B, and this difference was statistically significant (p < 0.001). CONCLUSIONS: The results from the present study demonstrated that individual VCA for distal femoral resection could enhance the accuracy of postoperative limb alignment restoration compared with fixed VCA. For clinical relevance, individual VCA should be recommended for routine use in all patients in order to achieve the expected postoperative neutral limb alignment and reduce the risk of postoperative malalignment due to the planning error of a fixed VCA. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 25552409 TI - Do some addictions interfere with fertility? AB - Management of infertile couples should focus on the effects of their professional environment and quality of life, such as stress, smoking, alcohol, weight, diet, and the use of electronic devices. It should also focus on reducing these negative factors and improving the couples' quality of life in conjunction with assisted reproduction treatments. The challenge for human reproduction now, and in the decades to come, is to introduce the concept of "ecofertility" in our practices. Early education and prevention are essential to preserve fertility. PMID- 25552408 TI - Are semen parameters related to birth weight? AB - Several experimental models suggest a link between maternal nutrition during gestation and reproductive function in offspring, but the impact of birth weight on male fertility in adulthood in humans is poorly documented. To study whether birth weight is associated with unexplained male subfertility later in life, we evaluated the relationship between birth weight and sperm parameters in adulthood in white subfertile men, partners of couples with primary idiopathic subfertility, and fertile men recruited within the ALIFERT (Diet and Its Relationship with Couple Infertility) study. Total sperm count, progressive motility, and sperm DNA fragmentation were analyzed in sperm, and metabolic assays were performed on blood. Birth weight was associated with sperm DNA fragmentation and inversely correlated with total sperm count, underlining the importance of the in utero environment for male reproductive function. CLINICAL TRIAL REGISTRATION NUMBER: NCT01093378. PMID- 25552410 TI - New media and how to make a quantum leap. PMID- 25552411 TI - Surfing the waves of change in reproductive medicine: past, present and future. A presentation of the 2014 ASRM Strategic Plan. AB - A presentation at the Opening Ceremony of the ASRM Seventieth Annual Meeting reviews advances in reproductive medicine and presents an overview of the 2014 Strategic Plan: "Global Impact Through Dynamic Engagement." PMID- 25552412 TI - Calcium infusion for the prevention of ovarian hyperstimulation syndrome: a double-blind randomized controlled trial. AB - OBJECTIVE: To evaluate the role of calcium infusion as a preventive strategy of ovarian hyperstimulation syndrome (OHSS) in women at high risk in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment cycles. DESIGN: Double-blinded randomized controlled trial. SETTING: University hospital department of obstetrics and gynecology and private IVF center. PATIENT(S): Two hundred women at risk to develop OHSS undergoing IVF/ICSI treatment cycle. INTERVENTION(S): The intervention group (group 1; n = 100) received intravenous infusion of 10 mL 10% calcium gluconate in 100 mL 0.9% saline solution on the day of ovum pick-up (OPU) and days 1, 2, and 3 after, and the placebo group (group 2; n = 100) received 100 mL 0.9% saline solution on the day of OPU and days 1, 2, and 3 after. MAIN OUTCOME MEASURE(S): Incidence of OHSS. RESULT(S): OHSS incidence was significantly higher in the placebo group (group 2) than in the calcium infusion group (group 1): 23 (23%) vs. 7 (7%); moderate OHSS was significantly higher in group 2 than in group 1: 8 (8%) vs. 1 (1%); and severe OHSS was significantly higher in group 2 than in group 1: 4 (4%) vs. 0. CONCLUSION(S): Intravenous calcium infusion effectively reduced the incidence of OHSS development without reduction in the pregnancy rate. CLINICAL TRIAL REGISTRATION NUMBER: NCT01427335. PMID- 25552413 TI - A robust assay to measure DNA topology-dependent protein binding affinity. AB - DNA structure and topology pervasively influence aspects of DNA metabolism including replication, transcription and segregation. However, the effects of DNA topology on DNA-protein interactions have not been systematically explored due to limitations of standard affinity assays. We developed a method to measure protein binding affinity dependence on the topology (topological linking number) of supercoiled DNA. A defined range of DNA topoisomers at equilibrium with a DNA binding protein is separated into free and protein-bound DNA populations using standard nitrocellulose filter binding techniques. Electrophoretic separation and quantification of bound and free topoisomers combined with a simple normalization procedure provide the relative affinity of the protein for the DNA as a function of linking number. Employing this assay we measured topology-dependent DNA binding of a helicase, a type IB topoisomerase, a type IIA topoisomerase, a non specific mitochondrial DNA binding protein and a type II restriction endonuclease. Most of the proteins preferentially bind negatively supercoiled DNA but the details of the topology-dependent affinity differ among proteins in ways that expose differences in their interactions with DNA. The topology-dependent binding assay provides a robust and easily implemented method to probe topological influences on DNA-protein interactions for a wide range of DNA binding proteins. PMID- 25552415 TI - Genome engineering using a synthetic gene circuit in Bacillus subtilis. AB - Genome engineering without leaving foreign DNA behind requires an efficient counter-selectable marker system. Here, we developed a genome engineering method in Bacillus subtilis using a synthetic gene circuit as a counter-selectable marker system. The system contained two repressible promoters (B. subtilis xylA (Pxyl) and spac (Pspac)) and two repressor genes (lacI and xylR). Pxyl-lacI was integrated into the B. subtilis genome with a target gene containing a desired mutation. The xylR and Pspac-chloramphenicol resistant genes (cat) were located on a helper plasmid. In the presence of xylose, repression of XylR by xylose induced LacI expression, the LacIs repressed the Pspac promoter and the cells become chloramphenicol sensitive. Thus, to survive in the presence of chloramphenicol, the cell must delete Pxyl-lacI by recombination between the wild type and mutated target genes. The recombination leads to mutation of the target gene. The remaining helper plasmid was removed easily under the chloramphenicol absent condition. In this study, we showed base insertion, deletion and point mutation of the B. subtilis genome without leaving any foreign DNA behind. Additionally, we successfully deleted a 2-kb gene (amyE) and a 38-kb operon (ppsABCDE). This method will be useful to construct designer Bacillus strains for various industrial applications. PMID- 25552414 TI - DNA polymerase beta deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. AB - We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase beta. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polbeta(+/-) mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations. PMID- 25552416 TI - A modular system of DNA enhancer elements mediates tissue-specific activation of transcription by high dietary zinc in C. elegans. AB - Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription. PMID- 25552417 TI - SUMO ligase PIAS1 functions as a target gene selective androgen receptor coregulator on prostate cancer cell chromatin. AB - Androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in the development and growth of prostate carcinoma. PIAS1 is an AR- and SUMO-interacting protein and a putative transcriptional coregulator overexpressed in prostate cancer. To study the importance of PIAS1 for the androgen-regulated transcriptome of VCaP prostate cancer cells, we silenced its expression by RNAi. Transcriptome analyses revealed that a subset of the AR regulated genes is significantly influenced, either activated or repressed, by PIAS1 depletion. Interestingly, PIAS1 depletion also exposed a new set of genes to androgen regulation, suggesting that PIAS1 can mask distinct genomic loci from AR access. In keeping with gene expression data, silencing of PIAS1 attenuated VCaP cell proliferation. ChIP-seq analyses showed that PIAS1 interacts with AR at chromatin sites harboring also SUMO2/3 and surrounded by H3K4me2; androgen exposure increased the number of PIAS1-occupying sites, resulting in nearly complete overlap with AR chromatin binding events. PIAS1 interacted also with the pioneer factor FOXA1. Of note, PIAS1 depletion affected AR chromatin occupancy at binding sites enriched for HOXD13 and GATA motifs. Taken together, PIAS1 is a genuine chromatin-bound AR coregulator that functions in a target gene selective fashion to regulate prostate cancer cell growth. PMID- 25552418 TI - Trends in diabetes incidence: the Framingham Heart Study. AB - OBJECTIVE: Obesity and type 2 diabetes continue to increase in prevalence in the U.S. Whether diabetes incidence continues to increase in recent times is less well documented. We examined trends in diabetes incidence over the previous four decades. RESEARCH DESIGN AND METHODS: Framingham Heart Study participants ages 40 55 years and free of diabetes at baseline (n = 4,795; mean age 45.3 years; 51.6% women) were followed for the development of diabetes in the 1970s, 1980s, 1990s, and 2000s. Diabetes was defined as either fasting glucose >=126 mg/dL or use of antidiabetes medication. Poisson regression was used to calculate sex-specific diabetes incidence rates for a 47-year-old individual in each decade. Rates were also calculated among obese, overweight, and normal weight individuals. RESULTS: The annualized rates of diabetes per 1,000 individuals were 2.6, 3.8, 4.7, and 3.0 (women) and 3.4, 4.5, 7.4, and 7.3 (men) in the 1970s, 1980s, 1990s, and 2000s, respectively. Compared with the 1970s, the age- and sex-adjusted relative risks of diabetes were 1.37 (95% CI 0.87-2.16; P = 0.17), 1.99 (95% CI 1.30-3.03; P = 0.001), and 1.81 (95% CI 1.16-2.82; P = 0.01) in the 1980s, 1990s, and 2000s, respectively. Compared with the 1990s, the relative risk of diabetes in the 2000s was 0.85 (95% CI 0.61-1.20; P = 0.36). CONCLUSIONS: In our community-based sample, the risk of new-onset diabetes continued to be higher in the 2000s compared with the 1970s. In the past decade, diabetes incidence remained steady despite the ongoing trend of rising adiposity. PMID- 25552419 TI - The risk of colorectal cancer in patients with type 2 diabetes: associations with treatment stage and obesity. AB - OBJECTIVE: To assess the risk of colorectal cancer associated with type 2 diabetes, as compared with a nondiabetic reference population, and to study additional associations between treatment stage and duration of obesity and colorectal cancer risk. RESEARCH DESIGN AND METHODS: We conducted an observational population-based cohort study within the Clinical Practice Research Datalink (1987-2012). All patients (>=18 years) with at least one prescription for an antidiabetic drug (n = 300,039) were matched (1:1) by birth year, sex, and practice to a comparison cohort without diabetes. Cox proportional hazards models were used to derive adjusted hazard ratios (HRs) for colorectal cancer associated with type 2 diabetes. Within the diabetic cohort, associations of colorectal cancer with treatment stages and duration of obesity (BMI >=30 kg/m(2)) were studied. RESULTS: After a median follow-up of 4.5 years, 2,759 cases of colorectal cancer were observed among the diabetic study population. Type 2 diabetes was associated with a 1.3-fold increased risk of colorectal cancer (HR 1.26 [95% CI 1.18-1.33]). Among diabetic patients, no association was found with treatment stages. A trend of increased colorectal cancer risk was observed with longer duration of obesity. Risk of colorectal cancer was significantly increased for patients with recorded duration of obesity of 4-8 years (HR 1.19 [1.06-1.34]) and >8 years (1.28 [1.11-1.49]). CONCLUSIONS: Type 2 diabetes is associated with a moderately increased risk of colorectal cancer. Among diabetic patients, an increased risk was observed for patients who suffered from obesity for a total duration of 4 years or more. PMID- 25552420 TI - Life years lost and lifetime health care expenditures associated with diabetes in the U.S., National Health Interview Survey, 1997-2000. AB - OBJECTIVE: This study analyzed the lifetime health care expenditures and life years lost associated with diabetes in the U.S. RESEARCH DESIGN AND METHODS: Data from the National Health Interview Survey (NHIS), the Medical Expenditure Panel Survey from 1997 to 2000, and the NHIS Linked Mortality Public-use Files with a mortality follow-up to 2006 were used to estimate age-, race-, sex-, and BMI specific risk of diabetes, mortality, and annual health care expenditures for both patients with diabetes and those without diabetes. A Markov model populated by the risk and cost estimates was used to compute life years and total lifetime health care expenditures by age, race, sex, and BMI classifications for patients with diabetes and without diabetes. RESULTS: Predicted life expectancy for patients with diabetes and without diabetes demonstrated an inverted U shape across most BMI classifications, with highest life expectancy being for the overweight. Lifetime health care expenditures were higher for whites than blacks and for females than males. Using U.S. adults aged 50 years as an example, we found that diabetic white females with a BMI >40 kg/m(2) had 17.9 remaining life years and lifetime health expenditures of $185,609, whereas diabetic white females with normal weight had 22.2 remaining life years and lifetime health expenditures of $183,704. CONCLUSIONS: Our results show that diabetes is associated with large decreases in life expectancy and large increases in lifetime health care expenditures. In addition to decreasing life expectancy by 3.3 to 18.7 years, diabetes increased lifetime health care expenditures by $8,946 to $159,380 depending on age-race-sex-BMI classification groups. PMID- 25552422 TI - Real-time continuous glucose monitoring in type 1 diabetes: a qualitative framework analysis of patient narratives. AB - OBJECTIVE: This study analyzed narratives about experiences of real-time continuous glucose monitoring (CGM) in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: People with type 1 diabetes using CGM and caregivers completed an online survey. Questions included duration of CGM, frequency of sensor wear, funding, and a free narrative about experiences or views about CGM. We used qualitative framework analysis to analyze 100 responses; 50% of participants were aged >= 18 years. RESULTS: Most participants (87%) used CGM with insulin pump therapy, 71% used sensors >= 75% of the time, and 66% received funding for CGM from the National Health Service. Four themes were identified: 1) metabolic control, 2) living with CGM (work and school, sleep, exercise, nutrition, frequency of self-monitoring of blood glucose [SMBG]), 3) psychological issues and patient/caregiver attitudes, and 4) barriers to CGM use (technical issues, financial issues, attitudes of healthcare professionals toward CGM). Despite some hassles, experiences were overwhelmingly positive, with improved glycemic control, diet and exercise management, quality of life, and physical and psychological well-being, as well as reduced frequency of SMBG. Technical problems included sensor inaccuracy and unreliability, and "alarm fatigue." The advantages of CGM used with an insulin pump with automatic suspension of insulin delivery during hypoglycemia were recorded by several participants, noting reduced hypoglycemia frequency and fear of nocturnal hypoglycemia. CONCLUSIONS: Patient and caregiver narratives indicate that CGM is a valuable addition to diabetes care for many with type 1 diabetes. PMID- 25552421 TI - Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 Trial. AB - OBJECTIVE: The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS: Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m(2); n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m(2); n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m(2); n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS: After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions >= 0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m(2) (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m(2) (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population. CONCLUSIONS: Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function. PMID- 25552423 TI - A simple algorithm for the offline recalibration of eye-tracking data through best-fitting linear transformation. AB - Poor calibration and inaccurate drift correction can pose severe problems for eye tracking experiments requiring high levels of accuracy and precision. We describe an algorithm for the offline correction of eye-tracking data. The algorithm conducts a linear transformation of the coordinates of fixations that minimizes the distance between each fixation and its closest stimulus. A simple implementation in MATLAB is also presented. We explore the performance of the correction algorithm under several conditions using simulated and real data, and show that it is particularly likely to improve data quality when many fixations are included in the fitting process. PMID- 25552424 TI - Modeling local dependence in longitudinal IRT models. AB - Measuring change in a latent variable over time is often done using the same instrument at several time points. This can lead to dependence between responses across time points for the same person yielding within person correlations that are stronger than what can be attributed to the latent variable. Ignoring this can lead to biased estimates of changes in the latent variable. In this paper we propose a method for modeling local dependence in the longitudinal 2PL model. It is based on the concept of item splitting, and makes it possible to correctly estimate change in the latent variable. PMID- 25552425 TI - Biomechanics of foetal movement. AB - Foetal movements commence at seven weeks of gestation, with the foetal movement repertoire including twitches, whole body movements, stretches, isolated limb movements, breathing movements, head and neck movements, jaw movements (including yawning, sucking and swallowing) and hiccups by ten weeks of gestational age. There are two key biomechanical aspects to gross foetal movements; the first being that the foetus moves in a dynamically changing constrained physical environment in which the freedom to move becomes increasingly restricted with increasing foetal size and decreasing amniotic fluid. Therefore, the mechanical environment experienced by the foetus affects its ability to move freely. Secondly, the mechanical forces induced by foetal movements are crucial for normal skeletal development, as evidenced by a number of conditions and syndromes for which reduced or abnormal foetal movements are implicated, such as developmental dysplasia of the hip, arthrogryposis and foetal akinesia deformation sequence. This review examines both the biomechanical effects of the physical environment on foetal movements through discussion of intrauterine factors, such as space, foetal positioning and volume of amniotic fluid, and the biomechanical role of gross foetal movements in human skeletal development through investigation of the effects of abnormal movement on the bones and joints. This review also highlights computational simulations of foetal movements that attempt to determine the mechanical forces acting on the foetus as it moves. Finally, avenues for future research into foetal movement biomechanics are highlighted, which have potential impact for a diverse range of fields including foetal medicine, musculoskeletal disorders and tissue engineering. PMID- 25552426 TI - Systemic mesenchymal stem cell administration enhances bone formation in fracture repair but not load-induced bone formation. AB - Mesenchymal stem cells (MSC) were shown to support bone regeneration, when they were locally transplanted into poorly healing fractures. The benefit of systemic MSC transplantation is currently less evident. There is consensus that systemically applied MSC are recruited to the site of injury, but it is debated whether they actually support bone formation. Furthermore, the question arises as to whether circulating MSC are recruited only in case of injury or whether they also participate in mechanically induced bone formation. To answer these questions we injected green fluorescent protein (GFP)-labelled MSC into C57BL/6J mice, which were subjected either to a femur osteotomy or to non-invasive mechanical ulna loading to induce bone formation. We detected GFP-labelled MSC in the early (day 10) and late fracture callus (day 21) by immunohistochemistry. Stromal cell-derived factor 1 (SDF-1 or CXCL-12), a key chemokine for stem cell attraction, was strongly expressed by virtually all cells near the osteotomy- indicating that SDF-1 may mediate cell migration to the site of injury. We found no differences in SDF-1 expression between the groups. Micro-computed tomography (uCT) revealed significantly more bone in the callus of the MSC treated mice compared to untreated controls. The bending stiffness of callus was not significantly altered after MSC-application. In contrast, we failed to detect GFP labelled MSC in the ulna after non-invasive mechanical loading. Histomorphometry and uCT revealed a significant load-induced increase in bone formation; however, no further increase was found after MSC administration. Concluding, our results suggest that systemically administered MSC are recruited and support bone formation only in case of injury but not in mechanically induced bone formation. PMID- 25552427 TI - Growth factor-induced osteogenesis in a novel radiolucent bone chamber. AB - Treatment of large bone defects is currently performed using mainly autograft or allograft bone. There are important drawbacks to bone grafting, such as limited availability, donor site morbidity in the case of autograft and inferior performance of allografts. Therefore, there is a great need for a suitable bone graft substitute. In order to evaluate efficiently newly developed biomaterials and factors intended for orthopaedic surgery, the bone chamber is a very suitable model. To allow longitudinal investigation of bone growth with MUCT, a new bone chamber made of radiolucent polyether ether ketone (PEEK) was developed and studied for its feasibility. Therefore, PEEK bone chambers were placed on rat tibiae, and filled with vehicle (Matrigel without growth factors, negative controls), with bone morphogenetic protein 2 (BMP-2, positive controls), or a mix of growth factors combining BMP-2, vascular endothelial growth factor and the chemokine stromal cell-derived factor 1alpha, all laden on gelatin microspheres for controlled release (combined growth factors). Growth factor presence led to a significant increase in bone formation after 8 weeks, which subsided after 12 weeks, underlining the importance of longitudinal analysis. We conclude that the PEEK-bone chamber is a suitable translational animal model to assess orthotopic bone formation in a longitudinal manner. PMID- 25552428 TI - A biodegradable gentamicin-hydroxyapatite-coating for infection prophylaxis in cementless hip prostheses. AB - A degradable, poly (lactic-co-glycolic acid) (PLGA), gentamicin-loaded prophylactic coating for hydroxyapatite (HA)-coated cementless hip prostheses is developed with similar antibacterial efficacy as offered by gentamicin-loaded cements for fixing traditional, cemented prostheses in bone. We describe the development pathway, from in vitro investigation of antibiotic release and antibacterial properties of this PLGA-gentamicin-HA-coating in different in vitro models to an evaluation of its efficacy in preventing implant-related infection in rabbits. Bone in-growth in the absence and presence of the coating was investigated in a canine model. The PLGA-gentamicin-HA-coating showed high-burst release, with antibacterial efficacy in agar-assays completely disappearing after 4 days, minimising risk of inducing antibiotic resistance. Gentamicin-sensitive and gentamicin-resistant staphylococci were killed by the antibiotic-loaded coating, in a simulated prosthesis-related interfacial gap. PLGA-gentamicin-HA coatings prevented growth of bioluminescent staphylococci around a miniature-stem mounted in bacterially contaminated agar, as observed using bio-optical imaging. PLGA-gentamicin-HA-coated pins inserted in bacterially contaminated medullary canals in rabbits caused a statistically significant reduction in infection rates compared to HA-coated pins without gentamicin. Bone ingrowth to PLGA-gentamicin HA-coated pins, in condylar defects of Beagle dogs was not impaired by the presence of the degradable, gentamicin-loaded coating. In conclusion, the PLGA gentamicin-HA-coating constitutes an effective strategy for infection prophylaxis in cementless prostheses. PMID- 25552429 TI - Antidepressant effects of abscisic acid mediated by the downregulation of corticotrophin-releasing hormone gene expression in rats. AB - BACKGROUND: Corticotrophin-releasing hormone (CRH) is considered to be the central driving force of the hypothalamic-pituitary-adrenal axis, which plays a key role in the stress response and depression. Clinical reports have suggested that excess retinoic acid (RA) is associated with depression. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share a similar molecular structure. Here, we proposed that ABA also plays a role in the regulation of CRH activity sharing with the RA signaling pathway. METHODS: [3H]-ABA radioimmunoassay demonstrated that the hypothalamus of rats shows the highest concentration of ABA compared with the cortex and the hippocampus under basal conditions. RESULTS: Under acute stress, ABA concentrations increased in the serum, but decreased in the hypothalamus and were accompanied by increased corticosterone in the serum and c-fos expression in the hypothalamus. Moreover, chronic ABA administration increased sucrose intake and decreased the mRNA expression of CRH and retinoic acid receptor alpha (RARalpha) in the hypothalamus of rats. Furthermore, ABA improved the symptom of chronic unpredictable mild stress in model rats, as indicated by increased sucrose intake, increased swimming in the forced swim test, and reduced mRNA expression of CRH and RARalpha in the rat hypothalamus. In vitro, CRH expression decreased after ABA treatment across different neural cells. In BE(2)-C cells, ABA inhibited a series of retinoid receptor expression, including RARalpha, a receptor that could facilitate CRH expression directly. CONCLUSIONS: These results suggest that ABA may play a role in the pathogenesis of depression by downregulating CRH mRNA expression shared with the RA signaling pathway. PMID- 25552430 TI - Impaired limbic cortico-striatal structure and sustained visual attention in a rodent model of schizophrenia. AB - BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia. METHODS: Here we used high resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. RESULTS: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex. CONCLUSIONS: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function. PMID- 25552431 TI - Acute nicotine administration increases BOLD fMRI signal in brain regions involved in reward signaling and compulsive drug intake in rats. AB - BACKGROUND: Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine. METHODS: Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1 Tesla magnetic resonance scanner. In the first experiment, nicotine naive rats were mildly anesthetized and the effect of nicotine (0.03-0.6 mg/kg) on the BOLD signal was investigated for 10 min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated. RESULTS: A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal. CONCLUSIONS: These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function. PMID- 25552432 TI - Effects of oxytocin on attention to emotional faces in healthy volunteers and highly socially anxious males. AB - BACKGROUND: Evidence suggests that individuals with social anxiety demonstrate vigilance to social threat, whilst the peptide hormone oxytocin is widely accepted as supporting affiliative behaviour in humans. METHODS: This study investigated whether oxytocin can affect attentional bias in social anxiety. In a double-blind, randomized, placebo-controlled, within-group study design, 26 healthy and 16 highly socially anxious (HSA) male volunteers (within the HSA group, 10 were diagnosed with generalized social anxiety disorder) were administered 24 IU of oxytocin or placebo to investigate attentional processing in social anxiety. Attentional bias was assessed using the dot-probe paradigm with angry, fearful, happy and neutral face stimuli. RESULTS: In the baseline placebo condition, the HSA group showed greater attentional bias for emotional faces than healthy individuals. Oxytocin reduced the difference between HSA and non-socially anxious individuals in attentional bias for emotional faces. Moreover, it appeared to normalize attentional bias in HSA individuals to levels seen in the healthy population in the baseline condition. The biological mechanisms by which oxytocin may be exerting these effects are discussed. CONCLUSIONS: These results, coupled with previous research, could indicate a potential therapeutic use of this hormone in treatment for social anxiety. PMID- 25552434 TI - Report of Two Cases of Combined Odontogenic Tumors: Ameloblastoma with Odontogenic Keratocyst and Ameloblastic Fibroma with Calcifying Odontogenic Cyst. AB - Combined odontogenic neoplasms have rarely been documented. Such tumors have also been described by other researchers as "hybrid" lesions. The histologic features are often identical to other individually well-established odontogenic neoplasms such as ameloblastoma, adenomatoid odontogenic tumor, ameloblastic fibroma (AF), and ameloblastic fibro-odontoma. Their clinical presentation is variable, ranging from cysts to neoplasms showing varying degrees of aggressive behavior. Most combined tumors contain features of one of the odontogenic tumors in combination with either a calcifying odontogenic cyst (COC) or a calcifying epithelial odontogenic tumor. We present two new cases of combined odontogenic tumors: an ameloblastoma with an odontogenic keratocyst and an AF with COC. Predicting clinical outcome is challenging when a combination tumor is encountered due to the paucity of such lesions. One must understand salient features of these entities and differentiate them from the more common conventional neoplasms to expand classification and provide prognostic criteria. PMID- 25552433 TI - Prefrontal cortical GABA modulation of spatial reference and working memory. AB - BACKGROUND: Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear. METHODS: We assessed the effects of pharmacological reduction of GABAA signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1-2 min intervals). RESULTS: Infusions of the GABAA receptor antagonist bicuculline (12.5-50 ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABAA antagonism only causes a slight and transient decrease in accuracy on a 2 arm spatial discrimination. CONCLUSIONS: These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder. PMID- 25552435 TI - A Rare Case of Carcinoma Cuniculatum Involving the Larynx in Association with a Saccular Cyst. AB - Carcinoma cuniculatum (CC), a rare, well-differentiated variant of squamous cell carcinoma, is uncommon in head and neck sites but when it does occur is most common in the oral cavity. Here we report a rare case of CC involving the larynx. A 49-year-old man presented with 10 months of worsening hoarseness and, despite multiple biopsies, no diagnosis of malignancy could be established. Eventual partial excision of the lesion and histologic review of prior specimens confirmed the diagnosis of CC. Focally, a transition to respiratory epithelium indicated the presence of an associated saccular cyst. Total laryngectomy was performed and 6 months later the patient is free of disease. Only two prior cases of CC have been reported in the larynx. Diagnosis of CC is challenging given the low grade histologic features and awareness of this entity for both treating physicians and the pathologist is important to reach a diagnosis of malignancy. This case highlights the challenges in diagnosis of CC, especially in unusual locations and when associated with other lesions such as a saccular cyst. Awareness of this rare tumor type combined with close communication between treating clinicians, radiologists and pathologists should allow earlier diagnosis and treatment. PMID- 25552437 TI - Vinamax: a macrospin simulation tool for magnetic nanoparticles. AB - We present Vinamax, a simulation tool for nanoparticles that aims at simulating magnetization dynamics on very large timescales. To this end, each individual nanoparticle is approximated by a macrospin. Vinamax numerically solves the Landau-Lifshitz equation by adopting a dipole approximation method, while temperature effects can be taken into account with two stochastic methods. It describes the influence of demagnetizing and anisotropy fields on magnetic nanoparticles at finite temperatures in a space- and time-dependent externally applied field. Vinamax can be used in biomedical research where nanoparticle imaging techniques are under development, e.g., to validate other higher-level models and study their limitations. PMID- 25552439 TI - [Also consider thoracic herniated disc]. PMID- 25552438 TI - Measures for the degree of overlap of gene signatures and applications to TCGA. AB - For cancer and many other complex diseases, a large number of gene signatures have been generated. In this study, we use cancer as an example and note that other diseases can be analyzed in a similar manner. For signatures generated in multiple independent studies on the same cancer type and outcome, and for signatures on different cancer types, it is of interest to evaluate their degree of overlap. Many of the existing studies simply count the number (or percentage) of overlapped genes shared by two signatures. Such an approach has serious limitations. In this study, as a demonstrating example, we consider cancer prognosis data under the Cox model. Lasso, which is representative of a large number of regularization methods, is adopted for generating gene signatures. We examine two families of measures for quantifying the degree of overlap. The first family is based on the Cox-Lasso estimates at the optimal tunings, and the second family is based on estimates across the whole solution paths. Within each family, multiple measures, which describe the overlap from different perspectives, are introduced. The analysis of TCGA (The Cancer Genome Atlas) data on five cancer types shows that the degree of overlap varies across measures, cancer types and types of (epi)genetic measurements. More investigations are needed to better describe and understand the overlaps among gene signatures. PMID- 25552440 TI - [Help, my patient needs "palliative care"!]. PMID- 25552441 TI - [CME. Biologics in vasculitis]. PMID- 25552443 TI - [Emergency department as final destination: perception and reception of the palliative patient" concept as well as approach toward improving interdisciplinary collaboration - a survey of emergency personnel of a Swiss emergency department]. AB - BACKGROUND: As the demand for palliative care (PC) in emergency wards continues to increase, emergency medicine is increasingly focusing on the care of extremely ill patients with incurable, chronic and/or advanced diseases. There is no consistent definition of the profile of PC or understanding of what PC involves. The mistake is often made of confusing PC with end-of-life or terminal care. The present study was intended to assess the situation at the Department of Emergency Medicine, Inselspital, Bern University Hospital (UNZ), which cares for about 32 400 patients annually. The plan was to find out how much staff members knew about PC and to survey their personal attitudes. METHODS: The employees of the UNZ were surveyed with an online questionnaire by a special institution outside the hospital. This is based on an instrument [1] developed in a comparative study in an emergency ward in the USA and used for physicians. RESULTS: 60 of 154 staff members (physicians and nurses) completed the questionnaire, corresponding to a response rate of 39%. The definition of palliative care (n=60) was very mixed and could be classified into 6 areas. In response to questions about specific services, the staff members mentioned that their access to existing patient data should be facilitated. They also expressed the wish for a 24 h palliative consultation service and thought that, during normal working days, more time should be allotted to discussing issues related to palliative care. CONCLUSIONS: It has been confirmed that the definition of palliative care is not consistent. Within the UNZ, there is no clear procedure, but lack of time for detailed discussions with patients needing palliative care. Patient wishes or living wills with the DNR/DNI procedure do not contradict the personal ethics of most staff members. UNZ staff members would welcome the 24 h availability of a specialized PC team, as well as the development of guidelines and increased training in PC. PMID- 25552444 TI - [Renal denervation: long-term Swiss experiences]. AB - Despite great advances in pharmacological and non-pharmacological treatment of patients with arterial hypertension, a significant proportion of patients do not reach the target values suggested by the guidelines. A therapy-resistant hypertension is defined as a blood pressure above the suggested target values despite an antihypertensive therapy with three medications at maximal dosis, including a diuretic. The renal denervation is a new and promising method for the treatment of refractory arterial hypertension. An optimal selection of the patients undergoing a renal denervation is extremely important, and this intervention should be performed in highly specialized centers only. PMID- 25552436 TI - Advancing a biopsychosocial and contextual model of sleep in adolescence: a review and introduction to the special issue. AB - Sleep problems in adolescence have been identified as an international public health issue. Over the past few decades, notable advances have been made in our understanding of the patterns and consequences of sleep in adolescence. Despite these important gains, there is much about the role of sleep in adolescence that remains to be understood. This Special Issue brings together studies that examine sleep as it specifically pertains to adolescent development and adjustment. In this introductory article, we argue for the importance of grounding the study of sleep and adolescence in developmental science and a developmental psychopathology framework. First, a review of the literature is used to outline a biopsychosocial and contextual model of sleep in adolescence. Second, attention deficit/hyperactivity disorder (ADHD) is used as an exemplar of the proposed model given the pervasiveness of sleep problems among youth with ADHD and the likelihood that sleep problems and ADHD symptoms are interconnected in complex ways. Finally, a brief introduction to the empirical articles included in the Special Issue is provided, with particular attention given to how these articles fit within the proposed biopsychosocial and contextual model. Along with the framework proposed in this article, the studies included in this Special Issue advance the current literature and point to critical directions for future research. PMID- 25552445 TI - [Sacroiliac joint pain - diagnostic algorithm and therapeutic approaches]. AB - The sacroiliac joints are causative for 13-30% of cases with low back pain and are still disregarded in the differential diagnosis. This is mainly due to its complex anatomy and the variety of pain patterns originating from the SI joints. The broad etiology of low back pain often misleads the physician into inadequate treatments. This article reviews the clinical presentation of patients suffering from a sacroiliac arthropathy and points out therapeutic strategies. It also provides a helpful diagnostic tool in daily routine. Eventually, any patient needs to experience a significant pain reduction resulting from an intrarticular injection before the diagnosis of non-inflammatory SI arthropathy is confirmed. In most cases, nonoperative treatment measures are sufficient. Operative strategies are available in selected cases with unsuccessful conservative therapy. PMID- 25552446 TI - [Three patients with the same diagnosis but very different symptoms]. AB - We present three cases of patients with a thoracic disc herniation with misinterpretation of the initial symptoms. In a first case, pulmonary symptoms were prominent; in a second case, the patient complained of cardiac symptoms; and in a third case, the patient reported neurological symptoms. Ineffective investigation of thoracic symptoms should raise the suspicion of a thoracic disc herniation. PMID- 25552448 TI - [Thrombolytic therapy in deep venous thrombosis?]. PMID- 25552449 TI - [Acupuncture with needles or lasers without clinically relevant effect on knee osteoarthritis]. PMID- 25552450 TI - [IIpswich-contact test in diabetic patients simple and reliable]. PMID- 25552452 TI - [CME EKG 47. Progressive exercise-induced dyspnea. Arrhythmogenic right ventricular cardiomyopathy]. PMID- 25552461 TI - Waterpipe tobacco smoking may undermine the progress made in curbing cigarette smoking. PMID- 25552460 TI - The characteristics and correlation between the ischemia-reperfusion and changes of redox status in the early stage of severe burns. AB - OBJECTIVE: Both the ischemia-reperfusion injury and the abnormal changes of redox status are the important pathologic changes in the burn shock stage for severe burns. The study of clinical dynamic, quantitative relevance about them was performed. METHODS: In this study, blood redox potential (ORP) values (DeltaORP value was adopted, as the quantitative index to reflect the overall redox status), plasma uric acid levels (important antioxidant, as antioxidant index), and the burn shock state-related indicators (lactic acid and hematocrit) of 48 burn patients were dynamically, quantitatively monitored during the early stage after injury. RESULTS: The results revealed that the duration of abnormal fluctuation of redox status in the early stage of severe burns was longer than that of the traditional clinical shock stage (2-3 days). The changes of overreduction soon after injury were closely related to the hypovolemia-related hypoxia, and the following overoxidation status was consistent with the pathophysiological changes related to the reperfusion, and the degrees of variation were closely related to the severity of burn injury and prognosis. Moreover, early surgery (3 days after injury) had no significant influence on the changing trend of abnormal redox status in the early stage of severe burns. CONCLUSION: The ischemia-reperfusion injury caused by burn shock appears the main factor contributing to the abnormal biphasic changes of redox status in the early stage of severe burns. Our findings provide useful information for the redox regulation treatment for burn shock. PMID- 25552462 TI - Scrub typhus with visual hallucinations. AB - The occurrence of psychiatric symptoms in scrub typhus is not commonly reported in literature. We present a case of scrub typhus with visual hallucinations. PMID- 25552463 TI - Leading campaigner for legalising assisted suicide dies from starvation. PMID- 25552464 TI - Margaret McCartney: Rectal feeding is torture masquerading as medicine. PMID- 25552465 TI - Structural and functional alterations of the right ventricle are common in adults operated for ventricular septal defect as toddlers. AB - AIMS: Patients with a surgically closed ventricular septal defect (VSD) contribute significantly to the increasing number of adults with congenital heart disease. The chronic effects of prior adverse haemodynamics in this population are incompletely understood. Our objective was to assess postoperative cardiac function and morphology in adult survivors of surgery in childhood. METHODS AND RESULTS: Patients (n = 27), median surgical age of 1.9 (95% CI 1.1-2.8 years) and 20.5 (95% CI 19.6-22.1 years) at the time of examination, and age-matched controls (n = 28) underwent cardiac magnetic resonance imaging. We performed offline analyses of biventricular cardiac deformations, myocardial mass indices, flow patterns, and chamber areas and dimensions. In comparison with controls, VSD operated patients had higher right ventricular (RV) areas; 36.8 +/- 9.0 vs. 30.4 +/- 6.4 cm(2) in end-diastole, P < 0.01, and 21.3 +/- 5.9 vs. 16.0 +/- 3.9 cm(2) in end-systole, P < 0.01. Furthermore, we found that fractional area change was lower among VSD-operated patients compared with controls; 0.42 +/- 0.07 vs. 0.47 +/- 0.05, P < 0.01, and we demonstrated a higher RV mass index in the VSD cohort compared with controls, P < 0.01. Radial strain was higher in the VSD group compared with controls; 30.2 +/- 10.4 vs. 22.4 +/- 7.7%, P < 0.01, whereas no difference was found in longitudinal strain; -20.1 +/- 3.8% among VSD-operated patients vs. -21.5 +/- 4.7% among controls, P = 0.28. CONCLUSION: Left ventricular function is normal, but changes in RV structure and function are demonstrable 20 years after surgical closure of VSD. The mechanisms and implications for these findings justify a further study in this increasingly large population of adult survivors of early surgery. PMID- 25552466 TI - Leukaemic myocardial infiltration presenting as acute heart failure. PMID- 25552467 TI - Uncommon intracardiac finding after cardiac transplantation mimicking pacemaker leads. PMID- 25552468 TI - A unique congenital aorto-caval fistula: multi-modality imaging role for successful treatment. PMID- 25552469 TI - Left ventricular global longitudinal strain is associated with exercise capacity in failing hearts with preserved and reduced ejection fraction. AB - AIMS: Heart failure patients with reduced and preserved left ventricular (LV) ejection fraction (EF) show reduced exercise capacity. We explored the relationship between exercise capacity and systolic and diastolic myocardial function in heart failure patients. METHODS AND RESULTS: Exercise capacity, by peak oxygen uptake (VO2), was assessed in 100 patients (56 +/- 12 years, NYHA functional class: 2.5 +/- 0.9, EF: 42 +/- 19%). LV systolic function, as EF and global longitudinal strain (GLS), and right ventricular function were assessed by echocardiography. Left atrial volume index and the ratio of peak early diastolic filling velocity (E) to early diastolic mitral annular velocity (e') were measures of diastolic function. Thirty-seven patients had heart failure with preserved EF (HFpEF), defined as EF >=50% and echocardiographic diastolic dysfunction. LV GLS and peak pulmonary arterial systolic pressure were independently correlated to peak VO2 in the total study population and in HFpEF separately. LV GLS was superior to EF in identifying patients with impaired peak VO2 <20 mL/kg/min as shown by receiver operating characteristic analyses [areas under curves 0.93 (0.89-0.98) vs. 0.85 (0.77-0.93), P < 0.05]. In patients with HFpEF, GLS was reduced below normal (-17.5 +/- 3.2%) and correlated to E/e' (R = 0.45, P = 0.005) and left atrial volume index (R = 0.48, P = 0.003), while EF did not. CONCLUSION: GLS correlated independently to peak VO2 in patients with reduced and preserved EF and was superior in identifying patients with reduced exercise capacity. In HFpEF, systolic function by GLS was impaired. There was a significant relationship between diastolic function and GLS, confirming a coupling between diastolic and longitudinal systolic function in HFpEF. PMID- 25552470 TI - Why it is important to use the correct dose of the non-vitamin K oral anticoagulants. PMID- 25552471 TI - Bringing holistic treatments to the attention of medicine: acupuncture as an effective poststroke rehabilitation tool. AB - This article reviews 3 studies that explore the effects of acupuncture on poststroke patients suffering from chronic stroke symptoms. The 3 studies selected strive to show how acupuncture can be a safe, noninvasive, and cost effect rehabilitation tool useful in adjunct with traditional rehabilitation. Chou et al (2009), Hopwood et al (2008), and Wayne et al (2005) all studied acupuncture's effects on quality of life. Additionally, both Hopwood et al and Wayne et al studied acupuncture's effects on mobility and activities of daily living. While the frequency, duration, and length of the entire treatment varied by study, overall, the results of all 3 studies suggest that acupuncture increases quality of life and improves mobility and activities of daily living. PMID- 25552473 TI - Low temperature inhibits root growth by reducing auxin accumulation via ARR1/12. AB - Plants exhibit reduced root growth when exposed to low temperature; however, how low temperature modulates root growth remains to be understood. Our study demonstrated that low temperature reduces both meristem size and cell number, repressing the division potential of meristematic cells by reducing auxin accumulation, possibly through the repressed expression of PIN1/3/7 and auxin biosynthesis-related genes, although the experiments with exogenous auxin application also suggest the involvement of other factor(s). In addition, we verified that ARABIDOPSIS RESPONSE REGULATOR 1 (ARR1) and ARR12 are involved in low temperature-mediated inhibition of root growth by showing that the roots of arr1-3 arr12-1 seedlings were less sensitive than wild-type roots to low temperature, in terms of changes in root length and meristem cell number. Furthermore, low temperature reduced the levels of PIN1/3 transcripts and the auxin level to a lesser extent in arr1-3 arr12-1 roots than in wild-type roots, suggesting that cytokinin signaling is involved in the low-temperature-mediated reduction of auxin accumulation. Taken together, our data suggest that low temperature inhibits root growth by reducing auxin accumulation via ARR1/12. PMID- 25552472 TI - A Novel Arabidopsis microRNA promotes IAA biosynthesis via the indole-3 acetaldoxime pathway by suppressing superroot1. AB - IAA is a plant hormone that plays important roles in regulating growth and responses to environmental changes. Indole-3-acetaldoxime (IAOx) has been proposed as an important intermediate in the biosynthesis of IAA and two other indole compounds, indole glucosinolates and camalexin. Although the IAOx dependent IAA biosynthesis pathway has been well studied, the mechanisms of its regulation remain elusive. Here, we report the identification of a novel microRNA, miR10515, which targets superroot1 (SUR1), the gene encoding an indole glucosinolate biosynthetic enzyme. miR10515 was induced by high temperature. Overexpression of MIR10515 resulted in a high-IAA phenotype, while the loss of function of miR10515 resulted in a low-IAA phenotype; these phenotypes were more severe at high temperature. Our results further demonstrated that miR10515 promoted IAA biosynthesis via the IAOx pathway by blocking the indole glucosinolate and camalexin biosynthetic pathways. Phytochrome interacting factor4 (PIF4), a dominant regulator of plant development in response to high temperature, was not required for miR10515 expression. These results provide information on the IAOx metabolic branching point and its biological importance. PMID- 25552474 TI - The Role of Interpersonal Traits in Social Decision Making: Exploring Sources of Behavioral Heterogeneity in Economic Games. AB - Economic games are well-established experimental paradigms for modeling social decision making. A large body of literature has pointed to the heterogeneity of behavior within many of these games, which might be partly explained by broad interpersonal trait dispositions. Using the Big Five and HEXACO (Honesty Humility, Emotionality, eXtraversion, Agreeableness, Conscientiousness, Openness to Experience) personality frameworks, we review the role of personality in two main classes of economic games: social dilemmas and bargaining games. This reveals an emerging role for Big Five agreeableness in promoting cooperative, egalitarian, and altruistic behaviors across several games, consistent with its core characteristic of maintaining harmonious interpersonal relations. The role for extraversion is less clear, which may reflect the divergent effects of its underlying agentic and affiliative motivational components. In addition, HEXACO honesty-humility and agreeableness may capture distinct aspects of prosocial behavior outside the bounds of the Five-Factor Model. Important considerations and directions for future studies are discussed within the emerging personality economics interface. PMID- 25552475 TI - Variation in the management of congestive cardiac failure in dogs. PMID- 25552476 TI - Use and safety of intratumoral application of European mistletoe (Viscum album L) preparations in Oncology. AB - BACKGROUND: Intratumoral (IT) injection of European mistletoe (Viscum album L) preparations might induce local tumor response through combined cytotoxic and immunomodulatory actions of the preparations. Although promising in vitro and in vivo data, along with clinical case studies suggest the need for validation of this hypothesis in prospective trials, the safety of IT mistletoe injections has yet to be thoroughly assessed. METHODS: The present study summarizes the practice and safety of off-label IT mistletoe therapy within the Network Oncology, a conjoint clinical registry of German hospitals and outpatients specialized in anthroposophic and integrative medicine. Demographic, diagnosis and treatment data of cancer patients who received IT mistletoe applications between 2007 and 2013 were assessed. Suspected adverse drug reactions (ADRs) were analyzed in terms of type, frequency, severity, seriousness and potential risk factors. RESULTS: A total of 123 cancer patients received 862 IT mistletoe injections (preparations from Abnoba, Helixor and Iscucin). The most commonly applied preparations were Abnoba viscum Fraxini (71 patients) and Helixor Mali (54 patients). Of the total patients, 26 patients (21.1%) experienced 74 ADRs. All ADRs were in response to either Abnoba viscum Fraxini (25.4% of exposed patients) or Helixor Mali (18.5% of exposed patients). ADRs were mostly body temperature or immune related and of mild (83.8%) or moderate (14.9%) intensity. Only one possible ADR was described as severe (hypertension) and no serious ADRs occurred. The frequency of ADRs to IT mistletoe injections was 3 times and 5 times higher than has previously been found for subcutaneous and intravenous applications of mistletoe, respectively. CONCLUSION: IT injection of mistletoe preparations resulted in a relatively high frequency of ADRs. Nearly all ADRs were mild to moderate however, and no serious ADRs occurred. Furthermore, it is possible that immune-related ADRs such as pyrexia and local inflammatory reactions might be critical for tumor response. In light of these results, IT mistletoe therapy seems to be safe and prospective trials are recommended. PMID- 25552477 TI - A new pathway regulating autophagy. PMID- 25552478 TI - Biventricular paced QRS predictors of left ventricular lead locations in relation to mortality in cardiac resynchronization therapy. AB - BACKGROUND: Left ventricular (LV) lead location during cardiac resynchronization therapy (CRT) has influenced mortality and heart failure events; however the biventricular paced QRS morphology has not been established as a predictor of LV lead location or mortality. METHODS: We evaluated the biventricular paced QRS morphology in 306 patients undergoing CRT in relation to specific anatomic locations. A logistic regression model and Kaplan-Meier survival estimates were used to determine predictors of LV lead location and survival. RESULTS: The mean age was 68+/-13years. Predictors of LV lead location from anterior, lateral, and posterior segments were: absence of R in V1, QS in aVL; and R in aVL, respectively. Absence of an R in II, III, or aVF predicted an inferior site. A QS in V4-V6 differentiated apical from basal sites (p=0.01). LV pacing from sites along the middle cardiac vein revealed a higher mortality (34%), than lateral sites (20%, p=0.02). CONCLUSIONS: Biventricular paced QRS criteria were predictive of LV lead locations. The proposed algorithm enhanced the predictive accuracy of these criteria. LV pacing sites along the middle cardiac vein were associated with increased mortality. PMID- 25552481 TI - Interprofessional, simulation-based technology-enhanced learning to improve physical healthcare in psychiatry: The RAMPPS course. AB - People with serious mental illness have reduced life expectancy compared with a control population, much of which is accounted for by significant physical comorbidity. Frontline clinical staff in mental health often lack confidence in recognition, assessment and management of such 'medical' problems. Simulation provides one way for staff to practise these skills in a safe setting. We produced a multidisciplinary simulation course around recognition and assessment of medical problems in psychiatric settings. We describe an audit of strategic and design aspects of the recognition and assessment of medical problems in psychiatric settings, using the Department of Health's 'Framework for Technology Enhanced Learning' as our audit standards. At the same time, as highlighting areas where recognition and assessment of medical problems in psychiatric settings adheres to these identified principles, such as the strategic underpinning of the approach, and the means by which information is collected, reviewed and shared, it also helps us to identify areas where we can improve. PMID- 25552479 TI - Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. AB - The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases. PMID- 25552480 TI - High-affinity DNA-binding domains of replication protein A (RPA) direct SMARCAL1 dependent replication fork remodeling. AB - SMARCAL1 catalyzes replication fork remodeling to maintain genome stability. It is recruited to replication forks via an interaction with replication protein A (RPA), the major ssDNA-binding protein in eukaryotic cells. In addition to directing its localization, RPA also activates SMARCAL1 on some fork substrates but inhibits it on others, thereby conferring substrate specificity to SMARCAL1 fork-remodeling reactions. We investigated the mechanism by which RPA regulates SMARCAL1. Our results indicate that although an interaction between SMARCAL1 and RPA is essential for SMARCAL1 activation, the location of the interacting surface on RPA is not. Counterintuitively, high-affinity DNA binding of RPA DNA-binding domain (DBD) A and DBD-B near the fork junction makes it easier for SMARCAL1 to remodel the fork, which requires removing RPA. We also found that RPA DBD-C and DBD-D are not required for SMARCAL1 regulation. Thus, the orientation of the high affinity RPA DBDs at forks dictates SMARCAL1 substrate specificity. PMID- 25552482 TI - Is routine hospital episode data sufficient for identifying individuals with chronic kidney disease? A comparison study with laboratory data. AB - Internationally, investment in the availability of routine health care data for improving health, health surveillance and health care is increasing. We assessed the validity of hospital episode data for identifying individuals with chronic kidney disease compared to biochemistry data in a large population-based cohort, the Grampian Laboratory Outcomes, Morbidity and Mortality Study-II (n = 70,435). Grampian Laboratory Outcomes, Morbidity and Mortality Study-II links hospital episode data to biochemistry data for all adults in a health region with impaired kidney function and random samples of individuals with normal and unmeasured kidney function in 2003. We compared identification of individuals with chronic kidney disease by hospital episode data (based on International Classification of Diseases-10 codes) to the reference standard of biochemistry data (at least two estimated glomerular filtration rates <60 mL/min/1.73 m(2) at least 90 days apart). Hospital episode data, compared to biochemistry data, identified a lower prevalence of chronic kidney disease and had low sensitivity (<10%) but high specificity (>97%). Using routine health care data from multiple sources offers the best opportunity to identify individuals with chronic kidney disease. PMID- 25552483 TI - Radiotherapy combined with the immunocytokine L19-IL2 provides long-lasting antitumor effects. AB - PURPOSE: Radiotherapy modifies the tumor microenvironment and causes the release of tumor antigens, which can enhance the effect of immunotherapy. L19 targets the extra domain B (ED-B) of fibronectin, a marker for tumor neoangiogenesis, and can be used as immunocytokine when coupled to IL2. We hypothesize that radiotherapy in combination with L19-IL2 provides an enhanced antitumor effect, which is dependent on ED-B expression. EXPERIMENTAL DESIGN: Mice were injected with syngeneic C51 colon carcinoma, Lewis lung carcinoma (LLC), or 4T1 mammary carcinoma cells. Tumor growth delay, underlying immunologic parameters, and treatment toxicity were evaluated after single-dose local tumor irradiation and systemic administration of L19-IL2 or equimolar controls. RESULTS: ED-B expression was high, intermediate, and low for C51, LLC, and 4T1, respectively. The combination therapy showed (i) a long-lasting synergistic effect for the C51 model with 75% of tumors being cured, (ii) an additive effect for the LLC model, and (iii) no effect for the 4T1 model. The combination treatment resulted in a significantly increased cytotoxic (CD8(+)) T-cell population for both C51 and LLC. Depletion of CD8(+) T cells abolished the benefit of the combination therapy. CONCLUSIONS: These data provide the first evidence for an increased therapeutic potential by combining radiotherapy with L19-IL2 in ED-B-positive tumors. This new opportunity in cancer treatment will be investigated in a phase I clinical study for patients with an oligometastatic solid tumor (NCT02086721). An animation summarizing our results is available at https://www.youtube.com/watch?v=xHbwQuCTkRc. PMID- 25552485 TI - The sleep-modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine. AB - To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-protein coupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype, N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2 methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala(11), d-Leu(15)]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of alpha-bungarotoxin-sensitive (presumably alpha7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder. PMID- 25552484 TI - Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. AB - PURPOSE: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density. EXPERIMENTAL DESIGN: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated. RESULTS: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023). CONCLUSIONS: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC. PMID- 25552486 TI - Repurposing the antipsychotic trifluoperazine as an antimetastasis agent. AB - Because cancer cell invasion is a critical determinant of metastasis, targeting invasion is a viable approach to prevent metastasis. Utilizing a novel three dimensional high-throughput invasion assay, we screened a National Cancer Institute compound library and discovered compounds demonstrating inhibitory effects on cancer cell invasion. One hit, trifluoperazine, suppresses invasion of human cancer cell lines while displaying a limited cytotoxicity profile. This inhibition is due to the interference with cancer cell migratory ability but not proteolytic activity. Treatment of cancer cells with trifluoperazine significantly reduces angiogenesis and prevents cancer cell invasion through a chorioallantoic basement membrane. Mechanistically, treatment results in decreased phosphorylated AKT (Ser(473) and Thr(308)) and beta-catenin (Ser(552)). Lack of phosphorylation of Ser(552) of beta-catenin prevents beta-catenin nuclear relocation, resulting in decreased expression of vascular endothelial growth factor, likely mediated through dopamine receptor D2. Taken together, we demonstrated that trifluoperazine is responsible for reducing the angiogenic and invasive potential of aggressive cancer cells through dopamine receptor D2 to modulate the beta-catenin pathway and propose that trifluoperazine may be used as an antimetastasis chemotherapeutic. PMID- 25552487 TI - A theoretical study of the initiation, maintenance and termination of gastric slow wave re-entry. AB - Gastric slow wave dysrhythmias are associated with motility disorders. Periods of tachygastria associated with slow wave re-entry were recently recognized as one important dysrhythmia mechanism, but factors promoting and sustaining gastric re entry are currently unknown. This study reports two experimental forms of gastric re-entry and presents a series of multi-scale models that define criteria for slow wave re-entry initiation, maintenance and termination. High-resolution electrical mapping was conducted in porcine and canine models and two spatiotemporal patterns of re-entrant activities were captured: single-loop rotor and double-loop figure-of-eight. Two separate multi-scale mathematical models were developed to reproduce the velocity and entrainment frequency of these experimental recordings. A single-pulse stimulus was used to invoke a rotor re entry in the porcine model and a figure-of-eight re-entry in the canine model. In both cases, the simulated re-entrant activities were found to be perpetuated by tachygastria that was accompanied by a reduction in the propagation velocity in the re-entrant pathways. The simulated re-entrant activities were terminated by a single-pulse stimulus targeted at the tip of re-entrant wave, after which normal antegrade propagation was restored by the underlying intrinsic frequency gradient. MAIN FINDINGS: (i) the stability of re-entry is regulated by stimulus timing, intrinsic frequency gradient and conductivity; (ii) tachygastria due to re-entry increases the frequency gradient while showing decreased propagation velocity; (iii) re-entry may be effectively terminated by a targeted stimulus at the core, allowing the intrinsic slow wave conduction system to re-establish itself. PMID- 25552488 TI - Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcome. AB - BACKGROUND: The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH. METHODS AND RESULTS: Forty-three consecutive children (median age, 8.0 years; range, 0.4-21.5) with idiopathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation-free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05). CONCLUSIONS: This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH. PMID- 25552490 TI - Transfemoral access assessment for transcatheter aortic valve replacement: evidence-based application of computed tomography over invasive angiography. AB - BACKGROUND: Although computed tomography (CT) is commonly used for iliofemoral evaluation for transfemoral transcatheter aortic valve replacement, many centers worldwide use invasive angiography alone for this purpose. No study to date has evaluated the value of CT over angiography for the prediction of vascular complications. In addition, no data exist for the value of noncontrast CT. METHODS AND RESULTS: Of the 588 transcatheter aortic valve replacement patients, we reviewed 496 consecutive transfemoral cases. Vessel diameters were measured by CT or angiography. Sheath-related complication (SRC) was defined as an iliofemoral arterial injury not including a cannulation site. Receiver operating characteristic models were generated using sheath-to-iliofemoral artery ratios as a variable and SRC as an end point. In patients undergoing both contrast CT and angiography (n=283; 35 SRCs), contrast CT showed a greater predictive value than angiography by area under the curve P<0.001): 0.87 (95% confidence interval: 0.82 0.91) versus 0.72 (95% confidence interval: 0.66-0.77). In patients undergoing both noncontrast CT and angiography (n=103; 17 SRCs), there was no difference between noncontrast CT and angiography: 0.79 (95% confidence interval: 0.70-0.86) versus 0.73 (95% confidence interval: 0.63-0.81). Three-dimensional assessments of calcification and tortuosity provided limited additional value for SRC prediction. CONCLUSIONS: Contrast CT has a greater predictive value for post transcatheter aortic valve replacement vascular complications than angiography. Because these complications increase mortality, an accurate assessment of the vasculature is a critical component of proper access selection. PMID- 25552489 TI - Association of a favorable cardiovascular health profile with the presence of coronary artery calcification. AB - BACKGROUND: To examine the association between the American Heart Association's 7 metrics of ideal cardiovascular health (ICH) and the presence of subclinical coronary atherosclerosis as assessed by coronary artery calcification (CAC) using electron-beam computed tomography. METHODS AND RESULTS: This study is a cross sectional analysis of data obtained on 3121 male and female patients evaluated at the Cooper Clinic in Dallas, Texas, between 1997 and 2007. We included men aged >=45 and women aged >=55 without known cardiovascular disease and for whom information on all ICH metrics and a CAC score were available. Patients were grouped into 3 categories according to their number of ICH metrics: favorable (4 7 ICH metrics), intermediate (3 metrics), and unfavorable (0-2 metrics). Patients with favorable ICH profiles had a lower prevalence and severity of subclinical atherosclerosis than those with unfavorable or intermediate ICH profiles as estimated by CAC. This inverse association of CAC with ICH metrics was evident whether the presence of coronary calcium was defined as CAC score>0, CAC score>100, or CAC score>400. Patients with favorable ICH profiles had odds of coronary calcium (CAC>0) less than half of those for patients with unfavorable profiles (odds ratio 0.41; 95% confidence interval, 0.34-0.50) and patients with intermediate ICH profiles had odds of detectable CAC 32% lower (odds ratio 0.68; 95% confidence interval, 0.57-0.82). CONCLUSIONS: A statistically significant association was found between a favorable level of ICH metrics and less or absent subclinical atherosclerosis as measured by CAC underscoring the importance of primordial prevention. PMID- 25552491 TI - Extracellular volume fraction is more closely associated with altered regional left ventricular velocities than left ventricular ejection fraction in nonischemic cardiomyopathy. AB - BACKGROUND: Nonischemic cardiomyopathy is a common cause of left ventricular (LV) dysfunction and myocardial fibrosis. The purpose of this study was to noninvasively evaluate changes in segmental LV extracellular volume (ECV) fraction, LV velocities, myocardial scar, and wall motion in nonischemic cardiomyopathy patients. METHODS AND RESULTS: Cardiac MRI including pre- and postcontrast myocardial T1 mapping and velocity quantification (tissue phase mapping) of the LV (basal, midventricular, and apical short axis) was applied in 31 patients with nonischemic cardiomyopathy (50+/-18 years). Analysis based on the 16-segment American Heart Association model was used to evaluate the segmental distribution of ECV, peak systolic and diastolic myocardial velocities, scar determined by late gadolinium enhancement, and wall motion abnormalities. LV segments with scar or impaired wall motion were significantly associated with elevated ECV (rs =0.26; P<0.001) and reduced peak systolic radial velocities (r= 0.43; P<0.001). Regional myocardial velocities and ECV were similar for patients with reduced (n=12; ECV=0.28+/-0.06) and preserved left ventricular ejection fraction (n=19; ECV=0.30+/-0.09). Patients with preserved left ventricular ejection fraction showed significant relationships between increasing ECV and reduced systolic (r=-0.19; r=-0.30) and diastolic (r=0.34; r=0.26) radial and long-axis peak velocities (P<0.001). Even after excluding myocardial segments with late gadolinium enhancement, significant relationships between ECV and segmental LV velocities were maintained indicating the potential of elevated ECV to identify regional diffuse fibrosis not visible by late gadolinium enhancement, which was associated with impaired regional LV function. CONCLUSIONS: Regionally elevated ECV negatively affected myocardial velocities. The association of elevated regional ECV with reduced myocardial velocities independent of left ventricular ejection fraction suggests a structure-function relationship between altered ECV and segmental myocardial function in nonischemic cardiomyopathy. PMID- 25552492 TI - Obese subjects show sex-specific differences in right ventricular hypertrophy. AB - BACKGROUND: As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy. METHODS AND RESULTS: Seven hundred thirty nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119+/-11/73+/-8 mm Hg), normoglycaemic (4.8+/-0.5 mmol/L), and normocholesterolaemic (4.8+/-0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001). CONCLUSIONS: A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling. PMID- 25552493 TI - Correlation of cardiac magnetic resonance imaging and histopathology in eosinophilic endomyocarditis. PMID- 25552494 TI - Disparities between ideal cardiovascular health metrics and subclinical atherosclerotic burden: more than meets the eye. PMID- 25552495 TI - A 3 month old boy with vomiting, intermittent crying, and lethargy. PMID- 25552496 TI - Who watches the GMC? PMID- 25552497 TI - The naked endosperm genes encode duplicate INDETERMINATE domain transcription factors required for maize endosperm cell patterning and differentiation. AB - The aleurone is the outermost layer of cereal endosperm and functions to digest storage products accumulated in starchy endosperm cells as well as to confer important dietary health benefits. Whereas normal maize (Zea mays [Zm]) has a single aleurone layer, naked endosperm (nkd) mutants produce multiple outer cell layers of partially differentiated cells that show sporadic expression of aleurone identity markers such as a viviparous1 promoter-beta-glucuronidase transgene. The 15:1 F2 segregation ratio suggested that two recessive genes were involved, and map-based cloning identified two homologous genes in duplicated regions of the genome. The nkd1 and nkd2 genes encode the INDETERMINATE1 domain (IDD) containing transcription factors ZmIDDveg9 and ZmIDD9 on chromosomes 2 and 10, respectively. Independent mutant alleles of nkd1 and nkd2, as well as nkd2 RNA interference lines in which both nkd genes were knocked down, also showed the nkd mutant phenotype, confirming the gene identities. In wild-type kernels, the nkd transcripts were most abundant around 11 to 16 d after pollination. The NKD proteins have putative nuclear localization signals, and green fluorescent protein fusion proteins showed nuclear localization. The mutant phenotype and gene identities suggest that NKD controls a gene regulatory network involved in aleurone cell fate specification and cell differentiation. PMID- 25552498 TI - Androgen Receptor Coregulator CTBP1-AS Is Associated With Polycystic Ovary Syndrome in Chinese Women: A Preliminary Study. AB - Polycystic ovary syndrome (PCOS) is currently considered a predominantly hyperandrogenic syndrome. In theory, hyperandrogenism can be caused by high level of testosterone (T) as well as by enhanced androgen receptor (AR) activity. C Terminal binding protein 1 antisense (CTBP1-AS) was a novel long noncoding RNA (lncRNA) to regulate AR activity. In this study, we found that expression level of CTBP1-AS in peripheral blood leukocytes was significantly higher in women with PCOS than that in controls after adjustment for age and body mass index (BMI). Individuals having higher expression of CTBP1-AS had significantly greater disease risk than those having lower expression. We also identified expression of CTBP1-AS as an independent risk factor for PCOS. A positive correlation was observed between the CTBP1-AS expression and the total T (TT) concentration either unadjusted or after adjusting for age, BMI, and homeostatic model assessment insulin resistance. Taken together, our current study presented the first evidence that the lncRNA CTBP1-AS, a novel AR modulator, is associated with PCOS in Chinese population and established the possibility that abnormal CTBP1-AS expression is a risk factor for PCOS and it is a predictor of variability in serum TT level in Chinese women with PCOS. PMID- 25552499 TI - [The use of immobilized ubiquitin for biosensor analysis of the mitochondrial subinteractome]. AB - Protein ubiquitination is considered as an important mechanism that is responsible not only for specific labeling of proteins for their subsequent degradation but also for localization of proteins in the cell and regulation of protein-protein interactions. In the context of protein-protein interactions binding of (mono/poly)ubiquitinated molecules to proteins containing specific ubiquitin binding domains appear to play the decisive role. Although formation of the ubiquitin interactome has been demonstrated for cytosol, involvement of mitochondria and associated extramitochondrial proteins into such interactions still requires detailed investigation. In this study using an optical biosensor we have demonstrated binding of proteins of mouse brain mitochondrial lysates to immobilized monomeric ubiquitin. Model purified proteins, which are known to be associated with the outer mitochondrial compartment (glyceraldehyde-3-phosphate dehydorgenase, creatine phosphokinase), interacted with immobilized ubiquitin as well as with each other. This suggests that (poly)ubiquitinated chains may be involved in protein-protein interactions between ubiquitinated and non ubiquitinated proteins and thus may contribute to formation of (mitochondrial) ubiquitin subinteractome. PMID- 25552500 TI - [The effect of a water-soluble vitamins on the activity of some enzymes in diabetes]. AB - Intramuscular injections of the vitamin complex containing: thiamine chloride (B1), riboflavin (B2), lipoic acid (N), calcium pantothenate (B5), pyridoxine hydrochloride (B6), folic acid (B9), ascorbic acid (C) can reduce the blood glucose level in serum of rats with alloxan diabetes, stabilize activity of some enzymes of energy metabolism, lactate dehydrogenase and pyruvate dehydrogenase complex. PMID- 25552501 TI - [The state of the mitochondrial energy-supplying system of blood leukocytes in the dynamics of Guerin's carcinoma growth under the low-level irradiation conditions]. AB - Mitochondrial NADH-dehydrogenase, succinate dehydrogenase and cytochrome oxidase activities of peripheral blood leukocytes of rats with the grafted Guerin's carcinoma were studied in the dynamics of oncogenesis under the conditions of the preliminary low-level irradiation. Tumor growth was accompanied by a decrease in NADH-dehydrogenase activity, an increase of succinate dehydrogenase activity. Cytochrome oxidase activity of leucocytes remained at the control level up to the terminal stages of tumor growth. Preliminary low-level irradiation of the tumor bearing animals caused a tendency to the decrease of enzymatic activities studied. This tendency was observed from the initial stages of oncogenesis. PMID- 25552502 TI - [In-vitro degradation of the chitosan membranes under various syntheses conditions]. AB - The hydrolytic degradation of polymer films, which were obtained by application of 2% and 3% chitosan solutions in 1% acetic acid on a base sheet has been investigated. As the solvent was removed, these firms were either treated with 0.5% NaOH for 3 min or with phosphate buffer (rN 8) for 10 min. The degrees of degradation for the obtained samples were studied during 1-96 h in solutions with pH values of 5.0, 7.0 and 8.5. The results revealed resistance of the films within the first 6 h, followed by their subsequent degradation. The rate of degradation depended on pH of the solution, chitosan percentage and the treatment methods of films. The materials with the initial chitosan content of 3% were more resistant to the hydrolytic degradation, but the decreasing in pH accelerated the weight loss of the film. However, if the membranes were treated with phosphate buffer, the rate and degree of sample degradation were slowed down. Thus, the results are considered as a basis for the further development of biomaterials to treat the skin surface damages. PMID- 25552503 TI - [The correcting effects of dihydroquercetin in cerebral ischemia-reperfusion injury]. AB - The dynamics of changes in the mitochondrial respiratory function, changes in the parameters of carbohydrate metabolism and some parameters of oxidative stress in the brain tissue have been investigated under conditions of ischemia-reperfusion and administration of dihydroquercetin. Dihydroquercetin (65 mg/kg) was administered per os 1 h before modeling of ischemia-reperfusion. Studies were carried 1 h after reperfusion. It was found that administration of dihydroquercetin caused a corrective effect to impairments of the respiratory function of mitochondria, indicators of carbohydrate metabolism and parameters of oxidative stress induced by ischemia-reperfusion. PMID- 25552504 TI - [HPLC analysis of dehydroepiandrosterone sulfate in serum with use of solid-phase extraction on hyper cross-linked polystyrene (Purosep-200)]. AB - We have developed a simple HPLC method for analysis of the dehydroepiandrosterone sulfate (DHEA-sulfate) in serum with use a new procedure of solid-phase extraction (SPE) on hyper cross-linked polystyrene (Purosep-200) and fast chromatographic separation on the monolithic column under isocratic elution and UV detection at 200 nm. Complete SPE procedure lasts for about 7 min, chromatographic separation takes less than 6 min. Simplicity and high reproducibility of this method makes it attractive in routine clinical practice. PMID- 25552505 TI - [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT]. AB - Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89+/-0.86 mg/kg/day and 7.77+/-0.17 mg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins. PMID- 25552506 TI - [Production of nitric oxide metabolites during transplanted tumors growth with different metastatic potential]. AB - The endogenous formation of metabolites of NO - nitrite (NI), nitrates (NA) and volatile nitrosamines in the body, tumor tissue and by abdominal cavity by macrophages for dynamics was investigated in mice F1(C57BlxCBA), Balb/c and BDF with subcutaneous transplanted tumors (Erlich carcinoma - EC and metastatic Lewis lung carcinoma - LLC). It was shown that growth of EC was accompanied by a statistically significant increase in the concentrations of NI and NA in tumor tissue to (7.3+/-4.67)'10-6 - (7.8+/-2.57)'10-5 (mol/kg) for the first three weeks and a sharp increase in urinary excretion of NI and NA. The maximum total concentration of NI and NA - (3.,6+/-0.46)'10-5 in tissue LLC was registered during the early stage of the tumor growth (7 days); it later declined, negatively correlating with the mass of the tumor. NI secretion by abdominal cavity macrophages demonstrated statistically significantly decrease at the stage of intensive growth LLC (14, 21 days). The tissue of EC contained varied concentration of cancerogenic N-nitrosodimethylamine and N-nitrosodiethylamine at all investigated time points. Thus, the ability of different gistogenesis tumor tissue to synthesize metabolites NO depended on time parameters and was more pronounced for EC, than LLC. PMID- 25552507 TI - [In vitro protein phosphorylation as a template for SRM method development]. AB - Phosphorylation is one of the most common posttranslational modification (PTM) of proteins. Main challenge of phosphoprotein detection is their low abundance comparing to abundance of unmodified proteins. The method of selected reactions monitoring (SRM) allows to perform very sensitive and selective analysis of desired PTMs. Using myelin basic protein (MBP) as a model we have developed a method for phosphoprotein detection by SRM. The method is based on obtaining of phosphoproteins in a reconstituted kinase system and following usage these phosphorylated protein as a template for the development of the SRM method. The developed method was successfully applied for detection of phosphopeptides of myelin basic protein in the samples of human brain glioma. PMID- 25552509 TI - [Membrane type 1 matrix metalloproteinase (MT1-MMP) and the regulators of its activity as invasive factors in squamous cell cervical carcinomas]. AB - Membrane type 1 matrix metalloproteinase (MT1MMP) is one of matrix metalloproteinases (MMP), which play a key role in tumor invasion and metastasis. The aim of this study was to elucidate the peculiarities of expression of MT1MMP and endogenous regulators of its activity: the activator - furin and the inhibitor - TIMP-2, as invasive factors of squamous cell cervical carcinomas (SCC). The study was carried out using 11 specimens of SCC and 11 specimens of morphologically normal tissue adjacent to the tumor. It was shown that the increase of MT1-MMP and furin expression and low of TIMP-2 expression makes the main contribution to the destructive (invasive) potential of SCC. Moreover, substantial expression of MT1-MMP was registered in the specimens of morphologically normal adjoining to tumor tissue. This expression was found to make an additional contribution to the destructive potential of the cervical tumor. PMID- 25552508 TI - [Thrombolysis with plasminogen activators: use and research of serine proteinases, promise and actuality]. AB - Physiological plasminogen activators of tissue and urokinase type (serine proteinases) are effective thrombolytic agents. Research and development of their novel forms contributed to progress of thrombolytic therapy, advanced treatment of acute coronary syndrome and a marked decrease in the lethal index. PMID- 25552510 TI - [Non-esterified fatty acids of blood serum in type 1 diabetic women during late pregnancy]. AB - Using gas chromatography a comparative study of the range and content of individual non-esterified fatty acids in serum of patients with diabetes mellitus type 1 in the third trimester of pregnancy, and healthy pregnant and non-pregnant women has been carried out. In groups of pregnant women there was activation of lipid metabolism, confirmed by corresponding changes in serum biochemical parameters, as well as in the content of non-esterified fatty acids. Intergroup differences in the non-esterified fatty acids were not found. However, there were significant differences between the examined groups in the quantitative content of non-esterified fatty acids. PMID- 25552511 TI - [Variability in the relative quantity of human DNA resulted from metagenomic analysis of gut microbiota]. AB - We conducted the comparative study of seven different methods of total DNA extraction from human feces. All these methods are recommended in protocols for metagenomic analysis of human gut microbiota. We studied the relative quantity of human DNA calculated from shotgun sequencing on a SOLiD 4 genetic analyzer of metagenomic samples. It was shown that either initial amount of feces or a method applied for total DNA extraction do not affect on final relative human DNA abundance, which is less than 1% in healthy people. Invariance of this parameter allows to consider increased abundance of human DNA in metagenomic samples as a potential marker of inflammatory bowel diseases. PMID- 25552513 TI - [A plain method of prediction of visibility of peptides in mass spectrometry with electrospray ionization]. AB - A new method for screening of essential peptides for protein detection and quantification analysis in the direct positive electrospray mass spectrometry has been proposed. Our method is based on the prediction of the normalized abundance of the mass spectrometric peaks using a linear regression model. This method has the following limitations: (i) selected peptides should be taken so that at pH 2.5 the tested peptides must be presented mainly as the 2+ and 3+ ions; (ii) only peptides having C-terminal lysine or arginine residues are considered. The amino acid composition of the peptide, the peptide concentration, the ratio of the polar surface of peptide to common surface and ratio of the polar volume to common volume are used as independent variables in equation. Several combinations of variables were considered and the best linear regression model had a determination coefficient in leave-one-out validation procedure equal 0.54. This model confidently discriminates peptides with high response ability and peptides with low response ability, and therefore it allows to select only the most promising peptides. This screening method, a plain and fast, can be successfully applied to reduce the list of observed peptides. PMID- 25552512 TI - [Peptide-agonist of protease-activated receptor (PAR 1), similar to activated protein C, promotes proliferation in keratinocytes and wound healing of epithelial layer]. AB - Activated protein C (APC) is serine protease hemostasis, independent of its anticoagulant activity, exhibits anti-inflammatory and anti-apoptotic properties that determine the possibility of the protective effects of APC in different diseases, including sepsis and chronic wound healing. APC, binding of endothelial protein C receptor (EPCR) and specifically cleaving PAR1 receptor and releasing peptide agonist PAR1 stabilizes not only endothelial cells, but also many others, including epidermal keratinocytes of the skin. We develop the hypothesis that the cytoprotective effect of APC on the cells, involved in wound healing, seem to imitate peptide - analogous of PAR1 "tethered ligand" that activate PAR1. In our work, we synthesized a peptide (AP9) - analogue of PAR1 tethered ligand, released by APC, and firstly showed that peptide AP9 (0.1-10 mM), like to APC (0.01-100 nM), stimulates the proliferative activity of human primary keratinocytes. Using a model of the formation of epithelial wounds in vitro we found that peptide AP9, as well as protease APC, accelerates wound healing. Using specific antibodies to the receptor PAR1 and EPCR was studied the receptor mechanism of AP9 action in wound healing compared with the action of APS. The necessity of both receptors - PAR1 and EPSR, for proliferative activity of agonists was revealed. Identified in our work imitation by peptide AP9 - PAR1 ligand, APC acts on keratinocytes suggests the possibility of using a peptide AP9 to stimulate tissue repair. PMID- 25552514 TI - [Development of targeted drug delivery system: synthesis of conjugates of address fragment (RA-COOH) with ligand (R-NH2)]. AB - One of the main ways to increase the effectiveness of well-known medical formulations well-established in clinical medicine - development of delivery systems using new technological approaches and nanomaterials. Currently, much attention is given to targeted delivery systems. At the same time drug carrier has in addition to medication the so-called vector/address with a high affinity for binding to specific receptors on cells/tissue target. In this paper it is described the method for producing of address conjugates to over-expressed receptors on the tumor cells. As address fragment it was folic acid and as a linker was dodecylamine, causing inclusion the conjugate into lipid nanoparticles. PMID- 25552517 TI - Dietary Sodium: Where Science and Policy Diverge. PMID- 25552515 TI - Association of Uric Acid With Vascular Stiffness in the Framingham Heart Study. AB - BACKGROUND: Uric acid is associated with increased risk of cardiovascular disease and arterial stiffness in patients with hypertension or stroke. It remains unknown if uric acid is associated with arterial stiffness in the general population. METHODS: We analyzed the association between serum uric acid levels and measures of arterial stiffness such as carotid-femoral pulse wave velocity (CF PWV), carotid-radial pulse wave velocity (CR PWV) and augmentation index (AI) in 4,140 participants from the Generation 3 Framingham cohort using linear regression. RESULTS: Mean (SD) age was 40.0 (8.8) years and mean (SD) serum uric acid levels were 5.3 (1.5) mg/dl. Mean (SD) CF PWV was 7.0 (1.4) m/s. Individuals in the highest quartile of uric acid were more likely to be male, have a higher prevalence of hypertension, higher BMI, fasting glucose and insulin, and lower estimated glomerular filtration rate (eGFR). Multivariate adjusted means of CF PWV were 6.90, 6.94, 7.06, and 7.15 m/s for uric acid quartile 1, 2, 3, and 4 respectively. In unadjusted analysis each 1mg/dl increase in uric acid was associated with higher CF-PWV (beta = 0.27; 95% CI = 0.25, 0.29; P < 0.0001). This was attenuated but remained significant after adjusting for age, sex, smoking, hypertension, BMI, fasting glucose, insulin, animal protein intake, and eGFR (beta= 0.06; 95% CI = 0.02, 0.09; P < 0.0007). There was no association between serum uric acid levels and AI upon adjustment for cardiovascular risk factors. CONCLUSIONS: Serum uric acid levels are significantly associated with CF PWV and CR PWV in a younger Caucasian population. PMID- 25552518 TI - Human mesenchymal stem cells as a novel platform for simultaneous evaluation of cytotoxicity and genotoxicity of pharmaceuticals. AB - The in vitro micronucleus test is a well-known test for the screening of genotoxic compounds. However until now, most studies have been performed on either human peripheral lymphocytes or established cancer cell lines. This study provides human mesenchymal stem cells as an alternative to the conventional micronucleus test. We grew umbilical cord mesenchymal stem cells (UC-MSCs) on coverslips eliminating the cumbersome technique involving hypotonic treatment, fixation and preparing smears required for suspension culture (lymphocytes). The background frequency of nuclear blebs and micronuclei in UC-MSCs was found to be 7+/-5, in lymphocytes 16+/-3.5 and 9+/-3 and that for A549 cell line was 65+/-5 and 15+/-5 per 1000 cells, respectively, suggesting differences in the repair mechanism of normal and cancer cell lines. We inspected the cytotoxic and genotoxic effects of two known mutagens, mitomycin-C and hydrogen peroxide (H2O2), on UC-MSCs, lymphocytes and A549 cells. Treatment with mitomycin-C and H2O2 demonstrated drastic differences in the degree of cytotoxicity and genotoxicity suggesting a constitutional difference between normal and cancer cells. In addition we tested two solvents, dimethyl sulfoxide (DMSO) and ethanol, and two drugs, metformin and rapamycin. DMSO above 1% was found to be cytotoxic and genotoxic, whereas ethanol at same concentration was neither cytotoxic nor genotoxic indicating the minimal non-toxic level of the solvents. This study thus offers UC-MSCs as a better substitute to peripheral lymphocytes and cancer cell lines for high throughput screening of compounds and reducing the animal studies. PMID- 25552519 TI - US campus and university debit card policies regarding tobacco and electronic cigarettes. PMID- 25552516 TI - Differential Effect of Renal Cortical and Medullary Interstitial Fluid Calcium on Blood Pressure Regulation in Salt-Sensitive Hypertension. AB - BACKGROUND: Hypercalciuria is a frequent characteristic of hypertension. In this report we extend our earlier studies investigating the role of renal interstitial fluid calcium (ISF(Ca))(2+) as a link between urinary calcium excretion and blood pressure in the Dahl salt-sensitive (DS) hypertensive model. METHODS: Dahl salt sensitive and salt-resistant (DR) rats were placed on control (0.45%) and high (8%) salt diets to determine if changes in renal cortical and medullary ISF(Ca)(2+)correlated with changes in urinary calcium excretion and blood pressure. RESULTS: We observed that renal ISFCa(2+) was predicted by urinary calcium excretion (P < 0.05) in DS rats but not DR rats. Renal cortical ISF(Ca)(2+) was negatively associated with blood pressure (P < 0.03) while renal medullary ISF(Ca)(2+) was positively associated with blood pressure in DS rats (P < 0.04). In contrast, neither urinary calcium excretion nor renal ISF(Ca)(2+) was associated with blood pressure in the DR rats under the conditions of this study. CONCLUSION: We interpret these findings to suggest that decreased renal cortical ISF(Ca)(2+) plays a role in the increase in blood pressure following a high salt diet in salt hypertension perhaps by mediating renal vasoconstriction; the role of medullary calcium remains to be fully understood. Further studies are needed to determine the mechanism of the altered renal ISF(Ca)(2+) and its role in blood pressure regulation. PMID- 25552520 TI - A new approach for the oocyte genotoxicity assay: adaptation of comet assay on mouse cumulus-oocyte complexes. AB - Conventional genotoxicity tests are technically difficult to apply to oocytes, and results obtained on somatic cells cannot be extrapolated to gametes. We have previously described a comet assay (original-CA) on denuded mouse oocytes, but, in vivo, oocytes are not isolated from their surrounding follicular cells. Our objective was to develop a comet assay on cumulus-oocyte complexes (COC-CA) for a more physiological approach to study the genotoxicity of environmental factors on oocytes. For COC-CA, whole COC were exposed directly to exogenous agents after ovulation and removal from oviducts. Three conditions were studied: a negative control group, and two positive control groups, one of which was exposed to hydrogen peroxide (H2O2) and the other group was incubated with cerium dioxide nanoparticles (CeO2 NPs). With both tests, DNA damage was significant in the presence of both H2O2 and CeO2 NPs compared with the negative control. COC-CA offers an interesting tool for assaying the genotoxicity of environmental agents towards germinal cells. Furthermore, COC-CA is less time-consuming and simplifies the protocol of the original-CA, because COC-CA is easier to perform without the washing-out procedure. PMID- 25552521 TI - Non-invasive blood pressure measurement: values, problems and applicability in the common marmoset (Callithrix jacchus). AB - The common marmoset (Callithrix jacchus, C. j.) is an established primate model in biomedical research and for human-related diseases. Monitoring of cardiovascular parameters including blood pressure (BP) is important for the health surveillance of these experimental animals and the quantification of diseases or pharmaceutical substances influencing BP. Measurement guidelines for C. j. do not exist yet; therefore, the present study was carried out to establish a practicable protocol based on recommendations of the American College of Veterinary Internal Medicine (ACVIM). Furthermore, BP data of 49 marmosets (13.8 202.4 months of age) were obtained via high-definition oscillometry to further knowledge of physiological parameters and gender-related differences in this primate. The thighs proved to be the most suitable measurement localization, since systolic values were less variable (left 4.03 +/- 2.90%, right 5.96 +/- 2.77%) compared with the tail (12.7 +/- 6.96%). BP values were similar in the morning and in the afternoon (P > 0.05). Data were highly reproducible within and between several sessions on three consecutive days (P > 0.05) as well as over the course of 20 months (P > 0.05). Furthermore, the measurement time for females was significantly shorter than for males (5:14 +/- 1:59 min versus 6:50 +/- 1:58 min, P = 0.007). Measurement recommendations for the common marmoset were successfully established. Standardized values enabled a reliable comparison of BP parameters, e.g. for cardiovascular, toxicological or metabolic research. PMID- 25552522 TI - Does adding a dietician to the liaison team after discharge of geriatric patients improve nutritional outcome: a randomised controlled trial. AB - OBJECTIVES: The objective was to test whether adding a dietician to a discharge Liaison-Team after discharge of geriatric patients improves nutritional status, muscle strength and patient relevant outcomes. DESIGN: Twelve-week randomized controlled trial. SETTING AND SUBJECTS: Geriatric patients (70 + years and at nutritional risk) at discharge. INTERVENTIONS: Participants were randomly allocated to receive discharge Liaison-Team vs. discharge Liaison-Team in cooperation with a dietician. The dietician performed a total of three home visits with the aim of developing and implementing an individual nutritional care plan. The first visit took place at the day of discharge together with the discharge Liaison-Team while the remaining visits took place approximately three and eight weeks after discharge and were performed by a dietician alone. MAIN MEASURES: Nutritional status (weight, and dietary intake), muscle strength (hand grip strength, chair-stand), functional status (mobility, and activities of daily living), quality of life, use of social services, re-/hospitalization and mortality. RESULTS: Seventy-one patients were included (34 in the intervention group), and 63 (89%) completed the second data collection after 12 weeks (31 in the intervention group). Odds ratios for hospitalization and mortality 6 months after discharge were 0.367 (0.129; 1.042) and 0.323 (0.060; 1.724). Nutritional status improved and some positive tendencies in favour of the intervention group were observed for patient relevant outcomes, i.e. activities of daily living, and quality of life. Almost 100% of the intervention group received three home visits by a dietician. CONCLUSION: Adding a dietician to the discharge Liaison-Team after discharge of geriatric patients can improve nutritional status and may reduce the number of times hospitalized within 6 months. A larger study is necessary to see a significant effect on other patient relevant outcomes. PMID- 25552523 TI - Functional outcomes of outpatient balance training following total knee replacement in patients with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To evaluate whether balance training after total knee replacement surgery improves functional outcomes and to determine whether postoperative balance is associated with mobility. DESIGN: A prospective intervention study and randomized controlled trial with an intention-to-treat analysis. SETTING: The rehabilitation center of a university-based teaching hospital. PARTICIPANTS: A total of 130 patients with knee osteoarthritis who had undergone total knee replacement surgery were recruited to attend an outpatient rehabilitation program. They were randomly allocated to additional balance rehabilitation and functional rehabilitation groups. INTERVENTIONS: During the eight-week outpatient rehabilitation program, both groups received general functional training. Patients in the balance rehabilitation group received an additional balance-based rehabilitation program. PRIMARY OUTCOME MEASURES: The functional reach test, single-leg stance test, 10-m walk test, Timed Up and Go Test, timed chair-stand test, stair-climb test, and Western Ontario and McMaster Universities Osteoarthritis Index were measured at baseline, eight weeks (T(1)), and 32 weeks (T(2)). RESULTS: The balance rehabilitation group patients demonstrated significant improvement in the results of the functional reach test at T(1) (37.6 +/-7.8 cm) and T(2) (39.3 +/-9.7 cm) compared with the baseline assessment (11.5 +/-2.9 cm) and Timed Up and Go Test at T(1) (8.9 +/-1.2 seconds) and T(2) (8.0 +/ 1.9 seconds) compared with the baseline assessment (12.5 +/-1.8 seconds). Moreover, the balance rehabilitation group patients exhibited significantly greater improvements in balance and mobility than did the functional rehabilitation group patients (all P < 0.001). Furthermore, improved balance was significantly associated with improved mobility at T(2). CONCLUSION: Postoperative outpatient rehabilitation with balance training improves the balance, mobility, and functional outcomes in patients with knee osteoarthritis after total knee replacement. PMID- 25552525 TI - A feasibility and pilot randomized controlled trial of the "Timing it Right Stroke Family Support Program". AB - OBJECTIVE: Examine feasibility of conducting a randomized controlled trial of the Timing it Right Stroke Family Support Program (TIRSFSP) and collect pilot data. DESIGN: Multi-site mixed method randomized controlled trial. SETTING: Acute and community care in three Canadian cities. SUBJECTS: Caregivers were family members or friends providing care to individuals who experienced their first stroke. INTERVENTION: The TIRSFSP offered in two formats, self-directed by the caregiver or stroke support person-directed over time, were compared to standard care. MAIN MEASURES: Caregivers completed baseline and follow-up measures 1, 3 and 6 months post-stroke including Centre for Epidemiological Studies Depression, Positive Affect, Social Support, and Mastery Scales. We completed in-depth qualitative interviews with caregivers and maintained intervention records describing support provided to each caregiver. RESULTS: Thirty-one caregivers received standard care (n=10), self-directed (n=10), or stroke support person-directed (n=11) interventions. We retained 77% of the sample through 6-months. Key areas of support derived from intervention records (n=11) related to caregiver wellbeing, caregiving strategies, patient wellbeing, community re-integration, and service delivery. Compared to standard care, caregivers receiving the stroke support person-directed intervention reported improvements in perceived support (estimate 3.1, P=.04) and mastery (estimate .35, P=.06). Qualitative caregiver interviews (n=19) reflected the complex interaction between caregiver needs, preferences and available options when reporting on level of satisfaction. CONCLUSIONS: Preliminary findings suggest the research design is feasible, caregivers' needs are complex, and the support intervention may enhance caregivers' perceived support and mastery. The intervention will be tested further in a large scale trial. PMID- 25552526 TI - Respiratory muscle training on pulmonary and swallowing function in patients with Huntington's disease: a pilot randomised controlled trial. AB - OBJECTIVE: To examine the effects of 4-month of respiratory muscle training on pulmonary and swallowing function, exercise capacity and dyspnoea in manifest patients with Huntington's disease. DESIGN: A pilot randomised controlled trial. SETTING: Home based training program. PARTICIPANTS: Eighteen manifest Huntington's disease patients with a positive genetic test and clinically verified disease expression, were randomly assigned to control group (n=9) and training group (n=9). INTERVENTION: Both groups received home-based inspiratory (5 sets of 5 repetitions) and expiratory (5 sets of 5 repetitions) muscle training 6 times a week for 4 months. The control group used a fixed resistance of 9 centimeters of water, and the training group used a progressively increased resistance from 30% to 75% of each patient's maximum respiratory pressure. MAIN MEASURES: Spirometric indices, maximum inspiratory pressure, maximum expiratory pressure, six minutes walk test, dyspnoea, water-swallowing test and swallow quality of life questionnaire were assessed before, at 2 and 4 months after training. RESULTS: The magnitude of increases in maximum inspiratory (d=2.9) and expiratory pressures (d=1.5), forced vital capacity (d=0.8), forced expiratory volume in 1 second (d=0.9) and peak expiratory flow (d=0.8) was substantially greater for the training group in comparison to the control group. Changes in swallowing function, dyspnoea and exercise capacity were small (d <= 0.5) for both groups without substantial differences between groups. CONCLUSIONS: A home based respiratory muscle training program appeared to be beneficial to improve pulmonary function in manifest Huntington's disease patients but provided small effects on swallowing function, dyspnoea and exercise capacity. PMID- 25552527 TI - Professional Service Use for a Serious Personal Problem: Comparing Older African Americans, Black Caribbeans, and Non-Hispanic Whites Using the National Survey of American Life. AB - OBJECTIVES: Examines combinations of professionals visited for a serious personal problem. METHOD: The sample includes those aged 55 and above (N = 862) from the National Survey of American Life (NSAL). Latent class analysis was used to identify groups of respondents based on types of professionals visited. Multinomial logistic regression was used to identify factors associated with group membership. RESULTS: Classes included health provider plus clergy, physician plus mental health provider, and limited provider use. Whites were more likely than African Americans to fall into the health provider plus clergy and physician plus mental health provider classes. Those with physical and emotional problems were more likely to be in the health provider plus clergy and physician plus mental health provider classes, respectively. DISCUSSION: Most respondents were in the limited provider use class suggesting that for many problems, minimal professional help is utilized. Physicians and clergy were important across all three classes. PMID- 25552528 TI - Older persons' views and experience of elder abuse in South Western Nigeria: a community-based qualitative survey. AB - OBJECTIVES: Conventionally, existing information on elder abuse has been institution based, professionally driven, and in high-income countries. This study addresses the prevailing gap in knowledge through direct consultation of older persons in the community about their perceptions of elder abuse. METHOD: Eight focus group discussions were carried out among males and females aged 60 years and above in a rural and an urban community in south western Nigeria. Data were transcribed and analyzed based on emergent themes. RESULTS: Findings from the study show that the perception of abuse by the respondents included the standard typologies except sexual abuse as well as societal issues such as disrespect and lack of recognition. DISCUSSION: Our study revealed a high level of awareness and experience of elder abuse among the participants in both communities. Effective social welfare and health services aided by targeted government policies are needed to improve the quality of life of the elderly. PMID- 25552529 TI - Mortality rates for same-sex married individuals compared with opposite-sex married individuals: potential analytical problems. PMID- 25552530 TI - Authors' response to: Mortality rates for same-sex married individuals compared with opposite-sex married individuals. PMID- 25552531 TI - Extreme features of the Galdieria sulphuraria organellar genomes: a consequence of polyextremophily? AB - Nuclear genome sequencing from extremophilic eukaryotes has revealed clues about the mechanisms of adaptation to extreme environments, but the functional consequences of extremophily on organellar genomes are unknown. To address this issue, we assembled the mitochondrial and plastid genomes from a polyextremophilic red alga, Galdieria sulphuraria strain 074 W, and performed a comparative genomic analysis with other red algae and more broadly across eukaryotes. The mitogenome is highly reduced in size and genetic content and exhibits the highest guanine-cytosine skew of any known genome and the fastest substitution rate among all red algae. The plastid genome contains a large number of intergenic stem-loop structures but is otherwise rather typical in size, structure, and content in comparison with other red algae. We suggest that these unique genomic modifications result not only from the harsh conditions in which Galdieria lives but also from its unusual capability to grow heterotrophically, endolithically, and in the dark. These conditions place additional mutational pressures on the mitogenome due to the increased reliance on the mitochondrion for energy production, whereas the decreased reliance on photosynthesis and the presence of numerous stem-loop structures may shield the plastome from similar genomic stress. PMID- 25552532 TI - A simple method for estimating the strength of natural selection on overlapping genes. AB - Overlapping genes, where one DNA sequence codes for two proteins with different reading frames, are not uncommon in viruses and cellular organisms. Estimating the direction and strength of natural selection acting on overlapping genes is important for understanding their functionality, origin, evolution, maintenance, and potential interaction. However, the standard methods for estimating synonymous (dS) and nonsynonymous (dN) nucleotide substitution rates are inapplicable here because a nucleotide change can be simultaneously synonymous and nonsynonymous when both reading frames involved are considered. We have developed a simple method that can estimate dN/dS and test for the action of natural selection in each relevant reading frame of the overlapping genes. Our method is an extension of the modified Nei-Gojobori method previously developed for nonoverlapping genes. We confirmed the reliability of our method using extensive computer simulation. Applying this method, we studied the longest human sense-antisense overlapping gene pair, LRRC8E and ENSG00000214248. Although LRRC8E (leucine-rich repeat containing eight family, member E) is known to regulate cell size, the function of ENSG00000214248 is unknown. Our analysis revealed purifying selection on ENSG00000214248 and suggested that it originated in the common ancestor of bony vertebrates. PMID- 25552533 TI - Basal Gnathostomes provide unique insights into the evolution of vitamin B12 binders. AB - The uptake and transport of vitamin B12 (cobalamin; Cbl) in mammals involves a refined system with three evolutionarily related transporters: transcobalamin 1 (Tcn1), transcobalamin 2 (Tcn2), and the gastric intrinsic factor (Gif). Teleosts have a single documented binder with intermediate features to the human counterparts. Consequently, it has been proposed that the expansion of Cbl binders occurred after the separation of Actinopterygians. Here, we demonstrate that the diversification of this gene family took place earlier in gnathostome ancestry. Our data indicates the presence of single copy orthologs of the Sarcopterygii/Tetrapoda duplicates Tcn1 and Gif, and Tcn2, in Chondrichthyes. In addition, a highly divergent Cbl binder was found in the Elasmobranchii. We unveil a complex scenario forged by genome, tandem duplications and lineage specific gene loss. Our findings suggest that from an ancestral transporter, exhibiting large spectrum and high affinity binding, highly specific Cbl transporters emerged through gene duplication and mutations at the binding pocket. PMID- 25552535 TI - Patterns of evolutionary conservation of ascorbic acid-related genes following whole-genome triplication in Brassica rapa. AB - Ascorbic acid (AsA) is an important antioxidant in plants and an essential vitamin for humans. Extending the study of AsA-related genes from Arabidopsis thaliana to Brassica rapa could shed light on the evolution of AsA in plants and inform crop breeding. In this study, we conducted whole-genome annotation, molecular-evolution and gene-expression analyses of all known AsA-related genes in B. rapa. The nucleobase-ascorbate transporter (NAT) gene family and AsA l galactose pathway genes were also compared among plant species. Four important insights gained are that: 1) 102 AsA-related gene were identified in B. rapa and they mainly diverged 12-18 Ma accompanied by the Brassica-specific genome triplication event; 2) during their evolution, these AsA-related genes were preferentially retained, consistent with the gene dosage hypothesis; 3) the putative proteins were highly conserved, but their expression patterns varied; and 4) although the number of AsA-related genes is higher in B. rapa than in A. thaliana, the AsA contents and the numbers of expressed genes in leaves of both species are similar, the genes that are not generally expressed may serve as substitutes during emergencies. In summary, this study provides genome-wide insights into evolutionary history and mechanisms of AsA-related genes following whole-genome triplication in B. rapa. PMID- 25552536 TI - Effects of carnosine, taurine, and betaine pretreatments on diethylnitrosamine induced oxidative stress and tissue injury in rat liver. AB - Several chemicals such as N-diethylnitrosamine (DEN) promote hepatocellular cancer in rodents and induce hepatocyte injury. DEN affects the initiation stage of carcinogenesis together with enhanced cell proliferation accompanied by hepatocellular necrosis. DEN-induced hepatocellular necrosis is reported to be related to enhanced generation of reactive oxygen species. Carnosine (CAR), taurine (TAU), and betaine (BET) are known to have powerful antioxidant properties. We aimed to investigate the effects of CAR, TAU, and BET pretreatments on DEN-induced oxidative stress and liver injury in male rats. Rats were given CAR (2 g L-1 in drinking water), TAU (2.5% in chow), and BET (2.5% in chow) for 6 weeks and DEN (200 mg kg-1 intraperitoneally) was given 2 days before the end of this period. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and gamma-glutamyl transferase activities were determined and a histopathologic evaluation was performed on the liver tissue. Oxidative stress was detected in the liver by measuring malondialdehyde, diene conjugate, protein carbonyl and nitrotyrosine levels, glutathione and glutathione peroxidase levels, and superoxide dismutase and glutathione transferase activities. Pretreatments with CAR, TAU, and BET decreased liver prooxidant status without remarkable changes in antioxidant parameters in DEN-treated rats. Pretreatments with TAU and BET, but not CAR, were also found to be effective to reduce liver damage in DEN-treated rats. In conclusion, TAU, BET, and possibly CAR may have an ameliorating effect on DEN induced hepatic injury by reducing oxidative stress in rats. PMID- 25552537 TI - The induction of lipid peroxidation during the acute oxidative stress response induced by intratracheal instillation of fine crystalline silica particles in rats. AB - Crystalline silica (SiO2) is an important material for industry but is considered potentially carcinogenic. Inhalation of a crystalline SiO2 aerosol may contribute to serious lung diseases. Crystalline SiO2 particles are commonly used as a positive control in toxicity assays of particulate materials (e.g. nanoparticles). Crystalline SiO2 induces oxidative stress resulting in lipid peroxidation, but the acute oxidative stress response in the lung is not well understood. Lipid peroxidation during the acute stage of oxidative stress after instillation of crystalline SiO2 into rats was examined by bronchoalveolar lavage fluid (BALF) analysis. The levels of 8-iso-prostaglandin F2alpha and hydroxyoctadecadienoic acid (HODE) in the BALF were measured using liquid chromatography coupled to quadrupole mass spectrometry. The concentration of the antioxidant protein heme oxygenase-1 (HO-1) in the BALF was determined using enzyme-linked immunosorbent assay. Intratracheal instillation of crystalline SiO2 increased the level of HODE and HO-1 in BALF at 24 h after administration. The levels of HODE and HO-1 returned to baseline at 72 h after instillation. Lactate dehydrogenase leakage was observed only after 1 h instillation. These results suggest that the contribution of oxidative stress to the pulmonary toxicity of crystalline SiO2 is minimal in the early acute stage after exposure. PMID- 25552534 TI - Genomics of ecological adaptation in cactophilic Drosophila. AB - Cactophilic Drosophila species provide a valuable model to study gene-environment interactions and ecological adaptation. Drosophila buzzatii and Drosophila mojavensis are two cactophilic species that belong to the repleta group, but have very different geographical distributions and primary host plants. To investigate the genomic basis of ecological adaptation, we sequenced the genome and developmental transcriptome of D. buzzatii and compared its gene content with that of D. mojavensis and two other noncactophilic Drosophila species in the same subgenus. The newly sequenced D. buzzatii genome (161.5 Mb) comprises 826 scaffolds (>3 kb) and contains 13,657 annotated protein-coding genes. Using RNA sequencing data of five life-stages we found expression of 15,026 genes, 80% protein-coding genes, and 20% noncoding RNA genes. In total, we detected 1,294 genes putatively under positive selection. Interestingly, among genes under positive selection in the D. mojavensis lineage, there is an excess of genes involved in metabolism of heterocyclic compounds that are abundant in Stenocereus cacti and toxic to nonresident Drosophila species. We found 117 orphan genes in the shared D. buzzatii-D. mojavensis lineage. In addition, gene duplication analysis identified lineage-specific expanded families with functional annotations associated with proteolysis, zinc ion binding, chitin binding, sensory perception, ethanol tolerance, immunity, physiology, and reproduction. In summary, we identified genetic signatures of adaptation in the shared D. buzzatii D. mojavensis lineage, and in the two separate D. buzzatii and D. mojavensis lineages. Many of the novel lineage-specific genomic features are promising candidates for explaining the adaptation of these species to their distinct ecological niches. PMID- 25552538 TI - Embryotoxicity of nitrophenols to the early life stages of zebrafish (Danio rerio). AB - The nitrophenols (NPs) are water-soluble compounds. These compounds pose a significant health threat since they are priority environmental pollutants. In this study, 2-Nitrophenol (2NP) and 2,4-dinitrophenol (DNP) were examined for embryo and early life stage toxicity in zebrafish (Danio rerio). Acute toxicity and teratogenicity of 2NP and DNP were tested for 4 days using zebrafish embryos. The typical lesions observed were no somite formation, incomplete eye and head development, tail curvature, weak pigmentation (<=48 hours postfertilization (hpf)), kyphosis, scoliosis, yolk sac deformity, and nonpigmentation (72 hpf). Also, embryo and larval mortality increased and hatching success decreased. The severity of abnormalities and mortalities were concentration- and compound dependent. Of the compounds tested, 2,4-DNP was found to be highly toxic to the fish embryos following exposure. The median lethal concentrations and median effective concentrations for 2NP are 18.7 mg/L and 7.9 mg/L, respectively; the corresponding values for DNP are 9.65 mg/L and 3.05 mg/L for 48 h. The chorda deformity was the most sensitive endpoint measured. It is suggested that the embryotoxicity may be mediated by an oxidative phosphorylation uncoupling mechanism. This article is the first to describe the teratogenicity and embryotoxicity of two NPs to the early life stages of zebrafish. PMID- 25552540 TI - Do estimated impacts on earnings depend on the source of the data used to measure them? Evidence from previous social experiments. AB - BACKGROUND: Impact evaluations draw their data from two sources, namely, surveys conducted for the evaluation or administrative data collected for other purposes. Both types of data have been used in impact evaluations of social programs. OBJECTIVE: This study analyzes the causes of differences in impact estimates when survey data and administrative data are used to evaluate earnings impacts in social experiments and discusses the differences observed in eight evaluations of social experiments that used both survey and administrative data. RESULTS: There are important trade-offs between the two data sources. Administrative data are less expensive but may not cover all income and may not cover the time period desired, while surveys can be designed to avoid these problems. We note that errors can be due to nonresponse or reporting, and errors can be balanced between the treatment and the control groups or unbalanced. We find that earnings are usually higher in survey data than in administrative data due to differences in coverage and likely overreporting of overtime hours and pay in survey data. Evaluations using survey data usually find greater impacts, sometimes much greater. CONCLUSIONS: The much lower cost of administrative data make their use attractive, but they are still subject to underreporting and other problems. We recommend further evaluations using both types of data with investigative audits to better understand the sources and magnitudes of errors in both survey and administrative data so that appropriate corrections to the data can be made. PMID- 25552539 TI - Genotoxicity in primary human peripheral lymphocytes after exposure to lithium titanate nanoparticles in vitro. AB - Lithium titanate (Li2TiO3) nanoparticles (LTT NPs; <100 nm) are widely used in battery technology, porcelain enamels, and ceramic insulating bodies. With the increased applications of LTT NPs, the concerns about their potential human toxicity effects and their environmental impact were also increased. However, toxicity data for LTT NPs relating to human health are very limited. Therefore, the purpose of this study was to evaluate whether LTT NPs are able to induce genetic damage in human peripheral lymphocytes in vitro when taking into consideration that DNA damage plays an important role in carcinogenesis. With this aim, the chromosome aberrations (CA), sister chromatid exchanges (SCE), and micronucleus (MN) assays were used as genotoxicity end points. Human peripheral lymphocytes obtained from five healthy male volunteers were exposed to LTT NPs at final dispersed concentrations ranging from 0 to 1000 MUg/mL for 72 h at 37 degrees C. The obtained results indicated that LTT NPs compound did not induce DNA damage in human peripheral lymphocytes as depicted by CA/cell, SCE/cell, and MN/1000 cell values in all concentrations tested. In summary, our results revealed that exposure to LTT NPs is not capable of inducing DNA lesions in human peripheral lymphocytes for the first time. PMID- 25552541 TI - The human IL-23 receptor rs11209026 A allele promotes the expression of a soluble IL-23R-encoding mRNA species. AB - The human IL23R gene single nucleotide polymorphism rs11209026 A allele confers protection against inflammatory diseases. However, although this difference has been associated with reductions in IL-23-induced IL-17A production and STAT3 phosphorylation, the molecular mechanism underlying these changes remains undefined. Th17 cell maturation depends on IL-23 signaling. Multiple splice forms of the human IL23R transcript exist, and one, Delta9, encodes a soluble form of the receptor. In this study, we asked whether this protective allele was associated with mRNA splicing. Using mini-gene constructs and competitive oligonucleotide binding, we showed that the A allele alters IL-23R alpha-chain mRNA splicing and favors exon 9 skipping by reducing the binding of the splicing enhancer SF2. This enhances expression of the Delta9 mRNA and consequently diminishes IL-23 signaling. Thus, the presence of the A allele increases expression of the soluble form of IL23R mRNA (which then functions as a decoy receptor) and lowers the ability to develop a Th17 phenotype upon IL-23 stimulation. We further showed that antisense oligonucleotides targeting the SF2 binding site could efficiently induce exon 9 skipping in the presence of the G allele, and thereby replicate the effect of the A allele. Antisense oligonucleotide treatment caused dose-responsive induction of the IL23RDelta9 mRNA and interfered with in vitro differentiation of human Th17 cells, reducing their expression of the signature Th17 cytokines IL-17A and IL-17F. This may represent a novel approach to therapy of Th17-mediated diseases by elevating soluble IL-23R while simultaneously reducing the remaining cell surface receptor density. PMID- 25552543 TI - Homeodomain-interacting protein kinase 2, a novel autoimmune regulator interaction partner, modulates promiscuous gene expression in medullary thymic epithelial cells. AB - Promiscuous expression of a plethora of tissue-restricted Ags (TRAs) by medullary thymic epithelial cells (mTECs) plays an essential role in T cell tolerance. Although the cellular mechanisms by which promiscuous gene expression (pGE) imposes T cell tolerance have been well characterized, the underlying molecular mechanisms remain poorly understood. The autoimmune regulator (AIRE) is to date the only validated molecule known to regulate pGE. AIRE is part of higher-order multiprotein complexes, which promote transcription, elongation, and splicing of a wide range of target genes. How AIRE and its partners mediate these various effects at the molecular level is still largely unclear. Using a yeast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain-interacting protein kinase 2 (HIPK2) as a novel partner. HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human mTECs in situ. Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of AIRE in a kinase-dependent manner. To evaluate the role of Hipk2 in modulating the function of AIRE in vivo, we compared whole genome gene signatures of purified mTEC subsets from TEC-specific Hipk2 knockout mice with control mice and identified a small set of differentially expressed genes. Unexpectedly, most differentially expressed genes were confined to the CD80(lo) mTEC subset and preferentially included AIRE-independent TRAs. Thus, although it modulates gene expression in mTECs and in addition affects the size of the medullary compartment, TEC-specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo. PMID- 25552544 TI - Can VBG analysis replace ABG analysis in emergency care? AB - Blood gas analysis is an integral part of the assessment of emergency department (ED) patients with acute respiratory or metabolic disease. Traditionally ABG analyses have been used, but increasingly, emergency clinicians are using venous blood gas (VBG) analyses. This has been challenged, especially by respiratory physicians, as being too inaccurate. This clinical review, using case examples, summarises the evidence supporting use of VBG to guide management decisions. Arteriovenous agreement for pH is such that values are clinically interchangeable and agreement for bicarbonate is also close. Agreement for pCO2 is poor with 95% limits of agreement of the order of 20 mm Hg (2.67 kPa); however, there is solid evidence that a venous pCO2 <=45 mm Hg (6 kPa) reliably excludes clinically significant hypercarbia. Evidence regarding arteriovenous agreement for base excess is unclear. Given knowledge of the performance characteristics of VBG analyses, integration of the clinical findings with VBG results is often sufficient to safely guide treatment decision making. PMID- 25552542 TI - Apoptosis-associated speck-like protein containing a CARD forms specks but does not activate caspase-1 in the absence of NLRP3 during macrophage swelling. AB - Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is a key adaptor molecule required for the inflammatory processes. ASC acts by bridging NLRP proteins, such as NLRP3, with procaspase-1 within the inflammasome complex, which subsequently results in the activation of caspase-1 and the secretion of IL-1beta and IL-18. In response to bacterial infection, ASC also forms specks by self-oligomerization to activate caspase-1 and induce pyroptosis. Hitherto, the role of these specks in NLRP3 inflammasome activation in response to danger signals, such as a hypotonic environment, largely has been unexplored. In this article, we report that, under hypotonic conditions and independently of NLRP3, ASC was able to form specks that did not activate caspase-1. These specks were not associated with pyroptosis and were controlled by transient receptor potential vanilloid 2 channel-mediated signaling. However, interaction with NLRP3 enhanced ASC speck formation, leading to fully functional inflammasomes and caspase-1 activation. This study reveals that the ASC speck can present different oligomerization assemblies and represents an essential step in the activation of functional NLRP3 inflammasomes. PMID- 25552545 TI - Prevalence and molecular characteristics of methicillin-resistant Staphylococcus aureus among skin and soft tissue infections in an emergency department in Guyana. AB - OBJECTIVE: The characteristics of staphylococcal skin and soft tissue infections (SSTIs) are poorly understood in northern South America and the Caribbean. The objectives of this study were to determine the frequency of methicillin resistance among Staphylococcus aureus isolates in an emergency department (ED) in Guyana and to identify specific molecular characteristics of these methicillin resistant Staphylococcus aureus (MRSA) strains. METHODS: This was a cross sectional study conducted at the main teaching hospital in Georgetown, Guyana. Eligible subjects included patients of all ages with SSTIs with obtainable purulent material. Purulent material was cultured, and S. aureus isolates were evaluated for antibiotic susceptibilities by disc diffusion. Molecular characterisation of MRSA isolates included identification of SCCmec type, assignment of genetic relatedness by rep-PCR and determination of the presence of two exotoxins, Panton-Valentine Leukocidin (PVL) and LukAB. RESULTS: Eighty-five samples were collected; of these, 47 grew S. aureus. 24 of the 47 S. aureus samples were MRSA (51%; 95% CI 37% to 65%), representing 28% of all samples. All MRSA isolates were SCCmec type IV, PVL positive, LukAB positive and were highly related to the current epidemic clone in the USA, USA300. CONCLUSIONS: Here, we demonstrate a clinically significant proportion of methicillin resistance in SSTI associated staphylococcal isolates. Guyanese isolates were highly related to the most common community-associated strain seen in the USA, USA300. These results have important implications for empiric antibiotic therapy and infection control policies in Guyana and similar settings. PMID- 25552546 TI - Repeated attempts at tracheal intubation by a single intubator associated with decreased success rates in emergency departments: an analysis of a multicentre prospective observational study. AB - OBJECTIVE: To determine whether the success rate of repeated attempts at tracheal intubation by a single intubator was lower than those by alternate intubators in the emergency department (ED). METHODS: An analysis of data from a multicentre prospective registry (Japanese Emergency Airway Network Registry) of 13 academic and community EDs in Japan between April 2010 and August 2012. We included all adult and paediatric patients who underwent repeated attempts at tracheal intubation in the ED. We compared the intubation success rates at the second and third attempts between attempts at intubation by a single intubator who performed the previous attempts, and the attempts by alternate intubators. RESULTS: We recorded 4094 patients (capture rate, 96%); 1289 patients with repeated attempts at tracheal intubation were eligible for this study. Among these, 871 patients (68%) had a second attempt at intubation by single intubators. At the second attempt, tracheal intubation by a single intubator was associated with a decreased success rate (adjusted odds ratio or AOR, 0.50; 95% CI 0.36 to 0.71), compared with alternate intubators. At the third attempt, intubation by a single intubator was also associated with a decreased success rate (58% vs 70%; unadjusted OR, 0.58; 95% CI 0.38 to 0.89). However, after adjustment for potential confounders, the association lost statistical significance (AOR, 0.89; 95% CI 0.52 to 1.56). CONCLUSIONS: In this large multicentre study of ED patients undergoing tracheal intubation, second attempts at intubation by a single intubator, compared with those by alternate intubators, were independently associated with a decreased success rate. PMID- 25552547 TI - Does undetectable troponin I at presentation using a contemporary sensitive assay rule out myocardial infarction? A cohort study. AB - AIM: Recent evidence suggests that an undetectable troponin level at emergency department (ED) presentation can rule out the presence of myocardial infarction (MI) in low-risk patients. The aim of this study was to investigate whether an undetectable troponin I (TnI) level at presentation using a contemporary troponin assay can accurately rule out MI at various front-door thrombolysis in myocardial infarction (fTIMI) score cut-offs. METHODS: Planned substudy of a prospective observational cohort study of patients presenting to ED with chest pain without ECG evidence of ischaemia who underwent a 'rule out' acute coronary syndrome process. Clinical, investigational and outcome data were collected. A contemporary TnI assay (Siemens TnI Ultra) was used. Primary outcome of interest was diagnostic accuracy for MI of undetectable initial TnI at presentation at various fTIMI scores (sensitivity, specificity, positive predictive value and negative predictive value (NPV)). RESULTS: 1076 patients were studied, of whom 156 had a final diagnosis of MI (14.5%). For patients with undetectable TnI and fTIMI scores 0, 0-1, 0-2 and 0-6, sensitivities were 98.7%, 98.1%, 97.4% and 97.4%, respectively, specificities were 22.6%, 41.7%, 53.8% and 69.9%, respectively, and NPV were 99%, 99.2%, 99.2% and 99.4%, respectively. If early presenters (<2 h of symptoms) were excluded, undetectable initial troponin had 100% sensitivity (95% CI 95.2% to 100%) and NPV (95% CI 98.8% to 100%). CONCLUSIONS: Using a contemporary TnI assay, undetectable initial TnI has high but not perfect sensitivity and NPV, unless early presenters are excluded. TRIAL REGISTRATION NUMBER: ACTRN12612000990820. PMID- 25552548 TI - Cell models lead to understanding of multi-cellular morphogenesis consisting of successive self-construction of cells. AB - Morphogenesis of multi-cellular organisms occurs through cell behaviours within a cell aggregate. Cell behaviours have been described using cell models involving equations of motion for cells. Cells in cell models construct shapes of the cell aggregate by themselves. Here, a history of cell models, the cell centre model and the vertex cell model, which we have constructed, are described. Furthermore, the application of these cell models is explained in detail. These cell models have been applied to transformation of cell aggregates to become spherical, formation of mammalian blastocysts and cell intercalation in elongating tissues. These are all elemental processes of morphogenesis and take place in succession during the whole developmental process. A chain of successive elemental processes leads to morphogenesis. Finally, we highlight that cell models are indispensable to understand the process whereby genes direct biological shapes. PMID- 25552549 TI - Glucocorticoid augments lipopolysaccharide-induced activation of the IkappaBzeta dependent genes encoding the anti-microbial glycoproteins lipocalin 2 and pentraxin 3. AB - Bacterial lipopolysaccharide (LPS), one of the most potent inducers of inflammation, activates the transcription factor NF-kappaB to induce expression of both proinflammatory mediators and anti-microbial glycoproteins such as lipocalin 2 (Lcn2) and pentraxin 3 (PTX3) in macrophages. Glucocorticoids are known to inhibit LPS-induced expression of proinflammatory cytokines via glucocorticoid receptor (GR)-mediated transrepression of NF-kappaB, whereas their effect on induction of anti-microbial effectors has remained to be elucidated. Here we show that the synthetic glucocorticoid dexamethasone (Dex) strongly enhances LPS-induced transcription of Lcn2 and Ptx3, although Dex by itself fails to trigger their transcription. In macrophages deficient in IkappaBzeta (an inducible coactivator of NF-kappaB), Lcn2 and Ptx3 are not activated by LPS either alone or in combination with Dex. Association of GR as well as Brg1 (a subunit of the chromatin remodelling Swi/Snf complex) with a functional glucocorticoid response element in Lcn2 requires both the costimulation with LPS and the presence of IkappaBzeta. Although Ptx3 does not contain the element, LPS induces recruitment of Dex-liganded GR to NF-kappaB-binding sites in regulatory regions of Ptx3, an event that does not occur in IkappaBzeta-deficient macrophages. Thus glucocorticoids likely regulate infection-induced inflammation by increasing anti-microbial effectors in an IkappaBzeta-dependent manner, while repressing proinflammatory genes. PMID- 25552550 TI - Reply to Wang and Zhang. PMID- 25552551 TI - Association of drug susceptibility testing results for first- and second-line drugs with treatment outcomes in patients with multidrug-resistant and extensively drug-resistant tuberculosis. PMID- 25552552 TI - Ferment in the family tree. PMID- 25552553 TI - Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells. AB - The malaria parasite, Plasmodium, must survive and develop in the mosquito vector to be successfully transmitted to a new host. The Plasmodium falciparum Pfs47 gene is critical for malaria transmission. Parasites that express Pfs47 (NF54 WT) evade mosquito immunity and survive, whereas Pfs47 knockouts (KO) are efficiently eliminated by the complement-like system. Two alternative approaches were used to investigate the mechanism of action of Pfs47 on immune evasion. First, we examined whether Pfs47 affected signal transduction pathways mediating mosquito immune responses, and show that the Jun-N-terminal kinase (JNK) pathway is a key mediator of Anopheles gambiae antiplasmodial responses to P. falciparum infection and that Pfs47 disrupts JNK signaling. Second, we used microarrays to compare the global transcriptional responses of A. gambiae midguts to infection with WT and KO parasites. The presence of Pfs47 results in broad and profound changes in gene expression in response to infection that are already evident 12 h postfeeding, but become most prominent at 26 h postfeeding, the time when ookinetes invade the mosquito midgut. Silencing of 15 differentially expressed candidate genes identified caspase-S2 as a key effector of Plasmodium elimination in parasites lacking Pfs47. We provide experimental evidence that JNK pathway regulates activation of caspases in Plasmodium-invaded midgut cells, and that caspase activation is required to trigger midgut epithelial nitration. Pfs47 alters the cell death pathway of invaded midgut cells by disrupting JNK signaling and prevents the activation of several caspases, resulting in an ineffective nitration response that makes the parasite undetectable by the mosquito complement-like system. PMID- 25552555 TI - Imaging local electric fields produced upon synchrotron X-ray exposure. AB - Electron-hole separation following hard X-ray absorption during diffraction analysis of soft materials under cryogenic conditions produces substantial local electric fields visualizable by second harmonic generation (SHG) microscopy. Monte Carlo simulations of X-ray photoelectron trajectories suggest the formation of substantial local electric fields in the regions adjacent to those exposed to X-rays, indicating a possible electric-field-induced SHG (EFISH) mechanism for generating the observed signal. In studies of amorphous vitreous solvents, analysis of the SHG spatial profiles following X-ray microbeam exposure was consistent with an EFISH mechanism. Within protein crystals, exposure to 12-keV (1.033-A) X-rays resulted in increased SHG in the region extending ~ 3 MUm beyond the borders of the X-ray beam. Moderate X-ray exposures typical of those used for crystal centering by raster scanning through an X-ray beam were sufficient to produce static electric fields easily detectable by SHG. The X-ray-induced SHG activity was observed with no measurable loss for longer than 2 wk while maintained under cryogenic conditions, but disappeared if annealed to room temperature for a few seconds. These results provide direct experimental observables capable of validating simulations of X-ray-induced damage within soft materials. In addition, X-ray-induced local fields may potentially impact diffraction resolution through localized piezoelectric distortions of the lattice. PMID- 25552558 TI - Percolation transition in dynamical traffic network with evolving critical bottlenecks. AB - A critical phenomenon is an intrinsic feature of traffic dynamics, during which transition between isolated local flows and global flows occurs. However, very little attention has been given to the question of how the local flows in the roads are organized collectively into a global city flow. Here we characterize this organization process of traffic as "traffic percolation," where the giant cluster of local flows disintegrates when the second largest cluster reaches its maximum. We find in real-time data of city road traffic that global traffic is dynamically composed of clusters of local flows, which are connected by bottleneck links. This organization evolves during a day with different bottleneck links appearing in different hours, but similar in the same hours in different days. A small improvement of critical bottleneck roads is found to benefit significantly the global traffic, providing a method to improve city traffic with low cost. Our results may provide insights on the relation between traffic dynamics and percolation, which can be useful for efficient transportation, epidemic control, and emergency evacuation. PMID- 25552556 TI - Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling. AB - Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and beta spectrin-binding activity with a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of beta4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kDa AnkG is a major component of the AIS membrane "undercoat' imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders. PMID- 25552559 TI - Trigger loop folding determines transcription rate of Escherichia coli's RNA polymerase. AB - Two components of the RNA polymerase (RNAP) catalytic center, the bridge helix and the trigger loop (TL), have been linked with changes in elongation rate and pausing. Here, single molecule experiments with the WT and two TL-tip mutants of the Escherichia coli enzyme reveal that tip mutations modulate RNAP's pause-free velocity, identifying TL conformational changes as one of two rate-determining steps in elongation. Consistent with this observation, we find a direct correlation between helix propensity of the modified amino acid and pause-free velocity. Moreover, nucleotide analogs affect transcription rate, suggesting that their binding energy also influences TL folding. A kinetic model in which elongation occurs in two steps, TL folding on nucleoside triphosphate (NTP) binding followed by NTP incorporation/pyrophosphate release, quantitatively accounts for these results. The TL plays no role in pause recovery remaining unfolded during a pause. This model suggests a finely tuned mechanism that balances transcription speed and fidelity. PMID- 25552560 TI - Protein design algorithms predict viable resistance to an experimental antifolate. AB - Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure. PMID- 25552562 TI - Profile of Carolina Barillas-Mury. PMID- 25552561 TI - Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors. AB - GABAA-receptor-based interneuron circuitry is essential for higher order function of the human nervous system and is implicated in schizophrenia, depression, anxiety disorders, and autism. Here we demonstrate that giant ankyrin-G (480-kDa ankyrin-G) promotes stability of somatodendritic GABAergic synapses in vitro and in vivo. Moreover, giant ankyrin-G forms developmentally regulated and cell-type specific micron-scale domains within extrasynaptic somatodendritic plasma membranes of pyramidal neurons. We further find that giant ankyrin-G promotes GABAergic synapse stability through opposing endocytosis of GABAA receptors, and requires a newly described interaction with GABARAP, a GABAA receptor-associated protein. We thus present a new mechanism for stabilization of GABAergic interneuron synapses and micron-scale organization of extrasynaptic membrane that provides a rationale for studies linking ankyrin-G genetic variation with psychiatric disease and abnormal neurodevelopment. PMID- 25552563 TI - Long-term results of transapical versus transfemoral TAVI in a real world population of 1000 patients with severe symptomatic aortic stenosis. AB - BACKGROUND: Transapical transcatheter aortic valve implantation is generally perceived to be associated with increased morbidity compared with transfemoral transcatheter aortic valve implantation. We aimed to compare access-related complications and survival using propensity score matching. METHODS AND RESULTS: Prospective, single-center registry of 1000 consecutive patients undergoing transapical and transfemoral transcatheter aortic valve implantation between May 2008 and April 2012. Transapical was performed in 413 patients and transfemoral in 587 patients. Patients with transapical access were less often women and less had pulmonary hypertension. Further they had more peripheral arterial disease, coronary artery disease, carotid stenosis, and recurrent surgery and a higher logistic EuroSCORE I (24.3% +/- 16.2% for transapical versus 22.2% +/- 16.2% for transfemoral; P < 0.01). After building 2 propensity score-matched groups of 354 patients each with either access route (total 708 patients), baseline characteristics were comparable. In this analysis, there was no significant difference in 30 day mortality (5.9% transapical versus 8.5% transfemoral; P = 0.19), the rate of myocardial infarction (2.5% transapical versus 2.0% transfemoral; P = 0.61), stroke (2.0% transapical versus 2.3% transfemoral; P = 0.79), bleeding complications, pacemaker implantation rates, or moderate aortic insufficiency. Stage 1 renal complications were more common in transapical patients (odds ratio, 2.81; 95% confidence interval, 1.93-4.09), whereas major vascular complications were less common (odds ratio, 0.14; 95% confidence interval, 0.06-0.29). Survival probability over the long term was not statistically different (hazard ratio, 0.89; 95% confidence interval, 0.72-1.10; log-rank Test, P = 0.27). CONCLUSIONS: The data demonstrate that in an experienced multidisciplinary heart team, either access route can be performed with comparable results. PMID- 25552564 TI - Effect of obesity on coronary atherosclerosis and outcomes of percutaneous coronary intervention: grayscale and virtual histology intravascular ultrasound substudy of assessment of dual antiplatelet therapy with drug-eluting stents. AB - BACKGROUND: Obesity is a cardiovascular risk factor, but the obesity paradox in patients undergoing percutaneous coronary intervention is poorly understood. METHODS AND RESULTS: Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) was a prospective, multicenter study of patients undergoing drug-eluting stent implantation. Overall, 780 patients (916 culprit lesions) were evaluated by grayscale and virtual histology-intravascular ultrasound pre percutaneous coronary intervention. Poststenting intravascular ultrasound was done in 780 patients (894 treated lesions). Patients were divided into body mass index (BMI) tertiles. The high-BMI group had more diabetes mellitus, hypertension, and hyperlipidemia and more frequent plaque ruptures compared with the low-BMI group. At the minimal lumen area site, the high-BMI group had a larger plaque area (11.7 [11.0-12.4] versus 9.8 [9.3-10.4] mm(2)) and a greater plaque burden (77.3% [76.1%-78.5%] versus 74.4% [73.1%-75.8%]) compared with the low-BMI group; however, a larger external elastic membrane area (14.6 [13.8-15.3] versus 12.7 [12.1-13.3] mm(2)) resulted in a similar minimal lumen area compared with the low-BMI group. Post stenting, the high-BMI group had a significantly larger stent area versus the lower-BMI group. At 1-year follow-up, the high-BMI group was associated with less clinically driven target lesion revascularization compared with the low-BMI group in both the overall and the propensity-matched cohorts. CONCLUSIONS: A high BMI was associated with a greater plaque burden; however, a larger external elastic membrane preserved lumen dimensions and was associated with a larger stent area during intravascular ultrasound-guided stent implantation. Thus, despite more comorbidities, greater plaque burden, and more plaque rupture, a high BMI was not associated with worse outcomes after drug eluting stent implantation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794. PMID- 25552565 TI - Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Morphine is recommended in patients with ST-segment-elevation myocardial infarction, including those undergoing primary percutaneous coronary intervention. Suboptimal antiplatelet effect during and after primary percutaneous coronary intervention is associated with increased thrombotic complications. It was hypothesized a potential drug-drug interaction between morphine and antiplatelet agents. We sought to assess platelet inhibition after a loading dose of the currently recommended antiplatelet agents in ST-segment elevation myocardial infarction patients according to morphine use. METHODS AND RESULTS: Three hundred patients undergoing primary percutaneous coronary intervention receiving either prasugrel (n = 95) or ticagrelor (n = 205) loading dose had platelet reactivity assessed by VerifyNow 1, 2, and 4 hours after loading dose. Patients treated with morphine (n = 95; 32%) had a higher incidence of vomit (15% versus 2%; P = 0.001). P2Y12 reactivity units 2 hours after the loading dose was 187 (153-221) and 133 (102-165) in patient with and without morphine (P < 0.001); the difference persisted after excluding patients with vomit (P < 0.0001). High residual platelet reactivity (P2Y12 reactivity units >= 208) at 2 hours was found in 53% and 29% patients with and without morphine (P < 0.001) and without difference between prasugrel and ticagrelor patients. The independent predictors of high residual platelet reactivity at 2 hours were morphine use (odds ratio, 2.91 [1.71-4.97]; P < 0.0001) and age (odds ratio, 1.03 [1.01-1.05]; P = 0.010). Morphine remained associated with high residual platelet reactivity after propensity score adjustment (c-statistic, 0.68; 95% confidence interval, 0.66-0.70; P = 0.879 for Hosmer-Lemeshow test). CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction, morphine use is associated with a delayed onset of action of the oral antiplatelet agents. This association persisted after adjusting for the propensity to receive morphine and after excluding patients with vomit. PMID- 25552566 TI - Comparison of renal artery, soft tissue, and nerve damage after irrigated versus nonirrigated radiofrequency ablation. AB - BACKGROUND: The long-term efficacy of radiofrequency ablation of renal autonomic nerves has been proven in nonrandomized studies. However, long-term safety of the renal artery (RA) is of concern. The aim of our study was to determine if cooling during radiofrequency ablation preserved the RA while allowing equivalent nerve damage. METHODS AND RESULTS: A total of 9 swine (18 RAs) were included, and allocated to irrigated radiofrequency (n=6 RAs, temperature setting: 50 degrees C), conventional radiofrequency (n=6 RAs, nonirrigated, temperature setting: 65 degrees C), and high-temperature radiofrequency (n=6 RAs, nonirrigated, temperature setting: 90 degrees C) groups. RAs were harvested at 10 days, serially sectioned from proximal to distal including perirenal tissues and examined after paraffin embedding, and staining with hematoxylin-eosin and Movat pentachrome. RAs and periarterial tissue including nerves were semiquantitatively assessed and scored. A total of 660 histological sections from 18 RAs were histologically examined by light microscopy. Arterial medial injury was significantly less in the irrigated radiofrequency group (depth of medial injury, circumferential involvement, and thinning) than that in the conventional radiofrequency group (P<0.001 for circumference; P=0.003 for thinning). Severe collagen damage such as denatured collagen was also significantly less in the irrigated compared with the conventional radiofrequency group (P<0.001). Nerve damage although not statistically different between the irrigated radiofrequency group and conventional radiofrequency group (P=0.36), there was a trend toward less nerve damage in the irrigated compared with conventional. Compared to conventional radiofrequency, circumferential medial damage in highest-temperature nonirrigated radiofrequency group was significantly greater (P<0.001). CONCLUSIONS: Saline irrigation significantly reduces arterial and periarterial tissue damage during radiofrequency ablation, and there is a trend toward less nerve damage. PMID- 25552567 TI - Medial prefrontal cortex reacts to unfairness if this damages the self: a tDCS study. AB - Neural correlates of unfairness perception depend on who is the target of the unfair treatment. These previous findings suggest that the activation of medial prefrontal cortex (MPFC) is related to unfairness perception only when the subject of the measurement is also the person affected by the unfair treatment. We aim at demonstrating the specificity of MPFC involvement using transcranial direct current stimulation (tDCS), a technique that induces cortical excitability changes in the targeted region. We use a modified version of the Ultimatum Game, in which responders play both for themselves (myself-MS condition) and on behalf of an unknown third-party (TP condition), where they respond to unfairness without being the target of it. We find that the application of cathodal tDCS over MPFC decreases the probability of rejecting unfair offers in MS, but not in TP; conversely, the same stimulation increases the probability of rejecting fair offers in TP, but not in MS. We confirm the hypothesis that MPFC is specifically related to processing unfairness when the self is involved, and discuss possible explanations for the opposite effect of the stimulation in TP. PMID- 25552569 TI - Motivational modes and learning in Parkinson's disease. AB - Learning and motivation are intrinsically related, and both have been linked to dopamine. Parkinson's disease results from a progressive loss of dopaminergic inputs to the striatum and leads to impairments in motivation and learning from feedback. However, the link between motivation and learning in Parkinson's disease is not well understood. To address this gap, we leverage a well established psychological theory of motivation, regulatory mode theory, which distinguishes between two functionally independent motivational concerns in regulating behavior: a concern with having an effect by initiating and maintaining movement (Locomotion) and a concern with establishing what is correct by critically evaluating goal pursuit means and outcomes (Assessment). We examined Locomotion and Assessment in patients with Parkinson's disease and age matched controls. Parkinson's disease patients demonstrated a selective decrease in Assessment motivation but no change in Locomotion motivation, suggesting that Parkinson's disease leads to a reduced tendency to evaluate and monitor outcomes. Moreover, weaker Assessment motivation was correlated with poorer performance on a feedback-based learning task previously shown to depend on the striatum. Together, these findings link a questionnaire-based personality inventory with performance on a well-characterized experimental task, advancing our understanding of how Parkinson's disease affects motivation with implications for well-being and treatment outcomes. PMID- 25552568 TI - Anticipation of peer evaluation in anxious adolescents: divergence in neural activation and maturation. AB - Adolescence is the time of peak onset for many anxiety disorders, particularly Social Anxiety Disorder. Research using simulated social interactions consistently finds differential activation in several brain regions in anxious (vs non-anxious) youth, including amygdala, striatum and medial prefrontal cortex. However, few studies examined the anticipation of peer interactions, a key component in the etiology and maintenance of anxiety disorders. Youth completed the Chatroom Task while undergoing functional magnetic resonance imaging. Patterns of neural activation were assessed in anxious and non-anxious youth as they were cued to anticipate social feedback from peers. Anxious participants evidenced greater amygdala activation and rostral anterior cingulate (rACC)<->amygdala coupling than non-anxious participants during anticipation of feedback from peers they had previously rejected; anxious participants also evidenced less nucleus accumbens activation during anticipation of feedback from selected peers. Finally, anxiety interacted with age in rACC: in anxious participants, age was positively associated with activation to anticipated feedback from rejected peers and negatively for selected peers, whereas the opposite pattern emerged for non-anxious youth. Overall, anxious youth showed greater reactivity in anticipation of feedback from rejected peers and thus may ascribe greater salience to these potential interactions and increase the likelihood of avoidance behavior. PMID- 25552570 TI - Neural dissociation of food- and money-related reward processing using an abstract incentive delay task. AB - Food is an innate reward stimulus related to energy homeostasis and survival, whereas money is considered a more general reward stimulus that gains a rewarding value through learning experiences. Although the underlying neural processing for both modalities of reward has been investigated independently from one another, a more detailed investigation of neural similarities and/or differences between food and monetary reward is still missing. Here, we investigated the neural processing of food compared with monetary-related rewards in 27 healthy, normal weight women using functional magnetic resonance imaging. We developed a task distinguishing between the anticipation and the receipt of either abstract food or monetary reward. Both tasks activated the ventral striatum during the expectation of a reward. Compared with money, greater food-related activations were observed in prefrontal, parietal and central midline structures during the anticipation and lateral orbitofrontal cortex (lOFC) during the receipt of food reward. Furthermore, during the receipt of food reward, brain activation in the secondary taste cortex was positively related to the body mass index. These results indicate that food-dependent activations encompass to a greater extent brain regions involved in self-control and self-reflection during the anticipation and phylogenetically older parts of the lOFC during the receipt of reward. PMID- 25552571 TI - Emotional task management: neural correlates of switching between affective and non-affective task-sets. AB - Although task-switching has been investigated extensively, its interaction with emotionally salient task content remains unclear. Prioritized processing of affective stimulus content may enhance accessibility of affective task-sets and generate increased interference when switching between affective and non affective task-sets. Previous research has demonstrated that more dominant task sets experience greater switch costs, as they necessitate active inhibition during performance of less entrenched tasks. Extending this logic to the affective domain, the present experiment examined (a) whether affective task-sets are more dominant than non-affective ones, and (b) what neural mechanisms regulate affective task-sets, so that weaker, non-affective task-sets can be executed. While undergoing functional magnetic resonance imaging, participants categorized face stimuli according to either their gender (non-affective task) or their emotional expression (affective task). Behavioral results were consistent with the affective task dominance hypothesis: participants were slower to switch to the affective task, and cross-task interference was strongest when participants tried to switch from the affective to the non-affective task. These behavioral costs of controlling the affective task-set were mirrored in the activation of a right-lateralized frontostriatal network previously implicated in task-set updating and response inhibition. Connectivity between amygdala and right ventrolateral prefrontal cortex was especially pronounced during cross-task interference from affective features. PMID- 25552572 TI - Neural and cortisol responses during play with human and computer partners in children with autism. AB - Children with autism spectrum disorder (ASD) exhibit impairment in reciprocal social interactions, including play, which can manifest as failure to show social preference or discrimination between social and nonsocial stimuli. To explore mechanisms underlying these deficits, we collected salivary cortisol from 42 children 8-12 years with ASD or typical development during a playground interaction with a confederate child. Participants underwent functional MRI during a prisoner's dilemma game requiring cooperation or defection with a human (confederate) or computer partner. Search region of interest analyses were based on previous research (e.g. insula, amygdala, temporal parietal junction-TPJ). There were significant group differences in neural activation based on partner and response pattern. When playing with a human partner, children with ASD showed limited engagement of a social salience brain circuit during defection. Reduced insula activation during defection in the ASD children relative to TD children, regardless of partner type, was also a prominent finding. Insula and TPJ BOLD during defection was also associated with stress responsivity and behavior in the ASD group under playground conditions. Children with ASD engage social salience networks less than TD children during conditions of social salience, supporting a fundamental disturbance of social engagement. PMID- 25552573 TI - Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage. AB - Based on studies in rodents, the basolateral amygdala (BLA) is considered a key site for experience-dependent neural plasticity underlying the acquisition of conditioned fear responses. In humans, very few studies exist of subjects with selective amygdala lesions and those studies have only implicated the amygdala more broadly leaving the role of amygdala sub-regions underexplored. We tested a rare sample of subjects (N = 4) with unprecedented focal bilateral BLA lesions due to a genetic condition called Urbach-Wiethe disease. In a classical delay fear conditioning experiment, these subjects showed impaired acquisition of conditioned fear relative to a group of matched control subjects (N = 10) as measured by fear-potentiation of the defensive eye-blink startle reflex. After the experiment, the BLA-damaged cases showed normal declarative memory of the conditioned association. Our findings provide new evidence that the human BLA is essential to drive fast classically conditioned defensive reflexes. PMID- 25552574 TI - Treating arterial disease to prevent brain injury: Break out the bubbly or back to the bench? PMID- 25552577 TI - Seeking best medical treatment for hyperacute intracerebral hemorrhage. PMID- 25552576 TI - Exercise for falls prevention in Parkinson disease: a randomized controlled trial. AB - OBJECTIVE: To determine whether falls can be prevented with minimally supervised exercise targeting potentially remediable fall risk factors, i.e., poor balance, reduced leg muscle strength, and freezing of gait, in people with Parkinson disease. METHODS: Two hundred thirty-one people with Parkinson disease were randomized into exercise or usual-care control groups. Exercises were practiced for 40 to 60 minutes, 3 times weekly for 6 months. Primary outcomes were fall rates and proportion of fallers during the intervention period. Secondary outcomes were physical (balance, mobility, freezing of gait, habitual physical activity), psychological (fear of falling, affect), and quality-of-life measures. RESULTS: There was no significant difference between groups in the rate of falls (incidence rate ratio [IRR] = 0.73, 95% confidence interval [CI] 0.45-1.17, p = 0.18) or proportion of fallers (p = 0.45). Preplanned subgroup analysis revealed a significant interaction for disease severity (p < 0.001). In the lower disease severity subgroup, there were fewer falls in the exercise group compared with controls (IRR = 0.31, 95% CI 0.15-0.62, p < 0.001), while in the higher disease severity subgroup, there was a trend toward more falls in the exercise group (IRR = 1.61, 95% CI 0.86-3.03, p = 0.13). Postintervention, the exercise group scored significantly (p < 0.05) better than controls on the Short Physical Performance Battery, sit-to-stand, fear of falling, affect, and quality of life, after adjusting for baseline performance. CONCLUSIONS: An exercise program targeting balance, leg strength, and freezing of gait did not reduce falls but improved physical and psychological health. Falls were reduced in people with milder disease but not in those with more severe Parkinson disease. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with Parkinson disease, a minimally supervised exercise program does not reduce fall risk. This study lacked the precision to exclude a moderate reduction or modest increase in fall risk from exercise. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12608000303347). PMID- 25552578 TI - Arterial stiffness and progression of structural brain changes: The SMART-MR study. AB - OBJECTIVE: To examine the cross-sectional and prospective associations between arterial stiffness and structural brain changes within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with manifest arterial disease. METHODS: Distension measurements of the common carotid arteries and a brain MRI were performed in 526 patients (mean age 59 +/- 10 years). After a mean follow-up of 4.1 years (range 3.6-5.8), brain MRI was repeated in 308 patients. Brain segmentation was used to quantify total brain volume, cortical gray matter volume, ventricular volume, and white matter lesion (WML) volume (relative to intracranial volume). Infarcts were rated visually. RESULTS: Cross-sectional multivariable regression analyses showed that 1 SD decrease in carotid distension, indicating increased arterial stiffness, was associated with smaller relative total brain and cortical gray matter volumes (B = -0.24%, 95% confidence interval [CI] -0.44 to -0.04%, and B = -0.47%, 95% CI -0.75 to -0.19%), with larger WML volume (B = 0.09%, 95% CI -0.01 to 0.19%), and with higher risk of having nonlacunar (cortical or large subcortical) brain infarcts (relative risk = 1.44, 95% CI 1.14 to 1.81). However, our prospective findings showed that carotid distension was not significantly associated with progression of brain atrophy, WML volume, or brain infarcts. CONCLUSION: In this population of patients with manifest arterial disease, stiffening of the carotid arteries was cross-sectionally associated with more brain atrophy, WML volume, and nonlacunar infarcts, but did not lead to changes in brain volumes or infarcts after 4 years. PMID- 25552579 TI - Clinicians' ability to diagnose dementia with Lewy bodies is not affected by beta amyloid load. AB - OBJECTIVE: To investigate whether an increasing load of beta-amyloid and/or neuritic plaques influences the phenotype, and thus the clinical diagnostic accuracy, of dementia with Lewy bodies (DLB). METHODS: A series of 64 subjects with autopsy-proven DLB was studied. Last diagnosis before death was used to determine the clinical diagnostic accuracy of DLB in relation to Lewy body distribution and extent of Alzheimer beta-amyloid and/or neuritic pathology. DLB pathologic diagnosis was made according to consensus criteria, using alpha synuclein immunostaining for Lewy body identification. beta-Amyloid immunostaining was used for quantifying beta-amyloid deposits. The Consortium to Establish a Registry for Alzheimer's Disease criteria and Braak stage were applied for semiquantitative grading of neuritic plaque and neurofibrillary tangle pathology. RESULTS: Overall clinical diagnostic accuracy for the entire DLB cohort was high (80%), reflecting the high prevalence of core clinical features (fluctuations [81%], parkinsonism [77%], visual hallucinations [70%]). Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution (p < 0.0001) and with increasing neuritic plaque pathology (p = 0.035), but not with the number of beta-amyloid plaque deposits. CONCLUSIONS: The likelihood of occurrence of the DLB clinical syndrome is positively related to the extent of Lewy body pathology and negatively related to the severity of Alzheimer neuritic pathology, while beta-amyloid load has no effect. PMID- 25552580 TI - Human Clostridium difficile infection: inhibition of NHE3 and microbiota profile. AB - Clostridium difficile infection (CDI) is principally responsible for hospital acquired, antibiotic-induced diarrhea and colitis and represents a significant financial burden on our healthcare system. Little is known about C. difficile proliferation requirements, and a better understanding of these parameters is critical for development of new therapeutic targets. In cell lines, C. difficile toxin B has been shown to inhibit Na(+)/H(+) exchanger 3 (NHE3) and loss of NHE3 in mice results in an altered intestinal environment coupled with a transformed gut microbiota composition. However, this has yet to be established in vivo in humans. We hypothesize that C. difficile toxin inhibits NHE3, resulting in alteration of the intestinal environment and gut microbiota. Our results demonstrate that CDI patient biopsy specimens have decreased NHE3 expression and CDI stool has elevated Na(+) and is more alkaline compared with stool from healthy individuals. CDI stool microbiota have increased Bacteroidetes and Proteobacteria and decreased Firmicutes phyla compared with healthy subjects. In vitro, C. difficile grows optimally in the presence of elevated Na(+) and alkaline pH, conditions that correlate to changes observed in CDI patients. To confirm that inhibition of NHE3 was specific to C. difficile, human intestinal organoids (HIOs) were injected with C. difficile or healthy and CDI stool supernatant. Injection of C. difficile and CDI stool decreased NHE3 mRNA and protein expression compared with healthy stool and control HIOs. Together these data demonstrate that C. difficile inhibits NHE3 in vivo, which creates an altered environment favored by C. difficile. PMID- 25552582 TI - Interaction between hydrogen sulfide-induced sulfhydration and tyrosine nitration in the KATP channel complex. AB - Hydrogen sulfide (H2S) is an endogenous gaseous mediator affecting many physiological and pathophysiological conditions. Enhanced expression of H2S and reactive nitrogen/oxygen species (RNS/ROS) during inflammation alters cellular excitability via modulation of ion channel function. Sulfhydration of cysteine residues and tyrosine nitration are the posttranslational modifications induced by H2S and RNS, respectively. The objective of this study was to define the interaction between tyrosine nitration and cysteine sulfhydration within the ATP sensitive K(+) (KATP) channel complex, a significant target in experimental colitis. A modified biotin switch assay was performed to determine sulfhydration of the KATP channel subunits, Kir6.1, sulphonylurea 2B (SUR2B), and nitrotyrosine measured by immunoblot. NaHS (a donor of H2S) significantly enhanced sulfhydration of SUR2B but not Kir6.1 subunit. 3-Morpholinosydnonimine (SIN-1) (a donor of peroxynitrite) induced nitration of Kir6.1 subunit but not SUR2B. Pretreatment with NaHS reduced the nitration of Kir6.1 by SIN-1 in Chinese hamster ovary cells cotransfected with the two subunits, as well as in enteric glia. Two specific mutations within SUR2B, C24S, and C1455S prevented sulfhydration by NaHS, and these mutations prevented NaHS-induced reduction in tyrosine nitration of Kir6.1. NaHS also reversed peroxynitrite-induced inhibition of smooth muscle contraction. These studies suggest that posttranslational modifications of the two subunits of the KATP channel interact to alter channel function. The studies described herein demonstrate a unique mechanism by which sulfhydration of one subunit modifies tyrosine nitration of another subunit within the same channel complex. This interaction provides a mechanistic insight on the protective effects of H2S in inflammation. PMID- 25552583 TI - The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump. AB - Human bile salt export pump (BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep(-/-) mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related ("coupled") to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep(-/-) mice. The secretion of the BS tauro-beta-muricholic acid (TbetaMCA) is relatively preserved in Bsep(-/-) mice. We infused Bsep(-/-) and Bsep(+/+) (control) mice with TbetaMCA in stepwise increasing dosages (150-600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep(-/-) and control mice. TbetaMCA infusion increased BS secretion in both Bsep(-/-) and control mice. The secreted PL or CH amount per BS, i.e., the "coupling," was continuously two- to threefold higher in Bsep(-/-) mice (P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45-55% higher in Bsep(-/-) mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep(-/-) mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep(-/-) mice is based on increased expression of the responsible canalicular transporter proteins. PMID- 25552581 TI - Human Clostridium difficile infection: altered mucus production and composition. AB - The majority of antibiotic-induced diarrhea is caused by Clostridium difficile (C. difficile). Hospitalizations for C. difficile infection (CDI) have tripled in the last decade, emphasizing the need to better understand how the organism colonizes the intestine and maintain infection. The mucus provides an interface for bacterial-host interactions and changes in intestinal mucus have been linked host health. To assess mucus production and composition in healthy and CDI patients, the main mucins MUC1 and MUC2 and mucus oligosaccharides were examined. Compared with healthy subjects, CDI patients demonstrated decreased MUC2 with no changes in surface MUC1. Although MUC1 did not change at the level of the epithelia, MUC1 was the primary constituent of secreted mucus in CDI patients. CDI mucus also exhibited decreased N-acetylgalactosamine (GalNAc), increased N acetylglucosamine (GlcNAc), and increased terminal galactose residues. Increased galactose in CDI specimens is of particular interest since terminal galactose sugars are known as C. difficile toxin A receptor in animals. In vitro, C. difficile is capable of metabolizing fucose, mannose, galactose, GlcNAc, and GalNAc for growth under healthy stool conditions (low Na(+) concentration, pH 6.0). Injection of C. difficile into human intestinal organoids (HIOs) demonstrated that C. difficile alone is sufficient to reduce MUC2 production but is not capable of altering host mucus oligosaccharide composition. We also demonstrate that C. difficile binds preferentially to mucus extracted from CDI patients compared with healthy subjects. Our results provide insight into a mechanism of C. difficile colonization and may provide novel target(s) for the development of alternative therapeutic agents. PMID- 25552585 TI - Nurses' perceptions of professional dignity in hospital settings. AB - BACKGROUND: The concept of dignity can be divided into two main attributes: absolute dignity that calls for recognition of an inner worth of persons and social dignity that can be changeable and can be lost as a result of different social factors and moral behaviours. In this light, the nursing profession has a professional dignity that is to be continually constructed and re-constructed and involves both main attributes of dignity. OBJECTIVES: The purpose of this study was to determine how nurses described nursing's professional dignity in internal medicine and surgery departments in hospital settings. RESEARCH DESIGN: The research design was qualitative. ETHICAL CONSIDERATIONS: This study was approved by the ethics committees of the healthcare organizations involved. All the participants were provided with information about the purpose and the nature of the study. PARTICIPANTS: A total of 124 nurses participated in this study. METHOD: The data were collected using 20 focus group sessions in different parts of Italy. The data were analysed by means of a conventional inductive content analysis starting from the information retrieved in order to extract meaning units and sorting the arising phenomena into conceptually meaningful categories and themes. RESULTS: Nursing's professional dignity was deeply embedded in the innermost part of individuals. Regarding the social part of dignity, a great importance was put on the values that compose nursing's professional identity, the socio-historical background and the evolution of nursing in the area considered. The social part of dignity was also linked to collaboration with physicians and with healthcare assistants who were thought to have a central role in easing work strain. Equally important, though, was the relationship with peers and senior nurses. CONCLUSION: The organizational environments under scrutiny with their low staffing levels, overload of work and hierarchical interactions did not promote respect for the dignity of nurses. To understand these professional values, it is pivotal to comprehend the role of different health professions in their cultural milieu and the evolution of the nursing profession in diverse countries. PMID- 25552584 TI - 'Choosing Wisely': a growing international campaign. AB - Much attention has been paid to the inappropriate underuse of tests and treatments but until recently little attention has focused on the overuse that does not add value for patients and may even cause harm. Choosing Wisely is a campaign to engage physicians and patients in conversations about unnecessary tests, treatments and procedures. The campaign began in the United States in 2012, in Canada in 2014 and now many countries around the world are adapting the campaign and implementing it. This article describes the present status of Choosing Wisely programs in 12 countries. It articulates key elements, a set of five principles, and describes the challenges countries face in the early phases of Choosing Wisely. These countries plan to continue collaboration including developing metrics to measure overuse. PMID- 25552586 TI - Ethical and methodological issues in qualitative health research involving children: A systematic review. AB - BACKGROUND: The right of children to have their voice heard has been accepted by researchers, and there are increasing numbers of qualitative health studies involving children. The ethical and methodological issues of including children in research have caused worldwide concerns, and many researchers have published articles sharing their own experiences. OBJECTIVES: To systematically review and synthesise experts' opinions and experiences about ethical and methodological issues of including children in research, as well as related solution strategies. RESEARCH DESIGN: The research design was a systematic review of opinion-based evidence, based on the guidelines by Joanna Briggs Institute. METHODS: A search of five computerised databases has been conducted in April 2014 and 2271 articles were found. After screening the titles, abstracts, full texts and appraising the quality, 30 articles were finally included in the review. A meta-aggregative approach was applied in the data analysis and synthesis process. ETHICAL CONSIDERATIONS: Ethical approval is not needed as it is a systematic review of published literature. RESULTS: Six themes were identified, including evaluating potential risks and benefits, gaining access, obtaining informed consent/assent, protecting confidentiality and privacy, building rapport and collecting rich data. The similarities and differences between research involving children and that involving adults were indicated. CONCLUSION: All potential incentives should be justified when designing the study. Further studies need to research how to evaluate individual capacity of children and how to balance protecting children's right to participate and their interests in the research. Cultural differences related to researching children in different regions should also be studied. PMID- 25552587 TI - Fear, danger and aggression in a Norwegian locked psychiatric ward: Dialogue and ethics of care as contributions to combating difficult situations. AB - BACKGROUND: Fear and aggression are often reported among professionals working in locked psychiatric wards and also among the patients in the same wards. Such situations often lead to coercive intervention. In order to prevent coercion, we need to understand what happens in dangerous situations and how patients and professionals interpret them. RESEARCH QUESTIONS: What happens when dangerous situations occur in a ward? How do professionals and patients interpret these situations and what is ethically at stake? RESEARCH DESIGN: Participant observation and interviews. PARTICIPANTS: A total of 12 patients and 22 professionals participated. ETHICAL CONSIDERATIONS: This study has been accepted by the Regional Committee for Medical and Health Research Ethics in Norway. FINDINGS: (a) Both atmosphere and material surroundings were interweaved within dangerous situations, (b) the professionals applied stereotypes when interpreting dangerous situations and (c) the professionals and the patients had different interpretations of what triggered dangerous situations. DISCUSSION: The discussion centres on how care ethics and a dialogical practice might contribute towards combating difficult situations and the ways in which change is an ongoing ethical process of becoming. CONCLUSION: The ethics of care and a dialogical approach are suggested as ethical frameworks for preventing fear, danger and aggression in psychiatric wards. Both frameworks can be understood as patient driven, including the relational and contextual perspectives. It means a shift from professionally driven processes to patient-driven dialogue. PMID- 25552588 TI - The meaning of vulnerability to older persons. AB - BACKGROUND: Vulnerability is an important concept in nursing and nursing ethics. Vulnerability and ageing have generally been associated with frailty, which gives a limited view of both vulnerability and ageing. OBJECTIVE: The aim of this study was to illuminate the meaning of vulnerability to older persons themselves. RESEARCH DESIGN: A qualitative design based on interpretive description was adopted. The data were collected by interviews that were analysed by qualitative content analysis as interplay between analysis, interpretation and meaning construction. PARTICIPANTS AND RESEARCH CONTEXT: In total, 14 older persons aged 70-96 years were interviewed, 2 men and 12 women. Some of the participants lived in their own homes, some in service houses and some in nursing homes. ETHICAL CONSIDERATIONS: The ethical principles of informed consent, confidentiality and non-identification were respected. FINDINGS: The core meaning was a deeper sense of vulnerability as you grow old. This was expressed in six themes: Being easily harmed, Becoming an old person, Being an old person in society, Reactions when being violated and hurt, Protection and Vulnerability as strength. DISCUSSION AND CONCLUSION: The themes include frailty and threats to the dignity of older persons and also capacity to feel and develop. The results showed that although the frailty perspective dominated, vulnerability also had positive meanings for the older persons. PMID- 25552589 TI - Confidentiality in participatory research: Challenges from one study. AB - AIM: This article presents key ethical challenges that were encountered when conducting a participatory qualitative research project with a very specific, small group of nurses, in this case with practice development nurses in Malta. BACKGROUND: With the small number of nurses employed in practice development roles in Malta, there are numerous difficulties of maintaining confidentiality. Poorly constructed interventions by the researcher could have resulted in detrimental effects to research participants and the overall trustworthiness of the research. Generally, ethical guidelines for research exist to reinforce validity of research; however, there is not an established consensus on how these strategies can be utilised in some types of qualitative field work. RESEARCH DESIGN: The researcher used an exploratory case study methodology. The sample consisted of 10 participants who were interviewed twice using face-to-face interviews, over a period of 2 months. ETHICAL CONSIDERATIONS: The study was ethically reviewed by the University Research Ethics Committee and the Faculty Research Ethics Committee, University of Malta. The participants referred to in this article have been given adequate information about the study and their consent has been obtained. DISCUSSION: Numerous strategies for ensuring confidentiality during recruitment of the participants, during data collection, during transcription and data analysis and during dissemination of research results assisted the researcher in responding to potential and actual ethical issues. CONCLUSION: This article emphasises the main strategies that can be used to respond to ethical challenges when researching with a small easily identifiable group. The learning discussed here may be relevant to or even transferable to other similar research studies or research contexts. These methods fostered a greater credibility throughout the research process and predisposed the participants to greater trust, and thus, they disclosed their experiences and speak more freely, thus enhancing the quality of the study. PMID- 25552590 TI - Cannabis and schizophrenia. AB - BACKGROUND: Many people with schizophrenia smoke cannabis, and it is unclear why a large proportion do so and if the effects are harmful or beneficial. It is also unclear what the best method is to allow people with schizophrenia to alter their cannabis intake. OBJECTIVES: To assess the effects of specific psychological treatments for cannabis reduction in people with schizophrenia. To assess the effects of antipsychotics for cannabis reduction in people with schizophrenia. To assess the effects of cannabinoids (cannabis-related chemical compounds derived from cannabis or manufactured) for symptom reduction in people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (August 2013) and all references of articles selected for further relevant trials. We contacted the first author of included studies for unpublished trials or data. SELECTION CRITERIA: We included all randomized controlled trials involving cannabinoids and schizophrenia/schizophrenia-like illnesses, which assessed: (1) treatments to reduce cannabis use in people with schizophrenia and (2) the effects of cannabinoids on people with schizophrenia. CONCLUSIONS: Results are limited and inconclusive due to the small number and size of randomized controlled trials available and quality of data reporting within these trials. Currently, there is no evidence to demonstrate that one type of adjunct psychological therapy or one type of drug therapy is more effective than another. There is also insufficient evidence to show that cannabidiol has an antipsychotic effect. PMID- 25552593 TI - Modifiable risk factors and thyroid cancer. AB - OBJECTIVE: To evaluate the association between modifiable patient risk factors including tobacco use, alcohol consumption, body mass index (BMI), and thyroid cancer. STUDY DESIGN: Retrospective study with chart review. SETTING: Midwest university hospital. SUBJECTS AND METHODS: Retrospective study comparing Midwest patients with thyroid cancer from our Thyroid Tumor and Cancer Registry with Midwest controls without a personal history of cancer. Descriptive statistics were created from patient questionnaires and chart reviews. Odds ratios (ORs) were reported for significant associations. RESULTS: There were 467 patients with cancer and 255 controls. The thyroid cancer group included 404 papillary, 47 follicular, 13 medullary, and 3 anaplastic cancers. When comparing all patients with cancer with controls, smoking more than 100 lifetime cigarettes was associated with a reduced cancer risk (OR, 0.68; 95% confidence interval [CI], 0.50-0.94). Secondhand smoke exposure did not show a statistically significant relationship to thyroid cancer. Compared with never drinking, current drinking was associated with a reduced cancer risk (OR, 0.46; 95% CI, 0.29-0.73) as was consuming 1 to 2 drinks daily compared to drinking <1 drink daily (OR, 0.58; 95% CI, 0.34-0.89). There was no difference between median BMI at age 20 years, lifetime maximum BMI, or current BMI between patients with cancer and controls. CONCLUSION: Our data showed no positive correlation between tobacco use, alcohol consumption, or obesity and thyroid cancer risk. Our data suggest that tobacco use and mild alcohol consumption may be associated with a slightly reduced risk of thyroid cancer. There was no association between BMI and thyroid cancer in our study population. PMID- 25552591 TI - Genome-wide association study for endothelial growth factors. AB - BACKGROUND: Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. METHODS AND RESULTS: We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40*10(-65) [rs2273720] and 3.64*10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05*10(-8) in Framingham Heart Study and 8.39*10(-5) in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84*10(-33) in Framingham Heart Study; P=2.53*10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07*10(-8) in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie 2) of the interindividual variation in biomarker levels. CONCLUSIONS: Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies. PMID- 25552575 TI - Optimal achieved blood pressure in acute intracerebral hemorrhage: INTERACT2. AB - OBJECTIVES: To investigate the effects of intensive blood pressure (BP) lowering according to baseline BP levels and optimal achieved BP levels in patients with acute intracerebral hemorrhage (ICH). METHODS: INTERACT2 was an open, blinded endpoint, randomized controlled trial in 2,839 patients with ICH within 6 hours of onset and elevated systolic BP (SBP) (150-220 mm Hg) who were allocated to receive intensive (target SBP <140 mm Hg within 1 hour, with lower limit of 130 mm Hg for treatment cessation) or guideline-recommended (target SBP <180 mm Hg) BP-lowering treatment. Outcome was physical function across all 7 levels of the modified Rankin Scale at 90 days. RESULTS: Analysis of the randomized comparisons showed that intensive BP lowering produced comparable benefits on physical function at 90 days in 5 subgroups defined by baseline SBP of <160, 160-169, 170 179, 180-189, and >=190 mm Hg (p homogeneity = 0.790). Analyses of achieved BP showed linear increases in the risk of physical dysfunction for achieved SBP above 130 mm Hg for both hyperacute (1-24 hours) and acute (2-7 days) phases while modest increases were also observed for achieved SBP below 130 mm Hg. CONCLUSIONS: Intensive BP lowering appears beneficial across a wide range of baseline SBP levels, and target SBP level of 130-139 mm Hg is likely to provide maximum benefit in acute ICH. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the effect of intensive BP lowering on physical function is not influenced by baseline BP. PMID- 25552594 TI - Reactivated CD4+Tm cells of T1D patients and siblings display an exaggerated effector phenotype with heightened sensitivity to activation-induced cell death. AB - Dysfunction in effector memory has been proposed to contribute to autoimmunity in type 1 diabetes (T1D). Using a unique cohort of age- and sex-matched T1D patients, nonaffected siblings, and unrelated control children, we undertook a detailed analysis of proliferation, activation, effector responses, and apoptosis in reactivated CD4(+)Tm cells during T-cell receptor stimulation. Across cohorts, there was no difference in the proliferation of reactivated CD4(+)Tm cells. In T1D patients and siblings, CD4(+)Tm cells easily acquired the activated CD25(+) phenotype and effectively transitioned from a central (CD62L(+)Tcm) to an effector memory (CD62L(-)Tem) phenotype with an elevated cytokine "signature" comprising interferon (IFN)-gamma and interleukin-10 in T1D patients and IFN gamma in siblings. This amplified Tem phenotype also exhibited an exaggerated immune shutdown with heightened sensitivity to activation-induced cell death and Fas-independent apoptosis. Apoptosis resulted in the elimination of one-half of the effector memory in T1D patients and siblings compared with one-third of the effector memory in control subjects. These data suggest genetic/environment driven immune alteration in T1D patients and siblings that manifests in an exaggerated CD4(+)Tem response and shutdown by apoptosis. Further immunological studies are required to understand how this exaggerated CD4(+)Tem response fits within the pathomechanisms of T1D and how the effector memory can be modulated for disease treatment and/or prevention. PMID- 25552592 TI - Variants for HDL-C, LDL-C, and triglycerides identified from admixture mapping and fine-mapping analysis in African American families. AB - BACKGROUND: Admixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African Americans. METHODS AND RESULTS: The present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. The analysis was performed in 1905 unrelated African American subjects from the National Heart, Lung and Blood Institute's Family Blood Pressure Program (FBPP). Regions showing admixture evidence were followed-up with family-based association analysis in 3556 African American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age(2), sex, body mass index, and genome-wide mean ancestry to minimize the confounding caused by population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (low-density lipoprotein cholesterol), 8 (high-density lipoprotein cholesterol), 14 (triglycerides), and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52 939 single nucleotide polymorphisms (SNPs) were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with high-density lipoprotein cholesterol (2 SNPs), low-density lipoprotein cholesterol (4 SNPs), and triglycerides (5 SNPs). The family data were used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions, including genes with known associations for cardiovascular disease. CONCLUSIONS: This study identified regions on chromosomes 7, 8, 14, and 19 and 11 SNPs from the fine-mapping analysis that were associated with high-density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides for further studies of cardiovascular disease in African Americans. PMID- 25552595 TI - Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets. AB - A polymorphism located in the G6PC2 gene, which encodes an islet-specific glucose 6-phosphatase catalytic subunit, is the most important common determinant of variations in fasting blood glucose (FBG) levels in humans. Studies of G6pc2 knockout (KO) mice suggest that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion (GSIS) that acts by hydrolyzing glucose-6 phosphate (G6P), thereby reducing glycolytic flux. However, this conclusion conflicts with the very low estimates for the rate of glucose cycling in pancreatic islets, as assessed using radioisotopes. We have reassessed the rate of glucose cycling in pancreatic islets using a novel stable isotope method. The data show much higher levels of glucose cycling than previously reported. In 5 mmol/L glucose, islets from C57BL/6J chow-fed mice cycled ~16% of net glucose uptake. The cycling rate was further increased at 11 mmol/L glucose. Similar cycling rates were observed using islets from high fat-fed mice. Importantly, glucose cycling was abolished in G6pc2 KO mouse islets, confirming that G6pc2 opposes the action of the glucose sensor glucokinase by hydrolyzing G6P. The demonstration of high rates of glucose cycling in pancreatic islets explains why G6pc2 deletion enhances GSIS and why variants in G6PC2 affect FBG in humans. PMID- 25552596 TI - Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. AB - Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-gamma-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes. PMID- 25552597 TI - Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner. AB - An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr(649) and Ser(711) in wild type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin. PMID- 25552599 TI - Role of plasminogen activator inhibitor-1 in glucocorticoid-induced diabetes and osteopenia in mice. AB - Long-term use of glucocorticoids (GCs) causes numerous adverse effects, including glucose/lipid abnormalities, osteoporosis, and muscle wasting. The pathogenic mechanism, however, is not completely understood. In this study, we used plasminogen activator inhibitor-1 (PAI-1)-deficient mice to explore the role of PAI-1 in GC-induced glucose/lipid abnormalities, osteoporosis, and muscle wasting. Corticosterone markedly increased the levels of circulating PAI-1 and the PAI-1 mRNA level in the white adipose tissue of wild-type mice. PAI-1 deficiency significantly reduced insulin resistance and glucose intolerance but not hyperlipidemia induced by GC. An in vitro experiment revealed that active PAI 1 treatment inhibits insulin-induced phosphorylation of Akt and glucose uptake in HepG2 hepatocytes. However, this was not observed in 3T3-L1 adipocytes and C2C12 myotubes, indicating that PAI-1 suppressed insulin signaling in hepatocytes. PAI 1 deficiency attenuated the GC-induced bone loss presumably via inhibition of apoptosis of osteoblasts. Moreover, the PAI-1 deficiency also protected from GC induced muscle loss. In conclusion, the current study indicated that PAI-1 is involved in GC-induced glucose metabolism abnormality, osteopenia, and muscle wasting in mice. PAI-1 may be a novel therapeutic target to mitigate the adverse effects of GC. PMID- 25552598 TI - Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. AB - Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3 hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice. PMID- 25552600 TI - Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. AB - Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by promoting an inflammatory environment within the vessel wall. In this study, we investigated the molecular mechanisms responsible for monocyte to-macrophage differentiation and, subsequently, the effect of metformin in regressing angiotensin II (Ang-II)-mediated atheromatous plaque formation in ApoE(-/-) mice. AMPK activity was dose and time dependently downregulated during phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, which was accompanied by an upregulation of proinflammatory cytokine production. Of note, AMPK activators metformin and AICAR significantly attenuated PMA-induced monocyte-to-macrophage differentiation and proinflammatory cytokine production. However, inhibition of AMPK activity alone by compound C was ineffective in promoting monocyte-to-macrophage differentiation in the absence of PMA. On the other hand, inhibition of c-Jun N-terminal kinase activity inhibited PMA-induced inflammation but not differentiation, suggesting that inflammation and differentiation are independent events. In contrast, inhibition of STAT3 activity inhibited both inflammation and monocyte-to-macrophage differentiation. By decreasing STAT3 phosphorylation, metformin and AICAR through increased AMPK activation caused inhibition of monocyte-to-macrophage differentiation. Metformin attenuated Ang-II-induced atheromatous plaque formation and aortic aneurysm in ApoE(-/-) mice partly by reducing monocyte infiltration. We conclude that the AMPK-STAT3 axis plays a pivotal role in regulating monocyte-to-macrophage differentiation and that by decreasing STAT3 phosphorylation through increased AMPK activity, AMPK activators inhibit monocyte-to-macrophage differentiation. PMID- 25552601 TI - Interspinous process device versus standard conventional surgical decompression for lumbar spinal stenosis: randomised controlled trial. AB - STUDY QUESTION: Is interspinous process device implantation more effective in the short term (eight weeks) than conventional surgical decompression for patients with intermittent neurogenic claudication due to lumbar spinal stenosis? SUMMARY ANSWER: The use of interspinous implants did not result in a better outcome than conventional decompression, but the reoperation rate was significantly higher. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Bony decompression and treatment with interspinous process devices are superior to conservative and non-surgical treatment for intermittent neurogenic claudication due to lumbar spinal stenosis. Interspinous implants surgery is not superior to bony decompression, and the reoperation rate is significantly higher. PMID- 25552602 TI - Exploration and confirmation of factors associated with uncomplicated pregnancy in nulliparous women: prospective cohort study. AB - STUDY QUESTION: Which variables at 15 and 20 weeks' gestation, particularly those amenable to modification before pregnancy, are associated with a subsequent uncomplicated pregnancy? SUMMARY ANSWER: Normalising body mass index, increasing fruit intake before pregnancy, reducing blood pressure, stopping misuse of drugs, and being in paid employment are all associated with subsequent uncomplicated pregnancy outcomes. PMID- 25552603 TI - Population genetics of Anopheles coluzzii immune pathways and genes. AB - Natural selection is expected to drive adaptive evolution in genes involved in host-pathogen interactions. In this study, we use molecular population genetic analyses to understand how natural selection operates on the immune system of Anopheles coluzzii (formerly A. gambiae "M form"). We analyzed patterns of intraspecific and interspecific genetic variation in 20 immune-related genes and 17 nonimmune genes from a wild population of A. coluzzii and asked if patterns of genetic variation in the immune genes are consistent with pathogen-driven selection shaping the evolution of defense. We found evidence of a balanced polymorphism in CTLMA2, which encodes a C-type lectin involved in regulation of the melanization response. The two CTLMA2 haplotypes, which are distinguished by fixed amino acid differences near the predicted peptide cleavage site, are also segregating in the sister species A. gambiae ("S form") and A. arabiensis. Comparison of the two haplotypes between species indicates that they were not shared among the species through introgression, but rather that they arose before the species divergence and have been adaptively maintained as a balanced polymorphism in all three species. We additionally found that STAT-B, a retroduplicate of STAT-A, shows strong evidence of adaptive evolution that is consistent with neofunctionalization after duplication. In contrast to the striking patterns of adaptive evolution observed in these Anopheles-specific immune genes, we found no evidence of adaptive evolution in the Toll and Imd innate immune pathways that are orthologously conserved throughout insects. Genes encoding the Imd pathway exhibit high rates of amino acid divergence between Anopheles species but also display elevated amino acid diversity that is consistent with relaxed purifying selection. These results indicate that adaptive coevolution between A. coluzzii and its pathogens is more likely to involve novel or lineage-specific molecular mechanisms than the canonical humoral immune pathways. PMID- 25552604 TI - Condensins exert force on chromatin-nuclear envelope tethers to mediate nucleoplasmic reticulum formation in Drosophila melanogaster. AB - Although the nuclear envelope is known primarily for its role as a boundary between the nucleus and cytoplasm in eukaryotes, it plays a vital and dynamic role in many cellular processes. Studies of nuclear structure have revealed tissue-specific changes in nuclear envelope architecture, suggesting that its three-dimensional structure contributes to its functionality. Despite the importance of the nuclear envelope, the factors that regulate and maintain nuclear envelope shape remain largely unexplored. The nuclear envelope makes extensive and dynamic interactions with the underlying chromatin. Given this inexorable link between chromatin and the nuclear envelope, it is possible that local and global chromatin organization reciprocally impact nuclear envelope form and function. In this study, we use Drosophila salivary glands to show that the three-dimensional structure of the nuclear envelope can be altered with condensin II-mediated chromatin condensation. Both naturally occurring and engineered chromatin-envelope interactions are sufficient to allow chromatin compaction forces to drive distortions of the nuclear envelope. Weakening of the nuclear lamina further enhanced envelope remodeling, suggesting that envelope structure is capable of counterbalancing chromatin compaction forces. Our experiments reveal that the nucleoplasmic reticulum is born of the nuclear envelope and remains dynamic in that they can be reabsorbed into the nuclear envelope. We propose a model where inner nuclear envelope-chromatin tethers allow interphase chromosome movements to change nuclear envelope morphology. Therefore, interphase chromatin compaction may be a normal mechanism that reorganizes nuclear architecture, while under pathological conditions, such as laminopathies, compaction forces may contribute to defects in nuclear morphology. PMID- 25552605 TI - hecd-1 modulates notch activity in Caenorhabditis elegans. AB - Notch is a receptor that mediates cell-cell interactions that specify binary cell fate decisions in development and tissue homeostasis. Inappropriate Notch signaling is associated with cancer, and mutations in Notch pathway components have been associated with developmental diseases and syndromes. In Caenorhabditis elegans, suppressors of phenotypes associated with constitutively active LIN 12/Notch have identified many conserved core components and direct or indirect modulators. Here, we molecularly identify sel(ar584), originally isolated as a suppressor of a constitutively active allele of lin-12. We show that sel(ar584) is an allele of hecd-1, the ortholog of human HECDT1, a ubiquitin ligase that has been implicated in several different mammalian developmental events. We studied interactions of hecd-1 with lin-12 in the somatic gonad and with the other C. elegans Notch gene, glp-1, in the germ line. We found that hecd-1 acts as a positive modulator of lin-12/Notch activity in a somatic gonad context--the original basis for its isolation--but acts autonomously as a negative modulator of glp-1/Notch activity in the germ line. As the yeast ortholog of HECD-1, Ufd4p, has been shown to function in quality control, and C. elegans HECD-1 has been shown to affect mitochondrial maintenance, we propose that the different genetic interactions between hecd-1 and Notch genes we observed in different cell contexts may reflect differences in quality control regulatory mechanisms or in cellular metabolism. PMID- 25552606 TI - Identification of new players in cell division, DNA damage response, and morphogenesis through construction of Schizosaccharomyces pombe deletion strains. AB - Many fundamental biological processes are studied using the fission yeast, Schizosaccharomyces pombe. Here we report the construction of a set of 281 haploid gene deletion strains covering many previously uncharacterized genes. This collection of strains was tested for growth under a variety of different stress conditions. We identified new genes involved in DNA metabolism, completion of the cell cycle, and morphogenesis. This subset of nonessential gene deletions will add to the toolkits available for the study of biological processes in S. pombe. PMID- 25552607 TI - The evolving puzzle of autosomal versus Y-linked male determination in Musca domestica. AB - Sex determination is one of the most rapidly evolving developmental pathways, but the factors responsible for this fast evolution are not well resolved. The house fly, Musca domestica, is an ideal model for studying sex determination because house fly sex determination is polygenic and varies considerably between populations. Male house flies possess a male-determining locus, the M factor, which can be located on the Y or X chromosome or any of the five autosomes. There can be a single M or multiple M factors present in an individual male, in heterozygous or homozygous condition. Males with multiple copies of M skew the sex ratio toward the production of males. Potentially in response to these male biased sex ratios, an allele of the gene transformer, Md-tra(D), promotes female development in the presence of one or multiple M factors. There have been many studies to determine the linkage and frequency of these male determining factors and the frequency of Md-tra(D) chromosomes in populations from around the world. This review provides a summary of the information available to date regarding the patterns of distribution of autosomal, X-linked and Y-linked M factors, the relative frequencies of the linkage of M, the changes in frequencies found in field populations, and the fitness of males with autosomal M factors vs. Y-linked M. We evaluate this natural variation in the house fly sex determination pathway in light of models of the evolution of sex determination. PMID- 25552608 TI - Comparison of an automated rapid plasma reagin (RPR) test with the conventional RPR card test in syphilis testing. AB - OBJECTIVE: We compared the automated non-treponemal reagin (rapid plasma reagin (RPR)) test with the conventional RPR card test for usefulness in clinical applications. SETTING: A comparative study of laboratory methods using clinical specimens in a single institute. PARTICIPANTS: A total of 112 serum samples including 59 Treponema pallidum particle agglutination (TPPA)-positive and 53 TPPA-negative specimens were evaluated. OUTCOME MEASURES: HiSens Auto RPR LTIA (HBI, Anyang, Korea) was compared with Macro-Vue RPR Card Tests (Becton Dickinson BD Microbiology Systems, Sparks, Maryland, USA). Treponemal-specific tests were performed by Serodia TPPA assay (Fujirebio, Tokyo, Japan). The percentage agreement, kappa value and overall sensitivity and specificity of the two RPR tests were compared. Seroconversion rates after treatment were also compared for each RPR test. RESULTS: The percentage agreement between the two RPR tests was 78.6% (kappa 0.565; 95% CI 0.422 to 0.709). Sensitivity and specificity of the automated RPR test relative to the TPPA test was 52.5% (95% CI 39.1% to 65.7%) and 94.3% (95% CI 84.3% to 98.8%), respectively, while the same values for the conventional RPR card test were 86.4% (95% CI 75% to 93.9%) and 94.3% (95% CI 84.3% to 98.8%), respectively. The conventional RPR card test showed overall higher positivity than the automated RPR test, whereas the automated RPR test showed higher seroconversion (43.5%, 10/23) than the conventional RPR card test (4.3%, 1/23) in treated patients. CONCLUSIONS: The automated RPR test showed overall lower sensitivity than the conventional RPR test based on the treponemal test, but higher seroconversion after treatment. The automated RPR test could be used to monitor treatment response, especially in the reverse screening algorithm in syphilis testing. PMID- 25552611 TI - The epidemiology of competence: protocol for a scoping review. AB - INTRODUCTION: Factors that are important to the competence of healthcare providers have important consequences for quality of healthcare. Although some previous research has discussed risks or supports to the competence of clinicians, a thorough exploration is currently lacking. The purpose of this review is to examine the literature examining risks and supports to clinical competence of healthcare practitioners and trainees engaged in field-based education. In this study, field-based education refers to teaching or training in a real-world/work-based setting. METHODS AND ANALYSIS: We will employ an established scoping review methodology. Eligible studies will include those that mention (1) a healthcare professional, (2) competence from field-based education throughout the lifespan/career and (3) a risk or support to competence. Four authors will independently apply the inclusion criteria to all studies, regardless of study design. Our data extraction will include information on study design, location and type of study and we will develop a comprehensive list of risks and supports that are discussed in the literature. ETHICS AND DISSEMINATION: Since this is a review of the literature, ethics approval is not indicated. We will disseminate the findings from this study in publications in peer-reviewed journals as well as presentations at relevant national and international conferences. PMID- 25552610 TI - The effect on quality of life of vitamin D administration for advanced cancer treatment (VIDAFACT study): protocol of a randomised controlled trial. AB - INTRODUCTION: Vitamin D is related to resistance to chronic diseases, physiological parameters and functional measures. All of these relationships underscore the potential benefits of cholecalciferol or D3 (nutritional vitamin D) in cancer. This is the first study designed to obtain conclusive evidence on the effect of cholecalciferol in advanced patients with cancer. The main goal is to assess its effects on the patient's perceived quality of life. Cholecalciferol's impact on fatigue and physical performance, as well as its cost utility, will also be assessed. METHODS AND ANALYSIS: A randomised triple-blind phase II/III placebo-controlled multicentre trial has been designed. Patients satisfying the inclusion and exclusion criteria will be randomly assigned to receive cholecalciferol or placebo. Eligible patients will be adults with a locally advanced or metastatic or inoperable solid cancer in palliative care, who have given signed informed consent and have matched inclusion and exclusion criteria. The randomisation will be based on a computer-generated procedure and centralised by the pharmacy service of the coordinating centre. The assigned treatment will be administered by the hospital's pharmacy to conceal group allocation for patients and healthcare providers. Cholecalciferol (4000 IU/day) or placebo, starting at day 15 and continuing up to day 42, will be added to palliative care treatment. Outpatient visits will be scheduled every 14 days. ETHICS AND DISSEMINATION: Ethical approval was received from the Medical Ethical Commitee of the HUAV (CEIC-1169). Participants and their families will receive the research findings which will also be disseminated on local and national media, presented at national and international meetings of the specialty, and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: EudraCT: 2013-003478-29. PMID- 25552609 TI - Trunk muscle exercises as a means of improving postural stability in people with Parkinson's disease: a protocol for a randomised controlled trial. AB - INTRODUCTION: Exercise has been shown to improve clinical measures of strength, balance and mobility, and in some cases, has improved symptoms of tremor and rigidity in people with Parkinson's disease (PD). However, to date, no research has examined whether improvements in trunk control can remedy deficits in dynamic postural stability in this population. The proposed randomised controlled trial aims to establish whether a 12-week exercise programme aimed at improving dynamic postural stability in people with PD; (1) is more effective than education; (2) is more effective when training frequency is increased; and (3) provides greater long-term benefits than education. METHODS/DESIGN: Forty-five community-dwelling individuals diagnosed with idiopathic PD with a falls history will be recruited. Participants will complete baseline assessments including tests of cognition, vision, disease severity, fear of falling, mobility and quality of life. Additionally, participants will complete a series of standing balance tasks to evaluate static postural stability, while dynamic postural control will be measured during walking using head and trunk-mounted three-dimensional accelerometers. Following baseline testing, participants will be randomly assigned to one of three intervention groups, who will receive either exercise once per week, exercise 3 days/week, or education. Participants will repeat the same battery of tests conducted at baseline after the 12-week intervention and again following a further 12-week sustainability period. DISCUSSION: This study has the potential to show that low-intensity and progressive trunk exercises can provide a non-invasive and effective means for maintaining or improving postural stability for people with PD. Importantly, if the programme is noted to be effective, it could be easily performed by patients within their home environment or under the guidance of available allied health professionals. TRIAL REGISTRATION NUMBER: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12613001175763). PMID- 25552612 TI - Representations of the health value of vitamin D supplementation in newspapers: media content analysis. AB - OBJECTIVE: To examine the nature of media coverage of vitamin D in relation to its role in health and the need for supplements. DESIGN: Media content analysis. SETTING: Print articles from elite newspapers in the UK, the USA and Canada. PARTICIPANTS: 294 print newspaper articles appearing over 5 years (2009-2014). RESULTS: Newspaper coverage of vitamin D generally supported supplementation. The most common framing of vitamin D in print articles was "adequate vitamin D is necessary for good health." Articles also framed vitamin D as difficult to obtain from food supply and framed vitamin D deficiency as a widespread concern. In discussions of supplementation, 80% articles suggested supplementation is or may be necessary for the general population, yet almost none of the articles discussed the potential harms of vitamin D supplementation in any detail. Print articles named 40 different health conditions in relationship to vitamin D. The most commonly cited conditions included bone health, cancer and cardiovascular health. Although print articles referred to a wide range of scholarly research on vitamin D with varying degrees of endorsement for supplementation, a general tone of support for vitamin D supplementation in media coverage persisted. CONCLUSIONS: Newspaper articles conveyed overall support for vitamin D supplementation. News articles linked vitamin D to a wide range of health conditions for which there is no conclusive scientific evidence. Media coverage downplayed the limitations of existing science and overlooked any potential risks associated with supplementation. PMID- 25552613 TI - Neural biomarkers for assessing different types of imagery in pictorial health warning labels for cigarette packaging: a cross-sectional study. AB - OBJECTIVE: Countries around the world have increasingly adopted pictorial health warning labels (HWLs) for tobacco packages to warn consumers about smoking related risks. Research on how pictorial HWLs work has primarily analysed self reported responses to HWLs; studies at the neural level comparing the brain's response to different types of HWLs may provide an important complement to prior studies, especially if self-reported responses are systematically biased. In this study we characterise the brain's response to three types of pictorial HWLs for which prior self-report studies indicated different levels of efficacy. METHODS: Current smokers rated pictorial HWLs and then observed the same HWLs during functional MRI (fMRI) scanning. Fifty 18-50-year-old current adult smokers who were free from neurological disorders were recruited from the general population and participated in the study. Demographics, smoking-related behaviours and self reported ratings of pictorial HWL stimuli were obtained prior to scanning. Brain responses to HWLs were assessed using fMRI, focusing on a priori regions of interest. RESULTS: Pictorial HWL stimuli elicited activation in a broad network of brain areas associated with visual processing and emotion. Participants who rated the stimuli as more emotionally arousing also showed greater neural responses at these sites. CONCLUSIONS: Self-reported ratings of pictorial HWLs are correlated with neural responses in brain areas associated with visual and emotional processing. Study results cross-validate self-reported ratings of pictorial HWLs and provide insights into how pictorial HWLs are processed. PMID- 25552614 TI - Health system reforms, violence against doctors and job satisfaction in the medical profession: a cross-sectional survey in Zhejiang Province, Eastern China. AB - OBJECTIVE: To explore the factors influencing doctors' job satisfaction and morale in China, in the context of the ongoing health system reforms and the deteriorating doctor-patient relationship. DESIGN: Cross-sectional survey using self-completion questionnaires. STUDY SETTING: The survey was conducted from March to May 2012 among doctors at the provincial, county and primary care levels in Zhejiang Province, China. RESULTS: The questionnaire was completed by 202 doctors. Factors which contributed most to low job satisfaction were low income and long working hours. Provincial level doctors were most dissatisfied while primary care doctors were the least dissatisfied. Three per cent of doctors at high-level hospitals and 27% of those in primary care were satisfied with the salary. Only 7% at high-level hospitals were satisfied with the work hours, compared to 43% in primary care. Less than 10% at high levels were satisfied with the amount of paid vacation time (3%) and paid sick leave (5%), compared with 38% and 41%, respectively, in primary care. Overall, 87% reported that patients were more likely to sue and that patient violence against doctors was increasing. Only 4.5% wanted their children to be doctors. Of those 125 who provided a reason, 34% said poor pay, 17% said it was a high-risk profession, and 9% expressed concerns about personal insecurity or patient violence. CONCLUSIONS: Doctors have low job satisfaction overall. Recruitment and retention of doctors have become major challenges for the Chinese health system. Measures must be taken to address this, in order to ensure recruitment and retention of doctors in the future. These measures must first include reduction of doctors' workload, especially at provincial hospitals, partly through incentivisation of appropriate utilisation of primary care, increase in doctors' salary and more effective measures to tackle patient violence against doctors. PMID- 25552615 TI - A randomised controlled trial of aerobic exercise after transient ischaemic attack or minor stroke to prevent cognitive decline: the MoveIT study protocol. AB - INTRODUCTION: Patients with transient ischaemic attack (TIA) or stroke are at risk for cognitive impairment and dementia. Currently, there is no known effective strategy to prevent this cognitive decline. Increasing evidence exists that physical exercise is beneficial for cognitive function. However, in patients with TIA or stroke who are at risk of cognitive impairment and dementia, only a few trials have been conducted. In this study, we aim to investigate whether a physical exercise programme (MoveIT) can prevent cognitive decline in patients in the acute phase after a TIA or minor ischaemic stroke. METHODS AND ANALYSIS: A single-blinded randomised controlled trial will be conducted to investigate the effect of an aerobic exercise programme on cognition compared with usual care. 120 adult patients with a TIA or minor ischaemic stroke less than 1 month ago will be randomly allocated to an exercise programme consisting of a 12-week aerobic exercise programme and regular follow-up visits to a specialised physiotherapist during the period of 1 year or to usual care. Outcome measures will be assessed at the baseline, and at the 1-year and 2-year follow-up. The primary outcome is cognitive functioning measured with the Montreal Cognitive Assessment (MoCA) test and with additional neuropsychological tests. Secondary outcomes include maximal exercise capacity, self-reported physical activity and measures of secondary prevention. ETHICS AND DISSEMINATION: The study received ethical approval from the VU University Amsterdam Ethics committee (2011/383). The results of this study will be published in peer-reviewed journals and presented at international conferences. We will also disseminate the main results to our participants in a letter. TRIAL REGISTRATION NUMBER: The Nederlands Trial Register NTR3884. PMID- 25552617 TI - A new year and a new face for www.ccjm.org. PMID- 25552616 TI - A randomised controlled non-inferiority trial of primary care-based facilitated access to an alcohol reduction website (EFAR Spain): the study protocol. AB - INTRODUCTION: Early identification (EI) and brief interventions (BIs) for risky drinkers are effective tools in primary care. Lack of time in daily practice has been identified as one of the main barriers to implementation of BI. There is growing evidence that facilitated access by primary healthcare professionals (PHCPs) to a web-based BI can be a time-saving alternative to standard face-to face BIs, but there is as yet no evidence about the effectiveness of this approach relative to conventional BI. The main aim of this study is to test non inferiority of facilitation to a web-based BI for risky drinkers delivered by PHCP against face-to-face BI. METHOD AND ANALYSIS: A randomised controlled non inferiority trial comparing both interventions will be performed in primary care health centres in Catalonia, Spain. Unselected adult patients attending participating centres will be given a leaflet inviting them to log on to a website to complete the Alcohol Use Disorders Identification Test (AUDIT-C) alcohol screening questionnaire. Participants with positive results will be requested online to complete a trial module including consent, baseline assessment and randomisation to either face-to-face BI by the practitioner or BI via the alcohol reduction website. Follow-up assessment of risky drinking will be undertaken online at 3 months and 1 year using the full AUDIT and D5-EQD5 scale. Proportions of risky drinkers in each group will be calculated and non inferiority assessed against a specified margin of 10%. Assuming reduction of 30% of risky drinkers receiving standard intervention, 1000 patients will be required to give 90% power to reject the null hypothesis. ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Commmittee of IDIAP Jordi Gol i Gurina P14/028. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02082990. PMID- 25552618 TI - Insulin therapy and cancer risk (October 2014). PMID- 25552619 TI - In reply. PMID- 25552620 TI - Short and sweet: writing better consult notes in the era of the electronic medical record. PMID- 25552621 TI - Joint pain in a man with lung cancer. PMID- 25552622 TI - Retroperitoneal cyst hemorrhage in polycystic kidney disease. PMID- 25552623 TI - Q: when should I discuss driving with my older patients? PMID- 25552624 TI - Enterovirus D68: a clinically important respiratory enterovirus. AB - Seasonal peaks of viral respiratory illnesses are common during late summer and early fall and have often been attributed to human rhinovirus. In the fall of 2014, the number of children hospitalized with severe lower respiratory symptoms and asthma suddenly increased, and the children tested positive by sequencing for enterovirus D68 (EV-D68). As the outbreak unfolded, a possible association was also observed between EV-D68 infection, polio-like acute flaccid paralysis, and cranial neuropathy in children. PMID- 25552625 TI - Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist. AB - As tuberculosis rates decline in the United States, clinicians are less likely to consider it early in a patient's illness. Certain clinical and radiographic features increase the likelihood of tuberculosis. This review covers the clinical and radiographic features of tuberculosis, the initial evaluation of the patient, the use of airborne infection isolation, and the utility of new molecular techniques in diagnosing tuberculosis. PMID- 25552626 TI - Quitting smoking: still a challenge, but newer tools show promise. AB - Smoking continues to be a major public health problem with devastating consequences in terms of morbidity and mortality. Physicians are strongly encouraged to engage patients in a serious, concerted, and consistent effort to overcome nicotine addiction. Brief counseling in combination with medications has been shown to be effective. This article provides physicians guidelines for helping patients to quit this addictive disorder. PMID- 25552628 TI - Second Ebola patient is treated in UK. PMID- 25552627 TI - Selecting antithrombotic therapy for patients with atrial fibrillation. AB - When considering anticoagulant therapy for patients with atrial fibrillation, one must balance the reduction in risk of thromboembolism that this therapy offers against the risk of bleeding that it poses. The American Heart Association, American College of Cardiology, and Heart Rhythm Society updated their atrial fibrillation guidelines in 2014. This review outlines a rationale for clinical decision-making based on the new guidelines and summarizes the currently approved drugs. PMID- 25552629 TI - Letter to the editor: Does low-frequency power of heart rate variability correlate with cardiac sympathetic tone in normal sheep? PMID- 25552630 TI - Reply to "Letter to the editor: Does low-frequency power of heart rate variability correlate with cardiac sympathetic tone in normal sheep?". PMID- 25552634 TI - Proteins targeted by pertussis vaccine are mutating unusually quickly, study finds. PMID- 25552633 TI - Safety and immunogenicity of an intranasal Sendai virus-based human parainfluenza virus type 1 vaccine in 3- to 6-year-old children. AB - Human parainfluenza virus type 1 (hPIV-1) is the most common cause of laryngotracheobronchitis (croup), resulting in tens of thousands of hospitalizations each year in the United States alone. No licensed vaccine is yet available. We have developed murine PIV-1 (Sendai virus [SeV]) as a live Jennerian vaccine for hPIV-1. Here, we describe vaccine testing in healthy 3- to 6-year-old hPIV-1-seropositive children in a dose escalation study. One dose of the vaccine (5 * 10(5), 5 * 10(6), or 5 * 10(7) 50% egg infectious doses) was delivered by the intranasal route to each study participant. The vaccine was well tolerated by all the study participants. There was no sign of vaccine virus replication in the airway in any participant. Most children exhibited an increase in antibody binding and neutralizing responses toward hPIV-1 within 4 weeks from the time of vaccination. In several children, antibody responses remained above incoming levels for at least 6 months after vaccination. Data suggest that SeV may provide a benefit to 3- to 6-year-old children, even when vaccine recipients have preexisting cross-reactive antibodies due to previous exposures to hPIV-1. Results encourage the testing of SeV administration in young seronegative children to protect against the serious respiratory tract diseases caused by hPIV 1 infections. PMID- 25552635 TI - Metabotropic glutamate receptors promote disinhibition of olfactory bulb glomeruli that scales with input strength. AB - Increasing evidence indicates that the neural circuitry within glomeruli of the olfactory bulb plays a major role in affecting information flow between olfactory sensory neurons (OSNs) and output mitral cells (MCs). Glutamatergic external tufted (ET) cells, located at glomeruli, can act as intermediary cells in excitation between OSNs and MCs, whereas activation of MCs by OSNs is, in turn, suppressed by inhibitory synapses onto ET cells. In this study, we used patch clamp recordings in rat olfactory bulb slices to examine the function of metabotropic glutamate receptors (mGluRs) in altering these glomerular signaling mechanisms. We found that activation of group II mGluRs profoundly reduced inhibition onto ET cells evoked by OSN stimulation. The mGluRs that mediated disinhibition were located on presynaptic GABAergic periglomerular cells and appeared to be activated by glutamate transients derived from dendrites in glomeruli. In terms of glomerular output, the mGluR-mediated reduction in GABA release led to a robust increase in the number of action potentials evoked by OSN stimulation in both ET cells and MCs. Importantly, however, the enhanced excitation was specific to when a glomerulus was strongly activated by OSN inputs. By being selective for strong vs. weak glomerular activation, mGluR mediated disinhibition provides a mechanism to enhance the contrast in odor signals that activate OSN inputs into a single glomerulus at varying intensities. PMID- 25552636 TI - Cortical neural responses to previous trial outcome during learning of a directional choice task. AB - The outcomes that result from previous behavior affect future choices in several ways, but the neural mechanisms underlying these effects remain to be determined. Previous studies have shown that the lateral (AGl) and medial (AGm) agranular areas of the rat frontal cortex are involved in the learning and selection of action. Here we describe the activity of single neurons in AGl and AGm as rats learned to perform a directional choice task. Our analysis shows that single-cell activity in AGl and AGm was modulated by the outcome of the previous trial. A larger proportion of neurons encoded the previous trial's outcome shortly after cue onset than during other time periods of a trial. Most of these neurons had greater activity after correct trials than after error trials, a difference that increased as behavioral performance improved. The number of neurons encoding the previous trial's outcome correlated positively with performance accuracy. In summary, we found that neurons in both AGl and AGm encode the outcome of the immediately preceding trial, information that might play a role in the successful selection of action based on past experience. PMID- 25552637 TI - Parallel coding schemes of whisker velocity in the rat's somatosensory system. AB - The function of rodents' whisker somatosensory system is to transform tactile cues, in the form of vibrissa vibrations, into neuronal responses. It is well established that rodents can detect numerous tactile stimuli and tell them apart. However, the transformation of tactile stimuli obtained through whisker movements to neuronal responses is not well-understood. Here we examine the role of whisker velocity in tactile information transmission and its coding mechanisms. We show that in anaesthetized rats, whisker velocity is related to the radial distance of the object contacted and its own velocity. Whisker velocity is accurately and reliably coded in first-order neurons in parallel, by both the relative time interval between velocity-independent first spike latency of rapidly adapting neurons and velocity-dependent first spike latency of slowly adapting neurons. At the same time, whisker velocity is also coded, although less robustly, by the firing rates of slowly adapting neurons. Comparing first- and second-order neurons, we find similar decoding efficiencies for whisker velocity using either temporal or rate-based methods. Both coding schemes are sufficiently robust and hardly affected by neuronal noise. Our results suggest that whisker kinematic variables are coded by two parallel coding schemes and are disseminated in a similar way through various brain stem nuclei to multiple brain areas. PMID- 25552638 TI - Individuals with autism spectrum disorder show abnormalities during initial and subsequent phases of precision gripping. AB - Sensorimotor impairments are common in autism spectrum disorder (ASD), but they are not well understood. Here we examined force control during initial pulses and the subsequent rise, sustained, and relaxation phases of precision gripping in 34 individuals with ASD and 25 healthy control subjects. Participants pressed on opposing load cells with their thumb and index finger while receiving visual feedback regarding their performance. They completed 2- and 8-s trials during which they pressed at 15%, 45%, or 85% of their maximum force. Initial pulses guided by feedforward control mechanisms, sustained force output controlled by visual feedback processes, and force relaxation rates all were examined. Control subjects favored an initial pulse strategy characterized by a rapid increase in and then relaxation of force when the target force was low (Type 1). When the target force level or duration of trials was increased, control subjects transitioned to a strategy in which they more gradually increased their force, paused, and then increased their force again. Individuals with ASD showed a more persistent bias toward the Type 1 strategy at higher force levels and during longer trials, and their initial force output was less accurate than that of control subjects. Patients showed increased force variability compared with control subjects when attempting to sustain a constant force level. During the relaxation phase, they showed reduced rates of force decrease. These findings suggest that both feedforward and feedback motor control mechanisms are compromised in ASD and these deficits may contribute to the dyspraxia and sensorimotor abnormalities often seen in this disorder. PMID- 25552639 TI - Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output. AB - In Parkinson's disease (PD), the dopamine (DA) neuron loss in the substantia nigra and the DA axon loss in the dorsal striatum are severe, but DA neurons in the ventral tegmental area and DA axons in middle and ventral striatal subregions are less affected. Severe DA loss leads to DA receptor supersensitivity, but it was not known whether the supersensitivity of the DA D1 receptors (D1Rs) on the striatonigral axon terminal is determined by the severe striatal or nigral DA loss. This question is important because these two possibilities affect the extent of the striatonigral terminals with supersensitive D1Rs and hence the strength of the direct pathway output. Here we have investigated this question in the transcription factor Pitx3 mutant mice that have a PD-like DA loss pattern. We found that the presynaptic D1R function was upregulated globally: the D1R mediated facilitation was equally enhanced for the striatonigral GABA output originated in the dorsal striatum where the DA loss is severe and the somatic D1Rs are supersensitive, and for the striatonigral GABA output originated in the middle and ventral striatum where the DA loss is moderate and the somatic D1Rs are not supersensitive. These results suggest that severe nigral DA loss is sufficient to induce functional upregulation of the D1Rs on striatonigral axon terminals. Consequently, in PD, the globally enhanced D1Rs on striatonigral axon terminals originated in broad striatal subregions may strongly enhance the striatonigral GABA output upon D1R stimulation, potentially contributing to D1R agonism's profound motor-stimulating effects. PMID- 25552640 TI - Activation of InsP3 receptors is sufficient for inducing graded intrinsic plasticity in rat hippocampal pyramidal neurons. AB - The synaptic plasticity literature has focused on establishing necessity and sufficiency as two essential and distinct features in causally relating a signaling molecule to plasticity induction, an approach that has been surprisingly lacking in the intrinsic plasticity literature. In this study, we complemented the recently established necessity of inositol trisphosphate (InsP3) receptors (InsP3R) in a form of intrinsic plasticity by asking if InsP3R activation was sufficient to induce intrinsic plasticity in hippocampal neurons. Specifically, incorporation of d-myo-InsP3 in the recording pipette reduced input resistance, maximal impedance amplitude, and temporal summation but increased resonance frequency, resonance strength, sag ratio, and impedance phase lead. Strikingly, the magnitude of plasticity in all these measurements was dependent on InsP3 concentration, emphasizing the graded dependence of such plasticity on InsP3R activation. Mechanistically, we found that this InsP3-induced plasticity depended on hyperpolarization-activated cyclic nucleotide-gated channels. Moreover, this calcium-dependent form of plasticity was critically reliant on the release of calcium through InsP3Rs, the influx of calcium through N-methyl-d aspartate receptors and voltage-gated calcium channels, and on the protein kinase A pathway. Our results delineate a causal role for InsP3Rs in graded adaptation of neuronal response dynamics, revealing novel regulatory roles for the endoplasmic reticulum in neural coding and homeostasis. PMID- 25552641 TI - Midcervical neuronal discharge patterns during and following hypoxia. AB - Anatomical evidence indicates that midcervical interneurons can be synaptically coupled with phrenic motoneurons. Accordingly, we hypothesized that interneurons in the C3-C4 spinal cord can display discharge patterns temporally linked with inspiratory phrenic motor output. Anesthetized adult rats were studied before, during, and after a 4-min bout of moderate hypoxia. Neuronal discharge in C3-C4 lamina I-IX was monitored using a multielectrode array while phrenic nerve activity was extracellularly recorded. For the majority of cells, spike-triggered averaging (STA) of ipsilateral inspiratory phrenic nerve activity based on neuronal discharge provided no evidence of discharge synchrony. However, a distinct STA phrenic peak with a 6.83 +/- 1.1 ms lag was present for 5% of neurons, a result that indicates a monosynaptic connection with phrenic motoneurons. The majority (93%) of neurons changed discharge rate during hypoxia, and the diverse responses included both increased and decreased firing. Hypoxia did not change the incidence of STA peaks in the phrenic nerve signal. Following hypoxia, 40% of neurons continued to discharge at rates above prehypoxia values (i.e., short-term potentiation, STP), and cells with initially low discharge rates were more likely to show STP (P < 0.001). We conclude that a population of nonphrenic C3-C4 neurons in the rat spinal cord is synaptically coupled to the phrenic motoneuron pool, and these cells can modulate inspiratory phrenic output. In addition, the C3-C4 propriospinal network shows a robust and complex pattern of activation both during and following an acute bout of hypoxia. PMID- 25552643 TI - The effect of sensory feedback on crayfish posture and locomotion: II. Neuromechanical simulation of closing the loop. AB - Neuromechanical simulation was used to determine whether proposed thoracic circuit mechanisms for the control of leg elevation and depression in crayfish could account for the responses of an experimental hybrid neuromechanical preparation when the proprioceptive feedback loop was open and closed. The hybrid neuromechanical preparation consisted of a computational model of the fifth crayfish leg driven in real time by the experimentally recorded activity of the levator and depressor (Lev/Dep) nerves of an in vitro preparation of the crayfish thoracic nerve cord. Up and down movements of the model leg evoked by motor nerve activity released and stretched the model coxobasal chordotonal organ (CBCO); variations in the CBCO length were used to drive identical variations in the length of the live CBCO in the in vitro preparation. CBCO afferent responses provided proprioceptive feedback to affect the thoracic motor output. Experiments performed with this hybrid neuromechanical preparation were simulated with a neuromechanical model in which a computational circuit model represented the relevant thoracic circuitry. Model simulations were able to reproduce the hybrid neuromechanical experimental results to show that proposed circuit mechanisms with sensory feedback could account for resistance reflexes displayed in the quiescent state and for reflex reversal and spontaneous Lev/Dep bursting seen in the active state. PMID- 25552642 TI - Influence of developmental nicotine exposure on spike-timing precision and reliability in hypoglossal motoneurons. AB - Smoothly graded muscle contractions depend in part on the precision and reliability of motoneuron action potential generation. Whether or not a motoneuron generates spikes precisely and reliably depends on both its intrinsic membrane properties and the nature of the synaptic input that it receives. Factors that perturb neuronal intrinsic properties and/or synaptic drive may compromise the temporal precision and the reliability of action potential generation. We have previously shown that developmental nicotine exposure (DNE) alters intrinsic properties and synaptic transmission in hypoglossal motoneurons (XIIMNs). Here we show that the effects of DNE also include alterations in spike timing precision and reliability, and spike-frequency adaptation, in response to sinusoidal current injection. Current-clamp experiments in brainstem slices from neonatal rats show that DNE lowers the threshold for spike generation but increases the variability of spike-timing mechanisms. DNE is also associated with an increase in spike-frequency adaptation and reductions in both peak and steady state firing rate in response to brief, square wave current injections. Taken together, our data indicate that DNE causes significant alterations in the input output efficiency of XIIMNs. These alterations may play a role in the increased frequency of obstructive apneas and altered suckling strength and coordination observed in nicotine-exposed neonatal humans. PMID- 25552644 TI - Experience-dependent plasticity of neurovascularization. AB - Experience powerfully shapes structural and functional organization of neurons during development and in adulthood. Recent experiments in the mouse primary somatosensory cortex now suggest that experience is also a critical factor in shaping neurovasculature and promoting angiogenesis. These results support the universality of brain plasticity and show that all structural cellular components in the brain, from neuron and glia to epithelia, are shaped by experience. PMID- 25552645 TI - Spatiotemporal dynamics of optogenetically induced and spontaneous seizure transitions in primary generalized epilepsy. AB - Transitions into primary generalized epileptic seizures occur abruptly and synchronously across the brain. Their potential triggers remain unknown. We used optogenetics to causally test the hypothesis that rhythmic population bursting of excitatory neurons in a local neocortical region can rapidly trigger absence seizures. Most previous studies have been purely correlational, and it remains unclear whether epileptiform events induced by rhythmic stimulation (e.g., sensory/electrical) mimic actual spontaneous seizures, especially regarding their spatiotemporal dynamics. In this study, we used a novel combination of intracortical optogenetic stimulation and microelectrode array recordings in freely moving WAG/Rij rats, a model of absence epilepsy with a cortical focus in the somatosensory cortex (SI). We report three main findings: 1) Brief rhythmic bursting, evoked by optical stimulation of neocortical excitatory neurons at frequencies around 10 Hz, induced seizures consisting of self-sustained spike wave discharges (SWDs) for about 10% of stimulation trials. The probability of inducing seizures was frequency-dependent, reaching a maximum at 10 Hz. 2) Local field potential power before stimulation and response amplitudes during stimulation both predicted seizure induction, demonstrating a modulatory effect of brain states and neural excitation levels. 3) Evoked responses during stimulation propagated as cortical waves, likely reaching the cortical focus, which in turn generated self-sustained SWDs after stimulation was terminated. Importantly, SWDs during induced and spontaneous seizures propagated with the same spatiotemporal dynamics. Our findings demonstrate that local rhythmic bursting of excitatory neurons in neocortex at particular frequencies, under susceptible ongoing brain states, is sufficient to trigger primary generalized seizures with stereotypical spatiotemporal dynamics. PMID- 25552646 TI - Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. AB - Accurate deleteriousness prediction for nonsynonymous variants is crucial for distinguishing pathogenic mutations from background polymorphisms in whole exome sequencing (WES) studies. Although many deleteriousness prediction methods have been developed, their prediction results are sometimes inconsistent with each other and their relative merits are still unclear in practical applications. To address these issues, we comprehensively evaluated the predictive performance of 18 current deleteriousness-scoring methods, including 11 function prediction scores (PolyPhen-2, SIFT, MutationTaster, Mutation Assessor, FATHMM, LRT, PANTHER, PhD-SNP, SNAP, SNPs&GO and MutPred), 3 conservation scores (GERP++, SiPhy and PhyloP) and 4 ensemble scores (CADD, PON-P, KGGSeq and CONDEL). We found that FATHMM and KGGSeq had the highest discriminative power among independent scores and ensemble scores, respectively. Moreover, to ensure unbiased performance evaluation of these prediction scores, we manually collected three distinct testing datasets, on which no current prediction scores were tuned. In addition, we developed two new ensemble scores that integrate nine independent scores and allele frequency. Our scores achieved the highest discriminative power compared with all the deleteriousness prediction scores tested and showed low false-positive prediction rate for benign yet rare nonsynonymous variants, which demonstrated the value of combining information from multiple orthologous approaches. Finally, to facilitate variant prioritization in WES studies, we have pre-computed our ensemble scores for 87 347 044 possible variants in the whole-exome and made them publicly available through the ANNOVAR software and the dbNSFP database. PMID- 25552648 TI - Early Parkinson's disease symptoms in alpha-synuclein transgenic monkeys. AB - Parkinson's disease (PD) is an age-dependent neurodegenerative disease that can be caused by genetic mutations in alpha-synuclein (alpha-syn) or duplication of wild-type alpha-syn; PD is characterized by the deposition of alpha-syn aggregates, indicating a gain of toxicity from accumulation of alpha-syn. Although the major neuropathologic feature of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra, non-motor symptoms including anxiety, cognitive defect and sleep disorder precede the onset of motor impairment, and many clinical symptoms of PD are not caused by degeneration of DA neurons. Non-human primate models of PD are important for revealing the early pathology in PD and identifying effective treatments. We established transgenic PD rhesus monkeys that express mutant alpha-syn (A53T). Six transgenic A53T monkeys were produced via lentiviral vector expressing A53T in fertilized monkey eggs and subsequent embryo transfer to surrogates. Transgenic A53T is expressed in the monkey brain and causes age-dependent non-motor symptoms, including cognitive defects and anxiety phenotype, without detectable sleeping disorders. The transgenic alpha-syn monkeys demonstrate the specific early symptoms caused by mutant alpha-syn and provide insight into treatment of early PD. PMID- 25552647 TI - The Fragile X proteins Fmrp and Fxr2p cooperate to regulate glucose metabolism in mice. AB - Fragile X syndrome results from loss of FMR1 expression. Individuals with the disorder exhibit not only intellectual disability, but also an array of physical and behavioral abnormalities, including sleep difficulties. Studies in mice demonstrated that Fmr1, along with its paralog Fxr2, regulate circadian behavior, and that their absence disrupts expression and cycling of essential clock mRNAs in the liver. Recent reports have identified circadian genes to be essential for normal metabolism. Here we describe the metabolic defects that arise in mice mutated for both Fmr1 and Fxr2. These mice have reduced fat deposits compared with age- and weight-matched controls. Several metabolic markers show either low levels in plasma or abnormal circadian cycling (or both). Insulin levels are consistently low regardless of light exposure and feeding conditions, and the animals are extremely sensitive to injected insulin. Glucose production from introduced pyruvate and glucagon is impaired and the mice quickly clear injected glucose. These mice also have higher food intake and higher VO2 and VCO2 levels. We analyzed liver expression of genes involved in glucose homeostasis and found several that are expressed differentially in the mutant mice. These results point to the involvement of Fmr1 and Fxr2 in maintaining the normal metabolic state in mice. PMID- 25552649 TI - Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype. AB - Charcot-Marie-Tooth disease (CMT) is the most commonly inherited neurological disorder with a prevalence of 1 in 2500 people worldwide. Patients suffer from degeneration of the peripheral nerves that control sensory information of the foot/leg and hand/arm. Multiple mutations in the neurofilament light polypeptide gene, NEFL, cause CMT2E. Previous studies in transfected cells showed that expression of disease-associated neurofilament light chain variants results in abnormal intermediate filament networks associated with defects in axonal transport. We have now generated knock-in mice with two different point mutations in Nefl: P8R that has been reported in multiple families with variable age of onset and N98S that has been described as an early-onset, sporadic mutation in multiple individuals. Nefl(P8R/+) and Nefl(P8R/P8R) mice were indistinguishable from Nefl(+/+) in terms of behavioral phenotype. In contrast, Nefl(N98S/+) mice had a noticeable tremor, and most animals showed a hindlimb clasping phenotype. Immunohistochemical analysis revealed multiple inclusions in the cell bodies and proximal axons of spinal cord neurons, disorganized processes in the cerebellum and abnormal processes in the cerebral cortex and pons. Abnormal processes were observed as early as post-natal day 7. Electron microscopic analysis of sciatic nerves showed a reduction in the number of neurofilaments, an increase in the number of microtubules and a decrease in the axonal diameters. The Nefl(N98S/+) mice provide an excellent model to study the pathogenesis of CMT2E and should prove useful for testing potential therapies. PMID- 25552652 TI - Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal alpha dystroglycan O-mannosylation, independent from sialic acid. AB - Binding of cellular alpha-dystroglycan (alpha-DG) to its extracellular matrix ligands is fully dependent on a unique O-mannose-linked glycan. Disrupted O mannosylation is the hallmark of the muscular dystrophy-dystroglycanopathy (MDDG) syndromes. SLC35A1, encoding the transporter of cytidine 5'-monophosphate-sialic acid, was recently identified as MDDG candidate gene. This is surprising, since sialic acid itself is dispensable for alpha-DG-ligand binding. In a novel SLC35A1 deficient cell model, we demonstrated a lack of alpha-DG O-mannosylation, ligand binding and incorporation of sialic acids. Removal of sialic acids from HAP1 wild type cells after incorporation or preventing sialylation during synthesis did not affect alpha-DG O-mannosylation or ligand binding but did affect sialylation. Lentiviral-mediated complementation with the only known disease mutation p.Q101H failed to restore deficient O-mannosylation in SLC35A1 knockout cells and partly restored sialylation. These data indicate a role for SLC35A1 in alpha-DG O mannosylation that is distinct from sialic acid metabolism. In addition, human SLC35A1 deficiency can be considered as a combined disorder of alpha-DG O mannosylation and sialylation, a novel variant of the MDDG syndromes. PMID- 25552651 TI - A genetic association study of activated partial thromboplastin time in European Americans and African Americans: the ARIC Study. AB - Reduced activated partial thromboplastin time (aPTT) is a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT are not well understood, especially in populations of non-European ancestry. The present study aimed to identify aPTT-related gene variants in both European Americans (EAs) and African Americans (AAs). We conducted a genetic association study for aPTT in 9719 EAs and 2799 AAs from the Atherosclerosis Risk in Communities (ARIC) study. Using the Candidate Gene Association Resource (CARe) consortium candidate gene array, the analyses were based on ~50 000 SNPs in ~2000 candidate genes. In EAs, the analyses identified a new independent association for aPTT in F5 (rs2239852, P-value = 1.9 * 10(-8)), which clusters with a coding variant rs6030 (P-value = 7.8 * 10(-7)). The remaining significant signals were located on F5, HRG, KNG1, F11, F12 and ABO and have been previously reported in EA populations. In AAs, significant signals were identified in KNG1, HRG, F12, ABO and VWF, with the leading variants in KNG1, HRG and F12 being the same as in the EAs; the significant variant in VWF (rs2229446, P-value = 1.2 * 10(-6)) was specific to the AA sample (minor allele frequency = 19% in AAs and 0.2% in EAs) and has not been previously reported. This is the first study to report aPTT related genetic variants in AAs. Our findings in AAs demonstrate transferability of previously reported associations with KNG1, HRG and F12 in EAs. We also identified new associations at F5 in EAs and VWF in AAs that have not been previously reported for aPTT. PMID- 25552650 TI - Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. AB - We report two siblings with infantile onset seizures, severe developmental delay and spastic paraplegia, in whom whole-genome sequencing revealed compound heterozygous mutations in the AP4S1 gene, encoding the sigma subunit of the adaptor protein complex 4 (AP-4). The effect of the predicted loss-of-function variants (p.Gln46Profs*9 and p.Arg97*) was further investigated in a patient's fibroblast cell line. We show that the premature stop mutations in AP4S1 result in a reduction of all AP-4 subunits and loss of AP-4 complex assembly. Recruitment of the AP-4 accessory protein tepsin, to the membrane was also abolished. In retrospect, the clinical phenotype in the family is consistent with previous reports of the AP-4 deficiency syndrome. Our study reports the second family with mutations in AP4S1 and describes the first two patients with loss of AP4S1 and seizures. We further discuss seizure phenotypes in reported patients, highlighting that seizures are part of the clinical manifestation of the AP-4 deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies. PMID- 25552653 TI - MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention. AB - Mitochondrial diseases often exhibit tissue-specific pathologies, but this phenomenon is poorly understood. Here we present regulation of mitochondrial translation by the Mitochondrial Translation Optimization Factor 1, MTO1, as a novel player in this scenario. We demonstrate that MTO1 mediates tRNA modification and controls mitochondrial translation rate in a highly tissue specific manner associated with tissue-specific OXPHOS defects. Activation of mitochondrial proteases, aberrant translation products, as well as defects in OXPHOS complex assembly observed in MTO1 deficient mice further imply that MTO1 impacts translation fidelity. In our mouse model, MTO1-related OXPHOS deficiency can be bypassed by feeding a ketogenic diet. This therapeutic intervention is independent of the MTO1-mediated tRNA modification and involves balancing of mitochondrial and cellular secondary stress responses. Our results thereby establish mammalian MTO1 as a novel factor in the tissue-specific regulation of OXPHOS and fine tuning of mitochondrial translation accuracy. PMID- 25552654 TI - Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration. AB - Mutations in components of the molecular motor dynein/dynactin lead to neurodegenerative diseases of the motor system or atypical parkinsonism. These mutations are associated with prominent accumulation of vesicles involved in autophagy and lysosomal pathways, and with protein inclusions. Whether alleviating these defects would affect motor symptoms remain unknown. Here, we show that a mouse model expressing low levels of disease linked-G59S mutant dynactin p150(Glued) develops motor dysfunction >8 months before loss of motor neurons or dopaminergic degeneration is observed. Abnormal accumulation of autophagosomes and protein inclusions were efficiently corrected by lowering dietary protein content, and this was associated with transcriptional upregulations of key players in autophagy. Most importantly this dietary modification partially rescued overall neurological symptoms in these mice after onset. Similar observations were made in another mouse strain carrying a point mutation in the dynein heavy chain gene. Collectively, our data suggest that stimulating the autophagy/lysosomal system through appropriate nutritional intervention has significant beneficial effects on motor symptoms of dynein/dynactin diseases even after symptom onset. PMID- 25552655 TI - Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. AB - Proper functioning of cilia, hair-like structures responsible for sensation and locomotion, requires nephrocystin-5 (NPHP5) and a multi-subunit complex called the Bardet-Biedl syndrome (BBS)ome, but their precise relationship is not understood. The BBSome is involved in the trafficking of membrane cargos to cilia. While it is known that a loss of any single subunit prevents ciliary trafficking of the BBSome and its cargos, the mechanisms underlying ciliary entry of this complex are not well characterized. Here, we report that a transition zone protein NPHP5 contains two separate BBS-binding sites and interacts with the BBSome to mediate its integrity. Depletion of NPHP5, or expression of NPHP5 mutant missing one binding site, specifically leads to dissociation of BBS2 and BBS5 from the BBSome and loss of ciliary BBS2 and BBS5 without compromising the ability of the other subunits to traffic into cilia. Depletion of Cep290, another transition zone protein that directly binds to NPHP5, causes additional dissociation of BBS8 and loss of ciliary BBS8. Furthermore, delivery of BBSome cargos, smoothened, VPAC2 and Rab8a, to the ciliary compartment is completely disabled in the absence of single BBS subunits, but is selectively impaired in the absence of NPHP5 or Cep290. These findings define a new role of NPHP5 and Cep290 in controlling integrity and ciliary trafficking of the BBSome, which in turn impinge on the delivery of ciliary cargo. PMID- 25552656 TI - Unveiling a common mechanism of apoptosis in beta-cells and neurons in Friedreich's ataxia. AB - Friedreich's ataxia (FRDA) is a neurodegenerative disorder associated with cardiomyopathy and diabetes. Effective therapies for FRDA are an urgent unmet need; there are currently no options to prevent or treat this orphan disease. FRDA is caused by reduced expression of the mitochondrial protein frataxin. We have previously demonstrated that pancreatic beta-cell dysfunction and death cause diabetes in FRDA. This is secondary to mitochondrial dysfunction and apoptosis but the underlying molecular mechanisms are not known. Here we show that beta-cell demise in frataxin deficiency is the consequence of oxidative stress-mediated activation of the intrinsic pathway of apoptosis. The pro apoptotic Bcl-2 family members Bad, DP5 and Bim are the key mediators of frataxin deficiency-induced beta-cell death. Importantly, the intrinsic pathway of apoptosis is also activated in FRDA patients' induced pluripotent stem cell derived neurons. Interestingly, cAMP induction normalizes mitochondrial oxidative status and fully prevents activation of the intrinsic pathway of apoptosis in frataxin-deficient beta-cells and neurons. This preclinical study suggests that incretin analogs hold potential to prevent/delay both diabetes and neurodegeneration in FRDA. PMID- 25552657 TI - Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). AB - Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure. PMID- 25552659 TI - Identifying glucose thresholds for incident diabetes by physiological analysis: a mathematical solution. AB - Plasma glucose thresholds for diagnosis of type 2 diabetes are currently based on outcome data (risk of retinopathy), an inherently ill-conditioned approach. A radically different approach is to consider the mechanisms that control plasma glucose, rather than its relation to an outcome. We developed a constraint optimization algorithm to find the minimal glucose levels associated with the maximized combination of insulin sensitivity and beta-cell function, the two main mechanisms of glucose homeostasis. We used a training cohort of 1,474 subjects (22% prediabetic, 7.7% diabetic) in whom insulin sensitivity was measured by the clamp technique and beta-cell function was determined by mathematical modeling of an oral glucose tolerance test. Optimized fasting glucose levels were <= 87 and <= 89 mg/dl in <= 45-yr-old women and men, respectively, and <= 92 and <= 95 mg/dl in >45-yr-old women and men, respectively; the corresponding optimized 2-h glucose levels were <= 96, <= 98, <= 103, and <= 105 mg/dl. These thresholds were validated in three prospective cohorts of nondiabetic subjects (Relationship Between Insulin Sensitivity and Cardiovascular Disease Study, Botnia Study, and Mexico City Diabetes Study) with baseline and follow-up oral glucose tolerance tests. Of 5,593 participants, 452 progressed to diabetes. Similarly, in the three cohorts, subjects with glucose levels above the estimated thresholds had an odds ratio of 3.74 (95% confidence interval = 2.64-5.48) of progressing, substantially higher than the risk carried by baseline conventionally defined prediabetes [odds ratio = 2.32 (95% confidence interval = 1.91-2.81)]. The concept that optimization of glucose concentrations by direct measures of insulin sensitivity and beta-cell function identifies gender- and age-specific thresholds that bear on disease progression is proven in a physiologically sound, quantifiable manner. PMID- 25552658 TI - Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy. AB - Toll-like receptor 4 (TLR4) recognizes specific structural motifs associated with microbial pathogens and also responds to certain endogenous host molecules associated with tissue damage. In Duchenne muscular dystrophy (DMD), inflammation plays an important role in determining the ultimate fate of dystrophic muscle fibers. In this study, we used TLR4-deficient dystrophic mdx mice to assess the role of TLR4 in the pathogenesis of DMD. TLR4 expression was increased and showed enhanced activation following agonist stimulation in mdx diaphragm muscle. Genetic ablation of TLR4 led to significantly increased muscle force generation in dystrophic diaphragm muscle, which was associated with improved histopathology including decreased fibrosis, as well as reduced pro-inflammatory gene expression and macrophage infiltration. TLR4 ablation in mdx mice also altered the phenotype of muscle macrophages by inducing a shift toward a more anti-inflammatory (iNOS(neg) CD206(pos)) profile. In vitro experiments confirmed that lack of TLR4 is sufficient to influence macrophage activation status in response to classical polarizing stimuli such as IFN-gamma and IL-4. Finally, treatment of dystrophic mice with glycyrrhizin, an inhibitor of the endogenous TLR4 ligand, high mobility group box (HMGB1), also pointed to involvement of the HMGB1-TLR4 axis in promoting dystrophic diaphragm pathology. Taken together, our findings reveal TLR4 and the innate immune system as important players in the pathophysiology of DMD. Accordingly, targeting either TLR4 or its endogenous ligands may provide a new therapeutic strategy to slow disease progression. PMID- 25552660 TI - Influence of gonadal hormones on the behavioral effects of intermittent hypoxia in mice. AB - Obstructive sleep apnea (OSA) is characterized by repetitive upper airway obstruction resulting in cyclic intermittent hypoxia (IH) during sleep in affected individuals. OSA occurs more frequently in postmenopausal than premenopausal women and the severity of OSA increases after menopause. Gonadal hormones can influence brain and behavior; testosterone and estrogens in particular can enhance spatial learning and memory. We hypothesized that estrogens may protect mice from IH-induced hippocampal morphological and behavioral changes. To test this hypothesis we exposed intact or gonadectomized male and female mice to room air or IH [15 cycles/h, 8 h/day, fraction of inspired oxygen (FiO 2) nadir of 5%] for a total of 30 days. During the final 4 days of IH, mice were tested for anxiety- and depressive-like behaviors. After cessation of IH exposure mice were tested on the Barnes maze and passive avoidance tests to assess learning and memory. Ovariectomy paired with IH treatment, impaired spatial learning and memory compared to all other female groups. Intact male mice receiving IH treatment also had impaired learning and memory compared with intact or castrated male mice exposed to room air. Learning and memory changes were mirrored by changes in basilar dendritic length of the CA1 region of the hippocampus. These data suggest that estrogens provide protection against IH-induced deficits, whereas androgens partially exacerbate IH induced deficits on learning and memory. PMID- 25552663 TI - The ethics of molecular memory modification. AB - Novel molecular interventions have recently shown the potential to erase, enhance and alter specific long-term memories. Unique features of this form of memory modification call for a close examination of its possible applications. While there have been discussions of the ethics of memory modification in the literature, molecular memory modification (MMM) can provide special insights. Previously raised ethical concerns regarding memory enhancement, such as safety issues, the 'duty to remember', selfhood and personal identity, require re evaluation in light of MMM. As a technology that exploits the brain's updating processes, MMM helps correct the common misconception that memory is a static entity by demonstrating how memory is plastic and subject to revision even in the absence of external manipulation. Furthermore, while putatively safer than other speculative technologies because of its high specificity, MMM raises notable safety issues, including potential insidious effects on the agent's emotions and personal identity. Nonetheless, MMM possesses characteristics of a more permissible form of modification, not only because it is theoretically safer, but because its unique mechanism of action requires a heightened level of cooperation from the agent. Discussions of memory modification must consider the specific mechanisms of action, which can alter the weight and relevance of various ethical concerns. MMM also highlights the need for conceptual accuracy regarding the term 'enhancement'; this umbrella term will have to be differentiated as new technologies are applied to a widening array of purposes. PMID- 25552661 TI - Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice. AB - The present study tested the hypotheses that 1) ERalpha in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERalpha mediates these protective actions. In this study, a "floxed" ERalpha transgenic mouse line (ERalpha(flox)) was used to create models in which ERalpha was knocked down in the brain or just in the SFO. Female mice with ERalpha ablated in the nervous system (Nestin-ERalpha(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERalpha knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERalpha(flox) mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERalpha in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERalpha(-) mice or Ad-Cre-injected ERalpha(flox) mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERalpha(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERalpha(-) mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERalpha in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERalpha is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. PMID- 25552662 TI - Mechanisms of C-peptide-mediated rescue of low O2-induced ATP release from erythrocytes of humans with type 2 diabetes. AB - The circulating erythrocyte, by virtue of the regulated release of ATP in response to reduced oxygen (O2) tension, plays a key role in maintaining appropriate perfusion distribution to meet tissue needs. Erythrocytes from individuals with Type 2 diabetes (DM2) fail to release ATP in response to this stimulus. However, the administration of C-peptide and insulin at a 1:1 ratio was shown to restore this important physiological response in humans with DM2. To begin to investigate the mechanisms by which C-peptide influences low O2-induced ATP release, erythrocytes from healthy humans and humans with DM2 were exposed to reduced O2 in a thin-film tonometer, and ATP release under these conditions was compared with release during normoxia. We determined that 1) low O2-induced ATP release from DM2 erythrocytes is rescued by C-peptide in the presence and absence of insulin, 2) the signaling pathway activated by C-peptide in human erythrocytes involves PKC, as well as soluble guanylyl cyclase (sGC) and 3) inhibitors of cGMP degradation rescue low O2-induced ATP release from DM2 erythrocytes. These results provide support for the hypothesis that both PKC and sGC are components of a signaling pathway activated by C-peptide in human erythrocytes. In addition, since both C-peptide and phosphodiesterase 5 inhibitors rescue low O2-induced ATP release from erythrocytes of humans with DM2, their administration to humans with DM2 could aid in the treatment and/or prevention of the vascular disease associated with this condition. PMID- 25552664 TI - Quackery or quality: the ethicolegal basis for a legislative framework for medical innovation. AB - Innovative therapy is a matter of recent public interest, particularly following Lord Saatchi's Medical Innovation Bill. The purpose of the Bill is to encourage responsible innovation in medical treatment. We argue for the need to achieve a balance between the risks of medical innovation and patient safety considerations. We make the case for statutory regulation of medical innovation on the basis of responsible innovation, choice and patient-centred care. At the heart of regulation of medical innovation is care delivered by a process which is accountable, transparent and allows full consideration of all relevant matters. This paper proposes a two-stage test (to assess applicability of medical innovation as well as suitability for the choice of intervention to be undertaken). It is suggested that this model would provide safeguards for patients as well as define limits for doctors in the context of innovative therapy. Implementation and application of such therapy must be underpinned by due process and governance oversight, which could be provided through context specific professional peer review. A combination of these ethicolegal principles would permit responsible medical innovation and maximise benefit in terms of therapy and patient-centred care. PMID- 25552666 TI - 111In-cetuximab-F(ab')2 SPECT and 18F-FDG PET for prediction and response monitoring of combined-modality treatment of human head and neck carcinomas in a mouse model. AB - Treatment of head and neck squamous cell carcinomas with radiotherapy and the epidermal growth factor receptor (EGFR) inhibitor cetuximab shows an improved response in a subgroup of patients. The aim of this study was to noninvasively monitor treatment response by visualizing systemically accessible EGFR with (111)In-cetuximab-F(ab')2 while simultaneously evaluating tumor metabolism with (18)F-FDG PET during combined-modality treatment. METHODS: Eighty mice with patient-derived head and neck squamous cell carcinomas xenografts, SCCNij202 or SCCNij185, were imaged with SPECT/CT using (111)In-cetuximab-F(ab')2 (5 MUg, 28 +/- 6.1 MBq, 24 h after injection), followed by PET imaging with (18)F-FDG (9.4 +/- 2.9 MBq, 1 h after injection). Scans were acquired on mice 10 d before treatment with either single-dose irradiation (10 Gy), cetuximab alone, or cetuximab-plus-irradiation combined or on untreated control mice. Scans were repeated 18 d after treatment. Tumor growth was monitored up to 120 d after treatment. EGFR expression was evaluated immunohistochemically. RESULTS: SCCNij202 responded to combined treatment (P < 0.01) and cetuximab treatment alone (P < 0.05) but not to irradiation alone (P = 0.13). SCCNij185 responded to combined treatment (P < 0.05) and irradiation (P < 0.05) but not to cetuximab treatment alone (P = 0.34). (111)In-cetuximab-F(ab')2 uptake (tumor-to-liver ratio, scan 2 - scan 1) predicted response to therapy. A positive response to treatment significantly correlated with a reduced tracer uptake in the tumor in the second SPECT scan, compared with the first scan (P < 0.005 and <0.05 for SCCNij202 and SCCNij185, respectively). Resistance to therapy was characterized by a significantly increased (111)In-cetuximab-F(ab')2 tumor uptake; tumor-to liver ratio was 2.2 +/- 0.6 to 3.5 +/- 1.2, P < 0.01, for (irradiated) SCCNij202 and 1.4 +/- 0.4 to 2.0 +/- 0.3, P < 0.05, for (cetuximab-treated) SCCNij185, respectively. (18)F-FDG PET tumor uptake (maximum standardized uptake value, scan 2 - scan 1) correlated with tumor response for SCCNij202 (P < 0.01) but not for SCCNij185 (P = 0.66). EGFR fractions were significantly different: 0.9 +/- 0.1 (SCCNij202) and 0.5 +/- 0.1 (SCCNij185) (P < 0.001). The EGFR fraction was significantly lower for irradiated SCCNij202 tumors than for controls (P < 0.005). CONCLUSION: (111)In-cetuximab-F(ab')2 predicted and monitored the effects of EGFR inhibition or irradiation during treatment in both head and neck carcinoma models investigated, whereas (18)F-FDG PET only correlated with tumor response in the SCCNij202 model. Thus, the additional value of the (111)In cetuximab-F(ab')2 tracer is emphasized and the tracer can aid in evaluating future treatments with EGFR-targeted therapies. PMID- 25552667 TI - Integrated 18F-FDG PET/MR imaging in the assessment of cardiac masses: a pilot study. AB - The objective of the present study was to evaluate whether integrated (18)F-FDG PET/MR imaging could improve the diagnostic workup in patients with cardiac masses. METHODS: Twenty patients were prospectively assessed using integrated cardiac (18)F-FDG PET/MR imaging: 16 patients with cardiac masses of unknown identity and 4 patients with cardiac sarcoma after surgical therapy. All scans were obtained on an integrated 3-T PET/MR device. The MR protocol consisted of half Fourier acquisition single-shot turbo spin-echo sequence, cine, and T2 weighted images as well as T1-weighted images before and after injection of gadobutrol. PET data were acquired simultaneously with the MR scan after injection of 199 +/- 58 MBq of (18)F-FDG. Patients were prepared with a high-fat, low-carbohydrate diet in a period of 24 h before the examination, and 50 IU/kg of unfractionated heparin were administered intravenously 15 min before (18)F-FDG injection. RESULTS: Cardiac masses were diagnosed as follows: metastases, 3; direct tumor infiltration via pulmonary vein, 1; local relapse of primary sarcoma after surgery, 2; Burkitt lymphoma, 1; scar/patch tissue after surgery of primary sarcoma, 2; myxoma, 4; fibroelastoma, 1; caseous calcification of mitral annulus, 3; and thrombus, 3. The maximum standardized uptake value (SUVmax) in malignant lesions was significantly higher than in nonmalignant cases (13.2 +/- 6.2 vs. 2.3 +/- 1.2, P = 0.0004). When a threshold of 5.2 or greater was used, SUVmax was found to yield 100% sensitivity and 92% specificity for the differentiation between malignant and nonmalignant cases. T2-weighted hyperintensity and contrast enhancement both yielded 100% sensitivity but a weak specificity of 54% and 46%, respectively. Morphologic tumor features as assessed by cine MR imaging yielded 86% sensitivity and 92% specificity. Consent interpretation using all available MR features yielded 100% sensitivity and 92% specificity. A Boolean 'AND' combination of an SUVmax of 5.2 or greater with consent MR image interpretation improved sensitivity and specificity to 100%. CONCLUSION: In selected patients, (18)F-FDG PET/MR imaging can improve the noninvasive diagnosis and follow-up of cardiac masses. PMID- 25552668 TI - Optoacoustic imaging of naphthalocyanine: potential for contrast enhancement and therapy monitoring. AB - We investigated in vitro and in vivo the optoacoustic responses of silicon 2,3 naphthalocyanine bi(trihexylsilyloxide) (SiNc), considered herein as a reporter molecule for optoacoustic imaging, elucidating its efficiency for optoacoustic (photoacoustic) signal generation and examining the in vivo performance achieved. METHODS: SiNc solutions were prepared using Cremophor EL in water and evaluated for light-absorbing and optoacoustic contrast-generating properties. Photostability and singlet oxygen generation were investigated under pulsed laser illumination and validated using photoabsorbance. HT-29 mouse tumor models were used to assess the biodistribution of the compound and its performance as an optoacoustic contrast agent in vivo. RESULTS: SiNc was found to generate superior optoacoustic signals compared with the commonly used indocyanine green. Multispectral optoacoustic tomography of mouse tumors efficiently resolved the biodistribution of SiNc and the underlying perfusion parameters in vivo. In addition, we demonstrate how light-triggered SiNc reactions with molecular oxygen can be potentially sensed and discuss the relation of these measurements to the biochemical process involved in photothermal treatment. CONCLUSION: SiNc appears to be a promising family of contrast agent for optoacoustic imaging. Further development possibilities promise to expand its use in purely contrast generation settings, as well as its photodynamic therapy application. PMID- 25552669 TI - Molecular imaging of prostate cancer: tapping into the opportunities. PMID- 25552671 TI - Catheter ablation as first-line treatment for paroxysmal atrial fibrillation: rarely a good value. PMID- 25552670 TI - Gleason score at diagnosis predicts the rate of detection of 18F-choline PET/CT performed when biochemical evidence indicates recurrence of prostate cancer: experience with 1,000 patients. AB - The objective of this study was to explore the ability of the initial Gleason score (GS) to predict the rate of detection of recurrent prostate cancer (PCa) with (18)F-choline PET/CT in a large cohort of patients. METHODS: Data from 1,000 patients who had undergone (18)F-choline PET/CT because of biochemical evidence of relapse of PCa between 2004 and 2013 were retrieved from databases at 4 centers. Continuous data were compared by the Student t test or ANOVA, and categoric variables were compared by the chi(2) test. Univariable and multivariable analyses were performed by logistic regression. RESULTS: The GS at diagnosis was less than or equal to 6 in 257 patients, 7 in 347 patients, and greater than 7 in 396 patients. The results of 645 PET/CT scans were positive for PCa recurrence. Eighty-one percent of the positive PET/CT results were found in patients with a PSA level of greater than or equal to 2 ng/mL, 43% were found in patients with a PSA level of 1-2 ng/mL, and 31% were found in patients with a PSA level of less than or equal to 1 ng/mL; 78.8% of patients with positive PET/CT results had a GS of greater than 7. The results of (18)F-choline PET/CT scans were negative in 300 patients; 44% had a GS of less than or equal to 6, 35% had a GS of 7, and 17% had a GS of greater than 7. PET/CT results were rated as doubtful in only 5.5% of patients (median PSA, 1.8 ng/mL). When the GS was greater than 7, the rates of detection of (18)F-choline PET/CT were 51%, 65%, and 91% for a PSA level of less than 1 ng/mL, 1-2 ng/mL, and greater than 2 ng/mL, respectively. In univariable and multivariable analyses, both a GS of 7 and a GS of greater than 7 were independent predictors for positive (18)F-choline PET/CT results (odds ratios, 0.226 and 0.330, respectively; P values for both, <0.001). CONCLUSION: A high GS at diagnosis is a strong predictive factor for positive (18)F-choline PET/CT scan results for recurrent PCa, even when the PSA level is low (i.e., <=1 ng/mL). PMID- 25552672 TI - Do cardiologists follow the European guidelines for cardiac pacing and resynchronization therapy? Results of the European Heart Rhythm Association survey. AB - The purpose of this European Heart Rhythm Association (EHRA) EP wire survey was to evaluate the implementation of the current guidelines for cardiac pacing and cardiac resynchronization therapy (CRT) in Europe. A total of 48 centres replied to the survey, 34 of them (71%) were university hospitals. All responding centres implement CRT in patients with classical indications, i.e. sinus rhythm, New York Heart Association (NYHA) functional class II, III, or ambulatory IV, left ventricular ejection fraction (LVEF) 35%, and left bundle-branch block (LBBB) with QRS duration >150 ms, while 31 centres (67%) would implant a CRT device in patients with the same characteristics but with a non-LBBB pattern. Forty-one centres (89%) would also implant CRT in patients with sinus rhythm, NYHA Class II, III, or ambulatory IV, LVEF <35%, and LBBB with QRS duration between 120 and 150 ms, while only eight centres (17%) would implant the device in patients with the same characteristics but with a non-LBBB pattern. In patients with LVEF <35% and QRS duration below 120 ms, the majority of the centres (80%) would implant a single- or dual-chamber implantable cardioverter-defibrillator, but in nine cases (20%) no device was considered to be indicated. The results of this survey showed a good adherence to some of the current recommendations. Still some reluctance exists when offering the device therapy to patients with QRS duration in the lower range. PMID- 25552673 TI - Another annual autumn epidemic. PMID- 25552674 TI - Building a primary care/research partnership: lessons learned from a telehealth intervention for diabetes and depression. AB - INTRODUCTION: Evidence-based interventions are often poorly translated into primary care settings due to inadequate integration into organizational cultures and clinical workflows. Study designs that blend evaluation of effectiveness and implementation may enhance uptake of interventions into primary care settings. Community-Based Participatory Research (CBPR) models are useful for developing partnerships between research teams and primary care clinical partners to test blended study designs. METHODS: We conducted a formative evaluation of partnership building between a health services research team and a primary care community in US Veterans Affairs Health System to conduct a randomized effectiveness trial of an intervention embedded in routine primary care. The formative evaluation used qualitative data drawn from research/clinical partnership meetings. Data were coded and analysed using qualitative framework analysis. RESULTS: The CBPR model guided development of a research/clinical partnership based on a facilitation team consisting of 'external facilitators' (research team), 'internal facilitators' (primary care leadership) and a 'clinical advisory committee' drawn from the primary care community. Qualitative themes focused on: how the intervention components ('evidence') aligned with local clinical cultures, barriers and facilitators to acceptance and adoption of the intervention processes within the context of clinical workflows and identified 'facilitators' of intervention uptake and sustainability. CONCLUSION: A CBPR model can guide the development of research/clinical partnerships. Partnerships can identify barriers and craft modifications to intervention procedures that promote integration and into primary care workflows. Formative research/clinical partnerships are critical for designing and testing interventions focused on implementation and sustainability of new evidence within routine primary care. PMID- 25552675 TI - DNA analysis of soil extracts can be used to investigate fine root depth distribution of trees. AB - Understanding the root distribution of trees by soil coring is time -: consuming as it requires the separation of roots from soil and classification of roots into particular size classes. This labour-intensive process can limit sample throughput and therefore sampling intensity. We investigated the use of quantitative polymerase chain reaction (qPCR) on soil DNA extractions to determine live fine root DNA density (RDD, mg DNA m(-2)) for mango (Mangifera indica) trees. The specificity of the qPCR was tested against DNA extracted from 10 mango cultivars and 14 weed species. All mango cultivars and no weeds were detected. Mango DNA was successfully quantified from control soil spiked with mango roots and weed species. The DNA yield of mango root sections stored in moist soil at 23-28 degrees C declined after 15 days to low concentrations as roots decayed, indicating that dead root materials in moist soil would not cause false-positive results. To separate large roots from samples, a root separation method for field samples was used to target the root fragments remaining in sieved (minimum 2 mm aperture) soil for RDD comparisons. Using this method we compared the seasonal RDD values of fine roots for five mango rootstock cultivars in a field trial. The mean cultivar DNA yields by depth from root fragments in the sieved soil samples had the strongest relationship (adjusted multiple R(2) = 0.9307, P < 0.001) with the dry matter (g m(-2)) of fine (diameter <0.64 mm) roots removed from the soil by sieving. This method provides a species-specific and rapid means of comparing the distribution and concentration of live fine roots of trees in orchards using soil samples up to 500 g. PMID- 25552676 TI - The history of Haematologica. PMID- 25552677 TI - Red cells in post-genomic era: impact of personalized medicine in the treatment of anemias. PMID- 25552680 TI - RNA sequencing reveals a unique fusion of the lysine (K)-specific methyltransferase 2A and smooth muscle myosin heavy chain 11 in myelodysplastic syndrome and acute myeloid leukemia. PMID- 25552679 TI - Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia. PMID- 25552678 TI - Deciphering the molecular landscape in chronic lymphocytic leukemia: time frame of disease evolution. AB - Dramatic advances in next generation sequencing technologies have provided a novel opportunity to understand the molecular genetics of chronic lymphocytic leukemia through the comprehensive detection of genetic lesions. While progress is being made in elucidating the clinical significance of recurrently mutated genes, layers of complexity have been added to our understanding of chronic lymphocytic leukemia pathogenesis in the guise of the molecular evolution and (sub)clonal architecture of the disease. As we prepare for an era of tailored therapy, we need to appreciate not only the effect mutations have on drug response but also the impact subclones containing specific mutations have at initial presentation, during therapy and upon relapse. Therefore, although the wealth of emerging genetic data has great potential in helping us devise strategies to improve the therapy and prognosis of patients, focused efforts will be required to follow disease evolution, particularly in the context of novel therapies, in order to translate this knowledge into clinical settings. PMID- 25552681 TI - Radotinib in the treatment of chronic phase chronic myeloid leukemia patients. PMID- 25552682 TI - Comment on: 'Should clinical hematologists put their microscopes on eBay?'. PMID- 25552683 TI - Answer to comment on the editorial 'Should hematologists put there microscopes on eBay?'. PMID- 25552685 TI - A hippo "AKT" regulates cardiomyocyte proliferation. PMID- 25552686 TI - miRNA208/Mef2 and TNF-alpha in right ventricular dysfunction: the transition from hypertrophy to failure. PMID- 25552687 TI - Releasing YAP from an alpha-catenin trap increases cardiomyocyte proliferation. PMID- 25552689 TI - Bone good to the heart: bone marrow cell characteristics and cardiac repair after STEMI in the CCTRN TIME cohort. PMID- 25552690 TI - Gary H. Gibbons: a career-defining question. PMID- 25552688 TI - Allogeneic cell therapy: a new paradigm in therapeutics. PMID- 25552691 TI - Reproducibility in science: improving the standard for basic and preclinical research. AB - Medical and scientific advances are predicated on new knowledge that is robust and reliable and that serves as a solid foundation on which further advances can be built. In biomedical research, we are in the midst of a revolution with the generation of new data and scientific publications at a previously unprecedented rate. However, unfortunately, there is compelling evidence that the majority of these discoveries will not stand the test of time. To a large extent, this reproducibility crisis in basic and preclinical research may be as a result of failure to adhere to good scientific practice and the desperation to publish or perish. This is a multifaceted, multistakeholder problem. No single party is solely responsible, and no single solution will suffice. Here we review the reproducibility problems in basic and preclinical biomedical research, highlight some of the complexities, and discuss potential solutions that may help improve research quality and reproducibility. PMID- 25552692 TI - Control of cardiac repolarization by phosphoinositide 3-kinase signaling to ion channels. AB - Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long-QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long-QT syndrome by direct block of the rapid delayed rectifier (IKr) also seem to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity. The importance of PI3K in regulating cardiac repolarization is underscored by evidence that QT interval prolongation in diabetes mellitus also may result from changes in multiple currents because of decreased insulin activation of PI3K in the heart. How PI3K signaling regulates ion channels to control the cardiac action potential is poorly understood. Hence, this review summarizes what is known about the effect of PI3K and its downstream effectors, including Akt, on sodium, potassium, and calcium currents in cardiac myocytes. We also refer to some studies in noncardiac cells that provide insight into potential mechanisms of ion channel regulation by this signaling pathway in the heart. Drug development and safety could be improved with a better understanding of the mechanisms by which PI3K regulates cardiac ion channels and the extent to which PI3K inhibition contributes to arrhythmogenic susceptibility. PMID- 25552693 TI - The GSK-3 family as therapeutic target for myocardial diseases. AB - Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer disease, aging, inflammation, and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review, we will focus on its expanding role in the heart, concentrating primarily on recent studies that have used cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis, and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3alpha specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction after myocardial infarction by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3beta as a regulator of myocardial fibrosis will also be discussed. We will review our recent findings that specific deletion of GSK-3beta in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK 3beta is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature. PMID- 25552695 TI - Cardiac MyBP-C regulates the rate and force of contraction in mammalian myocardium. AB - Cardiac myosin-binding protein-C (cMyBP-C) is a thick filament-associated protein that seems to contribute to the regulation of cardiac contraction through interactions with either myosin or actin or both. Several studies over the past several years have suggested that the interactions of cardiac myosin-binding protein-C with its binding partners vary with its phosphorylation state, binding predominantly to myosin when dephosphorylated and to actin when it is phosphorylated by protein kinase A or other kinases. Here, we summarize evidence suggesting that phosphorylation of cardiac myosin binding protein-C is a key regulator of the kinetics and amplitude of cardiac contraction during beta adrenergic stimulation and increased stimulus frequency. We propose a model for these effects via a phosphorylation-dependent regulation of the kinetics and extent of cooperative recruitment of cross bridges to the thin filament: phosphorylation of cardiac myosin binding protein-C accelerates cross bridge binding to actin, thereby accelerating recruitment and increasing the amplitude of the cardiac twitch. In contrast, enhanced lusitropy as a result of phosphorylation seems to be caused by a direct effect of phosphorylation to accelerate cross-bridge detachment rate. Depression or elimination of one or both of these processes in a disease, such as end-stage heart failure, seems to contribute to the systolic and diastolic dysfunction that characterizes the disease. PMID- 25552696 TI - Contemporary aspects of the biology and therapeutic regulation of the microsomal triglyceride transfer protein. AB - The microsomal triglyceride transfer protein (MTP), the product of the MTTP gene, is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins, but when defective causes abetalipoproteinemia. Abetalipoproteinemia is a rare autosomal recessive disorder characterized by the inability to produce chylomicrons or very low-density lipoproteins, with the absence of apolipoprotein B-containing lipoproteins in the circulation. Knowledge of the molecular basis for abetalipoproteinemia has led to the development of therapies for dyslipidemia that inhibit MTP. Partial MTP inhibition using small molecule inhibitors, such as lomitapide, can effectively lower plasma low-density lipoprotein-cholesterol and apolipoprotein B levels, but is associated with gastrointestinal side effects and hepatic steatosis, whose long-term sequelae remain unclear; lomitapide has accordingly only been approved as a treatment for homozygous familial hypercholesterolemia. Intestine-specific inhibitors of MTP decrease chylomicron biogenesis and improve insulin sensitivity in experimental animals and, while overcoming hepatic steatosis, may have significant gastrointestinal side effects that could limit their use in humans. We review contemporary aspects of the biology and therapeutic regulation of MTP and their significance for lipid metabolism and cardiovascular disease. PMID- 25552694 TI - Origin of cardiomyocytes in the adult heart. AB - This review article discusses the mechanisms of cardiomyogenesis in the adult heart. They include the re-entry of cardiomyocytes into the cell cycle; dedifferentiation of pre-existing cardiomyocytes, which assume an immature replicating cell phenotype; transdifferentiation of hematopoietic stem cells into cardiomyocytes; and cardiomyocytes derived from activation and lineage specification of resident cardiac stem cells. The recognition of the origin of cardiomyocytes is of critical importance for the development of strategies capable of enhancing the growth response of the myocardium; in fact, cell therapy for the decompensated heart has to be based on the acquisition of this fundamental biological knowledge. PMID- 25552698 TI - Letter by Villa Abrille et al regarding article, "hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation". PMID- 25552697 TI - Role of mineralocorticoid receptor antagonists in cardiovascular disease. AB - Aldosterone exerts its best known sodium homeostasis actions by controlling sodium excretion at the level of the distal tubules via activation of the apical epithelial sodium channel and the basolateral Na(+)/K(+)ATPase pump. Recently, this mineralocorticoid hormone has been demonstrated to act on the heart and blood vessels. Excess release of aldosterone in relation to the salt status induces both genomic and nongenomic effects that by promoting endothelial dysfunction, and vascular and cardiorenal adverse remodeling, contribute to the target organ damage found in hypertension, heart failure, myocardial infarction, and chronic renal failure. Mineralocorticoid receptor blockers have been shown to be highly effective in resistant hypertension and to slow down heart failure progression, and in experimental animals, the development of atherosclerosis. Blockade of the action of aldosterone and potentially other mineralocorticoid steroids has been increasingly demonstrated to be an extremely beneficial therapy in different forms of cardiovascular disease. This review provides a summary of the knowledge that exists on aldosterone actions in the cardiovascular system and, in providing the translational impact of this knowledge to the clinical arena, illustrates how much more needs to be achieved in exploring the use of mineralocorticoid receptor blockers in less advanced stages of heart, renal, and vascular disease. PMID- 25552699 TI - Response to letter from Villa-Abrille et al. PMID- 25552700 TI - Chronic lymphocytic leukemia cells in lymph nodes show frequent NOTCH1 activation. PMID- 25552702 TI - Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation. AB - The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5 group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification. PMID- 25552701 TI - Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology. AB - Clathrin-dependent endocytosis is an essential cellular process shared by all cell types. Despite this, precisely how endocytosis is regulated in a cell-type specific manner and how this key pathway functions physiologically or pathophysiologically remain largely unknown. PICALM, which encodes the clathrin adaptor protein PICALM, was originally identified as a component of the CALM/AF10 leukemia oncogene. Here we show, by employing a series of conditional Picalm knockout mice, that PICALM critically regulates transferrin uptake in erythroid cells by functioning as a cell-type-specific regulator of transferrin receptor endocytosis. While transferrin receptor is essential for the development of all hematopoietic lineages, Picalm was dispensable for myeloid and B-lymphoid development. Furthermore, global Picalm inactivation in adult mice did not cause gross defects in mouse fitness, except for anemia and a coat color change. Freeze etch electron microscopy of primary erythroblasts and live-cell imaging of murine embryonic fibroblasts revealed that Picalm function is required for efficient clathrin coat maturation. We showed that the PICALM PIP2 binding domain is necessary for transferrin receptor endocytosis in erythroblasts and absolutely essential for erythroid development from mouse hematopoietic stem/progenitor cells in an erythroid culture system. We further showed that Picalm deletion entirely abrogated the disease phenotype in a Jak2(V617F) knock-in murine model of polycythemia vera. Our findings provide new insights into the regulation of cell-type-specific transferrin receptor endocytosis in vivo. They also suggest a new strategy to block cellular uptake of transferrin-bound iron, with therapeutic potential for disorders characterized by inappropriate red blood cell production, such as polycythemia vera. PMID- 25552703 TI - Impact of additional genetic alterations on the outcome of patients with NPM1 mutated cytogenetically normal acute myeloid leukemia. PMID- 25552706 TI - Selective loss of vaccine-specific memory B cells in a rhesus macaque model of chemotherapy: influence of doxorubicin on immunological memory. PMID- 25552704 TI - Clinical and functional implications of microRNA mutations in a cohort of 935 patients with myelodysplastic syndromes and acute myeloid leukemia. PMID- 25552705 TI - Vincristine, dexamethasone and epratuzumab for older relapsed/refractory CD22+ B acute lymphoblastic leukemia patients: a phase II study. PMID- 25552707 TI - The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenstrom macroglobulinemia. PMID- 25552708 TI - The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I like receptor-dependent interferon production. AB - Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-inducible gene 1 (RIG-i) and Melanoma Differentiation-Associated protein 5 (MDA5), in sharp contrast to those of 14 other nonpathogenic arenaviruses. Inhibition of the RIG-i-like receptors (RLRs) by pathogenic Z proteins is mediated by the protein-protein interactions of Z and RLRs, which lead to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interfaces are located within the N-terminal domain (NTD) of the Z protein and the N-terminal CARD domains of RLRs. Swapping of the LCMV Z NTD into the nonpathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells but significantly inhibits the type I interferon (IFN) responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune-system-suppressive mechanism shared by the diverse pathogenic arenaviruses and thus shed important light on the pathogenic mechanism of human arenavirus pathogens. IMPORTANCE: We show that all known human-pathogenic arenaviruses share an innate immune suppression mechanism that is based on viral Z protein-mediated RLR inhibition. Our report offers important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and/or emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our report provides a better understanding of the mechanisms of viral immune suppression and host-pathogen interactions. PMID- 25552709 TI - Identification and characterization of nuclear and nucleolar localization signals in the adeno-associated virus serotype 2 assembly-activating protein. AB - Assembly-activating protein (AAP) of adeno-associated virus serotype 2 (AAV2) is a nucleolar-localizing protein that plays a critical role in transporting the viral capsid VP3 protein to the nucleolus for assembly. Here, we identify and characterize AAV2 AAP (AAP2) nuclear (NLS) and nucleolar (NoLS) localization signals near the carboxy-terminal region of AAP2 (amino acid positions 144 to 184) (AAP2(144-184)). This region contains five basic-amino-acid-rich (BR) clusters, KSKRSRR (AAP2BR1), RRR (AAP2BR2), RFR (AAP2BR3), RSTSSR (AAP2BR4), and RRIK (AAP2BR5), from the amino terminus to the carboxy terminus. We created 30 AAP2BR mutants by arginine/lysine-to-alanine mutagenesis or deletion of AAP2BRs and 8 and 1 green fluorescent protein (GFP)-AAP2BR and beta-galactosidase-AAP2BR fusion proteins, respectively, and analyzed their intracellular localization in HeLa cells by immunofluorescence microscopy. The results showed that AAP2(144 184) has redundant multipartite NLSs and that any combinations of 4 AAP2BRs, but not 3 or less, can constitute a functional NLS-NoLS; AAP2BR1 and AAP2BR2 play the most influential role for nuclear localization, but either one of the two AAP2BRs is dispensable if all 4 of the other AAP2BRs are present, resulting in 3 different, overlapping NLS motifs; and the NoLS is shared redundantly among the five AAP2BRs and functions in a context-dependent manner. AAP2BR mutations not only resulted in aberrant intracellular localization, but also attenuated AAP2 protein expression to various degrees, and both of these abnormalities have a significant negative impact on capsid production. Thus, this study reveals the organization of the intermingling NLSs and NoLSs in AAP2 and provides insights into their functional roles in capsid assembly. IMPORTANCE: Adeno-associated virus (AAV) has become a popular and successful vector for in vivo gene therapy; however, its biology has yet to be fully understood. In this regard, the recent discovery of the assembly-activating protein (AAP), a nonstructural, nucleolar localizing AAV protein essential for viral capsid assembly, has provided us a new opportunity to better understand the fundamental processes required for virion formation. Here, we identify clusters of basic amino acids in the carboxy terminus of AAP from AAV serotype 2 (AAV2) that act as nuclear and nucleolar localization signals. We also demonstrate their importance in maintaining AAP expression levels and efficient production of viral capsids. Insights into the functions of AAP can elucidate the requirements and process for AAV capsid assembly, which may lead to improved vector production for use in gene therapy. This study also contributes to the growing body of work on nuclear and nucleolar localization signals. PMID- 25552710 TI - Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1+ endolysosomes is a rate-defining step. AB - Ebola virus (EBOV) causes hemorrhagic fevers with high mortality rates. During cellular entry, the virus is internalized by macropinocytosis and trafficked through endosomes until fusion between the viral and an endosomal membrane is triggered, releasing the RNA genome into the cytoplasm. We found that while macropinocytotic uptake of filamentous EBOV viruslike particles (VLPs) expressing the EBOV glycoprotein (GP) occurs relatively quickly, VLPs only begin to enter the cytoplasm after a 30-min lag, considerably later than particles bearing the influenza hemagglutinin or GP from lymphocytic choriomeningitis virus, which enter through late endosomes (LE). For EBOV, the long lag is not due to the large size or unusual shape of EBOV filaments, the need to prime EBOV GP to the 19-kDa receptor-binding species, or a need for unusually low endosomal pH. In contrast, since we observed that EBOV entry occurs upon arrival in Niemann-Pick C1 (NPC1) positive endolysosomes (LE/Lys), we propose that trafficking to LE/Lys is a key rate-defining step. Additional experiments revealed, unexpectedly, that severe acute respiratory syndrome (SARS) S-mediated entry also begins only after a 30 min lag. Furthermore, although SARS does not require NPC1 for entry, SARS entry also begins after colocalization with NPC1. Since the only endosomal requirement for SARS entry is cathepsin L activity, we tested and provide evidence that NPC1(+) LE/Lys have higher cathepsin L activity than LE, with no detectable activity in earlier endosomes. Our findings suggest that both EBOV and SARS traffic deep into the endocytic pathway for entry and that they do so to access higher cathepsin activity. IMPORTANCE: Ebola virus is a hemorrhagic fever virus that causes high fatality rates when it spreads from zoonotic vectors into the human population. Infection by severe acute respiratory syndrome coronavirus (SARS-CoV) causes severe respiratory distress in infected patients. A devastating outbreak of EBOV occurred in West Africa in 2014, and there was a significant outbreak of SARS in 2003. No effective vaccine or treatment has yet been approved for either virus. We present evidence that both viruses traffic late into the endocytic pathway, to NPC1(+) LE/Lys, in order to enter host cells, and that they do so to access high levels of cathepsin activity, which both viruses use in their fusion-triggering mechanisms. This unexpected similarity suggests an unexplored vulnerability, trafficking to NPC1(+) LE/Lys, as a therapeutic target for SARS and EBOV. PMID- 25552711 TI - The herpes simplex virus 1 UL51 protein interacts with the UL7 protein and plays a role in its recruitment into the virion. AB - The alphaherpesvirus UL51 protein is a tegument component that interacts with the viral glycoprotein E and functions at multiple steps in virus assembly and spread in epithelial cells. We show here that pUL51 forms a complex in infected cells with another conserved tegument protein, pUL7. This complex can form in the absence of other viral proteins and is largely responsible for recruitment of pUL7 to cytoplasmic membranes and into the virion tegument. Incomplete colocalization of pUL51 and pUL7 in infected cells, however, suggests that a significant fraction of the population of each protein is not complexed with the other and that they may accomplish independent functions. IMPORTANCE: The ability of herpesviruses to spread from cell to cell in the face of an immune response is critical for disease and shedding following reactivation from latency. Cell-to cell spread is a conserved ability of herpesviruses, and the identification of conserved viral genes that mediate this process will aid in the design of attenuated vaccines and of novel therapeutics. The conserved UL51 gene of herpes simplex virus 1 plays important roles in cell-to-cell spread and in virus assembly in the cytoplasm, both of which likely depend on specific interactions with other viral and cellular proteins. Here we identify one of those interactions with the product of another conserved herpesvirus gene, UL7, and show that formation of this complex mediates recruitment of UL7 to membranes and to the virion. PMID- 25552713 TI - Human cytomegalovirus exploits interferon-induced transmembrane proteins to facilitate morphogenesis of the virion assembly compartment. AB - Recently, interferon-induced transmembrane proteins (IFITMs) have been identified to be key effector molecules in the host type I interferon defense system. The invasion of host cells by a large range of RNA viruses is inhibited by IFITMs during the entry step. However, the roles of IFITMs in DNA virus infections have not been studied in detail. In this study, we report that human cytomegalovirus (HCMV), a large human DNA virus, exploits IFITMs to facilitate the formation of the virion assembly compartment (vAC) during infection of human fibroblasts. We found that IFITMs were expressed constitutively in human embryonic lung fibroblasts (MRC5 cells). HCMV infection inhibited IFITM protein accumulation in the later stages of infection. Overexpression of an IFITM protein in MRC5 cells slightly enhanced HCMV production and knockdown of IFITMs by RNA interference reduced the virus titer by about 100-fold on day 8 postinfection, according to the findings of a virus yield assay at a low multiplicity of infection. Virus gene expression and DNA synthesis were not affected, but the typical round structure of the vAC was not formed after the suppression of IFITMs, thereby resulting in defective virion assembly and the production of less infectious virion particles. Interestingly, the replication of herpes simplex virus, a human herpesvirus that is closely related to HCMV, was not affected by the suppression of IFITMs in MRC5 cells. These results indicate that IFITMs are involved in a specific pathway required for HCMV replication. IMPORTANCE: HCMV is known to repurpose the interferon-stimulated genes (ISGs) viperin and tetherin to facilitate its replication. Our results expand the range of ISGs that can be exploited by HCMV for its replication. This is also the first report of a proviral function of IFITMs in DNA virus replication. In addition, whereas previous studies showed that IFITMs modulate virus entry, which is a very early stage in the virus life cycle, we identified a new function of IFITMs during the very late stage of virus replication, i.e., virion assembly. Virus entry and assembly both involve vesicle transport and membrane fusion; thus, a common biochemical activity of IFITMs is likely to be involved. Therefore, our findings may provide a new platform for dissecting the molecular mechanism of action of IFITMs during the blocking or enhancement of virus infection, which are under intense investigation in this field. PMID- 25552712 TI - Discovery of a novel coronavirus, China Rattus coronavirus HKU24, from Norway rats supports the murine origin of Betacoronavirus 1 and has implications for the ancestor of Betacoronavirus lineage A. AB - We discovered a novel Betacoronavirus lineage A coronavirus, China Rattus coronavirus (ChRCoV) HKU24, from Norway rats in China. ChRCoV HKU24 occupied a deep branch at the root of members of Betacoronavirus 1, being distinct from murine coronavirus and human coronavirus HKU1. Its unique putative cleavage sites between nonstructural proteins 1 and 2 and in the spike (S) protein and low sequence identities to other lineage A betacoronaviruses (betaCoVs) in conserved replicase domains support ChRCoV HKU24 as a separate species. ChRCoV HKU24 possessed genome features that resemble those of both Betacoronavirus 1 and murine coronavirus, being closer to Betacoronavirus 1 in most predicted proteins but closer to murine coronavirus by G+C content, the presence of a single nonstructural protein (NS4), and an absent transcription regulatory sequence for the envelope (E) protein. Its N-terminal domain (NTD) demonstrated higher sequence identity to the bovine coronavirus (BCoV) NTD than to the mouse hepatitis virus (MHV) NTD, with 3 of 4 critical sugar-binding residues in BCoV and 2 of 14 contact residues at the MHV NTD/murine CEACAM1a interface being conserved. Molecular clock analysis dated the time of the most recent common ancestor of ChRCoV HKU24, Betacoronavirus 1, and rabbit coronavirus HKU14 to about the year 1400. Cross-reactivities between other lineage A and B betaCoVs and ChRCoV HKU24 nucleocapsid but not spike polypeptide were demonstrated. Using the spike polypeptide-based Western blot assay, we showed that only Norway rats and two oriental house rats from Guangzhou, China, were infected by ChRCoV HKU24. Other rats, including Norway rats from Hong Kong, possessed antibodies only against N protein and not against the spike polypeptide, suggesting infection by betaCoVs different from ChRCoV HKU24. ChRCoV HKU24 may represent the murine origin of Betacoronavirus 1, and rodents are likely an important reservoir for ancestors of lineage A betaCoVs. IMPORTANCE: While bats and birds are hosts for ancestors of most coronaviruses (CoVs), lineage A betaCoVs have never been found in these animals and the origin of Betacoronavirus lineage A remains obscure. We discovered a novel lineage A betaCoV, China Rattus coronavirus HKU24 (ChRCoV HKU24), from Norway rats in China with a high seroprevalence. The unique genome features and phylogenetic analysis supported the suggestion that ChRCoV HKU24 represents a novel CoV species, occupying a deep branch at the root of members of Betacoronavirus 1 and being distinct from murine coronavirus. Nevertheless, ChRCoV HKU24 possessed genome characteristics that resemble those of both Betacoronavirus 1 and murine coronavirus. Our data suggest that ChRCoV HKU24 represents the murine origin of Betacoronavirus 1, with interspecies transmission from rodents to other mammals having occurred centuries ago, before the emergence of human coronavirus (HCoV) OC43 in the late 1800s. Rodents are likely an important reservoir for ancestors of lineage A betaCoVs. PMID- 25552714 TI - Transcriptome analysis of Kaposi's sarcoma-associated herpesvirus during de novo primary infection of human B and endothelial cells. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) infects many target cells (e.g., endothelial, epithelial, and B cells, keratinocytes, and monocytes) to establish lifelong latent infections. Viral latent-protein expression is critical in inducing and maintaining KSHV latency. Infected cells are programmed to retain the incoming viral genomes during primary infection. Immediately after infection, KSHV transcribes many lytic genes that modulate various cellular pathways to establish successful infection. Analysis of the virion particle showed that the virions contain viral mRNAs, microRNAs, and other noncoding RNAs that are transduced into the target cells during infection, but their biological functions are largely unknown. We performed a comprehensive analysis of the KSHV virion packaged transcripts and the profiles of viral genes transcribed after de novo infections of various cell types (human peripheral blood mononuclear cells [PBMCs], CD14(+) monocytes, and telomerase-immortalized vascular endothelial [TIVE] cells), from viral entry until latency establishment. A next-generation sequence analysis of the total transcriptome showed that several viral RNAs (polyadenylated nuclear RNA, open reading frame 58 [ORF58], ORF59, T0.7, and ORF17) were abundantly present in the KSHV virions and effectively transduced into the target cells. Analysis of the transcription profiles of each viral gene showed specific expression patterns in different cell lines, with the majority of the genes, other than latent genes, silencing after 24 h postinfection. We differentiated the actively transcribing genes from the virion-transduced transcripts using a nascent RNA capture approach (Click-iT chemistry), which identified transcription of a number of viral genes during primary infection. Treating the infected cells with phosphonoacetic acid (PAA) to block the activity of viral DNA polymerase confirmed the involvement of lytic DNA replication during primary infection. To further understand the role of DNA replication during primary infection, we performed de novo PBMC infections with a recombinant ORF59 deleted KSHV virus, which showed significantly reduced numbers of viral copies in the latently infected cells. In summary, the transduced KSHV RNAs as well as the actively transcribed genes control critical processes of early infection to establish KSHV latency. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of multiple human malignancies in immunocompromised individuals. KSHV establishes a lifelong latency in the infected host, during which only a limited number of viral genes are expressed. However, a fraction of latently infected cells undergo spontaneous reactivation to produce virions that infect the surrounding cells. These newly infected cells are primed early to retain the incoming viral genome and induce cell growth. KSHV transcribes a variety of lytic proteins during de novo infections that modulate various cellular pathways to establish the latent infection. Interestingly, a large number of viral proteins and RNA are encapsidated in the infectious virions and transduced into the infected cells during a de novo infection. This study determined the kinetics of the viral gene expression during de novo KSHV infections and the functional role of the incoming viral transcripts in establishing latency. PMID- 25552715 TI - Impact of natural IgM concentration on gene therapy with adenovirus type 5 vectors. AB - Natural IgM inhibits gene transfer by adenovirus type 5 (Ad5) vectors. We show that polyreactive natural IgM antibodies bind to Ad5 and that inhibition of liver transduction by IgM depends on Kupffer cells. By manipulating IgM concentration in vivo, we demonstrate that IgM inhibits liver transduction in a concentration dependent manner. We further show that differences in natural IgM between BALB/c and C57BL/6 mice contribute to lower efficiency of Ad5 gene transfer in BALB/c mice. PMID- 25552716 TI - Reverse genetics system for severe fever with thrombocytopenia syndrome virus. AB - Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick borne pathogen that was first reported in China in 2009. Phylogenetic analysis of the viral genome showed that SFTS virus represents a new lineage within the Phlebovirus genus, distinct from the existing sandfly fever and Uukuniemi virus groups, in the family Bunyaviridae. SFTS disease is characterized by gastrointestinal symptoms, chills, joint pain, myalgia, thrombocytopenia, leukocytopenia, and some hemorrhagic manifestations with a case fatality rate of about 2 to 15%. Here we report the development of reverse genetics systems to study STFSV replication and pathogenesis. We developed and optimized functional T7 polymerase-based M- and S-segment minigenome assays, which revealed errors in the published terminal sequences of the S segment of the Hubei 29 strain of SFTSV. We then generated recombinant viruses from cloned cDNAs prepared to the antigenomic RNAs both of the minimally passaged virus (HB29) and of a cell culture-adapted strain designated HB29pp. The growth properties, pattern of viral protein synthesis, and subcellular localization of viral N and NSs proteins of wild-type HB29pp (wtHB29pp) and recombinant HB29pp viruses were indistinguishable. We also show that the viruses fail to shut off host cell polypeptide production. The robust reverse genetics system described will be a valuable tool for the design of therapeutics and the development of killed and attenuated vaccines against this important emerging pathogen. IMPORTANCE: SFTSV and related tick-borne phleboviruses such as Heartland virus are emerging viruses shown to cause severe disease in humans in the Far East and the United States, respectively. Study of these novel pathogens would be facilitated by technology to manipulate these viruses in a laboratory setting using reverse genetics. Here, we report the generation of infectious SFTSV from cDNA clones and demonstrate that the behavior of recombinant viruses is similar to that of the wild type. This advance will allow for further dissection of the roles of each of the viral proteins in the context of virus infection, as well as help in the development of antiviral drugs and protective vaccines. PMID- 25552717 TI - Analysis of the functional interchange between the IE1 and pp71 proteins of human cytomegalovirus and ICP0 of herpes simplex virus 1. AB - Human cytomegalovirus (HCMV) immediate early protein IE1 and the tegument protein pp71 are required for efficient infection. These proteins have some functional similarities with herpes simplex virus 1 (HSV-1) immediate early protein ICP0, which stimulates lytic HSV-1 infection and derepresses quiescent HSV-1 genomes. All three proteins counteract antiviral restriction mediated by one or more components of promyelocytic leukemia (PML) nuclear bodies, and IE1 and pp71, acting together, almost completely complement ICP0 null mutant HSV-1. Here, we investigated whether ICP0 might substitute for IE1 or pp71 during HCMV infection. Using human fibroblasts that express ICP0, IE1, or pp71 in an inducible manner, we found that ICP0 stimulated replication of both wild-type (wt) and pp71 mutant HCMV while IE1 increased wt HCMV plaque formation and completely complemented the IE1 mutant. Although ICP0 stimulated IE2 expression from IE1 mutant HCMV and increased the number of IE2-positive cells, it could not compensate for IE1 in full lytic replication. These results are consistent with previous evidence that both IE1 and IE2 are required for efficient HCMV gene expression, but they also imply that IE2 functionality is influenced specifically by IE1, either directly or indirectly, and that IE1 may include sequences that have HCMV-specific functions. We discovered a mutant form of IE1 (YL2) that fails to stimulate HCMV infection while retaining 30 to 80% of the activity of the wt protein in complementing ICP0 null mutant HSV-1. It is intriguing that the YL2 mutation is situated in the region of IE1 that is shared with IE2 and which is highly conserved among primate cytomegaloviruses. IMPORTANCE: Herpesvirus gene expression can be repressed by cellular restriction factors, one group of which is associated with structures known as ND10 or PML nuclear bodies (PML NBs). Regulatory proteins of several herpesviruses interfere with PML NB-mediated repression, and in some cases their activities are transferrable between different viruses. For example, the requirement for ICP0 during herpes simplex virus 1 (HSV-1) infection can be largely replaced by ICP0-related proteins expressed by other alphaherpesviruses and even by a combination of the unrelated IE1 and pp71 proteins of human cytomegalovirus (HCMV). Here, we report that ICP0 stimulates gene expression and replication of wt HCMV but cannot replace the need for IE1 during infection by IE1-defective HCMV mutants. Therefore, IE1 includes HCMV-specific functions that cannot be replaced by ICP0. PMID- 25552718 TI - Heterosubtypic antibodies to influenza A virus have limited activity against cell bound virus but are not impaired by strain-specific serum antibodies. AB - The majority of influenza virus-specific antibodies elicited by vaccination or natural infection are effective only against the eliciting or closely related viruses. Rare stem-specific heterosubtypic monoclonal antibodies (hMAbs) can neutralize multiple strains and subtypes by preventing hemagglutinin (HA) mediated fusion of the viral membrane with the endosomal membrane. The epitopes recognized by these hMAbs are therefore considered promising targets for the development of pan-influenza virus vaccines. Here, we report the isolation of a novel human HA stem-reactive monoclonal antibody, hMAb 1.12, with exceptionally broad neutralizing activity encompassing viruses from 15 distinct HA subtypes. Using MAb 1.12 and two other monoclonal antibodies, we demonstrate that neutralization by hMAbs is virtually irreversible but becomes severely impaired following virus attachment to cells. In contrast, no interference by human anti influenza virus serum antibodies was found, indicating that apically binding antibodies do not impair access to the membrane-proximal heterosubtypic epitopes. Our findings therefore encourage development of new vaccine concepts aiming at the induction of stem-specific heterosubtypic antibodies, as we provide support for their effectiveness in individuals previously exposed to influenza virus. IMPORTANCE: The influenza A virus hemagglutinin (HA) can easily accommodate changes in its antigenic structures to escape preexisting immunity. This variability restricts the breadth and long-term efficacy of influenza vaccines. Only a few heterosubtypic antibodies (hMAbs), i.e., antibodies that can neutralize more than one subtype of influenza A virus, have been identified. The molecular interactions between these heterosubtypic antibodies and hemagglutinin are well characterized, yet little is known about the functional properties of these antibodies. Using a new, extraordinarily broad hMAb, we show that virus neutralization by hMAbs is virtually irreversible and that efficient neutralization is possible only if stem-specific hMAbs bind to HA before the virus attaches to the cell surface. No interference between strain-specific human serum immunoglobulin and hMAbs was found, indicating that preexisting humoral immunity to influenza virus does not limit the efficacy of stem-reactive heterosubtypic antibodies. This knowledge supports the development of a pan influenza virus vaccine. PMID- 25552719 TI - Mutations conferring a noncytotoxic phenotype on chikungunya virus replicons compromise enzymatic properties of nonstructural protein 2. AB - Chikungunya virus (CHIKV) (genus Alphavirus) has a positive-sense RNA genome. CHIKV nonstructural protein 2 (nsP2) proteolytically processes the viral nonstructural polyprotein, possesses nucleoside triphosphatase (NTPase), RNA triphosphatase, and RNA helicase activities, and induces cytopathic effects in vertebrate cells. Although alphaviral nsP2 mutations can result in a noncytotoxic phenotype, the effects of such mutations on nsP2 enzymatic activities are not well understood. In this study, we introduced a P718G (PG) mutation and selected for additional mutations in CHIKV nsP2 that resulted in a CHIKV replicon with a noncytotoxic phenotype in BHK-21 cells. Combinations of PG and either an E117K (EK) substitution or a GEEGS sequence insertion after residue T647 (5A) markedly reduced RNA synthesis; however, neither PG nor 5A prevented nsP2 nuclear translocation. Introducing PG into recombinant nsP2 inhibited proteolytic cleavage of nsP1/nsP2 and nsP3/nsP4 sites, reduced GTPase and RNA helicase activities, and abolished RNA stimulation of GTPase activity. 5A and EK modulated the effects of PG. However, only the RNA helicase activity of nsP2 was reduced by both of these mutations, suggesting that defects in this activity may be linked to a noncytotoxic phenotype. These results increase our understanding of the molecular basis for the cytotoxicity that accompanies alphaviral replication. Furthermore, adaptation of the CHIKV replicon containing both 5A and PG allowed the selection of a CHIKV replicon with adaptive mutations in nsP1 and nsP3 that enable persistence in human cell line. Such cell lines represent valuable experimental systems for discovering host factors and for screening inhibitors of CHIKV replication at lower biosafety levels. IMPORTANCE: CHIKV is a medically important pathogen that causes febrile illness and can cause chronic arthritis. No approved vaccines or antivirals are available for CHIKV. The attenuation of CHIKV is critical to the establishment of experimental systems that can be used to conduct virus replication studies at a lower biosafety level. We applied a functional selection approach to develop, for the first time, a noncytotoxic CHIKV replicon capable of persisting in human cell lines. We anticipate that this safe and efficient research tool will be valuable for screening CHIKV replication inhibitors and for identifying and analyzing host factors involved in viral replication. We also analyzed, from virological and protein biochemistry perspectives, the functional defects caused by mutations conferring noncytotoxic phenotypes; we found that all known enzymatic activities of CHIKV nsP2, as well as its RNA-binding capability, were compromised by these mutations, which led to a reduced capacity for replication. PMID- 25552720 TI - Inhibition of H3K27me3-specific histone demethylases JMJD3 and UTX blocks reactivation of herpes simplex virus 1 in trigeminal ganglion neurons. AB - Herpes simplex virus 1 (HSV-1) genomes are associated with the repressive heterochromatic marks H3K9me2/me3 and H3K27me3 during latency. Previous studies have demonstrated that inhibitors of H3K9me2/me3 histone demethylases reduce the ability of HSV-1 to reactivate from latency. Here we demonstrate that GSK-J4, a specific inhibitor of the H3K27me3 histone demethylases UTX and JMJD3, inhibits HSV-1 reactivation from sensory neurons in vitro. These results indicate that removal of the H3K27me3 mark plays a key role in HSV-1 reactivation. PMID- 25552721 TI - Analysis of geminivirus AL2 and L2 proteins reveals a novel AL2 silencing suppressor activity. AB - Both posttranscriptional and transcriptional gene silencing (PTGS and TGS, respectively) participate in defense against the DNA-containing geminiviruses. As a countermeasure, members of the genus Begomovirus (e.g., Cabbage leaf curl virus) encode an AL2 protein that is both a transcriptional activator and a silencing suppressor. The related L2 protein of Beet curly top virus (genus Curtovirus) lacks transcription activation activity. Previous studies showed that both AL2 and L2 suppress silencing by a mechanism that correlates with adenosine kinase (ADK) inhibition, while AL2 in addition activates transcription of cellular genes that negatively regulate silencing pathways. The goal of this study was to clarify the general means by which these viral proteins inhibit various aspects of silencing. We confirmed that AL2 inhibits systemic silencing spread by a mechanism that requires transcription activation activity. Surprisingly, we also found that reversal of PTGS and TGS by ADK inactivation depended on whether experiments were conducted in vegetative or reproductive Nicotiana benthamiana plants (i.e., before or after the vegetative-to reproductive transition). While AL2 was able to reverse silencing in both vegetative and reproductive plants, L2 and ADK inhibition were effective only in vegetative plants. This suggests that silencing maintenance mechanisms can change during development or in response to stress. Remarkably, we also observed that AL2 lacking its transcription activation domain could reverse TGS in reproductive plants, revealing a third, previously unsuspected AL2 suppression mechanism that depends on neither ADK inactivation nor transcription activation. IMPORTANCE: RNA silencing in plants is a multivalent antiviral defense, and viruses respond by elaborating multiple and sometimes multifunctional proteins that inhibit various aspects of silencing. The studies described here add an additional layer of complexity to this interplay. By examining geminivirus AL2 and L2 suppressor activities, we show that L2 is unable to suppress silencing in Nicotiana benthamiana plants that have undergone the vegetative-to-reproductive transition. As L2 was previously shown to be effective in mature Arabidopsis plants, these results illustrate that silencing mechanisms can change during development or in response to stress in ways that may be species specific. The AL2 and L2 proteins are known to share a suppression mechanism that correlates with the ability of both proteins to inhibit ADK, while AL2 in addition can inhibit silencing by transcriptionally activating cellular genes. Here, we also provide evidence for a third AL2 suppression mechanism that depends on neither transcription activation nor ADK inactivation. In addition to revealing the remarkable versatility of AL2, this work highlights the utility of viral suppressors as probes for the analysis of silencing pathways. PMID- 25552722 TI - Heat shock protein 70 regulates degradation of the mumps virus phosphoprotein via the ubiquitin-proteasome pathway. AB - Mumps virus (MuV) infection induces formation of cytoplasmic inclusion bodies (IBs). Growing evidence indicates that IBs are the sites where RNA viruses synthesize their viral RNA. However, in the case of MuV infection, little is known about the viral and cellular compositions and biological functions of the IBs. In this study, pulldown purification and N-terminal amino acid sequencing revealed that stress-inducible heat shock protein 70 (Hsp72) was a binding partner of MuV phosphoprotein (P protein), which was an essential component of the IB formation. Immunofluorescence and immunoblotting analyses revealed that Hsp72 was colocalized with the P protein in the IBs, and its expression was increased during MuV infection. Knockdown of Hsp72 using small interfering RNAs (siRNAs) had little, if any, effect on viral propagation in cultured cells. Knockdown of Hsp72 caused accumulation of ubiquitinated P protein and delayed P protein degradation. These results show that Hsp72 is recruited to IBs and regulates the degradation of MuV P protein through the ubiquitin-proteasome pathway. IMPORTANCE: Formation of cytoplasmic inclusion bodies (IBs) is a common characteristic feature in mononegavirus infections. IBs are considered to be the sites of viral RNA replication and transcription. However, there have been few studies focused on host factors recruited to the IBs and their biological functions. Here, we identified stress-inducible heat shock protein 70 (Hsp72) as the first cellular partner of mumps virus (MuV) phosphoprotein (P protein), which is an essential component of the IBs and is involved in viral RNA replication/transcription. We found that the Hsp72 mobilized to the IBs promoted degradation of the MuV P protein through the ubiquitin-proteasome pathway. Our data provide new insight into the role played by IBs in mononegavirus infection. PMID- 25552723 TI - Parainfluenza virus 5 expressing the G protein of rabies virus protects mice after rabies virus infection. AB - Rabies remains a major public health threat around the world. Once symptoms appear, there is no effective treatment to prevent death. In this work, we tested a recombinant parainfluenza virus 5 (PIV5) strain expressing the glycoprotein (G) of rabies (PIV5-G) as a therapy for rabies virus infection: we have found that PIV5-G protected mice as late as 6 days after rabies virus infection. PIV5-G is a promising vaccine for prevention and treatment of rabies virus infection. PMID- 25552724 TI - Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase. AB - Dolutegravir (DTG) is the latest antiretroviral (ARV) approved for the treatment of human immunodeficiency virus (HIV) infection. The G118R substitution, previously identified with MK-2048 and raltegravir, may represent the initial substitution in a dolutegravir resistance pathway. We have found that subtype C integrase proteins have a low enzymatic cost associated with the G118R substitution, mostly at the strand transfer step of integration, compared to either subtype B or recombinant CRF02_AG proteins. Subtype B and circulating recombinant form AG (CRF02_AG) clonal viruses encoding G118R-bearing integrases were severely restricted in their viral replication capacity, and G118R/E138K bearing viruses had various levels of resistance to dolutegravir, raltegravir, and elvitegravir. In cell-free experiments, the impacts of the H51Y and E138K substitutions on resistance and enzyme efficiency, when present with G118R, were highly dependent on viral subtype. Sequence alignment and homology modeling showed that the subtype-specific effects of these mutations were likely due to differential amino acid residue networks in the different integrase proteins, caused by polymorphic residues, which significantly affect native protein activity, structure, or function and are important for drug-mediated inhibition of enzyme activity. This preemptive study will aid in the interpretation of resistance patterns in dolutegravir-treated patients. IMPORTANCE: Recognized drug resistance mutations have never been reported for naive patients treated with dolutegravir. Additionally, in integrase inhibitor-experienced patients, only R263K and other previously known integrase resistance substitutions have been reported. Here we suggest that alternate resistance pathways may develop in non-B HIV-1 subtypes and explain how "minor" polymorphisms and substitutions in HIV integrase that are associated with these subtypes can influence resistance against dolutegravir. This work also highlights the importance of phenotyping versus genotyping when a strong inhibitor such as dolutegravir is being used. By characterizing the G118R substitution, this work also preemptively defines parameters for a potentially important pathway in some non-B HIV subtype viruses treated with dolutegravir and will aid in the inhibition of such a virus, if detected. The general inability of strand transfer-related substitutions to diminish 3' processing indicates the importance of the 3' processing step and highlights a therapeutic angle that needs to be better exploited. PMID- 25552726 TI - Serine phosphorylation of the hepatitis C virus NS5A protein controls the establishment of replication complexes. AB - The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is highly phosphorylated and involved in both virus genome replication and virion assembly. We and others have identified serine 225 in NS5A to be a phosphorylation site, but the function of this posttranslational modification in the virus life cycle remains obscure. Here we describe the phenotype of mutants with mutations at serine 225; this residue was mutated to either alanine (S225A; phosphoablatant) or aspartic acid (S225D; phosphomimetic) in the context of both the JFH-1 cell culture infectious virus and a corresponding subgenomic replicon. The S225A mutant exhibited a 10-fold reduction in genome replication, whereas the S225D mutant replicated like the wild type. By confocal microscopy, we show that, in the case of the S225A mutant, the replication phenotype correlated with an altered subcellular distribution of NS5A. This phenotype was shared by viruses with other mutations in the low-complexity sequence I (LCS I), namely, S229D, S232A, and S235D, but not by viruses with mutations that caused a comparable replication defect that mapped to domain II of NS5A (P315A, L321A). Together with other components of the genome replication complex (NS3, double-stranded RNA, and cellular lipids, including phosphatidylinositol 4-phosphate), the mutation in NS5A was restricted to a perinuclear region. This phenotype was not due to cell confluence or another environmental factor and could be partially transcomplemented by wild-type NS5A. We propose that serine phosphorylation within LCS I may regulate the assembly of an active genome replication complex. IMPORTANCE: The mechanisms by which hepatitis C virus replicates its RNA genome remain poorly characterized. We show here that phosphorylation of the viral nonstructural protein NS5A at serine residues is important for the efficient assembly of a complex that is able to replicate the viral genome. This research implicates cellular protein kinases in the control of virus replication and highlights the need to further understand the interplay between the virus and the host cell in order to develop potential avenues for future antiviral therapy. PMID- 25552725 TI - Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells. AB - Worldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN alpha), whereas the intragenotypic chimera Jc1 triggered massive IFN-alpha responses. Purified Jc1 retained full infectivity but no longer induced IFN alpha. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-alpha, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-alpha. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-alpha responses of pDC. These data showed that viral determinants shaped host innate IFN-alpha responses to HCV. IMPORTANCE: Although pegylated IFN-alpha plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the nonstructural genes of Japanese fulminant hepatitis C virus (JFH1) induced massive type I interferon responses, whereas the original genotype 2a JFH1 strain did not. Our detailed analyses revealed that, not the virus infectivity, but rather, the efficiency of virus assembly and core protein envelopment critically determined the magnitude of interferon responses. To our knowledge, this is the first example of hepatitis C virus-associated genetic variations that determine the magnitude of innate host responses. PMID- 25552728 TI - The ambition of the European Respiratory Journal: chapter 3. PMID- 25552727 TI - Development of a mouse-adapted live attenuated influenza virus that permits in vivo analysis of enhancements to the safety of live attenuated influenza virus vaccine. AB - The live attenuated influenza virus vaccine (LAIV) is preferentially recommended for use in persons 2 through 49 years of age but has not been approved for children under 2 or asthmatics due to safety concerns. Therefore, increasing safety is desirable. Here we describe a murine LAIV with reduced pathogenicity that retains lethality at high doses and further demonstrate that we can enhance safety in vivo through mutations within NS1. This model may permit preliminary safety analysis of improved LAIVs. PMID- 25552729 TI - Clean air in Europe: beyond the horizon? PMID- 25552730 TI - ESCAPEing from bad-quality air: a cleaner air, from Europe to elsewhere. PMID- 25552731 TI - Does COPD stand for "COmorbidity with Pulmonary Disease"? PMID- 25552732 TI - Developmental control of CFTR: from bioinformatics to novel therapeutic approaches. PMID- 25552733 TI - Detecting lung infections in breathprints: empty promise or next generation diagnosis of infections. PMID- 25552734 TI - Linezolid to treat MDR-/XDR-tuberculosis: available evidence and future scenarios. PMID- 25552735 TI - NO kidding: exhaled nitric oxide fraction in preschool children. PMID- 25552736 TI - More on the right ventricle in pulmonary hypertension. PMID- 25552738 TI - Breathlessness, physical activity and sustainability of healthcare. PMID- 25552739 TI - Low minimal inhibitory concentrations of linezolid against multidrug-resistant tuberculosis strains. PMID- 25552740 TI - Low minimal inhibitory concentrations of linezolid against multidrug-resistant tuberculosis strains. PMID- 25552741 TI - Key role of tuberculosis services funding mechanisms in tuberculosis control and elimination. PMID- 25552742 TI - Managing an extensively drug-resistant tuberculosis outbreak: the public health face of the medal. PMID- 25552743 TI - ERS/WHO Tuberculosis Consilium assistance in extensively drug-resistant tuberculosis. PMID- 25552745 TI - Convective heat transfer in foams under laminar flow in pipes and tube bundles. AB - The present study reports experimental data and scaling analysis for forced convection of foams and microfoams in laminar flow in circular and rectangular tubes as well as in tube bundles. Foams and microfoams are pseudoplastic (shear thinning) two-phase fluids consisting of tightly packed bubbles with diameters ranging from tens of microns to a few millimeters. They have found applications in separation processes, soil remediation, oil recovery, water treatment, food processes, as well as in fire fighting and in heat exchangers. First, aqueous solutions of surfactant Tween 20 with different concentrations were used to generate microfoams with various porosity, bubble size distribution, and rheological behavior. These different microfoams were flowed in uniformly heated circular tubes of different diameter instrumented with thermocouples. A wide range of heat fluxes and flow rates were explored. Experimental data were compared with analytical and semi-empirical expressions derived and validated for single-phase power-law fluids. These correlations were extended to two-phase foams by defining the Reynolds number based on the effective viscosity and density of microfoams. However, the local Nusselt and Prandtl numbers were defined based on the specific heat and thermal conductivity of water. Indeed, the heated wall was continuously in contact with a film of water controlling convective heat transfer to the microfoams. Overall, good agreement between experimental results and model predictions was obtained for all experimental conditions considered. Finally, the same approach was shown to be also valid for experimental data reported in the literature for laminar forced convection of microfoams in rectangular minichannels and of macrofoams across aligned and staggered tube bundles with constant wall heat flux. PMID- 25552746 TI - Performance of salmon fishery portfolios across western North America. AB - Quantifying the variability in the delivery of ecosystem services across the landscape can be used to set appropriate management targets, evaluate resilience and target conservation efforts. Ecosystem functions and services may exhibit portfolio-type dynamics, whereby diversity within lower levels promotes stability at more aggregated levels. Portfolio theory provides a framework to characterize the relative performance among ecosystems and the processes that drive differences in performance. We assessed Pacific salmon Oncorhynchus spp. portfolio performance across their native latitudinal range focusing on the reliability of salmon returns as a metric with which to assess the function of salmon ecosystems and their services to humans. We used the Sharpe ratio (e.g. the size of the total salmon return to the portfolio relative to its variability (risk)) to evaluate the performance of Chinook and sockeye salmon portfolios across the west coast of North America. We evaluated the effects on portfolio performance from the variance of and covariance among salmon returns within each portfolio, and the association between portfolio performance and watershed attributes. We found a positive latitudinal trend in the risk-adjusted performance of Chinook and sockeye salmon portfolios that also correlated negatively with anthropogenic impact on watersheds (e.g. dams and land-use change). High-latitude Chinook salmon portfolios were on average 2.5 times more reliable, and their portfolio risk was mainly due to low variance in the individual assets. Sockeye salmon portfolios were also more reliable at higher latitudes, but sources of risk varied among the highest performing portfolios. Synthesis and applications. Portfolio theory provides a straightforward method for characterizing the resilience of salmon ecosystems and their services. Natural variability in portfolio performance among undeveloped watersheds provides a benchmark for restoration efforts. Locally and regionally, assessing the sources of portfolio risk can guide actions to maintain existing resilience (protect habitat and disturbance regimes that maintain response diversity; employ harvest strategies sensitive to different portfolio components) or improve restoration activities. Improving our understanding of portfolio reliability may allow for management of natural resources that is robust to ongoing environmental change. Portfolio theory provides a straightforward method for characterizing the resilience of salmon ecosystems and their services. Natural variability in portfolio performance among undeveloped watersheds provides a benchmark for restoration efforts. Locally and regionally, assessing the sources of portfolio risk can guide actions to maintain existing resilience (protect habitat and disturbance regimes that maintain response diversity; employ harvest strategies sensitive to different portfolio components) or improve restoration activities. Improving our understanding of portfolio reliability may allow for management of natural resources that is robust to ongoing environmental change. PMID- 25552747 TI - Can retention forestry help conserve biodiversity? A meta-analysis. AB - Industrial forestry typically leads to a simplified forest structure and altered species composition. Retention of trees at harvest was introduced about 25 years ago to mitigate negative impacts on biodiversity, mainly from clearcutting, and is now widely practiced in boreal and temperate regions. Despite numerous studies on response of flora and fauna to retention, no comprehensive review has summarized its effects on biodiversity in comparison to clearcuts as well as un harvested forests. Using a systematic review protocol, we completed a meta analysis of 78 studies including 944 comparisons of biodiversity between retention cuts and either clearcuts or un-harvested forests, with the main objective of assessing whether retention forestry helps, at least in the short term, to moderate the negative effects of clearcutting on flora and fauna. Retention cuts supported higher richness and a greater abundance of forest species than clearcuts as well as higher richness and abundance of open-habitat species than un-harvested forests. For all species taken together (i.e. forest species, open-habitat species, generalist species and unclassified species), richness was higher in retention cuts than in clearcuts. Retention cuts had negative impacts on some species compared to un-harvested forest, indicating that certain forest-interior species may not survive in retention cuts. Similarly, retention cuts were less suitable for some open-habitat species compared with clearcuts. Positive effects of retention cuts on richness of forest species increased with proportion of retained trees and time since harvest, but there were not enough data to analyse possible threshold effects, that is, levels at which effects on biodiversity diminish. Spatial arrangement of the trees (aggregated vs. dispersed) had no effect on either forest species or open-habitat species, although limited data may have hindered our capacity to identify responses. Results for different comparisons were largely consistent among taxonomic groups for forest and open-habitat species, respectively. Synthesis and applications. Our meta-analysis provides support for wider use of retention forestry since it moderates negative harvesting impacts on biodiversity. Hence, it is a promising approach for integrating biodiversity conservation and production forestry, although identifying optimal solutions between these two goals may need further attention. Nevertheless, retention forestry will not substitute for conservation actions targeting certain highly specialized species associated with forest-interior or open-habitat conditions. Our meta-analysis provides support for wider use of retention forestry since it moderates negative harvesting impacts on biodiversity. Hence, it is a promising approach for integrating biodiversity conservation and production forestry, although identifying optimal solutions between these two goals may need further attention. Nevertheless, retention forestry will not substitute for conservation actions targeting certain highly specialized species associated with forest-interior or open-habitat conditions. PMID- 25552748 TI - A message from the editor. PMID- 25552749 TI - Surgeon General's perspectives: family health history:using the past to improve future health. PMID- 25552751 TI - What is behavioral health worth? PMID- 25552753 TI - Feasibility of shelter-based mental health screening for homeless children. AB - Homeless children are known to be at risk for mental health and behavioral disorders due to housing instability and family and environmental risk factors, such as domestic violence. However, homeless children seldom receive screening for mental health and behavioral disorders with validated instruments. Moreover, few examples exist of programs that integrate outreach, screening, referral to appropriate diagnostic and therapeutic services, and care coordination. We describe early results of the Medical Home for Homeless Children Project, whose nurse care coordinators work with homeless families to conduct standardized nursing assessments that include evidence-based screening for child mental health and behavioral disorders with referral and case management for mental and behavioral health services. Screening identified a group of children with mental health issues that warranted referral, and many of those referrals were successfully completed. PMID- 25552754 TI - Challenges to implementing communicable disease surveillance in New York City evacuation shelters after Hurricane Sandy, November 2012. AB - Hurricane Sandy hit New York City (NYC) on October 29, 2012. Before and after the storm, 73 temporary evacuation shelters were established. The total census of these shelters peaked at approximately 6,800 individuals. Concern about the spread of communicable diseases in shelters prompted the NYC Department of Health and Mental Hygiene (DOHMH) to rapidly develop a surveillance system to report communicable diseases and emergency department transports from shelters. We describe the implementation of this system. Establishing effective surveillance in temporary shelters was challenging and required in-person visits by DOHMH staff to ensure reporting. After system establishment, surveillance data were used to identify some potential disease clusters. For the future, we recommend pre-event planning for disease surveillance. PMID- 25552755 TI - Serotype 10A in case patients with invasive pneumococcal disease: a pilot study of PCR-based serotyping in New Jersey. AB - In 2008, the New Jersey Department of Health (NJDOH) identified a 21.1% increase in reported invasive pneumococcal disease (IPD). In 2009, NJDOH piloted nucleic acid-based serotyping to characterize serotypes causing IPD. From April through September, NJDOH received specimens from 149 of 302 (49%) case patients meeting our case definition. An uncommon serotype, 10A, accounted for 25.2% of IPD overall and was identified in 12 counties, but it was associated with one county (rate ratio = 5.4, 95% confidence interval [CI] 2.1, 11.8). NJDOH subsequently conducted a case-control study to assess the presentation of and clinical risk factors for 10A IPD. Case patients with 10A IPD were more likely to have had immunosuppression, asthma, and multiple chronic medical conditions than control subjects had (odds ratio [OR] = 2.6, 95% CI 1.1, 6.3; OR=4.7, 95% CI 1.7, 13.2; and OR=2.3, 95% CI 1.0, 5.2, respectively). State-based pneumococcal serotype testing identified an uncommon serotype in New Jersey. Continued pneumococcal serotype surveillance might help the NJDOH identify and respond to future serotype-specific increases. PMID- 25552752 TI - The National Vaccine Advisory Committee: reducing patient and provider barriers to maternal immunizations: approved by the National Vaccine Advisory Committee on June 11, 2014. PMID- 25552756 TI - Validation of selected items on the 2003 U.S. standard certificate of live birth: New York City and Vermont. AB - OBJECTIVE: We assessed the validity of selected items on the 2003 revised U.S. Standard Certificate of Live Birth to understand the accuracy of new and existing items. METHODS: We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of select variables reported on the birth certificate using the medical record as the gold standard for a representative sample of live births in New York City (n=603) and Vermont (n=664) in 2009. RESULTS: In both sites, sensitivity was excellent (>90%) for Medicaid coverage at delivery, any previous live births, and current method of delivery; sensitivity was moderate (70%-90%) for gestational diabetes; and sensitivity was poor (<70%) for premature rupture of the membranes and gestational hypertension. In both sites, PPV was excellent for Medicaid coverage, any previous live births, previous cesarean delivery, and current method of delivery, and poor for premature rupture of membranes. In both sites, almost all items had excellent (>90%) specificity and NPV. CONCLUSION: Further research is needed to determine how best to improve the quality of data on the birth certificate. Future revisions of the birth certificate may consider removing those items that have consistently proven difficult to report accurately. PMID- 25552758 TI - Targeting the use of pooled HIV RNA screening to reduce cost in health department STD clinics: New York City, 2009-2011. AB - OBJECTIVE: Staff at public New York City sexually transmitted disease (STD) clinics screen patients for acute HIV infection (AHI) using pooled nucleic acid amplification tests. AHI screening is expensive but important for populations at high risk of acquiring HIV. We analyzed if targeting AHI screening in STD clinics could reduce program costs while maintaining AHI case detection. METHODS: From January 2009 through May 2010, we screened all patients with negative rapid HIV tests for AHI. Using risk information on cases detected during this universal screening period, we developed criteria for targeted AHI screening and compared case yields and testing costs during 12 months of universal screening (June 2009 through May 2010) vs. 12 months of targeted screening (June 2010 through May 2011). RESULTS: During the defined period of universal screening, we identified 40 AHI cases, and during targeted screening, we identified 35 AHI cases. Because of targeting efforts, the number needed to test to find one AHI case dropped from 1,631 to 254. With targeted screening, it cost an average of $4,535 per case detected and 39.3 cases were detected per 10,000 specimens; using universal screening, $29,088 was spent per case detected and 6.1 cases were detected per 10,000 specimens processed. CONCLUSION: Targeted screening identified similar numbers of AHI cases as when screening all clinic patients seeking HIV testing, but at one-seventh the cost. PMID- 25552757 TI - Disparities in life expectancy of pacific northwest American Indians and Alaska natives: analysis of linkage-corrected life tables. AB - OBJECTIVES: American Indians and Alaska Natives (AI/ANs) experience a high burden of mortality and other disparities compared with the general population. Life tables are an important population health indicator; however, federal agencies have not produced life tables for AI/ANs, largely due to racial misclassification on death certificates. Our objective was to correct this misclassification and create life tables for AI/ANs who resided in the Pacific Northwest region of the U.S., making comparisons with the general population. METHODS: To correct racial misclassification, we conducted probabilistic record linkages between death certificates from three Northwest states-Idaho, Oregon, and Washington State issued during 2008-2010, and AI/AN patient registration records. We calculated mortality rates and generated period life tables for AI/ANs and non-Hispanic white (NHW) Americans. RESULTS: Overall life expectancy at birth for Northwest AI/ANs was 72.8 years, which was 6.9 years lower than that of NHW Americans. Male AI/ANs had a lower life expectancy (70.9 years) than female AI/ANs (74.6 years). The disparity in life expectancy between AI/ANs and their NHW counterparts was higher for females (with AI/ANs living 7.3 years fewer than NHW females) than for males (with AI/ANs living 6.7 years fewer than NHW males). The greatest disparity in mortality rates was seen among young adults. CONCLUSION: Data linkage with a registry of known AI/ANs allowed us to generate accurate life tables that had not previously been available for this population and revealed disparities in both life expectancy at birth and survival across the life span. These results represent an important tool to help AI/AN communities as they monitor their health and promote efforts to eliminate health disparities. PMID- 25552761 TI - Law, the health in all policies approach, and cross-sector collaboration. PMID- 25552759 TI - Distribution of cardiovascular disease and associated risk factors by county type and health insurance status: results from the 2008 Ohio Family Health Survey. AB - OBJECTIVES: Epidemiologic studies have documented a disproportionate burden of chronic diseases in Appalachia, showing the area to be underserved by the health care system. Nothing is known about how the health status of the Appalachian population compares with other rural or non-rural populations in the same state. We examined the associations among county type, health insurance category, and health outcomes in poorer adult Ohioans. METHODS: We obtained data from the 2008 Ohio Family Health Survey, a complex landline- and cell phone-based survey of 50,944 noninstitutionalized households. We constructed bivariate analyses examining health status measures across various insurance categories and metropolitan, suburban, rural, and Appalachian counties in Ohio. RESULTS: Medicaid enrollees living in Appalachian and rural counties tended to be in poorer health and have a greater prevalence of smoking than non-Medicaid enrollees. Within rural and Appalachian regions, Medicaid enrollees were more likely than non-Medicaid enrollees to have lower self-rated health (54.8%, 95% confidence interval [CI] 44.1, 65.5 in rural regions and 52.1%, 95% CI 44.7, 59.5 in Appalachian regions). Appalachian and rural Medicaid enrollees were at an increased likelihood of having several chronic diseases compared with non Medicaid enrollees. CONCLUSION: Our findings suggest that rural and Ohio Appalachian Medicaid enrollees were more likely to have hypertension, cardiovascular disease, and overall poorer health than non-Medicaid enrollees. These findings have important policy implications for health-care reform, highlighting regional disparities in provider coverage. These underserved regions would need an increase in the provider base to positively impact proposed Medicaid expansion programs. PMID- 25552763 TI - Characterizing the growth of the undergraduate public health major: U.S., 1992 2012. PMID- 25552765 TI - Health-system resilience: reflections on the Ebola crisis in western Africa. PMID- 25552766 TI - Health policy and systems research: building momentum and community. PMID- 25552768 TI - The last bastions of guinea-worm disease. PMID- 25552769 TI - Countries vindicate cautious stance on e-cigarettes. PMID- 25552770 TI - Peri-operative pulse oximetry in low-income countries: a cost-effectiveness analysis. AB - OBJECTIVE: To evaluate the cost-effectiveness of pulse oximetry--compared with no peri-operative monitoring--during surgery in low-income countries. METHODS: We considered the use of tabletop and portable, hand-held pulse oximeters among patients of any age undergoing major surgery in low-income countries. From earlier studies we obtained baseline mortality and the effectiveness of pulse oximeters to reduce mortality. We considered the direct costs of purchasing and maintaining pulse oximeters as well as the cost of supplementary oxygen used to treat hypoxic episodes identified by oximetry. Health benefits were measured in disability-adjusted life-years (DALYs) averted and benefits and costs were both discounted at 3% per year. We used recommended cost-effectiveness thresholds- both absolute and relative to gross domestic product (GDP) per capita--to assess if pulse oximetry is a cost-effective health intervention. To test the robustness of our results we performed sensitivity analyses. FINDINGS: In 2013 prices, tabletop and hand-held oximeters were found to have annual costs of 310 and 95 United States dollars (US$), respectively. Assuming the two types of oximeter have identical effectiveness, a single oximeter used for 22 procedures per week averted 0.83 DALYs per annum. The tabletop and hand-held oximeters cost US$ 374 and US$ 115 per DALY averted, respectively. For any country with a GDP per capita above US$ 677 the hand-held oximeter was found to be cost-effective if it prevented just 1.7% of anaesthetic-related deaths or 0.3% of peri-operative mortality. CONCLUSION: Pulse oximetry is a cost-effective intervention for low income settings. PMID- 25552771 TI - Effectiveness of travel restrictions in the rapid containment of human influenza: a systematic review. AB - OBJECTIVE: To assess the effectiveness of internal and international travel restrictions in the rapid containment of influenza. METHODS: We conducted a systematic review according to the requirements of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Health-care databases and grey literature were searched and screened for records published before May 2014. Data extraction and assessments of risk of bias were undertaken by two researchers independently. Results were synthesized in a narrative form. FINDINGS: The overall risk of bias in the 23 included studies was low to moderate. Internal travel restrictions and international border restrictions delayed the spread of influenza epidemics by one week and two months, respectively. International travel restrictions delayed the spread and peak of epidemics by periods varying between a few days and four months. Travel restrictions reduced the incidence of new cases by less than 3%. Impact was reduced when restrictions were implemented more than six weeks after the notification of epidemics or when the level of transmissibility was high. Travel restrictions would have minimal impact in urban centres with dense populations and travel networks. We found no evidence that travel restrictions would contain influenza within a defined geographical area. CONCLUSION: Extensive travel restrictions may delay the dissemination of influenza but cannot prevent it. The evidence does not support travel restrictions as an isolated intervention for the rapid containment of influenza. Travel restrictions would make an extremely limited contribution to any policy for rapid containment of influenza at source during the first emergence of a pandemic virus. PMID- 25552773 TI - Challenges facing the United States of America in implementing universal coverage. AB - In 2010, immediately before the United States of America (USA) implemented key features of the Affordable Care Act (ACA), 18% of its residents younger than 65 years lacked health insurance. In the USA, gaps in health coverage and unhealthy lifestyles contribute to outcomes that often compare unfavourably with those observed in other high-income countries. By March 2014, the ACA had substantially changed health coverage in the USA but most of its main features--health insurance exchanges, Medicaid expansion, development of accountable care organizations and further oversight of insurance companies--remain works in progress. The ACA did not introduce the stringent spending controls found in many European health systems. It also explicitly prohibits the creation of institutes- for the assessment of the cost-effectiveness of pharmaceuticals, health services and technologies--comparable to the National Institute for Health and Care Excellence in the United Kingdom of Great Britain and Northern Ireland, the Haute Autorite de Sante in France or the Pharmaceutical Benefits Advisory Committee in Australia. The ACA was--and remains--weakened by a lack of cross-party political consensus. The ACA's performance and its resulting acceptability to the general public will be critical to the Act's future. PMID- 25552772 TI - Post-licensure deployment of oral cholera vaccines: a systematic review. AB - OBJECTIVE: To describe and analyse the characteristics of oral cholera vaccination campaigns; including location, target population, logistics, vaccine coverage and delivery costs. METHODS: We searched PubMed, the World Health Organization (WHO) website and the Cochrane database with no date or language restrictions. We contacted public health personnel, experts in the field and in ministries of health and did targeted web searches. FINDINGS: A total of 33 documents were included in the analysis. One country, Viet Nam, incorporates oral cholera vaccination into its public health programme and has administered approximately 10.9 million vaccine doses between 1997 and 2012. In addition, over 3 million doses of the two WHO pre-qualified oral cholera vaccines have been administered in more than 16 campaigns around the world between 1997 and 2014. These campaigns have either been pre-emptive or reactive and have taken place under diverse conditions, such as in refugee camps or natural disasters. Estimated two-dose coverage ranged from 46 to 88% of the target population. Approximate delivery cost per fully immunized person ranged from 0.11-3.99 United States dollars. CONCLUSION: Experience with oral cholera vaccination campaigns continues to increase. Public health officials may draw on this experience and conduct oral cholera vaccination campaigns more frequently. PMID- 25552774 TI - Training clinicians treating HIV to diagnose cytomegalovirus retinitis. AB - PROBLEM: Acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis continues to be a neglected source of blindness in resource-poor settings. The main issue is lack of capacity to diagnose CMV retinitis in the clinical setting where patients receive care and all other opportunistic infections are diagnosed. APPROACH: We developed and implemented a four-day workshop to train clinicians working in human immunodeficiency virus (HIV) clinics how to perform binocular indirect ophthalmoscopy and diagnose CMV retinitis. Workshops comprised both classroom didactic instruction and direct clinical eye examinations in patients with advanced AIDS. Between 2007 and 2013, 14 workshops were conducted in China, Myanmar and the Russian Federation. LOCAL SETTING: Workshops were held with local clinicians at HIV clinics supported by nongovernmental organizations, public-sector municipal hospitals and provincial infectious disease referral hospitals. Each setting had limited or no access to locally- trained ophthalmologists, and an HIV-infected population with advanced disease. RELEVANT CHANGES: Clinicians learnt how to do binocular indirect ophthalmoscopy and to diagnose CMV retinitis. One year after the workshop, 32/38 trainees in Myanmar did systematic eye examination for early diagnosis of CMV retinitis as standard care for at-risk patients. In China and the Russian Federation, the success rates were lower, with 10/15 and 3/5 trainees, respectively, providing follow-up data. LESSONS LEARNT: Skills necessary for screening and diagnosis of CMV retinitis can be taught in a four-day task oriented training workshop. Successful implementation depends on institutional support, ongoing training and technical support. The next challenge is to scale up this approach in other countries. PMID- 25552776 TI - Defining disrespect and abuse of women in childbirth: a research, policy and rights agenda. PMID- 25552775 TI - Challenges facing HIV treatment in Guinea-Bissau: the benefits of international research collaborations. AB - PROBLEM: The introduction of antiretroviral therapy (ART) for HIV infection in sub-Saharan Africa has improved the quality of life of millions of people and reduced mortality. However, substantial problems with the infrastructure for ART delivery remain. APPROACH: Clinicians and researchers at an HIV clinic in Guinea Bissau identified problems with the delivery of ART by establishing a clinical database and by collaborating with international researchers. LOCAL SETTING: The Bissau HIV cohort study group was established in 2007 as a collaboration between local HIV physicians and international HIV researchers. Patients were recruited from the HIV clinic at the country's main hospital in the capital Bissau. RELEVANT CHANGES: Between 2005 and 2013, 5514 HIV-positive patients were treated at the clinic. Working together, local health-care workers and international researchers identified the main problems affecting ART delivery: inadequate drug supply; loss of patients to follow-up; and inadequate laboratory services. Solutions to these problems were devised. The collaborations encouraged local physicians to start their own research projects to find possible solutions to problems at the clinic. LESSONS LEARNT: The HIV clinic in Bissau faced numerous obstacles in delivering ART at a sufficiently high quality and patients' lives were put in jeopardy. The effectiveness of ART could be enhanced by delivering it as part of an international research collaboration since such collaborations can help identify problems, find solutions and increase the capacity of the health care system. PMID- 25552777 TI - Pharmacovigilance and tuberculosis: applying the lessons of thioacetazone. PMID- 25552779 TI - Reimagining cost recovery in Pakistan's irrigation system through willingness-to pay estimates for irrigation water from a discrete choice experiment. AB - It is widely argued that farmers are unwilling to pay adequate fees for surface water irrigation to recover the costs associated with maintenance and improvement of delivery systems. In this paper, we use a discrete choice experiment to study farmer preferences for irrigation characteristics along two branch canals in Punjab Province in eastern Pakistan. We find that farmers are generally willing to pay well in excess of current surface water irrigation costs for increased surface water reliability and that the amount that farmers are willing to pay is an increasing function of their existing surface water supply as well as location along the main canal branch. This explicit translation of implicit willingness-to pay (WTP) for water (via expenditure on groundwater pumping) to WTP for reliable surface water demonstrates the potential for greatly enhanced cost recovery in the Indus Basin Irrigation System via appropriate setting of water user fees, driven by the higher WTP of those currently receiving reliable supplies. PMID- 25552778 TI - Dilemmas of evaluation: health research capacity initiatives. PMID- 25552780 TI - GENERAL THEORY FOR INTERACTIONS IN SUFFICIENT CAUSE MODELS WITH DICHOTOMOUS EXPOSURES. AB - The sufficient-component cause framework assumes the existence of sets of sufficient causes that bring about an event. For a binary outcome and an arbitrary number of binary causes any set of potential outcomes can be replicated by positing a set of sufficient causes; typically this representation is not unique. A sufficient cause interaction is said to be present if within all representations there exists a sufficient cause in which two or more particular causes are all present. A singular interaction is said to be present if for some subset of individuals there is a unique minimal sufficient cause. Empirical and counterfactual conditions are given for sufficient cause interactions and singular interactions between an arbitrary number of causes. Conditions are given for cases in which none, some or all of a given set of causes affect the outcome monotonically. The relations between these results, interactions in linear statistical models and Pearl's probability of causation are discussed. PMID- 25552781 TI - INDISCRIMINATE BEHAVIOR OBSERVED IN THE STRANGE SITUATION AMONG INSTITUTIONALIZED TODDLERS: RELATIONS TO CAREGIVER REPORT AND TO EARLY FAMILY RISK. AB - Socially disinhibited or indiscriminate behavior (IB) has traditionally been investigated using caregiver reports. More recently, an observational measure based on the Strange Situation Procedure (M. Ainsworth, M. Blehar, E. Waters, & S. Wall, 1978), the Rating of Infant and Stranger Engagement (RISE; C. Riley, A. Atlas-Corbett, & K. Lyons-Ruth, 2005), was validated in home-reared at-risk children. The present study aimed to validate the RISE in an institutionally reared sample using the caregiver report, to assess whether IB assessed with the RISE was elevated among the institutionalized children, and to explore potential risk factors associated with IB. The study was conducted among 74 institutionalized toddlers aged 11 to 30 months. Sociodemographic questionnaires were used to assess pre-admission experiences, and aspects of institutional placement were coded from the children's files in the institution and staff's report. Institutionalized children displayed high frequencies of IB as assessed on the RISE, and this instrument was validated against caregiver report. Pre admission experiences of the institutionalized children in their biological families-namely, prenatal risk and maternal emotional neglect risk-predicted IB. Results suggest that the RISE is adequate to use among institutionally reared toddlers and point to aspects of the early familial environment that may be implicated in IB. PMID- 25552782 TI - VITALITY AFFECTS IN DANIEL STERN'S THINKING-A PSYCHOLOGICAL AND NEUROBIOLOGICAL PERSPECTIVE. AB - The goal of the present article is to deepen the theme of vitality, the topic of Daniel N. Stern's last book, Forms of Vitality, published in 2010, which further conceptualized the vitality affects originally proposed in his book The Interpersonal World of the Infant, published in 1985. Vitality forms characterize personal feelings as well dynamics of movements. They are therefore related to feelings of agency and efficacy, and may be shaped and influenced by early interactions between caregivers and infants. In this ambit, infants experience a sense of personal efficacy and a hedonic pleasure when they are recognized and confirmed by their caregivers. The interactional perspective is further discussed considering psychoanalytical contributions and recent infant research. However, vitality, as Stern (2010) highlighted, is grounded in the body and more specifically in the brain. From a neurobiological perspective, we discuss the role of mirror neurons by considering inter subjective exchanges and infantile matching experiences, which influence the sense of vitality. PMID- 25552783 TI - OPTIMIZATION BIAS IN ENERGY-BASED STRUCTURE PREDICTION. AB - Physics-based computational approaches to predicting the structure of macromolecules such as proteins are gaining increased use, but there are remaining challenges. In the current work, it is demonstrated that in energy based prediction methods, the degree of optimization of the sampled structures can influence the prediction results. In particular, discrepancies in the degree of local sampling can bias the predictions in favor of the oversampled structures by shifting the local probability distributions of the minimum sampled energies. In simple systems, it is shown that the magnitude of the errors can be calculated from the energy surface, and for certain model systems, derived analytically. Further, it is shown that for energy wells whose forms differ only by a randomly assigned energy shift, the optimal accuracy of prediction is achieved when the sampling around each structure is equal. Energy correction terms can be used in cases of unequal sampling to reproduce the total probabilities that would occur under equal sampling, but optimal corrections only partially restore the prediction accuracy lost to unequal sampling. For multiwell systems, the determination of the correction terms is a multibody problem; it is shown that the involved cross-correlation multiple integrals can be reduced to simpler integrals. The possible implications of the current analysis for macromolecular structure prediction are discussed. PMID- 25552784 TI - Risk of colon perforation during colonoscopy at Baylor University Medical Center. AB - Colonoscopy is an important procedure in preventing colon cancer. The risk of colonic perforation during colonoscopy at the Baylor University Medical Center (BUMC) Gastrointestinal Laboratory was chosen as a surrogate marker for the safety of colonoscopy. A recent 2-year experience at BUMC was examined and compared with reports in the medical literature. The results are presented here along with a discussion of problems inherent with different health care systems and their ability to accurately track complications. It was concluded that colonoscopy at BUMC is as safe as that reported by comparable health care systems. The risk of perforation at BUMC was 0.57 per 1000 procedures or 1 in 1750 colonoscopies. Continued efforts to make colonoscopy safer are needed. PMID- 25552785 TI - Impact of Henda's law on the utilization of screening breast magnetic resonance imaging. AB - Female breast tissue is composed of variable proportions of fat and fibroglandular tissue, and in general, an increased ratio of fibroglandular tissue to fat corresponds to increased mammographic density. Studies suggest that mammographic density is an independent risk factor for breast cancer, and the sensitivity of mammography can be lower with heterogeneously dense or extremely dense breasts. Nineteen states have legal statutes requiring that patients be notified if they have dense breasts, including the state of Texas. Henda's law, mandated on January 1, 2012 in Texas, suggests that patients with dense breasts could benefit from additional screening tests such as breast magnetic resonance imaging (MRI). Our study examined the impact of Henda's law by comparing the number of screening breast MRIs performed for dense breasts before and after the law's implementation. Results showed a 23-fold increase in the number of dense breast MRIs in the 2 years that this new legislation was in effect. This increase could have substantial implications for the health care economy, and further studies are needed to determine the cost-effectiveness of this additional screening tool. PMID- 25552786 TI - Comparison of length of stay and outcomes of patients with positive versus negative blood culture results. AB - In the United States, sepsis is the leading cause of death in critically ill patients. The fatality rate for severe sepsis is about 40%, and treatment costs over $16 billion annually. It is critical to identify and treat the source of sepsis. While there are varying guidelines determining when to draw blood for culture, at Baylor University Medical Center at Dallas, blood cultures are ordered for patients with new onset of fever, immunosuppression, or a suspicion of an underlying infectious etiology. We conducted a retrospective study of patients who had blood cultures after hospital admission or in the emergency department in December 2013. We compared length of stay and outcomes of patients with positive versus negative blood cultures. There was no significant difference for length of stay or outcomes among patients with positive and negative blood cultures. For patients admitted from the emergency department, there was a longer length of stay for patients with positive cultures; however, the overall prognosis was not worse. PMID- 25552787 TI - Redundancy and variability in quality and outcome reporting for cardiac and thoracic surgery. AB - Health care is evolving into a value-based reimbursement system focused on quality and outcomes. Reported outcomes from national databases are used for quality improvement projects and public reporting. This study compared reported outcomes in cardiac and thoracic surgery from two validated reporting databases the Society of Thoracic Surgeons (STS) database and the National Surgical Quality Improvement Program (NSQIP)-from January 2011 to June 2012. Quality metrics and outcomes included mortality, wound infection, prolonged ventilation, pneumonia, renal failure, stroke, and cardiac arrest. Comparison was made by chi-square analysis. A total of 737 and 177 cardiac surgery cases and 451 and 105 thoracic surgery cases were captured by the STS database and NSQIP, respectively. Within cardiac surgery, there was a statistically significant difference in the reported rates of prolonged ventilation, renal failure, and mortality. No significant differences were found for the thoracic surgery data. In conclusion, our data indicated a significant discordance in quality reporting for cardiac surgery between the NSQIP and the STS databases. The disparity between databases and duplicate participation strongly indicates that a unified national quality reporting program is required. Consolidation of reporting databases and standardization of morbidity definitions across all databases may improve participation and reduce hospital cost. PMID- 25552788 TI - Postextubation Dysphagia. AB - Postextubation dysphagia (PED) is a common problem in critically ill patients with recent intubation. Although several risk factors have been identified, most of them are nonmodifiable preexisting or concurrent conditions. Early extubation, small endotracheal tube size, and small bore of nasogastric tube potentially decrease the risk of PED. The majority of patients receive treatment based on only bedside swallow evaluations, which has an uncertain diagnostic accuracy as opposed to gold standard instrumental tests. Therefore, the treatment decision for patients may not be appropriately directed for each individual. Current treatments are mainly focused on dietary modifications and postural changes/compensatory maneuvers rather than interventions, but recent studies have shown limited proven benefits. Direct therapies in oromotor control, such as therapeutic exercises and neuromuscular stimulations, should be considered as potential effective treatments. PMID- 25552789 TI - Paul Revere Osler: the other child. AB - Sir William Osler (1849-1919) is among the most honored and esteemed physicians of our time. His life, and that of his wife Grace Revere Osler (1854-1928), has been examined in great detail by historians and biographers and continues to be the subject of intensive scrutiny. Their son "Revere" (Edward Revere Osler) (1895 1917), who died in the Great War, is often mistakenly referred to as their only child. Grace had two previous pregnancies, having given birth to Paul Revere Osler, who lived but a week, early in their marriage in 1893 and to a stillborn infant during her first marriage to Dr. Samuel W. Gross in 1877. Information regarding these two events is often ill defined, cursory, or incorrect. New research provides further knowledge of these events and their impact, giving a fuller understanding and a more lucid historiography of the Oslers. PMID- 25552790 TI - Ascending paralysis associated with HIV infection. AB - We present two patients with a high viral load of HIV-1 who developed symptoms of ascending paralysis leading to respiratory failure and autonomic instability. One patient had symptom improvement with highly active antiretroviral therapy (HAART) and a subsequent decrease in viral load. The other patient improved with intravenous immunoglobulin therapy and did not show much improvement on HAART alone. There are several proposed mechanisms for peripheral neuropathies seen in HIV-infected patients, including a direct action of HIV on the nerve by neurotropic strains or formation of autoantibodies against nerve elements. The comparison of the response to different therapies in these two cases highlights the importance of understanding different pathophysiologies, as the treatment modality may differ. PMID- 25552791 TI - Transient hypothermia in HIV-1 with insulin-like growth factor-1 deficiency and severe protein calorie malnutrition. AB - Hypothermia is a multifactorial process that results from decreased heat production or increased heat loss, with the former due to, but not limited to, endocrine dysfunction, malnutrition, and central nervous system pathologies. We report an HIV-1 patient with transient hypothermia secondary to severe protein calorie malnutrition and elevated HIV viral load. In this patient, it is hypothesized that the etiology of the hypothermia was multifactorial due to severe protein calorie malnutrition, evidenced by decreased insulin-like growth factor-1 levels, severe hypothyroidism, and an elevated HIV viral load, since the patient began to improve with the initiation of highly active antiretroviral therapy, improved nutrition, and continuation of thyroid supplementation. PMID- 25552792 TI - Metformin-induced lactic acidosis with emphasis on the anion gap. AB - The presence of an anion gap in a diabetic patient, especially if associated with evidence of compromised renal function, should prompt clinicians to consider metformin as a contributing factor. This consideration is especially important in patients with severe anion gaps associated with lactic acidosis out of proportion to the patient's clinical presentation. PMID- 25552793 TI - Preventing retrograde jejunoduodenogastric intussusception as a complication of a long-term indwelling gastrostomy tube. AB - Gastrostomy tubes are frequently used to provide enteral access in a variety of patient populations. Long-term complications are usually minor and include ulceration of the surrounding skin, clogging or dislodgment of the feeding tube, and superficial abscess; severe long-term complications are rare. Here we report a case of a life-threatening complication from an indwelling gastrostomy tube, specifically retrograde jejunoduodenogastric intussusception. Computed tomography and intraoperative images, as well as a review of literature, provide a detailed picture for diagnosis and treatment. Although feeding tubes are now routine and associated with low morbidity, physicians should remain aware of this potentially lethal complication in order to minimize the increased morbidity and mortality from intussusception and subsequent bowel ischemia. PMID- 25552794 TI - Second trimester placenta percreta presenting as acute abdomen. AB - Diagnosing placenta percreta can be difficult. We describe a 41-year-old woman presenting at 21 weeks' gestation with intraabdominal bleeding and no signs of placental abnormality on ultrasound. The disagreement between results of the ultrasound and magnetic resonance imaging made definitive diagnosis difficult. The bleeding resolved spontaneously after a blood transfusion, and the patient was hospitalized for the remainder of the pregnancy. Delivery was by scheduled repeat cesarean at 34 weeks' gestation. Spontaneous rupture of the entire fundus occurred at the time of delivery. Placenta percreta was confirmed by histologic examination of the operatively excised uterus. PMID- 25552795 TI - The Laugier-Hunziker syndrome. AB - We describe a 46-year-old Hispanic woman who was incidentally found to have hyperpigmentation of the oral mucosa and nails during a routine full body skin examination. The patient reported having these changes for years with no symptoms. A diagnosis of the Laugier-Hunziker syndrome (LHS) was made. LHS is an acquired, benign condition characterized by pigmentary skin changes involving the oral mucosa and is often associated with longitudinal melanonychia. PMID- 25552796 TI - Intracranial germinoma. AB - Pineal region tumors make up less than 1% of all intracranial neoplasms, with the majority being of germ cell origin. We describe the diagnostic evaluation and treatment of a patient presenting with neurological deficits who was found to have a germinoma of the pineal gland. PMID- 25552797 TI - Metastatic pancreatic neuroendocrine tumor with ectopic adrenocorticotropic hormone production. AB - We describe a 71-year-old man who presented with abdominal pain, lower-extremity edema, recent unintentional weight loss, hypertension, hyperglycemia, hypokalemia, and metabolic alkalosis. Serum cortisol levels remained elevated after overnight high-dose dexamethasone suppression. Magnetic resonance imaging revealed a small mass in the head of the pancreas with scattered liver metastases. Both endoscopic ultrasound-guided pancreatic biopsy and liver biopsy revealed a well-differentiated neuroendocrine tumor. These lesions did not show significant uptake on octreotide scan. Medical management and hepatic artery chemoembolization were attempted. Ultimately, the patient underwent bilateral adrenalectomy, but died within 4 months of symptom onset secondary to postoperative complications. PMID- 25552798 TI - Lobular carcinoma of the breast with gastrointestinal metastasis. AB - We present the case of a 74-year-old woman with metastatic lobular carcinoma with an occult breast primary presenting as a suspected ampullary tumor due to its ampullary metastasis. The patient's clinical presentation is of interest in two aspects. First, lobular carcinoma of the breast metastatic to the ampulla is extremely rare. Second, in the absence of a detectable primary lesion, prior history of malignancy, or distinguishing clinical, radiological, and endoscopic features, histopathological assessments are pivotal for arriving at the appropriate diagnosis and for optimizing treatment. PMID- 25552799 TI - Hepatic angiosarcoma associated with disseminated intravascular coagulation. AB - We present a case of hepatic angiosarcoma that presented with disseminated intravascular coagulopathy to highlight the difficulty in diagnosing this disease due its aggressive clinical course, the overlapping features of various coagulopathies, and the nonspecific appearance of angiosarcomas on imaging. PMID- 25552800 TI - Eosinophilic variant of chromophobe renal cell carcinoma. AB - Chromophobe renal cell carcinoma is a distinct subtype of renal cell carcinoma that accounts for 5% of all renal tumors. This subtype is further subdivided into two variants, classic and eosinophilic, with the latter variant being less frequent. We report two cases of the eosinophilic variant of chromophobe renal cell carcinoma diagnosed at our institution between January 2008 and December 2012. PMID- 25552801 TI - Pulmonary involvement of peripheral T-cell lymphoma manifesting as crazy paving pattern. AB - Crazy paving pattern is a finding on computed tomography of the chest that is characterized by interlobular septal thickening and ground-glass opacities. Though classically associated with pulmonary alveolar proteinosis, the differential diagnosis for this pattern is broad, and initial workup includes bronchoscopy with bronchoalveolar lavage to evaluate for malignancy, diffuse alveolar hemorrhage, pulmonary alveolar proteinosis, infection, and eosinophilic pneumonia. Herein we present an unusual case of peripheral T-cell lymphoma not otherwise specified (PTCL NOS) with pulmonary involvement that demonstrated crazy paving pattern. The diagnosis was confirmed after cytology from bronchoalveolar lavage revealed atypical lymphocytes with an immunologic profile consistent with the patient's known PTCL NOS. PMID- 25552802 TI - Sweet syndrome and its association with hematopoietic neoplasms. AB - The Sweet syndrome, or acute febrile neutrophilic dermatosis, is rare and has characteristic clinical, physical, and pathologic findings: abrupt onset of pyrexia, elevated neutrophil count, tender erythematous skin lesions, and a diffuse infiltrate of mature neutrophils in the reticular dermis with edema in the papillary dermis. The Sweet syndrome can be further classified based on the clinical setting: classical, malignancy-associated, and drug-induced. Diagnosis can alert the clinician to the presence of an underlying malignancy or the recurrence of a malignancy. The most commonly associated malignancy is acute myelogenous leukemia. We present three cases of Sweet syndrome associated with hematopoietic neoplasms. PMID- 25552803 TI - Hairy cell leukemia presenting with a lytic bone lesion. AB - Hairy cell leukemia (HCL) is an indolent neoplasm of small mature B lymphoid cells with characteristic morphologic features usually involving the peripheral blood, bone marrow, and spleen. It constitutes approximately 2% of adult leukemias and has a male predominance. Patients usually present with weakness, splenomegaly, and pancytopenia. The overall prognosis is favorable with appropriate treatment including purine analogs, interferon-alpha, and radiation. We report a patient with a history of breast cancer who presented with a left femoral lytic bone lesion that was subsequently diagnosed as HCL by morphology, immunohistochemistry, flow cytometry, and molecular genetic techniques. It was important to biopsy the lesion to establish the correct diagnosis, as HCL is a highly treatment-responsive malignancy. PMID- 25552804 TI - Benign neoplasms in the right ventricular outflow tract. AB - We describe benign neoplasms in the right ventricular outflow tract in two patients: one, a 2-month-old male with a rhabdomyoma, and the other, a 48-year old woman with a myxoma. Each of these tumors is rare in that location. PMID- 25552805 TI - Acute pulmonary embolism masquerading as acute myocardial infarction. AB - Pulmonary embolism can be extremely difficult to diagnose based on clinical presentation. Many studies have demonstrated certain electrocardiographic patterns commonly seen in pulmonary embolism, but few have described changes consistent with ST segment elevation myocardial infarction. In this report, we describe a patient who presented to the emergency department with electrocardiographic findings consistent with an anteroseptal myocardial infarction and his subsequent clinical course. PMID- 25552806 TI - Invited Commentary: The masquerading pulmonary embolism: why a high index of suspicion remains even today. PMID- 25552807 TI - Finger necrosis due to cryoglobulinemic vasculitis in association with membranous nephropathy. AB - Cryoglobulinemic vasculitis is a small vessel vasculitis that has been associated with chronic infections and autoimmune, lymphoproliferative, and neoplastic disorders. When no significant etiological factors are identified, it is called essential mixed cryoglobulinemia. A detailed and thorough laboratory investigation is required to exclude all possible causes of cryoglobulin formation. Although cryoglobulin testing is simple, careful temperature regulation is needed to avoid false-negative results. Consensus diagnosis should be developed and implemented for appropriate cryoglobulin detection and accurate clinical diagnosis for cryoglobulinemic vasculitis. Here we present an interesting, first-ever case report of a 54-year-old Hispanic-American woman with essential mixed cryoglobulinemia presenting with significant digital necrosis in association with membranous nephropathy. PMID- 25552808 TI - Virtual coaching for the high-intensity training of a powerlifter following coronary artery bypass grafting. AB - A 55-year-old powerlifter in Tennessee learned about the sport-specific, high intensity cardiac rehabilitation training available in Dallas, Texas, and contacted the staff by phone. He was recovering from quadruple coronary artery bypass grafting (CABG) and had completed several weeks of traditional cardiac rehabilitation in his hometown, but the exercise program no longer met his needs. He wanted help in returning both to his normal training regimen and to powerlifting competition but was unable to attend the Dallas program in person. An exercise physiologist with the program devised a virtual coaching model in which the patient was sent a wrist blood pressure cuff for self-monitoring and was advised about exercises that would not harm his healing sternum, even as the weight loads were gradually increased. After 17 weeks of symptom-limited, high intensity training that was complemented by phone and e-mail support, the patient was lifting heavier loads than he had before CABG. At a powerlifting competition 10 months after CABG, he placed first in his age group. This case report exemplifies the need for alternative approaches to the delivery of cardiac rehabilitation services. PMID- 25552809 TI - Reverse takotsubo cardiomyopathy with use of male enhancers. AB - Reverse takotsubo cardiomyopathy is a rare heart failure condition characterized by systolic dysfunction of the basal segments of the left ventricle in the absence of obstructive coronary artery disease. We present a case of a 54-year old man with an overdose of Extenze (a male enhancer pill containing yohimbine) who was hospitalized with heart failure due to reverse takotsubo cardiomyopathy. PMID- 25552810 TI - Consequence of patient substitution of nattokinase for warfarin after aortic valve replacement with a mechanical prosthesis. AB - This report describes a patient's self-substitution of nattokinase for the vitamin K antagonist warfarin after aortic valve replacement with a mechanical prosthesis. Nattokinase is an enzyme derived from a popular fermented soybean preparation in Japan (natto), which has fibrinolytic properties and is gaining popularity in nontraditional health journals and nonmedical health websites as an over-the-counter thrombolytic. After nearly a year of use of nattokinase without warfarin, the patient developed thrombus on the mechanical valve and underwent successful repeat valve replacement. We believe this is the first documented case of nattokinase being used as a substitute for warfarin after valve replacement, and we strongly discourage its use for this purpose. PMID- 25552811 TI - Slow regular rhythm in a disoriented patient. PMID- 25552812 TI - Anterior spinal cord syndrome of unknown etiology. AB - A spinal cord injury encompasses a physical insult to the spinal cord. In the case of anterior spinal cord syndrome, the insult is a vascular lesion at the anterior spinal artery. We present the cases of two 13-year-old boys with anterior spinal cord syndrome, along with a review of the anatomy and vasculature of the spinal cord and an explanation of how a lesion in the cord corresponds to anterior spinal cord syndrome. PMID- 25552813 TI - Vertebral artery dissection after a chiropractor neck manipulation. AB - The differential diagnosis for ischemic central nervous system infarcts in young patients includes paradoxic emboli through cardiac shunts, vasculitis, and vascular trauma. We report a young woman who developed headache, vomiting, diplopia, dizziness, and ataxia following neck manipulation by her chiropractor. A computed tomography scan of the head revealed an infarct in the inferior half of the left cerebellar hemisphere and compression of the fourth ventricle causing moderate acute obstructive hydrocephalus. Magnetic resonance angiography revealed severe narrowing and low flow in the intracranial segment of the left distal vertebral artery. The patient was treated with mannitol and a ventriculostomy and had an excellent functional recovery. This report illustrates the potential hazards associated with neck trauma, including chiropractic manipulation. The vertebral arteries are at risk for aneurysm formation and/or dissection, which can cause acute stroke. PMID- 25552815 TI - Paul Roscoe Ellis III, MD: a conversation with the editor. PMID- 25552814 TI - Use of an ultrasonic bone curette (Sonopet) in orbital and oculoplastic surgery. AB - The use of the Sonopet Omni, an ultrasonic bone curette, has been discussed for ear, nose, and throat, neurosurgical, and maxillofacial procedures. Its use in oculoplastic and orbital surgery has not been extensively described. The Sonopet has a number of advantages that impart particular utility when operating in the orbit. We present three illustrative cases highlighting the unique advantages of the Sonopet: 1) the ability to spare critical soft tissues; 2) the facility to sculpt and restore the complex contour of the orbit; 3) the capability to biopsy infiltrative lesions that may not be as amenable to manipulation with conventional drills; and 4) a small footprint ideal for small operative fields such as the orbit. PMID- 25552816 TI - Steven Marshall Frost, MD: a conversation with the editor. PMID- 25552817 TI - Teaching with questions. PMID- 25552818 TI - To see for oneself: Sir William Osler on autopsies, medical education, and economics. PMID- 25552820 TI - Facts and ideas from anywhere. PMID- 25552819 TI - Coffee: grounds for concern? PMID- 25552822 TI - The past, the present, and the future of pediatric surgery in India. PMID- 25552823 TI - We need to develop pediatric anesthesiology in India! PMID- 25552821 TI - Mother's little helper? Contrasting accounts of benzodiazepine and methadone use among drug-dependent parents in the UK. AB - AIMS: To explore the ways in which opioid-dependent parents accounted for their use of opioids and benzodiazepines during and after pregnancy. METHODS: Longitudinal qualitative interviews [n = 45] with 19 opioid-dependent adults recruited in Scotland, UK, were held during the antenatal and post-natal period. Interviews focused on parenting and parenting support within the context of problem drug use and were analysed using a narrative informed, thematic analysis. FINDINGS: The majority of participants described using benzodiazepines in addition to opioids. Almost all indicated a desire to stop or reduce opioid use, whereas cessation or reduction of benzodiazepines was rarely prioritised. In stark contrast to opioid dependence, benzodiazepine dependence was portrayed as unproblematic, therapeutic and acceptable in the context of family life. Whereas opioid dependence was framed as stigmatising, benzodiazepine use and dependence was normalised. An exception was benzodiazepine use by men which was occasionally associated with aggression and domestic abuse. CONCLUSIONS: Drug-dependent parents attach different meanings to opioid and benzodiazepine use and dependence in the context of parenthood. Divergent meanings, and stigma, may impact on stated commitment to stability or recovery from dependent drug-use. Attention should be paid to the way in which policy and practice regarding OST and benzodiazepines reflects this divergence. PMID- 25552824 TI - Anorectal malformations. AB - Anorectal malformations (ARMs) are among the more frequent congenital anomalies encountered in paediatric surgery, with an estimated incidence ranging between 1 in 2000 and 1 in 5000 live births. Antenatal diagnosis of an isolated ARM is rare. Most cases are diagnosed in the early neonatal period. There is a wide spectrum of presentation ranging from low anomalies with perineal fistula having simple management to high anomalies with complex management. Advances in the imaging techniques with improvement in knowledge of the embryology, anatomy and physiology of ARM cases have refined diagnosis and initial management. There has been marked improvement in survival of such patient over the last century. The management of ARM has moved forward from classical procedures to PSARP to minimal invasive procedures. But still the fecal and urinary incontinence can occur even with an excellent anatomic repair, mainly due to associated problems. There has been a paradigm shift in approach to these patients which involves holistic approach to the syndrome of Anorectal malformations with a long term goal of achievement of complete fecal and urinary continence with excellent quality of life. PMID- 25552825 TI - The current status of treatment of Wilms' tumor as per the SIOP trials. AB - This paper attempts to briefly describe the International Society of Paediatric Oncology (SIOP) policy of treatment of nephroblastoma since first study (SIOP 1) launched in 1971 until today. It focuses on the advantages of the preoperative chemotherapy and the stratification of patients induced this way. Marked efficacy of the pretreatment opened the way for less aggressive surgical management also in case of the "so-called" regular unilateral cases: Nephron-sparing surgery and minimal invasive techniques will probably find its place in this field of pediatric surgical oncology; however, very careful selection of cases must be the priority. PMID- 25552826 TI - Management of inguinal hernia in premature infants: 10-year experience. AB - AIM: Debatable issues in the management of inguinal hernia in premature infants remain unresolved. This study reviews our experience in the management of inguinal hernia in premature infants. MATERIALS AND METHODS: Retrospective chart review of premature infants with inguinal hernia from 1999 to 2009. Infants were grouped into 2: Group 1 had repair (HR) just before discharge from the neonatal intensive care unit (NICU) and Group 2 after discharge. RESULTS: Eighty four premature infants were identified. None of 23 infants in Group 1 developed incarcerated hernia while waiting for repair. Of the 61 infants in Group 2, 47 (77%) underwent day surgery repair and 14 were admitted for repair. At repair mean postconceptional age (PCA) in Group1 was 39.5 +/- 3.05 weeks. Mean PCA in Group 2 was 66.5 +/- 42.73 weeks for day surgery infants and 47.03 +/- 8.87 weeks for admitted infants. None of the 84 infants had an episode of postoperative apnea. Five (5.9%) infants presented subsequently with metachronous contralateral hernia and the same number of infants had hernia recurrence. CONCLUSIONS: Delaying HR in premature infants until ready for discharge from the NICU allows for repair closer to term without increasing the risk of incarceration. Because of low occurrence of metachronous hernia contralateral inguinal exploration is not justified. Day surgery HR can be performed in former premature infant if PCA is >47 weeks without increasing postoperative complications. PMID- 25552827 TI - Inguinal hernia in premature infants. PMID- 25552828 TI - Laparoscopic ipsilateral ureteroureterostomy for the management of children with duplication anomalies. AB - AIM: Ipsilateral ureteroureterostomy is an established method for the treatment of duplication anomalies in children. With the advent of pediatric laparoscopy, many urologic procedures in children are being performed using minimal access techniques. We present our experience with laparoscopic ipsilateral ureteroureterostomy (LIUU) for duplex anomalies. PATIENTS AND METHODS: The data of children who underwent LIUU was reviewed for demographic parameters, clinical and operative details, follow-up and results. RESULTS: Over 3 years period, LIUU was performed in eight children (age 6-60 months). Five children had complete ipsilateral duplication with ectopic upper moiety ureter, one child each had ipsilateral incomplete duplication and bilateral duplex systems (with ipsilateral ectopic upper moiety ureter). One child had ipsilateral complete duplex with Grade V vesicoureteric reflux into the lower moiety ureter. Four children had antenatal diagnosis of hydronephrosis; three children had a urinary infection and two children presented with urinary incontinence. The surgical procedure consisted of cystoscopy, retrograde studies and cannulation of the recipient ureter. Then, LIUU was performed using three ports. The ectopic (donor) ureter was divided at the pelvic brim; the recipient ureter was opened and end-to-side LIUU was performed with 5/0 vicryl stitches over a double J (DJ) stent placed in the recipient ureter. Bladder catheter was removed after 2 days, and DJ stent was removed after 4 weeks. At a mean follow-up of 19 months (3-36), all children are asymptomatic and continent, with a significant reduction in hydroureteronephrosis on ultrasound. The cosmetic results were excellent. CONCLUSION: LIUU is a safe and effective technique in the management of duplication anomalies in children. It could be performed with minimal blood loss, minimal postoperative pain, excellent cosmesis and good success. PMID- 25552829 TI - Pyeloplasty for hydronephrosis: Issues of double J stent versus nephrostomy tube as drainage technique. AB - AIMS: To compare the efficacy, complications, cost analysis and hospital stay between two methods of drainage of the kidney: double J (DJ) stent versus nephrostomy tube following open pyeloplasty for ureteropelvic junction obstruction hydronephrosis. PATIENTS AND METHODS: This was a prospective randomized study of 20 patients in each group over 14 months. Pre and post operative (3 months) function and drainage were assessed by ethylenedicysteine scan and intravenous urogram. RESULTS: Both groups showed similar good improvement in function and drainage. Nephrostomy group had significantly longer hospital stay (P < 0.001) but incurred less cost. Complications with nephrostomy included tube breakage (n = 1) and urine leak after tube removal (n = 2). DJ stents were associated with stent migration (n = 4), increased frequency of micturition (n = 9), dysuria (n = 4) and urinary tract infection (n = 1). CONCLUSION: Both methods of drainage did not interfere with improvement after pyeloplasty. Minor complications were more with DJ stent (P = 0.0003). Although overall cost of treatment was more with stents, they reduced length of hospital stay. Optimal length of stent is essential to reduce complications secondary to migration and bladder irritation. PMID- 25552830 TI - Absent upper blind Pouch in a case of tracheo-esophageal fistula. AB - A common upper airway and digestive tract is a rare congenital anomaly that is usually fatal and its exact incidence is not known. It is a diagnostic challenge as it requires high index of suspicion. It should be considered in a neonate with respiratory distress in a non-vigorous baby requiring endotracheal intubation, which is difficult even in expert hand. We present a newborn with suspected tracheo-esophageal fistula that was diagnosed intraoperatively to have absent upper blind pouch of the esophagus and on autopsy found to have laryngeal atresia with absent vocal cords and a common aerodigestive tract continuing distally with trachea. The neonate was ventilated with endotracheal tube (ETT) placement which in retrospect we came to know that it was in the esophagus. The neonate also had associated multiple congenital anomalies of VACTERL association. The importance of teamwork between neonatologist, pediatric surgeon, anesthesiologist, and radiologist is highlighted for diagnosis and management of such rare cases. PMID- 25552831 TI - Voiding urosonography: Contrast-enhanced ultrasound cystography to diagnose vesico-ureteric reflux: A pilot study. AB - We report two children with hydronephrosis, in whom we have utilized voiding urosonography (VUS) in the evaluation of vesico-ureteric reflux. With wider availability of ultrasound contrast agents and high-end ultrasound machines, VUS is likely to become a popular tool to diagnose or exclude VUR. PMID- 25552832 TI - A rare cause of glans penis masses in childhood: Fibroepithelial polyp. AB - Fibroepithelial polyps of glans penis are very rarely seen in childhood. A 6 month-old male admitted to our institution with a slowly enlarging glans penis mass on the ventral side of the glans penis. The mass was totally excised, and hystopathological diagnosis was a fibroepithelial polyp. All of the reported cases published previously, except one, are of adult age and all of them have been associated with the history of long-term condom catheter use. The presence of the case in childhood; however, suggests that the pathology might be congenital. This is the second pediatric case presented in the English literature. PMID- 25552833 TI - Ruptured rectal duplication with urogenital abnormality: Unusual presentation. AB - Rectal duplication (RD) accounts for 5% of alimentary tract duplication. A varied presentation and associated anomalies have been described in the literature. Antenatal rupture of the RD is very rare. We present an unusual case of a ruptured RD associated with urogenital abnormalities in newborn male. We are discussing diagnosis, embryology, management and literature review of ruptured RD. PMID- 25552834 TI - Incidentally found rectal duplication during surgery for rectovestibular fistula and its management. AB - Association of rectal duplication with rectovestibular fistula is rare. A 3-month old patient underwent primary posterior sagittal anorectoplasty (PSARP) for rectovestibular fistula. During surgery the patient was found to have a rectal duplication (RD). We managed the case by excising the common wall and fenestrating the two lumens together and completed the PSARP. PMID- 25552835 TI - Spontaneous resolution of antenatally diagnosed ureterocele. PMID- 25552837 TI - Reply. PMID- 25552836 TI - Bile in various hepatobiliary disease states. PMID- 25552838 TI - Laparoscopic sutureless cystogastrostomy in children for pseudocyst of pancreas: An innovative and simple technique. PMID- 25552839 TI - Novel use of gelatine sponge as primary dressing in Hypospadias surgery. PMID- 25552840 TI - Psychiatry in 21(st) century: The long and hard road ahead. PMID- 25552841 TI - Primary central nervous system lymphoma. PMID- 25552842 TI - Standardized surveillance of prion diseases in resource-poor settings is crucial for individual patient-care as well as for decision-making of healthcare authorities. PMID- 25552843 TI - Reassessing blood acetylcholinesterase in dementia. PMID- 25552845 TI - Commentary. PMID- 25552844 TI - Primary central nervous system diffuse large B-cell lymphoma in the immunocompetent: Immunophenotypic subtypes and Epstein-Barr virus association. AB - INTRODUCTION: Primary central nervous system diffuse large B-cell lymphoma (PCNSL DLBCL) in the immunocompetent is an uncommon tumor that has an activated B-cell immunophenotype resembling germinal center exit B cells. They also differ from primary central nervous diffuse large B-cell lymphomas in the immunocompromised as they show no association with the Epstein-Barr virus. OBJECTIVE: To determine if immunophenotypic subtyping of PCNS DLBCL from Asian subcontinent are also different similar to its systemic counterpart is unclear, as there are only limited studies from Asia, and none from India. MATERIAL AND METHODS: The immunohistochemical profile of 24 South Indian patients with primary central nervous system diffuse large B-cell lymphoma was studied using germinal center markers - CD10 and Bcl-6, and activation markers - MUM1 and CD138, which are markers for late/post germinal centre B cells. Insitu hybridization for EBV genome and LMP1 by immunohistochemistry was carried out in all cases to determine association with EBV. RESULTS: Centroblastic morphology and uniform activated B cell phenotype with positivity for MUM1 was seen in 91.6% of tumors. Co expression of Bcl-6 and MUM1 was evident in 50%, which is more frequent than in systemic diffuse large B-cell lymphomas. All cases were negative for Epstein-Barr virus using EBER in-situ hybridization and LMP1 immunohistochemistry. CONCLUSION: Primary diffuse large B-cell lymphoma in the immunocompetent is a distinct clinicopathological entity with centroblastic morphology, a uniform activated B cell immunophenotype that is not associated with the Epstein-Barr virus regardless of geographic origin. PMID- 25552846 TI - Diabetes mellitus and impaired glucose tolerance in patients with schizophrenia, before and after antipsychotic treatment. AB - BACKGROUND: Treatment with antipsychotics increases the risk of developing diabetes in patients of schizophrenia but this diabetogenic potential of different antipsychotics seems to be different. Moreover, there may be an independent link between schizophrenia and diabetes. So we plan to study the prevalence of glucose dysregulation in patients of schizophrenia before and after treatment with various antipsychotics. MATERIALS AND METHODS: Fifty patients (32 males and 18 females) diagnosed with schizophrenia were evaluated for glucose dysregulation using oral glucose tolerance test, initially (drug naive) and after antipsychotic treatment. Age- and sex-matched healthy volunteer group of 50 subjects (35 males and 15 females) was taken for comparison. Results were interpreted using American Diabetic Association criteria. RESULTS: Though the glycemic status of the patient group was comparable with healthy controls initially but antipsychotic treatment was associated with glucose dysregulation. For first 6 weeks the antipsychotic (olanzapine, risperidone, haloperidol and aripiprazole)-induced glucose dysregulation was comparable, which was seen to be maximum with the olanzapine-treated group at the end of this study, 14 weeks. CONCLUSION: We conclude that antipsychotic treatment of nondiabetic drug naive schizophrenia patients was associated with adverse effects on glucose regulation. For initial 6 weeks the antipsychotic-induced glucose dysregulation was comparable, which was seen to be maximum with olanzapine at the end of study, i.e. 14 weeks. Keeping this at the back of mind we can stabilize a patient initially with a more effective drug, olanzapine, and later on shift to one with less metabolic side effects. PMID- 25552847 TI - The natural history of Dandy-Walker syndrome in the United States: A population based analysis. AB - BACKGROUND: Dandy-Walker syndrome (DWS) is a congenital disorder typically manifesting with hydrocephalus. The classic anatomic hallmarks of DWS are hypoplasia of the cerebellar vermis, anterior-posterior enlargement of the posterior fossa, upward displacement of the torcula and transverse sinuses, and cystic dilatation of the fourth ventricle. AIMS: Although optimal treatment of DWS typically requires neurosurgical intervention to prevent intracranial pressure increases incompatible with life, the natural history of this disorder has yet to be evaluated on a nationwide level. SETTINGS AND DESIGN/MATERIALS AND METHODS: The Kids' Inpatient Database covering 1997-2003 was used for analysis. Children younger than age 18 admitted for DWS (ICD-9-CM = 742.3) were analyzed with a matched control group. The primary procedure codes for operative CSF drainage were coded into the analysis. The incidence of DWS was 0.136%; 14,599 DWS patients were included. STATISTICAL ANALYSIS USED: Multiple logistic regression models were used. Odds ratios (OR) were reported with 95% confidence intervals. RESULTS AND CONCLUSIONS: Mortality (OR = 10.02; P < 0.0001) and adverse discharge disposition (OR = 4.59; P < 0.0001) were significantly greater in DWS patients compared with controls. 20.4% of DWS patients received operative cerebrospinal fluid (CSF) drainage, 81-times more than controls (P < 0.0001). CSF drainage reduced mortality by 44% among DWS patients (P < 0.0001). Although DWS is associated with a 10-fold increase in mortality, operative CSF drainage nearly halves the mortality rate. Based on these findings (Class IIB evidence), it is likely that the increased mortality associated with DWS is directly attributable to the nearly 80% of DWS patients who did not receive operative CSF drainage for hydrocephalus. Consequently, increased access to neurosurgical intervention could reduce the mortality rate of DWS towards that of the general population. PMID- 25552848 TI - Neuroprotective effects of tetracyclines on blunt head trauma: An experimental study on rats. AB - BACKGROUND: Prevention of primary damage caused by head trauma may be avoided with protective measures and techniques which is a public health concern. Experimental and clinical studies about treatment of head trauma were all centered to prevent secondary damage caused by physiopathological changes following primary injury. Neuroprotective features of tetracyclines were the focus of several experimental studies in the last decade. In the present study we aimed to investigate the neuroprotective effects of tetracycline in an experimental model of blunt brain injury in rats. MATERIALS AND METHODS: 32 male Sprague-Dawley rats were divided into four experimental groups (n = 8). Head trauma was not performed in control group (group 1, craniectomy only). In the second group, head trauma and craniectomy were performed. Intraperitoneal saline was used in addition to trauma and craniectomy for treatment in group 3 whereas intraperitoneal tetracycline and saline were used for treatment in group 4. RESULTS: When histological examinations performed by transmission electron microscopy were evaluated, injury at ultrastructural level was demonstrated to be less pronounced in tetracycline group with decreased lipid peroxidation levels. CONCLUSION: In accordance with these findings, we conclude that systemic tetracycline administration is effective in reduction of secondary brain damage and brain edema and thus it may be considered as a therapeutic option. PMID- 25552849 TI - RBC acetyl cholinesterase: A poor man's early diagnostic biomarker for familial alzheimer's and Parkinson's disease dementia. AB - OBJECTIVE: Analysis of red blood cell acetyl cholinesterase (AChE) in a familial Alzheimer's diseases (AD) Parkinson's disease dementia (PDD) and their first generation. SETTING: General hospital, Mahad district, Raigad. PATIENTS AND METHODS: Clinically diagnosed patients of AD and PDD and their asymptomatic relatives. Their blood was collected in EDTA tube and transferred to laboratory at Mumbai. RESULT: Median red blood cell (RBC) cholinesterase levels amongst PDD, their first generation asymptomatic relatives, familial AD, asymptomatic relatives of AD, healthy controls, farmers exposed to pesticides (positive control) and other neurological condition without dementia (hypertension with TIA 1, sub-dural hematoma 2, hypothyroid 1, non-familial unilateral parkinsonism without dementia 3, writers cramps 2, hyponitremia 1 and cerebral palsy with non fluent aphasia 1). Median values of RBC AChE were 19086.78 U/L, 15666.05 U/L, 9013.11 U/L, 7806.19 U/L, 14334.57 U/L, 9785.05 U/L and 13162.60 U/L, respectively. As compared to controls, RBC AChE levels were statistically significant among PDD (P = 0.004) and significantly lowered among familial AD patients (P = 0.010), relatives of patients (P = 0.010). INTERPRETATIONS: Below the normal RBC AChE level is a potential biomarker in asymptomatic relatives of familial AD patients. RBC AChE is raised than normal level in patients suffering from PDD, where AChE inhibitors are helpful. However, RBC AChE level below the normal where AChE inhibitor may not be effective. PMID- 25552850 TI - A study of clinical profile, radiological and electroencephalographic characteristics of suspected Creutzfeldt-Jakob disease in a tertiary care centre in South India. AB - INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a progressive, fatal, neurodegenerative disease classified under transmissible spongiform encephalopathies (TSE) or prion diseases. It is characterized by long asymptomatic period followed by rapid clinical deterioration leading to the death within months. The disease is still under-reported in India. OBJECTIVE: The aim of this study was to describe the clinical, radiological and electroencephalographic characteristics of eight cases of CJD encountered in MS Ramaiah Medical college and Hospital, Bangalore over the past 3 years (2010 2013). This was retrospective, observational, hospital-based study. RESULTS: The mean age of patients was 66.6 years (range: 54-82) and there was female predominance (five patients). The main clinical manifestations were cognitive disturbance (8/8) and myoclonus (8/8), followed by behavioral disturbance (5/8), ataxia (5/8) and extra-pyramidal symptoms/signs (4/8). Time interval (mean) between onset of disease to death was 6.6 months (range: 3-14). Brain MRI abnormalities were noted in 6 patients: Fluid-attenuated inversion recovery hyperintensities with restriction on diffusion-weighted image/apparent diffusion coefficient (DWI/ADC) in caudate and putamen, and diffusion hyperintensities without restriction on ADC in parieto-occipital, frontal and temporal regions. Classical electroencephalogram (EEG) changes of periodic triphasic waves were seen in 87% of patients. The CSF 14-3-3 protein assay was positive in two patients (out of four). Seven cases were probable CJD and one was possible CJD. CONCLUSION: A strong clinical suspicion aided by characteristic brain MRI and EEG abnormalities is essential for timely diagnosis of this fatal disease. PMID- 25552851 TI - National sample survey organization survey report: An estimation of prevalence of mental illness and its association with age in India. AB - BACKGROUND: The Indian population suffers with significant burden of mental illness. The prevalence rate and its association with age and other demographic indicators are needed for planning purpose. OBJECTIVE: This study attempted to calculate age-wise prevalence of mental illness for rural and urban settings, and its association with age. MATERIALS AND METHODS: Data published in National Sample Survey Organization (2002) report on disability is used for the analysis. Spearman correlation for strength of association, z-test for difference in prevalence, and regression statistics for predicting the prevalence rate of mental illness are used. RESULT: Overall population have 14.9/1000 prevalence of mental illness. It is higher in rural setting 17.1/1000 than urban 12.7/1000 (P < 0.001). There is a strong correlation found with age in rural (rho = 0.910, P = 0.001) and urban (rho = 0.940, P = 0.001). CONCLUSION: Results of this study confirm other epidemiological research in India. Large-population epidemiological studies are recommended. PMID- 25552852 TI - Computerized tomographic study of normal Evans index in adult Nigerians. AB - BACKGROUND: The evaluation of degree of ventricular enlargement should be based on established indices rather than on personal experience as this is highly subjective. Our aim was to establish normal values for Evans index in a Nigerian adult population as none has been found in the Nigerian medical literature. MATERIALS AND METHODS: Axial computerized tomographic brain scans of 488 normal subjects were reviewed retrospectively. Of them, 319 (65.36%) of the patients were males and 169 (34.63%) were females; their ages ranged from 18 to 84 years with a mean age of 37.26 years. The images were acquired using a multi-slice GE Sigma excite scanner. Evans index was measured as the linear ratio of the total width of the frontal horns of the cerebral lateral ventricles to the maximum intracranial diameter. RESULTS: The mean value for Evans index for the studied population was 0.252 +/- 0.04. The EI increased with age and it was slightly higher among males. The difference in Evans value in males and females was not statistically significant. Individuals above 60 years old had the highest Evans values in both sexes. CONCLUSION: This study has established ranges of normal value for Evans index in a Nigerian population. It agrees with the diagnostic cut off value of > 0.3 for hydrocephalus and it compares well with that of the Caucasians. PMID- 25552853 TI - Pathophysiology of acute middle cerebral artery infarct by multimodal computed tomography: A pilot study in Thai patients. AB - AIMS: The purpose of this study was to study pathophysiology of acute middle cerebral artery infarct using multimodal CT and to evaluate the safety and feasibility of this method in our center. MATERIALS AND METHODS: Patients who had moderate to severe stroke (NIHSS score > 10), suspected of anterior circulation infarct and presented within 4 hours after stroke onset were prospectively included. Multimodal CTs, using low-osmolar contrast agents, were performed in all patients. RESULTS: Twenty-two patients were included. Mean NIHSS was 16. All patients received intravenous thrombolysis. Favorable outcome was found in nine patients (41%). CTP was unable to identify ischemic lesions in three patients with small subcortical infarct. Most patients (82%) with large middle cerebral artery infarct still had some salvageable brain (penumbra) which partly recovered in a follow-up imaging. Eleven patients (50%) had major artery occlusion. Two patients had creatinine rising within 72 hours. CONCLUSIONS: Multimodal CT does provide information about status of major artery and the volume of salvageable/infarct brain tissue and is safely and easily applicable in our center. PMID- 25552855 TI - Sensorineural hearing loss and status epilepticus associated with ulcerative colitis: Is there enough evidence to support immune-related mechanisms? AB - Ulcerative colitis (UC) is characterized by an inflammatory disorder of the gastrointestinal tract. Immune-mediated extraintestinal manifestations of UC have increasingly attracted attention in the literature recently, for which UC is now considered as a systemic disease. Neurologic involvement associated with UC is probably under-reported because of the unawareness of many physicians, although early recognition and treatment are crucial in preventing major morbidity and sequel. In this case report is presented a patient newly diagnosed as UC, who developed both sensorineural hearing loss and intractable status epilepticus that we suggest to have resulted from immune-mediated mechanisms. PMID- 25552856 TI - Commentary. PMID- 25552857 TI - Intraoperative diagnosis of glioblastomamultiforme with oligodendroglial and sarcomatous components. AB - Glioblastoma, the most frequent primary brain tumor and the most malignant neoplasm, can have the most heterogeneous morphological presentation. Along with classical morphological features, areas of oligodendroglial component and mesenchymal differentiation may be seen. The present case was a rare case of glioblastoma presenting with sarcomatous and oligodendroglial components. The case was diagnosed intraoperatively by squash and touch cytology and later on confirmed by histopathological study. PMID- 25552858 TI - Posterolateral approach in a neurofibromatosis type-I patient with severe dystrophic thoracic kyphoscoliosis: A case report, cadaver study, and literature review. AB - Neurofibromatosis type-I (NF-I) is an autosomal-dominant hereditary disorder, in which spinal skeletal deformities are one of the manifestations and manifest as acquired abnormalities and present as short, sharp, and angular (usually thoracic) curves. The scoliosis can be severe requiring surgical intervention. The surgical procedure can be difficult because of scalloping of the vertebral bodies and dural ectasia. We state that in selected cases of severe thoracic dystrophic kyphoscoliosis in NF-I, the posterolateral approach is the only possible method to visualize the anterior thoracic spinal cord, perform anterior decompression, and to stabilize the thoracic deformity, because of the anterior dural ectasias and the kyphosis limiting an anterior procedure. PMID- 25552854 TI - Psychiatric aspects of Parkinson's disease. AB - Parkinson's disease (PD) is essentially characterized by the motor symptoms in the form of resting tremor, rigidity and bradykinesia. However, over the years it has been recognized that motor symptoms are just the "tip of the iceberg" of clinical manifestations of PD. Besides motor symptoms, PD characterized by many non-motor symptoms, which include cognitive decline, psychiatric disturbances (depression, psychosis and impulse control), sleep difficulties, autonomic failures (gastrointestinal, cardiovascular, urinary, thermoregulation) and pain syndrome. This review evaluates the various aspects of psychiatric disorders including cognitive decline and sleep disturbances in patients with PD. The prevalence rate of various psychiatric disorders is high in patients with PD. In terms of risk factors, various demographic, clinical and treatment-related variables have been shown to be associated with higher risk of development of psychiatric morbidity. Evidence also suggests that the presence of psychiatric morbidity is associated with poorer outcome. Randomized controlled trials, evaluating the various pharmacological and non-pharmacological treatments for management of psychiatric morbidity in patients with PD are meager. Available evidence suggests that tricyclic antidepressants like desipramine and nortriptyline are efficacious for management of depression. Among the antipsychotics, clozapine is considered to be the best choice for management of psychosis in patients with PD. Among the various cognitive enhancers, evidence suggest efficacy of rivastigmine in management of dementia in patients with PD. To conclude, this review suggests that psychiatric morbidity is highly prevalent in patients with PD. Hence, a multidisciplinary approach must be followed to improve the overall outcome of PD. Further studies are required to evaluate the efficacy of various other measures for management of psychiatric morbidity in patients with PD. PMID- 25552859 TI - A rare case of thoracic myelocystocele associated with type 1 split cord malformation with low lying tethered cord, dorsal syrinx and sacral agenesis: Pentad finding. AB - Myelocystocele is a rare form of spinal dysraphism. Thoracic myelocystocele is still rarer. The occurrence of thoracic myelocystocele associated with type-1 split cord malformation, low lying tethered cord, dorsal syrinx and spina bifida is extremely rare. Clinical presentation of such a rare case and an early surgical management is discussed briefly. PMID- 25552860 TI - Occult falcine meningioma unmasked following nearly complete hemorrhagic transformation with resultant spontaneous acute interhemispheric subdural hematoma. AB - Sudden-onset monoplegia with features of vomiting and headache usually signals an intracranial cerebrovascular event. We describe a 62-year-old man in whom this presentation was the result of the rare occurrence of an almost complete hemorrhagic transformation of a falcine meningioma with resultant acute interhemispheric subdural hematoma, and discuss the risk factors and possible mechanisms that may lead to such an event. The need for careful examination of the available radiology and aggressive tumor removal is stressed. PMID- 25552861 TI - Delayed incidental diagnosis of postoperative extradural hematoma following ventriculoperitoneal shunt. AB - Ventriculo peritoneal (VP) shunt uncommonly complicates as intracranial hematomas which can still occur in patients with a functioning VP shunt leading to a delay in the diagnosis which can be extremely dangerous and lead to adverse outcomes. We report a case of an incidental diagnosis of delayed post-operative EDH following VP shunt in an young adult patient with a right cerebellar lesion and highlight the need for meticulous post-operative neurological examination. PMID- 25552862 TI - Vaginal extrusion of a ventriculo-peritoneal shunt catheter in an adult. AB - Ventriculo-peritoneal shunts (VPS) are commonly used in the treatment of various neurosurgical conditions, including hydrocephalus and pseudotumor cerebri. We report only the second case of vaginal extrusion of a VPS catheter in an adult, and the first case with a modern VPS silastic peritoneal catheter. A 45-year-old female with a history of VPS for pseudotumor cerebri, Behcet's syndrome, and hysterectomy presented to our institution with the chief complaint of tubing protruding from her vagina after urination. On gynecologic examination, the patient was found to have approximately 15 cm of VPS catheter protruding from her vaginal apex. A computed tomography scan of the abdomen and shunt X-ray series demonstrated no breaks in the tubing, but also confirmed the finding of the VPS catheter extruding through the vaginal cuff into the vagina. The patient had the VPS removed and an external ventricular drain was placed for temporary cerebrospinal fluid diversion. Ventricular catheter cultures were positive for diphtheroids. After an appropriate course of antibiotics, a contralateral ventriculo-pleural shunt was placed one week later. Although vary rare, vaginal extrusion can occur in adults, even with modern VPS catheters. PMID- 25552863 TI - Commentary. PMID- 25552864 TI - Orbital extension of trigeminal schwannoma. AB - Schwannomas, also known as neurilemmomas, are benign peripheral nerve sheath tumors. Trigeminal schwannomas are rare intracranial tumors. Here, we report a 35 year-old female presenting with an axial proptosis of right eyeball with right sided III, IV and VI cranial nerve palsy. Her best corrected visual acuity in the right eye was perception of light absent and in the left eye was 20/20. MRI scan revealed a large right-sided heterogeneous, extra-axial middle cranial fossa mass that extended to the intraconal space of right orbit. A diagnosis of intracranial trigeminal nerve schwannoma with right orbital extension was made. Successful surgical excision of the mass with preservation of the surrounding tissues and orbital exenteration was done. Post-operative period was uneventful. PMID- 25552865 TI - Diagnostic dilemma: Sturge-Weber syndrome, without facial nevus. AB - Sturge-Weber syndrome (SWS), a rare sporadic neurocutaneous disease, is characterized by a congenital unilateral port-wine nevus affecting the area innervated by V1, ipsilateral leptomeningeal angiomatosis, and calcification in the occipital or frontoparietal region and glaucoma/vascular eye abnormality. Three types of SWS have been described in literature: Type I (classic) demonstrates facial and leptomeningeal angioma, often with glaucoma; type II has facial angioma and glaucoma, with no evidence of intracranial lesions; and type III (rarest) presents with only leptomeningeal angioma. Only a few cases of type III SWS have been reported. Here, we report a case of a seven-year-old boy with focal complex partial seizure, who was diagnosed with SWS without facial nevus. Recognition of this type of SWS is important, as our patient had been misdiagnosed and received inappropriate antiepileptic drugs for six years. We suggest that in the appropriate clinical scenario, the diagnosis of SWS without facial nevus should be considered before labelling idiopathic or cryptogenic localization-related epilepsy, and gadolinium-enhanced magnetic resonance imaging (MRI) should be done in clinically suspicious cases of SWS, without facial nevus. PMID- 25552866 TI - Successful operative management of an upper lumbar spinal canal stenosis resulting in multilevel lower nerve root radiculopathy. AB - Lumbar stenosis is a common disorder, usually characterized clinically by neurogenic claudication with or without lumbar/sacral radiculopathy corresponding to the level of stenosis. We present a case of lumbar stenosis manifesting as a multilevel radiculopathy inferior to the nerve roots at the level of the stenosis. A 55-year-old gentleman presented with bilateral lower extremity pain with neurogenic claudication in an L5/S1 distribution (posterior thigh, calf, into the foot) concomitant with dorsiflexion and plantarflexion weakness. Imaging revealed grade I spondylolisthesis of L3 on L4 with severe spinal canal stenosis at L3-L4, mild left L4-L5 disc herniation, no stenosis at L5-S1, and no instability. EMG revealed active and chronic L5 and S1 radiculopathy. The patient underwent bilateral L3-L4 hemilaminotomy with left L4-L5 microdiscectomy for treatment of his L3-L4 stenosis. Postoperatively, he exhibited significant improvement in dorsiflexion and plantarflexion. The L5-S1 level was not involved in the operative decompression. Patients with radiculopathy and normal imaging at the level corresponding to the radiculopathy should not be ruled out for operative intervention should they have imaging evidence of lumbar stenosis superior to the expected affected level. PMID- 25552867 TI - Spinal accessory nerve schwannomas masquerading as a fourth ventricular lesion. AB - Schwannomas are benign lesions that arise from the nerve sheath of cranial nerves. The most common schwannomas arise from the 8(th) cranial nerve (the vestibulo-cochlear nerve) followed by trigeminal and facial nerves and then from glossopharyngeal, vagus, and spinal accessory nerves. Schwannomas involving the oculomotor, trochlear, abducens and hypoglossal nerves are very rare. We report a very unusual spinal accessory nerve schwannoma which occupied the fourth ventricle and extended inferiorly to the upper cervical canal. The radiological features have been detailed. The diagnostic dilemma was due to its midline posterior location mimicking a fourth ventricular lesion like medulloblastoma and ependymoma. Total excision is the ideal treatment for these tumors. A brief review of literature with tabulations of the variants has been listed. PMID- 25552868 TI - Antenatal and postnatal depression: A public health perspective. AB - Depression is widely prevalent among women in the child-bearing age, especially during the antenatal and postnatal period. Globally, post-partum depression has been reported in almost 10% to 20% of mothers, and it can start from the moment of birth, or may result from depression evolving continuously since pregnancy. The presence of depression among women has gained a lot of attention not only because of the rising incidence or worldwide distribution, but also because of the serious negative impact on personal, family and child developmental outcomes. Realizing the importance of maternal depression on different aspects-personal, child, and familial life, there is a crucial need to design a comprehensive public health policy (including a mental health strategy), to ensure that universal psychosocial assessment in perinatal women is undertaken within the primary health care system. To conclude, depression during pregnancy and in the postnatal period is a serious public health issue, which essentially requires continuous health sector support to eventually benefit not only the woman, but also the family, the community, and health care professionals. PMID- 25552869 TI - Neurofibromatosis type 2: Intracranial calcifications as a clue to diagnosis. PMID- 25552870 TI - Catatonic depression as the presenting manifestation of creutzfeldt-Jakob disease. PMID- 25552871 TI - Assessment of neuropathy by electrophysiology of visual pathway in welding workers. PMID- 25552872 TI - The anatomical variability of the emissary condylar veins, its identification and clinical significance. PMID- 25552873 TI - Reply to comment on "Prevalence of clinically important posterior fossa emissary veins on CT angiography". PMID- 25552874 TI - Neurology education: The role of assessment. PMID- 25552875 TI - Focus on teaching, not assessing, the surgeons and physicians of tomorrow. PMID- 25552876 TI - A rare initial neurological presentation of Sjogren's syndrome. PMID- 25552877 TI - Educational inequality in female cancer mortality in Korea. AB - We evaluated the influence of socioeconomic factors on female cancer mortality using death data from the Cause of Death Statistics and the Korean Population and Housing Census databases collected in 2001, 2006, and 2011. We estimated Relative Index of Inequality (RII) of female cancer mortality using Poisson regression analysis. RII greater than 1 indicates increased mortality risk for women at the lowest educational level compared with women at the highest educational level. The RII for cervical cancer mortality was persistently greater than 1 for the entire study period, with a gradual increase over time. Subgroup analysis stratified by age (25-44 and 45-64 yr) revealed that younger women had increased RIIs of mortality due to cervical cancer and ovarian cancer during the entire study period. Older women had higher RII only for cervical cancer mortality, but the value was much lower than that for younger women. The RII for breast cancer mortality was greater than 1 for younger women since 2006. In conclusion, socioeconomic inequality in female cancer mortality has persisted for the last decade in Korea, which was most evident for cervical cancer, and for younger women. PMID- 25552878 TI - A De-identification method for bilingual clinical texts of various note types. AB - De-identification of personal health information is essential in order not to require written patient informed consent. Previous de-identification methods were proposed using natural language processing technology in order to remove the identifiers in clinical narrative text, although these methods only focused on narrative text written in English. In this study, we propose a regular expression based de-identification method used to address bilingual clinical records written in Korean and English. To develop and validate regular expression rules, we obtained training and validation datasets composed of 6,039 clinical notes of 20 types and 5,000 notes of 33 types, respectively. Fifteen regular expression rules were constructed using the development dataset and those rules achieved 99.87% precision and 96.25% recall for the validation dataset. Our de-identification method successfully removed the identifiers in diverse types of bilingual clinical narrative texts. This method will thus assist physicians to more easily perform retrospective research. PMID- 25552879 TI - Clinicopathologic impacts of poorly differentiated cluster-based grading system in colorectal carcinoma. AB - Differentiation-based histologic grading of colorectal carcinoma (CRC) is widely used, but its clinical impact is limited by insufficient prognostic value, interobserver disagreement, and the difficulty of its application to CRC with specific histologic types such as mucinous and medullary carcinoma. A recently proposed novel grading system based on quantifying poorly differentiated clusters (PDCs) claims to have the advantages of reproducibility and improved prognostic value, and might apply to heterogeneous CRC. We aimed to validate the clinicopathologic significance of the PDCs-based grading system and to determine the relationship between this grading system and microsatellite instability (MSI). Two hundred and one patients who had undergone radical surgery were reviewed. Based on the number of PDCs, 85, 58, and 58 tumors were classified as grade (G) 1 (42.3%), G2 (28.9%), and G3 (28.9%), respectively. PDCs-based grade was significantly associated with T, N, and M stages; lymphovascular invasion; conventional histologic grade; and frequent tumor budding (all P <0.001). In multivariate analysis, PDCs-based grade was found to be an independent prognostic factor for disease-free survival (P = 0.022; hazard ratio, 3.709 [G2], 7.461 [G3]). G3 CRC significantly correlated with high MSI (MSI-H) compared to G1 and G2 (P = 0.002; odds ratio, 5.750). In conclusion, this novel grading would provide valuable prognostic information to a greater number of patients and would require continued verification. PDCs-based grading is feasible for CRCs with heterogeneous morphology, and we propose that the association between G3 and MSI H be further evaluated in different histological subtypes of CRC. PMID- 25552880 TI - Cardiac resynchronization therapy and QRS duration: systematic review, meta analysis, and meta-regression. AB - Cardiac resynchronization therapy (CRT) has been shown to reduce the risk of death and hospitalization in patients with advanced heart failure with left ventricular dysfunction. However, controversy remains regarding who would most benefit from CRT. We performed a meta-analysis, and meta-regression in an attempt to identify factors that determine the outcome after CRT. A total of 23 trials comprising 10,103 patients were selected for this meta-analysis. Our analysis revealed that CRT significantly reduced the risk of all-cause mortality and hospitalization for heart failure compared to control treatment. The odds ratio (OR) of all-cause death had a linear relationship with mean QRS duration (P=0.009). The benefit in survival was confined to patients with a QRS duration >=145 ms (OR, 0.86; 95% CI, 0.74-0.99), while no benefit was shown among patients with a QRS duration of 130 ms (OR, 1.00; 95% CI, 0.80-1.25) or less. Hospitalization for heart failure was shown to be significantly reduced in patients with a QRS duration >=127 ms (OR, 0.77; 95% CI, 0.60-0.98). This meta regression analysis implies that patients with a QRS duration >=150 ms would most benefit from CRT, and in those with a QRS duration <130 ms CRT implantation may be potentially harmful. PMID- 25552882 TI - Predictive value of echocardiographic parameters for clinical events in patients starting hemodialysis. AB - Echocardiographic parameters can predict cardiovascular events in several clinical settings. However, which echocardiographic parameter is most predictive of each cardiovascular or non-cardiovascular event in patients starting hemodialysis remains unresolved. Echocardiography was used in 189 patients at the time of starting hemodialysis. We established primary outcomes as follows: cardiovascular events (ischemic heart disease, cerebrovascular disease, peripheral artery disease, and acute heart failure), fatal non-cardiovascular events, all-cause mortality, and all combined events. The most predictable echocardiographic parameter was determined in the Cox hazard ratio model with a backward selection after the adjustment of multiple covariates. Among several echocardiographic parameters, the E/e' ratio and the left ventricular end diastolic volume (LVEDV) were the strongest predictors of cardiovascular and non cardiovascular events, respectively. After the adjustment of clinical and biochemical covariates, the predictability of E/e' remained consistent, but LVEDV did not. When clinical events were further analyzed, the significant echocardiographic parameters were as follows: s' for ischemic heart disease and peripheral artery disease, LVEDV and E/e' for acute heart failure, and E/e' for all-cause mortality and all combined events. However, no echocardiographic parameter independently predicted cerebrovascular disease or non-cardiovascular events. In conclusion, E/e', s', and LVEDV have independent predictive values for several cardiovascular and mortality events. PMID- 25552881 TI - Cardioprotective effect of fimasartan, a new angiotensin receptor blocker, in a porcine model of acute myocardial infarction. AB - Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F 18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI. PMID- 25552883 TI - Three-month treatment response and exacerbation in chronic obstructive pulmonary disease. AB - The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients. PMID- 25552884 TI - The association between asthma and invasive pneumococcal disease: a nationwide study in Korea. AB - The purpose of this study was to investigate the association between asthma and invasive pneumococcal disease (IPD) in Korea. A retrospective population-based cohort study was conducted using the Korean Health Insurance Review and Assessment database 2010-2011. The subjects included 935,106 (2010) and 952,295 (2011), of whom 398 (2010) and 428 (2011) patients with IPD were identified. There was significant difference in the prevalence of IPD in patients with and without asthma (0.07% vs. 0.02% in 2010 and 0.08% vs. 0.01% in 2011; P<0.001). After adjusting for age and gender, patients with asthma showed over a three-fold increased risk of IPD compared with patients without asthma (adjusted odds ratio [aOR] 3.90, 95% confidence interval [CI] 3.02-5.03 in 2010 / aOR, 5.44; 95% CI, 4.10-7.22 in 2011; P<0.001). These findings were also significant in children (aOR, 2.08; 95% CI, 1.25-3.45 in 2010; P=0.005 / aOR, 3.26; 95% CI, 1.74-6.11 in 2011; P<0.001). Although diabetes mellitus was also significantly associated with IPD, relatively low ORs compared with those of asthma were noted (aOR, 1.85; 95% CI, 1.35-2.54 in 2010 / aOR, 2.40; 95% CI, 1.78-3.24 in 2011; P<0.001). Both children and adults with asthma are at increased risk of developing IPD. PMID- 25552885 TI - A clinical analysis of brain metastasis in gynecologic cancer: a retrospective multi-institute analysis. AB - This study analyzes the clinical characteristics of the brain metastasis (BM) of gynecologic cancer based on the type of cancer. In addition, the study examines the factors influencing the survival. Total 61 BM patients of gynecologic cancer were analyzed retrospectively from January 2000 to December 2012 in terms of clinical and radiological characteristics by using medical and radiological records from three university hospitals. There were 19 (31.1%) uterine cancers, 32 (52.5%) ovarian cancers, and 10 (16.4%) cervical cancers. The mean interval to BM was 25.4 months (21.6 months in ovarian cancer, 27.8 months in uterine cancer, and 33.1 months in cervical cancer). The mean survival from BM was 16.7 months (14.1 months in ovarian cancer, 23.3 months in uterine cancer, and 8.8 months in cervical cancer). According to a multivariate analysis of factors influencing survival, type of primary cancer, Karnofsky performance score, status of primary cancer, recursive partitioning analysis class, and treatment modality, particularly combined therapies, were significantly related to the overall survival. These results suggest that, in addition to traditional prognostic factors in BM, multiple treatment methods such as neurosurgery and combined chemoradiotherapy may play an important role in prolonging the survival for BM patients of gynecologic cancer. PMID- 25552887 TI - Long-term outcome of cochlear implant in patients with chronic otitis media: one stage surgery is equivalent to two-stage surgery. AB - This study compared long-term speech performance after cochlear implantation (CI) between surgical strategies in patients with chronic otitis media (COM). Thirty patients with available open-set sentence scores measured more than 2 yr postoperatively were included: 17 who received one-stage surgeries (One-stage group), and the other 13 underwent two-stage surgeries (Two-stage group). Preoperative inflammatory status, intraoperative procedures, postoperative outcomes were compared. Among 17 patients in One-stage group, 12 underwent CI accompanied with the eradication of inflammation; CI without eradicating inflammation was performed on 3 patients; 2 underwent CIs via the transcanal approach. Thirteen patients in Two-stage group received the complete eradication of inflammation as first-stage surgery, and CI was performed as second-stage surgery after a mean interval of 8.2 months. Additional control of inflammation was performed in 2 patients at second-stage surgery for cavity problem and cholesteatoma, respectively. There were 2 cases of electrode exposure as postoperative complication in the two-stage group; new electrode arrays were inserted and covered by local flaps. The open-set sentence scores of Two-stage group were not significantly higher than those of One-stage group at 1, 2, 3, and 5 yr postoperatively. Postoperative long-term speech performance is equivalent when either of two surgical strategies is used to treat appropriately selected candidates. PMID- 25552886 TI - Hazardous drinking-related characteristics of depressive disorders in Korea: the CRESCEND study. AB - This study aimed to identify clinical correlates of hazardous drinking in a large cohort of Korean patients with depression. We recruited a total of 402 depressed patients aged > 18 yr from the Clinical Research Center for Depression (CRESCEND) study in Korea. Patients' drinking habits were assessed using the Korean Alcohol Use Disorder Identification Test (AUDIT-K). Psychometric scales, including the HAMD, HAMA, BPRS, CGI-S, SSI-Beck, SOFAS, and WHOQOL-BREF, were used to assess depression, anxiety, overall psychiatric symptoms, global severity, suicidal ideation, social functioning, and quality of life, respectively. We compared demographic and clinical features and psychometric scores between patients with and without hazardous drinking behavior after adjusting for the effects of age and sex. We then performed binary logistic regression analysis to identify independent correlates of hazardous drinking in the study population. Our results revealed that hazardous drinking was associated with current smoking status, history of attempted suicide, greater psychomotor retardation, suicidal ideation, weight loss, and lower hypochondriasis than non-hazardous drinking. The regression model also demonstrated that more frequent smoking, higher levels of suicidal ideation, and lower levels of hypochondriasis were independently correlates for hazardous drinking in depressed patients. In conclusion, depressed patients who are hazardous drinkers experience severer symptoms and a greater burden of illness than non-hazardous drinkers. In Korea, screening depressed patients for signs of hazardous drinking could help identify subjects who may benefit from comprehensive therapeutic approaches. PMID- 25552888 TI - Bone cement augmentation procedures for spinal pathologic fractures by multiple myeloma. AB - Efficacy and safety of bone cement augmentations for spinal pathologic fractures related to multiple myeloma, and usefulness of radionuclide studies for surgical decision were retrospectively evaluated. Forty eight vertebrae from 27 patients for bone cement augmentation procedures and 48 vertebrae from 29 patients for conservative treatment were enrolled. Clinical results using visual analogue scale (VAS) and Oswestry disability index (ODI), and radiologic results were assessed. For clinical decisions on treatment of spinal pathologic fracture, bone scan or single photon emission computed tomography was done for 20 patients who underwent surgery. Mean follow-up was 16.8 months. In terms of clinical results, immediate pain relief was superior in the operated group to that in the conservative group. ODI, maintenance of vertebral height and local kyphotic angle at the last follow-up were superior in the operated group in comparison to the conservative group. At one year follow-up, cumulative survival rate were 77.4% and 74.7% in the operated and conservative groups, respectively (log rank test> 0.05). Leakage of bone cement was noted at 10 treated vertebrae. Bone cement augmentations presented short-term pain relief for spinal pathologic fractures by myeloma with relative safety in highly selected patients, and radionuclide imaging studies were useful for the surgical decision on these procedures. PMID- 25552890 TI - The scene time interval and basic life support termination of resuscitation rule in adult out-of-hospital cardiac arrest. AB - We validated the basic life support termination of resuscitation (BLS TOR) rule retrospectively using Out-of-Hospital Cardiac Arrest (OHCA) data of metropolitan emergency medical service (EMS) in Korea. We also tested it by investigating the scene time interval for supplementing the BLS TOR rule. OHCA database of Seoul (January 2011 to December 2012) was used, which is composed of ambulance data and hospital medical record review. EMS-treated OHCA and 19 yr or older victims were enrolled, after excluding cases occurred in the ambulance and with incomplete information. The primary and secondary outcomes were hospital mortality and poor neurologic outcome. After calculating the sensitivity (SS), specificity (SP), and the positive and negative predictive values (PPV and NPV), tested the rule according to the scene time interval group for sensitivity analysis. Of total 4,835 analyzed patients, 3,361 (69.5%) cases met all 3 criteria of the BLS TOR rule. Of these, 3,224 (95.9%) were dead at discharge (SS,73.5%; SP,69.6%; PPV,95.9%; NPV, 21.3%) and 3,342 (99.4%) showed poor neurologic outcome at discharge (SS, 75.2%; SP, 89.9%; PPV, 99.4%; NPV, 11.5%). The cut-off scene time intervals for 100% SS and PPV were more than 20 min for survival to discharge and more than 14 min for good neurological recovery. The BLS TOR rule showed relatively lower SS and PPV in OHCA data in Seoul, Korea. PMID- 25552889 TI - Epidemiology and outcomes in out-of-hospital cardiac arrest: a report from the NEDIS-based cardiac arrest registry in Korea. AB - Sudden cardiac death (SCD) is a significant issue affecting national health policies. The National Emergency Department Information System for Cardiac Arrest (NEDIS-CA) consortium managed a prospective registry of out-of-hospital cardiac arrest (OHCA) at the emergency department (ED) level. We analyzed the NEDIS-CA data from 29 participating hospitals from January 2008 to July 2009. The primary outcomes were incidence of OHCA and final survival outcomes at discharge. Factors influencing survival outcomes were assessed as secondary outcomes. The implementation of advanced emergency management (drugs, endotracheal intubation) and post-cardiac arrest care (therapeutic hypothermia, coronary intervention) was also investigated. A total of 4,156 resuscitation-attempted OHCAs were included, of which 401 (9.6%) patients survived to discharge and 79 (1.9%) were discharged with good neurologic outcomes. During the study period, there were 1,662,470 ED visits in participant hospitals; therefore, the estimated number of resuscitation attempted CAs was 1 per 400 ED visits (0.25%). Factors improving survival outcomes included younger age, witnessed collapse, onset in a public place, a shockable rhythm in the pre-hospital setting, and applied advanced resuscitation care. We found that active advanced multidisciplinary resuscitation efforts influenced improvement in the survival rate. Resuscitation by public witnesses improved the short-term outcomes (return of spontaneous circulation, survival admission) but did not increase the survival to discharge rate. Strategies are required to reinforce the chain of survival and high-quality cardiopulmonary resuscitation in Korea. PMID- 25552891 TI - Megalocytic interstitial nephritis following acute pyelonephritis with Escherichia coli bacteremia: a case report. AB - Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis Gutmann bodies. The patient's renal function was markedly improved after short term treatment with high-dose steroid. PMID- 25552892 TI - Rebuttal to authors' reply, re: cancer risk in adult residents near nuclear power plants in Korea: a cohort study of 1992-2010. PMID- 25552894 TI - Towards Biomimetic Virtual Constraint Control of a Powered Prosthetic Leg. AB - This brief presents a novel control strategy for a powered prosthetic ankle based on a biomimetic virtual constraint. We first derive a kinematic constraint for the "effective shape" of the human ankle-foot complex during locomotion. This shape characterizes ankle motion as a function of the Center of Pressure (COP) the point on the foot sole where the resultant ground reaction force is imparted. Since the COP moves monotonically from heel to toe during steady walking, we adopt the COP as a mechanical representation of the gait cycle phase in an autonomous feedback controller. We show that our kinematic constraint can be enforced as a virtual constraint by an output linearizing controller that uses only feedback available to sensors onboard a prosthetic leg. Using simulations of a passive walking model with feet, we show that this novel controller exactly enforces the desired effective shape whereas a standard impedance (i.e., proportional-derivative) controller cannot. This work provides a single, biomimetic control law for the entire single-support period during robot-assisted locomotion. PMID- 25552895 TI - Developing a Framework for Intuitive Human-Computer Interaction. AB - Many technology marketing materials tout the intuitive nature of products, but current human-computer interaction (HCI) guidelines provide limited methods to help designers create this experience beyond making them easy to use. This paper proposes a definition for intuitive interaction with specific attributes to allow designers to create products that elicit the target experience. Review of relevant literatures provides empirical evidence for the suggested working definition of intuitive HCI: interactions between humans and high technology in lenient learning environments that allow the human to use a combination of prior experience and feedforward methods to achieve an individual's functional and abstract goals. Core concepts supporting this definition were compiled into an organizational framework that includes: seeking user goals, performing well learned behavior, determining what to do next, metacognition, knowledge in the head, and knowledge in the world. This paper describes these concepts and proposes design approaches that could facilitate intuitive behavior and suggests areas for further research. PMID- 25552896 TI - EMOTION RECOGNITION OF VIRTUAL AGENTS FACIAL EXPRESSIONS: THE EFFECTS OF AGE AND EMOTION INTENSITY. AB - People make determinations about the social characteristics of an agent (e.g., robot or virtual agent) by interpreting social cues displayed by the agent, such as facial expressions. Although a considerable amount of research has been conducted investigating age-related differences in emotion recognition of human faces (e.g., Sullivan, & Ruffman, 2004), the effect of age on emotion identification of virtual agent facial expressions has been largely unexplored. Age-related differences in emotion recognition of facial expressions are an important factor to consider in the design of agents that may assist older adults in a recreational or healthcare setting. The purpose of the current research was to investigate whether age-related differences in facial emotion recognition can extend to emotion-expressive virtual agents. Younger and older adults performed a recognition task with a virtual agent expressing six basic emotions. Larger age related differences were expected for virtual agents displaying negative emotions, such as anger, sadness, and fear. In fact, the results indicated that older adults showed a decrease in emotion recognition accuracy for a virtual agent's emotions of anger, fear, and happiness. PMID- 25552897 TI - Evaluation of the iPad as a low vision aid for improving reading ability. AB - PURPOSE: To evaluate the effect of the iPad as a low vision aid in improving the reading ability of low vision patients (LVPs). METHODS: In this study, 228 consecutive patients that came for their routine eye care examination at the University of Florida, Jacksonville eye clinic, were enrolled. Patients met inclusion criteria if they had best-corrected visual acuity (BCVA) of 20/100 or worse in the best corrected eye and were willing to participate in the study. The patient's reading ability was assessed both with the patient's own spectacles and an iPad. Patients were encouraged to enlarge the reading material as well as change the contrast until they could read comfortably. The number of patients able to read the text comfortably was recorded. RESULTS: Out of the total 228 participants who qualified, 103 (45%) were male and 125 (55%) were female. Only 22% could read standard newsprint-sized text (N8) without the help of an iPad. With the help of an iPad, 94% participants with impaired vision were able to read standard newsprint-sized text (N8) or smaller text (P<0.01). CONCLUSION: The iPad, a new portable electronic media device, can be adapted by LVPs to improve their reading ability. PMID- 25552898 TI - Temsirolimus for patients with metastatic renal cell carcinoma: outcomes in patients receiving temsirolimus within a compassionate use program in a tertiary referral center. AB - AIM: Temsirolimus has shown efficacy as first-line treatment of patients with metastatic renal cell carcinoma and poor prognostic features. The efficacy of temsirolimus in other clinical settings, such as second-line therapy, is unclear. The aim of this study was to investigate the outcomes of an unselected group of patients with renal cancer treated with temsirolimus in a compassionate use program. PATIENTS AND METHODS: This retrospective analysis included all patients receiving temsirolimus at a tertiary referral center between November 2007 and October 2008. Information was obtained through review of patient notes, electronic records, and pharmacy records. Baseline characteristics, prognostic features, and previous treatments were recorded for all patients. Outcome measures were response rate, progression-free survival (PFS), overall survival (OS), and toxicities. RESULTS: Thirty-eight patients were included in the analysis, with median age of 62 years, among whom 37% were untreated and 63% had received one or more previous treatments. Thirty-four percent of the patients had three or more poor prognostic factors. Four patients (11%) achieved a partial response (PR); in all four of these patients, the PR was confirmed by two subsequent computed tomography (CT) scans, and in one patient, the PR lasted for more than 18 months. A total of 34% achieved stable disease, and 50% had disease progression. Median OS was 7.6 months (95% confidence interval [CI] 4.8-10.5), and median PFS was 3.2 months (95% CI 1.0-5.5). Patients with two or fewer poor prognostic factors had a survival of 10.12 months compared with 5.03 months of those with three or more. Median survival was 14.9 months for untreated patients and 6.4 months for previously treated patients. CONCLUSION: Our results indicate some efficacy of temsirolimus in untreated patients with renal tumors and poor intermediate prognosis, although the limitations of small sample size and retrospective nature must be taken into account. The role of temsirolimus in previously treated patients remains controversial given the recently published results of the INTORSECT trial and the discrepancies between the few published series. PMID- 25552900 TI - Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy. AB - OBJECTIVE: The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen. METHODS: A total of 381 patients (age >=18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003. RESULTS: Mean recipient age at HTX was 51.2+/-10.5 years and the mean follow-up period after HTX was 9.7+/-5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy. CONCLUSION: This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy. PMID- 25552899 TI - An evidence-based update on the pharmacological activities and possible molecular targets of Lycium barbarum polysaccharides. AB - Lycium barbarum berries, also named wolfberry, Fructus lycii, and Goji berries, have been used in the People's Republic of China and other Asian countries for more than 2,000 years as a traditional medicinal herb and food supplement. L. barbarum polysaccharides (LBPs) are the primary active components of L. barbarum berries and have been reported to possess a wide array of pharmacological activities. Herein, we update our knowledge on the main pharmacological activities and possible molecular targets of LBPs. Several clinical studies in healthy subjects show that consumption of wolfberry juice improves general wellbeing and immune functions. LBPs are reported to have antioxidative and antiaging properties in different models. LBPs show antitumor activities against various types of cancer cells and inhibit tumor growth in nude mice through induction of apoptosis and cell cycle arrest. LBPs may potentiate the efficacy of lymphokine activated killer/interleukin-2 combination therapy in cancer patients. LBPs exhibit significant hypoglycemic effects and insulin-sensitizing activity by increasing glucose metabolism and insulin secretion and promoting pancreatic beta cell proliferation. They protect retinal ganglion cells in experimental models of glaucoma. LBPs protect the liver from injuries due to exposure to toxic chemicals or other insults. They also show potent immunoenhancing activities in vitro and in vivo. Furthermore, LBPs protect against neuronal injury and loss induced by beta-amyloid peptide, glutamate excitotoxicity, ischemic/reperfusion, and other neurotoxic insults. LBPs ameliorate the symptoms of mice with Alzheimer's disease and enhance neurogenesis in the hippocampus and subventricular zone, improving learning and memory abilities. They reduce irradiation- or chemotherapy-induced organ toxicities. LBPs are beneficial to male reproduction by increasing the quality, quantity, and motility of sperm, improving sexual performance, and protecting the testis against toxic insults. Moreover, LBPs exhibit hypolipidemic, cardioprotective, antiviral, and antiinflammatory activities. There is increasing evidence from preclinical and clinical studies supporting the therapeutic and health-promoting effects of LBPs, but further mechanistic and clinical studies are warranted to establish the dose-response relationships and safety profiles of LBPs. PMID- 25552901 TI - Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations. AB - Down syndrome (DS), also known as trisomy 21, is the most common genetic cause of intellectual disability (ID). Although ID can be mild, the average intelligence quotient is in the range of 40-50. All individuals with DS will also develop the neuropathology of Alzheimer's disease (AD) by the age of 30-40 years, and approximately half will display an AD-like dementia by the age of 60 years. DS is caused by an extra copy of the long arm of human chromosome 21 (Hsa21) and the consequent elevated levels of expression, due to dosage, of trisomic genes. Despite a worldwide incidence of one in 700-1,000 live births, there are currently no pharmacological treatments available for ID or AD in DS. However, over the last several years, very promising results have been obtained with a mouse model of DS, the Ts65Dn. A diverse array of drugs has been shown to rescue, or partially rescue, DS-relevant deficits in learning and memory and abnormalities in cellular and electrophysiological features seen in the Ts65Dn. These results suggest that some level of amelioration or prevention of cognitive deficits in people with DS may be possible. Here, we review information from the preclinical evaluations in the Ts65Dn, how drugs were selected, how efficacy was judged, and how outcomes differ, or not, among studies. We also summarize the current state of human clinical trials for ID and AD in DS. Lastly, we describe the genetic limitations of the Ts65Dn as a model of DS, and in the preclinical testing of pharmacotherapeutics, and suggest additional targets to be considered for potential pharmacotherapies. PMID- 25552903 TI - Designing biologic selectivity for inflammatory bowel disease--role of vedolizumab. AB - Crohn's disease and ulcerative colitis are two chronic inflammatory bowel conditions. Current approved biologic therapies are limited to blocking tumor necrosis factor alpha. Unfortunately, some patients are primary nonresponders, experiencing a loss of response, intolerance, or side effects. This defines an unmet need for novel therapeutic strategies. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. Here we discuss the clinical trial results of vedolizumab (anti-alpha4beta7, LDP-02, MLN-02, and MLN0002) and its impact on future management of inflammatory bowel disease. PMID- 25552902 TI - Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway. AB - Drug metabolizing enzymes (DMEs) and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC) is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE) on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2) cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(P)H: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate-cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant increase in the intracellular level of glutathione and total glutathione S-transferase content. SCE significantly elevated the messenger ribonucleic acid and protein levels of P-glycoprotein and multidrug resistance-associated protein 2 and 4, whereas the expression of organic anion transporting peptide 1A2 and 1B1 was significantly downregulated by SCE. Knockdown of Nrf2 by small interfering ribonucleic acid attenuated the regulatory effect of SCE on these DMEs and drug transporters. SCE significantly upregulated Nrf2 and promoted the translocation of Nrf2 from cytoplasm to the nuclei. Additionally, SCE significantly suppressed the expression of cytosolic Kelch-like ECH-associated protein 1 (the repressor of Nrf2) and remarkably increased Nrf2 stability in HepG2 cells. Taken together, our findings suggest that the hepatoprotective effects of SCE may be partially ascribed to the modulation of DMEs and drug transporters via Nrf2-mediated signaling pathway. SCE may alter the pharmacokinetics of other coadministered drugs that are substrates of these DMEs and transporters and thus cause unfavorable herb-drug interactions. PMID- 25552904 TI - Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). AB - Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists, appears to be the most effective agent in its class. Netupitant, is a new NK-1 receptor antagonist with a high binding affinity, a long half-life of 90 hours, is metabolized by CYP3A4, and is an inhibitor of CYP3A4. NEPA is an oral fixed-dose combination of netupitant and palonosetron which has recently been employed in Phase II and Phase III clinical trials for the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy (MEC and HEC). The clinical trials demonstrated that NEPA (300 mg of netupitant plus 0.50 mg of palonosetron) significantly improved the prevention of CINV compared to the use of palonosetron alone in patients receiving either HEC or MEC. The clinical efficacy was maintained over multiple cycles of chemotherapy. NEPA (Akynzeo((r))) has recently been approved by the Food and Drug Administration (FDA) to treat nausea and vomiting in patients undergoing cancer chemotherapy. PMID- 25552905 TI - Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma. AB - BACKGROUND: Several unfavorable prognostic factors have been proposed for peripheral cholangiocarcinoma (PCC) in patients undergoing hepatectomy, including gross type of tumor, vascular invasion, lymph node metastasis, a high carbohydrate antigen 19-9 level, and a positive resection margin. However, the clinical effect of a positive surgical margin on the survival of patients with PCC after hepatectomy still needs to be clarified due to conflicting results. METHODS: A total of 224 PCC patients who underwent hepatic resection with curative intent between 1977 and 2007 were retrospectively reviewed. Eighty-nine patients had a positive resection margin, with 62 having a microscopically positive margin and 27 a grossly positive margin (R2). The clinicopathological features, outcomes, and recurrence pattern were compared with patients with curative hepatectomy. RESULTS: PCC patients with hepatolithiasis, periductal infiltrative or periductal infiltrative mixed with mass-forming growth, higher T stage, and more advanced stage tended to have higher positive resection margin rates after hepatectomy. PCC patients who underwent curative hepatectomy had a significantly higher survival rate than did those with a positive surgical margin. When PCC patients underwent hepatectomy with a positive resection margin, the histological grade of the tumor, nodal positivity, and chemotherapy significantly affected overall survival. Locoregional recurrence was the most common pattern of recurrence. CONCLUSION: A positive resection margin had an unfavorable effect on overall survival in PCC patients undergoing hepatectomy. In these patients, the prognosis was determined by the biology of the tumor, including differentiation and nodal positivity, and chemotherapy increased overall survival. PMID- 25552907 TI - Cerebellar cryptococcosis characterized by a space-occupying lesion in an immunocompetent non-HIV patient. AB - Central nervous system (CNS) cryptococcosis is an opportunistic fungal infection that typically occurs in patients with reduced immunological function, such as patients with AIDS, patients receiving organ transplants, or patients receiving corticosteroid and immunosuppressive therapy. CNS cryptococcosis rarely occurs in immunocompetent patients. CNS cryptococcosis is characterized by meningitis and encephalitis and occasionally forms isolated granulomas. Isolated cerebellar cryptococcoma is a rare condition, especially in immunocompetent patients, and the misdiagnosis rate is high. A definite diagnosis must be based on pathology. To raise awareness of this disease, the clinical data of a patient with cryptococcomas in the right side of the cerebellum are reported. PMID- 25552906 TI - A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. AB - The effects of selexipag and its active metabolite ACT-333679 on cardiac repolarization were assessed in a thorough QT study as per International Conference on Harmonisation E14 guidance. In this randomized, double-blind, placebo/positive-controlled, parallel-group study, healthy male and female subjects were randomized to receive escalating doses of selexipag (n=91) or placebo/moxifloxacin (n=68). Ascending multiple doses of selexipag in the range of 400-1,600 MUg or placebo were administered twice daily for 21 days. Following a nested crossover design, subjects in the moxifloxacin/placebo treatment group received a single oral 400 mg dose of moxifloxacin on day 2 or 24. The primary endpoint (QT interval correction using individualized formula [QTcI]) was chosen based on a prospectively defined test applied to on-treatment data. The mean baseline-adjusted placebo-corrected DeltaQTcI (DeltaDeltaQTcI) for selexipag was small at all time points and never exceeded 1.4 msec (upper bound of 90% confidence interval [CI], 3.9 msec) on 800 MUg or -0.7 msec (upper bound of 90% CI, 2.1 msec) on 1,600 MUg. The mean DeltaDeltaQTcI peak effect for moxifloxacin was 7.5 msec (lower bound of 90% CI, 4.8 msec). The exposure-response analysis did not demonstrate a relevant relationship between plasma concentrations of selexipag or ACT-333679 and DeltaDeltaQTcI but, in contrast, a positive slope within the expected range for moxifloxacin. In conclusion, selexipag does not have an effect on cardiac repolarization. PMID- 25552908 TI - An antiaging skin care system containing alpha hydroxy acids and vitamins improves the biomechanical parameters of facial skin. AB - BACKGROUND: The demand for antiaging products has dramatically increased in recent years, driven by an aging population seeking to maintain the appearance of youth. This study investigates the effects of an antiaging skin care system containing alpha hydroxy acids (AHAs) in conjunction with vitamins B3, C, and E on the biomechanical parameters of facial skin. METHODS: Fifty two volunteers followed an antiaging skin care regimen comprising of cleanser, eye cream, day moisturizer, and night moisturizer for 21 days. Wrinkle depth (Ry ) and skin roughness (Ra ) were measured by skin surface profilometry of the crow's feet area, and skin elasticity parameters R2 (gross elasticity), R5 (net elasticity), R6 (viscoelastic portion), and R7 (recovery after deformation) were determined for facial skin by cutometer, preapplication and after 7, 14, and 21 days. Volunteers also completed a self-assessment questionnaire. RESULTS: Compared to baseline, Ry and Ra significantly improved by 32.5% (P<0.0001) and 42.9% (P<0.0001), respectively, after 21 days of antiaging skin care treatment. These results were observed by the volunteers with 9 out of 10 discerning an improvement in skin texture and smoothness. Compared to baseline, R2 and R5 significantly increased by 15.2% (P<0.0001) and 12.5% (P=0.0449), respectively, while R6 significantly decreased by 17.7% (P<0.0001) after 21 days. R7 increased by 9.7% after 21 days compared to baseline but this was not significant over this time period. CONCLUSION: An antiaging skin care system containing AHAs and vitamins significantly improves the biomechanical parameters of the skin including wrinkles and skin texture, as well as elasticity without significant adverse effects. PMID- 25552909 TI - The perceptions of cognitively impaired patients and their caregivers of a home telecare system. AB - Assistive and telecare technologies have been developed to support older adults with cognitive impairments, as well as their caregivers, from their homes. The way potential users perceive telecare and smart home systems plays a key role in their acceptance of this new technology. We evaluate the acceptance of home telecare technologies among patients suffering from cognitive impairment and their caregivers. Prototypes of telecare devices were developed to demonstrate their features and capabilities and to train patients, families, and health care professionals in their use. We conducted semistructured interviews to elicit the perceptions of 30 patients with mild cognitive impairment, 32 patients with Alzheimer's disease, and 30 caregivers, regarding the risks and advantages of home telecare and smart houses. Survey results reflected participants' largely positive reactions to these technologies. Regarding home telecare, the cognitive stimulation program earned the highest proportion of positive responses, followed by the devices' care of emergencies. The participants generally agreed that home telecare and smart houses could significantly improve their quality of life. However, some technical and ethical concerns, such as the way of provision, installation, and monitoring of the systems, were reported to be in need of addressing before implementation of this system. PMID- 25552911 TI - Oxidation Studies of Carbon Nanotubes for Applications as X-Ray Field Emitters Using an Aberration-Corrected, Environmental TEM. PMID- 25552910 TI - Effects of the neonatal intensive care unit environment on preterm infant oral feeding. AB - OBJECTIVE: To examine the effect of neonatal intensive care unit environmental characteristics (perceived levels of light and sound, and time of day) in open unit wards and single-family rooms (SFRs) on oral feeding outcomes in preterm infants. DESIGN: Data were collected at each scheduled oral feeding for 87 preterm infants from the first oral feeding until discharge. Data included the prescribed volume of feeding and the volume consumed, the infant's level of wakefulness before feeding, and the nurse's perception of light and sound. RESULTS: Data were collected on 5111 feedings in the ward unit and 5802 in the SFR unit from feedings involving 87 preterm infants. Light and sound were rated significantly lower in the SFR (chi2 = 139 and 1654.8, respectively). Feeding times of 9 am, 12 noon, and 3 pm were associated with the highest perceived levels of light and sound, regardless of unit design (P < 0.0001). Moderate light levels and feeding times of 12, 3, and 6 am were associated with improved feeding outcomes. Infants consumed a greater proportion of their prescribed feeding volume when fed in the open ward and when awake before feeding. CONCLUSION: Further study on the clinical effects of unit design is needed, as is study on the effects of environmental stimuli, so that interventions can be appropriately developed and tailored for infants needing the most support for optimal development. PMID- 25552912 TI - High reproducibility of adhesion formation in rat with meso-stitch approximation of injured cecum and abdominal wall. AB - OBJECTIVE: Peritoneal adhesions following surgery are a common, serious pathology with severe complications. Appropriate animal adhesion models are essential for the assessment of adhesion preventing medical devices. This study introduces a variation of an established rat model in which highest degree adhesions are induced with excellent reproducibility (OPAM=optimized peritoneal adhesion model). Thus, this model seems to be eligible to study effects of adhesion preventing devices. METHODS: 24 Lewis male rats were divided into four groups (OPAM, WSFX, sham-OPAM, sham-WSFX). The OPAM technique comprised cecal abrasion, creation of an abdominal wall defect plus approximation of injured areas by a suture, which was compared to a setting of lesions without suture fixation (WSFX). All rats were sacrificed at day 7. Macroscopic and histopathological evaluations were performed. RESULTS were statistically analyzed using ANOVA and Dunnett's test. RESULTS: In OPAM rats macroscopic analyses revealed a 90% incidence adhesion of cecum to the abdominal wall, all adhesions imposing as complete agglutination. In WSFX animals incidence of adhesions formation was 75%, while in both sham groups there were no adhesions at all. Histology showed the structure of adhesions with merged smooth muscle of colon and skeletal muscle of abdominal wall in all cases. CONCLUSION: OPAM technique provides adhesions of injured areas with a better probability than with conventional methods. All OPAM adhesions impressed as highest degree adhesions, i.e. agglutination. Due to high reproducibility in incidence and extend of adhesion formation, the OPAM is recommended for testing of adhesion prevention medical devices. PMID- 25552913 TI - The expression levels of transcription factors T-bet, GATA-3, RORgammat and FOXP3 in peripheral blood lymphocyte (PBL) of patients with liver cancer and their significance. AB - OBJECTIVES: To investigate the expression of transcriptional factors (TFs) T-bet, GATA-3, RORgammat and FOXP in peripheral blood mononuclear cells (PBMC) of patients with hepatocellular carcinoma (HCC) and to evaluate the correlation between the imbalances of Th1/Th2, Th17/Treg at the expression levels and liver cancer Methods: The peripheral venous blood was drawn from 20 HCC-patients (HCC group) and 20 health participants (C-group). The expression levels of Th1, Th2 and Th17 and the major Treg-specific TFs T-bet, GATA-3, RORgammat and FOXP3 in the PBMC were measured with quantitative real-time PCR(RT-qPCR). RESULTS: The mRNA level of Th1-specific TF T-bet in HCC-group was significantly lower than that of C-group (52.34+/-34.07 VS 104.01+/-56.00, P<0.01); the mRNA level of Th2 specifc TF, GATA-3, in HCC group was significantly higher than that in C-group (1.38+/-1.15 VS 0.58+/-0.65, P<0.05) and T-bet mRNA/GATA-3 mRNA ratio was significantly lower in HCC-group than in C-group (86.01+/-116.71 VS 461.88+/ 708.81, P<0.05). The mRNA level of Th17-specific TF RORgammat in HCC-group was significantly higher than that of C-group (72.32+/-32.82 VS 33.07+/-22.86, P<0.01). Treg-specific TF FOXP3 mRNA level was significant higher in HCC-group than in C-group (3.17+/-1.59 VS 1.39+/-1.13, P<0.01) CONCLUSION: T-bet mRNA level was reduced whereas GATA-3 mRNA level was increased and T-bet/GATA-3 ratio was significantly reduced in PBMC, indicating that Th1/Th2 ratio was of imbalance at TF levels in PBMC of HCC, displaying Th2 thrift phenomena. The mRNA levels of RORgammat and FOXP3 in PBMC of HCC were significantly increased, indicating the existence of a predominant phenomenon of Th17- and Treg-expressing PBMC in HCC. PMID- 25552914 TI - Quantitative detection of circulating nucleophosmin mutations DNA in the plasma of patients with acute myeloid leukemia. AB - OBJECTIVE: The aim of this study was to quantify the copies of circulating nucleophosmin (NPM) mutations DNA in the plasma of patients with acute myeloid leukemia (AML) and to explore the association of circulating NPM mutation levels with clinical characteristics. DESIGN AND METHODS: The presence of NPM mutations in 100 Chinese patients newly diagnosed with AML were identified by RT-PCR and sequencing analysis. Copies of circulating NPM mutation A (NPM mut.A) DNA in the plasma of mutation-positive cases were quantified by real-time quantitative PCR (qRT-PCR). Furthermore, the association of circulating NPM mutation levels and clinical characteristics was analyzed. RESULTS: NPM mutations were identified in 37 of the 100 patients and all cases were NPM mut.A. The circulating NPM mut.A levels ranged from 0.35*10(8) copies/ml to 6.0*10(8) copies/ml in the 37 mutation positive cases. The medium and quartile M (P25, P75) of the circulating NPM mut.A levels in patients classified as M2, M4 and M5 morphological subtypes were 1.35*10(8) (0.76*10(8), 1.91*10(8)) copies/ml, 1.81*10(8) (1.47*10(8), 2.2*10(8)) copies/ml and 2.50*10(8) (2.42*10(8), 3.05*10(8)) copies/ml, respectively. Circulating NPM mut.A levels were significantly higher in patients with the M5 subtype of AML compared to patients with the M2 and M4 subtypes (p=0.000, p=0.046). In addition, circulating NPM mut.A copies were significantly associated with a higher white blood cell count, platelet count and bone marrow blast percentage (p<0.05). CONCLUSION: Our results suggest that circulating NPM mutations DNA assay serves as a complementary to the routine investigative protocol of NPM-mutated leukemia. PMID- 25552915 TI - Genome-based proteomic analysis of Lignosus rhinocerotis (Cooke) Ryvarden sclerotium. AB - Lignosus rhinocerotis (Cooke) Ryvarden (Polyporales, Basidiomycota), also known as the tiger milk mushroom, has received much interest in recent years owing to its wide-range ethnobotanical uses and the recent success in its domestication. The sclerotium is the part with medicinal value. Using two-dimensional gel electrophoresis coupled with mass spectrometry analysis, a total of 16 non redundant, major proteins were identified with high confidence level in L. rhinocerotis sclerotium based on its genome as custom mapping database. Some of these proteins, such as the putative lectins, immunomodulatory proteins, superoxide dismutase, and aegerolysin may have pharmaceutical potential; while others are involved in nutrient mobilization and the protective antioxidant mechanism in the sclerotium. The findings from this study provide a molecular basis for future research on potential pharmacologically active proteins of L. rhinocerotis. PMID- 25552916 TI - A microsatellite polymorphism in IGF1 gene promoter and timing of natural menopause in Caucasian women. AB - BACKGROUND: Genes involved in the IGF-1 aging pathways in the human ovary can be considered strong candidates for predictors of the natural menopause timing. This study evaluates the association between a cytosine-adenine (CA) microsatellite polymorphism in the IGF1 gene promoter P1 and age at natural menopause. METHODS: Genomic DNA was extracted from the peripheral blood, PCR was performed using primers designed to amplify the polymorphic (CA) n repeat of the human IGF1 gene, an allele dose effect for the most common (CA)19 repeats allele, Cox proportional hazard regression models and the Kaplan-Meier cumulative survivorship method with the log-rank test were used to determine statistical significance of studied associations in a sample of 257 Polish women aged 40-58 years. RESULTS: Crude Cox proportional hazard regression analysis confirmed the association between the IGF1 gene polymorphism and the menopause timing (p=0.038). This relationship remained statistically significant after controlling for other menopause confounders in multivariate modelling. Out of the input variables, the (CA)n polymorphism in the IGF1 gene promoter, age at menarche and smoking status were independent covariates of the natural menopause timing (chi2=12.845; df=3; p=0.034). The onset of menopause at a younger age was likely associated with the IGF1 genotype variant not carrying the (CA)19 repeats allele, menarche before the age of 12 and a current cigarette smoker status (HR=1.6). CONCLUSION: This study provides evidence that a common cytosine-adenine (CA) microsatellite repeat polymorphism in the P1 promoter region of the IGF1 gene is an independent predictive factor for age at natural menopause in Caucasian women also after adjusting for other menopause covariates. PMID- 25552917 TI - Effect of helixor A on natural killer cell activity in endometriosis. AB - BACKGROUND AND AIM: NK cells are one of the major immune cells in endometriosis pathogenesis. While previous clinical studies have shown that helixor A to be an effective treatment for endometriosis, little is known about its mechanism of action, or its relationship with immune cells. The aim of this study is to investigate the effects of helixor A on Natural killer cell (NK cell) cytotoxicity in endometriosis MATERIALS AND METHODS: We performed an experimental study. Samples of peritoneal fluid were obtained from January 2011 to December 2011 from 50 women with endometriosis and 50 women with other benign ovarian cysts (control). Peritoneal fluid of normal control group and endometriosis group was collected during laparoscopy. Baseline cytotoxicity levels of NK cells were measured with the peritoneal fluid of control group and endometriosis group. Next, cytotoxicity of NK cells was evaluated before and after treatment with helixor A. NK-cell activity was determined based upon the expression of CD107a, as an activation marker. RESULTS: NK cells cytotoxicity was 79.38+/-2.13% in control cells, 75.55+/-2.89% in the control peritoneal fluid, 69.59+/-4.96% in endometriosis stage I/II endometriosis, and 63.88+/-5.75% in stage III/IV endometriosis. A significant difference in cytotoxicity was observed between the control cells and stage III/IV endometriosis, consistent with a significant decrease in the cytotoxicity of NK cells in advanced stages of endometriosis; these levels increased significantly after treatment with helixor A; 78.30% vs. 86.40% (p=0.003) in stage I/II endometriosis, and 73.67% vs. 84.54% (p=0.024) in stage III/IV. The percentage of cells expressing CD107a was increased significantly in each group after helixor A treatment; 0.59% vs. 1.10% (p=0.002) in stage I/II endometriosis, and 0.79% vs. 1.40% (p=0.014) in stage III/IV. CONCLUSIONS: Helixor A directly influenced NK-cell cytotoxicity through direct induction of CD107a expression. Our results open new role of helixor A as an imune modulation therapy, or in combination with hormonal agents, for the treatment of endometriosis. PMID- 25552918 TI - Astrocytes protect neurons from Abeta1-42 peptide-induced neurotoxicity increasing TFAM and PGC-1 and decreasing PPAR-gamma and SIRT-1. AB - One of the earliest neuropathological events in Alzheimer's disease is accumulation of astrocytes at sites of Abeta1-42 depositions. Our results indicate that Abeta1-42 toxic peptide increases lipid peroxidation, apoptosis and cell death in neurons but not in astrocytes in primary culture. Abeta1-42-induced deleterious neuronal effects are not present when neurons and astrocytes are mixed cultured. Stimulation of astrocytes with toxic Abeta1-42 peptide increased p-65 and decreased IkappaB resulting in inflammatory process. In astrocytes Abeta1-42 decreases protein expressions of sirtuin 1 (SIRT-1) and peroxisome proliferator-activated receptor gamma (PPAR-gamma) and over-expresses peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) and mitochondrial transcription factor A (TFAM), protecting mitochondria against Abeta1-42-induced damage and promoting mitochondrial biogenesis. In summary our data suggest that astrocytes may have a key role in protecting neurons, increasing neural viability and mitochondrial biogenesis, acquiring better oxidative stress protection and perhaps modulating inflammatory processes against Abeta1-42 toxic peptide. This might be a sign of a complex epigenetic process in Alzheimer's disease development. PMID- 25552919 TI - The effect of single embryo transfer on perinatal outcomes in Japan. AB - OBJECTIVE: In 2007 and 2008, the Japan Society for Reproductive Medicine and the Japan Society of Obstetrics and Gynecology issued a recommendation for single embryo transfer (SET). Thereafter, SET was implemented in 73% of in vitro fertilization (IVF) cases in Japan. The purpose of this study was to evaluate the effects of compliance with the SET recommendation on perinatal outcomes. METHODS: An electronic audit of the perinatal database of the Japanese Society of Obstetrics and Gynecology was conducted from 2001 through 2010. The database comprised data of 610,726 women. Totally, 20,923 women conceived through IVF. To compare perinatal outcomes, these women were categorized into two study groups depending on whether they conceived before (2004-2005, n=3,865) or after (2009 2010, n=6,842) the SET recommendation statement was issued. RESULTS: The proportion of women who conceived through IVF increased from 1.3% in 2001 to 4.8% in 2010. Compliance with the SET recommendation led to a decrease in the incidence of twin pregnancies (33.9% versus 13%, p<0.01), incidence of preterm delivery (odds ratio [OR]: 0.54, 95% confidence interval [CI]: 0.50-0.59), low birth weight (OR: 0.42, 95% CI: 0.39-0.45), and neonatal intensive care unit admission (OR 0.70, 95% CI 0.65-0.76), but an increase in the incidence of monochorionic twins (1.6% versus 2.5%, p<0.01). CONCLUSION: Compliance with the SET recommendation improved perinatal outcomes by reducing the incidence of twin pregnancies. PMID- 25552920 TI - Berberine inhibits the metastatic ability of prostate cancer cells by suppressing epithelial-to-mesenchymal transition (EMT)-associated genes with predictive and prognostic relevance. AB - BACKGROUND: Over 70% of cancer metastasis from prostate cancer develops bone metastases that are not sensitive to hormonal therapy, radiation therapy, or chemotherapy. The epithelial-to-mesenchymal transition (EMT) genetic program is implicated as a significant contributor to prostate cancer progression. As such, targeting the EMT represents an important therapeutic strategy for preventing or treating prostate cancer metastasis. Berberine is a natural alkaloid with significant antitumor activities against many types of cancer cells. In this study, we investigated the molecular mechanism by which berberine represses the metastatic potential of prostate cancer. METHODS: The effects of berberine on cell migration and invasion were determined by transwell migration assay and Matrigel invasion assay. Expressions of EMT-related genes were determined by an EMT PCR Array and a quantitative RT-PCR. The prognostic relevance of berberine's modulation of EMT-related genes in prostate cancer was evaluated using Kaplan Meier survival analysis. RESULTS: Berberine exerted inhibitory effects on the migratory and invasive abilities of highly metastatic prostate cancer cells. These inhibitory effects of berberine resulted in significant repression of a panel of mesenchymal genes that regulate the developmental EMT. Among EMT-related genes downregulated by berberine, high BMP7, NODAL and Snail gene expressions of metastatic prostate cancer tissues were associated with shorter survival of prostate cancer patients and provide potential therapeutic interventions. CONCLUSIONS: We concluded that berberine should be developed as a pharmacological agent for use in combination with other anticancer drug for treating metastatic prostate cancer. PMID- 25552921 TI - The regenerative medicine in oral and maxillofacial surgery: the most important innovations in the clinical application of mesenchymal stem cells. AB - Regenerative medicine is an emerging field of biotechnology that combines various aspects of medicine, cell and molecular biology, materials science and bioengineering in order to regenerate, repair or replace tissues. The oral surgery and maxillofacial surgery have a role in the treatment of traumatic or degenerative diseases that lead to a tissue loss: frequently, to rehabilitate these minuses, you should use techniques that have been improved over time. Since 1990, we started with the use of growth factors and platelet concentrates in oral and maxillofacial surgery; in the following period we start to use biomaterials, as well as several type of scaffolds and autologous tissues. The frontier of regenerative medicine nowadays is represented by the mesenchymal stem cells (MSCs): overcoming the ethical problems thanks to the use of mesenchymal stem cells from adult patient, and with the increasingly sophisticated technology to support their manipulation, MSCs are undoubtedly the future of medicine regenerative and they are showing perspectives unimaginable just a few years ago. Most recent studies are aimed to tissues regeneration using MSCs taken from sites that are even more accessible and rich in stem cells: the oral cavity turned out to be an important source of MSCs with the advantage to be easily accessible to the surgeon, thus avoiding to increase the morbidity of the patient. The future is the regeneration of whole organs or biological systems consisting of many different tissues, starting from an initial stem cell line, perhaps using innovative scaffolds together with the nano-engineering of biological tissues. PMID- 25552922 TI - Combination analysis in genetic polymorphisms of drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. AB - The Cytochrome P450 is the major enzyme involved in drug metabolism. CYP enzymes are responsible for the metabolism of most clinically used drugs. Individual variability in CYP activity is one important factor that contributes to drug therapy failure. We have developed a new straightforward TaqMan PCR genotyping assay to investigate the prevalence of the most common allelic variants of polymorphic CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. Moreover, we focused on the combination of each genotype for clinical treatment. The genotype analysis identified a total of 139 out of 483 genotype combinations of five genes in the 1,003 Japanese subjects. According to our results, most of subjects seemed to require dose modification during clinical treatment. In the near future, modifications should be considered based on the individual patient genotype of each treatment. PMID- 25552923 TI - Nerve growth factor protects the ischemic heart via attenuation of the endoplasmic reticulum stress induced apoptosis by activation of phosphatidylinositol 3-kinase. AB - BACKGROUND: Increased expression of nerve growth factor (NGF) has been found in the myocardium suffered from ischemia and reperfusion (I/R). The pro-survival activity of NGF on ischemic heart has been supposed to be mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Endoplasmic reticulum (ER) stress, which is activated initially as a defensive response to eliminate the accumulated unfolded proteins, has shown a critical involvement in the ischemia induced myocardial apoptosis. This study was aimed to investigate whether NGF induced heart protection against I/R injury includes a mechanism of attenuation of ER stress-induced myocardial apoptosis by activation of PI3K/Akt pathway. METHODS: Isolated adult rat hearts were perfused with a Langendorff perfusion system. Hearts in the Sham group were subjected to 225 min of continuous Krebs-Henseleit buffer (KHB) perfusion without ischemia. Hearts in I/R group were perfused with KHB for a 75-min of equilibration period followed by 30 min of global ischemia and 120 min of KHB reperfusion. Hearts in the NGF group accepted 45 min of euilibration perfusion and 30 min of NGF pretreatment (with a final concentration of 100 ng/ml in the KHB) before 30 min of global ischemia and 120 min of reperfusion. Hearts in K252a and LY294002 groups were pretreated with either a TrkA inhibitor, K252a or a phosphatidyl inositol 3-kinase inhibitor, LY294002 for 30 min before NGF (100 ng/ml) administration. Cardiac hemodynamics were measured from the beginning of the perfusion. Cardiac enzymes and cardiac troponin I (cTnI) were assayed before ischemia and at the end of reperfusion. Myocardial apoptosis rate was measured by TUNEL staining, and expression of glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, total- and phospho-(Ser473)-Akt were assessed by Western blot analyses. RESULTS: NGF pretreatment significantly improved the recovery of post-ischemia cardiac hemodynamics. Reduced creatine kinase-MB (CK MB), lactate dehydrogenase (LDH) activity and cTnI levels, as well as decreased myocardial apoptosis ratio were observed in the NGF group. The improvement of NGF on recovery of cardiac function and alleviation of myocardial injury were completely abolished by K252a or LY294002. GRP78, caspase-12 and CHOP were highly expressed in ischemic myocardium, while NGF significantly inhibited the overexpression of these proteins which were involved in ER stress-induced myocardial apoptosis. NGF pretreatment also induced phosphorylation of Akt. When the activation of PI3K/Akt pathway is blocked by LY294002, the NGF induced suppression of the apoptosis-related proteins expression was reversed. CONCLUSIONS: NGF pretreatment may protect the ischemic heart via inhibition of the ER stress-induced apoptosis; this pro-survival effect is mediated by PI3K/Akt pathway. PMID- 25552924 TI - Bmi1 drives stem-like properties and is associated with migration, invasion, and poor prognosis in tongue squamous cell carcinoma. AB - Bmi1 (B-cell-specific Moloney murine leukemia virus insertion site 1) had been found to involve in self -renewal of stem cells and tumorigenesis in various malignancies. The purpose of this study is to evaluate the role of Bmi1 in the development of tongue squamous cell carcinoma (TSCC) and its functional effect on the migration and invasion of TSCC. Initially, immunohistochemistry revealed that Bmi1 overexpression was a common event in premalignant dysplasia, primary TSCC, and lymph node metastases and was associated with a poor prognosis. A significant correlation between Bmi1 and SOD2 (manganese superoxide dismutase) expression was observed. Side population (SP) cells were used as cancer stem-like cells and further assessed by sphere and colony formation assays, and the expression of stem cell markers. TSCC cells with higher migration and invasion ability (UM1 cell lines) showed a higher proportion of SP cells and Bmi1 expression than TSCC cells with lower migration and invasion ability (UM2 cell lines). Knockdown of Bmi1 in UM1 or SP cells inhibited migration and invasion and decreased the sphere and colony formation, and the expression of stem cell markers and SOD2. Direct binding of C-myc to the Bmi1 promoter was demonstrated by chromatin immunoprecipitation and luciferase assays. Moreover, C-myc knockdown in SP cells inhibited their migration and invasion and decreased the expression of Bmi1 and SOD2. Our results indicate that the deregulation of Bmi1 expression is a frequent event during the progression of TSCC and may have a prognostic value for patients with this disease. The Bmi1-mediated migration and invasion of TSCC is related to cancer stem-like cells and involves the C-myc-Bmi1-SOD2 pathway. PMID- 25552925 TI - Molecular variation and horizontal gene transfer of the homocysteine methyltransferase gene mmuM and its distribution in clinical pathogens. AB - The homocysteine methyltransferase encoded by mmuM is widely distributed among microbial organisms. It is the key enzyme that catalyzes the last step in methionine biosynthesis and plays an important role in the metabolism process. It also enables the microbial organisms to tolerate high concentrations of selenium in the environment. In this research, 533 mmuM gene sequences covering 70 genera of the bacteria were selected from GenBank database. The distribution frequency of mmuM is different in the investigated genera of bacteria. The mapping results of 160 mmuM reference sequences showed that the mmuM genes were found in 7 species of pathogen genomes sequenced in this work. The polymerase chain reaction products of one mmuM genotype (NC_013951 as the reference) were sequenced and the sequencing results confirmed the mapping results. Furthermore, 144 representative sequences were chosen for phylogenetic analysis and some mmuM genes from totally different genera (such as the genes between Escherichia and Klebsiella and between Enterobacter and Kosakonia) shared closer phylogenetic relationship than those from the same genus. Comparative genomic analysis of the mmuM encoding regions on plasmids and bacterial chromosomes showed that pKF3-140 and pIP1206 plasmids shared a 21 kb homology region and a 4.9 kb fragment in this region was in fact originated from the Escherichia coli chromosome. These results further suggested that mmuM gene did go through the gene horizontal transfer among different species or genera of bacteria. High-throughput sequencing combined with comparative genomics analysis would explore distribution and dissemination of the mmuM gene among bacteria and its evolution at a molecular level. PMID- 25552926 TI - Differential transcriptional response in macrophages infected with cell wall deficient versus normal Mycobacterium Tuberculosis. AB - Host-pathogen interactions determine the outcome following infection by mycobacterium tuberculosis (Mtb). Under adverse circumstances, normal Mtb can form cell-wall deficient (CWD) variants within macrophages, which have been considered an adaptive strategy for facilitating bacterial survival inside macrophages. However, the molecular mechanism by which infection of macrophages with different phenotypic Mtb elicits distinct responses of macrophages is not fully understood. To explore the molecular events triggered upon Mtb infection of macrophages, differential transcriptional responses of RAW264.7 cells infected with two forms of Mtb, CWD-Mtb and normal Mtb, were studied by microarray analysis. Some of the differentially regulated genes were confirmed by RT-qPCR in both RAW264.7 cells and primary macrophages. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was used to analyze functions of differentially expressed genes. Distinct gene expression patterns were observed between CWD-Mtb and normal Mtb group. Mapt was up-regulated, while NOS2 and IL-11 were down-regulated in CWD Mtb infected RAW264.7 cells and primary macrophages compared with normal Mtb infected ones. Many deregulated genes were found to be related to macrophages activation, immune response, phagosome maturation, autophagy and lipid metabolism. KEGG analysis showed that the differentially expressed genes were mainly involved in MAPK signaling pathway, nitrogen metabolism, cytokine-cytokine receptor interaction and focal adhesion. Taken together, the present study showed that differential macrophage responses were induced by intracellular CWD-Mtb an normal Mtb infection, which suggested that interactions between macrophages and different phenotypic Mtb are very complex. The results provide evidence for further understanding of pathogenesis of CWD-Mtb and may help in improving strategies to eliminate intracellular CWD-Mtb. PMID- 25552927 TI - Epithelial cell polarity determinant CRB3 in cancer development. AB - Cell polarity, which is defined as asymmetry in cell shape, organelle distribution and cell function, is essential in numerous biological processes, including cell growth, cell migration and invasion, molecular transport, and cell fate. Epithelial cell polarity is mainly regulated by three conserved polarity protein complexes, the Crumbs (CRB) complex, partitioning defective (PAR) complex and Scribble (SCRIB) complex. Research evidence has indicated that dysregulation of cell polarity proteins may play an important role in cancer development. Crumbs homolog 3 (CRB3), a member of the CRB complex, may act as a cancer suppressor in mouse kidney epithelium and mouse mammary epithelium. In this review, we focus on the current data available on the roles of CRB3 in cancer development. PMID- 25552928 TI - Decrease in plasma cyclophilin A concentration at 1 month after myocardial infarction predicts better left ventricular performance and synchronicity at 6 months: a pilot study in patients with ST elevation myocardial infarction. AB - BACKGROUND: Cyclophilin A (CyPA) concentration increases in acute coronary syndrome. In an animal model of acute myocardial infarction, administration of angiotensin-converting-enzyme inhibitor was associated with lower left ventricular (LV) CyPA concentration and improved LV performance. This study investigated the relationships between changes in plasma CyPA concentrations and LV remodeling in patients with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We enrolled 55 patients who underwent percutaneous coronary intervention for acute STEMI. Plasma CyPA, matrix metalloproteinase (MMP), interleukin-6 and high-sensitivity C-reactive protein concentrations were measured at baseline and at one-month follow-up. Echocardiography was performed at baseline and at one-, three-, and six-month follow-up. Patients with a decrease in baseline CyPA concentration at one-month follow-up (n = 28) had a significant increase in LV ejection fraction (LVEF) (from 60.2 +/- 11.5% to 64.6 +/- 9.9%, p < 0. 001) and preserved LV synchrony at six months. Patients without a decrease in CyPA concentration at one month (n = 27) did not show improvement in LVEF and had a significantly increased systolic dyssynchrony index (SDI) (from 1.170 +/- 0.510% to 1.637 +/- 1.299%, p = 0.042) at six months. Multiple linear regression analysis showed a significant association between one-month CyPA concentration and six-month LVEF. The one-month MMP-2 concentration was positively correlated with one-month CyPA concentration and LV SDI. Conclusions : Decreased CyPA concentration at one-month follow-up after STEMI was associated with better LVEF and SDI at six months. Changes in CyPA, therefore, may be a prognosticator of patient outcome. PMID- 25552929 TI - Decrease of let-7f in low-dose metronomic Paclitaxel chemotherapy contributed to upregulation of thrombospondin-1 in breast cancer. AB - Low-dose metronomic (LDM) paclitaxel therapy displayed a stronger anti-angiogenic activity on breast tumors with fewer side effects. Upregulation of anti angiogenic factor Thrombospondin-1 (TSP-1) accords for therapeutic potency of LDM paclitaxel, but its molecular mechanism has not been elucidated yet. microRNAs (miRNAs) have emerged as new important regulators of tumor growth and metastasis. Here, we hypothesize that miRNAs are involved in TSP-1 overexpression in paclitaxel LDM therapy of breast tumors. The miRNA profile of tumor tissues from control, LDM and MTD groups in 4T1 mouse breast cancer model was detected by microarray, and then verified by quantitative real-time PCR (qRT-PCR). Luciferase assay and western blot were employed to explore the mechanisms of miRNAs involved in this process. We found that let-7f, let-7a, miR-19b and miR-340-5p were reduced by >2 fold, and miR-543* and miR-684 were upregulated by at least 50% in paclitaxel LDM therapy. qRT-PCR verification revealed that let-7f level was reduced most significantly in LDM therapy. Computational prediction using TargetScan and miRanda suggested THBS1 which encodes TSP-1 as a potential target for let-7f. Luciferase activity assay further confirmed that let-7f may bind to 3'UTR of THBS1 gene and inhibit its activity. Moreover, forced expression of let 7f led to a decrease of TSP-1 at both mRNA and protein levels in MCF-7 cells. Contrastly, let-7f inhibition induced an increased expression of THBS1 mRNA and TSP-1 protein, but did not affect the proliferation and apoptosis of MCF-7 cells. Paclitaxel LDM therapy led to a decrease of let-7f and the elevation of TSP-1 protein expression in MCF-7 cells, while overexpression of let-7f may abolish LDM induced the upregulation of TSP-1 in MCF-7 cells. In summary, let-7f inhibition contributed to the upregulation of TSP-1 in paclitaxel LDM therapy, independently of proliferation, cell cycle arrest and apoptosis of breast cancer. This study indicates let-7f as a potential therapeutic target for breast tumor. PMID- 25552930 TI - Coenzyme Q10 protects astrocytes from ROS-induced damage through inhibition of mitochondria-mediated cell death pathway. AB - Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species to protect neuronal cells against oxidative stress in neurodegenerative diseases. The present study was designed to examine whether CoQ10 was capable of protecting astrocytes from reactive oxygen species (ROS) mediated damage. For this purpose, ultraviolet B (UVB) irradiation was used as a tool to induce ROS stress to cultured astrocytes. The cells were treated with 10 and 25 MUg/ml of CoQ10 for 3 or 24 h prior to the cells being exposed to UVB irradiation and maintained for 24 h post UVB exposure. Cell viability was assessed by MTT conversion assay. Mitochondrial respiration was assessed by respirometer. While superoxide production and mitochondrial membrane potential were measured using fluorescent probes, levels of cytochrome C (cyto-c), cleaved caspase-9, and caspase-8 were detected using Western blotting and/or immunocytochemistry. The results showed that UVB irradiation decreased cell viability and this damaging effect was associated with superoxide accumulation, mitochondrial membrane potential hyperpolarization, mitochondrial respiration suppression, cyto-c release, and the activation of both caspase-9 and -8. Treatment with CoQ10 at two different concentrations started 24 h before UVB exposure significantly increased the cell viability. The protective effect of CoQ10 was associated with reduction in superoxide, normalization of mitochondrial membrane potential, improvement of mitochondrial respiration, inhibition of cyto-c release, suppression of caspase 9. Furthermore, CoQ10 enhanced mitochondrial biogenesis. It is concluded that CoQ10 may protect astrocytes through suppression of oxidative stress, prevention of mitochondrial dysfunction, blockade of mitochondria-mediated cell death pathway, and enhancement of mitochondrial biogenesis. PMID- 25552931 TI - Silencing the HaAK gene by transgenic plant-mediated RNAi impairs larval growth of Helicoverpa armigera. AB - Insect pests have caused noticeable economic losses in agriculture, and the heavy use of insecticide to control pests not only brings the threats of insecticide resistance but also causes the great pollution to foods and the environment. Transgenic plants producing double-stranded RNA (dsRNA) directed against insect genes have been is currently developed for protection against insect pests. In this study, we used this technology to silence the arginine kinase (AK) gene of Helicoverpa armigera (HaAK), encoding a phosphotransferase that plays a critical role in cellular energy metabolism in invertebrate. Transgenic Arabidopsis plants producing HaAK dsRNA were generated by Agrobacterium-mediated transformation. The maximal mortality rate of 55% was reached when H. armigera first-instar larvae were fed with transgenic plant leaves for 3 days, which was dramatically higher than the 18% mortality recorded in the control group. Moreover, the ingestion of transgenic plants significantly retarded larval growth, and the transcript levels of HaAK were also knocked down by up to 52%. The feeding bioassays further indicated that the inhibition efficiency was correlated with the integrity and concentration of the produced HaAK dsRNA in transgenic plants. These results strongly show that the resistance to H. armigera was improved in transgenic Arabidopsis plants, suggesting that the RNAi targeting of AK has the potential for the control of insect pests. PMID- 25552932 TI - Ligands binding and molecular simulation: the potential investigation of a biosensor based on an insect odorant binding protein. AB - Based on mimicking biological olfaction, biosensors have been applied for the detection of various ligands in complex environment, which could represent one of the most promising research fields. In this study, the basic characters of one insect odorant binding protein (OBP) as a biosensor were explored. To explore the molecular recognition process, the tertiary structure of the protein was modeled and the protein-ligand interactions with 1,536,550 chemicals were investigated by the molecular docking. The availability of large amount of recombinant SlitOBP1 overcame the difficulty to obtain biological sensing material. After obtained the purified recombinant protein, the result of fluorescence binding assays proved the candidate protein has good affinities with the majority of the tested chemicals. With the aid of simulation docking, the key conserved amino acids within the binding site were identified and then mutated to alanine. After mutation, the protein-ligand binding characteristics were recorded, and the competitive binding assays were carried out to provide experimental verification. The detailed information on its structure and affinities investigated in this study could allow the design of specific mutants with desired characteristics, which provides a solid base for tailoring OBP for biosensor and provides a role model for screening the other elements in olfactory system for different applications. PMID- 25552933 TI - Integrative genomic and transcriptomic characterization of matched primary and metastatic liver and colorectal carcinoma. AB - Metastasis is the main cause of cancer mortality but its process remains poorly understood and thus hampers more effective treatment and improved cancer prognosis. To search for metastasis driver genes responsible for tumor spread, we integrated genomic and transcriptomic profiles of 61 matched primary tumors and distant metastases of liver or colorectal carcinoma isolated by laser-capture microdissection and assayed by array-based technologies. We found that primary tumor lesions and their matched distant metastases were largely similar at the genomic and transcriptomic levels, but substantial differences could be found between primary tumors with or without accompanying metastases. Interestingly, metastasis genes were principally tumor type and organ site-specific. Despite distinct pathway enrichment, different metastasis gene sets shared common prognostic capacity and were predictive of hepatocellular carcinoma survival in an independent cohort. Thus, the metastatic propensity is inherent to the primary tumor and the lack of general metastasis genes necessitates the development of specific treatment modalities. PMID- 25552934 TI - CEP2 attenuates myoblast differentiation but does not affect proliferation. AB - CEP2 (CDC42EP2) is a member of the CDC42 subfamily that belongs to the Rho family. The Rho family plays an important role in a variety of cellular processes including skeletal myogenesis. Here, we find the expression of CEP2 increased significantly during C2C12 myogenesis. Overexpression of CEP2 could attenuate myoblast differentiation, while knockdown of CEP2 by siRNA results in enhancing myogenesis. Furthermore, we demonstrate for the first time that CEP2 attenuates myoblast differentiation via suppression of muscle regulatory factors (MRFs) rather than influencing myoblast proliferation. These results indicate that CEP2 acts as a repressor during myogenesis, which provides new insights into the role of CEP2 in muscle development. PMID- 25552936 TI - Efficient Inference of Gaussian-Process-Modulated Renewal Processes with Application to Medical Event Data. AB - The episodic, irregular and asynchronous nature of medical data render them difficult substrates for standard machine learning algorithms. We would like to abstract away this difficulty for the class of time-stamped categorical variables (or events) by modeling them as a renewal process and inferring a probability density over non-parametric longitudinal intensity functions that modulate the process. Several methods exist for inferring such a density over intensity functions, but either their constraints prevent their use with our potentially bursty event streams, or their time complexity renders their use intractable on our long-duration observations of high-resolution events, or both. In this paper we present a new efficient and flexible inference method that uses direct numeric integration and smooth interpolation over Gaussian processes. We demonstrate that our direct method is up to twice as accurate and two orders of magnitude more efficient than the best existing method (thinning). Importantly, our direct method can infer intensity functions over the full range of bursty to memoryless to regular events, which thinning and many other methods cannot do. Finally, we apply the method to clinical event data and demonstrate a simple example application facilitated by the abstraction. PMID- 25552937 TI - Disruptive technology and medical librarians. PMID- 25552935 TI - MiR-467a is upregulated in radiation-induced mouse thymic lymphomas and regulates apoptosis by targeting Fas and Bax. AB - It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR 467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a upregulated EL4 cells. Then we found that both Fas- and Bax-overexpression decreased cell viability with increase of apoptosis rate, indicating that downregulation of Fas and Bax may be at least partly responsible for apoptosis suppression by miR-467a. These data suggest that miR-467a may have oncogenic functions in radiation-induced thymic lymphoma cells and that its increased expression may confer a growth advantage on tumor cells via aberrant expression of Fas and Bax. PMID- 25552938 TI - Pivoting: leveraging opportunities in a turbulent health care environment. AB - PURPOSE: The purpose of this lecture is to challenge librarians in clinical settings to leverage the opportunities presented by the current health care environment and to develop collaborative relationships with health care practitioners to provide relevant services. DISCUSSION: Health care organizations are under financial and regulatory pressures, and many hospital librarians have been downsized or have had their positions eliminated. The lecture briefly reviews hospital librarians' roles in the past but focuses primarily on our current challenges. This environment requires librarians to be opportunity focused and pivot to a new vision that directs their actions. Many librarians are already doing this, and colleagues are encouraging us to embrace these opportunities. Evidence from publications, websites, discussion lists, personal communications, and the author's experience is explored. CONCLUSION: Developing interdisciplinary and collaborative relationships in our institutions and providing relevant services will mark our progress as vital, contributing members of our health care organizations. PMID- 25552939 TI - Metropolis revisited: the evolving role of librarians in informatics education for the health professions. AB - OBJECTIVE: The authors' goal was to assess changes in the role of librarians in informatics education from 2004 to 2013. This is a follow-up to "Metropolis Redux: The Unique Importance of Library Skills in Informatics," a 2004 survey of informatics programs. METHODS: An electronic survey was conducted in January 2013 and sent to librarians via the MEDLIB-L email discussion list, the library section of the American Association of Colleges of Pharmacy, the Medical Informatics Section of the Medical Library Association, the Information Technology Interest Group of the Association of College and Research Libraries/New England Region, and various library directors across the country. RESULTS: Librarians from fifty-five institutions responded to the survey. Of these respondents, thirty-four included librarians in nonlibrary aspects of informatics training. Fifteen institutions have librarians participating in leadership positions in their informatics programs. Compared to the earlier survey, the role of librarians has evolved. CONCLUSIONS: Librarians possess skills that enable them to participate in informatics programs beyond a narrow library focus. Librarians currently perform significant leadership roles in informatics education. There are opportunities for librarian interdisciplinary collaboration in informatics programs. IMPLICATIONS: Informatics is much more than the study of technology. The information skills that librarians bring to the table enrich and broaden the study of informatics in addition to adding value to the library profession itself. PMID- 25552940 TI - How accurately does the VIVO Harvester reflect actual Clinical and Translational Sciences Award-affiliated faculty member publications? AB - OBJECTIVE: The research tested the accuracy of the VIVO Harvester software in identifying publications authored by faculty members affiliated with a National Institutes of Health Clinical and Translational Sciences Award (CTSA) site. METHODS: Health sciences librarians created "gold standard" lists of references for the years 2001 to 2011 from PubMed for twenty-five randomly selected investigators from one CTSA site. These gold standard lists were compared to the same twenty-five investigators' reference lists produced by VIVO Harvester. The authors subjected the discrepancies between the lists to sensitivity and specificity analyses. RESULTS: The VIVO Harvester correctly identified only about 65% of the total eligible PubMed references for the years 2001-2011 for the CTSA affiliated investigators. The identified references produced by VIVO Harvester were precise yet incomplete. The sensitivity rate was 0.65, and the specificity rate was 1.00. CONCLUSION: While the references produced by VIVO Harvester could be confirmed in PubMed, the VIVO Harvester retrieved only two-thirds of the required references from PubMed. National Institutes of Health CTSA sites will need to supplement VIVO Harvester-produced references with the expert searching skills of health sciences librarians. IMPLICATIONS: Health sciences librarians with searching skills need to alert their CTSA sites about these deficiencies and offer their skills to advance their sites' missions. PMID- 25552941 TI - Building a gold standard to construct search filters: a case study with biomarkers for oral cancer. AB - OBJECTIVE: To support clinical researchers, librarians and informationists may need search filters for particular tasks. Development of filters typically depends on a "gold standard" dataset. This paper describes generalizable methods for creating a gold standard to support future filter development and evaluation using oral squamous cell carcinoma (OSCC) as a case study. OSCC is the most common malignancy affecting the oral cavity. Investigation of biomarkers with potential prognostic utility is an active area of research in OSCC. The methods discussed here should be useful for designing quality search filters in similar domains. METHODS: The authors searched MEDLINE for prognostic studies of OSCC, developed annotation guidelines for screeners, ran three calibration trials before annotating the remaining body of citations, and measured inter-annotator agreement (IAA). RESULTS: We retrieved 1,818 citations. After calibration, we screened the remaining citations (n = 1,767; 97.2%); IAA was substantial (kappa = 0.76). The dataset has 497 (27.3%) citations representing OSCC studies of potential prognostic biomarkers. CONCLUSIONS: The gold standard dataset is likely to be high quality and useful for future development and evaluation of filters for OSCC studies of potential prognostic biomarkers. IMPLICATIONS: The methodology we used is generalizable to other domains requiring a reference standard to evaluate the performance of search filters. A gold standard is essential because the labels regarding relevance enable computation of diagnostic metrics, such as sensitivity and specificity. Librarians and informationists with data analysis skills could contribute to developing gold standard datasets and subsequent filters tuned for their patrons' domains of interest. PMID- 25552942 TI - New Mexico practitioners' access to and satisfaction with online clinical information resources: an interview study using qualitative data analysis software. AB - QUESTIONS: What information resources are available to health care practitioners not affiliated with the University of New Mexico? How satisfied are they with those resources? SETTING: The state is rural and medically underserved. METHODS: The authors interviewed practitioners, using a nine-item guide. Interview transcripts were coded using QSR NVivo 9 software. MAIN RESULTS: Fifty-one practitioners were interviewed. Most use online information resources. Many have access to a point-of-care resource within an electronic health records system. They often expressed dissatisfaction with available patient education resources. CONCLUSION: New Mexico practitioners routinely use electronic information resources but indicate they need better patient information. PMID- 25552944 TI - The data life cycle applied to our own data. AB - Increased demand for data-driven decision making is driving the need for librarians to be facile with the data life cycle. This case study follows the migration of reference desk statistics from handwritten to digital format. This shift presented two opportunities: first, the availability of a nonsensitive data set to improve the librarians' understanding of data-management and statistical analysis skills, and second, the use of analytics to directly inform staffing decisions and departmental strategic goals. By working through each step of the data life cycle, library faculty explored data gathering, storage, sharing, and analysis questions. PMID- 25552943 TI - Community perceptions and utilization of a consumer health center. AB - The purpose of this study was to understand factors that may affect the usage of a consumer health center located in a public library. More specifically, the authors wanted to know what health resources are of interest to the community, what patrons' perceptions of their experience at the center are, and finally, how staff can increase utilization of the center. In general, perceptions of the center were positive. The findings support that participants appreciate efforts to provide health information in the public library setting and that utilization could be improved through marketing and outreach. PMID- 25552945 TI - Combining resources, combining forces: regionalizing hospital library services in a large statewide health system. AB - After a reduction in full-time equivalents, 2 libraries in large teaching hospitals and 2 libraries in small community hospitals in a western US statewide health system saw opportunity for expansion through a regional reorganization. Despite a loss of 2/3 of the professional staff and a budgetary decrease of 27% over the previous 3 years, the libraries were able to grow business, usage, awareness, and collections through organizational innovation and improved efficiency. This paper describes the experience--including process, challenges, and lessons learned--of an organizational shift to regionalized services, collections, and staffing. Insights from this process may help similar organizations going through restructuring. PMID- 25552946 TI - Into the gray: a modified approach to citation analysis to better understand research impact. PMID- 25552947 TI - D'Ou Venons Nous/Que Sommes Nous/Ou Allons Nous(Where Do We Come From? What Are We? Where Are We Going?). PMID- 25552948 TI - Response to "The ethics of scholarly publishing: exploring differences in plagiarism and duplicate publication across nations". PMID- 25552949 TI - Author's reply: To PMID 24860263. PMID- 25552950 TI - Response to "Improving medical education in Kenya: an international collaboration". PMID- 25552951 TI - Proceedings, 114th Annual Meeting Medical Library Association, Inc. Chicago, IL. PMID- 25552952 TI - Speculations about Bystander and Biophotons. AB - Mothersill and many others during the last hundred years have shown that cells and now whole animals may communicate with each other by electromagnetic waves called biophotons. This would explain the source of the bystander phenomena. These ultra-weak photons are coherent, appear to originate and concentrate in DNA of the cell nucleus and rapidly carry large amounts of data to each cell and to the trillions of other cells in the human body. The implications of such a possibility can be wonderfully important. PMID- 25552953 TI - French nuclear power plants and childhood leukemia. PMID- 25552954 TI - Hormesis and trade-offs: a comment. PMID- 25552955 TI - Does the number of irradiated cells influence the spatial distribution of bystander effects? AB - There is growing evidence that the radiation effects at low doses are not adequately described by a simple linear extrapolation from high doses, due, among others, to bystander effects. Though several studies have been published on this topic, the explanation of the mechanisms describing the bystander effects remains unclear. This study aims at understanding how the bystander signals are or can be propagated in the cell culture, namely if the number of irradiated cells influences the bystander response. An A549 cell line was exposed to several doses of alpha-particles, being the bystander response quantified in two non-irradiated areas. The radius of irradiated areas differs by a factor of 2, and the non irradiated areas were optimally designed to have the same number of cells. Our results show evidence for bystander effects occurring in cells far away from the irradiated ones, meaning that bystander signals can easily spread throughout the cell culture. Additionally, our study highlights that the damage caused by radiation on the surrounding of irradiated areas could be different according to the number of irradiated cells, i.e., for the same dose value; the overall cellular damage could be different. PMID- 25552956 TI - Dependence of Dandelion (Taraxacum officinale Wigg.) Seed Reproduction Indices on Intensity of Motor Traffic Pollution. AB - Dandelion (Taraxacum officinale Wigg.) seed reproduction indices such as the total number of seeds, the number of normally developed seeds and underdeveloped seeds per anthodium, and seed weight are suggested to assess the level of environmental pollution (bioindication). However, the non-monotonic dose-response dependences (hormesis and paradoxical effects) of these indices are insufficiently explored upon exposure to pollution. We studied the dependence of some T. officinale seed reproduction indices on intensity of motor traffic pollution in wide range of values over 2 years of observation. In 2010, the increase in traffic intensity induced a monotonic increase in the total seed number and the number of normally developed seeds. Besides, motor traffic pollution decreased the number of undeveloped seeds and seed weight in comparison with the control. In 2011, for all studied T. officinale indices except seed weight, complicated non-monotonic dependences on traffic intensity were found that could be attributed to paradoxical effects. It is hypothesised that the significant differences in the studied dependencies in 2010-2011 were caused by changes in weather conditions because traffic intensity did not differ significantly between the two observation years. PMID- 25552957 TI - Drosophila melanogaster show a threshold effect in response to radiation. AB - We investigate the biological effects of radiation using adult Drosophila melanogaster as a model organism, focusing on gene expression and lifespan analysis to determine the effect of different radiation doses. Our results support a threshold effect in response to radiation: no effect on lifespan and no permanent effect on gene expression is seen at incident radiation levels below 100 J/kg. We also find that it is more appropriate to compare radiation effects in flies using the absorbed energy rather than incident radiation levels. PMID- 25552958 TI - Low concentration of a dioxin (2, 3, 7, 8 TCDD) affects the glycosidases and Acid phosphatase activity in mice hepatocytes. AB - Present communication reports the effects of environmentally available, low doses of tetra chloro di benzo-p-dioxin (2,3,7,8 TCDD) to lysosomal enzymes in mice liver. The study tests the hypothesis, in vivo exposure of low dose TCDD provokes dose and duration dependent toxic effects to key lysosomal enzymes and thereby causes cellular apoptotic changes. Three groups of female Swiss albino mice were subjected to two doses of TCDD (0.004 mg/kg bw/d, 0.04 mg/kg bw/d) for 2, 4 and 6 days of exposure durations. The results indicated significant exposure duration dependent effects of TCDD in mice liver cells. The results suggested that TCDD possibly induced an increase in intracellular ions or ROS which in turn altered different physiological activities by affecting different metabolic pathway of the liver cells. The altered functions of key lysosomal enzymes by TCDD may also evoke the process of cellular apoptosis. PMID- 25552959 TI - Post-conditioning and reperfusion injury in the treatment of stroke. AB - Endogenous mechanisms of protection against ischemia can be demonstrated in brain and other organs. The induction of such protection is via a response to sub lethal stress which induces "preconditioning". The preconditioned organ is then "tolerant" to injury from subsequent severe stress of the same or different etiology. Protection is substantial (70% reduction) but delayed in onset and is transient. Gene expression is unique between brains preconditioned, injured (stroke) or made tolerant. Thus, preconditioning reprograms the response to lethal ischemic stress (stroke), reprogrammed from an injury induction response to a neuroprotective processes. Postconditioning refers to attenuation of injurious processes occurring during reperfusion of ischemic brain. Transient mechanical interruption of reperfusion induces post-conditioning which can attenuate reperfusion injury. Post-conditioning protects ischemic brain by decreasing reperfusion induced oxygen free radical formation. The free radicals produce injury via mitochondrial damage which can be repaired experimentally. Post-conditioning produces neuroprotection as potent as experimental preconditioning. The recognition of broad based gene silencing (suppression of thousands of genes) as the phenotype of the preconditioned, ischemic tolerant brain, may explain failure of all single target drugs for stroke. As risks of reperfusion injury accompany treatment for acute stroke, endogenous neuroprotective and repair mechanisms offer translational stroke therapy. PMID- 25552960 TI - Challenging oneself intermittently to improve health. AB - Humans and their predecessors evolved in environments where they were challenged intermittently with: 1) food scarcity; 2) the need for aerobic fitness to catch/kill prey and avoid or repel attackers; and 3) exposure to biological toxins present in foodstuffs. Accordingly, cells and organ systems acquired and retained molecular signaling and metabolic pathways through which the environmental challenges enhanced the functionality and resilience of the cells and organisms. Within the past 60 years there has been a precipitous diminution of such challenges in modern societies because of the development of technologies that provide a continuous supply of energy-dense processed foods and that largely eliminate the need for physical exertion. As a consequence of the modern 'couch potato' lifestyle, signaling pathways that mediate beneficial effects of environmental challenges on health and disease resistance are disengaged, thereby rendering people vulnerable to obesity, diabetes, cardiovascular disease, cancers and neurodegenerative disorders. Reversal of the epidemic of diseases caused by unchallenging lifestyles will require a society-wide effort to re-introduce intermittent fasting, exercise and consumption of plants containing hormetic phytochemicals into daily and weekly routines. PMID- 25552963 TI - "You Can't Always Get What You Want" - Linearity as the Golden Ratio of Toxicology. AB - Referring to the Golden Ratio (i.e. expressed in the Fibonacci sequence) in nature and art, we conclude that toxicology knows its own Golden Ration, namely linearity. The latter seems imposed on pharmaco-toxicological processes that in fact show far more complexity than simple linearity could hope to elucidate. Understanding physiological and pharmaco-toxicological processes as primarily linear is challenged in this contribution based on very straightforward principles and examples. PMID- 25552962 TI - From ischemic conditioning to 'hyperconditioning': clinical phenomenon and basic science opportunity. AB - Thousands of articles have been published on the topic of ischemic conditioning. Nevertheless, relatively little attention has been given to assessment of conditioning's dose-response characteristics. Specifically, the consequences of multiple conditioning episodes, what we will term "hyperconditioning", have seldom been examined. We propose that hyperconditioning warrants investigation because it; (1) may be of clinical importance, (2) could provide insight into conditioning mechanisms, and (3) might result in development of novel models of human disease. The prevalence of angina pectoris and intermittent claudication is sufficiently high and the potential for daily ischemia-reperfusion episodes sufficiently large that hyperconditioning is a clinically relevant phenomenon. In basic science, attenuation of conditioning-mediated infarct size reduction found in some studies after hyperconditioning offers a possible means to facilitate further discernment of cardioprotective signaling pathways. Moreover, hyperconditioning's impact extends beyond cytoprotection to tissue structural elements. Several studies demonstrate that hyperconditioning produces collagen injury (primarily fiber breakage). Such structural impairment could have adverse clinical consequences; however, in laboratory studies, selective collagen damage could provide the basis for models of cardiac rupture and dilated cardiomyopathy. Accordingly, we propose that hyperconditioning represents the dark, but potentially illuminating, side of ischemic conditioning - a paradigm that merits attention and prospective evaluation. PMID- 25552961 TI - Pre-conditioning with low-level laser (light) therapy: light before the storm. AB - Pre-conditioning by ischemia, hyperthermia, hypothermia, hyperbaric oxygen (and numerous other modalities) is a rapidly growing area of investigation that is used in pathological conditions where tissue damage may be expected. The damage caused by surgery, heart attack, or stroke can be mitigated by pre-treating the local or distant tissue with low levels of a stress-inducing stimulus, that can induce a protective response against subsequent major damage. Low-level laser (light) therapy (LLLT) has been used for nearly 50 years to enhance tissue healing and to relieve pain, inflammation and swelling. The photons are absorbed in cytochrome(c) oxidase (unit four in the mitochondrial respiratory chain), and this enzyme activation increases electron transport, respiration, oxygen consumption and ATP production. A complex signaling cascade is initiated leading to activation of transcription factors and up- and down-regulation of numerous genes. Recently it has become apparent that LLLT can also be effective if delivered to normal cells or tissue before the actual insult or trauma, in a pre conditioning mode. Muscles are protected, nerves feel less pain, and LLLT can protect against a subsequent heart attack. These examples point the way to wider use of LLLT as a pre-conditioning modality to prevent pain and increase healing after surgical/medical procedures and possibly to increase athletic performance. PMID- 25552964 TI - Crystal structures of 2-meth-oxy-isoindoline-1,3-dione, 1,3-dioxoisoindolin-2-yl methyl carbonate and 1,3-dioxo-2,3-di-hydro-1H-benzo[de]isoquinolin-2-yl methyl carbonate: three anti-convulsant compounds. AB - The title compounds, C9H7NO3, (1), C10H7NO5, (2), and C14H9NO5, (3), are three potentially anti-convulsant compounds. Compounds (1) and (2) are isoindoline derivatives and (3) is an iso-quinoline derivative. Compounds (2) and (3) crystallize with two independent mol-ecules (A and B) in their asymmetric units. In all three cases, the isoindoline and benzoiso-quinoline moieties are planar [r.m.s. deviations are 0.021 A for (1), 0.04 and 0.018 A for (2), and 0.033 and 0.041 A for (3)]. The substituents attached to the N atom are almost perpendicular to the mean planes of the heterocycles, with dihedral angles of 89.7 (3) degrees for the N-O-Cmeth-yl group in (1), 71.01 (4) and 80.00 (4) degrees for the N-O-C(=O)O-Cmeth-yl groups in (2), and 75.62 (14) and 74.13 (4) degrees for the same groups in (3). In the crystal of (1), there are unusual inter-molecular C=O?C contacts of 2.794 (1) and 2.873 (1) A present in mol-ecules A and B, respectively. There are also C-H?O hydrogen bonds and pi-pi inter actions [inter-centroid distance = 3.407 (3) A] present, forming slabs lying parallel to (001). In the crystal of (2), the A and B mol-ecules are linked by C H?O hydrogen bonds, forming slabs parallel to (10-1), which are in turn linked via a number of pi-pi inter-actions [the most significant centroid-centroid distances are 3.4202 (7) and 3.5445 (7) A], forming a three-dimensional structure. In the crystal of (3), the A and B mol-ecules are linked via C-H?O hydrogen bonds, forming a three-dimensional structure, which is consolidated by pi-pi inter-actions [the most significant inter-centroid distances are 3.575 (3) and 3.578 (3) A]. PMID- 25552965 TI - Definitive crystal structure of 1,1'-bis-[1,2-dicarba-closo-dodeca-borane(11)]. AB - In the title compound, C4H22B20, the two {1,2-closo-C2B10H11} cages are linked across a centre of inversion with a C-C distance of 1.5339 (11) A. By careful analysis of the structure, it is established that the non-linking cage C atom is equally disordered over cage vertices 2 and 3. PMID- 25552966 TI - Crystal structure of 2-(2,4-di-chloro-phen-yl)-4-hydroxy-9-phenyl-sulfonyl-9H carbazole-3-carbaldehyde. AB - In the title compound, C25H15Cl2NO4S, the di-chloro-phenyl ring is twisted by 68.69 (11) degrees from the mean plane of the carbazole ring system [r.m.s. deviation = 0.084 (2) degrees ]. The hy-droxy group is involved in an intra molecular O-H?O hydrogen bond, which generates an S(6) graph-set motif. In the crystal, pairs of C-H?Cl hydrogen bonds link mol-ecules into inversion dimers with an R (2) 2(26) motif. Weak C-H?O inter-actions further link these dimers into ribbons propagating in [100]. PMID- 25552967 TI - Crystal structure of the ternary silicide Gd2Re3Si5. AB - A single crystal of the title compound, the ternary silicide digadolinium trirhenium penta-silicide, Gd2Re3Si5, was isolated from an alloy of nominal composition Gd20Re30Si50 synthesized by arc melting and investigated by X-ray single-crystal diffraction. Its crystal structure belongs to the U2Mn3Si5 structure type. All atoms in the asymmetric lie on special positions. The Gd site has site symmetry m..; the two Mn atoms have site symmetries m.. and 2.22; the three Si atoms have site symmetries m.., ..2 and 4.. . The coordination polyhedra of the Gd atoms have 21 vertices, while those of the Re atoms are cubo-octa-hedra and 13-vertex polyhedra. The Si atoms are arranged as tricapped trigonal prisms, bicapped square anti-prisms, or 11-vertex polyhedra. The crystal structure of the title compound is also related to the structure types CaBe2Ge2 and W5Si3. It can be represented as a stacking of Gd-centred polyhedra of composition [GdSi9]. The Re atoms form infinite chains with an Re-Re distance of 2.78163 (5) A and isolated squares with an Re-Re distance of 2.9683 (6) A. PMID- 25552968 TI - Crystal structure of bis-(propane-1,3-diaminium) hexa-fluorido-aluminate di-aqua tetra-fluorido-aluminate tetra-hydrate. AB - The title compound, (C3H12N2)2[AlF6][AlF4(H2O)2].4H2O, was obtained by a solvothermal method in ethanol as solvent and with aluminium hydroxide, HF and 1,3-di-amino-propane as educts. The asymmetric unit contains a quarter each of two crystallographically independent propane-1,3-di-ammonium dicat-ions, [AlF6](3 ) and [AlF4(H2O)2](-) anions and four water mol-ecules. The cations, anions and three of the independent water mol-ecules are situated on special positions mm, while the fourth water mol-ecule is disordered about a mirror plane. In the crystal, inter-molecular N-H?F and O-H?F hydrogen bonds link the cations and anions into a three-dimensional framework with the voids filled by water mol ecules, which generate O-H?O hydrogen bonds and further consolidate the packing. PMID- 25552969 TI - Crystal structure of tin(II) perchlorate trihydrate. AB - The title compound, [Sn(H2O)3](ClO4)2, was synthesized by the redox reaction of copper(II) perchlorate hexa-hydrate and metallic tin in perchloric acid. Both the trigonal-pyramidal [Sn(H2O)3](2+) cations and tetra-hedral perchlorate anions lie on crystallographic threefold axes. In the crystal, the cations are linked to the anions by O-H?O hydrogen bonds, generating (001) sheets. PMID- 25552971 TI - Crystal structure of tin(IV) chloride octa-hydrate. AB - The title compound, [SnCl4(H2O)2].6H2O, was crystallized according to the solid liquid phase diagram at lower temperatures. It is built-up of SnCl4(H2O)2 octa hedral units (point group symmetry 2) and lattice water mol-ecules. An intricate three-dimensional network of O-H?O and O-H?Cl hydrogen bonds between the complex molecules and the lattice water molecules is formed in the crystal structure. PMID- 25552970 TI - Crystal structure of iron(III) perchlorate nona-hydrate. AB - Since the discovery of perchlorate salts on Mars and the known occurrence of ferric salts in the regolith, there is a distinct possibility that the title compound could form on the surface of Mars. [Fe(H2O)6](ClO4)3.3H2O was crystallized from aqueous solutions at low temperatures according to the solid liquid phase diagram. It consists of Fe(H2O)6 octa-hedra (point group symmetry 3.) and perchlorate anions (point group symmetry .2) as well as non-coordinating water mol-ecules, as part of a second hydrogen-bonded coordination sphere around the cation. The perchlorate appears to be slightly disordered, with major-minor component occupancies of 0.773 (9):0.227 (9). PMID- 25552972 TI - Crystal structure of hexa-kis-(MU2-4-tert-but-oxy-4-oxobut-2-en-2-olato)trizinc. AB - The title complex, systematic name hexa-kis-(MU2-4-tert-but-oxy-4-oxobut-2-en-2 olato)-1:2kappa(9) O (2),O (4):O (2);2:3kappa(9) O (2),O (4):O (2)-trizinc, [Zn3(C8H13O3)6], syn-the-sized from tert-butyl aceto-acetate and di-ethyl-zinc, consists of trinuclear centrosymmetric mol-ecules of an approximate C 3i symmetry. The three metal cations are arranged in a linear fashion, with the central Zn(II) atom located on a centre of symmetry. All three metal cations exhibit a distorted octa-hedral coordination geometry. The terminal Zn(II) cations are chelated by three tert-butyl aceto-acetate ligands and these units are connected to the central Zn(II) atom by the bridging enolate O atoms. PMID- 25552973 TI - Unexpected formation and crystal structure of tetra-kis-(1H-pyrazole-kappaN (2)) palladium(II) dichloride. AB - The title salt, [Pd(C3H4N2)4]Cl2, was obtained unexpectedly by the reaction of palladium(II) dichloride with equimolar amounts of 1-chloro-1-nitro-2,2,2-tris (pyrazol-yl)ethane in methanol solution. The Pd(2+) cation is located on an inversion centre and has a square-planar coordination sphere defined by four N atoms of four neutral pyrazole ligands. The average Pd-N distance is 2.000 (2) A. The two chloride anions are not coordinating to Pd(2+). They are connected to the complex cations through N-H?Cl hydrogen bonds. In addition, C-H?Cl hydrogen bonds are observed, leading to a three-dimensional linkage of cations and anions. PMID- 25552974 TI - Crystal structures of Ca(ClO4)2.4H2O and Ca(ClO4)2.6H2O. AB - The title compounds, calcium perchlorate tetra-hydrate and calcium perchlorate hexa-hydrate, were crystallized at low temperatures according to the solid-liquid phase diagram. The structure of the tetra-hydrate consists of one Ca(2+) cation eightfold coordinated in a square-anti-prismatic fashion by four water mol-ecules and four O atoms of four perchlorate tetra-hedra, forming chains parallel to [01 1] by sharing corners of the ClO4 tetra-hedra. The structure of the hexa-hydrate contains two different Ca(2+) cations, each coordinated by six water mol-ecules and two O atoms of two perchlorate tetra-hedra, forming [Ca(H2O)6(ClO4)]2 dimers by sharing two ClO4 tetra-hedra. The dimers are arranged in sheets parallel (001) and alternate with layers of non-coordinating ClO4 tetra-hedra. O-H?O hydrogen bonds between the water mol-ecules as donor and ClO4 tetra-hedra and water mol ecules as acceptor groups lead to the formation of a three-dimensional network in the two structures. Ca(ClO4)2.6H2O was refined as a two-component inversion twin, with an approximate twin component ratio of 1:1 in each of the two structures. PMID- 25552975 TI - Crystal structure of di-MU-chloro-acetato-hexa-kis-(di-methyl-formamide)-tetra kis-(MU-N,2-dioxido-benzene-1-carboximidato)tetra-manganese(III)disodium dimethyl formamide disolvate. AB - The synthesis, crystal structure, and FT-IR data for the title compound, [Na2Mn4(C2H2ClO2)2(C7H4NO3)4(C3H7NO)6].2C3H7NO or Na2(O2CCH2Cl)2[12-MCMn(III) N(shi)-4](DMF)6.2DMF, where MC is metallacrown, shi(3-) is salicyl-hydroximate, and DMF is N,N-di-methyl-formamide, is reported. The macrocyclic metallacrown consists of an -[Mn(III)-N-O]4- ring repeat unit and the metallacrown captures two Na(+) ions in the central cavity above and below the plane of the metallacrown. Each Na(+) ion is seven-coordinate and is bridged to two ring Mn(III) ions, through either a coordinating DMF mol-ecule or a chloro-acetate anion. The ring Mn(III) ions have either a tetra-gonally distorted octa-hedral geometry or a distorted square-pyramidal geometry. Weak C-H?O inter-actions, in addition to pure van der Waals forces, contribute to the overall packing of the mol-ecules. The complete molecule has inversion symmetry and is disordered over two sets of sites with an occupancy ratio of 0.8783 (7):0.1217 (7). The solvent molecule is also disordered over two sets of sites, with an occupancy ratio of 0.615 (5):0.385 (5). PMID- 25552976 TI - Crystal structure of (E)-4-{2-[4-(all-yloxy)phen-yl]diazen-yl}benzoic acid. AB - The title compound, C16H14N2O3, has an E conformation about the azo-benzene [-N=N = 1.2481 (16) A] linkage. The benzene rings are almost coplanar [dihedral angle = 1.36 (7) degrees ]. The O atoms of the carb-oxy-lic acid group are disordered over two sets of sites and were refined with an occupancy ratio of 0.5:0.5. The two disordered components of the carb-oxy-lic acid group make dihedral angles of 1.5 (14) and 3.8 (12) degrees with the benzene ring to which they are attached. In the crystal, mol-ecules are linked via pairs of O-H?O hydrogen bonds, forming inversion dimers. The dimers are connected via C-H?O hydrogen bonds, forming ribbons lying parallel to [120]. These ribbons are linked via C-H?pi inter actions, forming slabs parallel to (001). PMID- 25552977 TI - Crystal structure of a Cu(II) complex with a bridging ligand: poly[[penta-kis [MU2-1,1'-(butane-1,4-di-yl)bis-(1H-imidazole)-kappa(2) N (3):N (3')]dicopper(II)] tetranitrate tetra-hydrate]. AB - A novel two-dimensional->three-dimensional Cu(II) coordination polymer, {[Cu2(C10H14N4)5](NO3)4.4H2O} n , based on the 1,1'-(butane-1,4-di-yl)bis-(1H imidazole) (biim) ligand and containing one crystallographically unique Cu(II) atom, has been synthesized under hydro-thermal conditions. The Cu(II) atom is coordinated by five N atoms from biim ligands, one of which has crystallographically imposed inversion symmetry, giving rise to a slightly distorted CuN5 square-pyramidal geometry. The Cu(II) cations are linked by biim ligands to give a 4(4) layer; the layers are further bridged by biim ligands, generating a double sheet with a thickness of 14.61 A. The sheet features rhombic Cu4(biim)4 windows built up from four Cu(II) centers and four biim ligands with dimensions of 14.11 * 14.07 A(2). Each window of a layer is penetrated directly by the biim ligand of the adjacent net, giving a two-dimensional->three dimensional entangled framework. PMID- 25552978 TI - Crystal structure of a one-dimensional helical-type silver(I) coordination polymer: catena-poly[[silver(I)-MU-N-(pyridin-4-ylmeth-yl)pyridine-3-amine kappa(2) N:N'] nitrate dimethyl sulfoxide disolvate]. AB - The asymmetric unit of the title compound, {[Ag(C11H11N3)]NO3.2(CH3)2SO} n , comprises one Ag(I) atom, one N-(pyridine-4-ylmeth-yl)pyridine-3-amine ligand, one nitrate anion and two dimethyl sulfoxide mol-ecules. The Ag(I) atoms are bridged by two pyridine N atoms from two symmetry-related ligands, forming a helical chain and adopting a slightly distorted linear coordination geometry [N Ag-N = 175.37 (8) degrees ]. The helical chain, with a pitch length of 16.7871 (8) A, propagates along the b-axis direction. In the crystal, symmetry-related right- and left-handed helical chains are alternately arranged via Ag?Ag inter actions [3.4145 (4) A] and pi-pi stacking inter-actions [centroid-centroid distance = 3.650 (2) A], resulting in the formation of a two-dimensional supra molecular network extending parallel to (100). Weak Ag?O [2.775 (2), 3.169 (4) and 2.690 (2) A] inter-actions, as well as several N-H?O and C-H?O hydrogen bonding inter-actions, contribute to the stabilization of the crystal structure. Parts of the dimethyl sulfoxide solvent molecule are disordered over two sets of sites in a 0.937 (3):0.063 (3) ratio. PMID- 25552979 TI - Crystal structures of Sr(ClO4)2.3H2O, Sr(ClO4)2.4H2O and Sr(ClO4)2.9H2O. AB - The title compounds, strontium perchlorate trihydrate {di-MU-aqua-aquadi-MU perchlorato-strontium, [Sr(ClO4)2(H2O)3] n }, strontium perchlorate tetra-hydrate {di-MU-aqua-bis-(tri-aqua-diperchloratostrontium), [Sr2(ClO4)4(H2O)8]} and strontium perchlorate nona-hydrate {hepta-aqua-diperchloratostrontium dihydrate, [Sr(ClO4)2(H2O)7].2H2O}, were crystallized at low temperatures according to the solid-liquid phase diagram. The structures of the tri- and tetra-hydrate consist of Sr(2+) cations coordinated by five water mol-ecules and four O atoms of four perchlorate tetra-hedra in a distorted tricapped trigonal-prismatic coordination mode. The asymmetric unit of the trihydrate contains two formula units. Two [SrO9] polyhedra in the trihydrate are connected by sharing water mol-ecules and thus forming chains parallel to [100]. In the tetra-hydrate, dimers of two [SrO9] polyhedra connected by two sharing water mol-ecules are formed. The structure of the nona-hydrate contains one Sr(2+) cation coordinated by seven water mol-ecules and by two O atoms of two perchlorate tetra-hedra (point group symmetry ..m), forming a tricapped trigonal prism (point group symmetry m2m). The structure contains additional non-coordinating water mol-ecules, which are located on twofold rotation axes. O-H?O hydrogen bonds between the water mol-ecules as donor and ClO4 tetra-hedra and water mol-ecules as acceptor groups lead to the formation of a three-dimensional network in each of the three structures. PMID- 25552980 TI - Crystal structures of ZnCl2.2.5H2O, ZnCl2.3H2O and ZnCl2.4.5H2O. AB - The formation of different complexes in aqueous solutions is an important step in understanding the behavior of zinc chloride in water. The structure of concentrated ZnCl2 solutions is governed by coordination competition of Cl(-) and H2O around Zn(2+). According to the solid-liquid phase diagram, the title compounds were crystallized below room temperature. The structure of ZnCl2.2.5H2O contains Zn(2+) both in a tetra-hedral coordination with Cl(-) and in an octa hedral environment defined by five water mol-ecules and one Cl(-) shared with the [ZnCl4](2-) unit. Thus, these two different types of Zn(2+) cations form isolated units with composition [Zn2Cl4(H2O)5] (penta-aqua-MU-chlorido-tri-chlorido-di zinc). The trihydrate {hexa-aqua-zinc tetra-chlorido-zinc, [Zn(H2O)6][ZnCl4]}, consists of three different Zn(2+) cations, one of which is tetra-hedrally coordinated by four Cl(-) anions. The two other Zn(2+) cations are each located on an inversion centre and are octa-hedrally surrounded by water mol-ecules. The [ZnCl4] tetra-hedra and [Zn(H2O)6] octa-hedra are arranged in alternating rows parallel to [001]. The structure of the 4.5-hydrate {hexa-aqua-zinc tetra chlorido-zinc trihydrate, [Zn(H2O)6][ZnCl4].3H2O}, consists of isolated octa hedral [Zn(H2O)6] and tetra-hedral [ZnCl4] units, as well as additional lattice water mol-ecules. O-H?O hydrogen bonds between the water mol-ecules as donor and ZnCl4 tetra-hedra and water mol-ecules as acceptor groups leads to the formation of a three-dimensional network in each of the three structures. PMID- 25552981 TI - Crystal structure of bis-(2,2':6',2''-terpyridine-kappa(3) N,N',N'')nickel(II) dicyanidoaurate(I). AB - The title compound, [Ni(C15H11N3)2][Au(CN)2]2, is an ionic compound composed of bis-(2,2':6',2''-terpyridine)-nickel(II) dications and dicyanidoaurate(I) anions in a 1:2 ratio. The two tridentate terpyridine ligands define the coordination of the Ni(2+) cation, resulting in a nearly octa-hedral coordination sphere, although there is not any imposed crystallographic symmetry about the Ni(2+) site. The two nearly linear dicyanidoaurate(I) anions [C-Au-C = 179.0 (2) and 178.2 (2) degrees ] contain a short aurophilic inter-action of 3.1017 (3) A. The structure does not demonstrate any pi-pi stacking. Non-classical C-H?N inter actions between the cations and anions build up a three-dimensional network. PMID- 25552982 TI - Crystal structure of (3,5-di-chloro-2-hy-droxy-phen-yl){1-[(naphthalen-1 yl)carbon-yl]-1H-pyrazol-4-yl}methanone. AB - The title compound, C21H12Cl2N2O3, is a 1,4-diaroyl pyrazole derivative and has three aromatic rings. The dihedral angles between the naphthalene ring system and the pyrazole ring, the pyrazole and phenyl rings and the naphthalene ring system and the phenyl ring are 49.44 (13), 49.87 (16) and 0.58 (11) degrees , respectively. The phenolic proton forms an intra-molecular O-H?O hydrogen bond with an adjacent carbonyl O atom. In the crystal, the mol-ecules are linked through stacking inter-actions between the pyrazole rings [centroid-centroid distances = 3.546 (3)] and between the naphthalene ring system and the phenyl ring [centroid-centroid distances = 3.609 (4) A] along the a-axis direction. The mol-ecules are further connected through C-H?O hydrogen bonds, forming inversion dimers. PMID- 25552983 TI - Crystal structure of 2-benzyl-amino-4-(4-meth-oxy-phen-yl)-6,7,8,9-tetra-hydro-5H cyclo-hepta-[b]pyridine-3-carbo-nitrile. AB - The title compound, C25H25N3O, comprises a 2-amino-pyridine ring fused with a cyclo-heptane ring, which adopts a chair conformation. The central pyridine ring (r.m.s. deviation = 0.013 A) carries three substituents, viz. a benzyl-amino group, a meth-oxy-phenyl ring and a carbo-nitrile group. The N atom of the carbo nitrile group is significantly displaced [by 0.2247 (1) A] from the plane of the pyridine ring, probably due to steric crowding involving the adjacent substituents. The phenyl and benzene rings are inclined to one another by 58.91 (7) degrees and to the pyridine ring by 76.68 (7) and 49.80 (6) degrees , respectively. In the crystal, inversion dimers linked by pairs of N-H?Nnitrile hydrogen bonds generate R 2 (2)(14) loops. The dimers are linked by C-H?pi and slipped parallel pi-pi inter-actions [centroid-centroid distance = 3.6532 (3) A] into a three-dimensional structure. PMID- 25552984 TI - Two-dimensional hydrogen-bonded polymers in the crystal structures of the ammonium salts of phen-oxy-acetic acid, (4-fluoro-phen-oxy)acetic acid and (4 chloro-2-methyl-phen-oxy)acetic acid. AB - The structures of the ammonium salts of phen-oxy-acetic acid, NH4 (+).C8H6O3 (-), (I), (4-fluoro-phen-oxy)acetic acid, NH4 (+).C8H5FO3 (-), (II), and the herbicidally active (4-chloro-2-methyl-phen-oxy)acetic acid (MCPA), NH4 (+).C9H8ClO3 (-).0.5H2O, (III) have been determined. All have two-dimensional layered structures based on inter-species ammonium N-H?O hydrogen-bonding associations, which give core substructures consisting primarily of conjoined cyclic motifs. The crystals of (I) and (II) are isomorphous with the core comprising R 1 (2)(5), R 1 (2)(4) and centrosymmetric R 4 (2)(8) ring motifs, giving two-dimensional layers lying parallel to (100). In (III), the water mol ecule of solvation lies on a crystallographic twofold rotation axis and bridges two carboxyl O atoms in an R 4 (4)(12) hydrogen-bonded motif, creating two R 4 (3)(10) rings, which together with a conjoined centrosymmetric R 4 (2)(8) ring incorporating both ammonium cations, generate two-dimensional layers lying parallel to (100). No pi-pi ring associations are present in any of the structures. PMID- 25552985 TI - Crystal structure of tricarbon-yl(N-di-phenyl-phosphanyl-N,N'-diisopropyl-P phenyl-phospho-nous di-amide-kappa(2) P,P')cobalt(I) tetra-carbonyl-cobaltate(-I) toluene 0.25-solvate. AB - The asymmetric unit of the title compound, [Co(C24H30N2P2)(CO)3][Co(CO)4].0.25C7H8, consists of two crystallographically independent cations with similar conformations, two anions, and one-half of a toluene mol-ecule disordered about an inversion centre. In the cations, a Co/P/N/P four-membered slightly bent metallacycle is the key structural element. The pendant NH group is not coordinated to the Co(I) atom, which displays a distorted trigonal-bipyramidal coordination geometry. Weak inter-ionic hydrogen bonds are observed between the NH groups and a carbonyl group of the tetrahedral [Co(CO)4](-) anions. PMID- 25552986 TI - Crystal structures of bis-[2-(di-phenyl-phosphino-thio-yl)phen-yl] ether and bis {2-[diphen-yl(selanyl-idene)phosphan-yl]phen-yl} ether. AB - The title compounds, C36H28OP2S2, (1), and C36H28OP2Se2, (2), exhibit remarkably similar structures although they are not isomorphous. The whole mol-ecule of compound (2) is generated by twofold symmetry, with the ether O atom located on the twofold axis. Both compounds have intra-molecular pi-pi inter-actions between terminal phenyl rings with centroid-centroid distances of 3.6214 (16) and 3.8027 (14) A in (1) and (2), respectively. In the crystal of (1), short C-H?S hydrogen bonds link the mol-ecules, forming chains along [001], while in (2) there are no analogous C-H?Se inter-actions present. PMID- 25552987 TI - Crystal structure of ethyl (6-hy-droxy-1-benzo-furan-3-yl)acetate sesquihydrate. AB - In the title hydrate, C12H12O4.1.5H2O, one of the water mol-ecules in the asymmetric unit is located on a twofold rotation axis. The mol-ecule of the benzo furan derivative is essentially planar (r.m.s. deviation for the non-H atoms = 0.021 A), with the ester group adopting a fully extended conformation. In the crystal, O-H?O hydrogen bonds between the water mol-ecules and the hy-droxy groups generate a centrosymmetric R 6 (6)(12) ring motif. These R 6 (6)(12) rings are fused, forming a one-dimensional motif extending along the c-axis direction. PMID- 25552988 TI - Crystal structure of tetra-aqua-(5,5'-dimethyl-2,2'-bipyridyl-kappa(2) N,N')iron(II) sulfate. AB - In the title compound, [Fe(C12H12N2)(H2O)4]SO4, the central Fe(II) ion is coordinated by two N atoms from the 5,5'-dimethyl-2,2'-bi-pyridine ligand and four water O atoms in a distorted octa-hedral geometry. The Fe-O coordination bond lengths vary from 2.080 (3) to 2.110 (3) A, while the two Fe-N coordination bonds have practically identical lengths [2.175 (3) and 2.177 (3) A]. The chelating N-Fe-N angle of 75.6 (1) degrees shows the largest deviation from an ideal octa-hedral geometry; the other coordination angles deviate from ideal values by 0.1 (1) to 9.1 (1) degrees . O-H?O hydrogen bonding between the four aqua ligands of the cationic complex and four O-atom acceptors of the anion leads to the formation of layers parallel to the ab plane. Neighbouring layers further inter-act by means of C-H?O and pi-pi inter-actions involving the laterally positioned bi-pyridine rings. The perpen-dicular distance between pi-pi inter acting rings is 3.365 (2) A, with a centroid-centroid distance of 3.702 (3) A. PMID- 25552989 TI - Crystal structure of di-MU-iodido-bis-[(dimethyl sulfoxide-kappaO)(tri-phenyl phosphane-kappaP)copper(I)]. AB - The centrosymmetric dinuclear title compound, [Cu2I2(C2H6OS)2(C18H15P)2], represents the first example of a CuI complex ligated by an O-bound dimethyl sulfoxide ligand. In the crystal, the two tetrahedrally coordinated Cu(I) atoms are bridged by two MU2-iodido ligands in an almost symmetrical rhomboid geometry. The loose Cu?Cu contact of 2.9874 (8) A is longer than the sum of the van der Waals radii of two Cu atoms (2.8 A), excluding a significant cupriophilic inter action in the actual dimer. C-H?O and C-H?I hydrogen bonding interactions as well as C-H?pi(aryl) interactions stabilize the three-dimensional supramolecular network. PMID- 25552990 TI - Crystal structure of (1S,2R,6R,7R,8S,12S)-4,10,17-triphenyl-15-thia-4,10-diaza penta-cyclo[5.5.5.0(1,16).0(2,6).0(8,12)]hepta-deca-13,16-diene-3,5,9,11-tetrone p-xylene hemisolvate. AB - The title tetrone compound, C32H22N2O4S. 0.5C8H10, is the major product (50% yield) of an attempted Diels-Alder reaction of 2-(alpha-styr-yl)thio-phene with N phenyl-male-imide (2 equivalents) in toluene. Recrystallization of the resulting powder from p-xylene gave the title hemisolvate; the p-xylene mol-ecule is located about an inversion center. In the crystal, the primary tetrone contacts are between a carbonyl O atom and the four flagpole H atoms of the bi-cyclo [2.2.2]octene core, forming chains along [001]. PMID- 25552991 TI - About the polymorphism of [Li(C4H8O)3]I: crystal structures of trigonal and tetra gonal polymorphs. AB - Two new trigonal and tetra-gonal polymorphs of the title compound, iodido-tris (tetra-hydro-furan-kappaO)lithium, are presented, which both include the isolated ion pair Li(THF)3 (+).I(-). One Li-I ion contact and three tetra-hydro-furan (THF) mol-ecules complete the tetra-hedral coordination of the lithium cation. The three-dimensional arrangement in the two polymorphs differs notably. In the trigonal structure, the ion pair is located on a threefold rotation axis of space group P-3 and only one THF mol-ecule is present in the asymmetric unit. In the crystal, strands of ion pairs parallel to [001] are observed with an eclipsed conformation of the THF mol-ecules relative to the Li?I axis of two adjacent ion pairs. In contrast, the tetra-gonal polymorph shows a much larger unit cell in which all atoms are located on general positions of the space group I41 cd. The resulting three-dimensional arrangement shows helical chains of ion pairs parallel to [001]. Apart from van der Waals contacts, no remarkable inter molecular forces are present between the isolated ion pairs in both structures. PMID- 25552992 TI - Crystal structure of piperidinium 4-nitro-phenolate. AB - In the title mol-ecular salt, C5H12N(+).C6H4NO3 (-), the piperidine ring adopts a chair conformation and the cation is protonated at the N atom. In the anion, the nitro group is twisted at an angle of 10.30 (11) degrees with respect to the attached benzene ring. In the crystal, N-H?O hydrogen bonds link adjacent anions and cations into infinite chains propagating along [100]. The chains are linked by C-H?pi inter-actions, forming sheets lying parallel to (001). PMID- 25552993 TI - Crystal structure of 3-[({2-[bis-(2-hy-droxy-benz-yl)amino]-eth-yl}(2-hy-droxy benz-yl)amino)-meth-yl]-2-hydroxy-5-methyl-benzaldehyde. AB - The non-symmetric title mol-ecule, C32H34N2O5, is based on a tetra-substituted ethyl-enedi-amine backbone. The mol-ecular structure consists of three hy-droxy benzyl groups and one 2-hy-droxy-5-methyl-benzaldehyde group bonded to the N atoms of the di-amine unit. The ethyl-enedi-amine skeleton shows a regular extended conformation, while the spatial orientation of the phenol arms is governed by hydrogen bonds. In the 2-hy-droxy-5-methyl-benzaldehyde group, an intra-molecular S(6) O-H?O hydrogen bond is observed between the alcohol and aldehyde functions, and the neighbouring phenol arm participates in an intra molecular S(6) O-H?N hydrogen bond. The third phenol group is involved in a bifurcated intra-molecular hydrogen bond with graph-set notation S(6) for O-H?N and O-H?O intra-molecular hydrogen bonds between neighbouring amine and phenol arms, respectively. Finally, the fourth phenol group acts as an acceptor in a bifurcated intra-molecular hydrogen bond and also acts as donor in an inter molecular hydrogen bond, which connects inversion-related mol-ecules into dimers with R 4 (4)(8) ring motifs. PMID- 25552994 TI - Crystal structures of three lead(II) acetate-bridged di-amino-benzene coordination polymers. AB - Poly[tris-(acetato-kappa(2) O,O')(MU2-acetato-kappa(3) O,O':O)tetra-kis-(MU3 acetato-kappa(4) O,O':O:O')bis-(benzene-1,2-di-amine-kappaN)tetra-lead(II)], [Pb4(CH3COO)8(C6H8N2)2] n , (I), poly[(acetato-kappa(2) O,O')(MU3-acetato kappa(4) O,O':O:O')(4-chloro-benzene-1,2-diamine-kappaN)lead(II)], [Pb(CH3COO)2(C6H7ClN2)] n , (II), and poly[(kappa(2) O,O')(MU3-acetato-kappa(4) O,O':O:O')(3,4-di-amino-benzo-nitrile-kappaN)lead(II)], [Pb(CH3COO)2(C7H7N3)] n , (III), have polymeric structures in which monomeric units are joined by bridging acetate ligands. All of the Pb(II) ions exhibit hemidirected coordination. The repeating unit in (I) is composed of four Pb(II) ions having O6, O6N, O7 and O6N coordination spheres, respectively, where N represents a monodentate benzene-1,2 di-amine ligand and O acetate O atoms. Chains along [010] are joined by bridging acetate ligands to form planes parallel to (10-1). (II) and (III) are isotypic and have one Pb(II) ion in the asymmetric unit that has an O6N coordination sphere. Pb2O2 units result from a symmetry-imposed inversion center. Polymeric chains parallel to [100] exhibit hydrogen bonding between the amine and acetate ligands. In (III), additional hydrogen bonds between cyano groups and non coordinating amines join the chains by forming R 2 (2)(14) rings. PMID- 25552995 TI - Crystal structure of (Z)-1-(ferrocenylethyn-yl)-10-(phenyl-imino)-anthracen 9(10H)-one from synchrotron X-ray powder diffraction. AB - In the title compound, [Fe(C5H5)(C27H16NO)], designed and synthesized to explore a new electron-donor (D) and -acceptor (A) conjugated complex, the two cyclo penta-dienyl rings adopt an eclipsed conformation. The anthracene tricycle is distorted towards a butterfly conformation and the mean planes of the outer benzene rings are inclined each to other at 22.7 (3) degrees . In the crystal, mol-ecules are paired into inversion dimers via pi-pi inter-actions. Weak inter molecular C-H?pi inter-actions link further these dimers into one-dimensional columns along the b axis, with the ferrocenylethynyl arms arranged between the stacks to fill the voids. PMID- 25552997 TI - Crystal structure of 3-amino-1-propyl-pyridinium bromide. AB - The title mol-ecular salt, C8H13N2 (+).Br(-), crystallizes with two independent 3 amino-pyridinium cations and two bromide anions in the asymmetric unit (Z' = 2). In the pyridine ring, the N atom is alkyl-ated by a propyl group. The dihedral angle between the mean planes of the pyridinium ring and the propyl group is 84.84 (2) degrees in cation A, whereas the corresponding angle is 89.23 (2) degrees in cation B. In the crystal, the anions and cations are linked via N H?Br and C-H?Br hydrogen bonds, forming chains propagating along [100]. PMID- 25552996 TI - Crystal structure of [Y6(MU6-O)(MU3-OH)8(H2O)24]I8.8H2O. AB - The crystal structure of the title compound {systematic name: octa-MU3-hydroxido MU6-oxido-hexa-kis-[tetra-aqua-yttrium(III)] octa-iodide octa-hydrate}, is characterized by the presence of the centrosymmetric mol-ecular entity [Y6(MU6 O)(MU3-OH)8(H2O)24](8+), in which the six Y(3+) cations are arranged octa hedrally around a MU6-O atom at the centre of the cationic complex. Each of the eight faces of the Y6 octa-hedron is capped by an MU3-OH group in the form of a distorted cube. In the hexa-nuclear entity, the Y(3+) cations are coordinated by the central MU6-O atom, the O atoms of four MU3-OH and of four water mol-ecules. The resulting coordination sphere of the metal ions is a capped square-anti prism. The crystal packing is quite similar to that of the ortho-rhom-bic [Ln 6(MU6-O)(MU3-OH)8(H2O)24]I8.8H2O structures with Ln = La-Nd, Eu-Tb, Dy, except that the title compound exhibits a slight monoclinic distortion. The proximity of the cationic complexes and the lattice water mol-ecules leads to the formation of a three-dimensional hydrogen-bonded network of medium strength. PMID- 25552998 TI - Crystal structure of 2-hy-droxy-imino-2-(pyridin-2-yl)-N'-[1-(pyridin-2-yl)ethyl idene]acetohydrazide. AB - The mol-ecule of the title compound, C14H13N5O2, is approximately planar (r.m.s deviation for all non-H atoms = 0.093 A), with the planes of the two pyridine rings inclined to one another by 5.51 (7) degrees . The oxime group is syn to the amide group, probably due to the formation of an intra-molecular N-H?N hydrogen bond that forms an S(6) ring motif. In the crystal, mol-ecules are linked by pairs of bifurcated O-H?(O,N) hydrogen bonds, forming inversion dimers. The latter are linked via C-H?O and C-H?N hydrogen bonds, forming sheets lying parallel to (502). The sheets are linked via pi-pi stacking inter-actions [inter centroid distance = 3.7588 (9) A], involving the pyridine rings of inversion related mol-ecules, forming a three-dimensional structure. PMID- 25552999 TI - Crystal structure of bromido-fac-tricarbon-yl[5-phenyl-3-(pyridin-2-yl)-1H-1,2,4 triazole-kappa(2) N,N']rhenium(I). AB - In the title compound, [ReBr(C13H10N4)(CO)3], the Re(I) atom has a distorted octa hedral coordination environment. Two N atoms of the 5-phenyl-3-(pyridin-2-yl)-1H 1,2,4-triazole ligand and two of the three carbonyl groups occupy the equatorial plane of the complex, with the third carbonyl ligand and the bromide ligand in the axial positions. The three carbonyl ligands are arranged in a fac configuration around the Re(I) atom. Mutual N-H?Br hydrogen bonds arrange mol ecules into centrosymmetric dimers. Additional stabilization within the crystal structure is provided by C-H?O and C-H?Br hydrogen bonds, as well as by slipped pi-pi stacking inter-actions [centroid-to-centroid distance = 3.785 (5) A], defining a three-dimensional network. PMID- 25553000 TI - Crystal structure of the inter-metallic compound SrCdPt. AB - The crystal structure of the title compound, strontium cadmium platinum, adopts the TiNiSi structure type with the Sr atoms on the Ti, the Cd atoms on the Ni and the Pt atoms on the Si positions, respectively. The Pt atoms form cadmium-centred tetra-hedra that are condensed into a three-dimensional network with channels parallel to the b-axis direction in which the Sr atoms are located. The latter are bonded to each other in the form of six-membered rings with chair conformations. All atoms in the SrCdPt structure are situated on a mirror plane. PMID- 25553001 TI - Crystal structure of dimethyl 3,3'-[(3-fluoro-phenyl)methyl-ene]bis-(1H-indole-2 carboxyl-ate). AB - In the title compound, C27H21FN2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.0166 and 0.0086 A) are approximately perpendic ular to one another, making a dihedral angle of 87.8 (5) degrees ; the fluorobenzene ring is twisted with respect to the mean planes of the two indole ring systems at 82.7 (5) and 85.5 (3) degrees . In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into the inversion dimers, which are further linked by N-H?O hydrogen bonds into supra-molecular chains propagating along the b-axis direction. Weak C-H?pi inter-actions are observed between neighbouring chains. PMID- 25553002 TI - Crystal structure of N-(tert-but-oxy-carbon-yl)glycyl-(Z)-beta-bromo-dehydro alanine methyl ester [Boc-Gly-(beta-Br)((Z))DeltaAla-OMe]. AB - The title compound, C11H17BrN2O5, is a de-hydro-amino acid with a C=C bond between the alpha- and beta-C atoms. The amino acid residues are linked trans to each other and there are no strong intra-molecular hydrogen bonds. The torsion angles indicate a non-helical conformation of the mol-ecule. The dipeptide folding is influenced by an inter-molecular N-H?O hydrogen bond and also minimizes steric repulsion. In the crystal, mol-ecules are linked by strong N-H?O hydrogen bonds, generating (001) sheets. The sheets are linked by weak C-H?O and C-H?Br bonds and short Br?Br [3.4149 (3) A] inter-actions. PMID- 25553003 TI - Crystal structure of N-(tert-but-oxy-carbon-yl)phenyl-alanylde-hydro-alanine isopropyl ester (Boc-Phe-DeltaAla-OiPr). AB - In the title compound, the de-hydro-dipeptide (Boc-Phe-DeltaAla-OiPr, C20H28N2O5), the mol-ecule has a trans conformation of the N-methyl-amide group. The geometry of the de-hydro-alanine moiety is to some extent different from those usually found in simple peptides, indicating conjugation between the H2C=C group and the peptide bond. The bond angles around de-hydro-alanine have unusually high values due to the steric hindrance, the same inter-action influencing the slight distortion from planarity of the de-hydro-alanine. The mol ecule is stabilized by intra-molecular inter-actions between the isopropyl group and the N atoms of the peptide main chain. In the crystal, an N-H?O hydrogen bond links the mol-ecules into ribbons, giving a herringbone head-to-head packing arrangement extending along the [100] direction. In the stacks, the mol-ecules are linked by weak C-H?O hydrogen-bonding associations. PMID- 25553004 TI - Crystal structure of bis-{2,4-di-tert-butyl-6-[(iso-propyl-imino)-meth yl]phenolato-kappa(2) N,O}zinc di-chloro-methane mono-solvate. AB - In the title compound, [Zn(C18H28NO)2].CH2Cl2, the Zn(II) atom is N,O-chelated by two crystallographically independent salicyl-aldehyde imine ligands, leading to a distorted tetra-hedral coordination sphere. The dihedral angle between the planes of the two metallacycles is 88.69 (6) degrees . Intra-molecular non-classical C H?O hydrogen-bonding inter-actions are observed. In the crystal, the complex mol ecules stack into columns along the a axis. Di-chloro-methane solvent mol-ecules are situated in the voids of this arrangement. PMID- 25553006 TI - Crystal structure of {3-[3,5-bis-(2,6-di-methyl-phen-yl)-1,2-phenyl-ene]-1 (2,6,2'',6''-tetra-methyl-1,1':3',1''-ter-phen-yl-5'-yl)imidazol-2-yl idene}chlorido-(eta(6)-p-cymene)ruthenium(II) benzene disolvate. AB - The title compound, [Ru(C47H43N2)Cl(C10H14)].2C6H6, crystallized with two independent mol-ecules of benzene. One of the N-aryl moieties of the N heterocyclic carbene (NHC) ligand underwent cyclo-metallation to form a five membered ruthenacycle. The complex has a three-legged piano-stool structure with two C atoms incorporated in the five-membered ruthenacycle and a Cl atom as legs. The ruthenacycle is essentially coplanar with the imidazole ring of the NHC ligand, making a dihedral angle of 0.85 (8) degrees . PMID- 25553005 TI - Crystal structure of (2-{3-[4-(4'-cyano-biphenyl-4-yl-oxy)but-oxy]pyridin-2-yl kappaN}-5-(dodec-yloxy)phenyl-kappaC (1))(9-oxo-tetra-cos-7-en-7-olato-kappa(2) O,O')platinum(II). AB - The central Pt(II) atom in the title compound, [Pt(C40H47N2O3)(C24H45O2)], has a slightly distorted square-planar coordination environment. The dihedral angle between the plane formed by Pt and the chelating C and N atoms and that formed by Pt and the chelating O atoms is 2.1 (3) degrees . The angle between the planes of the two rings in the biphenyl-4-carbo-nitrile unit is 35.1 (5) degrees . One lateral alkane chain is disordered over two sets of sites with site occupancy factors in a 0.595 (7):0.405 (7) ratio. PMID- 25553007 TI - Crystal structure of bis-[1-(4-bromo-benz-yl)pyridinium] bis-(1,2-di-cyano-ethene 1,2-di-thiol-ato-kappa(2) S,S')nickelate(II). AB - The asymmetric unit of the title salt, (C12H11BrN)2[Ni(C4N2S2)2], consists of one 1-(4-bromo-benz-yl)pyridinium cation and one half of a complex [Ni(mnt)2](2-) (mnt(2-) is the maleo-nitrile-dithiol-ate dianion). The Ni(2+) ion is located on an inversion centre and is coordinated by four S atoms from two mnt(2-) ligands, exhibiting a square-planar coordination environment. In the cation, the planes of the pyridinium and benzene rings make a dihedral angle of 69.86 (19) degrees . The cations and anions are alternately arranged in layers parallel to (001) and are held together by non-classical C-H?N hydrogen bonds. PMID- 25553008 TI - Crystal structure of bis-[1,3,4,5-tetra-methyl-1H-imidazole-2(3H)-thione kappaS]chlorido-copper(I). AB - The mol-ecular structure of the title compound, [CuCl(C7H12N2S)2], shows a slightly distorted trigonal-planar coordination geometry of the Cu atom. The Cu Cl bond measures 2.2287 (9) A, and the two Cu-S bonds are significantly different from each other, with values of 2.2270 (10) and 2.2662 (10) A. Also, the S-Cu-Cl angles differ, with values of 113.80 (4) and 124.42 (4) degrees , while the S-Cu S angle is 121.51 (4) degrees . The two imidazole rings are almost parallel, making a dihedral angle of 2.1 (2) degrees . In the crystal, the shortest C-H?Cl interactions stabilize a three-dimensional network with molecules linked into centrosymmetric dimers that are stacked along the b-axis direction. PMID- 25553009 TI - Crystal structure of poly[MU6-adipato-di-aquadi-MU2-oxalato-didysprosium(III)]. AB - In the title coordination polymer, [Dy2(C6H8O4)(C2O4)2(H2O)2] n , the asymmetric unit consists of one Dy(3+) cation, one half of an adipate anion, two halves of oxalate anions and one coordinating water mol-ecule. The adipate and oxalate ions are located on centres of inversion. The Dy(3+) cation has a distorted tricapped trigonal-prismatic geometry and is coordinated by nine O atoms, four belonging to three adipate anions, four to two oxalate anions and one from an aqua ligand. The cations are bridged by adipate ligands, generating a two-dimensional network parallel to (010). This network is further extended into three dimensions by coordination of the rigid oxalate ligands and is further consolidated by O-H?O hydrogen bonds. A part of the adipate anion is disordered over two positions in a 0.75:0.25 ratio. PMID- 25553010 TI - Crystal structure of poly[[(2,2'-bi-pyridine)manganese(II)]-di-MU-thio-cyanato]. AB - In the crystal structure of the polymeric title compound, [Mn(NCS)2(C10H8N2)] n , the Mn(II) cations are coordinated by one chelating 2,2'-bi-pyridine ligand and four thio-cyanate anions (two N- and two S-coordinating), forming a distorted [MnN4S2] octa-hedron. The asymmetric unit consists of one manganese cation located on a twofold rotation axis and half of a 2,2'-bi-pyridine ligand, the other half being generated by the same twofold rotation axis, as well as one thio cyanate anion in a general position. The Mn(II) cations are linked by two pairs of MU1,3-bridging thio-cyanate ligands into chains along the c axis; because the N atoms of the 2,2'-bi-pyridine ligands, as well as the N and the S atoms of the thio-cyanate anions, are each cis-coordinating, these chains show a zigzag arrangement. PMID- 25553011 TI - Crystal structure of catena-poly[[(3-tert-butyl-pyridine-kappaN)(4-tert-butyl pyridine-kappaN)cadmium]-di-MU-thio-cyanato-kappa(2) N:S;kappa(2) S:N]. AB - In the crystal structure of the title compound, [Cd(NCS)2(C9H13N)2] n , the Cd(II) cations are coordinated in a slightly distorted octa-hedral geometry by one 3-tert-butyl-pyridine ligand, one 4-tert-butyl-pyridine ligand and two pairs of translationally-equivalent MU-1,3-bridging thio-cyanate ligands, all of which are in general positions. These MU-1,3-bridging thio-cyante anions bridge the Cd(II) cations, forming chains that propagate parallel to the b axis. PMID- 25553012 TI - Crystal structure of (R)-N-benzyl-1-phenylethanaminium (R)-4-chloro-mandelate. AB - The absolute configuration of the title mol-ecular salt, C15H18N(+).C8H6ClO3 (-), has been confirmed by resonant scattering. In the (R)-N-benzyl-1-phenyl-ethyl ammonium cation, the phenyl rings are inclined to one another by 44.65 (7) degrees . In the crystal, the (R)-4-chloro-mandelate anions are linked via O-H?O hydrogen bonds and bridged by N-H?O hydrogen bonds involving the cations, forming chains along [010]. There are C-H?O hydrogen bonds present within the chains, which are linked via C-H?pi inter-actions and a short Cl?Cl inter-action [3.193 (1) A] forming a three-dimensional framework. The structure was refined as a two component inversion twin giving a Flack parameter of 0.05 (4). PMID- 25553013 TI - Crystal strucutre of rac-methyl (11aR*,12S*,13R*,15aS*,15bS*)-11-oxo-11,11a,12,13 tetra-hydro-9H,15bH-13,15a-ep-oxy-isoindolo[1,2-c]pyrrolo[1,2 a][1,4]benzodiazepine-12-carboxyl-ate. AB - The title compound, C21H18N2O4, obtained as a racemate, contains a novel heterocyclic system, viz. isoindolo[1,2-c]pyrrolo-[1,2-a][1,4]benzodiazepine. The central diazepane ring has a distorted boat conformation with two phenyl-ene fused and one methine C atom deviating by 0.931 (1), 0.887 (1) and 0.561 (1) A, respectively, from the mean plane of the rest of the ring. The gamma-lactone ring has an envelope conformation, with the C atom opposite to amide bond deviating by 0.355 (1) A from its plane. In the crystal, mol-ecules form centrosymmetric dimers through pairs of C-H?O hydrogen bonds. PMID- 25553014 TI - Crystal structure of 1,3-di-cyclo-hexyl-4,5-dimethyl-1H-imidazol-3-ium-2-carbodi thio-ate chloro-form monosolvate. AB - The title compound, C18H28N2S2.CHCl3, crystallizes as a zwitterion. The C-S bonds are almost equivalent, with lengths of 1.666 (3) and 1.657 (3) A. The S-C-S bond angle is expanded to 129.54 (16) degrees and the N-C-N angle is reduced to the tetra-hedal value of 108.8 (2) degrees . In the crystal, adjacent mol-ecules are linked via C-H?S hydrogen bonds, forming chains along [100]. The chloro-form solvent mol-ecule, which is disordered over two positions [occupancy ratio = 0.51 (2):0.49 (2)], is linked to the chain by bifurcated C-H?(S,S) hydrogen bonds. PMID- 25553015 TI - Crystal structure of bis-(allyl-ammonium) oxalate. AB - The title salt, 2C3H8N(+).C2O4 (2-), crystallized with six independent allyl ammonium cations and three independent oxalate dianions in the asymmetric unit. One of the oxalate dianions is nearly planar [dihedral angle between CO2 planes = 1.91 (19) degrees ], while the other two are twisted with angles of 11.3 (3) and 26.09 (13) degrees . One cation has a synperiplanar (cis) conformation with an N C-C-C torsion angle of 0.9 (3) degrees , whereas the five remaining cations are characterized by gauche arrangements, with the N-C-C-C torsion angles ranging from 115.9 (12) to 128.8 (3) degrees . One of the allyl-ammonium cations is positionally disordered (fixed occupancy ratio = 0.45:0.55). In the crystal, the cations and anions are connected by a number of strong N-H?O and N-H?(O,O) hydrogen bonds, forming layers parallel to (001), with the vinyl groups protruding into the space between the layers. PMID- 25553016 TI - Crystal structure of 2-(adamantan-1-yl)-5-(4-bromo-phen-yl)-1,3,4-oxa-diazole. AB - In the title mol-ecule, C18H19BrN2O, the benzene ring is inclined to the oxa diazole ring by 10.44 (8) degrees . In the crystal, C-H?pi inter-actions link the mol-ecules in a head-to-tail fashion, forming chains extending along the c-axis direction. The chains are further connected by pi-pi stacking inter-actions, with centroid-centroid distances of 3.6385 (7) A, forming layers parallel to the bc plane. PMID- 25553017 TI - Crystal structure of 5-chloro-2,4,6-trimethyl-3-(4-methyl-phenyl-sulfin-yl)-1 benzo-furan. AB - In the title compound, C18H17ClO2S, the dihedral angle between the planes of the benzo-furan ring [r.m.s. deviation = 0.013 (1) A] and the 4-methyl-phenyl ring is 87.37 (5) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds and pi-pi inter-actions between the furan and benzene rings of neighbouring mol ecules [centroid-centroid distance = 3.525 (2) A]. In addition, an S?S [3.6584 (9) A] contact is observed. PMID- 25553018 TI - Crystal structure of (+/-)-3-[(benzo[d][1,3]dioxol-5-yl)meth-yl]-2-(3,4,5-tri meth-oxy-phen-yl)-1,3-thia-zolidin-4-one. AB - In the title thia-zolidine-4-one derivative, C20H21NO6S, the central thia zolidine ring is essentially planar (r.m.s. deviation for all non-H atoms = 0.0287 A) and forms a dihedral angle of 88.25 (5) degrees with the meth-oxy substituted benzene ring and 74.21 (4) degrees with the 1,3-benzodioxole ring. The heterocyclic ring (with two O atoms) fused to benzene ring adopts an envelope conformation with the non-ring-junction C atom as the flap. In the crystal, the mol-ecules are linked into chains along [001] through weak C-H?O inter-actions, forming R (4) 4(28) edge-fused rings. PMID- 25553019 TI - Crystal structure of 2-{[1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl oxy]carbon-yl}benzoic acid. AB - In the title compound, C15H15N3O6, the dihedral angle between the planes of the benzene and imidazole rings is 34.93 (10) degrees . An intra-molecular C-H?O hydrogen bond is observed. In the crystal, O-H?N hydrogen bonds link the mol ecules into chains parallel to the c axis. PMID- 25553020 TI - Crystal structure of hydro-cortisone 17-butyrate. AB - In the title compound, C25H36O6, the two central cyclo-hexane rings exhibit a chair conformation. The terminal cyclo-hexene and cyclo-pentane rings are in half chair and envelope conformations (with the C atom bearing the methyl substit-uent as the flap), respectively. The methyl group of the butyrate chain is disordered over two orientations, with a refined occupancy ratio of 0.742 (6):0.258 (6). Intra-molecular O-H?O and C-H?O hydrogen bonds are observed. In the crystal, mol ecules are linked by O-H?O hydrogen bonds into chains running parallel to the a axis. PMID- 25553021 TI - Crystal structure of bis-[(5-oxo-oxolan-3-yl)triphen-ylphosphanium] hexa-iodido tellurate(IV). AB - The asymmetric unit of the title salt, [C22H20O2P]2 (+)[TeI6](2-), consists of one triphenyl(5-oxooxolan-3-yl)phosphanium cation and one half of a hexa-iodido tellurate(IV) dianion. The Te atom is located at an inversion centre and is octa hedrally coordinated by six I atoms. The Te-I bond lengths range from 2.9255 (9) to 2.9439 (10) A. The I-Te-I angles between cis-iodide ligands are in the range 87.85 (3)-92.15 (3) degrees . In the crystal, the components are connected by C H?I inter-actions. In the final refinement of the compound a void of 32 A(3) was observed. PMID- 25553022 TI - Crystal structure of betulinic acid methanol monosolvate. AB - The title compound [systematic name: 3beta-hy-droxy-lup-20(29)-en-28-oic acid methanol monosolvate], C30H48O3.CH3OH, is a solvent pseudopolymorph of a naturally occurring plant-derived lupane-type penta-cyclic triterpenoid, which was isolated from the traditional Chinese medicinal plant Syzygium jambos (L.) Alston. The dihedral angle between the planes of the carb-oxy-lic acid group and the olefinic group is 12.17 (18) degrees . The A/B, B/C, C/D and D/E ring junctions are all trans-fused. In the crystal, O-H?O hydrogen bonds involving the hy-droxy and carb-oxy-lic acid groups and the methanol solvent mol-ecule give rise to a two-dimensional network structure lying parallel to (001). PMID- 25553023 TI - Crystal structure of 2-[12-methyl-14-phenyl-10,13,14,16-tetra-aza-tetra cyclo[7.7.0.0(2,7).0(11,15)]hexa-deca-1(16),2,4,6,9,11(15),12-heptaen-8-yl idene]propandi-nitrile. AB - In the title mol-ecule, C22H12N6, the fused tetracyclic core shows a small lengthwise twist as indicated by the dihedral of 2.7 (2) degrees between the outer rings. In the crystal, mol-ecules stack along the b-axis direction via offset pi-stacking [centroid-centroid distances = 3.5282 (13) and 3.5597 (14) A] with the stacks weakly associated through C-H?N hydrogen bonds. The phenyl ring is rotationally disordered over two orientations with an occupancy ratio of 0.516 (4):0.484 (4). PMID- 25553024 TI - Crystal structure of (E)-4-{[2-(2,4-di-nitro-phen-yl)hydrazin-1-yl-idene]meth-yl} 3-methyl-1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole. AB - The title compound, C21H17N7O4, is in an 'extended' conformation aided by an intra-molecular N-H?O hydrogen bond. The pyrazole ring makes dihedral angles of 29.17 (6), 65.47 (4) and 9.91 (7) degrees , respectively, with the phenyl, pyrrole and benzene rings. In the crystal, mol-ecules are connected by pairs of N H?O and C-H?O hydrogen bonds, forming inversion dimers which associate into ribbons running along the b axis through complementary C-H?O inter-actions. PMID- 25553025 TI - Crystal structure of 1-benzyl-3-methyl-1H-imidazolium hexa-fluorido-phosphate. AB - In the title salt, C11H13N2 (+).PF6 (-), the dihedral angle between the planes of the imidazole and benzene rings is 84.72 (4) degrees . In the crystal, C-H?F inter-actions connect the cation and anion pairs into a three-dimensional network. Weak pi-pi inter-actions are observed between the imidazolium ring and the aromatic benzene ring of an adjacent mol-ecule with C?C and C?N distances ranging from 3.3714 (16) to 3.4389 (15) A. PMID- 25553026 TI - Crystal structure of (E)-N'-(4-chloro-benzyl-idene)-4-methyl-benzene-sulfono hydrazide: a hexa-gonal polymorph. AB - The title compound, C14H13ClN2O2S, crystallized in the enanti-omorphic defining hexa-gonal space group P61 [Flack parameter = -0.02 (7)]. The partially hydrated form of the same compound, crystallizing in the triclinic space group P-1, has been reported previously [Kia et al. (2009b). Acta Cryst. E65, o1119], as has the crystal structure of the bromo derivative, also crystallizing in the space group P-1 [Kia et al. (2009a). Acta Cryst. E65, o821]. The title mol-ecule is non planar with the planes of the benzene rings being inclined to one another by 76.62 (13) degrees , and has an E conformation about the C=N bond. In the crystal, mol-ecules are linked via N-H?O hydrogen bonds forming 61 helical chains running along [001]. The chains are linked via C-H?O hydrogen bonds, C-H?pi inter actions and short Cl?O [3.015 (3) A] inter-actions, forming a three-dimensional structure. PMID- 25553027 TI - Crystal structure of 2-nitro-N-(5-nitro-1,3-thia-zol-2-yl)benzamide. AB - In the title compound, C10H6N4O5S, the mean plane of the non-H atoms of the central amide fragment C-N-C(=O)-C [r.m.s. deviation = 0.0294 A] forms dihedral angles of 12.48 (7) and 46.66 (9) degrees with the planes of the thia-zole and benzene rings, respectively. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming chains along [001]. In addition, weak C-H?O hydrogen bonds link these chains, forming a two-dimensional network, containing R (4) 4(28) ring motifs parallel to (100). PMID- 25553028 TI - Crystal structure of 1-(2,4-di-methyl-phen-yl)-2-(4-tri-methyl-silyl-1H-1,2,3 triazol-1-yl)ethanone. AB - The asymmetric unit of the title compound, C15H21N3OSi, contains two mol-ecules with similar conformations (r.m.s. overlay fit for the 20 non-H atoms = 0.163 A). The dihedral angles between the planes of the 1,2,3-triazole and 2,4-di-methyl benzene rings are 27.0 (3) and 19.5 (3) degrees . In the crystal, mol-ecules are linked by very weak C-H?O and C-H?N hydrogen bonds to generate [100] chains. The chains are cross-linked by C-H?pi inter-actions. PMID- 25553029 TI - Crystal structure of 4-(3-carb-oxy-pro-pan-amido)-2-hy-droxy-benzoic acid mono hydrate. AB - In the title hydrate, C11H11NO6.H2O, the organic mol-ecule is approximately planar (r.m.s. deviation for the non-H atoms = 0.129 A) and an intra-molecular O H?O hydrogen bond closes an S(6) ring. In the crystal, the benzoic acid group participates in an O-H?O hydrogen bond to the water mol-ecule and accepts a similar bond from another water mol-ecule. The other -CO2H group forms a carb-oxy lic acid inversion dimer, thereby forming an R 2 (2)(8) loop. These bonds, along with N-H?O and C-H?O inter-actions, generate a three-dimensional network. PMID- 25553030 TI - Crystal structure of 3-{1-[(1-allyl-1H-indazol-6-yl)amino]-ethyl-idene}-6-methyl 2H-pyran-2,4(3H)-dione. AB - In the title compound, C18H17N3O3, the dihedral angle between the planes of the indazole ring system [maximum deviation = 0.012 (1) A] and the pyran-2,4-dione ring is 54.03 (6) degrees . An intra-molecular N-H?O hydrogen bond closes an S(6) ring. The same H atom also participates in an inter-molecular N-H?O hydrogen bond, which generates an inversion dimer. The dimers are linked by weak C-H?O contacts, thereby forming a three-dimensional network. PMID- 25553031 TI - Crystal structure of (4R,5S)-4-methyl-3-methyl-sulfinyl-5-phenyl-1,3-oxazolidin-2 one. AB - The absolute structure of the chiral asymmetric indole precursor title compound, C11H13NO3S, was confirmed by refinement of the Flack and Hooft parameters and is that expected based on the starting materials for the synthesis. The phenyl group subtends a dihedral angle of 56.40 (5) degrees with the mean plane of the oxazolidinone ring, which adopts an envelope conformation, with the C atom bearing the methyl group as the flap. In the crystal, no significant directional inter-actions beyond van der Waals contacts are observed. PMID- 25553032 TI - Crystal structure of (2-benzyl-oxy-pyrimidin-5-yl)boronic acid. AB - The boronic acid group in the title compound, C11H11BN2O3, adopts a syn-anti conformation and is almost coplanar with the aromatic rings , making a dihedralangle of 3.8 (2) degrees . In the crystal, adjacent mol-ecules are linked via pairs of O-H?O inter-actions, forming centrosymmetric dimers with an R 2 (2)(8) motif, which have recently been shown to be energetically very favorable (Durka et al., 2012 ?, 2014 ?). The hy-droxy groups in an anti conformation are engaged in lateral hydrogen-bonding inter-actions with N atoms from neighbouring mol-ecules, leading to the formation of chains along [001]. O?B [3.136 (2) A] and C(pi)?B [3.393 (2) A] stacking inter-actions in turn link parallel chains of centrosymmetric dimers into layers parallel to (010). PMID- 25553033 TI - Crystal structure of 4-bromo-N-(2-hydroxy-phen-yl)benzamide. AB - In the title compound, C13H10BrNO2, the mean plane of the non-H atoms of the central amide C-N-C(=O)-C fragment (r.m.s. deviation = 0.004 A) forms a dihedral angle of 73.97 (12) degrees with the hy-droxy-substituted benzene ring and 25.42 (19) degrees with the bromo-substituted benzene ring. The two aromatic rings are inclined to one another by 80.7 (2) degrees . In the crystal, mol-ecules are linked by O-H?O and N-H?O hydrogen bonds, forming chains along [010]. The chains are linked by weak C-H?O hydrogen bonds, forming sheets parallel to (100), and enclosing R (3) 3(17) and R (3) 2(9) ring motifs. PMID- 25553034 TI - Crystal structure of 2-(4-methyl-benzyl-idene)malono-nitrile. AB - The mol-ecule of the title compound, C11H8N2, is approximately planar (r.m.s.deviation for all non-H atoms = 0.023 A). The malono-nitrile C-C-C angle is 113.54 (13) degrees . In the crystal, mol-ecules stack head-to-tail along [010]. There are no significant inter-molecular inter-actions present. PMID- 25553035 TI - Crystal structure of (2S,4S)-5,5-dimethyl-2-(pyridin-2-yl)-1,3-thia-zolidine-4 carb-oxy-lic acid. AB - In the title compound, C11H14N2O2S, the thia-zolidine ring has an envelope conformation with the C atom bonded to the carb-oxy-lic acid group at the flap. Two C atoms of the thia-zolidine ring adopt S conformations. In the crystal, O H?N hydrogen bonds between the amine and carb-oxy-lic acid groups construct a helical chain structure along the a-axis direction. The chains are further connected via weak C-H?pi contacts, forming a layer parallel to the ac plane. PMID- 25553036 TI - Crystal structure of fenpropathrin. AB - In the title compound [systematic name: cyano-(3-phen-oxy-phen-yl)methyl 2,2,3,3 tetra-methyl-cyclo-propane-carboxyl-ate], C22H23NO3, which is the pyrethroid insecticide fenpropathrin, the dihedral angle between the cyclo-propane ring plane and the carboxyl-ate group plane is 88.25 (11) degrees . The dihedral angle between the benzene and phenyl rings in the phen-oxy-benzyl group is 82.99 (4) degrees . In the crystal, C-H?N hydrogen bonds and weak C-H?pi inter-actions link adjacent mol-ecules, forming loop chains along the b-axis direction. PMID- 25553037 TI - Crystal structure of propaquizafop. AB - The title compound, C22H22ClN3O5 {systematic name: 2-(propan-2-yl-idene-amino oxy)ethyl (R)-2-[4-(6-chloro-quin-oxalin-2-yl-oxy)phen-oxy]propionate}, is a herbicide. The asymmetric unit comprises two independent mol-ecules in which the dihedral angles between the phenyl ring and the quinoxaline ring plane are 75.93 (7) and 82.77 (8) degrees . The crystal structure features C-H?O, C-H?N, and C H?Cl hydrogen bonds, as well as weak pi-pi inter-actions [ring-centroid separation = 3.782 (2) and 3.5952 (19) A], resulting in a three-dimensional architecture. PMID- 25553038 TI - Crystal structure of (Z)-3-{3-(4-chloro-phen-yl)-2-[(4-chloro-phen-yl)imino]-2,3 di-hydro-thia-zol-4-yl}-2H-chromen-2-one. AB - In the title compound, C24H14Cl2N2O2S, the 2H-chromene ring system is approximately planar, with a maximum deviation of 0.025 (2) A. The thia-zole ring is almost planar, with an r.m.s. deviation of 0.0022 A, and makes a dihedral angle of 58.52 (7) degrees with the chromene ring system. The chromene ring system is inclined at angles of 58.3 (1) and 55.39 (9) degrees with respect to the two chloro-phenyl rings. The two chloro-phenyl rings show significant deviation from coplanarity, with a dihedral angle between them of 47.69 (8) degrees . The crystal structure features C-H?Cl inter-actions extending in (100) and propagating along the a-axis direction and weak pi-pi inter-actions [centroid centroid separation = 3.867 (2) A]. PMID- 25553039 TI - Crystal structure of ethyl 2-(2-fluoro-benzyl-idene)-5-(4-fluoro-phen-yl)-7 methyl-3-oxo-2,3-di-hydro-5H-1,3-thia-zolo[3,2-a]pyrimidine-6-carb-oxy-late. AB - In the title mol-ecule, C23H18F2N2O3S, the 4-fluoro-substituted and 2-fluoro substituted benzene rings form dihedral angles of 88.16 (8) and 23.1 (1) degrees , respectively, with the thia-zole ring. The pyrimidine ring adopts a flattened sofa conformation with the sp (3)-hydridized C atom forming the flap. In the crystal, pairs of weak C-H?O hydrogen bonds link mol-ecules related by twofold rotation axes, forming R (2) 2(10) rings, which are in turn linked by weak C-H?N inter-actions to form chains of rings along [010]. In addition, weak C H?pi(arene) inter-actions link the chains into layers parallel to (001) and pi-pi inter-actions with a centroid-centroid distance of 3.836 (10) A connect these layers into a three-dimensional network. PMID- 25553040 TI - Crystal structure of 2-[(di-chloro-methane)sulfon-yl]pyridine. AB - The asymmetric unit of the title compound, C6H5Cl2NO2S, contains two mol-ecules with similar conformations (r.m.s. overlay fit for the non-H atoms = 0.067 A). Atoms attached to the pendent Csp (3)-S bond are arranged in a staggered conformation with one of the Cl atoms anti to the C atom in the aromatic ring [C S-C-Cl torsion angles = 178.41 (11) and -176.70 (13) degrees ]. In the crystal, mol-ecules are linked by C-H?N and C-H?O hydrogen bonds, generating a three dimensional network, and weak aromatic pi-pi stacking is also observed [centroid centroid separation = 3.8902 (17) A]. PMID- 25553041 TI - Crystal structure of 2,2,3,3-tetra-methyl-1,1,1,4,4,4-hexa-phenyl-tetra-germane. AB - The mol-ecule of the title compound, C40H42Ge4, lies with its central Ge-Ge bond on an inversion centre giving rise to a zigzag backbone of four tetra-hedrally coordinated Ge atoms. The symmetrically independent Ge-Ge bonds are slightly shorter than in other organo-tetra-germanes whereas the Ge-CPh (Ph = phen-yl) and Ge-CMe (Me = meth-yl) distances have their usual values. In the crystal, (010) layers of Ph6Me4Ge4 mol-ecules with a parallel orientation of the Ge4 backbone exist, held together by van der Waals forces only. Main bond lengths in organo substituted oligogermanes are compared. PMID- 25553042 TI - Crystal structure of methyl 2-(2H-1,3-benzodioxol-5-yl)-7,9-di-bromo-8-oxo-1-oxa spiro-[4.5]deca-2,6,9-triene-3-car-boxyl-ate. AB - The title compound, C18H12Br2O6, was synthesized from Morita-Baylis-Hillman adducts. It incorporates the bromin-ated spiro-hexa-dienone moiety typically exhibited by compounds of this class that exhibit biological activity. Both the brominated cyclo-hexa-dienone and the central five-membered rings are nearly planar (r.m.s. deviations of 0.044 and 0.016 A, respectively), being almost perpendicularly oriented [inter-planar angle = 89.47 (5) degrees ]. With respect to the central five-membered ring, the brominated cyclo-hexa-dienone ring, the benzodioxol ring and the carboxyl-ate fragment make C-O-C-C, O-C-C-C and C-C-C-O dihedral angles of -122.11 (8), -27.20 (11) and -8.40 (12) degrees , respectively. An intra-molecular C-H?O hydrogen bond occurs. In the crystal, mol ecules are linked by non-classical C-H?O and C-H?Br hydrogen bonds resulting in a molecular packing in which the brominated rings are in a head-to-head orientation, forming well marked planes parallel to the b axis. PMID- 25553043 TI - Crystal structure of a second polymorph of tetra-kis-(pyridin-2-yl)methane. AB - A second polymorph of the title compound, C21H16N4, is reported. The original polymorph was solved by our group [Matsumoto et al. (2003 ?). Tetra-hedron Lett. 44, 2861-2864] in the monoclinic space group C2/c and refined to R = 0.050. Now the crystal structure of a tetra-gonal polymorph (space group P-421 c) has been solved and refined to R = 0.036. In the crystal, there are no strong inter molecular inter-actions. Reflecting the high symmetry of the mol-ecular structure, the asymmetric unit is a quarter of the mol-ecule, and the mol-ecule exhibits S4 symmetry along the c axis in the crystal. PMID- 25553044 TI - Crystal structure of 4-meth-oxy-quinazoline. AB - The title compound, C9H8N2O, is almost planar, with the C atom of the meth-oxy group deviating from the mean plane of the quinazoline ring system (r.m.s. deviation = 0.011 A) by 0.068 (4) A. In the crystal, mol-ecules form pi-pi stacks parallel to the b-axis direction [centroid-centroid separation = 3.5140 (18) A], leading to a herringbone packing arrangement. PMID- 25553045 TI - Crystal structure of 2-phenyl-ethyl-amin-ium 4-nitro-phenolate monohydrate. AB - In the title hydrated mol-ecular salt, C8H12N(+).C6H4NO3 (-).H2O, the conformation of the side chain in the cation is anti [C-C-C-N = 179.62 (12) degrees ] and the dihedral angle between the aromatic ring and the nitro group in the anion is 3.34 (11) degrees . In the crystal, the components are linked by O H?O and N-H?O hydrogen bonds, generating (10-1) sheets, which feature R 4 (4)(21) loops. The sheets inter-act by weak aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.896 (3) A], forming a three-dimensional network. PMID- 25553047 TI - Crystal structure of 4,6-bis-[(E)-4-bromo-styr-yl]-2-(butyl-sulfan-yl)pyrimidine. AB - In the title compound, C24H22Br2N2S, the dihedral angles between the central pyrimidine ring and the pendant bromo-benzene rings are 11.02 (11) and 13.20 (12) degrees . The butyl side chain adopts a gauche conformation [C-C-C-C = -67.4 (4) degrees ]. In the crystal, weak aromatic pi-pi stacking is observed between the pyrimidine ring and one of the benzene rings [centroid-centroid separation = 3.6718 (17) A]. PMID- 25553046 TI - Crystal structure of 1-methyl-4-methyl-sulfanyl-1H-pyrazolo-[3,4-d]pyrimidine. AB - In the title compound, C7H8N4S, the non-H atoms of the pyrazolo-[3,4-d]pyrimidine ring system and the methyl-sulfanyl group lie on a crystallographic mirror plane. In the crystal, mol-ecules are linked via a number of pi-pi inter-actions [centroid-centroid distances vary from 3.452 (7) to 3.6062 (8) A], forming a three-dimensional structure. PMID- 25553048 TI - Crystal structure of 9-butyl-3-(9-butyl-9H-carbazol-3-yl)-9H-carbazole. AB - In the title carbazole derivative, C32H32N2, the mol-ecule resides on a crystallographic twofold axis, which runs through the central C-C bond. The carbazole ring system is almost planar, with a maximum deviation of 0.041 (1) A for one of the ring-junction C atoms. The crystal packing is stabilized by C-H?pi inter-actions only, which form a C(7) chain-like arrangement along [110] in the unit cell. PMID- 25553049 TI - Crystal structure of (-)-(2R,3S,4R,5R)-5-(1,3-di-thian-2-yl)-3-methyl-1-(triiso propyl-sil-yloxy)hexane-2,4-diol. AB - The title compound, C20H42O3S2Si, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. They consist of syn,anti,anti-stereo-tetrads with a 1,3-di-thiane motif and a primary alcohol protected as the triisopropyl silyl ether. The 1,3-di-thiane ring adopts a chair conformation, while the rest of each mol-ecule displays a common zigzag conformation. There is an intra-molecular O H?O hydrogen bond in each mol-ecule. In the crystal, the A and B mol-ecules are linked via O-H?O hydrogen bonds, forming -A-B-A--B-- chains along [010]. The absolute structure was determined by resonant scattering (anomalous scattering) [Flack parameter = 0.035 (8)]. PMID- 25553050 TI - Crystal structure of ethyl 4-[(1H-pyrazol-1-yl)meth-yl]benzoate. AB - In the title mol-ecule, C13H14N2O2, the dihedral angle between the pyrazole and benzene ring mean planes is 76.06 (11) degrees , and the conformation of the ethyl side chain is anti [C-O-C-C = -175.4 (3) degrees ]. In the crystal, the only directional inter-actions are very weak C-H ?pi inter-actions involving both the pyrazole and benzene rings, leading to the formation of a three-dimensional network. PMID- 25553051 TI - Crystal structure of 2-(di-phenyl-phos-phanyl)phenyl 4-(hy-droxy-meth yl)benzoate. AB - The title compound, C26H21O3P, was obtained as by-product due to the hydrolysis of the desired tosyl-ated compound. The dihedral angles between the three aromatic rings attached to the P atom lie in the range 78.1 (1)-87.6 (1) degrees . The hy-droxy-methyl group is disordered between two conformations in a 0.719 (9):0.281 (9) ratio. The hy-droxy H atom is not involved in inter-molecular inter actions, while the hy-droxy O atom serves as a donor for weak C-H?O hydrogen bonds, which link the mol-ecules into chains propagating in [0-11]. PMID- 25553052 TI - Crystal structure of bis-(1-benzyl-1H-1,2,4-triazole) perchloric acid monosolvate. AB - The title compound, 2C9H9N3.HClO4, was prepared by reaction of 1-benzyl-1H-1,2,4 triazole and HClO4 in ethanol at room temperature. The asymmetric unit consists of two mol-ecules of 1-benzyl-1H-1,2,4-triazole and one of HClO4 mol-ecule. The benzene and triazole rings make dihedral angles of 85.45 (8) and 84.76 (8) degrees in the two mol-ecules. The H-atom position of the perchloric acid mol ecule is split over two O atoms (real peaks on difference map), with site occupation factors of 0.5. These H atoms form two classical hydrogen bonds [2.546 (5) and 2.620 (4) A] with the same N atoms in both mol-ecules. Five inter molecular non-classical C-H?O inter-actions, with C?O distances in the range 3.147 (5)-3.483 (5) A, are found in the crystal structure. PMID- 25553053 TI - Crystal structure of (Z)-3-benz-yloxy-6-[(2-hy-droxy-anilino)methyl-idene]cyclo hexa-2,4-dien-1-one. AB - In the title compound, C20H17NO3, the methyl-idene-cyclo-hexa-2,4-dienone moiety is approximately planar [maximum deviation = 0.0615 (10) A] and is oriented at diherdral angles of 69.60 (7) and 1.69 (9) degrees to the phenyl and hy-droxy benzene rings, respectively. The amino group links with the carbonyl O atom via an intra-molecular N-H?O hydrogen bond, forming an S(6) ring motif. In the crystal, the mol-ecules are linked by O-H?O hydrogen bonds and weak C-H?O and C H?pi inter-actions, forming a three-dimensional supra-molecular architecture. PMID- 25553054 TI - Crystal structure of 4-amino-1-(4-methyl-benz-yl)pyridinium bromide. AB - The title mol-ecular salt, C13H15N2 (+).Br(-), crystallized with two independent ion pairs (A and B) in the asymmetric unit. In the cations, the planes of the pyridine and benzene rings are inclined to one another by 79.32 (8) and 82.30 (10) degrees in ion pairs A and B, respectively. In the crystal, the anions and cations are connected by N-H?Br hydrogen bonds, forming a centrosymmetric tetra mer-like unit enclosing an R 8 (4)(16) ring motif. These units are linked via C H?Br hydrogen bonds, forming a three-dimensional network. PMID- 25553055 TI - Crystal structure of methyl 1-methyl-3,5-diphenyl-7-tosyl-3,6,7,11b-tetra-hydro pyrazolo-[4',3':5,6]pyrano[3,4-c]quinoline-5a(5H)-carboxyl-ate. AB - In the title compound, C35H31N3O5S, the piperidine ring adopts an envelope conformation, with the methine C atom as the flap, and the pyran ring adopts a sofa conformation. The mean planes of these two rings are almost normal to one another, making a dihedral angle of 85.96 (5) degrees . The two phenyl rings, one attached to the pyrazole ring and the other to the pyran ring, are inclined to one another by 65.41 (11) degrees . They are inclined to the mean planes of the rings to which they are attached by 12.59 (11) and 70.09 (9) degrees , respectively. There is an intra-molecular C-H?pi inter-action involving the tosyl ate methyl group and the phenyl ring attached to the pyrazole ring. In the crystal, mol-ecules are linked by C-H?pi inter-actions, forming ribbons parallel to (10-2). The ribbons are linked by slipped parallel pi-pi inter-actions involving inversion-related pyrazole rings [inter-centroid distance = 3.672 (2) A], forming slabs parallel to (001). A preliminary report of this structure has been published [Bakthadoss et al. (2014 ?). Eur. J. Org. Chem. pp. 1505-1513]. PMID- 25553056 TI - Crystal structure of 1-(piperidin-1-yl)butane-1,3-dione. AB - In the title compound, C9H15NO2, the piperidine ring exhibits a chair conformation. The butane-dione subunit exhibits a conformation with the ketone C atom in an eclipsed position with respect to the amide carbonyl group. In the crystal, a two-dimensional layered arrangement is formed by hydrogen bonds of the C-H?O type between the methyl group and the exocyclic methyl-ene unit as donor sites and the amide carbonyl O atom as the acceptor of a bifurcated hydrogen bond. These layers are oriented parallel to the ab plane. PMID- 25553057 TI - Bisphenyl-Polymer/Carbon-Fiber-Reinforced Composite Compared to Titanium Alloy Bone Implant. AB - Aerospace/aeronautical thermoset bisphenyl-polymer/carbon-fiber-reinforced composites are considered as new advanced materials to replace metal bone implants. In addition to well-recognized nonpolar chemistry with related bisphenol-polymer estrogenic factors, carbon-fiber-reinforced composites can offer densities and electrical conductivity/resistivity properties close to bone with strengths much higher than metals on a per-weight basis. In vivo bone-marrow tests with Sprague-Dawley rats revealed far-reaching significant osseoconductivity increases from bisphenyl-polymer/carbon-fiber composites when compared to state-of-the-art titanium-6-4 alloy controls. Midtibial percent bone area measured from the implant surface increased when comparing the titanium alloy to the polymer composite from 10.5% to 41.6% at 0.8 mm, P < 10-4, and 19.3% to 77.7% at 0.1 mm, P < 10-8. Carbon-fiber fragments planned to occur in the test designs, instead of producing an inflammation, stimulated bone formation and increased bone integration to the implant. In addition, low-thermal polymer processing allows incorporation of minerals and pharmaceuticals for future major tissue-engineering potential. PMID- 25553058 TI - Effectiveness of enfuvirtide in a cohort of highly antiretroviral-experienced HIV 1-infected patients in Mexico. AB - BACKGROUND: Treatments in patients with multidrug resistance often involve the use of multiple agents with partial antiviral activity and overlapping metabolic toxicities. Enfuvirtide is therefore a welcome addition to the antiretroviral management of patients with multiclass resistant virus, given the low risk of systemic toxicities and novel mechanism of action relative to existing drug classes. The aim of this study was to evaluate the effectiveness of ENF plus optimized background regimen (OBR) in a Mexican cohort of highly HIV-1 ARV experienced patients. METHODS: Prospective cohort of treatment-experienced HIV-1 infected adults with virological failure who started therapy with an ENF containing regimen. The effectiveness of ENF treatment was evaluated with percentages of undetectable HIV-1 RNA viral load after 24 and 48 weeks of treatment, and changes in CD4+ cell counts. RESULTS: Forty patients >18 years were included. After 24 weeks of treatment, 91% of patients had HIV-1 RNA viral load <400 copies/mL and 65.8% had <50 copies/mL. At week 48 of treatment, 81.4% of the patients had HIV-1 RNA <400 copies/mL and 55.5% had <50 copies/mL; in both cases p <0.0001 compared to baseline. Increase CD4+ cells were also statistically significant at weeks 24 and 48 with respect to the baseline. Pain at the site of injection was the main adverse event in 100% of patients. CONCLUSION: Our study provides clinically important evidence of the effectiveness and safety of ENF in highly ARV-experienced HIV-1-infected patients. These findings strengthen the results of previous randomized controlled trials with this agent. PMID- 25553059 TI - Racial differences between African-American and white women in insulin resistance and visceral adiposity are associated with differences in apoCIII containing apoAI and apoB lipoproteins. AB - BACKGROUND: African-Americans have higher HDL, less visceral adipose tissue (VAT) and lower triglyceride (TG) and apoCIII concentrations than whites, despite being more insulin-resistant. We studied in African-American and white women the influences of insulin resistance and VAT on the apoAI concentrations of two HDL subspecies, one that contains apoCIII that is associated with increased risk of coronary heart disease (CHD) and one that does not have apoCIII that is associated with decreased CHD; and on the apoCIII concentrations of HDL and of the apoB lipoproteins. METHODS: The participants were 32 women (14 African Americans, 18 white) of similar age (39 +/- 12 vs. 42 +/- 11y). Mean BMI was 34 kg/m(2) in the African-Americans compared to 30 in the whites. A standard diet (33% fat, 52% carbohydrate, 15% protein) was provided for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model. RESULTS: After controlling for SI, African-Americans have a higher mean apoAI level in HDL with apoCIII compared with whites (12.9 +/- 2.8 and 10.9 +/- 2.9 mg/dL, respectively, P = 0.05). SI was associated with higher apoAI in HDL with apoCIII, whereas VAT was not associated with this HDL subspecies. This pattern of results was reversed for apoCIII concentrations in apoB lipoproteins. After adjusting for SI, African-Americans had lower apoCIII in apoB lipoproteins. SI was associated with lower apoCIII in total apoB lipoproteins, whereas VAT was associated with higher apoCIII in all the apoB lipoproteins. Additional adjustment for VAT tended to reduce the difference in apoCIII between the groups. CONCLUSIONS: African-American women have a higher HDL with apoCIII level than whites when controlled for insulin sensitivity. African-Americans have lower insulin sensitivity. Insulin sensitivity is associated with higher levels of HDL with apoCIII. ApoCIII levels in VLDL are lower in African-American women than whites, also affected by insulin sensitivity which is associated with low apoCIII in VLDL. VAT has a strong association with apoCIII in apoB lipoproteins but not with apoAI in HDL with apoCIII. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00484861. PMID- 25553060 TI - Power distance and mentor-protege relationship quality as moderators of the relationship between informal mentoring and burnout: evidence from China. AB - BACKGROUND: The topic of how to prevent and reduce burnout has drawn great attention from researchers and practitioners in recent years. However, we know little about how mentoring as a form of social support exerts influence on employee burnout. AIM: This study aims to examine the contingency side of the mentoring-burnout relationship by addressing the exploratory question of whether individual differences in power distance and relationship quality play important roles in mentoring effectiveness in terms of reducing a protege's burnout level. METHODS: A total of 210 employees from a technology communications company completed the survey questionnaire. RESULTS: (1) A proteges' power distance moderates the negative relationship between mentoring and burnout in such a way that the relationship is stronger for proteges who are lower rather than higher in power distance; (2) mentor-protege relationship quality moderates the negative relationship between mentoring and burnout in such a way that the relationship is stronger when the relationship quality is higher rather than lower. CONCLUSIONS: In sum, our results highlight the importance of studying the contingency side of mentoring effects on protege burnout. Our findings suggest that the individuals' different cultural values of power distance and mentor-protege relationship quality are the boundary conditions for the mentoring-burnout relationship. We therefore suggest that research on mentoring-burnout will be advanced by considering the role of the moderating process. PMID- 25553061 TI - Why evolutionary biologists should get seriously involved in ecological monitoring and applied biodiversity assessment programs. AB - While ecological monitoring and biodiversity assessment programs are widely implemented and relatively well developed to survey and monitor the structure and dynamics of populations and communities in many ecosystems, quantitative assessment and monitoring of genetic and phenotypic diversity that is important to understand evolutionary dynamics is only rarely integrated. As a consequence, monitoring programs often fail to detect changes in these key components of biodiversity until after major loss of diversity has occurred. The extensive efforts in ecological monitoring have generated large data sets of unique value to macro-scale and long-term ecological research, but the insights gained from such data sets could be multiplied by the inclusion of evolutionary biological approaches. We argue that the lack of process-based evolutionary thinking in ecological monitoring means a significant loss of opportunity for research and conservation. Assessment of genetic and phenotypic variation within and between species needs to be fully integrated to safeguard biodiversity and the ecological and evolutionary dynamics in natural ecosystems. We illustrate our case with examples from fishes and conclude with examples of ongoing monitoring programs and provide suggestions on how to improve future quantitative diversity surveys. PMID- 25553062 TI - Comparative evaluation of potential indicators and temporal sampling protocols for monitoring genetic erosion. AB - Genetic biodiversity contributes to individual fitness, species' evolutionary potential, and ecosystem stability. Temporal monitoring of the genetic status and trends of wild populations' genetic diversity can provide vital data to inform policy decisions and management actions. However, there is a lack of knowledge regarding which genetic metrics, temporal sampling protocols, and genetic markers are sufficiently sensitive and robust, on conservation-relevant timescales. Here, we tested six genetic metrics and various sampling protocols (number and arrangement of temporal samples) for monitoring genetic erosion following demographic decline. To do so, we utilized individual-based simulations featuring an array of different initial population sizes, types and severity of demographic decline, and DNA markers [single nucleotide polymorphisms (SNPs) and microsatellites] as well as decline followed by recovery. Number of alleles markedly outperformed other indicators across all situations. The type and severity of demographic decline strongly affected power, while the number and arrangement of temporal samples had small effect. Sampling 50 individuals at as few as two time points with 20 microsatellites performed well (good power), and could detect genetic erosion while 80-90% of diversity remained. This sampling and genotyping effort should often be affordable. Power increased substantially with more samples or markers, and we observe that power of 2500 SNPs was nearly equivalent to 250 microsatellites, a result of theoretical and practical interest. Our results suggest high potential for using historic collections in monitoring programs, and demonstrate the need to monitor genetic as well as other levels of biodiversity. PMID- 25553063 TI - How and why should we implement genomics into conservation? AB - Conservation genetics has provided important information into the dynamics of endangered populations. The rapid development of genomic methods has posed an important question, namely where do genetics and genomics sit in relation to their application in the conservation of species? Although genetics can answer a number of relevant questions related to conservation, the argument for the application of genomics is not yet fully exploited. Here, we explore the transition and rationale for the move from genetic to genomic research in conservation biology and the utility of such research. We explore the idea of a 'conservation prior' and how this can be determined by genomic data and used in the management of populations. We depict three different conservation scenarios and describe how genomic data can drive management action in each situation. We conclude that the most effective applications of genomics will be to inform stakeholders with the aim of avoiding 'emergency room conservation'. PMID- 25553064 TI - Using genomics to characterize evolutionary potential for conservation of wild populations. AB - Genomics promises exciting advances towards the important conservation goal of maximizing evolutionary potential, notwithstanding associated challenges. Here, we explore some of the complexity of adaptation genetics and discuss the strengths and limitations of genomics as a tool for characterizing evolutionary potential in the context of conservation management. Many traits are polygenic and can be strongly influenced by minor differences in regulatory networks and by epigenetic variation not visible in DNA sequence. Much of this critical complexity is difficult to detect using methods commonly used to identify adaptive variation, and this needs appropriate consideration when planning genomic screens, and when basing management decisions on genomic data. When the genomic basis of adaptation and future threats are well understood, it may be appropriate to focus management on particular adaptive traits. For more typical conservations scenarios, we argue that screening genome-wide variation should be a sensible approach that may provide a generalized measure of evolutionary potential that accounts for the contributions of small-effect loci and cryptic variation and is robust to uncertainty about future change and required adaptive response(s). The best conservation outcomes should be achieved when genomic estimates of evolutionary potential are used within an adaptive management framework. PMID- 25553066 TI - Continental-scale patterns of pathogen prevalence: a case study on the corncrake. AB - Pathogen infections can represent a substantial threat to wild populations, especially those already limited in size. To determine how much variation in the pathogens observed among fragmented populations is caused by ecological factors, one needs to examine systems where host genetic diversity is consistent among the populations, thus controlling for any potentially confounding genetic effects. Here, we report geographic variation in haemosporidian infection among European populations of corncrake. This species now occurs in fragmented populations, but there is little genetic structure and equally high levels of genetic diversity among these populations. We observed a longitudinal gradient of prevalence from western to Eastern Europe negatively correlated with national agricultural yield, but positively correlated with corncrake census population sizes when only the most widespread lineage is considered. This likely reveals a possible impact of local agriculture intensity, which reduced host population densities in Western Europe and, potentially, insect vector abundance, thus reducing the transmission of pathogens. We conclude that in the corncrake system, where metapopulation dynamics resulted in variations in local census population sizes, but not in the genetic impoverishment of these populations, anthropogenic activity has led to a reduction in host populations and pathogen prevalence. PMID- 25553067 TI - Rabbit haemorrhagic disease: virus persistence and adaptation in Australia. AB - In Australia, the rabbit haemorrhagic disease virus (RHDV) has been used since 1996 to reduce numbers of introduced European rabbits (Oryctolagus cuniculus) which have a devastating impact on the native Australian environment. RHDV causes regular, short disease outbreaks, but little is known about how the virus persists and survives between epidemics. We examined the initial spread of RHDV to show that even upon its initial spread, the virus circulated continuously on a regional scale rather than persisting at a local population level and that Australian rabbit populations are highly interconnected by virus-carrying flying vectors. Sequencing data obtained from a single rabbit population showed that the viruses that caused an epidemic each year seldom bore close genetic resemblance to those present in previous years. Together, these data suggest that RHDV survives in the Australian environment through its ability to spread amongst rabbit subpopulations. This is consistent with modelling results that indicated that in a large interconnected rabbit meta-population, RHDV should maintain high virulence, cause short, strong disease outbreaks but show low persistence in any given subpopulation. This new epidemiological framework is important for understanding virus-host co-evolution and future disease management options of pest species to secure Australia's remaining natural biodiversity. PMID- 25553065 TI - A field guide to whole-genome sequencing, assembly and annotation. AB - Genome sequencing projects were long confined to biomedical model organisms and required the concerted effort of large consortia. Rapid progress in high throughput sequencing technology and the simultaneous development of bioinformatic tools have democratized the field. It is now within reach for individual research groups in the eco-evolutionary and conservation community to generate de novo draft genome sequences for any organism of choice. Because of the cost and considerable effort involved in such an endeavour, the important first step is to thoroughly consider whether a genome sequence is necessary for addressing the biological question at hand. Once this decision is taken, a genome project requires careful planning with respect to the organism involved and the intended quality of the genome draft. Here, we briefly review the state of the art within this field and provide a step-by-step introduction to the workflow involved in genome sequencing, assembly and annotation with particular reference to large and complex genomes. This tutorial is targeted at scientists with a background in conservation genetics, but more generally, provides useful practical guidance for researchers engaging in whole-genome sequencing projects. PMID- 25553068 TI - Anthropogenic hybridization between endangered migratory and commercially harvested stationary whitefish taxa (Coregonus spp.). AB - Natural hybridization plays a key role in the process of speciation. However, anthropogenic (human induced) hybridization of historically isolated taxa raises conservation issues. Due to weak barriers to gene flow and the presence of endangered taxa, the whitefish species complex is an excellent study system to investigate the consequences of hybridization in conservation. We focused on three naturally reproductively isolated whitefish taxa in Germany: the endangered, anadromous North Sea houting (NSH) and Baltic houting (BH), which were reintroduced after local extinction, and the commercially stocked European whitefish (EW). To evaluate the genetic integrity of each taxon, source and reintroduced populations of NSH and BH, and EW populations were characterized based on two mitochondrial and 17 microsatellite loci. Additionally, we investigated gill raker counts as an adaptive phenotypic trait. Even though clear genetic and phenotypic differentiation confirmed the houtings as separate evolutionarily significant units, admixture analyses revealed an extensive hybrid zone. Hybridizations were introgressive, positively correlated with genetic diversity, and were reflected in the gill raker counts. The BH distribution range showed higher heterogeneity and stronger admixture than the NSH range. Erroneous stocking with non-native genotypes best explained these patterns, which pose challenges for the conservation of the endangered NSH and BH. PMID- 25553070 TI - Alternative reproductive tactics increase effective population size and decrease inbreeding in wild Atlantic salmon. AB - While nonanadromous males (stream-resident and/or mature male parr) contribute to reproduction in anadromous salmonids, little is known about their impacts on key population genetic parameters. Here, we evaluated the contribution of Atlantic salmon mature male parr to the effective number of breeders (Nb) using both demographic (variance in reproductive success) and genetic (linkage disequilibrium) methods, the number of alleles, and the relatedness among breeders. We used a recently published pedigree reconstruction of a wild anadromous Atlantic salmon population in which 2548 fry born in 2010 were assigned parentage to 144 anadromous female and 101 anadromous females that returned to the river to spawn in 2009 and to 462 mature male parr. Demographic and genetic methods revealed that mature male parr increased population Nb by 1.79 and 1.85 times, respectively. Moreover, mature male parr boosted the number of alleles found among progenies. Finally, mature male parr were in average less related to anadromous females than were anadromous males, likely because of asynchronous sexual maturation between mature male parr and anadromous fish of a given cohort. By increasing Nb and allelic richness, and by decreasing inbreeding, the reproductive contribution of mature male parr has important evolutionary and conservation implications for declining Atlantic salmon populations. PMID- 25553069 TI - Additive genetic variation for tolerance to estrogen pollution in natural populations of Alpine whitefish (Coregonus sp., Salmonidae). AB - The evolutionary potential of natural populations to adapt to anthropogenic threats critically depends on whether there exists additive genetic variation for tolerance to the threat. A major problem for water-dwelling organisms is chemical pollution, and among the most common pollutants is 17alpha-ethinylestradiol (EE2), the synthetic estrogen that is used in oral contraceptives and that can affect fish at various developmental stages, including embryogenesis. We tested whether there is variation in the tolerance to EE2 within Alpine whitefish. We sampled spawners from two species of different lakes, bred them in vitro in a full-factorial design each, and studied growth and mortality of embryos. Exposure to EE2 turned out to be toxic in all concentrations we tested (>=1 ng/L). It reduced embryo viability and slowed down embryogenesis. We found significant additive genetic variation in EE2-induced mortality in both species, that is, genotypes differed in their tolerance to estrogen pollution. We also found maternal effects on embryo development to be influenced by EE2, that is, some maternal sib groups were more susceptible to EE2 than others. In conclusion, the toxic effects of EE2 were strong, but both species demonstrated the kind of additive genetic variation that is necessary for an evolutionary response to this type of pollution. PMID- 25553071 TI - The effect of inbreeding rate on fitness, inbreeding depression and heterosis over a range of inbreeding coefficients. AB - Understanding the effects of inbreeding and genetic drift within populations and hybridization between genetically differentiated populations is important for many basic and applied questions in ecology and evolutionary biology. The magnitudes and even the directions of these effects can be influenced by various factors, especially by the current and historical population size (i.e. inbreeding rate). Using Drosophila littoralis as a model species, we studied the effect of inbreeding rate over a range of inbreeding levels on (i) mean fitness of a population (relative to that of an outbred control population), (ii) within population inbreeding depression (reduction in fitness of offspring from inbred versus random mating within a population) and (iii) heterosis (increase in fitness of offspring from interpopulation versus within-population random mating). Inbreeding rate was manipulated by using three population sizes (2, 10 and 40), and fitness was measured as offspring survival and fecundity. Fast inbreeding (smaller effective population size) resulted in greater reduction in population mean fitness than slow inbreeding, when populations were compared over similar inbreeding coefficients. Correspondingly, populations with faster inbreeding expressed more heterosis upon interpopulation hybridization. Inbreeding depression within the populations did not have a clear relationship with either the rate or the level of inbreeding. PMID- 25553072 TI - Can sexual selection theory inform genetic management of captive populations? A review. AB - Captive breeding for conservation purposes presents a serious practical challenge because several conflicting genetic processes (i.e., inbreeding depression, random genetic drift and genetic adaptation to captivity) need to be managed in concert to maximize captive population persistence and reintroduction success probability. Because current genetic management is often only partly successful in achieving these goals, it has been suggested that management insights may be found in sexual selection theory (in particular, female mate choice). We review the theoretical and empirical literature and consider how female mate choice might influence captive breeding in the context of current genetic guidelines for different sexual selection theories (i.e., direct benefits, good genes, compatible genes, sexy sons). We show that while mate choice shows promise as a tool in captive breeding under certain conditions, for most species, there is currently too little theoretical and empirical evidence to provide any clear guidelines that would guarantee positive fitness outcomes and avoid conflicts with other genetic goals. The application of female mate choice to captive breeding is in its infancy and requires a goal-oriented framework based on the needs of captive species management, so researchers can make honest assessments of the costs and benefits of such an approach, using simulations, model species and captive animal data. PMID- 25553073 TI - Museum DNA reveals the demographic history of the endangered Seychelles warbler. AB - The importance of evolutionary conservation - how understanding evolutionary forces can help guide conservation decisions - is widely recognized. However, the historical demography of many endangered species is unknown, despite the fact that this can have important implications for contemporary ecological processes and for extinction risk. Here, we reconstruct the population history of the Seychelles warbler (Acrocephalus sechellensis) - an ecological model species. By the 1960s, this species was on the brink of extinction, but its previous history is unknown. We used DNA samples from contemporary and museum specimens spanning 140 years to reconstruct bottleneck history. We found a 25% reduction in genetic diversity between museum and contemporary populations, and strong genetic structure. Simulations indicate that the Seychelles warbler was bottlenecked from a large population, with an ancestral N e of several thousands falling to <50 within the last century. Such a rapid decline, due to anthropogenic factors, has important implications for extinction risk in the Seychelles warbler, and our results will inform conservation practices. Reconstructing the population history of this species also allows us to better understand patterns of genetic diversity, inbreeding and promiscuity in the contemporary populations. Our approaches can be applied across species to test ecological hypotheses and inform conservation. PMID- 25553074 TI - Molecular detection of trophic interactions: emerging trends, distinct advantages, significant considerations and conservation applications. AB - The emerging field of ecological genomics contains several broad research areas. Comparative genomic and conservation genetic analyses are providing great insight into adaptive processes, species bottlenecks, population dynamics and areas of conservation priority. Now the same technological advances in high-throughput sequencing, coupled with taxonomically broad sequence repositories, are providing greater resolution and fundamentally new insights into functional ecology. In particular, we now have the capacity in some systems to rapidly identify thousands of species-level interactions using non-invasive methods based on the detection of trace DNA. This represents a powerful tool for conservation biology, for example allowing the identification of species with particularly inflexible niches and the investigation of food-webs or interaction networks with unusual or vulnerable dynamics. As they develop, these analyses will no doubt provide significant advances in the field of restoration ecology and the identification of appropriate locations for species reintroduction, as well as highlighting species at ecological risk. Here, I describe emerging patterns that have come from the various initial model systems, the advantages and limitations of the technique and key areas where these methods may significantly advance our empirical and applied conservation practices. PMID- 25553076 TI - The emerging role of miRNAs in inflammatory bowel disease: a review. AB - Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies. PMID- 25553077 TI - The role and utility of faecal markers in inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis are characterized by periods of symptomatic relapse and remission. Diagnosis and assessment of inflammatory bowel disease has so far been based on clinical evaluation, serum parameters, radiology and endoscopy. Faecal markers such as calprotectin or lactoferrin have emerged as new diagnostic tools to detect and monitor intestinal inflammation. This review focuses on their potential clinical applications and limitations in the management of inflammatory bowel disease. PMID- 25553079 TI - Clinicopathologic characteristics and management trends of cutaneous invasive and in situ melanoma in older patients: a retrospective analysis of the National Cancer Data Base. AB - BACKGROUND: The incidence of melanoma in older patients is on the rise. Prior studies have shown disparities in surgical management and poor survival of older patients with melanoma. METHODS: This is a retrospective study of adult patients diagnosed with cutaneous invasive and in situ melanoma between 2000 and 2011 in the National Cancer Data Base. Characteristics and management of older patients (>=60 years) were compared with younger patients (20-59 years) using chi(2) testing. RESULTS: Of 476,623 total cases, 54% (n = 258,153) were diagnosed among older patients. The reported cases in the older patients increased by 1.74-fold between 2000 and 2011. The majority were white (96%), men (65%), with early-stage disease (76% stage 0-II), and superficial spreading melanoma histology (39%). Older patients, compared with younger patients, were more likely to be men (65% versus 49%, p < 0.0001), and have in situ melanoma (28% versus 21%, p < 0.0001); less likely to have nodal metastases (7% versus 9%, p < 0.0001), receive care in academic centers (30% versus 35%, p < 0.0001), undergo wide excision or major amputation for stage I-III disease (68% versus 72%, p < 0.0001) and systemic therapy for stage III (18% versus 45%, p < 0.0001) and IV disease (30% versus 50%, p < 0.0001). CONCLUSION: Older patients with melanoma are less likely to receive care in academic centers, undergo wide excision for stage I-III disease and receive systemic therapy for stage III-IV disease. Particularly, the utilization of systemic therapy is markedly low. This disparity is particularly important with the availability of less intense more effective therapies. PMID- 25553078 TI - New insights and challenges in microscopic colitis. AB - Microscopic colitis (MC) is described as an inflammatory bowel disease characterized by chronic, bloodless diarrhea with normal or close to normal endoscopic findings. Histopathological examination reveals two subtypes: collagenous colitis (CC) and lymphocytic colitis (LC), which are indistinguishable clinically. The disease debuts typically in middle-aged patients, but can occur at all ages, including children. A female predominance is found in both CC and LC, but is not confirmed by others in LC. The etiology is unclear, but the disease has been assumed to be of autoimmune origin. However, several etiologies may render a microscopic inflammation in the mucosa; this is a common, universal reaction to a variety of irritants in contact with the intestinal lumen. Furthermore, some patients with a microscopic inflammation in their colonic mucosa have no symptoms, or are suffering from constipation or abdominal pain, rather than diarrhea. Recently, a discussion was initiated calling into question the overdiagnosing of symptoms and pointing out the danger of exacerbating people's perception of their ailments, of weakening their eligibility in health insurance, of overprescription of drugs, and thus the increasing cost to the society of health care. In the light of this discussion, this review will highlight histopathological and clinical features of MC, and discuss the diagnosis and management of this disease. Perhaps, the intestinal mucosa has no other mode by which to react than an inflammatory response, irrespective of the presence or absence of autoimmunity. Thus, to better identify and classify subgroups of MC, and to clarify and correctly handle the inflammatory changes, this field of research stands to benefit from a review of the results and experience gained to date. PMID- 25553080 TI - Anti-programmed death receptor 1 immunotherapy in melanoma: rationale, evidence and clinical potential. AB - Malignant melanoma is a significant public health problem; according to 2013 Surveillance, Epidemiology, and End Results data, its average incidence rate rose 2.6% each year for the last decade, and it is now the fifth most common cancer diagnosis in the United States. The rising incidence and historical poor response to chemotherapy have led to intense investigation of novel treatments for melanoma, including therapies to improve the immune-mediated destruction of cancer cells. Among the hallmarks of malignancy is the ability to evade this process: while early stages of tumor growth can induce functional CD8+ T-cell responses, cancer cells become increasingly embedded in an immune-suppressive tumor stroma. In the tumor microenvironment, T-cell proliferation and effector function are impaired due to engagement of T-cell programmed death receptor 1 (PD 1) with programmed death receptor ligand (PD-L1) expressed by cancer cells and antigen-presenting cells, which blocks T-cell-mediated cytotoxicity. This receptor-ligand engagement thereby inhibits immunity, allows the tumor to continue to grow, and contributes to the phenomenon of 'T-cell exhaustion'. One immunotherapy strategy currently under investigation is inhibition of the interaction between PD-L1 and PD-1, thereby overcoming a critical immune checkpoint to facilitate destruction of cancer cells. In this review we discuss the preclinical rationale for PD-1 pathway inhibition in cancer, recent results of clinical trials targeting PD-1 and PD-L1, and evaluate its potential as a future anticancer therapy. PMID- 25553082 TI - Adjuvant and/or neoadjuvant therapy for gastric cancer? A perspective review. AB - Surgery is still the only curative therapy for locoregional gastric cancer. Hereby it is important to achieve negative margins (R0 resection) and to perform an adequate lymph-node dissection (D2 lymphadenectomy). Unfortunately most cases of gastric cancer are diagnosed in a locally advanced tumor stage. The poor prognosis of patients with these tumors is due to the frequent recurrences after primary resection in curative intent. This observation led to the development of (neo)adjuvant treatment concepts. Beginning with the end of the 1980s, more and more patients with locally advanced tumors were subjected to a preoperative, perioperative, or postoperative treatment in order to improve the prognosis after curative resection. However, in different regions of the world, different regiments are preferred. While adjuvant chemotherapy is the established treatment in Asia, adjuvant chemoradiotherapy is favored in the USA and perioperative chemotherapy is considered the treatment of choice in Europe. However, recently a certain convergence of the different philosophies is to be observed. This article covers the relevant studies dealing with neoadjuvant and adjuvant treatment concepts and gives an overview on the latest developments in this field. PMID- 25553081 TI - Advances in thyroid cancer treatment: latest evidence and clinical potential. AB - Advanced thyroid carcinoma is an infrequent tumor entity with limited treatment possibilities until recently. The extraordinary improvement in the comprehension of genetic and molecular alterations involving the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin signaling and interacting pathways that are involved in tumor survival, proliferation, differentiation, motility and angiogenesis have been the rationale for the development of new effective targeted therapies. Data coming from phase II clinical trials have confirmed the efficacy of those targeted agents against receptors in cell membrane and cytoplasmic molecules. Moreover, four of those investigational drugs, vandetanib, cabozantinib, sorafenib and lenvatinib, have reached a phase III clinical trial with favorable results in progression-free survival and overall survival in medullary thyroid carcinoma and differentiated thyroid carcinoma. Further analysis for an optimal approach has been conducted according to mutational profile and tumor subtypes. However, consistent results are still awaited and the research for adequate prognostic and predictive biomarkers is ongoing. The following report offers a comprehensive review from the rationale to the basis of targeted agents in the treatment of thyroid carcinoma. In addition, current and future therapeutic developments by the inhibition of further molecular targets are discussed in this setting. PMID- 25553083 TI - Chemopreventive effects of korean red ginseng extract on rat hepatocarcinogenesis. AB - The objective of this study was to determine a chemopreventive activity of Korean red ginseng extract (KRG) in diethylnitrosamine (DEN) induced hepatocarcinogenesis in rats. After acclimatization for a week, Sprague-Dawley rats were randomized into five groups (n = 15) and fed either KRG (0.5, 1 or 2%) or control diets for 10 weeks. After two weeks of starting of experimental diets, the rats were initiated hepatocarcinogenesis by injection of DEN and were then subjected to two-thirds partial hepatectomy at five-week for developing the medium-term bioassay system. Both 0.5 and 1% KRG diets suppressed the area (55 and 60%; p= 0.0251 and 0.0144) and number (39 and 59%; p= 0.0433 and 0.0012) of glutathione S-transferase placental form (GST-P) positive foci when compared to the DEN-control group. The production of thiobarbituric acid reactive substances (TBARS) was significantly reduced in 0.5 and 1% KRG-treated rats. The supplementation of 1% KRG diet significantly elevated the levels of total glutathione (tGSH) and glutathione-related enzymes including cytosolic glutathione S-transferase (GST) and glutathione peroxidase (GPx) activities. It was also observed in cDNA microarray that the gene expressions (Cyp2c6, Cyp2e1, Cyp3a9, and Mgst1) involved in the xenobiotics metabolism via cytochrome P450 signaling pathway were down-regulated in the 1% KRG diet-treated group when compared to the DEN-control. The chemopreventive effects of KRG could be affected by 1) the decrease of lipid peroxidation, 2) the increase of tGSH content and GSH dependent enzyme activities, and 3) the decrease of the gene expression profile involved in cytochrome P450 signaling pathway. These results suggest that KRG may prove to be a therapeutic agent against hepatocarcinogenesis. PMID- 25553085 TI - Upregulation of miRNA3195 and miRNA374b Mediates the Anti-Angiogenic Properties of Melatonin in Hypoxic PC-3 Prostate Cancer Cells. AB - Recently microRNAs (miRNAs) have been attractive targets with their key roles in biological regulation through post-transcription to control mRNA stability and protein translation. Though melatonin was known as an anti-angiogenic agent, the underlying mechanism of melatonin in PC-3 prostate cancer cells under hypoxia still remains unclear. Thus, in the current study, we elucidated the important roles of miRNAs in melatonin-induced anti-angiogenic activity in hypoxic PC-3 cells. miRNA array revealed that 33 miRNAs (>2 folds) including miRNA3195 and miRNA 374b were significantly upregulated and 16 miRNAs were downregulated in melatonin-treated PC-3 cells under hypoxia compared to untreated control. Melatonin significantly attenuated the expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha and vascular endothelial growth factor (VEGF) at mRNA level in hypoxic PC-3 cells. Consistently, melatonin enhanced the expression of miRNA3195 and miRNA 374b in hypoxic PC-3 cells by qRT-PCR analysis. Of note, overexpression of miRNA3195 and miRNA374b mimics attenuated the mRNA levels of angiogenesis related genes such as HIF-1alpha, HIF-2 alpha and VEGF in PC-3 cells under hypoxia. Furthermore, overexpression of miRNA3195 and miRNA374b suppressed typical angiogenic protein VEGF at the protein level and VEGF production induced by melatonin, while antisense oligonucleotides against miRNA 3195 or miRNA 374b did not affect VEGF production induced by melatonin. Also, overexpression of miR3195 or miR374b reduced HIF-1 alpha immunofluorescent expression in hypoxic PC 3 compared to untreated control. Overall, our findings suggest that upregulation of miRNA3195 and miRNA374b mediates anti-angiogenic property induced by melatonin in hypoxic PC-3 cells. PMID- 25553086 TI - Cancer: we should not forget the past. AB - Cancer has been in existence longer than human beings, and man has been facing the illness ever since he made his appearance on Earth. Amazingly, the first human cancer gene was cloned only thirty years ago. This, and other extraordinary scientific goals achieved by molecular cancer research in the last 30 years, seems to suggest that definitive answers and solutions to this severe disease have been finally found. This was not the case, as cancer still remains to be defeated. To do so, cancer must be first understood. This review highlights how cancer onset and progression has been tackled from ancient times to present day. Old theories and achievements have provided the pillars of cancer understanding, in laying the basis of 'modern era' cancer research, are discussed. The review highlights the discovery of oncogenes and suppressor tumor genes, underlining the crucial role of these achievements in cancer diagnosis and therapies. Finally, an overview of how the modern technologies have given impetuous to expedite these goals is also considered. PMID- 25553087 TI - Differentiation between Malignant and Benign Solitary Lesions in the Liver with (18)FDG PET/CT: Accuracy of Age-related Diagnostic Standard. AB - OBJECTIVE: This study was to determine the reliability of age-stratified diagnostic index in differential diagnosis of malignant and benign solitary lesions in the liver using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ((18)FDG PET/CT). METHODS: The enrolled 272 patients with solitary lesions in the liver were divided into three age groups, younger group (under 50 years), middle-aged group (50-69 years), and elderly group (70 years and above). Patients' ages were compared, and the optimal cut offs of the standard uptake value (SUV) ratio (tumor-to-non-tumor ratio of the SUV), as well as areas under the curves (AUC), were evaluated in terms of malignant and benign lesions in each age group by using receiver operating characteristic (ROC) analysis. Based on optimal cut-offs, the sensitivity, specificity, accuracy were calculated, and the diagnostic accordance rate was compared between each age group and all patients, supported by (18)FDG PET/CT imaging data. RESULTS: There was a significant age difference between the malignant and benign groups (t=3.905 p=0.0001). ROC analysis showed that the optimal cut-off value in all patients, younger group, middle-aged group and elderly group was 1.25, 1.17, 1.45 and 1.25 for SUVratio, and 0.856, 0.962, 0.650, 0.973 for AUC. The chi-square test proved that diagnostic accordance rate of (18)FDG PET/CT in younger group and elderly group were superior to that in all patients (chi(2)=13.352, P=0.0003) and (chi(2)=8.494, P=0.0036). Conversely, overall diagnostic accordance rate in all patient group was higher than that in middle-aged group (chi(2)=9.057, P=0.0026). Representative (18)FDG PET/CT imaging findings are demonstrated. CONCLUSION: This study indicates that diagnostic optimal cut-offs of SUVratio of liver solitary lesions of (18)FDG PET/CT were different in each age group. In addition, the diagnostic performance of SUVratio was better in younger and elderly groups than that in all patients, and was poorer in middle-aged group than that in all patients. Therefore, age difference appears to be one of the important factors for discriminating malignant liver lesions from benign ones using (18) FDG PET/CT. PMID- 25553084 TI - Use of proteins as biomarkers and their role in carcinogenesis. AB - SUMMARY: Improved diagnostic methods and medical therapies are necessary for early detection and treatment and an improved prognosis. It is thus vital to both examine and evaluate the role of the various existing proteins as biomarkers in carcinogenesis and to assess the contribution of these proteins in anti-cancer activity, for consideration in therapeutic strategies. It is essential to both examine and evaluate the role of the various existing proteins as biomarkers in carcinogenesis and to assess the contribution of these proteins in anti-cancer activity, for consideration in therapeutic strategies. The purpose of this review is twofold. Firstly, it is to evaluate recent data about which proteins can be utilized as biomarkers in carcinogenesis. The proteins reviewed include: CPTP, IL 6, CCN, and S100. Secondly, it is to evaluate the contribution of dietary proteins in cancer activity. Specifically, how whey protein, soy proteins and lectin, a phytochemical could be useful in cancer prevention and treatment. RECENT FINDINGS: Whey protein, present in dairy products, is an excellent source of the sulphur amino acid cysteine, the rate limiting substrate in glutathione synthesis. Notably, this protein survives digestion and has been shown to have anti-carcinogenic properties in animal studies. Lectins are phytochemicals present in plant foods, and have active components which alters cancer initiation, promotion and progression. Lectins have been characterized as a useful tool in biochemistry, cell biology, immunology and in diagnostic and therapeutic purposes in cancer research. Soy proteins contain various compounds, including isoflavones, protease inhibitors and protein kinase inhibitors, which have been proven effective in tumor growth inhibition. They have therefore, been greatly emphasized in cancer prevention and treatment. It has been proved that soy food consumption was associated with decreased risk of death and recurrence of breast cancer. CPTP is a recently discovered protein whose main role is to transport C1P, a pro-inflammatory molecule. The discovery of CPTP may shine a light on the mechanism of inflammatory diseases, and hopefully offer a potential target for therapeutic purposes in cancer research. Interleukin-6 is a multifunctional cytokine that affects the activity of cancer cells. It is involved in tumor growth, and elevated levels is associated with an increased risk of cancer. S100B is a well-established biomarker for malignant melanoma, and useful in assessing tumor load, stage and prognosis for patients with this disease. Other members of this family of proteins include S100A4, which has been associated with several malignancies and S100A2, which has been found to be decreased in some cancers. CCN are a group of regulatory proteins, located in the extracellular matrix (maricellular). They are involved in cellular adhesion, mitogenesis, chemotaxis, cell survival, and wound healing. CCN proteins are also able to modulate the signals of several proteins, which may also influence skeletal development and angiogenesis. Many of the functions of these proteins are thus also related to tumor growth. Furthermore, CCN interacts with estrogen in the development of cancer, and is implicated in some breast and ovarian cancers. PMID- 25553088 TI - Upregulation of Acetylcholinesterase Mediated by p53 Contributes to Cisplatin Induced Apoptosis in Human Breast Cancer Cell. AB - BACKGROUND: The expression of acetylcholinesterase (AChE) could be induced during apoptosis in various cell types. And reduced AChE expression either by siRNA could prevent apoptosis. However, the detailed mechanisms underlying the AChE regulation are largely unknown in human breast cancer cell. MATERIAL AND METHODS: MCF-7 cells were cultured and treated by cisplatin in the absence or presence of p53 siRNA. RESULTS: In this study, the regulation of AChE expression during apoptosis induced by cisplatin, a current used anticancer drug, was investigated in human breast cancer cell line MCF-7. Exposure of MCF-7 cells to cisplatin resulted in apoptosis in a time- and concentration-dependent manner. Meanwhile, the upregulated AChE and p53 were also observed during apoptosis. Silencing interfering RNA directed against p53 blocked the expression of AChE. CONCLUSION: Taken together, these results suggested that AChE expression could be upregulated by the activation of p53 during apoptosis induced by cisplatin in MCF-7 cells. PMID- 25553090 TI - Spatial and temporal fracture pattern in breast and gynecologic cancer survivors. AB - OBJECTIVE(S): To assess skeletal wide fracture location and time of fracture after cancer treatment Study Design: One hundred thirty-nine women diagnosed with breast or gynecologic cancer between 2003 and 2012 that subsequently had a radiologic diagnosis of fracture were identified retrospectively using electronic medical records. RESULTS were compared with skeletal fracture pattern previously reported for a general population. RESULTS: Skeletal fractures in cancer patients occur throughout the entire skeleton similar to general population. The most common sites were vertebrae (16%), feet and toes (15%), ribs (12%), hands and fingers (10%), and pelvis (8%). Fracture incidence was observed starting within the first year of survivorship, and continued to after five years. The median time from cancer diagnosis to fracture varied by age (p<0.01), from a high of 3.2 years for ages 50-59 to a low of 1.2 years for patients older than 70. CONCLUSION: The pattern of skeletal fracture is similar between cancer survivor and general population. Contrary to general assumption, survivors can experience skeletal fracture early after cancer treatment, especially at an older age. Thus, cancer survivorship care should include assessment of early time points with improved management of cancer treatment related bone injury. PMID- 25553091 TI - ERCC1 Induction after Oxaliplatin Exposure May Depend on KRAS Mutational Status in Colorectal Cancer Cell Line: In Vitro Veritas. AB - INTRODUCTION: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance. MATERIAL AND METHODS: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor. RESULTS: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line. CONCLUSION: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC1. PMID- 25553092 TI - Changes in bone density after cancer treatment in patients with cervical and endometrial cancer. AB - OBJECTIVE: This study aimed to evaluate the impact of cancer treatment on bone mineral density (BMD) in the lumbar spine (LS) and femur in the postmenopausal women with cervical or endometrial cancer without bone metastasis compared to normal control postmenopausal women. METHODS: We retrospectively evaluated the BMD data in the LS, femur neck (FN) and trochanter (FT) by dual-energy X-ray absorptiometry and laboratory data of bone turnover markers at baseline and after one year in 130 patients with cervical cancer, 68 patients with endometrial cancer, and 225 healthy controls. RESULTS: There were no significant differences in the T-scores of basal BMD in LS and femur between patients with endometrial cancer and controls, and only T-score of basal BMD at the fourth lumbar vertebra (L4) was significantly lower in patients with cervical cancer compared to controls. One year later, T-scores of BMD at all LS sites and FN in patients with cervical cancer and T-scores of BMD at L3, L4, FN, and FT in those with endometrial cancer after cancer treatment were significantly lower compared to controls. Lower proportions of normal BMD at all skeletal sites except L2 in patients with endometrial cancer and those at L1, L4, and FN in patients with cervical cancer were observed compared to controls after cancer treatment. CONCLUSIONS: Our results suggest that cancer treatment increase bone loss in postmenopausal women with cervical and endometrial cancer. PMID- 25553089 TI - Pathway and network approaches for identification of cancer signature markers from omics data. AB - The advancement of high throughput omic technologies during the past few years has made it possible to perform many complex assays in a much shorter time than the traditional approaches. The rapid accumulation and wide availability of omic data generated by these technologies offer great opportunities to unravel disease mechanisms, but also presents significant challenges to extract knowledge from such massive data and to evaluate the findings. To address these challenges, a number of pathway and network based approaches have been introduced. This review article evaluates these methods and discusses their application in cancer biomarker discovery using hepatocellular carcinoma (HCC) as an example. PMID- 25553093 TI - Discovery of invasion routes for nasopharyngeal adenoid cystic carcinoma. AB - The aim of this study is to discover regional invasion routes for nasopharyngeal adenoid cystic carcinoma (NACC) through analyses of the magnetic resonance (MR) images and comparison with keratinizing squamous cell carcinoma (KSCC). Both MR results and clinical records were retrospectively reviewed for 18 patients with NACC and 182 patients with KSCC. The metastasis routes of NACC were identified by analysis of MR images of patients who underwent magnetic resonance imaging (MRI). There were significant differences in skull base invasion and cavernous sinus invasion (p = 0.020 and 0.028, respectively) while parapharyngeal space invasion rate was not. The laryngopharynx invasion rate and external pterygoid muscle invasion rate were higher in NACC patients than that in KSCC patients (16.7% vs. 0.5 %, p = 0.002; 27.8% vs. 11.0%, p = 0.040, respectively). Paralysis of the cranial nerves had a significant higher incidence in the NACC group compared to the KSCC group (66.7% vs. 8.2%, p < 0.001). There was significant difference in invasion to the neural foramen between the NACC and KSCC groups (66.7% vs. 36.3%, p = 0.020). Foramen ovale was a common invasion site, significantly higher in NACC patients than in KSCC patients (50.0% vs. 24.1%, p = 0.018). Based on the MRI findings, a regional invasion model of NACC with two possible routes has been built, including aggressive local infiltration along submucosa to laryngopharynx or external pterygoid muscle, and extension from pharyngonasal cavity, through cranial nerve canal to cavernous sinus. The significant difference in overall survival (OS) time between the two different invasion routs and the recurrent rates in different regions also supported the validity of the invasion model. PMID- 25553094 TI - Pancreas-targeted NIR fluorophores for dual-channel image-guided abdominal surgery. AB - OBJECTIVE: Pancreas-related complications are some of the most serious ones in abdominal surgery. The goal of this study was to develop and validate novel near infrared (NIR) fluorophores that would enable real-time pancreas imaging to avoid the intraoperative pancreatic injury. DESIGN: After initial screening of a large NIR fluorophore library, the performance of 3 selected pancreas-targeted 700 nm NIR fluorophores, T700-H, T700-F, and MB, were quantified in mice, rats, and pigs. Dose ranging using 25 and 100 nmol, and 2.5 umol of T700-F, and its imaging kinetics over a 4 h period were tested in each species. Three different 800 nm NIR fluorophores were employed for dual-channel FLARETM imaging in pigs: 2 MUmol of ZW800-1 for vessels and kidney, 1 MUmol of ZW800-3C for lymph nodes, and 2 MUmol of ESNF31 for adrenal glands. RESULTS: T700-F demonstrated the highest signal to background ratio (SBR), with peak SBR at 4 h postinjection in mice. In pigs, T700-F produced an SBR>=2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection. The combination of T700-F with each 800 nm NIR fluorophore provided simultaneous dual-channel intraoperative imaging of pancreas with surrounding organs in real time. CONCLUSION: Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries. PMID- 25553095 TI - Histone H3 phosphorylation in GBM: a new rational to guide the use of kinase inhibitors in anti-GBM therapy. AB - Histones post-translational modifications (PTMs) are crucial components of diverse processes that modulate chromatin. Among the histones PTMs, the histones phosphorylation appears such crucial since it plays a significant role into DNA repair structure, transcription and chromatin compaction during cell division and apoptosis. However, little is known about the prognostic value of the histone phosphorylation in human cancer. This point could be considerate such as an important gap in anti-cancer therapy since the use of adequate kinase inhibitors could remedy to the aberrant histone phosphorylation associated with a poor prognosis factor. To remedy at this situation, we analyzed the phosphorylation level of histone H3 at the residues T3, T6, S10, S28, Y41 and T45 in a collection of 42 glioblastoma multiformes (GBM). Our data indicated that the high level of pH3T6, pH3S10 and pH3Y41 are signatures associated with a poor prognosis of overall survival (OS) of GBM treated with the "temozolomide and irradiation standard" treatment of GBM (named TMZ+Irad treatment). Our data also showed that these signatures are correlated with the high activity of kinases already described as writers of the pH3T6, pH3S10 and pH3Y41 i.e. the PKC, Aurora-B and JAK2, respectively. Finally, our analysis revealed that the use of Enzastaurin, AZD1152, and AZD1480 abrogated the high level of pH3T6, pH3S10 and pH3Y41 while increasing the sensitivity to the "temozolomide and irradiation"-induced cell death. To conclude, it appears that this work provides biomarkers for patient stratification for a therapy including kinase inhibitors. PMID- 25553097 TI - Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery. AB - Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers. PMID- 25553098 TI - An array-based approach to determine different subtype and differentiation of non small cell lung cancer. AB - Simple and accurate methods of discriminating subtype or differentiation of human tumor are critical for designing treatment strategies and predicting disease prognosis, and the currently used method to determine the two important factors mainly depends on histological examination by microscopy observation, which is laborious, highly trained operator required, and prone to be disruptive due to individual-to-individual judgment. Here we report a novel array-based method based on the interaction of graphene oxide (GO) and single-strand DNA modified gold nanoparticles (ssDNA-AuNPs) to distinguish between different subtypes and grades of tumors through their overall intracellular proteome signatures. Strategically, we first select eight proteins at 0.5 nM concentration in buffer or 10 nM in human serum to verify the discriminant ability of our method, then choose adenocarcinoma and squamous-cell carcinoma that account for 90% non-small cell lung cancer, as well as their respective three tumor grades as model system to provide a realistic testing ground for clinical cancer analysis. Consequently, total differentiation between different subtype and grade of tumor tissues has been achieved with as little as 100 ng of intracellular protein, suggesting the high sensitivity and selectivity of this sensor array. Overall, this array-based approach may provide the possibility for unbiased and simplified personalized tumor classification diagnostics in the future. PMID- 25553096 TI - Nucleic acid aptamer-guided cancer therapeutics and diagnostics: the next generation of cancer medicine. AB - Conventional anticancer therapies, such as chemo- and/or radio-therapy are often unable to completely eradicate cancers due to abnormal tumor microenvironment, as well as increased drug/radiation resistance. More effective therapeutic strategies for overcoming these obstacles are urgently in demand. Aptamers, as chemical antibodies that bind to targets with high affinity and specificity, are a promising new and novel agent for both cancer diagnostic and therapeutic applications. Aptamer-based cancer cell targeting facilitates the development of active targeting in which aptamer-mediated drug delivery could provide promising anticancer outcomes. This review is to update the current progress of aptamer based cancer diagnosis and aptamer-mediated active targeting for cancer therapy in vivo, exploring the potential of this novel form of targeted cancer therapy. PMID- 25553099 TI - Copy number variation analysis by ligation-dependent PCR based on magnetic nanoparticles and chemiluminescence. AB - A novel system for copy number variation (CNV) analysis was developed in the present study using a combination of magnetic separation and chemiluminescence (CL) detection technique. The amino-modified probes were firstly immobilized onto carboxylated magnetic nanoparticles (MNPs) and then hybridized with biotin-dUTP products, followed by amplification with ligation-dependent polymerase chain reaction (PCR). After streptavidin-modified alkaline phosphatase (STV-AP) bonding and magnetic separation, the CL signals were then detected. Results showed that the quantification of PCR products could be reflected by CL signal values. Under optimum conditions, the CL system was characterized for quantitative analysis and the CL intensity exhibited a linear correlation with logarithm of the target concentration. To validate the methodology, copy numbers of six genes from the human genome were detected. To compare the detection accuracy, multiplex ligation dependent probe amplification (MLPA) and MNPs-CL detection were performed. Overall, there were two discrepancies by MLPA analysis, while only one by MNPs-CL detection. This research demonstrated that the novel MNPs-CL system is a useful analytical tool which shows simple, sensitive, and specific characters which are suitable for CNV analysis. Moreover, this system should be improved further and its application in the genome variation detection of various diseases is currently under further investigation. PMID- 25553100 TI - Codon-optimized human sodium iodide symporter (opt-hNIS) as a sensitive reporter and efficient therapeutic gene. AB - To generate a more efficient in vivo reporter and therapeutic gene, we optimized the coding sequence of the human sodium/iodide symporter (NIS) gene by replacing NIS DNA codons from wild type to new codons having the highest usage in human gene translation. The Codon Adaptation Index (CAI), representing the number of codons effective for human expression, was much improved (0.79 for hNIS, 0.97 for opt-hNIS). Both wild-type (hNIS) and optimized human NIS (opt-hNIS) were cloned into pcDNA3.1 and pMSCV vectors for transfection. Various cancer cell lines such as thyroid (TPC-1, FRO, B-CPAP), breast (MDA-MB-231), liver (Hep3B), cervical (HeLa), and glioma (U87MG) were transfected with pcDNA3.1/hNIS or pcDNA3.1/opt hNIS. 125I uptake by opt-hNIS-expressing cells was 1.6~2.1 times higher than uptake by wild-type hNIS-expressing cells. Stable cell lines were also established by retroviral transduction using pMSCV/hNIS or pMSCV/opt-hNIS, revealing higher NIS protein levels and 125I uptake in opt-hNIS-expressing cells than in hNIS-expressing cells. Moreover, scintigraphic images from cell plates and mouse xenografts showed stronger signals from opt-hNIS-expressing cells than hNIS-expressing cells, and radioactivity uptake by opt-hNIS-expressing tumors was 2.3-fold greater than that by hNIS-expressing tumors. To test the efficacy of radioiodine therapy, mouse xenograft models were established with cancer cells expressing hNIS or opt-hNIS. 131I treatment reduced tumor sizes of hNIS- and opt hNIS-expressing tumors to 0.57- and 0.27- fold, respectively, compared to their sizes before therapy, suggesting an improved therapeutic effect of opt-hNIS. In summary, this study shows that codon optimization strongly increases hNIS protein levels and radioiodine uptake, thus supporting opt-hNIS as a more sensitive reporter and efficient therapeutic gene. PMID- 25553101 TI - Theranostic mRNA-loaded microbubbles in the lymphatics of dogs: implications for drug delivery. AB - Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles. PMID- 25553102 TI - Chitosan/siRNA nanoparticles targeting cyclooxygenase type 2 attenuate unilateral ureteral obstruction-induced kidney injury in mice. AB - Cyclooxygenase type 2 (COX-2) plays a predominant role in the progression of kidney injury in obstructive nephropathy. The aim of this study was to test the efficacy of chitosan/small interfering RNA (siRNA) nanoparticles to knockdown COX 2 specifically in macrophages to prevent kidney injury induced by unilateral ureteral obstruction (UUO). Using optical imaging techniques and confocal microscopy, we demonstrated that chitosan/siRNA nanoparticles accumulated in macrophages in the obstructed kidney. Consistent with the imaging data, the obstructed kidney contained a higher amount of siRNA and macrophages. Chitosan formulated siRNA against COX-2 was evaluated on RAW macrophages demonstrating reduced COX-2 expression and activity after LPS stimulation. Injection of COX-2 chitosan/siRNA nanoparticles in mice subjected to three-day UUO diminished the UUO-induced COX-2 expression. Likewise, macrophages in the obstructed kidney had reduced COX-2 immunoreactivity, and histological examination showed lesser tubular damage in COX-2 siRNA-treated UUO mice. Parenchymal inflammation, assessed by tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 mRNA expression, was attenuated by COX-2 siRNA. Furthermore, treatment with COX-2 siRNA reduced heme oxygenase-1 and cleaved caspase-3 in UUO mice, indicating lesser oxidative stress and apoptosis. Our results demonstrate a novel strategy to prevent UUO-induced kidney damage by using chitosan/siRNA nanoparticles to knockdown COX-2 specifically in macrophages. PMID- 25553104 TI - Insights into the distinguishing stress-induced cytotoxicity of chiral gold nanoclusters and the relationship with GSTP1. AB - Chiral gold nanoclusters (Au NCs) exhibit attracting properties owing to their unique physical and chemical properties. Herein we report for the first time chiral gold nanoclusters' cytotoxicity and potential molecular mechanism. The L glutathione (i.e. L-GSH) and D-glutathione (i.e. D-GSH)-capped Au NCs were prepared and characterized by HRTEM, UV-vis, photoluminescence and circular dichroism (CD) spectroscopy. Results showed that the CD spectra of L-glutathione (i.e. L-GSH) and D-glutathione (i.e. D-GSH)-capped Au NCs exhibited multiple bands which were identically mirror-imaged, demonstrating that the chirality of GSH-capped NCs had contributions from both the metal core and the ligand. The effects of AuNCs@L-GSH and AuNCs@D-GSH on cells were similar based on the cell physiology related cytotoxicity, although the effects became more prominent in AuNCs@D-GSH treated cells, including ROS generation, mitochondrial membrane depolarization, cell cycle arrest and apoptosis. Global gene expression and pathway analysis displayed that both AuNCs@L-GSH and AuNCs@D-GSH caused the up regulation of genes involved in cellular rescue and stress response, while AuNCs@D-GSH individually induced up-regulation of transcripts involved in some metabolic- and biosynthetic-related response. MGC-803 cells were more sensitive to the oxidative stress damage induced by chiral Au NCs than GES-1 cells, which was associated with GSTP1 hypermethylation. In conclusion, chiral gold nanoclusters exhibit this chirality-associated regulation of cytotoxicity, different gene expression profiling and epigenetic changes should be responsible for observed phenomena. Our study highlights the importance of the interplays between chiral materials and biological system at sub-nano level. PMID- 25553103 TI - alphaVbeta3-targeted copper nanoparticles incorporating an Sn 2 lipase-labile fumagillin prodrug for photoacoustic neovascular imaging and treatment. AB - Photoacoustic (PA) tomography enables multiscale, multicontrast and high resolution imaging of biological structures. In particular, contrast-enhanced PA imaging offers high-sensitivity noninvasive imaging of neovessel sprout formation and nascent tubules, which are important biomarkers of malignant tumors and progressive atherosclerotic disease. While gold nanoparticles or nanorods have been used as PA contrast agents, we utilized high-density copper oleate small molecules encapsulated within a phospholipid surfactant (CuNPs) to generate a soft nanoparticle with PA contrast comparable to that from gold. Within the NIR window, the copper nanoparticles provided a 4-fold higher signal than that of blood. alphanubeta3-integrin targeting of CuNPs in a Matrigel(TM) angiogenesis mouse model demonstrated prominent (p<0.05) PA contrast enhancement of the neovasculature compared with mice given nontargeted or competitively inhibited CuNPs. Furthermore, incorporation of a Sn 2 lipase-labile fumagillin prodrug into the CuNP outer lipid membrane produced marked antiangiogenesis in the same model when targeted to the alphanubeta3-integrin, providing proof of concept in vivo for the first targeted PA - drug delivery agent. PMID- 25553106 TI - Fluorescent sensing of fluoride in cellular system. AB - Fluoride ions have the important roles in a lot of physiological activities related with biological and medical system, such as water fluoridation, caries treatment, and bone disease treatment. Great efforts have been made to develop new methods and strategies for F(-) detection in the past decades. Traditional methods for the detection of F(-) including ion chromatography, ion-selective electrodes, and spectroscopic techniques have the limitations in the biomedicine research. The fluorescent probes for F(-) are very promising that overcome some drawbacks of traditional fluoride detection methods. These probes exhibit high selectivity, high sensitivity as well as quick response to the detection of fluoride anions. The review commences with a brief description of photophysical mechanisms for fluorescent probes for fluoride, including photo induced electron transfer (PET), intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET), and excited-state intramolecular proton transfer (ESIPT). Followed by a discussion about common dyes for fluorescent fluoride probes, such as anthracene, naphalimide, pyrene, BODIPY, fluorescein, rhodamine, resorufin, coumarin, cyanine, and near-infrared (NIR) dyes. We divide the fluorescent probes for fluoride in cellular application systems into nine groups, for example, type of hydrogen bonds, type of cleavage of Si-O bonds, type of Si-O bond cleavage and cylization reactions, etc. We also review the recent reported carriers in the delivery of fluorescent fluoride probes. Seventy-four typical fluorescent fluoride probes are listed and compared in detail, including quantum yield, reaction medium, excitation and emission wavelengths, linear detection range, selectivity for F(-), mechanism, and analytical applications. Finally, we discuss the future challenges of the application of fluorescent fluoride probes in cellular system and in vivo. We wish that more and more excellent fluorescent fluoride probes will be developed and applied in the biomedicine field in the future. PMID- 25553105 TI - Macrophage targeted theranostics as personalized nanomedicine strategies for inflammatory diseases. AB - Inflammatory disease management poses challenges due to the complexity of inflammation and inherent patient variability, thereby necessitating patient specific therapeutic interventions. Theranostics, which integrate therapeutic and imaging functionalities, can be used for simultaneous imaging and treatment of inflammatory diseases. Theranostics could facilitate assessment of safety, toxicity and real-time therapeutic efficacy leading to personalized treatment strategies. Macrophages are an important cellular component of inflammatory diseases, participating in varied roles of disease exacerbation and resolution. The inherent phagocytic nature, abundance and disease homing properties of macrophages can be targeted for imaging and therapeutic purposes. This review discusses the utility of theranostics in macrophage ablation, phenotype modulation and inhibition of their inflammatory activity leading to resolution of inflammation in several diseases. PMID- 25553107 TI - In situ high throughput scattering light analysis of single plasmonic nanoparticles in living cells. AB - Plasmonic nanoparticles have been widely applied in cell imaging, disease diagnosis, and photothermal therapy owing to their unique scattering and absorption spectra based on localized surface plasmon resonance (LSPR) property. Recently, it is still a big challenge to study the detailed scattering properties of single plasmonic nanoparticles in living cells and tissues, which have dynamic and complicated environment. The conventional approach for measuring the scattering light is based on a spectrograph coupled to dark-field microscopy (DFM), which is time-consuming and limited by the small sample capacity. Alternatively, RGB-based method is promising in high-throughput analysis of single plasmonic nanoparticles in dark-field images, but the limitation in recognition of nanoparticles hinders its application for intracellular analysis. In this paper, we developed an automatic and robust method for recognizing the plasmonic nanoparticles in dark-field image for RGB-based analysis. The method involves a bias-modified fuzzy C-means algorithm, through which biased illumination in the image could be eliminated. Thus, nearly all of the gold nanoparticles in the recorded image were recognized both on glass slide and in living cells. As confirmed, the distribution of peak wavelength obtained by our method is well agreed to the result measured by conventional method. Furthermore, we demonstrated that our method is profound in cell imaging studies, where its advantages in fast and high-throughput analysis of the plasmonic nanoparticles could be applied to confirm the presence and location of important biological molecules and provide efficiency information for cancer drug selection. PMID- 25553108 TI - Percutaneous intramyocardial delivery of mesenchymal stem cells induces superior improvement in regional left ventricular function compared with bone marrow mononuclear cells in porcine myocardial infarcted heart. AB - AIM: To investigate the efficacy and feasibility of percutaneous intramyocardial injection of bone marrow mesenchymal stem cells (MSC) and autologous bone marrow derived mononuclear cells (BMMNC) on cardiac functional improvement in porcine myocardial infarcted hearts. METHODS AND RESULTS: Acute myocardial infarction (AMI) was induced in 22 minipigs by temporary balloon occlusion of the left anterior descending coronary artery for 60 min.Two weeks post AMI, BMMNC (n = 7, 245 +/- 98 * 10(6)), MSC (n = 8, 56 +/- 17 * 10(6)), or phosphate buffered saline (PBS; n = 7) were injected intramyocardially. Cardiac function and myocardial perfusion were analyzed by echocardiography and gated single-photon emission computed tomography/computed tomography (SPECT/CT) at 1 week before AMI and 2 and 10 weeks after AMI. Cell engraftment, proliferation, vascular density, and cardiac fibrosis were evaluated by histology analysis. In all groups, the echocardiography revealed no significant change in the left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), or left ventricular end-diastolic volume (LVEDV) at 10 weeks after AMI compared with those at 2 weeks after AMI. However, the wall motion score index (WMSI) and left ventricular systolic wall thickening (WT%) were significantly improved at 10 weeks compared with those at 2 weeks after AMI in the MSC group (WMSI 1.55 +/- 0.06 vs. 1.87 +/- 0.10, WT 33.4 +/- 2.3% vs.24.8 +/- 2.7%,p < 0.05) but not in the BMMNC group. In addition, myocardial perfusion quantified by SPECT/CT was improved in both the MSC and BMMNC groups, whereas the MSC group showed a superior improvement in vascular density and collagen volume fraction (p < 0.05). CONCLUSION: This preclinically relevant study suggests that when delivered by percutaneous (transcatheter) intramyocardial injection, MSC might be more effective than BMMNC to improve ischemia and reperfusion after AMI. PMID- 25553109 TI - Ultrasound molecular imaging of vascular endothelial growth factor receptor 2 expression for endometrial receptivity evaluation. AB - PURPOSE: Ultrasound (US) molecular imaging by examining the expression of vascular endothelial growth factor receptor 2 (VEGFR2) on uterus vascular endothelium was applied to evaluate the endometrial receptivity. METHODS: VEGFR2 targeted ultrasound contrast agents (UCA) and the control UCA (without VEGFR2) were prepared and characterized. Adhesion experiment in vitro was performed with mouse microvascular endothelial cells (bEnd.3) and the ratio of the number of UCA to that of cells at the same field was compared. In vivo study, randomized boluses of targeted or control UCA were injected into the animals of non pregnancy (D0), pregnancy on day 2 (D2) and day 4 (D4), respectively. Sonograms were acquired by an ultrasound equipment with a 40-MHz high-frequency transducer (Vevo 2100; VisualSonics, Toronto, Canada). The ultrasonic imaging signals were quantified as the video intensity amplitudes generated by the attachment of VEGFR2-targeted UCA. Immunoblotting and immunofluorescence assays were used for confirmation of VEGFR2 expression. RESULTS: Our results showed that VEGFR2 targeted UCA could bind to bEnd.3 cells with significantly higher affinity than the control UCA (9.8 +/- 1.0 bubbles/cell versus 0.7 +/- 0.3 bubbles/cell, P < 0.01) in vitro. The mean video intensity from the US backscattering of the retained VEGFR2-targeted UCA was significantly higher than that of the control UCA in D2 and D4 mice (D2, 10.5 +/- 2.5 dB versus 1.5 +/- 1.1 dB, P < 0.01; D4, 15.7 +/- 4.0 dB versus 1.5 +/- 1.2 dB, P < 0.01), but not significantly different in D0 mice (1.0 +/- 0.8 dB versus 0.9 +/- 0.6 dB, P > 0.05). Moreover, D4 mice showed the highest video intensity amplitude, indicating the highest VEGFR2 expression when compared with D2 and D0 mice (P < 0.01). This was further confirmed by our immunoblotting and immunofluorescence experiments. CONCLUSION: Ultrasound molecular imaging with VEGFR2-targeted UCA may be used for noninvasive evaluation of endometrial receptivity in murine models. PMID- 25553110 TI - Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon. AB - A recent study revealed that quantitative hepatitis B core antibody (qAnti-HBc) level could serve as a novel marker for predicting treatment response. In the present study, we further investigated the predictive value of qAnti-HBc level in HBeAg-positive patients undergoing PEG-IFN therapy. A total of 140 HBeAg-positive patients who underwent PEG-IFN therapy for 48 weeks and follow-up for 24 weeks were enrolled in this study. Serum samples were taken every 12 weeks post treatment. The predictive value of the baseline qAnti-HBc level for treatment response was evaluated. Patients were further divided into 2 groups according to the baseline qAnti-HBc level, and the response rate was compared. Additionally, the kinetics of the virological and biochemical parameters were analyzed. Patients who achieved response had a significantly higher baseline qAnti-HBc level (serological response [SR], 4.52+/-0.36 vs. 4.19+/-0.58, p=0.001; virological response [VR], 4.53+/-0.35 vs. 4.22+/-0.57, p=0.005; combined response [CR], 4.50+/-0.36 vs. 4.22+/-0.58, p=0.009)). Baseline qAnti-HBc was the only parameter that was independently correlated with SR (p=0.008), VR (p=0.010) and CR(p=0.019). Patients with baseline qAnti-HBc levels >=30,000 IU/mL had significantly higher response rates, more HBV DNA suppression, and better hepatitis control in PEG-IFN treatment. In conclusion, qAnti-HBc level may be a novel biomarker for predicting treatment response in HBeAg-positive patients receiving PEG-IFN therapy. PMID- 25553111 TI - 52Mn production for PET/MRI tracking of human stem cells expressing divalent metal transporter 1 (DMT1). AB - There is a growing demand for long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions. This work develops the production of (52)Mn and establishes proof of concept for the use of divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain. (52)Mn was produced via proton irradiation of a natural chromium target. In a comparison of two (52)Mn separation methods, solvent-solvent extraction was preferred over ion exchange chromatography because of reduced chromium impurities and higher (52)Mn recovery. In vitro uptake of Mn-based PET and MRI contrast agents ((52)Mn(2+) and Mn(2+), respectively) was enhanced in DMT1 over-expressing human neural progenitor cells (hNPC-DMT1) compared to wild-type control cells (hNPC-WT). After cell transplantation in the rat striatum, increased uptake of Mn based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese enhanced MRI (MEMRI) and ex vivo PET and autoradiography. These initial studies indicate that this approach holds promise for dual-modality PET/MR tracking of transplanted stem cells in the central nervous system and prompt further investigation into the clinical applicability of this technique. PMID- 25553112 TI - PEGylated exendin-4, a modified GLP-1 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction. AB - A Site-specifically PEGylated exendin-4 (denoted as PEG-Ex4) is an exendin-4 (denoted as Ex4) analog we developed by site-specific PEGylation of exendin-4 with a high molecular weight trimeric poly(ethylene glycol) (tPEG). It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified exendin-4 by our previous work. This study is sought to test whether PEG-Ex4 is suitable for treating myocardial infarction (MI). In the MI model, PEG-Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily. Animal survival rate, heart function, remodeling and neoangiogenesis were evaluated and compared. Tube formation was examined in endothelial cells. In addition, Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved. PEG-Ex4 and Ex4 showed comparable binding affinity to GLP-1 receptor. In MI mice, PEG-Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily, while Ex4 given at 3 days interval failed to produce protection. PEG-Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI. PEG-Ex4 increased Akt activity and VEGF production in a GLP-1R dependent manner in endothelial cells and antagonism of GLP-1R, Akt or VEGF abolished the protection of PEG-Ex4 in the MI model. PEG-Ex4 is a potent long acting GLP-1 receptor agonist for the treatment of chronic heart disease. Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and VEGF. PMID- 25553113 TI - Three-photon luminescence of gold nanorods and its applications for high contrast tissue and deep in vivo brain imaging. AB - Gold nanoparticles can be used as contrast agents for bio-imaging applications. Here we studied multi-photon luminescence (MPL) of gold nanorods (GNRs), under the excitation of femtosecond (fs) lasers. GNRs functionalized with polyethylene glycol (PEG) molecules have high chemical and optical stability, and can be used as multi-photon luminescent nanoprobes for deep in vivo imaging of live animals. We have found that the depth of in vivo imaging is dependent upon the transmission and focal capability of the excitation light interacting with the GNRs. Our study focused on the comparison of MPL from GNRs with two different aspect ratios, as well as their ex vivo and in vivo imaging effects under 760 nm and 1000 nm excitation, respectively. Both of these wavelengths were located at an optically transparent window of biological tissue (700-1000 nm). PEGylated GNRs, which were intravenously injected into mice via the tail vein and accumulated in major organs and tumor tissue, showed high image contrast due to distinct three-photon luminescence (3PL) signals upon irradiation of a 1000 nm fs laser. Concerning in vivo mouse brain imaging, the 3PL imaging depth of GNRs under 1000 nm fs excitation could reach 600 MUm, which was approximately 170 MUm deeper than the two-photon luminescence (2PL) imaging depth of GNRs with a fs excitation of 760 nm. PMID- 25553114 TI - Serum fucosylated prostate-specific antigen (PSA) improves the differentiation of aggressive from non-aggressive prostate cancers. AB - BACKGROUND: Clinically, it is still challenging to differentiate aggressive from non-aggressive prostate cancers (Pca) by non-invasive approaches. Our recent studies showed that overexpression of alpha (1-6) fucosyltransferase played an important role in Pca cells. In this study, we have investigated levels of glycoproteins and their fucosylated glycoforms in sera of Pca patients, as well as the potential utility of fucosylated glycoproteins in the identification of aggressive Pca. MATERIAL AND METHODS: Serum samples from histomorphology-proven Pca cases were included. Prostate-specific antigen (PSA), tissue inhibitor of metallopeptidase 1 (TIMP1) and tissue plasminogen activator (tPA), and their fucosylated glycoforms were captured by Aleuria Aurantia Lectin (AAL), followed by the multiplex magnetic bead-based immunoassay. The level of fucosylated glycoproteins was correlated with patients' Gleason score of the tumor. RESULT: Among three fucosylated glycoproteins, the fucosylated PSA was significantly increased and correlated with the tumor Gleason score (p<0.05). The ratio of fucosylated PSA showed a marked increase in aggressive tumors in comparison to non-aggressive tumors. ROC analysis also showed an improved predictive power of fucosylated PSA in the identification of aggressive Pca. CONCLUSIONS: Our data demonstrated that fucosylated PSA has a better predictive power to differentiate aggressive tumors from non-aggressive tumors, than that of native PSA and two other glycoproteins. The fucosylated PSA has the potential to be used as a surrogate biomarker. PMID- 25553115 TI - Nanogels from metal-chelating crosslinkers as versatile platforms applied to copper-64 PET imaging of tumors and metastases. AB - Metals are essential in medicine for both therapy and diagnosis. We recently created the first metal-chelating nanogel imaging agent, which employed versatile, reproducible chemistry that maximizes chelation stability. Here we demonstrate that our metal chelating crosslinked nanogel technology is a powerful platform by incorporating (64)Cu to obtain PET radiotracers. Polyacrylamide-based nanogels were crosslinked with three different polydentate ligands (DTPA, DOTA, NOTA). NOTA-based nanogels stably retained (64)Cu in mouse serum and accumulated in tumors in vivo as detected by PET/CT imaging. Measurement of radioactivity in major organs ex vivo confirmed this pattern, revealing a high accumulation (12.3% ID/g and 16.6% ID/g) in tumors at 24 and 48 h following administration, with lower accumulation in the liver (8.5% ID/g at 24 h) and spleen (5.5% ID/g). Nanogels accumulated even more efficiently in metastases (29.9% and 30.4% ID/g at 24 and 48 h). These metal-chelating nanogels hold great promise for future application as bimodal PET/MRI agents; chelation of beta-emitting radionuclides could enable radiation therapy. PMID- 25553118 TI - A lot of primary arterial hypertensions. Only one blood pressure therapeutic target? PMID- 25553116 TI - Prediction of tumor recurrence and therapy monitoring using ultrasound-guided photoacoustic imaging. AB - Selection and design of individualized treatments remains a key goal in cancer therapeutics; prediction of response and tumor recurrence following a given therapy provides a basis for subsequent personalized treatment design. We demonstrate an approach towards this goal with the example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, clinically-used technique that consumes oxygen to generate cytotoxic species, thus causing changes in blood oxygen saturation (StO2). We hypothesize that this change in StO2 can be a surrogate marker for predicting treatment efficacy and tumor recurrence. PAI is a technique that can provide a 3D atlas of tumor StO2 by measuring oxygenated and deoxygenated hemoglobin. We demonstrate that tumors responding to PDT undergo approximately 85% change in StO2 by 24-hrs post-therapy while there is no significant change in StO2 values in the non-responding group. Furthermore, the 3D tumor StO2 maps predicted whether a tumor was likely to regrow at a later time point post-therapy. Information on the likelihood of tumor regrowth that normally would have been available only upon actual regrowth (10-30 days post treatment) in a xenograft tumor model, was available within 24-hrs of treatment using PAI, thus making early intervention a possibility. Given the advances and push towards availability of PAI in the clinical settings, the results of this study encourage applicability of PAI as an important step to guide and monitor therapies (e.g. PDT, radiation, anti-angiogenic) involving a change in StO2. PMID- 25553119 TI - Assessment of Venous Thromboembolism Prophylaxis in Neurological Patients with Restricted Mobility - VTE-NEURO Study. AB - ABSTRACT: The authors present the data of a medical registry which evaluated if the physicians assess VTE risk in stroke patients, during hospitalization period and at hospital discharge and if the thromboprophylaxis is used according to National Guidelines for VTE Prophylaxis. 884 patients with acute ischemic stroke patients were enrolled between June 2010 and December 2011, from 62 centers, 51.4% male and 48.6% female with mean age 70.07 years (68.25 years in the male group and 71.92 years in the female one). There were two co-primary endpoints: the percentage of patients at risk for VTE at hospital admission assessed by the physician, and the percentage of patients with risk factors for VTE that persist at hospital discharge from the total number of patients hospitalized with ischemic stroke. The secondary endpoints were: the percentage of hospitalized patients receiving prophylaxis according to the National Guidelines of VTE Prophylaxis from the total number of patients at risk of VTE, the percentage of hospitalized patients with VTE risk receiving recommendation for thromboprophylaxis at discharge, the duration and the type of VTE prophylaxis in hospitalized patients, the duration and the type of VTE prophylaxis at discharge. RESULTS: 879 (99.4%) of the total number of patients at risk of VTE have received prophylaxis during hospitalization. The most frequently types of prophylaxis used during hospitalisation were LMWH in 96.3% of the patients and mechanic method in 16.6% that were in accordance with the National Guidelines of VTE Prophylaxis recommendations. CONCLUSIONS: There is a clear improvement in both assessment and thromprophylaxis recommendation in acute stroke patients with restricted mobility at VTE risk and in our country. LMWH is preferred to unfractionated heparin for venous thromboembolism prophylaxis in this high-risk patient population in view of its better clinical benefits to risk ratio and convenience of once daily administration. PMID- 25553117 TI - Parthenolide inhibits cancer stem-like side population of nasopharyngeal carcinoma cells via suppression of the NF-kappaB/COX-2 pathway. AB - Cancer stem cells play a central role in the pathogenesis of nasopharyngeal carcinoma and contribute to both disease initiation and relapse. In this study, cyclooxygenase-2 (COX-2) was found to regulate cancer stem-like side population cells of nasopharyngeal carcinoma cells and enhance cancer stem-like cells' characteristics such as higher colony formation efficiency and overexpression of stemness-associated genes. The regulatory effect of COX-2 on cancer stem-like characteristics may be mediated by ABCG2. COX-2 overexpression by a gain-of function experiment increased the proportion of side population cells and their cancer stemness properties. The present study also demonstrated that in contrast to the classical chemotherapy drug 5-fluorouracil, which increased the proportion of side population cells and upregulated the expression of COX-2, parthenolide, a naturally occurring small molecule, preferentially targeted the side population cells of nasopharyngeal carcinoma cells and downregulated COX-2. Moreover, we found that the cancer stem-like cells' phenotype was suppressed by using COX-2 inhibitors NS-398 and CAY10404 or knocking down COX-2 with siRNA and shRNA. These findings suggest that COX-2 inhibition is the mechanism by which parthenolide induces cell death in the cancer stem-like cells of nasopharyngeal carcinoma. In addition, parthenolide exhibited an inhibitory effect on nuclear factor-kappa B (NF-kappaB) nucler translocation by suppressing both the phosphorylation of IkappaB kinase complex and IkappaBalpha degradation. Taken together, these results suggest that parthenolide may exert its cancer stem cell-targeted chemotherapy through the NF-kappaB/COX-2 pathway. PMID- 25553120 TI - The relevance of inflammatory markers in metabolic syndrome. AB - ABSTRACT: OBJECTIVES: To identify how severe is inflammation in metabolic syndrome using as inflammatory markers: C-reactive protein and leukocytes. To asses these markers considering the diversity of metabolic syndrome elements. MATERIAL AND METHOD: We performed a study that enrolled 258 patients registered to a family physician and diagnosed with metabolic syndrome. The subjects included in the study were divided in two groups: group A-137 subjects diagnosed with metabolic syndrome that was defined by 3 elements: abdominal obesity+arterial hypertension+diabetes mellitus; group B-121 patients diagnosed with metabolic syndrome based on 5 elements: abdominal obesity+arterial hypertension+diabetes mellitus+decreased high density lipoprotein cholesterol (HDL-C)+increased triglycerides. RESULTS: We observed increased values of CRP and leukocytes for group B in comparison to group A: 0.9+/-0.8 mg/dl vs 0.79+/-0.8 mg/dl (p=0.02, significantly statistic). Leukocytes value was higher for group B, but not significantly statistic. CONCLUSIONS: Inflammation in patients with metabolic syndrome depends on the number and association of elements that define this entity and it is more accentuated for subjects who associate more elements. PMID- 25553121 TI - Cardiovascular risk in psoriatic arthritis - a cross-sectional study. AB - ABSTRACT: OBJECTIVES: The present study aims to estimate long term cardiovascular risk in psoriatic arthritis (PsA) patients and to identify clinical and/or laboratory features which influence this risk. OUTCOMES: The PsA group included 44 males and 59 females (p = 0.167) with an average age of 52 years (23-80). SCORE was significantly correlated with age of onset, BMI, triglycerides, FPG. Among these patients, males, smokers, those with axial involvement, with IHT, with AHT and those not treated with glucocorticoids had a significantly higher SCORE. The subgroup of 56 PsA women, age-matched with 56 normal women, had a significantly higher SCORE, even after controlling for covariates. CONCLUSIONS: Cardiovascular risk of PsA patients estimated on SCORE charts correlates with metabolic clinical and laboratory features and is associated with classical cardiovascular risk factors. The axial involvement in PsA is associated with a higher cardiovascular risk when compared to non-axial PsA. Women with PsA have a higher cardiovascular risk than normal women, which sustains the opinion that PsA may be considered an independent cardiovascular risk factor. PMID- 25553122 TI - Body composition in patients with chronic obstructive pulmonary disease. AB - ABSTRACT: OBJECTIVES: Body composition assessment in chronic obstructive pulmonary disease (COPD) is important, as weight loss and muscular wasting are responsible for low exercise capacity in these patients, and low body mass index (BMI) and fat free mass index (FFMI) are important prognostic factors. Our study aims were: (a) to describe body composition in COPD patients referred to a pulmonary rehabilitation center in Bucharest; (b) to examine the relationships between body composition and disease severity (bronchial obstruction, exercise capacity, quality of life); (c) to test if segmental wasting of lower limbs muscle mass (measured by segmental body composition analysis) correlates with decreased exercise capacity. MATERIAL AND METHODS: We studied 36 consecutive COPD patients referred to our clinic for pulmonary rehabilitation. Patients performed pulmonary function tests, six minutes walking test (6MWT), and health status was evaluated with COPD Assessment Test (CAT). Body composition measurements were performed by direct segmental multi-frequency bioelectrical impedance analysis (BIA). OUTCOMES: This study offers the first data on body composition of Romanian COPD patientsThe prevalence of nutritional depletion (defined by low BMI and/or low FFMI) among our COPD patients was 22.2%. Mean FFMI was significantly lower in normal or underweight patients versus overweight or obese patients. Patients with low FFMI had lower exercise capacity at the 6MWT and higher CAT scores than patients with normal FFMI.Depending on the BMI and FFMI values the patients were divided in four categories: normal, semistarvation, sarcopenia and cachexia. The group of patients with sarcopenia (low FFMI and normal BMI) had the lowest mean MIP (Maximal Inspiratory Pressure), the lowest mean 6MWD (six minutes walking distance) and the higher CAT mean scores among all groups. Exercise capacity was significantly lower in muscular depleted patients (with low skeletal muscle mass index - SSMI). MIP correlated significantly with FFMI and SMMI. No correlations were found between parameters of body composition and FEV1 or CAT. Segmental body composition assessment revealed that unbalanced upper/lower skeletal muscle mass is associated with a lower exercise capacity as measured by 6WMT. CONCLUSIONS: This study offers the first data on body composition of Romanian COPD patients. The prevalence of nutritional depletion is similar to that found in other European studies. No significant correlations were found between FFMI and severity of the disease (bronchial obstruction, distance walked, CAT score). FFMI and SSMI correlated significantly with MIP. Sarcopenic patients had the lowest mean 6MWD, the lowest mean MIP and the highest CAT mean scores. SMMI significantly correlated with 6MWD. Segmental body composition assessment of revealed that "unbalanced" patients had lower results at 6MWT. These results show that body composition evaluation is useful for the assessment of COPD patients referred to pulmonary rehabilitation and should be routinely performed. PMID- 25553123 TI - Skin Hydration Assessment through Modern Non-Invasive Bioengineering Technologies. AB - ABSTRACT: Non-invasive bioengineering technologies continuously discovered and developed in recent decades provide a significant input to research development and remarkably contribute to the improvement of medical education and care to our patients. AIM: Assessing skin hydration by using the capacitance method for a group of patients with allergic contact dermatitis versus healthy subjects, before and after applying a moisturiser (assessing the immediate and long-term effectiveness of hydration). RESULTS: For both groups, but especially for the patients with dry skin, there was a clear improvement of hydration, statistically significant after applying the moisturiser. In the case of the patients with allergic contact dermatitis, hydration was at a maximum immediately after the first application, and then maintained an increased level after 7 and 28 days, respectively. In the healthy subjects, the increase in hydration was lower, but progressive. The moisturiser determined an increase in hydration for all age groups, but those who showed the most obvious effect were the young adults (18-29 years old) with an increase of 19.9%.The maintenance effect of hydration lasted for 28 days, while the improvement was important for allergic skin (17.1%) and significant for healthy skin (10.9%). CONCLUSION: The assessment of epidermal hydration performed by using the corneometer showed very good hydration of the stratum corneum for both groups studied, with immediate and long-term effect. This study also showed that the degree of skin hydration was inversely proportional with age. The corneometer is easy to use, efficient and widely utilised in international studies for measurements in healthy or pathological conditions, for quantitative assessment of the effectiveness of various preparations intended for application to the skin surface, under well-controlled and standardised conditions. PMID- 25553124 TI - Study of preoperative predictive signs in management of facial nerve in parotid tumors. AB - ABSTRACT: OBJECTIVES: To find preoperative predictive signs for better surgical planning of the facial nerve in parotid tumors. METHODS: Prospective study in patients with primary parotid malignancies. Patients with primary parotid malignant tumor were investigated for preoperative clinical signs in correlation with histological findings and surgical management of the facial nerve. OUTCOMES: The study included 47 patients. Several clinical findings as facial pain, paresthesia, and rapid growth of tumor might suggest the risk of malignancy. Paresis/palsy of the facial nerve was correlates with direct neural involvement. CONCLUSION: There are several predictive clinical signs that might suggest malignancy of a parotid tumor. PMID- 25553125 TI - Osteosynthesis in fractures of the distal third of humeral diaphysis. AB - ABSTRACT: OBJECTIVES: To compare the clinical results of osteosynthesis with plate and screws versus anterograde locked intramedullary nail in fractures of the distal third of humeral diaphysis. MATERIAL AND METHODS: 184 patients with fractures of the distal third of humeral diaphysis were included in a prospective study. 82 patients underwent open reduction and internal fixation with plate and screws (Group 1), while in 102 cases, closed reduction and osteosynthesis with locked intramedullary nail was performed (Group 2). The 2 groups were similar in terms of age and gender distribution and pattern of fractures. The function of shoulder and elbow were assessed using the Oxford Shoulder Score (OSS) and Oxford Elbow Score (OES). Operating time, duration of hospital stay, complications and moment of union were recorded. OUTCOMES: 6 months after surgery the average OSS was 44.42 in Group I and 40.23 in Group II, while the mean OES was 40.88 in Group I and 46.54 in Group II. The average duration of the surgical procedure was 87 min in Group1 and 43 min in the nail group (p<0.001).The mean duration of hospital stay was 2.6 days in Group 1 and 1.8 days in Group 2 (p<0.05). The rate of non-unions was 3.66% in the plate group and 2.94% in the retrograde nail group (p>0.05). CONCLUSIONS: The clinical results of the 2 methods of osteosynthesis were similar, but the operating time and the duration of hospital stay were longer after plate osteosynthesis. Shoulder function was slightly impaired in the nail group but not statistically significant. PMID- 25553126 TI - Does physiotherapy contribute to the improvement of functional results and of quality of life after primary total hip arthroplasty? AB - ABSTRACT: INTRODUCTION: This paper aims to determine whether physiotherapy succeeds in improving the functional results (expressed by the Harris hip score) and the quality of life after primary total hip arthroplasty, especially in very elderly persons. MATERIAL AND METHOD: A prospective study has followed up 100 patients with coxarthrosis, who underwent a primary total hip arthroplasty and who were subject to an early initiation of a recovery treatment, adapted to each individual, focused on regaining functionality and independence and continued at home after discharge from hospital. After 3 months, the Harris hip score was compared with the preoperative one and the quality of life was assessed according to a simplified questionnaire derived from SF-36. RESULTS: The average preoperative Harris hip score was significantly lower in patients aged over 75 years, as compared to the other 3 age groups (under 40 years, between 41 and 60 years and between 61 and 75 years). After 3 months, the average Harris hip score was significantly improved, in comparison to the preoperative one (85.89 as compared to 40.06) and there were no statistically significant differences between the average Harris hip score in all 4 age groups. The quality of life was regarded by patients as being good on average, in all 4 age groups. CONCLUSION: Very elderly people benefit equally with the other age groups from a functional recovery after primary total hip arthroplasty, even if this recovery is initially more difficult and more cautious. PMID- 25553127 TI - Periprosthetic bone remodelling in total knee arthroplasty. AB - ABSTRACT: INTRODUCTION: The clinical studies have shown that the displacement of the prosthesis components, especially of the tibial one is higher during the first year, after which it reaches an equilibrum position compatible with a good long term functioning. This displacement takes place due to bone remodelling close to the implant secondary to different loading concentrations over different areas of bone. MATERIAL AND METHOD: Our study implies a simulation on a computational model using the finite element analysis. The simulation started taking into account arbitrary points because of non-linear conditions of bone prosthesis interface and it was iterative.. A hundred consecutive situations corresponding to intermediate bone remodelling phases have been calculated according to given loadings. Bone remodelling was appreciated as a function of time and bone density for each constitutive element of the computational model created by finite element method. For each constitutive element a medium value of stress during the walking cycle was applied. RESULTS: Analyse of proximal epiphysis-prosthesis complex slices showed that bone density increase is maintained all over the stem in the immediately post-operative period. At 10 months, the moment considered to be the end of bone remodelling, areas with increased bone density are fewer and smaller. Meanwhile, their distribution with a concentration toward the internal compartment in the distal metaphysis is preserved. CONCLUSIONS: After the total knee arthroplasty the tibial bone suffered a process of remodelling adapted to the new stress conditions. This bone remodelling can influence, sometimes negatively, especially in the cases with tibial component varus malposition, the fixation, respectively the survival of the prosthesis. This process has been demonstrated both by clinical trials and by simulation, using the finite elements method of periprosthetic bone remodelling. PMID- 25553128 TI - Metastatic Melanoma in the Femur - Case Report with Review of Literature: a Pathologist's Point of View. AB - ABSTRACT: The aim of this case report was to evaluate the histopathological characteristics on a patient with metastases in the femur from malignant melanoma. A review from the literature is also mentioned.We present a case of metastatic malignant melanoma in the femur with known primary site in a 44-year old-female. Diagnosis was confirmed by histopathology.Malignant melanoma is a cancer that may metastasise in the skeleton. However most of bone metastases are found in the axial skeleton and they rarely involve the femur, as in our case. Only a few case reports are published in the literature. Clinicians must be aware of the varied clinical manifestations of disseminated malignant melanoma.The diagnosis for metastatic malignant melanoma is confirmed due to pathological examination. Immunohistochemical study is useful in diagnosis, mainly when malignant melanoma is poorly differen-tiated. PMID- 25553129 TI - Non-Hodgkin's Malignant Lymphoma with Aggressive Development. AB - ABSTRACT: Non-Hodgkin's malignant lymphoma is a hematologic malignant disease which usually responds to the polychemotherapy. We present a clinical case report of a 50 years old patient who develops an aggressive type of lymphoma. Patient develops a nodal Non-Hodgkin's malignant lymphoma who present at hospital admission as a huge tumor at the right side of the neck. Any type of treatment was a failure, the patient having a particularly aggressive form of lymphoma, resistant to all three chemotherapy regimens tested. Death occurs quickly, about one year after diagnosis and initiation of therapy. PMID- 25553130 TI - IgM Myeloma or Waldenstrom's Macroglobulinemia Is the Big Question? AB - ABSTRACT: Although critical from therapeutic and prognostic perspectives, differentiating IgM Myeloma (MM) from Waldenstrom's macroglobulinemia (WM) is fraught with failure. WM can usually be distinguished from IgM MM by the lymphoplasmacytic versus pure plasmacytic morphology, absent versus present lytic bone lesions, and immunophenotypic findings. However, all these features have their own limitations; hence, it requires constant vigilance and periodic re evaluation. Here we describe a case of a 70-year-old woman initially diagnosed as smoldering IgM MM, who eventually turned out to have WM. PMID- 25553131 TI - Nose defects reconstruction with forehead flap - case report. AB - ABSTRACT: OBJECTIVES: Nasal reconstruction has be one of the most challenging procedures in reconstructive plastic surgery. Small nasal defects may be closed by primary suture or covered by small local flaps or skin graft. But in large nasal defects, we need to find a bigger source of color and texture matching tissue that will ensure functional and aesthetical outcomes. MATERIAL AND METHODS: We chose a case report of one patient admitted in our clinic in 2012, who represented a daring task for us. Best suited for paramedian forehead flap reconstruction, the patient underwent a procedure in 2 steps, which led to a very satisfying nose both for the patient and for the surgeon. CONCLUSIONS: In order to achieve a good coverage with the smallest donor site defect, we used a flap based only on the left supratrocheal artery, which gave us the possibility to rotate the flap without distorting the vessels. In such cases, the best option, aesthetically and functionally, for the patient still remains the paramedian flap, modified from the original version, and adapted to every case. PMID- 25553132 TI - Metatypical Basal cell carcinomas: a successful surgical approach to two cases with different tumor locations. AB - ABSTRACT: We present 2 rare cases of metatypical basal cell carcinoma - two 72 year-old male patients with ulcerative lesions localized either to the left forehead or the back. The biopsy revealed a metatypical basal cell carcinoma. The treatment consisted of a wide local elliptical excision with good cosmetic results. There was no sign of recurrence or metastasis during a 12 months follow up period.Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) make up 95% of the most common types of cancer in the world - the non-melanoma skin cancer (NMSC). BCC is known for its potential to be locally invasive while SCC for its potential to metastasize in lymph nodes. The meta-typical basal cell carcinoma (MTBC) is a rare type of tumor which combines the clinical and histopathological features of both BCC and SCC with a 5% risk for the development of metastases. The gold standard for diagnosis lies in the histopathological verification of the lesional tissue. Clinical examinations alone are not enough. PMID- 25553133 TI - A rare cause of Dysphagia - Dysphagia aortica - complicated with intravascular disseminated coagulopathy. AB - ABSTRACT: Dysphagia aortica is an uncommon condition defined by the difficulty in swallowing caused by extrinsic compression of the esophagus due to an ectatic, tortuous, or aneurysmatic atherosclerotic thoracic aorta. We report the case of a 93 year old woman with dysphagia secondary to extrinsic compression by a giant sacciform aneurysm of the descending thoracic aorta. As a consequence of small liniar dissection tracts of the aneurysm, the patient developed disseminated intravascular coagulopathy with spontaneous forearm hematoma and multiple bruising, a clinical setting with a difficult therapeutic approach. Taking into account that aneurysm of the thoracic aorta is a very rare cause of dysphagia, the case report on this rare cause should contribute to better diagnosis of dysphagia aortica and swallowing difficulties in general. Dissecting aneurysm of the thoracic aorta is a very rare cause of DIC so the combination of easy bruising or spontaneous hematoma and an aortic aneurysm demands special caution. PMID- 25553134 TI - Oral leukoplakia - an update. AB - ABSTRACT: The main purpose of this paper was to assess the current state of science on oral leukoplakia. Although it is considered a potentially malignant disorder the overall malignant progression of oral leukoplakia is of the order of 5% and even more. Nowadays there are no currently accepted markers to distinguish those that may progress to cancer from those that may not. The current golden standard is considered the presence of epithelial dysplasia on the tissue biopsy of the lesion. Proliferative verrucous leukoplakia is a rare form of OL which has multiple recurrences, is refractory to treatment and has malignant transformation in a short period. It is considered a true premalignant lesion. The management of oral leukoplakia varies from a "wait and see" attitude and topical chemopreventive agents to complete surgical removal. PMID- 25553135 TI - Is there a Link Between Atherothrombosis and Deep Venous Thrombosis? AB - ABSTRACT: Venous and arterial thromboses have traditionnally been regarded as separate diseases with different causes. Clinical experience shows, that the arterial atherothrombotic disease can be associated with venous thrombotic disease, but there is insufficient evidence to prove and explain the nature of this association.This review focuses on the risk factors associated with both arterial and venous thrombotic events, and recent epidemiological studies have documented an association between these vascular complications.According to the results of recent studies, atherosclerosis and venous thrombosis share common risk factors, including age, obesity, cigarette smoking, and metabolic syndrome.Several studies have demonstrated that subjects with idiopathic venous thrombosis have an increased risk of cardiovascular events compared with subjects with secondary thrombosis or control group. On the other hand, atherosclerosis has the potential to promote the development of thrombotic disorders in the venous system. Based on the results of population studies carried out in the United States, atherosclerosis is unlikely to constitute a risk factor for venous thrombosis. In conclusion, the separate nature of arterial and venous disorders has been challenged. Future studies are needed to clarify the nature of this association, and to evaluate its implications for clinical practice. PMID- 25553136 TI - Association of oral lichen planus with chronic C hepatitis. Review of the data in literature. AB - ABSTRACT: The relationship between chronic hepatitis C virus infection (HCV) and oral lichen planus (OLP) is a current topic in the field of oral medicine. Many studies of this association have been made over time. The geographic variation of the hepatitis C prevalence proved to be an important factor influencing the statistical results of the studies analyzing the association of the oral plan lichen with the hepatitis C virus. Approaching this issue is not to be neglected. Treatment outcomes in patients with oral lichen planus associated with chronic hepatitis C virus are often unsatisfactory compared to patients suffering from idiopathic oral lichen planus. Also, the evolution of oral lesions is often fluctuating, with repeated periods of relapse according to the degree of liver function decompensation. Background therapy for liver disease itself may influence lichen planus lesions. Thus, during therapy with interferon and ribavirin oral lesions may appear or become acute. PMID- 25553137 TI - Peripheral T and NK cell non-hodgkin lymphoma a challenge for diagnosis. AB - ABSTRACT: BACKGROUND: Peripheral T and natural killer (NK) cell lymphomas represent a heterogeneous group of diseases with varied clinical features, prognosis and response to treatment.Content and comments: Flow cytometric immunophenotyping facilitated the diagnosis and classification for T/NK-cell neoplasms, and is very useful in the identification of therapeutic target markers. Clinical, immunophenotypic, histopathological, immunohistochemical, molecular and genetic methods must be correlated because none of them is strong enough alone for diagnosis. CONCLUSION: The low incidence of NK/T-cell lymphoma poses real difficulties for a complete and correct assessment. The unspecified lymphomas represent a heterogeneous group, which requires additional studies to elucidate their biological and genetic bases, to separate them. The group of NK/T cell lymphomas remains a challenge for researchers. PMID- 25553138 TI - The importance of distinguishing pseudogenes from parental genes. PMID- 25553140 TI - The Use of Glass-fibers Ribbon and Composite for Prosthetic Restoration of Missing Primary Teeth-Laboratory and Clinical Research. AB - Very few modalities can be used for restoring missing primary anterior teeth, although the impact of missing anterior teeth during early childhood can be harmful. In the permanent dentition the use of glass-fibers ribbon and composite materials are frequently used for restoring missing teeth with no or minimal preparation. The purpose of this study was to examine the possibility to use the glass-fibers ribbon (ever-Stick from GC Corporation, Japan) together with esthetic composite materials (G-aenial A1 from GC Corporation, Japan) for restoring anterior primary teeth and to determine the best methodology and bonding system to be used. The effect of etching time was analyzed using 20-80 sec on primary buccal enamel with SEM and the results showed that at least 60 second is necessary in order to remove the prismless layer and to affect the prismatic layer similar (as observed by SEM) to the 20 sec etching time on permanent enamel. Three bonding systems (SE Bond by Kurary, Japan, Scotchbond Universal by 3M/ESPE, Germany and G-aenial bond by GC Company, Japan) were compared for bonding the glass-fibers ribbon to the primary enamel and microtensile strength analyses were performed. Mean tensile strength ranged from 10.9 to 13 MPa with no statistically significant differences between all three systems. Based on the laboratory results it can be concluded that the glass fibers ribbon together with the composite material can be used clinically to restore missing primary teeth for esthetic and functional reasons. Two clinical cases are presented that show favorable results. PMID- 25553139 TI - Metabolic syndrome in preeclampsia women in gorgan. AB - The aim of study was to assess the metabolic syndrome in preeclampsia women. The study was performed on 50 women. The metabolic syndrome prevalence was 66%. Serum glucose, triglyceride and LDL-cholesterol levels significantly were increased and HDL- cholesterol level significantly was decreased in metabolic syndrome patients. These patients showed high prevalence of components of the syndrome. Our results show the importance of dyslipidemia in preeclampsia in overweight and obese women. Preeclampsia and cardiovascular disease are important problems for the health of women. It may be useful to give a treat to people with a high normal blood pressure in early pregnancy. PMID- 25553141 TI - A positive association between foot posture index and medial compartment knee osteoarthritis in moroccan people. AB - OBJECTIVES: To compare foot posture in people with and without medial compartment knee osteoarthritis (OA), and to assess association between its abnormalities and medial compartment knee OA. METHODS: We compared the foot posture of patients with clinically and radiographically-confirmed medial compartment knee OA and asymptomatic healthy controls using the foot posture index (FPI), navicular height, and the medial arch. RESULTS: We included 100 patients and 80 asymptomatic controls. The mean age of patients was 59 +/- 7 (44-76) years and 48 +/- 9 (28-60) years in the control (p=0.06). Patients group have more pronated foot for FPI (1.50 +/- 2.68 vs 0.72 +/- 2.63; p=0.05), more flat foot (42% vs 22%; p=0.03), and less pes cavus than the control group (58% vs 77%; p=0.004). However, there was no significant difference between the groups in the navicular height (3.90 +/- 0.85 cm vs 4.00 +/- 0.76 cm; p=0.41). In multivariate statistical analysis, after adjusting for age and body mass index, pronated foot in FPI (OR=1.22, 95%IC= [1.06-1.40], p=0.005), and pes cavus (OR=0.32, 95%IC= [0.11-0.93], p=0.03) had a significant correlation with the knee osteoarthritis. CONCLUSION: Pronated foot posture and flat foot are significantly associated with medial compartment knee osteoarthritis. PMID- 25553144 TI - PSA screening: And now...a message from our experts. PMID- 25553143 TI - Relationship Agreements and Willingness to Participate in Couples HIV Testing and Counseling Among Heterosexuals in the U.S. AB - Couples HIV testing and counseling (CHTC) has been used for more than 20 years in African settings and more recently among men who have sex with men in the United States, but little is known about willingness of heterosexuals in the U.S. to use CHTC. We conducted an online survey of heterosexuals in sexual relationships to assess willingness to use CHTC and willingness to discuss relationship agreements within a couples counseling session. We found moderate levels of willingness to use CHTC and somewhat higher levels of willingness to discuss relationship agreements in a couples counseling session. The most frequently cited reason people were not willing was that they did not perceive themselves or their partners to be at risk for HIV. These results will be useful in planning for CHTC implementation for heterosexuals in the U.S. PMID- 25553142 TI - Disease caused by rotavirus infection. AB - Although rotavirus vaccines are available, rotaviruses remain the major cause of childhood diarrheal disease worldwide. The Rotarix (GlaxoSmithKline Biologicals Rixensart, Belgium) and RotaTeq (Merck and Co., Inc. Whitehouse Station, New Jersey, USA) vaccines are effective for reducing the morbidity and mortality of rotavirus infection. This article aims to assess the epidemiology of rotaviral gastroenteritis and the efficacy and effectiveness of licensed rotavirus vaccines. This review concludes by presenting challenges in the field that require further exploration by and perspectives from basic and translational research in the future. PMID- 25553145 TI - Making our voices heard. PMID- 25553147 TI - MRI use with artificial erection in cases of painful erections. PMID- 25553146 TI - [Not Available]. PMID- 25553148 TI - Author response: MRI use with artificial erection in cases of painful erections. PMID- 25553149 TI - Microscopic hematuria and urothelial malignancy. PMID- 25553150 TI - Author response: Microscopic hematuria and urothelial malignancy. PMID- 25553151 TI - Scientific evidence dispels false claims about circumcision. PMID- 25553152 TI - Evaluation of second-line and subsequent targeted therapies in metastatic renal cell cancer (mRCC) patients treated with first-line cediranib. AB - INTRODUCTION: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing. METHODS: In this study we evaluated mRCC patients who were initially treated on the first line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies. RESULTS: Twenty eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%-47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib. CONCLUSION: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease. PMID- 25553153 TI - Psychosocial mechanisms of the pain and quality of life relationship for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). AB - INTRODUCTION: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent, chronic pelvic pain condition largely unresponsive to medical interventions. Psychosocial risk factors are associated with poor outcomes in CP/CPPS, but have not been examined for their intervening roles between pain and reduced quality of life (QoL). This study aimed to determine if psychosocial risk factors (i.e., patient coping and catastrophizing) mediate the association between pain and QoL. METHODS: Using a cross sectional design, 175 men with CP/CPPS (mean age 46.83; SD 10.86) were recruited from tertiary care urology clinics and completed questionnaires on demographics, pain, QoL, pain coping, depression, and catastrophizing. An exploratory factor analysis was conducted and aggregate factor scores were examined to improve the amount of meaningful measurement to be used in multiple mediations. The models specified multiple risk factors as mechanisms between pain and both physical and mental QoL as the primary outcome measurements. RESULTS: Four aggregate psychosocial factor scores were produced from the psychosocial measures (i.e., illness and wellness-focused behavioural coping, depression and catastrophizing). Illness-focused coping partially mediated the relationship between pain and physical QoL. However, catastrophizing and illness-focused coping fully mediated the relation between pain and mental QoL, showing the association between pain and mental QoL was no longer significant when catastrophizing and illness-focused coping were in the model. CONCLUSION: Psychosocial factors function as mechanisms between higher pain and they are associated diminished mental QoL. These results introduce illness-focused coping as an important biopsychosocial target in CP/CPPS management. PMID- 25553154 TI - Practice patterns and perceptions of survivorship care in Canadian genitourinary oncology: A multidisciplinary perspective. AB - INTRODUCTION: There is little knowledge of survivorship care specific to genitourinary (GU) cancers. To improve care delivery to this patient population, we need to clearly define physician perceptions of survivorship care. We therefore conducted a study to determine the challenges to GU cancer survivorship care in Canada. METHODS: A web-based questionnaire was e-mailed to physicians treating GU cancers in Canada, including urologists, radiation oncologists, and medical oncologists. Five domains were assessed: demography, current post-cancer treatment care, perspectives on barriers to survivorship care, accessibility to survivorship resources, and perspectives about advocacy groups. RESULTS: There were 306 responses, with 260 eligible for study. A total of 82% of physicians involve primary care practitioners (PCPs) at some point in survivorship care. Most physicians provide some form of written follow-up plan to PCPs. However, only 25% provided lifestyle recommendations and 53% included persistent and late effects of therapy. Lack of time or resources dedicated to survivorship care was the most commonly reported barrier. There was variation in accessibility to survivorship support programs among different subspecialties and regions. Advocacy groups generally were underutilized, particularly in testis cancer. Low response rate and the potential response bias are the main limitations of this survey. CONCLUSION: To our knowledge this is the first study to address the challenges of GU cancer survivorship care in Canada. The barriers and accessibility of survivorship care quoted in this survey may be used to improve care for this group of patients. Underutilization of advocacy groups may stimulate the advocacy groups and institutions to address its causes and solutions. PMID- 25553155 TI - Enhanced recovery pathway for radical prostatectomy: Implementation and evaluation in a universal healthcare system. AB - INTRODUCTION: Enhanced recovery pathways are standardized, multidisciplinary, consensus-based tools that provide guidelines for evidence-based decision-making. This study evaluates the impact of the implementation of a clinical care pathway on patient outcomes following radical prostatectomy in a universal healthcare system. METHODS: Medical charts of 200 patients with prostate cancer who underwent open and minimally invasive radical prostatectomy at a single academic hospital from 2009 to 2012 were reviewed. A group of 100 consecutive patients' pre-pathway implementation was compared with 99 consecutive patients' post pathway implementation. Duration of hospital stay, complications, post-discharge emergency department visits and readmissions were compared between the 2 groups. RESULTS: Length of hospital stay decreased from a median of 3 (inter-quartile range [IQR] 4 to 3 days) days in the pre-pathway group to a median of 2 (IQR 3 to 2 days) days in the post-pathway group regardless of surgical approach (p < 0.0001). Complication rates, emergency department visits and hospital readmissions were not significantly different in the pre- and post-pathway groups (17% vs. 21%, p = 0.80; 12% vs. 12%, p = 0.95; and 3% vs. 7%, p = 0.18, respectively). These findings were consistent after stratification by surgical approach. Limitations of our study include lack of assessment of patient satisfaction, and the retrospective study design. CONCLUSIONS: The implementation of a standardized, multidisciplinary clinical care pathway for patients undergoing radical prostatectomy improved efficiency without increasing complication rates or hospital readmissions. PMID- 25553156 TI - Impact of penile degloving and proximal ventral dissection on curvature correction in children with proximal hypospadias. AB - INTRODUCTION: Penile degloving is an important step in orthoplasty. Although its role in correcting mild curvature in distal and midshaft hypospadias has been previously reported, its impact on ventral curvature (VC) correction in proximal defects warrants further investigation. Therefore, we sought to document the effect of degloving and proximal urethral dissection on VC correction in children with proximal hypospadias. METHODS: We retrospectively reviewed the records of 137 patients who underwent proximal hypospadias repair between 1998 and 2006. VC, defined as mild (<30%), moderate (30%-45%), and severe (>45%), was recorded before penile degloving and after erection test. Percent improvement in VC and need for further treatment (beyond degloving and proximal dissection) based on preoperative degree of curvature were assessed. ANOVA test was used to compare improvement among the 3 groups. RESULTS: Mean age at repair was 14 months (range: 6-24). Penile degloving associated with proximal urethral dissection when necessary was responsible for the improvement in the degree of curvature in 7 of 9 (77%) patients with mild VC, 23 of 44 (52%) with moderate and 35 of 84 (40%) with severe VC. Additionally, degloving alone was sufficient for VC correction in 7 of 9 (77%) mild cases, 14 of 44 (30%) moderate and only 2 of 84 (2%) severe cases. The difference among these 3 groups was statistically significant (p < 0.001). CONCLUSIONS: Penile degloving alone can correct VC. The percentage of improvement depends on the preoperative degree of curvature, with severe VC cases showing the least improvement. PMID- 25553157 TI - Symptomatic versus asymptomatic pyeloplasties: A single institution review. AB - INTRODUCTION: Historically, pyeloplasties have been performed after symptoms and radiographic confirmation of an ureteropelvic junction obstruction (UPJO). However, with prenatal ultrasonography, the approach to patients has fundamentally changed. Increasingly, patients are diagnosed and treated before the advent of morbidity, based on imaging findings alone. However, optimum screening strategies and thresholds for intervention vary significantly, are controversial, and are not founded on outcome-based evidence. We examined all pyeloplasties performed at our institution and reviewed their indication for surgery. We hypothesized that, despite ubiquitous screening for UPJO, most pyeloplasties had been performed secondary to symptoms and did not benefit from antenatal screening. METHODS: A retrospective chart review was performed of all pyeloplasties performed at the Stollery Children's Hospital, Edmonton, Alberta, over the past 8 years. Patients were categorized according to indication for surgery: symptomatic or asymptomatic. RESULTS: Most (60%) of our pyeloplasties were performed for symptomatic indications. Furthermore, 12% of these patients had antenatally detected hydronephrosis that was thought to have resolved spontaneously during follow-up. Of our symptomatic patients, 37% were undergoing surveillance with the expectation for spontaneous resolution. Of the 29 patients who underwent pyeloplasty, 8 suffered a preoperative loss of function on renal scans; however, only 50% returned to within 90% of their original function. CONCLUSION: Despite active surveillance of antenatally detected hydronephrosis, most pyeloplasties at our institution were performed for de-novo symptoms. We believe that this simple observation reinforces that our current surveillance strategies are unable to predict and eliminate all morbidity from UPJO. PMID- 25553158 TI - Development of a novel classification system for anatomical variants of the puboprostatic ligaments with expert validation. AB - INTRODUCTION: We propose a novel classification system with a validation study to help clinicians identify and typify commonly seen variants of the puboprostatic ligaments (PPL). METHODS: A preliminary dissection of 6 male cadavers and a prospective dataset of over 300 robotic-assisted laparoscopic radical prostatectomies (RARP) recorded on video were used to identify 4 distinct ligament types. Then the prospectively collected database of surgical videos was used to isolate images of the PPL from RARP. Over 300 surgical videos were reviewed and classified with 1 to 5 pictures saved for reference of the type of PPL. To validate the new classification system, we selected 5 independent, blinded expert robotic surgeons to classify 100 ligaments based on morphology into a 4-type system: parallel, V-shaped, inverted V-shape, and fused. One week later, a subset of 25 photographs was sent to the same experts and classified. Statistical analyses were performed to determine both the intra-rater and inter rater reliability of the proposed system. RESULTS: Inverted V-shaped ligaments were noted most frequently (29.97%), parallel and V-shaped ligaments were found at 19.19% and 11.11%, respectively and fused ligaments were noted less frequently (6.06%). There was good intra-rater agreement (kappa = 0.66) and inter-rater agreement (kappa = 0.67) for the classification system. CONCLUSIONS: This classification system provided standardized descriptions of ligament variations that could be adopted universally to help clinicians categorize the variants. The system, validated by several blinded expert surgeons, demonstrated that surgeons were able to learn and correctly classify the variants. The system may be useful in helping to predict peri- and postoperative outcomes; however, this will require further study. PMID- 25553159 TI - Attitudes and experiences of residents in pursuit of postgraduate fellowships: A national survey of Canadian trainees. AB - INTRODUCTION: There have been significant pressures on urology training in North America over the last decade due to both the constantly evolving skill set required and the external demands around delivery of urological care, particularly in Canada. We explore the attitudes and experience of Canadian urology residents toward their postgraduate decisions on fellowship opportunities. METHODS: The study consisted of a self-report questionnaire of 4 separate cohorts of graduating urology residents from 2008 to 2011. The first cohort graduating in 2008 and 2009 were sent surveys through SurveyMonkey.com after graduation from residency; those graduating in 2010 and 2011 were prospectively invited as a convenience sample attending a Queen's Urology Examination Skills Training Program review course just prior to graduation. The survey included both open- and closed-ended questions, employing a 5-point Likert scale, and explored the attitudes and experience of fellowship choices. Likert scores for each question were reported as means +/- standard deviation (SD). Descriptive and correlative statistics were used to analyze the responses. In addition, an agreement score was created for those responding with "strongly agree" and "agree" on the Likert scale. RESULTS: A total of 104 surveys were administered, with 84 respondents (80.8% response rate). As a whole, 84.9% of respondents agreed that they pursued fellowships; oncology and minimally invasive urology were the most popular choices throughout the 4 years. Respondents stated that reasons for pursuing a fellowship included: interest in pursuing an academic career (mean 3.73+/- 1.1 (SD): agreement score 61.1%) as well as acquiring marketable skills to obtain an urology position (3.59 +/- 1.3: 64.4%). Most agreed or strongly agreed (84.9%) that a reason for pursing a fellowship was an interest in focusing their practice to this sub-specialty area. In comparison, most graduates disagreed that a reason for pursuing a fellowship was that residency did not equip them with the necessary skills to practice urology (2.49 +/- 1.2: 19%). Most (81.2%) of graduates agreed they knew enough about academic urology to know if it would be a suitable career choice for them versus 54.7% regarding community urology (p < 0.0001). Surprisingly, only 61.7% of residents agreed that they completed a community elective during training, and most felt they would have benefited from additional elective time in the community. CONCLUSIONS: Urology residents graduating from Canadian programs pursue postgraduate training to enhance their surgical skill set and to achieve marketability, but also to facilitate a potential academic career. Responses from the trainees suggest that exposure to community practice appears suboptimal and may be an area of focus for programs to aid in career counselling and professional development. PMID- 25553160 TI - Update on medical expulsive therapy for distal ureteral stones: Beyond alpha blockers. AB - Medical expulsive therapy (MET) has been described as an effective conservative treatment option in the initial management of small distal ureteral stones. Therapies that have been investigated include alpha-blockers, calcium channel blockers, corticosteroids, and most recently phosphodiesterase-5 inhibitors (PDE5) inhibitors. While alpha-blockers are currently the only recommended monotherapy, corticosteroids have received increased attention as a potential useful adjunct in the medical management of distal stones. PDE5 inhibitors are a novel treatment alternative, requiring further investigation. This review provides an overview of recent MET best practices, with a focus on novel therapies beyond alpha-blockers. PMID- 25553161 TI - Is semen analysis necessary prior to the commencement of testosterone supplementation therapy in men of reproductive age? PMID- 25553162 TI - The effect of video-based education on patient anxiety in men undergoing transrectal prostate biopsy. AB - INTRODUCTION: We assess the effect of video-based education on patient anxiety during transrectal prostate biopsy. METHODS: A total of 246 patients who underwent transrectal prostate biopsy were prospectively enrolled in the study. Group 1 included 123 patients who received both written and video-based education, while Group 2 included 123 patients who received only written instructions regarding prostate biopsies. State-Trait Anxiety Inventory (STAI) was used to assess state and trait anxiety (STAI-S/T) After completing the STAI-S and STAI-T questionnaires, all patients in Group 1 received written information and video-based education and they again completed STAI-S before the biopsy. On the contrary, after completing the STAI-S and STAI-T questionnaires, the patients in Group 2 received only written information and then they completed the STAI-S before the biopsy. Moreover, a visual analog scale (VAS) was used to assess pain scores during digital rectal examination, probe insertion, periprostatic local anesthesic infiltration, and biopsy. RESULTS: No difference was noted between 2 groups regarding VAS scores. Comparing the 2 groups on baseline anxiety, we found that trait anxiety scores (STAI-T) were similar (p = 0.238). Pre-information STAI S scores were similar in both groups (p = 0.889) and they both indicated high anxiety levels (score >=42). While post-information STAI-S scores remained high in Group 2, post-information STAI-S scores significantly decreased in Group 1 (p = 0.01). CONCLUSIONS: Undergoing a prostate biopsy is stressful and may cause anxiety for patients. Video-based education about the procedure can diminish patient anxiety. PMID- 25553163 TI - A survey of cannabis (marijuana) use and self-reported benefit in men with chronic prostatitis/chronic pelvic pain syndrome. AB - INTRODUCTION: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a chronic pelvic pain condition largely refractory to treatment. Cannabis (marijuana) use has been reported for a wide variety of chronic pain conditions, but no study has examined prevalence of cannabis use, symptom benefit or side effects, or frequency in CP/CPPS. METHODS: Participants were recruited from an outpatient CP/CPPS urology clinic (n = 98) and online through the Prostatitis Foundation website (n = 244). Participants completed questionnaires (demographics, CP/CPPS, depression, cannabis). RESULTS: The clinic sample included Canadian patients and the online sample included primarily American patients. Due to differences, groups were examined separately. Almost 50% of respondents reported using cannabis (clinic n = 49; online n = 89). Of the cannabis users, 36.8% of clinic and 75% of online respondents reported that it improved their symptoms. Most of the respondents (from the clinic and online groups) reported that cannabis improved their mood, pain, muscle spasms, and sleep. However, they did not note any improvements for weakness, fatigue, numbness, ambulation, and urination. Overall, the effectiveness of cannabis for CP/CPPS was "somewhat/very effective" (57% clinic; 63% online). There were no differences between side effects or choice of consumption and most reported using cannabis rarely. CONCLUSIONS: These are the first estimates in men suffering from CP/CPPS and suggest that while cannabis use is prevalent, its medical use and benefit are unknown. This is an understudied area and the benefit or hazard for cannabis use awaits further study. PMID- 25553164 TI - Percutaneous nephrolithotomy versus open surgery for treatment of staghorn stones in pediatric patients. AB - INTRODUCTION: We compare percutaneous nephrolithotomy (PCNL) and open surgery in the treatment of staghorn stones in children. METHODS: We retrospectively reviewed the electronic records of children who underwent treatment for staghorn stones between September 2000 and August 2013. They were divided between Group 1 (patients who underwent PCNL) and Group 2 (patients who underwent open surgery). We compared stone-free and complications rates, need for multiple procedures, and hospital stay. RESULTS: The study included 41 patients (35 boys and 6 girls), with mean age 7.4 +/- 3.1 years (range: 2-15). Of these 41 patients, 26 had unilateral renal stone and 15 had bilateral renal stones. The total number of treated renal units was 56: 28 underwent PCNL and 28 underwent open surgery. The complication rate was comparable for both groups (32% for open surgery vs. 28.6%, p = 0.771). Multiple procedures were more needed in PCNL group (60.7% vs. 32% in open surgery, p = 0.032). The stone-free rate was 71.4% after PCNL and 78.6% after open surgery (p = 0.537). A significant difference was observed in shorter hospital stay after PCNL (5 vs. 8.8 days, p < 0.001). Our study's limitations include its retrospective design and relatively small sample size. CONCLUSIONS: For the treatment of staghorn stones in children, PCNL was comparable to open surgery in complication and stone-free rates. PCNL had the advantage of a shorter hospital stay and open surgery showed a decreased need for multiple procedures. PMID- 25553165 TI - [Not Available]. PMID- 25553166 TI - Transurethral holmium laser vaporization to the urethral tumour through a ureteroscope. AB - We present 2 cases of urethral cancers: one is recurrent bladder transitional cell carcinoma accompanied by urethral metastatic carcinoma located on the right side of verumontanum, and the other is primary bladder and metastatic urethral adenocarcinoma. The urethral tumour was treated by transurethral holmium laser vaporization to the urethral tumour through a ureteroscope and the bladder tumour was treated with transurethral resection and degeneration of the bladder tumour (TURD-Bt). After the second or third therapy, patients were free of urethral or bladder tumour recurrence; they also did not experience urethral stricture or urinary incontinence during the 24- to 36-month follow-up. Transurethral holmium laser vaporization and TURD-Bt could be performed to treat non-invasive urethral cancer accompanied with bladder cancer and preserve the urethra and bladder. PMID- 25553167 TI - Urethro-urethral fistula: A rare cause of post-TURP incontinence. AB - Prostatic abscess rarely follows acute prostatitis and can sometimes lead to a fistula by breaking into the prostatic urethra, peri-rectal tissues, the perineum, or the rectum. We report a case of a prostatic abscess tracking into the bulbar urethra after a transurethral resection of the prostate. This created a fistula, mimicking a urethral duplication and leading to urinary incontinence. PMID- 25553168 TI - Laparoscopic partial nephrectomy for renal cell carcinoma in a horseshoe kidney. AB - Horseshoe kidney has an incidence rate ranging from 1 in 400 to 1 in 1000, with a 2:1 ratio in men. It also has a predilection for chromosomal aneuploidies. From a pathophysiology standpoint, this anomaly occurs during the second to sixth week of gestation when the inferior portion of the metanephric blastema fuses to form an isthmus, commonly in the lower renal pole (90%). As a result of this fusion, the kidney may not bypass the inferior mesenteric artery and is impeded in its ascent. With an aberrant anatomical orientation and location, complications arise including hydronephrosis, renal calculi and a twofold risk of Wilms tumour. Despite these findings, the association of renal cell carcinoma (RCC) within a horseshoe kidney is extremely rare and fewer than 200 cases have been described. Therapeutically speaking, partial nephrectomies are the gold standard of treatment for renal tumours smaller than 4 cm in diameter, with a growing indication to accomplish this procedure by laparoscopic or robotic means. We report a case of an asymptomatic 58-year-old male with an incidental computed tomography scan finding of a 4-cm solid mass in the right moiety of a horseshoe kidney. He was treated by laparoscopic partial nephrectomy. There have only been 2 other reported cases to our knowledge on a laparoscopic partial nephrectomy in a horseshoe kidney for RCC. We believe that, in experienced hands, the laparoscopic approach may be used successfully for this clinical situation. PMID- 25553169 TI - Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer. AB - An 80-year-old man with an elevated prostate-specific antigen (PSA) level of 120 ng/mL) presented to the hospital in February 2011. A prostate needle biopsy was performed, and pathological examination revealed prostatic adenocarcinoma. The Gleason score was 4+5=9. Computed tomography revealed metastases of the pelvic lymph nodes. Combined androgen blockade was started. The PSA concentration decreased to 1.68 ng/mL, but started increasing again in August 2012 to 6.08 ng/mL. Although bicalutamide was discontinued due to antiandrogen withdrawal syndrome, the PSA concentration increased even more. The PSA concentration reached 21.62 ng/mL in September 2012, at which time ethnylestradiol was started. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years. To our knowledge, this is first case report describing a complete response to ethnylestradiol that lasted for almost 2 years in a patient with castration-resistant prostate cancer. PMID- 25553170 TI - Metastatic renal cell carcinoma to the testis: A case report and review of the literature. AB - This is a case of a 68-year-old male who presented with a chief compliant of a testicular mass, which was discovered to be a meta-static lesion of undiagnosed renal cell carcinoma. A computed tomography scan revealed a large right renal mass and multiple pulmonary metastasis. Shortly after diagnosis, the patient was initiated on systemic therapy and received a cytoreductive nephrectomy. We discuss the details of this case as well as a pertinent review of metastatic renal cell carcinoma to the testes. PMID- 25553171 TI - Papillary renal cell carcinoma within a renal oncocytoma: Case report of very rare coexistence. AB - Renal oncocytomas accounts for 3% to 9% of primary renal neoplasms. The coexistence of renal cell carcinoma (RCC) within the oncocytoma is extremely rare. We report the case of an asyptomatic 74-year-old man with papillary RCC within oncocytoma managed with left radical nephrectomy. PMID- 25553172 TI - Long-term administration of single-agent carboplatin (AUC 4) for advanced testicular seminoma safely achieved complete response in an 80-year-old man with chronic heart failure: A case report. AB - Carboplatin is often used instead of cisplatin as an alternative treatment for advanced testicular cancer. However, the safety, optimal dose, and optimal duration of this agent are unclear in patients with cardiac complications. We report the safety and effectiveness of long-term single-agent carboplatin for the treatment of testicular cancer in a patient with chronic heart failure (CHF). An 80-year-old man was referred to our institution for evaluation of painless swelling of the left scrotum. Computed tomography revealed lung metastases. Left radical inguinal orchiectomy was performed, and pathologic examination revealed a pure seminoma. Because he had CHF, there was high possibility of onset of acute heart failure secondary to fluid administration. Thus, single-agent carboplatin (AUC 4) was selected for therapy. A complete response was achieved after 8 of 13 cycles, and no serious adverse events occurred, including cardiac problems. Neither recurrence nor metastasis was detected during the 6-month follow-up. Low dose, long-term carboplatin is likely effective for patients who are unfit for cisplatin administration because of comorbidities, especially CHF. PMID- 25553173 TI - Elective gangrene of the corpus spongiosum of idiopathic origin: A case report. AB - Penile gangrene is rare and associated with significant morbidity and mortality. It can be dry or wet. Treatment for dry gangrene is based on surgery, watchful waiting allowing spontaneous amputation of necrotic tissue or revascularization. It often depends on the general condition of the patient. We report a case of a 54-year-old patient with no significant medical history who presented with necrosis of the glans penis. Upon surgical exploration, we found an elective necrosis of the entire corpus spongiosum for which partial penectomy was performed. No etiology was found. To our knowledge, this is the first such case to be reported in the literature. PMID- 25553174 TI - Total ureterectomy and ileal ureteric replacement for TCC ureter in a solitary kidney. AB - Traditional treatment of upper tract transitional cell carcinoma (TCC) is nephroureterectomy with a bladder cuff. This is in keeping with the nature of the disease, in that TCC is a panurothelial disease. However, there are a few rare occasions when this would mean making a subject anephric, as in a TCC in a solitary kidney or bilateral synchronous/metachronous disease. We present a case of a patient with a dysplastic, poorly functioning left kidney and with a TCC of the ureter on the right side. PMID- 25553175 TI - Bone marrow metastasis of prostatic adenocarcinoma with post-treatment foamy-like changes: A diagnostic pitfall. AB - Prostatic acinar adenocarcinoma (PAA) is the most common malignant tumour of the male genital system. Hormonal therapy and radiotherapy are widely-used treatment modalities in advanced stage disease. However, with hormonal therapy, the morphology of the neoplastic cells can be altered with a shift towards benign appearing cells with inconspicuous nucleoli and abundant cytoplasm. When the tumour spreads to the bone marrow, these neoplastic cells can mimic foamy histiocytes, which may lead to a misdiagnosis. This becomes more challenging if a concurrent bone marrow malignancy is identified. Attention should be paid if foamy cells are detected in bone marrow, particularly if the patient has a history of PAA. To the best of our knowledge, this is the first report of simultaneous bone marrow involvement by metastatic PAA with mimicking foamy histiocytes and lymphoplasmacytic lymphoma. PMID- 25553176 TI - [Not Available]. PMID- 25553177 TI - On-chip multi-gas incubation for microfluidic cell cultures under hypoxia. AB - We developed a simple system that regulates CO2 and O2 levels within a microfluidic chip. This system enables long-term cell culture under hypoxic conditions without the need of a CO2 incubator or a multi-gas incubator. Hypoxic conditions were generated using a miniature water jacket containing dissolved ascorbate as an oxygen scavenger. Formulations of the water jacket were determined that enables both 5% pCO2 and desired pO2 levels ranging from 5 to 15%. We also cultured PC-12 cells and primary neuronal cells from chick embryos under hypoxia and observed hypoxia-induced cell death and inhibition of neurite outgrowth. PMID- 25553178 TI - Smartphone-interfaced lab-on-a-chip devices for field-deployable enzyme-linked immunosorbent assay. AB - The emerging technologies on mobile-based diagnosis and bioanalytical detection have enabled powerful laboratory assays such as enzyme-linked immunosorbent assay (ELISA) to be conducted in field-use lab-on-a-chip devices. In this paper, we present a low-cost universal serial bus (USB)-interfaced mobile platform to perform microfluidic ELISA operations in detecting the presence and concentrations of BDE-47 (2,2',4,4'-tetrabromodiphenyl ether), an environmental contaminant found in our food supply with adverse health impact. Our point-of care diagnostic device utilizes flexible interdigitated carbon black electrodes to convert electric current into a microfluidic pump via gas bubble expansion during electrolytic reaction. The micropump receives power from a mobile phone and transports BDE-47 analytes through the microfluidic device conducting competitive ELISA. Using variable domain of heavy chain antibodies (commonly referred to as single domain antibodies or Nanobodies), the proposed device is sensitive for a BDE-47 concentration range of 10(-3)-10(4 ) MUg/l, with a comparable performance to that uses a standard competitive ELISA protocol. It is anticipated that the potential impact in mobile detection of health and environmental contaminants will prove beneficial to our community and low resource environments. PMID- 25553179 TI - Optical chromatographic sample separation of hydrodynamically focused mixtures. AB - Optical chromatography relies on the balance between the opposing optical and fluid drag forces acting on a particle. A typical configuration involves a loosely focused laser directly counter to the flow of particle-laden fluid passing through a microfluidic device. This equilibrium depends on the intrinsic properties of the particle, including size, shape, and refractive index. As such, uniquely fine separations are possible using this technique. Here, we demonstrate how matching the diameter of a microfluidic flow channel to that of the focusing laser in concert with a unique microfluidic platform can be used as a method to fractionate closely related particles in a mixed sample. This microfluidic network allows for a monodisperse sample of both polystyrene and poly(methyl methacrylate) spheres to be injected, hydrodynamically focused, and completely separated. To test the limit of separation, a mixed polystyrene sample containing two particles varying in diameter by less than 0.5 MUm was run in the system. The analysis of the resulting separation sets the framework for continued work to perform ultra-fine separations. PMID- 25553180 TI - Traceable clonal culture and chemodrug assay of heterogeneous prostate carcinoma PC3 cells in microfluidic single cell array chips. AB - Cancer heterogeneity has received considerable attention for its role in tumor initiation and progression, and its implication for diagnostics and therapeutics in the clinic. To facilitate a cellular heterogeneity study in a low cost and highly efficient manner, we present a microfluidic platform that allows traceable clonal culture and characterization. The platform captures single cells into a microwell array and cultures them for clonal expansion, subsequently allowing on chip characterization of clonal phenotype and response against drug treatments. Using a heterogeneous prostate cancer model, the PC3 cell line, we verified our prototype, identifying three different sub-phenotypes and correlating their clonal drug responsiveness to cell phenotype. PMID- 25553181 TI - A microfluidic device to apply shear stresses to polarizing ciliated airway epithelium using air flow. AB - Organization of airway epithelium determines ciliary beat direction and coordination for proper mucociliary clearance. Fluidic shear stresses have the potential to influence ciliary organization. Here, an in vitro fluidic flow system was developed for inducing long-term airflow shear stresses on airway epithelium with a view to influencing epithelial organization. Our system consists of a fluidic device for cell culture, integrated into a humidified airflow circuit. The fluidic device has a modular design and is made from a combination of polystyrene and adhesive components incorporated into a 6-well filter membrane insert. We demonstrate the system operates within physiologically relevant shear and pressure ranges and estimate the shear stress exerted on the epithelial cell layer as a result of air flow using a computational model. For both the bronchial epithelial cell line BEAS2B and primary human tracheal airway epithelial cells, we demonstrate that cells remain viable within the device when exposed to airflow for 24 h and that normal differentiation and cilia formation occurs. Furthermore, we demonstrate the utility of our device for exploring the impact of exposing cells to airflow: our tool enables quantification of cytoskeletal organization, and is compatible with in situ bead assays to assess the orientation of cilia beating. PMID- 25553182 TI - Development of a three-dimensional cell culture system based on microfluidics for nuclear magnetic resonance and optical monitoring. AB - A new microfluidic cell culture device compatible with real-time nuclear magnetic resonance (NMR) is presented here. The intended application is the long-term monitoring of 3D cell cultures by several techniques. The system has been designed to fit inside commercially available NMR equipment to obtain maximum readout resolution when working with small samples. Moreover, the microfluidic device integrates a fibre-optic-based sensor to monitor parameters such as oxygen, pH, or temperature during NMR monitoring, and it also allows the use of optical microscopy techniques such as confocal fluorescence microscopy. This manuscript reports the initial trials culturing neurospheres inside the microchamber of this device and the preliminary images and spatially localised spectra obtained by NMR. The images show the presence of a necrotic area in the interior of the neurospheres, as is frequently observed in histological preparations; this phenomenon appears whenever the distance between the cells and fresh nutrients impairs the diffusion of oxygen. Moreover, the spectra acquired in a volume of 8 nl inside the neurosphere show an accumulation of lactate and lipids, which are indicative of anoxic conditions. Additionally, a basis for general temperature control and monitoring and a graphical control software have been developed and are also described. The complete platform will allow biomedical assays of therapeutic agents to be performed in the early phases of therapeutic development. Thus, small quantities of drugs or advanced nanodevices may be studied long-term under simulated living conditions that mimic the flow and distribution of nutrients. PMID- 25553183 TI - Increasing label-free stem cell sorting capacity to reach transplantation-scale throughput. AB - Dielectrophoresis (DEP) has proven an invaluable tool for the enrichment of populations of stem and progenitor cells owing to its ability to sort cells in a label-free manner and its biological safety. However, DEP separation devices have suffered from a low throughput preventing researchers from undertaking studies requiring large numbers of cells, such as needed for cell transplantation. We developed a microfluidic device designed for the enrichment of stem and progenitor cell populations that sorts cells at a rate of 150,000 cells/h, corresponding to an improvement in the throughput achieved with our previous device designs by over an order of magnitude. This advancement, coupled with data showing the DEP-sorted cells retain their enrichment and differentiation capacity when expanded in culture for periods of up to 2 weeks, provides sufficient throughput and cell numbers to enable a wider variety of experiments with enriched stem and progenitor cell populations. Furthermore, the sorting devices presented here provide ease of setup and operation, a simple fabrication process, and a low associated cost to use that makes them more amenable for use in common biological research laboratories. To our knowledge, this work represents the first to enrich stem cells and expand them in culture to generate transplantation scale numbers of differentiation-competent cells using DEP. PMID- 25553184 TI - Electrowetting on dielectric device with crescent electrodes for reliable and low voltage droplet manipulation. AB - Digital microfluidics based on electrowetting on dielectric is an emerging popular technology that manipulates single droplets at the microliter or even the nanoliter level. It has the unique advantages of rapid response, low reagent consumption, and high integration and is mainly applied in the field of biochemical analysis. However, currently, this technology still has a few problems, such as high control voltage, low droplet velocity, and continuity in flow, limiting its application. In this paper, through theoretical analysis and numerical simulation, it is deduced that a drive electrode with a crescent configuration can reduce the driving voltage. The experimental results not only validate this deduction but also indicate that crescent electrode can improve the droplet motion continuity and the success in split rate. PMID- 25553185 TI - Label-free density difference amplification-based cell sorting. AB - The selective cell separation is a critical step in fundamental life sciences, translational medicine, biotechnology, and energy harvesting. Conventional cell separation methods are fluorescent activated cell sorting and magnetic-activated cell sorting based on fluorescent probes and magnetic particles on cell surfaces. Label-free cell separation methods such as Raman-activated cell sorting, electro physiologically activated cell sorting, dielectric-activated cell sorting, or inertial microfluidic cell sorting are, however, limited when separating cells of the same kind or cells with similar sizes and dielectric properties, as well as similar electrophysiological phenotypes. Here we report a label-free density difference amplification-based cell sorting (dDACS) without using any external optical, magnetic, electrical forces, or fluidic activations. The conceptual microfluidic design consists of an inlet, hydraulic jump cavity, and multiple outlets. Incoming particles experience gravity, buoyancy, and drag forces in the separation chamber. The height and distance that each particle can reach in the chamber are different and depend on its density, thus allowing for the separation of particles into multiple outlets. The separation behavior of the particles, based on the ratio of the channel heights of the inlet and chamber and Reynolds number has been systematically studied. Numerical simulation reveals that the difference between the heights of only lighter particles with densities close to that of water increases with increasing the ratio of the channel heights, while decreasing Reynolds number can amplify the difference in the heights between the particles considered irrespective of their densities. PMID- 25553186 TI - Melting analysis on microbeads in rapid temperature-gradient inside microchannels for single nucleotide polymorphisms detection. AB - A continuous-flow microchip with a temperature gradient in microchannels was utilized to demonstrate spatial melting analysis on microbeads for clinical Single Nucleotide Polymorphisms (SNPs) genotyping on animal genomic DNA. The chip had embedded heaters and thermometers, which created a rapid and yet stable temperature gradient between 60 degrees C and 85 degrees C in a short distance as the detection region. The microbeads, which served as mobile supports carrying the target DNA and fluorescent dye, were transported across the temperature gradient. As the surrounding temperature increased, the fluorescence signals of the microbeads decayed with this relationship being acquired as the melting curve. Fast DNA denaturation, as a result of the improved heat transfer and thermal stability due to scaling, was also confirmed. Further, each individual microbead could potentially bear different sequences and pass through the detection region, one by one, for a series of melting analysis, with multiplex, high-throughput capability being possible. A prototype was tested with target DNA samples in different genotypes (i.e., wild and mutant types) with a SNP location from Landrace sows. The melting temperatures were obtained and compared to the ones using a traditional tube-based approach. The results showed similar levels of SNP discrimination, validating our proposed technique for scanning homozygotes and heterozygotes to distinguish single base changes for disease research, drug development, medical diagnostics, agriculture, and animal production. PMID- 25553187 TI - Sub-nanomolar detection of thrombin activity on a microfluidic chip. AB - Bioluminescence resonance energy transfer (BRET) is a form of Forster resonance energy transfer. BRET has been shown to support lower limits of detection than fluorescence resonance energy transfer (FRET) but, unlike FRET, has not been widely implemented on microfluidic devices for bioanalytical sensing. We recently reported a microscope-based microfluidic system for BRET-based biosensing, using a hybrid, high quantum-efficiency, form of BRET chemistry. This paper reports the first optical fiber-based system for BRET detection on a microfluidic chip, capable of quantifying photon emissions from the low quantum-efficiency BRET(2) system. We investigated the effects of varying core diameter and numerical aperture of optical fibers, as well as varying microfluidic channel design and measurement conditions. We optimized the set-up in order to maximize photon counts and minimize the response time. The optimized conditions supported measurement of thrombin activity, with a limit of detection of 20 pM, which is lower than the microscope-based system and more than 20 times lower than concentrations reported to occur in plasma clots. PMID- 25553189 TI - Three-dimensional printing-based electro-millifluidic devices for fabricating multi-compartment particles. AB - In this work, we demonstrate the use of stereolithographic 3D printing to fabricate millifluidic devices, which are used to engineer particles with multiple compartments. As the 3D design is directly transferred to the actual prototype, this method accommodates 3D millimeter-scaled features that are difficult to achieve by either lithographic-based microfabrication or traditional macrofabrication techniques. We exploit this approach to produce millifluidic networks to deliver multiple fluidic components. By taking advantage of the laminar flow, the fluidic components can form liquid jets with distinct patterns, and each pattern has clear boundaries between the liquid phases. Afterwards, droplets with controlled size are fabricated by spraying the liquid jet in an electric field, and subsequently converted to particles after a solidification step. As a demonstration, we fabricate calcium alginate particles with structures of (1) slice-by-slice multiple lamellae, (2) concentric core-shells, and (3) petals surrounding the particle centers. Furthermore, distinct hybrid particles combining two or more of the above structures are also obtained. These compartmentalized particles impart spatially dependent functionalities and properties. To show their applicability, various ingredients, including fruit juices, drugs, and magnetic nanoparticles are encapsulated in the different compartments as proof-of-concepts for applications, including food, drug delivery, and bioassays. Our 3D printed electro-millifluidic approach represents a convenient and robust method to extend the range of structures of functional particles. PMID- 25553188 TI - Millifluidics as a simple tool to optimize droplet networks: Case study on drop traffic in a bifurcated loop. AB - We report that modular millifluidic networks are simpler, more cost-effective alternatives to traditional microfluidic networks, and they can be rapidly generated and altered to optimize designs. Droplet traffic can also be studied more conveniently and inexpensively at the millimeter scale, as droplets are readily visible to the naked eye. Bifurcated loops, ladder networks, and parking networks were made using only Tygon((r)) tubing and plastic T-junction fittings and visualized using an iPod((r)) camera. As a case study, droplet traffic experiments through a millifluidic bifurcated loop were conducted, and the periodicity of drop spacing at the outlet was mapped over a wide range of inlet drop spacing. We observed periodic, intermittent, and aperiodic behaviors depending on the inlet drop spacing. The experimentally observed periodic behaviors were in good agreement with numerical simulations based on the simple network model. Our experiments further identified three main sources of intermittency between different periodic and/or aperiodic behaviors: (1) simultaneous entering and exiting events, (2) channel defects, and (3) equal or nearly equal hydrodynamic resistances in both sides of the bifurcated loop. In cases of simultaneous events and/or channel defects, the range of input spacings where intermittent behaviors are observed depends on the degree of inherent variation in input spacing. Finally, using a time scale analysis of syringe pump fluctuations and experiment observation times, we find that in most cases, more consistent results can be generated in experiments conducted at the millimeter scale than those conducted at the micrometer scale. Thus, millifluidic networks offer a simple means to probe collective interactions due to drop traffic and optimize network geometry to engineer passive devices for biological and material analysis. PMID- 25553190 TI - Microfluidic perfusion culture system for multilayer artery tissue models. AB - We described an assembly technique and perfusion culture system for constructing artery tissue models. This technique differed from previous studies in that it does not require a solid biodegradable scaffold; therefore, using sheet-like tissues, this technique allowed the facile fabrication of tubular tissues can be used as model. The fabricated artery tissue models had a multilayer structure. The assembly technique and perfusion culture system were applicable to many different sizes of fabricated arteries. The shape of the fabricated artery tissue models was maintained by the perfusion culture system; furthermore, the system reproduced the in vivo environment and allowed mechanical stimulation of the arteries. The multilayer structure of the artery tissue model was observed using fluorescent dyes. The equivalent Young's modulus was measured by applying internal pressure to the multilayer tubular tissues. The aim of this study was to determine whether fabricated artery tissue models maintained their mechanical properties with developing. We demonstrated both the rapid fabrication of multilayer tubular tissues that can be used as model arteries and the measurement of their equivalent Young's modulus in a suitable perfusion culture environment. PMID- 25553191 TI - Monitoring the dielectric response of single cells following mitochondrial adenosine triphosphate synthase inhibition by oligomycin using a dielectrophoretic cytometer. AB - One of the main uses of adenosine triphosphate (ATP) within mammalian cells is powering the Na(+)/K(+) ATPase pumps used to maintain ion concentrations within the cell. Since ion concentrations determine the cytoplasm conductivity, ATP concentration is expected to play a key role in controlling the cytoplasm conductivity. The two major ATP production pathways within cells are via glycolysis within the cytoplasm and via the electron transport chain within the mitochondria. In this work, a differential detector combined with dielectrophoretic (DEP) translation in a microfluidic channel was employed to observe single cell changes in the cytoplasm conductivity. The DEP response was made sensitive to changes in cytoplasm conductivity by measuring DEP response versus media conductivity and using double shell models to choose appropriate frequencies and media conductivity. Dielectric response of Chinese hamster ovary (CHO) cells was monitored following inhibition of the mitochondria ATP production by treatment with oligomycin. We show that in CHO cells following exposure to oligomycin (8 MUg/ml) the cytoplasm conductivity drops, with the majority of the change occurring within 50 min. This work demonstrates that dielectric effects due to changes in ATP production can be observed at the single cell level. PMID- 25553192 TI - Polyphosphonium-based ion bipolar junction transistors. AB - Advancements in the field of electronics during the past few decades have inspired the use of transistors in a diversity of research fields, including biology and medicine. However, signals in living organisms are not only carried by electrons but also through fluxes of ions and biomolecules. Thus, in order to implement the transistor functionality to control biological signals, devices that can modulate currents of ions and biomolecules, i.e., ionic transistors and diodes, are needed. One successful approach for modulation of ionic currents is to use oppositely charged ion-selective membranes to form so called ion bipolar junction transistors (IBJTs). Unfortunately, overall IBJT device performance has been hindered due to the typical low mobility of ions, large geometries of the ion bipolar junction materials, and the possibility of electric field enhanced (EFE) water dissociation in the junction. Here, we introduce a novel polyphosphonium-based anion-selective material into npn-type IBJTs. The new material does not show EFE water dissociation and therefore allows for a reduction of junction length down to 2 MUm, which significantly improves the switching performance of the ion transistor to 2 s. The presented improvement in speed as well the simplified design will be useful for future development of advanced iontronic circuits employing IBJTs, for example, addressable drug delivery devices. PMID- 25553193 TI - Cascaded spiral microfluidic device for deterministic and high purity continuous separation of circulating tumor cells. AB - Inertial microfluidics is an emerging class of technologies developed to separate circulating tumor cells (CTCs). However, defining design parameters and flow conditions for optimal operation remains nondeterministic due to incomplete understanding of the mechanics, which has led to challenges in designing efficient systems. Here, we perform a parametric study of the inertial focusing effects observed in low aspect ratio curvilinear microchannels and utilize the results to demonstrate the isolation of CTCs with high purity. First, we systematically vary parameters including the channel height, width, and radius of curvature over a wide range of flow velocities to analyze its effect on size dependent differential focusing and migration behaviors of binary (10 MUm and 20 MUm) particles. Second, we use these results to identify optimal flow regimes to achieve maximum separation in various channel configurations and establish design guidelines to readily provide information for developing spiral channels tailored to potentially arbitrary flow conditions that yield a desired equilibrium position for optimal size based CTC separation. Finally, we describe a fully integrated, sheath-less cascaded spiral microfluidic device to continuously isolate CTCs. Human breast cancer epithelial cells were successfully extracted from leukocytes, achieving 86.76% recovery, 97.91% depletion rate, and sustaining high viability upon collection to demonstrate the versatility of the device. Importantly, this device was designed without the cumbersome trail-and-error optimization process that has hindered the development of designing such inertial microfluidic systems. PMID- 25553194 TI - A microfluidic co-culture system to monitor tumor-stromal interactions on a chip. AB - The living cells are arranged in a complex natural environment wherein they interact with extracellular matrix and other neighboring cells. Cell-cell interactions, especially those between distinct phenotypes, have attracted particular interest due to the significant physiological relevance they can reveal for both fundamental and applied biomedical research. To study cell-cell interactions, it is necessary to develop co-culture systems, where different cell types can be cultured within the same confined space. Although the current advancement in lab-on-a-chip technology has allowed the creation of in vitro models to mimic the complexity of in vivo environment, it is still rather challenging to create such co-culture systems for easy control of different colonies of cells. In this paper, we have demonstrated a straightforward method for the development of an on-chip co-culture system. It involves a series of steps to selectively change the surface property for discriminative cell seeding and to induce cellular interaction in a co-culture region. Bone marrow stromal cells (HS5) and a liver tumor cell line (HuH7) have been used to demonstrate this co-culture model. The cell migration and cellular interaction have been analyzed using microscopy and biochemical assays. This co-culture system could be used as a disease model to obtain biological insight of pathological progression, as well as a tool to evaluate the efficacy of different drugs for pharmaceutical studies. PMID- 25553195 TI - Development of flow through dielectrophoresis microfluidic chips for biofuel production: Sorting and detection of microalgae with different lipid contents. AB - In this study, a continuous flow dielectrophoresis (DEP) microfluidic chip was fabricated and utilized to sort out the microalgae (C. vulgaris) with different lipid contents. The proposed separation scheme is to allow that the microalgae with different lipid contents experience different negative or no DEP force at the separation electrode pair under the pressure-driven flow. The microalgae that experience stronger negative DEP will be directed to the side channel while those experience less negative or no DEP force will pass through the separation electrode pair to remain in the main channel. It was found that the higher the lipid content inside the microalgae, the higher the crossover frequency. Separation of the microalgae with 13% and 21% lipid contents, and 24% and 30%-35% lipid contents was achieved at the operating frequency 7 MHz, and 10 MHz, respectively. Moreover, separation can be further verified by measurement of the fluorescence intensity of the neutral lipid inside the sorted algal cells. PMID- 25553196 TI - Stretching of DNA confined in nanochannels with charged walls. AB - There is currently a growing interest in control of stretching of DNA inside nanoconfined regions due to the possibility to analyze and manipulate single biomolecules for applications such as DNA mapping and barcoding, which are based on stretching the DNA in a linear fashion. In the present work, we couple Finite Element Methods and Monte Carlo simulations in order to study the conformation of DNA molecules confined in nanofluidic channels with neutral and charged walls. We find that the electrostatic forces become more and more important when lowering the ionic strength of the solution. The influence of the nanochannel cross section geometry is also studied by evaluating the DNA elongation in square, rectangular, and triangular channels. We demonstrate that coupling electrostatically interacting walls with a triangular geometry is an efficient way to stretch DNA molecules at the scale of hundreds of nanometers. The paper reports experimental observations of lambda-DNA molecules in poly(dimethylsiloxane) nanochannels filled with solutions of different ionic strength. The results are in good agreement with the theoretical predictions, confirming the crucial role of the electrostatic repulsion of the constraining walls on the molecule stretching. PMID- 25553197 TI - Mechanical response of red blood cells entering a constriction. AB - Most work on the dynamic response of red blood cells (RBCs) to hydrodynamic stress has focused on linear velocity profiles. Relatively little experimental work has examined how individual RBCs respond to pressure driven flow in more complex geometries, such as the flow at the entrance of a capillary. Here, we establish the mechanical behaviors of healthy RBCs undergoing a sudden increase in shear stress at the entrance of a narrow constriction. We pumped RBCs through a constriction in a microfluidic device and used high speed video to visualize and track the flow behavior of more than 4400 RBCs. We show that approximately 85% of RBCs undergo one of four distinct modes of motion: stretching, twisting, tumbling, or rolling. Intriguingly, a plurality of cells (~30%) exhibited twisting (rotation around the major axis parallel to the flow direction), a mechanical behavior that is not typically observed in linear velocity profiles. We present detailed statistical analyses on the dynamics of each motion and demonstrate that the behavior is highly sensitive to the location of the RBC within the channel. We further demonstrate that the observed tumbling, twisting, and rolling rotations can be rationalized qualitatively in terms of rigid body mechanics. The detailed experimental statistics presented here should serve as a useful resource for modeling of RBC behavior under physiologically important flow conditions. PMID- 25553198 TI - Microfluidic impedance cytometry of tumour cells in blood. AB - The dielectric properties of tumour cells are known to differ from normal blood cells, and this difference can be exploited for label-free separation of cells. Conventional measurement techniques are slow and cannot identify rare circulating tumour cells (CTCs) in a realistic timeframe. We use high throughput single cell microfluidic impedance cytometry to measure the dielectric properties of the MCF7 tumour cell line (representative of CTCs), both as pure populations and mixed with whole blood. The data show that the MCF7 cells have a large membrane capacitance and size, enabling clear discrimination from all other leukocytes. Impedance analysis is used to follow changes in cell viability when cells are kept in suspension, a process which can be understood from modelling time dependent changes in the dielectric properties (predominantly membrane conductivity) of the cells. Impedance cytometry is used to enumerate low numbers of MCF7 cells spiked into whole blood. Chemical lysis is commonly used to remove the abundant erythrocytes, and it is shown that this process does not alter the MCF7 cell count or change their dielectric properties. Combining impedance cytometry with magnetic bead based antibody enrichment enables MCF7 cells to be detected down to 100 MCF7 cells in 1 ml whole blood, a log 3.5 enrichment and a mean recovery of 92%. Microfluidic impedance cytometry could be easily integrated within complex cell separation systems for identification and enumeration of specific cell types, providing a fast in-line single cell characterisation method. PMID- 25553199 TI - Effect of Joule heating on isoelectric focusing of proteins in a microchannel. AB - Electric field-driven separation and purification techniques, such as isoelectric focusing (IEF) and isotachophoresis, generate heat in the system that can affect the performance of the separation process. In this study, a new mathematical model is presented for IEF that considers the temperature rise due to Joule heating. We used the model to study focusing phenomena and separation performance in a microchannel. A finite volume-based numerical technique is developed to study temperature-dependent IEF. Numerical simulation for narrow range IEF (6 < pH < 10) is performed in a straight microchannel for 100 ampholytes and two model proteins: staphylococcal nuclease and pancreatic ribonuclease. Separation results of the two proteins are obtained with and without considering the temperature rise due to Joule heating in the system for a nominal electric field of 100 V/cm. For the no Joule heating case, constant properties are used, while for the Joule heating case, temperature-dependent titration curves and thermo-physical properties are used. Our numerical results show that the temperature change due to Joule heating has a significant impact on the final focusing points of proteins, which can lower the separation performance considerably. In the absence of advection and any active cooling mechanism, the temperature increase is the highest at the mid-section of a microchannel. We also found that the maximum temperature in the system is a strong function of the [Formula: see text] value of the carrier ampholytes. Simulation results are also obtained for different values of applied electric fields in order to find the optimum working range considering the simulation time and buffer temperature. Moreover, the model is extended to study IEF in a straight microchip where pH is formed by supplying H(+) and OH(-), and the thermal analysis shows that the heat generation is negligible in ion supplied IEF. PMID- 25553200 TI - Solution pH change in non-uniform alternating current electric fields at frequencies above the electrode charging frequency. AB - AC Faradaic reactions have been reported as a mechanism inducing non-ideal phenomena such as flow reversal and cell deformation in electrokinetic microfluidic systems. Prior published work described experiments in parallel electrode arrays below the electrode charging frequency (fc ), the frequency for electrical double layer charging at the electrode. However, 2D spatially non uniform AC electric fields are required for applications such as in plane AC electroosmosis, AC electrothermal pumps, and dielectrophoresis. Many microscale experimental applications utilize AC frequencies around or above fc . In this work, a pH sensitive fluorescein sodium salt dye was used to detect [H(+)] as an indicator of Faradaic reactions in aqueous solutions within non-uniform AC electric fields. Comparison experiments with (a) parallel (2D uniform fields) electrodes and (b) organic media were employed to deduce the electrode charging mechanism at 5 kHz (1.5fc ). Time dependency analysis illustrated that Faradaic reactions exist above the theoretically predicted electrode charging frequency. Spatial analysis showed [H(+)] varied spatially due to electric field non uniformities and local pH changed at length scales greater than 50 MUm away from the electrode surface. Thus, non-uniform AC fields yielded spatially varied pH gradients as a direct consequence of ion path length differences while uniform fields did not yield pH gradients; the latter is consistent with prior published data. Frequency dependence was examined from 5 kHz to 12 kHz at 5.5 Vpp potential, and voltage dependency was explored from 3.5 to 7.5 Vpp at 5 kHz. Results suggest that Faradaic reactions can still proceed within electrochemical systems in the absence of well-established electrical double layers. This work also illustrates that in microfluidic systems, spatial medium variations must be considered as a function of experiment time, initial medium conditions, electric signal potential, frequency, and spatial position. PMID- 25553201 TI - Effect of a dual inlet channel on cell loading in microfluidics. AB - Unwanted sedimentation and attachment of a number of cells onto the bottom channel often occur on relatively large-scale inlets of conventional microfluidic channels as a result of gravity and fluid shear. Phenomena such as sedimentation have become recognized problems that can be overcome by performing microfluidic experiments properly, such as by calculating a meaningful output efficiency with respect to real input. Here, we present a dual-inlet design method for reducing cell loss at the inlet of channels by adding a new " upstream inlet " to a single main inlet design. The simple addition of an upstream inlet can create a vertically layered sheath flow prior to the main inlet for cell loading. The bottom layer flow plays a critical role in preventing the cells from attaching to the bottom of the channel entrance, resulting in a low possibility of cell sedimentation at the main channel entrance. To provide proof-of-concept validation, we applied our design to a microfabricated flow cytometer system (MUFCS) and compared the cell counting efficiency of the proposed MUFCS with that of the previous single-inlet MUFCS and conventional FCS. We used human white blood cells and fluorescent microspheres to quantitatively evaluate the rate of cell sedimentation in the main inlet and to measure fluorescence sensitivity at the detection zone of the flow cytometer microchip. Generating a sheath flow as the bottom layer was meaningfully used to reduce the depth of field as well as the relative deviation of targets in the z-direction (compared to the x-y flow plane), leading to an increased counting sensitivity of fluorescent detection signals. Counting results using fluorescent microspheres showed both a 40% reduction in the rate of sedimentation and a 2-fold higher sensitivity in comparison with the single-inlet MUFCS. The results of CD4(+) T-cell counting also showed that the proposed design results in a 25% decrease in the rate of cell sedimentation and a 28% increase in sensitivity when compared to the single inlet MUFCS. This method is simple and easy to use in design, yet requires no additional time or cost in fabrication. Furthermore, we expect that this approach could potentially be helpful for calculating exact cell loading and counting efficiency for a small input number of cells, such as primary cells and rare cells, in microfluidic channel applications. PMID- 25553202 TI - Colored wax-printed timers for two-dimensional and three-dimensional assays on paper-based devices. AB - Microfluidic paper-based analytical devices (MUPADs) are widely used for performing diagnostic assays. However, in many assays, time-delay valves are required to improve the sensitivity and specificity of the results. Accordingly, this study presents a simple, low-cost method for realizing time-delay valves using a color wax printing process. In the proposed approach, the time-delay effect is controlled through a careful selection of both the color and the saturation of the wax content. The validity of the proposed method is demonstrated by performing nitrite and oxalate assays using both a simple two dimensional MUPAD and a three-dimensional MUPAD incorporating a colored wax printed timer. The experimental results confirm that the flow time can be controlled through an appropriate selection of the color and the wax content. In addition, it is shown that nitrite and oxalate assays can be performed simultaneously on a single device. In general, the results presented in this study show that the proposed MUPADs provide a feasible low-cost alternative to conventional methods for performing diagnostic assays. PMID- 25553203 TI - Fabrication of two dimensional polyethylene terephthalate nanofluidic chip using hot embossing and thermal bonding technique. AB - We present in this paper a method for obtaining a low cost and high replication precision 2D (two dimensional) nanofluidic chip with a PET (polyethylene terephthalate) sheet, which uses hot embossing and a thermal bonding technique. The hot embossing process parameters were optimized by both experiments and the finite element method to improve the replication precision of the 2D nanochannels. With the optimized process parameters, 174.67 +/- 4.51 nm wide and 179.00 +/- 4.00 nm deep nanochannels were successfully replicated into the PET sheet with high replication precision of 98.4%. O2 plasma treatment was carried out before the bonding process to decrease the dimension loss and improve the bonding strength of the 2D nanofluidic chip. The bonding parameters were optimized by bonding rate of the nanofluidic chip. The experiment results show that the bonding strength of the 2D PET nanofluidic chip is 0.664 MPa, and the total dimension loss of 2D nanochannels is 4.34 +/- 7.03 nm and 18.33 +/- 9.52 nm, in width and depth, respectively. The fluorescence images demonstrate that there is no blocking or leakage over the entire micro- and nanochannels. With this fabrication technology, low cost polymer nanochannels can be fabricated, which allows for commercial manufacturing of nano-components. PMID- 25553204 TI - Lithographically Patterned Nanoscale Electrodeposition of Plasmonic, Bimetallic, Semiconductor, Magnetic, and Polymer Nanoring Arrays. AB - Large area arrays of magnetic, semiconducting, and insulating nanorings were created by coupling colloidal lithography with nanoscale electrodeposition. This versatile nanoscale fabrication process allows for the independent tuning of the spacing, diameter, and width of the nanorings with typical values of 1.0 MUm, 750 nm, and 100 nm, respectively, and was used to form nanorings from a host of materials: Ni, Co, bimetallic Ni/Au, CdSe, and polydopamine. These nanoring arrays have potential applications in memory storage, optical materials, and biosensing. A modified version of this nanoscale electrodeposition process was also used to create arrays of split gold nanorings. The size of the split nanoring opening was controlled by the angle of photoresist exposure during the fabrication process and could be varied from 50% down to 10% of the ring circumference. The large area (cm2 scale) gold split nanoring array surfaces exhibited strong polarization-dependent plasmonic absorption bands for wavelengths from 1 to 5 MUm. Plasmonic nanoscale split ring arrays are potentially useful as tunable dichroic materials throughout the infrared and near infrared spectral regions. PMID- 25553205 TI - Single-Walled Carbon Nanotubes Modulate the B- to A-DNA Transition. AB - We study the conformational equilibrium between B-to-A forms of ds-DNA adsorbed onto a single-walled carbon nanotube (SWNT) using free energy profile calculations based on all-atom molecular dynamics simulations. The potential of mean force (PMF) of the B-to-A transition of ds-DNA in the presence of an uncharged (10,0) carbon nanotube for two dodecamers with poly-AT or poly-GC sequences is calculated as a function of a root-mean-square-distance (DeltaRMSD) difference metric for the B-to-A transition. The calculations reveal that in the presence of a SWNT DNA favors B-form DNA significantly in both poly-GC and poly AT sequences. Furthermore, the poly-AT DNA:SWNT complex shows a higher energy penalty for adopting an A-like conformation than poly-GC DNA:SWNT by several kcal/mol. The presence of a SWNT on either poly-AT or poly-GC DNA affects the PMF of the transition such that the B form is favored by as much as 10 kcal/mol. In agreement with published data, we find a potential energy minimum between A and B form DNA at DeltaRMSD ~ -1.5 A and that the presence of the SWNT moves this minimum by as much as DeltaRMSD = 3 A. PMID- 25553206 TI - Using VarScan 2 for Germline Variant Calling and Somatic Mutation Detection. AB - The identification of small sequence variants remains a challenging but critical step in the analysis of next-generation sequencing data. Our variant calling tool, VarScan 2, employs heuristic and statistic thresholds based on user-defined criteria to call variants using SAMtools mpileup data as input. Here, we provide guidelines for generating that input, and describe protocols for using VarScan 2 to (1) identify germline variants in individual samples; (2) call somatic mutations, copy number alterations, and LOH events in tumor-normal pairs; and (3) identify germline variants, de novo mutations, and Mendelian inheritance errors in family trios. Further, we describe a strategy for variant filtering that removes likely false positives associated with common sequencing- and alignment related artifacts. PMID- 25553207 TI - Phytochemical, Antimicrobial and Antiplasmodial Investigations of Terminalia brownii. AB - Phytochemical investigation of the ethyl acetate-soluble fraction of stem bark extract of an African medicinal plant Terminalia brownii led to the isolation of a new oleanane-type triterpenoid, along with seven known triterpenoids, seven ellagic acid derivatives, and 3-O-beta-D-glucopyranosyl-beta-sitosterol. The new compound was identified using spectroscopic methods, notably 1D- and 2D NMR, as 3beta,24-O-ethylidenyl-2alpha,19alpha-dihydroxyolean-12-en-28-oic acid. The isolated compounds were evaluated for their antimicrobial and antiplasmodial activities. Two compounds with a galloyl group (4 and 6) were found to be active against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum, whereas three ellagic acid derivatives (5-7) were found active against three species of fungi and one species of bacteria. PMID- 25553208 TI - Happy new year! PMID- 25553209 TI - The curveball as a risk factor for injury: a systematic review. AB - CONTEXT: The curveball is regarded by many as a potential risk factor for injury in youth baseball pitchers. OBJECTIVE: To critically evaluate the scientific evidence regarding the curveball and its impact on pitching biomechanics and the overall risk of arm injuries in baseball pitchers. STUDY TYPE: Systematic review. LEVEL OF EVIDENCE: Level 3. DATA SOURCES: Ovid MEDLINE from 1946 to 2012. STUDY SELECTION: Ten biomechanical studies on kinematic or electromyographic analysis of pitching a curveball were included, as well as 5 epidemiologic studies that assessed pain or injury incidence in pitchers throwing the curveball. DATA EXTRACTION: When possible, demographic, methodology, kinetics, and kinematics variables and pain/injury incidence were compiled. RESULTS: Two biomechanical studies found greater horizontal adduction of the shoulder at ball release and less shoulder internal torque during the curveball pitching motion. Two studies demonstrated less proximal force and less torque at the elbow as the arm accelerated when throwing a curveball compared with a fastball, as well as greater supination of the forearm and less wrist extension. Electromyographic data suggested increased activity of extensor and supinator muscles for curveballs. No studies found increased force or torque about the elbow or shoulder. Three epidemiologic studies showed no significant association between pitching a curveball and upper extremity pain or injury. One retrospective epidemiologic study reported a 52% increase in shoulder pain in pitchers throwing a curveball, although this may have been due to confounders. CONCLUSION: Despite much debate in the baseball community about the curveball's safety in youth pitchers, limited biomechanical and most epidemiologic data do not indicate an increased risk of injury when compared with the fastball. PMID- 25553211 TI - Current concepts: the role of mesenchymal stem cells in the management of knee osteoarthritis. AB - CONTEXT: The number of adults with osteoarthritis in the United States is expected to nearly double from 21.4 million in 2005 to 41.1 million by 2030. As a result, medical costs and associated comorbidity will exponentially increase in the coming decades. In the past decade, mesenchymal stem cells (MSCs) have emerged as a novel treatment for degenerative joint disease. EVIDENCE ACQUISITION: PubMed (from 1990 to 2013) was searched to identify relevant studies. Reference lists of included studies were also reviewed. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: We identified 9 animal and 7 human studies investigating the use of MSCs in the treatment of osteoarthritis, with varying levels of support for this therapy. CONCLUSION: While MSCs have shown potential for improving function and decreasing inflammation in animal studies, translation to patients is still in question. There is a great deal of heterogeneity in treatment methods. Standardizing the manufacturing and characterization of MSCs will allow for better comparisons. PMID- 25553210 TI - Cell therapy in joint disorders. AB - CONTEXT: Articular cartilage possesses poor natural healing mechanisms, and a variety of non-cell-based and cell-based treatments aim to promote regeneration of hyaline cartilage. DATA SOURCES: A review of the literature to December 2013 using PubMed with search criteria including the keywords stem cell, cell therapy, cell transplantation, cartilage, chondral, and chondrogenic. STUDY SELECTION: Forty-five articles were identified that employed local mesenchymal stem cell (MSC) therapy for joint disorders in humans. Nine comparative studies were identified, consisting of 3 randomized trials, 5 cohort studies, and 1 case control study. STUDY TYPE: Clinical review. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Studies were assessed for stem cell source, method of implantation, comparison groups, and concurrent surgical techniques. RESULTS: Two studies comparing MSC treatment to autologous chondrocyte implantation found similar efficacy. Three studies reported clinical benefits with intra-articular MSC injection over non-MSC controls for cases undergoing debridement with or without marrow stimulation, although a randomized study found no significant clinical difference at 2-year follow-up but reported better 18-month magnetic resonance imaging and histologic scores in the MSC group. No human studies have compared intra-articular MSC therapy to non-MSC techniques for osteoarthritis in the absence of surgery. CONCLUSION: Mesenchymal stem cell-based therapies appear safe and effective for joint disorders in large animal preclinical models. Evidence for use in humans, particularly, comparison with more established treatments such as autologous chondrocyte implantation and microfracture, is limited. PMID- 25553212 TI - Ability of preseason body composition and physical fitness to predict the risk of injury in male collegiate hockey players. AB - BACKGROUND: Injuries in collegiate ice hockey can result in significant time lost from play. The identification of modifiable risk factors relating to a player's physical fitness allows the development of focused training and injury prevention programs targeted at reducing these risks. PURPOSE: To determine the ability of preseason fitness outcomes to predict in-season on-ice injury in male collegiate ice hockey players. STUDY DESIGN: Prognostic cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: Athlete demographics, percentage body fat, aerobic capacity (300-m shuttle run; 1-, 1.5-, 5-mile run), and strength assessment (sit-ups, push ups, grip strength, bench press, Olympic cleans, squats) data were collected at the beginning of 8 successive seasons for 1 male collegiate ice hockey team. Hockey-related injury data and player-level practice/game athlete exposure (AE) data were also prospectively collected. Seventy-nine players participated (203 player-years). Injury was defined as any event that resulted in the athlete being unable to participate in 1 or more practices or games following the event. Multivariable logistic regression was performed to determine the ability of the independent variables to predict the occurrence of on-ice injury. RESULTS: There were 132 injuries (mean, 16.5 per year) in 55 athletes. The overall injury rate was 4.4 injuries per 1000 AEs. Forwards suffered 68% of the injuries. Seventy percent of injuries occurred during games with equal distribution between the 3 periods. The mean number of days lost due to injury was 7.8 +/- 13.8 (range, 1 127 days). The most common mechanism of injury was contact with another player (54%). The odds of injury in a forward was 1.9 times (95% CI, 1.1-3.4) that of a defenseman and 3 times (95% CI, 1.2-7.7) that of a goalie. The odds of injury if the player's body mass index (BMI) was >=25 kg/m(2) was 2.1 times (95% CI, 1.1 3.8) that of a player with a BMI <25 kg/m(2). The odds ratios for bench press, maximum sit-ups, and Olympic cleans were statistically significant but close to 1.0, and therefore the clinical relevance is unknown. CONCLUSION: Forwards have higher odds of injury relative to other player positions. BMI was predictive of on-ice injury. Aerobic fitness and maximum strength outcomes were not strongly predictive of on-ice injury. PMID- 25553213 TI - Protracted recovery from a concussion: a focus on gender and treatment interventions in an adolescent population. AB - BACKGROUND: Several studies have demonstrated that age and sex may influence concussion recovery time frames, with female athletes and adolescents being potentially more susceptible to a protracted recovery course. Currently, limited work has examined the influence sex may have on concussion management strategies and treatment interventions, especially for younger individuals suffering persistent concussion symptoms and cognitive dysfunctions. HYPOTHESIS: Female athletes are prescribed more treatment interventions than male athletes during a protracted recovery from a concussion. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 4. METHODS: Data were retrospectively collected for adolescent athletes presenting to a sports medicine concussion clinic between September 2010 and September 2011. RESULTS: A total of 266 adolescent athletes were evaluated and treated for concussion. Female athletes had a longer recovery course (P = 0.002) and required more treatment interventions (P < 0.001) for their symptoms and dysfunction. Female athletes were more likely to require academic accommodations (P < 0.001), vestibular therapy (P < 0.001), or medication (P < 0.001). CONCLUSION: Medical providers should be aware that during the recovery course, adolescent female athletes may require a management plan that will most likely include additional treatment interventions beyond the standard cognitive and physical rest. CLINICAL RELEVANCE: Treatment interventions are more commonly prescribed for adolescent female athletes than for adolescent male athletes during a protracted recovery from a concussion. This highlights the need for identifying evidence-based clinical management guidelines that focus on sex, especially when dealing with persistent concussion symptoms and cognitive dysfunctions. PMID- 25553214 TI - A Double-Blinded Placebo Randomized Controlled Trial Evaluating Short-term Efficacy of Platelet-Rich Plasma in Reducing Postoperative Pain After Arthroscopic Rotator Cuff Repair: A Pilot Study. AB - BACKGROUND: We aimed to determine whether patients with arthroscopically repaired rotator cuff (RC) tears would have reduced pain and improved function after ultrasound-guided platelet-rich plasma (PRP) injections compared with placebo injection. HYPOTHESIS: PRP compared with placebo (saline) was more effective in reducing pain at the site of an RC injury that has undergone arthroscopic repair. STUDY DESIGN: Randomized controlled trial. LEVEL OF EVIDENCE: Level 2. METHODS: We conducted a 2-centered, blinded, randomized controlled trial comparing the level of pain in patients undergoing arthroscopic repair. Patients were randomized to either PRP or saline (placebo). They received 2 ultrasound-guided injections of the randomized product: 1 intraoperatively and 1 at 4 weeks postoperatively. The primary outcome measure was shoulder pain demonstrated using a visual analog scale (VAS) at 6 weeks postoperatively. Secondary outcomes included the EuroQol-5 Dimensions (EQ-5D); the Western Ontario Rotator Cuff Index (WORC); and the Disabilities of the Arm, Shoulder, and Hand Score (DASH), as well as adverse events and revision surgeries. Patients were assessed clinically preoperatively and at 2, 4, and 6 weeks postsurgery. A prespecified interim analysis was conducted after 50% of patients were recruited and followed. RESULTS: We recruited 25 patients when interim power analysis led to an early trial termination. Follow-up was 96%. The mean difference between groups was not statistically significant (-1.81; 95% CI, -4.3 to 1.2; P = 0.16). The EQ-5D, WORC, and DASH scores also did not show significant differences between groups at week 6 (P = 0.5, 0.99, and 0.9, respectively). There were no revision surgeries, and 4 adverse events (3 PRP, 1 saline). CONCLUSION: There was no statistical difference in outcome measures when augmenting arthroscopically repaired RC tears with PRP. CLINICAL RELEVANCE: Identifying therapies that improve outcomes in patients with RC tears remains a challenge and deserves ongoing investigation. PMID- 25553215 TI - Injury and treatment characteristics of sport-specific injuries sustained in interscholastic athletics: a report from the athletic training practice-based research network. AB - BACKGROUND: The inclusion of clinical practice factors, beyond epidemiologic data, may help guide medical coverage and care decisions. HYPOTHESIS: Trends in injury and treatment characteristics of sport-specific injuries sustained by secondary school athletes will differ based on sport. STUDY DESIGN: Retrospective analysis of electronic patient records. LEVEL OF EVIDENCE: Level 4. METHODS: Participants consisted of 3302 boys and 2293 girls who were diagnosed with a sport-related injury or condition during the study years. Injury (sport, body part, diagnosis via ICD-9 codes) and treatment (type, amount, and duration of care) characteristics were grouped by sport and reported using summary statistics. RESULTS: Most injuries and treatments occurred in football, girls' soccer, basketball, volleyball, and track and field. Sprain or strain of the ankle, knee, and thigh/hip/groin and concussion were the most commonly documented injuries across sports. The injury pattern for boys' wrestling differed from other sports and included sprain or strain of the elbow and neck and general medical skin conditions. The most frequently reported service was athletic training evaluation/reevaluation treatment, followed by hot/cold pack, therapeutic exercise, manual therapy techniques, electrical stimulation, and strapping of lower extremity joints. Most sports required 4 to 5 services per injury. With the exception of boys' soccer and girls' softball, duration of care ranged from 10 to 14 days. Girls' soccer and girls' and boys' track and field reported the longest durations of care. CONCLUSION: Injury and treatment characteristics are generally comparable across sports, suggesting that secondary school athletic trainers may diagnose and treat similar injuries regardless of sport. CLINICAL RELEVANCE: Subtle sport trends, including skin conditions associated with boys' wrestling and longer duration of care for girls' soccer, are important to note when discussing appropriate medical coverage and care. PMID- 25553216 TI - Muscular activation during plyometric exercises in 90 degrees of glenohumeral joint abduction. AB - BACKGROUND: Plyometric exercises are frequently used to increase posterior rotator cuff and periscapular muscle strength and simulate demands and positional stresses in overhead athletes. The purpose of this study was to provide descriptive data on posterior rotator cuff and scapular muscle activation during upper extremity plyometric exercises in 90 degrees of glenohumeral joint abduction. HYPOTHESIS: Levels of muscular activity in the posterior rotator cuff and scapular stabilizers will be high during plyometric shoulder exercises similar to previously reported electromyographic (EMG) levels of shoulder rehabilitation exercises. STUDY DESIGN: Descriptive laboratory study. METHODS: Twenty healthy subjects were tested using surface EMG during the performance of 2 plyometric shoulder exercises: prone external rotation (PERP) and reverse catch external rotation (RCP) using a handheld medicine ball. Electrode application included the upper and lower trapezius (UT and LT, respectively), serratus anterior (SA), infraspinatus (IN), and the middle and posterior deltoid (MD and PD, respectively) muscles. A 10-second interval of repetitive plyometric exercise (PERP) and 3 repetitions of RCP were sampled. Peak and average normalized EMG data were generated. RESULTS: Normalized peak and average IN activity ranged between 73% and 102% and between 28% and 52% during the plyometric exercises, respectively, with peak and average LT activity measured between 79% and 131% and between 31% and 61%. SA activity ranged between 76% and 86% for peak and between 35% and 37% for average activity. Muscular activity levels in the MD and PD ranged between 49% and 72% and between 12% and 33% for peak and average, respectively. CONCLUSION: Moderate to high levels of muscular activity were measured in the rotator cuff and scapular stabilizers during these plyometric exercises with the glenohumeral joint abducted 90 degrees . PMID- 25553217 TI - Life span exercise among elite intercollegiate student athletes. AB - BACKGROUND: Despite prominent public attention, data on life span health and exercise outcomes among elite, competitive athletes are sparse and do not reflect the diversity of modern athletes. HYPOTHESIS: Life span exercise behavior differs between National Collegiate Athletic Association (NCAA) student athletes and a nonathlete control group. Sustained exercise is associated with improved cardiopulmonary health outcomes. STUDY DESIGN: Cross-sectional, descriptive epidemiology study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 496 students and alumni (age range, 17-84 year) at a large, NCAA Division I university, including student athletes and an age- and sex-matched nonathlete control group, completed anonymous, self-report health and exercise questionnaires. Age stratified, cross-sectional analysis evaluated previous week's total exercise volume (ExVol), self-rated exercise importance (ExImp), and compliance with American College of Sports Medicine (ACSM) exercise guidelines for healthy adults. The association of ACSM guideline compliance with lifetime cardiopulmonary health outcomes was also assessed. RESULTS: Current student athletes reported significantly greater ExVol (P < 0.001. Cohen d = 0.99, probability of clinically important difference [pCID] >99.5%), ExImp (P < 0.001, d = 1.96, pCID = 96%), and likelihood of compliance with ACSM guidelines (odds ratio [OR], 95% confidence interval [CI] = 30.6, 11.0-84.6) compared with nonathletes. No significant differences were found between alumni student athletes and nonathletes. Alumni student athletes demonstrated substantially lower ExVol (P < 0.001, d = -0.94, pCID >99.5%) and guideline compliance (OR = 0.09, 95% CI = 0.05-0.19) compared with current student athletes, whereas nonathletes had similar exercise behavior across the life span. Among alumni, ACSM guideline compliance was associated with significant attenuation of cardiopulmonary health concerns (P = 0.02, d = -0.50, pCID = 14%) independent of intercollegiate athletic participation. CONCLUSION: Although current NCAA Division I student athletes demonstrated significant, clinically important differences in exercise behavior compared with nonathletes, no group differences were evident later in life. Irrespective of collegiate athletic status, healthy exercise behavior among alumni was associated with cardiopulmonary health benefits. CLINICAL RELEVANCE: To realize life span health benefits, it is imperative that student athletes maintain consistent patterns of healthy exercise beyond retirement from competitive sports. PMID- 25553218 TI - Shoulder arthroplasty: return to sport. AB - CONTEXT: Increasingly, total shoulder arthroplasty is being performed not only to treat the pain associated with glenohumeral arthritis but also to return patients to the level of activity and function they enjoyed prior to the development of arthritis. While return to sport and activity have been studied in the total knee and total hip replacement literature, it is only relatively recently that the same focus has been placed on total shoulder replacements. EVIDENCE ACQUISITION: PubMed database from the years 2000 to 2014. All studies relevant to shoulder arthroplasty and return to sport were included in the review. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: An increasing number of patients seeking total shoulder arthroplasty are doing so with the expectation of not only decreased symptoms of glenohumeral arthritis but also of return to a high level of activity. The majority of patients are able to return to their prior level of activity within 6 months of surgery. In some series, patients saw an improvement in their ability to perform their chosen activity. CONCLUSION: Patients should be counseled that there is a high probability that they will be able to return to their preoperative activity level after total shoulder arthroplasty and, in some cases, see an improvement in their abilities to participate in sport. STRENGTH-OF-RECOMMENDATION TAXONOMY SORT: C. PMID- 25553220 TI - Clock drawing test in a space-occupying process. PMID- 25553221 TI - Postanoxic vegetative state: avoiding the self-fulfilling prophecy. PMID- 25553222 TI - The neurohospitalist in residency education: the role of supervision. PMID- 25553223 TI - A quality assurance initiative targeting radiation exposure to neuroscience patients in the intensive care unit. AB - BACKGROUND: Patients admitted to an intensive care unit (ICU) with a primary neurologic disorder often receive multiple radiation-based diagnostic studies of the head and neck. Although radiation exposure puts them at risk of intracranial and neck tumors, the amount of radiation received is largely unknown. METHODS: We sought to accurately collect cumulative radiation exposure data from radiation based studies in a retrospective cohort of patients admitted to the neuroscience ICU (NICU) at a single institution. Radiation doses of studies were converted to estimated effective doses in mSv via literature-published formulas. To impact ordering practices, we piloted an educational initiative on patient radiation exposure to a cohort of physicians caring for patients with a diagnosis of acute subarachnoid hemorrhage. Patients were randomized to have radiation exposure data posted at the bedside for physician viewing. RESULTS: We identified 641 patients from July 2010 to March 2011 who had received at least 1 computed tomography based study of the head. Patients received on average 18.4 mSv of radiation from head and neck imaging. Patients with subarachnoid hemorrhage received the highest average levels of radiation exposure (37.1 mSv). Attributable risk of carcinogenesis was estimated to be low. A pilot educational initiative did not reduce the total estimated effective dose per patient. CONCLUSIONS: Accurate reporting of estimated effective doses for NICU patients is feasible and can be provided to ordering physicians to assist with clinical decision making and potentially lower exposure risk. Further strategies are needed to reduce unnecessary radiation exposure at the physician ordering level. PMID- 25553224 TI - The tablet device in hospital neurology and in neurology graduate medical education: a preliminary study. AB - BACKGROUND AND PURPOSE: There is limited literature on tablet devices for neurohospitalists and in neurological graduate medical education. This study evaluated utilization, benefits, and limitations of customized tablets on inpatient neurology practice and resident education. The hypothesis was the perception of the tablet would be positive, given their portability, convenience to accessing point-of-care reference, and accessibility to the electronic medical record. METHODS: Second-generation iPads with neurology-specific applications and literature were provided to our in-hospital general, stroke, and consult neurology teams. After 1 year, residents on these teams were surveyed on demographic data, familiarity, and utilization of the iPad and their perceptions of the device. RESULTS: All 27 residents responded to the survey. Most participants (23 of 27) used a tablet while on inpatient service. Twelve regularly utilized the neurology-specific apps and/or accessed scientific articles. Technologically savvy residents felt significantly more comfortable using tablets and were more quickly acquainted with the features. Thirteen respondents wanted a formal orientation on the advanced features of the tablet independent of their familiarity with the device or level of technological comfort. CONCLUSION: Overall, the perception was that the tablet was beneficial for inpatient clinical care and as an educational reference. Participants became easily familiarized with the device features quickly, regardless of whether they owned one previously or not. Most physicians indicated interest in advanced features of tablets; however, a formal orientation may be beneficial for optimal utilization. A reliable network connection is essential to in-hospital use of tablet devices. Additional research pertaining to patient outcomes, objective educational benefit, and cost-effectiveness is necessary. PMID- 25553225 TI - Cervical angina: an overlooked source of noncardiac chest pain. AB - Cervical angina has been widely reported as a cause of chest pain but remains underrecognized. This series demonstrates the varied clinical presentation of patients with cervical angina, the delay in diagnosis, and the extensive cardiac examinations patients with this condition typically undergo prior to a definitive diagnosis. Recognition of this condition in patients with acute chest pain requires a high index of suspicion and an awareness of the common presenting features and clinical findings of cervical angina. PMID- 25553226 TI - Generalized myoclonus: a rare manifestation of stroke. AB - Movement disorders have been reported as rare complications of stroke. The basal ganglia have been implicated in the pathophysiology of most post-stroke dyskinesias. We outline different types of post-stroke myoclonus and their possible pathophysiology. A middle-aged man developed generalized myoclonus after an ischemic stroke in the superior midbrain and subthalamic nuclei. Spontaneous resolution was seen by 72 hours. A lesion to the subthalamic nuclei disrupted the normal thalamic inhibition, which likely led to the involuntary movements seen in our patient. In this case, myoclonus was generalized, which, to the best of our knowledge, has not been reported in the literature as a direct consequence of focal stroke. PMID- 25553227 TI - Hallucinogens causing seizures? A case report of the synthetic amphetamine 2,5 dimethoxy-4-chloroamphetamine. AB - Although traditional hallucinogenic drugs such as marijuana and lysergic acid diethylamide (LSD) are not typically associated with seizures, newer synthetic hallucinogenic drugs can provoke seizures. Here, we report the unexpected consequences of taking a street-bought hallucinogenic drug thought to be LSD. Our patient presented with hallucinations and agitation progressing to status epilepticus with a urine toxicology screen positive only for cannabinoids and opioids. Using liquid chromatography high-resolution mass spectrometry, an additional drug was found: an amphetamine-derived phenylethylamine called 2,5 dimethoxy-4-chloroamphetamine. We bring this to the attention of the neurologic community as there are a growing number of hallucinogenic street drugs that are negative on standard urine toxicology and cause effects that are unexpected for both the patient and the neurologist, including seizures. PMID- 25553229 TI - Neuro-behcet disease in an african american adolescent. PMID- 25553228 TI - Transitional care strategies from hospital to home: a review for the neurohospitalist. AB - Hospitals are challenged with reevaluating their hospital's transitional care practices, to reduce 30-day readmission rates, prevent adverse events, and ensure a safe transition of patients from hospital to home. Despite the increasing attention to transitional care, there are few published studies that have shown significant reductions in readmission rates, particularly for patients with stroke and other neurologic diagnoses. Successful hospital-initiated transitional care programs include a "bridging" strategy with both predischarge and postdischarge interventions and dedicated transitions provider involved at multiple points in time. Although multicomponent strategies including patient engagement, use of a dedicated transition provider, and facilitation of communication with outpatient providers require time and resources, there is evidence that neurohospitalists can implement a transitional care program with the aim of improving patient safety across the continuum of care. PMID- 25553230 TI - Reversible corona radiata diffusion restriction in hypoglycemic coma. PMID- 25553231 TI - A case of susac syndrome. PMID- 25553232 TI - Clozapine-induced liver injury and pleural effusion. AB - Clozapine, whilst associated commonly with a transient and benign increase in liver enzymes, has also been associated with varying presentations of hepatitis in existing case reports. This report describes what we believe to be the first documented case of acute liver injury and pleural effusion associated with clozapine, resolving after cessation of the agent. The case supports existing literature in advocating a high index of suspicion, particularly in the 4-5 weeks following clozapine initiation, when considering nonspecific clinical symptoms and signs. PMID- 25553233 TI - Thyrotoxicosis followed by hypothyroidism in a patient on lithium. AB - While hypothyroidism is common in lithium-treated patients, thyrotoxicosis is rarely reported. We present a female patient on lithium for maintenance therapy of bipolar affective disorder, who developed thyrotoxicosis for few months which was followed by hypothyroidism which continued. There was no further thyrotoxicosis episode during a five year follow up period. While she was treated for thyroid dysfunction, lithium was continued. There was no clinical impact on the maintenance of the bipolar affective disorder during the follow up period; she was maintained well in the community. PMID- 25553234 TI - Post-vasectomy depression: a case report and literature review. AB - Vasectomy is a commonly performed and relatively safe procedure, with low reported rates of psychological morbidity, though there is some variability across studies. Depression following a vasectomy is relatively infrequent. A married man aged 30 developed a chronic depressive episode, lasting four years and resistant to an adequate trial of fluoxetine, following a vasectomy. His depression was heralded by a post-operative panic attack, and was accompanied by medically unexplained symptoms and the attribution of all his symptoms to the procedure - a belief that was shared by his family. Psychological complications of vasectomy have generally been studied under four heads: sexual dysfunction, effects on marital relationships, chronic post-operative pain, and other complications including anxiety and depression. These complications have generally been reported at higher rates in developing countries, and are linked to poor knowledge about the procedure and inadequate pre-operative counseling. The implications of the existing literature for the patient's current complaints, and the mechanisms and risk factors involved, are discussed in the light of existing research. Suggestions for the prevention and treatment of post-vasectomy depression are also outlined. PMID- 25553235 TI - Mandatory physical exercise for the prevention of mental illness in medical students. AB - Medical students experience higher rates of mental illness than the general population. With competition rising for success in medical school, and residency, increasing incidence of distress are leading this population to experience higher rates of thoughts of dropping out of school, and even suicide. Since many stigmas deter medical students from receiving mental health counseling, such as the perceived inability to handle the stresses of medical school, and the potential lack of competitiveness for residencies if reported, prevention of mental illness may be a better course to take in reducing prevalence in this population. Regular exercise has demonstrated a positive effect on not only promoting physical health, but also mental health. Exercise encourages a healthy mood, positive self esteem, and better cognition, while decreasing the chances of depression, anxiety, and burnout. Implementing exercise time into medical school curriculums, just like the basic sciences, albeit for less time in the day, could provide a feasible way to ensure that all students are taking time to partake in this important activity for their well being. Though medical schools are rigid with attempts to make changes in their curriculum, thirty minutes a day, three to five times a week of exercise of the students' choice not only is more cost effective than counseling, but it also reduces the chances that they will experience burnout, which if left untreated could transcend into a compromised training experience. PMID- 25553236 TI - Lorazepam provocation test in purported schizophrenia with lack of treatment response. AB - Some patients with severe mental disorders are refractory to psychotherapeutic or psychopharmacological interventions. We present a patient who at the age of 19 developed several schizophrenia - suspect symptoms. Soon inexplicable general seizures where observed. He was treated with antipsychotics, but had two bouts of malignant neuroleptic syndrome. Electroconvulsive therapy (ECT) gave some symptom relief and he continued on maintenance ECT for years with weekly intervals. Interruption of this treatment pattern rapidly increased symptom load. After seven years a lorazepam provocation test was performed as he had a new relapse after 3 weeks without ECT. In the ensuing hours his aggressiveness and nonsense speaking rapidly diminished. Kahlbaums observation of seizures as part of a catatonia was not understood in this case. The publication of the new DSM-V diagnosis of catatonia may hopefully reduce the probability of treating a patient for schizophrenia for years without access to a more targeted medication and ECT plan. PMID- 25553237 TI - An examination of autism spectrum traits in adolescents with anorexia nervosa and their parents. AB - BACKGROUND: There may be a link between anorexia nervosa and autism spectrum disorders. The aims of this study were to examine whether adolescents with anorexia nervosa have autism spectrum and/or obsessive-compulsive traits, how many would meet diagnostic criteria for autism spectrum disorder, and whether these traits are shared by parents. METHODS: A total of 150 adolescents receiving outpatient treatment for anorexia nervosa or subthreshold anorexia nervosa and their parents completed the autism spectrum disorder and eating disorder sections of the Development and Well-being Assessment. Patients also completed the Children Yale-Brown Obsessive-Compulsive Scale and other measures of psychiatric morbidity, and parents completed the short Autism Quotient and Obsessive Compulsive Inventory Revised. RESULTS: Adolescents with anorexia nervosa had a below average social aptitude (19% below cut-off) and high levels of peer relationship problems (39% above cut-off) and obsessive-compulsive symptoms (56% above cut-off). Six cases (4%, all females) were assigned a possible (n = 5) or definite (n = 1) diagnosis of autism spectrum disorder. Parental levels of autism spectrum and obsessive-compulsive traits were within the normal range. CONCLUSIONS: This study suggests that adolescents with anorexia nervosa have elevated levels of autism spectrum traits, obsessive-compulsive symptoms, and a small proportion fulfil diagnostic criteria for a probable autism spectrum disorder. These traits did not appear to be familial. This comorbidity has been associated with a poorer prognosis. Therefore, adaptation of treatment for this subgroup may be warranted. TRIAL REGISTRATION: Controlled-trials.com: ISRCTN83003225. Registered on 29 September 2011. PMID- 25553238 TI - Beyond interferon: rationale and prospects for newer treatment paradigms for chronic hepatitis C. AB - Hepatitis C virus (HCV) infection results in a chronic carrier state in 80% of individuals infected with the virus and presently affects over 170 million people worldwide. Approximately 20% of those chronically infected will ultimately progress to develop cirrhosis and death due to end-stage liver disease or hepatocellular carcinoma (HCC). Unlike many other chronic viral infections, effective treatments for HCV are available. Cure from the infection is known as a sustained virologic response (SVR). SVR is associated with reversal of the long term outcomes of chronic liver disease, decrease in incidence of HCC, and decrease HCV attributable mortality. The current FDA approved therapies for hepatitis C virus genotype 1 (GT-1) include pegylated interferon (PEG-IFN) and ribavirin (RBV) in combination with a directly acting antiviral agent (DAA). New therapeutic advances are being made aiming to simplify management, improve the tolerability of treatment, and shorten the duration of therapy. Moreover, treatment regimens that will effectively eradicate hepatitis C without the use of interferon formulations (IFN) are being developed. In this review, we report the transition of HCV therapeutics from an interferon-alpha based combination therapy to an all-oral, directly acting antiviral therapy. PMID- 25553240 TI - Bilateral chylothorax: an unusual complication of cervical rib resection. AB - Bilateral chylothorax is a rare cause of pleural effusions. Here we report an unusual acute presentation of bilateral chylothorax following thoracic outlet surgery. Unique to this case was the disparate characteristics of pleural fluid analyses with an exudate on the left and a transudate on the right. This report describes the recognition and management of bilateral chylothoraces, an uncommon but potentially serious complication of this frequently performed surgical procedure. PMID- 25553239 TI - Treatment of painful diabetic neuropathy. AB - Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the gamma-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include alpha-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists. PMID- 25553241 TI - Effects of Chinese herbal medicine in combination with mitomycin C on gastric cancer cells. AB - Chinese herbal medicine (CHM) is frequently used by cancer patients in Chinese community. It remains largely unknown about the interaction between CHM and chemotherapeutic agents. Herein, we evaluated 3 commonly used CHM formulas for cancer patients: Bu-Zhong-Yi-Qi-Tang (BZYQT), Bao-Yuan-Tang (BYT), and Ju-Yuan Jian (JYJ). We examined the effects of these 3 formulas in human gastric cancer cells MKN-74, in terms of cytotoxicity and apoptosis induction when used alone or in combination with mitomycin C (MMC). Cytotoxicity was determined by tetrazolium dye colorimetric assay. The 10% inhibitory concentration of CHM was used in this study. Cells were first exposed to CHM or phosphate buffered saline (as control) for 48 h. Then MMC at final concentration of 0.25 MUg/ml was added to media for another 24-h. Among these 3 CHM formulas, BZYQT showed the most pronounced effect in augmenting MMC-induced cytotoxicity. The viability of MKN-74 cells was decreased to 43.1% when treated with BZYQT and MMC, compared to 94.9% with MMC alone. We subsequently examined apoptosis induction by quantitative florescent microscopy and single-strand DNA enzyme-linked immunosorbent assay, and found BZYQT did not enhance MMC-induced apoptosis. Our findings indicate BZYQT in combination with MMC induces cell death in gastric cancer cells via non-apoptotic mechanism. Our results provide a rationale for further investigation in the interaction of CHM and anti-cancer treatment. PMID- 25553242 TI - Human papilloma virus vaccination: impact and recommendations across the world. AB - Human papilloma virus (HPV) vaccination has been implemented in several countries for about the past 7 years, mainly in the adolescent female population, with varying coverage results. Although the impact of immunization on cervical and other HPV-related cancers will be evident in the next decades, a marked decrease of prevalent HPV infections, precancerous lesions and genital warts is already dramatic in the vaccinated cohorts, and also in their sexual partners, thus providing clear evidence of the effectiveness of HPV vaccination, including a herd-protection effect. Today, recommendations and implementation of universal HPV vaccination for adolescent girls are a public-health priority in all countries of the world. Countries with limited resources are presently involved in demonstration projects and, in some cases, have launched national programmes with the help of international agencies and alliances. Extension of immunization offer to young women and to adolescent male subjects has become an important additional opportunity for several countries, with a special focus needed on homosexual men with HIV infection who are at particularly increased risk of HPV related diseases. Public-health authorities are confronted with the need to enlarge HPV-vaccination offer to all target groups, especially pre-adolescent girls, so that they can be saved from dreadful cancers by reaching high immunization coverage. PMID- 25553243 TI - Prevention of rare diseases: how revolutionary techniques can help vulnerable individuals-the example of serogroup B meningococcal infection. AB - In countries with established programmes for vaccination of infants, toddlers and adolescents with meningococcal conjugate vaccines, serogroup B invasive meningococcal disease remains the major cause of septicaemia and meningitis in the paediatric and adolescent age groups. Novartis has developed a serogroup B meningococcal vaccine, 4CMenB, to meet this need. We reviewed all 4CMenB studies. The studies found 4CMenB to be highly immunogenic when administered in all schedules, with protective antibody levels (serum bactericidal antibody titres >=4 or >=5 with human complement, hSBA) against serogroup B strains expressing vaccine antigens in >95% of vaccinated cohorts. When antibody levels waned, all tested groups demonstrated booster responses. Although possibly an underestimation, the Meningococcal Antigen Typing System (MATS) technique predicts that global coverage of 4CMenB against all serogroup B strains is in the range 66% (Canada) to 91% (USA). The vaccine was found to be generally well tolerated, although local and systemic reactions, notably fever in infants, typical of many vaccines, were increased following concomitant administration of 4CMenB with routine vaccines. When tested, prophylactic paracetamol significantly decreased the frequency and severity of reactions in infants, with no clinically significant impact on immunogenicity of 4CMenB or concomitant routine vaccines. The vaccine is approved for use in the following age groups in the European Union (2 months+), Canada (2 months through 17 years), Australia (2 months+) and Chile (2 months+), following clinical evaluation in 4843 infants and toddlers, and 1712 adolescents and adults, in schedules including a three-dose (2, 3, 4 or 2, 4, 6 months) and a two-dose (6-11 months) infant series with a booster in the second year of life, a two-dose series in toddlers (12-23 months) and children (2-10 years) given 2 months apart (with a booster at least in the EU), and a two-dose series in adolescents (11-17 years) given 1-6 months apart. 4CMenB presents a solution to the unmet medical need of offering protection against serogroup B invasive meningococcal disease in all age groups above 2 months. PMID- 25553244 TI - Productivity losses in chronic obstructive pulmonary disease: a population-based survey. AB - OBJECTIVES: We aimed to estimate incremental productivity losses (sick leave and disability) of spirometry-defined chronic obstructive pulmonary disease (COPD) in a population-based sample and in hospital-recruited patients with COPD. Furthermore, we examined predictors of productivity losses by multivariate analyses. METHODS: We performed four quarterly telephone interviews of 53 and 107 population-based patients with COPD and controls, as well as 102 hospital recruited patients with COPD below retirement age. Information was gathered regarding annual productivity loss, exacerbations of respiratory symptoms and comorbidities. Incremental productivity losses were estimated by multivariate quantile median regression according to the human capital approach, adjusting for sex, age, smoking habits, education and lung function. Main effect variables were COPD/control status, number of comorbidities and exacerbations of respiratory symptoms. RESULTS: Altogether 55%, 87% and 31% of population-based COPD cases, controls and hospital patients, respectively, had a paid job at baseline. The annual incremental productivity losses were 5.8 (95% CI 1.4 to 10.1) and 330.6 (95% CI 327.8 to 333.3) days, comparing population-recruited and hospital recruited patients with COPD to controls, respectively. There were significantly higher productivity losses associated with female sex and less education. Additional adjustments for comorbidities, exacerbations and FEV1% predicted explained all productivity losses in the population-based sample, as well as nearly 40% of the productivity losses in hospital-recruited patients. CONCLUSIONS: Annual incremental productivity losses were more than 50 times higher in hospital-recruited patients with COPD than that of population-recruited patients with COPD. To ensure a precise estimation of societal burden, studies on patients with COPD should be population-based. PMID- 25553245 TI - Discrimination of sepsis stage metabolic profiles with an LC/MS-MS-based metabolomics approach. AB - BACKGROUND: To identify metabolic biomarkers that can be used to differentiate sepsis from systemic inflammatory response syndrome (SIRS), assess severity and predict outcomes. METHODS: 65 patients were involved in this study, including 35 patients with sepsis, 15 patients with SIRS and 15 normal patients. Small metabolites that were present in patient serum samples were measured by liquid chromatography mass spectrometry techniques and analysed using multivariate statistical methods. RESULTS: The metabolic profiling of normal patients and patients with SIRS or sepsis was markedly different. A significant decrease in the levels of lactitol dehydrate and S-phenyl-d-cysteine and an increase in the levels of S-(3-methylbutanoyl)-dihydrolipoamide-E and N-nonanoyl glycine were observed in patients with sepsis in comparison to patients with SIRS (p<0.05). Patients with severe sepsis and septic shock displayed lower levels of glyceryl phosphoryl-ethanolamine, Ne, Ne dimethyllysine, phenylacetamide and d-cysteine (p<0.05) in their sera. The profiles of patients with sepsis 48 h before death illustrated an obvious state of metabolic disorder, such that S-(3 methylbutanoyl)-dihydrolipoamide-E, phosphatidylglycerol (22:2 (13Z, 16Z)/0:0), glycerophosphocholine and S-succinyl glutathione were significantly decreased (p<0.05). The receiver operating characteristic curve of the differential expression of these metabolites was also performed. CONCLUSIONS: The body produces significant evidence of metabolic disorder during SIRS or sepsis. Seven metabolites may potentially be used to diagnose sepsis. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov identifier NCT01649440. PMID- 25553246 TI - Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations. AB - BACKGROUND: Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes. OBJECTIVE: To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server. METHODS: We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF. RESULTS: We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant. CONCLUSIONS: Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation. PMID- 25553247 TI - An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity. AB - BACKGROUND: Vitamin B12 and folic acid (referred to as vitamin supplementation) improves the toxicity profile of pemetrexed containing regimens. Low baseline vitamin B12 and folate levels are reflected in a raised total homocysteine level (HC). Studies have suggested that pretreatment HC levels predict neutropenia toxicity. We have tested supplementation with vitamin B12 and folate in non pemetrexed platinum-based regimens to decrease treatment-related toxicity and looked for a correlation between toxicity and change in homocysteine levels. PATIENT AND METHOD: Eighty-three patients with advanced lung cancer and malignant mesothelioma were randomly assigned to receive platinum-based chemotherapy with (arm A) or without (arm B) vitamin B12 and folic acid supplementation. The primary end point was grade 3/4 neutropenia and death within 30 days of treatment. Secondary end points included quality of life, overall survival (OS) and the relationship between baseline and post supplementation HC levels and toxicity. RESULTS: In the intention-to-treat population, no significant difference was seen between the two groups with respect to chemotherapy-induced grade 3/4 neutropenia and death within 30 days of chemotherapy (36% vs 37%; p=0.966, emesis (2% vs 6%; p=0.9) or OS (12.3 months vs 7 months; p=0.41). There was no significant difference in survival rates by baseline HC level (p=0.9). Decrease in HC with vitamin supplementation was less frequent than expected. High baseline HC levels decreased with vitamin supplementation in only 9/36 (25%) patients (successful supplementation). Post hoc analysis showed that patients in arm A who were successfully supplemented (9/36=25%) had less neutropenic toxicity (0% vs 69%; p=0.02) compared to unsupplemented patients. CONCLUSIONS: The addition of vitamin B12 and folic acid to platinum-containing regimens did not overall improve the toxicity, quality of life or OS. Rates of grade 3/4 neutropenia at 36/37% was as predicted. Further studies to increase the rate of successful supplementation and to further test the biomarker potential of post supplementation HC levels in predicting chemotherapy-induced neutropenia in platinum-based chemotherapy are warranted. TRIAL REGISTRATION NUMBER: EudracCT 2005-002736-10 ISRCTN8734355. PMID- 25553248 TI - A national survey of the diagnosis and management of suspected ventilator associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) affects up to 20% of patients admitted to intensive care units (ICU). It is associated with increased morbidity, mortality and healthcare costs. Despite published guidelines, variability in diagnosis and management exists, the extent of which remains unclear. We sought to characterise consultant opinions surrounding diagnostic and management practice for VAP in the UK. METHODS: An online survey was sent to all consultant members of the UK Intensive Care Society (n=~1500). Data were collected regarding respondents' individual practice in the investigation and management of suspected VAP including use of diagnostic criteria, microbiological sampling, chest X-ray (CXR), bronchoscopy and antibiotic treatments. RESULTS: 339 (23%) responses were received from a broadly representative spectrum of ICU consultants. All respondents indicated that microbiological confirmation should be sought, the majority (57.8%) stating they would take an endotracheal aspirate prior to starting empirical antibiotics. Microbiology reporting services were described as qualitative only by 29.7%. Only 17% of respondents had access to routine reporting of CXRs by a radiologist. Little consensus exists regarding technique for bronchoalveolar lavage (BAL) with the reported volume of saline used ranging from 5 to 500 mL. 24.5% of consultants felt inadequately trained in bronchoscopy. CONCLUSIONS: There is wide variability in the approach to diagnosis and management of VAP among UK consultants. Such variability challenges the reliability of the diagnosis of VAP and its reported incidence as a performance indicator in healthcare systems. The data presented suggest increased radiological and microbiological support, and standardisation of BAL technique, might improve this situation. PMID- 25553249 TI - Responding to symptoms suggestive of lung cancer: a qualitative interview study. AB - BACKGROUND: Late diagnosis of lung cancer can impact on survival rates. Patients delay seeking help for a number of reasons. This study explored symptom appraisal and help-seeking decisions among patients referred to specialist respiratory services with symptoms suggestive of lung cancer. METHODS: In-depth qualitative interviews with patients as soon as possible after referral, ideally before diagnosis and mainly within 10 weeks, explored factors impacting on their pathways prior to referral. Framework analysis, underpinned by the Model of Pathways to Treatment, was used to explore the data with particular focus on patients' beliefs and experiences, disease factors and healthcare professional influences. RESULTS: 35 patients were interviewed (aged 41-88 years, 15 women, 17 with lung cancer). All described similar presenting symptoms and triggers to seek help. Appraisal of symptoms was influenced by whether they had a lung comorbidity; seriousness of symptoms was interpreted within the context of previous illness experiences. Help-seeking was triggered when: symptoms failed to respond as expected; there was an increased awareness of symptoms of lung cancer; the public nature of a cough meant others were able to endorse help-seeking. Almost half visited the general practitioner (GP) two or more times before referral; during this period they reinterpreted initial symptoms and appraised new symptoms. The meaning given to symptoms changed over time and many became increasingly concerned they may have lung cancer. The GP played a role in ensuring timely further help-seeking but often there was little guidance on how to monitor symptoms or when to reconsult. CONCLUSIONS: Patients diagnosed with and without lung cancer had similar symptom pathways. Findings provide guidance for lung cancer awareness campaigns on the importance of social networks in endorsing patient help-seeking. The importance of appropriate advice, monitoring and safety-netting procedures by GPs for people presenting with symptoms suggestive of lung cancer is also highlighted. PMID- 25553250 TI - Idiopathic pulmonary fibrosis: a paradigm of late-onset, single-gene human disease? PMID- 25553251 TI - Changes in referral, treatment and outcomes in patients with systemic lupus erythematosus in Germany in the 1990s and the 2000s. AB - OBJECTIVE: To evaluate trends in the referral, treatment and outcome of patients with systemic lupus erythematosus (SLE) in Germany over two decades. METHODS: From 1993 to 2012, ~1200 patients with SLE were recorded annually in the national database of the German Collaborative Arthritis Centres. Treatment patterns, healthcare use and outcomes, such as disease activity, function and work participation, were evaluated over time. Furthermore, two distinct cohorts of patients (enrolment 1994-1998, n=467; and 2004-2008, n=376) observed over 5 years were assessed for changes in outcomes. RESULTS: The mean disease duration at the first visit to a rheumatologist decreased from 2.6 (1994) to 1.5 (2012) years. Glucocorticoids (69%), antimalarials (56%), azathioprine (22%), non-steroidal anti-inflammatory drugs (23%) and mycophenolate mofetil (15%) were the most frequently used treatments in 2012. A significant increase was observed in the use of antimalarials and mycophenolate mofetil. The use of glucocorticoids at >7.5 mg/day decreased from 27% (1994) to 10% (2012). The average length of sick leave taken due to SLE declined from 9 weeks (1997) to 6 weeks (2012). When comparing the two longitudinal cohorts, in the cohort from the 2000s, the intraindividual decline of disease activity was significantly stronger (p<0.001), and fewer patients retired early (36% vs 46%). CONCLUSIONS: The disease activity and resource use declined considerably over the observation period, and more patients remained in the labour force. Earlier treatment onset, faster modification of the treatment regimen and more intensive use of anti-inflammatory therapy may account for the improved outcomes in patients with SLE across the years. PMID- 25553252 TI - Increased Th17 cells in flow cytometer-sorted CD45RO-positive memory CD4 T cells from patients with systemic lupus erythematosus. AB - OBJECTIVES: Th17/IL-17 dysregulation is involved in human autoimmunity, and recent evidence suggests the character of long-lived differentiated memory cells in Th17. By directly measuring the peripheral blood mononuclear cells (PBMC), elevated circulating frequencies of Th17 cells have been reported in systemic lupus erythematosus (SLE) with inconsistent results regarding the correlation with disease activities. In this study, the association between circulating Th17 frequencies and disease activities or laboratory parameters was examined in flow cytometer-sorted CD45RO-positive memory CD4 T cells from SLE. METHODS: PBMC samples were obtained from 48 female lupus patients and another 48 age- and sex matched healthy individuals. We examined frequencies of Th17 cells by sorting the purified CD4 T cells bearing the CD45RO marker, followed by intracellular IL-17A staining after in vitro activation. Frequencies of Th1 and TFoxp3 cells were also measured by intracellular IFN-gamma and Foxp3 staining, respectively. The SLE disease activity index (SLEDAI) and other laboratory parameters were further correlated with frequencies of different T cell subsets. RESULTS: In SLE, increased frequencies of Th17 cells were found with a positive correlation in SLEDAI. Higher frequencies of Th17 cells were found in lupus nephritis. There was a positive correlation between frequencies of Th17 cells and daily proteinuria amount. CONCLUSIONS: By examining the sorted CD45RO-positive memory CD4 T cells, we confirm the dysregulation of Th17/IL-17 in SLE, implicating the potential to treat lupus patients with selective IL-17/IL-17R blockades. PMID- 25553253 TI - Dialogue: what can we learn about the relationship between systemic lupus erythematosus and haematological malignancies from linking disease registries? PMID- 25553254 TI - Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant. AB - Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (alpha-GalCer), a synthetic glycolipid agonist of natural killer T (NKT) cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including alpha GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with alpha-GalCer adjuvant. These results support the utility of alpha-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors. PMID- 25553255 TI - Laboratory Validation of Inertial Body Sensors to Detect Cigarette Smoking Arm Movements. AB - Cigarette smoking remains the leading cause of preventable death in the United States. Traditional in-clinic cessation interventions may fail to intervene and interrupt the rapid progression to relapse that typically occurs following a quit attempt. The ability to detect actual smoking behavior in real-time is a measurement challenge for health behavior research and intervention. The successful detection of real-time smoking through mobile health (mHealth) methodology has substantial implications for developing highly efficacious treatment interventions. The current study was aimed at further developing and testing the ability of inertial sensors to detect cigarette smoking arm movements among smokers. The current study involved four smokers who smoked six cigarettes each in a laboratory-based assessment. Participants were outfitted with four inertial body movement sensors on the arms, which were used to detect smoking events at two levels: the puff level and the cigarette level. Two different algorithms (Support Vector Machines (SVM) and Edge-Detection based learning) were trained to detect the features of arm movement sequences transmitted by the sensors that corresponded with each level. The results showed that performance of the SVM algorithm at the cigarette level exceeded detection at the individual puff level, with low rates of false positive puff detection. The current study is the second in a line of programmatic research demonstrating the proof-of-concept for sensor-based tracking of smoking, based on movements of the arm and wrist. This study demonstrates efficacy in a real-world clinical inpatient setting and is the first to provide a detection rate against direct observation, enabling calculation of true and false positive rates. The study results indicate that the approach performs very well with some participants, whereas some challenges remain with participants who generate more frequent non-smoking movements near the face. Future work may allow for tracking smoking in real-world environments, which would facilitate developing more effective, just-in-time smoking cessation interventions. PMID- 25553256 TI - Predictors of anaphylaxis in korean adults. PMID- 25553257 TI - Clinical application of exhaled nitric oxide measurements in a korean population. AB - Nitric oxide (NO) is a biologic mediator of various physiologic functions. Recent evidence suggests the clinical utility of fractional exhaled NO (FeNO) as a biomarker for assessing asthma and other respiratory diseases. FeNO methodologies have been recently standardized by international research groups and subsequently validated in several Korean population studies. Normal ranges for FeNO have been reported for various ethnic groups, and the clinical utility has been widely evaluated in asthma and various respiratory diseases. Based on current evidence including most of Korean population data, this position paper aims to introduce the methodological considerations, and provide the guidance for the proper clinical application of FeNO measurements in Korean populations. PMID- 25553258 TI - Chitotriosidase in the Pathogenesis of Inflammation, Interstitial Lung Diseases and COPD. AB - As a member of 18 glycosyl hydrolase (GH) family, chitotriosidase (Chitinase 1, CHIT1) is a true chitinase mainly expressed in the differentiated and polarized macrophages. CHIT1 is an innate immune mediator that digests the cell walls of chitin-containing eukaryotic pathogens, such as fungi. However, CHIT1 is dysregulated in granulomatous and fibrotic interstitial lung diseases characterized by inflammation and tissue remodeling. These include tuberclosis, sarcoidosis, idiopathic pulmonary fibrosis, scleroderma-associated interstitial lung diseases (SSc-ILD), and chronic obstructive lung diseases (COPD). CHIT1 serum concentration correlates with the progression or the severity of these diseases, suggesting a potential use of CHIT1 as a biomarker or a therapeutic target. Recent studies with genetically modified mice demonstrate that CHIT1 enhances TGF-beta1 receptor expression and signaling, suggesting a role in initiating or amplifying the response to organ injury and repair. This additional CHIT1 activity is independent of its enzymatic activity. These studies suggest that CHIT1 serves a bridging function; it is both an innate immune mediator and a regulator of tissue remodeling. This review will focus on recent data linking CHIT1 to the pathogenesis of inflammation, interstitial lung disease, and COPD. PMID- 25553259 TI - Predictors of the severity and serious outcomes of anaphylaxis in korean adults: a multicenter retrospective case study. AB - PURPOSE: Differences in definitions of the condition, relevant triggers, and the geographical locations of study centers, cause estimates of the prevalence of anaphylaxis to vary. Recent epidemiological data indicate that the incidence of anaphylaxis is rising. METHODS: To investigate the causes and clinical features of anaphylaxis in Korean adults, factors associated with the severity of the condition, and serious outcomes, a retrospective medical record review was performed on adult patients diagnosed with anaphylaxis between 2007 and 2011 in 15 University Hospitals of South Korea. RESULTS: A total of 1,806 cases (52% male, age 16-86 years) were reported. Cutaneous symptoms (84.0%), combined with respiratory (53.9%) and/or cardiovascular (55.4%) symptoms, were the most frequent presentations. Using a recognized grading system, 1,776 cases could be classified as either mild, 340; moderate, 690; or severe, 746. Although eliciting factors varied significantly by age, gender, and regional and seasonal factors, drugs (46.5%; including nonsteroidal anti-inflammatory drugs, antibiotics, and radiocontrast media) were the most common cause of anaphylaxis, followed by foods (24.2%), insect stings (16.4%), exercise (5.9%), and unknown etiology (7.0%). All of age, multi-organ involvement, a history of allergic disease, and drug-induced anaphylaxis, were significant predictors of serious outcomes requiring hospital admission or prolongation of hospital stay. Epinephrine auto-injectors were prescribed for 7.4% of reported cases. CONCLUSIONS: The principal causes of anaphylaxis in Korean adults were drugs, food, and insect stings. Drug-associated anaphylaxis, a history of allergic disease, multi-organ involvement, and older age, were identified as predictors of serious outcomes. PMID- 25553260 TI - Physician-prescribed Asthma Treatment Regimen does not differ Between Smoking and Non-smoking Patients With Asthma in Seoul and Gyunggi province of Korea. AB - PURPOSE: Smoking has detrimental effects on asthma symptom control and response to treatment and is prevalent among asthma patients in South Korea. The aim of this study is to determine the prevalence of smoking among asthma patients in South Korea and to compare the medication regimens of asthma patients who do and do not smoke. METHODS: A cross-sectional survey was conducted from August 2010 to January 2011. Participating physicians (N=25) recorded demographic and clinical data on all asthma patients presenting during the study period (N=2,032), and then recruited a subset of patients (N=500) for the survey such that half were self-reported current smokers. Recruited patients were between the ages of 18 and 60. RESULTS: Among presenting asthma patients, 17.3% were current smokers, 19.2% were former smokers, and 63.5% had never smoked. Within the analyzable study population (N=471), 212 patients reported smoking currently, 79 smoking formerly, and 180 never smoking. Among current and former smokers, 79.7% and 81.0%, respectively, were men, while women represented 80.5% of patients who had never smoked. Agreement was strong between physician-determined smoking status and patient-reported smoking status (kappa=0.82; P<0.001). However, asthma medication regimens examined according to GINA treatment steps did not differ by smoking status. In addition, mean quality of life scores and level of asthma control did not differ by smoking status. CONCLUSIONS: In South Korea, physicians are well aware of the smoking status of their patients. However, smoking status did not affect the prescribed medication regimens of this population of asthma patients. PMID- 25553261 TI - Significance of 40-, 45-, and 48-kDa Proteins in the Moderate-to-Severe Clinical Symptoms of Buckwheat Allergy. AB - PURPOSE: This study was aimed to investigate the relationship between the allergen components and moderate-to-severe allergic reactions in patients with buckwheat allergy. METHODS: Fifteen patients with a history of buckwheat ingestion and a buckwheat specific IgE level>=0.35 kU/L were enrolled. They were divided into 2 groups according to clinical severity scores, with 0-1 being asymptomatic-to-mild and 2-4 being moderate-to-severe symptoms. Immunoblotting was performed to investigate IgE reactivity toward buckwheat allergens and to measure intensity of each component by using a reflective densitometer. RESULTS: The proportions of positive band to the 16 kDa (62.5% vs 0%, P=0.026) and 40-50 kDa (87.5% vs 28.6%, P=0.041) buckwheat allergens in the grade 2-4 group were higher than those in grade 0-1 group. The level of buckwheat specific IgE of grade 2-4 group was higher than that of grade 0-1 group (41.3 kU/L vs 5.5 kU/L, P=0.037). The median optical densities (ODs) of IgE antibody binding to 40-50 kDa protein were higher in the grade 2-4 group, compared with those in the grade 0-1 group (130% OD vs 60.8% OD, P=0.037). CONCLUSIONS: The 40-50 kDa protein is implicated as an important allergen to predict moderate-to-severe clinical symptoms in Korean children with buckwheat allergy. PMID- 25553262 TI - The burden of rhinitis and rhinoconjunctivitis in adolescents. AB - PURPOSE: Rhinitis and conjunctivitis are common diseases worldwide that are frequently associated. Nevertheless, the risk factors for rhinoconjunctivitis are not well-described and the impact of conjunctivitis on rhinitis and asthma in children remains unknown. This study explored the different risk factors and evaluated the burden of rhinoconjunctivitis among adolescents. METHODS: This was a cross-sectional study conducted on a random sample of schoolchildren, aged 10 17 years, using skin prick tests and a self-administered questionnaire on respiratory health investigating the impact of rhinitis and rhinoconjunctivitis on daily activities. RESULTS: A complete evaluation was obtained for 2,150 children. The prevalence of rhinitis alone was 18.2% and rhinitis associated with conjunctivitis was 20.5%. Rhinoconjunctivitis was more frequently associated with females, a parental history of atopy, domestic exposure to mold/dampness, passive smoke exposure, and reported truck traffic in residential streets. Moreover, rhinoconjunctivitis was associated with a higher level of allergic sensitization. The prevalence of current asthma was 1.7% in subjects without rhinitis or rhinoconjunctivitis, 5.1% in rhinitis and 10.7% in rhinoconjunctivitis. In a logistic model, rhinoconjunctivitis yielded a 2-fold risk for current asthma with respect to rhinitis. Subjects with rhinoconjunctivitis had poorer quality of life (QoL); there was an impact on daily activities in 4.6% of rhinitis and 10.7% of rhinoconjunctivitis. CONCLUSIONS: Ocular symptoms increase the role of rhinitis as a risk factor for asthma and its impact on daily activities in children. PMID- 25553263 TI - Work-Related Asthma in Korea - Findings from the Korea Work-Related Asthma Surveillance (KOWAS) program, 2004-2009. AB - PURPOSE: To determine the incidence and epidemiological characteristics of work related asthma in Korea. METHODS: During 2004-2009, the Korea Work-Related Asthma Surveillance (KOWAS) program collected data on new cases of work-related asthma from occupational physicians, allergy and chest physicians, regional surveillance systems, and workers' compensation schemes. The incidence was calculated on the basis of industry, occupation, sex, age, and region. In addition, the distribution of causal agents was determined. RESULTS: During the study period, 236 cases of work-related asthma were reported, with 77 cases from more than 1 source. A total of 22.0% (n=52) were reported by occupational physicians, 52.5% (n=124) by allergy and chest physicians, 24.2% (n=57) by regional surveillance systems, and 43.2% (n=102) by workers' compensation schemes. The overall average annual incidence was 3.31 cases/million workers, with a rate of 3.78/million among men and 2.58/million among women. The highest incidence was observed in the 50-59-year age group (7.74/million), in the Gyeonggi/Incheon suburb of Seoul (8.50/million), in the furniture and other instrument manufacturing industries (67.62/million), and among craft and related trades workers (17.75/million). The most common causal agents were isocyanates (46.6%), flour/grain (8.5%), metal (5.9%), reactive dyes (5.1%), and solvents (4.2%). CONCLUSIONS: The incidence of work-related asthma in Korea was relatively low, and varied according to industry, occupation, gender, age, and region. Data provided by workers' compensation schemes and physician reports have been useful for determining the incidence and causes of work-related asthma. PMID- 25553264 TI - Cross-reactivity between the soybean protein p34 and bovine caseins. AB - PURPOSE: Soy-based formulas are widely used as dairy substitutes to treat milk allergy patients. However, reactions to soy have been reported in a small proportion of patients with IgE-mediated milk allergies. The aim of this work was to explore whether P34, a mayor soybean allergen, is involved in this cross reactivity. METHODS: In vitro recognition of P34 was evaluated by immunoblotting, competitive ELISA and basophil activation tests (BAT) using sera from allergic patients. In vivo cross-reactivity was examined using an IgE-mediated milk allergy mouse model. RESULTS: P34 was recognized by IgE antibodies from the sera of milk allergic patients, casein-specific monoclonal antibodies, and sera from milk-allergic mice. Spleen cells from sensitized mice incubated with milk, soy or P34 secreted IL-5 and IL-13, while IFN-gamma remained unchanged. In addition, the cutaneous test was positive with cow's milk proteins (CMP) and P34 in the milk allergy mouse model. Moreover, milk-sensitized mice developed immediate symptoms following sublingual exposure to P34. CONCLUSIONS: Our results demonstrate that P34 shares epitopes with bovine casein, which is responsible for inducing hypersensitivity symptoms in milk allergic mice. This is the first report of the in vivo cross-allergenicity of P34. PMID- 25553265 TI - Juvenile obesity aggravates disease severity in a rat model of atopic dermatitis. AB - PURPOSE: There is increasing epidemiological evidence of an association between childhood obesity and atopic dermatitis, but little is known about the underlying mechanism(s). In the present study, we used a rat model of atopic dermatitis to assess whether juvenile obesity, induced by reduction of litter size, aggravated the signs of atopic dermatitis and, if so, whether this aggravation was associated with changes in plasma concentration of adipokines, such as leptin and adiponectin. METHODS: Dermatitis was induced by neonatal capsaicin treatment. Body weight, dermatitis score, serum IgE, skin nerve growth factor (NGF), serum leptin and adiponectin, and cytokine mRNA expression in the skin lesion were compared between small (SL, 5 pups) and large litters (LL, 15 pups). RESULTS: The body weight of juvenile rats up to 6 weeks of age was significantly heavier in the SL group, compared with those in the LL group. The SL group showed more robust development of dermatitis, and higher levels of serum IgE and skin NGF than the LL group. Additionally, the SL group demonstrated higher levels of leptin and pro-inflammatory cytokine mRNA but lower levels of adiponectin than the LL group. CONCLUSIONS: These results suggest a causal link between a decrease in immunological tolerance, induced by juvenile obesity, and aggravation of atopic dermatitis. PMID- 25553266 TI - An intratracheal challenge murine model of asthma: can bronchial inflammation affect the nose? AB - PURPOSE: Extensive data support the influence of the upper airway on lower airway inflammation and pathophysiology in allergic disease. However, few studies have focused on allergic inflammation in the nose after an isolated lower airway allergen challenge, a situation that can exist clinically when human subjects breathe primarily through the mouth, as occurs when nasally congested. This study used a mouse model to investigate whether upper airway inflammation and hyperresponsiveness were induced by an isolated lower airway allergen challenge. METHODS: BALB/c mice were sensitized by systemic intraperitoneal injection of ovalbumin/saline and challenged with intratracheal ovalbumin/saline. Inflammation in the nose and lungs was assessed by cytology and histology of nasal tissues and bronchoalveolar lavage fluid (BALF), while nasal airway resistance and response were measured over 3 days post-challenge. RESULTS: Intratracheal application of an allergen in anaesthetized mice resulted in exclusive deposition in the lower airway. Compared to control animals, ovalbumin-sensitized mice after challenge showed bronchial hyperreactivity and increased IL-5 in the serum BALF, as well as eosinophil infiltration in the lungs. However, nasal histology of the ovalbumin sensitized mice showed no increase in eosinophil infiltration. The nasal lavage fluid revealed no increase in eosinophils or IL-5, and the nasal airway resistance did not increase after challenge either. CONCLUSIONS: In a mouse allergy model, exclusive allergen challenge of the lower airway can elicit a pulmonary and systemic allergic response, but does not induce upper airway inflammatory or physiological responses. PMID- 25553267 TI - Clinical factors affecting discrepant correlation between asthma control test score and pulmonary function. AB - The Asthma Control Test (ACT) score is widely used in asthma clinics, particularly with the recent emphasis on achievement and maintenance of optimal asthma control. However, this self-assessment score does not always correspond with lung function parameters, leading to uncertainty about each patient's control status; therefore, we investigated the clinical characteristics that are associated with discrepant correlation between the ACT score and pulmonary function. The 252 adult asthmatic subjects were divided into 5 groups according to their changes in FEV1% predicted values and ACT scores between 2 consecutive visits three months apart. The data were retrospectively reviewed and several clinical variables were compared. Elderly, non-eosinophilic, non-atopic asthma patients were more likely to show paradoxical changes of pulmonary function and ACT score. Female patients were prone to report exaggerated changes of ACT score compared with baseline lung function and changes in FEV1 levels. This group was using more medications for rhinosinusitis. Male patients seemed less sensitive to changes in lung function. From these findings, we conclude that when assessing asthma control status, physicians should carefully consider patient age, gender, atopy status, blood eosinophil levels, and comorbidities along with their ACT scores and pulmonary function test results. PMID- 25553268 TI - Superoxide Dismutase Gene (SOD1, SOD2, and SOD3) Polymorphisms and Antituberculosis Drug-induced Hepatitis. AB - PURPOSE: Drug-induced liver injury (DILI) is a serious issue often leading to discontinuation of the proper regimen of antituberculosis drugs (ATD). Previous studies have suggested that antioxidant enzymes play an important role in DILI. METHODS: We explored whether polymorphisms in superoxide dismutase genes, including Cu/Zn superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2) and extracellular superoxide dismutase (SOD3) are associated with ATD induced hepatitis. Genotype distributions of four single nucleotide polymorphisms (SNPs) in three genes (rs2070424, SOD1; rs4880, SOD2; rs2536512, and rs1799895, SOD3) were compared between 84 patients with ATD-induced hepatitis and 237 patients tolerant to ATD. RESULTS: Intron SNP rs2070424 of SOD1 showed a significant association with ATD-induced hepatitis. The frequency of genotypes carrying minor alleles (GA or GG) was significantly higher in the case group than that of controls (P=0.019, OR=2.26, 95% CI 1.14-4.49). For the other SNPs of SOD2 and SOD3, there were no differences in genotype frequencies between ATD-induced hepatitis and ATD-tolerant controls. CONCLUSIONS: These findings suggest that rs2070424 of SOD1 is significantly associated with ATD-induced hepatitis. This genetic variant may be a risk factor for ATD-induced hepatitis in individuals from Korea. PMID- 25553269 TI - Delayed Anaphylaxis to Red Meat Associated With Specific IgE Antibodies to Galactose. AB - A novel delayed anaphylactic reaction to red meat, associated with tick bites and IgE antibodies against galactose-alpha-1, 3-galactose (alpha-gal), was reported in 2009 in the US, Australia and Europe. In this case, serum specific IgE to galactose-alpha-1, 3-galactose (>100 kU/L) and IgE to multiple non-primate mammalian proteins were positive. However, the pathogenesis of this disease remains unclear. We report the first case in Asia of delayed anaphylactic reaction to red meat, which was induced by bites from the hard tick, Hematophagous ixodidae. We confirmed the increased concentration of IgE reactive epitopes in non-primate mammalian organs, which may be rich in alpha-gal proteins in lymphatic and endothelial tissues. All confirmed ticks associated with this disorder in the literature and in our case belonged to the hard tick family. We hypothesize that hard tick saliva is enriched with blood-type substances, such as oligosaccharides, from the non-primate mammal victim's blood after days to weeks of blood sucking, which sensitizes humans through the injection route while blood sucking. PMID- 25553270 TI - A Case of Anaphylaxis Induced by Contact with Young Radish (Raphanus sativus L). AB - Young radish (Raphanus sativus L), a member of the mustard family (Cruciferae), is a common ingredient of Kimchi. Although few reports have described anaphylaxis to cruciferous vegetables, we report the case of anaphylaxis induced by contact with young radish. A 46-year-old female with a history of contact allergy to metal presented to our emergency room (ER) with dizziness, generalized eruption and gastrointestinal upset. Her symptoms developed after re-exposure to young radish while chopping it. Hypotensive blood pressures were noted. Three days prior, the patient had experienced generalized urticaria with pruritus immediately after chopping the fresh young radish, which resolved spontaneously. In the ER, her symptoms improved by the administration of epinephrine (0.3 mL), antihistamine (chlorpheniramine) and isotonic saline hydration. A skin prick test with young radish extract showed positive reactivity. The same skin test was negative in five adult controls. IgE-mediated hypersensitivity could be an important immunologic mechanism in the development of young radish-induced anaphylaxis. PMID- 25553271 TI - Forecasting Significant Societal Events Using The Embers Streaming Predictive Analytics System. AB - Developed under the Intelligence Advanced Research Project Activity Open Source Indicators program, Early Model Based Event Recognition using Surrogates (EMBERS) is a large-scale big data analytics system for forecasting significant societal events, such as civil unrest events on the basis of continuous, automated analysis of large volumes of publicly available data. It has been operational since November 2012 and delivers approximately 50 predictions each day for countries of Latin America. EMBERS is built on a streaming, scalable, loosely coupled, shared-nothing architecture using ZeroMQ as its messaging backbone and JSON as its wire data format. It is deployed on Amazon Web Services using an entirely automated deployment process. We describe the architecture of the system, some of the design tradeoffs encountered during development, and specifics of the machine learning models underlying EMBERS. We also present a detailed prospective evaluation of EMBERS in forecasting significant societal events in the past 2 years. PMID- 25553272 TI - Data Integration for Heterogenous Datasets. AB - More and more, the needs of data analysts are requiring the use of data outside the control of their own organizations. The increasing amount of data available on the Web, the new technologies for linking data across datasets, and the increasing need to integrate structured and unstructured data are all driving this trend. In this article, we provide a technical overview of the emerging "broad data" area, in which the variety of heterogeneous data being used, rather than the scale of the data being analyzed, is the limiting factor in data analysis efforts. The article explores some of the emerging themes in data discovery, data integration, linked data, and the combination of structured and unstructured data. PMID- 25553273 TI - Patient, Physician and Contextual Factors Are Influential in the Treatment Decision Making of Older Adults Newly Diagnosed with Symptomatic Myeloma. AB - AIMS: To examine patient perspectives on their personal and contextual factors relevant to TDM. The second aim was to describe physician perspectives on the TDM in older adults (>=60 y.o.) diagnosed with symptomatic MM. STUDY DESIGN: Descriptive, cross-sectional. METHODOLOGY: A semi-structured interview schedule was administered. Directed content analysis procedures were used to develop major themes from the patient and physician participant interviews. RESULTS: Themes related to treatment decision making among patient participants include various decisional role preferences; several sources of information related to myeloma; contextual and patient-specific factors influence treatment decisions; negative perceptions related to the treatment decision-making process exist; strong desire to be in remission and to live a longer life; For physician participants, top themes related to decision making were: QOL or survival considerations or simultaneously considerations of treatment effectiveness, QOL and survival; screening patients for eligibility for autologous HSCT; time is a barrier to effective TDM; Various methods were used to assess patient decisional role preferences. CONCLUSIONS: Treatment decision making in older adults newly diagnosed with symptomatic myeloma is influenced by personal, social and contextual factors. Patients must be given the opportunity to choose the best possible treatment within the limits of the patient's personal, social and medical contexts. PMID- 25553274 TI - Mitochondrial DNA aberrations and pathophysiological implications in hematopoietic diseases, chronic inflammatory diseases, and cancers. AB - Mitochondria are important intracellular organelles that produce energy for cellular development, differentiation, and growth. Mitochondrial DNA (mtDNA) presents a 10- to 20-fold higher susceptibility to genetic mutations owing to the lack of introns and histone proteins. The mtDNA repair system is relatively inefficient, rendering it vulnerable to reactive oxygen species (ROS) produced during ATP synthesis within the mitochondria, which can then target the mtDNA. Under conditions of chronic inflammation and excess stress, increased ROS production can overwhelm the antioxidant system, resulting in mtDNA damage. This paper reviews recent literature describing the pathophysiological implications of oxidative stress, mitochondrial dysfunction, and mitochondrial genome aberrations in aging hematopoietic stem cells, bone marrow failure syndromes, hematological malignancies, solid organ cancers, chronic inflammatory diseases, and other diseases caused by exposure to environmental hazards. PMID- 25553275 TI - Influence of blood lipids on global coagulation test results. AB - BACKGROUND: High levels of blood lipids have been associated with high levels of coagulation factors. We investigated whether blood lipids influence the results of global coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA). METHODS: PT, aPTT, and TGA, along with procoagulant and anticoagulant factors, were measured in 488 normal individuals. Vitamin K status was assessed with prothrombin-induced by vitamin K absence-II (PIVKA-II). RESULTS: The procoagulant factors II, VII, IX, X, and XI and anticoagulant factors protein C and protein S showed significant correlations with triglyceride, and the procoagulant factors II, V, VII, IX, X, XI, and XII and anticoagulant factors antithrombin and protein C correlated with total cholesterol. There were no correlations of blood lipid levels with PIVKA-II levels. Subjects with high triglyceride levels (>=200 mg/dL) showed shorter PT values than those with lower triglyceride levels. However, aPTT value was not changed in terms of blood lipid levels. In both 1 and 5 pM tissue factor-induced TGAs, subjects in the high-triglyceride or high-cholesterol groups (>=240 mg/dL) had high levels of lag time, time-to-peak, and endogenous thrombin potential. Total cholesterol was a significant determinant of PT and TGA values. CONCLUSION: High blood lipids were related with increased coagulation activity in a normal population. Our findings are expected to help interpret the global coagulation test results in individuals with high lipid levels. PMID- 25553276 TI - Calreticulin exon 9 mutations in myeloproliferative neoplasms. AB - BACKGROUND: Calreticulin (CALR) mutations were recently discovered in patients with myeloproliferative neoplasms (MPNs). We studied the frequency and type of CALR mutations and their hematological characteristics. METHODS: A total of 168 MPN patients (36 polycythemia vera [PV], 114 essential thrombocythemia [ET], and 18 primary myelofibrosis [PMF] cases) were included in the study. CALR mutation was analyzed by the direct sequencing method. RESULTS: CALR mutations were detected in 21.9% of ET and 16.7% of PMF patients, which accounted for 58.5% and 33.3% of ET and PMF patients without Janus kinase 2 (JAK2) or myeloproliferative leukemia virus oncogenes (MPL) mutations, respectively. A total of five types of mutation were detected, among which, L367fs(*)46 (53.6%) and K385fs(*)47 (35.7%) were found to be the most common. ET patients with CALR mutation had lower leukocyte counts and ages compared with JAK2-mutated ET patients. CONCLUSION: Genotyping for CALR could be a useful diagnostic tool for JAK2-or MPL-negative ET or PMF patients. CALR mutation may be a distinct disease group, with different hematological characteristics than that of JAK2-positive patients. PMID- 25553277 TI - Flow cytometric white blood cell differential using CytoDiff is excellent for counting blasts. AB - BACKGROUND: The usefulness of the CytoDiff flow cytometric system (Beckman Coulter, USA) has been studied in various conditions, but its performance including rapidity in detecting and counting blasts, the most significant abnormal cells in the peripheral blood, has not been well evaluated. The objective of this study was to evaluate the performance of the CytoDiff differential counting method in challenging samples with blasts. METHODS: In total, 815 blood samples were analyzed. Samples flagged as "blasts" or "variant lymphocytes" and showing <10% blasts by manual counts were included. In total, 322 samples showed blasts on manual counts, ranging from 0.5% to 99%. The CytoDiff method was performed by flow cytometry (FC500; Beckman Coulter, USA) with a pre-mixed CytoDiff reagent and analyzing software (CytoDiff CXP 2.0; Beckman Coulter). RESULTS: The average time required to analyze 20 samples was approximately 60 min for manual counts, and the hands-on time for the CytoDiff method was 15 min. The correlation between the CytoDiff and manual counts was good (r>0.8) for neutrophils and lymphocytes but poor (r<0.8) for other cells. When the cutoff value of the CytoDiff blast count was set at 1%, the sensitivity was 94.4% (95% CI; 91.2-96.6) and specificity was 91.9% (95% CI; 89.0-94.1). The positive predictive value was 88.4% (95% CI; 84.4-91.5) (304/344 cases) and negative predictive value was 96.2% (95% CI; 93.9-97.7) (453/471 cases). The CytoDiff blast counts correlated well to the manual counts (r=0.9223). CONCLUSIONS: The CytoDiff method is a specific, sensitive, and rapid method for counting blasts. A cutoff value of 1% of at least 1 type of blast is recommended for positive CytoDiff blast counts. PMID- 25553278 TI - A novel marker for screening paroxysmal nocturnal hemoglobinuria using routine complete blood count and cell population data. AB - BACKGROUND: Final diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) may take years demanding a quick diagnosis measure. We used the facts that PNH cells are damaged in acid, and reagents for measuring reticulocytes in Coulter DxH800 (Beckman Coulter, USA) are weakly acidic and hypotonic, to create a new PNH screening marker. METHODS: We analyzed 979 complete blood counts (CBC) data from 963 patients including 57 data from 44 PNH patients. Standard criteria for PNH assay for population selection were followed: flow cytometry for CD55 and CD59 on red blood cells (RBCs) to a detection level of 1%; and fluorescent aerolysin, CD24 and CD15 in granulocytes to 0.1%. Twenty-four PNH minor clone-positive samples (minor-PNH+) were taken, in which the clone population was <5% of RBCs and/or granulocytes. Excluding PNH and minor-PNH+ patients, the population was divided into anemia, malignancy, infection, and normal groups. Parameters exhibiting a distinct demarcation between PNH and non-PNH groups were identified, and each parameter cutoff value was sought that includes the maximum [minimum] number of PNH [non-PNH] patients. RESULTS: Cutoff values for 5 selected CBC parameters (MRV, RDWR, MSCV, MN-AL2-NRET, and IRF) were determined. Positive rates were: PNH (86.0%), minor-PNH+ (33.3%), others (5.0%), anemia (13.4%), malignancy (5.3%), infection (3.7%), normal (0.0%); within anemia group, aplastic anemia (40.0%), immune hemolytic anemia (11.1%), iron deficiency anemia (1.6%). Sensitivity (86.0%), specificity (95.0%), PPV (52.1%), and NPV (99.1%) were achieved in PNH screening. CONCLUSION: A new PNH screening marker is proposed with 95% specificity and 86% sensitivity. The flag identifies PNH patients, reducing time to final diagnosis by flow cytometry. PMID- 25553279 TI - A simple and rapid method based on liquid chromatography-tandem mass spectrometry for the measurement of alpha-L-iduronidase activity in dried blood spots: an application to mucopolysaccharidosis I (Hurler) screening. AB - BACKGROUND: We developed an analytical method to measure alpha-L-iduronidase (IDUA) activity in dried blood spots. This was achieved by using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with electrospray ionization in the positive ion mode. METHODS: Chromatographic separation was completed using mobile phase involving water-formic acid and acetonitrile-formic acid over 2.8 min of run time on a column with a Kinetex XB-C18 (Phenomenex, USA). The detection of column effluent was performed using a Xevo TQ-S triple quadrupole mass spectrometer (Waters, USA) in the multiple-reaction monitoring mode. This method was verified with blank and control samples at four activity levels: base, low, medium, and high. Control materials were provided from Centers for Disease Control and Prevention (CDC). RESULTS: Intra- and inter-day precisions were between 2.6% and 16.5% and between 7.9% and 17.0%, respectively. A correlative regression study on the IDUA activity in CDC-control samples performed to assess the validity of the developed method showed a highly significant linear association (r(2)=0.9976) between the calculated and CDC reported values and an obvious difference in activity among the four levels. This reliable analytical method was applied to mucopolysaccharidosis I (Hurler) screening of patients under treatment (n=4) and in normal controls (n=129). IDUA activity ranged from 8.98 to 77.12 umol/hr/L) in normal controls, and patients undergoing medical treatment showed low IDUA activity. CONCLUSIONS: This method had advantages of simplicity, rapid sample preparation, and liquid chromatographic separation, which efficiently inhibited ionization suppression induced by matrix effects in mass spectrometric detection. PMID- 25553280 TI - Highly sensitive and novel point-of-care system, aQcare Chlamydia TRF kit for detecting Chlamydia trachomatis by using europium (Eu) (III) chelated nanoparticles. AB - BACKGROUND: The bacterium Chlamydia trachomatis is one of the leading causes of sexually transmitted diseases worldwide. Since no simple and effective tool exists to diagnose C. trachomatis infections, we evaluated a novel point-of-care (POC) test, aQcare Chlamydia TRF kit, which uses europium-chelated nanoparticles and a time-resolved fluorescence reader. METHODS: The test performance was evaluated by comparing the results obtained using the novel POC testing kit with those obtained using a nucleic acid amplification test (NAAT), using 114 NAAT positive and 327 NAAT-negative samples. RESULTS: The cut-off value of the novel test was 20.8 with a detection limit of 0.27 ng/mL. No interference or cross reactivity was observed. Diagnostic accuracy showed an overall sensitivity of 93.0% (106/114), specificity of 96.3% (315/327), positive predictive value (PPV) of 89.8% (106/118), and negative predictive value (NPV) of 97.5% (315/323). The sensitivity of the novel test was much higher than that of currently available POC tests. Furthermore, the relative ease and short turnaround time (30 min) of this assay enables C. trachomatis-infected individuals to be treated without a diagnostic delay. CONCLUSIONS: This simple and novel test is a potential tool to screen a larger population, especially those in areas with limited resources. PMID- 25553281 TI - Detection of the efflux-mediated erythromycin resistance transposon in Streptococcus pneumoniae. AB - BACKGROUND: The present analysis focuses on phenotypic and genotypic characterizations of efflux-mediated erythromycin resistance in Streptococcus pneumoniae due to an increase in macrolide resistance in S. pneumoniae worldwide. METHODS: We investigated the prevalence of efflux-mediated erythromycin resistance and its relevant genetic elements from 186 specimens of S. pneumonia isolated from clinical and normal flora from Tehran, Iran. The presence of erythromycin resistance genes was tested by PCR with two sets of primers, specific for erm(B) and mef(A/E), and their genetic elements with tetM, xis, and int genes. Isolates were typed with the BOX PCR method and tested for resistance to six antibiotics. RESULTS: Antibiotic susceptibility tests revealed that 100% and 47% isolates were resistant to tetracycline and erythromycin, respectively. The erythromycin and clindamycin double-disc diffusion test for macrolide lincosamide-streptograminB (MLSB) resistance phenotype showed 74 (84%) isolates with the constitutive MLSB phenotype and the remaining with the M phenotype. BOX PCR demonstrated the presence of 7 types in pneumococci with the M phenotype. Fourteen (16%) isolates with the M phenotype harbored mef(A/E), tetM, xis, and int genes. CONCLUSIONS: The present results suggest dissemination of polyclonal groups of S. pneumoniae with the M phenotype carrying resistance genes attributed to transposon 2009. PMID- 25553282 TI - Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry-based VITEK MS system for the identification of Acinetobacter species from blood cultures: comparison with VITEK 2 and MicroScan systems. AB - BACKGROUND: Acinetobacter species are the leading cause of bloodstream infection (BSI), but their correct identification is challenging. We evaluated the matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based VITEK MS (bioMerieux, France), and two automated systems, VITEK 2 (bioMerieux) and MicroScan (Siemens, USA) for identification of Acinetobacter BSI isolates. METHODS: A total of 187 BSI isolates recovered at a university hospital in Korea between 2010 and 2012 were analyzed. The identification results obtained using VITEK MS and two automated systems were compared with those of rpoB sequencing. RESULTS: Of 187 isolates analyzed, 176 were identified to the species level by rpoB sequencing: the Acinetobacter baumannii group (ABG; 101 A. baumannii, 43 A. nosocomialis, 10 A. pittii isolates) was most commonly identified (82.4%), followed by Acinetobacter genomic species 13BJ/14TU (5.3%), A. ursingii (2.1%), A. soli (2.1%), A. bereziniae (1.1%), and A. junii (1.1%). Correct identification rates to the species group (ABG) level or the species level was comparable among the three systems (VITEK MS, 90.3%; VITEK 2, 89.2%; MicroScan, 86.9%). However, VITEK MS generated fewer misidentifications (0.6%) than VITEK 2 (10.8%) and MicroScan (13.1%) (P<0.001). In addition, VITEK MS demonstrated higher specificity (100%) for discrimination between ABG and non-ABG isolates than the other systems (both, 31.8%) (P<0.001). CONCLUSIONS: The VITEK MS system is superior to the VITEK 2 and MicroScan systems for identification of Acinetobacter BSI isolates, with fewer misidentifications and better discrimination between the ABG and non-ABG isolates. PMID- 25553283 TI - Evaluation of VITEK mass spectrometry (MS), a matrix-assisted laser desorption ionization time-of-flight MS system for identification of anaerobic bacteria. AB - BACKGROUND: By conventional methods, the identification of anaerobic bacteria is more time consuming and requires more expertise than the identification of aerobic bacteria. Although the matrix-assisted laser desorption ionization time of-flight mass spectrometry (MALDI-TOF MS) systems are relatively less studied, they have been reported to be a promising method for the identification of anaerobes. We evaluated the performance of the VITEK MS in vitro diagnostic (IVD; 1.1 database; bioMerieux, France) in the identification of anaerobes. METHODS: We used 274 anaerobic bacteria isolated from various clinical specimens. The results for the identification of the bacteria by VITEK MS were compared to those obtained by phenotypic methods and 16S rRNA gene sequencing. RESULTS: Among the 249 isolates included in the IVD database, the VITEK MS correctly identified 209 (83.9%) isolates to the species level and an additional 18 (7.2%) at the genus level. In particular, the VITEK MS correctly identified clinically relevant and frequently isolated anaerobic bacteria to the species level. The remaining 22 isolates (8.8%) were either not identified or misidentified. The VITEK MS could not identify the 25 isolates absent from the IVD database to the species level. CONCLUSIONS: The VITEK MS showed reliable identifications for clinically relevant anaerobic bacteria. PMID- 25553284 TI - Evaluation of the iNtRON VRE vanA/vanB real-time PCR assay for detection of vancomycin-resistant enterococci. AB - BACKGROUND: Recently, the iNtRON VRE vanA/vanB real-time PCR (iNtRON; iNtRON Biotechnology, Korea) assay, a multiplex real-time PCR method, was introduced. In this prospective study, we compared the iNtRON assay with the Seeplex VRE ACE detection kit (Seeplex; Seegene, Korea), a conventional multiplex PCR assay. METHODS: A chromogenic agar-based culture, in which pre-selected vancomycin resistant enterococci (VRE) was grown and subsequently plated on blood agar with vancomycin disks, was regarded as the reference method. A total of 304 consecutive rectal swab specimens were tested for VRE by culture and by iNtRON and Seeplex PCR assays. For the PCR assays, specimens were enriched for 16-24 hr before PCR. RESULTS: VRE were isolated from 44 (14.5%) specimens by chromogenic agar-based culture. The clinical sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the iNtRON assay were 100% (95% confidence interval: 89.8%-100%), 99.2% (96.9%-99.9%), 95.6% (83.6%-99.2%), and 100% (98.2%-100%), respectively, while those of the Seeplex assay were 97.7% (86.2%-99.9%), 99.6% (97.5%-99.9%), 97.7% (86.2%-99.9%), and 99.6% (97.5%-99.9%), respectively. The iNtRON assay had a detection limit of 3,159 copies/uL and 13,702 copies/uL for the vanA and vanB genes, respectively. No cross-reactivity was observed in 11 non-VRE bacterial culture isolates. CONCLUSIONS: The overall performance of the iNtRON assay was comparable to that of a chromogenic agar based culture method for prompt identification of VRE-colonized patients in hospitals. This assay could be an alternative or supportive method for the effective control of nosocomial VRE infection. PMID- 25553285 TI - Evaluation of the impact of automated specimen inoculation, using Previ Isola, on the quality of and technical time for stool cultures. AB - BACKGROUND: This study was designed as a quasi-experiment to evaluate automatic inoculation of fecal specimens, using the automated specimen inoculator Previ Isola (bioMerieux, France). METHODS: We evaluated the quality of cultures, recovery rates of enteropathogenic bacteria (Salmonella, Shigella, Campylobacter, and Yersinia species), and cost-effectiveness in terms of technical time. The Previ Isola recovery rates for the two-year period from August 2009 to July 2011 were compared with historical manual inoculation data of the previous two years (August 2007 to July 2009). The regional (Baden-Wurttemberg) and nationwide (Germany) trends of recovery rates for this four-year period were referred. RESULTS: A total of 5,884 fecal specimens were collected over the study period. Most positive cultures were for Salmonella, followed by Campylobacter. Compared with the historical data, the numbers of Campylobacter-positive specimens for a year between August and July were increased significantly, from 19 in 2007-2008 and 10 in 2008-2009 to 32 in 2009-2010 (P=0.002) and 32 in 2010-2011 (P=0.003), respectively. During the study period, the official data for our region and nationwide did not show this increase in the recovery rate of Campylobacter. For Salmonella, Shigella, and Yersinia, no significant changes were observed. Compared with manual inoculation, the mean hands-on time with Previ Isola inoculation was significantly shortened, from 37:30 min to 8:42 min per 15 fecal specimens. CONCLUSIONS: Inoculation by Previ Isola improves the quality of routine culture of fecal specimens, with better sensitivity for Campylobacter and less hands-on time. PMID- 25553286 TI - Prevalence of antibody to toxic shock syndrome toxin-1 in burn patients. AB - BACKGROUND: Burn wounds lack normal barriers that protect against pathogenic bacteria, and burn patients are easily colonized and infected by Staphylococcus aureus. Toxic shock syndrome (TSS) is a rare but fatal disease caused by S. aureus. A lack of detectable antibodies to TSS toxin-1 (TSST-1) in serum indicates susceptibility to TSS. METHODS: A total of 207 patients (169 men and 38 women; median age, 42.5 yr) admitted to a burn center in Korea were enrolled in this study. The serum antibody titer to TSST-1 was measured by sandwich ELISA. S. aureus isolates from the patients' nasal swab culture were tested for TSST-1 toxin production by PCR-based detection of the TSST-1 toxin gene. RESULTS: One hundred seventy-four (84.1%) patients showed positive results for antibody against TSST-1. All patients aged >=61 yr (n=28) and <26 months (n=7) were positive for the anti-TSST-1 antibody. S. aureus was isolated from 70 patients (33.8%), and 58.6% of the isolates were methicillin resistant. Seventeen patients were colonized with TSST-1-producing S. aureus. The antibody positivity in these 17 carriers was 88.2%, and the positivity in the non-carriers was 83.7%. CONCLUSIONS: Most burn patients had antibody to TSST-1, and nasal colonization with TSST-1-producing S. aureus was associated with positive titers of anti-TSST 1 antibody. Additionally, patients with negative titers of anti-TSST-1 antibody might be susceptible to TSS. PMID- 25553287 TI - Antimicrobial susceptibility of clinical isolates of Bacteroides fragilis group organisms recovered from 2009 to 2012 in a Korean hospital. AB - BACKGROUND: Periodic monitoring of antimicrobial resistance trends of clinically important anaerobic bacteria such as Bacteroides fragilis group organisms is required. We determined the antimicrobial susceptibilities of clinical isolates of B. fragilis group organisms recovered from 2009 to 2012 in a tertiary-care hospital in Korea. METHODS: A total of 180 nonduplicate clinical isolates of B. fragilis group organisms were collected in a tertiary care hospital. The species were identified by conventional methods: the ATB 32A rapid identification system (bioMerieux, France) and the Vitek MS matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (bioMerieux). Antimicrobial susceptibility was determined by the CLSI agar dilution method. RESULTS: Imipenem and meropenem resistance rates were 0-6% for B. fragilis group isolates. The rate of resistance to piperacillin-tazobactam was 2% for B. fragilis and 0% for other Bacteroides species, but 17% for B. thetaiotaomicron isolates. High resistance rates to piperacillin (72% and 69%), cefotetan (89% and 58%), and clindamycin (83% and 69%) were observed for B. thetaiotaomicron and other Bacteroides spp. The moxifloxacin resistance rate was 27% for other Bacteroides spp. The MIC50 and MIC90 of tigecycline were 2-4 ug/mL and 8-16 ug/mL, respectively. No isolates were resistant to chloramphenicol or metronidazole. CONCLUSIONS: Imipenem, meropenem, chloramphenicol, and metronidazole remain active against B. fragilis group isolates. Moxifloxacin and tigecycline resistance rates are 2-27% and 8-15% for B. fragilis group isolates, respectively. PMID- 25553288 TI - Comparison of quantitation of cytomegalovirus DNA by real-time PCR in whole blood with the cytomegalovirus antigenemia assay. AB - BACKGROUND: Quantitation of cytomegalovirus (CMV) DNA using real-time PCR has been utilized for monitoring CMV infection. However, the CMV antigenemia assay is still the 'gold standard' assay. There are only a few studies in Korea that compared the efficacy of use of real-time PCR for quantitation of CMV DNA in whole blood with the antigenemia assay, and most of these studies have been limited to transplant recipients. METHOD: 479 whole blood samples from 79 patients, falling under different disease groups, were tested by real-time CMV DNA PCR using the Q-CMV real-time complete kit (Nanogen Advanced Diagnostic S.r.L., Italy) and CMV antigenemia assay (CINA Kit, ArgeneBiosoft, France), and the results were compared. Repeatedly tested patients were selected and their charts were reviewed for ganciclovir therapy. RESULTS: The concordance rate of the two assays was 86.4% (Cohen's kappa coefficient value=0.659). Quantitative correlation between the two assays was a moderate (r=0.5504, P<0.0001). Among 20 patients tested repeatedly with the two assays, 13 patients were transplant recipients and treated with ganciclovir. Before treatment, CMV was detected earlier by real-time CMV DNA PCR than the antigenemia assay, with a median difference of 8 days. After treatment, the antigenemia assay achieved negative results earlier than real-time CMV DNA PCR with a median difference of 10.5 days. CONCLUSIONS: Q-CMV real-time complete kit is a useful tool for early detection of CMV infection in whole blood samples in transplant recipients. PMID- 25553289 TI - Inflammatory cytokines and their prognostic ability in cases of major burn injury. AB - BACKGROUND: Major burn injuries induce inflammatory responses and changes in the levels of various cytokines. This study was conducted to assess early changes in the serum levels of inflammatory cytokines after burn injury, identify cytokines associated with mortality, and characterize correlations among cytokines. METHODS: Blood samples of 67 burn patients were collected on days 1 and 3 after burn injury, and the concentrations of 27 cytokines were measured using the Bio Plex Suspension Array System (Bio-Rad Laboratories, USA). Blood samples of 25 healthy subjects were used as controls. We analyzed statistical differences in the concentrations of each cytokine between the control and patient groups, between day 1 and day 3, and between survival and nonsurvival groups. Correlations among 27 cytokines were analyzed. RESULTS: Median concentrations of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), interleukin 1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 15 (IL-15), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1beta (MIP-1beta), and vascular endothelial growth factor (VEGF) were significantly higher in burn patients than in controls. IL-1RA, IL-6, and MCP-1 levels were significantly higher in the nonsurvival group than in the survival group on day 1 after burn injury. Correlation analysis of 27 cytokines showed different relationships with one another. Stronger correlations among interferon gamma (IFN-gamma), IL-2, IL-4, IL-7, IL-12p70, and IL-17 were found. CONCLUSIONS: IL-1RA, IL-6, and MCP-1 may be used as prognostic indicators of mortality in burn patients and the increase in cytokine concentrations is induced by interactions within a complex network of cytokine-related pathways. PMID- 25553290 TI - The impact of HLA and KIR ligand mismatching on unrelated allogeneic hematopoietic stem cell transplantation in Korean adult patients. AB - BACKGROUND: The impact of HLA and KIR ligand mismatching on the outcome of hematopoietic stem cell transplantation (HSCT) remains unclear. Previous reports have identified considerable ethnic differences in the impact of HLA and KIR ligand mismatches, as well as KIR ligand status, on HSCT; however, to date, no data has been acquired in Korean adult patients. METHODS: We investigated the association of high-resolution HLA matching on five loci (HLA-A, -B, -C, -DRB1, and -DQB1), KIR ligand mismatching, and KIR ligand status on the outcome of allogeneic HSCT from unrelated donors in 154 Korean adult patients treated at Seoul National University Hospital. RESULTS: In a multivariate analysis, less than 9/10 allelic matches in five HLA loci was an independent risk factor for acute graft-versus-host disease (GVHD) (grade II to IV) (P=0.019, odds ratio [OR]=2.7). In addition, HLA-A allele mismatching was increasingly prevalent in patients with acute GVHD compared to patients without (61.9% vs. 34.5%, P=0.06). For KIR ligand status, the patient and donor combination of both C1/C1 ligands showed better event-free and overall survival than combinations with C2 ligand patients or donors (P=0.048, P=0.034, respectively) by log-rank test. CONCLUSIONS: Korean adult transplant patients with less than 9 of 10 HLA allele matches in the HLA-A, -B, -C, -DRB1, and DQB1 loci have a higher likelihood of developing acute GVHD (grade II to IV). Impact of KIR ligand status on clinical outcome should be further studied in a larger patient population. PMID- 25553293 TI - Submicroscopic deletions of immunoglobulin heavy chain gene (IGH) in precursor B lymphoblastic leukemia with IGH rearrangements. AB - Translocations leading to fusions between the immunoglobulin heavy chain gene (IGH) and various partner genes have been reported in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, submicroscopic deletions within IGH in B ALL have not been rigorously assessed. In this study, we investigated characteristics of IGH submicroscopic deletions, by FISH, in B-ALL with IGH rearrangements. FISH was performed by using commercially available IGH dual-color break-apart rearrangement probes (Abbott/Vysis, Downers Grove, IL, USA; Kreatech, Amsterdam, Netherlands). The study group included seven B-ALL patients with IGH rearrangements, observed by FISH. Among them, two exhibited deletion of the 5' variable region of IGH by FISH. The B-ALL in these two patients included two kinds of abnormal cells; one had an IGH rearrangement without any IGH submicroscopic deletion, while the other had an IGH submicroscopic deletion, which showed that one normal fusion signal and one 3' IGH signal were detected. Thus, submicroscopic deletion of the IGH 5' variable region may have occurred in either the native or rearranged chromosome 14. These findings indicate that B-ALL with IGH rearrangements may be accompanied by submicroscopic deletions of the IGH 5' variable region, which can be detected by FISH. The clinical significance of such deletions is unclear, but the loss of part of the IGH gene in B-ALL warrants further study. PMID- 25553291 TI - Alteration of the SETBP1 gene and splicing pathway genes SF3B1, U2AF1, and SRSF2 in childhood acute myeloid leukemia. AB - BACKGROUND: Recurrent somatic SET-binding protein 1 (SETBP1) and splicing pathway gene mutations have recently been found in atypical chronic myeloid leukemia and other hematologic malignancies. These mutations have been comprehensively analyzed in adult AML, but not in childhood AML. We investigated possible alteration of the SETBP1, splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and serine/arginine-rich splicing factor 2 (SRSF2) genes in childhood AML. METHODS: Cytogenetic and molecular analyses were performed to reveal chromosomal and genetic alterations. Sequence alterations in the SETBP1, SF3B1, U2AF1, and SRSF2 genes were examined by using direct sequencing in a cohort of 53 childhood AML patients. RESULTS: Childhood AML patients did not harbor any recurrent SETBP1 gene mutations, although our study did identify a synonymous mutation in one patient. None of the previously reported aberrations in the mutational hotspot of SF3B1, U2AF1, and SRSF2 were identified in any of the 53 patients. CONCLUSIONS: Alterations of the SETBP1 gene or SF3B1, U2AF1, and SRSF2 genes are not common genetic events in childhood AML, implying that the mutations are unlikely to exert a driver effect in myeloid leukemogenesis during childhood. PMID- 25553292 TI - Performance of LIFECODES HLA-DQB1 typing kit using Luminex platform in Koreans. AB - Intermediate-resolution HLA-DQ typing has gained importance in organ transplantation recently. We evaluated the performance of the LIFECODES HLA-DQB1 typing kit (Immucor, USA) using sequence-specific oligonucleotide (SSO) probe and Luminex platform (Luminex Corp., USA) on 100 samples tested by sequence-based typing (SBT) using the AlleleSEQR HLA-DQB1 kit (Abbott Molecular, USA) in Korean individuals. No sample showed ambiguity in the assignment of 4-digit HLA-DQB1 allele with the LIFECODES HLA-DQB1 SSO typing kit, and the results were fully concordant with those of high-resolution typing of AlleleSEQR HLA-DQB1 SBT up to 4-digit level. Three samples required adjustment of false reactions (3/100, 3.0%): two samples with DQB1(*)03:03/(*)06:01 showed false-positive result in probe 253, and 1 sample with DQB1(*)04:02/(*)05:02 showed false-negative result in probe 217. We tested an additional sample with DQB1(*)03:03/(*)06:01, which showed same false-positivity in probe 253 and 2 samples with DQB1(*)04:02/(*)05:02, which showed no false reaction. The false reactions did not result in ambiguity or change in the HLA allele assignment. We could assign HLA-DQB1 alleles to 4 digit-level without ambiguity, with 100% concordance with the SBT results. Thus, LIFECODES HLA-DQB1 SSO typing kit showed good performance for intermediate-resolution HLA-DQB1 typing in clinical laboratory for organ transplantation in Koreans. PMID- 25553294 TI - Clinical relevance of high-resolution single nucleotide polymorphism array in patients with relapsed acute lymphoblastic leukemia with normal karyotype: a report of three cases. AB - We report three patients with normal karyotype (NK) ALL, who showed genetic aberrations as determined by high-resolution single nucleotide polymorphism array (SNP-A) analysis at both diagnosis and relapse. We evaluated the clinical relevance of the SNP-A assay for the detection of subtle changes in the size of affected genetic lesions at relapse as well as the prognostic value of the assay. In our patients, application of the SNP-A assay enabled sensitive detection of cryptic changes affecting clinically important genes in NK ALL. Therefore, this assay seems to be more advantageous compared to other conventional methods such as FISH assay, HemaVision (DNA Technology, Denmark), and conventional karyotyping for the detection of an "unstable genotype" at relapse, which may be associated with microscopic clonal evolution and poor prognosis. Further comprehensive studies are required to confirm the issues presented by our case patients in this report. PMID- 25553295 TI - ABO*Ael03/O genotype with ABO discrepancy: the first case in Korea. AB - The Ael subgroup expresses the least amount of A antigens and could only be detected by performing the adsorption-elution test. The frequency of the Ael subgroup is about 0.001% in Koreans, and the Ael02 allele, which originates from A102, is the most frequently identified allele in the Korean population. We report a Korean family with the Ael03 allele identified by molecular genetic analysis. To the best of our knowledge, this is the first such report in Korea to date. PMID- 25553297 TI - The new Sysmex XN-2000 automated blood cell analyzer more accurately measures the absolute number and the proportion of hematopoietic stem and progenitor cells than XE-2100 when compared to flow cytometric enumeration of CD34+ cells. PMID- 25553298 TI - Simultaneous occurrence of angioimmunoblastic T-cell lymphoma and plasma cell leukemia. PMID- 25553296 TI - Non-homologous end joining repair mechanism-mediated deletion of CHD7 gene in a patient with typical CHARGE syndrome. AB - CHARGE syndrome MIM #214800 is an autosomal dominant syndrome involving multiple congenital malformations. Clinical symptoms include coloboma, heart defects, choanal atresia, retardation of growth or development, genital hypoplasia, and ear anomalies or deafness. Mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene have been found in 65-70% of CHARGE syndrome patients. Here, we describe a 16-month-old boy with typical CHARGE syndrome, who was referred for CHD7 gene analysis. Sequence analysis and multiplex ligation dependent probe amplification were performed. A heterozygous 38,304-bp deletion encompassing exon 3 with a 4-bp insertion was identified. There were no Alu sequences adjacent to the breakpoints, and no sequence microhomology was observed at the junction. Therefore, this large deletion may have been mediated by non homologous end joining. The mechanism of the deletion in the current case differs from the previously suggested mechanisms underlying large deletions or complex genomic rearrangements in the CHD7 gene, and this is the first report of CHD7 deletion by this mechanism worldwide. PMID- 25553299 TI - The first case report of composite bone marrow involvement by simultaneously developed peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma. PMID- 25553300 TI - First report on familial hemophagocytic lymphohistiocytosis with an abnormal immunophenotype and T cell monoclonality in Korea. PMID- 25553301 TI - Two cases of acute lymphoblastic leukemia with an e1a3 BCR-ABL1 fusion transcript. PMID- 25553303 TI - Ultra-performance liquid chromatography-tandem mass spectrometry measurement of leukocyte arylsulfatase A activity using a natural substrate. PMID- 25553302 TI - Constitutional chromosomal abnormality identified in a sibling donor after bone marrow stem cell transplantation in a pediatric patient with acute megakaryoblastic leukemia. PMID- 25553304 TI - Peripheral blood smear contamination with Helicosporium fungi resembling microfilaria. PMID- 25553305 TI - The emergence of the 16S rRNA methyltransferase RmtB in a multidrug-resistant Serratia marcescens isolate in China. PMID- 25553306 TI - Three cases of candidiasis misidentified as Candida famata by the Vitek 2 system. PMID- 25553307 TI - Identification of somatic KRAS mutation in a Korean baby with nevus sebaceus syndrome. PMID- 25553309 TI - Erratum: Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis. AB - [This corrects the article on p. 219 in vol. 31.]. PMID- 25553308 TI - Identification of compound heterozygous mutations in the BBS7 gene in a Korean family with Bardet-Biedl syndrome. PMID- 25553310 TI - What does Self Rated Mental Health Represent. AB - BACKGROUND: Unlike the widely used self rated health, the self rated mental health was found unsuitable as a proxy for mental illness. This paper analyses the relationships between the self ratings of physical health, mental health and overall health, and their association of with the objective indicators for physical and mental health. DESIGN AND METHODS: The study is a secondary analysis of data from a nationwide representative sample of the non-institutionalized adult residents of Israel in 2003 that was collected via computer-assisted personal interview methods [n=4859]. RESULTS: The self rated physical health and the self rated mental health were strongly related to each other yet the self rated mental health was not related to chronic physical conditions and the self rated physical health was not related to mental disorders. In a multiple logistic regression analysis, those with positive self rated mental health had 93 times the odds of reporting positive overall health whereas those with positive self rated physical health had 40 times the odds of reporting positive overall health. CONCLUSIONS: The self rating of mental health presents a qualitatively different dimension from mental illness. The self rated mental health is two times more important than the self rated physical health in predicting the self rated overall health Significance for public healthThe present study is an original study on the self rated physical, mental and overall health measures. Because of the wide range of associations with other health indicators, and the simplicity with which they are collected, self-rated health measures are widely used in large population surveys.The present study questions the automatic assumption that the self rated mental health functions as a proxy measure of psychiatric morbidity, and suggests that the self rated mental health is more closely related to subjective well-being. The results show that self rated mental health predicts self rated general health better than self rated physical health. PMID- 25553311 TI - What makes Health Demand-Side Financing Schemes Work in Low-and Middle-Income Countries? A Realist Review. AB - This realist review explored causal pathways of the possible consumer effects of health sector demand-side financial (DSF) incentives, their contextual factors and mechanisms in low-and-middle-income countries. We searched six electronic data bases and identified 659 abstracts with different evaluation designs. Based on methodological rigor and content relevance, only 24 studies published up to April 2013 were selected for the final review. A conceptual framework consisting of various program theories on potential context-mechanism-outcome (C-M-O) configuration of DSF initiative was designed, tested and adapted during the review. Synthesized results were presented as a C-M-O configuration for each of the consumer -side effect. DSF was effective to improve health seeking behaviour considerably and health status to some extent. The causal pathway of DSF's functioning and effectiveness was not linear. Key demand-side contextual factors which affected DSF's consumer-side effects were background characteristics of the beneficiaries including their socio-cultural beliefs, motivations, and level of health awareness. At the supply-side, service availability status and provider incentives were contextual determinants. The mechanisms which enabled the interaction of contextual influence were consumer and provider accountability and consumer trust on providers. In order to enhance DSF programs' effectiveness, their design and implementation should carefully consider the potential contextual elements that may influence the causal pathways. Significance for public healthThis article focuses on a rare topic i.e. Realist Review, which is an emerging concept to explore causal factors behind every intervention that make it effective or ineffective. This manuscript is a first attempt on a Realist Review of health sector demand-side financing (DSF) in a number of low-and middle income countries. DSF is a widely employed health promotion strategy in many countries to improve health seeking behaviour. However, the existing evidence explores only its effectiveness and not the determinants of its effectiveness. It is also essential to understand the causal pathways of DSF's effectiveness, i.e. what are the factors affecting its effectiveness. This Realist Review attempts to explore the causal pathways of effectiveness of many prominent DSF initiatives in the world. The study findings have policy implications and will be widely referred to in future. PMID- 25553312 TI - Impact of patients' judgment skills on asthma self-management: a pilot study. AB - BACKGROUND: The majority of current health literacy tools assess functional skills including reading, writing, and numeracy. Although these tools have been able to underline the impact of such skills on individuals' health behaviour, there is a need for comprehensive measures to examine more advanced skills. The individual's ability to use health-related information considering his/her own health context, and judging positive and negative consequences of their decisions has been conceptualized as judgment skills. The present study used a newly developed judgment skills tool to explore asthma self-management practices. DESIGN AND METHODS: Eighty asthma patients were recruited from medical offices during the year 2013. The questionnaire was self-administered and contained health literacy questions, the judgment skill tool, the Asthma Control Test, and several self-management questions. RESULTS: Sixty-nine percent of participants had adequate health literacy, while 24% and 5% had marginal and inadequate levels, respectively. The high-judgment group referred more to their doctor when experiencing asthma problems t(76)=-2.18, P<0.032; complied more with the use of their control medicine t(77)=-3.24, P<0.002 and went more regularly to the doctor t(78)=-1.80, P<0.038 (one-tailed) than the low-judgment group. CONCLUSIONS: The judgment skills tool can help identify asthma patients' health information use and reveal how this use may affect some self-management practices. Significance for public healthPatients' health literacy has a great impact on their health behaviours and their health outcomes. Therefore, it has become more and more common to measure health literacy within the healthcare setting to determine the most effective approach to target patients. The measurement of asthma judgment skills contribute to a deeper understanding of patients' asthma self-management in crucial topics for asthma control, and have the advantage of assessing the specific abilities needed for this particular condition, which in turn benefits the translation of the findings from the use of this tool into strategies that directly tackle the needs of asthma patients. PMID- 25553313 TI - An ecological study of food desert prevalence and 4th grade academic achievement in new york state school districts. AB - BACKGROUND: This ecological study examines the relationship between food desert prevalence and academic achievement at the school district level. DESIGN AND METHODS: Sample included 232 suburban and urban school districts in New York State. Multiple open-source databases were merged to obtain: 4(th) grade science, English and math scores, school district demographic composition (NYS Report Card), regional socioeconomic indicators (American Community Survey), school district quality (US Common Core of Data), and food desert data (USDA Food Desert Atlas). Multiple regression models assessed the percentage of variation in achievement scores explained by food desert variables, after controlling for additional predictors. RESULTS: The proportion of individuals living in food deserts significantly explained 4th grade achievement scores, after accounting for additional predictors. School districts with higher proportions of individuals living in food desert regions demonstrated lower 4th grade achievement across science, English and math. CONCLUSIONS: Food deserts appear to be related to academic achievement at the school district level among urban and suburban regions. Further research is needed to better understand how food access is associated with academic achievement at the individual level. Significance for public healthThe prevalence of food deserts in the United States is of national concern. As poor nutrition in United States children continues to spark debate, food deserts are being evaluated as potential sources of low fruit and vegetable intake and high obesity rates. Cognitive development and IQ have been linked to nutrition patterns, suggesting that children in food desert regions may have a disadvantage academically. This research evaluates if an ecological relationship between food desert prevalence and academic achievement at the school district level can be demonstrated. Results suggest that food desert prevalence may relate to poor academic performance at the school district level. Significant variation in academic achievement among urban and suburban school districts is explained by food desert prevalence, above additional predictors. This research lays the groundwork for future studies at the individual level, with possible implications for community interventions in school districts containing food desert regions. PMID- 25553314 TI - Awareness, Treatment, and control of Hypertension among Adult Population in the Federation of Bosnia and Herzegovina over the Past Decade. AB - BACKGROUND: Many studies throughout the world show that hypertension is not effectively treated and controlled, which continued to pose an important challenge in health systems in the world. DESIGN AND METHODS: Population surveys were carried out in 2002 and 2012 in the Federation of Bosnia and Herzegovina (FBIH) on representative sample at the age of 25-64. The surveys used systematic stratified sample. Questionnaires and anthropometric measure protocols were adapted from internationally recommended surveys. RESULTS: In the past ten years there has been a slight increase in hypertension prevalence in researched population (41% vs. 42%). Percentage of hypertensive male and female respondents who are not aware of their hypertension actually dropped in the past decade from 54.3% to 51.4%. In 2002 total number of hypertensive respondents aware of their hypertension included 8.1% of male respondents and 10.3% female respondents whose condition was not treated and this rate effectively dropped during the 10-year period. Number of hypertensive, treated, and uncontrolled respondents dropped as reported in the 2012 survey; consequently percentage of hypertensive, treated, and controlled respondents in the 2012 survey increased, in particular in female population. CONCLUSIONS: Investments in primary health care, improved availability, and improved quality of health care in the FBIH in the past 10 years can explain increased rate of hypertension detection and treatment; however, efforts should be continued to introduce hypertension screening programs and hypertension control programs. Significance for public healthIn spite of wide knowledge of pathophysiology and epidemiology in development of hypertension, ability to easily diagnose it, availability of efficient medications, hypertension continues to have high prevalence and setting up hypertension controls poses significant public health challenge. Recently conducted cross sectional population surveys in the Federation of Bosnia and Herzegovina give us opportunity to follow the trend for hypertension and implement public health measures to reduce or eliminate causes of high blood pressure in population and at the same time with implementation of medical treatment. PMID- 25553315 TI - Application of chemometric methods for assessment and modelling of microbiological quality data concerning coastal bathing water in Greece. AB - BACKGROUND: Worldwide, the aim of managing water is to safeguard human health whilst maintaining sustainable aquatic and associated terrestrial, ecosystems. Because human enteric viruses are the most likely pathogens responsible for waterborne diseases from recreational water use, but detection methods are complex and costly for routine monitoring, it is of great interest to determine the quality of coastal bathing water with a minimum cost and maximum safety. DESIGN AND METHODS: This study handles the assessment and modelling of the microbiological quality data of 2149 seawater bathing areas in Greece over 10 year period (1997-2006) by chemometric methods. RESULTS: Cluster analysis results indicated that the studied bathing beaches are classified in accordance with the seasonality in three groups. Factor analysis was applied to investigate possible determining factors in the groups resulted from the cluster analysis, and also two new parameters were created in each group; VF1 includes E. coli, faecal coliforms and total coliforms and VF2 includes faecal streptococci/enterococci. By applying the cluster analysis in each seasonal group, three new groups of coasts were generated, group A (ultraclean), group B (clean) and group C (contaminated). CONCLUSIONS: The above analysis is confirmed by the application of discriminant analysis, and proves that chemometric methods are useful tools for assessment and modeling microbiological quality data of coastal bathing water on a large scale, and thus could attribute to effective and economical monitoring of the quality of coastal bathing water in a country with a big number of bathing coasts, like Greece. Significance for public healthThe microbiological protection of coastal bathing water quality is of great interest for the public health authorities as well as for the economy. The present study proves that this protection can be achieved by monitoring only two microbiological parameters, E. coli and faecal streptococci/enterococci instead four microbiological parameters (the two mentioned above plus Total coliforms and Faecal coliforms) that are usually monitored today. As a consequence, countries, especially those with large quantities of coastal bathing sites, can perform microbiological monitoring of their bathing waters by checking only the mentioned two parameters, thus ensuring economies of scale. Thus, funds can be used in other actions to preserve the quality of coastal water and human health. This in turn, would aid in the assessment of the quality of coastal bathing waters and provide a more timely indication of bathing water quality, hence contributing to the immediate health protection of bathers. PMID- 25553316 TI - Care for the Person, Protection of Health and Respect for the will of the Patient in Italy: Support Administration as a Tool to Jointly Promote Health and Respect for Autonomy in Incompetent Patients. AB - In Italy, advance health care directives are a subject of considerable debate in both legal theory and practice. This debate focuses in particular not only on the appropriateness of approving ad hoc statutory regulations but also on the extent to which similar advance indications of a person's wishes are applicable under the existing legal system, albeit in the absence of a law regulating them. The authors of this paper consider, in particular, guidelines relating to the possible use of the mechanism of support administration (amministrazione di sostegno) (Law No. 6/2004) as a procedure to be used for the legal recognition of advance health care directives, particularly in the light of the legal provision for the possible designation in advance of a support administrator by a beneficiary in anticipation of an eventual situation of incapacity. This underlines how the concept of health does not only exist in the abstract, but must be measured in relation to the particular patient in the particular situation and how beneficence and respect for autonomy are both essential elements in the choices aimed at promoting the health and the wellbeing of its citizens. Significance for public healthThe concept of health includes not only the physical, but also the psychosocial dimension in accordance with the will of people. The reference to the personal concept of quality of life, values, ethical and religious opinions of each subject are key components underlying the decision making process concerning a given patient in a given clinical condition: the concept of health does not only exist in the abstract, but must be measured in relation to the specific patient in the specific situation. The authors analyse the Italian debate about the possible designation in advance of the support administrator on the part of the beneficiary in anticipation of a potential situation of incapacity, as a tool to enforce advance care directives, to show how beneficence and respect for autonomy are both essential elements in the choices of the legal system aimed at promoting the health and the wellbeing of its citizens. PMID- 25553317 TI - Achieving the promise of digital health information systems. PMID- 25553318 TI - The differentiation of human multipotent adult progenitor cells into hepatocyte like cells induced by coculture with human hepatocyte line L02. AB - PURPOSE: The aim of this study was to establish an in vitro method to purify human multipotent adult progenitor cells (hMAPCs) and assess their possible differentiation into hepatocytes by coculture with human hepatocyte line L02. METHODS: hMAPCs were isolated by magnetic activated cell sorting (MACS) depletion selection using CD45 and GlyA microbeads. After indirect or direct coculture of hMAPCs and human hepatocyte line L02, the expression of albumin (ALB), alpha fetoprotein (AFP), cytokeratin (CK) 18, and CK19 by hMAPCs was detected by immunocytochemistry. RESULTS: With the MACS method, (5-10) * 10(4)/mL hMAPCs could be separated from 1 * 10(6)/mL bone marrow mononuclear cells. The purity of CD45-/GlyA- cells separated from bone marrow adherent cells was more than 98%, as determined by flow cytometry. In the coculture without cell-to-cell contact, hMAPCs expressed high AFP on day 1, and then tapered daily to low expression on day 7; ALB expression reached its peak on day 5, and remained high on day 7; CK18 was initially expressed on day 5 and was higher on day 7; CK19 was negative in all assays. In the coculture with cell-to-cell contact, ALB and CK18 were expressed by most cells while AFP appeared in only a few on day 5. CONCLUSION: hMAPCs were induced to differentiate into mature hepatocyte-like cells by coculture with a hepatocyte cell line, either with or without cell-to-cell contact, but the former seemed more effective. PMID- 25553319 TI - Comparison of long-term oncologic outcomes of stage III colorectal cancer following laparoscopic versus open surgery. AB - PURPOSE: The oncologic outcomes after performing laparoscopic surgery (LS) compared to open surgery (OS) are still under debate and a concern when treating patients with colon cancer. The aim of this study was to compare the long-term oncologic outcomes of LS and OS as treatment for stage III colorectal cancer patients. METHODS: From January 2001 to December 2007, 230 patients with stage III colorectal cancer who had undergone LS or OS in this single center were assessed. Data were analyzed according to intention-to-treat. The primary endpoints were disease-free survival and overall survival. RESULTS: A total of 230 patients were entered into the study (114 patients had colon cancer-33 underwent LS and 81 underwent OS; 116 patients had rectal cancer-44 underwent LS and 72 underwent OS). The median follow-up periods for the colon and rectal cancer groups were 54 and 53 months, respectively. The overall conversion rate was 12.1% (n = 4) for colon cancer, and 4.5% (n = 2) for rectal cancer. Disease free 5-year survival of colon cancer was 84.3% and 90% in LS group (LG) and OS group (OG), respectively, and that of rectal cancer was 83% and 74.6%, respectively (P > 0.05). Overall 5-year survival for colon cancer was 72.2% and 71.3% for LG and OG, respectively, and that for rectal cancer was 67.6% and 59.2%, respectively (P > 0.05). CONCLUSION: The long-term analyses for oncologic aspects of our study may confirm the safety of LS compared to OS in stage III colorectal cancer patients. PMID- 25553320 TI - Oncologic impact of pathologic response on clinical outcome after preoperative chemoradiotherapy in locally advanced rectal cancer. AB - PURPOSE: Downstaging after chemoradiotherapy (CRT) for rectal cancer usually occurs. The present study aimed to evaluate pathologic y-stage (yp-stage) and its influence on local recurrence and systemic recurrence in rectal cancer patients treated with CRT followed by surgical resection. METHODS: We retrospectively analyzed 261 patients underwent preoperative CRT and radical resection for rectal cancer between August 2004 and December 2010. Patients received preoperative CRT consisting of 5-fluorouracil and leucovorin delivered with concurrent pelvic radiation of 45.0-50.4 Gy, followed by radical surgery at 6-8 weeks after CRT. RESULTS: Of the 261 patients, 24 (9.2%) had yp-stage 0, 83 (31.8%) had yp-stage I, 86 (32.9%) had yp-stage II, and 68 (26.1%) had yp-stage III. Patients with yp stage III had a greater prevalence of preoperative CEA, poorly differentiated tumor, lymphovascular invasion (LVI) and perineural invasion (PNI) than patients with lower yp-stages. We found that yp-stage, preoperative CEA, LVI, PNI and tumor regression grade were significant prognostic factors for both local and systemic recurrence. In multivariate analysis, yp-stage, LVI and PNI were significant factors for local and systemic recurrence. During the median follow up of 37.5 months, the five-year local recurrence-free survival rate was 100.0%, 95.0%, 89.3%, and 80.6% of yp-stage 0-III, respectively. The five-year systemic recurrence-free survival was 95.8%, 75.3%, 71.4%, and 48.8% of yp-stages 0-III, respectively. CONCLUSION: The yp-stage after preoperative CRT for rectal cancer is closely correlated with local and systemic recurrence-free survival. Therefore, yp-stage should be considered as a prognostic factor for rectal cancer patients having a course of preoperative CRT. PMID- 25553321 TI - Impact of graft composition on the systemic inflammatory response after an elective repair of an abdominal aortic aneurysm. AB - PURPOSE: The present study aimed to evaluate the risk factors and the role of graft material in the development of an acute phase systemic inflammatory response, and the clinical outcome in patients who undergo endovascular aneurysm repair (EVAR) or open surgical repair (OSR) of an abdominal aortic aneurysm (AAA). METHODS: We retrospectively evaluated the risk factors and the role of graft material in an increased risk of developing systemic inflammatory response syndrome (SIRS), and the clinical outcome in patients who underwent EVAR or OSR of an AAA. RESULTS: A total of 308 consecutive patients who underwent AAA repair were included; 178 received EVAR and 130 received OSR. There was no significant difference in the incidence of SIRS between EVAR patients and OSR patients. Regardless of treatment modality, SIRS was observed more frequently in patients treated with woven polyester grafts. Postoperative hospitalization was significantly prolonged in patients that experienced SIRS. In multivariate analyses, the initial white blood cell count (P = 0.001) and the use of woven polyester grafts (P = 0.005) were significantly associated with an increased risk of developing SIRS in patients who underwent EVAR. By contrast, the use of woven polyester grafts was the only factor associated with an increased risk of developing SIRS in patients who underwent OSR, although this was not statistically significant (P = 0.052). CONCLUSION: The current study shows that the graft composition plays a primordial role in the development of SIRS, and it leads to prolonged hospitalization in both EVAR and OSR patients. PMID- 25553322 TI - Comparison of long-term results of above-the-knee femoro-popliteal bypass with autogenous vein and polytetrafluoroethylene grafts. AB - PURPOSE: To analyze the long-term results of above-the-knee femoro-popliteal bypass (ATKFPB) with vein grafts compared with polytetrafluoroethylene (PTFE) grafts. METHODS: A database of patients with chronic atherosclerotic occlusive disease who underwent ATKFPB was retrospectively reviewed. Characteristics of patient and arterial lesion, and follow-up results were compared between vein grafts and PTFE grafts. Graft patency was determined by periodic examinations of duplex ultrasonography or CT angiograms. Graft patency and limb salvage rates were calculated using the Kaplan-Meier method. RESULTS: In total, 253 ATKFPBs (107 vein grafts; 146 PTFE grafts; critical limb ischemia, 32%) were performed on 228 patients (mean age, 68.5 years; male, 87.7%). No significant differences were observed between the two groups with respect to demographic characteristics, characteristics of arterial lesions, or distal runoff score. During the mean follow-up period of 41 months (range, 1-122 months), 14.5% patients died, and 94% of all limbs were available for follow-up. The primary patency rates were not significantly different between the two groups at 10 years after treatment (75% vs. 42%, P = 0.330). However, the primary-assisted patency rates (88% vs. 42%, P = 0.003) and secondary patency rates (91% vs. 49%, P = 0.013) were significantly higher in the vein grafts compared with the PTFE grafts. Graft occlusion developed more often in the PTFE grafts (5.6% vs. 20.5%, P = 0.001). When graft occlusion occurred, acute limb ischemia was significantly more frequent in the PTFE grafts than in the vein grafts (0% vs. 53%, P = 0.027). CONCLUSION: After ATKFPB, autologous vein grafts showed significantly better long-term results compared with PTFE grafts. PMID- 25553323 TI - Long-term outcomes of infrainguinal bypass surgery for patients with diabetes mellitus and tissue loss. AB - PURPOSE: To determine the long-term outcomes of patients with diabetes mellitus (DM) and tissue loss who have undergone infrainguinal bypass surgery (IBS). METHODS: We retrospectively reviewed the medical records of 91 patients with DM and tissue loss who underwent IBS between July 2003 and December 2013. We determined the rates of overall survival (OS), amputation-free survival (AFS), limb salvage (LS), and graft patency (GP). In addition, we evaluated data to identify risk factors that affected long-term outcomes. RESULTS: The mean age of patients was 66 +/- 8 years, and 78 patients (85.7%) were men. The locations of tissue loss were toe on 76 limbs (71.6%), heel on 6 limbs (5.7%) and others on 24 limbs (22.6%). Single lesions were found in 81 limbs (76.4%). According to categorization by distal anastomosis artery, there were 57 popliteal (53.8%) and 49 infrapopliteal bypasses (46.2%). Among infrapopliteal bypasses, 5 cases (10.2%) were sequential bypasses. The OS at 1, 3, and 5 years was 90.5%, 70.9%, and 44.2%, respectively. At 1, 3, and 5 years, the LS was 92.1%, 88.9%, 88.9%, respectively; and AFS was 84.4%, 67.6%, 45.7%, respectively. At 1, 3, and 5 years, the GP was 84.8%, 74.5%, and 69.8%, respectively. Renal failure was a negative predictor for OS, and female gender was a negative predictor for GP. CONCLUSION: IBS for patients with DM and tissue loss led to acceptable OS, AFS, LS, and GP. Active revascularization for patients with DM and tissue loss can reduce the risk of major amputation. PMID- 25553324 TI - Simultaneous pancreas-kidney transplantation: lessons learned from the initial experience of a single center in Korea. AB - PURPOSE: The purpose of this study is to report the results of simultaneous pancreas-kidney (SPK) transplantations and describe the lessons learned from the early experiences of a single center. METHODS: Between January 2002 and June 2013, a total of 8 patients underwent SPK transplantation. Clinical and radiologic data were reviewed retrospectively. RESULTS: Seven patients were diagnosed with type I diabetes mellitus and one patient became insulin-dependent after undergoing a total pancreatectomy because of trauma. Pancreas exocrine drainage was performed by enteric drainage in 4 patients and bladder drainage in 4 patients. Three patients required conversion from initial bladder drainage to enteric drainage due to urinary symptoms and duodenal leakage. Four patients required a relaparotomy due to hemorrhage, ureteral stricture, duodenal leakage, and venous thrombosis. There was no kidney graft loss, and 2 patients had pancreas graft loss because of venous thrombosis and new onset of type II diabetes mellitus. With a median follow-up of 76 months (range, 2-147 months), the death-censored graft survival rates for the pancreas were 85.7% at 1, 3, and 5 years and 42.9% at 10 years. The patient survival rate was 87.5% at 1, 3, 5, and 10 years. CONCLUSION: The long-term grafts and patient survival in the current series are comparable to previous studies. A successful pancreas transplant program can be established in a single small-volume institute. A meticulous surgical technique and early anticoagulation therapy are required for further improvement in the outcomes. PMID- 25553325 TI - An unusual case of candidemia presenting as acute respiratory distress syndrome after a small bowel bezoar removal operation. AB - We report a rare case of sepsis with acute respiratory distress syndrome (ARDS) caused by Candida parapsilosis and Candida famata after a small bowel bezoar operation. The patient was successfully treated with intensive care including mechanical ventilation and systemic antifungal therapy. A strong association was observed between the intestinal obstruction caused by the bezoar and candidemia presenting as ARDS. This is the first case in which candidemia has led to ARDS after a bezoar removal operation in a patient who was neither immunocompromised nor self-administering an illicit intravenous drug. PMID- 25553326 TI - Acute ileofemoral artery thromboembolism due to left ventricle thrombi with spontaneous coronary artery dissection. AB - Spontaneous coronary artery dissection (SCAD) is a very rare cause of peripheral artery thromboembolism. It is especially rare to show symptoms of acute limb ischemia without chest symptoms during a hospital visit. In this case, a rare case of SCAD led to left heart failure and caused left ventricle thrombi, which in turn caused peripheral thromboembolism. PMID- 25553327 TI - Changes in sodium levels in chain restaurant foods in Canada (2010-2013): a longitudinal study. AB - BACKGROUND: Several restaurant chains have committed to reducing sodium levels in their foods; however, how much sodium levels have changed over the past few years is unknown. The objective was to measure changes in sodium in restaurant foods from 2010 to 2013. METHODS: Data for the serving size, calorie and sodium level of 3878 foods were collected from the websites of 61 Canadian restaurant chains in 2010 and 2013. A longitudinal study of changes in sodium levels in foods available from the restaurants in 2010 and 2013 (n = 2198) was conducted. Levels in newly reported and discontinued foods were also investigated. RESULTS: Sodium levels (mg/serving) decreased in 30.1% of foods, increased in 16.3% and were unchanged in 53.6%. The average change in foods with a decrease in sodium was 220 (standard deviation [SD] +/- 303) mg/serving (a decline of 19% [SD +/- 17%]), whereas the average change in foods with an increase in sodium was 251 (SD +/- 349) mg/serving (a 44% [SD +/- 104%] increase). The prevalence and magnitude of change varied depending on the restaurant and food category. Overall, there was a small, yet significant, decrease in sodium per serving (-25 [SD +/- 268] mg, p < 0.001); however, the percentage of foods exceeding the daily sodium adequate intake (1500 mg) and tolerable upper intake level (2300 mg) remained unchanged. INTERPRETATION: The observed increases and decreases in sodium show that industry efforts to voluntarily decrease sodium levels in Canadian restaurant foods have produced inconsistent results. Although the lower levels in some foods show that sodium reduction is possible, the simultaneous increase in other foods demonstrates the need for targets and timelines for sodium reduction in restaurants. PMID- 25553328 TI - Risk factors for mortality among patients with Staphylococcus aureus bacteremia: a single-centre retrospective cohort study. AB - INTRODUCTION: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. Given the paucity of recent Canadian data, we estimated the mortality rate associated with S. aureus bacteremia in a tertiary care hospital and identified risk factors associated with mortality. METHODS: We retrospectively reviewed the records of adults with S. aureus bacteremia admitted to a tertiary care centre in southwestern Ontario between 2008 and 2012. Cox regression analysis was used to evaluate associations between predictor variables and all-cause, in-hospital, and 90-day postdischarge mortality. RESULTS: Of the 925 patients involved in the study, 196 (21.2%) died in hospital and 62 (6.7%) died within 90 days after discharge. Risk factors associated with in-hospital and all-cause mortality included age, sepsis (adjusted hazard ratio [adjusted HR] 1.49, 95% confidence interval [CI] 1.08-2.06, p = 0.02), admission to the intensive care unit (adjusted HR 3.78, 95% CI 2.85-5.02, p < 0.0001), hepatic failure (adjusted HR 3.36, 95% CI 1.91-5.90, p < 0.0001) and metastatic cancer (adjusted HR 2.58, 95% CI 1.77-3.75, p < 0.0001). Methicillin resistance, hepatic failure, cerebrovascular disease, chronic obstructive pulmonary disease and metastatic cancer were associated with postdischarge mortality. INTERPRETATION: The all-cause mortality rate in our cohort was 27.9%. Identification of predictors of mortality may guide empiric therapy and provide prognostic clarity for patients with S. aureus bacteremia. PMID- 25553329 TI - Relapse Model among Iranian Drug Users: A Qualitative Study. AB - BACKGROUND: Relapse is a common problem in drug user's rehabilitation program and reported in all over the country. An in-depth study on patients' experiences can be used for exploring the relapse process among drug users. Therefore, this study suggests a model for relapse process among Iranian drug users. METHODS: In this qualitative study with grounded theory approach, 22 participants with rich information about the phenomenon under the study were selected using purposive, snowball and theoretical sampling methods. After obtaining the informed consent, data were collected based on face-to-face, in-depth, semi-structured interviews. All interviews were analyzed in three stages of axial, selective and open coding methods. RESULTS: Nine main categories emerged, including avoiding of drugs, concerns about being accepted, family atmosphere, social conditions, mental challenge, self-management, self-deception, use and remorse and a main category, feeling of loss as the core variable. Mental challenge has two subcategories, evoking pleasure and craving. Relapse model is a dynamic and systematic process including from cycles of drug avoidance to remorse with a core variable as feeling of loss. CONCLUSION: Relapse process is a dynamic and systematic process that needs an effective control. Determining a relapse model as a clear process could be helpful in clinical sessions. RESULTS of this research have depicted relapse process among Iranian drugs user by conceptual model. PMID- 25553330 TI - Effect of home visit training program on growth and development of preterm infants: a double blind randomized controlled trial. AB - BACKGROUND: Home visit program can be effective in infants' growth and development. The present study aimed to investigate the effect of home visit program on preterm infants' growth and development within 6 months. METHODS: It was a double-blind clinical trial study. The study was conducted in Hafez, Hazrat e-Zeinab, and Namazee Hospitals affiliated to Shiraz University of Medical Sciences, Shiraz, Iran from 2010 to 2011. Preterm infants were divided into intervention (n=30) and control groups (n=30) through blocked randomization. The intervention group received home visit training program for 6 months, while the control group only received the hospital's routine care. Then, the infants' growth indexes, including weight, height, and head circumference, and development criteria were compared on the first day of admission in Neonatal Intensive Care Unit, and then first, second, third, and sixth months. The data were analyzed using Chi-square, independent t-test, and repeated measures ANCOVA. RESULTS: The mean weight of the intervention and control group infants was 7207.3+/-1129.74 and 6366.7+/-922.26 gr in the sixth month. Besides, the intervention group infants' mean weight was higher compared to the control group after six months (t=-3.05, P=0.03). Also, a significant difference was found between the two groups regarding development indexes, such as following moving objects with the head, keeping the head stable when changing the position from lying to sitting, producing "Agha" sound, and taking objects by hand (P<0.05) during six months of age. CONCLUSION: The results showed that the home visit program was effective in preterm infants' weight gain and some development indexes at the sixth month. Considering the importance of infants' growth and development, healthcare staff is recommended to incorporate home visit training into their programs, so that steps can be taken towards improvement of preterm infants' health. TRIAL REGISTRATION NUMBER: IRCT2014082013690N3 PMID- 25553331 TI - Relationship between Awareness of Disease and Adherence to Therapeutic Regimen among Cardiac Patients. AB - BACKGROUND: Adherence to prescribed therapeutic regimen is an important element of self-care behaviors in cardiac patients. Awareness of disease may play an important role in patient adherence. Thus, this study was conducted to examine the relationship between awareness of the disease and adherence to therapeutic regimen among cardiac patients admitted to selected hospitals in Mashhad, Iran. METHODS: Using a descriptive correlational design, 340 patients with heart disease were selected using convenience sampling from five hospitals in Mashhad during December 2009 to May 2010. Data were collected using three questionnaires including demographic information, awareness of disease and treatment adherence (including medication, diet and physical activity). Validity and reliability of the questionnaires were examined by content validity and test-retest, respectively. Also, inter-rater reliability was examined for two data raters. Data were analyzed by SPSS software, using Spearman and Kruskal-Wallis tests. RESULTS: The results showed that only 15 percent of the study subjects had a good awareness of their disease. The majority of patients followed a good medication adherence (79 %), good diet adherence (60%), and weak physical activity adherence (61%). A significant correlation was found between knowledge and adherence to therapeutic regimen (P=0.001, rp=0.32). CONCLUSION: This study showed that awareness of disease and adherence to physical activity was low in the majority of patients. It is recommended that studies should be conducted to explore effective educational programs and strategies to improve adherence to therapeutic regimen among cardiac patients. PMID- 25553332 TI - The effects of laughter therapy on general health of elderly people referring to jahandidegan community center in shiraz, iran, 2014: a randomized controlled trial. AB - BACKGROUND: Aging and its social-biological process naturally impair the functions of different body organs and cause progressive disabilities in managing personal affairs and performing social roles. Laughter therapy is an important strategy which has been recommended by experts for increasing health promotion in older adults. Therefore, we aimed to investigate the effect of laughter therapy program on public health of senior citizens. METHODS: In a randomized controlled trial, we enrolled 72 senior citizens aged 60 and over referring to Jahandidegan (Khold-e-Barin) retirement community center in Shiraz, southwest Iran during January to February 2014. The participants were assigned into experimental (N=36) and control (N=36) groups. Data were collected using General Health Questionnaire (GHQ-28) and demographic questionnaire. The participants of experimental group attended a laughter therapy program consisting of two 90-minute sessions per week lasting for 6 weeks. RESULTS: We found a statistically significant correlation between laughter therapy program and factors such as general health (P=0.001), somatic symptoms (P=0.001), insomnia and anxiety (P=0.001). However, there was no statistically significant correlation among laughter therapy, social dysfunction (P=0.28) and depression (P=0.069). CONCLUSION: We concluded that laughter therapy can improve general health and its subscales in elderly people. TRIAL REGISTRATION NUMBER: IRCT2014061111691N4. PMID- 25553333 TI - Vaginal Delivery vs. Cesarean Section: A Focused Ethnographic Study of Women's Perceptions in The North of Iran. AB - BACKGROUND: Cesarean section (C-section) in the North of Iran accounts for 70% of childbirths, which is higher than the national average of 55%. Understanding women's perceptions towards modes of delivery in different cultures can pave the way for promoting programs and policies in support of vaginal delivery. We aimed to investigate women's perceptions towards modes of delivery in the North of Iran. METHODS: Using a focused ethnographic approach and purposive sampling, 12 pregnant women, 10 women with childbirth experience, nine non-pregnant women, seven midwives, and seven gynecologists were selected from hospitals, healthcare centers, and clinics of Tonekabon and Chaloos, Mazandaran, Iran, during 2012 2014. Data were collected through in-depth interviews and participant observation. Data analysis was performed using thematic analysis using MAXqda software. RESULTS: Two major themes emerged from the data including: "vaginal delivery, a facilitator of women's physical and mental health promotion", and "C section, a surgical intervention associated with decreased labor pain". Six sub themes subsumed within these major themes were: vaginal delivery as a safe mode of delivery, fullfilment of maternal instinct, a natural process with a pleasant ending, and C-section as a procedure associated with future complications, a surgical intervention and sometimes a life saving procedure, and a painless mode of delivery. CONCLUSION: In the North of Iran, women's justified cultural beliefs overshadow their micsconceptions, so it is hopped that through implementing appropriate training programs for raising awarness and correcting miscomceptions, vaginal delivery could be promoted even in regions with high rates of cesarean section. PMID- 25553334 TI - The effect of maternal relaxation training on reactivity of non-stress test, Basal fetal heart rate, and number of fetal heart accelerations: a randomized controlled trial. AB - BACKGROUND: Relaxation-training, as an anxiety-reducer intervention, plays an important role in fetal health. The present study aimed to analyze the effect of maternal relaxation on stress test (NST), basal fetal heart rate, and number of fetal heart accelerations. METHODS: In this randomized controlled trial, 84 pregnant women were randomly divided into two groups of teaching relaxation and control groups in 2012. In the intervention group, 60-90 minute classes were held every week lasting for 4 weeks. Besides, home practice charts were given to the mothers and researchers controlled the home practices by phone calls every week. The control group received routine prenatal care. In the 4(th) week, NST was performed in the intervention group 30 minutes before and after the 4(th) session. In the control group, NST was done in the 4(th) week. The quantitative variables in the two groups were compared through ANOVA and Chi-square test. RESULTS: The results of paired t-test showed that relaxation could improve the NST results (P=0.01). Mean and standard deviation of basal fetal heart rate was 138.95+/-8.18 before the intervention and 133.07+/-6.9 after the intervention. Paired t-test also showed that relaxation reduced the basal fetal heart rate (P=0.001). Mean and standard deviation of the number of fetal heart accelerations was 1.5+/-0.8 before the intervention and 2.2+/-0.9 after it. The results of paired t-test also showed that relaxation increased the number of fetal heart accelerations (P=0.001). CONCLUSIONS: Relaxation could improve the NST results, reduce the basal fetal heart rate, and increase the number of fetal heart accelerations. Therefore, relaxation is recommended during pregnancy. TRIAL REGISTRATION NUMBER: IRCT2012072810418N1. PMID- 25553335 TI - General Health in the Elderly and Younger Adults of Rural areas in Fars Province, Iran. AB - BACKGROUND: There are critical gaps in assessment and research on health among the elderly living in rural communities. The state of aging and health in rural areas provides a snapshot of our older adults's need to necessary public health measures .The aim of this study was to determine the self-rated general health of adults residing in rural areas and compare the general health of the elderly with younger adults. METHODS: In this population based study using multistage random sampling, 2259 adults aged (>=15 years old) were selected from rural areas of Shiraz, southern Iran. The participants were divided into three age groups: young adults (15-39 years old n=1574), middle aged adults (40-59 years old, n=530), and the elderly (>=60 years of age, n-155). Data were gathered using a translated version of the general health questionnaire (GHQ-28) and analyzed using Chi square, one-way ANOVA, Kruskal-Wallis tests and ANCOVA analysis. SPSS software, version 16, was used for analysis. RESULTS: 34.8%, 31.6%, 52.3% and 7.7% of the elderly had a probable mental disorder in the somatization, anxiety, social dysfunction and depression categories, respectively. Moreover, 9.7, 7.1, 3.9 and 4.5% of the elderly had a severe mental disorder in the four mentioned subscales, respectively. Compared with younger adults, the elderly showed a significantly higher disorder in all subscales except for anxiety. CONCLUSION: Our findings showed that chronic disease had a great effect on general health. Screening programs and prevention of chronic disease by the newly established family physician in rural districts can improve the overall community health. PMID- 25553336 TI - Effect of coping strategies training on its use by thalassemia major adolescents: a randomized controlled clinical trial. AB - BACKGROUND: Thalassemia is a chronic disease with serious clinical and psychological challenges. The incidence of thalassemia in a family member may cause a psychological crisis in all family members and in this case coping strategies are required. This clinical trial study aimed to determine the impact of training coping strategies on their use by major thalassemic adolescents referred to Dastgheib Hospital in Shiraz. METHODS: In this randomized clinical trial, 87 adolescents with major thalassemia who were randomly assigned to two groups of experiment and control were enrolled. Then the experiment group attended six sessions of coping strategies training program in isolation, each lasting for one and half hour. In order to examine the coping strategies, Jalowice's coping strategy questionnaire was used in three periods including pre intervention period and one month and two months after the intervention. The collected data were analyzed using independent t-test and Chi-square. RESULTS: Mean scores of problem-focused coping strategies in the experiment group increased in one month and two months after the intervention from 45+/-12.7 to 54.8+/-7.3 and 55.7+/-7.2, respectively. Also, the difference in mean scores of problem-focused coping strategies was significant in the two groups (P<0.001). Furthermore, the difference in mean scores of emotion-focused coping strategies was significantly different between the two groups in two months after the intervention (P=0.007). CONCLUSION: Based on the obtained results, teaching coping strategies has improved the use of problem-focused coping strategies and also effective coping with stress and disease problems in patients with thalassemia major. Therefore, it is recommended that authorities should consider this as a part of treatment program. TRIAL REGISTRATION NUMBER: IRCT2013112215484N1. PMID- 25553338 TI - Repeatability and Sample Size Assessment Associated with Computed Tomography Based Lung Density Metrics. AB - RATIONALE AND OBJECTIVES: Density-based metrics assess severity of lung disease but vary with lung inflation and method of scanning. The aim of this study was to evaluate the repeatability of single center, CT-based density metrics of the lung in a normal population and assess study sample sizes needed to detect meaningful changes in lung density metrics when scan parameters and volumes are tightly controlled. MATERIALS AND METHODS: Thirty-seven subjects (normal smokers and non smokers) gave consent to have randomly assigned repeated, breath-held scans at either inspiration (90% vital capacity: TLC) or expiration (20% vital capacity: FRC). Repeated scans were analyzed for: mean lung density (MLD), 15th percentile point of the density histogram (P15), low attenuation areas (LAA) and alpha (fractal measure of hole size distribution). Using inter-subject differences and previously reported bias, sample size was estimated from month or yearly change in density metrics obtained from published literature (i.e. meaningful change). RESULTS: Inter-scan difference measurements were small for density metrics (ICC > 0.80) and average ICCs for whole lung alpha-910 and alpha-950 were 0.57 and 0.64, respectively. Power analyses demonstrated that, under the control conditions with minimal extrinsic variation, population sizes needed to detect meaningful changes in density measures for TLC or FRC repeated scans ranged from a few (20-40) to a few hundred subjects, respectively. CONCLUSION: A meaningful sample size was predicted from this study using volume-controlled normal subjects in a controlled imaging environment. Under proper breath-hold conditions, high repeatability was obtained in cohorts of normal smokers and non-smokers. PMID- 25553337 TI - Neurophotonics applications to motor cortex research. AB - Neurophotonics methods offer powerful ways to access neuronal signals and circuits. We highlight recent advances and current themes in this area, emphasizing tools for mapping, monitoring, and manipulating excitatory projection neurons and their synaptic circuits in mouse motor cortex. PMID- 25553339 TI - Deep Learning for Cerebellar Ataxia Classification and Functional Score Regression. AB - Cerebellar ataxia is a progressive neuro-degenerative disease that has multiple genetic versions, each with a characteristic pattern of anatomical degeneration that yields distinctive motor and cognitive problems. Studying this pattern of degeneration can help with the diagnosis of disease subtypes, evaluation of disease stage, and treatment planning. In this work, we propose a learning framework using MR image data for discriminating a set of cerebellar ataxia types and predicting a disease related functional score. We address the difficulty in analyzing high-dimensional image data with limited training subjects by: 1) training weak classifiers/regressors on a set of image subdomains separately, and combining the weak classifier/regressor outputs to make the decision; 2) perturbing the image subdomain to increase the training samples; 3) using a deep learning technique called the stacked auto-encoder to develop highly representative feature vectors of the input data. Experiments show that our approach can reliably classify between one of four categories (healthy control and three types of ataxia), and predict the functional staging score for ataxia. PMID- 25553340 TI - Symmetric diarylsulfoxides as asymmetric sulfinylating reagents for dialkylmagnesium compounds. AB - At -78 degrees C, primary dialkylmagnesium compounds reacted with diarylsulfoxides when 1.5 equiv of the dilithium salt of (S)-BINOL was added as a promotor. Alkyl aryl sulfoxides resulted in up to quantitative yield and with up to 97% ee. This demonstrates the feasibility of asymmetric sulfinylations by achiral sulfinylating agents (from the perspective of Alkyl2Mg) as well as the feasibility of asymmetric sulfoxide-magnesium exchanges (from the perspective of Ar2SO). PMID- 25553341 TI - When the mask falls: the role of facial motor resonance in memory for emotional language. AB - The recognition and interpretation of emotional information (e.g., about happiness) has been shown to elicit, amongst other bodily reactions, spontaneous facial expressions occurring in accordance to the relevant emotion (e.g. a smile). Theories of embodied cognition act on the assumption that such embodied simulations are not only an accessorial, but a crucial factor in the processing of emotional information. While several studies have confirmed the importance of facial motor resonance during the initial recognition of emotional information, its role at later stages of processing, such as during memory for emotional content, remains unexplored. The present study bridges this gap by exploring the impact of facial motor resonance on the retrieval of emotional stimuli. In a novel approach, the specific effects of embodied simulations were investigated at different stages of emotional memory processing (during encoding and/or retrieval). Eighty participants underwent a memory task involving emotional and neutral words consisting of an encoding and retrieval phase. Depending on the experimental condition, facial muscles were blocked by a hardening facial mask either during encoding, during retrieval, during both encoding and retrieval, or were left free to resonate (control). The results demonstrate that not only initial recognition but also memory of emotional items benefits from embodied simulations occurring during their encoding and retrieval. PMID- 25553342 TI - Handedness in a virtual haptic environment: assessments from kinematic behavior and modeling. AB - This study evaluated hand asymmetries in performance of a dexterous, controlled task under haptic feedback. Participants punctured a virtual membrane with a pushing or pulling movement, using the left or right hand. For pulling movements, the dominant (right) hand exhibited faster average stopping latency and shorter skidding distance. When the kinematic data were fit to a three-phase model previously applied to this task (Klatzky et al., 2013), the right hand exhibited faster force decay attributable to biomechanical factors. Analyses of the aggregated performance measures and model parameters showed that the left and right hands are associated with two different distributions, supporting handedness effects. Furthermore, while the majority of participants expressed right-hand dominance, which was consistent with their self-reported hand preferences, others showed partial or no dominance. This approach could potentially be extended to quantify and differentiate individuals with difficulties in manual behavior due to abnormal motor control (e.g., dyspraxia), progressive deterioration (e.g., Parkinson's syndrome) or improvement (neural regrowth after transplant). PMID- 25553343 TI - Bridging music and speech rhythm: rhythmic priming and audio-motor training affect speech perception. AB - Following findings that musical rhythmic priming enhances subsequent speech perception, we investigated whether rhythmic priming for spoken sentences can enhance phonological processing - the building blocks of speech - and whether audio-motor training enhances this effect. Participants heard a metrical prime followed by a sentence (with a matching/mismatching prosodic structure), for which they performed a phoneme detection task. Behavioural (RT) data was collected from two groups: one who received audio-motor training, and one who did not. We hypothesised that 1) phonological processing would be enhanced in matching conditions, and 2) audio-motor training with the musical rhythms would enhance this effect. Indeed, providing a matching rhythmic prime context resulted in faster phoneme detection, thus revealing a cross-domain effect of musical rhythm on phonological processing. In addition, our results indicate that rhythmic audio-motor training enhances this priming effect. These results have important implications for rhythm-based speech therapies, and suggest that metrical rhythm in music and speech may rely on shared temporal processing brain resources. PMID- 25553344 TI - Functional plasticity of sensorimotor representations following short-term immobilization of the dominant versus non-dominant hands. AB - The main purpose of the present study was to investigate the functional plasticity of sensorimotor representations for dominant versus non-dominant hands following short-term upper-limb sensorimotor deprivation. All participants were right-handed. A splint was placed either on the right hand or on the left hand of the participants during a brief period of 48 h and was used for the input/output signal restrictions. The participants were divided into 3 groups: right hand immobilization, left hand immobilization and control (without immobilization). The immobilized participants performed the hand laterality task before (pre-test) and immediately after (post-test) splint removal. The pre-/post-test procedure was similar for the control group. The main results showed a significant response time improvement when judging the laterality of hand stimuli in the control group. In contrast, the results showed a weaker response time improvement for the left-hand immobilization group and no significant improvement for the right-hand immobilization group. Overall, these results revealed that immobilization-induced effects were lower for the non-dominant hand and also suggested that 48 h of upper-limb immobilization led to an inter-limb transfer phenomenon regardless of the immobilized hand. The immobilization-induced effects were highlighted by the slowdown of the sensorimotor processes related to manual actions, probably due to an alteration in a general cognitive representation of hand movements. PMID- 25553345 TI - Short-chain chlorinated paraffins in terrestrial bird species inhabiting an e waste recycling site in South China. AB - Short-chain chlorinated paraffins (SCCPs) are under review by the Stockholm Convention on Persistent Organic Pollutants. Currently, limited data are available about SCCPs in terrestrial organisms. In the present study, SCCP concentration in the muscles of seven terrestrial bird species (n = 38) inhabiting an e-waste recycling area in South China was determined. This concentration varied from 620 to 17,000 ng/g lipid. Resident birds accumulated significantly higher SCCP concentrations than migratory birds (p < 0.01). Trophic magnification was observed for migratory bird species but not for resident, which was attributed to high heterogeneity of SCCP in e-waste area. Two different homologue group patterns were observed in avian samples. The first pattern was found in five bird species dominated by C10 and C11 congeners, while the second was found in the remains, which show rather equal abundance of homologue groups. This may be caused by two sources of SCCPs (local and e-waste) in the study area. PMID- 25553346 TI - Acute and chronic toxicity of short chained perfluoroalkyl substances to Daphnia magna. AB - The aim of this study was to evaluate the aquatic toxicity of a C4-C6 chemistry based fluoroalkylated polymer and the perfluoroalkyl carboxylic acids, PFBA, PFHxA and PFOA to Daphnia magna. The acute toxicity decreased with decreasing carbon chain length, but the polymer did not show a dose related effect. In a chronic toxicity test performed with PFHxA, mortality was observed at similar concentrations as in the acute toxicity test, indicating that toxicity did not increase with increasing exposure time. Effects on mortality, reproduction and population growth rate occurred at similar concentrations, indicating no specific effect of PFHxA on sublethal endpoints. C4-C6 chemistry is thus less hazardous to daphnids than C7-C8 chemistry. Yet, these compounds are persistent, hard to remove from the environment and production volumes are increasing. PMID- 25553347 TI - Identification and characterisation of DfCHS, a chalcone synthase gene regulated by temperature and ultraviolet in Dryopteris fragrans. AB - Chalcone synthase (CHS) is an enzyme that catalyzes the first committed step in flavonoid biosynthesis, and its transcription level is regulated by light conditions. By using homology cloning and rapid amplification of cDNA ends, we cloned a chalcone synthase gene (DfCHS) from Dryopteris fragrans (L.) Schott. The full-length cDNA of DfCHS is 1,737 bp, with an open reading frame (ORF) of 1,122 bp (deposited in GenBank under Accession Number KF530802) encoding a predicted protein of 373 amino acids. The calculated molecular mass of DfCHS is 41.3 kDa. We studied the expression of DfCHS and total flavonoid contents in tissue culture seedlings cultured under the low temperature at 4oC, high temperature at 35oC and UV conditions, respectively. The results show that the expression of DfCHS are not the same, but all present rising trends, then flavonoid contents were increased. Overall, our results imply that the expression of DfCHS gene provide a certain theory basis in the status of evolution among ferns. PMID- 25553348 TI - Pluripotency properties of embryonic stem cells isolated from stage X blastoderm of Mazandaran native chicken. AB - The aim of this study was to isolate Embryonic Stem Cells (ESCs) from native chicken and to characterize their pluripotency properties through the cellular and molecular markers. Samples obtained from fertilized eggs from Mazandaran native hens. Cells were isolated from area of pellucida from stage X native hens' blastoderm. Then the cells were cultured on inactivated mouse SNL feeder cells in the presence of LIF, IGF-1, bFGF, CNTF, OSM, SCF, Il-6, and Il-11 growth factors. The native chickens' ESCs colonies were picked up and subsequently passaged. To characterize the cells, they were analyzed for their alkaline phosphatase activity, and also for the expression of SSEA-4, and TRA-1-60 as embryonic specific markers at the protein level. Furthermore, the expression of pluripotency (cPouV, Sox2, and Nanog) and cell lineage specific (Cvh, Brachyury, and Gata6) gene markers was evaluated at the level of mRNA using quantitative RT PCR. Isolated cells were passaged repeatedly and successfully up to ten passages. The stemness of embryonic cells has been approved by the activity of the alkaline phosphatase, presence of the SSEA-4, and TRA-1-60 protein, and expression of the molecular marker (cPouV, Nanog, and Sox-2) genes. The spontaneous differentiation of chicken ESCs confirmed the pluripotecy of the cells in differentiation into specialized cell lineages. Our observation showed that ESCs can be isolated successfully from stage X blastoderm of Mazandaran native chickens and these cells maintain their stemness properties during multi-passages in vitro. PMID- 25553349 TI - Short communication: Ischemia increases cortical Na+,K+-ATPase activity (K-Pase) in a model of kidney auto-transplantation in the large white pig. AB - Acute renal failure (ARF) induced by Ischemia-Reperfusion (I-R) is associated with a significant impairment of tubular sodium reabsorption. Na+,K+-ATPase has a crucial role in tubular sodium reabsorption and maintenance of water and ion homeostasis. In this study, we examined whether renal I-R affects Na+,K+-ATPase activity in a renal auto graft model (Large White Pig) with controlateral nephrectomy. Kidney samples were obtained from medulla (n = 4) and cortex (n = 3) after one hour of warm ischemia in autotransplanted models. These experimental groups were compared with a controlateral nephrectomy group (Control). Na+,K+ ATPase activity in purified membrane fractions was measured as ouabain-sensitive K+ -stimulated paranitrophenyl phosphatase (pNPPase) activity. The Na+,K+-ATPase activities of control, ischemia and ischemia -reperfusion were significantly higher in the medulla than in the cortex, irrespective of the experimental group (P<0.05). In cortices, Na+,K+-ATPase activity increased significantly (P<0.05) by 35% after ischemia compared to control group. In medullae, there was only a trend toward an activation of Na+,K+-ATPase activity after Ischemia (increased by 25%) and after Ischemia-Reperfusion (increased by 30%) compared to control group, and these differences did not reach statistical significance. These data suggest that renal ischemia induces a significant alteration of Na+,K+-ATPase by increasing its ouabain-sensitive K+-stimulated paranitrophenyl phosphatase (pNPPase) activity in isolated membrane from cortical renal tissues after one hour of ischemia. This change of activity seems to be a new regulation mechanism of an important membrane ion transporter during renal I-R in the large pig model of renal transplantation. PMID- 25553350 TI - The relationship of CASP 8 polymorphism and cancer susceptibility: a meta analysis. AB - Caspase-8 (CASP8), member of the caspase cysteine protease family, plays an important role in cancer development. CASP8 D302H (rs1045485) (D, Aspartate; H, Histidine) and CASP8 -652 6N del (rs3834129) polymorphisms have been reported to be associated with Cancer susceptibility. However, there are many controversies on this issue. Therefore we performed this meta-analysis with 32 publications, which include 25800 case and 31964 control subjects for CASP8 -652 6N del polymorphism, and 36883 cases and 41089 controls for D302H polymorphism. The results demonstrated that the -652 6N del frequency showed significant difference between case and control group (del versus ins: OR=0.92; 95% CI: 0.90-0.95, p<0.00001). Homozygous, dominant and recessive genotypes were significantly associated with cancer risks. For D302H polymorphism, data indicated the association of allele C with decreased cancer risk (Overall, C versus G: OR=0.93; 95% CI: 0.86-0.99, p=0.03). All genetic models also indicated the significant association with cancer risk especially in Asian population. Further subgroup analysis indicated that CASP8 -652 6N del polymorphism was associated with breast cancer, lung and gastrointestinal cancer susceptibility. CASP8 D302H was found to be only associated with breast cancer risk. Therefore, these two CASP8 variations could be regarded as potential biomarkers for cancer risk. PMID- 25553351 TI - Oridonin inhibits tumor growth in glioma by inducing cell cycle arrest and apoptosis. AB - Glioma is the most common malignant intracranial tumors. Despite newly developed therapies, these treatments mainly target oncogenic signals, and unfortunately, fail to provide enough survival benefit in both human patients and mouse xenograft models, especially the first-generation therapies. Oridonin is purified from the Chinese herb Rabdosia rubescens and considered to exert extensive anti cancer effects on human tumorigenesis. In this study, we systemically investigated the role of Oridonin in tumor growth and the underlying mechanisms in human glioma. We found that Oridonin inhibited cell proliferations in a dose- and time-dependent manner in both glioma U87 and U251 cells. Moreover, these anti cancer effects were also confirmed in a mouse model bearing glioma. Furthermore, cell cycle arrest in S phase was observed in Oridonin-mediated growth inhibition by flow cytometry. Cell cycle arrest in S phase led to eventual cell apoptosis, as revealed by Hoechst 33342 staining and annexin V/PI double-staining. The cell apoptosis might be accomplished through a mitochondrial manner. In all, we were the first to our knowledge to report that Oridonin could exert anti-cancer effects on tumor growth in human glioma by inducing cell cycle arrest and eventual cell apoptosis. The identification of Oridonin as a critical mediator of glioma growth may potentiate Oridonin as a novel therapeutic strategies in glioma treatments. PMID- 25553352 TI - Intraoperative findings, placental assessment and neonatal outcome in emergent cesarean deliveries for non-reassuring fetal heart rate. AB - OBJECTIVE: To correlate between intraoperative findings, placental histopathology and neonatal outcome in emergent cesarean deliveries (ECD) for non-reassuring fetal heart rate (NRFHR). STUDY DESIGN: Data on ECD for NRFHR were reviewed for labor, documented intraoperative findings, neonatal outcome parameters and placental histopathology reports. Results were compared between those with and without intraoperative findings. Placental lesions were classified to those related to maternal underperfusion or fetal thrombo-occlusive disease, and those related to maternal (MIR) and fetal (FIR) inflammatory responses. Neonatal outcome consisted of low Apgar score (<=7 at 5 min), cord blood pH<7.0, and evidence of respiratory distress, necrotizing enterocolitis, sepsis, transfusion, ventilation, seizure, hypoxic-ischemic encephalopathy, phototherapy, or death. RESULTS: Intraoperative findings were observed in 49.5% of 543 women, mostly cord complications (77%). Placental lesions were more common in those without intraoperative findings as compared to those with intraoperative findings: placental lesions related to maternal under-perfusion, vascular lesions, 9.1% vs. 4.1%, p=0.024, and villous changes, 39.2% vs. 30.7%, p=0.047, lesions consistent with fetal thrombo-occlusive disease, 13.6% vs. 7.4%, p=0.024, and inflammatory lesions, MIR and FIR, p=0.033, p=0.001, respectively. By using multivariate logistic regression analysis, adverse neonatal outcome was found to be dependent on maternal age, gestational age, preeclampsia placental weight <10th%, and MIR. CONCLUSION: NRFHR necessitating ECD may originate from different underlying mechanisms. In about half, the insult is probably acute and can be identified intraoperatively. In the remaining half, underlying placental compromise may be involved. PMID- 25553355 TI - Changes in latent fingerprint examiners' markup between analysis and comparison. AB - After the initial analysis of a latent print, an examiner will sometimes revise the assessment during comparison with an exemplar. Changes between analysis and comparison may indicate that the initial analysis of the latent was inadequate, or that confirmation bias may have affected the comparison. 170 volunteer latent print examiners, each randomly assigned 22 pairs of prints from a pool of 320 total pairs, provided detailed markup documenting their interpretations of the prints and the bases for their comparison conclusions. We describe changes in value assessments and markup of features and clarity. When examiners individualized, they almost always added or deleted minutiae (90.3% of individualizations); every examiner revised at least some markups. For inconclusive and exclusion determinations, changes were less common, and features were added more frequently when the image pair was mated (same source). Even when individualizations were based on eight or fewer corresponding minutiae, in most cases some of those minutiae had been added during comparison. One erroneous individualization was observed: the markup changes were notably extreme, and almost all of the corresponding minutiae had been added during comparison. Latents assessed to be of value for exclusion only (VEO) during analysis were often individualized when compared to a mated exemplar (26%); in our previous work, where examiners were not required to provide markup of features, VEO individualizations were much less common (1.8%). PMID- 25553353 TI - The effect of tubal sterilization with the Pomeroy technique and bipolar electrocauterization on the ovarian reserve and serum anti-Mullerian hormone levels in a rat model. AB - OBJECTIVE: To investigate the effects of tubal sterilization techniques on the ovarian reserve and serum anti-Mullerian hormone (AMH) levels in rats. STUDY DESIGN: Wistar Hannover rats (n=21) were assigned to the following 3 groups (7 rats/group): Pomeroy technique, bipolar electrocauterization, and control. Pre- and postoperative serum AMH levels, ovarian damage and ovarian follicle counts were assessed. RESULTS: Total ovarian damage was higher in the electrocauterization group than in the Pomeroy (p=0.008) and control (p<0.0001) groups. The large antral follicle count was higher in the Pomeroy group than in the electrocauterization (p=0.023) and control (p=0.003) groups. The electrocauterization group had a greater decrease in postoperative serum AMH levels than the Pomeroy and control groups (p=0.031). CONCLUSION: Bipolar electrocauterization may have a negative effect on the ovarian structure and ovarian reserve compared to the Pomeroy technique. PMID- 25553356 TI - Firing distance estimation based on the analysis of GSR distribution on the target surface using ICP-MS--an experimental study with a 7.65 mm * 17 mm Browning pistol (.32 ACP). AB - An experimental study aiming to estimate the firing distance was conducted using a 7.65 mm * 17 mm Browning (.32ACP) pistol. Briefly, test shots were made against a target of cotton tissue (35 cm * 35 cm), and the amounts of antimony (Sb), barium (Ba), and lead (Pb) deposited in quadrangular pieces (1 cm * 1 cm) of the target cut from four radial positions at increasing distances from the bullet entrance hole ("samples") were determined by inductively coupled plasma-mass spectrometry (ICP-MS). The data obtained were used to search for a mathematical model for estimating the firing distance. The best model was a simple linear correlation between FD (the firing distance) and ln c (where c is the content of Sb, Ba or Pb in the samples, expressed in MUg/g of target tissue). Best results were obtained with samples collected at radial distances within 2.0-3.0 cm from the bullet entrance hole. Using this approach, it was possible to accurately (+/ 6 cm) estimate the firing distance in the interval [20-90] cm from the target. PMID- 25553357 TI - A leave-one-out cross-validation SAS macro for the identification of markers associated with survival. AB - A proper internal validation is necessary for the development of a reliable and reproducible prognostic model for external validation. Variable selection is an important step for building prognostic models. However, not many existing approaches couple the ability to specify the number of covariates in the model with a cross-validation algorithm. We describe a user-friendly SAS macro that implements a score selection method and a leave-one-out cross-validation approach. We discuss the method and applications behind this algorithm, as well as details of the SAS macro. PMID- 25553358 TI - Numerical study of stenotic side branch hemodynamics in true bifurcation lesions. AB - Coronary bifurcation lesions are complex. Whether a critical condition exists in the stenotic side branch (SB) of bifurcation lesions, according to the Medina classification, is unassessed. Computational models of coronary bifurcations were developed with different stenosis severities and locations, in order to study the flow distribution and wall shear stress (WSS) in the SB. It was found that bifurcation lesion type (1,0,1) had a flow ratio of 0.25, much less than the corresponding normal ratio of 0.47, and the 0.46 and 0.39 ratios computed for lesion types (0,1,1) and (1,1,1), respectively. Bifurcation type (1,0,1) was associated with a 47% reduction from normal coronary flow, resulting in coronary branch steal. Blood flow to the SB decreased as the stenosis severity increased and approached the carina, in the proximal, distal, and side branches. Similarly, WSS values decreased with increasing stenosis severity. Bifurcation type (1,0,1) had the lowest WSS values in the SB, and were below the 0.5Pa threshold for atherosclerotic growth. In conclusion, the results suggest that lesion type (1,0,1) is at the greatest risk of coronary branch steal, leading to potential ischemia, as well as further atherosclerotic growth. This is counterintuitive to the Medina classification, where bifurcation type (1,1,1) is usually considered the most severe. PMID- 25553359 TI - Serotonergic modulation of spinal motor control. AB - Serotonin (5-HT) is a monoamine that powerfully modulates spinal motor control by acting on intrasynaptic and extrasynaptic receptors. Here we review the diversity of 5-HT actions on locomotor and motoneuronal activities. Two approaches have been used on in vitro spinal cord preparations: either applying 5-HT in the extracellular medium or inducing its synaptic release. They produced strikingly different results suggesting that the net effect of 5-HT depends on the identity of the activated receptors and their location. Recent findings suggest that moderate release of 5-HT facilitates locomotion and promotes the excitability of motoneurons, while stronger release inhibits rhythmic activity and motoneuron firing. This latter effect is responsible for central fatigue and secures rotation of motor units. PMID- 25553360 TI - Chemiluminescent labels released from long spacer arm-functionalized magnetic particles: a novel strategy for ultrasensitive and highly selective detection of pathogen infections. AB - Previously, the unique advantages provided by chemiluminescence (CL) and magnetic particles (MPs) have resulted in the development of many useful nucleic acid detection methods. CL is highly sensitive, but when applied to MPs, its intensity is limited by the inner filter-like effect arising from excess dark MPs. Herein, we describe a modified strategy whereby CL labels are released from MPs to eliminate this negative effect. This approach relies on (1) the magnetic capture of target molecules on long spacer arm-functionalized magnetic particles (LSA MPs), (2) the conjugation of streptavidin-alkaline phosphatase (SA-AP) to biotinylated amplicons of target pathogens, (3) the release of CL labels (specifically, AP tags), and (4) the detection of the released labels. CL labels were released from LSA-MPs through LSA ultrasonication or DNA enzymolysis, which proved to be the superior method. In contrast to conventional MPs, LSA-MPs exhibited significantly improved CL detection, because of the introduction of LSA, which was made of water-soluble carboxymethylated beta-1,3-glucan. Detection of hepatitis B virus with this technique revealed a low detection limit of 50 fM, high selectivity, and excellent reproducibility. Thus, this approach may hold great potential for early stage clinical diagnosis of infectious diseases. PMID- 25553361 TI - The building process of the functional paraspeckle with long non-coding RNAs. AB - Nuclei of mammalian cells are highly organized and composed of distinct subnuclear structures termed nuclear bodies. Paraspeckles are subnuclear structures that form around the long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) together with numerous RNA-binding proteins, many of which contain an RNA-binding domain and a prion-like domain and are related to specific neurodegenerative diseases. Paraspeckle formation proceeds in conjunction with NEAT1 lncRNA biogenesis and involves the cooperation of multiple paraspeckle-localized RNA-binding proteins. NEAT1 lncRNA likely sequesters these RNA-binding proteins in paraspeckle structures, which act as molecular sponges at which the nucleoplasmic activities of the sequestered proteins are modulated. This review presents, firstly, current knowledge regarding factors involved in the formation and function of paraspeckles. Secondly, the intracellular functions of all identified paraspeckle proteins, which are potentially controlled through their sequestration in paraspeckles, are categorized. Thirdly, recently identified nuclear bodies containing putative architectural lncRNAs are described and similarities among the architectures of lncRNA-dependent nuclear bodies are discussed. PMID- 25553362 TI - Multimodal imaging in nonlesional medically intractable focal epilepsy. AB - Identification and localization of epileptogenic zone (EZ) is vital in patients with medically-intractable focal epilepsy, who may be candidates for potentially curative resective epilepsy surgery. Presence of a lesion on magnetic resonance imaging (MRI) influences both diagnostic classification and selection for surgery. However, the implications for MRI-negative cases are not well-defined for such patients. Most of these patients undergo invasive long-term Electroencephalography recordings before a final decision regarding resection is possible. Recent developments in structural and functional neuroimaging which include quali-quantitative MRI, Positron Emission Tomography, Single Photon Emission Computed Tomography, and functional MRI have significantly changed presurgical epilepsy evaluation. Source analysis based on electrophysiological information, using either EEG or magnetoencephalography are also promising in order to noninvasively localize the EZ and to guide surgery in medically intractable focal epilepsy patients that exhibit nonlesional MRI. This chapter aims to review the value of the combined use of structural and functional imaging techniques, and how this multimodal approach improves both selection of surgical candidates and post-operative outcomes in medically-intractable nonlesional focal epilepsy. PMID- 25553363 TI - HPV and CSC in HNSCC cisplatin resistance. AB - Cisplatin (DNA intercalator), a standard chemotherapy drug often used to treat head and neck squamous cellular carcinoma (HNSCC) has very low response rates in recurrent disease of HNSCC, this is a major clinical problem today. However, a valuable window to look in to the underlying molecular aspects of a favorable and unfavorable cisplatin response is offered by a distinct disease entity in HNSCC - HPV+ OPSCC. It responds far more favorably to cisplatin than non-HPV driven HNSCC. Another intriguing aspect of head and neck cancer biology is the emergence of the CD44+ cancer stem cell - the tumor initiating population that in all likelihood is the root cause of therapeutic resistance. The critical question is, are there any differences between the CD44+ CSC population of an HPV+ OPSCC and a non-HPV HNSCC? In this regard, the inverse relation between EGFR levels and HPV status in OPSCC may be a common thread that connects the better response rates of HPV+ OPSCC with the contribution of CD44+ stem cells of HNSCC to chemoresistance. PMID- 25553365 TI - Neuroprotective agents and modulation of temporal lobe epilepsy. AB - Temporal Lobe Epilepsy (TLE) is a chronic condition characterized by epileptic seizures originating mainly in temporal lobe areas. Epileptogenesis is a process in which a central nervous system injury can lead surviving neuronal populations to generate abnormal, synchronous and recurrent epileptiform discharges producing focal or generalized seizures. Hipocampal sclerosis, a massive cell death in the hippocampal formation and in the other regions of temporal lobe, is considered as hallmark of TLE. Despite the numerous antiepileptic drugs (AEDs) commercially available, about 30-40% of patients remain with seizures refractory to pharmacological treatment. In addition, there is no drug with significant efficacy to modify the epileptogenesis process. In this review we present some data regarding the neuroprotective effect of some adenosinergic agents, erythropoietin and carisbamate regarding the disease- and epileptogenesis modifying effect. PMID- 25553364 TI - Metabolomic analysis of plasma and liver from surplus arginine fed Atlantic salmon. AB - The aim of this study was to determine the metabolic effect of surplus arginine (36.1 g/kg dry matter) compared to a control diet with required arginine (21.1 g/kg dry matter) in adult Atlantic salmon (Salmo salar L.). Although the feeding trial had no significant effect on growth, there were significant differences in the metabolite profile in both plasma and liver in experimental group as compared to the control group. There was increased concentrations of biliverdin, PGF-2 alpha, oxidized glutathione, selenocysteine, two monoacylglycerols and a tripeptide in the liver as well as decreased concentrations of valine and a vitamin D3 metabolite in plasma of arginine supplemented fish. These results indicate that while surplus arginine does not affect growth or body weight, it induces metabolic changes in Atlantic salmon. PMID- 25553366 TI - Natural supplements for improving insulin sensitivity and glucose uptake in skeletal muscle. AB - Type 2 diabetes is a common metabolic disorder characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. In light of the staggering financial/human cost of type 2 diabetes, there is considerable need for safe and effective agents that can be used to prevent and/or adjunctively treat the disease. Available evidence suggests that a number of natural supplements, including cinnamon, biotin, fenugreek, ginseng, banaba, and alpha lipoic acid, have the potential to reduce the risk for type 2 diabetes in the large at-risk population. The evidence also suggests that, when used adjunctively, these natural products are likely to help clinicians achieve optimal glycemic control, improve long-term prognosis, and/or minimize the need for insulin therapy in type 2 diabetics. More research, particularly well designed, long-term human clinical trials, is certainly needed to accurately define the value and place of these supplements in diabetes prevention and management. PMID- 25553367 TI - ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy. AB - Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias. PMID- 25553369 TI - Recurrent glomerular disease in the kidney allograft. AB - Glomerulonephritis is responsible for nearly 15% of prevalent end-stage renal disease, and many of these patients will receive kidney transplants with the potential for a long duration of allograft survival. Recurrent glomerular disease, however, is not uncommon and can lead to both substantial morbidity and/or loss of the kidney allograft. The timing of recurrence after transplantation as well as the prevalence of recurrent disease vary by study, especially accounting for differences in protocol versus clinically-indicated biopsies, the use of immunofluorescence or electron microscopy in histopathological evaluation, and length of follow-up. Transplant immunosuppression alone may be sufficient to keep some recurrent disease in a subclinical form, whereas other recurrent glomerular diseases may be clinically evident and progress to threaten the allograft. This review highlights the epidemiology, diagnosis, and treatment of five common glomerular diseases that may recur in the transplant: focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A nephropathy (IgAN), and lupus nephritis (LN). PMID- 25553368 TI - Ischemia-reperfusion injury in kidney transplantation. AB - Ischemia-reperfusion injury to the kidney is a complex pathophysiological process that has importance during transplantation as it affects graft function and survival. It starts with the physiological changes associated with the death of the donor, including the direct effects of hypoxia and metabolic stress. The injury continues through the organ procurement and preservation procedures. Upon reperfusion, the organ is then further damaged by a reactive inflammatory process which had been primed during the earlier injuries. Clinically, the damage from microvascular dysfunction and cytotoxic agents contributed by the immunologic response results in impaired graft function or graft loss. Recent advances in understanding the specific pathways involved in this injury have helped identify novel therapies. Nevertheless, ischemia-reperfusion injury continues to be a daunting problem even as these treatment strategies are being evaluated for clinical use. PMID- 25553370 TI - Renal transplantation in amyloidosis and MIDD. AB - Amyloidosis and monoclonal immunoglobulin deposition disease, though rare entities, can wreak havoc on the architecture and functioning of the kidneys. These diseases have a predilection to cause severe renal dysfunction leading to end stage renal disease (ESRD). In recent years, the available treatments for these diseases have expanded and afflicted patients are living longer, but with advanced kidney disease. Because of the complex nature of the pathophysiology and treatment of these diseases, it can be very challenging for a clinician to determine whether or not it is appropriate to refer an affected individual for kidney transplantation. PMID- 25553371 TI - Evaluation of high-risk living kidney donors. AB - Careful evaluation of potential living kidney donors is crucial to assure the well being of the donors, especially because they do not gain any direct medical benefit from donation. This process also helps assess the quality and safety of the organs donated to the recipients. While all programs share these goals, donor selection criteria vary significantly among U.S. transplant centers. In part, this is due to the limited data that exists as to long-term outcomes among donors who are medically complex, or at higher risk for complications, such as those with hypertension, obesity, or lower kidney function. This article reviews available evidence regarding outcomes after living donation and current trends in U.S. practices, and seeks to provide practical guidance in evaluating high-risk potential living kidney donors. PMID- 25553372 TI - Nitric oxide, a new player in L-DOPA-induced dyskinesia? AB - L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, the long-term use of L-DOPA causes, in combination with disease progression, the development of motor complications termed L-DOPA-induced dyskinesia (LID). LID is the result of profound modifications in the functional organization of the basal ganglia circuitry. There is increasing evidence of the involvement of non-dopaminergic systems on the pathophysiology of LID. This raises the possibility of novel promising therapeutic approaches in the future, including agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in preclinical testing or clinical development. Herein, we summarize the current knowledge of the pharmacology of LID in PD. More importantly, this review attempts to highlight the role of nitric oxide (NO) in PD and provide a comprehensive picture of recent preclinical findings from our group and others showing its potential involvement in dyskinesia. PMID- 25553373 TI - Biomonitoring of human exposure to arylamines. AB - Extensive industrial use of arylamines started in the middle of the 19th century in the dye industry. Because of the high incidence of bladder cancer, arylamines belong to the first and most intensively studied occupational and environmental carcinogens. In workers, biomonitoring of exposure to arylamines including ortho toluidine started in the first half of the 20th century. This review highlights the many gaps in our knowledge on the human carcinogen ortho-toluidine. PMID- 25553374 TI - Understanding the functional discrepancy of Pim-1 in cancer. AB - The Pim-1 gene encodes for a proto-oncogenic serine/threonine protein kinase and is generally involved in cytokine signaling as well as in various signaling pathways regulating cell cycle and apoptosis. Pim-1 kinase plays a role in the development of various tumors mainly, prostate cancer, Burkitt's lymphoma, oral cancer and various other hematopoietic lymphomas. This review will focus on the importance and mechanisms of Pim-1 in prostate cancer and the potential clinical relevance of its various inhibitors. PMID- 25553375 TI - Current strategies and challenges in engineering a bioartificial kidney. AB - Renal replacement therapy was an early pioneer in both extra-corporeal organ replacement and whole organ transplantation. Today, the success of this pioneering work is directly demonstrated in the millions of patients worldwide successfully treated with dialysis and kidney transplantation. However, there remain significant shortcomings to current treatment modalities that limit clinical outcomes and quality of life. To address these problems, researchers have turned to using cell-based therapies for the development of a bioartificial kidney. These approaches aim to recapitulate the numerous functions of the healthy kidney including solute clearance, fluid homeostasis and metabolic and endocrine functions. This review will examine the state-of-the-art in kidney bioengineering by evaluating the various techniques currently being utilized to create a bioartificial kidney. These promising new technologies, however, still need to address key issues that may limit the widespread adoption of cell therapy including cell sourcing, organ scaffolding, and immune response. Additionally, while these new methods have shown success in animal models, it remains to be seen whether these techniques can be successfully adapted for clinical treatment in humans. PMID- 25553376 TI - The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder. AB - Although there has been much research into autism or autistic spectrum disorder (ASD), there is room for considerable conjecture regarding the etiology of these developmental brain disorders. ASD is marked by a complex interaction between environmental factors and genetic predisposition, including epistasis. This manuscript argues that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD. Recent findings from our group and others provide evidence for abnormal thiol metabolism, marked by significant alteration in the deposition of several trace heavy metal species. Together with these, we find differences in thiamine homeostasis in ASD patients, which can be corrected by supplementation. We hypothesize that altered thiol metabolism from heavy metal toxicity, one of the key mechanisms for oxidative stress production, may be responsible for the biochemical alterations in transketolase, dysautonomia and abnormal thiamine homeostasis. Although it is unknown why these particular metals accumulate, we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. We maintain mercury accumulation is evidence of altered clearance. Together with concomitant oxidative stress, these findings may offer an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Regardless of the exact cause, these factors may be more important to the etiology of this symptomatically diverse disease spectrum. Here, we offer insight into new avenues of exploration as well as the development of novel treatment approaches for these growing and devastating diseases. PMID- 25553378 TI - Andrographolide and analogues in cancer prevention. AB - Andrographis paniculata is a medicinal plant traditionally used for treatment of cough and cold, fever, laryngitis, and several infectious diseases. Extracts of A. paniculata have shown versatile potency against various diseases including cancer. The active biomolecules of A. paniculata mainly are lactone and diterpene. Andrographolide and analogues have been widely used for prevention of different diseases. Andrographolides have shown potent antiinflammatory and anticancer activities. It showed potentials as chemopreventive agents by suppressing growth of cancer cells by inhibiting NF-kappaB, PI3K/AKT and other kinase pathways and by inducing apoptosis. Andrographolide induced both intrinsic and extrinsic apoptosis pathway in different cancer cells via expression of different anti-apoptotic protein like Bax, p53, and activated caspases. Andrographolide was successfully used as an antineoplastic drug in cancer chemotherapy. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide and analogues need to be subjected to further clinical and biomedical studies in cancer chemoprevention. Andrographolide could be potent anticancer agent when used in combination with other chemotherapeutic agents. PMID- 25553377 TI - Riboflavin as adjuvant with cisplatin: study in mouse skin cancer model. AB - Cisplatin used in treatment of solid tumor induces oxidative stress which leads to hepatotoxicity and nephrotoxicity. New strategies are therefore needed to combat toxicity and optimize its therapeutic potential. Riboflavin (VitaminB2) under photoillumination works as an anti proliferative agent and induces apoptosis. These properties of riboflavin have been exploited to mitigate cisplatin induced toxicities. 9,10-dimethylbenz(a)anthracene /12-O tetradecanoylphorbol-13-acetate were used to induce skin tumor in Swiss albino mice. The tumor induced mice were treated with cisplatin, riboflavin as well as their combination under photo illumination. In comparison to tumor control group the cisplatin and riboflavin treated groups showed a compromised level of antioxidant enzymes, functional markers and a higher degree of lipid peroxidation. However these parameters tended towards normal in the combination treated group. The results from histopathology indicate that apoptosis was favored mode of cell death and that necrosis was reduced in combination treated groups. Our findings indicate that combination of cisplatin with riboflavin under photo illumination synergizes its anti cancer activity towards cancer cells and attenuates the cisplatin induced toxicities. PMID- 25553379 TI - N-acetylation of aromatic amines: implication for skin and immune cells. AB - Frequently, aromatic amine (AA) contact to the skin occurs via occupational or 'life style' exposure to hair dye intermediates and couplers, usually monocyclic p-phenylenediamines and meta-substituted aminophenols. The transport of AA from the outer surface to the systemic circulation predominantly follows the intracellular route. Skin tends to have relatively higher phase II compared to phase I xenobiotic metabolizing enzyme capacity, and levels are generally regarded as lower than those in liver. Inside skin cells AA are primarily N acetylated and detoxified by N-acetyltransferase 1. AA activation via hydroxylation or chemical oxidation competes with acetylation and is only of importance under circumstances when N-acetylation capacities are limited. The reactive AA derivatives are able to elicit effects by virtue of their modifications of skin proteins resulting in irritant or allergic contact dermatitis. Overall, the effective acetylation of topically applied AAs in skin cells emphasizes a protective role of cutaneous acetylation mediating a classical "first-pass" effect, which attenuates systemic exposure. PMID- 25553380 TI - Selective chromatid segregation mechanism for Bruchus wings piebald color. AB - The mechanisms of asymmetric organ development have been under intensive investigation for years, yet the proposed mechanisms remain controversial (1-3). The female Bruchus quadrimaculatus beetle insect develops two black-colored spots bilaterally located on each upper elytra wing by an unknown mechanism. Fifty percent of the P (for piebald, two colors) gene homozygous mutant insects, described in 1925, had a normal left elytrum (with two black spots) and an abnormal right elytrum (with two red spots) and the balance supported the converse lateralized pigment arrangement (4). Rather than supporting the conventional morphogen model for the wings pigmentation development, their biological origin is explained here with the somatic strand-specific epigenetic imprinting and selective sister chromatid segregation (SSIS) mechanism (5). We propose that the P gene product performs the selective sister chromatid segregation function to produce symmetric cell division of a specific cell during embryogenesis to result in the bilateral symmetric development of elytra black color spots and that the altered chromatid segregation pattern of the mutant causes asymmetric cell division to confer the piebald phenotype. PMID- 25553381 TI - Tumour-associated macrophage polarisation and re-education with immunotherapy. AB - Monocytes/macrophages constitute important contributors of cancer-associated inflammation. Through their plasticity and capacity to become polarised by tumours towards less activatory and more immunosuppressive (M2) phenotypes, tumour-associated macrophages (TAM) are thought to support tumour progression. Orchestrated by T helper 2 (Th2)-biased stimuli, macrophage recruitment, activation and polarisation in tumour microenvironments is associated with poorer clinical outcomes. Their key roles in supporting tumour progression and their capacity for plasticity have focused targeted and immunotherapeutic strategies to counteract macrophage pro-tumourigenic activities and to re-ignite their tumour cytotoxic power. Therapeutic approaches include blockade of macrophage recruitment into tumours, suppression of TAM survival, re-polarisation towards an M1-like phenotype and antibody therapies to enhance TAM anti-tumoural activities. Future immunotherapeutic directions may include monoclonal antibodies with enhanced effector functions. Antibodies of different classes, including those of the IgE class, shown to restrict tumour growth by harnessing monocyte/macrophage cytotoxic properties in pre-clinical cancer models, may synergise or re-educate these potent immune sentinels to destroy rather than support tumours. Opportunities for monitoring monocyte/macrophage polarisation or activatory signatures in patients may inform clinical management. PMID- 25553382 TI - Pathological functions of hypoxia in endometriosis. AB - Endometriosis is one of the most common gynecological diseases that significantly reduce the life quality of affected women. Research results from the past decade clearly demonstrated that aberrant production of estrogen and cyclooxygenase-2 derived prostaglandin E2 play indispensable roles in the pathogenesis of this disease. However, the etiology of endometriosis remains obscure. Recent evidence reveals a new facet of endometriotic pathogenesis by showing that hypoxia induces the expression of many important downstream genes to regulate the implantation, survival, and maintenance of ectopic endometriotic lesions. These new findings shed lights on future investigations of delineating the etiology of endometriosis and designing new therapeutic strategy for endometriosis. PMID- 25553383 TI - Occurrence, uses, and carcinogenicity of arylamines. AB - Arylamines are chemically synthesized and contained in oxidants, epoxy polymers, explosives, fungicides, pesticides, colorants, polyurethanes, and used in rubber, pharmacology, cosmetics, and other chemical industries. Many arylamines are ubiquitously present in cigarette smoke, cooking fume hoods, foods, automobile exhaust, industrial sites, etc. Some arylamines can be generated through azo reduction by intestinal, skin, and environmental microorganisms from azo dyes that are widely used. Arylamines can also be generated by reduction of the nitro group containing polyhydrated hydrocarbons including muntions. Some arylamines are released by burning nitrogen containing organic materials at high temperatures. Some medical drugs are also arylamines. Furthermore, many arylamines are essential constituents of normal metabolism or the result of abnormal metabolism or dietary sources. Some arylamines are mutagenic, carcinogenic or the cause of other kinds of maladies. Some arylamine are considered the major etiological agents of bladder tumors in humans and animals but may also induce other types of cancers in various organs. The organ, tissue, and species specificity of the arylamine-inducing carcinogenesis may be determined by their availability, distribution, and the presence of metabolic activation/detoxicification enzymes of each organ or tissue of different species. The ubiquitous arylamines, therefore, pose serious hazards to human health and environment. This article will address the occurrence, uses, carcinogenicity, and other arylamines-induced diseases. PMID- 25553384 TI - Surgical aspects of live kidney donation: an updated review. AB - In the early 1990s, live kidney donation regained popularity to meet the demand of kidney transplantation. Significant developments in the field of live kidney donation have established live donation as the prime source of kidney transplants. Nowadays, management is focused on logistic and immunological innovations, and improvements in care of the live donor. However, a flawless surgical procedure in both donor and recipient is a prerequisite for further expansion of live kidney donor transplantation. From a surgical perspective, the introduction of the laparoscopic approach has been a major breakthrough. Less invasive techniques to procure live donor kidneys have been held responsible for a steep increase in the number of live donors. In addition, less invasive imaging, improvements in perioperative care, and novel insights in the follow-up have all improved the care of the live donor. Live kidney donation is developing as the most promising source of renal organs since artificial kidneys, xenografts and stem cell therapy for restoring intrinsic kidney function will probably not find application on a large scale in the near future. PMID- 25553385 TI - Survival of Pseudomonas aeruginosa exposed to sunlight resembles the phenom of persistence. AB - During exposure of Pseudomonas aeruginosa stationary phase cells to natural solar radiation, a reduction in the rate of loss of bacterial viability was observed when survival fractions were lower than 1/10,000. This reduction was independent of the growth medium used and of the initial bacterial concentration, and was also observed when irradiation was performed with artificial UVA radiation (365nm, 47Wm(-2)). These results indicate the presence of a small bacterial subpopulation with increased tolerance to radiation. Such a tolerance is non heritable, since survival curves comparable to those of the parental strain were obtained from survivors to long-term exposure to radiation. The radiation response described here resembles the phenomenon called persistence, which consists of the presence of a small subpopulation of slow-growing cells which are able to survive antibiotic treatment within a susceptible bacterial population. The condition of persister cells is acquired via a reversible switch and involves active defense systems towards oxidative stress. Persistence is probably responsible for biphasic responses of bacteria to several stress conditions, one of which may be exposure to sunlight. The models currently used to analyze the lethal action of sunlight overestimate the effect of high-dose irradiation. These models could be improved by including the potential formation of persister cells. PMID- 25553386 TI - Regeneration of siloxane-exhausted activated carbon by advanced oxidation processes. AB - In the context of the biogas upgrading, siloxane exhausted activated carbons need to be regenerated in order to avoid them becoming a residue. In this work, two commercial activate carbons which were proved to be efficient in the removal of octamethylcyclotetrasiloxane (D4) from biogas, have been regenerated through advanced oxidation processes using both O3 and H2O2. After the treatment with O3, the activated carbon recovered up to 40% of the original adsorption capacity while by the oxidation with H2O2 the regeneration efficiency achieved was up to 45%. In order to enhance the H2O2 oxidation, activated carbon was amended with iron. In this case, the regeneration efficiency increased up to 92%. PMID- 25553387 TI - A novel ultra performance liquid chromatography-tandem mass spectrometry method for the determination of sucrose octasulfate in dog plasma. AB - A novel, specific and sensitive bioanalytical method has been developed for the determination of sucrose octasulfate (SOS) in dog plasma and urine using ion-pair reversed-phase ultraperformance liquid chromatography coupled with electrospray triple quadruple mass spectrometry (IPRP-UPLC ESI MS/MS). (13)C-labeled sucrose octasulfate-(13)C12 sodium salt is used as the internal standard. 200 MUL of plasma or serum sample is extracted using weak anion exchange solid phase cartridge. In this method, a polar amide column is employed for the liquid chromatograph (LC) separation while the diethylamine and formic acid buffer is used as the ion-pairing reagent. The low limitation of quantitation of sucrose octasulfate is 0.20 ng on the column with a signal to noise ratio larger than 50. Parameters such as linearity, accuracy and precision have been validated in full compliance with the FDA guidelines for the bioanalytical method development and validation. A linear regression model fit the calibration curve very well with R>0.99. The bias and coefficient of variation of all levels of QCs are within the range of 15%. The selectivity, matrix effect and stabilities of analytes in solution and matrix have also been evaluated and the results met the acceptance criteria according to the guidelines. Based on these results, the method has qualified to analyze sucrose octasulfate in dog plasma for clinic research. This method has been applied to 1000 preclinical samples. PMID- 25553388 TI - Determinants of maternal hair cortisol concentrations at delivery reflecting the last trimester of pregnancy. AB - Hair cortisol concentrations (HCC) are emerging as a promising marker of chronic psychosocial stress. However, limited information on relevant correlates of this biomarker in late pregnancy is available. In the Ulm SPATZ Health Study mothers were recruited between 04/2012 and 05/2013 shortly after delivery in the University Medical Center Ulm, Germany. Cortisol concentrations of N=768 participants were determined by HPLC-MS/MS in the scalp-near 3cm of maternal hair reflecting stress exposure over the preceding three months. Sociodemographic characteristics, pregnancy-related variables and comorbidities were assessed. We conducted bivariate and multiple linear regression analyses using log transformed HCC. In bivariate analyses, significantly higher cortisol concentrations were found in obese compared to normal weight (b=0.32, p<0.001) and smoking as opposed to non-smoking mothers (b=0.34, p=0.002). Conversely, primary C-section was associated with lower HCC compared to spontaneous delivery. Besides, a strong impact of season of delivery with significantly higher HCC in summer and autumn as opposed to winter (both bs=0.58, p<0.001) was found. Further determinants of HCC were maternal education, number of persons in the household, premature delivery and hair characteristics. In a mutually adjusted model, all but education, multiple jobholding, hair characteristics and premature delivery remained statistically significant. Maternal hair cortisol in the last trimester of pregnancy is determined by many factors. Delivery mode, body mass index and season of delivery should be considered when investigating the association between HCC and further outcomes in mothers shortly after delivery. PMID- 25553389 TI - Morning cortisol secretion in school-age children is related to the sleep pattern of the preceding night. AB - Sleep disturbance in childhood is common and a risk factor for poor mental health. Evidence indicates that disturbed sleep is associated with altered hypothalamic-pituitary-adrenal axis (HPAA) activity. Knowledge regarding the association between HPAA-activity and objective sleep measures particularly regarding sleep architecture in school-age children is missing. Sleep electroencephalography was administered to 113 children aged 6-10 years (including 58 children born very preterm and 55 born at term) during one night at the children's homes and sleep duration, sleep continuity, and sleep architecture were assessed. To assess the cortisol awakening response at the following morning, cortisol secretion was measured at awakening, 10, 20, and 30min later. Regression analyses controlling child age, gender, prematurity status, and the awakening time revealed that morning cortisol secretion was negatively associated with sleep duration and slow wave sleep and positively associated with the relative amount of Stage 2 sleep during the preceding night. In addition, morning cortisol secretion linearly increased with age. In conclusion, associations of sleep disturbance with poor mental health may be confounded with altered HPAA activity. PMID- 25553391 TI - Expanding the therapeutic spectrum of anterior thalamic nucleus deep brain stimulation in intractable epilepsy: a postulation. PMID- 25553390 TI - Psychiatric and neuropsychological profiles of people with psychogenic nonepileptic seizures. AB - OBJECTIVE: This study examined the psychiatric and neuropsychological profiles of people with psychogenic nonepileptic seizures (PNES). METHODS: Twenty-people who had been diagnosed with psychogenic nonepileptic seizures (PNES), but not epilepsy, were recruited into this study. A healthy control group was also recruited and was matched for age and gender. All participants underwent structured psychiatric assessment and psychometric assessment. Neuropsychological assessment was carried out using the Cambridge Neuropsychological Test Battery (CANTAB) after participants passed the Medical Symptom Validity Test (MSVT) of effort. RESULTS: One patient failed the MSVT and was excluded from the analysis. Therefore, data from 19 people with PNES and their matched healthy controls were analyzed. Compared with controls, people with PNES had significantly higher levels of depressive symptoms, anxiety symptoms, dissociative experiences, and alexithymic traits. In addition, people with PNES had impairments in spatial working memory and attention when compared with healthy controls. CONCLUSION: To our knowledge, this is the first study to report that, compared with controls, people with PNES have abnormal cognitive functioning after controlling for effects of effort and FSIQ. People with PNES also have high levels of anxiety, depressive, and dissociative symptoms. In addition, they appear to particularly focus on health problems and show evidence of chronic emotional dysregulation. Further studies are required to replicate our results and to help clarify the pathogenic mechanisms underlying PNES. PMID- 25553392 TI - Defining dendritic cells. AB - Dendritic cells (DCs) are versatile controllers of the immune system, best known for their potent ability to initiate adaptive immunity. Traditionally, DCs have been defined on the basis of cell morphology, expression of specific markers and select functional attributes such as the ability to migrate to T cell areas of secondary lymphoid organs and activate T lymphocytes. However, such properties are not qualitative and often change in conditions of inflammation or infection. Phenotypic-based and function-based definitions can therefore lead to difficulties in cell identification. Here we review other approaches to try and solve questions of DC lineage attribution with an emphasis on recent insights arising from our increased understanding of DC ontogeny and differentiation. PMID- 25553394 TI - Protein synthesis regulation, a pillar of strength for innate immunity? AB - Recognition of pathogen derived molecules by Pattern Recognition Receptors (PRR) induces the production of cytokines (i.e. type I interferons) that stimulate the surrounding cells to transcribe and translate hundreds of genes, in order to prevent further infection and organize the immune response. Here, we report on the rising matter that metabolism sensing and gene expression control at the level of mRNA translation, allow swift responses that mobilize host defenses and coordinate innate responses to infection. PMID- 25553393 TI - C-type lectins in immunity: recent developments. AB - C-type lectin receptors (CLRs) comprise a large superfamily of proteins, which recognise a diverse range of ligands, and are defined by the presence of at least one C-type lectin-like domain (CTLD). Of particular interest are the single extracellular CTLD-containing receptors of the 'Dectin-1' and 'Dectin-2' clusters, which associate with signalling adaptors or possess integral intracellular signalling domains. These CLRs have traditionally been associated with the recognition of fungi, but recent discoveries have revealed diverse and unexpected functions. In this review, we describe their newly identified roles in anti-microbial host defence, homeostasis, autoimmunity, allergy and their functions in the recognition and response to dead and cancerous cells. PMID- 25553396 TI - Morphological and molecular evidence support a close relationship between the free-living archamoebae Mastigella and Pelomyxa. AB - Members of the archamoebae comprise free-living and endobiotic amoeboid flagellates and amoebae that live in anoxic/microoxic habitats. Recently, the group has been divided into four separate families, Mastigamoebidae, Entamoebidae, Pelomyxidae, and Rhizomastixidae, whose interrelationships have not been completely resolved. There still are several key members of the archamoebae, notably the genus Mastigella, from which sequence data are missing. We established 12 strains of 5 species of Mastigella and Pelomyxa in culture, examined their morphology and determined their actin gene sequences. In addition, we examined the ultrastructure of three strains and determined and analyzed SSU rDNA sequences of two strains. Our data strongly suggest that Mastigella is specifically related to Pelomyxa, and it is transferred into the family Pelomyxidae. Surprisingly, Mastigella is likely paraphyletic with Pelomyxa forming its internal branch. The two genera share several morphological features that point to their common evolutionary history. Three new species of Mastigella are described: M. erinacea sp. nov., M. rubiformis sp. nov. and M. ineffigiata sp. nov. PMID- 25553395 TI - Ambient air pollutant PM10 and risk of preterm birth in Lanzhou, China. AB - IMPORTANCE: Exposure to ambient particulate matter during pregnancy has been suggested as a risk factor for preterm birth. However results from limited epidemiologic studies have been inconclusive. Very few studies have been conducted in areas with high air pollution levels. OBJECTIVE: We investigated the hypothesis that high level exposure to particulate matter with aerodynamic diameter no larger than 10MUm (PM10) during pregnancy increases the risk of preterm birth. METHODS: A birth cohort study was carried out between 2010 and 2012 in Lanzhou, China, including 8969 singleton live births with available information on daily PM10 levels from four monitoring stations, individual exposures during pregnancy were calculated using inverse-distance weighting based on both home and work addresses. Unconditional logistic regression modeling was used to examine the associations between PM10 exposure and risk of preterm birth and its clinical subtypes. RESULTS: Increased risk of very preterm birth was associated with exposure to PM10 during the last two months of pregnancy (OR, 1.07; 95%CI, 1.02-1.13 per 10MUg/m(3) increase for last four weeks before delivery; 1.09; 1.02-1.15 for last six weeks before delivery; 1.10; 1.03-1.17 for last eight weeks before delivery). Compared to the U.S. National Ambient Air Quality Standard (150MUg/m(3)), higher exposure level (>=150MUg/m(3)) of PM10 during entire pregnancy was associated with an increased risk of preterm birth (1.48; 1.22-1.81) and the association was higher for medically indicated preterm birth (1.80, 1.24-2.62) during entire pregnancy and for very preterm during last 6weeks before delivery (2.03, 1.11-3.72). CONCLUSIONS AND RELEVANCE: Our study supports the hypothesis that exposure to high levels of ambient PM10 increases the risk of preterm birth. Our study also suggests that the risk may vary by clinical subtypes of preterm birth and exposure time windows. Our findings are relevant for health policy makers from China and other regions with high levels of air pollution to facilitate the efforts of reducing air pollution level in order to protect public health. PMID- 25553397 TI - Cognitive performances associate with measures of white matter integrity in bipolar disorder. AB - BACKGROUND: Neuropsychological deficits constitute enduring trait-like features in bipolar disorder (BD), and persist in euthymia. White matter (WM) abnormalities are one of the most consistently reported findings in neuroimaging studies of BD. We hypothesized that neuropsychological performances could correlate with WM integrity in a sample of bipolar patients in core WM tracts. METHODS: Seventy-eight patients affected by BD were evaluated for verbal memory, working memory, psychomotor coordination, executive functions, attention and information processing, and verbal fluency through the Brief Assessment of Cognition in Schizophrenia. White matter integrity was evaluated using DTI and tract-based spatial statistics with threshold free cluster enhancement (p>0.949). RESULTS: We observed that cognitive performances in attention and information processing, working memory, executive functions and psychomotor coordination were associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, cingulum bundle, corpus callosum, and corona radiata. LIMITATION: The drug treatments administered during the course of the illness could have influenced DTI measures and neurocognitive function. Other limitations include issues such as generalizability due to the lack of a control group, possible undetected past comorbidities, population stratification, and the presence of a 28% of patients which previously experienced delusions. CONCLUSIONS: This is the first study to use a validated cognitive battery to investigate the principal cognitive domains in BD. Our data confirm the importance of WM integrity as a neurobiological underpinning of cognitive deficits. PMID- 25553398 TI - Disability in bipolar I disorder: the 36-item World Health Organization Disability Assessment Schedule 2.0. AB - BACKGROUND: The WHODAS 2.0 is an ICF-based multidimensional instrument developed for measuring disability. The present study analyzes the utility of the 36-item interviewer-administered version in a sample of patients with bipolar disorder. There is no study to date that analyses how the scale works in a sample that only comprises such patients. METHODS: A total of 291 patients with bipolar disorder (42.6% males) according to DSM-IV-TR criteria from a cross-sectional study conducted in outpatient psychiatric clinics were enrolled. In addition to the WHODAS 2.0, patients completed a comprehensive assessment battery including measures on psychopathology, functionality and quality of life. Analyses were centered on providing evidence on the validity and utility of the Spanish version of the WHODAS 2.0 in bipolar patients. RESULTS: Participation domain had the highest percentage of missing data (2.7%). Confirmatory factorial analysis was used to test three models formulated in the literature: six primary correlated factors, six primary factors with a single second-order factor, and six primary factors with two second-order factors. The three models were plausible, although the one formed by six correlated factors produced the best fit. Cronbach's alpha values ranged between .73 for the Self-care domain and .92 for Life activities, and the internal consistency of the total score was .96. Relationships between the WHODAS 2.0 and measures of psychopathology, functionality and quality of life were in the expected direction, and the scale was found to be able to differentiate among patients with different intensity of clinical symptoms and work situation. LIMITATIONS: The percentage of euthymic patients was considerable. However, the assessment of euthymic patients is less influenced by mood. Some psychometric properties have not been studied, such as score stability and sensitivity to change. CONCLUSIONS: The Spanish version of the 36-item WHODAS 2.0 has suitable psychometric properties in terms of reliability and validity when applied to patients with bipolar disorder. Disability in bipolar patients is especially prominent in Cognition, Getting along, Life activities, and Participation domains, so functional remediation interventions should emphasize these areas in order to improve the daily living activities of these patients. PMID- 25553399 TI - Anterior cingulate volume predicts response to cognitive behavioral therapy in major depressive disorder. AB - BACKGROUND: Cognitive behavioral therapy (CBT) is widely used to treat major depressive disorder (MDD). Although improved response prediction could facilitate the development of individualized treatment plans, few studies have investigated whether underlying brain structure is related to CBT response in MDD. METHODS: Ten MDD patients who received individual CBT were studied in this study. We investigated the relationship between the regional gray matter (GM) volume and subsequent responses to CBT using voxel-based morphometry. RESULTS: The degree of improvement in depressive symptoms was positively correlated with GM volume in the caudal portion of the anterior cingulate cortex. LIMITATIONS: The sample size was small, and the effects of medication on the results could not be excluded. CONCLUSIONS: Our results, although preliminary, suggest that the anterior cingulate cortex is a key structure whose volume can be used to predict responses to CBT and is thus a potential prognostic marker in MDD. PMID- 25553400 TI - Effectiveness of psychological interventions in preventing recurrence of depressive disorder: meta-analysis and meta-regression. AB - BACKGROUND: Major depression is probably best seen as a chronically recurrent disorder, with patients experiencing another depressive episode after remission. Therefore, attention to reduce the risk of relapse or recurrence after remission is warranted. The aim of this review is to meta-analytically examine the effectiveness of psychological interventions to reduce relapse or recurrence rates of depressive disorder. METHODS: We systematically reviewed the pertinent trial literature until May 2014. The random-effects model was used to compute the pooled relative risk of relapse or recurrence (RR). A distinction was made between two comparator conditions: (1) treatment-as-usual and (2) the use of antidepressants. Other sources of heterogeneity in the data were explored using meta-regression. RESULTS: Twenty-five randomised trials met inclusion criteria. Preventive psychological interventions were significantly better than treatment as-usual in reducing the risk of relapse or recurrence (RR=0.64, 95% CI=0.53 0.76, z=4.89, p<0.001, NNT=5) and also more successful than antidepressants (RR=0.83, 95% CI=0.70-0.97, z=2.40, p=0.017, NNT=13). Meta-regression showed homogeneity in effect size across a range of study, population and intervention characteristics, but the preventive effect of psychological intervention was usually better when the prevention was preceded by treatment in the acute phase (b=-1.94, SEb=0.68, z=-2.84, p=0.005). LIMITATIONS: Differences between the primary studies in methodological design, composition of the patient groups and type of intervention may have caused heterogeneity in the data, but could not be evaluated in a meta-regression owing to poor reporting. CONCLUSIONS: We conclude that there is supporting evidence that preventive psychological interventions reduce the risk of relapse or recurrence in major depression. PMID- 25553401 TI - Attachment insecurity and obsessive-compulsive personality disorder among inpatients with serious mental illness. AB - BACKGROUND: Obsessive-compulsive personality disorder (OCPD) is characterized by traits such as extreme rigidity, perfectionism, and controlling behavior, all of which have a negative impact on interpersonal functioning. Attachment theory provides a useful framework to elucidate the interpersonal dysfunction characteristic of OCPD; yet, there is a dearth of attachment research on OCPD in the context of severe mental illness. METHODS: Attachment security and personality disorders were assessed in adult inpatients with severe mental illness. Propensity Score Matching (PSM) was used to match OCPD and control subjects on age, gender, number of psychiatric disorders, and number of criteria endorsed for borderline personality disorder. RESULTS: Consistent with hypotheses, the OCPD group (n=61) showed greater attachment avoidance than controls (n=61), and the avoidance was manifested in a predominance of the most insecure attachment style, fearful attachment. Correlations between attachment anxiety/avoidance with specific OCPD diagnostic criteria revealed that attachment avoidance was correlated with four of eight OCPD criteria across the full sample. Within the subset of OCPD patients, attachment avoidance was significantly correlated with OCPD criterion 3 (is excessively devoted to work and productivity to the exclusion of leisure activities and friendships). LIMITATIONS: The use of self-report measure of attachment and the high burden of illness in the SMI population may not generalize to interview based assessment or outpatients, respectively. CONCLUSIONS: Findings attest to the severity of impairment in interpersonal functioning and attachment avoidance, in particular, is characteristic of OCPD patients. These results suggest that viable treatment targets include interpersonal functioning along with more classical features of OCPD such as perfectionism and obsessiveness in task performance. PMID- 25553402 TI - Clinical significance of decreased protein expression of dehydroepiandrosterone sulfate in the development of depression: a meta-analysis. AB - BACKGROUND: Previous evidence has shown that adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEAS) have significant functions related to the control of mood, affect, and anxiety. Changes in their expression levels are reportedly related to several psychiatric disorders. The objective of this meta-analysis was to explore the role of DHEAS protein expression in patients with depression. METHOD: Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM) and China National Knowledge Infrastructure (CNKI) were electronically searched. Only those studies that analyzing DHEAS expression in depression patients were considered eligible for inclusion. Standardized mean differences (SMDs) were pooled with a 95% confidence interval (CI) in accordance with the random-effects model. RESULTS: Ten clinical case-control studies, consisting of 4496 subjects (493 patients with depression and 4003 healthy controls) were incorporated for analysis. Results revealed a lower DHEAS protein expression level in patients with depression than in normal controls (SMD=0.17, 95% CI: 0.06-0.27, P=0.002). Ethnicity-stratified analysis indicated that lower levels of DHEAS expression in depression patients were not observed in Caucasians or Asians (both P>0.05). CONCLUSION: Elevated DHEAS protein expression may be correlated with the biological pathophysiology of depression, indicating that checking DHEAS levels and administration of DHEAS could contribute to the effective treatment of depression. PMID- 25553404 TI - BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis. AB - BACKGROUND: Peripheral brain-derived neurotrophic factor (BDNF) is decreased in acute major depressive disorder (MDD) and bipolar disorder (BD) and recovered after treatment. Here we validated on a meta-analytical level whether BDNF restores differentially according to treatment response and whose measurements could be used as a biomarker, plasma or serum. METHODS: Using strict inclusion criteria, we compared BDNF in healthy controls and patients with MDD (38 studies, n=6619), and BD (17 studies, n=1447). Pre- and post-treatment BDNF levels were meta-analyzed according to treatment response in patients from 21 MDD studies (n=735) and 7 BD studies (n=88). Serum and plasma subgroups were analyzed, publication bias was assessed and heterogeneity was investigated. RESULTS: Serum and plasma BDNF were decreased in acute MDD and BD, and did not differ in euthymia in comparison with control subjects. Antidepressive treatment increased serum BDNF levels in MDD in responders (Cohen's d (d)=1.27, p=4.4E-07) and remitters (d=0.89, p=0.01), significantly more than in non-responders (d=0.11, p=0.69). For plasma BDNF in MDD and for BD, the evidence was insufficient for a meta-analysis. Although no significant difference was found between serum and plasma ES, variance of plasma ES was higher. LIMITATIONS: Between-study heterogeneity was explained only partially; signs of publication bias in serum studies. CONCLUSION: Serum BDNF might be regarded as a biomarker for the successful treatment of MDD. Serum measurements seem more reliable than plasma ones. Further research should focus on defining optimal time points for BDNF measurements and increase evidence for the usage of BDNF as a predictive biomarker in BD. PMID- 25553403 TI - Trajectories of maternal depression and offspring psychopathology at 6 years: 2004 Pelotas cohort study. AB - BACKGROUND: Few studies have addressed the course and severity of maternal depression and its effects on child psychiatric disorders from a longitudinal perspective. This study aimed to identify longitudinal patterns of maternal depression and to evaluate whether distinct depression trajectories predict particular psychiatric disorders in offspring. METHODS: Cohort of 4231 births followed-up in the city of Pelotas, Brazil. Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) at 3, 12, 24 and 48 months and 6 years after delivery. Psychiatric disorders in 6-year-old children were evaluated through the development and well-being assessment (DAWBA) instrument. Trajectories of maternal depression were calculated using a group based modelling approach. RESULTS: We identified five trajectories of maternal depressive symptoms: a "low" trajectory (34.8%), a "moderate low" (40.9%), a "increasing" (9.0%), a "decreasing" (9.9%), and a "high-chronic" trajectory (5.4%). The probability of children having any psychiatric disorder, as well as both internalizing and externalizing problems, increased as we moved from the "low" to the "high-chronic" trajectory. These differences were not explained by maternal and child characteristics examined in multivariate analyses. LIMITATIONS: Data on maternal depression at 3-months was available on only a sub sample. In addition, we had to rely on maternal report of child's behavior alone. CONCLUSIONS: The study revealed an additive effect on child outcome of maternal depression over time. We identified a group of mothers with chronic and severe symptoms of depression throughout the first six years of the child life and for this group child psychiatric outcome was particularly compromised. PMID- 25553405 TI - Suicidal behaviours in adjustment disorder and depressive episode. AB - BACKGROUND: Little is known about suicidal ideation and behaviours in adjustment disorder (AD). In this paper we sought to examine the variables independently associated with suicidal ideation and behaviour in patients diagnosed with AD or depressive (DE) episode among psychiatric outpatients and in liaison psychiatry. METHODS: 370 patients who were referred to the liaison psychiatry services (including those seen in the Emergency Department) at 3 Dublin hospitals, and were clinically diagnosed with either DE or AD, based on the ICD 10 diagnostic criteria, were recruited to the study. We examined their demographic and clinical characteristics, and the associations between these and suicidal ideation and behaviour on multivariate analysis. RESULTS: Younger age, single marital status, and greater severity of depressive symptoms were significantly associated with suicidality across both diagnoses. On multivariate analysis, greater severity of depressive symptoms was associated with suicidality in those with AD (p=0.012) and DE (p=0.009). Those with AD exhibited suicidality at lower symptom scores than did those with DE but in both groups it still occurred at the highest level of severity. There were differences in the objective circumstances measure of suicide intent. LIMITATIONS: We used clinical diagnosis rather as the main diagnostic classification. The generalisability of this paper may be limited to consultation-liaison psychiatry settings, where suicidal ideation and behaviours are common. CONCLUSIONS: Suicidality in AD and DE has broadly similar risk factors but differ in aspects of suicide intent. Different mechanisms may underpin suicidality in those with AD compared to DE. PMID- 25553406 TI - Symptom screening scales for detecting major depressive disorder in children and adolescents: a systematic review and meta-analysis of reliability, validity and diagnostic utility. AB - BACKGROUND: Depression symptom screening scales are often used to determine a clinical diagnosis of major depressive disorder (MDD) in prevention research. The aim of this review is to systematically examine the reliability, validity and diagnostic utility of commonly used screening scales in depression prevention research among children and adolescents. METHODS: We conducted a systematic review of the electronic databases PsycINFO, PsycEXTRA and Medline examining the reliability, validity and diagnostic utility of four commonly used depression symptom rating scales among children and adolescents: the Children's Depression Inventory (CDI), Beck Depression Inventory (BDI), Center for Epidemiologic Studies - Depression Scale (CES-D) and the Reynolds Adolescent Depression Scale (RADS). We used univariate and bivariate random effects models to pool data and conducted metaregression to identify and explain causes of heterogeneity. RESULTS: We identified 54 studies (66 data points, 34,542 participants). Across the four scales, internal reliability was 'good' (pooled estimate: 0.89, 95% Confidence Interval (CI): 0.86-0.92). Sensitivity and specificity were 'moderate' (sensitivity: 0.80, 95% CI: 0.76-0.84; specificity: 0.78, 95% CI: 0.74-0.83). For studies that used a diagnostic interview to determine a diagnosis of MDD, positive predictive power for identifying true cases was mostly poor. Psychometric properties did not differ on the basis of study quality, sample type (clinical vs. nonclinical) or sample age (child vs. adolescent). LIMITATIONS: Some analyses may have been underpowered to identify conditions in which test performance may vary, due to low numbers of studies with adequate data. CONCLUSIONS: Commonly used depression symptom rating scales are reliable measures of depressive symptoms among adolescents; however, using cutoff scores to indicate clinical levels of depression may result in many false positives. PMID- 25553407 TI - High serum uric acid level in adolescent depressive patients. AB - BACKGROUND: Depression disorder is a mental illness of high recurrence rate and its pathological mechanism is still unclear. 5-HT is the most widely studied neurotransmitter and high level of serum uric acid (SUA) can result from the increased oxygenolysis of nucleic acid. Aim of the present study is to explore the pathogenesis of adolescence depression through the study of SUA and 5-HT level in adolescent depressive patients. METHODS: The SUA of 152 adolescent depressive patients and normal adolescents were tested respectively and 5-HT levels among them were analyzed. RESULTS: The SUA level of cases (434.57+/ 102.34MUmol/L) was significantly higher than controls (330.18+/-62.59MUmol/L), P<0.001; the 5-HT level of cases (20.86+/-4.58) was significantly lower than controls (24.03+/-5.76) (P<0.005) and had a significant negative correlation with SUA level (r=-0.49, P<0.01). LIMITATIONS: The sample size was relatively small and the patients were only male from General Hospital of Beijing Military Region. CONCLUSIONS: High level of SUA can be used as a biochemical index for the early diagnose of adolescence depression; adolescence depression may be due to DNA oxidative damage of neurons in brain. PMID- 25553408 TI - Taking the fuel out of the fire: evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders. AB - BACKGROUND: Inflammation has emerged as a potentially important factor - and thus putative pharmacological target - in the pathology of bipolar disorders. However to date no systematic evaluations of the efficacy of add on anti-inflammatory treatment for the depressive and manic episodes have been carried out. METHODS: Sixteen articles were ultimately identified - by computer searches of databases (including PsycINFO, MEDLINE, and EMBASE), supplemented by hand searches and personal communication - as meeting study inclusion criteria. RESULTS: Anti-manic effects were evaluated in two trials, one of adjunctive n-acetyl cysteine (NAC), one of omega-3 fatty acids (O3FA), and significant improvements only emerged for NAC. Celecoxib had a rapid but short-lived antidepressant effect. Despite limited effects of O3FA on symptoms, imaging data demonstrated alterations in neuronal functioning that might have longer-term therapeutic effects. Evidence was strongest for adjunctive NAC in bipolar depression though conclusions are limited by small sample sizes. LIMITATIONS: Definitive conclusions are limited by the paucity of data, small study sizes, and the variability in methodology used. CONCLUSIONS: Current evidence for aspirin or celecoxib is insufficient though further investigation of the potential of celecoxib in early illness onset is warranted. Variable evidence exists for add-on O3FA though an indication of short term treatment effects on membrane fluidity and neuronal activity suggest longer follow-up assessment is needed. The strongest evidence emerged for NAC in depression and future studies must address the role of illness duration and patients' baseline medications on outcomes. Careful consideration of lithium toxicity in the elderly and renal impaired is essential. PMID- 25553409 TI - Antidepressant use and the risk of suicide: a population-based cohort study. AB - BACKGROUND: The existing literature provides contradictory evidence on antidepressant use and risk of suicide. Some studies have shown that the use of Selective Serotonin Reuptake Inhibitors (SSRIs) is associated with an increased risk of suicide, especially during the first months of treatment, whereas other studies did not confirm this association. For this reason, our objective was to investigate the association between antidepressant use and risk of suicide in incident antidepressant users in relation to time since starting therapy. METHODS: We conducted a population-based cohort study within the Dutch Integrated Primary Care Information (IPCI) database, in incident users of antidepressant therapy between 1994 and 2012 (n=27,712). Cox proportional hazard models were used to study the association between current use of SSRIs, tricyclic antidepressants (TCA) and other antidepressants and risk of suicide or attempted suicide. RESULTS: During follow-up, a total of 280 incident antidepressant users attempted or committed suicide. Current use of SSRIs (hazard ratio (HR): 0.78, 95% CI: 0.57-1.07), TCAs (HR: 0.82, 95% CI: 0.48-1.42) or other antidepressants (HR: 0.75, 95% CI: 0.47-1.18) was not statistically significantly associated with suicide compared to past use of any of the antidepressants. LIMITATIONS: Although a large healthcare database was used, the number of reported cases of suicide (attempt) was low. CONCLUSIONS: This study did not indicate an increase in risk of suicide after starting treatment with SSRIs, TCAs or other antidepressants compared with past antidepressant use. PMID- 25553410 TI - Preoperative oral carbohydrate improved postoperative insulin resistance in rats through the PI3K/AKT/mTOR pathway. AB - BACKGROUND: Preoperative oral carbohydrate (OCH) improves postoperative insulin resistance (PIR) and insulin sensitivity. However, the exact mechanisms involved in the improvement of PIR with respect to preoperative OCH are still not clear. The aim of this study was to investigate the involvement of preoperative OCH and PI3K/AKT/mTOR pathway in reducing PIR in rats. MATERIAL AND METHODS: Forty male Sprague-Dawley rats were randomly assigned to PreOp, glucose, saline, and fasting groups. Rats in the PreOp, glucose, and saline groups received OCH, 5% glucose solution, and saline, respectively. Rats in the fasting group did not receive anything but were fasted 3 h before surgery. Blood glucose, insulin and leucine levels, and insulin resistance, secretion, and sensitivity indexes were measured before and after surgery. mRNA and protein (total and phosphorylated) levels of mTOR, IRS-1, PI3K, PKB/AKT, and GlUT4 were measured using real-time polymerase chain reaction and Western blot in skeletal muscles. RESULTS: In the PIR experiment, blood glucose, serum insulin, insulin resistance, and serum leucine levels were all significantly lower in the PreOp group than in the other 3 groups (P<0.05) after surgery. HOMA-ISI were higher in the PreOp group vs the other 3 groups after surgery (P<0.05), and HOMA-b in the PreOp group was higher than that in the other 3 groups at 30 and 120 min after surgery. Additionally, post operative phosphorylated IRS-1, PI3K, and AKT protein levels were significantly higher in the PreOp group than in the other 3 groups (P<0.05), but no significant differences were observed in their respective protein levels (P>0.05). CONCLUSIONS: OCH decreases postoperative insulin resistance and improves postoperative insulin sensitivity in skeletal muscles through the PI3K/AKT/mTOR pathway. PMID- 25553411 TI - High pressure processing alters water distribution enabling the production of reduced-fat and reduced-salt pork sausages. AB - High pressure processing (HPP) was used to explore novel methods for modifying the textural properties of pork sausages with reduced-salt, reduced-fat and no fat replacement additions. A 2*7 factorial design was set up, incorporating two pressure levels (0.1 or 200 MPa) and seven fat levels (0, 5, 10, 15, 20, 25 and 30%). Sausages treated at 200 MPa exhibited improved tenderness at all fat levels compared with 0.1 MPa treated samples, and the shear force of sausages treated at 200 MPa with 15 or 20% fat content was similar to the 0.1 MPa treated sausages with 30% fat. HPP significantly changed the P2 peak ratio of the four water components in raw sausages, resulting in improved textural properties of emulsion type sausages with reduced-fat and reduced-salt. Significant correlations were found between pH, color, shear force and water proportions. The scanning and transmission micrographs revealed the formation of smaller fat globules and an improved network structure in the pressure treated sausages. In conclusion, there is potential to manufacture sausages with reduced-fat and reduced-salt by using HPP to maintain textural qualities. PMID- 25553412 TI - Effects of linseed oil and natural or synthetic vitamin E supplementation in lactating ewes' diets on meat fatty acid profile and lipid oxidation from their milk fed lambs. AB - Forty-eight Churra ewes with their new-born lambs were separated into four dietary treatments: Control (without added fat), LO (with 3% linseed oil), LO-Syn E (LO plus 400 mg/kg TMR of synthetic vitamin E) and LO-Nat E (LO plus 400 g/kg TMR of natural vitamin E). Linseed oil caused an increase in trans-11 C18:1 (VA), trans-10 C18:1, cis-9, trans-11 C18:2 (RA), trans-10, cis-12 C18:2 and C18:3 n-3 (ALA) in milk fat compared to the Control. The addition of vitamin E to the LO diets did not influence significantly the majority of milk fatty acids compared with the LO diet alone. Trans-10 C18:1, VA, RA, trans-10, cis-12 C18:2 and LA levels were higher in intramuscular lamb fat from treatments with linseed oil. No statistically significant differences were observed in these FA due to vitamin E supplementation or the type of vitamin E (synthetic vs. natural). Vitamin supplementation resulted in lipid oxidation levels below the threshold values for detection of rancidity in lamb meat. PMID- 25553413 TI - Microspectroscopic soft X-ray analysis of keratin based biofibers. AB - Scanning soft X-ray transmission microspectroscopy (STXM) and transmission electron microscopy (TEM) have been employed for a high-resolution morphological and chemical analysis of hair fibers from human, sheep and alpaca. STXM allows optimum contrast imaging of the main hair building blocks due to tuneable photon energy. Chemical similarities and deviations for the human hair building blocks as well as for the three investigated species are discussed on the basis of the local near-edge X-ray absorption fine structure (NEXAFS). The spectra of melanosomes corroborate the state-of-the-art model for the chemical structure of eumelanin. Complementary TEM micrographs reveal the occurrence of cortex sectioning in alpaca hair to some extent. A spectroscopic analysis for human hair cortex indicates low mass loss upon soft X-ray irradiation, but transformation of chemical species with decreasing amount of peptide bonds and increasing NEXAFS signal for unsaturated carbon-carbon bonds. PMID- 25553414 TI - Synthesis and in vitro evaluation of 3-(4-nitrophenyl)coumarin derivatives in tumor cell lines. AB - Coumarins are naturally-occurring compounds that have attracted considerable interest due to their numerous biological activities depending on their pattern of substitution on the coumarin molecule. In this present investigation, we synthesized 3-(4-nitrophenyl)coumarin derivatives (9a-e) and evaluated their in vitro cytotoxic effect on human lung (A549), breast (MDA-MB-231) and prostate (PC3) cancer cell lines for 48 h using crystal violet dye binding assay. Cytotoxic effects of the most active compound on normal human lung (MRC-9) and breast (MCF-10A) cell lines, cell cycle analysis using flow cytometry and mitochondrial membrane potential (MMP) using Tetramethyl Rhodamine Methyl Ester (TMRM; rhodamine-123) fluorescent dye were also examined. Among the compounds that were evaluated, 9c showed cytotoxic effect (active), caused significant cells arrest (p<0.05) in G0/G1 and S phases of cell cycle and loss of MMP in A459, MDA-MB-231 and PC3 cell lines. Additionally, the cytotoxic effect of 9c was compared to reference drugs (Coumarin and Docetaxel) for comparative study. These results further demonstrate that acetoxy group at C-7 and C-8 positions of 9c are responsible for the observed cytotoxic effect in these cancer cell lines. PMID- 25553415 TI - A case of synchronous double primary lung cancer presenting with pleomorphic carcinoma and adenocarcinoma. AB - BACKGROUND: Recently, synchronous multiple lung cancer (SMPLC) has sometimes been detected as a result of improved radiological imaging, although the occurrence of SPMLC is still rare. To the best of our knowledge, there have been no reported cases of with synchronous double primary lung cancer presenting with pleomorphic carcinoma and adenocarcinoma. We herein report such a case. CASE REPORT: A 64 year-old male was referred to our institution for an abnormal shadow in the apex of the left lung in April 2012. CT revealed 2 nodules that measured 15 mm in the left S(1+2b) and 20 mm in the left S3c. We suspected that the lesions were malignant, although the diagnosis could not be confirmed by transbronchial lung biopsy of the lesions. Therefore, we performed the left upper lobectomy. The results of the pathological examination of the nodule in S3c showed adenocarcinoma of pT1aN0M0, stage IA. The nodule in S(1+2b) was found to be pleomorphic carcinoma, pT1aN0M0, stage IA. In November 2012, the patient underwent an esophagogastroduodenoscopy because of anemia. The image findings showed a gastric ulcer on the greater curvature of his stomach. The pathological examination of the biopsy specimen from the ulcer revealed the metastatic cancer from pleomorphic carcinoma. In addition, abdominal CT revealed bilateral adrenal metastasis. Although the patient received chemotherapy, it was not effective. It was difficult to continue the chemotherapy because his performance status worsened. He died in May 2013. CONCLUSIONS: The present case was associated with a poor prognosis, even though the pathological stage of each tumor was stage IA. The prognosis of SMPLC may be associated with the histologic type, although the prognosis of SMPLC remains unclear due to its rarity. PMID- 25553416 TI - Oxidative damage induced by copper and beta-cypermethrin in gill of the freshwater crayfish Procambarus clarkii. AB - Copper (Cu) and pyrethroid are common contaminants found in the aquatic environment, and their potential toxicological effects on aquatic organisms have received extensive attention. However, the impact on crayfish species of exposure to the two chemicals are still largely unknown. The current study assessed the sublethal toxicities induced by Cu and commercial formulation of beta cypermethrin in the freshwater crayfish Procambarus clarkii. The static test method of acute toxicity test was used. Five biomarkers of oxidative effects, i.e. reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and protein carbonyls, and pathologic changes were determined. The results demonstrated that there was a significant increase in the contents of ROS, MDA and protein carbonyls accompanied by markedly decreased SOD and CAT activities in a concentration-dependent manner. The linear relationship between protein carbonyls induction and MDA formation was observed evidently in crayfish gills at 96h. Higher contents of ROS enhanced the risk of lipid peroxidation and protein carbonylation, thus impacting vital physiological functions of gills. The results indicated that protein oxidation may be one of the main mechanisms of pollution-induced toxicity to crayfish gills. Protein carbonyl levels could be considered as a potential biomarker of exposure to environmental contaminants. PMID- 25553418 TI - The effects of arbuscular mycorrhizal fungi on sex-specific responses to Pb pollution in Populus cathayana. AB - Using fast-growing trees to remediate soils polluted by heavy metals (HMs) has received increasingly more attention, especially for recalcitrant Pb, as one of the most seriously toxic HMs. However, little is known about the responses of plants to a diffused level of Pb pollution, and a more combined phytoremediation technique is needed to explore. In this study, an arbuscular mycorrhizal fungus (AMF), i.e., Funneliformis mosseae, isolated from Populus euphratica distributed in a tailing of Pb/Zn ore, was introduced to investigate its effects on sex specific responses of P. cathayana in morphology, physiology, and Pb phytoremediation capacity, when exposed to a diffused level of Pb pollution (100mg Pb(2+) kg(-1) dry soil). Symbiosis with exotic AMF did not significantly affect growth of both sexes and biomass allocation. However, when inoculated with AMF, both sexes absorbed more P, but not N in the roots, especially when exposed to the exogenous addition of Pb. The improvement of nutrient status under such conditions might be associated with a further increase in activity of antioxidant enzymes (particularly for superoxide dismutase (SOD) and catalase (CAT)), and the mitigation of oxidation stress induced by excessive reactive oxygen species (ROS). We also observed that exotic AMF could promote the uptake and accumulation of Pb in roots of females, but not in that of males. Therefore, under this diffused pollution level, the infected females might be more suitable for remediation of this metal than infected males, due to the higher capacity of HM accumulation without obvious negative effects on growth and physiological traits. Moreover, field surveys are needed to testify our experimental results, due to diversity of soil microbial community and complexities of their interaction. PMID- 25553417 TI - Aquatic degradation of Cry1Ab protein and decomposition dynamics of transgenic corn leaves under controlled conditions. AB - The increasing cultivation of genetically modified corn plants (Zea mays) during the last decades is suggested as a potential risk to the environment. One of these genetically modified variety expressed the insecticidal Cry1Ab protein originating from Bacillus thuringiensis (Bt), resulting in resistance against Ostrinia nubilalis, the European corn borer. Transgenic litter material is extensively studied regarding the decomposition in soils. However, only a few field studies analyzed the fate of the Cry1Ab protein and the impact of green and senescent leaf litter from corn on the decomposition rate and related ecosystem functions in aquatic environments. Consequently, a microbial litter decomposition experiment was conducted under controlled semi-natural conditions in batch culture using two maize varieties: one variety with Cry1Ab and another one with the appertaining Iso-line as control treatment. The results showed no significant differences between the treatment with Cry1Ab and the Iso-line regarding loss of total mass in dry weight of 43% for Iso-line and 45% for Bt-corn litter, lignin content increased to 137.5% (Iso-line) and 115.7% (Bt-corn), and phenol loss decreased by 53.6% (Iso-line), 62.2% (Bt-corn) during three weeks of the experiment. At the end of the experiment Cry1Ab protein was still detected with 6% of the initial concentration. A slightly but significant lower cellulose content was found for the Cry1Ab treatment compared to the Iso-line litter at the end of the experiment. The significant higher total protein (25%) and nitrogen (25%) content in Bt corn, most likely due to the additionally expression of the transgenic protein, may increase the microbial cellulose degradation and decrease microbial lignin degradation. In conclusion a relevant year by year input of protein and therefore nitrogen rich Bt corn litter into aquatic environments may affect the balanced nutrient turnover in aquatic ecosystems. PMID- 25553419 TI - Intracellular trafficking and PIN-mediated cell polarity during tropic responses in plants. AB - Subcellular trafficking and cell polarity are basic cellular processes crucial for plant development including tropisms - directional growth responses to environmental stimuli such as light or gravity. Tropisms involve auxin gradient across the stimulated organ that underlies the differential cell elongation and bending. The perception of light or gravity is followed by changes in the polar, cellular distribution of the PIN auxin transporters. Such re-specification of polar trafficking pathways is a part of the mechanism, by which plants adjust their phenotype to environmental changes. Recent genetic and biochemical studies provided the important insights into mechanisms of PIN polarization during tropisms. In this review, we summarize the present state of knowledge on dynamic PIN repolarization and its specific regulations during hypocotyl tropisms. PMID- 25553421 TI - Analysis of 10 metabolites of polymethoxyflavones with high sensitivity by electrochemical detection in high-performance liquid chromatography. AB - Polymethoxyflavones (PMFs) have been known as a type of bioactive flavones that possess various beneficial biological functions. Accumulating evidence demonstrated that the metabolites of PMFs, that is, hydroxyl PMFs (OH-PMFs), had more potent beneficial biological effects than their corresponding parent PMFs. To facilitate the further identification and quantification of OH-PMFs in biological samples, the aim of this study was to develop a methodology for the simultaneous determination of 10 OH-PMFs using high-performance liquid chromatography (HPLC) coupled with electrochemistry detection. The HPLC profiles of these 10 OH-PMFs affected by different chromatographic parameters (different organic composition in mobile phases, the concentration of trifluoroacetic acid, and the concentration of ammonium acetate) are fully discussed in this study. The optimal condition was selected for the following validation studies. The linearity of calibration curves, accuracy, and precision (intra- and interday) at three concentration levels (low, middle, and high concentration range) were verified. The regression equations were linear (r > 0.9992) over the range of 0.005-10 MUM. The limit of detection for 10 OH-PMFs was in the range of 0.8-3.7 ng/mL (S/N = 3, 10 MUL injection). The recovery rates ranged from 86.6 to 108.7%. The precisions of intraday and interday analyses were less than 7.37 and 8.63% for relative standard deviation, respectively. This validated method was applied for the analysis of a variety of samples containing OH-PMFs. This paper also gives an example of analyzing the metabolites of nobiletin in mouse urine using the developed method. The transformation from nobiletin to traces of 5-hydroxyl metabolites has been discovered by this effective method, and this is the first paper to report such an association. PMID- 25553420 TI - Elastin aging and lipid oxidation products in human aorta. AB - Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by 4-HNE. These data indicate a complex role for lipid peroxidation and in particular for 4-HNE in elastin homeostasis, in the vascular wall remodeling during aging and atherosclerosis development. PMID- 25553422 TI - Pentraxin 3 serum levels in celiac patients: evidences and perspectives. AB - Celiac disease (CD) is now considered, more than a just gluten sensitivity enteropathy, a multiple and systemic immune-mediate disorder triggered by the ingestion of wheat gluten and related proteins. Following the discovery of a link between gluten and CD, it was demonstrated that gliadin, one of the two principal protein groups comprising gluten, plays a key role in CD. It has since become clear that the different and crucial roles of gliadin in CD result from its ability to activate multiple signaling pathways that modulate CD pathology. Most of these pathways involve the host innate and adaptive immune responses, but some pathways are activated when gliadin interacts with the intestinal cellular compartment. The long pentraxin (PTX3), a marker of the acute-phase inflammatory response, plays an important role in innate immunity and in modulation of the adaptive immune response. We investigated whether CD patients, considered as a model of gluten-sensitivity condition, have increased PTX3 levels. Our data showed that PTX3 serum levels were high in active CD patients and serum levels of PTX3 correlated with DGP IgA levels. We provide evidences that the bad compliance of GFD in patients 2 concurred with a pathological PTX3 concentration that could follow the improvement of both gastrointestinal and extraintestinal symptoms. We hypothesized that PTX3 is able to modulate the innate response to gliadin in CD and it could regulate the adaptive immune response. It is also evidenced that a common "wooden horse" of CD and Non Celiac Gluten Sensitivity (NCGS) is the ingestion of gluten and related toxic peptides. At the moment we don't have adequate elements to suggest the use of PTX3 in diagnosis of NCGS, but we are obliged to speculate about the possible role of PTX3 molecules in NCGS pathogenesis. The identified new strategies and uses of PTX3 could improve the management of gluten sensitivity conditions in the next future. PMID- 25553423 TI - Down-regulating glypican-3 expression: molecular-targeted therapy for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) prognosis is very poor, its early treatment is of the utmost importance. Glypican-3 (GPC-3), a membrane-associated heparan sulfate proteoglycan, plays a crucial role in cell proliferation and metastasis, particularly in progression. GPC-3 mediated oncogenesis involves signaling pathways during the malignant transformation of hepatocyte carcinogenesis, with an increasing expression of GPC-3 observed from non-cancerous- to cancerous tissues, with brown granule-like staining localized in tumor parts of atypical hyperplasia and HCC formation. GPC-3 expression in HCC tissues or circulating blood was associated with tumor size or HBV infection. Circulation of GPC-3-mRNA was detected in HCC patients with relation to TNM stage, periportal cancerous embolus, and extra-hepatic metastasis. After hepatoma, cells were transfected with shRNA, GPC-3 expression or proliferation was inhibited with promoting apoptosis, cell cycle arrested in G1 phase, alteration of hepatoma cell migration and invasion behaviors with down-regulation of beta-catenin, IGF-II, and VEGF, and growth of nude mice xenograft tumors was significantly suppressed with the decreases in beta-catenin, p-GSK3beta, and cyclinD1 expression, suggesting that GPC-3 not only is a specific biomarker for HCC diagnosis, but also is a valuable molecular-target for HCC gene therapy. PMID- 25553424 TI - Recent advances on the green synthesis and antioxidant activities of pyrazoles. AB - Pyrazoles have a representative history in medicinal chemistry. These nucleuses, molecules of synthetic origin, constitute a group of nitrogen heterocyclic compounds. Available literature particularly shows a variety of pyrazoles with antioxidant effect. In this connection, this review describes the advances on the green synthesis of pyrazoles with antioxidant activity, mainly covering the data published over the last seven years (2008-2014). PMID- 25553425 TI - Small molecular inhibitors for the treatment of rheumatoid arthritis: progress so far. AB - Rheumatoid Arthritis (RA) is an autoimmune disease characterized by persistent inflammation and joint damage. The main aim of RA treatment is to control the disease progress. Despite the success of biologicals like Adalimumab, Atlizumab, infliximab, etc. in treatment of RA, the high cost and associated immunological adverse effects have triggered discovery of small molecules targeting RA. This review describes the last 15 years of small molecular drug discovery in RA, focused mainly on preclinical and clinical studies. PMID- 25553426 TI - Natural and Semi synthetic Antimalarial Compounds: Emphasis on the Terpene Class. AB - Malaria is one of the most important tropical diseases since more than 40% of the world population is at risk. This disease is endemic to more than 100 nations and remains one of the main leading causes of death in children less than five years of age worldwide. Natural product-derived compounds have played a major role in drug discovery, often as prototypes to obtain more active semi synthetic derivatives. Antimalarial pharmacotherapy is a significant example of plant derived medicines, such as quinine and artemisinin. This review highlights studies on terpenes and their semi synthetic derivatives from natural sources with antimalarial activity reported in the literature during eleven years (2002 2013). A total of 114 compounds are found among terpenes and their semi synthetic derivatives. Cytotoxicity of the compounds is also found in this review. Furthermore, the physicochemical properties of the terpenes addressed are discussed based on seven well established descriptors, which provide a useful source for the elaboration of a terpene library of antimalarial compounds. PMID- 25553427 TI - 3,4-DHQLO and Triazole and Its Related Analogues with Anticonvulsant Effects. AB - The derivatives of quinolinone and triazole exhibit antitumor, antiplatelet, antidepressant, and anticonvulsant properties in diverse experimental systems. In the past decades, we have developed increasingly potent anticonvulsant agents by the structural modification of compounds derived from 3,4-DHQLO, triazole, and their analogs. Herein, we report the design and synthesis of a new series of 3,4 DHQLO and triazole and their derivatives; their anticonvulsant activity was evaluated. Moreover, we also reviewed the anticonvulsant activity of 3,4-DHQLO and triazole and their derivatives and new approaches. PMID- 25553428 TI - Piperine: bioactivities and structural modifications. AB - Piperine is a simple alkaloid isolated from the seeds of Piper nigrum. Piperine and its derivatives exhibited a wide range of biological properties such as antitumor activity, antioxidant activity, antiinflammatory activity, antimycobacterial activity, insecticidal activity, etc. Although five excellent reviews have recently been described by Srinivasan in 2007, Mao in 2011, Butt in 2013, and Meghwal in 2013, respectively, their topics were mainly focused on the biological effects. Therefore, in the present review, the progress in the structural modifications on the aliphatic chain and the amide moiety of piperine was reported. Meanwhile, the biological activities and structure-activity relationship of piperine and its derivatives were also described. PMID- 25553429 TI - Recent advances in natural product-based anti-biofilm approaches to control infections. AB - Bacterial biofilms are highly organized surface-associated communities of bacteria encased within an extracellular matrix produced by themselves, capable of growing in connection with different biological or inert surfaces such as artificial joints or catheters. Biofilms are commonly associated with many health problems, such as endocarditis, otitis media, periodontitis, prostatitis, and urinary tract infections. Several bacteria, such as Escherichia coli, Staphylococcus aureus, Streptococcus mutans, and Pseudomonas aeruginosa, or fungal pathogen as Candida albicans, can form biofilms in the body tissues, leading to different infections. The inherently defensive character of the biofilm is demonstrated by enhanced persistence of bacteria grown in the sessile mode respect to bacteria grown planktonically. This makes most biofilm- associated infections difficult to eradicate, thus contributing to disease chronicity. Since natural products provide a diverse array of chemical structures and possess a wide variety of biological properties, natural resources are worldwide exploited in the search of new pharmaceuticals. In this context bioactive secondary metabolites from natural sources, useful for the new antimicrobial and anti-biofilm drugs, are of interest. In this review, the role of small molecules from plants and marine organisms in inhibiting and/or dispersing bacterial biofilms is discussed, as well as the approaches that have been applied to the discovery of lead small molecules that mediate biofilm development. Molecules inhibiting the formation of biofilm may have therapeutic potential. Several candidates, as halogenated furanones, 2-amminoimidazole alkaloids and flavonoids have been already isolated and characterized from many plants and from marine organisms. PMID- 25553430 TI - Immunomodulatory effects of endogenous and synthetic peptides activating opioid receptors. AB - The main role of endogenous opioid peptides is the modulation of pain. Opioid peptides exert their analgesic activity by binding to the opioid receptors distributed widely in the central nervous system (CNS). However, opioid receptors are also found on tissues and organs outside the CNS, including the cells of the immune system, indicating that opioids are capable of exerting additional effects in periphery. Morphine, which is a gold standard in the treatment of chronic pain, is well-known for its immunosuppressive effects. Much less is known about the immunomodulatory effects exerted by endogenous (enkephalins, endorphins, dynorphins and endomorphins) and synthetic peptides activating opioid receptors. In this review we tried to summarize opioid peptide-mediated modulation of immune cell functions which can be stimulatory as well as inhibitory. PMID- 25553431 TI - Strategies for development of antimalarials based on encapsulated porphyrin derivatives. AB - Despite the efforts in controlling the parasite and infection, and the significant progress achieved in recent years in its treatment, malaria is still prevalent in many regions and out of control in others. The repertoire of alternatives to fight malaria is being expanded, not only by designing new drugs but also by developing improved drug delivery systems able to enhance the antimalarial efficiency of conventional and new drugs. Among the new drugs that have been investigated, several publications report the use of porphyrin derivatives as antimalarials but their efficiency is contradictory. The low activity of porphyrins seems to be associated with low dispersibility and bioavailability. In this respect, Nanotechnology can provide efficient solutions to enhance bioavailability and delivery of conventional and new antimalarials, in order to assure high enough efficiency levels to inactivate the parasite. Thus, in this review we highlight the use of drug delivery systems for conventional and new antimalarials and we propose the encapsulation of porphyrins as a promising alternative for development of anti-malarial formulations. PMID- 25553432 TI - New Validated RP-HPLC Analytical Method for Simultaneous Estimation of Atorvastatin and Ezetimibe in Bulk Samples as Well in Tablet Dosage Forms by Using PDA Detector. AB - This paper describes a new RP-HPLC method for simultaneous quantification of these compounds in the bulk sample drug as well as in tablet dosage forms. The chromatographic separation was performed on an XTerra C8 (4.6 x 250 mm; 5 um), with phosphate buffer [pH 3.5] and acetonitrile in the ratio of 40:60 (v/v) as mobile phase. The detection was carried out at 240 nm. The accuracy was found to be 99.59% and 98.98% for atorvastatin and ezetimibe respectively. The linearity was 5-25 ug/ml for both the drugs. The intra-day RSD was 0.57% and inter-day RSD was 0.13% for atorvastatin calcium and intra-day RSD was 0.56% and inter-day RSD was 0.09% for ezetimibe. The validation of method was carried out utilizing ICH guidelines. PMID- 25553433 TI - An insight into purine, tyrosine and tryptophan derived marine antineoplastic alkaloids. AB - There is an ever-increasing need for the development of new drugs with safe and improved profile for the treatment of cancer. From time immemorial, nature has been considered as an abundant source of medicinal compounds having therapeutic properties. An enormous chemical diversity is present in thousands and millions of species of microorganisms, marine organisms, plants and animals that can act as potential therapeutic agents against various types of human cancer. Literature survey revealed that many alkaloids isolated from marine cyanobacteria, fungi, algae, sponges and tunicates displayed a wide range of anticancer properties like antiproliferative, antiangiogenic, induction of apoptosis, promoting cytotoxicity by inhibition of topoisomerase activities and tubulin polymerization. In this context, bastadins derived from tyrosine-based alkaloids have been reported as one the important class of anticancer agents. In particular bastadin 6 (24), seems to be a promising natural lead compound for the development of marine natural product-based anticancer therapeutic agents. This review mainly highlights the pharmacologically active scaffolds like purine, tyrosine and tryptophan containing marine alkaloids that exhibit biological activity, including anti-angiogenesis, cytotoxicity and anticancer activity. PMID- 25553434 TI - Recent trends of chalcones potentialities as antiproliferative and antiresistance agents. AB - Chalcones are natural compounds found in plants, fruits and vegetables. This class of compounds has shown many biological activities including antioxidant, antimicrobial, anti-inflammatory, antifungal and antihypertensive, among others. In cancer, it has been reported that chalcones interfere in several points of the signal transduction pathways related to cellular proliferation, angiogenesis, metastasis, apoptosis and the reversal of multidrug resistance. The large number of research articles and patents related to chalcones is already an indication of their importance as a lead class of compounds. This article gathers recent efforts to elucidate the molecular mechanisms of action of chalcones, associated with their anticancer and anti resistance potential. PMID- 25553435 TI - Anticancer Activity of Polyether Ionophore-Salinomycin. AB - Since the discovery of unusual anti-tumor activity of natural polyether antibiotic - Salinomycin, this compound, along with its derivatives, has been intensively studied against different human cancer cells, both in vivo and in vitro. Salinomycin has shown strong inhibition activity against the proliferation process of many different cancer cells, including multi-drug resistance (MDR) cancer cells, as well as cancer stem cells (CSCs), i.e. leukemic stem cells, colon carcinoma stem cells, prostate cancer stem cells and many others. Additionally, the application of Salinomycin has been proved to enhance the anti cancer effect of radio- and chemotherapy. Preliminary clinical studies have shown tumor regression and only transient acute side effects after application of Salinomycin. Up to now, major efforts have been devoted to elucidate the biological mechanisms of anti-tumor activity of Salinomycin and it is expected that the results may provide new therapeutic strategies based on biological modulation of Salinomycin activity. This review is focused on and describes the possible role of Salinomycin in cancer therapy and gives an overview of its properties. PMID- 25553437 TI - Coumarin: a promising scaffold for anticancer agents. AB - Coumarin enjoys an important place in drug discovery process due to its presence in diversity of biologically active compounds. Many compounds of plant origin are derivatives of coumarin. Taking these natural products as lead, research groups across the globe have designed and synthesized numerous coumarin analogues for treatment of varied diseases. Cancer is one of the dreadful chronic diseases, and many drugs are available for its treatment. However, due to heterogeneity of cancer, the search is still on to develop drugs for specific types of cancers. The present review is an attempt to study various coumarin derivatives of natural as well as synthetic origins, which are identified or developed for the treatment of different types of cancers. Herein, we have classified various anticancer coumarin derivatives on the basis of their origin as well as substitution around it. These are discussed under the headings of natural, semi-synthetic and synthetic coumarin derivatives. The synthetic coumarin derivatives are further classified as mono-, di- and poly-substituted and fused coumarin derivatives. Of the six positions available for substituents on coumarin nucleus, only three positions (C-3, C-4 and C-7) are exploited for the selection of functional groups appropriate for anticancer activity. The other positions (C-5, C-6 and C-8) are either unexplored or very less exploited. The present review is expected to provide the medicinal chemists a guide to choose new functional groups for substitution at different positions of coumarin nucleus for development of novel compounds for the treatment of a specific type of cancer. PMID- 25553436 TI - Curcumin as an adjuvant to breast cancer treatment. AB - Cancer is the second largest leading cause of death worldwide and breast cancer is the most prevailing cause of mortality among all cases of malignant neoplastic disease in adult females. The incidence rate of breast malignant neoplastic disease is predominantly higher in Western women, when compared to women in Asian nations. The definitive reason for this conflict is even unknown, but dietary factors have been conceived to account for approximately 30% of cancers in Western nations. It has been hypothesized that ethnicity, including use of a variety of spices in the food would be a major reason. Among all spices, turmeric (Curcuma longa) has been proven for its better anticancer potential. In this review different molecular mechanisms including cell cycle arrest; G0/G1 and/or G2/M phase cell cycle arrest by up-regulating Cdk inhibitor, p21/WAF/CIPI and p53, inhibition of transcriptional factors; NFkappaB, AP-1, TNFalpha, IL, STAT-3, and PPAR-gamma, downstream gene regulation; c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNFalpha, interleukins and MMP-9, growth factors; bFGF, EGF, GCSF, IL-8, PDGF, TGFalpha, TNF, VEGF and cell adhesion molecules; fibronectin, vitronectin, and collagen which are involved in angiogenesis and metastasis, alsothe effectiveness of curcumin, when given in combination with chemotherapeutics like cyclophosphamide, doxorubicin, mitomycin etc. in treating breast cancer have been reviewed. PMID- 25553438 TI - New treatments for cutaneous metastatic melanoma: MAPK pathway-targeted and immune based therapies. AB - Increasing knowledge on cellular biology has permitted rapid changes in the treatment of metastatic melanoma. Until 2011, dacarbazine was the gold standard treatment at our disposal. In 2011 the treatment landscape changed dramatically with the approval by the FDA of ipilimumab and vemurafenib. These drugs use two new therapeutic approaches: immunomodulation and the targeting of mutated cellular pathways in tumor cells. These two drugs, used as single agents have shown important increases in overall survival, unseen before in patients with advanced melanoma, but are limited by their toxicities and the appearance of acquired resistances. In this article, we review new therapeutic options in pathway-targeted -with the arrival of MEK inhibitors - and immune based melanoma therapies -with the arrival of anti-PD1 and anti-PDL1- as well as new therapeutic strategies developed to overcome acquired resistance and diminish drug toxicities. PMID- 25553439 TI - Post-transcriptional inducible gene regulation by natural antisense RNA. AB - Accumulating data indicate the existence of natural antisense transcripts (asRNAs), frequently transcribed from eukaryotic genes and do not encode proteins in many cases. However, their importance has been overlooked due to their heterogeneity, low expression level, and unknown function. Genes induced in responses to various stimuli are transcriptionally regulated by the activation of a gene promoter and post-transcriptionally regulated by controlling mRNA stability and translatability. A low-copy-number asRNA may post-transcriptionally regulate gene expression with cis-controlling elements on the mRNA. The asRNA itself may act as regulatory RNA in concert with trans-acting factors, including various RNA-binding proteins that bind to cis-controlling elements, microRNAs, and drugs. A novel mechanism that regulates mRNA stability includes the interaction of asRNA with mRNA by hybridization to loops in secondary structures. Furthermore, recent studies have shown that the functional network of mRNAs, asRNAs, and microRNAs finely tunes the levels of mRNA expression. The post transcriptional mechanisms via these RNA-RNA interactions may play pivotal roles to regulate inducible gene expression and present the possibility of the involvement of asRNAs in various diseases. PMID- 25553441 TI - The role of circulating microRNA in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a rapidly progressing disease that exerts a huge burden on patients and health care systems. Rapid progression and difficulty in detecting early disease are major obstacles in offering potentially curative treatments. Besides the lack of effective chemo- or immunotherapy for advanced disease, there are currently no reliable tumor markers or imaging technologies that can accurately diagnose early HCC or predict disease progression. Since the discovery of microRNA (miRNA) and its involvement in hepatocarcinogenesis, the literature describes their usefulness as potential new biomarkers and treatment targets. Some of these miRNAs can also be found in the systemic circulation. With advances in detection and sequencing technologies, an increasing amount of data demonstrate the possibility of using circulating miRNAs as biomarkers to improve our current management of HCC in a less-invasive manner. This paper will review circulating miRNAs with a known function in HCC, describing their role and function in tumorigenesis. This review discusses their potential use as biomarkers in conjunction with emerging treatments in the diagnosis and targeting of this disease. PMID- 25553442 TI - MicroRNAs in human glioblastoma: from bench to beside. AB - Glioblastoma (GBM) is the most common and malignant adult primary brain tumor and one of the most lethal types of all cancers. Currently, despite interventional therapy (e.g. multimodal treatments with surgery, radiotherapy and chemotherapy), the overall prognosis for GBM patients remains poor. Thus, it is necessary to understand the molecular pathogenesis of GBM, which provides new insight into modern therapy. As a novel molecule, microRNA (miRNA) contributes to the pathogenesis of various types of tumor, including GBM. So far, miRNA has been shown to function in regulating protein-coding gene expression. This allows miRNAs to have direct function in regulation of various cellular events, including cell proliferation, apoptosis, and differentiation. Great progress has been made in identifying novel tumor-related miRNAs and their potential target genes. In this review, we focus on the most current research in miRNAs and their role in GBM regulation. In addition, we summarize some miRNAs found as biomarkers in GBM and their role in treatment. PMID- 25553443 TI - The expression and function of microRNAs in bone homeostasis. AB - microRNAs (miRNAs) are a class of small, endogenous, non-coding single strand RNAs. miRNAs are involve in multiple developmental events during embryogenesis and adult tissue homeostasis. miRNAs regulate epigenetic regulating genes through post-transcriptional regulation and that epigenetic factors mediate the regulation of miRNA. Bone tissue homeostasis is maintained through the dynamic balance between osteoclastic bone resorption and osteoblastic bone formation. And miRNAs are important regulators of bone resorbing activity mediated by osteoclasts, as well as osteoblast proliferation and differentiation. This review summarizes recent studies bone-regulating miRNAs, which are divided into two major branches: the osteogenesis regulator and the osteoclastogenesis regulator. miRNAs can positively or negatively regulate osteogenesis and osteoclastogenesis. This review also discusses how miRNAs, target genes, intracellular effectors and transcription factors affect both the bone homeostasis and bone homeostasis processes. Disrupted the function of miRNAs is related to some bone diseases, such as osteoporosis. Studying the mechanisms underlying the role of miRNAs in the bone and mineral field may reveal potential therapeutic targets for treating metabolic bone disorders, bone loss and bone diseases. PMID- 25553444 TI - Isoflurane attenuates LPS-induced acute lung injury by targeting miR-155-HIF1 alpha. AB - Isoflurane alleviates the inflammatory response in endotoxin-induced acute lung injury (ALI). In this study, we investigated the protective mechanism of isoflurane postconditioning in lipopolysaccharide (LPS)induced ALI. Exposure to isoflurane decreased miR-155 and upregulated HIF-1 alpha and HO-1 mRNA and protein. The effects of isoflurane on HIF-1 alpha mRNA and protein could be inhibited by overexpression of miR-155. Furthermore, mice overexpressing miR-155 had higher levels of TNF-alpha and IL-1 beta in BALF when exposed to isoflurane after LPS challenge.Conversely, downregulation of miR-155 promoted isoflurane effects on HIF-1 alpha expression. These results suggest that isoflurane posttreatment hr alleviates LPS-induced ALI and cell injury by triggering miR-155 HIF-1 alpha pathway, leading to upregulation of HO-1. PMID- 25553445 TI - The role of mitochondrial fusion and fission in skeletal muscle function and dysfunction. AB - Classic textbook depictions of mitochondria portray these organelles to be static bean-shaped structures. However the mitochondrial population is quite heterogeneous, and can form small individual organelles or extended reticula throughout muscle. This morphological plasticity is controlled by fission and opposing fusion events. Skeletal muscle mitochondrial morphology has been demonstrated to be altered under various disease conditions, including diabetes, denervation, as well as during development, aging, and exercise. This implies that mitochondrial fission and fusion machinery components are involved in regulating the architecture of the organelle during various states of muscle use and disuse. Furthermore, disruptions in either of these opposing processes have been demonstrated to result in diseases, suggesting that proper maintenance of mitochondrial morphology is critical for proper cell function. PMID- 25553440 TI - The role of microRNAs in skeletal muscle health and disease. AB - Over the last decade non-coding RNAs have emerged as importance regulators of gene expression. In particular, microRNAs are a class of small RNAs of ~ 22 nucleotides that repress gene expression through a post-transcriptional mechanism. MicroRNAs have been shown to be involved in a broader range of biological processes, both physiological and pathological, including myogenesis, adaptation to exercise and various myopathies. The purpose of this review is to provide a comprehensive summary of what is currently known about the role of microRNAs in skeletal muscle health and disease. PMID- 25553446 TI - Critical analysis of Alzheimer's amyloid-beta toxicity to mitochondria. AB - Amyloid-beta peptide (Abeta) is believed to be a central player in the Alzheimer disease (AD) pathogenesis. However, its mechanisms of toxicity to the central nervous system are unknown. To explore this area, investigators have recently focused on Abeta-induced cellular dysfunction. Extensive research has been conducted to investigate Abeta monomers and oligomers, and these multiple facets have provided a wealth of data from specific models. Abeta appears to be accumulated in neuronal mitochondria and mediates mitochondrial toxicity. Mitochondrial dysfunction became a hallmark of Abeta-induced neuronal toxicity. Mitochondria are currently considered as primary targets in the pathobiology of neurodegeneration. This review provides an overview of the Abeta toxicity to isolated mitochondria, mitochondria in different tissues and cells in vitro and in vivo. Full texts and abstracts from all 530 biomedical articles listed in PubMed and published before January 2014 were analysed. The mechanisms underlying the interaction between Abeta and mitochondrial membranes and resulting mitochondrial dysfunction are most disputed issues. Understanding and discussing this interaction is essential to evaluating Abeta effects on various intracellular metabolic processes. PMID- 25553447 TI - Mitochondrial bioenergetics and disease in Caenorhabditis elegans. AB - Simple multicellular animal model systems are central to studying the complex mechanisms underlying a bewildering array of diseases involving dysfunctional mitochondria. Mutant nuclear- and mitochondrial-encoded subunits of the Caenorhabditis elegans mitochondrial respiratory chain (MRC) have been investigated, including GAS-1, NUO-1, NUO-6, MEV-1, SDHB-1, CLK-1, ISP-1, CTB-1, and ATP-2. These, as well as proteins that modify the MRC indirectly, have been studied on the molecular, cellular, and organismal levels through the variety of experimental approaches that are readily achievable in C. elegans. In C. elegans, MRC dysfunction can mimic signs and symptoms observed in human patients with primary mitochondrial disorders, such as neuromuscular deficits, developmental delay, altered anesthetic sensitivity, and increased lactate levels. Antioxidant dietary supplements, coenzyme Q substitutes, and flavin cofactors have been explored as potential therapeutic strategies. Furthermore, mutants with altered longevity have proved useful for probing the contributions of bioenergetics, reactive oxygen species, and stress responses to the process of aging. C. elegans will undoubtedly continue to provide a useful system in which to explore unanswered questions in mitochondrial biology and disease. PMID- 25553449 TI - Protective action of green tea catechins in neuronal mitochondria during aging. AB - Mitochondria are central players in the regulation of cell homeostasis. They are essential for energy production but at the same time, reactive oxygen species accumulate as byproducts of the electron transport chain causing mitochondrial damage. In the central nervous system, senescence and neurodegeneration occur as a consequence of mitochondrial oxidative insults and impaired electron transfer. The accumulation of several oxidation products in neurons during aging prompts the idea that consumption of antioxidant compounds may delay neurodegenerative processes. Tea, one of the most consumed beverages in the world, presents benefits to human health that have been associated to its abundance in polyphenols, mainly catechins, that possess powerful antioxidant properties in vivo and in vitro. In this review, the focus will be placed on the effects of green tea catechins in neuronal mitochondria. Although these compounds reach the brain in small quantities, there are several possible targets, signaling pathways and molecular machinery impinging in the mitochondria that will be highlighted. Accumulated evidence thus far seems to indicate that catechins help prevent neurodegeneration and delay brain function decline. PMID- 25553450 TI - Lipid rafts involvement in the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases affecting an increasing number of people worldwide with the aging society. Although the etiology of PD remains largely unknown, it is now clear that genetic factors contribute to the pathogenesis of the disease. Recently, several causative genes have been identified in mendelian forms of PD. Growing evidence indicates that their gene products play important roles in oxidative stress response, mitochondrial function, and the ubiquitin-proteasome system, which are also implicated in idiopathic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and idiopathic PD. Interestingly, several lines of evidence show that the gene products associate with lipid rafts which are thought to be involved in important cellular functions such as membrane trafficking, signal transduction, and cytoskeletal organization. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains on the cell membranes that provide a highly saturated and viscous physicochemical microenvironment to promote protein lipid and protein protein interactions. In this article, we will review studies focusing on PD in association with lipid rafts and discuss implication of lipid rafts in the pathogenesis of PD. PMID- 25553451 TI - Membrane lipid domains in the nervous system. AB - The structural properties of the lipids forming biological membranes determine a very high level of lateral organization within membranes. Lipid-driven membrane organization allows the segregation of membrane-associated components into membrane lipid domains, now worldwide known as lipid rafts, acting as dynamic platforms for signal transduction, protein processing and membrane turnover. Many processes necessary to the correct functions of nervous system occur in lipid rafts and are dependent on lipid raft organization. Thus, an altered lipid composition frequently occurring in neurodegenerative diseases leads to anomalous lipid raft organization and then to deregulated cell signaling. PMID- 25553448 TI - Morphological control of mitochondrial bioenergetics. AB - The major function of mitochondria is production and supply of cellular energy. Mitochondria are highly dynamic organelles undergoing frequent shape changes via fission and fusion. Many studies have elucidated the molecular components mediating fission and fusion and their regulatory mechanisms, and mitochondrial shape change is now recognized as an essential cellular process that is closely associated with functional states of mitochondria. This review updates the recent advancements in fission and fusion mechanisms, and discusses the bi-directional relationship between mitochondrial morphology and energetic states in physio pathological settings. PMID- 25553452 TI - Lipid rafts and their possible involvements in neuroimmunological disorders. AB - Multiple sclerosis (MS) and neuromyelitis optica (NMO) are presumed to be an autoimmune disease in the central nervous system (CNS). Although lipids are most abundant components in the nervous system, it has been believed that cellular and/or humoral immunity to various myelin proteins causes these neuroinflammatory diseases. Recent research advances enable us to study lipids in the membranes and some key molecules involved in various neurological disorders including Guillain Barre syndrome, Alzheimer's disease, Parkinson's disease, and prion disease, are localized in lipid rafts. In MS and NMO, the key molecules for the pathogenesis or the target molecules for the treatments of MS and NMO are also localized in lipid rafts. Here in this article, we highlight on the possible involvement of lipid rafts in the pathogenesis and treatment of MS and NMO and introduce our recent observation of aquaporin 4 regarding NMO. PMID- 25553453 TI - Amyloid beta-protein and lipid rafts: focused on biogenesis and catabolism. AB - Cerebral accumulation of amyloid beta-protein (Abeta) is thought to play a key role in the molecular pathology of Alzheimer's disease (AD). Three secretases (beta-, gamma-, and alpha-secretase) are proteases that control the production of Abeta from amyloid precursor protein. Increasing evidence suggests that cholesterol-rich membrane microdomains termed 'lipid rafts' are involved in the biogenesis and accumulation of Abeta as well as Abeta-mediated neurotoxicity. gamma-Secretase is enriched in lipid rafts, which are considered an important site for Abeta generation. Additionally, Abeta-degrading peptidases located in lipid rafts, such as neprilysin, appear to play a role in Abeta catabolism. This mini-review focuses on the roles of lipid rafts in the biogenesis and catabolism of Abeta, covering recent research on the relationship between lipid rafts and the three secretases or Abeta-degrading peptidases. Furthermore, the significance of lipid rafts in Abeta aggregation and neurotoxicity is briefly summarized. PMID- 25553454 TI - Involvement of glycosphingolipid-enriched lipid rafts in inflammatory responses. AB - Glycosphingolipids (GSLs) are membrane components consisting of hydrophobic ceramide and hydrophilic sugar moieties. GSLs cluster with cholesterol in cell membranes to form GSL-enriched lipid rafts. Biochemical analyses have demonstrated that GSL-enriched lipid rafts contain several kinds of transducer molecules, including Src family kinases. Among the GSLs, lactosylceramide (LacCer, CDw17) can bind to various microorganisms, is highly expressed on the plasma membranes of human phagocytes, and forms lipid rafts containing the Src family tyrosine kinase Lyn. LacCer-enriched lipid rafts mediate immunological and inflammatory reactions, including superoxide generation, chemotaxis, and non opsonic phagocytosis. Therefore, LacCer-enriched membrane microdomains are thought to function as pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) expressed on microorganisms. LacCer also serves as a signal transduction molecule for functions mediated by CD11b/CD18-integrin (alphaM/beta2-integrin, CR3, Mac-1), as well as being associated with several key cellular processes. LacCer recruits PCKalpha/epsilon and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and their adhesion to endothelial cells, as well as regulating beta1-integrin clustering and endocytosis on cell surfaces. This review describes the organizational and inflammation-related functions of LacCer-enriched lipid rafts. PMID- 25553455 TI - Single amino acid polymorphism in aldehyde dehydrogenase gene superfamily. AB - The aldehyde dehydrogenase gene superfamily comprises of 19 genes and 3 pseudogenes. These superfamily genes play a vital role in the formation of molecules that are involved in life processes, and detoxification of endogenous and exogenous aldehydes. ALDH superfamily genes associated mutations are implicated in various diseases, such as pyridoxine-dependent seizures, gamma hydroxybutyric aciduria, type II Hyperprolinemia, Sjogren-Larsson syndrome including cancer and Alzheimer's disease. Accumulation of large DNA variations data especially Single Amino acid Polymorphisms (SAPs) in public databases related to ALDH superfamily genes insisted us to conduct a survey on the disease associated mutations and predict their function impact on protein structure and function. Overall this study provides an update and highlights the importance of pathogenic mutations in associated diseases. Using KD4v and Project HOPE a computational based platform, we summarized all the deleterious properties of SAPs in ALDH superfamily genes by the providing valuable insight into structural alteration rendered due to mutation. We hope this review might provide a way to define the deleteriousness of a SAP and helps to understand the molecular basis of the associated disease and also permits precise diagnosis and treatment in the near future. PMID- 25553456 TI - Protein tyrosine phosphatases in pathological process. AB - Protein tyrosine phosphatases (PTPs) modulate the cellular level of tyrosine phosphorylation under normal and pathological conditions, and thus exert either stimulatory or inhibitory effect on signal transduction. Hence, PTPs are potential pharmacological targets for novel drugs being developed in order to treat numerous pathologies including cancer. For example, PTPs have been found to play a key role in pathogenesis of autoimmune disorders, allergic response, cardiovascular or neurodegenerative diseases, among others Alzheimer?'s disease. Moreover, since many PTPs fine-tune subtle regulation of microbial biochemistry controlling the viability and virulence, they can be candidates for new therapies of infection diseases. In this review, authors summarize the current knowledge on PTPs implication in etiopathogenesis of most common human diseases focusing on PTPs as potential therapeutical targets. PMID- 25553457 TI - From toxins to mammalian enzymes: the diversity of mono-ADP-ribosylation. AB - The ADP-ribosylation of proteins is a phylogenetically ancient mechanism that involves the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to specific amino acids of target proteins post-translationally. In the first part of this review, we briefly describe ADP-ribosylation as the mechanism of action of toxins, while giving particular emphasis to a non-conventional ADP ribosylation reaction that is mediated by the fungal toxin brefeldin A (BFA). This modification results in the loss of the membrane fission activity of the C terminal binding protein (CtBP)1/ BFA-ADP-ribosylated substrate (BARS), thus blocking progression of cells into mitosis, with important implications for the design of new anticancer drugs. In addition, we summarize the most recent findings on mammalian, intracellular mono-ADP-ribosyl transferase enzymes, underlining the emerging functional roles in which they are involved, including immune responses, transcriptional regulation, stress responses, cell survival. The observation that several mono-ADP-ribosyl transferases, such as PARP-10, PARP 12, PARP-13, are involved in a range of physiological processes points at the multifunctional feature of these proteins. PMID- 25553458 TI - State of the art of protein mono-ADP-ribosylation: biological role and therapeutic potential. AB - Mono-ADP-ribosylation is a post-translational modification that was discovered more than five decades ago, and it consists of the enzymatic transfer of ADP ribose from NAD+ to acceptor proteins. In viruses and prokaryotes, mono-ADP ribosylation is mainly, but not exclusively, a mechanism used to take control of the host cell. In mammals, mono-ADP-ribosylation serves to regulate protein functions, and it is catalysed by two families of toxin-related cellular ADP ribosyltransferases: ecto-enzymes that modify various cell-surface proteins, like integrins and receptors, and intracellular enzymes that act on a variety of nuclear and cytosolic proteins. These two families have been recently renamed the ARTCs (clostridia toxin like) and ARTDs (diphtheria toxin like), depending on their conserved structural features, and in terms of their relationships to the bacterial toxins. In addition, two members of the structurally non-related sirtuin family can also modify cellular proteins by mono-ADP-ribosylation. Recently, new examples of ADP-ribosylation of proteins involved in signal transduction and intracellular trafficking have been discovered, thus opening the route to the better molecular understanding of this reaction and of its role in human cell physiology and pathology. PMID- 25553459 TI - Past and current topics on ADP-ribosylation reactions. AB - The milestone of Adenosine Diphosphate-ribosylation studies was the paper by Paul Mandel's group in 1960s, first describing a "sort" of polyadenylic acid synthesized upon addition of nicotinamide mononucleotide in rat liver nuclear extracts. Nicotinic Acid or Niacin is the precursor of Nicotinamide Adenin Dinucleotide. In 1960s this compound was known mainly as coenzyme of most redox processes in metabolism. The discovery of enzymes that covalently transfer Adenosine Diphosphate-ribose moiety of Nicotinamide Adenin Dinucleotide to acceptor proteins, thereby altering their function, or are able to synthesize cyclic Adenosine Diphosphate-ribose, has given rise to the era of one of the most studied and still surprising reversible post - translational modification reactions. Over 50 years, developing the research on Adenosine Diphosphate ribosylation has provided the basis to interconnect several processes thought to be very distant each other, opening new perspectives in their regulation and in therapeutic intervention. Here a synthesis of the history and the main and recent goals reached studying Adenosine Diphosphate-ribose in all its features are provided by a series of reviews including the most advanced research. PMID- 25553460 TI - Poly-ADP-ribosylation signaling during DNA damage repair. AB - Poly-ADP-ribosylation is a post-translational modification generated in high amounts by poly-ADP-ribose polymerases (PARPs) in response to cellular stress, especially genotoxic stimuli. DNA damage-induced PARylation significantly changes local chromatin structure and triggers the accumulation of several DNA damage response (DDR) proteins at the DNA lesions. In this review, we will discuss the regulation of chromatin structure and DNA damage repair machineries by DNA damage induced poly-ADP-ribosylation. PMID- 25553461 TI - A new facet of ADP-ribosylation reactions: SIRTs and PARPs interplay. AB - Nicotinamide Adenine Dinucleotide (NAD+) is known mainly as coenzyme of redox reactions for energy transduction and is consumed as substrate in regulatory reactions removing nicotinamide and producing ADP-ribose. Several families of ADP ribose synthesizing enzymes use NAD+ as substrate and control processes like DNA repair, replication and transcription, chromatin structure, the activity of G proteins and others. Since NAD+-dependent reactions involve degradation of the dinucleotide, a constant supply of the pyridinic substrate is required for its homeostasis. NAD+-dependent signaling reactions include protein deacetylation by sirtuins, intracellular calcium signaling and mono-/poly-ADP-ribosylation. In the context of all NAD+-dependent reactions leading to ADP-ribose synthesis, this review focuses mainly on both the central role played by sirtuins and poly ADPribose polymerases as cellular NAD+ consumers and their crosstalk in signaling pathways. PMID- 25553462 TI - E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy. AB - E3 ubiquitin ligase Skp2 attaches ubiquitin to its target proteins and marks them for destruction by the 26S proteasome. This mechanism participates in a number of important cellular processes such as cell proliferation, DNA replication, V(D)J recombination, gene transcription, cellular metabolism and senescence. Skp2 is oncogenic. It is overexpressed in various solid tumors and hematological malignancies. Due to the antagonistic role Skp2 plays against p27, Skp2 overexpression is frequently associated with down-regulation of p27. Importantly, Skp2 overexpression in cancer cells is prognostic of cancer progression and overall survival. Recent studies have shown that Skp2 suppression might be an excellent strategy to inhibit tumorigenesis in tumors in which tumor suppressor genes such as VHL, RB or TP53 are mutated. In this review, we also summarize early efforts in the development of Skp2 inhibitors. The implications of continued, long-term Skp2 suppression is discussed. PMID- 25553463 TI - Functions and characteristics of PINK1 and Parkin in cancer. AB - Most of the Parkinson disease (PD) linked genes are also associated with cancers. In particular, phosphatase and tensin homologue-induced kinase 1 (PINK1) and Parkin, both of which are involved in recessively inherited familial forms of PD linked to mitochondrial dysfunction, appear to be abnormally expressed in cancers. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. Although PD and cancer are obviously disparate human disorders, there is an evidence for low cancer rates in patients with PD. The relationship between cancer rates and PD might be related to the involvement of common pathways in both diseases. This paper provides a concise overview on the cellular functions of the PINK1 and Parkin. PMID- 25553464 TI - Dehydroxymethylepoxyquinomicin selectively ablates T-CAEBV cells. AB - Chronic active Epstein-Barr virus infection (CAEBV) represents a new subtype of lymphoproliferative disorders characterized by high morbidity and mortality rates and often leads to malignant transformation of infected cells. Efficient therapeutic strategies are presently unavailable; therefore, the development of therapies to prevent CAEBV-mediated transformation and disease progression is crucial. Here, we used microarray analysis and luciferase reporter assays to reveal the potential role of activated nuclear factor kappa B (NF-kB) in T cell type of-CAEBV infection. Using a series of cellular and molecular experiments, we demonstrated that dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kB inhibitor, can selectively induce apoptosis in SNT-16 cells infected with CAEBV. Mechanistic studies suggested that DHMEQ induces SNT-16 cell apoptosis through NF kB inhibition coupled with oxidative stress generation. Thus, activated NF-kB could be a new target for CAEBV therapeutics. Owing to its selective targeting ability, DHMEQ may be a candidate for a novel therapeutic regimen to control the progression of CAEBV infections. PMID- 25553467 TI - Ghrelin receptor deficiency aggravates atherosclerotic plaque instability AB - Ghrelin has been found to be associated with anti-inflammatory effects, inhibition of atherosclerotic plaque formation, and plaque stability in the cardiovascular system. We investigated whether ghrelin affected atherosclerotic plaque and inflammation found in atherosclerosis. We crossed ghrelin receptor knock out mice (growth hormone secretagogue receptor (GHSR)-/-) and low-density lipoprotein receptor-null (low-density lipoprotein receptor (LDLR)-/-) mice. In this model, atherosclerotic lesions were promoted by administering a high-fat, high-cholesterol, Western-type diet for 18 weeks. Serum lipid levels, atherosclerotic plaque on the aortic arches, and expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), T cells, macrophages, and smooth muscle cells of atherosclerotic plaque were observed. Although serum lipid levels and atherosclerotic plaque in aortic arches were not significantly different between GHSR+/+/LDLR-/- and GHSR -/-LDLR-/- mice, ICAM-1 and VCAM-1 protein expression in atherosclerotic plaques were increased in GHSR -/-LDLR-/- mice compared with GHSR+/+/LDLR-/- mice. T cells and macrophages were increased, while smooth muscle cells of atherosclerotic plaques were less in GHSR -/-LDLR-/- mice than that in GHSR+/+/LDLR-/- mice. In conclusion, ghrelin receptor deficiency aggravates atherosclerotic plaque instability and vascular inflammation but not the surface area of atherosclerotic plaque. This information will provide novel avenues for the treatment of patients with atherosclerosis. PMID- 25553468 TI - MRI in differentiation of benign and malignant tongue tumors. AB - The differential diagnosis of benign and malignant tongue tumors is crucial to treatment and prognosis. Magnetic resonance imaging (MRI) is the preferred modality for the evaluation of tongue carcinomas. Dynamic contrast-enhanced (DCE) MRI can reflect the density, integrity, and leakiness of tumor vasculature, and the time-intensity curve (TIC) patterns derived from DCE-MRI results can differentiate benign from malignant tumors based on differences in vascular structure. Diffusion-weighted (DW)-MRI is based on the random thermal motion of water molecules and can provide information on the cellular and tissue microstructure of the tumor. A low apparent diffusion coefficient (ADC) derived from DW-MRIs may indicate a malignant tumor. Thus, ADC values and TIC parameters yield complementary information on tumors that may improve diagnostic accuracy. Indeed, the combination of DCE-MRI and DW-MRI is a comprehensive reflection of the pathological status of the tongue tumor, so utilization of these MRI modalities may facilitate the diagnostic differentiation of benign from malignant tumors of the tongue. PMID- 25553465 TI - Cilia/Ift protein and motor -related bone diseases and mouse models. AB - Primary cilia are essential cellular organelles projecting from the cell surface to sense and transduce developmental signaling. They are tiny but have complicated structures containing microtubule (MT)-based internal structures (the axoneme) and mother centriole formed basal body. Intraflagellar transport (Ift) operated by Ift proteins and motors are indispensable for cilia formation and function. Mutations in Ift proteins or Ift motors cause various human diseases, some of which have severe bone defects. Over the last few decades, major advances have occurred in understanding the roles of these proteins and cilia in bone development and remodeling by examining cilia/Ift protein-related human diseases and establishing mouse transgenic models. In this review, we describe current advances in the understanding of the cilia/Ift structure and function. We further summarize cilia/Ift-related human diseases and current mouse models with an emphasis on bone-related phenotypes, cilia morphology, and signaling pathways. PMID- 25553470 TI - HGF and c-Met in pathogenesis of endometrial carcinoma. AB - Hepatocyte growth factor (HGF) regulates cell growth, motility, and morphogenesis of various types of cells via its receptor c-Met. In the growth of endometrium, HGF/c-Met signaling promotes the proliferation of both endometrial epithelial cells and stromal cells. In the onset and development of several cancers, HGF/c Met signaling drives carcinogenesis and cancer invasion and metastasis. In endometrial carcinoma (EC), accounting for a majority of cancer-related morbidity and mortality among women, the increased expression of HGF and c-Met signaling is associated with a poor prognosis of EC patients. Thus, we will discuss the role of HGF and c-Met in the EC pathogenesis in this review. PMID- 25553471 TI - Molecular diagnosis in lung diseases. AB - The development of different molecular biology techniques in the past decade has led to an explosion of new research in molecular pathology with consequent important applications to diagnosis, prognosis, and therapeutics, as well as a clearer concept of the disease pathogenesis. Many methods used in molecular pathology are now validated and used in several areas of pathological diagnosis, particularly on infectious and neoplastic diseases. The spectrum of infectious diseases, especially lung infective diseases, is now broadening and modifying, thus the pathologist is increasingly involved in the diagnosis of these pathologies. The precise tissue characterization of lung infections has an important impact on specific therapeutic treatment. Increased knowledge of significant alterations in lung cancer has led today to a better understanding of the pathogenic substrate underlying the development, progression and metastasis of neoplastic processes. Molecular tests are now routinely performed in different lung tumors allowing a more precise patient stratification in terms of prognosis and therapy. This review focuses on molecular pathology of the principal infective lung diseases and tumors. PMID- 25553472 TI - Indications, outcomes, and complications of unicompartmental knee arthroplasty. AB - Improved prosthetic design and application of strict criteria in selection of patients have resulted in wide use of unicompartmental knee arthroplasty (UKA) in surgical treatment of damaged joints. Here, we review the contemporary indications, outcomes, and complications of procedures such as lateral and medial UKA and total knee arthroplasty (TKA), and compare the severity of these complications in UKA and TKA. Patients who received unicompartmental femorotibial osteoarthritis and patients who underwent UKA and ACL reconstruction for deficiency in anterior cruciate ligament (ACL), they all showed good clinical outcomes and survival. Reliable and successful options in the treatment of patients with isolated tibiofemoral osteoarthritis include lateral and medial UKA. PMID- 25553469 TI - Respiratory supercomplexes: plasticity and implications. AB - The plasticity model of the electron transport chain has slowly begun to replace both the liquid model of free complexes and the solid model of supercomplexes. The plasticity model predicts that respiratory complexes exist and function both as single complexes and as supercomplexes. The advantages of this system is an electron transport train which is able to adapt to changes in its environment. This review will investigate the current body of work on supercomplexes including their assembly, regulation, and plasticity, and particularly their role in the generation of reactive oxygen species and aging. PMID- 25553473 TI - Ciz1 promotes tumorigenicity of prostate carcinoma cells. AB - Prostate cancer is the most common malignancy in men and is the second leading cause of cancer-related mortality in developed countries. Recent work has revealed the significance of CIP-interacting zinc finger protein 1 (CIZ1) in cancer cell biology, but its roles in prostatic carcinoma are unknown. Our study compared CIZ1 gene expression in banked prostatic carcinomas versus matched paraneoplastic tissues and in tumor cell lines of varying origin. This study revealed that the expression of CIZ1 was higher in high-grade prostate cancer than in low-grade prostate cancer and normal tissues. Among the tumor cell lines, PC-3 exhibited the highest levels of CIZ1 expression. CIZ1 gene silencing in PC-3 cells reduced cell proliferation and colony formation, induced cell cycle arrest in G1, inhibited tumor formation in nude mice, and suppressed the expression of genes related to prostate carcinoma. These results suggest that CIZ1 may play an important role in the progression of human prostate carcinoma and us which may be used as a therapeutic target in prostate cancer. PMID- 25553474 TI - Differential effects of peripheral and transitional prostatic stromal cells on tumorigenesis. AB - The human prostate contains two types of stromal cells, peripheral stromal cells (PSCs) and transitional stromal cells (TSCs). Here, we demonstrate the effects of PSCs and TSCs on tumorigenesis in prostate cancer (PCa) and identify the mechanisms underlying these effects. Using microarray analysis, we identified 3,643 differentially expressed genes in cocultures of TSCs, PSCs, and DU145 cells, a human prostate cancer cell line. Expression of cell division cycle 25 homolog A (CDC25A) was lower and that of tumor-associated calcium signal transducer 2 (TACSTD2) was higher in TSCs than in PSCs. Additionally, increased CDC25A expression or decreased TACSTD2 expression modulated the survival, growth, and migration of DU145 cells. These data suggest that PSCs promote and TSCs inhibit tumorigenesis by regulating the expression of CDC25A and TACSTD2. PMID- 25553466 TI - Gene therapy for hemophilia. AB - Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID- 25553475 TI - Epigenetic programming contributes to development of drug resistance in hematological malignancies. AB - Epigenetics is the study of long term and stable but not necessarily heritable alterations in transcriptional potential and gene expression profile of a cell that are not due to any alterations in the DNA sequence. Epigenetic modifications include DNA methylation, posttranslational modifications of histone proteins and expression of small regulatory RNAs. In recent years, the role of epigenetic modifications in the development of hematological malignancies and drug resistance has been studied in depth and has shed light on this important issue. Here, we review the major epigenetic mechanisms that contribute to the generation and evolution of hematological malignancies and development of resistance to chemotherapy. We will also discuss the development of epigenetic drugs that can overcome resistance to conventional chemotherapy. PMID- 25553477 TI - Prediction of clinical outcome in severe traumatic brain injury. AB - Traumatic brain injury (TBI) is the main cause of death and disability in adults worldwide. Early detection of TBI would be useful for evaluating and designing treatment strategies. Both single predictors from early clinical examination and multiple hospitalization variables/parameters can be used to determine the long term prognosis of TBI. Predictive models like the IMPACT or CRASH prognosis calculator (based on large sample sizes) can predict mortality and unfavorable outcomes. Moreover, imaging techniques like MRI (Magnetic Resonance Imaging) can also predict consciousness recovery and mental recovery in severe TBI, while biomarkers associated with stress correlate with, and hence can be used to predict, severity and mortality. All predictors have limitations in clinical application. Further studies comparing different predictors and models are required to resolve limitations of current predictors. PMID- 25553478 TI - Inflammation in the pathogenesis of ischemic stroke. AB - Ischemic stroke is a common cause of permanent disability in adults worldwide. Inflammation plays a significant role in the pathogenesis of ischemic stroke and its mechanism is complex. Both pro-inflammatory and anti-inflammatory mediators are involved in the pathogenesis of ischemic stroke, an imbalance of which leads to inflammation. Inflammatory cells from both the innate and acquired immune systems are involved in ischemic stroke-related inflammation; processes that are linked by the action of interleukin-17A (IL-17A). Although most inflammatory cells promote inflammation, T regulatory cells (Tregs) may have a protective function at the early stages of an ischemic injury, but a negative role during later stages. However, the precise mechanism of inflammation in ischemic stroke remains elusive; further understanding of it may provide new ideas for the prevention and treatment of ischemic stroke. In this review, we discuss the role of pro-inflammatory and anti-inflammatory mediators and related immune cells in the pathogenesis of ischemic stroke. PMID- 25553476 TI - Rational clinical trial design for antibody mediated renal allograft injury. AB - Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID- 25553479 TI - Chronic kidney disease alters vascular smooth muscle cell phenotype. AB - Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes to the morbidity and mortality of chronic kidney disease (CKD) patients receiving hemodialysis. We hypothesized that the uremic conditions associated with CKD promote a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to neointimal hyperplasia. We analyzed the effect of culturing human VSMC with uremic serum. Expression of VSMC contractile marker genes was reduced 50-80% in cells exposed to uremic serum and the decreased expression was accompanied by changes in histone marks. There was an increase in proliferation in cells exposed to uremic conditions, with no change in the levels of apoptosis. Interestingly, we found that uremic serum inhibited PDGF-induced migration of VSMC. Histomorphometric analysis revealed venous neointimal hyperplasia in veins from chronic kidney disease (CKD) patients prior to any surgical manipulation as compared to veins from patients with no kidney disease. We conclude that uremia associated with CKD alters VSMC phenotype in vitro and contributes to neointimal hyperplasia formation in vivo contributing to the pathogenesis of vascular access dysfunction in CKD patients. PMID- 25553480 TI - Nutritional and regulatory roles of leucine in muscle growth and fat reduction. AB - The metabolic roles for L-leucine, an essential branched-chain amino acid (BCAA), go far beyond serving exclusively as a building block for de novo protein synthesis. Growing evidence shows that leucine regulates protein and lipid metabolism in animals. Specifically, leucine activates the mammalian target of rapamycin (mTOR) signaling pathway, including the 70 kDa ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1) to stimulate protein synthesis in skeletal muscle and adipose tissue and to promote mitochondrial biogenesis, resulting in enhanced cellular respiration and energy partitioning. Activation of cellular energy metabolism favors fatty acid oxidation to CO2 and water in adipocytes, lean tissue gain in young animals, and alleviation of muscle protein loss in aging adults, lactating mammals, and food-deprived subjects. As a functional amino acid, leucine holds great promise to enhance the growth, efficiency of food utilization, and health of animals and humans. PMID- 25553482 TI - Changes of cytoskeleton affect T cell biological behaviors. AB - T lymphocyte (T cell) is a crucial member in adaptive immunity that protects the organism against foreign pathogens and cancer by producing cytokines and cytotoxic molecules. In T cell, the cytoskeleton is in a stable and dynamic renewed condition and maintains shape and mechanical resistance to deformation. The cytoskeleton changes lead to morphological differences of T cell, and then affect local mechanical properties and cellular behavior, including development, differentiation, polarization, migration or adhesion. In this review, we will discuss the effect of cytoskeleton changes on T cell biological behaviors and its mechanism. PMID- 25553481 TI - Beneficial roles of dietary oleum cinnamomi in alleviating intestinal injury. AB - Cinnamon is a traditional herb used for treatment of many human diseases. The most important chemical compounds of the essential oil are cinnamaldehyde and eugenol. Oleum cinnamomi (OCM, cinnamon oil) is increasingly used as a feed additive to animal diets. Beneficial effects of OCM in protecting tissues from inflammation and injury by endogenous and exogenous agents (such as hydrogen peroxide and lipopolysaccharide (LPS)) may result, in part, from its action on regulating amino acid metabolism in cells to favor the synthesis of glutathione (a major low-molecular-weight antioxidant) from cysteine, glycine and glutamate. In support of this notion, results of recent studies indicate that supplementing OCM (50 mg/kg diet) to a corn- and soybean meal-based diet for piglets weaned at 21 days of age enhances intestinal anti-oxidative capacity and reduces the incidence of diarrhea. Additionally, dietary supplementation with OCM ameliorates LPS-induced mucosal barrier dysfunction and mucosal damage in the small intestine. OCM holds great promise for protecting the gut from injury under conditions of inflammation, infections, and oxidative stress. PMID- 25553483 TI - Aquaporins in the female reproductive system of mammals. AB - Water and ion accumulation is the driving force for rapid expansion of the amnion and allantois of mammalian placentae during early gestation, and, therefore, essential for embryonic/fetal growth and survival. Aquaporins (AQP) are a family of small integral plasma membrane proteins that primarily transport water across the plasma membrane. To date, thirteen AQP isoforms (AQP 0-12) have been identified in mammals. AQP 1, 2, 3, 4, 5, 6, 7, 8, 9, and 11 are expressed in the female reproductive tract. Based on their structural and functional properties, AQPs are divided into three subgroups: classical aquaporins (AQP 0, 1, 2, 4, 5, 6, and 8), aquaglyceroporins (AQP 3, 7, 9, and 10), and superaquaporins (AQP 11 and 12). Expression of AQPs in the uterus and placenta is regulated by hormones and nutrients to maintain fluid homeostasis in the conceptus. The underlying mechanisms may involve signal transduction pathways mediated by cAMP, MAPK, PKC, and PI3K/Akt/mTOR. Such new knowledge will advance basic understanding of mammalian reproductive biology to enhance embryonic/fetal survival, growth and development in women and livestock. PMID- 25553484 TI - N-acetylcysteine and intestinal health: a focus on its mechanism of action. AB - The integrity of the intestinal epithelium ensures its normal physiological function. Consequently, damage to the mucosal epithelium can impair the absorption of nutrients, thereby reducing the growth performance and compromising the health of animals. N-acetylcysteine (NAC) is pharmaceutically available either intravenously, orally, or by inhalation for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification, and transplant prolongation. NAC is rapidly metabolized by the small intestine to produce glutathione and can not be detected in animals without supplementation. The physiologic functions and therapeutic effects of NAC are largely associated with maintaining intracellular concentrations of reduced glutathione. Results from recent studies indicate that NAC reduces inflammation, alleviates oxidative stress, improves energy status, and ameliorates tissue damage in the intestine of lipopolysaccharide-challenged piglets. Moreover, dietary supplementation with NAC ameliorates acetic acid-induced colitis in a porcine model. The effects of NAC are associated with some intestinal cell signaling pathways, such as EGFR, TLR4, apoptosis and tight junction signaling. The current review focuses on the protective effects of NAC on intestinal health and the molecular mechanisms of its action. PMID- 25553485 TI - Mitochondria-targeted antioxidant SkQ1 reverses glaucomatous lesions in rabbits. AB - Glaucoma is the main cause of irreversible blindness worldwide. This disease is characterized by apoptosis of retinal ganglion cells (RGC) and visual field loss that seems to be related to elevated intraocular pressure (IOP). Several lines of evidences have implicated the crucial role of mitochondrial dysfunction in the pathogenesis of glaucoma. Increased mitochondrial oxidative stress in RGC may underlie or contribute to susceptibility of RGC to apoptosis. In our work we (i) designed a rabbit model of chronic, moderately elevated IOP for studying glaucoma and (ii) demonstrated efficacy of mitochondria-targeted antioxidant SkQ1 as a tool to reverse several traits of experimental glaucoma induced by a series of injections of hydroxypropylmethylcellulose (HPMC) to the anterior chamber of the rabbit eye. It is shown that 6 months instillations of drops of 0.2.5-5 microM solution of SkQ1 normalize IOP and eye hydrodynamics and abolish an increase in lens thickness that accompanies glaucoma. PMID- 25553486 TI - The aspartyl (asparaginyl) beta-hydroxylase in carcinomas. AB - Aspartyl-(asparaginyl)-beta-hydroxylase (AAH) is a member of the alpha ketoglutarate-dependent dioxygenase family that catalyzes the hydroxylation of aspartyl and asparaginyl residues epidermal growth factor (EGF)-like domains of protein. In human tumorous cell lines from main systems of body, including tumor cells of kidney, throat, breast, liver, bladder, cervical and ovary, the AAH can be detected at both the transcriptional level and the translational level, and moreover, the AAH expression is usually increased, which is associated with the development and progression of carcinomas. Thus, AAH may play an important role in different carcinomas and may be a potential hub in carcinogenesis. In this review, we will discuss the role of AAH in carcinomas, focusing on liver cancers and other digestive tumors, lung cancers, and tumors of nervous system. PMID- 25553487 TI - Cu(II)-promoted methanolysis of N,N-bis(2-picolyl)carbamates: rate-limiting metal ion delivery of coordinated alcoholate nucleophile followed by fast partitioning of a tetrahedral intermediate. AB - Five O-aryl/alkyl N,N-bis(2-picolyl)carbamates were prepared with the O aryl/alkyl portions being p-nitrophenoxy, m-nitrophenoxy, trifluoroethoxy, methoxy, and isopropoxy (4a,b,c,d,e, respectively) and the kinetics and reaction products of their methanolysis reactions in the presence of Cu(O3SCF3)2 determined. The catalyzed reactions have maximal rates for each substrate at a 1:1 ratio of [4]:[Cu2+] at (s)(s)pH 7.9, where the active forms are Cu(II):4:( OCH3). The reactions are fast, that for the complex of 4a having a t(1/2) of 30 s. The products of the reaction with 4a and 4b arise exclusively from C-OAr cleavage: those with 4d and 4e arise exclusively from C-N cleavage. With 4c, products from both C-O and C-N cleavage are observed in a 2.17:1 ratio. The common mechanism involves rate-limiting delivery of a Cu(II)-coordinated methoxide to the C?O unit to form a tetrahedral intermediate followed by fast partitioning to products by two pathways with relative barriers dependent on the (s)(s)pK(a)(HOAr/HOR). The data allow one to predict an effective (s)(s)pK(a) of ~15.6 for the (s)(s)pK(a)(NH) of Cu(II):bis(2-picolyl)amine. PMID- 25553488 TI - 1,3-Dipolar cycloaddition reactivities of perfluorinated aryl azides with enamines and strained dipolarophiles. AB - The reactivities of enamines and predistorted (strained) dipolarophiles toward perfluoroaryl azides (PFAAs) were explored experimentally and computationally. Kinetic analyses indicate that PFAAs undergo (3 + 2) cycloadditions with enamines up to 4 orders of magnitude faster than phenyl azide reacts with these dipolarophiles. DFT calculations were used to identify the origin of this rate acceleration. Orbital interactions between the cycloaddends are larger due to the relatively low-lying LUMO of PFAAs. The triazolines resulting from PFAA-enamine cycloadditions rearrange to amidines at room temperature, while (3 + 2) cycloadditions of enamines and phenyl azide yield stable, isolable triazolines. The 1,3-dipolar cycloadditions of norbornene and DIBAC also show increased reactivity toward PFAAs over phenyl azide but are slower than enamine-azide cycloadditions. PMID- 25553490 TI - Insurance, stigma, and women's mental health. PMID- 25553489 TI - Significant accumulation of polymyxin in single renal tubular cells: a medicinal chemistry and triple correlative microscopy approach. AB - Polymyxin is the last-line therapy against Gram-negative 'superbugs'; however, dose-limiting nephrotoxicity can occur in up to 60% of patients after intravenous administration. Understanding the accumulation and concentration of polymyxin within renal tubular cells is essential for the development of novel strategies to ameliorate its nephrotoxicity and to develop safer, new polymyxins. We designed and synthesized a novel dual-modality iodine-labeled fluorescent probe for quantitative mapping of polymyxin in kidney proximal tubular cells. Measured by synchrotron X-ray fluorescence microscopy, polymyxin concentrations in single rat (NRK-52E) and human (HK-2) kidney tubular cells were approximately 1930- to 4760-fold higher than extracellular concentrations. Our study is the first to quantitatively measure the significant uptake of polymyxin in renal tubular cells and provides crucial information for the understanding of polymyxin-induced nephrotoxicity. Importantly, our approach represents a significant methodological advancement in determination of drug uptake for single-cell pharmacology. PMID- 25553491 TI - Use of electroconvulsive therapy in bipolar depression. PMID- 25553492 TI - The prevention of detention. PMID- 25553493 TI - Can behavioral health organizations change health behaviors? The STRIDE study and lifestyle interventions for obesity in serious mental illness. PMID- 25553494 TI - Hypercalcemia and "primary" hyperparathyroidism during lithium therapy. PMID- 25553495 TI - Pigeon cave: a legendary place of suicide in Lebanon. PMID- 25553497 TI - No evidence for GADL1 variation as a bipolar disorder susceptibility factor in a Caucasian lithium-responsive cohort. PMID- 25553498 TI - Reversal of non-suppression of cortisol levels in a patient with refractory depression receiving ketamine. PMID- 25553499 TI - Realities after suicide can be a deterrent. PMID- 25553496 TI - Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia. AB - Sensory processing deficits, first investigated by Kraepelin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being recharacterized in the context of our current understanding of the molecular and neurobiological brain mechanisms involved. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia, such as hallucinations. The prepulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slight deviations in patterns of sensory stimulation eliciting the cortical mismatch negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and are in turn affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of schizophrenia and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients' sensory perception of the surrounding world, even during treatment sessions, may differ considerably from others' perceptions. A person's ability to understand and interact effectively with the surrounding world ultimately depends on an underlying sensory experience of it. PMID- 25553507 TI - Antioxidant potential of date (Phoenix dactylifera L.) seed protein hydrolysates and carnosine in food and biological systems. AB - Date seed protein hydrolysates were evaluated for antioxidant activity as well as solubility and water-holding capacity in food and biological model systems. Date seed protein hydrolysates as well as carnosine exhibited >80% of solubility over a pH range of 2-12. The hydrolysates and carnosine at 0.5% (w/w) were also found to be effective in enhancing water-holding capacity and cooking yield in a fish model system, which was nearly similar to sodium tripolyphosphate (STPP; 0.3%, w/w). Incorporation of hydrolysates (200 ppm) in fish model systems resulted in the highest inhibition (30%) of oxidation in comparison to butylated hydroxytoluene (BHT; 9%). In addition, hydrolysates and carnosine inhibited beta carotene oxidation by 75%. The hydrolysates (0.1 mg/mL) inhibited LDL cholesterol oxidation by 60%, whereas carnosine inhibited oxidation by 80% after 12 h of incubation. Additionally, hydrolysates and carnosine effectively inhibited hydroxyl (6 mg/mL) and peroxyl (0.1 mg/mL) radical-induced DNA scission. Therefore, date seed protein hydrolysates could be used as a potential functional food ingredient for health promotion. PMID- 25553506 TI - Etomidate-remifentanil is more suitable for monitored anesthesia care during gastroscopy in older patients than propofol-remifentanil. AB - BACKGROUND: This prospective and randomized study was designed to compare safety, potential complications, and patient and examiner satisfaction of 2 anesthetic combinations - etomidate-remifentanil and propofol-remifentanil - in elderly patients undergoing diagnostic gastroscopy. MATERIAL AND METHODS: A group of 720 patients, aged 60-80 years, scheduled for diagnostic gastroscopy under sedation were prospectively randomized. After 0.4-0.6 MUg kg-1 of remifentanil was infused, etomidate or propofol was administered. Patients in the etomidate group received doses of etomidate at 0.1-0.15 mg kg-1 followed by 4-6 mg. Patients in the propofol group received doses of propofol at 1-2 mg kg-1 followed by 20-40 mg. Physiological indexes were evaluated for the 715 of 720 patients that completed the treatment. The onset time, duration time, and discharge time were recorded. Physicians, anesthetists, and patients were surveyed to assess their satisfaction. RESULTS: Systolic pressure and diastolic pressure decreased significantly after the procedure in the propofol group (P<0.001). The average heart rate was significantly lower in the propofol group (P<0.05). No periods of desaturation (SpO2 <95%) were observed in either group. The onset time was earlier in the etomidate group (P=0.00). All adverse events, with the exception of myoclonus, were greater in the propofol group, and physician and patient satisfaction in both groups was similar. CONCLUSIONS: Etomidate-remifentanil administration for sedation and analgesia during gastroscopy resulted in more stable hemodynamic responses and less adverse events in older patients. PMID- 25553508 TI - Application of nanohydrogels in drug delivery systems: recent patents review. AB - Nanohydrogel combines the advantages of hydrogel and nano particulate systems. Similar to the hydrogel and macrogel, nanohydrogel can protect the drug and control drug release by stimuli responsive conformation or biodegradable bond into the polymer networks. Nanohydrogel has drawn huge interest due to their potential applications, such as carrier in target-specific controlled drug delivery, absorbents, chemical/biological sensors, and bio-mimetic materials. Similar to the nanoparticles, stimuli responsive nanohydrogel can easily be delivered in the liquid form for parenteral drug delivery application. This review highlights the methods to prepare nanohydrogel based on natural and synthetic polymers for diverse applications in drug delivery. It also encompasses the drug loading and drug release mechanism of the nanohydrogel formulation and patents related to the composition and chemical methods for preparation of nanohydrogel formulation with current status in clinical trials. PMID- 25553509 TI - Crystal Structures and Cytotoxicity of Ortho-Xylene Linked Bis-benzimidazolium Salts. AB - Azolium (imidazolium and benzimidazolium) salts are known as stable precursors for the synthesis of Metal-N-Heterocyclic Carbene (M-NHC) complexes. Recently, some reports have been compiled indicating that benzimidazolium salts have anticarcinogenic properties. The current research is the further investigation of this phenomenon. Three ortho-xylene linked bis-benzimidazolium salts (1-3) with octyl, nonyl and decyl terminal chain lengths have been synthesized. Each of the compounds was characterized using FT-IR and NMR spectroscopic techniques. The molecular geometries of two of the salts (1-2) have been established using X-ray crystallographic technique. The compounds were tested for their cytotoxic properties against three cancerous cell lines namely, human colon cancer (HCT 116), human colorectal adenocarcinoma (HT- 29) and human breast adenocarcinoma (MCF-7). Mouse embryonic fibroblast (3T3-L1) was used as the model cell line of normal cells. The compounds showed selective anti-proliferative activities against the colorectal carcinoma cells. For HCT 116 and HT-29 cells, the IC50 values ranged 0.9-2.6 uM and 4.0-10.0 uM, respectively. The salts 1 and 3 displayed moderate cytotoxicity against the breast cancer (MCF-7) cells with IC50 58.2 and 13.3 uM, respectively. However, the salt 2 produced strong cytotoxicity against MCF-7 cells with IC50 4.4 uM. Interestingly, the compounds demonstrated poor cytotoxic effects towards the normal cells (3T3-L1) as the IC50 was found to be as high as 48.0 uM. Salts 2 and 3 demonstrated more pronounced anti proliferative effect than the standard drugs used (5-Flourouracil and Tamoxifen). PMID- 25553510 TI - Binge drinking and the risk of suicidal thoughts, plans, and attempts. AB - BACKGROUND: Major depression is one of the strongest known risk factors for suicide. However, of the estimated 8.5 million adults with serious thoughts of suicide in the past year, only half had a major depressive episode (MDE). Identifying risk factors for suicide in the absence of depression may provide additional targets for prevention and intervention. This study uses nationally representative data to evaluate the association of binge drinking with suicidal thoughts, plans, and attempts in adults with and without MDE. METHODS: Combined 2008-2012 National Survey on Drug Use and Health data were analyzed. Sex stratified prevalence estimates of past year suicide indicators were generated by past month binge drinking and past year MDE status. Logistic regression was used to evaluate the association of binge drinking with suicide indicators by sex with and without MDE. RESULTS: Unadjusted prevalence estimates for suicide indicators in males and females were higher among binge drinkers than among nonbinge drinkers, regardless of MDE status. Regression analyses indicated that binge drinking was associated with suicidal thoughts (adjusted odds ratio [aOR]=1.51, 95% confidence interval [CI]=1.28-1.79), plans (aOR=1.75, CI=1.23-2.48), and attempts (aOR=2.57, CI=1.74-3.79) in females without MDE and with suicidal thoughts in males without MDE (aOR=1.25, CI=1.04-1.49). Among males and females with MDE, binge drinking was not associated with any of the suicide indicators (p>.05). CONCLUSIONS: Binge drinking in females without MDE may be an indicator for identifying at risk individuals for targeting suicide prevention activities. PMID- 25553512 TI - Multi-residue analysis of organic pollutants in hair and urine for matrices comparison. AB - Urine being currently the most classically used matrix for the assessment of human exposure to pesticides, a growing interest is yet observed in hair analysis for the detection of organic pollutants. The aim of the present work was to develop and to validate multi-residue analytical methods, as similar as possible, in order to determine pesticides and their metabolites in these two biological matrices despite their different nature. The list of parent compounds and their metabolites investigated here consisted of 56 compounds, including organochlorines, organophosphates, pyrethroids, carbamates, other pesticides and polychlorinated biphenyls (PCBs). Two different approaches were necessary for the analysis of non-polar compounds (mainly parents) on one hand and polar analytes (mainly metabolites) on the other hand. In the final procedure, extraction from hair was carried out with acetonitrile/water after sample decontamination and pulverization. Extract was split into two fractions, which were analyzed directly with solid phase microextraction (SPME) injection for non-polar compounds and after derivatization with liquid injection for polar compounds. In urine, non polar compounds were analyzed directly using SPME. Polar compounds were analyzed after acidic hydrolysis, liquid-liquid extraction with acetonitrile-cyclohexane ethyl acetate, derivatization and liquid injection. Analysis was performed with gas chromatography tandem mass spectrometry operating in negative chemical ionization (GC-MS/MS-NCI) for all the compounds (non-polar and polar) in the two matrices. In hair, limits of quantification (LOQ) ranged from 0.02 pg/mg for trifluralin to 5.5 pg/mg for diethylphosphate. In urine, LOQ ranged from 0.4 pg/mL for alpha-endosulfan to 4 ng/mL for dimethyldithiophosphate. The analysis of samples supplemented with standards and samples collected from an animal previously submitted to chronic exposure to pesticides confirmed that all the compounds were analyzable in both hair and urine. In addition, the levels of sensitivity reached with these methods were quite satisfactory with regard to previously published studies, and also considering the number of compounds investigated. PMID- 25553511 TI - Subjective response to nicotine by menstrual phase. AB - INTRODUCTION: The luteal menstrual phase might be a favorable time for smoking cessation when non-nicotine interventions (e.g. counseling, bupropion) are used, whereas the follicular menstrual phase appears favorable when nicotine interventions are used. Thus, there may be an interaction between menstrual phase and response to nicotine. We sought to examine the role of menstrual phase on response to nicotine during acute smoking abstinence. METHODS: In this controlled cross-over trial, women completed two identical experimental sessions (follicular [F] vs. luteal [L] phase) after four days of biochemically-verified smoking abstinence. During the sessions, nicotine nasal spray was administered, and participants provided a series of subjective assessments. RESULTS: Participants (n=140) were 29.7+/-6.6years old and smoked 12.6+/-5.8 cigarettes per day. Compared to the F phase, the L phase was associated with a greater increase in stimulation (7.2+/-2.2 vs. 14.4+/-2.3, p=0.01, respectively) and greater decrease in urge to smoke (-13.6+/-2.3 vs. -21.1+/-2.5, p=0.02, respectively) after the first dose of nicotine. No other significant differences were observed. CONCLUSIONS: Out of 13 total measures examined at two different time points, we observed only two significant menstrual phase differences in the subjective response to nicotine. Therefore, these data do not provide strong evidence for a menstrual phase difference in the subjective response to nicotine. Additional research is needed to confirm this relationship and explore how non-nicotine smoking reinforcements (such as sensory sensations) may vary by menstrual phase. PMID- 25553513 TI - Site-directed mutagenesis of rat alpha-parvalbumin: replacement of canonical CD site residues with their non-consensus counterparts from rat beta-parvalbumin. AB - Rat beta-parvalbumin (beta-PV) displays low divalent-ion affinity. Its CD site is distinguished by six non-consensus residues--the "CD-loop residues"--at positions 49, 50, 57-60. Additionally, leucine occupies position 85, rather than phenylalanine, the beta-lineage-consensus residue. Replacement of the CD-loop residues in rat beta with the canonical residues was previously found to have little effect on divalent-ion affinity, unless L85 is replaced by phenylalanine. Herein, we replace the canonical CD-loop residues in rat alpha-PV with their rat beta-PV counterparts. Although the mutations have a generally modest impact on affinity, E59D confers Ca(2+)-specificity on the CD site, in the presence or absence of the other mutations. Despite their minimal impact on DeltaG, several CD-loop mutations markedly alter DeltaH, evidently by perturbing the apo-protein conformation. The L85F mutation was also examined. In wild-type rat alpha, L85F increases EF-site Ca(2+) affinity. In the CD-loop variants, the mutation leaves the DeltaG for Ca(2+)-binding largely unaffected. However, several variants display highly exothermic binding enthalpies, indicative of ligation-linked protein-folding. Consistent with that idea, scanning-calorimetry data confirm that L85F has significantly destabilized those proteins. PMID- 25553514 TI - MYC-mediated synthetic lethality for treating tumors. AB - Deregulated c-MYC (hereafter MYC) is widely expressed in many human tumors. Myctransgenic mouse models produce diverse tumors. MYC is a strong driver of tumorigenesis and is required for tumor maintenance. MYC is therefore an attractive target for cancer treatment. However, genetic and pharmacological approaches for the targeted inactivation of MYC for the treatment of MYC overexpressing tumors have been shown to be unsatisfactory. MYC expression is regulated by different mechanisms at transcriptional, post-transcriptional, and post-translational levels. Turnover of MYC protein is an important step that influences the expression and function of MYC. MYC turnover is predominantly controlled by the GSK3/FBW7 axis that is regulated by multiple elements. Small molecule inhibitors (SMIs) can influence the stability and activity of MYC protein by targeting the axis and its regulator elements. Wang et al. (2004) first introduced the concept of MYC-mediated synthetic lethality (MYC-SL) induced by TRAIL and DR5-agonists. Researchers have turned to synthetic lethality as a treatment strategy for MYC-overexpressing tumors. MYC function is closely associated with MYC levels. Two strategies have been developed to treat MYC overexpressing tumors by upregulating or downregulating MYC. An SMI can induce MYC-SL by increasing MYC expression through the inactivation of the GSK3beta/FBW7 axis and CK1. Elevated MYC levels lead to DNA damage, senescence, and apoptosis. An SMI can also induce MYC-SL by decreasing MYC expression through the activation of the GSK3beta/FBW7 axis, the inactivation of PP2A inhibitors, and the inhibition of ARK5, AUK-A, Brd4, CDK1, CDK2, CHK1, and SAE1/2. Reduced MYC levels cause tumor regression. Some SMIs have entered phase I and II clinical trials. SMIs may be used in the near future to treat cancers co-overexpressing MYC and the corresponding MYC-SL genes. PMID- 25553515 TI - Suppression of hepatitis B virus DNA accumulation in chronically infected cells using a bacterial CRISPR/Cas RNA-guided DNA endonuclease. AB - Hepatitis B virus (HBV) remains a major human pathogen, with over 240 million individuals suffering from chronic HBV infections. These can persist for decades due to the lack of therapies that can effectively target the stable viral covalently closed circular (ccc) DNA molecules present in infected hepatocytes. Using lentiviral transduction of a bacterial Cas9 gene and single guide RNAs (sgRNAs) specific for HBV, we observed effective inhibition of HBV DNA production in in vitro models of both chronic and de novo HBV infection. Cas9/sgRNA combinations specific for HBV reduced total viral DNA levels by up to ~1000-fold and HBV cccDNA levels by up to ~10-fold and also mutationally inactivated the majority of the residual viral DNA. Together, these data provide proof of principle for the hypothesis that CRISPR/Cas systems have the potential to serve as effective tools for the depletion of the cccDNA pool in chronically HBV infected individuals. PMID- 25553516 TI - Replication-competent influenza A viruses expressing a red fluorescent protein. AB - Like most animal viruses, studying influenza A in model systems requires secondary methodologies to identify infected cells. To circumvent this requirement, we describe the generation of replication-competent influenza A red fluorescent viruses. These influenza A viruses encode mCherry fused to the viral non-structural 1 (NS1) protein and display comparable growth kinetics to wild type viruses in vitro. Infection of cells with influenza A mCherry viruses was neutralized with monoclonal antibodies and inhibited with antivirals to levels similar to wild-type virus. Influenza A mCherry viruses were also able to lethally infect mice, and strikingly, dose- and time-dependent kinetics of viral replication were monitored in whole excised mouse lungs using an in vivo imaging system (IVIS). By eliminating the need for secondary labeling of infected cells, influenza A mCherry viruses provide an ideal tool in the ongoing struggle to better characterize the virus and identify new therapeutics against influenza A viral infections. PMID- 25553518 TI - Specific nucleotides at the 3'-terminal promoter of viral hemorrhagic septicemia virus are important for virulence in vitro and in vivo. AB - Viral hemorrhagic septicemia virus (VHSV), a member of the Novirhabdovirus genus, contains an 11-nucleotide conserved sequence at the terminal 3'- and 5' untranslated regions (UTRs) that are complementary. To study the importance of nucleotides in the 3'-UTR of VHSV for replication of novirhabdoviruses, we performed site-directed mutagenesis of selected residues at the 3'-terminus and generated mutant viruses using a reverse genetics approach. Assessment of growth kinetics and in vitro real-time cytopathogenicity studies showed that the order of two nucleotides (A4G5) of the 3'-terminus of VHSV directly affects growth kinetics in vitro. The mutant A4G-G5A virus has reduced total positive-strand RNA synthesis efficiency (51% of wild-type) at 48h post-transfection and 70h delay in causing complete cytopathic effect in susceptible fish cells, as compared to the WT-VHSV. Furthermore, when the A4G-G5A virus was used to challenge zebrafish, it exhibited reduced pathogenicity (54% lower end-point mortality) compared to the WT-VHSV. From these studies, we infer that specific residues in the 3'-UTR of VHSV have a promoter function and are essential to modulate the virulence in cells and pathogenicity in fish. PMID- 25553519 TI - Detection of enteroviruses in pediatric patients with aseptic meningitis. AB - Aseptic meningitis is an acute viral infection of the central nervous system that occurs most frequently in infants and young children. This study was conducted on 100 pediatric patients with ages range from 1.5 months to 6 years. Cerebrospinal fluid (CSF) specimens were obtained with criteria of aseptic CNS infections as documented by pleocytosis, negative Gram stain and negative bacterial culture. Clinical and CSF findings of the affected children were analyzed and CSF specimens were submitted to viral culture and polymerase chain reaction (PCR) techniques to determine the enteroviral etiology. Fifty six percent patients had positive PCR results for the enteroviral genome, compared with 20% by virus culture. We can conclude that PCR is a rapid, reliable and sensitive diagnostic tool for the detection of enteroviral infections. A positive EV-PCR result may affect clinical decision making and may significantly alter the medical care offered to infected patients. PMID- 25553520 TI - A comparison of four methods for PCR inhibitor removal. AB - Biological samples collected from the crime scenes often contain some compounds that can inhibit the polymerase chain reaction (PCR). The removal of PCR inhibitors from the extracts prior to the PCR amplification is vital for successful forensic DNA typing. This paper aimed to evaluate the ability of four different methods (PowerClean(r) DNA Clean-Up kit, DNA IQTM System, Phenol Chloroform extraction and Chelex(r)-100 methods) to remove eight commonly encountered PCR inhibitors including: melanin, humic acid, collagen, bile salt, hematin, calcium ions, indigo and urea. Each of these PCR inhibitors was effectively removed by the PowerClean(r) DNA Clean-Up kit and DNA IQTM System as demonstrated by generating more complete short tandem repeat (STR) profiles from the cleaned up inhibitor samples than from the raw inhibitor samples. The Phenol Chloroform extraction and Chelex(r)-100 methods, however, could only remove some of eight PCR inhibitors. Our results demonstrated that the PowerClean(r) DNA Clean-Up kit and DNA IQTM System were very effective for the removal of known PCR inhibitors that are routinely found in DNA extracts from forensic samples. PMID- 25553517 TI - Recombinant influenza virus carrying the conserved domain of respiratory syncytial virus (RSV) G protein confers protection against RSV without inflammatory disease. AB - Respiratory syncytial virus (RSV) is one of the most important causes for viral lower respiratory tract disease in humans. There is no licensed RSV vaccine. Here, we generated recombinant influenza viruses (PR8/RSV.HA-G) carrying the chimeric constructs of hemagglutinin (HA) and central conserved-domains of the RSV G protein. PR8/RSV.HA-G virus showed lower pathogenicity without compromising immunogenicity in mice. Single intranasal inoculation of mice with PR8/RSV.HA-G induced IgG2a isotype dominant antibodies and RSV neutralizing activity. Mice with single intranasal inoculation of PR8/RSV.HA-G were protected against RSV infection as evidenced by significant reduction of lung viral loads to a detection limit upon RSV challenge. PR8/RSV.HA-G inoculation of mice did not induce pulmonary eosinophilia and inflammation upon RSV infection. These findings support a concept that recombinant influenza viruses carrying the RSV G conserved domain can be developed as a promising RSV vaccine candidate without pulmonary disease. PMID- 25553521 TI - Posttraumatic stress disorder symptoms impact the emotional experience of intimacy during couple discussions. AB - We examined the impact of PTSD symptom severity on emotional reactions to one's own and one's partner's intimacy behaviors. Heterosexual, community couples in which at least one partner reported elevated symptoms of PTSD were video-recorded discussing a relationship problem and self-reported their emotions immediately before and after the discussion. Each partner's intimacy behaviors were coded. Actor-Partner Interdependence Models indicate that, among those with greater PTSD symptom severity, partners' caring, understanding, and validation were associated with increased negative emotions, particularly fear. Among those with greater PTSD severity, provision of caring was associated with decreased anger, guilt, and sadness. Therefore, the receipt of intimacy was associated with increased negative emotions among individuals with elevated PTSD symptoms while provision of intimacy was associated with decreased negative emotions. Existing treatments for PTSD should consider the emotional context of provision and receipt of intimacy to more fully address relationship problems among couples dealing with PTSD. PMID- 25553522 TI - Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides. AB - Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation related genes. These results open new research ways to the regulation of allergy by Oleaceae family members. PMID- 25553525 TI - Five years with a rectal foreign body: A case report. AB - INTRODUCTION: Rectal foreign bodies are rare colorectal emergencies. They are important for the complications that may occur. Delayed response causes a wide range of complications or may even result in death. PRESENTATION OF CASE: A 22 years old male patient was seen at our hospital with anal pain, discharge, and complaining of incontinence. The patient stated that a bottle of beverage was placed into his anal canal in an inverted manner for sexual satisfaction 5 years previously. DISCUSSION: After clinical and radiological assessment under general anaesthesia in the lithotomy position the object was removed by a laparotomy. He was advised to seek legal help and he received psychiatric treatment in the postoperative period prior to his discharge. CONCLUSION: Complications such as abscess, perianal fistula complicated by severe pelvic sepsis and osteomyelitis were expected complications in this case. As in this case, a surgical approach may eliminate dissection planes, increasing morbidity and mortality related to the injuring of surrounding bodies during object extraction. PMID- 25553524 TI - Rare complication of ventriculoperitoneal shunt. Early onset of distal catheter migration into scrotum in an adult male: Case report and literature review. AB - INTRODUCTION: The role of shunt placement is to divert cerebrospinal fluid from within the ventricles to an alternative location in the setting of hydrocephalus. One of the rare shunt complications is distal catheter migration, and various body sites have been reported, including the scrotum. Although cases of scrotal migration of distal catheter have been reported in pediatric patients, cases in adult patients are rare due to obliterated processus vaginalis. Furthermore, there has not been a case reported for scrotal migration in an adult at an early onset. PRESENTATION OF CASE: 65-year-old male underwent shunt placement for normal-pressure hydrocephalus-like symptoms. On post-operative day seven patient developed right testicular edema, for which ultrasound was performed, revealing hydrocele along with the presence of distal catheter in the scrotum. On post operative day nine patient underwent distal catheter trimming via laparoscopic approach with general surgery, with post-operative imaging showing satisfactory location of distal catheter in the peritoneal cavity. DISCUSSION/CONCLUSION: Early onset of distal catheter migration into scrotum in an adult male is a unique case, as most cases are reported in pediatric patients, and it is the first case reported in the English literature to have occurrence at an early onset during the peri-operative period. As our case demonstrates, early occurrence and detection of scrotal migration of the distal catheter prevent shunt malfunction. Prompt surgical management of catheter repositioning is therefore recommended to avoid the risk of further complications. PMID- 25553526 TI - Spontaneous cervical-mediastinal hematoma caused by hemorrhage into parathyroid adenoma: A clinical case. AB - INTRODUCTION: Spontaneous cervical-mediastinal hematoma caused by extracapsular rupture of parathyroid gland occurs extremely rarely. There are no standard treatment approaches because of the peculiarities of each case. PRESENTATION OF CASE: We report herewith about a rare case of spontaneous cervical-mediastenal hematoma occured by hemorrhage in parathyroid adenoma, which was detected in an previously absolutely healthy female patient in the age of 29. This woman was hospitalized in 2 days after the manifestation, complaining about a neck ache. Indirect laryngoscopy: right-side larynx paresis. Blood test: parathyroid hormone 843pg/ml (norm 15-65), ionized calcium 1.8mmol/l (norm 0.9-1.1). Positive dynamics was observed throughout 8 days of anti-inflammatory therapy. Symptoms of neck organs compression increased acutely at the 9th day. The patient was operated - hematoma lancing with resection of walls. Histological examination discovered the fragments of parathyroid adenoma in the hematoma's wall. Level of ionized blood calcium got normal approximately in 24h after the surgery. The patient was examined 6 months after the surgery. The patient had no disphagy, voice quality was intact, breathing was not restricted. Level of parathyroid hormone in blood got normal. DISCUSSION: A rareness of this pathology and treatment variability does not allow to choose a unified medical and diagnostic tactics. CONCLUSION: Our case demonstrates that radical correction of primary hyperparathyroidism by excision of hematoma and its fibrous capsule with preservation of thyroid gland is possible in conditions of tense cervical mediastinal hematoma with inflammation process in the hemorrhage area. PMID- 25553523 TI - Characterization of a novel anti-lipopolysaccharide factor isoform (SpALF5) in mud crab, Scylla paramamosain. AB - Anti-lipopolysaccharide factors (ALFs), the potential antimicrobial peptides that bind and neutralize lipopolysaccharide (LPS), are common effectors of innate immunity in crustaceans. In this study, a novel isoform of ALFs (SpALF5) was isolated from the hemocytes of mud crab Scylla paramamosain. The full-length 975bp SpALF5 contains a 375bp open reading frame (ORF) encoding 125 amino acids. Although SpALF5 exhibits a low degree of nucleotide homology with other reported ALFs, it contains the conserved amino acid sequence with a signal peptide and a LPS-binding domain including two conservative cysteine residues. The genomic organization of SpALF5 consists of four exons and three introns, with each intron containing one or more tandem repeats. Unlike most of ALFs mainly distributed in crab hemocytes, SpALF5 transcript was predominantly observed in the brain, muscle and skin, while barely detected in the hemocytes in our study. In situ hybridization assay also showed that SpALF5 mRNA was localized in brain, muscle and skin tissues of mud crab. Further, SpALF5 transcript was significantly up regulated after challenge with LPS, polyinosinic polycytidylic acid (PolyI:C) (with the except of that in brain), Vibrio parahemolyticus or white spot syndrome virus (WSSV). The recombinant SpALF5 protein showed a varying degree of binding activity towards bacteria and fungus. Moreover, in vitro, the recombinant SpALF5 revealed a strong antimicrobial activity against Gram-negative bacteria (V. parahemolyticus, Vibrio alginolyticus, Escherichia coli, Aeromonas hydrophila) and fungus (Sacchromyces cerevisiae), but could only inhibited the growth of some Gram-positive bacteria like Staphylococcus aureus. The results suggest that SpALF5 is a potent immune protector and plays an important role in immune defense against invading pathogens in S. paramamosain. PMID- 25553527 TI - Side-to-side caval anastomosis in a patient receiving a liver graft from a marginal donor with situs inversus totalis. AB - INTRODUCTION: The donor situs inversus totalis status was considered an absolute contraindication to liver transplantation due to the technical difficulties involved. Only in recent years has a very young deceased donor with situs inversus totalis been considered as a potential donor. PRESENTATION OF CASE: We herein report a single case of 57-year-old male patient with hepatocellular carcinoma who received a liver transplantation from a 73-year-old woman with situs inversus totalis. Liver was implanted using a 1992-Belghiti piggyback technique positioning the larger hemiliver in the left upper quadrant and the left in the liver fossa. We assisted a good graft reperfusion without surgical or anesthetic problems. His hospital stay was relatively uneventful and he was discharged from hospital on postoperative day 7. At 8 months of follow-up the patient is alive and in good clinical condition. DISCUSSION: The donor situs inversus totalis does not require any modification of transplant procedure if the donor-recipient size match permits a comfortable placement of the graft in a standard anatomical position. To the best of our knowledge, this is the first case of liver transplantation with a graft from a "marginal" donor with situs inversus totalis using a 1992-Belghiti piggyback technique. CONCLUSION: The donor situs inversus totalis status should not be considered a contraindication for LT and the piggyback technique should be considered the surgery of choice. PMID- 25553528 TI - An unusual case of transverse mesocolic internal hernia with abnormality of both hands and high arched feet. AB - INTRODUCTION: An internal abdominal herniation is the protrusion of a viscus through a normal or abnormal mesenteric or peritoneal aperture. It is a rare cause of small bowel obstruction with a reported incidence of 0.2-0.9%. It can either be acquired through a trauma or surgical procedure or can be related to congenital peritoneal defects. Herniation through transverse mesocolon is very rare. PRESENTATION OF CASE: A case of acute intestinal obstruction due to internal herniation through a congenital rent in transverse mesocolon with rotation of gut approximately 180 degrees around axis of the band. Patient also had bilateral hypoplastic thenar muscles with rudimentary 1st metacarpals and high arched feet. Reduction along with derotation of gut, with closure of the rent in transverse mesocolon and fixation of the caecum to lateral peritoneum was performed. DISCUSSION: The preoperative diagnosis of mesenteric defect is difficult because of wide range of acute abdominal symptoms, and there are no specific radiographic findings. CT is the most important diagnostic tool is, with 77% accuracy in such cases. Due to the risk of strangulation of the hernial contents, even small internal hernias are dangerous and may be lethal. CONCLUSION: Internal hernia should be suspected in patients with signs and symptoms of intestinal obstruction, particularly in the absence of inflammatory intestinal diseases, external hernia or previous laparotomy. Surgical decision making is on the basis of clinical findings of intestinal strangulation or ischemia, and emergency laparotomy should be performed without preoperative diagnosis of such a rare disease. PMID- 25553529 TI - Giant retroperitoneal ancient schwannoma: Is preoperative biopsy always mandatory? AB - INTRODUCTION: Schwannoma is the term given to tumours arising from Schwann cells of any nerve sheath. It may arise in the retroperitoneum, where it can attain enormous sizes and cause considerable diagnostic and therapeutic difficulties. A variety of incapacitating symptoms may arise, depending on its size alone and the related contagious organs. PRESENTATION OF CASE: A 71-year-old female, who was incapacitated by a giant abdominal mass, associated with weight loss, immobility, general weakness and constipation. Radiologically, the presence of a huge pelviabdominal tumour was confirmed. A preoperative tissue diagnosis was entertained but omitted, and we resorted to direct surgical excision instead. During surgery, significant bleeding from the surrounding lumbar vessels was encountered, but it was controlled and the tumour was excised intact. Histopathologically, it showed the histologic features of ancient schwannoma. DISCUSSION: In the patient presented here, who was rendered immobile by the tumour, total excision or at least debulking seemed appropriate, regardless of any biopsy result. CONCLUSION: The diagnosis of retroperitoneal schwannoma and its variant "ancient schwannoma" should be considered when a huge pelviabdominal tumour is encountered. Although CT guided biopsy may be helpful in reaching a preoperative diagnosis, this might not change the decision for the need of total tumour excision or at least debulking, in the presence of incapacitating symptoms. With large tumours, the possibility of perioperative exanginating haemorrhage should be remembered and the necessary precautions activated. PMID- 25553530 TI - Laparoscopic approach in a case of retroperitoneal and mesorectal haematoma following STARR procedure. AB - INTRODUCTION: Stapled transanal rectal resection (STARR) is a widely accepted procedure for treatment of obstructed defecation syndrome. PRESENTATION OF CASE: We analyzed major bleeding following STARR and exposed our experience regarding its conservative management with particular attention about diagnostic and therapeutic aspects. DISCUSSION: A case by case discussion should be carried out and treatments should be driven by the features and the progression of the haematoma with regards to size, inflammatory signs or severe rectal obstruction. CONCLUSION: If a second surgical time and exploration is considered, laparoscopy should be an effective choice while laparotomy, stoma or rectal resection should be considered in those cases with strong suspicious of peritonitis and pelvic abscess. PMID- 25553532 TI - Adult Wilms tumor: Case report. AB - Wilms tumor (WT) occurs infrequently in adults. Even rarer is adult WT with extension by direct intravascular spread into the right side of the heart. The present report describes a WT with intracaval and intracardiac extension in a 38 year-young man. In addition, thrombus extension above the infrahepatic IVC represents a major technical topic for surgeons because of the possible occurrence of uncontrollable hemorrhages and tumor fragmentation. We report the results of a surgical approach to caval thrombosis including the isolation of the IVC from the liver as routinely performed during liver harvesting. The morphologic and immune-histochemical findings confirmed the diagnosis. PMID- 25553531 TI - Bilateral medial malleolus stress fractures due to osteoarthritis of knee: A case report and review of literature. AB - INTRODUCTION: Medial malleolar stress fracture is a relatively uncommon injury but it can occur in athletes participating in running and jumping activities. Stress fractures of pelvis, proximal tibia and metatarsals are well documented in the elderly population but medial malleolus involvement in this subgroup has never been reported. PRESENTATION OF CASE: We report a case of bilateral medial malleolus stress fractures secondary to bilateral knee osteoarthritis. DISCUSSION: Osteoporosis and mechanical malalignment have been postulated as the possible risk factors for stress fractures in the elderly population. The pathomechanics and management of the case are discussed here. CONCLUSION: A high index of suspicion is required to identify such fractures. Identification and treatment of the predisposing factors are a very important part of treatment. PMID- 25553533 TI - LC-MS/MS method for the determination of two metabolites of tribendimidine, deacylated amidantel and its acetylated metabolite in plasma, blood and dried blood spots. AB - Tribendimidine has emerged as potential alternative to praziquantel in the treatment of Opisthorchis viverrini infections. To support its clinical development program, a quantitative high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed for tribendimidine's degradation product deacylated amidantel (dADT) and its acetylated metabolite adADT. Analytical sample preparation included protein precipitation for blood and plasma, and direct processing of dried blood spots (DBS). The analytes were detected by multiple reaction monitoring with electrospray ionization in the positive mode (dADT: 178.3->133.1 m/z, adADT: 220.4->175.1 m/z, tribendimidine 294.3->249.0 m/z). A pentafluorophenyl (PFP) phase Kinetex analytical column (2.6 MUm, 100 A, 50 mm * 4.6 mm) with a 6 min lasting mobile phase gradient program of ammonium acetate and acetonitrile was applied. The method was validated with respect to precision, accuracy, linearity, sensitivity, and selectivity. The analytical range in plasma and blood was 1-1000 ng/ml and in DBS 10-2000 ng/ml (R(2)>0.99). Recoveries determined using four different human blood batches were in the range of 70-90%. Inter- and intra-assay accuracy and precision deviations were at least <=12.2%. dADT and adADT were stable within the autosampler for 72 h (10 degrees C), for 4 h at room temperature, for 3 month at -80 degrees C, and after three freeze and thaw cycles. DBS samples should be stored at -20 degrees C. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be applied for pharmacokinetic studies with tribendimidine. PMID- 25553534 TI - Does extending the dual-task functional exercises workout improve postural balance in individuals with ID? AB - Maintaining postural balance, overcoming visual and motor coordination disorders and experiencing problems with low general fitness - typical of intellectually disabled individuals - adversely affect the performance quality of their activities of daily living (ADLs). Physical fitness and postural balance can be improved by taking part in special intervention programs. Our study was designed to test whether extending the dual-task intervention program (combining ADLs with balance exercises on unstable surfaces) from 12 to 24 weeks additionally improved postural balance in individuals with intellectual disability (ID). We also attempted to assess whether the effects of the above intervention program were still noticeable after 8 weeks of holidays, in which participants did not take any rehabilitation exercises. A total of 34 adolescents, aged 14-16 years (15.06+/-0.9), with moderate ID took part in our study. The experimental group (E) consisted of 17 individuals, who continued the intervention program originated 3 months earlier, and the control group (C) comprised the same number of participants. Postural balance was assessed on a stabilometric platform Alfa. Having extended the workout period by another 12 weeks, we noticed that the path length of the center of pressure (COP) covered by participants on tests with their eyes open and closed significantly shortened. After a lapse of 8 weeks from the completion of the program, the experimental group revealed a statistically significant decrease in the velocity along the medio-lateral (M/L) and anterior posterior (A/P) axes. The remaining variables stayed at the same level and the control group did not demonstrate any statistically significant changes. Dual task exercises, in which enhancing functional tasks of daily living is combined with a parallel stimulation of balance reactions, may improve static balance in persons with ID. PMID- 25553535 TI - Separation of isomeric short-chain acyl-CoAs in plant matrices using ultra performance liquid chromatography coupled with tandem mass spectrometry. AB - Acyl coenzyme A (acyl-CoA) thioesters are important intermediates in cellular metabolism and being able to distinguish among them is critical to fully understanding metabolic pathways in plants. Although significant advances have been made in the identification and quantification of acyl-CoAs using liquid chromatography tandem mass spectrometry (LC-MS/MS), separation of isomeric species such as isobutyryl- and n-butyrl-CoA has remained elusive. Here we report an ultra-performance liquid chromatography (UPLC)-MS/MS method for quantifying short-chain acyl-CoAs including isomeric species n-butyryl-CoA and isobutyryl-CoA as well as n-valeryl-CoA and isovaleryl-CoA. The method was applied to the analysis of extracts of hop (Humulus lupulus) and provided strong evidence for the existence of an additional structural isomer of valeryl-CoA, 2-methylbutyryl CoA, as well as an unexpected isomer of hexanoyl-CoA. The results showed differences in the acyl-CoA composition among varieties of Humulus lupulus, both in glandular trichomes and cone tissues. When compared with the analysis of hemp (Cannabis sativa) extracts, the contribution of isobutyryl-CoAs in hop was greater as would be expected based on the downstream polyketide products. Surprisingly, branched chain valeryl-CoAs (isovaleryl-CoA and 2-methylbutyryl CoA) were the dominant form of valeryl-CoAs in both hop and hemp. The capability to separate these isomeric forms will help to understand biochemical pathways leading to specialized metabolites in plants. PMID- 25553536 TI - Large scale purification of puerarin from Puerariae Lobatae Radix through resins adsorption and acid hydrolysis. AB - Puerarin is the major isoflavone of Puerariae Lobatae Radix. A method for large scale purification of puerarin was developed through resins adsorption and acid hydrolysis. The adsorption properties of six macroporous resins (D101, S-8, H103, X-5, HPD600, AB-8) were compared through the adsorption kinetics and equilibrium adsorption isotherms. Results showed that H103 resin had the best adsorption rate and capacity. The mass transfer zone motion model was further used for analyzing the fixed bed adsorption of H103 resin. Its length of mass transfer zone with 2mg/ml of puerarin in water and 10% ethanol at flow rate of 10ml/min were 41.6 and 47.5cm, while the equilibrium adsorption capacity was 165.03 and 102.88mg/g, respectively. By using 75% ethanol, puerarin could be well desorbed from the resin with recovery of 97.4%. Subsequently, H103 resin was successfully used for puerarin purification from Puerariae Lobatae Radix. The content of total isoflavones and puerarin in the resin adsorption product were 69.25% and 41.78%, respectively, which were about three times increased compared to the crude extract. Then, the product was hydrolyzed by 2.5M HCl at 90 degrees C for 1h. Puerarin with purity of 90% and a byproduct daidzein with purity of 78% were obtained. PMID- 25553537 TI - Flowering time regulation in crops-what did we learn from Arabidopsis? AB - The change from vegetative to reproductive growth is a key developmental switch in flowering plants. In agriculture, flowering is a prerequisite for crop production whenever seeds or fruits are harvested. An intricate network with various (epi-) genetic regulators responding to environmental and endogenous triggers controls the timely onset of flowering. Changes in the expression of a single flowering time (FTi) regulator can suffice to drastically alter FTi. FTi regulation is of utmost importance for genetic improvement of crops. We summarize recent discoveries on FTi regulators in crop species emphasizing crop-specific genes lacking homologs in Arabidopsis thaliana. We highlight pleiotropic effects on agronomically important characters, impact on adaptation to new geographical/climate conditions and future perspectives for crop improvement. PMID- 25553539 TI - Bacteriostatic suppression in Norway lobster (Nephrops norvegicus) exposed to manganese or hypoxia under pressure of ocean acidification. AB - Future ocean acidification (OA) and warming following climate change elicit pervasive stressors to the inhabitants of the sea. Previous experimental exposure to OA for 16 weeks at pH levels predicted for 2100 has shown to result in serious immune suppression of the Norway lobster, Nephrops norvegicus. The lobsters are currently affected by stressors such as periodical hypoxia inducing high levels of bioavailable manganese (Mn). Here, we aimed to investigate possible effects of interactions between OA and these stressors on total hemocyte counts (THCs) and on recovery of inoculated bacteria in the lobsters, measured as a proxy for bacteriostatic response. The effects were judged by following numbers of culturable Vibrio parahaemolyticus in hepatopancreas, 4 and 24h post inoculation in lobsters kept in replicate tanks with six different treatments: either ambient (pCO2~500 MUatm/pH~8.1 U) or CO2-manipulated seawater (OA; pCO2~1550 MUatm/pH~7.6 U) for 8 weeks. During the last 2 weeks, additional stress of either hypoxia (~23% oxygen saturation) or Mn (~9 mg L(-1)) was added except in control treatments. Our results showed clear effect on bacteriostatic response in Norway lobsters exposed to these stressors. In lobsters kept in ambient seawater without additional stressors, the number of culturable bacteria in hepatopancreas was reduced by ~34%. In combined treatment of ambient seawater and hypoxia, the reduction was ~23%, while in the Mn-exposed animals, there was no reduction at all. This was also the case in all OA treatments where mean numbers of culturable V. parahaemolyticus tended to increase. In lobsters from ambient seawater with or without hypoxia, the THC was not significantly different as was also the case in OA without additional stressors. However, in OA treatments combined with either hypoxia or Mn, THC was reduced by ~35%. While the reduction of culturable V. parahaemolyticus in lobsters was clearly affected by these stressors, we found no notable effects on growth, survival or hemolytic properties of the bacteria itself. Thus, we conclude that this predicted stress scenario is beneficial for the pathogen in its interaction with the host. As OA proceeds, it may force the health of the ecologically and economically important N. norvegicus to a tipping point if exposed to more short-term stressors such as the periodical events of hypoxia and Mn. This could impact lobster condition and biomass and may as well increase the risk for bacterial transmission to consumers. PMID- 25553540 TI - 1,3,4-Thiadiazoles: a potent multi targeted pharmacological scaffold. AB - Despite a significant work on thiadiazoles, continuous efforts are still being made to identify novel heterocyclic compounds with potent biological activities. This review may help the medicinal chemists to develop new leads possessing 1,3,4 thiadiazole nucleus with higher efficacy and reduced side effects. This review throws light on the detailed synthetic approaches which have been used for the synthesis of thiadiazoles. This has been followed by the in depth analysis of the thiadiazoles with respect to their medicinal significance. PMID- 25553538 TI - Regulation of pregnane-X-receptor, CYP3A and P-glycoprotein genes in the PCB resistant killifish (Fundulus heteroclitus) population from New Bedford Harbor. AB - Killifish survive and reproduce in the New Bedford Harbor (NBH) in Massachusetts (MA), USA, a site severely contaminated with polychlorinated biphenyls (PCBs) for decades. Levels of 22 different PCB congeners were analyzed in liver from killifish collected in 2008. Concentrations of dioxin-like PCBs in liver of NBH killifish were ~400 times higher, and the levels of non-dioxin-like PCBs ~3000 times higher than in killifish from a reference site, Scorton Creek (SC), MA. The NBH killifish are known to be resistant to the toxicity of dioxin-like compounds and to have a reduced aryl hydrocarbon receptor (AhR) signaling response. Little is known about the responses of these fish to non-dioxin-like PCBs, which are at extraordinarily high levels in NBH fish. In mammals, some non-dioxin-like PCB congeners act through nuclear receptor 1I2, the pregnane-X-receptor (PXR). To explore this pathway in killifish, a PXR cDNA was sequenced and its molecular phylogenetic relationship to other vertebrate PXRs was determined. Killifish were also collected in 2009 from NBH and SC, and after four months in the laboratory they were injected with a single dose of either the dioxin-like PCB 126 (an AhR agonist) or the non-dioxin-like PCB 153 (a mammalian PXR agonist). Gills and liver were sampled three days after injection and transcript levels of genes encoding PXR, cytochrome P450 3A (CYP3A), P-glycoprotein (Pgp), AhR2 and cytochrome P450 1A (CYP1A) were measured by quantitative PCR. As expected, there was little effect of PCB exposure on mRNA expression of AhR2 or CYP1A in liver and gills of NBH fish. In NBH fish, but not in SC fish, there was increased mRNA expression of hepatic PXR, CYP3A and Pgp upon exposure to either of the two PCB congeners. However, basal PXR and Pgp mRNA levels in liver of NBH fish were significantly lower than in SC fish. A different pattern was seen in gills, where there were no differences in basal mRNA expression of these genes between the two populations. In SC fish, but not in NBH fish, there was increased mRNA expression of branchial PXR and CYP3A upon exposure to PCB126 and of CYP3A upon exposure to PCB153. The results suggest a difference between the two populations in non-AhR transcription factor signaling in liver and gills, and that this could involve killifish PXR. It also implies possible cross-regulatory interactions between that factor (presumably PXR) and AhR2 in liver of these fish. PMID- 25553541 TI - Artificial hydrogenases: biohybrid and supramolecular systems for catalytic hydrogen production or uptake. AB - There is an urgent need for cheap, abundant and efficient catalysts as an alternative to platinum for hydrogen production and oxidation in (photo)electrolyzers and fuel cells. Hydrogenases are attractive solutions. These enzymes use exclusively nickel and iron in their active sites and function with high catalytic rates at the thermodynamic equilibrium. As an alternative, a number of biomimetic and bioinspired catalysts for H2 production and/or uptake, based on Ni, Fe and Co, have been developed and shown to display encouraging performances. In this review we discuss specifically recent approaches aiming at incorporating these compounds within oligomeric and polymeric hosts. The latter are most often biological compounds (peptides, proteins, polysaccharides, etc.) but we also discuss non-biological scaffolds (synthetic polymers, Metal-organic Frameworks, etc.) which can provide the appropriate environment to tune the activity and stability of the synthetic catalysts. These supramolecular catalytic systems thus define a class of original compounds so-called artificial hydrogenases. PMID- 25553542 TI - Adaptive learning rate of SpikeProp based on weight convergence analysis. AB - A Spiking Neural Network (SNN) training using SpikeProp and its variants is usually affected by sudden rise in learning cost called surges. These surges cause diversion in the learning process and often cause it to fail as well. Researches have shown that proper learning rate is crucial to avoid these surges. In this paper, we perform weight convergence analysis to determine the proper step size in each iteration of weight update and derive an adaptive learning rate extension to SpikeProp that assures convergence of the learning process. We have analyzed the performance of this learning rate adaptation with existing methods via simulations on different benchmarks. The results show that using adaptive learning rate significantly improves the weight convergence and speeds up learning as well. PMID- 25553543 TI - Unravelling trophic subsidies of agroecosystems for biodiversity conservation: food consumption and nutrient recycling by waterbirds in Mediterranean rice fields. AB - Waterbirds can reallocate a considerable amount of nutrients within agricultural fields and between agriculture sites and wetlands. However their effects on biogeochemical cycles have rarely been quantified. We estimated bird numbers, diet (from stable isotope analysis), food supply, and the food consumption on rice fields by overwintering waterbirds in one of the most important areas for rice production in southwestern Europe and a key area for various migrating and resident waterbird species. Herein, we modelled the nutrient (N and P) recycling in rice fields, and their transport to reservoirs. The energy consumption by waterbirds (96,605+/-18,311 individuals) on rice fields during winter averaged at 89.9+/-39.0 kJ.m(-2), with its majority (89.9%) belonging to foraging on rice seeds. Thus, the birds removed about 26% of rice seeds leftover after harvest (estimated in 932.5+/-504.7 seeds.m(-2) in early winter) wherein common cranes and dabbling ducks (four species) were the most important consumers. Waterbirds foraging and roosting in the rice fields recycled more than 24.1 (1.0 kg.ha(-1)) of N and an additional 5.0 tons (0.2 kg.ha(-1)) of P in the Extremadura's rice fields during winter. Additionally, we estimated that 2.3 tons of N and 550 kg of P were removed from rice fields and transported to reservoirs. The seasonal foraging of wildlife should result in a direct benefit for rice farmers by improving nutrient recycling through defecation by waterbirds with respect to artificial fertilisation. Additionally, rice fields located in the cranes' core wintering areas can provide sufficient food supply to induce habitat shift from their traditional wintering habitat in 'dehesas' to rice fields, which causes indirect socioeconomic benefit through reduced acorn consumption by cranes. Our modelling approach may thus be especially helpful for management decisions regarding rice agroecosystems in areas which are also important for the conservation of migratory waterbirds. PMID- 25553544 TI - Evaluating the effectiveness of management practices on hydrology and water quality at watershed scale with a rainfall-runoff model. AB - The adverse influence of urban development on hydrology and water quality can be reduced by applying best management practices (BMPs) and low impact development (LID) practices. This study applied green roof, rain barrel/cistern, bioretention system, porous pavement, permeable patio, grass strip, grassed swale, wetland channel, retention pond, detention basin, and wetland basin, on Crooked Creek watershed. The model was calibrated and validated for annual runoff volume. A framework for simulating BMPs and LID practices at watershed scales was created, and the impacts of BMPs and LID practices on water quantity and water quality were evaluated with the Long-Term Hydrologic Impact Assessment-Low Impact Development 2.1 (L-THIA-LID 2.1) model for 16 scenarios. The various levels and combinations of BMPs/LID practices reduced runoff volume by 0 to 26.47%, Total Nitrogen (TN) by 0.30 to 34.20%, Total Phosphorus (TP) by 0.27 to 47.41%, Total Suspended Solids (TSS) by 0.33 to 53.59%, Lead (Pb) by 0.30 to 60.98%, Biochemical Oxygen Demand (BOD) by 0 to 26.70%, and Chemical Oxygen Demand (COD) by 0 to 27.52%. The implementation of grass strips in 25% of the watershed where this practice could be applied was the most cost-efficient scenario, with cost per unit reduction of $1m3/yr for runoff, while cost for reductions of two pollutants of concern was $445 kg/yr for Total Nitrogen (TN) and $4871 kg/yr for Total Phosphorous (TP). The scenario with very high levels of BMP and LID practice adoption (scenario 15) reduced runoff volume and pollutant loads from 26.47% to 60.98%, and provided the greatest reduction in runoff volume and pollutant loads among all scenarios. However, this scenario was not as cost efficient as most other scenarios. The L-THIA-LID 2.1 model is a valid tool that can be applied to various locations to help identify cost effective BMP/LID practice plans at watershed scales. PMID- 25553545 TI - Life cycle assessment for dredged sediment placement strategies. AB - Dredging to maintain navigable waterways is important for supporting trade and economic sustainability. Dredged sediments are removed from the waterways and then must be managed in a way that meets regulatory standards and properly balances management costs and risks. Selection of a best management alternative often results in stakeholder conflict regarding tradeoffs between local environmental impacts associated with less expensive alternatives (e.g., open water placement), more expensive measures that require sediment disposal in constructed facilities far away (e.g., landfills), or beneficial uses that may be perceived as risky (e.g., beach nourishment or island creation). Current sediment placement decisions often focus on local and immediate environmental effects from the sediment itself, ignoring a variety of distributed and long-term effects from transportation and placement activities. These extended effects have implications for climate change, resource consumption, and environmental and human health, which may be meaningful topics for many stakeholders not currently considered. Life-Cycle Assessment (LCA) provides a systematic and quantitative method for accounting for this wider range of impacts and benefits across all sediment management project stages and time horizons. This paper applies a cradle-to-use LCA to dredged-sediment placement through a comparative analysis of potential upland, open water, and containment-island placement alternatives in the Long Island Sound region of NY/CT. Results suggest that, in cases dealing with uncontaminated sediments, upland placement may be the most environmentally burdensome alternative, per ton-kilometer of placed material, due to the emissions associated with diesel fuel combustion and electricity production and consumption required for the extra handling and transportation. These results can be traded-off with the ecosystem impacts of the sediments themselves in a decision-making framework. PMID- 25553546 TI - Analysis of drugs of abuse by online SPE-LC high resolution mass spectrometry: communal assessment of consumption. AB - An online SPE-LC-HRMS method was developed to monitor the consumption of 18 drugs of abuse (DOAs) including amphetamines, opioids, cocainics, cannabinoids, lysergics, and their corresponding metabolites in a well characterized college campus setting via wastewater analysis. Filtered and diluted (10*) sewage water samples (5 mL inj.) were automatically pre-concentrated and analyzed in 15 min using a Thermo EQuan MAX online SPE system equipped with a HyperSepTM Retain PEP (20*2.1 mm*12 MUm) SPE column and a Hypersil GoldTM aQ (150*2.1 mm*3 MUm) analytical column. A Q ExactiveTM Hybrid Quadrupole-Orbitrap HRMS was used in full scan mode (R=140,000) for positive identification, and quantitation of target compounds. Method detection limits for all analytes ranged between 0.6 and 1.7 ng/L in sewage. A total of 14 DOAs were detected from two different locations (dorms and main college campus) within a one-year period. Most frequently detected drugs throughout the entire study were amphetamine (>96%) and THC's metabolite 11-nor-9-carboxy-Delta-9-THC (>100%) with maximum concentrations of 5956 and 2413 ng/L respectively. Daily doses per 1000 people were determined in order to assess consumption of THC, amphetamine, heroin and cocaine, in both dorms and main campus. PMID- 25553547 TI - Effect of fuel zinc content on toxicological responses of particulate matter from pellet combustion in vitro. AB - Significant amounts of transition metals such as zinc, cadmium and copper can become enriched in the fine particle fraction during biomass combustion with Zn being one of the most abundant transition metals in wood combustion. These metals may have an important role in the toxicological properties of particulate matter (PM). Indeed, many epidemiological studies have found associations between mortality and PM Zn content. The role of Zn toxicity on combustion PM was investigated. Pellets enriched with 170, 480 and 2300 mg Zn/kg of fuel were manufactured. Emission samples were generated using a pellet boiler and the four types of PM samples; native, Zn-low, Zn-medium and Zn-high were collected with an impactor from diluted flue gas. The RAW 264.7 macrophage cell line was exposed for 24h to different doses (15, 50,150 and 300 MUg ml(-1)) of the emission samples to investigate their ability to cause cytotoxicity, to generate reactive oxygen species (ROS), to altering the cell cycle and to trigger genotoxicity as well as to promote inflammation. Zn enriched pellets combusted in a pellet boiler produced emission PM containing ZnO. Even the Zn-low sample caused extensive cell cycle arrest and there was massive cell death of RAW 264.7 macrophages at the two highest PM doses. Moreover, only the Zn-enriched emission samples induced a dose dependent ROS response in the exposed cells. Inflammatory responses were at a low level but macrophage inflammatory protein 2 reached a statistically significant level after exposure of RAW 264.7 macrophages to ZnO containing emission particles. ZnO content of the samples was associated with significant toxicity in almost all measured endpoints. Thus, ZnO may be a key component producing toxicological responses in the PM emissions from efficient wood combustion. Zn as well as the other transition metals, may contribute a significant amount to the ROS responses evoked by ambient PM. PMID- 25553548 TI - Ecohydrological model parameter selection for stream health evaluation. AB - Variable selection is a critical step in development of empirical stream health prediction models. This study develops a framework for selecting important in stream variables to predict four measures of biological integrity: total number of Ephemeroptera, Plecoptera, and Trichoptera (EPT) taxa, family index of biotic integrity (FIBI), Hilsenhoff biotic integrity (HBI), and fish index of biotic integrity (IBI). Over 200 flow regime and water quality variables were calculated using the Hydrologic Index Tool (HIT) and Soil and Water Assessment Tool (SWAT). Streams of the River Raisin watershed in Michigan were grouped using the Strahler stream classification system (orders 1-3 and orders 4-6), k-means clustering technique (two clusters: C1 and C2), and all streams (one grouping). For each grouping, variable selection was performed using Bayesian variable selection, principal component analysis, and Spearman's rank correlation. Following selection of best variable sets, models were developed to predict the measures of biological integrity using adaptive-neuro fuzzy inference systems (ANFIS), a technique well-suited to complex, nonlinear ecological problems. Multiple unique variable sets were identified, all which differed by selection method and stream grouping. Final best models were mostly built using the Bayesian variable selection method. The most effective stream grouping method varied by health measure, although k-means clustering and grouping by stream order were always superior to models built without grouping. Commonly selected variables were related to streamflow magnitude, rate of change, and seasonal nitrate concentration. Each best model was effective in simulating stream health observations, with EPT taxa validation R2 ranging from 0.67 to 0.92, FIBI ranging from 0.49 to 0.85, HBI from 0.56 to 0.75, and fish IBI at 0.99 for all best models. The comprehensive variable selection and modeling process proposed here is a robust method that extends our understanding of watershed scale stream health beyond sparse monitoring points. PMID- 25553549 TI - Human health risk assessment, congener specific analysis and spatial distribution pattern of organochlorine pesticides (OCPs) through rice crop from selected districts of Punjab Province, Pakistan. AB - To evaluate the screening level risk assessment of OCPs in rice (Oryza sativa L.) straw (n=20) and rice grains (n=20), samples were collected from different districts of Punjab Province, Pakistan. ?OCPs' levels (ng g(-1)) in rice straw and grains ranged from 3.63 to 39.40, 2.72 to 49.89, respectively. DDTs were found predominant over the other detected OCP isomers followed by HCH and heptachlor. Results of one way ANOVA reflected no significant difference for OCPs' levels among sampling sites, except heptachlor for rice grains. ?OCPs' concentration in rice straw samples was exceeding the minimal residual levels (MRLs) (Australian and Japanese). Results of dietary intake and risk assessment suggested that rice straw is not safe for animals to consume as fodder. Human health was suggested to have some carcinogenic risks by consumption of rice grains, however, no considerable hazardous risk (non-carcinogenic) to human health was found. PMID- 25553550 TI - In situ N2O emissions are not mitigated by hippuric and benzoic acids under denitrifying conditions. AB - Ruminant urine patches deposited onto pasture are a significant source of greenhouse gas nitrous oxide (N2O) from livestock agriculture. Increasing food demand is predicted to lead to a rise in ruminant numbers globally, which, in turn will result in elevated levels of urine-derived N2O. Therefore mitigation strategies are urgently needed. Urine contains hippuric acid and together with one of its breakdown products, benzoic acid, has previously been linked to mitigating N2O emissions from urine patches in laboratory studies. However, the sole field study to date found no effect of hippuric and benzoic acid concentration on N2O emissions. Therefore the aim of this study was to investigate the in situ effect of these urine constituents on N2O emissions under conditions conducive to denitrification losses. Unadulterated bovine urine (0 mM of hippuric acid, U) was applied, as well as urine amended with either benzoic acid (96 mM, U+BA) or varying rates of hippuric acid (8 and 82 mM, U+HA1, U+HA2). Soil inorganic nitrogen (N) and N2O fluxes were monitored over a 66 day period. Urine application resulted in elevated N2O flux for 44 days. The largest N2O fluxes accounting for between 13% (U) and 26% (U+HA1) of total loss were observed on the day of urine application. Between 0.9 and 1.3% of urine-N was lost as N2O. Cumulative N2O loss from the control was 0.3 kg N2O-Nha(-1) compared with 11, 9, 12, and 10 kg N2O-Nha(-1) for the U, U+HA1, U+HA2, and U+BA treatments, respectively. Incremental increases in urine HA or increase in BA concentrations had no effect on N2O emissions. Although simulation of dietary manipulation to reduce N2O emissions through altering individual urine constituents appears to have no effect, there may be other manipulations such as reducing N content or inclusion of synthetic inhibitory products that warrant further investigation. PMID- 25553551 TI - Additive partitioning of testate amoeba species diversity across habitat hierarchy within the pristine southern taiga landscape (Pechora-Ilych Biosphere Reserve, Russia). AB - In order to better understand the distribution patterns of terrestrial eukaryotic microbes and the factors governing them, we studied the diversity partitioning of soil testate amoebae across levels of spatially nested habitat hierarchy in the largest European old-growth dark coniferous forest (Pechora-Ilych Biosphere Reserve; Komi Republic, Russia). The variation in testate amoeba species richness and assemblage structure was analysed in 87 samples from six biotopes in six vegetation types using an additive partitioning procedure and principal component analyses. The 80 taxa recorded represent the highest value of species richness for soil testate amoebae reported for taiga soils so far. Our results indicate that testate amoeba assemblages were highly aggregated at all levels and were mostly controlled by environmental factors rather than dispersal processes. The variation in species diversity of testate amoebae increased from the lowest to the highest hierarchical level. We conclude that, similarly to macroscopic organisms, testate amoeba species richness and community structure are primarily controlled by environmental conditions within the landscape and suggest that metacommunity dynamics of free-living microorganisms are driven by species sorting and/or mass effect processes. PMID- 25553552 TI - Morphology and molecular phylogeny of three marine Condylostoma species from China, including two new ones (Ciliophora, Heterotrichea). AB - The present study investigates the morphologic and molecular characteristics of three Condylostoma species isolated from brackish and marine tropical habitats of China, including Condylostoma tropicum spec. nov., Condylostoma elongatum spec. nov. and Condylostoma curvum Burkovsky, 1970. The two new species have slender and elongated bodies with the posterior portion distinctly narrowed, forming long tails, thus they obviously differ from most congeners. In addition, Condylostoma tropicum spec. nov. is characterized by its small buccal cavity, single frontal cirrus, 26-33 somatic kineties, and moniliform macronucleus composed of 8-22 nodules. Condylostoma elongatum spec. nov. is distinguished by its huge body size (1000-1200MUm long in vivo), the prominent buccal cavity, 5-7 frontal cirri and 37-43 somatic kineties. Condylostoma curvum is also reinvestigated in this paper using both protargol impregnation and molecular techniques. Phylogenetic analyses based on SSU rDNA sequence data indicate that the three organisms are located within the genus Condylostoma; the genus Condylostoma fails to form a monophyletic branch in both Maximum-likelihood tree and Bayesian inference analysis. Nonetheless, the AU test shows that the monophyly of Condylostoma could not be rejected. PMID- 25553553 TI - Material model calibration from planar tension tests on porcine linea alba. AB - The purpose of this study was to determine biomechanical properties of linea alba subjected to transverse planar tension and to compare its behavior at different locations of the abdominal wall. Samples of linea alba from five different porcine abdominal walls were tested in planar tension. During these tests, strain maps were measured for the first time ever using the stereo-digital image correlation (S-DIC) technique. The strain maps were used to derive the properties of different hyperelastic material models. It was shown that the Ogden model and the Holzapfel-Gasser-Ogden model are appropriate to reproduce the response in planar tension. The linea alba located above the umbilicus was significantly more compliant than below the umbilicus. This difference which is reported for the first time here is consistent with the tissue microstructure and it is discussed within the perspective of clinically-relevant numerical simulations. PMID- 25553554 TI - Velocity-based cardiac contractility personalization from images using derivative free optimization. AB - Model personalization is a key aspect for biophysical models to impact clinical practice, and cardiac contractility personalization from medical images is a major step in this direction. Existing gradient-based optimization approaches show promising results of identifying the maximum contractility from images, but the contraction and relaxation rates are not accounted for. A main reason is the limited choices of objective functions when their gradients are required. For complicated cardiac models, analytical evaluations of gradients are very difficult if not impossible, and finite difference approximations are computationally expensive and may introduce numerical difficulties. By removing such limitations with derivative-free optimization, we found that a velocity based objective function can properly identify regional maximum contraction stresses, contraction rates, and relaxation rates simultaneously with intact model complexity. Experiments on synthetic data show that the parameters are better identified using the velocity-based objective function than its position based counterpart, and the proposed framework is insensitive to initial parameters with the adopted derivative-free optimization algorithm. Experiments on clinical data show that the framework can provide personalized contractility parameters which are consistent with the underlying physiologies of the patients and healthy volunteers. PMID- 25553555 TI - Comparative study of Weibull characteristic strength and mean strength of GPCs to confirm the minimum number of samples needed for confident strength reporting. AB - This short communication determines the strength of two glass polyalkenoate cements that differ from each other through the composition of their glass phase. Sample sets of n=5, 10, 20 and 30 were formulated and tested in biaxial flexure. The derived mean for each sample set was compared against the Weibull characteristic strength. The mean and corresponding characteristic strength show a maximum percentage difference 10.1%, and the 95% confidence intervals calculated from the mean data encompass the corresponding characteristic strength down to a sample set of n=5. This suggests that, for brittle materials such as glass polyalkenoate cements, it is acceptable to test only five samples of each material in biaxial flexure and the resultant 95% confidence intervals will encompass the corresponding Weibull characteristic strength of the material. PMID- 25553556 TI - Local anisotropic mechanical properties of human carotid atherosclerotic plaques characterisation by micro-indentation and inverse finite element analysis. AB - Biomechanical models have the potential to predict failure of atherosclerotic plaques and to improve the risk assessment of plaque rupture. The applicability of these models depends strongly on the used material models. Current biomechanical models employ isotropic material models, although it is generally accepted that plaque tissue behaves highly anisotropic. The aim of the present study is to determine the local anisotropic mechanical properties of human atherosclerotic plaque tissue by means of micro-indentation tests. The indentation was performed on top of an inverted confocal microscope allowing the visualisation and quantification of the collagen fibre deformations perpendicular to the indentation direction of the plaque. Based on this, the anisotropic properties of plaque tissue perpendicular to the indentation direction (middle of the fibrous cap, shoulder of the cap, remaining intima tissue) were derived. There were no significant differences between the different indentation locations for the fibre stiffness (total median 80.6kPa, 25th-75th percentile 17.7 157.0kPa), and fibre dispersion. PMID- 25553557 TI - Fatigue surviving, fracture resistance, shear stress and finite element analysis of glass fiber posts with different diameters. AB - This study evaluated the shear stress presented in glass fiber posts with parallel fiber (0 degrees ) and different coronal diameters under fatigue, fracture resistance and FEA. 160 glass-fiber posts (N=160) with eight different coronal diameters were used (DT=double tapered, number of the post=coronal diameter and W=Wider - fiber post with coronal diameter wider than the conventional): DT1.4; DT1.8W; DT1.6; DT2W; DT1.8; DT2.2W; DT2; DT2.2. Eighty posts were submitted to mechanical cycling (3*10(6) cycles; inclination: 45 degrees ; load: 50N; frequency: 4Hz; temperature: 37 degrees C) to assess the surviving under intermittent loading and other eighty posts were submitted to fracture resistance testing (resistance [N] and shear-stress [MPa] values were obtained). The eight posts types were 3D modeled (Rhinoceros 4.0) and the shear stress (MPa) evaluated using FEA (Ansys 13.0). One-way ANOVA showed statistically differences to fracture resistance (DT2.2W and DT2.2 showed higher values) and shear stress values (DT1.4 showed lower values). Only the DT1.4 fiber posts failed after mechanical cycling. FEA showed similar values of shear stress between the groups and these values were similar to those obtained by shear stress testing. The failure analysis showed that 95% of specimens failed by shear. Posts with parallel fiber (0 degrees ) may suffer fractures when an oblique shear load is applied on the structure; except the thinner group, greater coronal diameters promoted the same shear stresses. PMID- 25553558 TI - Intervention based on Transtheoretical Model promotes anthropometric and nutritional improvements - a randomized controlled trial. AB - OBJECTIVE: To analyze the effects of an intervention based on the Transtheoretical Model on anthropometric and dietetic profile among women in the Primary Health Care in Brazil. DESIGN AND METHODS: Randomized controlled trial. The control group participated in physical activity and open group-education regarding nutrition of usual care. The intervention group participated in 10 workshops based on the Transtheoretical Model. RESULTS: Seventy-one women completed the study, with a mean age of 57.9+/-11.7years. Participants in the intervention group showed an improved body perception, reduced weight and body mass index post-intervention, and lower consumption of calories and foods high in fat. Significant weight reduction in the intervention group was associated with higher per capita income, reduced consumption of protein, reduced consumption of lipids, and the removal of visible fat from red meat and skin from chicken. CONCLUSION: An intervention based on the Transtheoretical Model promoted reduction in consumption of foods high in calories and fat, with positive effects on weight and body perception. These results provide evidence of the applicability and benefit of the Transtheoretical Model within primary care. PMID- 25553559 TI - Effects of an inverted seated position on single and sustained isometric contractions and cardiovascular parameters of trained individuals. AB - Previous research demonstrated higher maximal voluntary contraction (MVC) force with upright vs. inverted positions in untrained individuals. The purpose was to determine the effects of inversion on force, activation, and cardiovascular responses before and following fatigue in trained individuals. Twelve male athletes completed two trials: upright and inverted seated positions. At baseline (upright), either leg extension (LE) or elbow flexion (EF) evoked contractile properties and MVCs were performed. LE and EF contractions were randomly allocated and performed in separate sessions. The subject was then positioned for 150s in each posture, followed by a 30s MVC (MVC30). During each trial, stroke volume (SV), cardiac output (Q), heart rate (HR), time and frequency domain HR variability measures and mean arterial blood pressure (MAP) measurements were recorded. ANOVA showed no statistical differences in EF MVC force, but a tendency (p=.12) for LE MVC decline with inversion vs. upright. Evoked resting (p=.1) and potentiated peak twitch (p=.04) force were increased with inverted LE but tended to diminish with inverted EF (p=.06 and p=.1). Force-fatigue, electromyography fatigue relationships and HR variability during MVC30 fatigue were not affected. HR and Q were significantly (p=.01) lower with inversion following both LE and EF fatigue. Compared to the significant inversion-induced changes associated with untrained individuals in previously published studies, the lack of postural changes in resting force and CV measures may demonstrate that highly trained individuals adapt better to inversion. PMID- 25553560 TI - An EMG comparative analysis of quadriceps during isoinertial strength training using nonlinear scaled wavelets. AB - High-speed resistance training is used to increase power; however, momentum can reduce the effectiveness of high-speed (HS) training when using weight-stack (WS) machines. This study used a non-linear scaled wavelet analysis to assess differences between pneumatic (P) and WS during seven HS or controlled speed (CS) repetitions. Vastus medialis (VM) and lateralis (VL), and rectus femoris (RF) EMG data were collected during leg extension exercises performed by five regular weight-trainers (mean age +/- SD, 23.2 +/- 2.9 years). Data were analyzed using continuous wavelet analysis to assess temporal Intensity distribution across eight frequency bands. Significant differences occurred due to speed for all muscles (p<.0001). P produced higher Intensity than WS for all muscles during HS (p<.0001), and VM and RF during CS (p<.001). The CON phase produced higher Intensity than ECC for the vasti muscles during CS (p<.0003), and VM and RF during HS (p<.0001). Intensity increased across repetitions plateauing earlier for the vasti than RF during CS. Regardless of the machine, Intensity levels peaked between the 25-53 Hz and 46-82 Hz (2nd and 3rd wavelets) bands. The results indicate that when the objective is increasing power through isoinertial training, P machines at HS appear to be the most effective alternative. PMID- 25553561 TI - Alterations in stride-to-stride variability during walking in individuals with chronic ankle instability. AB - The aim of this study was to evaluate stride-to-stride variability of the lower extremity during walking in individuals with and without chronic ankle instability (CAI) using a nonlinear analysis. Twenty-five participants with self reported CAI and 27 healthy control participants volunteered for this study. Participants walked on a motor-driven treadmill for 3 min at their selected speed. Lower extremity kinematics in the sagittal and frontal planes were recorded using a passive retroreflective marker motion capture system. The temporal structure of walking variability was analyzed with sample entropy (SampEn). The CAI group produced lower SampEn values in frontal-plane ankle kinematics compared to the control group (P=.04). No significant group differences were observed for SampEn values of other kinematics (P>.05). Participants with CAI demonstrated less stride-to-stride variability of the frontal plane ankle kinematics compared to healthy controls. Decreased variability of walking patterns demonstrated by participants with CAI indicates that the presence of CAI may be associated with a less adaptable sensorimotor system to environmental changes. The altered sensorimotor function associated with CAI may be targets for clinical interventions, and it is critical to explore how interventions protocols affect sensorimotor system function. PMID- 25553562 TI - Steam gasification of acid-hydrolysis biomass CAHR for clean syngas production. AB - Main characteristics of gaseous product from steam gasification of acid hydrolysis biomass CAHR have been investigated experimentally. The comparison in terms of evolution of syngas flow rate, syngas quality and apparent thermal efficiency was made between steam gasification and pyrolysis in the lab-scale apparatus. The aim of this study was to determine the effects of temperature and steam to CAHR ratio on gas quality, syngas yield and energy conversion. The results showed that syngas and energy yield were better with gasification compared to pyrolysis under identical thermal conditions. Both high gasification temperature and introduction of proper steam led to higher gas quality, higher syngas yield and higher energy conversion efficiency. However, excessive steam reduced hydrogen yield and energy conversion efficiency. The optimal value of S/B was found to be 3.3. The maximum value of energy ratio was 0.855 at 800 degrees C with the optimal S/B value. PMID- 25553563 TI - Simultaneous saccharification and fermentation of delignified lignocellulosic biomass at high solid loadings by a newly isolated thermotolerant Kluyveromyces sp. for ethanol production. AB - Simultaneous saccharification and fermentation studies were carried out using thermotolerant newly isolated Kluyveromyces sp. with three different delignified lignocellulosic biomass viz. rice straw, wheat straw and sugarcane bagasse at 5 15% solid loading and 6-12 FPU g(-1) substrate enzyme loading for different time intervals 0-72 h at 42 degrees C. Maximum ethanol achieved from rice straw, wheat straw and sugarcane bagasse with in-house crude cellulases from Aspergillus terreus was 23.23, 18.29 and 17.91 mg mL(-1) at 60 h with 10% solid load and 9 FPU g(-1) substrate enzyme loading. Tween 80 1% (v/v) enhanced the ethanol yield by 8.39%, 9.26% and 8.14% in rice straw, wheat straw and sugarcane bagasse, respectively. External supplementation of beta-glucosidase to the crude as well commercial cellulases produced maximum theoretical ethanol yield of 71.76%, 63.77%, 57.15% and 84.56%, 72.47%, 70.55% from rice straw, wheat straw and sugarcane bagasse, respectively. PMID- 25553564 TI - Removal and toxicity reduction of naphthenic acids by ozonation and combined ozonation-aerobic biodegradation. AB - A commercial naphthenic acids (NAs) mixture (TCI Chemicals) and five model NA compounds were ozonated in a semibatch mode. Ozonation of 25 and 35 mg/L NA mixture followed pseudo first-order kinetics (k(obs)=0.11+/-0.008 min(-1); r(2)=0.989) with a residual NAs concentration of about 5 mg/L. Ozone reacted preferentially with NAs of higher cyclicity and molecular weight and decreased both cyclicity and the acute Microtox(r) toxicity by 3.3-fold. The ozone reactivity with acyclic and monocyclic model NAs varied and depended on other structural features, such as branching and the presence of tertiary or quaternary carbons. Batch aerobic degradation of unozonated NA mixture using a NA-enriched culture resulted in 83% NA removal and a 6.7-fold decrease in toxicity, whereas a combination of ozonation-biodegradation resulted in 89% NA removal and a 15-fold decrease in toxicity. Thus, ozonation of NA-bearing waste streams coupled with biodegradation are effective treatment processes. PMID- 25553565 TI - Comparative life cycle assessment of biogas plant configurations for a demand oriented biogas supply for flexible power generation. AB - The environmental performance of biogas plant configurations for a demand - oriented biogas supply for flexible power generation is comparatively assessed in this study. Those configurations indicate an increased energy demand to operate the operational enhancements compared to conventional biogas plants supplying biogas for baseload power generation. However, findings show that in contrast to an alternative supply of power generators with natural gas, biogas supplied on demand by adapted biogas plant configurations saves greenhouse gas emissions by 54-65 g CO(2-eq) MJ(-1) and primary energy by about 1.17 MJ MJ(-1). In this regard, configurations with flexible biogas production profit from reduced biogas storage requirements and achieve higher savings compared to configurations with continuous biogas production. Using thicker biogas storage sheeting material reduces the methane permeability of up to 6m(3) d(-1) which equals a reduction of 8% of the configuration's total methane emissions. PMID- 25553566 TI - Sorption characteristics of N-nitrosodimethylamine onto biochar from aqueous solution. AB - N-nitrosodimethylamine (NDMA) is an emerging carcinogenic disinfection by-product in water environment. Biochars utilized as sorbents for the removal of NDMA from aqueous solution, and the sorption characteristics and mechanism were investigate. Biochars were prepared from bamboo, rice straw and wood sawdust at 300-700 degrees C. The pseudo-second-order model provided the best fit for the sorption kinetics of NDMA onto biochar and the sorption isotherms were described best with the Slips model. Biochar produced at 500 degrees C removed NDMA from aqueous solution relatively efficiently, and the bamboo char demonstrated the best sorption potential among the three types of biochars. Solution chemistry such as pH and metal ions did not show obvious effect on NDMA removal. Three sorption mechanisms are suggested for NDMA sorption onto biochars, H-bond attraction between -N=O and the O-containing moieties, hydrophobic force between CH3 and the ordered graphitic structure, and partition process of NDMA into the non-carbonization part of biochar. PMID- 25553567 TI - Quantitative assessment of interfacial interactions with rough membrane surface and its implications for membrane selection and fabrication in a MBR. AB - The interfacial interactions between a foulant particle and rough membrane surface in a submerged membrane bioreactor (MBR) were quantitatively assessed by using a new-developed method. It was found that the profile of total interaction versus separation distance was complicated. There were an energy barrier and two negative energy ranges in the profile. Further analysis showed that roughness scale significantly affected the strength and properties of interfacial interactions. It was revealed that there existed a critical range of roughness scale within which the total energy in the separation distance ranged from 0 to several nanometers was continually repulsive. Decrease in foulant size would increase the strength of specific interaction energy, but did not change the existence of a critical roughness scale range. These findings suggested the possibility to "tailor" membrane surface morphology for membrane fouling mitigation, and thus gave significant implications for membrane selection and fabrication in MBRs. PMID- 25553568 TI - Toward energy-neutral wastewater treatment: a high-rate contact stabilization process to maximally recover sewage organics. AB - The conventional activated sludge process is widely used for wastewater treatment, but to progress toward energy self-sufficiency, the wastewater treatment scheme needs to radically improve energy balances. We developed a high rate contact stabilization (HiCS) reactor system at high sludge-specific loading rates (>2 kg bCOD kg(-1)TSS d(-1)) and low sludge retention times (<1.2 d) and demonstrate that it is able to recover more chemical energy from wastewater organics than high-rate conventional activated sludge (HiCAS) and the low-rate variants of HiCS and HiCAS. The best HiCS system recovered 36% of the influent chemical energy as methane, due to the combined effects of low production of CO2, high sludge yield, and high methane yield of the produced sludge. The HiCS system imposed a feast-famine cycle and a putative selection pressure on the sludge micro-organisms toward substrate adsorption and storage. Given further optimization, it is a promising process for energy recovery from wastewater. PMID- 25553569 TI - Generation of xylooligosaccharides from microwave irradiated agroresidues using recombinant thermo-alkali-stable endoxylanase of the polyextremophilic bacterium Bacillus halodurans expressed in Pichia pastoris. AB - The recombinant Pichia pastoris harboring the endoxylanase gene (TSEV1xyl) of Bacillus halodurans TSEV1 yielded a high titer of extracellular xylanase (502+/ 23 U ml(-1)) on induction with methanol. The purified recombinant xylanase (TSEV1xyl) displayed optimal activity at 80 degrees C and pH 9.0. The glycosylated recombinant xylanase exhibited higher thermostability (T1/2 of 45 min at 80 degrees C) than the native enzyme (T1/2 of 35 min at 80 degrees C). The agroresidues subjected to pretreatment (soaking in alkali followed by microwave irradiation) liberated xylooligosaccharides (XOS) upon hydrolysis with the recombinant xylanase. The removal of unhydrolyzed agroresidues, xylanase and xylose from the hydrolysate by two-step ultrafiltration led to the purification of XOS as confirmed by TLC as well as HPLC analysis. PMID- 25553570 TI - Using sulfite chemistry for robust bioconversion of Douglas-fir forest residue to bioethanol at high titer and lignosulfonate: a pilot-scale evaluation. AB - This study demonstrated at the pilot-scale (50 kg) use of Douglas-fir forest harvest residue, an underutilized forest biomass, for the production of high titer and high yield bioethanol using sulfite chemistry without solid-liquor separation and detoxification. Sulfite Pretreatment to Overcome the Recalcitrance of Lignocelluloses (SPORL) was directly applied to the ground forest harvest residue with no further mechanical size reduction, at a low temperature of 145 degrees C and calcium bisulfite or total SO2 loadings of only 6.5 or 6.6 wt% on oven dry forest residue, respectively. The low temperature pretreatment facilitated high solids fermentation of the un-detoxified pretreated whole slurry. An ethanol yield of 282 L/tonne, equivalent to 70% theoretical, with a titer of 42 g/L was achieved. SPORL solubilized approximately 45% of the wood lignin as directly marketable lignosulfonate with properties equivalent to or better than a commercial lignosulfonate, important to improve the economics of biofuel production. PMID- 25553571 TI - Evolution of process control parameters during extended co-composting of green waste and solid fraction of cattle slurry to obtain growing media. AB - This study aimed to monitor process parameters when two by-products (green waste GW, and the solid fraction of cattle slurry - SFCS) were composted to obtain growing media. Using compost in growing medium mixtures involves prolonged composting processes that can last at least half a year. It is therefore crucial to study the parameters that affect compost stability as measured in the field in order to shorten the composting process at composting facilities. Two mixtures were prepared: GW25 (25% GW and 75% SFCS, v/v) and GW75 (75% GW and 25% SFCS, v/v). The different raw mixtures resulted in the production of two different growing media, and the evolution of process management parameters was different. A new parameter has been proposed to deal with attaining the thermophilic temperature range and maintaining it during composting, not only it would be useful to optimize composting processes, but also to assess the hygienization degree. PMID- 25553572 TI - Fermentative hydrogen and methane cogeneration from cassava residues: effect of pretreatment on structural characterization and fermentation performance. AB - The physicochemical properties of cassava residues subjected to microwave (or steam)-heated acid pretreatment (MHAP or SHAP) were comparatively investigated to improve fermentative hydrogen and methane cogeneration. The hydrogen yield from cassava residues with MHAP and enzymolysis was higher (106.2 mL/g TVS) than that with SHAP and enzymolysis (102.1 mL/g TVS), whereas the subsequent methane yields showed opposite results (75.4 and 93.2 mL/g TVS). Total energy conversion efficiency increased to 24.7%. Scanning electron microscopy images revealed MHAP generated numerous regular micropores (~6 MUm) and SHAP generated irregular fragments (~23 MUm) in the destroyed lignocellulose matrix. Transmission electron microscopy images showed SHAP generated wider cracks (~0.2 MUm) in delaminated cell walls than MHAP (~0.1 MUm). X-ray diffraction patterns indicated MHAP caused a higher crystallinity index (33.00) than SHAP (25.88), due to the deconstruction of amorphous cellulose. Fourier transform infrared spectroscopy indicated MHAP caused a higher crystallinity coefficient (1.20) than SHAP (1.12). PMID- 25553573 TI - Co-pyrolysis characteristic of biomass and bituminous coal. AB - Co-pyrolysis characteristics of biomass and bituminous coal have been studied in this work. The temperature was up to 900 degrees C with the heating rates of 10, 15, 20, 25 and 30 degrees C/min. Rice straw, saw dust, microcrystalline cellulose, lignin and Shenfu bituminous coal were chosen as samples. Six different biomass ratios were used. The individual thermal behavior of each sample was obtained. The experimental weight fractions of the blended samples and the calculated values were compared. The results show that the weight fractions of the blended samples behave differently with calculated ones during the co pyrolysis process. With the increasing biomass ratio, relative deviations between experimental weight fractions and calculated ones are larger. H/C molar ratio, heat transfer properties of biomass would affect to the interaction between biomass and coal. The maximum degradation rates are slower than the calculated ones. The activation energy distributions also changed by adding some biomass into coal. PMID- 25553574 TI - Charge regulation and energy dissipation while compressing and sliding a cross linked chitosan hydrogel layer. AB - Interactions between a silica surface and a surface coated with a grafted cross linked hydrogel made from chitosan/PAA multilayers are investigated, utilizing colloidal probe atomic force microscopy. Attractive double-layer forces are found to dominate the long-range interaction over a broad range of pH and ionic strength conditions. The deduced potential at the hydrogel/aqueous interface is found to be very low. This situation is maintained in the whole pH-range investigated, even though the degree of protonation of chitosan changes significantly. This demonstrates that pH-variations change the concentration of counterions within the hydrogel to keep the interior close to uncharged, which is similar to what has been observed for polyelectrolyte brushes. Changes in pH and ionic strength affect the adhesion force and the friction force between the silica surface and the hydrogel layer, but not the friction coefficient. This suggests that the main energy dissipation mechanism arises from processes occurring within the hydrogel layer, rather than at the silica/hydrogel interface, and we suggest that it is related to stretching of polymer chains between the cross-linking points. We also find that an increased cross-linking density, from 40% to 100%, in the hydrogel reduces the friction coefficient. PMID- 25553576 TI - Assessment of trace metals in fish species of urban rivers in Bangladesh and health implications. AB - Levels of six metals i.e. chromium (Cr), nickel (Ni), copper (Cu), arsenic (As), cadmium (Cd) and lead (Pb) in three fish species (Channa punctatus, Heteropneustes fossilis and Trichogaster fasciata) from three urban rivers in Bangladesh were measured. Concentrations of Cr, Ni, Cu, As, Cd and Pb in fish species were 0.75-4.8, 0.14-3.1, 1.1-7.2, 0.091-0.53, 0.007-0.13, and 0.052 2.7mg/kg ww, respectively. The analyzed metals were significantly different between species and seasons (p<0.05). The target hazard quotients (THQs) and carcinogenic risk (CR) for individual metal showed that As and Pb in muscle was particularly hazardous and potential risk for the low, medium and high fish consumer in Bangladesh. Some of the trace metals' concentrations are higher than the recommended value, which suggest that the water and fish of these rivers are not completely safe for human health. PMID- 25553575 TI - Deoxynivalenol induces apoptosis in chicken splenic lymphocytes via the reactive oxygen species-mediated mitochondrial pathway. AB - We investigated the immunotoxicity and cytotoxicity of deoxynivalenol (DON), a mycotoxin, and the mechanism by which it induces apoptosis. Chicken splenic lymphocytes treated with 0-50MUg/mL DON for 48h inhibited growth of splenic lymphocytes in a dose-dependent manner, as revealed by the Cell Counting Kit-8 (CCK-8) bioassay. Annexin V-fluorescein isothiocyanate staining indicated that the number of apoptotic and necrotic cells were significantly higher compared with the control (P<0.01). DON treatment induced ROS accumulation, resulting in reduced mitochondrial transmembrane potential, as detected by flow cytometry and 2',7'-dichlorofluorescein acetate and rhodamine 123 labeling, respectively. Enzyme linked immunosorbent assays revealed that the concentrations of p53, Bax, Bak-1, and Caspase-3 increased with increasing DON concentration (P<0.05 or P<0.01), whereas the concentrations of Bcl-2 decreased (P<0.01) compared with the control. These data suggest that DON induces apoptosis in splenic lymphocytes via a ROS-mediated mitochondrial pathway. PMID- 25553577 TI - Predicting and preventing vascular complications following percutaneous coronary intervention in women. AB - The development of vascular complications is associated with increased morbidity and mortality in patients undergoing percutaneous coronary intervention. While the incidence of percutaneous coronary intervention-related vascular complications has greatly improved over time, female sex still persists as a significant and independent predictor of periprocedural vascular complications, which in turn is associated with a greater risk of short- and long-term mortality. This review provides a contemporary overview of the data on the important issues regarding the risk of percutaneous coronary intervention in women. It examines the intrinsic sex-related factors that may be contributing to women's heightened bleeding risk while also examining the various pharmacologic and procedural bleeding avoidance strategies currently in the literature, with a focus on their potential role and benefit in women specifically. PMID- 25553579 TI - Reactivity of the free and (5,5)-carbon nanotube-supported AuPt bimetallic clusters towards O2 activation: a theoretical study. AB - Density functional theory (DFT)-based calculations were carried out to predict the geometry, energy and electronic structures of the small bimetallic AumPtn (2 <=m + n<= 4) clusters deposited on a single-wall (5,5)-carbon nanotube (CNT). The chemical reactivity of these supported bimetallic clusters towards O2 reduction reaction was also considered. The calculations indicate that Au atoms tend to avoid the CNT atoms, whereas the opposite occurs for Pt atoms, a behavior which can be rationalized through analyses of the density of states plots. Compared to isolated clusters, the supported counterparts are found to have significant superiority in catalytic activity towards O2 reduction. The adsorption configuration and identity of the metal (Au or Pt) exposed to the O2 molecule adsorption are the dominant factors in determining the catalytic activity of the supported particles. Most notably, high catalytic activity of the supported clusters is associated with a drastic decrease in adsorption energy of the O2 molecule. PMID- 25553578 TI - Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease. AB - AIM: During ageing, advanced glycation end-products (AGEs) accumulate in extracellular matrix proteins like collagen and contribute to a decline in organ function. As skin autofluorescence (sAF) can assess subcutaneous accumulation of fluorescent AGEs, this study aimed to investigate the relationship between AGE modified cardiac tissue collagen and AGE-related sAF in coronary artery bypass graft (CABG) surgery patients. METHODS: Between January 2011 and January 2012, data from 72 consecutive male patients undergoing isolated CABG were prospectively recorded. Collagen fractions were isolated from the right atrial appendages of these patients by proteolysis and collagenase digestion. Collagen was quantified by hydroxyproline assay, and AGEs by AGE-related intrinsic fluorescence; sAF was measured using an autofluorescence reader. RESULTS: Biochemical analysis showed that the insoluble cardiac collagen fraction contained the highest amounts of accumulated AGEs; the AGE-related intrinsic fluorescence of this fraction increased with age (P=0.0001), blood glucose (P=0.002), HbA1c (P=0.01) and sAF (P=0.008). CONCLUSION: This study demonstrated for the first time a relationship between cardiac tissue glycation and AGE related sAF. In addition, cardiac tissue glycation was associated with age, blood glucose and long-term glucose values in patients with coronary artery disease. PMID- 25553580 TI - Update of information on perkinsosis in NW Mediterranean coast: Identification of Perkinsus spp. (Protista) in new locations and hosts. AB - This study addressed perkinsosis in commercially important mollusc species in the western Mediterranean area. Perkinsus olseni was found in Santa Gilla Lagoon (Sardinia) infecting Ruditapes decussatus, Cerastoderma glaucum and Venerupis aurea, in Balearic Islands infecting Venus verrucosa and in Delta de l'Ebre (NE Spain) parasitising Ruditapes philippinarum and R. decussatus. Perkinsus mediterraneus was detected infecting Ostrea edulis from the Gulf of Manfredonia (SE Italy) and Alacant (E Spain), V. verrucosa and Arca noae from Balearic Islands and Chlamys varia from Balearic Islands, Alacant and Delta de l'Ebre. PMID- 25553581 TI - Microbiota shifts in the surface mucopolysaccharide layer of corals transferred from natural to aquaria settings. AB - Bacteria associated with the surface mucopolysaccharide layer (SML) of corals have been proposed to be paramount to coral health, and are occasionally studied in aquaria. Using automated ribosomal intergenic spacer analysis (ARISA), this study examined the temporal changes in the SML microbiota of coral fragments (Siderastrea siderea) transferred from the reef to aquaria. In total, 460 amplicon peaks were detected, 155 of which were unique. Extensive microbiota shifts occurred one day after transfer, with stabilization between 14 and 28days. These results suggest that studies examining coral in laboratory settings should consider the observed temporal dynamics in the SML microbiota. PMID- 25553582 TI - Lettuce (Lactuca sativa L.) leaf-proteome profiles after exposure to cylindrospermopsin and a microcystin-LR/cylindrospermopsin mixture: a concentration-dependent response. AB - The intensification of agricultural productivity is an important challenge worldwide. However, environmental stressors can provide challenges to this intensification. The progressive occurrence of the cyanotoxins cylindrospermopsin (CYN) and microcystin-LR (MC-LR) as a potential consequence of eutrophication and climate change is of increasing concern in the agricultural sector because it has been reported that these cyanotoxins exert harmful effects in crop plants. A proteomic-based approach has been shown to be a suitable tool for the detection and identification of the primary responses of organisms exposed to cyanotoxins. The aim of this study was to compare the leaf-proteome profiles of lettuce plants exposed to environmentally relevant concentrations of CYN and a MC-LR/CYN mixture. Lettuce plants were exposed to 1, 10, and 100 MUg/l CYN and a MC-LR/CYN mixture for five days. The proteins of lettuce leaves were separated by two dimensional electrophoresis (2-DE), and those that were differentially abundant were then identified by matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF/TOF MS). The biological functions of the proteins that were most represented in both experiments were photosynthesis and carbon metabolism and stress/defense response. Proteins involved in protein synthesis and signal transduction were also highly observed in the MC-LR/CYN experiment. Although distinct protein abundance patterns were observed in both experiments, the effects appear to be concentration-dependent, and the effects of the mixture were clearly stronger than those of CYN alone. The obtained results highlight the putative tolerance of lettuce to CYN at concentrations up to 100 MUg/l. Furthermore, the combination of CYN with MC-LR at low concentrations (1 MUg/l) stimulated a significant increase in the fresh weight (fr. wt) of lettuce leaves and at the proteomic level resulted in the increase in abundance of a high number of proteins. In contrast, many proteins exhibited a decrease in abundance or were absent in the gels of the simultaneous exposure to 10 and 100 MUg/l MC LR/CYN. In the latter, also a significant decrease in the fr. wt of lettuce leaves was obtained. These findings provide important insights into the molecular mechanisms of the lettuce response to CYN and MC-LR/CYN and may contribute to the identification of potential protein markers of exposure and proteins that may confer tolerance to CYN and MC-LR/CYN. Furthermore, because lettuce is an important crop worldwide, this study may improve our understanding of the potential impact of these cyanotoxins on its quality traits (e.g., presence of allergenic proteins). PMID- 25553583 TI - Neuroprotective naphthalene and flavan derivatives from Polygonum cuspidatum. AB - Ten naphthalene derivatives including two unusual glycosides possessing a naphthalene-fused piceid via a [C8'-O-C6-C5-C7']-trans-dihydrofuran ring, two flavan derivatives, as well as sixteen known phenolic compounds, were isolated from Polygonum cuspidatum. The structures were determined by extensive NMR, MS, CD data, and chemical evidence. In the in vitro neuroprotective assays, at the concentration of 10 MUM, five of these compounds exhibited significant effects against PC12 cells injured by rotenone. PMID- 25553585 TI - Two-dimensional layered chalcogenides: from rational synthesis to property control via orbital occupation and electron filling. AB - Electron occupation of orbitals in two-dimensional (2D) layered materials controls the magnitude and anisotropy of the interatomic electron transfer and exerts a key influence on the chemical bonding modes of 2D layered lattices. Therefore, their orbital occupations are believed to be responsible for massive variations of the physical and chemical properties from electrocatalysis and energy storage, to charge density waves, superconductivity, spin-orbit coupling, and valleytronics. Especially in nanoscale structures such as nanoribbons, nanoplates, and nanoflakes, 2D layered materials provide opportunities to exploit new quantum phenomena. In this Account, we report our recent progress in the rational design and chemical, electrochemical, and electrical modulations of the physical and chemical properties of layered nanomaterials via modification of the electron occupation in their electronic structures. Here, we start with the growth and fabrication of a group of layered chalcogenides with varied orbital occupation (from 4d/5d electron configuration to 5p/6p electron configuration). The growth techniques include bottom-up methods, such as vapor-liquid-solid growth and vapor-solid growth, and top-down methods, such as mechanical exfoliation with tape and AFM tip scanning. Next, we demonstrate the experimental strategies for the tuning of the chemical potential (orbital occupation tuned with electron filling) and the resulting modulation of the electronic states of layered materials, such as electric-double-layer gating, electrochemical intercalation, and chemical intercalation with molecule and zerovalence metal species. Since the properties of layered chalcogenides are normally dominated by the specific band structure around which the chemical potential is sitting, their desired electronic states and properties can be modulated in a large range, showing unique phenomena including quantum electronic transport and extraordinary optical transmittance. As the most important part of this Account, we further demonstrate some representative examples for the tuning of catalytic, optical, electronic, and spintronic properties of 2D layered chalcogenides, where one can see not only edge-state induced enhancement of catalysis, quantum Aharonov-Bohm interference of the topological surface states, intercalation modulated extraordinary transmittance, and surface plasmonics but also external gating induced superconductivity and spin-coupled valley photocurrent. Since our findings reflect the critical influences of the electron filling of orbital occupation to the properties in 2D layered chalcogenides, we thus last highlight the importance and the prospective of orbital occupation in 2D layered materials for further exploring potential functionalized applications. PMID- 25553584 TI - Silencing the lettuce homologs of small rubber particle protein does not influence natural rubber biosynthesis in lettuce (Lactuca sativa). AB - Natural rubber, cis-1,4-polyisoprene, is an important raw material in chemical industries, but its biosynthetic mechanism remains elusive. Natural rubber is known to be synthesized in rubber particles suspended in laticifer cells in the Brazilian rubber tree (Hevea brasiliensis). In the rubber tree, rubber elongation factor (REF) and its homolog, small rubber particle protein (SRPP), were found to be the most abundant proteins in rubber particles, and they have been implicated in natural rubber biosynthesis. As lettuce (Lactuca sativa) can synthesize natural rubber, we utilized this annual, transformable plant to examine in planta roles of the lettuce REF/SRPP homologs by RNA interference. Among eight lettuce REF/SRPP homologs identified, transcripts of two genes (LsSRPP4 and LsSRPP8) accounted for more than 90% of total transcripts of REF/SRPP homologs in lettuce latex. LsSRPP4 displays a typical primary protein sequence as other REF/SRPP, while LsSRPP8 is twice as long as LsSRPP4. These two major LsSRPP transcripts were individually and simultaneously silenced by RNA interference, and relative abundance, polymer molecular weight, and polydispersity of natural rubber were analyzed from the LsSRPP4- and LsSRPP8-silenced transgenic lettuce. Despite previous data suggesting the implications of REF/SRPP in natural rubber biosynthesis, qualitative and quantitative alterations of natural rubber could not be observed in transgenic lettuce lines. It is concluded that lettuce REF/SRPP homologs are not critically important proteins in natural rubber biosynthesis in lettuce. PMID- 25553589 TI - An in-depth appraisal of career termination experiences in professional cricket. AB - This qualitative study explored the career termination experiences of 9 male, retired professional cricketers between the ages of 28 and 40 (mean value 34, s = 4.65 m). The participants took part in retrospective, semi-structured interviews. Data from the interviews were inductively content analysed within three transition phases of the retirement process: reasons for retirement, factors affecting adaptation and reactions to retirement. The reasons for retirement were multicausal with the majority of the participants highlighting contractual pressures and a lack of communication as important precursors to retirement. Three main themes accounted for the factors affecting adaptation: a limited pursuit of other interests, developmental experiences and coping strategies. In terms of reactions to retirement, all of the participants reflected negatively on the termination of their career, with a sense of loss and resentment characterising the post-retirement period. The findings illustrated the sport specific nature of career termination in professional cricket and added further support to the emerging consensus that the distinction between voluntary and involuntary retirement is, at best, unclear. PMID- 25553590 TI - The chemical biology of dimethylsulfoniopropionate. AB - Dimethylsulfoniopropionate is a highly abundant sulfur metabolite in marine ecosystems. Its biosynthesis by different organisms including plants, marine algae and dinoflagellates is discussed. Furthermore, the accumulated knowledge about bacterial uptake systems and its climatically relevant degradation by marine bacteria to methanethiol or dimethylsulfide is presented. Finally, uptake and degradation of synthetic DMSP analogs are addressed. PMID- 25553591 TI - The transcriptome recipe for the venom cocktail of Tityus bahiensis scorpion. AB - Scorpion venom is a mixture of peptides, including antimicrobial, bradykinin potentiating and anionic peptides and small to medium proteins, such as ion channel toxins, metalloproteinases and phospholipases that together cause severe clinical manifestation. Tityus bahiensis is the second most medically important scorpion species in Brazil and it is widely distributed in the country with the exception of the North Region. Here we sequenced and analyzed the transcripts from the venom glands of T. bahiensis, aiming at identifying and annotating venom gland expressed genes. A total of 116,027 long reads were generated by pyrosequencing and assembled in 2891 isotigs. An annotation process identified transcripts by similarity to known toxins, revealing that putative venom components represent 7.4% of gene expression. The major toxins identified are potassium and sodium channel toxins, whereas metalloproteinases showed an unexpected high abundance. Phylogenetic analysis of deduced metalloproteinases from T. bahiensis and other scorpions revealed a pattern of ancient and intraspecific gene expansions. Other venom molecules identified include antimicrobial, anionic and bradykinin-potentiating peptides, besides several putative new venom components. This report provides the first attempt to massively identify the venom components of this species and constitutes one of the few transcriptomic efforts on the genus Tityus. PMID- 25553592 TI - Citreoviridin induces ROS-dependent autophagic cell death in human liver HepG2 cells. AB - Citreoviridin (CIT) is one of toxic mycotoxins derived from fungal species in moldy cereals. Whether CIT exerts hepatotoxicity and the precise molecular mechanisms of CIT hepatotoxicity are not completely elucidated. In this study, the inhibitor of autophagosome formation, 3-methyladenine, protected the cells against CIT cytotoxicity, and the autophagy stimulator rapamycin further decreased the cell viability of CIT-treated HepG2 cells. Knockdown of Atg5 with Atg5 siRNA alleviated CIT-induced cell death. These finding suggested the hypothesis that autophagic cell death contributed to CIT-induced cytotoxicity in HepG2 cells. CIT increased the autophagosome number in HepG2 cells observed under a transmission electron microscope, and this effect was confirmed by the elevated LC3-II levels detected through Western blot. Reduction of P62 protein levels and the result of LC3 turnover assay indicated that the accumulation of autophagosomes in the CIT-treated HepG2 cells was due to increased formation rather than impaired degradation. The pretreatment of HepG2 cells with the ROS inhibitor NAC reduced autophagosome formation and reversed the CIT cytotoxicity, indicating that CIT-induced autophagic cell death was ROS-dependent. In summary, ROS-dependent autophagic cell death of HpeG2 cells described in this study may help to elucidate the underlying mechanism of CIT cytotoxicity. PMID- 25553593 TI - Effects of phytoplankton extracts containing the toxin microcystin-LR on the survival and reproduction of cladocerans. AB - The use of ecotoxicological techniques for the evaluation of the quality of limnetic waters allows the early detection of toxic agents that pose risks to human health. In this study Moina micrura (two clones), Daphnia laevis (two clones) and Daphnia similis, a temperate species, were used to evaluate the toxicity of six Microcystis extracts from two Colombian reservoirs. Toxin was detected and quantified by HPLC. Microcystin-LR was found in all extracts with the highest concentrations in one sample from each reservoir (434 MUg g(-1) and 538 MUg g(-1)). The extracts that had the highest toxin concentration also had the highest toxicities to cladocerans. Measurement of 48-h LC50 showed consistent differences between cladoceran species but not clones, Also, reproduction data in two species were consistent with the MC-LR content of one sample tested, with decreased reproduction and disruption of egg production. However, only some growth results of neonates exposed to extracts were consistent with the acute response. In conclusion, Daphnia species are a good model for monitoring cyanotoxins as they respond in a sensitive way to natural phytoplankton samples containing microcystin-LR. PMID- 25553594 TI - Identification of crotamine in the venom of Crotalus durissus collilineatus by three different methods. AB - The use of mice for the identification of crotamine has been the motive of discussions of bioethical character and technical (efficiency), so that a reassessment of the use of animals in experiments is global trend the search for alternative tests. The objective of this study was to standardize a method for HPLC-PDA to identify the presence of crotamine in the venom of rattlesnakes, aiming to propose an alternative methodology to reduce or replace the use of animals. The Cdc was evaluated as to the presence of crotamine by 3 methods: traditional test lethality in mice (Mus musculus) swiss albino male, 18-22 g (i.p.), polyacrylamide gel electrophoresis (SDS-PAGE) and HPLC-PDA. The venoms of 50 specimens of Crotalus durissus collilineatus, held in the serpentarium CEPB/PUC Goias, were obtained by manual massage of the gland, making the collection individually. To identify the band corresponding to crotamine, the venoms of specimens, analysis was performed on SDS-PAGE and references. Procedure in mice with 20% of the samples tested positive for crotamine, 24% negative and 56% uncertain outcome. With the SDS-PAGE was identified crotamine in 26% of samples, 26% negative and 48% continued with uncertain outcome. By HPLC method showed the presence myotoxin in 86% of samples, with 14% negative. The tests conducted in this study indicated that methodology which utilizes animals for identifying the presence of crotamine the venom of C. durissus can safely be replaced by the test SDS-PAGE and HPLC, since the methods are reproducible, and do not undergo any interference biological animal and mainly contribute to reducing the number of animals used for laboratory tests. PMID- 25553595 TI - Immunology of bovine respiratory syncytial virus in calves. AB - Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease in young calves. The virus is genetically and antigenically closely related to human (H)RSV, which is a major cause of respiratory disease in young infants. As a natural pathogen of calves, BRSV infection recapitulates the pathogenesis of respiratory disease in man more faithfully than semi-permissive, animal models of HRSV infection. With the increasing availability of immunological reagents, the calf can be used to dissect the pathogenesis of and mechanisms of immunity to RSV infection, to analyse the ways in which the virus proteins interact with components of the innate response, and to evaluate RSV vaccine strategies. Passively transferred, neutralising bovine monoclonal antibodies, which recognise the same epitopes in the HRSV and BRSV fusion (F) protein, can protect calves against BRSV infection, and depletion of different T cells subsets in calves has highlighted the importance of CD8(+) T cells in viral clearance. Calves can be used to model maternal-antibody mediated suppression of RSV vaccine efficacy, and to increase understanding of the mechanisms responsible for RSV vaccine-enhanced respiratory disease. PMID- 25553596 TI - Effects of resveratrol on doxorubicin induced testicular damage in rats. AB - The purpose of this study was to evaluate the likely protective effect of resveratrol (RES) on doxorubicin (DOX) induced testicular damage. Rats were divided into five groups: control, RES, dimethyl sulfoxide (DMSO), DOX and DOX+RES. At the end of treatment, the rats were sacrificed. Plasma testosterone levels, oxidative status, epididymal sperm parameters and testicular apoptosis were evaluated. MDA levels, GP-x and GSH activities were higher in the DOX group than in the control group. MDA levels were lower in the DOX+RES group than in the DOX group. The DOX group exhibited a significant decrease in plasma testosterone levels, sperm concentration and motility, and a significant increase in abnormal sperm rate and TUNEL (+) cells in the testis. A significant increase was observed in plasma testosterone levels and sperm concentration and motility, and a significant decrease in the abnormal sperm rate and TUNEL (+) cells in the DOX+RES group compared to the DOX group. A marked improvement in severe degenerative alterations in the germinative epithelium was also observed following treatment with RES. In conclusion, RES makes a positive contribution to fertility by exhibiting anti-apoptotic and antiperoxidative effects against DOX induced testicular damage. PMID- 25553597 TI - Two-year carcinogenicity study of acrylamide in Wistar Han rats with in utero exposure. AB - Acrylamide is an important chemical with widespread industrial and other uses in addition to generalized population exposure from certain cooked foods. Previous rat studies to assess the carcinogenic potential of acrylamide have been carried out exclusively in the Fischer 344 rat with identification of a number of tumors amongst which mesotheliomas of the tunica vaginalis is an important tumor endpoint in the classification of acrylamide as a 'probably human carcinogen. In a rat carcinogenicity study to determine the human relevance of mesotheliomas Wistar Han rats were exposed to 0, 0.5, 1.5, or 3.0mg acrylamide/kg body weight/day in drinking water starting at gestation day 6. At the end of two years, mammary gland fibroadenomas in females and thyroid follicular cell tumors in both sexes were the only tumors increased in acrylamide treated rats. These tumor endpoints have rat-specific modes of action suggesting less likelihood of human cancer risk than previously estimated. This study demonstrates that tunica vaginalis mesotheliomas are strain specific and not likely of genotoxic origin. PMID- 25553598 TI - Long-term follow up of feline leukemia virus infection and characterization of viral RNA loads using molecular methods in tissues of cats with different infection outcomes. AB - It is a remarkable feature for a retrovirus that an infection with feline leukemia virus (FeLV) can result in various outcomes. Whereas some cats contain the infection and show a regressive course, others stay viremic and succumb to the infection within a few years. We hypothesized, that differences in the infection outcome might be causally linked to the viral RNA and provirus loads within the host and these loads therefore may give additional insight into the pathogenesis of the virus. Thus, the goals of the present study were to follow-up on experimentally infected cats and investigate tissues from cats with different infection outcomes using sensitive, specific TaqMan real-time PCR and reverse transcriptase (RT)-PCR. Nineteen experimentally FeLV-A/Glasgow-1-infected cats were categorized into having regressive, progressive or reactivated FeLV infection according to follow-up of FeLV p27 antigen detection in the blood. Remarkably, regressively infected cats showed detectable provirus and viral RNA loads in almost all of the 27 tested tissues, even many years after virus exposure. Moreover, some regressively infected cats reactivated the infection, and these cats had intermediate to high viral RNA and provirus tissue loads. The highest loads were found in viremic cats, independent of their health status. Tissues that represented sites of virus replication and shedding revealed the highest viral RNA and provirus loads, while the lowest loads were present in muscle and nerve tissues. A supplementary analysis of 20 experimentally infected cats with progressive infection revealed a median survival time of 3.1 years (range from 0.6 to 6.5 years); ~70% (n=14) of these cats developed lymphoma, while leukemia and non-regenerative anemia were observed less frequently. Our results demonstrate that the different infection outcomes are associated with differences in viral RNA and provirus tissue loads. Remarkably, no complete clearance of FeLV viral RNA or provirus was detected in cats with regressive infection, even up to 12 years after exposure. In several cases FeLV reactivation could be observed. Thus, retroviruses integrated as provirus into the host's genome, could not be eliminated completely by the host and maintained their full potential for replication and reactivation. PMID- 25553599 TI - Effects of margarine enriched with plant sterol esters from rapeseed and tall oils on markers of endothelial function, inflammation and hemostasis. AB - BACKGROUND AND AIMS: The sterol profile of rapeseed oil differs from that of tall oil with higher contents of campesterol and brassicasterol. We previously found that margarines providing 2 g/day of sterols from rapeseed or tall oil resulted in similar reductions in LDL cholesterol of 8-9%. The aim of the present study was to investigate whether the consumption of these margarines affected markers of endothelial function, inflammation and hemostasis. METHODS: Blood samples were collected from 58 hypercholesterolemic volunteers who completed a double-blinded, randomized, crossover trial. Subjects consumed each of the two sterol margarines and a control non-sterol margarine for 4 weeks separated by one-week washout periods. All the margarines had the same fatty acid composition. Concentrations of vascular cell adhesion molecule-l (VCAM-1), E-selection, circulating tumor necrosis factor alpha (TNFalpha) and plasminogen activator inhibitor-1 (total, tPAI-1; active, PAI-1) were quantified. RESULTS: Rapeseed-sterol margarine reduced E-selection concentrations compared to the control margarine (p = 0.012) while tall-sterol margarine had no effect. The rapeseed-sterol margarine also reduced tPAI-1 (p = 0.008) compared to the tall-sterol margarine. No significant changes were observed in TNFalpha and VCAM-1. No association was found between LDL reduction and changes in E-selection and tPAI-1. CONCLUSION: Rapeseed-sterol margarine demonstrated favorable effects on vascular risk markers. PMID- 25553600 TI - Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation. AB - Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting approximately one in five pregnant women in Western countries. Many report moderate or severe symptoms and negative impact on sleep. There is very little information in the medical literature for practitioners on the management of this condition during pregnancy. Accordingly, a task force was chosen by the International RLS Study Group (IRLSSG) to develop guidelines for the diagnosis and treatment of RLS/WED during pregnancy and lactation. A committee of nine experts in RLS/WED and/or obstetrics developed a set of 12 consensus questions, conducted a literature search, and extensively discussed potential guidelines. Recommendations were approved by the IRLSSG executive committee, reviewed by IRLSSG membership, and approved by the WED Foundation Medical Advisory Board. These guidelines address diagnosis, differential diagnosis, clinical course, and severity assessment of RLS/WED during pregnancy and lactation. Nonpharmacologic approaches, including reassurance, exercise and avoidance of exacerbating factors, are outlined. A rationale for iron supplementation is presented. Medications for RLS/WED are risk/benefit rated for use during pregnancy and lactation. A few are rated "may be considered" when RLS/WED is refractory to more conservative approaches. An algorithm summarizes the recommendations. These guidelines are intended to improve clinical practice and promote further research. PMID- 25553601 TI - Obesity and onset of depression among U.S. middle-aged and older adults. AB - OBJECTIVES: This paper aims to examine the relationship between obesity and onset of depression among U.S. middle-aged and older adults. METHODS: Data came from 1994 to 2010 waves of the Health and Retirement Study. Study sample consisted of 6514 community-dwelling adults born between 1931 and 1941 who were free of clinically relevant depressive symptoms in 1994. Body mass index (BMI) was calculated from self-reported height/weight. Body weight status was classified into normal weight (18.5kg/m(2)<=BMI<25kg/m(2)), overweight (25kg/m(2)<=BMI<30kg/m(2)), and obesity (BMI>=30kg/m(2)). A score of >=3 on the 8 item Center for Epidemiologic Studies Depression Scale was used to define clinically relevant depressive symptoms. Kaplan-Meier estimator and time dependent Cox proportional hazards model were performed to examine the association between body weight status and onset of clinically relevant depressive symptoms. RESULTS: Unhealthy body weight was associated future onset of depression. Compared with their normal weight counterparts, overweight and obese participants were 13% (hazard ratio [HR]=1.13, 95% confidence interval [CI]=1.04-1.23) and 9% (HR=1.09, 95% CI=1.01-1.18) more likely to have onset of clinically relevant depressive symptoms during the 16years of follow-up, respectively. The relationship between obesity and depression onset appeared stronger among females and non-Hispanic whites than their male and racial/ethnic minority counterparts. CONCLUSIONS: Health care providers should be aware of the potential risk for depression among obese older adults. PMID- 25553602 TI - Selecting the surgical approach for revision total hip arthroplasty. AB - Selecting the approach for revision total hip arthroplasty is a crucial step in pre-operative planning. Whether the surgical objectives can be reached via a conventional approach or require a specific approach must be determined. The best approach depends on multiple factors including the reason for revision, patient's characteristics, implants requiring removal, previous approach, soft tissue and bone lesions, and surgeon's level of experience. These factors are discussed herein, as well as the potential and limitations of conventional approaches and the indications for specific approaches. PMID- 25553603 TI - Registries in orthopaedics. AB - The first nationwide orthopaedic registry was created in Sweden in 1975 to collect data on total knee arthroplasty (TKA). Since then, several countries have established registries, with varying degrees of success. Managing a registry requires time and money. Factors that contribute to successful registry management include the use of a single identifier for each patient to ensure full traceability of all procedures related to a given implant; a long-term funding source; a contemporary, rapid, Internet-based data collection method; and the collection of exhaustive data, at least for innovative implants. The effects of registries on practice patterns should be evaluated. The high cost of registries raises issues of independence and content ownership. Scandinavian countries have been maintaining orthopaedic registries for nearly four decades (since 1975). The first English-language orthopaedic registry was not created until 1998 (in New Zealand), and both the US and many European countries are still struggling to establish orthopaedic registries. To date, there are 11 registered nationwide registries on total knee and total hip replacement. The data they contain are often consistent, although contradictions occur in some cases due to major variations in cultural and market factors. The future of registries will depend on the willingness of health authorities and healthcare professionals to support the creation and maintenance of these tools. Surgeons feel that registries should serve merely to compare implants. Health authorities, in contrast, have a strong interest in practice patterns and healthcare institution performances. Striking a balance between these objectives should allow advances in registry development in the near future. PMID- 25553604 TI - Sequelae of pediatric osteoarticular infection. AB - The epidemiology and diagnosis of osteoarticular infections (OAI) have changed considerably in recent years, partly due to the development of molecular biology. Kingella kingae is now recognized as the most frequent pathogen in children under 4 years of age, while methicillin-resistant Staphylococcus aureus (SA) has been increasingly reported. Although the clinical course of OAI is mostly benign, with shorter antibiotic regimens and simplified treatments, serious functional impairments and life-threatening complications can still occur, especially in case of delayed diagnosis or infection caused by Panton-Valentine leukocidin producing strains of SA. Newborns and patients with sickle cell disease have greater risk of orthopaedic sequelae, which need to be detected and managed early. The main sequelae of osteomyelitis are angular limb deformity, due to partial growth arrest, and lower limb discrepancy. Therapeutic options are guided by the patient's age and predictions at maturity. The main complications of septic arthritis are joint stiffness and osteonecrosis. The procedures to consider are arthrodesis, joint reconstruction in immature children, and arthroplasty at the end of growth. PMID- 25553605 TI - Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma. AB - Multiple myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of malignant plasma cells (PCs) within the bone marrow (BM). The PCs are in close contact with stromal cells, which secrete growth factors and cytokines, promoting tumor cell growth and survival. Despite the availability of new drugs with immunomodulatory properties targeting the neoplastic clone and its microenvironment, MM is still an incurable disease, with patients experiencing subsequent phases of remission and relapse, eventually leading to disease resistance and patient death. It is now well established that the MM BM microenvironment is hypoxic, a condition required for the activation of the hypoxia-inducible factor 1 alpha (HIF-1alpha). It has been shown that HIF-1alpha is constitutively expressed in MM even in normoxic conditions, suggesting that HIF-1alpha suppression might be part of a therapeutic strategy. Constitutively activated HIF-1alpha enhances neovascularization, increases glucose metabolism, and induces the expression of antiapoptotic proteins. HIF-1alpha is thought to be one of the most important molecular targets in the treatment of cancer, and a variety of chemical inhibitors for HIF-1alpha have been developed to date. This review examines the role of HIF-1alpha in MM and recent developments in harnessing the therapeutic potential of HIF-1alpha inhibition in MM. PMID- 25553606 TI - Developmental networks in translational science. PMID- 25553607 TI - Safety of subcutaneous versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. AB - INTRODUCTION: Tocilizumab (TCZ), a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, has demonstrated efficacy and tolerability in several large randomized, controlled trials for the treatment of rheumatoid arthritis (RA). AREAS COVERED: This article compares the safety profile of the newer, subcutaneous (SC) formulation of TCZ with the original intravenous (IV) formulation, in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in patients with RA. Several pivotal clinical trials are included, highlighting data from: i) trials of TCZ-IV; ii) trials of TCZ-SC; and iii) trials comparing IV to SC TCZ. TCZ use in pediatric populations is beyond the scope of this review. EXPERT OPINION: The efficacy and safety of TCZ-IV in the treatment of RA has been demonstrated in multiple clinical trials, both as monotherapy and in combination with traditional DMARDs. The data for TCZ-SC is similar, albeit with a higher frequency of injection site reactions (ISRs). With careful patient selection, the benefit: risk ratio is favorable, offering patients a rapid and sustained reduction in disease activity, improved function and reduced structural damage. Given that most patients prefer SC to IV medication, TCZ-SC will likely become a mainstay, along with other biologic agents, for the treatment of RA patients who have failed traditional non-biologic DMARDs. PMID- 25553608 TI - Pyogenic granuloma of the ileum depicted by small-bowel radiography, capsule endoscopy and double balloon endoscopy. PMID- 25553609 TI - EZ-IO((r)) intraosseous device implementation in German Helicopter Emergency Medical Service. AB - BACKGROUND: Intraosseous access (IO) is a rapid and safe alternative when peripheral venous access is difficult. Our aim was to summarize the first three years experience with the use of a semi-automatic IO device (EZ-IO((r))) in German Helicopter Emergency Medical Service (HEMS). METHODS: Included were all patients during study period (January 2009-December 2011) requiring an IO access performed by HEMS team. Outcome variables were IO rate, IO insertion success rates, site of IO access, type of EZ-IO((r)) needle set used, strategy of vascular access, procedure related problems and operator's satisfaction. RESULTS: IO rate was 0.3% (348/120.923). Overall success rate was 99.6% with a first attempt success rate of 85.9%; there was only one failure (0.4%). There were three insertion sites: proximal tibia (87.2%), distal tibia (7.5%) and proximal humerus (5.3%). Within total study group IO was predominantly the second-line strategy (39% vs. 61%, p<0.001), but in children<7 years, in trauma cases and in cardiac arrest IO was more often first-line strategy (64% vs. 28%, p<0.001; 48% vs. 34%, p<0.032; 50% vs. 29%, p<0.002 respectively). Patients with IO access were significantly younger (41.7+/-28.7 vs. 56.5+/-24.4 years; p<0.001), more often male (63.2% vs. 57.7%; p=0.037), included more trauma cases (37.3% vs. 30.0%; p=0.003) and more often patients with a NACA-Score>=5 rating (77.0% vs. 18.6%; p<0.001). Patients who required IO access generally presented with more severely compromised vital signs associated with the need for more invasive resuscitation actions such as intubation, chest drains, CPR and defibrillation. In 93% EZ-IO((r)) needle set handling was rated "good". Problems were reported in 1.6% (needle dislocation 0.8%, needle bending 0.4% and parafusion 0.4%). CONCLUSIONS: The IO route was generally used in the most critically ill of patients. Our relatively low rate of usage would indicate that this would be compatible with the recommendations of established guidelines. The EZ-IO((r)) intraosseous device proved feasible with a high success rate in adult and pediatric emergency patients in HEMS. PMID- 25553610 TI - Off-label use of misoprostol for labor induction in Germany: a national survey. AB - OBJECTIVE: Misoprostol is safe and effective for labor induction in viable pregnancies. Little is known about the prevalence of off-label use of misoprostol, and the reasons for using or not using misoprostol for labor induction. As such, a national survey was conducted in Germany to assess reliable data about the use of misoprostol in clinical practice. STUDY DESIGN: A prospective study was performed in 2013 using a standardized survey questionnaire. All registered departments of obstetrics and gynecology in Germany were targeted. RESULTS: Out of 783 questionnaires, 542 (69%) were returned. Three hundred and fifty-five (66%) respondents reported that they use misoprostol for labor induction in viable term pregnancies, and 183 (34%) respondents reported that they never use misoprostol for this indication. The most common reasons given for using misoprostol in labor induction were: effectiveness (40%), good patient acceptance (35%), established/well proven in clinical practice (35%) and cost-effectiveness (32%). The most common reasons given for not using misoprostol were lack of licence (off-label use, 69%) and uncertainty of the legal situation (27%). CONCLUSION: Although misoprostol is not licensed in Germany for obstetric indications, the vast majority of respondents (66%) reported that they use misoprostol for labor induction. The main reasons for not using misoprostol for labor induction in Germany are legal concerns rather than lack of scientific evidence. Cost-effective medications with evidence-based effectiveness and safety should be supported by a clear statement from national medical societies. PMID- 25553611 TI - The effect of sugar stereochemistry on protein self-assembly: the case of beta casein micellization in different aldohexose solutions. AB - Protein self-assembly applications, such as nanoencapsulation of drugs and nutraceuticals, require deep understanding of the parameters governing the micellization process, including the effects of ionic and non-ionic co-solutes, like salts and sugars respectively, which is often overlooked. Herein, with the aim of shedding light on the effect of nonionic cosolute stereochemistry on protein self-assembly, we studied the ternary system of water-protein-sugar by examining the concentration-dependent effects of three aldohexoses, d-glucose (Glu), d-galactose (Gal) and d-mannose (Man) and that of urea, on the micellization of beta casein (beta-Cas), using pyrene as a fluorescent probe for the formation of hydrophobic domains. Pyrene's excitation spectra were recorded for several sets of samples with rising protein concentration (0-5 mg ml(-1)), each set with a different co-solute type and concentration. Critical micellization concentration (CMC) and cooperativity of micellization were evaluated according to changes in pyrene spectra as it partitioned from the aqueous environment to the hydrophobic cores of beta-Cas micelles. All sugars examined lowered the CMC of beta-Cas with increasing sugar concentration and with a diminishing degree of effectiveness (Glu > Gal > Man) which correlated well with the sugars' dynamic hydration number, defined by Uedaira, and correlated negatively with their hydrophobic to hydrophilic molecular surface ratio. These results support the hypothesis that sugars affect protein self-assembly through both changes in water structure and by hydrophobic interactions, both of which are evidenced to be highly sensitive to sugar stereochemistry. PMID- 25553612 TI - [Chronic pulmonary heart disease complicating hydatic embolism]. PMID- 25553613 TI - A ratiometric colorimetric detection of the folate receptor based on terminal protection of small-molecule-linked DNA. AB - Development of strategies for the sensitive and selective detection of the folate receptor (FR) that are simple and low cost is of great importance for assessing cancer therapeutics due to its crucial role in physiological, pharmacological and pathological processes. In this paper, gold nanoparticle (AuNP)-based novel ratiometric colorimetry for the detection of the folate receptor (FR) is proposed based on terminal protection of small-molecule-linked DNA. The single-stranded DNA (ssDNA) terminally tethered to folic acid (FA) is protected from degradation by exonuclease I (Exo I) when the FA moiety is bound to FR. The hybridization between FR-protected DNA and DNA-functionalized Au NPs generated a red-to-purple colour change, allowing the visual detection of FR. The detection limit of FR can be as low as 0.33 ng mL(-1) with the naked eye. It provides a promising strategy for visual detection of the binding event of FA to its protein receptor-FR with advantages such as simplicity, high selectivity, and a wide linear range. PMID- 25553615 TI - Morphological changes of radial glial cells during mouse embryonic development. AB - During brain development, the radial glial cell acts as a scaffold to support radial migration of postmitotic neurons. However, the morphological changes of radial glial cells during embryo development are poorly understood. We used in utero electroporation and immunohistochemistry to study the dynamics of radial glial cells accompanied by cortical development in mice from embryonic day 14 to postnatal day 0. We found that different segments of radial glial cells changed by the growth of different layers of cortex, such as marginal zone, cortical plate, intermediate zone and ventricular zone. Moreover, the length, angle and number of branches of the radial glial cell changed significantly at the late stage of neurogenesis. All these changes were consistent with the distinct phases of locomotion. Thus, we speculated that morphological changes of the radial glial cell were associated with the neuronal migration and dendritic development. PMID- 25553618 TI - Event-related brain potentials reveal correlates of the transformation of stimulus functions through derived relations in healthy humans. AB - This research aimed to explore the neural correlates of relational learning by recording high-density EEG during a behavioural task involving derivation levels of varying complexity. A total of 15 participants (5 male; age range 18-23 years; mean age=20.0 years) completed contextual cue training, relational learning, function training and a derivation task while 128-channel event-related potentials (ERPs) were recorded from the scalp (Background). Differences in response latencies were observed between the two derived (symmetry and equivalence) and directly trained relations, with longest latencies found for equivalence and shortest for the directly trained relations. This pattern failed to reach statistical significance. Importantly, ERPs revealed an early P3a positivity (from 230 to 350ms) over right posterior scalp sites. Significantly larger mean amplitudes were found at three channels (P6, E115 and E121) for the equivalence relations compared to the two other types (Results). We believe this may constitute a first demonstration of differences in brain electrophysiology in the transformation of stimulus functions through derived relations of hierarchical levels of complexity (Conclusions). PMID- 25553617 TI - Neurons and networks organizing and sequencing memories. AB - Hippocampal CA1 and CA3 neurons sampled randomly in large numbers in primate brain show conclusive examples of hierarchical encoding of task specific information. Hierarchical encoding allows multi-task utilization of the same hippocampal neural networks via distributed firing between neurons that respond to subsets, attributes or "categories" of stimulus features which can be applied in events in different contexts. In addition, such networks are uniquely adaptable to neural systems unrestricted by rigid synaptic architecture (i.e. columns, layers or "patches") which physically limits the number of possible task specific interactions between neurons. Also hierarchical encoding is not random; it requires multiple exposures to the same types of relevant events to elevate synaptic connectivity between neurons for different stimulus features that occur in different task-dependent contexts. The large number of cells within associated hierarchical circuits in structures such as hippocampus provides efficient processing of information relevant to common memory-dependent behavioral decisions within different contextual circumstances. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25553619 TI - Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI. AB - Post-traumatic stress disorder (PTSD) is a complex mental disorder with psychological and emotional components, caused by exposure to single or repeated extreme traumatic events found in war, terrorist attacks, natural or man-caused disasters, and by violent personal assaults and accidents. Mild traumatic brain injury (TBI) occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck as in contact sports, or when in close proximity to a blast pressure wave following detonation of explosives in the battlefield. Penetrating TBI occurs when an object penetrates the skull and damages the brain, and is caused by vehicle crashes, gunshot wound to the head, and exposure to solid fragments in the proximity of explosions, and other combat related head injuries. Despite clinical studies and improved understanding of the mechanisms of cellular damage, prevention and treatment strategies for patients with PTSD and TBI remain unsatisfactory. To develop an improved plan for treating and impeding progression of PTSD and TBI, it is important to identify underlying biochemical changes that may play key role in the initiation and progression of these disorders. This review identifies three common biochemical events, namely oxidative stress, chronic inflammation and excitotoxicity that participate in the initiation and progression of these conditions. While these features are separately discussed, in many instances, they overlap. This review also addresses the goal of developing novel treatments and drug regimens, aimed at combating this triad of events common to, and underlying, injury to the brain. PMID- 25553616 TI - Functional alpha7 nicotinic receptors are expressed on immature granule cells of the postnatal dentate gyrus. AB - Neurogenesis occurs throughout life in the subgranular zone of the dentate gyrus, and postnatal-born granule cells migrate into the granule cell layer and extend axons to their target areas. The alpha7*nicotinic receptor has been implicated in neuronal maturation during development of the brain and is abundant in interneurons of the hippocampal formation of the adult brain. Signalling through these same receptors is believed also to promote maturation and integration of adult-born granule cells in the hippocampal formation. We therefore aimed to determine whether functional alpha7*nicotinic receptors are expressed in developing granule cells of the postnatal dentate gyrus. For these experiments we used 2-3 week-old Wistar rats, and 2-9 week old transgenic mice in which GABAergic interneurons were marked by expression of green fluorescent protein. Immunohistochemistry indicated the presence of alpha7*nicotinic receptor subunits around granule cells close around the subgranular zone which correlated with the distribution of developmental markers for immature granule cells. Whole-cell patch clamp recording showed that a proportion of granule cells responded to puffed ACh in the presence of atropine, and that these cells possessed electrophysiological properties found in immature granule cells. The nicotinic responses were potentiated by an allosteric alpha7*nicotinic receptor modulator, which were blocked by a specific alpha7*nicotinic receptor antagonist and were not affected by ionotropic glutamate or GABA receptor antagonists. These results suggest the presence of functional somato-dendritic alpha7*nicotinic receptors on immature granule cells of the postnatal dentate gyrus, consistent with studies implicating alpha7*nicotinic receptors in dendritic maturation of dentate gyrus neurons in adult brain. PMID- 25553620 TI - A selective involvement of putamen functional connectivity in youth with internet gaming disorder. AB - Brain cortico-striatal circuits have consistently been implicated in the pathology of addiction related disorders. We applied a reliable seed-based analysis of the resting-state brain activity to comprehensively delineate the subdivisions of striatal functional connectivity implicated in internet gaming disorder. Among twelve right-handed male adolescents with internet gaming disorder and 11 right-handed and gender-matched healthy controls, we examined group differences in the functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen, as well as the association of these connectivity indices with behavioral measures of internet use. Adolescents with internet gaming disorder showed significantly reduced dorsal putamen functional connectivity with the posterior insula-parietal operculum. More time spent playing online games predicted significantly greater functional connectivity between the dorsal putamen and bilateral primary somatosensory cortices in adolescents with internet gaming disorder, and significantly lower functional connectivity between the dorsal putamen and bilateral sensorimotor cortices in healthy controls. The dorsal putamen functional connectivity was significantly and specifically different in adolescents with internet gaming disorder. The findings suggest a possible biomarker of internet gaming disorder. PMID- 25553621 TI - Alteration of spontaneous neuronal activity within the salience network in partially remitted depression. AB - Of major depression patients, 29-66% show only partial remission on a single antidepressant trial. Such patients are characterized by residual depressive symptoms such as anhedonia, psychic anxiety, sleep disturbance, and cognitive dysfunction. Despite having a tremendous impact on outcomes such as future relapse, morbidity, and mortality, the neural mechanisms of partially remitted depression remain unclear. Using the amplitude of low-frequency fluctuations (ALFF) approach, we investigated the intrinsic neural oscillation alterations during resting state in partially remitted depression. A total of 23 partially remitted depression patients and 68 healthy controls underwent magnetic resonance imaging for functional imaging. We compared ALFF differences between groups as well as correlations between clinical measurements and ALFF in the brain regions showing significant group differences. Compared with healthy controls, partially remitted depression patients showed increased ALFF in the left ventral anterior insula, bilateral posterior insula, and bilateral supramarginal gyrus, and decreased ALFF in the left calcarine gyrus. A trend positive correlation between the number of depressive episodes and ALFF values was found in the right posterior insula in the partially remitted depression group. In addition, the ALFF in the right supramarginal gyrus were negatively correlated with Hamilton Depression Rating Scale scores. Consistent with the emerging theory of the role of the salience network in sensing the changes of homeostasis that contributes to partially remitted depression, the current findings suggest that the increased intrinsic neural oscillation of the insula is related to the refractoriness to treatment and may be an imaging marker for predicting future depression recurrence. PMID- 25553622 TI - Long-term results of positron emission tomography-directed management of the neck in node-positive head and neck cancer after organ preservation therapy. AB - OBJECTIVES: The current study presents the long-term results from a study designed to evaluate a restaging positron emission tomography (PET) directed policy whereby neck dissections were omitted in all node positive head and neck squamous cell carcinoma (N+HNSCC) patients with PET-negative lymph nodes after definitive radiotherapy (RT), with or without chemotherapy. METHODS: A post therapy nodal response assessment with PET and computed tomography (CT) was performed in patients who achieved a complete response at the primary site after definitive radiotherapy. Patients with PET-negative lymph nodes were observed regardless of residual CT abnormalities. RESULTS: One hundred and twelve patients, the majority of whom (83 patients, 74%) had oropharyngeal primaries, were treated on protocol. Median follow-up was 62months. Negative and positive predictive values for the restaging PET was 97.1% and 77.8% respectively, with only one patient who was PET-negative after treatment experiencing an isolated nodal relapse. CONCLUSION: PET-guided management of the neck following organ preservation therapy effectively spares neck dissections in patients with N+HNSCC without compromising isolated nodal control or overall survival. PMID- 25553629 TI - The reply. PMID- 25553630 TI - Levothyroxine dose and measurement of TSH. PMID- 25553631 TI - The reply. PMID- 25553632 TI - Use of digoxin in chronic systolic heart failure in current era. PMID- 25553633 TI - The reply. PMID- 25553634 TI - Evidence of pulmonary disseminated cryptococcosis: diffuse multiple micronodules on thoracic computed tomography. PMID- 25553635 TI - 'Are there circumstances where I would refuse to participate in caring for a patient?' Comment to editorial. PMID- 25553636 TI - Football lingo in the medical world. PMID- 25553637 TI - All patients with leukemia are not equally at risk of contracting Pneumocystis jirovecii pneumonia. PMID- 25553641 TI - Anxiety-like behaviour and c-fos expression in rats that inhaled vetiver essential oil. AB - Vetiver essential oil (VEO) has been used in aromatherapy for relaxation. This study aimed to investigate the effects of VEO on an anxiety-related behavioural model (the elevated plus-maze, EPM) and immediate-early gene c-fos in amygdala, known to be involved in anxiety. Male Wistar rats were administered diazepam (1 mg/kg i.p.) for 30 min or inhalated with VEO (1%, 2.5% or 5% w/w) for 7 min prior to exposure to the EPM. Then, the effects of 2.5% VEO, the anxiolytic dose, on c fos expression in amygdala were investigated. The rats given either 2.5% VEO or diazepam exhibited an anxiolytic-like profile in the EPM. VEO and diazepam significantly increased c-fos expression in the lateral division of the central amygdaloid nucleus (CeL). Therefore, the anxiolytic properties of VEO might be associated with altering neuronal activation in CeL. However, future studies are needed to investigate the precise mechanism of action of VEO. PMID- 25553644 TI - Passing the gavel. PMID- 25553643 TI - Effect of food wastewater on biomass production by a green microalga Scenedesmus obliquus for bioenergy generation. AB - Effect of food wastewater (FW) on the biomass, lipid and carbohydrate production by a green microalga Scenedesmus obliquus cultivated in Bold's Basal Medium (BBM) was investigated. Different dilution ratios (0.5-10%) of BBM either with FW or salt solution (NaCl) or sea water (SW) were evaluated. S. obliquus showed the highest growth (0.41 g L(-1)), lipid productivity (13.3 mg L(-1) day L(-1)), carbohydrate productivity (14.7 mg L(-1) day L(-1)) and nutrient removal (38.9 mg TN L(-1) and 12.1 mg TP L(-1)) with 1% FW after 6 days of cultivation. The FW promoted algal autoflocculation due to formation of inorganic precipitates at an alkali pH. Fatty acid methyl ester analysis revealed that the palmitic and oleic acid contents were increased up to 8% with FW. Application of FW improved the growth, lipid/carbohydrate productivity and biomass recovery efficiency of S. obliquus, which can be exploited for cost effective production of microalgae biomass. PMID- 25553642 TI - Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. AB - BACKGROUND: Clinical observations suggest that anaphylaxis is more common in adult women compared with adult men, although the mechanistic basis for this sex bias is not well understood. OBJECTIVES: We sought to document sex-dependent differences in a mouse model of anaphylaxis and explore the role of female sex hormones and the mechanisms responsible. METHODS: Passive systemic anaphylaxis was induced in female and male mice by using histamine, as well as IgE or IgG receptor aggregation. Anaphylaxis was assessed by monitoring body temperature, release of mast cell mediators and/or hematocrit, and lung weight as a measure of vascular permeability. A combination of ovariectomy, estrogen receptor antagonism, and estrogen administration techniques were used to establish estrogen involvement. RESULTS: Anaphylactic responses were more pronounced in female than male mice. The enhanced severity of anaphylaxis in female mice was eliminated after pretreatment with an estrogen receptor antagonist or ovariectomy but restored after administration of estradiol in ovariectomized mice, demonstrating that the sex-specific differences are due to the female steroid estradiol. Estrogen did not affect mast cell responsiveness or anaphylaxis onset. Instead, it increased tissue expression of endothelial nitric oxide synthase (eNOS). Blockage of NOS activity with the inhibitor L-NG-nitroarginine methyl ester or genetic eNOS deficiency abolished the sex-related differences. CONCLUSION: Our study defines a contribution of estrogen through its regulation of eNOS expression and nitric oxide production to vascular hyperpermeability and intensified anaphylactic responses in female mice, providing additional mechanistic insights into risk factors and possible implications for clinical management in the further exploration of human anaphylaxis. PMID- 25553645 TI - Prevalence and clinical distribution of multidrug-resistant bacteria (3537 isolates) in a tertiary Chinese hospital (January 2012-December 2013). AB - OBJECTIVE: Multidrug-resistant organisms (MDROs) have become a widespread serious problem in recent years. Our objective was to determine the prevalence and clinical distribution of MDROs in a tertiary care hospital in China from January 1, 2012 to December 31, 2013. METHODS: The strains were cultured according to standard methods; bacterial identification and susceptibility testing were detected by Vitek 2 system. The prevalence and clinical distribution of extended spectrum beta-lactamases (ESBLs)-producing enterobacteriaceae, carbapenem resistant enterobacteriaceae (CRE), multiple-drug/pan-drug resistant P. aeruginosa (MDR/PDR-PA), carbapenem-resistant A. baumannii (CR-AB), methicillin resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) were analyzed by WHONET 5.6. RESULTS: A total of 3537 (33.4%) MDROs were found among 10,594 microbial isolates. ESBLs producing E. coli (ESBLs-ECO) (1153 cases) were the most frequent MDROs, followed by CR-AB (827 cases). The proportion of acquired resistance of A. baumannii (48.9%) accounted for the highest in all the MDROs. These MDROs were mainly isolated from respiratory (70.3%) and secretions (12.7%). Various types of intensive care unit (ICU) and surgery were the main source departments. The proportion of CRE and VRE were relatively few. CRE was most isolated from respiratory tract and closed body cavity fluid, while the distribution of VRE was relatively dispersed. CONCLUSION: High prevalence of MDROs has emerged in our hospital, particular in various ICU and surgical department. The effective way to prevent the further spread of MDROs is to strengthen the protection of respiratory tract and surgical wounds. PMID- 25553646 TI - [Serological analysis of phenotype Del among blood donors Rh D negative Moroccan]. PMID- 25553647 TI - Caring for the patient, not the disease. PMID- 25553649 TI - The permeability and transport mechanism of graphene quantum dots (GQDs) across the biological barrier. AB - As an emerging nanomaterial, graphene quantum dots (GQDs) have shown enormous potential in theranostic applications. However, many aspects of the biological properties of GQDs require further clarification. In the present work, we prepared two sizes of GQDs and for the first time investigated their membrane permeabilities, one of the key factors of all biomedical applications, and transport mechanisms on a Madin Darby Canine Kidney (MDCK) cell monolayer. The experimental results revealed that under ~300 mg L(-1), GQDs were innoxious to MDCK and did not affect the morphology and integrity of the cell monolayer. The Papp values were determined to be 1-3 * 10(-6) cm s(-1) for the 12 nm GQDs and 0.5-1.5 * 10(-5) cm s(-1) for the 3 nm GQDs, indicating that the 3 nm GQDs are well-transported species while the 12 nm GQDs have a moderate membrane permeability. The transport and uptake of GQDs by MDCK cells were both time and concentration-dependent. Moreover, the incubation of cells with GQDs enhanced the formation of lipid rafts, while inhibition of lipid rafts with methyl-beta cyclodextrin almost eliminated the membrane transport of GQDs. Overall, the experimental results suggested that GQDs cross the MDCK cell monolayer mainly through a lipid raft-mediated transcytosis. The present work has indicated that GQDs are a novel, low-toxic, highly-efficient general carrier for drugs and/or diagnostic agents in biomedical applications. PMID- 25553648 TI - Loss of Nfkb1 leads to early onset aging. AB - NF-kappaB is a major regulator of age-dependent gene expression and the p50/NF kappaB1 subunit is an integral modulator of NF-kappaB signaling. Here, we examined Nfkb1-/- mice to investigate the relationship between this subunit and aging. Although Nfkb1-/- mice appear similar to littermates at six months of age, by 12 months they have a higher incidence of several observable age-related phenotypes. In addition, aged Nfkb1-/- animals have increased kyphosis, decreased cortical bone, increased brain GFAP staining and a decrease in overall lifespan compared to Nfkb1+/+. In vitro, serially passaged primary Nfkb1-/- MEFs have more senescent cells than comparable Nfkb1+/+ MEFs. Also, Nfkb1-/- MEFs have greater amounts of phospho-H2AX foci and lower levels of spontaneous apoptosis than Nfkb1+/+, findings that are mirrored in the brains of Nfkb1-/- animals compared to Nfkb1+/+. Finally, in wildtype animals a substantial decrease in p50 DNA binding is seen in aged tissue compared to young. Together, these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-kappaB pathway and mammalian aging. PMID- 25553650 TI - A phase 2 study of bevacizumab in combination with carboplatin and paclitaxel in patients with non-squamous non-small-cell lung cancer harboring mutations of epidermal growth factor receptor (EGFR) after failing first-line EGFR-tyrosine kinase inhibitors (HANSHIN Oncology Group 0109). AB - OBJECTIVES: We have conducted a phase 2 study to evaluate the efficacy and safety of carboplatin, paclitaxel, and bevacizumab in patients with non-squamous non small-cell lung cancer (NSCLC) who are epidermal growth factor receptor (EGFR) mutation positive and for whom EGFR-tyrosine kinase inhibitor (TKI) 1st-line has failed. MATERIALS AND METHODS: Patients with stage IIIB or IV non-squamous NSCLC harbored activating EGFR mutations that has failed 1st-line EGFR-TKI and an Eastern Cooperative Oncology Group performance status of 0 or 1 were included in this study. Patients received carboplatin at an area under the concentration-time curve 5 or 6, paclitaxel 200mg/m(2), and bevacizumab 15mg/kg on D1. The combination therapy was repeated every 21 days for up to three to six cycles. Bevacizumab was continued until disease progression or unacceptable toxicity for patients without disease progression (PD). The primary endpoint was objective response rate (ORR). RESULTS: Thirty-one patients were enrolled between March 2010 and January 2013, with 30 patients being eligible. ORR was 37% (90% CI; 24 52%) and disease control rate, 83% (95% CI; 66-92%). The median progression free survival (PFS) was 6.6 months (95% CI; 4.8-12.0 months) and median overall survival, 18.2 months (95% CI; 12.0-23.4 months). The most common grade >=3 hematologic toxicity was neutropenia (93%), and non-hematologic toxicity, febrile neutropenia (20%). There were no clinically relevant grade >=3 bleeding events and no treatment-related deaths. CONCLUSION: The combination therapy of carboplatin, paclitaxel and bevacizumab did not achieve the initial treatment goal. PMID- 25553651 TI - Quantification and consequences of lung cancer CT overdiagnosis. PMID- 25553652 TI - Correlation between hindfoot joint three-dimensional kinematics and the changes of the medial arch angle in stage II posterior tibial tendon dysfunction flatfoot. AB - BACKGROUND: The aim of this study was to explore the correlation between the kinematics of the hindfoot joint and the medial arch angle change in stage II posterior tibial tendon dysfunction flatfoot three-dimensionally under loading. METHODS: Computed tomography (CT) scans of 12 healthy feet and 12 feet with stage II posterior tibial tendon dysfunction flatfoot were taken both in non- and full body-weight-bearing condition. The CT images of the hindfoot bones were reconstructed into three-dimensional models with Mimics and Geomagic reverse engineering software. The three-dimensional changes of the hindfoot joint were calculated to determine their correlation to the medial longitudinal arch angle. FINDINGS: The medial arch angle change was larger in stage II posterior tibial tendon dysfunction flatfoot compared to that in healthy foot under loading. The rotation and translation of the talocalcaneal joint, the talonavicular joint and the calcanocuboid joint had little influence on the change of the medial arch angle in healthy foot. However, the eversion of the talocalcaneal joint, the proximal translation of the calcaneus relative to the talus and the dorsiflexion of talonavicular joint could increase the medial arch angle in stage II posterior tibial tendon dysfunction flatfoot under loading. INTERPRETATION: Joint instability occurred in patients with stage II posterior tibial tendon dysfunction flatfoot under loading. Limitation of over movement of the talocalcaneal joint and the talonavicular joint may help correct the medial longitudinal arch in stage II posterior tibial tendon dysfunction flatfoot. PMID- 25553653 TI - Bifunctional redox tagging of carbon nanoparticles. AB - Despite extensive work on the controlled surface modification of carbon with redox moieties, to date almost all available methodologies involve complex chemistry and are prone to the formation of polymerized multi-layer surface structures. Herein, the facile bifunctional redox tagging of carbon nanoparticles (diameter 27 nm) and its characterization is undertaken using the industrial dye Reactive Blue 2. The modification route is demonstrated to be via exceptionally strong physisorption. The modified carbon is found to exhibit both well-defined oxidative and reductive voltammetric redox features which are quantitatively interpreted. The method provides a generic approach to monolayer modifications of carbon and carbon nanoparticle surfaces. PMID- 25553667 TI - Rik and me: reminiscences. PMID- 25553654 TI - Characterisation of oligosaccharides from Baizhu by HILIC-MS. AB - Polysaccharides from Baizhu were separated by preparative hydrophilic interaction liquid chromatography on an XAmide column and its components were characterised as inulin-type polysaccharides with structures of alpha-D-glucopyranosyl-[-(1 -> 2) -beta-D-fructofuranosyl-](n -1)-(1 -> 2) -beta-D-fructofuranoside (n = 3-20) by a combinatory application of electrospray-ionisation mass spectrometry, nuclear magnetic resonance and IR, as well as the chemical analysis of monosaccharide composition. In addition, the contents of nystose and 1F fructofranosylnystose in the crude and purified Baizhu polysaccharides were determined to be 5.81%, 4.92% and 0.70%, 0.84% (w/w), respectively. In addition, MTT assay indicated that the Baizhu polysaccharides could effectively promote spleen lymphocyte transformation for the enhancement of organism immunity. It is for the first time that inulin-type polysaccharides were discovered in Baizhu and its immuno-enhancing activity was reported, which is a vigorous evidence to explain the efficacy of Baizhu. PMID- 25553668 TI - Progressive aortic valve calcification: three-dimensional visualization and biomechanical analysis. AB - Calcific aortic valve disease (CAVD) is a progressive pathology characterized by calcification mainly within the cusps of the aortic valve (AV). As CAVD advances, the blood flow and associated hemodynamics are severely altered, thus influencing the mechanical performance of the AV. This study proposes a new method, termed reverse calcification technique (RCT) capable of re-creating the different calcification growth stages. The RCT is based on three-dimensional (3D) spatial computed tomography (CT) distributions of the calcification density from patient specific scans. By repeatedly subtracting the calcification voxels with the lowest Hounsfield unit (HU), only high calcification density volume is presented. RCT posits that this volume re-creation represents earlier calcification stages and may help identify CAVD initiation sites. The technique has been applied to scans from 12 patients (36 cusps) with severe aortic stenosis who underwent CT before transcatheter aortic valve implantation (TAVI). Four typical calcification geometries and growth patterns were identified. Finite elements (FE) analysis was applied to compare healthy AV structural response with two selected CAVD-RCT configurations. The orifice area decreased from 2.9cm(2) for the healthy valve to 1.4cm(2) for the moderate stenosis case. Local maximum strain magnitude of 0.24 was found on the edges of the calcification compared to 0.17 in the healthy AV, suggesting a direct relation between strain concentration and calcification geometries. The RCT may help predict CAVD progression in patients at early stages of the disease. The RCT allows a realistic FE mechanical simulation and performance of calcified AVs. PMID- 25553669 TI - In vitro comparison of Gunther Tulip and Celect filters: testing filtering efficiency and pressure drop. AB - In this study, the trapping ability of the Gunther Tulip and Celect inferior vena cava filters was evaluated. Thrombus capture rates of the filters were tested in vitro in horizontal position with thrombus diameters of 3 and 6mm and tube diameter of 19mm. The filters were tested in centered and tilted positions. Sets of 30 clots were injected into the model and the same process was repeated 20 times for each different condition simulated. Pressure drop experienced along the system was also measured and the percentage of clots captured was recorded. The Gunther Tulip filter showed superiority in all cases, trapping almost 100% of 6mm clots both in an eccentric and tilted position and trapping 81.7% of the 3mm clots in a centered position and 69.3% in a maximum tilted position. The efficiency of all filters tested decreased as the size of the embolus decreased and as the filter was tilted. The injection of 6 clots raised the pressure drop to 4.1mmHg, which is a reasonable value that does not cause the obstruction of blood flow through the system. PMID- 25553670 TI - A survey of micro-finite element analysis for clinical assessment of bone strength: the first decade. AB - Micro-Finite Element (micro-FE) analysis is now widely used in biomedical research as a tool to derive bone mechanical properties as they relate to its microstructure. With the development of in vivo high-resolution peripheral quantitative CT (HR-pQCT) scanners, it can now be applied to analyze bone in-vivo in the peripheral skeleton. In this survey, the results of several experimental and clinical studies are summarized that addressed the feasibility of this approach to predict bone strength in-vivo. Specific questions that will be addressed are: how accurate are strength predictions based on micro-FE; how reproducible are the results; and, is it a better predictor of bone fracture risk than DXA based measures? Based on results of experimental studies, it is first concluded that micro-FE based on HR-pQCT images can accurately predict the strength of the distal radius during a fall on the outstretched hand using either linear elastic analysis, implementing a 'Pistoia criterion' or similar criterion in combination with an 'effective' Young's modulus or using non-linear analyses. When evaluating results of clinical reproducibility studies, it is concluded that for single-center studies, errors at the radius are less than 4.4% and 3.7% and at the tibia less than 3.6% and 2.3% for stiffness and strength, respectively. In multicenter trials, however, these errors can be increased by some 1.8% and 1.4% for stiffness and strength, respectively. Finally, based on the results of large cohort studies, it is concluded that micro-FE calculated stiffness better separates cases from controls than bone density parameters for subjects with fragility fractures at any site, but not for subjects with only radius fractures. In this latter case, however, combinations of micro-FE derived parameters can significantly improve the separation. PMID- 25553671 TI - Biomechanical risk factors and flexor tendon frictional work in the cadaveric carpal tunnel. AB - Pathological changes in carpal tunnel syndrome patients include fibrosis and thickening of the subsynovial connective tissue (SSCT) adjacent to the flexor tendons in the carpal tunnel. These clinical findings suggest an etiology of excessive shear-strain force between the tendon and SSCT, underscoring the need to assess tendon gliding characteristics representative of repetitive and forceful work. A mechanical actuator moved the middle finger flexor digitorum superficialis tendon proximally and distally in eight fresh frozen cadaver arms. Eighteen experimental conditions tested the effects of three well-established biomechanical predictors of injury, including a combination of two wrist postures (0 degrees and 30 degrees flexion), three tendon velocities (50, 100, 150mm/sec), and three forces (10, 20, 40N). Tendon gliding resistance was determined with two light-weight load cells, and integrated over tendon displacement to represent tendon frictional work. During proximal tendon displacement, frictional work increased with tendon velocity (58.0% from 50 150mm/sec). There was a significant interaction between wrist posture and tendon force. In wrist flexion, frictional work increased 93.0% between tendon forces of 10 and 40N. In the neutral wrist posture, frictional work only increased 33.5% (from 10-40N). During distal tendon displacement, there was a similar multiplicative interaction on tendon frictional work. Concurrent exposure to multiple biomechanical work factors markedly increased tendon frictional work, thus providing a plausible link to the pathogenesis of work-related carpal tunnel syndrome. Additionally, our study provides the conceptual basis to evaluate injury risk, including the multiplicative repercussions of combined physical exposures. PMID- 25553672 TI - Cooperative contractility: the role of stress fibres in the regulation of cell cell junctions. AB - We present simulations of cell-cell adhesion as reported in a recent study [Liu et al., 2010, PNAS, 107(22), 9944-9] for two cells seeded on an array of micro posts. The micro-post array allows for the measurement of forces exerted by the cell and these show that the cell-cell tugging stress is a constant and independent of the cell-cell junction area. In the current study, we demonstrate that a material model which includes the underlying cellular processes of stress fibre contractility and adhesion formation can capture these results. The simulations explain the experimentally observed phenomena whereby the cell-cell junction forces increase with junction size but the tractions exerted by the cell on the micro-post array are independent of the junction size. Further simulations on different types of micro-post arrays and cell phenotypes are presented as a guide to future experiments. PMID- 25553673 TI - Quantitative measures of sagittal plane head-neck control: a test-retest reliability study. AB - Determining the reliability of measurements used to quantify head-neck motor control is necessary before they can be used to study the effects of injury or treatment interventions. Thus, the purpose of this study was to determine the within- and between-day reliability of position tracking, position stabilization and force tracking tasks to quantify head-neck motor control. Ten asymptomatic subjects performed these tasks on two separate days. Position and force tracking tasks required subjects to track a pseudorandom square wave input signal by controlling their head-neck angular position (position tracking) or the magnitude of isometric force generated against a force sensor by the neck musculature (force tracking) in the sagittal plane. Position stabilization required subjects to maintain an upright head position while pseudorandom perturbations were applied to the upper body using a robotic platform. Within-day and between-day reliability of the frequency response curves were assessed using coefficients of multiple correlations (CMC). Root mean square error (RMSE) and mean bandpass signal energy, were computed for each task and between-day reliability was calculated using intra-class correlation coefficients (ICC). Within- and between day CMCs for the position and force tracking tasks were all >=0.96, while CMCs for position stabilization ranged from 0.72 to 0.82. ICCs for the position and force tracking tasks were all >=0.93. For position stabilization, ICCs for RMSE and mean bandpass signal energy were 0.66 and 0.72, respectively. Measures of sagittal plane head-neck motor control using position tracking, position stabilization and force tracking tasks were demonstrated to be reliable. PMID- 25553675 TI - Role of cGMP in hydrogen sulfide signaling. AB - The importance of hydrogen sulfide (H2S) in physiology and disease is being increasingly recognized in recent years. Unlike nitric oxide (NO) that signals mainly through soluble guanyl cyclase (sGC)/cGMP, H2S is more promiscuous, affecting multiple pathways. It interacts with ion channels, enzymes, transcription factors and receptors. It was originally reported that H2S does not alter the levels of cyclic nucleotides. More recent publications, however, have shown increases in intracellular cGMP following exposure of cells or tissues to exogenously administered or endogenously produced H2S. Herein, we discuss the evidence for the participation of cGMP in H2S signaling and reconcile the seemingly divergent results presented in the literature on the role of this cyclic nucleotide in the biological actions of H2S. PMID- 25553676 TI - Simple and effective HPLC method development and its validation for Clindipine in human drug free plasma. AB - Simple and effective high performance liquid chromatographic (HPLC) method was developed for estimation of Clindipine in drug free human drug free blank plasma. The internal standard used as Nifidipine (IS). The current method was used protein precipitating extraction of Clindipine from blank plasma. Separation was achieved on reversed-phase c18 column (25cm * 4.6mm, 5MU) and the detection was monitored by UV detector at 260 nm. The optimized mobile phase was used acetonitrile: 5mM potassium dihydrogen orthophosphate (pH 4.5), in the ratio of 60:40% v/v at a flow rate of 1.0 ml/min. This linearity was achieved in this method range of 10.0-125.0 ng/ml with regression coefficient range is 0.99. The present method is suitable in terms of precise, accurate and specific during the study. The simplicity of the method allows for application in laboratories that lack sophisticated analytical instruments such as LC-MS/MS or GC-MS/MS that are complicated, costly and time consuming rather than a simple HPLC-UV method. The present method was successfully applied for pharmacokinetic studies. PMID- 25553677 TI - Haloperidol inhibits Memapsin 2: innovation by docking simulation and in vitro assay. AB - A number of drugs exhibit unexpected pharmacological effects related to their ability to bind more than one receptor in humans. Haloperidol a typical antipsychotic drug appeared in several reports to be used in schizophrenia patients in which the significant of Alzheimer's disease has been reduced. The etiology of the disease is characterized by aggregates of amyloid plaques, largely composed of amyloid-beta peptide formed from the amyloid precursor protein cleaved by Memapsin 2. To investigate if haloperidol can bind to Memapsin 2 active site, an initial molecular docking was performed as a preliminary in silico screening test followed by in vitro enzyme inhibition assay. Haloperidol was found to fit readily in Memapsin binding site with IC(50)value 250mM. Haloperidol can be considered as important lead or important target can be modified for more inhibitory activity, with the intention of protection or treatment for Alzheimer's disease. PMID- 25553678 TI - In vitro antioxidant and in vivo hepatoprotective effect on ethanol-mediated liver damage of spray dried Vernonia amygdalina water extract. AB - Vernonia amygdalina is a strong natural antioxidant that possessed various medicinal properties. In this study, the spray-dried water extract of V. amygdalina was evaluated for its in vitro antioxidant capacity and in vivo hepatoprotective effect against alcoholic-mediated liver damage. Total phenolic and flavonoid content of spray-dried V. amygdalina water extract were determined. Liver enzyme profiles, liver antioxidant level and nitric oxide level were evaluated in alcohol-induced liver injured mice or co-supplement with spray-dried V. amydalina. Water extract of spray-dried V. amygalina that contained phenolic content of 24.8+/-1.5 mg/g gallic acid equivalent and total flavonoid content of 25.7+/-1.3 mg/g catechin equivalent was able to inhibit 50% of xanthine and tyrosinase oxidation at 170 MUg/ml and 2 mg/mL, respectively. On the other hand, extracts at both 10 and 50 mg/kg body weight were able to reduce the levels of Alanine transaminase (ALT), Alkaline phosphatase (ALP), Aspartate transaminase (AST), triglyceride and total bilirubin content inthe alcohol-mediated liver injury in mice. Furthermore, it also helped to increase levels of Superoxide dismutase (SOD), Ferric reducing ability of plasma (FRAP) and reduce the levels of Nitric oxide (NO) and Malondialdehyde (MDA) in the liver of the treated mice. These resultssuggestedthat water extract of spray-dried V. amygdalina exhibited liver protective effect, which could be contributed by its antioxidant properties. PMID- 25553679 TI - Antibacterial, antioxidant, anti-cholinesterase potential and flavonol glycosides of Biscutella raphanifolia (Brassicaceae). AB - Different extracts of the aerial parts of Biscutella raphanifolia (Brassicaceae), which has not been the subject of any study, were screened for the phytochemical content, anti-microbial, antioxidant and anti-cholinesterase activities. We used four methods to identify the antioxidant activity namely, ABTS(*+), DPPH* scavenging, CUPRAC and ferrous-ions chelating methods. Since there is a relationship between antioxidants and cholinesterase enzyme inhibitors, we used two methods to determine the in vitro anti-cholinesterase activity by the use of the basic enzymes that occur in causing Alzheimer's disease: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extracts were also tested in vitro antimicrobial activity against various bacteria. The phytochemical study of B. raphanifolia afforded four flavonol glycosides; namely, quercetin-3-O-beta-D g1ucoside, quercetin-3-O-[beta-D-glucosyl(1->2)-O-beta-D-glucoside], quercetin-3 O-[beta-D-glucosyl(1->3)-O-beta-D-glucoside] and kaempferol-3-O-[beta-D glucosyl(1->2)-[(6'''p-coumaroyl)- beta-D-glucoside], being isolated here for the first time from Biscutella raphanifolia and the genus. The ethyl acetate extract showed the highest activity in ABTS(*+), DPPH* and CUPRAC assays, while the petroleum ether extract demonstrated optimum efficiency metal chelating activity. The dicloromethane and petroleum ether extracts showed a mild inhibition against AChE and BChE. However, the petroleum ether extract showed a good antibacterial activity against the pathovars Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC) and Enterococcus feacalis, whereas the Enterohemorrhagic E. coli (EHEC) strain was more sensitive to dichloromethane and n-butanol extracts. PMID- 25553680 TI - Effect of some plants' extracts used in Sudanese folkloric medicines on carrageenan-induced inflammation. AB - Investigations for anti-inflammatory potential and categorization of Sudanese medicinal plants according to their potency. Anti-inflammatory effect of plants' extracts of 17 genera were studied using the carrageenan induced inflammation in rats' paws. The plant extracts were obtained using methanol and dichloromethane as solvent and administered intra peritoneally at the concentration of 2g/kg body weight. The results obtained in this experiment strongly support and validate the traditional uses of these Sudanese medicinal plants to treat various inflammatory diseases. 63.9% of plants extracts showed marked inhibition of inflammation induced by carrageenan (78.3% out of this percentage represented by methanolic extract), 27.8% showed no activity and 8.3% enhanced the carrageenan induced inflammation. The anti-inflammatory effect of many of these plants has not been reported previously, yet they have been extensively used in Sudanese folkloric medicine. The result of this study justify the traditional medicinal use of the evaluated plants species in treating inflammatory disorders and helped in categorizing the investigated plants into most useful, moderately useful and least useful category for inflammatory diseases. Out of the 17 investigated plant species 05 belongs to most useful and 06 belongs to moderately useful category. However, toxicity studies are required to prove the safety of these plant materials. PMID- 25553681 TI - Teratogenic effect of Carbamazepine use during pregnancy in the mice. AB - Carbamazepine use is the first choice of antiepileptic drugs among epileptic pregnant females. There are many inconclusive studies regard the safety of carbamazepine use during pregnancy. This study aims to investigate the morphological and histopathological teratogenic effects of carbamazepine use during pregnancy. The healthy pregnant females mice divided into equal five groups (each n=20). The first (control) group received distilled water/day. Second, third, fourth and fifth group received 8.75, 22.75, 52.5, 65 mg of carbamazepine/day respectively. Carbamazepine and water were given by gastric gavage throughout gestational period. Fetuses were delivered on the 18th day of gestation by hysterectomy. Fetal measurements and appearance were assessed with investigation the histopathological changes of brain and spinal cord. There was a significant decrease of weight, different organs weight, length, upper and lower limb length of mice in the first day of delivery in fifth group. There was a significant increase of weight, different organs weight, length, upper and lower limb length in the third group. Many congenital anomalies such as spina bifida, meromelia, microphalmia, oligodactyly, anencephaly, neurodegeneration of brain and spinal cord were noticedin fifth group. Teratogenic effect of carbamazepine represented as growth retardation and neurodevelopmental toxicity depending on its overdose degree. PMID- 25553682 TI - Phytochemicals, in vitro antioxidant, total phenolic contents and phytotoxic activity of Cornus macrophylla Wall bark collected from the North-West of Pakistan. AB - Plants are one of the precious creatures of Allah, producing a verity of useful bioactive compounds having definite pharmacological actions on human body. Keeping in view this idea, the methanolic extract from the bark of Cornus macrophylla was investigated for phytochemicals, antioxidant, total phenolic conte nts (TPC) and phytotoxic activities. Phytochemical analysis of Cornus macrophylla revealed the presence of tannins, anthraquinones, glycosides, reducing sugar, saponins and flavonoids. The percent free radicals scavenging potential of DPPH at 20, 40, 60, 80 and 100MUg/ml was 72.69%, 73.32%, 73.51, 73.83% and 74.33% respectively and were compared to ascorbic acid (84.6%, 92.83%, 95.36%, 96.40% and 98.03%), gallic acid (85.49%, 92.47%, 95.14%, 98.22% and 98.03%) and quercetin (95.35%, 96.30%, 97.16%, 98.02% and 98.28%) as standards. The IC(50) value of Cornus macrophylla was 14.5/MUg/ml. The TPC of the methanolic bark extract was 2.916 mg gallic acid equivalents/g of extract. The extract displyed excellent phytotoxic activity against the tested plant Lemna minor and inhibited the growth at 1000 MUg/ml. Our findings revealed that the crude methanolic extract of Cornus macrophylla is a potential source of natural antioxidants and herbicidal. PMID- 25553683 TI - Novel approach of aceclofenac fast dissolving tablet. AB - Fast disintegrating tablets (FDTs) have received ever increasing demand during the last decade, and the field has become a hastily growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Aceclofenac, an NSAID, has been recommended orally for the treatment of bone and connective tissue disorder and thus the formulation of the same resulted in development of several FDT technologies. The present aim is to formulate a tablet which disintegrate and dissolve rapidly and give its rapid onset of action: analgesic, antipyretic and anti-inflammatory action. Besides, the conventional tablets also show poor patient compliance an attempt had been made to formulate for FDT of aceclofenac by using various super disintegrants like sodium starch glycolate, croscarmellose sodium and crosspovidone (polyplasdone XL) and PEG 6000 followed by novel technique. The tablets were evaluated for friability, hardness, weight variation, disintegration time, wetting time, in vitro dissolution studies and drug content studies. It was concluded that the batch which was prepared by using combination of crosspovidone and sodium starch glycolate as a super disintegrant shows excellent disintegration time, enhance dissolution rate, taste masking and hence lead to improve efficacy and bioavailability of drug. PMID- 25553684 TI - Clinical efficacy of polyherbal formulation Eezpain spray for muscular pain relief. AB - The topical herbal formulation Eezpain spray consisting of natural ingredients that have been clinically proved for its analgesic and anti-inflammatory activity. The designed formulation on application knee and wrist joints, back of neck and shoulder, forearms and lower back exhibited significant efficacy. A total of 20 subjects both male and female applied Eezpain spray consisting of Gaultheria oil, Eucalyptus oil, Turpentine oil, Clove Oil, Menthol and Camphor. All the active materials are cited that these have analgesic activity in myalgia and neuralgia. The study design was prospective and opens as pilot study followed the inclusion and exclusion criteria. All the sign and symptoms were noted at baseline and at the end of 14 days treatment performance was evaluated. The statistical analysis was done by using Microsoft Excel2007 and SPSS version 18.0. It is concluded that Eezpain spray has shown efficacy in mild to moderate cases on applying locally to the affected parts to relieve pain from different ailments. PMID- 25553685 TI - Molecular mechanisms that underlie the sexual stimulant actions of Avicennia marina (Forssk.) Vierh. and Crocus sativus L. AB - The effects of extracts and sub-fractions of Avicennia marina, Crocus sativus and sildenafil on the sexual behavior of male rats and their effects on the intracavernosal pressure (I.CV), intracavernosal cyclic GMP and dihydrotestosterone plasma level were examined. The sexual behavior was followed for four hours using infra-red video cameras to quantify the effects on various male sexual behaviors. The results revealed that the active sub-fraction in case of A. marina was the hexane fraction of the chloroform extracts (C/H) whereas that of C. sativus was the hexane fraction of the alcoholic extract (A/H). (C/H), (A/H) and sildenafil significantly increased the total sexual stimulation index from 53.8+/-2.7 (control) to 406+/-7.8, 225+/-4 and 401+/-30.1, respectively (P<0.001, N=6). They significantly increased the index of successful mounting and ejaculation from 2.6+/-0.5 (control) to 40+/-2.7, 21+/-2.3 and 18+/-1.7, respectively (P<0.01, N=6). They significantly increased the cyclic GMP level from 0.94+/-0.07 (control) to 3.1+/-0.13, 1.59+/-0.11 and 3.66+/-0.19 ng/mg wet tissue, respectively (P<0.05, N=7). They did not affect dihydrotestosterone plasma level. (C/H), (A/H) and sildenafil increased the (I.CV) pressure by 4.8+/ 0.3, 1.4+/-0.8 and 4.2+/-0.9 mmHg. The (C/H) seemed to be more active than sildenafil and twice active than (A/H). Both extracts and sildenafil acted via an increase in cyclic GMP. PMID- 25553686 TI - Biological screening of Elaeagnus umbellata Thunb. AB - The bark and fruit extracts of Elaeagnus umbellata have been investigated for their antibacterial, anti-fungal, insecticidal and phytotoxic activities. The petroleum ether extracts of the plant showed significant activity against E. faecalis. The activity of dichloromethane extract was also determined significant against S. aureus. The chloroform extract indicated low activity against E. coli, K. pneumoniae, B. subtilis and S. flexenari. The ethyl acetate fraction demonstrated significant activity against K. pneumoniae while methanolic extract exhibited significant activity against E. coli. All extracts showed low phytotoxic activity. The dichloromethane extract exhibited moderate insecticidal activity while other extract indicated low activity. PMID- 25553687 TI - Combined use of borneol or menthol with labrasol promotes penetration of baicalin through rabbit cornea in vitro. AB - The permeability of most drugs through the eyes is very limited, so finding safe and effective penetration enhancers is of high importance in current ophthalmology research. In this paper, we use a new approach that integrates Chinese and Western medicine to improve the corneal permeability of baicalin, a water- and fat-insoluble target drug, in vitro. Rabbits were divided into three groups. The first group was dosed with borneol (0.05%, 0.1%). menthol (0.1%, 0.2%), or Labrasol (1%, 2%) individually, the second was dosed with a combination of Labrasol with either borneol or menthol, and the third group received a control treatment. Compared with the control treatment, borneol, menthol, or Labrasol alone clearly improved the permeability of baicalin in vitro. Furthermore, the penetrating effects were significantly increased by combining the application of Labrasol with menthol or borneol. Among the various combined penetration enhancers, 0.1% borneol with 2% Labrasol achieved the best apparent permeability, approximately 16.35 times that of the control. Additionally, the calculation of corneal hydration level and the Draize test demonstrated the safety of these penetration enhancers to the rabbit corneas in vivo. This study confirms that the combined use of borneol or menthol, compounds both derived from Chinese herbs, with Labrasol can improve the corneal permeability of water- and fat-insoluble drugs. PMID- 25553689 TI - Formulation and in vitro release studies of pegylated mucin based matrix tablets. AB - The effects of polymer concentration on the flow properties of granules and in vitro release profiles from matrix tablets of three model drugs formulated from pegylated mucin base was investigated. Mucin was extracted from the African giant snail and in combination with PEG was used to produce a copolymer matrix base, which was mixed with the model drugs using wet granulation method. The granules and tablets were evaluated according to official and unofficial requirements. Results showed best flow with Acetylsalicylic acid (ASA) and Chloroquine Phosphate (CQ) granules with Hausner ratio of 1.04-1.2, Carr's index of 4.2-17.5% and angle of repose between 19 degrees -26 degrees . The tablets met B.P specifications with respect to tablet weights, friability and drug content. The release profiles showed faster release of the drug with high content of PEG and a slower release with high concentration of mucin. Pegylated mucin base will find useful application in the development of a wide range of formulations. PMID- 25553688 TI - Utilization of spray drying technique for improvement of dissolution and anti inflammatory effect of Meloxicam. AB - Meloxicam (MLX) is a poorly water-soluble non steroidal anti-inflammatory drug (NSAID). The main objective of the present work was to enhance the dissolution of MLX and thus its bioavailability by the aid of additives. The novelty of this work rises from the utilization of spray drying technology to produce micro particulates solid dispersion systems containing MLX in the presence of small amount of additives. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and Scan Electron Microscope (SEM) were used for studying the physico-chemical and morphological properties of MLX samples. The dissolution of MLX samples was investigated in two different pH media. The morphology of MLX solid dispersion micro-particles was spherical in shape according to SEM. FT-IR profiles indicated that a complex was formed between MLX and the additives. DSC patterns of the MLX micro-particles suggested a reduction in the crystallinity of MLX and probability of presence of an interaction between MLX and the additives. The rate of dissolution of the spray-dried MLX enhanced as compared with the unprocessed MLX in both acidic and neutral media. It was found that 100% of the added MLX released within 5 min in phosphate buffer dissolution medium (pH 7.4) compared to that of the unprocessed MLX (15% in 60 min). Such increase rate in the dissolution of the spray dried MLX could be attributed to the increase in wettability of MLX particles and the hydrophilic nature of the additives. The anti-inflammatory effect of the spray dried MLX was explored using formalin induced rat paw edema model. The spray-dried samples showed an increase in the anti-inflammatory activity of MLX as compared to the unprocessed MLX. This work reveals that the spray drying technique is suitable for preparation of micro particles with improved dissolution and anti-inflammatory effect of MLX. PMID- 25553690 TI - Quality evaluation and in vitro interaction studies between levofloxacin 250mg and diclofenac sodium 50mg tablets. AB - Fluoroquinolones are broad-spectrum antibiotics, work against Gram-positive and Gram-negative bacteria and are a clinically proven option for many resistant infections. Among fluoroquinolones Levofloxacin works best against acute sinusitis, inflammation of the lower airways, acute exacerbation of chronic bronchitis, community acquired pneumonia, complicated urinary tract infection including Pyelonephritis, chronic bacterial prostatitis and skin and soft tissue infection. Levofloxacin is a frequently prescribed antibacterial agent with Diclofenac Sodium for pain management in infectious conditions. The objective of the present work is to evaluate the level of interaction between Levofloxacin and Diclofenac Sodium. In this work market available brands of both drugs were also evaluated for quality.The physiochemical parameters like weight variation, thickness variation, and mechanical strength were determined. Similarly the percentage drug release and content uniformity test were also analyzed; the tested quality attributes were found within the recommended pharmacopeia ranges except brand L(6) that had high drug content 124.629+/-3.614 while brand L(4) and L(5) were not found similar in pH 1.2. When subjected to model dependent analysis Levofloxacin showed compliance with (first order, Higuchi, Hixson Crowell and Weibull) at pH (1.2, 4.5 and 6.8). However Diclofenac Sodium showed adherence with (first order, Hixson Crowell and Weibull) at pH (1.2, 4.5 and 6.8) but following Higuchi at pH 1.2 and 4.5 only. The interaction studies were also performed spectrophotometrically and simultaneous equation was used to estimate the percentage availability of both the drugs at pH 4.5, 6.8, FaSSGF and FaSSIF. The studies showed that the percent availability of Levofloxacin was increased significantly in FaSSIF i.e. 129.173+/-0.323 at 45 minutes in the presence of Diclofenac Sodium. PMID- 25553691 TI - Antioxidant and antibacterial activities of extracts from Conyza bonariensis growing in Yemen. AB - This study aims to examine the antioxidant and antibacterial activities and phenolic contents of Conyza bonariensis growing in Yemen. The whole plants of C. bonariensis were ultrasonically extracted by ethanol. The antioxidant activity of the extract was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and beta carotene bleaching (BCB). The effectiveness of the extract on the growth inhibition of some indicators of foodborne illness bacteria were investigated by agar well diffusion assay. The total phenols (TP), total flavonoids (TF), total tannins (TT), and total anthocyanins (TA) were determined by Folin-Ciocalteu method, aluminium chloride method, Folin and Ciocalteu method, and pH differential method, respectively. The extract of C. bonariensis possessed TP 144.1 mg/g, TF 143 mg/g, TT 0.99mg/g, and TA 0.97mg 100g, with 94.57% inhibition of DPPH and 92.47% inhibition of BCB, and strong inhibitory effects against tested bacteria, which was approximate to those of peel extract of Punica granatum. PMID- 25553692 TI - Antioxidant activities in vitro and in vivo of water-soluble polysaccharide isolated from Sparganium stoloniferum Buch.-Ham. AB - In this study, the crude polysaccharides from Sparganium stoloniferum Buch.-Ham were prepared using hot-water extraction and further deproteinzated by Sevage method. The purified fraction of crude polysaccharide was obtained using a DEAE 52 cellulose chromatography and named with WSSP. Then, the antioxidant capacities of WSSP were assessed in vitro and in vivo. The results in vitro indicated that the WSSP possessed notably free radical scavenging capacity. And the antioxidant abilities were dose-dependent and increased with increasing dose of sample. The findings in vivo showed the gavage administration of WSSP can increase SOD and TAOC activities, and decrease MDA levels in tissue and serum of mice. Therefore, the WSSP may serve as a potential antioxidant. PMID- 25553693 TI - Hypoglycaemic effects of methanolic extract of Canscora decussata (Schult) whole plant in normal and alloxan-induced diabetic rabbits. AB - In present study hypoglycaemic effects of the crude powdered C. decussata and its methanolic extract (ME) in alloxan diabetic rabbits were evaluated. The hypoglycaemic effect was measured by blood glucose, insulin level, HbA1c and his to pathology of pancreas. Glucose lowering effect of the ME was studied in diabetic rabbits. The effects of extract on blood glucose, body weight, food in take, fluid intake, OGTT were also evaluated. The results showed that 0.5,1 and 2g/kg of the powder significantly decreased blood glucose levels in normal rabbits and diabetic rabbits at the intervals checked. Oral intake of pioglitazone also reduced the levels in these rabbits. Synergistic hypoglycaemic effect of 600mg/kg of ME with different doses of insulin (2 & 3unit/kg, s/c) further reduced blood glucose levels of treated alloxan-diabetic rabbits. The oral glucose tolerance test revealed lowered area under curve values in ME treated rabbits. Treatment with ME (400 and 600 mg/kg) for 30 days showed highly significant decrease in blood glucose level by augmenting insulin secretion, HbA1cand significant increase in body weight, serum insulin levels in treated diabetic rabbits. Histopathology study showed regeneration of beta-cells. These studies have, therefore, supported the traditional use of this herb in diabetic patients. PMID- 25553694 TI - Prophylactic role of B vitamins against bulk and zinc oxide nano-particles toxicity induced oxidative DNA damage and apoptosis in rat livers. AB - The aim of this work is to explore the protective of B vitamins (B(3), B(6) and B(12)) against the hepatotoxic potency of either bulk zinc oxide (ZnO-bulk) or its nanoparticles (ZnO-NPs)-induced liver damage in rats. ZnO- bulk or its NPs were administered orally (500 mg/kg b.w.) for 10 successive days. The results revealed that oral co-administration of combination of B vitamins (250 mg B(3), 60 mg B(6) and 0.6 mg B(12)/Kg body weight) daily for 3 weeks to rats intoxicated by either ZnO- bulk or its NPs markedly ameliorated increases in serum of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehdrogenase (LDH). The B vitamins also down-regulated increases in serum glucose level as well as increases in immuno-inflammatory biomarkers, including tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein compared with intoxicated, untreated rats. Beside, the used agent successfully modulated the alterations in serum vascular endothelial growth factor (VEGF), attenuated liver oxidative DNA damage compared with ZnO intoxicated groups. We showed that the used B complex mitigated increased malondialdehyde (MDA), decrease in glutathione peroxidase (GPx) and increase in the apoptosis marker caspase 3 of liver tissue in response to either ZnO-bulk or its NP toxicity. In conclusion, early treatment with vitamin B complex may protect liver tissue from deleterious damage induced by the toxic effects of ZnO-bulk or its NPs. PMID- 25553695 TI - Formulation and evaluation of mini-tablets-filled-pulsincap delivery of lornoxicam in the chronotherapeutic treatment of rheumatoid arthritis. AB - In this present research work, we have designed a pulsincap formulation comprising mini-tablets, which to the best of our knowledge this combination has not been reported yet. We successfully combined the advantages of mini-tablets technology to meet the optimized requirements of our pulsincap formulation. Our main aim was to target lornoxicam to treat rheumatoid arthritis as per the chronotherapeutic pattern of the disease. Directly compressing method was used to prepare mini-tablets. The drug, polymers and combine mixtures of drug and polymers was evaluated for pre-formulation testing. Prepared mini-tablets were also evaluated for physicochemical, dissolution and stability studies. From FTIR and DSC evaluation, we found no interaction between the drug and polymers used. For mini-tablets, all the physico-chemical parameters were in limit. The mini tablets of lornoxicam were filled into an insoluble body of capsule, and its opening was sealed by plugging it with a polymer. The complete capsule body after sealing with a cap was given enteric coating. Different polymers in various concentrations were used as a plug, to identify the most suitable which gives a complete lag time of 5 hours when combined with 5% CAP coating. HPMC-K100M in 30% and sodium alginate in 40% concentrations were identified as the most suitable plugs. Our optimized pulsincap formulations releases lornoxicam after a lag time of 5 hrs and maximum portion of the drug will be released in the early morning hours. It was also found to be stable for a period of 6 months as per ICH guidelines. PMID- 25553696 TI - Antimicrobial activity of different solvent extracted samples from the flowers of medicinally important Plumeria obstusa. AB - The present research work was carried out to investigate the antimicrobial (eight bacteria and one fungus) activities of different solvent (ethanol, petroleum ether, chloroform, ethyl acetate and isobutanol) extracted samples from flowers of P. obstusa by disc diffusion method. Analysis of the data revealed that all the five extracts from flowers of P. obstusa showed different ranges of antimicrobial activities. Petroleum ether fractions showed inhibitory activities against all the nine microbial species except Klebsiella pneumonia. Ethyl acetate and isobutanol fractions showed inhibitory effects against all the tested microbial species except Pseudomonas aeruginosa. Chloroform and ethanol extracts had varying levels of inhibitions against all of the tested microorganisms. The most susceptible gram positive bacterium was Bacillus subtilis which was inhibited by all the five extracts while the most resistant gram positive bacterium was Staphylococcus aureus. Erwinia carotovora was the most susceptible gram negative bacterium while Pseudomonas aeruginosa was highly resistant among the gram negative bacteria. PMID- 25553697 TI - Tissue distribution study of salvianolic acid B long-circulating liposomes in mice by UPLC-MS/MS determination. AB - In targeting delivery system research on salvianolic acid B, it's vital but hard to evaluate the tissue distribution for its low concentrations in tissues. So the simple, rapid, selective and sensitive UPLC-MS/MS method was provided hereby to determine the concentration of salvianolic acid B in mice tissues after intravenous administration of salvianolic acid B injections, conventional liposomes and long-circulating liposomes. The UPLC was conducted by a C(18) column with a gradient mobile phase consisting of acetonitrile and water containing 0.1% formic acid. The tandem mass spectrometry was operated in negative-electrospray ionization selected-reaction-monitoring mode, and the optimized characteristic precursor to product ion transition m/z 717.3->519.1 was selected. The biosamples were homogenized and treated with a protein precipitation, which led to an acceptable matrix effect and extraction recovery. The linear calibration curves were plotted in the given concentration ranges. The intra-day and inter-day precisions were less than 13.9% and the accuracies were in the range of 86.3-109.2%. The tissue distribution results determined by UPLC MS/MS we developed showed that the conventional and long-circulating liposomes we made had succeeded in prolonging the retention time and increasing the level of salvianolic acid B in certain distribution tissues such as liver, kidney and brain. PMID- 25553698 TI - Anethum graveolens seeds aqueous extract stimulates whole brain 5 hydroxytryptamine metabolism and reduces feeding behavior and body weight in obese rats. AB - The percentage of overweight and obese person has increased markedly since several decays. Obesity is associated with increased risked factor for many diseases such as, diabetes, heart complications, arthritis and certain types of cancer. Feeding behavior is in controlled by a major interaction between central nervous system and many organs of the body. The role of serotonin (5-HT) in feeding behavior is well recognized. The aim of present study was to evaluate the effect of Anethum graveolens seeds aqueous extract (AGAE) on food intake, body weight and serotonin metabolism in over weight rats. Five weeks oral administration of AGAE shows significant decrease in body weight, food intake and significant increase in whole brain 5-HT, 5-HIAA and tryptophan level in brain and plasma of experimental animals. Increased level of 5-HT induced satiety and suppressed food intake and result is the reduction in body weight. PMID- 25553699 TI - Genotoxic and cytotoxic effects of Sunset Yellow and Brilliant Blue, colorant food additives, on human blood lymphocytes. AB - The synthetic dyes over fifty are used in many areas including the food industry around the world. Sunset Yellow FCF and Brilliant Blue FCF are used as colorant food additives in many food products. The present study investigated the genotoxic and cytotoxic effects of Sunset Yellow and Brilliant Blue. Genotoxic and cytotoxic activities of the food additives were evaluated in lymphocyte cell cultures using mitotic index, replication index and micronucleus assay. Mitotic index frequencies and replication index values were decreased and micronucleus frequency was increased with increasing concentrations of Sunset Yellow and Brilliant Blue. The changes in mitotic index and micronucleus are statistically significant (p<0.05). The results show that the Sunset Yellow and Brilliant Blue can have cytotoxic and genotoxic potential. It care must be taken when using these materials as a food additive. PMID- 25553700 TI - Short communication: in vitro assessment of antioxidant, antibacterial and phytochemical analysis of peel of Citrus sinensis. AB - Antibacterial effect of Citrus sinensis peel extracts was evaluated against several pathogenic bacteria associated with human and fish infections viz., Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus epidermidis, Serratia marcesnces, Shigella flexneri, Enterobacter amnigenus, Salmonella Typhimurium and Serratia odorifera. Methanol, ethanol, chloroform and diethyl ether solvents were used for extraction. In vitro antibacterial activity was analyzed by agar well and agar disc diffusion methods. It was found that ethanol extract showed highly significant inhibition of E. coli and K. pneumonia (12.6+/-0.94 mm and 11.6+/-1.2 mm) whereas methanol extract of C. sinensis also showed high zone of inhibition of S. odorifera (10.0+/-2.16 mm). The potential activity of active extracts was assessed and also compared with standard antibiotics through activity index formulation. The order of antioxidant activity through ABTS.+ and DPPH free radical scavenging activity was ethanol>methanol>chloroform>diethyl ether. Phytochemical screening of all solvents had determined the presence of terpenoids, alkaloids, steroids, glycosides and flavonoids. It was also found that Chloroform/Methanol (5:5) and Butanol/Ethanol/Water (4:1:2.2) solvent systems showed significant separation of active phytochemical constituents. These findings reveal the potential use of C. sinensis peel to treat infectious diseases, which are being caused by microorganisms. PMID- 25553701 TI - Report: antioxidant and nutraceutical value of wild medicinal Rubus berries. AB - Nutritional quality and antioxidant capacity of three edible wild berries (Rubus ellipticus Smith, Rubus niveus Thunb, Rubus ulmifolius L.) from Lesser Himalayan Range (LHR) were evaluated. Their edible portion was assayed for moisture, fats, ash, carbohydrates, proteins, fibers, essential minerals (Ca, P, Mg, K, Na, Cl, S, Mn, Zn, Fe, Cu, Se, Co, Ni) and DPPH free radical scavenging activity was applied to determine the antioxidant potential. The fruit of Rubus ulmifolius L. (blackberry) possessed the highest values of energy (403.29 Kcal), total protein (6.56g/100 g), Nitrogen (N) content (1500mg/100g), K (860.17mg/100g), Ca (620.56mg/100g), Zn (17.509mg/100g) and the strongest antioxidant activity (98.89% inhibition). While the raspberries (Rubus ellipticus Smith, Rubus niveus Thunb.) exhibited more significant contents of dietary fiber (5.90g/100g), carbohydrates (86.4 g/100 g) and Fe (4.249mg/100g). Significant variation was observed among the tested samples in all the investigated features. The combination of bio elements and active antioxidants clearly showed the applicability of these berries as a nutraceutical supplement. PMID- 25553702 TI - Report: effects of Camellia sinensis L. (green tea) extract on the body and testicular weight changes in adult Wistar rate. AB - This research was aimed to study the effects of oral administration of Camellia sinensis L. on the testicular and body weights of adult Wistar rats for short and long time periods. The adult Wistar rats were divided into 3 groups (A, B and C). Every group had ten rats. Green tea extract 0.692% (w/v) was given to groups A and B on daily basis. The extracts were prepared fresh and given for a period of ten and thirty days, respectively, while distilled water was given to the group C rats only. The adult Wistar rats were sacrificed on eleventh and thirty-first day of experiment for the particular groups. The testes were dissected out cautiously, free from the supporter tissues and weighed to the adjacent 1 mg. There is no significant difference in the body weight in all 3 groups. Moreover, it was observed that Wistar rat's testicular weight was considerably increased in group B but no major changes were seen in group A. Our results indicated that green tea when given for short period of time may be effective to the testes but has no consequence on Wistar rat's body weight. However, it is indistinct if these alterations are reversible. PMID- 25553703 TI - Report: a study of morbidity of induced abortion data from women belonging to Karachi, Pakistan. AB - The purpose of this study was to evaluate the morbidity of induced abortion in relation to facilities, service providers and social responses of general population of women, from Karachi, Pakistan. Cross-sectional survey, conducted from February to December 2010, through a researcher-administered questionnaire from 61 randomly selected women, who underwent for Induced Abortion, aged 18-50 years. The questionnaire included open and closed ended questions, regarding demography, facilities, service providers and various complications observed. Overall, 98 immediate health problems were reported by 40 (65.5%) of the respondents, 153 late adverse effects or chronic by 46 (75.4%); while 101 mental complications had been reported by 45 (73.8%) of the 61 aborting women; respectively. Private clinics surfaced as the most frequently adopted source as reported by 40.7% of the respondents. Two third majorities had the procedure in satisfactory, good hygienic conditions by skilled professionals. Around 59% of the aborting women were aware of the religious perspective of the subject. Marked incidence of complications had been registered, regardless of type of method adopted, hygienic condition of the procedure or skill of the provider. Although, awareness of religious perspective of the subject was there, still quite a lot opted for abortion. This suggests that strong socioeconomic factors influence women to take peril of such an attempt. It also reveals the existence of a big gap for the awareness services for educating the risks involved to the women's health. Study revealed that services are easily accessible; without any legal, religious or social barriers. Semi or un-educated women, mostly from low socioeconomic sector are opting the procedure in majority, being less aware and stalwartly influenced by environmental factors; hence excessive availability of abortion services should be revisited. Lack of deep awareness of the consequences also contributes for deteriorating future reproductive and mental health. Awareness and counseling services for aborting women, for their health risks, as well as about human perspective of the issue, needs to be initiated, for better management of their reproductive health and rights. PMID- 25553704 TI - Review: phage therapy: a modern tool to control bacterial infections. AB - The evolution of antibiotic-resistant in bacteria has aggravated curiosity in development of alternative therapy to conventional drugs. One of the emerging drugs that can be used alternative to antibiotics is bacteriophage therapy. The use of living phages in the cure of lethal infectious life threatening diseases caused by Gram positive and Gram negative bacteria has been reported. Another development in the field of bacteriophage therapy is the use of genetically modified and non replicating phages in the treatment of bacterial infection. Genetically engineered bacteriophages can be used as adjuvant along with antibiotic therapy. Phages encoded with lysosomal enzymes are also effectual in the treatment of infectious diseases. PMID- 25553705 TI - Review: progress in the diagnosis of dengue virus infections and importance of point of care test: a review. AB - It is an urgent need of highly sensitive, specific and economical diagnostic tools for early and fast diagnosis of highly challenging dengue virus infections. Many laboratory methods including virus detection, genome detection, antigen detection and serological detection of such short-lived viremia were explored but promising outcomes for economical immunochromatographic tests have been reported in this review. With the trend of fast, easy operation, rapid diagnostic tests (RDT) based on immunochromatographic assays are of great importance due to point of care test (POCT) in the dengue endemic regions where it is short of laboratory equipments and cold storage conditions. Such kind of point of care diagnosis is more efficient, fast and user friendly. Moreover, the development of highly advance RDT is dependent on the use of anti-dengue monoclonal antibodies highly specific for particular analyte/antigen. PMID- 25553706 TI - Physicochemical properties, in vitro release and skin permeation studies of a topical formulation of standardized pomegranate rind extract. AB - The aim of the present study was to develop a stable formulation containing standardized pomegranate rind extracts (SPRE) for topical use in the treatment of dermal diseases. Ellagic acid (EA) as the major active constituent of SPRE (not less than 13%) was quantified by HPLC as an indicator for studies on the stability, in vitro drug release, and skin penetration/retention. The formulation prepared with polyethylene glycols (PEG 400 and PEG 4000) containing 5% SPRE has been found to be stable and provide a release rate of 36.6741+/-5.0072 MUg/cm(2)/h that was best fitted to the zero-order kinetic model. EA from SPRE did not penetrate the full-thickness rat skin but the skin retention of EA was determined to be 2.22+/-0.16 MUg/cm(2) with a total recovery of 95.14+/-5.51%. The results indicated that this 5% SPRE PEG ointment was of satisfactory physicochemical properties and worth further in vivo investigations. PMID- 25553707 TI - Immunoreactivity and two-dimensional gel-electrophoresis characterization of Egyptian cobra venom proteome. AB - The first and second (two) dimensional gel electrophoresis has a broad protein resolution power. It was used to separate and identify cobra venom proteome. The importance of characterizing venom proteins contents from the Egyptian elapidae, specifically neurotoxins, is based on the need to produce effective anti-venom. About 30-55distinct protein spots were identified on silver stained two dimensional gels. Around two-thirds of the venom proteins displayed low a molecular weight and a migration into hydrophobic side. The venoms from Naja haja and Naja nigricollus showed 45-55 spots, while Walternnesia aegyptia had less (31 37) spots. The commercial prepared polyclonal antivenom had a strong signal for anionic and cationic venom protein spots with molecular weight 20-115 kDa. However, it showed weak or non immunoreactivity toward anionic low molecular weight spots (2.5-15 kDa). These results suggest the need to change the immunization schedule to include low molecular weight toxin-proteomes as separate dose or sequester injection. PMID- 25553708 TI - Research progress of the studies on the roots of Peucedanum praeruptorum dunn (Peucedani radix). AB - As a commonly employed traditional Chinese medicine, Peucedani Radix (Qian-hu in Chinese), which consists of the dried roots of Peucedanum praeruptorum Dunn, has a long history of application for the treatment of cough with thick sputum and dyspnea, nonproductive cough and upper air-way infections in traditional medicinal practice. The current review aims to summarize the research progress on the botany, phytochemistry, chemical analysis, pharmacological assay, and pharmacokinetic profile of this famous herbal drug. All available information on this traditional medicine was obtained via electronic search (using ACS, PubMed, Web of Science, Google Scholar, Baidu Scholar, and CNKI). Phytochemical investigations revealed that angular-type pyranocoumarins (APs), mainly (+/-) praeruptorin A (Pd-Ia), (+)-praeruptorin A, (+/-)-praeruptorin B, (+) praeruptorin B (Pd-II) and (+)-praeruptorin E (Pd-III), were the main active components in Qian-hu, while some other types of ingredients were also identified from this herb. The crude extract and pure compounds from Peucedani Radix exhibited a wide spectrum of in vitro and in vivo pharmacological activities, including vasorelaxant, cardioprotective, hepatoprotective, anti-tumor and anti platelet aggregative effects. Conversely to the well-defined chemical constituents and activities, the properties of absorption, pharmacokinetics, and metabolism were rarely characterized. However, further investigations are wistful for the development of new drugs and therapies for various diseases, especially cardiovascular disorders. Collectively, the present review on the phytochemistry, chemical analysis, pharmacological evaluation, and pharmacokinetic profile of Peucedani Radix will provide meaningful information for further studies and commercial exploitation of the herbal medicine. PMID- 25553709 TI - Cancer-specific chemoprevention and anti-metastatic potentials of Rheum emodi rhizome ethyl acetate extracts and identification of active principles through HPLC and GC-MS analysis. AB - Rheum emodi Wall. ex Meissn. (Polygonaceae) is a Himalayan perennial herb which has been cultivated over 5000 years for its medicinal properties by rural and tribal people of Kashmir, and has great significance for its traditional use in Ayurvedic, Unani and folk systems of medicine for cancer treatments. However, there is lack of reports pertaining to specific-chemopreventive properties of R. emodi rhizome. The present study investigates R. emodi rhizome hot and cold ethyl acetate extracts (EHR and ECR) for specific-chemopreventive properties. The extracts were found to be effective antioxidant sources, and showed significant (P<0.05) cancer-specific cytotoxicity towards MDA-MB-231 cells (when compared to WRL-68 [non-tumoral cells]) with IC(50) values of 56.59+/-1.29 MUg/ml (EHR) and 152.38+/-1.45 MUg/ml (ECR) respectively, and induced apoptosis significantly (P<0.05) high in MDA-MB-231 cells (estrogen receptor-(ER)-negative) when compared to MCF-7 cells (ER-positive). Extracts also demonstrated evident anti-metastatic activity. Further, the extracts were chemically characterized through HPLC analysis which revealed major polyphenolics and the GC-MS analysis of the effective extract EHR unveiled (Methyl 6,7-dideoxy-6-C-methyl-2,3-di-O-methyl-a-D gluco-oct-6-eno-1,5-pyranosid)urono-8,4-lactone,Chrysophanol, derivatives of cyclopropanes and a quinazoline derivative. Overall, EHR exhibited significantly better results on par with ECR, and thus could be considered for their use in designing cancer-specific chemopreventive agents against ER-negative breast cancer. PMID- 25553710 TI - Effect of repeated oral therapeutic doses of methylphenidate on food intake and growth rate in rats. AB - Central nervous system stimulants are known to produce anorexia. Previous data suggest that methylphenidate can have variable effects on caloric intake and growth rate. A dose-response study was performed to monitor caloric intake, liquid intake and growth rate in rats following repeated administration of human oral therapeutic doses 2 mg/kg/day, 5mg/kg/day and 8mg/kg/day of methylphenidate. We found that food intake and water intake, increased in all weeks and at all doses used in the study. Growth rate increased more at higher dose (8mg/kg/day) and at low dose (2mg/kg/day) of methylphenidate in 1(st) and 2(nd) week whereas more decreased by the above doses in 3(rd) week, suggesting that food stimulation leads to initial increase in growth rate but long term administration of methylphenidate attenuate growth rate that is not due to modulation of appetite but may be due to anxiety and increased activity produce by stimulants. A possible role of DA, 5HT receptors in modulation of appetite and anxiety is discussed. PMID- 25553711 TI - Effect of gonadotrophins, oestradiol and insulin on cumulus expansion of Nili Ravi buffalo oocytes. AB - The objective of the present study was to investigate the cumulus expansions of Nili Ravi buffalo oocytes during cultured in TCM-199 supplemented with 2 MUg/ml oestradiol (E(2)), 0.05 IU/ml recombinant human follicle stimulating hormone (rhFSH), 2IU/ml human chorionic gonadotrophin (hCG), and 0.12 IU/ml insulin (I). The cumulus oocytes complexes (COCs) were collected from 2-8mm follicles from local abattoir ovaries. Supplementation of medium with single hormones showed significant (P<0.0001) increase in mean diameter of COCs with rhFSH except E(2), hCG and insulin after 24 hours compared to the increase in the mean diameter of COCs matured in TCM-199 without any hormonal supplementation. With rhFSH even at 8th hour, significant increase (P<0.001) in cumulus expansion was observed. In combination of hormones the significant (P<0.0001) cumulus expansion was achieved in E(2)+rhFSH treatment group. The non significant (P>0.05) cumulus expansion was observed in treatment groups viz. E(2)+hCG, E(2)+Insulin, rhFSH+hCG, rhFSH+Insulin, hCG+Insulin, E(2)+rhFSH+hCG and E(2)+rhFSH+hCG+Insulin after 24 hours. In conclusion, supplementation of rhFSH alone and in combination with E(2)in TCM-199 has highly significant effect on cumulus expansion. PMID- 25553712 TI - Influence of the association between platelet-rich fibrin and bovine bone on bone regeneration. A histomorphometric study in the calvaria of rats. AB - This study aimed to investigate the effects of platelet-rich fibrin (PRF) associated or not with Bio-Oss on bone defects in the calvaria of rats. A critical-size defect of 5-mm diameter was performed in the calvaria of 48 rats. These animals were divided into six groups of eight animals each, according to the treatment received: homogeneous clot, autogenous clot, autogenous PRF, homogeneous PRF, Bio-Oss, or Bio-Oss associated with PRF. The animals were euthanized after 30 or 60 days. Bone regeneration was evaluated by histomorphometric analysis. The highest mean percentages of new bone formation at 30 days (54.05% +/- 5.78) and 60 days (63.58% +/- 5.78) were observed in the Bio Oss associated with PRF group; in particular, the percentage of new bone at 30 days was significantly higher than that of all of the other groups (P<0.01). At 60 days, the Bio-Oss associated with PRF (63.58% +/- 5.78) and Bio-Oss (57.34% +/ 5.78) groups had similar results, and both showed a statistical difference compared to the other groups. PRF had a positive effect on bone regeneration only when associated with Bio-Oss. PMID- 25553713 TI - Ultrasonic imaging of static objects through an aberrating layer using harmonic phase conjugation approach. AB - The main goal of this study is to develop a new image reconstruction approach for the ultrasonic detection of small objects (comparable to or smaller than the ultrasonic wavelength) behind an aberrating layer. Instead of conventional pulse echo experimental setup we used through transmission, as the backscattered field after going twice through the layer becomes much weaker than the through transmitted field. The proposed solution is based on the Harmonic Phase Conjugation (HPC) technique. The developed numerical model allows to calculate the amplitude and phase distributions of the through-transmitted acoustic field interacting with the objects and received by a linear transducer array either directly or after passing through an additional aberrating layer. Then, the digitized acoustic field received by the array is processed, phase-conjugated, and finally, numerically propagated back through the medium in order to reconstruct the image of the target objects. The reconstruction quality of the algorithm was systematically tested on a numerical model, which included a barrier, a medium behind it, and a group of three scatterers, by varying scatterer distances from the source transducer, their mutual arrangement, and the angle of the incident field. Subsequently, a set of laboratory experiments was conducted (at transmit frequency of 2 MHz) to verify the accuracy of the developed simulation. The results demonstrate feasibility of imaging multiple scattering objects through a barrier using the HPC method with better than 1mm accuracy. The results of these tests are presented, and the feasibility of implementing this approach for various biomedical and NDT imaging applications is discussed. PMID- 25553714 TI - Combined short and long-delay tandem shock waves to improve shock wave lithotripsy according to the Gilmore-Akulichev theory. AB - Extracorporeal shock wave lithotripsy is a common non-invasive treatment for urinary stones whose fragmentation is achieved mainly by acoustic cavitation and mechanical stress. A few years ago, in vitro and in vivo experimentation demonstrated that such fragmentation can be improved, without increasing tissue damage, by sending a second shock wave hundreds of microseconds after the previous wave. Later, numerical simulations revealed that if the second pulse had a longer full width at half maximum than a standard shock wave, cavitation could be enhanced significantly. On the other side, a theoretical study showed that stress inside the stone can be increased if two lithotripter shock waves hit the stone with a delay of only 20 MUs. We used the Gilmore-Akulichev formulation to show that, in principle, both effects can be combined, that is, stress and cavitation could be increased using a pressure pulse with long full width at half maximum, which reaches the stone within hundreds of microseconds after two 20 MUs delayed initial shock waves. Implementing the suggested pressure profile into clinical devices could be feasible, especially with piezoelectric shock wave sources. PMID- 25553715 TI - Hepatitis C vaccine clinical trials among people who use drugs: potential for participation and involvement in recruitment. AB - Candidate prophylactic HCV vaccines are approaching phase III clinical trial readiness, yet little is known about the potential for participation among target groups or innovative ways to promote enrollment within 'hard-to-reach' populations. This study describes HCV vaccine trial participation willingness among a high-risk sample of people who use drugs and their willingness to assist researchers by promoting the trial among peers. Willingness to participate in and encourage peers' participation in an HCV vaccine trial was assessed among injection and non-injection drug users enrolled in a cohort study in Kentucky using interviewer-administered questionnaires (n=165 and 415, respectively, with willingness to participate assessed among HCV-seronegative participants only). Generalized linear mixed models were used to determine correlates to being "very likely" to participate or encourage participation in a trial. Most reported being likely to participate or encourage participation in a vaccine trial (63% and 87%, respectively). Men were significantly less likely to report willingness to encourage others' participation, while willingness to encourage was higher among lower income, HCV-seropositive, heroin-using, and methamphetamine-using participants. Unemployment, lesser education, receipt of financial support from more peers, and nonmedical prescription drug use were positively associated with willingness to participate. Differential enrollment in HCV vaccine clinical trials by socioeconomic status may occur, underscoring ethical considerations and need for avoiding coercion. Notably, the data suggest that a peer-driven approach to promoting trial participation among people who use drugs could be feasible in this population and that HCV-seropositive individuals and women could be especially instrumental in these efforts. PMID- 25553716 TI - [Subcutaneous paraciliar nodule of rare origin]. PMID- 25553717 TI - [How is the implementation of the new legal framework for health care affecting HIV-infected immigrants in an irregular situation in Spain?]. AB - INTRODUCTION: The entry into force of Royal Decree (RD) 16/2012 in Spain in September 2012 led to the exclusion of the group of irregular immigrants from the National Healthcare System. With this work, GESIDA attempts to measure the impact of the entry into force of the RD in relation to its application by the Autonomous Communities (CCAA), and how it has affected the health care of irregular immigrants infected with HIV. METHODS: Information was requested from the 17 CCAA of the existence of measures to ensure the care and treatment of people with HIV infection that were left unprotected because of the implementation of the RD. Likewise, a survey was conducted on health professionals and NGOs involved in the care of these people, to find out how it has affected the implementation of the RD to their daily healthcare work and the availability of information on regulations to implement it. RESULTS: The response of the CCAA was variable, hardly contributing, in some cases, to mitigate the negative effect of the RD. To this is added a complex bureaucracy to access the benefits offered by some regions, often inaccessible to the most vulnerable subjects. Lack of information for health-care professionals and NGOs involved in the care of immigrants, hinders access of this population to health care and the establishment of control measures for diseases with an impact on the public health. CONCLUSIONS: The RD 16/2012 has had a negative impact on daily healthcare working, generating the appearance of deep inequities throughout the country. PMID- 25553718 TI - Use of opioid analgesics or sleeping medication and survival of cancer patients. AB - PURPOSE OF THE RESEARCH: Pain and sleep disturbance have been shown to have a profound influence on the outcomes of cancer treatment. This study sought to determine whether administering opioid analgesics or sleeping medication to cancer patients during their first admission to a hospital is associated with poor prognoses. METHODS AND SAMPLE: We conducted a population-based retrospective cohort study by analyzing data obtained from the National Health Insurance Research Database in Taiwan. The study population comprised cancer patients whose first admission to a hospital for initial cancer treatment was in 2004. KEY RESULTS: We collected data on 2302 cancer patients. To analyze the effect of opioid analgesic and sleeping medication usage on cancer patient survival, we compared the 3-year survival rates among 4 groups of patients (no use, sleeping medications-only, opioid analgesics-only, both used). The 3-year Kaplan-Meier plots for these 4 groups show that the difference was statistically significant (log rank 48.244, p < 0.001). The longevity of cancer patients was the greatest among the no-use group, followed by the sleeping medications-only group, then the opioid analgesics-only group, and finally, the group in which both sleeping medications and opioid analgesics were used. CONCLUSIONS: The use of opioid analgesics or sleeping medication was shown to be negatively correlated with the survival rate of cancer patients. PMID- 25553719 TI - Pin1-based diagnostic and therapeutic strategies for breast cancer. AB - Pin1 is the only known cis-to-trans isomerase that recognizes the phosphorylated pThr/pSer-Pro motifs in many signaling molecules, playing unique roles in the pathogenesis of breast cancer. First, Pin1 is prevalently over-expressed in kinds of breast cancer cell lines and tissues, such as MDA-MB-231 cell, MCF-7 cell, Her2+, ERalpha+, and basal-like breast cancer subtypes. Second, Pin1 amplifies many oncogenic signaling pathways, inhibits multiple tumor suppressors, promotes the angiogenesis and metastasis of breast cancer cells, and enhances the resistance of breast cancer cells to anti-tumor medicines. Third, inhibiting Pin1 blocks most of these detrimental effects in a great number of breast cancer cell lines. These findings suggest Pin1 as a promising diagnostic biomarker as well as an efficient therapeutic target for breast cancer. It is strongly expected that a Pin1-positive subtype of breast cancers should be extremely concerned and that the therapeutic efficacy of Pin1 inhibitors on breast cancer patients should be evaluated as soon as possible. Nonetheless, Pin1-based therapeutic strategies for breast cancer still deserve some debates. Hence, we give the predictions of several important issues, such as application precondition, side effects, and personalized medication, when Pin1 inhibitors are used in the breast cancer therapy. These proposals are meaningful for the further development of Pin1-based diagnostic and therapeutic strategies in order to conquer breast cancer. PMID- 25553721 TI - Confocal and fluorescence lifetime imaging sheds light on the fate of a pyrene tagged carbon monoxide-releasing Fischer carbene chromium complex. AB - The synthesis of a new pyrene-containing Fischer carbene complex is described. The complex has a broad absorbance spectrum between 300 and 400 nm and, on excitation at 345 nm in CH2Cl2 solution, emission is observed at 395 and 415 nm. Emission is also observed in PBS buffer, but in this case the resulting spectra are much broader. Confocal and fluorescence lifetime imaging indicate that emission occurs on treating HeLa cells with the complex and co-localisation studies demonstrate that this is from the mitochondria and lipid-rich regions of the cell. PMID- 25553722 TI - 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). PMID- 25553723 TI - Clinical features and expressions of Foxp3 and IL-17 in type 1 autoimmune pancreatitis in China. AB - BACKGROUND: Autoimmune pancreatitis (AIP) is a distinct type of pancreatitis associated with a presumed autoimmune mechanism. The aim of this study was to analyze the clinical features and expressions of forkhead box P3 (Foxp3) and interleukin-17 (IL-17) in type 1 AIP in China and to identify factors for differentiation of AIP from non-AIP chronic pancreatitis (CP). MATERIAL AND METHODS: We retrospectively reviewed pancreatic specimens with diagnosis of type 1 AIP and non-AIP CP at Sun Yat-Sen Memorial Hospital in China from January 2000 to December 2013. The clinical symptoms, serological data, imaging findings, histopathology, and immunohistochemical findings of Foxp3 and IL-17 in the 2 groups were analyzed. RESULTS: Twenty-nine patients with type 1 AIP and 20 patients with non-AIP CP were enrolled. Obstructive jaundice was more common in type 1 AIP than in non-AIP CP (62.1% vs. 30.0%, P=0.042). The diffuse or segmental enlargement of the pancreas was more frequent in type 1 AIP than in non AIP CP (72.4% vs. 40.0%, P=0.038). Histopathology of type 1 AIP presented dense lymphoplasmacytic infiltration, "snowstorm-like" fibrosis and abundant immunoglobulin (Ig) G4+ cells. Foxp3+ cells were more frequently observed in type 1 AIP than in non-AIP CP. IL-17+ cell infiltration was similar between the 2 groups. Furthermore, a positive correlation was found between Foxp3+ and IgG4+ cell counts in the pancreas of patients with type 1 AIP. CONCLUSIONS: Type 1 AIP has distinctive symptoms, image, and pathological characteristics, which could be used for differentiation from non-AIP CP. Foxp3+ cells might be helpful to distinguish type 1 AIP from non-AIP CP. PMID- 25553724 TI - Novel NF-kappaB inhibitors: a patent review (2011 - 2014). AB - IMPORTANCE OF THE FIELD: The NF-kappaB family of transcription factors has a vital role in coordinating the expression of a wide variety of genes that control immune responses. The dysfunction of NF-kappaB has been associated with diseases ranging from inflammation to cancer. AREAS COVERED: In this review, authors provided information on the role of NF-kappaB in human health and on recently developed inhibitors from patents granted in 2011 - 2014. The reader will gain an understanding of the mechanisms of NF-kappaB function as well as the structures and biological activities of recently developed NF-kappaB inhibitors. EXPERT OPINION: Constitutive NF-kappaB activation is likely involved in the pathogenesis of several diseases. Researchers need to consider the specific mechanism of each invented NF-kappaB inhibitor, as well as the properties of the cellular, in vitro and in vivo assays and targeted diseases. For new drug development, they need various biological tests to assess the potential side effects and optimization of the biological activity. PMID- 25553726 TI - Curcuma ecalcarata - new natural source of pinocembrin and piperitenone. AB - Phytochemical analysis of the rhizome extract of Curcuma ecalcarata, a hitherto uninvestigated south Western Ghats endemic species, resulted in the isolation and identification of the diaryl heptanoid trans, trans-1,7-diphenyl-5-hydroxy-4,6 heptadiene-3-one (1), steroid beta-sitosterol (2), flavanone pinocembrin (4) and monoterpenoids piperitenone (3) and 8-hydroxy piperitone (5). HPTLC estimation of pinocembrin in the rhizome revealed the plant as a rich source of pinocembrin (0.37% dry wt.). The rhizome essential oil was isolated by hydrodistillation and analysed by GC-FID, GC-MS and (13)C NMR. Among the 30 constituents identified in the oil, monoterpenoids predominated (94.2%) followed by sesquiterpenoids (5.8%). The major compound consisting of 65.2% of the oil was isolated and identified as piperitenone (3). The study highlights the plant as a rich source of the flavanone pinocembrin and the volatile aroma compound piperitenone. PMID- 25553727 TI - Body composition characteristics of elite Australian rugby union athletes according to playing position and ethnicity. AB - This study describes the body composition traits of modern-day elite rugby union athletes according to playing position and ethnicity. Thirty-seven international Australian rugby athletes of Caucasian and Polynesian descent undertook body composition assessment using dual-energy X-ray absorptiometry and surface anthropometry. Forwards were significantly taller, heavier and had a greater total fat mass and lean mass than backs. Backs displayed a higher percentage lean mass and lower sum of seven skinfolds and percentage fat mass. While no whole body composition differences were seen between ethnicities, significant regional differences were observed. In the periphery (arm and leg) regions, Polynesians had a greater proportion of fat mass (53.1% vs. 51.3%, P = 0.052, d = 0.5) and lean mass (49.7% vs. 48.6%, P = 0.040, d = 0.9), while in the trunk region a lower proportion of fat mass (37.2% vs. 39.5%, P = 0.019, d = 0.7) and lean mass (45.6% vs. 46.8%, P = 0.020, d = 1.1). Significant differences were also seen between Caucasian and Polynesian forwards in leg lean mass (31.4 kg vs. 35.9 kg, P = 0.014, d = 2.4) and periphery lean mass (43.8 kg vs. 49.6 kg, P = 0.022, d = 2.4). Elite Polynesian rugby athletes have different distribution patterns of fat mass and lean mass compared to Caucasians, which may influence their suitability for particular positions. PMID- 25553728 TI - Photocatalytic enhancement of hybrid C3N4/TiO2 prepared via ball milling method. AB - C3N4/TiO2 hybrid photocatalysts with highly enhanced photocatalytic performance were prepared by a facile ball milling method. A layered structure of g-C3N4 was formed on the surface of TiO2. The mechanochemical process can promote the dispersion of C3N4 on the surface of TiO2 particles, to form a single layer hybrid structure and a multi-layer core-shell structure. The photocatalytic activities of C3N4/TiO2 under visible and UV light irradiation were 3.0 and 1.3 times those of pure g-C3N4 and TiO2, respectively. Under visible light and UV irradiation, the photocurrent response was up to 2.5 times and 1.5 times as high as that of the pure TiO2 and C3N4, respectively. The evident performance enhancement of g-C3N4-TiO2 was mainly attributed to high separation and migration efficiency of electron-hole pairs. PMID- 25553725 TI - Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians. AB - Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population. PMID- 25553729 TI - Benchmark thermochemistry of chloramines, bromamines, and bromochloramines: halogen oxidants stabilized by electron correlation. AB - Chloramines, bromamines, and bromochloramines are halogen-containing oxidants that arise from the reaction of hypohalous acids with ammonia in water. Although relevant to both water disinfection chemistry and biochemistry, these molecules are difficult to study in the laboratory, and their thermochemical properties remain poorly established. We developed a benchmark level ab initio calculation protocol, termed TA14, adapted from the Weizmann theory and Feller-Peterson-Dixon approaches to determine the molecular structures and thermochemical properties of these compounds. We find that the halamine molecules are bound largely, and in some cases entirely, by electron correlation forces. This presumably explains their high reactivity as electrophilic oxidants. We provide computed heats of formation at 0 K (DeltafH(0)(0 K)) and at 298 K (DeltafH(0)(298 K)) and Gibbs free energies of formation at 298 K (DeltafG(0)(298 K)) for the 9 inorganic chloramines, bromamines, bromochloramines in gas phase. Based on comparisons to previous theoretical and experimental data for a set of 11 small molecules containing N, O, H, Cl, and Br, we propose uncertainties ranging from 1 to 3 kJ mol(-1) for computed thermodynamic properties of the halamines. Reported thermochemical data enable the determination of equilibrium constants for reactions involving halamines, opening possibilities for more quantitative studies of the chemistry of these poorly understood compounds. PMID- 25553730 TI - Exploring the scope of the isothiourea-mediated synthesis of dihydropyridinones. AB - The exploration and expansion of the scope of the isothiourea-mediated synthesis of dihydropyridinones is presented. The use of ketimines derived from alpha,beta unsaturated gamma-ketoesters as the Michael acceptor in a Michael addition/lactamisation cascade gives access to a range of dihydropyridinones with high enantioselectivity. The nature of the N-sulfonyl group present on the ketimine is extensively investigated, with further studies into derivatisation of the dihydropyridinone core also reported. PMID- 25553731 TI - Strontium eluting graphene hybrid nanoparticles augment osteogenesis in a 3D tissue scaffold. AB - The objective of this work was to prepare hybrid nanoparticles of graphene sheets decorated with strontium metallic nanoparticles and demonstrate their advantages in bone tissue engineering. Strontium-decorated reduced graphene oxide (RGO_Sr) hybrid nanoparticles were synthesized by the facile reduction of graphene oxide and strontium nitrate. X-ray diffraction, transmission electron microscopy, and atomic force microscopy revealed that the hybrid particles were composed of RGO sheets decorated with 200-300 nm metallic strontium particles. Thermal gravimetric analysis further confirmed the composition of the hybrid particles as 22 wt% of strontium. Macroporous tissue scaffolds were prepared by incorporating RGO_Sr particles in poly(epsilon-caprolactone) (PCL). The PCL/RGO_Sr scaffolds were found to elute strontium ions in aqueous medium. Osteoblast proliferation and differentiation was significantly higher in the PCL scaffolds containing the RGO_Sr particles in contrast to neat PCL and PCL/RGO scaffolds. The increased biological activity can be attributed to the release of strontium ions from the hybrid nanoparticles. This study demonstrates that composites prepared using hybrid nanoparticles that elute strontium ions can be used to prepare multifunctional scaffolds with good mechanical and osteoinductive properties. These findings have important implications for designing the next generation of biomaterials for use in tissue regeneration. PMID- 25553732 TI - Distribution of alpha-thalassemia mutations in Iranian population. AB - BACKGROUND: Alpha-thalassemia as one of the most common monogenetic disorders is widely spread over the Mediterranean, Southeast Asian, and Middle Eastern populations, including Iran. Although beta-thalassemia is much more common than alpha-thalassemia, alpha-thalassemia is still one of the main health problems in Iran with different mutation frequencies in various ethnic groups. So the evaluation of alpha-thalassemia mutations could be helpful to detect carriers as well as prevention strategy in Iranian population. OBJECTIVES: The aim of this study was to investigate the spectrum and frequencies of alpha-globin mutations in different ethnic groups of southern Iran. MATERIALS AND METHODS: Common alpha globin mutations were evaluated in 4010 Iranian population using a reverse dot blot for all point mutations and gap-polymerase chain reaction. RESULTS: Out of all individuals, 3993 were distinguished as carriers of alpha-thalassemia mutations. Thirteen types of alpha-thalassemia mutations were discovered. Allele of alpha(3.7) mutation was the most prevalent (43.84%) followed by the alpha(IVS1/-5NT) allele with the prevalence of 4.91%. The less frequent alleles were Hb ICARIA and alpha(codon16) with the prevalence of 0.04 and 0.01%, respectively. CONCLUSION: Our findings are essential for carrier screening, genetic counseling, and prenatal diagnosis in order to decrease the prevalence of alpha-thalassemia in Iran which is one of the goals of the national screening program. PMID- 25553733 TI - Stereospecific recognition and quantitative structure-activity relationship between antibodies and enantiomers: ofloxacin as a model hapten. AB - In this study, ofloxacin stereoisomers were chosen as a simple model to investigate the stereospecific recognition of chiral haptens and antibodies. Three polyclonal antibodies were studied and showed a relatively high enantioselectivity and an excellent sensitivity. Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to investigate the chiral recognition between the antibody and the ofloxacin enantiomer, and all the models yielded high correlation and predictive ability. It was found that the chiral discrimination was probably caused by steric hindrance; the antibody stereospecificity could be ascribed to the variation of the R1 and R3 groups of quinolones; the common structure of the quinolones is also essential in the hapten-antibody recognition. The recognition between the chiral haptens and the antibodies was co-affected by multiple interaction forces, and those forces were defined explicitly at the sub-structural level. An illustrative enhanced model with good simplicity and universality was also developed for a better understanding of the stereospecific recognition of ofloxacin enantiomers and antibodies for the first time. This work provides insights into the stereospecific recognition of chiral haptens and antibodies. PMID- 25553734 TI - Nanostructuring graphene for controlled and reproducible functionalization. AB - The 'graphene rush' that started almost a decade ago is far from over. The dazzling properties of graphene have long warranted a number of applications in various domains of science and technology. Harnessing the exceptional properties of graphene for practical applications however has proved to be a massive task. Apart from the challenges associated with the large-scale production of the material, the intrinsic zero band gap, the inherently low reactivity and solubility of pristine graphene preclude its use in several high- as well as low end applications. One of the potential solutions to these problems is the surface functionalization of graphene using organic building blocks. The 'surface-only' nature of graphene allows the manipulation of its properties not only by covalent chemical modification but also via non-covalent interactions with organic molecules. Significant amount of research efforts have been directed towards the development of functionalization protocols for modifying the structural, electronic, and chemical properties of graphene. This feature article provides a glimpse of recent progress in the molecular functionalization of surface supported graphene using non-covalent as well as covalent chemistry. PMID- 25553735 TI - The use of mass spectrometry imaging to predict treatment response of patient derived xenograft models of triple-negative breast cancer. AB - In recent years, mass spectrometry imaging (MSI) has been shown to be a promising technique in oncology. The effective application of MSI, however, is hampered by the complexity of the generated data. Bioinformatic approaches that reduce the complexity of these data are needed for the effective use in a (bio)medical setting. This holds especially for the analysis of tissue microarrays (TMA), which consist of hundreds of small tissue cores. Here we present an approach that combines MSI on tissue microarrays with principal component linear discriminant analysis (PCA-LDA) to predict treatment response. The feasibility of such an approach was evaluated on a set of patient-derived xenograft models of triple negative breast cancer (TNBC). PCA-LDA was used to classify TNBC tumor tissues based on the proteomic information obtained with matrix-assisted laser desorption ionization (MALDI) MSI from the TMA surface. Classifiers based on two different tissue microarrays from the same tumor models showed overall classification accuracies between 59 and 77%, as determined by cross-validation. Reproducibility tests revealed that the two models were similar. A clear effect of intratumor heterogeneity of the classification scores was observed. These results demonstrate that the analysis of MALDI-MSI data by PCA-LDA is a valuable approach for the classification of treatment response and tumor heterogeneity in breast cancer. PMID- 25553738 TI - Maralynne Mitcham: educator, mentor, and innovator. PMID- 25553740 TI - What is the evidence for the effectiveness of interventions to improve occupational performance after stroke? PMID- 25553739 TI - Advancing the value and quality of occupational therapy in health service delivery. PMID- 25553741 TI - Method for the evidence-based reviews on occupational therapy and stroke. AB - Evidence-based reviews of the literature relevant to adults with stroke are important to the practice of occupational therapy. We describe the four questions that served as the focus for the evidence-based reviews of the effectiveness of occupational therapy interventions for adults with stroke. The questions include occupation- and activity-based interventions to improve occupational performance and social participation after stroke, as well as interventions for motor, cognitive, and psychological and emotional impairments after stroke. We include the background for the reviews; the process followed for addressing each question, including search terms and search strategy; the databases searched; and the methods used to summarize and critically appraise the literature. The final number of articles included in each evidence-based review; a summary of the themes of the results; the strengths and limitations of the findings; and implications for practice, education, and research are presented. PMID- 25553742 TI - Effectiveness of interventions to improve occupational performance of people with motor impairments after stroke: an evidence-based review. AB - We conducted a review to determine the effectiveness of interventions to improve occupational performance in people with motor impairments after stroke as part of the American Occupational Therapy Association's Evidence-Based Practice Project. One hundred forty-nine studies met inclusion criteria. Findings related to key outcomes from select interventions are presented. Results suggest that a variety of effective interventions are available to improve occupational performance after stroke. Evidence suggests that repetitive task practice, constraint-induced or modified constraint-induced movement therapy, strengthening and exercise, mental practice, virtual reality, mirror therapy, and action observation can improve upper-extremity function, balance and mobility, and/or activity and participation. Commonalities among several of the effective interventions include the use of goal-directed, individualized tasks that promote frequent repetitions of task-related or task-specific movements. PMID- 25553743 TI - Effectiveness of interventions to improve occupational performance of people with cognitive impairments after stroke: an evidence-based review. AB - This evidence-based review was conducted to determine which interventions are effective in improving occupational performance after stroke. Forty-six articles met the inclusion criteria and were examined. Interventions for the following impairments were reviewed: general cognitive deficits, executive dysfunction, apraxia, memory loss, attention deficits, visual field deficits (included because of their close relationship with neglect), and unilateral neglect. Evidence is available from a variety of clinical trials to guide interventions regarding general cognition, apraxia, and neglect. The evidence regarding interventions for executive dysfunction and memory loss is limited. There is insufficient evidence regarding impairments of attention and mixed evidence regarding interventions for visual field deficits. The effective interventions have some commonalities, including being performance focused, involving strategy training, and using a compensatory as opposed to a remediation approach. The implications of the findings for practice, research, and education are discussed. PMID- 25553744 TI - Effectiveness of interventions for adults with psychological or emotional impairment after stroke: an evidence-based review. AB - This evidence-based review was conducted to evaluate the effectiveness of occupational therapy interventions to prevent or mitigate the effects of psychological or emotional impairments after stroke. Thirty-nine journal articles met the inclusion criteria. Six types of interventions were identified that addressed depression, anxiety, or mental health-related quality of life: exercise or movement based, behavioral therapy and stroke education, behavioral therapy only, stroke education only, care support and coordination, and community-based interventions that included occupational therapy. Evidence from well-conducted research supports using problem-solving or motivational interviewing behavioral techniques to address depression. The evidence is inconclusive for using multicomponent exercise programs to combat depression after stroke and for the use of stroke education and care support and coordination interventions to address poststroke anxiety. One study provided support for an intensive multidisciplinary home program in improving depression, anxiety, and health related quality of life. The implications of the findings for practice, research, and education are discussed. PMID- 25553746 TI - Sensory integration and praxis patterns in children with autism. AB - OBJECTIVE: We sought to characterize sensory integration (SI) and praxis patterns of children with autism spectrum disorder (ASD) and discern whether these patterns relate to social participation. METHOD: We extracted Sensory Integration and Praxis Tests (SIPT) and Sensory Processing Measure (SPM) scores from clinical records of children with ASD ages 4-11 yr (N=89) and used SIPT and SPM standard scores to describe SI and praxis patterns. Correlation coefficients were generated to discern relationships among SI and praxis scores and these scores' associations with SPM Social Participation scores. RESULTS: Children with ASD showed relative strengths in visual praxis. Marked difficulties were evident in imitation praxis, vestibular bilateral integration, somatosensory perception, and sensory reactivity. SPM Social Participation scores were inversely associated with areas of deficit on SIPT measures. CONCLUSION: Children with ASD characteristically display strengths in visuopraxis and difficulties with somatopraxis and vestibular functions, which appear to greatly affect participation. PMID- 25553747 TI - Efficacy of a Crisis Intervention in Improving Mother-Child Interaction and Children's Play Functioning. AB - OBJECTIVE: We examined the efficacy of a crisis-based intervention in improving mother-child interaction and children's play functioning for families who had experienced domestic violence. METHOD: Using a pretest-posttest two-group control study design, we assigned the intervention group (n=20 mother-child dyads) to the Family Intervention for Improving Occupational Performance (FI-OP) program and the control group (n=17 dyads) to a playroom program. Both programs consisted of eight 30-min sessions. We videotaped dyads during free play and used standardized tools to assess interactions, play skills, and playfulness. RESULTS: After the intervention, mother-child interaction was significantly better in the FI-OP group than in the playroom group. The children in the FI-OP group also demonstrated significantly greater improvement in play skills, but not in playfulness. CONCLUSION: FI-OP is a promising program for improving aspects of mother-child interaction and children's play functioning among survivors of domestic violence. PMID- 25553745 TI - Effectiveness of occupation-based interventions to improve areas of occupation and social participation after stroke: an evidence-based review. AB - This evidence-based review examined the evidence supporting the use of occupation based interventions to improve areas of occupation and social participation poststroke. A total of 39 studies met the inclusion criteria and were critically evaluated. Most of the literature targeted activity of daily living (ADL)-based interventions and collectively provided strong evidence for the use of occupation based interventions to improve ADL performance. The evidence related to instrumental ADLs was much more disparate, with limited evidence to support the use of virtual reality interventions and emerging evidence to support driver education programs to improve occupational performance poststroke. Only 6 studies addressed leisure, social participation, or rest and sleep, with sufficient evidence to support only leisure-based interventions. The implications of this review for research, education, and practice in occupational therapy are also discussed. PMID- 25553748 TI - Sensory processing disorder in children ages birth-3 years born prematurely: a systematic review. AB - This systematic review of multidisciplinary literature synthesizes evidence of the prevalence and patterns of sensory processing disorder (SPD) in children ages birth-3 yr born preterm. Forty-five articles including physiological, behavioral, temperament, and SPD research met the inclusion criteria and provided 295 findings related to SPD-130 (44%) positive (evidence of SPD) and 165 (56%) negative (no evidence of SPD). The majority of findings related to sensory modulation disorder (SMD; 43% positive). The most prevalent subcategory of SMD was sensory overresponsivity (82% of findings positive). Evidence of sensory underresponsivity and sensory-seeking SMD, sensory discrimination disorder, and sensory-based motor disorder was limited. This study supports the education of neonatologists, pediatricians, and caregivers about the symptoms and potential consequences of SPD and helps justify the need for follow-up screening for SPD in children ages birth-3 yr born preterm. Research using measures based on sensory processing theory is needed. PMID- 25553749 TI - Supervision of Occupational Therapy Level II Fieldwork Students: Impact on and Predictors of Clinician Productivity. AB - This study aimed to determine whether a difference in productivity exists between clinicians supervising and not supervising a Level II occupational therapy student and whether factors including clinician years of experience, practice setting, and clinician productivity without a student could predict clinician productivity while supervising a student. We used paired-sample t tests to examine clinician productivity with and without a student in 109 clinician student encounters and regression analysis to determine factors predictive of clinician productivity with a student. Results indicated no difference in clinician productivity with or without a student. Clinician years of experience, practice area, and productivity without a student were significant predictors of clinician productivity while supervising a student. Study results contradict the belief that supervising Level II fieldwork students lowers clinicians' productivity. Findings suggest that practice area and productivity without a student are important factors influencing the productivity of clinicians supervising a fieldwork student. PMID- 25553750 TI - Acquisition of Visual Perception in Blind Adults Using the BrainPort Artificial Vision Device. AB - OBJECTIVE: We sought to determine whether intensive low vision rehabilitation would confer any functional improvement in a sample of blind adults using the BrainPort artificial vision device. METHOD: Eighteen adults ages 28-69 yr (n=10 men and n=8 women) who had light perception only or worse vision bilaterally spent up to 6 hr per day for 1 wk undergoing structured rehabilitation interventions. The functional outcomes of object identification and word recognition were tested at baseline and after rehabilitation training. RESULTS: At baseline, participants were unable to complete the two functional assessments. After participation in the 1-wk training protocol, participants were able to use the BrainPort device to complete the two tasks with moderate success. CONCLUSION: Without training, participants were not able to perform above chance level using the BrainPort device. As artificial vision technologies become available, occupational therapy practitioners can play a key role in clients' success or failure in using these devices. PMID- 25553752 TI - Hand function, experienced pain, and disability after distal radius fracture. AB - OBJECTIVE: We sought to explore differences in range of motion (ROM), grip strength, and self-reported pain and disability over time after plate-fixation surgery for distal radius fracture. METHOD: We used a prospective repeated measures research design with four measure points for a study sample of 101 patients. The Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire; the Global Assessment Scale; and the Canadian Occupational Performance Measure were used to assess ROM, grip strength, and pain level. RESULTS: ROM and grip strength improved over time. Pain improved until 6 mo after surgery but greatly deteriorated from 6 to 24 mo. Concurrently, overall discomfort (global index) from the wrist extensively improved from 12 to 24 mo. DASH score decreased 20.1 points from 6 wk to 6 mo and remained stable until 24 mo. CONCLUSION: Even when ROM and grip strength were almost fully regained at 12 mo, pain at rest and during activity was still an issue at 24 mo. PMID- 25553751 TI - Lifestyle changes and pressure ulcer prevention in adults with spinal cord injury in the pressure ulcer prevention study lifestyle intervention. AB - Pressure ulcers (PrUs) are a major burden to patients with spinal cord injury (SCI), affecting their psychological, physical, and social well-being. Lifestyle choices are thought to contribute to the risk of developing PrUs. This article focuses on the interaction between lifestyle choices and the development of PrUs in community settings among participants in the University of Southern California Rancho Los Amigos National Rehabilitation Center Pressure Ulcer Prevention Study (PUPS II), a randomized controlled trial of a lifestyle intervention for adults with SCI. We conducted a secondary cross-case analysis of treatment notes of 47 PUPS II participants and identified four patterns relating PrU development to lifestyle changes: positive PrU changes (e.g., healing PrUs) with positive lifestyle changes, negative or no PrU changes with positive lifestyle changes, positive PrU changes with minor lifestyle changes, and negative or no PrU changes with no lifestyle changes. We present case studies exemplifying each pattern. PMID- 25553753 TI - Factors predicting client satisfaction in occupational therapy and rehabilitation. AB - Client satisfaction, a widely used outcome indicator of quality in health care, is inherently client centered and important in occupational therapy. We developed an instrument called the Satisfaction With Continuum of Care Revised (SCC-R) and tested a logistic regression model of satisfaction for six predictive research questions. Data collected from 769 clients from a large rehabilitation hospital using the SCC-R were paired with data that included demographics, functional status, and measures of the rehabilitation including occupational therapy. Satisfaction was stratified into two groups, satisfied and dissatisfied. The most robust and consistent predictors of satisfaction were functional status and improvements in functional status, presence of a neurological disorder, total rehabilitation hours, and admission to rehabilitation within 15 days of condition onset. The finding that improvements in functional status, especially self-care, were predictive of satisfaction is particularly relevant for occupational therapy. Implications for practice and future research are discussed. PMID- 25553755 TI - Performance-based testing in mild stroke: identification of unmet opportunity for occupational therapy. AB - Age at first stroke is decreasing, and most strokes are mild to moderate in severity. Executive function (EF) deficits are increasingly recognized in the stroke population, but occupational therapists have not altered their evaluation methods to fully accommodate changing patient needs. We present a hierarchical performance-based testing (PBT) pathway using data to illustrate how PBT could identify patients with mild stroke-related EF deficits in need of occupational therapy intervention. Data suggest that a substantial number of patients with EF deficits after mild stroke could benefit from occupational therapy services. PMID- 25553754 TI - Mental practice--triggered electrical stimulation in chronic, moderate, upper extremity hemiparesis after stroke. AB - OBJECTIVE: To determine the feasibility and impact of home-based, mental practice triggered electrical stimulation among stroke survivors exhibiting moderate upper extremity (UE) impairment. METHOD: Five participants with moderate, stable UE hemiparesis were administered the Fugl-Meyer Assessment, the Box and Block Test, and the Activities of Daily Living, Hand Function, and overall recovery domains of the Stroke Impact Scale (Version 3). They were then administered an 8-wk regimen consisting of 1 hr of mental practice-triggered electrical stimulation every weekday in their home. At the end of every 2 wk, participants attended supervised stimulation to progress therapeutic exercises and stimulation levels and monitor compliance. RESULTS: Six instances of device noncompliance were reported. Participants exhibited reduced UE motor impairment and increased UE dexterity and participation in valued activities. CONCLUSION: The regimen appears feasible and had a substantial impact on UE impairment, dexterity, and participation in valued activities as well as perceptions of recovery. PMID- 25553757 TI - The structure, magnetism and EPR spectra of a (MU-thiophenolato)(MU-pyrazolato N,N') double bridged dicopper(II) complex. AB - A new binuclear copper(ii) complex, namely [Cu2L(pz)(DMSO)], where L = 2,6-bis[(2 phenoxy)iminomethyl]-4-methylthiophenolate(3-) and pz = pyrazolate ligand, has been synthesized by a one-pot synthesis involving copper(ii) acetate monohydrate, the S-protected ligand precursor 2-(N,N-dimethylthiocarbamato)-5 methylisophthalaldehyde di-2'-hydroxy anil, (), and pyrazole, in which a metal promoted S-deprotection reaction occurs during the formation of the complex. This was characterized by routine physicochemical studies, single crystal X-ray diffraction and electron paramagnetic resonance (EPR) techniques. The structure analysis reveals that there are copper centres in two different environments, a slightly distorted square planar and a distorted square-pyramidal, arranged in binuclear units. The EPR study of these binuclear units performed at 9.4 GHz in the temperature range between 4 and 293 K shows an antiferromagnetic interaction between Cu(II) ions, and allows evaluating g factors gx = 2.068(1), gy = 2.091(1) and gz = 2.165(1), with = 2.108(1), an exchange coupling parameter J0 = 26(1) cm(-1) (defined as ), and a zero field splitting of the ground triplet state described by D = 86(2) * 10(-4) cm(-1) and E = -48(3) * 10(-4) cm(-1). These results are discussed and compared with the existing literature. PMID- 25553758 TI - Erratum: Moten A, Schafer D, Ferrari M. Redefining global health priorities: Improving cancer care in developing settings. J Glob Health 2014;4: 010304corr1. AB - [This corrects the article on p. 010304 in vol. 4, PMID: 24976959.]. PMID- 25553760 TI - Human kallikrein 10 in surgically removed human pituitary adenomas. AB - OBJECTIVE: Human kallikrein-like peptidase 10 (KLK10), a serine protease, plays an important role in the regulation of cell proliferation and tumor growth. In this work, we investigated KLK10 immunoexpression in various types of surgically removed human pituitary tumors. DESIGN: Specimens were fixed in formalin and embedded in paraffin. Immunostaining was performed by the streptavidin-biotin peroxidase complex protocol using the LSAB+ Kit and a KLK10-specific rabbit polyclonal antibody. RESULTS: Results showed that both treated and untreated prolactin-producing pituitary adenomas and carcinomas as well as TSH-producing pituitary adenomas and carcinomas were conclusively immunopositive for KLK10. Immunostaining was mainly localized in the cytoplasm and was clearly visible in many adenoma cells. In various other tumor types (oncocytoma, gonadotroph, somatotroph adenomas, and carcinomas), cytoplasmic immunopositivity was mild to moderate and seen only in a few unevenly distributed adenoma cells. Immunopositivity in the nuclei of various tumor types, as well as dual cytoplasmic and nuclear localization of KLK10 in some of the tumor types, was an intriguing finding. Immunoexpression in GH-producing adenomas exposed to octreotide, a long-acting somatostatin analog, was significantly increased when compared to unexposed GH-producing tumors. CONCLUSION: More studies are needed to ascertain the role of KLK10 in pituitary tumor development, prognosis, and progression. The question of whether genetic abnormalities and the microenvironment can affect KLK10 immunoexpression should also be investigated. PMID- 25553759 TI - Gonadotropin releasing hormone analog treatment in children with congenital adrenal hyperplasia complicated by central precocious puberty. AB - OBJECTIVE: Congenital adrenal hyperplasia (CAH) can be complicated by central precocious puberty (CPP) in children, which may compromise final height. We aimed to evaluate the effect of gonadotropin-releasing hormone analog (GnRHa) therapy on growth in children with CAH. DESIGN: Twelve children with CAH were enrolled in a follow-up study. Eight patients underwent the GnRH stimulation test. GnRHa treatment was administered at 3.75 mg every 4 weeks; the dose had to be increased to 7.5 mg in three patients. Bone age, growth velocities and body mass index of the patients were monitored during treatment. RESULTS: Median chronologic age and bone age at diagnosis were 6.8 (3.5) years and 11 (1.2) years, respectively. Median follow-up was 4.4 (4.9) years. A significant difference was found in the median ratio of bone age to chronological age between diagnosis and last visit (p=0.005) and between the beginning of GnRHa treatment and last visit (p=0.004). Median growth velocity was 4 (2.5) cm, 3.4 (5.2) cm and 5.5 (5.5) cm at the end of the first, second and third years of the therapy, respectively. Second-year growth velocity was inversely correlated with median bone age at diagnosis (rho: 0.758, p=0.004) and at the initiation of therapy (rho:-0.876, p<0.001). CONCLUSION: GnRHa therapy should be considered for augmentation of linear growth and diminishment of bone age advancement in children with CAH complicated by CPP, particularly in children who do not have extremely advanced bone age for chronological age. PMID- 25553761 TI - Does metformin have a "buffer effect" on serum TSH levels in euthyroid diabetic patients? AB - OBJECTIVE: In the last few years a number of studies have found that metformin has a thyrotropin (TSH)-lowering effect in patients with type 2 diabetes (DM2) and that this effect disappears after discontinuation of the drug. Initial studies were carried out in hypothyroid patients on levothyroxine (LT4) treatment. However, this effect was observed only when serum TSH levels were elevated. The aim of this study was to assess the effect of metformin treatment on serum TSH levels in euthyroid DM2 patients. DESIGN: A retrospective study was conducted in seven primary health care centers in Spain. The study included 278 DM2 patients (110 females). Serum TSH level was tested before and one year after the onset of metformin treatment. We compared both TSH levels by paired t-tests. The sample was divided into four hierarchical clusters (C1 to C4), according to the Euclidean distance of the initial TSH level. No patient received LT4 treatment. RESULTS: Pre-metformin serum TSH level (2.00 +/- 0.76 mU/L) was statistically significantly lower than post-metformin level (2.20 +/- 0.87 mU/L; P <0.001). Interestingly, this trend was observed only in clusters 1 and 2 (those with lower baseline TSH levels), whereas the trend was lost in clusters 3 and 4. The difference between pre- and post-metformin TSH levels follows a mathematical model. According to this model, the TSH threshold point level is 3.00 mU/L. CONCLUSION: Metformin seems to induce a "buffer effect" on TSH secretion in euthyroid diabetic individuals. Hence, our study found an unreported TSH behavior after metformin treatment. PMID- 25553762 TI - White blood cells levels and PCOS: direct and indirect relationship with obesity and insulin resistance, but not with hyperandogenemia. AB - OBJECTIVE: To study white blood cells count (WBC) in women suffering from PCOS and compare these results with age and BMI-matched healthy women. The specific aim of this study was to assess the possible correlations of WBC with the major components of PCOS, obesity, insulin resistance and hyperandrogenism. DESIGN: Anthropometrical, metabolic and hormonal data were analyzed from 203 women with PCOS (NIH criteria) and 76 age-matched controls. RESULTS: In the total population studied (N=279), WBC was significantly higher (P=0.003) in the PCOS group compared with age-matched healthy women and was positively correlated with BMI (r=0.461, p<0.001), total testosterone (r= 0.210, p<0.001), insulin (r=0.271, p<0.001), triglycerides (r=0.285, p<0.001), HOMA score (r=0.206, p=0.001), FAI (r=0.329, p<0.001) and negatively correlated with SHBG (r=-0.300, p<0.001) and HDL (r=-0.222, p<0.001). Due to the fact that WHR was only available in the group of PCOS women, the role of central adiposity is assessed only in this group. Multiple regression analysis in the PCOS group, including WHR, revealed BMI, SHBG and TGL as the main predicting factors of WBC. Multinomial logistic regression analysis was also conducted and overweight/obesity was the sole independent risk factor for elevated WBC (higher tertile) (OR:0.907 CI:0.85-0.96, p=0.002). After dividing the sample based on BMI in the lean subgroups, WBC did not differ significantly between PCOS and controls, while multiple regression analysis indicated SHBG as the main predicting factor of WBC. Finally, we picked out the group of overweight/obese (BMI >=25 kg/m2) women with PCOS and conducted another classification based on HOMA score (HOMA-IR<=2: insulin-sensitive women, HOMA IR>2: insulin-resistant women) in the group of overweight and obese women with PCOS separately. In overweight women with PCOS, WBC, although higher in the group of insulin-resistant, did not differ significantly between the two groups, while in the subcategory of overweight women WBC was significantly (p=0.02) higher in the group of insulin-resistant women (HOMA-IR >2). CONCLUSIONS: Chronic low-grade inflammation and increased white cell count do occur in PCOS. Obesity and insulin resistance are the two leading parameters that act accumulatively in the development of leucocytosis, whereas hyperandrogenism does not seem to affect it. PMID- 25553763 TI - Relationship between salivary and serum testosterone levels in response to different exercise intensities. AB - The anabolic hormone testosterone (T) continues to be researched extensively in exercise studies, with blood serum or plasma samples collected routinely. This method is considered both valid and reliable; however, the collection process can be invasive and difficult during exercise. For this reason, non-invasive sampling, such as saliva collections, is increasing in popularity. PURPOSE: To investigate the association between salivary and serum T before and after various intensities of exercise to assess the validity of saliva collection for T measurement. METHODS: 12 endurance-trained males (Mean +/- SD; VOVO2max 58.2 +/- 6.4 ml/kg/min, 22 +/- 4.6 years, BMI 21.6 +/- 1.9) completed three 30-minute exercise (cycling) sessions at 40% (Low), 60% (Moderate), and 80% (High) of VO2max as well as a 30-minute resting Control session on four separate days. Salivary (s) and serum (S) samples were assessed for T prior to (Pre), immediately post (Post), and 30 minutes post (30 Min Post) each session. RESULTS: Low exercise caused a significant (p<0.05) increase in ST, but not sT, while Moderate and High exercise caused an increase (p<0.01) in both ST and sT. A strong positive correlation (Spearman [rs]) existed between sT and ST in the Moderate (rs = 0.912 [p<0.001; n=36; 12 subjects x 3 measurement times-samples]), and High (rs = 0.898 [p<0.001]) sessions, but not as strong for the Low (rs = 0.517 [p=0.001]) session. CONCLUSIONS: These results suggest that sT and ST levels are strongly associated to exercise. However, the exercise-related sT and ST responses-changes were more closely aligned at Moderate and High intensities, suggesting a greater validity between the saliva and serum responses to higher intensity exercise. PMID- 25553764 TI - Predictors of post-traumatic pituitary failure during long-term follow-up. AB - OBJECTIVE: There is increasing awareness among physicians of the risks of traumatic brain injury (TBI)-induced hypopituitarism. We have assessed the prevalence and risk factors of post-traumatic hypopituitarism by analyzing the TBI database of the University of Pecs. DESIGN: This consecutive analysis of 126 TBI survivors (mean age: 42.4 years, average follow-up time: 48 months) revealed that 60.3% had severe and 39.7% moderately severe trauma based on GCS score. Subdural hemorrhage (29.3%) and diffuse injury (27%) were the most common types of injury; 17.5% of patients suffered basal skull fractures. RESULTS: The prevalence of major anterior pituitary failure was 57.1%. Occurrence of total and partial growth hormone deficiency (GHD/GHI) was 39.7%, while LH/FSH, TSH and ACTH deficiencies were less frequent, namely 23.0%, 16.7% and 10.3%, respectively. Of the 82 patients with multiple endocrine evaluations, 31.7% presented significant changes in hormonal deficiencies during the follow-up period: new hormone deficiencies developed in 16 patients, while hormonal disturbances resolved in 10 subjects. Looking for factors influencing the prevalence of pituitary dysfunction, endocrine results were analyzed in relation to age, gender, GCS scores, injury types, basal skull fracture, ventricular drain insertion and necessity of neurosurgical intervention. All hormonal disturbances were more prevalent after severe trauma (OR: 3.25, p=0.002), while the need for surgery proved to be an independent determinant of multiple and GH deficits (OR: 3.72 (p=0.004) and 9.33 (p=0.001)). CONCLUSION: Post-traumatic hypopituitarism is common and may evolve or resolve over time. Victims of severe TBI and/or patients who have undergone neurosurgical intervention for head injury are the most prone to post-traumatic hypopituitarism. PMID- 25553765 TI - Olfactory dysfunction in children with Kallmann syndrome: relation of smell tests with brain magnetic resonance imaging. AB - OBJECTIVE: Kallmann syndrome (KS) is a genetic disorder with the distinctive features of hyposmia or anosmia and hypogonadotropic hypogonadism. Though hyposmia/anosmia can be evaluated by both objective and subjective smell tests, there is no study comparing these two methods in KS. The aim of the present case series was to discuss the results of objective and subjective smell tests and compare them to volumetric magnetic resonance imaging (MRI). METHODS: A total of six adolescent males (aged between 14-18 years) with KS were examined by objective and subjective olfactometry to test smell function and by specific MRI sequences to measure the olfactory bulbs. RESULTS: The objective smell test showed anosmia in all six of the patients. However, the subjective test revealed anosmia in five patients and hyposmia in one patient. Brain MRI showed olfactory bulb aplasia in all six cases. CONCLUSION: MRI provides robust evaluation of the olfactory bulb volume. Our data show excellent compatibility between the results obtained via objective olfactometry and those obtained by measuring olfactory bulb volume as determined by MRI and therefore demonstrate that objective olfactometry remains a highly reliable test. Furthermore, although the number of subjects studied was small, these data also suggest that cheaper and more easily available subjective tests could be used in preference to the more expensive as well as labor-intensive and time-consuming objective smell tests. In the event of doubts as to the validity of the subjective tests, the objective olfactometry tests can confirm the diagnosis. The bulb volumetric MRI may be also used in difficult cases. PMID- 25553766 TI - Severe resistant hypoglycemia in a patient with a pancreatic neuroendocrine tumor on sunitinib treatment. AB - OBJECTIVE: Sunitinib is a tyrosine kinase inhibitor used in the therapy of pancreatic neuroendocrine tumors (PNETs), metastatic renal cancer and gastrointestinal stromal tumors. We describe a patient with PNET who presented with severe hypoglycemia following sunitinib administration. CASE REPORT: A 64 year old man with known metastatic PNET presented with a history of recurring episodes of severe, life-threatening hypoglycemia 3 months after initiation of sunitinib treatment. Investigations during symptomatic hypoglycemia revealed inappropriately increased plasma insulin and C-peptide levels, consistent with endogenous hyperinsulinemia. No immune staining for insulin was observed in tissue samples from peritoneal metastatic tumor lesions, and serum anti-insulin antibodies were negative. Medical management with diazoxide, methylprednisolone and ocreotide was ineffective; continuous intravenous infusion of glucagon was required to maintain euglycemia. Following discontinuation of sunitinib there was gradual improvement in both the severity and frequency of the hypoglycemia. Six months later, the patient remained free of hypoglycemic episodes. CONCLUSIONS: We describe a patient with PNET who experienced severe, life-threatening hypoglycemia following sunitinib use. It is important that glucose levels of patients treated with sunitinib are monitored on a regular basis; those patients with diabetes may need to have their antidiabetic treatment adjusted to prevent hypoglycemia. PMID- 25553767 TI - European Thyroid Association guidelines in comparison with the American Thyroid Association and Endocrine Society practice guidelines for the screening and treatment of hypothyroidism during pregnancy. PMID- 25553768 TI - The philosopher Socrates had exophthalmos (a term coined by Plato) and probably Graves' disease. AB - According to a previously published theory, Socrates was afflicted with temporal lobe epilepsy since his childhood. Plato, Xenophon, and Aristoxenus described Socrates as having exophthalmos, probably diplopia, and some symptoms compatible with hyperthyroidism. Using these data, we theorize that Socrates had Graves' disease. In order to determine a cause of his temporal lobe epilepsy, we speculate that the philosopher also had autoimmune thyroiditis and Hashimoto encephalopathy during his childhood and his epilepsy may have been a sequel to this hypothesized encephalopathy. PMID- 25553769 TI - Reversal of dilated cardiomyopathy after glucagonoma excision. PMID- 25553770 TI - Alterations in maxillary sinus volume among oral and nasal breathers. AB - BACKGROUND: Oral breathing causes many changes in the facial anatomical structures in adult patients. In this study we aimed to determine the effects of long-term oral breathing (>5 years) on the maxillary sinus volumes among adult male patients. MATERIAL/METHODS: We accessed medical records of 586 patients who had undergone cone beam computed tomography (CBCT) for any reason between September 2013 and April 2014. Patients who had undergone cone-beam dental volumetric tomography scans for any reason and who had answered a questionnaire about breathing were screened retrospectively. Cone beam dental volumetric tomography (I-Cat, Imaging Sciences International, Hatfield, PA, USA) was used to take the images of the maxillo-facial area at a setting of 120 kVp and 3.7 mA. This study involved male patients older than 21 years of age. RESULTS: The study included a total of 239 male patients, of which 68 were oral breathers and 171 were nasal breathers. The mean age of the oral breathers was 48.4 years and that of the nasal breathers was 46.7 years and the difference was not statistically significant (p>0.05). The mean maxillary sinus volumes of the oral and nasal breathers were 9043.49+/-1987.90 and 10851.77+/-2769.37, respectively, and the difference in maxillary sinus volume between the 2 groups was statistically significant (p<0.001). CONCLUSIONS: The volume of maxillary sinus in oral breathers (>5 years) was significantly lower than in nasal breathers, but it remains unclear whether this is due to malfunctioning of the nasal cavity or due to the underlying pathological condition. PMID- 25553772 TI - Farnesoid x receptor in human metabolism and disease: the interplay between gene polymorphisms, clinical phenotypes and disease susceptibility. AB - INTRODUCTION: Farnesoid x receptor (FXR) belongs to the group of nuclear receptors (NRs), which regulate the expression of various genes by binding to DNA either as a monomer or a heterodimer with retinoid x receptor. AREAS COVERED: FXR affects several metabolic pathways through its specific target genes, regulating bile acid (BA) synthesis and homeostasis, glucose and lipid metabolism, also exhibiting a crucial role in intestinal bacterial growth and liver regeneration. Additionally, FXR is involved in the pathogenesis of different cholestatic diseases, as well as non-alcoholic fatty liver disease, inflammatory bowel disease (IBD) and primary idiopathic BA malabsorption. EXPERT OPINION: Analyses of certain FXR polymorphisms revealed associations with clinical phenotypes and susceptibility to various human diseases. FXR single-nucleotide polymorphisms seem to be correlated with differences in glucose homeostasis, gallstone formation, intrahepatic cholestasis of pregnancy, IBD and therapeutic response to hypolipidemic therapy, among studied populations. Unfortunately, little data are still available and more studies remain to be done to determine the contribution of FXR polymorphisms in estimating risk factors and clinical outcomes for several diseases. PMID- 25553771 TI - Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform. AB - The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development--rodent models--and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work. PMID- 25553773 TI - Characterisation of alpha-chitin extracted from a lichenised fungus species Xanthoria parietina. AB - Lichens are symbiotic associations formed mainly by ascomycete fungi and green algae or cyanobacteria. The presence of chitin in the fungal cell wall has been revealed by previous studies. Considering the presence of fungi in the lichens, this work determines the presence of chitin in a cosmopolitan lichen species Xanthoria parietina. In this study, chitin was derived from a lichen species for the first time and its physicochemical properties were determined by Fourier transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, scanning electron microscopy and elemental analysis. The dry weight chitin content of X. parietina was 4.23%, and this chitin was in the alpha-form. The crystalline index value of the lichen chitin was calculated as 70.1%. The chitin from X. parietina had a smooth surface. PMID- 25553774 TI - Effect of gender on trunk and pelvis control during lateral movements with perturbed landing. AB - In lateral reactive movements, core stability may influence knee and hip joint kinematics and kinetics. Insufficient core stabilisation is discussed as a major risk factor for anterior cruciate ligament (ACL) injuries. Due to the higher probability of ACL injuries in women, this study concentrates on how gender influences trunk, pelvis and leg kinematics during lateral reactive jumps (LRJs). Perturbations were investigated in 12 men and 12 women performing LRJs under three different landing conditions: a movable landing platform was programmed to slide, resist or counteract upon landing. Potential group effects on three dimensional trunk, pelvic, hip and knee kinematics were analysed for initial contact (IC) and the time of peak pelvic medial tilt (PPT). Regardless of landing conditions, the joint excursions in the entire lower limb joints were gender specific. Women exhibited higher trunk left axial rotation at PPT (women: 4.0 +/- 7.5 degrees , men: -3.1 +/- 8.2 degrees ; p = 0.011) and higher hip external rotation at both IC and PPT (p < 0.01). But women demonstrated higher knee abduction compared to men. Men demonstrated more medial pelvic tilt at IC and especially PPT (men: -5.8 +/- 4.9 degrees , women: 0.3 +/- 6.3 degrees ; p = 0.015). Strategies for maintaining trunk, pelvis and lower limb alignment during lateral reactive movements were gender-specific; the trunk and hip rotations displayed by the women were associated with the higher knee abduction amplitudes and therefore might reflect a movement strategy which is associated with higher injury risk. However, training interventions are needed to fully understand how gender-specific core stability strategies are related to performance and knee injury. PMID- 25553776 TI - A kinetic study of the CH2OO Criegee intermediate self-reaction, reaction with SO2 and unimolecular reaction using cavity ring-down spectroscopy. AB - Criegee intermediates are important species formed during the ozonolysis of alkenes. Reaction of stabilized Criegee intermediates with various species like SO2 and NO2 may contribute significantly to tropospheric chemistry. In the laboratory, self-reaction can be an important loss pathway for Criegee intermediates and thus needs to be characterized to obtain accurate bimolecular reaction rate coefficients. Cavity ring-down spectroscopy was used to perform kinetic measurements for various reactions of CH2OO at 293 K and under low pressure (7 to 30 Torr) conditions. For the reaction CH2OO + CH2OO (8), a rate coefficient k8 = (7.35 +/- 0.63) * 10(-11) cm(3) molecule(-1) s(-1) was derived from the measured CH2OO decay rates, using an absorption cross section value reported previously. A rate coefficient of k4 = (3.80 +/- 0.04) * 10(-11) cm(3) molecule(-1) s(-1) was obtained for the CH2OO + SO2 (4) reaction. An upper limit for the unimolecular CH2OO loss rate coefficient of 11.6 +/- 8.0 s(-1) was deduced from studies of reaction (4). SO2 catalysed CH2OO isomerization or intersystem crossing is proposed to occur with a rate coefficient of (3.53 +/- 0.32) * 10(-11) cm(3) molecule(-1) s(-1). PMID- 25553775 TI - The levonorgestrel-releasing intrauterine system for endometrial protection during estrogen replacement therapy: a clinical review. AB - Estrogen replacement therapy (ERT) is a well-established method of managing climacteric symptoms in women approaching the menopause, but it is associated with a significant risk of endometrial hyperplasia if unopposed by concomitant progestogen administration. The levonorgestrel-releasing intrauterine system (LNG IUS) offers a highly effective method of minimizing this risk and has additional benefits beyond endometrial protection. The LNG-IUS provides excellent contraception, which may still be necessary in perimenopausal women, and is suitable for women with underlying conditions that may preclude their use of estrogen-containing contraceptive methods. It can effectively manage bleeding problems through the transition from perimenopause into menopause, with many women developing amenorrhea. The LNG-IUS is well tolerated with a favorable safety profile, which generally mirrors that of women of reproductive age using it for contraception only. Moreover, the LNG-IUS plus ERT combination does not appear to be associated with clinically relevant effects on plasma lipids or other markers of cardiovascular risk. Women using the LNG-IUS plus ERT also experience improvements in quality of life, and adherence and continuation rates are high. This review will summarize the clinical evidence for the use of the LNG IUS plus ERT in peri- and postmenopausal women and present the key attributes of this combined therapy. PMID- 25553777 TI - Surface-enhanced spectroscopy on plasmonic oligomers assembled by AFM nanoxerography. AB - Surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF) from individual plasmonic oligomers are investigated by confocal Raman micro spectroscopy and time-resolved fluorescence microscopy coupled to steady state micro-spectroscopy. The nanoparticle (NP) oligomers are made of either ligand protected Au or Au@SiO2 core-shell colloidal NPs, which were assembled into ordered arrays by atomic force microscopy (AFM) nanoxerography. A strong dependence of the SERS emission on the polarization of incident light relative to the specific geometry of the plasmonic oligomer was observed. The SEF studies, performed on a large collection of NP oligomers of various known configurations showed interesting fluorophore decay rate modification and red-shift of the emission spectra. The experimental results are analyzed theoretically by employing finite-difference time-domain (FDTD) simulations on equivalent realistic structures, within the local density of optical states (LDOS) framework. The presented results, together with the proven potential of the LDOS approach as a useful common tool for analyzing both SERS and SEF effects further the general understanding of plasmon-related phenomena in nanoparticle oligomers. PMID- 25553778 TI - Integration of behavioural and medical care: what was old is new again. PMID- 25553779 TI - What is integrated care? AB - Increasing awareness of mental illness's impact on medical and psychiatric health has accelerated global efforts to integrate medical and behavioural health services. As the field of integration has advanced, numerous integrated programmes have been implemented. In examining the impact of these programmes, it is important to maintain a standardized vocabulary to describe the various components of their integration. Additionally important is examination of how these programmes impact elements of patient care and the healthcare system. Specifically, what value do they bring? This article will discuss the importance of carefully assessing the value integrated services bring to patients, and questioning whether they do so in ways in which today's segregated world of medical and behavioural health cannot. This article will also explore the various settings in which medical and behavioural integration can bring added value. PMID- 25553780 TI - Using electronic health records to improve the physical healthcare of people with serious mental illnesses: a view from the front lines. AB - Individuals with serious mental illnesses (SMI) treated in the public mental health sector die decades younger than the general population. Poor quality and fragmentation of care are risk factors underlying the poor health of this population. Integrated electronic health records (EHR) can play a vital role in efforts to improve quality and outcomes of care in patients with SMI. The objective of this paper is to describe the current state of efforts to integrate and improve the mental and physical care of individuals with SMI in the public sector, with an emphasis on the use of electronic health records (EHR). While a range of encouraging initiatives exists throughout the country, technological and medico-legal challenges are providing significant barriers for the successful integration of care and EHRs for many partnering organizations. Furthermore, there is a lack of rigorous research studying the effectiveness and sustainability of these programmes. Recommendations are made for the alleviation of policy barriers and future areas of inquiry. PMID- 25553781 TI - Treating complexity: collaborative care for multiple chronic conditions. AB - Individuals with co-morbid chronic medical illness and psychiatric illness are a costly and complex patient population, at high risk for poor outcomes. Health risk behaviours (e.g. smoking, poor diet, and sedentary lifestyle), side effects from psychiatric medications, and poor quality medical care all contribute to poor outcomes. Individuals with major depression die, on average, 5 to 10 years before their age-matched counterparts. For individuals with severe mental illness such as bipolar disorder or schizophrenia, life expectancy may be up to 20 years shorter. As the majority of this premature mortality is due to cardiovascular disease, there is a critical need to engage these individuals around the care of chronic medical illness. PMID- 25553782 TI - Behavioural health interventions in the Johns Hopkins Community Health Partnership: integrated care as a component of health systems transformation. AB - Health systems in the USA have received a mandate to improve quality while reining in costs. Several opportunities have been created to stimulate this transformation. This paper describes the design, early implementation and lessons learned for the behavioural components of the John Hopkins Community Health Partnership (J-CHiP) programme. J-CHiP is designed to improve health outcomes and reduce the total healthcare costs of a group of high healthcare use patients who are insured by the government-funded health insurance programmes, Medicaid and Medicare. These patients have a disproportionately high prevalence of depression, other psychiatric conditions, and unhealthy behaviours that could be addressed with behavioural interventions. The J-CHiP behavioural intervention is based on integrated care models, which include embedding mental health professionals into primary sites. A four-session behaviour-based protocol was developed to motivate self-efficacy through illness management skills. In addition to staff embedded in primary care, the programme design includes expedited access to specialist psychiatric services as well as a community outreach component that addresses stigma. The progress and challenges involved with developing this programme over a relatively short period of time are discussed. PMID- 25553783 TI - Integrated management of major depression for people with cancer. AB - Major depression is an important complication of cancer. However, it is frequently inadequately treated. There are challenges both in identifying which cancer patients are depressed, and in ensuring that these patients receive effective treatment for their depression. Integration of depression management into cancer care has been advocated as a way to address these challenges. Such integrated approaches must include both the systematic identification of cases and the delivery of treatment. We describe here a system of depression care that includes both a screening programme to identify patients with depression and a linked treatment programme, based on the collaborative care model, called 'Depression Care for People with Cancer' (DCPC). The system of care was designed to be fully integrated with specialist cancer services and has been robustly evaluated in randomized trials. We describe how the system operates and explain why it is designed as it is. We also summarize the evidence for its effectiveness and cost-effectiveness and discuss its implementation in routine clinical practice. PMID- 25553784 TI - Integration of mental health into primary healthcare in low-income countries: avoiding medicalization. AB - Since 2008 the World Health Organization (WHO), through its mental health Gap Action Programme, has attempted to revitalize efforts to integrate mental health into non-specialized (e.g. primary) healthcare. While this has led to renewed interest in this potential method of mental health service delivery, it has also prompted criticism. Some concerns raised are that it would contribute to the medicalization of social and psychological problems, and narrowly focus on primary care without sufficient attention given to strengthening other levels of the healthcare system, notably community-based care and care on district levels. This paper discusses seven elements that may be critical to preventing inadvertently contributing to increasing a narrow biomedical approach to mental healthcare when integrating mental health into non-specialized healthcare: (1) using task shifting approaches within a system of stepped care, (2) ensuring primary mental healthcare also includes brief psychotherapeutic interventions, (3) promote community-based recovery-oriented interventions for people with disabling chronic mental disorders, (4) conceptualizing training as a continuous process of strengthening clinical competencies through supervision, (5) engaging communities as partners in psychosocial interventions, (6) embedding shifts to primary mental healthcare within wider health policy reforms, and (7) promoting inter-sectoral approaches to address social determinants of mental health. PMID- 25553785 TI - Olefinic C-H functionalization through radical alkenylation. AB - Direct olefinic C-H functionalization represents the ideal way of introducing an alkenyl group into organic molecules. A well-known process is the Heck reaction, which involves alkene insertion and beta-hydride elimination in the presence of a transition metal. However, the traditional Heck reaction mainly deals with the alkenylation of aryl or vinyl electrophiles. Recent developments have revealed that alkenylation can also be achieved through radical addition to alkenes and following single-electron-transfer (SET) oxidation/elimination. The radical alkenylation pathway allows alkenylation with a variety of carbon-centered radicals and even heteroatom-centered radicals. This tutorial review gives an overview of recent advances in this emerging field. PMID- 25553786 TI - An infrared spectral signature of human lymphocyte subpopulations from peripheral blood. AB - Metastatic melanomas are frequently refractory to most adjuvant therapies such as chemotherapies and radiotherapies. Recently, immunotherapies have shown good results in the treatment of some metastatic melanomas. Immune cell infiltration in the tumor has been associated with successful immunotherapy. More generally, tumor infiltrating lymphocytes (TILs) in the primary tumor and in metastases of melanoma patients have been demonstrated to correlate positively with favorable clinical outcomes. Altogether, these findings suggest the importance of being able to identify, quantify and characterize immune infiltration at the tumor site for a better diagnostic and treatment choice. In this paper, we used Fourier Transform Infrared (FTIR) imaging to identify and quantify different subpopulations of T cells: the cytotoxic T cells (CD8+), the helper T cells (CD4+) and the regulatory T cells (T reg). As a proof of concept, we investigated pure populations isolated from human peripheral blood from 6 healthy donors. These subpopulations were isolated from blood samples by magnetic labeling and purities were assessed by Fluorescence Activated Cell Sorting (FACS). The results presented here show that Fourier Transform Infrared (FTIR) imaging followed by supervised Partial Least Square Discriminant Analysis (PLS-DA) allows an accurate identification of CD4+ T cells and CD8+ T cells (>86%). We then developed a PLS regression allowing the quantification of T reg in a different mix of immune cells (e.g. Peripheral Blood Mononuclear Cells (PBMCs)). Altogether, these results demonstrate the sensitivity of infrared imaging to detect the low biological variability observed in T cell subpopulations. PMID- 25553787 TI - Detection of the nanomolar level of total Cr[(iii) and (vi)] by functionalized gold nanoparticles and a smartphone with the assistance of theoretical calculation models. AB - We report a method for rapid, effective detection of both Cr(iii) and Cr(vi) (in the form of Cr(3+) and Cr2O7(2-), the main species of chromium in the natural environment) by making use of meso-2,3-dimercaptosuccinic acid (DMSA) functionalized gold nanoparticles (Au NPs). The limit of detection (LOD) is 10 nM with the naked eye and the assay can be applied in detecting chromium in polluted soil from Yun-Nan Province in Southwest China. We use density functional theory to calculate the change of the Gibbs free energy (DeltaG) of the interactions between the DMSA-Au NP system and various metal ions, which shows that DMSA-Au NPs have high specificity for both Cr(3+) and Cr2O7(2-). PMID- 25553788 TI - Real-time air monitoring of mustard gas and Lewisite 1 by detecting their in-line reaction products by atmospheric pressure chemical ionization ion trap tandem mass spectrometry with counterflow ion introduction. AB - A new method enabling sensitive real-time air monitoring of highly reactive chemical warfare agents, namely, mustard gas (HD) and Lewisite 1 (L1), by detecting ions of their in-line reaction products instead of intact agents, is proposed. The method is based on corona discharge-initiated atmospheric pressure chemical ionization coupled with ion trap tandem mass spectrometry (MS(n)) via counterflow ion introduction. Therefore, it allows for highly sensitive and specific real-time detection of a broad range of airborne compounds. In-line chemical reactions, ionization reactions, and ion fragmentations of these agents were investigated. Mustard gas is oxygenated in small quantity by reactive oxygen species generated in the corona discharge. With increasing air humidity, the MS(2) signal intensity of protonated molecules of mono-oxygenated HD decreases but exceeds that of dominantly existing intact HD. This result can be explained in view of proton affinity. Lewisite 1 is hydrolyzed and oxidized. As the humidity increases from zero, the signal of the final product, namely, didechlorinated, dihydroxylated, and mono-oxygenated L1, quickly increases and reaches a plateau, giving the highest MS(2) and MS(3) signals among those of L1 and its reaction products. The addition of minimal moisture gives the highest signal intensity, even under low humidity. The method was demonstrated to provide sufficient analytical performance to meet the requirements concerning hygienic management and counter-terrorism. It will be the first practical method, in view of sensitivity and specificity, for real-time air monitoring of HD and L1 without sample pretreatment. PMID- 25553789 TI - In situ quantitation of intracellular microRNA in the whole cell cycle with a functionalized carbon nanosphere probe. AB - A method was designed for in situ quantitation and monitoring of the change in intracellular microRNA in the whole cell cycle with a functionalized carbon nanosphere probe. PMID- 25553792 TI - Biology of IgE production: IgE cell differentiation and the memory of IgE responses. AB - The generation of long-lived plasma cells and memory B cells producing high affinity antibodies depends on the maturation of B cell responses in germinal centers. These processes are essential for long-lasting antibody-mediated protection against infections. IgE antibodies are important for defense against parasites and toxins and can also mediate anti-tumor immunity. However, high affinity IgE is also the main culprit responsible for the manifestations of allergic disease, including life-threatening anaphylaxisAnaphylaxis . Thus, generation of high-affinity IgE must be tightly regulated. Recent studies of IgE B cell biology have unveiled two mechanisms that limit high-affinity IgE memory responses: First, B cells that have recently switched to IgE production are programmed to rapidly differentiate into plasma cells,Plasma cells and second, IgE germinal centerGerminal center cells are transient and highly apoptotic. Opposing these processes, we now know that germinal center-derived IgG B cells can switch to IgE production, effectively becoming IgE-producing plasma cells. In this chapter, we will discuss the unique molecular and cellular pathways involved in the generation of IgE antibodies. PMID- 25553793 TI - Molecular Mechanisms of IgE Class Switch Recombination. AB - Immunoglobulin (Ig) E is the most tightly regulated of all Ig heavy chain (IgH) isotypes and plays a key role in atopic disease. The gene encoding for IgH in mature B cells consists of a variable region exon-assembled from component gene segments via V(D)J recombination during early B cell development-upstream of a set of IgH constant region CH exons. Upon activation by antigen in peripheral lymphoid organs, B cells can undergo IgH class switch recombination (CSR), a process in which the initially expressed IgH MU constant region exons (CMU) are deleted and replaced by one of several sets of downstream CH exons (e.g., Cgamma, Cepsilon, and Calpha). Activation of the IL-4 receptor on B cells, together with other signals, can lead to the replacement of CMU with Cepsilon resulting in CSR to IgE through a series of molecular events involving irreversible remodeling of the IgH locus. Here, we discuss the molecular mechanisms of CSR and the unique features surrounding the generation of IgE-producing B cells. PMID- 25553794 TI - Anti-IgE therapy: clinical utility and mechanistic insights. AB - As the major trigger of acute allergic reactions, IgE has long been considered an ideal target for anti-allergy treatments. Omalizumab, first approved by the USA in 2003 and now in use in many other countries is a humanized monoclonal antibody that binds serum IgE. Anti-IgE therapy using omalizumab reduces circulating free IgE levels and blocks both early and late-phase reactions to allergen challenge. It has proven effective for allergic asthma and is currently being evaluated for use in a number of other atopic conditions including allergic rhinitis and chronic idiopathic urticaria. Clinical observations and mechanistic studies with omalizumab have shed new light on the multifaceted roles of IgE in immune homeostasis and in allergic disease. PMID- 25553795 TI - New insights on the signaling and function of the high-affinity receptor for IgE. AB - Clustering of the high-affinity receptor for immunoglobulin E (FcepsilonRI) through the interaction of receptor-bound immunoglobulin E (IgE) antibodies with their cognate antigen is required to couple IgE antibody production to cellular responses and physiological consequences. IgE-induced responses through FcepsilonRI are well known to defend the host against certain infectious agents and to lead to unwanted allergic responses to normally innocuous substances. However, the cellular and/or physiological response of individuals that produce IgE antibodies may be markedly different and such antibodies (even to the same antigenic epitope) can differ in their antigen-binding affinity. How affinity variation in the interaction of FcepsilonRI-bound IgE antibodies with antigen is interpreted into cellular responses and how the local environment may influence these responses is of interest. In this chapter, we focus on recent advances that begin to unravel how FcepsilonRI distinguishes differences in the affinity of IgE antigen interactions and how such discrimination along with surrounding environmental stimuli can shape the (patho) physiological response. PMID- 25553796 TI - Helminth-induced IgE and protection against allergic disorders. AB - The immune response against helminths and allergens is generally characterized by high levels of IgE and increased numbers of Th2 cells, eosinophils, and mast cells, yet the clinical outcome with respect to immediate hypersensitivity and inflammation is clearly not the same. High levels of IgE are seen to allergens during helminth infections; however, these IgE responses do not translate into allergy symptoms. This chapter summarizes the evidence of the association between helminth infections and allergic disorders. It discusses how helminth infection can lead to IgE cross-reactivity with allergens and how this IgE has poor biological activity. This information is important for developing new diagnostic methods and treatments for allergic disorders in low-to-middle-income countries. PMID- 25553798 TI - An improved procedure to prepare 3-methyl-4-nitroalkylenethylisoxazoles and their reaction under catalytic enantioselective Michael addition with nitromethane. AB - Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding gamma-nitroacids. PMID- 25553799 TI - Enhanced action of apigenin and naringenin combination on estrogen receptor activation in non-malignant colonocytes: implications on sorghum-derived phytoestrogens. AB - Activation of estrogen receptor-beta (ERbeta) is an important mechanism for colon cancer prevention. Specific sorghum varieties that contain flavones were shown to activate ER in non-malignant colonocytes at low concentrations. This study aimed to determine positive interactions among estrogenic flavonoids most relevant in sorghum. Apigenin and naringenin were tested separately and in combination for their ability to influence ER-mediated cell growth in non-malignant young adult mouse colonocytes (YAMC). Sorghum extracts high in specific flavanones and flavones were also tested. Apigenin reduced ER-mediated YAMC cell growth comparable to physiological levels of estradiol (E2, 1 nM) at 1 MUM; naringenin had similar effect at 10 MUM. However, when combined, 0.1 MUM apigenin plus 0.05 MUM naringenin produced similar effect as 1 nM E2; these concentrations represented 1/10th and 1/200th, respectively, of the active concentrations of apigenin and naringenin, demonstrating a strong enhanced action. A sorghum extract higher in flavones (apigenin and luteolin) (4.8 mg g(-1)) was more effective (5 MUg mL(-1)) at activating ER in YAMC than a higher flavanone (naringenin and eriodictyol) (28.1 mg g(-1)) sorghum extract (10 MUg mL(-1)). Enhanced actions observed for apigenin and naringenin were adequate to explain the level of effects produced by the high flavone and flavanone sorghum extracts. Strong positive interactions among sorghum flavonoids may enhance their ability to contribute to colon cancer prevention beyond what can be modeled using target compounds in isolation. PMID- 25553801 TI - Association of serum hepcidin levels with the presence and severity of obstructive sleep apnea syndrome. AB - BACKGROUND: Inflammation is thought to be involved in the pathogenesis of obstructive sleep apnea syndrome (OSAS). Hepcidin, a 25-kD peptide hormone produced by the liver, modulates acute inflammatory responses. This study aimed to determine the association of serum levels of hepcidin with the presence and severity of OSAS. MATERIAL/METHODS: We enrolled 184 patients with OSAS and 110 healthy subjects. Serum levels of hepcidin were evaluated using enzyme-linked immunosorbent assay (ELISA) method. RESULTS: OSAS patients had significantly higher serum hepcidin levels compared with healthy controls. Multivariable logistic regression analysis indicated that serum hepcidin levels were an independent determinant of the presence of OSAS (OR 1.224, 95% CI 1.159-1.292; P<0.001). Serum hepcidin levels were significantly elevated in severe OSAS patients compared with mild and moderate OSAS patients. Spearman correlation analysis revealed that serum hepcidin levels were correlated with the severity of OSAS. In addition, serum levels of hepcidin were correlated with apnea-hypopnea index (AHI) in patients with OSAS. CONCLUSIONS: Elevated serum hepcidin levels are associated with the presence and severity of OSAS. PMID- 25553797 TI - IgE immunotherapy against cancer. AB - The success of antibody therapy in cancer is consistent with the ability of these molecules to activate immune responses against tumors. Experience in clinical applications, antibody design, and advancement in technology have enabled antibodies to be engineered with enhanced efficacy against cancer cells. This allows re-evaluation of current antibody approaches dominated by antibodies of the IgG class with a new light. Antibodies of the IgE class play a central role in allergic reactions and have many properties that may be advantageous for cancer therapy. IgE-based active and passive immunotherapeutic approaches have been shown to be effective in both in vitro and in vivo models of cancer, suggesting the potential use of these approaches in humans. Further studies on the anticancer efficacy and safety profile of these IgE-based approaches are warranted in preparation for translation toward clinical application. PMID- 25553803 TI - Chemical composition, phytotoxic and antifungal properties of Ruta chalepensis L. essential oils. AB - The chemical composition, and phytotoxic and antifungal activities of the essential oils isolated by using hydrodistillation from the aerial parts of Tunisian rue were evaluated. Significant variations were observed among harvest periods. The analysis of the chemical composition by gas chromatography/mass spectrometry showed that 2-undecanone (33.4-49.8%), 2-heptanol acetate (13.5 15.4%) and alpha-pinene (9.8-11.9%) were the main components. The antifungal ability of rue essential oils was tested by using disc agar diffusion against ten plant pathogenic fungi. A high antifungal activity was observed for the essential oil isolated at flowering developmental phase. Furthermore, rue essential oils showed high level of herbicidal activity against several weeds. PMID- 25553802 TI - Age-associated changes in basal NF-kappaB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase. AB - Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-kappaB is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF kappaB -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-kappaB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-kappaB activity may contribute to the mild pro-inflammatory state of aging. PMID- 25553804 TI - Antimicrobial and inhibition on heat-induced protein denaturation of constituents isolated from Polygonatum verticillatum rhizomes. AB - This study was designed to assess the susceptibility of various microorganisms and inhibition on heat-induced protein denaturation against diosgenin and santonin, isolated from Polygonatum verticillatum rhizomes. Both diosgenin and santonin showed significant zone of inhibition when studied against various Gram positive (Bacillus subtilis, Bacillus cereus, Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative bacteria (Escherichia coli and Salmonella typhi). In antifungal assay, only santonin exhibited profound sensitivity against various fungi (Aspergillus flavus, Aspergillus niger, Trichoderma harzianum and Fusarium oxysporum) used in the test. Both diosgenin and santonin also exhibited marked attenuation on heat-induced protein denaturation in a concentration-dependent manner with EC50 values of 375 and 310 MUg/mL, respectively. In conclusion, both the isolated compounds have antimicrobial potential supported by strong inhibition on protein denaturation and thus support the antimicrobial uses of plant in traditional system of treatment. PMID- 25553805 TI - The pharmacokinetics, pharmacodynamics and clinical efficacy of elvitegravir + cobicistat + emtricitabine + tenofovir combination therapy for the treatment of HIV. AB - INTRODUCTION: Co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir (EVG/COBI/FTC/TDF or StribildTM) is the latest antiretroviral tablet approved in the EU. This review aims to provide an overview of its role in the management of HIV-1 infection. AREAS COVERED: This review covers material searched and obtained through Medline and Pubmed up to July 2014. EXPERT OPINION: Antiretroviral treatment prevents the progressive destruction of the immune system by the HIV, significantly reducing morbidity and mortality. The efficacy and tolerability of EVG/COBI/FTC/TDF compared to current standard of care as a single-tablet treatment choice has been shown in study 102 and study 103. Its use is restricted to patients without significant pre-existing renal impairment and may be limited by concomitant medications but undoubtedly increases treatment choice for HIV-1 infected adults. PMID- 25553807 TI - Constraints on dynamic stability during forward, backward and lateral locomotion in skilled football players. AB - The aim of this study was to investigate effects of speed and plane of motion on stability during locomotion in skilled football players. Ten male national-level football players participated in this study to run forward, backward and in lateral directions on a treadmill at 80%, 100% and 120% of their preferred running speeds. The coordinate data of passive reflective markers attached to body segments were recorded using motion capture systems. Time series data obtained from the ankle marker were used for further analyses. The largest finite time Lyapunov exponent and maximum Floquet multiplier were adopted to quantify local and orbital dynamic stabilities, respectively. Results showed that speed did not significantly change local and orbital dynamic stabilities in any of running patterns. However, both local and orbital dynamic stability were significantly higher in the secondary plane of progression. Data revealed that in running, unlike walking, stability in the direction perpendicular to the direction of running is significantly higher, implying that less active control is required in the secondary plane of progression. The results of this study could be useful in sports training and rehabilitation programmes where development of fundamental exercise programmes that challenge both speed and the ability to maintain stability might produce a tangible enhancement of athletic skill level. PMID- 25553806 TI - Periodontitis impacts quality of life in postmenopausal women. AB - AIM: Interrelationships between traditional dental variables are becoming more evident in far-reaching aspects of life such as psychosocial interaction, self esteem, overall health and even occupational performance. This study compares quality of life in postmenopausal women with chronic periodontitis with that of healthy postmenopausal women. METHOD: A total of 128 randomly recruited postmenopausal women received a comprehensive periodontal evaluation and completed the Utian Quality of Life Survey. The participants were divided into healthy and periodontitis groups based on comprehensive periodontal examination. Mean scores were calculated for each quality-of-life item, domain and the overall summary score. Periodontitis patients' quality-of-life outcomes were compared to those of healthy patients using the t-test with threshold of significance at p < 0.05. RESULTS: Quality-of-life scores in all fields measured were significantly poorer in the periodontitis patients compared to the healthy patients, occupational (25.74 +/- 8.25 vs. 21.40 +/- 9.19), health (26.46 +/- 5.93 vs. 19.64 +/- 10.24), emotional (21.04 +/- 10.20 vs. 16.40 +/- 10.84), sexual (9.23 +/- 4.92 vs. 5.96 +/- 5.20), and total score (82.48 +/- 23.74 vs. 63.69 +/- 26.61). CONCLUSION: This study has identified that postmenopausal women with chronic periodontitis report significantly poorer quality of life than healthy patients. Clinicians caring for postmenopausal women should be aware that periodontitis also impacts quality of life when making referral decisions for oral health care. PMID- 25553808 TI - Alternative alcohol-soluble conjugated small molecule electrolytes for high efficiency inverted polymer solar cells. AB - New alcohol-soluble conjugated small molecule electrolytes (CSMEs), 3,6-bis-(5 benzoic acid-thiophen-2-yl)-2,5-bis-(2-ethylhexyl)-2,5-dihydro-pyrrolo[3,4 c]pyrrole-1,4-dione liquid crystalline (DPP-COOH) and di-tetrabutylammonium cis bis(isothiocyanato)bis(2,2'-bipyridyl-4,4'-dicarboxylato)ruthenium(II) dye (N719), are developed as interfacial modification in inverted polymer solar cells (PSCs). Further optimization of the device architecture by combining the electrolytes as hole and electron buffer layers can significantly promote the photovoltaic performances of PSCs due to the integrated advantages of excellent alcohol processability, hole and electron mobility, interfacial dipole effect and good energy level alignment with electrodes. Moreover, the PSCs with the CSMEs interlayers based on narrow band-gap PTB7:PC71BM active layers show considerable improvement in power conversion efficiency (PCE), compared with P3HT:PCBM active layer-based devices. Devices with DPP-COOH and N719 modifications after thermal treatment at 120 degrees C exhibit the PCE of 8.0% and 7.6% under AM 1.5G irradiation, respectively, improving from 6.7% PCE of the pristine device without any interfacial layer. Encouragingly, the simultaneous use of CSMEs as hole and electron modification layers can boost the PCE to 8.2%. These findings demonstrate that the utilization of alcohol-soluble small molecule conjugated electrolytes with lower band gaps as interfacial modification layers is an effective and practical strategy for improving photovoltaic performance in PSCs. PMID- 25553809 TI - What are the active carbon species during graphene chemical vapor deposition growth? AB - The dissociation of carbon feedstock is a crucial step for understanding the mechanism of graphene chemical vapor deposition (CVD) growth. Using first principles calculations, we performed a comprehensive theoretical study for the population of various active carbon species, including carbon monomers and various radicals, CHi (i = 1, 2, 3, 4), on four representative transition-metal surfaces, Cu(111), Ni(111), Ir(111) and Rh(111), under different experimental conditions. On the Cu surface, which is less active, the population of CH and C monomers at the subsurface is found to be very high and thus they are the most important precursors for graphene CVD growth. On the Ni surface, which is more active than Cu, C monomers at the subsurface dominate graphene CVD growth under most experimental conditions. In contrast, on the active Ir and Rh surfaces, C monomers on the surfaces are found to be very stable and thus are the main precursors for graphene growth. This study shows that the mechanism of graphene CVD growth depends on the activity of catalyst surfaces and the detailed graphene growth process at the atomic level can be controlled by varying the temperature or partial pressure of hydrogen. PMID- 25553810 TI - Diastereoselective desymmetrization of diarylphosphinous acid-borane amides under Birch reduction. AB - Treatment of diarylphosphinous acid-borane amides possessing chiral amido functionality with an alkali metal solution in liquid ammonia induced a preferential dearomatization of one aryl substituent at phosphorus leading to the formation of non-equimolar amounts of diastereomers. Diastereoselectivity of dearomatization depends strongly on the structure of a chiral auxiliary. PMID- 25553811 TI - AKSmooth: enhancing low-coverage bisulfite sequencing data via kernel-based smoothing. AB - Whole-genome bisulfite sequencing (WGBS) is an approach of growing importance. It is the only approach that provides a comprehensive picture of the genome-wide DNA methylation profile. However, obtaining a sufficient amount of genome and read coverage typically requires high sequencing costs. Bioinformatics tools can reduce this cost burden by improving the quality of sequencing data. We have developed a statistical method Ajusted Local Kernel Smoother (AKSmooth) that can accurately and efficiently reconstruct the single CpG methylation estimate across the entire methylome using low-coverage bisulfite sequencing (Bi-Seq) data. We demonstrate the AKSmooth performance on the low-coverage (~ 4 *) DNA methylation profiles of three human colon cancer samples and matched controls. Under the best set of parameters, AKSmooth-curated data showed high concordance with the gold standard high-coverage sample (Pearson 0.90), outperforming the popular analogous method. In addition, AKSmooth showed computational efficiency with runtime benchmark over 4.5 times better than the reference tool. To summarize, AKSmooth is a simple and efficient tool that can provide an accurate human colon methylome estimation profile from low-coverage WGBS data. The proposed method is implemented in R and is available at https://github.com/Junfang/AKSmooth. PMID- 25553812 TI - IPED2X: a robust pedigree reconstruction algorithm for complicated pedigrees. AB - Reconstruction of family trees, or pedigree reconstruction, for a group of individuals is a fundamental problem in genetics. Some recent methods have been developed to reconstruct pedigrees using genotype data only. These methods are accurate and efficient for simple pedigrees which contain only siblings, where two individuals share the same pair of parents. A most recent method IPED2 is able to handle complicated pedigrees with half-sibling relationships, where two individuals share only one parent. However, the method is shown to miss many true positive half-sibling relationships as it removes all suspicious half-sibling relationships during the parent construction process. In this work, we propose a novel method IPED2X, which deploys a more robust algorithm for parent construction in the pedigrees by considering more possible operations rather than simple deletion. We convert the parent construction problem into a graph labeling problem and propose a more effective labeling algorithm. We show in our experiments that IPED2X is more powerful on capturing the true half-sibling relationships, which further leads to better reconstruction accuracy. PMID- 25553814 TI - [Mn2Ga4Sn4S20](8-) T3 supertetrahedral nanocluster directed by a series of transition metal complexes. AB - With different transition metal (TM) complexes as structure directing agents or building units, three new multinary chalcognidometalates based on T3 supertetrahedral nanocluster of [Mn2Ga4Sn4S20](8-) have been solvothermally synthesized and structurally characterized. In compound Mn2Ga4Sn4S20[Mn2(en)5]2.4H2O (, en = ethylenediamine), the neighboring [Mn2Ga4Sn4S20](8-) cores were bridged by two pairs of [Mn2(en)5](4+) complex cations via Mn-S bonds to form one-dimensional (1D) neutral chains. Compound Mn2Ga4Sn4S20[Mn(dien)2]4.2H2O (, dien = diethylenetriamine) contained discrete [Mn2Ga4Sn4S20](8-) cores separated by [Mn(dien)2](2+) cations. In compound Mn2Ga4Sn4S20[Mn(teta)]4 (, teta = triethylenetetramine), each [Mn2Ga4Sn4S20](8-) core was covalently attached by four [Mn(teta)](2+) complexes via terminal Mn-S bonds to form a neutral isolated cluster. The photocatalytic experiments indicate that compound was able to degrade rhodamine B (RhB) and crystal violet (CV) under visible irradiation. Furthermore, the luminescence properties and thermal stabilities of the title compounds, as well as the second-order nonlinear optical property of were also studied. PMID- 25553815 TI - Parasites infecting the cultured oyster Crassostrea gasar (Adanson, 1757) in Northeast Brazil. AB - The oyster Crassostrea gasar is a species widely used as food and a source of income for the local population of the estuaries of Northeast Brazil. Perkinsus marinus and Perkinsus olseni are deleterious parasites for oyster farming and were recently detected in Brazil. In this study, a histopathologic survey of the oyster C. gasar cultured in the estuary of the River Mamanguape (Paraiba State) was performed. Adult oysters were collected in December 2011 and March, May, August and October 2012 and processed for histology and Perkinsus sp. identification by molecular analyses. Histopathological analysis revealed the presence of parasitic organisms including viral gametocytic hypertrophy, prokaryote-like colonies, protozoans (Perkinsus sp. and Nematopsis sp.) and metazoans (Tylocephalum sp. and cestodes). Other commensal organisms were also detected (the protozoan Ancistrocoma sp. and the turbellarian Urastoma sp.). The protozoan parasite Perkinsus sp. had the highest overall prevalence among the symbiotic organisms studied (48.9%), followed by Nematopsis sp. (36.3%). The other organisms were only sporadically observed. Only the protozoan Perkinsus sp. caused alterations in the oysters' infected organs. Molecular analyses confirmed the presence of P. marinus, P. olseni and Perkinsus beihaiensis infecting the oyster C. gasar. This is the first report of P. beihaiensis in this oyster species. PMID- 25553820 TI - Manipulation of a VEGF-Notch signaling circuit drives formation of functional vascular endothelial progenitors from human pluripotent stem cells. PMID- 25553819 TI - Alcohol consumption after severe burn: a prospective study. AB - BACKGROUND: The number of patients with alcohol-related burns admitted to burn units has increased. It has been reported previously that alcohol-related burns are an indicator of alcohol dependence, but there are few studies addressing alcohol use several years after burn injury. OBJECTIVE: To investigate alcohol consumption 2-7 years after burn injury and to examine possible contributing factors. METHODS: Consecutive adult patients with burns (n = 67) were included during hospitalization, and an interview was performed at 2-7 (mean = 4.6) years after burn. Data assessed at baseline were injury characteristics, sociodemographic variables, coping, and psychiatric disorders. At follow-up, the Alcohol Use Disorders Identification Test was used to identify at-risk drinking. RESULTS: Overall, 22% of the burns were alcohol-related; however, this was not associated with at-risk drinking at follow-up. Of the former patients with burns, 17 (25%) were identified as having an at-risk drinking pattern at follow-up. One item in the Coping With Burns Questionnaire used in acute care, "I use alcohol, tobacco or other drugs to be able to handle my problems", was the only factor found to predict an at-risk drinking pattern several years after injury. CONCLUSION: There were more at-risk drinkers in this burn population as compared with in the general population. The results indicate that an avoidant coping pattern, including the use of alcohol to handle problems, can be considered a potentially modifiable factor. PMID- 25553821 TI - Agmatine enhances antidepressant potency of MK-801 and conventional antidepressants in mice. AB - Agmatine, an endogenous guanidine amine, has been shown to produce antidepressant like effects in animal studies. This study investigated the effects of the combined administration of agmatine with either conventional monoaminergic antidepressants or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in the tail suspension test (TST) in mice. The aim was to evaluate the extent of the antidepressant synergism by examining the ability of a fixed dose of agmatine to shift the antidepressant potency of fluoxetine, imipramine, bupropion and MK-801. A sub-effective dose of agmatine (0.0001 mg/kg, p.o.) significantly increased the potency by which fluoxetine, imipramine, bupropion and MK-801 decreased immobility time in the TST by 2-fold (fluoxetine), 10-fold (imipramine and bupropion) and 100-fold (MK-801). Combined with previous evidence indicating a role of monoaminergic systems in the effect of agmatine, the current data suggest that agmatine may modulate monoaminergic neurotransmission and augment the activity of conventional antidepressants. Moreover, this study found that agmatine substantially augmented the antidepressant-like effect of MK-801, reinforcing the notion that this compound modulates NMDA receptor activation. These preclinical data may stimulate future clinical studies testing the effects of augmentation therapy with agmatine for the management of depressive disorders. PMID- 25553822 TI - Erythropoietin improves synaptic plasticity and memory deficits by decrease of the neurotransmitter release probability in the rat model of Alzheimer's disease. AB - INTRODUCTION: Several studies indicate erythropoietin (Epo) to have remarkable neuroprotection in various central nervous system disorders, including Alzheimer's disease (AD). Amyloid beta (Abeta) is believed to be responsible for the synaptic dysfunction that occurs in AD. Therefore, the present study is aimed to investigate the effects of Epo on the Abeta-induced impairments in learning memory and hippocampal synaptic plasticity. MATERIALS AND METHODS: Male Sprague Dawley rats (200-250 g) were used in this study. After the injection of Abeta, they were injected intra-peritoneal with Epo in the Abeta+Epo group or its vehicle in the Abeta+V group every other day for 12 days. A shuttle box apparatus was used for the passive avoidance learning and memory study. Moreover, paired pulse ratio (PPR) was monitored before and after tetanic stimulation. RESULTS: Bilateral injection of Abeta decreased step-through latency (STL), whereas the 12 day administration of Epo significantly improved memory performance in Abeta+Epo group. The field potential recording demonstrated that the in vivo administration of Abeta25-35 led to extreme inhibition in long-term potentiation, this inhibition was accompanied by a significant increase of the normalized PPR (PPR after HFS/PPR before HFS) as an index for release probability. However, administration of Epo recovers the magnitude of the LTP and the extent of normalized PPR. CONCLUSION: The results of this study demonstrated that the injection of Abeta25-35 resulted in impaired LTP and the memory process, which is likely mediated through increasing the release probability of neurotransmitter vesicles. In addition, treatment with Epo improved the Abeta-induced deficits in memory and LTP induction, probably via recovering the release probability. PMID- 25553824 TI - Nasal delivery of Japanese cedar pollen Cryj1 by using self-gelling immunostimulatory DNA for effective induction of immune responses in mice. AB - To develop an immunotherapeutic vaccine for treatment of allergic rhinitis, we developed a controlled release formulation of Cryj1, a major Japanese cedar pollen allergen, with immunostimulatory potency. Two sets of hexapod-like structured DNA (hexapodna) were prepared using six oligodeoxynucleotides (ODNs) each, including ODNs with an unmethylated cytosine-phosphate-guanine (CpG) sequence (CpG motif), to obtain an immunostimulatory DNA hydrogel (sDNA hydrogel). A non-immunostimulatory DNA hydrogel (nsDNA hydrogel) was also prepared using ODNs with no CpG motifs. The sDNA hydrogel was more effective than its components or the nsDNA hydrogel for production of interleukin (IL)-12 after addition to murine macrophage-like RAW264.7 cells or after intranasal administration to mice. Then, a Cryj1-loaded sDNA hydrogel (Cryj1/sDNA hydrogel) formulation was prepared by mixing solutions containing both Cryj1 and hexapodna. Cryj1 was slowly released from the sDNA hydrogel in phosphate-buffed saline. After intranasal administration of the fluorescein isothiocyanate (FITC)-labeled Cryj1/sDNA hydrogel in mice, FITC-Cryj1 was retained in the nasal cavity for a longer period than FITC-Cryj1 mixed with hexapodna in solution. Intranasal immunization of mice with the Cryj1/sDNA hydrogel resulted in high levels of Cryj1-specific IgG in nasal lavage fluid (NFL), IL-12 and interferon-gamma release from spleen cells after re-stimulation with Cryj1 when compared with intranasal immunization with the other formulations examined. These results indicate that the self-gelling immunostimulatory DNA hydrogel is an effective formulation for controlled induction of allergen-specific immune responses. PMID- 25553823 TI - Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy. AB - Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. We have constructed a recombinant protein named anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability. Anti-EGFR-iRGD, which targets EGFR and alphavbeta3, spreads extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines, multicellular spheroids, and mice. Moreover, anti-EGFR-iRGD could improve anticancer drugs, such as doxorubicin (DOX), bevacizumab, nanoparticle permeability and efficacy in multicellular spheroids. This study draws attention to the importance of iRGD peptide in the therapeutic approach of anti-EGFR-iRGD. As a consequence, anti-EGFR-iRGD could be a drug candidate for cancer treatment and a useful adjunct of other anticancer drugs. PMID- 25553825 TI - Current and future delivery systems for engineered nucleases: ZFN, TALEN and RGEN. AB - Gene therapy by engineered nucleases is a genetic intervention being investigated for curing the hereditary disorders by targeting selected genes with specific nucleotides for establishment, suppression, abolishment of a function or correction of mutation. Here, we review the fast developing technology of targeted genome engineering using site specific programmable nucleases zinc finger nucleases (ZFNs), transcription activator like nucleases (TALENs) and cluster regulatory interspaced short palindromic repeat/CRISPR associated proteins (CRISPR/Cas) based RNA-guided DNA endonucleases (RGENs) and their different characteristics including pros and cons of genome modifications by these nucleases. We have further discussed different types of delivery methods to induce gene editing, novel development in genetic engineering other than nucleases and future prospects. PMID- 25553826 TI - Induced myogenic commitment of human chondrocytes via non-viral delivery of minicircle DNA. AB - Lineage conversion from one somatic cell type to another is an attractive approach for deriving specific therapeutic cell generation. In order to bypass inducing pluripotent stage, transdifferentiation/direct conversion technologies have been recently developed. We report the development of a direct conversion methodology in which cells are transdifferentiated through a plastic intermediate state induced by exposure to non-integrative minicircle DNA (MCDNA)-based reprogramming factors, followed by differentiation into myoblasts. In order to increase the MCDNA delivery efficiency, reprogramming factors were delivered into the chondrocytes via electroporation followed by poly (beta-amino esters) (PBAE) transfection. We used this approach to convert human chondrocytes to myoblast, and with treatment of SB-431542, an inhibitor of the activin receptor-like kinase receptors, to enhance myogenic commitment. Differentiated cells exhibited expression of myogenic markers such as MyoD and Myog. This methodology for direct lineage conversion from chondrocytes to myoblast represents a novel non-viral Method to convert hard-to-transfect cells to other lineage. PMID- 25553827 TI - Twin disulfides as opportunity for improving stability and transfection efficiency of oligoaminoethane polyplexes. AB - The synthesis of precise gene delivery vehicles by solid-supported chemistry is an effective way to establish structure-activity relationships and optimize existing transfection carriers. Sequence-defined cationic oligomers with different topologies were modified with twin disulfide-forming cysteine-arginine cysteine (CRC) motifs. The influence of this motif versus single disulfide on the biophysical properties and biological performance of polyplexes was investigated, with pDNA and siRNA as nucleic acid cargoes. Clear differences between structures with isolated cysteines and CRC motifs were observed with respect to properties like nucleic acid binding, serum stability, response to reducing agents, and gene transfer/silencing. The main observed effect of the CRC motif was to increase polyplex stability. The consequences for nucleic acid delivery were less predictable and depended on oligomer topology. For some oligomers intrinsically forming stable polyplexes (i.e., already in the absence of CRC motif), this further stabilization resulted in a reduction or even loss in transfection efficiency. For PEGylated and targeted oligomers with intrinsically less stable polyplex structures, this modification led to a significant enhancement in transfection efficiency. PMID- 25553828 TI - Transcorneal iontophoresis of dendrimers: PAMAM corneal penetration and dexamethasone delivery. AB - Iontophoresis of nanocarriers in the eye has been proposed to sustain drug delivery and maintain therapeutic concentrations. Fourth generation polyamidoamine (PAMAM) dendrimers are semi-rigid nanoparticles with surface groups that are easily modified. These dendrimers are known to modulate tight junctions, increase paracellular transport of small molecules and be translocated across epithelial barriers, exhibiting high uptake by different cell lines. The first aim of this study was to investigate the effect of iontophoresis on PAMAM penetration and distribution into the cornea. The second aim was to evaluate, ex vivo and in vivo, the effect of these dendrimers in dexamethasone (Dex) transcorneal iontophoresis. Anionic (PAMAM G3.5) and cationic (PAMAM G4) dendrimers were labeled with fluorescein isothiocyanate (FITC), and their distribution in the cornea was investigated using confocal microscopy after ex vivo anodal and cathodal iontophoresis for various application times. The particle size distribution and zeta potential of the dendrimers in an isosmotic solution were determined using dynamic light scattering and Nanoparticle Tracking Analysis (NTA), where the movement of small particles and the formation of large aggregates, from 5 to 100 nm, could be observed. Transcorneal iontophoresis increased the intensity and depth of PAMAM-FITC fluorescence in the cornea, suggesting improved transport of the dendrimers across the epithelium toward the stroma. PAMAM complexes with Dex were characterized by (13)C-NMR, (1)H-NMR and DOSY. PAMAM G3.5 and PAMAM G4 increased the aqueous solubility of Dex by 10.3 and 3.9-fold, respectively; however, the particle size distribution and zeta potential remained unchanged. PAMAM G3.5 decreased the Dex diffusion coefficient 48-fold compared with PAMAM G4. The ex vivo studies showed that iontophoresis increased the amount of Dex that penetrated into the cornea by 2.9, 5.6 and 3.0 fold for Dex, Dex-PAMAM G4 and Dex-PAMAM G3.5, respectively. In vivo experiments, however, revealed that iontophoresis of Dex-PAMAM-G3.5 increased Dex concentration in the aqueous humor by 6.6-fold, while iontophoresis of Dex-PAMAM G4 and Dex increased it 2.5 and 2-fold, respectively. Therefore, iontophoresis targeted PAMAM to the cornea but it is the sustained delivery of the Dex from PAMAM that prevents its rapid elimination from the aqueous humor. In conclusion, iontophoresis of PAMAM complexes represents a promising strategy for targeted and sustained topical drug delivery to the eye. PMID- 25553829 TI - Augmented EPR effect by photo-triggered tumor vascular treatment improved therapeutic efficacy of liposomal paclitaxel in mice bearing tumors with low permeable vasculature. AB - The effects of photo-triggered tumor vascular treatment (PVT) on the structural and functional properties of tumor vasculature were assessed in Colon-26 (C26) and B16/BL6 (B16) tumor-bearing mice. Furthermore, anti-tumor efficacy of subsequently injected PEG liposomal paclitaxel (PL-PTX) was also evaluated. As a photosensitizer, a hydrophobic porphyrin derivative was used and formulated in polymeric nanoparticle composed of polyethylene glycol-block-polylactic acid to avoid its non-specific in vivo disposition. In the mice bearing C26 with high permeable vasculature, the prominent anti-tumor activity was confirmed by PVT alone, but the subsequently injected PL-PTX did not show any additive effect. PVT itself initially induced apoptotic cell death of tumor vascular endothelial cells and platelet aggregation, which would have subsequently induced apoptosis of C26 tumor cells surrounding the vasculature. On the other hand, in the mice bearing B16 with low permeable vasculature, PVT enhanced the anti-tumor activity of subsequently injected PL-PTX, which would be attributed to the tumor disposition amount and area of PEG liposomes enhanced by PVT. These results clearly indicated that the treatment would have made it possible to provide more efficient extravasation of PL-PTX, leading to its more potent anti-tumor effect. PMID- 25553830 TI - Effects of cyclophosphamide on immune system and gut microbiota in mice. AB - Cyclophosphamide (CP) is the most commonly used drug in autoimmune disease, cancer, blood and marrow transplantation. Recent data revealed that therapy efficacy of CP is gut microbiota-dependent. So, it is very important to understand how CP affects intestinal microbiota and immune function. In this study, the effects of CP on mice immuno-activity were firstly evaluated, then, the fecal microbiota from normal and CP-treated mice was compared, and the characteristic bacterial diversity and compositions were identified, using 454 pyrosequencing technology. The results showed that CP reduced the diversity and shifted the fecal microbiota composition. Specifically, CP treatment decreased the proportion of Bacteroidetes while increased the proportion of Firmictutes in the microbial community. Most importantly, specific microbiota signatures belonging to Bacteroides acidifaciens, Streptococcaceae and Alistipes were also identified, which would provide new insight into the efficacy and side effects in clinical usage of CP. This should be helpful for further demonstration of CP's action mechanism, development of personalized therapy strategies, and prediction of potential side effects related to various treatment regimens of CP. PMID- 25553831 TI - Tocilizumab-associated cutaneous reactive endotheliomatosis in a patient with rheumatoid arthritis. PMID- 25553832 TI - Immune reconstitution inflammatory syndrome during treatment of Whipple's disease. AB - Immune reconstitution inflammatory syndrome is a rare complication of the treatment of Whipple's disease. Here, we report the case of a 65-year-old man treated for Whipple's disease affecting the joints, with positive Tropheryma whipplei PCR in CSF, who developed fever and nodular eruption on the trunk, arms and face in association with biological inflammatory syndrome 10 days after initiation of antimicrobial treatment. Skin manifestations and the patient's general condition improved on corticosteroids (0.5mg/kg prednisone), but as steroids were gradually tapered, new nodules appeared below a prednisone dose of 10-15mg. One year after starting treatment, lumbar puncture showed asymptomatic meningitis with negative T. whipplei PCR results which had regressed spontaneously. Two years after the diagnosis, on prednisone 5mg daily and antimicrobial treatment, the patient had only transient, episodic nodular rash without fever or inflammatory syndrome. PMID- 25553833 TI - Overview of biologic treatments in the elderly. AB - As life expectancies rise, the number of elderly people with inflammatory rheumatic diseases will continue to grow. Treatment of this frail population, whose clinical features differ from those of younger subjects, poses new challenges to healthcare systems. However, this issue is rarely addressed in the current literature. Thanks to their targeted mechanism of action, biologics represent one of the major therapeutic advances of the last 15 years, but their use in the elderly has been slow in developing. Published data, derived mainly from cohorts, focus on the use of TNF inhibitors in rheumatoid arthritis and show that these treatments are effective and generally well tolerated. Nevertheless, the risk of infection and cancer, particularly skin and lymphoid malignancies, must not be neglected. The use of these biologics as second-line treatment improves patient outcomes and comfort, while reducing consumption of the widely used and more deleterious drugs such as glucocorticoids and non-steroidal anti inflammatory drugs. Additional studies on biologics, focusing on the longer term and in indications apart from anti-TNF therapies in rheumatoid arthritis should help overcome some of the reluctance and promote the rational use of these drugs in the elderly. PMID- 25553834 TI - Lateral epicondylitis: new evidence for work relatedness. PMID- 25553835 TI - Clinical significance of serum interleukin-23 and A/G gene (rs17375018) polymorphism in Behcets disease: Relation to neuro-Behcet, uveitis and disease activity. PMID- 25553836 TI - Catastrophic antiphospholipid syndrome presenting with bilateral massive adrenal haemorrhage. A case report. PMID- 25553837 TI - Long-term safety of tocilizumab treatment on chronic active hepatitis C in a patient with adult onset Still's disease. PMID- 25553838 TI - Role of HIF-1alpha and HIF-2alpha in osteoarthritis. AB - The hallmark of OA is cartilage destruction, several factors such as catabolic enzymes and chondrocyte death include apoptosis and/or autophagy are considered for the pathogenesis. Articular cartilage is maintained in a low oxygen environment throughout life. Chondrocytes are therefore adapted to these hypoxic conditions. The increased HIF-1alpha and HIF-2alpha mediate the response of chondrocytes to hypoxia. HIF-1alpha regulates chondrogenesis by regulating SOX9 expression in the genetic level, HIF-1 also serves to regulate both autophagy and apoptosis. Therefore, HIF-1alpha may protect articular cartilage by promoting the chondrocyte phenotype, maintaining chondrocyte viability, and supporting metabolic adaptation to a hypoxic environment. In contrast with HIF-1alpha, HIF 2alpha is a catabolic factor in the osteoarthritic process. Although HIF-2alpha is essential for hypoxic induction of the human articular chondrocyte phenotype, HIF-2alpha directly induces the expression of catabolic factors in chondrocytes, and HIF-2alpha enhances Fas expression to mediate chondrocyte apoptosis and regulates autophagy in maturing chondrocytes. Taken together, manipulation of HIF 1alpha and HIF-2alpha could represent a promising approach to the treatment of OA. Further study should elucidate the exact machnism of HIF-1alpha and HIF 2alpha in cartilage and determine which is predominant in osteoarthritic process. PMID- 25553839 TI - Novel WISP3 mutations causing spondyloepiphyseal dysplasia tarda with progressive arthropathy in two unrelated Chinese families. AB - Spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) is an autosomal recessive skeletal disorder resulting from pathogenic mutations in the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. This disorder predominantly involves the skeletal system, with the leading features of platyspondyly, metaphyseal dysplasia of limbs and extremities, and progressive degeneration of joints. To date, 53 distinct forms of WISP3 mutations have been detected globally, eleven of which originated from Chinese patients. In the current study, we reported the clinical manifestations and radiographic features of two unrelated Chinese SEDT-PA patients. Through genetic analysis, two novel mutations (c.624delA, c.105dupT) as well as one recurrent mutation (c.342T>G) were identified in the WISP3 gene. Our study contributed to the further expansion of the WISP3 mutation spectrum, and demonstrated the genotype-phenotype relationship between mutations in the WISP3 gene and clinical findings of SEDT PA. PMID- 25553840 TI - Atrophy of the vocal fold: An usual cause of hoarseness in scleroderma. PMID- 25553841 TI - Intracranial pressure monitor in patients with traumatic brain injury. AB - BACKGROUND: Brain Trauma Foundation (BTF) guidelines recommend intracranial pressure (ICP) monitoring for traumatic brain injury (TBI) patients with a Glasgow Coma Scale score of 8 or less with an abnormal head computed tomography, or a normal head computed tomography scan with systolic blood pressure <=90 mm Hg, posturing, or in patients of age >=40. The benefits of these guidelines on outcome remain unproven. We hypothesized that adherence to BTF guidelines for ICP monitoring does not improve outcomes in patients with TBI. METHODS: All TBI patients with an admission Glasgow Coma Scale <=8 admitted to our level I trauma center over a 3-y period were identified. Adherence to the individual components of our institutional TBI Bundle (ICP monitoring, SpO2 >=95%, PaCO2 30-39 mm Hg, systolic blood pressure >=90 mm Hg, cerebral perfusion pressure >=60 mm Hg, ICP <=25 mm Hg, and temperature 36 degrees C-37 degrees C) was assessed. Patients were stratified into two groups as follows: patients with ICP monitoring (ICP) and patients without ICP monitoring (no-ICP). Outcome measures were survival and discharge disposition. Multivariate regression analysis was performed. RESULTS: We identified 2618 TBI patients, 261 of whom met the BTF criteria for ICP monitoring. After excluding those with nonsurvivable injuries (n = 67), 194 patients were available for analysis. The two groups were similar in demographics and severity of head injury. Survival rate was higher in the no-ICP group compared with that in the ICP group (98% versus 76%, P < 0.004). Non-monitored patients were discharged with higher levels of function per discharge location (28% home versus 4% home; P < 0.001). Patients without ICP monitoring were 1.21 times more likely to survive compared with that of patients with ICP monitoring (odds ratio: 1.21, 95% confidence interval [1.1-1.9], P = 0.01). In the ICP group, the overall compliance rate to the ICP and cerebral perfusion pressure goals as required by the BTF guidelines was poor. CONCLUSIONS: Our data suggest that there is a subset of patients meeting BTF criteria for ICP monitoring that do well without ICP monitoring. This finding should provoke reevaluation of the indication and utility of ICP monitoring in TBI patients. PMID- 25553842 TI - Assistant instructors facilitate simulation for medical students. AB - BACKGROUND: A procedural training protocol for medical students must be cognizant of faculty opportunity costs, which may preclude individually supervised practice. Meanwhile, sporadic exposure in large group settings yields suboptimal proficiency. The purpose of this study is to assess the effectiveness of undergraduate assistant instructors in providing one-on-one simulation-based instruction for basic invasive techniques. MATERIALS AND METHODS: Investigators designed proficiency-based checklists by faculty consensus for three simulation tasks as follows: orotracheal intubation, central venous catheterization, and suturing. Four undergraduate students were trained as instructors. Interrater agreement between instructors using the task checklists ranged from 0.754-0.866. Instructors conducted up to seven flexibly scheduled, one-on-one practice sessions with clinically inexperienced medical student participants. Sessions comprised repetitive task attempts with an evaluation after every attempt. On completion of the training protocol, participants underwent evaluation by an experienced surgeon blinded to practice session performance. Study participants were surveyed to assess satisfaction. RESULTS: Twenty-nine participants completed the study. Median total practice time was 8.75 h (interquartile range 7.12-8.75). Posttest pass rates were 93% (26/28), 71% (20/28), and 68% (19/28) for suturing, intubation, and central venous catheterization, respectively. Ninety-seven percent (27/28) of participants were satisfied with their experience, and 62% (18/29) advocated for protocol adoption into the standard preclinical curriculum. Estimated cost saved using student instructors, based on departmental collections for surgical faculty, was $43,760. CONCLUSIONS: Clinically inexperienced assistants may be trained as instructors for basic simulation tasks with excellent interrater reliability. Deploying these assistant instructors makes effective, one-on-one technical training for preclinical medical students financially feasible. PMID- 25553845 TI - Current role of melatonin in pediatric neurology: clinical recommendations. AB - BACKGROUND/PURPOSE: Melatonin, an indoleamine secreted by the pineal gland, plays a key role in regulating circadian rhythm. It has chronobiotic, antioxidant, anti inflammatory and free radical scavenging properties. METHODS: A conference in Rome in 2014 aimed to establish consensus on the roles of melatonin in children and on treatment guidelines. RESULTS AND CONCLUSION: The best evidence for efficacy is in sleep onset insomnia and delayed sleep phase syndrome. It is most effective when administered 3-5 h before physiological dim light melatonin onset. There is no evidence that extended-release melatonin confers advantage over immediate release. Many children with developmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and intellectual disability have sleep disturbance and can benefit from melatonin treatment. Melatonin decreases sleep onset latency and increases total sleep time but does not decrease night awakenings. Decreased CYP 1A2 activity, genetically determined or from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. Decreasing the dose can remedy this. Animal work and limited human data suggest that melatonin does not exacerbate seizures and might decrease them. Melatonin has been used successfully in treating headache. Animal work has confirmed a neuroprotective effect of melatonin, suggesting a role in minimising neuronal damage from birth asphyxia; results from human studies are awaited. Melatonin can also be of value in the performance of sleep EEGs and as sedation for brainstem auditory evoked potential assessments. No serious adverse effects of melatonin in humans have been identified. PMID- 25553846 TI - Comparison of expected health impacts for major cancers: integration of incidence rate and loss of quality-adjusted life expectancy. AB - PURPOSE: The study aims to quantify the expected impacts of different cancers through multiplying the incidence rate by loss-of-QALE (quality-adjusted life expectancy), with QALY (quality-adjusted life year) as the common unit, to aid prevention policy decisions. METHODS: 464,722 patients with pathologically verified cancer registered in the Taiwan Cancer Registry during 1998-2009 were used to estimate lifetime survival through Kaplan-Meier estimation combined with a semi-parametric method. A convenience sample for measuring the utility value with EQ-5D was conducted with 11,453 cancer patients, with the results then multiplied by the survival functions to estimate QALE. The loss-of-QALE was calculated by subtracting the QALE of each cancer cohort from the life expectancy of the corresponding age- and gender-matched reference population. The cumulative incidence rates from age 20 to 79 (CIR20-79) were calculated to estimate the lifetime risk of cancer for each organ-system. RESULTS: Liver and lung cancer were found the highest expected lifetime health impacts in males and females, or expected lifetime losses of 0.97 and 0.41 QALYs that could be averted, respectively. While the priority changes for prevention based on expected health impacts were slightly different for females based on standardized mortality rates, those of males involve a broader spectrum, including oral, colorectal, esophageal and stomach cancer. CONCLUSION: The integration of incidence rate with loss-of-QALE could be used to represent the expected losses that could be averted by prevention, which may be useful in prioritizing strategies for cancer control. PMID- 25553851 TI - The effect of fontanel on scalp EEG potentials in the neonate. AB - OBJECTIVE: To define how fontanels affect scalp EEG potentials in neonates. METHOD: Realistic finite element method head models were generated with and without fontanels. The electrical activity of the whole cortex was simulated using distributed 54,620 concurrently active cortical dipoles with a uniform random distribution of current densities (0-40 MUA/cm2). The overall effects of fontanels on scalp potentials were calculated from finite element forward solution in the vicinity the fontanel region by relative difference measure (RDM*) and magnification factor (MAG), and the skull conductivity was systematically varied from 0.003 to 0.3S/m. RESULTS: The neonatal scalp EEG topographies are comparable in models with and without fontanels, with highest amplitudes directly above the anterior fontanel. Quantitatively, comparison of these models elicits negligible differences (RDM*) ~2% and MAG ~1.0). However, fontanel contribution to scalp potential was shown to increase sharply with decreases in skull conductivity. CONCLUSIONS: These results suggest that fontanels may affect neonatal scalp EEG much less than traditionally assumed, and the effect is strongly dependent on skull conductivity. SIGNIFICANCE: Most neonatal EEG studies can be adequately performed without assuming distortions by fontanels. PMID- 25553852 TI - Editorial comment. PMID- 25553844 TI - Structure and interactions of the CS domain of human H/ACA RNP assembly protein Shq1. AB - Shq1 is an essential protein involved in the early steps of biogenesis and assembly of H/ACA ribonucleoprotein particles (RNPs). Shq1 binds to dyskerin (Cbf5 in yeast) at an early step of H/ACA RNP assembly and is subsequently displaced by the H/ACA RNA. Shq1 contains an N-terminal CS and a C-terminal Shq1 specific domain (SSD). Dyskerin harbors many mutations associated with dyskeratosis congenita. Structures of yeast Shq1 SSD bound to Cbf5 revealed that only a subset of these mutations is in the SSD binding site, implicating another subset in the putative CS binding site. Here, we present the crystal structure of human Shq1 CS (hCS) and the nuclear magnetic resonance (NMR) and crystal structures of hCS containing a serine substitution for proline 22 that is associated with some prostate cancers. The structure of hCS is similar to yeast Shq1 CS domain (yCS) and consists of two beta-sheets that form an immunoglobulin like beta-sandwich fold. The N-terminal affinity tag sequence AHHHHHH associates with a neighboring protein in the crystal lattice to form an extra beta-strand. Deletion of this tag was required to get spectra suitable for NMR structure determination, while the tag was required for crystallization. NMR chemical shift perturbation (CSP) experiments with peptides derived from putative CS binding sites on dyskerin and Cbf5 revealed a conserved surface on CS important for Cbf5/dyskerin binding. A HADDOCK (high-ambiguity-driven protein-protein docking) model of a Shq1-Cbf5 complex that defines the position of CS domain in the pre H/ACA RNP was calculated using the CSP data. PMID- 25553853 TI - Delayed bottom-up and amended simple method of dosing with once-daily tacrolimus application to achieve stable trough levels in liver transplantation. AB - BACKGROUND: Tacrolimus once-daily formulation (TacOD) was introduced as an alternative to twice-daily formulations de novo. Dosing recommendations range between 0.1 to 0.2 mg/kg BW/d. MATERIAL AND METHODS: Amended dosing with a simple bottom-up de novo algorithm is presented. Primary outcome measure was feasibility of establishing adequate target trough levels and avoidance of over immunosuppression, with adequate safety and efficacy after liver transplantation (LT). RESULTS: TacOD was given to 101 patients. Standard steroid-free immunosuppression consisted of MMF 2 g/d, basiliximab 20 mg on day 0 and 4, and delayed bottom-up IS with TacOD starting with 1 mg/d and doubling the dosage every day until target trough levels of 5 to 8 ng/ml were reached. By day 7 after LT, all except 3 patients had received TacOD. The earliest time point of introduction was day 2. A median of 9 mg/d (range: 0 to 25 mg/d) of TacOD were necessary to establish the trough levels by day 10, which was then 5.4 ng/ml (range: 1.5 to 20 ng/ml). Incidence of adverse events (AE), in particular neurological AEs (n=3), were low. Efficacy failure (acute rejection) was low (4.9%). Renal function was stable and did not deteriorate under CNI treatment. CONCLUSIONS: This is the first report of bottom-up, amended, and simple dosing of TacOD in LT. The algorithm is feasible, safe, and efficient, avoiding trough level peaks and top-down strategies. PMID- 25553854 TI - ? AB - An adolescent with a recent diagnostic of Behcet's Disease (BD) was admitted with fever and intracardiac lesions detected on a routine transthoracic echocardiography, suggestive of endocarditis. Due to the absence of improvement after several rounds of antibiotics the patient was submitted to contrast enhanced cardiac MRI that showed signs of intracardiac thrombosis, superior vena cava syndrome and pulmonary thromboembolism. The patient underwent surgery to excise the lesions and has been treated with cyclophosphamide and high dose prednisolone achieving complete remission. Intracardiac thrombosis is a rare manifestation of BD, and is associated with a poor prognosis. These patients usually require a combination of anticoagulation and immunosuppression to achieve remission. PMID- 25553855 TI - Recurrent parent genome recovery analysis in a marker-assisted backcrossing program of rice (Oryza sativa L.). AB - Backcross breeding is the most commonly used method for incorporating a blast resistance gene into a rice cultivar. Linkage between the resistance gene and undesirable units can persist for many generations of backcrossing. Marker assisted backcrossing (MABC) along with marker-assisted selection (MAS) contributes immensely to overcome the main limitation of the conventional breeding and accelerates recurrent parent genome (RPG) recovery. The MABC approach was employed to incorporate (a) blast resistance gene(s) from the donor parent Pongsu Seribu 1, the blast-resistant local variety in Malaysia, into the genetic background of MR219, a popular high-yielding rice variety that is blast susceptible, to develop a blast-resistant MR219 improved variety. In this perspective, the recurrent parent genome recovery was analyzed in early generations of backcrossing using simple sequence repeat (SSR) markers. Out of 375 SSR markers, 70 markers were found polymorphic between the parents, and these markers were used to evaluate the plants in subsequent generations. Background analysis revealed that the extent of RPG recovery ranged from 75.40% to 91.3% and from 80.40% to 96.70% in BC1F1 and BC2F1 generations, respectively. In this study, the recurrent parent genome content in the selected BC2F2 lines ranged from 92.7% to 97.7%. The average proportion of the recurrent parent in the selected improved line was 95.98%. MAS allowed identification of the plants that are more similar to the recurrent parent for the loci evaluated in backcross generations. The application of MAS with the MABC breeding program accelerated the recovery of the RP genome, reducing the number of generations and the time for incorporating resistance against rice blast. PMID- 25553862 TI - It's not just a vitamin: comment on "Rise in late onset vitamin K deficiency bleeding in young infants because of omission or refusal of prophylaxis at birth" by Schulte and colleagues. PMID- 25553863 TI - Functional food microstructures for macronutrient release and delivery. AB - There is a need to understand the role of fat, protein and carbohydrate in human health, and also how foods containing and/or structured using these macronutrients can be designed so that they can have a positive impact on health. This may include a reduction in fat, salt or sugar, the protection and targeted release of micronutrients or active ingredients from/to particular parts of the digestive system, improvement of gastrointestinal health or satiety enhancing properties. Such foods can be designed with various macro- and microstructures that will impact on macronutrient release and delivery. These include simple and double emulsions, the use of Pickering particles and shells, nanoparticles, liposomes, gelled networks, fluid gels and gel particles, foams, self-assembled structures, and encapsulated systems. In order to design foods that deliver these benefits understanding of how these structures behave in the gastrointestinal tract is also required, which should involve utilising both in vitro and in vivo studies. This review aims to draw together research in these areas, by focusing on the current state of the art, but also exciting possibilities for future research and food development. PMID- 25553866 TI - Isolation of a new flavanone from Daidai fruit and hypolipidemic activity of total flavonoids extracts. AB - In order to further discover the medicinal value of Daidai fruit, an exploration on the hypolipidemic activity of total flavonoids extracts of Daidai fruit (TFEODF) was conducted in high-fat diet-induced hyperlipemia rats. Results indicated that TFEODF exhibited significant hypolipidemic activity which resulted in the decline of serum total cholesterol, triglyceride, low density lipoprotein cholesterol, arteriosclerosis index and rise of high density lipoprotein cholesterol in hyperlipemia rats. For the purpose of expounding the chemical constituents of TFEODF, a phytochemical investigation of TFEODF was carried out for the first time. Research resulted in the isolation of a new compound together with 17 known compounds. This study lay a foundation for the development of a new hypolipidemic agent of traditional Chinese medicine whose chemical constituents were clarified. PMID- 25553867 TI - Authors' reply. PMID- 25553868 TI - Biochemical view on "Homocysteine and metabolic syndrome: From clustering to additional utility in prediction of coronary heart disease". PMID- 25553869 TI - Clinical implications of and factors influencing dissociated pulmonary vein potentials. AB - BACKGROUND: Factors influencing dissociated pulmonary vein (PV) potentials (DPVPs) in atrial fibrillation (AF) patients undergoing circumferential PV isolation have not been investigated. Furthermore, the clinical implications of such DPVPs remain controversial. METHODS: Circumferential PV isolation as a first ablation procedure was performed in 688 consecutive patients with AF (460 men; mean age, 58.9+/-10.5 years). The clinical implications of and factors influencing DPVPs were evaluated. RESULTS: Acute PV isolation was achieved in 679 (98.7%) patients. A total of 578 (42.6%) ipsilateral PVs with DPVPs were documented in 378 (55.7%) patients (DPVPs group). Multivariate analysis revealed that male gender [odds ratio (OR): 1.894; 95% confidence interval (CI): 1.344 2.667; p<0.001] and paroxysmal AF (OR: 1.715; 95% CI: 1.182-2.488; p=0.005) were independent factors for DPVPs. The incidence of acute and intraoperative PV reconnection (PVR) was higher in the DPVPs group than in the non-DPVPs group (33.1% vs. 17.9%; p<0.001 and 44.4% vs. 28.2%; p<0.001). After the first procedure, 244 (65.6%) DPVPs-group patients and 168 (56.4%; p=0.015) non-DPVPs group patients were free from AF recurrence. During repeat procedures, PVR incidence was similar in the DPVPs group (81.8%) and non-DPVPs groups (83.3%; p=0.863). CONCLUSION: Male gender and paroxysmal AF were independent risk factors for DPVPs in patients undergoing circumferential PV isolation. DPVPs had a significant impact on acute and intraoperative PVR. The outcomes of the first ablation procedure were better in patients with DPVPs. PMID- 25553870 TI - Stress hyperglycemia and microvascular obstruction after acute myocardial infarction. PMID- 25553871 TI - A randomized trial of levonorgestrel intrauterine system insertion 6 to 48 h compared to 6 weeks after vaginal delivery; lessons learned. AB - The objective of this randomized trial was to compare breastfeeding among women who received a levonorgestrel-releasing intrauterine system within 6-48 h (early) or 4-6 weeks (standard) after an uncomplicated vaginal birth. Analysis groups of 86 women in each arm were needed to demonstrate a 20% difference in any breastfeeding. Thirty-five women were randomized to the early (N=17) and standard (N=18) arms. The combination of unsuccessful placement (2/17; 12%), expulsions (7/17; 41%) and removals (3/17; 18%) reached 71% (12/17) in the early arm, so the study was stopped. In our small study cohort, levonorgestrel-releasing intrauterine system insertion between 6 and 48 h after vaginal birth was associated with a high rate of expulsion or removal soon after insertion. PMID- 25553872 TI - Contraceptive discontinuation and pregnancy postabortion in Nepal: a longitudinal cohort study. AB - OBJECTIVE: To examine postabortion contraceptive discontinuation and pregnancy in Nepal, where abortion was decriminalized in 2002. STUDY DESIGN: We conducted an observational cohort study of 654 women obtaining abortions from four public and nongovernmental facilities in 2011. Patients completed questionnaires at their abortion visit and 6 and 12 months later. We used Cox proportional hazards models to assess contraceptive discontinuation and pregnancy by method initiated postabortion and other sociodemographic and reproductive factors. RESULTS: Among the 78% (508/654) of women who initiated a modern contraceptive method within 3 months postabortion, the 1-year contraceptive discontinuation rate was 62 per 100 person-years. Discontinuation was far lower among the 5% of women using long acting reversible methods (21/100 person-years) than among those using condoms (74/100 person-years), pills (61/100 person-years) and the injectable [64/100 person-years; adjusted hazard ratio (aHR)=0.32 (0.15-0.68)]. Unmarried women and those not living with their husband experienced higher contraceptive discontinuation [aHR=2.16 (1.47-3.17)]. The 1-year pregnancy rate for all women was 9/100 person-years. Pregnancy was highest among those who initiated no modern method postabortion (13/100 person-years) and condoms (12/100 person-years), and pregnancy was lowest among users of long-acting reversible methods (3/100 person years). The poorest women were at increased pregnancy risk [aHR=2.31 (1.32 4.10)]. CONCLUSION: Women using intrauterine devices and implants experienced greatly reduced contraceptive discontinuation and pregnancy within a year postabortion, although initiation of these long-acting methods was low. Increased availability of long-acting methods in Nepal and similar settings may help to prevent unwanted pregnancy and attendant maternal mortality and morbidities. IMPLICATIONS: Initiation of modern contraception was high postabortion; however, 1-year discontinuation was high for the condom, pill and injectable, the methods most commonly used. Rates for intrauterine devices and implants were low. Results support efforts to facilitate patient knowledge and access to the full range of contraceptives, including long-acting reversible methods. PMID- 25553873 TI - An exploratory analysis of contraceptive method choice and symptoms of depression in adolescent females initiating prescription contraception. AB - OBJECTIVE: We examine the association between depressive symptoms and contraceptive method choice among adolescents initiating prescription contraception. STUDY DESIGN: This cross-sectional study analyzes baseline data of 220 urban, minority adolescent females (ages 15-19 years) presenting for prescription contraceptive initiation at a comprehensive, free-of-cost, adolescent health center in New York City. All participants met with a health care provider who provided standard contraception counseling before initiating contraception. Each participant then selected a short- or long-acting contraceptive: a 3-month supply of the pill, patch, ring or a medroxyprogesterone acetate depot injection (short-acting), or placement/referral for an intrauterine device (IUD; long-acting). We assess the independent association between contraceptive method selection and symptoms of depression [assessed by the Center for Epidemiological Studies - Depression (CES-D) scale]. RESULTS: Ten percent (n=21/220) of adolescent females selected an IUD. Bivariate analysis revealed that those with elevated levels of depressive symptoms were more likely to select an IUD as compared to those with minimal symptoms (mean CES-D score 20 vs. 13; t=3.052, p=.003). In multivariate logistic regressions, adolescent females had increased odds of selecting an IUD if they reported moderate to severe depressive symptoms (adjusted odds ratio=4.93; confidence interval, 1.53-15.83; p=.007) after controlling for ethnicity/race, education, number of lifetime partners and gravidity. CONCLUSIONS: Inner-city, minority adolescents with elevated symptoms of depression who present for prescription contraceptive initiation may be more likely to select an IUD rather than shorter-acting methods. By recognizing adolescent females with depressive symptoms, providers can strategize their approach to effective contraception counseling. PMID- 25553874 TI - Effects of heartbeat feedback on beliefs about heart rate and heartbeat counting: a cautionary tale about interoceptive awareness. AB - Heartbeat counting improves after exposure to heartbeat feedback either because feedback trains individuals to detect heartbeats or updates their knowledge/beliefs about heart rate. These possibilities were examined by assessing heartbeat counting, in different postures and following exercise, before and after exposure to immediate and delayed heartbeat feedback. Immediate and delayed feedback provided accurate information about heart rate and, therefore, either could update beliefs about heart rate. However, only immediate feedback marked each ventricular contraction and, thereby, could train participants to detect the beating of the heart by focusing attention on relevant internal sensations. Exposure to immediate and delayed feedback resulted in similar, significant increases in the accuracy of heartbeat counting, indicating that the feedback effect was mediated by non-sensory processes rather than by training participants to detect heartbeat sensations. The current findings demonstrate that the heartbeat counting task is not a valid method to assess cardioception. PMID- 25553875 TI - "The bio interface". PMID- 25553876 TI - Development of bioactive glass based scaffolds for controlled antibiotic release in bone tissue engineering via biodegradable polymer layered coating. AB - Highly porous 45S5 Bioglass((r))-based scaffolds coated with two polymer layers were fabricated to serve as a multifunctional device with controlled drug release capability for bone regeneration applications. An interior poly(d,l lactide)/poly(ethylene glycol)-(polypropylene glycol)-poly(ethylene glycol) triblock copolymer (Pluronic P123) coating improved the mechanical stability of Bioglass-based scaffolds, while an exterior natural polymer (alginate or gelatin) coating served as an antibiotic drug carrier. The results showed improved mechanical properties of Bioglass-based scaffolds by the bilayer polymer coating. In addition, hydrochloride tetracycline loaded in either alginate or gelatin coatings was released rapidly at the initial stage (~1 h), while the released rate subsequently decreased and was sustained for 14 days in phosphate buffered saline. Therefore, these layered polymer coated scaffolds exhibit attractive characteristics in terms of improved mechanical properties and controlled drug release, simultaneously with the added advantage that the drug release rate is decoupled from the intrinsic scaffold Bioglass degradation mechanism. The layered polymer coated scaffolds are of interest for drug-delivery enhanced bone regeneration applications. PMID- 25553877 TI - Fibrinogen adsorption and platelet adhesion to silica surfaces with stochastic nanotopography. AB - In this study, the effect of surface nanoscale roughness on fibrinogen adsorption and platelet adhesion was investigated. Nanorough silica surfaces with a low level of surface roughness (10 nm Rrms) were found to support the same level of fibrinogen adsorption as the planar silica surfaces, while nanorough silica surfaces with higher levels of surface roughness (15 nm Rrms) were found to support significantly less fibrinogen adsorption. All surfaces analyzed were found to support the same level of platelet adhesion; however, platelets were rounded in morphology on the nanorough silica surfaces while platelets were spread with a well-developed actin cytoskeleton on the planar silica. Unique quartz crystal microbalance with dissipation monitoring (QCM-D) responses was observed for the interactions between platelets and each of the surfaces. The QCM D data indicated that platelets were more weakly attached to the nanorough silica surfaces compared with the planar silica. These data support the role of surface nanotopography in directing platelet-surface interactions even when the adsorbed fibrinogen layer is able to support the same level of platelet adhesion. PMID- 25553878 TI - Toll like receptor 2/1 mediated platelet adhesion and activation on bacterial mimetic surfaces is dependent on src/Syk-signaling and purinergic receptor P2X1 and P2Y12 activation. AB - Platelets are considered to have important functions in inflammatory processes as key players in innate immunity. Toll like receptors (TLRs), expressed on platelets, recognize pathogen associated molecular patterns and trigger immune responses. Pathogens are able to adhere to human tissues and form biofilms which cause a continuous activation of the immune system. The authors aimed to investigate how immobilized Pam3CSK4 (a synthetic TLR2/1 agonist) and IgG, respectively, resembling a bacterial focus, affects adhesion and activation of platelets including release of two cytokines, regulated on activation normal T cell expressed and secreted (RANTES) and macrophage migration inhibitory factor (MIF). The authors also aim to clarify the signaling downstream of TLR2/1 and FcgammaRII (IgG receptor) and the role of adenine nucleotides in this process. Biolayers of Pam3CSK4 and IgG, respectively, were confirmed by null-ellipsometry and contact angle measurements. Platelets were preincubated with signaling inhibitors for scr and Syk and antagonists for P2X1 or P2Y1 [adenosine triphosphate (ATP), adenosine diphosphate (ADP) receptors] prior to addition to the surfaces. The authors show that platelets adhere and spread on both Pam3CSK4- and IgG-coated surfaces and that this process is antagonized by scr and Syc inhibitors as well as P2X1 and P2Y antagonists. This suggests that Pam3CSK4 activated platelets utilize the same pathway as FcgammaRII. Moreover, the authors show that ATP-ligation of P2X1 is of importance for further platelet activation after TLR2/1-activation, and that P2Y12 is the prominent ADP-receptor involved in adhesion and spreading. RANTES and MIF were secreted over time from platelets adhering to the coated surfaces, but no MIF was released upon stimulation with soluble Pam3CSK4. These results clarify the importance of TLR2/1 and FcgammaRII in platelet adhesion and activation, and strengthen the role of platelets as an active player in sensing bacterial infections. PMID- 25553879 TI - Lamellar slippage of bilayers--a hypothesis on low friction of natural joints. AB - The cartilage's amphoteric surface behavior is a physical phenomenon in biological lubrication. However, there is a lack of knowledge on amphoteric phospholipids bilayers and in overcoming friction in cartilage joints. In this paper, friction experiments were conducted, and the cartilage's surface was characterized using pH and wettability, while the interfacial energy and coefficients were determined. The lamellar slippage of bilayers and a short-range repulsion between the interfaces of negatively charged (-PO4 (-)) cartilage surfaces resulted in low frictional properties of the joint. PMID- 25553880 TI - Binary self-assembled monolayers modified Au nanoparticles as carriers in biological applications. AB - Gold nanoparticles (AuNPs) are good nonviral carriers because of their ease of synthesis and conjugation in biochemistry, and self-assembled monolayers (SAMs) provide a tunable system to change their interfacial properties. Using homogeneously mixed carboxylic acid and amine functional groups, a series of surface potentials and isoelectric points (IEPs) could be obtained and allow systematic study of the effect of surface potential. In this work, the result of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that binary-SAM modified AuNPs have high biocompatibility with HEK293T cells. The amount of AuNPs ingested by the cells was found to increase with increasing surface potential and the difference was also confirmed with a scanning transmission electron microscope. The ability of binary-SAM modified AuNPs as carriers was examined, and the plasmid deoxyribose nucleic acid (DNA)-containing eGFP reporter gene was used as the model cargo. Fluorescence imaging revealed that the transfection efficiency generally increased with increasing surface potential. More importantly, when the IEP of the AuNPs was higher than that of the environment of the endosome but lower than that of the cytoplasm, the plasmid DNA can be protected better and released more easily during the endocytosis process hence higher efficiency is obtained with 60% NH2 and 40% COOH in the binary-SAM. PMID- 25553881 TI - Applicability of the extended Derjaguin-Landau-Verwey-Overbeek theory on the adsorption of bovine serum albumin on solid surfaces. AB - Protein adsorption is the prerequisite for bacterial attachment and cellular adhesion, which are critical for many biomedical applications. To understand protein adsorption onto substrates, predictive models are generally informative prior to experimental studies. In this study, the extended Derjaguin-Landau Verwey-Overbeek (XDLVO) theory was employed to determine whether or not it could interpret the protein adsorption behaviors. The experimental results of fluorescein isothiocyanate labeled bovine serum albumin (BSA) adsorbed on six different surfaces: glass, octadecyltrichlorosilane modified glass, 2 [methoxypoly(ethyleneoxy)propyl]trimethoxy-silane (PEG)-modified glass, polystyrene, poly(dimethylsiloxane), and poly(methyl methacrylate) were utilized. The XDLVO interaction energy curves, especially from the contribution of acid base interactions, obtained using the surface properties of substrates and BSA molecules qualitatively predict/interpret the protein adsorption behaviors on these surfaces. Some derivation of the experimental results from the prediction was noticed for the glass and the PEG-modified glass. When including a hydration layer to the PEG-modified glass surface, the nonfouling result of such surface by proteins was also elucidated by the XDLVO theory. PMID- 25553883 TI - Comment on: Does the closure of mesenteric defects during laparoscopic gastric bypass surgery cause complications? PMID- 25553884 TI - Comment on: What is 'grazing'? Reviewing its definition, frequency, clinical characteristics, and impact on bariatric surgery outcomes, and proposing a standardized definition. PMID- 25553885 TI - Comment on: Bari-Active: a randomized controlled trial of a preoperative intervention to increase physical activity in bariatric surgery patients. PMID- 25553886 TI - Accuracy of routine postoperative swallow study in predicting leak or obstruction after gastric bypass. AB - BACKGROUND: Many bariatric surgeons use a routine postoperative day 1 swallow study after Roux-en-Y gastric bypass to rule out leak or obstruction. The authors' practice adheres to this dictum, but the aim of this study was to determine how accurate this testing is in properly predicting complications. METHODS: A retrospective chart review of all patients undergoing gastric bypass in the past 5 years (2008-2012) was performed; the results of their swallow study was examined and compared with their actual clinical outcome within 30 days of operation. RESULTS: The records of 501 patients were reviewed, and there were 15 leaks and 29 obstructions for a total prevalence rate of 9%. When the swallow study was negative, 33 complications were missed and 433 reports were correct. When the swallow study was positive, only 11 complications were correctly identified and 24 of the reports were false positive. The sensitivity of the test was only 25%. The positive predictive value was only 31%. The result of the swallow study was incorrect 12% of the time. CONCLUSION: Routine postoperative swallow study after gastric bypass was a poor method of accurately detecting clinically significant obstruction or leak. This test may be unnecessary for all patients and might best be used when clinically indicated. PMID- 25553887 TI - Acid suppression medications are associated with suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass in patients older than 40 years. AB - BACKGROUND: Bariatric surgery, including laparoscopic Roux-en-Y gastric bypass (LRYGB), achieves the greatest long-term weight loss in severe obesity. Approximately 50%-60% of severely obese patients have gastroesophageal reflux disease, and a substantial proportion is taking a proton pump inhibitor (PPI) or histamine-2 blocker (H2 B) at the time of LRYGB. The objective of this study was to explore the association of PPI/H2 B use before LRYGB with suboptimal percent weight loss (PWL) after LRYGB. METHODS: This was a cohort study of 472 consecutive patients who underwent LRYGB at a single center from 2004-2011. Suboptimal PWL was defined as<14% at 2 months,<25% at 6 months, and<30% at 12 months. Because of effect modification by age, stratified analyses (by median age of 40 yr) were performed. All models were adjusted for appropriate covariates, including obesity-associated co-morbidities. RESULTS: For patients aged <=40 years, PPI/H2 B use leading up to LRYGB was not associated with suboptimal PWL at 2 months (P = .86), 6 months (P = .47), or 12 months (P = .66). However, for patients aged>40 years, PPI/H2 B use leading up to LRYGB was associated with a nonsignificant increase in suboptimal PWL at 2 months (odds ratio [OR] 2.23; P = .08) and significant increases in suboptimal PWL at 6 months (OR 7.23; P = .002) and 12 months (OR 11.1; P = .02). Results were independent of GERD. CONCLUSIONS: Mechanisms for the poorer weight loss in patients aged>40 years who were using a PPI/H2 B just before LRYGB should be explored. PMID- 25553888 TI - Malabsorption plays a major role in the effects of the biliopancreatic diversion with duodenal switch on energy metabolism in rats. AB - BACKGROUND: The mechanisms underlying the metabolic benefits of the biliopancreatic diversion with duodenal switch (BPD/DS) have not been clarified. The objective of this study was to investigate the metabolic roles of sleeve gastrectomy (SG) and duodenal switch (DS) as main surgical components of BPD/DS. METHODS: BPD/DS, SG, and DS surgeries were performed on chow-fed nonobese Wistar rats. Weight and energy intake were recorded during 8 postsurgical weeks. Glucagon-like peptide 1 (GLP-1), peptide tyrosine-tyrosine (PYY), glucose dependent insulinotropic peptide, and ghrelin were measured pre- and postprandially at weeks 3 and 8, after surgery. Body composition, muscle, liver, and adipose tissue weights were measured. Gut morphometry and the presence and distribution of GLP-1 and PYY (L-cells) in the gut were determined using histochemical techniques. RESULTS: Compared with sham, BPD/DS and DS led to significant reductions in weight gain, percentage of fat, and adipose tissue weight. These effects were accompanied by a reduction in digestible energy intake associated with fecal energy loss due to DS. BPD/DS and DS produced intestinal hypertrophy, as well as higher plasma GLP-1 and PYY in both fasted and refed states. It is noteworthy that none of those alterations were observed after SG, which nonetheless led to transient postoperative reduction in gross energy intake and weight. Similar to BPD/DS, SG alone produced a reduced meal size and an enhanced postprandial depression of plasma ghrelin. CONCLUSION: BPD/DS results in metabolic benefits, which appear largely caused by food malabsorption due to DS. The elevation of anorectic GLP-1 and PYY are additional consequences of DS, which, together with malabsorption, could promote the metabolic benefits of BPD/DS. PMID- 25553889 TI - Efficacy and safety of brodalumab in subpopulations of patients with difficult-to treat moderate-to-severe plaque psoriasis. AB - BACKGROUND: Novel therapies are needed for difficult-to-treat populations of patients with psoriasis. OBJECTIVE: We sought to assess the efficacy and safety of the interleukin-17 Receptor A inhibitor brodalumab in patients with psoriasis with or without a self-reported history of psoriatic arthritis (PsA) and with or without a history of biologic use. METHODS: Subset analyses of a phase II, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis were performed. Improvement from baseline in Psoriasis Area and Severity Index score of 75%, 90%, and 100% at week 12; static Physician Global Assessment (0/1) score; Dermatology Life Quality Index response; and Psoriasis Symptom Inventory response were evaluated within subgroups. RESULTS: Efficacy and quality-of-life measures were generally similar between subgroups of patients with or without a history of PsA and with or without a history of biologic use across brodalumab doses and were significantly higher among patients who received brodalumab 140 mg every 2 weeks or 210 mg every 2 weeks versus placebo. LIMITATIONS: Differences between subgroups were not compared statistically, PsA was self-reported, only skin involvement/symptoms were reported, and reasons for discontinuation of prior biologic were not captured. CONCLUSION: Brodalumab is efficacious in patients with psoriasis with or without a history of PsA or biologic use. PMID- 25553890 TI - Drug interactions with new hepatitis C oral drugs. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection has recently become a curable disease with antiviral therapy. The knowledge of drug interactions using direct-acting antivirals (DAA) may permit maximizing antiviral efficacy and avoiding drug-related toxicities. Ageing in the chronic hepatitis C population, along with added co-morbidities that require other medications, has increased the attention on drug interactions using DAA. AREAS COVERED: This review provides an update of the most clinically significant pharmacokinetic and pharmacodynamic drug interactions occurring between currently available DAA and other medications. The review also revisits how drug interactions with DAA can be prevented and managed. EXPERT OPINION: Interactions between DAA and other drugs are frequent in clinical practice. The most frequent drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposures. Through this mechanism HCV protease inhibitors, especially when co-formulated with ritonavir as pharmacoenhancer, and non nucleoside HCV polymerase inhibitors interact with other medications. In contrast, NS5B nucleos(t)ide analog inhibitors (i.e., sofosbuvir) and some HCV NS5A inhibitors (i.e., ledipasvir), which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions. However, exposure to HCV nucleos(t)ide analogs may be influenced by induction/inhibition of drug transporters (i.e., P-glycoprotein) as well as by pharmacodynamic interference with other nucleos(t)ide analogs used as antivirals or cancer drugs. Drug interactions for some NS5A inhibitors (i.e., daclatasvir) are generally moderate and can be managed with dose adjustments. PMID- 25553891 TI - Structure activity relationships of human galactokinase inhibitors. AB - Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1 phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibitor. PMID- 25553892 TI - Characterization of TRIF selectivity in the AGP class of lipid A mimetics: role of secondary lipid chains. AB - TLR4 agonists that favor TRIF-dependent signaling and the induction of type 1 interferons may have potential as vaccine adjuvants with reduced toxicity. CRX 547 (4), a member of the aminoalkyl glucosaminide 4-phosphate (AGP) class of lipid A mimetics possessing three (R)-3-decanoyloxytetradecanoyl groups and d relative configuration in the aglycon, selectively reduces MyD88-dependent signaling resulting in TRIF-selective signaling, whereas the corresponding secondary ether lipid 6a containing (R)-3-decyloxytetradecanoyl groups does not. In order to determine which secondary acyl groups are important for the reduction in MyD88-dependent signaling activity of 4, the six possible ester/ether hybrid derivatives of 4 and 6a were synthesized and evaluated for their ability to induce NF-kappaB in a HEK293 cell reporter assay. An (R)-3 decanoyloxytetradecanoyl group on the 3-position of the d-glucosamine unit was found to be indispensable for maintaining low NF-kappaB activity irrespective of the substitutions (decyl or decanoyl) on the other two secondary positions. These results suggest that the carbonyl group of the 3-secondary lipid chain may impede homodimerization and/or conformational changes in the TLR4-MD2 complex necessary for MyD88 binding and pro-inflammatory cytokine induction. PMID- 25553894 TI - Bowel obstruction secondary to radiation enteritis: a case report. PMID- 25553893 TI - Accidental ingestion of magnets in pediatrics: emerging health problem. PMID- 25553895 TI - Hysteroscopy for infertile women: a review. AB - Hysteroscopy is widely performed in infertile women. A review of peer-reviewed, published literature from the PubMed database on uterine intracavitary pathology, proximal tubal occlusion, failed in vitro fertilization procedures, and first trimester miscarriages of infertile women was performed to examine the importance, feasibility, and success rates of diagnostic and operative hysteroscopy when evaluating and treating these conditions. PMID- 25553896 TI - Food composition influences metabolism, heart rate and organ growth during digestion in Python regius. AB - Digestion in pythons is associated with a large increase in oxygen consumption (SDA), increased cardiac output and growth in visceral organs assisting in digestion. The processes leading to the large postprandial rise in metabolism in snakes is subject to opposing views. Gastric work, protein synthesis and organ growth have each been speculated to be major contributors to the SDA. To investigate the role of food composition on SDA, heart rate (HR) and organ growth, 48 ball pythons (Python regius) were fed meals of either fat, glucose, protein or protein combined with carbonate. Our study shows that protein, in the absence or presence of carbonate causes a large SDA response, while glucose caused a significantly smaller SDA response and digestion of fat failed to affect metabolism. Addition of carbonate to the diet to stimulate gastric acid secretion did not increase the SDA response. These results support protein synthesis as a major contributor to the SDA response and show that increased gastric acid secretion occurs at a low metabolic cost. The increase in metabolism was supported by tachycardia caused by altered autonomic regulation as well as an increased non-adrenergic, non-cholinergic (NANC) tone in response to all diets, except for the lipid meal. Organ growth only occurred in the small intestine and liver in snakes fed on a high protein diet. PMID- 25553897 TI - Dependence of particle concentration effect on pH and redox for arsenic removal by FeS-coated sand under anoxic conditions. AB - FeS has been recognized as a good scavenger for arsenic under anoxic conditions. To create a suitable adsorbent for flow-through reactors such as permeable reactive barriers, it has been suggested that this material may be coated onto sand. However, previous work on FeS-coated sand has focused on batch reactors, while flow-through reactors usually have higher solid-solution ratios. To ascertain whether differences in the solid-solution ratio (SSR) are important in this system, batch sorption experiments were conducted as a function of pH using As(III) and FeS-coated sands at various solid-solution ratios. The results showed little variation in the distribution coefficient with SSR at pH 7 and 9. However, at pH 5, the results showed lower values of the distribution coefficient at lower SSRs, the reverse of typically reported SSR effects. Measured pe values showed a dependence on SSR, which, when coupled with chemical modeling of the Fe-As-S-H2O system, suggested a change in the removal mechanism with SSR, from adsorption to a reduced Fe(II) oxyhydroxide phase (represented by Fe2(OH)5) to precipitation as As2S3 or AsS. On the other hand, at pH 7 and 9, arsenite adsorption is the most probable removal mechanism regardless of the pe. Thus, this study identified variations in pH and redox conditions, and the removal mechanisms that these parameters govern, as the reason for the apparent SSR effect. PMID- 25553898 TI - The role of cell surfaces and cellular receptors in the mode of action of recombinant factor VIIa. AB - Recombinant factor VIIa (rFVIIa) has been developed to treat bleeding episodes in patients with inhibitor-complicated hemophilia. More recently, it has become apparent that rFVIIa is also useful in a prophylactic setting, although its prophylactic effect with a once-daily administration is difficult to explain given its half life of ~2h. The prohemostatic effects of rFVIIa have been ascribed to enhancement of thrombin generation and various downstream effects thereof. There is an ongoing debate on the tissue factor-dependency of rFVIIa, but accumulating evidence is in favor of a TF-independent mechanism. rFVIIa interacts with cellular surfaces and with various receptors on vascular cells. These interactions may contribute significantly to its mode of action in patients with hemophilia. In this review we will summarize laboratory and clinical evidence on the mode of action of rFVIIa in hemophilia with an emphasis on recent insights regarding the interactions of rFVIIa with cellular receptors. PMID- 25553908 TI - Cytotoxic flavonoids and other constituents from the stem bark of Ochna schweinfurthiana. AB - Seven flavonoids, hemerocallone (1), 6,7-dimethoxy-3',4'-dimethoxyisoflavone (2), amentoflavone (4), agathisflavone (6), cupressuflavone (8), robustaflavone (9) and epicatechin (10), together with three other compounds, lithospermoside (3), beta-D-fructofuranosyl-alpha-D-glucopyranoside (5) and 3beta-O-D-glucopyranosyl beta-stigmasterol (7), were isolated from the ethyl acetate extract of the stem bark of Ochna schweinfurthiana F. Hoffm. All the compounds were characterised by spectroscopic and mass spectrometric methods, and by comparison with literature data. Cytotoxicity of the extracts and compounds against cervical adenocarcinoma (HeLa) cells was evaluated by MTT assay. Compounds 4 and 6 exhibited good cytotoxic activity, with IC50 values of 20.7 and 10.0 MUM, respectively. PMID- 25553909 TI - Effect of pressure pulses at the interface valve on the stability of second dimension columns in online comprehensive two-dimensional liquid chromatography. AB - Users of online comprehensive two-dimensional liquid chromatography (LCxLC) frequently acknowledge that the mechanical instability of HPLC columns installed in these systems, particularly in the second dimension, is a significant impediment to its use. Such instability is not surprising given the strenuous operating environment to which these columns are subjected, including the large number (thousands per day) of fast and large pressure pulses resulting from interface valve switches (on the timescale of tens of milliseconds) associated with very fast second dimension separations. There appear to be no published reports of systematic studies of the relationship between second dimension column lifetime and any of these variables. In this study we focused on the relationship between the lifetimes of commercially available columns and the pressure pulses observed at the inlet of the second dimension column that occur during the switching of the valve that interfaces the two dimensions of a LCxLC system. We find that the magnitude of the pressure drop at the inlet of the second dimension column during the valve switch, which may vary between 10 and 95% of the column inlet pressure, is dependent on valve switching speed and design, and has a dramatic impact on column lifetime. In the worst case, columns fail within the first few hours of use in an LCxLC system. In the best case, using a valve that exhibits much smaller pressure pulses, the same columns exhibit much improved lifetimes and have been used continuously under LCxLC conditions for several days with no degradation in performance. This result represents a first step in understanding the factors that affect second dimension column lifetime, and will significantly improve the usability of the LCxLC technique in general. PMID- 25553907 TI - Uncovering the novel characteristics of Asian honey bee, Apis cerana, by whole genome sequencing. AB - BACKGROUND: The honey bee is an important model system for increasing understanding of molecular and neural mechanisms underlying social behaviors relevant to the agricultural industry and basic science. The western honey bee, Apis mellifera, has served as a model species, and its genome sequence has been published. In contrast, the genome of the Asian honey bee, Apis cerana, has not yet been sequenced. A. cerana has been raised in Asian countries for thousands of years and has brought considerable economic benefits to the apicultural industry. A cerana has divergent biological traits compared to A. mellifera and it has played a key role in maintaining biodiversity in eastern and southern Asia. Here we report the first whole genome sequence of A. cerana. RESULTS: Using de novo assembly methods, we produced a 238 Mbp draft of the A. cerana genome and generated 10,651 genes. A.cerana-specific genes were analyzed to better understand the novel characteristics of this honey bee species. Seventy-two percent of the A. cerana-specific genes had more than one GO term, and 1,696 enzymes were categorized into 125 pathways. Genes involved in chemoreception and immunity were carefully identified and compared to those from other sequenced insect models. These included 10 gustatory receptors, 119 odorant receptors, 10 ionotropic receptors, and 160 immune-related genes. CONCLUSIONS: This first report of the whole genome sequence of A. cerana provides resources for comparative sociogenomics, especially in the field of social insect communication. These important tools will contribute to a better understanding of the complex behaviors and natural biology of the Asian honey bee and to anticipate its future evolutionary trajectory. PMID- 25553910 TI - Bicyclic naphthenic acids in oil sands process water: identification by comprehensive multidimensional gas chromatography-mass spectrometry. AB - Although bicyclic acids have been reported to be the major naphthenic acids in oil sands process-affected water (OSPW) and a well-accepted screening assay indicated that some bicyclics were the most acutely toxic acids tested, none have yet been identified. Here we show by comprehensive multidimensional gas chromatography-mass spectrometry (GC*GC-MS), that >100 C8-15 bicyclic acids are typically present in OSPW. Synthesis or purchase allowed us to establish the GC*GC retention times of methyl esters of numerous of these and the mass spectra and published spectra of some additional types, allowed us to identify bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.3.0]nonane, bicyclo[3.3.1]nonane and bicyclo[4.4.0]decane acids in OSPW and a bicyclo[2.2.2]octane acid in a commercial acid mixture. The retention positions of authentic bicyclo[3.3.0]octane and bicyclo[4.2.0]octane carboxylic acid methyl esters and published retention indices, showed these were also possibilities, as were bicyclo[3.1.1]heptane acids. Bicyclo[5.3.0]decane and cyclopentylcyclopentane carboxylic acids were ruled out in the samples analysed, on the basis that the corresponding alkanes eluted well after bicyclo[4.4.0]decane (latest eluting acids). Bicyclo[4.2.1]nonane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, bicyclo[4.2.2]decane and spiro[4.5]decane carboxylic acids could not be ruled out or in, as no authentic compounds or literature data were available. Mass spectra of the methyl esters of the higher bicyclic C12-15 acids suggested that many were simply analogues of the acids identified above, with longer alkanoate chains and/or alkyl substituents. Our hypothesis is that these acids represent the biotransformation products of the initially somewhat more bio-resistant bicyclanes of petroleum. Although remediation studies suggest that many bicyclic acids can be relatively quickly removed from suitably treated OSPW, examination by GC*GC-MS may show which isomers are affected most. Knowledge of the structures will allow the toxicity of any residual isomers to be calculated and measured. PMID- 25553911 TI - Expedient access to alpha,beta-difunctionalized azepenes using alpha-halo eneformamides: application to the one-pot synthesis of 2-benzazepanes. AB - The regioselective synthesis of alpha,beta-difunctionalized (alkenyl, aryl, sulfonyl, allyl, or alkynyl) azepenes has been accomplished through alpha-halo eneformamides. A successful implementation of the vicinal functionalization strategy has led to a one-pot synthesis of 2-benzazepanes whose benzenoid portion is highly functionalized. PMID- 25553912 TI - Color properties of the motion detectors projecting to the goldfish tectum: II. Selective stimulation of different chromatic types of cones. AB - Sensitivity to the sign of contrast of direction-selective (DS) and orientation selective (OS) ganglion cells (GCs) was investigated with selective stimulation of different chromatic types of cones. It was shown that the DS GCs that were classified with the use of achromatic stimuli as belonging to the ON type responded to selective stimulation of the long-wave cones as the ON type also, while the stimulation of middle-wave or short-wave cones elicited the OFF type responses. Character of the responses of DS GCs of the OFF type was exactly the opposite. OS GCs, which responded to achromatic stimuli as the ON-OFF type, responded to selective stimulation of the long-wave cones as the ON-OFF type as well, responded to middle-wave stimulation as the OFF type and to stimulation of short-wave cones it responded mainly as the ON type. At the same time, under color-selective stimulation, both DS and OS GCs retained the directional and orientation selectivity with the same preferred directions. The results obtained are in favor of the idea that the signals from the different chromatic types of cones are combined in the outer synaptic layer of the retina at the inputs of bipolar cells using sign-inverting and/or sign-conserving synapses, while specific spatial properties of motion detectors are formed in the inner synaptic layer. PMID- 25553913 TI - Potential approaches for more successful dendritic cell-based immunotherapy. AB - INTRODUCTION: Dendritic cells (DCs) are the most important antigen-presenting cell population for activating antitumor T-cell responses; therefore, they offer a unique opportunity for specific targeting of tumors. AREAS COVERED: We will discuss the critical factors for the enhancement of DC vaccine efficacy: different DC subsets, types of in vitro DC manufacturing protocol, types of tumor antigen to be loaded and finally different adjuvants for activating them. We will cover potential combinatorial strategies with immunomodulatory therapies: depleting T-regulatory (Treg) cells, blocking VEGF and blocking inhibitory signals. Furthermore, recommendations to incorporate these criteria into DC-based tumor immunotherapy will be suggested. EXPERT OPINION: Monocyte-derived DCs are the most widely used DC subset in the clinic, whereas Langerhans cells and plasmacytoid DCs are two emerging DC subsets that are highly effective in eliciting cytotoxic T lymphocyte responses. Depending on the type of tumor antigens selected for loading DCs, it is important to optimize a protocol that will generate highly potent DCs. The future aim of DC-based immunotherapy is to combine it with one or more immunomodulatory therapies, for example, Treg cell depletion, VEGF blockage and T-cell checkpoint blockage, to elicit the most optimal antitumor immunity to induce long-term remission or even cure cancer patients. PMID- 25553914 TI - Hierarchically porous and nitrogen, sulfur-codoped graphene-like microspheres as a high capacity anode for lithium ion batteries. AB - Novel hierarchically porous and nitrogen, sulfur-codoped graphene-like microspheres (3D NS-GSs) are synthesized using Ni microspheres as the template and using poly(vinylpyrrolidone) and (NH4)2S2O8 as the carbon and nitrogen precursor, respectively. As an anode material in lithium ion batteries, the 3D NS GS electrode displays a superior capacity with excellent cycling stability. PMID- 25553916 TI - Garcinielliptone FC: antiparasitic activity without cytotoxicity to mammalian cells. AB - Garcinielliptone FC (GFC) is a natural prenylated benzophenone found in the seeds of Platonia insignis Mart. (Clusiaceae), a native Brazilian plant. It has been chemically characterized and it is known that GFC has several biological activities such as antioxidant and vasorelaxant properties. In this study, we report the in vitro effect of GFC against the blood fluke Schistosoma mansoni, the parasite responsible for schistosomiasis mansoni. The anti-S. mansoni activity and cytotoxicity toward mammalian cells were determined for the compound. GFC?6.25 MUM showed antischistosomal activity and confocal laser scanning microscopy analysis demonstrated several morphological alterations on the tegument of worms, and a correlation between viability and tegumental damage was observed. In addition, at sub-lethal concentrations of GFC (?3.125 MUM), the number of S. mansoni eggs was reduced. More importantly, GFC exhibited no activity toward mammalian cells and, therefore, there is an appreciable selectivity of this compound against the helminths. In conclusion, these findings indicate the potential of GFC as an antiparasitic agent. PMID- 25553915 TI - Morphometric assessment of toxicant induced neuronal degeneration in full and restricted contact co-cultures of embryonic cortical rat neurons and astrocytes: using m-Dinitrobezene as a model neurotoxicant. AB - With m-Dinitrobenzene (m-DNB) as a selected model neurotoxicant, we demonstrate how to assess neurotoxicity, using morphology based measurement of neurite degeneration, in a conventional "full-contact" and a modern "restricted-contact" co-culture of rat cortical neurons and astrocytes. In the "full-contact" co culture, neurons and astrocytes in complete physical contact are "globally" exposed to m-DNB. A newly emergent "restricted-contact" co-culture is attained with a microfluidic device that polarizes neuron somas and neurites into separate compartments, and the neurite compartment is "selectively" exposed to m-DNB. Morphometric analysis of the neuronal area revealed that m-DNB exposure produced no significant change in mean neuronal cell area in "full-contact" co-cultures, whereas a significant decrease was observed for neuron monocultures. Neurite elaboration into a neurite exclusive compartment in a compartmentalized microfluidic device, for both monocultures (no astrocytes) and "restricted" co cultures (astrocytes touching neurites), decreased with exposure to increasing concentrations of m-DNB, but the average neurite area was higher in co-cultures. By using co-culture systems that more closely approach biological and architectural complexities, and the directionality of exposure found in the brain, this study provides a methodological foundation for unraveling the role of physical contact between astrocytes and neurons in mitigating the toxic effects of chemicals such as m-DNB. PMID- 25553917 TI - Octylphenol induces changes in glycosylation pattern, calcium level and ultrastructure of bank vole spermatozoa in vitro. AB - Our previous studies revealed that in bank vole testicular cells octylphenol (OP) action is related either to its binding to estrogen receptors or increasing cAMP level that modulates spermatozoa motility and acrosome reaction (AR), (Kotula Balak et al., 2011, 2014). To better understand the mechanisms underlying these changes, in the present study we aimed at evaluating the glycosylation pattern, calcium (Ca(2+)) level and ultrastructure of OP-treated vole spermatozoa. Glycans were recognized by lectins and localized for the first time on the surface of acrosomal cap and tail of vole spermatozoa. Expression and localization of glycans were determined histochemically and analyzed quantitatively. Following OP the expression of glycans markedly changed with concomitant increase of intracellular Ca(2+) concentration. Altered Ca(2+) signaling pathway and ultrastructural changes in sperm acrosome region were revealed by immunoenzymatic assay and electron microscope analysis together with hypo-osmotic swelling test, respectively. In detail, AR advancement reflected by the presence of small vesicles in the close vicinity to the sperm head was observed, while tail membrane integrity remained intact. Our study provides a new insight on OP direct effects on precocious AR of vole spermatozoa through modulation of the glycan expression and its distribution concomitantly with changes in Ca(2+) signaling pathway and acrosome ultrastructure in vitro. PMID- 25553919 TI - Fluoride binding in water with the use of micellar nanodevices based on salophen complexes. AB - The use of micelles to transpose lipophilic receptors, such as uranyl-salophen complexes, into an aqueous environment is a valuable and versatile tool. Receptor 1 incorporated into CTABr micelles forms a supramolecular system that exhibits excellent binding properties towards fluoride in water, despite the competition of the aqueous medium. To fully evaluate the potential of micellar nanodevices, we extended our previous study to other types of surfactants and to a uranyl salophen receptor with a more extended aromatic surface. Paramagnetic relaxation enhancement experiments were used to obtain information on the location of the two receptors within the micelles and complementary information was obtained from dynamic light scattering experiments. With these data it is possible to account for the key factors necessary to obtain an efficient supramolecular device for anion binding in water. PMID- 25553918 TI - UHPLC-MS/MS determination of ochratoxin A and fumonisins in coffee using QuEChERS extraction combined with mixed-mode SPE purification. AB - A method was developed for simultaneous determination of the mycotoxins: ochratoxin A (OTA) and fumonisins B2 (FB2), B4 (FB4), and B6 (FB6) in green, roasted, and instant coffee. Extraction was performed by QuEChERS (quick, easy, cheap, effective, rugged, and safe) under acidic conditions followed by mixed mode reversed phase-anion exchange solid phase extraction. OTA and FB2 were detected at levels down to 0.5 and 2 MUg/kg by UHPLC-MS/MS and quantitated via isotope dilution using U-(13)C-labeled FB2 and OTA as internal standards. Mixing 20% isopropanol in the acetonitrile of the acidic UHPLC gradient system increased the signal intensity by 50% and decreased the ion-suppression with 50-75% in roasted coffee samples. About half of the roasted coffee samples (n = 57, from 9 countries) contained detectable levels of OTA, however, with only 5 samples above the EU regulatory limit of 5 MUg/kg and the highest with 21 MUg/kg. None of the 25 instant coffee samples contained OTA above the EU regulatory level of 10 MUg/kg. Nonetheless, the toxin could be detected in 56% of the analyzed instant coffee samples. Fumonisins were not detected in any of the roasted or instant coffee samples (n = 82). However, in the green coffee samples (n = 18) almost half of the samples were positive with a maximum value of 164 MUg/kg (sum of FB2, FB4, and FB6). This discrepancy between green coffee and processed coffees indicated that the fumonisins decompose during the roasting process, which was confirmed in roasting experiments. Here fumonisins could not be detected after roasting of the green, 164 MUg/kg coffee, sample. Under the same conditions, OTA was reduced from 2.4 to 0.5 MUg/kg. PMID- 25553920 TI - A quality assessment index framework for public health services: a Delphi study. AB - OBJECTIVES: This study sought consensus-based indices for quality assessment of the public health service (QAPHS) to evaluate the service quality of public health in Shenzhen and other cities in China. STUDY DESIGN: A qualitative study. METHODS: A list of quality assessment indices was formed based on Donabedian theory. These indices were presented to an expert panel in a two-round Delphi study to establish a consensus view. A weight of indices was established to validate the applicability and practicability of the framework. The specialist authority coefficient and Kendall's W were also calculated based on statistical analysis. RESULTS: A total of 30 experts participated in the Delphi study. Consensus was reached on four first-grade indices, nine second-grade indices and 28 third-grade indices. The specialist authority coefficient (Cr) was high (between 0.88 and 0.92), while Kendall's coefficient (W) of all the indices was >0.5 with statistical significant differences (P < 0.05). This indicated correlation among panelists and had high reliability. CONCLUSIONS: A unified and hierarchical quality assessment index framework for public health services was established. The framework should be further tested and improved in practice. PMID- 25553921 TI - The 'dirty downside' of global sporting events: focus on human trafficking for sexual exploitation. AB - OBJECTIVES: Human trafficking is as complex human rights and public health issue. The issue of human trafficking for sexual exploitation at large global sporting events has proven to be elusive given the clandestine nature of the industry. This piece examines the issue from a public health perspective. STUDY DESIGN: This is a literature review of the 'most comprehensive' studies published on the topic. METHODS: A PubMed search was done using MeSH terms 'human traffickings' and 'sex trafficking' and 'human rights abuses'. Subheadings included 'statistics and numerical data', 'legislation and jurispudence', 'prevention and control', and 'therapy'. Only papers published in English were reviewed. RESULTS: The search showed that very few well-designed empirical studies have been conducted on the topic and only one pertinent systematic review was identified. Findings show a high prevalence of physical violence among those trafficked compared to non-trafficked women. Sexually transmitted infections and HIV AIDS are prevalent and preventive care is virtually non-existent. CONCLUSION: Quantifying human trafficking for sexual exploitation at large global sporting events has proven to be elusive given the clandestine nature of the industry. This is not to say that human trafficking for sex as well as forced sexual exploitation does not occur. It almost certainly exists, but to what extent is the big question. It is a hidden problem on a global scale in plain view with tremendous public health implications. PMID- 25553922 TI - (L)-Lysine-assisted fabrication of PdxPt1-x/Ni(OH)2 (0 <= x <= 1) hybrids with composition-dependent catalytic properties. AB - A fast and facile self-assembly method has been developed to deposit 3-5 nm sized PdxPt1-x (0 <= x <= 1) nanoparticles (NPs) on Ni(OH)2 nanosheets. The biomolecule l-lysine has been used here as the linker to hybridize PdxPt1-x NPs and Ni(OH)2 nanosheets together. The catalytic properties of the obtained PdxPt1-x/Ni(OH)2 hybrids were evaluated by employing the reduction of 4-nitrophenol (4-NP) to 4 aminophenol (4-AP) by NaBH4 as a model reaction. The results reveal that the stability, activity and recyclability of PdxPt1-x NPs have been remarkably enhanced after being supported on Ni(OH)2 nanosheets. Moreover, the influence of the composition of noble metals on the catalytic properties has been studied in depth and Pd0.5Pt0.5/Ni(OH)2 hybrids show the optimal catalytic properties. PMID- 25553923 TI - Early growth response 2 (Egr-2) expression is triggered by NF-kappaB activation. AB - Transcription factors are known to play multiple roles in cellular function. Investigators report that factors such as early growth response (Egr) protein and nuclear factor kappa B (NF-kappaB) are activated in the brain during cancer, brain injury, inflammation, and/or memory. To explore NF-kappaB activity further, we investigated the transcriptomes of hippocampal slices following electrical stimulation of NF-kappaB p50 subunit knockout mice (p50-/-) versus their controls (p50+/+). We found that the early growth response gene Egr-2 was upregulated by NF-kappaB activation, but only in p50+/+ hippocampal slices. We then stimulated HeLa cells and primary cortical neurons with tumor necrosis factor alpha (TNFalpha) to activate NF-kappaB and increase the expression of Egr-2. The Egr-2 promoter sequence was analyzed for NF-kappaB binding sites and chromatin immunoprecipitation (ChIP) assays were performed to confirm promoter occupancy in vivo. We discovered that NF-kappaB specifically binds to an NF-kappaB consensus binding site within the proximal promoter region of Egr-2. Luciferase assay demonstrated that p50 was able to transactivate the Egr-2 promoter in vitro. Small interfering RNA (siRNA)-mediated p50 knockdown corroborated other Egr-2 expression studies. We show for the first time a novel link between NF-kappaB activation and Egr-2 expression with Egr-2 expression directly controlled by the transcriptional activity of NF-kappaB. PMID- 25553930 TI - Evaluation of the MeltPro TB/STR assay for rapid detection of streptomycin resistance in Mycobacterium tuberculosis. AB - Rapid and comprehensive detection of drug-resistance is essential for the control of tuberculosis, which has facilitated the development of molecular assays for the detection of drug-resistant mutations in Mycobacterium tuberculosis. We hereby assessed the analytical and clinical performance of an assay for streptomycin-resistant mutations. MeltPro TB/STR is a closed-tube, dual-color, melting curve analysis-based, real-time PCR test designed to detect 15 streptomycin-resistant mutations in rpsL 43, rpsL 88, rrs 513, rrs 514, rrs 517, and rrs 905-908 of M. tuberculosis. Analytical studies showed that the accuracy was 100%, the limit of detection was 50-500 bacilli per reaction, the reproducibility in the form of Tm variation was within 1.0 degrees C, and we could detect 20% STR resistance in mixed bacterial samples. The cross-platform study demonstrated that the assay could be performed on six models of real-time PCR instruments. A multicenter clinical study was conducted using 1056 clinical isolates, which were collected from three geographically different healthcare units, including 709 STR-susceptible and 347 STR-resistant isolates characterized on Lowenstein-Jensen solid medium by traditional drug susceptibility testing. The results showed that the clinical sensitivity and specificity of the MeltPro TB/STR was 88.8% and 95.8%, respectively. Sequencing analysis confirmed the accuracy of the mutation types. Among all the 8 mutation types detected, rpsL K43R (AAG -> AGG), rpsL K88R (AAG -> AGG) and rrs 514 A -> C accounted for more than 90%. We concluded that MeltPro TB/STR represents a rapid and reliable assay for the detection of STR resistance in clinical isolates. PMID- 25553931 TI - Male anorgasmia as initial symptom of transverse myelitis. PMID- 25553932 TI - Benefits of music therapy on behaviour disorders in subjects diagnosed with dementia: a systematic review. AB - INTRODUCTION: Dementia is characterised by cognitive deterioration and the manifestation of psychological and behavioural symptoms, especially changes in perception, thought content, mood, and conduct. In addition to drug therapy, non pharmacological treatments are used to manage these symptoms, and one of these latter treatments is music therapy. Since this novel technique in non-verbal, it can be used to treat patients with dementia at any stage, even when cognitive deterioration is very severe. Patients' responses to music are conserved even in the most advanced stages of the disease DEVELOPMENT: A literature research was carried out using the following databases: Academic Search Complete, PubMed, Science Direct y Dialnet. The period of publication was 2003 to 2013 and the search keywords were 'Music Therapy, Dementia, Behaviour, Behaviour Disorders y Behavioural Disturbances'. Out of the 2188 studies that were identified, 11 studies met inclusion criteria for the systematic review. CONCLUSIONS: Music therapy is beneficial and improves behavior disorders, anxiety and agitation in subjects diagnosed with dementia. PMID- 25553933 TI - Spinal arachnoid cysts as an unusual cause of exercise headache. PMID- 25553934 TI - Altered neurocognitive functions in a patient with carbon monoxide poisoning. PMID- 25553936 TI - Comments on the 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. PMID- 25553935 TI - Comments on the 2014 ESC Guidelines on the diagnosis and management of hypertrophic cardiomyopathy. A critical view from the perspective of Spanish cardiology. PMID- 25553937 TI - Blood glucose in acute coronary syndromes. How low should you go? AB - INTRODUCTION AND OBJECTIVES: Hyperglycemia at admission seems to identify a subgroup of patients with acute coronary syndromes with poorer outcome. The aim of this study was to evaluate the impact of the glycemic variation during hospitalization in long-term mortality in nondiabetic patients. METHODS: Retrospective study of 2043 consecutive patients without known diabetes mellitus admitted for acute coronary syndrome in a single coronary care unit from May 2007 through August 2013. The population was divided in quartiles regarding glycemia at admission (<= 90 mg/dL, n = 374; 90-140 mg/dL, n = 1307; 141-180 mg/dL, n = 230; >= 181mg/dL, n = 111) and the mortality rate quantified for patients with glycemic variation above/below the mean for their respective quartile. The median follow-up was about 1200 days. RESULTS: The all-cause mortality during follow-up was significantly and successively higher in the upper quartiles (9.1%, 9.7%, 13.5% and 18.9%; P = .007). Multivariate regression analysis showed that hyperglycemia at admission (>= 181mg/dL) was a strong independent predictor of mortality during follow-up (hazard ratio = 1.74; 95% confidence interval, 1.07 2.8; P = .027). In the fourth quartile (>= 181mg/dL), the mortality is higher in patients with higher variations of glycemia (37.5% vs 8.5%; P < .001). CONCLUSIONS: Hyperglycemia at admission is a predictor of all-cause mortality in our population. The mortality is higher in patients with higher glycemic variations. More studies are needed to confirm these data. PMID- 25553938 TI - Economic impact of heart failure according to the effects of kidney failure. AB - INTRODUCTION AND OBJECTIVES: To evaluate the use of health care resources and their cost according to the effects of kidney failure in heart failure patients during 2-year follow-up in a population setting. METHODS: Observational retrospective study based on a review of medical records. The study included patients >= 45 years treated for heart failure from 2008 to 2010. The patients were divided into 2 groups according to the presence/absence of KF. Main outcome variables were comorbidity, clinical status (functional class, etiology), metabolic syndrome, costs, and new cases of cardiovascular events and kidney failure. The cost model included direct and indirect health care costs. Statistical analysis included multiple regression models. RESULTS: The study recruited 1600 patients (prevalence, 4.0%; mean age 72.4 years; women, 59.7%). Of these patients, 70.1% had hypertension, 47.1% had dyslipidemia, and 36.2% had diabetes mellitus. We analyzed 433 patients (27.1%) with kidney failure and 1167 (72.9%) without kidney failure. Patients with kidney failure were associated with functional class III-IV (54.1% vs 40.8%) and metabolic syndrome (65.3% vs 51.9%, P<.01). The average unit cost was ?10,711.40. The corrected cost in the presence of kidney failure was ?14,868.20 vs ?9,364.50 (P=.001). During follow-up, 11.7% patients developed ischemic heart disease, 18.8% developed kidney failure, and 36.1% developed heart failure exacerbation. CONCLUSIONS: Comorbidity associated with heart failure is high. The presence of kidney failure increases the use of health resources and leads to higher costs within the National Health System. PMID- 25553939 TI - Radial versus femoral access for angioplasty of ST-segment elevation acute myocardial infarction with second-generation drug-eluting stents. AB - INTRODUCTION AND OBJECTIVES: Invasive and pharmacological treatment of ST-segment elevation acute myocardial infarction reduces the rate of ischemic events but not bleeding complications. The objective of this study was to compare clinical results and bleeding complications between femoral and radial access routes in patients with ST-segment elevation acute myocardial infarction. METHODS: An evaluation was performed of the population of the Examination study, a randomized, multicenter, clinical trial that included 1498 patients with ST segment elevation acute myocardial infarction who underwent emergency angioplasty. Subanalysis of this population was conducted to compare patients by type of access (femoral vs radial). The primary end point was a composite of: all cause death, myocardial infarction, revascularization, and bleeding. RESULTS: Femoral and radial access routes were used in 825 (55%) and 673 (45%) patients, respectively. More bleeding complications (major and minor) were seen with femoral access than radial access (5.9% vs 2.8%; P<.004), largely due to a greater incidence of minor bleeding with femoral access (4.6% vs 1.9%; P=.005). After adjustment for confounders, survival analysis showed a reduction in the primary composite end point in patients with radial access (hazard ratio=0.73; 95% confidence interval, 0.56-0.96; P=.022). CONCLUSIONS: In patients with ST segment elevation acute myocardial infarction, the radial approach is an effective technique that improves prognosis and reduces bleeding complications. PMID- 25553942 TI - Percutaneous closure of a giant multiperforated atrial septal aneurysm. PMID- 25553943 TI - Surgical treatment for complex coarctation of aorta. PMID- 25553944 TI - Parkes-Weber syndrome. PMID- 25553947 TI - Comparison of resistance to third-generation cephalosporins in Shigella between Europe-America and Asia-Africa from 1998 to 2012. AB - We conducted a systematic review to compare resistance to third-generation cephalosporins (TGCs) in Shigella strains between Europe-America and Asia-Africa from 1998 to 2012 based on a literature search of computerized databases. In Asia Africa, the prevalence of resistance of total and different subtypes to ceftriaxone, cefotaxime and ceftazidime increased markedly, with a total prevalence of resistance up to 14.2% [95% confidence interval (CI) 3.9-29.4], 22.6% (95% CI 4.8-48.6) and 6.2% (95% CI 3.8-9.1) during 2010-2012, respectively. By contrast, resistance rates to these TGCs in Europe-America remained relatively low--less than 1.0% during the 15 years. A noticeable finding was that certain countries both in Europe-America and Asia-Africa, had a rapid rising trend in the prevalence of resistance of S. sonnei, which even outnumbered S. flexneri in some periods. Moreover, comparison between countries showed that currently the most serious problem concerning resistance to these TGCs appeared in Vietnam, especially for ceftriaxone, China, especially for cefotaxime and Iran, especially for ceftazidime. These data suggest that monitoring of the drug resistance of Shigella strains should be strengthened and that rational use of antibiotics is required. PMID- 25553948 TI - Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society. AB - In Spain, according to the Di@bet.es study, 13.8% of the adult population suffers from diabetes and 14.8% from some form of prediabetes (impaired glucose tolerance, impaired fasting glucose or both). Since early detection of prediabetes can facilitate the implementation of therapeutic measures to prevent its progression to diabetes, we believe that preventive strategies in primary care and specialized clinical settings should be agreed. Screening for diabetes and prediabetes using a specific questionnaire (FINDRISC) and/or the measurement of fasting plasma glucose in high risk patients leads to detecting patients at risk of developing diabetes and it is necessary to consider how they should be managed. The intervention in lifestyle can reduce the progression to diabetes and reverse a prediabetic state to normal and is a cost-effective intervention. Some drugs, such as metformin, have also been shown effective in reducing the progression to diabetes but are not superior to non-pharmacological interventions. Finally, an improvement in some cardiovascular risk factors has been observed although there is no strong evidence supporting the effectiveness of screening in terms of morbility and mortality. The Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society has issued some recommendations that have been agreed by the Sociedad Espanola de Endocrinologia y Nutricion, Sociedad Espanola de Endocrinologia Pediatrica, Sociedad Espanola de Farmacia Comunitaria, Sociedad Espanola de Medicina Familiar y Comunitaria, Sociedad Espanola de Medicos Generales, Sociedad Espanola de Medicos de Atencion Primaria, Sociedad Espanola de Medicina Interna, Asociacion de Enfermeria Comunitaria and Red de Grupos de Estudio de la Diabetes en Atencion Primaria. PMID- 25553955 TI - NH3 assisted photoreduction and N-doping of graphene oxide for high performance electrode materials in supercapacitors. AB - Nitrogen-doped graphene was synthesized by simple photoreduction of graphene oxide (GO) deposited on nickel foam under NH3 atmosphere. The combination of photoreduction and NH3 not only reduces the GO in a shorter time but also induces nitrogen doping easily. The nitrogen doped content of N-rGO@NF reaches a high of 5.99 at% with 15 min of irradiation. The nitrogen-doped graphene deposited on Ni foam (N-rGO@NF) can be directly used as an electrode for supercapacitors, without any conductive agents and polymer binders. In the electrochemical measurement, N rGO@NF displays remarkable electrochemical performance. In particular, the N rGO@NF irradiated for 45 min at a high current density of 92.3 A g(-1) retained about 77% (190.4 F g(-1)) of its initial specific capacitance (247.1 F g(-1) at 0.31 A g(-1)). Furthermore, the stable voltage window could be extended to 2.0 and 1.5 V by using Li2SO4 and a mixed Li2SO4/KOH electrolyte, and the maximum energy density was high up to 32.6 and 21.2 Wh kg(-1), respectively. The results show that compared to Li2SO4, a mixed electrolyte (Li2SO4/KOH) more efficiently balances the relationship between the high energy densities and high power densities. PMID- 25553954 TI - Foot and mouth disease risk assessment in Mongolia--local expertise to support national policy. AB - To address weaknesses in the current foot and mouth disease (FMD) control system and to inform the formulation of a national control strategy, Mongolia conducted two separate risk assessments, one for the Eastern region which in the past has seen re-current introductions of infection, and one for the Western region, where freedom from disease had been demonstrated over several years until FMD was re introduced in 2013. The risk assessment was conducted in three stages: first local experts developed entry, exposure and consequence pathways during separate workshops in both regions, then data was collected, compiled and analysed, and finally, during a second workshop local experts provided risk estimations for both regions and identified recommendations for risk management. Risk estimates for each pathway were individually recorded, which ensured that views of all experts were equally represented in the risk estimation and which allowed assessing possible impact of different factors related to the background of participating local experts on risk estimates. Entry risk pathways with highest risk estimates were related to livestock movements and in the consequence assessment due to direct contacts. Uncertainty, for which disagreement between participants acted as a proxy, was high in entry pathways and in the assessment of effectiveness of control measures. The risk assessment was conducted with local experts who had no previous risk assessment experience. Through their involvement in the whole process however, they assumed a high level of ownership and despite lively discussions for some risk pathways, a high level of agreement was achieved and credible results were communicated to decision makers. Especially valuable were the derived recommendations. Through the risk assessment the local experts gained a thorough understanding of the FMD risk which resulted in sensible and realistic recommendations, which, if implemented, can lead to a sustainable strengthening of the Mongolian capacities to prevent, control and eradicate FMD. The process was underlined by extensive field data collection, which helped to address important data gaps and therefore to improve quality and reliability of findings. The Mongolian veterinary authority was very committed to the risk assessment and several recommendations have already been integrated in the revision of the national FMD strategy. PMID- 25553956 TI - Microsecond pulsed hydrogen/deuterium exchange of electrosprayed ubiquitin ions stored in a linear ion trap. AB - A pulse of D2O vapour on the order of microseconds is allowed to react with the +6 to +9 charge states of ubiquitin confined in a linear ion trap (LIT). Two envelopes of peaks are detected for the ions of ubiquitin, corresponding to the ions that exchange more quickly and more slowly. The deuterium uptake of the protonated sites on ubiquitin ions accounts for the ion population with the fast exchange. The hydrogen/deuterium exchange (HDX) kinetics of ubiquitin ions trapped in the LIT for 200 ms showed comparable structural transitions to those trapped for 300 ms. When ions are trapped for longer, i.e. up to 2000 ms, mainly the slow exchanging ion population is detected. In all experiments the +7 ions exchange the most, suggesting a short distance between the surface protonated sites and nearby charged sites, and concomitantly high accessibility of surface protonated sites towards D2O. The +6 ions are more compact than the +7 ions but have one fewer protonated site, therefore fewer surface availabilities for D2O attack. The data suggest that the +6 ions keep most of their solution-phase contacts intact while the hydrophobic core is slightly interrupted in the +7 ions, possibly due to the exposure of charged His68 that is normally buried in the hydrophobic pocket. The +8 and +9 ions have more protonated sites but are less compact than the +7 ions because of Coulombic repulsion, resulting in a larger distance between the protonated sites and the basic sites. The data indicate that the HDX mechanism of ions with the slower exchange corresponding to the second envelope of peaks is primarily governed via a relay mechanism. The results suggest that the pulsed HDX MS method is sampling a population of ubiquitin ions with a similar backbone fold to the solution. PMID- 25553959 TI - Mixed alkyl aryl phosphonate esters as quenched fluorescent activity-based probes for serine proteases. AB - Activity-based probes (ABPs) are powerful tools for the analysis of active enzyme species in whole proteomes, cells or animals. Quenched fluorescent ABPs (qABPs) can be applied for real time imaging, allowing the visualization of dynamic enzyme activation by fluorescent microscopy. Unfortunately, qABPs are only available for a few enzymes. We here describe the design and synthesis of qABPs for serine proteases based on a phosphonate ester scaffold. PMID- 25553960 TI - Loosening detection of the femoral component of hip prostheses with extracorporeal shockwaves: a pilot study. AB - The diagnosis of aseptic loosening of hip implants is often challenging. A vibrational analysis of the bone-implant interface could be an alternative method to analyze the fixation of endoprostheses. We assessed an innovative and new approach for excitation by using extracorporeal shockwaves in this study. In three cadaver specimens total hip arthroplasty was performed bilaterally. Four different states of implant loosening were simulated. Three accelerometers were fixed at the medial condyle, the greater trochanter, and the crest of the ilium. The bone-implant compound was excited with highly standardized extracorporeal shock waves. Resonance spectra between 100 Hz and 5000 Hz were recorded. This technique permitted a good adaptation to varying soft tissue conditions. The main resonance frequency of the hip joints occurred at about 2000 Hz. The analysis of the measured spectra showed an interrelation between the state of loosening and the frequency values of the resonances. In case of a stem loosening, there were significant shifts of the resonance into the lower frequency area between 386 Hz and 847 Hz. With this novel technique the degree of stem loosening could be assessed in a soft tissue considering configuration. This study forms a first step for future establishment of a non-invasive, non-radiological and fast applicable diagnostic procedure for early detection of endoprostheses loosening before manifest presence of clinical signs. PMID- 25553961 TI - Traumatic brain injury: increasing ICP attenuates respiratory modulations of cerebral blood flow velocity. AB - In vitro experiments have suggested that respiratory oscillations (R waves) in cerebral blood flow velocity are reduced as soon as the intracranial pressure volume reserve is exhausted. Could R waves hence, provide indication for increasing ICP after traumatic brain injury (TBI)? On days 1 to 4 after TBI, 22 sedated and ventilated patients were monitored for intracranial pressure (ICP) in brain parenchyma, Doppler flow velocity (FV) in the middle cerebral arteries (MCA), and arterial blood pressure (ABP). The analysis included the transfer function gains of R waves (respiratory rate of 9-20 cpm) between ABP and FV (GainFv) as well as between ABP and ICP (GainICP). Also, the index of the intracranial pressure-volume reserve (RAP) was calculated. The rise of ICP (day 1: 14.10 +/- 6.22 mmHg; to day 4: 29.69 +/- 12.35 mmHg) and increase of RAP (day 1: 0.72 +/- 0.22; to day 4: 0.85 +/- 0.18) were accompanied by a decrease of GainFv (right MCA; day 1: 1.78 +/- 1.0; day 4: 0.84 +/- 0.47; left MCA day 1: 1.74 +/- 1.10; day 4: 0.86 +/- 0.46; p < 0.01) but no significant change in GainICP day 1: 1.50 +/- 0.77; day 4: 1.15 +/- 0.47; p = 0.07). The transfer of ventilatory oscillations to the intracerebral arteries after TBI appears to be dampened by increasing ICP and exhausted intracranial pressure-volume reserves. Results warrant prospective studies of whether respiratory waves in cerebral blood flow velocity may anticipate intracranial hypertension non-invasively. PMID- 25553962 TI - Sensitivity analysis of human lower extremity joint moments due to changes in joint kinematics. AB - Despite the widespread applications of human gait analysis, causal interactions between joint kinematics and joint moments have not been well documented. Typical gait studies are often limited to pure multi-body dynamics analysis of a few subjects which do not reveal the relative contributions of joint kinematics to joint moments. This study presented a computational approach to evaluate the sensitivity of joint moments due to variations of joint kinematics. A large data set of probabilistic joint kinematics and associated ground reaction forces were generated based on experimental data from literature. Multi-body dynamics analysis was then used to calculate joint moments with respect to the probabilistic gait cycles. Employing the principal component analysis (PCA), the relative contributions of individual joint kinematics to joint moments were computed in terms of sensitivity indices (SI). Results highlighted high sensitivity of (1) hip abduction moment due to changes in pelvis rotation (SI = 0.38) and hip abduction (SI = 0.4), (2) hip flexion moment due to changes in hip flexion (SI = 0.35) and knee flexion (SI = 0.26), (3) hip rotation moment due to changes in pelvis obliquity (SI = 0.28) and hip rotation (SI = 0.4), (4) knee adduction moment due to changes in pelvis rotation (SI = 0.35), hip abduction (SI = 0.32) and knee flexion (SI = 0.34), (5) knee flexion moment due to changes in pelvis rotation (SI = 0.29), hip flexion (SI = 0.28) and knee flexion (SI = 0.31), and (6) knee rotation moment due to changes in hip abduction (SI = 0.32), hip flexion and knee flexion (SI = 0.31). Highlighting the "cause-and-effect" relationships between joint kinematics and the resultant joint moments provides a fundamental understanding of human gait and can lead to design and optimization of current gait rehabilitation treatments. PMID- 25553957 TI - MiRNA inhibition in tissue engineering and regenerative medicine. AB - MicroRNAs (miRNAs) are noncoding RNAs that provide an endogenous negative feedback mechanism for translation of messenger RNA (mRNA) into protein. Single miRNAs can regulate hundreds of mRNAs, enabling miRNAs to orchestrate robust biological responses by simultaneously impacting multiple gene networks. MiRNAs can act as master regulators of normal and pathological tissue development, homeostasis, and repair, which has motivated expanding efforts toward the development of technologies for therapeutically modulating miRNA activity for regenerative medicine and tissue engineering applications. This review highlights the tools currently available for miRNA inhibition and their recent therapeutic applications for improving tissue repair. PMID- 25553963 TI - Epigenetic mechanisms in Parkinson's disease. AB - Parkinson's disease (PD) is the second most common age-related neurodegenerative disease, but its pathogenesis is not fully understood. The selective neuronal cell death in PD has been considered to result from a complex interaction between genetic and environmental factors, but the nature of the relationship between the two chief modifiers remains to be elucidated. There is a growing body of evidence supporting the role of epigenetics in the development and progression of many neurodegenerative diseases including PD. Epigenetic modification refers to changes in gene expression or function without changes in DNA sequence, which mainly includes DNA methylation, post-modifications of histone, and non-coding RNAs. In this review, we will focus on the abnormal epigenetic modifications involved in the pathogenesis of PD and their implications for the development of future diagnostic and therapeutic strategies. PMID- 25553964 TI - Shrug exercises combined with shoulder abduction improve scapular upward rotator activity and scapular alignment in subjects with scapular downward rotation impairment. AB - The aim of this research was to investigate which shoulder abduction angle (30 degrees , 90 degrees , 150 degrees ) during shrug exercise is superior for (1) activating the scapular upward rotators and (2) improving scapular and clavicular position in subjects with scapular downward rotation impairment. Twenty subjects performed shrug exercises at three different shoulder abduction angles (30 degrees , 90 degrees , 150 degrees ) which were obtained and maintained actively. Surface EMG data were collected from the levator scapulae (LS), upper trapezius (UT), lower trapezius (LT), and serratus anterior (SA) during shrug exercises. Scapular downward rotation index (SDRI) and clavicular tilt angle (CTA) were measured immediately after each shrug exercise. Oneway repeated-measures analysis of variance was used to determine the significance. UT muscle activity was greater at 90 degrees and 150 degrees than at 30 degrees of shoulder abduction. UT/LS muscle activity ratio was greater at 90 degrees than at 30 degrees . LT and LT/LS increased as shoulder abduction angle increased. SA was greater at 150 degrees than at 30 degrees or 90 degrees . SA/LS was greater at 150 degrees than at 30 degrees . SDRI was lower at 90 degrees and 150 degrees than at 30 degrees . CTA was greater at 90 degrees and 150 degrees than at 30 degrees . In conclusion, shrug exercises at 90 degrees or 150 degrees of shoulder abduction angle may be advocated to activate scapular upward rotators, decrease SDRI, and increase CTA in patients with scapular downward rotation impairment. PMID- 25553965 TI - Decrease in ankle-foot dorsiflexion range of motion is related to increased knee flexion during gait in children with spastic cerebral palsy. AB - PURPOSE: To determine the effects of decreased ankle-foot dorsiflexion (A-Fdf) range of motion (ROM) on gait kinematics in children with spastic cerebral palsy (SCP). METHODS: All participants were children with spastic cerebral palsy (n = 10) who walked with knee flexion in midstance. Data were collected over 2-5 sessions, at 3-monthly intervals. A-Fdf ROM was quantified using a custom designed hand-held ankle dynamometer that exerted 4 Nm at the ankle. Ankle-foot and knee angles during gait were quantified on sagittal video recordings. Linear regression (cross-sectional analysis) and General Estimation Equation analysis (longitudinal analysis) were performed to assess relationships between (change in) A-Fdf ROM and (change in) ankle-foot and knee angle during gait. RESULTS: Cross-sectional analysis showed a positive relationship between A-Fdf ROM and both ankle-foot angle in midstance and terminal swing. Longitudinal analysis showed a positive relationship between individual decreases in A-Fdf ROM and increases of knee flexion during gait (lowest knee angle in terminal stance and angle in terminal swing). CONCLUSION: For this subgroup of SCP children, our results indicate that while changes in ankle angles during gait are unrelated to changes in A-Fdf ROM, changes in knee angles are related to changes in A-Fdf ROM. PMID- 25553967 TI - Magnitude and sources of bias in the detection of mixed strain M. tuberculosis infection. AB - High resolution tests for genetic variation reveal that individuals may simultaneously host more than one distinct strain of Mycobacterium tuberculosis. Previous studies find that this phenomenon, which we will refer to as "mixed infection", may affect the outcomes of treatment for infected individuals and may influence the impact of population-level interventions against tuberculosis. In areas where the incidence of TB is high, mixed infections have been found in nearly 20% of patients; these studies may underestimate the actual prevalence of mixed infection given that tests may not be sufficiently sensitive for detecting minority strains. Specific reasons for failing to detect mixed infections would include low initial numbers of minority strain cells in sputum, stochastic growth in culture and the physical division of initial samples into parts (typically only one of which is genotyped). In this paper, we develop a mathematical framework that models the study designs aimed to detect mixed infections. Using both a deterministic and a stochastic approach, we obtain posterior estimates of the prevalence of mixed infection. We find that the posterior estimate of the prevalence of mixed infection may be substantially higher than the fraction of cases in which it is detected. We characterize this bias in terms of the sensitivity of the genotyping method and the relative growth rates and initial population sizes of the different strains collected in sputum. PMID- 25553966 TI - Dermal filler complications: a clinicopathologic study with a spectrum of histologic reaction patterns. AB - Although dermal fillers are generally accepted as safe and well-tolerable cosmetic tools, adverse reaction still forms a prognostic problem. The aim of this study was to demonstrate the clinicopathologic patterns of dermal filler complications in our center. A 5-year single-center study that included patients complained from filler complications and referred to the dermatopathology unit in Al-Azhar University for histologic assessment. The study included 38 female patients with an average age of 47 years. The mean onset of complications was 14.6 +/- 5.27 months after injection. The injected material included hyaluronic acid (18.4%), silicone (52.6%), bovine collagen (15.8%) and polyacrylamide hydrogel (13.2%). Most lesions were located on the face (55.3%), less commonly on the hands (18.4%), buttocks (21%), and rarely on the vulva (5.3%). The clinical spectrum included indurated plaque (23.7%), nodular lesion (31.6%), inflammatory mass (15.8%), atrophic lesion (10.5%), skin discoloration (13.1%) and ulceration (5.3%). Histologically, granulomatous reaction was the major finding, either a foreign body granuloma (34.2%) or infectious granuloma (13.2%). Other histologic reactions included dermal pseudocysts with chronic inflammation (26.3%), dermal fibrosis (15.8%), and eosinophilic panniculitis (10.5%). Our results confirmed that dermal fillers could be manifested with variable clinical presentations and show different histologic reactions. Because of long-standing duration until complications occur, history taking is crucial and should be emphasized in every suspected patient. It is hoped that this article will increase awareness for recognition of these variable complications and help select the appropriate therapy. PMID- 25553968 TI - Fabrication and characterization of conductive chitosan/gelatin-based scaffolds for nerve tissue engineering. AB - This paper reports on the development of conductive porous scaffolds by incorporating conductive polyaniline/graphene (PAG) nanoparticles into a chitosan/gelatin matrix for its potential application in peripheral nerve regeneration. The effect of PAG content on the various properties of the scaffold is investigated and the results showed that the electrical conductivity and mechanical properties increased proportional to the increase in the PAG loading, while the porosity, swelling ratio and in vitro biodegradability decreased. In addition, the biocompatibility was evaluated by assessing the adhesion and proliferation of Schwann cells on the prepared scaffolds using SEM and MTT assay, respectively. In summary, this work supports the use of a porous conductive chitosan/gelatin/PAG scaffold with a low amount of PAG (2.5 wt.%) as a suitable material having proper conductivity, mechanical properties and biocompatibility that may be appropriate for different biomedical applications such as scaffold material in tissue engineering for neural repair or other biomedical devices that require electroactivity. PMID- 25553969 TI - Extranodal lymphoma of the head and neck: a 67-case series. AB - The present study sought to describe clinical presentation in extranodal lymphoma of the head and neck (ELHN), with the aim of improving diagnostic management. MATERIAL AND METHODS: A single-center retrospective observational study was conducted over the period 2001-13. Age, gender, histologic type, location, type of clinical presentation, time interval between symptom onset and histologic diagnosis and presence of specific symptoms were recorded, as were the specialty of the physician initially consulted and of the physician taking the diagnostic sample. RESULTS: Sixty-seven cases of ELHN were diagnosed: 39 male and 28 female patients, with a median age of 68 years. B-cell lymphoma (84%) was more frequent than plasmacytoma (7%) or T-cell lymphoma (6%). Location was mainly palatine tonsil (28%), nasal fossa and sinus (19%), nasopharynx (14%) or parotid (13%). Revelation often involved a mass (33%), and only rarely any specific symptoms (9%). Time interval from symptom onset to diagnosis was short in aggressive lymphoma and longer in low-grade lymphoma (mean 4 and 10 months respectively). The physician initially consulted was an ENT specialist in 67% of cases, and an ENT specialist performed diagnostic sampling in 97% of cases. CONCLUSION: ELHN is a rare pathology (5 cases per year in our department) of highly variable clinical presentation depending on location and histologic type. The ENT physician should be prepared for diagnosis regardless of anatomic location, so as to optimize diagnostic management. PMID- 25553970 TI - Intensity modulated radiation therapy in nasopharyngeal carcinoma. AB - Radiation therapy (with associated chemotherapy) is the standard treatment for nasopharyngeal carcinoma. Conformal intensity-modulated radiation therapy is a new and particularly interesting technique for these tumors, due to their complex volumes close to many critical organs. Better dosimetric results and improved protection of adjacent healthy tissue have been shown compared with conventional 2D or 3D radiation therapy, with significantly reduced side-effects, notably xerostomia. Excellent local control rates have been reported. PMID- 25553971 TI - Abecedarium: Who am I? Z'.... PMID- 25553972 TI - Trypanosoma cruzi infectivity assessment in "in vitro" culture systems by automated cell counting. AB - Chagas disease is an endemic, neglected tropical disease in Latin America that is caused by the protozoan parasite Trypanosoma cruzi. In vitro models constitute the first experimental approach to study the physiopathology of the disease and to assay potential new trypanocidal agents. Here, we report and describe clearly the use of commercial software (MATLAB((r))) to quantify T. cruzi amastigotes and infected mammalian cells (BeWo) and compared this analysis with the manual one. There was no statistically significant difference between the manual and the automatic quantification of the parasite; the two methods showed a correlation analysis r(2) value of 0.9159. The most significant advantage of the automatic quantification was the efficiency of the analysis. The drawback of this automated cell counting method was that some parasites were assigned to the wrong BeWo cell, however this data did not exceed 5% when adequate experimental conditions were chosen. We conclude that this quantification method constitutes an excellent tool for evaluating the parasite load in cells and therefore constitutes an easy and reliable ways to study parasite infectivity. PMID- 25553973 TI - Enhancement of L-phenylalanine production by engineered Escherichia coli using phased exponential L-tyrosine feeding combined with nitrogen source optimization. AB - Nitrogen source optimization combined with phased exponential L-tyrosine feeding was employed to enhance L-phenylalanine production by a tyrosine-auxotroph strain, Escherichia coli YP1617. The absence of (NH4)2SO4, the use of corn steep powder and yeast extract as composite organic nitrogen source were more suitable for cell growth and L-phenylalanine production. Moreover, the optimal initial L tyrosine level was 0.3 g L(-1) and exponential L-tyrosine feeding slightly improved L-phenylalanine production. Nerveless, L-phenylalanine production was greatly enhanced by a strategy of phased exponential L-tyrosine feeding, where exponential feeding was started at the set specific growth rate of 0.08, 0.05, and 0.02 h(-1) after 12, 32, and 52 h, respectively. Compared with exponential L tyrosine feeding at the set specific growth rate of 0.08 h(-1), the developed strategy obtained a 15.33% increase in L-phenylalanine production (L phenylalanine of 56.20 g L(-1)) and a 45.28% decrease in L-tyrosine supplementation. PMID- 25553974 TI - Characterization of bovine serum albumin partitioning behaviors in polymer-salt aqueous two-phase systems. AB - In this paper, a linear relationship is proposed relating the natural logarithm of partition coefficient, ln K for protein partitioning in poly (ethylene glycol) (PEG)-phosphate aqueous two-phase system (ATPS) to the square of tie-line length (TLL(2)). This relationship provides good fits (r(2) > 0.98) to the partition of bovine serum albumin (BSA) in PEG (1450 g/mol, 2000 g/mol, 3350 g/mol, and 4000 g/mol)-phosphate ATPS with TLL of 25.0-50.0% (w/w) at pH 7.0. Results also showed that the plot of ln K against pH for BSA partitioning in the ATPS containing 33.0% (w/w) PEG1450 and 8.0% (w/w) phosphate with varied working pH between 6.0 and 9.0 exhibited a linear relationship which is in good agreement (r(2) = 0.94) with the proposed relationship, ln K = alpha' pH + beta'. These results suggested that both the relationships proposed could be applied to correlate and elucidate the partition behavior of biomolecules in the polymer-salt ATPS. The influence of other system parameters on the partition behavior of BSA was also investigated. An optimum BSA yield of 90.80% in the top phase and K of 2.40 was achieved in an ATPS constituted with 33.0% (w/w) PEG 1450 and 8.0% (w/w) phosphate in the presence of 8.5% (w/w) sodium chloride (NaCl) at pH 9.0 for 0.3% (w/w) BSA load. PMID- 25553976 TI - alpha-Galactosidase A knockout mice: progressive organ pathology resembles the type 2 later-onset phenotype of Fabry disease. AB - Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of alpha-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. alpha-Galactosidase A gene knockout (Gla KO) mice have no alpha-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual alpha-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease. PMID- 25553975 TI - Quantification of the placental epigenetic signature of the SERPINB5 gene in maternal plasma of pregnancies complicated by small for gestational age. AB - INTRODUCTION: To investigate the association between pregnancies with small for gestational age (SGA) neonates and the concentration of cell-free fetal DNA or cell-free total DNA in maternal plasma during the first and second trimesters using tissue-specific epigenetic characteristics of the SERPINB5 gene. METHODS: A nested case-control study was conducted with maternal plasma collected at 11 to 26 gestational weeks from 51 women with SGA neonates and 102 controls. We performed a real-time quantitative methylation-specific PCR to quantify concentrations of unmethylated-SERPINB5 (U-SERPINB5) as a cell-free fetal DNA marker and methylated-SERPINB5 (M-SERPINB5) as a cell-free total DNA marker. RESULTS: A positive correlation was observed between U-SERPINB5 and M-SERPINB5 concentrations in both control (r = 0.363, p < 0.001) and SGA groups (r = 0.548, p < 0.001). Moreover, the concentration of U-SERPINB5 or M-SERPINB5 was significantly positive correlated with gestational age at sampling in both controls (U-SERPINB5: r = 0.397, p < 0.001; M-SERPINB5: r = 0.275, p = 0.005) and SGA (U-SERPINB5: r = 0.274, p = 0.052; M-SERPINB5: r = 0.439, p = 0.001). However, the concentration of U-SERPINB5 or M-SERPINB5 was not correlated with birthweight. At 11-14 weeks, U-SERPINB5 and M-SERPINB5 concentrations in SGA did not differ significantly from those of controls. There were also no statistically significant differences in the concentrations of U-SERPINB5 and M-SERPINB5 between SGA and controls at 15-26 weeks of gestation. DISCUSSION: Our findings suggest that U-SERPINB5 and M-SERPINB5 concentrations in maternal plasma during early pregnancy are not associated with pregnancies who delivered SGA neonates. PMID- 25553978 TI - Early visual processing deficits in patients with schizophrenia during spatial frequency-dependent facial affect processing. AB - Abnormal facial emotion recognition is considered as one of the key symptoms of schizophrenia. Only few studies have considered deficits in the spatial frequency (SF)-dependent visual pathway leading to abnormal facial emotion recognition in schizophrenia. Twenty-one patients with schizophrenia and 19 matched healthy controls (HC) were recruited for this study. Event-related potentials (ERP) were measured during presentation of SF-modulated face stimuli and their source imaging was analyzed. The patients showed reduced P100 amplitude for low-spatial frequency (LSF) pictures of fearful faces compared with the HC group. The P100 amplitude for high-spatial frequency (HSF) pictures of neutral faces was increased in the schizophrenia group, but not in the HC group. The neural source activities of the LSF fearful faces and HSF neutral faces led to hypo- and hyperactivation of the frontal lobe of subjects from the schizophrenia group and HC group, respectively. In addition, patients with schizophrenia showed enhanced N170 activation in the right hemisphere in the LSF condition, while the HC group did not. Our results suggest that deficits in the LSF-dependent visual pathway, which involves magnocellular neurons, impair early visual processing leading to dysfunctional facial emotion recognition in schizophrenia. Moreover, it suggests impaired bottom-up processing rather than top-down dysfunction for facial emotion recognition in these patients. PMID- 25553977 TI - Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies. AB - The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors. PMID- 25553979 TI - Resting-state theta-band connectivity and verbal memory in schizophrenia and in the high-risk state. AB - BACKGROUND: Disturbed functional connectivity is assumed to underlie neurocognitive deficits in patients with schizophrenia. As neurocognitive deficits are already present in the high-risk state, identification of the neural networks involved in this core feature of schizophrenia is essential to our understanding of the disorder. Resting-state studies enable such investigations, while at the same time avoiding the known confounder of impaired task performance in patients. The aim of the present study was to investigate EEG resting-state connectivity in high-risk individuals (HR) compared to first episode patients with schizophrenia (SZ) and to healthy controls (HC), and its association with cognitive deficits. METHODS: 64-channel resting-state EEG recordings (eyes closed) were obtained for 28 HR, 19 stable SZ, and 23 HC, matched for age, education, and parental education. The imaginary coherence-based multivariate interaction measure (MIM) was used as a measure of connectivity across 80 cortical regions and six frequency bands. Mean connectivity at each region was compared across groups using the non-parametric randomization approach. Additionally, the network-based statistic was applied to identify affected networks in patients. RESULTS: SZ displayed increased theta-band resting-state MIM connectivity across midline, sensorimotor, orbitofrontal regions and the left temporoparietal junction. HR displayed intermediate theta-band connectivity patterns that did not differ from either SZ or HC. Mean theta-band connectivity within the above network partially mediated verbal memory deficits in SZ and HR. CONCLUSIONS: Aberrant theta-band connectivity may represent a trait characteristic of schizophrenia associated with neurocognitive deficits. As such, it might constitute a promising target for novel treatment applications. PMID- 25553980 TI - Dpp/Gbb signaling is required for normal intestinal regeneration during infection. AB - Maintaining tissue homeostasis is a critical process during infection and inflammation. Tissues with a high intrinsic turnover, such as the intestinal epithelium, must launch a rapid response to infections while simultaneously coordinating cell proliferation and differentiation decisions. In this study, we searched for genes required for regeneration of the Drosophila intestine, and thereby affecting overall organism survival after infection with pathogenic bacteria. We found that Dpp/Gbb (BMP) signaling is essential for normal midgut regeneration, and that infection induces the BMP signaling ligands Dpp and Gbb. We demonstrate that Dpp is induced in visceral muscle and required for signaling activation. Subsequently, Gbb is induced in enterocytes after oral infection. Loss-of Dpp signaling in ISCs and transient committed progenitors called enteroblasts (EBs), or in EBs alone, led to a blockage in EC differentiation or maturation. Furthermore, our data show that down-regulation of Dpp signaling in the precursor cells including EBs also resulted in an increased number of abnormally small Pdm1-positive cells, suggesting a role of Dpp/Gbb signaling in EC growth. In addition, we show that Dpp/Gbb signaling acted downstream or in parallel to the Notch pathway to promote EC differentiation and growth. Our results suggest that Dpp/BMP signaling plays an important role in EBs to maintain tissue integrity and homeostasis during pathogenic infections. PMID- 25553981 TI - Recent advances in the study of zebrafish extracellular matrix proteins. AB - The zebrafish extracellular matrix (ECM) is a dynamic and pleomorphic structure consisting of numerous proteins that together regulate a variety of cellular and morphogenetic events beginning as early as gastrulation. The zebrafish genome encodes a similar complement of ECM proteins as found in other vertebrate organisms including glycoproteins, fibrous proteins, proteoglycans, glycosaminoglycans, and interacting or modifying proteins such as integrins and matrix metalloproteinases. As a genetic model system combined with its amenability to high-resolution microscopic imaging, the zebrafish allows interrogation of ECM protein structure and function in both the embryo and adult. Accumulating data have identified important roles for zebrafish ECM proteins in processes as diverse as cell polarity, migration, tissue mechanics, organ laterality, muscle contraction, and regeneration. In this review, I highlight recently published data on these topics that demonstrate how the ECM proteins fibronectin, laminin, and collagen contribute to zebrafish development and adult homeostasis. PMID- 25553982 TI - Connexins in migration during development and cancer. AB - Connexins, the gap junction proteins, through their multitude of actions are implicated in a variety of cell processes during animal development and cancer. They allow direct or paracrine/autocrine cell communication through their channel and hemi-channel functions. They enable adhesion and interact with a plethora of signalling molecules. Here, we review the common themes in developmental and pathological processes and we focus in their involvement in cell migration in four different systems: neurons, astrocytes, neural crest and cancer. PMID- 25553983 TI - Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease. AB - The association of NAFLD with chronic hepatitis C (CHC) has been extensively studied but little is known about its coexistence with chronic hepatitis B (CHB). AIMS: To investigate the prevalence and determinants of steatosis and insulin resistance (IR) in CHB and its consequences on liver injury compared with CHC and NAFLD. METHODS: Patients with CHB (N=110), CHC (N=111) and NAFLD (N=136) were evaluated by biomarkers of steatosis (SteatoTest>0.38 as a surrogate for steatosis >5%), IR (HOMA-IR>2.7 as a surrogate for IR) and fibrosis (FibroTest>0.48 as a surrogate for significant fibrosis, >=F2). RESULTS: HOMA-IR gradually increased in CHB, CHC and NAFLD: 2.3+/-1.8; 3+/-2.6 and 3.8+/-2.7 (p<0.001). The prevalence of steatosis >5% was 21% (CHB), 43% (CHC) and 82% (NAFLD), (p<0.001). The prevalence of fibrosis>=F2 was 10% (CHB), 42% (CHC) and 21% (NAFLD), p<0.001. In CHB, IR was related to host and not viral factors. CHB patients with steatosis had higher BMI (29+/-5.7kg/m(2) vs. 24+/-4kg/m(2), p<0.001), waist circumference (96+/-14cm vs. 84+/-11cm, p=0.001) and HOMA-IR (3.9+/-2.6 vs. 1.8+/-1.2, p<0.001) than those without steatosis. HOMA-IR independently predicted steatosis in CHB (OR=1.9, 95% CI, 1.09-3.27, p<0.05) and CHC (OR=1.38; 95% CI, 1.07-1.78, p<0.02). In CHB, metabolic risk factors and HOMA IR were not associated with significant fibrosis. HOMA-IR was an independent predictor of fibrosis in CHC. CONCLUSIONS: Steatosis may co-exist in CHB patients but with a lower prevalence than in CHC and NAFLD. In CHB steatosis is related to host and not viral factors, and is not associated with the severity of fibrosis. PMID- 25553984 TI - Abnormal expression of serum soluble E-cadherin is correlated with clinicopathological features and prognosis of breast cancer. AB - BACKGROUND: Increased amounts of soluble E-cadherin (E-cad) have been found in the serum in various cancers, but the role of serum soluble E-cad in the prognosis of breast cancer patients has not been explored in Asian populations. MATERIAL/METHOD: Blood samples from 111 consecutive patients diagnosed with breast cancer and 55 healthy controls were investigated.Serum soluble E-cad expression levels were measured by enzyme-linked immunosorbent assay(ELISA) with an immunoassay kit according to the manufacturer's directions. Kaplan-Meier analyses were used to evaluate the association between serum soluble E-cad expression level and survival. All statistical tests were 2-sided. RESULTS: The serum levels of soluble E-cad in breast cancer patients were significantly higher than those of the control group (2218.9+/-319.6 ng/ml vs. 742.8+/-91.7 ng/ml, p<0.001). Serum levels of soluble E-cad correlated significantly with TNM stage (P=0.007), tumor grade (P=0.03), and lymph node metastasis (P<0.001). Kaplan Meier analysis with the log-rank test indicated that high serum levels of soluble E-cad had a significant impact on overall survival (55.4% vs. 81.4%; P=0.032) and disease-free survival (36.8% vs. 67.8%; P=0.002) in breast cancer. Multivariate analysis revealed that serum levels of soluble E-cad were independently associated with overall survival and disease-free survival in breast cancer patients. CONCLUSIONS: Serum soluble E-cad level is an independent prognostic factor in Asian breast cancer patients. PMID- 25553993 TI - Risk factors for slowly resolving pneumonia in the intensive care unit. AB - BACKGROUND: Slowly resolving pneumonia (SRP) poses early challenges for identification and medical expense for clinicians in intensive care units (ICUs); to date, the literature has been very limited in this regard. METHODS: This was a retrospective and cohort-based study in the ICU of a university-affiliated hospital in Shanghai. Medical records of pneumonia patients in the ICU between April 2008 and February 2011were reviewed retrospectively to evaluate the risk factors for SRP. RESULTS: In all, 106 pneumonia patients in the ICU were identified as immune-competent with a diagnosis of bacterial pneumonia. There were 62 (58.49%) patients who showed SRP and their radiographic infiltrations were completely resolved between 5 weeks and 8 weeks. Multivariate logistic regression analysis demonstrated that initial treatment with an inappropriate antibiotic, multilobar infiltration, and a high CURB-65 score were independent risk factors for SRP, with odds ratio (OR) values of 8.338 [95% confidence interval (CI) 2.117-32.848], 11.184 (95% CI 2.526-49.514), and 2.329 (95% CI 1.172-4.626), respectively. The length of the ICU stay in the SRP group was twice as long as that of the normally resolving pneumonia (NRP) group (62.27 +/- 73.73 vs. 32.25 +/- 23, p = 0.002). The 28-day and 60-day mortality rates in the SRP group were 17.74% and 25.81%, respectively. In addition, the 60-day mortality rate was significantly higher in the SRP group than the NRP group (25.81% vs. 6.82%, respectively; p = 0.012). Moreover, SRP was an independent risk factor for 60-day mortality (OR 5.687, 95% CI 1.334-24.240). CONCLUSION: Treatment with an inappropriate antibiotic, multilobar infiltration, and a high CURB-65 score were independent risk factors for SRP. PMID- 25553994 TI - Risk factors of mortality in patients with carbapenem-resistant Acinetobacter baumannii bacteremia. AB - BACKGROUND/PURPOSE: Identification of risks of mortality for carbapenem-resistant Acinetobacter baumannii (CRAB), with early implementation of an appropriate therapy, is crucial for the patients' outcome. The aim of this study was to survey mortality risk factors in 182 patients with CRAB bacteremia in a medical center in Taiwan. METHODS: A total of 182 isolates of CRAB bacteremia were collected from 2009 to 2012 in Mackay Memorial Hospital, Taipei, Taiwan These isolates were identified by using the genotypic method. Risk of attributable mortality analysis was carried out with a Cox proportional hazards model. RESULTS: The 182 CRAB isolates belonged to 38 different pulsotypes. The attributable mortality rate of the 182 patients was 58.24%. The risk factors for attributable mortality included intensive care unit stay [hazard ratio (HR): 2.27; p = 0.011], an Acute Physiology and Chronic Health Evaluation II score of >20 (HR: 2.19; p < 0.001), respiratory tract as the origin of bacteremia (HR: 3.40; p < 0.001), and previous use of ceftriaxone (HR: 2.51; p = 0.011). The appropriateness of antimicrobial therapy was 18.87% (20/106) in the mortality group versus 88.16% (67/76) in the survivor group (p < 0.001). The sensitivity of CRAB to colistin was 100% and to tigecycline was 40.11%. CONCLUSION: The risk factors for mortality for CRAB included intensive care unit stay, a high Acute Physiology and Chronic Health Evaluation II score, respiratory tract as the origin of bacteremia, and previous use of ceftriaxone. Early implementation of an antimicrobial agent that had the highest in vitro activity against CRAB in patients at risk of CRAB bacteremia and high mortality may improve their outcome. PMID- 25553995 TI - Urinary tract infection due to NonO1 Vibrio cholerae. PMID- 25553996 TI - Low-volume multiplexed proteolytic activity assay and inhibitor analysis through a pico-injector array. AB - Secreted active proteases, from families of enzymes such as matrix metalloproteinases (MMPs) and ADAMs (a disintegrin and metalloproteinases), participate in diverse pathological processes. To simultaneously measure multiple specific protease activities, a series of parallel enzyme reactions combined with a series of inhibitor analyses for proteolytic activity matrix analysis (PrAMA) are essential but limited due to the sample quantity requirements and the complexity of performing multiple reactions. To address these issues, we developed a pico-injector array to generate 72 different reactions in picoliter volume droplets by controlling the sequence of combinational injections, which allowed simultaneous recording of a wide range of multiple enzyme reactions and measurement of inhibitor effects using small sample volumes (~10 MUL). Multiple MMP activities were simultaneously determined by 9 different substrates and 2 inhibitors using injections from a pico-injector array. Due to the advantages of inhibitor analysis, the MMP/ADAM activities of MDA-MB-231, a breast cancer cell line, were characterized with high MMP-2, MMP-3 and ADAM-10 activity. This platform could be customized for a wide range of applications that also require multiple reactions with inhibitor analysis to enhance the sensitivity by encapsulating different chemical sensors. PMID- 25554003 TI - Histone deacetylase inhibitor sodium butyrate attenuates gentamicin-induced hearing loss in vivo. AB - OBJECTIVE: Although histone deacetylase (HDAC) inhibition has been shown to protect against gentamicin (GM)-induced hearing loss in vitro, its protective effect has not been proven in vivo. In the present study, the aim was to investigate the protective effect of sodium butyrate (NaB), a specific HDAC inhibitor, on GM-induced ototoxicity in vivo. METHODS: Forty 8-week-old albino guinea pigs were divided into two experimental groups. Group 1 (n=10) underwent bilateral ear surgery to place sponges (0.3mm(3)) permeated with NaB (10MUl, 100mg/ml) and physiological saline (10MUl; control) in the right and left round window niches, respectively. The sponges were left in place for 15days to evaluate the effects of NaB at the applied concentration. Group 2 (n=30) underwent the same bilateral ear surgery described for Group 1, except three days after surgery, the animals received intramuscular GM injections (200mg/kg/day) for 5 consecutive days. Seven days after the final GM injection, the protective effects of NaB were examined. RESULTS: After 15days of NaB treatment (10MUl, 100mg/ml), an increase in histone acetylation was detected in Corti organ samples. Auditory brainstem response (ABR) threshold shifts and hair cell loss were also reduced in NaB-treated ears after GM administration. Furthermore, GM treatment increased HDAC1 expression in outer hair cells (OHCs) in vivo, and NaB blocked this action. CONCLUSION: GM increases HDAC1 expression in OHCs, and NaB is able to block this action. Thus, it appears that the HDAC inhibitor, NaB, attenuates GM-induced hearing loss in guinea pigs. PMID- 25554004 TI - Effects of serum zinc level on tinnitus. AB - OBJECTIVE: The aim of this study was to assess zinc levels in tinnitus patients, and to evaluate the effects of zinc deficiency on tinnitus and hearing loss. METHODS: One-hundred patients, who presented to an outpatient clinic with tinnitus between June 2009 and 2014, were included in the study. Patients were divided into three groups according to age: Group I (patients between 18 and 30years of age); Group II (patients between 31 and 60years of age); and Group III (patients between 61 and 78years of age). Following a complete ear, nose and throat examination, serum zinc levels were measured and the severity of tinnitus was quantified using the Tinnitus Severity Index Questionnaire (TSIQ). Patients were subsequently asked to provide a subjective judgment regarding the loudness of their tinnitus. The hearing status of patients was evaluated by audiometry and high-frequency audiometry. An average hearing sensitivity was calculated as the mean value of hearing thresholds between 250 and 20,000Hz. Serum zinc levels between 70 and 120MUg/dl were considered normal. The severity and loudness of tinnitus, and the hearing thresholds of the normal zinc level and zinc-deficient groups, were compared. RESULTS: Twelve of 100 (12%) patients exhibited low zinc levels. The mean age of the zinc-deficient group was 65.41+/-12.77years. Serum zinc levels were significantly lower in group III (p<0.01). The severity and loudness of tinnitus were greater in zinc-deficient patients (p=0.011 and p=0.015, respectively). Moreover, the mean thresholds of air conduction were significantly higher in zinc-deficient patients (p=0.000). CONCLUSION: We observed that zinc levels decrease as age increases. In addition, there was a significant correlation between zinc level and the severity and loudness of tinnitus. Zinc deficiency was also associated with impairments in hearing thresholds. PMID- 25554005 TI - Prognosis and therapy for ruptured hepatocellular carcinoma: problems with staging and treatment strategy. AB - BACKGROUND: There are no clear criteria established for treating a ruptured hepatocellular carcinoma (HCC). To elucidate the clinical features of affected patients, we examined prognosis and therapy choices. MATERIALS/METHODS: We enrolled 67 patients treated for a ruptured HCC (HCV 44, HBV 5, HBV+HCV 1, alcohol 2, others 15; naive HCC 34, recurrent 33) from 2000 to 2013, and investigated their clinical background and prognosis. RESULTS: Median survival time (MST) for all cases was 4 months. For patients who survived for more than 1 year after rupture, the percentages of Child-Pugh C and positive for portal vein tumor thrombosis (PVTT)/extrahepatic metastasis were less than for those who died within 1 year. Child-Pugh classification (A:B:C=14:15:5 vs. 4:9:20, P<0.001) was better, while the percentage of patients with multiple tumors was lower [19/34 (55.9%) vs. 29/33 (87.9%), respectively; P<0.001] in the naive group. The 1- and 3-year survival rates were better in the naive as compared to the recurrent group (60.6% and 33.3% vs. 12.6% and 0%, respectively; P<0.01). MST according to modified TNM stage (UICC 7th) calculated after exclusion of T4 factor of rupture, stage I was better than others (22.7 vs. (II) 2.2, (III) 1.2, and (IV) 0.7 months) (P=0.010). CONCLUSION: In patients with a ruptured HCC, especially those with a single tumor, and without decompensated liver cirrhosis and PVTT/extrahepatic metastasis, better prognosis can be expected with curative treatment. The present naive group included more of such cases than the recurrent group, indicating the effectiveness of curative therapy. PMID- 25554006 TI - One-stop-shop stroke imaging with functional CT. AB - Advanced imaging techniques have extended beyond traditional anatomic imaging and progressed to dynamic, physiologic and functional imaging. Neuroimaging is no longer a mere diagnostic tool. Multimodal functional CT, comprising of NCCT, PCT and CTA, provides a one-stop-shop for rapid stroke imaging. Integrating those imaging findings with pertinent clinical information can help guide subsequent treatment decisions, medical management and follow-up imaging selection. This review article will briefly discuss the indication and utility of each modality in acute stroke imaging. PMID- 25554007 TI - Value of diffusion-weighted MR imaging using various parameters for assessment and characterization of solitary pulmonary nodules. AB - OBJECTIVES: To determine the appropriate parameters and evaluation method for characterizing solitary pulmonary nodules (SPNs) using quantitative parameters of diffusion-weighted imaging (DWI). METHODS: Thirty-two subjects with 36 SPNs underwent DWI with seven different b values (0, 50, 100, 150, 300, 500, and 1000s/mm(2)). Five quantitative parameters were obtained from the region of interest drawn over each SPN: apparent diffusion coefficients (ADCs), true diffusion coefficients (DCs), and perfusion fractions (PFs), and signal-intensity ratios between lesion and spinal cord from DWI (b values: 1000 [LSR1000] and 500 [LSR500)]). All quantitative parameters and the diagnostic capabilities were statistically compared. RESULTS: SPNs were diagnosed as follow: malignant (n=27) and benign (n=9). Parameter comparisons for malignant and benign showed both LSRs differed significantly (p<0.05). Applying feasible threshold values showed LSR500 specificity (88.9% [8/9]) and accuracy (77.8% [28/36]) were significantly higher than ADC, DC, and PF specificity and accuracy (p<0.05). LSR1000 accuracy (72.2% [26/36]) was significantly higher than DC accuracy, and its specificity (88.9% [8/9]) was significantly higher than ADC, DC, and PF specificities (p<0.05). CONCLUSIONS: For quantitative differentiation of SPNs, LSR evaluation was more useful and practical than ADC, DC, and PF, and choice of b values showed little impact for the differentiation. PMID- 25554008 TI - Towards personalized compression in mammography: a comparison study between pressure- and force-standardization. AB - OBJECTIVE: To compare a conventional 14 decanewton (daN) force-standardized compression protocol with a personalized 10kilopascal (kPa) pressure-standardized protocol. METHODS: A new add-on contact area detector, which enables pressure standardized compression, is validated in a double-blinded intra-individual comparison study. Breast screening participants (433) received one craniocaudal (CC) and one mediolateral oblique (MLO) compression for both breasts. Three of these compressions were force-standardized, and one, blinded and randomly assigned, was pressure-standardized. Participants scored their pain experience on an 11-point numerical rating scale (NRS). Three experienced breast-screening radiologists, blinded for compression protocol, indicated which images required retakes. RESULTS: An unanticipated under-compression issue that occurred at forces below 5daN was effectively solved with minimal extra radiographer training during the study. For pressure-standardized compressions obtained at 5daN or more, the compressed breasts thickness increased on average 4.2% (MLO)-6.3% (CC), average pain scores were reduced by 10% (MLO)-17% (CC) and the proportion of women experiencing severe pain (NRS>=7) was reduced by 27% (MLO)-32% (CC), compared with force-standardized compressions (all p-values <0.05). Average glandular dose (AGD) and proportions of retakes were similar for both protocols. CONCLUSION: Pressure-standardized compressions resulted in AGD values and a retake proportion similar to force-standardized compressions, while pain was significantly reduced. PMID- 25554009 TI - First performance evaluation of software for automatic segmentation, labeling and reformation of anatomical aligned axial images of the thoracolumbar spine at CT. AB - OBJECTIVES: To evaluate software for automatic segmentation, labeling and reformation of anatomical aligned axial images of the thoracolumbar spine on CT in terms of accuracy, potential for time savings and workflow improvement. MATERIAL AND METHODS: 77 patients (28 women, 49 men, mean age 65.3+/-14.4 years) with known or suspected spinal disorders (degenerative spine disease n=32; disc herniation n=36; traumatic vertebral fractures n=9) underwent 64-slice MDCT with thin-slab reconstruction. Time for automatic labeling of the thoracolumbar spine and reconstruction of double-angulated axial images of the pathological vertebrae was compared with manually performed reconstruction of anatomical aligned axial images. Reformatted images of both reconstruction methods were assessed by two observers regarding accuracy of symmetric depiction of anatomical structures. RESULTS: In 33 cases double-angulated axial images were created in 1 vertebra, in 28 cases in 2 vertebrae and in 16 cases in 3 vertebrae. Correct automatic labeling was achieved in 72 of 77 patients (93.5%). Errors could be manually corrected in 4 cases. Automatic labeling required 1min in average. In cases where anatomical aligned axial images of 1 vertebra were created, reconstructions made by hand were significantly faster (p<0.05). Automatic reconstruction was time saving in cases of 2 and more vertebrae (p<0.05). Both reconstruction methods revealed good image quality with excellent inter-observer agreement. CONCLUSION: The evaluated software for automatic labeling and anatomically aligned, double angulated axial image reconstruction of the thoracolumbar spine on CT is time saving when reconstructions of 2 and more vertebrae are performed. Checking results of automatic labeling is necessary to prevent errors in labeling. PMID- 25554011 TI - Measuring ovarian cancer care: why are we still failing? PMID- 25554010 TI - National trends in the recommendation of radiotherapy after prostatectomy for prostate cancer before and after the reporting of a survival benefit in March 2009. AB - BACKGROUND: Three randomized trials demonstrated that postprostatectomy adjuvant radiotherapy improves biochemical disease-free survival for patients with adverse pathologic features, and 1 trial found adjuvant radiotherapy improves overall survival. We sought to determine whether postprostatectomy radiotherapy (PPRT) utilization changed after publication of the survival benefit in March 2009. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify men diagnosed with prostate cancer from 2004 to 2011 who met criteria for enrollment in the randomized trials (positive margins and/or pT3-4 disease at radical prostatectomy). Joinpoint regression identified inflection points in PPRT utilization. Logistic regression was used to evaluate factors associated with PPRT recommendation. RESULTS: Of 35,361 men, 5104 (14.4%) received a recommendation for PPRT. In joinpoint regression, 2009 was the inflection point in PPRT utilization. In multivariable analysis, PPRT recommendations were more likely after March 2009 than before 15.8% vs. 13.5%, adjusted odds ratio (AOR; 1.09; 95% confidence interval [CI], 1.02-1.16; P = .008), in men with pT3 (vs. pT2, AOR, 2.81; 95% CI, 2.53-3.11; P < .001), pT4 (vs. pT2 AOR, 4.62; 95% CI, 3.85-5.54; P < .001), or margin positive (AOR, 1.46; 95% CI, 1.34-1.58; P < .001) disease and in men who were younger (per year decrease, AOR, 1.02; 95% CI, 1.02-1.03; P < .001), married (AOR, 1.10; 95% CI, 1.02-1.19; P = .01), or lived in metropolitan areas (AOR, 1.30; 95% CI, 1.16 1.47; P < .001). CONCLUSION: PPRT recommendations increased after the reporting of a survival benefit in March 2009, but absolute utilization rates remain low, suggesting that the oncologic community remains unconvinced that PPRT is needed for most patients with adverse features. Further work is needed to identify patients who might benefit most from PPRT. PMID- 25554012 TI - PARP inhibition in ovarian cancer: state of the science. PMID- 25554013 TI - Effects of testosterone therapy on bipolar disorder with Klinefelter syndrome. AB - Klinefelter syndrome (KS) is widely associated with cognitive impairment and language problems. KS patients may also exhibit psychiatric symptoms. We present the case of an 18-year-old man with KS who experienced rapidly repeating relapses of manic episodes. He was unresponsive to the usual pharmacotherapies for bipolar disorders such as mood stabilizers and second-generation antipsychotics. Mood was eventually improved with testosterone therapy in addition to pharmacotherapy, with no relapse of manic episodes for 3 years after discharge. Testosterone therapy may prevent relapsing manic episodes of bipolar disorder in patients with KS. PMID- 25554015 TI - In vitro antioxidant and antiproliferative activities of six international basil cultivars. AB - The total phenolic, flavonoid and tannin contents in leaves extracts of Ocimum basilicum (OB) (Lamiaceae) international cultivars, as well as their overall antioxidant activities using DPPH and linoleic acid assays, were investigated. Furthermore, the antiproliferative and cytotoxic activities against line HeLa, MCF-7, Jurkat, HT-29, T24, MIAPaCa-2 cancer cells and one normal human cell line HEK-293 were examined. DPPH and linoleic acid assays ranged from 75.8% to 93.3% and from 74.5% to 97.1%; respectively. O. b. 'purple ruffle', O. b. 'dark opale', O. b. 'genovese', O. b. 'anise', O. b. 'bush green' and O. b. L. (OBL) varied in their antiproliferative and cytotoxic activities, influenced cell cycle progression and stimulated apoptosis in most cancer cells. OBL exhibited the highest antioxidant and antiproliferative activities. OB extracts not only improve taste but also have certain anticancer activity against diverse cancer cells due to the presence of compounds such as rosmarinic acid, chicoric acid and caftaric acid. Thus, OB represents a potent source of anticancer materials. PMID- 25554014 TI - Collaborative care for pain results in both symptom improvement and sustained reduction of pain and depression. AB - OBJECTIVE: Traditional analytic approaches may oversimplify the mechanisms by which interventions effect change. Transition probability models can quantify both symptom improvement and sustained reduction in symptoms. We sought to quantify transition probabilities between higher and lower states for four outcome variables and to compare two treatment arms with respect to these transitions. METHOD: Secondary analysis of a year-long collaborative care intervention for chronic musculoskeletal pain in veterans. Forty-two clinicians were randomized to intervention or treatment as usual (TAU), with 401 patients nested within clinician. The outcome variables, pain intensity, pain interference, depression and disability scores were dichotomized (lower/higher). Probabilities of symptom improvement (transitioning from higher to lower) or sustained reduction (remaining lower) were compared between intervention and TAU groups at 0- to 3-, 3- to 6- and 6- to 12-month intervals. General estimating equations quantified the effect of the intervention on transitions. RESULTS: In adjusted models, the intervention group showed about 1.5 times greater odds of both symptom improvement and sustained reduction compared to TAU, for all the outcomes except disability. CONCLUSIONS: Despite no formal relapse prevention program, intervention patients were more likely than TAU patients to experience continued relief from depression and pain. Collaborative care interventions may provide benefits beyond just symptom reduction. PMID- 25554016 TI - Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer. AB - Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110alpha and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo. PMID- 25554019 TI - Editorial: Change publication frequency in 2015. PMID- 25554017 TI - Demographic and practice characteristics of pathologists who enjoy breast tissue interpretation. AB - Physician attributes, job satisfaction and confidence in clinical skills are associated with enhanced performance and better patient outcomes. We surveyed 252 pathologists to evaluate associations between enjoyment of breast pathology, demographic/clinical characteristics and diagnostic performance. Diagnostic performance was determined by comparing pathologist assessments of a set of 60 cases with consensus assessments of the same cases made by a panel of experienced pathologists. Eighty-three percent of study participants reported enjoying breast pathology. Pathologists who enjoy breast interpretation were more likely to review >=10 cases/week (p = 0.003), report breast interpretation expertise (p = 0.013) and have high levels of confidence interpreting breast pathology (p < 0.001). These pathologists were less likely to report that the field was challenging (p < 0.001) and that breast cases make them more nervous than other types of pathology (p < 0.001). Enjoyment was not associated with diagnostic performance. Millions of women undergo breast biopsy annually, thus it is reassuring that although nearly a fifth of practicing pathologists who interpret breast tissue report not enjoying the field, precision is not impacted. PMID- 25554020 TI - Chaotic time series analysis in economics: balance and perspectives. AB - The aim of the paper is not to review the large body of work concerning nonlinear time series analysis in economics, about which much has been written, but rather to focus on the new techniques developed to detect chaotic behaviours in economic data. More specifically, our attention will be devoted to reviewing some of these techniques and their application to economic and financial data in order to understand why chaos theory, after a period of growing interest, appears now not to be such an interesting and promising research area. PMID- 25554021 TI - Analytical estimation of the correlation dimension of integer lattices. AB - Recently [L. Lacasa and J. Gomez-Gardenes, Phys. Rev. Lett. 110, 168703 (2013)], a fractal dimension has been proposed to characterize the geometric structure of networks. This measure is an extension to graphs of the so called correlation dimension, originally proposed by Grassberger and Procaccia to describe the geometry of strange attractors in dissipative chaotic systems. The calculation of the correlation dimension of a graph is based on the local information retrieved from a random walker navigating the network. In this contribution, we study such quantity for some limiting synthetic spatial networks and obtain analytical results on agreement with the previously reported numerics. In particular, we show that up to first order, the correlation dimension beta of integer lattices Z(d) coincides with the Haussdorf dimension of their coarsely equivalent Euclidean spaces, beta = d. PMID- 25554018 TI - Review of radiation dose estimates in digital breast tomosynthesis relative to those in two-view full-field digital mammography. AB - We examined how radiation dose levels in digital breast tomosynthesis (DBT) differ from those used in 2-view full-field digital mammography (FFDM). Acquisition parameter settings and information on the average absorbed dose to the glandular tissues within the breasts were reviewed based on clinical studies that evaluated DBT and FFDM. Dose ratios (DDBT/DFFDM) were derived from imaging protocols, which included tomosynthesis in 1- or 2-views alone, and as an adjunct technique to FFDM. Stand-alone DBT was associated with a much lower to a slightly higher radiation dose compared to that of comparable FFDM units, as summarized in dose ratio ranges of 0.34-1.0 for 1-view DBT, and 0.68-1.17 for 2-view DBT. One of the lowest reported dose estimates was obtained using a photon-counting DBT unit (avg. 0.70 mGy/scan; range: 0.28-1.26 mGy). Breast doses for DBT combined with FFDM are summarized in dose ratio ranges of 1.03-1.5 for 1-view DBT plus FFDM, and 2.0-2.23 for 2-view DBT plus FFDM. In the latter of these settings, the dose was reduced by ~45% when 2D-views, reconstructed from the DBT images ("synthetic 2D images"), were used as a substitute for FFDM. Stand-alone DBT operated at lower to slightly higher radiation doses in comparison to FFDM. For DBT combined with FFDM, radiation doses were elevated, at maximum by a factor ~2 1/4 of that of FFDM alone. In this setting, a replacement of FFDM with synthetic 2D-views reduced the breast dose approximately by half, which has substantial implications for population screening programs. PMID- 25554022 TI - Application of the Huang-Hilbert transform and natural time to the analysis of seismic electric signal activities. AB - The Huang method is applied to Seismic Electric Signal (SES) activities in order to decompose them into their components, named Intrinsic Mode Functions (IMFs). We study which of these components contribute to the basic characteristics of the signal. The Hilbert transform is then applied to the IMFs in order to determine their instantaneous amplitudes. The results are compared with those obtained from the analysis in a new time domain termed natural time, after having subtracted the magnetotelluric background from the original signal. It is shown that these instantaneous amplitudes, when combined with the natural time analysis, can be used for the distinction of SES from artificial noises. PMID- 25554023 TI - Transition from amplitude to oscillation death in a network of oscillators. AB - We report a transition from a homogeneous steady state (HSS) to inhomogeneous steady states (IHSSs) in a network of globally coupled identical oscillators. We perturb a synchronized population of oscillators in the network with a few local negative or repulsive mean field links. The whole population splits into two clusters for a certain number of repulsive mean field links and a range of coupling strength. For further increase of the strength of interaction, these clusters collapse into a HSS followed by a transition to IHSSs where all the oscillators populate either of the two stable steady states. We analytically determine the origin of HSS and its transition to IHSS in relation to the number of repulsive mean-field links and the strength of interaction using a reductionism approach to the model network. We verify the results with numerical examples of the paradigmatic Landau-Stuart limit cycle system and the chaotic Rossler oscillator as dynamical nodes. During the transition from HSS to IHSSs, the network follows the Turing type symmetry breaking pitchfork or transcritical bifurcation depending upon the system dynamics. PMID- 25554024 TI - High frequency stimulation of cardiac myocytes: a theoretical and computational study. AB - High-frequency stimulation (HFS) has recently been identified as a novel approach for terminating life-threatening cardiac arrhythmias. HFS elevates myocyte membrane potential and blocks electrical conduction for the duration of the stimulus. However, low amplitude HFS can induce rapidly firing action potentials, which may reinitiate an arrhythmia. The cellular level mechanisms underlying HFS induced electrical activity are not well understood. Using a multiscale method, we show that a minimal myocyte model qualitatively reproduces the influence of HFS on cardiac electrical activity. Theoretical analysis and simulations suggest that persistent activation and de-inactivation of ionic currents, in particular a fast inward window current, underlie HFS-induced action potentials and membrane potential elevation, providing hypotheses for future experiments. We derive analytical expressions to describe how HFS modifies ionic current amplitude and gating dynamics. We show how fast inward current parameters influence the parameter regimes for HFS-induced electrical activity, demonstrating how the efficacy of HFS as a therapy for terminating arrhythmias may depend on the presence of pathological conditions or pharmacological treatments. Finally, we demonstrate that HFS terminates cardiac arrhythmias in a one-dimensional ring of cardiac tissue. In this study, we demonstrate a novel approach to characterize the influence of HFS on ionic current gating dynamics, provide new insight into HFS of the myocardium, and suggest mechanisms underlying HFS-induced electrical activity. PMID- 25554025 TI - Design of time-delayed connection parameters for inducing amplitude death in high dimensional oscillator networks. AB - The present paper studies time-delayed-connection induced amplitude death in high dimensional oscillator networks. We provide two procedures for design of a coupling strength and a transmission delay: these procedures do not depend on the topology of oscillator networks (i.e., network structure and number of oscillators). A graphical procedure based on the Nyquist criterion is proposed and then is numerically confirmed for the case of five-dimensional oscillators, called generalized Rossler oscillators, which have two pairs of complex conjugate unstable roots. In addition, for the case of high-dimensional oscillators having two unstable roots, the procedure can be systematically carried out using only a simple algebraic calculation. This systematic procedure is numerically confirmed for the case of three-dimensional oscillators, called Moore-Spiegel oscillators, which have two positive real unstable roots. PMID- 25554026 TI - Suppression of epidemic spreading in complex networks by local information based behavioral responses. AB - The interplay between individual behaviors and epidemic dynamics in complex networks is a topic of recent interest. In particular, individuals can obtain different types of information about the disease and respond by altering their behaviors, and this can affect the spreading dynamics, possibly in a significant way. We propose a model where individuals' behavioral response is based on a generic type of local information, i.e., the number of neighbors that has been infected with the disease. Mathematically, the response can be characterized by a reduction in the transmission rate by a factor that depends on the number of infected neighbors. Utilizing the standard susceptible-infected-susceptible and susceptible-infected-recovery dynamical models for epidemic spreading, we derive a theoretical formula for the epidemic threshold and provide numerical verification. Our analysis lays on a solid quantitative footing the intuition that individual behavioral response can in general suppress epidemic spreading. Furthermore, we find that the hub nodes play the role of "double-edged sword" in that they can either suppress or promote outbreak, depending on their responses to the epidemic, providing additional support for the idea that these nodes are key to controlling epidemic spreading in complex networks. PMID- 25554027 TI - Non-stationary dynamics in the bouncing ball: a wavelet perspective. AB - The non-stationary dynamics of a bouncing ball, comprising both periodic as well as chaotic behavior, is studied through wavelet transform. The multi-scale characterization of the time series displays clear signatures of self-similarity, complex scaling behavior, and periodicity. Self-similar behavior is quantified by the generalized Hurst exponent, obtained through both wavelet based multi-fractal detrended fluctuation analysis and Fourier methods. The scale dependent variable window size of the wavelets aptly captures both the transients and non-stationary periodic behavior, including the phase synchronization of different modes. The optimal time-frequency localization of the continuous Morlet wavelet is found to delineate the scales corresponding to neutral turbulence, viscous dissipation regions, and different time varying periodic modulations. PMID- 25554028 TI - Experimental synchronization of chaos in a large ring of mutually coupled single transistor oscillators: phase, amplitude, and clustering effects. AB - In this paper, experimental evidence of multiple synchronization phenomena in a large (n = 30) ring of chaotic oscillators is presented. Each node consists of an elementary circuit, generating spikes of irregular amplitude and comprising one bipolar junction transistor, one capacitor, two inductors, and one biasing resistor. The nodes are mutually coupled to their neighbours via additional variable resistors. As coupling resistance is decreased, phase synchronization followed by complete synchronization is observed, and onset of synchronization is associated with partial synchronization, i.e., emergence of communities (clusters). While component tolerances affect community structure, the general synchronization properties are maintained across three prototypes and in numerical simulations. The clusters are destroyed by adding long distance connections with distant notes, but are otherwise relatively stable with respect to structural connectivity changes. The study provides evidence that several fundamental synchronization phenomena can be reliably observed in a network of elementary single-transistor oscillators, demonstrating their generative potential and opening way to potential applications of this undemanding setup in experimental modelling of the relationship between network structure, synchronization, and dynamical properties. PMID- 25554029 TI - Defect-mediated turbulence and transition to spatiotemporal intermittency in the Gray-Scott model. AB - In this paper, we show that the Gray-Scott model is able to produce defect mediated turbulence. This regime emerges from the limit cycle, close or far from the Hopf bifurcation, but always right before the Andronov homoclinic bifurcation of the homogeneous system. After this bifurcation, as the control parameter is further changed, the system starts visiting more and more frequently the stable node of the model. Consequently, the defect-mediated turbulence gradually turns into spatiotemporal intermittency. PMID- 25554030 TI - Noise tolerant spatiotemporal chaos computing. AB - We introduce and design a noise tolerant chaos computing system based on a coupled map lattice (CML) and the noise reduction capabilities inherent in coupled dynamical systems. The resulting spatiotemporal chaos computing system is more robust to noise than a single map chaos computing system. In this CML based approach to computing, under the coupled dynamics, the local noise from different nodes of the lattice diffuses across the lattice, and it attenuates each other's effects, resulting in a system with less noise content and a more robust chaos computing architecture. PMID- 25554031 TI - Phase-locked regimes in delay-coupled oscillator networks. AB - For an ensemble of globally coupled oscillators with time-delayed interactions, an explicit relation for the frequency of synchronized dynamics corresponding to different phase behaviors is obtained. One class of solutions corresponds to globally synchronized in-phase oscillations. The other class of solutions have mixed phases, and these can be either randomly distributed or can be a splay state, namely with phases distributed uniformly on a circle. In the strong coupling limit and for larger networks, the in-phase synchronized configuration alone remains. Upon variation of the coupling strength or the size of the system, the frequency can change discontinuously, when there is a transition from one class of solutions to another. This can be from the in-phase state to a mixed phase state, but can also occur between two in-phase configurations of different frequency. Analytical and numerical results are presented for coupled Landau Stuart oscillators, while numerical results are shown for Rossler and FitzHugh Nagumo systems. PMID- 25554032 TI - Coherence in a family of tree networks with an application of Laplacian spectrum. AB - In this paper, we study consensus problems in a family of tree networks and investigate first and second order consensus denoted as network coherence characterized by Laplacian spectrum. According to the tree structures, we obtain the recursive relationships of Laplacian matrix and its Laplacian eigenvalues at two successive generations. We then obtain the analytical expressions for the sum of the reciprocals and the square reciprocals of all nonzero Laplacian eigenvalues. Finally, we calculate first and second order network coherence and see that the scalings of first and second order coherence with network size N are lnN and N, which are smaller than some studied tree graphs, such as Peano basin fractal, T-graph, and generalized Vicsek fractal. PMID- 25554033 TI - Nonlinear scaling analysis approach of agent-based Potts financial dynamical model. AB - A financial agent-based price model is developed and investigated by one of statistical physics dynamic systems-the Potts model. Potts model, a generalization of the Ising model to more than two components, is a model of interacting spins on a crystalline lattice which describes the interaction strength among the agents. In this work, we investigate and analyze the correlation behavior of normalized returns of the proposed financial model by the power law classification scheme analysis and the empirical mode decomposition analysis. Moreover, the daily returns of Shanghai Composite Index and Shenzhen Component Index are considered, and the comparison nonlinear analysis of statistical behaviors of returns between the actual data and the simulation data is exhibited. PMID- 25554034 TI - Does chaos assist localization or delocalization? AB - We aim at a long-standing contradiction between chaos-assisted tunneling and chaos-related localization study quantum transport of a single particle held in an amplitude-modulated and tilted optical lattice. We find some near-resonant regions crossing chaotic and regular regions in the parameter space, and demonstrate that chaos can heighten velocity of delocalization in the chaos resonance overlapping regions, while chaos may aid localization in the other chaotic regions. The degree of localization enhances with increasing the distance between parameter points and near-resonant regions. The results could be useful for experimentally manipulating chaos-assisted transport of single particles in optical or solid-state lattices. PMID- 25554035 TI - Synchronizing spatio-temporal chaos with imperfect models: a stochastic surface growth picture. AB - We study the synchronization of two spatially extended dynamical systems where the models have imperfections. We show that the synchronization error across space can be visualized as a rough surface governed by the Kardar-Parisi-Zhang equation with both upper and lower bounding walls corresponding to nonlinearities and model discrepancies, respectively. Two types of model imperfections are considered: parameter mismatch and unresolved fast scales, finding in both cases the same qualitative results. The consistency between different setups and systems indicates that the results are generic for a wide family of spatially extended systems. PMID- 25554036 TI - Thermoconvective vortices in a cylindrical annulus with varying inner radius. AB - This paper shows the influence of the inner radius on the stability and intensity of vertical vortices, qualitatively similar to dust devils and cyclones, generated in a cylindrical annulus non-homogeneously heated from below. Little relation is found between the intensity of the vortex and the magnitude of the inner radius. Strong stable vortices can be found for both small and large values of the inner radius. The Rankine combined vortex structure, that characterizes the tangential velocity in dust devils, is clearly observed when small values of the inner radius and large values of the ratio between the horizontal and vertical temperature differences are considered. A contraction on the radius of maximum azimuthal velocity is observed when the vortex is intensified by thermal mechanisms. This radius becomes then nearly stationary when frictional force balances the radial inflow generated by the pressure drop in the center, despite the vortex keeps intensifying. These results connect with the behavior of the radius of the maximum tangential wind associated with a hurricane. PMID- 25554037 TI - Synchronization of networks of oscillators with distributed delay coupling. AB - This paper studies the stability of synchronized states in networks, where couplings between nodes are characterized by some distributed time delay, and develops a generalized master stability function approach. Using a generic example of Stuart-Landau oscillators, it is shown how the stability of synchronized solutions in networks with distributed delay coupling can be determined through a semi-analytic computation of Floquet exponents. The analysis of stability of fully synchronized and of cluster or splay states is illustrated for several practically important choices of delay distributions and network topologies. PMID- 25554038 TI - Networks of coupled circuits: from a versatile toggle switch to collective coherent behavior. AB - We study the versatile performance of networks of coupled circuits. Each of these circuits is composed of a positive and a negative feedback loop in a motif that is frequently found in genetic and neural networks. When two of these circuits are coupled with mutual repression, the system can function as a toggle switch. The variety of its states can be controlled by two parameters as we demonstrate by a detailed bifurcation analysis. In the bistable regimes, switches between the coexisting attractors can be induced by noise. When we couple larger sets of these units, we numerically observe collective coherent modes of individual fixed point and limit-cycle behavior. It is there that the monotonic change of a single bifurcation parameter allows one to control the onset and arrest of the synchronized oscillations. This mechanism may play a role in biological applications, in particular, in connection with the segmentation clock. While tuning the bifurcation parameter, also a variety of transient patterns emerges upon approaching the stationary states, in particular, a self-organized pacemaker in a completely uniformly equipped ensemble, so that the symmetry breaking happens dynamically. PMID- 25554039 TI - Nonreciprocal wave scattering on nonlinear string-coupled oscillators. AB - We study scattering of a periodic wave in a string on two lumped oscillators attached to it. The equations can be represented as a driven (by the incident wave) dissipative (due to radiation losses) system of delay differential equations of neutral type. Nonlinearity of oscillators makes the scattering non reciprocal: The same wave is transmitted differently in two directions. Periodic regimes of scattering are analyzed approximately, using amplitude equation approach. We show that this setup can act as a nonreciprocal modulator via Hopf bifurcations of the steady solutions. Numerical simulations of the full system reveal nontrivial regimes of quasiperiodic and chaotic scattering. Moreover, a regime of a "chaotic diode," where transmission is periodic in one direction and chaotic in the opposite one, is reported. PMID- 25554040 TI - Impact of pressure, salt concentration, and temperature on the convective dissolution of carbon dioxide in aqueous solutions. AB - The convective dissolution of carbon dioxide (CO2) in salted water is theoretically studied to determine how parameters such as CO2 pressure, salt concentration, and temperature impact the short-time characteristics of the buoyancy-driven instability. On the basis of a parameter-free dimensionless model, we perform a linear stability analysis of the time-dependent concentration profiles of CO2 diffusing into the aqueous solution. We explicit the procedure to transform the predicted dimensionless growth rate and wavelength of the convective pattern into dimensional ones for typical laboratory-scale experiments in conditions close to room temperature and atmospheric pressure. This allows to investigate the implicit influence of the experimental parameters on the characteristic length and time scales of the instability. We predict that increasing CO2 pressure, or decreasing salt concentration or temperature destabilizes the system with regard to convection, leading to a faster dissolution of CO2 into salted water. PMID- 25554041 TI - Does topological information matter for power grid vulnerability? AB - Power grids, which are playing an important role in supporting the economy of a region as well as the life of its citizens, could be attacked by terrorists or enemies to damage the region. Depending on different levels of power grid information collected by the terrorists, their attack strategies might be different. This paper groups power grid information into four levels: no information, purely topological information (PTI), topological information with generator and load nodes (GLNI), and full information (including component physical properties and flow parameters information), and then identifies possible attack strategies for each information level. Analyzing and comparing power grid vulnerability under these attack strategies from both terrorists' and utility companies' point of view give rise to an approach to quantify the relative values of these three types of information, including PTI, GLNI, and component parameter information (CPI). This approach can provide information regarding the extent to which topological information matters for power system vulnerability decisions. Taking several test systems as examples, results show that for small attacks with p <= 0.1, CPI matters the most; when taking attack cost into consideration and assuming that the terrorists take the optimum cost efficient attack intensity, then CPI has the largest cost-based information value. PMID- 25554042 TI - On noise induced Poincare-Andronov-Hopf bifurcation. AB - It has been numerically seen that noise introduces stable well-defined oscillatory state in a system with unstable limit cycles resulting from subcritical Poincare-Andronov-Hopf (or simply Hopf) bifurcation. This phenomenon is analogous to the well known stochastic resonance in the sense that it effectively converts noise into useful energy. Herein, we clearly explain how noise induced imperfection in the bifurcation is a generic reason for such a phenomenon to occur and provide explicit analytical calculations in order to explain the typical square-root dependence of the oscillations' amplitude on the noise level below a certain threshold value. Also, we argue that the noise can bring forth oscillations in average sense even in the absence of a limit cycle. Thus, we bring forward the inherent general mechanism of the noise induced Hopf bifurcation naturally realisable across disciplines. PMID- 25554043 TI - Bohmian trajectory from the "classical" Schrodinger equation. AB - The quantum-classical correspondence is studied for a periodically driven quartic oscillator exhibiting integrable and chaotic dynamics, by studying the Bohmian trajectory of the corresponding "classical" Schrodinger equation. Phase plots and the Kolmogorov-Sinai entropy are computed and compared with the classical trajectory as well as the Bohmian trajectory obtained from the time dependent Schrodinger equation. Bohmian mechanics at the classical limit appears to mimick the behavior of a dissipative dynamical system. PMID- 25554044 TI - Estimating the epidemic threshold on networks by deterministic connections. AB - For many epidemic networks some connections between nodes are treated as deterministic, while the remainder are random and have different connection probabilities. By applying spectral analysis to several constructed models, we find that one can estimate the epidemic thresholds of these networks by investigating information from only the deterministic connections. Nonetheless, in these models, generic nonuniform stochastic connections and heterogeneous community structure are also considered. The estimation of epidemic thresholds is achieved via inequalities with upper and lower bounds, which are found to be in very good agreement with numerical simulations. Since these deterministic connections are easier to detect than those stochastic connections, this work provides a feasible and effective method to estimate the epidemic thresholds in real epidemic networks. PMID- 25554045 TI - Mobility and density induced amplitude death in metapopulation networks of coupled oscillators. AB - We investigate the effects of mobility and density on the amplitude death of coupled Landau-Stuart oscillators and Brusselators in metapopulation networks, wherein each node represents a subpopulation occupied any number of mobile individuals. By numerical simulations in scale-free topology, we find that the systems undergo phase transitions from incoherent state to amplitude death, and then to frequency synchronization with increasing the mobility rate or density of oscillators. Especially, there exists an extent of intermediate mobility rate and density that can lead to global oscillator death. Furthermore, we show that such nontrivial phenomena are robust to diverse network topologies. Our findings may invoke further efforts and attentions to explore the underlying mechanism of collective behaviors in coupled metapopulation systems. PMID- 25554046 TI - Coexisting chaotic and multi-periodic dynamics in a model of cardiac alternans. AB - The spatiotemporal dynamics of cardiac tissue is an active area of research for biologists, physicists, and mathematicians. Of particular interest is the study of period-doubling bifurcations and chaos due to their link with cardiac arrhythmogenesis. In this paper, we study the spatiotemporal dynamics of a recently developed model for calcium-driven alternans in a one dimensional cable of tissue. In particular, we observe in the cable coexistence of regions with chaotic and multi-periodic dynamics over wide ranges of parameters. We study these dynamics using global and local Lyapunov exponents and spatial trajectory correlations. Interestingly, near nodes-or phase reversals-low-periodic dynamics prevail, while away from the nodes, the dynamics tend to be higher-periodic and eventually chaotic. Finally, we show that similar coexisting multi-periodic and chaotic dynamics can also be observed in a detailed ionic model. PMID- 25554047 TI - Extension of spatiotemporal chaos in glow discharge-semiconductor systems. AB - Generation of chaos in response systems is discovered numerically through specially designed unidirectional coupling of two glow discharge-semiconductor systems. By utilizing the auxiliary system approach, [H. D. I. Abarbanel, N. F. Rulkov, and M. M. Sushchik, Phys. Rev. E 53, 4528-4535 (1996)] it is verified that the phenomenon is not a chaos synchronization. Simulations demonstrate various aspects of the chaos appearance in both drive and response systems. Chaotic control is through the external circuit equation and governs the electrical potential on the boundary. The expandability of the theory to collectives of glow discharge systems is discussed, and this increases the potential of applications of the results. Moreover, the research completes the previous discussion of the chaos appearance in a glow discharge-semiconductor system [D. D. Sijacic U. Ebert, and I. Rafatov, Phys. Rev. E 70, 056220 (2004).]. PMID- 25554048 TI - Motion on constant curvature spaces and quantization using Noether symmetries. AB - A general approach is presented for quantizing a metric nonlinear system on a manifold of constant curvature. It makes use of a curvature dependent procedure which relies on determining Noether symmetries from the metric. The curvature of the space functions as a constant parameter. For a specific metric which defines the manifold, Lie differentiation of the metric gives these symmetries. A metric is used such that the resulting Schrodinger equation can be solved in terms of hypergeometric functions. This permits the investigation of both the energy spectrum and wave functions exactly for this system. PMID- 25554049 TI - A unified framework of mutual influence between two pathogens in multiplex networks. AB - There are many evidences to show that different pathogens may interplay each other and cause a variety of mutual influences of epidemics in multiplex networks, but it is still lack of a framework to unify all the different dynamic outcomes of the interactions between the pathogens. We here study this problem and first time present the concept of state-dependent infectious rate, in contrast to the constant infectious rate in previous studies. We consider a model consisting of a two-layered network with one pathogen on the first layer and the other on the second layer, and show that all the different influences between the two pathogens can be given by the different range of parameters in the infectious rates, which includes the cases of mutual enhancement, mutual suppression, and even initial cooperation (suppression) induced final suppression (acceleration). A theoretical analysis is present to explain the numerical results. PMID- 25554050 TI - Survival probability for open spherical billiards. AB - We study the survival probability for long times in an open spherical billiard, extending previous work on the circular billiard. We provide details of calculations regarding two billiard configurations, specifically a sphere with a circular hole and a sphere with a square hole. The constant terms of the long time survival probability expansions have been derived analytically. Terms that vanish in the long time limit are investigated analytically and numerically, leading to connections with the Riemann hypothesis. PMID- 25554051 TI - Do topological models contribute to decision making on post-disaster electric power system restoration? AB - This paper introduces two topological models and proposes several topology-based strategies to generate the restoration sequences of the damaged components in a post-disaster power system, and then compares their effectiveness with a random strategy (RS) and a power supply optimized strategy (PSOS, which considers the power flow for restoration optimization), where the strategy effectiveness is quantified by resilience loss defined as the area between real performance curve and target performance curve during the restoration period. Taking the IEEE 300 power system under node failures as an example, results show that under limited restoration resources, topology-based strategies can improve upon the RS-based resilience loss by 39%-46% at most, and their produced average minimum resilience loss is 1.14-1.46 times the PSOS-based resilience loss; when taking restoration sequences generated by topology-based strategies as an input of PSOS, better restoration sequences are found with the resilience loss improved by 16% at most. Similar results are also found under other system parameter settings, other failure types, and other power systems. PMID- 25554052 TI - On the chaotic behavior of the primal-dual affine-scaling algorithm for linear optimization. AB - We study a one-parameter family of quadratic maps, which serves as a template for interior point methods. It is known that such methods can exhibit chaotic behavior, but this has been verified only for particular linear optimization problems. Our results indicate that this chaotic behavior is generic. PMID- 25554053 TI - A class of scale-free networks with fractal structure based on subshift of finite type. AB - In this paper, given a time series generated by a certain dynamical system, we construct a new class of scale-free networks with fractal structure based on the subshift of finite type and base graphs. To simplify our model, we suppose the base graphs are bipartite graphs and the subshift has the special form. When embedding our growing network into the plane, we find its image is a graph directed self-affine fractal, whose Hausdorff dimension is related to the power law exponent of cumulative degree distribution. It is known that a large spectral gap in terms of normalized Laplacian is usually associated with small mixing time, which makes facilitated synchronization and rapid convergence possible. Through an elaborate analysis of our network, we can estimate its Cheeger constant, which controls the spectral gap by Cheeger inequality. As a result of this estimation, when the bipartite base graph is complete, we give a sharp condition to ensure that our networks are well-connected with rapid mixing property. PMID- 25554054 TI - On the modeling and nonlinear dynamics of autonomous Silva-Young type chaotic oscillators with flat power spectrum. AB - The nonlinear dynamics of fourth-order Silva-Young type chaotic oscillators with flat power spectrum recently introduced by Tamaseviciute and collaborators is considered. In this type of oscillators, a pair of semiconductor diodes in an anti-parallel connection acts as the nonlinear component necessary for generating chaotic oscillations. Based on the Shockley diode equation and an appropriate selection of the state variables, a smooth mathematical model (involving hyperbolic sine and cosine functions) is derived for a better description of both the regular and chaotic dynamics of the system. The complex behavior of the oscillator is characterized in terms of its parameters by using time series, bifurcation diagrams, Lyapunov exponents' plots, Poincare sections, and frequency spectra. It is shown that the onset of chaos is achieved via the classical period doubling and symmetry restoring crisis scenarios. Some PSPICE simulations of the nonlinear dynamics of the oscillator are presented in order to confirm the ability of the proposed mathematical model to accurately describe/predict both the regular and chaotic behaviors of the oscillator. PMID- 25554055 TI - Multi-scale dynamics of glow discharge plasma through wavelets: self-similar behavior to neutral turbulence and dissipation. AB - The multiscale dynamics of glow discharge plasma is analysed through wavelet transform, whose scale dependent variable window size aptly captures both transients and non-stationary periodic behavior. The optimal time-frequency localization ability of the continuous Morlet wavelet is found to identify the scale dependent periodic modulations efficiently, as also the emergence of neutral turbulence and dissipation, whereas the discrete Daubechies basis set has been used for detrending the temporal behavior to reveal the multi-fractality of the underlying dynamics. The scaling exponents and the Hurst exponent have been estimated through wavelet based detrended fluctuation analysis, and also Fourier methods and rescale range analysis. PMID- 25554056 TI - Stabilization of solitons under competing nonlinearities by external potentials. AB - We report results of the analysis for families of one-dimensional (1D) trapped solitons, created by competing self-focusing (SF) quintic and self-defocusing (SDF) cubic nonlinear terms. Two trapping potentials are considered, the harmonic oscillator (HO) and delta-functional ones. The models apply to optical solitons in colloidal waveguides and other photonic media, and to matter-wave solitons in Bose-Einstein condensates loaded into a quasi-1D trap. For the HO potential, the results are obtained in an approximate form, using the variational and Thomas Fermi approximations, and in a full numerical form, including the ground state and the first antisymmetric excited one. For the delta-functional attractive potential, the results are produced in a fully analytical form, and verified by means of numerical methods. Both exponentially localized solitons and weakly localized trapped modes are found for the delta-functional potential. The most essential conclusions concern the applicability of competing Vakhitov-Kolokolov (VK) and anti-VK criteria to the identification of the stability of solitons created under the action of the competing SF and SDF terms. PMID- 25554057 TI - A boundary integral formalism for stochastic ray tracing in billiards. AB - Determining the flow of rays or non-interacting particles driven by a force or velocity field is fundamental to modelling many physical processes. These include particle flows arising in fluid mechanics and ray flows arising in the geometrical optics limit of linear wave equations. In many practical applications, the driving field is not known exactly and the dynamics are determined only up to a degree of uncertainty. This paper presents a boundary integral framework for propagating flows including uncertainties, which is shown to systematically interpolate between a deterministic and a completely random description of the trajectory propagation. A simple but efficient discretisation approach is applied to model uncertain billiard dynamics in an integrable rectangular domain. PMID- 25554058 TI - Chaotic behavior of light-assisted physical aging in arsenoselenide glasses. AB - The theory of strange attractors is shown to be adequately applicable for analyzing the kinetics of light-assisted physical aging revealed in structural relaxation of Se-rich As-Se glasses below glass transition. Kinetics of enthalpy losses is used to determine the phase space reconstruction parameters. Observed chaotic behaviour (involving chaos and fractal consideration such as detrended fluctuation analysis, attractor identification using phase space representation, delay coordinates, mutual information, false nearest neighbours, etc.) reconstructed via the TISEAN program package is treated within a microstructure model describing multistage aging behaviour in arsenoselenide glasses. This simulation testifies that photoexposure acts as an initiating factor only at the beginning stage of physical aging, thus facilitating further atomic shrinkage of a glassy backbone. PMID- 25554059 TI - Study of turbulent energy dissipation rate of fluid flow in the vicinity of dispersed phase boundary using spatiotemporal tree model. AB - The hierarchical shell models of turbulence including a spatial dimension, namely, spatiotemporal tree models, reproduce the intermittent behavior of Navier Stokes equations in both space and time dimensions corresponding to high Reynolds number turbulent flows. This model is used, for the first time in this paper, in a one-dimensional flow zone containing a dispersed-phase particle that can be used in the study of dispersed-phase flows. In this paper, a straightforward method has been used to introduce discrete phase into the spatiotemporal tree model that leads to an increased amount of turbulent energy dissipation rate in the vicinity of the discrete phase. The effects of particle insertion and particle size on the turbulent energy dissipation rate are demonstrated. Moreover, the space-scale behavior of the time-averaged turbulent energy dissipation rate in the presence of dispersed phase is demonstrated by means of continuous wavelet transform. PMID- 25554060 TI - Diversity and time delays induce resonance in a modular neuronal network. AB - This paper focuses on the resonance dynamics of a modular neuronal network consisting of several small-world subnetworks. The considered network is composed of delay-coupled FitzHugh-Nagumo (FHN) neurons, whose characteristic parameters present diversity in the form of quenched noise. Our numerical results indicate that when such a network is subjected to an external subthreshold periodic signal, its collective response is optimized for an intermediate level of diversity, namely, a resonant behavior can be induced by an appropriate level of diversity. How the probabilities of intramodule and intermodule connections, as well as the number of subnetworks influence the diversity-induced resonance are also discussed. Further, conclusive evidences demonstrate the nontrivial role of time-delayed coupling on the diversity-induced resonance properties. Especially, multiple resonance is obviously detected when time delays are located at integer multiples of the oscillation period of the signal. Moreover, the phenomenon of fine-tuned delays in inducing multiple resonance remains when diversity is within an intermediate range. Our findings have implications that neural systems may profit from their generic diversity and delayed coupling to optimize the response to external stimulus. PMID- 25554061 TI - A development scenario connecting the ternary symmetric horseshoe with the binary horseshoe. AB - It is explained in which way the ternary symmetric horseshoe can be obtained along a development scenario starting with a binary horseshoe. We explain the case of a complete ternary horseshoe in all detail and then give briefly some further incomplete cases. The key idea is to start with a three degrees of freedom system with a rotational symmetry, reduce the system with the help of the conserved angular momentum to one with two degrees of freedom where the value of the conserved angular momentum acts as a parameter and then let its value go to zero. PMID- 25554062 TI - Spatio-temporal dynamics induced by competing instabilities in two asymmetrically coupled nonlinear evolution equations. AB - Pattern formation often occurs in spatially extended physical, biological, and chemical systems due to an instability of the homogeneous steady state. The type of the instability usually prescribes the resulting spatio-temporal patterns and their characteristic length scales. However, patterns resulting from the simultaneous occurrence of instabilities cannot be expected to be simple superposition of the patterns associated with the considered instabilities. To address this issue, we design two simple models composed by two asymmetrically coupled equations of non-conserved (Swift-Hohenberg equations) or conserved (Cahn Hilliard equations) order parameters with different characteristic wave lengths. The patterns arising in these systems range from coexisting static patterns of different wavelengths to traveling waves. A linear stability analysis allows to derive a two parameter phase diagram for the studied models, in particular, revealing for the Swift-Hohenberg equations, a co-dimension two bifurcation point of Turing and wave instability and a region of coexistence of stationary and traveling patterns. The nonlinear dynamics of the coupled evolution equations is investigated by performing accurate numerical simulations. These reveal more complex patterns, ranging from traveling waves with embedded Turing patterns domains to spatio-temporal chaos, and a wide hysteretic region, where waves or Turing patterns coexist. For the coupled Cahn-Hilliard equations the presence of a weak coupling is sufficient to arrest the coarsening process and to lead to the emergence of purely periodic patterns. The final states are characterized by domains with a characteristic length, which diverges logarithmically with the coupling amplitude. PMID- 25554063 TI - Genetic diversity in Trypanosoma theileri from Sri Lankan cattle and water buffaloes. AB - Trypanosoma theileri is a hemoprotozoan parasite that infects various ruminant species. We investigated the epidemiology of this parasite among cattle and water buffalo populations bred in Sri Lanka, using a diagnostic PCR assay based on the cathepsin L-like protein (CATL) gene. Blood DNA samples sourced from cattle (n=316) and water buffaloes (n=320) bred in different geographical areas of Sri Lanka were PCR screened for T. theileri. Parasite DNA was detected in cattle and water buffaloes alike in all the sampling locations. The overall T. theileri positive rate was higher in water buffaloes (15.9%) than in cattle (7.6%). Subsequently, PCR amplicons were sequenced and the partial CATL sequences were phylogenetically analyzed. The identity values for the CATL gene were 89.6-99.7% among the cattle-derived sequences, compared with values of 90.7-100% for the buffalo-derived sequences. However, the cattle-derived sequences shared 88.2-100% identity values with those from buffaloes. In the phylogenetic tree, the Sri Lankan CATL gene sequences fell into two major clades (TthI and TthII), both of which contain CATL sequences from several other countries. Although most of the CATL sequences from Sri Lankan cattle and buffaloes clustered independently, two buffalo-derived sequences were observed to be closely related to those of the Sri Lankan cattle. Furthermore, a Sri Lankan buffalo sequence clustered with CATL gene sequences from Brazilian buffalo and Thai cattle. In addition to reporting the first PCR-based survey of T. theileri among Sri Lankan-bred cattle and water buffaloes, the present study found that some of the CATL gene fragments sourced from water buffaloes shared similarity with those determined from cattle in this country. PMID- 25554064 TI - Mild training program in metabolic syndrome improves the efficiency of the oxygen pathway. AB - In sedentary patients suffering of metabolic syndrome, we evaluated the effects of mild exercise program (EP) on the efficiency of the oxygen delivery system. The prescription of exercise (40 min/session, 3 times/week) was tailored at workload corresponding to ~90% individual anaerobic threshold (AT). EP improved significantly by ~10% peak values of oxygen consumption (VO2) and heart rate (HR). Furthermore, in response to steady state workload at 90% AT, EP shortened the time constant of VO2, HR and the ratio VO2/HR (reflecting arterio-venous O2 concentration difference) by ~6s. EP also decreased the elastic respiratory work due to a change in breathing pattern implying a larger contribution of respiratory rate, at the expense of tidal volume during exercise hyperventilation. In all subjects the perceived fatigue (Borg) decreased after training. This study supports a positive effect of a mild EP for the adaptive response of the oxygen chain to face metabolic needs compatible with daily life in patients affected by metabolic syndrome. PMID- 25554065 TI - Editorial. SGLT-2 receptor inhibitors: An opportunity to revise our therapeutic strategy for type 2 diabetes? PMID- 25554066 TI - Familial renal glycosuria and modifications of glucose renal excretion. AB - Under physiological conditions, the kidneys contribute to glucose homoeostasis by producing glucose by gluconeogenesis and preventing glucose loss in urine. The glucose filtered by the glomeruli is completely reabsorbed in the renal proximal tubule. Renal gluconeogenesis produces 25% of the circulating glucose in the postabsorptive state, while the amount of glucose reabsorbed by the kidneys largely exceeds the quantity synthesized by kidney gluconeogenesis. Sodium glucose cotransporter type 2 (SGLT-2) and glucose transporter 2 (GLUT2) carry out more than 90% of renal glucose uptake. In diabetes, both gluconeogenesis and renal glucose reabsorption are increased. The augmentation of glucose uptake in diabetes is due to the overexpression of renal glucose transporters SGLT-2 and GLUT2 in response to the increase in expression of transcription activator hepatic nuclear factor 1-alpha (HNF1alpha). The rise in glucose uptake contributes to hyperglycaemia and induces glomerular hyperfiltration by increasing sodium and water reabsorption in the proximal tubule that, in turn, modifies urine flux at the macula densa. SGLT-2 inhibitors improve glycaemic control and prevent renal hyperfiltration in diabetes. Loss of SGLT-2 transporter function is a benign state characterized by glycosuria. In contrast, mutations of other glucose transporters expressed in the kidney are responsible for severe disorders. PMID- 25554067 TI - Beyond Glycosuria: Exploring the intrarenal effects of SGLT-2 inhibition in diabetes. AB - For millennia, the syndrome that has become known as diabetes was considered to be primarily a disease of the urinary system and, by association, of dysfunction in the kidneys (recognized as the source of urine). In the last decade, there has been renewed interest in the role of the kidneys in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodiumglucose cotransporter 2 (SGLT-2) as a means to control glucose levels and augment calorie-wasting leading to weight loss. However, beyond actions on glycaemic control, inhibition of proximal glucose absorption via SGLT-2 has significant direct effects to attenuate hyperfiltration and reduce renal hypertrophy. Increased distal sodium delivery may also act to suppress the intrarenal renin-angiotensin-aldosterone system, although systemic activity may be modestly increased due to osmotic diuresis. Reducing proximal glucose reabsorption may also protect the tubular cells from exposure to excess glucose and glucose-induced reactive oxygen species. On the other hand, distal glucose delivery following inhibition of SGLT-2 may increase glycogen deposition, the significance of which is unclear. However, subjects with familial glycosuria appear to have a benign renal prognosis. Some studies have demonstrated significant reductions in albumin excretion in various experimental models and as post-hoc observations in clinical trials. Whether these reflect renoprotection or are simply the result of intraglomerular haemodynamic changes remains unclear. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. PMID- 25554068 TI - SGLT-2 inhibition in patients with kidney disease. AB - Accustomed to managing diabetes with agents that mostly act by modulating the secretion and actions of insulin, with the advent of sodium-glucose linked transporter-2 (SGLT-2) inhibitors, physicians are now aware that the kidney also needs to be considered in the spectrum of action of anti-hyperglycaemic agents. Though familiar with the need for dose adjustment when prescribing many of our current anti-hyperglycaemic drugs in the setting of kidney dysfunction, with the SGLT-2 inhibitors pharmacodynamic as well as pharmacokinetic aspects also need to be considered. Finally, through their ability to reduce intraglomerular pressure, systemic blood pressure and plasma uric acid concentration, the SGLT-2 inhibitors offers the possibility of kidney protection. An hypothesis that will need to be tested with long term studies that address changes in the kidney beyond albuminuria, assessing the rate of decline in glomerular filtration rate and 'hard'kidneyrelated endpoints such as the need for renal replacement therapy (dialysis, transplantation) will be important in this setting. PMID- 25554069 TI - Adverse effects and safety of SGLT-2 inhibitors. AB - In type 2 diabetes (T2DM), glycaemic control delays the development and slows the progression of complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of T2DM patients achieve glycaemic control, while undesirable side-effects, such as hypoglycaemia and body weight gain, often impede treatment in those taking these medications. Thus, there is a need for novel agents and treatment options. Sodium-glucose cotransporter-2 inhibitors (SGLT-2-i) have recently been developed for the treatment of T2DM. The available data suggest a good tolerability profile for the three available drugs canagliflozin, dapagliflozin and empagliflozin - approved by the US Food and Drug Administration (FDA) for the American market as well as in other countries. The most frequently reported adverse events with SGLT-2-i are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to SGLT-2-i declines with increasing severity of renal impairment, requiring dosage adjustments or restrictions with moderate-to-severe renal dysfunction. Most patients treated with SGLT-2-i also have a modest reduction in blood pressure and modest effects on serum lipid profiles, some of which are beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others which are not (increased low-density lipoprotein cholesterol, LDL-C). A number of large-scale and longer-term cardiovascular trials are now ongoing. In patients treated with dapagliflozin, a non-significant excess number of breast and bladder cancers has been reported; considered as due to a bias, this is nevertheless being followed in the ongoing trials. No other significant safety issues have been reported so far. Although there is some benefit for several cardiovascular risk factors such as HbA1c, high blood pressure, obesity and increases in LDL-C, adequately powered trials are still required to determine the effects of SGLT-2-i on macrovascular outcomes. PMID- 25554070 TI - Metabolic effects of SGLT-2 inhibitors beyond increased glucosuria: A review of the clinical evidence. AB - Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) are new glucose-lowering agents that exert their therapeutic activity independently of insulin by facilitating glucose excretion through the kidneys. However, this simple renal mechanism that results in sustained glucose urinary loss leads to more complex indirect metabolic effects. First, by reduction of chronic hyperglycaemia and attenuation of glucose toxicity, SGLT-2 inhibitors can improve both insulin secretion by beta cells and peripheraltissue insulin sensitivity. In the case of canagliflozin, because of low-potency SGLT1 inhibition, a non-renal (intestinal) effect may also be considered, which may contribute to better control of postprandial hyperglycaemia, although this contribution remains to be better analyzed in humans. Second, chronic glucose loss most probably leads to compensatory mechanisms. One of them, although not well evidenced in humans, might involve an increase in energy intake, an effect that may limit weight loss in the long run. Another could be an increase in endogenous glucose production, most probably driven by increased glucagon secretion, which may somewhat attenuate the glucoselowering effect. Nevertheless, despite these compensatory mechanisms and most probably because of the positive effects of the reduction in glucotoxicity, SGLT-2 inhibitors exert clinically relevant glucose-lowering activity while promoting weight loss, a unique dual effect among oral antidiabetic agents. Furthermore, the combination of SGLT-2 inhibitors with other drugs that either have anorectic effects (such as incretin-based therapies) or reduce hepatic glucose output (like metformin) and, thus, may dampen these two compensatory mechanisms appears appealing for the management of type 2 diabetes mellitus. PMID- 25554071 TI - The usefulness of genotyping cytochrome P450 enzymes in the treatment of depression. AB - INTRODUCTION: Pharmacogenomics, which is derived from genome-wide association studies (GWAS), and pharmacogenetics, which involves candidate gene association studies (CGASs), are proving increasingly useful in personalized cancer care. Research in psychiatric applications has primarily involved genetic polymorphisms of P450 CYP enzymes, which mediate oxidative metabolism, particularly CYP2D6, which is involved in the metabolism of at least 30 psychotropic medications. This work has been supplemented by genotyping of proteins for the drug efflux pump P glycoprotein (P-gp), serotonin receptors, and the serotonin reuptake pump. AREAS COVERED: This review covers principles of pharmacogenetics and pharmacogenomics, previous analyses of pharmacokinetic and pharmacodynamics studies, newer studies of the predictive value of genetic testing in the treatment of depression, obstacles to implementation of genetic testing in predicting treatment response and side effects, and suggestions for future research. EXPERT OPINION: Studies of multiple genes have produced some positive results in groups of patients, but genetic testing does not yet seem to be applicable to choosing medications for a specific patient. PMID- 25554073 TI - Targeted activation of silent natural product biosynthesis pathways by reporter guided mutant selection. AB - The continuously increasing genome sequencing data has revealed numerous cryptic pathways, which might encode novel secondary metabolites with interesting biological activities. However, utilization of this hidden potential has been hindered by the observation that many of these gene clusters remain silent (or poorly expressed) under laboratory conditions. Here we present reporter-guided mutant selection (RGMS) as an effective and widely applicable method for targeted activation of silent gene clusters in the native producers. The strategy takes advantage of genome-scale random mutagenesis for generation of genetic diversity and a reporter-guided selection system for the identification of the desired target-activated mutants. It was first validated in the re-activation of jadomycin biosynthesis in Streptomyces venezuelae ISP5230, where high efficiency of activation was achieved. The same strategy was then applied to a hitherto unactivable pga gene cluster in Streptomyces sp. PGA64 leading to the identification of two new anthraquinone aminoglycosides, gaudimycin D and E. PMID- 25554072 TI - A randomized longitudinal dietary intervention study during pregnancy: effects on fish intake, phospholipids, and body composition. AB - BACKGROUND: Fish and meat intake may affect gestational weight gain, body composition and serum fatty acids. We aimed to determine whether a longitudinal dietary intervention during pregnancy could increase fish intake, affect serum phospholipid fatty acids, gestational weight gain and body composition changes during pregnancy in women of normal weight participating in the Pregnancy Obesity Nutrition and Child Health study. A second aim was to study possible effects in early pregnancy of fish intake and meat intake, respectively, on serum phospholipid fatty acids, gestational weight gain, and body composition changes during pregnancy. METHODS: In this prospective, randomized controlled study, women were allocated to a control group or to a dietary counseling group that focused on increasing fish intake. Fat mass and fat-free mass were measured by air-displacement plethysmography. Reported intake of fish and meat was collected from a baseline population and from a subgroup of women who participated in each trimester of their pregnancies. Serum levels of phospholipid arachidonic acid (s ARA), eicosapentaenoic acid (s-EPA), and docosahexaenoic acid (s-DHA) were measured during each trimester. RESULTS: Weekly fish intake increased only in the intervention group (n = 18) from the first to the second trimester (median difference 113 g, p = 0.03) and from the first to the third trimester (median difference 75 g, p = 0.01). In the first trimester, fish intake correlated with s EPA (r = 0.36, p = 0.002, n = 69) and s-DHA (r = 0.34, p = 0.005, n = 69), and meat intake correlated with s-ARA (r = 0.28, p = 0.02, n = 69). Fat-free mass gain correlated with reported meat intake in the first trimester (r = 0.39, p = 0.01, n = 45). CONCLUSIONS: Dietary counseling throughout pregnancy could help women increase their fish intake. Intake of meat in early pregnancy may increase the gain in fat-free mass during pregnancy. PMID- 25554074 TI - Principal component analysis of proteomics (PCAP) as a tool to direct metabolic engineering. AB - Targeted proteomics is a convenient method determining enzyme expression levels, but a quantitative analysis of these proteomic data has not been fully explored yet. Here, we present and demonstrate a computational tool (principal component analysis of proteomics, PCAP) that uses quantitative targeted proteomics data to guide metabolic engineering and achieve higher production of target molecules from heterologous pathways. The method is based on the application of principal component analysis to a collection of proteomics and target molecule production data to pinpoint specific enzymes that need to have their expression level adjusted to maximize production. We illustrated the method on the heterologous mevalonate pathway in Escherichia coli that produces a wide range of isoprenoids and requires balanced pathway gene expression for high yields and titers. PCAP guided engineering resulted in over a 40% improvement in the production of two valuable terpenes. PCAP could potentially be productively applied to other heterologous pathways as well. PMID- 25554084 TI - Radial growth of plasmon coupled gold nanowires on colloidal templates. AB - The library of plasmonic nanosystems keeps expanding with novel structures with the potential to provide new solutions to old problems in science and technology. We report the synthesis of a novel plasmonic system based on the growth of gold nanowires radially branching from the surface of silica particles. The nanowires length could be controlled by tuning the molar ratio between metal salt and surface-grafted seeds. Electron microscopy characterization revealed that the obtained one-dimensional nanoparticles are polycrystalline but uniformly distributed on the spherical template. The length of the nanowires in turn determines the optical response of the metallodielectric particles, so that longer wires display red-shifted longitudinal plasmon bands. Accurate theoretical modeling of these complex objects revealed that the densely organized nanowires display intrinsically coupled plasmon modes that can be selectively decoupled upon detachment of the nanowires from the surface of the colloidal silica template. PMID- 25554085 TI - Multifunctional polyelectrolyte multilayers as nanofiltration membranes and as sacrificial layers for easy membrane cleaning. AB - This manuscript investigates the modification of an ultra-filtration (UF) membrane support with polyelectrolyte multilayers (PEMs) consisting of the weak polyelectrolytes poly(allyl amine) hydrochloride (PAH) and poly(acrylic acid) (PAA). These prepared polyelectrolyte multilayer membranes have a dual function: They act as nanofiltration (NF) membranes and as sacrificial layers to allow easy cleaning of the membranes. In order to optimize the conditions for PEM coating and removal, adsorption and desorption of these layers on a model surface (silica) was first studied via optical reflectometry. Subsequently, a charged UF membrane support was coated with a PEM and after each deposited layer, a clear increase in membrane resistance against pure water permeation and a switch of the zeta potential were observed. Moreover these polyelectrolyte multilayer membranes, exhibited rejection of solutes in a range typical for NF membranes. Monovalent ions (NaCl) were hardly rejected (<24%), while rejections of >60% were observed for a neutral organic molecule sulfamethoxazole (SMX) and for the divalent ion SO3(2-). The rejection mechanism of these membranes seems to be dominated by size-exclusion. To investigate the role of these PEMs as sacrificial layers for the cleaning of fouled membranes, the prepared polyelectrolyte multilayers were fouled with silica nano particles. Subsequent removal of the coating using a rinse and a low pressure backwash with pH 3, 3M NaNO3 allowed for a drop in membrane resistance from 1.7?10(14)m(-1) (fouled membrane) to 9.9?10(12)m(-1) (clean membrane), which is nearly equal to that of the pristine membrane (9.7?10(12)m(-1)). Recoating of the support membrane with the same PEMs resulted in a resistance equal to the resistance of the original polyelectrolyte multilayer membrane. Interestingly, less layers were needed to obtain complete foulant removal from the membrane surface, than was the case for the model surface. The possibility for backwashing allows for an even more successful use of the sacrificial layer approach in membrane technology than on model surfaces. Moreover, these PEMs can be used to provide a dual function, as NF membranes and as a Sacrificial coating to allow easy membrane cleaning. PMID- 25554087 TI - Competitive adsorption of ibuprofen and amoxicillin mixtures from aqueous solution on activated carbons. AB - This work investigates the competitive adsorption under dynamic and equilibrium conditions of ibuprofen (IBU) and amoxicillin (AMX), two widely consumed pharmaceuticals, on nanoporous carbons of different characteristics. Batch adsorption experiments of pure components in water and their binary mixtures were carried out to measure both adsorption equilibrium and kinetics, and dynamic tests were performed to validate the simultaneous removal of the mixtures in breakthrough experiments. The equilibrium adsorption capacities evaluated from pure component solutions were higher than those measured in dynamic conditions, and were found to depend on the porous features of the adsorbent and the nature of the specific/dispersive interactions that are controlled by the solution pH, density of surface change on the carbon and ionization of the pollutant. A marked roll-up effect was observed for AMX retention on the hydrophobic carbons, not seen for the functionalized adsorbent likely due to the lower affinity of amoxicillin towards the carbon adsorbent. Dynamic adsorption of binary mixtures from wastewater of high salinity and alkalinity showed a slight increase in IBU uptake and a reduced adsorption of AMX, demonstrating the feasibility of the simultaneous removal of both compounds from complex water matrices. PMID- 25554086 TI - Aggregation of cationic p-phenylene ethynylenes on Laponite clay in aqueous dispersions and solid films. AB - Previous studies of cationic p-phenylene ethynylenes oligomers (OPEs) have revealed strong antimicrobial activity and strong photophysical changes upon their aggregation that can be utilized for sensing various chemicals and biomolecules. In this article, the adsorption of two types of OPEs with different placement of charged groups onto the synthetic clay Laponite is studied, and the changes to photophysical properties, photochemical degradation efficiency, and biocidal effectiveness are determined. In addition to solution-phase studies, the material and biocidal properties of solid films formed from the OPE-Laponite complex were assessed. The results of this study suggest that OPEs aggregate on Laponite and induce aggregation between Laponite discs, leading to drastic changes to their photophysical and material properties. Solid OPE-Laponite films were shown to have fair resistance to dissolution in aqueous solution compared with Laponite alone, and adhesion and minor killing of both Gram-negative and Gram-positive bacteria on the surface was observed. The results of this study give insight into controlling the colloidal phases of Laponite via molecular aggregation, may be useful for development of sensors and biocides involving Laponite as a scaffold, and lead to further control over slow-release and surface interactions of biocidal materials. PMID- 25554088 TI - Using a selective cadmium-binding peplipid to create responsive liquid crystalline nanomaterials. AB - A specific metal ion-responsive lipid liquid crystalline (LLC) dispersion system was fabricated, which can work in buffer solutions. The LLC matrix was prepared from phytantriol which spontaneously forms the reversed bicontinuous cubic phase in water, and a novel peptide-lipid conjugate (peplipid) consists of a myristate alkyl chain for anchoring into the phytantriol-based cubic bilayer and a peptide sequence for capturing a specific metal ion. The peplipid in its unbound state, when added into the phytantriol-based cubic system induces a positive effect on the bilayer curvature, resulting in the formation of the lamellar phase (vesicles) and the dispersion was transparent in appearance. Upon binding of the cadmium ion, the peplipid induces a negative effect on the lipid bilayer curvature and consequently leading to the formation of cubic phase and opaque appearance. In contrast, other metal ions, including buffering salts, could not sufficiently trigger the phase transition due to weak interaction with the peplipid. The high selectivity of metal ion interaction and triggered phase transition provide potential applications, such as in colloidal-mineral separation, triggered drug release and treatment of cadmium (II) pollution. PMID- 25554089 TI - Increased SSTR2A and SSTR3 expression in succinate dehydrogenase-deficient pheochromocytomas and paragangliomas. AB - Many neuroendocrine tumors, including pheochromocytomas (PCs) and paragangliomas (PGLs), express one or more somatostatin receptors (SSTR1-5). A number of studies have reported SSTR expression in PCs and PGLs. However, receptor expression patterns have been conflicting, and until recently, specific monoclonal antibodies were not available against SSTR1-5. The aim of this study was to compare SSTR1-5 expression in succinate dehydrogenase (SDH)-deficient PCs and PGLs (defined as having absent SDHB immunostaining) to those tumors with normal SDHB staining. Immunohistochemistry for SDHB and SSTR1-5 was performed using specific monoclonal antibodies on archived formalin-fixed, paraffin-embedded tissue from patients who had undergone surgery for PC or PGLs. A total of 182 PC/PGLs were included (129 adrenal, 44 extra-adrenal, 9 metastases); 32 tumors were SDH deficient, whereas 150 tumors had positive SDHB staining. SDH-deficient tumors were more likely to demonstrate moderate or strong staining for SSTR2A and SSTR3 when compared with SDH-sufficient tumors (91% versus 49% [P < .0001] and 50% versus 21% [P = .0008], respectively). Immunostaining for the other SSTRs was not different between SDH-deficient and tumors with preserved SDHB staining. SSTR2A and SSTR3 are more likely to be expressed in SDH-deficient PC/PGLs as compared with tumors demonstrating normal SDHB staining pattern. These findings suggest that the role of somatostatin analogue therapy (unlabeled or radiolabeled) should be reexamined in the context of the underlying SDHB immunohistochemistry pattern. PMID- 25554090 TI - Extranodal natural killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher frequency of T-cell lineage and poor survival for extranasal tumors. AB - Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a predominantly extranodal lymphoma associated with Epstein-Barr virus occurring most frequently in the upper aerodigestive tract. There are limited reports on cellular origin and prognostic factors. We retrospectively investigated 73 cases with a median age of 54 years and a male-female ratio of 2.0:1. The upper aerodigestive tract (nasal group) was the most common site of involvement (51 cases; 70%). The other organs (n = 22; extranasal group) included the skin (12 cases; 16%) and gastrointestinal tract (5; 7%). Of the 70 cases with complete staging, 71% had stage I/II disease. All cases were positive for Epstein-Barr virus by in situ hybridization. Using immunohistochemistry and clonality assay for T-cell receptor gene rearrangement, these tumors were classified into NK (n = 39; 53%), T (n = 13; 18%), and indeterminate lineage (n = 21; 29%). The only clinicopathological difference among these 3 groups was rare CD5 expression in the NK-cell group. Nasal tumors were more frequently of NK-cell origin, and extranasal tumors were equally of either T- or NK-cell origin. The 5-year overall survival rate was 35.6%. The overall survival time was shorter in the extranasal group, although there was no statistical difference in age, sex, and histologic or immunophenotypic features between the 2 groups. Excluding the cases with indeterminate lineage, 75% of cases were of NK lineage; and 25%, T lineage. Extranasal tumors were more aggressive than their nasal counterparts. A prospective national study is warranted for a better understanding of the clinicopathological and genetic features of this uncommon tumor and the prognostic factors. PMID- 25554091 TI - Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy. AB - PURPOSE: The cytochrome P450 (CYP) genes are oxygenases involved in estrogen biosynthesis and metabolism, generation of DNA damaging procarcinogens, and response to anti-estrogen therapies. Since lifetime estrogen exposure is an established risk factor for breast cancer, determining the role of CYP genes in breast cancer etiology may provide critical information for understanding tumorigenesis and response to treatment. METHODS: This review summarizes literature available in PubMed published between 1993 and 2013 that focuses on studies evaluating the effects of DNA variants in CYP genes on estrogen synthesis, metabolism, and generation of procarcinogens in addition to response to anti-estrogen therapies. RESULTS: Evaluation of DNA variants in estrogen metabolism genes was largely inconclusive. Meta-analyses of data from CYP19A1 support an association between the number of (TTTA) n repeats in intron 4 and breast cancer risk, but the biological mechanism for this relationship is unknown. Associations between single nucleotide polymorphism in CYP1B1 and DNA damage caused by procarcinogenic estrogen metabolites were ambiguous. Variants in CYP2D6 are associated with altered metabolism tamoxifen; however, current data do not support widespread clinical testing. The effect of variants in CYP19A1 in response to aromatase inhibitors is also questionable. CONCLUSION: Evaluation of DNA variants in CYP genes involved with estrogen metabolism or treatment response has been inconclusive, reflecting small samples sizes, tumor heterogeneity, and differences between populations. Better-powered studies that account for genetic backgrounds and tumor phenotypes are thus necessary. PMID- 25554092 TI - Thirty years brings major change. PMID- 25554096 TI - Regarding "Global discrepancies in the diagnosis, surgical management, and investigation of femoroacetabular impingement". PMID- 25554097 TI - Author's Reply. PMID- 25554098 TI - Regarding "Anterior hip dislocation 5 months after hip arthroscopy". PMID- 25554099 TI - Platelet-rich plasma in arthroscopic rotator cuff repair. PMID- 25554100 TI - Authors' reply. PMID- 25554101 TI - Two new beta-carboline alkaloids from the roots of Gypsophila oldhamiana. AB - Phytochemical investigation of the roots of Gypsophila oldhamiana afforded two new beta-carboline alkaloids, oldhamiaines A and B (1 and 2), along with a known analogue (3). Their structures were elucidated by using spectroscopic and chemical methods. This is the first report of beta-carboline alkaloids in the genus Gypsophila. PMID- 25554102 TI - Drug-induced lupus. AB - INTRODUCTION: Drug-induced lupus (DIL) refers to an idiosyncratic side effect of numerous, apparently unrelated, medications, in which symptoms overlap with those of systemic lupus erythematosus. DIL is reversible by discontinuation of the medication. The etiological mechanism underlying DIL is linked to the inherent susceptibility of the adaptive immune system to lapse into auto-reactivity. AREAS COVERED: Clinical and laboratory features of DIL will be compared with those of idiopathic systemic lupus and with other types of drug reactions with overlapping features. Formerly commonly-used drugs conferred very high risk of developing DIL, although the probability of developing DIL has not been established with most lupus-inducing drugs. Pharmacological or physiochemical properties of the parent compounds are uninformative, but the importance of reactive drug metabolites in initiating autoimmunity will be discussed. As with most systemic autoimmune diseases, the pathogenesis of DIL is complex and obscure. The role of complement and human leukocyte allotypes as well as drug acetylator phenotype inform the underlying mechanism, and several of these non-mutually exclusive concepts will be described. EXPERT OPINION: The pros and cons of proposed mechanisms for DIL will be discussed in the context of current understanding of autoimmunity and immune tolerance to self. PMID- 25554103 TI - The reduction of gene expression variability from single cells to populations follows simple statistical laws. AB - Recent studies on single cells and population transcriptomics have revealed striking differences in global gene expression distributions. Single cells display highly variable expressions between cells, while cell populations present deterministic global patterns. The mechanisms governing the reduction of transcriptome-wide variability over cell ensemble size, however, remain largely unknown. To investigate transcriptome-wide variability of single cells to different sizes of cell populations, we examined RNA-Seq datasets of 6 mammalian cell types. Our statistical analyses show, for each cell type, increasing cell ensemble size reduces scatter in transcriptome-wide expressions and noise (variance over square mean) values, with corresponding increases in Pearson and Spearman correlations. Next, accounting for technical variability by the removal of lowly expressed transcripts, we demonstrate that transcriptome-wide variability reduces, approximating the law of large numbers. Subsequent analyses reveal that the entire gene expressions of cell populations and only the highly expressed portion of single cells are Gaussian distributed, following the central limit theorem. PMID- 25554104 TI - Kinetic Interactions between Cyclolinopeptides and Immobilized Human Serum Albumin by Surface Plasmon Resonance. AB - Cyclolinopeptides (CLs) are octa-, nona-, and decapeptides present in flaxseed (Linum usitatissimum L.) that may have immunosuppressive and antitumor activities, but little is known of their pharmacokinetics. Human serum albumin (HSA), the most abundant blood protein, is an important mediator of organic solute flux, and hence when compounds bind this protein, it potentially affects both their availability and efficacy. Quantitative thermodynamic analysis of the interaction of compounds with HSA is important in the development of biomedical applications. A surface plasmon resonance (SPR) biosensor was utilized to reliably determine binding constants for several CLs with HSA. The maximum binding response of [1-9-NalphaC]-CLA/HSA was almost 20-fold higher than that of [1-8-NalphaC],[1-MetO]-CLE/HSA. Through analysis of an array of peptides, it was possible to correlate the impact of structural changes on CL binding. The oxidation of sulfur in methionine (Met) residues formed methionine S-oxide (MetO) and reduced binding significantly. Most strikingly, the further oxidation of MetO to S,S-dioxide (MetO2) produced CLs with stronger binding. The large impact on binding by relatively small modifications of methionine containing CLs suggested that small changes in methionine oxidation can disrupt hydrophobic interaction, the predominant intermolecular force stabilizing the complex between CLs and HSA. SPR binding studies may aid in understanding the fate of CLs after consumption of flaxseed or flaxseed products or the development of CLs as drugs or drug carriers. PMID- 25554106 TI - Acute poststreptococcal glomerulonephritis: the most common acute glomerulonephritis. AB - On the basis of strong research evidence, the prevalence of poststreptococcal glomerulonephritis (PSGN) is decreasing worldwide, although it still remains the leading cause of glomerulonephritis in children. The overall decrease in prevalence of PSGN has been mainly driven by a significant decrease in pyoderma seen in the last half-century, such that postpharyngitic PSGN is most commonly seen in developed nations. On the basis of primarily consensus because of a lack of relevant clinical studies, the latency period between streptococcal infection and the development of nephritis is a hallmark of PSGN, with this period lasting 1 to 2 weeks with pharyngeal infections or 2 to 6 weeks with skin infections. Concurrent infectious and nephritis symptoms should elicit further suspicion of other causes of glomerulonephritis. On the basis of expert opinion, PSGN is one of a handful of nephritic disorders with hypocomplementemia (low C3 level). The decrease in C3 is found in more than 90% of PSGN cases and is typically seen earlier than an increase in antistreptolysin O titers. Measuring C3 and C4 may also be helpful in the evaluation of other causes of acute nephritis. On the basis of primarily consensus because of a lack of relevantclinical studies, the main sequelae of PSGN (hypertension, edema,gross hematuria, and impaired renal function) are greatest in thefirst 7 to 10 days of disease. Therefore, this period requires themost vigilance for adverse effects. On the basis of some research evidence and consensus, the most effective treatment of hypertension and edema in PSGN is loop or thiazide diuretics, which may also address hyperkalemia. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be effective in hypertension control but carry the risk of hyperkalemia and temporarily impairing recovery of renal function. On the basis of some research evidence and consensus, the prognosis for PSGN, even long term, is good. Despite being the most prevalent of the childhood glomerulonephritides, it often does not cause chronic kidney disease, but persistent microscopic hematuria and proteinuria may be seen in less than 10% of patients. PMID- 25554107 TI - Epigenetics in pediatrics. AB - Epigenetic mechanisms are external modifications of DNA that cause changes in gene function and are involved in many diseases. Specific examples of pediatric diseases with a known or suspected epigenetic component include Beckwith Wiedemann syndrome, childhood leukemia, allergies, asthma, fetal alcohol spectrum disorders, childhood obesity, and type 2 diabetes mellitus. Currently, epigenetically active treatments are being used to treat childhood leukemia. Potential epigenetically active treatments and preventive regimens are under study for other diseases. Pediatricians need to be aware of the epigenetic basis of disease to help inform clinical decision making in the future. PMID- 25554108 TI - The patient-parent-pediatrician relationship: everyday ethics in the office. AB - Pediatricians and parents generally try to do what is best for children, but they do not always agree about what that is. Mothers and fathers may disagree with each other. Parents may disagree with pediatricians. Disagreements can arise about the goals, nature, and value of communication with children about health information. Disagreements can arise over the value of particular medical interventions. Some disagreements are grounded in different religious beliefs. Some are about moral values. Some are disagreements about ends, others about the best means to an agreed on end. If there is an intractable disagreement and discussion has failed to resolve that disagreement, pediatricians must decide whether to compromise their own values to preserve a therapeutic relationship, sever that relationship, or try to override a parental choice by referring a case to child protection authorities. Most cases can be resolved and a consensus found. This article discusses some common scenarios in which disagreements arise, including home birth, refusal of vitamin K, vaccine hesitancy, birth control for teens, corporal punishment, and surreptitious drug testing. PMID- 25554109 TI - Case 1: Rash, recalcitrant tachycardia, and hypertension in a 16-year-old girl. PMID- 25554110 TI - Case 2: Acute-onset tachypnea, tachycardia, and reduced activity in a 16-month old girl. PMID- 25554111 TI - Case 3: Bilateral heel pain in a 6-year-old boy. PMID- 25554112 TI - Antimicrobial stewardship: a national priority. PMID- 25554114 TI - Notice of retraction. Thrombocytopenia in infants and children. PMID- 25554113 TI - Parent-infant attachment. PMID- 25554115 TI - Visual diagnosis: 11-year-old boy with leukemia, fever, elbow, and leg pain. AB - The diagnosis of pyomyositis requires a high index of suspicion in patients with hematologic malignant neoplasms. Correct diagnosis might be delayed initially because of vague clinical presentation, overlapping symptoms, and nonspecific clinical signs. Pyomyositis should be included in the differential diagnosis when a patient develops swollen or tender muscles after chemotherapy with or without bacteremia. Prompt treatment with broad-spectrum antibiotics that cover S aureus and resistant emerging gram-negative organisms, specifically E coli, should be initiated immediately in patients with hematologic illnesses along with close monitoring and follow-up. PMID- 25554116 TI - A supramolecular topical gel derived from a non-steroidal anti-inflammatory drug, fenoprofen, is capable of treating skin inflammation in mice. AB - A new series of bioconjugates derived from a non-steroidal anti-inflammatory drug (NSAID), namely fenoprofen, has been synthesised by amidation with various biogenic molecules such as beta-alanine, aminocaproic acid and tyramine with the aim of converting the NSAID into a supramolecular gelator for plausible biomedical applications. One such bioconjugate (2) showed gelation ability with methylsalicylate (MS) and 1% menthol in methyl salicylate (MMS) solvents. These gels were characterized by table top rheology, high resolution-transmission electron microscopy (HR-TEM) and dynamic rheology. Gelator 2 was found to be biostable both in proteolytic enzymes and in blood serum of BALB/c mouse under physiological conditions. It was also found to be biocompatible, as revealed by the methyl thiazolyldiphenyl tetrazolium bromide (MTT) assay in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cells. The anti-inflammatory response (prostaglandin E2 assay, denoted PGE2 assay) of 2 was comparable to that of the parent drug fenoprofen calcium salt. Finally, a topical gel formulation of 2 displayed in vivo self-delivery application in treating imiquimod (IMQ) induced skin inflammation in BALB/c mice. PMID- 25554117 TI - [Splenic laceration: a rare complication of optical colonoscopy]. PMID- 25554118 TI - Bile duct tumors. AB - Bile duct tumors are benign or malignant lesions which may be associated to risk factors or potentially malignant lesions. They constitute an heterogenous entities group with a different biological behavior and prognosis according to location and growth pattern. We revise the role of the radiologist in order to detect, characterize and stage these tumors, specially the importance of their classification when deciding an appropriate management and treatment. PMID- 25554119 TI - Diagnostic management of renal colic. AB - Renal colic is a common reason for presentation to emergency departments, and imaging has become fundamental for the diagnosis and clinical management of this condition. Ultrasonography and particularly noncontrast computed tomography have good diagnostic performance in diagnosing renal colic. Radiologic management will depend on the tools available at the center and on the characteristics of the patient. It is essential to use computed tomography techniques that minimize radiation and to use alternatives like ultrasonography in pregnant patients and children. In this article, we review the epidemiology, clinical and radiologic presentations, and clinical management of ureteral lithiasis. PMID- 25554120 TI - Controlled synthesis of high molecular weight poly(3-hexylthiophene)s via Kumada catalyst transfer polycondensation with Ni(IPr)(acac)2 as the catalyst. AB - The controlled synthesis of poly(3-hexylthiophene)s (P3HTs) with number-average molecular weights (Mns) up to 350 kg mol(-1) has been realized with Ni(IPr)(acac)2 as the catalyst. PMID- 25554121 TI - cis-{MoO2}(2+) assisted Mannich-type addition of acetylacetonate methine to the azomethine of tridentate Schiff bases: racemic complexes with chiral transformed ligands. AB - Reactions of [MoO2(acac)2] (acac(-) = acetylacetonate) with the potential N2O donor 5,5-membered fused chelate rings forming Schiff bases 2-(2 pyridylaldimine)ethanol (HL(1)) and 4/5-R-2-(2-pyridylaldimine)phenols (HL(n); n = 2-5 for R = H, 4-Cl, 4-Me and 5-Me, respectively) lead to the facile formation of racemic complexes of the general formula cis-[MoO2(acacL(1-5))] () in 80-85% yield. Here, (acacL(n))(2-) represents a chiral N2O2-donor ligand system formed by a novel Mannich-type reaction that involves acetylacetonate and the azomethine fragment of HL(n) both coordinated to the cis-{MoO2}(2+) unit. The characterization of has been performed with the help of microanalytical (CHN), spectroscopic (ESI-MS, IR, UV-Vis and (1)H- and (13)C-NMR) and electrochemical measurements. The molecular structures of all the complexes except for are authenticated by single crystal X-ray crystallography. The Mo(vi) center in each of these analogous complexes is in a distorted octahedral N2O4 coordination sphere assembled by the chiral N2O2-donor transformed ligand (acacL(n))(2-) and the two mutually cis-oriented oxo ligands. In the crystal lattice, each of exists as a centrosymmetric discrete dimer via a pair of reciprocal N-HO hydrogen bonds between its enantiomeric pairs. PMID- 25554122 TI - Communication: Photoactivation of nucleobase bound platinum(II) metal complexes: probing the influence of the nucleobase. AB - We present UV laser action spectra (220-300 nm) of isolated nucleobase-bound Pt(II)(CN)4(2-) complexes, i.e., Pt(CN)4(2-)?M, where M = uracil, thymine, cytosine, and adenine. These metal complex-nucleobase clusters represent model systems for identifying the fundamental photophysical and photochemical processes occurring in photodynamic platinum (II) drug therapies that target DNA. This is the first study to explore the specific role of the nucleobase in the photophysics of the aggregate complex. Each of the complexes studied displays a broadly similar absorption spectra, with a strong lambdamax ~ 4.7 eV absorption band (nucleobase localized chromophore) and a subsequent increase in the absorption intensity towards higher spectral-energy (Pt(CN)4(2-) localized chromophore). However, strikingly different band widths are observed across the series of complexes, decreasing in the order Pt(CN)4(2-)?Thymine > Pt(CN)4(2 )?Uracil > Pt(CN)4(2-)?Adenine > Pt(CN)4(2-)?Cytosine. Changes in the bandwidth of the ~4.7 eV band are accompanied by distinctive changes in the photofragment product ions observed following photoexcitation, with the narrower-bandwidth complexes showing a greater propensity to decay via electron detachment decay. We discuss these observations in the context of the distinctive nucleobase-dependent excited state lifetimes. PMID- 25554123 TI - Communication: Microsecond peptide dynamics from nanosecond trajectories: a Langevin approach. AB - Based on a given time series, the data-driven Langevin equation (dLE) estimates the drift and the diffusion field of the dynamics, which are then employed to reproduce the essential statistical and dynamical features of the original time series. Because the propagation of the dLE requires only local information, the input data are neither required to be Boltzmann weighted nor to be a continuous trajectory. Similar to a Markov state model, the dLE approach therefore holds the promise of predicting the long-time dynamics of a biomolecular system from relatively short trajectories which can be run in parallel. The practical applicability of the approach is shown to be mainly limited by the initial sampling of the system's conformational space obtained from the short trajectories. Adopting extensive molecular dynamics simulations of the unfolding and refolding of a short peptide helix, it is shown that the dLE approach is able to describe microsecond conformational dynamics from a few hundred nanosecond trajectories. In particular, the dLE quantitatively reproduces the free energy landscape and the associated conformational dynamics along the chosen five dimensional reaction coordinate. PMID- 25554124 TI - Communication: Does force spectroscopy of biomolecules probe their intrinsic dynamic properties? AB - In single-molecule pulling experiments, the molecule of interest is attached to a much larger object such as an atomic force microscope tip or a micrometer sized bead. The measured dynamics of molecular transitions is therefore affected by the hydrodynamic drag on the pulling instrument itself. By considering the transitions within the combined system (the molecule and the instrument), it is shown here that two distinct physical regimes exist: when the intrinsic stiffness of the molecule is greater than that of the linker connecting the molecule to the pulling setup then the pulling experiment probes the intrinsic dynamics of the molecule with only relatively small (and quantifiable) corrections resulting from the pulling setup. In contrast, when the stiffness of the linker exceeds that of the molecule, the molecular transition in question involves concerted motion of the molecule and the pulling setup and the hydrodynamic drag on the pulling instrument becomes the dominant source of friction along the molecular reaction coordinate. An analytical formula interpolating between these two cases is further derived. These results explain recent conflicting observations where some single-molecule pulling measurements report anomalously low diffusion coefficients along molecular reaction coordinates while others do not. PMID- 25554125 TI - Communication: Visible line intensities of the triatomic hydrogen ion from experiment and theory. AB - The visible spectrum of H3(+) is studied using high-sensitivity action spectroscopy in a cryogenic radiofrequency multipole trap. Advances are made to measure the weak ro-vibrational transitions from the lowest rotational states of H3(+) up to high excitation energies providing visible line intensities and, after normalisation to an infrared calibration line, the corresponding Einstein B coefficients. Ab initio predictions for the Einstein B coefficients are obtained from a highly precise dipole moment surface of H3(+) and found to be in excellent agreement, even in the region where states have been classified as chaotic. PMID- 25554126 TI - Communication: Testing and using the Lewin-Lieb bounds in density functional theory. AB - Lewin and Lieb have recently proven several new bounds on the exchange correlation energy that complement the Lieb-Oxford bound. We test these bounds for atoms, for slowly-varying gases, and for Hooke's atom, finding them usually less strict than the Lieb-Oxford bound. However, we also show that, if a generalized gradient approximation is to guarantee satisfaction of the new bounds for all densities, new restrictions on the exchange-correlation enhancement factor are implied. PMID- 25554127 TI - Speeding up local correlation methods. AB - We present two techniques that can substantially speed up the local correlation methods. The first one allows one to avoid the expensive transformation of the electron-repulsion integrals from atomic orbitals to virtual space. The second one introduces an algorithm for the residual equations in the local perturbative treatment that, in contrast to the standard scheme, does not require holding the amplitudes or residuals in memory. It is shown that even an interpreter-based implementation of the proposed algorithm in the context of local MP2 method is faster and requires less memory than the highly optimized variants of conventional algorithms. PMID- 25554128 TI - Basis functions for electronic structure calculations on spheres. AB - We introduce a new basis function (the spherical Gaussian) for electronic structure calculations on spheres of any dimension D. We find general expressions for the one- and two-electron integrals and propose an efficient computational algorithm incorporating the Cauchy-Schwarz bound. Using numerical calculations for the D = 2 case, we show that spherical Gaussians are more efficient than spherical harmonics when the electrons are strongly localized. PMID- 25554129 TI - Ring-polymer molecular dynamics: rate coefficient calculations for energetically symmetric (near thermoneutral) insertion reactions (X + H2) -> HX + H(X = C(1D), S(1D)). AB - Following our previous study of prototypical insertion reactions of energetically asymmetric type with the RPMD (Ring-Polymer Molecular Dynamics) method [Y. Li, Y. Suleimanov, and H. Guo, J. Phys. Chem. Lett. 5, 700 (2014)], we extend it to two other prototypical insertion reactions with much less exothermicity (near thermoneutral), namely, X + H2 -> HX + H where X = C((1)D), S((1)D), in order to assess the accuracy of this method for calculating thermal rate coefficients for this class of reactions. For both chemical reactions, RPMD displays remarkable accuracy and agreement with the previous quantum dynamic results that make it encouraging for the future application of the RPMD to other barrier-less, complex forming reactions involving polyatomic reactants with any exothermicity. PMID- 25554130 TI - Seniority-based coupled cluster theory. AB - Doubly occupied configuration interaction (DOCI) with optimized orbitals often accurately describes strong correlations while working in a Hilbert space much smaller than that needed for full configuration interaction. However, the scaling of such calculations remains combinatorial with system size. Pair coupled cluster doubles (pCCD) is very successful in reproducing DOCI energetically, but can do so with low polynomial scaling (N(3), disregarding the two-electron integral transformation from atomic to molecular orbitals). We show here several examples illustrating the success of pCCD in reproducing both the DOCI energy and wave function and show how this success frequently comes about. What DOCI and pCCD lack are an effective treatment of dynamic correlations, which we here add by including higher-seniority cluster amplitudes which are excluded from pCCD. This frozen pair coupled cluster approach is comparable in cost to traditional closed shell coupled cluster methods with results that are competitive for weakly correlated systems and often superior for the description of strongly correlated systems. PMID- 25554131 TI - First order nonadiabatic coupling matrix elements between excited states: implementation and application at the TD-DFT and pp-TDA levels. AB - The recently proposed rigorous yet abstract theory of first order nonadiabatic coupling matrix elements (fo-NACME) between electronically excited states [Z. Li and W. Liu, J. Chem. Phys. 141, 014110 (2014)] is specified in detail for two widely used models: The time-dependent density functional theory and the particle particle Tamm-Dancoff approximation. The actual implementation employs a Lagrangian formalism with atomic-orbital based direct algorithms, which makes the computation of fo-NACME very similar to that of excited-state gradients. Although the methods have great potential in investigating internal conversions and nonadiabatic dynamics between excited states of large molecules, only prototypical systems as a first pilot application are considered here to illustrate some conceptual aspects. PMID- 25554132 TI - An efficient localization procedure for large systems using a sequential transformation strategy. AB - A fast and efficient fragment-based top-down localization scheme is developed to obtain occupied and virtual regionally localized molecular orbitals (RLMOs) for large systems. In the scheme, RLMOs in many fragments of the target system are constructed using a fragment-based sequential transformation strategy based on a series of singular value decomposition operations. The present localization scheme is a non-iterative procedure, which computationally scales cubically with the system size. The locality of RLMOs is quite close to that of localized molecular orbitals obtained with conventional localization schemes. For several large systems, we demonstrate that this approach is efficient for computing both occupied and virtual RLMOs. PMID- 25554133 TI - Lanczos-driven coupled-cluster damped linear response theory for molecules in polarizable environments. AB - We present an extension of a previously reported implementation of a Lanczos driven coupled-cluster (CC) damped linear response approach to molecules in condensed phases, where the effects of a surrounding environment are incorporated by means of the polarizable embedding formalism. We are specifically motivated by a twofold aim: (i) computation of core excitations in realistic surroundings and (ii) examination of the effect of the differential response of the environment upon excitation solely related to the CC multipliers (herein denoted the J matrix) in computations of excitation energies and transition moments of polarizable-embedded molecules. Numerical calculations demonstrate that the differential polarization of the environment due to the first-order CC multipliers provides only minor contributions to the solvatochromic shift for all transitions considered. We thus complement previous works by confirming numerically the validity of the routinely invoked neglect of the J matrix contribution as well as motivating future use of the approximation that offers a reduction of the dimensionality of the eigenvalue problem. Preliminary applications to K-edge absorption of liquid water and aqueous acrolein are presented and highlight the importance of the environment that gives rise to transition-specific shifts. PMID- 25554134 TI - Momentum conserving Brownian dynamics propagator for complex soft matter fluids. AB - We present a Galilean invariant, momentum conserving first order Brownian dynamics scheme for coarse-grained simulations of highly frictional soft matter systems. Friction forces are taken to be with respect to moving background material. The motion of the background material is described by locally averaged velocities in the neighborhood of the dissolved coarse coordinates. The velocity variables are updated by a momentum conserving scheme. The properties of the stochastic updates are derived through the Chapman-Kolmogorov and Fokker-Planck equations for the evolution of the probability distribution of coarse-grained position and velocity variables, by requiring the equilibrium distribution to be a stationary solution. We test our new scheme on concentrated star polymer solutions and find that the transverse current and velocity time auto-correlation functions behave as expected from hydrodynamics. In particular, the velocity auto correlation functions display a long time tail in complete agreement with hydrodynamics. PMID- 25554135 TI - Practical witness for electronic coherences. AB - The origin of the coherences in two-dimensional spectroscopy of photosynthetic complexes remains disputed. Recently, it has been shown that in the ultrashort pulse limit, oscillations in a frequency-integrated pump-probe signal correspond exclusively to electronic coherences, and thus such experiments can be used to form a test for electronic vs. vibrational oscillations in such systems. Here, we demonstrate a method for practically implementing such a test, whereby pump-probe signals are taken at several different pulse durations and used to extrapolate to the ultrashort-pulse limit. We present analytic and numerical results determining requirements for pulse durations and the optimal choice of pulse central frequency, which can be determined from an absorption spectrum. Our results suggest that for numerous systems, the required experiment could be implemented by many ultrafast spectroscopy laboratories using pulses of tens of femtoseconds in duration. Such experiments could resolve the standing debate over the nature of coherences in photosynthetic complexes. PMID- 25554136 TI - Accurate nonrelativistic ground-state energies of 3d transition metal atoms. AB - We present accurate nonrelativistic ground-state energies of the transition metal atoms of the 3d series calculated with Fixed-Node Diffusion Monte Carlo (FN-DMC). Selected multi-determinantal expansions obtained with the CIPSI (Configuration Interaction using a Perturbative Selection made Iteratively) method and including the most prominent determinants of the full configuration interaction expansion are used as trial wavefunctions. Using a maximum of a few tens of thousands determinants, fixed-node errors on total DMC energies are found to be greatly reduced for some atoms with respect to those obtained with Hartree-Fock nodes. To the best of our knowledge, the FN-DMC/(CIPSI nodes) ground-state energies presented here are the lowest variational total energies reported so far. They differ from the recently recommended non-variational values of McCarthy and Thakkar [J. Chem. Phys. 136, 054107 (2012)] only by a few percents of the correlation energy. Thanks to the variational property of FN-DMC total energies, our results provide exact lower bounds for the absolute value of all-electron correlation energies, |Ec|. PMID- 25554137 TI - Stochastic algorithm for size-extensive vibrational self-consistent field methods on fully anharmonic potential energy surfaces. AB - A stochastic algorithm based on Metropolis Monte Carlo (MC) is presented for the size-extensive vibrational self-consistent field methods (XVSCF(n) and XVSCF[n]) for anharmonic molecular vibrations. The new MC-XVSCF methods substitute stochastic evaluations of a small number of high-dimensional integrals of functions of the potential energy surface (PES), which is sampled on demand, for diagrammatic equations involving high-order anharmonic force constants. This algorithm obviates the need to evaluate and store any high-dimensional partial derivatives of the potential and can be applied to the fully anharmonic PES without any Taylor-series approximation in an intrinsically parallelizable algorithm. The MC-XVSCF methods reproduce deterministic XVSCF calculations on the same Taylor-series PES in all energies, frequencies, and geometries. Calculations using the fully anharmonic PES evaluated on the fly with electronic structure methods report anharmonic effects on frequencies and geometries of much greater magnitude than deterministic XVSCF calculations, reflecting an underestimation of anharmonic effects in a Taylor-series approximation to the PES. PMID- 25554138 TI - Direct path integral estimators for isotope fractionation ratios. AB - Fractionation of isotopes among distinct molecules or phases is a quantum effect which is often exploited to obtain insights on reaction mechanisms, biochemical, geochemical, and atmospheric phenomena. Accurate evaluation of isotope ratios in atomistic simulations is challenging, because one needs to perform a thermodynamic integration with respect to the isotope mass, along with time consuming path integral calculations. By re-formulating the problem as a particle exchange in the ring polymer partition function, we derive new estimators giving direct access to the differential partitioning of isotopes, which can simplify the calculations by avoiding thermodynamic integration. We demonstrate the efficiency of these estimators by applying them to investigate the isotope fractionation ratios in the gas-phase Zundel cation, and in a few simple hydrocarbons. PMID- 25554139 TI - A systematic way for the cost reduction of density fitting methods. AB - We present a simple approach for the reduction of the size of auxiliary basis sets used in methods exploiting the density fitting (resolution of identity) approximation for electron repulsion integrals. Starting out of the singular value decomposition of three-center two-electron integrals, new auxiliary functions are constructed as linear combinations of the original fitting functions. The new functions, which we term natural auxiliary functions (NAFs), are analogous to the natural orbitals widely used for the cost reduction of correlation methods. The use of the NAF basis enables the systematic truncation of the fitting basis, and thereby potentially the reduction of the computational expenses of the methods, though the scaling with the system size is not altered. The performance of the new approach has been tested for several quantum chemical methods. It is demonstrated that the most pronounced gain in computational efficiency can be expected for iterative models which scale quadratically with the size of the fitting basis set, such as the direct random phase approximation. The approach also has the promise of accelerating local correlation methods, for which the processing of three-center Coulomb integrals is a bottleneck. PMID- 25554140 TI - A complex guided spectral transform Lanczos method for studying quantum resonance states. AB - A complex guided spectral transform Lanczos (cGSTL) algorithm is proposed to compute both bound and resonance states including energies, widths, and wavefunctions. The algorithm comprises of two layers of complex-symmetric Lanczos iterations. A short inner layer iteration produces a set of complex formally orthogonal Lanczos polynomials. They are used to span the guided spectral transform function determined by a retarded Green operator. An outer layer iteration is then carried out with the transform function to compute the eigen pairs of the system. The guided spectral transform function is designed to have the same wavefunctions as the eigenstates of the original Hamiltonian in the spectral range of interest. Therefore, the energies and/or widths of bound or resonance states can be easily computed with their wavefunctions or by using a root-searching method from the guided spectral transform surface. The new cGSTL algorithm is applied to bound and resonance states of HO2, and compared to previous calculations. PMID- 25554141 TI - The time-resolved photoelectron spectrum of toluene using a perturbation theory approach. AB - A theoretical study of the intra-molecular vibrational-energy redistribution of toluene using time-resolved photo-electron spectra calculated using nuclear quantum dynamics and a simple, two-mode model is presented. Calculations have been carried out using the multi-configuration time-dependent Hartree method, using three levels of approximation for the calculation of the spectra. The first is a full quantum dynamics simulation with a discretisation of the continuum wavefunction of the ejected electron, whilst the second uses first-order perturbation theory to calculate the wavefunction of the ion. Both methods rely on the explicit inclusion of both the pump and probe laser pulses. The third method includes only the pump pulse and generates the photo-electron spectrum by projection of the pumped wavepacket onto the ion potential energy surface, followed by evaluation of the Fourier transform of the autocorrelation function of the subsequently propagated wavepacket. The calculations performed have been used to study the periodic population flow between the 6a and 10b16b modes in the S1 excited state, and compared to recent experimental data. We obtain results in excellent agreement with the experiment and note the efficiency of the perturbation method. PMID- 25554142 TI - Time-dependent quantum chemistry of laser driven many-electron molecules. AB - A Time-Dependent Configuration Interaction approach using multiple Feshbach partitionings, corresponding to multiple ionization stages of a laser-driven molecule, has recently been proposed [T.-T. Nguyen-Dang and J. Viau-Trudel, J. Chem. Phys. 139, 244102 (2013)]. To complete this development toward a fully ab initio method for the calculation of time-dependent electronic wavefunctions of an N-electron molecule, we describe how tools of multiconfiguration quantum chemistry such as the management of the configuration expansion space using Graphical Unitary Group Approach concepts can be profitably adapted to the new context, that of time-resolved electronic dynamics, as opposed to stationary electronic structure. The method is applied to calculate the detailed, sub-cycle electronic dynamics of BeH2, treated in a 3-21G bound-orbital basis augmented by a set of orthogonalized plane-waves representing continuum-type orbitals, including its ionization under an intense lambda = 800 nm or lambda = 80 nm continuous-wave laser field. The dynamics is strongly non-linear at the field intensity considered (I ? 10(15) W/cm(2)), featuring important ionization of an inner-shell electron and strong post-ionization bound-electron dynamics. PMID- 25554143 TI - Unbiased reduced density matrices and electronic properties from full configuration interaction quantum Monte Carlo. AB - Properties that are necessarily formulated within pure (symmetric) expectation values are difficult to calculate for projector quantum Monte Carlo approaches, but are critical in order to compute many of the important observable properties of electronic systems. Here, we investigate an approach for the sampling of unbiased reduced density matrices within the full configuration interaction quantum Monte Carlo dynamic, which requires only small computational overheads. This is achieved via an independent replica population of walkers in the dynamic, sampled alongside the original population. The resulting reduced density matrices are free from systematic error (beyond those present via constraints on the dynamic itself) and can be used to compute a variety of expectation values and properties, with rapid convergence to an exact limit. A quasi-variational energy estimate derived from these density matrices is proposed as an accurate alternative to the projected estimator for multiconfigurational wavefunctions, while its variational property could potentially lend itself to accurate extrapolation approaches in larger systems. PMID- 25554144 TI - A hybrid configuration interaction treatment based on seniority number and excitation schemes. AB - We present a configuration interaction method in which the Hamiltonian of an N electron system is projected on Slater determinants selected according to the seniority-number criterion along with the traditional excitation-based procedure. This proposed method is especially useful to describe systems which exhibit dynamic (weak) correlation at determined geometric arrangements (where the excitation-based procedure is more suitable) but show static (strong) correlation at other arrangements (where the seniority-number technique is preferred). The hybrid method amends the shortcomings of both individual determinant selection procedures, yielding correct shapes of potential energy curves with results closer to those provided by the full configuration interaction method. PMID- 25554145 TI - Collision induced ultraviolet structure in nitrogen radar REMPI spectra. AB - We present 2 + 2 radar REMPI measurements in molecular nitrogen under atmospheric conditions and observe a strong interference in the (1,0) vibrational band of the a(1)Pig <- X(1)Sigmag(+) electronic manifold. The interference is suppressed by using circularly polarized light, permitting rotational analysis of the 2 + 2 radar REMPI spectrum. It is observed in pure nitrogen, though the structure varies with gas composition. The structure also varies with temperature and pressure. These results indicate that it is collision induced. We hypothesize that the source of the interference is a 3 + 1 REMPI process through the a("1)Sigmag(+) electronic state. PMID- 25554146 TI - High resolution photoelectron imaging of UO(-) and UO2(-) and the low-lying electronic states and vibrational frequencies of UO and UO2. AB - We report a study of the electronic and vibrational structures of the gaseous uranium monoxide and dioxide molecules using high-resolution photoelectron imaging. Vibrationally resolved photoelectron spectra are obtained for both UO(-) and UO2(-). The spectra for UO2(-) are consistent with, but much better resolved than a recent study using a magnetic-bottle photoelectron analyzer [W. L. Li et al., J. Chem. Phys. 140, 094306 (2014)]. The electron affinity (EA) of UO is reported for the first time as 1.1407(7) eV, whereas a much more accurate EA is obtained for UO2 as 1.1688(6) eV. The symmetric stretching modes for the neutral and anionic ground states, and two neutral excited states for UO2 are observed, as well as the bending mode for the neutral ground state. These vibrational frequencies are consistent with previous experimental and theoretical results. The stretching vibrational modes for the ground state and one excited state are observed for UO. The current results for UO and UO2 are compared with previous theoretical calculations including relativistic effects and spin-orbit coupling. The accurate experimental data reported here provide more stringent tests for future theoretical methods for actinide-containing species. PMID- 25554147 TI - Polarization-dependent exciton dynamics in tetracene single crystals. AB - We conduct polarization-dependent ultrafast spectroscopy to study the dynamics of singlet fission (SF) in tetracene single crystals. The spectrotemporal species for singlet and triplet excitons in transient absorption spectra are found to be strongly dependent on probe polarization. By carefully analyzing the polarization dependence, the signals contributed by different transitions related to singlet excitons have been disentangled, which is further applied to construct the correlation between dynamics of singlet and triplet excitons. The anisotropy of exciton dynamics provides an alternative approach to tackle the long-standing challenge in understanding the mechanism of singlet fission in organic semiconductors. PMID- 25554148 TI - Monoxides of small terbium clusters: a density functional theory investigation. AB - To investigate the effect of oxygen atom on the geometrical structures, electronic, and magnetic properties of small terbium clusters, we carried out the first-principles calculations on TbnO (n = 1-14) clusters. The capping of an oxygen atom on one trigonal-facet of Tbn structures is always favored energetically, which can significantly improve the structural stability. The far infrared vibrational spectroscopies are found to be different from those of corresponding bare clusters, providing a distinct signal to detect the characteristic structures of TbnO clusters. The primary effect of oxygen atom on magnetic properties is to change the magnetic orderings among Tb atoms and to reduce small of local magnetic moments of the O-coordinated Tb atoms, both of which serve as the key reasons for the experimental magnetic evolution of an oscillating behavior. These calculations are consistent with, and help to account for, the experimentally observed magnetic properties of monoxide TbnO clusters [C. N. Van Dijk et al., J. Appl. Phys. 107, 09B526 (2010)]. PMID- 25554149 TI - Non-additivity between substitution and cooperative effects in enhancing hydrogen bonds. AB - Ternary systems XO2F:NCH:NCY and XO2F:CNH:CNY (X = P and As; Y = H and Li) as well as the corresponding binary ones were studied at the MP2/aug-cc-pVTZ level. Interestingly, the pi-hole pnicogen bond in the PO2F complex is stronger than that in the AsO2F counterpart. The substituent Li in the Lewis base strengthens the hydrogen bond and pnicogen bond, but the more prominent enhancing effect is found for the pnicogen bond. The substitution effect is governed mainly through electrostatic interaction for the hydrogen bond but a combination of electrostatic and polarization interactions for the pnicogen bond. In the ternary systems, the pi-hole pnicogen bond exhibits a positive cooperative effect with the hydrogen bond. Energy decomposition analysis indicates that the cooperativity is mainly attributed to the polarization energy. There is positive non-additivity between the substitution and cooperative effects, which is an effective measure for strengthening the hydrogen bond. The largest interaction energies occur in AsO2F:CNH:CNLi, amounting to -130.24 kJ/mol for the pnicogen bond and -119.90 kJ/mol for the hydrogen bond, and the former is a covalent interaction and the latter is an ion-pair hydrogen bond. PMID- 25554150 TI - The ground state and electronic structure of Gd@C82: a systematic theoretical investigation of first principle density functionals. AB - As a representative lanthanide endohedral metallofullerene, Gd@C82 has attracted a widespread attention among theorists and experimentalists ever since its first synthesis. Through comprehensive comparisons and discussions, as well as references to the latest high precision experiments, we evaluated the performance of different computational methods. Our results showed that the appropriate choice of the exchange-correlation functionals is the decisive factor to accurately predict both geometric and electronic structures for Gd@C82. The electronic structure of the ground state and energy gap between the septet ground state and the nonet low-lying state obtained from pure density functional methods, such as PBE and PW91, are in good agreement with current experiment. Unlike pure functionals, the popularly used hybrid functionals in previous studies, such as B3LYP, could infer the qualitative correct ground state only when small basis set for C atoms is employed. Furthermore, we also highlighted that other geometric structures of Gd@C82 with the Gd staying at different positions are either not stable or with higher energies. This work should provide some useful references for various theoretical methodologies in further density functional studies on Gd@C82 and its derivatives in the future. PMID- 25554151 TI - Collisions of low-energy electrons with cyclohexane. AB - We report calculated cross sections for elastic scattering of low-energy electrons by cyclohexane (c-C6H12). We employed the Schwinger multichannel method implemented with norm-conserving pseudopotentials in the static-exchange and static-exchange plus polarization approximations, for impact energies up to 30 eV. We compare our calculated integral cross section with experimental total cross sections available in the literature. We also compare our calculated differential cross sections (DCSs) with experimental results for benzene and experimental and theoretical results for 1,4-dioxane, in order to investigate the similarities between those molecules under electron collisions. Although benzene is a cyclic six-carbon molecule, as cyclohexane, we found that the differential cross sections of the latter are more similar to those of 1,4-dioxane than those of benzene. These similarities suggest that the geometry may play an important role in the behavior of the DCSs of these molecules. Our integral cross section displays a broad structure at around 8.5 eV, in agreement with the total cross section experimental data of 8 eV and vibrational excitation data of 7.5 eV. The present integral cross section also shows the presence of a Ramsauer-Townsend minimum at around 0.12 eV. In general, our integral cross section shows a qualitative agreement with the experimental total cross section. PMID- 25554152 TI - Composite thermochemistry of gas phase U(VI)-containing molecules. AB - Reaction energies have been calculated for a series of reactions involving UF6, UO3, UO2(OH)2, and UO2F2 using coupled cluster singles and doubles with perturbative triples, CCSD(T), with a series of correlation consistent basis sets, including newly developed pseudopotential (PP)- and all-electron (AE) Douglas-Kroll-Hess-based sets for the U atom. The energies were calculated using a Feller-Peterson-Dixon composite approach in which CCSD(T) complete basis set (CBS) limits were combined with a series of additive contributions for spin-orbit coupling, outer-core correlation, and quantum electrodynamics effects. The calculated reaction enthalpies (both PP and AE) were combined with the accurately known heat of formation of UF6 to determine the enthalpies of formation of UO3, UO2(OH)2, and UO2F2. The contribution to the reaction enthalpies due to correlation of the 5s5p5d electrons of U was observed to be very slowly convergent with basis set and at the CBS limit their impact on the final enthalpies was on the order of 1 kcal/mol or less. For these closed shell molecules, spin-orbit effects contributed about 1 kcal/mol to the final enthalpies. Interestingly, the PP and AE approaches yielded quite different spin orbit contributions (similar magnitude but opposite in sign), but the total scalar plus spin-orbit results from the two approaches agreed to within ~1 kcal/mol of each other. The final composite heat of formation for UO2F2 was in excellent agreement with experiment, while the two results obtained for UO3 were just outside the +/-2.4 kcal/mol error bars of the currently recommended experimental value. An improved enthalpy of formation (298 K) for UO2(OH)2 is predicted from this work to be -288.7 +/- 3 kcal/mol, compared to the currently accepted experimental value of -292.7 +/- 6 kcal/mol. PMID- 25554153 TI - In search of the X2BO and X2BS (X = H, F) free radicals: ab initio studies of their spectroscopic signatures. AB - The F2BO free radical is a known, although little studied, species but similar X2BY (X = H, D, F; Y = O, S) molecules are largely unknown. High level ab initio methods have been used to predict the molecular structures, vibrational frequencies (in cm(-1)), and relative energies of the ground and first two excited electronic states of these free radicals, as an aid to their eventual spectroscopic identification. The chosen theoretical methods and basis sets were tested on F2BO and found to give good agreement with the known experimental quantities. In particular, complete basis set extrapolations of coupled-cluster single and doubles with perturbative triple excitations/aug-cc-pVXZ (X = 3, 4, 5) energies gave excellent electronic term values, due to small changes in geometry between states and the lack of significant multireference character in the wavefunctions. The radicals are found to have planar C2v geometries in the X(2)B2 ground state, the low-lying A(2)B1 first excited state, and the higher B(2)A1 state. Some of these radicals have very small ground state dipole moments hindering microwave measurements. Infrared studies in matrices or in the gas phase may be possible although the fundamentals of H2BO and H2BS are quite weak. The most promising method of identifying these species in the gas phase appears to be absorption or laser-induced fluorescence spectroscopy through the allowed B X transitions which occur in the visible-near UV region of the electromagnetic spectrum. The ab initio results have been used to calculate the Franck-Condon profiles of the absorption and emission spectra, and the rotational structure of the B-X0(0)(0) bands has been simulated. The calculated single vibronic level emission spectra provide a unique, readily recognizable fingerprint of each particular radical, facilitating the experimental identification of new X2BY species in the gas phase. PMID- 25554154 TI - New observation and combined analysis of the Cs2 0g(-), 0u(+), and 1g states at the asymptotes 6S1/2 + 6P1/2 and 6S1/2 + 6P3/2. AB - We report on new observations of the photoassociation spectroscopy of ultracold cesium molecules using a highly sensitive detection technique and a combined analysis with all observed electronic states. The technique is achieved by directly modulating the frequency of the trapping lasers of a magneto-optical trap. New observations of the Cs2 0g(-), 0u(+), and 1g states at the asymptotes 6S1/2 + 6P1/2 and 6S1/2 + 6P3/2 are reported. The spectral range is extended to the red detuning of 112 cm(-1) below the 6S1/2 + 6P3/2 dissociation limit. Dozens of vibrational levels of the ultracold Cs2 0g(-), 0u(+), and 1g states are observed for the first time. The available experimental binding energies of these states are analyzed simultaneously in a framework of the generalized LeRoy Bernstein theory and the almost degenerate perturbation theory by Marinescu and Dalgarno [Phys. Rev. A: At., Mol., Opt. Phys. 52, 311 (1995)]. The unique atomic related parameter c3 governing the dispersion forces of all the molecular states is estimated as (10.29 +/- 0.05) a.u. PMID- 25554155 TI - Effects of reactant rotational excitations on H2 + NH2 -> H + NH3 reactivity. AB - Rotational mode specificity of the title reaction is examined using an initial state selected time-dependent wave packet method on an accurate ab initio based global potential energy surface. This penta-atomic reaction presents an ideal system to test several dynamical approximations, which might be useful for future quantum dynamics studies of polyatomic reactions, particularly with rotationally excited reactants. The first approximation involves a seven-dimensional (7D) model in which the two non-reactive N-H bonds are fixed at their equilibrium geometry. The second is the centrifugal sudden (CS) approximation within the 7D model. Finally, the J-shifting (JS) model is tested, again with the fixed N-H bonds. The spectator-bond approximation works very well in the energy range studied, while the centrifugal sudden and J-shifting integral cross sections (ICSs) agree satisfactorily with the coupled-channel counterparts in the low collision energy range, but deviate at the high energies. The calculated integral cross sections indicate that the rotational excitation of H2 somewhat inhibits the reaction while the rotational excitations of NH2 have little effect. These findings are compared with the predictions of the sudden vector projection model. Finally, a simple model is proposed to predict rotational mode specificity using K-averaged reaction probabilities. PMID- 25554156 TI - Toward spectroscopically accurate global ab initio potential energy surface for the acetylene-vinylidene isomerization. AB - A new full-dimensional global potential energy surface (PES) for the acetylene vinylidene isomerization on the ground (S0) electronic state has been constructed by fitting ~37,000 high-level ab initio points using the permutation invariant polynomial-neural network method with a root mean square error of 9.54 cm(-1). The geometries and harmonic vibrational frequencies of acetylene, vinylidene, and all other stationary points (two distinct transition states and one secondary minimum in between) have been determined on this PES. Furthermore, acetylene vibrational energy levels have been calculated using the Lanczos algorithm with an exact (J = 0) Hamiltonian. The vibrational energies up to 12,700 cm(-1) above the zero-point energy are in excellent agreement with the experimentally derived effective Hamiltonians, suggesting that the PES is approaching spectroscopic accuracy. In addition, analyses of the wavefunctions confirm the experimentally observed emergence of the local bending and counter-rotational modes in the highly excited bending vibrational states. The reproduction of the experimentally derived effective Hamiltonians for highly excited bending states signals the coming of age for the ab initio based PES, which can now be trusted for studying the isomerization reaction. PMID- 25554157 TI - Experimental and theoretical study on the excited-state dynamics of ortho-, meta , and para-methoxy methylcinnamate. AB - The S1 state dynamics of methoxy methylcinnamate (MMC) has been investigated under supersonic jet-cooled conditions. The vibrationally resolved S1-S0 absorption spectrum was recorded by laser induced fluorescence and mass-resolved resonant two-photon ionization spectroscopy and separated into conformers by UV UV hole-burning (UV-UV HB) spectroscopy. The S1 lifetime measurements revealed different dynamics of para-methoxy methylcinnamate from ortho-methoxy methylcinnamate and meta-methoxy methylcinnamate (hereafter, abbreviated as p-, o , and m-MMCs, respectively). The lifetimes of o-MMC and m-MMC are on the nanosecond time scale and exhibit little tendency of excess energy dependence. On the other hand, p-MMC decays much faster and its lifetime is conformer and excess energy dependent. In addition, the p-MMC-H2O complex was studied to explore the effect of hydration on the S1 state dynamics of p-MMC, and it was found that the hydration significantly accelerates the nonradiative decay. Quantum chemical calculation was employed to search the major decay route from S1(pipi(*)) for three MMCs and p-MMC-H2O in terms of (i) trans -> cis isomerization and (ii) internal conversion to the (1)npi(*) state. In o-MMC and m-MMC, the large energy barrier is created for the nonradiative decay along (i) the double-bond twisting coordinate (~1000 cm(-1)) in S1 as well as (ii) the linear interpolating internal coordinate (~1000 cm(-1)) from S1 to (1)npi(*) states. The calculation on p-MMC decay dynamics suggests that both (i) and (ii) are available due to small energy barrier, i.e., 160 cm(-1) by the double-bond twisting and 390 cm(-1) by the potential energy crossing. The hydration of p-MMC raises the energy barrier of the IC route to the S1/(1)npi(*) conical intersection, convincing that the direct isomerization is more likely to occur. PMID- 25554158 TI - Vibrational effects on valence electron momentum distributions of CH2F2. AB - We report an electron momentum spectroscopy study of vibrational effects on the electron momentum distributions for the outer valence orbitals of difluoromethane (CH2F2). The symmetric noncoplanar (e,2e) experiment has been performed at an incident electron energy of 1.2 keV. Furthermore, a theoretical calculation of the electron momentum distributions of the CH2F2 molecule has been carried out with vibrational effects being involved. It is shown from comparisons between experiment and theory that it is essential to take into account influences of the CH2 asymmetric stretching and CH2 rocking vibrational modes for a proper understanding of the electron momentum distribution of the 2b1 orbital having the CH-bonding character. The results of CH2F2and additional theoretical calculations for (CH3)2O and H2CO molecules strongly suggest that vibrational effects on electron momentum distributions tend to be appreciable for non-total symmetry molecular orbitals delocalized over some equivalent CH-bond sites. PMID- 25554159 TI - Vibrations of the S1 state of fluorobenzene-h5 and fluorobenzene-d5 via resonance enhanced multiphoton ionization (REMPI) spectroscopy. AB - We report resonance-enhanced multiphoton ionization spectra of the isotopologues fluorobenzene-h5 and fluorobenzene-d5. By making use of quantum chemical calculations, the changes in the wavenumber of the vibrational modes upon deuteration are examined. Additionally, the mixing of vibrational modes both between isotopologues and also between the two electronic states is discussed. The isotopic shifts lead to dramatic changes in the appearance of the spectrum as vibrations shift in and out of Fermi resonance. Assignments of the majority of the fluorobenzene-d5 observed bands are provided, aided by previous results on fluorobenzene-h5. PMID- 25554160 TI - Does the 4f-shell contribute to bonding in tetravalent lanthanide halides? AB - Lanthanide tetrahalide molecules LnX4 (Ln = Ce, Pr, Tb; X = F, Cl, Br, I) have been investigated by density functional theory at the levels of the relativistic Zero Order Regular Approximation and the relativistic energy-consistent pseudopotentials, using frozen small- and medium-cores. The calculated bond lengths and vibrational frequencies are close to the experimental data. Our calculations indicate 4f shell contributions to bonding in LnX4, in particular for the early lanthanides, which show significant overlap between the Ln 4f-shell and the halogen np-shells. The 4f shells contribute to Ln-X bonding in LnX4 about one third more than in LnX3. PMID- 25554161 TI - Bimodal dielectric relaxation of electrolyte solutions in weakly polar solvents. AB - The dielectric relaxation spectra of dilute electrolyte solutions in solvents of small dielectric constants are investigated both theoretically and experimentally. The theoretical calculation in our previous work [T. Yamaguchi, T. Matsuoka, and S. Koda, J. Chem. Phys. 135, 164511 (2011)] is reanalyzed, and it is shown that the dielectric relaxation spectra are composed of three components, namely, the relaxation of ionic atmosphere, the reorientational relaxation of ion pairs, and the collision between ions. The relaxation frequency of the slowest one increases with increasing the concentration, and the slower two relaxations, those of ionic atmosphere and ion pairs, merge into one at the concentration where the Debye length is comparable to the size of ions. Experimentally, the dielectric relaxation spectra of some electrolytes in two solvents, tetrahydrofuran and tetraglyme, are determined at frequencies from 300 kHz to 200 MHz, and the presence of the slower two relaxations was confirmed. The concentration dependence of the relaxation frequency is also in harmony with the theoretical calculation. The relationship between the dielectric relaxation spectra and the concentration dependence of the ionic conductivity is discussed. PMID- 25554162 TI - An extended topological model for binary phosphate glasses. AB - We present a topological model for binary phosphate glasses that builds on the previously introduced concepts of the modifying ion sub-network and the strength of modifier constraints. The validity of the model is confirmed by the correct prediction of Tg(x) for covalent polyphosphoric acids where the model reduces to classical constraint counting. The constraints on the modifying cations are linear constraints to first neighbor non-bridging oxygens, and all angular constraints are broken as expected for ionic bonding. For small modifying cations, such as Li(+), the linear constraints are almost fully intact, but for larger ions, a significant fraction is broken. By accounting for the fraction of intact modifying ion related constraints, qgamma, the Tg(x) of alkali phosphate glasses is predicted. By examining alkali, alkaline earth, and rare earth metaphosphate glasses, we find that the effective number of intact constraints per modifying cation is linearly related to the charge-to-distance ratio of the modifying cation to oxygen. PMID- 25554163 TI - A transferable force field for CdS-CdSe-PbS-PbSe solid systems. AB - A transferable force field for the PbSe-CdSe solid system using the partially charged rigid ion model has been successfully developed and was used to study the cation exchange in PbSe-CdSe heteronanocrystals [A. O. Yalcin et al., "Atomic resolution monitoring of cation exchange in CdSe-PbSe heteronanocrystals during epitaxial solid-solid-vapor growth," Nano Lett. 14, 3661-3667 (2014)]. In this work, we extend this force field by including another two important binary semiconductors, PbS and CdS, and provide detailed information on the validation of this force field. The parameterization combines Bader charge analysis, empirical fitting, and ab initio energy surface fitting. When compared with experimental data and density functional theory calculations, it is shown that a wide range of physical properties of bulk PbS, PbSe, CdS, CdSe, and their mixed phases can be accurately reproduced using this force field. The choice of functional forms and parameterization strategy is demonstrated to be rational and effective. This transferable force field can be used in various studies on II-VI and IV-VI semiconductor materials consisting of CdS, CdSe, PbS, and PbSe. Here, we demonstrate the applicability of the force field model by molecular dynamics simulations whereby transformations are initiated by cation exchange. PMID- 25554164 TI - The molecular charge distribution, the hydration shell, and the unique properties of liquid water. AB - The most essential features of a water molecule that give rise to its unique properties are examined using computer simulations of different water models. The charge distribution of a water molecule characterized by molecular multipoles is quantitatively linked to the liquid properties of water via order parameters for the degree (S(2)) and symmetry (DeltaS(2)) of the tetrahedral arrangement of the nearest neighbors, or "hydration shell." DeltaS(2) also appears to determine the long-range tetrahedral network and interfacial structure. From the correlations, some models are shown to be unable to reproduce certain properties due to the limitations of the model itself rather than the parameterization, which indicates that they are lacking essential molecular features. Moreover, since these properties depend not only on S(2) but also on DeltaS(2), the long-range structure in these models may be incorrect. Based on the molecular features found in the models that are best able to reproduce liquid properties, the most essential features of a water molecule in liquid water appear to be a charge distribution with a large dipole, a large quadrupole, and negative charge out of the molecular plane, as well as a symmetrically ordered tetrahedral hydration shell that results from this charge distribution. The implications for modeling water are also discussed. PMID- 25554165 TI - Intra- and intermolecular effects on the Compton profile of the ionic liquid 1,3 dimethylimidazolium chloride. AB - We present a comprehensive simulation study on the solid-liquid phase transition of the ionic liquid 1,3-dimethylimidazolium chloride in terms of the changes in the atomic structure and their effect on the Compton profile. The structures were obtained by using ab initio molecular dynamics simulations. Chosen radial distribution functions of the liquid structure are presented and found generally to be in good agreement with previous ab initio molecular dynamics and neutron scattering studies. The main contributions to the predicted difference Compton profile are found to arise from intermolecular changes in the phase transition. This prediction can be used for interpreting future experiments. PMID- 25554166 TI - Excellence of numerical differentiation method in calculating the coefficients of high temperature series expansion of the free energy and convergence problem of the expansion. AB - In this paper, it is shown that the numerical differentiation method in performing the coupling parameter series expansion [S. Zhou, J. Chem. Phys. 125, 144518 (2006); AIP Adv. 1, 040703 (2011)] excels at calculating the coefficients ai of hard sphere high temperature series expansion (HS-HTSE) of the free energy. Both canonical ensemble and isothermal-isobaric ensemble Monte Carlo simulations for fluid interacting through a hard sphere attractive Yukawa (HSAY) potential with extremely short ranges and at very low temperatures are performed, and the resulting two sets of data of thermodynamic properties are in excellent agreement with each other, and well qualified to be used for assessing convergence of the HS-HTSE for the HSAY fluid. Results of valuation are that (i) by referring to the results of a hard sphere square well fluid [S. Zhou, J. Chem. Phys. 139, 124111 (2013)], it is found that existence of partial sum limit of the high temperature series expansion series and consistency between the limit value and the true solution depend on both the potential shapes and temperatures considered. (ii) For the extremely short range HSAY potential, the HS-HTSE coefficients ai falls rapidly with the order i, and the HS-HTSE converges from fourth order; however, it does not converge exactly to the true solution at reduced temperatures lower than 0.5, wherein difference between the partial sum limit of the HS-HTSE series and the simulation result tends to become more evident. Something worth mentioning is that before the convergence order is reached, the preceding truncation is always improved by the succeeding one, and the fourth- and higher order truncations give the most dependable and qualitatively always correct thermodynamic results for the HSAY fluid even at low reduced temperatures to 0.25. PMID- 25554167 TI - Spatial-decomposition analysis of electrical conductivity in ionic liquid. AB - The electrical conductivity of room temperature ionic liquid (IL) is investigated with molecular dynamics simulation. A trajectory of 1 MUs in total is analyzed for the ionic liquid [C4mim][NTf2] (1-n-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, and the anion is also called TFSI or TFSA), and the ion motions are examined in direct connection to the conductivity within the framework formulated previously [K.-M. Tu, R. Ishizuka, and N. Matubayasi, J. Chem. Phys. 141, 044126 (2014)]. As a transport coefficient, the computed electrical conductivity is in fair agreement with the experiment. The conductivity is then decomposed into the autocorrelation term of Nernst-Einstein form and the cross-correlation term describing the two-body motions of ions, and the cross-correlation term is further decomposed spatially to incorporate the structural insights on ion configurations into the dynamic picture. It is observed that the ion-pair contribution to the conductivity is not spatially localized and extends beyond the first coordination shell. The extent of localization of the cross-correlation effect in the conductivity is in correspondence to that of the spatial correlation represented by radial distribution function, which persists over nanometer scale. PMID- 25554168 TI - Single ion dynamics in molten sodium bromide. AB - We present a study on the single ion dynamics in the molten alkali halide NaBr. Quasielastic neutron scattering was employed to extract the self-diffusion coefficient of the sodium ions at three temperatures. Molecular dynamics simulations using rigid and polarizable ion models have been performed in parallel to extract the sodium and bromide single dynamics and ionic conductivities. Two methods have been employed to derive the ion diffusion, calculating the mean squared displacements and the velocity autocorrelation functions, as well as analysing the increase of the line widths of the self dynamic structure factors. The sodium diffusion coefficients show a remarkable good agreement between experiment and simulation utilising the polarisable potential. PMID- 25554170 TI - The equilibrium shape of fluid-fluid interfaces: derivation and a new numerical method for Young's and Young-Laplace equations. AB - Many physical problems require explicit knowledge of the equilibrium shape of the interface between two fluid phases. Here, we present a new numerical method which is simply implementable and easily adaptable for a wide range of problems involving capillary deformations of fluid-fluid interfaces. We apply a simulated annealing algorithm to find the interface shape that minimizes the thermodynamic potential of the system. First, for completeness, we provide an analytical proof that minimizing this potential is equivalent to solving the Young-Laplace equation and the Young law. Then, we illustrate our numerical method showing two dimensional results for fluid-fluid menisci between vertical or inclined walls and curved surfaces, capillary interactions between vertical walls, equilibrium shapes of sessile heavy droplets on a flat horizontal solid surface, and of droplets pending from flat or curved solid surfaces. Finally, we show illustrative three-dimensional results to point out the applicability of the method to micro- or nano-particles adsorbed at a fluid-fluid interface. PMID- 25554169 TI - Quantum valley Hall states and topological transitions in Pt(Ni, Pd)-decorated silicene: a first-principles study. AB - The electronic states and topological behaviors of Pt(Ni, Pd)-decorated silicene are investigated by using an ab-initio method. All the three kinds of the adatoms prefer hollow sites of the silicene, guaranteeing the Dirac cones unbroken. The Pt(Ni, Pd)-decorated silicene systems all present quantum valley Hall (QVH) states with the gap opened exactly at the Fermi level. The gaps of the QVH states can be increased substantially by applying a positive electric field. Very fascinating phase transitions from QVH to quantum spin Hall (QSH) and then to QVH again are achieved in the Pt/Ni-decorated silicene when a negative electric field is applied. The QSH state in the Pd case with a negative electric field is, however, quenched because of relatively larger Rashba spin-orbit coupling (SOC) than the intrinsic SOC in the system. Our findings may be useful for the applications of silicene-based devices in valleytronics and spintronics. PMID- 25554171 TI - First-principle calculation of core level binding energies of LixPOyNz solid electrolyte. AB - We present first-principle calculations of core-level binding energies for the study of insulating, bulk phase, compounds, based on the Slater-Janak transition state model. Those calculations were performed in order to find a reliable model of the amorphous LixPOyNz solid electrolyte which is able to reproduce its electronic properties gathered from X-ray photoemission spectroscopy (XPS) experiments. As a starting point, Li2PO2N models were investigated. These models, proposed by Du et al. on the basis of thermodynamics and vibrational properties, were the first structural models of LixPOyNz. Thanks to chemical and structural modifications applied to Li2PO2N structures, which allow to demonstrate the relevance of our computational approach, we raise an issue concerning the possibility of encountering a non-bridging kind of nitrogen atoms (=N(-)) in LixPOyNz compounds. PMID- 25554172 TI - Two-phase flow in a chemically active porous medium. AB - We study the problem of the transformation of a given reactant species into an immiscible product species, as they flow through a chemically active porous medium. We derive the equation governing the evolution of the volume fraction of the species, in a one-dimensional macroscopic description, identify the relevant dimensionless numbers, and provide simple models for capillary pressure and relative permeabilities, which are quantities of crucial importance when tackling multiphase flows in porous media. We set the domain of validity of our models and discuss the importance of viscous coupling terms in the extended Darcy's law. We investigate numerically the steady regime and demonstrate that the spatial transformation rate of the species along the reactor is non-monotonous, as testified by the existence of an inflection point in the volume fraction profiles. We obtain the scaling of the location of this inflection point with the dimensionless lengths of the problem. Eventually, we provide key elements for optimization of the reactor. PMID- 25554173 TI - Numerical study of the effects of surface topography and chemistry on the wetting transition using the string method. AB - Droplets on a solid surface patterned with microstructures can exhibit the composite Cassie-Baxter (CB) state or the wetted Wenzel state. The stability of the CB state is determined by the energy barrier separating it from the wetted state. In this work, we study the CB to Wenzel transition using the string method [E et al., J. Chem. Phys. 126, 164103 (2007); W. Ren and E. Vanden-Eijnden, J. Chem. Phys. 138, 134105 (2013)]. We compute the transition states and energy barriers for a three-dimensional droplet on patterned surfaces. The liquid-vapor coexistence is modeled using the mean field theory. Numerical results are obtained for surfaces patterned with straight pillars and nails, respectively. It is found that on both type of surfaces, wetting occurs via infiltration of the liquid in a single groove. The reentrant geometry of nails creates large energy barrier for the wetting of the solid surface compared to straight pillars. We also study the effect of surface chemistry, pillar height, and inter-pillar spacing on the energy barrier and compare it with nails. PMID- 25554174 TI - Rigid linear particles confined on a spherical surface: phase diagram of nematic defect states. AB - A thin film of liquid crystal confined on a spherical surface displays topological defects, as demonstrated by experimental observation of micron-sized double-emulsion droplets. Proposals have been made in practical applications to design novel materials by using these patterned textures. Recent phenomenological models and Monte Carlo computer simulations revealed organized defect structures with different characteristics. Here, we theoretically investigate the structure of the nematic ordering resulted from the excluded-volume interaction between rigid molecules confined on a spherical surface. The free-energy model follows a basic idea originally proposed by Onsager for studying a nematic fluid made of rigid particles. We tackle this fundamental model numerically to produce high precision free-energy branches that enable structural determination. PMID- 25554175 TI - Analytic liquid-state theory of the interactions between colloids mediated by reversibly adsorbed polymers. AB - We develop an analytic liquid-state theory of the effective interactions induced by reversibly adsorbing polymers, acting between colloids immersed in a polymer melt. This theory is based on the polymer reference interaction site model that has no restrictions with respect to the density of the polymer system and colloid to-polymer size ratio. By making use of the developed theory, we calculate the potential of the polymer mediated interactions as a function of the colloid radius, strength and range of the adsorption potential, and the polymer density. In addition, we investigate the behavior of the second virial coefficient as a function of the polymer density in both the colloid and nano-particle limits. We found out that the presence of the adsorption interactions significantly changes the polymer mediated forces relative to the case of the pure entropic depletion interactions, showing most pronounced difference in the case of large polymer densities and small colloid-to-polymer size ratios. The significance of the above differences is determined by the relation between the range of the adsorption potential and polymer correlation length. PMID- 25554176 TI - Self-consistent field model for strong electrostatic correlations and inhomogeneous dielectric media. AB - Electrostatic correlations and variable permittivity of electrolytes are essential for exploring many chemical and physical properties of interfaces in aqueous solutions. We propose a continuum electrostatic model for the treatment of these effects in the framework of the self-consistent field theory. The model incorporates a space- or field-dependent dielectric permittivity and an excluded ion-size effect for the correlation energy. This results in a self-energy modified Poisson-Nernst-Planck or Poisson-Boltzmann equation together with state equations for the self energy and the dielectric function. We show that the ionic size is of significant importance in predicting a finite self energy for an ion in an inhomogeneous medium. Asymptotic approximation is proposed for the solution of a generalized Debye-Huckel equation, which has been shown to capture the ionic correlation and dielectric self energy. Through simulating ionic distribution surrounding a macroion, the modified self-consistent field model is shown to agree with particle-based Monte Carlo simulations. Numerical results for symmetric and asymmetric electrolytes demonstrate that the model is able to predict the charge inversion at high correlation regime in the presence of multivalent interfacial ions which is beyond the mean-field theory and also show strong effect to double layer structure due to the space- or field-dependent dielectric permittivity. PMID- 25554177 TI - Coarse-graining in simulations of multicomponent polymer systems. AB - We investigate the mapping required between the interaction parameters of two different coarse-grained simulation models to ensure a match of the long-range structural characteristics of multicomponent polymeric system. The basis for our studies is the recent work of Morse and workers, which demonstrated the existence of a mapping between the interaction parameters of different coarse-grained simulation models which allow for a matching of the peak of the disordered state structure factor in symmetric diblock copolymers. We investigate the extensibility of their results to other polymeric systems by studying a variety of systems, including, asymmetric diblock copolymers, symmetric triblock copolymers, and diblock copolymer-solvent mixtures. By using the mapping deduced in the context of symmetric diblock copolymers, we observe excellent agreement for peak in the inverse structure between both two popular coarse grained models for all sets of polymeric melt systems investigated, thus showing that the mapping function proposed for diblock copolymer melts is transferable to other polymer melts irrespective of the blockiness or overall composition. Interestingly, for the limited parameter range of polymer-solvent systems investigated in this article, the mapping functions developed for polymer melts are shown to be equally effective in mapping the structure factor of the coarse grained simulation models. We use our findings to propose a methodology to create ordered morphologies in simulations involving hard repulsive potentials in a computationally efficient manner. We demonstrate the outcomes of methodology by creating lamellar and cylindrical phases of diblock copolymers of long chains in the popularly used Kremer-Grest simulation model. PMID- 25554179 TI - Fluids confined in wedges and by edges: virial series for the line-thermodynamic properties of hard spheres. AB - This work is devoted to analyze the relation between the thermodynamic properties of a confined fluid and the shape of its confining vessel. Recently, new insights in this topic were found through the study of cluster integrals for inhomogeneous fluids that revealed the dependence on the vessel shape of the low density behavior of the system. Here, the statistical mechanics and thermodynamics of fluids confined in wedges or by edges is revisited, focusing on their cluster integrals. In particular, the well known hard sphere fluid, which was not studied in this framework so far, is analyzed under confinement and its thermodynamic properties are analytically studied up to order two in the density. Furthermore, the analysis is extended to the confinement produced by a corrugated wall. These results rely on the obtained analytic expression for the second cluster integral of the confined hard sphere system as a function of the opening dihedral angle 0 < beta < 2pi. It enables a unified approach to both wedges and edges. PMID- 25554178 TI - Accurate coarse-grained models for mixtures of colloids and linear polymers under good-solvent conditions. AB - A coarse-graining strategy, previously developed for polymer solutions, is extended here to mixtures of linear polymers and hard-sphere colloids. In this approach, groups of monomers are mapped onto a single pseudoatom (a blob) and the effective blob-blob interactions are obtained by requiring the model to reproduce some large-scale structural properties in the zero-density limit. We show that an accurate parametrization of the polymer-colloid interactions is obtained by simply introducing pair potentials between blobs and colloids. For the coarse grained (CG) model in which polymers are modelled as four-blob chains (tetramers), the pair potentials are determined by means of the iterative Boltzmann inversion scheme, taking full-monomer (FM) pair correlation functions at zero-density as targets. For a larger number n of blobs, pair potentials are determined by using a simple transferability assumption based on the polymer self similarity. We validate the model by comparing its predictions with full-monomer results for the interfacial properties of polymer solutions in the presence of a single colloid and for thermodynamic and structural properties in the homogeneous phase at finite polymer and colloid density. The tetramer model is quite accurate for q ? 1 (q=Rg/Rc, where Rg is the zero-density polymer radius of gyration and Rc is the colloid radius) and reasonably good also for q = 2. For q = 2, an accurate coarse-grained description is obtained by using the n = 10 blob model. We also compare our results with those obtained by using single-blob models with state-dependent potentials. PMID- 25554180 TI - Coil-to-globule transitions of homopolymers and multiblock copolymers. AB - We study the coil-to-globule transitions of both homopolymers and multiblock copolymers using integrated tempering sampling method, which is a newly proposed enhanced sampling method that can efficiently sample the energy space with low computational costs. For homopolymers, the coil-to-globule structure transition temperatures (Ttr) are identified by the radius of gyration of the chain. The transition temperature shows a primary scaling dependence on the chain length (N) with Ttr ~ N(-1/2). For multiblock copolymers, the coil-to-globule transition can be identified as first order, depending on the block size and the difference in attractive interactions of blocks. The influence of mutating a small portion of strongly attractive blocks to weakly attractive blocks on the coil-to-globule transition is found to be related to the position of the mutation. PMID- 25554181 TI - Concentration dependence of the Flory-Huggins interaction parameter in aqueous solutions of capped PEO chains. AB - The dependence on volume fraction phi of the Flory-Huggins interaction parameter chiwp(phi) describing the free energy of mixing of polymers in water is obtained by exploiting the connection of chiwp(phi) to the chemical potential of the water, for which quasi-chemical theory is satisfactory. We test this theoretical approach with simulation data for aqueous solutions of capped PEO (polyethylene oxide) oligomers. For CH3(CH2-O-CH2)mCH3 (m = 11), chiwp(phi) depends strongly on phi, consistent with experiment. These results identify coexisting water-rich and water-poor solutions at T = 300 K and p = 1 atm. Direct observation of the coexistence of these two solutions on simulation time scales supports that prediction for the system studied. This approach directly provides the osmotic pressures. The osmotic second virial coefficient for these chains is positive, reflecting repulsive interactions between the chains in the water, a good solvent for these chains. PMID- 25554182 TI - A new configurational bias scheme for sampling supramolecular structures. AB - We present a new simulation scheme which allows an efficient sampling of reconfigurable supramolecular structures made of polymeric constructs functionalized by reactive binding sites. The algorithm is based on the configurational bias scheme of Siepmann and Frenkel and is powered by the possibility of changing the topology of the supramolecular network by a non-local Monte Carlo algorithm. Such a plan is accomplished by a multi-scale modelling that merges coarse-grained simulations, describing the typical polymer conformations, with experimental results accounting for free energy terms involved in the reactions of the active sites. We test the new algorithm for a system of DNA coated colloids for which we compute the hybridisation free energy cost associated to the binding of tethered single stranded DNAs terminated by short sequences of complementary nucleotides. In order to demonstrate the versatility of our method, we also consider polymers functionalized by receptors that bind a surface decorated by ligands. In particular, we compute the density of states of adsorbed polymers as a function of the number of ligand-receptor complexes formed. Such a quantity can be used to study the conformational properties of adsorbed polymers useful when engineering adsorption with tailored properties. We successfully compare the results with the predictions of a mean field theory. We believe that the proposed method will be a useful tool to investigate supramolecular structures resulting from direct interactions between functionalized polymers for which efficient numerical methodologies of investigation are still lacking. PMID- 25554183 TI - Coarse-grained molecular dynamics simulations of depletion-induced interactions for soft matter systems. AB - Given the ubiquity of depletion effects in biological and other soft matter systems, it is desirable to have coarse-grained Molecular Dynamics (MD) simulation approaches appropriate for the study of complex systems. This paper examines the use of two common truncated Lennard-Jones (Weeks-Chandler-Andersen (WCA)) potentials to describe a pair of colloidal particles in a thermal bath of depletants. The shifted-WCA model is the steeper of the two repulsive potentials considered, while the combinatorial-WCA model is the softer. It is found that the depletion-induced well depth for the combinatorial-WCA model is significantly deeper than the shifted-WCA model because the resulting overlap of the colloids yields extra accessible volume for depletants. For both shifted- and combinatorial-WCA simulations, the second virial coefficients and pair potentials between colloids are demonstrated to be well approximated by the Morphometric Thermodynamics (MT) model. This agreement suggests that the presence of depletants can be accurately modelled in MD simulations by implicitly including them through simple, analytical MT forms for depletion-induced interactions. Although both WCA potentials are found to be effective generic coarse-grained simulation approaches for studying depletion effects in complicated soft matter systems, combinatorial-WCA is the more efficient approach as depletion effects are enhanced at lower depletant densities. The findings indicate that for soft matter systems that are better modelled by potentials with some compressibility, predictions from hard-sphere systems could greatly underestimate the magnitude of depletion effects at a given depletant density. PMID- 25554184 TI - Dissipative particle dynamics of triblock copolymer melts: a midblock conformational study at moderate segregation. AB - As thermoplastic elastomers, triblock copolymers constitute an immensely important class of shape-memory soft materials due to their unique ability to form molecular networks stabilized by physical, rather than chemical, cross links. The extent to which such networks develop in triblock and higher-order multiblock copolymers is sensitive to the formation of midblock bridges, which serve to connect neighboring microdomains. In addition to bridges, copolymer molecules can likewise form loops and dangling ends upon microphase separation or they can remain unsegregated. While prior theoretical and simulation studies have elucidated the midblock bridging fraction in triblock copolymer melts, most have only considered strongly segregated systems wherein dangling ends and unsegregated chains become relatively insignificant. In this study, simulations based on dissipative particle dynamics are performed to examine the self-assembly and networkability of moderately segregated triblock copolymers. Utilizing a density-based cluster-recognition algorithm, we demonstrate how the simulations can be analyzed to extract information about microdomain formation and permit explicit quantitation of the midblock bridging, looping, dangling, and unsegregated fractions for linear triblock copolymers varying in chain length, molecular composition, and segregation level. We show that midblock conformations can be sensitive to variations in chain length, molecular composition, and bead repulsion, and that a systematic investigation can be used to identify the onset of strong segregation where the presence of dangling and unsegregated fractions are minimal. In addition, because this clustering approach is robust, it can be used with any particle-based simulation method to quantify network formation of different morphologies for a wide range of triblock and higher-order multiblock copolymer systems. PMID- 25554185 TI - Viscoelasticity of model interphase chromosomes. AB - We investigated the viscoelastic response of model interphase chromosomes by tracking the three-dimensional motion of hundreds of dispersed Brownian particles of sizes ranging from the thickness of the chromatin fiber up to slightly above the mesh size of the chromatin solution. In agreement with previous computational studies on polymer solutions and melts, we found that the large-time behaviour of the diffusion coefficient and the experienced viscosity of moving particles as functions of particle size deviate from the traditional Stokes-Einstein relation and agree with a recent scaling theory of diffusion of non-sticky particles in polymer solutions. Interestingly, we found that at short times large particles are temporarily "caged" by chromatin spatial constraints, which thus form effective domains whose sizes match remarkably well with recent experimental results for micro-tracers inside interphase nuclei. Finally, by employing a known mathematical relation between the time mean-square displacement of tracked particles and the complex shear modulus of the surrounding solution, we calculated the elastic and viscous moduli of interphase chromosomes. PMID- 25554186 TI - Separation of the Stern and diffuse layer in coarse-grained models: the cases of phosphatidyl serine, phosphatidic acid, and PIP2 monolayers. AB - We present here a method to separate the Stern and diffuse layer in general systems into two regions that can be analyzed separately. The Stern layer can be described in terms of Bjerrum pairing and the diffuse layer in terms of Poisson Boltzmann theory (monovalent) or strong coupling theory plus a slowly decaying tail (divalent). We consider three anionic phospholipids: phosphatidyl serine, phosphatidic acid, and phosphatidylinositol(4,5)bisphosphate (PIP2), which we describe within a minimal coarse-grained model as a function of ionic concentration. The case of mixed lipid systems is also considered, which shows a high level of binding cooperativity as a function of PIP2 localization. Implications for existing experimental systems of lipid heterogeneities are also discussed. PMID- 25554187 TI - Mechanostability of cohesin-dockerin complexes in a structure-based model: anisotropy and lack of universality in the force profiles. AB - We use a structure-based coarse grained model to elucidate stretching of three cohesin-dockerin complexes that are found in the cellulosome. The average strength of mechanostability is comparable to that of the I27 domain of titin, but the force profiles depend on the pulling direction and anisotropy effects can be substantial. Even though the force profiles for individual cohesins and dockerins are similar, those for their complexes are visibly distinct for any pulling direction. PMID- 25554192 TI - High yield recombinant production of a self-assembling polycationic peptide for silica biomineralization. AB - We report the recombinant bacterial expression and purification at high yields of a polycationic oligopeptide, P5S3. The sequence of P5S3 was inspired by a diatom silaffin, a silica precipitating peptide. Like its native model, P5S3 exhibits silica biomineralizing activity, but furthermore has unusual self-assembling properties. P5S3 is efficiently expressed in Escherichia coli as fusion with ketosteroid isomerase (KSI), which causes deposition in inclusion bodies. After breaking the fusion by cyanogen bromide reaction, P5S3 was purified by cation exchange chromatography, taking advantage of the exceptionally high content of basic amino acids. The numerous cationic charges do not prevent, but may even promote counterion-independent self-assembly which in turn leads to silica precipitation. Enzymatic phosphorylation, a common modification in native silica biomineralizing peptides, can be used to modify the precipitation activity. PMID- 25554193 TI - Expression and purification of human WWP2 HECT domain in Escherichia coli. AB - WWP2 (WW domain-containing protein 2) is an E3 ubiquitin ligase belonging to the NEDD4-like protein family involved in various cell regulations, such as carcinogenesis, transcription control and cellular transport. Compared with homologues, WWP2 is difficult to express and no practical protocols have been developed for WWP2 preparation in large scale. Recently, domain structures of homologues of WWP2 have been determined by crystallography and NMR, but none for WWP2 has been attained. In this work, through a combination of extensive screening of ~100 constructs, expression strategies and host systems, we have found a soluble HECT domain truncation (WHP2) of WWP2 which is amendable for preparation scale expression in Escherichia coli. We have also established a relatively simple purification process to achieve highly pure WHP2 protein by employing immobilized metal-affinity chromatography followed by salting out, ion exchange chromatography and finally, size exclusion chromatography. We are able to obtain about 60mg/L of the soluble WHP2. The identity and structure of the expressed WHP2 have been analyzed by mass spectrometry and circular dichroism. The native ability of WHP2 to bind different partners has been revealed by pull down assay. PMID- 25554198 TI - [The use of benchmarking to manage the healthcare supply chain: effects on purchasing cost and quality]. AB - OBJECTIVE: Healthcare supply expenses consume a large part of the financial resources allocated to public health. The aim of this study was to analyze the use of a benchmarking process in the management of hospital purchases, as well as its effect on product cost reduction and quality improvement. METHODS: Data were collected through a survey conducted in 29 primary healthcare districts from 2010 to 2011, and through a healthcare database on the prices, quality, delivery time and supplier characteristics of 5373 products. RESULTS: The use of benchmarking processes reduced or eliminated products with a low quality and high price. These processes increased the quality of products by 10.57% and reduced their purchase price by 28.97%. CONCLUSIONS: The use of benchmarking by healthcare centers can reduce expenditure and allow more efficient management of the healthcare supply chain. It also facilitated the acquisition of products at lower prices and higher quality. PMID- 25554199 TI - [What does open access add? Not much, the main problems remain and new ones appear]. PMID- 25554200 TI - [Outstanding features of training in public health]. PMID- 25554201 TI - [When radon is beneficial to health]. PMID- 25554212 TI - Practical issues that should be considered when planning the implementation of pathogen reduction technology for plateletpheresis. AB - Pathogen reduction technology (PRT) is associated with increased blood safety through the inactivation of virus, bacteria and parasites. Dilution of platelet (PLT) concentrates in platelet additive solution (PAS) is a requirement for applying PRT, and that it is associated with various practical issues: increasing PLT target yields to compensate for loss of PLTs through PRT, extended apheresis donation time due to PAS addition at the end of the procedure, and the appearance of PLT aggregates. We proposed to program higher target PLT yields for plateletpheresis donations to compensate for PLTs lost due to PRT processing. To verify the feasibility of this approach, a paired study of the Amicus 3.11 and Trima 5.22 apheresis separators was performed using 196 procedures carried out on the same 98 donors. The Amicus 3.11 presented a higher collection efficiency (CE: 78.02 vs. 69.63; p < 0.0001) and collection rate (CR: 8.3 vs. 7.00; p < 0.0001); it was also faster (56.92 vs. 62.60; p < 0.0001) than the Trima 5.22 apheresis device. However, analysis of the donor group with higher pre-procedure PLT counts showed similar productivity results for the Amicus and Trima. The percentage of PLT aggregates detected was higher with the TA than the AM (8.62% vs. 3.88%, p = 0.04). Overall, both separators are entirely suitable for collecting hyper concentrated PLTs that are subsequently diluted in PAS for PRT, without excessively increasing the donation time. PLT aggregation can occur after apheresis collection but most of them disappear by day 1. Further investigation is needed to study the clinical impact of PLT aggregation. PMID- 25554214 TI - Identifying upper limb disability in patients with persistent whiplash. AB - BACKGROUND: Patients with persistent whiplash associated disorders (WAD) report upper limb (UL) symptoms and functional difficulties but there is limited information regarding the nature of these complaints. Impairments in motor performance may relate to functional deficits. OBJECTIVE: To identify symptoms and the degree and nature of UL functional difficulties. DESIGN: Cross sectional study. METHODS: Twenty-four age matched subjects with persistent WAD and healthy controls were surveyed using the Disabilities of the Arm, Shoulder and Hand (DASH), Neck Disability Index (NDI) and Patient Specific Functional Scale (PSFS). A series of case studies on six subjects with persistent WAD and thirteen age and gender matched controls also had their motor performance assessed using a specialised UL testing battery, including reaction time, movement speed, accuracy, co-ordination and tapping speed. RESULTS: The results suggest that UL symptoms and functional deficits are prevalent in persistent WAD. All individual item scores on the DASH, except one, were significantly higher in the WAD group and the DASH moderately correlated to pain, NDI and PSFS. Four-choice reaction time was the only motor performance measure that was significantly impaired in the WAD compared to control group and this correlated to pain levels. CONCLUSIONS: The findings suggest the DASH is a suitable measure for subjects with persistent WAD and could be administered when high NDI scores are present or the patient specifically reports difficulty with UL activities. Further investigation regarding UL motor performance in subjects with persistent WAD is warranted to determine relationships between symptoms and reported functional deficits. PMID- 25554213 TI - Targeting glycosaminoglycans in the lung by an engineered CXCL8 as a novel therapeutic approach to lung inflammation. AB - It is broadly recognized that chemokine-activated neutrophils play a crucial role in the inflammation and disruption of lung tissue observed in several acute and chronic lung diseases. Since glycosaminoglycan side chains of proteoglycans act as chemokine co-receptors in inflammation, we have used a CXCL8-based dominant negative mutant, dnCXCL8, to displace neutrophil-related chemokines in murine lungs using models of lung inflammation. Treatment with dnCXCL8 resulted in a dose-dependent reduction of neutrophil counts in bronchoalveolar lavage (BAL) of mice exposed to lipopolysaccharide after intravenous, subcutaneous and intratracheal administration. A strong and significant therapeutic effect was achieved already at a dose of 40 ug/kg of dnCXCL8. A similar dose response, but showing a broader spectrum of reduced inflammatory cells and soluble inflammatory markers, was observed in a murine model of tobacco smoke (TS)-induced lung inflammation. The broad spectrum of reduced inflammatory cells and markers can be due to the strong inhibition of neutrophil extravasation into the lung parenchyma, and/or to a relatively broad protein displacement profile of dnCXCL8 which may compete not only with wtCXCL8 for glycosaminoglycan-binding but possibly also with other related glycosaminoglycan-binding pro-inflammatory chemokines. Overall our results demonstrate that antagonizing CXCL8/glycosaminoglycan binding reduces lung inflammation as well as associated lung tissue damage due to LPS and TS and may therefore be a new therapeutic approach for lung pathologies characterized by a neutrophilic inflammatory phenotype. PMID- 25554217 TI - Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life. AB - Mechanisms of vascular complications in type-2 diabetes patients and animal models are matter of debate. We previously demonstrated that a double-stress model applied to male mice during nursing period produces enduring hyperfunction of endogenous opioid and adrenocorticotropin (ACTH)-corticosteroid systems, accompanied by type-2 diabetes-like alterations in adult animals. Administration of the opioid receptor antagonist naloxone, or of an antisense oligodeoxynucleotide versus proopiomelanocortin mRNA, capable to block the pro opiomelanocortin-derived peptides beta-endorphin and ACTH, selectively prevent these alterations. Here, we investigated alterations produced by our stress model on aorta endothelium-dependent relaxation and contractile responses. Mice, stressed during nursing period, showed in the adulthood hormonal and metabolic type-2 diabetes-like alterations, including hyperglycemia, increased body weight and increased plasma ACTH and corticosterone levels. Ex vivo isolated aorta rings, gathered from stressed mice, were less sensitive to noradrenaline-induced contractions versus controls. This effect was blocked by nitric-oxide synthase inhibitor l-N(G)-nitroarginine added to bath organ solution. Aorta rings relaxation caused by acetylcholine was enhanced in stressed mice versus controls, but following treatment with the nitric-oxide donor sodium nitroprusside, concentration-relaxation curves in aorta from stressed groups were similar to controls. Therefore, vascular response alterations to physiologic-pharmacologic stimuli were apparently due to nitric-oxide hyperfunction-dependent mechanisms. Aorta functional alterations, and plasma stress hormones enhancement, were prevented in mice stressed and treated with antisense oligodeoxinucleotide, addressed to reduce ACTH- and corticosteroid-mediated hyperfunction. This study demonstrates the key role of ACTH-corticosteroid axis hyperfunction for the triggering of vascular conditions in male adult rodents following postnatal stress in a type-2 diabetes model. PMID- 25554219 TI - Loneliness and cognitive function in the older adult: a systematic review. AB - BACKGROUND: Loneliness is a significant concern among the elderly, particularly in societies with rapid growth in aging populations. Loneliness may influence cognitive function, but the exact nature of the association between loneliness and cognitive function is poorly understood. The purpose of this systematic review was to synthesize current findings on the association between loneliness and cognitive function in older adults. METHOD: A comprehensive, electronic review of the literature was performed. Criteria for inclusion were original quantitative or qualitative research, report written in English, human participants with a mean age >= 60 years, and published from January 2000 through July 2013. The total number of studies included in this systematic review was ten. RESULTS: Main findings from the ten studies largely indicate that loneliness is significantly and negatively correlated with cognitive function, specifically in domains of global cognitive function or general cognitive ability, intelligence quotient (IQ), processing speed, immediate recall, and delayed recall. However, some initial correlations were not significant after controlling for a wide range of demographic and psychosocial risk factors thought to influence loneliness. CONCLUSIONS: Greater loneliness is associated with lower cognitive function. Although preliminary evidence is promising, additional studies are necessary to determine the causality and biological mechanisms underlying the relationship between loneliness and cognitive function. Findings should be verified in culturally diverse populations in different ages and settings using biobehavioral approaches. PMID- 25554220 TI - Laser-activated gold catalysts for liquid-phase growth of cadmium selenide nanowires. AB - A laser-activated-catalyst (LAC) technique was developed to grow CdSe nanowires in liquid medium at room temperature. The gold catalysts dispersed in the precursor solution were activated by a pulsed laser so as to decompose the precursor and catalyse the nanowire growth simultaneously. The LAC technique can achieve accurate positioning of nanowires, which is beneficial for device fabrication. PMID- 25554218 TI - ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth. AB - Bombesin receptor subtype (BRS)-3 is a G protein coupled receptor (GPCR) for the bombesin (BB)-family of peptides. BRS-3 is an orphan GPCR and little is known of its physiological role due to the lack of specific agonists and antagonists. PD168368 is a nonpeptide antagonist for the neuromedin B (NMB) receptor (R) whereas PD176252 is a nonpeptide antagonist for the gastrin releasing peptide (GRP) R and NMBR but not BRS-3. Here nonpeptide analogs of PD176252 e.g. the S enantiomer ML-18, and the R-enantiomer, EMY-98, were investigated as BRS-3 antagonists using lung cancer cells. ML-18 and EMY-98 inhibited specific (125)I BA1 (DTyr-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2)BB(6-14) binding to NCI-H1299 lung cancer cells stably transfected with BRS-3 with IC50 values of 4.8 and >100MUM, respectively. In contrast, ML-18 bound with lower affinity to the GRPR and NMBR with IC50 values of 16 and >100MUM, respectively. ML-18 (16MUM), but not its enantiomer EMY-98, inhibited the ability of 10nM BA1 to elevate cytosolic Ca(2+) in a reversible manner using lung cancer cells loaded with FURA2-AM. ML-18 (16MUM), but not EMY-98, inhibited the ability of 100nM BA1 to cause tyrosine phosphorylation of the EGFR and ERK in lung cancer cells. ML-18 but not EMY-98 inhibited the proliferation of lung cancer cells. The results indicate that ML-18 is a nonpeptide BRS-3 antagonist that should serve as a template to improve potency and selectivity. PMID- 25554221 TI - Study of baicalin on sympathoexcitation induced by myocardial ischemia via P2X3 receptor in superior cervical ganglia. AB - After the myocardial ischemia, injured myocardial tissues released large quantity of ATP, which activated P2X3 receptor in superior cervical ganglia and made the SCG postganglionic neurons excited. Excitatory of sympathetic postganglionic efferent neurons increased the blood pressure and heart rates, which aggravated the myocardial ischemic injury. Baicalin has anti-inflammatory and anti-oxidant properties. Our study showed that baicalin reduced the incremental concentration of serum CK-MB, cTn-T, epinephrine and ATP, decreased the up-regulated expression levels of P2X3 mRNA and protein in SCG after MI, and then inhibited the sympathetic excitatory activity triggered by MI injury. These results indicated that baicalin acted on P2X3 receptor was involved in the transmission of sympathetic excitation after the myocardial ischemic injury. Baicalin might decrease sympathetic activity via inhibiting P2X3 receptor in rat SCG to protect the myocardium. PMID- 25554223 TI - Tamoxifen in combination with temozolomide induce a synergistic inhibition of PKC pan in GBM cell lines. AB - BACKGROUND: Glioblastoma (GBM) is a highly proliferative, angiogenic grade IV astrocytoma that develops resistance to the alkylating agents used in chemotherapy, such as temozolomide (TMZ), which is considered the gold standard. The mean survival time for GBM patients is approximately 12 months, increasing to 14.6 months after TMZ treatment. The resistance of GBM to chemotherapy seems to be associated to genetic alterations and to the constitutive activation of several signaling pathways. Therefore, the combination of different drugs with different mechanisms of action may contribute to circumvent the chemoresistance of glioma cells. Here we describe the potential synergistic behavior of the therapeutic combination of tamoxifen (TMX), a known inhibitor of PKC, and TMZ in GBM. METHODS: We used two GBM cell lines incubated in absence and presence of TMX and/or TMZ and measured cell viability, proliferation, apoptosis, cell cycle, migration ability, cytoskeletal organization and the phosphorylated amount of the p-PKC-pan. RESULTS: The combination of low doses of TMX with increasing doses of TMZ shows an increased antiproliferative and apoptotic effect compared to the effect with TMX alone. CONCLUSIONS: The combination of TMX and TMZ seems to potentiate the effect of each other. These alterations seem to be associated to a decrease in the phosphorylation status of PKC. GENERAL SIGNIFICANCE: We emphasize that TMX is an inhibitor of the p-PKC-pan and that these combination is more effective in the reduction of proliferation and in the increase of apoptosis than each drug alone, which presents a new therapeutic strategy in GBM treatment. PMID- 25554226 TI - Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer? AB - PURPOSE: In recent years several papers have been published on radiation-induced cardiac toxicity, especially in breast cancer patients. However, in esophageal cancer patients the radiation dose to the heart is usually markedly higher. To determine whether radiation-induced cardiac toxicity is also a relevant issue for this group, we conducted a review of the current literature. METHODS: A literature search was performed in Medline for papers concerning cardiac toxicity in esophageal cancer patients treated with radiotherapy with or without chemotherapy. RESULTS: The overall crude incidence of symptomatic cardiac toxicity was as high as 10.8%. Toxicities corresponded with several dose-volume parameters of the heart. The most frequently reported complications were pericardial effusion, ischemic heart disease and heart failure. CONCLUSION: Cardiac toxicity is a relevant issue in the treatment of esophageal cancer. However, valid Normal Tissue Complication Probability models for esophageal cancer are not available at present. PMID- 25554227 TI - Structural characterization of amyloid fibrils from the human parathyroid hormone. AB - Amyloid deposits are common in various tissues as a consequence of misfolded proteins. However, secretory protein and peptides are often stored in membrane coated granules as functional amyloids. In this article, we present a detailed characterization of in vitro generated amyloid fibrils from human parathyroid hormone (hPTH(1-84)). Fully mature fibrils could be obtained after a short lag phase within less than one hour at 65 degrees C. These fibrils showed all characteristic of a cross-beta structure. Protease cleavage combined with mass spectrometry identified the central region of the peptide hormone involved in the fibril core formation. EGCG, an inhibitor of amyloid fibril formation, showed binding to residues in the peptide monomers corresponding to the later fibril core and thus explaining the inhibition of the fibril growth. Conformational and dynamic studies by solid-state NMR further corroborated the cross-beta core of the fibrils, but also identified highly mobile segments with a random coil structure not belonging to the rigid fibril core. PMID- 25554229 TI - Whither borderland? PMID- 25554231 TI - Advance directives for mental health care: innovation in law, policy, and practice. AB - Virginia appears to be the first state to commit itself to statewide implementation of psychiatric advance directives, and its experience may be highly instructive for other states. The project began with consensus building among stakeholders (2007-2009), followed by revisions to Virginia's Health Care Decisions Act (2009-2010) and designation of five of the state's 40 Community Services Boards as demonstration sites for facilitation efforts. Early implementation efforts quickly showed that psychiatric advance directives are not self-executing innovations. This column describes the early policy and practice innovations, lessons learned from initial implementation efforts, and three approaches to facilitating completion of advance directives by consumers. PMID- 25554228 TI - You are lost without a map: Navigating the sea of protein structures. AB - X-ray crystal structures propel biochemistry research like no other experimental method, since they answer many questions directly and inspire new hypotheses. Unfortunately, many users of crystallographic models mistake them for actual experimental data. Crystallographic models are interpretations, several steps removed from the experimental measurements, making it difficult for nonspecialists to assess the quality of the underlying data. Crystallographers mainly rely on "global" measures of data and model quality to build models. Robust validation procedures based on global measures now largely ensure that structures in the Protein Data Bank (PDB) are largely correct. However, global measures do not allow users of crystallographic models to judge the reliability of "local" features in a region of interest. Refinement of a model to fit into an electron density map requires interpretation of the data to produce a single "best" overall model. This process requires inclusion of most probable conformations in areas of poor density. Users who misunderstand this can be misled, especially in regions of the structure that are mobile, including active sites, surface residues, and especially ligands. This article aims to equip users of macromolecular models with tools to critically assess local model quality. Structure users should always check the agreement of the electron density map and the derived model in all areas of interest, even if the global statistics are good. We provide illustrated examples of interpreted electron density as a guide for those unaccustomed to viewing electron density. PMID- 25554232 TI - Embedding advance directives in routine care for persons with serious mental illness: implementation challenges. AB - For people with serious mental illness, research demonstrates the potential positive effects of having an advance directive with specific instructions for mental health care. The Commonwealth of Virginia has undertaken efforts to incorporate the completion of psychiatric advance directives into routine mental health services for individuals with serious mental illness. The inherent complexities of advance directives-a single legal tool for use by a heterogeneous array of consumers, providers, and organizations-have led to more barriers than had been anticipated. This article describes challenges encountered in the first three years of implementation efforts. Data are from feedback on early training attempts and experiences of staff at pilot sites and work groups convened for the implementation project. The authors describe a range of challenges, such as how to present a complete and clear message about the nature, purposes, and potential advantages of psychiatric advance directives to various audiences, in particular their use in recovery-oriented care; how to promote cross-system collaboration among potential users of these directives; and how to overcome resource constraints and sustain interest in the process. Virginia's experience reinforces the importance of developing multifaceted implementation strategies, such as the creation of informational and training tools to spread implementation more effectively, the identification of "champions" or staff members who are invested in implementation, and the development of multiple approaches to facilitating completion of advance directives by consumers. PMID- 25554234 TI - Healthy minds: promoting mental health for at-risk youths. PMID- 25554233 TI - Reengaging veterans with serious mental illness into care: preliminary results from a national randomized trial. AB - OBJECTIVE: This study compared effectiveness of an enhanced versus standard implementation strategy (Replicating Effective Programs [REP]) on site-level uptake of Re-Engage, a national program for veterans with serious mental illness. METHODS: Mental health providers at 158 Veterans Affairs (VA) facilities were given REP-based manuals and training in Re-Engage, which involved identifying veterans who had not been seen in VA care for at least one year, documenting their clinical status, and coordinating further health care. After six months, facilities not responding to REP (N=88) were randomized to receive six months of facilitation (enhanced REP) or continued standard REP. Site-level uptake was defined as percentage of patients (N=1,531) with updated documentation or with whom contact was attempted. RESULTS: Rate of Re-Engage uptake was greater for enhanced REP sites compared with standard REP sites (41% versus 31%, p=.01). Total REP facilitation time was 7.3 hours per site for six months. CONCLUSIONS: Added facilitation improved short-term uptake of a national mental health program. PMID- 25554235 TI - Wellness program for people with early psychosis: promoting skills and attitudes for recovery. PMID- 25554237 TI - The use of flow cytometric applications to measure the effects of PAHs on growth, membrane integrity, and relative lipid content of the benthic diatom, Nitzschia brevirostris. AB - This laboratory study measured the direct effects of three polycyclic aromatic hydrocarbon (PAH) compounds (naphthalene, pyrene, and benzo(a)pyrene) upon cell growth, membrane integrity, and BODIPY-stained lipid fluorescence intensity of the benthic diatom Nitzschia brevirostris using flow cytometry as an analysis tool. Previous field and laboratory studies have reported reductions in algal populations following PAH exposure, but specific, functional responses of the microalgae to these pollutants could not be revealed by cell numbers alone. Using flow-cytometric measurements, we confirmed that maximal cell densities in PAH exposed diatom cultures were significantly lower compared to controls; however, we also discovered increases in lipids and cells with compromised membranes in PAH-exposed cultures. These results highlight new tools for measuring the direct effects of organic pollutants upon the physiology of taxa comprising microphytobenthic communities important in estuarine food webs. PMID- 25554238 TI - Cardiac channelopathies in pediatric patients - 7-years single center experience. AB - INTRODUCTION: Channelopathies are associated with mutations of genes encoding proteins creating or interacting with the specialized ion channels in myocardial cell membranes, thus forming arrhythmogenic substrate predisposing the patient to sudden cardiac death. The study focuses the clinical and ECG presentation and management of children with channelopathies in Slovakia. SUBJECT AND METHODS: Twenty-two children with suspected channelopathy were admitted to Children's Cardiac Center Bratislava in the years 2007-2014. Genetic testing was made in 19 patients. RESULTS: Fourteen patients were symptomatic. Long QT syndrome was genetically proven in eight and catecholaminergic polymorphic ventricular tachycardia in five patients. Twenty children are treated with beta-blockers, five in combination with mexiletine or flecainide. Nine patients received implantable cardiac defibrillator and one underwent left cardiac sympathetic denervation. CONCLUSION: Both clinical presentation and genetic testing must be considered in the diagnostic and therapeutic process of channelopathies. Early diagnosis allows for adequate treatment and lifestyle modification. PMID- 25554239 TI - Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes. AB - Clofarabine, a second-generation nucleoside analog, has clinical activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of clofarabine in populations of patients not enrolled in clinical trials. We reviewed outcomes for 84 patients treated with clofarabine for relapsed or refractory AML or MDS, either with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR=CR+CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal variation in response rates when comparing different risk factors. The 30-day mortality was 21% and median survival was 3 months; a subset of 12 patients who were able to go to transplant had an 18-month median survival. Clofarabine's efficacy in a "real world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate. PMID- 25554240 TI - Short and long-term immunogenicity and safety following the 23-valent polysaccharide pneumococcal vaccine in juvenile idiopathic arthritis patients under conventional DMARDs with or without anti-TNF therapy. AB - OBJECTIVES: To assess immunogenicity and safety of the 23-valent polysaccharide pneumococcal vaccine (PPV23) in juvenile idiopathic arthritis (JIA) patients under conventional DMARDs with or without anti-TNF therapy. The influences of demographic data, disease activity and treatment on immune response and the potential deleterious effects of vaccine on disease itself were also evaluated. METHODS: 17 JIA patients immediately pre-etanercept (Group 1) and 10 JIA patients on stable dose of methotrexate (Group 2) received one dose of PPV23. All patients were evaluated pre-vaccination, 2 months and 12 months post-vaccination for seven pneumoccocal serotypes. Serology was performed by enzyme immunoassay and the immunogenicity endpoints included seroprotection (SP), seroconversion (SP) and geometric mean concentration of antibodies(GMC). Clinical and laboratorial parameters of JIA were evaluated before and after vaccination. RESULTS: Groups 1 and 2 were comparable regarding age, gender, disease duration and other DMARDs use (p>0.05). Pre-immunization SP and GMC were alike in patients with and without anti-TNF therapy (p>0.05). The frequencies of patients achieving adequate vaccine response (seroconversion in >=50% of all serotypes) at 2 months (53 vs. 30%, p=0.424) and 12 months (36 vs. 40%, p=1.0) were similar in JIA patients with and without anti-TNF therapy. Further comparison of patients with and without adequate response at 2 months revealed no influence of demographic, clinical and laboratorial JIA parameters (p>0.05). Serious adverse events were not observed. CONCLUSIONS: Anti-TNF therapy in JIA patients does not seem to have an additional deleterious effect on short/long-term PPV23 immunogenicity compared to MTX alone and no influence on disease parameters was observed with this vaccine. PMID- 25554241 TI - Protein-encapsulated bilirubin: paving the way to a useful probe for singlet oxygen. AB - When dissolved in a bulk solvent, bilirubin efficiently removes singlet molecular oxygen, O2(a(1)Deltag), through a combination of chemical reactions and by promoting the O2(a(1)Deltag)->O2(X(3)Sigmag(-)) nonradiative transition to populate the ground state of oxygen. To elucidate how such processes can be exploited in the development of a biologically useful fluorescent probe for O2(a(1)Deltag), pertinent photophysical and photochemical parameters of bilirubin encapsulated in a protein were determined. The motivation for studying a protein encapsulated system reflects the ultimate desire to (a) use genetic engineering to localize the probe at a specific location in a living cell, and (b) provide a controlled environment around the chromophore/fluorophore. Surprisingly, explicit values of oxygen- and O2(a(1)Deltag)-dependent parameters that characterize the behavior of a given chromophore/fluorophore encased in a protein are not generally available. To the end of quantifying the effects of such an encasing protein, a recently discovered bilirubin-binding protein isolated from a Japanese eel was used. The data show that this system indeed preferentially responds to O2(a(1)Deltag) and not to the superoxide ion. However, this protein not only shields bilirubin such that the rate constants for interaction with O2(a(1)Deltag) decrease relative to what is observed in a bulk solvent, but the fraction of the total O2(a(1)Deltag)-bilirubin interaction that results in a chemical reaction between O2(a(1)Deltag) and bilirubin also decreases appreciably. The rate constants thus obtained provide a useful starting point for the general design and development of reactive protein-encased fluorescent probes for O2(a(1)Deltag). PMID- 25554242 TI - DNA vaccine against infectious bursal disease virus: still more to explore. PMID- 25554243 TI - Muscovy duck reovirus infection rapidly activates host innate immune signaling and induces an effective antiviral immune response involving critical interferons. AB - Muscovy duck reovirus (MDRV) is a highly pathogenic virus in waterfowl and causes significant economic loss in the poultry industry worldwide. Because the host innate immunity plays a key role in defending against virus invasion, more and more attentions have been paid to the immune response triggered by viral infection. Here we found that the genomic RNA of MDRV was able to rapidly induce the production of interferons (IFNs) in host. Mechanistically, MDRV infection induced robust expression of IFNs in host mainly through RIG-I, MDA5 and TLR3 dependent signaling pathways. In addition, we observed that silencing VISA expression in 293T cells could significantly inhibit the secretion of IFNs. Remarkably, the production of IFNs was reduced by inhibiting the activation of NF kappaB or knocking down the expression of IRF-7. Furthermore, our study showed that treatment of 293T cells and Muscovy duck embryo fibroblasts with IFNs markedly impaired MDRV replication, suggesting that these IFNs play an important role in antiviral response during the MDRV infection. Importantly, we also detected the induced expression of RIG-I, MDA5, TLR3 and type I IFN in Muscovy ducks infected with MDRV at different time points post infection. The results from in vivo studies were consistent with those in 293T cells infected with MDRV. Taken together, our findings reveal that the host can resist MDRV invasion by activating innate immune response involving RIG-I, MDA5 and TLR3-dependent signaling pathways that govern IFN production. PMID- 25554244 TI - Prevalence and characteristics of Cyprinid herpesvirus 3 (CyHV-3) infection in common carp (Cyprinus carpio L.) inhabiting three rivers in Kochi Prefecture, Japan. AB - Cyprinid herpesvirus 3 (CyHV-3) causes lethal disease in common and koi carp. Mortality by CyHV-3 disease has not been reported since 2011 in Kochi Prefecture, Japan. Here, we detected and quantified CyHV-3 in common carp inhabiting three rivers in the prefecture to examine if the carp are carriers of CyHV-3 as a source of infection. CyHV-3 DNA was detected in 16.7% (12/72) of brain samples in Kagami River, 3.9% (3/76) of brain and 3.9% (3/76) of gill samples in Monobe River, and 5.1% (4/79) of brain and 1.3% (1/79) of gill samples in Wajiki River. CyHV-3 genotypes identified in the 23 samples were classified as the J genotype A1 that has been found in Japan. The CyHV-3 DNA load did not differ statistically between sampling months, indicating that CyHV-3 has been silent in common carp, unlike Lake Biwa where the annual reactivation occurs in spring. Taken together, our results represented definitive evidence that seasonal changes in water temperature do not affect CyHV-3 activity in carp. Considering that infectious virus was not isolated from CyHV-3 DNA-positive samples, it was suggested that CyHV-3 establishes a latent infection in carp populations inhabiting Kagami River, Monobe River and Wajiki River. Further, the presence of circular or concatameric CyHV-3 DNA was detected in five of 23 CyHV-3 DNA-positive samples. Common carp inhabiting Lake Biwa were reported previously to harbor linear but not circular CyHV-3 DNA. This difference suggested that the CyHV-3 genome may be circularized for long-term maintenance without active viral replication. PMID- 25554245 TI - Self-assembly polymorphism of 2,7-bis-nonyloxy-9-fluorenone: solvent induced the diversity of intermolecular dipole-dipole interactions. AB - In this present work, a scanning tunneling microscope (STM) operated under ambient conditions was utilized to probe the self-assembly behavior of 2,7-bis nonyloxy-9-fluorenone (F-OC9) at the liquid-solid (l/s) interface. On the highly oriented pyrolytic graphite (HOPG) surface, two-dimensional (2D) polymorphism with diversity of intermolecular dipole interactions induced by solvent was found. Solvents ranged from hydrophilic solvating properties with high polarity, such as viscous alkylated acids, to nonpolar alkylated aromatics and alkanes. 1 Octanol and dichloromethane were used to detect the assembly of F-OC9 at the gas solid (g/s) interface. The opto-electronic properties of F-OC9 were determined by UV-vis and fluorescence spectroscopy in solution. Our results showed that there were tremendous solvent-dependent self-assemblies in 2D ordering for the surface confined target molecules. When a homologous series of alkanoic acids ranging from heptanoic to nonanoic acid were employed as solvents, the self-assembled monolayer evolved from low-density coadsorbed linear lamellae to a semi-circle like pattern at relatively high concentrations, which was proven to be the thermodynamic state as it was the sole phase observed at the g/s interface after the evaporation of solvent. Moreover, by increasing the chain length of the alkylated acids, the weight of the carboxylic group, also being the group responsible for the dielectric properties, diminished from heptanoic to nonanoic acid, which could make the easier/earlier appearance of a linear coadsorption effect. However, this was not the case for nonpolar 1-phenyloctane and n tetradecane: no concentration effect was detected. It showed a strong tendency to aggregate to generate coexistence of separate domains of different phases due to the fast nucleation sites. Furthermore, thermodynamic calculations indicated that the stable structural coexistence of the fluorenone derivative was attributed to synergistic intermolecular dipole-dipole and van der Waals (vdWs) forces at l/s interface. It is believed that the results are of significance to the fields of solvent induced polymorphism assembly and surface science. PMID- 25554247 TI - Vigabatrin-induced CNS changes in juvenile rats: Induction, progression and recovery of myelin-related changes. AB - The purpose of this study was to expand on the knowledge previously published on the central nervous system effects of Vigabatrin in juvenile animals. By employing extended sectioning of the brain and by using four different tissue staining techniques it is demonstrated that oral administration of Vigabatrin to juvenile rats (treatment periods of post-natal day (PND) 4-7, 7-14 or 14-30) will cause histological CNS changes at dose levels of 15 and 50mg/kg/day, but not at a dose level of 5mg/kg/day. No evidence of neuronal degeneration or gliosis was seen at any stage of treatment. Consistent with previous reports microvacuolation, as well as effects on myelination and on oligodendrocytes were recorded. The present study expands on these findings and demonstrates that the variation in the location of the vigabatrin-induced lesions in the juvenile rat brain (both neuropil vacuolation and reduction of myelin) appears to be consistent with the process of myelination: In the youngest animals (PND 4-7) myelination occurs mainly in the hind brain (medulla oblongata and pons) where neuropil vacuolations is recorded. In animals dosed during PNDs 7-14 or during PNDs 14-30, the first changes were found in the thalamus. It seems likely that the earlier stages of myelination are more vulnerable to treatment related effects and the swollen oligodendrocytes seen as the initial change in the thalamus in animals treated during PNDs 4-7 and 7-14 represents an early stage in the development of the myelin lesion which is seen later as neuropil vacuolation. PMID- 25554246 TI - Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. AB - Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium. PMID- 25554248 TI - The impact of zinc sulfate addition on the dynamic metabolic profiling of Saccharomyces cerevisiae subjected to long term acetic acid stress treatment and identification of key metabolites involved in the antioxidant effect of zinc. AB - The mechanisms of how zinc protects the cells against acetic acid toxicity and acts as an antioxidant are still not clear. Here we present results of the metabolic profiling of the eukaryotic model yeast species Saccharomyces cerevisiae subjected to long term high concentration acetic acid stress treatment in the presence and absence of zinc supplementation. Zinc addition decreased the release of reactive oxygen species (ROS) in the presence of chronic acetic acid stress. The dynamic changes in the accumulation of intermediates in central carbon metabolism were observed, and higher contents of intracellular alanine, valine and serine were observed by zinc supplementation. The most significant change was observed in alanine content, which is 3.51-fold of that of the control culture in cells in the stationary phase. Subsequently, it was found that 0.5 g L(-1) alanine addition resulted in faster glucose consumption in the presence of 5 g L(-1) acetic acid, and apparently decreased ROS accumulation in zinc supplemented cells. This indicates that alanine exerted its antioxidant effect at least partially through the detoxification of acetic acid. In addition, intracellular glutathione (GSH) accumulation was enhanced by zinc addition, which is related to the protection of yeast cells from the oxidative injury caused by acetic acid. Our studies revealed for the first time that zinc modulates cellular amino acid metabolism and redox balance, especially biosynthesis of alanine and glutathione to exert its antioxidant effect. PMID- 25554254 TI - A facile and high-yield formation of dipyrrin-boronic acid dyads and triads: a light-harvesting system in the visible region based on the efficient energy transfer. AB - Artificial light-harvesting systems, Ar,O-BODIPY dyads and triads conjugated with a light harvester, were synthesized in high yield by the reaction of an N2O2-type dipyrrin with boronic acids. Dyad 2 having a pyrene unit underwent quantitative Forster resonance energy transfer (FRET) from the antenna unit, pyrene, to the fluorophore unit, Ar,O-BODIPY. Triads 3.5 and 4.5 were quantitatively prepared by mixing pyridine-appended compounds 3 and 4 with saloph.Zn complex 5, respectively. Triad 4.5 underwent efficient FRET from the saloph.Zn complex unit to the fluorophore unit at the rate of 2.0 * 10(11) s(-1). Interestingly, the fluorescence quenching process in the excited state of the triad 3.5 took place following the energy transfer event. Thus, appropriate positioning of the energy donor and acceptor is necessary to construct a highly efficient FRET system. PMID- 25554259 TI - Induced neural stem cells protect neuronal cells against apoptosis. AB - BACKGROUND: Neuronal cells are vulnerable to many stresses that can cause apoptosis. Reprogramming of fibroblasts into induced neural stem cells (iNSCs) is a potentially unlimited source of neurons. Discovering agents that can provide neuronal protection against these apoptotic stimuli is important for developing therapeutic strategies for various brain diseases. MATERIAL AND METHODS: We investigated the therapeutic effects of iNSCs against apoptosis activator II (AAII)-induced apoptosis of cortical neuronal cells. Apoptosis was confirmed by double immunocytochemistry with NeuN and 4',6-diamidino-2-phenylindole using terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling. We performed Western blot analyses for activated caspase-3, Bcl-2, phosphorylated Akt, and phosphorylated extracellular signal-regulated protein kinase (ERK). The level of vascular endothelial growth factor (VEGF) was analyzed using enzyme-linked immunosorbent assays (P<0.05). RESULTS: Cortical neuronal cells cultured with iNSCs had fewer apoptotic cells than those cultured without iNSCs. We found that cells cultured with iNSCs had a significantly lower caspase 3 level and a significantly higher Bcl-2 level than cells cultured without iNSCs. Cells cultured with iNSCs had higher VEGF levels than cells cultured without iNSCs. The levels of phosphorylated Akt and phosphorylated ERK were significantly higher in cells cultured with iNSCs than in cells cultured without iNSCs. CONCLUSIONS: Our findings suggest that iNSCs activate Akt and ERK, which are associated with the inhibition of neuronal apoptosis. Thus, treatment with iNSCs may help reduce neuronal loss in brain disease. Further studies aimed at proving this hypothesis might help establish therapeutic agents that can prevent neuronal cell death and help cure neurodegenerative diseases. PMID- 25554260 TI - Geographical analysis of socioeconomic factors in risk of domestic burn injury in London 2007-2013. AB - PURPOSE: This study aims to explore the geographical distribution of burn injuries in Greater London and the association of socioeconomic factors in areas at risk. METHODS: Data on burn injury cases classified as occurring in patients' own homes in Greater London and admitted to a specialised burns service for >=1 day during a 7-year period were obtained from the International Burn Injury Database (iBID). Age- and gender-adjusted standardised incidence ratios (SIRs) were calculated for each Lower Layer Super Output Area (LSOA) in Greater London. Bayesian methods were used to calculate relative risks as best estimates of spatially-smoothed SIRs. RESULTS: Of a total of 2911 admissions to specialised burns services in Greater London in the study period, 2100 (72.1%) cases occurred in patients' own homes. Percentage of ethnic minorities (p=0.005), Income Deprivation Affecting Children Index (p<0.001), Health Deprivation and Disability Score (p=0.031), percentage of families with 3 or more children (p=0.004) and Barriers to Housing and Services Score (p=0.001) remained independently associated with the relative risk of paediatric domestic burn injury in a multivariate linear regression model. Percentage of ethnic minorities (p<0.001), Health Deprivation and Disability Score (p<0.001) and Barriers to Housing and Services Score (p=0.036) remained independently associated with the relative risk of adult domestic burn injury in a multivariate linear regression model. CONCLUSIONS: Socioeconomic factors are associated with an increased risk of burn injury in Greater London, but may be more important in children than adults. The specific factors identified are ethnicity, poor general health, household structure, housing issues and income deprivation affecting children. PMID- 25554261 TI - A topical aqueous oxygen emulsion stimulates granulation tissue formation in a porcine second-degree burn wound. AB - BACKGROUND: Oxygen is an essential substance for wound healing. Limited studies have shown that topical oxygen can influence healing. This study evaluated the effects of a Topical Oxygen Emulsion (TOE) on burn wound healing. METHODS: A porcine second-degree burn wound model was used in the study. Burn wounds were randomly assigned to TOE, vehicle control, and no-treatment (air) groups. Effects of TOE on the granulation tissue formation and angiogenesis were studied using hematoxylin and eosin histological analysis. Protein production and gene expression of types I and III collagen and vascular endothelial growth factor (VEGF) were determined using immunofluorescent staining and Reverse Transcription and Polymerase Chain Reaction (RT-PCR), respectively. RESULTS: The TOE treated wounds exhibited better angiogenesis and granulation tissue formation by histology examination. The immunofluorescence staining and RT-PCR analysis demonstrated that protein production and mRNA expression of VEGF and collagen III were significantly higher in TOE treatment group than vehicle alone and air control groups, while there was no significant difference in the level of collagen I. CONCLUSIONS: Our data demonstrate that TOE enhances burn wound healing via stimulating the expression of VEGF and type III collagen and strongly indicates the potential use of TOE in wounds. PMID- 25554262 TI - The responsiveness of the Chelsea Critical Care Physical Assessment tool in measuring functional recovery in the burns critical care population: an observational study. AB - INTRODUCTION: Severe burn leads to a state of hypercatabolism, resulting in rapid muscle loss and long-term disability. As survival rates from severe burn are improving, early rehabilitation is essential to facilitate functional recovery. However, there is no way of measuring the degree of disability in the acute stages, and hence, no marker of functional recovery. This hampers both communication and research into interventions to improve functional outcomes. The Chelsea Critical Care Physical Assessment tool (CPAx) is a simple objective measure of function, designed and validated in the general Intensive Care Unit (ICU) cohort. The aim of this study was to test the responsiveness of the CPAx in the burns ICU (BICU) cohort and validate its use. METHODS: Observational study of 52 BICU patients admitted for over 48h. All patients were assessed on the CPAx retrospectively for pre-admission, and prospectively at ICU admission, ICU discharge (or final ICU assessment for non-survivors) and hospital discharge. Analysis of variance, post hoc between group differences in median CPAx score, and floor and ceiling effect (i.e. the percentage of patients scoring full marks (50), or zero) for the four time points were completed. Minimal clinically important difference (MCID) was estimated as half of the standard deviation of the CPAx score at ICU discharge. RESULTS: A total of 30 patients were included in the final analysis; mean age was 47.1 years (SD 21.2), 63.3% were male, with a median burn total body surface area (TBSA) of 30% (IQR 11.3-48.8). There was a significant difference in the analysis of variance in median CPAx scores at all four time points (p<.001). In survivors, the differences in CPAx scores post hoc were significant for all time points (p<.05), aside from ICU discharge and hospital discharge. The CPAx MCID for BICU patients was six. Twenty-three (86.7%) patients scored full marks or zero on the CPAx pre-admission. For survivors, no patients scored full marks or zero on the CPAx at ICU and hospital discharge. On ICU admission 66.7% (n=20) scored zero on the CPAx and no patients scored 50. CONCLUSIONS: The CPAx score appears to be able to detect improvements in physical function as patients recover from acute severe burn. It has a limited floor and ceiling effect in the acute setting and a change in CPAx score of 6 represents clinically important progress. Further work is required in a larger cohort. PMID- 25554264 TI - Invited Article: Autonomous assembly of atomically perfect nanostructures using a scanning tunneling microscope. AB - A major goal of nanotechnology is to develop the capability to arrange matter at will by placing individual atoms at desired locations in a predetermined configuration to build a nanostructure with specific properties or function. The scanning tunneling microscope has demonstrated the ability to arrange the basic building blocks of matter, single atoms, in two-dimensional configurations. An array of various nanostructures has been assembled, which display the quantum mechanics of quantum confined geometries. The level of human interaction needed to physically locate the atom and bring it to the desired location limits this atom assembly technology. Here we report the use of autonomous atom assembly via path planning technology; this allows atomically perfect nanostructures to be assembled without the need for human intervention, resulting in precise constructions in shorter times. We demonstrate autonomous assembly by assembling various quantum confinement geometries using atoms and molecules and describe the benefits of this approach. PMID- 25554263 TI - [Study of the effects of the implementation of a human milk donor bank in preterm newborns in Aragon]. AB - INTRODUCTION: Numerous obstacles may prevent a premature or sick neonate receiving their mother's milk. In these cases, pediatric scientific societies recommend feeding with donor human milk. In this article, it is explained what a milk bank is, how it works, the donors' selection method, and the benefits. We also describe the current situation in Aragon (Spain) is also described. MATERIAL AND METHODS: A retrospective and descriptive study was conducted on the perinatal sample characteristics, as well as an analytical observational study, comparing two sample groups: pre- and post-human milk bank. Finally, differences in the post-bank stage between those patients fed with own-mother's or donor human milk were determined. RESULTS: The study included a total of 234 patients: 104 females and 130 males. Two groups: pre and post-bank, with 152 and 82 patients, respectively, which had similar characteristics at birth; length and head circumference were significantly higher in the post-bank group and a lower rate of necrotizing enterocolitis was also found. No statistically significant differences were found in other variables between subgroups fed with own-mother's milk and donor human milk. DISCUSSION: The establishment of the human milk donor bank has a beneficial effect, as it reduces neonatal morbidity in cases of necrotizing enterocolitis. Human milk feeding could be a protective factor against neonatal sepsis due to improve immunity. CONCLUSIONS: The incidence of necrotizing enterocolitis is lower after the establishment of the milk bank. Studies with more patients may demonstrate differences in other variables. PMID- 25554265 TI - Contributed Review: The feasibility of a fully miniaturized magneto-optical trap for portable ultracold quantum technology. AB - Experiments using laser cooled atoms and ions show real promise for practical applications in quantum-enhanced metrology, timing, navigation, and sensing as well as exotic roles in quantum computing, networking, and simulation. The heart of many of these experiments has been translated to microfabricated platforms known as atom chips whose construction readily lend themselves to integration with larger systems and future mass production. To truly make the jump from laboratory demonstrations to practical, rugged devices, the complex surrounding infrastructure (including vacuum systems, optics, and lasers) also needs to be miniaturized and integrated. In this paper we explore the feasibility of applying this approach to the Magneto-Optical Trap; incorporating the vacuum system, atom source and optical geometry into a permanently sealed micro-litre system capable of maintaining 10(-10) mbar for more than 1000 days of operation with passive pumping alone. We demonstrate such an engineering challenge is achievable using recent advances in semiconductor microfabrication techniques and materials. PMID- 25554266 TI - Two-color interferometer for the study of laser filamentation triggered electric discharges in air. AB - We present a space and time resolved interferometric plasma diagnostic for use on plasmas where neutral-bound electron contribution to the refractive index cannot be neglected. By recording simultaneously the plasma optical index at 532 and 1064 nm, we are able to extract independently the neutral and free electron density profiles. We report a phase resolution of 30 mrad , corresponding to a maximum resolution on the order of 4*10(22) m(-3) for the electron density, and of 10(24) m(-3) for the neutral density. The interferometer is demonstrated on centimeter-scale sparks triggered by laser filamentation in air with typical currents of a few tens of A. PMID- 25554267 TI - Photon counting imaging with an electron-bombarded CCD: towards a parallel processing photoelectronic time-to-amplitude converter. AB - We have used an electron-bombarded CCD for optical photon counting imaging. The photon event pulse height distribution was found to be linearly dependent on the gain voltage. We propose on this basis that a gain voltage sweep during exposure in an electron-bombarded sensor would allow photon arrival time determination with sub-frame exposure time resolution. This effectively uses an electron bombarded sensor as a parallel-processing photoelectronic time-to-amplitude converter, or a two-dimensional photon counting streak camera. Several applications that require timing of photon arrival, including Fluorescence Lifetime Imaging Microscopy, may benefit from such an approach. A simulation of a voltage sweep performed with experimental data collected with different acceleration voltages validates the principle of this approach. Moreover, photon event centroiding was performed and a hybrid 50% Gaussian/Centre of Gravity + 50% Hyperbolic cosine centroiding algorithm was found to yield the lowest fixed pattern noise. Finally, the camera was mounted on a fluorescence microscope to image F-actin filaments stained with the fluorescent dye Alexa 488 in fixed cells. PMID- 25554268 TI - Design and development of an in-line sputtering system and process development of thin film multilayer neutron supermirrors. AB - Neutron supermirrors and supermirror polarizers are thin film multilayer based devices which are used for reflecting and polarizing neutrons in various neutron based experiments. In the present communication, the in-house development of a 9 m long in-line dc sputtering system has been described which is suitable for deposition of neutron supermirrors on large size (1500 mm * 150 mm) substrates and in large numbers. The optimisation process of deposition of Co and Ti thin film, Co/Ti periodic multilayers, and a-periodic supermirrors have also been described. The system has been used to deposit thin film multilayer supermirror polarizers which show high reflectivity up to a reasonably large critical wavevector transfer of ~0.06 A(-1) (corresponding to m = 2.5, i.e., 2.5 times critical wavevector transfer of natural Ni). The computer code for designing these supermirrors has also been developed in-house. PMID- 25554269 TI - Optimizations of spin-exchange relaxation-free magnetometer based on potassium and rubidium hybrid optical pumping. AB - The hybrid optical pumping atomic magnetometers have not realized its theoretical sensitivity, the optimization is critical for optimal performance. The optimizations proposed in this paper are suitable for hybrid optical pumping atomic magnetometer, which contains two alkali species. To optimize the parameters, the dynamic equations of spin evolution with two alkali species were solved, whose steady-state solution is used to optimize the parameters. The demand of the power of the pump beam is large for hybrid optical pumping. Moreover, the sensitivity of the hybrid optical pumping magnetometer increases with the increase of the power density of the pump beam. The density ratio between the two alkali species is especially important for hybrid optical pumping magnetometer. A simple expression for optimizing the density ratio is proposed in this paper, which can help to determine the mole faction of the alkali atoms in fabricating the hybrid cell before the cell is sealed. The spin-exchange rate between the two alkali species is proportional to the saturated density of the alkali vapor, which is highly dependent on the temperature of the cell. Consequently, the sensitivity of the hybrid optical pumping magnetometer is dependent on the temperature of the cell. We proposed the thermal optimization of the hybrid cell for a hybrid optical pumping magnetometer, which can improve the sensitivity especially when the power of the pump beam is low. With these optimizations, a sensitivity of approximately 5 fT/Hz(1/2) is achieved with gradiometer arrangement. PMID- 25554270 TI - Resonant third harmonic generation of KrF laser in Ar gas. AB - Investigations of emission of harmonics from argon gas jet irradiated by 700 fs, 5 mJ pulses from a KrF laser are presented. Harmonics conversion was optimized by varying the experimental geometry and the nozzle size. For the collection of the harmonic radiation silicon and solar-blind diamond semiconductor detectors equipped with charge preamplifiers were applied. The possibility of using a single-crystal CVD diamond detector for separate measurement of the 3rd harmonic in the presence of a strong pumping radiation was explored. Our experiments show that the earlier suggested 0.7% conversion efficiency can really be obtained, but only in the case when phase matching is optimized with an elongated gas target length corresponding to the length of coherence. PMID- 25554271 TI - High-order harmonic generation using a high-repetition-rate turnkey laser. AB - We generate high-order harmonics at high pulse repetition rates using a turnkey laser. High-order harmonics at 400 kHz are observed when argon is used as target gas. In neon, we achieve generation of photons with energies exceeding 90 eV (~13 nm) at 20 kHz. We measure a photon flux of up to 4.4 * 10(10) photons per second per harmonic in argon at 100 kHz. Many experiments employing high-order harmonics would benefit from higher repetition rates, and the user-friendly operation opens up for applications of coherent extreme ultra-violet pulses in new research areas. PMID- 25554272 TI - Two-dimensional electronic spectroscopy with birefringent wedges. AB - We present a simple experimental setup for performing two-dimensional (2D) electronic spectroscopy in the partially collinear pump-probe geometry. The setup uses a sequence of birefringent wedges to create and delay a pair of phase locked, collinear pump pulses, with extremely high phase stability and reproducibility. Continuous delay scanning is possible without any active stabilization or position tracking, and allows to record rapidly and easily 2D spectra. The setup works over a broad spectral range from the ultraviolet to the near-IR, it is compatible with few-optical-cycle pulses and can be easily reconfigured to two-colour operation. A simple method for scattering suppression is also introduced. As a proof of principle, we present degenerate and two-color 2D spectra of the light-harvesting complex 1 of purple bacteria. PMID- 25554273 TI - Digital signal processor-based high-precision on-line Voigt lineshape fitting for direct absorption spectroscopy. AB - To realize on-line high-accuracy measurement in direct absorption spectroscopy (DAS), a system-on-chip, high-precision digital signal processor-based on-line Voigt lineshape fitting implementation is introduced in this paper. Given that the Voigt lineshape is determined by the Gauss full width at half maximum (FWHM) and Lorentz FWHM, a look-up table, which covers a range of combinations of both, is first built to achieve rapid and accurate calculation of Voigt lineshape. With the look-up table and raw absorbance data in hand, Gauss-Newton nonlinear fitting module is implemented to obtain the parameters including both the Gauss and Lorentz FWHMs, which can be used to calculate the integrated absorbance. To realize the proposed method in hardware, a digital signal processor (DSP) is adopted to fit the Voigt lineshape in a real-time DAS measurement system. In experiment, temperature and H2O concentration of a flat flame are recovered from the transitions of 7444.36 cm(-1) and 7185.6 cm(-1) by the DSP-based on-line Voigt lineshape fitting and on-line integral of the raw absorbance, respectively. The results show that the proposed method can not only fit the Voigt lineshape on line but also improve the measurement accuracy compared with those obtained from the direct integral of the raw absorbance. PMID- 25554275 TI - Digitized detection of gamma-ray signals concentrated in narrow time windows for transient positron annihilation lifetime spectroscopy. AB - A pulsed slow-positron beam generated by an electron linear accelerator was directly used for positron annihilation lifetime spectroscopy without any positron storage devices. A waveform digitizer was introduced to simultaneously capture multiple gamma-ray signals originating from positron annihilation events during a single accelerator pulse. The positron pulse was chopped and bunched with the chopper signals also sent to the waveform digitizer. Time differences between the annihilation gamma-ray and chopper peaks were calculated and accumulated as lifetime spectra in a computer. The developed technique indicated that positron annihilation lifetime spectroscopy can be performed in a 20 MUs time window at a pulse repetition rate synchronous with the linear accelerator. Lifetime spectra of a Kapton sheet and a thermally grown SiO2 layer on Si were successfully measured. Synchronization of positron lifetime measurements with pulsed ion irradiation was demonstrated by this technique. PMID- 25554274 TI - An ion mobility mass spectrometer for investigating photoisomerization and photodissociation of molecular ions. AB - An ion mobility mass spectrometry apparatus for investigating the photoisomerization and photodissociation of electrosprayed molecular ions in the gas phase is described. The device consists of a drift tube mobility spectrometer, with access for a laser beam that intercepts the drifting ion packet either coaxially or transversely, followed by a quadrupole mass filter. An ion gate halfway along the drift region allows the instrument to be used as a tandem ion mobility spectrometer, enabling mobility selection of ions prior to irradiation, with the photoisomer ions being separated over the second half of the drift tube. The utility of the device is illustrated with photoisomerization and photodissociation action spectra of carbocyanine molecular cations. The mobility resolution of the device for singly charged ions is typically 80 and it has a mass range of 100-440 Da, with the lower limit determined by the drive frequency for the ion funnels, and the upper limit by the quadrupole mass filter. PMID- 25554276 TI - Multichannel photodiode detector for ultrafast optical spectroscopy. AB - Construction and characterization of a multichannel photodiode detector based on commercially available components with high signal to noise of ~10(6) and a rapid frame rate, suitable for time resolved femtosecond spectroscopy with high repetition femtosecond sources, is presented. PMID- 25554277 TI - Microcontroller-based locking in optics experiments. AB - Optics experiments critically require the stable and accurate locking of relative phases between light beams or the stabilization of Fabry-Perot cavity lengths. Here, we present a simple and inexpensive technique based on a stand-alone microcontroller unit to perform such tasks. Easily programmed in C language, this reconfigurable digital locking system also enables automatic relocking and sequential functioning. Different algorithms are detailed and applied to fringe locking and to low- and high-finesse optical cavity stabilization, without the need of external modulations or error signals. This technique can readily replace a number of analog locking systems advantageously in a variety of optical experiments. PMID- 25554278 TI - A Mach-Zender digital holographic microscope with sub-micrometer resolution for imaging and tracking of marine micro-organisms. AB - Digital holographic microscopy is an ideal tool for investigation of microbial motility. However, most designs do not exhibit sufficient spatial resolution for imaging bacteria. In this study we present an off-axis Mach-Zehnder design of a holographic microscope with spatial resolution of better than 800 nm and the ability to resolve bacterial samples at varying densities over a 380 MUm * 380 MUm * 600 MUm three-dimensional field of view. Larger organisms, such as protozoa, can be resolved in detail, including cilia and flagella. The instrument design and performance are presented, including images and tracks of bacterial and protozoal mixed samples and pure cultures of six selected species. Organisms as small as 1 MUm (bacterial spores) and as large as 60 MUm (Paramecium bursaria) may be resolved and tracked without changes in the instrument configuration. Finally, we present a dilution series investigating the maximum cell density that can be imaged, a type of analysis that has not been presented in previous holographic microscopy studies. PMID- 25554279 TI - A force calibration standard for magnetic tweezers. AB - To study the behavior of biological macromolecules and enzymatic reactions under force, advances in single-molecule force spectroscopy have proven instrumental. Magnetic tweezers form one of the most powerful of these techniques, due to their overall simplicity, non-invasive character, potential for high throughput measurements, and large force range. Drawbacks of magnetic tweezers, however, are that accurate determination of the applied forces can be challenging for short biomolecules at high forces and very time-consuming for long tethers at low forces below ~1 piconewton. Here, we address these drawbacks by presenting a calibration standard for magnetic tweezers consisting of measured forces for four magnet configurations. Each such configuration is calibrated for two commonly employed commercially available magnetic microspheres. We calculate forces in both time and spectral domains by analyzing bead fluctuations. The resulting calibration curves, validated through the use of different algorithms that yield close agreement in their determination of the applied forces, span a range from 100 piconewtons down to tens of femtonewtons. These generalized force calibrations will serve as a convenient resource for magnetic tweezers users and diminish variations between different experimental configurations or laboratories. PMID- 25554280 TI - Absolute determination of photoluminescence quantum efficiency using an integrating sphere setup. AB - An integrating sphere-based setup to obtain a quick and reliable determination of the internal quantum efficiency of strongly scattering luminescent materials is presented. In literature, two distinct but similar measurement procedures are frequently mentioned: a "two measurement" and a "three measurement" approach. Both methods are evaluated by applying the rigorous integrating sphere theory. It was found that both measurement procedures are valid. Additionally, the two methods are compared with respect to the uncertainty budget of the obtained values of the quantum efficiency. An inter-laboratory validation using the two distinct procedures was performed. The conclusions from the theoretical study were confirmed by the experimental data. PMID- 25554281 TI - Self-consistent iteration procedure in analyzing reflectivity and spectroscopic ellipsometry data of multilayered materials and their interfaces. AB - For multilayered materials, reflectivity depends on the complex dielectric function of all the constituent layers, and a detailed analysis is required to separate them. Furthermore, for some cases, new quantum states can occur at the interface which may change the optical properties of the material. In this paper, we discuss various aspects of such analysis, and present a self-consistent iteration procedure, a versatile method to extract and separate the complex dielectric function of each individual layer of a multilayered system. As a case study, we apply this method to LaAlO3/SrTiO3 heterostructure in which we are able to separate the effects of the interface from the LaAlO3 film and the SrTiO3 substrate. Our method can be applied to other complex multilayered systems with various numbers of layers. PMID- 25554282 TI - Horn-coupled, commercially-fabricated aluminum lumped-element kinetic inductance detectors for millimeter wavelengths. AB - We discuss the design, fabrication, and testing of prototype horn-coupled, lumped element kinetic inductance detectors (LEKIDs) designed for cosmic microwave background studies. The LEKIDs are made from a thin aluminum film deposited on a silicon wafer and patterned using standard photolithographic techniques at STAR Cryoelectronics, a commercial device foundry. We fabricated 20-element arrays, optimized for a spectral band centered on 150 GHz, to test the sensitivity and yield of the devices as well as the multiplexing scheme. We characterized the detectors in two configurations. First, the detectors were tested in a dark environment with the horn apertures covered, and second, the horn apertures were pointed towards a beam-filling cryogenic blackbody load. These tests show that the multiplexing scheme is robust and scalable, the yield across multiple LEKID arrays is 91%, and the measured noise-equivalent temperatures for a 4 K optical load are in the range 26+/-6 MUK?s. PMID- 25554283 TI - Transport of radioactive ion beams and related safety issues: the 132Sn+ case study. AB - The transport of intense radioactive ion beam currents requires a careful design in order to limit the beam losses, the contamination and thus the dose rates. Some investigations based on numerical models and calculations have been performed in the framework of the SPIRAL 2 project to evaluate the performance of a low energy beam transport line located between the isotope separation on line (ISOL) production cell and the experiment areas. The paper presents the results of the transverse phase-space analysis, the beam losses assessment, the resulting contamination, and radioactivity levels. They show that reasonable beam transmission, emittance growth, and dose rates can be achieved considering the current standards. PMID- 25554284 TI - Study of beam loading and its compensation in the Compact Ultrafast Terahertz Free-Electron Laser injector linac. AB - The RF properties of an accelerating structure, and the pulse structure and charge per bunch in the electron beam propagating through it are important parameters that determine the impact of beam loading in the structure. The injector linac of the Compact Ultrafast Terahertz Free-Electron Laser (CUTE-FEL) has been operated with two different pulse structures during initial commissioning experiments and the effect of beam loading on the accelerated electron beam parameters has been studied analytically for these two pulse structures. This paper discusses the analytical study of beam loading in a Standing Wave, Plane Wave Transformer linac employed in the CUTE-FEL setup, and a possible technique for its compensation for the electron beam parameters of the CUTE-FEL. A parametric study has been performed to study beam loading for different beam currents and to optimize injection time of the electron beam to compensate beam loading. Results from the parametric study have also been used to explain previously observed results from acceleration experiments in the CUTE-FEL setup. PMID- 25554285 TI - Coincidence ion imaging with a fast frame camera. AB - A new time- and position-sensitive particle detection system based on a fast frame CMOS (complementary metal-oxide semiconductors) camera is developed for coincidence ion imaging. The system is composed of four major components: a conventional microchannel plate/phosphor screen ion imager, a fast frame CMOS camera, a single anode photomultiplier tube (PMT), and a high-speed digitizer. The system collects the positional information of ions from a fast frame camera through real-time centroiding while the arrival times are obtained from the timing signal of a PMT processed by a high-speed digitizer. Multi-hit capability is achieved by correlating the intensity of ion spots on each camera frame with the peak heights on the corresponding time-of-flight spectrum of a PMT. Efficient computer algorithms are developed to process camera frames and digitizer traces in real-time at 1 kHz laser repetition rate. We demonstrate the capability of this system by detecting a momentum-matched co-fragments pair (methyl and iodine cations) produced from strong field dissociative double ionization of methyl iodide. PMID- 25554286 TI - Multi-purpose two- and three-dimensional momentum imaging of charged particles for attosecond experiments at 1 kHz repetition rate. AB - We report on the versatile design and operation of a two-sided spectrometer for the imaging of charged-particle momenta in two dimensions (2D) and three dimensions (3D). The benefits of 3D detection are to discern particles of different mass and to study correlations between fragments from multi-ionization processes, while 2D detectors are more efficient for single-ionization applications. Combining these detector types in one instrument allows us to detect positive and negative particles simultaneously and to reduce acquisition times by using the 2D detector at a higher ionization rate when the third dimension is not required. The combined access to electronic and nuclear dynamics available when both sides are used together is important for studying photoreactions in samples of increasing complexity. The possibilities and limitations of 3D momentum imaging of electrons or ions in the same spectrometer geometry are investigated analytically and three different modes of operation demonstrated experimentally, with infrared or extreme ultraviolet light and an atomic/molecular beam. PMID- 25554287 TI - A reconsideration of the noise equivalent power and the data analysis procedure for the infrared imaging video bolometers. AB - The infrared imaging video bolometer (IRVB) used for measurement of the two dimensional (2D) radiation profiles from the Large Helical Device has been significantly upgraded recently to improve its signal to noise ratio, sensitivity, and calibration, which ultimately provides quantitative measurements of the radiation from the plasma. The reliability of the quantified data needs to be established by various checks. The noise estimates also need to be revised and more realistic values need to be established. It is shown that the 2D heat diffusion equation can be used for estimating the power falling on the IRVB foil, even with a significant amount of spatial variation in the thermal diffusivity across the area of the platinum foil found experimentally during foil calibration. The equation for the noise equivalent power density (NEPD) is re derived to include the errors in the measurement of the thermophysical and the optical properties of the IRVB foil. The theoretical value estimated using this newly derived equation matches closely, within 5.5%, with the mean experimental value. The change in the contribution of each error term of the NEPD equation with rising foil temperature is also studied and the blackbody term is found to dominate the other terms at elevated operating temperatures. The IRVB foil is also sensitive to the charge exchange (CX) neutrals escaping from the plasma. The CX neutral contribution is estimated to be marginally higher than the noise equivalent power (NEP) of the IRVB. It is also established that the radiation measured by the IRVB originates from the impurity line radiation from the plasma and not from the heated divertor tiles. The change in the power density due to noise reduction measures such as data smoothing and averaging is found to be comparable to the IRVB NEPD. The precautions that need to be considered during background subtraction are also discussed with experimental illustrations. Finally, the analysis algorithm with all the improvements is validated and found to reproduce the input power well within 10% accuracy. This article answers many fundamental questions relevant to the IRVB and illustrates the care to be exercised while processing the IRVB data. PMID- 25554288 TI - A real-time laser feedback control method for the three-wave laser source used in the polarimeter-interferometer diagnostic on Joint-TEXT tokamak. AB - A three-wave laser polarimeter-interferometer, equipped with three independent far-infrared laser sources, has been developed on Joint-TEXT (J-TEXT) tokamak. The diagnostic system is capable of high-resolution temporal and phase measurement of the Faraday angle and line-integrated density. However, for long term operation (>10 min), the free-running lasers can lead to large drifts of the intermediate frequencies (~100-~500 kHz/10 min) and decay of laser power (~10% ~20%/10 min), which act to degrade diagnostic performance. In addition, these effects lead to increased maintenance cost and limit measurement applicability to long pulse/steady state experiments. To solve this problem, a real-time feedback control method of the laser source is proposed. By accurately controlling the length of each laser cavity, both the intermediate frequencies and laser power can be simultaneously controlled: the intermediate frequencies are controlled according to the pre-set values, while the laser powers are maintained at an optimal level. Based on this approach, a real-time feedback control system has been developed and applied on J-TEXT polarimeter-interferometer. Long-term (theoretically no time limit) feedback of intermediate frequencies (maximum change less than +/-12 kHz) and laser powers (maximum relative power change less than +/-7%) has been successfully achieved. PMID- 25554289 TI - Divertor impurity injection using high voltage arcs for impurity transport studies on the Mega Amp Spherical Tokamak. AB - The operation of next-generation fusion reactors will be significantly affected by impurity transport in the scrape-off layer (SOL). Current modelling efforts are restricted by a lack of detailed data on impurity transport in the SOL. In order to address this, a carbon injector has been designed and installed on the Mega Amp Spherical Tokamak (MAST). The injector creates short lived carbon plumes originating at the MAST divertor lasting less than 50 MUs. High voltage capacitor banks are used to create a discharge across concentric carbon electrodes located in a probe mounted on the Divertor Science Facility in the MAST lower divertor. This results in a very short plume duration allowing observation of the evolution of the plume and precise localisation of the plume relative to the X-point on MAST. The emission from the carbon plume was imaged using fast visible cameras filtered in order to isolate the carbon II and carbon III emission lines centered around 514 nm and 465 nm. PMID- 25554290 TI - Automated electrostatic probe device of high resolution and accuracy. AB - In this work, an automated apparatus for driving single electrostatic probes and acquiring the plasma-related data has been designed and fabricated. The voltage range of the present system is +/-110 V with an adjustable voltage step as low as 3 mV. Voltage and current measurements are carried out with high resolution and high accuracy circuits, both based on 16 bit analog-to-digital converters. The code embedded in a micro-controller, schedules the operation of the device and transfers the experimental data to a personal computer. The modular design of the system makes possible its modification and thus increases its adaptability to different plasma setups. Finally, the reliable operation of the entire device is confirmed by tests in Electron Cyclotron Resonance plasma. PMID- 25554291 TI - Characterization of solid state nuclear track detectors of the polyallyl-diglycol carbonate (CR-39/PM-355) type for light charged particle spectroscopy. AB - This paper presents a method which uses the characteristics of the etch pits induced in a polyallyl-diglycol-carbonate (PADC) detector of the CR-39/PM-355 type to estimate particle energy. This method is based on the data provided by a semiautomatic system that selects tracks according to two parameters, crater diameters, and mean gray level values. In this paper we used the results of the calibration measurements that were obtained in our laboratory in the period 2000 2014. Combining the information on the two parameters it is possible to determine unambiguously the incident projectile energy values. The paper presents the results of an attempt to estimate the energy resolution of the method when analyzing the tracks produced in the CR-39/PM-355 detector by energetic ions such as alpha particles, protons, and deuterons. We discuss the energy resolution of the measurement of light charged particle energy which is based on the parameters (crater diameter and mean gray level value) of tracks induced in solid state nuclear track detectors of the PADC type. PMID- 25554292 TI - Self characterization of a coded aperture array for neutron source imaging. AB - The neutron imaging system at the National Ignition Facility (NIF) is an important diagnostic tool for measuring the two-dimensional size and shape of the neutrons produced in the burning deuterium-tritium plasma during the stagnation stage of inertial confinement fusion implosions. Since the neutron source is small (~100 MUm) and neutrons are deeply penetrating (>3 cm) in all materials, the apertures used to achieve the desired 10-MUm resolution are 20-cm long, triangular tapers machined in gold foils. These gold foils are stacked to form an array of 20 apertures for pinhole imaging and three apertures for penumbral imaging. These apertures must be precisely aligned to accurately place the field of view of each aperture at the design location, or the location of the field of view for each aperture must be measured. In this paper we present a new technique that has been developed for the measurement and characterization of the precise location of each aperture in the array. We present the detailed algorithms used for this characterization and the results of reconstructed sources from inertial confinement fusion implosion experiments at NIF. PMID- 25554293 TI - Improved equilibrium reconstructions by advanced statistical weighting of the internal magnetic measurements. AB - In a Tokamak the configuration of the magnetic fields remains the key element to improve performance and to maximise the scientific exploitation of the device. On the other hand, the quality of the reconstructed fields depends crucially on the measurements available. Traditionally in the least square minimisation phase of the algorithms, used to obtain the magnetic field topology, all the diagnostics are given the same weights, a part from a corrective factor taking into account the error bars. This assumption unduly penalises complex diagnostics, such as polarimetry, which have a limited number of highly significant measurements. A completely new method to choose the weights, to be given to the internal measurements of the magnetic fields for improved equilibrium reconstructions, is presented in this paper. The approach is based on various statistical indicators applied to the residuals, the difference between the actual measurements and their estimates from the reconstructed equilibrium. The potential of the method is exemplified using the measurements of the Faraday rotation derived from JET polarimeter. The results indicate quite clearly that the weights have to be determined carefully, since the inappropriate choice can have significant repercussions on the quality of the magnetic reconstruction both in the edge and in the core. These results confirm the limitations of the assumption that all the diagnostics have to be given the same weight, irrespective of the number of measurements they provide and the region of the plasma they probe. PMID- 25554294 TI - Design of set-point weighting PIlambda + DMU controller for vertical magnetic flux controller in Damavand tokamak. AB - In this paper, a simple method is presented for tuning weighted PI(lambda) + D(MU) controller parameters based on the pole placement controller of pseudo second-order fractional systems. One of the advantages of this controller is capability of reducing the disturbance effects and improving response to input, simultaneously. In the following sections, the performance of this controller is evaluated experimentally to control the vertical magnetic flux in Damavand tokamak. For this work, at first a fractional order model is identified using output-error technique in time domain. For various practical experiments, having desired time responses for magnetic flux in Damavand tokamak, is vital. To approach this, at first the desired closed loop reference models are obtained based on generalized characteristic ratio assignment method in fractional order systems. After that, for the identified model, a set-point weighting PI(lambda) + D(MU) controller is designed and simulated. Finally, this controller is implemented on digital signal processor control system of the plant to fast/slow control of magnetic flux. The practical results show appropriate performance of this controller. PMID- 25554295 TI - Simultaneous measurement of anisotropic magnetoresistance and observation of magnetic domains by Kerr microscopy. AB - We report on a new instrument, which consists of a Kerr microscope combined with resistance measurements. This setup allows for the recording of magnetic domains while measuring the anisotropic magnetoresistance (AMR). For this purpose the development of a special sample holder and the extension of the measurement software was required. The sample holder is equipped with electrical contacts in such a way to apply a current, measure the voltage, and use it in the Kerr microscope. The extension of the measurement software enables the recording of resistance and Kerr images simultaneous. The new setup allows for a better microscopic understanding of the AMR behavior. PMID- 25554296 TI - A versatile LabVIEW and field-programmable gate array-based scanning probe microscope for in operando electronic device characterization. AB - Understanding the complex properties of electronic and spintronic devices at the micro- and nano-scale is a topic of intense current interest as it becomes increasingly important for scientific progress and technological applications. In operando characterization of such devices by scanning probe techniques is particularly well-suited for the microscopic study of these properties. We have developed a scanning probe microscope (SPM) which is capable of both standard force imaging (atomic, magnetic, electrostatic) and simultaneous electrical transport measurements. We utilize flexible and inexpensive FPGA (field programmable gate array) hardware and a custom software framework developed in National Instrument's LabVIEW environment to perform the various aspects of microscope operation and device measurement. The FPGA-based approach enables sensitive, real-time cantilever frequency-shift detection. Using this system, we demonstrate electrostatic force microscopy of an electrically biased graphene field-effect transistor device. The combination of SPM and electrical transport also enables imaging of the transport response to a localized perturbation provided by the scanned cantilever tip. Facilitated by the broad presence of LabVIEW in the experimental sciences and the openness of our software solution, our system permits a wide variety of combined scanning and transport measurements by providing standardized interfaces and flexible access to all aspects of a measurement (input and output signals, and processed data). Our system also enables precise control of timing (synchronization of scanning and transport operations) and implementation of sophisticated feedback protocols, and thus should be broadly interesting and useful to practitioners in the field. PMID- 25554297 TI - Microscopic diamond solid-immersion-lenses fabricated around single defect centers by focused ion beam milling. AB - Recent efforts to define microscopic solid-immersion-lenses (SIL) by focused ion beam milling into diamond substrates that are registered to a preselected single photon emitter are summarized. We show how we determine the position of a single emitter with at least 100 nm lateral and 500 nm axial accuracy, and how the milling procedure is optimized. The characteristics of a single emitter, a Nitrogen Vacancy (NV) center in diamond, are measured before and after producing the SIL and compared with each other. A count rate of 1.0 * 10(6) counts/s is achieved with a [111] oriented NV center. PMID- 25554298 TI - Atomic force microscopy deep trench and sidewall imaging with an optical fiber probe. AB - We report a method to measure critical dimensions of micro- and nanostructures using the atomic force microscope (AFM) with an optical fiber probe (OFP). This method is capable of scanning narrow and deep trenches due to the long and thin OFP tip, as well as imaging of steep sidewalls with unique profiling possibilities by laterally tilting the OFP without any modifications of the optical lever. A switch control scheme is developed to measure the sidewall angle by flexibly transferring feedback control between the Z- and Y-axis, for a serial scan of the horizontal surface (raster scan on XY-plane) and sidewall (raster scan on the YZ-plane), respectively. In experiments, a deep trench with tapered walls (243.5 MUm deep) and a microhole (about 14.9 MUm deep) have been imaged with the orthogonally aligned OFP, as well as a silicon sidewall (fabricated by deep reactive ion etching) has been characterized with the tilted OFP. Moreover, the sidewall angle of TGZ3 (AFM calibration grating) was accurately measured using the switchable scan method. PMID- 25554299 TI - High-speed tapping-mode atomic force microscopy using a Q-controlled regular cantilever acting as the actuator: proof-of-principle experiments. AB - We present the proof-of-principle experiments of a high-speed actuation method to be used in tapping-mode atomic force microscopes (AFM). In this method, we do not employ a piezotube actuator to move the tip or the sample as in conventional AFM systems, but, we utilize a Q-controlled eigenmode of a cantilever to perform the fast actuation. We show that the actuation speed can be increased even with a regular cantilever. PMID- 25554300 TI - Automated spherical aberration correction in scanning confocal microscopy. AB - Mismatch between the refractive indexes of immersion media and glass coverslips introduces spherical aberrations in microscopes especially for high numerical aperture objectives. This contribution demonstrates an automated adjustment of the coverslip correction collar in scanning confocal microscopy to compensate for spherical aberrations due to coverslip thickness mismatch. With a motorized coverslip correction collar, the adjustment procedure consists of xz image scans, image processing, correction quality evaluation, the mismatch estimation, and eventually the optimal adjustment of the correction collar. For fast correction with less photodamage, coarse-fine Gaussian fitting algorithms are proposed and evaluated with various specimen for their estimation accuracy. The benefits of the proposed automated correction are demonstrated for various coverslips with biological specimens, showing the optimized resolution of the confocal microscope. PMID- 25554301 TI - Nanorheology by atomic force microscopy. AB - We present an Atomic Force Microscopy (AFM) based method to investigate the rheological properties of liquids confined within a nanosize gap formed by an AFM tip apex and a solid substrate. In this method, a conventional AFM cantilever is sheared parallel to a substrate surface by means of a lock-in amplifier while it is approaching and retracting from the substrate in liquid. The normal solvation forces and lateral viscoelastic shear forces experienced by the AFM tip in liquid can be simultaneously measured as a function of the tip-substrate distance with sub-nanometer vertical resolution. A new calibration method is applied to compensate for the linear drift of the piezo transducer and substrate system, leading to a more precise determination of the tip-substrate distance. By monitoring the phase lag between the driving signal and the cantilever response in liquid, the frequency dependent viscoelastic properties of the confined liquid can also be derived. Finally, we discuss the results obtained with this technique from different liquid-solid interfaces. Namely, octamethylcyclotetrasiloxane and water on mica and highly oriented pyrolytic graphite. PMID- 25554302 TI - X-ray imaging of subsurface dynamics in high-Z materials at the Diamond Light Source. AB - In this paper, we describe a new approach enabling study of subsurface dynamics in high-Z materials using the unique combination of high-energy synchrotron X rays, a hybrid bunch structure, and a new dynamic loading platform. We detail the design and operation of the purpose-built, portable small bore gas-gun, which was installed on the I12 high-energy beamline at the Diamond Light Source and used to drive compression waves into solid and porous metal targets. Using a hybrid bunch structure and broadband X-ray pulses of up to 300 keV, radiographic snapshots were captured during various dynamic deformation processes in cm-scale specimens, thereby contributing to a more complete understanding of the evolution of mesoscale damage. Importantly, we highlight strategies for overcoming the challenges associated with using high-energy X-rays, and suggest areas for improvement needed to advance dynamic imaging through large-scale samples of relevance to engineering scenarios. These preliminary measurements demonstrate the feasibility of probing highly transient phenomena using the presented methodology. PMID- 25554303 TI - Effect of free surface roughness on the apparent glass transition temperature in thin polymer films measured by ellipsometry. AB - Ellipsometry is one of the standard methods for observation of glass transition in thin polymer films. This work proposes that sensitivity of the method to surface morphology can complicate manifestation of the transition in a few nm thick samples. Two possible mechanisms of free surface roughening in the vicinity of glass transition are discussed: roughening due to lateral heterogeneity and roughening associated with thermal capillary waves. Both mechanisms imply an onset of surface roughness in the glass transition temperature range, which affects the experimental data in a way that shifts apparent glass transition temperature. Effective medium approximation models are used to introduce surface roughness into optical calculations. The results of the optical modeling for a 5 nm thick polystyrene film on silicon are presented. PMID- 25554304 TI - A dynamic ball compression test for understanding rock crushing. AB - During crushing, rock particles are subjected to complicated loading. It is desired to establish the relation between the loading and the fragmentation parameters for better understanding rock crushing mechanism. In this work, a split Hopkinson pressure bar system in combination with high speed cameras is utilized in the dynamic ball compression test, in which the spherical rock sample is adopted to avoid the shape effect. Using elasticity theory, the loading rate and the dynamic indirect tensile strength are first calculated. With the aid of the moment-trap technique and high speed cameras, the surface energy is determined for each sample. The relations between the loading rate and the fragmentation parameters, i.e., the number of fragments and the surface energy are established. The application of this method to a granitic rock shows that it is flexible and can be applied to the crushing study of generic brittle solids. PMID- 25554305 TI - An innovative Yb-based ultrafast deep ultraviolet source for time-resolved photoemission experiments. AB - Time- and angle-resolved photoemission spectroscopy is a powerful technique to study ultrafast electronic dynamics in solids. Here, an innovative optical setup based on a 100-kHz Yb laser source is presented. Exploiting non-collinear optical parametric amplification and sum-frequency generation, ultrashort pump (hnu = 1.82 eV) and ultraviolet probe (hnu = 6.05 eV) pulses are generated. Overall temporal and instrumental energy resolutions of, respectively, 85 fs and 50 meV are obtained. Time- and angle-resolved measurements on BiTeI semiconductor are presented to show the capabilities of the setup. PMID- 25554306 TI - Time-resolved photoemission apparatus achieving sub-20-meV energy resolution and high stability. AB - The paper describes a time- and angle-resolved photoemission apparatus consisting of a hemispherical analyzer and a pulsed laser source. We demonstrate 1.48-eV pump and 5.92-eV probe measurements at the ?10.5-meV and ?240-fs resolutions by use of fairly monochromatic 170-fs pulses delivered from a regeneratively amplified Ti:sapphire laser system operating typically at 250 kHz. The apparatus is capable to resolve the optically filled superconducting peak in the unoccupied states of a cuprate superconductor, Bi2Sr2CaCu2O(8 + delta). A dataset recorded on Bi(111) surface is also presented. Technical descriptions include the followings: A simple procedure to fine-tune the spatio-temporal overlap of the pump-and-probe beams and their diameters; achieving a long-term stability of the system that enables a normalization-free dataset acquisition; changing the repetition rate by utilizing acoustic optical modulator and frequency-division circuit. PMID- 25554307 TI - Nanomanipulation-coupled nanospray mass spectrometry as an approach for single cell analysis. AB - Electrospray mass spectrometry is now a widely used technique for observing cell content of various biological tissues. However, electrospray techniques (liquid chromatography and direct infusion) often involve lysing a group of cells and extracting the biomolecules of interest, rather than a sensitive, individual cell method to observe local chemistry. Presented here is an approach of combining a nanomanipulator workstation with nanospray mass spectrometry, which allows for extraction of a single cell, followed by rapid mass analysis that can provide a detailed metabolic profile. Triacylglycerol content was profiled with this tool coupled to mass spectrometry to investigate heterogeneity between healthy and tumorous tissues as well as lipid droplet containing adipocytes in vitro as proof of concept. This selective approach provides cellular resolution and complements existing bioanalytical techniques with minimal invasion to samples. In addition, the coupling of nanomanipulation and mass spectrometry holds the potential to be used in a great number of applications for individual organelles, diseased tissues, and in vitro cell cultures for observing heterogeneity even amongst cells and organelles of the same tissue. PMID- 25554309 TI - Microwave heating device for internal heating convection experiments, applied to Earth's mantle dynamics. AB - We report the design, construction, and performances of a microwave (MW) heating device for laboratory experiments with non-contact, homogeneous internal heating. The device generates MW radiation at 2.47 GHz from a commercial magnetron supplied by a pulsed current inverter using proprietary, feedback based command and control hardware and software. Specially designed MW launchers direct the MW radiation into the sample through a MW homogenizer, devised to even the MW power distribution into the sample's volume. An adjustable MW circuit adapts the MW generator to the load (i.e., the sample) placed in the experiment chamber. Dedicated heatsinks maintain the MW circuits at constant temperature throughout the experiment. Openings for laser scanning for image acquisition with a CCD camera and for the cooling circuits are protected by special MW filters. The performances of the device are analyzed in terms of heating uniformity, long term output power stability, and load matching. The device is used for small scale experiments simulating Earth's mantle convection. The 30 * 30 * 5 cm(3) convection tank is filled with a water-based viscous fluid. A uniform and constant temperature is maintained at the upper boundary by an aluminum heat exchanger and adiabatic conditions apply at the tank base. We characterize the geometry of the convective regime as well as its bulk thermal evolution by measuring the velocity field by Particle Image Velocimetry and the temperature field by using Thermochromic Liquid Crystals. PMID- 25554308 TI - Pulsed-coil magnet systems for applying uniform 10-30 T fields to centimeter scale targets on Sandia's Z facility. AB - Sandia has successfully integrated the capability to apply uniform, high magnetic fields (10-30 T) to high energy density experiments on the Z facility. This system uses an 8-mF, 15-kV capacitor bank to drive large-bore (5 cm diameter), high-inductance (1-3 mH) multi-turn, multi-layer electromagnets that slowly magnetize the conductive targets used on Z over several milliseconds (time to peak field of 2-7 ms). This system was commissioned in February 2013 and has been used successfully to magnetize more than 30 experiments up to 10 T that have produced exciting and surprising physics results. These experiments used split magnet topologies to maintain diagnostic lines of sight to the target. We describe the design, integration, and operation of the pulsed coil system into the challenging and harsh environment of the Z Machine. We also describe our plans and designs for achieving fields up to 20 T with a reduced-gap split-magnet configuration, and up to 30 T with a solid magnet configuration in pursuit of the Magnetized Liner Inertial Fusion concept. PMID- 25554310 TI - In-circuit-measurement of parasitic elements in high gain high bandwidth low noise transimpedance amplifiers. AB - Parasitic elements play an important role in the development of every high performance circuit. In the case of high gain, high bandwidth transimpedance amplifiers, the most important parasitic elements are parasitic capacitances at the input and in the feedback path, which significantly influence the stability, the frequency response, and the noise of the amplifier. As these parasitic capacitances range from a few picofarads down to only a few femtofarads, it is nearly impossible to measure them accurately using traditional LCR meters. Unfortunately, they also cannot be easily determined from the transfer function of the transimpedance amplifier, as it contains several overlapping effects and its measurement is only possible when the circuit is already stable. Therefore, we developed an in-circuit measurement method utilizing minimal modifications to the input stage in order to measure its parasitic capacitances directly and with unconditional stability. Furthermore, using the data acquired with this measurement technique, we both proposed a model for the complicated frequency response of high value thick film resistors as they are used in high gain transimpedance amplifiers and optimized our transimpedance amplifier design. PMID- 25554312 TI - Error analysis for intrinsic quality factor measurement in superconducting radio frequency resonators. AB - In this paper, we discuss error analysis for intrinsic quality factor (Q0) and accelerating gradient (Eacc) measurements in superconducting radio frequency (SRF) resonators. The analysis is applicable for cavity performance tests that are routinely performed at SRF facilities worldwide. We review the sources of uncertainties along with the assumptions on their correlations and present uncertainty calculations with a more complete procedure for treatment of correlations than in previous publications [T. Powers, in Proceedings of the 12th Workshop on RF Superconductivity, SuP02 (Elsevier, 2005), pp. 24-27]. Applying this approach to cavity data collected at Vertical Test Stand facility at Fermilab, we estimated total uncertainty for both Q0 and Eacc to be at the level of approximately 4% for input coupler coupling parameter beta1 in the [0.5, 2.5] range. Above 2.5 (below 0.5) Q0 uncertainty increases (decreases) with beta1 whereas Eacc uncertainty, in contrast with results in Powers [in Proceedings of the 12th Workshop on RF Superconductivity, SuP02 (Elsevier, 2005), pp. 24-27], is independent of beta1. Overall, our estimated Q0 uncertainty is approximately half as large as that in Powers [in Proceedings of the 12th Workshop on RF Superconductivity, SuP02 (Elsevier, 2005), pp. 24-27]. PMID- 25554311 TI - 3D parallel-detection microwave tomography for clinical breast imaging. AB - A biomedical microwave tomography system with 3D-imaging capabilities has been constructed and translated to the clinic. Updates to the hardware and reconfiguration of the electronic-network layouts in a more compartmentalized construct have streamlined system packaging. Upgrades to the data acquisition and microwave components have increased data-acquisition speeds and improved system performance. By incorporating analog-to-digital boards that accommodate the linear amplification and dynamic-range coverage our system requires, a complete set of data (for a fixed array position at a single frequency) is now acquired in 5.8 s. Replacement of key components (e.g., switches and power dividers) by devices with improved operational bandwidths has enhanced system response over a wider frequency range. High-integrity, low-power signals are routinely measured down to -130 dBm for frequencies ranging from 500 to 2300 MHz. Adequate inter channel isolation has been maintained, and a dynamic range >110 dB has been achieved for the full operating frequency range (500-2900 MHz). For our primary band of interest, the associated measurement deviations are less than 0.33% and 0.5 degrees for signal amplitude and phase values, respectively. A modified monopole antenna array (composed of two interwoven eight-element sub-arrays), in conjunction with an updated motion-control system capable of independently moving the sub-arrays to various in-plane and cross-plane positions within the illumination chamber, has been configured in the new design for full volumetric data acquisition. Signal-to-noise ratios (SNRs) are more than adequate for all transmit/receive antenna pairs over the full frequency range and for the variety of in-plane and cross-plane configurations. For proximal receivers, in-plane SNRs greater than 80 dB are observed up to 2900 MHz, while cross-plane SNRs greater than 80 dB are seen for 6 cm sub-array spacing (for frequencies up to 1500 MHz). We demonstrate accurate recovery of 3D dielectric property distributions for breast-like phantoms with tumor inclusions utilizing both the in-plane and new cross-plane data. PMID- 25554313 TI - An ultrasonic contact-type position restoration mechanism. AB - An ultrasonic contact-type position restoration mechanism is proposed and investigated in this paper. In the mechanism, two driving points of an ultrasonic vibrator, excited by an AC voltage, produces a restoring force on a slider so that the slider can be pushed back to its equilibrium after it is perturbed away from its equilibrium. The restoring force is generated by the unbalance of ultrasonic frictional driving forces on the slider, which is caused by a pressure difference on the two driving points. A prototype of this mechanism is fabricated, and the effects of the driving voltage, preload between the slider and vibrator, and slider's size on the restoring characteristics are experimentally measured and analyzed. PMID- 25554314 TI - Aircraft engine-mounted camera system for long wavelength infrared imaging of in service thermal barrier coated turbine blades. AB - This paper announces the implementation of a long wavelength infrared camera to obtain high-speed thermal images of an aircraft engine's in-service thermal barrier coated turbine blades. Long wavelength thermal images were captured of first-stage blades. The achieved temporal and spatial resolutions allowed for the identification of cooling-hole locations. The software and synchronization components of the system allowed for the selection of any blade on the turbine wheel, with tuning capability to image from leading edge to trailing edge. Its first application delivered calibrated thermal images as a function of turbine rotational speed at both steady state conditions and during engine transients. In advance of presenting these data for the purpose of understanding engine operation, this paper focuses on the components of the system, verification of high-speed synchronized operation, and the integration of the system with the commercial jet engine test bed. PMID- 25554315 TI - Examining thermal transport through a frequency-domain representation of time domain thermoreflectance data. AB - Laser-based time-domain thermoreflectance (TDTR) and frequency-domain thermoreflectance (FDTR) techniques are widely used for investigating thermal transport at micro- and nano-scales. We demonstrate that data obtained in TDTR measurements can be represented in a frequency-domain form equivalent to FDTR, i.e., in the form of a surface temperature amplitude and phase response to time harmonic heating. Such a representation is made possible by using a large TDTR delay time window covering the entire pulse repetition interval. We demonstrate the extraction of frequency-domain data up to 1 GHz from TDTR measurements on a sapphire sample coated with a thin layer of aluminum, and show that the frequency dependencies of both the amplitude and phase responses agree well with theory. The proposed method not only allows a direct comparison of TDTR and FDTR data, but also enables measurements at high frequencies currently not accessible to FDTR. The frequency-domain representation helps uncover aspects of the measurement physics which remain obscured in a traditional TDTR measurement, such as the importance of modeling the details of the heat transport in the metal transducer film for analyzing high frequency responses. PMID- 25554316 TI - Development of a semi-adiabatic isoperibol solution calorimeter. AB - A semi-adiabatic isoperibol solution calorimeter has been indigenously developed. The measurement system comprises modules for sensitive temperature measurement probe, signal processing, data collection, and joule calibration. The sensitivity of the temperature measurement module was enhanced by using a sensitive thermistor coupled with a lock-in amplifier based signal processor. A microcontroller coordinates the operation and control of these modules. The latter in turn is controlled through personal computer (PC) based custom made software developed with LabView. An innovative summing amplifier concept was used to cancel out the base resistance of the thermistor. The latter was placed in the dewar. The temperature calibration was carried out with a standard platinum resistance (PT100) sensor coupled with an 81/2 digit multimeter. The water equivalent of this calorimeter was determined by using electrical calibration with the joule calibrator. The experimentally measured values of the quantum of heat were validated by measuring heats of dissolution of pure KCl (for endotherm) and tris (hydroxyl methyl) amino-methane (for exotherm). The uncertainity in the measurements was found to be within +/-3%. PMID- 25554317 TI - A wireless demodulation system for passive surface acoustic wave torque sensor. AB - Surface acoustic wave (SAW) resonators are utilized as torque sensors for their passive and wireless features. However, the response of a SAW torque sensor is difficult to detect because of the transient response duration and interruption of channel noise, which limit the application of SAW torque sensors. The sensitive mechanism and response function of a passive wireless SAW torque sensor are analyzed in this study. A novel demodulation system involving both hardware and software is developed for the SAW torque sensor. A clipping amplifier is utilized in the hardware to widen the dynamic response range and increase the length of the valid signal. Correlation extension and centroid algorithms are designed to lengthen the received signal and improve the estimation accuracy of the center frequency of the response signal, respectively. Meanwhile, a fast binary search algorithm is proposed to accelerate the scanning cycle according to the developed response function. Finally, the SAW torque sensor demodulation system is set up and SAW resonators with high sensitivity are fabricated on a quartz substrate. The presented demodulation system is tested, and a standard deviation of 0.28 kHz is achieved. This value is much smaller than that of classic and modern spectrum estimation methods. The sensitivity of resonance frequency shift versus torque on the shaft of the assembled senor is 2.03 kHz/Nm; the coefficient of determination is 0.999, and the linearity is 0.87%. Experimental results verify the validity and feasibility of the proposed SAW torque sensor demodulation system. PMID- 25554318 TI - Ultrasonic pressure measurement in pressure vessels. AB - Based on the reflected longitudinal wave, a new non-intrusive method for pressure measurement is proposed. The acoustoelastic theory and the thin-shell theory are introduced to develop the pressure measurement model in cylindrical pressure vessels. And a pressure measurement system is constructed to evaluate the effectiveness of the proposed method. The pressure measurement is implemented by measuring the travel-time change between two received ultrasonic sensors. The experimental results verify the feasibility and effectiveness of this new non intrusive method. Compared with the non-intrusive pressure measurement method based on the critically refracted longitudinal wave (LCR wave), the proposed non intrusive pressure measurement method has the advantages of higher sensitivity and higher signal-to-noise ratio. PMID- 25554319 TI - Testing accelerometer rectification error caused by multidimensional composite inputs with double turntable centrifuge. AB - Rectification error is a critical characteristic of inertial accelerometers. Accelerometers working in operational situations are stimulated by composite inputs, including constant acceleration and vibration, from multiple directions. However, traditional methods for evaluating rectification error only use one dimensional vibration. In this paper, a double turntable centrifuge (DTC) was utilized to produce the constant acceleration and vibration simultaneously and we tested the rectification error due to the composite accelerations. At first, we deduced the expression of the rectification error with the output of the DTC and a static model of the single-axis pendulous accelerometer under test. Theoretical investigation and analysis were carried out in accordance with the rectification error model. Then a detailed experimental procedure and testing results were described. We measured the rectification error with various constant accelerations at different frequencies and amplitudes of the vibration. The experimental results showed the distinguished characteristics of the rectification error caused by the composite accelerations. The linear relation between the constant acceleration and the rectification error was proved. The experimental procedure and results presented in this context can be referenced for the investigation of the characteristics of accelerometer with multiple inputs. PMID- 25554320 TI - Bipod flexure for 1-m primary mirror system. AB - We present an analytical formulation of the bipod flexure for mounting the 1-m primary mirror in a space telescope. Compliance and stiffness matrices of the bipod flexure are derived to estimate theoretical performance and to make initial design guidelines. We use finite element analysis to optimize the bipod design satisfying the application requirements. Experimental verification is achieved by vibration test with a dummy mirror system. PMID- 25554321 TI - A transverse bunch by bunch feedback system for Pohang Light Source upgrade. AB - The Pohang Light Source upgrade (PLS-II) project has successfully upgraded the Pohang Light Source (PLS). The main goals of the PLS-II project are to increase the beam energy to 3 GeV, increase the number of insertion devices by a factor of two (20 IDs), increase the beam current to 400 mA, and at the same time reduce the beam emittance to below 10 nm by using the existing PLS tunnel and injection system. Among 20 insertion devices, 10 narrow gap in-vacuum undulators are in operation now and two more in-vacuum undulators are to be installed later. Since these narrow gap in-vacuum undulators are most likely to produce coupled bunch instability by the resistive wall impedance and limit the stored beam current, a bunch by bunch feedback system is implemented to suppress coupled bunch instability in the PLS-II. This paper describes the scheme and performance of the PLS-II bunch by bunch feedback system. PMID- 25554322 TI - A high stability and repeatability electrochemical scanning tunneling microscope. AB - We present a home built electrochemical scanning tunneling microscope (ECSTM) with very high stability and repeatability. Its coarse approach is driven by a closely stacked piezo motor of GeckoDrive type with four rigid clamping points, which enhances the rigidity, compactness, and stability greatly. It can give high clarity atomic resolution images without sound and vibration isolations. Its drifting rates in XY and Z directions in solution are as low as 84 pm/min and 59 pm/min, respectively. In addition, repeatable coarse approaches in solution within 2 mm travel distance show a lateral deviation less than 50 nm. The gas environment can be well controlled to lower the evaporation rate of the cell, thus reducing the contamination and elongating the measurement time. Atomically resolved SO4(2-) image on Au (111) work electrode is demonstrated to show the performance of the ECSTM. PMID- 25554323 TI - Current waveform reconstruction from an explosively emissive cathode at a subnanosecond voltage front. AB - We describe the methods of registration and reconstruction of an envelope of explosive electron emission current from the edge of a cylindrical cathode, which provides a picosecond time reference of the emitted electron beam with a subnanosecond voltage front applied to the accelerating gap. Variation of the front steepness allows one to determine the beam onset time in the experiments, where a collector-type current probe can be used. The advanced method of dynamic time domain reflectometry provides exact data on electron beam current rise and track changes in the cathode emission from pulse to pulse with a precision of less than 10 ps. PMID- 25554324 TI - A non-intrusive oil temperature measurement method of hydraulic system. AB - This paper proposed a simple non-intrusive oil temperature measurement method to overcome the shortcomings of the traditional intrusive one. The heat transmission model between outer and inner tube wall, the temperature distribution model of oil near the inner tube wall, and the temperature distribution model of oil in tube were established, respectively, based on the energy conservation principle. With the constructed models, we can measure the temperature of oil in tube by surveying the temperature of outer tube wall and the temperature of air around the tube. An oil temperature measurement apparatus was designed to demonstrate the new method. We measured the temperature of No. 46 antiwear hydraulic oil under 5 MPa, 15 MPa, and 25 MPa, respectively. Comparative results with traditional intrusive oil temperature measurement method show that the measurement error of the presented method is less than 1 degrees C, and thus implies its superiority. PMID- 25554325 TI - Nondestructive synchronous beam current monitor. AB - A fast current transformer is mounted after the deflectors of the Berkeley 88 Inch Cyclotron. The measured signal is amplified and connected to the input of a lock-in amplifier. The lock-in amplifier performs a synchronous detection of the signal at the cyclotron second harmonic frequency. The magnitude of the signal detected is calibrated against a Faraday cup and corresponds to the beam intensity. It has exceptional resolution, long term stability, and can measure the beam current leaving the cyclotron as low as 1 nA. PMID- 25554326 TI - An algorithm for selecting the most accurate protocol for contact angle measurement by drop shape analysis. AB - In this study, an error analysis is performed to study real water drop images and the corresponding numerically generated water drop profiles for three widely used static contact angle algorithms: the circle- and ellipse-fitting algorithms and the axisymmetric drop shape analysis-profile (ADSA-P) algorithm. The results demonstrate the accuracy of the numerically generated drop profiles based on the Laplace equation. A significant number of water drop profiles with different volumes, contact angles, and noise levels are generated, and the influences of the three factors on the accuracies of the three algorithms are systematically investigated. The results reveal that the above-mentioned three algorithms are complementary. In fact, the circle- and ellipse-fitting algorithms show low errors and are highly resistant to noise for water drops with small/medium volumes and contact angles, while for water drop with large volumes and contact angles just the ADSA-P algorithm can meet accuracy requirement. However, this algorithm introduces significant errors in the case of small volumes and contact angles because of its high sensitivity to noise. The critical water drop volumes of the circle- and ellipse-fitting algorithms corresponding to a certain contact angle error are obtained through a significant amount of computation. To improve the precision of the static contact angle measurement, a more accurate algorithm based on a combination of the three algorithms is proposed. Following a systematic investigation, the algorithm selection rule is described in detail, while maintaining the advantages of the three algorithms and overcoming their deficiencies. In general, static contact angles over the entire hydrophobicity range can be accurately evaluated using the proposed algorithm. The ease of erroneous judgment in static contact angle measurements is avoided. The proposed algorithm is validated by a static contact angle evaluation of real and numerically generated water drop images with different hydrophobicity values and volumes. PMID- 25554327 TI - An improved self-alignment method for strapdown inertial navigation system based on gravitational apparent motion and dual-vector. AB - Analysis and simulation results indicate that two problems should be solved when the self-alignment method based on gravitational apparent motion and dual-vector can be used for Strapdown Inertial Navigation System. The first one is how to identify the apparent motion from accelerometer measurement containing random noise and the second is how to avoid the collinear problem between two vectors used in alignment solution. In this paper, a parameter identification and reconstruction algorithm is proposed to solve the first problem and simulation results indicate that proposed algorithm can identify apparent motion from accelerometer measurements effectively; and reconstruction algorithm based on current identified parameters for dual-vector is designed in detail to solve the second problem which can make full use of newest identification and avoid collinear problem completely. Simulation and turntable results show that the proposed alignment method can fulfill self-alignment in a swinging condition and the alignment accuracy can reach the theoretical values determined by the sensor precision. PMID- 25554328 TI - Programmable, very low noise current source. AB - We propose a new approach for the realization of very low noise programmable current sources mainly intended for application in the field of low frequency noise measurements. The design is based on a low noise Junction Field Effect Transistor (JFET) acting as a high impedance current source and programmability is obtained by resorting to a low noise, programmable floating voltage source that allows to set the sourced current at the desired value. The floating voltage source is obtained by exploiting the properties of a standard photovoltaic MOSFET driver. Proper filtering and a control network employing super-capacitors allow to reduce the low frequency output noise to that due to the low noise JFET down to frequencies as low as 100 mHz while allowing, at the same time, to set the desired current by means of a standard DA converter with an accuracy better than 1%. A prototype of the system capable of supplying currents from a few hundreds of MUA up to a few mA demonstrates the effectiveness of the approach we propose. When delivering a DC current of about 2 mA, the power spectral density of the current fluctuations at the output is found to be less than 25 pA/?Hz at 100 mHz and less than 6 pA/?Hz for f > 1 Hz, resulting in an RMS noise in the bandwidth from 0.1 to 10 Hz of less than 14 pA. PMID- 25554329 TI - A small-angle x-ray scattering system with a vertical layout. AB - A small-angle x-ray scattering (SAXS) system with a vertical layout (V-SAXS) has been designed and constructed for in situ detection on nanostructures, which is well suitable for in situ study on self-assembly of nanoparticles at liquid interface and polymer processing. A steel-tower frame on a reinforced basement is built as the supporting skeleton for scattering beam path and detector platform, ensuring the system a high working stability and a high operating accuracy. A micro-focus x-ray source combining parabolic three-dimensional multi-layer mirror and scatteringless collimation system provides a highly parallel beam, which allows us to detect the very small angle range. With a sample-to-detector distance of 7 m, the largest measurable length scale is 420 nm in real space. With a large sample zone, it is possible to install different experimental setups such as film stretching machine, which makes the system perfect to follow the microstructures evolution of materials during processing. The capability of the V SAXS on in situ study is tested with a drying experiment of a free latex droplet, which confirms our initial design. PMID- 25554330 TI - Smart monitoring system based on adaptive current control for superconducting cable test. AB - A smart monitoring system for superconducting cable test is proposed with an adaptive current control of a superconducting transformer secondary. The design, based on Fuzzy Gain Scheduling, allows the controller parameters to adapt continuously, and finely, to the working variations arising from transformer nonlinear dynamics. The control system is integrated in a fully digital control loop, with all the related benefits, i.e., high noise rejection, ease of implementation/modification, and so on. In particular, an accurate model of the system, controlled by a Fuzzy Gain Scheduler of the superconducting transformer, was achieved by an experimental campaign through the working domain at several current ramp rates. The model performance was characterized by simulation, under all the main operating conditions, in order to guide the controller design. Finally, the proposed monitoring system was experimentally validated at European Organization for Nuclear Research (CERN) in comparison to the state-of-the-art control system [P. Arpaia, L. Bottura, G. Montenero, and S. Le Naour, "Performance improvement of a measurement station for superconducting cable test," Rev. Sci. Instrum. 83, 095111 (2012)] of the Facility for the Research on Superconducting Cables, achieving a significant performance improvement: a reduction in the system overshoot by 50%, with a related attenuation of the corresponding dynamic residual error (both absolute and RMS) up to 52%. PMID- 25554331 TI - Synchronizing femtosecond laser with x-ray synchrotron operating at arbitrarily different frequencies. AB - The ability to synchronize a femtosecond laser to x-ray pulses is crucial for performing ultrafast time-resolved x-ray scattering experiments at synchrotrons. Conventionally, the task has been achieved by locking a harmonic frequency of the laser oscillator to the storage ring master radio-frequency (RF). However, when the frequency mismatch between the two sources cannot be compensated by small adjustments to the laser cavity length, synchronization to a harmonic frequency requires modifying the optical components of the laser system. We demonstrate a novel synchronization scheme, which is a flexible alternative for synchronizing these two sources operating at arbitrarily different frequencies. First, we find the greatest common divisor (GCD) of the two frequencies that is still within the limited tuning range of the laser cavity length. The GCD is generated by dividing down from the storage ring RF, and is separately multiplied up to provide a feedback signal for synchronizing the laser cavity. Unique to our scheme, the GCD also serves as a harmonic RF source for the laser amplifier such that only laser oscillator pulses at fixed integer multiples of the storage ring RF are selected for amplification and delivery to experiments. Our method is implemented at the Photon Test Facility beamline of Pohang Light Source where timing-jitter less than 4 ps (r.m.s.) is measured using a new shot-to-shot method. PMID- 25554332 TI - Design of a novel passive flexure-based mechanism for microelectromechanical system optical switch assembly. AB - In microelectromechanical system (MEMS) optical switch assembly, the collision always exists between the optical fiber and the edges of the U-groove due to the positioning errors between them. It will cause the irreparable damage since the optical fiber and the silicon-made U-groove are usually very fragile. Typical solution is first to detect the positioning errors by the machine vision or high resolution sensors and then to actively eliminate them with the aid of the motion of precision mechanisms. However, this method will increase the cost and complexity of the system. In this paper, we present a passive compensation method to accommodate the positioning errors. First, we study the insertion process of the optical fiber into the U-groove to analyze all possible positioning errors as well as the conditions of successful insertion. Then, a novel passive flexure based mechanism based on the remote center of compliance concept is designed to satisfy the required insertion condition. The pseudo-rigid-body-model method is utilized to calculate the stiffness of the mechanism along the different directions, which is verified by finite element analysis (FEA). Finally, a prototype of the passive flexure-based mechanism is fabricated for performance tests. Both FEA and experimental results indicate that the designed mechanism can be used to the MEMS optical switch assembly. PMID- 25554333 TI - Three axis electronic flight motion simulator real time control system design and implementation. AB - A three axis electronic flight motion simulator is reported in this paper including the modelling, the controller design as well as the hardware implementation. This flight motion simulator could be used for inertial navigation test and high precision inertial navigation system with good dynamic and static performances. A real time control system is designed, several control system implementation problems were solved including time unification with parallel port interrupt, high speed finding-zero method of rotary inductosyn, zero-crossing management with continuous rotary, etc. Tests were carried out to show the effectiveness of the proposed real time control system. PMID- 25554334 TI - A device to investigate the delamination strength in laminates at room and cryogenic temperature. AB - We construct an instrument to study the behavior of delamination strength in laminates which can be defined as the critical transverse stress at which an actual delamination occurs. The device allows the anvil measurements at room temperature or the liquid nitrogen temperature. For the electro-magnetic laminated materials (e.g., a superconducting YaBa2Cu3O(7-x) coated conductor which has a typical laminated structure), the delamination strength was measured while the properties of transport current were also recorded. Moreover, the influences of external magnetic field on the delamination strength were presented. PMID- 25554336 TI - Space magnetometer based on an anisotropic magnetoresistive hybrid sensor. AB - We report on the design and development of a low resource, dual sensor vector magnetometer for space science applications on very small spacecraft. It is based on a hybrid device combining an orthogonal triad of commercial anisotropic magnetoresistive (AMR) sensors with a totem pole H-Bridge drive on a ceramic substrate. The drive enables AMR operation in the more sensitive flipped mode and this is achieved without the need for current spike transmission down a sensor harness. The magnetometer has sensitivity of better than 3 nT in a 0-10 Hz band and a total mass of 104 g. Three instruments have been launched as part of the TRIO-CINEMA space weather mission, inter-calibration against the International Geomagnetic Reference Field model makes it possible to extract physical signals such as field-aligned current deflections of 20-60 nT within an approximately 45,000 nT ambient field. PMID- 25554335 TI - Pressure/temperature fluid cell apparatus for the neutron powder diffractometer instrument: probing atomic structure in situ. AB - This contribution describes a new local structure compatible gas/liquid cell apparatus for probing disordered materials at high pressures and variable temperatures in the Neutron Powder Diffraction instrument at the Lujan Neutron Scattering Center, Los Alamos National Laboratory. The new sample environment offers choices for sample canister thickness and canister material type. Finite element modeling is utilized to establish maximum allowable working pressures of 414 MPa at 15 K and 121 MPa at 600 K. High quality atomic pair distribution function data extraction and modeling have been demonstrated for a calibration standard (Si powder) and for supercritical and subcritical CO2 measurements. The new sample environment was designed to specifically target experimental studies of the local atomic structures involved in geologic CO2 sequestration, but will be equally applicable to a wide variety of energy applications, including sorption of fluids on nano/meso-porous solids, clathrate hydrate formation, catalysis, carbon capture, and H2 and natural gas uptake/storage. PMID- 25554337 TI - Note: "Lock-in accelerometry" to follow sink dynamics in shaken granular matter. AB - Understanding the penetration dynamics of intruders in granular beds is relevant not only for fundamental physics, but also for geophysical processes and construction on sediments or granular soils in areas potentially affected by earthquakes. While the penetration of intruders in two dimensional (2D) laboratory granular beds can be followed using video recording, this is useless in three dimensional (3D) beds of non-transparent materials such as common sand. Here, we propose a method to quantify the sink dynamics of an intruder into laterally shaken granular beds based on the temporal correlations between the signals from a reference accelerometer fixed to the shaken granular bed, and a probe accelerometer deployed inside the intruder. Due to its analogy with the working principle of a lock-in amplifier, we call this technique lock-in accelerometry. PMID- 25554338 TI - Note: High precision measurements using high frequency gigahertz signals. AB - Generalized lock-in amplifiers use digital cavities with Q-factors as high as 5 * 10(8) to measure signals with very high precision. In this Note, we show that generalized lock-in amplifiers can be used to analyze microwave (giga-hertz) signals with a precision of few tens of hertz. We propose that the physical changes in the medium of propagation can be measured precisely by the ultra-high precision measurement of the signal. We provide evidence to our proposition by verifying the Newton's law of cooling by measuring the effect of change in temperature on the phase and amplitude of the signals propagating through two calibrated cables. The technique could be used to precisely measure different physical properties of the propagation medium, for example, the change in length, resistance, etc. Real time implementation of the technique can open up new methodologies of in situ virtual metrology in material design. PMID- 25554339 TI - Note: Pre-pulse characterization of femtosecond laser pulse by filamentation in transparent media. AB - A new method and associating system has been presented to characterize pre-pulses of femtosecond laser using laser filamentation in transparent media. Pre-pluses of the laser system has been measured experimentally and it is in good agreement with the results obtained by third order cross-correlator. This method can be used for fast detection of temporal laser intensity relatively in order to avoid formation of pre-plasmas before laser matter interaction experiments. PMID- 25554340 TI - Note: Improving the performance of a geophone through suspension system configuration. AB - A suspension system of classical geophone was developed, adopting multiple pairs of leaf springs as a substitute for one pair. The finite element analysis was used as the solving means, and the results indicated that the geophone performance with developed suspension system was more favorable than that with conventional suspension system. First, the operating broadband of the improved geophone was wider than that of the conventional geophone. Second, the distortion of output signal for a geophone was slightly reduced, which was usually enlarged with improving the ratio of spurious resonant frequency to natural frequency. PMID- 25554341 TI - Note: Buoyant-force assisted liquid membrane electrochemical etching for nano-tip preparation. AB - A liquid membrane electrochemical etching process for preparing nano-tips is proposed by the introduction of buoyant force to the lower tip, in which the lower portion of the anodic wire is immersed into a floating layer. A mathematical model of this method is derived. Both calculation and experimental results demonstrate that the introduction of buoyant force can significantly decrease the tip radius. The lubricating oil and deionized water floating layers were tested for the processing of nano-tips. Further, high-aspect-ratio nano electrodes were prepared by applying a relative vertical movement to the anodic wire. PMID- 25554342 TI - Note: High-speed Z tip scanner with screw cantilever holding mechanism for atomic resolution atomic force microscopy in liquid. AB - High-speed atomic force microscopy has attracted much attention due to its unique capability of visualizing nanoscale dynamic processes at a solid/liquid interface. However, its usability and resolution have yet to be improved. As one of the solutions for this issue, here we present a design of a high-speed Z-tip scanner with screw holding mechanism. We perform detailed comparison between designs with different actuator size and screw arrangement by finite element analysis. Based on the design giving the best performance, we have developed a Z tip scanner and measured its performance. The measured frequency response of the scanner shows a flat response up to ~10 kHz. This high frequency response allows us to achieve wideband tip-sample distance regulation. We demonstrate the applicability of the scanner to high-speed atomic-resolution imaging by visualizing atomic-scale calcite crystal dissolution process in water at 2 s/frame. PMID- 25554343 TI - Note: 6Li III light intensity observation for 6Li3+ ion beam operation at Hyper Electron Cyclotron Resonance ion source. AB - The light intensity of (6)Li III line spectrum at lambda = 516.7 nm was observed during (6)Li(3+) beam tuning at the Hyper-Electron Cyclotron Resonance (ECR) ion source. Separation of ion species of the same charge to mass ratio with an electromagnetic mass analyzer is known to be an exceptionally complex process. However, (6)Li III line intensity observation conducted in this study gives new insights into its simplification of this process. The light intensity of (6)Li III line spectrum from the ECR plasma was found to have a strong correlation with the extracted (6)Li(3+) beam intensity from the RIKEN Azimuthal Varying Field cyclotron. PMID- 25554344 TI - Note: Sample chamber for in situ x-ray absorption spectroscopy studies of battery materials. AB - In situ x-ray absorption spectroscopy (XAS) provides element-specific characterization of both crystalline and amorphous phases and enables direct correlations between electrochemical performance and structural characteristics of cathode and anode materials. In situ XAS measurements are very demanding to the design of the experimental setup. We have developed a sample chamber that provides electrical connectivity and inert atmosphere for operating electrochemical cells and also accounts for x-ray interactions with the chamber and cell materials. The design of the sample chamber for in situ measurements is presented along with example XAS spectra from anode materials in operating pouch cells at the Zn and Sn K-edges measured in fluorescence and transmission modes, respectively. PMID- 25554345 TI - Note: A novel curvature-driven shape memory alloy torsional actuator. AB - This paper presents a novel, extremely simple torsional actuator which employs a special shape setting treated shape memory alloy coil. The actuator works with a so-called curvature-driven principle and can directly generate a rotary motion without any motion converting mechanism. Experiments were performed to study the output performances of several actuators with different geometry parameters. The test results show the actuator can output a rotary motion fluently, and the output torque is about several mN mm. PMID- 25554346 TI - Note: Precise phase and frequency comparator based on direct phase-time measurements. AB - We are reporting on the design, performance, and application results of a phase and frequency comparator based on the direct phase-time measurement using a high performance event timer. The advantages of this approach are the simple implementation, a broad frequency range, and the clear interpretation of the measured results. Primarily we analyzed the background instability of the instrument in a common-clock test when a 200 MHz clock signal was connected to both inputs and the noise bandwidth was kept at 5 Hz by a preprocessing of the measured data. The results show that the Allan deviation of the background instability follows 4 * 10(-14)/tau for a wide range of averaging intervals from 0.1 s up to 10(4) s. These results are better than background instability of commercially available state-of-the-art instruments based on the phase difference multiplication. Finally the instrument was used for comparison of two H-masers. This experiment proofed that one of possible applications is a comparison of low noise highly stable frequency sources and measurement of their frequency stability in the time-domain. The noise background of the instrument was negligible for averaging intervals longer than 100 ms. PMID- 25554348 TI - Maternal fructose consumption alters messenger RNA expression of hippocampal StAR, PBR, P450(11beta), 11beta-HSD, and 17beta-HSD in rat offspring. AB - Hippocampal functions such as neuronal protection and synapse formation are positively modulated by neurosteroids, which are synthesized de novo within the brain. However, the mechanisms regulating neurosteroidogenesis remain unclear. Fructose, which is used as a sweetener, affects steroid hormone synthesis in peripheral endocrine organs. This monosaccharide can penetrate the blood-brain barrier and impair hippocampal function. Also, fructose is secreted into milk and is thus delivered to the fetus. Based on these observations, we hypothesized that the hippocampal neurosteroidogenesis in the offspring may be affected by maternal fructose consumption. Female rats were fed with normal water or 20% fructose solution during gestation and lactation. Maternal calorie intake did not change significantly, and no significant change in body weight was observed. The levels of messenger RNAs (mRNAs) for steroidogenic enzymes and proteins in the hippocampus of the offspring were analyzed by real-time reverse transcriptase polymerase chain reaction. Maternal fructose consumption during gestation and lactation increased mRNA levels of P450(11beta)-2, 11beta-HSD-2, and 17beta-HSD-1 in the offspring hippocampus, and reduced levels of mRNAs for StAR, PBR, and 17beta-HSD-3. Maternal fructose consumption might influence hippocampal neurosteroidogenesis in offspring. PMID- 25554349 TI - Polysomnographic and actigraphic characteristics of patients with H1N1-vaccine related and sporadic narcolepsy. AB - OBJECTIVE: After the pandemic H1N1 influenza ASO3-adjuvanted vaccine, Pandemrix(c), was used in late 2009 and early 2010, the incidence of narcolepsy increased in many European countries. This incidence mainly increased in children and adolescents and, to a lesser degree, in adults. PATIENTS/METHODS: 125 unmedicated patients, aged 4 to 61 years, were included in this case-series study. Of these, 69 were diagnosed to have an H1N1-vaccine-related narcolepsy and 57 had sporadic narcolepsy. Most of these patients had: an actigraphy recording of 1-2 weeks, polysomnography, a Multiple Sleep Latency Test (MSLT), and cerebrospinal fluid hypocretin-1 concentration analysis. RESULTS: Patients with H1N1-vaccine-related narcolepsy had shorter diagnostic delays, lower periodic leg movement index during sleep, earlier sleep-wake rhythm, and were younger in age at diagnosis, compared with sporadic cases. They also had shorter sleep latency and more sleep onset REM periods in MSLT, but these results were strongly age dependent. Actigraphy showed quantitatively less sleep and more sleep fragmentation than polysomnography. CONCLUSION: Regarding polysomnographic and actigraphic characteristics, there were no dramatic deviations between H1N1 vaccine-related and sporadic narcolepsy. Circadian rhythms indicated some interesting new findings with respect to the H1N1-vaccine-related disease. An actigraphy recording of 1-2 weeks is useful when studying the nocturnal aspects of narcolepsy and sleep-wake rhythms of narcoleptic patients. PMID- 25554350 TI - Pharmacotherapy with oral Xa inhibitors for venous thromboembolism. AB - INTRODUCTION: Venous thromboembolism (VTE) causes substantial morbidity and mortality worldwide. The traditional treatment of VTE, with an initial therapy with (low molecular weight) heparin or fondaparinux and a continued treatment with vitamin K antagonists, is effective but has limitations. AREAS COVERED: The current review summarizes the results of the Phase III trials with the new oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and provides a meta-analysis of these trials in the subgroups of elderly patients (> 75 years) and patients with impaired renal function. EXPERT OPINION: The practical use of direct Xa inhibitors in the treatment of VTE in general and in specific subgroups is discussed. For elderly patients, patients with extremes of body weight, cancer patients or patients with moderate renal impairment, pooled data suggest that the direct oral Xa inhibitors are a reasonable alternative to standard therapy. For other indications, such as treatment of VTE in children, during pregnancy or in the context of heparin-induced thrombocytopenia, further data from clinical trials are needed. PMID- 25554352 TI - Bigger than Ebola. PMID- 25554351 TI - Nursing home practices following resident death: the experience of Certified Nursing Assistants. AB - This study examined certified nursing assistants' (CNAs) experiences of nursing home practices following resident death. Participants were 140 CNAs who had experienced recent resident death. In semi-structured, in-person interviews, CNAs were asked about their experiences with the removal of the resident's body, filling the bed with a new resident, and how they were notified about the death. The facilities' practice of filling the bed quickly was most often experienced as negative. Responses to body removal and staff notification varied, but negative experiences were reported by a substantial minority. Being notified prior to returning to work was associated with a more positive experience. Learning about the death by walking into a room to find the bed empty or already filled was the most negative experience. Study findings suggest that more mindful approaches to the transitions related to resident deaths would be valued by CNAs and could improve their work experience. PMID- 25554353 TI - The changing world of immunizations: knowing what to do and when. PMID- 25554354 TI - Internalized stigma and its psychosocial correlates in Korean patients with serious mental illness. AB - We aimed to examine internalized stigma of patients with mental illness in Korea and identify the contributing factors to internalized stigma among socio demographic, clinical, and psychosocial variables using a cross-sectional study design. A total of 160 patients were recruited from a university mental hospital. We collected socio-demographic data, clinical variables and administered self report scales to measure internalized stigma and levels of self-esteem, hopelessness, social support, and social conflict. Internalized stigma was identified in 8.1% of patients in our sample. High internalized stigma was independently predicted by low self-esteem, high hopelessness, and high social conflict among the psychosocial variables. Our finding suggests that simple psychoeducation only for insight gaining cannot improve internalized stigma. To manage internalized stigma in mentally ill patients, it is needed to promote hope and self-esteem. We also suggest that a relevant psychosocial intervention, such as developing coping skills for social conflict with family, can help patients overcome their internalized stigma. PMID- 25554355 TI - Association between Silent Information Regulator 1 (SIRT1) gene polymorphisms and schizophrenia in a Chinese Han population. PMID- 25554356 TI - Selective attention deficits in obsessive-compulsive disorder: the role of metacognitive processes. AB - While initial studies supported the hypothesis that cognitive characteristics that capture cognitive resources act as underlying mechanisms in memory deficits in obsessive-compulsive disorder (OCD), the influence of those characteristics on selective attention has not been studied, yet. In this study, we examined the influence of cognitive self-consciousness (CSC), rumination and worrying on performance in selective attention in OCD and compared the results to a depressive and a healthy control group. We found that 36 OCD and 36 depressive participants were impaired in selective attention in comparison to 36 healthy controls. In all groups, hierarchical regression analyses demonstrated that age, intelligence and years in school significantly predicted performance in selective attention. But only in OCD, the predictive power of the regression model was improved when CSC, rumination and worrying were implemented as predictor variables. In contrast, in none of the three groups the predictive power improved when indicators of severity of obsessive-compulsive (OC) and depressive symptoms and trait anxiety were introduced as predictor variables. Thus, our results support the assumption that mental characteristics that bind cognitive resources play an important role in the understanding of selective attention deficits in OCD and that this mechanism is especially relevant for OCD. PMID- 25554357 TI - Technology: multi-tasking CRISPR RNA scaffolds. PMID- 25554359 TI - Correction in article "Familial Left Ventricular Noncompaction Associated With a Novel Mutation in the Alphacardiac Actin Gene", Rev Esp Cardiol. 2014;67:857-9. PMID- 25554360 TI - Short-term dietary nitrate supplementation augments cutaneous vasodilatation and reduces mean arterial pressure in healthy humans. AB - Nitrate supplementation in the form of beetroot juice has been shown to increase nitric oxide (NO) where nitrate can be reduced to nitrite and, subsequently, to NO through both nitric oxide synthase (NOS)-dependent and -independent pathways. We tested the hypothesis that nitrate supplementation would augment the NO component of the cutaneous vasodilatation to local skin heating in young, healthy humans. Participants reported to the lab for pre- and post-supplement local heating protocols. Nitrate supplementation consisted of one shot (70 ml) of beetroot juice (0.45 g nitrate; 5mM) for three days. Six participants were equipped with two microdialysis fibers on the ventral forearm and randomly assigned to lactated Ringer's (control) or continuous infusion of 20mM l-NAME (NOS inhibitor). The control site was subsequently perfused with l-NAME once a plateau in skin blood flow was achieved to quantify NOS-dependent cutaneous vasodilatation. Skin blood flow via laser-Doppler flowmetry (LDF) and mean arterial pressure (MAP) were measured; cutaneous vascular conductance (CVC) was calculated as LDF/MAP and normalized to %CVCmax. Beetroot juice reduced MAP (Pre: 90 +/- 1 mmHg vs. Post: 83 +/- 1 mmHg) and DBP (Pre: 74 +/- 2 mmHg vs. Post: 62 +/- 3 mmHg) (P<0.05). The plateau phase of the local heating response at control sites was augmented post-beetroot juice (91 +/- 5%CVCmax) compared to pre beetroot juice (79 +/- 2%CVCmax) (P<0.05). There was no difference in the %NOS dependent vasodilatation from pre- to post-beetroot juice. These data suggest that nitrate supplementation via beetroot juice can reduce MAP and DBP as well as augment NOS-independent vasodilatation to local heating in the cutaneous vasculature of healthy humans. PMID- 25554362 TI - Personalising the evaluation of substance misuse treatment: a new approach to outcome measurement. PMID- 25554361 TI - Chemical composition of the essential oil of Moluccella spinosa L. (Lamiaceae) collected wild in Sicily and its activity on microorganisms affecting historical textiles. AB - In this study the chemical composition of the essential oil from aerial parts of Moluccella spinosa L. collected in Sicily was evaluated by GC and GC-MS. The main components of M. spinosa L. were alpha-pinene (26.6%), caryophyllene oxide (16.8%) and beta-caryophyllene (8.6%). A comparison with other studied oils of genus Moluccella is made. Antibacterial and antifungal activities against some microorganisms infesting historical textiles were also determined. PMID- 25554358 TI - RNA-mediated epigenetic regulation of gene expression. AB - Diverse classes of RNA, ranging from small to long non-coding RNAs, have emerged as key regulators of gene expression, genome stability and defence against foreign genetic elements. Small RNAs modify chromatin structure and silence transcription by guiding Argonaute-containing complexes to complementary nascent RNA scaffolds and then mediating the recruitment of histone and DNA methyltransferases. In addition, recent advances suggest that chromatin associated long non-coding RNA scaffolds also recruit chromatin-modifying complexes independently of small RNAs. These co-transcriptional silencing mechanisms form powerful RNA surveillance systems that detect and silence inappropriate transcription events, and provide a memory of these events via self reinforcing epigenetic loops. PMID- 25554363 TI - Long-circulating PEGylated manganese ferrite nanoparticles for MRI-based molecular imaging. AB - Magnetic resonance based molecular imaging has emerged as a very promising technique for early detection and treatment of a wide variety of diseases, including cancer, neurodegenerative disorders, and vascular diseases. The limited sensitivity and specificity of conventional MRI are being overcome by the development of a new generation of contrast agents, using nanotechnology approaches, with improved magnetic and biological properties. In particular, for molecular imaging, high specificity, high sensitivity, and long blood circulation times are required. Furthermore, the lack of toxicity and immunogenicity together with low-cost scalable production are also necessary to get them into the clinics. In this work, we describe a facile, robust and cost-effective ligand exchange method to synthesize dual T1 and T2 MRI contrast agents with long circulation times. These contrast agents are based on manganese ferrite nanoparticles (MNPs) between 6 and 14 nm in size covered by a 3 kDa polyethylene glycol (PEG) shell that leads to a great stability in aqueous media with high crystallinity and magnetization values, thus retaining the magnetic properties of the uncovered MNPs. Moreover, the PEGylated MNPs have shown different relaxivities depending on their size and the magnetic field applied. Thus, the 6 nm PEGylated MNPs are characterized by a low r2/r1 ratio of 4.9 at 1.5 T, hence resulting in good dual T1 and T2 contrast agents under low magnetic fields, whereas the 14 nm MNPs behave as excellent T2 contrast agents under high magnetic fields (r2 = 335.6 mM(-1) s(-1)). The polymer core shell of the PEGylated MNPs minimizes their cytotoxicity, and allows long blood circulation times. This combination of cellular compatibility and excellent T2 and r2/r1 values under low magnetic fields, together with long circulation times, make these nanomaterials very promising contrast agents for molecular imaging. PMID- 25554365 TI - Hybrid ZnO/ZnS nanoforests as the electrode materials for high performance supercapacitor application. AB - Heterostructured ZnO/ZnS nanoforests are prepared through a simple two-step thermal evaporation method at 650 degrees C and 1300 degrees C in a tube furnace under the flow of argon gas, respectively. A metal catalyst (Au) to form a binary alloy has been used in the process. The as-obtained ZnO/ZnS products are characterized by using a series of techniques, including scanning electron microscopy (SEM), X-ray diffraction (XRD), energy dispersion X-ray spectroscopy (EDS), Raman spectroscopy and photoluminescence. A possible growth mechanism is temporarily proposed. The hybrid structures are also directly functionalized as supercapacitor (SC) electrodes without using any ancillary materials such as carbon black or binder. Results show that the as-synthesized ZnO/ZnS heterostructures exhibit a greatly reduced ultraviolet emission and dramatically enhanced green emission compared to pure ZnO nanorods. The SCs data demonstrate high specific capacitance of 217 mF cm(-2) at 1 mA cm(-2) and excellent cyclic performance with 82% capacity retention after 2000 cycles at a current density of 2.0 mA cm(-2). PMID- 25554364 TI - Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence. AB - INTRODUCTION: Psychiatric disorders are among the leading causes of disability in Western societies. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs during pregnancy and the postpartum period. Over the last decade, conflicting findings regarding the safety of SSRI drugs during pregnancy and lactation have questioned whether such treatments should be used during this period. AREAS COVERED: We discuss the main criteria that should be considered in the risk/benefit assessment of SSRI treatment in pregnant and/or breastfeeding patients (i.e., risks associated with SSRI use and with untreated depression as well as therapeutic benefits of SSRI and some alternative treatment strategies). For each criterion, available evidence has been synthesized and stratified by methodological quality as well as discussed for clinical impact. EXPERT OPINION: Currently, it is impossible for most of the evaluated outcomes to distinguish between the effects related to the mother's underlying disease and those inherent to SSRI treatment. In women suffering from major depression and responding to a pharmacological treatment, introduction or continuation of an SSRI should be encouraged in order to prevent maternal complications and to preserve maternal-infant bonding. The choice of the right drug depends above all on individual patient characteristics such as prior treatment response, diagnoses and comorbid conditions. PMID- 25554366 TI - Fatty acid profile of different species of algae of the Cystoseira genus: a nutraceutical perspective. AB - The fatty acid (FA) composition of six macroalgae from the Cystoseira genus, namely Cystoseira compressa, Cystoseira humilis, Cystoseira tamariscifolia, Cystoseira nodicaulis, Cystoseira baccata and Cystoseira barbata, was determined. Polyunsaturated fatty acids (PUFA) corresponded to 29-46% of the total FA detected. C. compressa, C. tamariscifolia and C. nodicaulis stood out for their low PUFA/saturated fatty acid, low n-6 PUFA/n-3 PUFA ratios as well as favourable unsaturation, atherogenicity and thrombogenicity indices, suggesting a high nutritional value with potential applications in the nutraceutical industry. PMID- 25554367 TI - Eight pairs of epimeric triterpenoids involving a characteristic spiro-E/F ring from Abies faxoniana. AB - Five pairs of new epimeric lanostane-type triterpenoids, abiespirones A-D (1-4) and G (7), two pairs of new epimeric cycloartane-type triterpenoids, abiespirones E and F (5, 6), and a pair of new epimeric 7(8->9)abeo-spirolanostane abiespirones H (8) with spiro-B/C and -E/F ring systems were isolated from Abies faxoniana as inseparable mixtures of C-23 epimers in a specific proportion. The HPLC plots showed that each purified isomer rapidly equilibrated with the C-23 epimer in solution. The structures of compounds 1-8 were elucidated by analysis of the NMR spectra and single-crystal X-ray diffraction. Compound 6 showed cytotoxicity against three hepatoma cell lines, namely, HepG2, Huh7, and SMMC7721, with IC50 values of 9.8, 7.5, and 10.7 MUM, respectively, but exerted low cytotoxicity on normal QSG7701 hepatic cells, indicating its selective cytotoxicity for hepatoma cells. Compound 6 arrests the cell cycle at G2/M and induces cell apoptosis in Huh7 cells. In addition, the generation of reactive oxygen species (ROS) was detected in Huh7 cells when treated with compound 6, and a ROS scavenger partly blocked the effects of compound 6-induced Huh7 cell death, suggesting that compound 6-induced apoptosis is associated with elevated levels of ROS in Huh7 cells. PMID- 25554370 TI - Choosing wisely: adherence by physicians to recommended use of spirometry in the diagnosis and management of adult asthma. AB - PURPOSE: The National Asthma Education and Prevention Program (NAEPP) and the American Thoracic Society provide guidelines stating that physicians should use spirometry in the diagnosis and management of asthma. The aim of this study was to evaluate the trends, over a 10-year period, in the utilization of spirometry in patients newly diagnosed with asthma. We hypothesized that spirometry use would increase in physicians who care for asthma patients, especially since 2007, when the revised NAEPP guidelines were published. METHODS: This retrospective cohort analysis of spirometry use in subjects newly diagnosed with asthma used a privately insured adult population for the years 2002-2011. Our primary outcome of interest was spirometry performed within a year (+/- 365 days) of the initial date of asthma diagnosis. We also examined the type of asthma medications prescribed. RESULTS: In all, 134,208 patients were found to have a diagnosis of asthma. Only 47.6% had spirometry performed within 1 year of diagnosis. Younger patients, males, and those residing in the Northeast were more likely to receive spirometry. Spirometry use began to decline in 2007. Patients cared for by specialists were more likely to receive spirometry than those cared for by primary care physicians; 80.1% vs 23.3%, respectively. Lastly, even without spirometry, a significant portion of patients (78.3%) was prescribed asthma drugs. CONCLUSIONS: Our study suggests that spirometry is underutilized in newly diagnosed asthma patients. Moreover, the use of controller medications in those diagnosed with asthma without spirometry remains high. PMID- 25554369 TI - Beta-blocker Use and 30-day All-cause Readmission in Medicare Beneficiaries with Systolic Heart Failure. AB - BACKGROUND: Beta-blockers improve outcomes in patients with systolic heart failure. However, it is unknown whether their initial negative inotropic effect may increase 30-day all-cause readmission, a target outcome for Medicare cost reduction and financial penalty for hospitals under the Affordable Care Act. METHODS: Of the 3067 Medicare beneficiaries discharged alive from 106 Alabama hospitals (1998-2001) with a primary discharge diagnosis of heart failure and ejection fraction <45%, 2202 were not previously on beta-blocker therapy, of which 383 received new discharge prescriptions for beta-blockers. Propensity scores for beta-blocker use, estimated for each of the 2202 patients, were used to assemble a matched cohort of 380 pairs of patients receiving and not receiving beta-blockers who were balanced on 36 baseline characteristics (mean age 73 years, mean ejection fraction 27%, 45% women, 33% African American). RESULTS: Beta-blocker use was not associated with 30-day all-cause readmission (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.64-1.18) or heart failure readmission (HR 0.95; 95% CI, 0.57-1.58), but was significantly associated with lower 30-day all-cause mortality (HR 0.29; 95% CI, 0.12-0.73). During 4-year postdischarge, those in the beta-blocker group had lower mortality (HR 0.81; 95% CI, 0.67-0.98) and combined outcome of all-cause mortality or all-cause readmission (HR 0.87; 95% CI, 0.74-0.97), but not with all-cause readmission (HR 0.89; 95% CI, 0.76-1.04). CONCLUSIONS: Among hospitalized older patients with systolic heart failure, discharge prescription of beta-blockers was associated with lower 30-day all-cause mortality and 4-year combined death or readmission outcomes without higher 30-day readmission. PMID- 25554368 TI - Colchicine: old and new. AB - Although colchicine has been a focus of research, debate, and controversy for thousands of years, the US Food and Drug Administration just approved it in 2009. Over the past decade, advances in the knowledge of colchicine pharmacology, drug safety, and mechanisms of action have led to changes in colchicine dosing and to potential new uses for this very old drug. In this review, we discuss the pharmacologic properties of colchicine and summarize what is currently known about its mechanisms of action. We then discuss and update the use of colchicine in a variety of illnesses, including rheumatic and, most recently, cardiovascular diseases. PMID- 25554371 TI - Differences in anticoagulant therapy prescription in patients with paroxysmal versus persistent atrial fibrillation. AB - BACKGROUND: Patients with paroxysmal and persistent atrial fibrillation experience a similar risk of thromboembolism. Therefore, consensus guidelines recommend anticoagulant therapy in those at risk for thromboembolism irrespective of atrial fibrillation classification. We sought to examine whether there are differences in rates of appropriate oral anticoagulant treatment among patients with paroxysmal vs persistent atrial fibrillation in real-world cardiology practices. METHODS: We studied 71,316 outpatients with atrial fibrillation and intermediate to high thromboembolic risk (CHADS2 score >=2) enrolled in the American College of Cardiology PINNACLE Registry between 2008 and 2012. Using hierarchical modified Poisson regression models adjusted for patient characteristics, we examined whether anticoagulant treatment rates differed between patients with paroxysmal vs persistent atrial fibrillation. RESULTS: The majority of outpatients (78.4%, n = 55,905) had paroxysmal atrial fibrillation. In both unadjusted and multivariable adjusted analyses, patients with paroxysmal atrial fibrillation were less frequently prescribed oral anticoagulant therapy than those with persistent atrial fibrillation (50.3% vs 64.2%; adjusted risk ratio [RR] 0.74; 95% confidence interval [CI], 0.72-0.76). Instead, patients with paroxysmal atrial fibrillation were prescribed more frequently only antiplatelet therapy (35.1% vs 25.0%; adjusted RR 1.77; 95% CI, 1.69-1.86) or neither antiplatelet nor anticoagulant therapy (14.6% vs 10.8%; adjusted RR 1.35; 95% CI, 1.26-1.44; P < .0001 for differences across all 3 comparisons). CONCLUSIONS: In a large, real-world cardiac outpatient population, patients with paroxysmal atrial fibrillation with a moderate to high risk of stroke were less likely to be prescribed appropriate oral anticoagulant therapy and more likely to be prescribed less effective or no therapy for thromboembolism prevention. PMID- 25554373 TI - Exertion-related rhabdomyolysis observed with hyperthyroidism. PMID- 25554372 TI - The complex relationship of race to outcomes in heart failure with preserved ejection fraction. AB - BACKGROUND: An improved understanding of racial differences in the natural history, clinical characteristics, and outcomes of heart failure will have important clinical and public health implications. We assessed how clinical characteristics and outcomes vary across racial groups (whites, blacks, and Asians) in adults with heart failure with preserved ejection fraction. METHODS: We identified all adults with heart failure with preserved ejection fraction between 2005 and 2008 from 4 health systems in the Cardiovascular Research Network using hospital principal discharge and ambulatory visit diagnoses. RESULTS: Among 13,437 adults with confirmed heart failure with preserved ejection fraction, 85.9% were white, 7.6% were black, and 6.5% were Asian. After adjustment for potential confounders and use of cardiovascular therapies, compared with whites, blacks (adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.85) and Asians (HR, 0.75; 95% CI, 0.64-0.87) had a lower risk of death from any cause. Compared with whites, blacks had a higher risk of hospitalization for heart failure (HR, 1.48; 95% CI, 1.29-1.68); no difference was observed for Asians compared with whites (HR, 1.01; 95% CI, 0.86-1.18). Compared with whites, no significant differences were detected in risk of hospitalization for any cause for blacks (HR, 1.03; 95% CI, 0.95-1.12) and Asians (HR, 0.93; 95% CI, 0.85-1.02). CONCLUSIONS: In a diverse population with heart failure with preserved ejection fraction, we observed complex relationships between race and important clinical outcomes. More detailed studies of large populations are needed to fully characterize the epidemiologic picture and to elucidate potential pathophysiologic and treatment-response differences that may relate to race. PMID- 25554374 TI - Required Reading for Anyone Involved in Postgraduate Medical Education (Part 2). PMID- 25554375 TI - Trends and burden of firearm-related hospitalizations in the United States across 2001-2011. AB - BACKGROUND: Firearm-related hospitalizations are a major burden to the current health care infrastructure. We examined the trends in the incidence and case fatality rates of firearm-related hospitalizations over the past decade. We also hypothesized that major national economic perturbations would be partly responsible and correlate temporally with national firearm-related hospitalization trends. METHODS: We used the 2001-2011 Nationwide Inpatient Sample for analysis. Firearm-related hospitalizations were identified using International Classification of Diseases, 9(th) Revision codes. In addition, we examined the relationship between the US stock market performance (Dow Jones Industrial Average) and the annual firearm-related hospitalization incidence rates. RESULTS: In the last decade, there has been a modest decline in firearm related hospitalizations, interrupted by spikes in the annual incidence that closely corresponded to periods of national economic instability. In addition, the overall case-fatality rate following firearm-related hospitalization has been stable at ~8%; the highest rates being present among those who attempted suicide using firearms. Also, there has been an increase in the prevalence of mental health disorders among individuals admitted with firearm-related injuries. Moreover, there was an increase in the length of stay and the cost/charges associated with hospitalization over the last decade. CONCLUSION: Over 2001-2011, the national incidence of firearm-related hospitalizations has closely tracked the national stock market performance, suggesting that economic perturbations and resultant insecurities might underlie the perpetuation of firearm-related injuries. Although the case-fatality rates have remained stable, the length of stay and hospitalization costs have increased, imposing additional burden on existing health care resources. PMID- 25554376 TI - Outcomes with invasive vs conservative management of cardiogenic shock complicating acute myocardial infarction. AB - BACKGROUND: In the SHOCK trial, an invasive strategy of early revascularization was associated with a significant mortality benefit at 6 months when compared with initial stabilization in patients with cardiogenic shock complicating acute myocardial infarction. Our objectives were to evaluate the data on real-world practice and outcomes of invasive vs conservative management in patients with cardiogenic shock. METHODS: We analyzed data from the Nationwide Inpatient Sample from 2002 to 2011 with primary discharge diagnosis of acute myocardial infarction and secondary diagnosis of cardiogenic shock. Propensity score matching was used to assemble a cohort of patients managed invasively (with cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass graft surgery) vs conservatively with similar baseline characteristics. The primary outcome was in-hospital mortality. RESULTS: We identified 60,833 patients with cardiogenic shock, of which 20,644 patients (10,322 in each group) with similar propensity scores, including 11,004 elderly patients (>=75 years), were in the final analysis. Patients who underwent invasive management had 59% lower odds of in-hospital mortality (37.7% vs 59.7%; odds ratio [OR] 0.41; 95% confidence interval [CI], 0.39-0.43; P < .0001) when compared with those managed conservatively. This lower mortality was consistently seen across all tested subgroups; specifically in the elderly (>=75 years) (44.0% vs 63.6%; OR 0.45; 95% CI, 0.42-0.49; P < .0001) and those younger than 75 years (30.6% vs 55.1%; OR 0.36; 95% CI, 0.33-0.39; P < .0001), although the magnitude of risk reduction differed (Pinteraction < .0001). CONCLUSIONS: In this largest cohort of patients with cardiogenic shock complicating acute myocardial infarction, patients managed invasively had significantly lower mortality when compared with those managed conservatively, even in the elderly. Our results emphasize the need for aggressive management in this high-risk subgroup. PMID- 25554377 TI - Training and sustaining physician scientists: what is success? PMID- 25554378 TI - Discharge before noon: an urban legend. PMID- 25554380 TI - Antiviral treatment of Bell's palsy based on baseline severity: a systematic review and meta-analysis. AB - PURPOSE: We conducted a systematic review with meta-analysis to evaluate the efficacy of antiviral agents on complete recovery of Bell's palsy. METHODS: We searched CENTRAL, Embase, MEDLINE, International Pharmaceutical Abstracts, and sources of unpublished literature to November 1, 2014. Primary and secondary outcomes were complete and satisfactory recovery, respectively. To evaluate statistical heterogeneity, we performed subgroup analysis of baseline severity of Bell's palsy and between-study sensitivity analyses based on risk of allocation and detection bias. RESULTS: The 10 included randomized controlled trials (2419 patients; 807 with severe Bell's palsy at onset) had variable risk of bias, with 9 trials having a high risk of bias in at least 1 domain. Complete recovery was not statistically significantly greater with antiviral use versus no antiviral use in the random-effects meta-analysis of 6 trials (relative risk, 1.06; 95% confidence interval, 0.97-1.16; I(2) = 65%). Conversely, random-effects meta analysis of 9 trials showed a statistically significant difference in satisfactory recovery (relative risk, 1.10; 95% confidence interval, 1.02-1.18; I(2) = 63%). Response to antiviral agents did not differ visually or statistically between patients with severe symptoms at baseline and those with milder disease (test for interaction, P = .11). Sensitivity analyses did not show a clear effect of bias on outcomes. CONCLUSIONS: Antiviral agents are not efficacious in increasing the proportion of patients with Bell's palsy who achieved complete recovery, regardless of baseline symptom severity. PMID- 25554381 TI - Hyponatremia as a result of posttraumatic primary polydipsia. PMID- 25554379 TI - Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-up. AB - PURPOSE: Short-term outcomes have been well characterized in acute coronary syndromes; however, longer-term follow-up for the entire spectrum of these patients, including ST-segment-elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina, is more limited. Therefore, we describe the longer-term outcomes, procedures, and medication use in Global Registry of Acute Coronary Events (GRACE) hospital survivors undergoing 6-month and 2-year follow-up, and the performance of the discharge GRACE risk score in predicting 2-year mortality. METHODS: Between 1999 and 2007, 70,395 patients with a suspected acute coronary syndrome were enrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronary syndrome diagnosis in 57 sites. RESULTS: From 2004 to 2007, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge, 14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery, and 24.2% were re-hospitalized. In patients with 2-year follow-up, acetylsalicylic acid (88.7%), beta-blocker (80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heart failure occurred in 6.3%, (re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE risk score was highly predictive of all-cause mortality at 2 years (c-statistic 0.80). CONCLUSION: In this large multinational cohort of acute coronary syndrome patients, there were important later adverse consequences, including frequent morbidity and mortality. These findings were seen in the context of additional coronary procedures and despite continued use of evidence-based therapies in a high proportion of patients. The discriminative accuracy of the GRACE risk score in hospital survivors for predicting longer-term mortality was maintained. PMID- 25554383 TI - The effect of western juniper on the estrous cycle in beef cattle. AB - Numerous evergreen trees and shrubs contain labdane acids, including isocupressic acid, which can cause late-term abortions in cattle. Recent research has shown that the bark from western juniper trees can also cause late-term abortions in cattle. Additionally, ranchers have observed that cattle in western juniper infested rangelands tend to have decreased conception rates. The objective of this study was to determine if western juniper alters the estrous cycle of cattle. Fourteen heifers (10 treated and 4 control) were monitored for 74 days for signs of normal estrous behavior, with a 21 day feeding trial with western juniper bark from days 28-48, after which the cattle were bred naturally with a bull. The cattle were checked for pregnancy 30 days after all cattle had been bred. The data from this study indicate that exposure to western juniper bark does not affect normal estrus, estrous cycle or conception rates of cattle. PMID- 25554382 TI - The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. AB - Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses." PMID- 25554384 TI - Hypothesis: Activation of rapid signaling by environmental estrogens and epigenetic reprogramming in breast cancer. AB - Environmental and lifestyle factors are considered significant components of the increasing breast cancer risk in the last 50 years. Specifically, exposure to environmental endocrine disrupting compounds is correlated with cancer susceptibility in a variety of tissues. In both human and rodent models, the exposure to ubiquitous environmental estrogens during early life has been shown to disrupt normal mammary development and cause permanent adverse effects. Recent studies indicate that environmental estrogens not only have the ability to disrupt estrogen receptor (ER) signaling, but can also reprogram the epigenome by altering DNA and histone methylation through rapid, nongenomic ER actions. We have observed xenoestrogen-mediated activation of several nongenomic signaling pathways and have identified a target for epigenetic reprogramming in MCF-7 breast cancer cells. These observations, in addition to data from the literature, support the hypothesis that activation of rapid signaling by environmental estrogens can lead to epigenetic reprogramming and contribute to the progression of breast cancer. PMID- 25554386 TI - Investigation of coatings of natural organic matter on silver nanoparticles under environmentally relevant conditions by surface-enhanced Raman scattering. AB - The widespread use of engineered inorganic nanoparticles (EINP) leads to a growing risk for an unintended release into the environment. Despite the good characterization of EINP in regard to their function scale and the application areas, there is still a gap of knowledge concerning their behaviour in the different environmental compartments. Due to their high surface to volume ratio, surface properties and existence or development of a coating are of high importance for their stability and transport behaviour. However, analytical methods to investigate organic coatings on nanoparticles in aqueous media are scarce. We used Raman microspectroscopy in combination with surface-enhanced Raman scattering (SERS) to investigate humic acid coatings on silver nanoparticles under environmentally relevant conditions and in real world samples. This setup is more challenging than previous mechanistic studies using SERS to characterize the humic acids in tailored settings where only one type of organic matter is present and the concentrations of the nanoparticles can be easily adjusted to the experimental needs. SERS offers the unique opportunity to work with little sample preparation directly with liquid samples, thus significantly reducing artefacts. SERS spectra of different natural organic matter brought into contact with silver nanoparticles indicate humic acid in close proximity to the nanoparticles. This coating was also present after several washing steps by centrifugation and resuspension in deionized water and after an increase in ionic strength. PMID- 25554385 TI - Effect of maternal exposure to endocrine disrupting chemicals on reproduction and mammary gland development in female Sprague-Dawley rats. AB - The aim of the study is to determine whether low doses of "endocrine disrupting chemicals" (EDCs) affect the development and proliferative activity of the mammary glands (MGs). Adult parous/nulliparous female Sprague-Dawley (SD) rats were treated from post-natal day (PND) 1 until PND 180 with diethylphthalate (DEP), methylparaben (MPB), triclosan (TCS) and a mixture at doses comparable to human exposure. The doses (mg/kg b.w./day) were: DEP=0.173; MPB=0.105; TCS=0.05. EDC treatment resulted in mortality rates >20% in pups as early as lactation day 7. Significant morphological/histological changes were observed at the end of lactation in the MGs of EDC-treated dams. The total transcriptome profile as well as lactation-related genes in MGs also corroborate the morphological findings as more profound gene expression changes are present only at the weaning period. The study highlights the heightened sensitivity of the MGs during critical windows of exposure, particularly pregnancy and lactation, with an impact on pups' survival. PMID- 25554387 TI - Water resource management: a comparative evaluation of Brazil, Rio de Janeiro, the European Union, and Portugal. AB - This paper presents an overview of water resource management in Brazil, in particular the state of Rio de Janeiro, and in the European Union, with an emphasis on member country Portugal. The study examines the primary laws, governing bodies and water resource plans. The paper describes the concerns and interests of the scientific community and other sectors of society with regard to water resource management. The paper also draws attention to challenges and opportunities concerning the main objective of water resource management, which is to ensure the availability of water of high quality and sustainable quantity. Additionally, it also mentions good and poor management practices. Among the concerns highlighted are integrated water resource management and water resource monitoring. The objective of this study was to contribute to water resource management processes. The primary reasons for this study are the growing scarcity of freshwater in the world, recurrent problems in managing this resource and a desire to contribute to the improvement of the current situation. The study of water management in different contexts allows for a greater understanding of the subject, thereby assisting the decision-making of managers and society in general with regard to environmental quality and ecological and human health. There is an increasing interest in efficient water resource management, which creates a demand for information on the subject. Both Brazil and the European Union are facing problems related to quantity and quality of water. Problems like scarcity of freshwater, contamination, salinization, and floods. This makes the realities of them quite close, despite the physical distance between them. In general, Brazil, Rio de Janeiro, the European Union and Portugal have similar water resource management requirements. If these regions are to supply a consistent quantity of high-quality water to present and future generations, then they need effective laws and plans, efficient managing agencies, political interest and economic resources. Investments in research and developing water resource management plans are inefficient measures if they are not implemented with special emphasis on monitoring and inspection. PMID- 25554388 TI - Multiple drug-susceptibility screening in Mycobacterium bovis: new nucleotide polymorphisms in the embB gene among ethambutol susceptible strains. AB - OBJECTIVES: Pyrazinamide-resistant Mycobacterium bovis isolates of animal origin were assessed for drug susceptibility to five antituberculosis drugs by the agar based Middlebrook 7H11 method as gold standard as well as by a simplified, dichotomous resazurin microtitre assay (d-REMA). METHODS: A total of 53 M. bovis isolates were typed and tested against isoniazid, rifampin, streptomycin, ethambutol, kanamycin and the control drug pyrazinamide. On the basis of the results obtained, pncA and embB genes were PCR-amplified and DNA-sequenced for all isolates. RESULTS: All M. bovis isolates, classified into 21 spoligotype/MIRU VNTR profiles, were resistant to pyrazinamide by both methods, as expected. The pncA gene sequencing confirmed the presence of the resistance-conferring H57D mutation. All strains were found to be susceptible to the other five drugs by the agar based gold standard method. The d-REMA was in agreement with these results for all five drugs, with the exception of 12 isolates, which showed ambiguous and therefore inconclusive results in ethambutol testing. Mutations in the embB gene were observed in all 53 isolates: four new single-nucleotide polymorphisms were identified. No association was found between embB genetic profiles and ethambutol resistance results by the gold standard. CONCLUSION: All M. bovis isolates were sensitive to the most common antituberculosis drugs used for treatment. There was a good agreement between the d-REMA assay and the agar based reference method. Among ethambutol susceptible isolates, four new embB mutations were found. PMID- 25554389 TI - Validity of the International HIV Dementia Scale as assessed in a socioeconomically underdeveloped region of Southern China: assessing the influence of educational attainment. AB - In 2012, more than 80,000 cases of HIV infection were recorded in the Southern Chinese minority autonomous region of Guangxi Zhuang, where the occurrence of HIV associated dementia remains high. The International HIV Dementia Scale is a relatively simple-to-administer screening scale for HIV-associated neurocognitive disorders. However, clinical experience in utilizing the scale with large Chinese samples is currently lacking, especially among individuals with limited formal schooling. In this study, a full neuropsychological evaluation the gold standard was conducted to identify the incidence/prevalence of HIV-associated neurocognitive disorders in a socioeconomically underdeveloped region of Southern China and to locate the optimal cut-off scale value using receiver operating characteristic curves. The highest Youden index of the scale was 0.450, with a corresponding cut-off point of 7.25. The sensitivity and specificity were 0.737 and 0.713, respectively. These results suggest that the scale is an effective and feasible screening tool for HIV-associated neurocognitive disorders in poorer regions of China with fewer well-educated residents. PMID- 25554390 TI - Erratum to: Ploidy-dependent survival of progeny arising from crosses between natural allotriploid Cobitis females and diploid C. taenia males (Pisces, Cobitidae). PMID- 25554399 TI - [Usefulness of assessing hydration status in elderly patients over 70 years with suspected deep vein thrombosis]. AB - INTRODUCTION: Venous thromboembolism and dehydration are frequent conditions in elderly. The objective of this study was to assess the prevalence of dehydration in patients aged over 70 years suspected of deep vein thrombosis (DVT). METHODS: This is a prospective observational study that included patients aged over 70 years and suspected of deep vein thrombosis. Clinical and biological dehydration was diagnosed on the presence of a skin fold, a weight loss>=5%, a thirst, a plasmatic osmolality>295 mOsm/L or blood urea nitrogen/creatinine ratio>20. RESULTS: One hundred and forty-four patients (mean age 81.8+/-5.8 years) were included. A diagnosis of DVT was retained in 97 patients. Clinical dehydration was not more frequent in the DVT+ group (37.2% vs 35.1%). At baseline, 69.1% of DVT+ patients and 53.2% of DVT- patients had a plasma osmolality greater than 295 mosm/L (NS). BUN/creatinine ratio greater than 20 was found in 58.8% of DVT+ patients and 72.3% of DVT- patients (NS). Clinical and biological dehydration was present in 28.6% of DVT+ patients and in 33.3% of DVT- patients (NS). The positive predictive value of the Wells score>=3 was 86.5%, and negative predictive value of a Wells score<=0 was 85%. CONCLUSION: The presence of dehydration does not appear predictive of the occurrence of DVT and does not influence the statistical performance of the Wells score in elderly patients. PMID- 25554400 TI - [Psoriatic arthritis during rituximab treatment of granulomatosis with polyangiitis: a new paradoxical side effect?]. AB - INTRODUCTION: Rituximab is a monoclonal antibody targeting the CD20 molecule of the B lymphocyte. Its efficacy has been recently reported in ANCA-associated vasculitis. We report a case of psoriatic arthritis that occurs during a treatment with rituximab in granulomatosis with polyangiitis. CASE REPORT: A 66 year-old woman, without past history of psoriasis, presented with a relapsing granulomatosis with polyangiitis in July 2010 with sinus and lung involvement. Treatment with rituximab was started, allowing a complete remission in 6 months. Two months after the first two infusions of rituximab she developed asymmetric arthritis of 3 distal interphalangeal joints. A few months later, the clinical presentation showed asymmetrical arthritis of the hands and wrists and dactylitis. Standard radiographs and MRI showed an inflammatory impairment according with psoriatic arthritis. CONCLUSION: Accountability of rituximab was retained in the development of the disease given the chronology of psoriatic arthritis development. It may be a paradoxical reaction, by analogy to those observed in anti-TNFalpha. PMID- 25554402 TI - Analysis of high-throughput screening reveals the effect of surface topographies on cellular morphology. AB - Surface topographies of materials considerably impact cellular behavior as they have been shown to affect cell growth, provide cell guidance, and even induce cell differentiation. Consequently, for successful application in tissue engineering, the contact interface of biomaterials needs to be optimized to induce the required cell behavior. However, a rational design of biomaterial surfaces is severely hampered because knowledge is lacking on the underlying biological mechanisms. Therefore, we previously developed a high-throughput screening device (TopoChip) that measures cell responses to large libraries of parameterized topographical material surfaces. Here, we introduce a computational analysis of high-throughput materiome data to capture the relationship between the surface topographies of materials and cellular morphology. We apply robust statistical techniques to find surface topographies that best promote a certain specified cellular response. By augmenting surface screening with data-driven modeling, we determine which properties of the surface topographies influence the morphological properties of the cells. With this information, we build models that predict the cellular response to surface topographies that have not yet been measured. We analyze cellular morphology on 2176 surfaces, and find that the surface topography significantly affects various cellular properties, including the roundness and size of the nucleus, as well as the perimeter and orientation of the cells. Our learned models capture and accurately predict these relationships and reveal a spectrum of topographies that induce various levels of cellular morphologies. Taken together, this novel approach of high-throughput screening of materials and subsequent analysis opens up possibilities for a rational design of biomaterial surfaces. PMID- 25554401 TI - [Cryofibrinogenemia: a single-center study at the University Hospital of Toulouse, France]. AB - PURPOSE: Cryofibrinogenemia is an unknown disorder and studies dedicated to it are limited. The aim of our study was to report on the incidence, clinical manifestations and associated diseases in patients with isolated cryofibrinogenemia. METHODS: This is a retrospective single-center study. Patients included in this study had a positive and isolated detection of cryofibrinogen between January 1st, 2011 and December 31st, 2012. Identification was possible through the database of the laboratory of immunology. RESULTS: Two hundred and eighty-one consecutive orders of cryofibrinogenemia were identified. Seventy-three patients had a positive detection of cryofibrinogenemia. Among them, 12 had an isolated cryofibrinogenemia and sixty-one patients (84%) had concomitant cryofibrinogenemia and cryoglobulinemia. The mean age was 59+/ 19years. Seven patients were female (58%). Cutaneous manifestations were present in half case. Peripheral nerve involvement was present in 5 cases (42%) and rheumatic manifestations in 4 patients (33%). A thrombotic event was reported in 7 patients (58%). Renal impairment was present in 7 patients. The median cryofibrinogen concentration was 254+/-304mg/L. Five patients had a secondary cryofibrinogenemia. The most often prescribed treatment was corticosteroids. CONCLUSION: Cryofibrinogenemia is an unknown disorder. Testing for cryoglobulinemia is more frequent than for cryofibrinogenemia whereas clinical manifestations are similar. Detection of cryofibrinogen is positive in most of the cases, with an important prevalence of thrombotic events in this population. This study confirms the importance of conducting prospective studies on cryofibrinogenemia. PMID- 25554403 TI - Prevention of cardiomyopathy in Duchenne muscular dystrophy. PMID- 25554409 TI - THIRD MOLARS AND TMD. PMID- 25554404 TI - Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. METHODS: In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. FINDINGS: Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median DeltaEcc 1.0 [IQR 0.3-2.2] vs 2.2 [1.3-3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. INTERPRETATION: In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. FUNDING: BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health. PMID- 25554414 TI - Spatial characterization of a multifunctional pipette for drug delivery in hippocampal brain slices. AB - BACKGROUND: Among the various fluidic control technologies, microfluidic devices are becoming powerful tools for pharmacological studies using brain slices, since these devices overcome traditional limitations of conventional submerged slice chambers, leading to better spatiotemporal control over delivery of drugs to specific regions in the slices. However, microfluidic devices are not yet fully optimized for such studies. NEW METHOD: We have recently developed a multifunctional pipette (MFP), a free standing hydrodynamically confined microfluidic device, which provides improved spatiotemporal control over drug delivery to biological tissues. RESULTS: We demonstrate herein the ability of the MFP to selectively perfuse one dendritic layer in the CA1 region of hippocampus with CNQX, an AMPA receptor antagonist, while not affecting the other layers in this region. Our experiments also illustrate the essential role of hydrodynamic confinement in sharpening the spatial selectivity in brain slice experiments. Concentration-response measurements revealed that the ability of the MFP to control local drug concentration is comparable with that of whole slice perfusion, while in comparison the required amounts of active compounds can be reduced by several orders of magnitude. COMPARISON WITH EXISTING METHOD: The multifunctional pipette is applied with an angle, which, compared to other hydrodynamically confined microfluidic devices, provides more accessible space for other probing and imaging techniques. CONCLUSIONS: Using the MFP it will be possible to study selected regions of brain slices, integrated with various imaging and probing techniques, without affecting the other parts of the slices. PMID- 25554417 TI - MiR-10a and miR-181c regulate collagen type I generation in hypertrophic scars by targeting PAI-1 and uPA. AB - Urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been proposed to play key roles in extracellular matrix (ECM) deposition in hypertrophic scars (HS). Here, we found that in HS fibroblasts (HFs) miR-181c and miR-10a were differentially-expressed and targeted uPA and PAI 1, respectively. The production of Type 1 collagen (Col1) was inhibited by miR 181c knockdown or miR-10a overexpression in HFs, and this resulted in increased levels of metalloproteinase 1 (MMP1). These results suggest that the miR-181c-uPA and miR-10a-PAI-1 regulatory pathways have an integral role in HS pathogenesis. PMID- 25554415 TI - A novel method to study cerebrospinal fluid dynamics in rats. AB - BACKGROUND: Cerebrospinal fluid (CSF) flow dynamics play critical roles in both the immature and adult brain, with implications for neurodevelopment and disease processes such as hydrocephalus and neurodegeneration. Remarkably, the only reported method to date for measuring CSF formation in laboratory rats is the indirect tracer dilution method (a.k.a., ventriculocisternal perfusion), which has limitations. NEW METHOD: Anesthetized rats were mounted in a stereotaxic apparatus, both lateral ventricles were cannulated, and the Sylvian aqueduct was occluded. Fluid exited one ventricle at a rate equal to the rate of CSF formation plus the rate of infusion (if any) into the contralateral ventricle. Pharmacological agents infused at a constant known rate into the contralateral ventricle were tested for their effect on CSF formation in real-time. RESULTS: The measured rate of CSF formation was increased by blockade of the Sylvian aqueduct but was not changed by increasing the outflow pressure (0-3cm of H2O). In male Wistar rats, CSF formation was age-dependent: 0.39+/-0.06, 0.74+/-0.05, 1.02+/-0.04 and 1.40+/-0.06MUL/min at 8, 9, 10 and 12 weeks, respectively. CSF formation was reduced 57% by intraventricular infusion of the carbonic anhydrase inhibitor, acetazolamide. COMPARISON WITH EXISTING METHODS: Tracer dilution methods do not permit ongoing real-time determination of the rate of CSF formation, are not readily amenable to pharmacological manipulations, and require critical assumptions. Direct measurement of CSF formation overcomes these limitations. CONCLUSIONS: Direct measurement of CSF formation in rats is feasible. Our method should prove useful for studying CSF dynamics in normal physiology and disease models. PMID- 25554419 TI - miR-374a promotes cell proliferation, migration and invasion by targeting SRCIN1 in gastric cancer. AB - MicroRNAs (miRNAs) play a prominent role in gastric cancer (GC) initiation and progression. In this study, we found that miR-374a expression was up-regulated in human GC cell lines and tissues. Inhibition of miR-374a suppressed GC cell proliferation, migration and invasion in vitro and slowed tumor growth in vivo. SRC kinase signaling inhibitor 1 (SRCIN1) was identified as a direct target of miR-374a. Silencing of SRCIN1 significantly enhanced cell proliferation, migration and invasion, whereas SRCIN1 reintroduction partially abrogated the oncogenic effects of miR-374a. Taken together, these findings suggest that miR 374a functions as a candidate oncogene in GC by directly targeting SRCIN1. miR 374a may therefore be useful as a promising therapeutic target for malignant GC. PMID- 25554418 TI - Divergent signalling pathways regulate lipopolysaccharide-induced eRNA expression in human monocytic THP1 cells. AB - Recent studies have indicated that non-coding RNAs transcribed from enhancer regions are important regulators of enhancer function and gene expression. In this report, we have characterised the expression of six enhancer RNAs (eRNAs) induced in human monocytic THP1 cells following activation of the innate immune response by lipopolysaccharide (LPS). Specifically, we have demonstrated that LPS induced expression of individual eRNAs is mediated through divergent intracellular signalling pathways that includes NF-kappaB and the mitogen activated protein kinases, extracellular regulated kinase-1/2 and p38. PMID- 25554420 TI - Interaction of Bordetella adenylate cyclase toxin with complement receptor 3 involves multivalent glycan binding. AB - The interaction of Bordetella pertussis adenylate cyclase toxin (CyaA) with complement receptor 3 (CR3, CD11b/CD18) involves N-linked oligosaccharide chains. To investigate the relative importance of the individual N-glycans of CR3 for toxin activity, the asparagine residues of the consensus N-glycosylation sites of CR3 were substituted with glutamine residues that cannot be glycosylated. Examination of CR3 mutant variants and mass spectrometry analysis of the N glycosylation pattern of CR3 revealed that N-glycans located in the C-terminal part of the CD11b subunit are involved in binding and cytotoxic activity of CyaA. We suggest that these N-glycans form a defined clustered saccharide patch that enables multivalent contact of CR3 with CyaA, enhancing both affinity and specificity of the integrin-toxin interaction. PMID- 25554421 TI - Comparative study of phrenic and intercostal nerve transfers for elbow flexion after global brachial plexus injury. AB - BACKGROUND: Global brachial plexus injuries (BPIs) are devastating events frequently resulting in severe functional impairment. The widely used nerve transfer sources for elbow flexion in patients with global BPIs include intercostal and phrenic nerves. OBJECTIVE: The aim of this study was to compare phrenic and intercostal nerve transfers for elbow flexion after global BPI. METHODS: A retrospective review of 33 patients treated with phrenic and intercostal nerve transfer for elbow flexion in posttraumatic global root avulsion BPI was carried out. In the phrenic nerve transfer group, the phrenic nerve was transferred to the anterolateral bundle of the anterior division of the upper trunk (23 patients); in the intercostal nerve transfer group, three intercostal nerves were coapted to the anterolateral bundles of the musculocutaneous nerve. The British Medical Research Council (MRC) grading system, angle of elbow flexion, and electromyography (EMG) were used to evaluate the recovery of elbow flexion at least 3 years postoperatively. RESULTS: The efficiency of motor function in the phrenic nerve transfer group was 83%, while it was 70% in the intercostal nerve transfer group. The two groups were not statistically different in terms of the MRC grade (p=0.646) and EMG results (p=0.646). The outstanding rates of angle of elbow flexion were 48% and 40% in the phrenic and intercostal nerve transfer groups, respectively. There was no significant difference of outstanding rates in the angle of elbow flexion between the two groups. CONCLUSION: Phrenic nerve transfer had a higher proportion of good prognosis for elbow flexion than intercostal nerve transfer, but the effective and outstanding rate had no significant difference for biceps reinnervation between the two groups according to MRC grading, angle of elbow flexion, and EMG. PMID- 25554422 TI - Percutaneous iliosacral fixation in external rotational pelvic fractures. A biomechanical analysis. AB - INTRODUCTION: Although the gold standard in open book pelvic fractures remains the pubic symphysis (PS) plate fixation, the clinical outcomes are not satisfactory, despite the excellent anatomical reduction assessed radiologically. Some authors suggest that residual instability of the posterior pelvic elements may be responsible for the chronic pain and the early osteoarthritic changes in the sacroiliac joint (SIJ). OBJECTIVE: To evaluate whether the isolated posterior fixation with one or two iliosacral screws (ISSs) is sufficient to provide adequate stability for the treatment of Burgess Young APC-II (YB APC-II) type of pelvic ring injuries. METHODS: Biomechanical experimental study using 7 fresh human pelvises, where an YB APC-II pelvic injury was previously implemented. The isolated posterior fixation of the pelvic ring with 1 or 2 ISSs directed in the S1 vertebra body was analysed in each specimen following an axial load of 300N. The different displacement of the SIJ and of the PS were analysed in all three spatial axes, using the validated optical measurement system 3D PONTOS 5M. A multivariate version of Friedman test (non-parametric ANOVA for repeated measures) was performed. RESULTS: The isolated fixation of the SIJ with 1 ISS did not show any differences with respect to the intact pelvis (p=0.851). Regarding the PS, both type of fixations (with 1 or 2 ISSs) confirmed an acceptable correction and adequate control of the PS even though with some differences compared to the intact pelvis (p=0.01). The presence of the second ISS found not to offer any significant additional benefit. The three-dimensional analysis of the behaviour of the pelvic elements, in these two different types of fixation, did not show any statistical significant differences (p=0.645). CONCLUSION: The posterior fixation with ISS can represent an alternative option for treatment of pelvic injuries associated with rotational instability. Further prospective clinical studies are necessary to determine, the influence of the residual pubic symphysis mobility in the every day life, when the above-mentioned technique is applied. PMID- 25554423 TI - Hoffa's fracture - lateral meniscus obstructing the fracture reduction - a case report. AB - Hoffa's fracture is a coronal fracture of the posterior femoral condyle and is an unusual injury. It can be easily missed on plain radiographs. There is no dearth of literature on Hoffa's fracture, its various presentations, management and rehabilitation principles. The intra-articular nature of the fracture, vulnerable blood supply of the posterior femoral condyle, involvement of the weight bearing articular surface of the knee and the unstable fracture pattern necessitate the surgical management. We encountered an unusual case of Hoffa's fracture where the lateral meniscus was blocking the reduction of fractured fragments. The patient required mini arthrotomy to remove the meniscus from in between the bone fragments. The fracture was fixed with two anteroposterior screws and knee was immobilised in extension. A gentle knee range of movements was commenced after the wound had healed but weight bearing was delayed for 12 weeks. PMID- 25554424 TI - Evidence based update: open versus closed reduction. AB - Outcomes after operative treatment of displaced femoral neck fractures in young adults are fraught with high complications rates including non-union and avascular necrosis. Among the therapeutic controversies that persist is the role of open reduction, which would allow surgeons a direct means to improve the quality of reduction, a predictor of successful treatment. We performed a systematic review of the literature to compare the outcomes (nonunion, avascular necrosis, and deep infection) after open reduction with internal fixation (ORIF) to closed reduction with internal fixation (CRIF) of acute (surgery performed less than 6 weeks from injury) femoral neck fractures in young adults (average age of 50 or younger) followed for at least one year. Despite the large literature investigating outcomes after operative treatment of femoral neck fracture, relatively few studies aimed to determine the relative risk of complications associated with method of reduction. Therefore, both observational and randomised studies as well as case series with clear descriptions of surgical approach and outcomes were included. We identified 21 studies that matched our inclusion criteria. The incidence of nonunion was 11.6% in closed reduction and 14.9% in the open reduction group (P=0.25). The incidence of avascular necrosis for CRIF and ORIF were 17.2% and 17.7% respectively (P=0.91). The incidence of deep wound infection was 0.49% in the closed reduction group and 3.9% in the open reduction group (P=0.0019). Meta-analysis of risk ratios estimated from six of the studies with comparative data revealed no significant difference in the incidence of nonunion, avascular necrosis or total complications between the two reduction techniques. In summary, systematic review of the literature reveals a lack of evidence in support of ORIF versus CRIF as a means of treating displaced femoral neck fractures in young patients with respect to union and avascular necrosis; however, the incidence of surgical site infections may be lower with CRIF. Firm conclusions cannot be drawn given the lack of high quality prospective studies and patient reported outcomes. In the future, randomised controlled trials will be required to test the effect of reduction method. PMID- 25554425 TI - Ankle fractures: When can I drive, doctor? A simulation study. AB - Traumatic ankle fractures are common injuries. Following injury, patients ask their doctor 'when can I drive doctor?' The ability to safely drive depends on several variables including reaction time, force, range of movement and pain. Return of the braking force is essential for return to driving and to our knowledge has not been addressed previously in the literature. The aim of this study is to pilot a sample of patients with ankle fractures for the return of their normal power and visual reaction time following injury using a simulator (DTS: Drive Test Station). Normal parameters were defined by the patient's contra lateral non-injured limb. After confirming fracture union, 12 drivers with an isolated right ankle fracture were recruited 7.8 days after coming out of plaster (0-21 days). DTS was used to examine patients' ability to apply a braking force of 35 kg, representing the amount of force required to do an emergency stop at 70 mph. Visual reaction time was tested to assess patients' cognitive function. Results showed the average maximum brake pedal force to be 34.4 kg (range: 32-35 kg). Paired sample t-test for the total visual reaction time and visual pathway reaction time showed the p-value>0.05 indicating no statistical difference between the injured limb and non-injured control side at the time of the examination. In conclusion, the DTS can be used to simulate an emergency stop to assess the motor power and cognitive function (visual reaction time) in case of right ankle fractures as this can give the patient an idea regarding their ability to apply brake force and the return of their visual reaction time. It is a practical assessment tool that could be used in fracture clinic setting. We still reserve our ability to advise patients to return to driving as this could bear significant medicolegal responsibility. PMID- 25554427 TI - [Reply]. PMID- 25554426 TI - Loss of Nogo-A-expressing neurons in a rat model of Parkinson's disease. AB - The myelin-associated protein Nogo-A is among the most potent neurite growth inhibitors in the adult CNS. Recently, Nogo-A expression was demonstrated in a number of neuronal subpopulations of the adult and developing CNS but at present, little is known about the expression of Nogo-A in the nigrostriatal system, a brain structure severely affected in Parkinson's disease (PD). The present study sought to characterize the expression pattern of Nogo-A immunoreactive (ir) cells in the adult ventral mesencephalon of control rats and in the 6-hydroxydopamine (6-OHDA) rat model of PD. Immunohistochemical analyses of normal adult rat brain showed a distinct expression of Nogo-A in the ventral mesencephalon, with the highest level in the substantia nigra pars compacta (SNc) where it co-localized with dopaminergic neurons. Analyses conducted 1week and 1 month after unilateral striatal injections of 6-OHDA disclosed a severe loss of the number of Nogo-A-ir cells in the SNc. Notably, at 1week after treatment, more dopaminergic neurons expressing Nogo-A were affected by the 6-OHDA toxicity than Nogo-A-negative dopaminergic neurons. However, at later time points more of the surviving dopaminergic neurons expressed Nogo-A. In the striatum, both small and large Nogo A-positive cells were detected. The large cells were identified as cholinergic interneurons. Our results suggest yet unidentified functions of Nogo-A in the CNS beyond the inhibition of axonal regeneration and plasticity, and may indicate a role for Nogo-A in PD. PMID- 25554429 TI - Ketamine interactions with biomarkers of stress: a randomized placebo-controlled repeated measures resting-state fMRI and PCASL pilot study in healthy men. AB - Ketamine, an NMDA receptor antagonist, is increasingly used to study the link between glutamatergic signaling dysregulation and mood and chronic pain disorders. Glutamatergic neurotransmission and stress corticosteroids (cortisol in human) are critical for Ca(2+) mediated neuroplasticity and behavioral adaptation. The mechanisms of action of glutamatergic neurotransmission and stress corticosteroids on the NMDA-receptors of the hippocampus have been long investigated in animals, but given little attention in human studies. In this randomized single-blinded placebo-controlled crossover study (12 healthy young men), five sets of resting-state fMRI (RSFMRI), pseudocontinuous arterial spin labeling (PCASL), and corresponding salivary cortisol samples were acquired over 4h, at given intervals under pharmacokinetically-controlled infusion of subanesthetic ketamine (20 & 40mg/70kg/h). An identical procedure was repeated under a sham placebo condition. Differences in the profile of ketamine versus placebo effect over time were examined. Compared to placebo, ketamine mimicked a stress-like response (increased cortisol, reduced calmness and alertness, and impaired working memory). Ketamine effects on the brain included a transient prefrontal hyperperfusion and a dose-related reduction of relative hippocampal perfusion, plus emerging hyperconnectivity between the hippocampus and the occipital, cingulate, precuneal, cerebellar and basal ganglia regions. The spatiotemporal profiles of ketamine effects on different hippocampal subnetworks suggest a topographically dissociable change in corticohippocampal functional connectivity. We discuss our findings in the context of the negative feedback inhibition theory of the hippocampal stress-control. This pilot study provides a methodological framework for multimodal functional neuroimaging under resting state conditions, which may be generalized for translational studies of glutamatergic- or stress-related etiology of neuropsychiatric disorders. PMID- 25554431 TI - Identifying Granger causal relationships between neural power dynamics and variables of interest. AB - Power modulations of oscillations in electro- and magnetoencephalographic (EEG/MEG) signals have been linked to a wide range of brain functions. To date, most of the evidence is obtained by correlating bandpower fluctuations to specific target variables such as reaction times or task ratings, while the causal links between oscillatory activity and behavior remain less clear. Here, we propose to identify causal relationships by the statistical concept of Granger causality, and we investigate which methods are bests suited to reveal Granger causal links between the power of brain oscillations and experimental variables. As an alternative to testing such causal links on the sensor level, we propose to linearly combine the information contained in each sensor in order to create virtual channels, corresponding to estimates of underlying brain oscillations, the Granger-causal relations of which may be assessed. Such linear combinations of sensor can be given by source separation methods such as, for example, Independent Component Analysis (ICA) or by the recently developed Source Power Correlation (SPoC) method. Here we compare Granger causal analysis on power dynamics obtained from i) sensor directly, ii) spatial filtering methods that do not optimize for Granger causality (ICA and SPoC), and iii) a method that directly optimizes spatial filters to extract sources the power dynamics of which maximally Granger causes a given target variable. We refer to this method as Granger Causal Power Analysis (GrangerCPA). Using both simulated and real EEG recordings, we find that computing Granger causality on channel-wise spectral power suffers from a poor signal-to-noise ratio due to volume conduction, while all three multivariate approaches alleviate this issue. In real EEG recordings from subjects performing self-paced foot movements, all three multivariate methods identify neural oscillations with motor-related patterns at a similar performance level. In an auditory perception task, the application of GrangerCPA reveals significant Granger-causal links between alpha oscillations and reaction times in more subjects compared to conventional methods. PMID- 25554430 TI - Correlates of a single cortical action potential in the epidural EEG. AB - To identify the correlates of a single cortical action potential in surface EEG, we recorded simultaneously epidural EEG and single-unit activity in the primary somatosensory cortex of awake macaque monkeys. By averaging over EEG segments coincident with more than hundred thousand single spikes, we found short-lived (~ 0.5 ms) triphasic EEG deflections dominated by high-frequency components >800 Hz. The peak-to-peak amplitude of the grand-averaged spike correlate was 80 nV, which matched theoretical predictions, while single-neuron amplitudes ranged from 12 to 966 nV. Combining these estimates with post-stimulus-time histograms of single unit responses to median-nerve stimulation allowed us to predict the shape of the evoked epidural EEG response and to estimate the number of contributing neurons. These findings establish spiking activity of cortical neurons as a primary building block of high-frequency epidural EEG, which thus can serve as a quantitative macroscopic marker of neuronal spikes. PMID- 25554432 TI - [Intrathoracic goitre associated with vertigo]. PMID- 25554428 TI - Common and distinct neural correlates of personal and vicarious reward: A quantitative meta-analysis. AB - Individuals experience reward not only when directly receiving positive outcomes (e.g., food or money), but also when observing others receive such outcomes. This latter phenomenon, known as vicarious reward, is a perennial topic of interest among psychologists and economists. More recently, neuroscientists have begun exploring the neuroanatomy underlying vicarious reward. Here we present a quantitative whole-brain meta-analysis of this emerging literature. We identified 25 functional neuroimaging studies that included contrasts between vicarious reward and a neutral control, and subjected these contrasts to an activation likelihood estimate (ALE) meta-analysis. This analysis revealed a consistent pattern of activation across studies, spanning structures typically associated with the computation of value (especially ventromedial prefrontal cortex) and mentalizing (including dorsomedial prefrontal cortex and superior temporal sulcus). We further quantitatively compared this activation pattern to activation foci from a previous meta-analysis of personal reward. Conjunction analyses yielded overlapping VMPFC activity in response to personal and vicarious reward. Contrast analyses identified preferential engagement of the nucleus accumbens in response to personal as compared to vicarious reward, and in mentalizing-related structures in response to vicarious as compared to personal reward. These data shed light on the common and unique components of the reward that individuals experience directly and through their social connections. PMID- 25554433 TI - [Potentially inappropriate prescription according to the "STOPP" Criteria in heavily polymedicated elderly patients]. AB - INTRODUCTION: Appropriate prescribing is especially relevant in elderly people. The objective of this study is to analyse the potentially inappropriate prescription (PIP) in heavily polymedicated elderly patients according to the criteria Screening Tool of Older Person's Prescriptions. PATIENTS AND METHODS: A descriptive cross-sectional study was conducted in Primary Care on patients assigned to the Siero-Sariego (Asturias) Health Centre, who were over 64 years old and heavily polymedicated (consumption >10 drugs for six months). The 65 Screening Tool of Older Person's Prescriptions criteria were reviewed in the electronic Primary Care patient records, collecting sociodemographic variables, prescribed medications, and chronic diseases. Frequency distributions were made for each criterion, and causes related to PIP were explored using contingency tables, the Spearman correlation coefficient, and logistic regression. RESULTS: A total of 349 polymedicated elderly patients were analysed with a prevalence of 6.4 (95% CI:5.76-7.08), a mean age of 79.2 years (SD:3.7), 62.2% were female, 14% institutionalised, a Charlson index of 2.9. The mean of number of drugs was 11.5 (SD:1.7), and the most frequent pathologies were high blood pressure (64%), diabetes (46%), and osteoarticular diseases (41%). There was at least one PIP in 72.9% of heavily polymedicated elderly patients [(Mean: 1.32 (SD:1.2)]. The Screening Tool of Older Person's Prescriptions criteria least complied with were: therapeutic duplication (25.2%), use of long-acting benzodiazepines (15.8%), and inappropriate use of aspirin (10.9%). An association was found between having any inappropriate prescription and the number of medications prescribed (OR=1.22 [95% CI:1.04-1.43]) and inversely to the Charlson index (OR=0.76 [95% CI:0.65-0.89]). CONCLUSIONS: PIP is common in heavily polymedicated elderly patients. Special attention must be paid to the use of psychotropic drugs, which are implicated in a high volume of PIP. PMID- 25554435 TI - A molecular pathway analysis informs the genetic background at risk for schizophrenia. AB - BACKGROUND: Schizophrenia is a complex mental disorder marked by severely impaired thinking, delusional thoughts, hallucinations and poor emotional responsiveness. The biological mechanisms that lead to schizophrenia may be related to the genetic background of patients. Thus, a genetic perspective may help to unravel the molecular pathways disrupted in schizophrenia. METHODS: In the present work, we used a molecular pathway analysis to identify the molecular pathways associated with schizophrenia. We collected data of genetic loci previously associated with schizophrenia, identified the genes located in those positions and created the metabolic pathways that are related to those genes' products. These pathways were tested for enrichment (a number of SNPs associated with the phenotype significantly higher than expected by chance) in a sample of schizophrenic patients and controls (4486 and 4477, respectively). RESULTS: The molecular pathway that resulted from the identification of all the genes located in the loci previously found to be associated with schizophrenia was found to be enriched, as expected (permutated p(10(6))=9.9999e-06).We found 60 SNPs amongst 30 different genes with a strong association with schizophrenia. The genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPK cascade. CONCLUSIONS: The pathway related to the toll like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia. This pathway is related to the innate immune system, further stressing the role of immunological related events in increasing the risk to schizophrenia. PMID- 25554436 TI - A haplotype of the norepinephrine transporter gene (SLC6A2) is associated with visual memory in attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood onset psychiatric disorder with impaired visual memory. Based on the evidence from treatment effect of atomoxetine, which interacts directly with the norepinephrine transporter, on visual memory in children with ADHD, this study examined the linkage disequilibrium structure of the norepinephrine transporter gene (SLC6A2) and the association between SLC6A2 and ADHD and visual memory, a promising endophenotype for ADHD. This family-based association sample consisted of 382 probands with DSM-IV ADHD and their family members (n=1298 in total) of Han Chinese in Taiwan. Visual memory was assessed by the Pattern Recognition Memory (PRM) and Spatial Recognition Memory (SRM) tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We screened 21 polymorphisms across SLC6A2 and used the Family-Based Association Test (FBAT) to test the associations of SLC6A2 polymorphisms with ADHD and the PRM and SRM measures. In haplotype analyses, a haplotype rs36011 (T)/rs1566652 (G) was significantly associated with ADHD (minimal p=0.045) after adjustment for multiple testing. In quantitative analyses, this TG haplotype also demonstrated significant associations with visual memory measures, including mean latency of correct responses in PRM (minimal p=0.019), total correct responses in PRM (minimal p=0.018), and total correct responses in SRM (minimal p=0.015). Our novel finding of the haplotype rs36011 (T)/rs1566652 (G) as a novel genetic marker involved in both ADHD disease susceptibility and visual memory suggests that allelic variations in SLC6A2 could provide insight into the pathways leading from genotype to phenotype of ADHD. PMID- 25554437 TI - Bone-anchored hearing device surgery: Linear incision without soft tissue reduction. A prospective study. AB - INTRODUCTION AND OBJECTIVES: The classic surgical procedure for percutaneous bone anchored hearing devices involves removal of a large area of subcutaneous tissue down to the periosteum. This leads to alopecia and raises the risk of devascularization of the overlying skin with the potential for infection and scarring. The objective of this study was to determine the results of implant placement using a single, linear incision with no underlying soft tissue reduction. MATERIAL AND METHOD: A prospective study was conducted in our hospital over a period of 14 months in all consecutive surgeries performed using this technique in adults. Patients were reviewed regularly (week 1, week 3, weeks 4-6 and months 3, 6 and 12) to assess wound healing including evaluation with the Holgers scale. RESULTS: Corresponding to 34 patients, 34 cases were consecutively enrolled in this study. We found that 15% of the patients had minor skin reactions during the first visit (Holgers grade 1 or 2); this number raised to 20% in week 3, but at week 4 only 1 patient had a reaction score of 1 (which was solved by week 6). None of the cases required revision surgery and all skin reactions were treated topically. CONCLUSIONS: Our results suggest that the tissue preservation technique is a simple and effective insertion technique with a favourable healing process and cosmesis. PMID- 25554444 TI - Capacious and programmable multi-liposomal carriers. AB - Spherical polycationic brushes (SPBs) were synthesized by grafting polycationic chains onto 100 nm polystyrene particles. These particles were exposed to unilamellar egg-lecithin (EL) liposomes with a mean diameter of 40 nm that had been rendered anionic via the presence of 10 molar% of phosphatidylserine (PS(1 )). The liposomes also contained 30 mole% of a morpholinocyclohexanol-based lipid (MOCH) that undergoes a conformational flip when the pH is decreased from 7.0 to 5.0. Mixtures of SPBs and liposomes at pH 7 gave an electrostatically-driven complex possessing, on average, about 40 liposomes for each SPB particle. It was found that the bound liposomes rapidly release much of their contents when the pH is reduced from 7.0 to 5.0 owing mostly to a MOCH conformational change that creates defects in the bilayer membrane. The drop in pH does not, however, induce a separation of the liposomes from the SPBs. Around 50-60% of the liposome contents escape before, it is reasoned, lateral and transmembrane motion of the membrane components heals the defects and prevents further release. Remarkably, the liposomes complexed with SPB release their cargo much faster than the identical but non-complexed liposomes. PMID- 25554445 TI - Triple positive breast cancer: a distinct subtype? AB - Breast cancer is a heterogeneous disease, and within the HER-2 positive subtype this is highly exemplified by the presence of substantial phenotypical and clinical heterogeneity, mostly related to hormonal receptor (HR) expression. It is well known how HER-2 positivity is commonly associated with a more aggressive tumor phenotype and decreased overall survival and, moreover, with a reduced benefit from endocrine treatment. Preclinical studies corroborate the role played by functional crosstalks between HER-2 and estrogen receptor (ER) signaling in endocrine resistance and, more recently, the activation of ER signaling is emerging as a possible mechanism of resistance to HER-2 blocking agents. Indeed, HER-2 positive breast cancer heterogeneity has been suggested to underlie the variability of response not only to endocrine treatments, but also to HER-2 blocking agents. Among HER-2 positive tumors, HR status probably defines two distinct subtypes, with dissimilar clinical behavior and different sensitivity to anticancer agents. The triple positive subtype, namely, ER/PgR/Her-2 positive tumors, could be considered the subset which most closely resembles the HER-2 negative/HR positive tumors, with substantial differences in biology and clinical outcome. We argue on whether in this subgroup the "standard" treatment may be considered, in selected cases, i.e., small tumors, low tumor burden, high expression of both hormonal receptors, an overtreatment. This article review the existing literature on biologic and clinical data concerning the HER-2/ER/PgR positive tumors, in an attempt to better define the HER-2 subtypes and to optimize the use of HER-2 targeted agents, chemotherapy and endocrine treatments in the various subsets. PMID- 25554446 TI - AATF RNome has the potential to define post mortem interval. AB - Keeping in view the fact that the circadian rhythm governs human behavioral characteristics, metabolism and body function, the present study was directed to explore whether or not there exists any cooperativity between AATF RNome (comprising AATF mRNA and its encoded microRNA miR-2909) rhythmicity and post mortem interval (PMI). Such a study unambiguously revealed that circadian rhythm exhibited by AATF RNome has a direct correlation with PMI in Balb/c mice. AATF RNome has the potential to act as biomarker for PMI with reasonably good accuracy and hence may turn out to be of crucial importance in forensic investigation. PMID- 25554447 TI - Aberrant zinc binding to immature conformers of metal-free copper-zinc superoxide dismutase triggers amorphous aggregation. AB - Superoxide dismutase 1 (SOD1) is a Cu/Zn metalloenzyme that aggregates in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Correct metal insertion during SOD1 biosynthesis is critical to prevent misfolding; however Zn(2+) can bind to the copper-site leading to an aberrantly metallated protein. These effects of Zn(2+) misligation on SOD1 aggregation remain to be explored, even though Zn(2+) levels are upregulated in ALS motor neurons. Here we use complementary biophysical methods to investigate Zn(2+) binding and its effects on the aggregation of three immature metal-free SOD1 conformers that represent biogenesis intermediates: dimeric, monomeric and reduced monomeric SOD1. Using isothermal titration calorimetry we determined that Zn(2+) binds to all conformers both at the zinc- as well as to the copper-site; however Zn(2+) binding mechanisms to the zinc-site have distinct characteristics across immature conformers. We show that this 'zinc overload' of immature SOD1 promotes intermolecular interactions, as evidenced by dynamic light scattering and ThT fluorescence kinetic studies. Analysis of aged zinc-induced aggregates by energy dispersive X-ray and electron energy-loss spectroscopy shows that aggregates integrate some Zn(2+). In addition, electron diffraction analysis identifies nano scaled crystalline materials and amyloid fibril-like reflections. Transmission electron microscopy reveals that Zn(2+) diverts the SOD1 aggregation pathway from fibrils to amorphous aggregate, and electrophoretic analysis evidences an increase in insoluble materials. Overall, we provide evidence that aberrant zinc coordination to immature conformers broadens the population of SOD1 misfolded species at early aggregation stages and provide evidence for a high structural polymorphism and heterogeneity of SOD1 aggregates. PMID- 25554456 TI - Mortality in obesity-hypoventilation syndrome and prognostic risk factors. PMID- 25554457 TI - The role of pulmonology in the National Health System Chronicity Strategy. AB - Longer life expectancy and the progressive aging of the population is changing the epidemiological pattern of healthcare, with a reduction in the incidence of acute diseases and a marked increase in chronic diseases. This change brings important social, healthcare and economic consequences that call for a reorganization of patient care. In this respect, the Spanish National Health System has developed a Chronicity strategy that proposes a substantial change in focus from traditional rescue medicine to patient- and environment-centered care, with a planned, proactive, participative and multidisciplinary approach. Some of the more common chronic diseases are respiratory. In COPD, this integrated approach has been effective in reducing exacerbations, improving quality of life, and even reducing costs. However, the wide variety of management strategies, not only in COPD but also in asthma and other respiratory diseases, makes it difficult to draw definitive conclusions. Pulmonologists can and must participate in the new chronicity models and contribute their knowledge, experience, innovation, research, and special expertise to the development of these new paradigms. PMID- 25554458 TI - [Cardiology was born with the modern medical science]. AB - Modern medical science was born in the post-Renaissance age and began to consolidate towards the middle of the XVII century thanks to physicists, physiologists and biologists, most of whom were direct or indirect pupils of Galileo. The discovery of blood circulation by Harvey is now considered the only progress in physiology at the beginning of the XVII century, comparable to the current advances seen in physical sciences. The history of this exploit could be written from view point of the progressive advance in knowledge. In his experiments, Harvey referred to the authentic not imaginary experiments, and put forward irrefutable quantitative arguments. We can therefore claim that his discovery of blood circulation was the first proper explanation of an organic process and the starting point leading to experimental physiology. So it seems justified to assert that modern medical science did not all rise suddenly, but was gradually structured starting from the middle of the XVII century following the path traced by William Harvey in light of Galileo's thought. PMID- 25554459 TI - [Cardiac computed tomography: new applications of an evolving technique]. AB - During the last years we have witnessed an increasing development of imaging techniques applied in Cardiology. Among them, cardiac computed tomography is an emerging and evolving technique. With the current possibility of very low radiation studies, the applications have expanded and go further coronariography In the present article we review the technical developments of cardiac computed tomography and its new applications. PMID- 25554460 TI - Continuous cognitive task promotes greater postural stability than an internal or external focus of attention. AB - Research has demonstrated clear advantages of using an external focus of attention in postural control tasks, presumably since it allows a more automatic control of posture to emerge. However, the influence of cognitive tasks on postural stability has produced discordant results. This study aimed to compare the effects of an internal focus of attention, an external focus of attention and a continuous cognitive task on postural control. Twenty healthy participants (21.4+/-2.6 years) were recruited for this study. They were asked to stand quietly on a force platform with their feet together in three different attentional focus conditions: an internal focus condition (minimizing movements of the hips), an external focus condition (minimizing movements of markers placed on the hips) and a cognitive task condition (silently counting the total number of times a single digit was verbalized in a 3-digit sequence comprised of 30 numbers). Results demonstrated improved stability while performing the cognitive task as opposed to the internal and external focus conditions, as evidenced by a reduction in sway area, sway variability in the anterior-posterior (AP) and medial-lateral (ML) directions, and mean velocity (ML only). Results suggest that the use of a continuous cognitive task permits attention to be withdrawn from the postural task, thereby facilitating a more automatic control of posture. PMID- 25554466 TI - Performance improvement of multilayer InSe transistors with optimized metal contacts. AB - This work is focused on achieving high performance multilayer InSe field-effect transistors by a systematic experiment study on metal contacts. The high performance can be achieved by choosing an ideal contact metal and adopting a proper thickness of InSe nanosheets. By choosing a proper thickness (33 nm), the performance of multilayer InSe FETs was improved by the following sequence of Al, Ti, Cr and In contacts. The extracted mobility values are 4.7 cm(2) V(-1) s(-1), 27.6 cm(2) V(-1) s(-1), 74 cm(2) V(-1) s(-1) and 162 cm(2) V(-1) s(-1) for Al, Ti, Cr and In, respectively. The on/off ratios are 10(7)-10(8). The device electronic properties and the interface morphology of the deposition metals/InSe indicate that the contact interface between the metals and InSe plays a significant role in forming low resistance. Our study may pave the way for multilayer InSe applications in nano-electrical and nano-optoelectronic devices. PMID- 25554467 TI - Role of radiation and androgen deprivation therapy for advanced prostate cancer. PMID- 25554468 TI - Long-term effects of an antimicrobial stewardship programme at a tertiary-care teaching hospital. AB - Antimicrobial stewardship has been shown to reduce unnecessary antibiotic use, but there are few data on the long-term benefits of such a programme. Antimicrobial use over a 13-year period since implementing an antimicrobial stewardship programme (ASP) at our institution was examined. Nosocomial rates of Clostridium difficile infection (CDI) and antimicrobial susceptibility patterns of common nosocomial micro-organisms over the same period were also reviewed. Total antimicrobial use decreased by 62.8% (P<0.0001). There were decreases in use of aminoglycosides (-91.3%; P<0.0001), cephalosporins (-68.3%; P<0.0001), extended-spectrum penicillins (-77.7%; P<0.0001), macrolides (-27.2%; P=0.002), clindamycin (-95.9%; P<0.0001) and quinolones (-78.7%; P<0.0001). Antifungal use decreased by 71.0% (P<0.0001). There were increases in the use of carbapenems (+736%, P<0.0001) and anti-MRSA drugs (+73.3%; P<0.0001). There was a 56.7% (P=0.007) reduction in nosocomial MRSA infections. Nosocomial CDI rates decreased by 42.6% (P=0.005) between 2003 and 2010 and then increased to near baseline levels following implementation of more sensitive testing for detection of CDI in 2011. There were decreases in the rate (-71.9%; P=0.001) and percentage (-51.4%; P<0.0001) of quinolone-resistant Pseudomonas aeruginosa. There were decreases in the rate (P<0.0001) and percentage (P=0.02) of carbapenem-resistant P. aeruginosa following implementation of a policy restricting ciprofloxacin use. We have demonstrated sustained reductions in both antimicrobial use and drug-resistant organisms following implementation of an ASP. PMID- 25554469 TI - Murine pharmacokinetics of rifapentine delivered as an inhalable dry powder. AB - A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue samples were collected and drug levels were quantified at time points up to 24h. Concentration time data were analysed using a mixed-effects modelling approach to provide model based estimates of area under the concentration-time curve from time 0 to infinity (AUC0-infinity). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0-infinity compared with IP delivery. The plasma AUC0-infinity following IT dry powder delivery was ca. four fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity. PMID- 25554470 TI - Effects of sulfur on lead partitioning during sludge incineration based on experiments and thermodynamic calculations. AB - Experiments in a tubular furnace reactor and thermodynamic equilibrium calculations were conducted to investigate the impact of sulfur compounds on the migration of lead (Pb) during sludge incineration. Representative samples of typical sludge with and without the addition of sulfur compounds were combusted at 850 degrees C, and the partitioning of Pb in the solid phase (bottom ash) and gas phase (fly ash and flue gas) was quantified. The results indicate that three types of sulfur compounds (S, Na2S and Na2SO4) added to the sludge could facilitate the volatilization of Pb in the gas phase (fly ash and flue gas) into metal sulfates displacing its sulfides and some of its oxides. The effect of promoting Pb volatilization by adding Na2SO4 and Na2S was superior to that of the addition of S. In bottom ash, different metallic sulfides were found in the forms of lead sulfide, aluminosilicate minerals, and polymetallic-sulfides, which were minimally volatilized. The chemical equilibrium calculations indicated that sulfur stabilizes Pb in the form of PbSO4(s) at low temperatures (<1000 K). The equilibrium calculation prediction also suggested that SiO2, CaO, TiO2, and Al2O3 containing materials function as condensed phase solids in the temperature range of 800-1100 K as sorbents to stabilize Pb. However, in the presence of sulfur or chlorine or the co-existence of sulfur and chlorine, these sorbents were inactive. The effect of sulfur on Pb partitioning in the sludge incineration process mainly depended on the gas phase reaction, the surface reaction, the volatilization of products, and the concentration of Si, Ca and Al-containing compounds in the sludge. These findings provide useful information for understanding the partitioning behavior of Pb, facilitating the development of strategies to control the volatilization of Pb during sludge incineration. PMID- 25554478 TI - Bovine leukemia virus: a major silent threat to proper immune responses in cattle. AB - Bovine leukemia virus (BLV) infection is widespread in the US dairy industry and the majority of producers do not actively try to manage or reduce BLV incidence within their herds. However, BLV is estimated to cost the dairy industry hundreds of millions of dollars annually and this is likely a conservative estimate. BLV is not thought to cause animal distress or serious pathology unless infection progresses to leukemia or lymphoma. However, a wealth of research supports the notion that BLV infection causes widespread abnormal immune function. BLV infection can impact cells of both the innate and adaptive immune system and alter proper functioning of uninfected cells. Despite strong evidence of abnormal immune signaling and functioning, little research has investigated the large scale effects of BLV infection on host immunity and resistance to other infectious diseases. This review focuses on mechanisms of immune suppression associated with BLV infection, specifically aberrant signaling, proliferation and apoptosis, and the implications of switching from BLV latency to activation. In addition, this review will highlight underdeveloped areas of research relating to BLV infection and how it causes immune suppression. PMID- 25554479 TI - Determination of major, minor and trace elements in Glyceric Macerates and Mother Tinctures and in the starting plant materials. AB - Glyceric Macerates (GMs) and Mother Tinctures (MTs) are liquid preparations obtained from plant buds (for GMs) and flowers, leaves or roots (for MT) by extraction with a mixture of solvents. Their quality depends on the quality of the plant materials and on the preparation procedures. In this work we determined the concentrations of major, minor and trace elements in buds, flowers and other plant components and in the GMs and MTs obtained from them by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) after microwave mineralization. To the best of our knowledge, this procedure has been applied for the first time here to the analysis of buds. We have taken into account spectral interferences and other causes of errors. Analogies and differences with regard to the method reported by European Pharmacopoeia for heavy metal determination in herbal drugs have been highlighted. The experimental results have been interpreted with chemometric techniques. No significant contamination was detected during the manufacturing step. Element concentrations in GMs and MTs, taking into account their daily dosages, are lower than acceptable intake levels. PMID- 25554481 TI - Oxytocin decreases sweet taste sensitivity in mice. AB - Oxytocin (OXT) suppresses food intake and lack of OXT leads to overconsumption of sucrose. Taste bud cells were recently discovered to express OXT-receptor. In the present study we tested whether administering OXT to wild-type mice affects their licking behavior for tastants in a paradigm designed to be sensitive to taste perception. We injected C57BL/6J mice intraperitoneally (i.p.) with 10mg/kg OXT and assayed their brief-access lick responses, motivated by water deprivation, to NaCl (300mM), citric acid (20mM), quinine (0.3mM), saccharin (10mM), and a mix of MSG and IMP (100mM and 0.5mM respectively). OXT had no effect on licking for NaCl, citric acid, or quinine. A possible effect of OXT on saccharin and MSG+IMP was difficult to interpret due to unexpectedly low lick rates to water (the vehicle for all taste solutions), likely caused by the use of a high OXT dose that suppressed licking and other behaviors. A subsequent experiment focused on another preferred tastant, sucrose, and employed a much lower OXT dose (0.1mg/kg). This modification, based on our measurements of plasma OXT following i.p. injection, permitted us to elevate plasma [OXT] sufficiently to preferentially activate taste bud cells. OXT at this low dose significantly reduced licking responses to 0.3M sucrose, and overall shifted the sucrose concentration - behavioral response curves rightward (mean EC50saline=0.362M vs. EC50OXT=0.466M). Males did not differ from females under any condition in this study. We propose that circulating oxytocin is another factor that modulates taste-based behavior. PMID- 25554480 TI - Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue. AB - Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine. PMID- 25554483 TI - Effects of maternal exposure to the galactagogue Sulpiride on reproductive parameters in female rats. AB - The antipsychotic Sulpiride has been documented as an effective galactagogue that acts blocking dopamine receptors, increasing prolactin concentrations. However, this drug passes through the milk exposing neonates during postnatal development, which may result in functional and morphological alterations in adult life. Therefore, the aim of this study was to investigate whether maternal exposure to Sulpiride during lactation could impair reproductive development of female offspring. The dams were treated daily by gavage with Sulpiride doses of 2.5mg/Kg (SUL 2.5mg group) and 25mg/Kg (SUL 25mg group), or distilled water (Control group) throughout the lactation period. During early life, body weight, anogenital distance, and vaginal opening were analyzed on the female offspring. In adulthood, estrous cycle, sexual behavior, estrogen levels as well as the weight of the reproductive organs were evaluated. There were no differences regarding body weight, anogenital distance, puberty onset, frequency and duration of the estrous cycle and estradiol levels on female offspring. Nonetheless, there were changes in sexual behavior. There was an increase in the number of observations in reflex magnitude 0 (absence of lordosis) and reflex magnitude 2 as well as a reduction of reflex magnitude 3 in the rats of SUL 25mg group in relation to the Control group, suggesting a decrease in sexual receptivity of these animals. These results demonstrate that maternal exposure to Sulpiride can alter reproductive function in female offspring rats. PMID- 25554482 TI - Prenatal exposure to vanilla or alcohol induces crawling after these odors in the neonate rat: The role of mu and kappa opioid receptor systems. AB - Rat fetuses can perceive chemosensory stimuli derived from their mother's diet, and they may learn about those stimuli. In previous studies we have observed that prenatal exposure to alcohol during the last days of gestation increases the acceptance and liking of an alcohol flavor in infant and adolescent rats. While these results were not found after prenatal exposure to vanilla, cineole or anise, suggesting that the pharmacological properties of alcohol, mediated by the opioid system, underlie the effects observed with this drug. Considering that other studies report enhanced acceptance of non-alcohol flavors experienced prenatally when subjects were tested before infancy, we explore the possibility of observing similar results if testing 1-day old rats exposed prenatally to vanilla. Using an "odor-induced crawling" testing procedure, it was observed that neonates exposed prenatally to vanilla or alcohol crawl for a longer distance towards the experienced odor than to other odors or than control pups. Blocking mu, but not kappa opioid receptors, reduced the attraction of vanilla odor to neonates exposed to vanilla in utero, while the response to alcohol in pups exposed prenatally to this drug was affected by both antagonists. Results confirm that exposure to a non-alcohol odor enhances postnatal responses to it, observable soon after birth, while also suggesting that the mu opioid receptor system plays an important role in generating this effect. The results also imply that with alcohol exposure, the prenatal opioid system is wholly involved, which could explain the longer retention of the enhanced attraction to alcohol following prenatal experience with the drug. PMID- 25554485 TI - Suppression of ERK activation in urethral epithelial cells infected with Neisseria gonorrhoeae and its isogenic minD mutant contributes to anti-apoptosis. AB - In gonococci-infected transduced human urethral epithelial cells (THUEC), the role of ERK, a mitogen-activated protein kinase (MAPK), in apoptosis is unknown. We observed lowering of ERK activation in THUEC following infection with anti apoptosis-inducing Neisseria gonorrhoeae strain CH811. An isogenic cell division mutant of this strain, Ng CJSD1 (minD deficient), which is large and abnormally shaped, reduced ERK phosphorylation levels even more than its parental strain in THUEC. This led to higher anti-apoptosis in mutant-infected cells as compared to the parental strain-infected cells. Our results suggest that N. gonorrhoeae infection reduces ERK activation in THUEC contributing to anti-apoptosis. PMID- 25554484 TI - Prevalence and Predictors of Depression in Korean American Elderly: Findings from the Memory and Aging Study of Koreans (MASK). AB - OBJECTIVES: To estimate the prevalence and identify the predictors of depression among community-dwelling Korean American elderly (KAE). DESIGN: A cross-sectional descriptive epidemiological survey using a two-step sampling strategy to obtain a representative community sample. SETTING: The authors recruited study participants at religious, service, and business establishments in the KA community (26 churches, 6 senior centers, 2 medical daycare centers, 1 supermarket). PARTICIPANTS: Community-dwelling first-generation KAE (N = 1,118; mean age +/- SD: 70.5 +/- 7.0 years; female: 67.2%). MEASUREMENTS: Trained bilingual nurses and community health workers interviewed participants face-to face for demographic information, chronic conditions, and depression using the Korean versions of the Patient Health Questionnaire (PHQ-9K). RESULTS: 30.3% of KAEs were classified as having either mild (PHQ-9K score 5-9; N = 218, 19.5%) or clinical depression (PHQ-9K score >=10; N = 120, 10.8%), respectively. One of seven KAE (N = 164, 14.7%) endorsed thoughts of death or self-injury, but only 63 (5.7%) reported utilizing mental health services. The authors also identified several predictors of depression, including living arrangement (living alone versus living with family/spouse); having chronic conditions such as diabetes, arthritis, digestive disorders, or chronic bronchitis; years of education; and cognitive impairment. CONCLUSIONS: The authors' findings reveal a high prevalence of depression among KAE and a low level of mental health service utilization. Because there are urgent needs for culturally and contextually relevant interventions, the authors also discuss the feasibility of community-based interventions to reduce the burden of depression, which should be incorporated into a management system for multiple chronic conditions. PMID- 25554486 TI - Dok proteins are recruited to the phagosome and degraded in a GP63-dependent manner during Leishmania major infection. AB - Three adaptor molecules of the Dok family, Dok-1, Dok-2 and Dok-3 are expressed in macrophages and are involved in the negative regulation of signaling in response to lipopolysaccharide and various cytokines and growth factors. We investigated the role and the fate of these proteins following infection with Leishmania major promastigotes in macrophages. The protozoan parasite L. major causes cutaneous leishmaniasis and is known for its capacity to alter host-cell signaling and function. Dok-1/Dok-2(-/-) bone marrow-derived macrophages displayed normal uptake of L. major promastigotes. Following Leishmania infection, Dok-1 was barely detectable by confocal microscopy. By contrast, phagocytosis of latex beads or zymosan led to the recruitment of Dok-1 to phagosomes. In the absence of the Leishmania pathogenesis-associated metalloprotease GP63, Dok-1 was also, partially, recruited to phagosomes containing L. major promastigotes. Further biochemical analyses revealed that similar to Dok-1, Dok-2 and Dok-3 were targets of GP63. Moreover, we showed that upon infection with wild-type or Deltagp63 L. major promastigotes, production of nitric oxide and tumor necrosis factor by interferon-gamma-primed Dok-1/Dok-2(-/ ) macrophages was reduced compared to WT macrophages. These results suggest that Dok proteins may be important regulators of macrophage responses to Leishmania infection. PMID- 25554487 TI - E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase) of Leishmania amazonensis inhibits macrophage activation. AB - Leishmania amazonensis, the causal agent of diffuse cutaneous leishmaniasis, is known for its ability to modulate the host immune response. Because a relationship between ectonucleotidase activity and the ability of Leishmania to generate injury in C57BL/6 mice has been demonstrated, in this study we evaluated the involvement of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) activity of L. amazonensis in the process of infection of J774-macrophages. Our results show that high-activity parasites show increased survival rate in LPS/IFN gamma-activated cells, by inhibiting the host-cell NO production. Conversely, inhibition of E-NTPDase activity reduces the parasite survival rates, an effect associated with increased macrophage NO production. E-NTPDase activity generates substrate for the production of extracellular adenosine, which binds to A2B receptors and reduces IL-12 and TNF-alpha produced by activated macrophages, thus inhibiting NO production. These results indicate that E-NTPDase activity is important for survival of L. amazonensis within macrophages, showing the role of the enzyme in modulating macrophage response and lower NO production, which ultimately favors infection. Our results point to a new mechanism of L. amazonensis infection that may pave the way for the development of new treatments for this neglected disease. PMID- 25554488 TI - Development of a high-throughput assay for human proprotein convertase 5/6 for detecting uterine receptivity. AB - Embryo implantation requires a healthy embryo and a receptive uterus. In women, the inner lining of the uterus, the endometrium, remains in a hostile state and becomes receptive for embryo implantation for only a short period during each menstrual cycle. Determining endometrial receptivity is vital in in vitro fertilization (IVF) treatment because the timing of embryo transfer needs to be synchronized with endometrial receptivity. We have previously demonstrated that proprotein convertase 5/6A (PC6) is highly expressed in the receptive endometrium and that PC6 is critical for receptivity establishment in women. Furthermore, endometrial PC6 is secreted into the uterine fluid, and levels correlate with receptivity status. Detection of PC6 in uterine fluids, therefore, would provide a nonsurgical assessment of endometrial receptivity. However, to date no assays are available for human PC6. In this study, we produced three PC6 monoclonal antibodies (mAbs) and developed a sandwich enzyme-linked immunosorbent assay (ELISA) for PC6 detection in human uterine fluids. The PC6 mAbs were confirmed to be highly specific to PC6, and the ELISA detected PC6 in human uterine fluids with a significantly higher level during the receptive phase. This newly established PC6 ELISA provides an important tool in the development of noninvasive strategies to detect endometrial receptivity in women. PMID- 25554489 TI - Involvement of indole-3-acetic acid produced by Azospirillum brasilense in accumulating intracellular ammonium in Chlorella vulgaris. AB - Accumulation of intracellular ammonium and activities of the enzymes glutamine synthetase (GS) and glutamate dehydrogenase (GDH) were measured when the microalgae Chlorella vulgaris was immobilized in alginate with either of two wild type strains of Azospirillum brasilense or their corresponding indole-3-acetic acid (IAA)-attenuated mutants. After 48 h of immobilization, both wild types induced higher levels of intracellular ammonium in the microalgae than their respective mutants; the more IAA produced, the higher the intracellular ammonium accumulated. Accumulation of intracellular ammonium in the cells of C. vulgaris followed application of four levels of exogenous IAA reported for A. brasilense and its IAA-attenuated mutants, which had a similar pattern for the first 24 h. This effect was transient and disappeared after 48 h of incubation. Immobilization of C. vulgaris with any bacteria strain induced higher GS activity. The bacterial strains also had GS activity, comparable to the activity detected in C. vulgaris, but weaker than when immobilized with the bacteria. When net activity was calculated, the wild type always induced higher GS activity than IAA-attenuated mutants. GDH activity in most microalgae/bacteria interactions resembled GS activity. When complementing IAA-attenuated mutants with exogenous IAA, GS activity in co-immobilized cultures matched those of the wild type A. brasilense immobilized with the microalga. Similarity occurred when the net GS activity was measured, and was higher with greater quantities of exogenous IAA. It is proposed that IAA produced by A. brasilense is involved in ammonium uptake and later assimilation by C. vulgaris. PMID- 25554490 TI - Augmentation of multiple protein kinase activities associated with secondary imatinib resistance in gastrointestinal stromal tumors as revealed by quantitative phosphoproteome analysis. AB - Mutations in the Kit receptor tyrosine kinase gene (KIT), which result in constitutive activation of the protein (KIT), are causally related to the development of gastrointestinal stromal tumors (GISTs). Imatinib, a targeted anticancer drug, exerts a therapeutic effect against GISTs by repressing the kinase activity of KIT. Long-term administration of this drug, however, causes the emergence of imatinib-resistant GISTs. We performed quantitative phosphoproteome analysis using a cell-based GIST model system comprising an imatinib-sensitive GIST cell line (GIST882), GIST882 under treatment with imatinib (GIST882-IM), and secondary imatinib-resistant GIST882 (GIST882-R). Phosphorylated peptides were purified from each cell line using titania-based affinity chromatography or anti-phosphotyrosine immunoprecipitation, and then subjected to LC-MS/MS based quantitative phosphoproteome analysis. Using this method we identified augmentation of the kinase activities of multiple elements of the signal transduction pathway, especially KIT and EGFR. Although, these elements were up-regulated in GIST882-R, no additionally mutated KIT mRNA was found in secondary imatinib-resistant GIST cells. Treatment of GIST882-R with imatinib in combination with gefitinib, an EGFR inhibitor, partially prevented cell growth, implying that EGFR may be involved in acquisition of secondary imatinib resistance in GIST. BIOLOGICAL SIGNIFICANCE: In this study, we performed a quantitative phosphoproteome analysis using a cell culture-based GIST model system. The goal of the study was to investigate the mechanism of acquired resistance in GISTs against imatinib, a molecularly targeted drug that inhibits kinase activity of the KIT protein and that has been approved for the treatment of GISTs. In imatinib-resistant GIST cells, we observed elevated expression of KIT and restoration of its kinase activity, as well as activation of multiple proliferative signaling pathways. Our results indicate that the effects of even so-called 'molecularly targeted' drugs, are broad rather than convergent, and that the mechanisms of action of such drugs during continuous administration are extremely complex. PMID- 25554491 TI - [Evolution of ideas and techniques, and future prospects in epilepsy surgery]. AB - INTRODUCTION: The aim of this article was to review and evaluate the published literature related to the outcome of epilepsy surgery, while placing it in an historical perspective, and to describe the future prospects in this field. STATE OF ART: Temporal lobe surgery achieves seizure freedom in about 70% of cases. Seizure outcome is similar in the pediatric population. Extratemporal resections impart good results to 40% to 60% of patients, with a better prognosis in the case of frontal lobe surgery. Pediatric hemispherotomy leads to seizure control in about 80% of children. Radiosurgery used as a treatment for temporal mesial epilepsy has an outcome quite similar to that obtained with surgical resection, but provides a neuropsychological advantage. Radiosurgery is also effective in 60% of children treated for seizures related to hypothalamic hamartoma. Regarding palliative surgery, callosotomy and multiple subpial transections show satisfactory outcomes in over 60% of cases. Neuromodulation techniques (vagus nerve stimulation and bilateral stimulation of the anterior nucleus of the thalamus) allow a 50% reduction of seizures in half of patients. PERSPECTIVES: Transcranial magnetic stimulation combined with electroencephalography seems a promising technique because of its diagnostic, prognostic and therapeutic applications. Transcranial ultrasound stimulation, which can reversibly control neuronal activity, is also under consideration. Concerning neuromodulation, trigeminal nerve stimulation may become an alternative to vagus nerve stimulation; while other targets of deep brain stimulation are being evaluated. Also, the possibility of coupling SEEG seizure focus detection with concomitant laser or radiofrequency focus destruction is under development. CONCLUSIONS: Constant evolution of epilepsy surgery has improved patient outcomes over time. Current research and development axes suggest the continuation of this trend and a reduction of the invasiveness of surgical procedures. PMID- 25554493 TI - CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2 induced angiogenesis in Alzheimer's disease. AB - In Alzheimer's disease (AD), large populations of endothelial cells undergo angiogenesis due to brain hypoxia and inflammation. Substantial evidence from epidemiologic, pathologic, and clinical reports suggests that vascular factors are critical for the pathogenesis of AD. However, the precise mechanistic correlation between inflammation and angiogenesis in AD has not been well elucidated. Prostaglandin E2 (PGE2), a key factor of the inflammatory response, has been known to promote angiogenesis. In this study, we demonstrated that PGE2 acts through EP4 receptor and protein kinase A to modulate CCAAT/enhancer-binding protein delta (CEBPD) abundance in astrocytes. Attenuated vessel formation was observed in the brains of AppTg/Cebpd(-/-) mice. We showed that miR135a was responsive to the induction of CEBPD and further negatively regulated thrombospondin 1 (THBS1) transcription by directly targeting its 3'-untranslated region (3'UTR) in astrocytes. Furthermore, conditioned media from astrocytes expressing miR135a promoted Human umbilical vein endothelial cells (HUVECs) tube like formation, which correlated with the effects of PGE2 on angiogenesis. Our results indicated that CEBPD contributes to the repression of THBS1 transcription by activating the expression of miR135a in astrocytes following PGE2 treatment. We provided new evidence that astrocytic CEBPD increases angiogenesis during AD pathogenesis. This discovery supports the negative influence of CEBPD activation in astrocytes with respect to AD pathogenesis and implies that the CEBPD/miR135a/THBS1 axis could be a therapeutic target of AD. PMID- 25554492 TI - Declines in inflammation predict greater white matter microstructure in older adults. AB - Protracted systemic inflammation has been associated with adverse effects on cognition and brain structure and may accelerate neurodegenerative disease processes; however, it is less clear whether changes in inflammation are associated with brain structure. We studied 276 black and white older adults (mean age = 83 years at time of imaging) enrolled in a prospective study of aging. Inflammation (measured with c-reactive protein, CRP) was assessed repeatedly over 6 years (i.e., year 2, 4, 6, and 8). Brain magnetic resonance imaging (MRIs) were obtained at years 10-11 with diffusion tensor imaging; regions of interest included late-myelinating areas vulnerable to aging, including frontal-parietal (superior longitudinal fasciculus [SLF]-dorsal) and temporal (SLF-temporal; uncinate) white matter tracts. Mean CRP values significantly declined (t = -5.54, p < 0.0001) over 6 years, and subject-specific slopes (best linear unbiased predictors of slopes) all showed a decline (mean = 0.57, standard deviation = 0.53) for our participant sample. More than 50% of study participants were still in the moderate to high cardiovascular risk range based on CRP values at year 8. After controlling for demographics, vascular risk factors and MRI white matter hyperintensities, larger decreases in CRP values over time were significantly associated with higher fractional anisotropy in the SLF-dorsal (beta = -0.0052, standard error [SE] = 0.003; 95% confidence interval [CI] = -0.0103 to -0.0025, p = 0.04), SLF-temporal (beta = -0.0109, SE = 0.004; 95% CI = -0.0189 to -0.0029, p = 0.008), and uncinate (beta = -0.0067, SE = 0.003; 95% CI = -0.0132 to -0.0001, p = 0.05) fasciculi. Results suggest that in a prospective cohort of older individuals, faster declines in inflammation over time are related to indicators of white matter health, even after accounting for vascular risk factors. PMID- 25554494 TI - BDNF prevents amyloid-dependent impairment of LTP in the entorhinal cortex by attenuating p38 MAPK phosphorylation. AB - The oligomeric form of the amyloid peptide Abeta(1-42) is capable of perturbing synaptic plasticity in different brain areas. Here, we evaluated the protective role of brain-derived neurotrophic factor (BDNF) in beta amyloid (Abeta) dependent impairment of long-term potentiation in entorhinal cortex (EC) slices. We found that BDNF (1 ng/mL) supplied by perfusion was able to rescue long-term potentiation in Abeta(1-42)-treated slices; BDNF protection was mediated by TrkB receptor as assessed by using the tyrosine kinase inhibitor K252a (200 nM). We also investigated the function of endogenous BDNF using a soluble form of TrkB receptor (TrkB IgG). Incubation of slices with TrkB IgG (1 MUg/mL) increased the EC vulnerability to Abeta. Finally, we investigated the effect of BDNF on the cell stress-kinase p38 mitogen-activated protein kinase (MAPK) in primary cortical cell cultures exposed to Abeta(1-42). We found that Abeta induces p38 MAPK phosphorylation, although pretreatment with BDNF prevented Abeta-dependent p38 MAPK phosphorylation. This result was confirmed by an immunoassay in tissue extracts from EC slices collected after electrophysiology. PMID- 25554495 TI - Link between the SNCA gene and parkinsonism. AB - The groundbreaking discovery of mutations in the SNCA gene in a rare familial form of Parkinson's disease (PD) has revolutionized our basic understanding of the etiology of PD and other related disorders. Genome-wide Association Studies has demonstrated a wide array of single-nucleotide polymorphisms associated with the increasing risk of developing the more common type, sporadic PD, further corroborating the genetic etiology of PD. Among them, SNCA is a gene responsible for encoding alpha-synuclein, a protein found to be the major component of Lewy body and Lewy neurite, both of these components are the pathognomonic hallmarks of PD. Thus, it has been postulated that this gene plays specific roles in pathogenesis of PD. Here, we summarize the basic biological characteristics of the wild type of the protein (wt-alpha-synuclein) as well as genetic and epigenetic features of its encoding gene (SNCA) in PD. Based on these characteristics, SNCA may be involved in PD pathogenesis in at least 2 ways: wt alpha-synuclein overexpression and its mutation types via different mechanisms. Associations between SNCA mutations and other Lewy body disorders, such as dementia with Lewy bodies and multiple system atrophy, are also mentioned. Finally, it is necessary to explore the influences which SNCA exerts on clinical and neuropathological phenotypes by promoting the transfer of scientific research into practice, such as clinical evaluation, diagnosis, and treatment of the disease. We believe it is promising to target SNCA for developing novel therapeutic strategies for parkinsonism. PMID- 25554496 TI - Factors associated with mental health status of medical residents: a model-guided study. AB - Residency is a stressful period in a physician's development, characterized by long work hours, time pressure, and excessive work load, that can exert negative effects on residents' mental health. Job burnout and negative work-home interference may play a major role in residents' mental health problems. The present study used the job demands-resources model as a theoretical framework to examine the way in which job demands (e.g., workload, emotional demands) and job resources (e.g., supervisor support, job autonomy) were associated with residents' mental health. From a pool of 290 medical residents, 264 (91 %) completed the questionnaires. Applying structural equation modeling techniques, the results showed that greater emotional exhaustion (beta = -.65, SE = .09, p < .001) and more work-home interference (beta = -.26, SE = .10, p < .05) were related to poor mental health. Specific job demands (i.e., high workload) and particular job resources (i.e., low opportunities for professional development and low supervisor support) were related to poor mental health not directly but only indirectly, via emotional exhaustion or work-home interference. Thus, through work-related emotional exhaustion, the impact of work conditions might be transmitted to and interfere with non-work related domains such as family life, as well as with domain-unspecific aspects of well-being, such as mental health and psychological distress. Implications of the results and suggestions for future research and practice are outlined. PMID- 25554497 TI - Safety of venous thromboembolism prophylaxis with fondaparinux in ischemic stroke. AB - INTRODUCTION: Unfractionated heparin (UFH), low molecular weight heparin or fondaparinux are recommended for venous thromboembolism (VTE) prophylaxis in acutely ill medical patients. There are limited data on the safety of fondaparinux for VTE prophylaxis in ischemic stroke. We examined adverse event frequency in hospitalized patients with ischemic stroke who received VTE prophylaxis with fondaparinux versus UFH. MATERIALS AND METHODS: We performed a propensity score matched analysis on a retrospective cohort of 644 consecutive patients with acute ischemic stroke receiving fondaparinux (n=322) or UFH (n=322) for VTE prophylaxis. Patients who received intravenous tPA and continuous intravenous infusions of UFH were excluded. The primary outcome was major hemorrhage (intracranial or extracranial) and the secondary outcome was total hemorrhage (major and minor hemorrhage) during hospitalization. We also examined the rate of symptomatic VTE. RESULTS: Mean age of the matched cohort was 71.3+/ 14.1 years, median NIHSS score was 4 (IQR 1-11), median duration of anticoagulant exposure was 5 (IQR 3-8) days, and 98.1% received antiplatelet medications. In the matched cohort, there were less observed major hemorrhages in the fondaparinux group 1.2% (4/322) compared to UFH 3.7% (12/322), but this difference was not significant (OR=0.33, 95% CI 0.08-1.10, p=0.08). There were also no significant differences in total hemorrhage (p=0.15), intracranial hemorrhage (p=0.48), major extracranial hemorrhage (p=0.18) and symptomatic VTE (p=1.00) between the groups. CONCLUSIONS: Fondaparinux is not associated with increased hemorrhagic complications compared with UFH in patients with ischemic stroke. There were low rates of symptomatic VTE in both groups. PMID- 25554498 TI - Imbalance between CD205 and CD80/CD86 in dendritic cells in patients with immune thrombocytopenia. AB - INTRODUCTION: CD205(DEC-205), a tolerance-associated receptor, is a member of the macrophage mannose receptor family of C-type lectin receptors. Antigen uptake via CD205 induces regulatory T cells, thereby regulating peripheral immune tolerance. However, the contribution of CD205 to autoimmune diseases has not been elucidated. Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by overdestruction of platelets. A previous study by the present authors found that CD205 expression in dendritic cells (DCs) was upregulated during induction of immune tolerance in patients with ITP. METHODS: CD205 expression in monocyte derived DCs and spleens from patients with ITP was analysed prior to and after high-dose dexamethasone (HD-DXM) treatment. Expression of CD80, CD86 and HLA-DR was also analysed in order to identify and define the maturation status of the DCs more precisely. RESULTS: In patients with ITP, CD205 expression was found to be significantly decreased in DCs, and rare or absent in the border region of the spleen. However, the expression of CD80 and CD86 was increased in both monocyte derived DCs and spleens in patients with ITP compared with controls. HD-DXM treatment may upregulate CD205 expression and downregulate CD80/CD86 expression, then rebalance the expression of CD205 and CD80/CD86 in DCs in patients with ITP. CONCLUSION: Imbalance between CD205 and CD80/CD86 may contribute to the development of ITP. Therapies that aim to restore the balance between CD205 and CD80/CD86 may help to re-establish tolerance in patients with ITP. PMID- 25554499 TI - Importance of contact lens power and thickness in oxygen transmissibility. AB - PURPOSE: The aim of this work was to study the central and peripheral thickness of several contact lenses (CL) with different powers and analyze how thickness variation affects CL oxygen transmissibility. METHODS: Four daily disposable and five monthly or biweekly CL were studied. The powers of each CL were: the maximum negative power of each brand; -6.00 D; -3.00 D; zero power (-0.25 D or -0.50 D), +3.00 D and +6.00 D. Central and peripheral thicknesses were measured with an electronic thickness gauge. Each lens was measured five times (central and 3mm paracentral) and the mean value was considered. Using the values of oxygen permeability given by the manufacturers and the measured thicknesses, the variation of oxygen transmissibility with lens power was determined. RESULTS: For monthly or biweekly lenses, central thickness changed between 0.061 +/- 0.002 mm and 0.243 +/- 0.002 mm, and peripheral thickness varied between 0.084 +/- 0.002 mm and 0.231 +/- 0.015 mm. Daily disposable lenses showed central values ranging between 0.056 +/- 0.0016 mm and 0.205 +/- 0.002 mm and peripheral values between 0.108 +/- 0.05 and 0.232 +/- 0.011 mm. Oxygen transmissibility (in units) of monthly or biweekly CL ranged between 39.4 +/- 0.3 and 246.0 +/- 14.4 and for daily disposable lenses the values range between 9.5 +/- 0.5 and 178.1 +/- 5.1. CONCLUSIONS: The central and peripheral thicknesses change significantly when considering the CL power and this has a significant impact on the oxygen transmissibility. Eyecare practitioners must have this fact in account when high power plus or minus lenses are fitted or when continuous wear is considered. PMID- 25554500 TI - New Scheimpflug camera device in measuring corneal power changes after myopic laser refractive surgery. AB - PURPOSE: To assess the accuracy of a combined Scheimpflug camera-Placido disk device (Sirius, CSO, Italy) in evaluating corneal power changes after myopic photorefractive keratectomy (PRK). METHODS: Two hundred and thirty-seven eyes of 237 patients that underwent myopic PRK with a refractive error, measured as spherical equivalent, ranging from -10.75 D to -0.5D (mean -4.63 +/- 2.21D), were enrolled in this study. Corneal power evaluation using Sirius were performed before, 1, 3 and 6 months after myopic PRK. Mean simulated keratometry (SimK) and mean pupil power (MPP) were measured. Correlations between changes in corneal power, measured with SimK and MPP, and variations in subjective refraction, calculated at corneal plane, were evaluated using Pearson test at every follow up; differences between preoperative and postoperative data were evaluated with the Student paired t-test. RESULTS: A good correlation has been detected between the variations in subjective refraction measured at corneal plane 1, 3 and 6 months after myopic PRK and both SimK (R(2) = 0.8463; R(2) = 0.8643; R(2) = 0.7102, respectively) and MPP (R(2) = 0.6622; R(2) = 0.5561; R(2) = 0.5522, respectively) but corneal power changes are statistically undervalued for both parameters (p < 0.001). CONCLUSIONS: Even if our data should be confirmed in further studies, SimK and MPP provided by this new device do not seem to accurately reflect the changes in corneal power after myopic PRK. PMID- 25554506 TI - Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non-Small-Cell Lung Cancer. AB - INTRODUCTION: The present study investigated the effects of patients' genetic variations in the pharmacokinetics of gefitinib at steady-state. We analyzed 31 Japanese patients with non-small-cell lung cancer (NSCLC) who had been treated with gefitinib. We focused on common polymorphisms within important gefitinib exposure genes, including cytochromes P450 (CYPs) CYP3A4*1G, CYP3A5 (*3), and CYP2D6 (*5 and *10) and ATP-binding cassette (ABC) ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T). MATERIALS AND METHODS: Fourteen days after beginning 250 mg of gefitinib therapy, when the patients were in steady-state, blood samples were collected just before and 1, 2, 4, 6, 8, 12, and 24 hours after oral gefitinib administration. The plasma concentrations of gefitinib were measured using high-performance liquid chromatography. RESULTS: The median area under the concentration-time curve from 0 to 24 hours (AUC0-24) and trough plasma concentration (C0) of gefitinib was 10,086 ng . h/mL (range, 3247-24,726 ng . h/mL) and 334 ng/mL (range, 77.9-813 ng/mL), respectively. No significant differences were found in the AUC0-24 or C0 for gefitinib or in the frequency of diarrhea, skin rash or hepatotoxicity among the CYP3A4, CYP3A5, CYP2D6, ABCG2 (421C>A), and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genotype groups. However, the AUC0-24 and C0 levels of gefitinib in the patients with diarrhea or hepatotoxicity were significantly greater than in those without (diarrhea: AUC0 24, 14,246 vs. 8918 ng . h/mL, P = .006; C0: 421 vs. 261 ng/mL, P = .002; hepatotoxicity: AUC0-24, 12,967 vs. 8473 ng . h/mL, P = .024; C0: 420 vs. 248 ng/mL, P = .002). CONCLUSION: The side effects from gefitinib were related to exposure but not genetic polymorphism. Therefore, therapeutic drug monitoring after beginning gefitinib therapy rather than the analysis of polymorphism before initiating therapy might be beneficial. PMID- 25554515 TI - Ezrin interacts with the scaffold protein IQGAP1 and affects its cortical localization. AB - The cortical cytoskeleton constitutes an important subcellular structure that determines cell shape and regulates cell migration as well as membrane traffic to and from the plasma membrane. Many components of the cortical cytoskeleton have been identified including structural and scaffolding proteins, membrane cytoskeleton linker proteins and signaling intermediates. We describe here an association of the membrane-F-actin linker protein ezrin with the scaffolding protein IQGAP1 that serves as a hub for concentrating different signaling complexes. Both, ezrin and IQGAP1 bind in a Ca2+-dependent manner to the EF hand protein S100P and complexes consisting of Ca2+-bound S100P, IQGAP1 and ezrin can be isolated by immunoprecipitation. Ezrin and IQGAP1 also interact in the absence of Ca2+, thus independent of S100P. Direct ezrin-IQGAP1 interaction can be shown with the purified proteins. It is mediated via the N-terminal FERM domain of ezrin and the IQ domain of IQGAP1, respectively. Ezrin and IQGAP1 colocalize in the submembraneous cytoskeleton and in cellular protrusions of human epithelial cells and knockdown of ezrin reduces the cortical localization of IQGAP1. Thus, ezrin appears to participate in recruiting IQGAP1 to the cell cortex thereby establishing a close connection between membrane-F-actin contacts and actin regulators that can be assembled by IQGAP1. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25554516 TI - Characterization and modeling of Ca2+ oscillations in mouse primary mesothelial cells. AB - Brief changes in the cytosolic and intra-organellar Ca2+ concentration serve as specific signals for various physiological processes. In mesothelial cells lining the surface of internal organs and the walls of body cavities, a re-entry in the cell cycle (G0-G1 transition) evoked by serum re-administration induces long lasting Ca2+ oscillations with a slowly decreasing frequency. Individual mesothelial cells show a wide range of different oscillatory patterns within a single, supposedly homogenous cell population. Changes in the cytoplasmic Ca2+ concentration (ccyt) show baseline oscillatory patterns i.e., discrete Ca2+ transients starting from a constant basal ccyt level. The ER Ca2+ concentration (cER) displays a sawtooth wave at a semi-depleted ER state; the minimum level is reached just briefly after the maximal value for ccyt. These oscillations depend on plasmalemmal Ca2+ influx and on the inositol trisphosphate concentration [InsP3]; the Ca2+ influx is a crucial determinant of the oscillation frequency. Partial blocking of SERCA pumps modifies the oscillation frequency in both directions, i.e. increasing it in some cells and lowering it in others. Current mathematical models for Ca2+ oscillations mostly fail to reproduce two experimentally observed phenomena: the broad range of interspike intervals and constant basal ccyt levels between two Ca2+ spikes. Here we developed a new model based on--and fitted to--Ca2+ recordings of ccyt and cER recorded in primary mouse mesothelial cells. The model allowed for explaining many features of experimentally observed Ca2+ oscillations. We consider this model to be suitable to simulate various types of InsP3 receptor-based baseline Ca2+ oscillations. PMID- 25554517 TI - Efficient export of human growth hormone, interferon alpha2b and antibody fragments to the periplasm by the Escherichia coli Tat pathway in the absence of prior disulfide bond formation. AB - Numerous therapeutic proteins are expressed in Escherichia coli and targeted to the periplasm in order to facilitate purification and enable disulfide bond formation. Export is normally achieved by the Sec pathway, which transports proteins through the plasma membrane in a reduced, unfolded state. The Tat pathway is a promising alternative means of export, because it preferentially exports correctly folded proteins; however, the reducing cytoplasm of standard strains has been predicted to preclude export by Tat of proteins that contain disulfide bonds in the native state because, in the reduced state, they are sensed as misfolded and rejected. Here, we have tested a series of disulfide-bond containing biopharmaceuticals for export by the Tat pathway in CyDisCo strains that do enable disulfide bond formation in the cytoplasm. We show that interferon alpha2b, human growth hormone (hGH) and two antibody fragments are exported with high efficiency; surprisingly, however, they are efficiently exported even in the absence of cytoplasmic disulfide formation. The exported proteins acquire disulfide bonds in the periplasm, indicating that the normal disulfide oxidation machinery is able to act on the proteins. Tat-dependent export of hGH proceeds even when the disulfide bonds are removed by substitution of the Cys residues involved, suggesting that these substrates adopt tertiary structures that are accepted as fully-folded by the Tat machinery. PMID- 25554519 TI - Tutorial: strategies addressing detection bias were reviewed and implemented for investigating the statins-diabetes association. AB - OBJECTIVES: Literature on specific analytic methods for addressing detection bias is fragmented. We illustrate some analytic strategies to account for detection bias. STUDY DESIGN AND SETTING: Several tools addressing detection bias are described, namely (1) sensitivity analysis, (2) conditioning on outcome detectability, and (3) use of negative controls. These tools are applied in a population-based cohort study on the association between adherence to statins and start of antidiabetic therapy (as proxy of type 2 diabetes mellitus onset). RESULTS: Compared with patients on very low adherence to statins, those with high adherence had hazard ratio (HR) for diabetes of 1.53 (95% confidence interval: 1.44, 1.64). The observed association was potentially affected by detection bias because long-term exposure to statins implies a more regular use of primary care services, triggering the search for diabetes. Nevertheless, from the considered tools, (1) we showed that the HR for diabetes risk decreased to 1.28 if diabetes detection was assumed to be 20% more likely in highly adherent patients; (2) an increased risk of diabetes was found among patients with no specialist visits during the first year of follow-up; (3) no association was found between adherence to bisphosphonates (negative exposure) and diabetes nor between adherence to statins and initiation of antihypertensive pharmacotherapy (negative outcome). CONCLUSION: Implementation of analytic strategies for addressing detection bias is advisable whenever this is suspected. As illustrated, several methods could be considered. Their implementation suggested that detection bias had a limited impact in our application. PMID- 25554518 TI - Bisphenol-A exposure during adolescence leads to enduring alterations in cognition and dendritic spine density in adult male and female rats. AB - We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescents in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40MUg/kg/bodyweight, or control treatments for one week. In adulthood, subjects were tested for anxiety and locomotor activity, spatial memory, non-spatial visual memory, and sucrose preference. Additionally, stress-induced serum corticosterone levels and dendritic spine density in the mPFC and CA1 were measured. BPA-treated males, but not females, had decreased arm visits on the elevated plus maze, but there was no effect on anxiety. Non-spatial memory, object recognition, was also decreased in BPA treated males, but not in females. BPA exposure did not alter spatial memory, object placement, but decreased exploration during the tasks in both sexes. No significant group differences in sucrose preference or serum corticosterone levels in response to a stress challenge were found. However, BPA exposure, regardless of sex, significantly decreased spine density of both apical and basal dendrites on pyramidal cells in CA1 but had no effect in the mPFC. Current data are discussed in relation to BPA dependent changes, which were present during adolescence and did, or did not, endure into adulthood. Overall, adolescent BPA exposure, below the current reference safe daily limit set by the U.S.E.P.A., leads to alterations in some behaviors and neuronal morphology that endure into adulthood. PMID- 25554520 TI - Bayesian methods including nonrandomized study data increased the efficiency of postlaunch RCTs. AB - OBJECTIVES: Findings from nonrandomized studies on safety or efficacy of treatment in patient subgroups may trigger postlaunch randomized clinical trials (RCTs). In the analysis of such RCTs, results from nonrandomized studies are typically ignored. This study explores the trade-off between bias and power of Bayesian RCT analysis incorporating information from nonrandomized studies. STUDY DESIGN AND SETTING: A simulation study was conducted to compare frequentist with Bayesian analyses using noninformative and informative priors in their ability to detect interaction effects. In simulated subgroups, the effect of a hypothetical treatment differed between subgroups (odds ratio 1.00 vs. 2.33). Simulations varied in sample size, proportions of the subgroups, and specification of the priors. RESULTS: As expected, the results for the informative Bayesian analyses were more biased than those from the noninformative Bayesian analysis or frequentist analysis. However, because of a reduction in posterior variance, informative Bayesian analyses were generally more powerful to detect an effect. In scenarios where the informative priors were in the opposite direction of the RCT data, type 1 error rates could be 100% and power 0%. CONCLUSION: Bayesian methods incorporating data from nonrandomized studies can meaningfully increase power of interaction tests in postlaunch RCTs. PMID- 25554522 TI - Systematic review of cell adhesion molecules and estrogen receptor expression in the endometrium of patients with polycystic ovary syndrome. AB - BACKGROUND: Infertility associated with polycystic ovary syndrome (PCOS) could be related to many mechanisms including endometrial factors. OBJECTIVES: To review cell adhesion molecule and estrogen receptor expression in the endometrium. SEARCH STRATEGY: A systematic review was performed of the Medline and Cochrane databases for papers published in any language between 2004 and 2014. The search term was "'polycystic ovary syndrome' OR 'Stein Leventhal syndrome' OR 'anovulation' AND 'endometrium' OR 'endometria.'" SELECTION CRITERIA: Research studies on endometrial cell adhesion molecules and estrogen receptor expression among women with PCOS diagnosed according to the Rotterdam criteria were included. DATA COLLECTION AND ANALYSIS: Data were extracted from identified studies and the quality of assessment was analyzed. MAIN RESULTS: Six studies were included. Data were controversial with respect to MUC1 and alphaVbeta3 integrin expression with significantly higher and lower levels, respectively, in women with PCOS. Estrogen receptor expression was enhanced among patients with PCOS as compared with healthy women. CONCLUSIONS: Endometrial factors influence embryo receptivity as indicated by the molecular mediators identified in the studies, including cell adhesion molecules and the estrogen receptor. PMID- 25554523 TI - From farm to fat cell: why aren't we all fat? PMID- 25554521 TI - Citation searches are more sensitive than keyword searches to identify studies using specific measurement instruments. AB - OBJECTIVES: To compare the effectiveness of two search methods in identifying studies that used the Control Preferences Scale (CPS), a health care decision making instrument commonly used in clinical settings. STUDY DESIGN AND SETTING: We searched the literature using two methods: (1) keyword searching using variations of "Control Preferences Scale" and (2) cited reference searching using two seminal CPS publications. We searched three bibliographic databases [PubMed, Scopus, and Web of Science (WOS)] and one full-text database (Google Scholar). We report precision and sensitivity as measures of effectiveness. RESULTS: Keyword searches in bibliographic databases yielded high average precision (90%) but low average sensitivity (16%). PubMed was the most precise, followed closely by Scopus and WOS. The Google Scholar keyword search had low precision (54%) but provided the highest sensitivity (70%). Cited reference searches in all databases yielded moderate sensitivity (45-54%), but precision ranged from 35% to 75% with Scopus being the most precise. CONCLUSION: Cited reference searches were more sensitive than keyword searches, making it a more comprehensive strategy to identify all studies that use a particular instrument. Keyword searches provide a quick way of finding some but not all relevant articles. Goals, time, and resources should dictate the combination of which methods and databases are used. PMID- 25554524 TI - Changes in Caenorhabditis elegans immunity and Staphylococcal virulence factors during their interactions. AB - The nematode Caenorhabditis elegans is used as a model system for the study of host-pathogen interactions. Lipoteichoic acid (LTA) is one of the major virulent and immunostimulatory components found in gram positive bacteria. The current study used LTA isolated from Staphylococcus aureus and pathogenic and non pathogenic Staphylococcus epidermidis. The overall physiological assays revealed that LTA exposed C. elegans show a significant reduction in the life span, production of eggs and progenies. To understand the involvement of innate immune specific players at the mRNA level, the regulation of few candidate antimicrobial genes was studied during Staphylococcal LTA exposures. qPCR analysis indicated an upregulation of antimicrobial peptides during LTA exposures. To understand the involvement of LTA and other virulent genes during infection, the regulation of LTA synthase and a few virulence genes was monitored during host exposure. The qPCR analyses indicated the upregulation of ltaS and other virulence genes (atoxin, sak, ssaA and fbe) during infection. Ability of the pathogens to modify their internal machinery during host presence was monitored by Fourier transform infrared spectroscopy, electrochemical impedance spectroscopy and cyclic voltametric analyses. The FTIR results indicated distinct alterations of peaks from Staphylococcal LTA composition between control and the host exposed. Further, EIS and CV data displayed clear differences between the host exposed Staphylococcal samples compared to their respective unexposed controls. The pathogenic and non-pathogenic strains showed different types of regulations and interactions during host exposures. The observed modifications clearly suggest that the Gram positive pathogen changes its LTA production and possibly the structure to cause a severe pathogenic effect on an interacting host. PMID- 25554525 TI - Examining evolutionary relationships and shifts in depth preferences in batfishes (Lophiiformes: Ogcocephalidae). AB - Batfishes (Ogcocephalidae) are an understudied, group of marine anglerfishes that are dorsoventrally flattened and have an illicium and esca (terminal lure) used to attract prey. The family contains 10 genera and 75 recognized species from nearly all tropical and subtropical seas. Relationships among these taxa, as well as the position of Ogcocephalidae within Lophiiformes, remain poorly understood with previous studies showing conflicting, and poorly resolved results. The timing of divergence and depth of origination in the water column have also not been explored in any detail. In this study a concatenated nuclear (three genes) and mitochondrial (two genes) dataset was constructed across several anglerfish families to elucidate phylogenetic relationships among all ten batfish genera, to clarify the placement of Ogcocephaloidei within Lophiiformes, and to estimate divergence times using fossil calibrations. An ancestral state reconstruction was also conducted to examine the history of shifts in preferred habitat depths within batfishes. Phylogenetic analyses supported monophyly of each sub-order within Lophiiformes and placed Ogcocephaloidei as the sister group to Antennarioidei. Batfish genera were divided into an Eastern Pacific/Western Atlantic clade and an Indo-Pacific clade; Halieutaea was recovered as the sister group to all other batfishes. Based on divergence time estimations and ancestral state reconstructions of preferred depth, Ogcocephalidae is Eocene in age and originated on the lower continental shelf/upper continental slope (disphotic zone). PMID- 25554526 TI - Differential introgression and effective size of marker type influence phylogenetic inference of a recently divergent avian group (Phasianidae: Tympanuchus). AB - Life history strategies can influence the effective population size (Ne) of loci differently based on their mode of inheritance. Recognizing how this may affect the rate of lineage sorting among marker types is important for studies focused on resolving phylogenetic relationships among recently divergent taxa. In this study, we use gene tree, coalescent-based species tree, and isolation-with migration analyses to explore the differences between marker types (autosomal, Z linked, and mitochondrial) in resolving phylogenetic relationships among North American prairie grouse (Tympanuchus). We found that Z-linked loci were more likely to identify monophyletic relationships among prairie grouse species compared to autosomal and mtDNA loci in both species and gene tree analyses, with species tree analyses outperforming gene trees. These results were further supported with isolation-with-migration analyses, where Z-linked loci largely followed a strict isolation model while autosomal loci were more likely to fit a model with gene flow between species following population divergence. While accounting for differences in inheritance pattern (or Ne) for marker type, results suggest that additional factors, such as strong sexual selection and sex biased introgression (i.e., male-biased postzygotic hybrid behavioral isolation or "unsexy son"), may further explain the decreased diversity levels and increased rate of lineage sorting observed with the Z-linked loci relative to autosomal and mtDNA loci. In fact, to our knowledge no hybrid male prairie grouse have been observed breeding in the wild, yet hybrid females along with backcross females are known to produce viable offspring. Overall, this study highlights that more work is needed to determine how complex models of gene flow (i.e., sex biased introgression) and differences in the effective size among marker types based on differing life history strategies influence divergence date estimation and species delimitation. PMID- 25554527 TI - [Laparoscopic transposition of lower polar vessels for pyelo-ureteral junction obstruction: preliminary experience]. AB - AIM OF THE STUDY: Lower pole vessels are a classical cause of PUJO even in children. The "gold standard" in the management of PUJ obstructions remains a dismembered pyeloplasty as described by Anderson and Hynes. However, some authors have developed an alternative procedure to this approach with encouraging results. The aim of our study was to evaluate our preliminary results concerning laparoscopic vascular hitch for crossing vessels. MATERIAL AND METHODS: We conducted a retrospective, monocentric study of all patients managed by this technique from January 2010 to December 2012. RESULTS: Eleven patients (7 boys, 4 girls) were managed by laparoscopy at a mean age of 10.7 years (5.4-17). They were referred to our center for clinical symptoms (intermittent pain 7, high blood pressure 1, UTI 1), antenatal diagnosis or accidental discovery. Obstruction was confirmed by MAG3 nephrogram and the presence of obstructive vessels by tomodensitometry or MRI. Mean operative time was 90.2minutes (48-184). Seven patients over 11 were strictly managed by laparoscopic transposition of lower pole vessels. Four required a classical video-assisted dismembered pyeloplasty due to a potential intraluminal stenosis. The latter were suspected by a distension test with furosemid in all four cases. Mean follow-up was 12.9+/ 3 months. Nine patients over 11 were totally non symptomatic, whereas 2 still present mild intermittent pain. In all cases, ultrasound scans show an improvement of the pelvic dilatation. CONCLUSION: Laparoscopic transposition of lower pole vessels is a suitable and feasible alternative for the management of obstructive PUJ. Our preliminary experience emphasizes the need for a precise preoperative selection of patients along with a per operative evaluation of the obstruction. Further experience seems required to improve our criteria in this indication. LEVEL OF EVIDENCE: 5. PMID- 25554528 TI - Nanoparticles in food. Epigenetic changes induced by nanomaterials and possible impact on health. AB - Disturbed epigenetic mechanisms, which developmentally regulate gene expression via modifications to DNA, histone proteins, and chromatin, have been hypothesized to play a key role in many human diseases. Recently it was shown that engineered nanoparticles (NPs), that already have a wide range of applications in various fields including food production, could dramatically affect epigenetic processes, while their ability to induce diseases remains poorly understood. Besides the obvious benefits of the new technologies, it is critical to assess their health effects before proceeding with industrial production. In this article, after surveying the applications of NPs in food technology, we review recent advances in the understanding of epigenetic pathological effects of NPs, and discuss their possible health impact with the aim of avoiding potential health risks posed by the use of nanomaterials in foods and food-packaging. PMID- 25554529 TI - Stevia-derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: a transcriptomic and metabolomic study. AB - There is a close interaction between Type 2 Diabetes, obesity and liver disease. We have studied the effects of the two most abundant Stevia-derived steviol glycosides, stevioside and rebaudioside A, and their aglycol derivative steviol on liver steatosis and the hepatic effects of lipotoxicity using a mouse model of obesity and insulin resistance. We treated ob/ob and LDLR-double deficient mice with stevioside (10 mg?kg(-1)?day-1 p.o., n = 8), rebaudioside A (12 mg?kg( 1)?day-1 p.o., n = 8), or steviol (5 mg?kg(-1)?day(-1) p.o., n = 8). We determined their effects on liver steatosis and on the metabolic effects of lipotoxicity by histological analysis, and by combined gene-expression and metabolomic analyses. All compounds attenuated hepatic steatosis. This could be explained by improved glucose metabolism, fat catabolism, bile acid metabolism, and lipid storage and transport. We identified PPARs as important regulators and observed differences in effects on insulin resistance, inflammation and oxidative stress between Stevia-derived compounds. We conclude that Stevia-derived compounds reduce hepatic steatosis to a similar extent, despite differences in effects on glucose and lipid metabolism, and inflammation and oxidative stress. Thus our data show that liver toxicity can be reduced through several pathophysiological changes. Further identification of active metabolites and underlying mechanisms are warranted. PMID- 25554534 TI - Analysis of clinical parameters and cardiac magnetic resonance imaging as predictors of outcome in pediatric myocarditis. AB - Myocarditis causes significant morbidity and mortality in pediatric patients, with potential adverse outcomes including heart failure, transplantation requirement, and/or death. The objective of this study was to determine predictors of early and late poor outcomes, defined as requirement for extracorporeal membrane oxygenation, ventricular assist device, transplantation, or death in pediatric myocarditis patients. A retrospective cohort study was conducted to evaluate pediatric myocarditis presenting over a 5-year period at a pediatric institution. Patients were identified using an institutional heart failure database and International Classification of Diseases, Ninth Revision, discharge diagnosis codes for myocarditis and confirmed by review of medical records. Data extraction included epidemiologic factors, the presenting ejection fraction (EF), initial and peak troponin levels, brain natriuretic peptide (BNP) level, pathogen identification, cardiac magnetic resonance imaging (MRI), and outcomes. Univariate and multivariate regression was performed to identify variables predictive of outcomes. Because published pediatric cardiac MRI data are sparse, whether late enhancement was associated with specific clinical variables or predictive of outcomes was also evaluated. Fifty-eight patients were identified. The mean age was 10.5 years, 64% were male, 62% were Caucasian, 15% were African-American, and 23% were Hispanic or Asian. Eighty-one percent presented at the institution <1 week after symptom onset. Presenting EFs were normal (>50%) or mildly decreased (40% to 50%) in 48%, moderately decreased (30% to 40%) in 9%, and severely decreased (<30%) in 42%. Thirty patients (52%) underwent viral studies; 17 of these (56%) had acute viral origins of myocarditis identified, including 8 with parvovirus (2 with influenza coinfection), 7 with enterovirus, 1 with Epstein-Barr virus, and 1 with cytomegalovirus. Twenty-eight percent had poor outcomes. Univariate analysis identified Hispanic or Asian race (odds ratio [OR] 4.5, p = 0.05), a severely decreased EF (OR 13, p = 0.002), initial BNP >10,000 pg/ml (OR 5.6, p = 0.01), and peak BNP >10,000 pg/ml (OR 13.65, p = 0.001) as risk factors for poor outcomes; initial and peak troponin >1 ng/ml were correlated significantly with good outcomes (OR 0.22, p = 0.04, and OR 0.26, p = 0.05, respectively). Multivariate analysis adjusting for severe EF, troponin, BNP, and cardiac MRI revealed peak BNP >10,000 ng/L (OR 27.71, p = 0.04), a severely decreased EF (OR 12.8, p = 0.03), and late enhancement on cardiac MRI (OR 24.51, p = 0.04) as risk factors for poor outcomes. Thirty-four patients underwent cardiac MRI (50% with abnormal and 50% with normal results). No significant differences were found between these groups with respect to gender, race, symptom duration, the EF, BNP, troponin, inflammation on cardiac biopsy, or pathogen identification. In conclusion, this study provides data from a large cohort of pediatric myocarditis patients. A presenting EF <30%, peak BNP >10,000 ng/L, and cardiac MRI late enhancement were identified as predictors of poor outcomes. PMID- 25554535 TI - Erroneous event count in a meta-analysis (dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus). PMID- 25554536 TI - Effect of statin therapy on incident type 2 diabetes mellitus in patients with clinically manifest vascular disease. AB - Several trials and cohort studies have shown an increased incidence of type 2 diabetes mellitus (T2DM) in patients using statins. Whether this only applies to patients at already high risk for the development of T2DM or for all patients is still a matter of debate. In the present prospective cohort study of 4,645 patients with established vascular disease without DM at baseline, 3,057 patients used statins at baseline, of whom 1,608 used intensive statin therapy, defined as statin therapy theoretically lowering low-density lipoprotein cholesterol with >=40%. Cox proportional hazards models were used to estimate the risk of incident T2DM with (intensive) statin therapy. Statin therapy was associated with increased risk of incident T2DM (hazard ratio 1.63; 95% confidence interval 1.15 to 2.32) when adjusted for age, gender, body mass index, plasma high-density lipoprotein cholesterol, and plasma triglyceride levels. Intensive statin therapy tended to be related to a higher risk of T2DM compared with moderate statin therapy (hazard ratio 1.22; 95% confidence interval 0.92 to 1.61, adjusted for age, gender, body mass index, plasma high-density lipoprotein cholesterol, and plasma triglyceride levels). The increase in risk was regardless of the number of metabolic syndrome characteristics or insulin resistance but was particularly present in patients with low baseline glucose levels (<5.6 mmol/L; p for interaction 2.9 * 10(-7)). In conclusion, statin use increases the risk of incident T2DM in patients with clinically manifest vascular disease. The increase in risk was independent of the number of metabolic syndrome criteria and was even more pronounced in patients with low baseline glucose levels. PMID- 25554537 TI - The use of shear rate-diameter dose-response curves as an alternative to the flow mediated dilation test. AB - The brachial artery flow-mediated dilation test (FMD) is the non-invasive gold standard used to test endothelial function. Reduced FMD precedes the development of atherosclerosis and provides an early marker for predicting future cardiovascular disease events. Although, this test is of high potential, it is somewhat limited by poor reproducibility. By utilizing hand warming and grip exercise combined with hierarchical linear modeling, shear rate-diameter dose response curves may provide a novel and more accurate way to assess endothelial function in humans. Shear rate-diameter dose-response curves could potentially improve upon the traditional FMD measurement and serve as a superior clinical and research tool for assessing cardiovascular disease risk in a variety of populations. The current paper presents testable hypotheses and methodology for assessing the validity and reliability of an alternative to the current FMD test. PMID- 25554538 TI - The prestige model of spectrum bipolarity. AB - Because affective pathogenesis is a hard problem for psychiatry, it behoves researchers to develop and test novel models of causality. We examine the notion that the adaptive drive to social investment - prestige - provides clues to the bipolar spectrum. A seven node bipolar spectrum is proposed, based on a putative gradient of "bipolarity". It is conceived that this gradient may correlate with the drive to social investment (prestige). In order to test this hypothesis with proof of concept data, a case control study categorised 228 subjects into a seven node bipolar spectrum. Whilst controlling for mood elevation and depression, differences in strategic prestige (leadership) motivation (MSPM) between spectrum groups were examined. The bipolar I (S1) node had a greater strategic prestige (leadership) motivation score than the controls (S7) by 21.17 points, 95% CI [8.16, 34.18], p<.001, d=1.05, while the bipolar II (S2) node was higher than the control group by 16.73 points, 95% CI [0.92, 32.54], p=.030, d=0.84. Whilst the pseudounipolar (S3) node (those with depression and bipolar family histories; n=17) had only a marginally statistical difference in MSPM compared to controls (p=.051), the mean difference (16.98) and d value (0.86) indicated an elevated MSPM level. Prestige (leadership) motivation score positively correlated with dimensional lifetime bipolarity (Mood Disorder Questionnaire) score (rp=0.47), supporting the spectrum prestige motivation gradient notion. Evidence is presented for a genetic disposition to elevated strategic prestige (leadership) motivation. Sensitivity to Social Inclusion (MSIS), Contingency of Self-Worth (CSW.av) and tension significantly predicted strategic prestige (leadership) motivation (MSPM) score in a multiple regression. - suggesting that a vulnerability of the social self may be a feature of bipolar disorders. The prestige model of spectrum bipolarity offers a new conceptualisation of affective disorders and has received preliminary support. PMID- 25554539 TI - Clinical significance of HAX-1 expression in laryngeal carcinoma. AB - OBJECTIVE: HS1-associated protein X-1 (HAX-1) is a multifunctional protein that has been highlighted as an important marker in many types of cancers. However, little is known about the role of HAX-1 in laryngeal carcinoma. The purpose of the present study is to explore HAX-1 expression status and its associations with clinicopathologic features and survival in a well-defined cohort of laryngeal carcinoma. METHODS: We examined the expression of HAX-1 at protein and mRNA levels in laryngeal carcinoma tissues and adjacent non-tumor tissues by immunohistochemistry, Western blotting and two-step quantitative real-time PCR analysis, respectively. RESULTS: We observed that HAX-1 was significantly elevated in laryngeal carcinoma. The relationship between the levels of HAX-1 expression and clinicopathologic characteristics was then analyzed. Overexpression of HAX-1 was significantly correlated with T classification, lymph node metastasis, clinical stage, and pathology. Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. We find that patients with overexpression of HAX-1 had shorter overall survival rates. Finally, the significance of various survival variables was analyzed using multivariate Cox proportional hazards model. We found that overexpression of HAX 1 was an independent prognostic factor for patients with laryngeal carcinoma. CONCLUSION: Our findings hinted that overexpression of HAX-1 was a potentially unfavorable factor in the progression and prognosis of laryngeal carcinoma. PMID- 25554540 TI - Volume and landmark analysis: comparison of MRI measurements obtained with an endorectal coil and with a phased-array coil. AB - AIM: To compare prostate volumes and distances between anatomical landmarks on MRI images obtained with a phased-array coil (PAC) only and with a PAC and an endorectal coil (ERC). MATERIALS AND METHODS: Informed consent was waived for this Health Insurance Portability and Accountability Act-compliant study. Fifty nine men underwent PAC-MRI and ERC-MRI at 1.5 (n = 3) or 3 T (n = 56). On MRI images, two radiologists independently measured prostate volume and distances between the anterior rectal wall (ARW) and symphysis pubis at the level of the verumontanum; ARW and symphysis pubis at the level of the mid-symphysis pubis; and bladder neck and mid-symphysis pubis. Differences between measurements from PAC-MRI and ERC-MRI were assessed with the Wilcoxon RANK SUM test. Inter-reader agreement was assessed using the concordance correlation coefficient (CCC). RESULTS: Differences in prostate volume between PAC-MRI and ERC-MRI [median: 0.75 mm(3) (p = 0.10) and median: -0.84 mm(3) (p = 0.06) for readers 1 and 2, respectively] were not significant. For readers 1 and 2, median differences between distances were as follows: -10.20 and -12.75 mm, respectively, ARW to symphysis pubis at the level of the verumontanum; -6.60 and -6.08 mm, respectively, ARW to symphysis pubis at the level of the mid-symphysis pubis; -3 and -3 mm respectively, bladder neck to mid-symphysis pubis. All differences in distance were significant for both readers (p <= 0.0005). Distances were larger on PAC-MRI (p <= 0.0005). Inter-reader agreement regarding prostate volume was almost perfect on PAC-MRI (CCC: 0.99; 95% CI: 0.98-1.00) and ERC-MRI (CCC: 0.99; 95% CI: 0.99-1.00); inter-reader agreement for distance measurements varied (CCCs: 0.54-0.86). CONCLUSION: Measurements of distances between anatomical landmarks differed significantly between ERC-MRI and PAC-MRI, although prostate volume measurements did not. PMID- 25554541 TI - Model-based iterative reconstruction for improvement of low-contrast detectability in liver CT at reduced radiation dose: ex-vivo experience. AB - AIM: To compare low-contrast detectability, and qualitative and quantitative image parameters on standard and reduced radiation dose abdominal CT reconstructed with filtered back projection (FBP) and model-based iterative reconstruction (MBIR). MATERIALS AND METHODS: A custom built liver phantom containing 43 lesions was imaged at 120 kVp and four radiation dose levels (100% = 188 mAs, 50%, 25%, and 10%). Image noise and contrast-to-noise ratios (CNR) were assessed. Lesion detection and qualitative image analysis (five-point Likert scale with 1 = worst, 5 = best for confidence) was performed by three independent radiologists. RESULTS: CNR on MBIR images was significantly higher (mean 246%, range 151-383%) and image noise was significantly lower (69%, 59-78%) than on FBP images at the same radiation dose (both p < 0.05). On MBIR 10% images, CNR (3.3 +/- 0.3) was significantly higher and noise (15 +/- 1HU) significantly lower than on FBP 100% images (2.5 +/- 0.1; 21 +/- 1 HU). On 100% images, lesion attenuation was significantly lower with MBIR than with FBP (mean difference -2 HU). Low contrast detectability and qualitative results were similar with MBIR 50% and FBP 100%. CONCLUSION: Low-contrast detectability with MBIR 50% and FBP 100% were equal. Quantitative parameters on even lower dose MBIR images are superior to 100%-dose FBP images. Some attenuation values differ significantly with MBIR compared with FBP. PMID- 25554542 TI - The complexities of recruiting bereaved family members into a research study in the critical care environment: a discussion paper. AB - Research on the effects of stressful events on human health and wellbeing has progressed in recent years. One such stress, bereavement, is considered one of life's greatest stresses, requiring significant readjustment. The Cardiovascular Risk in Bereavement study (CARBER) investigated in detail cardiovascular risk factors during the first weeks following the death of a partner or adult child in the critical care environment. The purpose of this paper is to explore the once held perception that the bereaved population should not be involved in research, using an actual illustrative project. The paper specifically focuses on the challenges regarding acceptability and feasibility of recruitment of recently bereaved individuals from the critical care environment. The question of whether bereaved individuals have capacity to consent to involvement in research immediately after loss is considered. The appropriateness of asking newly bereaved individuals to participate in research immediately after the death of their relative is also discussed. The work of the research team demonstrates that early recruitment of bereaved family members into a research project is feasible and acceptable to participants, especially when a multidisciplinary collaborative approach is employed and a personal mode of recruitment used. PMID- 25554547 TI - Viral outbreaks in an age of global citizenship. PMID- 25554549 TI - Nasal colonization and lower respiratory tract infections with methicillin resistant Staphylococcus aureus. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus is a cause of lower respiratory tract infections, particularly health care- and ventilator-associated pneumonia. Although many health systems use nasal screening for this microorganism for infection control, correlation between nasal carriage of the organism and development of infections due to it is not clear. METHODS: Records of patients admitted to medical intensive care between January 1, 2011, and December 31, 2012, were reviewed retrospectively. Patients' data were included if the patients were 18 years or older, satisfied clinical criteria for pneumonia, and had both nasal swabbing and culturing of respiratory specimens within 24 hours of admission. RESULTS: A total of 165 patients met the inclusion criteria. Most had either community-acquired or health care-associated pneumonia. Of the 28 patients with a nasal swab positive for methicillin-resistant S aureus, 8 (4.8%) also had respiratory tract cultures positive for the microorganism. Among the 165 patients, 2 (1.2%) had negative nasal swabs but positive respiratory cultures. Sensitivity and specificity of nasal colonization with methicillin-resistant S aureus for subsequent infection with the pathogen were 80% and 87.1%, respectively; positive and negative predictive values were 28.6% and 98.5%, respectively. CONCLUSIONS: Nasal screening for methicillin-resistant S aureus may be a valuable tool for de-escalation of empiric therapy targeted to the organism, especially in patients admitted for severe community-acquired or health care associated pneumonia. The high negative predictive value suggests that patients with a negative nasal swab most likely do not have a lower respiratory tract infection caused by the organism. PMID- 25554551 TI - Manual vs automated lateral rotation to reduce preventable pulmonary complications in ventilator patients. AB - PURPOSE: To estimate effect sizes for a trial to compare preventable pulmonary complications (PPCs), turning-related adverse events, mechanical ventilation duration, intensive care unit (ICU) length of stay, and ICU mortality between patients randomized to 2-hourly manual or continuous automated lateral rotation. METHODS: Randomized controlled trial pilot study with 15 patients selected randomly from eligible medical-surgical ICU patients from 2 tertiary hospitals and assigned randomly to the manual-turn or automated-turn protocol for up to 7 consecutive days. A radiologist blinded to group and site assessed serial chest radiographs for PPCs. Repeated-measures analysis with linear mixed models was used to estimate change in PPC score, and Wilcoxon rank sum or Fisher exact test was used to compare group differences in the secondary outcomes. RESULTS: Of 16 patients enrolled, 12 (75%) completed the study. Data from 15 patients, 7 manual turn and 8 automated turn, were analyzed. Between-group differences in PPC incidence (67% overall), change in PPC score (beta = 0.15, manual turn and beta = -0.44, automated turn), and secondary outcomes were not significant (P > .05). Standardized effect sizes were small to moderate for the outcome variables. A sample size of 54 patients would be needed to detect statistically significant between-group differences in PPC over time. CONCLUSIONS: The incidence of PPCs in adult patients receiving mechanical ventilation in a medical-surgical ICU was high. Automated turning decreased PPCs with time but had little effect on secondary outcomes. Safety outcomes were not substantially different between groups. A modest efficacy effect supported reduced PPCs with automated turning to the lateral position. PMID- 25554552 TI - Physical recovery in intensive care unit survivors: a cohort analysis. AB - BACKGROUND: Some survivors of critical illness experience poor physical recovery, but which patients experience the most compromise during recovery is unknown. OBJECTIVE: To identify factors associated with physical recovery by using the 6 minute walk test in adult survivors of critical illness 26 weeks after discharge from the hospital. METHODS: A total of 195 adult survivors of a critical illness were enrolled in a multicenter trial of physical rehabilitation after discharge from the hospital. The 6-minute walk test, the 36-Item Short Form Health Survey, and sleep rated on a 5-point scale were completed at weeks 1 and 26. Clinical and demographic data were obtained from patient records. RESULTS: A total of 145 patients completed the 26-week test. Of these, 94 (65%) increased the distance walked in 6 minutes by at least 75 m from the 1-week value and were therefore considered to have improved on the test. Factors associated with improvement included moderate to severe sleeping problems in week 1, moderate to vigorous exercise in week 26, and higher vitality in week 26. Conversely, respiratory problems and higher social functioning in week 1 were associated with less improvement in the distance walked. CONCLUSION: Multiple factors are associated with physical recovery after critical illness. Interventions to target multidimensional aspects of recovery such as sleep and exercise may result in improved physical function after critical illness. PMID- 25554553 TI - Measuring height in recumbent critical care patients. AB - BACKGROUND: Estimates of the height of patients in the intensive care unit are required to adhere to clinical guidelines for drug dosages, ventilatory support, and nutrition. The gold standard of standing height cannot be used because these patients are often unconscious and recumbent. The ability of physiotherapists or dietitians to measure height in unconscious, recumbent patients has not been evaluated. OBJECTIVES: To compare the accuracy of physicians, physiotherapists, and dietitians in estimating the height of recumbent critical care patients by using existing practice methods. METHODS: A total of 35 patients were recruited from the cardiothoracic preadmission clinic, where standing height is routinely measured by a physiotherapist. After surgery, in the intensive care unit, 1 physician, 2 physiotherapists, and 2 dietitians measured each recumbent patient's height. Three methods were used: observation, whole-body measurement, and height estimated by using length of the forearm and the British Association for Parenteral and Enteral Nutrition normative chart. Difference from standing height was measured from zero and was compared across professions and methods, with zero indicating no difference. RESULTS: Overall, 17 physicians, 4 dietitians, and 9 physiotherapists consented to measure patients. After adjustments for method, measurements by physiotherapists did not differ significantly from the gold standard (P = .59), whereas those of physicians (P = .02) and dietitians (P < .001) did. CONCLUSIONS: Physiotherapists' measurements of supine height of recumbent critical care patients, obtained by using a nonrigid measuring tape, are more accurate than measurements obtained by physicians and dietitians. PMID- 25554550 TI - Body temperature and mortality in patients with acute respiratory distress syndrome. AB - BACKGROUND: Little is known about the relationship between body temperature and outcomes in patients with acute respiratory distress syndrome (ARDS). A better understanding of this relationship may provide evidence for fever suppression or warming interventions, which are commonly applied in practice. OBJECTIVE: To examine the relationship between body temperature and mortality in patients with ARDS. METHODS: Secondary analysis of body temperature and mortality using data from the ARDS Network Fluid and Catheter Treatment Trial (n = 969). Body temperature at baseline and on study day 2, primary cause of ARDS, severity of illness, and 90-day mortality were analyzed by using multiple logistic regression. RESULTS: Mean baseline temperature was 37.5 degrees C (SD, 1.1 degrees C; range, 27.2 degrees C-40.7 degrees C). At baseline, fever (>= 38.3 degrees C) was present in 23% and hypothermia (< 36 degrees C) in 5% of the patients. Body temperature was a significant predictor of 90-day mortality after primary cause of ARDS and score on the Acute Physiology and Chronic Health Evaluation III were adjusted for. Higher temperature was associated with decreased mortality: for every 1 degrees C increase in baseline temperature, the odds of death decreased by 15% (odds ratio, 0.85; 95% CI, 0.73-0.98, P = .03). When patients were divided into 5 temperature groups, mortality was lower with higher temperature (P for trend = .02). CONCLUSIONS: Early in ARDS, fever is associated with improved survival rates. Fever in the acute phase response to lung injury and its relationship to recovery may be an important factor in determining patients' outcome and warrants further study. PMID- 25554554 TI - Delirium monitoring and patient outcomes in a general intensive care unit. AB - BACKGROUND: Use of an evidence-based tool for routine assessment for delirium by bedside nurses in the intensive care unit is recommended. However, little is known about patient outcomes after implementation of such a tool. OBJECTIVE: To evaluate the implementation and effects of the Confusion Assessment Method for the Intensive Care Unit as a bedside assessment for delirium in a general intensive care unit in a tertiary care hospital. METHODS: Charts of patients admitted to the unit during a 3-month period before implementation of the assessment tool and 1 year after implementation were reviewed retrospectively. Patient outcomes were incidence of delirium diagnosis, duration of mechanical ventilation, length of stay in the intensive care unit, and time spent in restraints. RESULTS: The 2 groups of patients did not differ in demographics, clinical characteristics, or predisposing factors. The groups also did not differ significantly in delirium diagnosis, duration of mechanical ventilation, length of stay in the intensive care unit, or time spent in restraints. Barriers to use of the tool included nurses' lack of confidence in performing the assessment, concerns about use of the tool in patients receiving mechanical ventilation, and lack of interdisciplinary response to findings obtained with the tool. CONCLUSIONS: No change in patient outcomes or diagnosis of delirium occurred 1 year after implementation of the Confusion Assessment Method for the Intensive Care Unit. Lessons learned and barriers to adoption and use, however, were identified. PMID- 25554555 TI - Head-of-bed elevation and early outcomes of gastric reflux, aspiration and pressure ulcers: a feasibility study. AB - BACKGROUND: Guidelines recommending head of bed (HOB) elevation greater than 30o to prevent ventilator-associated pneumonia conflict with guidelines to prevent pressure ulcers, which recommend HOB elevation less than 30o. OBJECTIVES: To examine the feasibility of 45o HOB elevation and describe and compare the occurrence of reflux, aspiration, and pressure ulcer development at 30o and 45o HOB elevation. METHODS: A randomized 2-day crossover trial was conducted. HOB angle was measured every 30 seconds. Oral and tracheal secretions were analyzed for pepsin presence. Skin was assessed for pressure ulcers. Wilcoxon signed rank tests and Kendall tau correlations were conducted. RESULTS: Fifteen patients were enrolled; 11 completed both days. Patients were maintained at 30o (mean, 30o) for 96% of minutes and at 45o (mean, 39o) for 77% of minutes. No patients showed signs of pressure ulcers. A total of 188 oral secretions were obtained, 82 (44%) were pepsin-positive; 174 tracheal secretions were obtained, 108 (62%) were pepsin-positive. The median percentage of pepsin-positive oral secretions was not significantly higher (P = .11) at 30o elevation (54%) than at 45o elevation (20%). The median percentage of pepsin-positive tracheal secretions was not significantly higher (P = .37) at 30o elevation (71%) than 45o elevation (67%). Deeper sedation correlated with increased reflux (P = .03). CONCLUSIONS: HOB elevation greater than 30o is feasible and preferred to 30o for reducing oral secretion volume, reflux, and aspiration without pressure ulcer development in gastric-fed patients receiving mechanical ventilation. More deeply sedated patients may benefit from higher HOB elevations. PMID- 25554556 TI - Differences in alarm events between disposable and reusable electrocardiography lead wires. AB - BACKGROUND: Disposable electrocardiographic lead wires (ECG-LWs) may not be as durable as reusable ones. OBJECTIVE: To examine differences in alarm events between disposable and reusable ECG-LWs. METHOD: Two cardiac telemetry units were randomized to reusable ECG-LWs, and 2 units alternated between disposable and reusable ECG-LWs for 4 months. A remote monitoring team, blinded to ECG-LW type, assessed frequency and type of alarm events by using total counts and rates per 100 patient days. Event rates were compared by using generalized linear mixed effect models for differences and noninferiority between wire types. RESULTS: In 1611 patients and 9385.5 patient days of ECG monitoring, patient characteristics were similar between groups. Rates of alarms for no telemetry, leads fail, or leads off were lower in disposable ECG-LWs (adjusted relative risk [95% CI], 0.71 [0.53-0.96]; noninferiority P < .001; superiority P = .03) and monitoring (artifact) alarms were significantly noninferior (adjusted relative risk [95% CI]: 0.88, [0.62-1.24], P = .02; superiority P = .44). No between-group differences existed in false or true crisis alarms. Disposable ECG-LWs were noninferior to reusable ECG-LWs for all false-alarm events (N [rate per 100 patient days], disposable 2029 [79.1] vs reusable 6673 [97.9]; adjusted relative risk [95% CI]: 0.81 [0.63-1.06], P = .002; superiority P = .12.) CONCLUSIONS: Disposable ECG-LWs with patented push-button design had superior performance in reducing alarms created by no telemetry, leads fail, or leads off and significant noninferiority in all false-alarm rates compared with reusable ECG-LWs. Fewer ECG alarms may save nurses time, decrease alarm fatigue, and improve patient safety. PMID- 25554557 TI - Recent advances in multidisciplinary critical care. AB - The intensive care unit is a work environment where superior dedication is crucial for optimizing patients' outcomes. As this demanding commitment is multidisciplinary in nature, it requires special qualities of health care workers and organizations. Thus research in the field covers a broad spectrum of activities necessary to deliver cutting-edge care. However, given the numerous research articles and education activities available, it is difficult for modern critical care clinicians to keep up with the latest progress and innovation in the field. This article broadly summarizes new developments in multidisciplinary intensive care. It provides elementary information about advanced insights in the field via brief descriptions of selected articles grouped by specific topics. Issues considered include care for heart patients, mechanical ventilation, delirium, nutrition, pressure ulcers, early mobility, infection prevention, transplantation and organ donation, care for caregivers, and family matters. PMID- 25554558 TI - Quality improvement strategies for critical care nursing. PMID- 25554559 TI - Heart-rate induced conduction defects. PMID- 25554560 TI - Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. AB - PURPOSE: The goal of this study was to assess the effect of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on lipid profiles in patients with type 2 diabetes. METHODS: The MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched from inception through October 31, 2013. Randomized controlled trials with available data were selected if they compared GLP-1 RAs with placebo and traditional antidiabetic drugs with a duration >=8 weeks. The weighted mean difference for changes in lipid profiles was estimated by using the random effects model, and a network meta-analysis was performed to supplement direct comparisons. FINDINGS: Thirty-five trials with 13 treatments were included in the analysis. GLP-1 RAs decreased HDL-C with a range of -0.06 mmol/L (95% CI, 0.11 to -0.01) to -0.13 mmol/L (95% CI, -0.17 to -0.10) compared with thiazolidinediones, whereas thiazolidinediones were associated with a significant increase in HDL-C compared with placebo (0.09 mmol/L [95% CI, 0.06 to 0.12]). A significant reduction in LDL-C was detected for all GLP-1 RAs versus placebo (range, -0.08 to -0.16 mmol/L), insulin (range, -0.10 to -0.19 mmol/L), and thiazolidinediones (range, -0.16 to -0.24 mmol/L). Exenatide, liraglutide 1.8 mg once daily, and taspoglutide decreased total cholesterol with a range of -0.16 mmol/L (95% CI, -0.26 to -0.06) to -0.27 mmol/L (95% CI, -0.41 to -0.12) versus placebo and thiazolidinediones (range, -0.26 to -0.37 mmol/L). The decreased effect was more evident in exenatide long-acting release and liraglutide 1.8 mg once daily. A significant reduction in triglyceride levels was observed with liraglutide 1.8 mg once daily (-0.30 mmol/L [95% CI, -0.49 to -0.11]) and taspoglutide 20 mg once weekly (-0.17 mmol/L [95% CI, -0.31 to -0.01]) versus placebo. IMPLICATIONS: GLP-1 RAs were associated with modest reductions in LDL-C, total cholesterol, and triglycerides but no significant improvement in HDL-C. Further evidence is needed to determine if improvements in lipid profiles might translate into reductions in cardiovascular outcomes. PMID- 25554561 TI - Influence of sensory information on static balance in older patients with vestibular disorder. AB - INTRODUCTION: With aging, the sensory systems suffer an accumulation of degenerative, infectious and/or traumatic processes that may hinder the body balance maintenance. OBJECTIVE: To assess the influence of sensory information on static body balance of elderly individuals with vestibular disorders. METHODS: Cross-sectional study of elderly individuals with vestibular disorders. The Clinical Test of Sensory Interaction and Balance and posturography integrated with virtual reality (Balance Rehabilitation Unit) were used. Posturography parameters analyzed included center of pressure and velocity of body sway. RESULTS: 123 individuals with mean age of 73.11 were assessed. Worst performance was observed in the Clinical Test of Sensory Interaction and Balance condition of visual dome-unstable surface. Differences between conditions were: firm surface open eyes/firm surface-closed eyes, unstable surface-open eyes/unstable surface closed eyes (p<0.001), and unstable surface-closed eyes/unstable surface-visual dome. Considering center of pressure and velocity of body sway, significant differences were observed between the following conditions: firm surface-open eyes/firm surface-closed eyes: firm surface-saccadic stimulus/firm surface vertical optokinetic stimulus; firm surface-optokinetic stimuli/firm surface visual-vestibular interaction; and firm surface-visual-vestibular interaction/unstable surface. Worse performances were observed in conditions firm surface-closed eyes, firm surface-vertical optokinetic stimulus, F-visual vestibular interaction, and unstable surface-closed eyes. There was a difference in the center of pressure between firm surface-closed eyes/firm surface-saccadic stimulus, with a worse performance in the condition of firm surface-closed eyes, and of velocity of body sway, between firm surface-saccadic stimulus/firm surface horizontal optokinetic stimulus (p<0.001). CONCLUSION: Static body balance in elderly individuals with vestibular disorders is worse when the sensory conditions are more challenging, i.e. stable and unstable surfaces, visual stimuli, such as optokinetic and visual-vestibular interaction, and with the eyes closed. PMID- 25554562 TI - Rhinosinusitis: evidence and experience. A summary. PMID- 25554563 TI - Impact of BPRS interview length on ratings reliability in a schizophrenia trial. AB - Signal detection in clinical trials relies on ratings reliability. We conducted a reliability analysis of site-independent rater scores derived from audio-digital recordings of site-based rater interviews of the structured Brief Psychiatric Rating Scale (BPRS) in a schizophrenia study. "Dual" ratings assessments were conducted as part of a quality assurance program in a 12-week, double-blind, parallel-group study of PF-02545920 compared to placebo in patients with sub optimally controlled symptoms of schizophrenia (ClinicalTrials.gov identifier NCT01939548). Blinded, site-independent raters scored the recorded site-based BPRS interviews that were administered in relatively stable patients during two visits prior to the randomization visit. We analyzed the impact of BPRS interview length on "dual" scoring variance and discordance between trained and certified site-based raters and the paired scores of the independent raters. Mean total BPRS scores for 392 interviews conducted at the screen and stabilization visits were 50.4+/-7.2 (SD) for site-based raters and 49.2+/-7.2 for site-independent raters (t=2.34; p=0.025). "Dual" rated total BPRS scores were highly correlated (r=0.812). Mean BPRS interview length was 21:05+/-7:47min ranging from 7 to 59min. 89 interviews (23%) were conducted in less than 15min. These shorter interviews had significantly greater "dual" scoring variability (p=0.0016) and absolute discordance (p=0.0037) between site-based and site-independent raters than longer interviews. In-study ratings reliability cannot be guaranteed by pre study rater certification. Our findings reveal marked variability of BPRS interview length and that shorter interviews are often incomplete yielding greater "dual" scoring discordance that may affect ratings precision. PMID- 25554565 TI - The chemical interaction between adrenochrome, three different classes of antipsychotic drugs and metabolites of the kynurenine pathway. AB - Two kynurenine metabolites, 3-hydroxykynurenine and 3-hydroxyanthranilic acid, are known to inhibit melanin polymer formation in in vitro reactions catalyzed by tyrosinase. The present study expands that finding to include inhibition of chlorpromazine-stimulated melanin formation from the endogenous melanin precursor adrenochrome. Several kynurenine pathway metabolites tested had no measurable effect on the reaction: tryptophan, kynurenine, kynurenic acid, quinolinic acid and nicotinic acid. However, at a concentration of 0.5mM in a pH 7.4 reaction mix, 3-hydroxykynurenine exerted~72% inhibition on product formation and the same concentration of 3-hydroxyanthranilic acid caused complete inhibition. Two other classes of antipsychotic drugs were evaluated in this paradigm, represented by olanzapine and minocycline. Although the adrenochrome reaction of both drugs was strongly inhibited by 3-hydroxyanthranilic acid, 3-hydroxykynurenine inhibited product formation from only the minocycline reaction. The results are discussed in terms of the well-studied kynurenine pathway upregulation in psychotic disorders and how such upregulation may either influence the efficacy of antipsychotic drug treatment or relate to the mechanism of action of these drugs. PMID- 25554564 TI - The atypical antipsychotic clozapine selectively inhibits interleukin 8 (IL-8) induced neutrophil chemotaxis. AB - Clozapine is the most effective antipsychotic to date, but its benefits are counterbalanced by the risk of severe hematological effects. In this study, we analyzed whether clozapine inhibits polymorphonuclear (PMN) leukocyte chemotaxis. We found that clozapine, within the therapeutic concentration range, potently and selectively inhibits PMN chemotaxis induced by interleukin 8 (IL-8), a chemokine inducing neutrophil migration. The effect was not due to its action at dopamine, serotonin and muscarinic receptors, or to a direct antagonism to IL-8 receptors. Furthermore, clozapine did not inhibit PMN chemotaxis by its presumed toxic mechanism. In fact, after an overnight incubation in cell culture, the drug did not increase the physiological PMN apoptosis. An interference of clozapine with the autocrine release of leukotriene B4 (LTB4), a secondary chemoattractant secreted by neutrophils in response to the primary chemoattractant IL-8, was hypothesized. In agreement with this hypothesis, clozapine attenuated the IL-8 induced release of LTB4 in PMNs. A series of experiments with an antagonist of the LTB4 receptor, U75302, and an inhibitor of LTB4 synthesis, zileuton, provided support to this conjecture. Intriguingly MK-571, an inhibitor of the multi-drug resistance protein MRP4, playing a pivotal role in effluxing LTB4, completely blocked PMN chemotaxis induced by IL-8, but gave conflicting results when tested for its ability to reduce LTB4 release, increasing LTB4 efflux by itself but reducing the release when in combination with IL-8. The reduction of PMN chemotaxis due to clozapine could predispose patients to infections. Whether this effect is a prelude to clozapine agranulocytosis requires further investigation. PMID- 25554566 TI - Prevalence of podiatric conditions seen in Special Olympics athletes: a comparison of USA data to an international population. AB - BACKGROUND: Persons with intellectual disabilities frequently have podiatric conditions. Limited information exists on their prevalence in international cohorts of Special Olympics (SO) athletes. Findings from multiple United States (US) venues are compared to those from athletes screened at the 2011 Special Olympics World Summer Games in Athens, Greece (ATHENS). METHODS: Data from Fit Feet screenings from 2096 ATHENS participants was compared to 7192 US participants. RESULTS: Frequently noted in the ATHENS population were motion restriction in both the ankle and the first metatarsal phalangeal joint (1st MTPJ), pes planus, metatarsus adductus, brachymetatarsia, hallux abducto valgus (HAV), onychomycosis, onychocryptosis, and tinea pedis. ATHENS differed from the US cohort as HAV and restricted ankle joint and 1st MTPJ joint motion was less frequent. Significantly more tinea pedis, xerosis, and hyperhidrosis were present in the ATHENS population. DISCUSSION/CONCLUSION: SO athletes have a higher prevalence of podiatric structural conditions compared to the general population, and some vary between ATHENS versus US. Less prevalent in ATHENS was HAV, and restricted motion in both the ankle and 1st MTPJ. This may reflect differences due to varied clinical observers. The higher rates of several dermatological conditions in ATHENS may reflect venue seasonal climate, or social factors. PMID- 25554572 TI - Transmyringeal ventilation tube treatment in children: hearing outcome after 10 years. AB - OBJECTIVE: This ten-year cohort study intended to determine any hearing impairment and eardrum sequelae comparing children treated with ventilation tubes (VT) with an age- and gender-matched control group. METHODS: A cohort of children who received ventilation tubes in 1996 was during 2006 compared with a control group, with no history of VT treatment, using standard audiometry, high frequency audiometry and otomicroscopy. RESULTS: In the spectrum of the standard audiometry, the differences between the groups were minimal. In the high frequency spectrum, even in a subgroup with normal eardrums, there were significant and major differences with inferior hearing thresholds in treated ears compared with the ears of the control group. The ventilation tube treated group presented a higher prevalence of eardrum pathology. CONCLUSION: The ears treated with ventilation tubes had significantly higher hearing levels than the control group in the high frequency spectrum. This could be caused by the history of middle ear disease, the VT treatment or both combined. PMID- 25554573 TI - Does the introduction of newborn hearing screening improve vocabulary development in hearing-impaired children? A population-based study in Japan. AB - OBJECTIVE: Permanent hearing impairment has a life-long impact on children and its early identification is important for language development. A newborn hearing screening (NHS) program has started in Okayama Prefecture, Japan, in 1999 to detect hearing impairment immediately after birth. We aim to examine the effect of this screening program on vocabulary development in pre-school children in a before and after comparative study design. METHODS: A total of 107 5-year-old children who graduated from Okayama Kanariya Gakuen (an auditory center for hearing-impaired children) between 1998 and 2011 were enrolled in this study. The pre-NHS group (n=40) was defined as those who graduated between 1998 and 2003, while the post-NHS group (n=67) was defined as those who graduated between 2004 and 2011. The primary outcome was receptive vocabulary, which was assessed by the Picture Vocabulary Test [score <18 (low) vs. score >=18 (high)]. The secondary outcome was productive vocabulary, or the number of productive words, which was assessed by an original checklist [<1773 words (low) vs. >=1773 (high)]. We calculated odds ratios and 95% confidence intervals for vocabulary development and compared both groups. RESULTS: The adjusted Picture Vocabulary Test score and number of productive words were significantly higher (p<0.01) in the post-NHS group than the pre-NHS group. Odds ratios were 2.63 (95% confidence interval: 1.17-5.89) for receptive vocabulary and 4.17 (95% confidence interval: 1.69 10.29) for productive vocabulary. CONCLUSIONS: The introduction of NHS in Okayama Prefecture significantly improved both receptive and productive vocabulary development in hearing-impaired children. PMID- 25554574 TI - Translation and cross-cultural adaptation of the Pediatric Sleep Questionnaire into Portuguese language. AB - OBJECTIVE: The need for culturally appropriate and linguistically accessible instruments for assessing sleep quality among children has expanded. The Pediatric Sleep Questionnaire (PSQ) is a validated tool for sleep disordered breathing among children. Our aim was to cross-culturally translate and adapt the PSQ into Portuguese language for use in clinical and research settings. METHODS: The PSQ was translated into Portuguese language in accordance with the stages recommended by International Guidelines and reviewed by a panel of experts. The caregivers of 180 children (aged from 4 to 12 years) answered the Portuguese version of PSQ. The reliability of the translated questionnaire was measured by Cronbach alpha, Pearson correlation and Kappa statistics. RESULTS: Reliability analysis yielded an overall Cronbach alpha of 0.781, confirming the survey's consistency. The Cronbach alpha of the Portuguese PSQ domains ranged between 0.61 and 0.7. Test-retest reliability for all items was robust with correctness of >90.0% in all items, and the Kappa statistic ranged between 0.5 and 0.8. CONCLUSION: The Portuguese version of PSQ has sufficient reliability and validity to measure sleep disordered breathing outcomes, and showed to be linguistically accurate and acceptable for use by children in Portugal. PMID- 25554575 TI - Readability and quality assessment of websites related to microtia and aural atresia. AB - OBJECTIVE: Many parents and children utilize the Internet for health-related information, but the quality of these websites can vary. The objective of this study was to assess the quality and readability of microtia and aural atresia related websites. METHODS: The search engine Google was queried with the terms 'microtia' and 'aural atresia.' The first 30 results were evaluated, and those websites containing original information written in English were reviewed. Quality of content was assessed with the DISCERN instrument, and readability was assessed with the Flesch-Kincaid Reading Grade Level (FKGL) and the Flesch Reading Ease Score (FRES) tests. Each website was also reviewed for ownership and the date of last update. RESULTS: Sixteen microtia and 14 aural atresia websites were included for full review. The mean DISCERN score for microtia websites was 54.4 (SD=8.3), and for aural atresia websites it was 47.6 (SD=10.7), which indicates 'good' and 'fair' quality of content, respectively. Readability assessments showed an average reading level requiring a grade 10 education on FKGL, and only one microtia (6.3%) and one aural atresia (7.1%) websites were deemed to be at 'reasonable' reading level on FRES. CONCLUSION: High-quality websites that are considered easily comprehensible to the general public were lacking. Since parents and children may use websites when making treatment decisions, physicians should be aware of the quality of health information pertaining to their area of expertise available on the Internet. PMID- 25554576 TI - Prevalence of smoke exposure amongst children who undergo tonsillectomy for recurrent tonsillitis. AB - PURPOSE: The hypothesis tested was that smoke exposure has a detrimental effect on the developing upper respiratory tract. The purpose of this study was to determine if more children undergoing tonsillectomy for recurrent tonsillitis had smoke exposure in comparison to a control group of children undergoing hernia repair. METHODS: This was a retrospective case-control study. Medical records of children less than 15 years of age that underwent tonsillectomy for recurrent tonsillitis at Penn State Hershey Medical Center from July 2009 to October 2012 were retrospectively reviewed to determine exposure to smoking contacts. Records of children less than 15 years of age that underwent hernia repair surgery at this facility during the same time, were also retrospectively reviewed for smoke exposure. RESULTS: A total of 256 children who underwent tonsillectomy for recurrent tonsillitis and 241 children who underwent hernia repair surgery met the inclusion criteria. Of the children in the tonsillectomy for recurrent tonsillitis group, 121 (47.27%) had previous smoke exposure, compared to 67 (27.80%) in the hernia repair group. Further analysis of the data using logistic regression yielded an odds ratio of 2.49 (P=0.004), indicating that children with smoke exposure had more than twice the odds of having tonsillectomy for recurrent tonsillitis compared to those with no exposure. CONCLUSIONS: Exposure to smoking contacts was more common in children who underwent tonsillectomy for recurrent tonsillitis than children who underwent hernia repair surgery. Future studies could address the relation of smoke exposure quantity to health outcomes in children. PMID- 25554577 TI - Workshop on measuring estrogen exposure and metabolism: Summary of the presentations. PMID- 25554578 TI - Incorporation of beta-sitosterol into the membrane prevents tumor necrosis factor alpha-induced nuclear factor-kappaB activation and gonadotropin-releasing hormone decline. AB - It has been demonstrated that hypothalamus has a programmatic role in aging development, and this role of hypothalamus is mediated by nuclear factor-kappaB (NF-kappaB)-directed gonadotropin-releasing hormone (GnRH) decline. beta Sitosterol (BS), one of the most common phytosterols in the diet, is able to inhibit pro-inflammatory NF-kappaB signaling. It has been demonstrated that dietary BS can enter the brain and accumulates in brain cell membranes. However, it is unknown whether and how membrane BS affects GnRH release. Using GT1-7 cells, a cell line of GnRH neurons, this study investigated if membrane BS had an influence on GnRH release. It was found that incorporation of BS into the membrane could prevent tumor necrosis factor-alpha (TNF-alpha)-induced GnRH decline. The underlying basis involves inhibition of NF-kappabeta activation via estrogen receptor (ER)-mediated inhibition of inhibitor of nuclear factor kappaB (Ikappabeta) processing. These results extend existing data regarding the beneficial effects of BS, and suggest the use of BS-enriched foods as anti-aging nutrients. PMID- 25554579 TI - First synthesis and characterization for the stereoisomers of Ulipristal acetate. AB - The three stereoisomers, 11alpha,17alpha-isomer I, 11alpha,17beta-isomer II and 11beta,17beta-isomer III are related substances of the selective progesterone receptor modulator Ulipristal acetate. Herein, we presented an efficient and practical synthesis approach to deliver these three stereoisomers for the first time, and also confirmed the structure of the key intermediate 5a by single crystal X-ray analysis. Our research will be of immense help for organic chemists to study the impurity profile of Ulipristal acetate. PMID- 25554580 TI - Deltonin inhibits angiogenesis by regulating VEGFR2 and subsequent signaling pathways in endothelial cells. AB - Deltonin is a steroidal saponin which could suppress tumor growth through suppressing angiogenesis, but the mechanisms have not been directly elucidated yet. In the present study, we showed that deltonin inhibited the proliferation of primary cultured human umbilical vein endothelial cells (HUVECs) in vitro; notably, it could significantly inhibit HUVECs migration, invasion, and tube formation, which are indispensable progresses of angiogenesis. We further demonstrated that deltonin could inhibit VEGF-induced blood vessel formation in vivo. What is more, we found that deltonin blocked VEGF triggered phosphorylation of key intracellular angiogenic molecules, such as VEGFR2, Src family kinase, focal adhesion kinase (FAK), extracellular signal-related kinase (Erk1/2) and AKT kinase, accompanied with the increase of phosphorylated P38MAPK. Taken together, the present study demonstrates that deltonin inhibits angiogenesis through regulating VEGFR2 signaling pathway as well as AKT/MAPK signaling pathways in endothelial cells. PMID- 25554581 TI - Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: A critical appraisal of current science. AB - A systematic review of the literature on sex steroid measurement in breast tissue identified only 19 articles meeting the following criteria: menopausal status given; steroids measured in tissue homogenates by conventional RIA with a purification step or by mass spectrometry; and values reported per g tissue or per g protein. Twelve articles were analyzed in detail for: ratios of sex steroid hormone levels in cancerous or benign tissues to blood levels, stratified by menopausal status; ratios between the different hormone levels within tissues or within blood; and difference in these ratios between tissue and blood compartments. Estrogen and androgen concentrations varied greatly in benign and cancerous tissues and in blood between individuals. Postmenopausal, but not premenopausal, estradiol concentrations were significantly higher in cancerous compared to benign breast tissue. The estradiol/estrone ratio was lowest in premenopausal benign tissue, and substantially higher in premenopausal cancerous tissue and postmenopausal benign and cancerous tissues. Estradiol and estrone levels were considerably higher in tissue than in plasma in both premenopausal and postmenopausal women. Androgen levels were generally higher in the benign than the cancerous tissue, and tissue androgen levels were higher than in plasma, suggesting in situ aromatization of androgens to estrogens in breast cancer tissue. Limited available data on levels of hydroxylated estrogens in breast tissue compared to corresponding levels in plasma or urine were reviewed, but due to the paucity of studies no conclusions can presently be drawn regarding the relationship of the 2-hydroxyestrone:16alpha-hydroxyestrone ratio to breast cancer risk and genotoxic effects of 4-hydroxylated estrogens. Finally, data on hormone levels in breast adipose tissue were analyzed; high levels of androstenedione and testosterone and significant estrone and estradiol levels in breast adipocytes from postmenopausal breast cancer patients are consistent with an obesity-inflammation-aromatase axis occurring locally in breast tissue. The controversies regarding the source of intratumoral estrogens in the breast are summarized. PMID- 25554582 TI - Improvements in body composition, cardiometabolic risk factors and insulin sensitivity with trenbolone in normogonadic rats. AB - Trenbolone (TREN) is used for anabolic growth-promotion in over 20 million cattle annually and continues to be misused for aesthetic purposes in humans. The current study investigated TREN's effects on body composition and cardiometabolic risk factors; and its tissue-selective effects on the cardiovascular system, liver and prostate. Male rats (n=12) were implanted with osmotic infusion pumps delivering either cyclodextrin vehicle (CTRL) or 2mg/kg/day TREN for 6 weeks. Dual-energy X-ray Absorptiometry assessment of body composition; organ wet weights and serum lipid profiles; and insulin sensitivity were assessed. Cardiac ultrasound examinations were performed before in vivo studies assessed myocardial susceptibility to ischemia-reperfusion (I/R) injury. Circulating sex hormones and liver enzyme activities; and prostate and liver histology were examined. In 6 weeks, fat mass increased by 34+/-7% in CTRLs (p<0.01). Fat mass decreased by 37+/-6% and lean mass increased by 11+/-4% with TREN (p<0.05). Serum triglycerides, HDL and LDL were reduced by 62%, 57% and 78% (p<0.05) respectively in TREN rats. Histological examination of the prostates from TREN-treated rats indicated benign hyperplasia associated with an increased prostate mass (149% compared to CTRLs, p<0.01). No evidence of adverse cardiac or hepatic effects was observed. In conclusion, improvements in body composition, lipid profile and insulin sensitivity (key risk factors for cardiometabolic disease) were achieved with six-week TREN treatment without evidence of adverse cardiovascular or hepatic effects that are commonly associated with traditional anabolic steroid misuse. Sex hormone suppression and benign prostate hyperplasia were confirmed as adverse effects of the treatment. PMID- 25554583 TI - Pulmonary and cardiovascular toxicity in long-term testicular cancer survivors. AB - Testicular cancer (TC) is the most common solid organ malignancy among young men at their peak of family life, education, and career. The exceptionally high cure rates are hampered by an increased risk of several treatment-related toxicities that may emerge several years after treatment. In this article, we review the current knowledge regarding pulmonary and cardiovascular toxicity in long-term survivors of TC. Bleomycin pulmonary toxicity is associated with the cumulative bleomycin dose, renal function, age and smoking status and can be avoided by a careful patient evaluation before chemotherapy. Lung function assessments are not routinely recommended for detecting bleomycin pulmonary toxicity. Long-term decreased pulmonary function may also be related to other chemotherapy agents such as cisplatin. Cardiovascular disease represents one of the most serious late effects of cytotoxic treatment in TC survivors and typically appears several years to decades after treatment. The increased risk for cardiovascular disease is probably mediated by a direct vascular damage from cytotoxic treatment that may stimulate the endothelium, possibly ultimately inducing the atherosclerotic process, as well as an indirect cytotoxic effect by increasing the levels of cardiovascular risk factors. Follow-up of these cancer survivors should include recommendations for maintaining a healthy lifestyle to reduce the risk of future cardiovascular events and to avoid declining pulmonary function. PMID- 25554584 TI - A multiscale structural investigation of the annulus-endplate anchorage system and its mechanisms of failure. AB - BACKGROUND CONTEXT: The annulus-endplate anchorage system performs a critical role in the disc, creating a strong structural link between the compliant annulus and the rigid vertebrae. Endplate failure is thought to be associated with disc herniation, a recent study indicating that this failure mode occurs more frequently than annular rupture. PURPOSE: The aim was to investigate the structural principles governing annulus-endplate anchorage and the basis of its strength and mechanisms of failure. STUDY DESIGN: Loading experiments were performed on ovine lumbar motion segments designed to induce annulus-endplate failure, followed by macro- to micro- to fibril-level structural analyses. METHODS: The study was funded by a doctoral scholarship from our institution. Samples were loaded to failure in three modes: torsion using intact motion segments, in-plane tension of the anterior annulus-endplate along one of the oblique fiber angles, and axial tension of the anterior annulus-endplate. The anterior region was chosen for its ease of access. Decalcification was used to investigate the mechanical influence of the mineralized component. Structural analysis was conducted on both the intact and failed samples using differential interference contrast optical microscopy and scanning electron microscopy. RESULTS: Two main modes of anchorage failure were observed--failure at the tidemark or at the cement line. Samples subjected to axial tension contained more tidemark failures compared with those subjected to torsion and in-plane tension. Samples decalcified before testing frequently contained damage at the cement line, this being more extensive than in fresh samples. Analysis of the intact samples at their anchorage sites revealed that annular subbundle fibrils penetrate beyond the cement line to a limited depth and appear to merge with those in the vertebral and cartilaginous endplates. CONCLUSIONS: Annulus-endplate anchorage is more vulnerable to failure in axial tension compared with both torsion and in-plane tension and is probably due to acute fiber bending at the soft-hard interface of the tidemark. This finding is consistent with evidence showing that flexion, which induces a similar pattern of axial tension, increases the risk of herniation involving endplate failure. The study also highlights the important strengthening role of calcification at this junction and provides new evidence of a fibril-based form of structural integration across the cement line. PMID- 25554585 TI - In search of optimal DBS paradigms to treat epilepsy: bilateral versus unilateral hippocampal stimulation in a rat model for temporal lobe epilepsy. AB - BACKGROUND: In many temporal lobe epilepsy (TLE) patients both hippocampi are seizure onset zones. These patients are unsuitable candidates for epilepsy surgery but may be amenable to hippocampal deep brain stimulation (DBS). The optimal DBS parameters for these patients are unknown. Recent observations suggest that even in patients with a unilateral focus switching from unilateral hippocampal DBS to bilateral hippocampal DBS could improve seizure control. OBJECTIVE: Compare the effect of unilateral with bilateral hippocampal DBS on seizures in a rat model for TLE. METHODS: In the post status epilepticus (SE) kainic acid rat model for TLE continuous EEG monitoring was performed for 50 days during which rats were subjected to 10 days of unilateral and 10 days of bilateral Poisson-distributed high frequency hippocampal DBS in a cross-over trial. During bilateral DBS, each hippocampus was stimulated with a separate stimulator and its own generated Poisson distribution with a mean and variance of 1/130 s. RESULTS: Electrographic seizure rate was 23% lower during bilateral compared to unilateral hippocampal DBS (P < 0.05). No effect of unilateral nor bilateral hippocampal DBS was observed on seizure duration. When bilateral hippocampal DBS was applied, lower stimulation intensities were required to evoke after discharges (P < 0.05), reflecting a higher potency of bilateral hippocampal DBS compared to unilateral hippocampal DBS to affect hippocampal networks. CONCLUSIONS: Superior outcome in seizure control with bilateral compared to unilateral hippocampal DBS indicates that targeting larger regions of the hippocampal formation with more than one stimulation electrode may be more successful in suppressing seizures in TLE. PMID- 25554586 TI - Report of new haplotype for ABCC2 gene: rs17222723 and rs8187718 in cis. AB - The ATP-binding cassette, subfamily C [CFTR/MRP], member 2 (ABCC2) gene is a member of the ATP-binding cassette transporters and is involved in the transport of molecules across cellular membranes. Substrates transported by ABCC2 include antiepileptics, statins, tenofovir, cisplatin, irinotecan, and carbamazepine. Because of the pharmacogenomics implications, we developed a clinical laboratory developed assay to test for seven variants in the ABCC2 gene: c.3563T>A (p.V1188E, rs17222723), c.1249G>A (p.V417I, rs2273697), c.3972C>T (p.I1324I, rs3740066), c.2302C>T (p.R768W, rs56199535), c.2366C>T (p.S789F, rs56220353), c. 24C>T (5'UTR, rs717620), and c.4544G>A (p.C1515Y, rs8187710). During the validation process, we noted several DNA samples, obtained from the Coriell Cell Repository, that contained both c.3563T>A, c.4544G>A, and a third variant, suggesting that c.3563T>A and c.4544G>A are in cis on the chromosome in some individuals. We obtained DNA samples from a trio (father, mother, and child), tested their ABCC2 variants, and confirmed that c.3563T>A and c.4544G>A were in cis on the same chromosome. Here, we report a new haplotype in ABCC2. PMID- 25554587 TI - High-throughput sequencing using the Ion Torrent personal genome machine for clinical evaluation of somatic hypermutation status in chronic lymphocytic leukemia. AB - For patients with chronic lymphocytic leukemia, an important prognostic indicator is the somatic hypermutation status of immunoglobulin heavy chain variable region nucleic acid within the clonal cell population. Current clinical assays for this evaluation rely on Sanger sequencing and are complex, such that availability of testing for patients is limited and costly. However, advances in high-throughput sequencing provide an opportunity to improve complex clinical sequencing applications. Our goal was to determine whether high-throughput sequencing technology could reliably perform the sequencing required for somatic hypermutation analysis and improve clinical testing for chronic lymphocytic leukemia patients. Blood or liquid bone marrow aspirate samples from 50 different patients were evaluated in parallel using a validated clinical assay based on Sanger sequencing and a modified protocol in which the sequencing was performed using an Ion Torrent personal genome machine. In each case, both methods gave identical results with respect to interpreted somatic hypermutation status and dominant immunoglobulin heavy chain variable region gene reported. The personal genome machine-based method had significant advantages over the Sanger-based method for use in clinical laboratories that perform long-read, high-throughput sequencing. PMID- 25554588 TI - A DNA real-time quantitative PCR method suitable for routine monitoring of low levels of minimal residual disease in chronic myeloid leukemia. AB - The BCR-ABL1 sequence has advantages over the BCR-ABL1 transcript as a molecular marker in chronic myeloid leukemia and has been used in research studies. We developed a DNA real-time quantitative PCR (qPCR) method for quantification of BCR-ABL1 sequences, which is also potentially suitable for routine use. The BCR ABL1 breakpoint was sequenced after isolation by nested short-range PCR of DNA from blood, marrow, and cells on slides, obtained either at diagnosis or during treatment, or from artificial mixtures. PCR primers were chosen from a library of presynthesized and pretested BCR (n = 19) and ABL1 (n = 568) primers. BCR-ABL1 sequences were quantified relative to BCR sequences in 521 assays on 266 samples from 92 patients. For minimal residual disease detectable by DNA qPCR and RT qPCR, DNA qPCR gave similar minimal residual disease results as RT-qPCR but had better precision at low minimal residual disease levels. The limit of detection of DNA qPCR depended on the amount of DNA assayed, being 10(-5.8) when 5 MUg was assayed and 10(-7.0) when 80 MUg was assayed. DNA qPCR may be useful and practical for monitoring the increasing number of patients with minimal residual disease around or below the limit of detection of RT-qPCR as the assay itself is simple and the up-front costs will be amortized if sequential assays are performed. PMID- 25554589 TI - Two novel methods for rapid detection and quantification of DNMT3A R882 mutations in acute myeloid leukemia. AB - DNMT3A mutations represent one of the most frequent gene alterations detectable in acute myeloid leukemia with normal karyotype. Although various recurrent somatic mutations of DNMT3A have been described, the most common mutation is located at amino acid R882 in the methyltransferase domain of the gene. DNMT3A mutations have been reported to be stable during disease progression and are associated with unfavorable outcome in acute myeloid leukemia patients with normal karyotype. Because of their prognostic significance and high stability during disease evolution, DNMT3A mutations might represent highly informative biomarkers for minimal residual disease monitoring. We describe a new rapid diagnostic RT-PCR assay based on TauI restriction enzyme reaction to identify DNMT3A R882 mutations at diagnosis. In addition, we developed a sensitive and specific test based on peptide nucleic acid real-time PCR technology to monitor DNMT3A R882H mutation. We identified 24 DNMT3A R882H mutated patients out of 134 acute myeloid leukemia screened samples and we analyzed in these patients the kinetics of minimal residual disease after induction and consolidation therapy. This assay may be useful to better assess response to therapy in patients with acute myeloid leukemia bearing the DNMT3A R882H mutation. PMID- 25554591 TI - Temporomandibular joint meniscopexy using the Arthrex Corkscrew(r) mini anchor system: technical note. PMID- 25554590 TI - Blunt wires in oral and maxillofacial surgery. PMID- 25554592 TI - Intralesional radiofrequency in venous malformations. AB - Venous malformations are usually asymptomatic and managed conservatively. Treatment, in the form of laser, sclerotherapy, or resection, is needed only if lesions present with symptoms or cosmetic deformity. The aim of this study was to find out how effective radiofrequency ablation was in patients with incomplete or unsatisfactory resolution of a venous malformation after an intralesional injection of bleomycin. During the 5 year period 2008-2012, we organised a prospective, clinical study at a tertiary care centre. Patients were selected from the outpatient department of the Lady Hardinge Medical College and associated hospitals, New Delhi, India. Five patients with venous malformations were treated by intralesional injection of bleomycin in a dose of 0.5U/kg body weight, which was repeated every 2 weeks for a total of 8 injections. They then had multiple intralesional radiofrequency ablation every 2 months until a satisfactory outcome was achieved. After the initial 8 doses the reduction in the size of the lesions was minimal (less than 50%). After 2-4 applications of radiofrequency ablation there was appreciable reduction in the size of the lesions (about 80%) with good functional and cosmetic outcomes. Radiofrequency ablation is an effective adjunct for patients with venous malformations of the head and neck that have not responded satisfactorily to intralesional injection of bleomycin. To our knowledge radiofrequency ablation after intralesional injection of bleomycin has not previously been described as a treatment for venous malformations. PMID- 25554594 TI - Channel-forming activity of syringomycin E in two mercury-supported biomimetic membranes. AB - The lipodepsipeptide syringomycin E (SR-E) interacts with two mercury-supported biomimetic membranes, which consist of a self-assembled phospholipid monolayer (SAM) and of a tethered bilayer lipid membrane (tBLM) separated from the mercury surface by a hydrophilic tetraethyleneoxy (TEO) spacer that acts as an ionic reservoir. SR-E interacts more rapidly and effectively with a SAM of dioleoylphosphatidylserine (DOPS) than with one of dioleoylphosphatidylcholine (DOPC). The proximal lipid monolayer of the tBLM has no polar head region, being linked to the TEO spacer via an ether bond, while the distal monolayer consists of either a DOPC or a DOPS leaflet. The ion flow into or out of the spacer through the lipid bilayer moiety of the tBLM was monitored by potential step chronocoulometry and cyclic voltammetry. With the distal monolayer bathed by aqueous 0.1M KCl and 0.8MUM SR-E, an ion flow in two stages was monitored with DOPC at pH3 and 5.4 and with DOPS at pH3, while a single stage was observed with DOPS at pH5.4. This behavior was compared with that already described at conventional bilayer lipid membranes. The sigmoidal shape of the chronocoulometric charge transients points to an aggregation of SR-E monomers forming an ion channel via a mechanism of nucleation and growth. The ion flow is mainly determined by potassium ions, and is inhibited by calcium ions. The contribution to the transmembrane potential from the distal leaflet depends more on the nature of the lipid than that of the ion channel. PMID- 25554593 TI - Magnetic resonance imaging: a useful tool to distinguish between keratocystic odontogenic tumours and odontogenic cysts. AB - In contrast to odontogenic cysts, keratocystic odontogenic tumours often recur and require more aggressive surgical treatment, so we tried to find features that distinguished between them on magnetic resonance imaging (MRI). Without knowing the diagnosis, two radiologists reviewed intensity (low, intermediate, or high) and homogeneity (homogeneous or heterogeneous) of signals in short-tau-inversion recovery (STIR), T1- and T2-weighted, and fat-suppressed, contrast-enhanced MRI in 20 consecutive patients with oval, radiolucent lesions of the mandible on panoramic radiography, and who were subsequently confirmed histopathologically to have either an odontogenic cyst or a keratocystic odontogenic tumour (n=10 in each group). Fisher's exact test was statistically significant at p<0.05. Delineation of a contrast-enhanced wall of a cyst with high signal intensity distinguished odontogenic cysts (9/10 and 8/10, respectively) from keratocystic odontogenic tumours (3/10, p=0.02, and 1/10, p=0.01, respectively). One radiologist found odontogenic cysts were more likely to be homogeneous on unenhanced T1-weighted images (odontogenic cysts 9/10, keratocystic odontogenic tumours 3/10, p=0.02) and one on contrast-enhanced MRI, when the cyst wall was enhanced (odontogenic cysts 7/9, keratocystic odontogenic tumours 0/3, p=0.01). There were no other significant distinguishing features on MRI. In conclusion, the signal intensity of the enhanced wall seems to be a feature on contrast enhanced MRI that differentiates odontogenic cysts from keratocystic odontogenic tumours. PMID- 25554595 TI - Study of the putative fusion regions of the preS domain of hepatitis B virus. AB - In a previous study, it was shown that purified preS domains of hepatitis B virus (HBV) could interact with acidic phospholipid vesicles and induce aggregation, lipid mixing and leakage of internal contents which could be indicative of their involvement in the fusion of the viral and cellular membranes (Nunez, E. et al. 2009. Interaction of preS domains of hepatitis B virus with phospholipid vesicles. Biochim. Biophys. Acta 17884:417-424). In order to locate the region responsible for the fusogenic properties of preS, five mutant proteins have been obtained from the preS1 domain of HBV, in which 40 amino acids have been deleted from the sequence, with the starting point of each deletion moving 20 residues along the sequence. These proteins have been characterized by fluorescence and circular dichroism spectroscopy, establishing that, in all cases, they retain their mostly non-ordered conformation with a high percentage of beta structure typical of the full-length protein. All the mutants can insert into the lipid matrix of dimyristoylphosphatidylglycerol vesicles. Moreover, we have studied the interaction of the proteins with acidic phospholipid vesicles and each one produces, to a greater or lesser extent, the effects of destabilizing vesicles observed with the full-length preS domain. The ability of all mutants, which cover the complete sequence of preS1, to destabilize the phospholipid bilayers points to a three-dimensional structure and/or distribution of amino acids rather than to a particular amino acid sequence as being responsible for the membrane fusion process. PMID- 25554597 TI - CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG. AB - CCN family protein 2/connective tissue growth factor (CCN2/CTGF) is a multi potent factor for mesenchymal cells such as chondrocytes, osteoblasts, osteoclasts, and endothelial cells. CCN2 is also known as a modulator of other cytokines and receptors via direct molecular interactions with them. We screened additional factors binding to CCN2 and found receptor activator of NF-kappa B (RANK) as one of them. RANK is also known as TNF-related activation-induced cytokine (TRANCE) receptor, and its signaling plays a critical role in osteoclastogenesis. Notable affinity between CCN2 and RANK was confirmed by using surface plasmon resonance (SPR) analysis. In fact, CCN2 enhanced the RANK mediated signaling, such as occurs in NF-kappa B, p38 and JNK pathways, in pre osteoclastic RAW264.7 cells; whereas CCN2 had no influence on RANK-RANK ligand (RANKL) binding. Moreover, CCN2 also significantly bound to osteoprotegerin (OPG), which is a decoy receptor of RANKL. Of note, OPG markedly inhibited the binding between CCN2 and RANK; and CCN2 canceled the inhibitory effect of OPG on osteoclast differentiation. These findings suggest CCN2 as a candidate of the fourth factor in the RANK/RANKL/OPG system for osteoclastogenesis, which regulates OPG and RANK via direct interaction. PMID- 25554596 TI - Structural features, evolutionary relationships, and transcriptional regulation of C-type lectin-domain proteins in Manduca sexta. AB - C-type lectins (CTLs) are a large family of Ca(2+)-dependent carbohydrate-binding proteins recognizing various glycoconjugates and functioning primarily in immunity and cell adhesion. We have identified 34 CTLDP (for CTL-domain protein) genes in the Manduca sexta genome, which encode proteins with one to three CTL domains. CTL-S1 through S9 (S for simple) have one or three CTL domains; immulectin-1 through 19 have two CTL domains; CTL-X1 through X6 (X for complex) have one or two CTL domains along with other structural modules. Nine simple CTLs and seventeen immulectins have a signal peptide and are likely extracellular. Five complex CTLs have both an N-terminal signal peptide and a C-terminal transmembrane region, indicating that they are membrane anchored. Immulectins exist broadly in Lepidoptera and lineage-specific gene duplications have generated three clusters of fourteen genes in the M. sexta genome, thirteen of which have similar expression patterns. In contrast to the family expansion, CTL S1~S6, S8, and X1~X6 have 1:1 orthologs in at least four lepidopteran/dipteran/coleopteran species, suggestive of conserved functions in a wide range of holometabolous insects. Structural modeling suggests the key residues for Ca(2+)-dependent or independent binding of certain carbohydrates by CTL domains. Promoter analysis identified putative kappaB motifs in eighteen of the CTL genes, which did not have a strong correlation with immune inducibility in the mRNA or protein levels. Together, the gene identification, sequence comparisons, structure modeling, phylogenetic analysis, and expression profiling establish a solid foundation for future studies of M. sexta CTL-domain proteins. PMID- 25554599 TI - Unique micro- and nano-scale mineralization pattern of human osteogenesis imperfecta type VI bone. AB - Osteogenesis imperfecta (OI) is a heterogeneous group of inheritable connective tissue disorders characterized by mutation in genes involved in collagen synthesis and leading to increased bone fragility, low bone mass, impaired bone material properties and abnormally high bone matrix mineralization. Recessive OI type VI is caused by mutation in SERPINF1 leading to a loss-of-function of pigment epithelium-derived factor (PEDF) a collagen-binding protein with potent antiangiogenic activity. Affected patients develop a severe OI phenotype with a striking histological characteristic, rare in other OI types, of an excess of osteoid tissue and prolonged mineralization lag time. To get insights into matrix mineralization, we evaluated biopsies from 9 affected children by quantitative and by high-resolution backscattered electron imaging and assessed bone mineralization density distribution. Thickness, shape and arrangement of mineral particles were measured in a subset of 4 patients by synchrotron small angle X ray scattering. Typical calcium content in the bone matrix was found to be increased compared to controls, even exceeding values found previously in OI patients with collagen-gene mutations. A main characteristic however, is the coexistence of this highly mineralized bone matrix with seams showing abnormally low mineral content. Atypical collagen fibril organization was found in the perilacunar region of young osteocytes, suggesting a disturbance in the early steps of mineralization. These observations are consistent with the presence of a heterogeneous population of mineral particles with unusual size, shape and arrangement, especially in the region with lower mineral content. The majority of the particles in the highly mineralized bone areas were less disorganized, but smaller and more densely packed than in controls and in previously measured OI patients. These data suggest that the lack of PEDF impairs a proper osteoblast osteocyte transition and consequently affects the early steps of mineralization, downstream collagen assembly making OI type VI different from "classical" OI with mutations in collagen-type I encoding genes, despite the typical hypermineralization of the bone matrix. PMID- 25554598 TI - MUCT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy. AB - Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a MUCT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our MUCT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r=0.72-0.83) confirm the accuracy of this method. Bone remodeling parameters measured through MUCT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed. PMID- 25554600 TI - Gastrodin: an ancient Chinese herbal medicine as a source for anti-osteoporosis agents via reducing reactive oxygen species. AB - Increased levels of reactive oxygen species (ROS) are a crucial pathogenic factor of osteoporosis. Gastrodin, isolated from the traditional Chinese herbal agent Gastrodia elata, is a potent antioxidant. We hypothesized that gastrodin demonstrates protective effects against osteoporosis by partially reducing reactive oxygen species in human bone marrow mesenchymal stem cells (hBMMSCs) and a macrophage cell line (RAW264.7 cells). We investigated gastrodin on osteogenic and adipogenic differentiation under oxidative stress in hBMMSCs. We also tested gastrodin on osteoclastic differentiation in RAW264.7 cells. Hydrogen peroxide (H2O2) was used to establish an oxidative cell injury model. Our results showed that gastrodin significantly promoted the proliferation of hBMMSCs, improved some osteogenic markers, reduced lipid generation and inhibited the mRNA expression of several adipogenic genes in hBMMSCs. Moreover, gastrodin reduced the number of osteoclasts, TRAP activity and the expression of osteoclast-specific genes in RAW264.7 cells. Gastrodin suppressed the production of reactive oxygen species in both hBMMSCs and RAW264.7 cells. In vivo, we established a murine ovariectomized (OVX) osteoporosis model. Our data revealed that gastrodin treatment reduced the activity of serum bone degradation markers, such as CTX-1 and TRAP. Importantly, it ameliorated the micro-architecture of trabecular bones. Gastrodin decreased osteoclast numbers in vivo by TRAP staining. To conclude, these results indicated that gastrodin shows protective effects against osteoporosis linking to a reduction in reactive oxygen species, suggesting that gastrodin may be useful in the prevention and treatment of osteoporosis. PMID- 25554601 TI - Src blockage by siRNA inhibits VEGF-induced vascular hyperpemeability and osteoclast activity - an in vitro mechanism study for preventing destructive repair of osteonecrosis. AB - INTRODUCTION: Destructive repair is the pathological feature of ONFH characterized with the elevated vascular permeability and persistent bone resorption, which is associated with higher VEGF expression, activated c-Src, and vascular leakage. Activated c-Src also participates in mediating endothelial permeability and osteoclasts activity. However, the molecular mechanism of the VEGF and c-Src contributing to the destructive repair process remains unknown. The purpose of this study is to delineate the role of VEGF and c-Src in triggering destructive repair of osteonecrosis in vitro, as well as to elucidate if VEGF mediating vascular permeability and osteoclastic bone resorption are Src dependent. METHODS: We employed pharmacological VEGF to induce higher endothelial permeability and osteoclasts activity for simulating related pathological features of destructive repair in vitro. Src specific pp60(c-src)siRNA was used for determining the contribution of VEGF and Src to destructive repair. The primary endothelial cells and osteoclasts were treated with 50ng/ml VEGF and/or transfected with the pp60(c-src)siRNA, while equivalent PBS and non-targeting siRNA were treated in the control groups. RESULTS: VEGF enhanced Src bioactivity through promoting dephosphorylation of Src at Y527 and phosphorylation of Src at Y416. Meanwhile, Src specific pp60(c-src)siRNA significantly reduced Src expression in both cells. VEGF destroyed the junctional integrity of endothelial cells resulting in higher endothelial permeability. However, Src blockade significantly relieved VEGF induced actin stress and inhibited caveolae and VVOs formation, meanwhile further stabilized the complex beta-catenin/VE-cadherin/Flk 1 through decreasing phosphorylation of VE-cadherin, ultimately decreasing VEGF mediating higher vascular permeability. In addition, VEGF promoted osteoclasts formation and function without affecting the adhesion activity and cytoskeleton. We further found that Src blockade significantly impaired cytoskeleton resulting in a lower adhesion activity through down-regulation of phosphorylation of Src, Pyk2 and Cbl, and ultimately inhibited osteoclasts formation and function. CONCLUSIONS: These findings provide a new insight into VEGF and c-Src mode of reaction in triggering destructive repair of osteonecrosis and further indicate that VEGF mediating vascular permeability and osteoclasts activity are Src dependent. Blockade of Src may have great potential as an effective therapy targeting destructive repair in osteonecrosis. PMID- 25554602 TI - Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins. AB - Human mesenchymal stem cells (MSCs) differentiate into osteoblasts on microstructured titanium (Ti) surfaces without addition of medium supplements, suggesting that surface-dependent endogenous mechanisms are involved. They produce bone morphogenetic proteins (BMPs), which regulate MSC differentiation and bone formation via autocrine/paracrine mechanisms that are modulated by changes in BMP mRNA and protein, receptors, and inhibitors (Noggin, Cerberus, Gremlin 1, and Chordin). We examined expression of BMPs, their receptors and their inhibitors over time and used BMP2-silenced cells to determine how modulating endogenous BMP signaling can affect the process. MSCs were cultured on tissue culture polystyrene or Ti [PT (Ra<0.4 MUm); sandblasted/acid-etched Ti (SLA, Ra=3.2 MUm); or hydrophilic-SLA (modSLA)]. BMP mRNAs and proteins increased by day 4 of culture. Exogenous BMP2 increased differentiation whereas differentiation was decreased in BMP2-silenced cells. Noggin was regulated by day 2 whereas Gremlin 1 and Cerberus were regulated after 6days. Osteoblastic differentiation increased in cells cultured with blocking antibodies against Noggin, Gremlin 1, and Cerberus. Endogenous BMPs enhance an osteogenic microenvironment whereas exogenous BMPs are inhibitory. Antibody blocking of the BMP2 inhibitor Cerberus resulted in IL-6 and IL-8 levels that were similar to those observed when treating cells with exogenous BMP2, while antibodies targeting the inhibitors Gremlin or Noggin did not. These results suggest that microstructured titanium implants supporting therapeutic stem cells may be treated with appropriately selected agents antagonistic to extracellular BMP inhibitors in order to enhance BMP2 mediated bone repair while avoiding undesirable inflammatory side effects observed with exogenous BMP2 treatment. PMID- 25554603 TI - Three-dimensional differentiation of bone marrow-derived mesenchymal stem cells into insulin-producing cells. AB - Fibrin glue (FG) is used in a variety of clinical applications and in the laboratory for localized and sustained release of factors potentially important for tissue engineering. The aim of this study was to evaluate FG scaffold effect on differentiation of insulin-producing cells (IPCs) from bone marrow-derived mesenchymal stem cells (BM-MSCs). In this experimental study BM-MSCs were cultured and the cells characterized by analysis of cell surface markers using flow cytometry. BM-MSCs were seeded in FG scaffold (3D culture) and then treated with induction media. After induction, the presence of IPCs was demonstrated using gene expression profiles for pancreatic cell differentiation markers (PDX 1, GLUT-2 and insulin) and insulin detection in cytoplasm. Release of insulin by these cells was confirmed by radioimmunoassay. Expression of the islet-associated genes PDX-1, GLUT-2 and Insulin genes in 3D cultured cells was markedly higher than the 2D cultured cells exposure differentiation media. Compared to 2D culture of BM-MSCs-derived IPCs, the insulin release from 3D BM-MSCs-derived IPCs showed a nearly 3 fold (p<0.05) increase when exposed to a high glucose (25 mM) medium. Percentage of insulin positive cells in 3D experimental group showed an approximately 3.5-fold increase in compared to 2D experimental culture cells. The results of this study demonstrated that FG scaffold can enhance the differentiation of IPCs from rats BM-MSCs. PMID- 25554604 TI - The sperm ultrastructure of Stictoleptura cordigera (Fussli, 1775) (Insecta, Coleoptera, Cerambycidae). AB - The spermatozoa of the longhorn beetles Stictoleptura cordigera were ultrastructurally described in this paper. They have an apical bilayered acrosome, an elongated nucleus, a centriole with star-shape links, two asymmetric mitochondrial derivatives partially crystallized and a 9+9+2 flagellar axoneme with accessory tubules provided with 16 protofilaments in their wall. A centriole adjunct is present and gives rise to two thick laminae as accessory bodies, also asymmetrical, to which two relatively small puff-like structures of different size are connected. These features were previously found in the sperm of the cerambycid Morimus asper. The strict similarity of the cerambycid sperm characters with those of curculionoids indicates a clear phylogenetic relationship between Chrysomeloidea and Curculionoidea. PMID- 25554605 TI - Evolution of primary care referrals to urology. Impact of a protocol on prostate disease and continuing education. AB - OBJECTIVE: To analyze the evolution of primary care referrals to the Urology Department after the implementation of a joint protocol on prostate disease and a continuing education program in our healthcare area. MATERIAL AND METHODS: In January 2011, we launched an action protocol on prostate disease, which was complemented by training sessions and an e-mail-based consultation system. We analyzed primary care referrals to the Urology Department between 2011 and 2013 and determined the reasons for the consultations and the compliance with the established criteria on prostate disease. We obtained data from the "Request for Appointment in Specialized Care" program of the Community of Madrid. We calculated the sample size with a 95% confidence level and a 50% heterogeneity. RESULTS: A total of 19,048 referrals were conducted. The most common reason for the referrals was lower urinary tract symptoms associated with benign prostate hyperplasia, with a 27% reduction and a compliance that went from 46% at 67%. Although prostate-specific antigen consultations increased by 40%, they improved their appropriateness (from 55% to 72%). This was the main type of consultation for suspicion of malignancy (30%). Also worth mentioning were female incontinence, which doubled in number, and a 41% reduction in erectile dysfunction, which could be due to the primary care training. CONCLUSIONS: The collaboration between the Department of Urology and primary care succeeded in improving the appropriateness of prostate disease referrals and modified the tendency to refer the rest of the diseases included in the project. PMID- 25554606 TI - Comparative analysis of the incidence of bladder cancer in the communities of Andalusia, Catalonia and Madrid in 2011. AB - OBJECTIVES: To determine the incidence of bladder cancer (BC) in the autonomous communities that include the largest number of cases in the national hospital BC registry (Andalusia, Catalonia and Madrid) and report the clinical, pathological and diagnostic differences and similarities of BC in these regions. MATERIAL AND METHODS: An observational epidemiological study was performed in 2011 in 12 public hospitals with reference population areas according to the National Health System (Spain). Demographic and clinical variables were collected from new cases and relapses, with histopathologic confirmation of BC. The raw incidence rate was calculated using the number of diagnosed cases in all the participating centers compared with the aggregate total population assigned to each center. The raw rates by age and sex were obtained from the National Institute of Statistics (2011) by weighting the assigned population with the distribution by age and sex. RESULTS: The 3 autonomous communities recorded 51% of the 4285 cases included in the national registration, with relapses corresponding to 42.8% of these cases. The raw annual incidence rate for new episodes was 22.6 (95% CI: 20.7; 24.6) in Andalusia, 23.5 (95% CI: 20.9; 26.0) in Catalonia and 22.0 (95% CI: 19.9; 24.1) in Madrid. CONCLUSIONS: Except for the larger proportion of smokers and lower tumor grade of lesions in Andalusia, the 3 autonomous communities studied are similar in terms of clinical characteristics, comorbidities, patient symptoms and diagnostic processes for BC. PMID- 25554607 TI - Tripolar mitosis in human cells and embryos: occurrence, pathophysiology and medical implications. AB - Tripolar mitosis is a specific case of cell division driven by typical molecular mechanisms of mitosis, but resulting in three daughter cells instead of the usual count of two. Other variants of multipolar mitosis show even more mitotic poles and are relatively rare. In nature, this phenomenon was frequently observed or suspected in multiple common cancers, infected cells, the placenta, and in early human embryos with impaired pregnancy-yielding potential. Artificial causes include radiation and various toxins. Here we combine several pieces of the most recent evidence for the existence of different types of multipolar mitosis in preimplantation embryos together with a detailed review of the literature. The related molecular and cellular mechanisms are discussed, including the regulation of centriole duplication, mitotic spindle biology, centromere functions, cell cycle checkpoints, mitotic autocorrection mechanisms, and the related complicating factors in healthy and affected cells, including post-mitotic cell cell fusion often associated with multipolar cell division. Clinical relevance for oncology and embryo selection in assisted reproduction is also briefly discussed in this context. PMID- 25554608 TI - Non-alcoholic fatty liver disease in women with polycystic ovary syndrome - clinical and metabolic aspects and lipoprotein lipase gene polymorphism. AB - INTRODUCTION: The aim was to assess associations among PCOS and NAFLD, the lipoprotein lipase polymorphism gene, and metabolic disorders in PCOS. MATERIAL AND METHODS: In 184 women with PCOS and 125 healthy, premenopausal volunteers, sex steroids, lipids, glucose, insulin, aminotransferases, free androgen index (FAI), HOMA-IR and E2/T were calculated. Hepatic steatosis was determined by ultrasound. Whole genomic DNA was isolated from blood leucocytes. Lipoprotein lipase polymorphisms rs268 and rs328 were analysed by polymerase chain reaction (PCR) and minisequencing. RESULTS: 57.6% of PCOS women had NAFLD, while women without PCOS had NAFLD in 49.6%. PCOS-NAFLD women had higher BMI, WHR and waist circumference compared to women with PCOS without NAFLD and women without PCOS. PCOS-NAFLD women had lower SHBG, E2/T ratio, and higher FAI compared to other groups. ALT levels were higher in PCOS women with NAFLD compared to other groups. PCOS women with and without NAFLD had higher fasting glucose and insulin and HOMA compared to women without PCOS. Women with PCOS had higher triglycerides and lower HDL-C compared to women without PCOS. There was no evidence that evaluated polymorphisms influenced hepatic steatosis in women with and without PCOS. CONCLUSIONS: PCOS is not an independent factor influencing NAFLD in women. The influences on NAFLD incidence in women are BMI > 25 kg/m2, glucose level > 80 mg/dL, E2/T < 80 and ALT > 19 IU/L as independent factors. Hyperandrogenism in PCOS may increase the risk of NAFLD indirectly by obesity, insulin resistance, and directly by the hepatotoxic effect. Polymorphisms rs328 and rs268 of the lipoprotein lipase gene do not affect the occurrence of NAFLD in women with PCOS or without PCOS. PMID- 25554609 TI - First one-step nucleic acid amplification testing in papillary thyroid cancer lymph nodes - a comparison with histopathology and real-time PCR. AB - INTRODUCTION: The significance of lymph node metastases and the optimal extent of lymphadenectomy remain matters of controversy in papillary thyroid cancer. This study was designed to assess the feasibility and reliability of OSNA and real time PCR for CK19 and TG mRNA in papillary thyroid cancer lymph nodes evaluation compared to standard histopathology. MATERIAL AND METHODS: Each of 92 randomised lymph nodes from 32 papillary thyroid cancer patients were divided into representative parts and assessed using the three studied methods. RESULTS: Eighteen (19.6%) lymph nodes from ten (31.3%) patients were positive according to histopathology. When the cut-off value distinguishing metastatic from non metastatic lymph nodes in the OSNA assay was set at 250 copies per microlitre, the results were positive in 16 (17.4%) lymph nodes from 11 (34.4%) patients. Twenty three (25%) lymph nodes were tested positive in real-time PCR for TG mRNA. Real-time PCR for CK19 mRNA was positive in 18 (19.6%) lymph nodes from 13 (40.6%) patients. No statistically significant differences were noted between the diagnostic accuracy of either molecular method compared to the histopathological examination (p = 0.81). Overall, 20 positive molecular biology results were noted in patients with negative histopathology results. Conversely, in 18 lymph nodes, despite a metastasis finding in histopathology, at least one molecular test yielded a negative result. CONCLUSIONS: It was revealed that OSNA is a reliable technique for the evaluation of lymph node metastases in papillary thyroid cancer. This method was shown to have equivalent accuracy to histopathology and real-time PCR. PMID- 25554610 TI - New classification of thyroid FNAB results - a three-year observation from one clinic. AB - INTRODUCTION: Fine needle aspiration biopsy (FNAB) is the main examination in diagnostics of thyroid nodules. Yet, it does not allow the differentiation of follicular lesions (FL). A new classification of thyroid biopsy results (newC) might improve pre-operative diagnostics mainly due to the introduction of a new subcategory of 'follicular lesion of undetermined significance', as well as the clarification of definitions of other categories. The aim of this study was to analyse the impact of the newC on the distribution of the cytological results among main diagnostic categories and on the values of the parameters describing the effectiveness of FNAB in detecting malignancy. MATERIAL AND METHODS: 34,371 FNABs outcomes and 3,557 results of surgical follow up were analysed. The frequencies of five main diagnostic categories in two periods: before (years: 2000-2009, 24,271 FNAB) and after the newC had been introduced (years: 2010-2012, 10,100 FNAB) were compared, as well as parameters describing the biopsy effectiveness, with a special focus on FL. RESULTS: In the second analysed period, the frequency of the 'suspicious for malignancy' results was three times lower, while diagnoses of 'malignant neoplasm' were 33% more frequent and the results corresponding to FL decreased by 10%. In respect to FL, specificity of FNAB increased (22.6% vs. 57.4%), but sensitivity decreased (78.8% vs. 50.0%). In respect to other diagnostic categories considered jointly, the sensitivity of FNAB (61.2% vs. 85.7%) and PPV (57.4% vs. 77.8%) increased, and the specificity was similar (95-97%) for both periods. NPV exceeded 95% irrespective of applied classification. CONCLUSIONS: Separation of FL with low risk of malignancy affects the values of the parameters describing the effectiveness of FNAB. The improved diagnostic effectiveness of FNAB is also a consequence of epidemiological changes and better selection of thyroid lesions for biopsy. PMID- 25554611 TI - Selected adipose tissue hormones, bone metabolism, osteoprotegerin and receptor activator of nuclear factor-kB ligand in postmenopausal obese women. AB - INTRODUCTION: It has been suggested that changes in the production of adipose tissue hormones in obese postmenopausal women might affect their bone status. The aim of this study was to determine whether obese postmenopausal women exhibited any relationship between serum levels of LP, ADIPO, RES, VISF, APE and bone metabolism markers (OC and CTx), OPG, sRANKL, the OPG/sRANKL ratio as well as BMD. MATERIAL AND METHODS: 80 postmenopausal women (60 obese and 20 healthy) underwent BMD measurement using dual-energy X-ray absorptiometry (DXA) at lumbar spine L2-L4. Serum levels of selected adipose tissue hormones, OC, CTx, OPG and its soluble ligand, sRANKL, were assessed by ELISA. RESULTS: Obese postmenopausal women demonstrated a significant increase in body mass, BMI and WHR associated with significant increases in LP and RES levels, a decrease in ADIPO concentration, suppression of OC, CTx, OPG and sRANKL and an increase in the OPG/sRANKL ratio and BMD. BMI correlated positively with BMD, LP, RES, OPG and the OPG/sRANKL ratio, whereas in the case of ADIPO, OC, CTx, sRANKL the relationship was negative. WHR was positively correlated with the OPG/sRANKL ratio, and negatively with ADIPO and APE. A positive correlation was found between BMD and LP, APE and the OPG/sRANKL ratio, while the correlation between BMD and ADIPO, CTx, sRANKL was negative. Significant positive correlations were also revealed between OC, CTx and ADIPO; OPG and ADIPO; sRANKL and ADIPO, RES; the OPG/sRANKL ratio and LP. OC correlated negatively with LP, RES, VISF, APE; CTx with LP, VISF, APE; OPG with LP; sRANKL with LP and APE; the OPG/sRANKL ratio with VISF. ADIPO was an independent predictor of OC, OPG and sRANKL, while LP turned out to be an independent predictor of CTx, OPG, sRANKL and the OPG/sRANKL ratio. CONCLUSIONS: Obesity in postmenopausal women can lead to changes in BMD, circulating levels of bone markers, OPG, sRANKL and/or the OPG/sRANKL ratio; these changes are associated with alterations in the concentrations of adipose tissue hormones under investigation. The relationships between bone status indicators and adipose tissue hormones, especially LP and ADIPO, seem to suggest that changes in these hormones observed in obese postmenopausal women might have a protective effect on bone tissue, most probably via a shift in the OPG/sRANKL ratio towards a functional excess of OPG. PMID- 25554612 TI - Accumulation of abdominal fat in relation to selected proinflammatory cytokines concentrations in non-obese Wroclaw inhabitants. AB - INTRODUCTION: Metabolically obese normal weight (MONW) subjects, despite their normal BMI, present metabolic disturbances characteristic of abdominal obesity. One of the reasons might be subclinical inflammation caused by the fat tissue excess. The aim of this study was to assess the association between the accumulation of fat (especially abdominal) and the concentration of selected proinflammatory cytokines - interleukins (IL-6, IL-18) and C-reactive protein (CRP). MATERIAL AND METHODS: The study population consisted of 342 subjects (218 women, 124 men; age 20-40 years, BMI < 27 kg/m2) recruited from a community centre in Wroclaw. The group was divided based on the homeostasis assessment insulin resistance index (HOMA) value: 90 MONW subjects with HOMA > 1.69 and 252 subjects as control group. Anthropometric parameters, serum IL-6, IL-18, CRP, glucose, insulin concentrations and insulin sensitivity/resistance indexes were evaluated. RESULTS: CRP levels were significantly higher (3.26 vs. 1.97, p = 0.03) in MONW women than in the control group. Serum IL-6, IL-18 levels in males and females did not differ in both groups. IL-6 showed a significant correlation with the abdominal to gynoidal fat tissue deposit ratio in women. There were correlations between the CRP and BMI, WHR, waist circumference, total fat, abdominal fat deposit, and abdominal to gynoidal fat deposit ratio in both sexes. In women, positive correlations between CRP and HOMA, FIRI and negative with QUICKI index were present. CONCLUSIONS: Increased accumulation of abdominal adipose tissue in non-obese, young and healthy subjects is related to increased CRP levels. PMID- 25554613 TI - Five-year longitudinal evaluation of mild primary hyperparathyroidism - medical treatment versus clinical observation. AB - INTRODUCTION: Primary hyperparathyroidism (PHPT) is an increasingly common endocrine disorder. Most patients with PHPT do not have disease-specific symptoms. The management of these patients has been widely debated. Recent studies have shown the importance of following up asymptomatic patients in order to reduce co-morbidity. However, there are conflicting opinions as to medical management. The aim of our study was to compare the outcome of PHPT patients on antiresorptive therapy vs. observation only. MATERIAL AND METHODS: We longitudinally evaluated 157 PHPT patients (126 females) aged 22-90 years. Patients who did not undergo surgery were divided into two groups: those on anti resorptive therapy (N = 52), and those without any treatment (N = 37). Patients who were disease-free after surgery (N = 50) served as controls. RESULTS: The values of serum calcium (S-Ca), parathyroid hormone (PTH) and indices of bone metabolism did not differ significantly among the three groups of subjects. No differences in 25(OH)-vitamin D levels were noted. Bone mineral density (BMD) was not significantly different at the spinal level. Finally, we found no evidence of an effect of medical treatment on quality of life (QoL). However, QoL significantly improved in the surgery group after parathyroidectomy (PTX). CONCLUSIONS: This study provided up-to-date information in terms of biochemical progression on the natural history of PHPT patients. No significant differences emerged between anti-resorptive therapy and observation only. It is not yet possible to assess the effect of pharmacological treatments on QoL in statistical terms. PMID- 25554614 TI - Treatment with statins and testosterone levels in men. AB - INTRODUCTION: Statins belong to the most commonly used medicines worldwide. They affect cholesterol synthesis and thus they may suppress steroidogenesis. Our aim was to evaluate whether the use of statins is associated with the concentration of sex hormones.Material and methods/Results: In a population sample of men (n = 237) we found that subjects receiving statins had significantly lower concentrations of: total testosterone (14.9 vs. 16.35 nmol/L, p = 0.008 after correction for body mass), free testosterone (32 vs. 39 pmol/L, p = 0.004), calculated free testosterone (0.32 vs. 0.36 nmol/L, p < 0.001) and bioavailable testosterone (6.10 vs. 7.56 nmol/L, p < 0.001) than age-matched controls. CONCLUSIONS: We conclude that the use of statins may have an impact on the diagnosis of age-related testosterone deficiency in men. PMID- 25554615 TI - Expression of follicle stimulating hormone receptors in pituitary adenomas - a marker of tumour aggressiveness? AB - INTRODUCTION: In our earlier study, we found that pituitary adenomas, like other human tumours, express ectopically follicle stimulating hormone receptors (FSHR) in intratumoural blood vessels endothelia and/or tumoural cells. The aim of the present paper was to provide more detailed data on FSHR expression in different subtypes of pituitary adenomas and to evaluate its possible role as a prognostic and/ or predictive biomarker in these tumours. MATERIAL AND METHODS: Forty two pituitary adenomas, surgically removed, were immunostained with antibodies against the pituitary hormones, antigen Ki-67 and 1-190 fragment of FSHR. RESULTS: The positive FSHR immunostaining was found in blood vessels endothelia of 88% of adenomas and in tumoural cells of 40% adenomas. In tumoural cells, the incidence of at least moderate FSHR immunostaining is significantly higher in invasive tumours (68%) compared to non-invasive (12%) ones, and higher (albeit not statistically significantly) in invasive-proliferating adenomas (Ki-67 > 3%, grade 2b) compared to invasive but non-proliferating (Ki-67 < 3%, grade 2a) ones. CONCLUSIONS: The present study confirms that pituitary adenomas ectopically express FSHR in intratumoural blood vessels endothelia and tumoural cells. Moreover, the expression in tumoural cells is prevalent in invasive and proliferating adenomas vs. non-invasive and non-proliferating tumours. PMID- 25554616 TI - Assessment of the safety and efficiency of sunitinib malate in metastatic neuroendocrine tumours of the pancreas (NEN G1/G2) depending on the number and type of earlier therapeutic lines - initial report. AB - INTRODUCTION: The objective of this paper was to assess the safety and efficacy of sunitinib malate in patients with well-differentiated metastatic pancreatic neuroendocrine neoplasms (PNENs) who relapsed on standard therapy. MATERIAL AND METHODS: Overall, eight patients with well-differentiated pancreatic neuroendocrine tumours/neoplasm (NET/NEN G1/G2, Ki-67 < 20%), who had relapsed on a standard therapy approach, were treated. All had non-resectable, progressive disease. All received therapy using a standard dose of sunitinib malate. Adverse events were evaluated using NCI-CTC AE v. 3.0. RESULTS: Of the eight patients, seven had non-secretor and single secretor tumour (gastrinoma). Partial remission (PR) was noted in three patients (one after a single therapeutic line, two after two lines), five patients had stabilisation (SD) - including three individuals after three lines, one patient after two lines and another after a single line. Haematological adverse events: leukopenia (25%) - occurred in one patient after three lines and in one patient after two lines; anaemia (25%) - in one patient after three lines and in one patient after one therapeutic line. Mucocutaneous lesions were noted in 37.5% of patients after 2-3 lines of treatment. All of them experienced fatigue syndrome irrespective of the number of therapies. The majority of the patients simultaneously received somatostatin analogues, which did not exacerbate the toxicity profile. The median progression-free survival time (PFS) was 11 months. CONCLUSIONS: Sunitinib may be considered as a fairly well-tolerated and effective therapeutic option in progressive non-resectable PNEN patients in the second and subsequent lines of treatment, irrespective of the types of treatment previously applied. PMID- 25554617 TI - Neutrophil gelatinase-associated lipocalin and Cathepsin L as early predictors of kidney dysfunction in children with type 1 diabetes. AB - INTRODUCTION: The aim of this study was to evaluate serum levels and urinary excretion of neutrophil-gelatinase associated lipocalin (respectively sNGAL and uNGAL) and urinary excretion of Cathepsin L (uCathL) in children with type 1 diabetes mellitus (DM1) who presented normoalbuminuria and the estimated glomerular filtration rate (eGFR) above 90 mL/min/1.73 m2. MATERIAL AND METHODS: The study group consisted of 63 children with a diabetes duration of 5.16 +/- 3.39 years. The degree of albuminuria was based on urine albumin-to-creatinine ratio (ACR), while eGFR was based on serum cystatin C. Glomerular hyperfiltration (GH) was defined as an eGFR value above 135 mL/min/1.73 m2. RESULTS: Children with DM1 showed significantly higher concentrations of uNGAL, and lower sNGAL and uCathL. Significant changes of uNGAL and uCathL levels were even found in children without GH and with optimal glycaemic control (HbA1c < 7.5%). Positive correlations between uNGAL, ACR and eGFR were shown, as well as between uCathL and eGFR. CONCLUSIONS: Significant changes in the concentration of markers of early kidney injury: sNGAL, uNGAL, and uCathL, can occur in children with DM1 and normoalbuminuria. The changes of uNGAL and uCathL can be even found in children without GH and with optimal glycaemic control. The earliest signs of diabetic kidney dysfunction seem to result from tubular damage. PMID- 25554618 TI - Effect of tributyltin on the food intake and brain neuropeptide expression in rats. AB - INTRODUCTION: Tributyltin (TBT) is a largely diffused environmental pollutant. Several studies have demonstrated that TBT is involved in the development of obesity. However, few studies addressing the effects of TBT on the brain neuropeptides involved in appetite and body weight homeostasis have been published. MATERIAL AND METHODS: Experiments were carried out on female and male Sprague-Dawley rats. Animals were exposed to TBT (0.5 MUg/kg body weight) for 54 days. The hepatic triglyceride and total cholesterol were determined using commercial enzyme kits. The NPY, AgRP, POMC and CART mRNA expression in brains were quantified by real-time PCR. RESULTS: TBT exposure resulted in significant increases in the hepatic total cholesterol and triglyceride concentration of both male and female rats. Interestingly, increases in body weight and fat mass were only found in the TBT-treated male rats. TBT exposure also led to a significant increase in food intake by the female rats, while no change was observed in the male rats. Moreover, the neuropeptides expression was different between males and females after TBT exposure. TBT induced brain NPY expression in the female rats, and depressed brain POMC, AgRP and CART expression in the males. CONCLUSIONS: TBT can increase food intake in female rats, which is associated with the disturbance of NPY in brains. TBT had sex-different effects on brain NPY, AgRP, POMC and CART mRNA expression, which indicates a complex neuroendocrine mechanism of TBT. PMID- 25554619 TI - Adrenocortical cancer (ACC) - literature overview and own experience. AB - Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non operative patients. The role of radio- and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers. PMID- 25554620 TI - Uncommon constellation of multiglandular deficiency with 2 mutations in AIRE gene in an 18-year-old girl - 12 years of observation. AB - Autoimmune polyglandular syndromes (APS) consist of a variety of endocrine and non-endocrine disorders. The syndromes are complex and their occurrence in life does not follow any pattern. Early detection of such disorders may prevent many serious clinical consequences which are usually a result of delayed diagnosis. We present the case of a female patient whose clinical symptoms very strongly suggested APS, however neither autoimmune background except elevated anti-thyroid peroxidase and anti-thyroglobulin antibodies of multiglandular deficiency, nor critical mutations in the AIRE gene have been confirmed or detected, yet we identified five polymorphisms and two mutations in exon1 of gene AIRE during 12 years of observation and treatment. PMID- 25554621 TI - Ultrasound sonoelastography in the evaluation of thyroiditis and autoimmune thyroid disease. AB - Sonoelastography (USE) is a constantly evolving imaging technique used for the noninvasive and objective estimation of tissue stiffness. Several USE methods have been developed, including Quasi-Static or Strain Elastography and Shear Wave Elastography. The utility of USE has been demonstrated in differentiating between malignant and benign thyroid lesions. Recently, USE has been applied in the evaluation of thyroiditis and autoimmune thyroid disease (AITD).Thyroid inflammatory illnesses constitute a diverse group of diseases and may manifest various symptoms. These conditions may share some parallel clinical, biochemical, and ultrasonographic features, which can lead to diagnostic difficulties. USE may be an additional tool, supporting other methods in the diagnosis and treatment monitoring of thyroid diseases, other than thyroid nodular disease.The aim of this article was to analyse and summarise the available literature on the applicability of different elastographic techniques in the diagnosis, differentiation and monitoring of various types of thyroiditis and AITD. Advantages and limitations of this technique are also discussed. PMID- 25554622 TI - Personality features in ultra-high risk for psychosis: a comparative study with schizophrenia and control subjects using the Temperament and Character Inventory Revised (TCI-R). AB - Several variables have been identified as risk factors for conversion to overt psychosis in ultra-high risk for psychosis (UHR) individuals. Although almost two thirds of them do not experience a transition to psychosis, they still exhibit functional disabilities. Other subjective developmental features may be useful for a more precise identification of individuals at UHR. Avoidant behaviors are consistently reported in schizophrenia and in UHR individuals and may be the reflection of a pattern of personality. Thus, personality features in UHR individuals deserves further research. The objective of the present study was to compare temperament and character dimensions between UHR individuals, patients with schizophrenia and healthy controls. One hundred participants (25 UHR individuals, 25 schizophrenia patients and 50 control subjects) where evaluated with the Temperament and Character Inventory-Revised (TCI-R). Univariate ANOVAs followed by Bonferroni tests were used. UHR individuals and schizophrenia patients exhibited higher levels of Harm Avoidance (HA) when compared to control subjects. For HA1 Anticipatory worry vs Uninhibited optimism and HA4 Fatigability & asthenia, UHR and schizophrenia groups showed similar scores and both groups were higher compared to control subjects. With respect to Cooperativeness (CO), UHR and schizophrenia reported lower scores than control subjects, in particular CO2 Empathy vs Social disinterest and CO3 Helpfulness vs unhelpfulness. This study replicates and extends the consideration of HA as a psychopathological related endophenotype and gives us further information of the possible role of personality features in the expression of some of the social dysfunctions observed both in prodromal subjects and schizophrenia patients. PMID- 25554623 TI - Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings. AB - The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1 g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test-Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 h in >= 200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP D-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR glycine site treatments for specific psychiatric entities. ClinicalTrials.gov: Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor (NMDAR) Co agonist D-serine in Healthy Humans; http://www.clinicaltrials.gov/ct2/show/NCT02051426?term=NCT02051426&rank=1; NCT02051426. PMID- 25554624 TI - The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. AB - ATP-binding cassette (ABC) transporters represent one of the largest and oldest families of membrane proteins in all extant phyla from prokaryotes to humans, which couple the energy derived from ATP hydrolysis essentially to translocate, among various substrates, toxic compounds across the membrane. The fundamental functions of these multiple transporter proteins include: (1) conserved mechanisms related to nutrition and pathogenesis in bacteria, (2) spore formation in fungi, and (3) signal transduction, protein secretion and antigen presentation in eukaryotes. Moreover, one of the major causes of multidrug resistance (MDR) and chemotherapeutic failure in cancer therapy is believed to be the ABC transporter-mediated active efflux of a multitude of structurally and mechanistically distinct cytotoxic compounds across membranes. It has been postulated that ABC transporter inhibitors known as chemosensitizers may be used in combination with standard chemotherapeutic agents to enhance their therapeutic efficacy. The current paper reviews the advance in the past decade in this important domain of cancer chemoresistance and summarizes the development of new compounds and the re-evaluation of compounds originally designed for other targets as transport inhibitors of ATP-dependent drug efflux pumps. PMID- 25554628 TI - Respiratory consequences of late preterm birth. AB - In developed countries most preterm births occur between 34 and 37 weeks' gestation. Deliveries during this 'late preterm' period are increasing and, since even mild prematurity is now recognised to be associated with adverse health outcomes, this presents healthcare challenges. Respiratory problems associated with late preterm birth include neonatal respiratory distress, severe RSV infection and childhood wheezing. Late preterm birth prematurely interrupts in utero lung development and is associated with maternal and early life factors which adversely affect the developing respiratory system. This review considers 1) mechanisms underlying the association between late preterm birth and impaired respiratory development, 2) respiratory morbidity associated with late preterm birth, particularly long-term outcomes, and 3) interventions which might protect respiratory development by addressing risk factors affecting the late preterm population, including maternal smoking, early life growth restriction and vulnerability to viral infection. PMID- 25554634 TI - A rapid, modular and marker-free chloroplast expression system for the green alga Chlamydomonas reinhardtii. AB - In search of alternative expression platforms heterologous protein production in microalgae has gained increasing importance in the last years. Particularly, the chloroplast of the green alga Chlamydomonas reinhardtii has been adopted to successfully express foreign proteins like vaccines and antibodies. However, when compared with other expression systems, the development of the algal chloroplast to a powerful production platform for recombinant proteins is still in its early stages. In an effort to further improve methods for a reliable and rapid generation of transplastomic Chlamydomonas strains we constructed the key plasmid pMM2 containing the psbA gene and a multiple cloning site for foreign gene insertion. The psbA gene allows a marker-free selection procedure using as a recipient the Fud7 strain of Chlamydomonas, which grows on media containing acetate as a carbon source, but is unable to grow photoautotrophically due to the lack of an intact psbA gene. Biolistic transformation of Fud7 with vectors containing this gene restores photoautotrophic growth and thus permits selection in the light on media without carbon sources and antibiotics. The multiple cloning site with a BsaI recognition sequence allows type IIs restriction enzyme based modular cloning which rapidly generates new gene constructs without sequences, which could influence the expression and characteristics of the foreign protein. In order to demonstrate the feasibility of this approach, a codon optimized version of the gene for the bacterial protein MPT64 has been integrated into the plastome. Several strains with different promoter/UTR combinations show a stable expression of the HA tagged MPT64 protein in Chlamydomonas chloroplasts. PMID- 25554633 TI - Silent pituitary infarction of an uncommon etiology. PMID- 25554635 TI - Photosynthetic production of itaconic acid in Synechocystis sp. PCC6803. AB - Here, we report the photosynthetic production of itaconic acid (IA), a promising building block, from carbon dioxide (CO2) by Synechocystis sp. PCC6803. The engineered PCC6803 strain expressing cis-aconitate decarboxylase, the key enzyme in IA biosynthesis, produced 0.9 mg/L and 14.5 mg/L of IA at production rates of 42.8 MUgL(-1)day(-1) and 919.0 MUgL(-1)day(-1), under conditions of constant bubbling with air and 5% CO2, respectively. This is the first report on the possibility of IA production from CO2 via the photosynthetic process in cyanobacteria. PMID- 25554636 TI - Development and evaluation of multiplexed immunoassay for detection of antibodies to HPV vaccine types. AB - Reliable antibody based-assays are needed to evaluate the immunogenicity of current vaccines, impact of altered dosing schemes or of new vaccine formulations. An ideal assay platform would allow multiplex type-specific detection with minimal sample requirement. We used the Meso Scale Discovery (MSD) electrochemiluminescence based detection platform to develop a multiplex direct virus-like particle (VLP) ELISA to detect antibodies to HPV 6, 11, 16, and 18 with a protocol developed for detection using the SI 6000 imager (M4ELISA). MSD prepared the plates in the 7-spot/well format, using the purified VLPs (4 spots) and PBS+BSA pH7.4 (3 blank spots). Three-point titrations and the parallel line method were used to calculate antibody levels. Dynamic range, precision, and stability of pre-printed plates were determined using a panel of previously characterized sera. Cut-off values using children's sera were established using 99% RLU limits based on the 4-parameter Johnson Su best fit curve. Results of the M4ELISA were compared to competitive Luminex Immunoassay (cLIA) on n = 4454 sera from a predominantly unvaccinated cohort. Using a VLP coating concentration of 80 MUg/ml with BSA provided the most robust RLU signal for all types. The dynamic range of the assay was about 1000 fold, with assay variability under 25% for each of the four vaccine types. Long-term stability of the plates extended to about 7 months from the time plates was received in the laboratory after printing. There was moderate agreement (kappa = 0.38-0.54) between M4ELISA and cLIA, with antibody detection for each of the 4 types more frequent with M4ELISA. Quantitative analysis however showed a good correlation between concordant samples by both assays (rho >= 0.6). The MSD platform shows promise for simultaneous quantitation of the antibody responses to four HPV vaccine types in a high-throughput manner. PMID- 25554637 TI - Red Ginseng and Semen Coicis can improve the structure of gut microbiota and relieve the symptoms of ulcerative colitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Many Chinese herbs are traditionally used as medicine to improve the functions of gastrointestinal tract. Some of these herbs are also promising agents for the improvement of the gut microbiota and the treatment of ulcerative colitis. MATERIALS AND METHODS: By screening seven traditional Chinese herbs, we found that Red Ginseng and Semen Coicis were the most effective in promoting the growth of probiotics including Lactobacillus and Bifidobacterium in vitro. We then evaluated the effects of Red Ginseng and Semen Coicis on the growth of the bacterial pathogens (Escherichia coli, Staphylococcus aureus, and Salmonella spp.) in vitro. In in vivo experiment, we gavage administrated trinitro-benzene-sulfonic acid induced ulcerative colitis (UC) rats with Red Ginseng and Semen Coicis extracts. After two weeks treatment, we analyzed the structure of the gut microbiota and examined the UC symptoms by employing qPCR and animal pathology detection techniques. RESULTS: Both Red Ginseng and Semen Coicis promoted the growth of probiotics - Bifidobacterium and Lactobacillus in vitro. Red Ginseng also inhibited the growth of some pathogen strains. In vivo, Red Ginseng and Semen Coicis improved the structure of gut microbiota and relieved the symptoms of ulcerative colitis in vivo. Compared with Semen Coicis, Red Ginseng was more effective in relieving the symptoms of ulcerative colitis. CONCLUSIONS: Red Ginseng could promote the growth of probiotic bacteria in vitro. Red Ginseng and, to a lesser extent Semen Coicis, gave positive results in an experimental in vivo model for ulcerative colitis. PMID- 25554638 TI - Anti-metastatic effect and mechanisms of Wenshen Zhuanggu Formula in human breast cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Zhuanggu Formula (WSZG), a traditional Chinese medicine (TCM) empirical prescription, has been used to treat the patients with breast cancer bone metastasis as an adjuvant in clinical practice. To explore the anti-metastatic activity and potential mechanisms of WSZG containing serum (WSZG-CS) on highly bone-metastatic human breast cancer MDA-MB 231BO cells. MATERIALS AND METHODS: MDA-MB-231BO cells were cultured alone or co cultured with bone marrow-derived mesenchymal stem cells (BMSCs). Invasion assays were carried out in Matrigel-coated Transwell chambers. CC chemokine 5 (CCL5) and interleukin (IL)-17B secretion levels were detected by ELISA. CCR5 and IL-17BR protein expression levels were determined by immunocytochemistry and Western blot analysis. RESULTS: Compared with control serum, WSZG-CS significantly inhibited BMSC induced MDA-MB-231BO breast cancer cell invasion, reduced CCL5 and IL-17B levels in co-culture supernatants, and downregulated CCR5 and IL-17BR protein expression in breast cancer cells co-cultured with BMSCs. CONCLUSIONS: WSZG-CS exerts an anti-metastatic activity against MDA-MB-231BO breast cancer cells, due to its ability to mitigate the interaction between BMSCs and breast cancer cells mediated via the CCL5/CCR5 and IL-17B/IL-17BR signaling pathways. PMID- 25554639 TI - A Chinese medicinal formulation ameliorates dextran sulfate sodium-induced experimental colitis by suppressing the activity of nuclear factor-kappaB signaling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) is generally associated with a set of debilitating symptoms including abdominal pain, tenesmus, diarrhea and bloody stool. The standard approaches for treating IBD, which are the application of pharmaceuticals, are often unsatisfactory. IBD patients may suffer from repeated relapses and even exacerbation after taking these medications. Thus, patients are increasingly seeking relief through the use of complementary and alternative medicines. AIM OF STUDY: To provide scientific ground for the mode of actions of a Chinese medicinal formulation-modified ZenWu Decoction (MZWD) in ulcerative colitis. MATERIALS AND METHODS: C57BL6 mice were fed with 3 cycles of 2% dextran sulfate sodium (DSS) in drinking water for the induction of chronic colitis and then given MZWD at 17.47 g/kg/day. Effects of MZWD were evaluated by histopathological and biochemical assays. RESULTS: When MZWD was given, inflammatory responses namely immune-cell infiltration, elevated serum levels of pro-inflammatory cytokines and mucosal lesions were notably suppressed. Further, MZWD treatment attenuated the activation of nuclear factor kappaB (NF-kappaB), the vital regulator of inflammatory cascades, while lessening the degradation of I-kappaB-alpha and reducing the activity of protease-activated receptor 2 in DSS-induced colonic tissues. Consequently, diarrhea, bloody stool and colon shortening were reduced whilst mucosal integrity was improved in MZWD treated colitis mice. CONCLUSIONS: Our findings suggest that MZWD is a potential remedy for treating IBD, and the mechanism of its efficacy is an anti inflammatory effect associated with the suppression of the NF-kappaB pathway. PMID- 25554640 TI - Are meta-analyses of Chinese herbal medicine trials trustworthy and clinically applicable? A cross-sectional study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Meta-analysis (MA) on Chinese herbal medicine (CHM) trials is increasingly published and indexed in major international databases but their trustworthiness and clinical applicability is uncertain. We aimed to assess the characteristics and methodological quality of MA on CHM. MATERIALS AND METHODS: Cross-sectional study. MA published during 1993-2013 was sampled from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effect. Bibliographical characteristics were abstracted and methodological quality was assessed using the validated AMSTAR tool by two independent reviewers. RESULTS: Total of 201 MA were included and half were published in or after 2009. Only 7.5% being updates of previous reviews. Majority are published in journals with low or no impact factor, with a median of 1.5. These MA demonstrated methodological strengths in ensuring comprehensive literature search, providing characteristics of the included studies, assessing the scientific quality of included studies and appropriately using the scientific quality of included studies in formulating conclusions. Nevertheless, weaknesses in protocol provision, listing of included and excluded studies, inclusion of grey literature, use of appropriate meta-analytic technique as well as reporting of funding sources were prevalent. CHM and control interventions pooled in majority of MA are found to have substantial clinical heterogeneity in terms of composition, dosage form and route of administration. CONCLUSIONS: There are rooms for improvement in methodological rigor, and in choosing clinically homogenous interventions and control for statistical pooling. These shortcomings limit the trustworthiness and clinical applicability of existing MA on CHM trials. To overcome the limitations of pair-wise meta-analysis in synthesizing trials comparing different CHM and control interventions, the potential of network meta-analysis should be explored. PMID- 25554641 TI - Ethnomycological survey of traditional usage and indigenous knowledge on desert truffles among the native Sahara Desert people of Algeria. AB - ETHNOPHARMACROLOGICAL RELEVANCE: Desert truffles are edible hypogeous fungi, highly appreciated by the inhabitants of hot-desert settlements. Native Saharan people use truffles for food, promoting tourism, increasing fertility, and treatment of eye diseases and fatigue. AIM OF THE STUDY: This study consists of a cross-sectional survey focusing on the knowledge, use and ethnomycological practices of desert truffles among the native people of the Algerian Northern Sahara. MATERIALS AND METHODS: The study was conducted through direct interviews with 60 truffle-hunters in the regions of Ouargla and Ghardaia. RESULTS: Three species were harvested and consumed by the surveyed subjects: Terfezia claveryi was the most appreciated and most expensive species, followed by Terfezia areanaria moderately preferred, then Tirmania nivea the least appreciated and least expensive. Among the 60 interviewees, 90% rely on the abundance of symbiotic plants (Helianthemum lippii) to harvest truffles, 65% begin harvesting from mid-February to March, after rains of the autumn (38%) and winter (36%), particularly in the Wadi beds (37%) and Daya landscapes (32%). Interviewees harvested truffles mainly for home consumption; however 26.7% sell any harvest surplus, and of those only 15% generate significant revenue from this source, and 73% considered the sale of desert truffles to have low financial value. Desert truffles are used in traditional medicine, especially against eye infections (22%), weakness (19%) and to promote male fertility (19%). In the case of desert truffles for consumption, the surveyed population preferred to prepare the truffles with couscous and meat, or in porridge. Respondents used price as the main criterion for deciding whether to purchase desert truffles. CONCLUSIONS: The surveyed trufflers use the knowledge passed from one generation to the next to help ensure a good harvest of truffles during each foray into the desert. Our findings highlight the various uses of truffles in the Sahara Desert, and how these relate to the lifestyle of local people. PMID- 25554642 TI - Growth inhibition of human liver carcinoma HepG2 cells and alpha-glucosidase inhibitory activity of Murdannia bracteata (C.B. Clarke) Kuntze ex J.K. Morton extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The juice of the entire fresh herb and infusion of dried sample of Murdannia bracteata are consumed to treat liver cancer and diabetes in Malaysia. However, no scientific evidence of these bioactivities has been reported. MATERIALS AND METHODS: To verify the therapeutic potentials of sequential extracts and infusion of this plant by determining its cytotoxicity against human liver carcinoma HepG2 cells and alpha-glucosidase inhibitory activity. The cytotoxic activities of the extracts against HepG2 were determined using a methylene blue assay, and an alpha-glucosidase inhibitory assay was used to assess anti-diabetic activity. The molecular basis of the anti-hepatocellular carcinoma activity of the most active extract was determined using RT-PCR. Chemical profiling of the most active extract was performed using GC-MS and UPLC analyses. RESULTS: The results obtained from the cytotoxic screening revealed the dose-dependent growth inhibition of the HepG2 cells by only the hexane extract, with an EC50 value of 37.17+/-1.00 ug/ml. The HepG2 cell death was found to be apoptotic in nature and based on the significant biphasic induction of caspase-3, suggesting that the extract inhibited cell growth through a caspase-3-dependent pathway. The hexane extract also displayed alpha-glucosidase inhibitory activity, with an EC50 of 117.04+/-2.34 ug/ml. GC-MS analysis revealed that alpha tocopherol was the major volatile compound in the hexane extract, and two phenolics (apigenin and caffeic acid derivatives) were detected using UPLC. CONCLUSIONS: Based on various published reports, it could be suggested that alpha tocopherol and apigenin derivatives might be involved in the apoptosis-based cytotoxicity of the active extract of this plant against HepG2 carcinoma cells. The effects of this plant in the treatment of diabetes can be related to the presence of alpha-glucosidase inhibitors, such as the caffeic acid derivative identified in the active extract. PMID- 25554643 TI - Cartilage boundary lubrication of ovine synovial fluid following anterior cruciate ligament transection: a longitudinal study. AB - OBJECTIVE: To assess ovine synovial fluid (oSF) from different post-injury time points for (1) proteoglycan-4 (PRG4) and hyaluronan (HA) concentration, (2) HA molecular weight (MW) distribution, (3) cartilage boundary lubrication function, and (4) lubricant composition-function relationships. The association between cartilage boundary lubrication and gross cartilage changes after injury was also examined. METHODS: oSF was collected 2, 4, 10, and 20 weeks post anterior cruciate ligament (ACL) transection in five skeletally mature sheep. PRG4 and HA concentrations were measured using sandwich enzyme-linked immunosorbent assay, and HA MW distribution by agarose gel electrophoresis. Cartilage boundary lubrication of oSF was assessed using a cartilage-cartilage friction test. Gross damage to articular cartilage was also quantified at 20 weeks using modified Drez scoring protocol. RESULTS: Early (2-4 weeks) after ACL injury, PRG4 concentrations were significantly higher (P = 0.045, P = 0.037), and HA concentrations were substantially lower (P = 0.005, P = 0.005) compared to 20 weeks. The HA MW distribution also shifted towards lower ranges in the early post injury stage. The kinetic friction coefficients were significantly higher 2-4 weeks post injury (P = 0.008 and P = 0.049) compared to 20 weeks. Poor cartilage boundary lubricating ability early after injury was associated with cartilage damage at 20 weeks. CONCLUSION: Altered composition and diminished boundary lubrication of oSF early after ACL transection may pre-dispose the articular cartilage to degenerative changes and initiate osteoarthritis (OA). These observations also provide potential motivation for biotherapeutic interventions at earlier time points post injury. PMID- 25554645 TI - Laminated ceramics with elastic interfaces: a mechanical advantage? AB - OBJECTIVES: As CAD/CAM technologies improve we question whether adhesive lamination of ceramic materials could offer mechanical advantages over monolithic structures and improve clinical outcomes. The aim was to identify whether an adhesive interface (a chemically cured resin-cement) would influence the biaxial flexure strength (BFS) and slow-crack growth in a machinable dental ceramic. METHODS: Monolithic and adhesively laminated (with a chemically cured dimethacrylate resin-cement) feldspathic ceramic discs of identical dimensions were fabricated. BFS testing was performed on the Group A monolithic specimens (n = 20), on Group B laminated specimens with the adhesive interface positioned below the neutral bending axis (n = 20) and Group C laminated specimens with the adhesive interface positioned above the neutral bending axis (n = 20). To study subcritical crack growth additional laminated specimens received controlled indentations and were exposed to thermo-mechanical fatigue. BFS data was analysed using parametric statistics (alpha = 0.05). Fractographic analyses were qualitatively assessed. RESULTS: No significant differences between the mean BFS data of Groups A and B were observed (p = 0.92) but the mean BFS of Group C was slightly reduced (p < 0.01). Lamination reduced the stiffness of the structure and fractographic analysis demonstrated that energy consuming crack deflection occurred. Thermo-mechanical fatigue caused subcritical extension of radial cracks associated with indentations adjacent to the adhesive interface. Crack growth was limited to parallel to the interface and was arrested or deflected in a direction normal to the interface. CONCLUSIONS: Ceramic lamination increased the damage tolerance of the structure and could limit or arrest subcritical crack growth at regions near the 'interlayer'. CLINICAL SIGNIFICANCE: Lamination of a dental ceramic with a polymeric 'interlayer' could offer toughening effects which could potentially delay or arrest sub-critical crack growth at regions near the interface and thereby improve restoration longevity. PMID- 25554644 TI - Macrophage depletion ameliorates nephritis induced by pathogenic antibodies. AB - Kidney involvement affects 40-60% of patients with lupus, and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, and BUN seen in control treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with lupus nephritis. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis. PMID- 25554651 TI - Tumoral expression of nuclear cofactor FHL2 is associated with lymphatic metastasis in sporadic but not in HNPCC-associated colorectal cancer. AB - BACKGROUND: Four and a half LIM domain protein-2 (FHL2) is part of the focal adhesion structures modulating cell motility. FHL2 may translocate into the nucleus serving as a transcriptional cofactor binding several transcription factors. Overexpression of FHL2 has been linked to cancer progression in various neoplasias. The aim of the present study was to determine, whether FHL2's function as nuclear cofactor plays a prognostic role in invading tumor cells of sporadic and HNPCC-associated colorectal cancer (CRC). DESIGN: Immunohistochemical staining intensity of nuclear FHL2 was quantified by Remmele score analysing 47 sporadic and 42 HNPCC-associated colorectal cancers. Analysis was restricted to carcinoma cells of the tumoral invasion front. RESULTS: Confocal microscopy detected nuclear expression of FHL2 in colon cancer cells and absence of nuclear FHL2 signal in normal colon enterocytes. In colon cancer, nuclear FHL2 expression was predominantly observed in low-differentiated, often mucinous tumor areas. 42.55% of sporadic and 54.76% of HNPCC-associated CRC showed enhanced (Remmele score 6-12) nuclear FHL2 expression in the carcinoma cells of the tumoral advancing edge. Enhanced nuclear FHL2 expression was significantly linked to lymphatic metastasis in sporadic CRC (p=0.0197) and almost reached significance in HNPCC-associated CRC (p=0.0545). In contrast, nuclear FHL2 expression was neither associated with hematogenic metastasis in sporadic (p=0.7087) nor in HNPCC-associated colorectal cancer (p=0.3007). CONCLUSIONS: We recently demonstrated that enhanced nuclear FHL2 expression in tumor stroma of sporadic colon cancer is associated with lymphatic metastasis. The results of the present study indicate a synergistic effect of nuclear cofactor FHL2 in tumor cells as well as in peritumoral stroma cells promoting lymphatic metastasis in sporadic CRC. As HNPCC-associated tumors did not show a significant association between tumoral nuclear FHL2 expression and lymphatic metastasis we speculate, that the intensive lymphocytic immune response in HNPCC precludes a direct contact of tumor cells and stromal cells resulting in reduced lymphatic spread. PMID- 25554652 TI - Malignant solitary fibrous tumor with high-grade nuclear atypia: an alternate entity for the undetermined tumor group. AB - Recently, a novel fusion transcript, NAB2-STAT6, and its variants have also been reported to be specific diagnostic markers for solitary fibrous tumors (SFTs). In this study, we validated the existence of the NAB2-STAT6 fusion gene in SFTs and examined its relation with the pathological features. Frozen samples from 9 tumors were assessed for fusion gene. The detected fusion genes exhibited large intron sequences and the insertion of unknown and previously unreported sequences. The fusion genes were not detected in the 2 malignant cases with high grade nuclear atypia, nuclear pleomorphism and necrosis, that was confirmed by multiplex PCR method. In addition, 1 of the 2 NAB2-STAT6 fusion gene-negative tumors showed amplification of the MDM2 and CDK4 genes. It was suggested that a certain proportion of tumors previously diagnosed as malignant SFTs with high grade nuclear atypia lacking NAB2-STAT6 should be categorized into a special subtype of SFT, which is genetically different from conventional SFTs, and which cannot be apparently distinguished from dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma. PMID- 25554653 TI - [Unusual consequences of foam sclerotherapy]. AB - Neurological disorders are rare complications of foam sclerotherapy. Visual disturbances and headache are the most commonly reported events and are thought to be equivalent to migraine with aura. Exceptionally, strokes have been reported. Papillary fibroelastoma is a rare cardiac tumor, which may embolize in cerebral arteries. We report the case of a patient in whom neurological disorders occurred during a session of foam sclerotherapy, and led to the discovery of a cardiac fibroelastoma. PMID- 25554654 TI - When the going gets tough: Mental toughness and its relationship with behavioural perseverance. AB - OBJECTIVES: This study examined the association between self-reported mental toughness and behavioural perseverance among a sample of male Australian footballers in a naturalistic context. DESIGN: Cross-sectional field study, with the multistage 20m shuttle run test (MST) employed as a proxy for behavioural perseverance. METHODS: 330 male Australian footballers aged between 15 and 18 years (M=16.86; SD=.71) with between 2 and 14 years playing experience (M=9.32; SD=2.51) participated. Initially, footballers completed a mental toughness questionnaire, before having their height and body mass measurements taken. Subsequently, a performance testing session was completed, which included the 20m sprint, Australian football-specific agility run, vertical jump, and the MST. Bayesian estimation was employed to allow for the simultaneous examination of existing findings with our new data in a way that provides an automatic meta analysis of evidence in this area. RESULTS: The analysis indicated a 95% probability that the association between mental toughness and behavioural perseverance lies between .14 and .34, even when controlling for other factors known to influence MST performance, including age, height, body mass, and years playing experience. CONCLUSIONS: Taken together with previous research, these findings support the theoretical proposition that persistence, effort or perseverance represents a behavioural signature of mental toughness. PMID- 25554655 TI - Motor competence and health related physical fitness in youth: A systematic review. AB - OBJECTIVES: This study aimed to review the scientific evidence on associations between motor competence (MC) and components of health related physical fitness (HRPF), in children and adolescents. DESIGN: Systematic review. METHODS: Systematic search of Academic Search Premier, ERIC, PubMed, PsycInfo, Scopus, SportDiscus, and Web of Science databases was undertaken between October 2012 and December 2013. Studies examining associations between MC and HRPF components (body weight status, cardiorespiratory fitness, musculoskeletal fitness and flexibility) in healthy children and adolescents, published between 1990 and 2013, were included. Risk of bias within studies was assessed using CONSORT and STROBE guidelines. The origin, design, sample, measure of MC, measure of the HRPF, main results and statistics of the studies were analyzed and a narrative synthesis was conducted. RESULTS: Forty-four studies matched all criteria; 16 were classified as low risk of bias and 28 as medium risk. There is strong scientific evidence supporting an inverse association between MC and body weight status (27 out of 33 studies) and a positive association between MC and cardiorespiratory fitness (12 out of 12 studies) and musculoskeletal fitness (7 out of 11 studies). The relationship between MC and flexibility was uncertain. CONCLUSIONS: Considering the noted associations between various assessments of MC and with multiple aspects of HRPF, the development of MC in childhood may both directly and indirectly augment HRPF and may serve to enhance the development of long-term health outcomes in children and adolescents. PMID- 25554656 TI - [Immunisation schedule of the Spanish Association of Paediatrics: 2015 recommendations]. AB - The Advisory Committee on Vaccines of the Spanish Association of Paediatrics updates the immunisation schedule every year, taking into account epidemiological data as well as evidence on the safety, effectiveness and efficiency of current vaccines, including levels of recommendation. In our opinion, this is the optimal vaccination calendar for all children resident in Spain. Regarding the vaccines included in the official unified immunization schedule, the Committee emphasizes the administration of the first dose of hepatitis B either at birth or at 2 months of life; the recommendation of the first dose of MMR and varicella vaccine at the age of 12 months, with the second dose at the age of 2-3 years; DTaP or Tdap vaccine at the age of 6 years, followed by another Tdap booster dose at 11 12 years old; Tdap strategies for pregnant women and household contacts of the newborn, and immunization against human papillomavirus in girls aged 11-12 years old with a 2 dose scheme (0, 6 months). The Committee reasserts its recommendation to include vaccination against pneumococcal disease in the routine immunisation schedule, the same as it is being conducted in Western European countries. The recently authorised meningococcal B vaccine, currently blocked in Spain, exhibits the profile of a universal vaccine. The Committe insists on the need of having the vaccine available in communitary pharmacies. It has also proposed the free availability of varicella vaccines. Their efectiveness and safety have been confirmed when they are administred from the second year of life. Vaccination against rotavirus is recommended in all infants. The Committee stresses the need to vaccinate population groups considered at risk against influenza and hepatitis A. PMID- 25554661 TI - [Metastatic cervical fasciitis revealing invasive lobular breast carcinoma]. AB - BACKGROUND: We describe the case of a 71-year-old woman presenting cervical metastatic fasciitis with invasive lobular carcinoma (ILC) of the breast. PATIENTS AND METHODS: The patient consulted for a deep and painless skin infiltration of the neck associated with dysphagia and restricted cervical mobility. Skin and muscle biopsies were normal. Muscle fascia biopsy showed a linear infiltration of metastatic cells in "single file", revealing ILC of the right breast. DISCUSSION: ILCs have a particular metastatic pattern. They can permeate through tissue planes, infiltrate solid organs and spread on serous membranes in an insidious fashion. CONCLUSION: Our case shows that ILC can metastasise into muscular fascia, causing "fasciitis-like" symptoms. Dermatologists should be aware of this particular pattern of dissemination. PMID- 25554662 TI - [Allgrove syndrome]. AB - BACKGROUND: Allgrove syndrome or "Triple A syndrome" involves adrenal insufficiency as a result of resistance to adrenocorticotropic hormone (ACTH), achalasia and alacrima, often associated with neurological signs. Herein, we report a new case of this rare genetic disease, which is of interest because of its dermatological mode of discovery. PATIENTS AND METHODS: A 4-year-old child, born to parents related by first-degree consanguinity, presented oral hyperpigmentation and diffused acquired melanoderma, as well as long-standing dry eye syndrome. Laboratory tests confirmed low adrenal insufficiency. The combination of alacrima and adrenal insufficiency prompted screening for Allgrove syndrome, which was confirmed by genetic analysis showing homozygous c.1331+1G>A mutation within intron 14 of the gene encoding for ALADIN protein. Both parents were heterozygous for the same mutation. Two years later, the onset of vomiting raised concerns about achalasia, which was confirmed by oesophageal manometry. The child received symptomatic treatment consisting of supplementary hydrocortisone and oesophageal dilatation. DISCUSSION: The present case serves as a reminder that Allgrove syndrome may be diagnosed by dermatologists. Therapy is cross-disciplinary, being based upon medical treatment for adrenal insufficiency with prescription of artificial tears in the event of alacrima. Achalasia is treated by oesophageal dilatation or by surgery. PMID- 25554663 TI - [Pemetrexed-induced scleroderma-like changes in the lower legs]. AB - BACKGROUND: Pemetrexed (Alimta((r))) is a new-generation antifolate used to treat malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). We report two cases of a new toxicity induced by pemetrexed: scleroderma-like induration of the lower extremities. PATIENTS AND METHODS: The first case concerned a 66-year old man diagnosed with pulmonary adenocarcinoma metastatic from the outset and in whom maintenance treatment comprised pemetrexed after first-line therapy comprising six courses of cisplatin-pemetrexed. After the fourth cycle of pemetrexed, he presented an erythematous oedema of the left leg, which was subsequently bilateral. Clinically, there was painful cellulitis associated with areas of bruising. The lesions had an appearance of erysipeloid-like infection, and there was no fever. The second case concerned a 70-year-old woman diagnosed with metastatic NSCLC. From the first course of pemetrexed, given as maintenance therapy, she presented erythematous oedema of both legs, without fever. After the second course, we observed the recurrence of the lesions consisting of erythemato violaceous plaques on both legs, with severe bilateral indurated and painful oedema, associated with major functional disability. A diagnosis of bilateral erysipelas was made, and antibiotic treatment with cloxacillin was given. In both cases, pemetrexed was discontinued and the local outcome was very slowly favourable, with persistence of scleroderma. DISCUSSION: This cutaneous adverse effect is unrecognized, resulting in delayed diagnosis. It is often initially confused with bilateral erysipelas, despite absence of fever. According to some studies, the severity of the cutaneous toxicity may be connected with patients' folate status. Thus folate and vitamin B12 supplementation combined with dexamethasone could decrease the incidence of this side effect. There was no recurrence and no worsening with taxanes, chemotherapy agents known to induce scleroderma. We feel that this cutaneous toxicity must be recognised on account of its potential severity. PMID- 25554664 TI - [Extranodal NK/T-cell lymphoma, nasal-type, revealed by cutaneous breast involvement]. AB - BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTL) is a rare form of non-Hodgkin's lymphoma and carries a poor prognosis. Depending on the primary sites of anatomical involvement, it is subcategorized into nasal or extra-nasal ENKTL. Cutaneous involvement is the second localization reported for these lymphomas. PATIENTS AND METHODS: A woman was admitted for erythematous infiltrative patches on the breasts having an ulcerative course. Cutaneous histopathology showed a dense, diffuse infiltrate of atypical lymphocytes. Immunohistochemistry revealed expression of specific markers for NK-cells and of cytotoxic molecules (TIA-1, granzyme B and perforin), lack of expression of T-cell markers (except positivity of cytoplasmic CD3 and CD2), and the presence of EBV-DNA in lymphoma cells. Positron emission tomography-computed tomography revealed sub- and supra diaphragmatic multi-organ involvement (kidneys, breasts, stomach, duodenum, lungs, pleural cavity, uterus, bones). No bone marrow infiltration was noted. PCR (polymerase chain reaction) showed high circulating levels of EBV-DNA in peripheral blood. A systemic nasal-type ENKTL was diagnosed. A chemotherapy regimen including high-dose methotrexate, oxaliplatin, gemcitabine, L asparaginase and dexamethasone was started. Despite good initial therapeutic response, the outcome was rapidly fatal with bone marrow involvement and multi organ failure. DISCUSSION: Major cutaneous manifestations of ENKTL comprise erythematous infiltrative patches mimicking panniculitis or cellulitis and evolving towards ulceration or necrosis. Subcutaneous nodules may also be noted. Late diagnosis at an advanced stage accounts for the poorer prognosis in extra nasal ENKTL. In the advanced stages, treatment is based on a chemotherapy regimen including L-asparaginase, possibly followed by autologous or allogeneic hematopoietic stem cell transplantation. PMID- 25554665 TI - [Adult kwashiorkor: a rare complication of bariatric surgery]. AB - INTRODUCTION: Kwashiorkor is a clinical manifestation of global protein-calorie malnutrition that is described mainly in children in developing countries initially presenting eczema-like skin disease associated with hydrops. OBSERVATION: We report the case of a 44-year-old woman with dark skin who had undergone bariatric surgery for treatment of stage-III obesity without regular monitoring and who was hospitalized in our dermatology department four years later. She had diffuse oedema and asteatotic eczema-like cutaneous lesions on pigmented skin that had developed for two months despite daily application of topical corticosteroids. Clinical signs, the collapse of serum albumin and histopathological analysis of skin tissue were evocative of kwashiorkor. Her symptoms subsided after several weeks of a nutritional programme. DISCUSSION: Kwashiorkor is a clinical entity described chiefly in children in developing countries. Cutaneous involvement comprising asteatotic eczema-like skin associated with diffuse oedema is prominent. Treatment with protein supplementation alone is effective and avoids many complications such as infections and haemodynamic disorders. Obesity is a serious and common disease in Western countries affecting one third of the world's population, and for which treatment with bariatric surgery may be indicated. Without regular monitoring, this surgery can cause severe protein deficiency. Consequently, in the future there will seemingly be a greater likelihood of kwashiorkor in adults as an iatrogenic complication of obesity treatment. Its semiology needs to be underlined because of the simplicity and efficacy of treatment. PMID- 25554666 TI - Depression and its association with functional status and physical activity in the elderly in Karachi, Pakistan. AB - OBJECTIVE: The aim of the study was to determine the functional status and level of physical activity and their association with depression in the elderly population (age 60 and above) in Karachi, Pakistan. METHODS: This was a cross sectional study. Subjects were recruited through multi-stage cluster sampling technique. Questionnaire-based interviews were conducted from July to September 2008. Functional status and physical activity were assessed using activities of daily living (ADL) and physical activity questionnaires, respectively. Depression was evaluated using the 15-item geriatric depression scale (GDS). RESULTS: Both mean ADL score (9.9+/-0.2 vs. 9.6+/-0.2) as well as time spent in physical activity/week (377.3+/-26.9min vs. 251.7+/-15.4min) was higher in men than women, respectively. Subjects spending more than 310min (>5.2h) per week in physical activity were 60% less likely to be depressed compared to those who spent less than 120min (<2h) per week (Adjusted OR=0.4, 95% CI=0.2-0.7). A one unit increase in ADL score showed a 10% decrease in depression after adjusting for other variables (Adjusted OR=0.9, 95% CI=0.8-0.9). CONCLUSIONS: We found a strong association between depression and time spent in physical activities as well as activities of daily living. Our results indicate the potentially important positive role of higher functional status and physical activity in prevention of depression in the elderly in Karachi. PMID- 25554668 TI - Hepatic perivascular epithelioid cell tumor: five case reports and literature review. AB - Perivascular epithelioid cell tumor (PEComa) is a rare tumor. Here, we present data regarding clinical presentations, diagnoses, management, and prognosis of five cases of hepatic PEComa between January 2002 and December 2008. Ultrasonography showed hyperechoic masses in all patients. Precontrast computed tomography (CT) showed that all lesions scanned were heterogeneous in density and were heterogeneously enhanced in arterial phase images. In two cases, magnetic resonance imaging showed hypointensity on T1-weighted images and hyperintensity on T2-weighted images. In enhanced scanning, lesions showed asymmetrical enhancement during arterial phase imaging. All tumors were composed of varying proportions of smooth muscle, adipose tissue, and thick-walled blood vessels, and showed positive immunohistochemical staining for Human Melanoma Black-45. All patients underwent hepatectomy, and there was no evidence of recurrence or metastasis during the follow-up period. PMID- 25554667 TI - Cutaneous alternariosis in a renal transplant recipient: a case report and literature review. AB - Organ transplant recipients under immunosuppressive therapy have a highly increased risk of acquiring unusual opportunistic infections. Diagnosis of the etiology of infection may be difficult in clinical manifestations, which need further histological and biological investigations. We recently treated a male renal transplant recipient with a cutaneous phaeohyphomycosis due to Alternaria species. The diagnosis was based on microscopy and culture of the skin lesions. Treatment with oral itraconazole for 5 weeks was ineffective, then clinical improvement was achieved by combination of amphotericin B wet-packing and systemic antifungal therapy with oral voriconazole. Alternaria species are ubiquitous plant-inhabiting saprobes, which are increasingly associated with opportunistic phaeohyphomycosis in immunocompromised individuals. To the best of our knowledge, this is the second case report noting sporotrichoid pattern as the manifestation of cutaneous alternariosis. In this context, we reviewed recent renal-transplant-related cutaneous alternariosis reported in the English-language literature during 1995 to 2011 to summarize its clinical features and outcomes, and to guide clinicians in the care of kidney transplant patients with cutaneous alternariosis. PMID- 25554669 TI - Draft genome sequence of a marine actinobacteria Sciscionella strain SE31. AB - The bacterium strain SE31, a member of the genus Sciscionella, was isolated from intertidal sediments collected from Cape Rachado, Malaysia. The high quality draft genome sequence of Sciscionella strain SE31 with a genome size of approximately 7.4 Mbp is reported. Preliminary analysis revealed 46 putative gene clusters involved in the biosynthesis of secondary metabolites and 113 putative genes that are associated with bacterial virulence, disease and defense. Availability of the genome sequence of Sciscionella SE31 will contribute to a better understanding of the genus Sciscionella. PMID- 25554670 TI - [Phthalate exposure in the neonatal intensive care unit]. AB - There are growing concerns on long-term health consequences, notably on fertility rates, of plasticizers such as phthalates. While di(2-ethylhexyl)phthalate (DEHP) is currently used in several medical devices, newborns in the neonatal intensive care unit are both more exposed and more vulnerable to DEHP. The objectives of this study were to identify, count, and describe possible sources of DEHP in a neonatal care unit. Our method consisted in the listing and the inspection of the information on packaging, complemented by contact with manufacturers when necessary. According to the results, 6% of all products and 10% of plastic products contained some DEHP; 71% of these involved respiratory support devices. A vast majority of the items showed no information on the content of DEHP. Further research is needed, particularly to determine the effects of such an early exposure and to study and develop safer alternatives. PMID- 25554671 TI - [Is prophylaxis against ophthalmia neonatorum justified in French maternity wards?]. PMID- 25554672 TI - [Very preterm births in French Polynesia: update and proposal for follow-up]. AB - INTRODUCTION: The care of premature infants in French Polynesia is complicated by this country's geographic isolation. We undertook an evaluation of the medical care of very premature infants (VPIs) to find local solutions to this problem. OBJECTIVES: The objectives were to determine the incidence, mortality, and the short- and long-term outcome of very preterm infants in French Polynesia. METHODS: We retrospectively reviewed the medical charts of all infants born alive at<32 gestational age (GA) and>24 GA from January 2007 to December 2011. Perinatal characteristics and outcomes were examined by univariate and multivariate analysis. RESULTS: In total, 204 VPIs were born during the 5-year study period, comprising 0.9% of all births. Infants less than 28 GA comprised 0.1% of all births. Sixty-two percent of mothers were of extreme age including 43% less than 25 years old. Prematurity was attributed to spontaneous preterm labor in 63% of cases and preeclampsia in 29%. Spontaneous multiple pregnancies comprised 15% of the cases. Alcohol and tobacco consumption were frequently noted (>8% and 26% mothers, respectively). Seventy-eight percent of VPIs had received prenatal steroids. Intrauterine growth was normal in 89%. Mortality occurred in 9.3% (19 patients). Mortality was higher with lower gestational age (P<0.05) and absence of prenatal steroids (P<0.05) in univariate and multivariate analysis. The primary cause of death was sepsis. Hyaline membrane disease occurred in 44% of patients, 80% of whom received surfactant therapy. In total, 16.2% newborns developed bronchodysplasia, 3.4% necrotizing enterocolitis, 3% cerebral hemorrhage, and 1.5% leukomalacia. Long-term outcome was marked by 52% of the patients lost to follow-up by 2 years of age, mostly because of geographic isolation. For the 72 patients followed-up, four developed asthma and three cerebral palsy; 70% were attending school by 3 years of age. CONCLUSIONS: The incidence, mortality, and morbidity of very preterm birth in French Polynesia are comparable to reports from metropolitan centers in France. Conversely, nearly one half of the patients were lost to follow-up, precluding meaningful information on intellectual development and other outcomes. We recommend organizing a long-term follow-up network to detect cognitive sequelae and adapting such a system to the geographical residence of French Polynesian families. PMID- 25554673 TI - Appreciation: Judy Johnson. PMID- 25554674 TI - Status of obstetric anesthesiology fellowship research education in the USA and Canada: a 2013 survey of fellowship program directors. PMID- 25554680 TI - Peritonectomy and hyperthermic intraperitoneal chemotherapy: cost analysis and sustainability. AB - BACKGROUND: Malignancies of the peritoneum remain a challenge in any hospital that accepts to manage them, due not only to difficulties associated with the complexity of the procedures involved but also the costs, which - in Italy and other countries that use a diagnosis-related group (DRG) system - are not adequately reimbursed. MATERIAL AND METHODS: We analyzed data relative to 24 patients operated on between September 2010 and May 2013 with special regard to operating room expenditure, ICU stay, duration of hospitalization, and DRG reimbursement. The total costs per patient included clinical, operating room, procedure, pathology, imaging, ward care, allied healthcare, pharmaceutical, and ICU costs. RESULTS: Postoperative hospital stay, drugs and materials, and operating room occupancy were the main factors affecting the expenditure for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. We had a median hospitalization of 14 days, median ICU stay of 2.4 days, and median operating room occupancy of 585 min. The median expenditure for each case was ? 21,744; the median reimbursement by the national health system ? 8,375. CONCLUSIONS: In a DRG reimbursement system, the economic effort in the management of patients undergoing peritonectomy procedures may not be counterbalanced by adequate reimbursement. Joint efforts between medical and administration parties are mandatory to develop appropriate treatment protocols and keep down the costs. PMID- 25554679 TI - Translating the MAM model of psychosis to humans. AB - Elevated dopamine function and alterations in medial temporal lobe (MTL) structure and function are two of the most robust findings in schizophrenia, but how interactions between these abnormalities underlie the onset of psychosis is unclear. The methylazoxymethanol acetate (MAM) rodent model proposes that psychosis develops as a result of a perturbation of MTL function, leading to elevated striatal dopamine dysfunction. Here, we review several recent neuroimaging studies that examine components of the putative model in humans with an ultra high risk (UHR) of the psychosis. While data from these studies are broadly consistent with the MAM model, caution is required when comparing data across animal and human studies. PMID- 25554681 TI - MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. AB - Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54 or 162 MUg/mouse of a small, curled (CNT(Small), 0.8 +/- 0.1 MUm in length) or large, thick MWCNT (CNT(Large), 4 +/- 0.4 MUm in length). The two MWCNTs were extensively characterized by SEM and TEM imaging, thermogravimetric analysis, and Brunauer-Emmett-Teller surface area analysis. Lung tissues were harvested 24h, 3 days and 28 days post-exposure. DNA microarrays were used to analyze gene expression, in parallel with analysis of bronchoalveolar lavage fluid, lung histology, DNA damage (comet assay) and the presence of reactive oxygen species (dichlorodihydrofluorescein assay), to profile and characterize related pulmonary endpoints. Overall changes in global transcription following exposure to CNT(Small) or CNT(Large) were similar. Both MWCNTs elicited strong acute phase and inflammatory responses that peaked at day 3, persisted up to 28 days, and were characterized by increased cellular influx in bronchoalveolar lavage fluid, interstitial pneumonia and gene expression changes. However, CNT(Large) elicited an earlier onset of inflammation and DNA damage, and induced more fibrosis and a unique fibrotic gene expression signature at day 28, compared to CNT(Small). The results indicate that the extent of change at the molecular level during early response phases following an acute exposure is greater in mice exposed to CNT(Large), which may eventually lead to the different responses observed at day 28. PMID- 25554682 TI - Loss of MXD3 induces apoptosis of Reh human precursor B acute lymphoblastic leukemia cells. AB - MXD3 is a transcription factor that plays an important role in proliferation of human DAOY medulloblastoma cells. Here, we demonstrate that MXD3 is highly enriched in human precursor B acute lymphoblastic leukemia (preB ALL) samples compared to mobilized peripheral blood mononuclear cells, bone marrow, or hematopoietic stem cells from healthy donors. MXD3 knock-down in the preB ALL cell line Reh resulted in decreased cell numbers with no change in G0/G1, S or G2/M populations but increased apoptosis compared to control cells. Our results suggest that MXD3 is important for survival of Reh preB ALL cells, possibly as an anti-apoptotic factor. PMID- 25554683 TI - Visual grids for managing data completeness in clinical research datasets. AB - Missing data arise in clinical research datasets for reasons ranging from incomplete electronic health records to incorrect trial data collection. This has an adverse effect on analysis performed with the data, but it can also affect the management of a clinical trial itself. We propose two graphical visualization schemes to aid in managing the completeness of a clinical research dataset: the binary completeness grid (BCG) for single patient observation, and the gradient completeness grid (GCG) for an entire dataset. We use these tools to manage three clinical trials. Two are ongoing observational trials, while the other is a cohort study that is complete. The completeness grids revealed unexpected patterns in our data and enabled us to identify records that should have been purged and identify missing follow-up data from sets of observations thought to be complete. Binary and gradient completeness grids provide a rapid, convenient way to visualize missing data in clinical datasets. PMID- 25554684 TI - Link-topic model for biomedical abbreviation disambiguation. AB - INTRODUCTION: The ambiguity of biomedical abbreviations is one of the challenges in biomedical text mining systems. In particular, the handling of term variants and abbreviations without nearby definitions is a critical issue. In this study, we adopt the concepts of topic of document and word link to disambiguate biomedical abbreviations. METHODS: We newly suggest the link topic model inspired by the latent Dirichlet allocation model, in which each document is perceived as a random mixture of topics, where each topic is characterized by a distribution over words. Thus, the most probable expansions with respect to abbreviations of a given abstract are determined by word-topic, document-topic, and word-link distributions estimated from a document collection through the link topic model. The model allows two distinct modes of word generation to incorporate semantic dependencies among words, particularly long form words of abbreviations and their sentential co-occurring words; a word can be generated either dependently on the long form of the abbreviation or independently. The semantic dependency between two words is defined as a link and a new random parameter for the link is assigned to each word as well as a topic parameter. Because the link status indicates whether the word constitutes a link with a given specific long form, it has the effect of determining whether a word forms a unigram or a skipping/consecutive bigram with respect to the long form. Furthermore, we place a constraint on the model so that a word has the same topic as a specific long form if it is generated in reference to the long form. Consequently, documents are generated from the two hidden parameters, i.e. topic and link, and the most probable expansion of a specific abbreviation is estimated from the parameters. RESULTS: Our model relaxes the bag-of-words assumption of the standard topic model in which the word order is neglected, and it captures a richer structure of text than does the standard topic model by considering unigrams and semantically associated bigrams simultaneously. The addition of semantic links improves the disambiguation accuracy without removing irrelevant contextual words and reduces the parameter space of massive skipping or consecutive bigrams. The link topic model achieves 98.42% disambiguation accuracy on 73,505 MEDLINE abstracts with respect to 21 three letter abbreviations and their 139 distinct long forms. PMID- 25554685 TI - Mapping patient path in the Pediatric Emergency Department: A workflow model driven approach. AB - The workflow models of the patient journey in a Pediatric Emergency Department (PED) seems to be an effective approach to develop an accurate and complete representation of the PED processes. This model can drive the collection of comprehensive quantitative and qualitative service delivery and patient treatment data as an evidence base for the PED service planning. Our objective in this study is to identify crowded situation indicators and bottlenecks that contribute to over-crowding. The greatest source of delay in patient flow is the waiting time from the health care request, and especially the bed request to exit from the PED for hospital admission. It represented 70% of the time that these patients occupied in the PED waiting rooms. The use of real data to construct the workflow model of the patient path is effective in identifying sources of delay in patient flow, and aspects of the PED activity that could be improved. The development of this model was based on accurate visits made in the PED of the Regional University Hospital Center (CHRU) of Lille (France). This modeling, which has to represent most faithfully possible the reality of the PED of CHRU of Lille, is necessary. It must be detailed enough to produce an analysis allowing to identify the dysfunctions of the PED and also to propose and to estimate prevention indicators of crowded situations. Our survey is integrated into the French National Research Agency (ANR) project, titled: "Hospital: Optimization, Simulation and avoidance of strain" (HOST). PMID- 25554687 TI - Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity. AB - Friedreich's ataxia (FA) is a recessive, predominantly neurodegenerative disorder caused in most cases by mutations in the first intron of the frataxin (FXN) gene. This mutation drives the expansion of a homozygous GAA repeat that results in decreased levels of FXN transcription and frataxin protein. Frataxin (Fxn) is a ubiquitous mitochondrial protein involved in iron-sulfur cluster biogenesis, and a decrease in the levels of this protein is responsible for the symptoms observed in the disease. Although the pathological manifestations of FA are mainly observed in neurons of both the central and peripheral nervous system, it is not clear if changes in non-neuronal cells may also contribute to the pathogenesis of FA, as recently suggested for other neurodegenerative disorders. Therefore, the aims of this study were to generate and characterize a cell model of Fxn deficiency in human astrocytes (HAs) and to evaluate the possible involvement of non-cell autonomous processes in FA. To knockdown frataxin in vitro, we transduced HAs with a specific shRNA lentivirus (shRNA37), which produced a decrease in both frataxin mRNA and protein expression, along with mitochondrial superoxide production, and signs of p53-mediated cell cycle arrest and apoptotic cell death. To test for non-cell autonomous interactions we cultured wild-type mouse neurons in the presence of frataxin-deficient astrocyte conditioned medium, which provoked a delay in the maturation of these neurons, a decrease in neurite length and enhanced cell death. Our findings confirm a detrimental effect of frataxin silencing, not only for astrocytes, but also for neuron-glia interactions, underlining the need to take into account the role of non-cell autonomous processes in FA. PMID- 25554686 TI - Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations. AB - Germline mutations in the PTEN tumor-suppressor gene cause autosomal-dominant conditions such as Cowden and Bannayan-Riley-Ruvalcaba syndromes with variable presentations, including hamartomatous gastrointestinal tumors, dermatologic abnormalities, neurologic symptoms, and elevated cancer risk. We describe a father and son with extensive hamartomatous gastrointestinal polyposis who both developed early-onset esophageal cancer. Exome sequencing identified a novel germline PTEN frameshift mutation (c.568_569insC, p.V191Sfs*11). In addition, a missense mutation of SMAD7 (c.115G>A, p.G39R) with an allele frequency of 0.3% in the Exome Variant Server was detected in both affected individuals. Fluorescence in situ hybridization for PTEN in the resected esophageal cancer specimen demonstrated no PTEN copy loss in malignant cells; however, results of an immunohistochemical analysis demonstrated a loss of PTEN protein expression. While the risks of many cancers are elevated in the PTEN hamartoma tumor syndromes, association between esophageal adenocarcinoma and these syndromes has not been previously reported. Esophageal adenocarcinoma and extensive polyposis/ganglioneuromatosis could represent less common features of these syndromes, potentially correlating with this novel PTEN frameshift and early protein termination genotype. Alternatively, because simultaneous disruption of both the PTEN and TGF-beta/SMAD4 pathways is associated with development of esophageal cancer in a mouse model and because SMAD4 mutations cause gastrointestinal hamartomas in juvenile polyposis syndrome, the SMAD7 mutation may represent an additional modifier of these individuals' PTEN-mutant phenotype. PMID- 25554695 TI - Proteome screening of pleural effusions identifies IL1A as a diagnostic biomarker for non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is a common malignant disease, and in ~10-20% of patients, pleural effusion is the first symptom. The pleural effusion proteome contains information on pulmonary disease that directly or indirectly reflects pathophysiological status. However, the proteome of pleural effusion in NSCLC patients is not well understood, nor is the variability in protein composition between malignant and benign pleural effusions. Here, we investigated the different proteins in pleural effusions from NSCLC and tuberculosis (TB) patients by using nano-scale liquid chromatography-tandem mass spectrometry (nLC-MS/MS) analysis. In total, 363 proteins were identified in the NSCLC pleural effusion proteome with a low false discovery rate (<1%), and 199 proteins were unique to NSCLC. The proteins in the NSCLC patients' pleural effusion were involved in cell adhesion, proteolysis, and cell migration. Furthermore, interleukin 1 alpha (IL1A), a protein that regulates tumor growth, angiogenesis, and metastasis, was significantly more abundant in the NSCLC group compared to the TB group, a finding that was validated with an ELISA assay. PMID- 25554688 TI - Genetic deletion of neuronal pentraxin 1 expression prevents brain injury in a neonatal mouse model of cerebral hypoxia-ischemia. AB - Neonatal hypoxic-ischemic (HI) brain injury is a leading cause of mortality and morbidity in infants and children for which there is no promising therapy at present. Previously, we reported induction of neuronal pentraxin 1 (NP1), a novel neuronal protein of the long-pentraxin family, following HI injury in neonatal brain. Here, we report that genetic deletion of NP1 expression prevents HI injury in neonatal brain. Elevated expression of NP1 was observed in neurons, not in astrocytes, of the ipsilateral cortical layers (I-IV) and in the hippocampal CA1 and CA3 areas of WT brains following hypoxia-ischemia; brain areas that developed infarcts (at 24-48 h), showed significantly increased numbers of TUNEL-(+) cells and tissue loss (at 7 days). In contrast, NP1-KO mice showed no evidence of brain infarction and tissue loss after HI. The immunofluorescence staining of brain sections with mitochondrial protein COX IV and subcellular fractionation analysis showed increased accumulation of NP1 in mitochondria, pro-death protein Bax activation and NP1 co-localization with activated caspase-3 in WT, but not in the NP1-KO brains; corroborating NP1 interactions with the mitochondria-derived pro death pathways. Disruption of NP1 translocation to mitochondria by NP1-siRNA in primary cortical cultures significantly reduced ischemic neuronal death. NP1 was immunoprecipitated with activated Bax [6A7] proteins; HI caused increased interactions of NP1 with Bax, thereby, facilitating Bax translocation to mitochondrial and neuronal death. To further delineate the specificity of NPs, we found that NP1 but not the NP2 induction is specifically involved in brain injury mechanisms and that knockdown of NP1 only results in neuroprotection. Furthermore, live in vivo T2-weighted magnetic resonance imaging (MRI) including fractional anisotropy (FA) mapping showed no sign of delayed brain injury or tissue loss in the NP1-KO mice as compared to the WT at different post-HI periods (4-24 weeks) examined; indicating a long-term neuroprotective efficacy of NP1 gene deletion. Collectively, our results demonstrate a novel mechanism of neuronal death and predict that inhibition of NP1 expression is a promising strategy to prevent hypoxic-ischemic injury in immature brain. PMID- 25554698 TI - [Tourism as a healthy and active ageing strategy: The effects of tourism on the health of the elederly]. PMID- 25554696 TI - Three-dimensional quantification and visualization of aortic calcification by multidetector-row computed tomography: a simple approach using a volume-rendering method. AB - OBJECTIVE: Three-dimensional (3-D) visualization and quantification of vascular calcification (VC) are important to accelerate the multidisciplinary investigation of VC. Agatston scoring is the standard approach for evaluating coronary artery calcification. However, regarding aortic calcification (AC), quantification methods appear to vary among studies. The aim of this study was to introduce a simple technique of simultaneous quantification and 3-D visualization of AC and provide validation data. METHODS: The main study comprised of 126 patients who underwent the thoracoabdominal plain computed tomography scan as preoperative general evaluation. AC was quantified using a volume-rendering (VR) method (VR AC volume) by extracting the volume with a density >=130 HU within the total aorta. The concordance and reproducibility of the VR AC volume were validated in comparison with the conventional slice-by-slice voxel-based AC quantification (volumetric AC score) using the Agatston scoring software. RESULTS: Excellent concordance between the VR AC volume and volumetric AC score was confirmed (Spearman correlation coefficient = 0.9997, mean difference = -0.05 +/- 0.23 mL, p <0.0001). Excellent intraobserver and interobserver reliabilities were demonstrated using the Bland-Altman analysis as the mean intraobserver difference was 0.00 mL (p = 0.9863) and the mean interobserver difference was 0.01 mL (p = 0.6612). CONCLUSION: The VR method was validated to be feasible. This simple approach could overcome the limitation of the current method based on slice-by-slice pixel or voxel summation, which lacks 3-D visual information. Accordingly, this approach would be promising for accelerating the investigation of VC. PMID- 25554697 TI - [Doctor, sometimes I hear clicks in the medical consultations! Mouseitis]. PMID- 25554699 TI - Evaluating midwife-led antenatal care: choice, experience, effectiveness, and preparation for pregnancy. AB - OBJECTIVE: to evaluate midwife-led care (MLC) antenatal care compared with antenatal care provided in traditional obstetric-led hospital antenatal clinics (usual care). DESIGN: a mixed methods approach involving a chart audit, postal survey, focus group and in-depth interviews. SETTING: data were collected at a large maternity hospital and satellite clinics in Dublin from women attending for antenatal care between June 2011 and May 2012. PARTICIPANTS: 300 women with low risk pregnancy who attended midwife-led antenatal care or usual clinics during the study period were randomly selected to participate. MEASUREMENTS: data were collected from 292 women's charts and from 186 survey participants (63% response rate). Nine women participated in in-depth interviews and a focus group. FINDINGS: MLC was as effective as usual care in relation to number of antenatal visits and ultrasound scans, referral to other clinicians, women's health in pregnancy, gestation at childbirth, and birth weight. Women attending MLC booked significantly earlier, fewer women attending MLC were admitted to hospital antenatally and more women breast fed their infant. Women attending MLC reported better choice and that shorter waiting times and having more time for discussion were important reasons for choosing MLC. Women attending MLC reported a better experience overall, and recorded better outcomes in relation to how they were treated, along with easier access to antenatal care and shorter waiting times to see a midwife. Although women attending MLC clinics reported higher satisfaction with the information that they received, they also identified that antenatal education could be improved in relation to labour, breast-feeding, depression and emotional well-being, and caring for the infant. KEY CONCLUSIONS: midwife-led antenatal care was as effective as usual care for women with low-risk pregnancy and better in relation to choice, breast feeding and women's experience of care. PMID- 25554700 TI - Calcium signaling mediates antifungal activity of triazole drugs in the Aspergilli. AB - Azoles are widely applied and largely effective as antifungals; however, the increasing prevalence of clinically resistant isolates has yet to be matched by approaches to improve the efficacy of antimicrobial therapy. In this study, using the model fungus Aspergillus nidulans and one of the most common human pathogen Aspergillus fumigatus as research materials, we present the evidence that calcium signaling is involved in the azole-antifungals-induced stress-response reactions. In normal media, antifungal-itraconazole (ITZ) is able to induce the [Ca(2+)]c increased sharply but the addition of calcium chelator-EGTA or BAPTA almost blocks the calcium influx responses, resulted in the dramatically decreasing of [Ca(2+)]c transient. Real-time PCR analysis verified that six-tested Ca(2+) inducible genes-two calcium channels (cchA/midA), a calmodulin-dependent phosphatase-calcineurin (cnaA), a transcription factor-crzA, and two calcium transporters (pmrA/pmcA)-could be transiently up-regulated by adding ITZ, indicating these components are involved in the azole stress-response reaction. Defect of cnaA or crzA caused more susceptibility to azole antifungals than did single mutants or double deletions of midA and cchA. Notably, EGTA may influence Rh123 accumulation as an azole-mimicking substrate through the process of the drug absorption. In vivo studies of a Galleria mellonella model identified that the calcium chelator works as an adjunct antifungal agent with azoles for invasive aspergillosis. Most importantly, combination of ITZ and EGTA or ITZ with calcium signaling inhibitor-FK506 greatly enhances the ITZ efficacy. Thus, our study provides potential clues that specific inhibitors of calcium signaling could be clinically useful adjuncts to conventional azole antifungals in the Aspergilli. PMID- 25554702 TI - MERIS (Medical Error Reporting Information System) as an innovative patient safety intervention: a health policy perspective. AB - The economic crisis in Greece poses the necessity to resolve problems concerning both the spiralling cost and the quality assurance in the health system. The detection and the analysis of patient adverse events and medical errors are considered crucial elements of this course. The implementation of MERIS embodies a mandatory module, which adopts the trigger tool methodology for measuring adverse events and medical errors an intensive care unit [ICU] environment, and a voluntary one with web-based public reporting methodology. A pilot implementation of MERIS running in a public hospital identified 35 adverse events, with approx. 12 additional hospital days and an extra healthcare cost of ?12,000 per adverse event or of about ?312,000 per annum for ICU costs only. At the same time, the voluntary module unveiled 510 reports on adverse events submitted by citizens or patients. MERIS has been evaluated as a comprehensive and effective system; it succeeded in detecting the main factors that cause adverse events and discloses severe omissions of the Greek health system. MERIS may be incorporated and run efficiently nationally, adapted to the needs and peculiarities of each hospital or clinic. PMID- 25554703 TI - The utility of frozen section examination for determining the extent of thyroidectomy in patients with a thyroid nodule and "atypia/follicular lesion of undetermined significance". AB - BACKGROUND: The purpose of this study was to evaluate the role of frozen section examination (FSE) for determining the extent of thyroidectomy in patients with nodular thyroid disease and fine-needle aspiration categorized as atypia/follicular lesion of undetermined significance (AFLUS). METHODS: A retrospective review of all patients operated on for a thyroid nodule and AFLUS was completed to determine the role of clinical examination and FSE in intraoperative decision making. RESULTS: One hundred twenty patients with AFLUS underwent thyroidectomy; 18 (15%) had carcinoma. FSE altered management in 36 (62%) of the 58 patients-32 with benign disease and 4 with cancer who underwent lobectomy and total thyroidectomy, respectively. Total thyroidectomy without FSE was performed in 61 (51%) patients with sonographically confirmed bilateral disease. FSE had a 36.4% sensitivity, 100% specificity, 100% positive predictive value, 87% negative predictive value, and 88% accuracy. CONCLUSION: Ultrasound in combination with FSE is of value for determining the extent of thyroidectomy in patients with AFLUS. PMID- 25554701 TI - Leu1 plays a role in iron metabolism and is required for virulence in Cryptococcus neoformans. AB - Amino acid biosynthetic pathways that are absent in mammals are considered an attractive target for antifungal therapy. Leucine biosynthesis is one such target pathway, consisting of a five-step conversion process starting from the valine precursor 2-keto-isovalerate. Isopropylmalate dehydrogenase (Leu1) is an Fe-S cluster protein that is required for leucine biosynthesis in the model fungus Saccharomyces cerevisiae. The human pathogenic fungus Cryptococcus neoformans possesses an ortholog of S. cerevisiae Leu1, and our previous transcriptome data showed that the expression of LEU1 is regulated by iron availability. In this study, we characterized the role of Leu1 in iron homeostasis and the virulence of C. neoformans. We found that deletion of LEU1 caused leucine auxotrophy and that Leu1 may play a role in the mitochondrial-cytoplasmic Fe-S cluster balance. Whereas cytoplasmic Fe-S protein levels were not affected, mitochondrial Fe-S proteins were up-regulated in the leu1 mutant, suggesting that Leu1 mainly influences mitochondrial iron metabolism. The leu1 mutant also displayed increased sensitivity to oxidative stress and cell wall/membrane disrupting agents, which may have been caused by mitochondrial dysfunction. Furthermore, the leu1 mutant was deficient in capsule formation and showed attenuated virulence in a mouse inhalation model of cryptococcosis. Overall, our results indicate that Leu1 plays a role in iron metabolism and is required for virulence in C. neoformans. PMID- 25554704 TI - In tribute: Janet H. Carr. PMID- 25554705 TI - On "The American Physical Therapy Association's top five choosing wisely recommendations." White NT, Delitto A, Manal TJ, Miller S. Phys Ther. doi: 10.2522/ptj.20140287. PMID- 25554706 TI - Switching Schools: Reconsidering the Relationship Between School Mobility and High School Dropout. AB - Youth who switch schools are more likely to demonstrate a wide array of negative behavioral and educational outcomes, including dropping out of high school. However, whether switching schools actually puts youth at risk for dropout is uncertain, since youth who switch schools are similar to dropouts in their levels of prior school achievement and engagement, which suggests that switching schools may be part of the same long-term developmental process of disengagement that leads to dropping out. Using data from the National Longitudinal Survey of Youth 1997, this study uses propensity score matching to pair youth who switched high schools with similar youth who stayed in the same school. We find that while over half the association between switching schools and dropout is explained by observed characteristics prior to 9th grade, switching schools is still associated with dropout. Moreover, the relationship between switching schools and dropout varies depending on a youth's propensity for switching schools. PMID- 25554707 TI - Scent marking increases male reproductive success in wild house mice. AB - Scent marking is often assumed to be a secondary sexual trait that increases males' mating and reproductive success, although direct evidence for this hypothesis is lacking. We conducted a study with wild-derived house mice, Mus musculus musculus, to test whether scent marking increases males' reproductive success when females can freely choose between two territorial males. We also experimentally manipulated males' competitive scent marking by exchanging scent marked tiles between the neighbouring males' territories (intrusion treatment) or relocating males' tiles within their own territory (control). Experimental animals were tested twice and we examined whether individual males were consistent in their marking. We found that males marked more in the intrusion treatment than controls and more at shared territorial borders than elsewhere. We found high day-to-day variation in most individuals' scent marking, and yet the sum of individuals' scent marking was consistent over time and across different social conditions. Genetic paternity analyses revealed that males' scent marking significantly increased their reproductive success in both the intrusion treatment and the controls. Surprisingly, however, female social preference was not positively correlated with male scent marking. These results provide direct evidence that scent marking increases males' reproductive success when females can choose their mates, even though it did not increase females' social preferences. PMID- 25554709 TI - Controlled Reduction with Unactuated Cyclic Variables: Application to 3D Bipedal Walking with Passive Yaw Rotation. AB - This paper shows that viscous damping can shape momentum conservation laws in a manner that stabilizes yaw rotation and enables steering for underactuated 3D walking. We first show that unactuated cyclic variables can be controlled by passively shaped conservation laws given a stabilizing controller in the actuated coordinates. We then exploit this result to realize controlled geometric reduction with multiple unactuated cyclic variables. We apply this underactuated control strategy to a five-link 3D biped to produce exponentially stable straight ahead walking and steering in the presence of passive yawing. PMID- 25554710 TI - Highly Stable Amine Functionalized Iron Oxide Nanoparticles Designed for Magnetic Particle Imaging (MPI). AB - Magnetic particle imaging (MPI) is a promising medical imaging technology that uses iron oxide nanoparticles (NPs) as clinically safe tracers. The core and hydrodynamic size of these NPs determine the signal intensity and spatial resolution in MPI, whilst their monodispersity when preserved during the biomedical applications, generates a consistently high quality MPI image. Using an effective process to coat the synthesized NPs with amine terminated PEG molecules, we show by dynamic light scattering (DLS) that they are water-soluble with long-term stability in biological media such as phosphate buffered saline (PBS) and sodium bicarbonate buffers and Dulbecco's modified Eagle medium (DMEM) enriched with 10% fetal bovine serum (FBS). Further, using magnetic particle spectroscopy (MPS), to measure the particle response function (PRF), defined as the derivative of the magnetization of the nanoparticles, we predict the MPI performance of these nanoparticles at a driving field frequency of 25 kHz. The MPS efficacy of the functionalized nanoparticles was also monitored over time, and both signal intensity and resolution remained unchanged even after seven days of incubation. This is attributed to the dominant contribution of the Neel relaxation mechanism of the monodisperse and highly stable nanoparticles, which was preserved through the incubation period. PMID- 25554711 TI - The Distribution of the Product Explains Normal Theory Mediation Confidence Interval Estimation. AB - The distribution of the product has several useful applications. One of these applications is its use to form confidence intervals for the indirect effect as the product of 2 regression coefficients. The purpose of this article is to investigate how the moments of the distribution of the product explain normal theory mediation confidence interval coverage and imbalance. Values of the critical ratio for each random variable are used to demonstrate how the moments of the distribution of the product change across values of the critical ratio observed in research studies. Results of the simulation study showed that as skewness in absolute value increases, coverage decreases. And as skewness in absolute value and kurtosis increases, imbalance increases. The difference between testing the significance of the indirect effect using the normal theory versus the asymmetric distribution of the product is further illustrated with a real data example. This article is the first study to show the direct link between the distribution of the product and indirect effect confidence intervals and clarifies the results of previous simulation studies by showing why normal theory confidence intervals for indirect effects are often less accurate than those obtained from the asymmetric distribution of the product or from resampling methods. PMID- 25554708 TI - An Augmented Two-Layer Model Captures Nonlinear Analog Spatial Integration Effects in Pyramidal Neuron Dendrites. AB - In pursuit of the goal to understand and eventually reproduce the diverse functions of the brain, a key challenge lies in reverse engineering the peculiar biology-based "technology" that underlies the brain's remarkable ability to process and store information. The basic building block of the nervous system is the nerve cell, or "neuron," yet after more than 100 years of neurophysiological study and 60 years of modeling, the information processing functions of individual neurons, and the parameters that allow them to engage in so many different types of computation (sensory, motor, mnemonic, executive, etc.) remain poorly understood. In this paper, we review both historical and recent findings that have led to our current understanding of the analog spatial processing capabilities of dendrites, the major input structures of neurons, with a focus on the principal cell type of the neocortex and hippocampus, the pyramidal neuron (PN). We encapsulate our current understanding of PN dendritic integration in an abstract layered model whose spatially sensitive branch-subunits compute multidimensional sigmoidal functions. Unlike the 1-D sigmoids found in conventional neural network models, multidimensional sigmoids allow the cell to implement a rich spectrum of nonlinear modulation effects directly within their dendritic trees. PMID- 25554712 TI - New strategies for natural products containing chroman spiroketals. AB - Two cycloaddition strategies are described that lead to various chroman spiroketals from assorted exocyclic enol ethers. Unlike conventional thermodynamic ketalization strategies, the stereochemical outcome for this approach is determined by a kinetic cycloaddition reaction. Thus, the stereochemical outcome reflects the olefin geometry of the starting materials along with the orientation of the associated transition state. However, the initial kinetic product can also be equilibrated by acid catalysis and reconstituted into a thermodynamic stereochemical arrangement. Thus, these strategies uniquely enable synthetic access to either the thermodynamic or kinetic conformation of the spiroketal stereocenter itself. Applications of these strategies in the syntheses of berkelic acid, beta-rubromycin, and paecilospirone are presented along with the use of a chroman spiroketal for the construction of heliespirones A and C. PMID- 25554713 TI - What's So Special about STEM? A Comparison of Women's Retention in STEM and Professional Occupations. AB - We follow female college graduates in the National Longitudinal Survey of Youth 1979 and compare the trajectories of women in science, technology, engineering, and mathematics (STEM)-related occupations to other professional occupations. Results show that women in STEM occupations are significantly more likely to leave their occupational field than professional women, especially early in their career, while few women in either group leave jobs to exit the labor force. Family factors cannot account for the differential loss of STEM workers compared to other professional workers. Few differences in job characteristics emerge either, so these cannot account for the disproportionate loss of STEM workers. What does emerge is that investments and job rewards that generally stimulate field commitment, such as advanced training and high job satisfaction, fail to build commitment among women in STEM. PMID- 25554714 TI - SYNTHETICALLY USEFUL INTERMEDIATES BY DIAZOSULFONE AND SULFONATE C-H INSERTION. AB - Intramolecular C-H insertion on diazosulfone and diazosulfonate substrates was used to prepare synthetically useful intermediates from easily available starting materials. PMID- 25554715 TI - Optimal restricted estimation for more efficient longitudinal causal inference. AB - Efficient semiparametric estimation of longitudinal causal effects is often analytically or computationally intractable. We propose a novel restricted estimation approach for increasing efficiency, which can be used with other techniques, is straightforward to implement, and requires no additional modeling assumptions. PMID- 25554716 TI - Gender moderates the relationship between impulsivity and sexual risk-taking in a cocaine-using psychiatric outpatient population. AB - Adults who abuse substances are at increased risk for contracting sexually transmitted infections, including HIV. Within this population, sexual risk behaviors have been associated with increased impulsivity. Studies in non clinical populations showing gender-related differences in sexual decision-making and casual sexual partnering suggest impulsivity has a greater influence on men than women, but these differences have not been documented in substance-using patients. In a sample of 89 adults with recent cocaine use and receiving outpatient psychiatric treatment, we tested the hypothesis that gender moderates the effect of impulsivity on sexual risk-taking. Using logistic regression modeling, we tested the main and gender-moderated effects of task-related impulsivity on the probability of having a casual sexual partner and multiple sexual partners. Results confirmed a significant gender-by-impulsivity interaction; men who were more impulsive on a continuous performance task had significantly higher rates of sexual risk-taking than less impulsive men, but women's impulsivity was unrelated to these outcomes. Impulsive men were over three times as likely as less impulsive men to have a recent casual partner. Implications of these results and suggestions for future research are discussed. PMID- 25554718 TI - Comparison of Bayesian Sample Size Criteria: ACC, ALC, and WOC. AB - A challenge for implementing performance based Bayesian sample size determination is selecting which of several methods to use. We compare three Bayesian sample size criteria: the average coverage criterion (ACC) which controls the coverage rate of fixed length credible intervals over the predictive distribution of the data, the average length criterion (ALC) which controls the length of credible intervals with a fixed coverage rate, and the worst outcome criterion (WOC) which ensures the desired coverage rate and interval length over all (or a subset of) possible datasets. For most models, the WOC produces the largest sample size among the three criteria, and sample sizes obtained by the ACC and the ALC are not the same. For Bayesian sample size determination for normal means and differences between normal means, we investigate, for the first time, the direction and magnitude of differences between the ACC and ALC sample sizes. For fixed hyperparameter values, we show that the difference of the ACC and ALC sample size depends on the nominal coverage, and not on the nominal interval length. There exists a threshold value of the nominal coverage level such that below the threshold the ALC sample size is larger than the ACC sample size, and above the threshold the ACC sample size is larger. Furthermore, the ACC sample size is more sensitive to changes in the nominal coverage. We also show that for fixed hyperparameter values, there exists an asymptotic constant ratio between the WOC sample size and the ALC (ACC) sample size. Simulation studies are conducted to show that similar relationships among the ACC, ALC, and WOC may hold for estimating binomial proportions. We provide a heuristic argument that the results can be generalized to a larger class of models. PMID- 25554717 TI - Mediators of the Associations Between Externalizing Behaviors and Internalizing Symptoms in Late Childhood and Early Adolescence. AB - This study tests the predictive associations between externalizing behaviors and internalizing symptoms and examines the mediating roles of social competence, parent-child conflicts, and academic achievement. Using youth-, parent-, and teacher-reported longitudinal data on a sample of 523 boys and 460 girls from late childhood to early adolescence, we found evidence for pathways between externalizing behaviors and internalizing symptoms in both directions. Parent child conflict, but not social competence and academic achievement, was found to be a significant mediator such that externalizing behaviors predicted parent child conflicts, which in turn, predicted internalizing symptoms. Internalizing symptoms showed more continuity during early adolescence for girls than boys. For boys, academic achievement was unexpectedly, positively predictive of internalizing symptoms. The results highlight the importance of facilitating positive parental and caregiver involvement during adolescence in alleviating the risk of co-occurring psychopathology. PMID- 25554719 TI - ATTRIBUTES OF FORM IN THE BUILT ENVIRONMENT THAT INFLUENCE PERCEIVED WALKABILITY. AB - A recent focus of design and building regulations, including form-based codes and the Leadership in Energy and Environmental Design for Neighborhood Development rating system, has been on promoting pedestrian activity. This study assessed perceptions of walkability for residential and commercial streetscapes with different design attributes in order to inform form-based regulations and codes that aim to impact walkability. We scored 424 images on four design attributes purported to influence walkability: variation in building height, variation in building plane, presence of ground-floor windows, and presence of a street focal point. We then presented the images to 45 adults, who were asked to rate the images for walkability. The results showed that perceived walkability varied according to the degree to which a particular design attribute was present, with the presence of ground-floor windows and a street focal point most consistently associated with a space's perceived walkability. Understanding if and which design attributes are most related to walkability could allow planners and developers to focus on the most salient built-environment features influencing physical activity, as well as provide empirical scientific evidence for form based regulations and zoning codes aimed at impacting walkabilit. PMID- 25554720 TI - Horizontal and Vertical Cultural Differences in the Content of Advertising Appeals. AB - The distinction between vertical (emphasizing hierarchy) and horizontal (valuing equality) cultures yields novel predictions regarding the prevalence of advertising appeals. A content analysis of 1211 magazine advertisements in five countries (Denmark, Korea, Poland, Russia, U.S.) revealed differences in ad content that underscore the value of this distinction. Patterns in the degree to which ads emphasized status benefits and uniqueness benefits corresponded to the countries' vertical/horizontal cultural classification. These and other patterns of ad benefits are analyzed and the predictions afforded by the vertical/horizontal distinction versus the broader individualism-collectivism distinction are compared and tested. PMID- 25554721 TI - Uncovering Clinical Principles and Techniques to Address Minority Stress, Mental Health, and Related Health Risks Among Gay and Bisexual Men. AB - Gay and bisexual men disproportionately experience depression, anxiety, and related health risks at least partially because of their exposure to sexual minority stress. This paper describes the adaptation of an evidence-based intervention capable of targeting the psychosocial pathways through which minority stress operates. Interviews with key stakeholders, including gay and bisexual men with depression and anxiety and expert providers, suggested intervention principles and techniques for improving minority stress coping. These principles and techniques are consistent with general cognitive behavioral therapy approaches, the empirical tenets of minority stress theory, and professional guidelines for LGB-affirmative mental health practice. If found to be efficacious, the psychosocial intervention described here would be one of the first to improve the mental health of gay and bisexual men by targeting minority stress. PMID- 25554722 TI - Functional and psychosocial status of Haitians who became users of lower extremity prostheses as a result of the 2010 earthquake. AB - The January 12, 2010 earthquake devastated Port-Au-Prince, the capital of the Republic of Haiti, and its surroundings. Among the 300,000 injured, 1,200 to 1,500 people underwent traumatic /surgical amputations. The purpose of this study was to describe the functional and psychosocial impact of prostheses users who suffered a traumatic lower-limb amputation after the earthquake of 2010 in Haiti. We recruited 140 participants in collaboration with a large health care organization in Port-au-Prince from October 2011 to May 2012. Participants underwent an evaluation of physical impairments and completed questionnaires translated into Haitian Creole. The Trinity Amputation and Prosthesis Experience Scale (TAPES), and the Locomotor Capabilities Index (LCI) were used in this study. The questionnaires were administered verbally in Haitian Creole by a trained staff. We conducted descriptive statistics and t-tests using SPSS for data analysis. Participants had a mean age of 34.9 +/- 12.0; 51.4% were women; 48.6% were transfemoral amputees. The mean of TAPES general adjustment (3.65 +/- 0.59) and adjust to limitation (3.67 +/- 0.86) were higher than the score for the social adjustment (2.58 +/- 0.49). The LCI showed over 90% of subjects were physically independent in self-care; fewer were independent walking on uneven ground or inclement weather (69%). The relatively poor social adjustment is consistent with the literature that describes limited acceptance of people with physical disabilities in Haitian society. Prostheses users in Haiti would benefit from a health delivery infrastructure that also addresses the psychosocial reintegration of individuals with physical disabilities. PMID- 25554723 TI - Maternal Avoidant Coping Mediates the Effect of Parenting Stress on Depressive Symptoms during Early Adolescence. AB - We examined maternal avoidant coping as a mediator between maternal parenting stress and maternal depressive symptoms during early adolescence. Three years of self-report data were collected from 173 mothers, beginning when mothers' adolescents were in 6th grade and aged 11-13 years. Utilizing longitudinal path analysis, results indicated that avoidant coping at time two mediated the association between parenting stress at time one and depressive symptoms at time three. Additionally, the reverse direction of effects was examined, revealing that the relation between parenting stress and avoidant coping was unidirectional, while the relation between avoidant coping and depressive symptoms was bidirectional. Our results suggest that during early adolescence, mothers who experience more stress in the parenting role are more likely to engage in higher levels of avoidant coping when faced with parenting problems. In turn, a mother's long-term avoidant reactions to parenting problems may predict increases in depressive symptoms. Moreover, our findings of a bidirectional relation between avoidant coping and depressive symptoms suggest that prior levels of depression might serve as a barrier to efficient and effective coping. The present study may inform preventive intervention efforts aimed at decreasing the use of avoidance in response to parenting stressors by increasing adaptive parental coping with stressors, and providing appropriate support and resources for parents. PMID- 25554724 TI - Not getting lost in translational science: A tool for navigating the pre implementation phase of multi-site pharmacological clinical trials. AB - BACKGROUND: The compelling need to improve the efficiency of multi-site pharmacological clinical trials has received increasing attention and a number of challenges needing to be addressed have been delineated. PURPOSE: The present paper discusses one of the challenges, how to avoid a lengthy pre-implementation phase, and proposes the strategy of using a Pre-implementation Timeline "Calculator." The Calculator is a Microsoft Excel worksheet designed to assist investigators in planning for, and completing, the pre-implementation phase of multi-site pharmacological clinical trials in a timely manner. METHODS: Preliminary data are presented comparing the pre-implementation phase length of pharmacological trials that did (n=3) and did not (n=4) use the Calculator. RESULTS: The amount of time taken to complete the stage between having a sponsor approved protocol and the initiation of recruitment at a study site averaged nine months for the Calculator trials compared to 15 months for the Non-Calculator trials. The period between the Investigators' meeting and the initiation of recruitment at a study site averaged two months for the Calculator trials compared to five months for the Non-Calculator trials. An estimate of the site staffing costs associated with the later time frame was calculated for a hypothetical trial conducted at 10 sites. The results revealed that the extra three months were associated with a cost of $388,000. LIMITATIONS: An important limitation of the present paper is the reliance on a sample of convenience for the Calculator and Non-Calculator trials. CONCLUSIONS: The Calculator is a free, easily implemented, tool that may provide significant benefits in reducing the time and financial resources required to complete the pre-implementation phase of multi-site pharmacological clinical trials; thus, its more wide-spread use in multi-site pharmacological clinical trials seems warranted. PMID- 25554725 TI - Chlamydia trachomatis Infection: Screening and Management. AB - OBJECTIVE: To review current criteria and rationale for Chlamydia trachomatis screening, testing methods, and treatment of infection. METHODS: Review of the literature. RESULTS: C. trachomatis urogenital infections are an important public health problem. Screening for C. trachomatis in women age 25 and younger and men and women of any age at increased risk allows for the early treatment of disease, avoiding morbidity such as pelvic inflammatory disease, ectopic pregnancy, and chronic pelvic pain, and reducing health care costs. CONCLUSION: Current screening recommendations are not being implemented satisfactorily. Home-based methods of screening are acceptable and may improve universal screening rates. PMID- 25554726 TI - Working Memory Differences Between Children Living in Rural and Urban Poverty. AB - This study was designed to investigate if the working memory profiles of children living in rural poverty are distinct from the working memory profiles of children living in urban poverty. Verbal and visuospatial working memory tasks were administered to sixth-grade students living in low-income rural, low-income urban, high-income rural, and high-income urban developmental contexts. Both low income rural and low-income urban children showed working memory deficits compared with their high-income counterparts, but their deficits were distinct. Low-income urban children exhibited symmetrical verbal and visuospatial working memory deficits compared with their high-income urban counterparts. Meanwhile, low-income rural children exhibited asymmetrical deficits when compared with their high-income rural counterparts, with more extreme visuospatial working memory deficits than verbal working memory deficits. These results suggest that different types of poverty are associated with different working memory abilities. PMID- 25554727 TI - GROUP INEQUALITY. AB - We explore the combined effect of segregation in social networks, peer effects, and the relative size of a historically disadvantaged group on the incentives to invest in market-rewarded skills and the dynamics of inequality between social groups. We identify conditions under which group inequality will persist in the absence of differences in ability, credit constraints, or labor market discrimination. Under these conditions, group inequality may be amplified even if initial group differences are negligible. Increases in social integration may destabilize an unequal state and make group equality possible, but the distributional and human capital effects of this depend on the demographic composition of the population. When the size of the initially disadvantaged group is sufficiently small, integration can lower the long-run costs of human capital investment in both groups and result in an increase the aggregate skill share. In contrast, when the initially disadvantaged group is large, integration can induce a fall in the aggregate skill share as the costs of human capital investment rise in both groups. We consider applications to concrete cases and policy implications. PMID- 25554728 TI - Reshaping the chromatin landscape after spinal cord injury. AB - The pathophysiology underlying spinal cord injury is complex. Mechanistic understanding of the adaptive responses to injury is critical for targeted therapy aimed at reestablishing lost connections between proximal and distal neurons. After injury, cell-type specific gene transcription programs govern distinct cellular behaviors, and chromatin regulators play a central role in shaping the chromatin landscape to adjust transcriptional profiles in a context dependent manner. In this review, we summarize recent progress on the pleiotropic roles of chromatin regulators in mediating the diverse adaptive behaviors of neurons and glial cells after spinal cord injury, and wherever possible, discuss the underlying mechanisms and genomic targets. We specifically draw attention to the perspective that takes into consideration the impact of epigenetic modulation on axon growth potential, together with its effect on wound-healing properties of glial cells. Epigenetic modulation of chromatin state represents an emerging therapeutic direction to promote neural repair and axon regeneration after spinal cord injury. PMID- 25554729 TI - dsRNA binding protein PACT/RAX in gene silencing, development and diseases. AB - PACT (Protein kinase, interferon-inducible double stranded RNA dependent activator) and its murine ortholog RAX (PKR-associated protein X) were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase (PKR). Endogenous PACT/RAX activates PKR in response to diverse stress signals such as serum starvation, and peroxide or arsenite treatment. PACT/RAX heterodimerized with PKR and activated it with its third motif in the absence of dsRNA. The activation of PKR leads to enhanced eIF2alpha phosphorylation followed by apoptosis or inhibition of growth. Besides the role of activating PKR, PACT is associated with a ~500 kDa complex that contains Dicer, hAgo2, and TRBP (TAR RNA binding protein) and it associates with Dicer to facilitate the production of small interfering RNA. PACT/RAX plays an important role in diverse physiological and pathological processes. Pact-/- mice exhibit notable developmental abnormalities including microtia, with craniofacial ear, and hearing defects. Pact-/- mice had smaller body sizes and fertility defects, both of which were caused by defective pituitary functions. It was found that dRAX disrupted fly embryos homozygous, displayed highly abnormal commissural axon structure of the central nervous system, and 70% of the flies homozygous for the mutant allele died prior to adulthood. Using high density SNP genotyping arrays, it was found that a mutation in PRKRA (the PACT/RAX gene) is the causative genetic mutation in DYT16, a novel autosomal recessive dystonia-parkinsonism syndrome in Brazilian patients. PMID- 25554731 TI - Coordinate great circle descent algorithm with application to single-index models. AB - Coordinate descent algorithm has been widely used to solve high dimensional optimization problems with a non-differentiable objective function recently. To provide theoretical justification, Tseng (2001) showed that it leads to a stationary point when the non-differentiable part of the objective function is separable. Motivated by the single index model, we consider optimization problems with a unit-norm constraint in this article. Because of this unit-norm constraint, the coordinate descent algorithm cannot be applied. In addition, non separability of the non-differentiable part of the objective function makes the result of Tseng (2001) not directly applicable. In this paper, we propose a novel coordinate great circle descent algorithm to solve this family of optimization problems. The validity of the algorithm is justified both theoretically and via simulation studies. We also use the Boston housing data to illustrate this algorithm by applying it to fit single-index models. PMID- 25554732 TI - Heavy Drinking, Poor Mental Health, and Substance Use Among Asian Americans in the NLAAS: A Gender-Based Comparison. AB - The severity of heavy drinking among Asian Americans has often been dismissed because of relatively low rates compared to other racial/ethnic groups. However, higher depression and suicide rates among Asian Americans and their association to alcohol use suggest serious detrimental effects of heavy alcohol use among Asian Americans. Gender differences in heavy drinking have been documented among other immigrant based ethnic minorities, little is known of this pattern for Asian Americans. The purpose of the present study was to examine gender differences in heavy drinking, poor mental health, and substance use among a national sample of Asian Americans (N = 581) in the National Latino and Asian American Study (NLAAS). Using National Institute on Alcohol Abuse and Alcoholism (NIAAA) guidelines, heavy drinkers were categorized as those who exceeded the recommended weekly number of drinks (>=14 drinks/week for male and >=7 drinks/week for female). Accordingly, six comparison groups were created (male non, light, and heavy drinkers, and female non, light, and heavy drinkers). Pearson's chi-square test was conducted to examine percentage distribution for the six groups for mental health disorders (i.e., suicidality, DSM-IV mental health endorsement for past 12-month and lifetime). Logistic regression was followed to determined predictors for heavy drinking behavior for men and for women. Female heavy drinkers reported significantly poorer mental health than non drinkers, light drinkers and male heavy drinkers, as indicated by higher rates of lifetime generalized anxiety, and depressive disorders. In contrast, male heavy drinkers were more likely to have lifetime substance use disorders. Findings suggest the need to develop gender-specific drinking interventions for Asian Americans that focus on improving mental health among women and substance treatment among men. PMID- 25554733 TI - Structure-activity relationship studies of SETD8 inhibitors. AB - SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1, and interesting SAR trends. PMID- 25554734 TI - SIMULTANEOUS CONTROL OF AN ANKLE-FOOT PROSTHESIS MODEL USING A VIRTUAL CONSTRAINT. AB - Amputee locomotion can benefit from recent advances in robotic prostheses, but their control systems design poses challenges. Prosthesis control typically discretizes the nonlinear gait cycle into phases, with each phase controlled by different linear controllers. Unfortunately, real-time identification of gait phases and tuning of controller parameters limit implementation. Recently, biped robots have used phase variables and virtual constraints to characterize the gait cycle as a whole. Although phase variables and virtual constraints could solve issues with discretizing the gait cycle, the virtual constraints method from robotics does not readily translate to prosthetics because of hard-to-measure quantities, like the interaction forces between the user and prosthesis socket, and prosthesis parameters which are often altered by a clinician even for a known patient. We use the simultaneous stabilization approach to design a low-order, linear time-invariant controller for ankle prostheses independent of such quantities to enforce a virtual constraint. We show in simulation that this controller produces suitable walking gaits for a simplified amputee model. PMID- 25554735 TI - Nanoporous sorbent material as an oral phosphate binder and for aqueous phosphate, chromate, and arsenate removal. AB - Phosphate removal is both biologically and environmentally important. Biologically, hyperphosphatemia is a critical condition in end-stage chronic kidney disease patients. Patients with hyperphosphatemia are treated long-term with oral phosphate binders to prevent phosphate absorption to the body by capturing phosphate in the gastrointestinal (GI) tract followed by fecal excretion. Environmentally, phosphate levels in natural water resources must be regulated according to limits set forth by the US Environmental Protection Agency. By utilizing nanotechnology and ligand design, we developed a new material to overcome limitations of traditional sorbent materials such as low phosphate binding capacity, slow binding kinetics, and negative interference by other anions. A phosphate binder based on iron-ethylenediamine on nanoporous silica (Fe-EDA-SAMMS) has been optimized for substrates and Fe(III) deposition methods. The Fe-EDA-SAMMS material had a 4-fold increase in phosphate binding capacity and a broader operating pH window compared to other reports. The material had a faster phosphate binding rate and was significantly less affected by other anions than Sevelamer HCl, the gold standard oral phosphate binder, and AG(r) 1-X8, a commercially available anion exchanger. It had less cytotoxicity to Caco-2 cells than lanthanum carbonate, another prescribed oral phosphate binder. The Fe-EDA-SAMMS also had high capacity for arsenate and chromate, two of the most toxic anions in natural water. PMID- 25554736 TI - Systematic evaluation of skin and adnexa in mutant laboratory mice. AB - The skin and its adnexa (hair and nails) comprise one of the easiest organ systems to evaluate, as they are the most accessible. However, mice are small and have lots of very fine hairs of multiple types. Thus, while major abnormalities are obvious, subtle abnormalities or the basis for these defects can be difficult to define. To assist in outlining basic approaches to evaluating mice clinically as well as microscopically with the help of a pathologist, methods are provided here that are used routinely in many laboratories. The mouse is a very useful mammalian model system for studying normal and abnormal (disease) development, and there is a high degree of correlation not only with human biology and medicine but with that of most other mammalian species. Utilizing basic approaches standardizes analysis and provides quality samples for analysis. PMID- 25554730 TI - RNA-binding proteins in pluripotency, differentiation, and reprogramming. AB - Embryonic stem cell maintenance, differentiation, and somatic cell reprogramming require the interplay of multiple pluripotency factors, epigenetic remodelers, and extracellular signaling pathways. RNA-binding proteins (RBPs) are involved in a wide range of regulatory pathways, from RNA metabolism to epigenetic modifications. In recent years we have witnessed more and more studies on the discovery of new RBPs and the assessment of their functions in a variety of biological systems, including stem cells. We review the current studies on RBPs and focus on those that have functional implications in pluripotency, differentiation, and/or reprogramming in both the human and mouse systems. PMID- 25554737 TI - Biological Activity of N-Hydroxyethyl-4-aza-2,3-didehydropodophyllotoxin Derivatives upon Colorectal Adenocarcinoma Cells. AB - Etoposide is a chemotherapy drug derived from the natural lignin podophyllotoxin. Our novel generated Aza-podophyllotoxin compounds (AZP 8a & AZP 9a) are analogues of podophyllotoxin and were previously screened for anti-cancer activity through the NCI 60 cell line screening panel showing activity on various cell types including colon cancer. This study expands the toxicological screening by studying apoptosis and various hallmark events as part of the mechanism of action of these compounds on colon cancer cells. The COLO 205 cell line was selected and exposed to AZP to determine the IC50 doses at 24 hours treatment. Apoptosis hallmark events such as migration of phosphatidylserine (PS) to the cell membrane, DNA fragmentation, cell cycle effects, mitochondrial membrane permeabilization and caspase activation were included. Experiments were performed in triplicates for all tested compounds including AZP 8a, AZP 9a, camptothecin as positive control and vehicle as negative control. Our results present contrasting apoptotic activity between the experimental compounds. Compound 8a presented migration of PS (annexin V assay), DNA fragmentation and cell cycle arrest at S phase. Compound 9a presented PS migration with fragmented DNA, cell cycle arrest at S phase, mitochondrial membrane permeabilization and activation of caspase 3, 8 and 9. Compound 8a without the oxygen atoms in ring A appears to cause effects similarly to autophagy as induced by etoposide, a cancer drug analogue of our heterocyclic compounds. Compound 9a with the oxygen atoms in expanded ring A presented induction of cell death following activation of a classical apoptosis pathway. Our results suggest that minor structural differences among these AZP can account for the difference in biological response and cancer cell toxicity. PMID- 25554738 TI - A cluster randomized trial of an organizational process improvement intervention for improving the assessment and case planning of offenders: a Study Protocol. AB - BACKGROUND: The Organizational Process Improvement Intervention (OPII), conducted by the NIDA-funded Criminal Justice Drug Abuse Treatment Studies consortium of nine research centers, examined an organizational intervention to improve the processes used in correctional settings to assess substance abusing offenders, develop case plans, transfer this information to community-based treatment agencies, and monitor the services provided by these community based treatment agencies. METHODS/DESIGN: A multi-site cluster randomized design was used to evaluate an inter-agency organizational process improvement intervention among dyads of correctional agencies and community based treatment agencies. Linked correctional and community based agencies were clustered among nine (9) research centers and randomly assigned to an early or delayed intervention condition. Participants included administrators, managers, and line staff from the participating agencies; some participants served on interagency change teams while other participants performed agency tasks related to offender services. A manualized organizational intervention that includes the use of external organizational coaches was applied to create and support interagency change teams that proceeded through a four-step process over a planned intervention period of 12 months. The primary outcome of the process improvement intervention was to improve processes associated with the assessment, case planning, service referral and service provision processes within the linked organizations. DISCUSSION: Providing substance abuse offenders with coordinated treatment and access to community-based services is critical to reducing offender recidivism. Results from this study protocol will provide new and critical information on strategies and processes that improve the assessment and case planning for such offenders as they transition between correctional and community based systems and settings. Further, this study extends current knowledge of and methods for, the study of evidence-based practice adoption and implementation. PMID- 25554740 TI - Locus-specific DNA methylation analysis of retrotransposons in ES, somatic and cancer cells using High-Throughput Targeted Repeat Element Bisulfite Sequencing. AB - DNA methylation is a major epigenetic mark associated with multiple aspects of retrotransposons within the mammalian genome. In order to study DNA methylation of a large number of retrotransposons on an individual-locus basis, we have developed a new protocol termed High-Throughput Targeted Repeat Element Bisulfite Sequencing (HT-TREBS) (Ekram and Kim, 2014 [1]). We have used this technique to characterize the locus-specific patterns of DNA methylation of 4799 members of the mouse IAP LTR (Intracisternal A Particle Long Terminal Repeat) retrotransposon family in embryonic stem, somatic and Neuro2A cells (Bakshi and Kim, 2014 [2]). Here we describe in detail the sample preparation and bioinformatics analyses used for these studies. The somatic cell data may be accessed under GEO accession number GSE49222. The ES and Neuro2A data are deposited under GEO accession number GSE60007. PMID- 25554739 TI - Ion channels and drug transporters as targets for anthelmintics. AB - Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance. PMID- 25554741 TI - An X-linked tumor suppressor in T-ALL. PMID- 25554742 TI - Limited effect of chemotherapy in cutaneous lymphoma. PMID- 25554743 TI - Dendritic cells and lymphoma cells: come together right now. PMID- 25554744 TI - CDK6 is a regulator of stem cells "Egr" to wake up. PMID- 25554745 TI - Genes break barrier between MDS and AML. PMID- 25554746 TI - ST2: the biomarker at the heart of GVHD severity. PMID- 25554747 TI - Volume Expansion of Tissue Engineered Human Nasal Septal Cartilage. AB - IMPORTANCE: Cartilaginous craniofacial defects range in size and autologous cartilaginous tissue is preferred for repair of these defects. Therefore, it is important to have the ability to produce large size cartilaginous constructs for repair of cartilaginous abnormalities. OBJECTIVES: To produce autologous human septal neocartilage constructs substantially larger in size than previously produced constructsTo demonstrate that volume expanded neocartilage constructs possess comparable histological and biochemical properties to standard size constructsTo show that volume expanded neocartilage constructs retain similar biomechanical properties to standard size constructs. DESIGN: Prospective, basic science. SETTING: Laboratory. PARTICIPANTS: The study used remnant human septal specimens removed during routine surgery at the University of California, San Diego Medical Center or San Diego Veterans Affairs Medical Center. Cartilage from a total of 8 donors was collected. MAIN OUTCOMES MEASURED: Human septal chondrocytes from 8 donors were used to create 12mm and 24mm neocartilage constructs. These were cultured for a total of 10 weeks. Photo documentation, histological, biochemical, and biomechanical properties were measured and compared. RESULTS: The 24mm diameter constructs were qualitatively similar to the 12mm constructs. They possessed adequate strength and durability to be manually manipulated. Histological analysis of the constructs demonstrated similar staining patterns in standard and volume expanded constructs. Proliferation, as measured by DNA content, was similar in 24mm and 12mm constructs. Additionally, glycosaminoglycan (GAG) and total collagen content did not significantly differ between the two construct sizes. Biomechanical analysis of the 24mm and 12mm constructs demonstrated comparable compressive and tensile properties. CONCLUSION AND RELEVANCE: Volume expanded human septal neocartilage constructs are qualitatively and histologically similar to standard 12mm constructs. Biochemical and biomechanical analysis of the constructs demonstrated equivalent properties. This study shows that modification of existing protocols is not required to successfully produce neocartilage constructs in larger sizes for reconstruction of more substantial craniofacial defects. LEVEL OF EVIDENCE: NA. PMID- 25554748 TI - Pioneering the Transdisciplinary Team Science Approach: Lessons Learned from National Cancer Institute Grantees. AB - The National Cancer Institute has been a leader in supporting transdisciplinary (TD) team science. From 2005-2010, the NCI supported Transdisciplinary Research on Energetic and Cancer I (TREC I), a center initiative fostering the TD integration of social, behavioral, and biological sciences to examine the relationships among obesity, nutrition, physical activity and cancer. In the final year of TREC I, we conducted qualitative in-depth-interviews with 31 participating investigators and trainees to learn more about their experiences with TD team science, including challenges, facilitating factors, strategies for success, and impacts. Five main challenges emerged: (1) limited published guidance for how to engage in TD team science, when TREC I was implemented; (2) conceptual and scientific challenges inherent to efforts to achieve TD integration; (3) discipline-based differences in values, terminology, methods, and work styles; (4) project management challenges involved in TD team science; and (5) traditional incentive and reward systems that do not recognize or reward TD team science. Four main facilitating factors and strategies for success emerged: (1) beneficial attitudes and beliefs about TD research and team science; (2) effective team processes; (3) brokering and bridge-building activities by individuals holding particular roles in a research center; and (4) funding initiative characteristics that support TD team science. Broad impacts of participating in TD team science in the context of TREC I included: (1) new positive attitudes about TD research and team science; (2) new boundary-crossing collaborations; (3) scientific advances related to research approaches, findings, and dissemination; (4) institutional culture change and resource creation in support of TD team science; and (5) career advancement. Funding agencies, academic institutions, and scholarly journals can help to foster TD team science through funding opportunities, institutional policies on extra-departmental and cross-school collaboration, promotion and tenure policies, and publishing opportunities for TD research. PMID- 25554749 TI - Classification of Histology Sections via Multispectral Convolutional Sparse Coding. AB - Image-based classification of histology sections plays an important role in predicting clinical outcomes. However this task is very challenging due to the presence of large technical variations (e.g., fixation, staining) and biological heterogeneities (e.g., cell type, cell state). In the field of biomedical imaging, for the purposes of visualization and/or quantification, different stains are typically used for different targets of interest (e.g., cellular/subcellular events), which generates multi-spectrum data (images) through various types of microscopes and, as a result, provides the possibility of learning biological-component-specific features by exploiting multispectral information. We propose a multispectral feature learning model that automatically learns a set of convolution filter banks from separate spectra to efficiently discover the intrinsic tissue morphometric signatures, based on convolutional sparse coding (CSC). The learned feature representations are then aggregated through the spatial pyramid matching framework (SPM) and finally classified using a linear SVM. The proposed system has been evaluated using two large-scale tumor cohorts, collected from The Cancer Genome Atlas (TCGA). Experimental results show that the proposed model 1) outperforms systems utilizing sparse coding for unsupervised feature learning (e.g., PSD-SPM [5]); 2) is competitive with systems built upon features with biological prior knowledge (e.g., SMLSPM [4]). PMID- 25554750 TI - Fabrication of graphene oxide decorated with nitrogen-doped graphene quantum dots and its enhanced electrochemiluminescence for ultrasensitive detection of pentachlorophenol. AB - Nitrogen-doped graphene quantum dots (NGQDs), as a new class of quantum dots, have potential applications in fuel cells and optoelectronics fields due to their electrocatalytic activity, tunable luminescence and biocompatibility. Herein, a facile hydrothermal approach for cutting nitrogen-doped graphene into NGQDs has been proposed for the first time. The resulting NGQDs were homogeneously modified onto the surface of graphene oxide (GO) to form NGQDs-GO nanocomposites. Compared with NGQDs, the as-prepared NGQDs-GO nanocomposites exhibited excellent electrochemiluminescence (ECL) performances including 3.8-fold enhancement of ECL intensity and a decrease by 200 mV of the ECL onset potential, which are ascribed to the introduction of GO. Based on the selective inhibitory effect of pentachlorophenol (PCP) on the ECL intensity of the NGQDs-GO system, a novel ECL sensor for PCP concentration determination was constructed, with a wide linear response ranging from 0.1 to 10 pg mL(-1) and a detection limit of 0.03 pg mL( 1). The practicability of the sensing platform in real water samples showed satisfactory results, which could open the possibility of using NGQDs-based nanocomposites in the electroanalytical field. PMID- 25554751 TI - A versatile reversed phase-strong cation exchange-reversed phase (RP-SCX-RP) multidimensional liquid chromatography platform for qualitative and quantitative shotgun proteomics. AB - An automatable, robust, high-performance online multidimensional liquid chromatography (MDLC) platform comprising of pH 10 reversed-phase (RP), strong cation exchange (SCX), and pH 2 RP separation stages has been integrated into a modified commercial off-the-shelf LC instrument with a simple rewiring, enabling accelerated routine qualitative and quantitative proteomics analyses. This system has been redesigned with a dual-trap column configuration to improve the throughput by greatly decreasing the system idle time. The performance of this new design has been benchmarked through analysis of the total lysate of S. cerevisiae, in comparison with that of the former tailor-made system featuring more complicated components; the total run time per "load-and-go" LC/MS analysis was approximately 24 h, with minimal idle time and no labor-intensive steps. This platform features high-resolution fractionations, ease of use and a high degree of user programmability in the first two chromatographic dimensions, allowing flexible and effective sampling with (RP-SCX-RP) or without (RP-RP) the inclusion of SCX sub-fractionation; good proteome coverage and reproducibility was demonstrated through the analyses of bacterial, cell culture, and monkey brain tissue proteomes. The viability of the 3D RP-SCX-RP has been proven in proteome wide studies of STO fibroblasts and yeast tryptic digests, resulting in extended proteome and protein coverages with high reproducibility-in particular, discovering extra-hydrophilic peptides-at the expense of the acquisition time. The identified inventory of the rat pheochromocytoma PC12 cell proteome-a total of 6345 proteins and 97 309 unique peptides is the most comprehensive dataset to date-provides an example of the value of the 3D RP-SCX-RP. The use of orthogonal chromatographic dimensions in the 3D RP-SCX-RP also circumvents the issues of isobaric interference of mass-tagging background contaminations, while significantly improving the accuracy of isobaric tags for relative and absolute quantitation (iTRAQ)-based protein quantitation experiments. PMID- 25554752 TI - A colorimetric method of analysis for trace amounts of hydrogen peroxide with the use of the nano-properties of molybdenum disulfide. AB - Molybdenum disulfide (MoS2) is an emerging material with some unique physical and electronic properties somewhat comparable to those of graphene. It was prepared with the use of a simple hydrothermal process, and has a layered structure similar to that of graphene. Also, it has a peroxidase-like catalytic activity and is able to catalyze the oxidation of the colorless peroxidase substrate, 3,3',5,5'-tetramethylbenzidine (TMB), in the presence of H2O2 to produce a blue product. This reaction used MoS2 as a useful peroxidase, which involved a colorimetric method for trace analysis of H2O2 in water, e.g. lake waters. This method is uncomplicated, inexpensive and highly sensitive for H2O2 in the 0.125 1.75 MUM range (LOD: 0.08 MUM). It is also quite stable in the presence of many common inorganic and organic potentially interfering compounds, e.g. metal ions as well as amino acids and sugars. PMID- 25554753 TI - Diagnosis and management of bacteremic urinary tract infection in infants. AB - OBJECTIVES: To report the prevalence of bacteremia by age in a sample of infants<1 year of age with urinary tract infections (UTIs), to compare characteristics of infants with UTIs with and without bacteremia, and to describe treatment courses and 30-day outcomes in infants with UTIs with and without bacteremia. METHODS: We used a retrospective cross-sectional design to determine the prevalence of bacteremia in infants with UTIs at our institution. A double cohort design matching for age and gender was used to compare clinical characteristics and outcomes between infants with bacteremic versus nonbacteremic UTIs. RESULTS: We identified 1379 UTIs, with blood cultures obtained in 52% of cases. The prevalence of bacteremia was 4.1% (95% confidence interval 3.1%-5.3%) for all UTIs and 8% (95% confidence interval 6.1%-10.2%) for UTIs in which blood culture was obtained. Fifty-five infants with bacteremic UTIs were compared with 110 infants with nonbacteremic UTIs. Except for minor differences in the urinalysis and serum band count, there were no significant differences in clinical presentation between the 2 groups. Bacteremic infants received longer parenteral treatment courses than nonbacteremic infants (mean 6.7 vs 2.4 days, P<.001). Treatment courses in the bacteremic group were variable and predicted by age but not severity of illness. No bacteremic infant had recurrent UTI or bacteremia with the same organism within 30 days of discharge. CONCLUSIONS: Treatment was variable but outcomes were excellent in infants with bacteremic UTIs. PMID- 25554754 TI - Serum magnesium levels in pediatric inpatients: a study in laboratory overuse. AB - BACKGROUND AND OBJECTIVE: Hypomagnesemia, defined as a serum magnesium (Mg) level<1.5 mg/dL (0.62 mmol/L), is often asymptomatic. The goals of this study were to determine the incidence of clinically significant abnormal Mg levels in the inpatient setting and to identify diagnoses for which testing would be diagnostically helpful. METHODS: We obtained data from 2010 through 2011 on charges for serum Mg levels and Mg supplementation for all non-ICU inpatients from the 43 tertiary care children's hospitals in the Pediatric Health Information System database. A manual chart review was performed for all patients at our institution with charges for both Mg levels and Mg supplementation. RESULTS: A median of 13.5% (interquartile range: 7.7-22.1) of non-ICU inpatients from Pediatric Health Information System centers had charges for Mg levels, at a total charge of $41 million in the 2010-2011 period. At our institution, 19.1% of non-ICU inpatients had charges for Mg levels, at a charge of $67.32/patient-day. Of the 4608 patients with Mg laboratory charges at our institution, 171 (3.7%) had an intervention, defined as addition or modification of an Mg supplement dose in response to a serum Mg level. The 4 most common groups of diagnoses (oncologic, abdominal surgery requiring total parenteral nutrition, solid organ transplant, and short bowel syndrome) accounted for 143 (83.6%) of these interventions. CONCLUSIONS: Serum Mg levels were frequently ordered in non-ICU inpatients, but levels were seldom abnormal and rarely resulted in changes in clinical management. These findings raise concerns about resource overutilization and provide a target for more judicious laboratory ordering practices. PMID- 25554755 TI - Pain Outcomes in a US Children's Hospital: A Prospective Cross-Sectional Survey. AB - BACKGROUND AND OBJECTIVES: Pain in hospitalized children may be underrecognized and undertreated. The objective of this survey was to benchmark pain prevalence, intensity, assessment, and pharmacologic as well as integrative treatment of pain in inpatients in a US children's hospital. METHODS: This was a single-day, cross sectional survey and electronic medical record review of inpatients who received medical care at a pediatric hospital. Inpatients and emergency department patients were asked to report their experience with pain and its management during the previous 24 hours. RESULTS: Of 279 inpatients listed on the morning census, 178 children and parents were located and completed the survey. Seventy six percent had experienced pain during the previous 24 hours, usually acute or procedural pain, 12% of whom possibly suffered from chronic pain. Twenty percent of all children surveyed experienced moderate and 30% severe pain in that time period. The worst pain reported by patients was caused by needle pokes (40%), followed by trauma/injury (34%). Children and their parents rated 5 integrative, nonpharmacologic modalities as more effective than medications. Pain assessments and management were documented in the medical record for 58% of patients covering the 24-hour period before the morning census. The most commonly prescribed analgesics were acetaminophen, morphine, and ibuprofen. CONCLUSIONS: Despite existing hospital policies and a pain consult team, significant room for improvement in pain management was identified. A hospital-wide, 3-year Lean quality improvement initiative on reducing pain was commenced as a result of this survey. PMID- 25554756 TI - Rate of preventable early unplanned intensive care unit transfer for direct admissions and emergency department admissions. AB - BACKGROUND AND OBJECTIVE: Appropriate patient placement at the time of admission to avoid unplanned transfers to the ICU and codes outside of the ICU is an important safety goal for many institutions. The objective of this study was to determine if the overall rate of unplanned ICU transfers within 12 hours of admission to the inpatient medical/surgical unit was higher for direct admissions compared with emergency department (ED) admissions. METHODS: This was a retrospective cohort study of all unplanned ICU transfers within 12 hours of admission to an inpatient unit at a tertiary care children's hospital from January 2010 to December 2012. Proportions of preventable unplanned transfers from the ED and from direct admission were calculated and compared. RESULTS: Over the study period, there were a total of 46,998 admissions; 279 unplanned ICU transfers occurred during the study period of which 101 (36%) were preventable. Preventable unplanned transfers from each portal of entry were calculated and compared with the total number of admissions from those portals. The portals of entry evaluated included admissions from our internal ED versus all outside facility transfers. The rates of early unplanned transfer (per 1000 admissions) by portal of entry were 3.50 for direct admissions and 3.18 for ED. There was no difference between direct admissions and ED admissions resulting in preventable unplanned transfers to the ICU (P=.64). CONCLUSIONS: Rates of unplanned ICU transfers within 12 hours of admission to an inpatient unit are not higher for direct admissions compared with ED admissions. Further studies are required to determine clinical risk factors associated with unplanned ICU transfer after admission, thus allowing for more accurate initial patient placement. PMID- 25554757 TI - A pilot program to improve vaccination status for hospitalized children. AB - OBJECTIVES: Screening of immunization status at each health care encounter is recommended to improve immunization coverage rates but is often limited to primary care practices. A pilot intervention study was performed to ascertain the immunization status of hospitalized children and determine if development of an immunization plan before discharge would improve the vaccination status for such children. METHODS: On the basis of power calculations estimated to detect an increase in immunization status from 60% to 70% with 80% power, 356 randomly selected children were enrolled between March 6, 2012 and June 14, 2012. Immunization records were obtained, immunization status determined, and parent/guardian informed if catch-up dose(s) were needed. If parent requested vaccine dose(s), they were administered before discharge. RESULTS: Vaccination status was current per Advisory Committee on Immunization Practices guidelines in 73% of hospitalized children, and 27% children required catch-up dose(s) (200 doses for 95 children). Human papilloma virus vaccine (dose 1), varicella zoster vaccine (dose 2), and meningococcal conjugate vaccine were the most commonly identified dose(s) needed. Of those requiring catch-up dose(s), 25% were caught up, increasing vaccination status to 80% at 1-month post hospital discharge. CONCLUSIONS: This is the first study to determine the immunization status of hospitalized pediatric patients of all ages, including adolescents, providing new data on the immunization status of the inpatient pediatric population. A pilot intervention consisting of obtaining immunization records, determining immunization status, and discussing catch-up dose(s) before discharge resulted in improvement of immunization status, suggesting that the inpatient setting may be used along with many other national strategies to help address missed vaccination opportunities. PMID- 25554758 TI - Overuse in pediatrics: time to "pull the trigger"? PMID- 25554759 TI - Venous thromboembolism in hospitalized adolescents: an approach to risk assessment and prophylaxis. AB - BACKGROUND: Pediatric hospital-acquired venous thromboembolism (VTE) is an increasingly prevalent and morbid disease. A multidisciplinary team at a tertiary children's hospital sought to answer the following clinical question: "Among hospitalized adolescents, does risk assessment and stratified VTE prophylaxis compared with no prophylaxis reduce VTE occurrence without an increase in significant adverse effects?" METHODS: Serial literature searches using key terms were performed in the following databases: Medline, Cochrane Database, CINAHL (Cumulative Index to Nursing and Allied Health), Scopus, EBMR (Evidence Based Medicine Reviews). Pediatric studies were sought preferentially; when pediatric evidence was sparse, adult studies were included. Abstracts and titles were screened, and relevant full articles were reviewed. Studies were rated for quality using a standard rating system. RESULTS: Moderate evidence exists to support VTE risk assessment in adolescents. This evidence comes from pediatric studies that are primarily retrospective in design. The results of the studies are consistent and cite prominent factors such as immobilization and central venous access. There is insufficient evidence to support specific prophylactic strategies in pediatric patients because available pediatric evidence for thromboprophylaxis efficacy and safety is minimal. There is, however, high quality, consistent evidence demonstrating efficacy and safety of thromboprophylaxis in adults. CONCLUSIONS: On the basis of the best available evidence, we propose a strategy for risk assessment and stratified VTE prophylaxis for hospitalized adolescents. This strategy involves assessing risk factors and considering prophylactic measures based on level of risk. We believe this strategy may reduce risk of VTE and appropriately balances the adverse effect profile of mechanical and pharmacologic prophylactic methods. PMID- 25554760 TI - Family-centered care and evidence-based medicine in conflict: lessons for pediatricians. PMID- 25554761 TI - Journal club: house of pain. PMID- 25554763 TI - Data, eternal. PMID- 25554765 TI - Genomics. Inching toward the 3D genome. PMID- 25554766 TI - Scientific publishing. Geoscientists aim to magnify specialized Web searching. PMID- 25554767 TI - Biomedicine. The bad luck of cancer. PMID- 25554768 TI - Scientific community. Targets of misconduct probe launch a legal counterattack. PMID- 25554769 TI - Exodus from the East. PMID- 25554770 TI - Ukraine mourns a lost science jewel. PMID- 25554771 TI - Inflammation's stop signals. PMID- 25554774 TI - Physiology. Killer fat. PMID- 25554775 TI - Evolutionary genomics. Conundrum of jumbled mosquito genomes. PMID- 25554776 TI - Organic chemistry. Construction and deconstruction of aldehydes by transfer hydroformylation. PMID- 25554777 TI - Microbiology. Persisters unmasked. PMID- 25554778 TI - Cell biology. Lysosomal lipid lengthens life span. PMID- 25554779 TI - Education research. Rebooting MOOC research. PMID- 25554780 TI - Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I. AB - Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the "deactive" form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization change mechanism of proton pumping. PMID- 25554781 TI - Organic chemistry. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. AB - At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction. PMID- 25554782 TI - Organic chemistry. Rh-catalyzed C-C bond cleavage by transfer hydroformylation. AB - The dehydroformylation of aldehydes to generate olefins occurs during the biosynthesis of various sterols, including cholesterol in humans. Here, we implement a synthetic version that features the transfer of a formyl group and hydride from an aldehyde substrate to a strained olefin acceptor. A Rhodium (Xantphos)(benzoate) catalyst activates aldehyde carbon-hydrogen (C-H) bonds with high chemoselectivity to trigger carbon-carbon (C-C) bond cleavage and generate olefins at low loadings (0.3 to 2 mole percent) and temperatures (22 degrees to 80 degrees C). This mild protocol can be applied to various natural products and was used to achieve a three-step synthesis of (+)-yohimbenone. A study of the mechanism reveals that the benzoate counterion acts as a proton shuttle to enable transfer hydroformylation. PMID- 25554783 TI - Reaction dynamics. Extremely short-lived reaction resonances in Cl + HD (v = 1) > DCl + H due to chemical bond softening. AB - The Cl + H2 reaction is an important benchmark system in the study of chemical reaction dynamics that has always appeared to proceed via a direct abstraction mechanism, with no clear signature of reaction resonances. Here we report a high resolution crossed-molecular beam study on the Cl + HD (v = 1, j = 0) -> DCl + H reaction (where v is the vibrational quantum number and j is the rotational quantum number). Very few forward scattered products were observed. However, two distinctive peaks at collision energies of 2.4 and 4.3 kilocalories per mole for the DCl (v' = 1) product were detected in the backward scattering direction. Detailed quantum dynamics calculations on a highly accurate potential energy surface suggested that these features originate from two very short-lived dynamical resonances trapped in the peculiar H-DCl (v' = 2) vibrational adiabatic potential wells that result from chemical bond softening. We anticipate that dynamical resonances trapped in such wells exist in many reactions involving vibrationally excited molecules. PMID- 25554784 TI - The type VI secretion system of Vibrio cholerae fosters horizontal gene transfer. AB - Natural competence for transformation is a common mode of horizontal gene transfer and contributes to bacterial evolution. Transformation occurs through the uptake of external DNA and its integration into the genome. Here we show that the type VI secretion system (T6SS), which serves as a predatory killing device, is part of the competence regulon in the naturally transformable pathogen Vibrio cholerae. The T6SS-encoding gene cluster is under the positive control of the competence regulators TfoX and QstR and is induced by growth on chitinous surfaces. Live-cell imaging revealed that deliberate killing of nonimmune cells via competence-mediated induction of T6SS releases DNA and makes it accessible for horizontal gene transfer in V. cholerae. PMID- 25554785 TI - Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. AB - Adipocytes have been suggested to be immunologically active, but their role in host defense is unclear. We observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423(nur12) mice or in mice given inhibitors of peroxisome proliferator activated receptor gamma. This host defense function was mediated through the production of cathelicidin antimicrobial peptide from adipocytes because cathelicidin expression was decreased by inhibition of adipogenesis, and adipocytes from Camp(-/-) mice lost the capacity to inhibit bacterial growth. Together, these findings show that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin. PMID- 25554786 TI - Structure and inhibition of EV-D68, a virus that causes respiratory illness in children. AB - Enterovirus D68 (EV-D68) is a member of Picornaviridae and is a causative agent of recent outbreaks of respiratory illness in children in the United States. We report here the crystal structures of EV-D68 and its complex with pleconaril, a capsid-binding compound that had been developed as an anti-rhinovirus drug. The hydrophobic drug-binding pocket in viral protein 1 contained density that is consistent with a fatty acid of about 10 carbon atoms. This density could be displaced by pleconaril. We also showed that pleconaril inhibits EV-D68 at a half maximal effective concentration of 430 nanomolar and might, therefore, be a possible drug candidate to alleviate EV-D68 outbreaks. PMID- 25554787 TI - Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. AB - In Eukarya, stalled translation induces 40S dissociation and recruitment of the ribosome quality control complex (RQC) to the 60S subunit, which mediates nascent chain degradation. Here we report cryo-electron microscopy structures revealing that the RQC components Rqc2p (YPL009C/Tae2) and Ltn1p (YMR247C/Rkr1) bind to the 60S subunit at sites exposed after 40S dissociation, placing the Ltn1p RING (Really Interesting New Gene) domain near the exit channel and Rqc2p over the P site transfer RNA (tRNA). We further demonstrate that Rqc2p recruits alanine- and threonine-charged tRNA to the A site and directs the elongation of nascent chains independently of mRNA or 40S subunits. Our work uncovers an unexpected mechanism of protein synthesis, in which a protein--not an mRNA--determines tRNA recruitment and the tagging of nascent chains with carboxy-terminal Ala and Thr extensions ("CAT tails"). PMID- 25554788 TI - Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. AB - Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. PMID- 25554790 TI - My liberation through science. PMID- 25554789 TI - Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. AB - Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans. PMID- 25554791 TI - 2D materials. Graphene, related two-dimensional crystals, and hybrid systems for energy conversion and storage. AB - Graphene and related two-dimensional crystals and hybrid systems showcase several key properties that can address emerging energy needs, in particular for the ever growing market of portable and wearable energy conversion and storage devices. Graphene's flexibility, large surface area, and chemical stability, combined with its excellent electrical and thermal conductivity, make it promising as a catalyst in fuel and dye-sensitized solar cells. Chemically functionalized graphene can also improve storage and diffusion of ionic species and electric charge in batteries and supercapacitors. Two-dimensional crystals provide optoelectronic and photocatalytic properties complementing those of graphene, enabling the realization of ultrathin-film photovoltaic devices or systems for hydrogen production. Here, we review the use of graphene and related materials for energy conversion and storage, outlining the roadmap for future applications. PMID- 25554793 TI - Disease spectrum and treatment patterns in a local male infertility clinic. AB - OBJECTIVE: To review disease spectrum and treatment patterns in a local male infertility clinic. DESIGN: Case series. SETTING: Male infertility clinic in a teaching hospital in Hong Kong. PATIENTS: Patients who were seen as new cases in a local male infertility clinic between January 2008 and December 2012. INTERVENTION: Infertility assessment and counselling on treatment options. MAIN OUTCOME MEASURES: Disease spectrum and treatment patterns. RESULTS: A total of 387 new patients were assessed in the male infertility clinic. The mean age of the patients and their female partners was 37.2 and 32.1 years, respectively. The median duration of infertility was 3 years. Among the patients, 36.2% had azoospermia, 8.0% had congenital absence of vas deferens, and 48.3% of patients had other abnormalities in semen parameters. The commonest causes of male infertility were unknown (idiopathic), clinically significant varicoceles, congenital absence of vas deferens, mumps after puberty, and erectile or ejaculatory dysfunction. Overall, 66.1% of patients chose assisted reproductive treatment and 12.4% of patients preferred surgical correction of reversible male infertility conditions. Altogether 36.7% of patients required either surgical sperm retrieval or correction of male infertility conditions. CONCLUSIONS: The present study provided important local data on the disease spectrum and treatment patterns in a male infertility clinic. The incidences of azoospermia and congenital absence of vas deferens were much higher than those reported in the contemporary literature. A significant proportion of patients required either surgical sperm retrieval or correction of reversible male infertility conditions. PMID- 25554794 TI - Allergy in Hong Kong: an unmet need in service provision and training. AB - Many children in Hong Kong have allergic diseases and epidemiological data support a rising trend. Only a minority of children will grow out of their allergic diseases, so the heavy clinical burden will persist into adulthood. In an otherwise high-quality health care landscape in Hong Kong, allergy services and training are a seriously unmet need. There is one allergy specialist for 1.5 million people, which is low not only compared with international figures, but also compared with most other specialties in Hong Kong. The ratio of paediatric and adult allergists per person is around 1:460 000 and 1:2.8 million, respectively, so there is a severe lack of adult allergists, while the paediatric allergists only spend a fraction of their time working with allergy. There are no allergists and no dedicated allergy services in adult medicine in public hospitals. Laboratory support for allergy and immunology is not comprehensive and there is only one laboratory in the public sector supervised by accredited immunologists. These findings clearly have profound implications for the profession and the community of Hong Kong and should be remedied without delay. Key recommendations are proposed that could help bridge the gaps, including the creation of two new pilot allergy centres in a hub-and-spoke model in the public sector. This could require recruitment of specialists from overseas to develop the process if there are no accredited allergy specialists in Hong Kong who could fulfil this role. PMID- 25554795 TI - Iron promotes protein insolubility and aging in C. elegans. AB - Many late-onset proteotoxic diseases are accompanied by a disruption in homeostasis of metals (metallostasis) including iron, copper and zinc. Although aging is the most prominent risk factor for these disorders, the impact of aging on metallostasis and its role in proteotoxic disease remain poorly understood. Moreover, it is not clear whether a loss of metallostasis influences normal aging. We have investigated the role of metallostasis in longevity ofCaenorhabditis elegans. We found that calcium, copper, iron, and manganese levels increase as a function of age, while potassium and phosphorus levels tend to decrease. Increased dietary iron significantly accelerated the age-related accumulation of insoluble protein, a molecular pathology of aging. Proteomic analysis revealed widespread effects of dietary iron in multiple organelles and tissues. Pharmacological interventions to block accumulation of specific metals attenuated many models of proteotoxicity and extended normal lifespan. Collectively, these results suggest that a loss of metallostasis with aging contributes to age-related protein aggregation. PMID- 25554797 TI - Transient energy deficit induced by exercise increases 24-h fat oxidation in young trained men. AB - Whole body fat oxidation increases during exercise. However, 24-h fat oxidation on a day with exercise often remains similar to that of sedentary day, when energy intake is increased to achieve an energy-balanced condition. The present study aimed to examine a possibility that time of the day when exercise is performed makes differences in 24-h fat oxidation. As a potential mechanism of exercise affecting 24-h fat oxidation, its relation to exercise-induced transient energy deficit was examined. Nine young male endurance athletes underwent three trials of indirect calorimetry using a metabolic chamber, in which they performed a session of 100 min of exercise before breakfast (AM), after lunch (PM), or two sessions of 50 min of exercise before breakfast and after lunch (AM/PM) at 65% of maximal oxygen uptake. Experimental meals were designed to achieve individual energy balance. Twenty-four-hour energy expenditure was similar among the trials, but 24-h fat oxidation was 1,142 +/- 97, 809 +/- 88, and 608 +/- 46 kcal/24 h in descending order of its magnitude for AM, AM/PM, and PM, respectively (P < 0.05). Twenty-four-hour carbohydrate oxidation was 2,558 +/- 110, 2,374 +/- 114, and 2,062 +/- 96 kcal/24 h for PM, AM/PM, and AM, respectively. In spite of energy balanced condition over 24 h, exercise induced a transient energy deficit, the magnitude of which was negatively correlated with 24-h fat oxidation (r = -0.72, P < 0.01). Similarly, transient carbohydrate deficit after exercise was negatively correlated with 24-h fat oxidation (r = -0.40, P < 0.05). The time of the day when exercise is performed affects 24-h fat oxidation, and the transient energy/carbohydrate deficit after exercise is implied as a factor affecting 24-h fat oxidation. PMID- 25554792 TI - Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes. AB - Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts. PMID- 25554796 TI - TAp73 promotes anti-senescence-anabolism not proliferation. AB - TAp73, a member of the p53 family, has been traditionally considered a tumor suppressor gene, but a recent report has claimed that it can promote cellular proliferation. This assumption is based on biochemical evidence of activation of anabolic metabolism, with enhanced pentose phosphate shunt (PPP) and nucleotide biosynthesis. Here, while we confirm that TAp73 expression enhances anabolism, we also substantiate its role in inhibiting proliferation and promoting cell death. Hence, we would like to propose an alternative interpretation of the accumulating data linking p73 to cellular metabolism: we suggest that TAp73 promotes anabolism to counteract cellular senescence rather than to support proliferation. PMID- 25554798 TI - Identification of a conserved set of upregulated genes in mouse skeletal muscle hypertrophy and regrowth. AB - The purpose of this study was to compare the gene expression profile of mouse skeletal muscle undergoing two forms of growth (hypertrophy and regrowth) with the goal of identifying a conserved set of differentially expressed genes. Expression profiling by microarray was performed on the plantaris muscle subjected to 1, 3, 5, 7, 10, and 14 days of hypertrophy or regrowth following 2 wk of hind-limb suspension. We identified 97 differentially expressed genes (>=2 fold increase or >=50% decrease compared with control muscle) that were conserved during the two forms of muscle growth. The vast majority (~90%) of the differentially expressed genes was upregulated and occurred at a single time point (64 out of 86 genes), which most often was on the first day of the time course. Microarray analysis from the conserved upregulated genes showed a set of genes related to contractile apparatus and stress response at day 1, including three genes involved in mechanotransduction and four genes encoding heat shock proteins. Our analysis further identified three cell cycle-related genes at day and several genes associated with extracellular matrix (ECM) at both days 3 and 10. In conclusion, we have identified a core set of genes commonly upregulated in two forms of muscle growth that could play a role in the maintenance of sarcomere stability, ECM remodeling, cell proliferation, fast-to-slow fiber type transition, and the regulation of skeletal muscle growth. These findings suggest conserved regulatory mechanisms involved in the adaptation of skeletal muscle to increased mechanical loading. PMID- 25554799 TI - Heat shock proteins: in vivo heat treatments reveal adipose tissue depot-specific effects. AB - Heat treatments (HT) and the induction of heat shock proteins (HSPs) improve whole body and skeletal muscle insulin sensitivity while decreasing white adipose tissue (WAT) mass. However, HSPs in WAT have been understudied. The purpose of the present study was to examine patterns of HSP expression in WAT depots, and to examine the effects of a single in vivo HT on WAT metabolism. Male Wistar rats received HT (41 degrees C, 20 min) or sham treatment (37 degrees C), and 24 h later subcutaneous, epididymal, and retroperitoneal WAT depots (SCAT, eWAT, and rpWAT, respectively) were removed for ex vivo experiments and Western blotting. SCAT, eWAT, and rpWAT from a subset of rats were also cultured separately and received a single in vitro HT or sham treatment. HSP72 and HSP25 expression was greatest in more metabolically active WAT depots (i.e., eWAT and rpWAT) compared with the SCAT. Following HT, HSP72 increased in all depots with the greatest induction occurring in the SCAT. In addition, HSP25 increased in the rpWAT and eWAT, while HSP60 increased in the rpWAT only in vivo. Free fatty acid (FFA) release from WAT explants was increased following HT in the rpWAT only, and fatty acid reesterification was decreased in the rpWAT but increased in the SCAT following HT. HT increased insulin responsiveness in eWAT, but not in SCAT or rpWAT. Differences in HSP expression and induction patterns following HT further support the growing body of literature differentiating distinct WAT depots in health and disease. PMID- 25554801 TI - Magnetic resonance imaging--key to understanding and monitoring disease progression in spondyloarthritis? PMID- 25554800 TI - Periodic breathing in healthy humans at exercise in hypoxia. AB - Periodic breathing is frequent in heart failure or ventilatory disorders during sleep, and common during sleep at high altitude, but has been rarely studied in wakefulness and during exercise. A retrospective analysis of ventilation from hypoxia exercise tests was realized in 82 healthy subjects separated into two groups with either high or low ventilatory response to hypoxia at exercise (HVRe). A fast Fourier transform spectral analysis of the breath-by-breath ventilation (Ve) signal, O2 saturation, and end-tidal PCO2 evidenced a periodic pattern with a period of 11.1 to 12.0 s. The peak power of the Ve spectrum was higher in the high HVRe group (P < 0.001). A prospective study (25 subjects) was performed to evaluate the influence of cardiorespiratory factors on the amplitude and period of oscillations in various conditions of exercise (20 to 40% maximal aerobic power) and hypoxia (0 to 4,000 m altitude). The period of Ve was shorter at exercise (vs. rest, P < 0.001) and hypoxia (vs. normoxia, P < 0.001), and inversely related with cardiac output and Ve (P < 0.001). Ve peak power was higher at exercise (P < 0.001) and hypoxia (P < 0.001), and was positively related with cardiac output and Ve (P < 0.001). Ve peak power in hypoxia was positively related with the ventilatory response to CO2 (HCVR). This novel observation suggests that healthy subjects demonstrate a spontaneous periodic breathing, not clearly observable at rest and in normoxia, but triggered by hypoxic exercise. The periodic pattern is enhanced in subjects with high HVRe and high HCVR, suggesting that oxygen and CO2 play synergistic roles in the modulation of these oscillations. PMID- 25554802 TI - Surfactant protein d family: potential for diagnosis or monitoring therapy in autoimmune diseases? PMID- 25554803 TI - Progress in the evolution of systemic sclerosis classification criteria and recommendation for additional comparative specificity studies. PMID- 25554804 TI - Systemic sclerosis classification: a rose by any other name would smell as sweet? PMID- 25554805 TI - Arthritis clinical trials at a crossroad. PMID- 25554806 TI - Delivering future clinical trials in rheumatology. PMID- 25554807 TI - Pulmonary nodular amyloidosis in Sjogren syndrome. PMID- 25554809 TI - Spontaneous bronchopleural fistula caused by a cavitating rheumatoid mass. PMID- 25554808 TI - Hydroxychloroquine-induced hyperpigmentation of the skin. PMID- 25554810 TI - Spondyloarthritis in African blacks. PMID- 25554811 TI - Anti-NMDA receptor encephalitis in a patient with rheumatoid arthritis. PMID- 25554813 TI - Breastfeeding duration and weight gain trajectory in infancy. AB - BACKGROUND AND OBJECTIVES: Short breastfeeding duration may exacerbate accelerated early growth, which is linked to higher obesity risk in later life. This study tested the hypothesis that infants at higher risk for obesity were more likely to be members of a rising weight-for-length (WFL) z score trajectory if breastfed for shorter durations. METHODS: This prospective, observational study recruited women from an obstetric patient population in rural central New York. Medical records of children born to women in the cohort were audited for weight and length measurements (n = 595). We identified weight gain trajectories for infants' WFL z scores from 0 to 24 months by using maximum likelihood latent class models. Individual risk factors associated with weight gain trajectories (P <= .05) were included in an obesity risk index. Logistic regression analysis was performed to investigate whether the association between breastfeeding duration (<2 months, 2-4 months, >4 months) and weight gain trajectory varied across obesity risk groups. RESULTS: Rising and stable weight gain trajectories emerged. The obesity risk index included maternal BMI, education, and smoking during pregnancy. High-risk infants breastfed for <2 months were more likely to belong to a rising rather than stable weight gain trajectory (odds ratio, 2.55; 95% confidence interval, 1.14-5.72; P = .02). CONCLUSIONS: Infants at the highest risk for rising weight patterns appear to benefit the most from longer breastfeeding duration. Targeting mothers of high-risk infants for breastfeeding promotion and support may be protective against overweight and obesity during a critical window of development. PMID- 25554816 TI - Neuroimaging of extremely preterm infants: perils of prediction. PMID- 25554815 TI - Early weight loss nomograms for exclusively breastfed newborns. AB - BACKGROUND: The majority of newborns are exclusively breastfed during the birth hospitalization, and weight loss is nearly universal for these neonates. The amount of weight lost varies substantially among newborns with higher amounts of weight loss increasing risk for morbidity. No hour-by-hour newborn weight loss nomogram exists to assist in early identification of those on a trajectory for adverse outcomes. METHODS: For 161 471 term, singleton neonates born at >=36 weeks' gestation at Northern California Kaiser Permanente hospitals in 2009-2013, data were extracted from the birth hospitalization regarding delivery mode, race/ethnicity, feeding type, and weights from electronic records. Quantile regression was used to create nomograms stratified by delivery mode that estimated percentiles of weight loss as a function of time among exclusively breastfed neonates. Weights measured subsequent to any nonbreastmilk feeding were excluded. RESULTS: Among this sample, 108 907 newborns had weights recorded while exclusively breastfeeding with 83 433 delivered vaginally and 25 474 delivered by cesarean. Differential weight loss by delivery mode was evident 6 hours after delivery and persisted over time. Almost 5% of vaginally delivered newborns and >10% of those delivered by cesarean had lost >=10% of their birth weight 48 hours after delivery. By 72 hours, >25% of newborns delivered by cesarean had lost >=10% of their birth weight. CONCLUSIONS: These newborn weight loss nomograms demonstrate percentiles for weight loss by delivery mode for those who are exclusively breastfed. The nomograms can be used for early identification of neonates on a trajectory for greater weight loss and related morbidities. PMID- 25554817 TI - Incidental findings of nonparentage should be disclosed. PMID- 25554818 TI - Findings of nonparentage: a case for autonomy. PMID- 25554819 TI - Author's response: re: findings of nonparentage: a case for autonomy. PMID- 25554821 TI - Vibrational Stark effects to identify ion pairing and determine reduction potentials in electrolyte-free environments. AB - A recently developed instrument for time-resolved infrared detection following pulse radiolysis has been used to measure the nu(C=N) IR band of the radical anion of a CN-substituted fluorene in tetrahydrofuran. Specific vibrational frequencies can exhibit distinct frequency shifts due to ion pairing, which can be explained in the framework of the vibrational Stark effect. Measurements of the ratio of free ions and ion pairs in different electrolyte concentrations allowed us to obtain an association constant and free energy change for ion pairing. This new method has the potential to probe the geometry of ion pairing and allows the reduction potentials of molecules to be determined in the absence of electrolyte in an environment of low dielectric constant. PMID- 25554822 TI - A luminescent poly(amidoamine)-iridium complex as a new singlet-oxygen sensitizer for photodynamic therapy. AB - A polymer complex (1P) was synthesized by binding bis(cyclometalated) Ir(ppy)2(+) fragments (ppy = 2-phenylpyridyl) to phenanthroline (phen) pendants of a poly(amidoamine) copolymer (PhenISA, in which the phen pendants involved ~6% of the repeating units). The corresponding molecular complex [Ir(ppy)2(bap)](+) (1M, bap = 4-(butyl-4-amino)-1,10-phenanthroline) was also prepared for comparison. In water solution 1P gives nanoaggregates with a hydrodynamic diameter of 30 nm in which the lipophilic metal centers are presumed to be segregated within polymer tasks to reduce their interaction with water. Such confinement, combined with the dilution of triplet emitters along the polymer chains, led to 1P having a photoluminescence quantum yield greater than that of 1M (0.061 vs 0.034, respectively, in an aerated water solution) with a longer lifetime of the (3)MLCT excited states and a blue-shifted emission (595 nm vs 604 nm, respectively). NMR data supported segregation of the metal centers. Photoreaction of O2 with 1,5 dihydroxynaphthalene showed that 1P is able to sensitize (1)O2 generation but with half the quantum yield of 1M. Cellular uptake experiments showed that both 1M and 1P are efficient cell staining agents endowed with two-photon excitation (TPE) imaging capability. TPE microscopy at 840 nm indicated that both complexes penetrate the cellular membrane of HeLa cells, localizing in the perinuclear region. Cellular photodynamic therapy tests showed that both 1M and 1P are able to induce cell apoptosis upon exposure to Xe lamp irradiation. The fraction of apoptotic cells for 1M was higher than that for 1P (74 and 38%, respectively) 6 h after being irradiated for 5 min, but cells incubated with 1P showed much lower levels of necrosis as well as lower toxicity in the absence of irradiation. More generally, the results indicate that cell damage induced by 1M was avoided by binding the iridium sensitizers to the poly(amidoamine). PMID- 25554823 TI - Multidisciplinary predictors of adherence to contemporary dance training: findings from the UK Centres for Advanced Training. AB - Little is known about the predictors of adherence in a dance context. The aim of this study was to investigate adherence to a dance talent programme using a multidisciplinary set of variables representing psychological correlates of adherence, maturation and physical factors relating to dance talent. Psychological (passion, motivational climate perceptions, eating attitudes), physical competence (vertical jump height, handgrip strength, hamstring flexibility, external hip rotation, aerobic fitness), and maturation-related (age of menarche) variables were gathered from female students enrolled on a dance talent programme. Participation behaviour (adherence/dropout) was collected from the talent programme's records approximately two years later. Logistic regression analysis of 287 participants revealed that greater levels of harmonious passion predicted greater likelihood of adherence to the programme, and greater ego involving motivational climate perceptions predicted less likelihood of adherence. Neither measures of physical competence nor maturation distinguished adhering from dropout participants. Overall, the results of this study indicate that psychological factors are more important than physical competence and maturation in the participation behaviour of young talented dancers. PMID- 25554824 TI - "Highly qualified loser"? Harvey Cushing and the Nobel Prize. AB - Neurosurgery, in particular surgery of the brain, was recognized as one of the most spectacular transgressions of the traditional limits of surgical work. With their audacious, technically demanding, laboratory-based, and highly promising new interventions, prominent neurosurgeons were primary candidates for the Nobel Prize. Accordingly, neurosurgical pioneers such as Victor Horsley and, in particular, Harvey Cushing continued to be nominated for the prize. However, only Antonio Egas Moniz was eventually awarded the prestigious award in 1949 for the introduction of frontal lobotomy, an intervention that would no longer be prize worthy from today's perspective. Horsley and Cushing, who were arguably the most important proponents of early neurosurgery, remained "highly qualified losers," as such cases have been called. This paper examines the nominations, reviews, and discussions kept in the Nobel Archives to understand the reasons for this remarkable choice. At a more general level, the authors use the example of neurosurgery to explore the mechanisms of scientific recognition and what could be called the enacting of excellence in science and medicine. PMID- 25554825 TI - Prognostic value of premorbid hypertension and neurological status in aneurysmal subarachnoid hemorrhage: pooled analyses of individual patient data in the SAHIT repository. AB - OBJECT: The literature has conflicting reports about the prognostic value of premorbid hypertension and neurological status in aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to investigate the prognostic value of premorbid hypertension and neurological status in the SAH International Trialists repository. METHODS: Patient-level meta-analyses were conducted to investigate univariate associations between premorbid hypertension (6 studies; n = 7249), admission neurological status measured on the World Federation of Neurosurgical Societies (WFNS) scale (10 studies; n = 10,869), and 3-month Glasgow Outcome Scale (GOS) score. Multivariable analyses were performed to sequentially adjust for the effects of age, CT clot burden, aneurysm location, aneurysm size, and modality of aneurysm repair. Prognostic associations were estimated across the ordered categories of the GOS using proportional odds models. Nagelkerke's R(2) statistic was used to quantify the added prognostic value of hypertension and neurological status beyond those of the adjustment factors. RESULTS: Premorbid hypertension was independently associated with poor outcome, with an unadjusted pooled odds ratio (OR) of 1.73 (95% confidence interval [CI] 1.50-2.00) and an adjusted OR of 1.38 (95% CI 1.25-1.53). Patients with a premorbid history of hypertension had higher rates of cardiovascular and renal comorbidities, poorer neurological status (p <= 0.001), and higher odds of neurological complications including cerebral infarctions, hydrocephalus, rebleeding, and delayed ischemic neurological deficits. Worsening neurological status was strongly independently associated with poor outcome, including WFNS Grades II (OR 1.85, 95% CI 1.68-2.03), III (OR 3.85, 95% CI 3.32-4.47), IV (OR 5.58, 95% CI 4.91-6.35), and V (OR 14.18, 95% CI 12.20-16.49). Neurological status had substantial added predictive value greater than the combined value of other prognostic factors (R(2) increase > 10%), while the added predictive value of hypertension was marginal (R(2) increase < 0.5%). CONCLUSIONS: This study confirmed the strong prognostic effect of neurological status as measured on the WFNS scale and the independent but weak prognostic effect of premorbid hypertension. The effect of premorbid hypertension could involve multifactorial mechanisms, including an increase in the severity of initial bleeding, the rate of comorbid events, and neurological complications. PMID- 25554826 TI - Composite scaffolds of dicalcium phosphate anhydrate /multi-(amino acid) copolymer: in vitro degradability and osteoblast biocompatibility. AB - This study aims to evaluate in vitro degradability and osteoblast biocompatibility of dicalcium phosphate anhydrate/multi-(amino acid) (DCPA/MAA) composites prepared by in situ polymerization method. The results revealed that the composites could be slowly degraded in PBS solution, with weight loss of 9.5 +/- 0.2 wt.% compared with 12.2 +/- 0.2 wt.% of MAA copolymer after eight weeks, and the changes of pH value were in the range of 7.18-7.4 and stabilized at 7.24. In addition, the compressive strength of the composite decreased from 98 to 62 MPa while that of MAA copolymer from 117 to 86 MPa. Furthermore, with non toxicity demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, the addition of DCPA to the MAA copolymer evidenced an enhancement of osteoblast differentiation and attachment compared with pure MAA materials regarding to alkaline phosphatase activity as well as initial cell adhesion. The results indicated that the DCPA/MAA scaffolds with good osteoblast biocompatibility, degradability, and sufficient strength had promising potential application in bone tissue engineering. PMID- 25554827 TI - Diethylaminobenzaldehyde is a covalent, irreversible inactivator of ALDH7A1. AB - There is growing interest in aldehyde dehydrogenases (ALDHs) because of their overexpression in cancer stem cells and the ability to mediate resistance to cancer drugs. Here, we report the first crystal structure of an aldehyde dehydrogenase complexed with the inhibitor 4-diethylaminobenzaldehyde (DEAB). Contrary to the widely held belief that DEAB is a reversible inhibitor of ALDHs, we show that DEAB irreversibly inactivates ALDH7A1 via formation of a stable, covalent acyl-enzyme species. PMID- 25554828 TI - Sexual and reproductive health and rights of adolescent girls: evidence from low- and middle-income countries. AB - This paper reviews the evidence on sexual and reproductive health and rights (SRHR) of adolescent girls in low-income and middle-income countries (LMIC) in light of the policy and programme commitments made at the International Conference on Population and Development (ICPD), analyses progress since 1994, and maps challenges in and opportunities for protecting their health and human rights. Findings indicate that many countries have yet to make significant progress in delaying marriage and childbearing, reducing unintended childbearing, narrowing gender disparities that put girls at risk of poor SRH outcomes, expanding health awareness or enabling access to SRH services. While governments have reaffirmed many commitments, policy development and programme implementation fall far short of realising these commitments. Future success requires increased political will and engagement of young people in the formulation and implementation of policies and programmes, along with increased investments to deliver at scale comprehensive sexuality education, health services that are approachable and not judgemental, safe spaces programmes, especially for vulnerable girls, and programmes that engage families and communities. Stronger policy-making and programming also require expanding the evidence on adolescent health and rights in LMICs for both younger and older adolescents, boys and girls, and relating to a range of key health matters affecting adolescents. PMID- 25554829 TI - Strain shielding from mechanically activated covalent bond formation during nanoindentation of graphene delays the onset of failure. AB - Mechanical failure of an ideal crystal is dictated either by an elastic instability or a soft-mode instability. Previous interpretations of nanoindentation experiments on suspended graphene sheets,1,2 however, indicate an anomaly: the inferred strain in the graphene sheet directly beneath the diamond indenter at the measured failure load is anomalously large compared to the fracture strains predicted by both soft-mode and acoustic analyses. Through multiscale modeling combining the results of continuum, atomistic, and quantum calculations, and analysis of experiments, we identify a strain-shielding effect initiated by mechanochemical interactions at the graphene-indenter interface as the operative mechanism responsible for this anomaly. Transmission electron micrographs and a molecular model of the diamond indenter's tip suggest that the tip surface contains facets comprising crystallographic {111} and {100} planes. Ab initio and molecular dynamics (MD) simulations confirm that a covalent bond (weld) formation between graphene and the crystallographic {111} and {100} facets on the indenter's surface can be induced by compressive contact stresses of the order achieved in nanoindentation tests. Finite element analysis (FEA) and MD simulations of nanoindentation reveal that the shear stiction provided by the induced covalent bonding restricts relative slip of the graphene sheet at its contact with the indenter, thus initiating a local strain-shielding effect. As a result, subsequent to stress-induced bonding at the graphene-indenter interface, the spatial variation of continuing incremental strain is substantially redistributed, locally shielding the region directly beneath the indenter by limiting the buildup of strain while imparting deformation to the surrounding regions. The extent of strain shielding is governed by the strength of the shear stiction, which depends upon the level of hydrogen saturation at the indenter's surface. We show that at intermediate levels of hydrogen saturation the strain shielding effect can enable the graphene to support experimentally determined fracture loads and displacements without prematurely reaching locally limiting states of stress and deformation. PMID- 25554820 TI - Neuroimaging and neurodevelopmental outcome in extremely preterm infants. AB - BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3 6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging. PMID- 25554831 TI - Trapping and V3-radial artery graft-V4 bypass for ruptured dissecting aneurysm of the vertebral artery. AB - The authors show a surgical technique of trapping/resection of ruptured dominant vertebral artery aneurysm in conjunction with reconstruction of vertebral artery by V3-radial artery (RA) graft-V4 bypass through suboccipital craniotomy and far lateral approach. Step by step muscle dissection in posterior fossa enable fine exposure of occipital artery for possible OA-PICA bypass and V3 portion of vertebral artery. Extradural drilling of posterior one-third condyle and condylar fossa facilitate exposure of triangular surgical corridor made by medulla, spinal root of 11th nerve and lower cranial nerves, and thus enabling aneurismal resection and RA-V4 anastomosis. The video can be found here: http://youtu.be/LxsARGdHSVw . PMID- 25554830 TI - A survey of tremetone, dehydrotremetone, and structurally related compounds in Isocoma spp. (goldenbush) in the southwestern United States. AB - Isocoma pluriflora, a plant prevalent on land used for livestock production and native to Arizona, New Mexico, West Texas, and Northern Mexico, is poisonous and causes trembles in livestock. Tremetone and dehydrotremetone have been suggested as the toxic compounds in I. pluriflora. In this study several different Isocoma spp., including I. pluriflora, I. tenuisecta, I. azteca, I. acradenia, and I. rusbyi, that are native to land used for grazing livestock in the southwestern United States were analyzed by high performance liquid chromatography (HPLC) for tremetone, dehydrotremetone, and other structurally related compounds. This is the first report of tremetone, dehydrotremetone, and 3-oxyangeloyltremetone in I. tenuisecta, I. azteca, I. acradenia, I. rusbyi, and several other Isocoma spp. In addition, this is the first report of 4-hydroxy-3-(3-methyl-2 butenyl)acetophenone and 7-isopentenyloxycoumarin in Isocoma spp. PMID- 25554832 TI - Microsurgical clipping of an unruptured basilar apex aneurysm. AB - Unruptured posterior circulation aneurysms pose a treatment challenge. Although data supports the use of endovascular technique for select ruptured cases, in unruptured cases, there may be clinical equipoise. Furthermore, wide-necked basilar apex aneurysms commonly require the use of stents and placement of patients on dual therapy. We present a case of a healthy 50-year-old woman with an incidental basilar tip aneurysm treated via an orbitozygomatic craniotomy. This video highlights the steps of dynamic retraction, which is retraction without placement of permanent rigid retraction system, and the added maneuverability afforded by the use of the mouthpiece on the microscope. The video can be found here: http://youtu.be/jVfC6CCXdZY . PMID- 25554833 TI - Far-lateral approach for surgical treatment of fusiform PICA aneurysm. AB - Ruptured fusiform posterior inferior cerebellar artery (PICA) aneurysms can be technically challenging lesions. Surgeons must be ready to employ a variety of strategies in the successful treatment of these aneurysms. Strategies include complex clip techniques including clip-wrapping or trapping and revascularization. The case presented here is of a man with subarachnoid hemorrhage from a fusiform ruptured PICA aneurysm. The technique demonstrated is a far-lateral approach and a clip-wrap technique using muslin gauze. The patient was given aspirin preoperatively in preparation for possible occipital-PICA bypass if direct repair was not feasible. It is the authors' preference to perform direct vessel repair as a primary goal and use bypass techniques when this is not possible. Vessel patency was evaluated after clip-wrapping using intraoperative Doppler. Intraoperative somatosensory and motor evoked potential monitoring is used in such cases. The patient recovered well. The video can be found here: http://youtu.be/iwLqufH47Ds . PMID- 25554834 TI - Surgical clipping of a ruptured posterior inferior cerebellar artery aneurysm. AB - Posterior circulation aneurysms are commonly treated with endovascular techniques. In select cases, microsurgery remains an essential tool for treating these lesions. We present a case of a ruptured posterior inferior cerebellar artery (PICA) aneurysm approached via a craniotomy. Given the labyrinth of neurovascular bundles present in the posterior fossa, surgical exposure of PICA aneurysms can be challenging. This video demonstrates the steps of the craniotomy, subarachnoid dissection, mobilization of the vertebral artery and lower cranial nerves, and clipping of the aneurysm. The video can be found here: http://youtu.be/fQSxQj7oL0U . PMID- 25554835 TI - Surgical clipping of a large left middle cerebral artery aneurysm. AB - Middle cerebral artery aneurysms, especially those with complex morphology, are considered excellent aneurysms for surgical clipping, given the challenges that exist with current endovascular techniques. We present a case of a large, complex, left middle cerebral artery aneurysm treated with microsurgical clipping. This video highlights critical steps in obtaining proximal and distal control as well as subarachnoid dissection necessary to prepare the aneurysm for final clipping. The video can be found here: http://youtu.be/RlKH2Km9z5Y . PMID- 25554836 TI - Repair of intraoperative aneurysm neck tear utilizing the cotton-clipping technique. AB - Intraoperative rupture of an intracranial aneurysm is a potentially devastating but controllable complication. The authors have successfully used the previously described cotton-clip technique to repair tears at the necks of aneurysms. (1-4) A tear on the neck of the aneurysm is covered with a piece of cotton and held in place with a suction device. The cotton is then clipped onto the tear with an aneurysm clip, using the cotton as a bolster. This simple, effective method has been useful in repairing a partial avulsion of the neck of an aneurysm. (1 , 3) The video can be found here: http://youtu.be/nT86RYVQWpc . PMID- 25554837 TI - Combined interhemispheric and pterional approach for ACOM and left MCA aneurysms. AB - This video demonstrates combined two separate craniotomies for two difficult unruptured cerebral aneurysms. The anterior communicating artery (ACOM) aneurysm existed at a high position, projected posteriorly, and thus necessitated an interhemispheric approach. Left middle cerebral artery (MCA) aneurysm with complex figure was treated through a separate pterional approach. Meticulous micro-cisternal opening under high magnification enabled safe and effective exposure of both aneurysms with minimal brain retraction, which alleviated brain damage as shown in postoperative images. The video can be found here: http://youtu.be/mBYsaAVekCA . PMID- 25554839 TI - Direct clipping of large basilar trunk aneurysm. AB - A large basilar trunk aneurysm was incidentally found in a 77-year-old woman in examination for headache. Though it was asymptomatic, high signal intensity was noticed in the brainstem around the aneurysm on FLAIR image of MRI. As she was otherwise healthy, surgical clipping was performed through anterior temporal approach. The video can be found here: http://youtu.be/0soWM8meCW8 . PMID- 25554838 TI - Microsurgical clipping following failed coiling of a giant ophthalmic aneurysm. AB - With the advent of endovascular modalities, endovascular coiling has become a progressively more common method of addressing intracranial aneurysms. When despite coiling, an aneurysm continues to enlarge, open microsurgical clipping is a viable, though technically demanding option. We present a unique case of failed coiling of a giant ophthalmic region aneurysm, in which the aneurysm was successfully managed via open microsurgical approach. We highlight the unique challenges faced and demonstrate the surgical process in an operative video presentation. The video can be found here: http://youtu.be/k2P4c4Lvq7g . PMID- 25554840 TI - Clipping of a partially thrombosed giant VA aneurysm. AB - Microsurgical aspects of clipping of a giant partially thrombosed VA aneurysm in a 57-year-old female are presented and explained in the form of a short video. The presentation includes preparation of the VA, PICA and perforating arteries, the clipping of the aneurysm itself as well as the reduction of the aneurysm mass using ultrasonic tissue ablation. In addition pre- and post-operative imaging and superimposed text is used to illustrate the presented anatomy. The video can be found here: http://youtu.be/7so8qPMQ1Jk . PMID- 25554841 TI - Clipping of bilateral MCA aneurysms and a coiled ACOM aneurysm through a modified lateral supraorbital craniotomy. AB - We showcase the microsurgical clipping of a left middle cerebral artery (MCA) aneurysm-(B) done through a modified right lateral supraorbital craniotomy, as well as clipping of a previously coiled anterior communicating (ACOM) artery aneurysm-(C) and a bilobed right MCA aneurysm-(A). Splitting of the right sylvian fissure is initially performed following which a subfrontal approach is used to expose and dissect the contralateral sylvian fissure. The left MCA aneurysm is identified and clipped. The ACOM aneurysm is then clipped following multiple clip repositioning based on flow measurements. The right MCA aneurysm is then identified and each lobe is clipped separately. The first picture showcased in this video is a side to side right and left ICA injection in AP projection. In this picture, (A) points to the bilobed right MCA aneurysm, (B) to the left middle cerebral artery (MCA) aneurysm, and (C) to the previously coiled anterior communicating (ACOM) artery aneurysm. The red dotted line shows that both MCA aneurysms lie within the same plane which makes it easier to clip both of them, through one small craniotomy. The video can be found here: http://youtu.be/4cQC7nHsL5I . PMID- 25554842 TI - Clipping and STA-MCA bypass for unruptured AcomA aneurysm associated with unilateral MCA occlusion. AB - The authors show a surgical technique of clipping in conjunction with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass to treat unruptured anterior communicating artery (AcomA) aneurysm associated with unilateral MCA occlusion. First, through MCA occlusion side, fronto-temporal craniotomy, extra dural drilling of lesser sphenoid wing, and followed by wide exposure of Sylvian fissure, STA-MCA bypass was performed. Then, through trans-Sylvian, fronto-basal, and lateral trajectory, interhemispheric fissure was dissected from the base, which enabled good exposure and clipping of high positioned AcomA aneurysm. The video can be found here: http://youtu.be/GWItnRSs3m4 . PMID- 25554843 TI - Clip reconstruction of an 8 cm giant internal carotid artery bifurcation aneurysm: microsurgical technique. AB - Thrombosed giant intracranial aneurysms usually present with symptoms and signs from their mass effect. Although multiple treatment options are available, direct clip reconstruction with thromboendarterectomy remains the gold standard. Here we present a 66-year-old man with seizure, aphasia and hemiparesis. Work-up revealed a giant partially thrombosed aneurysm of the internal carotid artery bifurcation with surrounding vasogenic edema. He underwent clip reconstruction of the aneurysm via a cranio-orbital approach. Although we prepared for bypass with the radial artery and/or the superficial temporal artery, we were able to clip reconstruct the aneurysm without bypass. The patient improved upon his pre-morbid state after surgery and made an excellent recovery. The video can be found here: http://youtu.be/P_10hRQFuPo . PMID- 25554844 TI - Combined microsurgical PICA-PICA bypass and endovascular parent artery occlusion for a ruptured dissecting vertebral artery aneurysm. AB - Dissecting vertebral artery (VA) aneurysms are difficult to obliterate when the parent artery cannot be safely occluded. In this video, we demonstrate a combined microsurgical and endovascular treatment technique for a ruptured, dissecting VA aneurysm incorporating the origin of the posterior inferior cerebellar artery (PICA). We first performed a PICA-PICA side-to-side bypass to preserve flow through the right PICA. An endovascular approach was then utilized to embolize the proximal portion of the aneurysm from the right VA and the distal portion of the aneurysm from the left VA. The video can be found here: http://youtu.be/dkkKsX2BiJI . PMID- 25554845 TI - Clipping of ipsilateral posterior communicating and superior cerebellar artery aneurysms. AB - The case is a 55-year-old female who presented with dizziness as the chief complaint. She has a family history of two relatives with subarachnoid hemorrhage. Digital subtraction angiography revealed the presence of a left-sided posterior communicating artery aneurysm and an ipsilateral superior cerebellar artery (SCA) aneurysm. Due to the smaller nature of the SCA, a decision was made to proceed with surgical clipping of both lesions through a pterional approach. A narrated video with illustrations depicts the intraoperative management of these lesions with postoperative angiography results. The video can be found here: http://youtu.be/HCHToSsXv-4 . PMID- 25554846 TI - Subtemporal approach for distal basilar occlusion for giant aneurysm. Nuances and advantages of the subtemporal approach. AB - We described the subtemporal approach, which was used for distal basilar artery occlusion in a patient with a symptomatic giant unclippable aneurysm. We discuss issues related to positioning and lumbar drainage. We illustrate the basic steps: identification of the tentorial notch; sharp opening of the arachnoid behind the third nerve; placement of a fixed mechanical retractor to "hold" the brain; identification of the third nerve and mobilization from arachnoid attachments; identification of the course and insertion of the fourth nerve; division and retraction of the tentorial edge to enhance exposure; preparation of the "perforator-free zone"; and final clip application followed by ICG fluorescein angiography. We show some of the areas exposed with this approach. The video can be found here: http://youtu.be/S_NLIjKQL_o . PMID- 25554847 TI - Anterior communicating artery aneurysm clipping using standard small fronto pterional approach, clipping with 3 Lazic clips. AB - An 80-year-old female presented 5 months previous for nonspecific gait disturbance, during which an MRI was performed. A large based anterior communicating artery aneurym was found independent of neurology. An interdisciplinary discussion favored surgical treatment, on which the patient insisted. Surgery was performed using standard anesthesia techniques with intraoperative burst supression during surgery, neuromonitoring with MEP and SEP, as well as ICG angiography, microdoppler and neuronavigation. Successful clipping was performed with 2 fenestrated straight and one bayoneted straight Lazic clip. Temporary clipping was 6.1 minutes. Postoperative angiography showed exclusion of the aneurysm, and there was no neurological deficit. The video can be found here: http://youtu.be/WKjOHG8irFo . PMID- 25554848 TI - Surgical treatment of a large ruptured internal carotid artery bifurcation aneurysm. AB - Ruptured aneurysms with intraparenchymal hematoma and mass effect are primarily treated by surgical clipping. In this video presentation, a 68 year old male with a large ruptured right ICA bifurcation aneurysm is presented. Patient's neurological exam was rapidly deteriorating, therefore the patient was transferred to the operating theater after initial evaluation by CT and CT angiogram. A pterional craniotomy was performed, the frontal hematoma was partially removed and the aneurysm was clipped. Residual hematoma was removed after securing the aneurysm and the aneurysm dome was punctured(detail of surgical clipping in the video). Patient made a good recovery at 2 weeks post-op with complete recovery of left sided weakness, and some remaining cognitive deficit. The video can be found here: http://youtu.be/dKFWptdgC4M . PMID- 25554849 TI - Clip ligation of contralateral P1 aneurysm: extending the working depth of microsurgery along the skull base. AB - Clip ligation of posterior circulation aneurysms can be challenging because of limited operative working space and angles. Certain proximal posterior cerebral (P1) aneurysms are especially challenging because of their locations within the lateral anterior interpeduncular fossa. We present a 52-year-old woman who had previously undergone coil embolization of a ruptured right-sided posterior communicating artery aneurysm. She also had two other small aneurysms (left posterior communicating artery and right P1 aneurysms). She underwent clip ligation of the latter two unruptured aneurysms through a left-sided pterional craniotomy. The microsurgical techniques to clip ligate a contralateral P1 aneurysm are discussed in the video. The video can be found here: http://youtu.be/YBE7FcFGlpQ . PMID- 25554850 TI - High flow EC-IC bypass for a giant left MCA aneurysm. AB - Giant cerebral aneurysms may be treated through a variety of options, including aneurysm trapping with concurrent bypass. This video describes the case of a large, recurrent, left middle cerebral artery aneurysm that was treated using a high flow, radial artery bypass graft, from the external carotid artery to the left temporal M2 branch. A step-by-step operative description, with emphasis on proper microsurgical technique, is included. The video can be found here: http://youtu.be/9xTMC6InivQ . PMID- 25554851 TI - Introduction: intracranial aneurysm surgery. PMID- 25554852 TI - State discretion over Medicaid coverage for mental health and addiction services. AB - Approximately one-third of adults who enroll in Medicaid because of a disability have a serious mental illness. Arguably, this population stands to benefit from insurance coverage that complies with the Mental Health Parity and Addiction Equity Act (MHPAEA). The MHPAEA and the Affordable Care Act (ACA) do not guarantee such coverage for this beneficiary group; however, they provide a variety of mechanisms by which states may provide parity-compliant coverage for mental health and substance use disorder treatment. This column explains key interactions between the MHPAEA, the ACA, and the Medicaid program that permit states to determine whether and how to provide parity-consistent coverage to beneficiaries with disabilities. PMID- 25554853 TI - Novel transgenic lines to label sarcolemma and myofibrils of the musculature. PMID- 25554854 TI - Increase in untreated cases of psychiatric disorders during the transition to adulthood. AB - OBJECTIVE: During the transition to adulthood, youths face challenges that may limit their likelihood of obtaining services for psychiatric problems. The goal of this analysis was to estimate changes in rates of service use and untreated psychiatric disorders during the transition from adolescence to adulthood. METHODS: In a prospective, population-based study, participants were assessed up to four times in adolescence (ages 13-16; 3,983 observations of 1,297 participants, 1993-2000) and three times in young adulthood (ages 19, 21, and 24 26; 3,215 observations of 1,273 participants, 1999-2010). Structured diagnostic interviews were used to assess service need (participants meeting DSM-IV diagnostic criteria for a psychiatric disorder) and use of behavioral services in 21 service settings in the past three months. RESULTS: During young adulthood, 28.9% of cases of psychiatric disorders were associated with some treatment, compared with a rate of 50.9% for the same participants during adolescence. This decrease included a near-complete drop in use of educational and vocational services as well as declines in use of specialty behavioral services. Young adults most frequently accessed services in specialty behavioral or general medical settings. Males, African Americans, participants with substance dependence, and participants living independently were least likely to get treatment. For cases of psychiatric disorders among young adults, insurance and poverty status were unrelated to likelihood of service use. CONCLUSIONS: Young adults were much less likely to receive treatment for psychiatric problems than they were as adolescents. Public policy must address gaps in service use during the transition to adulthood. PMID- 25554855 TI - Classification of middle fossa floor dehiscence syndromes. AB - OBJECT: Middle fossa floor dehiscence (MFFD) can present as multiple syndromes depending on dehiscence location, tissue herniation, and dural integrity. The authors propose a classification system for MFFD with the potential to guide clinical decision making. METHODS: A retrospective analysis of the electronic medical records (years 1995-2012) of patients who had undergone temporal craniotomy for the surgical repair of an MFFD syndrome at a single institution was undertaken. Reviewed data included demographic, operative, presentation, and outcome details. Middle fossa floor dehiscence was classified as follows: Class A, bony dehiscence without herniation of the brain and/or meninges; Class B, herniation of the brain and/or meninges through the middle fossa floor without CSF leakage; Class C, dehiscence with CSF leakage without meningitis; or Class D, dehiscence with meningitis. RESULTS: Fifty-one patients, 22 males and 29 females, were included in the analysis. The mean age was 48.7 +/- 15.5 years, mean body mass index was 32.65 +/- 6.86 kg/m(2), and mean symptom duration was 33 +/- 42 months. Seven patients underwent repeat surgery for symptomatic recurrence; therefore, there were 58 surgical encounters. Repair included bony reconstruction with hydroxyapatite with or without resection of encephaloceles and/or repair of a dural defect. According to the MFFD classification system described, 15, 8, 27, and 8 cases were categorized as Class A, B, C, and D, respectively. The prevalence of hearing loss was 87%, 63%, and 70% in Classes A, B, and C, respectively. Vestibular symptoms were more prevalent in Class A. Seven patients reported persistent symptoms at the last follow-up. Transient complications were similar in each classification (13%-25%), and a single permanent complication related to anesthesia was observed. There were no mortalities or severe neurological morbidities in the series. CONCLUSIONS: Middle fossa floor dehiscence has a spectrum of clinical presentations. A classification system may help to clarify the diagnosis and guide therapy. Surgery, the mainstay of treatment, is safe and well tolerated. PMID- 25554856 TI - Weight, Length, and Body Mass Index Growth of Children Under 2 Years of Age With Cleft Lip and Palate. AB - OBJECTIVE: To study the growth of length-for-age (L/A), weight-for-age (W/A), and body mass index (BMI) of children with cleft lip and palate receiving a normal diet; to establish specific growth curves for children with cleft palate with or without cleft lip (CLP/ICP) who had not undergone palatoplasty and for children with isolated cleft lip (ICL); and to assess if CLP/ICP growth differed from ICL growth and if CLP/ICP and ICL growth differed from growth for typical children. DESIGN: Prospective and cross-sectional study. SETTING: Hospital for Rehabilitation of Craniofacial Anomalies, Bauru, Sao Paulo, Brazil. MAIN OUTCOME MEASURES: Weight and length of 381 children with cleft lip and palate and who were younger than 2 years were recorded and used to calculate W/A, L/A, and BMI growth curves. The 2006 World Health Organization growth charts were used as a reference for typical children. All children received a normal diet for age. RESULTS: Children with CLP/ICP had median W/A and BMI growth curves below growth curves for typical children but showed spontaneous recovery starting at approximately 5 months of age, even with nonoperated cleft palate. Children with ICL had growth similar to that of typical children. Children with CLP/ICP, who initially had W/A and BMI values less than those of the ICL group, had W/A and BMI equal to or higher than the ICL group after 9 months of age. CONCLUSION: Children with CLP/ICP had impaired W/A and BMI growth with spontaneous recovery starting early in childhood. This study established specific W/A, BMI, and L/A growth curves for children with cleft lip and palate. PMID- 25554857 TI - Multidisciplinary Aspects of 104 Patients With Pierre Robin Sequence. AB - OBJECTIVE: To describe Pierre Robin sequence patients with a cleft palate from a multidisciplinary perspective. PATIENTS: A total of 104 individuals with Pierre Robin sequence and cleft palate, born between 1980 and 2010. METHOD: Data were collected retrospectively and compared with large control groups. RESULTS: Of 104 patients, 19 (18.3%) were treated with a nasopharyngeal or oropharyngeal tube, continuous positive airway pressure, and/or a tracheotomy. The mean weight percentile for newborns with Pierre Robin sequence was 30.9. It decreased to 29.9 at the time of cleft palate repair (mean age, 13.7 months) (P = .78). Of 87 patients, 30 (34.5%) developed normal speech after cleft palate repair. Of 93 nonsyndromic Pierre Robin sequence patients, 31 (33.3%) had or are having surgery for velopharyngeal insufficiency, a rate that is significantly higher when compared with a control group of cleft palate-only patients (19.4%; P = .004). Of 31 patients, 25 (80.6%) developed normal resonance after surgery for velopharyngeal insufficiency. There was no significant difference in the rate of syndromes between the Pierre Robin sequence patients and a control group of cleft palate patients without Pierre Robin sequence (P = .25). Seven of 39 boys (17.9%) with Pierre Robin sequence had a diagnosis of autism spectrum disorder. CONCLUSION: Even though the mean weight percentile for newborns with Pierre Robin sequence was low, the patients did not show a growth spurt during the first year of life. The high rate of velopharyngeal insufficiency after cleft palate repair in patients with Pierre Robin sequence needs further investigation. Also, the high rate of autism spectrum disorder among boys with Pierre Robin sequence prompts further investigation. PMID- 25554858 TI - The influence of dentin demineralization on morphological features of cavities using Er:YAG laser. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of erbium doped: yttrium-aluminum-garnet (Er:YAG) laser parameters and different degrees of demineralization on morphological features, diameter, and depth of prepared cavities. BACKGROUND DATA: Minimally invasive dentin caries removal has been recommended. Ablation of deep caries lesions using Er:YAG laser should preserve remaining demineralized dentin; however, the influence of the degree of mineralization of this substrate had not been entirely described. MATERIALS AND METHODS: A randomized, factorial design was used to study the effects of two factors. Laser parameter was tested at two levels (250 mJ/4 Hz vs. 200 mJ/2 Hz) and degree of demineralization was tested at four levels (control, two-four-eight cycles). Twelve slabs of human dentin were divided into four groups according to the number of cycles induced by pH-cycling: G1, zero cycles; G2, two cycles, G3, four cycles, and G4, eight cycles. An Er:YAG laser was used at an output energy of 250 mJ/4 Hz and 200 mJ/2 Hz for all groups, for 10 sec at 12 mm distance focus/object. Circumference and depth of the cavities were measured on scanning electron microscopy (SEM) images using image analysis software. The mean values were subjected to two way analysis of variance (ANOVA) and Tukey tests. RESULTS: When using 250 mJ/4 Hz, the mean values of circumferential area increased significantly in relation to control (503.54 MUm(2)) with increasing demineralization level (eight cycles) (555.45 MUm(2)). Regardless of the demineralization level, there was also significant statistical difference in the studied measurements of the cavities when 250 mJ/4 Hz and 200 mJ/2 Hz were used. SEM also showed that laser cavity preparations left no smear layer, and the dentinal tubules were clear. CONCLUSIONS: The circumferential area and depth measurements were affected by laser parameter and demineralization level (eight cycles). Energy level output represents a relevant factor for increased circumferential area and depth measurements. High demineralized artificially caries-affected dentin may also imply higher ablation. Appropriated parameter of laser pulse frequency/power density for demineralized dentin should be used for effective less-invasive caries treatment. PMID- 25554859 TI - Site of interstage outpatient care and growth after the Norwood operation. AB - BACKGROUND: Recent efforts have focused on optimising interstage outcomes, including growth, for infants following the Norwood operation. The impact of the site of interstage care remains unclear, and it has been hypothesised that care at the surgical site may be beneficial due to greater access to resources such as nutritional support. This study evaluated the relationship between site of interstage care and weight gain in a large multicentre cohort. METHODS: Infants enrolled in the National Paediatric Cardiology Quality Improvement Collaborative (2008-2013) surviving up to Stage 2 were included. Change in weight-for-age z score between Norwood discharge and Stage 2 admission was compared in those receiving care at the surgical versus non-surgical site. RESULTS: Of the 487 interstage survivors, 60% received all care at the surgical site, and 40% received care at a non-surgical site. There was no significant difference between groups in change in weight-for-age z-score: +0.36+/-0.96 for the surgical site group versus +0.46+/-1.02 for the non-surgical site group, p=0.3. Results were unchanged in multivariable analysis adjusting for differences in important baseline characteristics, duration of interstage, and home surveillance strategy. The proportion of all patients with weight-for-age z-score <-2 decreased from 40% at Norwood discharge to 29% at Stage 2, with no significant difference in change between the two groups (p=0.1). CONCLUSIONS: The site of interstage care was not associated with weight gain during the interstage period. Nearly one-third of patients overall had a weight-for-age z-score <-2 at Stage 2. Further study is required to identify methods to optimise weight gain in these patients. PMID- 25554860 TI - In vivo analysis of biodegradable liposome gold nanoparticles as efficient agents for photothermal therapy of cancer. AB - We report biodegradable plasmon resonant liposome gold nanoparticles (LiposAu NPs) capable of killing cancer cells through photothermal therapy. The pharmacokinetic study of LiposAu NPs performed in a small animal model indicates in situ degradation in hepatocytes and further getting cleared through the hepato biliary and renal route. Further, the therapeutic potential of LiposAu NPs tested in mouse tumor xenograft model using NIR laser (750 nm) illumination resulted in complete ablation of the tumor mass, thus prolonging disease-free survival. PMID- 25554861 TI - Two-dimensional colloidal metal chalcogenides semiconductors: synthesis, spectroscopy, and applications. AB - CONSPECTUS: Semiconductors are at the basis of electronics. Up to now, most devices that contain semiconductors use materials obtained from a top down approach with semiconductors grown by molecular beam epitaxy or chemical vapor deposition. Colloidal semiconductor nanoparticles have been synthesized for more than 30 years now, and their synthesis is becoming mature enough that these nanoparticles have started to be incorporated into devices. An important development that recently took place in the field of colloidal quantum dots is the synthesis of two-dimensional (2D) semiconductor nanoplatelets that appear as free-standing nanosheets. These 2D colloidal systems are the newborn in the family of shaped-controlled nanoparticles that started with spheres, was extended with rods and wires, continued with tetrapods, and now ends with platelets. From a physical point of view, these objects bring 1D-confined particles into the colloidal family. It is a notable addition, since these platelets can have a thickness that is controlled with atomic precision, so that no inhomogeneous broadening is observed. Because they have two large free interfaces, mirror charges play an important role, and the binding energy of the exciton is extremely large. These two effects almost perfectly compensate each other, it results in particles with unique spectroscopic properties such as fast fluorescent lifetimes and extreme color purity (narrow full width at half-maximum of their emission spectra). These nanoplatelets with extremely large confinement but very simple and well-defined chemistry are model systems to check and further develop, notably with the incorporation in the models of the organic/inorganic interface, various theoretical approaches used for colloidal particles. From a chemical point of view, these colloidal particles are a model system to study the role of ligands since they have precisely defined facets. In addition, the synthesis of these highly anisotropic objects triggered new research to understand at a mechanistic level how this strong anisotropy could be generated. Luckily, some of the chemical know-how built with the spherical and rod-shaped particles is being transferred, with some adaptation, to 2D systems, so that 2D core/shell and core/crown heterostructures have recently been introduced. These objects are very interesting because they suggest that multiple quantum wells could be grown in solution. From the application point of view, 2D colloidal nanoplatelets offer interesting perspectives when color purity, charge conductivity, or field tunable absorption are required. In this Account, we review the chemical synthesis, the physical properties, and the applications of colloidal semiconductor nanoplatelets with an emphasis on the zinc-blende nanoplatelets that were developed more specifically in our group. PMID- 25554862 TI - Completing the picture for the smallest eigenvalue of real Wishart matrices. AB - Rectangular real N*(N+nu) matrices W with a Gaussian distribution appear very frequently in data analysis, condensed matter physics, and quantum field theory. A central question concerns the correlations encoded in the spectral statistics of WW^{T}. The extreme eigenvalues of WW^{T} are of particular interest. We explicitly compute the distribution and the gap probability of the smallest nonzero eigenvalue in this ensemble, both for arbitrary fixed N and nu, and in the universal large N limit with nu fixed. We uncover an integrable Pfaffian structure valid for all even values of nu>=0. This extends previous results for odd nu at infinite N and recursive results for finite N and for all nu. Our mathematical results include the computation of expectation values of half integer powers of characteristic polynomials. PMID- 25554863 TI - Entanglement and spin squeezing in non-Hermitian phase transitions. AB - We show that non-Hermitian dynamics generate substantial entanglement in many body systems. We consider the non-Hermitian Lipkin-Meshkov-Glick model and show that its phase transition occurs with maximum multiparticle entanglement: There is full N-particle entanglement at the transition, in contrast to the Hermitian case. The non-Hermitian model also exhibits more spin squeezing than the Hermitian model, showing that non-Hermitian dynamics are useful for quantum metrology. Experimental implementations with trapped ions and cavity QED are discussed. PMID- 25554864 TI - Computational advantage from quantum-controlled ordering of gates. AB - It is usually assumed that a quantum computation is performed by applying gates in a specific order. One can relax this assumption by allowing a control quantum system to switch the order in which the gates are applied. This provides a more general kind of quantum computing that allows transformations on blackbox quantum gates that are impossible in a circuit with fixed order. Here we show that this model of quantum computing is physically realizable, by proposing an interferometric setup that can implement such a quantum control of the order between the gates. We show that this new resource provides a reduction in computational complexity: we propose a problem that can be solved by using O(n) blackbox queries, whereas the best known quantum algorithm with fixed order between the gates requires O(n^{2}) queries. Furthermore, we conjecture that solving this problem in a classical computer takes exponential time, which may be of independent interest. PMID- 25554865 TI - Experimental observation of Hardy-like quantum contextuality. AB - Contextuality is a fundamental property of quantum theory and a critical resource for quantum computation. Here, we experimentally observe the arguably cleanest form of contextuality in quantum theory [A. Cabello et al., Phys. Rev. Lett. 111, 180404 (2013)] by implementing a novel method for performing two sequential measurements on heralded photons. This method opens the door to a variety of fundamental experiments and applications. PMID- 25554866 TI - General transfer-function approach to noise filtering in open-loop quantum control. AB - We present a general transfer-function approach to noise filtering in open-loop Hamiltonian engineering protocols for open quantum systems. We show how to identify a computationally tractable set of fundamental filter functions, out of which arbitrary transfer filter functions may be assembled up to arbitrary high order in principle. Besides avoiding the infinite recursive hierarchy of filter functions that arises in general control scenarios, this fundamental filter function set suffices to characterize the error suppression capabilities of the control protocol in both the time and the frequency domain. We prove that the resulting notion of filtering order reveals conceptually distinct, albeit complementary, features of the controlled dynamics as compared to the order of error cancellation, traditionally defined in the Magnus sense. Examples and implications are discussed. PMID- 25554868 TI - Using entanglement against noise in quantum metrology. AB - We analyze the role of entanglement among probes and with external ancillas in quantum metrology. In the absence of noise, it is known that unentangled sequential strategies can achieve the same Heisenberg scaling of entangled strategies and that external ancillas are useless. This changes in the presence of noise; here we prove that entangled strategies can have higher precision than unentangled ones and that the addition of passive external ancillas can also increase the precision. We analyze some specific noise models and use the results to conjecture a general hierarchy for quantum metrology strategies in the presence of noise. PMID- 25554867 TI - Work measurement as a generalized quantum measurement. AB - We present a new method to measure the work w performed on a driven quantum system and to sample its probability distribution P(w). The method is based on a simple fact that remained unnoticed until now: Work on a quantum system can be measured by performing a generalized quantum measurement at a single time. Such measurement, which technically speaking is denoted as a positive operator valued measure reduces to an ordinary projective measurement on an enlarged system. This observation not only demystifies work measurement but also suggests a new quantum algorithm to efficiently sample the distribution P(w). This can be used, in combination with fluctuation theorems, to estimate free energies of quantum states on a quantum computer. PMID- 25554869 TI - Novel method for incorporating model uncertainties into gravitational wave parameter estimates. AB - Posterior distributions on parameters computed from experimental data using Bayesian techniques are only as accurate as the models used to construct them. In many applications, these models are incomplete, which both reduces the prospects of detection and leads to a systematic error in the parameter estimates. In the analysis of data from gravitational wave detectors, for example, accurate waveform templates can be computed using numerical methods, but the prohibitive cost of these simulations means this can only be done for a small handful of parameters. In this Letter, a novel method to fold model uncertainties into data analysis is proposed; the waveform uncertainty is analytically marginalized over using with a prior distribution constructed by using Gaussian process regression to interpolate the waveform difference from a small training set of accurate templates. The method is well motivated, easy to implement, and no more computationally expensive than standard techniques. The new method is shown to perform extremely well when applied to a toy problem. While we use the application to gravitational wave data analysis to motivate and illustrate the technique, it can be applied in any context where model uncertainties exist. PMID- 25554870 TI - What the timing of millisecond pulsars can teach us about their interior. AB - The cores of compact stars reach the highest densities in nature and therefore could consist of novel phases of matter. We demonstrate via a detailed analysis of pulsar evolution that precise pulsar timing data can constrain the star's composition, through unstable global oscillations (r modes) whose damping is determined by microscopic properties of the interior. If not efficiently damped, these modes emit gravitational waves that quickly spin down a millisecond pulsar. As a first application of this general method, we find that ungapped interacting quark matter is consistent with both the observed radio and x-ray data, whereas for ordinary nuclear matter some additional enhanced damping mechanism is required. PMID- 25554871 TI - Unidentified line in x-ray spectra of the Andromeda galaxy and Perseus galaxy cluster. AB - We report a weak line at 3.52+/-0.02 keV in x-ray spectra of the Andromeda galaxy and the Perseus galaxy cluster observed by the metal-oxide-silicon (MOS) and p-n (PN) CCD cameras of the XMM-Newton telescope. This line is not known as an atomic line in the spectra of galaxies or clusters. It becomes stronger towards the centers of the objects; is stronger for Perseus than for M31; is absent in the spectrum of a deep "blank sky" data set. Although for each object it is hard to exclude that the feature is due to an instrumental effect or an atomic line, it is consistent with the behavior of a dark matter decay line. Future (non-)detections of this line in multiple objects may help to reveal its nature. PMID- 25554872 TI - Dark energy from the string axiverse. AB - String theories suggest the existence of a plethora of axionlike fields with masses spread over a huge number of decades. Here, we show that these ideas lend themselves to a model of quintessence with no super-Planckian field excursions and in which all dimensionless numbers are order unity. The scenario addresses the "Why now?" problem-i.e., Why has accelerated expansion begun only recently? by suggesting that the onset of dark-energy domination occurs randomly with a slowly decreasing probability per unit logarithmic interval in cosmic time. The standard axion potential requires us to postulate a rapid decay of most of the axion fields that do not become dark energy. The need for these decays is averted, though, with the introduction of a slightly modified axion potential. In either case, a universe like ours arises in roughly 1 in 100 universes. The scenario may have a host of observable consequences. PMID- 25554873 TI - Exact correlation functions in SU(2) N=2 superconformal QCD. AB - We report an exact solution of 2- and 3-point functions of chiral primary fields in SU(2) N=2 super-Yang-Mills theory coupled to four hypermultiplets. It is shown that these correlation functions are nontrivial functions of the gauge coupling, obeying differential equations which take the form of the semi-infinite Toda chain. We solve these equations recursively in terms of the Zamolodchikov metric that can be determined exactly from supersymmetric localization on the four sphere. Our results are verified independently in perturbation theory with a Feynman diagram computation up to 2 loops. This is a short version of a companion paper that contains detailed technical remarks, additional material, and aspects of an extension to the SU(N) gauge group. PMID- 25554874 TI - Search for millicharged particles using optically levitated microspheres. AB - We report results from a search for stable particles with charge ?10^{-5}e in bulk matter using levitated dielectric microspheres in high vacuum. No evidence for such particles was found in a total sample of 1.4 ng, providing an upper limit on the abundance per nucleon of 2.5*10^{-14} at the 95% confidence level for the material tested. These results provide the first direct search for single particles with charge ?0.1e bound in macroscopic quantities of matter and demonstrate the ability to perform sensitive force measurements using optically levitated microspheres in vacuum. PMID- 25554875 TI - Magnetic moments of light nuclei from lattice quantum chromodynamics. AB - We present the results of lattice QCD calculations of the magnetic moments of the lightest nuclei, the deuteron, the triton, and ^{3}He, along with those of the neutron and proton. These calculations, performed at quark masses corresponding to m_{pi}~800 MeV, reveal that the structure of these nuclei at unphysically heavy quark masses closely resembles that at the physical quark masses. In particular, we find that the magnetic moment of ^{3}He differs only slightly from that of a free neutron, as is the case in nature, indicating that the shell-model configuration of two spin-paired protons and a valence neutron captures its dominant structure. Similarly a shell-model-like moment is found for the triton, MU_{^{3}H}~MU_{p}. The deuteron magnetic moment is found to be equal to the nucleon isoscalar moment within the uncertainties of the calculations. Furthermore, deviations from the Schmidt limits are also found to be similar to those in nature for these nuclei. These findings suggest that at least some nuclei at these unphysical quark masses are describable by a phenomenological nuclear shell model. PMID- 25554876 TI - Elliptic and triangular flow in p-Pb and peripheral Pb-Pb collisions from Parton scatterings. AB - Using a multiphase transport model (AMPT) we calculate the elliptic v_{2} and triangular v_{3} Fourier coefficients of the two-particle azimuthal correlation function in proton-nucleus (p-Pb) and peripheral nucleus-nucleus (Pb-Pb) collisions. Our results for v_{3} are in a good agreement with the CMS data collected at the Large Hadron Collider. The v_{2} coefficient is very well described in p-Pb collisions and is underestimated for higher transverse momenta in Pb-Pb interactions. The characteristic mass ordering of v_{2} in p-Pb is reproduced, whereas for v_{3}, this effect is not observed. We further predict the pseudorapidity dependence of v_{2} and v_{3} in p-Pb and observe that both are increasing when going from a proton side to a Pb-nucleus side. Predictions for the higher-order Fourier coefficients, v_{4} and v_{5}, in p-Pb are also presented. PMID- 25554877 TI - Spectroscopic properties of nuclear skyrme energy density functionals. AB - We address the question of how to improve the agreement between theoretical nuclear single-particle energies (SPEs) and observations. Empirically, in doubly magic nuclei, the SPEs can be deduced from spectroscopic properties of odd nuclei that have one more or one less neutron or proton. Theoretically, bare SPEs, before being confronted with observations, must be corrected for the effects of the particle vibration coupling (PVC). In the present work, we determine the PVC corrections in a fully self-consistent way. Then, we adjust the SPEs, with PVC corrections included, to empirical data. In this way, the agreement with observations, on average, improves; nevertheless, large discrepancies still remain. We conclude that the main source of disagreement is still in the underlying mean fields, and not in including or neglecting the PVC corrections. PMID- 25554878 TI - Large low-energy M1 strength for ^{56,57}Fe within the nuclear shell model. AB - A strong enhancement at low gamma-ray energies has recently been discovered in the gamma-ray strength function of ^{56,57}Fe. In this work, we have for the first time obtained theoretical gamma decay spectra for states up to ~8 MeV in excitation for ^{56,57}Fe. We find large B(M1) values for low gamma-ray energies that provide an explanation for the experimental observations. The role of mixed E2 transitions for the low-energy enhancement is addressed theoretically for the first time, and it is found that they contribute a rather small fraction. Our calculations clearly show that the high-l(=f) diagonal terms are most important for the strong low-energy M1 transitions. As such types of 0homega transitions are expected for all nuclei, our results indicate that a low-energy M1 enhancement should be present throughout the nuclear chart. This could have far reaching consequences for our understanding of the M1 strength function at high excitation energies, with profound implications for astrophysical reaction rates. PMID- 25554879 TI - Theoretical tracking of resonance-enhanced multiple ionization pathways in X-ray free-electron laser pulses. AB - We present an extended Monte Carlo rate equation approach to examine the inner shell ionization dynamics of atoms in an intense x-ray free-electron laser (XFEL) pulse. In addition to photoionization, Auger decay, and fluorescence processes, we include bound-to-bound transitions in the rate equation calculations. Using an efficient computational scheme, we account for "hidden resonances" unveiled during the course of an XFEL pulse. For Ar, the number of possible electron configurations is increased ten-billion-fold over that required under nonresonant conditions. We investigated the complex ionization dynamics of Ar atoms exposed to an 480-eV XFEL pulse, where production of ions above charge state 10+ is not allowed via direct one-photon ionization. We found that resonance-enhanced x-ray multiple ionization pathways play a dominant role in producing these nominally inaccessible charge states. Our calculated results agree with the measured Ar ion yield and pulse-duration dependence. We also predict the surprising ion yields reported earlier for Kr and Xe. The Monte Carlo rate equation method enables theoretical exploration of the complex dynamics of resonant high-intensity x-ray processes. PMID- 25554880 TI - Universality in molecular halo clusters. AB - The ground state of weakly bound dimers and trimers with a radius extending well into the classically forbidden region is explored, with the goal to test the predicted universality of quantum halo states. The focus of the study is molecules consisting of T?, D?, ^{3}He, ^{4}He, and alkali atoms, where the interaction between particles is much better known than in the case of nuclei, which are traditional examples of quantum halos. The study of realistic systems is supplemented by model calculations in order to analyze how low-energy properties depend on the interaction potential. The use of variational and diffusion Monte Carlo methods enabled a very precise calculation of both the size and binding energy of the trimers. In the quantum halo regime, and for large values of scaled binding energies, all clusters follow almost the same universal line. As the scaled binding energy decreases, Borromean states separate from tango trimers. PMID- 25554881 TI - Low-threshold bidirectional air lasing. AB - Air lasing refers to the remote optical pumping of the constituents of ambient air that results in a directional laserlike emission from the pumped region. Intense current investigations of this concept are motivated by the potential applications in remote atmospheric sensing. Different approaches to air lasing are being investigated, but, so far, only the approach based on dissociation and resonant two-photon pumping of air molecules by deep-UV laser pulses has produced measurable lasing energies in real air and in the backward direction, which is of the most relevance for applications. However, the emission had a high pumping threshold, in hundreds of GW/cm^{2}. We demonstrate that the threshold can be virtually eliminated through predissociation of air molecules with an additional nanosecond laser. We use a single tunable pump laser system to generate backward propagating lasing in both oxygen and nitrogen in air, with energies of up to 1 MUJ per pulse. PMID- 25554882 TI - Macroscopic manipulation of high-order-harmonic generation through bound-state coherent control. AB - We propose a paradigm for macroscopic control of high-order harmonic generation by modulating the bound-state population of the medium atoms. A unique result of this scheme is that apart from regular spatial quasi-phase-matching (QPM), also purely temporal QPM of the emitted radiation can be established. Our simulations demonstrate temporal QPM by inducing homogenous Rabi oscillations in the medium and also spatial QPM by creating a grating of population inversion using the process of rapid adiabatic passage. In the simulations a scaled version of high order harmonic generation is used: a far off-resonance 2.6 MUm source generates UV-visible high-order harmonics from alkali-metal-atom vapor, while a resonant near IR source is used to coherently control the medium. PMID- 25554883 TI - Asymptotic phase for stochastic oscillators. AB - Oscillations and noise are ubiquitous in physical and biological systems. When oscillations arise from a deterministic limit cycle, entrainment and synchronization may be analyzed in terms of the asymptotic phase function. In the presence of noise, the asymptotic phase is no longer well defined. We introduce a new definition of asymptotic phase in terms of the slowest decaying modes of the Kolmogorov backward operator. Our stochastic asymptotic phase is well defined for noisy oscillators, even when the oscillations are noise dependent. It reduces to the classical asymptotic phase in the limit of vanishing noise. The phase can be obtained either by solving an eigenvalue problem, or by empirical observation of an oscillating density's approach to its steady state. PMID- 25554884 TI - Approaching the asymptotic regime of rapidly rotating convection: boundary layers versus interior dynamics. AB - Rapidly rotating Rayleigh-Benard convection is studied by combining results from direct numerical simulations (DNS), laboratory experiments, and asymptotic modeling. The asymptotic theory is shown to provide a good description of the bulk dynamics at low, but finite Rossby number. However, large deviations from the asymptotically predicted heat transfer scaling are found, with laboratory experiments and DNS consistently yielding much larger Nusselt numbers than expected. These deviations are traced down to dynamically active Ekman boundary layers, which are shown to play an integral part in controlling heat transfer even for Ekman numbers as small as 10^{-7}. By adding an analytical parametrization of the Ekman transport to simulations using stress-free boundary conditions, we demonstrate that the heat transfer jumps from values broadly compatible with the asymptotic theory to states of strongly increased heat transfer, in good quantitative agreement with no-slip DNS and compatible with the experimental data. Finally, similarly to nonrotating convection, we find no single scaling behavior, but instead that multiple well-defined dynamical regimes exist in rapidly rotating convection systems. PMID- 25554885 TI - Laminar, turbulent, and inertial shear-thickening regimes in channel flow of neutrally buoyant particle suspensions. AB - The aim of this Letter is to characterize the flow regimes of suspensions of finite-size rigid particles in a viscous fluid at finite inertia. We explore the system behavior as a function of the particle volume fraction and the Reynolds number (the ratio of flow and particle inertia to viscous forces). Unlike single phase flows, where a clear distinction exists between the laminar and the turbulent states, three different regimes can be identified in the presence of a particulate phase, with smooth transitions between them. At low volume fractions, the flow becomes turbulent when increasing the Reynolds number, transitioning from the laminar regime dominated by viscous forces to the turbulent regime characterized by enhanced momentum transport by turbulent eddies. At larger volume fractions, we identify a new regime characterized by an even larger increase of the wall friction. The wall friction increases with the Reynolds number (inertial effects) while the turbulent transport is weakly affected, as in a state of intense inertial shear thickening. This state may prevent the transition to a fully turbulent regime at arbitrary high speed of the flow. PMID- 25554886 TI - Universal profile of the vortex condensate in two-dimensional turbulence. AB - An inverse turbulent cascade in a restricted two-dimensional periodic domain creates a condensate-a pair of coherent system-size vortices. We perform extensive numerical simulations of this system and carry out theoretical analysis based on momentum and energy exchanges between the turbulence and the vortices. We show that the vortices have a universal internal structure independent of the type of small-scale dissipation, small-scale forcing, and boundary conditions. The theory predicts not only the vortex inner region profile, but also the amplitude, which both perfectly agree with the numerical data. PMID- 25554887 TI - Demonstration of single-crystal self-seeded two-color x-ray free-electron lasers. AB - A scheme for generating two simultaneous hard-x-ray free-electron laser pulses with a controllable difference in photon energy is described and then demonstrated using the self-seeding setup at the Linac Coherent Light Source (LCLS). The scheme takes advantage of the existing LCLS equipment, which allows two independent rotations of the self-seeding diamond crystal. The two degrees of freedom are used to select two nearby crystal reflections, causing two wavelengths to be present in the forward transmitted seeding x-ray pulse. The free-electron laser system must support amplification at both desired wavelengths. PMID- 25554888 TI - Experimental demonstration of longitudinal beam phase-space linearizer in a free electron laser facility by corrugated structures. AB - Removal of the undesired time-energy correlations in the electron beam is of paramount importance for efficient lasing of a high-gain free-electron laser. Recently, it has been theoretically and experimentally demonstrated that the longitudinal wakefield excited by the electrons themselves in a corrugated structure allows for precise control of the electron beam phase space. In this Letter, we report the first utilization of a corrugated structure as a beam linearizer in the operation of a seeded free-electron laser driven by a 140 MeV linear accelerator, where a gain of ~10 000 over spontaneous emission was achieved at the second harmonic of the 1047 nm seed laser, and a free-electron laser bandwidth narrowing by 50% was observed, in good agreement with the theoretical expectations. PMID- 25554889 TI - In-depth plasma-wave heating of dense plasma irradiated by short laser pulses. AB - We investigate the mechanism by which relativistic electron bunches created at the surface of a target irradiated by a very short and intense laser pulse transfer energy to the deeper parts of the target. In existing theories, the dominant heating mechanism is that of resistive heating by the neutralizing return current. In addition to this, we find that large amplitude plasma waves are induced in the plasma in the wake of relativistic electron bunches. The subsequent collisional damping of these waves represents a source of heating that can exceed the resistive heating rate. As a result, solid targets heat significantly faster than has been previously considered. A new hybrid model, capable of reproducing these results, is described. PMID- 25554890 TI - Rotation and kinetic modifications of the tokamak ideal-wall pressure limit. AB - The impact of toroidal rotation, energetic ions, and drift-kinetic effects on the tokamak ideal wall mode stability limit is considered theoretically and compared to experiment for the first time. It is shown that high toroidal rotation can be an important destabilizing mechanism primarily through the angular velocity shear; non-Maxwellian fast ions can also be destabilizing, and drift-kinetic damping can potentially offset these destabilization mechanisms. These results are obtained using the unique parameter regime accessible in the spherical torus NSTX of high toroidal rotation speed relative to the thermal and Alfven speeds and high kinetic pressure relative to the magnetic pressure. Inclusion of rotation and kinetic effects significantly improves agreement between measured and predicted ideal stability characteristics and may provide new insight into tearing mode triggering. PMID- 25554891 TI - Creation of ultracold ^{87}Rb^{133}Cs molecules in the rovibrational ground state. AB - We report the creation of a sample of over 1000 ultracold ^{87}Rb^{133}Cs molecules in the lowest rovibrational ground state, from an atomic mixture of ^{87}Rb and ^{133}Cs, by magnetoassociation on an interspecies Feshbach resonance followed by stimulated Raman adiabatic passage (STIRAP). We measure the binding energy of the RbCs molecule to be hc*3811.576(1) cm^{-1} and the |v^{''}=0,J^{''}=0? to |v^{''}=0,J^{''}=2? splitting to be h*2940.09(6) MHz. Stark spectroscopy of the rovibrational ground state yields an electric dipole moment of 1.225(3)(8) D, where the values in parentheses are the statistical and systematic uncertainties, respectively. We can access a space-fixed dipole moment of 0.355(2)(4) D, which is substantially higher than in previous work. PMID- 25554892 TI - Chladni solitons and the onset of the snaking instability for dark solitons in confined superfluids. AB - Complex solitary waves composed of intersecting vortex lines are predicted in a channeled superfluid. Their shapes in a cylindrical trap include a cross, spoke wheels, and Greek Phi, and trace the nodal lines of unstable vibration modes of a planar dark soliton in analogy to Chladni's figures of membrane vibrations. The stationary solitary waves extend a family of solutions that include the previously known solitonic vortex and vortex rings. Their bifurcation points from the dark soliton indicating the onset of new unstable modes of the snaking instability are predicted from scale separation for Bose-Einstein condensates (BECs) and superfluid Fermi gases across the BEC-BCS crossover, and confirmed by full numerical calculations. Chladni solitons could be observed in ultracold gas experiments by seeded decay of dark solitons. PMID- 25554893 TI - Scaling shift in multicracked fiber bundles. AB - Bundles of fibers, wires, or filaments are ubiquitous structures in both natural and artificial materials. We investigate the bundle degradation induced by an external damaging action through a theoretical model describing an assembly of parallel fibers, progressively damaged by a random population of cracks. Fibers in our model interact by means of a lateral linear coupling, thus retaining structural integrity even after substantial damage. Monte Carlo simulations of the Young's modulus degradation for increasing crack density demonstrate a remarkable scaling shift between an exponential and a power-law regime. Analytical solutions of the model confirm this behavior, and provide a thorough understanding of the underlying physics. PMID- 25554894 TI - Interplay of driving and frequency noise in the spectra of vibrational systems. AB - We study the spectral effect of the fluctuations of the vibration frequency. Such fluctuations play a major role in nanomechanical and other mesoscopic vibrational systems. We find that, for periodically driven systems, the interplay of the driving and frequency fluctuations results in specific spectral features. We present measurements on a carbon nanotube resonator and show that our theory allows not only the characterization of the frequency fluctuations but also the quantification of the decay rate without ring-down measurements. The results bear on identifying the decoherence of mesoscopic oscillators and on the general problem of resonance fluorescence and light scattering by oscillators. PMID- 25554895 TI - Asymptotic scaling behavior of self-avoiding walks on critical percolation clusters. AB - We study self-avoiding walks on three-dimensional critical percolation clusters using a new exact enumeration method. It overcomes the exponential increase in computation time by exploiting the clusters' fractal nature. We enumerate walks of over 10^{4} steps, far more than has ever been possible. The scaling exponent nu for the end-to-end distance turns out to be smaller than previously thought and appears to be the same on the backbones as on full clusters. We find strong evidence against the widely assumed scaling law for the number of conformations and propose an alternative, which perfectly fits our data. PMID- 25554896 TI - Prediction of near-room-temperature quantum anomalous Hall effect on honeycomb materials. AB - Recently, the long-sough quantum anomalous Hall effect was realized in a magnetic topological insulator. However, the requirement of an extremely low temperature (approximately 30 mK) hinders realistic applications. Based on ab initio band structure calculations, we propose a quantum anomalous Hall platform with a large energy gap of 0.34 and 0.06 eV on honeycomb lattices comprised of Sn and Ge, respectively. The ferromagnetic (FM) order forms in one sublattice of the honeycomb structure by controlling the surface functionalization rather than dilute magnetic doping, which is expected to be visualized by spin polarized STM in experiment. Strong coupling between the inherent quantum spin Hall state and ferromagnetism results in considerable exchange splitting and, consequently, an FM insulator with a large energy gap. The estimated mean-field Curie temperature is 243 and 509 K for Sn and Ge lattices, respectively. The large energy gap and high Curie temperature indicate the feasibility of the quantum anomalous Hall effect in the near-room-temperature and even room-temperature regions. PMID- 25554897 TI - Coherent quasiparticles with a small fermi surface in lightly doped Sr(3)Ir(2)O(7). AB - We characterize the electron doping evolution of (Sr_{1-x}La_{x})_{3}Ir_{2}O_{7} by means of angle-resolved photoemission. Concomitant with the metal insulator transition around x~0.05 we find the emergence of coherent quasiparticle states forming a closed small Fermi surface of volume 3x/2, where x is the independently measured La concentration. The quasiparticle weight Z remains large along the entire Fermi surface, consistent with the moderate renormalization of the low energy dispersion, and no pseudogap is observed. This indicates a conventional, weakly correlated Fermi liquid state with a momentum independent residue Z~0.5 in lightly doped Sr_{3}Ir_{2}O_{7}. PMID- 25554898 TI - Topological tuning in three-dimensional dirac semimetals. AB - We study with first-principles methods the interplay between bulk and surface Dirac fermions in three dimensional Dirac semimetals. By combining density functional theory with the coherent potential approximation, we reveal a topological phase transition in Na_{3}Bi_{1-x}Sb_{x} and Cd_{3}[As_{1 x}P_{x}]_{2} alloys, where the material goes from a Dirac semimetal to a trivial insulator upon changing Sb or P concentrations. Tuning the composition allows us to engineer the position of the bulk Dirac points in reciprocal space. Interestingly, the phase transition coincides with the reversal of the band ordering between the conduction and valence bands. PMID- 25554899 TI - Momentum-space entanglement spectrum of bosons and fermions with interactions. AB - We study the momentum space entanglement spectra of bosonic and fermionic formulations of the spin-1/2 XXZ chain with analytical methods and exact diagonalization. We investigate the behavior of the entanglement gaps, present in both formulations, across quantum phase transitions in the XXZ chain. In both cases, finite size scaling suggests that the entanglement gap closure does not occur at the physical transition points. For bosons, we find that the entanglement gap observed in Thomale et al. [Phys. Rev. Lett. 105, 116805 (2010)] depends on the scaling dimension of the conformal field theory as varied by the XXZ anisotropy. For fermions, the infinite entanglement gap present at the XX point persists well past the phase transition at the Heisenberg point. We elaborate on how these shifted transition points in the entanglement spectra may support the numerical study of phase transitions in the momentum space density matrix renormalization group. PMID- 25554900 TI - Topological pair-density-wave superconducting states. AB - We show that the pair-density-wave (PDW) superconducting state emergent in extended Heisenberg-Hubbard models in two-leg ladders is topological in the presence of an Ising spin symmetry and supports a Majorana zero mode (MZM) at an open boundary and at a junction with a uniform d-wave one-dimensional superconductor. Similarly to a conventional finite-momentum paired state, the order parameter of the PDW state is a charge-2e field with finite momentum. However, the order parameter here is a quartic electron operator and conventional mean-field theory cannot be applied to study this state. We use bosonization to show that the 1D PDW state has a MZM at a boundary. This superconducting state is an exotic topological phase supporting Majorana fermions with finite-momentum pairing fields and charge-4e superconductivity. PMID- 25554901 TI - Interfacial Fermi loops from interfacial symmetries. AB - We propose a concept of interfacial symmetries such as interfacial particle-hole symmetry and interfacial time-reversal symmetry, which appear in interfaces between two regions related to each other by particle-hole or time-reversal transformations. These symmetries result in novel dispersion of interface states. In particular, for the interfacial particle-hole symmetry, the gap closes along a loop ("Fermi loop") at the interface. We numerically demonstrate this for the Fu Kane-Mele tight-binding model. We show that the Fermi loop originates from a sign change of a Pfaffian of a product between the Hamiltonian and a constant matrix. PMID- 25554902 TI - Nonequilibrium probing of two-level charge fluctuators using the step response of a single-electron transistor. AB - We report a new method to study two-level fluctuators (TLFs) by measuring the offset charge induced after applying a sudden step voltage to the gate electrode of a single-electron transistor. The offset charge is measured for more than 20 h for samples made on three different substrates. We find that the offset charge drift follows a logarithmic increase over 4 orders of magnitude in time and that the logarithmic slope increases linearly with the step voltage. The charge drift is independent of temperature, ruling out thermally activated TLFs and demonstrating that the charge fluctuations involve tunneling. These observations are in agreement with expectations for an ensemble of TLFs driven out of equilibrium. From our model, we extract the density of TLFs assuming either a volume density or a surface density. PMID- 25554903 TI - Spin-relaxation anisotropy in a GaAs quantum dot. AB - We report that the electron spin-relaxation time T_{1} in a GaAs quantum dot with a spin-1/2 ground state has a 180 degrees periodicity in the orientation of the in-plane magnetic field. This periodicity has been predicted for circular dots as being due to the interplay of Rashba and Dresselhaus spin orbit contributions. Different from this prediction, we find that the extrema in the T_{1} do not occur when the magnetic field is along the [110] and [11[over -]0] crystallographic directions. This deviation is attributed to an elliptical dot confining potential. The T_{1} varies by more than 1 order of magnitude when rotating a 3 T field, reaching about 80 ms for the optimal angle. We infer from the data that in our device the signs of the Rashba and Dresselhaus constants are opposite. PMID- 25554904 TI - Electrical and thermal control of magnetic exchange interactions. AB - We investigate the far-from-equilibrium nature of magnetic anisotropy and exchange interactions between molecular magnets embedded in a tunnel junction. By mapping to an effective spin model, these magnetic interactions can be divided into three types: isotropic Heisenberg, anisotropic Ising, and anisotropic Dzyaloshinski-Moriya contributions, which are attributed to the background nonequilibrium electronic structures. We further demonstrate that both the magnetic self- and exchange interactions can be controlled either electrically by gating and tuning the voltage bias, or thermally by adjusting the temperature bias. We show that the Heisenberg and Ising interactions scale linearly, while the Dzyaloshinski-Moriya interaction scales quadratically, with the molecule-lead coupling strength. The interactions scale linearly with the effective spin polarizations of the leads and the molecular coherence. Our results pave a way for smart control of magnetic exchange interactions at atomic and molecular levels. PMID- 25554905 TI - Topological transitions from multipartite entanglement with tensor networks: a procedure for sharper and faster characterization. AB - Topological order in two-dimensional (2D) quantum matter can be determined by the topological contribution to the entanglement Renyi entropies. However, when close to a quantum phase transition, its calculation becomes cumbersome. Here, we show how topological phase transitions in 2D systems can be much better assessed by multipartite entanglement, as measured by the topological geometric entanglement of blocks. Specifically, we present an efficient tensor network algorithm based on projected entangled pair states to compute this quantity for a torus partitioned into cylinders and then use this method to find sharp evidence of topological phase transitions in 2D systems with a string-tension perturbation. When compared to tensor network methods for Renyi entropies, our approach produces almost perfect accuracies close to criticality and, additionally, is orders of magnitude faster. The method can be adapted to deal with any topological state of the system, including minimally entangled ground states. It also allows us to extract the critical exponent of the correlation length and shows that there is no continuous entanglement loss along renormalization group flows in topological phases. PMID- 25554906 TI - Topological nature of optical bound states in the continuum. AB - Optical bound states in the continuum (BICs) have recently been realized in photonic crystal slabs, where the disappearance of out-of-plane radiation turns leaky resonances into guided modes with infinite lifetimes. We show that such BICs are vortex centers in the polarization directions of far-field radiation. They carry conserved and quantized topological charges, defined by the winding number of the polarization vectors, which ensure their robust existence and govern their generation, evolution, and annihilation. Our findings connect robust BICs in photonics to a wide range of topological physical phenomena. PMID- 25554907 TI - Geometry of thin nematic elastomer sheets. AB - A thin sheet of nematic elastomer attains 3D configurations depending on the nematic director field upon heating. In this Letter, we describe the intrinsic geometry of such a sheet and derive an expression for the metric induced by general nematic director fields. Furthermore, we investigate the reverse problem of constructing a director field that induces a specified 2D geometry. We provide an explicit recipe for how to construct any surface of revolution using this method. Finally, we show that by inscribing a director field gradient across the sheet's thickness, one can obtain a nontrivial hyperbolic reference curvature tensor, which together with the prescription of a reference metric allows dictation of actual configurations for a thin sheet of nematic elastomer. PMID- 25554908 TI - Scaling of gene expression with transcription-factor fugacity. AB - The proteins associated with gene regulation are often shared between multiple pathways simultaneously. By way of contrast, models in regulatory biology often assume these pathways act independently. We demonstrate a framework for calculating the change in gene expression for the interacting case by decoupling repressor occupancy across the cell from the gene of interest by way of a chemical potential. The details of the interacting regulatory architecture are encompassed in an effective concentration, and thus, a single scaling function describes a collection of gene expression data from diverse regulatory situations and collapses it onto a single master curve. PMID- 25554909 TI - Energy dissipation and noise correlations in biochemical sensing. AB - To measure chemical concentrations, cells need to extract information from stochastic receptor signals via signaling networks which are also inherently stochastic. Here, we study how the accuracy of sensing depends on the correlations between these extrinsic and intrinsic sources of noise. We find that the sensing precision of signaling networks that are not driven out of equilibrium is fundamentally limited by the fluctuation-dissipation theorem, which generates a tradeoff between the removal of extrinsic and intrinsic noise. As a result, the sensing precision of equilibrium systems is limited by the number of receptors; the downstream network can never improve sensing. To lift the tradeoff, energy dissipation is essential. This allows the receptor to transduce the signal as a catalyst and enables time integration of the receptor state. To beat the sensing limit of equilibrium systems, a canonical nonequilibrium signaling network based on the push-pull motif needs to dissipate at least 1k_{B}T per receptor. PMID- 25554910 TI - Firefly light flashing: oxygen supply mechanism. AB - Firefly luminescence is an intriguing phenomenon with potential technological applications, whose biochemistry background was only recently established. The physics side of this phenomenon, however, was still unclear, specifically as far as the oxygen supply mechanism for light flashing is concerned. This uncertainty is due to the complex microscopic structure of the tracheal system: without fully knowing its geometry, one cannot reliably test the proposed mechanisms. We solved this problem using synchrotron phase contrast microtomography and transmission x ray microscopy, finding that the oxygen consumption corresponding to mitochondria functions exceeds the maximum rate of oxygen diffusion from the tracheal system to the photocytes. Furthermore, the flashing mechanism uses a large portion of this maximum rate. Thus, the flashing control requires passivation of the mitochondria functions, e.g., by nitric oxide, and switching of the oxygen supply from them to photoluminescence. PMID- 25554911 TI - Vortex arrays and mesoscale turbulence of self-propelled particles. AB - Inspired by the Turing mechanism for pattern formation, we propose a simple self propelled particle model with short-range alignment and antialignment at larger distances. It is able to produce orientationally ordered states, periodic vortex patterns, and mesoscale turbulence, which resembles observations in dense suspensions of swimming bacteria. The model allows a systematic derivation and analysis of a kinetic theory as well as hydrodynamic equations for density and momentum fields. A phase diagram with regions of pattern formation as well as orientational order is obtained from a linear stability analysis of these continuum equations. Microscopic Langevin simulations of self-propelled particles are in agreement with these findings. PMID- 25554912 TI - High strength, molecularly thin nanoparticle membranes. AB - The unique strength observed in molecular thin films consisting of assemblies of nanoparticles encoded with short organic chains opens an intriguing new realm of controllable materials. Here the fundamental mechanisms underlying this unique mechanical strength are probed by molecular dynamics simulations. Using nanoparticles encoded with short hydrocarbon chains, we show that the mechanical response and failure of single nanoparticle thick membranes depend on subtle changes of the coating. Extremely high moduli were observed in agreement with experiment. We calculate Young's modulus for the membrane system based on properties of the individual components and find that ligand end-group interactions explain the observed changes in mechanical properties. Specifically, for dodecanethiol chains on 6 nm diameter gold cores, Young's modulus is 2.5 GPa for CH_{3} terminated chains and increases by 50% when end groups are replaced by COOH. PMID- 25554913 TI - Multiple glass singularities and isodynamics in a core-softened model for glass forming systems. AB - We investigate the slow dynamics of a simple glass former whose interaction potential is the sum of a hard core and a square shoulder repulsion. According to mode coupling theory, the competition between the two repulsive length scales gives rise to a complex dynamic scenario: besides the fluid-glass line, the theory predicts a glass-glass line in the temperature-packing fraction plane with two end points. Interestingly, for critical values of the square-shoulder parameters, such end points can be accessed from the liquid phase. We verify, via extensive numerical simulations, the existence of both points through the observation of an unconventional subdiffusive/logarithmic dynamical behavior. Unexpectedly, we also discover that the simultaneous presence of two end points generates special loci in the state diagram along which the dynamics is identical at all length and time scales. PMID- 25554914 TI - mTOR signaling in cellular and organismal energetics. AB - Mammalian TOR (mTOR) signaling controls growth, metabolism and energy homeostasis in a cell autonomous manner. Recent findings indicate that mTOR signaling in one tissue can also affect other organs thereby affecting whole body metabolism and energy homeostasis in a non-cell autonomous manner. It is thus not surprising that mTOR signaling mediates aging and is often deregulated in metabolic disorders, such as obesity, diabetes and cancer. This review discusses the regulation of cellular and whole body energy metabolism by mTOR, with particular focus on the non-cell autonomous function of mTOR. PMID- 25554917 TI - Janus magneto-electric nanosphere dimers exhibiting unidirectional visible light scattering and strong electromagnetic field enhancement. AB - Steering incident light into specific directions at the nanoscale is very important for future nanophotonics applications of signal transmission and detection. A prerequisite for such a purpose is the development of nanostructures with high-efficiency unidirectional light scattering properties. Here, from both theoretical and experimental sides, we conceived and demonstrated the unidirectional visible light scattering behaviors of a heterostructure, Janus dimer composed of gold and silicon nanospheres. By carefully adjusting the sizes and spacings of the two nanospheres, the Janus dimer can support both electric and magnetic dipole modes with spectral overlaps and comparable strengths. The interference of these two modes gives rise to the narrow-band unidirectional scattering behaviors with enhanced forward scattering and suppressed backward scattering. The directionality can further be improved by arranging the dimers into one-dimensional chain structures. In addition, the dimers also show remarkable electromagnetic field enhancements. These results will be important not only for applications of light emitting devices, solar cells, optical filters, and various surface enhanced spectroscopies but also for furthering our understanding on the light-matter interactions at the nanoscale. PMID- 25554916 TI - Mechanical and structural characterization of tibial prosthetic interfaces before and after aging under simulated service conditions. AB - Prosthesis interface is one of the most important components to promote individual's health and comfort, as it establishes direct contact with the skin and transfers loads generated during gait. The aim of this study was to mechanically characterize, three commercial interfaces (block copolymer, silicone gel and silicone elestomer), under static and dynamic conditions, before and after undergoing a process of chemical aging in synthetic sweat for periods up to 90 days. Static mechanical compression tests were performed on the materials, as well as fatigue tests to assess their static and dynamic mechanical behaviors, respectively. For the second, a sinusoidal load was applied with an appropriate range of deformation for each material. Several analytical techniques were also used to characterize the materials, namely Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), and morphology characterization by Scanning Electron Microscopy (SEM). All the tested materials have strong viscoelastic behavior, showing a linear response for small deformations, followed by a nonlinear behavior for higher deformation. The block copolymer and the silicone gel are affected by aging in synthetic sweat in a similar way, with a significant increase of their rigidity after 30 days, followed by a progressive reduction. The silicone elastomer displays a continuous increase of rigidity along the 90 days of storage, being the most sensitive to aging affects. It also exhibits the lowest stiffness value, being suitable for uses that require maximum comfort. All materials demonstrate chemical and structural stability under service simulated conditions. PMID- 25554915 TI - Identifying and intervening with substance-using women exposed to intimate partner violence: phenomenology, comorbidities, and integrated approaches within primary care and other agency settings. AB - Substance use and/or disorders (SUDs) have been identified as a significant correlate of intimate partner violence (IPV) exposure and present complex issues that intersect with the topography of IPV, attendant mental health, and physical co-morbidities and may pose barriers to primary care- and other agency-based screening and intervention efforts. Despite substantial research indicating significantly higher rates of all types and severity of IPV victimization among women with SUDs and bidirectional associations between partner or self-use of drugs or alcohol and IPV victimization, effective screening, brief interventions, coordinated systems of care, and treatment approaches to address these co occurring problems remain very limited. We integrated select research examining the intersection of IPV victimization and SUDs and several comorbidities that have significant public health impact and provided recommendations for scaling up targeted interventions to redress these co-occurring problems among women in primary, emergency, and other care settings. PMID- 25554918 TI - Transmission electron microscopy of thiol-capped Au clusters on C: Structure and electron irradiation effects. AB - High-resolution transmission electron microscopy is used to study interactions between thiol-capped Au clusters and amorphous C support films. The morphologies of the clusters are found to depend both on their size and on the local structure of the underlying C. When the C is amorphous, larger Au clusters are crystalline, while smaller clusters are typically disordered. When the C is graphitic, the Au particles adopt either elongated shapes that maximize their contact with the edge of the C film or planar arrays when they contain few Au atoms. We demonstrate the influence of electron beam irradiation on the structure, shape and stability of the Au clusters, as well as on the formation of holes bounded by terraces of graphitic lamellae in the underlying C. PMID- 25554919 TI - Atomistic modeling of two-dimensional electronic spectra and excited-state dynamics for a Light Harvesting 2 complex. AB - The Light Harvesting 2 (LH2) complex is a vital part of the photosystem of purple bacteria. It is responsible for the absorption of light and transport of the resulting excitations to the reaction center in a highly efficient manner. A general description of the chromophores and the interaction with their local environment is crucial to understand this highly efficient energy transport. Here we include this interaction in an atomistic way using mixed quantum-classical (molecular dynamics) simulations of spectra. In particular, we present the first atomistic simulation of nonlinear optical spectra for LH2 and use it to study the energy transport within the complex. We show that the frequency distributions of the pigments strongly depend on their positions with respect to the protein scaffold and dynamics of their local environment. Furthermore, we show that although the pigments are closely packed the transition frequencies of neighboring pigments are essentially uncorrelated. We present the simulated linear absorption spectra for the LH2 complex and provide a detailed explanation of the states responsible for the observed two-band structure. Finally, we discuss the energy transfer within the complex by analyzing population transfer calculations and 2D spectra for different waiting times. We conclude that the energy transfer from the B800 ring to the B850 ring is mediated by intermediate states that are delocalized over both rings, allowing for a stepwise downhill energy transport. PMID- 25554921 TI - The effect of heavy resistance exercise on repeated sprint performance in youth athletes. AB - This investigation assessed whether prior heavy resistance exercise would improve the repeated sprint performance of 16 trained youth soccer players (Age 17.05 +/- 0.65 years; height 182.6 +/- 8.9 cm; body mass 77.8 +/- 8.2 kg). In session 1, individual 1 repetition max was measured utilising a squat movement. In sessions 2 and 3, participants performed a running-based repeated anaerobic sprint test with and without prior heavy resistance exercise of 91% of their 1 repetition max. Times were recorded for each of the 6 sprints performed in the repeated sprint test and summed to provide total time. T-tests compared the two exercise conditions via differences in corresponding sprint times and total time. Analysis revealed significantly reduced total time with use of heavy resistance exercise (33.48 (+/-1.27) vs. 33.59 (+/-1.27); P = 0.01). Sprints 1 (P = 0.05) and 2 (P = 0.02) were also faster in the heavy resistance exercise condition (5.09 (+/-0.16) vs. 5.11 (+/-0.16) and 5.36 (+/-0.24) vs. 5.45 (+/-0.26) seconds respectively) although no other differences were shown. Findings demonstrate improved sprint times of trained adolescent soccer players after heavy resistance exercise although benefits appear not as sustained as in adult participants. PMID- 25554920 TI - Dementia attitudes and help-seeking intentions: an investigation of responses to two scenarios of an experience of the early signs of dementia. AB - OBJECTIVES: To investigate associations between dementia-attitudes and help seeking intentions. METHOD: An online survey of 611 Australian adults (45-60 years) assessed dementia-related attitudes and help-seeking intentions in response to two scenarios of an experience of early dementia: for themselves (Scenario 1); and for a significant other (proxy help-seeking) (Scenario 2). Logistic regression models examined the relationship between four dementia related attitudes (labelled Personal Avoidance, Fear of Labelling, Fear of Discrimination and Person Centredness) and help-seeking intentions. RESULTS: Most participants indicated they would seek help from a general practitioner (GP) for themselves (82.2%) or for a proxy (78.7%) in response to the scenarios. Whilst only 7.2% indicated they would seek help from no-one, 21.3% would delay seeking help. In response to Scenario 1, Personal Avoidance and Fear of Labelling were associated with intentions to delay help-seeking. Fear of both Labelling and Discrimination were associated with intentions to seek help from no-one. In response to Scenario 2, Personal Avoidance was associated with intentions to delay proxy help-seeking and a reduced likelihood of seeking help by phone or and with Fear of Discrimination, via a GP. Fear of Labelling was also associated with an intention to delay proxy help-seeking. CONCLUSION: Efforts to improve help seeking for dementia should address attitudes relating to stigma including negative labelling and a desire for the avoidance of people with dementia. Fears relating to discrimination indicate a need to build public confidence regarding the capacity of the health and workforce sectors to support people with dementia ethically and appropriately. PMID- 25554922 TI - Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: synthesis and anticancer activity. AB - A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 +/- 0.08 MUM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity. PMID- 25554923 TI - Hypertriglyceridemia in the genomic era: a new paradigm. AB - Hypertriglyceridemia (HTG) is a highly prevalent condition that is associated with increased cardiovascular disease risk. HTG may arise as a result of defective metabolism of triglyceride-rich lipoproteins and their remnants, ie, impaired clearance, or increased production, or both. Current categorization of HTG segregates primary and secondary cases, implying genetic and nongenetic causes for each category. Many common and rare variants of the genes encoding factors involved in these pathways have been identified. Although monogenic forms of HTG do occur, most cases are polygenic and often coexist with nongenetic conditions. Cumulative, multiple genetic variants can increase the risks for HTG, whereas environmental and lifestyle factors can force expression of a dyslipidemic phenotype in a genetically susceptible person. HTG states are therefore best viewed as a complex phenotype resulting from the interaction of cumulated multiple susceptibility genes and environmental stressors. In view of the heterogeneity of the HTG states, the absence of a unifying metabolic or genetic abnormality, overlap with the metabolic syndrome and other features of insulin resistance, and evidence in some patients that accumulation of numerous small-effect genetic variants determines whether an individual is susceptible to HTG only or to HTG plus elevated low-density lipoprotein cholesterol, we propose that the diagnosis of primary HTG and further delineation of familial combined hyperlipidemia from familial HTG is neither feasible nor clinically relevant at the present time. The hope is that with greater understanding of genetic and environmental causes and their interaction, therapy can be intelligently targeted in the future. PMID- 25554925 TI - Working alone or in the presence of others: exploring social facilitation in baggage X-ray security screening tasks. AB - This study investigated whether the mere presence of a human audience would evoke a social facilitation effect in baggage X-ray security screening tasks. A 2 (target presence: present vs. absent) * 2 (task complexity: simple vs. complex) * 2 (social presence: alone vs. human audience) within-subject experiment simulating a real baggage screening task was conducted. This experiment included 20 male participants. The participants' search performance in this task was recorded. The results showed that the presence of a human audience speeded up responses in simple tasks and slowed down responses in complex tasks. However, the social facilitation effect produced by the presence of a human audience had no effect on response accuracy. These findings suggested that the complexity of screening tasks should be considered when designing work organisation modes for security screening tasks. Practitioner summary: This study investigated whether the presence of a human audience could evoke a social facilitation effect in baggage X-ray security screening tasks. An experimental simulation was conducted. The results showed that the presence of a human audience facilitated the search performance of simple tasks and inhibited the performance of complex tasks. PMID- 25554924 TI - New insights into innate immune restriction of West Nile virus infection. AB - West Nile virus (WNV) is an encephalitic flavivirus that has provided a valuable experimental system for studying viral pathogenesis and immunity. Although in vitro approaches and mouse models of infection have identified pattern recognition receptor and interferon pathways that control WNV infection, our appreciation of specific antiviral effectors has been more limited. In this review, we highlight recent advances in our understanding of the host factors that restrict WNV infection in mammals and insects, especially those resulting from large-scale screening approaches. PMID- 25554927 TI - Dominant-non-dominant asymmetry of kicking a stationary and rolling ball in a futsal context. AB - The aim of this study was to analyse the characteristics of the asymmetries in the dominant and non-dominant limbs when kicking stationary and rolling balls. Ten experienced Brazilian amateur futsal players participated in this study. Each participant performed kicks under two conditions (stationary ball vs. rolling ball) with the dominant and non-dominant limbs (five kicks per condition per limb). We analysed the kicking accuracy, ball and foot velocities, angular joint displacement and velocity. The asymmetry between the dominant and non-dominant limbs was analysed by symmetry index and two-way repeated measures ANOVA. The results did not reveal any interaction between the condition and limb for ball velocity, foot velocity and accuracy. However, kicking with the dominant limb in both kicks showed higher ball velocity (stationary ball: dominant - 24.27 +/- 2.21 m . s(-1) and non-dominant - 21.62 +/- 2.26 m . s(-1); rolling ball: dominant - 23.88 +/- 2.71 m . s(-1) and non-dominant - 21.42 +/- 2.25 m . s(-1)), foot velocity (stationary ball: dominant - 17.61 +/- 1.87 m . s(-1) and non dominant - 15.58 +/- 2.69 m . s(-1); rolling ball: dominant - 17.25 +/- 2.26 m . s(-1) and non-dominant - 14.77 +/- 2.35 m . s(-1)) and accuracy (stationary ball: dominant - 1.17 +/- 0.84 m and non-dominant - 1.56 +/- 1.30 m; rolling ball: dominant - 1.31 +/- 0.91 m and non-dominant - 1.97 +/- 1.44 m). In addition, the angular joint adjustments were dependent on the limb in both kicks (the kicks with non-dominant limb showed lower hip external rotation than the kicks with the dominant limb), indicating that the hip joint is important in kick performance. In conclusion, the kicks with the non-dominant limb showed different angular adjustments in comparison to kicks with the dominant limb. In addition, kicking a rolling ball with the non-dominant limb showed higher asymmetry for accuracy, indicating that complex kicks are more asymmetric. PMID- 25554931 TI - What is your diagnosis? Paralytic ileus in a beaver. PMID- 25554932 TI - Anesthesia case of the month. Iatrogenic pneumothorax. PMID- 25554933 TI - Animal behavior case of the month. Petting intolerance. PMID- 25554934 TI - Pathology in practice. Symmetric lupoid onychodystrophy of the claw bed epithelium. PMID- 25554935 TI - Pathology in practice. P tomentosa infection in zebrafish. PMID- 25554936 TI - Comparison of anamnestic responses to rabies vaccination in dogs and cats with current and out-of-date vaccination status. AB - OBJECTIVE: To compare anamnestic antibody responses of dogs and cats with current versus out-of-date vaccination status. DESIGN: Cross-sectional study. ANIMALS: 74 dogs and 33 cats. PROCEDURES: Serum samples were obtained from dogs and cats that had been exposed to rabies and brought to a veterinarian for proactive serologic monitoring or that had been brought to a veterinarian for booster rabies vaccination. Blood samples were collected on the day of initial evaluation (day 0) and then again 5 to 15 days later. On day 0, a rabies vaccine was administered according to label recommendations. Paired serum samples were analyzed for antirabies antibodies by means of a rapid fluorescent focus inhibition test. RESULTS: All animals had an antirabies antibody titer >= 0.5 IU/mL 5 to 15 days after booster vaccination. Dogs with an out-of-date vaccination status had a higher median increase in titer, higher median fold increase in titer, and higher median titer following booster vaccination, compared with dogs with current vaccination status. Most (26/33) cats, regardless of rabies vaccination status, had a titer >= 12 IU/mL 5 to 15 days after booster vaccination. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dogs with out-of-date vaccination status were not inferior in their antibody response following booster rabies vaccination, compared with dogs with current vaccination status. Findings supported immediate booster vaccination followed by observation for 45 days of dogs and cats with an out-of-date vaccination status that are exposed to rabies, as is the current practice for dogs and cats with current vaccination status. PMID- 25554937 TI - Evaluation of the effects of hospital visit stress on physiologic variables in dogs. AB - OBJECTIVE: To evaluate differences in pulse rate, rectal temperature, respiratory rate, and systolic arterial blood pressure in dogs between the home and veterinary hospital environments. DESIGN: Prospective observational study. ANIMALS: 30 client-owned healthy dogs. PROCEDURES: Study dogs had respiratory rate, pulse rate, rectal temperature, and systolic arterial blood pressure measured in their home environment. Dogs were then transported to the veterinary hospital, and measurements were repeated. RESULTS: Significant differences in blood pressure, rectal temperature, and pulse rate were observed between measurements obtained in the home and hospital environments. Mean blood pressure increased by 16% (95% confidence interval [CI], 8.8% to 24%), rectal temperature increased by < 1% (95% CI, 0.1% to 0.6%), and pulse rate increased by 11% (95% CI, 5.3% to 17.6%). The number of dogs panting in the hospital environment (19/30 [63%]) was significantly higher than the number of dogs panting in the home environment (5/30 [17%]) CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggested that practitioners should consider stress from transportation and environmental change when canine patients have abnormalities of vital signs on initial examination, and the variables in question should be rechecked before a definitive diagnosis of medical illness is reached or extensive further workup is pursued. PMID- 25554938 TI - Double pigtail ureteral stenting and renal pelvic lavage for renal-sparing treatment of obstructive pyonephrosis in dogs: 13 cases (2008-2012). AB - OBJECTIVE: To describe the technical aspects and clinical outcome of endoscopic- and fluoroscopic-guided ureteropelvic lavage and ureteral stent placement for treatment of obstructive pyonephrosis in dogs. DESIGN: Retrospective case series. ANIMALS: 13 client-owned dogs (14 obstructed ureters). PROCEDURES: All patients with obstructive pyonephrosis were treated with a ureteral stent. Medical records were reviewed for history, clinical signs, pre- and postprocedural clinical and imaging data, and short- and long-term outcomes. RESULTS: 13 dogs (14 ureters) had unilateral or bilateral ureteral obstructions and pyonephrosis due to ureterolithiasis (n = 13) or a suspected ureteral stricture (1). Eleven dogs had positive results of bacteriologic culture of urine obtained from the bladder, renal pelvis, or both. Ten were thrombocytopenic, and 8 were azotemic. Stents were placed fluoroscopically with endoscopic (n = 11) or surgical (3) assistance. Median hospitalization time was 48 hours (range, 6 to 260 hours). Median follow up time was 480 days (range, 2 to 1,460 days). Intraoperative complications occurred in 2 patients (stent occlusion from shearing of a guide wire, and wire penetration of the ureter at the location of a stone). Short-term complications included a bladder hematoma (n = 1) and transient dysuria (1). Long-term complications included stent encrustation (n = 1), stent migration (1), and tissue proliferation at the ureterovesicular junction (5), which had no clinical implications. Recurrent urinary tract infections were documented in 7 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Ureteral stenting was a successful renal sparing treatment for obstructive pyonephrosis in dogs and could often be performed in a minimally invasive manner. There were few major complications. This technique may be considered as an effective treatment option for this condition in dogs. PMID- 25554939 TI - Triceps brachii muscle reconstruction with a latissimus dorsi muscle flap in a dog. AB - CASE DESCRIPTION: A 6-year-old spayed female Border Collie was examined for a severe deformity of the right forelimb. Three months prior to examination, the patient awkwardly fell off the couch and became acutely lame in the right forelimb, progressing to non-weight bearing over the following 72 hours. CLINICAL FINDINGS: On physical examination, the dog carried the limb caudally against the thoracic wall, with the shoulder flexed and elbow in extension. The right triceps brachii muscle was atrophied and contracted, resulting in a resistant tension band effect that precluded manipulation of the right elbow joint. The physical changes in the triceps muscle were considered the primary cause of the patient's loss of limb function. TREATMENT AND OUTCOME: Surgical treatment by means of elevation and transposition of the ipsilateral latissimus dorsi muscle was performed. The exposed triceps brachii muscles were transected 3 cm proximal to the tendons of insertion. Via a separate incision, the right latissimus dorsi muscle was elevated and tunneled subcutaneously beneath the interposing skin between the 2 surgical incisions. The muscle was then positioned and sutured to the proximal and distal borders of the divided triceps muscle group. Two weeks later, physical therapy was initiated. After 2 months, the patient regularly walked on the limb most of the time (9/10 steps). CLINICAL RELEVANCE: The surgical procedure for elevation and transposition of the latissimus dorsi muscle was relatively simple to perform. Physical therapy was an essential component to achieving the successful functional outcome in this case. This technique may be considered for treatment of similar patients in which the triceps muscle group is severely compromised. PMID- 25554940 TI - Unilateral choristoma of the nictitating membrane in a horse. AB - CASE DESCRIPTION: A 2-year-old Morgan mare was evaluated because of a corneal ulceration. CLINICAL FINDINGS: An irregular, deep stromal corneal ulcer in an area of malacia was noted in the left eye. Hypopyon was present in the ventral portion of the anterior chamber with moderate aqueous flare. The nictitating membrane of the left eye had hairs originating from its leading edge that contacted the corneal surface. TREATMENT AND OUTCOME: General anesthesia was induced, and a bulbar pedicle conjunctival graft was performed. The conjunctiva at the leading edge of the nictitating membrane, including the aberrant hair follicles, was excised. Microscopically, a nonkeratinized stratified squamous epithelium, sebaceous glands, and hair shafts were present, confirming a choristoma of pilosebaceous origin at the leading edge of the nictitating membrane. Six weeks after surgery, the horse had no signs of discomfort, with no regrowth of the hairs; no loss of vision was evident. CLINICAL RELEVANCE: Ocular choristomas develop secondary to defective fetal cellular differentiation and are rarely reported in the equine literature. The choristoma in this horse contained ectopic hair follicles with hair growth as well as sebaceous glands. This finding emphasizes the importance of a thorough adnexal examination in horses with corneal disease. PMID- 25554941 TI - Sensitivity and specificity of repeated test results from a commercial milk enzyme-linked immunosorbent assay for detection of Mycobacterium avium subspecies paratuberculosis in dairy cattle. AB - OBJECTIVE: To investigate the sensitivity and specificity of results of initial and repeated milk ELISAs (at 6- or 12-month intervals) to detect cows that were shedding Mycobacterium avium subsp paratuberculosis (ie, were infectious) and to evaluate factors influencing the probability that the results of a repeated milk ELISA would be positive for an infectious cow if the results of the initial milk ELISA were negative. DESIGN: Prospective cohort study. ANIMALS: 3,145 dairy cows from 32 herds. PROCEDURES: Herds from the 3 Maritime provinces in Canada (Prince Edward Island, New Brunswick, and Nova Scotia), participating in a Dairy Herd Improvement program, and that had undergone a prior Mycobacterium avium subsp paratuberculosis awareness project were selected for the study. Sample collection occurred between April 2009 and March 2011 with milk and fecal samples collected from all lactating cows in study herds every 6 months. Herds completing < 3 herd visits with collection of individual cow fecal or milk samples, within this sampling timeframe, were excluded from analyses. Fecal samples were cultured in liquid medium and a cow was defined as infectious if >= 1 sample was culture positive (reference test). A milk ELISA (index test) was completed with a commercial kit, following manufacturer's instructions. RESULTS: For a 6-month test interval, sensitivities of the milk ELISA to detect infectious cows were 22.0% and 32.6% for initial and combined initial and repeated tests (parallel interpretation), respectively. Specificity of the initial ELISA was 99.6% and was 99.2% for combined tests. For a 12-month test interval, sensitivities of the milk ELISA to detect infectious cows were 25.6% and 45.3% for initial and combined initial and repeated tests (parallel interpretation), respectively. Specificity of the initial ELISA was 99.6% and was 98.9% for combined tests. In infectious cows, magnitude of the initial negative ELISA result was a positive predictor for a positive repeated ELISA result. CONCLUSIONS AND CLINICAL RELEVANCE: Results of a repeated milk ELISA improved detection of Mycobacterium avium subsp paratuberculosis infectious cows, with minimal loss of specificity. A 12-month test interval provided a greater increase in sensitivity, relative to an initial test, than did a 6-month interval. Infectious cows with an initial negative milk ELISA result close to the cutoff for a positive test were more likely to have positive results on a repeated ELISA. Repeated testing improved detection of infectious cows and reduced risk of misclassification compared with a single ELISA result. PMID- 25554942 TI - Evaluation of plasma fibrinogen concentration as a diagnostic indicator of inflammation in red-eared sliders (Trachemys scripta elegans). AB - OBJECTIVE: To critically evaluate plasma fibrinogen concentration as a diagnostic indicator of inflammation in red-eared sliders (Trachemys scripta elegans). DESIGN: Prospective induced-disease model and prospective cross-sectional study. SAMPLE: Plasma samples from 12 purpose-bred red-eared sliders and 153 farm-raised red-eared sliders. PROCEDURES: A modification of the Jacobsson method was developed to measure fibrinogen concentration in platelet-poor plasma from red eared sliders. Purpose-bred turtles had been inoculated with a ranavirus (n = 4) or sterile PBS solution (8) as part of another study. Farm-raised red-eared sliders were categorized as healthy (n = 138) or overtly ill (15) on the basis of physical examination findings at the time of blood sample collection. Samples from 124 of the 138 healthy red-eared sliders were used to establish a fibrinogen concentration reference interval as measured by the modified Jacobsson method. Fibrinogen concentrations in ranavirus-infected and physically ill turtles were compared with those of healthy turtles to determine whether fibrinogen concentration would be a useful diagnostic indicator of inflammation in red-eared sliders. RESULTS: The modified Jacobsson method was reliably used to measure fibrinogen concentration. The fibrinogen concentration reference interval from healthy reproductively active female red-eared sliders was right skewed. Fibrinogen concentration did not differ significantly between healthy red-eared sliders and ranavirus-infected or overtly ill red-eared sliders. CONCLUSIONS AND CLINICAL RELEVANCE: A reference interval for red-eared slider plasma fibrinogen concentration was established and partitioned by sex to account for considerable right skewing observed for females. Fibrinogen concentration was not a useful indicator of inflammation in red-eared sliders with ranavirus infection or other overt illnesses. PMID- 25554943 TI - Parahydrogen discriminated PHIP at low magnetic fields. AB - Parahydrogen induced polarization (PHIP) is a powerful hyperpolarization technique. However, as the signal created has an anti-phase characteristic, it is subject to signal cancellation when the experiment is carried out in inhomogeneous magnetic fields or in low fields that lack the necessary spectral resolution. The use of benchtop spectrometers and time domain (TD) analyzers has continuously grown in the last years and many applications are found in the food industry, for non-invasive compound detection or as a test bench for new contrast agents among others. In this type of NMR devices the combination of low and inhomogeneous magnetic fields renders the application of PHIP quite challenging. We have recently shown that the acquisition of J-spectra in high magnetic fields not only removes the anti-phase peak cancellation but also produces a separation of thermal from hyperpolarized signals, providing Parahydrogen Discriminated (PhD PHIP) spectra. In this work we extend the use of PhD-PHIP to low and inhomogeneous fields. In this case the strong coupling found for the protons of the sample renders spin-echo spectra that have a great complexity, however, a central region in the spectrum with only hyperpolarized signal is clearly identified. This experimental approach is ideal for monitoring real time chemical reaction of pure PHIP signals. PMID- 25554944 TI - Solid-state Hadamard NMR spectroscopy: simultaneous measurements of multiple selective homonuclear scalar couplings. AB - Unambiguous measurement of homonuclear scalar couplings (J) in multi-spin scalar network systems is not straightforward. Further, the direct measurement of J couplings is obscured in solid-state samples due to the dipolar and chemical shift anisotropy (CSA)-dominated line broadening, even under the magic angle spinning (MAS). We present a new multiple frequency selective spin-echo method based on Hadamard matrix encoding, for simultaneous measurement of multiple homonuclear scalar couplings (J) in the solid-state. In contrast to the Hadamard encoded selective excitation schemes known for the solution-state, herein the selectivity is achieved during refocusing period. The Hadamard encoded refocusing scheme concurrently allows to create the spin-spin commutation property between number of spin-pairs of choice in uniformly labelled molecules, which, therefore avoids (1) the repetition of the double selective refocusing experiments for each spin-pair and (2) the synthesis of expensive selective labelled molecules. The experimental scheme is exemplified for determining (1)JCC and (3)JCC values in (13)C6l-Histidine.HCl molecule, which are found to be in excellent agreement with those measured in conventional double frequency selective refocusing mode as well as in the solution-state. This method can be simply extended to 2D/3D pulse schemes and be applied to small bio-molecular solids. PMID- 25554945 TI - Tabletop magnetic resonance elastography for the measurement of viscoelastic parameters of small tissue samples. AB - We demonstrate the feasibility of low-cost tabletop MR elastography (MRE) for quantifying the complex shear modulus G(*) of small soft biological tissue samples as provided by pathologists. The MRE system was developed based on a tabletop MRI scanner equipped with a 0.5 T permanent magnet and a tissue sample holder mounted to a loudspeaker. A spin echo sequence was enhanced with motion encoding gradients of 250 mT/m amplitude synchronized to acoustic vibration frequencies. Shear wave images suitable for elastography were acquired between vibration frequencies of 0.5 and 1 kHz in agarose, ultrasound gel, porcine liver, porcine skeletal muscle, and bovine heart with a spatial resolution of 234 MUm pixel edge length. The measured frequency dependence of G(*) agreed well with previous work based on high-field MR systems. The ratio between loss and storage moduli was highest in liver and ultrasound gel, followed by muscle tissue and agarose gel while ultrasound gel and liver showed similarly low storage moduli compared to the other samples. The shear wave to noise ratio is an important imaging criteria for MRE and was about 4.2 times lower for the preliminary setup of the 0.5 T tabletop system compared to a 7 T animal scanner. In the future, the new tabletop MRE system may serve as a low cost device for preclinical research on the correlation of viscoelastic parameters with histopathology of biological samples. PMID- 25554947 TI - Mulberry and mulberry wine extract increase the number of mitochondria during brown adipogenesis. AB - Mulberry extract (ME) has been shown to possess beneficial effects towards obesity, but its mechanism is still unclear. In small mammals, mitochondria enriched brown adipose tissue (BAT) is known to convert protein's electrochemical energy to heat and maintain a constant body temperature. Improving the mitochondrial function or increasing the number of mitochondria could promote the metabolism of carbohydrate and fat. Thus, this study was designed to investigate the mitochondrial function regulated by ME and mulberry wine extract (MWE) during the brown adipogenesis. The C3H10T1/2 mesenchymal stem cell was treated with ME and MWE, both of which significantly (p < 0.05) increased the expression levels of fatty acid oxidation related genes such as peroxisome proliferator-activated receptor-gamma coactivator-1alpha, PR domain-containing 16 and carnitine palmitoyltransferase 1alpha during brown adipogenesis. These changes were accompanied with increases in mitochondrial oxidative complex proteins upon ME and/or MWE exposure. Notably, ME and/or MWE also significantly (p < 0.05) increased the expression of the transcription factor A and the nuclear respiratory factor-1, which are the key transcription factors of mitochondrial biogenesis. In parallel, the mitochondrial copy number and brown adipose tissue specific gene-uncoupling protein-1 expression were dramatically (p < 0.05) elevated after ME or MWE treatment. Cyanidin-3-glucoside (Cy-3-glu) was found to be one of the most abundant anthocyanins in ME and MWE. Therefore, the BAT regulatory activity of ME and MWE might be, at least in part, due to the effect of Cy-3-glu. These results suggested that ME and MWE could ameliorate metabolic disease through an improvement in mitochondrial functions. PMID- 25554946 TI - Exploring the mechanisms of the reductase activity of neuroglobin by site directed mutagenesis of the heme distal pocket. AB - Neuroglobin (Ngb) is a six-coordinate globin that can catalyze the reduction of nitrite to nitric oxide. Although this reaction is common to heme proteins, the molecular interactions in the heme pocket that regulate this reaction are largely unknown. We have shown that the H64L Ngb mutation increases the rate of nitrite reduction by 2000-fold compared to that of wild-type Ngb [Tiso, M., et al. (2011) J. Biol. Chem. 286, 18277-18289]. Here we explore the effect of distal heme pocket mutations on nitrite reduction. For this purpose, we have generated mutations of Ngb residues Phe28(B10), His64(E7), and Val68(E11). Our results indicate a dichotomy in the reactivity of deoxy five- and six-coordinate globins toward nitrite. In hemoglobin and myoglobin, there is a correlation between faster rates and more negative potentials. However, in Ngb, reaction rates are apparently related to the distal pocket volume, and redox potential shows a poor relationship with the rate constants. This suggests a relationship between the nitrite reduction rate and heme accessibility in Ngb, particularly marked for His64(E7) mutants. In five-coordinate globins, His(E7) facilitates nitrite reduction, likely through proton donation. Conversely, in Ngb, the reduction mechanism does not rely on the delivery of a proton from the histidine side chain, as His64 mutants show the fastest reduction rates. In fact, the rate observed for H64A Ngb (1120 M(-1) s(-1)) is to the best of our knowledge the fastest reported for a heme nitrite reductase. These differences may be related to a differential stabilization of the iron-nitrite complexes in five- and six coordinate globins. PMID- 25554948 TI - Highly sensitive and selective detection of miRNA: DNase I-assisted target recycling using DNA probes protected by polydopamine nanospheres. AB - Based on the protective properties of polydopamine nanospheres for DNA probes against nuclease digestion, we have developed a DNase I-assisted target recycling signal amplification method for highly sensitive and selective detection of miRNA. PMID- 25554949 TI - Thermodynamic and spectroscopic analysis of the conformational transition of poly(vinyl alcohol) by temperature-dependent FTIR. AB - The conformational change of poly(vinyl alcohol) has been studied by Fourier transform infrared spectroscopy at various temperatures in the 4000-400 cm(-1) region. The molecular motion and the trans/gauche content are sensitive to the C H, C-C stretching modes. FTIR spectra show that the I2920/I2849 decreases from 1.84 to 1.0 with increasing temperature, companying the decrease in I1047/I1095 from 0.78 to 0.58, implying the conformational transition from trans to gauche in alkyl chain. Based on the van't Hoff relation, the enthalpies and entropies have been calculated in different temperatures, which are 4.61 kJ mol(-1) and 15.23 J mol(-1) K(-1), respectively, in the region of 80-140 degrees C. From the C=O stretching mode and O-H band, it can be concluded that the intermolecular hydrogen bonds decrease owing to elevating temperature, which leads to more gauche conformers. PMID- 25554950 TI - Hydrolysis of Letrozole catalyzed by macrocyclic Rhodium (I) Schiff-base complexes. AB - Ten mononuclear Rhodium (I) complexes were synthesized by macrocyclic ligands having N4 and N2O2 donor sites. Square planar geometry is assigned based on the analytical and spectral properties for all complexes. Rh(I) complexes were investigated as catalysts in hydrolysis of Nitrile group containing pharmaceutical drug Letrozole. A comparative study showed that all the complexes are efficient in the catalysis. The percent yields of all the catalytic reaction products viz. drug impurities were determined by spectrophotometric procedures and characterized by spectral studies. PMID- 25554951 TI - TDDFT study on the excited-state proton transfer of 8-hydroxyquinoline: key role of the excited-state hydrogen-bond strengthening. AB - Density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations have been employed to study the excited-state intramolecular proton transfer (ESIPT) reaction of 8-hydroxyquinoline (8HQ). Infrared spectra of 8HQ in both the ground and the lowest singlet excited states have been calculated, revealing a red-shift of the hydroxyl group (-OH) stretching band in the excited state. Hence, the intramolecular hydrogen bond (O-H...N) in 8HQ would be significantly strengthened upon photo-excitation to the S1 state. As the intramolecular proton-transfer reaction occurs through hydrogen bonding, the ESIPT reaction of 8HQ is effectively facilitated by strengthening of the electronic excited-state hydrogen bond (O-H...N). As a result, the intramolecular proton-transfer reaction would occur on an ultrafast timescale with a negligible barrier in the calculated potential energy curve for the ESIPT reaction. Therefore, although the intramolecular proton-transfer reaction is not favorable in the ground state, the ESIPT process is feasible in the excited state. Finally, we have identified that radiationless deactivation via internal conversion (IC) becomes the main dissipative channel for 8HQ by analyzing the energy gaps between the S1 and S0 states for the enol and keto forms. PMID- 25554952 TI - Synthesis, characterization and theoretical investigations of the structure, electronic properties and third-order nonlinearity optics (NLO) of M(DPIP)2. AB - Three complexes of M(DPIP)2 (M=Cu, Co, Zn as 1, 2, 3) were synthesized and characterized by elemental analysis, IR, UV-Vis, thermogravimetry, and X-ray diffraction. Their nonlinear optical properties were measured by the Z-scan technique and yielded a normalized transmittance of about 70% for complex 1 (45 MUJ pulse), and 93% for complex 3 (68 MUJ pulse at the focus point). The nonlinear absorption coefficient, beta, is 1.4*10(-11) m/W for 1 and 5.6*10(-13) m/W for 3, and the third-order nonlinear refraction index, n2, is 1.0*10(-18) m(2)/W for 3. Complex 1 shows self-defocusing property, while complex 3 exhibits self-focusing property. The thermogravimetric results show that the frame structure of compounds 1-3 begin to collapse at 400, 250 and 280 degrees C, respectively, which suggests that they elicit excellent thermal stability. This research aims to provide better understanding of these compounds, and offer preliminary explanations for the significant differences between compounds 1-3, in order to potentially help in the designing of future novel materials with NLO properties. PMID- 25554953 TI - Fluorescence analysis of iodinated acetophenone derivatives. AB - In the present paper the synthesis and optical characterization of iodinated acetophenone, 4-hydroxy-3-iodoacetophenone and 4-hydroxy-3,5-diiodoacetophenone obtained from 4-hydroxyacetophenone, were carried out. The optical features of iodinated molecules were determined by performing the UV-Vis absorption, fluorescence and thermal lens spectroscopies. The results showed that the optical properties of the 4-hydroxyacetophenone is altered when the iodine atom is inserted, as substituent, in the aromatic ring. Although it was determined that the optical feature was changed when one iodine atom was inserted in the aromatic ring (4-hydroxy-3-iodoacetophenone), the results revealed that emission behavior was strongly altered when two iodine atoms (4-hydroxy-3,5-diiodoacetophenone) were acting as substituents: the fluorescence quantum efficiency increases approximately 60%. PMID- 25554954 TI - Novel olefinic-centered macroacyclic compounds involving tetrasubstituted 4 hydroxybenzoic acid fragments: synthesis, structural characterization and comparison of experimental and computational results. AB - Dialkyl 4,4'-(2-(1,3-bis(4-(alkoxycarbonyl)phenoxy)propan-2-ylidene)propane-1,3 diyl)bis (oxy)dibenzoate 6a,b were synthesized through the reaction of ethene 1,1,2,2,-tetra-yl-tetra methylene tetra bromide 1 with methyl 4-hydroxy benzoate or ethyl 4-hydroxy benzoate 2a,b. In addition, compounds 6a,b were obtained by using the esterification reaction from the reaction compound 5 with methyl and ethyl alcohol in high yields. Compound 4 was synthesized from the reaction of ethene-1,1,2,2,-tetra-yl-tetra methylene tetra bromide 1 with 4-hydroxy benzonitrile 3. The structures of the novel synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR, COSY, elemental analysis, and mass spectral data. Compound 6b, C42H44O12, was also characterized with additional analysis such as UV-vis, and X-ray spectral techniques. The electronic structure of compound 6b was studied by DFT level 6-31G*(d,p) using X-ray crystallographic data. The results obtained from this study are consistent with the X-ray data. In order to understand the electronic transitions of the compound 6b, time dependent density functional theory (TD-DFT) calculations were carried out. TD-DFT studies showed that the low-energy excitations are consistent with the experimental results. PMID- 25554955 TI - Conformations of n-butyl imidazole: matrix isolation infrared and DFT studies. AB - Conformations of n-butyl imidazole (B-IMID) were studied using matrix isolation infrared spectroscopy by trapping in argon, xenon and nitrogen matrixes using an effusive nozzle source. The experimental studies were supported by DFT computations performed at the B3LYP/6-311++G(d,p) level. Computations identified nine unique minima for B-IMID, corresponding to conformers with tg(+/-)tt, tg(+/ )g(?)t, tg(+/-)g(+/-)t, tg(+/-)tg(+/-), tg(+/-)tg(?), tg(+/-)g(?)g(?), tg(+/ )g(+/-)g(+/-), tg(+/-)g(?)g(+/-) and tg(+/-)g(+/-)g(?) structures, given in order of increasing energy. Computations of the transition state structures connecting the higher energy conformers to the global minimum, tg(+/-)tt structure were carried out. The barriers for the conformer inter-conversion were found to be ~2 kcal/mol. Natural Bond Orbital (NBO) analysis was performed to understand the reasons for conformational preferences in B-IMID. PMID- 25554956 TI - Spectral investigations on undoped and Cu2+ doped ZnO-CdS composite nanopowders. AB - Undoped and Cu(2+) doped ZnO-CdS composite nanopowders were synthesized by simple chemical precipitation method. Structural and spectroscopic properties of the prepared samples have been characterized by XRD, SEM with EDS, TEM, FT-IR, UV Vis, EPR and Photoluminescence studies. X-ray diffraction pattern contains a series of peaks corresponds to hexagonal phase of ZnO and CdS. The average crystallite sizes of undoped and Cu(2+) doped samples are determined and are in the range of 25-30 nm. SEM and TEM micrographs reveal that the samples show spherical like structures with little agglomeration. FT-IR spectra show the fundamental mode of vibrations of ZnO at 515 cm(-1), CdS at 621 cm(-1) and other functional groups. Optical absorption spectrum of Cu(2+) doped sample consists of three bands at 665, 823 and 1192 nm attributed to the transitions (2)B1g->(2)Eg, (2)B2g and (2)A1g respectively. Crystal field and tetragonal field parameters are evaluated as Dq=1214, Ds=1610 and Dt=389 cm(-1). From EPR, spin-Hamiltonian and hyperfine splitting parameters are evaluated for Cu(2+) doped sample as g||=2.3391, g?=2.0550 and A||=130*10(-4) cm(-1), A?=36*10(-4) cm(-1). The optical and EPR data suggests that Cu(2+) entered into host lattice as tetragonally distorted octahedral site symmetry. PL spectra consists two emission bands at 367, 380 nm in UV region. A sharp blue emission peak at 425 nm and a broad green emission peak in the range of 450-570 nm are observed. The enhanced visible emission is observed after doping. PMID- 25554957 TI - X-ray diffraction and vibrational spectroscopic study of trans bis(acetylacetonato)-bis(4-methylpyridine)cobalt(III). AB - Trans-bis(acetylacetonato)-bis(4-methylpyridine)cobalt(III)hexafluorophosphate, [AMPC]PF6, was synthesized and characterized by X-ray diffraction and vibrational spectroscopy. The title compound C22H28N2O4Co crystallizes with Z=2 in space group P-1 (#2). The molecular structure and vibrational spectra of this compound were investigated by means of density functional theory (DFT) calculations and the results were compared with the experimental data. The measured IR bands were interpreted in terms of the calculated vibrational normal modes and compared with the tris(acetylacetonate)Co(III) (Co(acac)3) and 4-methylpyridine (4-Mepy) vibrational spectra. The scaled theoretical wavenumbers and the structural parameters were in excellent agreement with the experimental data. PMID- 25554958 TI - X-ray, vibrational and theoretical studies of weak hydrogen bonds in bis(4 nitroanilinium) hexachloridostannate. AB - Crystal structure of bis(4-nitroanilinium) hexachloridostannate, (H4NA)2SnCl6, was determined by means of X-ray single crystal diffraction. In the crystal structure, weak N-H...Cl hydrogen bonds are present. These interactions were taken into consideration in calculations of vibrational spectra for the [(H4NA)Cl4O](5-) anion. Very good agreement between theoretical and experimental frequencies was achieved. The calculations were done at the B3LYP/6-311+G(2d,1p) level including Grimme's correction for dispersion. The relaxed potential energy surface indicated that the energy of H4NA(+) ion is approximately independent upon rotation of the ammonio group. The energy barrier is 0.01 kcal/mol. Therefore the position of the ammonio group can be easily modified the other interacting molecules during molecular self-assembly and crystal growth processes. The energy of the H4NA(+) ion significantly depends on the relative position of the nitro group towards the aromatic ring. The energy barrier of the nitro group is 4.35 kcal/mol. PMID- 25554959 TI - Synthesis, characterization, computational calculation and biological studies of some 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oxime derivatives. AB - A new series of 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17-24) were designed and synthesized from 2,6-diarylpiperidin-4-one oximes (9-16) with propargyl bromide. Unambiguous structural elucidation has been carried out by investigating IR, NMR ((1)H, (13)C, (1)H-(1)H COSY and HSQC), mass spectral techniques and theoretical (DFT) calculations. Further, crystal structure of compound 17 was evaluated by single crystal X-ray diffraction analysis. Single crystal X-ray structural analysis of compound 17 evidenced that the configuration about CN double bond is syn to C-5 carbon (E-form). The existence of chair conformation was further confirmed by theoretical DFT calculation. All the synthesized compounds were screened for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains using Ciprofloxacin and Ketoconazole as standards. The minimum inhibition concentration (MIC) results revealed that most of the 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17, 19, 20 and 23) exhibited better activity against the selected bacterial and fungal strains. PMID- 25554960 TI - Specific fluorescent sensing of aluminium using naphthalene benzimidazole derivative in aqueous media. AB - Naphthalene benzimidazole conjugate bearing a hydroxyl group was synthesized. Its binding properties towards various metal ions were examined and it showed a high selectivity and sensitivity towards Al(3+) ions in aqueous media. The recognition processes follows a photo induced electron transfer (PET) mechanism assisted with the restricted intramolecular C-C single bond rotation and are scarcely influenced by other coexisting metal ions. In addition, determination of Al(3+) in a variety of sewage water samples was also determined. PMID- 25554961 TI - Synthesis, characterization and photoluminescence properties of Bi3+ co-doped CaSiO3:Eu3+ nanophosphor. AB - Ceramic luminescent powders with the composition Ca(0.96-x)Eu0.04Bi(x)SiO3 (x=0.01-0.05) were prepared by solution combustion method. The nanopowders are characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) and photoluminescence (PL) techniques. PXRD patterns of calcined (950 degrees C for 3h) Ca(0.96-x)Eu0.04Bi(x)SiO3 powders exhibit monoclinic phase with mean crystallite sizes ranging from 28 to 48 nm. SEM micrographs show the products are foamy, agglomerated and fluffy in nature due to the large amount of gases liberated during combustion reaction. TEM micrograph shows the crystalline characteristics of the nanoparticles. Upon 280 nm excitation, the photoluminescence of the Ca(0.96-x)Eu0.04Bi(x)SiO3 particles show red emission at 611 nm corresponding to 5D0->7F2 transition. It is observed that PL intensity increases with Bi(3+) concentration. Our work demonstrates very interesting energy transfer from Bi(3+) to Eu(3+) in CaSiO3 host. PMID- 25554962 TI - Application of montmorillonite-Cu(II)ethylenediamine catalyst for the decolorization of Chromotrope 2R with H2O2 in aqueous solution. AB - The kinetics of decolorization of Chromotrope 2R (C2R) was studied spectrophotometrically using the montmorilloniteK10-Cu(II)ethylenediamine composite (MMTK10-Cu(en)2) as catalyst and H2O2 as oxidant in aqueous solution. The catalyst was prepared and characterized by SEM, FTIR, XRD and TGA techniques. The dependence of reaction rate on H2O2 concentration was examined under UV irradiation in the presence and absence of the catalyst, and in the presence of the catalyst without the UV irradiation. In all these reaction systems, the rate increased up to a maximum value and then decreased. The rate increased with increasing the concentration of the dye reaching a maximum. Also, the rate of decolorization reaction showed a significant increase with increasing the amount of the catalyst and temperature. The addition of NaCl to the reaction medium has accelerated the rate effectively. A similar catalyst, MMTKSF-Cu(en)2, has also been employed and was found to be less efficient compared with MMTK10-Cu(en)2. PMID- 25554963 TI - Spectroscopic studies on sidewall carboxylic acid functionalization of multi walled carbon nanotubes with valine. AB - The valine functionalized multi-walled carbon nanotubes (MWCNTS) were prepared and characterized by using XRD, UV-Vis, FT-IR, EPR, SEM, and EDX, spectroscopic techniques. The enhanced XRD peak (002) intensity was observed for valine functionalized MWCNTs compared with oxidized MWCNTs, which is likely due to sample purification by acid washing. UV-Vis study shows the formation of valine functionalized MWCNTs. FT-IR study confirms the presence of functional groups of oxidized MWCNTs and valine functionalized MWCNTs. The ESR line shape analysis indicates that the observed EPR line shape is a Gaussian line shape. The g-values indicate that the systems are isotropic in nature. The morphology study was carried out for oxidized MWCNTs and valine functionalized MWCNTs by using SEM. The EDX spectra revealed that the high purity of oxidized MWCNTs and valine functionalized MWCNTs. The functionalization has been chosen because, functionalization of CNTs with amino acids makes them soluble and biocompatible. Thus, they have potential applications in the field of biosensors and targeted drug delivery. PMID- 25554964 TI - FT-IR, Laser-Raman spectra and computational analysis of 5-Methyl-3 phenylisoxazole-4-carboxylic acid. AB - In this study the experimental and theoretical vibrational frequencies of a newly synthesized anti-tumor, antiviral, hypoglycemic, antifungal and anti-HIV agent namely, 5-Methyl-3-phenylisoxazole-4-carboxylic acid has been investigated. The experimental FT-IR (4000-400 cm(-1)) and Laser-Raman spectra (4000-100 cm(-1)) of the molecule in solid phase have been recorded. The theoretical vibrational frequencies and optimized geometric parameters (bond lengths, bond angles and torsion angles) have been calculated by using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr and DFT/M06-2X: highly parametrized, empirical exchange correlation function) with 6-311++G(d,p) basis set by Gaussian 09W software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis by using VEDA 4 software. The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data and results in the literature. In addition, the highest occupied molecular orbital (HOMO) energy, the lowest unoccupied molecular orbital (LUMO) energy and the other related molecular energy values of the compound have been investigated by using the same theoretical calculations. PMID- 25554965 TI - Determinants of engagement in mental health consumer-run organizations. AB - OBJECTIVE: Mental health consumer-run organizations (CROs) are a low-cost, evidence-based strategy for promoting recovery. To increase CRO utilization, characteristics that promote engagement need to be identified and encouraged. The study examined individual and organizational characteristics that predict three types of engagement in CROs-attendance, leadership involvement, and socially supportive involvement. METHODS: Surveys were administered to 250 CRO members attending 20 CROs. Leaders of each CRO reported organizational characteristics through a separate questionnaire. Multilevel regression models examined relationships between predictors and indicators of CRO engagement. RESULTS: Perceived sense of community was the only characteristic that predicted attendance, leadership involvement, and socially supportive involvement (p<.001). Perceived organizational empowerment, shared leadership, peer counseling, and several demographic characteristics also predicted some measures of engagement. CONCLUSIONS: CROs that can effectively promote sense of community, organizational empowerment, shared leadership, and peer counseling may be better able to engage participants. The discussion considers several strategies to enhance these characteristics, such as collectively establishing values and practicing shared decision making. PMID- 25554966 TI - Association of keratinization with 5-year disease-specific survival in oropharyngeal squamous cell carcinoma. AB - IMPORTANCE: Keratinization is a histologic feature on hematoxylin-eosin staining associated with adverse outcomes in head and neck cancer, particularly oral cavity squamous cell carcinoma. However, the prognostic value of keratinization has not been demonstrated in oropharyngeal squamous cell carcinoma (OPSCC) in a large cohort of patients. OBJECTIVE: To quantify the prognostic value of keratinization in a large cohort of patients with OPSCC with subgroup analysis based on p16 status, basaloid differentiation, and smoking status. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cross-sectional study using a prospectively collected database that identified 208 patients with OPSCC diagnosed and treated at a single tertiary cancer center from 2002 to 2009. Tissue microarrays (TMAs) were generated from 208 patient specimens stained with hematoxylin-eosin and immunohistochemical markers. Digital images from stained TMAs were scored for the presence of keratinization and/or basaloid differentiation and for p16 status. INTERVENTIONS: Patients were treated with curative intent with surgery, radiation, and/or chemotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome measure was 5-year disease-specific survival (DSS) in OPSCC according to keratinization. Univariate and multivariate survival analyses were performed to estimate survival according to histopathologic profile and smoking status. RESULTS: In the 208 samples, 96 were keratinizing and 112 were nonkeratinizing. Patients with keratinizing tumors were more likely to have advanced-stage disease and be p16 negative. Keratinization was independently associated with adverse outcomes. The 5-year DSS was significantly higher for nonkeratinizing tumors (63.3%) compared with keratinizing tumors (44.8%; P = .007). In subgroup analysis, nonkeratinization was associated with improved DSS in those with nonbasaloid and p16-negative tumors and in patients who were smokers. When stratifying patients based on keratinization, p16-status, and smoking status, patients with p16-negative keratinizing tumors who were smokers had the lowest 5-year DSS (26.7%). CONCLUSIONS AND RELEVANCE: Patients with nonkeratinized OPSCC have improved survival compared with those with keratinizing tumors. Information on keratinization is most useful prognostically in those who have p16-negative and nonbasaloid tumors and in patients who are smokers. Survival can be stratified using keratinization, p16 status, and smoking status. PMID- 25554967 TI - Prospective evaluation of quality-of-life improvement after correction of the alar base in the flaccidly paralyzed face. AB - IMPORTANCE: Nasal valve collapse caused by facial palsy is an often overlooked but disturbing sequela of flaccid facial paralysis. OBJECTIVE: To prospectively study the effect of fascia lata sling placement for correction of external nasal valve compromise in patients with flaccid facial paralysis, using a validated disease-specific quality-of-life outcome survey. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective study of 68 patients from March 2009 to December 2013 who underwent fascia lata sling placement for correction of external nasal valve compromise. INTERVENTION: Fascia lata sling placement for the correction of external nasal valve compromise . MAIN OUTCOME AND MEASURE: Nasal Obstruction Symptom Evaluation (NOSE) scale. RESULTS: Sixty-eight disease specific quality-of-life determinations were performed using the NOSE scale. Ratings were ascertained preoperatively and postoperatively. Sixty patients completed a NOSE scale prior to surgical intervention, and 40 completed the survey after intervention. There was a statistically significant difference in NOSE scores after fascia lata sling placement The mean preoperative NOSE score was 37.6 (27.1), and the mean postoperative score was 16.6 (17.37) (Wilcoxon signed-rank test; P < .001). All patients had improvement in their nasal obstruction, which persisted uniformly in follow-up. CONCLUSIONS AND RELEVANCE: The nasal valve is a zone that has historically been neglected, despite the fact that a highly effective surgical solution has existed for decades. We highlight the significance of nasal valve dysfunction in patients with flaccid facial paralysis, demonstrate a quantitative benefit in disease-specific quality of life after fascia late sling placement for external nasal valve compromise, and suggest an updated treatment algorithm. This method offers a predictably successful, straightforward surgical solution to an overlooked functional problem in the patient with flaccid facial paralysis. LEVEL OF EVIDENCE: 4. PMID- 25554969 TI - Practical Applications in Immunohistochemistry: Evaluation of Diffuse Large B Cell Lymphoma and Related Large B-Cell Lymphomas. AB - CONTEXT: Diffuse large B-cell lymphoma is the most commonly diagnosed subtype of lymphoma worldwide. The current World Health Organization (WHO) classification includes several subtypes, based on a combination of clinical, immunohistochemical, and genetic differences. Immunohistochemical staining is essential in evaluating diffuse large B-cell lymphoma and many related large B cell lymphomas and aggressive B-cell lymphomas. OBJECTIVE: To address different immunohistochemical features used for identification, subclassification, prognosis and in some cases, therapy, of diffuse large B-cell lymphoma and related lymphomas. DATA SOURCES: The information outlined in this review article is based on our experiences with routine cases, on the current WHO classification of hematopoietic and lymphoid tumors, and on a review of English-language articles published throughout 2014. CONCLUSIONS: Features and diagnostic criteria of diffuse large B-cell lymphoma, aggressive variants of B-cell lymphomas, including Burkitt lymphoma and "double-hit" lymphomas, are discussed. Identification of cell of origin (germinal center type versus activated B-cell type) is discussed at length. Finally, practical approaches for diagnosis are discussed. PMID- 25554968 TI - Thermoacoustic contrast of prostate cancer due to heating by very high frequency irradiation. AB - Applying the thermoacoustic (TA) effect to diagnostic imaging was first proposed in the 1980s. The object under test is irradiated by high-power pulses of electromagnetic energy, which heat tissue and cause thermal expansion. Outgoing TA pressure pulses are detected by ultrasound transducers and reconstructed to provide images of the object. The TA contrast mechanism is strongly dependent upon the frequency of the irradiating electromagnetic pulse. When very high frequency (VHF) electromagnetic irradiation is utilized, TA signal production is driven by ionic content. Prostatic fluids contain high levels of ionic metabolites, including citrate, zinc, calcium, and magnesium. Healthy prostate glands produce more ionic metabolites than diseased glands. VHF pulses are therefore expected to generate stronger TA signal in healthy prostate glands than in diseased glands. A benchtop system for performing ex vivo TA computed tomography with VHF energy is described and images are presented. The system utilizes irradiation pulses of 700 ns duration exceeding 20 kW power. Reconstructions frequently visualize anatomic landmarks such as the urethra and verumontanum. TA reconstructions from three freshly excised human prostate glands with little, moderate, and severe cancerous involvement are compared with histology. TA signal strength is negatively correlated with percent cancerous involvement in this small sample size. For the 45 regions of interest analyzed, a reconstruction value of 0.4 mV provides 100% sensitivity but only 29% specificity. This sample size is far too small to draw sweeping conclusions, but the results warrant a larger volume study including comparison of TA images to the gold standard, histology. PMID- 25554970 TI - Shear wave elastography using amplitude-modulated acoustic radiation force and phase-sensitive optical coherence tomography. AB - Investigating the elasticity of ocular tissue (cornea and intraocular lens) could help the understanding and management of pathologies related to biomechanical deficiency. In previous studies, we introduced a setup based on optical coherence tomography for shear wave elastography (SWE) with high resolution and high sensitivity. SWE determines tissue stiffness from the propagation speed of shear waves launched within tissue. We proposed acoustic radiation force to remotely induce shear waves by focusing an ultrasound (US) beam in tissue, similar to several elastography techniques. Minimizing the maximum US pressure is essential in ophthalmology for safety reasons. For this purpose, we propose a pulse compression approach. It utilizes coded US emissions to generate shear waves where the energy is spread over a long emission, and then numerically compressed into a short, localized, and high-energy pulse. We used a 7.5-MHz single-element focused transducer driven by coded excitations where the amplitude is modulated by a linear frequency-swept square wave (1 to 7 kHz). An inverse filter approach was used for compression. We demonstrate the feasibility of performing shear wave elastography measurements in tissue-mimicking phantoms at low US pressures (mechanical index < 0.6) PMID- 25554972 TI - Objective characterization of bruise evolution using photothermal depth profiling and Monte Carlo modeling. AB - Pulsed photothermal radiometry (PPTR) allows noninvasive determination of laser induced temperature depth profiles in optically scattering layered structures. The obtained profiles provide information on spatial distribution of selected chromophores such as melanin and hemoglobin in human skin. We apply the described approach to study time evolution of incidental bruises (hematomas) in human subjects. By combining numerical simulations of laser energy deposition in bruised skin with objective fitting of the predicted and measured PPTR signals, we can quantitatively characterize the key processes involved in bruise evolution (i.e., hemoglobin mass diffusion and biochemical decomposition). Simultaneous analysis of PPTR signals obtained at various times post injury provides an insight into the variations of these parameters during the bruise healing process. The presented methodology and results advance our understanding of the bruise evolution and represent an important step toward development of an objective technique for age determination of traumatic bruises in forensic medicine. PMID- 25554971 TI - Utilizing spatial and spectral features of photoacoustic imaging for ovarian cancer detection and diagnosis. AB - A composite set of ovarian tissue features extracted from photoacoustic spectral data, beam envelope, and co-registered ultrasound and photoacoustic images are used to characterize malignant and normal ovaries using logistic and support vector machine (SVM) classifiers. Normalized power spectra were calculated from the Fourier transform of the photoacoustic beamformed data, from which the spectral slopes and 0-MHz intercepts were extracted. Five features were extracted from the beam envelope and another 10 features were extracted from the photoacoustic images. These 17 features were ranked by their p-values from t tests on which a filter type of feature selection method was used to determine the optimal feature number for final classification. A total of 169 samples from 19 ex vivo ovaries were randomly distributed into training and testing groups. Both classifiers achieved a minimum value of the mean misclassification error when the seven features with lowest p-values were selected. Using these seven features, the logistic and SVM classifiers obtained sensitivities of 96.39 +/- 3.35% and 97.82 +/- 2.26%, and specificities of 98.92 +/- 1.39% and 100%, respectively, for the training group. For the testing group, logistic and SVM classifiers achieved sensitivities of 92.71 +/- 3.55% and 92.64 +/- 3.27%, and specificities of 87.52 +/- 8.78% and 98.49 +/- 2.05%, respectively. PMID- 25554973 TI - Enhanced capacitance performance of Al2O3-TiO2 composite thin film via sol-gel using double chelators. AB - Titanium dioxide (TiO2) is usually introduced into dielectric layer of aluminum electrolytic capacitor to enhance capacitance performance via forming Al2O3-TiO2 composite film. However, there is a big obstacle caused by high crystallization temperature of TiO2 to capacitance enhancement. In present work, a facile route was proposed to synthesize crystalline TiO2 with the size of 3-10 nm at room temperature using lactic acid (LA) and acetylacetone (Acac) as double chelators. After being introduced into the surface of etched aluminum foils as dielectric layer, TiO2 boosted the specific capacitance by about 24% compared to that without TiO2, and about 11% compared to that with TiO2 using lactic acid as only chelator. PMID- 25554976 TI - Using provider performance incentives to increase HIV testing and counseling services in Rwanda. AB - Paying for performance provides financial rewards to medical care providers for improvements in performance measured by utilization and quality of care indicators. In 2006, Rwanda began a pay for performance scheme to improve health services delivery, including HIV/AIDS services. Using a prospective quasi experimental design, this study examines the scheme's impact on individual and couples HIV testing. We find a positive impact of pay for performance on HIV testing among married individuals (10.2 percentage points increase). Paying for performance also increased testing by both partners by 14.7 percentage point among discordant couples in which only one of the partners is an AIDS patient. PMID- 25554977 TI - Controversial role of topical antibiotics in endophthalmitis prophylaxis for cataract surgery--reply. PMID- 25554978 TI - The emering role of helminths in treatment of the inflammatory bowel disorders. AB - The problem of immune-mediated diseases, such as inflammatory bowel disorders (IBDs), still remains a significant clinical and therapeutic problem. Therefore, the tendency to search for safer and more effective methods of reducing their incidence and increasing the efficiency of therapy of this group of diseases is understandable. Recently, attention has been drawn to the potential therapeutic influence of intestinal helminths on the inflammatory process induced by the immune response, as well as the observed significant potential of these organisms for modulating the host immune response, which is beneficial both for the dwelling parasite and the host with an IBD. It has been proven that the effects of certain intestinal helminths on the host immune system are complex and omni directional. They involve the modulation of TLRs expression, causing proliferation and activation of TH2 lymphocytes, leading to proliferation of regulatory T cells (TREG), and production of immunomodulatory proteins, such as cystatins and glycoprotein ES-62. In the developing countries of Africa, South America and Asia, where the level of personal and environmental hygiene is relatively low, the incidence of autoimmune diseases is also significantly lower. Limited exposure to common bacterial and parasitic pathogens in populations of very highly developed countries has probably contributed to depletion of immunological memory and the development of hypersensitivity mechanisms. Thus, reasonable suggestions have been made that the host-parasite biocenotic relationship between humans and nematodes of the gastrointestinal tract can be considered as a mutualism, rather than a typical parasitism, and may in the future be used as an alternative therapeutic model for IBD patients. PMID- 25554979 TI - The role of urocortins in the cardiovascular system. AB - Urocortins (Ucn) 1, 2 and 3 are a group of endogenous peptide hormones belonging to the corticotropin-releasing hormone (CRH) family of peptides. The presence of urocortins has been detected in the central nervous system as well as in peripheral tissues. They play an important role in a stress response (with respect to its duration, intensity and restoration of homeostasis). They also act as regulatory factors of the cardiovascular, gastrointestinal, reproductive and immune systems. Urocortins act by binding to G-protein-coupled receptors (GPCR). The "central" effects of urocortins are mediated mainly by activation of CRH receptor 1 (CRH-R1), and the "peripheral" effects by activation of CRH-R2. Ucn2 and Ucn3 are selective CRH-R2 agonists and have much higher binding affinity to this receptor than CRH and Ucn1. Recent studies have shown that urocortins exert various biological effects in the cardiovascular system, such as vasodilation, positive inotropic and lusitropic effects, as well as cardioprotection against ischemia-reperfusion injury. They also suppress the renin-angiotensin system and may have an impact on the sympathetic nervous system. Urocortins and CRH-R2 may be a potential therapeutic target in coronary heart disease, congestive heart failure and hypertension. This review summarizes the data published to date on the role of urocortins in the cardiovascular system. PMID- 25554980 TI - p-ERK involvement in the neuroprotection exerted by ischemic preconditioning in rat hippocampus subjected to four vessel occlusion. AB - Global brain ischemia-reperfusion causes delayed cell death in hippocampal CA1 (cornus ammonis 1) pyramidal neurons after reperfusion. Ischemic tolerance evoked by preconditioning (IPC) represents a phenomenon of CNS adaptation to any subsequent ischemia. This paper was designed to describe changes in the mitogen activated protein kinases (MAPK) protein pathways of the hippocampal area following by IPC. Ischemia was induced by a 4-vessels occlusion (4VO) and the rats were preconditioned by a non-injurious ischemia. Apoptotic markers were used to follow the degeneration process. Western blot and immunohistochemistry identified p-ERK (phosphorylated extracellular signal-regulated protein kinase) and p38 proteins in injured hippocampal areas. P-ERK quantification increased after IPC and reached the highest level at 24 hours after ischemia. Interestingly, neuroprotection induced by IPC lead to the opposite effect on MAPK/p38, where the level was lowest at 24 hours after ischemia. Taken together, the present study clearly demonstrates that p-ERK takes part in complex cascades triggered by IPC in the selectively vulnerable hippocampal region. In addition, paper describes a crosstalk between p-ERK and p-p38 which occurs after preconditioning maneuver in 4VO model of global ischemia. PMID- 25554981 TI - The influence od melatonin receptors antagonists, luzindole and 4-phenyl-2 propionamidotetralin (4-P-PDOT), on melatonin-dependent vasopressin and adrenocorticotropic hormone (ACTH) release from the rat hypothalamo-hypophysial system. In vitro and in vivo studies. AB - Melatonin exerts its biological role acting via G protein-coupled membrane receptors - MT1 and MT2, as well as through cytoplasmic and/or nuclear receptors. Melatonin has previously been shown to change vasopressin (AVP) and adrenocorticotropic hormone (ACTH) secretion dependently on its concentration. To determine whether the response of vasopressinergic neurones to different concentrations of melatonin is mediated through the membrane MT1 and/or MT2 receptors, the influence of luzindole - an antagonist of both MT1 and MT2 receptors, and 4-phenyl-2-propionamidotetralin (4-P-PDOT) - a selective MT2 receptor antagonist, on melatonin-dependent AVP release from the rat hypothalamo neurohypophysial (H-NH) system was studied in vitro (melatonin at the concentrations of 10(-9), 10(-7) and 10(-3) M) and in vivo (melatonin at the concentrations of 10(-9) and 10(-7) M). Moreover, the second goal of this study was to find out whether melatonin receptors MT1 and/or MT2 are involved in the regulation of ACTH and corticosterone secretion into the blood. We have demonstrated that melatonin, at the concentrations of 10(-9) and 10(-7) M, significantly inhibited AVP secretion from isolated rat H-NH explants when antagonists solvent (i.e. 0.1% DMSO) was present in the medium. Neither luzindole, nor 4-P-PDOT, applied without melatonin, did influence AVP release in vitro. Luzindole applied together with melatonin (10(-7) M and 10(-9) M) significantly suppressed melatonin-dependent effect, while 4-PPDOT did not eliminate the inhibitory influence of 10(-7) M and 10(-9) M melatonin on AVP secretion from isolated rat H-NH explants. Melatonin at a concentration of 10(-3) M significantly increased AVP release when the H-NH explants were incubated in the medium containing luzindole or 4-P-PDOT. Under present experimental in vivo conditions, infused intracerebroventricularly (i.c.v.) melatonin, at a concentration close to its physiological level in the blood, significantly diminished AVP secretion into the blood, however, at higher concentration (10(-7) M) it remained inactive in this process. Moreover, melatonin at both concentrations of 10(-9) M and 10(-7) M, was able to inhibit AVP secretion into the blood (and increase its neurohypophysial content) when animals were previously i.c.v. injected with 4-P-PDOT, but not with luzindole. Blood plasma concentration of ACTH was diminished significantly by 10(-7) M melatonin in DMSO infused, but not in luzindole- or 4-P-PDOT-injected rats, however, it remained inactive in modifying the corticosterone blood plasma concentrations in any of the studied subgroups. The present study demonstrates that subtype MT1 membrane receptor may contribute to the inhibitory effect of physiological concentration of melatonin on functional regulation of vasopressinergic neurones in the rat. However, for the stimulatory effect of pharmacological dose of the hormone on AVP secretion in vitro, mechanisms different from membrane MT1/MT2 receptors are involved. The present experiment do not determines whether MT1 and/or MT2 receptors affect the function of the rat pituitary-adrenal cortex axis. PMID- 25554982 TI - Effect of piperine, a major component of black pepper, on the pharmacokinetics of domperidone in rats. AB - The present study was aimed to investigate the effect of piperine, a major active ingredient of black pepper, on the pharmacokinetics of domperidone in rats. Animals were given oral (p.o.) or intraperitoneal (i.p.) domperidone (20 mg/kg) alone or together with piperine (20 mg/kg, p.o.). Plasma samples were collected at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 12 hours after drug administration. The concentration of domperidone in the plasma was measured using a HPLC method. The concomitant administration of piperine with oral or intraperitoneal domperidone resulted in a significant (P<0.05) increase in the maximum plasma concentration (Cmax), the mean area under the plasma concentration time curve (AUC), and the elimination half-life (t1/2) of domperidone as compared to those obtained for domperidone alone. These results suggest that an important pharmacokinetic interaction may occur if piperine is administered concurrently with domperidone. PMID- 25554983 TI - The dynamics of heat shock system activation in Monomac-6 cells upon Helicobacter pylori infection. AB - Immune system cells, particularly phagocytes, are exposed to direct contact with pathogens. Because of its nature - elimination of pathogenes - their cytoprotective systems supposed to be quick and forceful. Physiological consequence of phagocytosis for the phagocyte is the apoptotic death to prevent the eventual survival of bacteria as intracellular parasites. However, in some cases, defense systems used by the bacteria force the immune cells to prolong the contact with the pathogen for its effective elimination. Experiments were performed on Monomac-6 cells exposed to live CagA, VacA expressing Helicobacter pylori (H. pylori) over different period of time. Total cellular RNA, cytoplasmic and nuclear proteins were isolated for polymerase chain reaction, Western-blot and electrophoretic mobility shift assay, respectively. We found that Monomac-6 cells infection with H. pylori resulted in the translocation of the entire cellular content of the heat shock protein 70 (HSP70) into the cytoplasm, where its presence could protect cell against toxic products of engulfed bacteria and premature apoptosis. At the same time the nuclear translocation of heat shock factor 1 (HSF-1) and activation of HSP70 gene transcription was noticed. Action of HSP70 might to postpone monocyte apoptosis through protecting cytoplasmic and nuclear proteins from damaging effect of bacterial products, what could be the defending mechanism against the toxic stress caused by engulfed bacteria and provide the immune cell with the sufficient amount of time required for neutralization of the bacteria from phagosomes, even at the expense of temporary lack of the protection of nuclear proteins. PMID- 25554984 TI - Genotypic and clinical differences of seropositive Helicobacter pylori children and adults in the Polish population. AB - Helicobacter pylori (H. pylori) plays an important role in the pathogenesis of the upper gastrointestinal tract diseases in both children and adults. The aim of this paper was to assess the differences between the clinical course of the disease in children and adults. This paper also presents an analysis of clinical symptoms, endoscopic and histopathological findings, H. Pylori cagA and vacA genotypes rates and analysis of the sensitivity of these strains to antibiotics in the Polish population, with possible practical and therapeutic implications. The multicenter study on the frequency of H. pylori infections assessed by the presence of antibodies in IgG class against H. pylori in serum was conducted in the years 2002 and 2003. The study group included 6565 children and adults, in 3827 of whom antibodies levels were above 24 U/mL. The authors analyzed clinical and endoscopic symptoms and in some patients with H. pylori seropositivity also histopathological changes, and cagA and vacA genes. Sensitivity of H. pylori strains to antibiotics were also analyzed. Differences between the frequency of infection between children and adults were determined. Endoscopic examination in adults revealed more frequent cases of gastropathy (P=0.003) and erosive gastritis (P=0.001), and in children-thick mucosal folds (P<0.0001). Histopathological examinations carried out in adults have revealed atrophic gastritis and intestinal metaplasia. In children, cagA(+) s1m1 was observed more frequently than in adults (34.0% versus 23.1%; P=0.02) contrary to cagA(-)s2m2 which occurred more frequently in adults (27.1% versus 14.0%; P=0.003). No effect of the infection on nausea, regurgitation, vomiting, heartburn, and abdominal pain in children was detected. However, adults infected with H. pylori suffered from more frequent episodes of heartburn and abdominal pain. The H. pylori strain exhibited a high resistance to metronidazole (higher in adults: 41.7% versus 27.4%; P=0.002), and to clarithromycin (higher in children: 20.2% versus 15.4%; P>0.05), and dual resistance to metronidazole and clarithromycin (higher in children: 9.9% versus 8.4%; P>0.05). Resistance of the H. pylori to amoxicillin and tetracycline was not detected. The conducted study indicated clinical differences in the H. pylori infection in children and adults. Among the differences in children, especially the more frequent infections by the cagA(+)s1m1/m2 strain could have an influence on further consequences of the infection. The obtained results could be useful in therapeutic decisions. PMID- 25554985 TI - Esophagoprotective activity of angiotensin-(1-7) in experimental model of acute reflux esophagitis. Evidence for the role of nitric oxide, sensory nerves, hypoxia-inducible factor-1alpha and proinflammatory cytokines. AB - Gastroesophageal reflux disease (GERD) is a global disease rapidly increasing among world population. The pathogenesis of reflux esophagitis which is considered as the early stage of GERD is complex, resulting from an imbalance between aggressive factors damaging the esophagus and a number of the natural defense mechanisms. The esophageal mucosa is in a state of continuous exposure to potentially damaging endogenous and exogenous factors. Important aggressive components of gastric refluxate include acid and pepsin and also pancreatic enzymes and bile. Among aggressive factors of exogenous origin, cigarette smoking, non-steroidal anti-inflammatory drugs (NSAID), and steroids are of the utmost importance. The basic level of esophageal defense against acid-pepsin damage consists of the anti-reflux mechanisms such as the luminal acid clearance and removal of the esophageal contents and neutralization of luminal acidity. In addition the esophageal mucosal protection includes the presence of pre epithelial, epithelial and post-epithelial cellular and functional components. Recently, the progress have been made in the understanding of role of the heptapeptide member of the renin-angiotensin system (RAS), angiotensin-(1-7) (Ang (1-7)) in the control of gastrointestinal functions. It has been shown that all components of local RAS including Ang-(1-7) are detectable in the gastrointestinal wall including not only the stomach but also the esophagus. Previous studies revealed that Ang-(1-7), which is an important component of the RAS, exerts vasodilatory, anti-inflammatory and antioxidant activities in the stomach. Ang-(1-7) was recently implicated in gastroprotection, but its effects on esophageal mucosa in a rodent model of reflux esophagitis and in human subjects presenting GERD symptoms have not been explored. The present study was aimed to evaluate the possible protective effects of Ang-(1-7) and Mas-receptors upon esophageal mucosal damage in acute reflux esophagitis (RE) induced in anesthetized rats by ligating the pylorus and the limiting ridge (a transitional region between the forestomach and the corpus of stomach). Consequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Because Mas receptors are functionally linked to nitric oxide (NO) formation, we also studied involvement of endogenous NO in the mediation of protective and circulatory effects of exogenous Ang-(1-7). Moreover, an attempt was made to assess the possible role of sensory neurons in the modulation of the protective effects exerted by Ang-(1 7)/Mas receptor system. Six series of rats were pretreated 30 min before induction of RE with 1) vehicle (saline), 2) Ang-(1-7) (5-50 MUg/kg i.p.), 3) A779 (50 MUg/kg i.p.), the selective Mas receptor antagonist applied alone, 4) Ang-(1-7) (50 MUg/kg i.p.) combined with A779, 5) L-NNA (20 mg/kg i.p.) administered alone, and 6) Ang-(1-7) (50 MUg/kg i.p.) combined with L-NNA. In separate group of rats, capsaicin (total dosage of 125 mg/kg within three days) was administered s.c. 2 weeks before the induction of RE to induce functional ablation of sensory nerves. Rats with intact sensory nerves and those with capsaicin-induced sensory denervation received vehicle (saline) or Ang-(1-7) (50 MUg/kg i.p.) to determine whether this vasoactive metabolite of angiotensin I could be also effective in rats with capsaicin-induced impairment of the synthesis and release of sensory neuropeptides such as CGRP. Four hours after induction of RE, the mucosal damage was graded with mucosal lesion index (LI) from 0 to 6, the esophageal microcirculatory blood flow (EBF) was determined by H2-gas clearance technique and plasma level of pro-inflammatory cytokines interleukin-1b (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) was determined by ELISA. The expression of proinflammatory factors including COX-2, cytokine IL-1beta and hypoxia inducible factor 1alpha (Hif1alpha) was analyzed in the esophageal mucosal biopsies. In rats with RE, the esophageal LI was significantly elevated comparing its value observed in intact rats, and the EBF was significantly decreased as compared with intact mucosa. Pretreatment with Ang (1-7) of control rats without esophagitis induced increase in EBF by about 25% without any macroscopic changes in the esophageal mucosa or in the plasma level of cytokines. In animals with RE, pretreatment with Ang-(1-7) significantly reduced gross and histological esophageal mucosal injury and significantly increased EBF in comparison to vehicle-pretreated animals. The observed gross and histologic esophagoprotective effect of Ang-(1-7) was totally abolished by A779 so in rats with combined treatment of A779 with Ang-(1-7), the LI was identical with this observed in control RE and the EBF was decreased in these animals by about 39%. Inhibition of NO synthase by L-NNA significantly reduced the LI and the rise in EBF caused by Ang-(1-7). Similarly, the capsaicin denervation also significantly attenuated the vasodilatory and the esophagoprotective effects of Ang-(1-7). The expression of proinflammatory factors COX-2, Hif1alpha and IL 1beta which was negligible in intact esophageal mucosa, was upregulated in esophageal mucosa of rats with RE. In contrast, the administration of Ang-(1-7) resulted in a downregulation of mRNA for COX-2, Hif1 and IL-1beta in esophageal mucosa an this effect was abolished in A779-dependent manner. The Ang-(1-7) significantly decreased the RE-induced elevation of plasma levels of IL-1beta and TNF-alpha, and this effect was also reversed by pretreatment with A779, and significantly attenuated by pretreatment with L-NNA and capsaicin-induced sensory denervation. The present study indicates that the protective effect of Ang-(1-7) observed in the esophageal mucosa during early acute stage of gastroesophageal reflux depends upon the enhancement of esophageal microcirculatory blood flow via the activation of Mas receptor possibly due to NO synthase/NO system activation, stimulation of sensory nerves, the inhibition of expression of pro-inflammatory factors including COX-2, Hif1alpha and IL-1beta and release of proinflammatory cytokines IL-1beta and TNF-alpha. PMID- 25554986 TI - Thymoquinone and curcumin prevent gentamicin-induced liver injury by attenuating oxidative stress, inflammation and apoptosis. AB - This study was conducted to assess the preventive effect of two plant constituents, thymoquinone and curcumin, on gentamicin-induced deleterious effect on liver function, integrity and histological architecture. The gentamicin was intraperitoneally injected to rats at dose level of 100 mg/kg b.w. (every other day) for 21 days. The thymoquinone and curcumin were concurrently and orally administered at dose level of 20 mg/kg b.w. (every other day) to gentamicin injected rats. The present data indicated that thymoquinone and curcumin significantly prevented the gentamicin-induced elevations of serum AST, ALT and LDH activities as well as tumor necrosis factor alpha (TNF-alpha) and total bilirubin levels. On the other hand, both agents markedly ameliorated the gentamicin-induced decrease in serum total protein, albumin and albumin/globulin ratio. In addition, the gentamicin-induced liver histological alterations including hydropic degeneration of hepatocytes, fatty changes, inflammatory cell infiltration and congestion of portal vein were successfully amended by thymoquinone and curcumin. The elevated proapoptotic proteins caspase 3 and Bax expression in cytoplasm and nucleus of hepatocytes of gentamicin-injected rats were reduced to normal value as a result of thymoquinone and curcumin administration while the lowered expression of antiapoptotic protein Bcl-2 was increased. Based on the previous findings, it can be concluded that thymoquinone and curcumin successfully prevents the deleterious effects on liver function and histological integrity to more or less the same degree by enhancing anti-oxidant defense system, suppression of oxidative stress and attenuation of inflammation and apoptosis. PMID- 25554987 TI - Disturbances of autonomic nervous system activity and diminished response to stress in patients with celiac disease. AB - Celiac disease (CED) is immune-mediated enteropathy caused by gluten intolerance affecting genetically predisposed individuals. CED may exert a number of various symptoms, including extra intestinal manifestations. Neurological symptoms can be the first sign of gluten intolerance. However, affected autonomic nervous system (ANS) activity may be linked to other symptoms. We evaluated the frequency of ANS impairment and resting ANS response to several stimuli in CED patients without neurological manifestations. Twenty five neurologically asymptomatic patients with CED were studied. The medical history was taken and ANS activity was determined. ANS tests included heart rate variability (HRV) at rest and after stimulation (sympathetic - stress, and parasympathetic - deep breathing). The results were compared with those of the control group comprising of 30 healthy asymptomatic volunteers. Both the resting HRV parameters and the HRV indices recorded after deep breathing (parasympathetic stimulation) were significantly lower in patients with CED than in the controls (P<0.05). Also the stress-induced increase in normalized low frequency parameter (LFnu) was significantly lower in the CED group than in the control group (P<0.05). Overall, about 20% of CED patients presented with parasympathetic dominancy but 36% with sympathetic dominancy, and 44% of patients did not show changes in sympathetic-vagal balance of the autonomic nervous system. We conclude that sympathetic-parasympathetic imbalance, in favour of more often sympathetic than parasympathetic overactivity occurs among neurologically asymptomatic CED patients. The ANS impairment observed in the course of CED may result from prolonged intestinal inflammation. Therefore, routine ANS testing might be considered in patients presenting with this condition. PMID- 25554988 TI - Antiangiogenic potential of grape stem extract through inhibition of vascular endothelial growth factor expression. AB - The aim of the present study was to investigate the antiangiogenic potential of a grape stem extract against tube formation by human endothelial cells (EA.hy926). The results showed that at low and non-cytotoxic concentrations (50 and 100 MUg/ml) the grape stem extract inhibited tube formation, indicating a possible antiangiogenic activity. Moreover, the results showed that this extract inhibited the expression levels of vascular endothelial growth factor (VEGF), one of the most potent proangiogenic factors, suggesting that the tube formation inhibition by the extract may be exerted through inhibition of VEGF levels. Since it is well established that VEGF prevents apoptosis, the previous finding was further supported by the fact that the grape stem extract induced apoptosis in EA.hy926 cells. Furthermore, it was shown that the extract treatment did not change the levels of the proangiogenic molecules hypoxia inducible factor 1 alpha (HIF 1alpha) and cyclooxygenase-1 (COX-1). Therefore, these findings indicate that the grape stem extract reduces VEGF levels through mechanisms that may be HIF-1alpha- and COX-1-independent. The present study is the first showing that grape stem extracts possess antiangiogenic potential. Thus, our findings suggest that since grape stem extracts possess important bioactivities such as antiangiogenic potential, they could be exploited for developing chemopreventive and anticancer agents, while simultaneously protecting the environment through the use of a harmful waste. PMID- 25554989 TI - The effects of aneurysm repair using an aortic prosthesis on the electrical parameters of the muscular layer of the abdominal aorta. AB - The study was carried out on 10 swine of 20-30 kg body weight. Five animals were assigned to each of 2 groups. An aneurysm of the abdominal aorta was created experimentally in animals from the first and second study group. After 4 weeks, animals from the second group were subject to aneurysm repair using an aortic prosthesis. During the experiment, we measured the myoelectric activity of the muscular layer of the abdominal aorta and aneurysmal lesion with the ultrasonographic technique. Measurements of the aorta and aneurysmal lesion and histopathological analyses were carried out post-mortem. We found a statistically significant decrease in the myoelectric activity of the aorta on the aorta straight prosthesis interface and a significant decrease in the thickness of the muscular layer of the aorta on the aorta-prosthesis interface. No similar changes were found for experimentally induced aneurysms of the abdominal aorta. A straight prosthesis graft may not be the perfect option in the treatment of abdominal aortic aneurysm, as it contributes to the remodelling of the tissue on the prosthesis-aorta interface. This may result in the relapse of an aneurysm and post-operative complications. PMID- 25554990 TI - Bronchodilator, vasodilator and spasmolytic activities of Cymbopogon martinii. AB - Cymbopogon martinii (Cm.Cr) is traditionally used in south Asian communities for the management of multiple ailments including gastrointestinal, respiratory and vascular disorders and the present study was undertaken to validate these folkloric uses. The application of a methanol extract of the plant (Cm.Cr) to isolated rabbit jejunum preparation exhibited relaxation through decrease in magnitude and frequency of spontaneous contractions. The Cm.Cr also exerted relaxant effect on high K(+) (80 mM) induced contractions in isolated rabbit jejunum preparations. The Cm.Cr and its dichloromethane (Cm.Dcm) and aqueous (Cm.Aq) fractions also caused concentration-dependent relaxation in spontaneous and K(+) (80 mM) induced contractions which are comparables to effects produced by verapamil. Cm.Cr caused shifting of the Ca(2+)-curves toward right, suggesting the presence of a Ca(2+) channel blocking activity. Subsequently, Cm.Cr, Cm.Dcm and Cm.Aq caused relaxation of CCh (1 MUM) and K(+) (80 mM) induced contractions in isolated rabbit tracheal preparations, suggesting that the observed relaxant effect can be mediated through antimuscarinic and/or Ca(2+) channel blocking activities. Cm.Cr tested against phenylephrine (PE; 1 MUM) and K(+) (80 mM) induced contractions exhibited partial relaxation of isolated rabbit aortic preparations. The above-mentioned studies provided a scientific basis for the folkloric use of Cymbopogon martini in the management of multiple ailments in traditional systems of medicines. PMID- 25554991 TI - The role of peroxisome-proliferator-activating receptor gamma agonists: rosiglitazone and 15-deoxy-delta12,14-prostaglandin J2 in chronic experimental cyclosporine A-induced nephrotoxicity. AB - Cyclosporine A(CsA) is an immunosuppressor frequently used in the transplant surgery and in the treatment of autoimmune diseases. The therapeutic benefits of CsA are often limited by it's main side effect-nephrotoxicity. Mechanisms of chronic CsA- induced renal damage include: activation of renin-angiotensin aldosterone system, upregulation of transforming growth factor beta (TGF-beta), oxidative stress. This study was undertaken to investigate the protective effect of the peroxisome-proliferator-activated receptors gamma (PPARs-gamma) agonists: rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (PGDJ2), against CsA induced kidney injury in male Wistar rats. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPAR-gamma agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 MUg/kg/day. CsA induced renal failure was evidenced by increased serum levels of urea, uric acid and creatinine. Serum concentrations of GSH and GSSG, lipid peroxidation products as well as NAD+/NADH, NADP+/NADPH and ADP/ATP ratios showed, that CsA induced oxidative stress and evoked an imbalanced red-ox state in the kidney. Light and electron microscope studies showed degenerative changes within renal tubules with damage to their mitochondria, interstitial fibrosis and arteriolopathy. Immunohistochemical expression of profibrotic TGF-beta was assessed. The biochemical and morphological changes induced by CsA were limited by administration of both rosiglitazone and PGDJ2. Ultrastructural examination of renal tubular epithelial cells showed marked improvement within mitochondria. Our results indicate that both PPAR-gamma agonists used in the experiment may play an important role in protecting against CsA-induced damage in the kidney. PMID- 25554992 TI - Significant deterioration of anti-atherogenic efficacy of nebivolol in a double (apolipoprotein E and endothelial nitric oxide synthase) knockout mouse model of atherosclerosis in comparison to single (apolipoprotein E) knockout model. AB - Anti-atherogenic action of nebivolol in apolipoprotein E (apoE)-single knockout mouse model can be explained by its beneficial effect on endothelium, especially on endothelial nitric oxide synthase (eNOS). We, therefore, decided to use apoE and eNOS-double knockout mouse model to confirm that mechanism of nebivolol beneficial action. In apoE-single knockout mice, lesion area measured by "cross section" of aortic roots was 79,244 +/- 6,143 MUm(2) in the control group versus 65,347 +/- 6,152 MUm(2) in nebivolol-treated group (P<0.05). However, in apoE and eNOS-double knockout mice, lesion area measured by "cross-section" of aortic roots was 92,319 +/- 8,876 MUm(2) in the control group versus 98,609 +/- 9,164 MUm(2) in nebivolol-treated group (P>0.05). The comparison between apoE-single knockout mice and apoE & eNOS-double knockout mice without treatment also showed statistically significant difference: 81,232 +/- 8,264 MUm(2) versus 92,319 +/- 8,876 MUm(2) (P<0.05). This is the first report that describes the effect of nebivolol on atherogenesis in apoE and eNOS-double knockout mice, proving directly the necessity of the presence of eNOS in endothelium for nebivolol to show its an anti-atherogenic potency. PMID- 25554993 TI - A web-based preventive intervention program for bipolar disorder: outcome of a 12 months randomized controlled trial. AB - BACKGROUND: The Internet is used to deliver information on many psychiatric disorders such as bipolar disorder. This paper reports on the results of a 12 months randomised controlled trial, which examined the efficacy of an Internet based preventive program for bipolar disorder, adjunctive to usual pharmacological management. METHODS: Participants were recruited by completing an online screening questionnaire accessed through the Black Dog Institute and Sentiens websites based in Australia. The treatment was predominantly psycho educational with cognitive behavioral therapy optional elements. The attention control treatment comprised directing subjects to a variety of websites focused on 'healthy living'. Time to recurrence was determined using Kaplan-Meier survival analysis. The main outcome measures were recurrence as defined by: (i) depressive and/or hypomanic symptomatology and functional capacity (using Beck Depression Inventory, Internal State Scale and Sheehan Disability Scale) and (ii) hospitalization. RESULTS: Two-hundred-and-thirty-three subjects were randomized to the active or control treatment groups. There were no significant differences between the active and control treatment groups on any of the definitions of recurrence. LIMITATIONS: Reliance on an online self-report tool to confirm diagnosis and hospitalization rates may have potentially allowed for inclusion of individuals with other diagnoses such as borderline personality disorder. The 'attention control' treatment may have included more 'active' components than intended. CONCLUSIONS: This is the first report examining the efficacy of a randomized controlled web-based psychological intervention in a large sample of subjects with bipolar disorder. The potential reasons for failing to demonstrate a significant difference compared to the active control are discussed. PMID- 25554994 TI - Impairment and distress patterns distinguishing the melancholic depression subtype: an iSPOT-D report. AB - BACKGROUND: This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress. METHODS: Participants were assessed pre treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress. RESULTS: Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants. LIMITATIONS: Due to the cross-sectional nature of this study, causal pathways cannot be concluded. CONCLUSIONS: Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one's emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment. PMID- 25554995 TI - Depression outcome in alcohol dependent patients: an evaluation of the role of independent and substance-induced depression and other predictors. AB - BACKGROUND: Depression commonly co-occurs with alcohol use disorders but predictors of depression treatment outcome in patients with both conditions are not well established. METHODS: Outpatients with alcohol dependence and major depression (n=138) were prescribed naltrexone and randomized to citalopram or placebo for 12 weeks, followed by a 12-week naturalistic outcome phase. General linear mixed models examined predictors of Montgomery Asberg Depression Rating Scale (MADRS) score over 24 weeks. Predictors included whether depression was independent or substance-induced, and demographic, alcohol use, and personality variables (Temperament and Character Inventory subscales). RESULTS: Most improvement in drinking and depression occurred between baseline and week 3. During follow-up, patients with substance-induced depression reduced their drinking more and they had better depression outcomes than those with independent depression. However, greater reduction in drinking was associated with better depression outcomes for both independent and substance-induced groups, while antidepressant therapy had no effect for either group. Baseline demographic and alcohol use variables did not predict depression outcomes. Among personality variables, high self-directedness was a strong predictor of better depression outcomes. LIMITATIONS: Subjects were not abstinent at baseline. The influence of naltrexone on depression outcomes could not be tested. CONCLUSION: Alcohol dependent patients with substance-induced depression have better short term depression outcomes than those with independent depression, but this is largely because they reduce their drinking more during treatment. PMID- 25554996 TI - Gender differences in depression and condom use among sexually active Canadians. AB - BACKGROUND: Given the gendered distribution of depression, this paper aims at exploring the gender disparities in the effect of depression on condom use in last sexual intercourse in a nationally representative sample of sexually active Canadians. METHODS: Data in this study came from the Canadian Community Health Survey 2009-2010 (n=124,188 aged >=12 years). The analysis in this study was restricted to 7238 respondents aged 15-49 years who had sexual intercourse in the 12-months preceding the survey. Multivariable logistic regression, stratified by gender, was used to estimate the effect of depression on condom use adjusting for potential confounders. RESULTS: Reported condom use was lower in females (46.9%) than in males (60.9%), while depression was more in females (13.5%) than in males (8.4%). Condom use was less among people with depression, in both males and females. However, condom use was far less frequent among females (41.2%) with depression than their male counterparts (58.1%). Depression was found to reduce the odds of condom use in last sexual intercourse both in males and females. However, the effect was statistically significant in females only (adjusted odds ratio: 0.81; 95% CI: 0.66-0.99). LIMITATIONS: Cross-sectional data, and inability to capture socio-economic status and alcohol use rigorously are some of the limitations of this study. CONCLUSIONS: Depression was found to reduce condom use significantly in females. Public health programs aimed at increasing condom use should address the issues of improving self-efficacy in condom negotiation skills in females, along with addressing mental health issues, especially depression, with a gender-sensitive perspective. PMID- 25554997 TI - Influence of depression on cardiometabolic responses to a lifestyle intervention in at-risk individuals. AB - BACKGROUND: Cardiometabolic diseases and depression are public health problems that are often related. The benefits of behavioral interventions on lifestyle are well documented. However, the influence of depression in these interventions is unclear. OBJECTIVE: To evaluate whether depression affects the impact of a lifestyle intervention on cardiometabolic response in an at-risk sample. METHODS: 129 individuals identified by the public health system to be at risk for cardiometabolic disease were allocated to 18-month interventions on diet and physical activity. Socio-demographic and clinical data were obtained. Depressive symptoms were assessed by the Beck Depression Inventory. Changes by at least 10% in each of 6 cardiometabolic risk factors were used to define responses to intervention. Logistic regression models were employed for each gender. RESULTS: Approximately 42% of individuals had depressive symptoms. They had higher adiposity, cholesterol, and blood pressure levels and lower quality of life and physical activity levels than non-depressed individuals. In adjusted models, only women with depression at baseline had lower chance of improving plasma glucose (OR: 0.32) and lower chance of improving mean blood pressure (OR: 0.29) after the follow-up, compared with non-depressed women. LIMITATIONS: The small sample size may have diminished the power of the results and the instrument used to measure depression does not provide clinical diagnosis according to DSM criteria. CONCLUSION: Depression at baseline of lifestyle interventions predicted a lower chance of improving long-term cardiometabolic risk, particularly in women, suggesting that screening and management of depression as part of lifestyle interventions can potentially improve cardiometabolic risk profile. PMID- 25554998 TI - Monitoring the cytosolic entry of cell-penetrating peptides using a pH-sensitive fluorophore. AB - We report a simple, effective method to assess the cytosolic delivery efficiency and kinetics of cell-penetrating peptides using a pH-sensitive fluorescent probe, naphthofluorescein. PMID- 25554999 TI - Chronic stress-like syndrome as a consequence of medial site subthalamic stimulation in Parkinson's disease. AB - Considering the functional organization of the subthalamic nucleus (STN), we hypothesized that subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease might have a differential impact on the hypothalamic-pituitary-adrenal axis in relation to the position of active stimulating contact within the STN. In addition, we searched for any STN-DBS-related morning plasma cortisol changes in association with postoperative anxiety and weight gain. A plasma cortisol measurement was performed on the day of initiation of bilateral STN-DBS and repeated after 1 and 17 months in twenty patients with advanced Parkinson's disease. The body weight change and anxiety scores following the implantation were assessed as well. The electrode positions in the STN were determined on T1 weighted magnetic resonance images. After initiation of stimulation, cortisol levels significantly decreased and the cortisol changes after 1 and 17 months strongly correlated with the position of active contact in the subthalamic area. Patients with at least one contact located more medially in the STN experienced a significantly greater decrease of cortisol than those with one or both active contacts more laterally. Furthermore, the lower cortisol levels were strongly associated with higher trait anxiety and weight gain. These changes mimicked the effects of chronic stress and suggest the disturbing impact of STN-DBS on limbic and motivational systems. PMID- 25555000 TI - The reproductive biology and larvae of the first tadpole-bearing frog, Limnonectes larvaepartus. AB - Most of the reproductive modes of frogs include an exotrophic tadpole, but a number of taxa have some form of endotrophic development that lacks a feeding tadpole stage. The dicroglossid frog genus Limnonectes ranges from China south into Indonesia. The breeding biologies of the approximately 60 described species display an unusual diversity that range from exotrophic tadpoles to endotrophic development in terrestrial nests. There have been mentions of oviductal production of typical, exotrophic tadpoles in an undescribed species of Limnonectes from Sulawesi, Indonesia. Here we examine newly collected specimens of this species, now described as L. larvaepartus and present the first substantial report on this unique breeding mode. Typical exotrophic tadpoles that are retained to an advanced developmental stage in the oviducts of a female frog are birthed into slow-flowing streams or small, non-flowing pools adjacent to the streams. PMID- 25555001 TI - [Molecular detection of Saint Louis encephalitis virus in mosquitoes in Buenos Aires]. AB - During March 2013 a population of eared doves (Zenaida auriculata) was established in the center of City of Buenos Aires. Considering the role of these birds as host competent for Saint Louis encephalitis virus (SLEV), a CDC light trap was put in place to perform entomologic surveillance. During this month 5 pools of mosquitoes (n = 48) were collected and taxonomically determined. Three of them were classified as Culex pipiens (n = 10) and the other two were Culex spp. (n = 38). In this case, the mosquitoes species could not be determined due to that individuals were damaged. One of the Culex spp. pool was found to be positive for Saint Louis encephalitis virus by molecular techniques. This was then sequenced and classified as genotype III. PMID- 25555002 TI - [Surgically treated bronchopulmonary carcinoid tumours. Prognostic value of TNM staging 7a edition]. AB - We analyzed 43 women (61%) and 28 men (39%) surgically treated for carcinoid tumors from Jan/1975 to Dec/2011. Median age: 38 years (13-67). Typical carcinoid (TC) appeared in 63 (89%) patients, 8 (11%) suffered from atypical carcinoid (AC). Median follow-up: 4 years (1-24). TC stages were: IA = 33 (52%), IB = 10 (16%), IIA = 2 (3%), IIB = 2 (3%), IIIA = 12 (19%) and IIIB = 2 (3%); AC stages were: IA = 1 (12.5%), IIB = 1 (12.5%), IIIA = 2 (25%) and IIIB = 4 (50%). TNM classification did not show significant differences on 5-years survival period by stage (p = 0.689), even according to histological type (TC: p = 0.547; AC: p = 0.592). The disease-free survival rate was significantly lower (TC: 3 years vs. AC: 2 years, p = 0.000) and relapses were more frequent in AC (AC: 50% vs. TC: 2%, p = 0.000). The 7th TNM staging was not influential in estimating survival from carcinoid tumours in our population. The histological subtype was a better prognostic factor. PMID- 25555003 TI - [Early repolarization in soccer players' ECG. Prevalence, characteristics and evolution]. AB - Early repolarization (RP) on the electrocardiogram (ECG) of the athlete has been considered a benign finding. In some publications it has been associated with increased risk of sudden death. The objectives of this study were to evaluate the prevalence of infero-lateral RP in a population of trained players, to describe variables associated with this pattern and investigate the occurrence of events in the follow up. ECG of players with a normal cardiovascular physical examination and without family and personal history of heart disease, were analyzed. RP was considered the J-point elevation = 0.1 mV over baseline in at least 2 inferior and / or lateral precordial leads, associated or not with positive deflection or notch in the end of the QRS. RP is related to the voltage of R in V5 or V6, the PR interval, heart rate (HR) and age. They were contacted at 60 +/- 5 months after the initial assessment ECG. STATISTICS: chi square and t test for unpaired data. We evaluated ECG of 210 soccer players, of European-South American origin, with high intensity training. Age: 18 +/- 4.6 years. The RP ECG was present in 86 (40.9%), including the lower subtype in 17 (8.1%). One ECG showed PR in lower face in isolation. RP footballers were older, with less FC, prolonged PR and lower voltage of R. None of the players presented cardiovascular events in a 5 years follow up after this evaluation. PMID- 25555004 TI - [Primary epiploic appendagitis: clinical features in 73 cases]. AB - Primary epiploic appendagitis is a relatively rare disease in the differential diagnosis of acute abdomen, nonetheless it is an entity that should not be ignored by physicians and surgeons in order to prevent unnecessary interventions and overuse of antibiotics. To substantiate this concept a search was conducted at the Hospital Aleman, Buenos Aires between April 2007 and July 2013. The aim was clinical histories containing sonographic and tomographic images with diagnosis of omental appendagitis; and subsequently their electronic medical records were reviewed. The clinical features and outcome of a case series of 73 primary omental appendagitis were selected; the mean age was 45 years (+/- 16); 54 (74%) were men. Abdominal pain (left lower quadrant in 89% of cases) was the most common symptom. Abdominal ultrasound was performed on 44 (60%) of patients, computed tomography on 21 (29%), and both studies on 8 (11%) of cases in this series. In 49% of cases surgery consultation was requested. Fifteen patients (21%) were treated with antibiotics, 73% of them were prescribed by a clinician. Sixty seven patients (92%) were treated as outpatients with non steroidal anti inflammatory drugs (NSAIDs); two required laparoscopic surgery, two required hospitalization and two others were treated with opioids. Epiploic apendagitis is uncommon in the differential diagnosis of acute abdomen, but is an entity that should not be ignored by physicians to prevent unnecessary interventions and overuse of antibiotics. PMID- 25555005 TI - [Factors associated with academic success of medical students at Buenos Aires University]. AB - The aim of this study was to identify common factors relating to the academic success of medical students who were distinguished with honors at the Buenos Aires University. In 2011, 142 graduates were surveyed; the questionnaire included 59 questions on their sociodemographic environment, living conditions and social integration, motivation to study, learning capacity and health quality during their career. Compared to other students, these distinguished students more often lived in the city, far from their families; had been educated at private or universitary high schools, their economic needs were financed by their parents, who were on the whole professionals. Most of them were single and childless. The possibility of future employment oportunities (work) did not influence their choice of a medical career, academic success was important to them and they believed that success depended largely on personal effort; they knew how to handle anxiety, were sociable but independent and preferred solid experience to abstract conceptuality in order to obtain information. Our conclusion, within the current system of candidate selection, these results serve to calculate the covert self-selection mechanisms during the career, or in a more restrictive regime, to select those likely to reach academic success due to their privileged ambience. The analysis of demographic factors indicates some degree of inequality for socially disadvantaged students. Perhaps, a selection system based only on intellectual abilities would help identify and support the best candidates regardless of their social context. PMID- 25555006 TI - [Normocalcemic primary hyperparathyroidism]. AB - This report shows our conclusions on the clinical, biochemical and densitometry characteristics of 35 normocalcemic primary hyperparathyroidism (PHPT) patients. This condition is defined by a high level of intact parathyroid hormone (iPTHI) with persistently normal serum and ionized calcium in the absence of secondary hyperparathyroidism. Our selection consisted of 30 women (90%) and 5 men (10%). The control group of 55 hypercalcemic patients with primary hyperparathyroidism included 51 women (93%) and 4 men (7%). The average age at diagnosis of normocalcemic PHPT was 61.4 +/- 11.7 years and 56.4 +/- 11.3 years in hypercalcemic PHPT. Besides the expected differences in serum calcium, ionized calcium, phosphorus and 24 h urinary calcium, we found no significant changes in other biochemical variables, and no differences in densitometry evaluations such as the presence of osteopenia or osteoporosis and the number of fractures in the two types of PHPT. But there was a significant difference in the presence of renal lithiasis between normocalcemic PHPT (11.4%) and clasic PHPT (49.1%) p < 0.0005, to some extent associated to the presence of hypercalciuria in classic PHPT. Two of the 35 patients with normocalcemic PHPT became classic hypercalcemic PHPT over a 4 year follow-up period. Our findings support the hypothesis that the normocalcemic PHPT could be an early stage of the classic PHPT, both having similar clinical effects to metabolic renal and bone levels. PMID- 25555007 TI - [Serum uric acid levels and risk of developing preeclampsia]. AB - It is well known that preeclampsia is associated to high uric acid levels, but the clinical assessment of this relationship is still under consideration. Our research was to evaluate if periodic doses of uric acid during pregnancy might help to identify a high risk group prior to the onset of preeclampsia. We conducted a retrospective investigation in 79 primary gestates with normal blood pressure and 79 women with preeclampsia who were assisted at Hospital Nacional Posadas during 2010. Serum uric acid levels, creatininemia, uremia, and proteinuria data from the clinical records of the pregnant women were considered. Uric acid levels were similar in both groups during the first half of gestation. However, as of the 20th week, uric acid increased 1.5-times in preeclamptic women with no changes in creatinine and urea, confirming that these patients had no renal complications. Furthermore, we noted that higher levels of uric acid correlated with low birth weight. We also observed that pregnant women with a family history of hypertension were more likely to develop this condition. Moreover, we did not find a direct relationship with the fetal sex or the appearance of clinical symptoms. The analytical evidence suggests that changes in uric acid concentrations may be due to metabolic alterations at the initial stages of preeclampsia. Therefore, we propose that monitoring levels of uric acid during pregnancy might contribute to the early control of this condition. PMID- 25555008 TI - [IgE myeloma. Laboratory typing difficulties]. AB - The IgE multiple myeloma is a rare neoplasm of plasma cell accounting for 0.01% of all plasma cell dyscrasias. They are generally of more aggressive development and to date there are no more than 50 cases published in current literature. Laboratory studies are, in these cases, essential for the classification of the monoclonal component in serum and urine. The aim of this presentation is to report a patient diagnosed with IgE myeloma and to point out that the laboratory difficulties noted in these rare cases can lead to an erroneous report. PMID- 25555009 TI - [Pharyngeal-cervical-brachial variant of Guillain-Barre syndrome]. AB - Guillain-Barre syndrome is an acute inflammatory demyelinating polyneuropathy. Infrequent loco-regional variants, like the pharyngeal-cervical-brachial, have been described. We report the case of a 63-year-old male admitted to the emergency department with cervical and upper limb weakness, inability to swallow and chew, he also presented a rapidly progressive acute respiratory failure due to weakness of the respiratory muscles secondary to the pharyngeal-cervical brachial variant of Guillain-Barre syndrome. This variant, although unusual, presents a well-defined clinical pattern and diagnostic criteria, which is important in order to start an early treatment to improve the prognosis, not always favorable, to these patients. PMID- 25555011 TI - [Emphysematous cholecystitis]. PMID- 25555010 TI - [Tenosynovitis due to Chikungunya virus]. AB - We report the case of a man from Dominican Republic who consulted for a tenosynovitis of the right middle finger extensor; in the immediate convalescence second febrile curve, after 48 hours of no symptoms of an acute febrile illness, with marked fatigue, itchy rash, polyarthralgia, functional impairment and general stiffness. Biochemical tests did not provide useful data for diagnosis. Dengue virus serology was negative. Detection of IgM and neutralizing antibodies (PRNT) for Chikundunya virus (CHIKV) were positive. PMID- 25555012 TI - [Congenital bronchial atresia]. PMID- 25555013 TI - [Non-autoimmune thyroiditis]. AB - The term thyroiditis comprises a group of thyroid diseases characterized by the presence of inflammation, including autoimmune and non-autoimmune entities. It may manifest as an acute illness with severe thyroid pain (subacute thyroiditis and infectious thyroiditis), and conditions in which the inflammation is not clinically evident evolving without pain and presenting primarily thyroid dysfunction and/or goiter (drug-induced thyroiditis and Riedel thyroiditis). The aim of this review is to provide an updated approach on non-autoimmune thyroiditis and its clinical, diagnostic and therapeutic aspects. PMID- 25555014 TI - [Retirement and cognitive health]. PMID- 25555015 TI - [Life ages]. PMID- 25555016 TI - [Subarachnoid hemorrhage and thrombocytopenia associated to staphylococcal bacteremia]. PMID- 25555017 TI - [Laboratory preparation for the diagnosis of Ebola virus disease in Argentina]. PMID- 25555018 TI - [Anti PF4/heparin antibodies detection by immunoturbidimetry in the diagnosis of heparin-induced thrombocytopenia]. PMID- 25555019 TI - [Health and indigenous communities in Formosa]. PMID- 25555020 TI - Single- and multi-frequency detection of surface displacements via scanning probe microscopy. AB - Piezoresponse force microscopy (PFM) provides a novel opportunity to detect picometer-level displacements induced by an electric field applied through a conducting tip of an atomic force microscope (AFM). Recently, it was discovered that superb vertical sensitivity provided by PFM is high enough to monitor electric-field-induced ionic displacements in solids, the technique being referred to as electrochemical strain microscopy (ESM). ESM has been implemented only in multi-frequency detection modes such as dual AC resonance tracking (DART) and band excitation, where the response is recorded within a finite frequency range, typically around the first contact resonance. In this paper, we analyze and compare signal-to-noise ratios of the conventional single-frequency method with multi-frequency regimes of measuring surface displacements. Single-frequency detection ESM is demonstrated using a commercial AFM. PMID- 25555021 TI - Measures of activity-based pedestrian exposure to the risk of vehicle-pedestrian collisions: space-time path vs. potential path tree methods. AB - Research on the extent to which pedestrians are exposed to road collision risk is important to the improvement of pedestrian safety. As precise geographical information is often difficult and costly to collect, this study proposes a potential path tree method derived from time geography concepts in measuring pedestrian exposure. With negative binomial regression (NBR) and geographically weighted Poisson regression (GWPR) models, the proposed probabilistic two-anchor point potential path tree (PPT) approach (including the equal and weighted PPT methods) are compared with the deterministic space-time path (STP) method. The results indicate that both STP and PPT methods are useful tools in measuring pedestrian exposure. While the STP method can save much time, the PPT methods outperform the STP method in explaining the underlying vehicle-pedestrian collision pattern. Further research efforts are needed to investigate the influence of walking speed and route choice. PMID- 25555022 TI - Patients' views of consent for research enrollment during acute myocardial infarction. AB - OBJECTIVE: The goal of this study was to improve understanding of patients' perspectives of informed consent for clinical trial enrollment during ST elevation myocardial infarction (STEMI). BACKGROUND: STEMI research poses challenges regarding informed consent due to time constraints, symptom severity, and potential cognitive impairment. METHODS: An interview study was embedded within a clinical trial of an ischemic post-conditioning procedure for STEMI. An interactive, structured interview guide was used. RESULTS: Twenty interviews were conducted (median 1.5 days after initial procedure). Only 11/20 (55%) initially remembered being asked to participate in a trial. Comprehension of study details and the research process was limited; for example, many patients believed their decision was primarily clinical or that the study intervention was clearly superior. Patients described limitations regarding their ability to make a decision, including pain, discomfort, lack of time, and stress. However, patients generally felt they were able to make a decision at presentation and wanted to be the primary decision maker; few supported surrogate decision-making by family or physicians. CONCLUSIONS: This study demonstrates that patients recognize barriers to understanding but value elements of consent. Further research is needed to develop approaches that meet patients' goals while recognizing the limitations inherent to this context. PMID- 25555023 TI - The validity and reliability of an iPhone app for measuring vertical jump performance. AB - The purpose of this investigation was to analyse the concurrent validity and reliability of an iPhone app (called: My Jump) for measuring vertical jump performance. Twenty recreationally active healthy men (age: 22.1 +/- 3.6 years) completed five maximal countermovement jumps, which were evaluated using a force platform (time in the air method) and a specially designed iPhone app. My jump was developed to calculate the jump height from flight time using the high-speed video recording facility on the iPhone 5 s. Jump heights of the 100 jumps measured, for both devices, were compared using the intraclass correlation coefficient, Pearson product moment correlation coefficient (r), Cronbach's alpha (alpha), coefficient of variation and Bland-Altman plots. There was almost perfect agreement between the force platform and My Jump for the countermovement jump height (intraclass correlation coefficient = 0.997, P < 0.001; Bland-Altman bias = 1.1 +/- 0.5 cm, P < 0.001). In comparison with the force platform, My Jump showed good validity for the CMJ height (r = 0.995, P < 0.001). The results of the present study showed that CMJ height can be easily, accurately and reliably evaluated using a specially developed iPhone 5 s app. PMID- 25555024 TI - The role of microscope-integrated near-infrared indocyanine green videoangiography in the surgical treatment of intracranial dural arteriovenous fistulas. AB - OBJECT: The successful treatment of an intracranial dural arteriovenous fistula (dAVF) requires complete obliteration of blood flow through the fistulous point. Surgical ligation is often used along with endovascular techniques. Digital subtraction angiography (DSA) can be used to confirm fistula obliteration; however, this technique can be cumbersome intraoperatively and difficult to correlate anatomically with the surgical field. Near-infrared indocyanine green (ICG) videoangiography has been described as a complementary tool for this purpose. METHODS: The authors examined intracranial dAVF cases in which microscope-integrated intraoperative ICG videoangiography was used to identify and/or confirm obliteration of the dAVF during surgery. Retrospective evaluation of all intracranial dAVF cases treated with surgical ligation over a 10-year period at the Barrow Neurological Institute (n = 47) revealed 28 cases in which ICG videoangiography was used. The results were compared with findings on preoperative and intraoperative or postoperative DSA. RESULTS: ICG videoangiography successfully confirmed the fistulous point intraoperatively in 96% (22/23) of the cases. It also revealed complete obliteration of fistulas, comparable to intraoperative or postoperative DSA, in 91% (21/23) of the cases. The false-negative rate of ICG was 8.7% (2/23), which is similar to the false negative rate of intraoperative DSA alone (10.5% [2/19]). CONCLUSIONS: Microscope based ICG videoangiography provides real-time information about the intraoperative anatomy of dAVFs. In addition, it can confirm complete obliteration of a fistula. This technique may be useful during dAVF surgery as an independent form of angiography or as an adjunct to intraoperative or postoperative DSA. PMID- 25555025 TI - Enzymatically and reductively degradable alpha-amino acid-based poly(ester amide)s: synthesis, cell compatibility, and intracellular anticancer drug delivery. AB - A novel and versatile family of enzymatically and reductively degradable alpha amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-l phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N dimethylformamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained, depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with a glass transition temperature (Tg) in the range of 35.2-39.5 degrees C. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL alpha-chymotrypsin and bulk degradation under a reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or reductive condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL alpha-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and -resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching that of free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and reductively degradable alpha-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications. PMID- 25555028 TI - ? PMID- 25555026 TI - A 3D endoscopic transtubular transcallosal approach to the third ventricle. AB - OBJECT: Surgical approaches to deep-seated brain pathologies, specifically lesions of the third ventricle, have always been a challenge for neurosurgeons. In certain cases, the transcallosal approach remains the most suitable option for targeting lesions of the third ventricle, although retraction of the fornices and wall of the third ventricle have been associated with neuropsychological and hypothalamic deficits. The authors investigated the feasibility of an interhemispheric 3D endoscopic transcallosal approach through a minimally invasive tubular retractor system for the management of third ventricular lesions. METHODS: Three-dimensional endoscopic transtubular transcallosal approaches were performed on 5 preserved cadaveric heads (10 sides). A parasagittal bur hole was placed using neuronavigation, and a tubular retractor was inserted under direct endoscopic visualization. Following observation of the vascular structures, fenestration of the corpus callosum was performed and the retractor was advanced through the opening. Transforaminal, interforniceal, and transchoroidal modifications were all performed and evaluated by 3 surgeons. RESULTS: This approach provided enhanced visualization of the third ventricle and more stable retraction of corpus callosum and fornices. Bayonetted instruments were used through the retractor without difficulty, and the retractor applied rigid, constant, and equally distributed pressure on the corpus callosum. CONCLUSIONS: A transtubular approach to the third ventricle is feasible and facilitates blunt dissection of the corpus callosum that may minimize retraction injury. This technique also provides an added degree of safety by limiting the free range of instrumental movement. The combination of 3D endoscopic visualization with a clear plastic retractor facilitates safe and direct monitoring of the surgical corridor. PMID- 25555027 TI - Sexual and reproductive health: progress and outstanding needs. AB - We examine progress towards the 1994 International Conference on Population and Development (ICPD) commitment to provide universal access to sexual and reproductive health (SRH) services by 2014, with an emphasis on changes for those living in poor and emerging economies. Accomplishments include a 45% decline in the maternal mortality ratio (MMR) between 1990 and 2013; 11.5% decline in global unmet need for modern contraception; ~21% increase in skilled birth attendance; and declines in both the case fatality rate and rate of abortion. Yet aggregate gains mask stark inequalities, with low coverage of services for the poorest women. Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 80 developing countries highlight persistent disparities in skilled birth attendance by household wealth: in 70 of 80 countries (88%), >=80% of women in the highest quintile were attended by a skilled provider at last birth; in only 23 of the same countries (29%) was this the case for women in the lowest wealth quintile. While there have been notable declines in HIV incidence and prevalence, women affected by HIV are too often bereft of other SRH services, including family planning. Achieving universal access to SRH will require substantially greater investment in comprehensive and integrated services that reach the poor. PMID- 25555029 TI - Extended elution of phospholipid from silicone hydrogel contact lenses. AB - Characterization of phospholipid release from an experimental reusable wear silicone hydrogel contact lens was performed to assess the possible use of these lenses for phospholipid delivery to increase eye comfort to patients who prefer reusable wear lenses. Contact lenses were loaded with 200 MUg of radio-labeled 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) from a solution of n-propanol. To simulate 30 days of diurnal use with overnight cleaning, these lenses were eluted for 16 h at 35 degrees C into artificial tear fluid (ATF), and then eluted at room temperature (~22 degrees C) for 8 h in one of three commercial contact lens cleaning systems. This was repeated for 30 days. The elution of DMPC into ATF was greater on the first day, followed by a fairly constant amount of elution each day thereafter. The type of cleaning system had a statistically significant effect on the elution rate during daily exposure to ATF. The rate of elution into cleaning solutions did not show any enhanced elution on the first day; there was a fairly constant elution rate. Again, the type of cleaning system significantly influenced the elution rate into the nightly cleaner. PMID- 25555030 TI - Cerebral aneurysms and accelerated atherosclerosis in Russell-Silver syndrome: a new subtype? Case report. AB - The authors describe the case of a 32-year-old woman known to have Russell-Silver syndrome who presented with repeated aneurysmal subarachnoid hemorrhage. Multiple intracranial aneurysms and advanced peripheral vascular disease were demonstrated. The authors postulate a link between these vascular features and the patient's genetic condition. PMID- 25555031 TI - National estimates of behavioral health conditions and their treatment among adults newly insured under the ACA. AB - OBJECTIVE: Approximately 25 million individuals are projected to gain insurance as a result of the Affordable Care Act (ACA). This study estimated the prevalence of behavioral health conditions and their treatment among individuals likely to gain coverage. METHODS: Pooled 2008-2011 National Survey on Drug Use and Health data for adults (ages 18-64) were used. Estimates were created for all adults, current Medicaid beneficiaries, and uninsured adults with incomes that might make them eligible for the Medicaid expansion or tax credits for use in the health insurance marketplace. RESULTS: Individuals who may gain insurance under the ACA had lower rates of serious mental illnesses (5.4%, Medicaid expansion; 4.7%, marketplace) compared with current Medicaid beneficiaries (9.6%). They had higher rates of substance use disorders (13.6%, Medicaid expansion; 14.3%, marketplace) compared with Medicaid recipients (11.9%). CONCLUSIONS: There is significant need for behavioral health treatment among individuals who may gain insurance under the ACA. PMID- 25555032 TI - Resin-dentin bonding interface after photochemical surface treatment. AB - OBJECTIVE: The aim of this study is to elucidate the structure of the resin dentin interface formed by photochemical dentin treatment using an argon fluoride (ArF) excimer laser. BACKGROUND DATA: The ArF excimer laser processes material by photochemical reaction without generating heat, while also providing surface conditioning that enhances material adhesion. In the case of bonding between resin and dentin, we demonstrated in a previous study that laser etching using an ArF excimer laser produced bonding strength comparable to that of the traditional bonding process; however, conditions of the bonding interface have not been fully investigated. METHODS: A dentin surface was irradiated in air with an ArF excimer laser followed by bonding treatment. Cross sections were observed under light microscope, transmission electron microscope (TEM), and scanning electron microscope, then analyzed using an energy dispersive X-ray spectroscope (EDS): EDS line profiles of the elements C, O, Si, Cl, P, and Ca at the resin-dentin interface were obtained. RESULTS: The density of C in resin decreased as it approached the interface, reaching its lowest level within the dentin at a depth of 2 MUm from the resin-dentin interface on EDS. There was no hybrid layer observed at the interface on TEM. Therefore, it was suggested that the resin monomer infiltrated into the microspaces produced on the dentin surface by laser abrasion. CONCLUSIONS: The monomer infiltration without hybrid layer is thought to be the adhesion mechanism after laser etching. Therefore, the photochemical processes at the bonding interface achieved using the ArF excimer laser has great potential to be developed into a new bonding system in dentistry. PMID- 25555033 TI - First adaptation of a family-based ACT model in mainland China: a pilot project. AB - OBJECTIVE: This study reports findings from a preliminary evaluation of the first implementation of the assertive community treatment (ACT) model in mainland China. METHODS: Over six months, the pilot study compared a group of patients (N=15) and family caregivers who received ACT services with a control group (N=16) who received standard community services. Data on hospitalization days, relapse frequency, psychiatric symptoms, social and vocational functioning, general mental health status, family burden, and level of social support for family caregivers were examined. RESULTS: ACT patients had no admissions, compared with two in the control group; they also had significantly lower psychopathology and higher social functioning scores. No significant differences in outcome measures for family caregivers were found. CONCLUSIONS: The study found preliminary support for implementing ACT in mainland China. Implementation could contribute to reducing admission and psychopathology and improving social functioning. Further research on ways to enhance family caregivers' experience is warranted. PMID- 25555034 TI - Intimate partner violence and repeat induced abortion in Italy: A cross sectional study. AB - OBJECTIVE: To investigate the impact of intimate partner violence (IPV) on the risk of repeat induced abortion (RIA), we compared IPV history among women with and without previous induced abortion (IA). METHODS: All consecutive women aged 18 years or more requiring IA in 12 Italian abortion clinics were eligible for inclusion in the study. They were asked to fill in an anonymous, self-developed questionnaire assessing sociodemographic data and their history of different types of violence and related risk factors. RESULTS: The analysis included 1030 women, 624 (60.6%) of whom reported a previous IA. Past or current IPV was reported by 19.3%: 7.0% reported sexual violence, 11.3% physical abuse and 12.1% psychological abuse. Past or current IPV was reported by 22.3% of women with RIA and 14.8% of those undergoing their first IA (adjusted odds ratio 1.57, 95% confidence interval 1.07-2.30; p = 0.02). When we considered sexual, psychological and physical abuse separately, we found that any kind of abuse was more frequent in women with RIA than in women with no previous IA. CONCLUSION: This study underlines the impact of IPV on the risk of RIA and suggests the need for screening for IPV among women requiring abortion, in order to identify women at risk of RIA and to improve their general and reproductive health. PMID- 25555035 TI - The match demands of international rugby sevens. AB - The purpose of this study was to quantify the global match demands of international rugby sevens and to compare the match demands of forwards and backs, and between tournament rounds. To assess the match demands, global positioning system (GPS) and video analysis were collected from 27 international rugby sevens players from the same team across an entire International Rugby Board Sevens World Series season. Differences in running demands and match activities between forwards and backs were mostly trivial and small (ES = 0.05 0.84) while differences in running demands and match activities between Pool and Cup rounds were trivial (ES = 0.001-0.12). Cup round matches showed an increase in long-duration ball-in-play sequences (proportion ratio 0.46). These findings suggest international rugby sevens forwards and backs experience similar match demands while overall match demands remain consistent across tournament rounds. PMID- 25555036 TI - Stabilisation of health as the centre point of a health psychology of ageing. AB - Current health psychological theories and research mainly cover improvement of health, recovery from illness or maintenance of health. With this theoretical manuscript, we argue that in ageing societies in which chronic illness and multimorbidity become the norm rather than the exception, this focus of health psychology is no longer sufficient. Instead, in line with a recent conceptualisation of health as "the ability to adapt and to self-manage", we suggest that the centre point of a health psychology of ageing needs to be the stabilisation of health. Current theories of lifespan development, such as the model of selection, optimisation and compensation, the motivational theory of life span development, the two-process model of assimilative and accommodative coping and the recently introduced functional quality of life model are described with regard to their assumptions and related research focussing on stabilisation. All of these models explicitly comprise stabilisation as an important process of successful, healthy ageing. So far, however, the empirical research examining these models does not take stabilisation into account. Implications for research methods and practise of health stabilisation are discussed. PMID- 25555037 TI - Scales of Lewis basicities toward C-centered Lewis acids (carbocations). AB - Equilibria for the reactions of benzhydryl cations (Ar2CH(+)) with phosphines, tert-amines, pyridines, and related Lewis bases were determined photometrically in CH2Cl2 and CH3CN solution at 20 degrees C. The measured equilibrium constants can be expressed by the sum of two parameters, defined as the Lewis Acidity (LA) of the benzhydrylium ions and the Lewis basicity (LB) of the phosphines, pyridines, etc. Least-squares minimization of log K = LA + LB with the definition LA = 0 for (4-MeOC6H4)2CH(+) gave a Lewis acidity scale for 18 benzhydrylium ions covering 18 orders of magnitude in CH2Cl2 as well as Lewis basicities (with respect to C-centered Lewis acids) for 56 bases. The Lewis acidities correlated linearly with the quantum chemically calculated (B3LYP/6-311++G(3df,2pd)//B3LYP/6 31G(d,p) level) methyl anion affinities of the corresponding benzhydrylium ions, which can be used as reference compounds for characterizing a wide variety of Lewis bases. The equilibrium measurements were complemented by isothermal titration calorimetry studies. Rates of SN1 solvolyses of benzhydryl chlorides, bromides, and tosylates derived from E(13-33)(+), i.e., from highly reactive carbocations, correlate excellently with the corresponding Lewis acidities and the quantum chemically calculated methyl anion affinities. This correlation does not hold for solvolyses of derivatives of the better stabilized amino-substituted benzhydrylium ions E(1-12)(+). In contrast, the correlation between electrophilic reactivities and Lewis acidities (or methyl anion affinities) is linear for all donor-substituted benzhydrylium ions E(1-21)(+), while the acceptor-substituted benzhydrylium ions E(26-33)(+) react more slowly than expected from their thermodynamic stabilities. The boundaries of linear rate-equilibrium relationships were thus defined. PMID- 25555038 TI - Isotope evidence for preferential dispersal of fast-spreading invasive gobies along man-made river bank structures. AB - Invasive round goby Neogobius melanostomus and bighead goby Ponticola kessleri have successfully colonized freshwater and coastal habitats worldwide. The objective was to use stable isotope analyses to study the foraging and movement of both species at small spatial scales in the Upper Danube River, considering 861 samples from two different years, seasons and sides of the river in an area where limited mixing at a confluence occurs. A difference in delta(13)C of 1 0/00 between gobies from both river sides was observed in both species and reflected the isotope spacing in their dominant benthic prey Dikerogammarus villosus. These results suggest an absence of goby movement across the Danube River which was unexpected, given the fast spread of gobies at invasion fronts. It can be concluded that their dispersal is highly preferential with longitudinal movement likely being facilitated by artificial rip-rap structures along river banks, which provide shelter and food. PMID- 25555039 TI - Children with chronic illnesses: factors influencing family hardiness. AB - The current study assessed factors related to family hardiness in families of children coping with medical procedures related to a chronic illness. Participants were 68 parents of children with chronic illnesses, who were receiving complex medical treatment at a local hospital. Parents completed a scale assessing family hardiness and a semi-structured interview assessing their positive and negative coping strategies and those of their child. A linear regression analysis was used to examine the relationship between several predictors, including child age, number of medical conditions for the child, family income, number of positive and negative parent and child coping strategies, and family hardiness (outcome variable). Results indicated that parents of older children and children who exhibited negative coping strategies reported lower family hardiness. Older children may have had their chronic illness for a longer period of time, which could be wearing for the children and their families. Results of this study suggested that negative child coping may have deleterious effects on the family, and nurses and other health professionals should provide ideas for positive child coping and consider collaboration with mental health providers when they identify children facing emotional problems. PMID- 25555040 TI - Cardiovascular risk associated with acarbose versus metformin as the first-line treatment in patients with type 2 diabetes: a nationwide cohort study. AB - CONTEXT: Metformin is the first-line oral therapy for type 2 diabetes with proven benefits against cardiovascular risk. Recent evidence suggested that acarbose might be similar to metformin in glucose-lowering efficacy and cardiovascular risk reduction. Therefore, international guidelines have suggested the use of acarbose as alternative first-line antidiabetic therapy. OBJECTIVE: To compare the cardiovascular outcomes in the first-line users of acarbose vs metformin. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: A nationwide cohort study was conducted by analyzing the Taiwan National Health Insurance (NHI) Database. A total of 17,366 acarbose initiators and 230,023 metformin initiators were identified between January 1, 2009 and December 31, 2010. The primary outcome is hospitalization due to any cardiovascular events, including acute myocardial infarction, congestive heart failure, and ischemic stroke. The propensity score method was used to adjust for baseline differences between the two groups. Patients were followed from drug initiation to the earliest of outcome occurrence, death or disenrollment from NHI, or study termination. RESULTS: In intention-to-treat analyses, acarbose was associated with a higher risk of any cardiovascular event (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI], 1.01-1.09), heart failure (HR, 1.08; 95% CI, 1.00-1.16), and ischemic stroke (HR, 1.05, 95% CI, 1.00-1.10) than metformin. No significant difference in risk was found in subgroups of patients with or without underlying hypertension, ischemic heart disease, or cerebrovascular disease. Similar results were found in auxiliary as-treated analyses or analyses stratified by propensity score quintiles. CONCLUSION: Our data do not support that acarbose has a cardio protective effect similar to metformin as a first-line antidiabetic agent. PMID- 25555041 TI - Influence of antimuscarinic therapy on cognitive functions and quality of life in geriatric patients treated for overactive bladder. AB - OBJECTIVES: Incidences of overactive bladder (OAB) and cognitive dysfunction increase with aging. Treatment of OAB with antimuscarinic agents may result in cognitive decline, especially in patients with Alzheimer's disease (AD). The aim of this study is to evaluate the effect of antimuscarinic treatment on cognitive functions, depression, and quality of life (QOL) of patients with OAB. METHODS: This non-interventional prospective observational study was conducted in a geriatric medicine outpatient clinic. Overall, 168 OAB patients were enrolled. Patients were followed up in five groups: oxybutynin, darifenacin, tolterodine, trospium, and control groups. Follow-up visits were done at second, third, and sixth months. Comprehensive geriatric assessment, cognitive and mood assessment, QOL scales (IIQ-7, UDI-6) were performed. RESULTS: Mean age of the patients was 73.5 +/- 6.1. Of the 168 patients, 92.3% were female, 83.3% benefited from the treatment, and 37.1% discontinued the medication. Discontinuation rate and frequency of side effects were more frequent in the oxybutynin group. Mini Mental State Examination scores did not decline after treatment, even in AD patients. Geriatric Depression Scale scores, Activities of Daily Living scores, and QOL scores significantly improved after treatment. CONCLUSION: Antimuscarinic agents are effective in OAB treatment. They have a positive impact on daily life activities, depression, and QOL indices. Furthermore, they do not have a negative effect on cognitive function in older adults with or without AD. PMID- 25555042 TI - A new muscle co-activation index for biomechanical load evaluation in work activities. AB - Low-back disorders (LBDs) are the most common and costly musculoskeletal problem. Muscle co-activation, a mechanism that stabilises the spine, is adopted by the central nervous system to provide added protection and avoid LBDs. However, during high-risk lifting tasks, the compressive load on the spine grows owing to increased co-activation. The aim of this study was to develop a method for the sample-by-sample monitoring of the co-activation of more than two muscles, and to compare this method with agonist-antagonist methods. We propose a time-varying multi-muscle co-activation function that considers electromyographic (EMG) signals as input. EMG data of 10 healthy subjects were recorded while they manually lifted loads at three progressively heavier conditions. The repeated measures ANOVA revealed a significant effect of lifting condition on our co activation index. Heavier conditions resulted in higher muscle co-activation values. Significant correlations were found between the time-varying multi-muscle co-activation index and other agonist-antagonist methods. Practitioner Summary: We have developed a method to quantify muscle co-activation during the execution of a lifting task. To do this we used surface electromyography. Our algorithm provides a measure of time-varying co-activation between more than two muscles. PMID- 25555044 TI - Ionothermal synthesis of tetranuclear borate clusters containing f- and p-block metals. AB - The reactions of simple oxides or halides of trivalent lanthanides and actinides or bismuth with boric acid in the ionic liquid 1-butyl-3-methylimidazolium chloride at 150 degrees C result in the formation and crystallization of a series of isomorphous tetranuclear borate clusters with the general formula M4B22O36(OH)6(H2O)13 (M = La, Ce, Pr, Nd, Sm, Eu, Gd, Pu, and Bi). These clusters do not assemble with trivalent cations smaller than Gd(3+), suggesting that the formation of the clusters is dictated by the size of the metal ion. The cations are found in cavities along the periphery of a cage assembled from the corner- and edge-sharing interactions of BO3 triangles and BO4 tetrahedra, yielding a complex chiral cluster. Both enantiomers cocrystallize. The metal ions are nonacoordinate, and their geometries are best described as distorted tridiminished icosahedra. This coordination environment is new for both Pu(3+) and Bi(3+). In addition to detailed structural information, UV/vis-NIR absorption and photoluminescence spectra are also provided. PMID- 25555043 TI - Drug resistance and molecular epidemiology of aerobic bacteria isolated from puerperal infections in Bangladesh. AB - Puerperal infection is a common complication during postnatal period in developing countries. Bacterial species, drug resistance, and genetic characteristics were investigated for a total of 470 isolates from puerperal infections in Bangladesh for a 2-year period (2010-2012). The most common species was Escherichia coli (n=98), followed by Enterococcus faecalis (n=54), Staphylococcus haemolyticus (n=33), Proteus mirabilis (n=32), Staphylococcus aureus (n=27), Klebsiella pneumoniae (n=22), and Enterobacter cloacae (n=21). S. aureus and Acinetobacter baumannii were isolated at a higher frequency from wound infections after cesarean section, while E. coli, E. cloacae, and K. pneumoniae were isolated from community-acquired endometritis and urinary tract infections. Resistance to third-generation cephalosporins was frequent for Enterobacteriacae, and was mainly mediated by blaCTX-M-1 group beta-lactamases. The CTX-M gene in E. coli from the four phylogroups was identified as blaCTX-M-15, and phylogroup B2 isolates with blaCTX-M-15 were classified into ST131 with O25b allele, harboring aac(6')-Ib-cr and various virulence factors. Carbapenemase genes blaNDM-1 and blaNDM-7 were identified in one isolate each of phylogroup A E. coli. Methicillin resistant S. aureus isolates had type IV or V SCCmec, including isolates of ST361 (CC672), which is related to an emerging ST672 clone in the Indian subcontinent. This study revealed the recent epidemiological status of aerobic bacteria causing puerperal infections in Bangladesh, providing useful information to improve clinical practice and infection control. PMID- 25555045 TI - Robust triboelectric nanogenerator based on rolling electrification and electrostatic induction at an instantaneous energy conversion efficiency of ~ 55%. AB - In comparison to in-pane sliding friction, rolling friction not only is likely to consume less mechanical energy but also presents high robustness with minimized wearing of materials. In this work, we introduce a highly efficient approach for harvesting mechanical energy based on rolling electrification and electrostatic induction, aiming at improving the energy conversion efficiency and device durability. The rolling triboelectric nanogenerator is composed of multiple steel rods sandwiched by two fluorinated ethylene propylene (FEP) thin films. The rolling motion of the steel rods between the FEP thin films introduces triboelectric charges on both surfaces and leads to the change of potential difference between each pair of electrodes on back of the FEP layer, which drives the electrons to flow in the external load. As power generators, each pair of output terminals works independently and delivers an open-circuit voltage of 425 V, and a short-circuit current density of 5 mA/m(2). The two output terminals can also be integrated to achieve an overall power density of up to 1.6 W/m(2). The impacts of variable structural factors were investigated for optimization of the output performance, and other prototypes based on rolling balls were developed to accommodate different types of mechanical energy sources. Owing to the low frictional coefficient of the rolling motion, an instantaneous energy conversion efficiency of up to 55% was demonstrated and the high durability of the device was confirmed. This work presents a substantial advancement of the triboelectric nanogenerators toward large-scope energy harvesting and self-powered systems. PMID- 25555046 TI - Inkjet printed nanohydrogel coated carbon nanotubes electrodes for matrix independent sensing. AB - Polyacrylamide (PA) based hydrogels are used in several applications including polyacrylamide gel electrophoresis and sensing devices. Homogeneous and compact PA films can be prepared based on chemical or photopolymerization processes. However, the accurate and reproducible coating of substrates with nanohydrogel patterns is challenging due to the in situ polymerization and deposition requirements. Herein, we report an inkjet printing (IJP) concept with simultaneously performed UV photopolymerization of a specifically prepared acrylamide/N,N'-methylenebis(acrylamide) containing ink. A prepolymerization step of the hydrogel precursor molecules was implemented in the ink formulation protocol to adjust the viscosity of the ink and to enhance the rate of polymerization during printing. After the optimization of the printing parameters, a nanometer thin PA hydrogel coating with well distributed nanopores was achieved on top of a stand-alone carbon nanotubes (CNTs) pattern. Batches of fully inkjet printed PA/CNT modified electrodes were prepared that showed outstanding improvements for the electrochemical detection of antioxidants in complex matrices such as untreated orange juice and red wine samples thanks to the properties of the PA coating. PMID- 25555048 TI - Optical high-throughput screening for activity and electrochemical stability of oxygen reducing electrode catalysts for fuel cell applications. AB - A fluorescence-based electro-optical high-throughput method and setup for testing the oxygen reduction reaction (ORR) activity and electrochemical stability of 60 materials in parallel is described. We present thus a quantitative method for activity measurements for ORR-catalysts by optical fluorescence data acquisition. The fluorescence behavior of fluorescein, phloxine B, and umbelliferone as indicators is presented. The effect of oxygen concentration, saturation, and supply on electrochemical response is presented. Corrections for internal resistance differences and intensity differences are described. The final method allowed position independent determination of activities on the working-electrode library, containing up to 60 different electrocatalysts. A total of 378 selected mixed oxides have been studied. Cu/Ni/Mn and Co/Ni/Mn oxides proved electrochemically most active and comparable to a Pt-containing reference catalyst. PMID- 25555049 TI - Metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion: case report. AB - Peripheral nerve tumors are soft-tissue tumors that can occur in any nerve throughout the body. The majority of peripheral nerve tumors arise from elements of the nerve sheath with the two most common being neurofibromas and schwannomas. More than 90% of all peripheral nerve tumors are benign. When there is peripheral nerve involvement in metastatic carcinoma, it is often via contiguous spread from the primary mass; hematogenous seeding to a peripheral nerve is seldom seen. In this report the authors describe the even rarer case of metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion. Cases from the literature show the rarity of this finding and its late clinical appearance. Given that survival in patients with metastatic carcinoma continues to increase, dorsal root ganglion metastasis may become more common over time. PMID- 25555051 TI - Letter to the editor: craniocervical instability. PMID- 25555050 TI - Stabilization with the Dynamic Cervical Implant: a novel treatment approach following cervical discectomy and decompression. AB - OBJECT: Although cervical total disc replacement (TDR) has shown equivalence or superiority to anterior cervical discectomy and fusion (ACDF), potential problems include nonphysiological motion (hypermobility), accelerated degeneration of the facet joints, particulate wear, and compromise of the mechanical integrity of the endplate during device fixation. Dynamic cervical stabilization is a novel motion preserving concept that facilitates controlled, limited flexion and extension, but prevents axial rotation and lateral bending, thereby reducing motion across the facet joints. Shock absorption of the Dynamic Cervical Implant (DCI) device is intended to protect adjacent levels from accelerated degeneration. METHODS: The authors conducted a prospective evaluation of 53 consecutive patients who underwent DCI stabilization for the treatment of 1-level (n = 42), 2-level (n = 9), and 3-level (n = 2) cervical disc disease with radiculopathy or myelopathy. Forty-seven patients (89%) completed all clinical and radiographic outcomes at a minimum of 24 months. Clinical outcomes consisted of Neck Disability Index (NDI) and visual analog scale (VAS) scores, neurological function at baseline and at latest follow-up, as well as patient satisfaction. Flexion-extension radiography was evaluated for device motion, implant migration, subsidence, and heterotopic ossification. Cervical sagittal alignment (Cobb angle), functional spinal unit (FSU) angle, and range of motion (ROM) at index and adjacent levels were evaluated with WEB 1000 software. RESULTS: The NDI score, VAS neck and arm pain scores, and neurological deficits were significantly reduced at each postoperative time point compared with baseline (p < 0.0001). At 24 months postoperatively, 91% of patients were very satisfied and 9% somewhat satisfied, while 89% would definitely and 11% would probably elect to have the same surgery again. In 47 patients with 58 operated levels, the radiographic assessment showed good motion (5 degrees -12 degrees ) of the device in 57%, reduced motion (2 degrees -5 degrees ) in 34.5%, and little motion (0-2 degrees ) in 8.5%. The Cobb and FSU angles improved, showing a clear tendency for lordosis with the DCI. Motion greater than 2 degrees of the treated segment could be preserved in 91.5%, while 8.5% had a near segmental fusion. Mean ROM at index levels demonstrated satisfying motion preservation with DCI. Mean ROM at upper and lower adjacent levels showed maintenance of adjacent-level kinematics. Heterotopic ossification, including 20% minor and 15% major, had no direct impact on clinical results. There were 2 endplate subsidences detected with an increased segmental lordosis. One asymptomatic anterior device migration required reoperation. Three patients underwent a secondary surgery in another segment during follow-up, twice for a new disc herniation and once for an adjacent degeneration. There was no posterior migration and no device breakage. CONCLUSIONS: Preliminary results indicate that the DCI implanted using a proper surgical technique is safe and facilitates excellent clinical outcomes, maintains index-and adjacent-level ROM in the majority of cases, improves sagittal alignment, and may be suitable for patients with facet arthrosis who would otherwise not be candidates for cervical TDR. Shock absorption together with maintained motion in the DCI may protect adjacent levels from early degeneration in longer follow-up. PMID- 25555052 TI - Vincenzo Quercioli (1876-1939), researcher and pioneer of the atlas fracture. AB - A review of early 20th century literature regarding fractures of the atlas led the authors to discover a paper written in Italian by Professor Vincenzo Quercioli in 1908, at that time an assistant surgeon at the University of Siena. The work was published in the journal Il Policlinico, which at that time was directed by Professor Francesco Durante. The paper described the first case of a quadripartite fracture of the atlas, and it accurately reported the mechanism of injury, symptoms, neurological examination, treatment, complications, and cause of death of the patient. Quercioli performed an autopsy on the patient and gave a detailed description of anatomopathological features. In particular, he identified the 4 symmetrical fracture lines related to the arches of the atlas and the substantial integrity of the atlantoaxial ligaments, particularly the transverse ligament. Based on those findings, Quercioli concluded that the mechanism of trauma was an axial force. This force passed through the center of the vertebral ring and caused symmetrical displacement and compression of the articular masses. These concepts of dynamic physics led Quercioli to conclude that, because the atlas is wedge shaped, the masses of the atlas reacted to stress by moving away from the center. This reaction resulted in stretching the front and rear arches, which then fractured at their 4 points of weakness. The integrity of the spinal cord was intact, based on a negative neurological examination for CNS lesions. Thus, he concluded that these injuries were not fatal and could be cured by appropriate treatment with a Minerva cast and, in the presence of swallowing disorders, with a nasogastric tube. The case described by Quercioli was later mentioned in two classic works on atlas fractures by Sir Geoffrey Jefferson, published in 1920 and 1927. In those works, Jefferson proposed his classification of 5 different anatomopathological classes; this work is widely cited in the literature and should be considered a classic. The patterns and deductions that Jefferson reported on these fractures appeared to draw upon the scientific experience of Quercioli and his description of the quadripartite atlas fracture, which appeared to be unique, even in Jefferson's review. Therefore, the authors believe that they have identified another scientist and pioneer of the atlas fracture in Professor Vincenzo Quercioli. With his brilliant insights, which remain useful and valid, Quercioli led the way to further research on the subject. PMID- 25555053 TI - Odontoid balloon kyphoplasty associated with screw fixation for Type II fracture in 2 elderly patients. AB - Anterior screw fixation is a well-recognized technique that is used to stabilize Type IIB fractures of the odontoid process in the elderly. However, advanced age and osteoporosis are 2 risk factors for pseudarthrosis. Kyphoplasty has been described in the treatment of lytic lesions in C-2. The authors decided to combine these 2 techniques in the treatment of unstable fractures of the odontoid. Two approximately 90-year-old patients were treated for this type of fracture. Instability was demonstrated on dynamic radiography in one patient, and the fracture was seen on static radiography in the other. Clinical parameters, pain, range of motion, 36-Item Short Form Health Survey (SF-36) score (for the first patient), and radiological examinations (CT scans and dynamic radiographs) were studied both before and after surgery. After inflating the balloon both above and below the fracture line, the authors applied a high-viscosity polymethylmethacrylate cement. Some minor leakage of cement was noted in both cases but proved to be harmless. The screws were correctly positioned. The clinical result was excellent, both in terms of pain relief and in the fact that there was no reduction in the SF-36 score. The range of motion remained the same. A follow-up CT scan obtained 1 year later in one of the patients showed no evidence of change in the materials used, and the dynamic radiographs showed no instability. This combination of kyphoplasty and anterior screw fixation of the odontoid seems to be an interesting technique in osteoporotic Type IIB fractures of the odontoid process in the elderly, with good results both clinically and radiologically. PMID- 25555054 TI - Spinal cord compression secondary to metastasis of malignant chondroid syringoma: case report. AB - The authors describe a case of spinal cord compression due to an epidural metastasis of malignant chondroid syringoma. Chondroid syringoma is a rare mixed tumor of the skin composed of both epithelial and mesenchymal elements. Although most are benign, malignant forms have been reported. Malignant chondroid syringoma may progress very slowly and the metastatic spread occurs late, appearing years after the original diagnosis. There is only one other report of spinal cord compression secondary to metastasis of malignant chondroid syringoma, which was finally diagnosed by microscopic examination of an autopsy specimen. This 63-year-old woman presented with a 4-week history of progressive paraparesis. Admission MRI of the thoracic spine showed an extradural mass arising from the posterior elements and left pedicle of T-9, which caused posterior compression of the spinal cord. Surgical decompression resulted in resolution of the neurological impairments. The histological results were consistent with metastasis of malignant chondroid syringoma. The patient underwent adjuvant radiotherapy and a favorable outcome was noted at the 2-year follow-up visit. This represents the first reported case of spinal cord compression from a metastasis of a malignant chondroid syringoma histologically confirmed in vivo. The authors' experience in this case suggests that resection followed by radiotherapy might be an acceptable means for achieving short-term, progression-free survival. PMID- 25555055 TI - Extensive spinal epidural abscess treated with "apical laminectomies" and irrigation of the epidural space: report of 2 cases. AB - Spinal epidural abscess (SEA) is a rare but often devastating infection of the epidural space around the spinal cord. When an SEA is widespread, extensive decompression with laminectomy is often impossible, as it may subject the patient to very long operative times, extensive blood loss, and mechanical instability. A technique called "skip laminectomy" has been described in the literature, in which laminectomies are performed at the rostral and caudal ends of an abscess that spans 3-5 levels and a Fogarty catheter is used to mechanically drain the abscess, much like in an embolectomy. In this report of 2 patients, the authors present a modification of this technique, which they call "apical laminectomies" to allow for irrigation and drainage of an extensive SEA spanning the entire length of the vertebral column (C1-2 to L5-S1). Two patients presented with cervico-thoraco-lumbar SEA. Laminectomies were performed at the natural apices of the spine, namely, at the midcervical, midthoracic, and midlumbar spine levels. Next, a pediatric feeding tube was inserted in the epidural space from the thoracic laminectomies up toward the cervical laminectomy site and down toward the lumbar laminectomy site, and saline antibiotics were used to irrigate the SEA. Both patients underwent this procedure with no adverse effects. Their SEAs resolved both clinically and radiologically. Neither patient suffered from mechanical instability at 1 year after treatment. For patients who present with extensive SEAs, apical laminectomies seem to allow for surgical cure of the infectious burden and do not subject the patient to extended operating room time, an increased risk of blood loss, and the risk of mechanical instability. PMID- 25555056 TI - Letter to the editor: treatment of craniocervical instability using a posterior only approach. PMID- 25555057 TI - Ultrafast dynamic computed tomography myelography for the precise identification of high-flow cerebrospinal fluid leaks caused by spiculated spinal osteophytes. AB - OBJECT: Precise localization and understanding of the origin of spontaneous high flow spinal CSF leaks is required prior to targeted treatment. This study demonstrates the utility of ultrafast dynamic CT myelography for the precise localization of high-flow CSF leaks caused by spiculated spinal osteophytes. METHODS: This study reports a series of 14 patients with high-flow CSF leaks caused by spiculated spinal osteophytes who underwent ultrafast dynamic CT myelography between March 2009 and December 2010. There were 10 male and 4 female patients, with an average age of 49 years (range 37-74 years). The value of ultrafast dynamic CT myelography in depicting the CSF leak site was qualitatively assessed. RESULTS: In all 14 patients, ultrafast dynamic CT myelography was technically successful at precisely demonstrating the site of the CSF leak, the causative spiculated osteophyte piercing the dura, and the relationship of the implicated osteophyte to adjacent structures. Leak sites included 3 cervical, 11 thoracic, and 0 lumbar levels, with 86% of the leaks occurring from C-5 to T-7. Information obtained from the ultrafast dynamic CT myelogram was considered useful in all treated CSF leaks. CONCLUSIONS: Spinal osteophytes piercing the dura are a more frequent cause of high-flow CSF leaks than previously recognized. Ultrafast dynamic CT myelography adds value beyond standard dynamic myelography or digital subtraction myelography in the diagnosis and anatomical characterization of high-flow spinal CSF leaks caused by these osteophytes. This information allows for appropriate planning for percutaneous or surgical treatment. PMID- 25555058 TI - Smoking as an independent predictor of reoperation after lumbar laminectomy: a study of 500 cases. AB - OBJECT: This study aimed to identify the factors predicting an increased risk for reoperation in patients who had undergone a lumbar laminectomy. METHODS: The authors retrospectively reviewed the electronic medical records of all patients who had undergone firsttime, bilateral laminectomy at 1, 2, or 3 levels for lumbar spondylosis at the authors' institution. Patients who underwent fusion, laminotomy, discectomy, or complete facetectomy were excluded. The patients' preoperative symptoms and comorbidities were also obtained from their medical records. RESULTS: Over an average follow-up period of 46.8 months, of 500 patients who had undergone laminectomy at 1, 2, or 3 levels, 81 patients (16.2%) developed subsequent spinal disorders that required a reoperation. A multiple logistic regression analysis identified smoking as an independent predictor of reoperation (OR 2.15, p = 0.01). Smoking was also an independent predictor of reoperation after a single-level laminectomy (OR 11.3, p = 0.02) and after a multilevel (that is, involving 2 or 3 levels) laminectomy (OR 1.98, p = 0.05). For 72 patients undergoing reoperation only for spinal degeneration, smoking remained an independent, statistically significant predictor of reoperation (OR 2.06, p = 0.04). Nine patients underwent reoperation for nondegenerative conditions (hematoma, wound infection, or wound dehiscence), and in these patients, chronic obstructive pulmonary disease was the only statistically significant predictor of reoperation (OR 8.92, p = 0.03). CONCLUSIONS: Smoking was the strongest predictor of reoperation in patients who had undergone single level laminectomy, multilevel laminectomy, or reoperation for progression of spinal degeneration. These findings suggest that smokers have worse outcomes of lumbar decompression than nonsmokers. PMID- 25555059 TI - A virtual screening approach for identifying plants with anti H5N1 neuraminidase activity. AB - Recent outbreaks of highly pathogenic and occasional drug-resistant influenza strains have highlighted the need to develop novel anti-influenza therapeutics. Here, we report computational and experimental efforts to identify influenza neuraminidase inhibitors from among the 3000 natural compounds in the Malaysian Plants Natural-Product (NADI) database. These 3000 compounds were first docked into the neuraminidase active site. The five plants with the largest number of top predicted ligands were selected for experimental evaluation. Twelve specific compounds isolated from these five plants were shown to inhibit neuraminidase, including two compounds with IC50 values less than 92 MUM. Furthermore, four of the 12 isolated compounds had also been identified in the top 100 compounds from the virtual screen. Together, these results suggest an effective new approach for identifying bioactive plant species that will further the identification of new pharmacologically active compounds from diverse natural-product resources. PMID- 25555060 TI - Identification of potent phosphodiesterase inhibitors that demonstrate cyclic nucleotide-dependent functions in apicomplexan parasites. AB - Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human pathogenesis is the asexual cycle, in which parasites undergo rounds of host cell invasion, replication, and egress (exit), destroying host cell tissue in the process. Previous work has identified important roles for Protein Kinase G (PKG) and Protein Kinase A (PKA) in parasite egress and invasion, yet little is understood about the regulation of cyclic nucleotides, cGMP and cAMP, that activate these enzymes. To address this, we have focused upon the development of inhibitors of 3',5'-cyclic nucleotide phosphodiesterases (PDEs) to block the breakdown of cyclic nucleotides. This was done by repurposing human PDE inhibitors noting various similarities of the human and apicomplexan PDE binding sites. The most potent inhibitors blocked the in vitro proliferation of P. falciparum and T. gondii more potently than the benchmark compound zaprinast. 5 Benzyl-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (BIPPO) was found to be a potent inhibitor of recombinant P. falciparum PfPDEalpha and activated PKG dependent egress of T. gondii and P. falciparum, likely by promoting the exocytosis of micronemes, an activity that was reversed by a specific Protein Kinase G inhibitor. BIPPO also promotes cAMP-dependent phosphorylation of a P. falciparum ligand critical for host cell invasion, suggesting that the compound inhibits single or multiple PDE isoforms that regulate both cGMP and cAMP levels. BIPPO is therefore a useful tool for the dissection of signal transduction pathways in apicomplexan parasites. PMID- 25555061 TI - Using the thickness of graphene to template lateral subnanometer gaps between gold nanostructures. AB - This work demonstrates the use of single-layer graphene as a template for the formation of subnanometer plasmonic gaps using a scalable fabrication process called "nanoskiving." These gaps are formed between parallel gold nanowires in a process that first produces three-layer thin films with the architecture gold/single-layer graphene/gold, and then sections the composite films with an ultramicrotome. The structures produced can be treated as two gold nanowires separated along their entire lengths by an atomically thin graphene nanoribbon. Oxygen plasma etches the sandwiched graphene to a finite depth; this action produces a subnanometer gap near the top surface of the junction between the wires that is capable of supporting highly confined optical fields. The confinement of light is confirmed by surface-enhanced Raman spectroscopy measurements, which indicate that the enhancement of the electric field arises from the junction between the gold nanowires. These experiments demonstrate nanoskiving as a unique and easy-to-implement fabrication technique that is capable of forming subnanometer plasmonic gaps between parallel metallic nanostructures over long, macroscopic distances. These structures could be valuable for fundamental investigations as well as applications in plasmonics and molecular electronics. PMID- 25555062 TI - Adsorption and viscoelastic analysis of polyelectrolyte-surfactant complexes on charged hydrophilic surfaces. AB - The aggregation of surfactants around oppositely charged polyelectrolytes brings about a peculiar bulk phase behavior of the complex, known as coacervation, and can control the extent of adsorption of the polyelectrolyte at an aqueous-solid interface. Adsorption kinetics from turbid premixed polyelectrolyte-surfactant mixtures have been difficult to measure using optical techniques such as ellipsometry and reflectometry, thus limiting the correlation between bulk phases and interfacial adsorption. Here, we investigated the adsorption from premixed solutions of a cationic polysaccharide (PQ10) and the anionic surfactant sodium dodecyl sulfate (SDS) on an amphoteric alumina surface using quartz crystal microbalance with dissipation (QCMD). The surface charge on the alumina was tuned by changing the pH of the premixed solutions, allowing us to assess the role of electrostatic interactions by studying the adsorption on both negatively and positively charged surfaces. We observed a maximum extent of adsorption on both negatively and positively charged surfaces from a solution corresponding to the maximum turbidity. Enhanced adsorption upon diluting the redissolved complexes at a high SDS concentration was seen only on the negatively charged surface, and not on the positively charged one, confirming the importance of electrostatic interactions in controlling the adsorption on a hydrophilic charged surface. Using the Voight based viscoelastic model, QCMD also provided information on the effective viscosity, effective shear modulus, and thickness of the adsorbed polymeric complex. The findings of viscoelastic analysis, corroborated by atomic force microscopy measurements, suggest that PQ10 by itself forms a flat, uniform layer, rigidly attached to the surface. The PQ10-SDS complex shows a heterogeneous surface structure, where the underlayer is relatively compact and tightly attached and the top is a loosely bound diffused overlayer, accounting for most of the adsorbate, which gets washed away upon rinsing. Understanding of the surface structure will have important implications toward understanding lubrication. PMID- 25555063 TI - Design for approaching Cicada-wing reflectance in low- and high-index biomimetic nanostructures. AB - Natural nanostructures in low refractive index Cicada wings demonstrate <= 1% reflectance over the visible spectrum. We provide design parameters for Cicada wing-inspired nanotip arrays as efficient light harvesters over a 300-1000 nm spectrum and up to 60 degrees angle of incidence in both low-index, such as silica and indium tin oxide, and high-index, such as silicon and germanium, photovoltaic materials. Biomimicry of the Cicada wing design, demonstrating gradient index, onto these material surfaces, either by real electron cyclotron resonance microwave plasma processing or by modeling, was carried out to achieve a target reflectance of ~ 1%. Design parameters of spacing/wavelength and length/spacing fitted into a finite difference time domain model could simulate the experimental reflectance values observed in real silicon and germanium or in model silica and indium tin oxide nanotip arrays. A theoretical mapping of the length/spacing and spacing/wavelength space over varied refractive index materials predicts that lengths of ~ 1.5 MUm and spacings of ~ 200 nm in high index and lengths of ~ 200-600 nm and spacings of ~ 100-400 nm in low-index materials would exhibit <= 1% target reflectance and ~ 99% optical absorption over the entire UV-vis region and angle of incidence up to 60 degrees . PMID- 25555064 TI - Dynamic biostability, biodistribution, and toxicity of L/D-peptide-based supramolecular nanofibers. AB - Self-assembling peptide nanofibers (including naturally L-amino acid-based and unnaturally D-amino acid-based ones) have been widely utilized in biomedical research. However, there has been no systematic study on their in vivo stability, distribution, and toxicity. Herein we systematically study the in vivo dynamic biostability, biodistribution, and toxicity of supramolecular nanofibers formed by Nap-GFFYGRGD (L-amino acid-based, L-fibers) and Nap-G(D)F(D)F(D)YGRGD (D-amino acid-based, D-fibers), respectively. The D-fibers have better in vitro and in vivo biostabilities than L-fibers. It is found that D-fibers keep a good integrity in plasma during 24 h, while half of l-fibers are digested upon incubation in plasma for 6 h. The biodistributions of L- and D-fibers are also studied using the iodine-125 radiolabeling technique. The results reveal that L fibers mainly accumulate in stomach, whereas d-fibers preferentially distribute in liver. Successive administrations of both L- and D-fibers with the dose of 30 mg/kg/dose cause no significant inflammation, liver and kidney function damages, immune reaction, and dysfunction of hematopoietic system. This study will provide fundamental guidelines for utilization of self-assembling peptide-based supramolecular nanomaterials in biomedical applications, such as drug delivery, bioimaging, and regenerative medicine. PMID- 25555065 TI - Correction to Bright, Color-Tunable Fluorescent Dyes Based on pi-Expanded Diketopyrrolopyrroles. PMID- 25555066 TI - Mental health and quality of life among veterans employed as peer and vocational rehabilitation specialists. AB - OBJECTIVE: The study compared employment experiences, mental health recovery, and quality of life among peer specialists and vocational rehabilitation (VR) specialists hired by the U.S. Department of Veterans Affairs (VA), the VR specialists under the Homeless Veterans Supported Employment Program. Employment characteristics associated with mental health recovery were examined. METHODS: The study was a national, observational survey of 152 peer specialists and 222 VR specialists across 138 VA health care systems in 49 states. The survey, administered over the Internet, included measures describing participant characteristics, employment factors, mental health, and quality of life. The two cohorts were compared by using t tests or chi square tests. Multiple regression analysis controlling for participant characteristics was used to identify employment factors associated with mental health and quality of life. RESULTS: Peer specialists were more likely than VR specialists to share recovery stories, serve as a role model or mentor, and advocate for veterans. Activities by VR specialists tended to focus more narrowly on job skills. Overall, after adjusting for multiple comparisons, the analysis found high levels of mental health and average quality of life for both cohorts, with no significant differences between the groups. Satisfaction with amount of supervision was consistently associated with aspects of mental health recovery, including work-related and helping related quality of life, for both cohorts. CONCLUSIONS: The results highlight the value of work and the importance of supervision in realizing both the adoption of recovery-oriented services and the promotion of mental health in a community of veterans serving each other. PMID- 25555067 TI - Systematic study on the sensitivity enhancement in graphene plasmonic sensors based on layer-by-layer self-assembled graphene oxide multilayers and their reduced analogues. AB - The use of graphene in conventional plasmonic devices was suggested by several theoretic research studies. However, the existing theoretic studies are not consistent with one another and the experimental studies are still at the initial stage. To reveal the role of graphenes on the plasmonic sensors, we deposited graphene oxide (GO) and reduced graphene oxide (rGO) thin films on Au films and their refractive index (RI) sensitivity was compared for the first time in SPR based sensors. The deposition of GO bilayers with number of deposition L from 1 to 5 was carried out by alternative dipping of Au substrate in positively- and negatively charged GO solutions. The fabrication of layer-by-layer self-assembly of the graphene films was monitored in terms of the SPR angle shift. GO-deposited Au film was treated with hydrazine to reduce the GO. For the rGO-Au sample, 1 bilayer sample showed a higher RI sensitivity than bare Au film, whereas increasing the rGO film from 2 to 5 layers reduced the RI sensitivity. In the case of GO-deposited Au film, the 3 bilayer sample showed the highest sensitivity. The biomolecular sensing was also performed for the graphene multilayer systems using BSA and anti-BSA antibody. PMID- 25555070 TI - The challenge of feedback-insights from non-medical educational research. PMID- 25555069 TI - Issues involved in the quantitative 3D imaging of proton doses using optical CT and chemical dosimeters. AB - Dosimetry of proton beams using 3D imaging of chemical dosimeters is complicated by a variation with proton linear energy transfer (LET) of the dose-response (the so-called 'quenching effect'). Simple theoretical arguments lead to the conclusion that the total absorbed dose from multiple irradiations with different LETs cannot be uniquely determined from post-irradiation imaging measurements on the dosimeter. Thus, a direct inversion of the imaging data is not possible and the proposition is made to use a forward model based on appropriate output from a planning system to predict the 3D response of the dosimeter. In addition to the quenching effect, it is well known that chemical dosimeters have a non-linear response at high doses. To the best of our knowledge it has not yet been determined how this phenomenon is affected by LET. The implications for dosimetry of a number of potential scenarios are examined.Dosimeter response as a function of depth (and hence LET) was measured for four samples of the radiochromic plastic PRESAGE((r)), using an optical computed tomography readout and entrance doses of 2.0 Gy, 4.0 Gy, 7.8 Gy and 14.7 Gy, respectively. The dosimeter response was separated into two components, a single-exponential low-LET response and a LET-dependent quenching. For the particular formulation of PRESAGE((r)) used, deviations from linearity of the dosimeter response became significant for doses above approximately 16 Gy. In a second experiment, three samples were each irradiated with two separate beams of 4 Gy in various different configurations. On the basis of the previous characterizations, two different models were tested for the calculation of the combined quenching effect from two contributions with different LETs. It was concluded that a linear superposition model with separate calculation of the quenching for each irradiation did not match the measured result where two beams overlapped. A second model, which used the concept of an 'effective dose' matched the experimental results more closely. An attempt was made to measure directly the quench function for two proton beams as a function of all four variables of interest (two physical doses and two LET values). However, this approach was not successful because of limitations in the response of the scanner. PMID- 25555071 TI - Olodaterol (Striverdi Respimat) for COPD. PMID- 25555072 TI - Oritavancin (Orbactiv) for skin and skin structure infections. PMID- 25555073 TI - Triumeq--a 3-drug combination for HIV. PMID- 25555074 TI - Trumenba: a serogroup B meningococcal vaccine. PMID- 25555075 TI - Siltuximab (Sylvant) for treatment of multicentric castleman's disease. PMID- 25555076 TI - Conducting core-shell nanowires by amyloid nanofiber templated polymerization. AB - The preparation of conducting polymer nanowires in aqueous solutions is a challenging goal, especially for applications in nanobioelectronics. Here, we show that amyloid nanofibers template the formation of conducting polyaniline nanowires with a core-shell architecture. The nanofibers exhibit hydrophobic pockets that presumably preassemble the aniline monomers. The template directs polymer morphology as it favors the formation of linear polymer chains, suppresses defects in the polymer chain which are detrimental to charge transport and induces chiral helicity into the polymer. This strategy has the potential of being applied to other polymers than polyaniline and might open up new possibilities to synthesize biocompatible and conducting polymer nanowires with prospects for applications in, for example, sensing, neuronal tissue engineering, and electrostimulated stem cell differentiation. PMID- 25555077 TI - Rain influences the physiological and metabolic responses to exercise in hot conditions. AB - Outdoor exercise often proceeds in rainy conditions. However, the cooling effects of rain on human physiological responses have not been systematically studied in hot conditions. The present study determined physiological and metabolic responses using a climatic chamber that can precisely simulate hot, rainy conditions. Eleven healthy men ran on a treadmill at an intensity of 70% VO2max for 30 min in the climatic chamber at an ambient temperature of 33 degrees C in the presence (RAIN) or absence (CON) of 30 mm . h(-1) of precipitation and a headwind equal to the running velocity of 3.15 +/- 0.19 m . s(-1). Oesophageal temperature, mean skin temperature, heart rate, rating of perceived exertion, blood parameters, volume of expired air and sweat loss were measured. Oesophageal and mean skin temperatures were significantly lower from 5 to 30 min, and heart rate was significantly lower from 20 to 30 min in RAIN than in CON (P < 0.05 for all). Plasma lactate and epinephrine concentrations (30 min) and sweat loss were significantly lower (P < 0.05) in RAIN compared with CON. Rain appears to influence physiological and metabolic responses to exercise in heat such that heat-induced strain might be reduced. PMID- 25555078 TI - Preliminary experience with self-expanding closed-cell stent placement in small arteries less than 2 mm in diameter for the treatment of intracranial aneurysms. AB - OBJECT: The purpose of this study was to report the authors' preliminary experience using self-expanding closed-cell stents deployed in small arteries (< 2 mm in diameter) to treat intracranial aneurysms. METHODS: A total of 31 patients were studied. All subjects met the following criteria: 1) they received an Enterprise stent for treatment of a wide-necked aneurysm or a dissecting aneurysm or as part of a stent-salvage procedure; and 2) they had an Enterprise stent deployed in a small parent artery (< 2 mm in diameter) that had no atherosclerotic stenosis. Procedure-related complications and follow-up sizes of the parent arteries were evaluated for safety and patency. RESULTS: There were 16 ruptured aneurysms and 15 unruptured aneurysms. Three (9.7%) of the 31 patients experienced procedure-related complications, and they all were asymptomatic. Follow-up angiography was performed in 27 patients (87.1%) (at a mean 15.5 months after surgery). Parent arteries with 2 acute angles (n = 4) were occluded in 3 cases (75.0%), and those with no acute angles (n = 13) or 1 acute angle (n = 6) showed 100% patency on follow-up angiography. There was a significant difference between the follow-up sizes (mean 1.72 +/- 0.30 mm) of parent arteries and their sizes (mean 1.59 +/- 0.26 mm) before treatment (95% CI - 0.254 to - 0.009 mm; p = 0.037, paired-samples t-test). CONCLUSIONS: In the current series the deployment of self-expanding closed-cell stents in small arteries was safe and resulted in good patency, especially when the stents were deployed in segments of the parent artery with no acute angles or only 1 acute angle. PMID- 25555079 TI - Microsurgical anatomy of the central lobe. AB - OBJECT: The central lobe consists of the pre- and postcentral gyri on the lateral surface and the paracentral lobule on the medial surface and corresponds to the sensorimotor cortex. The objective of the present study was to define the neural features, craniometric relationships, arterial supply, and venous drainage of the central lobe. METHODS: Cadaveric hemispheres dissected using microsurgical techniques provided the material for this study. RESULTS: The coronal suture is closer to the precentral gyrus and central sulcus at its lower rather than at its upper end, but they are closest at a point near where the superior temporal line crosses the coronal suture. The arterial supply of the lower two-thirds of the lateral surface of the central lobe was from the central, precentral, and anterior parietal branches that arose predominantly from the superior trunk of the middle cerebral artery. The medial surface and the superior third of the lateral surface were supplied by the posterior interior frontal, paracentral, and superior parietal branches of the pericallosal and callosomarginal arteries. The venous drainage of the superior two-thirds of the lateral surface and the central lobe on the medial surface was predominantly through the superior sagittal sinus, and the inferior third of the lateral surface was predominantly through the superficial sylvian veins to the sphenoparietal sinus or the vein of Labbe to the transverse sinus. CONCLUSIONS: The pre- and postcentral gyri and paracentral lobule have a morphological and functional anatomy that differentiates them from the remainder of their respective lobes and are considered by many as a single lobe. An understanding of the anatomical relationships of the central lobe can be useful in preoperative planning and in establishing reliable intraoperative landmarks. PMID- 25555080 TI - Commentary: Investing in the poorest girls in the poorest communities early enough to make a difference. PMID- 25555081 TI - Sorting of human mesenchymal stem cells by applying optimally designed microfluidic chip filtration. AB - Human bone marrow-derived mesenchymal stem cells (hMSCs) consist of heterogeneous subpopulations with different multipotent properties: small and large cells with high and low multipotency, respectively. Accordingly, sorting out a target subpopulation from the others is very important to increase the effectiveness of cell-based therapy. We performed flow-based sorting of hMSCs by using optimally designed microfluidic chips based on the hydrodynamic filtration (HDF) principle. The chip was designed with the parameters rigorously determined by the complete analysis of laminar flow for flow fraction and complicated networks of main and multi-branched channels for hMSCs sorting into three subpopulations: small (<25 MUm), medium (25-40 MUm), and large (>40 MUm) cells. By focusing with a proper ratio between main and side flows, cells migrate toward the sidewall due to a virtual boundary of fluid layers and enter the branch channels. This opens the possibility of sorting stem cells rapidly without damage. Over 86% recovery was achieved for each population of cells with complete purity in small cells, but the sorting efficiency of cells is slightly lower than that of rigid model particles, due to the effect of cell deformation. Finally, we confirmed that our method could successfully fractionate the three subpopulations of hMSCs by analyzing the surface marker expressions of cells from each outlet. PMID- 25555082 TI - Organotemplate-free synthesis of an open-framework magnesium aluminophosphate with proton conduction properties. AB - A new open-framework magnesium aluminophosphate MgAlP2O7(OH)(H2O)2 (denoted as JU102) has been hydrothermally synthesized by using an organotemplate-free synthetic route in the Al2O3-P2O5-MgO-H2O system. JU102 exhibits novel 4 connected zeolite-like topology with 8-ring channels. The existence of coordinated water and extensive H-bonds in the structure endows JU102 with unique proton conduction properties. PMID- 25555084 TI - Musical chairs and the role of specialist palliative care. PMID- 25555085 TI - "Why are we doing this?": clinician helplessness in the face of suffering. AB - BACKGROUND: When the brutality of illness outstrips the powers of medical technology, part of the fallout lands squarely on front-line clinicians. In our experience, this kind of helplessness has cognitive, emotional, and somatic components. OBJECTIVES: Could we approach our own experiences of helplessness differently? Here we draw on social psychology and neuroscience to define a new approach. METHODS: First, we show how clinicians can reframe helplessness as a self-barometer indicating their level of engagement with a patient. Second, we discuss how to shift deliberately from hyper- or hypo-engagement toward a constructive zone of clinical work, using an approach summarized as "RENEW": recognizing, embracing, nourishing, embodying, and weaving--to enable clinicians from all professional disciplines to sustain their service to patients and families. PMID- 25555086 TI - Hospice revocation with pleasure. PMID- 25555087 TI - Aspirin is associated with an increased risk of subdural hematoma in normal pressure hydrocephalus patients following shunt implantation. AB - OBJECT: In this paper the authors investigate whether shunt-treated patients with normal-pressure hydrocephalus receiving aspirin therapy are at increased risk of developing subdural hematoma (SDH). METHODS: Records from 80 consecutive patients who had undergone implantation of a cerebrospinal fluid shunt for the treatment of normal-pressure hydrocephalus were retrospectively reviewed. RESULTS: Eleven cases of symptomatic SDH occurred, all among patients receiving aspirin or clopidogrel. The 5-year survival estimate was 0.3 (p < 0.0001) for users of aspirin and the hazard ratio was 12.8 (95% CI 3.1-53). CONCLUSIONS: Patients on an aspirin therapy regimen have a markedly increased risk of SDH after a shunt has been implanted for the treatment of normal-pressure hydrocephalus. Users of clopidogrel may have an even greater risk. PMID- 25555089 TI - Biodegradable hydrogels composed of oxime crosslinked poly(ethylene glycol), hyaluronic acid and collagen: a tunable platform for soft tissue engineering. AB - In situ crosslinking hydrogels are attractive for application as injectable hydrogel-based tissue scaffolds that adapt to fill patient-specific cavities. Oxime click chemistry was used to crosslink hydrogels that were biodegradable, soft and supportive of cell adhesion. Linear poly(ethylene glycol)s (PEGs, Mn 2 or 4 kDa) terminated at both ends with aminooxy moieties and hyaluronic acid (HA, Mn 2 MDa) derivatives displaying aldehydes were non-toxic towards primary Schwann cells. The PEG and HA derivatives form oxime crosslinked hydrogels with mechanical and swelling properties that were tunable based on the composition of the hydrogels to values analogous to soft tissues such as those found in the central or peripheral nervous system. Gels incorporating collagen-1 supported the adhesion of human mesenchymal stem cells. Such chemistry has the potential to generate clinically relevant injectable hydrogels for minimally invasive personalized medical procedures in the central or peripheral nervous systems. PMID- 25555090 TI - Efficacy of surface roughness and bond strength of Y-TZP zirconia after various pre-treatments. AB - OBJECTIVE: The aim of this study was to evaluate surface roughness (SR) and the influence of various surface treatments (STs) on the veneer ceramic shear bond strength (SBS) to Y-TZP zirconia. BACKGROUND DATA: STs can improve the bonding properties of zirconia ceramics. However, little is known about the effect of Er,Cr:YSGG laser irradiation on SBS between zirconia and veneer ceramic/resin cement. METHODS: Eighty ceramic discs of yttria-tetragonal zirconia polycrystals (Y-TZP) were prepared, and specimens were divided into eight groups (n=10): untreated (control), air abrasion, and Er,Cr:YSGG laser irradiation with different energy intensities (1-6 W). Average SR of each specimen was determined with a profilometer, and a veneering ceramic recommended for zirconia was fired into cylinder-shaped Y-TZP specimens. SBS test was performed for each specimen at a crosshead speed of 1 mm/min, and the average means of SBS and SR were calculated. Fracture modes and the surface topography were evaluated with various microscopes after STs. Data were analyzed by using one way analysis of variance (ANOVA) and Tukey honest significant difference (HSD) tests. RESULTS: The highest mean force value was observed in the air abrasion group, and followed by 6 and 5 W laser irradiations, respectively. The difference between control and air abrasion groups was found to be statistically significant (p<0.05). All laser irradiations increased the SBS value, but 1 and 2 W laser irradiations showed no statistically significant differences compared with the control group. However, the SR value for air abrasion group was significantly higher than that of the control group and 1 W (p<0.05), and there were no significant differences between the SR of all the laser groups and the control group. CONCLUSIONS: The result of this study showed that STs with air abrasion and high laser energy intensities (3 6W), can improve the bonding properties of Y-TZP zirconia. PMID- 25555092 TI - State Partnerships for First-Episode Psychosis Services. AB - The RAISE (Recovery After an Initial Schizophrenia Episode) Connection Program was a partnership that involved state mental health authorities (SMHAs) in Maryland and New York with research funding from the National Institute of Mental Health. The SMHAs collaborated with researchers to implement a team-based approach designed to serve people with newly emerged schizophrenia to maximize recovery and minimize disability. This column explains why states are interested in first-episode psychosis services and describes the development of the successful partnership, financing mechanisms, and plans to add teams in both states. PMID- 25555091 TI - Thyroid dysfunction associated with follicular cell steatosis in obese male mice and humans. AB - Adult thyroid dysfunction is a common endocrine disorder associated with an increased risk of cardiovascular disease and mortality. A recent epidemiologic study revealed a link between obesity and increased prevalence of hypothyroidism. It is conceivable that excessive adiposity in obesity might lead to expansion of the interfollicular adipose (IFA) depot or steatosis in thyroid follicular cells (thyroid steatosis, TS). In this study, we investigated the morphological and functional changes in thyroid glands of obese humans and animal models, diet induced obese (DIO), ob/ob, and db/db mice. Expanded IFA depot and TS were observed in obese patients. Furthermore, DIO mice showed increased expression of lipogenesis-regulation genes, such as sterol regulatory element binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor gamma (PPARgamma), acetyl coenzyme A carboxylase (ACC), and fatty acid synthetase (FASN) in the thyroid gland. Steatosis and ultrastructural changes, including distension of the endoplasmic reticulum (ER) and mitochondrial distortion in thyroid follicular cells, were uniformly observed in DIO mice and genetically obese mouse models, ob/ob and db/db mice. Obese mice displayed a variable degree of primary thyroid hypofunction, which was not corrected by PPARgamma agonist administration. We propose that systemically increased adiposity is associated with characteristic IFA depots and TS and may cause or influence the development of primary thyroid failure. PMID- 25555093 TI - Reliability and validity of a GPS-enabled iPhone "app" to measure physical activity. AB - This study assessed the validity and reliability of an iPhone "app" and two sport specific global positioning system (GPS) units to monitor distance, intensity and contextual physical activity. Forty (23 female, 17 male) 18-55-year-olds completed two trials of six laps around a 400-m athletics track wearing GPSports Pro and WiSpi units (5 and 1 Hz) and an iPhone(TM) with a Motion X GPS(TM) "app" that used the inbuilt iPhone location services application programming interface to obtain its sampling rate (which is likely to be <=1 Hz). Overall, the statistical agreement, assessed using t-tests and Bland-Altman plots, indicated an underestimation of the known track distance (2.400 km) and average speed by the Motion X GPS "app" and GPSports Pro while the GPSports WiSpi(TM) device overestimated these outcomes. There was a <=3% variation between trials for distance and average speed when measured by any of the GPS devices. Thus, the smartphone "app" trialled could be considered as an accessible alternative to provide high-quality contextualised data to enable ubiquitous monitoring and modification of programmes to ensure appropriate intensity and type of physical activity is prescribed and more importantly adhered to. PMID- 25555094 TI - First case studies of successful ABO-incompatible living-related liver transplantation in infants in Germany. AB - AIM: A series study mainly from Asia suggests that ABO-incompatible (ABOi) living related liver transplantation (LRLT) for pediatric recipients is associated with excellent short- and long-term graft and patient survival. Until now, ABOi LRLT has been rarely performed in Europe. The aim of this study was to analyze the safety and early results of an ABOi LRLT in a German high-volume pediatric liver transplant center. METHODS: Six consecutive pediatric patients (four males and two females) were included in this prospective study from January, 2010 to January, 2013 with a median age of 13 months (range, 6-30 months) receiving ABOi LRLT and were matched with six patients receiving ABO-compatible LRLT in the same period. In the ABOi group, titers of IgG and IgM isoagglutinins against the donor's blood group were determined at day 14 before the transplantation and from day 1 to 14 after the transplantation, and then twice a week for another 8 weeks. The titer results were determined as the reciprocal number of the highest serum dilution that caused macroscopical reaction. RESULTS: The patients receiving ABOi and those receiving ABO-compatible LRLT were comparable regarding the recipient's preoperative pediatric end-stage liver disease (PELD), age, gender, and technical aspects of transplantation. The median follow-up was 2.6 years (range, 1-4.5 years). At the time of operation, the mean body weight was 7.7 kg (range, 5.7-16 kg) in ABO-compatible LRLT recipients and 8.8 kg (range, 5.5-18 kg) in ABOi LRLT recipients. In each group, the median PELD score was 28 (range, 28-35), respectively. All recipients received tacrolimus plus mycophenolate mofetil-based standard immunosuppression and four ABOi transplanted patients received intravenous immunoglobulins at days 1, 3, and 5 after liver transplantation. Patient and graft survival in this group was 83%. One female patient died within 24 hours due to fulminant gram-negative sepsis. Another patient developed acute cellular rejection at the 8th postoperative day, which responded to steroid treatment. No further complications occurred. In the ABO-compatible group, patient survival was 100% and graft survival was 83%; one patient in this group received retransplantation after 4 days. During follow-up, two patients of the ABOi group had maximum alloantibody titers of four against the donor's blood group; all other patients had titers below four. CONCLUSION: ABOi LRLT seems to be safe without an escalation of immunosuppression and should be considered as an additional option to timely facilitate the transplantation. PMID- 25555096 TI - Prevention of hydroxychloroquine-related retinal toxic effects. PMID- 25555097 TI - Effects of an exercise programme with people living with HIV: research in a disadvantaged setting. AB - This study aimed to analyse the physical health effects of a community based 10 week physical activity programme with people living with HIV. It was developed, implemented and evaluated in a disadvantaged community in South Africa. A pre post research design was chosen. Major recruitment and adherence challenges resulted in a small sample. Among the 23 participants who took part in both baseline and final testing, compliant participants (n = 12) were compared to non compliant participants (n = 11). Immunological (CD4, viral load), anthropometric (height, weight, skinfolds and waist to hip ratio), muscular strength (h1RM) and cardiopulmonary fitness (time on treadmill) parameters were measured. The compliant and non-compliant groups were not different at baseline. Muscular strength was the parameter most influenced by compliance with the physical activity programme (F = 4.516, p = 0.047). Weight loss and improvement in cardiopulmonary fitness were restricted by the duration of the programme, compliance and influencing factors (e.g. nutrition, medication). The increase in strength is significant and meaningful in the context, as the participants' goals were to look healthy and strong to avoid HIV related stigma. The improvements in appearance were a motivational factor, especially since the changes were made visible in a short time. Practical implications for health promotion are described. More research contextualised in disadvantaged settings is needed. PMID- 25555098 TI - The influence of biological factors on students' sexual behaviour at the University of KwaZulu-Natal, South Africa. AB - Studies in South African universities reveal that the prevalence of sexual risk behaviour is very high, putting many students at high risk of HIV infection. This study explored the biological influences on students' sexual taking behaviour at the University of KwaZulu-Natal, South Africa. A qualitative approach was used, comprising a total of 80 in-depth interviews and 4 focus group discussions. These were conducted between late 2008 and early 2010. The research had equal representation of male and female students, different races, two campuses and different levels of study. Factors associated with students' sexual behaviour were identified. The data were analysed using thematic analysis, and the themes identified form the basis for discussion in this paper. Students' sexual behaviour was positively associated with the influence of a range of biological factors. Factors such as age, judgement of the health of the partner by looking at appearances, pursuit of physical beauty, sexual debut, sexual fit, and search for sexual pleasure encouraged students to engage in sexual behaviour. Most students are young and lack experience in assessing the influence of biological factors on their sexual behaviours, and need education on biological factors. This poses a big challenge to controlling students' sexual behaviour, especially if HIV and sexually transmitted diseases prevention interventions are to be successful. PMID- 25555100 TI - HIV in Harare: the role and relevance of social stigma. AB - HIV is a significant social, political and economic problem in Zimbabwe. However, few researchers have explored peoples' experiences of living with HIV in that country. Drawing on 60 qualitative interviews conducted with Zimbabweans living in Harare in 2010, this paper focuses on how people from four different urban communities cope with HIV-related social stigma. To provide theoretical context to this issue, we utilised the ideas of Erving Goffman for exploring the individual experience of stigma and the concept of structural violence to understand stigma as a social phenomenon. This paper considers the relevance and role of stigma in the context of a country undergoing significant social, political and economic crisis. We investigated the strategies adopted by the Zimbabwean state and the influence of traditional and religious interpretations to appreciate the historical roots of HIV-related stigma. We took into account the ways in which the articulation of HIV with gender has caused women to experience stigma differently than men, and more intensely, and how grassroots activism and biomedical technologies have transformed the experience of stigma. PMID- 25555099 TI - Mobile health for early retention in HIV care: a qualitative study in Kenya (WelTel Retain). AB - Many people newly diagnosed with HIV are lost to follow-up before timely initiation of antiretroviral therapy (ART). A randomised controlled trial (RCT), WelTel Kenya1, demonstrated the effectiveness of the WelTel text messaging intervention to improve clinical outcomes among patients initiating ART. In preparation for WelTel Retain, an RCT that will evaluate the effect of the intervention to retain patients in care immediately following HIV diagnosis, we conducted an informative qualitative study with people living with HIV (n = 15) and healthcare providers (HCP) (n = 5) in October 2012. Study objectives included exploring the experiences of people living with HIV who have attempted to engage in HIV care, the use of cell phones in everyday life, and perceptions of communicating via text message with HCP. Participants were recruited through convenience sampling. Semi-structured, qualitative interviews were conducted and recorded, transcribed verbatim and analysed using NVivo software. Analysis was guided by the Theory of Reasoned Action and the Technology Acceptance Model. Results indicate that while individuals have many motivators for engaging in care after diagnosis, structural and individual barriers including poverty, depression and fear of stigma prevent them from doing so. All participants had access to a mobile phone, and most were comfortable communicating through text messages, or were willing to learn. Both people living with HIV and HCP felt that increased communication via the text messaging intervention has the potential to enable early identification of problems, leading to timely problem solving that may improve retention and engagement in care during the first year after diagnosis. PMID- 25555101 TI - Generational inversions: 'working' for social reproduction amid HIV in Swaziland. AB - How do people envision social reproduction when regular modes of generational succession and continuity are disrupted in the context of HIV/AIDS? How and where can scholars identify local ideas for restoring intergenerational practices of obligation and dependency that produce mutuality rather than conflict across age groups? Expanding from studies of HIV/AIDS and religion in Africa, this article pushes for an analytic engagement with ritual as a space and mode of action to both situate local concerns about and practices for restoring dynamics of social reproduction. It describes how the enduring HIV/AIDS epidemic in Swaziland contoured age patterns of mortality where persons identified socially and chronologically as youth have predeceased their elders. Based on discourse analyses of ethnography at church worship services and life cycle rites between 2008 and 2011, the findings show how both elders and youth understood this crisis of 'generational inversions' as a non-alignment of age groups and articulated projects to restore succession and continuity in vernacular idioms of 'work' as moralised social and ritual action. PMID- 25555102 TI - Racing risk, gendering responsibility: a qualitative study of how South African students talk about sexual risk and responsibility. AB - Individuals' perceptions of risk have implications for whether and how they engage with protective strategies. This study investigated how sexual risk, specifically HIV and pregnancy and responsibility for these risks were constructed in discussions across five groups of youth in KwaZulu-Natal, South Africa. The qualitative study used focus groups and interviews with a sample of 28 tertiary level students and 7 peri-urban youth. The constructions of risk intersected with raced and gendered narratives around sexual risk and responsibility. These constructions were used by the participants to assign and displace responsibility for the risks of HIV and pregnancy, rendering some groups immune to these risks. This constitutes a form of stigmatisation and also has implications for participants' prevention practices. PMID- 25555103 TI - Communication characteristics of young children with HIV in South Africa as reported by some physicians. AB - HIV has been shown to have significant effects on the development of a child. Currently, there is limited South African research regarding HIV and specific characteristics of communication development, and the treatment thereof, in the child infected with HIV. The objective of the research was to describe the communication characteristics of a group of children between the ages of 0 and 5 years infected with HIV at a hospital in Gauteng, South Africa. Clinic records of 203 children infected with HIV between the ages of 0 and 5 years were reviewed using a pre-designed checklist within the outreach clinic of a large regional hospital. A questionnaire was completed by four medical practitioners working with this population within the outreach clinic. A total of 91.62% of the infected children were diagnosed as being either in Stage III or IV of the disease (according to the WHO classification system of 2005), with all infants presenting with a CD4 count of <= 60. Most (75.37% of the total sample) were receiving Highly Active Antiretroviral Therapy (HAART) at the time the data were collected. According to their medical, social, communication and general development, almost all the children qualified for Early Communication Intervention (ECI) but were not recorded as being referred for such services. A large proportion of the target population presented with opportunistic infections and/or HIV associated conditions. The results highlight the developmental characteristics of children living with HIV, and identify the need for medical doctors and allied health professionals to be provided with relevant literature or training regarding the communication development of children infected with HIV. This will facilitate appropriate referrals for ECI services. PMID- 25555104 TI - Practice of sumo kodhi among the Luo and implications for HIV transmission in western Kenya. AB - This paper discusses the practice of sumo kodhi among the Luo ethnic group and its implications for spread of HIV in western Kenya. Sumo kodhi is a practice in which a woman arranges to have sex with a man other than her legitimate sexual partner (husband or levir/inheritor) to give birth to children with specific qualities she wants in them. Data were drawn from a 16-month ethnographic study on reproductive aspirations of women living with HIV/AIDS (WLWHA). The study found that WLWHA engaged in sumo kodhi as they believe they will get gender balanced, beautiful, and academically talented and healthy children who are free from HIV. The WLWHA targeted agnates of their husbands living in distant villages, former boyfriends (before marriage) and other men who were new in the area such as civil servants, employees in local institutions and businessmen who would not suspect their HIV status. These WLWHA kept their HIV status secret and exposed the targeted men to the risk of being infected with HIV. It can be deduced that having knowledge of HIV status does not always translate into taking action towards protecting sexual partner(s). Moreover, continued childbearing is not always as a result of unmet contraceptives needs. It is apparent from this study that social factors sometimes overrule health considerations. The study recommends that further research be conducted among other ethnic groups to gauge whether they also have a practice similar to sumo kodhi. Women living with HIV/AIDS should be involved in HIV/AIDS control and prevention strategies. There is also need for an intervention that would ensure that WLWHA meet their reproductive aspirations without putting their sexual partners at risk of contracting HIV. PMID- 25555105 TI - Willingness to participate in future HIV prevention trials in Beira, Mozambique. AB - In preparation for trials of new HIV prevention methods, willingness to participate (WTP) was assessed in Beira, Mozambique. A total of 1 019 women participating in an HIV incidence study, and 97 men participating in a separate WTP survey, were interviewed. When comparing the answers to questions that were identical in the two studies, WTP was higher among women than men for all prevention methods. Among women, WTP was highest for trials evaluating daily oral pre-exposure prophylaxis (PrEP; 84.4% reporting very likely to participate), followed by vaccination (77.8%), daily vaginal gel use (67.7%), coital vaginal gel use (67.1%) and monthly vaginal ring use (47.7%). Among men, WTP was highest for trials evaluating vaccination (57.6%), followed by daily vaginal gel use for female sexual partners (52.5%), daily oral PrEP (49.5%), coital vaginal gel use for female sexual partners (46.4%) and monthly vaginal ring use for female sexual partners (39.4%). Among men, the most important motivators for trial participation were social benefits, whereas personal risks (most notably receiving injections and/or blood draws) were deterrents; this was not assessed in women. Other important lessons learnt are that male circumcision and antiretroviral drugs were not generally recognised as ways to prevent HIV, that having to use hormonal contraception during trial participation will likely reduce WTP, and that evening clinics are not likely to be popular. The barriers reported in this and other studies may be challenging but are not impossible to overcome. PMID- 25555106 TI - Indications, clinical course, and postoperative outcomes of urgent adenotonsillectomy in children. AB - IMPORTANCE: Children undergoing urgent adenotonsillectomy have been poorly described in literature. OBJECTIVE: To characterize the clinical course and outcomes of patients who underwent urgent adenotonsillectomy. DESIGN, SETTING, AND PARTICIPANTS: A 7-year retrospective medical record review of patients undergoing urgent adenotonsillectomy (study group) at a tertiary care pediatric hospital was undertaken. Comparisons were made between the study group and the control group consisting of children undergoing adenotonsillectomy following diagnostic polysomnography. INTERVENTIONS: Retrospective medical record review with no study interventions. MAIN OUTCOMES AND MEASURES: Demographics, hospital course, and clinical outcomes. RESULTS: A total of 35 patients (21 boys [60%] and 14 girls [40%]; mean age, 3.8 years) were identified as having undergone urgent adenotonsillectomy defined as severe obstructive sleep apnea with associated hypoxemia unresponsive to oxygen. The control group included 301 patients who received a diagnostic polysomnogram prior to nonurgent adenotonsillectomy. Patients undergoing urgent adenotonsillectomy patients were more likely to be younger than 3 years (54%) than nonurgent patients (P < .001) and were characterized by elevated obstructive apnea-hypopnea indices (average, 39.4 events per hour). Persistent desaturation below 80% despite at least 0.5 L of supplemental oxygen was the most common admission indication (83%). Obesity was the most frequent comorbidity (9 patients [31%]). Two patients (6%) experienced a major postoperative complication requiring intervention. Fifteen patients (43%) were discharged with supplemental oxygen. Two patients (6%) were admitted to the hospital more than 72 hours after surgery. CONCLUSIONS AND RELEVANCE: Patients requiring urgent adenotonsillectomy are marked by younger age, elevated obstructive apnea-hypopnea indices, and persistent desaturations below 80% unresponsive to supplemental oxygen. Following surgery, some children have a dramatic improvement in gas exchange and will no longer require supplemental oxygen. PMID- 25555110 TI - RUNX2: A Master Bone Growth Regulator That May Be Involved in the DNA Damage Response. AB - RUNX2 is a member of the RUNX family of transcription factors, also containing the RUNX1 and RUNX3 proteins. These factors control the expression of genes essential for proper development in many cell lineages. RUNX2 plays a crucial role in the proliferation and differentiation of osteoblasts, required for bone formation. The cellular level of RUNX2 oscillates in a cell phase-specific manner, reaching a maximum at G2/M in some cells and overexpression of RUNX2 in osteoblasts blocked G1 to S phase progression. Recent studies have shown that RUNX2 may interact with p53 and change the activity of a histone deacetylase. Moreover, RUNX2 may act as an oncogene in cancer transformation, inevitably associated with genomic instability evoked by increased occurrence of DNA damage. We showed that some RUNX2 modifiers changed the sensitivity of differentiating preosteoblasts to DNA damage induced by oxidative stress. All these data suggest the involvement of RUNX2 in cellular DNA damage response (DDR), which is particularly important in osteogenesis as the process of osteoblast differentiation is associated with increasing oxidative stress. However, the mechanism underlying DDR involvement of RUNX2 is unknown. The basic question, whether RUNX2 plays a positive or destructive role in DDR in differentiating cells is still open. PMID- 25555109 TI - Improvement in binocular summation after strabismus surgery. AB - IMPORTANCE: Binocular summation (BiS), or improvement in visual acuity using binocular vision compared with the better eye alone, is diminished in patients with strabismus. However, it is still not known how strabismus surgery affects BiS. OBJECTIVE: To determine whether BiS improves after strabismus surgery. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 97 patients undergoing strabismus surgery between September 1, 2011, and January 31, 2014, comparing preoperative and postoperative measures of BiS. Patients were recruited within 1 month before undergoing strabismus surgery. The study took place at an academic pediatric ophthalmology and strabismus practice. INTERVENTION: Strabismus surgery. MAIN OUTCOMES AND MEASURES: All patients underwent high- and low contrast visual acuity testing binocularly and monocularly at preoperative and 2 month postoperative visits. Binocular summation was calculated for high-contrast Early Treatment of Diabetic Retinopathy Study charts and Sloan low-contrast acuity charts at 2.5% and 1.25% contrast as the difference between the binocular score and that of the better eye. Preoperative and postoperative values were compared. RESULTS: There was an improvement in BiS at the 2 low-contrast levels for all patients and for all contrast levels in the 75 patients in whom surgery successfully restored binocular alignment. For low-contrast acuity, the proportion of patients with a BiS score of at least 5 letters postoperatively was almost twice that of preoperatively (21% to 30% and 13% to 26% for 2.5% contrast and 1.25% contrast, respectively). Similarly, the proportion of patients with binocular inhibition (BiS score worse by at least 5 letters than the better eye score) was decreased postoperatively at all contrast levels (from 22% to 14% for 1.25% contrast). Thirty-one percent of patients experienced improvement in BiS scores postoperatively at the lowest contrast level. CONCLUSIONS AND RELEVANCE: Binocular summation scores improved postoperatively in most patients undergoing strabismus surgery. This occurred most frequently at the lowest contrast level. These findings suggest that improved BiS could represent a newly recognized functional benefit from the surgical correction of strabismus. Further studies evaluating the correlation of BiS with stereopsis, visual field expansion, and quality of life will be necessary to fully evaluate the role that improved BiS has in improving binocularity postoperatively. PMID- 25555107 TI - The activating oxydianion binding domain for enzyme-catalyzed proton transfer, hydride transfer, and decarboxylation: specificity and enzyme architecture. AB - The kinetic parameters for activation of yeast triosephosphate isomerase (ScTIM), yeast orotidine monophosphate decarboxylase (ScOMPDC), and human liver glycerol 3 phosphate dehydrogenase (hlGPDH) for catalysis of reactions of their respective phosphodianion truncated substrates are reported for the following oxydianions: HPO3(2-), FPO3(2-), S2O3(2-), SO4(2-) and HOPO3(2-). Oxydianions bind weakly to these unliganded enzymes and tightly to the transition state complex (E.S(?)), with intrinsic oxydianion Gibbs binding free energies that range from -8.4 kcal/mol for activation of hlGPDH-catalyzed reduction of glycolaldehyde by FPO3(2 ) to -3.0 kcal/mol for activation of ScOMPDC-catalyzed decarboxylation of 1-beta d-erythrofuranosyl)orotic acid by HOPO3(2-). Small differences in the specificity of the different oxydianion binding domains are observed. We propose that the large -8.4 kcal/mol and small -3.8 kcal/mol intrinsic oxydianion binding energy for activation of hlGPDH by FPO3(2-) and S2O3(2-), respectively, compared with activation of ScTIM and ScOMPDC reflect stabilizing and destabilizing interactions between the oxydianion -F and -S with the cationic side chain of R269 for hlGPDH. These results are consistent with a cryptic function for the similarly structured oxydianion binding domains of ScTIM, ScOMPDC and hlGPDH. Each enzyme utilizes the interactions with tetrahedral inorganic oxydianions to drive a conformational change that locks the substrate in a caged Michaelis complex that provides optimal stabilization of the different enzymatic transition states. The observation of dianion activation by stabilization of active caged Michaelis complexes may be generalized to the many other enzymes that utilize substrate binding energy to drive changes in enzyme conformation, which induce tight substrate fits. PMID- 25555111 TI - Charging YOYO-1 on capillary wall for online DNA intercalation and integrating this approach with multiplex PCR and bare narrow capillary-hydrodynamic chromatography for online DNA analysis. AB - Multiplex polymerase chain reaction (PCR) has been widely utilized for high throughput pathogen identification. Often, a dye is used to intercalate the amplified DNA fragments, and identifications of the pathogens are carried out by DNA melting curve analysis or gel electrophoresis. Integrating DNA amplification and identification is a logic path toward maximizing the benefit of multiplex PCR. Although PCR and gel electrophoresis have been integrated, replenishing the gels after each run is tedious and time-consuming. In this technical note, we develop an approach to address this issue. We perform multiplex PCR inside a capillary, transfer the amplified fragments to a bare narrow capillary, and measure their lengths online using bare narrow capillary-hydrodynamic chromatography (BaNC-HDC), a new technique recently developed in our laboratory for free-solution DNA separation. To intercalate the DNA with YOYO-1 (a fluorescent dye) for BaNC-HDC, we flush the capillary column with a YOYO-1 solution; positively charged YOYO-1 is adsorbed (or charged) onto the negatively charged capillary wall. As DNA molecules are driven down the column for separation, they react with the YOYO-1 stored on the capillary wall and are online-intercalated with the dye. With a single YOYO-1 charging, the column can be used for more than 40 runs, although the fluorescence signal intensities of the DNA peaks decrease gradually. Although the dye-DNA intercalation occurs during the separation, it does not affect the retention times, separation efficiencies, or resolutions. PMID- 25555112 TI - Craniopharyngioma arising in a Rathke's cleft cyst: case report. AB - Craniopharyngioma is one of the most common non-glial intracranial tumors of childhood. Its relation to Rathke's cleft cyst (RCC) is controversial, and both lesions have been hypothesized to lie on a continuum of cystic ectodermal lesions of the sellar region. The authors report on a 7-year-old boy who presented with decreased visual acuity, presumably of at least 2 years' duration, and was found to have a 5.2-cm sellar lesion with rim enhancement. Histological examination of the resected lesion showed a mixture of areas with simple RCC morphology with focal squamous metaplasia and areas with typical craniopharyngioma morphology. Immunohistochemical staining with CK20 and Ki 67 differentially highlighted the 2 morphological components. Testing for beta-catenin and BRAF mutations was negative in the craniopharyngioma component, precluding definitive molecular classification. Follow-up imaging showed minimal residual enhancement and the patient will be closely followed up with serial MRI. Given the clinical and histological findings in the case, a progressive transformation of the RCC to craniopharyngioma seems to be the most plausible explanation for the co occurrence of the 2 lesion types in this patient. An extensive review of previously proposed theories of the relationship between craniopharyngioma and RCC is also presented. PMID- 25555113 TI - Extent of collateralization predicting symptomatic cerebral vasospasm among pediatric patients: correlations among angiography, transcranial Doppler ultrasonography, and clinical findings. AB - OBJECT: Although the development and prevalence of cerebral vasospasm (CV) has been extensively investigated in adults, little data exist on the development of CV in children. The authors hypothesized that even though children have highly vasoreactive arteries, because of a robust cerebral collateral blood flow, they rarely develop symptomatic CV. METHODS: The authors retrospectively reviewed their university hospital's neurointerventional database for children (that is, patients <= 18 years) who were examined or treated for aneurysmal or traumatic subarachnoid hemorrhage (SAH) during the period 1990-2013. Images from digital subtraction angiography (DSA) were analyzed for the extent of CV and collateralization of the cerebral circulation. Results from transcranial Doppler (TCD) ultrasonography were correlated with those from DSA. Cerebral vasospasm on TCD ultrasonography was defined according to criteria developed for adults. Clinical outcomes of CV were assessed with the pediatric modified Rankin Scale (mRS). RESULTS: Among 37 children (21 boys and 16 girls ranging in age from 8 months to 18 years) showing symptoms of an aneurysmal SAH (comprising 32 aneurysms and 5 traumatic pseudoaneurysms), 17 (46%) had CV confirmed by DSA; CV was mild in 21% of these children, moderate in 50%, and severe in 29%. Only 3 children exhibited symptomatic CV, all of whom had poor collateralization of cerebral vessels. Among the 14 asymptomatic children, 10 (71%) showed some degree of vessel collateralization. Among 16 children for whom TCD data were available that could be correlated with the DSA findings, 13 (81%) had CV according to TCD criteria. The sensitivity and specificity of TCD ultrasonography for diagnosing CV were 95% and 59%, respectively. The time to CV onset detected by TCD ultrasonography was 5 +/- 3 days (range 2-10 days). Twenty-five (68%) of the children had good long-term outcomes (that is, had mRS scores of 0-2). CONCLUSIONS: Children have a relatively high incidence of angiographically detectable, moderate-to-severe CV. Children rarely develop symptomatic CV and have good long-term outcomes, perhaps due to robust cerebral collateral blood flow. Criteria developed for detecting CV with TCD ultrasonography in adults overestimate the prevalence of CV in children. Larger studies are needed to define TCD ultrasonography-based CV criteria for children. PMID- 25555114 TI - Flow diversion for complex intracranial aneurysms in young children. AB - Pediatric intracranial aneurysms are exceedingly rare and account for less than 5% of all intracranial aneurysms. Open surgery to treat such aneurysms has been shown to be more durable than endovascular techniques, and durability of treatment is particularly important in the pediatric population. Over the past 2 decades, however, a marked shift in aneurysm treatment from open surgery toward endovascular procedures has occurred for adults. The authors describe their early experience in treating 3 unruptured pediatric brain aneurysms using the Pipeline embolization device (PED). The first patient, a girl with Majewski osteodysplastic primordial dwarfism Type II who was harboring multiple intracranial aneurysms, underwent two flow diversion procedures for a vertebrobasilar aneurysm and a supraclinoid internal carotid artery aneurysm. The second patient underwent PED placement on a previously coiled but enlarging posterior communicating artery aneurysm. All procedures were uneventful, with no postsurgical complications, and led to complete angiographic obliteration of the aneurysms. To the authors' knowledge, this is the first series of flow diversion procedures in children reported in the medical literature. While flow diversion is a new and relatively untested technology in children, outcomes in adults have been promising. For challenging lesions in the pediatric population, flow diversion may have a valuable role as a well-tolerated, safe treatment with durable results. Many issues remain to be addressed, such as the durability of flow diverters over a very long follow-up and vessel response to growth in the presence of an endoluminal device. PMID- 25555115 TI - Occipital aneurysmal bone cyst rupture following head trauma: case report. AB - Aneurysmal bone cysts (ABCs) are benign, expansile, osteolytic lesions that represent 1%-2% of primary bone tumors. Cranial ABCs are even more rare and represent 3%-6% of these unique lesions. The authors describe the case of a 3 year-old girl who presented with an acute posterior fossa epidural hematoma after minor trauma. Imaging workup revealed a previously undiagnosed suboccipital ABC that appeared to have ruptured as a result of her trauma, leading to a life threatening hemorrhage. To the authors' knowledge, a ruptured ABC has never before been presented in the pediatric literature. In this case report, the authors review the imaging findings, natural history, clinical course, and treatment of these rare lesions. PMID- 25555116 TI - High occurrence of head and spine injuries in the pediatric population following motocross accidents. AB - OBJECT: Off-road motorcycling is a very popular sport practiced by countless people worldwide. Despite its popularity, not much has been published on the severity and distribution of central nervous system-related injuries associated with this activity in the pediatric population. The purpose of this study was to confirm, characterize, and document the rate of head and spine injuries associated with off-road motorcycling in this population. METHODS: All patients aged 18 years or less who were treated for a motorbike injury at the authors' institution (a Level 1 regional trauma center) between 2000 and 2007 were identified through in-house surgical and trauma registries. Type, mechanism, and severity of CNS-related injuries were assessed, including: incidence of traumatic brain injury (TBI), loss of consciousness (LOC), Glasgow Coma Scale (GCS) score, head CT findings, neurological deficits, spinal fractures, cervical strain, and use of protective gear, including helmets. RESULTS: During the 8-year period of study, 298 accidents were evaluated in 248 patients. The patients' mean age at the time of injury was 14.2 +/- 2.7 years. Head injury or TBI was identified in 60 (20.1%) of 298 cases (involving 58 of 248 patients). Fifty-seven cases were associated with LOC, and abnormalities were identified on head CT in 10 patients; these abnormalities included skull fractures and epidural, subdural, subarachnoid, and intraparenchymal hemorrhages. The GCS score was abnormal in 11 cases and ranged from 3 to 15, with an overall mean of 14.5. No patients required cranial surgery. Helmet use was confirmed in 43 (71.6%) of the cases involving TBI. Spine fractures were identified in 13 patients (4.3%) and 5 required surgical fixation for their injury. CONCLUSIONS: The authors found a high occurrence of head injuries following pediatric off-road motorcycle riding or motocross accidents despite the use of helmets. Additionally, this study severely underestimates the rate of mild TBIs in this patient population. Our data indicate that motocross is a high-risk sport despite the use of protective gear. Riders and parents should be counseled accordingly about the risks prior to participation. PMID- 25555117 TI - Ventriculoiliac shunt: a cadaveric feasibility study. AB - OBJECT: Additional distal sites for placement of CSF diversionary shunts may be necessary in some patients. The present study aimed to investigate the marrow space of the ilium as a potential receptacle for CSF in patients with hydrocephalus. METHODS: Cannulation of the marrow space of the ilium was performed in 5 fresh human cadavers less than 4 hours from time of death. Tap water was infused via a metal trocar for approximately 60 minutes. RESULTS: A total of 30 L of water was easily injected into all cadaveric specimens without overflow from the infusion site or noticeable edema of the body. Upon inspection of the thoracic and abdominal cavities, no fluid accumulation was identified, ensuring that all infused fluid had gone into the vascular system. CONCLUSIONS: Based on this cadaveric study, the ilium appears to be an ideal location for placement of the distal end of a CSF diversionary shunt when other anatomical receptacles are not an option. In vivo human studies are now required to verify these findings. PMID- 25555118 TI - The feasibility and safety of using sublaminar polyester bands in hybrid spinal constructs in children and transitional adults for neuromuscular scoliosis. AB - OBJECT: The authors have previously reported on their early experience with sublaminar polyester bands in spine surgery. In this paper, the authors describe the use of sublaminar polyester bands in long-segment posterior instrumented spinal fusions from the upper thoracic spine to the ilium in 21 children and transitional adults with progressive neuromuscular scoliosis. Transitional adults were patients older than 18 years of age with a spinal disorder of pediatric onset, such as spina bifida. This dedicated study represents the first reported use of polyester bands in spine surgery for neuromuscular scoliosis in this patient population in the US. METHODS: The authors retrospectively reviewed the demographics and procedural data of patients who underwent posterior instrumented fusion using sublaminar polyester bands for neuromuscular scoliosis. RESULTS: Twenty-one pediatric and adult transitional patients, ranging in age from 10 to 20 years (mean 14 years), underwent posterior instrumented fusion for progressive neuromuscular scoliosis. The average coronal Cobb angle measured 66 degrees before surgery (range 37 degrees -125 degrees ). Immediately after surgery, the mean coronal Cobb angle was 40 degrees (range 13 degrees -85 degrees ). At last follow-up, the average coronal Cobb angle was maintained at 42 degrees (range 5 degrees -112 degrees ). Regarding sagittal parameters, thoracic kyphosis was restored by 8%, and lumbar lordosis improved by 20% after surgery. Mean follow-up duration was 17 months (range 2-54 months). One patient with an aborted procedure due to loss of intraoperative evoked potentials was excluded from the analysis of radiographic outcomes. Mean surgical time was 7 hours 43 minutes (range 3 hours 59 minutes to 10 hours 23 minutes). All patients received either a 12- or 24-mg dose of recombinant human bone morphogenetic protein-2. Average estimated blood loss was 976 ml (range 300-2700 ml). Complications directly related to the use of sublaminar instrumentation included transient proprioceptive deficit (1 patient) and prolonged paraparesis (1 patient). Other complications noted in this series included disengagement of the rod from an iliac screw (1 patient), proximal junctional kyphosis (1 patient), noninfected wound drainage (2 patients), and perioperative death (1 patient). The lessons learned from these complications are discussed. CONCLUSIONS: Pedicle screws, laminar/pedicle/transverse process hooks, and sublaminar metal wires have been incorporated into posterior spinal constructs and widely reported and used in the thoracic and lumbar spines and sacrum with varying success. This report demonstrates the satisfactory radiological outcomes of hybrid posterior spinal constructs in pediatric and adult neuromuscular scoliosis that include sublaminar polyester bands that promise the technical ease of passing sublaminar instrumentation with the immediate biomechanical rigidity of pedicle screws and hooks. However, the high neurological complication rate associated with this technique (2/21, or 10%) tempers the acceptable radiographic outcomes. PMID- 25555119 TI - Subdural to subgaleal shunts: alternative treatment in infants with nonaccidental traumatic brain injury? AB - OBJECT: The ideal treatment for subdural hematomas (SDHs) in infants remains debated. The aim of this study was to analyze the safety and efficiency of subduro-subgaleal drainage in SDH. METHODS: The authors conducted a single-center open-label study between August 2011 and May 2012. Data were prospectively collected in a database and retrospectively analyzed. RESULTS: Eighteen patients (male/female ratio 1.25) with a median age of 5 months were surgically treated. All had preoperative symptoms of intracranial hypertension or seizures. The SDH was bilateral in 16 cases, with a median width of 12 mm. Success of the procedure was noted in 14 of the 18 patients. There was no intraoperative complication or postoperative infection. Drainage failure was attributable to suboptimal positioning of the subdural drain in 2 cases and to migration in 1 case. CONCLUSIONS: Subduro-subgaleal drainage is an efficient treatment that could be proposed as an alternative to external subdural drainage or subduroperitoneal drainage. PMID- 25555120 TI - Degenerative changes in adolescent spines: a comparison of motocross racers and age-matched controls. AB - OBJECT: Motocross racing is a popular sport; however, its impact on the growing/developing pediatric spine is unknown. Using a retrospective cohort model, the authors compared the degree of advanced degenerative findings in young motocross racers with findings in age-matched controls. METHODS: Patients who had been treated for motocross-related injury at the authors' institution between 2000 and 2007 and had been under 18 years of age at the time of injury and had undergone plain radiographic or CT examination of any spinal region were eligible for inclusion. Imaging was reviewed in a blinded fashion by 3 physicians for degenerative findings, including endplate abnormalities, loss of vertebral body height, wedging, and malalignment. Acute pathological segments were excluded. Spine radiographs from age-matched controls were similarly reviewed and the findings were compared. RESULTS: The motocross cohort consisted of 29 riders (mean age 14.7 years; 82% male); the control cohort consisted of 45 adolescents (mean age 14.3 years; 71% male). In the cervical spine, the motocross cohort had 55 abnormalities in 203 segments (average 1.90 abnormalities/patient) compared with 20 abnormalities in 213 segments in the controls (average 0.65/patient) (p = 0.006, Student t-test). In the thoracic spine, the motocross riders had 51 abnormalities in 292 segments (average 2.04 abnormalities/patient) compared with 25 abnormalities in 299 segments in the controls (average 1.00/patient) (p = 0.045). In the lumbar spine, the motocross cohort had 11 abnormalities in 123 segments (average 0.44 abnormalities/patient) compared with 15 abnormalities in 150 segments in the controls (average 0.50/patient) (p = 0.197). CONCLUSIONS: Increased degenerative changes in the cervical and thoracic spine were identified in adolescent motocross racers compared with age-matched controls. The long-term consequences of these changes are unknown; however, athletes and parents should be counseled accordingly about participation in motocross activities. PMID- 25555121 TI - Concussion symptoms in youth motocross riders: a prospective, observational study. AB - OBJECT: Action motorsports, including motocross, have been gaining popularity among children and adolescents, raising concerns for increased risk of concussions in participating youth. The authors undertook this study to test the following hypotheses: 1) that there is a high rate of concussion symptoms associated with a number of preventable or adjustable risk factors, and 2) that a high percentage of these symptoms are not be reported to adults and medical personnel. METHODS: The authors identified all motocross riders under the age of 18 at a regional racetrack during the riding season between May and October 2010. The participants completed questionnaires pertaining to demographic characteristics and variables associated with motocross. The questionnaire results were compared with the incidence of self-reported concussion symptoms. RESULTS: Two hundred two riders were identified who met the criteria for participation in the study, and 139 of them completed the study questionnaire. Of these 139 riders, 67 (48%) reported at least 1 concussion symptom during the season. The majority of riders (98%) reported "always" wearing a helmet, and 72% received professional help with fitting of their helmets. Proper helmet fitting was associated with a 41% decreased risk of concussion symptoms (RR 0.59, 95% CI 0.44-0.81, p < 0.01). Sixty-six riders (47%) reported having received sponsor support for motocross participation. Sponsor support conferred a relative risk for concussion symptoms of 1.48 (95% CI 1.05-2.08, p = 0.02). CONCLUSIONS: Nearly half of all motocross competitors under the age of 18 reported concussion symptoms. Preventive measures are necessary to limit the negative impact from concussions. The risk of concussive injury can be decreased for pediatric motocross riders if they receive professional help with proper helmet fitting and through implementation of stricter guidelines regarding sponsorship. PMID- 25555122 TI - Primitive neuroectodermal tumors of the brainstem in children treated according to the HIT trials: clinical findings of a rare disease. AB - OBJECT: Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) arising in the brainstem are extremely rare, and knowledge about them is limited. The few existing case series report fatal outcomes. The purpose of this study was to analyze clinical characteristics of and outcome for brainstem CNS-PNET patients treated according to the consecutive, population-based HIT studies covering a 19-year time period. METHODS: Between September 1992 and November 2011, 6 eligible children with histologically proven brainstem CNS-PNET not otherwise specified and 2 children with brainstem ependymoblastomas (3, partial resection; 3, subtotal resection; 2, biopsy), median age 3.3 years (range 1.2 10.6 years), were treated according to consecutive multimodal HIT protocols for CNS-PNET/medulloblastoma. Postoperative treatment was according to maintenance chemotherapy protocols (3, craniospinal irradiation [CSI] followed by maintenance chemotherapy), sandwich chemotherapy protocols (2, neoadjuvant chemotherapy, CSI, maintenance chemotherapy), or a therapy protocol for children younger than 4 years (3, postoperative chemotherapy followed by CSI). RESULTS: The median duration of prediagnostic symptoms, predominantly cranial nerve deficits (n = 7), pyramidal tract signs (n = 5), or ataxia (n = 5), was 5 weeks (range 1-13 weeks). The tumors were all located in the pons. Most involved more than half of the pontine axial diameter and were sharply marginated. All patients had postoperative residual disease, including metastasis in 1 case. With 1 exception all tumors progressed early during treatment within 3.9 months (range 2.5-10.4 months), leading to a 1-year event-free survival rate (+/- standard error) of 13% +/- 12%. After progression, patients succumbed early to their disease resulting in a 1-year overall survival rate of 25% +/- 15%. The only surviving patient had a partially resected CNS-PNET, received a sandwich chemotherapy protocol, and is without disease progression 14 months after diagnosis. CONCLUSIONS: CNS-PNET is a rare but important differential diagnosis in childhood brainstem tumors. So far, efficient therapies are lacking. The sampling of tumor material for improved biological understanding and identification of new therapeutic targets is important. PMID- 25555124 TI - About the effect of eye blinking on drug release from pHEMA-based hydrogels: an in vitro study. AB - The development of new ophthalmic drug delivery systems capable of increasing the residence time of drugs in the eye and improve its bioavailability relatively to eyedrops has been object of intense research in recent years. Several studies have shown that drug-loaded therapeutic soft contact lenses (SCLs) constitute a promising approach, with several potential advantages as compared with collyria. The main objective of this work is to study the effect of repetitive load and friction cycles caused by the eye blinking, on the drug release from hydrogels used in SCLs which, as far as we know, was never investigated before. Two poly-2 hydroxyethylmethacrylate-based hydrogels, pHEMA-T and pHEMA-UV, were used as model materials. Levofloxaxin was chosen as model drug. The hydrogels were fully characterized in what concerns structural and physicochemical properties. pHEMA UV revealed some superficial porosity and a lower short-range order than pHEMA-T. We observe that the load and friction cycles enhanced the drug release from pHEMA UV hydrogels. The application of a simple mathematical model, which takes into account the drug dilution caused by the tear flow, showed that the enhancement of the drug release caused by blinking on this hydrogel may be relevant in in vivo conditions. Conversely, the more sustained drug release from pHEMA-T is not affected by load and friction cycles. The conclusion is that, depending on the physicochemical and microstructural characteristics of the hydrogels, blinking is a factor that may affect the amount of drug delivered to the eye by SCLs and should thus be considered. PMID- 25555125 TI - Evaluating input device usability as a function of task difficulty in a tracking task. AB - Game controllers are emerging as a preferred choice for the manual control of unmanned vehicles, but an understanding of their usability characteristics has yet to emerge. We compared the usability of an Xbox 360 game controller in a dual task situation using MATB II to the traditional joystick and keyboard interface in two experiments. In the first experiment, performance with the game controller was associated with fewer tracking errors. In a second experiment, we trained users on the devices, and found that even after training the game controller was still associated with fewer tracking errors as well as higher usability and lower workload ratings. These results are consistent with the idea that game controllers are highly usable input devices and do not require high mental workload to operate, thus making them suitable for complex control tasks. PMID- 25555126 TI - Nanotubular J-aggregates and quantum dots coupled for efficient resonance excitation energy transfer. AB - Resonant coupling between distinct excitons in organic supramolecular assemblies and inorganic semiconductors is supposed to offer an approach to optoelectronic devices. Here, we report on colloidal nanohybrids consisting of self-assembled tubular J-aggregates decorated with semiconductor quantum dots (QDs) via electrostatic self-assembly. The role of QDs in the energy transfer process can be switched from a donor to an acceptor by tuning its size and thereby the excitonic transition energy while keeping the chemistry unaltered. QDs are located within a close distance (<4 nm) to the J-aggregate surface, without harming the tubular structures and optical properties of J-aggregates. The close proximity of J-aggregates and QDs allows the strong excitation energy transfer coupling, which is around 92% in the case of energy transfer from the QD donor to the J-aggregate acceptor and approximately 20% in the reverse case. This system provides a model of an organic-inorganic light-harvesting complex using methods of self-assembly in aqueous solution, and it highlights a route toward hierarchical synthesis of structurally well-defined supramolecular objects with advanced functionality. PMID- 25555127 TI - Catalytic divergent synthesis of 3H or 1H pyrroles by [3 + 2] cyclization of allenoates with activated isocyanides. AB - The cyclization of allenoates with activated isocyanides was reported for the first time. While Ag catalysis led to an unprecedented enantioselective synthesis of 3H pyrroles, a simple procedure using PPh3 produced a wide range of polysubstituted 1H pyrroles with high efficiency. PMID- 25555128 TI - High electrokinetic energy conversion efficiency in charged nanoporous nitrocellulose/sulfonated polystyrene membranes. AB - The synthesis, characterization, and electrokinetic energy conversion performance have been investigated experimentally in a charged polymeric membrane based on a blend of nitrocellulose and sulfonated polystyrene. The membrane is characterized by a moderate ion exchange capacity and a relatively porous structure with average pore diameter of 11 nm. With electrokinetic energy conversion, pressure can be converted directly into electric energy and vice versa. From the electrokinetic transport properties, a remarkably large intrinsic maximum efficiency of 46% is found. It is anticipated that the results are an experimental verification of theoretical models that predict high electrokinetic energy conversion efficiency in pores with high permselectivity and hydrodynamic slip flow. Furthermore, the result is a promising step for obtaining efficient low-cost electrokinetic generators and pumps for small or microscale applications. PMID- 25555129 TI - Site-specific reactivity of nonenzymatic lysine acetylation. AB - Protein acetylation of lysine epsilon-amino groups is abundant in cells, particularly within mitochondria. The contribution of enzyme-catalyzed and nonenzymatic acetylation in mitochondria remains unresolved. Here, we utilize a newly developed approach to measure site-specific, nonenzymatic acetylation rates for 90 sites in eight native purified proteins. Lysine reactivity (as second order rate constants) with acetyl-phosphate and acetyl-CoA ranged over 3 orders of magnitude, and higher chemical reactivity tracked with likelihood of dynamic modification in vivo, providing evidence that enzyme-catalyzed acylation might not be necessary to explain the prevalence of acetylation in mitochondria. Structural analysis revealed that many highly reactive sites exist within clusters of basic residues, whereas lysines that show low reactivity are engaged in strong attractive electrostatic interactions with acidic residues. Lysine clusters are predicted to be high-affinity substrates of mitochondrial deacetylase SIRT3 both in vitro and in vivo. Our analysis describing rate determination of lysine acetylation is directly applicable to investigate targeted and proteome-wide acetylation, whether or not the reaction is enzyme catalyzed. PMID- 25555131 TI - Core-shell structure, biodegradation, and drug release behavior of poly(lactic acid)/poly(ethylene glycol) block copolymer micelles tuned by macromolecular stereostructure. AB - Poly(ethylene glycol)-b-poly(L-lactic acid)-b-poly(D-lactic acid) (PEG-b-PLLA-b PDLA) stereoblock copolymers were synthesized by sequential ring-opening polymerization. Their micelle formation, precise micelle structure, biodegradation, and drug release behavior were systematically investigated and compared with the PEG-b-poly(lactic acid) (PEG-b-PLA) diblock copolymers with various PLA stereostructures and PEG-b-PLLA/PEG-b-PDLA enantiomeric mixture. Stereoblock copolymers having comparable PLLA and PDLA block lengths and enantiomerically-mixed copolymers assemble into the stereocomplexed core-shell micelles, while the isotactic and atactic PEG-b-PLA copolymers formed the homocrystalline and amorphous micelles, respectively. The PLA segments in stereoblock copolymer micelles show smaller crystallinity than those in the isotactic and enantiomerically-mixed ones, attributed to the short block length and presence of covalent junction between PLLA and PDLA blocks. As indicated by the synchrotron radiation small-angle X-ray scattering results, the stereoblock copolymer micelles have larger size, micellar aggregation number, core radius, smaller core density, and looser packing of core-forming segments than the isotactic and enantiomerically-mixed copolymer micelles. These unique structural characteristics cause the stereoblock copolymer micelles to possess higher drug loading content, slower degradation, and drug release rates. PMID- 25555130 TI - Phenotypic regulation of the sphingosine 1-phosphate receptor miles apart by G protein-coupled receptor kinase 2. AB - The evolutionarily conserved DRY motif at the end of the third helix of rhodopsin like, class-A G protein-coupled receptors (GPCRs) is a major regulator of receptor stability, signaling activity, and beta-arrestin-mediated internalization. Substitution of the DRY arginine with histidine in the human vasopressin receptor results in a loss-of-function phenotype associated with diabetes insipidus. The analogous R150H substitution of the DRY motif in zebrafish sphingosine-1 phosphate receptor 2 (S1p2) produces a mutation, miles apart m(93) (mil(m93)), that not only disrupts signaling but also impairs heart field migration. We hypothesized that constitutive S1p2 desensitization is the underlying cause of this strong zebrafish developmental defect. We observed in cell assays that the wild-type S1p2 receptor is at the cell surface whereas in distinct contrast the S1p2 R150H receptor is found in intracellular vesicles, blocking G protein but not arrestin signaling activity. Surface S1p2 R150H expression could be restored by inhibition of G protein-coupled receptor kinase 2 (GRK2). Moreover, we observed that beta-arrestin 2 and GRK2 colocalize with S1p2 in developing zebrafish embryos and depletion of GRK2 in the S1p2 R150H miles apart zebrafish partially rescued cardia bifida. The ability of reduced GRK2 activity to reverse a developmental phenotype associated with constitutive desensitization supports efforts to genetically or pharmacologically target this kinase in diseases involving biased GPCR signaling. PMID- 25555132 TI - Broca's area - thalamic connectivity. AB - Broca's area is crucially involved in language processing. The sub-regions of Broca's area (pars triangularis, pars opercularis) presumably are connected via corticocortical pathways. However, growing evidence suggests that the thalamus may also be involved in language and share some of the linguistic functions supported by Broca's area. Functional connectivity is thought to be achieved via corticothalamic/thalamocortical white matter pathways. Our study investigates structural connectivity between Broca's area and the thalamus, specifically ventral anterior nucleus and pulvinar. We demonstrate that Broca's area shares direct connections with these thalamic nuclei and suggest a local Broca's area thalamus network potentially involved in linguistic processing. Thalamic connectivity with Broca's area may serve to selectively recruit cortical regions storing multimodal features of lexical items and to bind them together during lexical-semantic processing. In addition, Broca's area-thalamic circuitry may enable cortico-thalamo-cortical information transfer and modulation between BA 44 and 45 during language comprehension and production. PMID- 25555133 TI - Anticancer activity expressed by a library of 2,9-diazaperopyrenium dications. AB - Polyaromatic compounds are well-known to intercalate DNA. Numerous anticancer chemotherapeutics have been developed upon the basis of this recognition motif. The compounds have been designed such that they interfere with the role of the topoisomerases, which control the topology of DNA during the cell-division cycle. Although many promising chemotherapeutics have been developed upon the basis of polyaromatic DNA intercalating systems, these candidates did not proceed past clinical trials on account of their dose-limiting toxicity. Herein, we discuss an alternative, water-soluble class of polyaromatic compounds, the 2,9 diazaperopyrenium dications, and report in vitro cell studies for a library of these dications. These investigations reveal that a number of 2,9 diazaperopyrenium dications show similar activities as doxorubicin toward a variety of cancer cell lines. Additionally, we report the solid-state structures of these dications, and we relate their tendency to aggregate in solution to their toxicity profiles. The addition of bulky substituents to these polyaromatic dications decreases their tendency to aggregate in solution. The derivative substituted with 2,6-diisopropylphenyl groups proved to be the most cytotoxic against the majority of the cell lines tested. In the solid state, the 2,6 diisopropylphenyl-functionalized derivative does not undergo pi...pi stacking, while in aqueous solution, dynamic light scattering reveals that this derivative forms very small (50-100 nm) aggregates, in contrast with the larger ones formed by dications with less bulky substituents. Alteration of the aromaticitiy in the terminal heterocycles of selected dications reveals a drastic change in the toxicity of these polyaromatic species toward specific cell lines. PMID- 25555135 TI - Two-liquid phase partitioning biotrickling filters for methane abatement: exploring the potential of hydrophobic methanotrophs. AB - The potential of two-liquid phase biotrickling filters (BTFs) to overcome mass transfer limitations derived from the poor aqueous solubility of CH4 has been scarcely investigated to date. In this context, the abatement of diluted methane emissions in two-liquid phase BTFs was evaluated using two different inocula: a type II methanotrophs culture in BTF 1 and a hydrophobic microbial consortium capable of growing inside silicone oil in BTF 2. Both BTFs supported stable elimination capacities above 45 g m(-3) h(-1) regardless of the inoculum, whereas no improvement derived from the presence of hydrophobic microorganisms compared to the type II metanotrophs culture was observed. Interestingly, the addition of silicone oil mediated a reduced metabolites concentration in the recycling aqueous phase, thus decreasing the needs for mineral medium renewal. Moreover, a 78% similarity was recorded between the microbial communities enriched in both BTFs at the end of the experimental period in spite of the differences in the initial inoculum structure. The results obtained confirmed the superior performance of two-liquid phase BTFs for CH4 abatement compared with conventional biotrickling filters. PMID- 25555134 TI - Identification, phylogeny and expression analysis of suppressors of cytokine signaling in channel catfish. AB - The suppressors of cytokine signaling (SOCS) family genes play important roles in regulating a variety of signal transduction pathways that are involved in immunity, growth and development. Because of their importance, they have been extensively studied in mammalian species, but they have not been systematically studied among teleost fish species. In this study, a total of 12 SOCS genes were characterized to understand the molecular mechanisms of SOCS function in channel catfish. Phylogenetic analyses suggested that all SOCS were clustered into two main clusters. Further syntenic analysis confirmed the phylogenetic analyses and allowed the annotation of SOCS genes in channel catfish. This work, for the first time, determined the expression profiles of the 12 SOCS genes after bacterial infections with Flavobacterium columnare and Edwardsiella ictaluri in channel catfish. The SOCS1a and SOCS3a were significantly up-regulated at 4h after F. columnare challenge in the gill, but were down-regulated at later stages of pathogenesis. Similarly, SOCS1a and CISH were significantly up-regulated at 3h in intestine under E. ictaluri infection, but were down-regulated at later stages of pathogenesis at 24h and 3 days after infection. These expression patterns may indicate that SOCS genes could be induced in acute immune responses after bacterial infections, but the massive cytokine expression, especially chemokine expression after the first day of infection may have had negative feedback leading to the overall down-regulation of the expression of SOCS genes. Moreover, the differential expression patterns of SOCS genes in the catfish gill and intestine after F. columnare and E. ictaluri infection demonstrated that the regulation of SOCS gene expression was both tissue-specific and time-dependent. Taken together, these results suggested that SOCS genes were involved in immune responses to bacterial invasions, and these results set the foundation for future studies of SOCS gene functions. PMID- 25555137 TI - Individuals with bipolar disorder and their relationship with the criminal justice system: a critical review. AB - OBJECTIVE: Bipolar disorder is a severe and prevalent psychiatric disease. Poor outcomes include a high frequency of criminal acts, imprisonments, and repeat offenses. This critical review of the international literature examined several aspects of the complex relationship between individuals with bipolar disorder and the criminal justice system: risk factors for criminal acts, features of bipolar patients' incarceration, and their postrelease trajectories. METHODS: Publications were obtained from the PubMed and Google Scholar electronic databases by using the following MeSH headings: prison, forensic psychiatry, criminal law, crime, and bipolar disorder. RESULTS: Among patients with bipolar disorder, the frequency of violent criminal acts is higher than in the general population (odds ratio [OR]=2.8, 95% confidence interval [CI]=1.8-4.3). The frequency is higher among patients with bipolar disorder and a comorbid substance use disorder than among those without either disorder (OR=10.1, CI=5.3-19.2). As a result, the prevalence of bipolar disorder among prisoners is high (2%-7%). In prison, patients' bipolar disorder symptoms can complicate their relationship with prison administrators, leading to an increased risk of multiple incarcerations. Moreover, the risk of suicide increases for these prisoners. CONCLUSIONS: Criminal acts are common among patients with bipolar disorder and are often associated with problems such as addiction. Thus it is important to improve the diagnosis and treatment of inmates with bipolar disorder. PMID- 25555136 TI - Life cycle assessment of resource recovery from municipal solid waste incineration bottom ash. AB - Bottom ash, the main solid output from municipal solid waste incineration (MSWI), has significant potential for the recovery of resources such as scrap metals and aggregates. The utilisation of these resources ideally enables natural resources to be saved. However, the quality of the recovered scrap metals may limit recycling potential, and the utilisation of aggregates may cause the release of toxic substances into the natural environment through leaching. A life cycle assessment (LCA) was applied to a full-scale MSWI bottom ash management and recovery system to identify environmental breakeven points beyond which the burdens of the recovery processes outweigh the environmental benefits from valorising metals and mineral aggregates. Experimental data for the quantity and quality of individual material fractions were used as a basis for LCA modelling. For the aggregates, three disposal routes were compared: landfilling, road sub base and aggregate in concrete, while specific leaching data were used as the basis for evaluating toxic impacts. The recovery and recycling of aluminium, ferrous, stainless steel and copper scrap were considered, and the importance of aluminium scrap quality, choice of marginal energy technologies and substitution rates between primary and secondary aluminium, stainless steel and ferrous products, were assessed and discussed. The modelling resulted in burdens to toxic impacts associated with metal recycling and leaching from aggregates during utilisation, while large savings were obtained in terms of non-toxic impacts. However, by varying the substitution rate for aluminium recycling between 0.35 and 0.05 (on the basis of aluminium scrap and secondary aluminium alloy market value), it was found that the current recovery system might reach a breakeven point between the benefits of recycling and energy expended on sorting and upgrading the scrap. PMID- 25555138 TI - Engineering the plant rhizosphere. AB - Plant natural products are low molecular weight compounds playing important roles in plant survival under biotic and abiotic stresses. In the rhizosphere, several groups of plant natural products function as semiochemicals that mediate the interactions of plants with other plants, animals and microorganisms. The knowledge on the biosynthesis and transport of these signaling molecules is increasing fast. This enables us to consider to optimize plant performance by changing the production of these signaling molecules or their exudation into the rhizosphere. Here we discuss recent advances in the understanding and metabolic engineering of these rhizosphere semiochemicals. PMID- 25555139 TI - STR profiling of epithelial cells identified by X/Y-FISH labelling and laser microdissection using standard and elevated PCR conditions. AB - During the investigation of allegations of sexual assault, samples are frequently encountered that contain DNA from a female and a male donor. These may represent contributions of DNA from the complainant and potentially, the offender. Many semen stained samples successfully undergo DNA analysis and interpretation using a differential extraction method that separates sperm from the epithelial cells present in the stain. However, for those mixed cell samples that contain only epithelial cells, separation of any male cells from female cells is problematic. This paper describes the application of fluorescent in situ hybridisation (FISH) for the gender identification of epithelial cells and subsequent recovery of target cells using laser microdissection (LMD). The profiling results obtained from samples of known cell numbers using the IdentifilerTM multiplex at standard 28-cycle PCR conditions and, when cell numbers are low, the SGM PlusTM multiplex at elevated 34-cycle PCR conditions (also known as Low Copy Number DNA analysis (LCN)) are described. PMID- 25555140 TI - Mild palladium-catalyzed cyanation of (hetero)aryl halides and triflates in aqueous media. AB - A mild, efficient, and low-temperature palladium-catalyzed cyanation of (hetero)aryl halides and triflates is reported. Previous palladium-catalyzed cyanations of (hetero)aryl halides have required higher temperatures to achieve good catalytic activity. This current reaction allows the cyanation of a general scope of (hetero)aryl halides and triflates at 2-5 mol % catalyst loadings with temperatures ranging from rt to 40 degrees C. This mild method was applied to the synthesis of lersivirine, a reverse transcriptase inhibitor. PMID- 25555142 TI - Development of certain novel N-(2-(2-(2-oxoindolin-3 ylidene)hydrazinecarbonyl)phenyl)-benzamides and 3-(2-oxoindolin-3-ylideneamino) 2-substituted quinazolin-4(3H)-ones as CFM-1 analogs: design, synthesis, QSAR analysis and anticancer activity. AB - The reaction of N-(2-(hydrazinecarbonyl)aryl)benzamides 2a, b with indoline-2,3 diones 4ae in acidified ethanolic solution furnished the corresponding N-(2-(2-(2 oxoindolin-3-ylidene)hydrazinecarbonyl)phenyl)benzamides 5aj, respectively. Furthermore, 3-(2-oxoindolin-3-ylideneamino)-2-substituted quinazolin-4(3H)-ones 6aj were prepared by the reaction of 3-amino-2-arylquinazolin-4(3H)-one 3a, b with 4ae. Six derivatives of the twenty newly synthesized compounds showed remarkable antitumor activity against most of the tested cell lines, Daoy, UW228 2, Huh-7, Hela and MDA-MB231. Although these six compounds were more potent than the standard drug (CFM-1), indeed compounds 5b, 5d and 6b were the best candidates with IC50 values in the range 1.866.87, 4.4210.89 and 1.468.60 MUg/ml and percentage inhibition in the range 77.188.7, 59.4184.8 and 75.488.0%, respectively. QSAR analyses on the current series of derivatives also have been performed for all five cancer cell lines and thus 10 statistically significant models were developed and internally cross validated. PMID- 25555141 TI - Structural exploration, synthesis and pharmacological evaluation of novel 5 benzylidenethiazolidine-2,4-dione derivatives as iNOS inhibitors against inflammatory diseases. AB - In our previous work, 3I inhibited the LPS-induced iNOS activity and NO production in RAW 264.7 cells and improved joint inflammation and cartilage destruction in inflammatory model. In this study, we synthesized 59 derivatives and bioisosteres on the basis of 3I by Knoevenagel condensation and biologically evaluated for the study of structure-activity relationship (SAR). We found that 7 44 suppressed the iNOS activity (IC50 25.2 MUM) and LPS-induced NO production (IC50 45.6 MUM) in RAW 264.7 cells. As for the SAR study, the dimethoxylphenyl group of 7-44 was potential for a further modification. At a dose of 10 mg/kg, oral administration of 7-44 possessed protective properties in both carrageenan induced paw edema of male ICR mice and adjuvant-induced arthritis of Lewis female rats. Although the activity of 7-44 was slightly inferior, the PK profiles of 7 44 were superior to those of 3I. PMID- 25555144 TI - New excited-state proton transfer mechanisms for 1,8 dihydroxydibenzo[a,h]phenazine. AB - The excited state intramolecular proton transfer (ESIPT) mechanisms of 1,8 dihydroxydibenzo[a,h]phenazine (DHBP) in toluene solvent have been investigated based on time-dependent density functional theory (TD-DFT). The results suggest that both a single and double proton transfer mechanisms are relevant, in constrast to the prediction of a single one proposed previously (Piechowska et al. J. Phys. Chem. A 2014, 118, 144-151). The calculated results show that the intramolecular hydrogen bonds were formed in the S0 state, and upon excitation, the intramolecular hydrogen bonds between -OH group and pyridine-type nitrogen atom would be strengthened in the S1 state, which can facilitate the proton transfer process effectively. The calculated vertical excitation energies in the S0 and S1 states reproduce the experimental UV-vis absorption and fluorescence spectra well. The constructed potential energy surfaces of the S0 and S1 states have been used to explain the proton transfer process. Four minima have been found on the S1 state surface, with potential barriers between these excited state minima of less than 10 kcal/mol, which supports concomitant single and double proton transfer mechanisms. In addition, the fluorescence quenching can be explained reasonably based on the proton transfer process. PMID- 25555143 TI - Towards novel 5-HT7versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: design, synthesis, and antidepressant properties. Part II. AB - A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4 tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970. PMID- 25555145 TI - Case report and review of lumbar hernia. AB - Lumbar hernias are uncommon and about 300 cases have been reported till date. They commonly occur due to trauma, surgery and infection. They are increasingly being reported after motor vehicle collision injuries. However, spontaneous lumbar hernias are rare and are reported infrequently. It is treated with different surgical approaches and methods. We report a case of primary spontaneous lumbar hernia which was repaired by transperitonial laparoscopic approach using Vypro (polypropylene/polyglactin) mesh and covered with a peritoneal flap. PMID- 25555146 TI - Group A Streptococci: A rare and often misdiagnosed cause of spontaneous bacterial peritonitis in adults. AB - INTRODUCTION: Acute primary peritonitis due to group A Streptococci (GAS) is a rare but life-threatening infection. Unlike other forms of primary peritonitis it affects predominantly young previously healthy individuals and thus is often confused with the more frequent secondary peritonitis. A case series of three patients is presented as well as a review of the literature focusing on pitfalls in the diagnose and therapy of GAS peritonitis. METHODS: A retrospective analysis of three patients with primary GAS peritonitis was performed. Furthermore a systematic review of all cases of primary GAS peritonitis published from 1990 to 2013 was performed comparing demographics and clinical presentation, as well as radiological imaging, treatment and outcome. RESULTS: All three female patients presented initially with high fever, nausea and severe abdominal pain. Radiological imaging revealed intraperitoneal fluid collections of various degrees, but no underlying cause of peritonitis. Broad antibiotic treatment was started and surgical exploration was performed for acute abdomen in all three cases. Intraoperatively fibrinous peritonitis was observed, but the correct diagnosis was not made until microbiological analysis confirmed GAS peritonitis. One patient died within 24h after admission. The other two patients recovered after multiple surgeries and several weeks on the intensive care unit due to multiple organ dysfunction syndrome. The fulminant clinical course of the three patients resembled those of many of the published cases: flu-like symptoms, high fever, severe acute abdominal pain and fibrinous peritonitis without obvious infectious focus were the most common symptoms reported in the literature. CONCLUSION: GAS primary peritonitis should be considered in particular in young, previously healthy women who present with peritonitis but lack radiological findings of an infectious focus. The treatment of choice is immediate antibiotic therapy. Surgical intervention is difficult to avoid, since the diagnosis of GAS peritonitis is usually not confirmed until other causes of secondary peritonitis have been excluded. PMID- 25555147 TI - Piezosurgery: A new and safe technique for distraction osteogenesis in Pierre Robin sequence review of the literature and case report. AB - INTRODUCTION: Pierre Robin sequence (PRS) is characterized by microgenia and retrognathia. Cleft palate and glossoptosis are frequently associated with airway obstruction and difficulty in swallowing. Distraction osteogenesis with micro distractors has recently been considered as a surgical option during the neonatal age. CASE PRESENTATION: A 6-week-old female with PRS underwent mandibular lengthening in neonatal age. Mandibular osteotomies were performed with the piezoelectric scalpel. DISCUSSION: Piezosurgery represents an innovative technique as it offers the maxillofacial surgeon the opportunity to make precise bone cuts without damaging the soft tissue, minimizing the invasiveness of the surgical procedure, and the opportunity of working in a field which is almost totally blood free. CONCLUSION: The use of a piezoelectric device to perform this kind of surgery provides clinical and surgical results which would be difficult with traditional instruments, not only for the patient's benefit but also for the surgeon's. Preservation of the original bony structure, especially of the cancellous bone, will benefit the bone healing process due to its high estrogenic potential. PMID- 25555148 TI - Measurement of intracellular ribavirin mono-, di- and triphosphate using solid phase extraction and LC-MS/MS quantification. AB - Ribavirin (RBV) is a nucleoside analog used to treat a variety of DNA and RNA viruses. RBV undergoes intracellular phosphorylation to a mono- (MP), di- (DP), and triphosphate (TP). The phosphorylated forms have been associated with the mechanisms of antiviral effect observed in vitro, but the intracellular pharmacology of the drug has not been well characterized in vivo. A highly sensitive LC-MS/MS method was developed and validated for the determination of intracellular RBV MP, DP, and TP in multiple cell matrix types. For this method, the individual MP, DP, and TP fractions were isolated from lysed intracellular matrix using strong anion exchange solid phase extraction, dephosphorylated to parent RBV, desalted and concentrated and quantified using LC-MS/MS. The method utilized a stable labeled internal standard (RBV-(13)C5) which facilitated accuracy (% deviation within +/-15%) and precision (coefficient of variation of <=15%). The quantifiable linear range for the assay was 0.50 to 200 pmol/sample. The method was applied to the measurement of RBV MP, DP, and TP in human peripheral blood mononuclear cells (PBMC), red blood cells (RBC), and dried blood spot (DBS) samples obtained from patients taking RBV for the treatment of chronic Hepatitis C virus infection. PMID- 25555149 TI - Identification of a cell cycle-dependent duplicating complex that assembles basal bodies de novo in Naegleria. AB - During the differentiation of the amoeba Naegleria pringsheimi into a flagellate, a transient complex containing gamma-tubulin, pericentrin-like protein, and myosin II (GPM complex) is formed, and subsequently a pair of basal bodies is assembled from the complex. It is not understood, however, how a single GPM is formed nor how the capability to form this complex is acquired by individual cells. We hypothesized that the GPM is formed from a precursor complex and developed an antibody that recognizes Naegleria (Ng)-transacylase, a component of the precursor complex. Immunostaining of differentiating cells showed that Ng transacylase is concentrated at a site in the amoeba and that gamma-tubulin is transiently co-concentrated at the site, suggesting that the GPM is formed from a precursor, GPMp, which contains Ng-transacylase and is already present in the amoeba. Immunostaining of growing N. pringsheimi with Ng-transacylase antibody revealed the presence of one GPMp in interphase cells, but two GPMps in mitotic cells, suggesting that N. pringsheimi maintains one GPMp per cell by duplicating and segregating the complex according to its cell cycle. Our results demonstrate the existence of a cell cycle-dependent duplicating complex that provides a site for the de novo assembly of the next generation of basal bodies. PMID- 25555150 TI - Comparison of similar Arctic and Antarctic morphotypes of heterotrophic protists regarding their genotypes and ecotypes. AB - The polar regions offer the opportunity to study possible diversification processes of spatially and temporally separated populations. We focused our study on similar morphotypes/species (e. g. species with the same morphology) of heterotrophic flagellates and ciliates originating from both, Antarctic and Arctic waters: 38 populations of six choanoflagellate morphospecies (Acanthocorbis unguiculata, Helgoeca nana, Diaphanoeca grandis, Savillea micropora, Stephanoeca apheles, Salpingoeca tuba), four other flagellate morphospecies (Cafeteria roenbergensis, Podomonas magma, Procryptobia sorokini, Protaspis sp.) and three ciliate morphospecies (Holosticha sp., Uronema marinum, Pseudocohnilembus persalinus). We analysed similarities and differences regarding their genotypes (SSU rDNA) and for several species regarding morphotypes and autecology (temperature and salinity tolerance). Most of the investigated polar protists were psychrophilic and showed a high salinity tolerance. Morphologically well defined acanthoecid choanoflagellates isolated from both poles showed the lowest intraspecific diversity (< 0.5% p-distance). No intragenomic polymorphism of SSU rDNA within one individual and among clones from one population occurred. The way of dispersal for acanthoecid choanoflagellates still remains unclear. Even under extreme stress none of the examined cultures formed cysts. Single cell PCR appeared to be an appropriate method to investigate species not available as monoclonal cultures. As a prerequisite for barcoding, acanthoecid choanoflagellate species have a very low intraspecific variability regarding SSU rDNA. There was a clear correlation between autecological, morphological and molecular data sets, which may help interpreting molecular data from clone libraries or next generation sequencing. PMID- 25555151 TI - Adaptive amino acid substitutions enhance the virulence of a reassortant H7N1 avian influenza virus isolated from wild waterfowl in mice. AB - H7 avian influenza viruses (AIVs) have caused a number of human infections, highlighting the pandemic potential of them. However, the factors that promote their replication in mammals remain poorly understood. Here, we generated mouse adapted variants of a reassortant H7N1 virus to identify adaptive changes that confer enhanced virulence in mammals. The mouse lethal doses (MLD50) of the variants were reduced >10,000-fold compared to the parental virus. Adapted variants displayed enhanced replication kinetics in vitro and vivo, and were capable of replicating in multiple organs. Analysis of the variant virus genomes revealed amino acid changes in the PB2 (E627K), HA (H3 numbering; E114K, G205E, and G218E), and NA (S350N) proteins. Notably, some amino acid changes have been identified in natural H7 isolates. Our results implicate a number of amino acid substitutions that collectively enhance the ability of a wild bird-origin H7N1 AIV to replicate and cause severe disease in mice. PMID- 25555153 TI - Systolic and diastolic short-term blood pressure variability and its determinants in patients with controlled and uncontrolled hypertension: a retrospective cohort study. AB - Absolute blood pressure (BP) values are not the only causes of adverse cardiovascular consequences. BP variability (BPV) has also been demonstrated to be a predictor of mortality for cardiovascular events; however, its determinants are still unknown. This study considers 426 subjects with ambulatory BP monitoring (ABPM) measuring 24-h, diurnal and nocturnal absolute BP values and their standard deviations of the mean, along with nocturnal fall, age, sex and current treatment. Patients were divided in two subgroups, controlled and uncontrolled BP, and BPV of patients with "true" and "false" resistant hypertension was also analyzed. Nocturnal and 24-h BPV were higher in the group with uncontrolled hypertension. Multiple regression analysis showed that absolute BP, age, nocturnal fall, but not sex predicted BPV. Patients with "true" resistant hypertension had greater BPV than "false" resistant hypertension patients. Absolute BP resulted as the main determinant of 24-h and nocturnal BPV but not daytime BPV. Also nocturnal BP fall and age resulted as predictors of BPV in treated and untreated patients. Patients with "true" resistant hypertension have a higher BPV, suggesting a higher sympathetic activation. Evidence is still limited regarding the importance of short-term BPV as a prognostic factor and assessment of BPV cannot yet represent a parameter for routine use in clinical practice. Future prospective trials are necessary to define which targets of BPV can be achieved with antihypertensive drugs and whether treatment-induced reduction in BPV is accompanied by a corresponding reduction in cardiovascular events. PMID- 25555152 TI - Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays. AB - The HIV-1 envelope glycoprotein, gp120, binds the host cell receptor, CD4, in the initial step of HIV viral entry and infection. This process is an appealing target for the development of inhibitory drugs and neutralizing antibodies. To study gp120 binding and intracellular trafficking, we engineered a fluorescent fusion of the humanized gp120 JRFL HIV-1 variant and GFP. Gp120-sfGFP is glycosylated with human sugars, robustly expressed, and secreted from cultured human cells. Protein dynamics, quality control, and trafficking can be visualized in live cells. The fusion protein can be readily modified with different gp120 variants or fluorescent proteins. Finally, secreted gp120-sfGFP enables a sensitive and easy binding assay that can quantitatively screen potential inhibitors of gp120-CD4 binding on live cells via fluorescence imaging or laser scanning cytometry. This adaptable research tool should aid in studies of gp120 cell biology and the development of novel anti-HIV drugs. PMID- 25555154 TI - Predicting treatment failure in pathological gambling: the role of personality traits. AB - INTRODUCTION: The aim of this study was twofold: First, to assess the personality profile of treatment-seeking adult outpatients with pathological gambling compared to a matched control group under the Alternative Five Factor Model perspective, and second, to determine which personality variables would predict treatment outcome. METHODS: The final total sample consisted of 44 consecutive treatment-seeking pathological gamblers (PGs) and 88 controls paired by age and sex who completed the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). Twelve months after starting an open program of individual cognitive-behavioral therapy, PGs were categorized as abstinent or treatment failure. RESULTS: PGs scored significantly higher on Neuroticism-Anxiety. Those who had relapsed or dropped out showed higher Impulsivity and Sensation Seeking scores. Impulsivity emerged as a significant predictor of treatment failure. Treatment-seeking PGs scored higher on Neuroticism-Anxiety and Impulsivity appeared as a risk factor of relapsing or dropping out. CONCLUSIONS: Our findings support the importance of individual differences in personality on therapy outcomes. The ZKPQ may constitute a useful tool to identify these individual differences that might be considered when making personalized treatment decisions to improve the effectiveness and quality of treatment interventions. PMID- 25555155 TI - Serum protein layers on parylene-C and silicon oxide: effect on cell adhesion. AB - Among the range of materials used in bioengineering, parylene-C has been used in combination with silicon oxide and in presence of the serum proteins, in cell patterning. However, the structural properties of adsorbed serum proteins on these substrates still remain elusive. In this study, we use an optical biosensing technique to decipher the properties of fibronectin (Fn) and serum albumin adsorbed on parylene-C and silicon oxide substrates. Our results show the formation of layers with distinct structural and adhesive properties. Thin, dense layers are formed on parylene-C, whereas thicker, more diffuse layers are formed on silicon oxide. These results suggest that Fn acquires a compact structure on parylene-C and a more extended structure on silicon oxide. Nonetheless, parylene C and silicon oxide substrates coated with Fn host cell populations that exhibit focal adhesion complexes and good cell attachment. Albumin adopts a deformed structure on parylene-C and a globular structure on silicon oxide, and does not support significant cell attachment on either surface. Interestingly, the co incubation of Fn and albumin at the ratio found in serum, results in the preferential adsorption of albumin on parylene-C and Fn on silicon oxide. This finding is supported by the exclusive formation of focal adhesion complexes in differentiated mouse embryonic stem cells (CGR8), cultured on Fn/albumin coated silicon oxide, but not on parylene-C. The detailed information provided in this study on the distinct properties of layers of serum proteins on substrates such as parylene-C and silicon oxide is highly significant in developing methods for cell patterning. PMID- 25555157 TI - Enhancement and wavelength-shifted emission of Cerenkov luminescence using multifunctional microspheres. AB - Cerenkov luminescence (CL) imaging is a new molecular imaging modality that utilizes the photons emitted during radioactive decay when charged particles travel faster than the phase velocity of light in a dielectric medium. Here we present a novel agent to convert and increase CL emission at longer wavelengths using multimodal protein microspheres (MSs). The (64)Cu-labeled protein microspheres contain quantum dots (QDs) encapsulated within a high-refractive index-oil core. Dark box imaging of the MSs was conducted to demonstrate the improvement in CL emission at longer wavelengths. To illustrate the versatile design of these MSs and the potential of CL in disease diagnosis, these MSs were utilized for in vitro cell targeting and ex vivo CL-excited QD fluorescence (CL FL) imaging of atherosclerotic plaques in rats. It was shown that by utilizing both QDs and MSs with a high-refractive-index-oil core, the CL emission increases by four-fold at longer wavelengths. Furthermore, we demonstrate that these MSs generate both an in vivo and ex vivo contrast signal. The design concept of utilizing QDs and high-index core MSs may contribute to future developments of in vivo CL imaging. PMID- 25555158 TI - Crystal structure of human U1 snRNP, a small nuclear ribonucleoprotein particle, reveals the mechanism of 5' splice site recognition. AB - U1 snRNP binds to the 5' exon-intron junction of pre-mRNA and thus plays a crucial role at an early stage of pre-mRNA splicing. We present two crystal structures of engineered U1 sub-structures, which together reveal at atomic resolution an almost complete network of protein-protein and RNA-protein interactions within U1 snRNP, and show how the 5' splice site of pre-mRNA is recognised by U1 snRNP. The zinc-finger of U1-C interacts with the duplex between pre-mRNA and the 5'-end of U1 snRNA. The binding of the RNA duplex is stabilized by hydrogen bonds and electrostatic interactions between U1-C and the RNA backbone around the splice junction but U1-C makes no base-specific contacts with pre-mRNA. The structure, together with RNA binding assays, shows that the selection of 5'-splice site nucleotides by U1 snRNP is achieved predominantly through basepairing with U1 snRNA whilst U1-C fine-tunes relative affinities of mismatched 5'-splice sites. PMID- 25555159 TI - Proteomic analysis of the response to cell cycle arrests in human myeloid leukemia cells. AB - Previously, we analyzed protein abundance changes across a 'minimally perturbed' cell cycle by using centrifugal elutriation to differentially enrich distinct cell cycle phases in human NB4 cells (Ly et al., 2014). In this study, we compare data from elutriated cells with NB4 cells arrested at comparable phases using serum starvation, hydroxyurea, or RO-3306. While elutriated and arrested cells have similar patterns of DNA content and cyclin expression, a large fraction of the proteome changes detected in arrested cells are found to reflect arrest specific responses (i.e., starvation, DNA damage, CDK1 inhibition), rather than physiological cell cycle regulation. For example, we show most cells arrested in G2 by CDK1 inhibition express abnormally high levels of replication and origin licensing factors and are likely poised for genome re-replication. The protein data are available in the Encyclopedia of Proteome Dynamics ( PMID- 25555160 TI - LOR-interleaving image reconstruction for PET imaging with fractional-crystal collimation. AB - Positron emission tomography (PET) has become an important modality in medical and molecular imaging. However, in most PET applications, the resolution is still mainly limited by the physical crystal sizes or the detector's intrinsic spatial resolution. To achieve images with better spatial resolution in a central region of interest (ROI), we have previously proposed using collimation in PET scanners. The collimator is designed to partially mask detector crystals to detect lines of response (LORs) within fractional crystals. A sequence of collimator-encoded LORs is measured with different collimation configurations. This novel collimated scanner geometry makes the reconstruction problem challenging, as both detector and collimator effects need to be modeled to reconstruct high-resolution images from collimated LORs. In this paper, we present a LOR-interleaving (LORI) algorithm, which incorporates these effects and has the advantage of reusing existing reconstruction software, to reconstruct high-resolution images for PET with fractional-crystal collimation. We also develop a 3D ray-tracing model incorporating both the collimator and crystal penetration for simulations and reconstructions of the collimated PET. By registering the collimator-encoded LORs with the collimator configurations, high-resolution LORs are restored based on the modeled transfer matrices using the non-negative least-squares method and EM algorithm. The resolution-enhanced images are then reconstructed from the high resolution LORs using the MLEM or OSEM algorithm. For validation, we applied the LORI method to a small-animal PET scanner, A-PET, with a specially designed collimator. We demonstrate through simulated reconstructions with a hot-rod phantom and MOBY phantom that the LORI reconstructions can substantially improve spatial resolution and quantification compared to the uncollimated reconstructions. The LORI algorithm is crucial to improve overall image quality of collimated PET, which can have significant implications in preclinical and clinical ROI imaging applications. PMID- 25555161 TI - Chronic myelomonocytic leukemia in younger patients: molecular and cytogenetic predictors of survival and treatment outcome. AB - In patients with chronic myelomonocytic leukemia (CMML), age>65 years is an adverse prognostic factor. Our objective in the current study was to examine risk factors for survival and treatment outcome in 261 'young' adults with CMML, as defined by age ?65 years. In multivariable analysis, lower HB (P=0.01), higher circulating blast % (P=0.002), ASXL1 (P=0.0007) and SRSF2 mutations (P=0.008) and Mayo-French cytogenetic stratification (P=0.04) negatively impacted survival. Similarly, leukemia-free survival was independently affected by higher circulating blast % (P<0.0001), higher bone marrow blast % (P=0.0007) and the presence of circulating immature myeloid cells (P=0.0002). Seventy-five (29%) patients received hypomethylating agents (HMA), with the median number of cycles being 5, and the median duration of therapy being 5 months. The over-all response rate was 40% for azacitidine and 30% for decitabine. Fifty-three (24%) patients underwent an allogeneic hematopoietic stem cell transplant (AHSCT), with a response rate of 56% and a non-relapse mortality of 19%. Survival in young adults with CMML, although higher than in older patients, is poor and even worse in the presence of ASXL1 and SRSF2 mutations. Treatment outcome was more impressive with AHSCT than with HMA and neither was influenced by ASXL1/SRSF2 mutations or karyotype. PMID- 25555164 TI - Interfacial tension-hindered phase transfer of polystyrene-b-poly(ethylene oxide) polymersomes from a hydrophobic ionic liquid to water. AB - We examine the phase transfer of polystyrene-b-poly(ethylene oxide) (PS-PEO) polymersomes from a hydrophobic ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]), into water. The dependence of the phase transfer on the molecular weight and PEO volume fraction (fPEO) of the PS-PEO polymersomes was systematically studied by varying the molecular weight of PS (10,000-27,000 g/mol) as well as by varying the volume fraction of PEO (fPEO) between 0.1 and 0.3. We demonstrate a general boundary for the phase transfer in terms of a reduced tethering density for PEO (sigmaPEO), which is independent of the molecular weight of the hydrophobic PS. The reduced PEO tethering density was controlled by changing the polymersome size (i.e., increased polymersome sizes increase sigmaPEO), confirming that it is the driving force in the transfer of PS PEO polymersomes at room temperature. The phase transfer dependence on sigmaPEO was also analyzed in terms of the free energy of polymersomes in the biphasic system. The quality of the aqueous phase, which affects the interfacial tension of the PS membrane, influenced the phase transfer. We systematically reduced the interfacial tension by adding a water-selective solvent, THF, which has a similar effect to increasing sigmaPEO. The results indicate that the interfacial tension between the membrane and water plays an important role in the phase transfer with the corona and that the phase transfer can be controlled either by the dimensions of the polymersomes or by the suitability of the solvent for the membrane. The interfacial tension-hindered phase transfer of polymersomes in the biphasic water [EMIM][TFSI] system will inform the design of temperature-sensitive and reversible nanoreactors and the separation of polydisperse particles according to size by tuning the quality of the solvent. PMID- 25555163 TI - The effects of resistance exercise with and without different degrees of blood flow restriction on perceptual responses. AB - The aim was to compare exercise with and without different degrees of blood-flow restriction on perceived exertion (RPE) and discomfort. Participants were assigned to Experiment 1, 2, or 3. Each completed protocols differing by pressure, load, and/or volume. RPE and discomfort were taken before and after each set. For pressure and RPE, the 20% one repetition maximum (1RM) blood-flow restriction conditions were affected by increasing the pressure from 40% to 50% blood-flow restriction (~12 vs. ~14). This did not appear to happen within the 30% 1RM blood-flow restriction conditions or the higher pressures in the 20% 1RM conditions. The similar RPE between 20% and 30% 1RM to failure was expected given both were to failure. For discomfort, ratings were primarily affected by load at the lowest pressure. Increasing pressure to 50% blood-flow restriction increased discomfort at 20% 1RM (~2.6 vs. ~4). There was a further increase when increasing to 60% blood-flow restriction (~4 vs. ~4.8). The high-load condition had the lowest discomfort, while ratings were highest with 20% 1RM to failure. In conclusion, exercise with blood-flow restriction does not appear to augment the perceptual response observed with low-load exercise to failure. PMID- 25555162 TI - Racial differences in primary cytogenetic abnormalities in multiple myeloma: a multi-center study. AB - We examined four clinically assessed cytogenetic subtypes (t(11;14), t(4;14), monosomy 13/del13q and monosomy 17/del17p in 292 black patients with newly diagnosed multiple myeloma (MM) from four medical centers, who had fluorescent in situ hybridization testing results available in their medical records. We then compared the prevalence of these abnormalities with a previously characterized Mayo Clinic cohort of 471 patients with MM. We found a significant difference in the prevalence of the t(11;14) immunoglobulin heavy chain (IgH) translocation between blacks and whites, 6.5% versus 17.6%, respectively, P<0.0001. Blacks also had lower rates of the t(4;14) IgH translocation, (5.5% versus 10%); monosomy 13/del13q (29.1 versus 49.3%); and monosomy 17/del17p (7.9% versus 13%). Consequently, 63.4% of blacks versus 34.6% of whites did not have any of the four abnormalities that we studied, P<0.001. As almost all MM is associated with either an IgH translocation or trisomies, we hypothesize that MM in blacks is associated with either excess prevalence of either the trisomic (hyperdiploid) form of MM or an IgH translocation besides t(11;14) or t(4;14). We conclude that there are significant differences in the cytogenetic subtypes of MM that occur in blacks and whites. PMID- 25555165 TI - Long-term quality of life in patients with vestibular schwannoma: an international multicenter cross-sectional study comparing microsurgery, stereotactic radiosurgery, observation, and nontumor controls. AB - OBJECT: The optimal treatment for sporadic vestibular schwannoma (VS) is highly controversial. To date, the majority of studies comparing treatment modalities have focused on a narrow scope of technical outcomes including facial function, hearing status, and tumor control. Very few publications have investigated health related quality of life (HRQOL) differences between individual treatment groups, and none have used a disease-specific HRQOL instrument. METHODS: All patients with sporadic small- to medium-sized VSs who underwent primary microsurgery, stereotactic radiosurgery (SRS), or observation between 1998 and 2008 were identified. Subjects were surveyed via postal questionnaire using the 36-Item Short Form Health Survey (SF-36), the 10-item Patient-Reported Outcomes Measurement Information System short form (PROMIS-10), the Glasgow Benefit Inventory (GBI), and the Penn Acoustic Neuroma Quality-of-Life (PANQOL) scale. Additionally, a pool of general population adults was surveyed, providing a nontumor control group for comparison. RESULTS: A total of 642 respondents were analyzed. The overall response rate for patients with VS was 79%, and the mean time interval between treatment and survey was 7.7 years. Using multivariate regression, there were no statistically significant differences between management groups with respect to the PROMIS-10 physical or mental health dimensions, the SF-36 Physical or Mental Component Summary scores, or the PANQOL general, anxiety, hearing, or energy subdomains. Patients who underwent SRS or observation reported a better total PANQOL score and higher PANQOL facial, balance, and pain subdomain scores than the microsurgical cohort (p < 0.02). The differences in scores between the nontumor control group and patients with VS were greater than differences observed between individual treatment groups for the majority of measures. CONCLUSIONS: The differences in HRQOL outcomes following SRS, observation, and microsurgery for VS are small. Notably, the diagnosis of VS rather than treatment strategy most significantly impacts quality of life. Understanding that a large number of VSs do not grow following discovery, and that intervention does not confer a long-term HRQOL advantage, small- and medium-sized VS should be initially observed, while intervention should be reserved for patients with unequivocal tumor growth or intractable symptoms that are amenable to treatment. Future studies assessing HRQOL in VS patients should prioritize use of validated disease-specific measures, such as the PANQOL, given the significant limitations of generic instruments in distinguishing between treatment groups and tumor versus nontumor subjects. PMID- 25555167 TI - Comparison of DNA and RNA Adduct Formation: Significantly Higher Levels of RNA than DNA Modifications in the Internal Organs of Aristolochic Acid-Dosed Rats. AB - Prolonged exposure to aristolochic acid (AA)contaminated slimming drugs and food is believed to be associated with the development of endemic nephropathy in Belgian women and in farmers living alongside the Danube River. Decades of research has revealed the pathophysiology of carcinogenesis of AA,and the molecular mechanisms underlying renal interstitial fibrosis remain unclear. We hypothesized that RNA modification may have contributed to the observed toxicity of AA. Thus, a highly sensitive and selective ultra-high performance liquid chromatography-coupled tandem mass spectrometric method was developed to quantify RNA-AA adducts in target and nontarget organs of AA-dosed rats. The results revealed, for the first time, that AA forms RNA adducts in vitro and in vivo. Comparative studies on DNA revealed that RNA is modified by AA at frequencies approximately 6-fold higher than that of DNA in both kidney and liver tissue in AA-dosed rats. Results also demonstrated that guanosine is modified by AA at frequencies significantly higher than that of adenosine, 2-deoxyadenosine, and 2 deoxyguanosinein both organs of the AA-dosed. This finding suggests that guanosine is a major target for AA and that guanosine adducts of AA might be critical lesions in the pathophysiology of AA-induced toxicity. It is anticipated that the results of our study may open up a new area of investigating the nephrotoxicity and/or carcinogenicity by quantifying RNA adducts using the UPLC MS/MS technique of high sensitivity and selectivity. PMID- 25555168 TI - 64-detector CT angiography within 24 hours after carotid endarterectomy and correlation with postoperative stroke. AB - OBJECT: Carotid endarterectomy (CEA) carries a small but not insignificant risk of stroke/transient ischemic attack (TIA), most frequently observed within 24 hours of surgery, which can lead to the need for urgent vascular imaging in the immediate postoperative period. However, distinguishing expected versus pathological postoperative changes may not be straightforward on imaging studies of the carotid artery early after CEA. The authors aimed to describe routine versus pathological anatomical findings on CTA performed within 24 hours of CEA, and to evaluate associations between these CTA findings and postoperative stroke/TIA. METHODS: The authors reviewed 113 consecutive adult patients who underwent postoperative CTA within 24 hours of CEA at a single academic institution. Presence and location of arterial "flaps," luminal "step-off," intraluminal thrombus and hematoma were documented from postoperative CTA scans. Medical records were reviewed to determine the incidence of new postoperative neurological findings. RESULTS: Postoperative CTA findings included common carotid artery (CCA) step-off (63.7%), one or more intraarterial flaps (27.4%), hematoma at the surgical site (15.9%), and new intraluminal thrombus (7.1%). Flaps were seen in the external carotid artery (ECA), internal carotid artery (ICA), and CCA in 18.6%, 9.7%, and 6.2% of patients, respectively. New postoperative neurological findings were present in 7.1% of patients undergoing CTA. Flaps (especially ICA/CCA) and/or intraluminal thrombi were more frequently seen in patients undergoing CTA for new postoperative stroke/TIA (85.7%) versus patients undergoing CTA for routine postoperative imaging (14.3%, p = 0.002). CONCLUSIONS: CTA within 24 hours of CEA demonstrates characteristic anatomical findings. CCA step-offs and ECA flaps are relatively common and clinically insignificant, whereas ICA/CCA flaps and thrombi are less frequently seen and are associated with postoperative stroke/TIA. PMID- 25555170 TI - A dual-boron-cored luminogen capable of sensing and imaging. AB - A new dual-boron-cored luminogen ligated with a nitrogen-containing multidentate ligand and four bulky phenyl rings was readily synthesized. The unique molecular structure endows this BN-containing luminogen with rich photophysical properties in either solution or in the solid state, including a large Stokes shift, aggregation induced emission activity and reversible piezochromism. Furthermore, this BN-containing luminogen exhibits good capabilities for imaging living cells and sensing of fluoride anions. PMID- 25555171 TI - Key parameters of the swimming start and their relationship to start performance. AB - The swimming start is typically broken into three sub-phases; on-block, flight, and underwater phases. While overall start performance is highly important to elite swimming, the contribution of each phase and important technical components within each phase, particularly with the new kick-start technique, has not been established. The aim of this study was to identify technical factors associated with overall start performance, with a particular focus on the underwater phase. A number of parameters were calculated from 52 starts performed by elite freestyle and butterfly swimmers. These parameters were split into above-water and underwater groupings, before factor analysis was used to reduce parameter numbers for multiple regression. For the above-water phases, 81% of variance in start performance was accounted for by take-off horizontal velocity. For the underwater water phase, 96% of variance was accounted for with time underwater in descent, time underwater in ascent and time to 10 m. Therefore, developing greater take-off horizontal velocity and focussing on the underwater phase by finding the ideal trajectory will lead to improved start performance. PMID- 25555172 TI - Functional helquats: helical cationic dyes with marked, switchable chiroptical properties in the visible region. AB - Helquat dyes are the first helicene-like cationic styryl dyes obtained as separate enantiomers. Their remarkable chiroptical properties are due to the unique combination of a cationic hemicyanine chromophore and a helicene-like motif. The magnitude of the ECD response and the pH switching along with their positioning in the visible region are unprecedented among helicenoids. PMID- 25555173 TI - A randomized controlled trial comparing dexamethasone with loteprednol etabonate on postoperative photorefractive keratectomy. AB - PURPOSE: To compare loteprednol etabonate 0.5%/tobramycin 0.3% (Zylet((r))) with dexamethasone 0.1%/tobramycin 0.3% (Tobradex((r))) in terms of the epithelial healing time, postoperative visual acuity, corneal haziness score, and intraocular pressure (IOP) in postoperative treatment after photorefractive keratectomy (PRK). METHODS: This prospective, randomized, double-masked (participants and assessors blinded) controlled study included 32 patients who underwent PRK. The patients were allocated equally into 2 groups by block randomization to receive either loteprednol etabonate (Lot) or dexamethasone (Dex) for 1 month after the surgery. The epithelial healing time, uncorrected visual acuity (UCVA), corneal haziness score, and IOP were evaluated at 1 week, 1 month, and 3 months. RESULTS: The corneal epithelium was healed within 3 days in both groups; however, the epithelium was closed on the second day in 3 cases in the Lot group compared with 1 case in the Dex group. No significant differences were found for UCVA at 1 and 3 months (Fisher exact test, P>0.01). Similarly, there was no statistically significant difference in corneal haziness scores between the 2 groups at 1 and 3 months (Mann-Whitney U test, P>0.05). The number of patients experiencing significantly increased IOP (>=5 mmHg) from baseline at any visit for the Lot group (1/16 patients) was fewer than for the Dex group (3/16 patients). CONCLUSIONS: Loteprednol etabonate was effective in postoperative PRK management and was significantly less likely to produce elevations in IOP than was dexamethasone. PMID- 25555174 TI - Combining network analysis with Cognitive Work Analysis: insights into social organisational and cooperation analysis. AB - Cognitive Work Analysis (CWA) allows complex, sociotechnical systems to be explored in terms of their potential configurations. However, CWA does not explicitly analyse the manner in which person-to-person communication is performed in these configurations. Consequently, the combination of CWA with Social Network Analysis provides a means by which CWA output can be analysed to consider communication structure. The approach is illustrated through a case study of a military planning team. The case study shows how actor-to-actor and actor-to-function mapping can be analysed, in terms of centrality, to produce metrics of system structure under different operating conditions. PRACTITIONER SUMMARY: In this paper, a technique for building social network diagrams from CWA is demonstrated.The approach allows analysts to appreciate the potential impact of organisational structure on a command system. PMID- 25555175 TI - Highly Effective Birth Control Use Before and After Women's Incarceration. AB - BACKGROUND: We examined factors associated with women's use of highly effective birth control before and after incarceration, since women with ongoing criminal justice involvement bear a disproportionate burden of sexual and reproductive health problems, including high rates of unintended pregnancy and inconsistent contraceptive use. METHODS: Using a longitudinal study design, we conducted surveys with 102 women in an urban midwestern jail and then followed up with 66 of them 6 months after incarceration. We used stepwise logistic regression to assess individual, interpersonal, resource-based, organizational, and environmental factors associated with utilizing highly effective birth control. RESULTS: Forty-two percent of women reported utilizing highly effective birth control (e.g., sterilization or other highly effective reversible methods) prior to incarceration, and 54% reported using these methods after release from jail (p<0.001). Ninety percent of women reported not wanting to get pregnant. Consistent use of birth control (p=0.001) and alcohol problems (p=0.027) were associated with utilization of highly effective birth control prior to incarceration. Previous pregnancies (p=0.012) were the only factor associated with utilization of highly effective birth control after release from jail. CONCLUSIONS: Clinicians and public health practitioners can use findings from this study to develop clinical and intervention efforts aimed at improving unintended-pregnancy prevention among incarcerated women both during their confinement and during the tumultuous period after their release from jail. PMID- 25555176 TI - Practical Monitoring of Treatment Fidelity: Examples From a Team-Based Intervention for People With Early Psychosis. AB - Mental health programs can address many components of fidelity with routinely available data. Information from client interviews can be used to corroborate these administrative data. This column describes a practical approach to measuring fidelity that used both data sources. The approach was used in the Recovery After an Initial Schizophrenia Episode (RAISE) Connection Program, a team-based intervention designed to implement evidence-based practices for people experiencing early psychosis suggestive of schizophrenia. Data indicated that the intervention was implemented as intended, including program elements related to shared decision making and a range of evidence-based clinical interventions. PMID- 25555177 TI - My heart is racing! Psychophysiological dynamics of skilled racecar drivers. AB - Our purpose was to test the multi-action plan model assumptions in which athletes' psychophysiological patterns differ among optimal and suboptimal performance experiences. Nine professional drivers competing in premier race categories (e.g. Formula 3, Porsche GT3 Cup Challenge) completed the study. Data collection involved monitoring the drivers' perceived hedonic tone, accuracy on core components of action, posture, skin temperature, respiration rate and heart rate responses during a 40-lap simulated race. Time marks, gathered at three standardised sectors, served as the performance variable. The A1GP racing simulator (Allinsport, Modena) established a realistic race platform. Specifically, the Barcelona track was chosen because of its inherently difficult nature characterised by intermittent deceleration points. Idiosyncratic analyses showed large individual differences in the drivers' psychophysiological profile, as well as distinct patterns in regards to optimal and suboptimal performance experiences. Limitations and future research avenues are discussed. Action- (e.g. attentional control) and emotion (e.g. biofeedback training)-centred applied sport psychology implications are advanced. PMID- 25555178 TI - Energy transfer between amphiphilic porphyrin polymer shells and upconverting nanoparticle cores in water-dispersible nano-assemblies. AB - The synthesis of water-dispersible nano-assemblies containing upconverting nanoparticles (UCNPs) and porphyrin molecules using a one-pot method is described. When the nano-assemblies are excited by 980 nm near-infrared light, the intensity of the 'green emission' band of the UCNP is reduced due to a combination of Foster Resonace Energy Transfer (FRET) and emission-reabsorption. This process is also responsible for the emission from the porphyrin chromophores despite the fact they do not absorb near-infrared light. PMID- 25555179 TI - The sclerostin story: from human genetics to the development of novel anabolic treatment for osteoporosis. AB - Sclerosteosis and Van Buchem disease are two rare bone sclerosing disorders characterized by increased bone mineral density, tall stature and entrapment of cranial nerves due to overgrowth of a highly dense bone. Recent advances in human genetics have revealed the genetic background of these disorders by cloning the SOST gene, which is localized on chromosome region 17q12-q21 and codes for sclerostin. Sclerostin is a protein produced almost exclusively from osteocytes inhibiting bone formation by both osteoblasts and osteocytes. At the molecular level, sclerostin inhibits the Wnt signaling pathway, which plays a critical role in osteoblast development and function. Induced sclerostin deficiency in mice reproduces the bone sclerosing human diseases, while sclerostin excess leads to bone loss and reduced bone strength. The extracellular nature of sclerostin has rendered it a promising target for the development of novel anti-osteoporotic treatment. Otherwise healthy carriers of the SOST mutation present with increased bone mass and low levels of sclerostin in serum in contrast to patients with sclerosteosis, who exhibit undetectable levels, thus pointing to the possibility of titration of sclerostin levels in the circulation. Based on these unique characteristics, human anti-sclerostin antibodies have been developed and tested in ovariectomized rats and monkeys, demonstrating very promising results in bone formation. Clinical phase II and III trials are currently underway thereby translating human genetics to drug development. PMID- 25555180 TI - A review on osteoporosis in men. PMID- 25555181 TI - The role of ghrelin in weight-regulation disorders: implications in clinical practice. AB - Ghrelin, an orexigenic protein with a unique lipid chain modification, is considered to be an important gut-brain signal for appetite control and energy balance. The ghrelin receptor, growth-hormone secretagogue receptor type 1a, is able to bind acylated ghrelin. The first recognised effect of ghrelin was the induction of growth hormone release from the somatotroph cells of the anterior pituitary. Moreover, by acting on vagal afferents or centrally, ghrelin can activate hypothalamic arcuate neurons that secrete the orexigenic peptides neuropeptide Y and agouti-related peptide, and inhibit the anorexigenic neurons secreting pro-opiomelanocortin and alpha-melanocyte-stimulating hormone. The orexigenic signalling pathway of ghrelin involves adenosine monophosphate activated protein kinase. It has been proposed that ghrelin can also increase dopaminergic transmission from the ventral tegmental area to the nucleus accumbens, leading to augmentation of afferent reward signals. Present evidence suggests that ghrelin plays an important role in obesity, eating disorders, and cachexia, as well as in regulating appetite and energy balance in healthy individuals. In pathological states, ghrelin can be lower than normal as is seen in obese individuals, or can be higher than normal as has been reported for Prader-Willi syndrome, anorexia nervosa, bulimia nervosa, and certain types of cachexia. In the future, the application of compounds targeting the ghrelin pathway could involve the use of pharmacotherapies of ghrelin agonists, antagonists or inverse agonists, neutralisation of ghrelin by vaccines and spiegelmers, desacyl ghrelin analogues, as well as inhibitors of the GOAT enzyme which attaches the lipid modification to desacyl ghrelin to synthetise ghrelin. PMID- 25555182 TI - The benefit-to-risk ratio of common treatments in PCOS: effect of oral contraceptives versus metformin on atherogenic markers. AB - OBJECTIVE: To compare the effects of oral contraceptives (OCPs) and metformin on atherogenic markers, including serum levels of advanced glycated end products (AGEs) and C-reactive protein (CRP), in lean women (Body Mass Index below 25 kg/m(2)) with polycystic ovary syndrome (PCOS), defined by NIH criteria. DESIGN: Prospective open-label study. RESULTS: One hundred and twenty women with PCOS were treated for 6 months with one of the following treatments: ethinylestradiol plus cyproterone acetate (OCP 1, n=40) or ethinylestradiol plus drospirenone (OCP2, n=40) or metformin (MET, n=40). The three groups were age and BMI-matched (mean age: 22 +/- 0.56 yrs in group OCP1; 23.24 +/- 0.64 yrs in group OCP2; 21.50 +/- 0.53 yrs in group MET; mean BMI 21.80 +/- 0.35 kg/m(2) in group OCP1; 22.37 +/- 0.48 kg/m(2) in group OCP2; 23.03 +/- 0.67 kg/m(2) in group MET). At 6 months serum AGEs were decreased in group OCP1 (P=0.005) and group MET (P=0.001), whereas these were marginally decreased in group OCP2 (P=0.069). Treatment with metformin was associated with a greater percent decrease of AGEs. CRP was decreased with metformin (P<0.001), but was increased with OCPs (P<0.001). CONCLUSIONS: This study evaluates common therapeutic options in women with PCOS by reconsidering and prioritizing the goals of treatment. OCPs and metformin appear to have differential effects on atherogenic molecules in lean PCOS patients, but metformin was superior in reducing serum AGEs and CRP. Clinicians should individualize the benefit-to-risk ratio of pharmaceutical intervention in women with PCOS in order to choose the formulation with the greatest overall efficacy as well as safety in terms of cardiovascular risk. PMID- 25555183 TI - Implementation of a stress management program in outpatients with type 2 diabetes mellitus: a randomized controlled trial. AB - OBJECTIVE: Although there is scientific evidence that stress adversely affects metabolic control, only a few studies have examined the role of stress management in improving glycemic control in patients with type 2 diabetes mellitus (DM). In this study, we investigated the effect of a relaxation technique on levels of stress and glycemic control. DESIGN: A total of 53 patients with type 2 DM were randomly assigned to undergo either an 8-week stress management program, consisting of 10 min of diaphragmatic breathing and 15 min of progressive muscle relaxation twice per day (n=25, intervention group), or not (n=28, control group). Perceived stress, health locus of control and HbA1c were primary outcomes and were measured before and after intervention. RESULTS: In the intervention group, perceived stress score (PSS) and HbA1c had decreased significantly (P<0.05) by the end of the program. Specifically concerning the PSS, the higher the initial levels of perceived stress the greater the benefit of the intervention. No other significant changes were found. CONCLUSIONS: Our results show a beneficial role of stress management for patients with type 2 DM, as regards both stress levels and glycemic control. It is recommended to consider this type of treatment as an adjunct to conventional therapy. We deem that our study could encourage future studies in this area with larger samples, longer duration and more objective measurements. PMID- 25555184 TI - Tracheal mass. Malignant melanoma metastatic to the trachea. PMID- 25555185 TI - Preparation and characterization of a laboratory scale selenomethionine-enriched bread. Selenium bioaccessibility. AB - This study focuses on the preparation at lab scale of selenomethionine-enriched white and wholemeal bread. Selenium was supplemented either by adding selenite directly to the dough or by using lab-made selenium-enriched yeast. The best results were obtained when using fresh selenium-enriched yeast. The optimum incubation time for selenomethionine-enriched yeast preparation, while keeping formation of selenium byproducts to a minimum, was 96 h. Selenium content measured by isotope dilution analysis (IDA)-ICP-MS in Se-white and Se-wholemeal bread was 1.28 +/- 0.02 MUg g-1 and 1.16 +/- 0.02 MUg g-1 (expressed as mean +/- SE, 3 replicates), respectively. HPLC postcolumn IDA-ICP-MS measurements revealed that selenomethionine was the main Se species found in Se-enriched bread, which accounted for ca. 80% of total selenium. In vitro gastrointestinal digestion assay provided selenium bioaccessibility values of 100 +/- 3% and 40 +/- 1% for white and wholemeal Se-enriched bread, respectively, being selenomethionine the main bioaccessible Se species in white bread, while in wholemeal bread this compound was undetectable. PMID- 25555187 TI - Controversial role of topical antibiotics in endophthalmitis prophylaxis for cataract surgery. PMID- 25555188 TI - Incorporating primary and secondary prevention approaches to address childhood obesity prevention and treatment in a low-income, ethnically diverse population: study design and demographic data from the Texas Childhood Obesity Research Demonstration (TX CORD) study. AB - BACKGROUND: There is consensus that development and evaluation of a systems oriented approach for child obesity prevention and treatment that includes both primary and secondary prevention efforts is needed. This article describes the study design and baseline data from the Texas Childhood Obesity Research Demonstration (TX CORD) project, which addresses child obesity among low-income, ethnically diverse overweight and obese children, ages 2-12 years; a two-tiered systems-oriented approach is hypothesized to reduce BMI z-scores, compared to primary prevention alone. METHODS: Our study aims are to: (1) implement and evaluate a primary obesity prevention program; (2) implement and evaluate efficacy of a 12-month family-centered secondary obesity prevention program embedded within primary prevention; and (3) quantify the incremental cost effectiveness of the secondary prevention program. Baseline demographic and behavioral data for the primary prevention community areas are presented. RESULTS: Baseline data from preschool centers, elementary schools, and clinics indicate that most demographic variables are similar between intervention and comparison communities. Most families are low income (<=$25,000) and Hispanic/Latino (73.3-83.8%). The majority of parents were born outside of the United States. Child obesity rates exceed national values, ranging from 19.0% in preschool to 35.2% in fifth-grade children. Most parents report that their children consume sugary beverages, have a television in the bedroom, and do not consume adequate amounts of fruits and vegetables. CONCLUSIONS: Interventions to address childhood obesity are warranted in low-income, ethnically diverse communities. Integrating primary and secondary approaches is anticipated to provide sufficient exposure that will lead to significant decreases in childhood obesity. PMID- 25555189 TI - Voxel-based analysis of fractional anisotropy in post-stroke apathy. AB - OBJECTIVE: To explore the structural basis of post-stroke apathy by using voxel based analysis (VBA) of fractional anisotropy (FA) maps. METHODS: We enrolled 54 consecutive patients with ischemic stroke during convalescence, and divided them into apathy (n = 31) and non-apathy (n = 23) groups. We obtained magnetic resonance images of their brains, including T1, T2 and DTI sequences. Age, sex, education level, Hamilton Depression Scale (HAMD) scores, Mini-Mental State Examination (MMSE) scores, National Institutes of Health Stroke Scale (NIHSS) scores, and infarct locations for the two groups were compared. Finally, to investigate the structural basis of post-stroke apathy, VBA of FA maps was performed in which we included the variables that a univariate analysis determined had P-values less than 0.20 as covariates. RESULTS: HAMD (P = 0.01) and MMSE (P<0.01) scores differed significantly between the apathy and non-apathy groups. After controlling for age, education level, HAMD scores, and MMSE scores, significant FA reduction was detected in four clusters with peak voxels at the genu of the corpus callosum (X = -16, Y = 30, Z = 8), left anterior corona radiata (-22, 30, 10), splenium of the corpus callosum (-24, -56, 18), and right inferior frontal gyrus white matter (52, 24, 18), after family-wise error correction for multiple comparisons. CONCLUSIONS: Post-stroke apathy is related to depression and cognitive decline. Damage to the genu of the corpus callosum, left anterior corona radiata, splenium of the corpus callosum, and white matter in the right inferior frontal gyrus may lead to apathy after ischemic stroke. PMID- 25555190 TI - Mapping metals incorporation of a whole single catalyst particle using element specific X-ray nanotomography. AB - Full-field transmission X-ray microscopy has been used to determine the 3D structure of a whole individual fluid catalytic cracking (FCC) particle at high spatial resolution and in a fast, noninvasive manner, maintaining the full integrity of the particle. Using X-ray absorption mosaic imaging to combine multiple fields of view, computed tomography was performed to visualize the macropore structure of the catalyst and its availability for mass transport. We mapped the relative spatial distributions of Ni and Fe using multiple-energy tomography at the respective X-ray absorption K-edges and correlated these distributions with porosity and permeability of an equilibrated catalyst (E-cat) particle. Both metals were found to accumulate in outer layers of the particle, effectively decreasing porosity by clogging of pores and eventually restricting access into the FCC particle. PMID- 25555191 TI - A 50% vs 30% dose of verteporfin (photodynamic therapy) for acute central serous chorioretinopathy: one-year results of a randomized clinical trial. AB - IMPORTANCE: A randomized clinical trial is needed to evaluate what is the best photodynamic therapy (PDT) protocol to use for acute central serous chorioretinopathy. OBJECTIVE: To compare the efficacy and safety of a 50% dose of verteporfin (a method of PDT) with the efficacy and safety of a 30% dose for acute central serous chorioretinopathy. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, noninferiority, double-masked, randomized, controlled, clinical trial in which 131 patients (131 eyes) with acute central serous chorioretinopathy for less than 6 months were recruited with a follow-up of 12 months from university-based ophthalmology practices. INTERVENTIONS: Patients were randomly assigned to either a 50% dose of verteporfin (the 50%-dose PDT group) or a 30% dose (the 30%-dose PDT group). MAIN OUTCOMES AND MEASURES: The 2 primary outcome measures were the proportion of eyes with complete absorption of subretinal fluid and the proportion of eyes with complete disappearance of fluorescein leakage at 6 and 12 months. The secondary outcome measures included the subretinal fluid recurrent rate, the fluorescein leakage recurrent rate at 12 months, the mean best-corrected visual acuity, the retinal thickness of the foveal center, and the maximum retinal thickness at each scheduled visit. RESULTS: The noninferiority of the 30%-dose PDT compared with the 50%-dose PDT for the primary outcomes was not demonstrated. The optical coherence tomography based improvement rate in the 30%-dose PDT group was less than that in the 50% dose PDT group both at 6 months (73.8% vs 92.9%; alpha = 0.0125, P = .006) and at 12 months (75.4% vs 94.6%; alpha = 0.0125, P = .004). The fluorescein angiography based improvement rate in the 30%-dose PDT group was less than that in the 50% dose PDT group both at 6 months (68.9% vs 91.1%; alpha = 0.0125, P = .003) and at 12 months (68.9% vs 92.9%; alpha = 0.0125, P = .001). The subretinal fluid recurrence rate in the 30%-dose PDT group was greater than that in the 50%-dose PDT group (24.0% vs 5.7% at 12 months; P = .010, determined by use of the log rank test). The fluorescein leakage recurrent rate in the 30%-dose PDT group was significantly higher than that in the 50%-dose PDT group (16.7% vs 3.8% at 12 months; P = .03, determined by use of the log-rank test). No ocular adverse event was encountered in the study. CONCLUSIONS AND RELEVANCE: A 50% dose of verteporfin may be more effective at resolving subretinal fluid and fluorescein leakage, and with better visual outcomes, than a 30% dose for acute central serous chorioretinopathy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01574430. PMID- 25555193 TI - Gamma Knife radiosurgery for meningiomas in patients with neurofibromatosis Type 2. AB - OBJECT: Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder predisposing patients to meningiomatosis. The role of stereotactic radiosurgery (SRS) is poorly defined in NF2, and although the procedure has excellent control rates in the non-NF2 population, its utility has been questioned because radiation has been hypothesized to predispose patients to malignant transformation of benign tumors. To the authors' knowledge, this is the first study to examine the use of SRS specifically for meningiomas in patients with NF2. METHODS: The authors searched a tumor registry for all patients with NF2 who had undergone Gamma Knife radiosurgery (GKRS) for meningioma in the period from January 1, 1999, to September 19, 2013, at a single tertiary care cancer center. Medical records were retrospectively reviewed for patient and tumor characteristics and outcomes. RESULTS: Among the 12 patients who met the search criteria, 125 meningiomas were identified, 87 (70%) of which were symptomatic or progressive and thus treated with GKRS. The median age at the first GKRS was 31 years (interquartile range [IQR] 27-37 years). Five patients (42%) had multiple treatments with a median of 27 months (IQR 14-50 months) until the subsequent GKRS. The median follow-up in surviving patients was 43 months (IQR 34-110 months). The 5-year local tumor control and distant treatment failure rates were 92% and 77%, respectively. Toxicities occurred in 25% of the GKRS treatments, although the majority were Grade 1 or 2. At the last follow-up, 4 patients (33%) had died a neurological death at a median age of 39 years (IQR 37-46 years), and their cases accounted for 45% of all tumors, 55% of all treated tumors, and 58% of all GKRSs. Univariate analysis revealed several predictive variables for distant failure, including male sex (HR 0.28, 95% CI 0.086-0.92, p = 0.036), age at distant failure (HR 0.92, 95% CI 0.90-0.95, p < 0.0001), and prior number of GKRS treatments (HR 1.2, 95% CI 1.1-1.4, p = 0.0049). Local failure, maximum size of the treated tumor, delivered tumor margin dose, and WHO grade were not significant. On multivariate analysis, age at distant failure (HR 0.91, 95% CI 0.88-0.95, p < 0.0001) and prior number of GKRSs (HR 1.3, 95% CI 1.1-1.5, p = 0.004) remained significant. No malignant transformation events among treated tumors were observed. CONCLUSIONS: Radiosurgery represents a feasible modality with minimal toxicity for NF2-associated meningiomas. Increasing patient age was associated with a decreased rate of distant failure, whereas an increasing number of prior GKRS treatments predicted distant failure. Further studies are necessary to determine the long-term patterns of treatment failure in these patients. PMID- 25555192 TI - The balancing act: exploring stigma, economic need and disclosure among male sex workers in Ho Chi Minh City, Vietnam. AB - In Vietnam, there is an emerging HIV epidemic among men who have sex with men (MSM). Male sex workers engage in high-risk sexual behaviours that make them particularly vulnerable to HIV infection. In 2010, 23 MSM in Ho Chi Minh City (HCMC) who recently received payment for sex with another man completed in-depth qualitative interviews exploring motivations for sex work, patterns of sex work disclosure and experiences of social stigma. Interviews were recorded, transcribed and translated into English and analysed using a qualitative descriptive approach. Low wages, unstable employment and family remittances were motivating factors for MSM in HCMC to sell sex. Participants described experiences of enacted and felt social stigma related to their involvement in sex work. In response, they utilised stigma management techniques aimed at concealment of involvement in sex work. Such strategies restricted sexual communication with non-paying sex partners and potentially limited their ability to seek social support from family and friends. Departing from decontextualized depictions of sex work disclosure, our findings describe how decisions to reveal involvement in sex work are shaped by social and structural factors such as social stigma, techniques to minimise exposure to stigma, economic imperatives and familial responsibilities. PMID- 25555194 TI - Paramecium: a promising non-animal bioassay to study the effect of 808 nm infrared diode laser photobiomodulation. AB - OBJECTIVE: Photobiostimulation and photobiomodulation (PBM) are terms applied to the manipulation of cellular behavior using low intensity light sources, which works on the principle of inducing a biological response through energy transfer. The aim of this investigation was to identify a laboratory assay to test the effect of an infrared diode laser light (808 nm) on cell fission rate. MATERIALS AND METHODS: Sixty cells of Paramecium primaurelia were divided in two groups of 30. The first group (test group) was irradiated, at a temperature of 24 degrees C, for 50 sec by a 808 nm diode laser with a flat top handpiece [1 cm of spot diameter, 1 W in continuous wave (CW), 50 sec irradiation time, 64 J/cm(2) of fluence]. The second group (control group) received no laser irradiation. All cells were transferred onto a depression slide, fed, and incubated in a moist chamber at a temperature of 24 degrees C. The cells were exposed and monitored for 10 consecutive fission rates. Changes in temperature and pH were also evaluated. RESULTS: The exposed cells had a fission rate rhythm faster than the control cells, showing a binary fission significantly (p<0.05) shorter than unexposed cells. No significant effects of laser irradiation on pH and temperature of Paramecium's lettuce infusion medium were observed. CONCLUSIONS: The 808 nm infrared diode laser light, at the irradiation parameters used in our work, results in a precocious fission rate in P. primaurelia cells, probably through an increase in metabolic activity, secondary to an energy transfer. PMID- 25555195 TI - Xerophilusin B induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma cells and does not cause toxicity in nude mice. AB - Esophageal cancer is the eighth most common cancer in the world and ranks as the sixth leading cause of cancer-related mortality. Esophageal cancer has a poor prognosis partially due to its low sensitivity to chemotherapy agents, and the development of new therapeutic agents is urgently needed. Here, the antitumor activity of a natural ent-kaurane diterpenoid, xerophilusin B (1), which was isolated from Isodon xerophilus, a perennial herb frequently used in Chinese folk medicine for tumor treatment, was investigated. Compound 1 exhibited antiproliferative effects against esophageal squamous cell carcinoma (ESCC) cell lines in a time- and dose-dependent manner with lower toxicity against normal human and murine cell lines. In vivo studies demonstrated that 1 inhibited tumor growth of a human esophageal tumor xenograft in BALB/c nude mice without significant secondary adverse effects, indicating its safety in treating ESCC. Furthermore, 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines. In conclusion, the observations herein reported showed that 1 is a potential chemotherapeutic agent for ESCC and merits further preclinical and clinical investigation for cancer drug development. PMID- 25555197 TI - Synthesis of highly functionalized tri- and tetrasubstituted alkenes via Pd catalyzed 1,2-hydrovinylation of terminal 1,3-dienes. AB - An efficient method for the construction of Csp(2)-Csp(3) bond in a regio- and stereoselective fashion involving 1,3-terminal dienes, enol triflates/nonaflates, and sodium formate under Pd(0)-catalysis is described. The three component assembly allows trapping of a pi-allyl intermediate, after the initial migratory insertion of the diene, by a hydride source that leads to structurally complex and synthetically challenging tri- and tetrasubstituted alkene building blocks. PMID- 25555198 TI - Dye functionalized cryogel columns for reversible lysozyme adsorption. AB - In this study, poly (methyl methacrylate-glycidyl methacrylate) [poly(MMA-GMA)] cryogels were prepared by radical cryocopolymerization of MMA with GMA as a functional comonomer. Reactive Green 19 dye was then attached to the cryogel by nucleophilic substitution reaction, and this dye-attached cryogel column was used for lysozyme adsorption. Characterization of the cryogel was performed by Fourier transform infrared spectroscopy, environmental scanning electron microscopy, Brunauer-Emmett-Teller, and energy dispersive X-ray analysis. Pore size of the cryogels was 15-30 MUm and pores were interconnected structure. Attached amount of Reactive Green 19 to cryogel support was calculated as 106.25 MUmol/g cryogel. Lysozyme adsorption studies were carried out by using a continuous system. It was found that the maximum amount of lysozyme adsorption (32 mg/g cryogel) obtained from experimental results was found to be approximately same with the calculated Langmuir adsorption capacity (33 mg/g cryogel). Desorption of adsorbed lysozyme was carried out by using 1.5 M NaCl in pH 4.5 acetate buffer, and desorption yield was found to be 97.4%. Cryogels were very stable, and it was found that there was no remarkable reduction in the adsorption capacity at the end of ten adsorption-desorption cycles. As a result, Reactive Green 19-attached cryogels have great advantages such as easy preparation, rapid adsorption, and desorption, being economic and allowing the direct separation of proteins. PMID- 25555199 TI - Paper-based origami triboelectric nanogenerators and self-powered pressure sensors. AB - Discovering renewable and sustainable power sources is indispensable for the development of green electronics and sensor networks. In this paper, we present origami triboelectric nanogenerators (TENGs) using paper as the starting material, with a high degree of flexibility, light weight, low cost, and recyclability. Slinky- and doodlebug-shaped TENGs can be easily fabricated by properly folding printer papers. The as-fabricated TENGs are capable of harvesting ambient mechanical energy from various kinds of human motions, such as stretching, lifting, and twisting. The generated electric outputs have been used to directly light-up commercial LEDs. In addition, the as-fabricated TENGs can also serve as self-powered pressure sensors. PMID- 25555200 TI - A case report of Nosema ceranae infection in honey bees in Minnesota, USA. PMID- 25555201 TI - Enhanced photochemistry of ethyl chloride on Ag nanoparticles. AB - Enhanced photodecomposition of ethyl chloride (EC) adsorbed on SiO2/Si (100) supported silver nanoparticles (Ag NPs) under ultrahigh vacuum (UHV) conditions has been studied in order to assess the potential contribution of plasmonic effects. The cross section for photodecomposition of EC and overall photoyield were found to increase with increasing photon energy regardless of the plasmon resonant wavelength and with Ag coverage without any noticeable particle size effect. The influence of EC-Ag NPs separation distance on the rate of EC decomposition was studied in order to examine potential local electric field influence on the photodissociation process. Long (~5 nm) photoactivity decay distance has been observed which excludes local surface plasmon dominance in the photodecomposition event. These findings suggest that the alignment of excited electron energy and adsorbate affinity levels is central for efficient photochemical reactions, whereas short-range electric field enhancement by plasmon excitation on top and at the immediate vicinity of silver nanoparticles does not have any measurable effect. PMID- 25555202 TI - Single-layer MoS2 electronics. AB - CONSPECTUS: Atomic crystals of two-dimensional materials consisting of single sheets extracted from layered materials are gaining increasing attention. The most well-known material from this group is graphene, a single layer of graphite that can be extracted from the bulk material or grown on a suitable substrate. Its discovery has given rise to intense research effort culminating in the 2010 Nobel Prize in physics awarded to Andre Geim and Konstantin Novoselov. Graphene however represents only the proverbial tip of the iceberg, and increasing attention of researchers is now turning towards the veritable zoo of so-called "other 2D materials". They have properties complementary to graphene, which in its pristine form lacks a bandgap: MoS2, for example, is a semiconductor, while NbSe2 is a superconductor. They could hold the key to important practical applications and new scientific discoveries in the two-dimensional limit. This family of materials has been studied since the 1960s, but most of the research focused on their tribological applications: MoS2 is best known today as a high performance dry lubricant for ultrahigh-vacuum applications and in car engines. The realization that single layers of MoS2 and related materials could also be used in functional electronic devices where they could offer advantages compared with silicon or graphene created a renewed interest in these materials. MoS2 is currently gaining the most attention because the material is easily available in the form of a mineral, molybdenite, but other 2D transition metal dichalcogenide (TMD) semiconductors are expected to have qualitatively similar properties. In this Account, we describe recent progress in the area of single-layer MoS2-based devices for electronic circuits. We will start with MoS2 transistors, which showed for the first time that devices based on MoS2 and related TMDs could have electrical properties on the same level as other, more established semiconducting materials. This allowed rapid progress in this area and was followed by demonstrations of basic digital circuits and transistors operating in the technologically relevant gigahertz range of frequencies, showing that the mobility of MoS2 and TMD materials is sufficiently high to allow device operation at such high frequencies. Monolayer MoS2 and other TMDs are also direct band gap semiconductors making them interesting for realizing optoelectronic devices. These range from simple phototransistors showing high sensitivity and low noise, to light emitting diodes and solar cells. All the electronic and optoelectronic properties of MoS2 and TMDs are accompanied by interesting mechanical properties with monolayer MoS2 being as stiff as steel and 30* stronger. This makes it especially interesting in the context of flexible electronics where it could combine the high degree of mechanical flexibility commonly associated with organic semiconductors with high levels of electrical performance. All these results show that MoS2 and TMDs are promising materials for electronic and optoelectronic applications. PMID- 25555203 TI - Atomistic study on dopant-distributions in realistically sized, highly P-doped Si nanowires. AB - The dependency of dopant-distributions on channel diameters in realistically sized, highly phosphorus-doped silicon nanowires is investigated with an atomistic tight-binding approach coupled to self-consistent Schrodinger-Poisson simulations. By overcoming the limit in channel sizes and doping densities of previous studies, this work examines electronic structures and electrostatics of free-standing circular silicon nanowires that are phosphorus-doped with a high density of ~ 2 * 10(19) cm(-3) and have 12 nm-28 nm cross-sections. Results of analysis on the channel energy indicate that the uniformly distributed dopant profile would be hardly obtained when the nanowire cross-section is smaller than 20 nm. Insufficient room to screen donor ions and shallower impurity bands are the primary reasons of the nonuniform dopant-distributions in smaller nanowires. Being firmly connected to the recent experimental study (Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 15254-15258), this work establishes the first theoretical framework for understanding dopant-distributions in over-10 nm highly doped silicon nanowires. PMID- 25555204 TI - Computational insights on crystal structures of the oxygen-evolving complex of photosystem II with either Ca(2+) or Ca(2+) substituted by Sr(2+). AB - The oxygen-evolving complex of photosystem II can function with either Ca(2+) or Sr(2+) as the heterocation, but the reason for different turnover rates remains unresolved despite reported X-ray crystal structures for both forms. Using quantum mechanics/molecular mechanics (QM/MM) calculations, we optimize structures with each cation in both the resting state (S1) and in a series of reduced states (S0, S-1, and S-2). Through comparison with experimental data, we determine that the X-ray crystal structures with either Ca(2+) or Sr(2+) are most consistent with the S-2 state (i.e., Mn4[III,III,III,II] with O4 and O5 protonated). As expected, the QM/MM models show that Ca(2+)/Sr(2+) substitution results in the elongation of the heterocation bonds and the displacement of terminal waters W3 and W4. The optimized structures also show that hydrogen bonded W5 is displaced in all S states with Sr(2+) as the heterocation, suggesting that this water may play a critical role during water oxidation. PMID- 25555205 TI - Hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts against cell death induced by nutrient deprivation, but not against apoptosis evoked by oxidized LDL. AB - The neutral type 2 sphingomyelinase (nSMase2) hydrolyzes sphingomyelin and generates ceramide, a major bioactive sphingolipid mediator, involved in growth arrest and apoptosis. The role of nSMase2 in apoptosis is debated, and apparently contradictory results have been observed on fibroblasts isolated from nSMase2 deficient fragilitas ossium (homozygous fro/fro) mice. These mice exhibit a severe neonatal dysplasia, a lack of long bone mineralization and delayed apoptosis patterns of hypertrophic chondrocytes in the growth plate. We hypothesized that apoptosis induced by nutrient deprivation, which mimics the environmental modifications of the growth plate, requires nSMase2 activation. In this study, we have compared the resistance of fro/fro fibroblasts to different death inducers (oxidized LDL, hydrogen peroxide and nutrient starvation). The data show that nSMase2-deficient fro/fro cells resist to apoptosis evoked by nutrient starvation (fetal calf serum/glucose/pyruvate-free DMEM), whereas wt fibroblasts die after 48h incubation in this medium. In contrast, oxidized LDL and hydrogen peroxide are similarly toxic to fro/fro and wt fibroblasts, indicating that nSMase2 is not involved in the mechanism of toxicity evoked by these agents. Interestingly, wt fibroblasts treated with the SMase inhibitor GW4869 were more resistant to starvation-induced apoptosis. The resistance of fro/fro cells to starvation-induced apoptosis is associated with an increased expression of hyaluronan synthase 2 (HAS2) mRNAs and protein, which is inhibited by ceramide. In wt fibroblasts, this HAS2 rise and its protective effect did not occur, but exogenously added HA exhibited a protective effect against starvation induced apoptosis. The protective mechanism of HAS2 involves an increased expression of the heat-shock protein Hsp72, a chaperone with antiapoptotic activity. Taken together, these results highlight the role of nSMase2 in apoptosis evoked by nutrient starvation that could contribute to the delayed apoptosis of hypertrophic chondrocytes in the growth plate, and emphasize the antiapoptotic properties of HAS2. PMID- 25555206 TI - Modeling global distribution of agricultural insecticides in surface waters. AB - Agricultural insecticides constitute a major driver of animal biodiversity loss in freshwater ecosystems. However, the global extent of their effects and the spatial extent of exposure remain largely unknown. We applied a spatially explicit model to estimate the potential for agricultural insecticide runoff into streams. Water bodies within 40% of the global land surface were at risk of insecticide runoff. We separated the influence of natural factors and variables under human control determining insecticide runoff. In the northern hemisphere, insecticide runoff presented a latitudinal gradient mainly driven by insecticide application rate; in the southern hemisphere, a combination of daily rainfall intensity, terrain slope, agricultural intensity and insecticide application rate determined the process. The model predicted the upper limit of observed insecticide exposure measured in water bodies (n = 82) in five different countries reasonably well. The study provides a global map of hotspots for insecticide contamination guiding future freshwater management and conservation efforts. PMID- 25555207 TI - Biosorption of nonylphenol by pure algae, field-collected planktons and their fractions. AB - Algal samples were fractionated into lipid (LP), lipid free (LF), alkaline nonhydrolyzable carbon (ANHC), and acid nonhydrolyzable carbon (NHC) fractions, and were characterized by the quantitative (13)C multiCP NMR technique. The biosorption isotherms for nonylphenol (NP) were established and compared with previously published data for phenanthrene (Phen). The log KOC values are significantly higher for the field-collected plankton samples than for the commercial algae and cultured algae samples, correlating with their lipid contents and aliphatic carbon structure. As the NHC fraction contains more poly(methylene) carbon, it exhibits a higher biosorption capacity. The sorption capacities are negatively related to the polarity index, COO/N-C=O, polar C and O alkyl C concentrations, but are positively related to the H/O atomic ratios and poly(methylene) carbon. The higher sorption capacities observed for NP than for Phen on the investigated samples are explained by specific interactions such as hydrogen bonding and pi-pi interaction. PMID- 25555208 TI - Development and implementation of a cohort review for latent tuberculosis infection. AB - The Centers for Disease Control and Prevention (CDC) recommends that, in low incidence settings for tuberculosis (TB), health departments periodically review their cases of latent TB infection (LTBI). The objective of this study was to evaluate the design and implementation of an LTBI cohort review that can be used to assess program performance. The methods used for the LTBI cohort review were developed and modified from those described previously by the CDC for TB disease. A stratified random sample of LTBI cases was selected from three U.S. Army installations to compare program outcomes. A total of 295 TB tests were performed on 215 patients. Sixty-one (76%) of the 80 repeat tests performed were positive. Of the 194 patients who were recommended therapy, 146 (75%) initiated therapy and 114 (59%) completed therapy. The U.S. Army's TB control program can be improved by reducing unnecessary testing of low-risk groups, increasing completion of LTBI treatment, reducing treatment delays, and ensuring data accuracy. The LTBI cohort review should be performed at least annually at the installation level to improve the quality of TB control programs. PMID- 25555209 TI - Brief report: number of tuberculosis tests and diagnoses of latent tuberculosis infection in active component service members, U.S. Armed Forces, January 2004 December 2014. PMID- 25555210 TI - Incidence of Campylobacter infections among service members of the active and reserve components of the U.S. Armed Forces and among other beneficiaries of the Military Health System, 2000-2013. AB - This report reviews the incidence of illness due to Campylobacter bacteria based on diagnoses recorded in healthcare records and reported through the Armed Forces reportable medical event (RME) system. During 2000-2013, incident cases of Campylobacter infection were diagnosed in 1,393 active component service members, 188 members of the reserve component, and 3,891 retirees and family members. Among members of the active component, incidence rates tended to be higher among females, those aged 40 years or older, members of the Army and Air Force, and offi cers. Incidence rates declined from 2002 through 2007 but have risen steadily since, especially from 2010 through 2013. Among retirees and family members, the highest numbers of cases were diagnosed among those aged 5 years or younger and those aged 75 years or older. Cases identifi ed through RME reports (n=2,938) showed the highest numbers of cases in May-August, especially July, and that cases reported from Fort Shafter, HI, accounted for 20% of all cases. Measures and precautions important in preventing Campylobacter infections as well as other food- and waterborne infections are discussed. PMID- 25555211 TI - Glaucoma, active component, U.S. Armed Forces, 1998-2013. AB - Glaucoma is an eye disease that involves progressive optic nerve damage and vision loss, leading to blindness if undetected or untreated. This report describes an analysis using the Defense Medical Surveillance System (DMSS) to identify all active component service members with an incident diagnosis of glaucoma during 1998-2013. The analysis identified 117,075 incident cases of glaucoma and an overall incidence rate of 5.3 per 1,000 person-years (p-yrs). The majority of cases (94.5%) were diagnosed at an early stage as borderline glaucoma. Over the study period, 5.9% of incident case service members were eventually diagnosed with open-angle glaucoma. There were 26 cases of absolute glaucoma, or total blindness. Rates of glaucoma were higher among black, non Hispanic (8.8 per 1,000 p-yrs), Asian (6.6), and Hispanic (5.4) service members, compared with white, non-Hispanic (4.2) service members. Rates among female service members (6.0 per 1,000 p-yrs) were higher than those among male service members (5.1). Between 1998 and 2013, incidence rates of glaucoma declined by 48% among service members older than 44 years of age, while rates increased slightly among service members younger than 30 years of age. PMID- 25555212 TI - Phase behavior, diffusion, structural characteristics, and pH of aqueous hydrophobic ionic liquid confined media: insights into microviscosity and microporsity in the [C4C4im][NTf2] + water system. AB - We present our studies on the physicochemical properties of water confined in Dibutylimidazolium bis(trifluoromethanesulfonylimide) ([C4C4im][NTf2]) reverse micelles through the NMR relaxation measurements that provide us an understanding of microviscosity and pH in the confined condition. We present experimental results on phase behavior, diffusion, structural characteristics and pH in aqueous ionic liquid-confined media. The ternary phase diagram was constructed by the cloud point measurements and the microheterogeneous regions were detected by the measurement of bulk viscosity and diffusion coefficients of K4[Fe(CN)6] inside the homogeneous microemulsion systems through the cyclic voltammetric (CV) measurements. The size of the microemulsion systems was characterized by the dynamic light scattering (DLS) method. The (1)H NMR spectra of homogeneous microemulsion systems were taken which indicates the presence of bound and free water molecules inside the microemulsion system. The NMR spin-lattice relaxation time (T1) of water molecules in its homogeneous microemulsion systems were measured and the reorientational correlation time (tauc) of water molecules obtained from it indicates that the fluidity of homogeneous confined media decreases with the decrease in the composition of water. Microviscosity of the aqueous confined media was calculated from the measured T1 relaxation time values by applying the Debye-Stokes equation and correlated with the bulk viscosity of the samples. It was observed that both the microviscosity and bulk viscosity show inverse relationship. The fraction of bound and free water molecules were calculated from the measured T1 values. NMR spin-spin relaxation time (T2) of water molecules in its homogeneous microemulsion systems were measured with the varying pH of the aqueous core. A change in the T2 relaxation time of the water proton was observed proposing an exchange of proton between the H2O and -OH group of the TX-100 molecules. Finally, methyl orange (MO) was used as a UV-vis spectrophotometric molecular probe and the measured lambdamax values of the probe were used for the detection of micropolarity of the homogeneous aqueous confined media and was found to be increase with the increase in the size of the confined media. PMID- 25555214 TI - Metabolically normal obese people are protected from adverse effects following weight gain. AB - BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 +/- 4 kg/m2 who were matched for BMI and fat mass. RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain-induced metabolic dysfunction. TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170. FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation. PMID- 25555213 TI - TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. AB - While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-gamma ratio in respiratory secretions. The IL-4/IFN-gamma ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL 4/IFN-gamma ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention. PMID- 25555215 TI - Differentiation of hypothalamic-like neurons from human pluripotent stem cells. AB - The hypothalamus is the central regulator of systemic energy homeostasis, and its dysfunction can result in extreme body weight alterations. Insights into the complex cellular physiology of this region are critical to the understanding of obesity pathogenesis; however, human hypothalamic cells are largely inaccessible for direct study. Here, we developed a protocol for efficient generation of hypothalamic neurons from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) obtained from patients with monogenetic forms of obesity. Combined early activation of sonic hedgehog signaling followed by timed NOTCH inhibition in human ESCs/iPSCs resulted in efficient conversion into hypothalamic NKX2.1+ precursors. Application of a NOTCH inhibitor and brain derived neurotrophic factor (BDNF) further directed the cells into arcuate nucleus hypothalamic-like neurons that express hypothalamic neuron markers proopiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AGRP), somatostatin, and dopamine. These hypothalamic-like neurons accounted for over 90% of differentiated cells and exhibited transcriptional profiles defined by a hypothalamic-specific gene expression signature that lacked pituitary markers. Importantly, these cells displayed hypothalamic neuron characteristics, including production and secretion of neuropeptides and increased p-AKT and p-STAT3 in response to insulin and leptin. Our results suggest that these hypothalamic-like neurons have potential for further investigation of the neurophysiology of body weight regulation and evaluation of therapeutic targets for obesity. PMID- 25555216 TI - Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. AB - The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3'-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB 1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3 dependent metabolic markers and gene expression profiles in Tx rats. PMID- 25555217 TI - Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. AB - Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit's functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems. PMID- 25555221 TI - Generation of dense plume fingers in saturated-unsaturated homogeneous porous media. AB - Flow under variable-density conditions is widespread, occurring in geothermal reservoirs, at waste disposal sites or due to saltwater intrusion. The migration of dense plumes typically results in the formation of vertical plume fingers which are known to be triggered by material heterogeneity or by variations in source concentration that causes the density variation. Using a numerical groundwater model, six perturbation methods are tested under saturated and unsaturated flow conditions to mimic heterogeneity and concentration variations on the pore scale in order to realistically generate dense fingers. A laboratory scale sand tank experiment is numerically simulated, and the perturbation methods are evaluated by comparing plume fingers obtained from the laboratory experiment with numerically simulated fingers. Dense plume fingering for saturated flow can best be reproduced with a spatially random, time-constant perturbation of the solute source. For unsaturated flow, a spatially and temporally random noise of solute concentration or a random conductivity field adequately simulate plume fingering. PMID- 25555219 TI - Designer aminoglycosides prevent cochlear hair cell loss and hearing loss. AB - Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum beta lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics. PMID- 25555222 TI - Improving antipsychotic adherence among patients with schizophrenia: savings for states. AB - This column presents findings of an analysis conducted to quantify the potential net savings to state budgets from interventions to improve adherence to antipsychotic drugs among patients with schizophrenia. Using a financial model based on published data, the authors estimated costs of direct medical care and criminal justice system involvement at state and national levels and validated it against findings from other cost studies. The model estimated an annual cost of $21.4 billion (in 2013 dollars) to Medicaid programs and other state agencies for people with schizophrenia. On the basis of data on the effect on outcomes of increased medication adherence, better adherence could yield annual net savings of $3.28 billion to states or $1,580 per patient per year. Innovations to improve adherence to antipsychotic drugs among schizophrenia patients can yield substantial savings in state budgets. States should consider interventions shown to increase medication adherence in this patient group. PMID- 25555218 TI - F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. AB - The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis. PMID- 25555220 TI - Proximity ligation assay evaluates IDH1R132H presentation in gliomas. AB - For a targeted cancer vaccine to be effective, the antigen of interest needs to be naturally processed and presented on MHC by the target cell or an antigen presenting cell (APC) in the tumor stroma. The presence of these characteristics is often assumed based on animal models, evaluation of antigen-overexpressing APCs in vitro, or assays of material-consuming immune precipitation from fresh solid tissue. Here, we evaluated the use of an alternative approach that uses the proximity ligation assay (PLA) to identify the presentation of an MHC class II restricted antigen in paraffin-embedded tissue sections from patients with brain tumors. This approach required a specific antibody directed against the epitope that was presented. We used an antibody that specifically binds an epitope of mutated isocitrate dehydrogenase type 1 (IDH1R132H), which is frequently expressed in gliomas and other types of tumors. In situ PLA showed that the IDH1R132H epitope colocalizes with MHC class II in IDH1R132H-mutated glioma tissue. Moreover, PLA demonstrated colocalization between the class II epitope containing melanoma antigen New York esophageal 1 and MHC class II. Collectively, our data suggest that PLA may be a useful tool to acquire information on whether an antigen is presented in situ, and this technique has potential to guide clinical studies that use antigen-specific cancer immunotherapy. PMID- 25555224 TI - Magnetite impregnation effects on the sorbent properties of activated carbons and biochars. AB - This paper discusses the sorbent properties of magnetic activated carbons and biochars produced by wet impregnation with iron oxides. The sorbents had magnetic susceptibilities consistent with theoretical predictions for carbon-magnetite composites. The high BET surface areas of the activated carbons were preserved in the synthesis, and enhanced for one low surface area biochar by dissolving carbonates. Magnetization decreased the point of zero charge. Organic compound sorption correlated strongly with BET surface areas for the pristine and magnetized materials, while metal cation sorption did not show such a correlation. Strong sorption of the hydrophobic organic contaminant phenanthrene to the activated carbon or biochar surfaces was maintained following magnetite impregnation, while phenol sorption was diminished, probably due to enhanced carbon oxidation. Copper, zinc and lead sorption to the activated carbons and biochars was unchanged or slightly enhanced by the magnetization, and iron oxides also contributed to the composite metal sorption capacity. While a magnetic biochar with 219 +/- 3.7 m(2)/g surface area nearly reached the very strong organic pollutant binding capacity of the two magnetic activated carbons, a magnetic biochar with 68 +/- 2.8 m(2)/g surface area was the best metal sorbent. Magnetic biochars thus hold promise as more sustainable alternatives to coal derived magnetic activated carbons. PMID- 25555223 TI - Hepatic proteomic responses in marine medaka (Oryzias melastigma) chronically exposed to antifouling compound butenolide [5-octylfuran-2(5H)-one] or 4,5 dichloro-2-N-octyl-4-isothiazolin-3-one (DCOIT). AB - The pollution of antifoulant SeaNine 211, with 4,5-dichloro-2-n-octyl-4 isothiazolin-3-one (DCOIT) as active ingredient, in coastal environment raises concerns on its adverse effects, including endocrine disruption and impairment of reproductive function in marine organisms. In the present study, we investigated the hepatic protein expression profiles of both male and female marine medaka (Oryzias melastigma) exposed to low concentrations of DCOIT at 2.55 MUg/L (0.009 MUM) or butenolide, a promising antifouling agent, at 2.31 MUg/L (0.012 MUM) for 28 days. The results showed that proteins involved in phase I (CYP450 enzyme) metabolism, phase II (UDPGT and GST) conjugation as well as mobilization of retinoid storage, an effective nonenzymatic antioxidant, were consistently up regulated, possibly facilitating the accelerated detoxification of butenolide. Increased synthesis of bile acid would promote the immediate excretion of butenolide metabolites. Activation of fatty acid beta-oxidation and ATP synthesis were consistent with elevated energy consumption for butenolide degradation and excretion. However, DCOIT did not significantly affect the detoxification system of male medaka, but induced a marked increase of vitellogenin (VTG) by 2.3-fold in the liver of male medaka, suggesting that there is estrogenic activity of DCOIT in endocrine disruption. Overall, this study identified the molecular mechanisms and provided sensitive biomarkers characteristic of butenolide and DCOIT in the liver of marine medaka. The low concentrations of butenolide and DCOIT used in the exposure regimes highlight the needs for systematic evaluation of their environmental risk. In addition, the potent estrogenic activity of DCOIT should be considered in the continued applications of SeaNine 211. PMID- 25555225 TI - Development of an automated ballast water treatment verification system utilizing fluorescein diacetate hydrolysis as a measure of treatment efficacy. AB - Methods for verifying ballast water treatments in foreign vessels are needed to protect the Great Lakes from the discharge of live non-native organisms or pathogens. A prototype automated viability test system using fluorescein diacetate (FDA), a membrane permeable fluorogen, to differentiate live from dead bacteria and algae is described. The automated fluorescence intensity detection device (AFIDD) captures cultured algae or organisms in Detroit River water (simulated ballast water) on 0.2 MUm filters, backwashes them from the filter into a cuvette with buffer and FDA for subsequent fluorescence intensity measurements, and washes the filters with sterile water for serial automated reuse. Preliminary manual versions of these procedures were also tested. Tests of various buffers determined N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, N,N-Bis(2-hydroxyethyl)taurine (BES) and 3-(N-morpholino)propanesulfonic acid (MOPS) at pH 7.0 to be the best buffers, causing the least spontaneous FDA breakdown without inhibiting enzymatic activity. Fluorescence in the presence of live organisms increased linearly over time, and the rate of increase was dependent on the sample concentration. Following simulated ballast water treatments with heat or chlorine, the fluorescence produced by Detroit River samples decreased to near control (sterile water) levels. Automated measurements of FDA hydrolysis with a reusable filter backwash system should be applicable to near real-time remote-controlled monitoring of live organisms in ballast water. PMID- 25555226 TI - Improvement of stress tolerance and leavening ability under multiple baking associated stress conditions by overexpression of the SNR84 gene in baker's yeast. AB - During the bread-making process, industrial baker's yeast cells are exposed to multiple baking-associated stresses, such as elevated high-temperature, high sucrose and freeze-thaw stresses. There is a high demand for baker's yeast strains that could withstand these stresses with high leavening ability. The SNR84 gene encodes H/ACA snoRNA (small nucleolar RNA), which is known to be involved in pseudouridylation of the large subunit rRNA. However, the function of the SNR84 gene in baker's yeast coping with baking-associated stresses remains unclear. In this study, we explored the effect of SNR84 overexpression on baker's yeast which was exposed to high-temperature, high-sucrose and freeze-thaw stresses. These results suggest that overexpression of the SNR84 gene conferred tolerance of baker's yeast cells to high-temperature, high-sucrose and freeze thaw stresses and enhanced their leavening ability in high-sucrose and freeze thaw dough. These findings could provide a valuable insight for breeding of novel stress-resistant baker's yeast strains that are useful for baking. PMID- 25555227 TI - Toxigenic potential and heat survival of spore-forming bacteria isolated from bread and ingredients. AB - Fifty-four spore-forming bacterial strains isolated from bread ingredients and bread, mainly belonging to the genus Bacillus (including Bacillus cereus), together with 11 reference strains were investigated to evaluate their cytotoxic potential and heat survival in order to ascertain if they could represent a risk for consumer health. Therefore, we performed a screening test of cytotoxic activity on HT-29 cells using bacterial culture filtrates after growing bacterial cells in Brain Heart Infusion medium and in the bread-based medium Bread Extract Broth (BEB). Moreover, immunoassays and PCR analyses, specifically targeting already known toxins and related genes of B. cereus, as well as a heat spore inactivation assay were carried out. Despite of strain variability, the results clearly demonstrated a high cytotoxic activity of B. cereus strains, even if for most of them it was significantly lower in BEB medium. Cytotoxic activity was also detected in 30% of strains belonging to species different from B. cereus, although, with a few exceptions (e.g. Bacillus simplex N58.2), it was low or very low. PCR analyses detected the presence of genes involved in the production of NHE, HBL or CytK toxins in B. cereus strains, while genes responsible for cereulide production were not detected. Production of NHE and HBL toxins was also confirmed by specific immunoassays only for B. cereus strains even if PCR analyses revealed the presence of related toxin genes also in some strains of other species. Viable spore count was ascertained after a heat treatment simulating the bread cooking process. Results indicated that B. amyloliquefaciens strains almost completely survived the heat treatment showing less than 2 log cycle reductions similarly to two strains of B. cereus group III and single strains belonging to Bacillus subtilis, Bacillus mojavensis and Paenibacillus spp. Importantly, spores from strains of the B. cereus group IV exhibited a thermal resistance markedly lower than B. cereus group III with high values of log-cycle reductions. In conclusion, our results indicate that spore-forming bacteria contaminating bread ingredients and bread could represent a source of concern for consumer health related to the presence of strains, such as strains of B. cereus group III and single strains of other species, showing the ability to produce toxic substances associated to a thermal resistance enough to survive the bread cooking conditions. PMID- 25555228 TI - Airborne dissemination of Escherichia coli in a dairy cattle farm and its environment. AB - There are multiple ways bacteria can be transported from its origin to another area or substrate. Water, food handlers, insects and other animals are known to serve as a vehicle for bacterial dispersion. However, the importance of the air in open areas as a possible way of bacterial dissemination has not been so well analyzed. In this study, we investigated the airborne dissemination of Escherichia coli from the inside of a dairy cattle farm to the immediate environment. The air samples were taken inside the farm (area 0) and from the immediate outside farm surroundings at distance of 50, 100 and 150m in four directions (north, south, east, and west). At each point, the air was collected at different heights: 40cm, 70cm and 1m. The sampling was carried out in two weather seasons (November and July). E. coli was isolated in both inside and outside air, even in samples taken 150m from the farm. A seasonal effect was observed with more bacterial isolates when temperature was higher. Regarding the distribution of the isolates, wind direction appeared as a determining factor. In order to verify that E. coli strains isolated from animal housing facilities were identical to those isolated from the air of the immediate farm environment, their genomic DNA profiles were analyzed by pulsed-field gel electrophoresis (PFGE) after digestion with the endonuclease XbaI. The comparison of genetic profiles suggested that the strains isolated from inside and outside the farm were related, leading to the conclusion that the air is an important vehicle for E. coli dissemination. PMID- 25555229 TI - Bayesian modelling to identify the risk factors for Yersinia enterocolitica contamination of pork carcasses and pluck sets in slaughterhouses. AB - The probability of contamination by pathogenic Yersinia enterocolitica of carcasses and pluck sets at slaughterhouse was determined by means of a Bayesian analysis. Prior information of the prevalence of Y. enterocolitica in faeces and the seroprevalence of Yersinia in serum of pigs collected at farms were obtained from previous studies and introduced in the models as beta prior informative distributions. Samples of intestinal content, tonsils, and swabs of carcasses and pluck set surfaces were collected at slaughterhouses. The posterior probabilities, odds ratio (OR) and their probability interval (PI) were calculated by means of a generalized linear model constructed in WinBugs. Occurrence of Y. enterocolitica in intestinal content (OR: 35.6, 95%PI 2.8-8285), tonsils (OR: 38.4, 95%PI 5.0-854), and pluck set (OR: 16.6, 95%PI 1.9-1111) was a risk for the contamination of pork carcasses, and an increased risk of contaminated pluck set was observed when Y. enterocolitica was isolated in intestinal content (OR: 40.6, 95%PI 2.1-10510) and tonsils (OR: 17.6, 95%PI 3.4 230.6). This increased risk indicated a potential cross-contamination at the slaughterhouse. PMID- 25555231 TI - Heterochrony and early left-right asymmetry in the development of the cardiorespiratory system of snakes. AB - Snake lungs show a remarkable diversity of organ asymmetries. The right lung is always fully developed, while the left lung is either absent, vestigial, or well developed (but smaller than the right). A 'tracheal lung' is present in some taxa. These asymmetries are reflected in the pulmonary arteries. Lung asymmetry is known to appear at early stages of development in Thamnophis radix and Natrix natrix. Unfortunately, there is no developmental data on snakes with a well developed or absent left lung. We examine the adult and developmental morphology of the lung and pulmonary arteries in the snakes Python curtus breitensteini, Pantherophis guttata guttata, Elaphe obsoleta spiloides, Calloselasma rhodostoma and Causus rhombeatus using gross dissection, MicroCT scanning and 3D reconstruction. We find that the right and tracheal lung develop similarly in these species. By contrast, the left lung either: (1) fails to develop; (2) elongates more slowly and aborts early without (2a) or with (2b) subsequent development of faveoli; (3) or develops normally. A right pulmonary artery always develops, but the left develops only if the left lung develops. No pulmonary artery develops in relation to the tracheal lung. We conclude that heterochrony in lung bud development contributes to lung asymmetry in several snake taxa. Secondly, the development of the pulmonary arteries is asymmetric at early stages, possibly because the splanchnic plexus fails to develop when the left lung is reduced. Finally, some changes in the topography of the pulmonary arteries are consequent on ontogenetic displacement of the heart down the body. Our findings show that the left-right asymmetry in the cardiorespiratory system of snakes is expressed early in development and may become phenotypically expressed through heterochronic shifts in growth, and changes in axial relations of organs and vessels. We propose a step-wise model for reduction of the left lung during snake evolution. PMID- 25555232 TI - Eating disorders and sense of self: a learning theory conceptualization. AB - The learning theory view of sense of self is that problems in one's knowledge about the self arise when: (1) caregivers fail to recognize indicators of a child's private emotional and visceral experiences and (2) subsequently fail to offer appropriate labels that discriminate among those experiences. The purpose of this study was to evaluate the relationship of the process believed to build a sense of self to level of interoceptive awareness (IA) and to risk for eating disorders. One hundred twenty seven undergraduate and graduate students (112 women) completed the Eating Disorders Inventory-3 (EDI-3). Authors assigned (EDI 3) subscales to one of two groups based on their relevance to IA (i.e., IA relevant and Not IA-relevant.) The classification was supported by factor analysis. Subscales from the EDI-3 were thus used as a measure of a respondent's IAlevel. Students also completed the Experience of Self Scale (EOSS). The EOSS was used as a measure of a respondent's likely exposure to the experiential process believed to build sense of self. Product-moment correlations and multiple regression modeling were used to test the relationships between EOSS and EDI-3 IA relevant, Not IA-relevant, and Eating Disorder risk scores. With few exceptions, results suggested that IAlevel and sense of selfprocess are related. These findings warrant further exploration of the relationship between IAlevel and sense of selfprocess. A link between the two would inform our understanding of how problems in IA develop and how best to prevent and treat them. PMID- 25555233 TI - National characteristics and variation in Arabic handwriting. AB - From each of four Arabic countries; Morocco, Tunisia, Jordan and Oman, 150 participants produced handwriting samples which were examined to assess whether national characteristics were discernible. Ten characters, which have different configurations depending upon their position in the word, along with one short word, were classified into distinguishable forms, and these forms recorded for each handwriting sample. Tests of independence showed that character forms used were not independent of country (p<0.001) for all but one character-position (this was dropped from subsequent analyses). A correspondence analysis ordination plot and analysis of similarity (R=0.326, p=0.0002) showed that whole samples were discernibly grouped by country, and a tree analysis produced a classification which was 71% accurate for the original data and 83% accurate for 80 new handwriting samples that underwent 'blind' classification. When the countries were combined into two regions, North Africa and Middle East, the grouping was more marked. Thus, there appears to be some scope for narrowing down the nationality, and particularly the wider geographical region of an author based upon the character forms they use in Arabic handwriting. PMID- 25555234 TI - Flattening mountains: micro-fabrication of planar replicas for bullet lateral striae analysis. AB - The application of replica molding has proven to be a valuable tool in the analysis of different forensic evidences in particular for its ability to extract the toolmarks from complex sample surfaces. A well known problem in the analysis of ballistic evidences is the accurate characterization of the lateral striae of real bullets seized on crime scenes after shots, due primarily to impact deformations and to unpredictable issues related to laboratory illumination setup. To overcome these problems a possible way is to confine over a flat surface all the features still preserving their three dimensionality. This can be achieved by a novel application of replica molding performed onto the relevant lateral portion of the bullet surface. A quasi-two-dimensional negative copy of the original tridimensional indented surface has been thus fabricated. It combines the real tridimensional topography of class characteristics (land and groove impressions) and of individual caracteristics (striae) impressed by rifled barrels on projectiles, moreover with the possibility of quantitative characterization of these features in a planar configuration, that will allow one shot comparison of the "whole striae landscape" without the typical artifacts arising from the bullet shape and the illumination issue. A detailed analysis has been carried on at the morphological level by standard optical and scanning electron microscopy, while the 3D topography has been characterized by white light optical profilometry. A quantitative characterization of toolmarks of bullets derived from ammunitions shot by guns of large diffusion, as the Beretta 98 FS cal. 9*21 mm, has been performed and will be presented ranging between the whole landscape and the sub-MUm resolution. To investigate the real potentiality of this technique, the experiment has been extended to highly impact-deformed projectiles. PMID- 25555235 TI - Association of anemia, pre-eclampsia and eclampsia with seasonality: a realist systematic review. AB - Seasonal patterns influencing maternal health have been documented globally and are of particular importance for women in developing countries who disproportionately suffer from anemia, pre-eclampsia and eclampsia. This paper adopts a realist systematic approach to investigate the maternal outcome of anemia and eclampsia in relation to seasonality. A review of 23 published studies shows a statistically significant link between these maternal disorders and seasonality in developing countries in Sub-Saharan Africa and Central and South Asia. Anemia and eclampsia tend to decrease during the dry season, only to increase with greater rainfall, low and cold temperatures. Numerous studies suggest that the seasonality of anemia and eclampsia is associated with changes in malaria transmission. This was observed during the rainy season, suggesting a potential seasonal relationship with malaria as a driver of these disorders in Sub-Saharan Africa. Anemia and eclampsia were principally exacerbated among primigravidae and young women. Food insecurity, access to antenatal care, poverty, and environmental factors may also play a crucial role in the predisposition to these disorders. More research is required to identify the seasonal link between malaria and eclampsia particularly as climate change may exacerbate the rate of the disorders in tropical and sub-tropical areas. PMID- 25555237 TI - Eugenic metal-free sensitizers with double anchors for high performance dye sensitized solar cells. AB - A series of new phenothiazine-based dyes (HL5-HL7) with double acceptors/anchors have been synthesized and used as the sensitizers for highly efficient dye sensitized solar cells (DSSCs). Among them, the HL7-based cell exhibits the best efficiency of 8.32% exceeding the N719-based cell (7.35%) by ~13%. PMID- 25555236 TI - Size at birth by gestational age and hospital mortality in very preterm infants: results of the area-based ACTION project. AB - BACKGROUND: Size at birth is an important predictor of neonatal outcomes, but there are inconsistencies on the definitions and optimal cut-offs. AIMS: The aim of this study is to compute birth size percentiles for Italian very preterm singleton infants and assess relationship with hospital mortality. STUDY DESIGN: Prospective area-based cohort study. SUBJECTS: All singleton Italian infants with gestational age 22-31 weeks admitted to neonatal care in 6 Italian regions (Friuli Venezia-Giulia, Lombardia, Marche, Tuscany, Lazio and Calabria) (n. 1605). OUTCOME MEASURE: Hospital mortality. METHODS: Anthropometric reference charts were derived, separately for males and females, using the lambda (lambda) mu (MU) and sigma (sigma) method (LMS). Logistic regression analysis was used to estimate mortality rates by gestational age and birth weight centile class, adjusting for sex, congenital anomalies and region. RESULTS: At any gestational age, mortality decreased as birth weight centile increased, with lowest values observed between the 50th and the 89th centiles interval. Using the 75th-89th centile class as reference, adjusted mortality odds ratios were 7.94 (95% CI 4.18 15.08) below 10th centile; 3.04 (95% CI 1.63-5.65) between the 10th and 24th; 1.96 (95% CI 1.07-3.62) between the 25th and the 49th; 1.25 (95% CI 0.68-2.30) between the 50(h) and the 74th; and 2.07 (95% CI 1.01-4.25) at the 90th and above. CONCLUSIONS: Compared to the reference, we found significantly increasing adjusted risk of death up to the 49th centile, challenging the usual 10th centile criterion as risk indicator. Continuous measures such as the birthweight z-score may be more appropriate to explore the relationship between growth retardation and adverse perinatal outcomes. PMID- 25555238 TI - Comparative fracture toughness of multilayer graphenes and boronitrenes. AB - We report the comparative in situ fracture toughness testing on single-edge V/U notched multilayer graphenes and boronitrenes in a high-resolution transmission electron microscope (HRTEM). The nanostructures of notch tips and fracture edges of the tested specimens are unambiguously resolved using HRTEM. By analyzing the notch tip stresses using finite element method, the fracture toughness of multilayer graphenes and boronitrenes is determined to be 12.0 +/- 3.9 and 5.5 +/ 0.7 MPa?m, respectively, taking into account the notch tip blunting effects. PMID- 25555240 TI - Volume estimation of low-contrast lesions with CT: a comparison of performances from a phantom study, simulations and theoretical analysis. AB - Measurements of lung nodule volume with multi-detector computed tomography (MDCT) have been shown to be more accurate and precise compared to conventional lower dimensional measurements. Quantifying the size of lesions is potentially more difficult when the object-to-background contrast is low as with lesions in the liver. Physical phantom and simulation studies are often utilized to analyze the bias and variance of lesion size estimates because a ground truth or reference standard can be established. In addition, it may also be useful to derive theoretical bounds as another way of characterizing lesion sizing methods. The goal of this work was to study the performance of a MDCT system for a lesion volume estimation task with object-to-background contrast less than 50 HU, and to understand the relation among performances obtained from phantom study, simulation and theoretical analysis. We performed both phantom and simulation studies, and analyzed the bias and variance of volume measurements estimated by a matched-filter-based estimator. We further corroborated results with a theoretical analysis to estimate the achievable performance bound, which was the Cramer-Rao's lower bound (CRLB) of minimum variance for the size estimates. Results showed that estimates of non-attached solid small lesion volumes with object-to-background contrast of 31-46 HU can be accurate and precise, with less than 10.8% in percent bias and 4.8% in standard deviation of percent error (SPE), in standard dose scans. These results are consistent with theoretical (CRLB), computational (simulation) and empirical phantom bounds. The difference between the bounds is rather small (for SPE less than 1.9%) indicating that the theoretical- and simulation-based performance bounds can be good surrogates for physical phantom studies. PMID- 25555241 TI - Minor salivary gland basal cell adenocarcinoma: a systematic review and report of a new case. AB - IMPORTANCE: Basal cell adenocarcinoma (BCAC) of the minor salivary gland is an extremely rare disease: the most recent substantive literature review reports only 25 cases. Owing to the rarity of this disease, it has not yet been well characterized in the literature. OBJECTIVE: We sought to expand the knowledge of minor salivary gland BCAC by performing an exhaustive literature review and adding to it a new case that is rare owing to the tumor's size, aggressive nature, and mixed histologic pattern. The review emphasizes epidemiologic patterns, diagnostic characteristics, treatment patterns, and expected prognosis for minor salivary gland BCAC. EVIDENCE ACQUISITION: In June 2012, PubMed was queried using the term "salivary gland basal cell adenocarcinoma," and the resultant articles were reviewed. Those specifically mentioning a minor salivary gland BCAC were included in this study. Those that did not differentiate minor salivary gland BCAC from major salivary gland BCAC were excluded. The search was not limited by language and included articles from North America, Europe, Africa, and Asia from 1978 to June 2012. RESULTS: The PubMed search resulted in 195 articles, of which 33 articles reported at least 1 case of minor salivary gland BCAC. We report herein 72 cases of minor salivary gland BCAC (71 cases from the literature review and 1 new case reported herein). The mean patient age at the time of presentation was 56 years (range, 24-90 years), and the disease showed no sex predilection. The most common location was the palate, and the average lesions size was 2.4 cm (range, 0.7-4.2 cm). The treatment modality of choice was wide local excision (n = 57; 79%). There was a high local recurrence rate (n = 30; 41%) but a low rate of distant metastasis (n = 8; 11%). CONCLUSIONS AND RELEVANCE: We present a comprehensive review of minor salivary gland BCAC, describing nearly 3 times as many cases as has been previously reported. This review characterizes a rare disease and increases awareness of the disease among otolaryngologists. Minor salivary gland BCAC is similar to major salivary gland BCAC and minor salivary gland tumors in general with regard to patient age, sex, tumor site, treatment modality, recurrence, metastasis, and mortality. PMID- 25555242 TI - Prevention of hydroxychloroquine-related retinal toxic effects--reply. PMID- 25555239 TI - OsGL1-3 is involved in cuticular wax biosynthesis and tolerance to water deficit in rice. AB - Cuticular wax covers aerial organs of plants and functions as the outermost barrier against non-stomatal water loss. We reported here the functional characterization of the Glossy1(GL1)-homologous gene OsGL1-3 in rice using overexpression and RNAi transgenic rice plants. OsGL1-3 gene was ubiquitously expressed at different level in rice plants except root and its expression was up regulated under ABA and PEG treatments. The transient expression of OsGL1-3-GFP fusion protein indicated that OsGL1-3 is mainly localized in the plasma membrane. Compared to the wild type, overexpression rice plants exhibited stunted growth, more wax crystallization on leaf surface, and significantly increased total cuticular wax load due to the prominent changes of C30-C32 aldehydes and C30 primary alcohols. While the RNAi knockdown mutant of OsGL1-3 exhibited no significant difference in plant height, but less wax crystallization and decreased total cuticular wax accumulation on leaf surface. All these evidences, together with the effects of OsGL1-3 on the expression of some wax synthesis related genes, suggest that OsGL1-3 is involved in cuticular wax biosynthesis. Overexpression of OsGL1-3 decreased chlorophyll leaching and water loss rate whereas increased tolerance to water deficit at both seedling and late-tillering stages, suggesting an important role of OsGL1-3 in drought tolerance. PMID- 25555243 TI - Meaning in Life and depressive symptoms: a person-oriented approach in residential and community-dwelling older adults. AB - OBJECTIVES: In current society, an increasing population of older adults and a high prevalence of depressive symptoms in late life is noticeable. A possible protective resource is 'Meaning in Life'. The objective of this study is to identify from a person-oriented view (a) Meaning in Life-profiles, based on Presence of Meaning and Search for Meaning dimensions, and (b) their associations with depressive symptoms. METHODS: A sample of 205 residential older adults (M = 83.20 years, SD = 7.26) and 280 community-dwelling older adults (M = 75.98 years, SD = 4.76) completed questionnaires of Meaning in Life and depressive symptoms. First, cluster analyses examined potential Meaning in Life-profiles. Second, analyses of variance tested associations between these distinct profiles and depressive symptoms. RESULTS: In both samples, three distinguishable profiles emerged, a 'Low Presence Low Search', a 'High Presence High Search' and a 'High Presence Low Search'. Furthermore, older adults with a High Presence Low Search profile witnessed less depressive symptoms, compared to those with a Low Presence Low Search profile. Residential older adults within the High Presence High Search cluster scored in-between the two other clusters for depressive symptoms. However, community-dwelling older adults within this cluster reported similar levels of depressive symptoms as the High Presence Low Search group. CONCLUSION: Similar Meaning in Life-profiles were detected in residential as well as community-dwelling older adults. In both samples, older adults with a High Presence Low Search profile reported less depressive feelings, pointing to the importance of spontaneously experiencing Meaning in Life in this life stage. PMID- 25555244 TI - Bioimaging of the microRNA-294 expression-dependent color change in cells by a dual fluorophore-based molecular beacon. AB - A dual fluorophore-based color-tunable molecular beacon visualized the microRNA 294 expression-dependent color change in cells. PMID- 25555246 TI - International Validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma. AB - IMPORTANCE: Although an accurate uveal melanoma staging system is needed to improve research and patient care, the evaluation of eye cancer staging systems requires international multicenter data sharing to acquire a statistically significant analysis. OBJECTIVE: To assess patient mortality outcomes associated with uveal melanoma staging according to the 7th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. DESIGN, SETTING, PARTICIPANTS: A committee was formed to create patient-specific data fields for patients with uveal melanoma. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma from April 1, 2001, to April 1, 2011, adequate records to allow tumor staging by the AJCC criteria, and follow-up for metastatic melanoma. INTERVENTIONS: Primary treatments included local resection, radiation therapy, and enucleation. MAIN OUTCOMES AND MEASURES: Metastasis after initial tumor staging with 5- and 10-year Kaplan-Meier metastasis-free point estimates, depending on AJCC prognostic stages I through IV, tumor size category, and subclassification (defined by the presence of ciliary body involvement and/or extrascleral extension). RESULTS: A total of 3809 patients were entered into the database. Of these, 3377 records (88.7%) were complete. Primary ciliary body and choroidal melanoma was the diagnosis for 3217, and 160 had primary iris melanoma. Tumor size categories were T1 in 1115 (34.7%) of the 3217 patients, T2 in 1128 patients (35.1%), T3 in 789 patients (24.5%), and T4 in 185 patients (5.8%). The 5- and 10-year Kaplan-Meier metastasis-free point estimates by tumor size categories were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for T1 tumors, 85% (95% CI, 82%-88%) and 80% (95% CI, 75%-84%) for T2 tumors, 77% (95% CI, 73%-80%) and 68% (95% CI, 60%-74%) for T3 tumors, and 61% (95% CI, 49%-71%) (5-year only) for T4 tumors, respectively. Increasing tumor size was consistent with increased metastasis risk (P < .001). Subclassifications were significantly associated with increased risk of metastasis (P < .001). The AJCC prognostic and anatomical groupings were as follows: stage I, 1030 (32.0%); stage IIA, 1095 (34.0%); stage IIB, 710 (22.1%); stage IIIA, 282 (8.8%); stage IIIB, 79 (2.5%); and stage IIIC, 21 (0.7%). The 5- and 10-year Kaplan-Meier metastasis-free estimates for prognostic stages were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for stage I, 89% (95% CI, 86%-91%) and 84% (95% CI, 80% 88%) for stage IIA, 79% (95% CI, 75%-83%) and 70% (95% CI, 62%-76%) for stage IIB, 67% (95% CI, 59%-73%) and 60% (95% CI, 51%-68%) for stage IIIA, 50% (95% CI, 33%-65%) and 50% (95% CI, 33%-65%) for stage IIIB, and 25% (95% CI, 4%-53%) (5 year only) for stage IIIC, respectively. The 160 iris melanomas were too few for subgroup analysis. CONCLUSIONS AND RELEVANCE: Multicenter, worldwide, Internet based data sharing was used to study a heterogenous patient population in ophthalmic oncology. Our results support the continued use of the 7th edition of the AJCCCancer Staging Manual for uveal melanoma. PMID- 25555247 TI - The molecular basis of primary aldosteronism: from chimeric gene to channelopathy. AB - Primary aldosteronism (PA) is the most common endocrine cause of high blood pressure. Only a minority of the PA cases are familial and due to known (CYP11B2/CYP11B1 chimeric gene or mutations in the KCNJ5 gene) or unknown causes. In the most common sporadic cases the mechanisms by which the excess aldosterone production persists in spite of high blood pressure, sodium retention, suppression of the renin angiotensin system and low potassium levels, all factors that by themselves would be expected to shut off aldosterone production, were a puzzle for decades. Only recently the discovery of functional mutations and down regulation of potassium channels provided some explanations. We herein reviewed these recent findings and their mechanistic implications. We also propose a clinical molecular classification of familial hyperaldosteronism, which can be important from the practical standpoint as it considers besides the molecular features also the responsiveness to treatment and the imaging features. PMID- 25555248 TI - Bilingual exposure influences infant VOT perception. AB - Linking the discrimination of voice onset time (VOT) in infancy with infant language background, we examine the perceptual changes of two VOT contrasts (/b/ /p/ and /p(h)/-/p/) by Dutch monolingual and bilingual infants from 8 to 15 months of age. Results showed that language exposure and language dominance had a strong impact on monolingual and bilingual infant VOT perceptual patterns. In addition, perceptual turbulence was found at 8-9 months for bilingual infants, and stabilized perception was presented for all infants from 11 months onwards. We thus report a general input-driven developmental VOT perception in both monolingual and bilingual infants, with perceptual turbulence for bilinguals in the second half of the first year of life. PMID- 25555249 TI - Postantifungal-like effect of sublethal treatment of Candida albicans with acid electrolyzed water. AB - OBJECTIVE: Acid-electrolyzed water (AEW) has been applied to the treatment of oral candidiasis. We evaluated the postantifungal effect (PAFE)-like activity of AEW against Candida albicans under sublethal conditions by exposing C. albicans to dilute AEW. DESIGN: The growth of C. albicans after a short-term exposure to dilute AEW was evaluated in broth and on agar culture. The involvement of reactive oxygen species (ROS) in the PAFE was examined by flow cytometric analysis with hydroxyphenyl fluorescein (HPF) as a fluorescence probe. RESULTS: The dilute AEW exerted PAFE-like activity against C. albicans. ROS were produced in the cells treated with AEW diluted 16 times or fewer. The increase in HPF fluorescence after treatment with dilute AEW was cancelled by dimethyl sulfoxide, a hydroxyl radical (OH) scavenger. CONCLUSION: It would be expected that the ROS, especially OH, produced in the C. albicans cells treated with sublethal dilutions of AEW could exert PAFE-like activity against the fungal cells. PMID- 25555250 TI - Rho kinase mediates Porphyromonas gingivalis outer membrane vesicle-induced suppression of endothelial nitric oxide synthase through ERK1/2 and p38 MAPK. AB - OBJECTIVE: To investigate the effect of Rho kinase (ROCK) on Porphyromonas gingivalis outer membrane vesicles (OMVs)-induced suppression of endothelial nitric oxide synthase (eNOS) and explore the potential mechanism. DESIGN: Firstly, we investigated the effect of OMVs on total eNOS expression and eNOS activity in Human Umbilical Vein Endothelial Cells (HUVECs) and if ROCK activation is involved. Furthermore, we estimated the effect of ROCK in regulating eNOS expression and the possible underlying mechanism in vitro. At last we confirmed the results by immunohisochemisty for eNOS expression in mouse aorta endothelium exposed to OMVs and inhibitors. RESULTS: We found that OMVs suppressed eNOS expression both at RNA and protein levels in a time- and dose dependent manner. ROCK activity was observed in this process by detecting phosphorylation of myosin light chain (MLC) and myosin-associated phosphatase type 1 (MYPT-1), which lead to reduced eNOS expression. The suppression of eNOS was significantly reversed by ROCK inhibitor Y-27632. Moreover, Y-27632 pretreatment obviously inhibited the activation of ERK1/2 and p38 MAPKs induced by OMVs, whereas that of JNK was not affected. In addition, blocking ERK1/2 or p38 MAPK by PD98059 and SB203580, respectively attenuated the OMVs-induced eNOS phosphorylation. Ex vivo study shows that OMVs reduced eNOS expression in mouse aorta endothelium. Co-treatment with OMVs and inhibitors could significantly reverse the eNOS suppression. Taken together, these results demonstrate that ROCK mediated OMVs-induced eNOS suppression through ERK1/2 and p38 MAPK. CONCLUSIONS: These data suggest that ROCK may mediate OMVs-induced eNOS expression through ERK1/2 and p38 MAPK. PMID- 25555251 TI - ACE insertion/deletion polymorphism is associated with periodontal disease in Korean population. AB - OBJECTIVE: Angiotensin-converting enzyme (ACE) is the core enzyme in the renin angiotensin system (RAS), which catalyzes the production of angiotensin II (Ang II). The aim of this study was to determine whether ACE gene is associated with the development of the periodontal disease. DESIGN: To investigate whether ACE is involved in the development of the periodontal disease, 199 periodontal disease patients and 165 control subjects were studied. The ACE insertion/deletion polymorphism was analyzed using polymerase chain reaction (PCR). SNPStats and SPSS 18.0 were used for the analysis of genetic data. Logistic regression models were performed to determine odds ratio (OR), 95% confidence interval (CI), and P value. RESULTS: Genotypic frequencies of I/I, I/D, and D/D were 25.4%, 42.3%, and 32.3% vs. 35.3%, 41.7%, and 23.1% (periodontal disease group vs. control group), respectively. In the genotype analysis of the ACE insertion/deletion polymorphism, codominant and log-additive models both showed significant association with periodontal disease [OR = 1.94, 95% CI = 1.05-3.61, P=0.036 in the codominant model (I/I vs. D/D); OR = 1.39, 95% CI = 1.02-1.90, P = 0.034 in the log-additive model (I/I vs. I/D vs. D/D)]. CONCLUSIONS: These results suggest that the ACE insertion/deletion polymorphism may be associated with the susceptibility to the periodontal disease in the Korean population. PMID- 25555252 TI - Lithium inhibits palatal fusion and osteogenic differentiation in palatal shelves in vitro. AB - OBJECTIVE: Glycogen synthase kinase-3beta (Gsk-3beta)/beta-catenin signaling regulates development of the secondary palate. It has been unclear about the effects of Gsk-3beta/beta-catenin signaling on palatal fusion and osteogenic differentiation in palatal shelves. DESIGN: In this study, palatal shelves from mouse embryonic day 13 (E13) were cultured in vitro with or without lithium chloride (LiCl). Palatal fusion was evaluated by haematoxylin-eosin staining. The expression of osteogenic markers in palatal shelves was measured by quantitative PCR, and immunohistochemical staining. Cell proliferation and apoptosis were examined by Ki-67 immunohistochemical and TUNEL staining, respectively. Gsk-3beta expression was evaluated by quantitative PCR and Western blotting. beta-catenin protein expression was evaluated by Western blotting. RESULTS: After the treatment with 10 mM LiCl, palatal shelves failed to fuse, and the mRNA and protein levels of osteogenic markers were reduced compared with controls. The number of Ki67-positive cell in the palatal osteoid was significantly higher in the LiCl group than in the controls. The apoptotic cells in the midline epithelial seam were reduced by LiCl. Gsk-3beta mRNA and protein expression levels decreased and beta-catenin protein expression levels increased by treatment of LiCl. CONCLUSION: Our findings show that LiCl-mediated GSK3beta inhibition prevents palatal fusion and osteogenic differentiation in palatal shelves by increased beta-catenin signaling. It indicated that overactivation of canonical Wnt signaling might impair the fusion of the secondary palate. PMID- 25555253 TI - Are antimicrobial peptides related to cyclosporine A-induced gingival overgrowth? AB - OBJECTIVE: The aim of the present study was to investigate the effect of cyclosporine-A (CsA) medication on gingival crevicular fluid (GCF) LL-37, human neutrophil peptide (HNP)1-3 and adrenomedullin (ADM) levels. DESIGN: CsA-treated renal transplant recipients with GO (CsA GO+) and without GO (CsA GO-), tacrolimus-medicated renal transplant recipients (n = 20/group), systemically healthy subjects with gingivitis (n = 21) and individuals free of periodontal and systemic diseases (n = 20) were included in the present study. Periodontal parameters were recorded and GCF samples were obtained from the study participants. GCF LL-37, HNP1-3 and ADM levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: GCF LL-37 total amount was higher at GO+ sites than the other study sites (p < 0.05). Total amount of GCF HNP1-3 was higher in immunosuppressive treatment groups than healthy and gingivitis groups, regardless of GO presence (p < 0.05). GCF ADM total amount was similar in all study groups. GCF volume, papillary bleeding index and hyperplastic index (p < 0.05) were significantly correlated with GCF LL-37 total amounts (p < 0.05), but not with GCF HNP1-3 and ADM total amount at GO+ sites (p > 0.05). CONCLUSION: Neutrophil infiltration due to extended inflammation might have increased GCF LL-37 levels at GO+ sites and contributed to the pathogenesis of CsA-induced GO. PMID- 25555254 TI - Eight species in the Nebela collaris complex: Nebela gimlii (Arcellinida, Hyalospheniidae), a new species described from a Swiss raised bog. AB - We describe here a new species of sphagnicolous testate amoeba found abundantly in the forested part of the Le Cachot peatland (Jura Mountains, Neuchatel, Switzerland) based on microscopical observations (LM, SEM). The new species, called Nebela gimlii was placed in a phylogenetic tree based on mitochondrial cytochrome oxidase sequences (COI), and branched robustly within the N. collaris complex next to the morphologically similar N. guttata and N. tincta. It is however genetically clearly distinct from these two species, and differs morphologically from them by its smaller size and stouter shape of the shell. This new species completes the phylogeny of the Nebela collaris species complex, with now eight species described, mostly from peatlands and acidic forest litter, and further demonstrates the existence of an unknown diversity within testate amoebae. Improving the taxonomy of testate amoebae in peatlands and clarifying the ecology of newly discovered species should make these organisms even more valuable as bioindicator and for palaeoecological reconstruction. PMID- 25555255 TI - Early childhood WIC participation, cognitive development and academic achievement. AB - For the 22% of American children who live below the federal poverty line, and the additional 23% who live below twice that level, nutritional policy is part of the safety net against hunger and its negative effects on children's development. The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) provides steadily available food from the food groups essential for physical and cognitive development. The effects of WIC on dietary quality among participating women and children are strong and positive. Furthermore, there is a strong influence of nutrition on cognitive development and socioeconomic inequality. Yet, research on the non-health effects of U.S. child nutritional policy is scarce, despite the ultimate goal of health policies directed at children-to enable productive functioning across multiple social institutions over the life course. Using two nationally representative, longitudinal surveys of children-the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) and the Child Development Supplement (CDS) of the Panel Study of Income Dynamics-I examine how prenatal and early childhood exposure to WIC is associated in the short-term with cognitive development, and in the longer-term with reading and math learning. Results show that early WIC participation is associated with both cognitive and academic benefits. These findings suggest that WIC meaningfully contributes to children's educational prospects. PMID- 25555256 TI - The effect of leaving radical on the formation of tetrahydroselenophene by SHi ring closure: an experimental and computational study. AB - Competition kinetic studies augmented with laser-flash photolysis and high-level computational techniques [G3(MP2)-RAD], with [COSMO-RS, SMD] and without solvent correction, provide kinetic parameters for the ring closures of a series of 4 (alkylseleno)butyl radicals 1. At 22 degrees C rate constants (kc) that lie between 10(4)-10(7) s(-1) were determined experimentally and correlate with expectations based on leaving group ability. Activation energies (Eact) were determined to lie between 10.6 (R = Ph2CH) and 28.0 (R = n-Bu) kJ mol(-1), while log(A/s(-1)) values were generally between 9 and 10 in benzene. Computationally determined rate constants were in good-to-excellent agreement with those determined experimentally, with the COSMO-RS solvation model providing values that more closely resemble those from experiment than SMD. PMID- 25555257 TI - Identification of the typical metal particles among haze, fog, and clear episodes in the Beijing atmosphere. AB - For a better understanding of metal particle morphology and behaviors in China, atmospheric aerosols were sampled in the summer of 2012 in Beijing. The single particle analysis shows various metal-bearing speciations, dominated by oxides, sulfates and nitrates. A large fraction of particles is soluble. Sources of Fe bearing particles are mainly steel industries and oil fuel combustion, whereas Zn and Pb-bearing particles are primarily contributed by waste incineration, besides industrial combustion. Other trace metal particles play a minor rule, and may come from diverse origins. Mineral dust and anthropogenic source like vehicles and construction activities are of less importance to metal-rich particles. Statistics of 1173 analyzed particles show that Fe-rich particles (48.5%) dominate the metal particles, followed by Zn-rich particles (34.9%) and Pb-rich particles (15.6%). Compared with the abundances among clear, haze and fog conditions, a severe metal pollution is identified in haze and fog episodes. Particle composition and elemental correlation suggest that the haze episodes are affected by the biomass burning in the southern regions, and the fog episodes by the local emission with manifold particle speciation. Our results show the heterogeneous reaction accelerated in the fog and haze episodes indicated by more zinc nitrate or zinc sulfate instead of zinc oxide or carbonate. Such information is useful in improving our knowledge of fine airborne metal particles on their morphology, speciation, and solubility, all of which will help the government introduce certain control to alleviate metal pollution. PMID- 25555258 TI - Effect of inundation, oxygen and temperature on carbon mineralization in boreal ecosystems. AB - The inundation of boreal forests and peatlands through the construction of hydroelectric reservoirs can increase carbon dioxide (CO2) and methane (CH4) emission. To establish controls on emission rates, we incubated samples of forest and peat soils, spruce litter, forest litter and peatland litter collected from boreal ecosystems in northern Quebec for 16 weeks and measured CO2 and CH4 production rates under flooded or non-flooded conditions and varying oxygen concentration and temperature. CO2 production under flooded conditions was less than under non-flooded conditions (5-71 vs. 5-85 mg Cg(-1) C), but CH4 production under flooded conditions was larger than under non-flooded conditions (1-8158 vs. 0-86 MUg Cg(-1) C). The average CO2 and CH4 production rate factor for flooded:non-flooded conditions was 0.76 and 1.32, respectively. Under flooded conditions, high oxygen concentrations increased CO2 production in peat soils but decreased CH4 production in forest and peat soils and spruce litter. Warmer temperatures (from 4 to 22 degrees C) raised both CO2 production in peat soils and peatland litter, and CH4 production in peat soils and spruce litter. This study shows that the direction and/or strength of CO2 and CH4 fluxes change once boreal forests and peatlands are inundated. PMID- 25555259 TI - Differential expression of CYP1A1 and CYP1A2 genes in H4IIE rat hepatoma cells exposed to TCDD and PAHs. AB - Rat hepatoma cells H4IIE were treated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs) (dibenz(a,h)anthracene, benzo(a)pyrene, benz(a)anthracene, chrysene), low-concentration mixtures of PAHs and TCDD, and environmental mixtures contaminated by PAHs and their derivatives. Expression of the gene battery comprising cytochrome P450 Cyp1a1, Cyp1a2, Cyp1b1, and glutathione-s-transferase Gsta2 and Gstp was investigated using quantitative real time polymerase chain reaction (qRT-PCR) analysis. The results revealed that TCDD induce Cyp1a1>Cyp1a2>Cyp1b1, while PAHs and PAH-containing environmental mixtures induce Cyp1a2>Cyp1a1>Cyp1b1 gene expression pattern. While low concentration mixtures elicited a more pronounced response in comparison to single treatments, the typical gene expression patterns were not observed. In all samples, Gsta2 was predominantly expressed relative to Gstp. These findings indicate that differential Cyp1a1 and Cyp1a2 expression in the H4IIE cells might be used for detection of PAHs in highly contaminated environmental mixtures, but not in low-concentration mixtures of these compounds. PMID- 25555260 TI - Anticedants and natural prevention of environmental toxicants induced accelerated aging of skin. AB - Skin is frequently exposed to a variety of environmental and chemical agents that accelerate ageing. External stress such as UV radiations (UVR) and environmental pollutants majorly deteriorate the skin morphology, by activating certain intrinsic factors such as Reactive Oxygen Species (ROS) which trigger the activation of Matrix Metalloproteinases (MMPs) and inflammatory responses hence damaging the extracellular matrix (ECM) components. To counter this, an exogenous supply of anti-oxidants, is required since the endogenous anti-oxidant system cannot alone suffice the need. Bio-prospecting of natural resources for anti oxidants has hence been intensified. Immense research is being carried out to identify potential plants with potent anti-oxidant activity against skin ageing. This review summarizes the major factors responsible for premature skin ageing and the plants being targeted to lessen the impact of those. PMID- 25555261 TI - Dissecting cancer evolution at the macro-heterogeneity and micro-heterogeneity scale. AB - Intratumour heterogeneity complicates biomarker discovery and treatment personalization, and pervasive cancer evolution is a key mechanism leading to therapy failure and patient death. Thus, understanding subclonal heterogeneity architectures and cancer evolution processes is critical for the development of effective therapeutic approaches which can control or thwart cancer evolutionary plasticity. Current insights into heterogeneity are mainly limited to the macroheterogeneity level, established by cancer subclones that have undergone significant clonal expansion. Novel single cell sequencing and blood-based subclonal tracking technologies are enabling detailed insights into microheterogeneity and the dynamics of clonal evolution. We assess how this starts to delineate the rules governing cancer evolution and novel angles for more effective therapeutic intervention. PMID- 25555262 TI - Protein profile of exhaled breath condensate determined by high resolution mass spectrometry. AB - A method based on liquid chromatography/high resolution tandem mass spectrometry coupled with electrophoretic separation, for determination and relative quantification of the protein composition of exhaled breath condensate (EBC), was developed. Application of the procedure to a sample of EBC, pooled from nine healthy subjects, resulted in the identification of 167 unique gene products, 113 of which not previously reported in EBC samples. The abundance of the protein identified was estimated by means of the exponentially modified protein abundance index protocol (emPAI). Cytokeratins were by far the most abundant proteins in EBC samples. Many of the identified proteins were associated with multiple cellular location with cytoplasm constituting the largest group. Cytosol, nucleus, membrane, cytoskeleton and extracellular were other abundantly represented locations. No amylase was detected, suggesting the absence of saliva protein contamination. The profile obtained represents the most comprehensive protein characterization of EBC so far reported and demonstrates that this approach provides a powerful tool for investigating the protein profile of EBC samples. Compared with analogous investigations, this study also shows that the protein profile of EBC is strongly affected by the sampling method adopted. PMID- 25555263 TI - Identification of new phytoconstituents and antimicrobial activity in stem bark of Mangifera indica (L.). AB - Mangifera indica, commonly called mango or amra belonging to a family of Anacardiaceae, is an important medicinal plant widely used in a variety of Ayurvedic preparations. Extract of its bark, leaves, flowers and kernels are being extensively used for curing various chronic diseases. Mango wood is used in yagya as base fire through which medicated smoke is generated. Three new compounds have been isolated from methanolic and hexane extracts of stem bark: 1,2-benzenedicarboxylic acid, mono(2-ethylhexyl)ester and 9,12-tetradecadiene-1 ol-acetate from the hexane extract and 3-chloro-N-(2-phenylethyl) propanamide from the methanolic extract. These were first separated by thin layer chromatography and later in a silica gel column and identified by characteristic infrared bands corresponding to respective functional groups. The compounds were further confirmed on the basis of GC-MS fragmentation pattern after comparing the data with NIST mass spectral database. All three compounds exhibited antimicrobial activity due to triterpenoids and flavonoids. Elemental analyses by INAA show it to be enriched in essential nutrient elements such as Ca, Fe, K, Mn and Zn which all play an important role in enzymatic processes. PMID- 25555264 TI - Developmental specialization of the left parietal cortex for the semantic representation of Arabic numerals: an fMR-adaptation study. AB - The way the human brain constructs representations of numerical symbols is poorly understood. While increasing evidence from neuroimaging studies has indicated that the intraparietal sulcus (IPS) becomes increasingly specialized for symbolic numerical magnitude representation over developmental time, the extent to which these changes are associated with age-related differences in symbolic numerical magnitude representation or with developmental changes in non-numerical processes, such as response selection, remains to be uncovered. To address these outstanding questions we investigated developmental changes in the cortical representation of symbolic numerical magnitude in 6- to 14-year-old children using a passive functional magnetic resonance imaging adaptation design, thereby mitigating the influence of response selection. A single-digit Arabic numeral was repeatedly presented on a computer screen and interspersed with the presentation of novel digits deviating as a function of numerical ratio (smaller/larger number). Results demonstrated a correlation between age and numerical ratio in the left IPS, suggesting an age-related increase in the extent to which numerical symbols are represented in the left IPS. Brain activation of the right IPS was modulated by numerical ratio but did not correlate with age, indicating hemispheric differences in IPS engagement during the development of symbolic numerical representation. PMID- 25555265 TI - Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT). AB - OBJECTIVE: Heterozygous familial hypercholesterolaemia (FH) is a common autosomal dominant disorder. The vast majority of affected individuals remain undiagnosed, resulting in lost opportunities for preventing premature heart disease. Better use of routine primary care data offers an opportunity to enhance detection. We sought to develop a new predictive algorithm for improving identification of individuals in primary care who could be prioritised for further clinical assessment using established diagnostic criteria. METHODS: Data were analysed for 2,975,281 patients with total or LDL-cholesterol measurement from 1 Jan 1999 to 31 August 2013 using the Clinical Practice Research Datalink (CPRD). Included in this cohort study were 5050 documented cases of FH. Stepwise logistic regression was used to derive optimal multivariate prediction models. Model performance was assessed by its discriminatory accuracy (area under receiver operating curve [AUC]). RESULTS: The FH prediction model (FAMCAT), consisting of nine diagnostic variables, showed high discrimination (AUC 0.860, 95% CI 0.848-0.871) for distinguishing cases from non-cases. Sensitivity analysis demonstrated no significant drop in discrimination (AUC 0.858, 95% CI 0.845-0.869) after excluding secondary causes of hypercholesterolaemia. Removing family history variables reduced discrimination (AUC 0.820, 95% CI 0.807-0.834), while incorporating more comprehensive family history recording of myocardial infraction significantly improved discrimination (AUC 0.894, 95% CI 0.884-0.904). CONCLUSION: This approach offers the opportunity to enhance detection of FH in primary care by identifying individuals with greatest probability of having the condition. Such cases can be prioritised for further clinical assessment, appropriate referral and treatment to prevent premature heart disease. PMID- 25555266 TI - Subclinical atherosclerosis and increased risk of hearing impairment. AB - OBJECTIVE: The study's purpose was to test if subclinical atherosclerosis was associated with the risk of developing HI in a large cohort of middle-aged participants. METHODS: Study subjects were members of the Beaver Dam Offspring Study (BOSS), a longitudinal study of adult children of participants in the population-based Epidemiology of Hearing Loss Study (1993-present). BOSS examinations took place in 2005-2008 (baseline) and 2010-2013 (5-year follow-up). The 5-year incidence of hearing impairment was defined as a pure-tone average (PTA) of thresholds at 0.5, 1, 2 and 4 kHz > 25 dB Hearing Level (dB HL) in either ear at follow-up among participants at risk (baseline PTA in both ears < = 25 dB HL; n = 2436, mean age = 47.7 years). Atherosclerosis was measured as the mean carotid intima-media thickness and the presence of carotid artery plaque. RESULTS: Among the 1984 participants at-risk with a follow-up audiometric examination, the 5-year incidence of hearing impairment was 8.3% (95% Confidence Interval (C.I.) 7.1, 9.5). With multivariable adjustment, carotid intima-media thickness was positively associated with hearing impairment incidence (Relative Risk (RR) = 1.14 per 0.1 mm, 95% C.I. 1.04, 1.24). The number of sites (0-6) with plaque was also positively associated with the incidence of impairment (RR = 1.16 per site, 95% C.I. 1.01, 1.32). CONCLUSION: Atherosclerosis was associated with the 5-year incidence of hearing impairment in this predominantly middle-aged cohort. Interventions targeting atherosclerosis prevention may help to prevent or delay the onset of hearing impairment. PMID- 25555268 TI - Circulating gamma glutamyltransferase and prediction of cardiovascular disease. AB - BACKGROUND: The value of measuring levels of gamma glutamyltransferase (GGT) for the prediction of first cardiovascular events is uncertain. We aimed to determine whether adding information on GGT values to conventional cardiovascular risk factors is associated with improvement in prediction of CVD risk. METHODS: Circulating GGT levels were measured at baseline in the PREVEND prospective cohort study. We included 6969 participants without a prevalent history of CVD. Hazard ratios (95% confidence intervals [CI]) and measures of risk discrimination for CVD outcomes (e.g., C-index) and reclassification (i.e., net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5%to <7.5%), and high (>=7.5%) risk were assessed. RESULTS: During a median follow-up of 10.5 years, 735 incident CVD events were recorded. Loge GGT was linearly associated with CVD risk. In analyses adjusted for conventional plus several potential cardiovascular risk factors, the hazard ratio (95% CI) for CVD per 1 standard deviation increase in loge GGT was 1.24 (1.12 1.37; P < 0.001), which was attenuated somewhat after further adjustment for C reactive protein 1.18 (1.06-1.30; P = 0.002). Addition of information on GGT to a CVD risk prediction model containing conventional risk factors was associated with a C-index change of 0.0003 (-0.0015 to 0.0022; P = 0.73) and a net reclassification improvement of 1.19% (-0.11-2.49%; P = 0.07) for the categories of predicted 10-year CVD risk. CONCLUSIONS: In the general population, adding GGT to conventional CVD risk factors is unlikely to improve prediction of first-ever cardiovascular events. PMID- 25555270 TI - Intima media thickness measurement in children: A statement from the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention endorsed by the Association for European Paediatric Cardiology. AB - Atherosclerosis causing cardiovascular disease is the most common cause of death in the developed world. Early precursors of vascular changes - subclinical atherosclerosis - warrant special attention as this process can be stabilized or even reversed if treated in time. Sonographic Intima Media Thickness measurement of the carotid artery (cIMT: carotid Intima-Media-Thickness) is considered a valid surrogate marker for cardiovascular risk allowing assessment of atherosclerotic changes at a very early stage. It is easy to apply due to its non invasive character. Moreover, cIMT has been proven to provide reliable and reproducible results both in adult and adolescent patients. For the paediatric age group, several characteristics deserve special consideration. The heterogeneity of techniques of scanning, measurement and interpretation impede the comparison and interpretation of IMT values so far. Also, age- and sex dependent normative data have to be considered for interpretation. Thus, the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention concludes to refer a statement on cIMT scanning, measurement and interpretation with special focus on paediatric patients. This statement includes an overview on normative data available as well as a practical guideline for the setting, scanning, measurement and interpretation of IMT values. Synchronizing different measurement methods will allow for comparing the results of several research centers. By that, in a large patient number, sufficient information may be given to assess the long-term endpoints of cardiovascular morbidity and mortality. PMID- 25555271 TI - Seasonal pattern in acute aortic diseases: US results confirm Italian findings. PMID- 25555269 TI - Serum chemokine CCL17/thymus activation and regulated chemokine is correlated with coronary artery diseases. AB - OBJECTIVE: It was recently reported that chemokine CC-motif ligand 17 (CCL17) expressing dendritic cells drove atherosclerosis by restraining regulatory T cell homeostasis in an animal model. Our preliminary study has shown that serum CCL17 levels may be associated with coronary artery disease (CAD). The aim of this study was to confirm the relationship between serum CCL17 levels and CAD. METHODS: Patients presenting to our center for coronary angiography between January 2013 and December 2013 were recruited for the study. Serum CCL17 levels were determined by enzyme-linked immunosorbent assay. Atherosclerosis severity was assessed in each patient according to the Gensini score. RESULTS: In total, 971 consecutive patients were enrolled in this study, including 158 non-CAD patients and 813 CAD patients (238 with stable angina pectoris, 321 with unstable angina, 128 with non-ST elevation myocardial infarction, and 126 with ST elevation myocardial infarction). CAD patients had higher serum CCL17 levels compared to patients without CAD [265.90 (170.80-376.65) pg/mL versus 218.35 (142.83-293.45) pg/mL, p < 0.001]. After adjusting for traditional risk factors, serum CCL17 levels remained associated with CAD. Meanwhile, there was a significant linear trend between serum CCL17 levels and the different CAD subtypes (p for linear trend = 0.002). Finally, serum CCL17 levels (per 100 pg/mL) were positively associated with the Gensini score (B 2.310; 95% CI 0.503 4.118; p = 0.012) even after adjusting for confounding factors. CONCLUSION: Serum CCL17 levels are associated with CAD and atherosclerosis severity independently of traditional cardiovascular risk factors. PMID- 25555272 TI - Safety of short-term dual antiplatelet therapy after drug-eluting stents: An updated meta-analysis with direct and adjusted indirect comparison of randomized control trials. AB - BACKGROUND: Duration of dual antiplatelet therapy (DAPT) following drug-eluting stents (DES) remains controversial and is a topic of ongoing research. METHODS: Direct and adjusted indirect comparisons of all the recent randomized control trials (RCTs) were performed to evaluate the safety of short-term versus long term DAPT following DES. RESULTS: 8 RCTs were identified and 7 (16,318 subjects) were included. 4 groups of 3 vs 12 months, 6 vs 12 months, 6 vs 24 months and 12 vs 24 months of DAPT were used for direct comparison. There was no significant difference in stent thrombosis, myocardial infarction (MI), stroke and revascularization, cardiovascular and all-cause mortality between the different durations in all 4 groups. Pooling trials of 3-6 months of DAPT against 12 months, we found a significant reduction in the risk of total bleeding (RR 0.61, 95% CI 0.43-0.87). Adjusted indirect comparison between 3 vs 6 months, 3 vs 24 months and 6 vs 24 month duration of DAPT showed no significant differences in risk of death or MI, or revascularization between 3 or 6 months and 24 months. However, 24months of DAPT was associated with significantly more bleeding than 3 or 6 months. CONCLUSIONS: 3 to 6 months of DAPT following second generation DES and above is safe with no increased risk of thrombotic complications and mortality, and lower bleeding risk. However a tailored approach may be more appropriate for high-risk patients. PMID- 25555273 TI - A complete bicameral pacemaker pocket decubitus. PMID- 25555274 TI - Coronary chronic total occlusion: Not only a therapeutic nihilism but also a lack of requisite expertise. PMID- 25555275 TI - Giant left atrium in 72 year old male. PMID- 25555277 TI - Management of ALCAPA in two pregnancies. PMID- 25555276 TI - Improved renal function in a patient with hypertrophic obstructive cardiomyopathy after multidetector computed tomography-guided percutaneous transluminal septal myocardial ablation. PMID- 25555278 TI - Interferon regulatory factors: New targets for intervention of cardiovascular diseases. PMID- 25555267 TI - Relationship between carotid intima-media thickness and non valvular atrial fibrillation type. AB - OBJECTIVE: Carotid intima-media thickness (cIMT) is a surrogate marker of subclinical atherosclerosis and it is able to predict both coronary and cerebral vascular events. No data exist on the association between cIMT and non valvular atrial fibrillation (NVAF) type. We conduct this study with the aim to analyze the association between abnormal cIMT and NVAF type. METHODS: A cross-sectional study of the "Atrial fibrillation Registry for Ankle-brachial index Prevalence Assessment-Collaborative Italian Study (ARAPACIS)" has been performed. Among 2027 patients enrolled in the ARAPACIS, 673 patients, who underwent carotid ultrasound examination to assess cIMT, were included in the study. RESULTS: Among the entire population, 478 patients (71%) had cIMT > 0.90 mm. Patients with an abnormal cIMT (>0.90 mm) were significantly older and more likely hypertensive, diabetic and with a previous history of stroke than those with normal cIMT (<=0.90 mm). These patients had more permanent/persistent NVAF and CHA2DS2-VASc score >= 2 (p < 0.0001) compared to those with cIMT <0.90 mm. Excluding all patients affected by previous cardiovascular disease, logistic regression analysis showed that independent predictors of abnormal cIMT were: age class 65-74 yrs. (p < 0.001), age class >=75 yrs. (p < 0.001), arterial hypertension (p < 0.001), calcium channel blockers use (p < 0.001) and persistent/permanent NVAF (p = 0.001). CONCLUSION: Our findings show a high prevalence of abnormal cIMT in NVAF patients, reinforcing the concept that NVAF and systemic atherosclerosis are closely associated. Abnormal cIMT was particularly evident in persistent/permanent NVAF suggesting a more elevated atherosclerotic burden in patients with long-standing NVAF. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01161251. PMID- 25555279 TI - Takotsubo cardiomyopathy associated with complete atrioventricular block and Torsades de pointes. PMID- 25555280 TI - Exercise as the master polypill of the 21st century for the prevention of cardiovascular disease. PMID- 25555282 TI - A multimarker approach to diagnose and stratify heart failure. AB - BACKGROUND: We have previously demonstrated that circulating NT-proBNP is truncated at the N and C termini. Aims of this study are three-fold: firstly to determine whether the NT-proBNP levels correlate with NYHA functional classes when measuring with different antibody pairs; secondly to evaluate the diagnostic potential of ProBNP and; thirdly to investigate whether combining NT-proBNP assays with or without ProBNP would lead to better diagnostic accuracies. METHODS: Plasma samples were collected from healthy controls (n=52) and HF patients (n=46). Customized AlphaLISA(r) immunoassays were developed and validated to measure the concentrations of proBNP and NT-proBNP (with antibodies targeting 13-45, 13-76, 28-76). The diagnostic performance and predictive value of proBNP and NT-proBNP assays and their combinations were evaluated. RESULTS: Plasma proBNP assay showed acceptable diagnostic performance. NT-proBNP13-76 assay is useful in diagnosing and stratifying HF patients. The diagnostic performance of NT-proBNP13-76 demonstrated improvement over commercial NT-proBNP tests. The combination of NT-proBNP13-76 with NT-proBNP28-76 assays gave the best diagnostic assay performance. CONCLUSION: Our results demonstrate that while there is major heterogeneity in circulating NT-proBNP, specific epitopes of the peptides are extraordinarily stable, providing ideal targets for clinically useful diagnostic assays. Future new clinical diagnostic clinical trials should include a multimarker approach rather than using a single marker to diagnose HF. PMID- 25555283 TI - Ranolazine: Drug overview and possible role in primary microvascular angina management. AB - Ranolazine is a novel well-tolerated anti-ischemic drug, which selectively inhibits late sodium current and exerts metabolic properties without any hemodynamic effect. Ranolazine has been approved as a second-line medical treatment for symptomatic stable coronary artery disease. Primary microvascular angina (MVA) is suspected when angina symptoms occur in patients with demonstrated myocardial ischemia, absence of myocardial disease and normal coronary artery angiography. Recent clinical data suggest that MVA represents a complex entity, which has been increasingly recognized as a significant cause of morbidity. High variability and low response to traditional anti-anginal treatment characterize primary MVA. Despite the fact that clinical and preclinical evidence provides information regarding ranolazine usefulness in primary MVA management, only three recent small randomized trials have investigated this issue. By selecting peer-reviewed literature in Pubmed and Cochrane Library, this review provides an overview on ranolazine pharmacology and efficacy, focusing on recent evidence suggesting its usefulness in management of primary MVA. PMID- 25555281 TI - The prognostic impact of diastolic dysfunction in patients with chronic heart failure and post-acute myocardial infarction: Can age-stratified E/A ratio alone predict survival? AB - OBJECTIVE: To determine the prognostic implications of diastolic filling grades and identify whether age-stratified E/A ratio alone can identify patients at high risk of death post-AMI and HF. We hypothesized that in response to ageing and pathology, a normal E/A (>1) could be considered abnormal in patients post-AMI older than 65years, and that in patients with symptomatic HF, a normal E/A always represents advanced diastolic dysfunction. METHODS AND RESULTS: This is a sub analysis of the Meta-analysis Research Group in Echocardiography (MeRGE) which combined individual patient data from 30 prospective studies and demonstrated that restrictive filling was an important and independent predictor of all-cause mortality. This sub-analysis is restricted to those studies in which continuous E/A data were available (20 studies) and includes a total of 3082 AMI and 2321 HF patients. Patients were classified at the time of echocardiography into four filling patterns: normal, abnormal relaxation, pseudonormal, and restrictive filling. Post-AMI patients were divided into four groups on the basis of age and E/A, while patients with HF were classified into three groups, based on only E/A. Mortality across groups was compared using Kaplan-Meier survival analysis and Cox proportional hazards. In multivariable analyses in the AMI patients, age stratified E/A was an independent predictor of outcome (HR 1.43 (95% CI: 1.31 1.56)), and in the HF cohort, E/A was confirmed as an independent predictor of mortality (HR 1.12 (95% CI 1.09-1.16)) alongside age and ejection fraction. CONCLUSIONS: Age-stratified E/A is an independent predictor of mortality after AMI and in HF patients, regardless of left ventricular ejection fraction, age and gender. E/A ratio could be a first step echocardiographic risk stratification, which could precede and indicate the need for more advanced diagnostic and prognostic considerations in high-risk AMI and HF patients. PMID- 25555285 TI - Some observations on and controversies about coronary arterial spasm. AB - The pathogenesis, clinical features, diagnosis, and treatment of spasm of epicardial coronary arteries are reviewed briefly, especially with regard to some issues that remain controversial. For diagnosis, emphasis is placed on the need for objective observations during an attack, even if that requires an attempt at pharmacologic provocation during coronary arteriography, or during echocardiography when prior arteriography has demonstrated the absence of severe coronary stenosis. PMID- 25555284 TI - High altitude-induced borderline pulmonary hypertension impaired cardiorespiratory fitness in healthy young men. AB - OBJECTIVE: High altitude exposure has been suggested to cause borderline elevation of pulmonary artery pressure (PAP) in quite a few healthy individuals. This cohort study was to investigate the impact of altitude induced borderline pulmonary hypertension (PH) on cardiorespiratory fitness in healthy subjects. METHODS: 299 healthy Chinese young men with normal PAP were consecutively studied between July 2011 and September 2013. Among these subjects 114 kept living at low altitude (450m), 91 ascended to high altitude (3700m) from low altitude within 24h (acute exposure), and 94 resided at 3700m for more than 1year (chronic exposure). Mean PAP and cardiac function were examined by echocardiography, and cardiorespiratory fitness was determined by predicted work capacity at a heart rate of 170beats per minute (PWC170). RESULTS: Mean PAP remained within normal range (<20mmHg) in 113 of 114 participants (99%) at low altitude. In contrast, the incidence of borderline PH (mPAP between 20 and 25mmHg) was 29% and 37% for respective acute and chronic exposures. Compared to the subjects with normal mPAP within each of the exposure groups, the subjects with borderline PH had increased right ventricular Tei index (RV-Tei), which correlated with the decline of PWC170 (acute exposure: r=-0.296, p=0.004; chronic exposure: r=-0.247, p=0.016). However, these changes were relatively milder than those with confirmed PH (mPAP>25mmHg). CONCLUSION: Borderline PH compromised cardiorespiratory fitness in healthy young men. The decline of cardiorespiratory fitness was related at least in part with the impaired right ventricular function, which was correlated with the elevated mPAP. PMID- 25555286 TI - Stable coronary artery disease: Seeking best practice by looking at diagnostic accuracy and prognostic stratification. PMID- 25555287 TI - Self and environmental exposures to drinking, smoking, gambling or video game addiction are associated with adult hypertension, heart and cerebrovascular diseases, allergy, self-rated health and happiness: Japanese General Social Survey, 2010. AB - BACKGROUND: It was aimed to study the relationships between addiction behaviors and human health and well-being in East Asians in a national and population-based setting. METHODS: Data were retrieved from Japanese General Social Survey, 2010. Information on demographics, lifestyle factors, addiction behaviors and self reported health conditions and well-being in Japanese adults was obtained by household interview. Analysis included chi-square test, logistic and multi nominal regression modeling. RESULTS: Of 5003 Japanese adults (aged 20-89) included in the study cohort, 13.8%, 14.7%, 4.8% and 5.5% were addicted to drinking, smoking, gambling and video games, respectively while 10.6%, 13.8%, 4.3% and 11.4% were exposed to co-residing family member's drinking, smoking, gambling and video game addiction behaviors, respectively. People who reported addiction to drinking had poor self-rated health, hypertension and food allergy. People who reported addiction to smoking had fair to poor self-rated health, unhappiness, cerebrovascular disease and itchy skin. People who reported addiction to gambling had fair to poor self-rated health and unhappiness. People who reported addiction to video games had poor self-rated health and heart disease. People who were exposed to addiction to drinking, smoking, gambling and video games from co-residing family member(s) also reported hay fever, poor self rated health and unhappiness. CONCLUSION: Self and environmental exposures to drinking, smoking, gambling or video game addiction are associated with adult hypertension, heart and cerebrovascular diseases, allergy, self-rated health and happiness. Future public health programs continuing to minimize self and environmental exposures to addiction behaviors tackling health concerns would still be encouraged. PMID- 25555288 TI - Antiplatelet properties of oral anticoagulants. PMID- 25555289 TI - Carvedilol protects the peritubular capillaries and kidney structure in spontaneously hypertensive rats. PMID- 25555290 TI - Episodic elaboration: Investigating the structure of retrieved past events and imagined future events. AB - Five experiments investigated the cognitive processes involved in the elaboration of past and future events. A production listing procedure was used, in which participants listed details of each event in forwards chronological order, backwards chronological order, or free order. For both past and future events, forwards and free ordering conditions were reliably faster than backwards order. Production rates between past and future temporal directions did not differ in Experiments 1a, 1b, and 3. However, in Experiment 2, the elaboration of future events was faster than the elaboration of past events. This pattern can be explained by the findings of Experiment 4, in which production rates were faster for likely events than for unlikely events but only in the future condition. Overall, the findings suggest that the elaboration of future, but not past, events, is facilitated when constructed around current goals. PMID- 25555294 TI - Delirium induced by a new synthetic legal intoxicating drug: phenazepam. PMID- 25555295 TI - It's all about the social media. PMID- 25555296 TI - The impact of social media on the sexual and social wellness of adolescents. AB - For most adolescents in the United States, the use of social media is an integral part of daily life. While the advent of the Internet has enhanced information dispersal and communication worldwide, it has also had a negative impact on the sexual and social wellness of many of its adolescent users. The objective of this review is to describe the role of social media in the evolution of social norms, to illustrate how online activity can negatively impact adolescent self-esteem and contribute to high-risk adolescent behaviors, to elucidate how this activity can result in real-world consequences with life-long results, and to provide guidance regarding social media use for those who care for adolescents. Although research is now aimed at use of social media for positive health and wellness interventions, much work needs to be done to determine the utility of these programs. Adolescent healthcare providers are important contributors to this new field of study and must resolve to stay informed and to engage this up-and-coming generation on the benefits and risks of social media use. PMID- 25555297 TI - Factors influencing the recommendation of the human papillomavirus vaccine by Serbian pediatricians. AB - OBJECTIVES: This research was undertaken to investigate the knowledge and attitudes regarding Human Papillomavirus infection and the Human Papillomavirus (HPV) vaccine among pediatricians who work in primary health care and to determine their intention to recommend the HPV vaccine as an important measure for the primary prevention of cervical cancer. We assessed the factors associated with the intention to recommend the vaccine. STUDY DESIGN: This cross-sectional study was conducted in March and April 2012. This research included all pediatricians who worked with school children in public primary health care institutions in Belgrade. A research instrument questionnaire had been designed for this study. RESULTS: The response rate was 78.7%. The knowledge of pediatricians related to HPV infection and the HPV vaccine was estimated as poor. However, pediatricians recognized the need for additional education in this field. The most-frequently reported barrier to HPV vaccination was the financial concern (68.2%). Alternatively, according to the pediatricians, the most common parental barrier to vaccination was the lack of information on the vaccine (67.2%). Nearly two-thirds of the pediatricians were willing to recommend the vaccine (60.2%). The factors associated with the pediatricians' intention to recommend the vaccine included the parents' attitudes. CONCLUSION: The majority of pediatricians accept the HPV vaccine and recommend it to their patients. It is necessary to improve cooperation between parents and pediatricians to increase immunization coverage and develop national consulting strategies with a focus on the prevention of HPV infection. PMID- 25555298 TI - Use of hysteroscope for vaginoscopy or hysteroscopy in adolescents for the diagnosis and therapeutic management of gynecologic disorders: a systematic review. AB - STUDY OBJECTIVE: The purpose of this article is to review the published literature and perform a systematic review to evaluate the effectiveness and feasibility of the use of a hysteroscope for vaginoscopy or hysteroscopy in diagnosing and establishing therapeutic management of adolescent patients with gynecologic problems. DESIGN: A systematic review. SETTING: PubMed, Web of science, and Scopus searches were performed for the period up to September 2013 to identify all the eligible studies. Additional relevant articles were identified using citations within these publications. PARTICIPANTS: Female adolescents aged 10 to 18 years. RESULTS: A total of 19 studies were included in the systematic review. We identified 19 case reports that described the application of a hysteroscope as treatment modality for some gynecologic conditions or diseases in adolescents. No original study was found matching the age of this specific population. CONCLUSIONS: A hysteroscope is a useful substitute for vaginoscopy or hysteroscopy for the exploration of the immature genital tract and may help in the diagnosis and treatment of gynecologic disorders in adolescent patients with an intact hymen, limited vaginal access, or a narrow vagina. PMID- 25555299 TI - Factors associated with contraceptive satisfaction in adolescent women using the IUD. AB - STUDY OBJECTIVE: To estimate satisfaction and to identify factors contributing to an adolescent woman's satisfaction with the levonorgestrel-containing or copper intrauterine device (IUD). DESIGN: Adolescent women presenting to an urban clinic within 1 month of IUD insertion completed survey questionnaires about prior use of contraception, gynecologic/obstetric history, and a pain scale. Participants were contacted at 3 and 6 months post-insertion to complete surveys regarding satisfaction with the IUD, their menstrual bleeding patterns, and pain and cramping due to the IUD. Chi-square test, Fisher exact test, and logistic regression were used for analysis. SETTING: Mount Sinai Adolescent Health Center in New York City. PARTICIPANTS: Seventy-nine adolescent women aged 15-24 y. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Satisfaction was measured at 3 and 6 months post-IUD insertion as a 10-point Likert item. RESULTS: 82% and 76% percent of participants were available for follow-up at 3 and 6 months, respectively. Satisfaction with the IUD was high overall with 75.4% (49/65) of participants choosing a satisfaction rating of eight or higher on the 10-point scale at 3 months and 76.7 % (46/60) at 6 months. Prior history of pregnancy and selecting the levonorgestrel containing IUD were predictive of higher satisfaction at 3 months, but not at 6 months. Parity and prior use of contraceptive methods were not predictive of satisfaction. CONCLUSION: The finding of high satisfaction across participants supports the current recommendation for the IUD as a first line contraceptive for adolescents. Nulliparous young women and those who are naive to contraception should be considered as candidates for the IUD. PMID- 25555300 TI - Trends in standard workup performed by pediatric subspecialists for the diagnosis of adolescent polycystic ovary syndrome. AB - OBJECTIVE: The purpose of this study is to identify trends in the clinical workup, diagnosis, and treatment of polycystic ovary syndrome by pediatric endocrinologists, pediatric gynecologists, and adolescent medicine specialists. DESIGN: Retrospective chart review. SETTING: Tertiary care medical center. PARTICIPANTS: Females aged 11-18 y who were evaluated for PCOS from June 2009 to October 2011 were included. Any patients with coexisting diagnoses of other primary etiology for amenorrhea were excluded. Patients were identified by ICD-9 codes for PCOS, hypersecretion of ovarian androgens, irregular menses, hirsutism, oligomenorrhea, or amenorrhea. 261 patients were included: 144 from endocrinology, 9 from gynecology, and 108 from adolescent pediatric practices. RESULTS: There were no significant differences in the androgen labs ordered by the subspecialties. Gynecologists ordered pelvic ultrasonography for 89% (n = 8) of patients, compared to 9% (n = 10) by adolescent medicine specialists and 24% (n = 34) by endocrinologists (P < .0001). Endocrinologists were most likely to treat patients who met diagnostic criteria for PCOS with metformin (58%, n = 66), compared to gynecologists (14%, n = 1) and adolescent medicine specialists (5%, n = 3) (P < .0001). Gynecologists (43%, n = 3) and adolescent medicine specialists (58%, n = 39) were more likely than endocrinologists (24%, n = 27) to treat patients with oral contraceptive pills (P < .0001). CONCLUSIONS: Inconsistent diagnosis and treatment strategies for young women with PCOS are evident among pediatric subspecialties, reflecting lack of standardized care for adolescents. Quantifying outcomes based on diagnostic and therapeutic approaches are important next steps. PMID- 25555301 TI - Awareness of a rape crisis center and knowledge about sexual violence among high school adolescents. AB - STUDY OBJECTIVE: This study examined awareness among adolescents of a local rape crisis center as well as their knowledge about sexual violence. DESIGN: The Cleveland Rape Crisis Center (CRCC) conducts sexual violence prevention programs for high school students. A written, anonymous survey was distributed to students prior to the start of the program. Students were asked if they had heard of the CRCC; knowledge about sexual violence was assessed with a series of 7 statements (rape myths) that participants identified as true or false. Surveys were reviewed retrospectively. Analyses were carried out for individual questions and frequencies compared using chi-square analysis. RESULTS: A total of 1633 surveys were collected; 1118 (68.5%) participants were female and 514 (31.5%) were male; ages ranged from 12 to 19 years. Respondents described themselves as being of European descent (45.9%), African descent (26.2%), or mixed race (17.7%). Just over half (863, 52.9%) of survey respondents had heard of the CRCC. Over half (950, 58.2%) of participants answered 5 or more questions correctly (range of correct answers 0 to 7). In general, more participants who were aware of the CRCC were able to identify statements about rape correctly (P < .01 for statements 1, 4, 5, 6, and 7, P < .001 for >= 5 correct). Age, gender, and race were all significantly associated with knowledge about rape. Females were consistently more likely to get an answer correct, as were participants of European descent. CONCLUSION: Awareness of the CRCC was associated with increased knowledge about sexual violence. PMID- 25555302 TI - Early initiation of postpartum contraception: does it decrease rapid repeat pregnancy in adolescents? AB - STUDY OBJECTIVE: Rapid repeat adolescent pregnancy is a significant public health concern. An effective and practical means of decreasing unintended second adolescent pregnancies needs to be identified. The objective of this study is to determine if early initiation of contraception, and in particular long acting reversible contraception (LARC), decreases rapid repeat pregnancy among first time adolescent mothers. DESIGN: Retrospective cohort study. SETTING: Urban teaching hospital. PARTICIPANTS: 340 first-time adolescent mothers age <= 19. INTERVENTIONS: None, study was retrospective. MAIN OUTCOME MEASURES: Repeat pregnancy within 2 years. RESULTS: 340 first time adolescent mothers with a documented follow-up time of 2 years had a repeat pregnancy rate of 35%. Average time from delivery to repeat pregnancy was 9.9 +/- 6.4 months. Logistic regression analysis comparing adolescents with and without repeat pregnancy revealed that leaving the hospital postpartum without initiating any contraception was associated with significant increase risk of repeat pregnancy (OR = 2.447, 95% CI 1.326-4.515). Follow-up within 8 weeks postpartum was associated with lower chance of repeat pregnancy (OR = 0.322, 95% CI 0.172 0.603). Initiation of a LARC method (either an intrauterine device or etonogestrel subdermal implant) by 8 weeks postpartum was also associated with decreased chance of rapid repeat pregnancy (OR = 0.118, 95% CI 0.035-0.397). CONCLUSION: Adolescent mothers who initiate a LARC method within 8 weeks of delivery are less likely to have a repeat pregnancy within 2 years than those who choose other methods or no method. First time adolescent mothers should be counseled about this advantage of using LARC. PMID- 25555303 TI - The role of hypoxia at primary dysmenorrhea, utilizing a novel hypoxia marker- SCUBE1. AB - STUDY OBJECTIVE: To determine the SCUBE1 levels in adolescents with primary dysmenorrhea. DESIGN: A prospective cross-sectional study. SETTING: A university hospital outpatient clinic, Rize, Turkey. PARTICIPANTS: A total of 40 adolescent girls, 15 on menses and 25 not on menses. INTERVENTIONS AND MAIN OUTCOME MEASURES: Demographic features and menstrual history of the participants were assessed and blood samples were obtained for detecting the platelet volume, platelet counts, and SCUBE1 levels of the participants. RESULTS: No difference was detected between the 2 groups in mean platelet volume, platelet count, and SCUBE1 levels. CONCLUSION: Future trials are required to investigate the relation between SCUBE1 levels and primary dysmenorrhea. PMID- 25555304 TI - Investigations of motor-cortex cortical plasticity following facilitatory and inhibitory transcranial theta-burst stimulation in schizophrenia: a proof-of concept study. AB - Impaired neural plasticity has been proposed as an important pathophysiological feature underlying the neurobiology and symptomatology of schizophrenia. In this proof-of-concept study, we aimed to explore cortical plasticity in schizophrenia patients with two different transcranial theta-burst (TBS) paradigms. TBS induces Ca(2+)-dependent long-term-potentiation (LTP)-like and long-term-depression (LTP) like plasticity in the human motor cortex. A total of 10 schizophrenia patients and 10 healthy controls were included in this study. Cortical excitability was investigated using transcranial magnetic stimulation in each study participant before and after TBS applied to the left primary motor-cortex on two different days. cTBS600 was used to induce LTD-like and cTBS300 was used to induce LTP-like plasticity in the absence of any prior motor-cortex activation. Repeated measures ANOVAs showed a significant interaction between the timecourse, the study group and the stimulation paradigm (cTBS600 vs. cTBS300) for the left, but not for the right hemisphere. Healthy controls showed an MEP amplitude decrease at a trend level following cTBS600 and a numeric, but not significant, increase in MEP amplitudes following cTBS300. Schizophrenia patients did not show an MEP amplitude decrease following cTBS600, but surprisingly a significant MEP decrease following cTBS300. The proportion of subjects showing the expected changes in motor-cortex excitability following both cTBS paradigms was higher in healthy controls. These preliminary results indicate differences in cortical plasticity following two different cTBS protocols in schizophrenia patients compared to healthy controls. However, the incomplete plasticity response in the healthy controls and the proof-of-concept nature of this study need to be considered as important limitations. PMID- 25555305 TI - Depressed suicide attempters have smaller hippocampus than depressed patients without suicide attempts. AB - BACKGROUND: Despite known relationship between hippocampal volumes and major depressive episodes (MDE) and the increased suicidality in MDE, the links between hippocampal volumes and suicidality remain unclear in major depressive disorders (MDD). If the hippocampus could be a biomarker of suicide attempts in depression, it could be useful for prevention matters. This study assessed the association between hippocampal volumes and suicide attempts in MDD. METHODS: Hippocampal volumes assessed with automatic segmentation were compared in 63 patients with MDD, with (n = 24) or without (n = 39) suicide attempts. Acute (one month) suicide attempts were studied. RESULTS: Although not different in terms of socio-demographic, MDD and MDE clinical features, suicide attempters had lower total hippocampus volumes than non-attempters (4.61 (+/- 1.15) cm(3) vs 5.22 (+/- 0.99) cm(3); w = 625.5; p = 0.03), especially for acute suicide attempts (4.19 (+/- 0.81) cm(3) vs 5.22 (+/- 0.99) cm(3); w = 334; p = 0.005), even after adjustment on brain volumes, sex, age, Hamilton Depression Rating Scale (HDRS) scores and MDD duration. A ROC analysis showed that a total hippocampal volume threshold of 5.00 cm(3) had a 98.2% negative predictive value for acute suicide attempts. CONCLUSION: Depressed suicide attempters have smaller hippocampus than depressed patients without suicide attempts, independently from socio-demographics and MDD characteristics. This difference is related to acute suicide attempts but neither to past suicide attempts nor to duration since the first suicide attempt, suggesting that hippocampal volume could be a suicidal state marker in MDE. Further studies are required to better understand this association. PMID- 25555306 TI - A low cost real-time motion tracking approach using webcam technology. AB - Physical therapy is an important component of gait recovery for individuals with locomotor dysfunction. There is a growing body of evidence that suggests that incorporating a motor learning task through visual feedback of movement trajectory is a useful approach to facilitate therapeutic outcomes. Visual feedback is typically provided by recording the subject's limb movement patterns using a three-dimensional motion capture system and displaying it in real-time using customized software. However, this approach can seldom be used in the clinic because of the technical expertise required to operate this device and the cost involved in procuring a three-dimensional motion capture system. In this paper, we describe a low cost two-dimensional real-time motion tracking approach using a simple webcam and an image processing algorithm in LabVIEW Vision Assistant. We also evaluated the accuracy of this approach using a high precision robotic device (Lokomat) across various walking speeds. Further, the reliability and feasibility of real-time motion-tracking were evaluated in healthy human participants. The results indicated that the measurements from the webcam tracking approach were reliable and accurate. Experiments on human subjects also showed that participants could utilize the real-time kinematic feedback generated from this device to successfully perform a motor learning task while walking on a treadmill. These findings suggest that the webcam motion tracking approach is a feasible low cost solution to perform real-time movement analysis and training. PMID- 25555307 TI - Elongation of the collateral ligaments after cruciate retaining total knee arthroplasty and the maximum flexion of the knee. AB - The mechanisms that affect knee flexion after total knee arthroplasty (TKA) are still debatable. This study investigated the elongation of the superficial medial (sMCL) and lateral collateral ligaments (LCL) before and after a posterior cruciate retaining (CR) TKA. We hypothesized that overstretching of the collateral ligaments in high flexion after TKA could reduce maximal flexion of the knee. Three-dimensional models of 11 osteoarthritic knees of 11 patients including the insertions of the collateral ligaments were created using MR images. Each ligament was divided into three equal portions: anterior, middle and posterior portions. The shortest 3D wrapping length of each ligament portion was determined before and after the TKA surgery along a weight-bearing, single leg flexion path. The relationship between the changes of ligament elongation and the changes of the maximal knee flexion after TKAs was quantitatively analyzed. The sMCL showed significant increases in length only at low flexion after TKA; the LCL showed decreases in length at full extension, but increases with further flexion after TKA. The amount of increases of the maximum flexion angle after TKA was negatively correlated with the increases of the elongations of the anterior portion (p=0.010, r=0.733) and middle portion (p=0.049, r=0.604) of the sMCL as well as the anterior portion (p=0.010, r=0.733) of the LCL at maximal flexion of the knee. The results indicated that the increases of the length of the collateral ligaments at maximal flexion after TKA were associated with the decreases of the maximal flexion of the knee. Our data suggest that collateral ligament management should also be evaluated at higher knee flexion angles in order to optimize maximal flexion of the knee after TKAs. PMID- 25555308 TI - Importance of ventricular function in the election of electro heart mode. AB - The integration of the ventricular function is essential when making decisions over a patient subjected to cardiac electrostimulation in order to understand the structure followed in the new cardiac stimulation and resynchronising therapy guides. To support the importance of ventricular function in cardiac electrostimulation it is important to know: (i)the deleterious effect of stimulation on the right ventricle apex; (ii)the effect over the left ventricular function produced by complete blockage of the left branch, and (iii)left ventricular disfunction as arrythmogenic substrate. When it comes to decide what type of cardiac electrostimualtion to apply we will know: the percentage of ventricular stimulation needed and its ventricular function. A normal ventricular function will enable electrostimulation from the right ventricle apex or alternative site. On the contrary, if this value is lower than 50% the most recommended electrostimulation is cardiac resynchronisation (CRT-P), which will be accompanied by defibrillation (CRT-D) if FEVI is lower than 35%. PMID- 25555309 TI - [Complications of cardiopulmonary resuscitation telephone assisted]. PMID- 25555310 TI - Optimizing specimen processing for ancient soft tissue specimens. AB - Despite many reports concerning processing of ancient soft tissues, scant attention has been paid to optimizing procedures for processing soft tissues that have been altered by taphonomic processes. To determine the best procedures, we investigated the rehydration solution, time of exposure to the solutions, fixative solution and exposure to heat. Processes were evaluated based on the minimum section thickness, degree of tissue fragmentation, definition of tissue architecture and penetration of stains. We found that in desiccated samples, tissue architecture was optimized by using Ruffer's solution for rehydration and Schaffer's solution as fixative, because these tissues require water restoration within the tissues due to their compacted character. Heating enhanced penetration of dyes in these specimens, which improved diagnosis. Saponified tissues that had suffered extensive decomposition were more labile and required slow water uptake. The best histological sections were obtained using Sandison's solution followed by fixation with formaldehyde and avoiding heat. To obtain the best results with paleohistological specimens, the procedure must be determined by the condition of the sample and by accounting for the nature of its damage. PMID- 25555311 TI - Quirks of dye nomenclature. 4. Fuchsine: four shades of magenta. AB - Fuchsine, also called magenta, was the second coal tar dye to be produced after mauveine. Fuchsine is composed of a mixture of up to four triphenylmethane dyes that differ only in the number of substituent methyl groups. Unlike mauveine, fuchsine still is widely used today as a biological stain. We describe the progress of fuchsine from its birth as the second coal tar dye, through a variety of modes of manufacture and industrial application, to its current use. We discuss complexities of nomenclature and identification, and the hazards and risks of its various applications. PMID- 25555312 TI - Prospects for vaccination against the ticks of pets and the potential impact on pathogen transmission. AB - Diseases transmitted by arthropod vectors such as ticks greatly impact human and animal health. In particular, many diseases of dogs and cats are potentially transmissible to people by arthropod vectors and therefore their control is important for the eradication of vector-borne diseases (VBD). Vaccination is an environmentally friendly alternative for vector control that allows control of several VBD by targeting their common vector. Recent results have shown that it is possible to use vector protective antigens for the control of arthropod vector infestations and pathogen infection. However, as reviewed in this paper, very little progress has been made for the control of ectoparasite infestations and VBD in pets using vaccination with vector protective antigens. The growing interaction between pets and people underlines the importance of developing new interventions for the monitoring and control of VBD. PMID- 25555313 TI - Intrafractional organs movement in three-dimensional image-guided adaptive pulsed dose-rate cervical cancer brachytherapy: assessment and dosimetric impact. AB - PURPOSE: To prospectively evaluate the intrafractional movements of organs at risk (OARs) and their dosimetric impact during the delivery of pulsed-dose-rate brachytherapy in cervical cancer. PATIENTS AND METHODS: An MRI on Day 1 was used for treatment planning in 19 patients. CT scans were acquired at Days 1, 2, and 3 with delineation of the OARs. The MRI plan was transferred to each CT. The intersection volume between the 10 Gy isodose and the OARs were monitored, reflecting movement. Lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ and lower dose evaluated in the maximally exposed 2 cm(3) of an organ (D(2cm3)) were evaluated on each CT and compared. Results were averaged considering that each CT reflected one-third of the treatment course to evaluate the delivered dose. RESULTS: No major movements of the sigmoid and bladder were observed, whereas the rectum got significantly closer to the implant at Day 2. The consequence was an increase of 6% +/- 5.3 (3.7 Gy, alpha/beta = 3 Gy) of the delivered D(2cm3) from the planned dose, in contrast to 0.2% +/- 6.1 for the bladder and 1.1% +/- 6.4 for the sigmoid. The increase of the D(2cm3) of the rectum was reported in 17 patients, ranging from 0.4 to 9.4 Gy, leading to a 10.5% overcoming of the dose constraint (75 Gy). Similar tendencies were reported for lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ. CONCLUSIONS: A significant systematic variation was observed for the rectum (+3.7 Gy). As significant random variations were observed, caution should be exercised when the planned D(2cm3) is close to the dose constraints. PMID- 25555314 TI - Progressive computed tomography (CT) appearances preceding malignant spinal cord compression (MSCC) in men with castration-resistant prostate cancer. AB - AIM: To test the hypothesis that computed tomography (CT)-based signs might precede symptomatic malignant spinal cord compression (MSCC) in men with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: A database was used to identify suitable mCRPC patients. Staging CT images were retrospectively reviewed for signs preceding MSCC. Signs of malignant paravertebral fat infiltration and epidural soft-tissue disease were defined and assessed on serial CT in 34 patients with MSCC and 58 control patients. The presence and evolution of the features were summarized using descriptive statistics. RESULTS: In MSCC patients, CT performed a median of 28 days prior to the diagnostic magnetic resonance imaging (MRI) demonstrated significant epidural soft tissue in 28 (80%) patients. The median time to MSCC from a combination of overt malignant paravertebral and epidural disease was 2.7 (0-14.6) months. Conversely, these signs were uncommon in the control cohort. CONCLUSIONS: Significant malignant paravertebral and/or epidural disease at CT precede MSCC in up to 80% of mCRPC patients and should prompt closer patient follow-up and consideration of early MRI evaluation. These CT-based features require further prospective validation. PMID- 25555315 TI - Breast DWI at 3 T: influence of the fat-suppression technique on image quality and diagnostic performance. AB - AIM: To evaluate two fat-suppression techniques: short tau inversion recovery (STIR) and spectral adiabatic inversion recovery (SPAIR) regarding image quality and diagnostic performance in diffusion-weighted imaging (DWI) of breast lesions at 3 T. MATERIALS AND METHODS: Ninety-two women (mean age 48 +/- 12.1 years; range 21-78 years) underwent breast MRI. Two DWI pulse sequences, with b-values (50 and 1000 s/mm(2)) were performed with STIR and SPAIR. The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), suppression homogeneity, and apparent diffusion coefficient (ADC) values were quantitatively assessed for each technique. Values were compared between techniques and lesion type. Receiver operating characteristics (ROC) analysis was used to evaluate lesion discrimination. RESULTS: One hundred and fourteen lesions were analysed (40 benign and 74 malignant). SNR and CNR were significantly higher for DWI-SPAIR; fat-suppression uniformity was better for DWI-STIR (p < 1 * 10(-4)). ADC values for benign and malignant lesions and normal tissue were 1.92 * 10(-3), 1.18 * 10( 3), 1.86 * 10(-3) s/mm(2) for DWI-STIR and 1.80 * 10(-3), 1.11 * 10(-3), 1.79 * 10(-3) s/mm(2) for SPAIR, respectively. Comparison between fat-suppression techniques showed significant differences in mean ADC values for benign (p = 0.013) and malignant lesions (p = 0.001). DWI-STIR and -SPAIR ADC cut-offs were 1.42 * 10(-3) and 1.46 * 10(-3) s/mm(2), respectively. Diagnostic performance for DWI-STIR versus SPAIR was: accuracy (81.6 versus 83.3%), area under curve (87.7 versus 89.2%), sensitivity (79.7 versus 85.1%), and specificity (85 versus 80%). Positive predictive value was similar. CONCLUSION: The fat-saturation technique used in the present study may influence image quality and ADC quantification. Nevertheless, STIR and SPAIR techniques showed similar diagnostic performances, and therefore, both are suitable for use in clinical practice. PMID- 25555316 TI - Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism. AB - INTRODUCTION: Rivaroxaban is non-inferior to warfarin for the treatment of venous thromboembolism, with regard to clinical efficacy and safety. The ex-vivo effects of warfarin versus therapeutic dose rivaroxaban on in-vivo markers of coagulation activation and thrombin generation remain undefined. The aim of this study was to compare the effects of warfarin and therapeutic dose rivaroxaban on ex-vivo thrombin generation (TG), and the in-vivo markers of coagulation activation, prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D dimer. METHODS: Eighty-five patients with venous thromboembolism were studied, 45 on warfarin, target INR 2.5 and 40 on rivaroxaban 20mg once daily. RESULTS: Anticoagulation was in therapeutic range in 71% (32/45) warfarin and 65% (26/40) rivaroxaban treated patients. 8 patients on warfarin and 9 patients on rivaroxaban had subtherapeutic INR and rivaroxaban levels respectively. Both rivaroxaban and warfarin reduced endogenous thrombin potential (ETP) and peak thrombin, and prolonged lag time and time to peak, compared to normal controls (p<0.0001). The lag time and time to peak TG were longer, and peak thrombin was lower in patients receiving rivaroxaban (p<0.0001) compared with warfarin, although warfarin-treated patients had lower ETP (p=0.0008). In-vivo coagulation activation markers were within the normal ranges in all rivaroxaban-treated patients (including those with levels considered to be subtherapeutic) and in 37/45 warfarin-treated patients who had an INR>=2.0. The warfarin-treated patients with subtherapeutic INRs exhibited slightly raised F1.2 and/or TAT. CONCLUSION: In conclusion, both rivaroxaban and warfarin provided effective anticoagulation, as assessed by inhibition of TG and makers of in-vivo coagulation activation. PMID- 25555317 TI - Dietary flavonoids intake and the risk of coronary heart disease: a dose-response meta-analysis of 15 prospective studies. AB - INTRODUCTION: Epidemiological studies evaluating the association of flavonoids intake with risk of coronary heart disease (CHD) have produced inconsistent results. We conducted a meta-analysis to summarize the evidence from prospective cohort studies regarding the association between flavonoids intake and risk of CHD. MATERIALS AND METHODS: Pertinent studies were identified by searching Web of Knowledge, Pubmed and Wan Fang Med Online up to April 2014. Fixed-effect or random-effect model was used to combine the results based on the heterogeneity. Dose-response relationship was assessed by restricted cubic spline. Publication bias was estimated using Begg' funnel plot and Egger's regression asymmetry test. RESULTS: Fourteen articles with 15 prospective studies involving 7,233 CHD cases and 452,564 participants were included in this meta-analysis. Pooled results suggested that highest flavonoids intake versus lowest intake was significantly associated with the risk of CHD [summary relative risk (RR) = 0.850, 95% confidence interval (CI) = 0.794-0.910, I(2) = 26.0%, tau(2) = 0.041]. Inverse associations were found both in Europe and in USA. Linear dose-response relationship was found between flavonoids intake and CHD risk. However, no significant association was found through the dose-response analysis (an increment of 20 mg/day, summary incidence rate ratios (IRR) = 0.95, 95%CI = 0.88 1.02). CONCLUSIONS: Our results from this meta-analysis suggested that elevated flavonoids intake might have a protective effect on CHD. PMID- 25555318 TI - Thromboembolic and bleeding outcomes of extended duration low-intensity warfarin following elective total knee arthroplasty. AB - INTRODUCTION: The purpose of this study was to describe the incidence of symptomatic venous thromboembolism (VTE), clinically-relevant bleeding, and death among a real-world population receiving warfarin prophylaxis targeting an international normalized ratio (INR) of 1.5 to 2.5 for four weeks following total knee arthroplasty (TKA). MATERIALS AND METHODS: This retrospective, observational study included patients receiving warfarin following a TKA between August 1, 2005 and July 31, 2009 identified in the Kaiser Permanente Total Joint Replacement Registry. Patients<18 years, receiving warfarin for another indication, or without continuous KPCO membership during the study period were excluded. RESULTS: There were 1487 patients with TKA included in the analysis. Mean patient age was 67.7 years and 61.7% were female. The median percent of time in therapeutic INR range during follow-up was 55% (interquartile range=35%-75%). Nineteen cases of symptomatic VTE [1.3%; 95% confidence interval (CI) 0.8%-2.0%] including ten pulmonary emboli (PE) (0.7%) were identified within 90 days of surgery. Clinically-relevant bleeding occurred in 1.7% (95% CI 1.1%-2.5%) of patients during warfarin prophylaxis and there were no deaths within 90 days of surgery. CONCLUSIONS: The rates of symptomatic VTE and clinically-relevant bleeding following TKA in patients receiving warfarin prophylaxis with a target INR of 1.5 to 2.5 were low. Additional studies should include low-intensity warfarin to identify the regimen that optimally balances risks of bleeding and symptomatic VTE after major orthopedic surgery. PMID- 25555320 TI - Breast and ovarian cancer survivors' experience of participating in a cognitive existential group intervention addressing fear of cancer recurrence. AB - PURPOSE: Currently, very few clinical approaches are offered to cancer survivors dealing with fear of cancer recurrence (FCR). This paper provides an overview of cancer survivors' experience and satisfaction after taking part in a six-week, cognitive-existential (CE) group intervention that aimed to address FCR. METHOD: In this qualitative descriptive study, 12 women with breast or ovarian cancer provided in-depth interviews of their experience in taking part in the CE group intervention. RESULTS: Analysis of their accounts revealed struggles to face their fears. Yet, by embracing their group experience, the women learned how to confront their fears and gain emotional control. The women reported that the group work was highly valuable. CONCLUSION: From the women's analysed accounts, the authors have proposed recommendations for changes to the group work process before moving the study to a full clinical trial. The study's findings also provide valuable insights to other cancer survivor groups who may also be experiencing FCR. PMID- 25555319 TI - Daily hospitalization costs in patients with deep vein thrombosis or pulmonary embolism treated with anticoagulant therapy. AB - BACKGROUND: Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), affects about 900,000 persons in the United States each year. OBJECTIVES: To quantify the progression of daily hospitalization costs among DVT and PE patients. PATIENTS/METHODS: A retrospective claims analysis was conducted from 01/01/2009 to 03/01/2013 using the Premier Perspective Comparative Hospital Database. Patients>= 18years of age with an admitting/primary diagnosis of DVT or PE and receiving anticoagulant therapy were identified. Treatment patterns, mean daily costs, and total hospitalization costs were reported for the DVT and PE populations. Comparisons of mean daily costs with those of the previous day were presented to identify statistical cost differences between hospitalization days. RESULTS: A total of 28,953 and 35,550 patients were identified with a diagnosis of DVT and PE, respectively. The daily costs were at their highest during the first three days for DVT patients at $2,321, $1,875, and $1,558, respectively. Similar results were found for PE patients with costs at their highest in the first three days, at $2,981, $2,034, and $1,564, respectively. Among the DVT and PE populations, mean daily costs were $1,594 and $1,735, respectively, and daily hospitalization costs became stable on the third day of the hospitalization (standardized differences<10%). CONCLUSIONS: Daily hospitalization costs of patients with an admitting/primary diagnosis of DVT or PE were high in the first days and became stable on the third day. It was further suggested that any change in the LOS could significantly affect hospitalization costs. PMID- 25555321 TI - Ternary copper(II) complexes with amino acid chains and heterocyclic bases: DNA binding, cytotoxic and cell apoptosis induction properties. AB - Nowadays, chemotherapy is a common means of oncology. However, it is difficult to find excellent chemotherapy drugs. Here we reported three new ternary copper(II) complexes which have potential chemotherapy characteristics with reduced Schiff base ligand and heterocyclic bases (TBHP), [Cu(phen)(TBHP)]H2O (1), [Cu(dpz)(TBHP)]H2O (2) and [Cu(dppz)(TBHP)]H2O (3) (phen=1,10-phenanthroline, dpz=dipyrido [3,2:2',3'-f]quinoxaline, dppz=dipyrido [3,2-a:2',3'-c]phenazine, H2TBHP=2-(3,5-di-tert-butyl-2-hydroxybenzylamino)-2-benzyl-acetic acid). The DNA binding properties of the complexes were investigated by spectrometric titrations, ethidium bromide displacement experiments and viscosity measurements. The results indicated that the three complexes, especially the complex 13, can strongly bind to calf-thymus DNA (CT-DNA). The intrinsic binding constants Kb of the ternary copper(II) complexes with CT-DNA were 1.37*10(5), 1.81*10(5) and 3.21*10(5) for 1, 2 and 3 respectively. Comparative cytotoxic activities of the copper(II) complexes were also determined by 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The results showed that the ternary copper(II) complexes had significant cytotoxic activity against the human lung cancer (A549), human esophageal cancer (Eca109) and human gastric cancer (SGC7901) cell lines. Cell apoptosis were detected by AnnexinV/PI flow cytometry and by Western blotting with the protein expression of p53, Bax and Bcl-2. All the three copper complexes can effectively induce apoptosis of the three human tumor cells. PMID- 25555322 TI - [SPECT, coronary angio-CT, invasive coronary angiography and fusion images in stable coronary disease]. AB - OBJECTIVES: To evaluate the usefulness of the information obtained with SPECT, coronary angio-CT and fusion images, in patients with stable ischemic disease who need invasive coronary angiography (IA). MATERIAL AND METHODS: Forty-six patients (65.98+/-8.3 years) with coronary disease were prospectively included. The fusion images generated after undergoing IA were used to evaluate the performance of these techniques in the diagnosis of multi-vessel coronary disease, the detection of the culprit vessel and the therapeutic management of these patients. RESULTS: In the IA, 29 of the 46 patients (63%) had multi-vessel disease. SPECT could detect it in 48.2% and coronary angio-CT could detect it in 89.6%. Concordance between coronary angio-CT and IA in the diagnosis of the culprit vessel was 77% (kappa 0.6), and between SPECT and IA it was 73% (kappa 0.56). Although fusion images could have been obtained prior to IA, they would not have changed the therapeutic approach derived from SPECT and IA. CONCLUSIONS: Coronary angio-CT has a high ability for the diagnosis of multi-vessel disease and the culprit lesion, and SPECT is a good functional complement of the IA in the detection of the most ischemic territory. However, the performance of fusion images in patients with stable ischemic disease, who have undergone a SPECT as the first non-invasive study and need IA, does not seem indicated because they would not have changed the therapeutic management derived from SPECT and IA information. PMID- 25555323 TI - Early detection of encephalitis with (18)F-FDG PET/CT. AB - Encephalitis is a relatively rare condition for which making an accurate diagnosis can be challenging. In fact, clinical features are not specific and structural imaging can be normal in a considerable number of cases. However, an early diagnosis is important as many forms of treatment are effective if started promptly. Even though recent guidelines do not recommend (18)F-FDG PET/CT for patients with suspected encephalitis, the case presented suggests that (18)F-FDG PET/CT may play a relevant role for the early diagnosis of this clinical condition. PMID- 25555324 TI - Diet and haemostasis - a comprehensive overview. AB - Dietary factors are known to influence cardiovascular disease risk. They can do so via several mechanisms, including effects on blood lipids, antioxidant status, blood pressure, body composition and also haemostasis. Dietary factors influence the haemostatic system through several pathways related to different haemostatic components namely platelets, coagulation and fibrinolysis. This review provides a comprehensive overview on the inter-relations of dietary factors with all three components of the haemostatic system. Dietary factors reviewed include energy intake, alcohol consumption, dietary fat (quantity and composition), carbohydrates, micronutrients and miscellaneous food items. This review also provides information on the relationship of diet with fibrin network structure and genetics of haemostasis. In conclusion, diet has a clear impact on the various components of the haemostatic process. PMID- 25555326 TI - Domain-specific and domain-general processes in social perception--A complementary approach. AB - In this brief discussion, we explicate and evaluate Heyes and colleagues' deflationary approach to interpreting apparent evidence of domain-specific processes for social perception. We argue that the deflationary approach sheds important light on how functionally specific processes in social perception can be subserved at least in part by domain-general processes. On the other hand, we also argue that the fruitfulness of this approach has been unnecessarily hampered by a contrastive conception of the relationship between domain-general and domain specific processes. As an alternative, we propose a complementary conception: the identification of domain-general processes that are engaged in instances of social perception can play a positive, structuring role by adding additional constraints to be accounted for in modelling the domain-specific processes that are also involved in such instances. PMID- 25555335 TI - [Anterior and anterolateral approach in the treatment of thoracic and lumbar vertebral metastasis causing spinal cord compression]. AB - OBJECTIVES: To analyse the results of the anterior and anterolateral approaches in the treatment of thoracic and lumbar spine metastasis. MATERIALS AND METHODS: Patients who underwent surgery between 2003 and 2012 in our institution using an anterior or an anterolateral approach for the treatment of thoracic or lumbar spine metastasis were retrospectively reviewed. RESULTS: Twenty-two patients with median age of 49.5 years (26-73 years) and median follow-up of 9.5 months (0-96 months) were analysed. The most common primary malignancies were renal cell carcinomas and breast adenocarcinomas. Before the intervention, 12 (54.5%) patients were able to walk (Frankel D and E). Preoperative arteriography was performed in 14 (63.6%) patients, and 7 (31.8%) of them underwent tumour embolisation. Medical complications occurred in 5 (22.7%) patients during the immediate postoperative period, 2 (9.1%) of whom died. At the end of follow-up, 16 (72%) of the remaining 20 patients were able to walk (Frankel D and E). Ninety percent of the patients could reduce at least 50% of their analgesic drug requirements. During follow-up 16 patients died, with a median survival of 10 months (range 0-48 months). CONCLUSIONS: Resection of thoracolumbar vertebral metastases by an anterior/anterolateral approach, despite its considerable risk of morbidity and mortality, offers the possibility of significant improvement in the quality of life of the patient; and it does so not only by preserving or restoring their ability to walk but also by ameliorating pain. Preoperative angiography, considering the embolisation of the lesion, is an important tool. PMID- 25555325 TI - How we will treat chronic myeloid leukemia in 2016. AB - Imatinib will become generic in 2016; assuming that its price will decrease precipitously, we expect that the economic forces will change our current practice habits. We reviewed the literature on the current recommendations to treat chronic myeloid leukemia and highlight how we plan to deal with these changes. Specifically, we propose to better characterize patients according to prognostic scores, to allow more attention to those at high risk for disease progression, e.g., 3-month guidelines and BCR/ABL1 message half-time, emphasize compliance by using contemporary technologies, and increase the importance of early monitoring. We hope that our message will open communication between providers, insurance companies and healthcare authorities to offer the best care for our patients. PMID- 25555336 TI - Increased serum concentrations of adiponectin in canine hypothyroidism. AB - Serum concentrations of adiponectin were compared between sex-matched hypothyroid (n = 18) and euthyroid (n = 18) client-owned dogs with comparable ages and body condition scores (BCS). Concentrations of adiponectin (mean; 95% confidence interval) were significantly (P < 0.01) higher in hypothyroid (17.2 ug/mL; 12.1 20.5 ug/mL) than healthy (8.0 ug/mL; 5.6-11.4 ug/mL) dogs following adjustment for potential confounders (BCS, age and sex). Serum concentrations of adiponectin were significantly negatively associated with concentrations of total thyroxine (P <0.05) and positively correlated with concentrations of cholesterol (r = 0.6, P <0.01) in hypothyroid dogs. In conclusion, this study demonstrated increased serum concentrations of adiponectin in dogs with hypothyroidism. Suggestive of the presence of resistance to adiponectin that could have contributed to development of hyperlipidemia and insulin resistance in these dogs or alternatively, could be a consequence of these metabolic alterations. PMID- 25555337 TI - Rhodococcus equi pneumonia in foals: an assessment of the early diagnostic value of serum amyloid A and plasma fibrinogen concentrations in equine clinical practice. AB - Early diagnosis and prevention of Rhodococcus equi pneumonia in foals represent important goals for equine clinicians. Recent protocols for diagnosis and treatment of Rhodococcosis in foals typically rely on a multimodal approach based on sonographic evidence suggestive of pyogranulomas, sonographic abscess scores and laboratory findings including plasma fibrinogen concentrations, blood biochemistry testing and platelet and leukocyte counts. The aim of this study was to assess the utility of weekly testing of serum amyloid A (SAA) and plasma fibrinogen concentrations in foals to achieve early diagnosis of R. equi pneumonia prior to the onset of clinical signs. This testing was used to simulate a clinically practical screening procedure and compared with thoracic ultrasonography performed in parallel. The present study suggests that SAA does not represent a reliable early marker of Rhodococcosis when plasma concentrations are tested weekly. However, when clinical signs of R. equi pneumonia are present, SAA concentrations may allow clinicians to obtain 'real-time' indications concerning both the progress of infection and the effectiveness of therapy. This study raises the possibility that plasma fibrinogen monitoring starting at 1 week of age and repeated on a weekly basis, could serve as a screening test allowing clinicians to identify foals as suspected of R. equi infection. Future investigations regarding both physiological plasma fibrinogen concentrations in foals as well as fibrinogen kinetics in foals affected with R. equi pneumonia, including the establishment of appropriate reference intervals for the test method employed in this study, will be necessary in order to clarify this possibility. PMID- 25555339 TI - Amino acid needs in horses. PMID- 25555338 TI - Body conformation in Great Danes with and without clinical signs of cervical spondylomyelopathy. AB - It has been suggested that a combination of large head and long neck cause abnormal forces on the cervical vertebral column and are involved in the pathogenesis of cervical spondylomyelopathy (CSM) in Great Danes. The aim of this study was to compare the body conformation of 15 clinically normal and 15 CSM affected Great Danes. There were no statistically significant differences between clinically normal and CSM-affected Great Danes in any body measurements. There were no significant associations between body conformation and the severity of neurological signs or cervical vertebral body dimensions determined by magnetic resonance imaging in CSM-affected Great Danes. The results of this study do not support the hypothesis that differences in body conformation related to head size, neck length, and body height and length, play a role in the pathogenesis of CSM in Great Danes. PMID- 25555340 TI - Serum paraoxonase 1 and butyrylcholinesterase in dogs with hyperadrenocorticism. AB - The aim of this study was to evaluate serum activities of paraoxonase 1 (PON1) using three substrates; (1) 4-nitrophenylacetate (PON1n), (2) phenylacetate (PON1p), and (3) 5-thiobutyl butyrolactonase (PON1t), and butyrylcholinesterase (BChE) in dogs with hyperadrenocorticism (HAC). Serum activities of PON1 and BChE were higher in dogs with HAC than healthy dogs. There were strong positive correlations between PON1 activity measured with the three different substrates. This study demonstrated increased serum PON1 and BChE activities in dogs with HAC that could be attributed to the direct effect of glucocorticoids and lipid mobilisation. PMID- 25555341 TI - Sex differences in cognitive functioning in at-risk mental state for psychosis, first episode psychosis and healthy control subjects. AB - BACKGROUND: Several sex differences in schizophrenia have been reported including differences in cognitive functioning. Studies with schizophrenia patients and healthy controls (HC) indicate that the sex advantage for women in verbal domains is also present in schizophrenia patients. However, findings have been inconsistent. No study focused on sex-related cognitive performance differences in at-risk mental state for psychosis (ARMS) individuals yet. Thus, the aim of the present study was to investigate sex differences in cognitive functioning in ARMS, first episode psychosis (FEP) and HC subjects. We expected a better verbal learning and memory performance of women in all groups. METHODS: The neuropsychological data analysed in this study were collected within the prospective Fruherkennung von Psychosen (FePsy) study. In total, 118 ARMS, 88 FEP individuals and 86 HC completed a cognitive test battery covering the domains of executive functions, attention, working memory, verbal learning and memory, IQ and speed of processing. RESULTS: Women performed better in verbal learning and memory regardless of diagnostic group. By contrast, men as compared to women showed a shorter reaction time during the working memory task across all groups. CONCLUSION: The results provide evidence that women generally perform better in verbal learning and memory, independent of diagnostic group (ARMS, FEP, HC). The finding of a shorter reaction time for men in the working memory task could indicate that men have a superior working memory performance since they responded faster during the target trials, while maintaining a comparable overall working memory performance level. PMID- 25555342 TI - Heart rate variability and Omega-3 Index in euthymic patients with bipolar disorders. AB - BACKGROUND: Affective disorders are associated with an increased risk of cardiovascular disease, which, at least partly, appears to be independent of psychopharmacological treatments used to manage these disorders. Reduced heart rate variability (SDNN) and a low Omega-3 Index have been shown to be associated with increased risk for death after myocardial infarction. Therefore, we set out to investigate heart rate variability and the Omega-3 Index in euthymic patients with bipolar disorders. METHODS: We assessed heart rate variability (SDNN) and the Omega-3 Index in 90 euthymic, mostly medicated patients with bipolar disorders (Bipolar-I, Bipolar-II) on stable psychotropic medication, free of significant medical comorbidity and in 62 healthy controls. Heart rate variability was measured from electrocardiography under a standardized 30 minutes resting state condition. Age, sex, BMI, smoking, alcohol consumption and caffeine consumption as potential confounders were also assessed. RESULTS: Heart rate variability (SDNN) was significantly lower in patients with bipolar disorders compared to healthy controls (35.4 msec versus 60.7 msec; P<0.0001), whereas the Omega-3 Index did not differ significantly between the groups (5.2% versus 5.3%). In a linear regression model, only group membership (patients with bipolar disorders versus healthy controls) and age significantly predicted heart rate variability (SDNN). CONCLUSION: Heart rate variability (SDNN) may provide a useful tool to study the impact of interventions aimed at reducing the increased risk of cardiovascular disease in euthymic patients with bipolar disorders. The difference in SDNN between cases and controls cannot be explained by a difference in the Omega-3 Index. PMID- 25555343 TI - Characterization of pathogenic vibrios isolated from bivalve hatcheries in Galicia, NW Atlantic coast of Spain. Description of Vibrio tubiashii subsp. europaeus [corrected] subsp. nov. AB - The taxonomic position of the bivalve pathogen PP-638 was studied together with five similar isolates. The strains were isolated from flat oyster (Ostrea edulis) and Manila clam (Venerupis philippinarum) cultures during outbreaks of disease in two shellfish hatcheries (Galicia, NW Spain). The pathogenicity, previously established for PP-638, was demonstrated with all isolates and for several bivalve species, including the original hosts. On the basis of phenotypic characterization and 16S rRNA gene sequences, a tight group was defined within the genus Vibrio. Multilocus sequence analysis (MLSA) based on concatenated sequences of the 16S rRNA gene and the five housekeeping genes recA, rpoA, pyrH, gyrB and ftsZ revealed that these strains form a cluster within the Orientalis clade, close to the species Vibrio tubiashii. The results of MLSA, the DDH rate and the phenotypic differences with the type strain of V. tubiashii supported the differentiation of the Galician isolates as a new subspecies within V. tubiashii, for which the name V. tubiashii subsp. europaeus [corrected] subsp. nov. is proposed (type strain PP-638(T)=CECT 8136(T)=DSM 7349(T)) The emended description of V. tubiashii is included. The pathogenicity assays widen the host range of V. tubiashii to add two unreported species, Venerupis decussata and Donax trunculus, and the described as relatively resistant species V. philippinarum. PMID- 25555349 TI - Mechanism of subunit coordination of an AAA+ hexameric molecular nanomachine. AB - Simian virus 40 large tumor antigen (LT) is both a potent oncogenic protein and an efficient hexameric nanomachine that harnesses the energy from ATP binding/hydrolysis to melt origin DNA and unwind replication forks. However, how the six subunits of the helicase motor coordinate during ATP hydrolysis and DNA unwinding/translocation is unresolved. Here we investigated the subunit coordination mechanisms "binomial distribution mutant doping" experiments in the presence of various DNA substrates. For ATP hydrolysis, we observed multiple coordination modes, ranging from random and semi-random, and semi-coordinated modes, depending on which type of DNA is present. For DNA unwinding, however, the results indicated a fully-coordinated mode for the natural origin-containing duplex DNA, but a semi-coordinated mode for a pre-existing fork-DNA, providing direct evidence for LT to use potentially different mechanisms to unwind the two types of substrates. The results of this study provide insights into DNA translocation and unwinding mechanisms for LT hexameric biomotor. From the clinical editor: The study describes the subunit coordination of simian virus 40 large tumor antigen (LT) showing that multiple mechanisms exist that handle the specific needs of different stages of DNA replication. PMID- 25555350 TI - Uptake efficiency of surface modified gold nanoparticles does not correlate with functional changes and cytokine secretion in human dendritic cells in vitro. AB - Engineering nanoparticles (NPs) for immune modulation require a thorough understanding of their interaction(s) with cells. Gold NPs (AuNPs) were coated with polyethylene glycol (PEG), polyvinyl alcohol (PVA) or a mixture of both with either positive or negative surface charge to investigate uptake and cell response in monocyte-derived dendritic cells (MDDCs). Inductively coupled plasma optical emission spectrometry and transmission electron microscopy were used to confirm the presence of Au inside MDDCs. Cell viability, (pro-)inflammatory responses, MDDC phenotype, activation markers, antigen uptake and processing were analyzed. Cell death was only observed for PVA-NH2 AuNPs at the highest concentration. MDDCs internalize AuNPs, however, surface modification influenced uptake. Though limited uptake was observed for PEG-COOH AuNPs, a significant tumor necrosis factor-alpha release was induced. In contrast, (PEG+PVA)-NH2 and PVA-NH2 AuNPs were internalized to a higher extent and caused interleukin-1beta secretion. None of the AuNPs caused changes in MDDC phenotype, activation or immunological properties. From the clinical editor: This team of authors investigated the influence of gold nano-particles with different surface modifications on immunological properties in monocyte-derived dendritic cells. AuNPs triggered responses in these cells that has to be further investigated in terms of development of novel vaccine carriers. PMID- 25555351 TI - 3D electrospun silk fibroin nanofibers for fabrication of artificial skin. AB - Tissue-engineered skin substitutes such as nanofibers from traditional electrospinning may offer an effective therapeutic option for the treatment of patients suffering from skin damages such as burns and diabetic ulcers. However, it is generally difficult for cells to infiltrate the nanofibers due to their small pore size and sheets-like appearance. In the present study, a facile and efficient strategy has successfully been introduced that can produce 3D silk fibroin nanofibers, obviating an intrinsic limitation of traditional and salt leaching electrospinning by introducing cold-plate electrospinning. The cell attachment and infiltration studies indicated the use of 3D nanofiber scaffolds by cold-plate electrospinning as a potential candidate to overcome intrinsic barriers of electrospinning techniques. The 3D nanofiber scaffolds using this technique presented a high porosity with controlled thickness and an easy contouring of facial shape; these properties can contribute to the ideal candidate for artificial skin reconstruction. From the clinical editor: Electrospun nanofibers are considered as promising scaffolds for tissue engineering due to extracellular matrix mimicking factor resulting in a controllable 3D nanofibrous form. The cold-plate electrospinning technique can facilitate the fabrication of these biomaterials to create structures that could resemble the dermis. PMID- 25555352 TI - Recent advances in targeted nanoparticles drug delivery to melanoma. AB - Melanoma is one of the most aggressive skin cancers, notorious for its high multidrug resistance and low survival rate. Conventional therapies (e.g., dacarbazine, interferon-alpha-2b and interleukin-2) are limited by low response rate and demonstrate no overall survival benefit. Novel targeted therapies (e.g., vemurafenib, dabrafenib and trametinib) have higher initial response rate and clear impact on the overall survival, but relapse usually occurs within 6 to 9 months. Although immunotherapy (e.g., ipilimumab, pembrolizumab and nivolumab) can achieve long-term and durable response, rate of adverse events is extremely high. With the development of nanotechnology, the applications of nanocarriers are widely expected to change the landscape of melanoma therapy for foreseeable future. In this review, we will relate recent advances in the application of multifunctional nanocarriers for targeted drug delivery to melanoma, in melanoma nanotheranostics and combination therapy, and nanopharmaceutical associated melanoma clinical trials, followed by challenges and perspectives. From the clinical editor: The team of authors describes the current treatment regimes of malignant melanoma emphasizing the importance of achieving a better efficacy and the need to develop a better understanding of melanoma tumorigenesis. PMID- 25555353 TI - Liposome-protein corona in a physiological environment: challenges and opportunities for targeted delivery of nanomedicines. AB - Active targeting that exploits the (over)expression of surface receptors in target cells by ligand incorporation is a central concept in nanomedicine research. Despite unprecedented efforts, no targeted liposome-based therapeutics is commercially available for clinical practice. What is inhibiting the efficient translation of targeted liposome technology from bench to bedside? After introduction in the bloodstream, the lipid surface is immediately modified by the adsorption of a "protein corona" and preserving the surface functionality appears to be challenging. On the other hand, a long-standing corona with receptor binding sites could associate with the target cell long enough to activate the cell's uptake machinery, triggering liposome endocytosis and intracellular cargo delivery. This opens the intriguing possibility to manipulate the corona composition by liposome design. This review will focus on the emerging field of liposome-protein corona research from basic, descriptive research to readily applicable knowledge and technologies for implementation in drug improvement and development. From the clinical editor: This review is addressing the liposome protein corona research concerning the potential gains in drug improvement and for drug development. PMID- 25555355 TI - Radium-223 dichloride: a new paradigm in the treatment of prostate cancer. AB - Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while beta-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients' profile that make them suitable to therapy and chances for further studies. PMID- 25555354 TI - The effects of aspirin on platelet function and lysophosphatidic acids depend on plasma concentrations of EPA and DHA. AB - Aspirin's prevention of cardiovascular disease (CVD) events in individuals with type 2 diabetes mellitus is controversial. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and aspirin all affect the cyclooxygenase enzyme. The relationship between plasma EPA and DHA and aspirin's effects has not been determined. Thirty adults with type 2 diabetes mellitus ingested aspirin (81 mg/day) for 7 days, then EPA+DHA (2.6g/day) for 28 days, then both for another 7 days. Lysophosphatidic acid (LPA) species and more classic platelet function outcomes were determined. Plasma concentrations of total EPA+DHA were associated with 7-day aspirin reduction effects on these outcomes in a "V"-shaped manner for all 11 LPA species and ADP-induced platelet aggregation. This EPA+DHA concentration was quite consistent for each of the LPA species and ADP. These results support aspirin effects on lysolipid metabolism and platelet aggregation depending on plasma EPA+DHA concentrations in individuals with a disturbed lipid milieu. PMID- 25555356 TI - WGA-Alexa transsynaptic labeling in the phrenic motor system of adult rats: Intrapleural injection versus intradiaphragmatic injection. AB - BACKGROUND: Intrapleural injection of CTB-Alexa 488, a retrograde tracer, provides an alternative labeling technique to the surgically invasive laparotomy required for intradiaphragmatic injection. However, CTB-Alexa 488 is incapable of crossing synapses restricting the tracer to the phrenic nuclei and the intercostal motor nuclei in the spinal cord. NEW METHOD: Intrapleural injection of WGA-Alexa 488, a transsynaptic tracer, provides a method to label the respiratory motor pathway in both the spinal cord and medulla. Intradiaphragmatic injection of WGA-Alexa 594 and vagal nerve injections of True blue were used to confirm the phrenic nuclei and to differentiate between the rVRG and the NA in the medulla. RESULTS: Following intrapleural injection, WGA-Alexa 488 was retrogradely transported to the phrenic nuclei and to the intercostal motor nuclei. Subsequently WGA-Alexa 488 was transsynaptically transported from the phrenic motoneurons to the pre-motor neurons in the rVRG that provide the descending drive to the phrenic neurons during inspiration. In addition WGA-Alexa 488 was identified in select cells of the NA confirmed by a dual label of both WGA-Alexa 488 and True blue. COMPARISON WITH EXISTING METHOD: WGA-Alexa 488 demonstrates retrograde transsynaptic labeling following intrapleural injection whereas the previous method of injecting CTB-Alexa 488 only demonstrates retrograde labeling. CONCLUSIONS: Intrapleural injection of WGA-Alexa fluor conjugates is an effective method to transsynaptically label the phrenic motor system providing an alternative for the invasive laparotomy required for intradiaphragmatic injections. Furthermore, the study provides the first anatomical evidence of a direct synaptic relationship between rVRG and select NA cells. PMID- 25555357 TI - Lignans and aromatic glycosides from Piper wallichii and their antithrombotic activities. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Piper wallichii (Miq.) Hand.-Mazz. is a medicinal plant used widely for the treatment of rheumatoid arthritis, inflammatory diseases, cerebral infarction and angina in China. Previous study showed that lignans and neolignans from Piper spp. had potential inhibitory activities on platelet aggregation. In the present study, we investigated the chemical constituents of Piper wallichii and their antithrombotic activities, to support its traditional uses. MATERIALS AND METHODS: The methanolic extract of the air dried stems of Piper wallichii was separated and purified using various chromatographic methods, including semi-preparative HPLC. The chemical structures of the isolates were determined by detailed spectroscopic analysis, and acidic hydrolysis in case of the new glycoside 2. Determination of absolute configurations of the new compound 1 was facilitated by calculated electronic circular dichroism using time-dependent density-functional theory. All compounds were tested for their inhibitory effects on platelet aggregation induced by platelet activating factor (PAF) in rabbits' blood model, from which the active ones were further evaluated the in vivo antithrombotic activity in zebrafish model. RESULTS: A new neolignan, piperwalliol A (1), and four new aromatic glycosides, piperwalliosides A-D (2-5) were isolated from the stems of Piper wallichii, along with 25 known compounds, including 13 lignans, six aromatic glycosides, two phenylpropyl aldehydes, and four biphenyls. Five known compounds (6-10) showed in vitro antiplatelet aggregation activities. Among them, (-) syringaresinol (6) was the most active compound with an IC50 value of 0.52 mM. It is noted that in zebrafish model, the known lignan 6 showed good in vivo antithrombotic effect with a value of 37% at a concentration of 30 MUM, compared with the positive control aspirin with the inhibitory value of 74% at a concentration of 125MUM. CONCLUSION: This study demonstrated that lignans, phenylpropanoid and biphenyl found in Piper wallichii may be responsible for antithrombotic effect of the titled plant. PMID- 25555358 TI - Impact of a novel decision support tool on adherence to Neonatal Resuscitation Program algorithm. AB - AIM: Studies have shown that healthcare professionals (HCPs) display a 16-55% error rate in adherence to the Neonatal Resuscitation Program (NRP) algorithm. The aim of this study was to evaluate adherence to the Neonatal Resuscitation Program algorithm by subjects working from memory as compared to subjects using a decision support tool that provides auditory and visual prompts to guide implementation of the Neonatal Resuscitation Program algorithm during simulated neonatal resuscitation. METHODS: Healthcare professionals (physicians, nurse practitioners, obstetrical/neonatal nurses) with a current NRP card were randomized to the control or intervention group and performed three simulated neonatal resuscitations. The scenarios were evaluated for the initiation and cessation of positive pressure ventilation (PPV) and chest compressions (CC), as well as the frequency of FiO2 adjustment. The Wilcoxon rank sum test was used to compare a score measuring the adherence of the control and intervention groups to the Neonatal Resuscitation Program algorithm. RESULTS: Sixty-five healthcare professionals were recruited and randomized to the control or intervention group. Positive pressure ventilation was performed correctly 55-80% of the time in the control group vs. 94-95% in the intervention group across all three scenarios (p<0.0001). Chest compressions were performed correctly 71-81% of the time in the control group vs. 82-93% in the intervention group in the two scenarios in which they were indicated (p<0.0001). FiO2 was addressed three times more frequently in the intervention group compared to the control group (p<0.001). CONCLUSIONS: Healthcare professionals using a decision support tool exhibit significantly fewer deviations from the Neonatal Resuscitation Program algorithm compared to those working from memory alone during simulated neonatal resuscitation. PMID- 25555359 TI - Relationships between pre-hospital characteristics and outcome in victims of foreign body airway obstruction during meals. AB - OBJECTIVE: The purpose of this study is to determine the outcome of foreign body airway obstruction according to the initial actions taken for choking victims during meals. METHODS: Our subjects were patients who became unresponsive or unconscious because of foreign body airway obstruction (FBAO) during meals in the presence of bystander witnesses. We investigated the associations between outcome and the following factors: age, gender, type of foreign body, chest compressions after the patient became unresponsive or unconscious, episode of cardiac arrest, efforts by a bystander to remove the foreign body, eating-related activities of daily living, time elapsed from the 119 call to arrival of emergency medical technicians (EMTs), and time elapsed from the 119 call to hospital arrival (primary endpoint). RESULTS: Of the 138 patients enrolled during the study period, 35 (25.4%) received chest compressions by bystanders after becoming unresponsive or unconscious and 69 (50.0%) suffered cardiac pulmonary arrest. Chest compressions by a bystander after the victim became unresponsive or unconscious (p<0.0001) and no CPA (p<0.0001) were significantly related to good outcome. Chest compressions by a bystander were both associated with good neurological outcome (odds ratio, 10.57; 95% CI, 2.472-65.059, p<0.0001). No CPA after FBAO was another independent predictor (odds ratio, 50.512; 95% CI, 13.45 284.41; p<0.0001), but efforts to remove the foreign body before the arrival of EMTs did not affect outcome. CONCLUSION: Chest compressions by a bystander, a support received by only 25% of the patients, proved to be essential for improved outcome for choking victims who became unresponsive or unconscious. Education for lay-rescuer response to choking might further improve overall outcome. PMID- 25555360 TI - Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice. AB - Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17beta-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders. PMID- 25555361 TI - Intra-session test-retest reliability of magnitude and structure of center of pressure from the Nintendo Wii Balance BoardTM for a visually impaired and normally sighted population. AB - Individuals with visual impairment (VI) have irreparable damage to one of the input streams contributing to postural stability. Here, we evaluated the intra session test-retest reliability of the Wii Balance Board (WBB) for measuring Center of Pressure (COP) magnitude and structure, i.e. approximate entropy (ApEn) in fourteen legally blind participants and 21 participants with corrected-to normal vision. Participants completed a validated balance protocol which included four sensory conditions: double-leg standing on a firm surface with eyes open (EO firm); a firm surface with eyes closed (EC-firm); a foam surface with EO (EO foam); and a foam surface with EC (EC-foam). Participants performed the full balance protocol twice during the session, separated by a period of 15min, to determine the intraclass correlation coefficient (ICC). Absolute reliability was determined by the standard error of measurement (SEM). The minimal difference (MD) was estimated to determine clinical significance for future studies. COP measures were derived from data sent by the WBB to a laptop via Bluetooth. COP scores increased with the difficulty of sensory condition indicating WBB sensitivity (all p<0.01). ICCs in the VI group ranged from 0.73 to 0.95, indicating high to very high correlations, and the normal group showed moderate to very high ICCs (0.62-0.94). The SEM was comparable between groups regardless of between-subject variability. The reliability of the WBB makes it practical to screen for balance impairment among VI persons. PMID- 25555362 TI - Possibilities and limitations of current technologies for quantification of biological extracellular vesicles and synthetic mimics. AB - Nano-sized extracelullar vesicles (EVs) released by various cell types play important roles in a plethora of (patho)physiological processes and are increasingly recognized as biomarkers for disease. In addition, engineered EV and EV-inspired liposomes hold great potential as drug delivery systems. Major technologies developed for high-throughput analysis of individual EV include nanoparticle tracking analysis (NTA), tunable resistive pulse sensing (tRPS) and high-resolution flow cytometry (hFC). Currently, there is a need for comparative studies on the available technologies to improve standardization of vesicle analysis in diagnostic or therapeutic settings. We investigated the possibilities, limitations and comparability of NTA, tRPS and hFC for analysis of tumor cell-derived EVs and synthetic mimics (i.e. differently sized liposomes). NTA and tRPS instrument settings were identified that significantly affected the quantification of these particles. Furthermore, we detailed the differences in absolute quantification of EVs and liposomes using the three technologies. This study increases our understanding of possibilities and pitfalls of NTA, tRPS and hFC, which will benefit standardized and large-scale clinical application of (engineered) EVs and EV-mimics in the future. PMID- 25555363 TI - Abnormal cone ERGs in a family with congenital nystagmus and photophobia harboring a p.X423Lfs mutation in the PAX6 gene. AB - PURPOSE: To describe the clinical, functional, and genetic findings in a young Caucasian girl and her father, in whom a mutation of the PAX6 gene was identified. METHODS: Detailed histories, eye examinations, and flash electroretinograms (ERGs) were acquired from both patients, and molecular genetic diagnostic testing was performed. Both patients were followed over a 2-year period. RESULTS: At presentation, the proband displayed congenital nystagmus, photophobia, posterior embryotoxon, foveal hypoplasia, and coarse peripheral retinal pigment epithelium mottling. Light-adapted cone-driven ERG responses were delayed and reduced. The father had similar findings, but additionally displayed corneal clouding and pannus, decreased best-corrected visual acuity, and his ERG demonstrated a larger reduction in ERG cone-driven responses. PAX6 testing of the proband revealed a heterozygous mutation in exon 13 resulting in a p.X423Lfs (p.Stop423Leufs) frameshift amino acid substitution, predicting aberrant protein elongation by either 14 or 36 amino acids (p.X423Lext14 or p.X423Lext36) and subsequent disruption of normal protein function. CONCLUSIONS: The p.X423Lfs mutation has previously been described in cases of atypical aniridia, but this is the first report demonstrating abnormal cone-driven ERG responses associated with this particular mutation of the PAX6 gene. ERG abnormalities have been documented in other mutations of the PAX6 gene, and we propose that the retinal pathology causing these ERG abnormalities may contribute to the photophobia experienced by patients with aniridia. Systematic ERG testing can aid in the diagnosis of PAX6 related disorders and may prove to be a useful tool to objectively assess responses to future treatments. PMID- 25555364 TI - Receptor-mediated transfer of IgG and albumin at cerebrospinal fluid interfaces. AB - Receptor-mediated transfer of IgG and albumin has been suggested to occur also at cerebrospinal fluid interfaces. We point out findings of statistically unchanging IgG/albumin ratios along the lumbar CSF column which propose that such transfer should be absent or very small at cerebrospinal fluid interfaces. PMID- 25555365 TI - miR-210 is a prognostic marker in clear cell renal cell carcinoma. AB - Accurate assessment of prognosis of clear cell renal cell carcinoma (ccRCC) is key in optimizing management plans to fit individual patient needs. miRNAs are short noncoding single-stranded RNAs that control the expression of target genes and may act as cancer biomarkers. We analyzed the expression of miR-210 in 276 cases of primary ccRCC and compared its expression in 40 pairs of adjacent normal and cancerous tissues. We assessed its expression in primary and metastatic tumors, in the common RCC subtypes, and the benign oncocytoma. The results were validated with an independent data set from The Cancer Genome Atlas. miR-210 was significantly overexpressed in ccRCC compared with normal kidney. miR-210(+) patients had a statistically higher chance of disease recurrence [hazard ratio (HR), 1.82; P = 0.018] and shorter overall survival (HR, 2.46; P = 0.014). In multivariate analysis, miR-210 lost its statistically significant association with shorter disease-free survival and overall survival after adjusting for tumor size and tumor, node, metastasis stage. Papillary RCC showed comparable miR-210 overexpression, whereas decreased up-regulation was seen in chromophobe RCC and oncocytoma. A number of predicted targets that might be involved in carcinogenesis and aggressive tumor behavior were identified. miR-210 is a potential therapeutic target and independent marker of poor prognosis of ccRCC. PMID- 25555367 TI - Kouksundo, a traditional Korean mind-body practice, regulates oxidative stress profiles and stress hormones. AB - BACKGROUND: Kouksundo is a traditional Korean mind-body practice that has been practiced for thousands of years. We investigated the effects of Kouksundo on oxidative stress-related biomarkers and stress hormones. METHODS: A single-arm observational study was conducted on 57 Kouksundo trainees (34 males and 23 females). Blood samples were collected 30 min before and after Kouksundo practice (25 min for warm-up, 45 min for breathing meditation, and 20 min for cool-down). RESULTS: Kouksundo significantly reduced serum levels of oxidant markers, including reactive oxygen species (p<0.01), nitric oxide (p<0.01), and malondialdehyde (p<0.05), induced elevation of superoxide dismutase (p<0.01), and reduction of catalase (p<0.001). No significant changes were observed in total antioxidant capacity or total glutathione content levels (p>0.05). Kouksundo practice also significantly reduced the serum level of cortisol (p<0.001), norepinephrine (p<0.001), and dopamine (p<0.05), and significantly increased serum epinephrine concentrations (p<0.05). CONCLUSION: The traditional Korean mind-body practice Kouksundo provided health benefits by regulating oxidative stress and levels of stress hormones. This study is the first investigation of the changes in oxidative stress and stress hormones induced by mind-body therapy, producing reference data for mechanistic studies on these practices. PMID- 25555366 TI - [Validation of a Spanish version of the Childhood Asthma Control Test (Sc-ACT) for use in Spain]. AB - OBJECTIVE: The Childhood Asthma Control Test (c-ACT) is a validated tool for determining pediatric asthma control. However, it is not validated in the Spanish language in Spain. We evaluated the psychometric properties of the Spanish version of the Childhood Asthma Control Test (Sc-ACT) for assessing asthma control in children ages 4 to11. METHODS: This national, multicentre, prospective study was conducted in Spain with asthmatic children and their caregivers. Patients were assessed at 3 visits (Baseline, 2 Weeks, and 4 Months). Clinical variables included: symptoms, exacerbations, FEV1, asthma classification, PAQLQ and PACQLQ questionnaire scores, and asthma control as perceived by physicians, patients and caregivers. The Sc-ACT feasibility, validity, reliability, and sensitivity to change were assessed. RESULTS: A total of 394 children were included; mean (SD) time to complete the Sc-ACT was 5.3 (4.4) minutes. Sc-ACT score was correlated with asthma control as perceived by physician (-0.52), patient (-0.53), and caregiver (-0.51) and with the PAQLQ (0.56) and PACQLQ (0.55) scores. Sc-ACT was found to be significantly related to intensity and frequency of asthma symptoms. Cronbach alpha coefficient alpha was 0.81 and intraclass correlation coefficient was >=0.85 for all of the items. The global effect size of Sc-ACT was 0.55. The cutoff point scores of 21 or higher indicated a good asthma control and their MCID was 4 points. CONCLUSION: The Spanish version of the c-ACT was found to be a reliable and valid questionnaire for evaluating asthma control in Spanish-speaking children ages 4 to 11 in Spain. PMID- 25555368 TI - Different clinical effects upon separate inhibition of coexisting EGFR and PI3KCA mutations in a lung adenocarcinoma patient. AB - We present a very interesting case of lung adenocarcinoma carrying an uncommon EGFR exon 19 insertion with concomitant PIK3CA mutation showing dramatic and persisting improvement upon erlotinib therapy, after progression during PI3K inhibitor. PMID- 25555369 TI - Clinical risk model assessment for cardiovascular autonomic dysfunction in the general Chinese population. AB - BACKGROUND: The aim of this study was to evaluate the prevalence of cardiovascular autonomic (CA) dysfunction in the general Chinese population (instead of focusing on only patients with diabetes) and to develop a clinical risk model for the disease. METHODS AND MATERIALS: We evaluated CA dysfunction prevalence in a dataset based on a population sample consisting of 2,092 individuals. Clinical risk models were derived from exploratory sets using multiple logistic regression analysis. The performance of the clinical risk models was tested in the validation sets. RESULTS: CA dysfunction prevalence was 18.50% in the general Chinese population, while the prevalence was 24.14% in individuals aged >=60 years. Its prevalence was 31.17, 24.69, and 21.26% in patients with diabetes, and hypertensive, and metabolic syndrome populations, respectively. Finally, we developed clinical risk models involving seven risk factors. The mean area under the receiver-operating curve was 0.758 (95% CI 0.724 0.793) for these models. The mean sensitivity and specificity of the clinical risk models was 75.0 and 66.2%, respectively. CONCLUSION: CA dysfunction prevalence was high in the general Chinese population, and its prevalence was more frequent in individuals with diabetes, and hypertensive, and metabolic syndrome. Clinical risk models with a high value for predicting CA dysfunction were developed. CA dysfunction has become a major public health problem in China that requires strategies aimed at the prevention and treatment of the disease. PMID- 25555370 TI - Transient sinus bradycardia during the course of Crimean-Congo hemorrhagic fever in children. AB - Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne viral zoonotic disease which is endemic in Turkey. Bradycardia has been reported among pediatric and adult patients with CCHF. But, it remains unclear, whether bradycardia is associated with ribavirin treatment or the severity of CCHF. In this study 26 hospitalized CCHF patients were reviewed in terms of age, gender, history of tick bite, duration of hospitalization, presence of bradycardia, laboratory features, ribavirin treatment, and blood products requirement. The demographic, clinical, laboratory and treatment characteristics of CCHF patients with or without bradycardia were compared. The mean age of the patients was 126.42+/-48.21 months. There were 8 female and 18 male patients. Sinus bradycardia was noted in 15 patients (mean age was 120.20+/-50.59 months, 5 female). Ribavirin had been administered 18 (69.2%) patients and 11 of them had bradycardia. There was not statistically significant relationships between bradycardia and ribavirin treatment (p=0.683). Furthermore the occurrence of bradycardia was not associated with disease severity according to Swanepoel severity criteria (p=0.683). We concluded that independent of the disease severity and the ribavirin treatment, transient sinus bradycardia might occur during the clinical course of CCHF in pediatric patients. For this reason clinicians should be aware of this finding and all CCHF patients should be monitored closely. PMID- 25555371 TI - Preischemic neuroprotective effect of minocycline and sodium ozagrel on transient cerebral ischemic rat model. AB - We investigated the neuroprotective properties of single doses of minocycline and ozagrel when administered prior to stroke. Male Sprague-Dawley rats were assigned randomly to one of the following groups: (1) control (Con) group (n=10), (2) minocycline (Mino) group (n=10), (3) sodium ozagrel (SO) group (n=10). Rats were treated with a single dose of minocycline or ozagrel at 30min before stroke. A middle cerebral artery occlusion (MCAO) was made at 30min after drug administration and reperfusion was done. The rats were subjected to a neurobehavioral test at days 1, 3 and 7 after MCAO. The cerebral ischemic volume was quantified by MetaMorph imaging software after TTC staining. The neuronal cell survival and astrocytes expansion were assessed by the NeuN and GFAP immunohistofluorescence staining. Apoptosis was detected by the TUNEL assay. We statistically analyzed and compared the results with each other. Mino and SO groups had neuroprotective effect and showed a better behavioral performance of adhesive removal and treadmill test at 7 days after stroke. Mino and SO groups also showed a smaller infarct volume than control group at 7 days after stroke. Immunohistofluorescence staining showed a higher number of NeuN positive cells, lower activated astrocytes in GFAP and a lower apoptosis in TUNEL staining. This study showed that single doses of minocycline and ozagrel prior to stroke had neuroprotective effects. These agents will be useful not only in post-stroke therapy but also in stroke prevention in several cerebrovascular procedures like carotid endarterectomy, bypass procedure, endovascular angioplasty, thromboembolectomy or thrombolysis. PMID- 25555372 TI - MCP-1 stimulates spinal microglia via PI3K/Akt pathway in bone cancer pain. AB - Accumulating evidence suggests that chemokine monocyte chemoattractant protein-1 (MCP-1) is significantly involved in the activation of spinal microglia associated with pathological pain, at the same time that the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) pathway localized in spinal microglia is involved in both neuropathic and inflammatory pain. However, whether there is a connection between MCP-1 and the PI3K/Akt pathway and in their underlying mechanisms in bone cancer pain (BCP) has not yet been elucidated. In the current study, we investigated the expression changes of p-Akt in microglia and OX-42 (microglia marker) after being stimulated with MCP-1 in vitro, as well as in a BCP model that was established by an intramedullary injection of mammary gland carcinoma cells(Walker 256 cells) into the tibia of rats. We observed a significant increase in expression levels of p-Akt and OX-42 in microglia as well as in spinal dorsal horns of BCP rats. Furthermore, the intrathecal administration of an anti-MCP-1 neutralizing antibody or PI3K inhibitor LY294002 reduced the expression of p-Akt or OX-42, and LY294002 attenuated the mechanical allodynia of BCP rats. These results suggest that MCP-1 may stimulate spinal microglia via the PI3K/Akt pathway in BCP. PMID- 25555373 TI - A three-dimensional digital atlas of the dura mater based on human head MRI. AB - OBJECTIVE: The goal of this paper was to design a three-dimensional (3D) digital dural atlas of the human brain for assisting neurosurgeons during the planning of an operation, medical research and teaching activities in neurosurgical anatomy. METHODS: The 176 sagittal head magnetic resonance(MR) images of a 54-year-old female who suffered from the left posterior fossa tumor were processed and outlined, based on which a 3D dural model was created using the softwares of 3ds max and Mimics. Then the model and images/anatomy photos were matched using the softwares of Z-brush and Photoshop to form the 3-D dural atlas. Dural anatomic photographs were needed to produce the 3D atlas in dural vault and skull base areas. RESULTS: The 3D dural atlas of the brain and related structures was successfully constructed using 73 dural delineations, the contours of dural model match very well on the dural structures of the original images in three orthogonal (axial, coronal and sagittal view) MR cross-sections. The atlas can be arbitrarily rotated and viewed from any direction. It can also be zoomed in and out directly using the zoom function. CONCLUSION: We successfully generated a 3D dural atlas of human brain, which can be used for repeated observation and research without limitations of time and shortage of corpses. In addition, the atlas has many potential applications in operative planning, surgical training, teaching activities, and so on. PMID- 25555374 TI - The characterization of the human cell line Calu-3 under different culture conditions and its use as an optimized in vitro model to investigate bronchial epithelial function. AB - In this study we have investigated the effects of different cell culture conditions on the Calu-3 epithelial cell model. Calu-3 cells were cultured in media A-MEM at the air-liquid (A-L) or liquid-liquid (L-L) interface for one or three wks (weeks). Different cryomethods were tested and the cell line was characterized using histochemistry, immunofluorescence, transmission and scanning electron microscopy, transepithelial resistance (TEER) measurements, permeability studies, and gene profiling of 84 drug transporters. Cell culture was successful in A-MEM with only 2.5% FBS. Cell proliferation and viability depended on the cryopreservation method. All Calu-3 models expressed CK7, occludin, and E cadherin. The A-L interface resulted in a more biomimetic native bronchial epithelium displaying pseudostratified columnar epithelium with more microvilli and secretory vesicles than at the L-L interface, where the epithelium was cuboidal, but exhibited higher TEER values and lower dextran permeabilities. Longer time in culture significantly decreased dextran permeability and increased the expression of specific drug transporters. Drug transporter expression was also notably influenced by the culture interface, where the A-L interface yielded a higher expression of drug transporter genes than the L-L interface. Since cell culture interface and time in culture affect Calu-3 cell differentiation, barrier integrity, permeability properties, and drug transporter expression, culture conditions need to be considered and standardized when using the Calu-3 cell line as an in vitro model for aerosol drug delivery and screening of bronchial drug candidates. PMID- 25555375 TI - Quantitative and qualitative analyses of the bacterial microbiota of tilapia (Oreochromis niloticus) cultured in earthen ponds in the Philippines. AB - The quantity and composition of the bacterial microbiota in the rearing water, sediment, gills and intestines of tilapia Oreochromis niloticus collected every 2 weeks from Day 30 to Day 120 after stocking for grow-out culture in 6 earthen brackish water ponds in the Philippines were examined. The total heterotrophic aerobic bacterial counts obtained in the water, sediment, gills and intestines of tilapia ranged from 10(3) to 10(4) c.f.u. ml(-1), 10(3)-10(5), 10(5)-10(7) and 10(4)-10(7) c.f.u. g(-1), respectively. In terms of composition, a total of 20 bacterial genera and 31 species were identified with the preponderance of gram negative bacteria constituting 84 % of all bacterial isolates examined. Aeromonas hydrophila, Bacillus spp., Plesiomonas shigelloides, Shewanella putrefaciens, Pseudomonas fluorescens, Staphylococcus spp. and Vibrio cholerae were the dominant bacteria identified in the gills and intestine of tilapia. These bacteria also dominated in the pond sediment and rearing water, except for the nil isolation of S. putrefaciens and V. cholerae in the water samples examined, indicating that resident bacteria in the pond water and sediment congruently typify the composition of bacterial microbiota in the gills and intestine of tilapia which under stressful conditions may propel the ascendance of disease epizootics. PMID- 25555376 TI - Construction and gene expression analysis of a single-stranded DNA minivector based on an inverted terminal repeat of adeno-associated virus. AB - The plasmid vectors currently used for nonviral gene transfer have the disadvantage of carrying a bacterial backbone and an antibiotic resistance gene, which may cause side effects. The adeno-associated virus (AAV) genome is a linear single-stranded DNA (ssDNA) molecule with palindromic inverted terminal repeat (ITR) sequences forming double-stranded DNA (dsDNA) hairpin (HP) structures at each end. Based on the AAV genome, we constructed an AAV-ITR ssDNA minivector that consists of a GFP expression cassette flanked by both ITR sequences of 125 nucleotides. The minivectors were produced by digestion of the parental plasmids followed by denaturation. The self-complementary inverted T-shaped HP structure of the minivector was automatically formed. The HEK 293T cells were transfected with the AAV-ITR ssDNA minivector, plasmid, and dsDNA expression cassette. The results showed that AAV-ITR ssDNA minivector had relatively low gene expression efficiency in vitro. However, we found that the GFP expression efficiency of the D sequence-deleted AAV-ITR ssDNA minivector was significantly increased and was similar to those obtained with the plasmid and dsDNA expression cassette. Our data suggest that the AAV-ITR ssDNA minivector may be a new type of gene expression vector for gene therapy besides the virus and plasmid. PMID- 25555377 TI - Production of recombinant human growth hormone conjugated with a transcytotic peptide in Pichia pastoris for effective oral protein delivery. AB - Among the possible delivery routes, the oral administration of a protein is simple and achieves high patient compliance without pain. However, the low bioavailability of a protein drug in the intestine due to the physical barriers of the intestinal epithelia is the most critical problem that needs to be solved. To overcome the low bioavailability of a protein drug in the intestine, we aimed to construct a recombinant Pichia pastoris expressing a human growth hormone (hGH) fusion protein conjugated with a transcytotic peptide (TP) that was screened through peroral phage display to target goblet cells in the intestinal epithelia. The TP-conjugated hGH was successfully produced in P. pastoris in a secreted form at concentrations of up to 0.79 g/l. The function of the TP conjugated hGH was validated by in vitro and in vivo assays. The transcytotic function of the TP through the intestinal epithelia was verified only in the C terminus conjugated hGH, which demonstrated the induction of IGF-1 in a HepG2 cell culture assay, a higher translocation of recombinant hGH into the ileal villi after oral administration in rats and both IGF-1 induction and higher body weight gain in rats after oral administration. The present study introduces the possibility for the development of an effective oral protein delivery system in the pharmaceutical and animal industries through the introduction of an effective TP into hGH. PMID- 25555378 TI - AealRACK1 expression and localization in response to stress in C6/36 HT mosquito cells. AB - The Receptor for Activated C Kinase 1 (RACK1), a scaffold protein member of the tryptophan-aspartate (WD) repeat family, folds in a seven-bladed beta-propeller structure that permits the association of proteins to form active complexes. Mosquitoes of the genus Aedes sp., are vectors of virus producing important diseases such as: dengue, chikungunya and yellow fever. Based on the highly conserved gene sequence of AeaeRACK1 of the mosquito Aedes aegypti we characterized the mRNA and protein of the homologous AealRACK1 from the Ae. albopictus-derived cell line C6/36 HT. Two protein species differing in MW/pI values were observed at 35kDa/8.0 and 36kDa/6.5. The behavior of AealRACK1 was studied inducing stress with serum deprivation and the glucocorticoid dexamethasone. Both stressors induced increase of the expression of AealRACK1 mRNA and proteins. In serum-deprived cells AealRACK1 protein was located cortically near the plasma membrane in contrast to dexamethasone-treated cells where the protein formed a dotted pattern in the cytoplasm. In addition, 33 protein partners were identified by immunoprecipitation and mass spectrometry. Most of the identified proteins were ribosomal, involved in signaling pathways and stress responses. Our results suggest that AealRACK1 in C6/36 HT cells respond to stress increasing its synthesis and producing phosphorylated activated form. BIOLOGICAL SIGNIFICANCE: Insect cells adapt to numerous environmental stressors, including chemicals and invasion of pathogenic microorganisms among others, coordinating cellular and organismal responses. Individual cells sense the environment using receptors that trigger signaling pathways that regulate expression of specific effector proteins and/or cellular responses as movement or secretion. In the coordination of responses to stress, scaffold proteins are pivotal molecules that recruit other proteins forming active complexes. The Receptor for Activated C Kinase 1 (RACK1) is the best studied member of the conserved tryptophan-aspartate (WD) repeat family. RACK1 folds in a seven-bladed beta-propeller structure and it could be activated during stress, participating in different signaling pathways. The presence and activities of RACK1 in mosquitoes had not been documented before, in this work the molecule is demonstrated in an Aedes albopictus-derived cell line and its reaction to stress is observed under the effect of serum deprivation and the presence of glucocorticoid analog dexamethasone, a chemical used to cause stress in vitro. PMID- 25555379 TI - Determining scaphoid waist fracture union by conventional radiographic examination: an analysis of reliability and validity. AB - INTRODUCTION: Conventional radiographic imaging is the first imaging tool of choice in scaphoid fractures. The majority of undisplaced scaphoid waist fractures unite after 6 weeks of cast immobilization. We hypothesized that conventional radiographic imaging at 6 weeks after injury can both accurately and reliably predict union in undisplaced scaphoid waist fractures. MATERIALS AND METHODS: Fleiss' kappa statistics were used concerning the opinions of four observers reviewing 47 sets of good-quality scaphoid radiographs of undisplaced scaphoid waist fractures. As reference standard for union, radiographs were taken at a minimum of 6 months after injury to determine validity. RESULTS: Overall agreement was defined as moderate. (kappa = 0.583) "No consolidation" (kappa = 0.816), "full consolidation" (kappa = 0.517) and "partial consolidation" (kappa = 0.390) were defined as good, moderate and fair agreement, respectively. The average sensitivity and specificity of diagnosing scaphoid waist fracture union on standard scaphoid radiographs were 0.65 and 0.67, respectively. The positive predictive value for diagnosing union was 0.93 and the negative predictive value was 0.22. CONCLUSIONS: Conventional radiographic imaging is accurate and moderately reliable in diagnosing union, and reliable but inaccurate in diagnosing nonunion of scaphoid waist fractures at 6 weeks follow-up. PMID- 25555380 TI - Comparison of Bryan versus ProDisc-C total disk replacement as treatment for single-level cervical symptomatic degenerative disk disease. AB - PURPOSE: The purpose of this retrospective trial was to compare the role of the Bryan with ProDisc-C total disk replacement (TDR). MATERIALS AND METHODS: Data were collected before surgery and 1, 3, 6, 12, and 24 months after surgery. Disability and pain were assessed using the Neck Disability Index (NDI) and the Visual Analog Scale of the neck and of the arm pain. SF-36 outcome measures were obtained including the physical component score as well as the mental component score. Functional spinal unit (FSU) was examined on lateral radiographs at 24 month follow-up. Occurrences of heterotopic ossification (HO) were detected from 24-month follow-up X-rays. RESULTS: The mean NDI, mean VAS, and mean SF-36 scores were not statistically different between groups before surgery and at 24-month follow-up. At 24 months: Bryan 49 and ProDisc-C 53 (P > 0.05). The FSU angle increased slightly for the Bryan group (from 0.7 to 0.8 degrees , P > 0.05), while for the ProDisc-C group, it increased significantly (from 0.5 to 2.3 degrees , P < 0.05). There were 2 additional operations in this series: 1 in the Bryan group and 1 in the ProDisc-C group. There were no intraoperative complications, no vascular or neurologic complications, no spontaneous fusions, and no device failures or explantation. No significant difference was noted in terms of HO formation. CONCLUSION: Both the Bryan and the ProDisc-C TDR resulted in satisfactory clinical outcome. Moreover, Bryan TDR can maintain the lordosis of FSU, whereas ProDisc-C TDR can restore the lordosis of FSU, whether or not this radiographic evidence leads to more favorable clinical outcome for ProDisc-C TDR requires further investigation. PMID- 25555381 TI - Comparison of intramuscular and subcutaneous administration of a herpes zoster live-attenuated vaccine in adults aged >=50 years: a randomised non-inferiority clinical trial. AB - Zostavax((r)) is a live, attenuated varicella zoster virus (VZV) vaccine developed specifically for the prevention of HZ and PHN in individuals aged >=50 years. During the clinical development of Zostavax, which was mainly in the US, the vaccine was administrated by the subcutaneous (SC) route. In Europe, many healthcare professionals prefer administering vaccines by the intramuscular (IM) route. This was an open-label, randomised trial conducted in 354 subjects aged >=50 years. The primary objectives were to demonstrate that IM administration is both non-inferior to SC administration in terms of 4-week post-vaccination geometric mean titres (GMTs), and elicits an acceptable geometric mean fold-rise (GMFR) of antibody titres measured by glycoprotein enzyme-linked immunosorbent assay. Pre-specified non-inferiority was set as the lower bound of the 95% confidence interval (CI) of the GMT ratio (IM/SC) being >0.67. An acceptable GMFR for the IM route was pre-specified as the lower bound of its 95% CI being >1.4. Description of the VZV immune response using the interferon-gamma enzyme-linked immunospot (IFN-gamma ELISPOT) assay and of the safety were secondary objectives. Participants were randomised to IM or SC administration (1:1). The baseline demographics were comparable between groups; mean age: 62.6 years (range: 50.0 90.5). The primary immunogenicity objectives were met (per protocol analysis): GMT ratio (IM/SC): 1.05 (95% CI: 0.93-1.18); GMFR: 2.7 (2.4-3.0). VZV immune response using IFN-gamma ELISPOT were comparable between groups. Frequencies of systemic adverse events were comparable between groups. Injection-site reactions were less frequent with IM than SC route: erythema (15.9% versus 52.5%), pain (25.6% versus 39.5%) and swelling (13.6% versus 37.3%), respectively. In adults aged >=50 years, IM administration of Zostavax elicited similar immune responses to SC administration and was well tolerated, with fewer injection-site reactions than with SC administration. PMID- 25555382 TI - Over-expression of bael quinolone synthase in tobacco improves plant vigor under favorable conditions, drought, or salt stress. AB - Type III polyketide synthases (PKSs) catalyze the biosynthesis of various medicinally important secondary metabolites in plants, but their role in growth and stress response is unclear. Here, we overexpressed quinolone synthase (QNS) from bael in tobacco. QNS-overexpressing plants showed an overall increase in growth, photosynthetic efficiency and chlorophyll content compared to wild type plants. Second-generation (T2) transgenic plants grew to maturity, flowered early and set viable seeds under favorable conditions without yield penalty. An increased accumulation of flavonoids, phenols and alkaloids was associated with higher tolerance to drought and salinity stress in transgenic plants. Thus, bael QNS seems to function as a positive regulator of plant growth and stress response, and could be potentially used for engineering plants tolerant to abiotic stress. PMID- 25555383 TI - Challenges and opportunities facing maternal and child health (MCH) professionals. PMID- 25555386 TI - The impact of bacterial DNA translocation on early postoperative outcomes in Crohn's patients undergoing abdominal surgery. AB - BACKGROUND AND AIMS: Bacterial DNA (bactDNA) translocation occurs frequently in patients with Crohn's disease and can be present in patients with a negative blood microbiological culture. We aimed to determine the effects of bactDNA translocation on postoperative outcomes in Crohn's disease patients undergoing abdominal surgery. METHODS: Patients with Crohn's disease who underwent abdominal surgery between January 2012 and March 2014 were identified. General and postoperative outcome-related information was retrieved from a database, and the data were compared between patients with and without bactDNA translocation. Multivariate analysis was used to determine the independent effect of bactDNA translocation on postoperative morbidity. RESULTS: One hundred and seven patients who underwent abdominal surgery were included in our study. The presence of bactDNA in blood samples was identified in 29 patients (27.1%). There was a total of 55 complications in 28 patients (26.2%). Patients with bactDNA in their blood had a mean postoperative hospital stay of 12.7+/-4.2 days and patients without DNA translocation had a mean postoperative hospital stay of 10.1+/-4.8 days (p = 0.009). The readmission rate was increased in patients with bactDNA translocation (p = 0.032). A low preoperative level of serum albumin (p = 0.024), preoperative immunosuppressive agent use (p = 0.046), and the presence of bactDNA in blood (p = 0.005) were independently associated with increased postoperative adverse outcomes. CONCLUSIONS: Preoperative bactDNA translocation into the blood increases the incidence of postoperative adverse outcomes in patients with Crohn's disease who undergo abdominal surgery. PMID- 25555385 TI - Nicotine Dependence, Nicotine Metabolism, and the Extent of Compensation in Response to Reduced Nicotine Content Cigarettes. AB - INTRODUCTION: The Food and Drug Administration has the authority to regulate tobacco product constituents, including nicotine, to promote public health. Reducing the nicotine content in cigarettes may lead to lower levels of addiction. Smokers however may compensate by smoking more cigarettes and/or smoking more intensely. The objective of this study was to test whether individual differences in the level of nicotine dependence (as measured by the Fagerstrom Test of Cigarette Dependence [FTCD]) and/or the rate of nicotine metabolism influence smoking behavior and exposure to tobacco toxicants when smokers are switched to reduced nicotine content cigarettes (RNC). METHODS: Data from 51 participants from a previously published clinical trial of RNC were analyzed. Nicotine content of cigarettes was progressively reduced over 6 months and measures of smoking behavior, as well as nicotine metabolites and tobacco smoke toxicant exposure, CYP2A6 and nicotinic CHRNA5-A3-B4 (rs1051730) genotype were measured. RESULTS: Higher baseline FTCD predicted smoking more cigarettes per day (CPD), higher cotinine and smoke toxicant levels while smoking RNC throughout the study, with no interaction by RNC level. Time to first cigarette (TFC) was associated with differences in compensation. TFC within 10 min was associated with a greater increase in CPD compared to TFC greater than 10 min. Neither rate of nicotine metabolism, nor CYP2A6 or nicotinic receptor genotype, had an effect on the outcome variables of interest. CONCLUSIONS: FTCD is associated with overall exposure to nicotine and other constituents of tobacco smoke, while a short TFC is associated with an increased compensatory response after switching to RNC. PMID- 25555388 TI - Pharmacists react angrily to government plans requiring them to check prescription exemptions. PMID- 25555389 TI - The use of laboratory biomarkers for surveillance, diagnosis and prediction of clinical outcomes in neonatal sepsis and necrotising enterocolitis. AB - Biomarkers have been used to differentiate systemic neonatal infection and necrotising enterocolitis (NEC) from other non-infective neonatal conditions that share similar clinical features. With increasing understanding in biochemical characteristics of different categories of biomarkers, a specific mediator or a panel of mediators have been used in different aspects of clinical management in neonatal sepsis/NEC. This review focuses on how these biomarkers can be used in real-life clinical settings for daily surveillance, bedside point-of-care testing, early diagnosis and predicting the severity and prognosis of neonatal sepsis/NEC. In addition, with recent development of 'multi-omic' approaches and rapid advancement in knowledge of bioinformatics, more novel biomarkers and unique signatures of mediators would be discovered for diagnosis of specific diseases and organ injuries. PMID- 25555387 TI - Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation. AB - Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues. PMID- 25555390 TI - Effects of performing morning versus afternoon exercise on glycemic control and hypoglycemia frequency in type 1 diabetes patients on sensor-augmented insulin pump therapy. AB - BACKGROUND: Although physical exercise (PE) is recommended for individuals with type 1 diabetes (DM1), participation in exercise is challenging because it increases the risk of severe hypoglycemia and the available therapeutic options to prevent it frequently result in hyperglycemia. There is no clear recommendation about the best timing for exercise. The aim of this study was to compare the risk of hypoglycemia after morning or afternoon exercise sessions up to 36 hours postworkout. METHODS: This randomized crossover study enrolled subjects with DM1, older than 18 years of age, on sensor-augmented insulin pump (SAP) therapy. Participants underwent 2 moderate-intensity exercise sessions; 1 in the morning and 1 in the afternoon, separated by a 7 to 14 day wash-out period. Continuous glucose monitoring (CGM) data were collected 24 hours before, during and 36 hours after each session. RESULTS: Thirty-five subjects (mean age 30.31 +/- 12.66 years) participated in the study. The rate of hypoglycemia was significantly lower following morning versus afternoon exercise sessions (5.6 vs 10.7 events per patient, incidence rate ratio, 0.52; 95% CI, 0.43-0.63; P < .0001). Most hypoglycemic events occurred 15-24 hours after the session. On days following morning exercise sessions, there were 20% more CGM readings in near euglycemic range (70-200 mg/dL) than on days prior to morning exercise (P = .003). CONCLUSIONS: Morning exercise confers a lower risk of late-onset hypoglycemia than afternoon exercise and improves metabolic control on the subsequent day. PMID- 25555391 TI - The benefits, limitations, and cost-effectiveness of advanced technologies in the management of patients with diabetes mellitus. AB - Hypoglycemia mitigation is critical for appropriately managing patients with diabetes. Advanced technologies are becoming more prevalent in diabetes management, but their benefits have been primarily judged on the basis of hemoglobin A1c. A critical appraisal of the effectiveness and limitations of advanced technologies in reducing both A1c and hypoglycemia rates has not been previously performed. The cost of hypoglycemia was estimated using literature rates of hypoglycemia events resulting in hospitalizations. A literature search was conducted on the effect on A1c and hypoglycemia of advanced technologies. The cost-effectiveness of continuous subcutaneous insulin infusion (CSII) and real time continuous glucose monitors (RT-CGM) was reviewed. Severe hypoglycemia in insulin-using patients with diabetes costs $4.9-$12.7 billion. CSII reduces A1c in some but not all studies. CSII improves hypoglycemia in patients with high baseline rates. Bolus calculators improve A1c and improve the fear of hypoglycemia but not hypoglycemia rates. RT-CGM alone and when combined with CSII improve A1c with a neutral effect on hypoglycemia rates. Low-glucose threshold suspend systems reduce hypoglycemia with a neutral effect on A1c, and low-glucose predictive suspend systems reduce hypoglycemia with a small increase in plasma glucose levels. In short-term studies, artificial pancreas systems reduce both hypoglycemia rates and plasma glucose levels. CSII and RT-CGM are cost-effective technologies, but their wide adoption is limited by cost, psychosocial, and educational factors. Most currently available technologies improve A1c with a neutral or improved rate of hypoglycemia. Advanced technologies appear to be cost effective in diabetes management, especially when including the underlying cost of hypoglycemia. PMID- 25555393 TI - British Society for Heart Failure 17th annual autumn meeting. AB - The British Society for Heart Failure recently held its 17th annual meeting in London, attracting over 700 delegates for the 2-day conference. The meeting covered a wide range of topics, including common co-morbidities, diagnostic dilemmas, latest guidelines/clinical trials and managing clinically challenging scenarios. The British Society for Heart Failure meeting provides an entertaining and informative forum to learn from internationally renowned experts in both the field of heart failure and allied specialties. Future meetings are highly recommended. PMID- 25555394 TI - The cold facts of long-term ECG monitoring. AB - Two recently published trials have provided evidence in favor of longer ECG monitoring among patients with cryptogenic stroke (CS). In the CRYSTAL-AF trial, new atrial fibrillation (AF) was detected in 12.4% of patients with implantable monitor when compared with 2% among those receiving standard follow-up. A similar result was observed in the EMBRACE trial in which AF was detected in 16.1% of patients who received 30-day event recorder (3.2% in controls). These data are compelling in convincing us that long-term ECG technologies have superior sensitivity for the detection of AF in CS; however, clinical specificity for the definition of CS etiology of such findings cannot be established and can be lower than expected, leaving open questions about the etiologic weight of AF in CS. The causative role of AF in this subpopulation remains to be proven, and diagnostic routes cannot be solely unbalanced toward the research of AF. PMID- 25555392 TI - The SIX1-EYA transcriptional complex as a therapeutic target in cancer. AB - INTRODUCTION: The SIX homeodomain proteins and the eyes absent (EYA) family of co activators form a bipartite transcription factor complex that promotes the proliferation and survival of progenitor cells during organogenesis and is down regulated in most adult tissues. Abnormal over-expression of SIX1 and EYA in adult tissue is associated with the initiation and progression of diverse tumor types. Importantly, SIX1 and EYA are often co-overexpressed in tumors, and the SIX1-EYA2 interaction has been shown to be critical for metastasis in a breast cancer model. The EYA proteins also contain protein tyrosine phosphatase activity, which plays an important role in breast cancer growth and metastasis as well as directing cells to the repair pathway upon DNA damage. AREAS COVERED: This review provides a summary of the SIX1/EYA complex as it relates to development and disease and the current efforts to therapeutically target this complex. EXPERT OPINION: Recently, there have been an increasing number of studies suggesting that targeting the SIX1/EYA transcriptional complex will potently inhibit tumor progression. Although current attempts to develop inhibitors targeting this complex are still in the early stages, continued efforts toward developing better compounds may ultimately result in effective anti-cancer therapies. PMID- 25555397 TI - Further understanding of tau phosphorylation: implications for therapy. AB - Tau is a brain microtubule-associated protein that regulates microtubule structure and function. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders collectively referred to as tauopathies, the most common of which is Alzheimer's disease. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have unveiled novel important tau cellular functions that may also play a pivotal role in pathogenesis and render novel targets for therapeutic intervention. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, especially phosphorylation, which has significant implications for the development of novel therapeutic approaches in a number of neurodegenerative disorders. PMID- 25555396 TI - Dynamic response of RNA editing to temperature in Drosophila. AB - BACKGROUND: Adenosine-to-inosine RNA editing is a highly conserved process that post-transcriptionally modifies mRNA, generating proteomic diversity, particularly within the nervous system of metazoans. Transcripts encoding proteins involved in neurotransmission predominate as targets of such modifications. Previous reports suggest that RNA editing is responsive to environmental inputs in the form of temperature alterations. However, the molecular determinants underlying temperature-dependent RNA editing responses are not well understood. RESULTS: Using the poikilotherm Drosophila, we show that acute temperature alterations within a normal physiological range result in substantial changes in RNA editing levels. Our examination of particular sites reveals diversity in the patterns with which editing responds to temperature, and these patterns are conserved across five species of Drosophilidae representing over 10 million years of divergence. In addition, we show that expression of the editing enzyme, ADAR (adenosine deaminase acting on RNA), is dramatically decreased at elevated temperatures, partially, but not fully, explaining some target responses to temperature. Interestingly, this reduction in editing enzyme levels at elevated temperature is only partially reversed by a return to lower temperatures. Lastly, we show that engineered structural variants of the most temperature-sensitive editing site, in a sodium channel transcript, perturb thermal responsiveness in RNA editing profile for a particular RNA structure. CONCLUSIONS: Our results suggest that the RNA editing process responds to temperature alterations via two distinct molecular mechanisms: through intrinsic thermo-sensitivity of the RNA structures that direct editing, and due to temperature sensitive expression or stability of the RNA editing enzyme. Environmental cues, in this case temperature, rapidly reprogram the Drosophila transcriptome through RNA editing, presumably resulting in altered proteomic ratios of edited and unedited proteins. PMID- 25555399 TI - Neural circuits that drive binocular eye movements: implications for understanding and correcting strabismus. PMID- 25555400 TI - Exploring an effective tobacco prevention programme for Indian adolescents. AB - OBJECTIVES: Tobacco use is among the most significant public health issues faced by the world today. It is estimated that approximately 5500 adolescents start using tobacco every day in India, adding to the four million youths aged <15 years who are already regular users. School-based smoking prevention programmes have been shown to increase knowledge about the negative effects of tobacco and prevent tobacco use, but the majority of evidence on effectiveness comes from Western countries. This study investigated the impact of a school-based short term educational intervention regarding tobacco use on adolescents' knowledge, attitudes, intentions and behaviours (KAIB) in Bangalore, India. STUDY DESIGN: An intervention trial was conducted among 720 adolescents aged 15-16 years in Bangalore, India. METHODS: Educational interventions were imparted to all study subjects in a phased manner, along with two interactive sessions held six months apart. The impact of the programme was measured using questionnaires administered before the first intervention (pre-intervention) and after the second intervention (post-intervention). RESULTS: Mean (+/-standard deviation) pre intervention KAIB scores of the subjects were 5.9 +/- 1.87 (knowledge), 23.6 +/- 3.15 (attitude) and 18.9 +/- 3.27 (practice), which improved to 7.8 +/- 2.01, 26.7 +/- 2.43 and 12.3 +/- 2.52, respectively, postintervention. The differences in mean KAIB scores were significant (P < 0.0001, df = 1400), suggesting that the intervention had a major positive impact. CONCLUSION: School-based short-term educational intervention programmes are effective for preventing and reducing tobacco use among Indian adolescents. PMID- 25555398 TI - Identification of horizontally transferred genes in the genus Colletotrichum reveals a steady tempo of bacterial to fungal gene transfer. AB - BACKGROUND: Horizontal gene transfer (HGT) is the stable transmission of genetic material between organisms by means other than vertical inheritance. HGT has an important role in the evolution of prokaryotes but is relatively rare in eukaryotes. HGT has been shown to contribute to virulence in eukaryotic pathogens. We studied the importance of HGT in plant pathogenic fungi by identifying horizontally transferred genes in the genomes of three members of the genus Colletotrichum. RESULTS: We identified eleven HGT events from bacteria into members of the genus Colletotrichum or their ancestors. The HGT events include genes involved in amino acid, lipid and sugar metabolism as well as lytic enzymes. Additionally, the putative minimal dates of transference were calculated using a time calibrated phylogenetic tree. This analysis reveals a constant flux of genes from bacteria to fungi throughout the evolution of subphylum Pezizomycotina. CONCLUSIONS: Genes that are typically transferred by HGT are those that are constantly subject to gene duplication and gene loss. The functions of some of these genes suggest roles in niche adaptation and virulence. We found no evidence of a burst of HGT events coinciding with major geological events. In contrast, HGT appears to be a constant, albeit rare phenomenon in the Pezizomycotina, occurring at a steady rate during their evolution. PMID- 25555403 TI - Developing dual hemofiltration plus cardiopulmonary bypass in rodents. AB - BACKGROUND: Emerging therapies for prolonged cardiac arrest (CA) include advanced circulatory interventions like emergency cardiopulmonary bypass (ECPB) and continuous venovenous hemofiltration (CVVHF). However, preclinical studies are limited because of the absence of a practical method of using CVVHF along with ECPB in rodents. METHODS: We modified a CA model with ECPB resuscitation to include the CVVHF circuit. Adult rats were cannulated via the femoral artery or vein and the jugular vein for the ECPB circuit. A new circuit for CVVHF was added to allow ECPB and CVVHF to be started simultaneously. CVVHF blood flow at 3 mL/min could be controlled with a screw clamp during ECPB. After cessation of ECPB, the CVVHF flow was maintained using a roller pump. The filtration rate was controlled at 40 mL/h/kg in the standard volume of CVVHF and 120 mL/h/kg in the high volume (HV) of CVVHF. The driving force of hemofiltration was evaluated by monitoring transmembrane pressure and filter clearance (FCL). RESULTS: Transmembrane pressure in both groups was stable for 6 h throughout CVVHF. FCL of blood urea nitrogen and potassium in the standard volume group was significantly less than the HV group (P < 0.01). FCL of blood urea nitrogen and potassium was stable throughout the CVVHF operation in both groups. CONCLUSIONS: We developed a method of CVVHF along with ECPB in rodents after CA. We further demonstrated the ability to regulate both standard and HV filtration rates. PMID- 25555404 TI - Liver innervation and hepatic function: new insights. AB - The hepatic nervous system has a well-known impact on the regulation of liver function and organism homeostasis. The aim of this review is to summarize the new available data regarding the role of hepatic nerves. In the last decade, studies have shown that hepatic nerves exert subtle but significant modifications on the regulation of glucose and lipid metabolism, food intake, and liver regeneration. They also play a role in liver disease pathogenesis, and hepatic denervation has beneficial results to liver graft ischemia-reperfusion injury. Available data are still limited, and further research toward neural pathways involving the liver that can modify response to disease is required. PMID- 25555405 TI - Early hemodynamic effects after extended liver radiofrequency ablation. AB - BACKGROUND: The purpose of the present study was to assess early intestinal and systemic hemodynamic effects after extended radiofrequency ablation (RFA) of the liver in terms of investigating their potential contribution to gut barrier disruption. MATERIALS AND METHODS: Ten rabbits were assigned to two groups of five animals each and were subjected to either 30% liver RFA (group RFA-1) or sham operation (group sham-1). Blood flow rate at the superior mesenteric artery (SMA) was monitored for 90 min after operation. Ileal tissue was excised at 48 h for histomorphometric and histopathologic analysis. Eight pigs were assigned to two groups of four animals each and were also subjected to either 30% liver RFA (group RFA-2) or sham operation (group sham-2). A panel of systemic hemodynamic parameters was serially measured up to 90 min after operation. RESULTS: In group RFA-1, SMA blood flow rate was lower than that in group sham-1 throughout the study period. Intestinal mucosa atrophy and a deterioration of histopathologic profile were noted in group RFA-1. In group RFA-2, diastolic pulmonary artery pressure was lower (60-90 min), central venous pressure was gradually decreased, arterial pressure was higher (30-90 min), and systemic vascular resistance was higher (30-90 min) than those in group sham-2. No change was noted in the cardiac output. CONCLUSIONS: In conclusion, SMA blood flow was reduced during the early post-RFA period, justifying an ischemic insult at the intestine. In addition, a gradual decrease of the preload was counterbalanced by an increase of systemic vascular resistance leaving the cardiac output unaffected. PMID- 25555406 TI - [Geriatric teaching at undergraduate level: are Spanish Medical Schools following European recommendations?]. AB - OBJECTIVES: To compare the learning objectives proposed by the European Union of Medical Specialists Geriatric section (UEMS-GS) with those approved in Spain for undergraduate teaching. MATERIAL AND METHODS: Learning objectives included in the European Undergraduate Curriculum in Geriatric Medicine developed by the UEMS-GS in 2013 were compared with those listed in different Spanish official documents: Boletin Oficial del Estado (BOE, Spanish State Gazette), white book on Medicine of the Spanish Accreditation Agency (ANECA), and list of learning objectives of Spanish Medical Schools. RESULTS: the European curriculum recommends to teach 42 competencies divided in 10 sections, while the BOE mentions 37 general competencies and some other specific competencies, and the ANECA mentions 23 generic and 34 specific competencies (similar to the 37 of the BOE), and a list of common contents in which Geriatrics is included. The BOE includes 38% of the European competencies (range 17-100% of competencies in different sections), while the ANECA includes 52% of them (range 17-100%). CONCLUSIONS: Spanish regulations include from one third to half of the European recommendations for Geriatrics teaching at undergraduate level. In the future, it seems advisable that official requirements in Spain should converge with European recommendations. This task should also be performed by Spanish Medical Schools. PMID- 25555407 TI - Derivatization method for sensitive determination of 3-hydroxybenzo[a]pyrene in human urine by liquid chromatography-electrospray tandem mass spectrometry. AB - While urinary 3-hydroxybenzo[a]pyrene (3-OHBaP) can indicate exposure to carcinogenic benzo[a]pyrene (BaP) in humans, most previous analytical methods could not detect it in the general population due to a lack of sufficient sensitivity. In this study, a new liquid chromatography-electrospray mass-mass spectrometry (LC-ESI-MS/MS) method was developed to analyze 3-OHBaP by employing an optimized derivatization reaction with dansyl chloride (DNS) in the aqueous phase. The instrument detection limit (IDL) of the newly developed method was 10ng/L, which is 60-fold lower than without derivatization. The method was successfully applied to analyze 3-OHBaP and 1-hydroxypyrene (1-OHPy) in human urine combined with enzymatic hydrolysis, C18 enrichment, liquid-liquid extraction and silica cartridge cleanup. The overall method recoveries were 68.7+/-5.47% for 3-OHBaP and 72.3+/-4.96% for 1-OHPy, with matrix effects of <10%. The limits of quantification (LOQs) in urine were 0.3+/-0.02ng/L and 0.5+/ 0.02ng/L (n=3), respectively. The method was applied to analyze seven urine samples of volunteers, and 3-OHBaP was detected in five samples. The concentration of urinary 3-OHBaP ranged from A polymorphism of the gene encoding beta fibrinogen subunit (FGB) and the Thr312Ala polymorphism of the gene for the alpha fibrinogen subunit (FGA) in childhood ischemic stroke are insufficient. Therefore the aim of the study was to evaluate a possible association between these two polymorphisms and arterial ischemic stroke. METHODS: The study group consisted of 85 children after ischemic stroke, 146 of their parents and 159 controls. Both polymorphisms were genotyped using the restriction fragment length polymorphism method. Two study designs were used: a case-control model and a family-based transmission-disequilibrium test. Statistica 7.1 and EpiInfo 6 softwares were used in all analyses. RESULTS: In the TDT test, a tendency to a higher transmission of the 312Ala allele of the FGA gene and the -455A allele of the FGB gene was observed, however, it was statistically non-significant. The frequencies of alleles and genotypes of both FGA and FGB genes polymorphisms did not differentiate children from both groups also in the case-control model. Additive or synergistic effects between FGA and FGB genes polymorphisms were not observed. CONCLUSION: An analysis of the results obtained in this study and a critical review of previously published data indicate that examined gene polymorphisms are not related to ischemic stroke in children. PMID- 25555435 TI - [Axillary hyperhidrosis, botulinium A toxin treatment: Review]. AB - Injection of type A botulinum toxin in the armpits is a temporary treatment for axillary hyperhidrosis. This technique described in 1996 by Bushara et al., is known to be efficient and safe. The purpose of this article was to review the data concerning the treatment of axillary hyperhidrosis with botulinum toxin type A, and discuss the other treatment modalities for this socially disabling entity. PMID- 25555434 TI - Zosteriform configuration of multiple eccrine spiradenomas of the scalp. AB - BACKGROUND: Eccrine spiradenoma (ES) is a benign adnexal tumor predominantly located in the head and neck regions. Multiple neoplasms located on the scalp have been reported but never with a zosteriform configuration on the first trigeminal area. CASE REPORT: We describe an original case report of a 75-year old Caucasian man presenting multiple subcutaneous blue and purple nodules disseminated on the first left trigeminal dermatome. All the nodules appeared gradually on a one-year period. Biopsy revealed a nodular adnexal tumor in the dermis without malignant eccrine spiradenoma (MES) transformation. The surgical procedure was performed in a manner to protect the galea aponeurotica in the upper half on the first left trigeminal area. The frontalis muscle was raised with the surgical specimen in the lower half of the first trigeminal area. A split-thickness skin graft was applied on the surgical defect. Histological examination revealed multilobular well-defined tumors located in the dermis. CONCLUSION: The presence of multiple subcutaneous nodules in a trigeminal pattern should suggest a multiple localized zosteriform ES. The diagnosis is focused on clinical findings and the treatment is based on a large surgical excision. The histological examination is essential for not to fail a MES transformation. PMID- 25555436 TI - Dying for a good night's sleep. PMID- 25555437 TI - Association between 25-hydroxyvitamin D and type 2 diabetes--authors' reply. PMID- 25555438 TI - Association between 25-hydroxyvitamin D and type 2 diabetes. PMID- 25555439 TI - Rhizoctonia bataticola lectin (RBL) induces phenotypic and functional characteristics of macrophages in THP-1 cells and human monocytes. AB - We have previously reported that a fungal lectin, Rhizoctonia bataticola lectin (RBL), stimulates proliferation and secretion of Th1/Th2 cytokines in human peripheral blood mononuclear cells (PBMC). In the present study, we evaluated the ability of RBL to differentiate human monocytes to macrophages. RBL induced morphological changes indicative of differentiation in primary monocytes and THP 1 cells. Stimulation with RBL resulted in significant up-regulation of differentiation markers - CD54, HLA-DR, CD11b and CD11c and secretion of proinflammatory cytokines - IL-1beta, TNF-alpha and IL-6. Functionally, RBL profoundly increased phagocytic activity in monocytes. In THP-1 cells, RBL induced phagocytosis was higher compared to the effect induced by combination of phorbol-12-myristate-13-acetate (PMA) and lipopolysaccharide (LPS). RBL induced a significant increase in matrix metalloproteinase-9 (MMP-9) activity in comparison with a combined treatment of PMA+LPS. Mechanistic studies revealed the involvement of the NF-kappaB pathway in RBL-induced differentiation of monocytes. The data suggest that RBL mimics the combined action of PMA and LPS to induce morphological and functional differentiation in human monocytes and monocytic cell line - THP-1 to macrophages. Human monocytes differentiated to macrophages with RBL have the potential as an in vitro model to study macrophage biology. PMID- 25555440 TI - Neurodevelopment of children exposed to anesthesia: design of the Mayo Anesthesia Safety in Kids (MASK) study. AB - There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994 and 2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8 and 12 years or 15 and 19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4 hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks. PMID- 25555444 TI - Do gamma oscillations play a role in cerebral cortex? AB - Gamma rhythm (which has a center frequency between 30 and 80 Hz) is modulated by cognitive mechanisms such as attention and memory, and has been hypothesized to play a role in mediating these processes by supporting communication channels between cortical areas or encoding information in its phase. We highlight several issues related to gamma rhythms, such as low and inconsistent power, its dependence on low-level stimulus features, problems due to conduction delays, and contamination due to spike-related activity that makes accurate estimation of gamma phase difficult. Gamma rhythm could be a potentially useful signature of excitation-inhibition interactions in the brain, but whether it also provides a mechanism for information processing or coding remains an open question. PMID- 25555445 TI - Massage, Music, and Art Therapy in Hospice: Results of a National Survey. AB - CONTEXT: Complementary and alternative medicine (CAM) provides clinical benefits to hospice patients, including decreased pain and improved quality of life. Yet little is known about the extent to which U.S. hospices employ CAM therapists. OBJECTIVES: To report the most recent national data regarding the inclusion of art, massage, and music therapists on hospice interdisciplinary teams and how CAM therapist staffing varies by hospice characteristics. METHODS: A national cross sectional survey of a random sample of hospices (n = 591; 84% response rate) from September 2008 to November 2009. RESULTS: Twenty-nine percent of hospices (169 of 591) reported employing an art, massage, or music therapist. Of those hospices, 74% employed a massage therapist, 53% a music therapist, and 22% an art therapist, and 42% expected the therapist to attend interdisciplinary staff meetings, indicating a significant role for these therapists on the patient's care team. In adjusted analyses, larger hospices compared with smaller hospices had significantly higher odds of employing a CAM therapist (adjusted odds ratio 6.38; 95% CI 3.40, 11.99) and for-profit hospices had lower odds of employing a CAM therapist compared with nonprofit hospices (adjusted odds ratio 0.52; 95% CI 0.32, 0.85). Forty-four percent of hospices in the Mountain/Pacific region reported employing a CAM therapist vs. 17% in the South Central region. CONCLUSION: Less than one-third of U.S. hospices employ art, massage, or music therapists despite the benefits these services may provide to patients and families. A higher proportion of large hospices, nonprofit hospices, and hospices in the Mountain/Pacific region employ CAM therapists, indicating differential access to these important services. PMID- 25555446 TI - Which treatment is better? Ascertaining patient preferences with crossover randomized controlled trials. AB - CONTEXT: The difference in patient-reported outcomes between study arms can often be difficult to ascertain in randomized controlled trials (RCTs) using a parallel design because of wide interindividual variations in baseline characteristics and how patients interpret the outcome measures. Furthermore, the minimal clinically significant difference is often not available for many outcomes, and even when available, not individualized for each patient. Crossover RCTs are designed for intraindividual comparisons, which can address these issues by asking patients to directly compare the interventions with regard to effectiveness, adverse effects, and ease of use and to provide an overall choice. OBJECTIVES: We discuss the key design elements for crossover trials, their advantages and disadvantages relative to parallel designs, and their utility in palliative care research using a number of case examples. METHODS: This is a narrative review. RESULTS: Crossover studies randomize patients to a sequence of treatments. In addition to facilitating intraindividual comparisons, they often require a smaller sample size for the same statistical power compared with parallel designs and are thus less costly. However, crossover studies are only feasible when the condition being studied is relatively stable and the intervention has a short-term effect. Crossover studies with inadequate washout periods may be difficult to interpret. The risk of attrition also may increase because of prolonged study duration. CONCLUSION: By facilitating intraindividual comparisons and eliciting patient preferences, crossover studies can provide unique information on the superior intervention. Crossover designs should be considered for selected palliative care studies. PMID- 25555447 TI - Disparities in utilization of autologous hematopoietic cell transplantation for treatment of multiple myeloma. AB - Autologous hematopoietic cell transplantation (AHCT) is an established therapy for multiple myeloma (MM), with an impact on quality of remission and survival. We analyzed the role of race, ethnicity, sex, and age disparities in AHCT utilization in the United States. We combined MM incidence derived from the Surveillance, Epidemiology and End Results program with transplantation activity reported to the Center for International Blood and Marrow Transplant Research for the period of 2005 to 2009 to assess the impact of disparities in AHCT. Utilization (number of transplantations/new cases) was compared between groups using the relative utilization ratio (RUR), defined as [utilization for a given category]/[utilization for the entire population]. Data were obtained from 22,462 actual MM cases and 13,311 AHCT. The age-adjusted RUR was 1.17 (95% confidence interval [CI], 1.15 to 1.19) among non-Hispanic Whites (NHW), higher than in non Hispanic Blacks (NHB) (age-adjusted RUR, .69; 95% CI, .67 to .72; P < .0002), Hispanics (age-adjusted RUR, .64; 95% CI, .60 to .69; P < .002), and Asians (age adjusted RUR, .65; 95% CI, .58 to .73; P < .0002]. AHCT utilization was higher in men than in women among Hispanics (age-adjusted RUR .72 versus .56, P = .007), but not among NHW, NHB, or Asians. Sex disparity prevents 1.3% of potential AHCTs in patients with MM (10.4% among Hispanics). Racial-ethnic disparities prevent 13.8% of AHCTs (44.7% in Hispanic and Asians, 39.9% in NHBs). Race-ethnicity disparity greatly affects AHCT utilization in MM. Sex disparity plays a lesser role, except among Hispanics. The ongoing decrease in age disparity will continue to drive major increase of AHCT activity. Two-year and 5-year increases in the age of the AHCT population would result in 12% and 32% increases, respectively, in volume of AHCT. PMID- 25555449 TI - Expansion and homing of umbilical cord blood hematopoietic stem and progenitor cells for clinical transplantation. AB - The successful expansion of hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood (UCB) for transplantation could revolutionize clinical practice by improving transplantation-related outcomes and making available UCB units that have suboptimal cell doses for transplantation. New cytokine combinations appear able to promote HSPC growth with minimal differentiation into mature precursors and new agents, such as insulin-like growth factor-binding protein 2, are being used in clinical trials. Molecules that simulate the HSPC niche, such as Notch ligand, have also shown promise. Further improvements have been made with the use of mesenchymal stromal cells, which have made possible UCB expansion without a potentially deleterious prior CD34/CD133 cell selection step. Chemical molecules, such as copper chelators, nicotinamide, and aryl hydrocarbon antagonists, have shown excellent outcomes in clinical studies. The use of bioreactors could further add to HSPC studies in future. Drugs that could improve HSPC homing also appear to have potential in improving engraftment times in UCB transplantation. Technologies to expand HSPC from UCB and to enhance the homing of these cells appear to have attained the goal of accelerating hematopoietic recovery. Further discoveries and clinical studies are likely to make the goal of true HSPC expansion a reality for many applications in future. PMID- 25555450 TI - Single and multiple dose MultiStem (multipotent adult progenitor cell) therapy prophylaxis of acute graft-versus-host disease in myeloablative allogeneic hematopoietic cell transplantation: a phase 1 trial. AB - We conducted a multicenter, phase 1 dose escalation study evaluating the safety of the allogeneic multipotent adult progenitor cell (MAPC, MultiStem, Athersys, Inc., Cleveland, OH) stromal product administered as an adjunct therapy to 36 patients after myeloablative allogeneic hematopoietic cell transplantation (HCT). Patients received increasing doses of MAPC (1, 5, or 10 million cells per kilogram recipient weight) as a single i.v. dose on day +2 after HCT (n = 18), or once weekly for up to 5 doses (1 or 5 million cells per kilogram; n = 18). Infusional and regimen-related toxicities were assessed for 30 days after the last MAPC dose. Of 36 allogeneic HCT donors (17 related and 19 unrelated), 35 were 6/6 HLA matched. MAPC infusions were well tolerated without associated infusional toxicity, graft failure, or increased incidence of infection. Median times to neutrophil (n = 36) and platelet (n = 31) engraftment were 15 (range, 11 to 25) and 16 (range, 11 to 41) days, respectively. The overall cumulative incidences of grades II to IV and III and IV acute graft-versus-host disease (GVHD) at day 100 were 37% and 14%, respectively (n = 36). In the group that received the highest single MAPC dose (10 million cells/kg), day 100 incidence of grade II to IV GVHD was 11.1% (1 of 9) with no observed cases of grade III and IV GVHD. We found no evidence for MHC class II allogeneic antibody induction, although some patients showed an increase in serum anticlass I titers compared with baseline. MAPC contribution to blood chimerism was negligible. These phase I data support the safety of stromal stem cell therapy and suggest that MAPC should be tested prospectively as a novel therapeutic option for GVHD prophylaxis after HCT. PMID- 25555451 TI - Resected pancreatic cancer outcomes in the elderly. AB - OBJECTIVE: To determine if age affects outcome in patients with resected pancreatic head cancer. MATERIALS AND METHODS: An IRB-approved pancreatic cancer database was queried for patients with upfront resected pancreatic head cancer treated at our institution between 2000 and 2012. Overall survival (OS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis was performed using the Cox proportional hazard model. RESULTS: We identified 193 patients. Patients >=70 years were less likely to receive adjuvant treatment (p = 0.002); however there were no other significant differences between age groups. There was a trend towards increased pancreatic leaks in the elderly group (p = 0.06), but no difference in post-operative complications or mortality. There was no difference in overall survival based on age. Median and 5-year OS were 23 months and 26.7% in patients <70 years, 23.4 months and 23% in those 70-75, 16.1 months and 0% in those 76-80, and 18.7 months and 15.4% in those >80 years (p = 0.62). On univariate analysis, there was increased OS in patients with lower T stage, N0 status, post-operative CA19-9 level <90, and use of chemoradiotherapy (p< 0.05). Multivariate analysis revealed that lower tumor stage, N0, post-operative CA19-9 level <90, and use of any adjuvant therapy predicted decreased mortality (p < 0.05). Age, gender, tumor site, tumor grade, and positive margins were not prognostic on multivariate analysis. CONCLUSIONS: There is no difference in outcomes when comparing elderly patients with resected pancreatic cancer to those patients <70 years of age. PMID- 25555448 TI - New cancers after autotransplantations for multiple myeloma. AB - We describe baseline incidence and risk factors for new cancers in 4161 persons receiving autotransplants for multiple myeloma in the United States from 1990 to 2010. Observed incidence of invasive new cancers was compared with expected incidence relative to the US population. The cohort represented 13,387 person years at-risk. In total, 163 new cancers were observed, for a crude incidence rate of 1.2 new cancers per 100 person-years and cumulative incidences of 2.6% (95% confidence interval [CI], 2.09 to 3.17), 4.2% (95% CI, 3.49 to 5.00), and 6.1% (95% CI, 5.08 to 7.24) at 3, 5, and 7 years, respectively. The incidence of new cancers in the autotransplantation cohort was similar to age-, race-, and gender-adjusted comparison subjects with an observed/expected (O/E) ratio of 1.00 (99% CI, .81 to 1.22). However, acute myeloid leukemia and melanoma were observed at higher than expected rates with O/E ratios of 5.19 (99% CI, 1.67 to 12.04; P = .0004), and 3.58 (99% CI, 1.82 to 6.29; P < .0001), respectively. Obesity, older age, and male gender were associated with increased risks of new cancers in multivariate analyses. This large data set provides a baseline for comparison and defines the histologic type specific risk for new cancers in patients with MM receiving postautotransplantation therapies, such as maintenance. PMID- 25555452 TI - A high-fat diet rich in corn oil reduces spontaneous locomotor activity and induces insulin resistance in mice. AB - Over the last few decades, polyunsaturated fatty acid (PUFA), especially n-6 PUFA, and monounsaturated fatty acid content in 'Western diets' has increased manyfold. Such a dietary shift also parallels rising sedentary behavior and diabetes in the Western world. We queried if a shift in dietary fats could be linked to physical inactivity and insulin insensitivity in mice. Eight-week old female C57/Bl6 mice were fed either high-fat (HF) diets [40% energy corn oil (CO) or isocaloric olive oil (OO) diets] or chow (n=10/group) for 6 weeks, followed by estimation of spontaneous locomotor activity, body composition and in vivo metabolic outcomes. Although lean mass and resting energy expenditure stayed similar in both OO- and CO-fed mice, only CO-fed mice demonstrated reduced spontaneous locomotor activity. Such depressed activity in CO-fed mice was accompanied by a lower respiratory ratio, hyperinsulinemia and impaired glucose disposal following intraperitoneal glucose tolerance and insulin tolerance tests compared to OO-fed mice. Unlike the liver, where both HF diets increased expression of fat oxidation genes like PPARs, the skeletal muscle of CO-fed mice failed to up-regulate such genes, thereby supporting the metabolic insufficiencies observed in these mice. In summary, this study demonstrates a specific contribution of n-6 PUFA-rich oils like CO to the loss of spontaneous physical activity and insulin sensitivity in mice. If these data hold true for humans, this study could provide a novel link between recent increases in dietary n-6 PUFA to sedentary behavior and the development of insulin resistance in the Western world. PMID- 25555453 TI - Immune-mediated bone marrow failure in C57BL/6 mice. AB - We established a model of immune-mediated bone marrow (BM) failure in C57BL/6 (B6) mice with 6.5 G total-body irradiation followed by the infusion of 4-10 * 10(6) lymph node (LN) cells/recipient from Friend leukemia virus B/N (FVB) donors. Forty-three percent of animals succumbed, with surviving animals showing marked declines in blood neutrophils, red blood cells, platelets and total BM cells at 8 to 14 days following LN cell infusion. Lowering the total-body irradiation dose to 5 G or altering the LN source from FVB to BALB/cBy donors failed to produce BM destruction. Affected animals showed significant expansion and activation of CD8 T lymphocytes in both the blood and BM; cytotoxic T cells had elevated Fas ligand expression and were oligoclonal, mainly displaying Vbeta7 and Vbeta17 T cell receptors. There were significant increases in blood plasma interferon gamma and tissue necrosis factor alpha in affected animals. Chemokine ligands CCL3, CCL4, CCL5, CCL20, CXCL2, and CXCL5 and hematopoietic growth factors G-CSF, M-CSF, GM-CSF, VEGF were also elevated. In B6 mice carrying a Fas gene mutation, BM failure was attenuated when they were infused with FVB LN cells. Our model establishes a useful platform to define the roles of individual genes and their products in immune-mediated BM failure. PMID- 25555454 TI - Development of sustained and dual drug release co-extrusion formulations for individual dosing. AB - In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 +/- 0.2 degrees C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 +/- 2.0 N and 26.4 +/- 2.8 N and E-modulus of 118.1 +/- 8.4 and 33.9 +/- 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification. PMID- 25555455 TI - Rhizobium capsici sp. nov., isolated from root tumor of a green bell pepper (Capsicum annuum var. grossum) plant. AB - A novel, Gram-staining-negative, rod-shaped, aerobic and motile bacterium, designated strain CC-SKC2(T), was isolated from the root tumor of a green bell pepper (Capsicum annuum var. grossum) plant in Taiwan. Cells were positive for oxidase and catalase activities and exhibited growth at 25-37 degrees C, pH 4.0 9.0 and tolerated NaCl concentrations up to 4.0 % (w/v). Strain CC-SKC2(T) is able to trigger nodulation in soybean (Glycine max Merr.), but not in Capsicum annuum var. grossum, red bean (Vigna angularis), sesbania (Sesbania roxburghii Merr.) or alfalfa (Medicago varia Martin.). The novel strain shared highest 16S rRNA gene sequence similarity to Rhizobium rhizoryzae KCTC 23652(T) and Rhizobium straminoryzae CC-LY845(T) (both 97.5 %) followed by Rhizobium lemnae L6-16(T) (97.3 %), Rhizobium pseudoryzae KCTC 23294(T) (97.1 %), and Rhizobium paknamense NBRC 109338(T) (97.0 %), whereas other Rhizobium species shared <96.7 % similarity. The DNA-DNA relatedness values of strain CC-SKC2(T) with R. rhizoryzae KCTC 23652(T), R. pseudoryzae KCTC 23294(T) and R. paknamense NBRC 109338(T) were 11.4, 17.2 and 17.0 %, respectively (reciprocal values were 11.1, 28.3 and 24.0 %, respectively). Phylogenetic analysis based on 16S rRNA, atpD and recA genes revealed a distinct taxonomic position attained by strain CC-SKC2(T) with respect to other Rhizobium species. The major fatty acids in strain CC SKC2(T) were C16:0, C19:0 cyclo omega8c, C14:0 3-OH and/or C16:1 iso I and C18:1 omega7c and/or C18:1 omega6c. The polyamine pattern showed predominance of spermidine and moderate amounts of sym-homospermidine. The predominant quinone system was ubiquinone (Q-10) and the DNA G+C content was 60.5 mol%. On the basis of polyphasic taxonomic evidence presented here, strain CC-SKC2(T) is proposed to represent a novel species within the genus Rhizobium, for which the name Rhizobium capsici sp. nov. is proposed. The type strain is CC-SKC2(T) (=BCRC 80699(T) = JCM 19535(T)). PMID- 25555456 TI - Host factors for retroviral integration site selection. AB - To achieve productive infection, retroviruses such as HIV stably integrate their reverse transcribed RNA genome into a host chromosome. Each retroviral family preferentially integrates near a unique subset of genomic features. HIV integrase (IN) is targeted to the body of active transcription units through interaction with lens epithelium-derived growth factor (LEDGF/p75). We describe the successful effort to develop inhibitors of the interaction between IN and LEDGF/p75, referred to as LEDGINs. Gammaretroviruses display a distinct integration pattern. Recently, BET (bromo- and extraterminal domain) proteins were identified as the LEDGF/p75 counterparts that target the integration of gammaretroviruses. The identification of the chromatin-readers LEDGF/p75 and BET as cellular cofactors that orchestrate lentiviral or gammaretroviral integration opens new avenues to developing safer viral vectors for gene therapy. PMID- 25555458 TI - Monepantel induces hepatic cytochromes p450 in sheep in vitro and in vivo. AB - Monepantel (MOP), a new amino-acetonitrile anthelmintic for the treatment and control of gastrointestinal nematode infections and associated diseases in sheep, is approved and marketed as oral solution under the trade name Zolvix(r) (Novartis Animal Health Inc., Switzerland). The effect of MOP on hepatic cytochromes P450 (CYP) has been investigated in sheep. In an in vivo experiment, castrated rams (9-months old) were treated with the recommended therapeutic dose of MOP. Non-treated animals represented the controls. After 24 h, the animals were stunned and exsanguinated. Microsomal fractions and total RNA were prepared from liver homogenates. The activities towards alkyloxyresorufins, 7-methoxy-4 trifluoromethylcoumarin and midazolam were assayed and mRNAs of individual CYP isoforms were quantified. In an in vitro procedure, primary cultures of ovine hepatocytes were incubated with or without MOP (10 MUM) for 24 h and then expression levels of individual CYP isoforms were analyzed. Results showed that MOP significantly increased all CYP-related activities and CYP3A24 mRNA in sheep. The induction effect of MOP on CYP3A was similar or even higher than those of dexamethasone and rifampicin, well-known CYP3A inducers. As CYP3A enzymes belongs to the most important biotransformation enzymes, their induction may have serious pharmacological and/or toxicological consequences. These facts should be taken into account when other drugs together with or after MOP (Zolvix(r)) are administered to sheep. PMID- 25555459 TI - Effectiveness of certolizumab pegol in chronic anterior uveitis associated to Crohn's disease and ankylosing spondylitis. PMID- 25555457 TI - Screening baccharin analogs as selective inhibitors against type 5 17beta hydroxysteroid dehydrogenase (AKR1C3). AB - Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17beta-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5alpha dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3alpha-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3. PMID- 25555460 TI - Prevotella copri and the microbial pathogenesis of rheumatoid arthritis. PMID- 25555461 TI - The distorting effect of varying diets on fecal glucocorticoid measurements as indicators of stress: a cautionary demonstration using laboratory mice. AB - The physiological stress response is frequently gauged in animals, non invasively, through measuring glucocorticoids in excreta. A concern with this method is, however, the unknown effect of variations in diets on the measurements. With an energy dense diet, leading to reduced defecation, will low concentrations of glucocorticoids be artificially inflated? Can this effect be overcome by measuring the total output of glucocorticoids in excreta? In a controlled laboratory setting we explored the effect in mice. When standard mouse chow - high in dietary fiber - was replaced with a 17% more energy-dense diet, fecal mass was significantly reduced. As circulating levels of corticosterone and the total output of corticosterone metabolites over time remained unaffected, the result was an overestimation - more than a doubling - of the corticosterone metabolite excretion if expressed as concentrations. Similar results were obtained for testosterone metabolites. Although measuring the total output is not feasible in, for example, wildlife studies, the present findings highlight the perilousness of relying on concentrations of hormones in excreta with no associated information of the dietary intake as even moderate changes can exert a great influence. PMID- 25555462 TI - Utility estimates for patients with Type 2 diabetes mellitus after experiencing a myocardial infarction or stroke: a systematic review. AB - A systematic review identified studies eliciting utility decrements from myocardial infarction (MI) and stroke in patients with Type 2 diabetes mellitus (T2DM) and examined their use in economic models of new diabetes treatments. In 16 utility studies in patients with T2DM, utility decrements in the first year ranged from 0.017 to 0.226 for MI and from 0.034 to 0.590 for stroke. Sixteen of 19 economic evaluations of new treatments for T2DM included utility decrements for an MI and/or stroke from one of the 16 utility studies. Decrements for MI ranged from 0.012 to 0.180 in the first year. Decrements for stroke ranged from 0.044 to 0.690 in the first year. Utility studies in patients with T2DM provide little information about changes in utility decrements by time since the event and by disease severity. Cost-effectiveness studies do not always indicate how these values were used in the analysis. PMID- 25555463 TI - Solid-state UV-MALDI mass spectrometric quantitation of fluroxypyr and triclopyr in soil. AB - The work presented here refers firstly to solid-state UV-MALDI-Orbitrap-mass spectrometric analysis of fluroxypyr (A) and triclopyr (B) in soils under laboratory conditions. The experimental design has involved the following: (a) determination of analytes A and B in polycrystalline composites of organic materials 1-7, based on 2-piperidine (pyrrolidine or piperazine)-1-yl-ethyl ammonium salts in order to determine the effect of sample preparation techniques on method performance using commercial herbicide formulations and (b) analysis of non-(X j,k,l (i) ) and sterilized (Y j,k,l (i) ) soil samples (i-fold rate 1, 10, 100, or 1,000; j-pesticide type A or B; k-time (0, 5, 10, 20, and 50 days) and l = 1-3 replicated samples) having clay content ? 5.0-12.0 %, silt ? 23.0-51.1 %, sand ? 7.2-72.0 %, and pH ? 4.0-8.1. In order to obtain a high representativeness of the data toward real-field experiments, the pollution scheme has involved 1-, 10-, 100-, and 1,000-fold rates. The firstfold rate has concentration of pollutant A of 2.639 * 10(-4) g in 625 cm(2) soil horizon of 0-25 cm(2) (5 cm depth) according to registration report (PSM-Zulassungbericht) of German Federal Office of Consumer Protection and Food Safety (Bundesamt fur Verbraucherschutz und Lebensmittelsicherheit) 6337/26.10.2009. The experimental design has involved quincunx systematic statistical approach for collection of soil samples. The performance has been compared with the corresponding statistical variable obtained, using an independent HPLC-ESI-(APCI-)-MS/MS analysis. PMID- 25555464 TI - Distribution of formins in cardiac muscle: FHOD1 is a component of intercalated discs and costameres. AB - The formin homology domain-containing protein1 (FHOD1) suppresses actin polymerization by inhibiting nucleation, but bundles actin filaments and caps filament barbed ends. Two polyclonal antibodies against FHOD1 were generated against (i) its N-terminal sequence (residues 1-339) and (ii) a peptide corresponding the sequence from position 358-371, which is unique for FHOD1 and does not occur in its close relative FHOD3. After affinity purification both antibodies specifically stain purified full length FHOD1 and a band of similar molecular mass in homogenates of cardiac muscle. The antibody against the N terminus of FHOD1 was used for immunostaining cells of established lines, primary neonatal (NRC) and adult (ARC) rat cardiomyocytes and demonstrated the presence of FHOD1 in HeLa and fibroblastic cells along stress fibers and within presumed lamellipodia and actin arcs. In NRCs and ARCs we observed a prominent staining of presumed intercalated discs (ICD). Immunostaining of sections of hearts with both anti-FHOD1 antibodies confirmed the presence of FHOD1 in ICDs and double immunostaining demonstrated its colocalisation with cadherin, plakoglobin and a probably slightly shifted localization to connexin43. Similarly, immunostaining of isolated mouse or pig ICDs corroborated the presence of FHOD1 and its colocalisation with the mentioned cell junctional components. Anti-FHOD1 immunoblots of isolated ICDs demonstrated the presence of an immunoreactive band comigrating with purified FHOD1. Conversely, an anti-peptide antibody specific for FHOD3 with no cross-reactivity against FHOD1 immunostained on sections of cardiac muscle and ARCs the myofibrils in a cross-striated pattern but not the ICDs. In addition, the anti-peptide-FHOD1 antibody stained the lateral sarcolemma of ARCs in a banded pattern. Double immunostaining with anti-cadherin and integrin-beta1 indicated the additional localization of FHOD1 in costameres. Immunostaining of cardiac muscle sections or ARCs with antibodies against mDia3 FH2-domain showed colocalisation with cadherin along the lateral border of cardiomyocytes suggesting also its presence in costameres. PMID- 25555465 TI - Osteopontin is a novel prognostic biomarker in early-stage non-small cell lung cancer after surgical resection. AB - PURPOSES: Osteopontin (OPN), an extracellular matrix-secreted phosphorylated glycoprotein, has been reported overexpressed in many solid tumors. As an important part of lung cancer, the high recurrence of non-small cell lung cancer (NSCLC) also attracted great attention of scientists. METHODS: In this study, we investigated the expression of OPN and the relationship with prognosis of NSCLC patients. We measured the expression of OPN among 163 NSCLC samples by immunohistochemical method and compared the expression of these 28 matched cDNA between tumor and peritumoral tissue by real-time polymerase chain reaction. RESULTS: We demonstrated that the percentages of positive OPN expression is 66.8 % and OPN expression in tumor site was much higher than the tissue adjacent to carcinoma (p = 0.0046). By further analysis, we found that OPN expression was significantly correlated with poor prognosis of NSCLC. Moreover, for early-stage patients, OS and DFS rates of OPN (-) group were significantly higher than OPN (+) group. For advanced-stage patients, OPN expression was only associated with OS rates. CONCLUSIONS: These results suggest that OPN is commonly expressed in NSCLC and may guide the evaluation of prognosis with NSCLC, especially for early stage patients. PMID- 25555466 TI - Assessing the validity of the Global Activity Limitation Indicator in fourteen European countries. AB - BACKGROUND: The Global Activity Limitation Indicator (GALI), the measure underlying the European indicator Healthy Life Years (HLY), is widely used to compare population health across countries. However, the comparability of the item has been questioned. This study aims to further validate the GALI in the adult European population. METHODS: Data from the European Health Interview Survey (EHIS), covering 14 European countries and 152,787 individuals, were used to explore how the GALI was associated with other measures of disability and whether the GALI was consistent or reflected different disability situations in different countries. RESULTS: When considering each country separately or all combined, we found that the GALI was significantly associated with measures of activities of daily living, instrumental activity of daily living, and functional limitations (P < 0.001 in all cases). Associations were largest for activity of daily living and lowest though still high for functional limitations. For each measure, the magnitude of the association was similar across most countries. Overall, however, the GALI differed significantly between countries in terms of how it reflected each of the three disability measures (P < 0.001 in all cases). We suspect cross-country differences in the results may be due to variations in: the implementation of the EHIS, the perception of functioning and limitations, and the understanding of the GALI question. CONCLUSION: The study both confirms the relevance of this indicator to measure general activity limitations in the European population and the need for caution when comparing the level of the GALI from one country to another. PMID- 25555467 TI - The effect of extended passaging on the phenotype and osteogenic potential of human umbilical cord mesenchymal stem cells. AB - Retaining biological characteristics in the extended passaging is crucial for human umbilical cord mesenchymal stem cells (hUCMSCs) in tissue engineering. We aimed to assess morphology, viability, MSC marker expression, and osteogenic activity of hUCSMCs after extended passaging. Passages 4 (P4) and 16 (P16) hUCMSCs displayed similar morphology and viability. The flow cytometry results showed that CD73, CD90, and CD105 were highly expressed at P1-P16. CD166 expression decreased progressively from 90 % at P2 to 61.5 % at P5 (p < 0.05), followed by stable expression through P16. Results from calcium deposition alkaline phosphatase activity and RT-PCR assay showed that both P4 and P16 hUCMSCs differentiated down an osteogenic lineage, with no significant difference in osteogenic capacity (p < 0.05). High-passage UMCSCs maintained stable expression of MSC CD markers as well as stable osteogenic activity. hUCMSCs may thus be suitable for tissue engineering and regenerative medicine applications. PMID- 25555468 TI - Punicalagin attenuated cerebral ischemia-reperfusion insult via inhibition of proinflammatory cytokines, up-regulation of Bcl-2, down-regulation of Bax, and caspase-3. AB - Punicalagin (PG) is a hydrolysable tannin compound found in Punica granatum L. The purpose of the present work is to explore the neuroprotective mechanism of PG against ischemia-reperfusion (I/R) injury in rat model of middle cerebral artery occlusion (MCAO). Rats were randomly divided into sham, MCAO, and PG-treated groups. PG (15 and 30 mg/kg), the vehicle was administered orally for 7 days prior to MCAO. Rats were anesthetised with ketamine (100 mg/kg/im), xylazine (10 mg/kg/im) and subjected to 2 h occlusion and 22 h reperfusion. The effects of PG on behavioral deficit and infarct volume, the levels of glutamate and calcium as well as the levels of inflammatory cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) were evaluated. Moreover, the expressions of caspase-3, Bcl-2, and Bax were detected by Western blotting. As compared with MCAO group, PG-treated rats showed dose-dependent reduction in infarct volume and substantial improvement in behavioral deficit. The levels of glutamate, calcium, TNF-alpha, IL-1beta, and IL-6 were restored significantly. The Western blotting results revealed that the expression of Bcl-2 was up-regulated and that of caspase-3, Bax were down-regulated when exposed to PG. From our results, it can be concluded that PG showed an ameliorative effect against cerebral I/R injury in rats through its anti-inflammatory, antioxidant actions besides it inhibits excitotoxicity. It also suppresses apoptosis through regulating, Bcl-2, caspase-3, and Bax protein expressions, perhaps another mechanism by which PG employs its neuroprotective action. PMID- 25555469 TI - The modulation of NMDA receptors and L-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test. AB - The modulation of N-methyl-D-aspartate receptor (NMDAR) and L-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and L-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/L-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), D-serine (30 ug/mouse, icv, glycine site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), L arginine (750 mg/kg, ip, NO precursor), SNAP (25 MUg/mouse, icv, NO donor), L NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 ug/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by L-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability. PMID- 25555470 TI - Estrogen and bone health in men and women. AB - Estrogen is the key regulator of bone metabolism in both men and women. Menopause and the accompanying loss of ovarian estrogens are associated with declines in bone mineral density (BMD): 10-year cumulative loss was 9.1% at the femoral neck and 10.6%, lumbar spine. Estradiol concentrations also predict fractures. Total estradiol levels, <5 pg/ml were associated with a 2.5-fold increase in hip and vertebral fractures in older women, an association that was independent of age and body weight. Similar associations were found in men. Despite the lower BMD and higher fracture risk in hypogonadal men, there is little association between circulating testosterone, fracture and bone loss. Nevertheless, the combination of any low sex steroid hormone and 25-hydroxyvitamin D was associated with an increased fracture risk. Menopausal hormone therapy has been shown to reduce hip and all fractures in the Women's Health Initiative with little difference between the estrogen-alone and the estrogen plus progestin trials. The risk reductions were attenuated in both trials post intervention; however, a significant hip fracture benefit persisted over 13 years for women assigned to the combination therapy. Clinical trials of testosterone replacement in older men give tantalizing but inconclusive results. The results suggest that testosterone treatment probably improves BMD, but the results are less conclusive in older versus younger men. The Testosterone Trial is designed to test the hypothesis that testosterone treatment of men with unequivocally low serum testosterone (<275 ng/dL) will increase volumetric BMD (vBMD) of the spine. Results of the Testosterone Trials are expected in 2015. PMID- 25555471 TI - Non-genomic effects of the NR4A1/Nur77/TR3/NGFIB orphan nuclear receptor. AB - The orphan nuclear receptor NR4A1/Nur77/TR3/NGFIB acts primarily as a transcription factor to regulate the expression of multiple genes. However, increasing research attention has recently been given to non-genomic activities of NR4A1. The first description of a non-genomic action of NR4A1 referred to the conversion of anti-apoptotic Bcl-2 into a pro-apoptotic protein by direct interaction with NR4A1. In response to certain apoptotic stimuli, NR4A1 translocates from the nucleus to the mitochondrial outer membrane (MOM) where it associates with Bcl-2 and thereby causes apoptosis. Afterwards, it appeared that NR4A1 could also bind and convert other anti-apoptotic Bcl-2 family members. The latest studies indicate a significant role of NR4A1 in the process of autophagy. For example, a new NR4A1-mediated pathway specific for melanoma cells has been described where NR4A1 interacts with the adenine nucleotide translocase 1 (ANT1) on the mitochondrial inner membrane (MIM) leading to induction of the autophagy pathway. Moreover, NR4A1 interaction with cytoplasmic p53 may also contribute to the induction of autophagy. In addition to mitochondria, NR4A1 could be translocated to the outer membrane of the endoplasmic reticulum (ER) and associate with Bcl-2 or translocon-associated protein subunit gamma (TRAPgamma) causing ER stress-induced apoptosis. NR4A1 also contributes to the proteasomal degradation of beta-catenin in colon cancer cells in vitro and in vivo, as well as to the stabilization of hypoxia-inducible factor-1alpha (HIF-1alpha) under non hypoxic conditions. This review summarizes research findings on non-genomic effects of NR4A1 in normal and cancer cells. PMID- 25555472 TI - TXA9, a cardiac glycoside from Streptocaulon juventas, exerts a potent anti-tumor activity against human non-small cell lung cancer cells in vitro and in vivo. AB - Non-small cell lung cancer is the most common type of lung cancer and the most common cause of cancer-related death in humans. TXA9, which is a natural product separated from an anti-tumor-active fraction of the roots of Streptocaulon juventas, may possess potent anti-proliferative activity according to the present study. In this study, the anti-tumor effects and toxicity of TXA9 were tested against human non-small cell lung cancer cell lines (A549, NCI-H1299, Ltep alpha2, PC-9, and Lu99) and a normal human lung embryonic fibroblast cell (HE lung) in vitro, and then toward A549 cells in vivo in a murine xenograft model. The results show that TXA9 exhibits potent cytotoxic activities against non-small lung cancer cells and has no toxic effect on the normal human lung embryonic fibroblast cells. The mechanistic studies demonstrate that TXA9 can induce the apoptosis of A549 cells through the extrinsic pathway. The in vivo study results reveal that the intravenous administration of TXA9 at high-dose (15 mg kg(-1)) induces significant tumor growth inhibition of non-small cell lung cancer xenografts with tumor inhibition rate up to 64.2%, compared with mice in the control group. The inhibitory effect was similar to that of taxol (62.5%). In particular, no significantly adverse effects were exerted by TXA9, which suggests that it is well tolerated. This promising natural product may be useful as a potential novel anti-tumor candidate. PMID- 25555473 TI - Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. AB - Data from laboratory and epidemiologic studies support a relationship between endogenous hormones and the increased risk of several female cancers. In epidemiologic studies, consistent associations have been observed between risk of breast, ovarian and endometrial cancers and reproductive and hormonal risk factors such as high postmenopausal body mass index (BMI) and postmenopausal hormone use, which suggest the importance of endogenous hormones in the etiology of these diseases. The relationship between circulating estrogen levels in postmenopausal women and the risk of breast cancer is well established, with an approximately 2-fold higher risk among women in the top 20-25% (versus bottom 20 25%) of levels. However, data evaluating the relationship between endogenous estrogens and premenopausal breast cancer risk are more limited and less consistent. Two studies to date have evaluated the relationship between circulating estrogens and breast cancer risk by menstrual cycle phase at blood collection and only one study has examined this relationship by menopausal status at diagnosis. Three prospective studies have evaluated circulating estrogen levels and endometrial cancer risk in postmenopausal women, with consistent strong positive associations reported (with relative risks of 2-4 comparing high versus low hormone levels), while this relationship has not been studied in premenopausal women. Compared to breast and endometrial cancers, reproductive and hormonal characteristics such as postmenopausal hormone use are generally weaker and less consistent risk factors for ovarian cancer, and the only small prospective study conducted to date indicated a non-significant positive relationship between circulating estrogen levels and ovarian cancer risk. In this review, we summarize current evidence and identify key areas to be addressed in future epidemiologic studies of endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. PMID- 25555474 TI - Localization of resistin and its possible roles in the ovary of a vespertilionid bat, Scotophilus heathi. AB - The aim of the present study was to evaluate the expression and effect of resistin on ovarian activities of Scotophilus heathi. Immunohistochemical study showed marked variation in resistin immunostaining during different reproductive phases. Most intense immunostaining of resistin was noticed in thecal interstitial cells in ovary during the period of delayed ovulation, the period of increased androgen synthesis and suppressed ovulation. The changes in ovarian resistin level also correlated positively with circulating leptin level and body white adipose tissue accumulation. The in vitro study showed that resistin alone preferentially stimulated progesterone synthesis, but with luteinizing hormone (LH) stimulated androgen secretion. Resistin alone dose-dependently increased expression of LH-receptor, steroidogenic acute regulatory protein and insulin receptor proteins in the ovary, whereas together with LH showed dose-dependent stimulatory effect on expression of androgen receptor and insulin receptor proteins in the ovary. In conclusion, during the period of fat accumulation increased ovarian resistin level may be responsible for increased androgen synthesis through insulin receptor mediated pathways in the ovary of S. heathi. PMID- 25555478 TI - [Renal medullary carcinoma in a young white adult without sickle cell trait or disease]. PMID- 25555479 TI - [Critical reading of articles about diagnostic tests (part II): Analyzing results]. AB - A new diagnostic test needs to be validated through comparison with a reference standard in an appropriate spectrum of patients. Diagnostic tests are not perfectly accurate; on the contrary, there can be false-positive and false negative findings. A good diagnostic test is that which provides an acceptable proportion of positive results when a determinate condition is present in patients and an acceptable proportion of negative results when it is absent. The best measure of the usefulness of a diagnostic test is the likelihood ratio, which informs us to what degree a particular result is more likely in a person in whom a condition is present than in a person in whom the condition is absent. The present article discusses the fundamental statistical concepts necessary to interpret the results section of an article about a diagnostic test; however, the approach is clearly oriented toward clinical practice, with emphasis on concepts rather than mathematics. PMID- 25555480 TI - A case of clonally distinct relapse of Burkitt lymphoma 9 years after complete remission. AB - We report a case of HIV-negative Burkitt lymphoma (BL) that relapsed 9 years after complete remission. We performed a polymerase chain reaction analysis of three regions of the VDJ junction of the immunoglobulin heavy chain (IGH) gene and compared the clonality of the first and second BL lesions, which were found to be clonally distinct. The patient received the R-Hyper CVAD/R-MA regimen; however, leukoencephalopathy subsequently developed due to the effect of cytarabine, and the regimen was changed to R-IVAM. The patient achieved complete remission and received high-dose chemotherapy following autologous stem cell transplantation. He maintained the complete remission for 72 months after transplantation. Given this outcome, we suggest that clonally distinct relapse of HIV-negative BL may exhibit a good prognosis. PMID- 25555481 TI - The genetics of impulsivity: evidence for the heritability of delay discounting. AB - BACKGROUND: Delay discounting (DD), a decline in the subjective value of reward with increasing delay until its receipt, is an established behavioral model of impulsive choice, a key component of a broader impulsivity construct. Greater DD, i.e., a tendency to choose smaller immediate over larger delayed rewards, has been implicated as a potential intermediate phenotype (endophenotype) for addictive disorders and comorbid externalizing psychopathology, particularly in adolescence. However, genetic and environmental origins of DD remain unclear. Accordingly, the goal of the present study was to assess heritability of DD, an important aspect of its utility as an endophenotype. METHODS: A commonly used computerized procedure involving choice between varying amounts of money available immediately and a standard amount of $100 presented at variable delays was administered to a population-based sample of twins aged 16 and 18 (n = 560, including 134 monozygotic and 142 dizygotic pairs). DD was quantified using area under the discounting curve and the k coefficient estimated by fitting a hyperbolic model to individual data. Heritability was assessed using linear structural equation modeling of twin data. RESULTS: The genetic analysis revealed significant heritability of both DD measures (area under the discounting curve: 46% and 62%; k: 35% and 55% at age 16 and 18, respectively). CONCLUSIONS: The present study provides evidence for heritability of both model-based and model free DD measures and suggests that DD is a promising intermediate phenotype for genetic dissection of impulsivity and externalizing spectrum disorders. PMID- 25555482 TI - Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European Americans. AB - BACKGROUND: We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerstrom Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations. METHODS: Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered Fagerstrom Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset. RESULTS: In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 * 10(-8) (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 * 10(-10)). Two chromosome 8 regions were associated: p = 4.45 * 10(-8) at DLC1 SNP rs289519 (unadjusted) and p = 1.10 * 10(-9) at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 * 10( 7)) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs. CONCLUSIONS: The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology. PMID- 25555490 TI - Neuroprotection induced by sevoflurane-delayed post-conditioning is attributable to increased phosphorylation of mitochondrial GSK-3beta through the PI3K/Akt survival pathway. AB - BACKGROUND AND PURPOSE: Post-conditioning with volatile anesthetics can create ischemic tolerance against cerebral ischemia-reperfusion injury. The present study was designed to determine whether delayed exposure to sevoflurane could induce ischemic tolerance and if this effect was dependent on increasing phosphorylated Akt-Ser473 and GSK-3beta-Ser9 expression in the mitochondria, via a mechanism involving the PI3K/Akt pathway. METHODS: Adult male Sprague-Dawley rats were subjected to focal cerebral ischemia. Sevoflurane post-conditioning was achieved by administration of 2.5% sevoflurane for 60 min, 15 min after reperfusion. Phosphorylated Akt-Ser473 and GSK-3beta-Ser9 in the cytosol and mitochondria of the ischemic penumbra were evaluated 4, 12, 24, and 72 h after reperfusion. Neurological deficit score and activity of caspase-3 and -9 were evaluated 24 and 72 h after reperfusion. Apoptosis, as measured by TUNEL staining and cerebral infarct size,was determined 24h after reperfusion. RESULTS: Sevoflurane-delayed post-conditioning significantly increased levels of phosphorylated Akt-Ser473 and GSK-3beta-Ser9 in the mitochondria and inhibited the activities of caspase-3 and -9, showing an improved neurological deficit score and a decreased infarct size. However, LY294002, a selective PI3K inhibitor, not only eliminated the neuroprotection of sevoflurane, as indicated by an increased infarct size and a larger number of TUNEL-positive cells, but also reversed the elevation of p-Akt and p-GSK-3beta expression in the mitochondria induced by sevoflurane post-conditioning. CONCLUSIONS: Our data suggested that delayed application of sevoflurane after reperfusion provides neuroprotection by activating phosphorylated Akt-Ser473 and GSK-3beta-Ser9 in the mitochondria via the PI3K/Akt pathway. PMID- 25555491 TI - [Knowledge and attitudes of health professionals to the living will declaration process]. AB - OBJECTIVE: To identify the underlying interests of the Living Will Declaration (LWD) process and to determine the consensus, using a questionnaire, of the knowledge and attitudes of health professionals. DESIGN: A study was performed in two phases using a Delphi technique with a Rand method. 1. Dimensions proposed: generation of ideas and their subsequent prioritizing; 2. Proposal and prioritizing of items grouped into blocks of Knowledge and Attitudes, developed between August 2012 and January 2013. SETTING: The work was carried out by initial telephone contact with panellists, and then later by the panellists belonged to the Andalusia Public Health System. PARTICIPANTS: The criteria for selecting the eight components of the panel were knowledge and experience in the field of the freedom of the patient in Andalusia. RESULTS: The Knowledge identified included: 1 A) Legal and general aspects; 2 A) A conceptual definition; 3 A) Standardised LWD documents: 4 A) Practical experience; 5 A) Procedure and registering of the LWDs. The second block included Attitudes: 1 B) Attitudes of the professional in the application of LWDs in clinical practice, and 2 B) Attitudes of the professional in "complex" ethical scenarios The 7 panellists who finally took part proposed 165 items. After applying the prioritizing criteria, scores, and scenario selection, 58 (35.2%) items were identified as suitable scenarios. CONCLUSIONS: The proposed questionnaire included wide parcels of concepts and contents that, once validated, will help to measure the training interventions carried out on health professionals in order to improve knowledge and attitudes on the subject of LWDs. PMID- 25555483 TI - Aberrant Cortical Morphometry in the 22q11.2 Deletion Syndrome. AB - BACKGROUND: There is increased risk of developing psychosis in 22q11.2 deletion syndrome (22q11DS). Although this condition is associated with morphologic brain abnormalities, simultaneous examination of multiple high-resolution measures of cortical structure has not been performed. METHODS: Fifty-three patients with 22q11DS, 30 with psychotic symptoms, were compared with demographically matched nondeleted youths: 53 typically developing and 53 with psychotic symptoms. High resolution magnetic resonance imaging measures of cerebral volume, cortical thickness, surface area, and an index of local gyrification were obtained and compared between groups. RESULTS: Patients with 22q11DS demonstrated global increases in cortical thickness associated with reductions in surface area, reduced index of local gyrification, and lower cerebral volumes relative to typically developing controls. Findings were principally in the frontal lobe, superior parietal lobes, and in the paramedian cerebral cortex. Focally decreased thickness was seen in the superior temporal gyrus and posterior cingulate cortex in 22q11DS relative to nondeleted groups. Patterns between nondeleted participants with psychotic symptoms and 22q11DS were similar but with important differences in several regions implicated in schizophrenia. Post hoc analysis suggested that like the 22q11DS group, cortical thickness in nondeleted individuals with psychotic symptoms differed from typically developing controls in the superior frontal gyrus and superior temporal gyrus, regions previously linked to schizophrenia. CONCLUSIONS: Simultaneous examination of multiple measures of cerebral architecture demonstrates that differences in 22q11DS localize to regions of the frontal, superior parietal, superior temporal, and paramidline cerebral cortex. The overlapping patterns between nondeleted participants with psychotic symptoms and 22q11DS suggest partially shared neuroanatomic substrates. PMID- 25555493 TI - Can an adverse density difference across a surface be stabilized by heating from above? AB - We investigate the possibility of stabilizing a Rayleigh-Taylor experiment by imposing a small upward temperature gradient. We find that if the two fluids have equal thermal conductivities nothing can be accomplished. If either thermal conductivity is much greater than the other, the small gradient is always stabilizing. If the thermal conductivities are of the same order of magnitude the small gradient can be stabilizing or destabilizing depending on the thermal expansion coefficients. We have used a Darcy model so that we can derive formulas and present a physical explanation of what we find. PMID- 25555492 TI - [Cost-effectiveness analysis of dapagliflozin compared to DPP4 inhibitors and other oral antidiabetic drugs in the treatment of type-2 diabetes mellitus in Spain]. AB - OBJECTIVE: To assess the efficiency of the combined therapy with metformin and dapagliflozin, a new oral anti-diabetic drug with an insulin-independent mechanism of action, in the treatment of type-2 diabetes mellitus (T2DM) compared to DPP4 inhibitors, sulphonylureas and thiazolidindiones, also combined with metformin. DESIGN: Cost-effectiveness analysis using a discrete event simulation model based on the results of the available clinical trials and considering patient's entire life as time horizon. SETTING: National Health System perspective. PARTICIPANTS: The model simulated the natural history of 30,000 patients with T2DM for each of the options compared. MAIN MEASUREMENTS: Quality adjusted life-years (QALY) and economic consequences of managing the disease and its complications. The analysis considered direct costs updated to 2013. A discount rate of 3% was applied to costs and health outcomes. RESULTS: In the main analysis comparing dapagliflozin with DPP4 inhibitors, dapagliflozin resulted in a treatment option that would provide a slightly higher effectiveness (0.019 QALY) and lower overall associated costs (-?42). In the additional analyses, dapagliflozin was a cost-effective option compared with sulphonylureas and thiazolidinediones resulting in a cost per QALY gained of ?3,560 and ?2,007, respectively. The univariate and probabilistic sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: The results of the analyses performed suggested that dapagliflozin, in combination with metformin, would be a cost effective alternative in the Spanish context for the treatment of T2DM. PMID- 25555494 TI - [Targeted therapy in thyroid cancer: Towards a treatment card]. AB - Thyroid cancer is an uncommon cancer. Molecular biology plays a vital role in its development. Chemotherapy showed unsatisfactory results in advanced stages where surgery and iodine therapy are not appropriate. These last ten years have been marked by a major advance in understanding the molecular features of this cancer and therapeutic correlations, moreover, clinical trials have focused on the treatment of this disease on metastatic stages and led to a significant therapeutic panel targeting angiogenesis, mutations frequently found in cervical cancer: RET, BRAF, RAS... these are the motesanib, axitinib, sunitinib, pazopanib, vandetanib, cabozotinib and sorafenib. The last three molecules have already the autorisation of FDA and EMA. In this review, we will put the item on oncogenetic characteristics of thyroid carcinoma as well as new targeted therapies in patients refractory to conventional treatment. PMID- 25555495 TI - Family-based association study of HLA class II with type 1 diabetes in Moroccans. AB - BACKGROUND: The T1D is a multifactorial disease; with a strong genetic control. The human leukocyte antigen (HLA) system plays a crucial role in the autoimmune process leading to childhood diabetes. About 440,000 of the childhood population of the world (1.8 billion children under 14 years of age), have type 1 diabetes, and each year an additional 70,000 develop this disorder. The objective of this study was to investigate the distribution of HLA class II in Moroccan families of diabetic children to identify susceptibility alleles of the Moroccan population. SUBJECTS AND METHODS: We included in this study, Moroccan families who have at least one child with T1D. The age of onset of diabetes was less than 15 years. HLA class II (DRB1* and DQB1*) was carried out by molecular biology techniques (PCR-SSP and PCR-SSO). The FBAT test (family-based association test) was used to highlight the association between T1D and the HLA-DRB1* and -DQB1* polymorphism. RESULTS: The association of HLA class II (DRB1*, DQB1*) in type 1 diabetes was analyzed in fifty-one Moroccan families, including 90 diabetics. The results revealed that the most susceptible haplotypes are the DRB1*03:01-DQB1*02:01, DRB1*04:05-DQB1*03:02 (Z=3.674, P=0.000239; Z=2.828, P=0.004678, respectively). And the most protective haplotype is the DRB1*15-DQB1*06. CONCLUSION: This is the first family-based association study searching for an association between HLA class II and T1D in a Moroccan population. Despite the different ethnic groups forming Morocco, Moroccan diabetics share the most susceptible and protective HLA haplotypes with other Caucasians populations, specifically the European and Mediterranean populations. PMID- 25555496 TI - [Mucositis after allogeneic stem cell transplantation: Risk factors, clinical consequences and prophylaxis]. AB - AIM: Oral mucositis is a very common complication of allograft. However, preventive treatments are still limited. The objective of this study is to identify risk factors for onset of oral mucositis in patients undergoing allogeneic hematopoietic stem cells transplantation (HSCT), to measure clinical consequences and to study their evolution according to type of prevention. PATIENTS AND METHODS: All patients undergoing HSCT in hematology unit of CHU Besancon between January 2009 and August 2010 were included, and received according to their choice, either the standard protocol: solution of sodium bicarbonate 1.4% associated with chlorhexidine-chlorobutanol (Eludril((r))) (n=49), or the experimental treatment by the ionic solution, Caphosol((r)) (n=42). RESULTS: The overall incidence of severe mucositis and mucositis is respectively 69% and 36%. In multivariate analysis, a myeloablative conditioning (OR=11.1) and prevention of GVHD (graft-versus-host disease) including methotrexate (OR=7.5) appear such as the two significant mucositis risk factors. The presence of mucositis resulting in a significant increase in the incidence of febrile aplasia (P=0.008) and the use of opioid analgesics and parenteral nutrition (P<10(-3)). The risk of acute gastrointestinal GVHD is also increased in severe mucositis (P=0.01). The duration of post-transplant hospitalization is not changed. The type of prevention does not influence the incidence of mucositis (P=0.11). CONCLUSION: The consequences of mucositis are significant and the risk factors identified. The interest of the ionic solution Caphosol((r)) seems limited, the incidence of mucositis is not decreased by this prevention. PMID- 25555497 TI - Cutaneous immune mechanisms in canine leishmaniosis due to Leishmania infantum. AB - Canine leishmaniosis (CanL) caused by the parasite Leishmania infantum is a systemic disease with variable clinical signs. The disease is endemic in the Mediterranean countries and dogs are the main domestic reservoir of the parasite. The quite complicated immune response against the parasite is crucial for the evolution of CanL infection with the skin playing a major role in its immunopathogenesis. After the inoculation of Leishmania promastigotes into the dermis by sand fly bites, complement factors, Langerhan's cells, neutrophils, fibroblasts and keratinocytes are involved in the activation of the innate arm of the skin immune system, with the macrophages and dendritic cells to play a major key role. The effective activation of cellular immunity is the cornerstone of dog's resistance against the parasite. Promastigotes reaching the dermis are engulfed, processed and transferred by APCs to draining lymph nodes to stimulate naive T-cells for proliferation and differentiation into armed effector T-cells. Th1 cells activate the infected macrophages to kill Leishmania, whereas Th2 cells divert the immune response to humoral immunity and down regulation of cellular immunity with Th1 cell anergy. Inhibition of co-stimulatory molecules expression by infected macrophages contributes to T-cell anergy. In canine subclinical infections cutaneous lymphocytic infiltrate and parasites are absent, as opposed to dogs with clinical leishmaniosis. CD8+ cells constitute a significant population of cellular immunity in CanL since they outnumber CD4+ cells in the dermis, producing IFN-gamma in sub clinically infected dogs and high levels of IL 4 in dogs with clinical leishmaniosis. Numerous B-lymphocytes have been shown to heavily infiltrate the dermis at least in exfoliative dermatitis in CanL. A mixed Th1/Th2 cytokine profile has been found in the dermis of naturally infected with L. infantum dogs. In the skin of dogs with clinical leishmaniosis, where plasma cells outnumber T lymphocytes in the dermal infiltrate, there is an overproduction of IL-4, IL-13 and TNF-alpha leading to Th2-biased humoral immune response. The issue of humoral immunity polarization in CanL remains controversial. Much still needs to be learned about other mechanisms underlying the complex interaction between the skin immune system and the parasite. PMID- 25555499 TI - Gene expression profile in cardiovascular disease and preeclampsia: a meta analysis of the transcriptome based on raw data from human studies deposited in Gene Expression Omnibus. AB - INTRODUCTION: Cardiovascular disease (CVD) and preeclampsia (PE) share common clinical features. We aimed to identify common transcriptomic signatures involved in CVD and PE in humans. METHODS: Meta-analysis of individual raw microarray data deposited in GEO, obtained from blood samples of patients with CVD versus controls and placental samples from women with PE versus healthy women with uncomplicated pregnancies. Annotation of cases versus control samples was taken directly from the microarray documentation. Genes that showed a significant differential expression in the majority of experiments were selected for subsequent analysis. Hypergeometric gene list analysis was performed using Bioconductor GOstats package. Bioinformatic analysis was performed in PANTHER. RESULTS: Seven studies in CVD and 5 studies in PE were eligible for meta analysis. A total of 181 genes were found to be differentially expressed in microarray studies investigating gene expression in blood samples obtained from patients with CVD compared to controls and 925 genes were differentially expressed between preeclamptic and healthy placentas. Among these differentially expressed genes, 22 were common between CVD and PE. DISCUSSION: Bioinformatic analysis of these genes revealed oxidative stress, p-53 pathway feedback, inflammation mediated by chemokines and cytokines, interleukin signaling, B-cell activation, PDGF signaling, Wnt signaling, integrin signaling and Alzheimer disease pathways to be involved in the pathophysiology of both CVD and PE. Metabolism, development, response to stimulus, immune response and cell communication were the associated biologic processes in both conditions. Gene set enrichment analysis showed the following overlapping pathways between CVD and PE: TGF-beta-signaling, apoptosis, graft-versus-host disease, allograft rejection, chemokine signaling, steroid hormone synthesis, type I and II diabetes mellitus, VEGF signaling, pathways in cancer, GNRH signaling, Huntingtons disease and Notch signaling. CONCLUSION: CVD and PE share same common traits in their gene expression profile indicating common pathways in their pathophysiology. PMID- 25555498 TI - PET/CT imaging reveals unrivaled placental avidity for glucose compared to other tissues. AB - INTRODUCTION: The goal of this study was to define the kinetics of glucose transport from maternal blood to placenta to fetus using real time imaging. METHODS: Positron emission tomography (PET) imaging of the glucose-tracer [(18)F]fluorodeoxyglucose (FDG) was used to temporally and spatially define, in vivo, the kinetics of glucose transport from maternal blood into placentae and fetuses, in the late gestational gravid rat. Computed tomography (CT), with intravenous contrast, co-registered to the PET images allowed anatomic differentiation of placentae from fetal and maternal tissues. RESULTS: FDG was rapidly taken up by placentae and subsequently appeared in fetuses with minimal temporal lag. FDG standardized uptake values in placentae and fetuses approached that of maternal brain. In both anesthetized and awake dams, one quarter of the administered FDG ultimately was accrued in the collective fetuses and placentae. Accordingly, kinetic modeling demonstrated that the placentae had very high avidity for FDG, 2-fold greater than that of the fetus and maternal brain, when accounting for the fact that fetal FDG necessarily must first be taken up by placentae. Consistent with this, placental expression of glucose transporter 1 exceeded that of all other tissues. DISCUSSION: Fetal and placental tissues place a substantial glucose metabolic burden on the mother, owing to very high avidity of placentae for glucose coupled with the large relative mass of fetal and placental tissues. CONCLUSIONS: The placenta has a tremendous capacity to uptake and transport glucose. PET/CT imaging is an ideal means to study metabolite transport kinetics in the fetoplacental unit. PMID- 25555500 TI - Impaired trophoblast invasion and increased numbers of immune cells at day 18 of pregnancy in the mesometrial triangle of type 1 diabetic rats. AB - INTRODUCTION: Type 1 diabetes (T1D) is associated with adverse pregnancy outcome, usually attributed to hyperglycemia. Recently, we showed that pregnancy outcome in normoglycemic T1D rats was characterized by decreased fetal and placental weight, suggesting impaired placental development. In the present study, we tested the hypothesis that trophoblast invasion and spiral artery (SA) remodeling is impaired in T1D rats ant that this is associated with aberrant local presence of NK cells and macrophages in the mesometrial triangle (MT). METHODS: Placentae with MT from pregnant biobreeding diabetes-prone (BBDP; T1D model) rats, control biobreeding diabetes-resistant (BBDR) and Wistar-rats were dissected at day 18 of gestation and stained for trophoblast invasion, SA remodeling, uNK cells and macrophages. RESULTS: Interstitial trophoblast invasion and SA remodeling was impaired in BBDP-rats vs. control rats, coinciding with increased presence of NK cells and an increased iNOS+/CD206+ ratio of macrophages. DISCUSSION: Decreased fetal and placental weight in BBDP-rats was associated with diminished interstitial trophoblast invasion and less optimal SA remodeling, increased numbers of NK cells and increased iNOS+/CD206+ macrophage ratio in the MT of BBDP rats. CONCLUSIONS: The impaired trophoblast invasion and SA remodeling may be due to an aberrant local immune-response and may result in damage to the fetal placenta and insufficient supply of nutrients towards the fetus with eventually decreased fetal weight as a consequence. PMID- 25555501 TI - Low molecular weight heparin therapy during pregnancy is associated with elevated circulatory levels of placental growth factor. AB - INTRODUCTION: Low molecular weight heparin (LMWH) has been shown to be effective in decreasing the recurrence of placenta-mediated complications of pregnant women. The aim of this study was to determine the effect of LMWH on circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PLGF) in pregnant women who required anticoagulation therapy. METHODS: A longitudinal prospective cohort study was performed including pregnant women in whom anticoagulation therapy by LMWH during pregnancy was clinically indicated (n = 33). Healthy pregnant women, matched for gestational age, who did not require thromboprophylaxis served as controls (n = 29). Maternal plasma samples were obtained throughout gestation every 4 weeks and stored at -70 degrees C. Maternal plasma concentrations of sFlt-1, sEng and PLGF were determined by ELISA and compared between the two groups. RESULTS: Patients treated with LMWH had significantly increased circulatory levels of PLGF during the third trimester compared with controls (28-34 weeks: 719.2 pg/ml vs 558.6 pg/ml at, p < 0.01; 35-40 weeks: 975.6 pg/ml vs 511.2 pg/ml, p < 0.01, respectively). In contrast, circulatory levels of sFlt-1 and sEng were similar between the LMWH treatment group and controls throughout gestation. Consistent with these findings, the ratio of sFlt-1/PLGF was lower in patients treated with LMWH compared to controls (28-34 weeks: 1.9 vs 7.2, p < 0.05; 35-40 weeks: 5 vs 12.9, p < 0.05, respectively). DISCUSSION: Anticoagulation treatment of pregnant women with LMWH is associated with a pro-angiogenic state. These findings may explain the effectiveness of LMWH in the prevention of placenta-mediated complications of pregnancy. PMID- 25555502 TI - [Does a tumor size higher than 7cm impact partial nephrectomy outcomes for the treatment of renal cancer?]. AB - OBJECTIVE: To assess the impact of a tumor size higher than 7cm on partial nephrectomy (PN) outcomes compared to a tumor size ranging between 4 and 7cm and to compare this impact to one of the RENAL score. PATIENTS AND METHODS: Data from patients who underwent PN between 2006 and 2013 were retrospectively analysed. Patients with cT1b tumors and cT2 were included. Functional and oncological outcomes were compared. Analysis of the achievement of Trifecta (defined as a combination of warm ischemia time<25min, negative surgical margins and no perioperative complications) was performed according to the tumor size and the RENAL score. RESULTS: Among 334 PN, 57 patients were included, (41 cT1b and 16 cT2), with a median follow-up of 23.5 months (6-88). There was no difference between the groups regarding intraoperative parameters except for the conversion rate, which was higher in the cT2 group (30% vs. 4.3%; P=0.02). The cT2 group also presented higher renal function impairment at postoperative day 4 (P=0.04) which did not persist at 6 months. There was no significant difference in oncologic outcomes between the 2 groups. The rate of achievement of the Trifecta did not differ between cT1b and cT2 groups. Conversely, Trifecta rate was higher in case of low complexity renal masses (RENAL score 4-6) compared to complex renal tumors (RENAL score 7-9 and 10-12). CONCLUSION: Our results showed that a tumor size higher than 7cm had no impact on PN outcomes in selected tumors according to complexity scores such as the RENAL score. Furthermore, a lower RENAL score appeared to be significantly associated with the Trifecta achievement. LEVEL OF EVIDENCE: 5. PMID- 25555503 TI - [Elastography shows promise in testicular cancer detection]. AB - PURPOSE: Elastography is a novel imaging technology that shows promise in the identification of anatomic structures. The widespread use of ultrasound for screening testicular tumors in patients with cancer risk factors highlights unclassified testicular micronodules. We investigated the ability of elastography to accurately diagnose testicular nodules. MATERIAL: Patients with clinical testicular nodules were assigned to undergo elastography in a prospective study. The imaging was carried out by a single radiologist using a static elastography unit with a 9-14MHz frequency linear transducer, to identify hardness score, loss of architecture of testicular parenchyma, and surrounding effect. When orchidectomy was required, the corresponding specimens were subjected to hematoxylin and eosin staining for histologic correlation. RESULTS: We imaged 34 testicular lesions: 26/34 (76%) malignant tumors and 8/34 (24%) non-tumor lesion including 4 hematomas, 3 orchitis and 1 ischemia. Se, Sp, PPV and NPV of hardness in elastography in differentiating between malignant and benign tissue was found to be 96.2%, 37.5%, 83%, and 75%, respectively. Further, for recognizing cancer, the loss of architecture of the testicular parenchyma detecting in elastography was 92.3%, 75%, 92.3%, and 75%, respectively, and the surrounding effect was 84.6%, 87.5%, 95.6% and 63.6%, respectively. CONCLUSION: Elastography may be a promising tool at diagnosing testicular tumor when the loss of architecture and the surrounding effect were present. Further studies are needed to evaluate whether the utility of elastography is worth pursuing to identify of unclassified testicular micronodules. LEVEL OF EVIDENCE: 3. PMID- 25555504 TI - Magnetoencephalography in the presurgical evaluation of epilepsy. AB - Magnetoencephalography (MEG) is an important tool in the presurgical evaluation of patients with medically refractory epilepsy. The appropriate utilization and interpretation of MEG studies can increase the proportion of patients who may be able to further pursue surgical evaluation, refine surgical planning, and potentially increase the probability of seizure freedom after surgery. The aim of this paper is to provide the reader with a comprehensive but accessible guide to MEG, with particular emphasis on acquiring a working knowledge of MEG analysis, identifying patient groups that are most likely to benefit, and clarifying the limitations of this technology. PMID- 25555505 TI - Frontal lobe hypoactivation in medication-free adults with bipolar II depression during response inhibition. AB - In executive function, specifically in response inhibition, numerous studies support the essential role for the inferior frontal cortex (IFC). Hypoactivation of the IFC during response-inhibition tasks has been found consistently in subjects with bipolar disorder during manic and euthymic states. The aim of this study was to examine whether reduced IFC activation also exists in unmedicated subjects with bipolar disorder during the depressed phase of the disorder. Participants comprised 19 medication-free bipolar II (BP II) depressed patients and 20 healthy control subjects who underwent functional magnetic resonance imaging (fMRI) while performing a Go/NoGo response-inhibition task. Whole-brain analyses were conducted to assess activation differences within and between groups. The BP II depressed group, compared with the control group, showed significantly reduced activation in right frontal regions, including the IFC (Brodmann's area (BA) 47), middle frontal gyrus (BA 10), as well as other frontal and temporal regions. IFC hypoactivation may be a persistent deficit in subjects with bipolar disorder in both acute mood states as well as euthymia, thus representing a trait feature of bipolar disorder. PMID- 25555517 TI - Characterization of the species-dependent ketoprofen/albumin binding modes by induced CD spectroscopy and TD-DFT calculations. AB - The stereospecificity of high-affinity biorecognition phenomena at the basis of the activity of drugs is an important topic of active research in medicinal chemistry. The binding of drugs to their targets or to carrier proteins may lead to the onset of an induced circular dichroism (ICD) signal, which can be detected experimentally. Quantum mechanical (QM) calculations based on density functional theory (DFT) and its time-dependent formulation (TD-DFT) can be used to determine the theoretical chiroptical response of all the possible conformations of drugs bound to their hosts; by comparison with the experimental ICD spectra of drug host complexes, this approach can lead to the identification of possible binding modes in the absence of X-ray crystallography or NMR data. The present article reports the application of experimental electronic circular dichroism (ECD) spectroscopy, DFT conformational analysis and TD-DFT calculations to the investigation of the binding modes of (S)-ketoprofen to serum albumins. The peculiar species-dependent ICD spectra observed for the binding of (S)-ketoprofen to different serum albumins can be explained by the selection of different mutual arrangements of the phenyl moieties inside the binding pocket. Such structural elucidations contribute to a better understanding of the changes in the pharmacokinetic and pharmacodynamic profiles of drugs among different species. PMID- 25555516 TI - Effects of growth hormone-releasing hormone on visceral fat, metabolic, and cardiovascular indices in human studies. AB - Increased visceral adipose tissue (VAT) is associated with reductions in endogenous GH secretion, possibly as a result of hyperinsulinemia, increased circulating free fatty acid, increased somatostatin tone, and reduced ghrelin. Reduced GH may, in turn, further exacerbate visceral fat accumulation because of decreased hormone-sensitive lipolysis in this depot. Data from multiple populations demonstrate that both reduced GH and increased VAT appear to contribute independently to dyslipidemia, increased systemic inflammation, and increased cardiovascular risk. The reductions in GH in states of visceral adiposity are characterized by reduced basal and pulsatile GH secretion with intact pulse frequency. Treatment with GH-releasing hormone (GHRH) provides a means to reverse these abnormalities, increasing endogenous basal and pulsatile GH secretion without altering pulse frequency. This review describes data from HIV-infected individuals and individuals with general obesity showing that treatment with GHRH significantly reduces visceral fat, ameliorates dyslipidemia, and reduces markers of cardiovascular risk. Further research is needed regarding the long-term efficacy and safety of this treatment modality. PMID- 25555518 TI - Microbial screening for quinolones residues in cow milk by bio-optical method. AB - The use of antibiotics on lactating cows should be monitored for the possible risk of milk contamination with residues. Accordingly, Maximum Residue Levels (MRLs) are established by the European Commission to guarantee consumers safety. As pointed out by Dec 2002/657/EC, screening is the first step in the strategy for antibiotic residue control, thus playing a key role in the whole control procedure. However, current routine screening methods applied in milk chain still fail to detect residues of quinolones at concentrations of interest. This paper reports the findings of a new bio-optical method for the screening of quinolones residues in bovine milk, based on E. coli ATCC 11303 growth inhibition. The effect of blank and spiked cow milk samples (aliquots equivalents to 0.8%, v/v) is evaluated in Mueller Hinton Broth (MHb) and MHb enriched with MgSO4 2% (MHb Mg) inoculated with the test strain at the concentration of 10(4)CFU/mL. The presence of quinolones inhibits the cellular growth in MHb, while this effect is neutralized in MHb-Mg allowing both detection and presumptive identification of quinolones. Growth of the test strain is monitored at 37 degrees C in a Bioscreen C automated system, and Optical Density (OD) at 600 nm is recorded every 10 min after shaking for 10s. Growth curves (OD vs. time) of E. coli ATCC 11303 are assessed in milk samples, with and without quinolones, and their differences in terms of DeltaOD (DeltaOD600nm=ODMHb-Mg-ODMHb) are calculated. The presence of quinolones is detected by the cellular growth inhibition (OD vs time, none increase in the value OD) and presumptively identified through the increase of the slope of DeltaOD600nm curve (DeltaOD vs. time), after about 3h of incubation. The detection limit for ciprofloxacin and enrofloxacin is at the level of MRL, for marbofloxacin is at 2-fold the MRL whereas for danofloxacin is at 4-fold the MRL. Although the sensitivity of the method could be further improved and the procedure automated, it is a promising step forward to integrate screening assays into the control process and, in particular, to fill in the gap for quinolones; moreover, these technological developments contribute to the One Health perspective through the monitoring of safe and correct use of veterinary antibiotics. PMID- 25555519 TI - In vitro bioassays to screen for endocrine active pharmaceuticals in surface and waste waters. AB - In the context of the European Water Framework Directive (WFD) it is fully recognized that pharmaceuticals can represent a relevant issue for the achievement of the good chemical and ecological status of European surface water bodies. The recent European Directive on the review of priority substances in surface water bodies has included three pharmaceuticals of widespread use (diclofenac, 17alpha-ethinylestradiol (EE2), 17beta-estradiol (E2)) in the European monitoring list, the so-called watch list. Endocrine active pharmaceuticals such as EE2 and E2 (also occurring as natural hormone) can cause adverse effects on aquatic ecosystems at very low levels. However, monitoring of these pharmaceuticals within the watch list mechanism of the WFD and national monitoring programs can be difficult because of detection problems of most routine analytical methods. With proposed annual average Environmental Quality Standards (AA-EQS) of 0.035 ng/L and 0.4 ng/L, respectively, the estrogenic pharmaceutical EE2 and the natural hormone E2 are among those substances. Sensitive in vitro bioassays could reduce the current detection problems by measuring the estrogenic activity of environmental samples. In a short review article the application of this approach to screen and assess the risks of endocrine active pharmaceuticals with a focus on estrogenic pharmaceuticals in environmental waters is discussed. PMID- 25555522 TI - Extractable nitrogen and microbial community structure respond to grassland restoration regardless of historical context and soil composition. AB - Grasslands have a long history of invasion by exotic annuals, which may alter microbial communities and nutrient cycling through changes in litter quality and biomass turnover rates. We compared plant community composition, soil chemical and microbial community composition, potential soil respiration and nitrogen (N) turnover rates between invaded and restored plots in inland and coastal grasslands. Restoration increased microbial biomass and fungal : bacterial (F : B) ratios, but sampling season had a greater influence on the F : B ratio than did restoration. Microbial community composition assessed by phospholipid fatty acid was altered by restoration, but also varied by season and by site. Total soil carbon (C) and N and potential soil respiration did not differ between treatments, but N mineralization decreased while extractable nitrate and nitrification and N immobilization rate increased in restored compared with unrestored sites. The differences in soil chemistry and microbial community composition between unrestored and restored sites indicate that these soils are responsive, and therefore not resistant to feedbacks caused by changes in vegetation type. The resilience, or recovery, of these soils is difficult to assess in the absence of uninvaded control grasslands. However, the rapid changes in microbial and N cycling characteristics following removal of invasives in both grassland sites suggest that the soils are resilient to invasion. The lack of change in total C and N pools may provide a buffer that promotes resilience of labile pools and microbial community structure. PMID- 25555521 TI - Echocardiographic measures associated with early postsurgical myocardial dysfunction in pediatric patients with mitral valve regurgitation. AB - BACKGROUND: The assessment of left ventricular (LV) systolic function using conventional echocardiographic measures is problematic in the setting of mitral regurgitation (MR) given that altered loading conditions can mask underlying ventricular dysfunction. The purpose of this study was to characterize LV function and deformation before and after effective mitral valve repair or replacement to determine echocardiographic measures associated with early postoperative myocardial dysfunction. METHODS: Baseline LV function was assessed retrospectively by conventional echocardiography and speckle-tracking strain analysis pre- and postoperatively in patients diagnosed with MR between January 2000 and March 2013, excluding patients with less than mild to moderate MR preoperatively, left-sided obstructive lesions, large septal defects, or more than mild MR postoperatively. RESULTS: Forty-six pediatric patients were evaluated (average age, 8.2 +/- 6.4 years). Thirteen patients had normal preoperative ejection fractions but significant postoperative dysfunction (defined as an ejection fraction < 50%). Compared with the 33 patients with normal postoperative function, age (11.5 +/- 7.1 vs 7.3 +/- 5.7 years, P = .04), global circumferential strain (-13.2 +/- 5.6% vs -17.1 +/- 4.6%, P = .02), and global circumferential strain rate (-0.94 +/- 0.40 vs -1.36 +/- 0.42 sec(-1), P = .004) were found to be statistically different. Using receiver operating characteristic curves, an older preoperative age (area under the curve, 0.67; P = .03), lower global circumferential strain magnitude (area under the curve, 0.74; P = .007), and lower global circumferential strain rate magnitude (area under the curve, 0.80; P = .0004) were determined to be factors associated with early postoperative LV dysfunction after surgical repair of MR. CONCLUSIONS: Strain measurements may be useful as part of the echocardiographic assessment of patients with MR and can guide timing for surgical repair in the pediatric population. PMID- 25555520 TI - Left ventricular rotational mechanics in Tanzanian children with sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD) is a common inherited hemoglobinopathy. Adults with SCD manifest both systolic and diastolic cardiac dysfunction, though the age of onset of dysfunction has not been defined. Left ventricular (LV) rotational mechanics have not been studied in children with SCD. The aim of this study was to investigate whether cardiac rotational mechanics differed between children with SCD and age-matched controls. METHODS: Basal and apical LV short axis images were acquired prospectively in 213 patients with SCD (mean age, 14.1 +/- 2.6 years) and 49 controls (mean age, 13.3 +/- 2.8 years) from the Muhimbili Sickle Cohort in Dar es Salaam, Tanzania. The magnitude of basal and apical rotation, net twist angle, torsion, and untwist rate were obtained by two dimensional speckle-tracking. The timing of events was normalized to aortic valve closure. RESULTS: Mean basal rotation was significantly lower in patients with SCD compared with controls (P = .012), although no difference was observed in apical rotation (P = .37). No statistically significant differences in torsion or net twist angle were detected. Rotation rate at the apex (P = .001) and base (P = .0004) were significantly slower in subjects with SCD compared with controls. Mean peak untwisting rate was also significantly slower in patients with SCD (P = .006). No associations were found between hemoglobin concentration and apical rotation, basal rotation, net twist, and torsion. CONCLUSION: This study demonstrates alterations in LV rotational mechanics in children with SCD, including lower basal rotation, peak differential twist, and untwist rate. These abnormalities denote subclinical changes in LV systolic and diastolic performance in children with SCD. Future work may reveal an association between rotational metrics and long-term patient outcomes. PMID- 25555523 TI - Transcutaneous Electrical Nerve Stimulation Reduces Post-Thoractomy Ipsilateral Shoulder Pain. A Prospective Randomized Study. AB - OBJECTIVES: The patient's position during an axillary thoracotomy can cause postoperative pain and decrease mobility of the ipsilateral shoulder. In this study, we assessed whether the implementation of a standardized analgesia program using transcutaneous electrical nerve stimulation (TENS) decreases local pain and improves ipsilateral shoulder mobility. METHOD: Randomized, single-blind, single center clinical trial of 50 patients who had undergone anatomical lung resection via axillary muscle-sparing thoracotomy. Patients were treated with TENS devices for 30 minutes every 8 hours, beginning on postoperative day 1. Pain and mobility of the affected limb were recorded at the same time on postoperative days 1 through 3. A visual analogue scale was used for pain assessment and shoulder mobility was assessed with a goniometer. Results were compared using a non parametric test. RESULTS: Twenty-five patients were randomized to each group. Mean age of the control group was 62.7+/-9.3 years and 63.4+/-10.2 years in the experimental group. Shoulder mobility parameters were similar in both groups on all postoperative days. However, pain during flexion significantly decreased on day 2 (P=.03) and day 3 (P=.04) in the experimental group. CONCLUSION: The use of TENS decreases pain from shoulder flexion in patients undergoing axillary thoracotomy for pulmonary resection. PMID- 25555524 TI - GEMIN4 functions as a coregulator of the mineralocorticoid receptor. AB - The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily. Pathological activation of the MR causes cardiac fibrosis and heart failure, but clinical use of MR antagonists is limited by the renal side effect of hyperkalemia. Coregulator proteins are known to be critical for nuclear receptor-mediated gene expression. Identification of coregulators, which mediate MR activity in a tissue-specific manner, may allow for the development of novel tissue-selective MR modulators that confer cardiac protection without adverse renal effects. Our earlier studies identified a consensus motif among MR interacting peptides, MPxLxxLL. Gem (nuclear organelle)-associated protein 4 (GEMIN4) is one of the proteins that contain this motif. Transient transfection experiments in HEK293 and H9c2 cells demonstrated that GEMIN4 repressed agonist induced MR transactivation in a cell-specific manner. Furthermore, overexpression of GEMIN4 significantly decreased, while knockdown of GEMIN4 increased, the mRNA expression of specific endogenous MR target genes. A physical interaction between GEMIN4 and MR is suggested by their nuclear co-localization upon agonist treatment. These findings indicate that GEMIN4 functions as a novel coregulator of the MR. PMID- 25555525 TI - Neural activity related to cognitive and emotional empathy in post-traumatic stress disorder. AB - The aim of this study is to evaluate the empathic ability and its functional brain correlates in post-traumatic stress disorder subjects (PTSD). Seven PTSD subjects and ten healthy controls, all present in the L'Aquila area during the earthquake of the April 2009, underwent fMRI during which they performed a modified version of the Multifaceted Empathy Test. PTSD patients showed impairments in implicit and explicit emotional empathy, but not in cognitive empathy. Brain responses during cognitive empathy showed an increased activation in patients compared to controls in the right medial frontal gyrus and the left inferior frontal gyrus. During implicit emotional empathy responses patients with PTSD, compared to controls, exhibited greater neural activity in the left pallidum and right insula; instead the control group showed an increased activation in right inferior frontal gyrus. Finally, in the explicit emotional empathy responses the PTSD group showed a reduced neural activity in the left insula and the left inferior frontal gyrus. The behavioral deficit limited to the emotional empathy dimension, accompanied by different patterns of activation in empathy related brain structures, represent a first piece of evidence of a dissociation between emotional and cognitive empathy in PTSD patients. The present findings support the idea that empathy is a multidimensional process, with different facets depending on distinct anatomical substrates. PMID- 25555528 TI - OSTEONECROSIS OF THE JAW: Authors' response. PMID- 25555526 TI - Molecular characteristics of Salmonella enterica Paratyphi A in Yunnan Province, southwest China. AB - Previously, the prevalence of Salmonella enterica Paratyphi A in Yunnan was high; and recently Yunnan was the predominant endemic province in China. To identify the molecular epidemiology, antibiotic resistance profile and genotypic diversity of the S. Paratyphi A isolates from 1995 to 2013 in Yunnan, we performed the study. Antibiotic susceptibility tests, pulse-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to identify the characteristics of the bacterial isolates. The results showed from 1995 to 2013, 366 S. Paratyphi A were isolated: 295 isolates (80.6%) from Yuxi and 68 isolates (18.58%) from Honghe. All of the strains were resistant to nalidixic acid, and some were resistant to ampicillin and trimethoprim/sulfamethoxazole in different years. All the isolates were sensitive to cefotaxime and ciprofloxacin. Identical PFGE with two enzyme digestion patterns were found for 339 isolates. Some environmental isolates in different years were homologous with the strains isolated from food and patients. MLST showed 349 strains were ST85, only 17 isolates were ST129. S. Paratyphi A isolates from Yunnan showed a high similarity, and we found the pathogen isolated from patients, the environment and food had the close epidemiological relationship, forming a transmission circulation. These findings have important implications for paratyphoid-control strategies. PMID- 25555530 TI - Plasma cytokine expression in adolescent chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescents. The pathophysiology is poorly understood, but low-grade systemic inflammation has been suggested as an important component. This study compared circulating levels of individual cytokines and parameters of cytokine networks in a large set of adolescent CFS patients and healthy controls, and explored associations between cytokines and symptoms in the CFS group. CFS patients (12 18years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring three months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Thus, the case definition was broader than the Fukuda-criteria of CFS. Healthy controls having comparable distribution of gender and age were recruited from local schools. Twenty-seven plasma cytokines, including interleukins, chemokines and growth factors were assayed using multiplex technology. The results were subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and patients were subgrouped according to the Fukuda-criteria. A total of 120 CFS patients and 68 healthy controls were included. CFS patients had higher scores for fatigue (p<0.001) and inflammatory symptoms (p<0.001) than healthy controls. All cytokine levels and cytokine network parameters were similar, and none of the differences were statistically different across the two groups, also when adjusting for adherence to the Fukuda criteria of CFS. Within the CFS group, there were no associations between aggregate cytokine network parameters and symptom scores. Adolescent CFS patients are burdened by symptoms that might suggest low-grade systemic inflammation, but plasma levels of individual cytokines as well as cytokine network measures were not different from healthy controls, and there were no associations between symptoms and cytokine expression in the CFS group. Low-grade systemic inflammation does not appear to be a central part of adolescent CFS pathophysiology. PMID- 25555531 TI - Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome. AB - Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin 6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p?0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1beta and IL-6 levels compared with the low TRAJ group (p?0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (chi(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome. PMID- 25555532 TI - Refractive outcome of wavefront guided laser in situ keratomileusis and wavefront guided photorefractive keratectomy in high pre-existing higher order aberration. AB - PURPOSE: To compare visual outcome and higher order aberrations (HOA) between wavefront-guided LASIK (WF-LASIK) and wavefront guided PRK (WF-PRK) in patients with high preoperative HOA. METHODS: Randomized prospective interventional study. Conducted at Guru Nanak Eye Centre, Maulana Azad Medical College, Delhi, India. Eighty myopic eyes of forty patients were included. INCLUSION CRITERIA: age more than 21 years, best corrected visual acuity of 20/20 or better, a stable refraction, to be off soft contact lens for minimum 14 days prior to preoperative examination, preoperative RMS HOA more than 0.35 MU, preoperative central corneal thickness at least 500 MUm, estimated residual stromal bed thickness of at least 275 MUm in patients undergoing WF-LASIK and 350 MUm in patients undergoing WF PRK. Exclusion criteria were severe dry eye, blepharitis, corneal disease and warpage, uveitis, posterior segment abnormalities involving the macula or optic nerve and systemic diseases. Patients were randomly divided into two groups. They underwent either WF-LASIK (group A) or WF-PRK (group B) over 2 years (40 eyes each). Patients were followed up for 6 months. Main outcome measures were efficacy, safety, stability, predictability and HOA. RESULTS: At 6 months mean uncorrected visual acuity (logMAR) in group A was -0.01 +/- 0.04 and group B was 0.00 +/- 0.07 (P = 0.23). HOA RMS (6mm pupil) in group A was 0.61 +/- 0.24 MUm and group B was 0.55 +/- 0.25 MUm. The increase was statistically significant in both the groups (P < 0.05). Both the groups showed similar efficacy, predictability and safety. CONCLUSION: WF-LASIK and WF-PRK have similar efficacy, safety and predictability, though WF-PRK induces less HOA. PMID- 25555534 TI - Lights and (Some) shadows in the management of acute coronary syndrome in Spain: the DIOCLES Study. PMID- 25555533 TI - Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels. AB - H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl(-). Normotensive, L NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1 umol kg(-1)i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca(2+) channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca(2+) ryanodine (RyR2) and Cl(-) single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1 umol kg(-1) i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca(2+) current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl(-) channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby (*)NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl(-) cardiac membrane channels might be involved in its biological actions. PMID- 25555535 TI - Cardiologists and electronic cigarettes. PMID- 25555536 TI - A cultural understanding of Chinese immigrant mothers' feeding practices. A qualitative study. AB - Differences in parental feeding practices revealed across and within different ethnic/cultural groups indicate that cultural examinations of feeding practices in understudied non-European-American populations require urgent attention. China ranks as the second largest source country for children in foreign-born U.S. households. Contrary to the stereotype of slender Asians, Chinese-American young children are at high risk for obesity but have not received sufficient attention from researchers and practitioners dealing with parental feeding practices and childhood obesity. The present study aimed to understand food-related parenting practices among Chinese immigrants in the U.S. using qualitative focus groups. Twenty-two mothers with preschool aged children participated in a discussion regarding parent-child food-related interactions and feeding practices. A thematic approach was adopted to analyze the focus group data following five stages of framework analysis. Thirteen key themes of feeding practices were identified, including 9 that are in existing feeding measures (pre-exiting practices) and 4 practices that have not been documented or emphasized in previous feeding measures (culturally-emphasized practices), including regulating healthy routines and food energy, spoon-feeding, using social comparison to pressure the child to eat, and making an effort to prepare/cook specific foods. Through the use of an emic approach and meaning-centered evidence, the complexities of parent-child interactions and unique nuances of parental feeding in this understudied population were revealed. Our findings can guide future development of culturally-appropriate measurement and inform intervention programs to promote the healthy development of Chinese-American children. PMID- 25555537 TI - The impact of induced positive mood on symptomatic behaviour in eating disorders. An experimental, AB/BA crossover design testing a multimodal presentation during a test-meal. AB - OBJECTIVE: The aim of this study was to test the impact of a multimodal positive mood vodcast including pleasant images, background uplifting music and a script designed to elicit positive mood on eating disorders-related symptoms in participants suffering from an Eating Disorder (ED) and healthy controls (HCs). METHOD: Forty-two women with an ED (Anorexia Nervosa [AN]: N = 19; Bulimia Nervosa [BN]: N = 23) and 36 HCs were included in an AB/BA cross-over design which compared the use of a positive mood induction procedure ("positive mood vodcast") with a control condition (i.e. blue static background, neutral music, and script describing objective facts) during a test-meal. Self-report measures and behavioural tasks were completed before and after the test-meal. RESULTS: The positive mood vodcast was associated with greater consumption of the test meal in the AN group; reduced vigilance to food stimuli and lower anxiety in the BN sample; and no significant changes in the HC group. DISCUSSION: The use of a positive mood vodcast was associated with some beneficial effects in the context of an experimental test-meal in participants with an ED. PMID- 25555538 TI - Associations between general parenting, restrictive snacking rules, and adolescent's snack intake. The roles of fathers and mothers and interparental congruence. AB - INTRODUCTION: Little research has been done on the role of fathers and parenting congruence between mothers and fathers. This study aimed to clarify the roles of general parenting and restrictive snacking rules set by fathers and mothers, and to explore parenting congruence in explaining adolescents' snack intake. METHODS: Adolescents aged 11 to 15 completed a questionnaire assessing their perception of general parenting constructs (i.e. nurturance, structure, behavioral control, coercive control, and overprotection), restrictive snacking rules set by their fathers and mothers, and their own energy-dense snack intakes between meals. RESULTS: Scores for mothers were significantly higher on all constructs than for fathers, except for coercive control. Generally, higher scores on general parenting constructs were associated with higher scores on restrictive snacking rules (most of the associations being significant). Most general parenting constructs were unrelated to the respondents' number of snacks consumed. The use of restrictive snacking rules by both fathers and mothers was significantly and negatively related to respondents' snack intake. Moderation analyses indicated that high levels of incongruence between parents attenuated the favorable impact of fathers' rules and nurturance on their children's snacking, but interactions of congruence with three other paternal scales and all maternal scales were absent. DISCUSSION: Our findings indicate that both paternal and maternal general parenting and restrictive snacking rules play important roles in adolescents' snacking, and that high parental incongruence regarding restrictive snacking rules and nurturance could be undesirable. PMID- 25555539 TI - Longitudinal relations between observed parenting behaviors and dietary quality of meals from ages 2 to 5. AB - OBJECTIVES: Parents influence a child's diet by modeling food choices, selecting the food they make available, and controlling the child's intake. Few studies have examined the covariation between parent's behavior management practices and their guidance and support for a young child's nutritional environment in early childhood. We hypothesized that parents' positive behavior support (PBS), characterized as skillful behavior management and proactive structuring of children's activities, would predict dietary quality over the course of early childhood (age 2 to 5 years), a critical period for the development of a dietary lifestyle. METHODS: Participants included 731 culturally diverse, low-income families in a randomized, controlled trial of the Family Check-Up. Families participated in a yearly home visit videotaped assessment PBS and dietary quality of meals parents served to their children were assessed by coding videotapes of structured parent-child interactions. A cross-lagged panel model was used to evaluate the longitudinal relation between PBS and the dietary quality of meals served during a meal preparation task. RESULTS: Analyses revealed that PBS repeatedly predicted meals' dietary quality the following year: age 2-3 (beta = .30), age 3-4 (beta = 0.14), age 4-5 (beta = 0.37). Dietary quality significantly predicted PBS 1 year later: age 3-4 (beta = 0.16), age 4-5 (beta = 0.14). As expected, the relative strength of the relationship from PBS to dietary quality was significantly stronger than the reverse, from dietary quality to PBS. CONCLUSIONS: Positive behavior management and proactive parenting practices are an important foundation for establishing a healthy nutritional environment for young children. These findings suggest that family-centered prevention interventions for pediatric obesity may benefit from targeting PBS in service of promoting better dietary quality. PMID- 25555540 TI - 'Why don't you try it again?' A comparison of parent led, home based interventions aimed at increasing children's consumption of a disliked vegetable. AB - Previous research suggests that the use of modelling and non-food rewards may be effective at increasing tasting, and consequential liking and acceptance, of a previously disliked food. Although successful school-based interventions have been developed, there is a lack of research into home-based interventions using these methods. This study aimed to develop and investigate the efficacy of a parent led home-based intervention for increasing children's acceptance of a disliked vegetable. A total of 115 children aged 2-4 years were allocated to one of four intervention groups or to a no-treatment control. The four intervention conditions were: repeated exposure; modelling and repeated exposure; rewards and repeated exposure; or modelling, rewards and repeated exposure. Children in all of the intervention conditions were exposed by a parent to daily offerings of a disliked vegetable for 14 days. Liking and consumption of the vegetable were measured pre and post-intervention. Significant increases in post-intervention consumption were seen in the modelling, rewards and repeated exposure condition and the rewards and repeated exposure condition, compared to the control group. Significant post-intervention differences in liking were also found between the experimental groups. Liking was highest (>60%) in the modelling, rewards and repeated exposure group and the rewards and repeated exposure group, intermediate (>26%) in the modelling and repeated exposure and repeated exposure groups, and lowest in the control group (10%). Parent led interventions based around modelling and offering incentives may present cost efficient ways to increase children's vegetable consumption. PMID- 25555541 TI - A systematic review of the use of rituximab as induction therapy in renal transplantation. AB - Rituximab is a B-lymphocyte depleting agent used to treat lymphoma and autoimmune diseases. There has been recent interest in its use both for management of highly sensitised and ABO-incompatible recipients but also for induction therapy before transplantation. This systematic review evaluates the evidence for its use as part of induction protocols in ABO-compatible, non-sensitised recipients. 4 databases and 3 trial registries were searched for studies of the use of rituximab as part of induction protocols. The small number of identified studies precluded meta-analysis and thus a narrative review was conducted. 12 manuscripts met the inclusion criteria, relating to 5 individual studies. No significant improvements in patient and graft survival or acute rejection rates were identified with rituximab induction. A single small study reported a trend towards improved graft function with the addition of rituximab induction to a standard immunosuppressive regimen. Rituximab was not found to be associated with increased infectious complications in any study but concerns were raised over possible associations with leukopaenia and cardiovascular mortality. Overall, no convincing benefit of rituximab induction was found and some safety concerns were identified. The results of on-going trials are awaited but further studies may be required before we can draw firm conclusions regarding the efficacy and safety of rituximab in this setting. PMID- 25555542 TI - Dynamics of an SIR model with vaccination dependent on past prevalence with high order distributed delay. AB - This paper investigates the dynamics of an SIR model of childhood vaccination under the assumption that the vaccination uptake rate depends on past values of disease prevalence. The delay kernel is a high order Erlang function, which allows no instantaneous feedback between prevalence at time t and vaccinations at time t. Multiple types of endemic equilibria are found, as are stable and unstable equilibria, periodic orbits, dependence on initial conditions, and apparent chaos. PMID- 25555543 TI - Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis. AB - Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12 months of age, cell proliferation and survival of newborn neurons were reduced not only in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6 months, hippocampal neurogenesis was altered in CADASIL mice independent of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL. PMID- 25555544 TI - Abnormal paroxysmal nocturnal behavior due to insulinoma. PMID- 25555545 TI - Head and neck cancer with metastatic spread to the breast. PMID- 25555546 TI - Severe cardiomyopathy in the setting of relapsing catastrophic antiphospholipid antibody syndrome. PMID- 25555547 TI - Late effusive-constrictive pericarditis after lung transplantation. PMID- 25555548 TI - Vasospasm and type 2 AMI? PMID- 25555549 TI - Danger on a half shell: Vibrio vulnificus septicemia. PMID- 25555550 TI - Vomiting and hiccup as the first presentation of thyrotoxicosis. PMID- 25555551 TI - 'Atypical pneumonia': acute mitral regurgitation presenting with unilateral infiltrate. PMID- 25555552 TI - A twin-sibling study on early growth and hormone levels in adolescents. AB - This study addresses how growth during sensitive developmental periods and genes may affect hormone levels in late adolescence. We analyzed hormone levels of dehydroepiandrosterone sulfate (DHEAS) and insulin-like growth factor-I (IGF-I), which are hypothesized to be two pathways linking early growth with adult diseases (such as type 2 diabetes and cardiovascular disease) via their effects on enhanced insulin resistance. In a twin-sibling study, we tested whether there is an association between reduced intra-uterine growth and higher DHEAS or IGF-I levels in serum during adolescence, and we examined the contribution of insulin to the link between early growth and higher DHEAS and/or IGF-I levels. Anthropometric and hormone data were collected in 18-year-old twins (184 pairs) and their non-twin siblings (n = 98). Neither birth weight nor current body size predicted serum DHEAS and IGF-I levels. In the subsample of children who showed catch-up growth in weight during infancy, the children of lower birth weight had significantly higher serum DHEAS and IGF-I levels, but these were not related to insulin levels. Variation in serum DHEAS, IGF-I and fasting insulin levels was largely explained by genetic factors (73, 78 and 61 % respectively). Thus, early growth affects hormone levels in adolescence, but only in children with catch-up growth after birth. No evidence was found that early growth enhances insulin resistance via the hormones DHEAS or IGF-I. PMID- 25555553 TI - A novel one-step Helicobacter pylori saliva antigen test. AB - BACKGROUND: A rapid, reliable, and sufficiently accurate test for diagnosing Helicobacter pylori infection is required for screening dyspeptic patients before a referral for endoscopy. The purpose of this article is two-fold: first, to evaluate the accuracy of a one-step H. pylori saliva antigen (HPS) test; and second, to compare noninvasive and invasive H. pylori tests in Taiwanese population. METHODS: A total of 104 consecutive dyspeptic patients admitted for gastroenterology into the outpatient department underwent a one-step HPS test, rapid urease test, histology, and (13)C-urea breath test (13)C-UBT (proto C-13 urea kit). The accuracy of the HPS test was compared with a gold standard defined by at least two positive H. pylori test results from three H. pylori tests (histology, rapid urease test, and (13)C-UBT). RESULTS: The 104 patients eligible for analysis (mean age: 58 years, range 22-87 years), 21 (20%) were gold standard positive. Among them, the positive of the one-step H. pylori saliva Ag test, rapid urease test, (13)C-UBT, histology were (52; 50%), (17; 16%), (27; 25%) and (22; 21%) respectively. The sensitivity and specificity of the HPS tests, rapid urease test, (13)C-UBTs, and histology were 71.43% and 55.42%, 76.19% and 98.80%, 100% and 92.77%, and 85.71% and 95.18%, respectively, relative to the gold standard. The one-step HPS test exhibited a sensitivity of 71.43%, nearly equivalent to that of the rapid urea test. CONCLUSION: The one-step HPS test exhibited a high sensitivity and low specificity compared with the other tests, indicating that it is not sufficiently accurate for use in a clinical setting for diagnosing H. pylori infection. However, the test is simple to use (requiring only a saliva sample), inexpensive, and noninvasive in its application, and thus appealing for use in population-based prevalence surveys of the epidemiology of H. pylori infection. PMID- 25555554 TI - High numbers of circulating pigmented polymorphonuclear neutrophils as a prognostic marker for decreased birth weight during malaria in pregnancy. AB - During gestational malaria, Plasmodium falciparum-infected erythrocytes can sequester within the placenta, contributing to poor pregnancy outcomes, especially low birth weight. In children and non-pregnant adults, pigmented leukocytes may serve as markers of sequestered parasite burden and predict clinical outcomes. Here, we investigated circulating pigmented leukocyte numbers as predictors of clinical outcomes in pregnant women presenting with malaria at enrolment. The number of circulating pigmented neutrophils at enrolment negatively correlated with birth weight (Rho=-25, P=.04), suggesting these cells may have a pathogenic role in, and could serve as prognostic markers for, malaria associated low birth weight. PMID- 25555555 TI - Dose modification of anti-TNF in rheumatoid arthritis and estimated economical impact: a review of observational studies. AB - Anti-TNF drugs indicated for the treatment of moderate-to-severe active rheumatoid arthritis (RA) presents similar efficacy, safety and potential toxicity profiles, with more than 10 years' treatment experience. Several pharmacoeconomic evaluations had demonstrated their favorable cost-effectiveness profile in RA patients, based on pivotal clinical studies data from different countries and perspectives. However, in clinical practice, individual profiles of patients and drugs leads to dose modifications that may be associated with substantial cost deviations. Here, we further discuss the effect of dose titration of these biological drugs in clinical practice over their RA cost effectiveness profiles. PMID- 25555556 TI - Spatial and temporal variability of organic C and N concentrations and export from 30 boreal rivers induced by land use and climate. AB - Climate change scenarios for northern boreal regions indicate that there will be increasing temperature and precipitation, and the changes are expected to be larger in winter than in summer. These precipitation and discharge patterns, coupled with shorter ice cover/soil frost periods in the future would be expected to contribute significantly to changing flow paths of organic matter over a range of land use patterns. In order to study the impact of climate change on the seasonality of organic matter export we compared total organic carbon (TOC) and total organic nitrogen (TON) concentrations and export, during different seasons and climatically different years, over 12 years for 30 Finnish rivers separated into forest, agriculture and peat dominated catchments. The mean monthly TOC concentrations were highest during autumn and there was also a peak in May during the highest flow period. The mean monthly concentrations of TON were lowest during winter, increased in spring and remaining high throughout summer and autumn. The TOC/TON ratios were lowest during summer and highest during winter, and in all seasons the ratios were lowest in catchments with a high proportion of agricultural land and highest in peat-dominated catchments. The seasonality of TOC and TON exports reflected geographical location, hydrology and land use patterns. Most of the TOC and TON were transported during the high flow following the spring snowmelt and during rainfall in autumn. In all catchments the relative importance of the spring snowmelt decreased in wet and warm years. However, in peat-dominated catchments the proportion of spring period was over 30% of the annual export even in these wet and warm years, while in other catchments the proportion was about 20%. This might be linked to the northern location of the peat-dominated catchments and the permanent snow cover and spring snowmelt, even in warm years. PMID- 25555558 TI - 'A blessing in disguise': myxoma cordis and Tako Tsubo cardiomyopathy. PMID- 25555557 TI - A risk of digestive tract neoplasms susceptibility in miR-146a and miR-196a2. AB - Genome-wide association studies have identified many genes associated with digestive tract neoplasms. However, the published findings have been conflicting. The aim of our study was to evaluate the involvement of two polymorphisms (miR 146a rs2910164, miR-196a2 rs11614913) in digestive tract neoplasms risk and explore how miR-146a and miR-196a2 influence this risk. Systemic research of the PubMed, EBSCO, CBM and VIP databases was performed. The software STATA 12.0 was used to calculate odd ratios and 95% confidence intervals. There were 14 studies (6,053 cases and 6,527 controls) available for rs2910164 and 15 studies (5,648 cases and 6,607 controls) involved in rs11614913. Rs2910164G>C was statistically significantly associated with digestive tract neoplasms (OR 1.134, 95% CI 1.076 1.194, P < 0.001). In the subgroup analysis by ethnicity, significant association was observed in Asian individuals (OR 1.145, 95% CI 1.084-1.209, P < 0.001). We found a correlation between rs11614913 and only colorectal cancer (OR 1.325, 95% CI 1.102-1.594, P = 0.003). This study suggested that digestive tract neoplasms might associate with miR-146a variants, but not miR-196a2 variants. PMID- 25555559 TI - A bi-directional assessment of spontaneous coronary artery dissection by three dimensional flythrough rendering of optical coherence tomography images. PMID- 25555560 TI - Environmental cleaning and disinfection. AB - The guidelines in this article provide veterinarians, veterinary technicians, and veterinary health care workers with an overview of evidence-based recommendations for the best practices associated with environmental cleaning and disinfection of a veterinary clinic that deals with small animals. Hospital-associated infections and the control and prevention programs necessary to alleviate them are addressed from an environmental perspective. Measures of hospital cleaning and disinfection include understanding mechanisms and types of contamination in veterinary settings, recognizing areas of potential concern, addressing appropriate decontamination techniques and selection of disinfectants, the management of potentially contaminated equipment, laundry, and waste management, and environmental surveillance strategies. PMID- 25555561 TI - Legal implications of zoonotic disease transmission for veterinary practices. AB - Increased recognition of veterinarians' capabilities and their role in public health raises concerns as to their legal duty to both clients and the public. With the numerous potential situations and variety of clients, the veterinarians' role in public health issues associated with zoonotic agents seems vague. However, analysis of the legal duty provides a more precise road map to the responsibilities and actions needed in companion animal medicine. The authors discuss mitigation measures to apply to potential situations regarding the ethical and legal requirements of zoonotic diseases and the legal repercussions of failing to act. PMID- 25555562 TI - Postprandial effects of polydextrose on satiety hormone responses and subjective feelings of appetite in obese participants. AB - BACKGROUND: Dietary fibers are associated with enhanced satiety. However, the mechanism of different dietary fibers contributing to satiety-related gastrointestinal (GI) peptide release, especially in an obese population, is still poorly understood. Polydextrose (PDX), a water-soluble glucose polymer, has demonstrated its ability to reduce energy intake at a subsequent meal, but its mechanism of action requires further research. Also, there is limited evidence on its capacity to regulate subjective feelings of appetite. This study examines the effects of PDX on postprandial secretion of satiety-related GI peptides, short chain fatty acids (SCFAs), lactic acid, and subjective appetite ratings in obese participants. METHODS: 18 non-diabetic, obese participants (42.0 y, 33.6 kg/m2) consumed a high-fat meal (4293 kJ, 36% from fat) with or without PDX (15 g) in an acute, multicenter, randomized, double-blind, placebo-controlled and crossover trial. Postprandial plasma concentrations of satiety-related peptides, namely ghrelin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY), as well as SCFAs and lactic acid were assessed. GI peptide, SCFA and lactate concentrations were then modeled using a linear mixed-effects model.The subjective feelings of hunger, satisfaction, and desire to eat were evaluated using visual analogue scales (VAS), which were analyzed as incremental areas under the curve (iAUC) during the satiation and satiety periods. RESULTS: We found that PDX supplementation increased plasma GLP-1 levels more than the placebo treatment (P = 0.02). In the whole group, GLP-1 concentrations found in participants older than 40 years old were significantly lower (P = 0.01) as compared to those aged 40 years or less. There were no statistically significant differences in postprandial ghrelin, CCK, or PYY responses. The lactic acid concentrations were significantly (P = 0.01) decreased in the PDX group, while no significant changes in SCFAs were found. PDX reduced iAUC for hunger by 40% (P = 0.03) and marginally increased satisfaction by 22.5% (P = 0.08) during the post meal satiety period. CONCLUSION: Polydextrose increased the postprandial secretion of the satiety hormone GLP-1 and reduced hunger after a high-fat meal. PDX also reduced the elevated postprandial lactic acid levels in plasma. Therefore, PDX may offer an additional means to regulate inter-meal satiety and improve postprandial metabolism in obese participants. PMID- 25555564 TI - Anaplastic oligoastrocytoma: is molecular stratification based on 1p/19q status alone appropriate? PMID- 25555563 TI - Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center. AB - Aggressive pituitary adenomas (PAs) are clinically challenging for endocrinologists and neurosurgeons due to their locally invasive nature and resistance to standard treatment (surgery, medical or radiotherapy). Two pituitary-directed drugs have recently been proposed: temozolomide (TMZ) for aggressive PA, and pasireotide for ACTH-secreting PA. We describe the experience of our multidisciplinary team of endocrinologists, neurosurgeons, neuroradiologists, oncologists, otolaryngologists and pathologists with TMZ and pasireotide treatment for aggressive PAs in terms of their radiological shrinkage and genetic features. We considered five patients with aggressive PA, three of them non-secreting (two ACTH-silent and one becoming ACTH secreting), and two secreting (one GH and one ACTH). TMZ was administrated orally at 150-200 mg/m(2) daily for 5 days every 28 days to all 5 patients, and 2 of them also received pasireotide 600-900 ug bid sc. We assessed the MRI at the baseline and during TMZ or pasireotide treatment. We also checked for MGMT promoter methylation and IDH, BRAF and kRAS mutations. Considering TMZ, two patients showed PA progression, one stable disease and two achieved radiological and clinical response. Pasireotide was effective in reducing hypercortisolism and mass volume, combined with TMZ in one case. Both treatments were generally well tolerated; one patient developed a grade 2 TMZ-induced thrombocytopenia. None of patients developed hypopituitarism while taking TMZ or pasireotide treatment. No genetic anomalies were identified in the adenoma tissue. TMZ and pasireotide may be important therapies for aggressive PA, alone or in combination. PMID- 25555565 TI - A snapshot is all it takes to encode object locations into spatial memory. AB - This study examines the encoding of multiple object locations into spatial memory by comparing localization accuracy for stimuli presented at different exposure durations. Participants in the longest duration condition viewed masked displays containing 1-10 discs for 1-10 s (durations typically used in simple span tasks), and then reported the locations of these discs on a blank screen. Compared to conditions that presented the same stimuli briefly for 50 or 200 ms (exposures more typical of simultaneous spatial arrays), localization accuracy did not improve significantly under longer viewing durations. Additionally, a clustering analysis found that responses were spread among different clusters of discs and not focused on individual clusters, regardless of viewing duration. A second experiment tested this performance for displays containing two distinct clusters of discs to determine if clearly grouped subsets of objects would improve performance, but there was no substantial improvement for these two-cluster displays when compared to displays with one cluster. Overall, the results indicate that spatial information for a set of objects is extracted globally and quickly, with little benefit from extended encoding durations that should have favored some deliberative form of grouping. Such results cast doubt on the validity of Corsi blocks or equivalent common neuropsychological tests purportedly designed to evaluate specifically spatial short-term memory spans. PMID- 25555566 TI - Dynamic resolution of ambiguity during tri-stable motion perception. AB - Multi-stable perception occurs when an image falling onto the retina has multiple incompatible interpretations. We probed this phenomenon in psychophysical experiments using a moving barber-pole visual stimulus configured as a square to generate three competing perceived directions, horizontal, diagonal and vertical. We characterised patterns in reported switching type and percept duration, classifying switches into three groups related to the direction cues driving such transitions i.e. away from diagonal, towards diagonal and between cardinals. The proportions of each class reported by participants depended on contrast. The two including diagonals dominated at low contrast and those between cardinals increased in proportion as contrast was increased. At low contrasts, the less frequent cardinals persisted for shorter than the dominant diagonals and this was reversed at higher contrasts. This observed asymmetry between the dominance of transition classes appears to be driven by different underlying dynamics between cardinal and the oblique cues and their related transitions. At trial onset we found that transitions away from diagonal dominate, a tendency which later in the trial reverses to dominance by transitions excluding the diagonal, most prominently at higher contrasts. Thus ambiguity is resolved over a contrast dependent temporal integration similar to, but lasting longer than that observed when resolving the aperture problem to estimate direction. When the diagonal direction dominates perception, evidence is found for a noisier competition seen in broader duration distributions than during dominance of cardinal perception. There remain aspects of these identified differences in cardinal and oblique dynamics to be investigated in future. PMID- 25555567 TI - Interactions of the antimalarial amodiaquine with lipid model membranes. AB - A detailed molecular description of the mechanism of action of the antimalarial drug amodiaquine (AQ) is still an open issue. To gain further insights on that, we studied the interactions of AQ with lipid model membranes composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylserine (DPPS) by spin labeling electron spin resonance (ESR) and differential scanning calorimetry (DSC). Both techniques indicate a coexistence of an ordered DPPS-rich domain with a disordered DPPC-rich domain in the binary DPPC/DPPS system. We found that AQ slightly lowered the melting transition temperatures associated to both domains and significantly increased the enthalpy change of the whole DPPC/DPPS phase transition. DSC and ESR data also suggest that AQ increases the number of DPPC molecules in the DPPC-rich domains. AQ also causes opposing ordering effects on different regions of the bilayer: while the drug increases the ordering of the lipid acyl chains from carbon 7 to 16, it decreases the order parameter of the lipid head group and of carbon 5. The gel phase was mostly affected by the presence of AQ, suggesting that AQ is able to influence more organized lipid domains. Moreover, the effects of AQ and cholesterol on lipid acyl chain ordering and mobility were compared at physiological temperature and, in a general way, they are similar. Our results suggest that the quinoline ring of AQ is located completely inside the lipid bilayers with its phenol ring and the tertiary amine directed towards the head group region. The nonspecific interaction between AQ and DPPC/DPPS bilayers is a combination of electrostatic and hydrophobic interactions. PMID- 25555568 TI - Estimated functional renal parenchymal volume predicts the split renal function following renal surgery. AB - PURPOSE: The change in functional renal volume (FRV) has an absolute influence on renal function after nephrectomy (Nx) or nephron-sparing surgery (NSS). In this study, we prospectively examined whether the postoperative renal function following Nx and NSS could be accurately predicted and assessed the reproducibility of our newly developed 3-D image reconstruction system (Kashihara) to measure the FRV. METHODS: We enrolled 98 patients who underwent Nx and 41 patients who underwent NSS from April 2006 to September 2009 to predict postoperative FRV and renal function. FRV was measured before and after (1 month and 1 year) renal surgery. The postoperative estimated glomerular filtration rate (eGFR) was predicted from the preoperative eGFR calculated from the serum creatinine (sCr) level and the ratio of the postoperative/preoperative FRV. To assess the reproducibility and accuracy of our newly developed 3-dimensional (3 D) image reconstruction system, FRV was measured by five examiners using images obtained by CT (five cases) and MRI (five cases). RESULTS: Significant correlation was found both for FRV and for renal function between the predictive values and the actually measured values at 1 month and 1 year after surgery, not only in the Nx group, but also in the NSS group. The accuracy and reproducibility could be confirmed both with CT and MRI studies. CONCLUSIONS: The postoperative FRV and renal function could be predicted preoperatively using a 3-D image reconstructive system, preoperative routine diagnostic imaging, and preoperative sCr level. PMID- 25555569 TI - Laparoscopic adenomectomy versus Eraser laser enucleation of the prostate. AB - PURPOSE: To evaluate functional outcomes and morbidity rates after laparoscopic adenomectomy (LA) and Eraser laser enucleation of the prostate (ELEP). MATERIALS AND METHODS: Forty patients with lower urinary tract symptoms suggesting bladder outlet obstruction, with a prostate heavier than 70 g on transrectal ultrasound, were selected to undergo laparoscopic adenomectomy or Eraser laser enucleation of the prostate. All patients were consecutively enrolled without randomization and assessed preoperatively, 3 and 6 months postoperatively. Baseline characteristics, perioperative data, and postoperative outcomes were compared. RESULTS: The total operating time was significantly longer in the LA group (138.8 +/- 11.4 vs. 78.4 +/- 10.0 min, p < 0.000001). Catheter removal was performed earlier (61.2 +/- 21.3 vs. 174.0 +/- 13.2 h, p < 0.000001) and the hospital stay was significantly shorter (62.4 +/- 21.2 vs. 187.2 +/- 12.6 h, p < 0.000001) in the ELEP group. The latter group experienced significantly less perioperative hemoglobin (Hb) loss (0.71 +/- 0.25 vs. 2.15 +/- 1.08 g/dl, p < 0.000001), and their postoperative Hb levels (14.1 +/- 1.21 vs. 11.7 +/- 1.31 g/dl, p < 0.000001) were significantly higher. The resected tissue was significantly greater in the LA group (58.5 +/- 23.3 vs. 87.9 +/- 22.4 g, p = 0.0002). Significant improvements in Qmax, Qol, and symptom scores from baseline to each follow-up time point were noted in both groups. No statistically significant difference in symptom scores or Qmax was registered between the LA and the ELEP group throughout the follow-up period. CONCLUSION: Laparoscopic adenomectomy and ELEP were equally effective for relieving bladder outflow obstruction and lower urinary tract symptoms. The advantages of ELEP include less blood loss, shorter catheterization times, and shorter hospital stays. PMID- 25555570 TI - Immune checkpoint combinations from mouse to man. AB - The discovery that antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can restore tumor immunity against many murine transplantable tumors leading to complete rejection of established cancer forever changed the field of immunotherapy. In more robust murine models as well as human cancer, however, CTLA-4 blockade alone can slow tumor growth and extend patient survival, but is rarely curative. Subsequent studies have revealed a large family of T cell immune checkpoint receptors which tumors engage to shield themselves from host immunity. As with CTLA-4, blockade of one of these additional inhibitory receptors, programmed death 1, has led to remarkable therapeutic responses against tumors of multiple lineages. Checkpoint monotherapy has demonstrated that durable, immune-mediated cures of established metastatic cancers are possible, yet the percentage of patients experiencing these outcomes remains low due to both redundant mechanisms of immune suppression in the tumor and limiting toxicity associated with some therapies. Thus, extending the curative potential of immunotherapy to a larger percentage of patients with a broader spectrum of malignancies will likely require combinations of co-inhibitory blockade and co-stimulatory activation designed to peel back multiple layers of tumor immune suppression while at the same time minimizing immune-mediated toxicity. As over a dozen T cell immune checkpoints and an additional dozen more co-stimulatory receptors have now been described, the challenge before us is to identify the most advantageous combinations of these agents based on the knowledge of their underlying biology and preclinical studies in murine tumor models. PMID- 25555572 TI - Visualization of lncRNA by single-molecule fluorescence in situ hybridization. AB - Single-molecule RNA fluorescence in situ hybridization is a technique that holds great potential for the study of long noncoding RNA. It enables quantification and spatial resolution of single RNA molecules within cells via hybridization of multiple, labeled nucleic acid probes to a target RNA. It has recently become apparent that single-molecule RNA FISH probes targeting noncoding RNA are more prone to off-target binding yielding spurious results than when targeting mRNA. Here we present a protocol for the application of single-molecule RNA FISH to the study of noncoding RNA as well as an experimental procedure for validating legitimate signals. PMID- 25555573 TI - Super-resolution imaging of nuclear bodies by STED microscopy. AB - The sizes of nuclear bodies and other nuclear structures are normally no more than a few hundred nanometers. This size is below the resolution limit of light microscopy and thus requires electron microscopy for direct observation. Recent developments in super-resolution microscopy have extended the resolution of light microscopy to beyond 100 nm. Here, we describe a super-resolution technique, gated STED, for the analysis of the structure of nuclear bodies, with emphasis on the sample preparation and other technical tips that are important to obtain high quality super-resolution images. PMID- 25555574 TI - High-resolution 3D DNA FISH using plasmid probes and computational correction of optical aberrations to study chromatin structure at the sub-megabase scale. AB - Characterizing the three-dimensional organization of chromosomes is a fundamental goal in molecular biology and will be critical to understand how gene expression is regulated by distal regulatory sequences such as enhancers. Chromosome conformation capture (3C) techniques have recently revealed that the interactions between regulatory elements appear to occur in the context of topologically associating domains (TADs), each spanning few hundreds kilobases, within which the chromatin fiber preferentially interacts. However, 3C-based data represent average interaction probabilities of the chromatin fiber over millions of cells. To understand how variable chromatin conformation is within each TAD, one needs to employ single-cell techniques such as 3D DNA FISH. Given the small size of TADs however (typically <1 Mb), classical DNA FISH design needs to be adapted to achieve high genomic and spatial resolution. Here, we describe a high-resolution 3D DNA FISH approach we recently developed, based on a combination of short plasmid probes and computational correction of optical aberrations. We describe probe design and generation and the 3D DNA FISH procedure. We further discuss how to optimize microscope settings and to implement calibration-bead-assisted computational corrections in order to achieve 50 nm resolution in two-color distance measurements between probes that can be as close as 50 kb along the genome. PMID- 25555571 TI - Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma. AB - Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population. PMID- 25555575 TI - Time-lapse imaging of nuclear bodies. AB - Fluorescence microscopy is a powerful technique that has become central in the study of the structure and function of biological specimens. This is due in large part to its specificity and versatility. Although an understanding of structure typically through high-resolution imaging of fixed material-has proved an important tool to understanding function, fluorescence microscopy also offers a mechanism to interrogate cells in the living state, providing a means to explore dynamic process within the specimen over long time periods at high temporal resolution. The cell nucleus is a highly compartmented environment whose components are often highly motile and in a constant state of flux. The ability to monitor the dynamic behavior of nuclear bodies by live-cell imaging provides the researcher with important information regarding underlying mechanistic processes relating to their formation and maintenance. Two techniques have proved particularly valuable to our study of cellular dynamics and molecular mobility, namely, time-lapse imaging and fluorescence recovery after photobleaching (FRAP). Time-lapse microscopy allows for qualitative and quantitative analysis of a wide range of events at the cellular and subcellular level. FRAP provides a mechanism to study the mobility of a population of proteins in a range of conditions within discrete areas of the biological specimen. Therefore, fluorescence microscopy is unique in its ability to provide data at high temporal resolution and in such exquisite detail. PMID- 25555576 TI - Visualization of nucleic acids with synthetic exciton-controlled fluorescent oligonucleotide probes. AB - Engineered probes to adapt new photochemical properties upon recognition of target nucleic acids offer powerful tools to DNA and RNA visualization technologies. Herein, we describe a rapid and effective visualization method of nucleic acids in both fixed and living cells with hybridization-sensitive fluorescent oligonucleotide probes. These probes are efficiently quenched in an aqueous environment due to the homodimeric, excitonic interactions between fluorophores but become highly fluorescent upon hybridization to DNA or RNA with complementary sequences. The fast hybridization kinetics and quick fluorescence activation of the new probes allow applications to simplify the conventional fluorescent in situ hybridization protocols and reduce the amount of time to process the samples. Furthermore, hybridization-sensitive fluorescence emission of the probes allows monitoring dynamic behaviors of RNA in living cells. PMID- 25555577 TI - Live CLEM imaging to analyze nuclear structures at high resolution. AB - Fluorescence microscopy (FM) and electron microscopy (EM) are powerful tools for observing molecular components in cells. FM can provide temporal information about cellular proteins and structures in living cells. EM provides nanometer resolution images of cellular structures in fixed cells. We have combined FM and EM to develop a new method of correlative light and electron microscopy (CLEM), called "Live CLEM." In this method, the dynamic behavior of specific molecules of interest is first observed in living cells using fluorescence microscopy (FM) and then cellular structures in the same cell are observed using electron microscopy (EM). Following image acquisition, FM and EM images are compared to enable the fluorescent images to be correlated with the high-resolution images of cellular structures obtained using EM. As this method enables analysis of dynamic events involving specific molecules of interest in the context of specific cellular structures at high resolution, it is useful for the study of nuclear structures including nuclear bodies. Here we describe Live CLEM that can be applied to the study of nuclear structures in mammalian cells. PMID- 25555578 TI - Ultrastructural analysis of nuclear bodies using electron microscopy. AB - Recent immunofluorescent (IF) studies have discovered a variety of nuclear foci that have no known ultrastructurally defined counterpart. Using antibodies as ligands, immuno-electron microscopy (I-EM) is the method of choice for high resolution recognition of these newly described nuclear compartments. However, noncoding RNAs (ncRNAs) have also been shown to be frequent components, sometimes essential, of nuclear bodies so that electron microscopic in situ hybridization (EM-ISH) can be used as an alternative means to characterize nuclear foci at the EM level. Among the array of protocols available, Lowicryl embedding of chemically fixed cells allows for high preservation of both nuclear structures and antigenicity and provides stable cell and tissue samples that can be re probed whenever new antibodies or probes become available. Rapid and robust protocols are available for both I-EM and EM-ISH post-embedding techniques so that they can be combined on the same sections, providing ultrastructural and molecular insights into newly "emerging" nuclear bodies. PMID- 25555579 TI - Analyses of nuclear proteins and nucleic acid structures using atomic force microscopy. AB - Since the inception of atomic force microscopy (AFM) in 1986, the value of this technology for exploring the structure and biophysical properties of a variety of biological samples has been increasingly recognized. AFM provides the opportunity to both image samples at nanometer resolution and also measure the forces on the surface of the sample. Here, we describe a variety of methods for studying nuclear samples including single nucleic acid molecules, higher-order chromatin structures, the nucleolus, and the nucleus. Protocols to prepare nucleic acids, nucleic acid-protein complexes, reconstituted chromatin, the cell nucleus, and the nucleolus are included, as well as protocols describing how to prepare the AFM substrate and the AFM tip. Finally, we describe how to perform conventional imaging, high-speed imaging, recognition imaging, force spectroscopy, and nanoindentation experiments. PMID- 25555580 TI - Genome-wide co-localization screening of nuclear body components using a fluorescently tagged FLJ cDNA clone library. AB - Mammalian cell nuclei contain multiple granular structures, which are termed nuclear bodies. These structures are involved in various molecular events in the nucleus; they provide platforms for biogenesis of macromolecular complexes that are essential for gene expression, such as the ribosome and spliceosome; they act as reservoirs of various regulatory factors; and they are involved in the regulation of specific gene loci. Nuclear bodies are usually visualized by immunostaining for specific marker proteins. Although each type of nuclear body contains a distinct set of proteins, the protein components of most types of nuclear bodies remain to be identified. This chapter introduces a new approach to identify the protein components of specific types of nuclear bodies. PMID- 25555581 TI - Purification of specific chromatin regions using oligonucleotides: capture hybridization analysis of RNA targets (CHART). AB - Identification of genomic binding sites and proteins associated with noncoding RNAs will lead to more complete mechanistic characterization of the regulatory activities of noncoding RNAs. Capture hybridization analysis of RNA targets (CHART) is a powerful technique wherein specific RNA molecules are isolated from cross-linked nuclear extracts using complementary, biotinylated capture oligonucleotides, allowing subsequent identification of genomic DNA and proteins cross-linked to the RNA of interest. Here, we describe the procedure for CHART and list strategies to optimize nuclear extract preparation, capture oligonucleotide design, and isolation of nucleic acids and proteins enriched through CHART. PMID- 25555582 TI - RNA antisense purification (RAP) for mapping RNA interactions with chromatin. AB - RNA-centric biochemical purification is a general approach for studying the functions and mechanisms of noncoding RNAs. Here, we describe the experimental procedures for RNA antisense purification (RAP), a method for selective purification of endogenous RNA complexes from cell extracts that enables mapping of RNA interactions with chromatin. In RAP, the user cross-links cells to fix endogenous RNA complexes and purifies these complexes through hybrid capture with biotinylated antisense oligos. DNA loci that interact with the target RNA are identified using high-throughput DNA sequencing. PMID- 25555583 TI - In situ dissection of RNA functional subunits by domain-specific chromatin isolation by RNA purification (dChIRP). AB - Here we describe domain-specific chromatin isolation by RNA purification (dChIRP), a technique for dissecting the functional domains of a target RNA in situ. For an RNA of interest, dChIRP can identify domain-level intramolecular and intermolecular RNA-RNA, RNA-protein, and RNA-DNA interactions and maps the RNA's genomic binding sites with higher precision than domain-agnostic methods. We illustrate how this technique has been applied to the roX1 lncRNA to resolve its domain-level architecture, discover its protein- and chromatin-interacting domains, and map its occupancy on the X chromosome. PMID- 25555584 TI - Extracting, enriching, and identifying nuclear body sub-complexes using label based quantitative mass spectrometry. AB - Determining the proteome of a nuclear body is a crucial step toward understanding its function; however, it is extremely challenging to obtain pure nuclear body preparations. Moreover, many nuclear proteins dynamically associate with multiple bodies and subnuclear compartments, confounding analysis. We have found that a more practical approach is to carry out affinity purification of nuclear body sub complexes via the use of tagged nuclear-body-specific marker proteins. Here we describe in detail the method to identify new nuclear body protein sub-complexes through SILAC (stable isotope labeling by amino acids in culture)-based affinity purification followed by quantitative mass spectrometry. PMID- 25555585 TI - Studying RNA-binding protein interactions with target mRNAs in eukaryotic cells: native ribonucleoprotein immunoprecipitation (RIP) assays. AB - Post-transcriptional regulation of mRNA can potently dictate protein expression patterns in eukaryotic cells. This mode of regulation occurs through cis-acting regulatory regions in the mRNA transcript that mediate direct interactions with trans-acting RNA-binding proteins (RBPs). This mRNA/protein interaction can be studied in numerous ways that range from in vitro to in vivo through messenger ribonucleoprotein immunoprecipitation (mRNP-IP or RIP) assays. This modified immunoprecipitation approach is an important and sensitive method to determine the regulation of gene expression by specific RBPs under different cellular stressors. PMID- 25555586 TI - Cross-linking and immunoprecipitation of nuclear RNA-binding proteins. AB - The systematic identification of in vivo targets of nuclear RNA-binding proteins (RBPs) is crucial to elucidate the physiological functions of each RBP. However, it has been difficult to distinguish real targets from nonspecifically bound RNAs and to determine the exact binding sites of each RBP by using a conventional RNA immunoprecipitation (RIP) method. Photoactivatable Ribonucleoside-Enhanced Cross linking and Immunoprecipitation (PAR-CLIP) is a recently developed method that relies on RNA-protein cross-linking to reduce the contamination of nonspecifically bound RNAs. Furthermore, in combination with high-throughput sequencing followed by bioinformatic analysis, the exact RBP-binding sites can be identified at a single nucleotide resolution. Here, we describe in detail a PAR CLIP protocol to prepare cDNA libraries for high-throughput sequencing from RNA fragments that are bound to RBPs not only in the nucleus but also in the cytoplasm. PMID- 25555587 TI - Purification of noncoding RNA and bound proteins using FLAG peptide-conjugated antisense-oligonucleotides. AB - To understand the function of certain RNAs, including noncoding RNAs, it is important to identify the proteins that interact with the RNAs. Here we describe the method for purification of ribonucleoprotein (RNP) complexes composed of specific cellular RNAs by pull-down with FLAG peptide-conjugated antisense oligonucleotide (ASO). Using this method, we identified a novel protein component of U7 snRNP complex. PMID- 25555588 TI - MMCT-mediated chromosome engineering technique applicable to functional analysis of lncRNA and nuclear dynamics. AB - Recent evidence implicated several long noncoding RNA (lncRNA) in gene expression in cis or trans through regulating the local chromosomal architecture. However, the mechanisms underlying the lncRNA mediated silencing of multiple genes remain unknown. We believe that Microcell Mediated Chromosome Transfer (MMCT) is a suitable approach for functional analysis of lncRNAs and nuclear dynamics. MMCT is a unique research technique that can be generally used to transfer a single chromosome from one mammalian cell to another. Transferred chromosomes can be stably maintained as functioning in the recipient cells. Since there is no size limit to introducing genomic locus, an approach using the chromosome transfer technique is suitable for functional analysis of a large chromosomal domain. Here we describe a general strategy of MMCT, applications of which have potential to be an alternative tool of existing gene delivery system. PMID- 25555589 TI - Reconstitution of nucleocytoplasmic transport using digitonin-permeabilized cells. AB - Nucleocytoplasmic transport is crucial not only for basic cellular activities but also for the physiological adaptation of cells to various environmental stimuli that affect development, cell-fate determination, or disease development. The basic transport mechanisms have been revealed during the past two decades through the identification and biochemical characterizations of factors mediating the transport, dissecting the transport process and examining the function of nuclear pore complexes (NPCs). In this chapter, we describe methods for a nuclear transport reconstitution assay using digitonin-permeabilized mammalian cells. The transport assay can be generally conducted in the lab without special equipment. The assay system is efficient and significantly contributes to the study of nucleocytoplasmic transport. PMID- 25555590 TI - Genome-wide analysis of long noncoding RNA turnover. AB - Genome-wide analysis for determining RNA turnover is an advanced method in RNA biology that examines the specific half-life of nuclear noncoding RNA (ncRNA). In particular, a pulse-labeling method using uridine analogs enables the determination of RNA stability under physiologically undisturbed conditions. The technique involves pulse labeling of endogenous RNAs in mammalian cells with 5' bromo-uridine (BrU), followed by measuring the chronological decrease of BrU labeled RNAs using deep sequencing. The method is called BrU immunoprecipitation chase assay (BRIC) or BRIC through deep sequencing (BRIC-seq). Here, we describe a detailed protocol and technical tips for BRIC-seq. PMID- 25555591 TI - Knockdown of nuclear-retained long noncoding RNAs using modified DNA antisense oligonucleotides. AB - Long noncoding RNAs (lncRNAs) have recently emerged as important players in diverse cellular processes. Among them, a large fraction of lncRNAs are localized within cell nucleus. And several of these nuclear-retained lncRNAs have been found to regulate key nuclear processes, which brings up the requirement of effective genetic tools to explore the functions of this "dark matter" inside the nucleus. While siRNAs and shRNAs are widely used tools in loss-of-function studies, their general efficiency in depleting nuclear-retained lncRNAs is limited, due to the fact that the RNAi machinery is located mainly in the cytoplasm of mammalian cells. Here, we describe the usage of chemically modified chimeric DNA antisense oligonucleotides (ASO) in effective knockdown of nuclear retained lncRNAs, with a focus on the detailed workflow from the design and synthesis of ASOs, to in vitro and in vivo delivery methods. PMID- 25555592 TI - SiRNA screening of nuclear proteins. AB - Functional gene screening is a basic strategy for identifying candidate genes that are responsible for biological processes of interest to researchers. RNA mediated interference (RNAi)-based screening is one such approach. Although the knockdown technique using siRNA is widely accepted, careful evaluation is required to avoid false positive candidates as much as possible, because various cellular responses can be caused by events other than the target gene disruption. In this chapter, we introduce a method for a relatively small-scale siRNA screening that is capable of finding RNA binding proteins that regulate a specific RNA that is a structural component of a nuclear compartment. PMID- 25555593 TI - A multicenter, randomized, double-blind clinical study on Wufuxinnaoqing Soft Capsule () in treatment of chronic stable angina patients with blood stasis syndrome. AB - OBJECTIVE: To confirm the efficacy and safety of Wufuxinnaoqing Soft Capsule (, WSC) in the treatment of chronic stable angina (blood stasis syndrome). METHODS: A multicenter, randomized, double-blind, placebo-controlled trial with superiority test was designed. A total of 240 patients with chronic stable angina (blood stasis syndrome) from multiple centers were randomly and equally assigned to the treatment group and the control group. Based on standard treatment of Western medicine, the treatment group was given WSC, while the control group was given WSC mimetic, both for 12 weeks. Observed indicators included the efficacy in angina, the efficacy in Chinese medicine syndrome, the withdrawal or reduce rate of nitroglycerin and routine safety indices. RESULTS: After 12-week treatment, the significant effective rate and total effective rate of the treatment group were significantly better than those of the control group (23.5% vs. 9.2%, 64.7% vs. 30.8%), respectively, with statistically significant difference (P<0.01). After 12-week treatment, the decreased points and the decreased rate of angina symptom score in the treatment group were better than in the control group (5.1+/-4.2 points vs. 2.8+/-3.5 points, 44.9%+/-37.2% vs. 25.4%+/-30.7%) respectively, with significant difference (P<0.01). After 12-week treatment, the significant effective rate and total effective rate of the treatment group were better than the control group (respectively, 30.3% vs. 15.0%, 67.2% vs. 45.0%,P<0.01). After 8- or 12-week treatment, the decreased points and the decreased rate of Chinese medicine syndrome score in the treatment group were better than the control group (P<0.05 orP<0.01). After 12-week treatment, nitroglycerin withdrawal rate and the withdrawal or reduce rate in treatment group were better than the control group (P<0.01). On safety evaluation, the incidence of adverse events (7.563% vs. 7.500%) and the incidence of cardiovascular events (0.840% vs. 0.000%) in the treatment group were similar with the control group, and the difference was not statistically significant (P>0.05). CONCLUSION: In treatment of chronic stable angina (blood stasis syndrome), WSC can reduce angina attacks and consumption of nitroglycerin, decrease angina severity degree, effectively relieve the blood stasis syndromes, such as chest pain, chest tightness, palpitations, dark purple tongue and other symptoms. Besides, adverse events and cardiovascular adverse events in the treatment group and the control group showed no difference. All shows that the drug is safe and effective. [This study was registered in Chinese Clinical Trial Registry (ChiCTR), with registration number: ChiCTR-TRC-14005158.]. PMID- 25555595 TI - Immunosuppressive effect of Chinese medicine on T helper 17 cells. AB - T helper (Th)17 cells have been proposed to play important roles in several human diseases. The literatures about Chinese medicine studies, which related to inhibiting Th17, were reviewed, and the Chinese medicine which could inhibit Th17 cells was summarized in this paper. PMID- 25555594 TI - Effective dose of the combination of salvianolic acids and tanshinones against inflammatory injury in human umbilical vein endothelial cells injured by thrombin. AB - OBJECTIVE: To investigate the pharmacological effective doses of Chinese Danshen components, (salvianolic acids and tanshinones) combinations on vascular endothelia cells against inflammatory injury. METHODS: Thrombin (50 U/mL) was incubated in human umbilical vein endothelia cells (HUVECs) with 50 and 100 MUg/L (1:0, 0:1, 3:1, 2:1, 1:1, and 1:2) salvianolic acids and tanshinones or without the components of Danshen extract. Cell viability was confirmed in (4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium (MTT) assay and cell death was confirmed in lactate dehydrogenase (LDH) released into the cell culture supernatant. RESULTS: Six hours treatment of HUVECs with 50 or 100 MUg/L salvianolic acids and tanshinones combinations at ratios 1:0, 0:1, 3:1, 2:1, 1:1, and 1:2 significantly (P<0.05 or P<0.01) improved cell proliferation in vitro compared with model group when assayed in MTT, whereas 100 MUg/L groups displayed trend toward upshift in potency compared with 50 MUg/L groups (2:1, 1:1, and 1:2), respectively, in addition to inhibition of cell death confirmed in reduced LDH released into the culture medium. CONCLUSIONS: These findings provided some useful information for safe and effective use of Danshen preparations in clinical practice. We made observations regarding the protective effect of Danshen components combinations in vascular endothelial against inflammatory injury caused by thrombin activation of endothelial cell. PMID- 25555596 TI - Improving clinical practice guideline development in integration of traditional Chinese medicine and Western medicine. PMID- 25555597 TI - Current status and future prospects of acupuncture and traditional Chinese medicine in Canada. AB - Traditional Chinese medicine (TCM) and acupuncture has been gradually accepted by the mainstream society since the 1970s and has been rapidly expanding, accompanying the tide of Chinese immigration since the 1980s. Acupuncture legislation has been approved by the governments of 5 provinces in Canada between 1988 and 2014. After the acceptance of self-regulation, 5 corresponding colleges were established, one after another. The code of ethics and professional practice standard were developed by the Colleges. British Columbia (BC) became the first Canadian province to offer acupuncture treatments as a supplementary benefit for its Medical Services Plan premium assistance recipients beginning in 2008. The 5 colleges united to form the Canadian Alliance of Regulatory Bodies of Traditional Chinese Medicine Practitioners and Acupuncturists (CARBTCMPA) in the same year. The Entry-level Occupational Competencies for the Practice of TCM in Canada were developed by CARB-TCMPA in 2010. The Pan-Canadian registration examinations for acupuncturists, herbalists and TCM practitioners have been administered and scheduled since 2013. The Entry-level Occupational Competencies for Doctors of TCM were developed by College of Traditional Chinese Medicine Practitioners and Acupuncturists of British Columbia (CTCMA-BC) in 2014. It sketches the blueprint for future development of the TCM profession in Canada. PMID- 25555602 TI - Relationship between clinical signs and results of impulse oscillometry in pigs originating from the field. AB - The aim of the present study was to assess the contribution of clinical data to the variability of impulse oscillometric test results observed previously by Pullen et al. (2014). Fifty-eight German hybrid pigs from 29 different herds with unknown respiratory status were examined in the context of routine diagnostics as part of herd health service. Routine clinical examination was extended to a total set of 29 parameters, representing detailed clinical signs of the respiratory system, and to lung function testing applying the impulse oscillometry system (IOS). The resulting linear relationship between clinical data and variables of pulmonary mechanics had a mean r(2) of 0.52. Clinical parameters predominantly representing the lower respiratory tract closely correlated with established impulse oscillometric indices reflecting peripheral airways. Because of a restricted relationship between pulmonary functional disorders and clinical data, additional diagnostic methods are required to reveal the proportion of variance undefined by clinical examination. PMID- 25555603 TI - Expression profile of Toll-like receptor mRNA in pigs co-infected with porcine reproductive and respiratory syndrome virus and porcine circovirus type 2. AB - Field and experimental studies have shown that co-infection of pigs with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) increases the severity of the disease. The present study investigates the mRNA expression profile of Toll-like receptors (TLRs) in pigs co-infected with PRRSV and PCV2. SPF pigs were infected with PRRSV, PCV2 or in a combination of both. The mRNA expression levels of TLRs and related cytokines in peripheral blood mononuclear cells (PBMCs) of pigs were determined by quantitative real-time RT-PCR. The mRNA expression profiles of TLRs by PBMCs from pigs co-infected with PRRSV and PCV2 displayed two distinct patterns: an increased expression profile for TLRs2, 4 and 8, and a decreased expression profile for TLRs3, 7 and 9. An up regulated expression of IL-1beta and IL-10 mRNA and a down-regulated expression of INF-alpha and TNF-alpha mRNA in PBMCs of co-infected pigs were also observed. PMID- 25555604 TI - Do low field magnetic resonance imaging abnormalities correlate with macroscopical and histological changes within the equine deep digital flexor tendon? AB - Correlating magnetic resonance (MR) imaging and histopathological findings is essential to validate low field MR imaging in lame horses. This study aimed to compare signal changes in the deep digital flexor tendon (DDFT) of the distal limb on low field MR imaging with macroscopical and histological findings. Cadaver limbs from lame horses with DDFT lesions were selected. The DDFT MR imaging findings and histopathological results were graded, and macroscopical abnormalities were recorded. There was a strong correlation between MR imaging and histopathology grades (rs = 0.76, p < 0.001) in the foot. There was moderate agreement (Kappa statistic 0.52) between the MR and histopathology grades; agreement was superior further proximal in the foot. The presence and severity of pathology in the DDFT are well represented by the presence and severity of MR imaging signal changes. The study supports the use of low field MR imaging for diagnosis of equine distal limb DDFT lesions. PMID- 25555605 TI - Letters to the Editor. PMID- 25555606 TI - Are temporomandibular disorders associated with habitual sleeping body posture or nasal septal deviation? AB - Numerous factors can be considered for the etiology of temporomandibular disorders (TMD). The aim of the present study was to investigate whether the presence of both nasal septal deviation (NSD) and habitual prone sleeping posture (HPSP) predisposes TMD. We evaluated 200 subjects in 4 groups. Group I (NSD-, HPSP-/control group), Group II (NSD+, HPSP-), Group III (NSD-, HPSP+), Group IV (NSD+, HPSP+). All patients were examined according to the research diagnostic criteria to determine the presence of TMD. Group IV had the highest value for TMD incidence (44 %). Thus, we found that the presence of both NSD and HPSP parameters increased TMD incidence in Group IV compared to the control group (p = 0.000). Additionally, Group IV showed significantly higher values than Group II (p = 0.012) and Group III (p = 0.039). For Group III (NSD-, HPSP+), TMD was determined higher compared to the control group (p = 0.009). A statistically higher value of presence of TMD was determined in Group II (NSD+, HPSP-) than control group (p = 0.029). The incidence of TMD was significantly higher in women than men (p = 0.020). We concluded that one having an unilateral obstructive nasal septal deviation in addition to a habit of sleeping in prone position must be alert for potential TMD. PMID- 25555607 TI - Age-related morphological changes in the basement membrane in the stria vascularis of C57BL/6 mice. AB - Basement membrane anionic sites (BMAS) are involved in the selective transport of electrically charged macromolecules in cochlear capillaries. Using cationic polyethyleneimine (PEI), we examined age-related changes in BMAS in the cochleae of C57BL/6 mice. The mice were grouped according to age as follows: 3 days, 4 weeks, 8 weeks, 6 months, and 12 months. In the right bony labyrinths, widths of the stria vascularis were measured in paraffin-embedded sections using light microscopy. The left bony labyrinths were immersed in a 0.5 % cationic PEI solution and embedded in epoxy resin. Ultrathin sections of the left cochlea were examined using transmission electron microscopy. A significant difference in stria vascularis width was observed between the 4-week-old and 12-month-old mice. The PEI distribution in the capillary and epithelial basement membranes (BMs) of the cochlea was observed. In all animals, PEI particles were evenly distributed in the capillary BM of the spiral ligament and in the subepithelial BM of Reissner's membrane. In the stria vascularis, PEI particles were evenly distributed in the capillary BM in 3-day-old mice. In 4- and 8-week-old mice, PEI particle sizes were markedly lower than those observed in 3-day-old mice. In 6- and 12-month-old mice, PEI particles were hardly detected in the strial capillary BM. In the strial capillary BM in these mice, the laminae rarae externa and interna disappeared, but the lamina densa became larger. We speculated that age related changes of strial capillary BMAS may affect electrically charged macromolecule transport systems in the stria vascularis of C57BL/6 mice. PMID- 25555608 TI - Designing a safeguarding tool for Japanese professionals to identify, understand and respond to adolescent sexual behaviours. AB - OBJECTIVES: This study sought to construct a developmental and context-sensitive framework that could be used to identify, understand and respond to adolescent sexual behaviours. METHODS: We reviewed work being conducted on adolescent sexual development, health and safety, interviewed UK-based professionals working on sexual health and child protection, and, having identified the Traffic Light Tool (TLT) designed by Family Planning Queensland and then developed by Brook in the UK, we conducted expert interviews. Finally, we reviewed in-house consultation, training and evaluation documentation provided by Brook. RESULTS: We identified the Traffic Light Safeguarding Project as offering a framework for thinking about and responding to youth sexuality. The concept of safeguarding allows us to go beyond the narrower mandate of child protection, and link up the activities of different stakeholders working around child and adolescent sexual health. We were able to confirm that the TLT was functioning as an effective safeguarding tool to: (1) identify and respond to adolescent sexual behaviours, and (2) support professionals to communicate confidently with adolescents about sexuality and risk taking. We confirmed the possibilities for developing a Japanese version of the tool. CONCLUSIONS: A safeguarding perspective can help us to move away from a narrowly risk-based approach to child and adolescent sexuality. Development and dissemination of a Japanese version of the TLT can help professionals distinguish between healthy (normal) and unhealthy (risky) sexual behaviours at each developmental stage and more confidently respond to these behaviours. PMID- 25555616 TI - Seasonal variability and flux of particulate trace elements from the Yellow River: impacts of the anthropogenic flood event. AB - In this study, the suspended particulate matter (SPM) of the Yellow River (Huanghe) was collected biweekly at the outlet and analyzed for particulate trace element contents. The seasonal variations of the trace elements were primarily controlled by hydrological processes, which determined different sources of the SPM. Moreover, As, Co, Cr, and Ni primarily originated from lithogenic sources, whereas Cd, Cu, Pb and Zn were influenced by anthropogenic activities. The Yellow River has suffered moderate to considerable ecological risk during the late stage of Water and Sediment Regulation (WSR). Using the discharge-weighted contents method, the annual trace element fluxes were estimated, with ca. 30% of the annual fluxes occurring within the short WSR period (6% of one year). More specifically, 75% of the Cd flux was from an anthropogenic source, which likely posed a significant threat to the estuary and the adjacent coastal ecosystems. PMID- 25555617 TI - Instantaneous stabilization of floating oils by surface application of natural granular materials (beach sand and limestone). AB - When granular materials are applied to hydrophobic liquids floating over another liquid (i.e., water), particles form aggregates which can be separated from the floating phase. This concept can be used for controlling mobility of floating oils, especially after oil spills near coastal areas. The objectives of this research were to characterize oil capture efficiency and determine effectiveness of particles for converting the floating phase to a heavier phase for effective separation. Experiments were conducted with South Louisiana crude oil contaminated salt water, limestone and quartz sand. Although the oil removal efficiency increased with the increasing amount of granular material applied, it did not increase linearly. About 50% of the floating oil was removed by aggregates, regardless of the material used, when granular material to floating oil ratio was about 1 g/g. The aggregates separated had higher amounts of oil content when smaller amounts of granular materials were added. PMID- 25555618 TI - Do counteracting external frontal plane moments alter the intraarticular contact force distribution in the loaded human tibiofemoral joint? AB - BACKGROUND: There are strong indications that asymmetric medio-lateral load distribution in the knee joint is a risk factor for osteoarthritis. Externally applied frontal plane moments (adduction and abduction) might affect the distribution of knee joint compartment loading. However, this is not confirmed through intraarticular measurements in loaded human knee joints. The purpose of the study was to determine the force distribution and the movement of the centre of pressure in the loaded tibiofemoral joint as a function of varied externally applied counteracting frontal plane moments and in dependence of the knee flexion angle. METHODS: Adduction and abduction moments of 2.5 Nm and 5 Nm were applied to six cadaveric knees exhibiting varus, valgus and normal alignments. The joints were mounted in a knee joint loading simulator. During simulated muscle-driven extension-flexion cycles, intraarticular forces were determined using capacitive pressure sensors inserted into the medial and lateral knee joint compartments. Motion of femur and tibia were assessed by a motion analysis system. RESULTS: Externally applied frontal plane moments altered the intraarticular force distribution and caused shifts in the centre of pressure up to 4.3mm in all knee joints. Larger redistribution effects were found in higher knee flexion angles. The medial compartment load increased during the flexion in all investigated knee joints. CONCLUSIONS: The application of counteracting frontal plane moments for the conservative treatment of osteoarthritis can redistribute the forces and might slow down the progression of the disease. CLINICAL RELEVANCE: The findings of this study offer novel insights to guide the development and optimization of mechanical aids for the treatment of osteoarthritic knees. PMID- 25555619 TI - Pathogenesis of infection with 2009 pandemic H1N1 influenza virus in isogenic guinea pigs after intranasal or intratracheal inoculation. AB - To elucidate the pathogenesis and transmission of influenza virus, the ferret model is typically used. To investigate protective immune responses, the use of inbred mouse strains has proven invaluable. Here, we describe a study with isogenic guinea pigs, which would uniquely combine the advantages of the mouse and ferret models for influenza virus infection. Strain 2 isogenic guinea pigs were inoculated with H1N1pdm09 influenza virus A/Netherlands/602/09 by the intranasal or intratracheal route. Viral replication kinetics were assessed by determining virus titers in nasal swabs and respiratory tissues, which were also used to assess histopathologic changes and the number of infected cells. In all guinea pigs, virus titers peaked in nasal secretions at day 2 after inoculation. Intranasal inoculation resulted in higher virus excretion via the nose and higher virus titers in the nasal turbinates than intratracheal inoculation. After intranasal inoculation, infectious virus was recovered only from nasal epithelium; after intratracheal inoculation, it was recovered also from trachea, lung, and cerebrum. Histopathologic changes corresponded with virus antigen distribution, being largely limited to nasal epithelium for intranasally infected guinea pigs and more widespread in the respiratory tract for intratracheally infected guinea pigs. In summary, isogenic guinea pigs show promise as a model to investigate the role of humoral and cell-mediated immunities to influenza and their effect on virus transmission. PMID- 25555620 TI - The beneficial effect of extracorporeal shockwave myocardial revascularization in patients with refractory angina. AB - OBJECTIVES: The incidence of patients with refractory angina (RA) is increasing. Medical therapy for RA is limited and prognosis is poor. Experimental data suggest that the use of Extracorporeal shockwave myocardial revascularization (ESMR) may contribute to angiogenesis and improve symptoms of angina in patients with RA. Purpose of our study is to determine the efficacy of cardiac shock wave therapy (ESMR) in the management of patients with nonrevascolarized coronary artery disease (CAD). METHODS: We performed a prospective cohort study to examine the efficacy of ESMR applcation in patients with RA despite optimal medical therapy, not suitable for further PCI or CABG. Characteristics such as angina class scores (CCS class score), nitroglycerin consumption and hospitalization rate among cases (patients with RA who received ESMR) and controls (patients with RA who did not receive ESMR) were compared at baseline and 6 months after ESMR therapy. In patients receiveing d ESMR the effect of on cardiac perfusion was assessed. RESULTS: There were 43 patients in the case group and 29 patients in the control group. The mean age of the patients was 70 +/- 9.5 years in the case group and 71 +/- 5.3 years in the control group. Other characteristics (diabetes, coronary artery bypass graft, percutaneus coronary intervention, baseline CCS class score) were similar in both groups. There was a significant improvement in CCS class score (1.33 +/- 0.57 in cases and 1.92 +/- 0.69 in controls; p = 0.0002), nitroglycerin consumption (20% in case cases, and 44.8% in controls; P < 0.03) and hospitalization rate significantly reduced (13.9% in case cases, and 37.9% in controls; P < 0.03). The patients who received ESMR, there was a significantly improvement in myocardial perfusion after 6 months with a 33% relative reduction of summed stress score (SSS) (p = 0.002). CONCLUSION: This case control study demonstrates the beneficial effect of ESMR therapy on cardiac symptoms, myocardial perfusion and reduced hospitalization in patients with refractory angina. Ther current study supports a role for ESMR as a non-invasive therapuetic option for patients with RA. PMID- 25555621 TI - Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone. AB - BACKGROUND: Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared behavioral naltrexone therapy (BNT) to compliance enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving adherence to oral naltrexone. METHODS: A 24-week, randomized, placebo-controlled trial (n=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+placebo injection; (3) CE+XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. RESULTS: Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X3(2)=9.19, p=0.027). For low severity patients (<= 6 bags/day), retention was highest in the BNT-XR-NTX group (60% at 6 months), as hypothesized. For high-severity (>6 bags/day) patients, BNT XR-NTX did not perform as well, due to high early attrition. CONCLUSION: For low severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly. PMID- 25555624 TI - Analysis of clinical and CT characteristics of patients with Klebsiella pneumoniae liver abscesses: an insight into risk factors of metastatic infection. AB - PURPOSE: To compare the clinical and CT characteristics of patients with Klebsiella pneumoniae liver abscess (KPLA), with or without metastatic infection. MATERIALS AND METHODS: Clinical information (age, sex, clinical symptoms, underlying disease, hematological parameters, abscess-related mortality) and CT characteristics of abscesses were analyzed to investigate associations with metastatic infection. Metastatic infections were divided into septic pulmonary embolism (SPE) and extra-pulmonary metastatic infection (EMI). RESULTS: We identified 66 consecutive patients with KPLA. Metastatic infection occurred in 22/66 patients (33.3%); 8/66 (12.1%) patients had SPE, 6/66 (9.09%) patients had EMI; and 8/66 (12.1%) patients had both SPE and EMI. Patients with SPE were younger than patients without SPE (47.7+/-13.7 y vs.55.6+/-12.0 y; p=0.03). Unilocular abscess was significantly more common in patients with SPE than the non-SPE group (43.75% vs 18.0%, p=0.036). The mean maximal diameter of EMI was 56.5+/-21.3 mm and was significantly smaller than that of the non-EMI which was 79.9+/-31.4 (p=0.011). SPE was significantly associated with development of EMI (50% vs 17.3%, p=0.011). CONCLUSION: Unilocular liver abscess is associated with SPE, and SPE is strongly associated with EMI among patients with KPLA. A maximal diameter of KPLA<55 mm can be used as a predictor of EMI. PMID- 25555623 TI - Primary case of human pneumonic plague occurring in a Himalayan marmot natural focus area Gansu Province, China. AB - A case of primary pneumonic plague (PPP) caused by Yersinia pestis is reported. This case occurred in the largest plague area in China. The patient died after contact with a dog that had captured an infected marmot. Three of 151 contacts were shown to be positive for antibody against F1 antigen by indirect hemagglutination assay, but none had clinical symptoms. There was no secondary case. PMID- 25555626 TI - Academic Outcomes Following a School-Based RCT for ADHD: 6-Year Follow-Up. AB - OBJECTIVE: For children with high levels of ADHD symptoms, to investigate the impact of early school-based interventions on academic outcomes in mid-childhood. METHOD: A 6-year follow-up of 4- to 5-year-olds (N = 52,075) whose schools participated in a cluster randomized controlled trial for children at risk of ADHD. School-level interventions involved the provision of a booklet with evidence-based information (book) and/or feedback of names (identification) of children with high levels of ADHD symptoms. At ages 10 to 11 years, outcome measures were scores in English and mathematics tests. RESULTS: For children with high levels of ADHD symptoms, the interventions had no impact on academic outcomes. When all children were analyzed, the book intervention had a positive impact on mathematics. Baseline inattention was associated with poorer academic outcomes, whereas impulsiveness was associated with better academic outcomes. CONCLUSION: The provision of evidence-based information about helping children with ADHD at school may have wider academic benefits. PMID- 25555627 TI - Weekly Calendar Planning Activity for University Students: Comparison of Individuals With and Without ADHD by Gender. AB - OBJECTIVE: To introduce a revised version of the Weekly Calendar Planning Activity (WCPA) adapted for university students (Weekly Calendar Performance Activity for students [WCPA-S]) and compare the performance of this activity between students with and without ADHD and across gender groups. METHOD: Participants included a total of 157 students, ages 20 to 30, enrolled in universities/colleges and divided into two groups: students with ADHD (male = 23, female = 38) and without ADHD (male = 33, female = 63). A two-way ANOVA was used for data analyses. The WCPA-S was administered to each student individually. RESULTS: Significant differences were found between students with and without ADHD and across genders in performance, duration of performance, and in the number of strategies used. CONCLUSION: The WCPA-S proved to be an effective performance-based diagnostic tool for the utilization of executive functions in the daily life of university students. This instrument can be used to predict success in higher education and to support learning among university students with ADHD. PMID- 25555625 TI - PTSD and Risk of Incident Cardiovascular Disease in Aging Veterans. AB - OBJECTIVES: To determine if late-life posttraumatic stress disorder (PTSD) is associated with cardiovascular disease in a sample of older veterans, and whether the association is independent of medical and psychiatric comorbities. DESIGN: Retrospective cohort study conducted using the Department of Veterans Affairs (VA) National Patient Care Database (2000-2011). SETTING: VA medical centers in the United States. PARTICIPANTS: A total of 138,341 veterans 55 years and older without cardiovascular disease at study baseline (2000-2003). MEASUREMENTS: PTSD and cardiovascular disease (as defined by diagnoses of: cerebrovascular disease [CVD], congestive heart failure [CHF], myocardial infarction [MI], and peripheral vascular disease [PVD]) were identified by ICD-9 codes during study baseline (2000-2003) and follow-up (2004-2011), respectively. RESULTS: 3% of veterans (N = 4,041) had a baseline diagnosis of PTSD. Unadjusted increased risk of incidence of CVD was 80%, CHF was 56%, MI was 82%, and PVD was 60% in veterans with PTSD compared with those without PTSD. After adjustment for demographics, medical comorbidities, substance use, and psychiatric comorbidities, veterans with late life PTSD were at a 45% increased risk for incident CVD, 26% increased risk for incident CHF, 49% increased risk for incident MI, and 35% increased risk for PVD compared with veterans without late-life PTSD. CONCLUSIONS: Findings highlight the longitudinal impact of PTSD on increasing the incidence of cardiovascular disease in older adults. This study implies the need for greater monitoring and treatment of PTSD in older persons, particularly older veterans, to assist in preventing adverse outcomes, such as cardiovascular disease, over the long term. PMID- 25555628 TI - Association Between Restless Legs Syndrome and Adult ADHD in a German Community Based Sample. AB - OBJECTIVE: Previous research in clinical samples indicated a significant association between ADHD and restless legs syndrome (RLS). The present study examined the association between adult ADHD and RLS in the German population. METHOD: Self-rating instruments to assess RLS, childhood ADHD, and adult ADHD were administered to a community-based sample ( N = 1,632). In addition, current depression and anxiety, sleep disturbances, weight, and height were assessed by self-report. RESULTS: Adult ADHD was associated with statistically significant increases in the odds of meeting diagnostic criteria for RLS even when adjusting for potential confounding variables such as weight (odds ratio [OR] = 3.18, 95% confidence interval [CI] = [1.29, 7.63], p< .001). However, the association did not hold true after adjusting for the presence of sleep disturbances (OR = 2.02, 95% CI = [0.82, 4.96], p = .13). CONCLUSION: The findings suggest a strong link between RLS and adult ADHD symptoms. Clinicians should be aware of RLS among adult ADHD patients, especially as there might be a negative interactive effect. PMID- 25555622 TI - Binge drinking and risky sexual behavior among HIV-negative and unknown HIV status men who have sex with men, 20 US cities. AB - BACKGROUND: Men who have sex with men (MSM) represent over half of new HIV infections in the United States. It is important to understand the factors associated with engaging in risky sexual behavior to develop effective prevention interventions. Binge drinking (>=5 drinks on >=1 occasion) is the most common form of excessive alcohol consumption. This study examines the relationship between binge drinking and sexual risk behaviors among MSM who are current drinkers and who were either HIV-negative or unaware of their HIV status. METHODS: Using the 2011 National HIV Behavioral Surveillance system and multivariable Poisson models with robust error estimates, we assessed the association between binge drinking and sexual risk behaviors among current drinkers. Prevalence ratios (PR) and 95% confidence intervals (CI) are presented. RESULTS: Overall, 85% of MSM were current drinkers, and 59% of MSM who drank reported >=1 episode of binge drinking in the preceding 30 days. In multivariable models, binge drinking was associated with condomless anal intercourse (CAI) at last sex with an HIV-positive or unknown status partner (receptive: PR 1.3, 95% CI 1.1-1.6; insertive: PR 1.2, 95% CI 1.0-1.4), having exchanged sex for money or drugs at last sex (PR: 1.4, 95% CI 1.1-1.7), having concurrent partners in the past year (PR: 1.1, 95% CI 1.1-1.2), and having more CAI partners in the past year (PR: 1.2, 95% CI 1.0-1.4) compared to non-binge drinkers. CONCLUSIONS: Evidence-based strategies for reducing binge drinking could help reduce risky sexual behavior among MSM. PMID- 25555629 TI - Occupational Status Is Compromised in Adults With ADHD and Psychometrically Defined Executive Function Deficits. AB - OBJECTIVE: Problems related to executive function (EF) are frequently reported in adults with ADHD. However, only a subgroup of patients show deficits on common neuropsychological tests designed to measure EF. We investigated whether this subgroup also had higher levels of functional impairments, including unemployment, than the ADHD group without such deficits. METHOD: We defined executive function deficit (EFD) from selected tests from the Delis-Kaplan Executive Function System (D-KEFS) and assessed ADHD symptoms and psychiatric comorbidity with the use of questionnaires in 79 ADHD patients and 77 controls (IQ above 80 in both groups). RESULTS: In the ADHD group, 24.3% had EFD. This subgroup showed significantly higher frequency of unemployment, more reading and writing problems, lower IQ scores, and more self-reported ADHD symptoms in childhood than the ADHD subgroup without EFD. CONCLUSION: These findings indicate that it may be possible to identify individuals at risk of functional impairments, and emphasizes the importance of effective treatment programs targeting EF. PMID- 25555630 TI - Exploring Parent Beliefs and Behavior: The Contribution of ADHD Symptomology Within Mothers and Fathers. AB - OBJECTIVE: To use a multi-method approach to examine the association of parental ADHD and gender with observed and self-reported parenting beliefs and behaviors. METHOD: Seventy-nine mother-father dyads completed measures of child behavior and impairment, parenting beliefs and behaviors, and self- and partner ratings of ADHD symptoms and functional impairment. Forty-five parents also completed structured parent-child interactions. RESULTS: A hierarchical linear model suggests impairment in functional domains may be associated with negative emotions about parenting and less effective parenting strategies. For fathers, greater severity of partner-reported symptoms of ADHD may be associated with greater frequency of negative talk during parent-child interactions. CONCLUSION: Findings suggest that higher levels of parental ADHD symptoms and functional impairment may be associated with reported beliefs and behaviors related to parenting. Differences emerged among mothers' and fathers' use of parenting strategies when self- and other-report of ADHD symptoms and impairment were assessed. PMID- 25555631 TI - Aggressive, solid variant of alveolar rhabdomyosarcoma with cutaneous involvement in a juvenile labrador retriever. AB - An 8.5-month-old male Labrador retriever presented with a cutaneous mass in the right maxillofacial region and swelling of the gingiva. The dog received antibiotic and anti-inflammatory treatment. After 3 weeks the dog returned, presenting with disseminated cutaneous tumours on the neck, trunk and groin. One of the nodules was resected and a cutaneous round cell tumour was diagnosed on microscopical examination. The dog was humanely destroyed. Necropsy examination revealed disseminated tumours in the skin, internal organs and skeletal muscles. Microscopically, all of the tumours were composed of small round cells, arranged in nests. Immunohistochemically, the neoplastic cells expressed vimentin, desmin, MyoD1, myogenin and smooth muscle actin, but were negative for CD3, CD18, CD79alphacy, cytokeratin AE1/AE3, chromogranin A, class II molecules of the major histocompatibility complex, neuron-specific enolase and S100. The average Ki67 index was 89.5%. The final diagnosis was a solid variant of alveolar rhabdomyosarcoma (ARMS). This is the first report of the cutaneous multifocal form of ARMS in veterinary oncology. PMID- 25555632 TI - Cutaneous pythiosis in a goat. AB - Pythiosis is reported for the first time in a goat. The affected goat had daily access to an aquatic environment and had developed an ulcerative lesion on the skin of the left hindlimb. Microscopically, there were dermal pyogranulomas with 'negatively stained' hyphae, which were identified immunohistochemically as Pythium insidiosum. PMID- 25555633 TI - University of Pretoria One Health Summer School 2014. PMID- 25555634 TI - Upregulation of alveolar levels of activin B, but not activin A, in lungs of west highland white terriers with idiopathic pulmonary fibrosis and diffuse alveolar damage. AB - Activins, cytokines belonging to the transforming growth factor-beta superfamily, have an important role in inflammation and fibrosis. Activin A has been suggested to participate in the pathophysiology of human idiopathic pulmonary fibrosis (IPF), but studies on the role of activin B are sparse. Canine IPF (CIPF) is an incurable interstitial lung disease occurring particularly in West Highland white terriers (WHWTs). During the disease course there are acute exacerbations (AEs) and the condition has a poor prognosis. Microscopically, AEs of CIPF are characterized by diffuse alveolar damage, which is also a key feature of acute respiratory distress syndrome (ARDS). The aim of this study was to study expression of activin A and B in lung tissue of WHWTs with CIPF and WHWTs with CIPF and concurrent AE, and dogs of various breeds with ARDS and to compare these findings with those of healthy WHWTs. In addition, western blot analysis of activin B from bronchoalveolar lavage fluid (BALF) from WHWTs with CIPF and healthy WHWTs was conducted. Activin B, but not activin A, was strongly expressed in the altered alveolar epithelium in the lungs of WHWTs with CIPF as well as in the lungs of dogs with ARDS. Activin B was detected in the BALF of WHWTs with CIPF, most notably in samples from dogs with AE, but activin B was not detected in BALF from healthy WHWTs. These findings suggest that activin B may be part of the pathophysiology of CIPF and might act as a marker of alveolar epithelial damage. PMID- 25555636 TI - Absence of transmission from HIV-infected individuals with HAART to their heterosexual serodiscordant partners. AB - BACKGROUND: Further studies are needed to evaluate the level of effectiveness and durability of HAART to reduce the risk of HIV sexual transmission in serodiscordant couples having unprotected sexual practices. METHODS: A cross sectional study was conducted with prospective cohort of heterosexual HIV serodiscordant couples where the only risk factor for HIV transmission to the uninfected partner (sexual partner) was the sexual relationship with the infected partner (index case). HIV prevalence in sexual partners at enrolment and seroconversions in follow-up were compared by antiretroviral treatment in the index partner, HIV plasma viral load in index cases and sexual risk exposures in sexual partners. In each visit, an evaluation of the risks for HIV transmission, preventive counselling and screening for genitourinary infections in the sexual partner was performed, as well as the determination of the immunological and virological situation and antiretroviral treatment in the index case. RESULTS: At enrolment no HIV infection was detected in 202 couples where the index case was taking HAART. HIV prevalence in sexual partners was 9.6% in 491 couples where the index case was not taking antiretroviral treatment (p<0.001). During follow-up there was no HIV seroconversion among 199 partners whose index case was taking HAART, accruing 7600 risky sexual exposures and 85 natural pregnancies. Among 359 couples whose index case was not under antiretroviral treatment, over 13,000 risky sexual exposures and 5 HIV seroconversions of sexual partners were recorded. The percentage of seroconversion among couples having risky sexual intercourse was 2.5 (95% confidence interval [CI]: 1.1-5.6) when the index case did not undergo antiretroviral treatment and zero (95% CI: 0-3.2) when the index case received HAART. CONCLUSIONS: The risk of sexual transmission of HIV from individuals with HAART to their heterosexual partners can become extremely low. PMID- 25555635 TI - Sleep variability and cardiac autonomic modulation in adolescents - Penn State Child Cohort (PSCC) study. AB - OBJECTIVE: To investigate the effects of objectively measured habitual sleep patterns on cardiac autonomic modulation (CAM) in a population-based sample of adolescents. METHODS: We used data from 421 adolescents who completed the follow up examination in the Penn State Children Cohort study. CAM was assessed by heart rate (HR) variability (HRV) analysis of beat-to-beat normal R-R intervals from a 39-h electrocardiogram, on a 30-min basis. The HRV indices included frequency domain (HF, LF, and LF/HF ratio), and time domain (SDNN, RMSSD, and heart rate or HR) variables. Actigraphy was used for seven consecutive nights to estimate nightly sleep duration and time in bed. The seven-night mean (SD) of sleep duration and sleep efficiency were used to represent sleep duration, duration variability, sleep efficiency, and efficiency variability, respectively. HF and LF were log-transformed for statistical analysis. Linear mixed-effect models were used to analyze the association between sleep patterns and CAM. RESULTS: After adjusting for major confounders, increased sleep duration variability and efficiency variability were significantly associated with lower HRV and higher HR during the 39-h, as well as separated by daytime and nighttime. For instance, a 1 h increase in sleep duration variability is associated with -0.14(0.04), 0.12(0.06), and -0.16(0.05) ms(2) decrease in total, daytime, and nighttime HF, respectively. No associations were found between sleep duration, or sleep efficiency and HRV. CONCLUSION: Higher habitual sleep duration variability and efficiency variability are associated with lower HRV and higher HR, suggesting that an irregular sleep pattern has an adverse impact on CAM, even in healthy adolescents. PMID- 25555637 TI - Quality of life after adenotonsillectomy in children with obstructive sleep apnea: short-term and long-term results. AB - OBJECTIVE: To assess short-term and long-term changes in quality of life after adenotonsillectomy (T&A) in children with obstructive sleep apnea (OSA). MATERIALS AND METHODS: Children aged 2-18 years old were enrolled. All subjects had clinical symptoms, overnight polysomnography diagnosis of OSA, and received T&A as treatment. Caregivers were asked to complete the OSA-18 survey before surgery, within 6 months after surgery (short-term), and more than 6 months after surgery (long-term). RESULTS: A total of 114 children were included (mean age, 7.0+/-3.5 years; 75% boys). The mean OSA-18 total score was 71.5+/-16.0 before surgery. After surgery, the mean OSA-18 total score was significantly decreased in both the short-term (40.3+/-12.2, p<0.001) and the long-term (42.0+/-13.7, p<0.001). All five OSA-18 domains were also significantly decreased during short term and long-term postoperative follow up (p<0.001). Short-term and long-term outcomes were compared. Mean OSA-18 total scores, sleep disturbance score, emotional distress score, daytime function score, and caregiver concerns score did not differ significantly between the short-term and long-term periods, while the physical symptom score was slightly higher in the long-term than the short term period (9.7+/-3.3 vs. 8.7+/-3.0, p=0.02). Additionally, the physical symptoms score was higher in the long-term period in the female (p=0.01), older age (>6 years) (p=0.03), and non-obese (p=0.04) subgroups. CONCLUSION: T&A improves short-term and long-term quality of life in children with OSA. Nevertheless, caregivers observed children with aggravation of physical symptoms of quality of life during long-term follow up, especially in the female, older, and non-obese subgroups. PMID- 25555638 TI - Spontaneous recovery of bilateral congenital idiopathic laryngeal paralysis: systematic non-meta-analytical review. AB - OBJECTIVES: To systematically review the frequency and time to spontaneous recovery in pediatric patients with bilateral congenital idiopathic laryngeal paralysis (BCILP). METHODS: The databases of Medline, EMBASE, Scopus, CINAHL, Cochrane Library and Proquest Dissertations were searched for English language articles reporting on laryngeal paralysis in pediatric patients. A bibliography search of the selected studies was done to identify additional articles. We included prospective or retrospective case-series studies of children and neonates diagnosed with BCILP at age <60 days and confirmed by direct laryngoscopy, with sufficient follow up and objective assessment for recovery. Two authors independently extracted the data and assessed the quality of each study. Discrepancies were resolved by consensus and adjudication by a third author. RESULTS: Of the 4229 articles identified by the search, only one study met our inclusion criteria. The study was a retrospective case series, and was of low quality. The mean age at diagnosis was fourteen days. Sixty-five percent of the patients recovered spontaneously, and the mean time to recovery was twenty five months. Tracheostomy was performed in 71% of the patients. CONCLUSIONS: The available literature is of low quality and provides weak evidence on the natural history of BCILP in pediatric population. PMID- 25555639 TI - Apoptosis in chronic tonsillitis and tonsillar hypertrophy. AB - OBJECTIVE: Chronic tonsillitis is the persistent inflammation of the tonsillar tissue that occurs due to recurrent, acute or subclinical infection. The recurrent and chronic inflammation of palatine tonsils sometimes results in hypertrophy. Apoptosis provides an important balance between lymphocytes in tonsillar lymphoid tissue. The aim of this study is to investigate the apoptosis in tonsillar diseases. METHODS: 43 patients with chronic tonsilitis and tonsillar hypertrophy underwent tonsillectomy. The specimens were examined immunohistochemically for apoptosis. Tonsils were assembled into groups according to their size. Specimens were compared for their apoptotic cell count. RESULTS: The apoptosis difference between the tonsil size groups is not statistically significant (p>0.05). However, when the study group was divided into two at age 6, the difference was not statistically significant for patients at and below 6 years of age; but, the difference was statistically significant for patients above 6 years of age (p<0.05). The comparison of apoptosis in microcompartments of tonsil tissue (intrafollicular, interfollicular, subepithelial and intraepithelial) between tonsil size stages and between chronic tonsillitis and tonsillar hypertrophy groups revealed no statistical significance (p>0.05). There was a statistically significant positive correlation between intrafollicular and interfollicular, interfollicular and intraepithelial & subepithelial and intraepithelial areas (p<0.05). CONCLUSIONS: In the light of these findings, it was concluded that apoptosis played a role in the tonsillar hypertrophy and atrophy. Apoptosis functioned to balance lymphocyte proliferation in tonsil tissue. The association of apoptosis with tonsillar hypertrophy seemed to be age dependent. PMID- 25555640 TI - Etiological approach in patients with unidentified hearing loss. AB - OBJECTIVES: Etiological diagnosis of hearing impairment is of great importance to ensure early and adequate management. Even after thorough history taking, clinical and audiometric evaluation, the cause of hearing loss remains unclear in a majority of patients. Further examinations can imply imaging, ophthalmologic investigations, laboratory tests, electrocardiography and genetic testing. Lately, the latter has taken an increasingly prominent place within this diagnostic work-up. However, clear guidelines about optimal implementation and sequence of these tests are required. METHODS: Records of patients who visited the consultation for otogenetics at Ghent University Hospital (Belgium) during the period 2006-2012 were retrospectively reviewed. In order to optimize the etiological-diagnostic work-up of unidentified hearing loss, application patterns and results of various diagnostic tests, audiometric and etiological data of each patient were collected and analyzed. RESULTS: Data of 191 patients were analyzed. In 81.2% of the patients, a cause of hearing loss could be determined or suspected. In total, 65.4% had a (presumably) genetic etiology, with connexin 26 (GJB2) mutations as the leading cause. Inquiry of risk factors, associated with congenital hearing loss, and pedigree analysis were found to have the highest diagnostic gain (61.3% and 41.8%). Connexin 26 gene mutations were only present in bilateral hearing impairment, whereas CT abnormalities were related to unilateral (P=0.003), profound (P<0.001) hearing loss. An enlarged vestibular aqueduct was present in 42.9% of all CT abnormalities. Ophthalmologic anomalies were detected in 35.7% of the studied patients. CONCLUSIONS: A sequential approach for the etiological diagnosis of unidentified hearing loss could determine or suggest a cause in more than 80% of patients. The approach may vary based on the presenting phenotype. PMID- 25555641 TI - Finding mutation within non-coding region of GJB2 reveals its importance in genetic testing of hearing loss in Iranian population. AB - OBJECTIVE: Hereditary hearing loss is the most common neurosensory disorder in humans. Half of the cases have genetic etiology with extraordinary genetic heterogeneity. Mutations in one gene, GJB2, are the most common cause for autosomal recessive non-syndromic hearing loss (ARNSHL) in many different populations. GJB2 encodes a gap junction channel protein (connexin 26), and is located on DFNB1 locus on chromosome 13q12.11 which also involve another connexin gene, GJB6. Mutation screening of GJB2 revealed that a high number of patients with deaf phenotype have heterozygous genotype and carry only one mutant allele. As the first comprehensive study in Iran, we have targeted GJB2-related Iranian heterozygotes, looking for second mutant allele which leads to hearing impairment. They bear first mutation in their coding exon of GJB2. METHOD: Using PCR-based direct sequencing, we assessed 103 patients with ARNSHL for variants in non-coding exon and promoter region of this gene, for the first time in Iran. RESULT: We have identified the second mutant allele in splice site of exon-1 of GJB2 which is known as IVS1+1G>A in 17 probands. We found no mutation in promoter region of GJB2. CONCLUSION: Our findings reveal that IVS1+1G>A mutation in noncoding exon of GJB2 is the most common mutation after 35delG within multi ethnical Iranian heterozygote samples. It emphasizes to approach exon1 of GJB2 in case of ARNSHL genetic diagnosis. PMID- 25555642 TI - Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. AB - Genetic sequencing has become a critical part of the diagnosis of certain forms of pancreatic beta cell dysfunction. Despite great advances in the speed and cost of DNA sequencing, determining the pathogenicity of variants remains a challenge, and requires sharing of sequence and phenotypic data between laboratories. We reviewed all diabetes and hyperinsulinism-associated molecular testing done at the Seattle Children's Molecular Genetics Laboratory from 2009 to 2013. 331 probands were referred to us for molecular genetic sequencing for Neonatal Diabetes (NDM), Maturity-Onset Diabetes of the Young (MODY), or Congenital Hyperinsulinism (CHI) during this period. Reportable variants were identified in 115 (35%) patients with 91 variants in one of 6 genes: HNF1A, GCK, HNF4A, ABCC8, KCNJ11, or INS. In addition to identifying 23 novel variants, we identified unusual mechanisms of inheritance, including mosaic and digenic MODY presentations. Re-analysis of all reported variants using more recently available databases led to a change in variant interpretation from the original report in 30% of cases. These results represent a resource for molecular testing of monogenic forms of diabetes and hyperinsulinism, providing a mutation spectrum for these disorders in a large North American cohort. In addition, they highlight the importance of periodic review of molecular testing results. PMID- 25555643 TI - The relationship between 19th century BMIs and family size: Economies of scale and positive externalities. AB - The use of body mass index values (BMI) to measure living standards is now a well accepted method in economics. Nevertheless, a neglected area in historical studies is the relationship between 19th century BMI and family size, and this relationship is documented here to be positive. Material inequality and BMI are the subject of considerable debate, and there was a positive relationship between BMI and wealth and an inverse relationship with inequality. After controlling for family size and wealth, BMI values were related with occupations, and farmers and laborers had greater BMI values than workers in other occupations. PMID- 25555644 TI - Clinical postcards. PMID- 25555645 TI - [Breastfeeding preterm infants at 6 months in Morocco: prevalence and associated factors]. AB - PURPOSE: Evaluate the rate of breastfeeding at hospital discharge and then at 3 and 6 months in a population of premature infants. Analyze demographic and neonatal characteristics that may influence breastfeeding. METHOD: Prospective study in children born before 37 weeks of gestation from 1 June 2011 to 31 December 2011 hospitalized in the neonatology department at the Rabat children's hospital. The sociodemographic data and initial breastfeeding decision were collected from mothers. Newborns were reviewed in consultation at 1, 3, and 6 months to determine dietary habits. The association of variables with breastfeeding was analyzed by univariate and multivariate analysis using a logistic regression model. RESULTS: The analysis was based on 170 mother-infant pairs. At discharge, 80% of preterm infants received partial breastfeeding and 12.4% exclusive breastfeeding. At 6 months, 8.8% of mothers breastfed exclusively, 32.4% partially, and 58.8% had stopped breastfeeding. The factors associated with breastfeeding at 6 months were the duration of hospitalization in a neonatology unit and a neonatal intensive care unit, the time to first expressing breast milk, and breastfeeding. There was an inverse link between breastfeeding rates and duration of stay in neonatology in multivariate analysis with an odds ratio (OR) of 1.3 and a 95% confidence interval (1,1; 1,7); P=0.015. CONCLUSION: In our context, the rates of breastfeeding in premature infants remain below the recommended goals. The negative impact of the length of stay in the neonatal unit on breastfeeding is a challenge for health professionals who must adapt and strengthen the strategy of encouragement and support breastfeeding during the stay in neonatology and after discharge to ensure adequate nutrition for premature infants. PMID- 25555655 TI - Acute myocardial ischemia in adults secondary to missed Kawasaki disease in childhood. AB - Coronary artery aneurysms that occur in 25% of untreated Kawasaki disease (KD) patients may remain clinically silent for decades and then thrombose resulting in myocardial infarction. Although KD is now the most common cause of acquired heart disease in children in Asia, the United States, and Western Europe, the incidence of KD in Egypt is unknown. We tested the hypothesis that young adults in Egypt presenting with acute myocardial ischemia may have coronary artery lesions because of KD in childhood. We reviewed a total of 580 angiograms of patients <=40 years presenting with symptoms of myocardial ischemia. Coronary artery aneurysms were noted in 46 patients (7.9%), of whom 9 presented with myocardial infarction. The likelihood of antecedent KD as the cause of the aneurysms was classified as definite (n = 10), probable (n = 29), or equivocal (n = 7). Compared with the definite and probable groups, the equivocal group had more traditional cardiovascular risk factors, smaller sized aneurysms, and fewer coronary arteries affected. In conclusion, in a major metropolitan center in Egypt, 6.7% of adults aged <=40 years who underwent angiography for evaluation of possible myocardial ischemia had lesions consistent with antecedent KD. Because of the unique therapeutic challenges associated with these lesions, adult cardiologists should be aware that coronary artery aneurysms in young adults may be because of missed KD in childhood. PMID- 25555656 TI - Relation between paradoxical decrease in high-density lipoprotein cholesterol levels after statin therapy and adverse cardiovascular events in patients with acute myocardial infarction. AB - Statin therapy moderately increases high-density lipoprotein cholesterol (HDL-C) levels. Contrary to this expectation, a paradoxical decrease in HDL-C levels after statin therapy is seen in some patients. We evaluated 724 patients who newly started treatment with statins after acute myocardial infarction (AMI). These patients were divided into 2 groups according to change in HDL-C levels between baseline and 6 to 9 months after initial AMI (DeltaHDL). In total, 620 patients had increased HDL-C levels and 104 patients had decreased HDL-C levels. Both groups achieved follow-up low-density lipoprotein cholesterol levels <100 mg/dl. Adverse cardiovascular events (a composite of all-cause death, myocardial infarction, and stroke) have more frequently occurred in the decreased HDL group compared with the increased HDL group (15.4% vs 7.1%, p = 0.01). Multivariate analysis showed that decreased HDL, onset to balloon time, and multivessel disease were the independent predictors of adverse cardiovascular events (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.08 to 3.52; HR 1.05, 95% CI 1.01 to 1.09; and HR 2.08, 95% CI 1.22 to 3.56, respectively). In conclusion, a paradoxical decrease in serum HDL-C levels after statin therapy might be an independent predictor of long-term adverse cardiovascular events in patients with AMI. PMID- 25555658 TI - Noninvasive prenatal testing: the importance of pretest trisomy risk and posttest predictive values. PMID- 25555659 TI - Antibiotic prophylaxis for term or near-term premature rupture of membranes: metaanalysis of randomized trials. AB - OBJECTIVE: The objective of the study was to evaluate the efficacy of antibiotic prophylaxis in women with term or near-term premature rupture of membranes. STUDY DESIGN: Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, ScienceDirect.com, MEDSCAPE, and the Cochrane Central Register of Controlled Trials with the use of a combination of key words and text words related to antibiotics, premature rupture of membranes, term, and trials from inception of each database to September 2014. We included all randomized trials of singleton gestations with premature rupture of membranes at 36 weeks or more, who were randomized to antibiotic prophylaxis or control (either placebo or no treatment). The primary outcomes included maternal chorioamnionitis and neonatal sepsis. A subgroup analysis on studies with latency more than 12 hours was planned. Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration number CRD42014013928). The metaanalysis was performed following the Preferred Reporting Item for Systematic Reviews and Meta-analyses statement. RESULTS: Women who received antibiotics had the same rate of chorioamnionitis (2.7% vs 3.7%; relative risk [RR], 0.73, 95% confidence interval [CI], 0.48-1.12), endometritis (0.4% vs 0.9%; RR, 0.44, 95% CI, 0.18-1.10), maternal infection (3.1% vs 4.6%; RR, 0.48, 95% CI, 0.19-1.21), and neonatal sepsis (1.0% vs 1.4%; RR, 0.69, 95% CI, 0.34-1.39). In the planned subgroup analysis, women with latency longer than 12 hours, who received antibiotics, had a lower rate of chorioamnionitis (2.9% vs 6.1%; RR, 0.49, 95% CI, 0.27-0.91) and endometritis (0% vs 2.2%; RR, 0.12, 95% CI, 0.02 0.62) compared with the control group. CONCLUSION: Antibiotic prophylaxis for term or near-term premature rupture of membranes is not associated with any benefits in either maternal or neonatal outcomes. In women with latency longer than 12 hours, prophylactic antibiotics are associated with significantly lower rates of chorioamnionitis by 51% and endometritis by 88%. PMID- 25555657 TI - Murine model: maternal administration of stem cells for prevention of prematurity. AB - OBJECTIVE: Using a mouse model of intrauterine inflammation, we have demonstrated that exposure to inflammation induces preterm birth and perinatal brain injury. Mesenchymal stem cells (MSCs) have been shown to exhibit immunomodulatory effects in many inflammatory conditions. We hypothesized that treatment with human adipose tissue-derived MSCs may decrease the rate of preterm birth and perinatal brain injury through changes in antiinflammatory and regulatory milieu. STUDY DESIGN: A mouse model of intrauterine inflammation was used with the following groups: (1) control; (2) intrauterine inflammation (lipopolysaccharide); and (3) intrauterine lipopolysaccharide+intraperitoneal (MSCs). Preterm birth was investigated. Luminex multiplex enzyme-linked immunosorbent assays were performed for protein levels of cytokines in maternal and fetal compartments. Immunofluorescent staining was used to identify and localize MSCs and to examine microglial morphologic condition and neurotoxicity in perinatal brain. Behavioral testing was performed at postnatal day 5. RESULTS: Pretreatment with MSCs significantly decreased the rate of preterm birth by 21% compared with the lipopolysaccharide group (P<.01). Pretreatment was associated with increased interleukin-10 in maternal serum, increased interleukin-4 in placenta, decreased interleukin-6 in fetal brain (P<.05), decreased microglial activation (P<.05), and decreased fetal neurotoxicity (P<.05). These findings were associated with improved neurobehavioral testing at postnatal day 5 (P<.05). Injected MSCs were localized to placenta. CONCLUSION: Maternally administered MSCs appear to modulate maternal and fetal immune response to intrauterine inflammation in the model and decrease preterm birth, perinatal brain injury, and motor deficits in offspring mice. PMID- 25555660 TI - Current practices in the prediction and prevention of preterm birth in patients with higher-order multiple gestations. AB - OBJECTIVE: We sought to determine the interventions utilized by maternal-fetal medicine specialists in the prediction and prevention of preterm labor in higher order multiple (HOM) gestations. STUDY DESIGN: Online questionnaires and email surveys were sent to all the maternal-fetal medicine specialists in Canada (n=122). Questionnaire items included interventions physicians routinely recommended for HOM gestations including: (1) bed rest; (2) cervical length measurement on transvaginal ultrasound; (3) corticosteroids use; (4) cerclage; and (5) tocolytic therapy. RESULTS: Response rate was 66% (81/122), with 68% of respondents in practice for >10 years. Of physicians, 91% did not routinely recommend bed rest (95% confidence interval [CI], 84.7-97.2). In all, 82% (95% CI, 73.63-90.4%) recommended routine cervical length assessment with 32.3% (95% CI, 20.7-43.2) and 37.1% (95% CI, 25.3-48.6) of this group suggesting assessment at 16-18 and 19-21 weeks, respectively. Frequency of assessment varied from biweekly (53.3%; 95% CI, 40.9-65.0), to monthly (23.3%; 95% CI, 12.8-33.1), to a single measurement repeated only if abnormal (12.5%; 95% CI, 4.5-20.8). In all, 28% (95% CI, 18.2-37.8) recommended routine administration of corticosteroids for lung maturation. Timing of administration varied, with 24% initiating steroids between 24-26 weeks, 59% between 27-28 weeks, and 17% after 28 weeks. None reported routine cerclage placement. However, 71% (95% CI, 61.1-80.8) would perform cerclage based on history or ultrasound. Of respondents, 81% (95% CI, 72.4-89.5) would consider using tocolytic agents for threatened preterm labor including calcium channel blockers (94%), nonsteroidal antiinflammatory drugs (5%), and nitroglycerin transdermal patch (24%). CONCLUSION: The variable practice guidelines and paucity of data for management of HOM pregnancy places the onus on individual practitioners to develop their own management schemes. This results in heterogeneous management, which is based on conflicting international guidelines, studies, expert opinion, or past experience. PMID- 25555661 TI - Getting to safer and smarter medication use during pregnancy. PMID- 25555662 TI - Complications and continuation rates associated with 2 types of long-acting contraception. AB - OBJECTIVE: We sought to compare complication and continuation rates of the levonorgestrel intrauterine system (LNG-IUS) with the subdermal etonogestrel (ENG) implant across the United States among girls and women 15-44 years of age. STUDY DESIGN: A retrospective study of health insurance claims records from 2007 through 2011 identified a cohort of women who had LNG-IUS (n = 79,920) or ENG implants (n = 7374) inserted and had insurance coverage for 12 months postinsertion. Claims for complications were examined 12 months after insertion, or until removal of either device within each of 3 age groups. RESULTS: After its introduction in 2007, the frequency of ENG implants increased each year and almost a third of all insertions were in teenagers. However, among women <=24 years old who had delivered an infant in the prior 8 weeks, a LNG-IUS was more likely to be inserted than an ENG implant (P < .05). The most frequent complications with both methods were related to abnormal menstruation, which was more likely to occur among ENG implant users. Overall, 83-88% of the entire sample used their chosen method for at least 12 months. The odds of continuation were similar for both methods among teenagers, but ENG implants were more likely to be removed prematurely among women 20-24 years old (odds ratio, 1.21; 95% confidence interval, 1.06-1.39) and 25-44 years old (odds ratio, 1.49; 95% confidence interval, 1.35-1.64). CONCLUSION: Both of these long-acting contraceptive methods are well tolerated among women of all ages, and demonstrate high continuation rates. PMID- 25555663 TI - Food waste-to-energy conversion technologies: current status and future directions. AB - Food waste represents a significantly fraction of municipal solid waste. Proper management and recycling of huge volumes of food waste are required to reduce its environmental burdens and to minimize risks to human health. Food waste is indeed an untapped resource with great potential for energy production. Utilization of food waste for energy conversion currently represents a challenge due to various reasons. These include its inherent heterogeneously variable compositions, high moisture contents and low calorific value, which constitute an impediment for the development of robust, large scale, and efficient industrial processes. Although a considerable amount of research has been carried out on the conversion of food waste to renewable energy, there is a lack of comprehensive and systematic reviews of the published literature. The present review synthesizes the current knowledge available in the use of technologies for food-waste-to-energy conversion involving biological (e.g. anaerobic digestion and fermentation), thermal and thermochemical technologies (e.g. incineration, pyrolysis, gasification and hydrothermal oxidation). The competitive advantages of these technologies as well as the challenges associated with them are discussed. In addition, the future directions for more effective utilization of food waste for renewable energy generation are suggested from an interdisciplinary perspective. PMID- 25555664 TI - Leaching characteristics of toxic constituents from coal fly ash mixed soils under the influence of pH. AB - Leaching behaviors of Arsenic (As), Barium (Ba), Calcium (Ca), Cadmium (Cd), Magnesium (Mg), Selenium (Se), and Strontium (Sr) from soil alone, coal fly ash alone, and soil-coal fly ash mixtures, were studied at a pH range of 2-14 via pH dependent leaching tests. Seven different types of soils and coal fly ashes were tested. Results of this study indicated that Ca, Cd, Mg, and Sr showed cationic leaching pattern while As and Se generally follows an oxyanionic leaching pattern. On the other hand, leaching of Ba presented amphoteric-like leaching pattern but less pH-dependent. In spite of different types and composition of soil and coal fly ash investigated, the study reveals the similarity in leaching behavior as a function of pH for a given element from soil, coal fly ash, and soil-coal fly ash mixtures. The similarity is most likely due to similar controlling mechanisms (e.g., solubility, sorption, and solid-solution formation) and similar controlling factors (e.g., leachate pH and redox conditions). This offers the opportunity to transfer knowledge of coal fly ash that has been extensively characterized and studied to soil stabilized with coal fly ash. It is speculated that unburned carbon in off-specification coal fly ashes may provide sorption sites for Cd resulting in a reduction in concentration of these elements in leachate from soil-coal fly ash mixture. Class C fly ash provides sufficient CaO to initiate the pozzolanic reaction yielding hydrated cement products that oxyanions, including As and Se, can be incorporated into. PMID- 25555669 TI - Thioredoxin-like protein 2b facilitates colon cancer cell proliferation and inhibits apoptosis via NF-kappaB pathway. AB - Our previous work identified thioredoxin-like protein 2 (Txl-2), a novel thioredoxin family member, as the target of the monoclonal antibody MC3 which can detect colon cancer with high sensitivity and specificity. In the present study, the function of the most abundant isoform Txl-2b in cell proliferation and apoptosis was investigated. Txl-2 overexpression correlated with increased clinical stages. Inhibition of Txl-2b suppressed cell proliferation, induced cell cycle arrest at the G1/S phase, and led to responsiveness to the vincristine induced apoptosis in SW620 cells. Txl-2b overexpression in LoVo cells had the opposite effect, which was dependent on Trx domain function. In vivo studies validated that Txl-2b expression promoted colon cancer tumorigenesis in nude mice. Further studies revealed that nuclear factor-kappaB (NF-kappaB) signaling was activated by Txl-2b. Inhibition of NF-kappaB activation partly abrogated the pro-proliferation and anti-apoptotic phenotypes mediated by Txl-2b via reduced Cyclin D1, Bcl-2, Bcl-xL and Survivin expression and increased Caspase-3 activation. Overall, our results indicate that Txl-2b expression stimulates cancer cell proliferation, accelerates the cell cycle and contributes to apoptosis resistance in colon cancer and provides a potential therapeutic target for colon cancer treatment. PMID- 25555670 TI - Thioredoxin is a novel diagnostic and prognostic marker in patients with ischemic stroke. AB - Serum thioredoxin (TRX), a redox-regulating protein with antioxidant activity, was recognized as an oxidative-stress marker. The purpose of this study was to investigate the potential diagnostic and prognostic role of TRX in Chinese patients with acute ischemic stroke (AIS). From January 1, 2012, to December 31, 2013, all patients with first-ever acute ischemic stroke were recruited to participate in the study. Serum levels of TRX were assayed with solid-phase sandwich ELISA, and severity of stroke was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score on admission. Short-term functional outcome was measured by a modified Rankin scale (mRS) 3 months after admission. Multivariate analyses were performed using logistic regression models. We found the serum TRX reflected the disease severity of AIS. There was a significant positive association between serum TRX levels and NIHSS scores (r= 0.476, P<0.0001). Based on the ROC curve, the optimal cutoff value of serum TRX levels as an indicator for auxiliary diagnosis of AIS was projected to be 11.0 ng/ml, which yielded a sensitivity of 80.3% and a specificity of 73.7%, with the area under the curve at 0.807 (95% CI, 0.766-0.847). Elevated TRX (>= 20.0 ng/ml) was an independent prognostic marker of short-term functional outcome [odds ratio (OR) 9.482 (95% CI, 3.11-8.15) P<0.0001; adjusted for NIHSS, other predictors and vascular risk factors] in patients with AIS. TRX improved the area under the receiver operating characteristic curve of the NHISS score for functional outcome from 0.722 (95% CI, 0.662-0.782) to 0.905 (95% CI, 0.828-0.962; P<0.0001). Our study demonstrated that elevated serum TRX level at admission was a novel diagnostic and prognostic marker in patients with acute ischemic stroke. PMID- 25555671 TI - Insights into the mechanism of the reaction between hydrogen sulfide and peroxynitrite. AB - Hydrogen sulfide and peroxynitrite are endogenously generated molecules that participate in biologically relevant pathways. A revision of the kinetic features of the reaction between peroxynitrite and hydrogen sulfide revealed a complex process. The rate constant of peroxynitrite decay, (6.65 +/- 0.08) * 10(3) M(-1) s(-1) in 0.05 M sodium phosphate buffer (pH 7.4, 37 degrees C), was affected by the concentration of buffer. Theoretical modeling suggested that, as in the case of thiols, the reaction is initiated by the nucleophilic attack of HS(-) on the peroxide group of ONOOH by a typical bimolecular nucleophilic substitution, yielding HSOH and NO2(-). In contrast to thiols, the reaction then proceeds to the formation of distinct products that absorb near 408 nm. Experiments in the presence of scavengers and carbon dioxide showed that free radicals are unlikely to be involved in the formation of these products. The results are consistent with product formation involving the reactive intermediate HSSH and its fast reaction with a second peroxynitrite molecule. Mass spectrometry and UV-Vis absorption spectra predictions suggest that at least one of the products is HSNO2 or its isomer HSONO. PMID- 25555672 TI - An experimental model for training in renal transplantation surgery with human cadavers preserved using W. Thiel's embalming technique. AB - OBJECTIVE: To describe a novel cadaver-based model for practicing renal transplant (RT) surgery. DESIGN: A simulating model using cadavers preserved by Thiel's method is developed to teach surgical anatomy and operative skills in RT surgery. Participants were asked to complete a voluntary, anonymous survey evaluating perceptions of the model and comparing cadaver sessions to other types of learning (rating questions from 0-10). SETTING: Large university teaching hospital. PARTICIPANTS: A total of 28 residents, junior transplant surgeons, and faculty members were participants in the cadaver simulation. RESULTS: Overall, 9 cadavers were used with 17 grafts transplanted. Kidney procurement in human cadavers preserved using Thiel's embalming technique was performed following the conventional protocol; en bloc nephrectomy with the trunk of aorta and inferior vena cava. Bench surgery was performed, perfusing artery with saline and checking vascular permeability. Once suitability is established, RT was performed as is done in clinical practice. This embalming method enables tissue dissection that is comparable to the living body and provides suitable conditions for realistic RT simulation; handling human tissues and vessels in the same surgical field as the clinical scenario. This experimental model approximates to in vivo RT, providing a realistic and interesting learning to inexperienced surgeons. Overall, participants held a positive view of the cadaver sessions, believed them to be useful in their daily practice, and felt that the proposed model was similar to the clinical setting. Trainees believed that these practices improved skills and confidence in performing an RT. CONCLUSIONS: The proposed method of kidney procurement and RT in human cadavers preserved by Thiel's embalming technique is a promising, realistic, and reproducible method of practicing RT surgery. PMID- 25555673 TI - Porcine cadaver organ or virtual-reality simulation training for laparoscopic cholecystectomy: a randomized, controlled trial. AB - OBJECTIVES: As conventional laparoscopic procedural training requires live animals or cadaver organs, virtual simulation seems an attractive alternative. Therefore, we compared the transfer of training for the laparoscopic cholecystectomy from porcine cadaver organs vs virtual simulation to surgery in a live animal model in a prospective randomized trial. DESIGN: After completing an intensive training in basic laparoscopic skills, 3 groups of 10 participants proceeded with no additional training (control group), 5 hours of cholecystectomy training on cadaver organs (= organ training) or proficiency-based cholecystectomy training on the LapMentor (= virtual-reality training). Participants were evaluated on time and quality during a laparoscopic cholecystectomy on a live anaesthetized pig at baseline, 1 week (= post) and 4 months (= retention) after training. SETTING: All research was performed in the Center for Surgical Technologies, Leuven, Belgium. PARTICIPANTS: In total, 30 volunteering medical students without prior experience in laparoscopy or minimally invasive surgery from the University of Leuven (Belgium). RESULTS: The organ training group performed the procedure significantly faster than the virtual trainer and borderline significantly faster than control group at posttesting. Only 1 of 3 expert raters suggested significantly better quality of performance of the organ training group compared with both the other groups at posttesting (p < 0.01). There were no significant differences between groups at retention testing. The virtual trainer group did not outperform the control group at any time. CONCLUSIONS: For trainees who are proficient in basic laparoscopic skills, the long-term advantage of additional procedural training, especially on a virtual but also on the conventional organ training model, remains to be proven. PMID- 25555674 TI - Ophiocordyceps myrmicarum, a new species infecting invasive Myrmica rubra in Maine. AB - Myrmica rubra L. (Formicidae: Hymenoptera), an invasive ant species in Maine, has been problematic in coastal communities over the past 15years and the subject of studies on its ecology, effects, and management. In recent years we observed a fungus growing from moribund M. rubra (in vitro) and have isolated multiple cultures of this previously unreported fungus over 2 y. We analyzed morphology and DNA molecular sequences of this fungus and identified it as a member of the genus Hirsutella Pat. (Ophiocordycipitaceae; Hypocreales), the use of which is suppressed in favor of a monophyletic Ophiocordyceps clade. Molecular and morphological characters support the description of this fungus as a new species, O. myrmicarum, which is the first species in this genus to be isolated from North American M. rubra. PMID- 25555675 TI - Assays to monitor aggrephagy. AB - The presence of ubiquitinated protein inclusions is a hallmark of most adult onset neurodegenerative disorders. Results from several neurodegenerative model systems indicate that elimination of the disease-associated inclusions can lead to symptomatic reversal, and a better understanding of the mechanisms involved in accumulation and turnover of aggregation-prone proteins is therefore important. Autophagy has been found to contribute to protein aggregate clearance, and the term aggrephagy is used to describe the selective degradation of aggregation prone proteins by autophagy. Here, we provide an overview of different disease related model systems and assays that can be used to distinguish non-aggregated from aggregation-prone proteins, and how these assays can be used to determine turnover of protein aggregates by autophagy. PMID- 25555676 TI - Obstructive sleep apnoea in children with craniofacial syndromes. AB - Obstructive sleep apnoea syndrome (OSAS) is common in children. Craniofacial anomalies such as cleft palate are among the most common congenital conditions. Children with a variety of craniofacial conditions, including cleft palate, micrognathia, craniosynostosis, and midface hypoplasia are at increased risk for OSAS. Available evidence, which is largely limited to surgical case series and retrospective studies, suggests that OSAS can be successfully managed in these children through both surgical and non-surgical techniques. Prospective studies using larger cohorts of patients and including polysomnograms are needed to better understand the risk factors for this patient population and the efficacy of treatment options for OSAS and their underlying conditions. PMID- 25555677 TI - Cognitive frailty, a novel target for the prevention of elderly dependency. AB - Frailty is a complex and heterogeneous clinical syndrome. Cognitive frailty has been considered as a subtype of frailty. In this study, we refine the definition of cognitive frailty based on existing reports about frailty and the latest progress in cognition research. We obtain evidence from the literature regarding the role of pre-physical frailty in pathological aging. We propose that cognitive impairment of cognitive frailty results from physical or pre-physical frailty and comprises two subtypes: the reversible and the potentially reversible. Reversible cognitive impairment is indicated by subjective cognitive decline (SCD) and/or positive fluid and imaging biomarkers of amyloid-beta accumulation and neurodegeneration. Potentially reversible cognitive impairment is MCI (CDR=0.5). Based on the severity of cognitive impairment, it is possible to determine the primary and secondary preventative measures for cognitive frailty. We further determine whether SCD is a component of pre-clinical AD or the early stage of other neurodegenerative diseases, which is required for guiding personal clinical intervention. PMID- 25555679 TI - RecQ helicases and PARP1 team up in maintaining genome integrity. AB - Genome instability represents a primary hallmark of aging and cancer. RecQL helicases (i.e., RECQL1, WRN, BLM, RECQL4, RECQL5) as well as poly(ADP-ribose) polymerases (PARPs, in particular PARP1) represent two central quality control systems to preserve genome integrity in mammalian cells. Consistently, both enzymatic families have been linked to mechanisms of aging and carcinogenesis in mice and humans. This is in accordance with clinical and epidemiological findings demonstrating that defects in three RecQL helicases, i.e., WRN, BLM, RECQL4, are related to human progeroid and cancer predisposition syndromes, i.e., Werner, Bloom, and Rothmund Thomson syndrome, respectively. Moreover, PARP1 hypomorphy is associated with a higher risk for certain types of cancer. On a molecular level, RecQL helicases and PARP1 are involved in the control of DNA repair, telomere maintenance, and replicative stress. Notably, over the last decade, it became apparent that all five RecQL helicases physically or functionally interact with PARP1 and/or its enzymatic product poly(ADP-ribose) (PAR). Furthermore, a profound body of evidence revealed that the cooperative function of RECQLs and PARP1 represents an important factor for maintaining genome integrity. In this review, we summarize the status quo of this molecular cooperation and discuss open questions that provide a basis for future studies to dissect the cooperative functions of RecQL helicases and PARP1 in aging and carcinogenesis. PMID- 25555680 TI - Protein synthesis as an integral quality control mechanism during ageing. AB - Ageing is manifested as functional and structural deterioration that affects cell and tissue physiology. mRNA translation is a central cellular process, supplying cells with newly synthesized proteins. Accumulating evidence suggests that alterations in protein synthesis are not merely a corollary but rather a critical factor for the progression of ageing. Here, we survey protein synthesis regulatory mechanisms and focus on the pre-translational regulation of the process exerted by non-coding RNA species, RNA binding proteins and alterations of intrinsic RNA properties. In addition, we discuss the tight relationship between mRNA translation and two central pathways that modulate ageing, namely the insulin/IGF-1 and TOR signalling cascades. A thorough understanding of the complex interplay between protein synthesis regulation and ageing will provide critical insights into the pathogenesis of age-related disorders, associated with impaired proteostasis and protein quality control. PMID- 25555678 TI - Mitochondria to nucleus signaling and the role of ceramide in its integration into the suite of cell quality control processes during aging. AB - Mitochondria to nucleus signaling has been the most extensively studied mode of inter-organelle communication. The first signaling pathway in this category of information transfer to be discovered was the retrograde response, with its own set of signal transduction proteins. The finding that this pathway compensates for mitochondrial dysfunction to extend the replicative lifespan of yeast cells has generated additional impetus for its study. This research has demonstrated crosstalk between the retrograde response and the target of rapamycin (TOR), small GTPase RAS, and high-osmolarity glycerol (HOG) pathways in yeast, all of which are key players in replicative lifespan. More recently, the retrograde response has been implicated in the diauxic shift and survival in stationary phase, extending its operation to the yeast chronological lifespan as well. In this capacity, the retrograde response may cooperate with other, related mitochondria to nucleus signaling pathways. Counterparts of the retrograde response are found in the roundworm, the fruit fly, the mouse, and even in human cells in tissue culture. The exciting realization that the retrograde response is embedded in the network of cellular quality control processes has emerged over the past few years. Most strikingly, it is closely integrated with autophagy and the selective brand of this quality control process, mitophagy. This coordination depends on TOR, and it engages ceramide/sphingolipid signaling. The yeast LAG1 ceramide synthase gene was the first longevity gene cloned as such, and its orthologs hyl-1 and hyl-2 determine worm lifespan. Thus, the involvement of ceramide signaling in quality control gives these findings cellular context. The retrograde response and ceramide are essential components of a lifespan maintenance process that likely evolved as a cytoprotective mechanism to defend the organism from diverse stressors. PMID- 25555681 TI - Expression of (pro)renin receptor and its upregulation by high salt intake in the rat nephron. AB - A functional receptor for renin and prorenin ((P)RR) was identified as a new component of the renin-angiotensin system. The precise localization of (P)RR in the kidney has not been clarified. The present study was designed to determine the localization of (P)RR in the rat nephron and to investigate the regulation of renal (P)RR expression by high salt (HS) intake. (P)RR mRNA levels in the kidney sections and isolated nephron segments were examined using reverse transcription and polymerase chain reaction (RT-PCR), and (P)RR protein levels were examined by immunoblot and immunohistochemical analyses. Renal (P)RR mRNA and protein levels in rats fed a HS diet for 4 weeks were also compared with those fed a normal salt diet. (P)RR mRNA was expressed in various nephron segments of the cortex and medulla; glomeruli (Glm), proximal tubules (PT), thick ascending limbs (TAL) and collecting ducts (CD). (P)RR protein was highly expressed in the PT, medullary TAL (MTAL) and inner medullary CD (IMCD), and lowly in the preglomerular arterioles (Art) and Glm. HS intake increased (P)RR protein levels in the Glm, PT and tubules of medullary rays. These results indicated that (P)RR is expressed throughout various nephron segments and Art, and that (P)RR protein is expressed predominantly in the PT, MTAL and IMCD. HS intake appears to upregulate the (P)RR expression in the Glm, PT and tubules of medullary rays, suggesting that (P)RR may be involved in the regulation of renal function and HS-induced disorders. PMID- 25555682 TI - Application of a cDNA microarray for profiling the gene expression of Echinococcus granulosus protoscoleces treated with albendazole and artemisinin. AB - Cystic echinoccocosis (CE) is a neglected zoonosis that is caused by the dog tapeworm Echinococcus granulosus. The disease is endemic worldwide. There is an urgent need for searching effective drug for the treatment of the disease. In this study, we sequenced a cDNA library constructed using RNA isolated from oncospheres, protoscoleces, cyst membrane and adult worms of E. granulosus. A total of 9065 non-redundant or unique sequences were obtained and spotted on chips as uniEST probes to profile the gene expression in protoscoleces of E. granulosus treated with the anthelmintic drugs albendazole and artemisinin, respectively. The results showed that 7 genes were up-regulated and 38 genes were down-regulated in the protoscoleces treated with albendazole. Gene analysis showed that these genes are responsible for energy metabolism, cell cycle and assembly of cell structure. We also identified 100 genes up-regulated and 6 genes down-regulated in the protoscoleces treated with artemisinin. These genes play roles in the transduction of environmental signals, and metabolism. Albendazole appeared its drug efficacy in damaging cell structure, while artemisinin was observed to increase the formation of the heterochromatin in protoscolex cells. Our results highlight the utility of using cDNA microarray methods to detect gene expression profiles of E. granulosus and, in particular, to understand the pharmacologic mechanism of anti-echinococcosis drugs. PMID- 25555683 TI - Calcium binding proteins and calcium signaling in prokaryotes. AB - With the continued increase of genomic information and computational analyses during the recent years, the number of newly discovered calcium binding proteins (CaBPs) in prokaryotic organisms has increased dramatically. These proteins contain sequences that closely resemble a variety of eukaryotic calcium (Ca(2+)) binding motifs including the canonical and pseudo EF-hand motifs, Ca(2+)-binding beta-roll, Greek key motif and a novel putative Ca(2+)-binding domain, called the Big domain. Prokaryotic CaBPs have been implicated in diverse cellular activities such as division, development, motility, homeostasis, stress response, secretion, transport, signaling and host-pathogen interactions. However, the majority of these proteins are hypothetical, and only few of them have been studied functionally. The finding of many diverse CaBPs in prokaryotic genomes opens an exciting area of research to explore and define the role of Ca(2+) in organisms other than eukaryotes. This review presents the most recent developments in the field of CaBPs and novel advancements in the role of Ca(2+) in prokaryotes. PMID- 25555685 TI - Recent developments in biocatalysis beyond the laboratory. AB - Recent developments in biocatalysis, where implementation beyond the laboratory has been demonstrated, are explored: the use of transglutaminases to modify foods, reduce allergenicity and produce advanced materials, lipases for biodiesel production, and transaminases for biochemical production. The availability and application of enzymes at pilot and larger scale opens up possibilities for further improvements of biocatalyst-based processes and the development of new processes. Enzyme production, stability, activity, re-use, and product retrieval are common challenges for biocatalytic processes. We explore recent advances in biocatalysis within the process chain, such as protein engineering, enzyme expression, and biocatalyst immobilization, in the context of these challenges. PMID- 25555684 TI - Inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum: A single channel point of view. AB - As an intracellular Ca(2+) release channel at the endoplasmic reticulum membrane, the ubiquitous inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) plays a crucial role in the generation, propagation and regulation of intracellular Ca(2+) signals that regulate numerous physiological and pathophysiological processes. This review provides a concise account of the fundamental single channel properties of the InsP3R channel: its conductance properties and its regulation by InsP3 and Ca(2+), its physiological ligands, studied using nuclear patch clamp electrophysiology. PMID- 25555686 TI - Propensity score studies are unlikely to underestimate treatment effects in critical care medicine: a critical reanalysis. PMID- 25555687 TI - Pandemic preparedness with live attenuated influenza vaccines based on A/Leningrad/134/17/57 master donor virus. AB - Continuously evolving avian influenza viruses pose a constant threat to the human public health. In response to this threat, a number of pandemic vaccine candidates have been prepared and evaluated in animal models and clinical trials. This review summarizes the data from the development and preclinical and clinical evaluation of pandemic live attenuated influenza vaccines (LAIV) based on Russian master donor virus A/Leningrad/134/17/57. LAIV candidates of H5N1, H5N2, H7N3, H1N1 and H2N2 subtypes were safe, immunogenic and protected animals from challenge with homologous and heterologous viruses. Clinical trials of the pandemic LAIVs demonstrated their safety and immunogenicity for healthy adult volunteers. The vaccine viruses were infectious, genetically stable and did not transmit to unvaccinated contacts. In addition, here we discuss criteria for the assessment of pandemic LAIV immunogenicity and efficacy necessary for their licensure. PMID- 25555689 TI - Critical incident stress management: the whole team. PMID- 25555690 TI - Identifying domestic violence victims--it's our job. PMID- 25555688 TI - Characterization of mariner-like transposons of the mauritiana Subfamily in seven tree aphid species. AB - Mariner-like elements (MLEs) are Class II transposons present in all eukaryotic genomes in which MLEs have been searched for. This article reports the detection of MLEs in seven of the main fruit tree aphid species out of eight species studied. Deleted MLE sequences of 916-919 bp were characterized, using the terminal-inverted repeats (TIRs) of mariner elements belonging to the mauritiana Subfamily as primers. All the sequences detected were deleted copies of full length elements that included the 3'- and 5'-TIRs but displayed internal deletions affecting Mos1 activity. Networks based on the mtDNA cytochrome oxidase subunit-I (CO-I) and MLE sequences were incongruent, suggesting that mutations in transposon sequences had accumulated before speciation of tree aphid species occurred, and that they have been maintained in this species via vertical transmissions. This is the first evidence of the widespread occurrence of MLEs in aphids. PMID- 25555691 TI - Joys of cAMP nursing. PMID- 25555692 TI - Compression dressings to stop digital bleeding: a cautionary note. PMID- 25555693 TI - Pregnant with H1N1 Influenza. PMID- 25555694 TI - Leadership's role in eliminating workplace violence and changing perceptions in the emergency department. PMID- 25555695 TI - Response. PMID- 25555696 TI - September special disaster issue. PMID- 25555698 TI - Long-term care facilities--just the facts: part two. PMID- 25555699 TI - Research as problem solving: theoretical frameworks as tools. PMID- 25555700 TI - Strangulation: know the symptoms, save a life. PMID- 25555702 TI - A kinetic study of textile dyeing wastewater degradation by Penicillium chrysogenum. AB - The potential of Penicillium chrysogenum to decolorize azo dyes and a real industrial textile wastewater was studied. P. chrysogenum was able to decolorize and degrade three azo dyes (200 mg L(-1)), either independently or in a mixture of them, using glucose as a carbon source. A kinetic model for degradation was developed and it allowed predicting the degradation kinetics of the mixture of the three azo dyes. In addition, P. chrysogenum was able to decolorize real industrial wastewater. The kinetic model proposed was also able to predict the decolorization of the real wastewater. The calibration of the proposed model makes it a useful tool for future wastewater facilities' design and for practical applications. PMID- 25555703 TI - Microparticle-enhanced Aspergillus ficuum phytase production and evaluation of fungal morphology in submerged fermentation. AB - Phytase can be used in animal's diets to increase the absorption of several divalent ions, amino acids and proteins and to decrease the excessive phosphorus release in manure to prevent negative effects on the environment. This study aimed to enhance the current submerged fungal phytase productions with a novel fermentation technique by evaluating the effect of the various microparticles on Aspergillus ficuum phytase production. It was observed that microparticles prevented bulk fungal pellet growth, decreased average fungal pellet size and significantly increased phytase activity in the submerged fermentation. Microbial structure imaging results showed that the average fungal pellet radius decreased from 800 to 500 and 200 um by addition of 15 g/L aluminum oxide and talcum, respectively, in shake-flask fermentation. Also, addition of 15 g/L of talcum and aluminum oxide increased phytase activity to 2.01 and 2.93 U/ml, respectively, compared to control (1.02 U/ml) in shake-flask fermentation. Additionally, phytase activity reached 6.49 U/ml within 96 h of fermentation with the addition of 15 g/L of talcum, whereas the maximum phytase activity was only 3.45 U/ml at 120 h of fermentation for the control in the 1-L working volume bioreactors. In conclusion, microparticles significantly increased fungal phytase activity and production yield compared to control fermentation. PMID- 25555704 TI - Significance of corneal biomechanical properties in patients with progressive normal-tension glaucoma. AB - AIM: To investigate the clinical significance of corneal biomechanical properties assessed using an ocular response analyser in patients with progressing normal tension glaucoma (NTG). METHODS: In this retrospective study, we included 82 eyes of 82 NTG patients who had been receiving topical anti-glaucoma medications. Patients were allocated to two groups based on the mean value of corneal hysteresis (CH) and the status of progression. The assessment of progression was based on the trend analysis using mean deviation slope. Uni- and multivariable logistic analyses were constructed to identify factors associated with increased odds of progression, including CH, central corneal thickness (CCT), and retinal nerve fibre layer (RNFL) thickness. RESULTS: Forty-six eyes (56.1%) reached the progression criteria. Eyes with progression had lower CCT (530.2+/-38.6 vs 549.4+/-38.3 MUm, p=0.03), thinner average RNFL thickness (70.6+/-16.1 vs 82.8+/ 17.4 MUm, p<0.01), lower CH (9.4+/-1.3 vs 10.8+/-1.4 mm Hg, p<0.01), and lower corneal resistance factor (9.3+/-1.3 vs 10.4+/-1.8 mm Hg, p<0.01) than eyes without progression. CH and CCT were significantly correlated (r=0.44, p<0.01). Upon multivariable analysis, CH (beta (B)=0.32 per mm Hg lower, p<0.01) and average RNFL thickness (beta=0.96 per MUm lower, p=0.04) remained statistically significant. CONCLUSIONS: Corneal biomechanical properties are correlated and associated with the progression of visual field damage in NTG patients. These findings suggest that CH can be used as one of the prognostic factors for progression, independent of corneal thickness or intraocular pressure. PMID- 25555705 TI - Introduction to special issue in honor of Michael D. Norenberg: a pathologist who incorporated glutamine to the astrocytic-neuronal crosstalk. PMID- 25555707 TI - SIRT3 attenuates MPTP-induced nigrostriatal degeneration via enhancing mitochondrial antioxidant capacity. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. There is a growing consensus that mitochondrial dysfunction and oxidative stress play a crucial role in PD pathogenesis. Sirtuin3 (SIRT3) is the major mitochondria NAD(+)-dependent deacetylase that acts as a regulator of mitochondrial protein function; it is essential for maintaining mitochondrial integrity. Although SIRT3 was reported to have anti-oxidative stress activity in an in vitro study, there is no explicit in vivo evidence for the involvement of SIRT3 in the etiology of PD. The present study shows that SIRT3 null mice do not exhibit motor and non-motor deficits compared with wild-type controls. However, SIRT3 deficiency dramatically exacerbated the degeneration of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mice. SIRT3 null mice exposed to MPTP also exhibited decreased superoxide dismutase 2, a specific mitochondrial antioxidant enzyme, and reduced glutathione peroxidase expression compared with wild-type controls. Taken together, these findings strongly support that SIRT3 has a possible role in MPTP induced neurodegeneration via preserving free radical scavenging capacity in mitochondria. PMID- 25555706 TI - Role of the Astrocytic Na(+), K(+)-ATPase in K(+) Homeostasis in Brain: K(+) Uptake, Signaling Pathways and Substrate Utilization. AB - This paper describes the roles of the astrocytic Na(+), K(+)-ATPase for K(+) homeostasis in brain. After neuronal excitation it alone mediates initial cellular re-accumulation of moderately increased extracellular K(+). At higher K(+) concentrations it is assisted by the Na(+), K(+), 2Cl(-) transporter NKCC1, which is Na(+), K(+)-ATPase-dependent, since it is driven by Na(+), K(+)-ATPase created ion gradients. Besides stimulation by high K(+), NKCC1 is activated by extracellular hypertonicity. Intense excitation is followed by extracellular K(+) undershoot which is decreased by furosemide, an NKCC1 inhibitor. The powerful astrocytic Na(+), K(+)-ATPase accumulates excess extracellular K(+), since it is stimulated by above-normal extracellular K(+) concentrations. Subsequently K(+) is released via Kir4.1 channels (with no concomitant Na(+) transport) for re uptake by the neuronal Na(+), K(+)-ATPase which is in-sensitive to increased extracellular K(+), but stimulated by intracellular Na(+) increase. Operation of the astrocytic Na(+), K(+)-ATPase depends upon Na(+), K(+)-ATPase/ouabain mediated signaling and K(+)-stimulated glycogenolysis, needed in these non excitable cells for passive uptake of extracellular Na(+), co-stimulating the intracellular Na(+)-sensitive site. A gradual, spatially dispersed release of astrocytically accumulated K(+) will therefore not re-activate the astrocytic Na(+), K(+)-ATPase. The extracellular K(+) undershoot is probably due to extracellular hypertonicity, created by a 3:2 ratio between Na(+), K(+)-ATPase mediated Na(+) efflux and K(+) influx and subsequent NKCC1-mediated volume regulation. The astrocytic Na(+), K(+)-ATPase is also stimulated by beta1 adrenergic signaling, which further stimulates hypertonicity-activation of NKCC1. Brain ischemia leads to massive extracellular K(+) increase and Ca(2+) decrease. A requirement of Na(+), K(+)-ATPase signaling for extracellular Ca(2+) makes K(+) uptake (and brain edema) selectively dependent upon beta1-adrenergic signaling and inhibitable by its antagonists. PMID- 25555708 TI - A unique glyceryl diglycoside identified in the thermophilic, radiation-resistant bacterium Rubrobacter xylanophilus. AB - The solute pool of the actinobacterium Rubrobacter xylanophilus has been investigated as a function of the growth temperature and concentration of NaCl in the medium (Empadinhas et al. Extremophiles 11: 667-673, 2007). Changing the carbon source from glucose to maltose in a minimal growth medium led to the accumulation of an unknown organic compound whose structure was investigated by NMR and confirmed by chemical synthesis in the present study as: (2R)-2-(1-O alpha-D-mannopyranosyl)-3-(1-O-alpha-D-glucopyranosyl)-D-glycerate (MGlyG). In addition to this newly identified diglycoside, the solute pool of R. xylanophilus included trehalose, mannosylglycerate, di-myo-inositol phosphate and di-N-acetyl glucosamine phosphate. The structure of MGlyG was established by NMR and confirmed by chemical synthesis. The availability of g-amounts of the synthetic material allowed us to perform stabilization tests on three model enzymes (malate dehydrogenase, staphylococcal nuclease, and lysozyme), and compare the efficacy of MGlyG with other natural glyceryl glycosides, such as alpha-D-mannosyl-D glycerate, alpha-D-glucosyl-D-glycerate and alpha-D-glucosyl-(1 -> 6)-alpha-D glucosyl-(1 -> 2)-D-glycerate. PMID- 25555709 TI - Insights into the interaction between Cren7 and DNA: the role of loop beta3 beta4. AB - Sulfolobus synthesizes large amounts of small chromatin proteins Cren7 and Sul7d. The two proteins share overall structural similarity, but differ distinctly in the DNA-binding region between beta3- and beta4-strands. While Sul7d possesses a hinge of two amino acid residues, Cren7 contains a flexible seven-residue loop (loop beta3-beta4) in the region. Here, we report the role of loop beta3-beta4 in the interaction of Cren7 with duplex DNA. We show that all residues with a large side chain on the loop, i.e., Pro30, Lys31, Arg33 and Lys34, contributed significantly to the binding of Cren7 to DNA. The three basic amino acids affected the ability of Cren7 to constrain negative DNA supercoils in a residue number-dependent manner. The crystal structure of a complex between a mutant Cren7 protein (GR) with loop beta3-beta4 replaced by two residues (Gly and Arg) to mimic the hinge at the corresponding position in Sul7d and an 8-bp dsDNA has been determined. Structural comparison between the GR-DNA and Cren7-DNA complexes shows that GR resembles Sul7d more than Cren7 in DNA-binding size and in the effect on the width of the major groove of DNA and the pattern of DNA bending. However, GR induces smaller DNA curvature than Sul7d. Our results suggest that Cren7 and Sul7d package chromosomal DNA in a slightly different fashion, presumably permitting different chromosomal accessibility by proteins functioning in DNA transactions. PMID- 25555710 TI - The role of vaginal cuff brachytherapy in endometrial cancer. AB - OBJECTIVE: The purpose of this article is to review the data, rationale, and recommendations of vaginal brachytherapy (VBT) in the post-operative treatment of endometrial cancer patients. METHODS: The authors performed a thorough review of the medical literature regarding the use of adjuvant VBT in the treatment of endometrial cancer. Relevant data are presented in this review. Additionally, personal and institutional practices from the authors are incorporated where relevant. RESULTS: VBT for the adjuvant treatment of early stage endometrial cancer patients results in a low rate of recurrence (0-3.1%) with very low rates of toxicity. PORTEC-2 supports the use of adjuvant VBT versus external beam radiotherapy specifically for high-intermediate risk endometrial cancer patients. VBT has low rates of acute and chronic gastrointestinal and genitourinary toxicity and very low rates of second primary malignancy. The primary toxicity of VBT is vaginal atrophy and stenosis with controversy regarding the use of vaginal dilators for prevention. Data support that patients prefer to be involved in the decision making process for their adjuvant therapy, and patients have a lower minimal desired benefit of adjuvant VBT than do physicians. Guidelines exist from the American Brachytherapy Society and American Society of Radiation Oncology with support from the Society for Gynecologic Oncologists regarding the use of adjuvant VBT. CONCLUSIONS: VBT decreases the risk of recurrence with minimal toxicity in the adjuvant treatment of endometrial cancer. Adjuvant therapy should be discussed in a multi-disciplinary setting with detailed counseling of the risks and benefits with the patient so that she ultimately makes an informed decision regarding her adjuvant therapy. PMID- 25555715 TI - Ex vivo use of a Rho-kinase inhibitor during renal preservation improves graft function upon reperfusion. AB - BACKGROUND: Activation of the Rho-Rho-kinase pathway has been shown to cause vasoconstriction in renal afferent arterioles. Vascular dysfunction plays a pivotal role in triggering reperfusion injury after kidney transplantation. Therefore, the effect of a Rho-kinase inhibitor, added to the preservation solution, on renal function after 18 h of storage at 4 degrees C was evaluated. METHODS: Porcine kidneys were preserved with cold HTK-solution. During preservation, in the study group, HTK was supplemented with the Rho-kinase inhibitor HA1077, whereas the control group received no further treatment (n=6, respectively). Kidney function after 18 h of storage at 4 degrees C was evaluated by 90 min of isolated reperfusion in vitro. RESULTS: Rho-kinase inhibition (RKI) was associated with significantly higher renal perfusate flow compared to the control group. Endothelial function, as measured by perfusate levels of nitric oxide and gene expression of eNOS, was significantly increased in the study group. In our model, RKI also significantly improved glomerular function (clearance of creatinine) as well as tubular cell integrity as reflected by reduced fractional sodium excretion and release of fatty acid binding protein, a specific tubular cell marker. CONCLUSION: Our results indicate that blocking the Rho-kinase pathway during cold preservation may lead to a better graft function upon reperfusion. PMID- 25555716 TI - Moderate hypothermia initiated during oxygen-glucose deprivation preserves HL-1 cardiomyocytes. AB - OBJECTIVES: Therapeutic hypothermia (TH) is an acknowledged strategy for neuroprotection for patients suffering from hypoxic-anoxic brain injury (HAI). Albeit similar pathomechanisms of HAI for both brain and heart, moderate TH (32 34 degrees C) has not been established as a heart-protective measure. Therefore, we investigated the cardioprotective effects of moderate TH on oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced injury in HL-1 cardiomyocytes. METHODS: Cardiac OGD/R injury was induced by exposing HL-1 cardiomyocytes to 0.2% oxygen in serum/glucose-free medium for 6h. OGD injured cells were subsequently re-oxygenated with 21% oxygen in complete medium. Two hypothermic protocols were investigated: Post-OGD cooling to 33.5 degrees C for 24 h initiated at the start of re-oxygenation and intra-OGD cooling to 33.5 degrees C for 24 h initiated after 3 h of OGD and maintained throughout the re-oxygenation phase. Cell viability was determined by LDH and cTnT releases. Mitochondria dysfunction was evaluated by intracellular ATP content and cellular metabolic activity was accessed by MTT reduction. Activation of caspase 3 was analyzed by Western blot. RESULTS: OGD/R-induced injury resulted in increased cell death (higher LDH and cTnT releases), mitochondrial impairment (decreased ATP content), and decreased cellular metabolic activity (decreased MTT reduction). Only intra-OGD cooling attenuated both OGD and OGD-R-induced injuries (significantly decreased LDH and cTnT releases and increased ATP contents and MTT reduction). Furthermore, caspase 3 activation was abated by intra-OGD cooling. No protective effects were observed by post-OGD cooling. CONCLUSIONS: Moderate TH initiated during OGD is a promising intervention for the protection of cardiomyocytes from OGD/R-induced injury. The attenuation of mitochondrial dysfunction and apoptosis by intra-OGD cooling are beneficial effects of hypothermia-induced cardioprotection, resulting in minimized myocardial cell death after OGD and OGD-R-induced injuries. PMID- 25555717 TI - Development of chronic pain after episiotomy. AB - OBJECTIVE: To analyze the incidence of chronic pain 5 months after episiotomy, as well as potential prognostic factors. METHODS: A prospective cohort observational study was conducted on pregnant women age>=18 years who had undergone an episiotomy. The presence of pain was evaluated in the area of episiotomy at 24 and 48 h of delivery using a structured face-to-face questionnaire, and by telephone questionnaire at 5 months. The primary endpoint was the presence of persistent pain at 5 months. A record was made of the presence of pain at delivery, and its intensity, the presence or absence of epidural analgesia, instrumental delivery, perineal tear, and pain when episiotomy was performed, as well as the presence of dyspareunia and urinary incontinence at 5 months post episiotomy. RESULTS: A total of 87 parturient patients were included, of whom 78 completed the study. Of the patients who completed the study, 12.8% reported chronic episiotomy pain. Epidural analgesia was associated with a higher incidence of instrumental delivery and less pain at the time of episiotomy and expulsion (P<.0005, P<.02, and P<.01, respectively). Chronic pain is associated with operative delivery (P<.017), and with the presence of pain at rest at 24 and 48 h (P<.01), of wound complications (P<.026), and of dyspareunia (P<.001). CONCLUSION: An incidence of 12.8% of women developing chronic pain after delivery with episiotomy suggests a health problem. More studies are needed to confirm our results. PMID- 25555718 TI - De novo peptide structure prediction: an overview. AB - Peptide structure identification is an important contribution to the further characterization of the residues involved in functional interactions. De novo structure peptide prediction has, in the past few years, made significant progresses that make reasonable, for peptides up to 50 amino acids, its use for the fast identification of their structural topologies. Here, we introduce some of the concepts underlying approaches of the field, together with their limits. PMID- 25555719 TI - Molecular modeling of peptides. AB - This article presents a review of the field of molecular modeling of peptides. The main focus is on atomistic modeling with molecular mechanics potentials. The description of peptide conformations and solvation through potentials is discussed. Several important computer simulation methods are briefly introduced, including molecular dynamics, accelerated sampling approaches such as replica exchange and metadynamics, free energy simulations and kinetic network models like Milestoning. Examples of recent applications for predictions of structure, kinetics, and interactions of peptides with complex environments are described. The reliability of current simulation methods is analyzed by comparison of computational predictions obtained using different models with each other and with experimental data. A brief discussion of coarse-grained modeling and future directions is also presented. PMID- 25555721 TI - Building MHC class II epitope predictor using machine learning approaches. AB - Identification of T-cell epitopes binding to MHC class II molecules is an important step in epitope-based vaccine development. This process has since been accelerated with the use of bioinformatics tools to aid in the prediction of peptide binding to MHC class II molecules and also to systematically scan for candidate peptides in antigenic proteins. There have been many prediction software developed over the years using various methods and algorithms and they are becoming increasingly sophisticated. Here, we illustrate the use of machine learning algorithms to train on MHC class II peptide data represented by feature vectors describing their amino acid physicochemical properties. The developed prediction model can then be used to predict new peptide data. PMID- 25555720 TI - Improved methods for classification, prediction, and design of antimicrobial peptides. AB - Peptides with diverse amino acid sequences, structures, and functions are essential players in biological systems. The construction of well-annotated databases not only facilitates effective information management, search, and mining but also lays the foundation for developing and testing new peptide algorithms and machines. The antimicrobial peptide database (APD) is an original construction in terms of both database design and peptide entries. The host defense antimicrobial peptides (AMPs) registered in the APD cover the five kingdoms (bacteria, protists, fungi, plants, and animals) or three domains of life (bacteria, archaea, and eukaryota). This comprehensive database ( http://aps.unmc.edu/AP ) provides useful information on peptide discovery timeline, nomenclature, classification, glossary, calculation tools, and statistics. The APD enables effective search, prediction, and design of peptides with antibacterial, antiviral, antifungal, antiparasitic, insecticidal, spermicidal, anticancer activities, chemotactic, immune modulation, or antioxidative properties. A universal classification scheme is proposed herein to unify innate immunity peptides from a variety of biological sources. As an improvement, the upgraded APD makes predictions based on the database-defined parameter space and provides a list of the sequences most similar to natural AMPs. In addition, the powerful pipeline design of the database search engine laid a solid basis for designing novel antimicrobials to combat resistant superbugs, viruses, fungi, or parasites. This comprehensive AMP database is a useful tool for both research and education. PMID- 25555722 TI - Brownian dynamics simulation of peptides with the University of Houston Brownian Dynamics (UHBD) program. AB - This chapter provides the background theory and a practical protocol for performing Brownian dynamics simulation of peptides. Brownian dynamics simulation represents a complementary approach to Monte Carlo and molecular dynamics methods. Unlike Monte Carlo methods, it could provide dynamical information in a timescale longer than the momentum relaxation time. On the other hand, it is faster than molecular dynamics by approximating the solvent by a continuum and by operating in the over-damped limit. This chapter introduces the use of the University of Houston Brownian Dynamics (UHBD) program [1, 2] to perform Brownian dynamics simulation on peptides. PMID- 25555723 TI - Computational prediction of short linear motifs from protein sequences. AB - Short Linear Motifs (SLiMs) are functional protein microdomains that typically mediate interactions between a short linear region in one protein and a globular domain in another. SLiMs usually occur in structurally disordered regions and mediate low affinity interactions. Most SLiMs are 3-15 amino acids in length and have 2-5 defined positions, making them highly likely to occur by chance and extremely difficult to identify. Nevertheless, our knowledge of SLiMs and capacity to predict them from protein sequence data using computational methods has advanced dramatically over the past decade. By considering the biological, structural, and evolutionary context of SLiM occurrences, it is possible to differentiate functional instances from chance matches in many cases and to identify new regions of proteins that have the features consistent with a SLiM mediated interaction. Their simplicity also makes SLiMs evolutionarily labile and prone to independent origins on different sequence backgrounds through convergent evolution, which can be exploited for predicting novel SLiMs in proteins that share a function or interaction partner. In this review, we explore our current knowledge of SLiMs and how it can be applied to the task of predicting them computationally from protein sequences. Rather than focusing on specific SLiM prediction tools, we provide an overview of the methods available and concentrate on principles that should continue to be paramount even in the light of future developments. We consider the relative merits of using regular expressions or profiles for SLiM discovery and discuss the main considerations for both predicting new instances of known SLiMs, and de novo prediction of novel SLiMs. In particular, we highlight the importance of correctly modelling evolutionary relationships and the probability of false positive predictions. PMID- 25555724 TI - Peptide toxicity prediction. AB - Last decade has witnessed the revival of interest in peptides as potential therapeutics candidates. However, one of the bottlenecks in the success of therapeutic peptides in clinics is their toxicity towards eukaryotic cells. Therefore, considerable efforts have been made over the years both in wet and dry lab to overcome this limitation. With the advances in peptide synthesis, now it is possible to fine-tune the physicochemical properties of peptides by incorporating several chemical modifications and thus to optimize the peptide functionality in order to minimize the toxicity without compromising their therapeutic activity. Also various in silico tools for peptide toxicity prediction and peptide designing have been developed, which facilitates designing of therapeutic peptides with desired toxicity. In this chapter, we have discussed both wet lab and dry lab approaches used to optimize peptide toxicity. More emphasis has been given to describe the in silico method, ToxinPred, to predict the toxicity of peptide and about how to design a peptide or protein with desired toxicity by mutating minimum number of amino acids. PMID- 25555725 TI - Synthetic and structural routes for the rational conversion of peptides into small molecules. AB - The demand for modified peptides with improved stability profiles and pharmacokinetic properties is driving extensive research effort in this field. The conversion of peptides into organic molecules, as traditional drugs, is a long and puzzled way. Many and versatile approaches have been described for designing peptide mimetics: the substitution of natural residues with modified amino acids and the rigidification and modification of the backbone are the main structural and chemical routes walked in medicinal chemistry. All of these strategies have been successfully applied to obtain active new compounds in molecular biology, drug discovery and design. Here we propose a panoramic review of the most common methods for the preparation of modified peptides and the most interesting findings of the last decade. PMID- 25555726 TI - In silico design of antimicrobial peptides. AB - The rapid spread of drug-resistant pathogenic microbial strains has created an urgent need for the development of new anti-infective molecules, having different mechanism of action in comparison to existing drugs. Natural antimicrobial peptides (AMPs) represent a novel class of molecules with a broad spectrum of activity and a low rate in inducing bacterial resistance. In particular, linear alpha-helical cationic antimicrobial peptides are among the most widespread membrane-disruptive AMPs in nature, representing a particularly successful structural arrangement of the innate defense against microbes. However, until now, many AMPs have failed in clinical trials because of several drawbacks that strongly limit their applicability such as degradation, cytotoxicity, and high production cost. Thus, to overcome the limitations of native peptides, a rational in silico approach to AMPs design becomes a promising strategy that drastically reduce production costs and the time required for evaluation of activity and toxicity. This chapter focuses on the strategies and methods for de novo design of potentially active AMPs. In particular, statistical-based design strategies and MD methods for modelling AMPs are elucidated. PMID- 25555727 TI - Information-driven modeling of protein-peptide complexes. AB - Despite their biological importance in many regulatory processes, protein-peptide recognition mechanisms are difficult to study experimentally at the structural level because of the inherent flexibility of peptides and the often transient interactions on which they rely. Complementary methods like biomolecular docking are therefore required. The prediction of the three-dimensional structure of protein-peptide complexes raises unique challenges for computational algorithms, as exemplified by the recent introduction of protein-peptide targets in the blind international experiment CAPRI (Critical Assessment of PRedicted Interactions). Conventional protein-protein docking approaches are often struggling with the high flexibility of peptides whose short sizes impede protocols and scoring functions developed for larger interfaces. On the other side, protein-small ligand docking methods are unable to cope with the larger number of degrees of freedom in peptides compared to small molecules and the typically reduced available information to define the binding site. In this chapter, we describe a protocol to model protein-peptide complexes using the HADDOCK web server, working through a test case to illustrate every steps. The flexibility challenge that peptides represent is dealt with by combining elements of conformational selection and induced fit molecular recognition theories. PMID- 25555728 TI - Computational approaches to developing short cyclic peptide modulators of protein protein interactions. AB - Cyclic peptides are a promising class of bioactive molecules potentially capable of modulating "difficult" targets, such as protein-protein interactions. Cyclic peptides have long been used as therapeutics derived from natural product derivatives, but remain an underexplored class of compounds from the perspective of rational drug design, possibly due to the known weaknesses of peptide drugs in general. While cyclic peptides are non"druglike" by the accepted empirical rules, their unique structure may lend itself to both membrane permeability and proteolytic resistance-the main barriers to oral delivery. The constrained shape of cyclic peptides also lends itself better to virtual screening approaches, and new tools and successes in this area have been recently noted. An increasing number of strategies are available, both to generate and screen cyclic peptide libraries, and best practises and current successes are described within. This chapter will describe various computational strategies for virtual screening cyclic peptides, along with known implementations and applications. We will explore the generation and screening of diverse combinatorial virtual libraries, incorporating a range of cyclization strategies and structural modifications. More advanced approaches covered include evolutionary algorithms designed to aid in screening large structural libraries, machine learning approaches, and harnessing bioinformatics resources to bias cyclic peptide virtual libraries towards known bioactive structures. PMID- 25555729 TI - A use of homology modeling and molecular docking methods: to explore binding mechanisms of nonylphenol and bisphenol A with antioxidant enzymes. AB - Bisphenol A (BPA) and nonylphenol (NP) are phenolic compounds used widely by the industries. BPA and NP are endocrine disruptors possessing estrogenic properties. Several studies have reported that BPA and NP induce oxidative stress in various organs or cell types in animals, by inhibiting the activities of antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. However, it is not understood how BPA and NP interact with these enzymes and inhibit their functions. Hence, it would be significant to check, whether binding sites are available for NP and BPA in antioxidant enzymes. In the present study three-dimensional structures of antioxidant enzymes, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase were modeled and docked with BPA and NP. Docking studies revealed that BPA and NP have binding pockets in the antioxidant enzymes. Among the antioxidant enzymes, Catalase was maximally inhibited by BPA and superoxide was maximally inhibited by NP. PMID- 25555730 TI - Computational peptide vaccinology. AB - Immunoinformatics focuses on modeling immune responses for better understanding of the immune system and in many cases for proposing agents able to modify the immune system. The most classical of these agents are vaccines derived from living organisms such as smallpox or polio. More modern vaccines comprise recombinant proteins, protein domains, and in some cases peptides. Generating a vaccine from peptides however requires technologies and concepts very different from classical vaccinology. Immunoinformatics therefore provides the computational tools to propose peptides suitable for formulation into vaccines. This chapter introduces the essential biological concepts affecting design and efficacy of peptide vaccines and discusses current methods and workflows applied to design successful peptide vaccines using computers. PMID- 25555731 TI - Computational modeling of peptide-aptamer binding. AB - Evolution is the progressive process that holds each living creature in its grasp. From strands of DNA evolution shapes life with response to our ever changing environment and time. It is the continued study of this most primitive process that has led to the advancement of modern biology. The success and failure in the reading, processing, replication, and expression of genetic code and its resulting biomolecules keep the delicate balance of life. Investigations into these fundamental processes continue to make headlines as science continues to explore smaller scale interactions with increasing complexity. New applications and advanced understanding of DNA, RNA, peptides, and proteins are pushing technology and science forward and together. Today the addition of computers and advances in science has led to the fields of computational biology and chemistry. Through these computational advances it is now possible not only to quantify the end results but also visualize, analyze, and fully understand mechanisms by gaining deeper insights. The biomolecular motion that exists governing the physical and chemical phenomena can now be analyzed with the advent of computational modeling. Ever-increasing computational power combined with efficient algorithms and components are further expanding the fidelity and scope of such modeling and simulations. This chapter discusses computational methods that apply biological processes, in particular computational modeling of peptide aptamer binding. PMID- 25555732 TI - Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors. AB - Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings. PMID- 25555733 TI - Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors. AB - A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100 MUM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200 nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases. PMID- 25555735 TI - Complete Genome Sequences of T4-Like Bacteriophages RB3, RB5, RB6, RB7, RB9, RB10, RB27, RB33, RB55, RB59, and RB68. AB - T4-like bacteriophages have been explored for phage therapy and are model organisms for phage genomics and evolution. Here, we describe the sequencing of 11 T4-like phages. We found a high nucleotide similarity among the T4, RB55, and RB59; RB32 and RB33; and RB3, RB5, RB6, RB7, RB9, and RB10 phages. PMID- 25555734 TI - Ferrocenes as potential chemotherapeutic drugs: synthesis, cytotoxic activity, reactive oxygen species production and micronucleus assay. AB - Three new ferrocene complexes were synthesized with 4-(1H-pyrrol-1-yl)phenol group appended to one of the Cp ring. These are: 1,1'-4-(1H-pyrrol-1-yl)phenyl ferrocenedicarboxylate, ('Fc-(CO2-Ph-4-Py)2'), 1,4-(1H-pyrrol-1-yl)phenyl, 1' carboxyl ferrocenecarboxylate ('Fc-(CO2-Ph-4-Py)CO2H') and 4-(1H-pyrrol-1 yl)phenyl ferroceneacetylate ('Fc-CH2CO2-Ph-4-Py'). The new species were characterized by standard analytical methods. Cyclic voltammetry experiments showed that Fc-CH2CO2-Ph-4-Py has redox potential very similar to the Fc/Fc(+) redox couple whereas Fc-(CO2-Ph-4-Py)2 and Fc-(CO2-Ph-4-Py)CO2H have redox potentials of over 400 mV higher than Fc/Fc(+) redox couple. The in vitro studies on Fc-(CO2-Ph-4-Py)2 and Fc-(CO2-Ph-4-Py)CO2H revealed that these two compounds have moderate anti-proliferative activity on MCF-7 breast cancer cell line. In contrast Fc-CH2CO2-Ph-4-Py which displayed low anti-proliferative activity. In the HT-29 colon cancer cell line, the new species showed low anti-proliferative activity. Cytokinesis-block micronucleus assay (CBMN) was performed on these ferrocenes and it was determined they induce micronucleus formation on binucleated cells and moderate genotoxic effects on the MCF-7 breast cancer cell line. There is a correlation between the IC50 values of the ferrocenes and the amount of micronucleus formation activity on binucleated cells and the reactive oxygen species (ROS) production on MCF-7 cell line. PMID- 25555736 TI - Draft Genome Sequence of Nocardia seriolae ZJ0503, a Fish Pathogen Isolated from Trachinotus ovatus in China. AB - Nocardia seriolae is a pathogen that causes nocardiosis in marine and freshwater fish. Here, we report the draft genome sequence of N. seriolae strain ZJ0503, which was isolated from Trachinotus ovatus in Guangdong, China. PMID- 25555737 TI - Draft Genome Sequence of the Cellulolytic Bacterium Clavibacter sp. CF11, a Strain Producing Cold-Active Cellulase. AB - Clavibacter sp. strain CF11, which was isolated from soil at a tomato-planting greenhouse in Inner Mongolia, North China, has a high capability for producing cold-active cellulase at low temperatures. Here, we report the draft genome sequence of strain CF11, which comprises 2,437 protein-coding sequences and 49 RNA-coding sequences. PMID- 25555738 TI - Whole-Genome Sequence of Quorum-Sensing Vibrio tubiashii Strain T33. AB - Vibrio tubiashii strain T33 was isolated from the coastal waters of Morib, Malaysia, and was shown to possess quorum-sensing activity similar to that of its famous relative Vibrio fischeri. Here, the assembly and annotation of its genome are presented. PMID- 25555739 TI - Insights into the Quorum-Sensing Activity in Aeromonas hydrophila Strain M013 as Revealed by Whole-Genome Sequencing. AB - Aeromonas hydrophila species can be found in warm climates and can survive in different environments. They possess the ability to communicate within their populations, which is known as quorum sensing. In this work, we present the draft genome sequence of A. hydrophila M013, a bacterium isolated from a Malaysian tropical rainforest waterfall. PMID- 25555741 TI - Two metagenomes from late pleistocene northeast siberian permafrost. AB - The present study reports metagenomic shotgun sequencing of microbial communities of two ancient permafrost horizons of the Russian Arctic. Results demonstrate a significant difference in microbial community structure of the analyzed samples in general and microorganisms of the methane cycle in particular. PMID- 25555740 TI - Draft Genome Sequence of Oenococcus oeni Strain X2L (CRL1947), Isolated from Red Wine of Northwest Argentina. AB - We report the draft genome sequence of Oenococcus oeni strain X2L, a potential starter culture of malolactic fermentation, isolated from Malbec wine of Argentina. Genes encoding for enzymes involved in the metabolism of malate, citrate, and nitrogen compounds, as well as aroma compounds, were found in this genome, showing its ability to improve the sensorial characteristics of wines. PMID- 25555742 TI - Variability of P-wave morphology predicts the outcome of circumferential pulmonary vein isolation in patients with recurrent atrial fibrillation. AB - INTRODUCTION: Severe atrial structural remodeling may reflect irreversible damage of the atrial tissue in patients with atrial fibrillation (AF) and is associated with changes of P-wave duration and morphology. Our aim was to study whether variability of P-wave morphology (PMV) is associated with outcome in patients with AF after circumferential PV isolation (CPVI). METHODS AND RESULTS: 70 consecutive patients (aged 60+/-9years, 46 men) undergoing CPVI due to symptomatic AF were studied. After cessation of antiarrhythmic therapy, standard 12-lead ECG during sinus rhythm was recorded for 10min at baseline and transformed to orthogonal leads. Beat-to-beat P-wave morphology was subsequently defined using a pre-defined classification algorithm. The most commonly observed P-wave morphology in a patient was defined as the dominant morphology. PMV was defined as the percentage of P waves with non-dominant morphology in the 10-min sample. At the end of follow-up, 53 of 70 patients had no arrhythmia recurrence. PMV was greater in patients without recurrence (19.5+/-17.1% vs. 8.2+/-6.7%, p<0.001). In the multivariate logistic regression model, PMV>=20% (upper tertile) was the only independent predictor of ablation success (OR=11.4, 95% CI 1.4-92.1, p=0.023). A PMV>=20% demonstrated a sensitivity of 41.5%, a specificity of 94.1%, a PPV of 96.7%, and an NPV of 34.0% for free of AF after CPVI. CONCLUSIONS: We report a significant association between increased PMV and 6-month CPVI success. PMV may help to identify patients with very high likelihood of freedom of AF 6 months after CPVI. PMID- 25555743 TI - Recent advances in bioactive pyrazoles. AB - Pyrazole is a five membered and two-nitrogen containing heterocyclic ring. These structures have been investigated in the development of novel compounds with hypoglycemic, analgesic, anti-inflammatory, antimicrobial, anticonvulsant, antidepressant, antimycobacterial, antioxidant, antiviral, insecticidal and antitumor activities. Therefore, these compounds have been synthesized as target structures by many researchers and were evaluated for their biological activities. We hope that the bioactivity of pyrazole derivatives will be beneficial for the rational design of new generation of small molecule drugs. In this review, we report the structures of 1H-pyrazoles with their corresponding biological activities for 21st (in 2000-2014 years) century. PMID- 25555744 TI - First report of a novel missense CLDN19 mutations causing familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a Chinese family. AB - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder caused by mutations in the CLDN16 or CLDN19 genes, encoding claudin-16 and claudin-19 in the thick ascending limb of Henle's loop. In patients with claudin-19 mutations, severe ocular involvement (macular coloboma, pigmentary retinitis, nystagmus, or visual loss) has been described. In this report, we presented a 12-year-old girl with rickets, polyuria, and polydipsia. She was the daughter of consanguineous parents, and she had a history of recurred hypocalcemic and hypomagnesemic tetany. On physical examination, bilateral horizontal nystagmus and severe myopia were detected. Laboratory examination revealed hypomagnesemia, hypocalcemia, hypercalciuria, nephrocalcinosis, and renal stone. A clinical diagnosis of FHHNC caused possibly by claudin-19 mutation was decided with the ocular findings. DNA analysis revealed a novel homozygous missense mutation c.241C>T in the CLDN19 gene. In conclusion, in a patient with hypomagnesemia, hypercalciuria, nephrocalcinosis, and ocular findings, a diagnosis of FHHNC caused by claudin-19 mutation should be considered. This is the first study of FHHNC in Chinese population. Our findings of the novel mutation c.241C>T in exon 2 add to the list of more than 16 mutations of CLDN19 gene reported. PMID- 25555745 TI - [Contributions of the Mexican electrovectorcardiography]. AB - We narrate the main stages of the long journey that led to the structuring of modern electrovectorcardiography based on the fundamentals established by Willem Einthoven (1860-1927), who held the physiology chair of the Leyden University (The Netherlands), and presented his string electrocardiograph in 1901. The Mexican electrovectorcardiography became strong thanks to the endeavor of Dr. Demetrio Sodi Pallares, a disciple of F.N. Wilson of Ann Arbor. Dr. Sodi Pallares founded the Mexican School of Electrovectorcardiography, which was a cornerstone in the field and was widely recognized internationally for several decades. This fact is due to the rational and not empirical approach to the electrical exploration of the heart, thanks to the application of the inductive-deductive Galilean procedure. It was then possible to obtain these results, through the study of myocardial depolarization and repolarization processes, under normal conditions and with bundle branch block, performed by Dr. Gustavo A. Medrano and collaborators, in the 1950 decade. The electrovectorcardiographic manifestations of the non complicated myocardial infarct were the object of studies, as well as those of the infarction complicated with rhythm and conduction disorders. Likewise, proximal and distal or peripheral blocks were studied. The current disciples of that School are now studying of cardiac arrhythmias with promising results. PMID- 25555746 TI - Training pair-housed Rhesus macaques (Macaca mulatta) using a combination of negative and positive reinforcement. AB - When training animals, time is sometimes a limiting factor hampering the use of positive reinforcement training (PRT) exclusively. The aim of this study was to evaluate the effects of a combination of negative and positive reinforcement training (NPRT). Twenty naive female Rhesus macaques (Macaca mulatta) were trained in 30 sessions with either PRT (n=8) or NPRT (n=12) to respond to a signal, move into a selected cage section and accept confinement. In the NPRT group a signal preceded the presentation of one or several novel, and thus aversive, stimuli. When the correct behaviour was performed, the novel stimulus was removed and treats were given. As the animal learned to perform the correct behaviour, the use of novel stimuli was decreased and finally phased out completely. None of the PRT-trained animals finished the task. Ten out of 12 monkeys in the NPRT-group succeeded to perform the task within the 30 training sessions, a significant difference from the PRT-group (p=0.0007). A modified approach test showed no significant difference between the groups (p=0.67) in how they reacted to the trainer. The results from this study suggest that carefully conducted NPRT can be an alternative training method to consider, especially when under a time constraint. PMID- 25555747 TI - Sandhopper orientation under natural conditions: comparing individual tracks. AB - The analysis of animal movements may help to understand orientation strategies. While there have been many studies on sandhoppers' orientation mechanisms through the analysis of their orientation angles, no attempts have been made to analyze individual tracks under (varying) natural conditions. The species Talitrus saltator (Montagu, 1808) has the ability to recover the optimal zone of the beach at or below the drift-line and burrow into moist sand when released in the upper beach during the day. On dry sand sandhoppers typically jump and leave tracks; we measured the tracks in relation to the starting point. For each track we calculated: the mean angle of direction, distance covered from the starting point, number of jumps, number of effective turnings, rectilinearity and efficiency (how well the track was directed to the goal). We proposed a classification of the tracks based on both rectilinearity and efficiency. Freshly collected adult individuals from the population of San Rossore beach (Pisa, Italy) were compared to laboratory-born ones so as to highlight eventual differences related to experience. Most of the wild individuals made tracks with high rectilinearity and efficiency. This good orientation suggests that these individuals had developed experience of their beach rapidly recovering the optimal zone. Laboratory-born individuals showed a higher scatter in orientation and winding tracks. The factors that influenced the individuals during their movements could also be inferred by the track course. In addition to the sun azimuth (sun compass), wind direction appeared to be a major factor influencing orientation. The individuals released with onshore winds were more efficiently oriented seawards than those released with winds from other directions. PMID- 25555749 TI - Structural definitions of Jumonji family demethylase selectivity. AB - The Jumonji (Jmj) family of demethylases has a crucial role in regulating epigenetic processes through the removal of methyl groups from histone tails. The ability of Jmj demethylases to recognise their targets selectively has been elegantly addressed by structural studies. Reviewing recent structural literature, we provide an overview of selectivity mechanisms that demethylases use, including specific residues, methylation states and contextual requirements. We also report the presence of a common JmjN support domain across the family. The ability to use structural information for this enzyme class will be a crucial component of future drug discovery. PMID- 25555748 TI - Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery. AB - Advances in the application of nanotechnology in medicine have given rise to multifunctional smart nanocarriers that can be engineered with tunable physicochemical characteristics to deliver one or more therapeutic agent(s) safely and selectively to cancer cells, including intracellular organelle specific targeting. Dendrimers having properties resembling biomolecules, with well-defined 3D nanopolymeric architectures, are emerging as a highly attractive class of drug and gene delivery vector. The presence of numerous peripheral functional groups on hyperbranched dendrimers affords efficient conjugation of targeting ligands and biomarkers that can recognize and bind to receptors overexpressed on cancer cells for tumor-cell-specific delivery. The present review compiles the recent advances in dendrimer-mediated drug and gene delivery to tumors by passive and active targeting principles with illustrative examples. PMID- 25555751 TI - Structural and genetic relationships of closely related O-antigens of Cronobacter spp. and Escherichia coli: C. sakazakii G2594 (serotype O4)/E. coli O103 and C. malonaticus G3864 (serotype O1)/E. coli O29. AB - O-Antigen (O-polysaccharide) variation is the basis for bacterial serotyping and is important in bacterial virulence and niche adaptation. In this work, we present structural and genetic evidences for close relationships between the O antigens of the Cronobacter spp. and Escherichia coli. Cronobacter sakazakii G2594 (serotype O4) and Cronobacter malonaticus G3864 (serotype O1) are structurally related to those of E. coli O103 and O29, respectively, and some other members of the Enterobacteriaceae family differing in the patterns of lateral glucosylation (C. sakazakii G2594) or O-acetylation (C. malonaticus G3864). The O-antigen gene clusters of the corresponding Cronobacter and E. coli strains contain the same genes with high-level similarity, and the structural differences within both O-antigen pairs were suggested to be due to modification genes carried by prophages. PMID- 25555752 TI - Victim Responses to Violence: The Effect of Alcohol Context on Crime Labeling. AB - The labeling of an incident as a crime is an essential precursor to the use of criminal law, but the contextual factors that influence this decision are unknown. One such context that is a frequent setting for violence is the barroom. This study explored how the setting of a violent incident is related to the decision by victims to label it as a crime. It tested the hypothesis that violent incidents that took place in or around a licensed premises were less likely to be regarded as crimes than violence in other settings. The hypothesis was tested using a pooled sample of respondents from successive waves of the British Crime Survey (2002/2003-2010/2011). Logistic regression models controlled for demographic factors, victim behavioral characteristics, and incident-specific factors including the seriousness of the violence. Respondents who were in or around a licensed premises at the time of victimization were less likely to regard that violence as a crime (adjusted odds ratio = 0.48, 95% confidence intervals [CIs] = [0.34, 0.67]) than respondents who were victimized in other locations. Despite a disproportionate amount of violence taking place in barrooms, it appears that the criminal nature of violence in these spaces is discounted by victims. The findings emphasize how context affects victim interpretations of crime and suggest a victim-centered reconceptualization of the "moral holiday" hypothesis of alcohol settings. PMID- 25555750 TI - Sublingual injection of microparticles containing glycolipid ligands for NKT cells and subunit vaccines induces antibody responses in oral cavity. AB - Natural Killer T (NKT) cells are a unique type of innate immune cells which exert paradoxical roles in animal models through producing either Th1 or Th2 cytokines and activating dendritic cells. Alpha-galactosylceramide (alphaGalCer), a synthetic antigen for NKT cells, was found to be safe and immune stimulatory in cancer and hepatitis patients. We recently developed microparticle-formulated alphaGalCer, which is selectively presented by dendritic cells and macrophages, but not B cells, and thus can avoid the anergy of NKT cells. In this study, we have examined the immunogenicity of microparticles containing alphaGalCer and protein vaccine components through sublingual injection in mice. The results showed that sublingual injection of microparticles containing alphaGalCer and ovalbumin triggered IgG responses in serum (titer >1:100,000), which persisted for more than 3months. Microparticles containing ovalbumin alone also induced comparable level of IgG responses. However, immunoglobulin subclass analysis showed that sublingually injected microparticles containing alphaGalCer and ovalbumin induced 20 fold higher Th1 biased antibody (IgG2c) than microparticles containing OVA alone (1:20,000 as compared to 1:1000 titer). Sublingual injection of microparticles containing alphaGalCer and ovalbumin induced secretion of both IgG (titer >1:1000) and IgA (titer=1:80) in saliva secretion, while microparticles containing ovalbumin alone only induced secretion of IgG in saliva. Our results suggest that sublingual injection of microparticles and their subsequent trafficking to draining lymph nodes may induce adaptive immune responses in mucosal compartments. Ongoing studies are focused on the mechanism of antigen presentation and lymphocyte biology in the oral cavity, as well as the toxicity and efficacy of these candidate microparticles for future applications. PMID- 25555753 TI - Measurement uncertainty analysis of low-dose-rate prostate seed brachytherapy: post-implant dosimetry. AB - The minimal dose covering 90 % of the prostate volume--D 90--is arguably the most important dosimetric parameter in low-dose-rate prostate seed brachytherapy. In this study an analysis of the measurement uncertainties in D 90 from low-dose rate prostate seed brachytherapy was conducted for two common treatment procedures with two different post-implant dosimetry methods. The analysis was undertaken in order to determine the magnitude of D 90 uncertainty, how the magnitude of the uncertainty varied when D 90 was calculated using different dosimetry methods, and which factors were the major contributors to the uncertainty. The analysis considered the prostate as being homogeneous and tissue equivalent and made use of published data, as well as original data collected specifically for this analysis, and was performed according to the Guide to the expression of uncertainty in measurement (GUM). It was found that when prostate imaging and seed implantation were conducted in two separate sessions using only CT images for post-implant analysis, the expanded uncertainty in D 90 values were about 25 % at the 95 % confidence interval. When prostate imaging and seed implantation were conducted during a single session using CT and ultrasound images for post-implant analysis, the expanded uncertainty in D 90 values were about 33 %. Methods for reducing these uncertainty levels are discussed. It was found that variations in contouring the target tissue made the largest contribution to D 90 uncertainty, while the uncertainty in seed source strength made only a small contribution. It is important that clinicians appreciate the overall magnitude of D 90 uncertainty and understand the factors that affect it so that clinical decisions are soundly based, and resources are appropriately allocated. PMID- 25555754 TI - The effects of instrumental reminiscence on resilience and coping in elderly. AB - OBJECTIVES: Aging, as a stage of development is marked by major changes to which the subject must adapt. Instrumental reminiscence is based on recalling times one coped with stressful circumstances, and analyzing what it took to adapt in those situations. The purpose of the present study was to analyze the effectiveness of an instrumental reminiscent program to enhance adaptive capacity (problem-focused coping and emotion-focused) and resilience in older adults. METHOD: Thirty participants noninstitutionalized conducted a pre and post assessment on a treatment consisting of the Mini-Mental State Examination (MMSE), Brief Resilient Coping Scale and Stress Coping Questionnaire (CAE). The program was developed over 8 sessions of 60 min. RESULTS: Repeated measures analysis of variance showed significant differences in time-group interaction for treatment effectiveness of resilience measures, problem-solving coping, positive reappraisal and avoidance coping that it increased, and on emotion-focused coping and overt emotional expression that gets decreased after treatment. CONCLUSION: The instrumental reminiscence has proven to be a highly useful tool and is a potentially efficient way to improve adaptive capacity and resilience in the elderly to cope with adverse situations. Through non-pharmacological therapies, the quality of life has been improved, and subjects are provided with tools, strategies and skills that allow to achieve a satisfactory adaptation. PMID- 25555756 TI - Improving the Mann-Whitney statistical test for feature selection: an approach in breast cancer diagnosis on mammography. AB - OBJECTIVE: This work addresses the theoretical description and experimental evaluation of a new feature selection method (named uFilter). The uFilter improves the Mann-Whitney U-test for reducing dimensionality and ranking features in binary classification problems. Also, it presented a practical uFilter application on breast cancer computer-aided diagnosis (CADx). MATERIALS AND METHODS: A total of 720 datasets (ranked subsets of features) were formed by the application of the chi-square (CHI2) discretization, information-gain (IG), one rule (1Rule), Relief, uFilter and its theoretical basis method (named U-test). Each produced dataset was used for training feed-forward backpropagation neural network, support vector machine, linear discriminant analysis and naive Bayes machine learning algorithms to produce classification scores for further statistical comparisons. RESULTS: A head-to-head comparison based on the mean of area under receiver operating characteristics curve scores against the U-test method showed that the uFilter method significantly outperformed the U-test method for almost all classification schemes (p<0.05); it was superior in 50%; tied in a 37.5% and lost in a 12.5% of the 24 comparative scenarios. Also, the performance of the uFilter method, when compared with CHI2 discretization, IG, 1Rule and Relief methods, was superior or at least statistically similar on the explored datasets while requiring less number of features. CONCLUSIONS: The experimental results indicated that uFilter method statistically outperformed the U-test method and it demonstrated similar, but not superior, performance than traditional feature selection methods (CHI2 discretization, IG, 1Rule and Relief). The uFilter method revealed competitive and appealing cost-effectiveness results on selecting relevant features, as a support tool for breast cancer CADx methods especially in unbalanced datasets contexts. Finally, the redundancy analysis as a complementary step to the uFilter method provided us an effective way for finding optimal subsets of features without decreasing the classification performances. PMID- 25555755 TI - Management of paediatric acute appendicitis in the general hospital setting: a national survey of preferred surgical technique. AB - BACKGROUND: The advent of laparoscopic surgery has facilitated the management of acute appendicitis in the adult population. In the paediatric population (<12 years), management varies according to institution and/or consultant expertise. The aim of this study was to analyse consultant preference for laparoscopic versus open appendicectomy in the management of acute appendicitis in children under 12 years presenting to general hospitals. METHODS: A 15-point questionnaire was distributed to 81 consultant surgeons identified from the specialist register of the Irish Medical Council and practicing as general surgeons outside of specialist paediatric centres. RESULTS: A response rate of 83 % (67/81) was obtained. Of the 67 surgeons surveyed, 11 (16 %) had formal paediatric training. Sixty percent (40/67) of surgeons expressed a preference for the open technique. The median frequency of on-call rota was >1 in 5 (32/67) and only 3 % (2/67) claimed that the on-call commitment influenced decision-making regarding surgical approach. The average minimum age (9.3 years, range 1-14) and average minimum weight (25 kg, range 12-70) at which the operating surgeon would perform a laparoscopic appendicectomy were also recorded. Thirty percent (20/67) of consultant general surgeons had immediate access to specialist paediatric laparoscopic equipment. DISCUSSION: This study has shown wide variability amongst consultant general surgeons when considering open versus laparoscopic appendicectomy in children under 12 years. Restricted access to specialist paediatric laparoscopic equipment, combined with declining exposure to paediatric surgical training, may continue to limit the numbers of paediatric laparoscopic appendicectomies performed in the general setting. PMID- 25555757 TI - Design and implementation of adaptive PI control schemes for web tension control in roll-to-roll (R2R) manufacturing. AB - In this paper, two adaptive Proportional-Integral (PI) control schemes are designed and discussed for control of web tension in Roll-to-Roll (R2R) manufacturing systems. R2R systems are used to transport continuous materials (called webs) on rollers from the unwind roll to the rewind roll. Maintaining web tension at the desired value is critical to many R2R processes such as printing, coating, lamination, etc. Existing fixed gain PI tension control schemes currently used in industrial practice require extensive tuning and do not provide the desired performance for changing operating conditions and material properties. The first adaptive PI scheme utilizes the model reference approach where the controller gains are estimated based on matching of the actual closed loop tension control systems with an appropriately chosen reference model. The second adaptive PI scheme utilizes the indirect adaptive control approach together with relay feedback technique to automatically initialize the adaptive PI gains. These adaptive tension control schemes can be implemented on any R2R manufacturing system. The key features of the two adaptive schemes is that their designs are simple for practicing engineers, easy to implement in real-time, and automate the tuning process. Extensive experiments are conducted on a large experimental R2R machine which mimics many features of an industrial R2R machine. These experiments include trials with two different polymer webs and a variety of operating conditions. Implementation guidelines are provided for both adaptive schemes. Experimental results comparing the two adaptive schemes and a fixed gain PI tension control scheme used in industrial practice are provided and discussed. PMID- 25555758 TI - Using the law and the courts. PMID- 25555759 TI - Contesting the cruel treatment of abortion-seeking women. AB - This article draws on legal arguments made by civil society organisations to challenge the legal reasoning that apparently produced the decision in the Ms Y case in Ireland in August 2014. I show how legal standards of reasonableness and practicality ought to be interpreted in ways that are respectful of the patient's wishes and rights. The case concerned a decision by the Health Service Executive, the Irish public health authority, to refuse an abortion to a pregnant asylum seeker and rape survivor on the grounds that a caesarean section and early live delivery were practicable and reasonable alternatives justified by the need to protect fetal life. I argue that the abortion refusal may not have been a reasonable decision, as required by the terms of relevant legislation, for four different reasons. First, the alternative of a caesarean section and early live delivery was not likely to avert the risk of suicide, and in fact did not do so. Second, the consent to the caesarean section alternative may not have been a real consent in the legal sense if it was not voluntary. Third, an abortion refusal and forcible treatment fall below the norms of good medical practice as interpreted through a patient-centred perspective. Fourth, an abortion refusal that entails forms of cruel, inhumane and degrading treatment ought not to be a reasonable action under the legislation. PMID- 25555760 TI - Procedural abortion rights: Ireland and the European Court of Human Rights. AB - The Irish Protection of Life During Pregnancy Act seeks to clarify the legal ground for abortion in cases of risk to life, and to create procedures to regulate women's access to services under it. This article explores the new law as the outcome of an international human rights litigation strategy premised on state duties to implement abortion laws through clear standards and procedural safeguards. It focuses specifically on the Irish law reform and the jurisprudence of the European Court of Human Rights, including A. B. and C. v. Ireland (2010). The article examines how procedural rights at the international level can engender domestic law reform that limits or expands women's access to lawful abortion services, serving conservative or progressive ends. PMID- 25555761 TI - Considering strategic litigation as an advocacy tool: a case study of the defence of reproductive rights in Colombia. AB - Women's Link Worldwide developed a test to determine when an environment is conducive to social change through strategic litigation. We first present our understanding of strategic litigation, and then discuss four conditions for successful and sustainable change using strategic litigation: (1) an existing rights framework; (2) an independent and knowledgeable judiciary; (3) civil society organizations with the capacity to frame social problems as rights violations and to litigate; and (4) a network able to support and leverage the opportunities presented by litigation. Next, we present examples from our work in Colombia that show how analysis of these conditions informed our litigation strategy when confronting a powerful public official who opposes reproductive rights. Two litigation strategies were adopted. The first case was not successful in the courts, but allowed us to introduce our message and build support amongst civil society. The second case built on this momentum and resulted in a victory. Strategic litigation is a powerful tool to advance rights as well as hold governments accountable and ensure compliance with human rights obligations. The strategies developed can be adapted for use in other contexts. We hope they inspire others to protect and promote reproductive rights through strategic litigation when women cannot fully enjoy their rights. PMID- 25555762 TI - Movement and counter-movement: a history of abortion law reform and the backlash in Colombia 2006-2014. AB - In 2006, the Constitutional Court of Colombia issued Decision C-355/2006, which liberalized the country's abortion law. The reform was groundbreaking in its argumentation, being one of the first judicial decisions in the world to uphold abortion rights on equality grounds, and the first by a constitutional court to rule on the constitutionality of abortion within a human rights framework. It was also the first of a series of reforms that would liberalize the abortion regulation in four other Latin American countries. The Colombian case is also notable for the process of strategic litigation carried out by feminist organizations after the Court's decision, in order to ensure its implementation and counter the opposition from conservative actors working in State institutions, as well as for the active role played by the Court in that process. Based on fieldwork carried out in Colombia in 2013, this article analyzes the process of progressive implementation and reactionary backlash after Decision C 355/2006, with an emphasis on strategic litigation by the feminist movement and subsequent decisions by the Constitutional Court, which consolidated its jurisprudence in the field of abortion rights. It highlights the role of both feminists and of conservative activists within State institutions as opposing social movements, and the dynamics of political and legal mobilization and counter-mobilization in that process. PMID- 25555763 TI - Using litigation to defend women prosecuted for abortion in Mexico: challenging state laws and the implications of recent court judgments. AB - While women in Mexico City can access free, safe and legal abortion during the first trimester, women in other Mexican states face many barriers. To complicate matters, between 2008 and 2009, 16 state constitutions were amended to protect life from conception. While these reforms do not annul existing legal abortion indications, they have created additional obstacles for women. Health providers increasingly report women who seek life-saving care for complications such as haemorrhage to the police, and some cases eventually end up in court. The Grupo de Informacion en Reproduccion Elegida (GIRE) has successfully litigated such cases in state courts, with positive outcomes. However, state courts have mainly focused on procedural issues. The Mexican Supreme Court ruling supporting Mexico City's law has had a positive effect, but a stronger stance is needed. This paper discusses the constitutional framework and jurisprudence regarding abortion in Mexico, and the recent Costa Rica decision of the Inter-American Court of Human Rights. We assert that Mexican states must guarantee women's access to abortion on the legal grounds established in law. We continue to support litigation at the state level to oblige courts to exonerate women prosecuted for illegal abortion. Advocacy should, of course, also address the legislative and executive branches, while working simultaneously to set legal precedents on abortion. PMID- 25555764 TI - Abortion in Chile: the practice under a restrictive regime. AB - This article examines, from a human rights perspective, the experience of women, and the practices of health care providers regarding abortion in Chile. Most abortions, as high as 100,000 a year, are obtained surreptitiously and clandestinely, and income and connections play a key role. The illegality of abortion correlates strongly with vulnerability, feelings of guilt and loneliness, fear of prosecution, physical and psychological harm, and social ostracism. Moreover, the absolute legal ban on abortion has a chilling effect on health care providers and endangers women's lives and health. Although misoprostol use has significantly helped to prevent greater harm and enhance women's agency, a ban on sales created a black market. Against this backdrop, feminists have taken action in aid of women. For instance, a feminist collective opened a telephone hotline, Linea Aborto Libre (Free Abortion Line), which has been crucial in informing women of the correct and safe use of misoprostol. Chile is at a crossroads. For the first time in 24 years, abortion law reform seems plausible, at least when the woman's life or health is at risk and in cases of rape and fetal anomalies incompatible with life. The political scenario is unfolding as we write. Congressional approval does not mean automatic enactment of a new law; a constitutional challenge is highly likely and will have to be overcome. PMID- 25555765 TI - Conservative litigation against sexual and reproductive health policies in Argentina. AB - In Argentina, campaigns for the recognition of sexual and reproductive rights have sparked opposition through litigation in which the dynamics of legal action have come from self-proclaimed "pro-life" NGOs, particularly since 1998, when the conservative NGO Portal de Belen successfully achieved the banning of emergency contraception through the courts. The activities of these groups, acting as a "civil arm" of religion, are focused primarily on obstructing access to legally permissible abortions and bringing about the withdrawal of a number of recognized public policies on sexual and reproductive health, particularly the 2002 National Programme for Sexual Health and Responsible Procreation. This paper analyzes the litigation strategies of these conservative NGOs and how their use of the courts in Argentina has changed over the years. It gives examples of efforts in local courts to block individual young women from accessing legal abortion following rape, despite a ruling by the National Supreme Court of Justice in 2012 that no judicial permission is required. In spite of major advances, the renewed influence of the Catholic hierarchy in the Argentine political scene with the accession of the new Pope poses challenges to the work by feminists and women's movements to extend and consolidate sexual and reproductive rights. PMID- 25555766 TI - Robbed of choice and dignity: Indian women dead after mass sterilization: situational assessment of sterilization camps in Bilaspur District, Chhattisgarh: report by a multi-organizational team, December 1, 2014. PMID- 25555767 TI - Sexual and reproductive health and rights in the sustainable development goals and the post-2015 development agenda: less than a year to go. AB - Since the International Conference on Population and Development (ICPD) in Cairo in 1994 there have been significant achievements in moving towards the goal of sexual and reproductive health and rights. Yet there have also been disappointments, as demonstrated in the Millennium Development Goals, even though in 2007 a target on reproductive health was added. Most recently, the 20-year review of the implementation of the ICPD Programme of Action, ICPD Beyond 2014, has taken place, which has moved forward the sexual and reproductive health and rights agenda. But, the main arena for future negotiations has changed and the UN is in the process of negotiating the post-2015 development agenda and the sustainable development goals (SDGs). This paper assesses what has been taking place since 2013 and provides information as to how the process for the post-2015 development agenda and the SDGs are likely to move forward. An understanding of what has been achieved, the processes as they are now proceeding and their future development are important for moving towards the ultimate goal of achieving sexual and reproductive health and rights in the next 15 years. PMID- 25555768 TI - The shifting politics in multilateral development and human rights negotiations and the absence of accountability. PMID- 25555769 TI - The Holy See on sexual and reproductive health rights: conservative in position, dynamic in response. AB - The Holy See has engaged extensively in United Nations negotiations on issues concerning sexual and reproductive health rights as they have emerged and evolved in a dynamic global agenda over the past two decades. A meta-narrative review of the mission's official statements was conducted to examine the positions, discourses and tensions across the broad range of agendas. The Holy See represents a fundamentally conservative and stable position on a range of sexual and reproductive health rights concerns. However, the mission has been dynamic in the ways in which it has forwarded its arguments, increasingly relying upon secularised technical claims and empirical evidence; strategically interpreting human rights norms in ways consistent with its own position; and framing sexuality and reproduction in the context of "the family". Seen in the broader context of a "religious resurgence" in international relations, and in light of the fact that the Holy See has frequently sought to form alliances with conservative State and non-State actors, these findings make an important contribution to understanding the slow progress as well as the potential obstacles that lie ahead in the battle to realise sexual and reproductive health rights in a changing global political environment. PMID- 25555770 TI - The Global Commission on HIV and the Law: recommendations for legal reform to promote sexual and reproductive health and rights. AB - The Global Commission on HIV and the Law was established in 2010 to identify and analyse the complex framework of international, national, religious and customary law shaping national responses to HIV and the well-being of people living with HIV and key populations. Two years of deliberation, based on an exhaustive review of international public health and human rights scholarship, as well as almost 700 testimonials from individuals and organizations in more than 130 countries, informed the Commission's recommendations on reform to laws and practices that criminalize those living with and vulnerable to HIV, sustain or mitigate violence and discrimination lived by women, facilitate or impede access to HIV-related treatment, and/or pertain to children and young people in the context of HIV. This paper presents the Commission's findings and recommendations as they relate to sexual and reproductive health and rights, and examines how the Commission's work intersects with strategic litigation on forced sterilization of women living with HIV, legal reform on the status of transgender individuals, initiatives to improve police treatment of female sex workers, and equal property rights for women living with HIV in sub-Saharan Africa and Latin America. PMID- 25555771 TI - Righting the mismatch between law, policy and the sexual and reproductive health needs of young people in the Asia-Pacific Region. AB - The context of sexual relations is changing in the Asia-Pacific. While the age of sexual debut remains the same, young people are generally marrying later and sex outside of marriage is increasing. The first systematic review of how laws and policies govern young people's access to sexual and reproductive health services was conducted in 2013. The study considered >400 national documents and held focus group discussions with >60 young people across three countries in the region. This paper examines the study findings in light of epidemiological data on young people's sexual behaviour and health, exposing a critical mismatch between the onset of sexual activity and laws and policies governing consent (to sex and medical treatment), and the restriction and orientation of services to married persons. An enabling legal and policy environment is an essential foundation for efforts to improve young people's sexual and reproductive health. This paper argues that international guidance and commitments (including the widely ratified Convention on the Rights of the Child) provide a framework for recognising young people's evolving capacity for independent decision-making, including in the realm of sexual and reproductive health. A number of countries in the region are using these frameworks to expand access to services, providing valuable examples for others to build on. PMID- 25555772 TI - Can a restrictive law serve a protective purpose? The impact of age-restrictive laws on young people's access to sexual and reproductive health services. AB - This article explores the purpose, function and impact of legal restrictions imposed on children's and young people's involvement in sexual activity and their access to sexual and reproductive health services. Whilst there is no consensus on the age at which it is appropriate or acceptable for children and young people to start having sex, the existence of a minimum legal age for sexual consent is almost universal across national jurisdictions, and many states have imposed legal rules that place restrictions on children's and young people's independent access to health services, including sexual health services. The article draws on evidence and analysis from a recent study conducted by the International Planned Parenthood Federation in collaboration with the Coram Children's Legal Centre, UK, which involved a global mapping of laws in relation to sexual and reproductive rights, and exploratory qualitative research in the UK, El Salvador and Senegal amongst young people and health care providers. The article critically examines the social and cultural basis for these rules, arguing that the legal concept of child protection is often founded on gendered ideas about the appropriate boundaries of childhood knowledge and behaviour. It concludes that laws which restrict children's access to services may function to place children and young people at risk: denying them the ability to access essential information, advice and treatment. PMID- 25555774 TI - HIV and gender-based violence: welcome policies and programmes, but is the research keeping up? AB - The global HIV policy arena has seen a surge of interest in gender-related dimensions of vulnerability to HIV and violence. UNAIDS and other prominent actors have named gender-based violence a key priority, and there seems to be genuine understanding and commitment to addressing gender inequalities as they impact key populations in the AIDS response. In the quest for evidence-informed interventions, there is usually a strong connection between the research conducted and the policies and programmes that follow. Regarding gender, HIV and violence, is this the case? This discussion paper asks whether the relevant peer reviewed literature is suitably representative of all affected populations- including heterosexual men, transgender men and women, women who have sex with women, and men who have sex with men--as well as whether the literature sufficiently considers gender norms and dynamics in how research is framed. Conclusions about violence in the context of heterosexual relationships, and with specific attention to heterosexual women, should not be presented as insights about gender-based violence more generally, with little attention to gender dynamics. Research framed by a more comprehensive understanding of what is meant by gender-based violence as it relates to all of the diverse populations affected by HIV would potentially guide policies and programmes more effectively. PMID- 25555773 TI - Reducing high maternal mortality rates in western China: a novel approach. AB - Among the Millennium Development Goals, maternal mortality reduction has proven especially difficult to achieve. Unlike many countries, China is on track to meeting these goals on a national level, through a programme of institutionalizing deliveries. Nonetheless, in rural, disadvantaged, and ethnically diverse areas of western China, maternal mortality rates remain high. To reduce maternal mortality in western China, we developed and implemented a three-level approach as part of a collaboration between a regional university, a non-profit organization, and local health authorities. Through formative research, we identified seven barriers to hospital delivery in a rural Tibetan county of Qinghai Province: (1) difficulty in travel to hospitals; (2) hospitals lack accommodation for accompanying families; (3) the cost of hospital delivery; (4) language and cultural barriers; (5) little confidence in western medicine; (6) discrepancy in views of childbirth; and (7) few trained community birth attendants. We implemented a three-level intervention: (a) an innovative Tibetan birth centre, (b) a community midwife programme, and (c) peer education of women. The programme appears to be reaching a broad cross-section of rural women. Multilevel, locally-tailored approaches may be essential to reduce maternal mortality in rural areas of western China and other countries with substantial regional, socioeconomic, and ethnic diversity. PMID- 25555775 TI - Sexual and reproductive health and rights of older men and women: addressing a policy blind spot. AB - Global debate on required policy responses to issues of older persons has intensified over the past 15 years, fuelled by a growing awareness of the rapid ageing of populations. Health has been a central focus, but scrutiny of global policies, human rights instruments and reports reveals that just as older people are excluded from sexual and reproductive health and rights agendas, so are issues of sexual and reproductive health and rights wholly marginal to current agendas focused on older people. A critical question is whether the policy lacuna reflects a dearth of research evidence or a faulty translation of existing knowledge. A reading of the current research landscape and literature, summarised in this paper, strongly suggests it is the former. To be sure, sexuality in old age is a burgeoning field of scientific inquiry. What the existing knowledge and discourse fail to provide is an engagement with, and elucidation of, the broader sexual and reproductive health and rights agenda as it relates to older persons. A concerted research effort is needed to provide a basis for developing policy guidance and for pinpointing essential indicators and establishing necessary data systems to enable a routine tracking of progress. PMID- 25555776 TI - Termination of pregnancy for fetal abnormality: a meta-ethnography of women's experiences. AB - Due to technological advances in antenatal diagnosis of fetal abnormalities, more women face the prospect of terminating pregnancies on these grounds. Much existing research focuses on women's psychological adaptation to this event. However, there is a lack of holistic understanding of women's experiences. This article reports a systematic review of qualitative studies into women's experiences of pregnancy termination for fetal abnormality. Eight databases were searched up to April 2014 for peer-reviewed studies, written in English, that reported primary or secondary data, used identifiable and interpretative qualitative methods, and offered a valuable contribution to the synthesis. Altogether, 4,281 records were screened; 14 met the inclusion criteria. The data were synthesised using meta-ethnography. Four themes were identified: a shattered world, losing and regaining control, the role of health professionals and the power of cultures. Pregnancy termination for fetal abnormality can be considered as a traumatic event that women experience as individuals, in their contact with the health professional community, and in the context of their politico-socio legal environment. The range of emotions and experiences that pregnancy termination for fetal abnormality generates goes beyond the abortion paradigm and encompasses a bereavement model. Coordinated care pathways are needed that enable women to make their own decisions and receive supportive care. PMID- 25555777 TI - Gender inequality in Russia: the perspective of participatory gender budgeting. AB - Gender-based discrimination is found in all economies in the world. Women's unpaid work accounts for about half of the world GDP, yet women remain under valued and under-represented in national policies worldwide. The question of gender budgeting and citizens' participation in budgeting and governance processes has gained attention in recent years, but Russia is far from implementing these. Instead, blindness to gender issues dominates in national strategies and budgets. This paper explores these issues and looks in-depth at them in the decentralisation process in Bashkortostan, a central Russian republic. Civil society institutions whose role is to strengthen the links between government, civil society and the community in Bashkortostan, such as Public Chambers and Municipalities, lack the capacity to introduce participatory gender budgeting. As a result, no systematic participatory planning, let alone planning that is gender-sensitive, has taken place there. PMID- 25555778 TI - Multipurpose prevention technologies for reproductive and sexual health. AB - Global statistics on unplanned pregnancies, abortions and STIs show that unprotected sex is still widely practised. More needs to be done to provide women and men with a wider choice of convenient protective options. To address this need, international efforts are focusing on developing multipurpose prevention technologies (MPTs) that address two or more indications simultaneously. These technologies would have significant advantages over single-indication products. They include inter alia novel barrier devices, drugs administered either as oral tablets or vaginal/rectal gels, drugs used in combination with medical devices, and genetically engineered organisms which secrete antimicrobial substances. As an example of progress in the MPT field, this paper describes an on-demand contraceptive/antimicrobial vaginal gel, Amphora (previously known as Acidform), now in an advanced stage of development. Clinical trials are currently being planned to find out whether this product's promising antimicrobial profile translates into protective and preventive choices. PMID- 25555789 TI - RISK OF PARESTHESIA: Author's response. PMID- 25555793 TI - It's cold, mom! It's cyclic GMP. PMID- 25555794 TI - Cellular stress response cross talk maintains protein and energy homeostasis. PMID- 25555796 TI - Valproic acid prevents retinal degeneration in a murine model of normal tension glaucoma. AB - Valproic acid (VPA) is widely used for treatment of epilepsy, mood disorders, migraines and neuropathic pain. It exerts its therapeutic benefits through modulation of multiple mechanisms including regulation of gamma-aminobutyric acid and glutamate neurotransmissions, activation of pro-survival protein kinases and inhibition of histone deacetylase. The evidence for neuroprotective properties associated with VPA is emerging. Herein, we investigated the therapeutic potential of VPA in a mouse model of normal tension glaucoma (NTG). Mice with glutamate/aspartate transporter gene deletion (GLAST KO mice) demonstrate progressive retinal ganglion cell (RGC) loss and optic nerve degeneration without elevated intraocular pressure, and exhibit glaucomatous pathology including glutamate neurotoxicity and oxidative stress in the retina. VPA (300mg/kg) or vehicle (PBS) was administered via intraperitoneal injection in GLAST KO mice daily for 2 weeks from the age of 3 weeks, which coincides with the onset of glaucomatous retinal degeneration. Following completion of the treatment period, the vehicle-treated GLAST KO mouse retina showed significant RGC death. Meanwhile, VPA treatment prevented RGC death and thinning of the inner retinal layer in GLAST KO mice. In addition, in vivo electrophysiological analyses demonstrated that visual impairment observed in vehicle-treated GLAST KO mice was ameliorated with VPA treatment, clearly establishing that VPA beneficially affects both histological and functional aspects of the glaucomatous retina. We found that VPA reduces oxidative stress induced in the GLAST KO retina and stimulates the cell survival signalling pathway associated with extracellular signal-regulated kinases (ERK). This is the first study to report the neuroprotective effects of VPA in an animal model of NTG. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be a novel candidate for treatment of glaucoma. PMID- 25555795 TI - Dynamic loading and redistribution of the Mcm2-7 helicase complex through the cell cycle. AB - Eukaryotic replication origins are defined by the ORC-dependent loading of the Mcm2-7 helicase complex onto chromatin in G1. Paradoxically, there is a vast excess of Mcm2-7 relative to ORC assembled onto chromatin in G1. These excess Mcm2-7 complexes exhibit little co-localization with ORC or replication foci and can function as dormant origins. We dissected the mechanisms regulating the assembly and distribution of the Mcm2-7 complex in the Drosophila genome. We found that in the absence of cyclin E/Cdk2 activity, there was a 10-fold decrease in chromatin-associated Mcm2-7 relative to the levels found at the G1/S transition. The minimal amounts of Mcm2-7 loaded in the absence of cyclin E/Cdk2 activity were strictly localized to ORC binding sites. In contrast, cyclin E/Cdk2 activity was required for maximal loading of Mcm2-7 and a dramatic genome-wide reorganization of the distribution of Mcm2-7 that is shaped by active transcription. Thus, increasing cyclin E/Cdk2 activity over the course of G1 is not only critical for Mcm2-7 loading, but also for the distribution of the Mcm2-7 helicase prior to S-phase entry. PMID- 25555797 TI - Patient-controlled intranasal fentanyl analgesia: a pilot study to assess practicality and tolerability during childbirth. AB - BACKGROUND: Intranasal administration of fentanyl is a non-invasive method of analgesic delivery which has been shown to be effective. This pilot study aimed to assess the practicality and tolerability of patient-controlled intranasal fentanyl for relieving pain during childbirth. METHODS: This prospective, non randomised, clinical trial recruited women with a singleton pregnancy during November 2009 to October 2011. Exclusion criteria included respiratory disease, gestation <37 weeks and pregnancy complications. The device administered fentanyl 54 MUg per spray, incorporating a 3-min lock-out. Data collected included demographics, dose, additional analgesia, adverse events, pain relief and delivery outcomes. Follow-up data were obtained within 48 h regarding tolerability of the device. RESULTS: The final sample included 32 women: mean age was 28.7 years and gestation 39.8 weeks. Mean fentanyl dose was 734 MUg and duration of use was 3.5 h. Most women (78.2%) reported satisfactory to excellent pain relief using the nasal device. Four neonates (12.5%) required bag-mask ventilation at birth: three had adequate respiration within 5 min and one required short-term observation in the special-care nursery. For all items, there was a trend towards an adverse outcome, including neonatal respiratory support, as the dose of fentanyl increased. On follow-up, 84.4% reported they would use intranasal fentanyl for their next childbirth experience. CONCLUSIONS: Patient controlled intranasal fentanyl provides an acceptable level of analgesia during childbirth. It may, however, increase the risk of neonatal respiratory depression. Future, randomised studies should evaluate the safety and efficacy of patient-controlled intranasal fentanyl compared with existing analgesia options. PMID- 25555798 TI - Submacular hemorrhage in polypoidal choroidal vasculopathy treated by vitrectomy and subretinal tissue plasminogen activator. AB - PURPOSE: To evaluate vitrectomy with subretinal tissue plasminogen activator (t PA) injection, and air tamponade, followed by intravitreal anti-vascular endothelial growth factor (VEGF) therapy for submacular hemorrhage in polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, interventional case series. METHODS: setting: Two clinics. PATIENTS: Fifteen eyes of 15 consecutive patients (mean age 72 +/- 7 years) with submacular hemorrhage attributable to PCV. INCLUSION CRITERIA: PCV diagnosis with unorganized submacular hemorrhage greater than 500 MUm thick. EXCLUSION CRITERIA: Submacular hemorrhage attributable to macular diseases (eg, high myopia, typical age-related macular degeneration, retinal angiomatous proliferation, and angioid streaks). INTERVENTION: Vitrectomy with 4000 IU t-PA injected subretinally and fluid/air exchange. Patients remained facedown for 3 days after surgery. Anti-VEGF drugs were administered as exudative changes required. MAIN OUTCOME MEASURES: Submacular hemorrhage displacement from the macula and changes in best-corrected visual acuities (BCVAs). RESULTS: Mean time from onset to surgery was 9.5 +/- 4.5 (range, 5-21) days. Mean follow-up period was 9.4 +/- 3.1 (range, 6-17) months. Surgery successfully displaced submacular hemorrhages from the macula in all eyes. Mean BCVA at baseline (0.98 +/- 0.44) had improved significantly both 1 month after surgery (0.41 +/- 0.25, P < .01) and at final visits (0.23 +/- 0.25, P < .001). In all eyes, exudative retinal changes relapsed after surgery but were completely resolved by anti-VEGF injections. No complications occurred in any patients. CONCLUSION: Treating submacular hemorrhage with vitrectomy and subretinal t-PA injection, followed by intravitreal anti-VEGF therapy, is a promising strategy for improving visual acuity in PCV patients warranting further investigation. PMID- 25555799 TI - Short-term changes in choroidal thickness after aflibercept therapy for neovascular age-related macular degeneration. AB - PURPOSE: To investigate changes in choroidal thickness after aflibercept therapy for neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, consecutive, interventional case series. METHODS: This study included 102 eyes of 102 patients with treatment-naive neovascular AMD. All 102 eyes underwent 3 consecutive monthly 2.0 mg intravitreal aflibercept injections at baseline, 1 month, and 2 months. Choroidal thickness during 3 months were evaluated using either swept-source optical coherence tomography (OCT) or enhanced-depth imaging OCT. RESULTS: Of the 102 eyes, 46 eyes (45.1%) were diagnosed as typical neovascular AMD and 56 eyes (54.9%) as polypoidal choroidal vasculopathy. After intravitreal aflibercept injections, the mean subfoveal choroidal thickness decreased from 252.0 +/- 99.7 MUm at baseline to 217.9 +/- 95.6 MUm at 3 months (P < .0001; percentage change from baseline, 86.5%). Mean choroidal thickness measured at 3 mm from the foveal center in the superior, inferior, temporal, and nasal directions also decreased significantly from 258.7 +/- 85.9 MUm to 236.4 +/ 84.6 MUm, 229.9 +/- 93.0 MUm to 208.6 +/- 86.5 MUm, 237.4 +/- 86.5 MUm to 214.6 +/- 79.5 MUm, and 183.7 +/- 97.0 MUm to 162.3 +/- 90.6 MUm, respectively (P < .0001 for all directions). Both subtypes of neovascular AMD demonstrated a similar trend toward decreasing choroidal thickness during the follow-up period. CONCLUSIONS: Choroidal thickness significantly decreased not only at the foveal center but also in the entire macula after 3 monthly intravitreal aflibercept injections for neovascular AMD. PMID- 25555800 TI - Importance of tear film instability in dry eye disease in office workers using visual display terminals: the Osaka study. AB - PURPOSE: To evaluate the relationship between subjective symptoms and clinical signs in dry eye disease (DED) in office workers using visual display terminals (VDTs). DESIGN: Cross-sectional study. METHODS: This study involved 672 Japanese young and middle-aged office workers who use VDTs. The subjects completed questionnaires designed to detect subjective symptoms and risk factors for DED. Dry eye tests, including tear film break-up time (TBUT), corneal-conjunctival staining with fluorescein and lissamine green, and the Schirmer test, were performed. Based on the Japanese diagnostic criteria for DED, the subjects were classified into 3 groups: definite DED, probable DED, and non-DED. Between each group, subjective symptoms and clinical signs were compared. RESULTS: Of the 672 subjects, 561 (374 male, 187 female) completed the questionnaire (response rate: 83.5%). Definite DED was diagnosed in 65 subjects (11.6%), probable DED in 303 subjects (54.0%), and non-DED in 193 subjects (34.4%). The mean subjective symptom score was significantly less in subjects with probable DED (2.05 +/- 0.42) and non-DED (1.63 +/- 0.38) than in those with definite DED (2.19 +/- 0.40) (P < .05 and P < .01, respectively). In the subjects with probable DED, a subgroup with positive subjective symptoms and abnormal TBUT (<=5 seconds) was categorized as short TBUT-type DED, and it was found that they had a higher subjective symptom score (2.09 +/- 0.40), equivalent to that of those with definite DED (P = .269). CONCLUSIONS: Despite no or minor epithelial damage, the severity of subjective symptoms was greater in short TBUT-type DED, most likely attributable to tear film instability. Thus, it might prove important to evaluate TBUT to successfully treat those patients. PMID- 25555801 TI - Predictors of visual outcomes following Boston type 1 keratoprosthesis implantation. AB - PURPOSE: To identify predictors of visual outcomes following Boston type 1 Keratoprosthesis (KPro) implantation. DESIGN: Retrospective chart review. METHODS: Data regarding preoperative clinical and demographic characteristics and postoperative course were collected. PATIENTS: Fifty-nine eyes of 59 adult patients who underwent KPro implantation between January 2006 and March 2012 at a single tertiary care center. MAIN OUTCOME MEASURES: Preoperative factors associated with all-cause and glaucoma-related loss of visual acuity from the best postoperative visual acuity noted. RESULTS: Fifty-two of 59 eyes (88%) achieved improved vision post implantation, with 7 eyes failing to gain vision as a result of pre-existing glaucoma (n = 4) or retino-choroidal disease (n = 3). Twenty-one eyes (21/52, 40%) maintained their best-ever visual acuity at last visit (mean follow-up period was 37.8 months). The likelihood of maintaining best ever vision was 71% at 1 year, 59% at 2 years, and 48% at 3 years. Primary KPro implantation was associated with a higher likelihood of losing best-ever vision as compared to KPro implantation as a repeat corneal procedure (hazard ratio [HR] = 3.06; P = 006). The main reasons for postimplantation vision loss was glaucoma (12/31, 39%), and the risk of glaucomatous visual acuity loss was 15% at 2 years and 27% at 3 years. Prior trabeculectomy was associated with a higher rate of vision loss from glaucoma (HR = 3.25, P = .04). CONCLUSION: Glaucoma is the primary reason for loss of visual acuity after KPro implantation. Conditions necessitating primary KPro surgery are associated with more frequent all-cause vision loss. Prospective trials are necessary to better determine which clinical features best predict KPro success. PMID- 25555802 TI - Correlation between fundus autofluorescence and central visual function in chronic central serous chorioretinopathy. AB - PURPOSE: To find possible correlations between the morphologic macular changes revealed by fundus autofluorescence (FAF) and the functional parameters such as visual acuity and retinal sensitivity in patients with chronic central serous chorioretinopathy (CSC). DESIGN: Prospective, cross-sectional study. METHODS: Forty-six eyes (39 consecutive patients) with chronic CSC were studied with FAF and microperimetry (MP). Retinal sensitivity value maps were exactly superimposed over FAF images. The following microperimetric parameters were applied: central 10-degree visual field, 4-2-1 strategy, 61 stimulation spots, white monochromatic background, stimulation time 200 ms, stimulation spot size Goldmann III. A possible relationship between MP and FAF was investigated. RESULTS: Mean best corrected visual acuity (BCVA) was 20/32 (median 20/25, range 20/20-20/200). BCVA was significantly correlated with FAF findings (Mann-Whitney test; P < .0001). A positive concordance between FAF and MP evaluation was also found (total concordance of 0.720 with a kappa of Cohen of 0.456). The hypo-autofluorescent areas showed decreased retinal sensitivity, while adjacent areas of increased FAF could be associated to both normal and decreased retinal sensitivity. Absolute scotoma, defined as 0 dB retinal sensitivity, corresponded with absence of autofluorescence. CONCLUSIONS: Altered FAF in chronic CSC patients has a functional correlation quantified by microperimetry. This study confirms the impact of FAF changes on retinal sensitivity and their value to reflect the functional impairment in chronic CSC. PMID- 25555804 TI - Sports-related overuse injuries in children. AB - Increased intensity of sports activities combined with a decrease in daily physical activity is making overuse injuries in children more common. These injuries are located mainly in the epiphyseal cartilage. The broad term for these injuries is osteochondrosis, rather than osteochondritis, which more specifically refers to inflammatory conditions of bone and cartilage. The osteochondrosis may be epiphyseal, physeal, or apophyseal, depending on the affected site. The condition can either be in the primary deformans form or the dissecans form. While there is no consensus on the etiology of osteochondrosis, multiple factors seem to be involved: vascular, traumatic, or even microtraumatic factors. Most overuse injuries involve the lower limbs, especially the knees, ankle and feet. The most typical are Osgood-Schlatter disease and Sever's disease; in both conditions, the tendons remain relatively short during the pubescent grown spurt. The main treatment for these injuries is temporary suspension of athletic activities, combined with physical therapy in many cases. Surgery may be performed if conservative treatment fails. It is best, however, to try to prevent these injuries by analyzing and correcting problems with sports equipment, lifestyle habits, training intensity and the child's level of physical activity, and by avoiding premature specialization. Pain in children during sports should not be considered normal. It is a warning sign of overtraining, which may require the activity to be modified, reduced or even discontinued. PMID- 25555803 TI - Dissociation of mitochondrial from sarcoplasmic reticular stress in Drosophila cardiomyopathy induced by molecularly distinct mitochondrial fusion defects. AB - Mitochondrial dynamism (fusion and fission) is responsible for remodeling interconnected mitochondrial networks in some cell types. Adult cardiac myocytes lack mitochondrial networks, and their mitochondria are inherently "fragmented". Mitochondrial fusion/fission is so infrequent in cardiomyocytes as to not be observable under normal conditions, suggesting that mitochondrial dynamism may be dispensable in this cell type. However, we previously observed that cardiomyocyte specific genetic suppression of mitochondrial fusion factors optic atrophy 1 (Opa1) and mitofusin/MARF evokes cardiomyopathy in Drosophila hearts. We posited that fusion-mediated remodeling of mitochondria may be critical for cardiac homeostasis, although never directly observed. Alternately, we considered that inner membrane Opa1 and outer membrane mitofusin/MARF might have other as-yet poorly described roles that affect mitochondrial and cardiac function. Here we compared heart tube function in three models of mitochondrial fragmentation in Drosophila cardiomyocytes: Drp1 expression, Opa1 RNAi, and mitofusin MARF RNA1. Mitochondrial fragmentation evoked by enhanced Drp1-mediated fission did not adversely impact heart tube function. In contrast, RNAi-mediated suppression of either Opa1 or mitofusin/MARF induced cardiac dysfunction associated with mitochondrial depolarization and ROS production. Inhibiting ROS by overexpressing superoxide dismutase (SOD) or suppressing ROMO1 prevented mitochondrial and heart tube dysfunction provoked by Opa1 RNAi, but not by mitofusin/MARF RNAi. In contrast, enhancing the ability of endoplasmic/sarcoplasmic reticulum to handle stress by expressing Xbp1 rescued the cardiomyopathy of mitofusin/MARF insufficiency without improving that caused by Opa1 deficiency. We conclude that decreased mitochondrial size is not inherently detrimental to cardiomyocytes. Rather, preservation of mitochondrial function by Opa1 located on the inner mitochondrial membrane, and prevention of ER stress by mitofusin/MARF located on the outer mitochondrial membrane, are central functions of these "mitochondrial fusion proteins". PMID- 25555805 TI - Open Latarjet procedure for failed arthroscopic Bankart repair. AB - INTRODUCTION: This retrospective study assessed the functional results of open Latarjet operation for recurrence of instability after arthroscopic Bankart repair in a consecutive series of patients. MATERIALS AND METHODS: Fifty two patients (mean age 28.4 [range 17-62] years, 45 men) were operated on using open Latarjet operation after one (n=46) or two (n=6) failed arthroscopic Bankart repairs. The indication for revision surgery was recurrent dislocation or subluxation. Fifty patients had a Hill-Sachs lesion and 32 patients had glenoid bone lesions on plain radiographs. No attempt was made to grade the severity of bony pathology. Functional outcome and stability of 49 shoulders were assessed after an average follow-up of 38 (range 24-85) months using Western Ontario Shoulder Instability (WOSI) score, Oxford shoulder instability score, and subjective shoulder value (SSV). RESULTS: Forty-two patients had a stable shoulder at follow-up. Seven of 49 (14%) had symptoms of instability; one patient had recurrent dislocation, and six patients had subluxations. Mean WOSI, Oxford, and SSV scores were 83.9, 19.9, and 84.9, respectively. All scores were significantly better in patients who had a stable shoulder compared with those who had an unstable shoulder (WOSI 86.8 vs. 64.3; Oxford 18.2 vs. 30.8; and SSV 88.3 vs. 61.7; P<0.01). One patient needed a reoperation. There were no intraoperative or postoperative complications. CONCLUSIONS: Open Latarjet operation is a good option for failed arthroscopic Bankart repair. The instability recurrence rate is acceptable and the reoperation rate was low. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25555806 TI - NEDL2 is an essential regulator of enteric neural development and GDNF/Ret signaling. AB - Although glial cell line-derived neurotrophic factor (GDNF)/Ret signaling is essential for enteric nervous system (ENS) development, the positive regulators regulating GDNF/Ret signaling and controlling ENS development are poorly understood. Here, we show that Nedd4-related E3 ubiquitin ligase-2 (NEDL2) plays an essential and positive physiological role in regulating ENS development and GDNF/Ret signaling. All of the NEDL2-deficient mice die within 2weeks after birth, showing low body weight. These mice showed a progressive bowel motility defect resulting from intestinal aganglionosis. We show that NEDL2 positively regulates enteric neural precursor proliferation through the GDNF/Akt signaling pathway. Together, these findings unveil the physiological function of NEDL2 in vivo. PMID- 25555807 TI - Detrimental effect of CO2-driven seawater acidification on a crustacean brine shrimp, Artemia sinica. AB - The effects of the decline in ocean pH, termed as ocean acidification due to the elevated carbon dioxide in the atmosphere, on calcifying organisms such as marine crustacean are unclear. To understand the possible effects of ocean acidification on the physiological responses of a marine model crustacean brine shrimp, Artemia sinica, three groups of the cysts or animals were raised at different pH levels (8.2 as control; 7.8 and 7.6 as acidification stress according to the predictions for the end of this century and next century accordingly) for 24 h or two weeks, respectively, followed by examination of their hatching success, morphological appearance such as deformity and microstructure of animal body, growth (i.e. body length), survival rate, expression of selected genes (involved in development, immunity and cellular activity etc), and biological activity of several key enzymes (participated in antioxidant responses and physiological reactions etc). Our results clearly demonstrated that the cysts hatching rate, growth at late stage of acidification stress, and animal survival rate of brine shrimp were all reduced due to lower pH level (7.6 & 7.8) on comparison to the control group (pH 8.2), but no obvious change in deformity or microstructure of brine shrimp was present under these acidification stress by microscopy observation and section analysis. In addition, the animals subjected to a lower pH level of seawater underwent changes on their gene expressions, including Spatzle, MyD88, Notch, Gram-negative bacteria binding protein, prophenoloxidase, Apoptosis inhibitor 5, Trachealess, Caveolin-1 and Cyclin K. Meanwhile, several key enzyme activities, including superoxide dismutase, catalase, peroxidase, alkaline phosphatase and acid phosphatase, were also affected by acidified seawater stress. Taken together, our findings supports the idea that CO2-driven seawater acidification indeed has a detrimental effect, in case of hatching success, growth and survival, on a model crustacean brine shrimp, which will increase the risk of juvenile brine shrimp and possibly also other crustaceans, as important live feeds for aquaculture being introduced in the ecosystem especially the marine food webs. PMID- 25555809 TI - An EPD/WSD motifs containing C-type lectin from Argopectens irradians recognizes and binds microbes with broad spectrum. AB - C-type lectins are a superfamily of Ca(2+)-dependent carbohydrate-recognition proteins consisting of at least one carbohydrate-recognition domain (CRD), which play significant roles in nonself-recognition and clearance of invaders. The immune function of a C-type lectin (AiCTL-7) with EPD/WSD motifs from Argopectens irradians was investigated in the present study. The recombinant protein of AiCTL 7 (rAiCTL-7) could bind LPS, PGN, mannan, yeast glucan and poly I:C in vitro, and displayed a broader microbes binding spectrum towards Gram-positive bacteria Staphylococcus aureus, Gram-negative bacteria Escherichia coli, Vibrio anguillarum, as well as fungi Pichia pastoris and Yarrowia lipolytica. Moreover, it could also inhibit the growth of E. coli and significantly (P < 0.01) mediate the cell-cell adhesion in vitro. The results clearly suggested that EPD/WSD motifs containing lectin AiCTL-7 could serve as PRR with wider recognition spectrum, and function both as collectin and selectin participating in the immunity against invaders in scallops. It could be inferred that the diversity and complexity of motifs in Ca(2+) binding site 2 in CRDs endowed C-type lectins with comprehensive recognition spectrum and multiple immune functions against complex living environment. PMID- 25555808 TI - Characterization of c-Jun from orange-spotted grouper, Epinephelus coioides involved in SGIV infection. AB - The nuclear phosphoprotein c-Jun is a member of the AP1 family of transcription activating complex, can be induced by various extracellular stimuli such as virus infection. In this study, the c-Jun gene (Ec-c-Jun) was cloned from orange spotted grouper, Epinephelus coioides. The full-length Ec-c-Jun cDNA is composed of 2046 bp and encodes a polypeptide of 328 amino acids with 81% identity of zebrafish. Amino acid alignment analysis indicated that Ec-c-Jun contained three conserved domains including a transactivation domain (TAD), a DNA-binding domain (DBD) and leucine zipper domain (LZD). RT-PCR results showed that Ec-c-Jun transcript was most abundant in spleen, kidney, heart and gill. The expression of Ec-c-Jun was up-regulated after challenged with Singapore grouper iridovirus (SGIV). To investigate the roles of Ec-c-Jun during SGIV infection, we constructed its dominant-negative mutant (DN-Ec-c-Jun) by deleting the major TAD that lacks amino acids 3-122. Fluorescence microscopy observation revealed that Ec-c-Jun and DN-Ec-c-Jun were expressed predominantly in the nucleus in transfected cells. Interestingly, the green fluorescence of Ec-c-Jun was congregated and co-localized with virus assembly sites at the late stage of SGIV infection. However, in DN-Ec-c-Jun transfected cells, no virus assembly sites were observed, and the distribution of fluorescence remained unchanged. Moreover, overexpression of DN-Ec-c-Jun in vitro delayed the occurrence of CPE induced by SGIV infection and inhibited the virus gene transcription. In addition, ectopic expression of DN-Ec-c-Jun was able to inhibit SGIV induced c-Jun/AP1 promoter activity in GS cells. Thus, we proposed that c-Jun transcription factor was essential for SGIV replication in vitro. Our results will contribute to understanding the crucial roles of JNK signaling pathway in fish virus infection. PMID- 25555810 TI - Characterization of a gC1qR from the giant freshwater prawn, Macrobrachium rosenbergii. AB - gC1qR, as a multicompartmental and a multifunctional protein, plays an important role in innate immunity. In this study, a gC1qR homolog (MrgC1qR) in the giant freshwater prawn, Macrobrachium rosenbergii was identified. MrgC1qR, a 258-amino acid polypeptide, shares high identities with gC1qR from other species. MrgC1qR gene was expressed in different tissues and was highest expressed in the hepatopancreas. In addition, the MrgC1qR transcript was significantly enhanced after 6 h of white spot syndrome virus (WSSV) infection or post 2 h, 24 h of Vibrio anguillarum challenge compared to appropriate controls. Moreover, recombinant MrgC1qR (rMrgC1qR) had bacterial binding activity, the result also revealed that rMrgC1qR could bind pathogen-associated molecular patterns (PAMPs) such as LPS or PGN, suggesting that MrgC1qRmight function as a pathogen recognition receptor (PRR). Furthermore, glutathione S-transferase (GST) pull down assays showed that rMrgC1qR with GST-tag could bind to rMrFicolin1 or rMrFicolin2 with His-tag. Altogether, these results may demonstrate a role for MrgC1qR in innate immunity in the giant freshwater prawns. PMID- 25555812 TI - Immune gene expression profile of Penaeus monodon in response to marine yeast glucan application and white spot syndrome virus challenge. AB - Immunostimulant potential of eight marine yeast glucans (YG) from Candida parapsilosis R20, Hortaea werneckii R23, Candida spencermartinsiae R28, Candida haemulonii R63, Candida oceani R89, Debaryomyces fabryi R100, Debaryomyces nepalensis R305 and Meyerozyma guilliermondii R340 were tested against WSSV challenge in Penaeus monodon post larvae (PL). Structural characterization of these marine yeast glucans by proton nuclear magnetic resonance (NMR) indicated structures containing (1-6)-branched (1-3)-beta-D-glucan. PL were fed 0.2% glucan incorporated diet once in seven days for a period of 45 days and the animals were challenged with white spot syndrome virus (WSSV). The immunostimulatory activity of yeast glucans were assessed pre- and post-challenge WSSV by analysing the expression profile of six antimicrobial peptide (AMP) genes viz., anti lipopolysaccharide factor (ALF), crustin-1, crustin-2, crustin-3, penaeidin-3 and penaeidin-5 and 13 immune genes viz., alpha-2-macroglobulin (alpha-2-M), astakine, caspase, catalase, glutathione peroxidase, glutathione-s-transferase, haemocyanin, peroxinectin, pmCathepsinC, prophenol oxidase (proPO), Rab-7, superoxide dismutase and transglutaminase. Expression of seven WSSV genes viz., DNA polymerase, endonuclease, protein kinase, immediate early gene, latency related gene, thymidine kinase and VP28 were also analysed to detect the presence and intensity of viral infection in the experimental animals post-challenge. The study revealed that yeast glucans (YG) do possess immunostimulatory activity against WSSV and also supported higher survival (40-70 %) post-challenge WSSV. Among the various glucans tested, YG23 showed maximum survival (70.27%), followed by YG20 (66.66%), YG28 (60.97%), YG89 (58.53%), YG100 (54.05%), YG63 (48.64%), YG305 (45.7%) and YG340 (43.24%). PMID- 25555813 TI - An immune-enriched oligo-microarray analysis of gene expression in Manila clam (Venerupis philippinarum) haemocytes after a Perkinsus olseni challenge. AB - Parasites of the genus Perkinsus cause high mortality and economic losses in bivalves commonly produced in global aquaculture. Although the immune responses of oysters and clams naturally infected with Perkinsus marinus or Perkinsus olseni have been extensively studied, there is not much information on host response at the early stages of infection. In this study, we analysed how P. olseni influences the gene expression profiles of haemocytes from the Manila clam (Venerupis philippinarum) using temporal experimental infections and an immune enriched microarray. We identified an early phase of infection that was characterised by no mortality and by the increased expression of genes associated with pathogen recognition, production of nitrogen radicals and antimicrobial activity. Cellular processes such as inhibition of serine proteases and proliferation were also involved in this early response. This phase was followed by an intermediate stage, when the pathogen was most likely multiplying and infecting new areas of the body, and animals began to die. In this stage, many genes related to cell movement were over-expressed. Thirty days after infection metabolic pathway genes were the most affected. Apoptosis appears to be important during pathogenesis. Our results provide novel observations of the broader innate immune response triggered by P. olseni at different infection stages. PMID- 25555811 TI - Insights into molecular profiles and genomic evolution of an IRAK4 homolog from rock bream (Oplegnathus fasciatus): immunogen- and pathogen-induced transcriptional expression. AB - As a pivotal signaling mediator of toll-like receptor (TLR) and interleukin (IL) 1 receptor (IL-1R) signaling cascades, the IL-1R-associated kinase 4 (IRAK4) is engaged in the activation of host immunity. This study investigates the molecular and expressional profiles of an IRAK4-like homolog from Oplegnathus fasciatus (OfIRAK4). The OfIRAK4 gene (8.2 kb) was structured with eleven exons and ten introns. A putative coding sequence (1395bp) was translated to the OfIRAK protein of 464 amino acids. The deduced OfIRAK4 protein featured a bipartite domain structure composed of a death domain (DD) and a kinase domain (PKc). Teleost IRAK4 appears to be distinct and divergent from that of tetrapods in terms of its exon-intron structure and evolutionary relatedness. Analysis of the sequence upstream of translation initiation site revealed the presence of putative regulatory elements, including NF-kappaB-binding sites, which are possibly involved in transcriptional control of OfIRAK4. Quantitative real-time PCR (qPCR) was employed to assess the transcriptional expression of OfIRAK4 in different juvenile tissues and post-injection of different immunogens and pathogens. Ubiquitous basal mRNA expression was widely detected with highest level in liver. In vivo flagellin (FLA) challenge significantly intensified its mRNA levels in intestine, liver and head kidney indicating its role in FLA-induced signaling. Meanwhile, up-regulated expression was also determined in liver and head kidney of animals challenged with potent immunogens (LPS and poly I:C) and pathogens (Edwardsiella tarda and Streptococcus iniae and rock bream iridovirus (RBIV)). Taken together, these data implicate that OfIRAK4 might be engaged in antibacterial and antiviral immunity in rock bream. PMID- 25555814 TI - Involvement of fish signal transducer and activator of transcription 3 (STAT3) in nodavirus infection induced cell death. AB - The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is an important signaling pathway activated by interferons in response to virus infection. Fish STAT3 has been demonstrated to be involved in Singapore grouper iridovirus (SGIV) infection and virus induced paraptosis, but its effects on the replication of other fish viruses still remained uncertain. Here, the roles of grouper STAT3 (Ec-STAT3) in red spotted grouper nervous necrosis virus (RGNNV) infection were investigated. The present data showed that the distribution of phosphorylated Ec-STAT3 was altered in RGNNV infected fish cells, and the promoter activity of STAT3 was significantly increased during virus infection, suggesting that STAT3 activation was involved in RGNNV infection. Using STAT3 specific inhibitor, we found that inhibition of Ec-STAT3 in vitro did not affect the transcription and protein synthesis of RGNNV coat protein (CP), however, the severity of RGNNV induced vacuolation and autophagy was significantly increased. Meanwhile, at the late stage of virus infection, RGNNV induced necrotic cell death was significantly decreased after inhibition of Ec-STAT3. Further studies indicated that Ec-STAT3 inhibition significantly increased the transcript level of autophagy related genes, including UNC-51-like kinase 2 (ULK2) and microtubule-associated protein 1 light chain 3-II (LC3-II) induced by RGNNV infection. Moreover, the expression of several pro-inflammatory factors, including TNFalpha, IL-1beta and IL-8 were mediated by Ec-STAT3 during RGNNV infection. Together, our results not only firstly revealed that STAT3 exerted novel roles in response to fish virus infection, but also provided new insights into understanding the roles of STAT3 in different forms of programmed cell death. PMID- 25555815 TI - Urinary trypsin inhibitor levels are reduced in cerebrospinal fluid of multiple sclerosis and neuromyelitis optica patients during relapse. AB - BACKGROUND: Neutrophil-mediated inflammation plays an important role in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO). Concentrations of urinary trypsin inhibitor (UTI) have attracted attention as a useful index of the status of inflammatory response. Evidence suggests serum UTI levels are increased in some inflammatory diseases, but little attention has been paid to cerebrospinal fluid (CSF) levels of UTI. OBJECTIVE: To measure CSF concentration of UTI and determine its relationship with disease activity in MS and NMO. METHODS: CSF UTI was measured by an enzyme-linked immunosorbent assay in 18 MS patients, 28 NMO patients and eight controls. RESULTS: CSF UTI concentrations in MS and NMO groups were both significantly lower than those in controls. Expanded disability status scale scores of MS and NMO revealed a trend of increased disease disability with decreased CSF UTI level. The CSF UTI concentrations were not significantly associated with CSF white blood cell counts, total protein, glucose and chlorine concentrations in MS and NMO subgroups. CONCLUSIONS: Our results indicate a reduced UTI level in CSF of MS and NMO patients. The levels were associated with the severity of the two demyelinating diseases during relapse. PMID- 25555816 TI - Patterns of 21-gene assay testing and chemotherapy use in black and white breast cancer patients. AB - BACKGROUND: In women with early stage, hormone receptor (HR)-positive (HR(+)) breast cancer, the 21-gene recurrence score (RS) assay quantifies recurrence risk and predicts chemotherapy responsiveness. Recent data suggest that not all women with early-stage, HR(+) disease receive this testing. We examined sociodemographic, clinical, and attitudinal factors associated with RS testing receipt and the RS testing effect on chemotherapy use in black and white patients. PATIENTS AND METHODS: Women with newly diagnosed invasive, nonmetastatic breast cancer were recruited and interviewed to collect sociocultural and health care process data; clinical data were collected from charts. Of the sample (n = 359), 270 had HR(+) disease. Primary analysis focused on those with HR(+) node-negative disease (n = 143); secondary analyses included node-positive women. Logistic regression models evaluated factors associated with receipt of RS testing and chemotherapy. RESULTS: Among women eligible for the 21 gene assay, 62 patients [43%] received RS testing. In multivariable analysis, older age (odds ratio, 1.04 per 1 year increase; 95% confidence interval, 1.01 1.08) was associated with RS testing after adjustment for covariates. Chemotherapy use was 23%. In multivariable analysis, positive attitudes about chemotherapy and greater risk of recurrence were associated with chemotherapy use (P < .05). CONCLUSION: Patterns of genomic testing might vary according to age. Efforts to understand factors associated with low testing rates will be important. PMID- 25555817 TI - The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 247 consecutive cases. AB - AIM: To analyse the clinical features, laboratory data, foetal-maternal outcomes, and follow-up in a cohort of 247 women with obstetric antiphospholipid syndrome (OAPS). METHODS: The European Registry on APS became a Registry within the framework of the European Forum on Antiphospholipid Antibody projects and placed on a website in June 2010. Cases with obstetric complaints related to aPL who tested positive for aPL prospectively and retrospectively were included. The three-year survey results are reported. RESULTS: 338 women with 1253 pregnancy episodes were included; 915 were historical and 338 were latest episodes. All these women tested positive for aPL. 247 of the 338 fulfilled the Sydney criteria. According to the laboratory categories, 84/247 were in category I, 42 in IIa, 66 in IIb and 55 in IIc. Obstetric complications other than foetal losses, appeared in 129 cases (52.2%). 192 (77.7%) had a live birth and 55 (22.3%) did not. The latter group of only 38 cases (69%) received adequate treatment and 17 (31%) did not. 177/247 (72%) women were put on heparin plus LDA. Thrombosis appeared in two during pregnancy and in 14 during the puerperium. 7 (3%) women evolved to complete SLE. CONCLUSIONS: OAPS shows differential characteristics than classical APS. All laboratory test categories are needed to avoid false-negative diagnoses. In some cases, complement levels could act as a serological marker. OAPS has very good foetal-maternal outcomes when treated. Thrombosis and progression to SLE in mothers with OAPS are scarce compared with "classical APS", suggesting that they have different aPL-mediated pathogenic mechanisms. PMID- 25555818 TI - State of the art: Reproduction and pregnancy in rheumatic diseases. AB - Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their children's birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes. PMID- 25555819 TI - A high throughput colorimetric assay of beta-1,3-D-glucans by Congo red dye. AB - Mushroom strains contain complex nutritional biomolecules with a wide spectrum of therapeutic and prophylactic properties. Among these compounds, beta-d-glucans play an important role in immuno-modulating and anti-tumor activities. The present work involves a novel colorimetric assay method for beta-1,3-d-glucans with a triple helix tertiary structure by using Congo red. The specific interaction that occurs between Congo red and beta-1,3-d-glucan was detected by bathochromic shift from 488 to 516 nm (>20 nm) in UV-Vis spectrophotometer. A micro- and high throughput method based on a 96-well microtiter plate was devised which presents several advantages over the published methods since it requires only 1.51 MUg of polysaccharides in samples, greater sensitivity, speed, assay of many samples and very cheap. beta-D-Glucans of several mushrooms (i.e., Coriolus versicolor, Ganoderma lucidum, Pleurotus ostreatus, Ganoderma carnosum, Hericium erinaceus, Lentinula edodes, Inonotus obliquus, Auricularia auricular, Polyporus umbellatus, Cordyseps sinensis, Agaricus blazei, Poria cocos) were isolated by using a sequence of several extractions with cold and boiling water, acidic and alkaline conditions and quantified by this microtiter plate method. FTIR spectroscopy was used to study the structural features of beta-1,3-D-glucans in these mushroom samples as well as the specific interaction of these polysaccharides with Congo red. The effect of NaOH on triple helix conformation of beta-1,3-D-glucans was investigated in several mushroom species. PMID- 25555820 TI - Actinomyces naeslundii GroEL-dependent initial attachment and biofilm formation in a flow cell system. AB - Actinomyces naeslundii is an early colonizer with important roles in the development of the oral biofilm. The effects of butyric acid, one of short chain fatty acids in A. naeslundii biofilm formation was observed using a flow cell system with Tryptic soy broth without dextrose and with 0.25% sucrose (TSB sucrose). Significant biofilms were established involving live and dead cells in TSB sucrose with 60mM butyric acid but not in concentrations of 6, 30, 40, and 50mM. Biofilm formation failed in 60mM sodium butyrate but biofilm level in 60mM sodium butyrate (pH4.7) adjusted with hydrochloric acid as 60mM butyric media (pH4.7) was similar to biofilm levels in 60mM butyric acid. Therefore, butyric acid and low pH are required for significant biofilm formation in the flow cell. To determine the mechanism of biofilm formation, we investigated initial A. naeslundii colonization in various conditions and effects of anti-GroEL antibody. The initial colonization was observed in the 60mM butyric acid condition and anti GroEL antibody inhibited the initial colonization. In conclusion, we established a new biofilm formation model in which butyric acid induces GroEL-dependent initial colonization of A. naeslundii resulting in significant biofilm formation in a flow system. PMID- 25555821 TI - Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. AB - OBJECTIVES: To summarise the evidence and evaluate the validity of the associations between type 2 diabetes and the risk of developing or dying from cancer. DESIGN: An umbrella review of the evidence across meta-analyses of observational studies of type 2 diabetes with risk of developing or dying from any cancer. DATA SOURCES: PubMed, Embase, Cochrane database of systematic reviews, and manual screening of references. ELIGIBILITY CRITERIA: Meta-analyses or systematic reviews of observational studies in humans that examined the association between type 2 diabetes and risk of developing or dying from cancer. RESULTS: Eligible meta-analyses assessed associations between type 2 diabetes and risk of developing cancer in 20 sites and mortality for seven cancer sites. The summary random effects estimates were significant at P=0.05 in 20 meta-analyses (74%); and all reported increased risks of developing cancer for participants with versus without diabetes. Of the 27 meta-analyses, eventually only seven (26%) compiled evidence on more than 1000 cases, had significant summary associations at P <= 0.001 for both random and fixed effects calculations, and had neither evidence of small study effects nor evidence for excess significance. Of those, only six (22%) did not have substantial heterogeneity (I(2)>75%), pertaining to associations between type 2 diabetes and risk of developing breast, cholangiocarcinoma (both intrahepatic and extrahepatic), colorectal, endometrial, and gallbladder cancer. The 95% prediction intervals excluded the null value for four of these associations (breast, intrahepatic cholangiocarcinoma, colorectal, and endometrial cancer). CONCLUSIONS: Though type 2 diabetes has been extensively studied in relation to risk of developing cancer and cancer mortality and strong claims of significance exist for most of the studied associations, only a minority of these associations have robust supporting evidence without hints of bias. PMID- 25555822 TI - Type 2 diabetes and risk of cancer. PMID- 25555823 TI - The pioneers of transparency. PMID- 25555824 TI - New year brings new transparency for drug company payments to doctors in UK. PMID- 25555825 TI - I would scrap the internal market. PMID- 25555826 TI - The evidence base for orthopaedics and sports medicine. PMID- 25555827 TI - Meta-analysis: testing for reporting bias. PMID- 25555828 TI - New US rules ban aggressive debt collection by charitable hospitals. PMID- 25555829 TI - [Transient ischemic attack: as well a paediatric emergency]. PMID- 25555830 TI - Effectiveness of an additional individualized multi-component complementary medicine treatment on health-related quality of life in breast cancer patients: a pragmatic randomized trial. AB - The aim of this study was to evaluate the effectiveness of an additional, individualized, multi-component complementary medicine treatment offered to breast cancer patients at the Merano Hospital (South Tyrol) on health-related quality of life compared to patients receiving usual care only. A randomized pragmatic trial with two parallel arms was performed. Women with confirmed diagnoses of breast cancer were randomized (stratified by usual care treatment) to receive individualized complementary medicine (CM group) or usual care alone (usual care group). Both groups were allowed to use conventional treatment for breast cancer. Primary endpoint was the breast cancer-related quality of life FACT-B score at 6 months. For statistical analysis, we used analysis of covariance (with factors treatment, stratum, and baseline FACT-B score) and imputed missing FACT-B scores at 6 months with regression-based multiple imputation. A total of 275 patients were randomized between April 2011 and March 2012 to the CM group (n = 136, 56.3 +/- 10.9 years of age) or the usual care group (n = 139, 56.0 +/- 11.0). After 6 months from randomization, adjusted means for health-related quality of life were higher in the CM group (FACT-B score 107.9; 95 % CI 104.1-111.7) compared to the usual care group (102.2; 98.5-105.9) with an adjusted FACT-B score difference between groups of 5.7 (2.6-8.7, p < 0.001). Thus, an additional individualized and complex complementary medicine intervention improved quality of life of breast cancer patients compared to usual care alone. Further studies evaluating specific effects of treatment components should follow to optimize the treatment of breast cancer patients. PMID- 25555832 TI - Autoimmune diseases and breast cancer recurrence: a Danish nationwide cohort study. AB - Autoimmune diseases (ADs) comprise a large group of heterogeneous diseases in which the immune system attacks healthy organs. Both intrinsic changes in the body and AD treatment can compromise immune function. Impaired immune function could increase the risk of recurrent cancer. We aimed to investigate this hypothesis in a population-based epidemiological study. We examined the risk of breast cancer (BC) recurrence associated with an AD diagnosis among patients with incident stages I-III BC diagnosed during 1980-2007. Data were obtained from Danish population-based medical registries. ADs were categorized dichotomously and according to organ system of origin. Follow-up was up to 10 years or until 31 December 2009. Multivariate Cox proportional hazard regression was used to compute hazard ratios (HRs) and associated 95 % confidence intervals (95 % CIs) to evaluate the association between AD diagnosis and BC recurrence. 78,095 women with stages I-III BC were identified. Median age-at-diagnosis was 61 years (19 102 years), median follow-up was 5.7 years, and 13,545 women had a recurrence during follow-up. 6,716 women had at least one AD. In adjusted models, the association between ADs and BC recurrence was near null: HRadjusted 0.96 (95 % CI 0.89, 1.04). These results held in all AD subcategories, except for central nervous/neuromuscular system ADs, with HRadjusted 0.56 (95 % CI 0.40, 0.78). Among women with BC, a history of at least one AD diagnosis was not associated with BC recurrence, with the possible exception of ADs of the central nervous/neuromuscular system. PMID- 25555831 TI - Taking the next step: a systematic review and meta-analysis of physical activity and behavior change interventions in recent post-treatment breast cancer survivors. AB - Research has shown that recent post-treatment breast cancer survivors face significant challenges around physical activity as they transition to recovery. This review examined randomized controlled trials targeting physical activity behavior change in breast cancer survivors <5 years post-treatment and described (1) characteristics of interventions for breast cancer survivors as well as (2) effect size estimates for these studies. A systematic search was conducted following PRISMA guidelines with Medline, PubMed, PsycINFO, CINAHL, and Scopus databases. Data were abstracted for primary intervention strategies and other details (e.g., setting, duration, theory use). A subgroup analysis was conducted to assess intensity of exercise supervision/monitoring and intervention effectiveness. The search produced 14 unique behavior intervention trials from the US and abroad published 2005-2013. The mean sample size was 153 participants per study. All interventions included moderate-intensity activities plus various behavioral change strategies. Most interventions were partially or entirely home based. The overall standardized mean difference was 0.47 (0.23, 0.67) with p < 0.001. Most interventions were effective in producing short-term behavior changes in physical activity, but varied greatly relative to intervention strategies and intensity of supervision/monitoring. Highly structured interventions tended to produce larger behavior change effects overall, but many larger effect sizes came from interventions supported by phone counseling or e-mail. We observed that 'more' may not be better in terms of direct supervision/monitoring in physical activity behavior interventions. This may be important in exploring less resource intensive options for effective behavior change strategies for recent post treatment survivors. PMID- 25555833 TI - Patient-initiated breath-holds in MRI: an alternative for reducing respiratory artifacts and improving image quality. AB - PURPOSE: To investigate MRI image quality using two different breath-hold techniques. MATERIALS AND METHODS: Thirty patients remitted for MRI, 2D-dual gradient echo acquisition of the liver conducted two separate breath-hold acquisitions in randomized order, operator-instructed and patient-initiated. The images were reviewed by two radiologists. RESULTS: There were no significant differences in image quality between the two breath-hold techniques either in overall image quality or respiratory motion artifacts. This assessment was equal and concordant for both radiologists. CONCLUSION: In terms of image quality, the patient self-initiated breath-hold was shown to be an equal alternative to conventional breath-hold imaging. PMID- 25555834 TI - Response to K. Page et al., 'Costing the Australian National Hand Hygiene Initiative'. PMID- 25555835 TI - 3D ultrasound compared to magnetic resonance imaging and 2D ultrasound in assessing rheumatoid arthritis activity: A 6-month pilot study. PMID- 25555836 TI - Reliability and validity of the Dutch-translated Body Image Scale. AB - PURPOSE: Lacking a comprehensible and widely applicable Dutch test to assess body image changes in cancer patients, we validated Hopwood's Body Image Scale (BIS) for the Dutch language. METHODS: The BIS consists of 10 items scored 0-3. Total scores range from 0 (minimum body image-related distress) to 30 (maximum distress). After forward and backward translation of the BIS, we evaluated its psychometric characteristics in breast cancer patients. We assessed feasibility by missing answer rates and positive response prevalence (score >= 1) per item (criterion >= 30 %), test-retest reliability with a 2-week interval, internal consistence using Cronbach's alpha and discriminant ability by comparing body image after breast-conserving therapy (BCT) versus mastectomy. RESULTS: Psychometric evaluation of 108 BCT and 101 mastectomy patients showed high feasibility (0.2 % missing answers), high positive response prevalence of >= 30 % in 9/10 items and high internal consistency (alpha > 0.90). Test-retest reliability and correlation were high with 5.78 (test) versus 5.75 (retest; P = 0.86) and Spearman's rho = 0.92 (P < 0.01). Discriminant ability was good with BIS scores of 4.56 after BCT versus 7.19 after mastectomy (P < 0.01). All results were comparable to the results of the original BIS. CONCLUSION: The Dutch translated BIS showed excellent psychometric results very similar to the original BIS. Its concise and simple design further supports wide application in clinical practice. PMID- 25555838 TI - Folic acid binds DNA and RNA at different locations. AB - We located multiple binding sites for folic acid on DNA and tRNA at physiological conditions, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Structural analysis revealed that folic acid binds DNA and tRNA at multiple sites via hydrophilic, hydrophobic and H-bonding contacts with overall binding constants of Kfolic acid-DNA=1.1 (+/-0.3)*10(4) M(-1) and Kfolic acid tRNA=6.4 (+/-0.5)*10(3) M(-1). Molecular modeling showed the participation of several nucleobases in folic acid complexes with DNA and tRNA, stabilized by H bonding network. Two types of complexes were located for folic acid-tRNA adducts, one at the major groove and the other with TPsiC loop, while acid binding occurs at major and minor grooves of DNA duplex. Folic acid complexation induced more alterations of DNA structure than tRNA. PMID- 25555837 TI - Reliability and validity of the EQ-5D-5L compared to the EQ-5D-3L in patients with osteoarthritis referred for hip and knee replacement. AB - PURPOSE: To assess the test-retest reliability of the EQ-5D-5L (5L) and compare the validity of the 5L and EQ-5D-3L (3L) in osteoarthritis patients referred to an orthopaedic surgeon for total joint replacement. METHODS: We mailed questionnaires to 306 consecutive patients following referral and a second questionnaire after 2 weeks to assess reliability. Questionnaires included the 5L, EQ-VAS, Short Form-12, Oxford hip and knee scores, pain VAS, and the 3L. We compared the ceiling effect, redistribution properties, convergent and discriminant validity, and discriminatory power of the 5L and 3L. RESULTS: We obtained 176 respondents (response rate 58 %), 60 % female, 64 % knee patients, mean age 65 years (SD 11), with no significant differences between responders versus non-responders. Intraclass correlation coefficients were 0.61-0.77 for the 5L dimensions and 0.87 for the 5L index. For the 3L, most patients used level 2 (some/moderate problems) for mobility (87 %), usual activities (78 %), and pain/discomfort (71 %). In comparison, 5L responses were spread out with only 52, 42, and 50 %, respectively, using the middle level. All convergent validity coefficients were stronger with the 5L (Spearman coefficients 0.51-0.75). Absolute informativity (Shannon's index) showed higher results for all dimensions of the 5L compared with the 3L (average difference 0.74). Relative informativity (Shannon's evenness index) showed an increase from the 3L to the 5L in mobility, usual activities, and pain/discomfort. CONCLUSIONS: The 5L provided stronger validity evidence than the 3L, especially for dimensions relevant to this patient population-mobility, usual activities, and pain/discomfort. PMID- 25555839 TI - Effect of gamma-irradiation on the physical and mechanical properties of kefiran biopolymer film. AB - In this study, the effect of different gamma-ray dosages (3, 6, and 9 kGy) on the functional properties of kefiran biopolymer was investigated. The obtained results showed that increasing gamma-ray dosage brought about an increase in the tensile strength of film specimens up to three-times. However, elongation at break, and tensile energy to break of gamma-irradiated kefiran films decreased in the wake of increasing gamma-ray dosage. gamma-Irradiation could improve surface hydrophobicity, sensitivity of kefiran film specimens to water, and water vapor permeability, but yellowness of films increased, simultaneously. XRD spectrum confirmed increased crystallinity of gamma-irradiated films. Melting point of films was constant but glass transition temperature decreased drastically at high gamma-ray dosage (9 kGy). ATR-FTIR analysis confirmed that gamma-ray engendered no changes in chemical functional groups. According to the result, a mechanism was proposed to percept the effects of gamma-irradiation on kefiran biopolymer and its role on the functional properties of kefiran film. Hence, the functional properties of kefiran films were depend on the ratio of cross-linkages between polymer chains and produced mono and disaccharide by gamma-irradiation. PMID- 25555846 TI - [Contribution of arterial spin labeling to the diagnosis of sudden and transient neurological deficit]. AB - MRI is the gold standard exploration for sudden transient neurological events. If diffusion MRI is negative, there may be a diagnostic doubt between transient ischemic attack and other causes of transient neurological deficit. We illustrate how sequence arterial spin labeling (ASL), which evaluates cerebral perfusion, contributes to the exploration of transient neurological events. An ASL sequence was performed in seven patients with a normal diffusion MRI explored for a transient deficit. Cortical hyperperfusion not systematized to an arterial territory was found in three and hypoperfusion systematized to an arterial territory in four. ASL helped guide early management of these patients. PMID- 25555840 TI - Differential regenerative capacity of neonatal mouse hearts after cryoinjury. AB - Neonatal mouse hearts fully regenerate after ventricular resection similar to adult zebrafish. We established cryoinjury models to determine if different types and varying degrees of severity in cardiac injuries trigger different responses in neonatal mouse hearts. In contrast to ventricular resection, neonatal mouse hearts fail to regenerate and show severe impairment of cardiac function post transmural cryoinjury. However, neonatal hearts fully recover after non transmural cryoinjury. Interestingly, cardiomyocyte proliferation does not significantly increase in neonatal mouse hearts after cryoinjuries. Epicardial activation and new coronary vessel formation occur after cryoinjury. The profibrotic marker PAI-1 is highly expressed after transmural but not non transmural cryoinjuries, which may contribute to the differential scarring. Our results suggest that regenerative medicine strategies for heart injuries should vary depending on the nature of the injury. PMID- 25555847 TI - [Recurrence and de novo trigeminal neuralgia induced by fampridine]. PMID- 25555848 TI - [Meningeal tertiary lymphoid organs: Major actors in intrathecal autoimmunity]. AB - Multiple sclerosis (MS) is characterized by an intrathecal synthesis of immunoglobulins synthesized by B-cell clones and by a brain infiltrate of clonal T-cells. The clonal maturation of these lymphocytes takes place in tertiary lymphoid organs (TLO) developed in the intrathecal compartment. TLO are acquired lymphoid organs able to develop in the vicinity of the inflammatory sites, where they mount a complete antigen-driven immune response. We here review TLO pathophysiology in animal models of MS and human MS. Several pieces of evidence suggest that intrathecal TLO may play a major role in the clinical impairment. Potential therapeutic applications are examined. PMID- 25555849 TI - [Dysphagia as the only presentation of medullary infraction]. PMID- 25555850 TI - Surgical management of Moyamoya disease and syndrome: Current concepts and personal experience. AB - In this focus, we review, in the light of the recent literature, the modalities and indications of surgical cerebral revascularization for Moyamoya (MM) disease or syndrome. We also report our experience in the surgical management of adult MM. In symptomatic forms, with presence of severe disturbances of perfusion or cerebrovascular reactivity on multimodal imaging work-up, the risks of recurrent ischemic or hemorrhagic stroke is high (respectively 10-13%/yr and 2-7%/yr). The objective of treatment is to augment cerebral perfusion (in ischemic forms) or to reduce lenticulo-striate neovessel overload (in hemorrhagic forms), by initiating the development of a cortical neovascularization and/or by directly increasing cerebral blood flow. The risk of immediate postoperative death or stroke is similar between indirect and direct or combined techniques and respectively 0 0.5% and 3-6%, provided a strict perioperative anesthetic management is applied (normocapnia, normoxia and controlled hypertension). Indirect techniques (i.e. encephalo-duro-arterio-myo-periosteo-synangiosis or multiple burr-holes) are technically easy, allow wide cortical revascularization and are very efficient in children: absence of clinical recurrence in more than 95% of cases and presence of a good neovascularization in 83%. However, their effect is delayed for several months, the impact on the hemorrhagic risk is moderate and the global response is uncertain in adults. Direct (superficial temporal artery to middle cerebral artery bypass) or combined techniques improve cerebral blood flow immediately and significantly. They are associated with a higher rate of stroke-free survival at 5 years (95% vs 85%). A recent randomized study has proven that they could reduce the hemorrhagic risk by 2- to 3-fold in comparison with conservative treatment alone. However, their feasibility in children is limited by the very small size of vessels. We present also our results in the surgical management of 12 adult MM patients (mean age 41.3, sex ratio=1) operated between 2009 and 2014 (14 revascularization procedures: EDAMS 2, multiple burr-holes 1, combined revascularization procedures 11). MM types according to clinical presentation were the following: ischemic 8, hemorrhagic 2, combined 2. All patients were recently symptomatic, with recurrent ischemic/hemorrhagic events (2/3) or crescendo neurological deficit (1/3) in association with severe alterations of cerebral blood flow. Mean clinical and radiological follow-up was 22 months. Postoperative mRS at 6 months was improved or stable in 92%. None of the patients suffered recurring stroke. In conclusion, surgical treatment should be discussed quickly in symptomatic forms of MM (progressive or recurring) because of their poor outcome. Indirect techniques are favored in pediatric patients due to their simplicity and good clinical results. Direct, or preferentially combined techniques would be more effective in adult patients to prevent the recurrence of ischemic or hemorrhagic stroke. PMID- 25555851 TI - [Craniocervical mass in a chronic hemodialyzed patient]. PMID- 25555852 TI - [Moyamoya disease: Diagnosis, clinical features, evolution and treatment in 10 patients]. AB - INTRODUCTION: Moyamoya disease is a rare chronic cerebrovascular disease. The objective of this article is to report the different clinical and radiological presentations and describe treatments and clinical course of this disease. METHODS: We searched for patients with Moyamoya disease diagnosed at a French university hospital. The diagnosis was based on arteriographic records showing uni- or bilateral stenosis of distal intracranial internal carotid arteries or middle cerebral arteries associated with a classic collateral network imparting a puff of smoke aspect. Data about clinical and radiological symptoms were analyzed for all identified patients. RESULTS: Ten patients were recorded between 2009 and 2014 including one child and nine adults. The initial presentation was intracerebral hemorrhage in two patients, ischemic stroke in six, and either exercice-related transient ischemic attacks or syncope in two. Recurrent events were noted in four patients. Four patients had one or several recurrent vascular events. Eight patients were given medical treatment and none underwent surgery. Secondary Moyamoya syndrome was suspected in two patients, all the others one were considered idiopathic. CONCLUSION: Moyamoya disease is a rare but potentially severe illness. The initial presentation is more frequently an ischemic stroke; recurrences are frequent. The diagnosis is based on arteriography, which is also recommended to search for a cause. PMID- 25555853 TI - [Imaging Moya-Moya disease]. AB - Moya-Moya disease is a rare arterial occlusive disease affecting the internal carotid artery and its branches. It is found in both pediatric and adult populations, and it may lead to severe clinical presentations such as stroke and intracranial hemorrhage. Several surgical procedures have been developed to improve its clinical outcome. Imaging techniques have a key role in management of Moya-Moya disease, as they are necessary for diagnosis, choice of treatment and follow-up. Although catheter angiography remains the diagnostic gold standard, and nuclear-medicine techniques best perform hemodynamic studies, less invasive imaging techniques have become efficient in serving these purposes. Conventional MRI and MR angiography, as well as MR functional and metabolic studies, are now widely used in each stage of disease management, from diagnosis to follow-up. CT scan and Doppler sonography may also help assess severity of disease and effects of treatment. The aim of this review is to clarify the utility, efficiency and latest developments of each imaging modality in management of Moya-Moya disease. PMID- 25555854 TI - Caval tumor thrombus volume influences outcomes in renal cell carcinoma with venous extension. AB - INTRODUCTION: Surgery for renal cell carcinoma with tumor thrombus has a high potential morbidity rate, and the current classification system based on proximal tumor thrombus level (TTL) has not been shown to consistently predict outcomes. AIM: To assess the prognostic value of inferior vena cava tumor thrombus volume (IVC-TV) for determining the perioperative complications as well as with survival end points. METHODS: From June 2001 to June 2012, we identified 147 patients who underwent radical nephrectomy with venous thrombi. In total, 66 patients had IVC involvement and available imaging for review. IVC-TV was measured by cross sectional area and height measurement for each axial slice. Linear, logistic models and Cox proportional hazard was used for analysis. RESULTS: Median IVC-TV was 16.5 cm(3), and 18 patients had TTL>=III. In total, 57 Clavien I-V complications were documented in 32 patients including 3 deaths. On multivariate analysis, age>65 years, American Society of Anesthesiologists>3, and IVC-TV>15 cm(3) were independent predictors for perioperative complications. Disease progression (PoD) occurred in 78% of patients, and metastatic disease (hazard ratio [HR] = 3.33, P<0.01) and non-clear cell histology (HR = 2.98, P = 0.02) were independent predictors of PoD. Median time to death was 16 months (interquartile range: 5.2-42.9). On Cox regression analysis, metastatic disease, non-clear cell histology, IVC-TV>15 cm(3), and TTL III/IV were significantly associated with overall survival. As a preoperative variable, IVC-TV>15 cm(3) was shown to be an independent predictor of PoD (HR = 2.3, P = 0.01) and overall survival (HR = 2.21, P = 0.03). CONCLUSION: IVC-TV has value as a prognostic indicator, which is superior to TTL in the setting of renal cell carcinoma with IVC venous thrombus. PMID- 25555855 TI - Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. AB - Protocols of systematic reviews and meta-analyses allow for planning and documentation of review methods, act as a guard against arbitrary decision making during review conduct, enable readers to assess for the presence of selective reporting against completed reviews, and, when made publicly available, reduce duplication of efforts and potentially prompt collaboration. Evidence documenting the existence of selective reporting and excessive duplication of reviews on the same or similar topics is accumulating and many calls have been made in support of the documentation and public availability of review protocols. Several efforts have emerged in recent years to rectify these problems, including development of an international register for prospective reviews (PROSPERO) and launch of the first open access journal dedicated to the exclusive publication of systematic review products, including protocols (BioMed Central's Systematic Reviews). Furthering these efforts and building on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, an international group of experts has created a guideline to improve the transparency, accuracy, completeness, and frequency of documented systematic review and meta-analysis protocols--PRISMA-P (for protocols) 2015. The PRISMA-P checklist contains 17 items considered to be essential and minimum components of a systematic review or meta-analysis protocol.This PRISMA-P 2015 Explanation and Elaboration paper provides readers with a full understanding of and evidence about the necessity of each item as well as a model example from an existing published protocol. This paper should be read together with the PRISMA-P 2015 statement. Systematic review authors and assessors are strongly encouraged to make use of PRISMA-P when drafting and appraising review protocols. PMID- 25555856 TI - The effect of audio therapy to treat postoperative pain in children undergoing major surgery: a randomized controlled trial. AB - PURPOSE: To evaluate the analgesic effect of music and audiobooks in children undergoing major surgical procedures when compared to a control (silence) group. METHODS: The study was a prospective and randomized trial. Children undergoing major surgeries were randomized to one of the three groups: music, audiobook or control (silence). The primary outcome was the pain burden reduction by two treatments within 48 h postoperatively. Pain burden was measured using the area under the pain scale versus the 30 min interval for each treatment. RESULTS: 60 patients were recruited and 56 completed the study. Pain burden was reduced in the music and audiobook groups compared to control, median (IQR) of -60 (-90 to 0), -45 (-90 to 0) and 0 (-30 to 90) (min * pain score), respectively, P = 0.04. A linear regression analysis demonstrated an independent group effect on pain reduction even after adjusting for the mean pain scores recorded at the beginning of the treatment, slope of regression line -56.8 +/- 24 goodness of fit r (2) = 0.25 and slope significantly different from 0 (P = 0.02). CONCLUSIONS: Audio therapy is an efficacious adjunct method to decrease post-surgical pain in children undergoing major surgeries. Audio therapy should be considered as an important strategy to minimize pain in children undergoing major surgery. PMID- 25555857 TI - Letter to the editor, in response to the letter entitled: Mean platelet volume in retinal vein occlusions? PMID- 25555858 TI - Mean platelet volume in retinal vein occlusions. PMID- 25555859 TI - Attention to Infliximab adverse events: chimeric monoclonal antibodies can induce anti chimeric antibodies that may result in Kounis hypersensitivity associated acute coronary syndrome. PMID- 25555860 TI - Comparison of cerebral-cardiac syndrome caused by nonaneurysmal or aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To investigate the difference between myocardial injuries caused by nonaneurysmal subarachnoid hemorrhage (SAH) or aneurysmal SAH. PATIENTS AND METHODS: A total of 92 inpatients with SAH at early stage (within 48h), who were treated in our hospital from 2008 to 2014 were enrolled in this study. Differences in cerebral-cardiac syndrome seen in perimesencephalic subarachnoid hemorrhage (PMSAH), non-perimesencephalic subarachnoid hemorrhage (n-PMSAH), and aneurysmal subarachnoid hemorrhage (aSAH) were recorded based Hunt-Hess scores, electrocardiogram/echocardiography findings, and serum myocardial enzymes. RESULTS: The Hunt-Hess grade was relatively lower in the PMSAH group (mainly at grades I and II) than in aSAH group and n-PMSAH group. The ECG score was significantly lower in the PMSAH Group than in the aSAH or n-PMSAH Group. In the PMSAH group, the left ventricular function was normal; in contrast, the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular wall thickness, and left ventricular ejection fraction showed certain abnormalities in the aSAH group and n-PMSAH group. The myocardial enzymes remarkably increased only in the aSAH group. CONCLUSIONS: In PMSAH patients, the lower Hunt-Hess grade, milder ECG abnormalities, less changes in cardiac enzymes and echocardiography are associated with better prognosis. The clinical course and myocardial injuries are poorer in n-PMSAH patients when compared with the PMSAH patients but better than aSAH patients. PMID- 25555861 TI - Multivessel spontaneous dissection of the left coronary tree in the postpartum period: case report and review of the literature. AB - Spontaneous coronary artery dissection is a rare cause of myocardial infarction predominantly associated with young women during the third trimester of pregnancy or during the postpartum period. Multivessel spontaneous coronary artery dissection is an even less frequent condition with limited reports in medical literature. Hormonal changes as well as hemodymanic stress are some of the factors that have been implicated in the etiology of this condition. However, the exact pathophysiological process leading to spontaneous coronary artery dissection has not yet been elucidated. The spectrum of clinical presentation ranges from mild symptoms to cardiac arrest. Herein, we report the case of a 39 year-old woman with spontaneous two coronary vessel dissection during her postpartum period presented with ST elevation myocardial infarction on electrocardiogram complicated with pulmonary edema and cardiorespiratory arrest. PMID- 25555862 TI - Metallothionein 2A genetic polymorphism and its correlation to coronary heart disease. AB - OBJECTIVE: To investigate the gene polymorphism of metallothionein 2A (MT2A) 838G/C and its correlation to coronary heart disease in the Han population of Jiangsu, China. PATIENTS AND METHODS: The MT2A-838G/C was examined in 287 patients with coronary heart disease (CHD group) and 226 healthy controls (control group) by using mono-labeled fluorescent probes. Meanwhile, relevant variables of all subjects were measured, including blood lipid and glucose profiles and body mass index (BMI). The extent of the coronary artery disease was evaluated based on Gensini's coronary artery scoring method. RESULTS: Three distinct genotypes were identified. The highest frequency was observed for genotype GG, followed by genotype GC and CC. There were statistically significant differences in the genotype and allele frequency distribution of the MT2A gene 838G/C polymorphism between the CHD and the control group (p < 0.05). The allele frequency of MT2A-838C in the CHD patients were higher than that in the healthy controls (31.4% vs 24.6%, p = 0.016). The CHD risk in C allele carriers (including genotype GC+CC) was 1.562 folds as high as in GG allele carriers (OR = 1.562, 95% confidence intervals (CI): 1.099-2.218, p = 0.013). According to the results of logistic regression analysis, the C allele was an independent risk factor for CHD (p < 0.05). Gensini's coronary artery disease score were higher in C allele carriers than in non-C allele carriers (p < 0.05). CONCLUSIONS: The gene polymorphism of MT2A-838G/C is correlated to CHD. The C allele might be a CHD susceptible gene and might also have an effect on the extent of coronary artery disease. PMID- 25555863 TI - Mitral annular tissue velocity in the diagnosis of coronary artery disease. AB - OBJECTIVE: Non-invasive methods of coronary disease detection are immediately needed. Recent work suggested that mitral annular tissue velocity measurements could be helpful for assessing left ventricular function. We aim to determine the effect of coronary artery lesion on left ventricular function using tissue Doppler imaging (TDI), and to discuss the role of mitral annular tissue velocity in the diagnosis of coronary heart disease (CHD). PATIENTS AND METHODS: Coronary angiographic examinations were conducted for 68 patients with suspected CHD. Left ventricular ejection fraction (LVEF), early diastolic mitral flow velocity E, late diastolic mitral flow velocity A, mean systolic (Sa) and mean early diastolic velocity (Ea) of the septal and lateral mitral annulus were measured before the angiographic examination. Patients were grouped according to the number of branches with >= 50% stenosis. The control group has 15 individuals. The remaining 53 patients with stenosis in 1, 2 and 3 branches were grouped into 1-Branch, 2-Branch, 3-Branch-Light-Condition and 3-Branch-Heavy-Condition groups, respectively. No significant differences in the other general health parameters of the patients were found. RESULTS: There was no significant difference in LVEF and E/A but in Sa, Ea and E/Ea values between CHD and non-CHD patients. The E/Ea value was significantly elevated in CHD patients, aggravated by this pathological condition. The area bounded by the ROC (receiver operating characteristic) curve of E/Ea is the largest. The sensitivity and specificity of using E/Ea > 8.34 as the diagnostic criterion to pinpoint CHD were 77.4% and 100%, respectively. CONCLUSIONS: E/Ea is a good indicator of diastolic function and can be useful to diagnose CHD. PMID- 25555864 TI - Variability in lipid profile among patients presented with acute myocardial infarction, unstable angina and stable angina pectoris. AB - OBJECTIVE: Despite the amply evidence and guidelines in treating coronary artery disease (CAD) with lipid-lowering therapy, physicians still have concerns in treating acute myocardial infarction (AMI) patients who have the low serum lipid level. We explored the adequacy of lipid-lowering therapy in treating AMI patients. PATIENTS AND METHODS: Over 3000 CAD lipid profile data were collected, their data were divided into 3 groups (AMI; stable angina pectoris (SAP) and unstable angina pectoris (UAP) group) based their clinical characteristics. Statistical analyses were performed to compare their baseline lipid levels and clinical feature. RESULTS: The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) level in AMI patients were the lowest, followed by UAP patient group and SAP patient group. There were significant differences in white blood count (WBC) and ejection fraction (EF) between 3 groups. A good correlation was confirmed between EF% and the lipid parameters of TC, LDL-c, HDL-c, non-HDL-c. WBC did not correlate with the lipid except HDL-c. AMI is an acute inflammatory reaction that is accompanied with the change of lipid level. CONCLUSIONS: Although the level of TC, LDL-c and HDL-c are lower in AMI, but it is related with acute inflammatory reaction during the rupture of atherosclerotic plaques. Lipid-lowering therapy should not be delayed in treating AMI patients with lower lipid level. PMID- 25555865 TI - Long-term result of bilateral pectoralis major muscle advancement flap in median sternotomy wound infections. AB - OBJECTIVE: Deep sternal wound infection (DSWI) is an uncommon but serious complication of open heart surgery being characterized by a high mortality rate and a considerable economic weight. Repair of sternal defects, compromised with infection, can be achieved in several ways. The aim of our study is to report our case load in the management of sternal wound infection. PATIENTS AND METHODS: In this study, we will report our twelve-year case load with bilateral pectoralis major advancement flap as the sole treatment modality for deep sternal wound infection. RESULTS: This surgical approach has given excellent results in terms of resolution of the infection of the sternum, with few complications and a good cosmetic result. CONCLUSIONS: We propose bilateral pectoralis major advancement flap as the first choice treatment for deep sternal wound infection. PMID- 25555866 TI - Lipid peroxidation and protein oxidation are related to the severity of OSAS. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is associated with elevated cardiovascular morbidity and mortality. Considering that oxidative stress is involved in endothelial dysfunction and atherosclerosis development, our aim was to examine lipid peroxidation and protein oxidation, two parameters of oxidative status, in a group of subjects with OSAS. PATIENTS AND METHODS: We consecutively enrolled 48 patients (36 men and 12 women; mean age 49.7+/-14.6 yrs) with OSAS, subsequently subdivided according to the apnea/hypopnea index (AHI) value in two subgroups: Low (L= 21 subjects with AHI<30) and High (H= 27 subjects with AHI>30). We examined lipid peroxidation, expressed as TBARS, and protein oxidation, measured as carbonyl groups in plasma samples from fasting venous blood. RESULTS: We observed that TBARS and carbonyl groups were significantly higher in subjects with AHI > 30 in comparison with the L subgroup and the whole group of OSAS subjects. In addition, we found that these parameters were positively correlated with neck and waist circumference, with the AHI value and with the oxygen desaturation index, and negatively correlated with the mean oxygen saturation. CONCLUSIONS: Lipid peroxidation and protein oxidation in OSAS patients are significantly correlated with the severity of the disease. PMID- 25555867 TI - Diagnostic value of different patient positions during expiratory low-dose thin layer MDCT for evaluating air trapping after allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVE: To investigate the diagnostic value of different patient positions during expiratory low-dose thin-layer multidetector computed tomography (MDCT) for detecting air trapping after allogeneic hematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: Expiratory lung MDCT scanning was done for 51 post-allo-HSCT patients in both the supine and prone positions to determine if they had air trapping lesions. We assessed the volume fraction of an air trapping region (CT value of <=700HU at expiratory phase) against the whole lung area with a GE workstation and graded these results. RESULTS: In the supine position, multiple air trapping lesions were found in 16 of 51 patients, which were scattered and mainly distributed in the dorsal sides of both lower lobes. In the prone position, in addition to these 15 patients, air trapping lesions were also found in 11 other patients, which were mainly distributed in the anterior load-bearing area of the lung lower lobes and lobe-connected areas. Compared with that in the supine position, the graded score of air trapping in the prone position was significantly different (p = 0.006). CONCLUSIONS: When performing expiratory thin-layer MDCT for patients with chronic rejection reactions after allo-HSCT, scanning in the prone position should also be performed, not only to more accurately observe lesions, but also for a preliminary evaluation of air trapping severity. This provides a basis for an early clinical diagnosis and treatment. PMID- 25555868 TI - Alendronate: new formulations of an old and effective drug to improve adherence avoiding upper gastrointestinal side effects. AB - OBJECTIVE: Alendronate is a second generation bisphosphonate which has been widely used in medical practice for two decades to treat osteoporosis and prevent fragility fractures both in elderly people and in younger patients. METHODS: Since many papers have been recently published and new formulations or dosages have been developed, our aim was to review the most significant medical literature addressing the issues of efficacy, safety, posology and formulations of the treatment with alendronate in osteoporotic patients. RESULTS: The efficacy of alendronate in reducing the risk of vertebral and non-vertebral fractures has been demonstrated in several studies. Despite favourable data coming from clinical trials, tolerability of alendronate represented a critical issue since its introduction into real clinical practice, possibly leading to early discontinuation of the therapy, especially when combined with lack of motivation of the patient. For this reason, new dosages and formulations of alendronate have been developed, alone or in combination with vitamin D, which have shown to reduce the impact of gastro-oesophageal adverse events, and minimize discomfort due to the need of adopting unfavourable postural positions every day, fasting for at least one hour. CONCLUSIONS: Alendronate is the most frequently used antifracture therapy among those currently available. The increasing use of the 70 mg weekly dosages and newest formulations of this drug are expected to reduce adverse events and increase adherence to the antifracture therapy, thus resulting in better clinical outcomes when treating osteoporotic patients. PMID- 25555869 TI - The treatment of severe and multiple injuries in intensive care unit: report of 80 cases. AB - OBJECTIVE: To summarize our case load in managing severe and multiple injuries (SMI) in the Intensive Care Unit (ICU). PATIENTS AND METHODS: The clinical data of 80 SMI patients treated in our ICU from January 2009 to June 2013 were analyzed. RESULTS: Results of these 80 SMI patients, 60 (75%) were salvaged and 15 (18.75%) died. The causes of death included severe head injury (n=7), severe chest injury (n=3), destruction of injured abdominal organs (n=2), and multiple organ dysfunction syndrome (n=3). Five patients (7.50%) gave up treatment and were discharged upon their own requests. Early application of continuous renal replacement therapy (CRRT) and enteral nutrition (EN) improved outcomes. CONCLUSIONS: The key interventions during the ICU treatment of SMI include: adequate analgesia and appropriate sedation; timely management of hypoxemia; reasonable fluid resuscitation and CRRT. PMID- 25555870 TI - Knockdown of ERK/Slug signals sensitizes HL-60 Leukemia cells to Cytarabine via upregulation of PUMA. AB - OBJECTIVE: To study the mechanism of early chemosensitivity and later chemoresistance of Cytarabine (Cyt) to HL-60 cells to regulate ERK/Slug signal pathway. MATERIALS AND METHODS: HL-60 cells were stably transfected with NF kappaBp65 siRNA,P53 up-regulated modulator of apoptosis (PUMA) siRNA (PUMA siRNA) and Slug siRNA respectively or exposed to 25 nM U0126 for 24h, then the cells were exposed to Cyt (250 nM) respectively. In different time point after Cyt treatment, the activity of NF-kappaB and the expression of Erk1/2, NF-kappaBp65, Slug and PUMA protein were detected. The cells survival rate and apoptotic index were detected by MTT and TUNEL methods. RESULTS: After the HL-60 cells were exposed to Cyt (250 nM) for 24 h, the activity of NF-kappaB reached maximum value, and reached minimum value for 48 h. The expressions of NF-kappaBp65 and PUMA reached maximum value after exporser to Cyt (250 nM) for 24 h, and reached minimum value after 48 h. Erk1/2 phosphorylation and Slug expression began to increase after exporser to Cyt (250 nM) for 24 h, and reached maximum value for 48 h. The cells survival rate was decreased, and arrived to minimum value (29.5 +/- 4.6, F = 12.74, p < 0.01). The cells apotosis rate was increased, and arrived to maximum value (14.2 +/- 2.8, F = 15.02, p < 0.01). By inhibiting NF-kappaBp65 or PUMA by siRNA transfection, the cells survival rate was enhanced and the apotosis rate was significantly declined after exporsed to Cyt (250 nM). When NF kappaBp65 was inhibited, the expression of PUMA was decreased. By inhibiting Erk1/2 phosphorylation and Slug expression, the cells survival rate began to decrease for 24 h, and reached the fewest at 48 h after exporsed to Cyt (250 nM) (19.8 +/- 2.7, F = 11.4, p < 0.01 and 17.4 +/- 0.6, F = 15.3, p < 0.01). The cells apotosis rate began to increase from 24 h, and reach a head at 48 h after exporser to Cyt (250 nM) (28.6 +/- 4.7, F = 9.84, p < 0.01 and 27.6 +/- 6.4, F = 10.31, p < 0.01. After Erk1/2 phosphorylation inhibited, Slug expression was lowered and PUMA expression was significantly increased. The changes are most distinct after the cells were exporser to Cyt (250 nM) for 48 h. By Slug inhibition had no effect on Erk1/2 phosphorylation, but increase the expression of PUMA. CONCLUSIONS: The chemosensitiveness of HL-60 cells to Cyt were relation to the up-regulation of PUMA induced by NF-kappaB. The chemoresistance to Cyt was related to the up-regulation of Slug induced by Erk1/2, which inhibited the expression of PUMA. PMID- 25555871 TI - Thrombosis and risk factors in female patients with a rare acquired thrombophilia: chronic myeloproliferative disorder - polycythaemia vera and essential thrombocythaemia. AB - OBJECTIVE: In polycythaemia vera (PV) and essential thrombocythaemia (ET), the life expectancy of the patients is greatly affected by thrombotic events. An investigation was performed of the potential association of PV/ET, and thrombotic complications with cardiovascular (CV) risk factors, a leukocyte count at the haematological diagnosis > 11.1 G/L, and the JAK2V617F mutation. PATIENTS AND METHODS: In the period 1998-2011, 128 women with a median age of 62 years were enrolled. RESULTS: The risk of thrombotic events before the diagnosis was 32.8% (42/128), while in the follow-up period it was 10.2% (13/128). The difference in the probability of thrombosis-free survival between those with at most one CV risk factor and those with two or more CV risk factors was significant (p = 0.005). The presence of two or more CV risk factors (univariate: p = 0.011; multivariate: relative risk: 4.728, 95% CI 1.312-17.040; p = 0.018) significantly increased the risk of thrombosis. Univariate analyses revealed that high blood pressure (p = 0.001), hyperlipidaemia (p = 0.005) and cigarette smoking (p = 0.051) were associated with a significantly higher risk of thrombosis. Analyses of the influence of the leukocyte count (univariate: p = 0.424; multivariate: relative risk: 1.407, 95% CI 0.359-5.507; p = 0.624) and the JAK2V617F mutation (univariate: p = 0.367; multivariate: relative risk: 1.428, 95% CI 0.316-6.460; p = 0.643) on subsequent thrombotic complications resulted in a non-signicant tendency. CONCLUSIONS: Female patients who display CV risk factors (high blood pressure, hyperlipidaemia and/or cigarette smoking) and PV or ET may well be at a higher risk of thrombotic events and require special consideration as concerns as the prevention and management of thrombotic events. PMID- 25555872 TI - Cbl-b gene silencing in splenic T lymphocytes as a therapeutic strategy to target the prostate cancer RM-1 cell tumors in immune competent mice. AB - OBJECTIVE: In recent years, the field of cancer immunotherapy has become a research hotspot and is currently faced with numerous challenges. The objective of this study was to assess the success of cbl-b gene silencing in splenic T lymphocytes as an immune strategy to target the murine prostate cancer RM-1 cells in vitro and solid tumors in vivo. MATERIALS AND METHODS: For this purpose, cbl-b gene-specific siRNA was designed, synthesized, and was transfected into mouse splenic T lymphocytes, followed by assessment of T cell activation, TH1 cytokine production, and in vitro cytotoxicity against RM-1 cell targets. For in vivo cytotoxicity studies, first the RM-1 tumor model was established in immune competent mice that were later tumor-injected with splenic T lymphocytes transfected with specific shRNA for cbl-b gene silencing. RESULTS: The data show that the cbl-b gene silencing in T lymphocytes resulted in an enhanced surface expression of CD69 activation marker, elevated production of interleukin (IL)-2 and interferon (IFN)-gamma, and their increased cytotoxicity as effectors against RM-1 prostate cancer cells. The tumor injection with cbl-b shRNA-transfected T lymphocytes also resulted in significant reduction of the tumor size as compared with controls. CONCLUSIONS: cbl-b gene silencing strategy enhanced the immune function of T lymphocytes, increased their cytotoxic potential against RM-1 prostate cancer cells, as well as caused significant suppression of the tumor growth in immune competent mice. PMID- 25555873 TI - Experience with the treatment of testicular yolk sac tumor in children: a report of 14 cases. AB - OBJECTIVE: This paper discusses the optimal treatment for testicular yolk sac tumor at stage I in children. PATIENTS AND METHODS: Fourteen children with testicular yolk sac tumor (including 10 cases of stage I and 4 cases of stage II) underwent high ligation of internal spermatic cord vein and orchiectomy. Among these, seven cases of stage I were below 1 year of age. Retroperitoneal lymph node dissection without postoperative systemic chemotherapy was implemented in 9 cases (5 cases of stage I and 4 cases of stage II), and only one was positive. RESULTS: Among the 12 cases followed, 9 cases were alive (of these, 5 children < 1 year old, in stage I, underwent high ligation of internal spermatic cord vein and orchiectomy, with a survival time of 25 months to 10 years and 4 cases with radical retroperitoneal lymph node dissection). Three cases older than 1 year died of retroperitoneal lymph node and lung metastases. CONCLUSIONS: For the high ligation of internal spermatic cord vein, orchiectomy is a kind of simple and effective treatment for children younger than 1 year with stage I, without recurrence and metastases. However, attention to the accuracy of staging and close observation are important aspects of the treatment. PMID- 25555874 TI - The TLR4/NF-kappaB signaling pathway mediates the growth of colon cancer. AB - OBJECTIVE: We studied the involvement of the TLR4/NF-kappaB pathway in the growth of colon cancer using human colon cancer specimens, human colon cancer SW620 cell line, and nude mouse xenograft model. MATERIALS AND METHODS: Tissue samples were surgically harvested. The human colon cancer SW620 cell line was pre-treated with the TLR4 inhibitor CRX-526 and stimulated with LPS. The nude mouse xenograft model was established by subcutaneous injection of SW620 cells with or without CRX-526, the TLR4 inhibitor. The study outcomes were mRNA and protein expressions of TLR4 and NF-kappaB p65 in specimens of colon cancer and adjacent normal tissue, SW620 cell line, and xenografts. In addition, we studied production of interleukin (IL)-6 and IL-8 in culture supernatants of LPS-stimulated SW620 cells. RESULTS: Both mRNA and protein expressions of TLR4 and NF-kappaB in colon cancer specimens were higher than those in the adjacent normal tissue. LPS up regulated expression of TLR4 and NF-kappaB, and stimulated production of IL-6 and IL-8 in SW620 cells. These effects were attenuated by CRX-526. TLR4 inhibition was also effective in the nude mouse xenograft model, as tumor sizes were significantly smaller, and expressions of TLR4 and NF-kappaB significantly lower, in the mice treated with CRX-526. CONCLUSIONS: The TLR4/NF-kappaB signaling pathway is activated in colon cancer, causing production of IL-6 and IL-8, and, thereby, tumor growth and metastasization. Inhibition of TLR4 attenuates up regulation of NF-kappaB and inhibits tumor growth. PMID- 25555875 TI - Blocking TGF-beta inhibits breast cancer cell invasiveness via ERK/S100A4 signal. AB - OBJECTIVE: Targeted down-regulation of TGF-beta expression inhibits invasion and metastasis in breast cancer cells. However, the mechanism that TGF-beta functions by remains largely unknown. In the present study we report the mechanism of ERK1/2 dependant S100A4 regulation by TGF-beta and its possible role in TGF-beta mediated tumour invasion in vitro. MATERIALS AND METHODS: Small interfering RNA targeting TGF-beta1 (TGF-beta1 siRNA) were stably transfected into the breast cancer cell line MDA231. The TGF-beta1 siRNA/9MDA231 cells were then treated with TGF-beta1 (5 ng/ml) or treated with PD98059 (25 MUM) or transfected into S100A4 siRNA before TGF-beta1 treatment. The cells were used in several in vitro analyses, including migration, invasion, angiogenesis, and signaling assays. A wound-healing assay was used to determine migration of the cells in culture and a Boyden chamber transwell assay was used for invasion. In vitro angiogenesis studies using conditioned medium in HMEC-1 cells. RESULTS: Inhibition of TGF beta1 expression by TGF-beta1 siRNA transfection in MDA231 cells showed significant decrease migration, invasion and angiogenesis in vitro. TGF-beta1 siRNA/MDA231 cells treated with 5 ng/ml TGF-beta1 for 24 hs restored the invasive ability of TGF-beta1 siRNA/MDA231 cells. TGF-beta1 treatment could not increase migration, invasion and angiogenesis in TGF-beta1 siRNA/MDA231 cells when treated with 25 MUM PD98059 or transfected with S100A4 siRNA before TGF-beta1 treatment. Analysis of TGF-beta1 signaling pathways showed a decrease in p-ERK1/2 activation and an decrease in S100A4 expression. Interestingly, TGF-beta1 regulated S100A4 via ERK1/2 signalling. CONCLUSIONS: Our findings showed that blocking TGF-beta inhibits breast cancer cell invasiveness, migration and angiogenesis via ERK/S100A4 signalling. Therapies targeting the TGF-beta signaling pathway may be more effective to prevent progression in breast cancer. PMID- 25555876 TI - Reduced EBP50 expression or mis-localization of the EBP50 protein is associated with the malignant progression of esophageal squamous cell carcinoma. AB - PURPOSE: The aim of this study was to examine the significance of EBP50 (ezrin radixin-moesin binding phosphoprotein 50) expression in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Real-time PCR (qRT-PCR), western blotting, and immunohistochemical staining were performed to detect EBP50 expression in pairs of ESCCs and matched non-tumor tissues, and the relationships between EBP50 expression and other clinical factors in ESCC were analyzed. An iRNA targeting EBP50 was transfected into EC9706 cells. MTT and plate colony assays were performed to assess the effects of EBP50 down-regulation on cell growth, and flow cytometry was used to evaluate the influence of inhibiting EBP50 on cell cycle progression. RESULTS: The real-time PCR (qRT-PCR), western blotting, and immunohistochemical staining results showed that EBP50 expression was significantly lower in ESCCs compared to matched non-tumor tissues. In addition, decreased EBP50 expression correlated with differentiation, T stage, lymph node (LN) metastasis, and poor prognosis in patients with ESCC. The down regulation of EBP50 may significantly promote the growth and proliferation of EC9706 cells while accelerating cell cycle progression from the G1to S phase. CONCLUSIONS: EBP50 expression was decreased in ESCC, indicating that EBP50 might play a significant role in the malignant progression of ESCC and be a prognostic marker for patients with ESCC. PMID- 25555878 TI - Clinical application and prognostic assessment of serum Tumor Associated Material (TAM) from esophageal cancer patients. AB - OBJECTIVE: To explore the correlation between serum levels of Tumor Associated Materials (TAM) and clinicopathological parameters and prognosis in patients with esophageal cancer (EC). PATIENTS AND METHODS: The levels of TAM were determined by chemical colorimetry in 100 EC patients and 100 healthy controls. RESULTS: Serum TAM levels were significantly higher in patients with esophageal carcinoma than in the control group (p < 0.001). High levels of TAM were associated with tumor size (p = 0.004), tumor depth (p < 0.001), stage (p < 0.001), lymph node metastases (p < 0.001), tumor differentiation (p = 0.001), tumor respectability (p = 0.002) and disease progression (p < 0.001). The poor prognostic outcomes were correlated with an elevated level of TAM (p = 0.001). Kaplan-Meier analysis showed patients with increased levels of TAM after operation had an lower overall survival (p < 0.001) and disease-free survival (p < 0.001). In addition, multivariate Cox proportional hazard analyses revealed that TAM may be an independent factor affecting the overall survival and disease-free survival (p < 0.001). CONCLUSIONS: The detection of TAM could be used to screen for tumor and assess unfavorable prognosis in patients with EC. PMID- 25555877 TI - Effects of stellate ganglionic block on hemodynamic changes and intrapulmonary shunt in perioperative patients with esophageal cancer. AB - OBJECTIVE: The aim of this study was to observe the effects of stellate ganglion block (SGB) on hemodynamic changes and intrapulmonary shunt during one-lung ventilation (OLV). PATIENTS AND METHODS: Thirty ASA class I-II patients undergoing elective esophageal surgery were randomly divided into two groups: general anesthesia group (group N, n=15) and general anesthesia combined SGB group (group S, n=15), patients in group S were received left SGB before induction. Radial artery was cannulated for arterial blood pressure (ABP) monitoring and blood sampling and Swan-Ganz catheter was position in the pulmonary artery via right internal jugular vein under local anesthesia. ECG, MAP, HR, CVP, continuous cardiac output (CCO) index and BIS were continuously monitored during anesthesia. General anesthesia was induced with propofol 1.5-2.0 mg/kg, sufentanil 0.4 MUg/kg, and Rocuronium 0.6-0.9 mg/kg. Endobronchial occluder was placed blindly after tracheal indubation and the correct position was verified by auscultation and fiberoptic bronchoscopy. The patients were mechanically ventilated. The ventilation conditions were Fio2=100%, VT = 8-10 ml/kg, I: E = 1:2 and respiratory rate was adjusted to maintained PETCO2 at 35-45 mmHg during both two-lung ventilation (TLV) and OLV. Anesthesia was maintained with continuous infusion of propofol 4-10 mg/kg.h, sufentanil 0.2 MUg/kg.h, vecuronium o.1 mg/kg.h, BIS was maintained at 45-55. Blood samples were taken from radial artery and S-G catheter for blood gas analysis at following intervals: during spontaneous breathing when the patient was awake (T0), 1 min after tracheal indubation (T1), 1 min after patient was placed in lateral position (T2) and 15 min after it (T3), 1 min after ribs was braced (T4), 30, 60, 120 min during the course of OLV (T5, T6, T7), the two lungs were ventilated again for 30 min (T8) and Qs/Qt was calculated. RESULTS: SVRI, MAP, HR in group N increased significantly at T1, T2, T4 compared with group S (p < 0.05). Qs/Qt was significantly increased after patient was placed in lateral position and increased further during OLV; the calculated Qs/Qt values were highest at T5. PaO2 was significantly lower after OLV was started and reached the lowest level at T6 then was gradually increasing. There was no significant difference in Qs/Qt and PaO2 at all time points between two groups. CONCLUSIONS: SGB before induction effectively suppress the stress response work as stable blood dynamics and does not affect Qs/Qt and arterial oxygenation during OLV, SGB is a safe technique of anesthesia for general thoracic surgery. PMID- 25555879 TI - Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. AB - OBJECTIVE: To further understand the synergistic mechanism of As2O3 and asscorbic acid (AA) in human osteosarcoma MG-63 cells by systems biology analysis. MATERIALS AND METHODS: Human osteosarcoma MG-63 cells were treated by As2O3 (1 umol/L), AA (62.5 umol/L) and combined drugs (1 umol/L As2O3 plus 62.5 umol/L AA). Dynamic morphological characteristics were recorded by Cell-IQ system, and growth rate was calculated. Illumina beadchip assay was used to analyze the differential expression genes in different groups. Synergic effects on differential expression genes (DEGs) were analyzed by mixture linear model and singular value decomposition model. KEGG pathway annotations and GO enrichment analysis were performed to figure out the pathways involved in the synergic effects. RESULTS: We captured 1987 differential expression genes in combined therapy MG-63 cells. FAT1 gene was significantly upregulated in all three groups, which is a promising drug target as an important tumor suppressor analogue; meanwhile, HIST1H2BD gene was markedly downregulated in the As2O3 monotherapy group and the combined therapy group, which was found to be upregulated in prostatic cancer. These two genes might play critical roles in synergetic effects of AA and As2O3, although the exact mechanism needs further investigation. KEGG pathway analysis showed many DEGs were related with tight junction, and GO analysis also indicated that DEGs in the combined therapy cells gathered in occluding junction, apical junction complex, cell junction, and tight junction. CONCLUSIONS: AA potentiates the efficacy of As2O3 in MG-63 cells. Systems biology analysis showed the synergic effect on the DEGs. PMID- 25555880 TI - Effects of low dose pre-irradiation on hepatic damage and genetic material damage caused by cyclophosphamide. AB - OBJECTIVE: Cyclophosphamide (CTX) can attack tumour cells, but can also damage the other cells and microstructures of an organism at different levels, such as haematopoietic cells, liver cells, peripheral lymphocyte DNA, and genetic materials. Low dose radiation (LDR) can induce general adaptation reaction. In this study, we explore the effects of low dose radiation on hepatic damage and genetic material damage caused by CTX. MATERIALS AND METHODS: Mice were implanted subcutaneously with S180 cells in the left groin (control group excluded). On days 8 and 11, mice of the LDR and LDR+CTX groups were given 75 mGy of whole-body gamma-irradiation; whereas mice of the CTX and LDR+CTX groups were injected intraperitoneally with 3.0 mg of CTX. All mice were sacrificed on day 13. DNA damage of the peripheral lymphocytes, alanine aminotransferase (ALT) activity, total protein (TP), albumin (ALB) of the plasma, malonyl-dialdheyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity of the hepatic homogenate, and micronucleus frequency (MNF) of polychromatoerythrocytes in the bone marrow were analysed. RESULTS: The control group had the lowest MDA content and the highest SOD and GSH-PX activity, whereas the CTX group had the highest MDA content and the lowest SOD and GSH-PX activity. Compared with the CTX group, the MDA content decreased significantly (p < 0.01) and the SOD and GSH-PX activity increased significantly (p < 0.05) in the LDR+CTX group. TP and ALB in control group were higher than that of the other groups. Compared with the sham-irradiated group, TP and ALB in the LDR group elevated significantly (p < 0.05). The control group had the lightest DNA damage, whereas the CTX group had the severest. DNA damage in LDR+CTX group was much lighter compared with that of the CTX group (p < 0.05). MNF in the CTX group increased significantly compared with the control and the sham-irradiated groups (p < 0.01). Compared with the CTX group, MNF in LDR+CTX group had a tendency of decline, but without statistical significance (p > 0.05). CONCLUSIONS: Pre chemotherapeutic LDR can induce the activities of anti-oxidative enzymes and promote the elimination of free radicles to alleviate the damaging effects of oxidative stress to hepatic tissue caused by high-dose CTX. At the same time, LDR has no obvious effect on the ALT activity of plasma, but may have protective effect on the protein synthesis function of the liver. High-dose CTX chemotherapy can cause DNA damage of peripheral lymphocytes; however, LDR before chemotherapy may have certain protective effect on DNA damage. Moreover, CTX has potent mutagenic effect; however, LDR may have no protective effect against the genetic toxicity of CTX chemotherapy. PMID- 25555881 TI - Musculo-skeletal tumors incidence and surgical treatment - A single center 5-year retrospective. AB - OBJECTIVE: Muscle-skeletal tumors represent a challenging pathology for orthopedic surgeons worldwide. The extremely invasive character, the local destruction, the high recurrence rate, the high incidence in young patients and the unfavorable prognosis are all very well known. For these patients it is very important to produce an accelerated functional, social and psychological postoperative rehabilitation. We studied 121 cases of muscle-skeletal tumors which were treated in our hospital over a 5 years period. PATIENTS AND METHODS: We noticed a high prevalence in males and mainly between the 2nd-3rd and 5th-7th decades of their life. At our observation, most patients were suffering in advanced stages of malignant lesions. RESULTS: We try to manage amputations below 5%, with a significant reduction in introducing reconstructive surgical methods as a choice of treatment (10 prostheses and 12 cases of filling with acrylic cement or bone substituent increased with internal fixation). In this way we could observe an unusual ratio between benign and malignant tumors, probably caused by the patient's lack of concern for minimal symptoms. The rural citizen's addressability towards the medical system is alarmingly low, due to the big gap existing from diagnosis to treatment. CONCLUSIONS: There is still an hard effort to develop better reconstructive techniques for the treatment of muscle-skeletal tumors and more studies must be made in order to achieve this goal. PMID- 25555882 TI - Evaluation methods on the nutritional status of stroke patients. AB - OBJECTIVE: This study was designed to assess the effect of particular tools on the nutritional status of patients with stroke risk factors; to analyze these risk factors; to construct an assessment table; and to enable nurses to conduct fast and accurate assessment of the nutritional status of patients with stroke. PATIENTS AND METHODS: Various nutritional assessment tools were employed to assess the nutritional status of stroke patients [(Nutritional Risk Screening 2002, NRS2002); (mini nutritional assessment, MNA), (subjective global assessment SGA), (malnutrition universal screening, MUST); (body composition, BCA)]. The leading disease-related factors of cerebral apoplexy were observed in patients with malnutrition. And a statistical analysis was conducted. RESULTS: The significant risk factors of cerebral apoplexy in malnourished patients older than 70 years were swallowing dysfunctions, disturbance of consciousness and reliance or half-reliance on feeding practices. The significant risk factors of malnutrition in patients with cerebral apoplexy were the decline in upper limb muscle strength, decline in the performance of various activities, loss of appetite and gastrointestinal symptoms. CONCLUSIONS: Disorders that affect the nutritional status of stroke patients can be used as evaluation tools, as described in the evaluation table. The clinical relevance of this study includes the following: to enable the clinical nursing staff to easily assess the patient's nutritional status in a timely manner; to improve compliance with nutritional evaluation; to provide clinical nutrition support to patients with stroke; and to provide a scientific basis for the improvement of the clinical outcomes of patients with cerebral apoplexy. PMID- 25555883 TI - The prevalence of Parkinson's disease continues to rise after 80 years of age: a cross-sectional study of Chinese veterans. AB - OBJECTIVE: The purpose of this study was to examine whether the prevalence of Parkinson's disease (PD) continues to rise after 80 years of age. METHODS: This is a two-stage, multi-center, cross-sectional study using a stratified cluster sampling approach was employed. Subjects included veterans at >= 60 years of age living in veterans' communities for at least one month in 18 major cities across China. In the first step, possible PD was screened using a PD screening scale. Demographic and relevant information were collected. In the second step, PD diagnosis was established using the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) diagnostic criteria. RESULTS: The study was conducted during the period from December 2009 to December 2012. The study included 277 veterans' communities. Among the approached 11,593 subjects, 9676 subjects, (9096 men, 580 women) responded. The response rate was 83.46%.The age was >= 80 years in 6722 (69.47%) subjects. A diagnosis of PD was established in 228 subjects (2.36%) in the entire sample. The rate of PD was 2.65% in those with an age of >= 80 years. The rate of PD increased with increasing age (0%, 1.84%, 2.60% and 3.68% in the subjects at < 70, 70-79, 80-89 and >= 90 years of age, respectively; chi2 = 10.891, p = 0.001 in chi-square test). The rate of PD was higher in men (2.44%) than in women (1.46%) on the surface. However, no significant difference was detected (p = 0.241). CONCLUSIONS: The prevalence of PD continues to increase beyond the age of 80 years. The prevalence of PD in Chinese veterans is not lower than that in other countries and regions. PMID- 25555884 TI - Chronic anisakidosis presenting with intestinal intussusception. AB - OBJECTIVE: Anisakidosis is a parasitic infection caused by the ingestion of row or uncooked fish, containing larval nematodes from the Anisakidae family. Intestinal anisakidosis represents about 4% of all cases, the majority being localized in the small bowel, with rare colonic involvement. Here we present an infrequent case of chronic anisakidosis, presenting with intestinal intussusception. CASE REPORT: A 52 years old woman, chronically treated with immunosuppressants, presented to our Institution with acute abdominal pain and vomiting, due to colocolic intussusception. Colonoscopy successfully reduced the intussusception and revealed the presence of a voluminous colonic submucosal mass, near the hepatic flexure. Therefore, the patient underwent laparoscopic right hemicolectomy. The diagnosis of anisakidosis was made when the histological examination of the surgical specimen revealed the infestation of the intestinal wall by a nematode of the Anisakidae family, with an intense erosive-inflammatory adjacent reaction. PMID- 25555885 TI - Efficacy of endoscopic stapled transanal rectal resection for the treatment of rectocele. AB - OBJECTIVE: The objective of the study was to determine the efficacy of endoscopic stapled transanal rectal resection for the treatment of rectocele. PATIENTS AND METHODS: For this purpose, the data were collected from 61 patients with severe rectocele that underwent endoscopic stapled transanal rectal resection within the time period from April 2010 to April 2012. The pre- and post-operative Longo's obstructed defecation syndrome (ODS) were compared. The reduction of the rectocele was assessed by defecography on visit and from patients' satisfaction obtained through following up. RESULTS: We found that the postoperative Longo's ODS was significantly lower than the preoperative value (p < 0.01); and defecography showed that the rectocele was significantly reduced or disappeared. Furthermore, 57 of the 61 (93.4%) patients expressed their satisfaction at follow up. CONCLUSIONS: The endoscopic stapled transanal rectal resection can be recommended as the treatment of choice for rectocele since it is an easy-to perform procedure that has satisfactory short and mid to long-term therapeutic efficacy. PMID- 25555886 TI - Topical tacrolimus vs medium-dose ultraviolet A1 phototherapy in the treatment of atopic dermatitis - a preliminary study in relation to parameters of the epidermal barrier function and high-frequency ultrasonography. AB - INTRODUCTION: Atopic dermatitis (AD) is a chronic, relapsing skin disorder, which is characterized by intense pruritus, skin dryness and concomitant epidermal barrier dysfunction. The basic therapy involves the application of anti inflammatory topical drugs like; glucocorticosteroids and calcineurin inhibitors. Phototherapy in AD is regarded as an additional form of treatment. The latest invention, ultraviolet A1-UVA1 phototherapy (340-400 nm), was introduced to the treatment of AD by Krutmann et al in 1992. It appears that the main mode of action of UVA1 phototherapy in AD is through activation of apoptosis of T lymphocytes. Additionally, new studies show that UVA1 can also inhibit the activity of calcineurin phosphatase, similarly to calcineurin inhibitors such as cyclosporin A or tacrolimus. The aim of this study is to, for the first time, compare the efficacy of medium dose UVA1 phototherapy and tacrolimus ointment in patients with moderate-severe AD. PATIENTS AND METHODS: This study involved 20 AD patients. Half of the patients were treated with UVA1 phototherapy, while another 10 participants were treated with the application of tacrolimus ointment. The severity of the disease progress was assessed on the basis of EASI score (Eczema Area Severity Index). Moreover, the clinical condition of patients was assessed using non-invasive techniques such as measurement of transepidermal water loss - TEWL and skin capacitance, as well as high-frequency ultrasonography (20 MHz). RESULTS: This study described above confirmed the beneficial influence of both therapies on the course of moderate-severe AD. Tacrolimus induced a greater reduction in TEWL, while phototherapy caused the reduction of subepidermal low echogenic band-SLEB within sites affected with pathological lesions. CONCLUSIONS: Both tacrolimus and phototherapy treatment seemed to significantly reduce EASI. PMID- 25555887 TI - Predictors of long term opioid withdrawal outcome after short-term stabilization with buprenorphine. AB - OBJECTIVE: We aim to examine predictors of opiate abstinence status 3 months after the end of buprenorphine/naloxone treatment for opioid-dependent participants. PATIENTS AND METHODS: Participants (n= 516, age > 15 years) received buprenorphine/ naloxone treatment for 4 weeks and then randomly assigned to undergo dose tapering over either 7 days or 28 days. Bivariate analysis was performed to identify possible predictors of successful opiate abstinence outome (p-value < 0.10). Logistic regression analysis with backward stepwise selection was, then, performed to produce final model containing independent predictors at p-value < 0.05. RESULTS: Bivariate analysis identified several possible predictors including: opioid and drug urine tests result at the end taper; employment status, family problems, and alcohol use domains of addiction severity index (ASI) score; and clinical opiate withdrawal scale (COWS) at the end of stabilization. Final predictor list identified by logistic regression include: ASI score for family and alcohol problems, COWS at the end of stabilization and opiate urine test at the end of taper. CONCLUSIONS: Participants presenting with a negative urine test for opiate, more severe alcohol, more severe family problems, or more symptoms of opiate withdrawal at the end of stabilization were more likely to have a successful opiate abstinence. PMID- 25555888 TI - The effects of glycyrrhizin on acute pancreatitis in mice. AB - OBJECTIVE: This study aimed to investigate the effects of glycyrrhizin on acute pancreatitis in mice. MATERIALS AND METHODS: Sixty Balb/c mice were randomly divided into four groups as control group, model group, low dose group and high dose group (n=15). Acute pancreatitis was induced by intraperitoneal injection of Caerulein (100 ug/kg) hourly for 6 times. Mice in low dose group and high dose group received intraperitoneal administration of 15 mg/kg and 45 mg/kg glycyrrhizin respectively 4 hours before Caerulein injection. Mice in four groups were sacrificed in three equal lots at 8, 16 and 24 hours after model construction. High Mobility Group Box-1 (HMGB1) expression and serum levels of amylase, TNF-alpha and IL-6 were determined. The pancreatic tissues were taken for histopathologic analysis. RESULTS: Amylase, TNF-alpha, IL-6 and HMGB1 levels were significantly higher and pancreas lesion was severer in model group than in control group. However, Amylase, TNF-alpha, IL-6 and HMGB1 levels in low dose group and high dose group decreased significantly compared with model group. The pancreas lesion was also improved after administration of glycyrrhizin. CONCLUSIONS: Glycyrrhizin could decrease the levels of pro-inflammatory cytokines and downregulate the expression of HMGB1 which finally improved the pancreas lesion in mice with acute pancreatitis. PMID- 25555889 TI - Omne Ignotum pro Magnifico: characterization of commercial Bilberry extracts to fight adulteration. AB - Thanks to their chemical composition, extracts from the bilberry are commonly used to manufacture food, health products, supplements and cosmetics. However, in this field, as in others, "the process is the product" and a careful characterization of the entire supply and production chain, from purity and quality of raw material to extraction procedures needs to be implemented by using validated, sensitive and specific techniques of analysis. This position paper discusses the importance of the characterization of bilberry extracts, in order to fight adulteration. PMID- 25555890 TI - Characteristic changes in estradiol and leptin levels in patients with subarachnoid hemorrhage induced cerebral-cardiac syndrome. AB - OBJECTIVE: To investigate the characteristic changes in serum estradiol and leptin levels in patients with cerebral-cardiac syndrome (CCS) induced by subarachnoid hemorrhage (SAH). PATIENTS AND METHODS: Ninety-six female patients with early stage of SAH (within 48 h of onset), who were admitted in our department between February 2008 and February 2014, were included in this study. Clinical conditions of patients were rated using Hunt-Hess scale. Serum levels of estradiol, leptin and echocardiography were determined in patients with various neurological injuries as well as in post-SAH patients and patients with SAH induced CCS. RESULTS: No significant differences (p > 0.05) were observed in the levels of estradiol or leptin between patients with different Hunt-Hess grades. While serum levels of estradiol and leptin were significantly elevated in SAH and CCS patients compared to normal controls (p < 0.05) but the elevated levels were more profound in CCS patients. Meanwhile there were also variable extents of left ventricular expansion and decrease of ejection fraction in CCS patients, with the same trends of estradiol and leptin. CONCLUSIONS: Thus the results show that a significant increase in estradiol and leptin levels occurred in post-SAH CCS patients. PMID- 25555891 TI - Meriva(r)+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study. AB - OBJECTIVE: Osteoarthritis (OA) is a major cause of physical disability and impaired quality of life. Non-steroidal anti-inflammatory drugs are the most used treatment for OA, but they are frequently associated to adverse events. Alternative therapies are under investigation for the treatment of OA. Meriva(r) is a lecithin delivery form of curcumin, a powerful promoter of anti-oxidant response studied in a number of conditions related to chronic inflammation and pain. PATIENTS AND METHODS: This 4-month observational study, conducted in a 'real-life' scenario, compares the association of Meriva and glucosamine (n=63) with chondroitin sulphate+glucosamine (n=61) in 124 patients with grade 1-2 OA of the knee. RESULTS: Patients treated with Meriva+glucosamine had significantly higher Karnofsky Index and WOMAC score (both in the physical and emotional domains), compared to those in the chondroitin+glucosamine group. Noteworthy, the walking distance at the treadmill test after 1 month was also significantly higher in the meriva+glucosamine group; this advantage was sustained until the end of the study. Although the need for concomitant drugs and medical attention decreased in both groups, this reduction was more evident for patients treated with Meriva+glucosamine. CONCLUSIONS: Taken together, the results of this study shows that the 4-month administration of the association of Meriva and glucosamine can result in a faster onset of action and improved outcomes than the administration of an association of chondroitin sulphate and glucosamine in patients with OA. PMID- 25555892 TI - Extremely long posterior communicating artery diagnosed by MR angiography: report of two cases. AB - We report two cases of an extremely long left posterior communicating artery (PCoA) diagnosed by magnetic resonance (MR) angiography. The PCoA arose from the normal point of the supraclinoid internal carotid artery and fused with the posterior cerebral artery (PCA) at its posterior ambient segment, forming an extremely long PCoA and extremely long precommunicating segment of the PCA. To our knowledge, this is the first report of such variation. Careful observation of MR angiographic images is important for detecting rare arterial variations. To identify these anomalous arteries on MR angiography, partial maximum-intensity projection images are useful. PMID- 25555893 TI - Mechanical properties of collagen membranes: are they sufficient for orbital floor reconstructions? AB - INTRODUCTION: The most common reconstruction materials for orbital floor fractures are PDS (polydioxanone) foil and titanium meshes. These materials have advantages and disadvantages. Therefore, new materials are needed to improve surgical outcomes. MATERIALS AND METHODS: Three resorbable collagen membranes (Smartbrane((r)), BioGide((r)), Creos((r))) were tested for their mechanical properties (puncture strength) in mint and artificially aged (3, 6, 8 weeks) conditions and were compared to PDS foil, titanium meshes (0.25 mm, 0.5 mm) and human orbital floors (n = 7). RESULTS: The following puncture strengths were evaluated: human orbital floor, 0.81 +/- 0.49 N/mm(2); 0.25 mm titanium mesh, 5.36 +/- 0.25 N/mm(2); 0.5 mm titanium mesh, 16.08 +/- 5.17 N/mm(2); Smartbrane, 0.74 +/- 0.31 N/mm(2); BioGide, 1.65 +/- 0.45 N/mm(2); and Creos, 2.81 +/- 0.27 N/mm(2). After artificial aging, the puncture strengths were significantly reduced (p <= 0.05) at 3, 6 and 8 weeks as follows: Smartbrane, 0.05 +/- 0.03 N/mm(2), 0.03 +/- 0.02 N/mm(2), and 0.01 +/- 0.01 N/mm(2), respectively; BioGide, 0.42 +/- 0.06 N/mm(2), 0.41 +/- 0.12 N/mm(2), and 0.32 +/- 0.08 N/mm(2), respectively; and Creos, 2.02 +/- 0.37 N/mm(2), 1.49 +/- 0.42 N/mm(2), and 1.36 +/- 0.42 N/mm(2), respectively. CONCLUSION: The tested materials showed sufficient puncture strength for orbital floor reconstruction in mint condition. Moreover, after artificial aging, the Creos and BioGide membranes showed sufficient resistance, while Smartbrane showed equivocal data after eight weeks. Therefore, collagen membranes have adequate properties for further in vivo investigations for orbital floor reconstructions. PMID- 25555894 TI - Quality of life associated factors in head and neck cancer patients in a developing country using the FACT-H&N. AB - Health-related quality of life (HRQoL) associated factors are vital considerations prior to treatment decision-making for head and neck cancer patients. The study aimed to identify potential socio-demographic and clinical prognostic value of HRQoL in head and neck cancer patients in a developing country. The Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N)-V4 in Urdu language was administered among 361 head and neck cancer patients. Data were statistically tested through multivariate analysis of variance (MANOVA) and regression modeling to identify the potentially associated factors. Treatment status, tumor stage and tumor site had the strongest negative impact on patients HRQoL, with a statistically significant decrement in FACT summary scales (effect size >0.15). Moderate associated factors of HRQoL included treatment type, marital status, employment status and age (effect size range 0.06-0.15). Weak associated factors of HRQoL with a small effect size (>0.01-0.06) included tumor size and type, gender, education level and ethnicity. This study reports 12 socio demographic and clinical variables that have a significant impact on HRQoL of head, and neck cancer patients, and that should be considered during treatment decision-making by multidisciplinary teams and also in future HRQoL studies conducted in other developing countries. PMID- 25555895 TI - Assessment of the RIVET fixation system for cranioplasty using the pull-out technique. AB - Cranioplasty using custom-made hydroxyapatite (HAP) ceramic implants is a common procedure to repair skull defects. However, commercially available titanium screws are only minimally stabilized due to characteristic brittleness. We developed the RIVET technique which involves fixing a bioabsorbable plate atop a HAP block using bioabsorbable screws extending beyond both layers, and evaluated fixation strength using the pull-out test and microtomography. Three experimental conditions were compared: a non-RIVET group, RIVET group, and dry skull control group. Pull-out strength significantly differed across groups (non-RIVET group, 1.33 +/- 1.21 kgf; RIVET group, 4.46 +/- 0.84 kgf; and control group, 6.99 +/- 1.14 kgf, P < 0.01). Microtomography of the dry skull control group revealed thread grooves fitted to the screws. The non-RIVET and RIVET groups presented fewer thread grooves than the control group, and the screws did not fit perfectly to the HAP block. However, fixation in the RIVET group was more stable, as the rivet was firmly lodged into the implant. In conclusion, by melting and creating the rivet, pull-out strength can be increased and rigid stabilization of HAP can be obtained. This technique uses commercially available absorbable plate and screws, and thus can be used widely in clinical applications involving HAP blocks with different porosities and thicknesses. PMID- 25555896 TI - Incidence and management of severe odontogenic infections-a retrospective analysis from 2004 to 2011. AB - The management of odontogenic infections is a typical part of the spectrum of maxillofacial surgery. Normally these infections can be managed in a straight forward way however under certain conditions severe and complicated courses can arise which require interdisciplinary treatment including intensive care. A retrospective analysis of all patients affected by an odontogenic infection that received surgical therapy from 2004 to 2011 under stationary conditions was performed. Surgical treatment consisted in incision and drainage of the abscess supported by additional i.v. antibiotic medication in all patients. Detailed analysis of all patients that required postoperative intensive medical care was additionally performed with respect to special risk factors. During 8 years 814 patients affected by odontogenic infections received surgical treatment under stationary conditions representing 4% of all patients that have been treated during that period (n = 18981). In 14 patients (1.7%) intensive medical therapy after surgery was required, one lethal outcome was documented (0.12%). In all of these 14 patients a history of typical risk factors was present. According to these results two patients per week affected by an odontogenic infection required stationary surgical treatment, about two patients per year were likely to require additional intensive medical care. If well-known risk factors are present in patients affected by odontogenic infection appropriate interdisciplinary management should be considered as early as possible. PMID- 25555897 TI - Reliability and validity of the L test in participants with chronic stroke. AB - OBJECTIVE: Many clinical mobility tests have been used for individuals who have suffered a stroke; however, the ceiling effect has been identified as a limitation for relatively high functioning individuals. The L test, a variation of the timed up and go test (TUG), was developed as a mobility test for patients after amputation. The objective of this study was to examine the reliability and validity of the L test among patients following a stroke. DESIGN: Cross sectional. SETTING: Rehabilitation hospital. PARTICIPANTS: Thirty-three chronic stroke survivors {20 males and 13 females, mean age 52.4 [standard deviation (SD) 11.2] years; mean time since stroke 29.1 (SD 13.3) months}. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Validity was assessed by correlating the L test with other mobility tests (TUG, 10-m walk test and 2-minute walk test). Intra-class correlation coefficients (ICCs) were used to investigate reliability. The minimal detectable change (MDC) was used to determine true change. RESULTS: The L test was strongly correlated with the TUG test (r=0.887), and had excellent intra-rater (ICC3,1=0.99) and inter-rater reliability (ICC2,1=0.99). The MDC with a 95% confidence interval was 4seconds. CONCLUSIONS: The L test is a reliable, valid tool for evaluating gait in patients following a stroke. It is a more applicable method to assess individuals who are able to walk greater distances and have better gait in more functional situations. PMID- 25555898 TI - Practical approach to determine sample size for building logistic prediction models using high-throughput data. AB - An empirical method of sample size determination for building prediction models was proposed recently. Permutation method which is used in this procedure is a commonly used method to address the problem of overfitting during cross validation while evaluating the performance of prediction models constructed from microarray data. But major drawback of such methods which include bootstrapping and full permutations is prohibitively high cost of computation required for calculating the sample size. In this paper, we propose that a single representative null distribution can be used instead of a full permutation by using both simulated and real data sets. During simulation, we have used a dataset with zero effect size and confirmed that the empirical type I error approaches to 0.05. Hence this method can be confidently applied to reduce overfitting problem during cross-validation. We have observed that pilot data set generated by random sampling from real data could be successfully used for sample size determination. We present our results using an experiment that was repeated for 300 times while producing results comparable to that of full permutation method. Since we eliminate full permutation, sample size estimation time is not a function of pilot data size. In our experiment we have observed that this process takes around 30min. With the increasing number of clinical studies, developing efficient sample size determination methods for building prediction models is critical. But empirical methods using bootstrap and permutation usually involve high computing costs. In this study, we propose a method that can reduce required computing time drastically by using representative null distribution of permutations. We use data from pilot experiments to apply this method for designing clinical studies efficiently for high throughput data. PMID- 25555899 TI - Considering the base rates of low performance in cognitively healthy older adults improves the accuracy to identify neurocognitive impairment with the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB). AB - It is common for some healthy older adults to obtain low test scores when a battery of neuropsychological tests is administered, which increases the risk of the clinician misdiagnosing cognitive impairment. Thus, base rates of healthy individuals' low scores are required to more accurately interpret neuropsychological results. At present, this information is not available for the German version of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-NAB), a frequently used battery in the USA and in German-speaking Europe. This study aimed to determine the base rates of low scores for the CERAD-NAB and to tabulate a summary figure of cut-off scores and numbers of low scores to aid in clinical decision making. The base rates of low scores on the ten German CERAD-NAB subscores were calculated from the German CERAD-NAB normative sample (N = 1,081) using six different cut-off scores (i.e., 1st, 2.5th, 7th, 10th, 16th, and 25th percentile). Results indicate that high percentages of one or more "abnormal" scores were obtained, irrespective of the cut-off criterion. For example, 60.6% of the normative sample obtained one or more scores at or below the 10th percentile. These findings illustrate the importance of considering the prevalence of low scores in healthy individuals. The summary figure of CERAD-NAB base rates is an important supplement for test interpretation and can be used to improve the diagnostic accuracy of neurocognitive disorders. PMID- 25555900 TI - High flux priapism, an exceptional complication of rectal cancer surgery. PMID- 25555901 TI - Preliminary molecular epidemiological investigation of hepatitis E virus sequences from Quebec, Canada. AB - Our study objective was to describe the Canadian Hepatitis E virus (HEV) sequences currently cataloged in GenBank from three populations: commercially raised pigs, retail pork, and locally acquired Hepatitis E cases, and to interpret the molecular evidence they provide. We searched the GenBank for any/all Canadian HEV sequences from these populations, and identified highly similar matches using the Basic Local Alignment Search Tool (BLAST) algorithm, studying sequences of the partial ORF2 gene. We validated the findings made using Multiple Sequence Comparison by Log-Expectation (MUSCLE) and Clustal 2 programs for multiple sequence alignments, as inputs to estimate dendrograms using both neighbour-joining and Unweighted Pair Group Method with Arithmetic Mean (UPGMA) methods. The GenBank search yielded 47 sequences collected from pigs: 32 sequences from two to four month old commercial pigs in Quebec, one from three to four month old pigs at a research station in Ontario, one from two month old pigs in a commercial Saskatchewan herd, and 13 collected from finisher pigs in a national survey. Additionally, 14 sequences were collected from a national survey of Canadian retail pork livers, and seven sequences from two Canadian pediatric patients with locally acquired Hepatitis E, both from the province of Quebec. All sequences belonged to genotype 3. Eight of the 14 sequences from retail pork livers had human-derived sequences in their top ten BLAST matches; six did not. Those eight sequences having close human BLAST matches clustered within a dendrogram, as did those with no close human BLAST matches. Human sequences with close matches to the eight retail sequences included both of the Quebec Hepatitis E cases, as well as sequences from Japanese Hepatitis E cases, and Japanese blood donors. Seven of the eight HEV sequences from retail liver with close human BLAST matches originated in Quebec. Kulldorff's spatial scan statistic showed a significant (P<0.05) spatial cluster of these sequences, but not of the overall dataset of 12 HEV sequences collected from Quebec retail livers. All seven retail liver sequences with close human matches were processed in-store. We conclude that some Canadian sequences of HEV collected from pigs/pork are more closely related to human sequences than others, and hypothesize that detection of some HEV sequences recovered from Canadian retail pork livers may be associated with exposure to human shedding. More research needs to be conducted at the processing level to help understand the molecular epidemiology of HEV in Canadian retail pork. PMID- 25555902 TI - Transmission of antibiotic-resistant Escherichia coli between cattle, humans and the environment in peri-urban livestock keeping communities in Morogoro, Tanzania. AB - Urban and peri-urban livestock farming is expanding world-widely because of increased urbanization and demands for food of animal origin. Such farming practices pose a public health risk as livestock are reservoirs of several zoonotic pathogens. In an attempt to determine the fecal transmission between livestock and people, 100 household clusters keeping cattle in close proximity of humans were selected in urban and peri-urban areas of Morogoro in Tanzania. One hundred eighteen ampicillin and tetracycline resistant Escherichia coli (40 from human stool, 50 from cattle feces, 21 from soil and seven from water samples) were isolated from 44 different clusters. Pulsed-field gel electrophoresis (PFGE) of XbaI digested chromosomal DNA was used to compare the genetic relatedness of the ampicillin- and tetracycline-resistant E. coli isolates. Indistinguishable PFGE band patterns of the ampicillin- and tetracycline-resistant E. coli isolates were found in samples from 23 (52%) clusters. This suggests that transfer of fecal microorganisms between cattle, humans, water and soils within the farms and from livestock farms to the neighborhood occurred commonly. Logistic regression showed that animal housing infrastructures (Odd Ratio=11.2, 95% CI=1.1-119.3) were associated with E. coli showing identical PFGE types within and between clusters. There is a need to improve animal husbandry and manure management practices to reduce risks of transmission of enteropathogens between livestock and humans in urban and peri-urban farming. PMID- 25555903 TI - Hippocampal diffusion tensor imaging microstructural changes in vascular dementia. AB - To explore microstructural integrity of hippocampus in vascular dementia (VD) using DTI. Twenty-five individuals with VD, without magnetic resonance imaging (MRI) evidence of gray matter pathology, and 25 matched healthy control (HC) individuals underwent a 3T MRI protocol including T2, FLAIR, and PD in the axial plane, 3D whole-brain T1-weighted with an isotropic resolution of 1 mm, and DTI acquired using 64 diffusion sensitizing directions, b value of 1,500 s/mm(2), 65 axial slices, isotropic resolution of 1.8 mm. Images were processed to obtain indices of microstructural variations of bilateral hippocampi. Mean diffusivity (MD) in the hippocampus of patients with VD was significantly increased (p < 0.05) bilaterally with respect to that of the group of HC examinees. In VD group left hippocampal MD (10(-6 )* mm(2)/s) was 833.4 +/- 92.8; in HC group left MD was 699.8 +/- 56. In VD group, right hippocampal MD was 859.1 +/- 69.8; in HC group right MD was 730.4 +/- 40.2. No group differences were found in hippocampal FA. DTI shows microstructural hippocampal damage in VD in patients with normal appearing gray matter structures on conventional MRI, indicating the need for further research on the link between VD and AD. PMID- 25555904 TI - Optimization and evaluation of reconstruction-based compensation methods and reconstruction parameters for Tc-99m MIBI parathyroid SPECT. AB - The value of Tc-99m MIBI parathyroid SPECT for localizing parathyroid hyperplasia in chronic renal failure patients remains inconclusive due to limited image quality. Advanced reconstruction methods to improve image quality have been developed but require optimization and evaluation. The goal of this study was to optimize and evaluate compensation methods and reconstruction parameters for Tc 99m MIBI parathyroid SPECT. A phantom population and projection data that modelled clinically realistic variations found in patients were simulated. The 3D OS-EM reconstruction with compensation for attenuation, detector response and scatter in various combinations were studied. For each compensation, the number of updates for OS-EM and the cutoff frequency of a 3D Butterworth filter were optimized and evaluated using anthropomorphic model observer. With optimal parameters, the method with compensation for attenuation and detector response, with or without the addition of scatter compensation, provided the highest lesion detectability for Tc-99m MIBI parathyroid SPECT. PMID- 25555905 TI - Novel biomedical applications of Cerenkov radiation and radioluminescence imaging. AB - The main goals of this review is to provide an up-to-date account of the different uses of Cerenkov radiation (CR) and radioluminescence imaging for pre clinical small animal imaging. We will focus on new emerging applications such as the use of Cerenkov imaging for monitoring radionuclide and external radiotherapy in humans. Another novel application that will be described is the monitoring of radiochemical synthesis using microfluidic chips. Several pre-clinical aspects of CR will be discussed such as the development of 3D reconstruction methods for Cerenkov images and the use of CR as excitation source for nanoparticles or for endoscopic imaging. We will also include a discussion on radioluminescence imaging that is a more general method than Cerenkov imaging for the detection using optical methods of alpha and gamma emitters. PMID- 25555906 TI - Phantom based qualitative and quantitative evaluation of artifacts in MR images of metallic hip prostheses. AB - PURPOSE: To develop methods for qualitative and quantitative evaluation of MRI artifacts near metallic prostheses, and to compare the efficiency of different artifact suppression techniques with different types of hip prostheses. METHODS: Three hip prostheses of cobalt-chromium, stainless steel, and titanium were embedded in agarose gel together with a rectilinear grid. Coronal MR images of the prostheses were acquired on a 1.5T scanner. Three pulse sequences were evaluated; TSE: a high-bandwidth turbo spin echo; VAT: TSE with view angle tilting, SEMAC: TSE with both VAT and slice distortion correction (6, 10 or 16 z phase-encoding steps). Through-plane distortions were assessed as the length of visible gridlines, in-plane artifacts as the artifact area, and total artifacts by subtraction of an ideal, undistorted image from the actual image. RESULTS: VAT reduced in-plane artifacts by up to 50% compared to TSE, but did not reduce through-plane artifacts. SEMAC reduced through-plane artifacts by 60-80% compared to TSE and VAT. SEMAC in-plane artifacts were from 20% higher (6 encoding steps) to 50% lower (16 steps) than VAT. Total artifacts were reduced by 60-80% in the best sequence (SEMAC, 16 steps) compared to the worst (TSE). The titanium prosthesis produced 3-4 times lower artifact scores than the other prostheses. CONCLUSIONS: A rectilinear grid phantom is useful for qualitative and quantitative evaluation of artifacts provoked by different MRI protocols and prosthesis models. VAT and SEMAC were superior to TSE with high bandwidth. A proper number of z-encoding steps in SEMAC was critical. The titanium prosthesis caused least artifacts. PMID- 25555907 TI - Endoscopic transoral and transmaxillary excision of the infratemporal fossa hemangioma. AB - Hemangiomas in the infratemporal fossa (ITF) are extremely rare benign vascular tumors. For many tumors of the ITF, with the exception of some small hemangiomas, a lateral facial approach has often been required. Recently, however, there have been some reports that minimally invasive endoscopic surgery can be used in the ITF; this would reduce the risk of surgical complications. To date, there has been no report of a hemangioma of the ITF exceeding 6 cm being resected by the endoscopic approach without facial incisions. Here, however, we report two cases of ITF hemangiomas that were completely extracted endoscopically, using a transmaxillary and transoral approach, without facial incisions or surgical complications. PMID- 25555908 TI - CD36 binds oxidized low density lipoprotein (LDL) in a mechanism dependent upon fatty acid binding. AB - The association of unesterified fatty acid (FA) with the scavenger receptor CD36 has been actively researched, with focuses on FA and oxidized low density lipoprotein (oxLDL) uptake. CD36 has been shown to bind FA, but this interaction has been poorly characterized to date. To gain new insights into the physiological relevance of binding of FA to CD36, we characterized FA binding to the ectodomain of CD36 by the biophysical method surface plasmon resonance. Five structurally distinct FAs (saturated, monounsaturated (cis and trans), polyunsaturated, and oxidized) were pulsed across surface plasmon resonance channels, generating association and dissociation binding curves. Except for the oxidized FA HODE, all FAs bound to CD36, with rapid association and dissociation kinetics similar to HSA. Next, to elucidate the role that each FA might play in CD36-mediated oxLDL uptake, we used a fluorescent oxLDL (Dii-oxLDL) live cell assay with confocal microscopy imaging. CD36-mediated uptake in serum-free medium was very low but greatly increased when serum was present. The addition of exogenous FA in serum-free medium increased oxLDL binding and uptake to levels found with serum and affected CD36 plasma membrane distribution. Binding/uptake of oxLDL was dependent upon the FA dose, except for docosahexaenoic acid, which exhibited binding to CD36 but did not activate the uptake of oxLDL. HODE also did not affect oxLDL uptake. High affinity FA binding to CD36 and the effects of each FA on oxLDL uptake have important implications for protein conformation, binding of other ligands, functional properties of CD36, and high plasma FA levels in obesity and type 2 diabetes. PMID- 25555909 TI - Contributions of ionic interactions and protein dynamics to cytochrome P450 2D6 (CYP2D6) substrate and inhibitor binding. AB - P450 2D6 contributes significantly to the metabolism of >15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety of thioridazine forms a charge-stabilized hydrogen bond with Asp-301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge stabilized hydrogen bond with Glu-222. Incubation of the crystalline open thioridazine complex with alternative ligands, prinomastat, quinidine, quinine, or ajmalicine, displaced both thioridazines. Quinine and ajmalicine formed charge stabilized hydrogen bonds with Glu-216, whereas the protonated nitrogen of quinidine is equidistant from Asp-301 and Glu-216 with protonated nitrogen H bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side-chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu-216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme after replacement of thioridazine with alternative compounds. PMID- 25555910 TI - Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5. AB - Mutations in the X-linked CDKL5 (cyclin-dependent kinase-like 5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged, whereas in more mature neurons, NMDA receptor stimulation induces a protein phosphatase 1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome-dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape, and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation, and refinement. PMID- 25555911 TI - Proteolytic regulation of epithelial sodium channels by urokinase plasminogen activator: cutting edge and cleavage sites. AB - Plasminogen activator inhibitor 1 (PAI-1) level is extremely elevated in the edematous fluid of acutely injured lungs and pleurae. Elevated PAI-1 specifically inactivates pulmonary urokinase-type (uPA) and tissue-type plasminogen activators (tPA). We hypothesized that plasminogen activation and fibrinolysis may alter epithelial sodium channel (ENaC) activity, a key player in clearing edematous fluid. Two-chain urokinase (tcuPA) has been found to strongly stimulate heterologous human alphabetagamma ENaC activity in a dose- and time-dependent manner. This activity of tcuPA was completely ablated by PAI-1. Furthermore, a mutation (S195A) of the active site of the enzyme also prevented ENaC activation. By comparison, three truncation mutants of the amino-terminal fragment of tcuPA still activated ENaC. uPA enzymatic activity was positively correlated with ENaC current amplitude prior to reaching the maximal level. In sharp contrast to uPA, neither single-chain tPA nor derivatives, including two-chain tPA and tenecteplase, affected ENaC activity. Furthermore, gamma but not alpha subunit of ENaC was proteolytically cleaved at ((177)GR?KR(180)) by tcuPA. In summary, the underlying mechanisms of urokinase-mediated activation of ENaC include release of self-inhibition, proteolysis of gamma ENaC, incremental increase in opening rate, and activation of closed (electrically "silent") channels. This study for the first time demonstrates multifaceted mechanisms for uPA-mediated up-regulation of ENaC, which form the cellular and molecular rationale for the beneficial effects of urokinase in mitigating mortal pulmonary edema and pleural effusions. PMID- 25555912 TI - Subunit-specific regulation of N-methyl-D-aspartate (NMDA) receptor trafficking by SAP102 protein splice variants. AB - Synapse-associated protein 102 (SAP102) is a scaffolding protein abundantly expressed early in development that mediates glutamate receptor trafficking during synaptogenesis. Mutations in human SAP102 have been reported to cause intellectual disability, which is consistent with its important role during early postnatal development. SAP102 contains PDZ, SH3, and guanylate kinase (GK)-like domains, which mediate specific protein-protein interactions. SAP102 binds directly to N-methyl-D-aspartate receptors (NMDARs), anchors receptors at synapses, and facilitates transduction of NMDAR signals. Proper localization of SAP102 at the postsynaptic density is essential to these functions. However, how SAP102 is targeted to synapses is unclear. In the current study we find that synaptic localization of SAP102 is regulated by alternative splicing. The SAP102 splice variant that possesses a C-terminal insert (I2) between the SH3 and GK domains is highly enriched at dendritic spines. We also show that there is an intramolecular interaction between the SH3 and GK domains in SAP102 but that the I2 splicing does not influence SH3-GK interaction. Previously, we have shown that SAP102 expression promotes spine lengthening. We now find that the spine lengthening effect is independent of the C-terminal alternative splicing of SAP102. In addition, expression of I2-containing SAP102 isoforms is regulated developmentally. Knockdown of endogenous I2-containing SAP102 isoforms differentially affect NMDAR surface expression in a subunit-specific manner. These data shed new light on the role of SAP102 in the regulation of NMDAR trafficking. PMID- 25555913 TI - beta2-Glycoprotein I-specific T cells are associated with epitope spread to lupus related autoantibodies. AB - Systemic lupus erythematosus (SLE) is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous and molecularly distinct self antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting the apoptotic cell-binding protein beta2-glycoprotein I (beta2GPI). Notably, mice immunized with beta2GPI and LPS display a remarkably similar pattern of autoantibody emergence to that seen in human SLE. Here, we used this model to investigate whether epitope spread to SLE-related autoantibodies is associated with a unique or limited beta2GPI-specific T cell response. We ask whether MHC class II haplotype and its associated T cell epitope restriction impact epitope spread to SLE-related autoantibodies. We found that beta2GPI/LPS-immunized mice produced similar SLE-related autoantibody profiles regardless of their beta2GPI T cell epitope specificity or MHC class II haplotype. Although beta2GPI T cell epitope specificity was clearly determined by MHC class II haplotype, a number of different beta2GPI T cell epitopes were associated with epitope spread to SLE related autoantibodies. Notably, one beta2GPI T cell epitope (peptide 23, NTGFYLNGADSAKCT) was also recognized by T cells from an HLA-DRB1*0403(+) autoimmune patient. These data suggest that the generation of a beta2GPI-reactive T cell response is associated with epitope spread to SLE-related autoantibodies, independent of epitope specificity or MHC class II restriction. On the basis of these findings, we propose that factors enabling a beta2GPI-reactive T cell response may predispose individuals to the development of SLE-related autoantibodies independent of their MHC class II haplotype. PMID- 25555914 TI - Prolyl oligopeptidase enhances alpha-synuclein dimerization via direct protein protein interaction. AB - Prolyl oligopeptidase (PREP) accelerates the aggregation of alpha-synuclein (aSyn), a key protein involved in development of Parkinson disease and other synucleinopathies. PREP inhibitors reduce aSyn aggregation, but the mechanism has remained unknown. We have now used protein-fragment complementation assays (PCA) and microscale thermophoresis in parallel to show that PREP interacts directly with aSyn in both intact cells and in a cell-free system. Using split luciferase based PCA, we first showed that PREP enhances the formation of soluble aSyn dimers in live Neuro-2A neuroblastoma cells. A PREP inhibitor, KYP-2047, reduced aSyn dimerization in PREP-expressing cells but not in cells lacking PREP expression. aSyn dimerization was also enhanced by PREP(S554A), an enzymatically inactive PREP mutant, but this was not affected by KYP-2047. PCA and microscale thermophoresis studies showed that aSyn interacts with both PREP and PREP(S554A) with low micromolar affinity. Neither the proline-rich, C-terminal domain of aSyn nor the hydrolytic activity of PREP was required for the interaction with PREP. Our results show that PREP binds directly to aSyn to enhance its dimerization and may thus serve as a nucleation point for aSyn aggregation. Native gel analysis showed that KYP-2047 shifts PREP to a compact monomeric form with reduced ability to promote aSyn nucleation. As PREP inhibition also enhances autophagic clearance of aSyn, PREP inhibitors may reduce accumulation of aSyn inclusions via a dual mechanism and are thus a novel therapeutic candidate for synucleinopathies. Our results also suggest that PREP has other cellular functions in addition to its peptidase activity. PMID- 25555915 TI - The Atlastin C-terminal tail is an amphipathic helix that perturbs the bilayer structure during endoplasmic reticulum homotypic fusion. AB - Fusion of tubular membranes is required to form three-way junctions found in reticular subdomains of the endoplasmic reticulum. The large GTPase Atlastin has recently been shown to drive endoplasmic reticulum membrane fusion and three-way junction formation. The mechanism of Atlastin-mediated membrane fusion is distinct from SNARE-mediated membrane fusion, and many details remain unclear. In particular, the role of the amphipathic C-terminal tail of Atlastin is still unknown. We found that a peptide corresponding to the Atlastin C-terminal tail binds to membranes as a parallel alpha helix, induces bilayer thinning, and increases acyl chain disorder. The function of the C-terminal tail is conserved in human Atlastin. Mutations in the C-terminal tail decrease fusion activity in vitro, but not GTPase activity, and impair Atlastin function in vivo. In the context of unstable lipid bilayers, the requirement for the C-terminal tail is abrogated. These data suggest that the C-terminal tail of Atlastin locally destabilizes bilayers to facilitate membrane fusion. PMID- 25555916 TI - A novel mechanism of latency in matrix metalloproteinases. AB - The matrix metalloproteinases (MMPs) are a family of secreted soluble or membrane anchored multimodular peptidases regularly found in several paralogous copies in animals and plants, where they have multiple functions. The minimal consensus domain architecture comprises a signal peptide, a 60-90-residue globular prodomain with a conserved sequence motif including a cysteine engaged in "cysteine-switch" or "Velcro" mediated latency, and a catalytic domain. Karilysin, from the human periodontopathogen Tannerella forsythia, is the only bacterial MMP to have been characterized biochemically to date. It shares with eukaryotic forms the catalytic domain but none of the flanking domains. Instead of the consensus MMP prodomain, it features a 14-residue propeptide, the shortest reported for a metallopeptidase, which lacks cysteines. Here we determined the structure of a prokarilysin fragment encompassing the propeptide and the catalytic domain, and found that the former runs across the cleft in the opposite direction to a bound substrate and inhibits the latter through an "aspartate switch" mechanism. This finding is reminiscent of latency maintenance in the otherwise unrelated astacin and fragilysin metallopeptidase families. In addition, in vivo and biochemical assays showed that the propeptide contributes to protein folding and stability. Our analysis of prokarilysin reveals a novel mechanism of latency and activation in MMPs. Finally, our findings support the view that the karilysin catalytic domain was co-opted by competent bacteria through horizontal gene transfer from a eukaryotic source, and later evolved in a specific bacterial environment. PMID- 25555919 TI - Massive transfusion prediction with inclusion of the pre-hospital Shock Index. AB - BACKGROUND: Detecting occult bleeding can be challenging and may delay resuscitation. The Shock Index (SI) defined as heart rate divided by systolic blood pressure has attracted attention. Prediction models using combinations of pre-hospital SI (phSI) and the trauma centre SI (tcSI) values may be effective in identifying patients requiring massive blood transfusions (MT). AIM: To explore whether combinations of the phSI and the tcSI augment MT prediction. METHODS: The scores were retrospectively developed using all major trauma patients that presented to The Alfred Hospital between 2006 and 2012. The first PH and TC observations were used. To avoid exclusion of the 'sickest' patients, the SI was imputed to 2 where SBP was missing, but HR was present. We developed 4 models. (i) 'Dichotomised', defined as positive when both phSI and tcSI were >=1. (ii) 'Formulaic', defined by logistic regression analysis. (iii) 'Combination', defined pragmatically based on the logistic regression. (iv) 'Trending', defined as: tcSI minus phSI. RESULTS: There were 6990 major trauma patients and 360 (5.2%) received MT. There were 1371 cases with either phSI or tcSI missing and were thus excluded from the analysis. The 'Dichotomised' had higher positive predictive value than the tcSI with a further 5 per 100 patients identified. The 'Formulaic' model, defined as: log Odds (MT)=2.16*tcSI+0.89*phSI-5.42, and the 'Combination' model, defined as: phSI*0.5+tcSI, performed equally (AUROC 0.83 versus 0.83, chi(2)=0.86, p=0.35). The 'Formulaic' performed marginally, but statistically significantly, more accurate than the tcSI alone (AUROC 0.83 versus 0.82, chi(2)=6.89, p<0.01). An 'Upward Trending' SI was observed in 1758 patients, revealing a 4.6-fold univariate association with MT (OR 4.55; 95%CI 2.64-7.83), and an AUROC of 0.79 (95%CI 0.74-0.83). The 'Downward Trending' SI was protective against MT (OR 0.44; 95%CI 0.34-0.57). CONCLUSION: The initial pre hospital SI is associated with MT. However, this relationship did not clinically augment MT decision when combined with the in-hospital SI. The simplicity of the SI makes it a favourable option to explore further. Computer-assisted technology in data capturing, analysis and prognostication presents avenues for further research. PMID- 25555918 TI - Enriched environment-induced maternal weight loss reprograms metabolic gene expression in mouse offspring. AB - The global prevalence of weight loss is increasing, especially in young women. However, the extent and mechanisms by which maternal weight loss affects the offspring is still poorly understood. Here, using an enriched environment (EE) induced weight loss model, we show that maternal weight loss improves general health and reprograms metabolic gene expression in mouse offspring, and the epigenetic alterations can be inherited for at least two generations. EE in mothers induced weight loss and its associated physiological and metabolic changes such as decreased adiposity and improved glucose tolerance and insulin sensitivity. Relative to controls, their offspring exhibited improved general health such as reduced fat accumulation, decreased plasma and hepatic lipid levels, and improved glucose tolerance and insulin sensitivity. Maternal weight loss altered gene expression patterns in the liver of offspring with coherent down-regulation of genes involved in lipid and cholesterol biosynthesis. Epigenomic profiling of offspring livers revealed numerous changes in cytosine methylation depending on maternal weight loss, including reproducible changes in promoter methylation over several key lipid biosynthesis genes, correlated with their expression patterns. Embryo transfer studies indicated that oocyte alteration in response to maternal metabolic conditions is a strong factor in determining metabolic and epigenetic changes in offspring. Several important lipid metabolism-related genes have been identified to partially inherit methylated alleles from oocytes. Our study reveals a molecular and mechanistic basis of how maternal lifestyle modification affects metabolic changes in the offspring. PMID- 25555925 TI - Rehabilitation assessments for patients with stroke in Australian hospitals do not always reflect the patients' rehabilitation requirements. AB - OBJECTIVES: To examine the frequency and factors associated with patients with stroke in Australian hospitals receiving documented rehabilitation assessments; to examine the criteria used when rehabilitation was not recommended; and to examine whether being assessed for rehabilitation affected access to rehabilitation. DESIGN: Retrospective medical record audit of patients with a diagnosis of stroke who were discharged consecutively between 2013 and 2014. SETTING: Acute care public hospitals. PARTICIPANTS: Adults with stroke (N=333) receiving care in participating hospitals. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Documented assessment regarding patient suitability for rehabilitation during acute hospitalization. RESULTS: Data from 292 patients were included for analysis (60% men; mean age, 72y). Of the patients, 42% were assessed for rehabilitation by a health professional providing care in the hospital, 43% were assessed for rehabilitation by a representative from a rehabilitation service, and 37% did not receive any documented rehabilitation assessment. In multivariable analysis, patients were significantly more likely to be assessed for rehabilitation if they lived in the community before their stroke, had moderate severity strokes, or received occupational therapy during hospital admission. Rehabilitation was not recommended in 9% of assessments despite the presence of stroke-related symptoms. Patients not assessed for rehabilitation were significantly less likely to access rehabilitation than patients who were assessed. CONCLUSIONS: More than one third of patients were not assessed for rehabilitation. When assessed, rehabilitation was not consistently recommended for patients with stroke-related symptoms. This study highlights factors that increase the likelihood of being assessed for rehabilitation. PMID- 25555917 TI - Efficient delivery and functional expression of transfected modified mRNA in human embryonic stem cell-derived retinal pigmented epithelial cells. AB - Gene- and cell-based therapies are promising strategies for the treatment of degenerative retinal diseases such as age-related macular degeneration, Stargardt disease, and retinitis pigmentosa. Cellular engineering before transplantation may allow the delivery of cellular factors that can promote functional improvements, such as increased engraftment or survival of transplanted cells. A current challenge in traditional DNA-based vector transfection is to find a delivery system that is both safe and efficient, but using mRNA as an alternative to DNA can circumvent these major roadblocks. In this study, we show that both unmodified and modified mRNA can be delivered to retinal pigmented epithelial (RPE) cells with a high efficiency compared with conventional plasmid delivery systems. On the other hand, administration of unmodified mRNA induced a strong innate immune response that was almost absent when using modified mRNA. Importantly, transfection of mRNA encoding a key regulator of RPE gene expression, microphthalmia-associated transcription factor (MITF), confirmed the functionality of the delivered mRNA. Immunostaining showed that transfection with either type of mRNA led to the expression of roughly equal levels of MITF, primarily localized in the nucleus. Despite these findings, quantitative RT-PCR analyses showed that the activation of the expression of MITF target genes was higher following transfection with modified mRNA compared with unmodified mRNA. Our findings, therefore, show that modified mRNA transfection can be applied to human embryonic stem cell-derived RPE cells and that the method is safe, efficient, and functional. PMID- 25555926 TI - Input materials and processing conditions control compost dissolved organic carbon quality. AB - Dissolved organic carbon (DOC) has been proposed as an indicator of compost maturity and stability. Further fractionation of compost DOC may be useful for determining how particular composting conditions will influence DOC quality. Eleven composts ranging in input materials and processing techniques were analyzed; concentrations of DOC ranged from 428 mg kg(-1) to 7300 mg kg(-1). Compost DOC was qualified by fractionation into pools of humic acids (HA), fulvic acids (FA), hydrophobic neutrals (HoN), and hydrophilic (Hi) compounds. The range in proportion of DOC pools was highly variable, even for composts with similar total DOC concentrations. Longer composting time and higher temperatures consistently corresponded with a depletion of hydrophilics, suggesting a preferential turnover of these compounds during the thermophilic composting phase. Qualification of DOC pools through fractionation may be an informative tool in predicting the effects of a processing technique on compost quality and, ultimately, soil functional processes. PMID- 25555927 TI - Ultrasound enhanced ethanol production from Parthenium hysterophorus: A mechanistic investigation. AB - This study presents mechanistic investigations in ultrasound-assisted bioethanol fermentation using Parthenium hysterophorus biomass. Ultrasound (35 kHz, 10% duty cycle) has been used for sonication. Experimental results were fitted to mathematical model; the kinetic and physiological parameters in the model were obtained using Genetic Algorithm (GA) based optimization. In control experiments (mechanical shaking), maximum ethanol titer of 10.93 g/L and cell mass concentration of 5.26 g/L was obtained after 18 h. In test experiments (mechanical shaking and intermittent sonication), ethanol titer of 12.14 g/L and cell mass concentration of 5.7 g/L was obtained in 10h. This indicated ~ 2 * enhanced productivity of ethanol and cell mass with sonication. Trends in model parameters obtained after fitting of model to experimental data essentially revealed that beneficial influence of ultrasound on fermentation is a manifestation of enhanced trans-membrane transportation and dilution of toxic substances due to strong micro-convection induced by ultrasound. PMID- 25555933 TI - Invited commentary. PMID- 25555928 TI - Age-dependent long-term structural and functional effects of early-life seizures: evidence for a hippocampal critical period influencing plasticity in adulthood. AB - Neural activity promotes circuit formation in developing systems and during critical periods permanently modifies circuit organization and functional properties. These observations suggest that excessive neural activity, as occurs during seizures, might influence developing neural circuitry with long-term outcomes that depend on age at the time of seizures. We systematically examined long-term structural and functional consequences of seizures induced in rats by kainic acid, pentylenetetrazol, and hyperthermia across postnatal ages from birth through postnatal day 90 in adulthood (P90). Magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and electrophysiological methods at ?P95 following seizures induced from P1 to P90 demonstrated consistent patterns of gross atrophy, microstructural abnormalities in the corpus callosum (CC) and hippocampus, and functional alterations in hippocampal circuitry at ?P95 that were independent of the method of seizure induction and varied systematically as a function of age at the time of seizures. Three distinct epochs were observed in which seizures resulted in distinct long-term structural and functional outcomes at ?P95. Seizures prior to P20 resulted in DTI abnormalities in CC and hippocampus in the absence of gross cerebral atrophy, and increased paired-pulse inhibition (PPI) in the dentate gyrus (DG) at ?P95. Seizures after P30 induced a different pattern of DTI abnormalities in the fimbria and hippocampus accompanied by gross cerebral atrophy with increases in lateral ventricular volume, as well as increased PPI in the DG at ?P95. In contrast, seizures between P20 and P30 did not result in cerebral atrophy or significant imaging abnormalities in the hippocampus or white matter, but irreversibly decreased PPI in the DG compared to normal adult controls. These age-specific long-term structural and functional outcomes identify P20-30 as a potential critical period in hippocampal development defined by distinctive long-term structural and functional properties in adult hippocampal circuitry, including loss of capacity for seizure-induced plasticity in adulthood that could influence epileptogenesis and other hippocampal-dependent behaviors and functional properties. PMID- 25555930 TI - The development of lasting impairments: a mild pediatric brain injury alters gene expression, dendritic morphology, and synaptic connectivity in the prefrontal cortex of rats. AB - Apart from therapeutic discovery, the study of mild traumatic brain injury (mTBI) has been focused on two challenges: why do a majority of individuals recover with little concern, while a considerable proportion suffer with persistent and often debilitating symptomology; and, how do mild injuries significantly increase risk for an early-onset neurodegeneration? Owing to a lack of observable damage following mTBI, this study was designed to determine if there were changes in neuronal morphology, synaptic connectivity, and epigenetic patterning that could contribute to the manifestation of persistent neurological dysfunction. Prefrontal cortex tissue from male and female rats was used for Golgi-Cox analysis along with the profiling of changes in gene expression (BDNF, DNMT1, FGF2, IGF1, Nogo-A, OXYR, and TERT) and telomere length (TL), following a single mTBI or sham injury in the juvenile period. Golgi-Cox analysis of dendritic branch order, dendritic length, and spine density demonstrate that an early mTBI increases complexity of pyramidal neurons in the mPFC. Furthermore, there are also substantial changes in the expression levels of the seven genes of interest and TL following a single mild injury in this brain region. The results from the neuroanatomical measures and changes in gene expression indicate that the mTBI disrupts normal pruning processes that are typically underway at this point in development. In addition, there are significant interactions between the social environment and epigenetic processes that work in concert to perpetuate neurological dysfunction. PMID- 25555929 TI - Expansion of the dentate mossy fiber-CA3 projection in the brain-derived neurotrophic factor-enriched mouse hippocampus. AB - Structural changes that alter hippocampal functional circuitry are implicated in learning impairments, mood disorders and epilepsy. Reorganization of mossy fiber (MF) axons from dentate granule cells is one such form of plasticity. Increased neurotrophin signaling is proposed to underlie MF plasticity, and there is evidence to support a mechanistic role for brain-derived neurotrophic factor (BDNF) in this process. Transgenic mice overexpressing BDNF in the forebrain under the alpha-calcium/calmodulin-dependent protein kinase II promoter (TgBDNF mice) exhibit spatial learning deficits at 2-3months of age, followed by the emergence of spontaneous seizures at ~6months. These behavioral changes suggest that chronic increases in BDNF progressively disrupt hippocampal functional organization. To determine if the dentate MF pathway is structurally altered in this strain, the present study employed Timm staining and design-based stereology to compare MF distribution and projection volumes in transgenic and wild-type mice at 2-3months, and at 6-7months. Mice in the latter age group were assessed for seizure vulnerability with a low dose of pilocarpine given 2h before euthanasia. At 2-3months, TgBDNF mice showed moderate expansion of CA3-projecting MFs (~20%), with increased volumes measured in the suprapyramidal (SP-MF) and intra/infrapyramidal (IIP-MF) compartments. At 6-7months, a subset of transgenic mice exhibited increased seizure susceptibility, along with an increase in IIP-MF volume (~30%). No evidence of MF sprouting was seen in the inner molecular layer. Additional stereological analyses demonstrated significant increases in molecular layer (ML) volume in TgBDNF mice at both ages, as well as an increase in granule cell number by 8months of age. Collectively, these results indicate that sustained increases in endogenous BDNF modify dentate structural organization over time, and may thereby contribute to the development of pro-epileptic circuitry. PMID- 25555934 TI - Invited commentary. PMID- 25555935 TI - Invited commentary. PMID- 25555936 TI - Invited commentary. PMID- 25555937 TI - Invited commentary. PMID- 25555938 TI - Invited commentary. PMID- 25555939 TI - Invited commentary. PMID- 25555940 TI - Invited commentary. PMID- 25555941 TI - Invited commentary. PMID- 25555942 TI - Invited commentary. PMID- 25555943 TI - Invited commentary. PMID- 25555944 TI - Invited commentary. PMID- 25555945 TI - Invited commentary. PMID- 25555946 TI - Initial clinical experience with the Symphony heart assist system. AB - PURPOSE: Current cardiac assist devices provide full support, require a major operation, and function asynchronously to the native heart. In contrast, we developed a novel circulatory support device that provides synchronous partial support and can be placed with a minor operation. We report the first clinical implantation with the Symphony device (Abiomed, Danvers, MA). DESCRIPTION: Patients with advanced heart failure despite optimal therapy who had exhausted all options were evaluated. A 64-year-old man with ischemic cardiomyopathy underwent implantation of the Symphony device in the right infraclavicular fossa. EVALUATION: After initiating device support, the cardiac index increased from 1.7 to 2.5 L/min/m(2), pulmonary capillary wedge pressure decreased from 26 to 13 mm Hg, right atrial pressure decreased from 12 to 7 mm Hg, creatinine level decreased from 2.3 to 1.5 mg/dL, and New York Heart Association (NYHA) class improved from IIIB to II. CONCLUSIONS: Placement of the Symphony device resulted in improvements in hemodynamics and functional status. Further clinical data will help define the role for this approach of partial synchronous support through a less invasive operation in patients with advanced heart failure. PMID- 25555947 TI - Paraplegia due to intramedullary hemorrhage after mitral valve repair. AB - We report the case of a patient who developed paraplegia after mitral valve repair and maze procedure. The first day after surgery, marked weakness of both lower extremities was noted. Neurologic examination showed almost complete loss of sensory and motor function below the level of the first thoracic vertebrae. Magnetic resonance imaging showed intramedullary hemorrhage ranging from the C7 to Th2 segments. Preoperative anticoagulation therapy and general heparinization during heart surgery may cause this rare complication. PMID- 25555948 TI - Novel TGFBR2 and known missense SMAD3 mutations: two case reports of thoracic aortic aneurysms. AB - We report the clinical presentation and genetic screening of 2 patients with thoracic aortic aneurysms. A novel TGFBR2 mutation in the 5'untranslated region (c.-59C>T) was identified in a 31-year-old man with a Stanford type A aortic dissection. Bioinformatics tools showed that c.-59C>T variant was predicted to affect exonic splicing enhancer, as validated by quantitative real-time RT-PCR, revealing a sixfold increase of TGFBR2 mRNA in aneurysmal aortic tissue collected during surgery. A previously described missense mutation, p.E239K, in the SMAD3 gene was identified in a 60-year-old man who presented with diffuse vasculopathy. These findings suggest that the features of aneurysmal disease extending beyond the ascending aorta may help to target SMAD3 genetic screening and that alterations in the core splicing machinery can contribute to aneurysmal disease. PMID- 25555949 TI - Lymphoma of prosthetic aortic graft presenting as recurrent embolization. AB - We describe the case of a patient who presented with transient ischemic attack 4 years after bicuspid aortic valve repair, ascending aorta, and hemiarch replacement. Workup included cross-sectional imaging consistent with thrombus in the ascending aorta graft. Warfarin was initiated, but another episode of cerebral ischemia occurred despite therapeutic anticoagulation. Surgery was performed to avoid further embolization as re-replacement with a homograft aorta. Histologic analysis of the material found within the graft demonstrated large B cell lymphoma. At 39 months' follow-up, there have been no additional episodes of embolization and no evidence of recurrent cancer. PMID- 25555950 TI - Concomitant femoro-femoral bypass graft during surgery for acute type A dissection to treat lower limb malperfusion. AB - We report the case of a 69-year-old male patient who was admitted to our department with an acute type A dissection complicated by ischemia of the left lower limb. During surgery for acute type A dissection, the patient underwent concomitant femoro-femoral crossover bypass graft placement to ensure blood supply of the left lower limb during surgery and minimize ischemia-reperfusion injury. The patient underwent supracoronary replacement of the ascending aorta while in deep circulatory arrest with a deepest core temperature of 25 degrees C. Postoperative computed tomography showed antegrade perfusion and patency of the crossover bypass. Postoperative course was eventless without sequelae, especially of the left lower limb. We conclude that concomitant crossover bypass graft reduces the risk of ischemia-reperfusion injury in lower limb ischemia in patients undergoing surgery for acute type A dissection. PMID- 25555951 TI - Valve-sparing neoaortic root replacement late after the Norwood and Fontan procedures. AB - Neoaortic root dilatation is a significant and inevitable late complication in patients after the Norwood operation. In this report, we describe a patient who had left pulmonary artery compression and severe neoaortic regurgitation from a severely dilated neoaortic root 11 years after the Norwood operation and subsequent Fontan procedure. We performed successful valve-sparing neoaortic root replacement in this patient. PMID- 25555952 TI - Biventricular repair of double-outlet right ventricle and closing ventricular septal defect. AB - We report an infant with double-outlet right ventricle and progressive left ventricular failure caused by a closing apical muscular ventricular septal defect detected during follow-up, who achieved successful biventricular repair after surgical opening and enlargement of a closed perimembranous ventricular septal defect. PMID- 25555953 TI - Congenital aneurysm of the aortomitral intervalvular fibrosa. AB - A 5-year-old boy was found to have a congenital left ventricular outflow tract (LVOT) aneurysm of the intervalvular fibrosa, LVOT obstruction after repair of a perimembranous ventricular septal defect, and aortic coarctation. The patient underwent successful plication of the aneurysm, resection of the fibrous subaortic stenosis, and septal myectomy. PMID- 25555954 TI - Histologic evolution from adenocarcinoma to squamous cell carcinoma after gefitinib treatment. AB - We report two cases of lung cancer with histologic transformation from adenocarcinoma to squamous cell carcinoma after gefitinib treatment. Both cases involved advanced lung cancers, initially confirmed as adenocarcinomas with sensitive epidermal growth factor gene mutations. After gefitinib treatment, the second pathologic examination in each case revealed squamous cell carcinoma retaining identical mutations without newly acquired resistance mutations. The underlying mechanism may have been pluripotent tumor cells with divergent differentiation or mixed lung cancer including both adenocarcinomatous and squamous cell carcinomatous components. This report widens the spectrum of histologic evolution as a mechanism underlying the acquisition of drug resistance. PMID- 25555956 TI - Extracellular matrix pleural tent for persistent air leak and air space in a child after upper lobectomy. AB - Creation of a pleural tent is effective in reducing persistent air leaks after pulmonary resection. I report a case of a pleural-like tent being created out of extracellular matrix to treat a persistent air leak in child after upper lobectomy for a large congenital pulmonary airway malformation type II. Over the next year, ipsilateral lung expansion and growth occurred with near complete resolution of the apical air space. PMID- 25555955 TI - Pneumonectomy and contralateral metastasectomy through a single thoracotomy in a 9-year-old girl with a giant tumor. AB - A 9-year-old girl with a giant tumor of the right lung and an isolated metastasis of the left lower lobe underwent combined pneumonectomy and metastasectomy through means of a right thoracotomy. Her postoperative course was uneventful. The operative approach of a tumor of this scale and the concurrent contralateral metastasectomy are described and discussed. PMID- 25555957 TI - Right lower lobe autotransplantation for locally advanced central lung cancer. AB - A 44-year-old man with locally advanced central lung cancer was treated by right lower lobe lung autotransplantation after pneumonectomy using an extracellular phosphate-buffered solution for cold lung preservation. The advantage of the ex vivo operation made it possible to perform safe and definitive cancer resection without massive bleeding. Cold lung preservation brought some advantages, such as reducing the risk of ischemia-reperfusion injury compared with warm ischemia and allowing enough time to achieve microscopically negative margins. The patient returned to normal life with minimum loss of pulmonary reserve and no recurrence of lung cancer for 6 months. PMID- 25555958 TI - Diffuse lipomatosis of the chest wall: report of a neonatal case. AB - Diffuse lipomatosis is a very rare condition, the nature of which, neoplastic or hamartomatous, has not yet been defined. We report the case of a small child with a right thoracic lesion of neonatal onset and extremely rapid growth, who successfully underwent complete surgical resection. The differential diagnoses and proper surgical treatment are discussed. PMID- 25555959 TI - Congenital tracheobiliary fistula in an adolescent patient. AB - Congenital tracheobiliary fistula is a rare malformation that allows communication between the respiratory system and hepatobiliary tract. We describe a male adolescent patient who was admitted with a destroyed lung caused by repetitive bile pneumonitis with a congenital tracheobiliary fistula. Left pneumonectomy was performed, and the fistula tract was successfully divided. PMID- 25555960 TI - Thoracoscopic esophageal repair of a spontaneous Barrett's ulcer perforation. AB - Spontaneous esophageal perforation of a Barrett's ulcer is a rare condition that is associated with high morbidity and mortality. It occurs as a result of a missed diagnosis of underlying Barrett's esophagus or because of unresponsiveness to medical management. Owing to the life-threatening nature of this disease, emergency surgical intervention is indicated. Here, we report the first case of spontaneous Barrett's esophageal perforation that has been managed using a thoracoscopic approach. This case highlights the feasibility of minimally invasive methodology for emergent esophageal disorders. It also demonstrates the altered esophageal wall properties of Barrett's esophagus through musculofibrous thickening and muscularis mucosae duplication that may contribute to the technical outcomes of esophageal surgical management. PMID- 25555961 TI - Resection of esophageal carcinoma during pregnancy. AB - Esophageal carcinoma diagnosed during pregnancy is a rare occurrence. A 26-year old pregnant patient was referred to our hospital with dysphagia. A thorough examination showed a tumor in the esophagus. Laparotomy, thoracotomy, and cervical exploration were performed. There are only 2 cases reported in the literature about esophageal carcinoma diagnosed during pregnancy and treated surgically. However, ethical dilemmas arise in managing such situations. Here we report a case of esophageal squamous cell carcinoma diagnosed at 27 weeks of gestation in which surgical resection was performed successfully. PMID- 25555962 TI - Long esophageal segment laceration caused by an orogastric tube during laparoscopic sleeve gastrectomy. PMID- 25555963 TI - Embolized methyl methacrylate to the right atrium after kyphoplasty. PMID- 25555964 TI - Unruptured aneurysm of right coronary sinus of Valsalva with cystic mitral valve. PMID- 25555965 TI - A scimitar syndrome variant: anomalous systemic arterial supply to the right lung with normal pulmonary venous return. PMID- 25555966 TI - Hilum-to-hilum Gore-Tex tube replacement of central pulmonary arteries. AB - Patients born with hypoplastic pulmonary arteries require recurrent procedures of shunting, patch reconstructions, balloon dilatations, and occasionally stenting to achieve adult-size vessels. We have applied a hilum-to-hilum Gore-Tex conduit replacement for the stenosed central pulmonary arteries to 12 consecutive patients with a Gore-Tex tube of 14 mm (9 patients) or 12 mm (3 patients) at a median age of 6.7 years (range, 1.6 to 16.9). There were 8 patients with biventricular repair (2 patients with heart transplantation) and 4 patients with Fontan completions. After a follow-up time of 25 +/- 22 months, there was no mortality, reintervention, or restenosis. PMID- 25555967 TI - Use of barbed suture in robot-assisted mitral valvuloplasty. AB - Robot-assisted annuloplasty using a mitral band has a major issue: suturing is time consuming because knot tying is performed mechanically under endoscopic view. We suture the mitral band to the native valve by running sutures using the V-Loc barbed suture nonabsorbable wound closure device (Covidien, Mansfield, MA) with 3-0 monofilament. This technique allows rapid suturing of the band to the valve. Although conventional interrupted sutures leave multiple knots protruding on the band, using the V-Loc eliminates the need to tie surgical knots and leaves a clean surface, which may potentially reduce the risk of thrombogenesis. This method is highly useful for robotic mitral annuloplasty. PMID- 25555968 TI - Modified end-to-end anastomosis for the treatment of congenital tracheal stenosis with a bridging bronchus. AB - An infant with a ventricular septal defect; Vertebral anomalies, Anal atresia, Cardiac anomalies, Tracho Esophageal fistula (TEF), Renal anomalies, Limb anomalies syndrome; and tracheal stenosis with a bridging bronchus underwent repair of the ventricular septal defect and trachea-bronchial reconstruction at age 11 months. Herein we describe our surgical approach to resection of the bridging bronchus and a technique using a modified end-to-end tracheal anastomosis for the correction of this complex anomaly. PMID- 25555969 TI - Modified incision and closure techniques for single-incision thoracoscopic lobectomy. AB - Single-incision video-assisted thoracoscopic surgery (VATS) lobectomy has recently gained attention due to its various advantages. However, this technique requires direct insertion of the chest tube into the thoracic cage; thus, leakage of intrathoracic fluid or air around the tube frequently occurs. Additionally, cosmetic problems may develop due to direct fixation of the chest tube at the site of the skin incision. To solve these problems we designed new incision and closure techniques for VATS lobectomy. In our technique the skin is incised lower than an intercostal muscle incision, and the chest tube transpierces the chest wall muscle about 1 cm below the incision. Finally, nylon is used for tube fixation and is anchored through the subcutaneous suture. PMID- 25555970 TI - The Society of Thoracic Surgeons and the European Society of Thoracic Surgeons general thoracic surgery databases: joint standardization of variable definitions and terminology. AB - The European Society of Thoracic Surgery (ESTS) and the Society of Thoracic Surgeons (STS) general thoracic surgery databases collect thoracic surgical data from Europe and North America, respectively. Their objectives are similar: to measure processes and outcomes so as to improve the quality of thoracic surgical care. Future collaboration between the two databases and their integration could generate significant new knowledge. However, important discrepancies exist in terminology and definitions between the two databases. The objective of this collaboration between the ESTS and STS is to identify important differences between databases and harmonize terminology and definitions to facilitate future endeavors. PMID- 25555971 TI - Reply: To PMID 24360092. PMID- 25555972 TI - How important is dental clearance for elective open heart operations? PMID- 25555973 TI - Reply: To PMID 24360092. PMID- 25555974 TI - Dental workup before cardiac surgery: must or risk. PMID- 25555975 TI - Reply: To PMID 24045075. PMID- 25555976 TI - Why don't we take advantage of perfusion? PMID- 25555977 TI - Ipsilateral lung palpation and survival after pulmonary metastasectomy. PMID- 25555978 TI - Thoracic surgery experience: the role of simulation. PMID- 25555979 TI - Reply: To PMID 24928676. PMID- 25555980 TI - Thalassemia and heart surgery: aortic valve repair after endocarditis. AB - Outcome after heart valve surgery in patients affected by thalassemia is an unreported issue and to the best of our knowledge only 7 cases have been described in the literature. Heart valve disease is commonly encountered in thalassemia patients and heart valve replacement carries high risk of prosthesis complications including thrombosis and embolization despite optimal anticoagulation management. We report a successful long-term outcome after a case of aortic valve repair after mycotic valve endocarditis. PMID- 25555982 TI - Thoracoscopic tracheal resection and reconstruction for adenoid cystic carcinoma. AB - We describe a novel technique of thoracoscopic circumferential tracheal resection and end-to-end anastomosis. A 60-year-old woman presented with wheezing and progressive dyspnea. Computed tomography scan revealed a mass at the lower trachea, and a nitinol mesh stent was implanted by bronchoscopy. After 2 weeks, a complete thoracoscopic tracheal resection and reconstruction was performed. The postoperative course was uneventful. The final pathologic examination confirmed the diagnosis of primary adenoid cystic carcinoma of the trachea. PMID- 25555981 TI - Myasthenic crisis caused by preoperative chemotherapy with steroid for advanced thymoma. AB - We report the case of a 44-year-old woman with Masaoka stage IV, World Health Organization type B1 thymoma associated with pure red cell aplasia, thrombocytopenia, and myasthenia gravis, which occurred during preoperative chemotherapy with high-dose methylprednisolone. Noninvasive positive-pressure ventilation, intravenous immunoglobulin infusion, and methylprednisolone pulse therapy were performed for the myasthenic crisis. Disseminated thymoma was markedly reduced after these treatments, and macroscopic complete resection was performed after achieving control of pure red cell aplasia, myasthenia gravis, and thrombocytopenia using cyclosporine A. Chemotherapy, including high-dose methylprednisolone, may carry a risk of myasthenic crisis, although the regimen is effective against lymphocyte-rich thymoma. PMID- 25555983 TI - Congenital bronchial artery to pulmonary artery fistula presenting as hemoptysis. AB - A 51-year-old male presented with 2 weeks of hemoptysis. Pulmonary angiography was performed and identified a bronchial artery to pulmonary artery fistula of the right upper lobe. Despite angioembolization, the hemoptysis recurred 1 year later. It was hypothesized that the recurrence occurred due to retrograde filling from the pulmonary arterial side of the abnormality. Right upper lobectomy was performed and resulted in resolution of hemoptysis. We present a case report of a rare, congenital bronchial artery to pulmonary artery fistula. PMID- 25555984 TI - Airway stent insertion simulated with a three-dimensional printed airway model. AB - A 30-year-old man underwent right single-lung transplantation for chronic obstructive pulmonary disease. The bronchial anastomosis developed ischemic change, resulting in stenosis of the intermediate bronchus. A modified Y-shaped airway stent with the fabricated orifice of the upper lobe was inserted by rigid bronchoscopy. Before the operation, a three-dimensional printed bronchial model of this patient was made for surgical simulation. This model enabled us to perform the operation easily, quickly, and successfully. The patient's condition improved after airway stent insertion. The three-dimensional printed airway model provided sufficient preoperative understanding of the patient's anatomy for planning the surgical procedure. PMID- 25555985 TI - Pseudoaneurysm of the descending aorta complicating an untreated aortic coarctation. AB - A 22-year-old man was referred for severe aortic coarctation. Contrast-enhanced computed tomography confirmed the aortic coarctation diagnosis and showed an aortic pseudoaneurysm arising from the anterior and left surface of the descending aorta, communicating with the aortic lumen with a small neck. Under cardiopulmonary bypass through the femoral vessels, the patient underwent closure of the pseudoaneurysm neck using a synthetic patch and interposition of a prosthetic graft between the left subclavian artery and the descending aorta below the pseudoaneurysm. The patient's postoperative course was uneventful. PMID- 25555986 TI - Unicentric, multifocal Castleman disease of the mediastinum associated with cerebellitis. AB - A 30-year-old man presented with rapidly progressive cerebellar symptoms. Brain magnetic resonance imaging was consistent with cerebellitis. A subsequent chest computed tomography revealed a multilobulated anterior mediastinal mass, which was diagnosed on the surgical biopsy specimen as hyaline vascular Castleman disease. After resection of the mediastinal mass and multiple involved adjacent mediastinal lymph nodes, the cerebellitis resolved. To the best of our knowledge, this is the first report of Castleman disease associated with cerebellitis. This rare case of suspected paraneoplastic cerebellitis related to a multifocal unicentric Castleman disease confined to the mediastinum is discussed. PMID- 25555987 TI - The ABCs of eye color in Tribolium castaneum: orthologs of the Drosophila white, scarlet, and brown Genes. AB - In Drosophila melanogaster, each of the three paralogous ABC transporters, White, Scarlet and Brown, is required for normal pigmentation of the compound eye. We have cloned the three orthologous genes from the beetle Tribolium castaneum. Conceptual translations of Tribolium white (Tcw), scarlet (Tcst), and brown (Tcbw) are 51, 48, and 32% identical to their respective Drosophila counterparts. We have identified loss-of-eye-pigment strains that bear mutations in Tcw and Tcst: the Tcw gene in the ivory (i) strain carries a single-base transversion, which leads to an E -> D amino-acid substitution in the highly conserved Walker B motif, while the Tcst gene in the pearl (p) strain has a deletion resulting in incorporation of a premature stop codon. In light of these findings, the mutant strains i and p are herein renamed white(ivory) (w(i)) and scarlet(pearl) (st(p)), respectively. In addition, RNA inhibition of Tcw and Tcst recapitulates the mutant phenotypes, confirming the roles of these genes in normal eye pigmentation, while RNA interference of Tcbw provides further evidence that it has no role in eye pigmentation in Tribolium. We also consider the evolutionary implications of our findings. PMID- 25555988 TI - An enhanced gene targeting toolkit for Drosophila: Golic+. AB - Ends-out gene targeting allows seamless replacement of endogenous genes with engineered DNA fragments by homologous recombination, thus creating designer "genes" in the endogenous locus. Conventional gene targeting in Drosophila involves targeting with the preintegrated donor DNA in the larval primordial germ cells. Here we report G: ene targeting during O: ogenesis with L: ethality I: nhibitor and C: RISPR/Cas (Golic+), which improves on all major steps in such transgene-based gene targeting systems. First, donor DNA is integrated into precharacterized attP sites for efficient flip-out. Second, FLP, I-SceI, and Cas9 are specifically expressed in cystoblasts, which arise continuously from female germline stem cells, thereby providing a continual source of independent targeting events in each offspring. Third, a repressor-based lethality selection is implemented to facilitate screening for correct targeting events. Altogether, Golic+ realizes high-efficiency ends-out gene targeting in ovarian cystoblasts, which can be readily scaled up to achieve high-throughput genome editing. PMID- 25555990 TI - Why is nuclear organization dynamic, hierarchical and intricate? Implications for gene regulation, cellular differentiation and disease. PMID- 25555991 TI - By any means necessary: discovering a Bcl-xL specific domain. PMID- 25555989 TI - Titin and obscurin: giants holding hands and discovery of a new Ig domain subset. PMID- 25555993 TI - Potentially preventable premature lung cancer deaths in the USA if overall population rates were reduced to those of educated whites in lower-risk states. AB - PURPOSE: Death rates for lung cancer, the leading cause of cancer death in the USA, vary substantially by the level of education at the national level, but this has not previously been analyzed by state. METHODS: We examined age-standardized lung cancer death rates by educational attainment, race/ethnicity, and state in men and women (aged 25-64 years) in the USA in 2008-2010 and estimated the proportion of potentially avoidable premature lung cancer deaths for each state if rates were reduced to those achieved among more educated non-Hispanic whites in five states with low lung cancer rates, using data on 134,869 lung cancer deaths. RESULTS: Age-standardized lung cancer mortality rates differed substantially by state and education level. Among non-Hispanic white men, for example, rates per 100,000 ranged from below 6 in more educated men (>=16 years of education) in Utah, Colorado, and Montana to >75 in less educated men (<=12 years of education) in Mississippi, Oklahoma, and Kentucky. An estimated 73 % of lung cancer deaths in the USA (32,700 deaths annually in 25- to 64-year-old individuals alone) would be prevented. This proportion was >=85 % among men in Arkansas, Alabama, Kentucky, and Mississippi, and >=80 % among women in West Virginia and Kentucky. CONCLUSION: Most premature lung cancer deaths in the USA are potentially avoidable. As most of these deaths can be attributed to smoking, our findings underscore the importance of increasing tobacco control measures in high-risk states and targeting tobacco control interventions to less educated populations in all states. PMID- 25555992 TI - Sex differences in the relationship of IL-6 signaling to cancer cachexia progression. AB - A devastating aspect of cancer cachexia is severe loss of muscle and fat mass. Though cachexia occurs in both sexes, it is not well-defined in the female. The Apc(Min/+) mouse is genetically predisposed to develop intestinal tumors; circulating IL-6 is a critical regulator of cancer cachexia in the male Apc(Min/+) mouse. The purpose of this study was to examine the relationship between IL-6 signaling and cachexia progression in the female Apc(Min/+) mouse. Male and female Apc(Min/+) mice were examined during the initiation and progression of cachexia. Another group of females had IL-6 overexpressed between 12 and 14 weeks or 15-18 weeks of age to determine whether IL-6 could induce cachexia. Cachectic female Apc(Min/+) mice lost body weight, muscle mass, and fat mass; increased muscle IL-6 mRNA expression was associated with these changes, but circulating IL-6 levels were not. Circulating IL-6 levels did not correlate with downstream signaling in muscle in the female. Muscle IL-6r mRNA expression and SOCS3 mRNA expression as well as muscle IL-6r protein and STAT3 phosphorylation increased with severe cachexia in both sexes. Muscle SOCS3 protein increased in cachectic females but decreased in cachectic males. IL-6 overexpression did not affect cachexia progression in female Apc(Min/+) mice. Our results indicate that female Apc(Min/+) mice undergo cachexia progression that is at least initially IL-6-independent. Future studies in the female will need to determine mechanisms underlying regulation of IL-6 response and cachexia induction. PMID- 25555994 TI - Smoking as an independent determinant of Barrett's esophagus and, to a lesser degree, of reflux esophagitis. AB - PURPOSE: To evaluate the role of smoking in Barrett's esophagus (BE) and erosive esophagitis (E) compared to endoscopic controls with no BE or E. Smoking is considered a cause of both BE and E, but results on this topic are quite controversial. METHODS: Patients with BE (339), E (462) and controls (619: 280 with GERD (gastroesophageal reflux disease)-negative and 339 with GERD-positive anamnesis) were recruited in 12 Italian endoscopy units. Data were obtained from structured questionnaires. RESULTS: Among former smokers, a remarkable upward linear trend was found in BE for all smoking-related predictors. In particular, having smoked for more than 32 years increased the risk more than two times (OR 2.44, 95 % CL 1.33-4.45). When the analysis was performed in the subgroup of subjects with GERD-negative anamnesis, the risk of late quitters (<9 years) passed from OR 2.11 (95 % CL 1.19-3.72) to OR 4.42 (95 % CL 1.52-12.8). A noticeably positive dose-response relationship with duration was seen also among current smokers. As regards E, no straightforward evidence of association was detected, but for an increased risk of late quitters (OR 1.84, 95 % CL 1.14-2.98) in former smokers and for early age at starting (OR 3.63, 95 % CL 1.19-11.1) in GERD-negative current smokers. CONCLUSIONS: Smoking seems to be an independent determinant of BE and, to a lesser degree, of E. The elevation in risk is independent from GERD and is already present in light cigarette smokers. Smoking cessation may reduce, but not remove this risk. PMID- 25555995 TI - DAT1 and DRD4 genes involved in key dimensions of adult ADHD. AB - Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 * 10(-4)) and trait anger scores (p = 7.66 * 10(-4)). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48 bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder. PMID- 25555996 TI - The use of non-animal alternatives in the safety evaluations of cosmetics ingredients by the Scientific Committee on Consumer Safety (SCCS). AB - In Europe, the safety evaluation of cosmetics is based on the safety evaluation of each individual ingredient. Article 3 of the Cosmetics Regulation specifies that a cosmetic product made available on the market is to be safe for human health when used normally or under reasonably foreseeable conditions. For substances that cause some concern with respect to human health (e.g., colourants, preservatives, UV-filters), safety is evaluated at the Commission level by a scientific committee, presently called the Scientific Committee on Consumer Safety (SCCS). According to the Cosmetics Regulations, in the EU, the marketing of cosmetics products and their ingredients that have been tested on animals for most of their human health effects, including acute toxicity, is prohibited. Nevertheless, any study dating from before this prohibition took effect is accepted for the safety assessment of cosmetics ingredients. The in vitro methods reported in the dossiers submitted to the SCCS are here evaluated from the published reports issued by the scientific committee of the Directorate General of Health and Consumers (DG SANCO); responsible for the safety of cosmetics ingredients. The number of studies submitted to the SCCS that do not involve animals is still low and in general the safety of cosmetics ingredients is based on in vivo studies performed before the prohibition. PMID- 25555997 TI - Immunological response and markers of cell damage in seropositive horses for Toxoplasma gondii. AB - Toxoplasmosis is an important parasitic disease affecting several species of mammals, but little is known about this disease in horses. This study aimed to investigate the levels of several immunological variables and markers of cell damage in the serum of seropositive horses for Toxoplasma gondii. Sera samples of adult horses from the Santa Catarina State, Brazil used on a previous study were divided into groups according to their antibody levels for T. gondii determined by immunofluorescence assay, i.e. 20 samples from seronegative horses (Group A - control), 20 samples from horses with titers of 1:64 (Group B), 20 samples of horses with titers of 1:256 (Group C), and five samples from horses with titers of 1:1024 (Group D). Positive animals (Groups B, C, and D) had higher levels of immunoglobulins (IgM and IgG), pro-inflammatory cytokines (TNF-alpha, IFN-gamma, IL-1, IL-4, and IL-6) and protein C-reactive protein, as well as lower levels of IL-10 (anti-inflammatory cytokine) when compared to seronegative horses (Group A). The nitric oxide levels were also elevated in seropositive horses. Therefore, we have found humoral and cellular immune responses in seropositive horses, and a correlation between high antibody levels and inflammatory mediators. Markers of cell injury by lipid peroxidation (TBARS) and protein oxidation (AOPP) were elevated in animals seropositives for T. gondii when compared to seronegatives. Therefore, seropositive horses to T. gondii can keep active immune responses against the parasite. As a consequence with chronicity of disease, they show cellular lesions that may lead to tissue damage with the appearance of clinical disease. PMID- 25555998 TI - Fiber estimation and tractography in diffusion MRI: development of simulated brain images and comparison of multi-fiber analysis methods at clinical b-values. AB - Advances in diffusion-weighted magnetic resonance imaging (DW-MRI) have led to many alternative diffusion sampling strategies and analysis methodologies. A common objective among methods is estimation of white matter fiber orientations within each voxel, as doing so permits in-vivo fiber-tracking and the ability to study brain connectivity and networks. Knowledge of how DW-MRI sampling schemes affect fiber estimation accuracy, tractography and the ability to recover complex white-matter pathways, differences between results due to choice of analysis method, and which method(s) perform optimally for specific data sets, all remain important problems, especially as tractography-based studies become common. In this work, we begin to address these concerns by developing sets of simulated diffusion-weighted brain images which we then use to quantitatively evaluate the performance of six DW-MRI analysis methods in terms of estimated fiber orientation accuracy, false-positive (spurious) and false-negative (missing) fiber rates, and fiber-tracking. The analysis methods studied are: 1) a two compartment "ball and stick" model (BSM) (Behrens et al., 2003); 2) a non negativity constrained spherical deconvolution (CSD) approach (Tournier et al., 2007); 3) analytical q-ball imaging (QBI) (Descoteaux et al., 2007); 4) q-ball imaging with Funk-Radon and Cosine Transform (FRACT) (Haldar and Leahy, 2013); 5) q-ball imaging within constant solid angle (CSA) (Aganj et al., 2010); and 6) a generalized Fourier transform approach known as generalized q-sampling imaging (GQI) (Yeh et al., 2010). We investigate these methods using 20, 30, 40, 60, 90 and 120 evenly distributed q-space samples of a single shell, and focus on a signal-to-noise ratio (SNR = 18) and diffusion-weighting (b = 1000 s/mm(2)) common to clinical studies. We found that the BSM and CSD methods consistently yielded the least fiber orientation error and simultaneously greatest detection rate of fibers. Fiber detection rate was found to be the most distinguishing characteristic between the methods, and a significant factor for complete recovery of tractography through complex white-matter pathways. For example, while all methods recovered similar tractography of prominent white matter pathways of limited fiber crossing, CSD (which had the highest fiber detection rate, especially for voxels containing three fibers) recovered the greatest number of fibers and largest fraction of correct tractography for complex three fiber crossing regions. The synthetic data sets, ground-truth, and tools for quantitative evaluation are publically available on the NITRC website as the project "Simulated DW-MRI Brain Data Sets for Quantitative Evaluation of Estimated Fiber Orientations" at http://www.nitrc.org/projects/sim_dwi_brain. PMID- 25555999 TI - Insights into the preferential order of strand exchange in the Cre/loxP recombinase system: impact of the DNA spacer flanking sequence and flexibility. AB - The Cre/loxP system is widely used as a genetic tool to manipulate DNA. Cre recombinase catalyzes site-specific recombination between 34 bp loxP sites. Each loxP site is recognized by two Cre molecules assuming a cleaving (CreC) and non cleaving (CreNC) activity. Despite the symmetry in the sequences of the arms of loxP, available biochemical data show strong evidence that the recombination reaction is asymmetric with a preferred strand exchange order. The asymmetry comes from the spacer separating the two sets of palindromic arms of the loxP sequence. However, it remains to be understood how this preferential order is established. We apply computational structure-based methods and perform a thorough detailed analysis of available structural and biochemical information on the Cre/loxP system in order to investigate such asymmetry in the recombination, and we propose a rationale to explain the determinants favoring the strand exchange order. We show that the structural properties of the DNA flanking sequence of the spacer guide the recombination, and we establish the role of residues R118, R121 and K122 from CreC, which contact the spacer region and by clamping the DNA inhibit the cleavage on the second arm of loxP. Our studies give an atomistic insight on the synapsis state of the recombination process in the Cre/loxP system and highlight the importance of the flexibility and other intrinsic properties of the flanking regions of the DNA spacer to establish a preferential strand exchange order. PMID- 25556000 TI - Small heat shock proteins: Role in cellular functions and pathology. AB - Small heat shock proteins (sHsps) are conserved across species and are important in stress tolerance. Many sHsps exhibit chaperone-like activity in preventing aggregation of target proteins, keeping them in a folding-competent state and refolding them by themselves or in concert with other ATP-dependent chaperones. Mutations in human sHsps result in myopathies, neuropathies and cataract. Their expression is modulated in diseases such as Alzheimer's, Parkinson's and cancer. Their ability to bind Cu2+, and suppress generation of reactive oxygen species (ROS) may have implications in Cu2+-homeostasis and neurodegenerative diseases. Circulating alphaB-crystallin and Hsp27 in the plasma may exhibit immunomodulatory and anti-inflammatory functions. alphaB-crystallin and Hsp20 exhitbit anti-platelet aggregation: these beneficial effects indicate their use as potential therapeutic agents. sHsps have roles in differentiation, proteasomal degradation, autophagy and development. sHsps exhibit a robust anti-apoptotic property, involving several stages of mitochondrial-mediated, extrinsic apoptotic as well as pro-survival pathways. Dynamic N- and C-termini and oligomeric assemblies of alphaB-crystallin and Hsp27 are important factors for their functions. We propose a "dynamic partitioning hypothesis" for the promiscuous interactions and pleotropic functions exhibited by sHsps. Stress tolerance and anti-apoptotic properties of sHsps have both beneficial and deleterious consequences in human health and diseases. Conditional and targeted modulation of their expression and/or activity could be used as strategies in treating several human disorders. The review attempts to provide a critical overview of sHsps and their divergent roles in cellular processes particularly in the context of human health and disease. PMID- 25556001 TI - Detection and differentiation of 22 kDa and 20 kDa Growth Hormone proteoforms in human plasma by LC-MS/MS. AB - Human growth hormone (GH) is suspected to be widely and illegally used in sport to improve athletes' performance. For the detection of GH abuse, blood samples are screened for abnormal ratios between the 22 and 20 kDa GH proteoforms that demonstrate the administration of the synthetic hormone. Current detection methods are based on classical immunoassays as they provide sufficient sensitivity for the detection of GH proteoforms. These antibody based methods, however, suffer from unclear selectivity and potential cross-reactivity towards similar proteins. For unambiguous GH detection, we report a Mass Spectrometry ImmunoAssay (MSIA) that first enriches GH from plasma with an antibody of relatively low specificity, and subsequently quantifies the 22 and 20 kDa proteoforms by Selected Reaction Monitoring (SRM) LC-MS/MS analysis. This method proved superior to an antibody-free strategy based on GH purification by protein precipitation. Using GH-MSIA we successfully quantified the 22/20 kDa GH ratio in post-exercise capillary plasma extracted from two individuals. This GH-MSIA is applicable to anti-doping and GH-related disease analysis. PMID- 25556002 TI - Mass spectrometry-based proteomic quest for diabetes biomarkers. AB - Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia, which affects hundreds of millions of individuals worldwide. Early diagnosis and complication prevention of DM are helpful for disease treatment. However, currently available DM diagnostic markers fail to achieve the goals. Identification of new diabetic biomarkers assisted by mass spectrometry (MS) based proteomics may offer solution for the clinical challenges. Here, we review the current status of biomarker discovery in DM, and describe the pressure cycling technology (PCT)-Sequential Window Acquisition of all Theoretical fragment-ion (SWATH) workflow for sample-processing, biomarker discovery and validation, which may accelerate the current quest for DM biomarkers. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25556003 TI - Can the effects of noninvasive brain stimulation alleviating neuropsychiatric symptoms result from a common beneficial regulation of the hypothalamic-pituitary adrenal axis? PMID- 25556004 TI - TMS brain mapping in less than two minutes. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) corticospinal excitability maps are a valuable tool to study plasticity in the corticospinal tract. Traditionally, data acquisition for a single map is time consuming, limiting the method's applicability when excitability changes quickly, such as during motor learning, and in clinical investigations where assessment time is a limiting factor. OBJECTIVE: To reduce the time needed to create a reliable map by 1) investigating the minimum interstimulus interval (ISI) at which stimuli may be delivered, and 2) investigating the minimum number of stimuli required to create a map. METHOD: Frameless stereotaxy was used to monitor coil position as the coil was moved pseudorandomly within a 6 * 6 cm square. Maps were acquired using 1-4 s ISIs in 12 participants. The minimum number of stimuli was determined by randomly extracting data and comparing the resulting map to the original data set. To confirm validity, the pseudorandom walk method was compared against a traditional mapping method. RESULTS: Reliable maps could be created with 63 stimuli recorded with a 1 s ISI. Maps created acquiring data using the pseudorandom walk method were not significantly different from maps acquired following the traditional method. CONCLUSIONS: To account for inter-participant variability, outliers, coil positioning errors and, most importantly, participant comfort during data acquisition, we recommend creating a map with 80 stimuli and a 1.5 s ISI. This makes it possible to acquire TMS maps in 2 min, making mapping a more feasible tool to study short- and long-term changes in cortical organization. PMID- 25556005 TI - Enhancement of nitrate removal at the sediment-water interface by carbon addition plus vertical mixing. AB - Wetlands and ponds are frequently used to remove nitrate from effluents or runoffs. However, the efficiency of this approach is limited. Based on the assumption that introducing vertical mixing to water column plus carbon addition would benefit the diffusion across the sediment-water interface, we conducted simulation experiments to identify a method for enhancing nitrate removal. The results suggested that the sediment-water interface has a great potential for nitrate removal, and the potential can be activated after several days of acclimation. Adding additional carbon plus mixing significantly increases the nitrate removal capacity, and the removal of total nitrogen (TN) and nitrate nitrogen (NO3(-)-N) is well fitted to a first-order reaction model. Adding Hydrilla verticillata debris as a carbon source increased nitrate removal, whereas adding Eichhornia crassipe decreased it. Adding ethanol plus mixing greatly improved the removal performance, with the removal rate of NO3(-)-N and TN reaching 15.0-16.5 g m(-2) d(-1). The feasibility of this enhancement method was further confirmed with a wetland microcosm, and the NO3(-)-N removal rate maintained at 10.0-12.0 g m(-2) d(-1) at a hydraulic loading rate of 0.5 m d(-1). PMID- 25556006 TI - Degradation and dissipation of the veterinary ionophore lasalocid in manure and soil. AB - Lasalocid is a veterinary ionophore antibiotic used for prevention and treatment of coccidiosis in poultry. It is excreted from the treated animals mostly in its active form and enters the environment with the use of contaminated manure on agricultural land. To properly assess the risk that lasalocid poses to the environment, it is necessary to know its environmental concentrations as well as the rates of its degradation in manure and dissipation in soil. These values are still largely unknown. A research was undertaken to ascertain the rate of lasalocid degradation in manure under different storage conditions (aging in a pile or composting) and on agricultural soil after using lasalocid-contaminated manure. The results have shown that there is considerable difference in lasalocid degradation between aging manure with no treatment (t1/2=61.8+/-1.7 d) and composting (t1/2=17.5+/-0.8 d). Half-lives in soil are much shorter (on average 3.1+/-0.4 d). On the basis of the measured concentrations of lasalocid in soil after manure application, we can conclude that it can potentially be harmful to soil organisms (PEC/PNEC ratio of 1.18), but only in a worst-case scenario of using the maximum permissible amount of manure and immediately after application. To make certain that no harmful effects occur, composting is recommended. PMID- 25556007 TI - Effect of trace metals and electron shuttle on simultaneous reduction of reactive black-5 azo dye and hexavalent chromium in liquid medium by Pseudomonas sp. AB - This study demonstrates the role of electron shuttles and trace metals in the biotransformation of azo dye reactive black-5 and hexavalent chromium (CrVI) that are released simultaneously in tannery effluent. Previously isolated bacterial strain Pseudomonas putida KI was used for the simultaneous reduction of the dye (100 mg L(-1)) and CrVI (2 mg L(-1)) in a mineral salts medium (MSM). Among various trace metals, only Cu(II) had a stimulating effect on the bacterial mediated reduction process. Application of electron shuttles such as hydroquinone and uric acid at a low concentration (1mM) had a positive effect on the reduction process and caused simultaneous reduction of 100% dye and 97% CrVI in 12-18 h. Mannitol, EDTA and sodium benzoate at all concentrations (ranging from 1 to 9 mM) showed an inhibitory effect on the reduction of reactive black-5 and CrVI. An inverse linear relationship between the velocity of reaction (V) and the concentration [S] of electron shuttles was observed. The results imply that both types and concentration of an electron shuttle and trace metals can affect the simultaneous reduction of reactive black-5 and CrVI. PMID- 25556008 TI - Influence of nitrate and sulfate reduction in the bioelectrochemically assisted dechlorination of cis-DCE. AB - This paper investigated the reductive dechlorination (RD) of cis-dichloroethylene (cis-DCE) (average influent 14.2+/-0.7 MUM) by a bioelectrochemical system (BES), in the presence of real contaminated groundwater containing high levels of nitrate and sulfate. The BES enhanced both the RD and competing reactions, such as nitrate and sulfate reductions, which occurred with neither an external organic carbon source nor any inoculum other than the indigenous microbial consortia in the real groundwater. In preliminary batch tests, RD and full nitrate removal occurred after a short lag phase, whereas sulfate reduction occurred slowly and alongside the RD. Under continuous flow conditions (hydraulic retention time, HRT, 1.4 d), the competition of different electron acceptors was strongly affected by the cathodic potential in the range -550 to -750 mV vs. standard hydrogen electrode (SHE). Nitrate reduction was driven to completion at all tested cathodic potentials, whereas sulfate reduction and the RD rate increased as the cathodic potential became more negative. At -750 mV vs. SHE, strong methanogenesis was also observed and became the most important sink of electrons. The overall coulombic efficiency decreased while the potential became more negative. The RD contribution was always less than 1%. Hence, greater energy consumption was required to obtain higher RD rate and better conversion. Anodic oxidation was only observed at -750 mV vs. SHE where almost 39% of residual vinyl chloride (VC) was oxidized and the sulfate was formed back from sulfide (further contributing to electric waste). PMID- 25556009 TI - Identification, expression pattern and functional characterization of As-MyD88 in bacteria challenge and during different developmental stages of Artemia sinica. AB - Myeloid differentiation factor 88 (MYD88), a key adapter protein in Toll-like receptor signaling, affects the immune response and the formation of the dorsal ventral axis. Here, the 1555bp full-length cDNA of MyD88 from Artemia sinica (As MyD88) was obtained. Molecular characterization revealed that the sequence includes an 1182bp open reading frame encoding a predicted protein of 393 amino acids. The predicted protein contains a death domain in the N-terminus, and box1 and 2 motifs of the TIR domain in the C-terminus. Real-time quantitative PCR, Western blotting and immunohistochemistry were used to determine the expression level, protein production and location of As-MYD88 during embryonic development and bacterial challenge. The highest expression level during embryonic development was at the 0h and 5h stages of A. sinica. As-MYD88 was remarkably upregulated after bacterial challenge. Our results suggested that As-MYD88 plays a vital role in response to bacterial challenge, and during post-diapause embryonic development of A. sinica. PMID- 25556010 TI - Electromyography in the four competitive swimming strokes: a systematic review. AB - The aim of this paper is to give an overview on 50 years of research in electromyography in the four competitive swimming strokes (crawl, breaststroke, butterfly, and backstroke). A systematic search of the existing literature was conducted using the combined keywords "swimming" and "EMG" on studies published before August 2013, in the electronic databases PubMed, ISI Web of Knowledge, SPORT discus, Academic Search Elite, Embase, CINAHL and Cochrane Library. The quality of each publication was assessed by two independent reviewers using a custom made checklist. Frequency of topics, muscles studied, swimming activities, populations, types of equipment and data treatment were determined from all selected papers and, when possible, results were compared and contrasted. In the first 20 years of EMG studies in swimming, most papers were published as congress proceedings. The methodological quality was low. Crawl stroke was most often studied. There was no standardized manner of defining swimming phases, normalizing the data or of presenting the results. Furthermore, the variability around the mean muscle activation patterns is large which makes it difficult to define a single pattern applicable to all swimmers in any activity examined. PMID- 25556011 TI - Constitutive modeling of an electrospun tubular scaffold used for vascular tissue engineering. AB - In this study, we sought to model the mechanical behavior of an electrospun tubular scaffold previously reported for vascular tissue engineering with hyperelastic constitutive equations. Specifically, the scaffolds were made by wrapping electrospun polycaprolactone membranes that contain aligned fibers around a mandrel in such a way that they have microstructure similar to the native arterial media. The biaxial stress-stretch data of the scaffolds made of moderately or highly aligned fibers with three different off-axis fiber angles alpha (30 degrees , 45 degrees , and 60 degrees ) were fit by a phenomenological Fung model and a series of structurally motivated models considering fiber directions and fiber angle distributions. In particular, two forms of fiber strain energy in the structurally motivated model for a linear and a nonlinear fiber stress-strain relation, respectively, were tested. An isotropic neo-Hookean strain energy function was also added to the structurally motivated models to examine its contribution. The two forms of fiber strain energy did not result in significantly different goodness of fit for most groups of the scaffolds. The absence of the neo-Hookean term in the structurally motivated model led to obvious nonlinear stress-stretch fits at a greater axial stretch, especially when fitting data from the scaffolds with a small alpha. Of the models considered, the Fung model had the overall best fitting results; its applications are limited because of its phenomenological nature. Although a structurally motivated model using the nonlinear fiber stress-strain relation with the neo-Hookean term provided fits comparably as good as the Fung model, the values of its model parameters exhibited large within-group variations. Prescribing the dispersion of fiber orientation in the structurally motivated model, however, reduced the variations without compromising the fits and was thus considered to be the best structurally motivated model for the scaffolds. It appeared that the structurally motivated models could be further improved for fitting the mechanical behavior of the electrospun scaffold; fiber interactions are suggested to be considered in future models. PMID- 25556012 TI - Racial disparities in failure-to-rescue among children undergoing congenital heart surgery. AB - OBJECTIVE: To determine if racial/ethnic disparities exist among children undergoing congenital heart surgery, using failure-to-rescue (FTR) as a measure of hospital-based quality. STUDY DESIGN: This is a retrospective, repeated cross sectional analysis using admissions from the 2003, 2006, and 2009 Kids' Inpatient Database. All pediatric admissions (<= 18 years) with a Risk Adjustment for Congenital Heart Surgery procedure were included. Logistic regression models examining complications, FTR, and overall mortality were constructed. RESULTS: Hispanic ethnicity (OR 1.13, 95% CI 1.01-1.26) was associated with increased odds of experiencing a complication when compared with white race. However, black race (OR 1.66, 95% CI 1.33-2.07) and other race/ethnicity (OR 1.40, 95% CI 1.10-1.79) were risk factors for FTR. Although Hispanic ethnicity was associated with increased odds of experiencing a complication, it was not associated with FTR. In hospital fixed-effects models, black race and other race/ethnicity remained as "within hospital" risk factors for FTR. CONCLUSIONS: Black children and children of other race/ethnicity had higher rates of mortality after experiencing a complication. This suggests that racial disparities may exist in hospital-based cardiac care or response to care. PMID- 25556015 TI - Overuse and underutilization in youth sports: time to seek equipoise. PMID- 25556014 TI - Brainstem and spinal cord lesions associated with skin changes and hearing loss: think of biotinidase deficiency. PMID- 25556013 TI - Markers of cardiovascular risk, insulin resistance, and ventricular dysfunction and remodeling in obese adolescents. AB - OBJECTIVES: To test our hypothesis that obese adolescents have left ventricular (LV) dysfunction and remodeling that are associated with markers of cardiovascular risk and insulin resistance (IR). STUDY DESIGN: In a cross sectional study of 44 obese and 14 lean age-, sex-, Tanner stage-, and race matched adolescents, IR, markers of cardiovascular risks, conventional and 2 dimensional speckle tracking echocardiography measures of LV function and structure were evaluated and compared. RESULTS: The obese adolescents had significantly increased body mass index Z-score, systolic blood pressure, fasting insulin, IR, and atherogenic lipids compared with the lean adolescents. A subgroup of obese adolescents had LV remodeling characterized by significantly increased LV mass index (g/m(2.7)) and relative wall thickness. Almost all obese adolescents had LV dysfunction with peak LV global longitudinal strain (GLS, %), systolic GLS rate (GLSR, %/s), and early diastolic GLSR significantly lower than in lean adolescents and in the normal pediatric population. Body mass index Z score predicted LV remodeling (LV mass index [R(2) = 0.34] and relative wall thickness [R(2) 0.10]), and peak LV GLS (R(2) 0.15), and along with systolic blood pressure, predicted systolic GLSR (R(2) 0.16); (P <= .01 for all). Fasting insulin predicted early diastolic GLSR (R(2) 0.17, P <= .01). CONCLUSIONS: Obese adolescents have subclinical ventricular dysfunction associated with the severity of obesity, increased systolic blood pressure, and IR. Ventricular remodeling is present in a subgroup of obese adolescents in association with the severity of obesity. These findings suggest that obesity may have an early impact on the cardiovascular health of obese adolescents. PMID- 25556016 TI - Gestational age at birth affects maturation of baroreflex control. AB - OBJECTIVES: To assess the effect of prone sleeping, the major risk factor for sudden infant death syndrome, in the control of blood pressure (BP) in preterm infants born across a range of gestational ages. STUDY DESIGN: Daytime polysomnography was performed at 2-4 weeks, 2-3 months, and 5-6 months postterm age. The participants were 21 very preterm (mean gestation 29.4 +/- 0.3 weeks), 14 preterm (mean gestation 33.1 +/- 0.3 weeks), and 17 term (mean gestation 40.1 +/- 0.3 weeks). BP was measured via a Finometer cuff (Finapres Medical Systems, Amsterdam, The Netherlands) placed around the wrist. Data were recorded both supine and prone. Baroreflex sensitivity (BRS) was calculated via cross-spectral analysis of spontaneous fluctuations in BP. RESULTS: BRS was lower in the prone position in very preterm infants at 2-4 weeks in active sleep (P < .05). Maturation of BRS was delayed in very preterm compared with both preterm and term infants. CONCLUSIONS: Maturation of BRS after term-equivalent age is altered in very preterm infants. Reduced BRS may result in an impaired ability of very preterm infants to respond to cardiovascular stress during infancy and may predispose them to cardiovascular disease later in life. PMID- 25556017 TI - No effect of proton pump inhibitors on crying and irritability in infants: systematic review of randomized controlled trials. AB - Proton pump inhibitors are increasingly being used to treat infants with crying and/or irritability based on the assumption that these symptoms are attributable to gastroesophageal reflux. However, the data from a systematic review of randomized controlled trials do not support the use of proton pump inhibitors to decrease infant crying and irritability. PMID- 25556018 TI - Detection of intra-abdominal testicles with 16beta-[(18)F]-fluoro-5alpha dihydrotestosterone positron emission tomography/computed tomography in a pubertal boy. PMID- 25556019 TI - Bronchopulmonary dysplasia: another step along the path. PMID- 25556021 TI - Breastfeeding is associated with reduced childhood hospitalization: evidence from a Scottish Birth Cohort (1997-2009). AB - OBJECTIVE: To evaluate the risk of childhood hospitalization associated with infant feeding patterns at 6-8 weeks of age in Scotland. STUDY DESIGN: A retrospective population level study based on the linkage of birth, death, maternity, infant health, child health surveillance, and admission records for children born as single births in Scotland between 1997 and 2009 (n = 502 948) followed up to March 2012. Descriptive analyses, Kaplan Meier tests, and Cox regression were used to quantify the association between the mode of infant feeding and risk of childhood hospitalization for respiratory, gastrointestinal, and urinary tract infections, and other common childhood ailments during the study period. RESULTS: Within the first 6 months of life, there was a greater hazard ratio (HR) of hospitalization for common childhood illnesses among formula fed infants (HR 1.40; 95% CI 1.35-1.45) and mixed-fed infants (HR 1.18; 95% CI 1.11-1.25) compared with infants exclusively breastfed after adjustment for parental, maternal, and infant health characteristics. Within the first year of life and beyond, a greater relative risk of hospitalization was observed among formula-fed infants for a range of individual illnesses reported in childhood including gastrointestinal, respiratory, and urinary tract infections, otitis media, fever, asthma, diabetes, and dental caries. CONCLUSIONS: Using linked administrative data, we found greater risks of hospitalization in early childhood for a range of common childhood illnesses among Scottish infants who were not exclusively breastfed at 6-8 weeks of age. PMID- 25556020 TI - Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden. AB - OBJECTIVE: To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. STUDY DESIGN: We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. RESULTS: Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). CONCLUSIONS: Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial. PMID- 25556025 TI - India cuts health budget by 20%. PMID- 25556024 TI - Photoselective Vaporesection of the Prostate with a Front-firing Lithium Triborate Laser: Surgical Technique and Experience After 215 Procedures. AB - BACKGROUD: Although photoselective vaporization of the prostate (PVP) is considered one of the most promising alternatives to transurethral radical prostatectomy, a longer operative time, an unsatisfactory tissue removal rate, and the absence of postoperative pathology samples remain the main criticisms for this procedure. OBJECTIVE: To describe the novel technique of photoselective vaporesection of the prostate (PVRP) with a front-firing lithium triborate (LBO) laser and to report our initial experience. DESIGN, SETTING, AND PARTICIPANTS: This is a prospective study of 215 patients undergoing PVRP between November 2011 and March 2013. Their average age, prostate size, and International Prostate Symptom Score (IPSS) were 70.3 +/- 7.3 yr, 70.4 +/- 34.0 ml, and 24.9 +/- 5.0, respectively. SURGICAL PROCEDURE: The operative technique is detailed in the accompanying video. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative data were collected. The patients were followed up at 3, 6, 12 mo after PVRP, and functional outcomes and complications were assessed. RESULTS AND LIMITATIONS: The mean operation time was 44.1 +/- 22.6 min. The mean hemoglobin decrease was 0.37 +/- 0.21 g/dl. The catheterization time was 23.9 +/- 15.2 h and the postoperative hospital stay was 1.8 +/- 0.8 d. Significant improvements were observed in maximum flow, IPSS, and postvoid residual urine at each follow-up time point. Compared to preoperative values, prostate volume and serum prostate-specific antigen fell by 67% and 63%, respectively, at 3 mo after PVRP. No major complications were noted. Application of a hemostat for a front-firing LBO laser makes it easy to handle intractable intraoperative bleeding. The main limitation of this study is the short follow-up period. The influence of PVRP on sexual function and the learning curve remain to be evaluated. CONCLUSIONS: PVRP is a novel technique that is effective and safe for treatment of benign prostatic hyperplasia. This technique retains the excellent hemostatic property of LBO lasers and has a short operation time and a high tissue removal rate. The problem of the lack of postoperative tissue samples for PVP is also overcome in PVRP. PATIENT SUMMARY: We have developed a novel technique named photoselective vaporesection of the prostate (PVRP) with a front-firing green laser. Our results show that PVRP retains the excellent hemostatic property of a green laser, but has a much shorter operation time and a higher rate of tissue removal than photoselective vaporization of the prostate (PVP). This technique also solves the problem of the lack of postoperative tissue specimens and the difficulty of handling intractable intraoperative bleeding. According to our initial results, PVRP is a novel technique superior to PVP in the treatment of benign prostatic hyperplasia. PMID- 25556022 TI - Severe obesity and comorbid condition impact on the weight-related quality of life of the adolescent patient. AB - OBJECTIVES: To assess links between comorbid health status, severe excess weight, and weight-related quality of life (WRQOL) in adolescents with severe obesity and undergoing weight-loss surgery (WLS) to inform clinical care. STUDY DESIGN: Baseline (preoperative) data from Teen Longitudinal Assessment of Bariatric Surgery, a prospective multicenter observational study of 242 adolescents with severe obesity (MedianBMI = 50.5 kg/m(2); Meanage = 17.1; 75.6% female; 71.9% white) undergoing WLS, were used to examine the impact of demographics, body mass index (BMI), presence/absence of 16 comorbid conditions, and a cumulative comorbidity load (CLoad) index on WRQOL scores (Impact of Weight on Quality of Life-Kids). RESULTS: WRQOL was significantly lower than reference samples of healthy weight, overweight, and obese samples. Of 16 comorbid conditions, the most prevalent were dyslipidemia (74.4%), chronic pain (58.3%), and obstructive sleep apnea (56.6%). Male subjects had a greater CLoad (P = .01) and BMI (P = .01), yet less impairment in total WRQOL (P < .01) than females. CLoad was a significant predictor of male WRQOL. For females, psychosocial (vs physical) comorbidities, BMI, and white race were significant predictors of WRQOL impairment. Less prevalent conditions (eg, stress urinary incontinence) also emerged as contributors to lower WRQOL. CONCLUSIONS: WRQOL impairment is substantial for adolescents with severe obesity undergoing WLS, with predictors varying by sex. These patient-data highlight targets for education, support, and adjunctive care referrals before WLS. Furthermore, they provide a comprehensive empirical base for understanding heterogeneity in adolescent WRQOL outcomes after WLS, as weight and comorbidity profiles change over time. PMID- 25556023 TI - miR-183 in prostate cancer cells positively regulates synthesis and serum levels of prostate-specific antigen. AB - BACKGROUND: Factors affecting serum prostate-specific antigen (PSA) levels in men are clinically important, but apart from effects mediated through the androgen receptor, they are poorly understood. OBJECTIVE: To investigate whether microRNA (miRNA) affects the synthesis and serum levels of PSA. DESIGN, SETTING, AND PARTICIPANTS: Reporter assays with PSA and KLK2 3' untranslated regions (UTRs) to confirm posttranscriptional regulation was followed by high-throughput screening of the effect of 1129 miRNAs on PSA levels using reverse phase protein arrays (RPPAs) to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by Western blot, immunofluorometrics, activity assays, quantitative reverse transcriptase polymerase chain reaction, reporter assays, and growth assays. Prostate levels of miR-183 were compared with PSA transcript and serum PSA levels in prostate cancer cohorts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RankProd was used to evaluate the RPPAs, and the Student t test was used for the in vitro experiments. The Spearman and Cuzick tests were used in the patient material, and overall survival was analysed by Kaplan-Meier and log-rank analysis. RESULTS AND LIMITATIONS: Gain-of-function screenings identified 32 miRNAs that increase PSA levels. One of these, miR-183, was found to bind the 3' UTR of PSA directly and increase both protein and messenger RNA levels. Prostatic levels of miR-183 and serum PSA showed correlation in a cohort of 74 men. In addition, miR-183 promotes cellular growth in vitro and correlates to clinical parameters such as World Health Organisation grade and clinical progression. CONCLUSIONS: The synthesis and serum levels of PSA are directly affected by miR-183 and may be a factor to consider when PSA values are evaluated in clinical settings. PATIENT SUMMARY: These findings offer novel insights into the regulation of prostate-specific antigen and may eventually affect clinical decision making in prostate cancer. PMID- 25556026 TI - Positive effect of reduced aeration rate on growth and stereospecificity of DL malic acid consumption by Azospirillum brasilense: improving the shelf life of a liquid inoculant formulation. AB - Azospirillum brasilense has significance as a growth promoter in plants of commercial interest. Two industrial native strains (Start and Calf), used as a part of an inoculant formulation in Mexico during the last 15 years, were incubated in laboratory-scale pneumatic bioreactors at different aeration rates. In both strains, the positive effect of decreased aeration was observed. At the lowest (0.1 vvm, air volume/liquid volume*minute), the highest biomass were obtained for Calf (7.8 * 10(10)CFU/ml), and Start (2.9 * 10(9)CFU/ml). These were higher in one magnitude order compared to cultures carried out at 0.5 vvm, and two compared to those at 1.0 vvm. At lower aeration, both stereoisomeric forms of malic acid were consumed, but at higher aeration, just L-malate was consumed. A reduction in aeration allows an increase of the shelf life and the microorganism saved higher concentrations of polyhydroxybutyrate. The selected fermentation conditions are closely related to those prevalent in large-scale bioreactors and offer the possibility of achieving high biomass titles with high shelf life at a reduced costs, due to the complete use of a carbon source at low aeration of a low cost raw material as DL-malic acid mixture in comparison with the L-malic acid stereoisomer. PMID- 25556027 TI - Complete genome sequence of Bacillus thuringiensis serovar galleriae strain HD 29, a typical strain of commercial biopesticide. AB - Bacillus thuringiensis serovar galleriae is highly toxic to Lepidoptera insect pests, and has been widely used as Bt biopesticide in many countries. Here we reported the complete genome of strain HD-29, a standard serotype strain in galleriae serovariety. More than previous work reported, it harbors ten plasmids, and three large ones carry eight insecticidal protein genes (cry1Aa, cry1Ac, cry1Ca, cry1Da, cry1Ia, cry2Ab, cry9Ea and vip3Aa) and an intact zwittermicin A biosynthetic gene cluster. PMID- 25556029 TI - Pan-body computed tomographic scanning for patients with intracranial hemorrhage after low-energy falls. AB - BACKGROUND: We sought to determine if a liberal policy of pan-body computerized tomography (CT) scanning was useful in patients with intracranial hemorrhage after low falls. METHODS: Patients with intracranial hemorrhage after low falls, with a Glasgow Coma Score of greater than or equal to 14 and systolic blood pressure of greater than 100 mm Hg, were included. The primary outcome was any torso or spine injury requiring surgical or radiologic intervention. The secondary outcome was any torso or spine injury. RESULTS: Of 365 patients, 71% underwent pan-body CT. Eight (2%) patients had a primary outcome and 66 (18%) a secondary outcome. Only signs and symptoms of cervical injury were associated with a cervical-related outcome (4/23 vs 3/316, P = .005). Only signs and symptoms of torso injury were associated with a torso-related outcome. CONCLUSIONS: A liberal policy of pan-body CT in these patients is of low yield. Signs and symptoms of trauma should dictate the judicious use of CT. PMID- 25556028 TI - Is intraoperative parathyroid hormone testing in patients with renal insufficiency undergoing parathyroidectomy for primary hyperparathyroidism accurate? AB - BACKGROUND: Our aim was to determine whether chronic renal insufficiency (CRI) impacted intraoperative parathyroid hormone (ioPTH) monitoring during parathyroidectomy. We hypothesized that ioPTH monitoring in patients with CRI would show slower decline, but would still accurately predict cure. METHODS: A retrospective review was conducted of patients with primary hyperparathyroidism who underwent curative single adenoma parathyroidectomy. The percentage of patients reaching 50% decline of ioPTH was compared between groups stratified by renal function. RESULTS: Between 2000 and 2013, 950 patients met inclusion criteria. At 5 minutes, 66% of patients with CRI met curative criteria versus 77% of normal renal function patients (P = .001). At 10 minutes, 89% vs 92% met criteria (P = .073), and by 15 minutes, the gap narrowed to 95% vs 97% (P = .142), respectively. CONCLUSIONS: Despite CRI patients with primary hyperparathyroidism having slower ioPTH decline after curative parathyroidectomy, 95% met ioPTH criteria by 15 minutes. Standard ioPTH criteria can be used with CRI patients. PMID- 25556031 TI - Bioavailability of cadmium, copper, mercury, lead, and zinc in subtropical coastal lagoons from the southeast Gulf of California using mangrove oysters (Crassostrea corteziensis and Crassostrea palmula). AB - Cadmium (Cd), copper (Cu), mercury (Hg), lead (Pb), and zinc (Zn) were assessed in the edible tissues of Crassrotrea corteziensis oysters collected during the rainy and dry seasons in 27 sites from 8 coastal lagoons of the southeast Gulf of California. In addition, C. palmula oysters were sampled at 9 sites from the same mangrove roots where C. corteziensis oysters were collected. Metal analyses were performed by flame atomic absorption spectrophotometry (Cd, Cu, and Zn), graphite furnace (Pb), and cold vapor detection (Hg). The obtained mean levels were (ug g( 1) dry weight) as follows: Cd 6.05 +/- 2.77, Cu 60.0 +/- 33.4, Hg 0.38 +/- 0.17, Pb 1.11 +/- 0.63, and Zn 777 +/- 528 ug g(-1). For all metals except Hg, the concentrations were greater during dry season than during rainy seasons. The high levels, particularly that for Cd, were related to upwelling along the eastern Gulf of California. High Hg levels in the rainy season were associated with the transport of materials from the watershed to the lagoon. Shrimp farming, agriculture, and other sources were considered as potential sources to explain the differences in metal bioavailability in the 8 lagoons. The mean concentrations of Cd (Santa Maria-La Reforma lagoon), Cu [San Ignacio-Navachiste El Macapule (SINM), Urias (URI), and Altata-Ensenada del Pabellon lagoons], and zinc (Zn) (URI, Santa Maria-Ohuira-Topolobampo, El Colorado, and SINM lagoons) during the dry season were greater than the maximum permissible limits. C. palmula collected in 8 sites where they were present simultaneously with C. corteziensis had consistently greater metal levels than C. corteziensis, but correlation analyses showed a high and significant (P < 0.05) correlation between metal concentrations in both species. The correlation equations obtained are useful where the same species is not distributed and is necessary to compare results from distinct regions. PMID- 25556030 TI - Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study. AB - PURPOSE: Bevacizumab or temsirolimus regimens have clinical activity in the first line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. METHODS: In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS. RESULTS: Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5 23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. CONCLUSIONS: Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population. PMID- 25556037 TI - The management of chronic breathlessness in patients with advanced and terminal illness. PMID- 25556038 TI - MRI scanning in patients with new and existing CapSureFix Novus 5076 pacemaker leads: randomized trial results. AB - BACKGROUND: Magnetic resonance imaging (MRI) can be safely performed in patients with magnetic resonance (MR)-conditional pacemaker systems but remains relatively contraindicated with non-MR-conditional pacemaker systems. OBJECTIVE: The purpose of this study was to evaluate the safety of MRI without positioning restrictions in patients with an MR-conditional pacemaker and currently a non-MR-conditional Medtronic CapSureFix Novus 5076 lead(s). METHODS: The study randomized 266 patients in a 2:1 ratio to the MRI group (177 patients) or to the control group (89 patients). At 9-12 weeks postimplant, the MRI group underwent MRI at 1.5 T. Primary end points were MRI-related complication-free rate and noninferiority of the MRI group compared to the control group with regard to the proportion of patients with an increase of <=0.5 V in right atrial (RA) and right ventricular (RV) pacing capture thresholds from immediately before MRI to 1-month after MRI. RESULTS: No MRI-related complications occurred in 156 MRI-scanned patients who were followed through 1-month post-MRI. Differences in the proportion of patients with <=0.5 V pacing capture threshold changes from pre-MRI to 1-month post-MRI were minimal between the groups for RA (proportions of 100% in both groups; a P value cannot be calculated) and RV leads (proportions of 99.3% in the MRI group and 100% in the control group; noninferiority test, P < .0001). Proportions of patients with acceptable sensing amplitude changes from pre-MRI to 1-month post MRI were also similar between the 2 groups for RA and RV leads (noninferiority test, P < .0001 and P = .0004, respectively). No arrhythmias occurred during MRI. CONCLUSION: MRI scans can be performed safely without positioning restrictions in patients with Medtronic CapSureFix Novus 5076 leads connected to an MR conditional pacemaker. PMID- 25556039 TI - Sexual dimorphism of canine volume: a pilot study. AB - Sex assessment is a crucial part of the biological profile in forensic and archaeological context, but it can be hardly performed in cases of commingled and charred human remains where DNA tests often are not applicable. With time literature have analyzed the sexual dimorphism of teeth (and especially canines), but very few articles take into consideration the teeth volume, although with time several technologies have been introduced in order to assess 3D volume (CT scan, laser scanner, etc.). This study aims at assessing the sexual dimorphism of dental and pulp chamber volumes of a sample of canines. Cone beam computed tomography analyses were performed by 87 patients (41 males and 46 females, aged between 15 and 83 years) for clinical purposes, and were acquired in order to measure canine volumes. Results show that the dental volume amounted to 0.745 cm(3) (SD 0.126 cm(3)) in males, 0.551 cm(3) (SD 0.130 cm(3)) with a statistically significant difference (p<0.01). A diagnostic threshold of 0.619 cm(3) was stated, which provides a percentage of correct answer of 80.5% in the chosen sample. The novel method was then applied with success to 7 archaeological: where in all the cases the results were concordant with those provided by the assessment of the cranium and pelvis. The study adds a contribution to the wide analysis of dental sexual dimorphism confirming the statistically significant differences of volume between males and females and providing a method for the diagnosis of sex applicable to forensic cases. PMID- 25556040 TI - Intended and non-intended kinematic effects of atlanto-axial rotational high velocity, low-amplitude techniques. AB - INTRODUCTION: The study of neck kinematics during high-velocity, low-amplitude manipulations of the atlanto-axial segment is essential to understanding cervical motion mechanisms and their impact and possible risk for soft-tissue injuries during treatment of spine disorders. METHODS: Twenty fresh-frozen specimens were tested during manual application of an axial rotation technique. FINDINGS: The kinematics indicate the thrust induced motion components of approximately 1 degrees at the treated segment around all three axes of the local embedded reference frame. Moreover, an equal amount of axial rotation motion took place at the adjacent atlanto-occipital joint. INTERPRETATION: Overall atlanto-axial motion remained below the level of slow regional mobilization of the cervical spine. These findings can be correlated to literature data concerning the limited increase in vertebral artery strain during high-velocity, low-amplitude manipulation. PMID- 25556041 TI - Geographic variations in hospital charges and Medicare payments for major joint arthroplasty. AB - National data on hospital-level charges and Medicare payments have shown that joint arthroplasty is the most common surgical procedure among the elderly. Yet, no study has investigated micro and macro level geographic variations in hospital charges and payment. We used the Medicare Provider Charge Data to investigate Medicare payments and charges for 2750 hospitals accounting for 427,207 patients who underwent major joint arthroplasty and 932 hospitals for 18,714 patients who had a complication/comorbidity. We found a significant difference in hospital charges and payments based on geographic region (P<0.001). We concluded that hospital charges demonstrate a high variability even when using areas to control for differences in hospital wages and high variation in reimbursements in some areas remains unexplained by Medicare's current method of calculating reimbursement. PMID- 25556042 TI - The Northern Norway Mother-and-Child Contaminant Cohort (MISA) Study: PCA analyses of environmental contaminants in maternal sera and dietary intake in early pregnancy. AB - BACKGROUND: Although predictors of contaminants in serum or whole blood are usually examined by chemical groups (e.g., POPs, toxic and/or essential elements; dietary sources), principal component analysis (PCA) permits consideration of both individual substances and combined variables. OBJECTIVES: Our study had two primary objectives: (i) Characterize the sources and predictors of a suite of eight PCBs, four organochlorine (OC) pesticides, five essential and five toxic elements in serum and/or whole blood of pregnant women recruited as part of the Mother-and-Child Contaminant Cohort Study conducted in Northern Norway (The MISA study); and (ii) determine the influence of personal and social characteristics on both dietary and contaminant factors. METHODS: Recruitment and sampling started in May 2007 and continued for the next 31 months until December 2009. Blood/serum samples were collected during the 2nd trimester (mean: 18.2 weeks, range 9.0-36.0). A validated questionnaire was administered to obtain personal information. The samples were analysed by established laboratories employing verified methods and reference standards. PCA involved Varimax rotation, and significant predictors (p<=0.05) in linear regression models were included in the multivariable linear regression analysis. RESULTS: When considering all the contaminants, three prominent PCA axes stood out with prominent loadings of: all POPs; arsenic, selenium and mercury; and cadmium and lead. Respectively, in the multivariate models the following were predictors: maternal age, parity and consumption of freshwater fish and land-based wild animals; marine fish; cigarette smoking, dietary PCA axes reflecting consumption of grains and cereals, and food items involving hunting. PCA of only the POPs separated them into two axes that, in terms of recently published findings, could be understood to reflect longitudinal trends and their relative contributions to summed POPs. CONCLUSIONS: The linear combinations of variables generated by PCA identified prominent dietary sources of OC groups and of prominent toxic elements and highlighted the importance of maternal characteristics. PMID- 25556043 TI - Comparison of vanA gene mRNA levels between vancomycin-resistant Enterococci presenting the VanA or VanB phenotype with identical Tn1546-like elements. AB - BACKGROUND/PURPOSE: During the routine screening of vancomycin-resistant Enterococci faecium (VREfm) we found that VanA phenotype-vanA genotype and VanB phenotype-vanA genotype isolates had an identical Tn1546-like element structure. This study aimed to evaluate the genetic background and vanA gene expression to identify the mechanisms of the development of the VanB phenotype-vanA genotype VREfm. METHODS: Twelve VREfm isolates were collected from a 1500-bed tertiary care teaching hospital in Beijing. Genetic variations of the Tn1546-like element were determined by an overlapping polymerase chain reaction assay and sequencing. The genetic background was determined by pulsed-field gel electrophoresis and mutilocus sequence typing. vanA gene expression was evaluated using a TaqMan quantitative real-time polymerase chain reaction. RESULTS: For the 12 isolates, six isolates with the VanA phenotype-vanA genotype and six with the VanB phenotype-vanA genotype were identified. According to the structure analysis of the Tn1546-like elements, our isolates were divided into two types. In the four isolates of type A, IS1542 and IS1216V were inserted into the orf2-vanR and vanX vanY regions, respectively. In the eight isolates of type D, a similar insertion as type A occurred, except for an ISEfa4 insertion into IS1542. A significant difference in vanA gene expression was observed between the VanA and VanB phenotype isolates in type A, but not in type D. Mutilocus sequence typing and pulsed-field gel electrophoresis analysis showed that these isolates have a different genetic background. CONCLUSION: Our results indicated that the occurrence of the VanB phenotype-vanA genotype might not completely depend on the structure of Tn1546-like elements and vanA gene expression. PMID- 25556044 TI - Associated factors and clinical implications of serum aminotransferase elevation in scrub typhus. AB - BACKGROUND/PURPOSE: Timely diagnosis and prompt treatment can reduce the complications of scrub typhus. It is thus important to find easy laboratory tests to help in the diagnosis, especially in patients without eschar at initial presentation. Because serum aminotransferase elevation is common in scrub typhus, its associated factors and clinical implications need further investigations. METHODS: We conducted a retrospective study in Kinmen, Taiwan, to collect clinically suspected scrub typhus patients notified to Taiwan Centers for Disease Control for confirmation during 2005-2010. Scrub typhus was diagnosed and Orientia tsutsugamushi was genotyped by serological or molecular assays. The laboratory data and clinical information were recorded for analysis. RESULTS: Overall, 344 suspected scrub typhus patients were reported to Taiwan Centers for Disease Control and 288 of them were certified scrub typhus. Scrub typhus patients had significantly more thrombocytopenia, serum aminotransferase elevation (76% vs. 54%, p = 0.001), higher frequency of fever, eschar, and lymphadenopathy, compared with nontyphus patients. Hepatic dysfunction in scrub typhus was associated with older age, longer fever duration, and absence of lymphadenopathy, but seemed to be unrelated to the rickettsial genotypes. Multivariate analysis showed that serum aminotransferase elevation (odds ratio: 3.75; p = 0.003; 95% confidence interval: 1.56-9.01) independently predicted scrub typhus. Furthermore, in suspected scrub typhus patients without eschar, 92% of true typhus patients had serum aminotransferase elevation compared with the nontyphus ones (odds ratio: 6.47; p = 0.028, 95% confidence interval: 1.23 34.11). CONCLUSION: Hepatic dysfunction in scrub typhus patients is associated with older age, longer fever duration, and absence of lymphadenopathy. Serum aminotransferase elevation can aid in the diagnosis of scrub typhus, especially in suspected patients without eschar. PMID- 25556045 TI - Intravenous immunoglobulin, pharmacogenomics, and Kawasaki disease. AB - Kawasaki disease (KD) is a systemic vasculitis of unknown etiology and it is therefore worth examining the multifactorial interaction of genes and environmental factors. Targeted genetic association and genome-wide association studies have helped to provide a better understanding of KD from infection to the immune-related response. Findings in the past decade have contributed to a major breakthrough in the genetics of KD, with the identification of several genomic regions linked to the pathogenesis of KD, including ITPKC, CD40, BLK, and FCGR2A. This review focuses on the factors associated with the genetic polymorphisms of KD and the pharmacogenomics of the response to treatment in patients with intravenous immunoglobulin resistance. PMID- 25556046 TI - Impact of IL-22 gene polymorphism on human immunodeficiency virus infection in Han Chinese patients. AB - BACKGROUND/PURPOSE: To analyze the polymorphism of the IL-22 gene in Han Chinese patients and to evaluate the influence of IL-22 polymorphism on human immunodeficiency virus (HIV) infection. METHODS: IL-22 gene polymorphism was analyzed in 73 blood samples from healthy participants. The influence of the genotype and allele distribution of three single nucleotide polymorphisms (rs2227484, rs2227485, and rs2227513) of IL-22 on HIV infection was evaluated in 619 HIV seropositive patients and 619 healthy controls. To determine the association between the rs2227513 genotype and IL-22 levels in plasma, we randomly selected 29 HIV seropositive blood samples and 15 healthy blood samples and measured the levels of IL-22. RESULTS: Nine single nucleotide polymorphism loci of the IL-22 gene were found (rs2227484, rs2227485, rs2227491, rs2227508, rs2227513, rs1179249, rs1179250, rs1179251, and rs1182844). Stratified analysis (by sex) showed a higher association of HIV infection and the A/G genotype and G allele at rs2227513 in women, but not in men (A/G genotype odds ratio = 5.24, 95% confidence interval = 1.13-24.27; allele G odds ratio = 5.27, 95% confidence interval 1.15-24.23). The rs2227513 A/G genotype was also associated with significantly higher levels of plasma IL-22, regardless of whether the patient was HIV seropositive or seronegative. CONCLUSION: Our results suggest that IL-22 production in blood might act as a pathogenic factor in HIV infection. PMID- 25556047 TI - Severe macrolide-resistant Mycoplasma pneumoniae pneumonia associated with macrolide failure. AB - We investigated differences in outcomes between 68 children hospitalized with macrolide-sensitive Mycoplasma pneumoniae pneumonia (MSMP group) and 25 children hospitalized with macrolide-resistant M. pneumoniae pneumonia (MRMP group). In the MRMP group, 19 children received macrolides and clinical failure occurred in six of which five had pneumonia progression during therapy. PMID- 25556048 TI - Effect of 2013 National Healthcare Safety Network definition changes on central line bloodstream infection rates: audit results from the New York State Department of Health. AB - Surveillance criteria for central line-associated bloodstream infections (CLABSIs) are continually being refined to more accurately reflect infections related to central lines. An audit of 567 medical records from adult, pediatric, and neonatal intensive care unit patients with a central line and a positive blood culture showed a 16% decrease in CLABSI rates after the 2013 National Healthcare Safety Network definitions compared with the 2012 definitions. PMID- 25556049 TI - A randomized, double-blind comparison of the effectiveness of environmental cleaning between infection control professionals and environmental service workers. AB - The hospital environment is a reservoir for pathogens, and environmental service workers (ESWs) play an important role in infection prevention. A randomized, double-blind comparison was carried out in a 23-bed intensive care unit of a traditional Chinese medical-Western medical hospital. Aerobic colony counts (ACC) and methicillin-resistant Staphylococcus aureus (MRSA) were used to compare the effectiveness of environmental cleaning between infection control professionals and ESWs. The results suggest that high-touch surfaces around MRSA patients are often not sufficiently cleaned and are even cross-contaminated by ESWs after cleaning. Further educational intervention is needed for improvement of environmental cleaning. PMID- 25556050 TI - [Repeating the PlateliaTM Aspergillus test in samples positive for serum galactomannan: Is it necessary?]. AB - BACKGROUND: The manufacturers of the PlateliaTM Aspergillus test recommend retesting every sample with a positive result to galactomannan detection. AIMS: To evaluate the repeated results of the PlateliaTM Aspergillus test on initially positive samples, and their association with clinical and microbiological studies. METHODS: A total of 150 positive sera belonging to 92 patients were studied. More than one positive sample was obtained from 31 (33.6%) patients. Nine patients were diagnosed with probable invasive aspergillosis and two with proven Fusarium oxysporum and Scedosporium prolificans invasive fungal infection, respectively. RESULTS: Only 35 out of 150 (23.3%) sera remained positive upon test repetition. The average OD-index difference between the initially positive and subsequently negative samples was 0.76. Sera from 3 patients out of 9 diagnosed with probable invasive aspergillosis yielded negative results after repetition. CONCLUSIONS: Our study shows poor reproducibility of the positive samples for the PlateliaTM Aspergillus test. These results reinforce the need to evaluate a second sample and to consider simultaneously repeating the first positive serum to enhance the diagnosis of invasive fungal infection. PMID- 25556051 TI - Molecular characterization and antifungal susceptibility of Cryptococcus neoformans strains collected from a single institution in Lima, Peru. AB - BACKGROUND: Cryptococcosis is a fungal infection with a worldwide distribution, mainly caused by Cryptococcus neoformans and Cryptococcus gattii. AIMS: To molecularly characterize the mating-types, serotypes, genotypes and antifungal susceptibility profiles of a set of retrospectively isolated C. neoformans strains from Lima, Peru. METHODS: A set of 32 Cryptococcus spp. strains from the Institute of Tropical Medicine of the National University of San Marcos, Lima, Peru, were included in this retrospective study. Twenty-four strains were isolated from patients, while the remaining 8 were isolated from the environment. RESULTS: Using conventional PCR, 27 (84.4%) of the isolates were identified as C. neoformans var. grubii mating-type alpha and serotype A. Using the AFLP fingerprinting, it was shown that 16 (50%) of the C. neoformans strains were genotype AFLP1, 13 (40.6%) were genotype AFLP1B, 2 (6.3%) were genotype AFLP2, and 1 (3.1%) was found to be a hybrid between both C. neoformans varieties (genotype AFLP3). The antifungal susceptibility profiles for amphotericin B, fluconazole and voriconazole showed that all the 32 C. neoformans are sensitive to these antifungal compounds. CONCLUSIONS: In this study we observed that C. neoformans var. grubii (AFLP1 and AFLP1B) and C. neoformans var. neoformans (AFLP2) were the only cryptococcal varieties involved. All strains were found to be sensitive to the antifungals tested, results that are consistent with those found in the international literature. PMID- 25556052 TI - Investigation into the dosage form attributes of currently UK licensed cardiovascular and Parkinson's disease drug products. AB - Globally, there is a continuous rise in the older population (over 65 years), particularly in developed countries. As many diseases are age-related, older adults represent a highly heterogeneous cohort. This presents a major challenge for both the pharmaceutical industry and healthcare professionals. The purpose of this research was to attract attention towards the appropriateness of geriatric formulations by investigating the dosage form attributes of currently UK licensed cardiovascular and Parkinson's disease drug products. Medication available in the UK for cardiovascular disorders and Parkinson's disease were screened and the available formulations, packaging and patient information leaflets of these medicines were analysed, with the goal of raising awareness of the need to cater for elderly patients with increasing difficulty in managing their medication. It emerged that although cardiovascular disorders and Parkinson's disease are more prevalent in older people, many treatment options have not been optimised for this cohort. In particular, older patient centred dosage forms, specific dosing requirements, excipients, patient-friendly packaging and easy-to-follow patient information were highlighted as areas to be considered in order to optimise health outcomes in the ageing population. PMID- 25556053 TI - Silk fibroin/gelatin electrospun nanofibrous dressing functionalized with astragaloside IV induces healing and anti-scar effects on burn wound. AB - Functional wound dressing has provided new challenges for researchers who focus on burn to improve skin graft quality, reduce scarring, and develop a pluristratified dermal or epidermal construct of a burn wound. This study aimed to investigate the effect of a silk fibroin/gelatin (SF/GT) electrospun nanofibrous dressing loaded with astragaloside IV (AS) on deep partial-thickness burn wound. AS-loaded SF/GT-blended nanofibrous dressing was prepared by electrospinning nanotechnology. The optimal ratio (25:75) of silk fibroin to gelatin was further optimized by evaluating ATR-FTIR characteristics, mechanical properties, porosity, swelling rate, degradation, and release profile of the AS loaded SF/GT nanofibrous dressing. In contrast to the blank control, the AS loaded SF/GT nanofibrous dressing promoted cell adhesion and proliferation with good biocompatibility in vitro (p<0.01). This dressing also accelerated wound healing and inhibited scar formation in vivo by stimulating wound closure (p<0.05), increasing angiogenesis, regulating newly formed types of collagen, and improving collagen organization. These results showed that SF/GT nanofibrous dressing is a promising topical drug delivery system. Furthermore, AS functionalized SF/GT nanofibrous dressing is an excellent topical therapeutic that could be applied to promote healing and elicit anti-scar effects on partial thickness burn wound. PMID- 25556054 TI - Design of chitospheres loaded with pristine polymer particles for extended drug delivery via polyelectrolyte complexation and particulate leaching. AB - The aim of this study was to investigate the drug release from swellable chitospheres laden with pristine polymethylmethacrylate (PMMA) nanoparticles. Chitosan matrices were prepared by sodium tripolyphosphate crosslinking from a chitosan suspension containing the model BCS class II drug, indomethacin. PMMA particles were added to the chitospheres as the modulator for drug release. Swelling and erosion studies in conjunction with textural profiling provided an understanding of the dominant and underlying drug release mechanisms of the ionically crosslinked chitospheres loaded with the pristine PMMA particles. A series of drug release studies performed in PBS pH 7.4 showed that the pristine particle-loaded chitospheres released indomethacin over 144 h in a first-order manner with 50% drug release occurring over 48 h. The study also revealed that in situ porogen leaching for pore creation and polyelectrolyte complex formation were the main mechanisms of release from the chitospheres. The results of this study may be utilized for the development of neuro-implants for controlled delivery of bioactives to the brain where scaffolds of superior mechanical strength and reduced swelling properties are required. PMID- 25556055 TI - Inhibition of the spontaneous polymorphic transition of pyrazinamide gamma form at room temperature by co-spray drying with 1,3-dimethylurea. AB - The present study focuses on the ability of excipients to induce the crystallization of a specific polymorphic form of pyrazinamide (PZA) and more interestingly, to block the irreversible solid-solid transition of the metastable forms of the PZA to the stable form at room temperature. We outline an experimental protocol for the production of a structurally pure gamma form of PZA by means of spray drying. Without any particular treatment, phase transition to delta form was detected after 14 days of storage under ambient conditions. In order to prevent this irreversible phase transition, different excipients were co spray dried with PZA. By co-spray drying 5% in mass of 1,3-dimethylurea (DMU) with PZA, we noticed its ability in preventing phase transitions and thus to maintain PZA under its gamma form up to 12 months of storage at room temperature. Raman spectroscopy evidenced how DMU crystals surround particles of gamma PZA which suggest that DMU might interact with the surface of PZA particles, thus blocking the phase transition. On the other hand, the co-spray drying of PZA with the polymerpolyvinylpyrrolidone (PVP) resulted in the crystallization of delta form of PZA. The physical mixture was intact over 12 months of storage at room temperature. PMID- 25556056 TI - Effects of topical corticosteroids on cell proliferation, cell cycle progression and apoptosis: in vitro comparison on HaCaT. AB - Topical-corticosteroids are mainly used for the treatment of inflammatory or hyperproliferative skin diseases. The in vivo assay to rank topical corticosteroids potency, based on the skin blanching, is not adapted to compare their anti-proliferative efficacy. We have compared the antiproliferative effect of six topical-corticosteroids on a model of hyperproliferant keratinocytes (HaCaT). Betamethasone-dipropionate; clobetasol-propionate; betamethasone valerate; desonide; hydrocortisone-butyrate and hydrocortisone-base, at different concentrations (10(-8)-10(-4)M) have been compared. HaCaT proliferation has been evaluated by MTT-assay and the mechanism of the death was evaluated by annexin V/propidium iodide staining and cell cycle phases analysis. Topical corticosteroids reduced cell growth in a dose-dependent manner. At 10(-4)M, betamethasone dipropionate was the most antiproliferative compound while hydrocortisone-butyrate was the less. Hydrocortisone-base which is usually considered as the less potent topical-corticosteroids showed a clear cytotoxic effect. Betamethasone-dipropionate and betamethasone-valerate induced more apoptosis than necrosis whereas the reverse has been observed for other topical corticosteroids. All topical-corticosteroids, except clobetasol-propionate, arrested cell cycle mainly in G2-phase. Clobetasol-propionate arrested cell cycle in S-phase population. At 10(-8)M, topical-corticosteroids induced HaCaT proliferation. In terms of antiproliferative effect at 10(-4)M, we propose to rank topical corticosteroids as follow: betamethasone dipropionate>desonide>=betamethasone-valerate=hydrocortisone-base=clobetasol propionate>hydrocortisone-butyrate. This classification differs from the current ranking, based on the vasoconstrictive effect, but is more adapted for hyperproliferative disease treatment. PMID- 25556057 TI - [Posttraumatic aneurysm of the distal radial artery leading to digital ischemia]. AB - Distal radial artery aneurysms are rare. We relate a case of non-iatrogenic distal radial artery aneurysm in the anatomical snuffbox leading to digital ischemia in a 43-year-old man. PMID- 25556058 TI - The natural tumorcide Manumycin-A targets protein phosphatase 1alpha and reduces hydrogen peroxide to induce lymphoma apoptosis. AB - Numerous compounds for treating human disease have been discovered in nature. Manumycin-A (Man-A) is a natural, well-tolerated microbial metabolite and a potent experimental tumoricide. We recently showed that Man-A stimulated reactive oxygen species (ROS) which were upstream of serine/threonine (Ser/Thr) dephosphorylation and caspase-dependent cleavage of MEK and Akt in lymphoma apoptosis. Conversely, activation-specific, Ser/Thr phosphorylation of MEK and Akt proteins was stable in Man-A-resistant tumors suggesting that stimulation of Ser/Thr PPase activity might be required for Man-A tumoricidal activity. Pre treatment with Calyculin-A, an equipotent inhibitor of PP1 and PP2A, blocked all downstream effects of Man-A whereas, the PP2A-selective inhibitor, Okadaic acid did not, suggesting that PP1 and not PP2A played a role in Man-A action. Phosphorylation of PP1alpha on Thr320 inhibits its activity. Hence, we posited that if PP1alpha was important for Man-A action, then Man-A treatment should promote dephosphorylation of PP1alpha on Thr320. Indeed, T320 was only dephosphorylated in the tumors that underwent apoptosis. Lastly, stable over expression of a constitutively active PP1alpha mimetic (PP1alphaT320A mutant), elevated basal ROS levels and enhanced Man-A-stimulated apoptosis. Taken together, we conclude that PP1alpha is an important proximal effector of Man-A mediated lymphoma apoptosis and that the mechanisms of Man-A action warrant further investigation. PMID- 25556059 TI - Anticancer and multidrug-resistance reversing potential of traditional medicinal plants and their bioactive compounds in leukemia cell lines. AB - Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds. PMID- 25556060 TI - Methanolic extract of Momordica cymbalaria enhances glucose uptake in L6 myotubes in vitro by up-regulating PPAR-gamma and GLUT-4. AB - The present study was undertaken to evaluate the influence of the methanolic fruit extract of Momordica cymbalaria (MFMC) on PPARgamma (Peroxisome Proliferator Activated Receptor gamma) and GLUT-4 (Glucose transporter-4) with respect to glucose transport. Various concentrations of MFMC ranging from 62.5 to 500 MUg.mL(-1) were evaluated for glucose uptake activity in vitro using L6 myotubes, rosiglitazone was used as a reference standard. The MFMC showed significant and dose-dependent increase in glucose uptake at the tested concentrations, further, the glucose uptake activity of MFMC (500 MUg.mL(-1)) was comparable with rosigilitazone. Furthermore, MFMC has shown up-regulation of GLUT 4 and PPARgamma gene expressions in L6 myotubes. In addition, the MFMC when incubated along with cycloheximide (CHX), which is a protein synthesis inhibitor, has shown complete blockade of glucose uptake. This indicates that new protein synthesis is required for increased GLUT-4 translocation. In conclusion, these findings suggest that MFMC is enhancing the glucose uptake significantly and dose dependently through the enhanced expression of PPARgamma and GLUT-4 in vitro. PMID- 25556061 TI - Chemical composition, antimicrobial, insecticidal, phytotoxic and antioxidant activities of Mediterranean Pinus brutia and Pinus pinea resin essential oils. AB - Essential oils of the resins of Pinus brutia and Pinus pinea were evaluated for their biological potential. Essential oils were characterized using GC-MS and GC/FID. in vitro antimicrobial, phytotoxic, antioxidant, and insecticidal activities were carried out using the direct contact and the fumigant assays, respectively. The chemical profile of the essential oils of the resins of P. pinea and P. brutia included mainly alpha-pinene (21.39% and 25.40%), beta-pinene (9.68% and 9.69%), and caryophyllene (9.12% and 4.81%). The essential oils of P. pinea and P. brutia exerted notable antimicrobial activities on Micrococcus luteus and Bacillus subtilis, insecticidal activities on Ephestia kuehniella eggs, phytotoxic activities on Lactuca sativa, Lepidium sativum, and Portulaca oleracea, as well as antioxidant potential. Indications of the biological activities of the essential oils suggest their use in the formulation of ecofriendly and biocompatible pharmaceuticals. PMID- 25556062 TI - Modified Si-Miao-San inhibits inflammation and promotes glucose disposal in adipocytes through regulation of AMP-kinase. AB - Modified Si-Miao-San (mSMS) is composed of Rhizoma Coptidis, Cortex Phellodendri, Rhizoma Coptidis Semen Coicis and Atractylodes Rhizome. The prescription is used for the management of diabetes and insulin resistance in the clinic. This study aims to investigate its regulation of glucose disposal in adipocytes. Differentiated 3T3-L1 adipocytes were stimulated with conditioned medium derived from activated macrophages to induce insulin resistance and observed the effects of Mac-CM on insulin-mediated glucose uptake along the insulin receptor substrate 1/PI3K/Akt signaling pathway. Moreover, its regulation of AMPK phosphorylation was also investigated. mSMS enhanced AMPK phosphorylation and promoted basal glucose uptake in adipocytes; mSMS inhibited NF-kappaB activation by reducing P65 phosphorylation and improved insulin-stimulated IRS-1 tyrosine and Akt phosphorylation, leading to the restoration of insulin-mediated glucose uptake when cells were exposed to inflammatory stimulation. These beneficial effects were diminished in the presence of the AMPK inhibitor compound C. mSMS positively regulated AMPK activity, and this action contributed to improving insulin PI3K signaling by the beneficial regulation of IRS-1 function through inhibition of inflammation in adipocytes. PMID- 25556063 TI - Qifu-Yin attenuates AGEs-induced Alzheimer-like pathophysiological changes through the RAGE/NF-kappaB pathway. AB - Qifu-Yin (QFY), a widely used formula of traditional Chinese medicine (TCM) derived from "Jingyue Quanshu", is one of the most commonly used TCM prescriptions for the clinical treatment of Alzheimer disease. The role of advanced glycation end products (AGEs) and its receptor RAGE have attracted increasing attention as the pivotal role of Abeta has been questioned. The present study was designed to test the neuroprotective effects of QFY, and the possible mechanism in AGE-induced Alzheimer model rats. After injection of AGE in the CA3 area of the hippocampus, QFY (8.6, 4.3, and 2.15 g.kg(-1)), and a positive control drug donepezil (2 mg.kg(-1)) were administrated through gastric intubation to rats once daily for thirty consecutive days. Another positive control group was the AGE + anti-RAGE group, which was simultaneously injected with anti-RAGE antibody before AGE treatment. The control group, sham-operated group, as well as the AGE + anti-RAGE group received saline at the same dosage. The Morris water maze test and the step-down passive avoidance test were conducted to evaluate the cognitive function of the rats. The expression of RAGE and NF-kappaB were assayed by immunohistochemical staining. The levels of Abeta, TNF-alpha, and IL-1beta in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that QFY could significantly attenuate the memory impairment induced by AGE, decrease the expressions of RAGE and NF-kappaB, and reduce the levels of Abeta, TNF-alpha, and IL-1beta in the hippocampus in a dose-dependent manner. Also, the blockage of RAGE could significantly reduce the impairments caused by AGEs. In conclusion, QFY could attenuate AGEs-induced, Alzheimer-like pathophysiological changes. These neuroprotective effects might be related to the RAGE/NF-kappaB pathway and its anti-inflammatory activity. PMID- 25556064 TI - Synthesis and cytotoxic activity of 3, 4, 11-trihydroxyl modified derivatives of bergenin. AB - To synthesize a series of 3-, 4-, and/or 11-trihydroxy modified bergenin derivatives and evaluated their cytotoxic activity in vitro. The phenolic hydroxyl groups of bergenin were protected by benzyl groups with benzyl bromide. Treatment of dibenzyl bergenin with the corresponding acid in the presence of EDC.HCl and DMAP in CH2Cl2, followed by hydrogenation over Pd/C catalysts, afforded derivatives of bergenin esters. All of the target compounds were identified by IR, MS, and (1)H NMR. Twenty-six novel and three known derivatives of bergenin esters were synthesized. Their cytotoxicity values were evaluated by the MTT assay on the inhibition of DU-145 and BGC-823 cells in vitro. Several triply-substituted (3a, 4a, 5a, 6a, 7a) and doubly-substituted (8b, 9b) bergenin derivatives exhibited higher cytotoxic activity than bergenin. The result showed that the size of substituents and the lipophilicity of the bergenin esters displayed an important role on their cytotoxic activity. PMID- 25556065 TI - Synthesis, characterization, and anti-cancer activity of emodin-Mn(II) metal complex. AB - To synthesize and characterize a novel metal complex of Mn (II) with emodin, and evaluate its anti-cancer activity. The elemental analyses, IR, UV-vis, atomic absorption spectroscopy, TG-DSC, (1)H NMR, and (13)C NMR data were used to characterize the structure of the complex. The cytotoxicity of the complex against the human cancer cell lines HepG2, HeLa, MCF-7, B16, and MDA-MB-231 was tested by the MTT assay and flow cytometry. Emodin was coordinated with Mn(II) through the 9-C=O and 1-OH, and the general formula of the complex was Mn(II) (emodin)2.2H2O. In studies of the cytotoxicity, the complex exhibited significant activity, and the IC50 values of the complex against five cancer cell lines improved approximately three-fold compared with those of emodin. The complex could induce cell morphological changes, decrease the percentage of viability, and induce G0/G1 phase arrest and apoptosis in cancer cells. The coordination of emodin with Mn(II) can improve its anticancer activity, and the complex Mn(II) (emodin)2.2H2O could be studied further as a promising anticancer drug. PMID- 25556066 TI - A LC-ESI-MS method for the simultaneous determination of madecassoside and its metabolite madecassic acid in rat plasma: comparison pharmacokinetics in normal and collagen-induced arthritic rats. AB - To develop a simple and highly sensitive high performance liquid chromatography with electrospray ionization mass spectrometric (LC-ESI-MS) method for the simultaneous determination of madecassoside and its major metabolite madecassic acid in rat plasma, and compare the pharmacokinetics of the two compounds in normal and collagen-induced arthritis (CIA) rats. Glycyrrhetinic acid was used as the internal standard (IS). Chromatographic separation was accomplished on an Inertsil ODS-3 column, using a gradient elution with the mobile phase composed of acetonitrile and water acidified with 0.1% (V/V) formic acid. Detection was achieved by ESI-MS under the negative selected ion monitoring (SIM) mode. In normal and CIA rats, madecassoside (30 mg.kg(-1)) was orally administered for 21 consecutive days from the day of arthritis onset. For madecassoside, the linear range was 10-1 000 ng.mL(-1) with the square regression coefficient (r) of 0.998 9, while for madecassic acid, the linear range was 10-500 ng.mL(-1) with the square regression coefficient (r) of 0.996 1. The lower limit of quantification was 10 ng.mL(-1) for both analytes. The intra- and inter-day precision ranged from 1.78% to 13.42% for madecassoside and 2.30% to 14.90% for madecassic acid, and the accuracy was between -0.95% and 6.30% for madecassoside and between 1.48% and 5.34% for madecassic acid. The average recoveries of madecassoside, madecassic acid and IS from spiked plasma samples were > 81%. The developed method was successfully applied to the pharmacokinetic study of madecassoside and madecassic acid in rats after an oral administration of madecassoside. During initial 7 days of dosing, the cmax and AUC of madecassoside were greatly decreased and Vd/F was markedly increased in CIA rats, and no significant difference was observed on the first day of dosing. In contrast, the T1/2, cmax and AUC of madecassic acid were significantly increased, and Ke of madecassic acid was greatly decreased in CIA rats compared with normal rats. Along with repeated administration of madecassoside, the differences of pharmacokinetic parameters of both madecassoside and madecassic acid between CIA and normal rats gradually subsided. The pharmacokinetic characteristics of both madecassoside and madecassic acid in rats were significantly altered by arthritis status, and the differences of pharmacokinetic parameters between arthritis and normal rats coincide with the severity of arthritis. PMID- 25556067 TI - Development and validation of a HPLC-UV-ESI-MS method for the simultaneous quantitation of ten bioactive compounds in Dahuang Fuzi Tang. AB - AIM: To develop a high performance liquid chromatography (HPLC) coupled with electrospray ionization mass spectrometry (ESI-MS) and ultraviolet (UV) detector method for the acid-alkaline simultaneous determination of ten bioactive compounds, and analyze the effect of compatible medicinal plants on the concentration of components in Dahuang Fuzi Tang (DFT). METHOD: The chromatographic separation was performed on a Hypersil BDS C18 analytical column by gradient elution with acetonitrile and formate buffer (containing 0.15% formic acid, V/V) at 25 degrees C with a flow rate of 1.0 mL.min(-1) and UV detection at 280 nm. Four of the ten compounds in DFT were identified and their MS fragments were elucidated by HPLC-ESI-MS, and the contents of the six compounds were determined by HPLC-UV. RESULTS: All calibration curves showed good linear regression (r(2) >= 0.9990). The limits of detection and limits of quantification were 0.021-0.155 -g.mL(-1) and 0.076-0.520 -g.mL(-1), respectively. Overall precision RSD (intra-day and inter-day) were less than 2.96%, and the average recoveries were 98.35%-101.45%, with RSD ranging from 1.54% to 3.01% for the analytes. CONCLUSION: The developed method can be applied for the quality control and provide analytical evidence on the chemical basis and combinational principles of DFT. PMID- 25556068 TI - Total glucosides of paeony inhibit the inflammatory responses of mice with allergic contact dermatitis by restoring the balanced secretion of pro-/anti inflammatory cytokines. AB - The present study aimed to investigate the regulation exerted by the total glucosides of paeony (TGP) on the production of interleukin-2 (IL-2), IL-4, IL-10 and IL-17 in the serum and lymphocytes of mice with allergic contact dermatitis (ACD). ACD in mice was induced by the repeated application of 2,4 dinitrochlorobenzene (DNCB) to their skins. The mice were orally administered TGP (35, 70, and 140mg/kg/d) and prednisone (Pre, 5mg/kg/d) from day 1 to day 7 after immunization. The inflammatory responses were evaluated by ear swelling and histological examination. Thymocyte proliferation was assayed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide assay. The cytokine production in the serum and lymphocytes supernatant was measured by enzyme-linked immunosorbent assay. The results indicated that the topical application of DNCB to the skin provoked obvious inflammatory responses. The oral administration of TGP (70 and 140mg/kg/d) and Pre (5mg/kg/d) significantly inhibited skin inflammation, decreased the thymus and spleen indices, and inhibited thymocyte proliferation in mice treated with DNCB. Further study indicated that TGP increased IL-4 and IL-10 production but decreased the production of IL-2 and IL 17 in the serum and lymphocyte supernatant. The correlation analysis suggested significantly positive correlations between IL-2 and IL-17 production and the severity of skin inflammation, whereas negative correlations were obtained for IL 4 and IL-10 production and skin inflammation. In summary, these results suggest that the therapeutic effects of TGP on ACD may result from its regulation of the imbalanced secretion of IL-2/IL-4 and IL-10/IL-17. PMID- 25556069 TI - Study on the Mechanical Properties of Three-Dimensional Directly Binding Hydroxyapatite Powder. AB - In the three-dimensional directly fabricating hydroxyapatite composite artificial bone scaffold process, the liquid bio-binder is sprayed on the surface of bioceramics powder layer. The spraying volume and the powder size directly influence the mechanical properties of the bone scaffold and the future biodegradation performance. When the size of powder is stable, the amount of binder spraying will directly affect the mechanical strength of bone scaffold. In order to figure out the solidification mechanism of alpha-n-butyl cyanoacrylate (NBCA) bio-binder on the hydroxyapatite (HA) powder layer, the molecular dynamics simulation method is applied to investigate the binding energy shifts between NBCA on HA crystallographic planes. The mechanical properties can be deduced from this methodology; furthermore, the Knoop identification experiments are used to investigate the effective elastic modules of pure HA system and HA/NBCA composite model. Both the simulation and the experiments results elucidate that HA (110) has the highest binding energy with NBCA as the high planar atom density and the mechanical properties of HA/NBCA mixed system are stronger than the pure HA system on three-dimensional crystallographic; in this sense, the bone scaffolds with different strengths could be fabricated by controlling various NBCA binders liquid doses on the surface of HA powder layers during the 3D printing process. PMID- 25556070 TI - Comparison Between Sporadic and Misdiagnosed Sporadic Creutzfeldt-Jakob Disease: A Report of Two Cases. AB - Definite accurate diagnosis for Creutzfeldt-Jakob disease (CJD) depends on neuropathologic examination of brain biopsy or autopsy. However, transmissible nature makes the invasive examination dangerous. This study was set to determine that the clinical features are for the diagnosis of CJD through a comparison study. We compared clinical features of two cases with initial diagnosis of sporadic CJD. One case was finally diagnosed as definite sporadic CJD. According to World Health Organization diagnosis criteria, the other one, which had been diagnosed as probable sporadic CJD, was confirmed as limbic encephalitis after long-term follow-up. Compared with the case of definite sporadic CJD, the misdiagnosed case did not present typical electroencephalogram (EEG) and diffusion-weighted in magnetic resonance images (DWI) of CJD. However, cerebrospinal fluid in the misdiagnosed patient showed 14-3-3 protein positivity. The patient conditions improved after treatment. Through this case comparison, we conclude that EEG and DWI are necessary for accurate diagnosis of sporadic CJD. Further, long-term follow-up is crucial to diagnosis and treatment of CJD. PMID- 25556071 TI - Effect of Cyclophosphamide on Expression of MMP-9 and TGF-beta1 in Renal Tissue of Rats with Diabetes Mellitus. AB - Diabetic nephropathy (DN) is a severe microvascular complication that occurs in diabetes patients. In this study, we investigated the effect of cyclophosphamide (CTX) on expression of matrix metalloproteinases (MMP-9) and transforming growth factor-beta1 (TGF-beta1) in renal tissue of rats with DN. We found CTX significantly reduces KI and blood glucose levels, microalbuminuria, and blood urea nitrogen. It also decreases the expression of TGF-beta1 and increases the expression of MMP-9. Our data suggest CTX may reduce the excretion of urine proteins, alleviate kidney hypertrophy, and reduce blood glucose level through regulation of TGF-beta1 and MMP-9 gene expression. PMID- 25556072 TI - Dormant Cells: The Original Cause of Tumor Recurrence and Metastasis. AB - Tumor dormancy is one of the stages in tumor development without clinical symptoms. Tumor dormant cells may appear in early stages of tumor development, as well as in micrometastasis and minimal residual disease. The mechanism for the switch of dormant cells between quiescent and proliferative stages is still largely unknown. Potential mechanisms that may account for the transition between dormant tumor cells and proliferative cells include angiogenesis, immune response, cellular factors, and signaling pathways. The clinical and therapeutic importance of dormant cells requires further studies to provide therapeutic strategies for inhibition of metastasis and tumor recurrence. PMID- 25556073 TI - Sushi Domain-Containing Protein 3: A Potential Target for Breast Cancer. AB - Aromatase inhibitors (AIs) are the most effective endocrine treatment for estrogen receptor alpha-positive (ERalpha+) postmenopausal breast cancer. Identification of biomarkers that are able to predict AIs responsiveness of patients is a key for successful treatment. The currently used biomarkers for tamoxifen responsiveness, which including ERalpha as well as progesterone receptor can only predict part of the potential responders to AIs treatment. Sushi domain-containing protein 3 (SUSD3) is a potential novel biomarker of AIs responsiveness. The lack of SUSD3 expression in breast cancer tissue can be an important predictor for non-responsiveness to AI. Here we reviewed the property and function of SUSD3, its usage as a biomarker and the practicability for SUSD3 to become a target for immune therapy. We suggest this protein can be potentially measured or targeted for prevention, diagnostic, and therapeutic purposes for estrogen or progesterone-dependent disorders including breast cancer in women. PMID- 25556074 TI - Six new examples of the bipartite trapezoid bone: morphology, significant population variation, and an examination of pre-existing criteria to identify bipartition of individual carpal bones. AB - Carpal bone bipartition is a developmental variant resulting in the division of a normally singular carpal into two distinct segments. Cases involving the scaphoid are best known, though many other carpals can be affected, including the trapezoid. Six new examples of bipartite trapezoids, identified in African and Asian anatomical and archeological samples, are reported here and compared with the eight previously known. While the site of bipartition is consistent, the resulting segments exhibit variability in their articulations with neighboring carpals. Five of the six affected trapezoids were identified in African or African-derived samples, yielding a significantly higher frequency (0.323%) of bipartite trapezoid than seen in anatomical or archeological series of European origin. Bilateral bipartite trapezoids in archeological remains from the Mid Holocene site of Gobero (Niger) are potentially the oldest bipartite carpals yet identified in humans. Their discovery may indicate that trapezoid bipartition is a condition that has been present in African populations since prehistoric times, though more data are needed. Because bipartite carpals may be symptomatic and can occur as part of syndromes, the significant population variation in frequency identified here has potential utility in both anatomical and clinical contexts. However, a comparison of the morphological appearance of bipartite trapezoids with the suggested criteria for bipartite scaphoid diagnosis indicates that these criteria are not equally applicable to other carpals. Fortunately, due to the rarity of fracture, identification of the bipartite trapezoid and separating it from pathological conditions is considerably easier than diagnosing a bipartite scaphoid. PMID- 25556075 TI - A comparison of the insertion pain associated with three different types of intrauterine device. PMID- 25556076 TI - Cesarean delivery or induction of labor does not prevent vertical transmission of toxoplasmosis in late pregnancy. PMID- 25556077 TI - Fulminant type 1 diabetes mellitus associated with pregnancy in China. PMID- 25556078 TI - A population-based study of the prevalence of HPV in three districts of Tamil Nadu, India. AB - OBJECTIVE: To evaluate the prevalence of HPV infection among women from three districts of Tamil Nadu (Erode, Salem, and Namakkal). METHODS: Between January 27, 2007, and December 15, 2009, 1800 women aged 20-70years who had normal cervical cytology were enrolled into a cross-sectional study. Participants completed interviews and provided first void urine samples for assessment of HPV infection. RESULTS: Among 1699 eligible samples, 179 (10.5%) were HPV positive. HPV16 was the most common type (affecting 68 [4.0%] women), followed by HPV6 (58 [3.4%]). Among the 179 HPV-positive women, 71 (39.7%) were aged 36-45years. An annual income of less than 25 000 INR was significantly associated with HPV infection in all three districts (P<0.05). Regular intercourse was also associated with HPV in Erode and Salem (P<0.05). CONCLUSION: Screening and prophylactic vaccines containing HPV16 and HPV6 should be promoted in western Tamil Nadu. PMID- 25556079 TI - Sensory gating deficits in the attenuated psychosis syndrome. AB - BACKGROUND: Individuals with an "Attenuated Psychosis Syndrome" (APS) have a 20 40% chance of developing a psychotic disorder within two years; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether P50 gating deficits could help to discriminate individuals with APS and also those who are particularly likely to make a transition to psychosis. METHOD: 36 cases meeting PACE (Personal Assessment and Crisis Evaluation) criteria for the APS, all free of antipsychotics, and 60 controls performed an auditory conditioning-testing experiment while their electroencephalogram was recorded. The P50 ratio and its C T difference were compared between groups. Subjects received follow-up for up to 2 years to determine their clinical outcome. RESULTS: The P50 ratio was significantly higher and C-T difference lower in the APS group compared to controls. Of the individuals with APS who completed the follow-up (n=36), nine (25%) developed psychosis. P50 ratio and the C-T difference did not significantly differ between those individuals who developed psychosis and those who did not within the APS group. CONCLUSION: P50 deficits appear to be associated with the pre-clinical phase of psychosis. However, due to the limitations of the study and its sample size, replication in an independent cohort is necessary, to clarify the role of P50 deficits in illness progression and whether this inexpensive and non-invasive EEG marker could be of clinical value in the prediction of psychosis outcomes amongst populations at risk. PMID- 25556080 TI - Comparative efficacy between clozapine and other atypical antipsychotics on depressive symptoms in patients with schizophrenia: analysis of the CATIE phase 2E data. AB - BACKGROUND: The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E. METHODS: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n=49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n=19], quetiapine [n=15], or risperidone [n=16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. >=6 on the CDSS), using mixed models. RESULTS: No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p<.01 for the whole sample and p=.01 for those with an MDE), and comparable to olanzapine and risperidone. CONCLUSION: The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE. PMID- 25556081 TI - Progressive brain changes in children and adolescents with early-onset psychosis: A meta-analysis of longitudinal MRI studies. AB - BACKGROUND: Studies on longitudinal brain volume changes in patients with early onset psychosis (EOP) are particularly valuable for understanding the neurobiological basis of brain abnormalities associated with psychosis. However, findings have not been consistent across studies in this population. We aimed to conduct a meta-analysis on progressive brain volume changes in children and adolescents with EOP. METHODS: A systematic literature search of magnetic resonance imaging (MRI) studies comparing longitudinal brain volume changes in children and adolescents with EOP and healthy controls was conducted. The annualized rates of relative change in brain volume by region of interest (ROI) were used as raw data for the meta-analysis. The effect of age, sex, duration of illness, and specific diagnosis on volume change was also evaluated. RESULTS: Five original studies with 156 EOP patients (mean age at baseline MRI in the five studies ranged from 13.3 to 16.6years, 67.31% males) and 163 age- and sex-matched healthy controls, with a mean duration of follow-up of 2.46years (range 2.02 3.40), were included. Frontal gray matter (GM) was the only region in which significant differences in volume change over time were found between patients and controls (Hedges' g -0.435, 95% confidence interval (CI): -0.678 to -0.193, p<0.001). Younger age at baseline MRI was associated with greater loss of temporal GM volume over time in patients as compared with controls (p=0.005). Within patients, a diagnosis of schizophrenia was related to greater occipital GM volume loss over time (p=0.001). CONCLUSIONS: Compared with healthy individuals, EOP patients show greater progressive frontal GM loss over the first few years after illness onset. Age at baseline MRI and diagnosis of schizophrenia appear to be significant moderators of particular specific brain volume changes. PMID- 25556082 TI - Protective effect of focal adhesion kinase against skeletal muscle reperfusion injury after acute limb ischemia. AB - OBJECTIVES: In cardiac muscle, ischemia reperfusion (IR) injury is attenuated by mitochondrial function, which may be upregulated by focal adhesion kinase (FAK). The aim of this study was to determine whether increased FAK levels reduced rhabdomyolysis in skeletal muscle too. MATERIAL AND METHODS: In a translational in vivo experiment, rat lower limbs were subjected to 4 hours of ischemia followed by 24 or 72 hours of reperfusion. FAK expression was stimulated 7 days before (via somatic transfection with pCMV-driven FAK expression plasmid) and outcomes were measured against non-transfected and empty transfected controls. Slow oxidative (i.e., mitochondria-rich) and fast glycolytic (i.e., mitochondria poor) type muscles were analyzed separately regarding rhabdomyolysis, apoptosis, and inflammation. Severity of IR injury was assessed using paired non-ischemic controls. RESULTS: After 24 hours of reperfusion, marked rhabdomyolysis was found in non-transfected and empty plasmid-transfected fast-type glycolytic muscle, tibialis anterior. Prior transfection enhanced FAK concentration significantly (p = 0.01). Concomitantly, levels of BAX, promoting mitochondrial transition pores, were reduced sixfold (p = 0.02) together with a blunted inflammation (p = 0.01) and reduced rhabdomyolysis (p = 0.003). Slow oxidative muscle, m. soleus, reacted differently: although apoptosis was detectable after IR, rhabdomyolysis did not appear before 72 hours of reperfusion; and FAK levels were not enhanced in ischemic muscle despite transfection (p = 0.66). CONCLUSIONS: IR-induced skeletal muscle rhabdomyolysis is a fiber type-specific phenomenon that appears to be modulated by mitochondria reserves. Stimulation of FAK may exploit these reserves constituting a potential therapeutic approach to reduce tissue loss following acute limb IR in fast-type muscle. PMID- 25556083 TI - Response to 'Re: Kakkos et al. Efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials'. PMID- 25556084 TI - Re: 'Kakkos et al. Efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials'. PMID- 25556087 TI - MORE QUESTIONS: Author's response. PMID- 25556089 TI - Unraveling the impact of lipid domains on the dimerization processes of single molecule EGFRs of live cells. AB - Epidermal growth factor receptor (EGFR/ErbB1) is a transmembrane protein that can drive cell growth and survival via the ligand-induced dimerization of receptors. Because dimerization is a common mechanism for signal transduction, it is important to improve our understanding of how the dimerization process and membrane structure regulate signal transduction. In this study, we examined the effect of lipid nanodomains on the dimerization process of EGFR molecules. We discovered that after ligand binding, EGFR molecules may move into lipid nanodomains. The lipid nanodomains surrounding two liganded EGFRs can merge during their correlated motion. The transition rates between different diffusion states of liganded EGFR molecules are regulated by the lipid domains. Our method successfully captures both the sensitivity of single-molecule processes and statistic accuracy of data analysis, providing insight into the connection between the mobile clustering process of receptors and the hierarchical structure of plasma membrane. PMID- 25556085 TI - Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support. AB - BACKGROUND: Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. OBJECTIVE: The aim of this study was to provide recommendations for systematic evaluation of evidence for DDIs from the scientific literature, drug product labeling, and regulatory documents. METHODS: A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 18 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar 12 times from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. RESULTS: We developed expert consensus answers to the following three key questions. (i) What is the best approach to evaluate DDI evidence? (ii) What evidence is required for a DDI to be applicable to an entire class of drugs? (iii) How should a structured evaluation process be vetted and validated? CONCLUSION: Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug compendia and clinical decision support systems in which these recommendations are implemented should be able to provide higher-quality information about DDIs. PMID- 25556090 TI - Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility. AB - Herein we report the optimization efforts to ameliorate the potent CYP3A4 time dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies. PMID- 25556091 TI - Synthesis and in vitro transfection efficiency of spermine-based cationic lipids with different central core structures and lipophilic tails. AB - Twelve spermine-based cationic lipids with four different central core structures (di(oxyethyl)amino, di(oxyethyl)amino carboxy, 3-amino-1,2-dioxypropyl and 2 amino-1,3-dioxypropyl) and three hydrophobic tails (lauric acid, myristic acid and palmitic acid) were synthesized. The liposomes containing lipids and DOPE showed moderate to good in vitro DNA delivery into HeLa cells. GFP expression experiments revealed that liposomes composed of lipids with 3-amino-1,2 dioxypropyl as a central core structure exhibited highest transfection efficiency under serum-free condition. Whereas, lipid with 2-amino-1,3-dioxypropyl core structure showed highest transfection under 10% serum condition. Moreover, the liposomes and lipoplexes composted of these cationic lipids exhibited low cytotoxicity. PMID- 25556092 TI - Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds. AB - Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia. PMID- 25556093 TI - Evaluation of gambierol and its analogs for their inhibition of human Kv1.2 and cytotoxicity. AB - Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel Kv1.2 (hKv1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from -80mV to 40mV. The IC50 values for the three compounds were 0.75+/-0.15nM, 7.6+/-1.2nM, and 28+/-4.0nM (the mean+/-SEM, n=3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hKv1.2. The IC50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild type CHO cells were 95+/-7.1MUM, 6.5+/-0.8MUM (the mean+/-SEM, n=3), and >100MUM (n=3), respectively, whereas those in the CHO cells stably expressing hKv1.2 were 78+/-5.8MUM, 6.0+/-1.0MUM (the mean+/-SEM, n=3), and >100MUM (n=3). These results suggested that cytotoxicity is not triggered by inhibition of the human Kv1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells. PMID- 25556094 TI - In vitro studies of antimicrobial activity of Gly-His-Lys conjugates as potential and promising candidates for therapeutics in skin and tissue infections. AB - In this Letter, we presented in vitro studies of antimicrobial activity of Gly His-Lys conjugates that are important point in preliminary biological evaluation of their potential application in skin and tissue therapies. The novel compounds include the conjugation of fatty acids with a modification of the amino acid sequence in the primary structure of Gly-His-Lys (6i). All the compounds exhibited strong to moderate activity. Compound 1d had the most potent antimicrobial activity at MIC ranges 31.3-125.0MUg/mL (against Escherichia coli spp. and Staphylococcus aureus spp.), 375.0-500.0MUg/mL (against Pseudomonas aeruginosa spp.). Conjugate 5b expressed activity against Staphylococcus aureus spp. and Escherichia coli spp. at MIC ranges 250.0-500.0MUg/mL and 62.5 125.0MUg/mL, respectively. Both conjugates 1d and 5b possessed rapid bactericidal activity against Gram-positive bacteria at 2MIC or 4MIC. Conjugates 1b-c, 1e, 2a b and 4b showed noticeable effect against both Gram-positive and Gram-negative bacteria. Compounds 1d, 1e and 2e were the most active against fungus. PMID- 25556095 TI - A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety. AB - Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical delta, MU and kappa opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented. PMID- 25556096 TI - Characterization of glycerol phosphate oxidase from Streptococcus pneumoniae and its application for ketose synthesis. AB - Glycerol phosphate oxidase from Streptococcus pneumoniae (GPOS.pne) was purified and characterized. By the actions of GPOS.pne and dihydroxyacetone phosphate (DHAP)-dependent aldolases, various ketoses including rare sugars were synthesized with glyceraldehydes as acceptors in a one-pot four-enzyme system. PMID- 25556098 TI - Selective CB2 receptor agonists. Part 1: the identification of novel ligands through computer-aided drug design (CADD) approaches. AB - Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling. PMID- 25556097 TI - Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands. AB - A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors. PMID- 25556099 TI - Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach. AB - Matriptase is a cell-surface trypsin-like serine protease of epithelial origin, which cleaves and activates proteins including hepatocyte growth factor/scatter factor and proteases such as uPA, which are involved in the progression of various cancers. Here we report a fragment-linking approach, which led to the discovery of O-(3-carbamimidoylphenyl)-l-serine amides as potent matriptase inhibitors. The co-crystal structure of one of the potent inhibitors, 6 in complex with matriptase catalytic domain validated the working hypothesis guiding the development of this congeneric series and revealed the structural basis for matriptase inhibition. Replacement of a naphthyl group in 6 with 2,4,6-tri isopropyl phenyl resulted in 10 with improved matriptase inhibition, which exhibited significant primary tumor growth inhibition in a mouse model of prostate cancer. Compounds such as 10, identified using a fragment-linking approach, can be explored further to understand the role of matriptase as a drug target in cancer and inflammation. PMID- 25556100 TI - Design, synthesis and biological evaluation of 5-aminolaevulinic acid/3 hydroxypyridinone conjugates as potential photodynamic therapeutical agents. AB - 5-Aminolaevulinic acid (ALA) prodrugs have been widely used in photodynamic therapy (PDT) as precursors to the natural photosensitizer, protoporphyrin IX (PpIX). The main disadvantage of this therapy is that ALA is poorly absorbed by cells due to its high hydrophilicity. In order to improve the therapeutical effect and induce higher yields of PpIX, a range of prodrugs of ALA conjugated to 3-hydroxypyridin-4-ones (HPO) were synthesized. Pharmacokinetic studies indicated that some of the ALA-HPO conjugates are more efficient than ALA for PpIX production in the human breast adenocarcinoma cell line (MDA-MB-468). The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, suggesting the potential application of the ALA-HPO conjugates in photodynamic therapy. PMID- 25556101 TI - Identification of indole-3-carboxylic acids as non-ATP-competitive Polo-like kinase 1 (Plk1) inhibitors. AB - A series of indole-3-carboxylic acids were designed as novel small molecular non ATP-competitive Plk1 inhibitors. The designed compounds were synthesized and evaluated. Most of the targeted compounds showed potent Plk1 inhibitory activities and anti-proliferative characters. Particularly, 4f and 4g showed Plk1 inhibitory activity with IC50 values of 0.41 and 0.13MUM, which were about 5 and 17 times more potent compared to thymoquinone, respectively. Compound 4g also showed inhibitory activity to HeLa and MCF-7 cell lines with IC50 values of 0.72 and 1.15MUM, which was almost 3 and 4 times more potent than thymoquinone. Study of mechanism of action suggested that 4g was an ATP-independent and substrate dependent Plk1 inhibitor. Moreover, 4g showed excellent Plk1 inhibitory selectivity against Plk2 and Plk3. Fluorescein isothiocyanate Annexin V/propidium iodide (PI) double-staining assay and western-blot results indicate that induction of apoptosis by 4g is involved in its anti-tumor activity. This study may provide a support for further optimization of non-ATP-competitive Plk1 inhibitors. PMID- 25556102 TI - Identification of trichostatin derivatives from Streptomyces sp. CPCC 203909. AB - Four new trichostatin analogues (1-4) and six known analogues have been isolated from the rice fermentation of the Streptomyces sp. CPCC 203909. The structures and absolute configurations of these compounds were determined by extensive spectroscopic analysis including 2D NMR and electronic circular dichroism (ECD) calculations based on the quantum-mechanical time-dependent density functional theory (TDDFT). Compounds 2, 5-7, 9, and 10 up-regulated the transcriptional activity of human high density lipoprotein receptor (CLA-1) with EC50 values of 0.38-78.83MUM. PMID- 25556103 TI - Synthesis, antimycobacterial and antifungal evaluation of some new 1-ethyl-5 (hetero)aryl-6-styryl-1,6-dihydropyrazine-2,3-dicarbonitriles. AB - The Petasis reaction of 6-hydroxy adducts of 1-alkyl-2,3-dicyano-5-arylpyrazinium salts with trans-styrylboronic acids proved to proceed smoothly at room temperature to give the corresponding 5-(hetero)aryl-6-styryl substituted 1,6 dihydropyrazine derivatives. Also it has been found that C(6) unsubstituted 1,6 dihydro- or 1,4,5,6-tetrahydropyrazine derivatives can be easy prepared in high yields from the corresponding pyrazinium salts by reduction with triethylsilane. All synthesized compounds were screened in vitro for their antifungal activities against seven pathogenic fungal strains and antimycobacterial activities against Mycobacterium tuberculosis H37Rv, avium, terrae and multi-drug-resistant strains isolated from tuberculosis patients in the Ural region (Russia). PMID- 25556104 TI - Nanostructured lipid carriers used for oral delivery of oridonin: an effect of ligand modification on absorption. AB - Oridonin (Ori) is a natural compound with notable anti-inflammation and anti cancer activities. However, therapeutic use of this compound is limited by its poor solubility and low bioavailability. Here a novel biotin-modified nanostructured lipid carrier (NLC) was developed to enhance the bioavailability of Ori. The effect of ligand (biotin) modification on oral absorption of Ori encapsulated in NLCs was also explored. Ori-loaded NLCs (Ori-NLCs) were prepared by the melt dispersion-high pressure homogenization method. Biotin modification of Ori-NLCs was achieved by EDC and NHS in aqueous phase. The obtained biotin decorated Ori-NLCs (Bio-Ori-NLCs) were 144.9nm in size with an entrapment efficiency of 49.54% and a drug load of 4.81%. Oral bioavailability was enhanced by use of Bio-Ori-NLCs with a relative bioavailability of 171.01%, while the value of non-modified Ori-NLCs was improved to 143.48%. Intestinal perfusion showed that Ori solution unexpectedly exhibited a moderate permeability, indicating that permeability was not a limiting factor of Ori absorption. Ori could be rapidly metabolized that was the main cause of low bioavailability. However, there was a difference in the enhancement of bioavailability between Bio Ori-NLCs and conventional NLCs. Although severe lipolyses happened both on Bio Ori-NLCs and non-modified NLCs, the performance of Bio-Ori-NLCs in the bioavailability improvement was more significant. Overall, Bio-Ori-NLCs can further promote the oral absorption of Ori by a ligand-mediated active transport. It may be a promising carrier for the oral delivery of Ori. PMID- 25556105 TI - Novice Nurses' Experiences With Palliative and End-of-Life Communication. AB - Health care providers recognize that delivery of effective communication with family members of children with life-threatening illnesses is essential to palliative and end-of-life care (PC/EOL). Parents value the presence of nurses during PC/EOL of their dying child. It is vital that nurses, regardless of their years of work experience, are competent and feel comfortable engaging family members of dying children in PC/EOL discussions. This qualitative-descriptive study used focus groups to explore the PC/EOL communication perspectives of 14 novice pediatric oncology nurses (eg, with less than 1 year of experience). Audio taped focus group discussions were reviewed to develop the following 6 theme categories: (a) Sacred Trust to Care for the Child and Family, (b) An Elephant in the Room, (c) Struggling with Emotional Unknowns, (d) Kaleidoscope of Death: Patterns and Complexity, (e) Training Wheels for Connectedness: Critical Mentors during PC/EOL of Children, and (f) Being Present with an Open Heart: Ways to Maintain Hope and Minimize Emotional Distress. To date, this is the first study to focus on PC/EOL communication perspectives of novice pediatric oncology nurses. PMID- 25556107 TI - Parents' Experience With Their Child's Cancer Diagnosis: Do Hopefulness, Family Functioning, and Perceptions of Care Matter? AB - OBJECTIVES: This study assessed the experience of parents who have a child diagnosed with cancer and whether parental hope, family functioning, and perceptions of care distinguish those parents who have adapted to the diagnosis versus those who have not adapted. METHODS: Fifty parents completed an interview about the diagnosis experience and questionnaires about hopefulness, family functioning, and family-centered care. RESULTS: A majority of parents had come to terms with the diagnosis; however, a subset indicated feeling emotionally disengaged from the experience and having persistent thoughts about why this had happened to them. In addition, parents who were having a difficult time adapting reported lower hopefulness and felt that they received more information about support services from medical providers compared with parents who had come to terms with the diagnosis. CONCLUSIONS: By recognizing families who continue to struggle with the diagnosis, nurses may be better equipped to approach families and evaluate their needs, including coping and adaptation. Asking parents about their experience can also lead to more appropriate and timely care and referral and allows nurses to provide care that engenders hopefulness. PMID- 25556106 TI - Effective Prevention and Management of Tumor Lysis Syndrome in Children With Cancer: The Important Contributions of Pediatric Oncology Nurses. AB - The practice guidelines aimed to identify appropriate nursing management for the prevention and treatment of tumor lysis syndrome, in line with the current evidence-based medical guidelines. Using a systematic approach, 15 relevant articles were identified for the review. The evaluation of patient risk factors for tumor lysis syndrome and the appropriate medical and nursing assessment were identified. The treatment algorithms for the prevention of tumor lysis syndrome from both the medical and nursing perspectives have been established. In particular, the guidelines highlight the importance of pediatric oncology nurses in contributing to the prevention and management of tumor lysis syndrome. PMID- 25556108 TI - Treatment of Anxiety and Depression in Adolescents and Young Adults With Cancer. AB - Adolescents and young adults (AYAs) with cancer are a unique population of patients who experience a period of intense and dramatic life changes when they are diagnosed. Overall, AYAs with cancer are resilient; however, their psychosocial needs are often underestimated or unmet. Currently, there are inconsistencies in how AYAs are screened and treated for anxiety and depression. Barriers to treatment include clinicians' lack of confidence in distinguishing between side effects of treatment and depression/anxiety. Additional barriers include the black box warning for prescribing antidepressants and difficulty partnering with mental health professionals. This article seeks to provide recommendations for pediatric oncology clinicians on how to identify and address anxiety and depression in AYAs and how to partner with mental health professionals in their treatment, and it suggests directions for future research. PMID- 25556109 TI - Nutrient-based dietary patterns and endometrial cancer risk: an Italian case control study. AB - Diet has been suggested to have a role on endometrial cancer risk, but few data are available on the role of dietary patterns on this neoplasm. A case-control study was carried out in Italy, including 454 women with endometrial cancer and 908 hospital controls admitted to the same hospitals for acute, non-neoplastic diseases. Dietary information was based on a reproducible and valid food frequency questionnaire. A posteriori dietary patterns were obtained using principal component factor analysis on 28 nutrients. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were obtained from multiple logistic regression models conditioned on age and study center, and adjusted for major known confounding factors. Positive associations were found for the "Western-type diet" (OR=1.63, 95% CI: 1.12-2.38, for the highest versus the lowest quartile category) and the "Animal-derived nutrients and polyunsaturated fatty acids" patterns (OR=1.76, 95% CI: 1.23-2.52). The corresponding risk estimates among women with a body mass index >=30 were 2.08 (95% CI: 0.92-4.69) and 2.30 (95% CI: 1.03-5.16) for the two patterns, respectively. No association was found for the other three patterns (i.e., "Vitamins and fiber", OR=0.96, 95% CI: 0.67-1.37, "Starch-rich", OR=0.99, 95% CI: 0.69-1.42, and "Other fats", OR=1.03, 95% CI: 0.70-1.52). This study indicates that dietary habits characterized by high intakes of animal products increase endometrial cancer risk, the association being appreciably stronger for obese women. PMID- 25556110 TI - Corticotropin-releasing factor 1 receptor mediates the activity of the reward system evoked by morphine-induced conditioned place preference. AB - Different neurotransmitter systems are involved in behavioural and molecular responses to morphine. The brain stress system is activated by acute administration of drugs of abuse, being CRF the main neuropeptide of this circuitry. In this study we have studied the role of CRF1R in the rewarding effects of morphine using the CPP paradigm. For that, animals were treated with a CRF1R antagonist (CP-154,526) or vehicle during 6 days. Thirty min after receiving the antagonist, mice were injected with morphine on the same days that CP-154,526 was administered; another group received saline on the same days that vehicle was administered, and both groups were immediately conditioned. Control animals received vehicle and saline every day. On day 7, animals were tested for morphine-induced CPP. c-Fos, TH and OXA immunohistochemistry, NA turnover (HPLC), and corticosterone plasma concentration (RIA) were evaluated. Administration of a CRF1R antagonist CP-154,526 blocked the morphine-induced CPP and the increased NA turnover in the NAc in morphine-paired mice. CP-154-526 antagonised the enhancement in c-Fos expression evoked by morphine-induced CPP in the VTA and NAc, and the activation of the orexinergic neurons in the LLH. Present work demonstrates that morphine-induced CPP activates different brain areas involved in reward, and points out a critical role of CRF1R in molecular changes involved in morphine-conducted behaviours. Thus, our study supports a therapeutic potential of CRF1R antagonists in addictive disorders. PMID- 25556111 TI - Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner. AB - The relationship between gene dosage imbalance and phenotypes associated with Trisomy 21, including the etiology of abnormal bone phenotypes linked to Down syndrome (DS), is not well understood. The Ts65Dn mouse model for DS exhibits appendicular skeletal defects during adolescence and adulthood but the developmental and genetic origin of these phenotypes remains unclear. It is hypothesized that the postnatal Ts65Dn skeletal phenotype originates during embryonic development and results from an increased Dyrk1a gene copy number, a gene hypothesized to play a critical role in many DS phenotypes. Ts65Dn embryos exhibit a lower percent bone volume in the E17.5 femur when compared to euploid embryos. Concomitant with gene copy number, qPCR analysis revealed a ~1.5 fold increase in Dyrk1a transcript levels in the Ts65Dn E17.5 embryonic femur as compared to euploid. Returning Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a(+/-) embryos did not correct the trisomic skeletal phenotype but did return Dyrk1a gene transcript levels to normal. The size and protein expression patterns of the cartilage template during embryonic bone development appear to be unaffected at E14.5 and E17.5 in trisomic embryos. Taken together, these data suggest that the dosage imbalance of genes other than Dyrk1a is involved in the development of the prenatal bone phenotype in Ts65Dn embryos. PMID- 25556112 TI - The FlyCatwalk: a high-throughput feature-based sorting system for artificial selection in Drosophila. AB - Experimental evolution is a powerful tool for investigating complex traits. Artificial selection can be applied for a specific trait and the resulting phenotypically divergent populations pool-sequenced to identify alleles that occur at substantially different frequencies in the extreme populations. To maximize the proportion of loci that are causal to the phenotype among all enriched loci, population size and number of replicates need to be high. These requirements have, in fact, limited evolution studies in higher organisms, where the time investment required for phenotyping is often prohibitive for large-scale studies. Animal size is a highly multigenic trait that remains poorly understood, and an experimental evolution approach may thus aid in gaining new insights into the genetic basis of this trait. To this end, we developed the FlyCatwalk, a fully automated, high-throughput system to sort live fruit flies (Drosophila melanogaster) based on morphometric traits. With the FlyCatwalk, we can detect gender and quantify body and wing morphology parameters at a four-old higher throughput compared with manual processing. The phenotyping results acquired using the FlyCatwalk correlate well with those obtained using the standard manual procedure. We demonstrate that an automated, high-throughput, feature-based sorting system is able to avoid previous limitations in population size and replicate numbers. Our approach can likewise be applied for a variety of traits and experimental settings that require high-throughput phenotyping. PMID- 25556113 TI - Cytomegalovirus retinitis in HIV-negative patients: a practical management approach. PMID- 25556114 TI - Rates of decline in regions of the visual field defined by frequency-domain optical coherence tomography in patients with RPGR-mediated X-linked retinitis pigmentosa. AB - PURPOSE: To determine whether annual decline in visual field sensitivity is greater in the transition zone at the edge of the frequency-domain optical coherence tomography (fdOCT) inner segment ellipsoid zone (EZ) than at other locations in the visual field. DESIGN: Prospective, longitudinal, observational study. PARTICIPANTS: Forty-four patients with X-linked retinitis pigmentosa (XLRP) resulting from a mutation in the RPGR gene. METHODS: Static perimetric fields (Humphrey 30-2; Carl Zeiss Meditec, Dublin, CA) were obtained annually for 4 years. Beginning with year 2, fdOCT scans were obtained annually with a Heidelberg Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). MAIN OUTCOME MEASURES: The rate of visual field decline at locations near the edge of the EZ compared with the rates for the macula and in the mid periphery. RESULTS: Sensitivity just inside and outside the edge of the EZ declined at rates of 0.84 and 0.92 dB/year, respectively. By comparison, average sensitivity in the macula and mid periphery declined by 0.38 and 0.61 dB/year, respectively. CONCLUSIONS: The edge of the EZ in each patient with XLRP indicates a transition zone between relatively healthy and relatively degenerate retina. The annual loss of sensitivity in the transition zone is more rapid than it is elsewhere in the retina. PMID- 25556115 TI - Optic nerve head changes after short-term intraocular pressure elevation in acute primary angle-closure suspects. AB - PURPOSE: To investigate changes in the optic nerve head morphology after acute intraocular pressure (IOP) elevation during a dark room prone provocative test (DRPPT). DESIGN: Prospective cohort study. PARTICIPANTS: Acute primary angle closure (APAC) suspects underwent DRPPT. METHODS: Study participants stayed in a dark room for 2 hours with the forehead placed on a desk. At baseline and within 5 minutes after DRPPT, tonometry and enhanced depth imaging by spectral-domain optical coherence tomography (SD OCT) were performed. MAIN OUTCOME MEASURES: Changes in 3-dimensional optic nerve head topography. RESULTS: The study included 114 eyes of 65 participants with a mean age of 58.3+/-8.7 years and a mean IOP elevation of 10.1+/-10.9 mmHg during DRPPT. When all eyes were included, the mean value of most optic disc parameters did not change significantly, except for a decrease in the temporal minimal rim width (P = 0.005). By including only eyes with an IOP increase greater than 15 mmHg, the mean value of cup width (P = 0.001) and cup depth (P = 0.002) increased, whereas the lamina cribrosa (LC) thickness (P = 0.035), temporal minimal rim width (P = 0.001), and nasal minimal rim width (P < 0.001) decreased. The LC depth and Bruch's membrane opening (BMO) did not differ between the baseline and the end of DRPPT. An IOP increase was significantly associated with widening (P < 0.001; r = 0.46) and deepening (P < 0.001; r = 0.52) of the optic cup, thinning of the LC (P = 0.003; r = -0.35), temporal minimal rim width (P < 0.001; r = -0.34), and nasal minimal rim width (P < 0.001; r = -0.35). CONCLUSIONS: Angle-closure suspect eyes showed a widening and deepening of the optic cup, decrease in neuroretinal rim width, and thinning of the LC after a darkness-induced IOP increase of >15 mmHg. The diameter of the BMO and position of the anterior LC surface remained unchanged. This suggests that a short-term IOP increase leads to a condensation of neuroretinal rim, prelaminar tissue, and LC, without major changes in the optic disc size and position of the anterior LC surface. PMID- 25556116 TI - The epidemiology of vitreoretinal interface abnormalities as detected by spectral domain optical coherence tomography: the beaver dam eye study. AB - PURPOSE: To describe the prevalence and interrelationships of epiretinal membranes (ERMs), vitreomacular traction (VMT), macular cysts, paravascular cysts (PVCs), lamellar macular holes (LMHs), full-thickness macular holes (FTMHs), and visual impairment in a population-based study of older adults. DESIGN: Cross sectional study. PARTICIPANTS: There were 1913 participants aged 63 to 102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008-2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD OCT) scans of the macula in at least 1 eye. METHODS: The presence of ERMs and other retinal lesions was determined by standardized grading of macular SD OCT scans and photographs of 3 standard fields. MAIN OUTCOME MEASURES: Epiretinal membranes, VMT, macular cysts, PVCs, LMHs, FTMHs, and visual impairment. RESULTS: By using SD OCT, the prevalence of ERMs (34.1%), VMT (1.6%), macular cysts (5.6%), PVCs (20.0%), LMHs (3.6%), and FTMHs (0.4%) was estimated. The prevalence of macular cysts (P < 0.001), ERMs (P < 0.001), and VMT (P = 0.005) increased with age; the prevalence of PVCs (P = 0.05) decreased with age; and the prevalence of LMHs was not associated with age (P = 0.70). The prevalence of macular cysts, LMHs, and ERMs was higher in eyes with a history of cataract surgery. Macular cysts and ERMs were more common in eyes with retinal diseases, such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment, than in eyes without these conditions. Macular cysts, ERMs, and FTMHs were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR], 3.96; P < 0.0001), PVCs (OR, 1.45, P = 0.007), LMHs (OR, 10.62; P < 0.001), VMT (OR, 2.72, P = 0.01), and visual impairment (OR, 3.23; P < 0.001) were more frequent in eyes with ERMs compared with eyes without ERMs. CONCLUSIONS: Epiretinal membranes are associated with macular cysts, PVCs, LMHs, VMT, and visual impairment. Further follow-up will allow better understanding of the natural history of ERMs and VMT and their relationships to the development of macular cysts and LMHs in the aging population. PMID- 25556117 TI - Sensitivity of pharmacokinetic-pharmacodynamic analysis for detecting small magnitudes of QTc prolongation in preclinical safety testing. AB - INTRODUCTION: Preclinical concentration-effect (pharmacokinetic-pharmacodynamic, PKPD) modeling has successfully quantified QT effects of several drugs known for significant QT prolongation. This study investigated its sensitivity for detecting small magnitudes of QT-prolongation in a typical preclinical cardiovascular (CV) safety study in the conscious telemetered dog (crossover study in 4-8 animals receiving a vehicle and three dose levels). Results were compared with conventional statistical analysis (analysis of covariance, ANCOVA). METHODS: A PKPD model predicting individual QTc was first developed from vehicle arms of 28 typical CV studies and one positive control study (sotalol). The model quantified between-animal, inter-occasion and within-animal variability and described QTc over 24h as a function of circadian variation and drug concentration. This "true" model was used to repeatedly (n = 500) simulate studies with typical drug-induced QTc prolongation (?QTc) of 1 to 12 ms at high dose peak concentrations. Simulated studies were re-analyzed by both PKPD analysis (with varying complexity) and ANCOVA. Sensitivity (power) was calculated as the percentage of studies in which a significant (alpha = 0.05) drug effect was found. One simulation scenario did not include a concentration-effect relationship and served to investigate false-positive rates. Exposure-effect relationships were derived from both PKPD analysis (linear concentration-effect) and ANCOVA (linear trend test for dose) and compared. RESULTS: PKPD analysis/ANCOVA had a sensitivity of 80% to detect the effects of 7/13 ms (n = 4), 5/10 ms (n = 6) and 4.5/8 ms (n = 8), respectively. The false-positive rate was much higher using ANCOVA (40%) compared to PKPD analysis (1%). Typical drug effects were more precisely predicted using estimated concentration-effect slopes (+/- 1.5-2.8 ms) than dose-effect slopes (+/- 3.3-3.7 ms). DISCUSSION: Preclinical PKPD analysis can increase the confidence in the quantification of small QTc effects and potentially allow reducing the number of animals while maintaining the required study sensitivity. This underscores the value of PKPD modeling in preclinical safety testing. PMID- 25556118 TI - Silver nanoparticles: their potential toxic effects after oral exposure and underlying mechanisms--a review. AB - Because of their antimicrobial properties, the use of silver nanoparticles (AgNPs) is increasing fast in industry, food, and medicine. In the food industry, nanoparticles are used in packaging to enable better conservation products such as sensors to track their lifetime, and as food additives, such as anti-caking agents and clarifying agents for fruit juices. Nanoemulsions, used to encapsulate, protect and deliver additives are also actively developed. Nanomaterials in foods will be ingested and passed through the digestive tract. Those incorporated in food packaging may also be released unintentionally into food, ending up in the gastrointestinal tract. It is therefore important to make a risk assessment of nanomaterials to the consumer. Thus, exposure to AgNPs is increasing in quantity and it is imperative to know their adverse effects in man. However, controversies still remain with respect to their toxic effects and their mechanisms. Understanding the toxic effects and the interactions of AgNPs with biological systems is necessary to handle these nanoparticles and their use. They usually generate reactive oxygen species resulting in increased pro-inflammatory reactions and oxidative stress via intracellular signalling pathways. Here, we mainly focus on the routes of exposure of AgNPs, toxic effects and the mechanisms underlying the induced toxicity. PMID- 25556119 TI - Behavior of mammalian cells on magnesium substituted bare and hydroxyapatite deposited (Ti,Mg)N coatings. AB - TiN and (Ti,Mg)N thin film coatings were deposited on titanium substrates by using cathodic arc physical vapor deposition (arc-PVD) technique with magnesium contents of 0, 4.24 at% (low Mg) and 10.42 at% (high Mg). The presence of magnesium on both normal (hFOB) and cancer (SaOS-2) osteoblast cell behavior was investigated in (Ti,Mg)N surfaces with or without prior hydroxyapatite (HA) deposition (in simulated body fluid, SBF). Mg incorporation on TiN films was found to have no apparent effect on the cell proliferation in bare surfaces but cell spreading was better on low Mg content surface for hFOB cells. SaOS-2 cells, on the other hand, showed an increased extra cellular matrix (ECM) deposition on low Mg surfaces but ECM deposition almost disappeared when Mg content was increased above 10 at%. HA deposited surfaces with high Mg content was shown to cause a significant decrease in cell viability. While the cells were flattened, elongated and spread over the surface in contact with each other via cellular extensions on unmodified and low Mg doped surfaces, unhealthy morphologies of cells with round shape with a limited number of extended arms was visualized on high Mg containing samples. In summary, Mg incorporation into the TiN coatings by arc-PVD technique and successive HA deposition led to promising cell responses on low Mg content surfaces for a better osteointegration performance. PMID- 25556120 TI - Response surface optimization of experimental conditions for carbamazepine biodegradation by Streptomyces MIUG 4.89. AB - Carbamazepine an iminostilbene derivative compound with a tricyclic structure is one of the most widely prescribed drugs for the treatment of epilepsy. It is hardly or not degraded during the conventional technology used in wastewater treatment plants (WWTPs) (up to 7%) and many studies have found it ubiquitous in various environmental matrices in concentrations typically ranging from MUg L(-1) to ng L(-1). Streptomyces MIUG 4.89 was previously studied for its ability in carbamazepine biodegradation (up to 14%) during cultivation in submerged system under aerobic conditions at an initial CBZ concentration of 0.2 mg L(-1). The influence of some factors (independent variables) upon biodegradation potential was examined by Plackett-Burman analysis. Central composite design of experiments (CCD) and response surface methodology (RSM) were used to get more information about the significant effects and their interactions of the five parameters selected upon their biodegradation potential in order to increase the elimination yield of this drug from a liquid medium. The investigated ranges of the independent variables were: 1.0-3.0 g L(-1) yeast extract, 3.0-10.0 g L(-1) glucose, 4.0-10.0% (v/v) inoculation level, pH 5.0-7.0 and 50-250 mL of medium at a constant initial concentration of carbamazepine (CBZ) of 0.2 mg L(-1). The response surface analysis results showed that the capacity of the selected strain Streptomyces MIUG 4.89 to degrade carbamazepine was high in submerged cultivation system by cultivation in a liquid medium containing 6.5 g L(-1) glucose and 2 g L(-1) yeast extract, inoculated at 7% (v/v) and cultivated at pH 6.0, during 7 days of incubation at 25 degrees C and 150 rpm. Under these culture conditions the achieved experimental CBZ biotransformation yield was 30%. PMID- 25556121 TI - Dual purpose system that treats anaerobic effluents from pig waste and produce Neochloris oleoabundans as lipid rich biomass. AB - Dual purpose systems that treat wastewater and produce lipid rich microalgae biomass have been indicated as an option with great potential for production of biodiesel at a competitive cost. The aim of the present work was to develop a dual purpose system for the treatment of the anaerobic effluents from pig waste utilizing Neochloris oleoabundans and to evaluate its growth, lipid content and lipid profile of the harvested biomass and the removal of nutrients from the media. Cultures of N. oleoabundans were established in 4 L flat plate photobioreactors using diluted effluents from two different types of anaerobic filters, one packed with ceramic material (D1) and another one packed with volcanic gravel (D2). Maximum biomass concentration in D1 was 0.63 g L(-1) which was significantly higher than the one found in D2 (0.55 g L(-1)). Cultures were very efficient at nutrient removal: 98% for NNH4(+) and 98% for PO4(3-). Regarding total lipid content, diluted eflluents from D2 promoted a biomass containing 27.4% (dry weight) and D1 a biomass containing 22.4% (dry weight). Maximum lipid productivity was also higher in D2 compared to D1 (6.27+/-0.62 mg L(-1) d(-1) vs. 5.12+/-0.12 mg L(-1) d(-1)). Concerning the FAMEs profile in diluted effluents, the most abundant one was C18:1, followed by C18:2 and C16:0. The profile in D2 contained less C18:3 (linolenic acid) than the one in D1 (4.37% vs. 5.55%). In conclusion, this is the first report demonstrating that cultures of N. oleoabundans treating anaerobic effluents from pig waste are very efficient at nutrient removal and a biomass rich in lipids can be recovered. The maximum total lipid content and the most convenient FAMEs profile were obtained using effluents from a digester packed with volcanic gravel. PMID- 25556123 TI - Reactivation of hepatitis B virus 40 months after discontinuation of rituximab maintenance treatment and 5 months after cessation of entecavir administration. PMID- 25556124 TI - ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders. AB - Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed. PMID- 25556122 TI - The effect of the aquatic contaminants bisphenol-A and PCB-95 on the zebrafish lateral line. AB - Environmental toxicants such as bisphenol-A (BPA) and polychlorinated biphenyls (PCBs) are prevalent in our water supply, soil, and many food products and can profoundly affect the central nervous system. Both BPA and PCBs can disrupt endocrine signaling, which is important for auditory development and function, but the effect of these toxicants on the auditory periphery is not understood. In this study we investigated the effect of PCB-95 and BPA on lateral line development, function, and regeneration in larval zebrafish. The lateral line is a system of mechanosensory hair cells on the exterior of the fish that are homologous to the hair cells located in the mammalian inner ear. We found that PCB-95 had no effect on lateral line development or hair cell survival. BPA also did not affect lateral line development, but instead had a significant effect on both hair cell survival and regeneration. BPA-induced hair cell loss is both dose and time-dependent, with concentrations of 1 MUM or higher killing lateral line hair cells during a 24h exposure period. Pharmacologic manipulation experiments suggest that BPA kills hair cells via activation of oxidative stress pathways, similar to prior reports of BPA toxicity in other tissues. We also observed that hair cells killed with neomycin, a known ototoxin, failed to regenerate normally when BPA was present, suggesting that BPA in aquatic environments could impede innate regenerative responses in fishes. Collectively, these data demonstrate that BPA can have detrimental effects on sensory systems, both in aquatic life and perhaps in terrestrial organisms, including humans. PMID- 25556125 TI - Differentiation of BHV-1 isolates from vaccine virus by high-resolution melting analysis. AB - An efficacious bovine herpesvirus type-1 (BHV-1) vaccine has been used for many years. However, in the past few years, abortion and respiratory diseases have occurred after administration of the modified live vaccine. To investigate whether BHV-1 isolates from disease outbreaks are identical to those of the vaccines used, selected regions of the BHV-1 genome were investigated by high resolution melting (HRM) analysis and PCR-DNA sequencing. When a target region within the thymidine kinase (TK) gene was examined by HRM analysis, 6 out of the 11 isolates from abortion cases and 22 out of the 25 isolates from bovine respiratory disease (BRD) cases had different melting curves compared to the vaccine virus. Surprisingly, when a conserved region within the US6 gene that encodes glycoprotein D (gD) was examined by HRM analysis, 5 out of the 11 abortion isolates and 18 out of the 23 BRD isolates had different melting curves from the vaccine virus. To determine whether SNPs within the coding regions of glycoprotein E (gE) and TK genes can be used to differentiate the isolates from the vaccine virus, PCR-DNA sequencing was used to examine these SNPs in all the isolates. This revealed that only 1 out of 11 of the abortion isolates and 4 out of 24 of the BRD isolates are different in the target region of gE from the vaccine virus, while 5 out of 11 abortion isolates and 4 out of 22 BRD isolates are different in the target region of TK from the vaccine virus. No DNA sequence differences were observed in glycoprotein G (gG) region between disease and vaccine isolates. Our study demonstrated that many disease isolates had genetic differences from the vaccine virus in regions examined by HRM and PCR-DNA sequencing analysis. In addition, many isolates contained more than one type of mutation and were composed of mixed variants. Our study suggests that a mixture of variants were present in isolates collected post-vaccination. HRM is a rapid diagnostic method that can be used for rapid differentiation of clinical isolates from vaccine strains. PMID- 25556127 TI - One numerical target hit, and one missed, in the 2014 badger culls. PMID- 25556126 TI - Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis. AB - OBJECTIVE: To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer. DESIGN: Systematic review and dose-response meta-analysis of prospective observational studies. DATA SOURCES: Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. ELIGIBILITY CRITERIA: Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations. RESULTS: Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer. CONCLUSIONS: Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer. PMID- 25556129 TI - Index ranks countries on animal welfare standards. PMID- 25556128 TI - European endorsement for the UK's TB eradication programme. PMID- 25556130 TI - Contract awarded for postmortem examination services in Wales. PMID- 25556131 TI - State of the profession: where are we now? AB - The veterinary profession is changing rapidly. But which of the many changes taking place are likely to have the most impact and, more importantly, what can be done about them? A panel discussion at the BVA Congress at the London Vet Show sought delegates' views on the matter with a purpose of steering a way forward. Laura Honey reports. PMID- 25556132 TI - The winding path to a PhD in veterinary education. AB - Masters and PhD degrees specific to veterinary education are relatively novel, but the number of students in this area is growing. As two current students, Tierney Kinnison and Sylvain Dernat, explain, those undertaking these degrees have vastly different backgrounds and are researching a variety of topics. By sharing the experiences of those involved, they hope to encourage the next generation of veterinary educators to begin their research careers. PMID- 25556133 TI - Suspected adverse events, 2013. AB - Increase in the number of reports of suspected adverse events in animals, Fewer reports of human adverse events to veterinary medicines, Notable increase in reports relating to products used for treating canine epilepsy. These are some of the results from the surveillance work carried out by the pharmacovigilance unit at the Veterinary Medicines Directorate (VMD), as discussed by Giles Davis and colleagues from the VMD. PMID- 25556134 TI - Focus on: human adverse events to companion animal spot-ons and sprays. AB - Recently, the Veterinary Products Committee has taken great interest in the number of human adverse events reported following the use of companion animal products that are applied topically to prevent and treat parasite infestations. One particular question it has is whether the legal category of some of these products means that current point of sale advice is insufficient to influence pet owner behaviour in preventing these incidents. This article by the Veterinary Medicines Directorate (VMD) seeks to respond to these concerns, and to remind veterinary professionals of their responsibility to inform clients how to use the products supplied to them in a manner that is safe, not only for their pets, but also for themselves. PMID- 25556135 TI - Palatal dysfunction in horses: where next? PMID- 25556136 TI - Wearing hard hats around horses. PMID- 25556137 TI - Mind matters initiative. PMID- 25556145 TI - Debunking the myths around expert witnesses. AB - The expert witness is a well known legal role, which conjures up images of a glowering judge and fierce cross-examination by a Rumpole of the Bailey-style barrister. Nick Deal is a barrister who works for Bond Solon, a company that provides training for expert witnesses. Here, he considers some of the points raised during a course for pathologists at the Royal Veterinary College. PMID- 25556146 TI - Diary of a parliamentary intern. AB - Hannah Jordan, parliamentary intern to Lord Trees, reflects on a year in which she feels veterinary interests have been well represented in Parliament. PMID- 25556147 TI - Light protection of chemotherapy drugs for infusion. AB - Specific chemotherapy drugs which require to be delivered by continuous infusion over time can have their effectiveness impaired by exposure to optical radiation. Mechanisms and processes of drug preparation and patient administration associated with light sensitive drugs were monitored within a Chemotherapy Unit. Levels of ambient light at locations of drug preparation/administration and levels of protection afforded by optical filter elements such as infusion lines were determined using a double grating Bentham Dmc150 spectroradiometer. Models of light exposure were developed for separate components of drug preparation and infusion delivery systems where the latter included the fluid bag with protective light cover, drip chamber and giving set line. In addition, the attenuation coefficient of Dacarbazine at the concentration typically used in patient treatments was determined using specially manufactured measurement cells. The relative contributions to light absorption of the drug bag, drip chamber and patient line were identified for specific types of giving sets, spectral content/intensity of light exposure and specific drug light absorption profiles. This indicated significant differences in the level of light protection afforded by specific giving sets and either single or double layer protection of the drug bag reservoir. It is not clear, however, if these variations could lead to significant differences of levels of drug de-activation and/or creation of undesirable photo-products such as in the case of Dacarbazine. Such techniques, however, provide a means of identifying how light exposure can be maintained at levels as low as reasonably possible as a precautionary measure. PMID- 25556148 TI - Restoration of parathyroid function after change of phosphate binder from calcium carbonate to lanthanum carbonate in hemodialysis patients with suppressed serum parathyroid hormone. AB - Control of phosphate is the most critical in the treatment of chronic kidney disease with mineral and bone disorder (CKD-MBD). Because calcium-containing phosphate binder to CKD patients is known to induce adynamic bone disease with ectopic calcification by increasing calcium load, we examined the effect of lanthanum carbonate (LaC), a non-calcium containing phosphate binder, to restore bone turnover in 27 hemodialysis patients with suppressed parathyroid function (serum intact parathyroid hormone [iPTH] ? 150 pg/mL). At the initiation of LaC administration, the dose of calcium-containing phosphate binder calcium carbonate (CaC) was withdrawn or reduced based on serum phosphate. After initiation of LaC administration, serum calcium and phosphate decreased significantly by 4 weeks, whereas whole PTH and iPTH increased. A significant and positive correlation between decreases of serum calcium, but not phosphate, with increases of whole PTH and iPTH, suggested that the decline in serum calcium with reduction of calcium load by LaC might increase parathyroid function. Serum bone resorption markers, such as serum tartrate-resistant acid phosphatase 5b, and N-telopeptide of type I collagen increased significantly by 4 weeks after LaC administration, which was followed by increases of serum bone formation markers including serum bone alkaline phosphatase, intact procollagen N-propeptide, and osteocalcin. Therefore, it was suggested that LaC attenuated CaC-induced suppression of parathyroid function and bone turnover by decreasing calcium load. In conclusion, replacement of CaC with LaC, either partially or totally, could increase parathyroid function and resultant bone turnover in hemodialysis patients with serum iPTH ? 150 pg/mL. PMID- 25556149 TI - Role of uremic toxins in erythropoiesis-stimulating agent resistance in chronic kidney disease and dialysis patients. AB - Patients with advanced chronic kidney disease are exposed to uremic toxins. In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. Indoxyl sulfate (IS) increases oxygen consumption in tubules, aggravating hypoxia of the kidney, and progression of the kidney disease. IS also induces endoplasmic reticulum stress and thereby contributes the progression of cellular damages in tubular epithelial cells. Hypoxia-inducible factor (HIF) is a master transcriptional regulator of adaptive responses against hypoxia and regulates expression of erythropoietin (EPO). IS suppresses EPO expression via HIF-dependent and HIF-independent manner. IS impedes the recruitment of transcriptional coactivators to HIF via upregulation of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 through a mechanism of posttranscriptional messenger RNA stabilization. Furthermore, IS induces activating transcription factor 4 via endoplasmic reticulum stress, decreasing EPO expression. Although erythropoiesis-stimulating agent (ESA) resistance is generally defined as lack of responses to exogenous ESA administration, suppression of endogenous production of EPO under uremic conditions may aggravate ESA resistance. Uremia is associated with increased formation of advanced glycation end products (AGE). Studies of transgenic rats overexpressing glyoxalse 1 (GLO1), which detoxifies precursors of advanced glycation end products, demonstrated that glycative stress causes renal senescence and vascular endothelial dysfunction. Glycative stress also suppresses HIF activation making the kidney susceptible to hypoxia as a final common pathway to end-stage kidney disease. PMID- 25556150 TI - Rac1 promotes diethylnitrosamine (DEN)-induced formation of liver tumors. AB - To elucidate the function of the Ras-homologous GTPase Rac1 in hepatocarcinogenesis induced by diethylnitrosamine (DEN), mice lacking hepatic Rac1 expression were treated with DEN and compared to the wild-type (WT). Rac1 knock-out (KO) mice were found to have a lower tumor yield as compared to Rac1 proficient mice. The small-sized tumors formed in the absence of Rac1 lack an activated Ras/Raf/mitogen-activated protein kinase pathway, as indicated by the absence of p-ERK expression. Apparently, Rac1 is required for Ras-driven oncogenic pathways. Moreover, tumors in Rac1 deficient mice were glutamine synthase (GS) negative. They displayed a high number of p-H3-positive and cyclinB1 expressing cells, pointing to a defect in mitotic progression. To elucidate the influence of Rac1 on mechanisms of tumor initiation, acute DEN induced hepatic stress responses were monitored. Rac1 deficiency caused fairly complex, partially time-dependent, alterations in both basal and/or DEN-induced messenger RNA (mRNA) and protein levels of susceptibility-related genes. Basal protein expression of DNA repair factors Brca1 and DNA repair protein RAD51 homolog (Rad51) and the cell cycle regulatory factor p27 was enhanced in the absence of Rac1. Following DEN treatment, p21 mRNA and protein expression was stimulated independent of the Rac1 status. Lack of Rac1 increased mechanisms of the DNA damage response (DDR), as shown by elevated protein levels of p-ATR, p p53 and gammaH2AX 24h after DEN treatment. The data show that Rac1 is essential for DEN-stimulated hepatocarcinogenesis. We hypothesize that it promotes tumor initiation by counteracting the elimination of initiated cells and, moreover, alleviates the outgrowth of transformed cells. Hence, pharmacological targeting of Rac1 could be suitable for chemoprevention. PMID- 25556151 TI - Antitumor effects of hyaluronan inhibition in desmoid tumors. AB - Desmoid tumors (DTs) are rare, mesenchymal tumors that exhibit features of an abundant wound healing process. Previously, we showed that mesenchymal stem cells (MSCs) are constituents of DTs and may contribute to desmoid tumorigenesis via activities associated with wound healing. Hyaluronan (HA) is a long-charged chain of repeating glucuronate and N-acetylglucosamine disaccharides that is synthesized by HA synthases (HAS) and degraded by hyaluronidases (HYAL). HA is secreted into the extracellular matrix by injured stroma and is important for normal tissue repair and neoplastic progression. Here, we investigated the presence of HA in DTs and the antitumor effects of the HA inhibitor, 4 methylumbelliferone (4-MU), on DT-derived mesenchymal cells. By immunohistochemistry and enzyme-linked immunosorbent assay, we found abundant expression of HA in 29/30 DTs as well as >5-fold increased HA levels in DT derived cell lines relative to controls. Immunohistochemistry also demonstrated high expression of HAS2 in DTs, and quantitative PCR analysis showed increased HAS2 upregulation in frozen DTs and DT-derived cells. 4-MU treatment of DT derived cells significantly decreased proliferation as well as HA and HAS2 levels. Fluorescent immunohistochemistry showed that MSCs in DTs coexpressed HA, HAS2, HYAL2, as well as the major HA receptor CD44 and HA coreceptor TLR4. Taken together, our results suggest that paracrine regulation of HA signaling in DTs may contribute to MSC recruitment and tumor proliferation. Future studies investigating the role of HA in tumor-stroma crosstalk and inhibition of HA-MSC interactions as a novel therapeutic target in DTs and other solid tumors are warranted. PMID- 25556153 TI - Cerebral paragonimiasis: an unusual manifestation of a rare parasitic infection. AB - BACKGROUND: Paragonimiasis is a parasitic disease that typically produces a subacute to chronic inflammatory disease of the lung. Although rare in the United States, paragonimiasis is sporadically observed in the immigrant population. Rarely, paragonimiasis can affect the nervous system. This infection is even more unusual in the pediatric population, and therefore can be challenging to diagnose. PATIENTS: Here we present a child with cerebral paragonimiasis. She presented with new onset seizures in the setting of a febrile illness. Magnetic resonance imaging of the brain with contrast revealed a ring-enhancing lesion within the right frontal lobe and a second lesion in the left parietal lobe extending from the cortex to the centrum semiovale. Extensive evaluation including stool ova and parasite analysis confirmed the diagnosis of Paragonimus westermani. She was treated with praziquantel and prednisone and improved both clinically and radiographically. CONCLUSIONS: Cerebral paragonimiasis is diagnosable and treatable and therefore is important to consider in the differential of immigrants presenting with cavitary lung lesions and central nervous system findings. PMID- 25556152 TI - Medical therapies in pituitary adenomas: Current rationale for the use and future perspectives. AB - Pituitary adenomas (PA) represent in the majority of cases, benign tumors whose treatment currently associate surgery, medical therapies and radiotherapy in a multidisciplinary approach. While trans-sphenoidal surgery remains, except for prolactin-secreting adenomas, the first-line treatment of PA, it can considerably be hampered by the existence of an invasive and/or aggressive tumor for which medical therapies are often requested. In this review, we extensively discuss, both at molecular and clinical levels, the medical therapies currently used and in development in the different phenotypes of pituitary adenomas. PMID- 25556154 TI - Answer to the Letter to the Editor of H. Sarman et al. concerning "the prevalence of depressive symptoms before and after surgery and its association with disability in patients undergoing lumbar spinal fusion" by M. Wahlman et al.; Eur Spine J (2014) 23:129-134. PMID- 25556155 TI - The Michel Benoist and Robert Mulholland yearly European Spine Journal Review: a survey of the "surgical research" articles in the European Spine Journal 2014. AB - This is a review of some 50 papers published in the European Spine Journal in the year 2014. They are selected on the basis that the author felt they were significant contributions to the spinal literature in that year. A brief precis is provided of each paper, and each is accompanied by a short discussion explaining its importance and relevance. PMID- 25556156 TI - Feasibility study of dual-task-managing training to improve gait performance of older adults. AB - INTRODUCTION: Dual task (DT) training is becoming prominent in fall prevention. However, DT training should include task-managing strategies like task switching or task prioritization to be beneficial to improve gait performance under DT conditions. The aim of this pilot study was to evaluate the effect of a task managing training on gait stability. METHODS: A DT training (12 sessions; 60 min each; 12 weeks) was compared to a non-training control group within a RCT (38 independent living participants; 72.7 +/- 4.7 years). Single Task (ST) and DT walking (visual verbal Stroop task) were measured on a treadmill (FDM-T, 3.5 km/h, 100 HZ). Gait parameters like step length, step width, gait line, maximum forces and gait variability were compared. RESULTS: The training group improved their gait performance under ST and DT conditions as revealed by significant group * time interaction effects. DISCUSSION AND CONCLUSIONS: The training successfully improved gait performance and therefore might be a promising approach to prevent falls. Additional fall prevention studies should focus on motor-cognitive performance and reinforce outcomes of task managing strategies. PMID- 25556157 TI - Effect of triple antibiotic paste with or without ethylenediaminetetraacetic acid on surface loss and surface roughness of radicular dentine. AB - This study aimed to compare the effect of two concentrations of triple antibiotic paste (TAP) with or without ethylenediaminetetraacetic acid (EDTA) on surface loss and surface roughness of radicular dentine. Human radicular dentine specimens were randomized into six experimental groups (n = 16 per group). The first and second groups were treated with 1,000 mg/mL or 1 mg/mL of TAP for 4 weeks. The third and fourth groups were treated with 1,000 mg/mL or 1 mg/mL of TAP for 4 weeks followed by 17 % EDTA for 5 min. The fifth group was treated with 17 % EDTA for 5 min and the sixth group received no treatment (control). Dentine surface loss and surface roughness were quantified after various treatments using optical and contact profilometry, respectively. One-way ANOVA followed by Fisher's protected least significant differences was used for statistical analyses. All treatment groups showed significantly higher surface loss compared to the untreated dentine. Dentine treated with 1,000 mg/mL had significant increase in surface loss and surface roughness compared to dentine treated with 1 mg/mL of TAP. The use of EDTA after both concentrations of TAP did not have significant additive effect on surface loss and surface roughness of dentine. The clinically used concentration of TAP (1,000 mg/mL) caused significantly higher surface loss and surface roughness of radicular dentine compared to the use of 1 mg/mL of TAP. Furthermore, the substantial amount of dentine surface loss and surface roughness detected in the current study may be attributed to TAP rather than EDTA. PMID- 25556158 TI - [Position of Interdisciplinary Spanish Committee for Cardiovascular Prevention about dyslipemia treatment guidelines]. PMID- 25556160 TI - Topochemical and morphological characterization of wood cell wall treated with the ionic liquid, 1-ethylpyridinium bromide. AB - MAIN CONCLUSION : [EtPy][Br] is more reactive toward lignin than toward the PSs in wood cell walls, and [EtPy][Br] treatment results in inhomogenous changes to the cell wall's ultrastructural and chemical components. The effects of the ionic liquid 1-ethylpyridinium bromide ([EtPy][Br]), which prefers to react with lignin rather than cellulose on the wood cell walls of Japanese cedar (Cryptomeria japonica), were investigated from a morphology and topochemistry point of view. The [EtPy][Br] treatment induced cell wall swelling, the elimination of warts, and the formation of countless pores in the tracheids. However, many of the pit membranes and the cellulose crystalline structure remained unchanged. Raman microscopic analyses revealed that chemical changes in the cell walls were different for different layers and that the lignin in the compound middle lamella and the cell corner resists interaction with [EtPy][Br]. Additionally, the interaction of [EtPy][Br] with the wood cell wall is different to that of other types of ionic liquid. PMID- 25556159 TI - Early etiology of Alzheimer's disease: tipping the balance toward autophagy or endosomal dysfunction? AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly. This brain neuropathology is characterized by a progressive synaptic dysfunction and neuronal loss, which lead to decline in memory and other cognitive functions. Histopathologically, AD manifests via synaptic abnormalities, neuronal degeneration as well as the deposition of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. While the exact pathogenic contribution of these two AD hallmarks and their abundant constituents [aggregation-prone amyloid beta (Abeta) peptide species and hyperphosphorylated tau protein, respectively] remain debated, a growing body of evidence suggests that their development may be paralleled or even preceded by the alterations/dysfunctions in the endolysosomal and the autophagic system. In AD-affected neurons, abnormalities in these cellular pathways are readily observed already at early stages of disease development, and even though many studies agree that defective lysosomal degradation may relate to or even underlie some of these deficits, specific upstream molecular defects are still deliberated. In this review we summarize various pathogenic events that may lead to these cellular abnormalities, in light of our current understanding of molecular mechanisms that govern AD progression. In addition, we also highlight the increasing evidence supporting mutual functional dependence of the endolysosomal trafficking and autophagy, in particular focusing on those molecules and processes which may be of significance to AD. PMID- 25556161 TI - Glutamate presynaptic vesicular transporter and postsynaptic receptor levels correlate with spatial memory status in aging rat models. AB - In humans, memory capacities are generally affected with aging, even without any reported neurologic disorders. The mechanisms behind cognitive decline are not well understood. We studied here whether postsynaptic glutamate receptor and presynaptic vesicular glutamate transporters (VGLUTs) levels may change in the course of aging and be related to cognitive abilities using various age-impaired (AI) or age-unimpaired rat strains. Twenty-four-month-old Long-Evans (LE) rats with intact spatial memory maintained postsynaptic ionotropic glutamate receptor levels in the hippocampal-adjacent cortex similar to those of young animals. In contrast, AI rats showed significantly reduced expression of ionotropic glutamate receptor GluR2, NR2A and NR2B subunits. In AI LE rats, VGLUT1 and VGLUT2 levels were increased and negatively correlated with receptor levels as shown by principal component analysis and correlation matrices. We also investigated whether glutamatergic receptors and VGLUT levels were altered in the obesity resistant LOU/C/Jall (LOU) rat strain which is characterized by intact memory despite aging. No difference was observed between 24-month-old LOU rats and their young counterparts. Taken together, the unaltered spatial memory performance of 24-month-old age-unimpaired LE and LOU rats suggests that intact coordination of the presynaptic and postsynaptic hippocampal-adjacent cortex glutamatergic networks may be important for successful cognitive aging. Accordingly, altered expression of presynaptic and postsynaptic glutamatergic components, such as in AI LE rats, could be considered a marker of age-related cognitive deficits. PMID- 25556163 TI - Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib. AB - Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive non small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable. PMID- 25556162 TI - Reduction of beta-amyloid and gamma-secretase by calorie restriction in female Tg2576 mice. AB - Research indicates that female risk of developing Alzheimer's disease (AD) is greater than that of males. Moderate reduction of calorie intake, known as calorie restriction (CR), reduces pathology in AD mouse models and is a potentially translatable prevention measure for individuals at-risk for AD, as well as an important tool for understanding how the brain endogenously attenuates age-related pathology. Whether sex influences the response to CR remains unknown. In this study, we assessed the effect of CR on beta-amyloid peptide (Abeta) pathology and hippocampal CA1 neuron specific gene expression in the Tg2576 mouse model of cerebral amyloidosis. Relative to ad libitum (AL) feeding, CR feeding significantly reduced hippocampal Abeta burden in 15-month-old female, but not age-matched male, Tg2576 mice. Sustained CR also significantly reduced expression of presenilin enhancer 2 (Psenen) and presenilin 1, components of the gamma secretase complex, in Tg2576 females. These results indicate that long-term CR significantly reduces age-dependent female Tg2576 Abeta pathology, which is likely to involve CR-mediated reductions in gamma-secretase-dependent amyloid precursor protein (APP) metabolism. PMID- 25556164 TI - Slug signaling is up-regulated by CCL21/CCR7 [corrected] to induce EMT in human chondrosarcoma. AB - In recent decades, the CXC chemokine receptor 7 (CCR7) [corrected] and its ligand CCL21 have been extensively reported to be associated with tumorigenesis. Meanwhile, Slug signaling induces the epithelial-mesenchymal transition (EMT) process in chondrosarcoma development. In the present study, we explored the functions of CCL21/CCR7 [corrected] in Slug-mediated EMT in the chondrosarcoma. We analyzed protein expression of CCR7 [corrected] and Slug in human chondrosarcoma samples. Effects of CCR7 [corrected] on chondrosarcoma cells were assessed by in vitro assays. Additionally, CCR7 [corrected] pathways were further investigated by pharmacological and genetic approaches. We found that the altered CCR7 [corrected] (81.7 %) and Slug (85.0 %) expression in human chondrosarcoma tissues were significantly associated with grade, recurrence, and 5-year overall survival. According to in vitro assays, CCL21 stimulation induced the expression of phosph-ERK, phosph-AKT, Slug and N-cadherin in SW1353 cells, while the expression of E-cadherin was down-regulated. Furthermore, Slug signaling modulated E- to N-cadherin switch, which was influenced by the kinase inhibitor PD98059 and LY294002. In addition, the genetic silencing of Slug inhibited the capacity of migration and invasion of SW1353 cells. In conclusion, CCL21/CCR7 [corrected] pathway activates ERK and PI3K/AKT signallings to up-regulate Slug pathway, leading to the occurrence of EMT process in human chondrosarcoma. This study lays a new foundation for molecule-targeted therapy of human chondrosarcoma. PMID- 25556165 TI - Assessing the Validity of Surrogate Outcomes for ESRD: A Meta-Analysis. AB - Validation of current and promising surrogate outcomes for ESRD in randomized controlled trials (RCTs) has been limited. We conducted a systematic review and meta-analysis of RCTs to further inform the ability of surrogate outcomes for ESRD to predict the efficacy of various interventions on ESRD. MEDLINE, EMBASE, and CENTRAL (from inception through September 2013) were searched. All RCTs in adults with proteinuria, diabetes, or CKD stages 1-4 or renal transplant recipients reporting >=10 ESRD events and a surrogate outcome (change in proteinuria or doubling of serum creatinine [DSCR]) for ESRD during a >=1-year follow-up were included. Two reviewers abstracted trial characteristics and outcome data independently. To assess the correlation between the surrogate outcomes and ESRD, we determined the treatment effect ratio (TER), defined as the ratio of the treatment effects on ESRD and the effects on the change in surrogate outcomes. TERs close to 1 indicate greater agreement between ESRD and the surrogate, and these ratios were pooled across interventions. We identified 27 trials (97,458 participants; 4187 participants with ESRD). Seven trials reported the effects on change in proteinuria and showed consistent effects for proteinuria and ESRD (TER, 0.82; 95% confidence interval, 0.59 to 1.16), with minimal heterogeneity. Twenty trials reported on DSCR. Treatment effects on DSCR were consistent with the effects on ESRD (TER, 0.98; 95% confidence interval, 0.85 to 1.14), with moderate heterogeneity. In conclusion, DSCR is generally a good surrogate for ESRD, whereas data on proteinuria were limited. Further assessment of the surrogacy of proteinuria using prospective RCTs is warranted. PMID- 25556166 TI - Kelch-Like Protein 2 Mediates Angiotensin II-With No Lysine 3 Signaling in the Regulation of Vascular Tonus. AB - Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. The AngII-induced decrease in KLHL2 was not caused by decreased transcription but increased autophagy-mediated degradation. Furthermore, knockdown of sequestosome 1/p62 prevented the decrease in KLHL2, suggesting that the mechanism of KLHL2 autophagy could be selective autophagy mediated by sequestosome 1/p62. Thus, we identified a novel component of signal transduction in AngII-induced vascular contraction that could be a promising drug target. PMID- 25556167 TI - Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism. AB - The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca(2+)i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca(2+)o). Similar pHo effects were observed for Ca(2+)o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca(2+)i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo. PMID- 25556169 TI - Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis. AB - Tamm-Horsfall protein (THP) is a glycoprotein uniquely expressed in the kidney. We recently showed an important role for THP in mediating tubular cross-talk in the outer medulla and in suppressing neutrophil infiltration after kidney injury. However, it remains unclear whether THP has a broader role in neutrophil homeostasis. In this study, we show that THP deficiency in mice increases the number of neutrophils, not only in the kidney but also in the circulation and in the liver, through enhanced granulopoiesis in the bone marrow. Using multiplex ELISA, we identified IL-17 as a key granulopoietic cytokine specifically upregulated in the kidneys but not in the liver of THP(-/-) mice. Indeed, neutralization of IL-17 in THP(-/-) mice completely reversed the systemic neutrophilia. Furthermore, IL-23 was also elevated in THP(-/-) kidneys. We performed real-time PCR on laser microdissected tubular segments and FACS-sorted renal immune cells and identified the S3 proximal segments, but not renal macrophages, as a major source of increased IL-23 synthesis. In conclusion, we show that THP deficiency stimulates proximal epithelial activation of the IL 23/IL-17 axis and systemic neutrophilia. Our findings provide evidence that the kidney epithelium in the outer medulla can regulate granulopoiesis. When this novel function is added to its known role in erythropoiesis, the kidney emerges as an important regulator of the hematopoietic system. PMID- 25556168 TI - Central Role of CD45RA- Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance. AB - The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with demethylated Foxp3 and a specific expansion of CD4(+) CD45RA(-) Foxp3(hi) memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4(+)CD45RA(-) Foxp3(hi) memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance. PMID- 25556171 TI - Begin at the Beginning to Prevent the End. PMID- 25556170 TI - Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms' Tumor 1 Target Genes in Podocyte Differentiation and Maintenance. AB - The Wilms' tumor suppressor gene 1 (WT1) encodes a zinc finger transcription factor. Mutation of WT1 in humans leads to Wilms' tumor, a pediatric kidney tumor, or other kidney diseases, such as Denys-Drash and Frasier syndromes. We showed previously that inactivation of WT1 in podocytes of adult mice results in proteinuria, foot process effacement, and glomerulosclerosis. However, the WT1 dependent transcriptional network regulating podocyte development and maintenance in vivo remains unknown. Here, we performed chromatin immunoprecipitation followed by high-throughput sequencing with glomeruli from wild-type mice. Additionally, we performed a cDNA microarray screen on an inducible podocyte specific WT1 knockout mouse model. By integration of cistromic and transcriptomic analyses, we identified the WT1 targetome in mature podocytes. To further analyze the function and targets of WT1 in podocyte maturation, we used an Nphs2-Cre model, in which WT1 is deleted during podocyte differentiation. These mice display anuria and kidney hemorrhage and die within 24 hours after birth. To address the evolutionary conservation of WT1 targets, we performed functional assays using zebrafish as a model and identified Nphs2, Mafb, and Magi2 as novel WT1 target genes required for podocyte development. Our data also show that both Mafb and Magi2 are required for normal development of the embryonic zebrafish kidney. Collectively, our work provides insights into the transcriptional networks controlled by WT1 and identifies novel WT1 target genes that mediate the function of WT1 in podocyte differentiation and maintenance. PMID- 25556174 TI - A new editor-in-chief for Nicotine & Tobacco Research. PMID- 25556172 TI - IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury. AB - IL-25 is an important immune regulator that can promote Th2 immune response dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL 25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL 25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPP(type2)) cells in kidney. IL 25-responsive ILC2 and MPP(type2) cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPP(type2) cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPP(type2) cells regulate macrophage phenotype in kidney and prevent renal IRI. PMID- 25556179 TI - Children whose parents attempted suicide are at raised risk of similar behaviour, study finds. PMID- 25556173 TI - Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts. AB - Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria. PMID- 25556180 TI - Max Birnstiel 1933-2014: Gene pioneer. PMID- 25556182 TI - Identification of pluripotent cells in bovine uterus: in situ and in vitro studies. AB - The aim of this study was to identify uterine pluripotent cells both in bovine uterine tissues as well in epithelial, stromal, and myometrial uterine cell populations. Moreover, the relationship of pluripotent markers expression with age and the uterine horn side was considered. Uterine tissue was collected from ipsilateral and contralateral horns (days 8-10 of the estrous cycle). Immunohistostaining for C-KIT, OCT3/4, NANOG, and SOX2 in uterine tissue was determined. mRNA expression of C-KIT, OCT3/4, NANOG and SOX2 was evaluated in uterine tissue relative to the age of the cow and uterine horn side. Gene and protein expression of these markers in the uterine luminal epithelial, stromal, and myometrial cells was evaluated by real-time PCR and western blotting respectively. The expression of pluripotent cell markers OCT3/4, NANOG, and SOX2 was identified by flow cytometry assay in epithelial, stromal, and myometrial cells. Multilineage differentiation of the bovine uterine cells was performed. mRNA expression of OCT3/4, NANOG, and SOX2 in uterine tissue was higher in the ipsilateral horn than in the contralateral horn. Flow cytometry assay revealed positive fluorescence for OCT3/4, NANOG, and SOX2 in all uterine cell types. Results showed the age-dependent expression of pluripotent markers in uterine tissue. Beside, the different expression of pluripotent cells in each horn of uterus suggests the influence of ovarian hormones on these characteristics. The highest mRNA and protein expression for pluripotent markers was observed in stromal cells among uterine cells, which indicates this population of cells as the main site of pluripotent cells in the cow uterus. PMID- 25556181 TI - Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. AB - Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2 weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (P<0.0001), were associated with higher IGF1 levels (P=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (P<0.0001). Acromegalic men tended to be younger at diagnosis than women (P=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (P<0.0001), whereas in women optic chiasm compression of macroadenomas occurred more often (P=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies. PMID- 25556183 TI - Role of Tec1 in the development, architecture, and integrity of sexual biofilms of Candida albicans. AB - MTL-homozygous ( A: / A: or alpha/alpha) white cells form a complex sexual biofilm that exhibits the same architecture as that of MTL-heterozygous ( A: /alpha) pathogenic biofilms. However, the former is regulated by the mitogen activated protein (MAP) kinase pathway, while the latter is regulated by the Ras1/cyclic AMP (cAMP) pathway. We previously demonstrated that in the formation of an MTL-homozygous, mature (48 h) sexual biofilm in RPMI 1640 medium, the MAP kinase pathway targets Tec1 rather than Cph1, the latter of which is the target of the same pathway, but for the opaque cell mating response. Here we continued our analysis of the role of Tec1 by comparing the effects of deleting TEC1 on initial adhesion to silicone elastomer, high-resolution confocal microscopy assessments of the stages and cellular phenotypes during the 48 h of biofilm development, human white cell penetration, and biofilm fragility. We show that although Tec1 plays only a minor role in initial adhesion to the silicone elastomer, it does play a major role in the growth of the basal yeast cell polylayer, vertical extension of hyphae and matrix deposition in the upper portion of the biofilm, final biofilm thickness, penetrability of human white blood cells, and final biofilm integrity (i.e., resistance to fluid flow). These results provide a more detailed description of normal biofilm development and architecture and confirm the central role played by the transcription factor Tec1 in the biofilm model employed here. PMID- 25556184 TI - Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation. AB - Several studies have recently identified strong epigenetic signals related to tobacco smoking. However, an aspect that did not receive much attention is the evolution of epigenetic changes with time since smoking cessation. We conducted a series of epigenome-wide association studies to capture the dynamics of smoking induced epigenetic changes after smoking cessation, using genome-wide methylation profiles obtained from blood samples in 745 women from 2 European populations. Two distinct classes of CpG sites were identified: sites whose methylation reverts to levels typical of never smokers within decades after smoking cessation, and sites remaining differentially methylated, even more than 35 years after smoking cessation. Our results suggest that the dynamics of methylation changes following smoking cessation are driven by a differential and site specific magnitude of the smoking-induced alterations (with persistent sites being most affected) irrespective of the intensity and duration of smoking. Analyses of the link between methylation and expression levels revealed that methylation predominantly and remotely down-regulates gene expression. Among genes whose expression was associated with our candidate CpG sites, LRRN3 appeared to be particularly interesting as it was one of the few genes whose methylation and expression were directly associated, and the only gene in which both methylation and gene expression were found associated with smoking. Our study highlights persistent epigenetic markers of smoking, which can potentially be detected decades after cessation. Such historical signatures are promising biomarkers to refine individual risk profiling of smoking-induced chronic disease such as lung cancer. PMID- 25556185 TI - Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. AB - Functional defects of the mitochondrial translation machinery, as a result of mutations in nuclear-encoded genes, have been associated with combined oxidative phosphorylation (OXPHOS) deficiencies. We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver. One of the siblings had a more severe phenotype showing progressive hepatic and renal failure. Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings. MRPS7 is a 12S ribosomal RNA-binding subunit of the small mitochondrial ribosomal subunit, and is required for the assembly of the small ribosomal subunit. Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts. Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function. Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7. Our data demonstrate the pathogenicity of the identified MRPS7 mutation as a novel cause of mitochondrial RC dysfunction, congenital sensorineural deafness and progressive hepatic and renal failure. PMID- 25556187 TI - Ultrasonography of Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (MADSAM). PMID- 25556186 TI - TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome. AB - T-box transcription factor TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS, DiGeorge syndrome/Velo-cardio-facial syndrome), whose phenotypes include craniofacial malformations such as dental defects and cleft palate. In this study, Tbx1 was conditionally deleted or over-expressed in the oral and dental epithelium to establish its role in odontogenesis and craniofacial developmental. Tbx1 lineage tracing experiments demonstrated a specific region of Tbx1-positive cells in the labial cervical loop (LaCL, stem cell niche). We found that Tbx1 conditional knockout (Tbx1(cKO)) mice featured microdontia, which coincides with decreased stem cell proliferation in the LaCL of Tbx1(cKO) mice. In contrast, Tbx1 over-expression increased dental epithelial progenitor cells in the LaCL. Furthermore, microRNA-96 (miR-96) repressed Tbx1 expression and Tbx1 repressed miR-96 expression, suggesting that miR-96 and Tbx1 work in a regulatory loop to maintain the correct levels of Tbx1. Cleft palate was observed in both conditional knockout and over-expression mice, consistent with the craniofacial/tooth defects associated with TBX1 deletion and the gene duplication that leads to 22q11.2DS. The biochemical analyses of TBX1 human mutations demonstrate functional differences in their transcriptional regulation of miR-96 and co-regulation of PITX2 activity. TBX1 interacts with PITX2 to negatively regulate PITX2 transcriptional activity and the TBX1 N-terminus is required for its repressive activity. Overall, our results indicate that Tbx1 regulates the proliferation of dental progenitor cells and craniofacial development through miR-96-5p and PITX2. Together, these data suggest a new molecular mechanism controlling pathogenesis of dental anomalies in human 22q11.2DS. PMID- 25556188 TI - Microbial production of aliphatic (S)-epoxyalkanes by using Rhodococcus sp. strain ST-10 styrene monooxygenase expressed in organic-solvent-tolerant Kocuria rhizophila DC2201. AB - We describe the development of biocatalysis for producing optically pure straight chain (S)-epoxyalkanes using styrene monooxygenase of Rhodococcus sp. strain ST 10 (RhSMO). RhSMO was expressed in the organic solvent-tolerant microorganism Kocuria rhizophila DC2201, and the bioconversion reaction was performed in an organic solvent-water biphasic reaction system. The biocatalytic process enantioselectively converted linear terminal alkenes to their corresponding (S) epoxyalkanes using glucose and molecular oxygen. When 1-heptene and 6-chloro-1 hexene were used as substrates (400 mM) under optimized conditions, 88.3 mM (S) 1,2-epoxyheptane and 246.5 mM (S)-1,2-epoxy-6-chlorohexane, respectively, accumulated in the organic phase with good enantiomeric excess (ee; 84.2 and 95.5%). The biocatalysis showed broad substrate specificity toward various aliphatic alkenes, including functionalized and unfunctionalized alkenes, with good to excellent ee. Here, we demonstrate that this biocatalytic system is environmentally friendly and useful for producing various enantiopure (S) epoxyalkanes. PMID- 25556189 TI - Environmental surveillance of poliovirus in sewage water around the introduction period for inactivated polio vaccine in Japan. AB - Environmental virus surveillance was conducted at two independent sewage plants from urban and rural areas in the northern prefecture of the Kyushu district, Japan, to trace polioviruses (PVs) within communities. Consequently, 83 PVs were isolated over a 34-month period from April 2010 to January 2013. The frequency of PV isolation at the urban plant was 1.5 times higher than that at the rural plant. Molecular sequence analysis of the viral VP1 gene identified all three serotypes among the PV isolates, with the most prevalent serotype being type 2 (46%). Nearly all poliovirus isolates exhibited more than one nucleotide mutation from the Sabin vaccine strains. During this study, inactivated poliovirus vaccine (IPV) was introduced for routine immunization on 1 September 2012, replacing the live oral poliovirus vaccine (OPV). Interestingly, the frequency of PV isolation from sewage waters declined before OPV cessation at both sites. Our study highlights the importance of environmental surveillance for the detection of the excretion of PVs from an OPV-immunized population in a highly sensitive manner, during the OPV-to-IPV transition period. PMID- 25556190 TI - Enhancing the secretion efficiency and thermostability of a Bacillus deramificans pullulanase mutant (D437H/D503Y) by N-terminal domain truncation. AB - Pullulanase (EC 3.2.1.41), an important enzyme in the production of starch syrup, catalyzes the hydrolysis of alpha-1,6 glycosidic bonds in complex carbohydrates. A double mutant (DM; D437H/D503Y) form of Bacillus deramificans pullulanase was recently constructed to enhance the thermostability and catalytic efficiency of the enzyme (X. Duan, J. Chen, and J. Wu, Appl Environ Microbiol 79:4072-4077, 2013, http://dx.doi.org/10.1128/AEM.00457-13). In the present study, three N terminally truncated variants of this DM that lack the CBM41 domain (DM-T1), the CBM41 and X25 domains (DM-T2), or the CBM41, X25, and X45 domains (DM-T3) were constructed. Upon expression, DM-T3 existed as inclusion bodies, while 72.8 and 74.8% of the total pullulanase activities of DM-T1 and DM-T2, respectively, were secreted into the medium. These activities are 2.8- and 2.9-fold that of the DM enzyme, respectively. The specific activities of DM-T1 and DM-T2 were 380.0 * 10(8) and 449.3 * 10(8) U . mol(-1), respectively, which are 0.94- and 1.11-fold that of the DM enzyme. DM-T1 and DM-T2 retained 50% of their activity after incubation at 60 degrees C for 203 and 160 h, respectively, which are 1.7- and 1.3-fold that of the DM enzyme. Kinetic studies showed that the Km values of DM T1 and DM-T2 were 1.5- and 2.7-fold higher and the Kcat/Km values were 11 and 50% lower, respectively, than those of the DM enzyme. Furthermore, DM-T1 and DM-T2 produced d-glucose contents of 95.0 and 94.1%, respectively, in a starch saccharification reaction, which are essentially identical to that produced by the DM enzyme (95%). The enhanced secretion and improved thermostability of the truncation mutant enzymes make them more suitable than the DM enzyme for industrial processes. PMID- 25556191 TI - Acid-adapted strains of Escherichia coli K-12 obtained by experimental evolution. AB - Enteric bacteria encounter a wide range of pHs throughout the human intestinal tract. We conducted experimental evolution of Escherichia coli K-12 to isolate clones with increased fitness during growth under acidic conditions (pH 4.5 to 4.8). Twenty-four independent populations of E. coli K-12 W3110 were evolved in LBK medium (10 g/liter tryptone, 5 g/liter yeast extract, 7.45 g/liter KCl) buffered with homopiperazine-N,N'-bis-2-(ethanosulfonic acid) and malate at pH 4.8. At generation 730, the pH was decreased to 4.6 with HCl. By 2,000 generations, all populations had achieved higher endpoint growth than the ancestor at pH 4.6 but not at pH 7.0. All evolving populations showed a progressive loss of activity of lysine decarboxylase (CadA), a major acid stress enzyme. This finding suggests a surprising association between acid adaptation and moderation of an acid stress response. At generation 2,000, eight clones were isolated from four populations, and their genomes were sequenced. Each clone showed between three and eight missense mutations, including one in a subunit of the RNA polymerase holoenzyme (rpoB, rpoC, or rpoD). Missense mutations were found in adiY, the activator of the acid-inducible arginine decarboxylase (adiA), and in gcvP (glycine decarboxylase), a possible acid stress component. For tests of fitness relative to that of the ancestor, lacZ::kan was transduced into each strain. All acid-evolved clones showed a high fitness advantage at pH 4.6. With the cytoplasmic pH depressed by benzoate (at external pH 6.5), acid-evolved clones showed decreased fitness; thus, there was no adaptation to cytoplasmic pH depression. At pH 9.0, acid-evolved clones showed no fitness advantage. Thus, our acid-evolved clones showed a fitness increase specific to low external pH. PMID- 25556192 TI - Isolation and screening of thermophilic bacilli from compost for electrotransformation and fermentation: characterization of Bacillus smithii ET 138 as a new biocatalyst. AB - Thermophilic bacteria are regarded as attractive production organisms for cost efficient conversion of renewable resources to green chemicals, but their genetic accessibility is a major bottleneck in developing them into versatile platform organisms. In this study, we aimed to isolate thermophilic, facultatively anaerobic bacilli that are genetically accessible and have potential as platform organisms. From compost, we isolated 267 strains that produced acids from C5 and C6 sugars at temperatures of 55 degrees C or 65 degrees C. Subsequently, 44 strains that showed the highest production of acids were screened for genetic accessibility by electroporation. Two Geobacillus thermodenitrificans isolates and one Bacillus smithii isolate were found to be transformable with plasmid pNW33n. Of these, B. smithii ET 138 was the best-performing strain in laboratory scale fermentations and was capable of producing organic acids from glucose as well as from xylose. It is an acidotolerant strain able to produce organic acids until a lower limit of approximately pH 4.5. As genetic accessibility of B. smithii had not been described previously, six other B. smithii strains from the DSMZ culture collection were tested for electroporation efficiencies, and we found the type strain DSM 4216(T) and strain DSM 460 to be transformable. The transformation protocol for B. smithii isolate ET 138 was optimized to obtain approximately 5 * 10(3) colonies per MUg plasmid pNW33n. Genetic accessibility combined with robust acid production capacities on C5 and C6 sugars at a relatively broad pH range make B. smithii ET 138 an attractive biocatalyst for the production of lactic acid and potentially other green chemicals. PMID- 25556193 TI - Alginate lyases from alginate-degrading Vibrio splendidus 12B01 are endolytic. AB - Alginate lyases are enzymes that degrade alginate through beta-elimination of the glycosidic bond into smaller oligomers. We investigated the alginate lyases from Vibrio splendidus 12B01, a marine bacterioplankton species that can grow on alginate as its sole carbon source. We identified, purified, and characterized four polysaccharide lyase family 7 alginates lyases, AlyA, AlyB, AlyD, and AlyE, from V. splendidus 12B01. The four lyases were found to have optimal activity between pH 7.5 and 8.5 and at 20 to 25 degrees C, consistent with their use in a marine environment. AlyA, AlyB, AlyD, and AlyE were found to exhibit a turnover number (kcat) for alginate of 0.60 +/- 0.02 s(-1), 3.7 +/- 0.3 s(-1), 4.5 +/- 0.5 s(-1), and 7.1 +/- 0.2 s(-1), respectively. The Km values of AlyA, AlyB, AlyD, and AlyE toward alginate were 36 +/- 7 MUM, 22 +/- 5 MUM, 60 +/- 2 MUM, and 123 +/- 6 MUM, respectively. AlyA and AlyB were found principally to cleave the beta 1,4 bonds between beta-d-mannuronate and alpha-l-guluronate and subunits; AlyD and AlyE were found to principally cleave the alpha-1,4 bonds involving alpha-l guluronate subunits. The four alginate lyases degrade alginate into longer chains of oligomers. PMID- 25556194 TI - Non-O1/non-O139 Vibrio cholerae carrying multiple virulence factors and V. cholerae O1 in the Chesapeake Bay, Maryland. AB - Non-O1/non-O139 Vibrio cholerae inhabits estuarine and coastal waters globally, but its clinical significance has not been sufficiently investigated, despite the fact that it has been associated with septicemia and gastroenteritis. The emergence of virulent non-O1/non-O139 V. cholerae is consistent with the recognition of new pathogenic variants worldwide. Oyster, sediment, and water samples were collected during a vibrio surveillance program carried out from 2009 to 2012 in the Chesapeake Bay, Maryland. V. cholerae O1 was detected by a direct fluorescent-antibody (DFA) assay but was not successfully cultured, whereas 395 isolates of non-O1/non-O139 V. cholerae were confirmed by multiplex PCR and serology. Only a few of the non-O1/non-O139 V. cholerae isolates were resistant to ampicillin and/or penicillin. Most of the isolates were sensitive to all antibiotics tested, and 77 to 90% carried the El Tor variant hemolysin gene hlyAET, the actin cross-linking repeats in toxin gene rtxA, the hemagglutinin protease gene hap, and the type 6 secretion system. About 19 to 21% of the isolates carried the neuraminidase-encoding gene nanH and/or the heat-stable toxin (NAG-ST), and only 5% contained a type 3 secretion system. None of the non O1/non-O139 V. cholerae isolates contained Vibrio pathogenicity island-associated genes. However, ctxA, ace, or zot was present in nine isolates. Fifty-five different genotypes showed up to 12 virulence factors, independent of the source of isolation, and represent the first report of both antibiotic susceptibility and virulence associated with non-O1/non-O139 V. cholerae from the Chesapeake Bay. Since these results confirm the presence of potentially pathogenic non O1/non-O139 V. cholerae, monitoring for total V. cholerae, regardless of serotype, should be done within the context of public health. PMID- 25556195 TI - The association between immigrant generational status, child maltreatment history and intimate partner violence (IPV): evidence from a nationally representative survey. AB - PURPOSE: The extent to which immigrant-specific factors influence the intergenerational transmission of family violence is unknown. The objectives of this paper are to examine the associations between immigrant generational status (IGS), child maltreatment (CM), intimate partner violence (IPV) and acculturation (i.e., the extent to which an individual adopts the values, language and attitudes of a new culture). METHODS: The sample was drawn from wave two of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; n = 34,653), a nationally representative survey of United States (US) residents aged 20 years and older. Logistic regression was used to estimate the associations between IGS, CM history, IPV, and acculturation. RESULTS: Compared to 3rd generation (or later) respondents, 1st generation immigrants were less likely to report a history of sexual (AOR = 0.74, CI0.95 = 0.62, 0.90) and emotional abuse (AOR = 0.69, CI0.95 = 0.55, 0.87), but were more likely to report physical neglect (AOR = 1.30, CI0.95 = 1.11, 1.52). After adjusting for covariates, IGS was not associated with IPV among respondents with or without a CM history. Among those without a CM history, highly acculturated 1st generation immigrants (AOR = 1.07, CI0.95 = 1.01, 1.13) were more likely to report perpetrating IPV, with highly acculturated 3rd generation respondents having lower odds of reporting IPV perpetration (AOR = 0.93, CI0.95 = 0.88-1.00). CONCLUSION: IGS and acculturation are important factors in CM and IPV. Longitudinal studies are needed to clarify the influence of IGS, recency of immigration, acculturation and acculturative stress on the experiences and relationship between CM and IPV. PMID- 25556196 TI - Role of patient treatment beliefs and provider characteristics in establishing patient-provider relationships. AB - BACKGROUND: Positive patient-provider relationships have been associated with improved depression treatment outcomes. Little is known about how patient treatment beliefs influence patient-provider relationships, specifically treatment alliance and shared decision making in primary care (PC). OBJECTIVE: We evaluated the relationship between patient treatment beliefs and patient-provider relationships by gender, race and current depression. METHODS: We used a deductive parallel convergent mixed method design with cross-sectional data. Participants were 227 Black and White patients presenting with depression symptoms in PC settings. Individuals were randomized into either a quantitative survey (n = 198) or qualitative interview (n = 29) group. We used multiple ordinary least squares regression to evaluate the association between patient beliefs, as measured by the Treatment Beliefs Scale and the Medication Beliefs Scale, and treatment alliance or shared decision making. We concurrently conducted thematic analyses of qualitative semistructured interview data to explicate the nature of patient-provider relationships. RESULTS: We found that patients who believed their provider would respectfully facilitate depression treatment reported greater bond, openness and shared decision making with their provider. We also identified qualitative themes of physicians listening to, caring about and respecting patients. Empathy and emotive expression increased patient trust in PC providers as facilitators of depression treatment. CONCLUSIONS: This work systematically demonstrated what many providers anecdotally believe: PC environments in which individuals feel safe sharing psychological distress are essential to early identification and treatment of depression. Interprofessional skills-based training in attentiveness and active listening may influence the effectiveness of depression intervention. PMID- 25556197 TI - Intimate partner violence and ways of coping with stress: cross-sectional survey of female patients in Russian general practice. AB - BACKGROUND: Despite World Health Organization guidelines on health service responses to intimate partner violence (IPV) against women general practitioners (GPs) often overlook the problem. Training on IPV addresses GPs' barriers to asking women patients about abuse and responding appropriately. One of the barriers is stereotype of women as passive victims. Little is known about coping behaviour of women patients with a history of IPV. OBJECTIVES: The objectives are (i) to compare problem- and emotion-focused coping used by patients who have experienced IPV with those who have not; (ii) to examine whether greater coping resources (health, education, employment and income) would be associated with more problem-focused coping. METHODS: The Russian Ways of Coping Questionnaire was administered to every fifth woman who participated in a cross-sectional survey on IPV prevalence in 24 St Petersburg general practices. Linear regression was used (n = 159) to test associations between life-time IPV, coping resources and ways of coping. RESULTS: Mean problem-focused coping scores were 0.2-4.7 units higher in those patients who have experienced IPV compared with those who have not [95% confidence interval (CI): -4.2, 11.9; P = 0.16-0.92], while mean emotion-focused coping scores were 2.5-4.2 units higher (95% CI: -3.0, 11.0; P = 0.12-0.57). After adjustment for coping resources there was no evidence for an association between IPV and problem-focused coping. CONCLUSIONS: Patients who have experienced IPV use as much problem-focused and emotion-focused coping, as those patients who have not experienced IPV. These findings should be incorporated into training on IPV to address GPs' stereotypes towards patients who have experienced IPV. PMID- 25556200 TI - Voices from other lands. AB - Since the early 1990s, research in public understanding of science has significantly increased and become more systematic and academic. However, most of papers published by the main journals in the field have as origin the English speaking world of the United States, the United Kingdom, Canada, Australia and New Zealand: for example, in this very journal, PUS, two-thirds of the empirical material come from these countries. This paper aims both to call attention to unheard voices, and make space for new ones, from other parts of the world, aiming to open space for new voices. PMID- 25556198 TI - Effects of NMDA and GABA-A Receptor Antagonism on Auditory Steady-State Synchronization in Awake Behaving Rats. AB - BACKGROUND: The auditory steady-state response, which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human electroencephalogram studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia show a deficit in auditory steady-state response at 40 Hz, and therefore this may be a useful biomarker to study this disorder. METHODS: We used auditory steady-state response recordings from the primary auditory cortex, hippocampus, and vertex electroencephalogram sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimics auditory steady-state response abnormalities in schizophrenia. RESULTS: We found the most robust response to auditory stimuli in the primary auditory cortex, in line with previous studies suggesting this region is the primary generator of the auditory steady-state response in humans. Acute MK-801 (0.1mg/kg i.p.) increased primary auditory cortex intertrial coherence during auditory steady-state response at 20 and 40 Hz. Chronic MK-801 (21-day exposure at this daily dose) had no significant effect on 40-Hz auditory steady-state response. Furthermore, we found no effect of acute or chronic picrotoxin (a GABA-A antagonist) on intertrial coherence. CONCLUSIONS: Our data indicate that acute N-methyl-d-aspartate receptor antagonism increases synchronous activity in the primary auditory cortex in a frequency-specific manner, supporting the widely held view that acute N-methyl-d-aspartate antagonism augments gamma oscillations. Thus, rodent auditory steady-state response could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies. PMID- 25556199 TI - Alcohol Withdrawal-Induced Seizure Susceptibility is Associated with an Upregulation of CaV1.3 Channels in the Rat Inferior Colliculus. AB - BACKGROUND: We previously reported increased current density through L-type voltage-gated Ca(2+) (CaV1) channels in inferior colliculus (IC) neurons during alcohol withdrawal. However, the molecular correlate of this increased CaV1 current is currently unknown. METHODS: Rats received three daily doses of ethanol every 8 hours for 4 consecutive days; control rats received vehicle. The IC was dissected at various time intervals following alcohol withdrawal, and the mRNA and protein levels of the CaV1.3 and CaV1.2 alpha1 subunits were measured. In separate experiments, rats were tested for their susceptibility to alcohol withdrawal-induced seizures (AWS) 3, 24, and 48 hours after alcohol withdrawal. RESULTS: In the alcohol-treated group, AWS were observed 24 hours after withdrawal; no seizures were observed at 3 or 48 hours. No seizures were observed at any time in the control-treated rats. Compared to control-treated rats, the mRNA level of the CaV1.3 alpha1 subunit was increased 1.4-fold, 1.9-fold, and 1.3 fold at 3, 24, and 48 hours, respectively. In contrast, the mRNA level of the CaV1.2 alpha1 subunit increased 1.5-fold and 1.4-fold at 24 and 48 hours, respectively. At 24 hours, Western blot analyses revealed that the levels of the CaV1.3 and CaV1.2 alpha1 subunits increased by 52% and 32%, respectively, 24 hours after alcohol withdrawal. In contrast, the CaV1.2 and CaV1.3 alpha1 subunits were not altered at either 3 or 48 hours during alcohol withdrawal. CONCLUSIONS: Expression of the CaV1.3 alpha1 subunit increased in parallel with AWS development, suggesting that altered L-type CaV1.3 channel expression is an important feature of AWS pathogenesis. PMID- 25556202 TI - Open-angle glaucoma and paraoptic cyst: first description of a series of 11 patients. AB - We report 11 patients who were referred to our institution for severe open-angle glaucoma who had a paraoptic cyst on MR imaging. All cysts were extraoptic and retrolaminar; most were deforming the adjacent optic nerve. Cysts had a high signal on T2 and FLAIR sequences, and a variable signal on T1 and variable echogenicity, suggesting different proteinaceous content. Arterial vascularization of the optic nerve was normal. Cyst volumes were inversely correlated with the severity of glaucoma on the same eye (P < .01-.05, Spearman correlation coefficient). We hypothesized that such cysts may reflect a valve mechanism, which would allow preservation of the translamina cribrosa pressure and thus could preserve visual function. The rarity of this association, together with the frequent mass effect of the cyst on the optic nerve, stresses the necessity of long-term follow-up in these patients. PMID- 25556203 TI - Predictors of Multigland Disease in Primary Hyperparathyroidism: A Scoring System with 4D-CT Imaging and Biochemical Markers. AB - BACKGROUND AND PURPOSE: Multigland disease represents a challenging group of patients with primary hyperparathyroidism. Additional lesions may be missed on imaging because they are not considered or are too small to be seen. The aim of this is study was to identify 4D-CT imaging and biochemical predictors of multigland disease. MATERIALS AND METHODS: This was a retrospective study of 155 patients who underwent 4D-CT and successful surgery with a biochemical cure that compared patients with multigland and single-gland disease. Variables studied included the size of the largest lesion on 4D-CT, the number of lesions prospectively identified on 4D-CT, serum calcium levels, serum parathyroid hormone levels, and the Wisconsin Index (the product of serum calcium and parathyroid hormone levels). Imaging findings and the Wisconsin Index were used to calculate a composite multigland disease scoring system. We evaluated the predictive value of individual variables and the scoring system for multigland disease. RESULTS: Thirty-six patients with multigland disease were compared with 119 patients with single-gland disease. Patients with multigland disease had significantly lower Wisconsin Index scores, smaller lesion size, and a higher likelihood of having either multiple or zero lesions identified on 4D-CT (P <= .01). Size cutoff of <7 mm had 85% specificity for multigland disease, but including other variables in the composite multigland disease score improved the specificity. Scores of >=4, >=5, and 6 had specificities of 81%, 93%, and 98%, respectively. CONCLUSIONS: The composite multigland disease scoring system based on 4D-CT imaging findings and biochemical data can identify patients with a high likelihood of multigland disease. Communicating the suspicion for multigland disease in the radiology report could influence surgical decision-making, particularly when considering re-exploration in a previously operated neck or initial limited neck exploration. PMID- 25556205 TI - Association of superior oblique muscle volumes with the presence or absence of the trochlear nerve on high-resolution MR imaging in congenital superior oblique palsy. AB - BACKGROUND AND PURPOSE: Congenital superior oblique palsy is known to relate to trochlear nerve absence and a variable degree of superior oblique muscle hypoplasia. The purpose of this study was to determine whether superior oblique muscle volume predicts trochlear nerve absence in congenital superior oblique palsy. MATERIALS AND METHODS: A retrospective study of high-resolution MR imaging to evaluate the presence of the trochlear nerve and to measure superior oblique muscle areas and volumes with the image analysis tools of a PACS was performed in 128 consecutive patients with unilateral congenital superior oblique palsy and 34 age-matched healthy controls. RESULTS: Of the 128 patients with congenital superior oblique palsy, 88 had an ipsilateral trochlear nerve absence (absent group) and 40 had both trochlear nerves (present group). In patients with congenital superior oblique palsy, the paretic side superior oblique muscle volume was significantly smaller compared with the normal side only in the absent group (P < .001). The left and right side superior oblique muscle volumes were not significantly different in controls (P = .750), and the paretic and normal side superior oblique muscle volumes were not significantly different in the present group (P = .536). The cutoff value of the paretic/normal side superior oblique muscle volume ratio for diagnosing trochlear nerve absence was <=0.75 (sensitivity 98.9%, specificity 95.0%) in patients with congenital superior oblique palsy. CONCLUSIONS: The ratio of paretic/normal side superior oblique muscle area and volume has an excellent predictability in diagnosing trochlear nerve absence in congenital superior oblique palsy. PMID- 25556204 TI - Increased number of white matter lesions in patients with familial cerebral cavernous malformations. AB - BACKGROUND AND PURPOSE: Familial cerebral cavernous malformations, an autosomal dominant disorder, result in excess morbidity and mortality in affected patients. The disorder is most prevalent in the Southwest United States, where the affected families are most often carriers of the CCM1-KRIT1 Common Hispanic Mutation. The brain and spinal cord parenchyma in these individuals is usually affected by multiple cavernous malformations. Previous studies have shown abnormalities of endothelial cell junctions and the blood-brain barrier in cerebral cavernous malformations. Endothelial cell abnormalities have also been described in pathologic studies of white matter hyperintensities. We compared the prevalence of white matter hyperintensities in a population with known familial cerebral cavernous malformations. MATERIALS AND METHODS: We examined 191 subjects with familial cerebral cavernous malformations who were enrolled into an institutional review board-approved study. All carry the same Common Hispanic Mutation in the CCM1 gene. Each subject underwent 3T MR imaging, including gradient recalled echo, SWI, and FLAIR sequences. The number of cavernous malformations and the number of nonhemorrhagic white matter hyperintensities were counted. Subjects older than 60 years of age were excluded due to the high prevalence of white matter lesions in this population, and children younger than 6 were excluded due to potential sedation requirements. Logistic regression analysis was performed to determine the prevalence of abnormal white matter hyperintensities in those with familial cerebral cavernous malformations compared with healthy controls or those with sporadic cerebral cavernous malformation within the familial cerebral cavernous malformations group; it was also performed to evaluate the associations between abnormal white matter hyperintensities and age, sex, headaches, thyroid disease, diabetes, hypertension, hyperlipidemia, seizure history, or modified Rankin Scale score. RESULTS: Familial CCM1 carriers have a higher prevalence of abnormal white matter hyperintensities (15.4%) compared with both control populations (2.1% and 2.5%, respectively) (P < .05). Logistic regression showed no statistical association with sex, headaches, hyperlipidemia, hypertension, thyroid disease, seizure history, number of cerebral cavernous malformations, or modified Rankin Scale score among those with familial cerebral cavernous malformation. An expected correlation with age was shown. CONCLUSIONS: Familial CCM1 carriers have not only an increased number of cerebral cavernous malformations but also an increased number of white matter T2 hyperintensities, spatially distinct from cerebral cavernous malformations, which exceeded that of a healthy population. Clinical findings did not explain the association with abnormal white matter hyperintensities in the familial cerebral cavernous malformation population. To our knowledge, these relationships have not been previously reported. This finding suggests an additional manifestation of endothelial abnormalities in this population. PMID- 25556207 TI - DTB Select: 1 | January 2015. AB - Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned. We also include comments on, for example, the strengths of the information, whether it contains anomalies, ambiguities, apparent error or omissions, or whether or how it affects current practice. PMID- 25556206 TI - Increased arterial blood pressure and vascular remodeling in mice lacking salt inducible kinase 1 (SIK1). AB - RATIONALE: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. OBJECTIVE: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. METHODS AND RESULTS: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal- or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1(+/+) mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. CONCLUSIONS: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta1-signaling inhibition. PMID- 25556208 TI - Designing a Culturally Appropriate Visually Enhanced Low-Text Mobile Health App Promoting Physical Activity for Latinos: A Qualitative Study. AB - Rapid proliferation of smartphone ownership and use among Latinos offers a unique opportunity to employ innovative visually enhanced low-text (VELT) mobile health applications (mHealth app) to promote health behavior change for Latinos at risk for lifestyle-related diseases. Using focus groups and in-depth interviews with 16 promotores and 5 health care providers recruited from California clinics, this qualitative study explored perceptions of visuals for a VELT mHealth app promoting physical activity (PA) and limiting sedentary behavior (SB) for Latinos. In this Phase 1 study, participants endorsed visuals portraying PA guidelines and recommended visuals depicting family and socially oriented PA. Overall, participants supported a VELT mHealth app as an alternative to text based education. Findings will inform the future Phase 2 study development of a culturally appropriate VELT mHealth app to promote PA for Latinos, improve health literacy, and provide an alternative to traditional clinic text-based health education materials. PMID- 25556209 TI - Competition between frontoparietal control and default networks supports social working memory and empathy. AB - An extensive body of literature has indicated that there is increased activity in the frontoparietal control network (FPC) and decreased activity in the default mode network (DMN) during working memory (WM) tasks. The FPC and DMN operate in a competitive relationship during tasks requiring externally directed attention. However, the association between this FPC-DMN competition and performance in social WM tasks has rarely been reported in previous studies. To investigate this question, we measured FPC-DMN connectivity during resting state and two emotional face recognition WM tasks using the 2-back paradigm. Thirty-four individuals were instructed to perform the tasks based on either the expression [emotion (EMO)] or the identity (ID) of the same set of face stimuli. Consistent with previous studies, an increased anti-correlation between the FPC and DMN was observed during both tasks relative to the resting state. Specifically, this anti correlation during the EMO task was stronger than during the ID task, as the former has a higher social load. Intriguingly, individual differences in self reported empathy were significantly correlated with the FPC-DMN anti-correlation in the EMO task. These results indicate that the top-down signals from the FPC suppress the DMN to support social WM and empathy. PMID- 25556210 TI - Online processing of moral transgressions: ERP evidence for spontaneous evaluation. AB - Experimental studies using fictional moral dilemmas indicate that both automatic emotional processes and controlled cognitive processes contribute to moral judgments. However, not much is known about how people process socio-normative violations that are more common to their everyday life nor the time-course of these processes. Thus, we recorded participants' electrical brain activity while they were reading vignettes that either contained morally acceptable vs unacceptable information or text materials that contained information which was either consistent or inconsistent with their general world knowledge. A first event-related brain potential (ERP) positivity peaking at ~200 ms after critical word onset (P200) was larger when this word involved a socio-normative or knowledge-based violation. Subsequently, knowledge-inconsistent words triggered a larger centroparietal ERP negativity at ~320 ms (N400), indicating an influence on meaning construction. In contrast, a larger ERP positivity (larger late positivity), which also started at ~320 ms after critical word onset, was elicited by morally unacceptable compared with acceptable words. We take this ERP positivity to reflect an implicit evaluative (good-bad) categorization process that is engaged during the online processing of moral transgressions. PMID- 25556211 TI - Interactive effects of trait and state affect on top-down control of attention. AB - Few studies have investigated how attentional control is affected by transient affective states while taking individual differences in affective traits into consideration. In this study, participants completed a color-word Stroop task immediately after undergoing a positive, neutral or negative affective context manipulation (ACM). Behavioral performance was unaffected by any ACM considered in isolation. For individuals high in trait negative affect (NA), performance was impaired by the negative but not the positive or neutral ACM. Neuroimaging results indicate that activity in primarily top-down control regions of the brain (inferior frontal gyrus and dorsal anterior cingulate cortex) was suppressed in the presence of emotional arousal (both negative and positive ACMs). This effect appears to have been exacerbated or offset by co-occurring activity in other top down control regions (parietal) and emotion processing regions (orbitofrontal cortex, amygdala and nucleus accumbens) as a function of the valence of state affect (positive or negative) and trait affect (trait NA or trait PA). Neuroimaging results are consistent with behavioral findings. In combination, they indicate both additive and interactive influences of trait and state affect on top-down control of attention. PMID- 25556212 TI - Attachment style moderates partner presence effects on pain: a laser-evoked potentials study. AB - Social support is crucial for psychological and physical well-being. Yet, in experimental and clinical pain research, the presence of others has been found to both attenuate and intensify pain. To investigate the factors underlying these mixed effects, we administered noxious laser stimuli to 39 healthy women while their romantic partner was present or absent, and measured pain ratings and laser evoked potentials (LEPs) to assess the effects of partner presence on subjective pain experience and underlying neural processes. Further, we examined whether individual differences in adult attachment style (AAS), alone or in interaction with the partner's level of attentional focus (manipulated to be either on or away from the participant) might modulate these effects. We found that the effects of partner presence vs absence on pain-related measures depended on AAS but not partner attentional focus. The higher participants' attachment avoidance, the higher pain ratings and N2 and P2 local peak amplitudes were in the presence compared with the absence of the romantic partner. As LEPs are thought to reflect activity relating to the salience of events, our data suggest that partner presence may influence the perceived salience of events threatening the body, particularly in individuals who tend to mistrust others. PMID- 25556215 TI - Modifying effect of COMT gene polymorphism and a predictive role for proteomics analysis in children's intelligence in endemic fluorosis area in Tianjin, China. AB - Cumulative fluoride exposure has adverse influences on children's intelligence quotient (IQ). In addition, catechol-O-methyltransferase (COMT) gene Val158Met polymorphism (rs4680) is associated with cognitive performance. This study aimed to evaluate the associations of COMT polymorphism and alterations of protein profiles with children's intelligence in endemic fluorosis area. We recruited 180 schoolchildren (10-12 years old) from high fluoride exposure (1.40 mg/l) and control areas (0.63 mg/l) in Tianjin City, China. The children's IQ, fluoride contents in drinking water (W-F), serum (S-F), and urine (U-F); serum thyroid hormone levels, COMT Val158Met polymorphism, and plasma proteomic profiling were determined. Significant high levels of W-F, S-F, U-F, along with poor IQ scores were observed in the high fluoride exposure group compared with those in control (all P < 0.05). S-F and U-F were inversely related with IQ (r(s) = -0.47, P < 0.01; r(s) = -0.45, P = 0.002). Importantly, higher fluoride exposure was associated with steeper cognitive decline among children with the reference allele Val compared with those homozygous or heterozygous for the variant allele Met (95% CI, -16.80 to 2.55; P interaction < 0.01). Additionally, 5 up-regulated protein spots related to cell immunity and metabolism were detected in children with high fluoride exposure compared with the control. In conclusion, fluoride exposure was adversely associated with children's intelligence, whereas the COMT polymorphism may increase the susceptibility to the deficits in IQ due to fluoride exposure. Moreover, the proteomic analysis can provide certain basis for identifying the early biological markers of fluorosis among children. PMID- 25556216 TI - Effect of the ostreolysin A/pleurotolysin B pore-forming complex on neuroblastoma cell morphology and intracellular Ca2+ activity. AB - Ostreolysin A (OlyA) and pleurotolysin B (PlyB), isolated from edible oyster mushrooms, form a cytolytic complex (OlyA/PlyB) in membrane cells that causes respiratory arrest. This study evaluated the mechanisms underlying cytotoxic OlyA/PlyB activity in neuroblastoma NG108-15 cells. Confocal microscopy with morphometric analysis revealed that OlyA/PlyB increased the 3-dimensional projected area of differentiated cells. Iso-osmotic replacement of NaCl by sucrose or Na-isethionate prevented the cellular swelling. This suggests that formation of cellular edema requires the presence of Na(+) and/or Cl(-) in the extracellular space and may be related to an influx of Na(+) and/or a shift in Cl(-), which induce a marked influx of water that is ultimately responsible for cellular swelling. In addition, extracellular Ca(2+) moderately contributed to the swelling because benzamil (10 uM), a 3Na(+)/Ca(2+) exchange (NCX) inhibitor, and Ca(2+)-free medium partially prevented this response. Fluorometric measurements revealed that OlyA/PlyB, at approximately 15-fold higher concentrations, increased the intracellular Ca(2+) activity [Ca(2+)]i. This increase was dependent on the presence of Na(+) and Ca(2+) in the external medium and was sensitive to benzamil. It is thus likely that a switch in the NCX mode, associated with the de novo formation of non-selective ion pores by OlyA/PlyB in cellular plasma membranes, plays an important role in this effect. Overall, OlyA/PlyB affects neuroblastoma cell morphology and Ca(2+) homeostasis to influence the toxin-induced respiratory arrest. PMID- 25556214 TI - Sexual motivation is reflected by stimulus-dependent motor cortex excitability. AB - Sexual behavior involves motivational processes. Findings from both animal models and neuroimaging in humans suggest that the recruitment of neural motor networks is an integral part of the sexual response. However, no study so far has directly linked sexual motivation to physiologically measurable changes in cerebral motor systems in humans. Using transcranial magnetic stimulation in hetero- and homosexual men, we here show that sexual motivation modulates cortical excitability. More specifically, our results demonstrate that visual sexual stimuli corresponding with one's sexual orientation, compared with non corresponding visual sexual stimuli, increase the excitability of the motor cortex. The reflection of sexual motivation in motor cortex excitability provides evidence for motor preparation processes in sexual behavior in humans. Moreover, such interrelationship links theoretical models and previous neuroimaging findings of sexual behavior. PMID- 25556217 TI - The Correlation of Different Cotinine Levels With Questionnaire Results: A Comparative Study for Different Measurement Methods of the Adolescent Smoking Rate in Korea. AB - This study compares the results of the Korea National Health and Nutrition Examination Survey (Self-Reported; KNHANEs [SR]) survey with urine-cotinine concentration (UCC) and the official index issued by the Korea Youth Risk Behavior Web-based Survey (KYRBS). We established standard cutoffs of 20 ng/mL, 30 ng/mL, 50 ng/mL, and 100 ng/mL to compare the results of UCC testing with those of self-reporting methods. The KYRBS demonstrated an overall current smoking rate of 12.25%, while the KNHANEs measured an overall rate of 9.63%. The UCC20 reported the highest current smoking rate at 25.6% overall. Methods that detected a lower prevalence of current smoking, in declining order, were the UCC30, UCC50, UCC100, online survey, and the KNHANEs (SR). The results of this study show that online surveys on smoking administered to adolescents have fewer false responses compared with the KNHANEs (SR). However, compared with UCC testing, online surveys still significantly underreport adolescent smoking rates. PMID- 25556213 TI - Emotional and movement-related body postures modulate visual processing. AB - Human body postures convey useful information for understanding others' emotions and intentions. To investigate at which stage of visual processing emotional and movement-related information conveyed by bodies is discriminated, we examined event-related potentials elicited by laterally presented images of bodies with static postures and implied-motion body images with neutral, fearful or happy expressions. At the early stage of visual structural encoding (N190), we found a difference in the sensitivity of the two hemispheres to observed body postures. Specifically, the right hemisphere showed a N190 modulation both for the motion content (i.e. all the observed postures implying body movements elicited greater N190 amplitudes compared with static postures) and for the emotional content (i.e. fearful postures elicited the largest N190 amplitude), while the left hemisphere showed a modulation only for the motion content. In contrast, at a later stage of perceptual representation, reflecting selective attention to salient stimuli, an increased early posterior negativity was observed for fearful stimuli in both hemispheres, suggesting an enhanced processing of motivationally relevant stimuli. The observed modulations, both at the early stage of structural encoding and at the later processing stage, suggest the existence of a specialized perceptual mechanism tuned to emotion- and action-related information conveyed by human body postures. PMID- 25556218 TI - Rate of Utilization of Skilled Birth Attendant and the Influencing Factors in an Urban Myanmar Population. AB - A survey study aimed at identifying rates and predictive factors on utilization of skilled birth attendant (SBA) among pregnant women. A stratified random sampling technique was used to select 200 Myanmar women aged 18 to 49 years in Kalay Township. Data were collected by interview questionnaire from March 1 to 15, 2012, and data were analyzed by frequency, percentage, mean and standard deviation, chi(2) test, and multiple logistic regression analysis. The utilization rate of SBA was 74%. Factors significantly predicting utilization of SBA (P < .05) were level of maternal and child health (MCH) knowledge, attitude toward SBA, and accessibility to MCH services. The women who had a moderate to good level of knowledge utilized SBA 2.7 times more than those who had a poor level of knowledge (odds ratio = 2.705, 95% confidence interval = 1.31-5.57). The women who had a positive attitude toward SBA utilized SBA 7.7 times more than those who had a negative attitude (odds ratio = 7.708, 95% confidence interval = 3.71-15.98). The women who had high accessibility to MCH services utilized SBA 1.4 times more than those who had low accessibility (odds ratio = 1.477, 95% confidence interval = 1.05-2.21). These factors were able to correctly predict utilization of SBA at 74.9%. MCH knowledge and information on utilization of SBA should be strengthened during every antenatal care visit to enhance positive attitude on utilization of SBA and to increase accessibility to MCH services by providing community antenatal care or home visits. PMID- 25556219 TI - Age-dependent healing potential of anterior cruciate ligament remnant-derived cells. AB - BACKGROUND: The anterior cruciate ligament (ACL) does not heal spontaneously after injury, and ACL patients of different ages respond differently to treatment. Although ACL-derived CD34-positive cells contribute to bone-tendon healing after ACL reconstruction, the relationship between the healing potential of ACL-derived cells and a patient's age is unknown. HYPOTHESIS: ACL-derived cells from young patients will have a greater effect on the maturation of bone tendon integration in an immunodeficient rat model of ACL reconstruction compared with cells derived from older patients. STUDY DESIGN: Controlled laboratory study. METHODS: Sixty 10-week-old female immunodeficient rats underwent ACL reconstruction (using the autologous flexor digitorum longus tendon as a graft) followed by intracapsular administration of ACL-derived cells from patients aged 10 to 19 years (younger group) or patients aged 30 to 39 years (older group), or they were given phosphate-buffered saline (PBS; PBS group). Histologic, radiographic, and biomechanical examinations were performed 2 to 8 weeks after surgery. In addition, intrinsic and human cell-derived angiogenesis and osteogenesis were examined by immunohistochemistry. RESULTS: In the younger group, histologic assessment demonstrated early bone-tendon healing, which induced endochondral ossification-like integration. Micro-computed tomography showed a statistically significant reduction in the area of tibial bone tunnel in the younger group (week 4, 20.0% +/- 11.2% reduction; week 8, 25.7% +/- 5.6% reduction) compared with the older group (week 4, 1.8% +/- 3.0% reduction; week 8, 4.0% +/- 5.9% reduction) and the PBS group (week 4, -0.5% +/- 3.2% reduction; week 8, 3.3% +/- 5.2% reduction) (week 4, P < .05; week 8, P < .01). Failure loads during tensile testing demonstrated a significantly higher ultimate load to failure in the younger group (17.52 +/- 4.01 N) compared with the older (8.05 +/- 2.91 N) and PBS (7.01 +/- 3.16 N) groups (P < .05), and isolectin B4 and rat osteocalcin immunostaining indicated enhanced intrinsic angiogenesis and osteogenesis in the younger group. There was no statistically significant difference in the results of radiographic and biomechanical examinations between the older and PBS groups. Double immunohistochemistry for human-specific endothelial cell and osteoblast markers demonstrated a greater ability of differentiation into endothelial cells and osteoblasts in the younger group. CONCLUSION: ACL-derived cells from younger patients enhanced early bone-tendon healing in an immunodeficient rat model of ACL reconstruction. CLINICAL RELEVANCE: Surgeons should consider a patient's age when performing ACL reconstruction with remnant preservation or ruptured tissue incorporation, as this can predict healing ability. PMID- 25556220 TI - Cyclic displacement after meniscal root repair fixation: a human biomechanical evaluation. AB - BACKGROUND: Recent biomechanical evidence suggests that the meniscus-suture interface contributes the most displacement to the transtibial pull-out repair for meniscal root tears. Therefore, optimization of surgical technique at the meniscus-suture interface may minimize displacement and improve the strength of meniscal root repairs. PURPOSE/HYPOTHESIS: The purpose of this study was to investigate the cyclic displacement and ultimate failure loads of 4 different meniscus-suture fixation techniques for posterior medial meniscal root repairs in human meniscus tissue. The hypothesis was that there would be no significant difference between the two simple sutures (TSS) technique and 3 other techniques in cyclic displacement or ultimate failure load. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 32 fresh-frozen, human, medial meniscal transplant specimens were randomly assigned to 4 meniscus-suture fixation techniques used for transtibial pull-out repair in posterior medial meniscal root tears (n = 8 per group). The suture techniques studied were (1) TSS, (2) modified Mason-Allen (MMA), (3) single double-locking loop (S-DLL), and (4) double double locking loop (D-DLL). The menisci were subjected to a cyclic tensioning protocol representative of postoperative rehabilitation (10-30 N for 1000 cycles) and pulled to failure at a rate of 0.5 mm/s. RESULTS: After 1000 cycles, the TSS group displaced the least (mean +/- SD, 1.78 +/- 0.64 mm), followed by the MMA (2.14 +/- 0.65 mm), D-DLL (2.97 +/- 0.57 mm), and S-DLL (3.81 +/- 0.78 mm) groups. After 100, 500, and 1000 cycles, suture displacements using the TSS and MMA techniques were not significantly different (P > .13), while the TSS technique resulted in significantly less displacement than the S-DLL and D-DLL (P < .03) techniques. The ultimate failure loads of the MMA (325 +/- 77 N) and D-DLL (320 +/- 50 N) techniques were significantly greater than those of the TSS (192 +/- 52 N) and S-DLL (217 +/- 51 N) techniques (P < .05). CONCLUSION: The TSS and MMA fixation techniques were not significantly different, while the TSS was significantly better at resisting displacement when compared with the S-DLL and D DLL stitch configurations. The MMA and D-DLL techniques exhibited significantly greater failure loads than did the TSS and S-DLL techniques; however, all techniques demonstrated ultimate failure loads above the currently accepted rehabilitation force threshold. CLINICAL RELEVANCE: The TSS fixation technique combines the lowest technical difficulty and the ability to resist displacement at time zero. The MMA technique, although more technically challenging, may provide an alternative means to resist displacement while enhancing the failure load. PMID- 25556221 TI - The biomechanical function of the anterolateral ligament of the knee. AB - BACKGROUND: Recent anatomic investigations of the lateral structures of the knee have identified a new ligament, called the anterolateral ligament (ALL). To date, the anterolateral ligament has not been biomechanically tested to determine its function. HYPOTHESIS: The ALL of the knee will resist internal rotation at high angles of flexion but will not resist anterior drawer forces. STUDY DESIGN: Controlled laboratory study. METHODS: Eleven cadaveric knees were subjected to 134 N of anterior drawer at flexion angles between 0 degrees and 90 degrees and separately to 5 N.m of internal rotation at the same flexion angles. The in situ forces of the ALL, anterior cruciate ligament (ACL), and lateral collateral ligament (LCL) were determined by the principle of superposition. RESULTS: The contribution of the ALL during internal rotation increased significantly with increasing flexion, whereas that of the ACL decreased significantly. At knee flexion angles greater than 30 degrees , the contribution of the ALL exceeded that of the ACL. During anterior drawer, the forces in the ALL were significantly less than the forces in the ACL at all flexion angles (P < .001). The forces in the LCL were significantly less than those in either the ACL or the ALL at all flexion angles for both anterior drawer and internal rotation (P < .001). CONCLUSION: The ALL is an important stabilizer of internal rotation at flexion angles greater than 35 degrees ; however, it is minimally loaded during anterior drawer at all flexion angles. The ACL is the primary resister during anterior drawer at all flexion angles and during internal rotation at flexion angles less than 35 degrees . CLINICAL RELEVANCE: Damage to the ALL of the knee could result in knee instability at high angles of flexion. It is possible that a positive pivot-shift sign may be observed in some patients with an intact ACL but with damage to the ALL. This work may have implications for extra-articular reconstruction in patients with chronic anterolateral instability. PMID- 25556225 TI - SNMMI comments on NRC part 35 and part 20 rules. PMID- 25556222 TI - Surgical management of osteochondritis dissecans lesions of the patella and trochlea in the pediatric and adolescent population. AB - BACKGROUND: There is a paucity of published data regarding the management of osteochondritis dissecans (OCD) lesions of the patellofemoral joint in children and adolescents. PURPOSE: To evaluate the functional outcomes of surgical management of OCD lesions of the patella and trochlea in children and adolescents. Secondary aims included elucidating predictors for higher functional outcomes and determining complication rates, surgical satisfaction, and ability to return to sports. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients aged 18 years and younger who were surgically treated for OCD of the patella or trochlea were identified. Charts were queried to record patient/lesion data, surgical procedure, results, and complications. Pre- and postoperative imaging was reviewed. Patients were asked to complete a follow-up athletic questionnaire and a Pediatric International Knee Documentation Committee (Pedi IKDC) questionnaire. Statistical analysis was conducted to look for predictors for reoperation, residual pain, ability to return to sports, and lower Pedi-IKDC scores. RESULTS: A total of 26 children (9 females, 17 males, 3 with bilateral lesions; thus, 29 lesions) were identified. The mean age was 14.7 years (range, 9 18, years), 21 of the 29 knees with lesions (72%) had open physes, and median follow-up was 3.8 years (range, 1-9 years). The most common location was the trochlea (17/29 lesions; 59%). Twenty-two lesions (76%) underwent transarticular drilling (n = 14) or drilling with fixation (n = 8), while 7 underwent excision and marrow stimulation. Four patients (14%) required unplanned reoperation. Internal fixation was predictive of reoperation (odds ratio [OR] = 8.7; 95% CI, 2.8-26.9; P = .04). At final follow-up, 14 knees (48%) were pain free, and 14 (48%) had mild residual pain. Female sex was predictive of residual pain (OR, 9; 95% CI, 2-56; P = .02). Twenty-two patients (85%) returned to sports. Longer duration of preoperative pain negatively affected return to sports (OR, 0.32; 95% CI, 0.05-0.97; P = .04). On postoperative MRI, the lesion appeared completely healed in 2 cases (18%) and partially healed in 9 cases (82%). All 15 survey respondents were satisfied with surgery. The mean Pedi-IKDC score was 82.4 +/- 17.8 (range, 40.2-100). CONCLUSION: Surgical treatment of patellofemoral OCD in children and adolescents produces a high rate of satisfaction and return to sports. Female sex, prolonged duration of symptoms, and internal fixation may be associated with worse outcomes. PMID- 25556226 TI - ACR white paper targets thyroid incidentaloma reporting. PMID- 25556227 TI - Joint NCI/SNMMI workshop on targeted radionuclide therapy. PMID- 25556228 TI - Nuclear medicine residency programs ranked. PMID- 25556230 TI - SNMMI leadership update: facilitation and collaboration to lead the future. PMID- 25556232 TI - 2015 Medicare final rules. PMID- 25556233 TI - Cerebrospinal fluid peptides as potential Parkinson disease biomarkers: a staged pipeline for discovery and validation. AB - Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent technical limitations associated with imaging or antibody-based protein assays. To circumvent the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter study consisting of training and validation sets, a total of 178 subjects were randomly selected from a retrospective cohort, matching age and sex between PD patients, healthy controls, and neurological controls with Alzheimer disease (AD). From ~14,000 unique peptides displaying differences between PD and healthy control in proteomic investigations, 126 peptides were selected based on relevance and observability in CSF using bioinformatic analysis and MS screening, and then quantified by highly accurate and sensitive selected reaction monitoring (SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1, LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of 0.873 (sensitivity = 76.7%, specificity = 80.0%) for PD versus healthy controls in the training set. The performance was essentially confirmed in the validation set (AUC = 0.853, sensitivity = 82.5%, specificity = 82.5%). Additionally, this panel could also differentiate the PD and AD groups (AUC = 0.990, sensitivity = 95.0%, specificity = 97.4%). Furthermore, a combination of two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the training (r = 0.381, p = 0.038)j and the validation (r = 0.339, p = 0.032) sets. The novel panel of CSF peptides, if validated in independent cohorts, could be used to assist in clinical diagnosis of PD and has the potential to help monitoring or predicting disease progression. PMID- 25556234 TI - New host factors important for respiratory syncytial virus (RSV) replication revealed by a novel microfluidics screen for interactors of matrix (M) protein. AB - Although human respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in infants and elderly worldwide, there is no licensed RSV vaccine or effective drug treatment available. The RSV Matrix protein plays key roles in virus life cycle, being found in the nucleus early in infection in a transcriptional inhibitory role, and later localizing in viral inclusion bodies before coordinating viral assembly and budding at the plasma membrane. In this study, we used a novel, high throughput microfluidics platform and custom human open reading frame library to identify novel host cell binding partners of RSV matrix. Novel interactors identified included proteins involved in host transcription regulation, the innate immunity response, cytoskeletal regulation, membrane remodeling, and cellular trafficking. A number of these interactions were confirmed by immunoprecipitation and cellular colocalization approaches. Importantly, the physiological significance of matrix interaction with the actin-binding protein cofilin 1, caveolae protein Caveolin 2, and the zinc finger protein ZNF502 was confirmed. siRNA knockdown of the host protein levels resulted in reduced RSV virus production in infected cells. These results have important implications for future antiviral strategies aimed at targets of RSV matrix in the host cell. PMID- 25556235 TI - The effect of species representation on the detection of positive selection in primate gene data sets. AB - Over evolutionary time, both host- and virus-encoded genes have been continually selected to modify their interactions with one another. This has resulted in the rapid evolution of the specific codons that govern the physical interactions between host and virus proteins. Virologists have discovered that these evolutionary signatures, acquired in nature, can provide a shortcut in the functional dissection of host-virus interactions in the laboratory. However, the use of evolution studies in this way is complicated by the fact that many nonhuman primate species are endangered, and biomaterials are often difficult to acquire. Here, we assess how the species representation in primate gene data sets affects the detection of positive natural selection. Our results demonstrate how targeted primate sequencing projects could greatly enhance research in immunology, virology, and beyond. PMID- 25556237 TI - The evolution and functional impact of human deletion variants shared with archaic hominin genomes. AB - Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn's disease. Our analyses suggest that these "exonic" deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes. PMID- 25556238 TI - 1,25-dihydroxyvitamin D3 causes ADAM10-dependent ectodomain shedding of tumor necrosis factor receptor 1 in vascular smooth muscle cells. AB - 1,25-Dihydroxyvitamin D3 (1,25D3) has a potential antiatherosclerotic effect through anti-inflammatory actions. We investigated how 1,25D3 regulates tumor necrosis factor-alpha (TNF-alpha)-induced lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in cultured human aortic smooth muscle cells. TNF-alpha activated Rac1/reactive oxygen species/spleen tyrosine kinase and transcriptional factors, activator protein-1, and nuclear factor kappaB, which led to LOX-1 expression. 1,25D3 inhibited TNF-alpha-induced LOX-1 expression by inhibiting Rac1 activation and thereby its downstream signals. 1,25D3 rapidly induced extracellular Ca(2+) influx. Verapamil, an inhibitor of L type calcium channels, inhibited 1,25D3-induced Ca(2+) influx and counteracted the inhibitory effects of 1,25D3 on Rac1 activation, whereas Bay K8644 [1,4 dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester], an L-type calcium channel agonist, attenuated TNF-alpha induced Rac1 activation, as 1,25D3 did. 1,25D3 induced the ectodomain shedding of TNF receptor 1 (TNFR1), which was abolished by verapamil and in Ca(2+)-free media. Like 1,25D3, Bay K8644 induced the ectodomain shedding of TNFR1. Both 1,25D3 and Bay K8644 caused the translocation of a disintegrin and metalloprotease (ADAM) 10 from the cytoplasm to the plasma membrane, which was dependent on extracellular Ca(2+) influx. In contrast, depletion of ADAM10 by transfection of ADAM10-small interfering RNA prevented 1,25D3- or Bay K8644 induced ectodomain shedding of TNFR1 and abolished the suppressive effect of 1,25D3 on TNF-alpha-induced Rac1 activation. Taken together, these findings suggest that 1,25D3 induces extracellular Ca(2+) influx via L-type calcium channel, triggering ADAM10-mediated ectodomain shedding of TNFR1, and it thereby decreases responsiveness to TNF-alpha. By shedding TNFR1 from the cell surface, 1,25D3 may regulate inflammation and atherogenesis, whereas this effect could be attenuated by calcium channel blockers. PMID- 25556243 TI - Models of lung branching morphogenesis. AB - Vertebrate airway has a tree-like-branched structure. This structure is generated by repeated tip splitting, which is called branching morphogenesis. Although this phenomenon is extensively studied in developmental biology, the mechanism of the pattern formation is not well understood. Conversely, there are many tree-like structures in purely physical or chemical systems, and their pattern formation mechanisms are well-understood using mathematical models. Recent studies correlate these biological observations and mathematical models to understand lung branching morphogenesis. These models use slightly different mechanisms. In this article, we will review recent progress in modelling lung branching morphogenesis, and future directions to experimentally verify the models. PMID- 25556242 TI - Shedding light on glioblastoma cellular heterogeneity. PMID- 25556244 TI - Temporal expression of growth factors triggered by epiregulin regulates inflammation development. AB - In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-alpha, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases. PMID- 25556246 TI - Sterile DJH rearrangements reveal that distance between gene segments on the human Ig H chain locus influences their ability to rearrange. AB - Rearrangement of the Ig locus occurs in two steps. First, a JH gene is rearranged to a D gene followed by a VH gene rearranging to the DJH rearrangement. By next generation sequencing, we analyzed 9969 unique DJH rearrangements and 5919 unique VHDJH rearrangements obtained from peripheral blood B cells from 110 healthy adult donors. We found that DJH rearrangements and nonproductive VHDJH rearrangements share many features but differ significantly in their use of D genes and propensity for somatic hypermutation. In D to JH gene rearrangements, the D genes proximal to the JH locus are used more frequently than JH locus distal D genes, whereas VH locus proximal D genes were observed more frequently in nonproductive VHDJH rearrangements. We further demonstrate that the distance between VH, D, and JH gene segments influence their ability to rearrange within the human Ig locus. PMID- 25556248 TI - Auxin transporters and binding proteins at a glance. AB - The plant hormone auxin is a key regulator of plant growth and development. Differences in auxin distribution within tissues are mediated by the polar auxin transport machinery, and cellular auxin responses occur depending on changes in cellular auxin levels. Multiple receptor systems at the cell surface and in the interior operate to sense and interpret fluctuations in auxin distribution that occur during plant development. Until now, three proteins or protein complexes that can bind auxin have been identified. SCF(TIR1) [a SKP1-cullin-1-F-box complex that contains transport inhibitor response 1 (TIR1) as the F-box protein] and S-phase-kinase-associated protein 2 (SKP2) localize to the nucleus, whereas auxin-binding protein 1 (ABP1), predominantly associates with the endoplasmic reticulum and cell surface. In this Cell Science at a Glance article, we summarize recent discoveries in the field of auxin transport and signaling that have led to the identification of new components of these pathways, as well as their mutual interaction. PMID- 25556249 TI - Cells on film - the past and future of cinemicroscopy. AB - Movie making is now a ubiquitous experimental tool that biologists use alongside more traditional techniques such as molecular biology and biochemistry. It is no longer just cell biologists, but scientists from many other disciplines, such as immunology and neuroscience, that utilise movies to dissect their processes of interest. When did filming become such a standard laboratory technique? Who developed the use of the movie as an experimental tool? The Wellcome Library has recently restored and digitized a number of original 16-mm films from two pioneering cinemicroscopists, Ronald Canti and Michael Abercrombie, which are now freely available to the scientific community. In light of these films, this Essay will give a brief history of the early cinemicroscopists and discuss what is driving the use of movies in the laboratory today. PMID- 25556245 TI - The V gene repertoires of classical and atypical memory B cells in malaria susceptible West African children. AB - Immunity to Plasmodium falciparum malaria is naturally acquired in individuals living in malaria-endemic areas of Africa. Abs play a key role in mediating this immunity; however, the acquisition of the components of Ab immunity, long-lived plasma cells and memory B cells (MBCs), is remarkably inefficient, requiring years of malaria exposure. Although long-lived classical MBCs (CD19(+)/CD20(+)/CD21(+)/CD27(+)/CD10(-)) are gradually acquired in response to natural infection, exposure to P. falciparum also results in a large expansion of what we have termed atypical MBCs (CD19(+)/CD20(+)/CD21(-)/CD27(-)/CD10(-)). At present, the function of atypical MBCs in malaria is not known, nor are the factors that drive their differentiation. To gain insight into the relationship between classical and atypical IgG(+) MBCs, we compared the Ab H and L chain V gene repertoires of children living in a malaria-endemic region in Mali. We found that these repertoires were remarkably similar by a variety of criteria, including V gene usage, rate of somatic hypermutation, and CDR-H3 length and composition. The similarity in these repertoires suggests that classical MBCs and atypical MBCs differentiate in response to similar Ag-dependent selective pressures in malaria-exposed children and that atypical MBCs do not express a unique V gene repertoire. PMID- 25556247 TI - Diverse roles for T-bet in the effector responses required for resistance to infection. AB - The transcription factor T-bet has been most prominently linked to NK and T cell production of IFN-gamma, a cytokine required for the control of a diverse array of intracellular pathogens. Indeed, in mice challenged with the parasite Toxoplasma gondii, NK and T cell responses are characterized by marked increases of T-bet expression. Unexpectedly, T-bet(-/-) mice infected with T. gondii develop a strong NK cell IFN-gamma response that controls parasite replication at the challenge site, but display high parasite burdens at secondary sites colonized by T. gondii and succumb to infection. The loss of T-bet had a modest effect on T cell production of IFN-gamma but did not impact on the generation of parasite-specific T cells. However, the absence of T-bet resulted in lower T cell expression of CD11a, Ly6C, KLRG-1, and CXCR3 and fewer parasite-specific T cells at secondary sites of infection, associated with a defect in parasite control at these sites. Together, these data highlight T-bet-independent pathways to IFN gamma production and reveal a novel role for this transcription factor in coordinating the T cell responses necessary to control this infection in peripheral tissues. PMID- 25556250 TI - How is facial expression coded? AB - Facial expression is theorized to be visually represented in a multidimensional expression space, relative to a norm. This norm-based coding is typically argued to be implemented by a two-pool opponent coding system. However, the evidence supporting the opponent coding of expression cannot rule out the presence of a third channel tuned to the center of each coded dimension. Here we used a paradigm not previously applied to facial expression to determine whether a central-channel model is necessary to explain expression coding. Participants identified expressions taken from a fear/antifear trajectory, first at baseline and then in two adaptation conditions. In one condition, participants adapted to the expression at the center of the trajectory. In the other condition, participants adapted to alternating images from the two ends of the trajectory. The range of expressions that participants perceived as lying at the center of the trajectory narrowed in both conditions, a pattern that is not predicted by the central-channel model but can be explained by the opponent-coding model. Adaptation to the center of the trajectory also increased identification of both fear and antifear, which may indicate a functional benefit for adaptive coding of facial expression. PMID- 25556236 TI - Intraspecific polymorphism, interspecific divergence, and the origins of function altering mutations in deer mouse hemoglobin. AB - Major challenges for illuminating the genetic basis of phenotypic evolution are to identify causative mutations, to quantify their functional effects, to trace their origins as new or preexisting variants, and to assess the manner in which segregating variation is transduced into species differences. Here, we report an experimental analysis of genetic variation in hemoglobin (Hb) function within and among species of Peromyscus mice that are native to different elevations. A multilocus survey of sequence variation in the duplicated HBA and HBB genes in Peromyscus maniculatus revealed that function-altering amino acid variants are widely shared among geographically disparate populations from different elevations, and numerous amino acid polymorphisms are also shared with closely related species. Variation in Hb-O2 affinity within and among populations of P. maniculatus is attributable to numerous amino acid mutations that have individually small effects. One especially surprising feature of the Hb polymorphism in P. maniculatus is that an appreciable fraction of functional standing variation in the two transcriptionally active HBA paralogs is attributable to recurrent gene conversion from a tandemly linked HBA pseudogene. Moreover, transpecific polymorphism in the duplicated HBA genes is not solely attributable to incomplete lineage sorting or introgressive hybridization; instead, it is mainly attributable to recurrent interparalog gene conversion that has occurred independently in different species. Partly as a result of concerted evolution between tandemly duplicated globin genes, the same amino acid changes that contribute to variation in Hb function within P. maniculatus also contribute to divergence in Hb function among different species of Peromyscus. In the case of function-altering Hb mutations in Peromyscus, there is no qualitative or quantitative distinction between segregating variants within species and fixed differences between species. PMID- 25556251 TI - Granzymes regulate proinflammatory cytokine responses. AB - Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing. PMID- 25556252 TI - HIV infection Worsens Age-Associated Defects in Antibody Responses to Influenza Vaccine. AB - BACKGROUND: Antibody responses to seasonal influenza vaccines are defective during older age and human immunodeficiency virus (HIV) infection. The effect of HIV on immune function in aging is relatively unknown. METHODS: HIV-infected and HIV-uninfected young women (age, 19-54 years) and older women (age, >55 years) were evaluated for B-cell and T-cell responses before and 4 weeks after influenza vaccination. RESULTS: Frequencies of seroprotection pre-vaccination and vaccine responsiveness (>=4-fold increase in antibody titer) were lower in HIV-infected participants than in age-matched HIV-uninfected participants. A subgroup of vaccine nonresponders were compared to responders and found to have reduced frequencies of memory B cells and antigen-specific antibody-secreting cells after vaccination. Frequencies of peripheral T-follicular helper (pTfh) cells correlated with memory B-cell function and influenza A(H1N1) antibody titers. Serologic and immunologic deficits were most frequent in older HIV-infected participants. Underlying CD4(+) T-cell immune activation and inflammation correlated negatively with antibody titers and B-cell function, which was not enhanced by exogenous interleukin 21 supplementation in HIV-infected, older vaccine nonresponders. CONCLUSIONS: Immune activation associated with HIV infection and impaired pTfh function heighten deficiencies in antibody responses to influenza vaccine in older individuals. Strategies to reduce immune activation or augment pTfh function may enhance antibody responses in the aging HIV-infected population. PMID- 25556254 TI - Chemical quandary: chemicals are essential to our way of life, but who's ensuring their safe use? PMID- 25556253 TI - Changes in the Population Structure of Invasive Neisseria meningitidis in the United States After Quadrivalent Meningococcal Conjugate Vaccine Licensure. AB - BACKGROUND: Meningococcal conjugate vaccines against serogroups A, C, W, and Y (MenACWY) are recommended for routine use in adolescents aged 11-18 years. The impact of these vaccines on the meningococcal population structure in the United States have yet to be evaluated. METHODS: Meningococcal isolates recovered during 2006-2010 (ie, after introduction of MenACWY) collected through Active Bacterial Core surveillance (ABCs) were characterized; serogroup distribution and molecular features of these isolates were compared to previously published data on ABCs isolates recovered from 2000 to 2005 (ie, before introduction of MenACWY). P values were generated using chi(2) statistics and exact methods. RESULTS: There was a significant change (P < .05) in serogroup distribution among all age groups between the 2 periods. A small proportion of isolates showed evidence of capsular switching in both periods. Between the 2 periods, significant changes were observed in the distribution of porin A, ferric enterobactin transport, and strain genotypes among vaccine and nonvaccine serogroups. CONCLUSIONS: The population structure of US meningococcal isolates is dynamic; some changes occurred over time, but the basic structure remained. Vaccine-induced serogroup replacement was not observed, although a small proportion of isolates had undergone capsule switching, possibly driven by non-vaccine-mediated selection. Changes in the distribution of molecular features are likely due to horizontal gene transfer and changes in serogroup distribution. PMID- 25556255 TI - The use of digital media by women using the maternity services in a developed country. AB - The provision of high quality healthcare information about pregnancy is important to women and to healthcare professionals and it is 1 driven, in part, by a desire to improve clinical outcomes,. The objective of this study was to examine the use of digital media by women' to access pregnancy information. A questionnaire was distributed to women attending a large maternity hospital. Of the 522 respondents, the mean age was 31.8 years, 45% (235/522) were nulliparous, 62% (324/522) lived in the capital city and 29% (150/522) attended the hospital as private patients. Overall 95% (498/522) used the internet for pregnancy information, 76% (399/522) had a smartphone and 59% (235/399) of smartphone owners had used a pregnancy smartapp. The nature of internet usage for pregnancy information included discussion forums (70%), social networks (67%), video media (48%), e-books (15%), blogs (13%), microblogs (9%) and podcasts (4%). Even women who were socially disadvantaged reported high levels of digital media usage. In contemporary maternity care women use digital media extensively for pregnancy information. All maternity services should have a digital media strategy. PMID- 25556256 TI - A pilot cross-sectional study of patients presenting with cellulitis to emergency departments. AB - To characterise the Emergency Department (ED) prevalence of cellulitis, factors predicting oral antibiotic therapy and the utility of the Clinical Resource Efficiency Support Team (CREST) guideline in predicting patient management in the ED setting, a prospective, cross-sectional study of consecutive adult patients presenting to 3 Irish EDs was performed. The overall prevalence of cellulitis was 12 per 1,000 ED visits. Of 59 patients enrolled, 45.8% were discharged. Predictors of treatment with oral antibiotics were: CREST, Class 1 allocation (odds ratio (OR) 6.81, 95% Cl =1.5-30.1, p=0.012), patient self-referral (OR= 6.2, 95% Cl 1.9- 20.0, p=0.03) and symptom duration longer than 48 hours (OR 1.2, 95% Cl = 1.0-1.5,p=0.049). In conflict with guideline recommendation, 43% of patients in CREST Class 1 received IV therapy. Treatment with oral antibiotics was predicted by CREST Class 1 allocation, self-referral, symptom duration of more than 48 hours and absence of pre-EO antibiotic therapy. PMID- 25556257 TI - The feasibility of audiologists removing earwax. AB - Although cerumen management (CM) is routinely performed by audiologists in some countries, this is currently not the case in the Republic of Ireland. This study involved surveying the opinions of Audiologists and Ear Nose and Throat specialists (ENTs) in relation to audiologists conducting CM. In total, 20 ENT Consultants (29%) and 51 audiologists (64%) in the public services responded to an online survey. There was agreement that CM should be within audiologists' remit. However, with regard to risk, opinions were significantly different, with 15 ENTs (75%), compared to 14 audiologists (27%), in agreement that CM management by audiologists was more risky to patients. Nevertheless, 62 respondents (87%) supported future CM training for audiologists. The. overall similarities of opinion between the two groups contrasted to previous studies that reported strong opposition from ENTs with regard to audiologists managing earwax. PMID- 25556258 TI - A quantitative analysis of diabetic retinopathy screening in a regional treatment centre. AB - The aim of the study was to assess the current diabetic retinopathy screening infrastructure and implications on workload for a designated treatment centre following roll-out of a national screening programme. A combination of chart analysis and patient questionnaire was undertaken over a 4-week period in 2011 at Cork University Hospital (CUH). Data were collected on 97 patients and categorized. as demographic, medical, and screening-related. The majority of patients (80; 82.5%} had either no retinopathy or background retinopathy only. One (1.0%) patient was deemed to be ungradable due to dense cataract, while 6 (6.2%) patients had non-diabetic ocular pathology requiring follow-up. Only 11% were screened through retinal photography. In all, 74 (76.3%) patients were deemed suitable for community rather than hospital screening. Digital retinal photography is an underused screening resource Significant numbers of patients could be discharged from hospital-based to community screening to offset the increased workload expected from the national screening programme. PMID- 25556259 TI - Implementation and evaluation of a clinical data management programme in a primary care centre. AB - Electronic health records (EHR)support clinical management, administration, quality assurance, research, and service planning. The aim of this study was to evaluate a clinical data management programme to improve consistency, completeness and accuracy of EHR information in a large primary care centre with 10 General Practitioners (GPs). A Clinical Data Manager was appointed to implement a Data Management Strategy which involved coding consultations using ICPC-2 coding, tailored support and ongoing individualised feedback to clinicians. Over an eighteen month period there were improvements in engagement with and level of coding. Prior to implementation (August 2011) 4 of the 10 GPs engaged in regular coding and 69% of their consultation notes were coded. After 12 months, all 10 GPs and 6 nurses were ICPC-2 coding their consultations and monthly coding levels had increased to 98%. This structured Data Management Strategy provides a feasible sustainable way to improve information management in primary care. PMID- 25556260 TI - Workforce strategies to improve children's oral health. AB - (1) Tooth decay is the most common chronic disease for children. (2) As millions receive dental coverage under the Affordable Care Act, the demand for dental services is expected to strain the current workforce's ability to meet their needs. (3) States have adopted various workforce approaches to improve access to dental care for underserved populations. PMID- 25556261 TI - Methadone and prescription drug overdose. AB - (1) Methadone accounted for 2 percent of painkiller prescriptions and more than 30 percent of prescription painkiller deaths in 2009. (2) Data suggest that the rise in deaths from methadone overdose is not related to its use in treating drug abuse but, rather, to its use for pain management. (3) Preferred drug lists in most Medicaid programs identify methadone as a preferred drug for managing chronic pain, but most experts do no recommend it as a first choice. PMID- 25556262 TI - Authors reply. PMID- 25556263 TI - Mullerian adenosarcoma: a review of cases and literature. AB - OBJECTIVE: Mullerian adenosarcoma usually originates in the endometrium and grows as a polypoid mass in post-menopausal women presenting as abnormal vaginal bleeding. This report reviewed Miillerian adenosarcoma cases to clarify the clinical and pathologic characteristics. MATERIALS AND METHODS: Fifteen cases ofMiillerian adenosarcoma in two medical centers covering a 15-year period were reviewed. Their clinical characteristics, pathologic findings, treatment, and outcomes were compared. RESULTS: Of the 15 cases, three originated from the endometrium, six arose from uterine adenomyosis, three from the adnexa, and three from the cervix. There was only one post-menopausal case. One case was of breast cancer with tamoxifen (TMX) therapy. There were four Miillerian adenosarcoma with sarcomatous overgrowth (MASO) cases, three of which died within one year after surgery. Only the focal MASO case survived. CONCLUSION: The rare variant of MASO is very aggressive and associated with poor prognosis. PMID- 25556264 TI - Adult granulosa cell tumor of the ovary: a retrospective study of 37 cases. AB - AIM: to evaluate the recurrence rate and the overall survival in women with adult granulosa cell tumor (AGCT), who were treated at the Department of Obstetrics and Gynecology, Aalborg University Hospital during the period January 1985 to January 2010. MATERIALS AND METHODS: Data from 38 women with AGCT were collected retrospectively. The histological slides were re-evaluated by a gynecologic pathologist. Surgical and pathological characteristics were analyzed. Results: Thirty-seven women with AGCT were diagnosed. 92% were diagnosed in FIGO Stage I and 8% in Stage II. The majority of patients (27 patients, 73%) were treated with total abdomi- nal hysterectomy and bilateral salpingooophorectomy. Only one patient received postoperative pelvic irradiation. The recurrence rate was 5.6%. CONCLUSION: The recurrent rate was 5.6%, which is low according to the literature. Primary surgical treatment with radical removal of tumor seemed to be appropriate treatment. PMID- 25556265 TI - The relationship between gene expression of Forkhead box C2 and tumor progression in cervical carcinoma. AB - To investigate the correlation between FOXC2 expression and human cervical cancer, the authors detected FOXC2 expression in cervical cancer cell lines, C33a, SiHa, and Hela. Moreover, FOXC2 expression was measured after TGF-beta1 treatment in C33a cells. Furthermore, the expression level of FOXC2 and microvessel density (MVD) were detected by indirect double-labeled immunofluorescence and laser scanning confocal microscopy in cervix tissue samples, 86 of cervical carcinoma, 54 of cervical intraepithelial neoplasia (CIN), and 30 of normal cervix as controls. The results showed that FOXC2 was expressed in all of the cell lines, and FOXC2 expression in C33a cells can be significantly up-regulated by the treatment of TGF-beta1 and the stimulus was highest when TGF-beta1 is five ng/ml. In cervix tissues, FOXC2 expression gradually increased during the transformation from normal to cancer, and this increase was significantly associated with tumor progression (p < 0.01), lymph node status (p < 0.01), and tumor grade (p < 0.05). FOXC2 expression was positively correlated with MVD (p < 0.05). These results suggest that FOXC2 may promote the development of cervical cancer via regulation of angiogenesis. PMID- 25556266 TI - Multiple primary cancers in women with gynaecological malignancies: a cancer registry-based study in Umbria region of Italy. AB - To investigate the risk of developing multiple primary cancers (MPCs) in patients with previous gynaecological malignancies (cervical, uterine, and ovarian). The study's subjects included all the women on the Umbrian Cancer Registry who were first diagnosed with gynaecological cancer between 1994 and 2009. MPCs were defined according to the rules defined by International Association of Cancer Registries (IACR) and International Agency for Research on Cancer (IARC). Standardized incidence ratios (SIRs) of observed to expected cases were used as the measure of relative risk; its significance and 95% confidence intervals were determined assuming a Pois- son distribution. During the analysed period, the authors observed a total of 346 cases of MPCs in women with cervix (54 cases), corpus of uterus (196 cases), and ovarian (96 cases) malignancies. Significant SIRs were found in all of them, considering all sites combined: 2.43 (95% CI: 1.87-3.14) for cervix, 1.75 (95% CI: 1.52-2.01) for corpus of uterus, and 2.32 (95% CI: 1.90-2.84) for ovary malignancies, with different site-specific risks. Current data confirmed an excess risk of MPCs among women with gynaecological malignancies compared to the general population. The observed site-specific associations are useful to investigate shared risk factors and set up specific follow-up patients. PMID- 25556267 TI - Female sexuality after female cancer treatment: a clinical issue. AB - PURPOSE OF INVESTIGATION: The aim of the present study was to record how the treatment of female cancer may affect sexuality and interpersonal relations in the couple. MATERIAL AND METHODS: From September 2008 until February 2012, the authors prospectively studied 67 patients with breast cancer (Group A) and 43 with gynecological cancers (Group B). As control groups 33 patients with benign breast and 30 patients with benign gynecological lesions (group 0a and 0b respectively) were used. Sexuality and interpersonal relations were evaluated by a questionnaire. The authors also evaluated interpersonal relations focusing on sexual function at the time of diagnosis and a year after the initial treatment for cancer. RESULTS: A significant reduction of the "sexual desire", "sexual Arousal", and "orgasm" dimension was found in both cancer groups, in contrast to the control group, revealing no significant change. The "sexual enjoyment" scale was significantly decreased in gynecological cancer group but not in breast cancer group. While the score on the "relationship quality" dimension significantly increased in both cancer groups. In all groups, there was a significantly positive correlation between sexual function and enjoyment; on the contrary, there was a significantly negative correlation between relationship quality and sexual function and enjoyment. CONCLUSION: Sexual dysfunctions is a clinical problem which should be evidenced at the beginning of therapy, from the oncologists in order to provide integrated treatment to their patients. PMID- 25556268 TI - Clinical outcomes of patients with adenocarcinoma in situ of the cervix treated by conization. AB - OBJECTIVE: To describe the clinical outcomes of histologically confirmed adenocarcinoma in situ (AIS) of the cervix treated with cervical conization. MATERIALS AND METHODS: A retrospective chart review of patients with histologically confirmed AIS from July 1998 to February 2011 included 52 patients. The rates of residual disease in subsequent excisions, the clinical recurrence rate, the average disease-free interval, and risk of progression to adenocarcinoma were described. The clinical outcomes of patients treated with cold knife cone (CKC) and loop electrosurgical excisional procedure (LEEP) were compared. RESULTS: Fifteen LEEPs and 37 CKC procedures were performed as initial treatment and 26 patients (50%) had positive margins. There was no significant difference in rate of positive margins between LEEP and CKC (40% vs. 54%, respectively. p = 0.55). LEEPs and CKCs resulted in similar volumes of cervical tissue resected (4.98 cm3 vs. 5.04 cm3, p = 0.40). Of patients with positive margins, ten underwent immediate hysterectomy, six underwent a second cone biopsy, seven were managed expectantly, and four were lost to follow up. Residual AIS was found in 47% (eight of 17) of repeat cone biopsy and hysterectomy specimens performed for positive cone margins. Of the 26 patients with negative cone margins, no residual or recurrent disease was found after an average follow up of 32 months. CONCLUSIONS: A positive surgical margin was associated with residual disease in 47% of patients with AIS treated with conization. No patient with negative cone margins had recurrent or progressive disease. Cervical conization with negative margins appears to be a safe treatment option for patients with AIS but requires further investigation. CKC and LEEP were equally efficacious treatments in our study population. PMID- 25556269 TI - Clinicopathological features and prognostic factors of the uterine sarcomas: 20 years of experience at Cukurova University. AB - OBJECTIVE: Uterine sarcomas (US) are rare, malignant, and aggressive tumors of the uterus. In this study the authors aimed to evalu- ate retrospectively the clinical and pathologic features and to investigate the prognostic factors of the U.S. patients who were treated in their department in the last 20 years. MATERIALS AND METHODS: The archive files, medical, and pathological records of the 132 US patients who were operated on and regularly followed up in the clinic between March 1991-March 2011 were reviewed. Clinical features, operation characteristics, pathological findings, adjuvant therapies, and follow-up data of the patients and their effects on survival were investigated. Analysis of disease free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier and Cox regression tests. Thep value was taken <0.05 to maintain the statistical significance level for all results. Results: Seventy of the patients were diagnosed with leiomyosarcomas (LMS), 33 were with carcinosarcomas, 12 were with endometrial stromal sarcomas (ESS), nine were with undifferentiated endometrial sarcomas, five were with adenosarcomas, and three were with botryoid rhabdomyosarcomas. The average patients' age was 53.7 +/- 12.6 (17-78). About two thirds of the patients were in postmenopausal and one-third were in pre- menopausal period. Vaginal bleeding was detected as the most common reason for patients' admission (68.9%). All cases underwent surgery and a procedure of total abdominal hysterectomy + bilateral salpingo-oophorectomy (TAH + BSO) was performed for most of them (88%). The mean duration of follow-up was 36 months (4 198). The two- and five-year OS rates were 65% and 36%, respectively, with a median time of 37 months (95% CI, 28-45). The two- and five-year DFS rates were 59% and 33%, respectively, with a median time of 29 months (95% CI, 18-40). CONCLUSION: As a result of multivariate analysis, while age, stage, lymphovascular space invasion (LVSI), and lymphadenectomy were found to be independent prognostic factors affecting DFS, only stage was detected as an independent prognostic factor for OS. PMID- 25556270 TI - Identification of microRNAs and target genes involved in serous ovarian carcinoma and their influence on survival. AB - AIMS: To identify the expression of key microRNAs and their predicted target genes involved in serous ovarian carcinoma (SOC) and correlation between miRNAs and prognosis. MATERIALS AND METHODS: The authors used quantitative polymerase chain reaction (qPCR) to detect the expression of miR-145, miR-143, miR-146a, miR 93, miR-29a, miR-18a, and miR-200a in tissues of 56 primary SOC patients and 30 benign lesion patients. Four protein (MUC1, FAP, MMP2, MMP9) expressions were identified by western blotting and immunohistochemical stain. The Kaplan-Meier method was used to estimate the relationship of these miRNAs with overall survival rate. RESULTS: In SOC tissue, expression of miR-200a, miR-93, miR-146a, and miR-18a were up-regulated, while miR-145, miR-143, miR-29a were down regulated. MUC1, FAP, MMP2, and MMP9 were overexpressed in SOC. MiR-143 or miR 145 higher expressed patients had significantly higher overall survival (OS) rates, while miR-93 or miR-200a lower expressed patients also had higher OS rates. DISCUSSION: These results suggested that several miRNAs and their regulated target transcripts may have important roles in the initiation and development of SOC. MiR-145/miR-143, miR-200a, and miR-93 could be used as prognostic biomarkers. PMID- 25556271 TI - Impact of surgery and radiotherapy in women with uterine malignancies. AB - According to the National Health and Social Life Survey, sexual dysfunction affects about 43% of perimenopausal women. A diagnosis of cancer has a profound physical, emotional, and social impact, influencing the relationship with the body, the perception of illness and death, family, social and professional relationships, and the relationship with the partner and, consequently, sexuality. Loss of desire, dyspareunia, orgasmic disorder, difficulties in emotional and physical closeness to the partner, feelings of shame, and inadequacy commonly occur after treatment for uterine cancer; however, if these problems are associated with surgery or with radiotherapy, still remains unclear. According to this study, the authors may conclude that the experience of cancer could lead patients to a rediscovery of. their own sexuality and to an improvement in the relationship with their partner, showing that, sometimes, the relational and psychological factors assume greater importance than physical effects on sexuality, and they can somewhere compensate the morphofunctional failure. PMID- 25556272 TI - Tomosynthesis improves breast cancer detection: our experience. AB - Breast tomosynthesis (BT) is a novel imaging technology in which an x-ray fan beam sweeps in an arc across the breast, producing tomographic images and it can reduce tissue overlap encountered in conventional two-dimensional (2D) and thus has the potential to improve detection of breast cancer and facilitate accurate differentiation of lesion types. The purpose of this article was to assess the positive predictive value (PPV) of breast cancer with BT versus full-field digital mammography (FFDM) and the assessment of detec- tion of both techniques in the present series. PMID- 25556273 TI - Epidemiology and histopathology of benign breast diseases and breast cancer in southern Thailand. AB - BACKGROUND: Most palpable breast masses and lesions are benign; less than 30% of women with palpable masses have a diagnosis of cancer. MATERIALS AND METHODS: The aim of this study was to describe the epidemiological and pathological characteristics of benign breast disease (BBD) and breast cancer (BC) among women who underwent a breast biopsy in the Department of Pathology, Hatyai Hospital, Songkhla, Thailand from January 2003 to December 2011. RESULTS: Of the 2,532 biopsy reports of breast reviewed, there were 1,846 (72.9%) women with BBD and 686 (27.1%) women with BC. The most common form of breast disease diagnosed was fibroadenoma, followed by BC and fibrocystic change. BBD occurred in women under 40 years of age whereas BC occurred in women over 40 years of age (p < 0.001, OR = 8.629, 95% CI = 6.939 - 10.729). Fibroadenoma occurred in women less than 40 years of age while BC occurred in women over 40 years of age (p < 0.001, OR = 23.906, 95%CI = 18.359 - 31.129). Fibrocystic change occurred in patients less than 40 years of age while BC commonly occurred in patients 40 years of age and over (p < 0.001, OR = 3.865, 95% CI = 2.993 - 4.991). CONCLUSION: The overall incidence of BBD and BC has increased over the past nine years. It is important for pathologists and oncologists to recognise BBD especially fibroadenoma and fibrocystic change to assess a patient's risk of developing BC and to establish the most appropriate treatment for each case. Moreover, continued vigilance, and mammographic screening should be established for early diagnosis of BC. PMID- 25556274 TI - The inhibitory role of miR-214 in cervical cancer cells through directly targeting mitochondrial transcription factor A (TFAM). AB - Mitochondrial transcription factor A (TFAM) is a high-mobility group (HMG) protein and acts as a key regulator in mitochondrial DNA (mtDNA) replication, transcription, and inheritance. Accumulating evidence has demonstrated that TFAM plays an important role in tumorigenesis; however, the regulatory mechanism of TFAM in cervical cancer has not been revealed. In the current study, the au- thors found that with malignancy of cervical cancer, the protein expression of TFAM was gradually increased, while the expression of miRNA-214 was gradually downregulated. They further identified that TFAM is a target of miR-214. Forced overexpression of miRNA-214 significantly suppressed cell proliferation, cell cycle progression, colony-formation, and migration of cervical cancer Hela and Caski cells; however, upregulation of TFAM notably promoted cell proliferation, cell cycle progression, colony-formation, and migration of Hela and Caski cells. The authors further showed that miR-214 enhanced the susceptibility of Hela and Caski cells to the chemotherapy drug cisplatin. In conclusion, the current study provides a new sight for the regulatory pattern of miRNA-214 and TFAM in cervical cancer in vitro, indicating that miRNA-214 and MTFA may become important candidates for developing promising therapeutic strategies for the treatment of cervical cancer. PMID- 25556275 TI - Can adenocarcinoma in situ of the uterine cervix be treated safely by conisation in combination with endocervical curettage? AB - OBJECTIVE: To evaluate the prognostic value of endocervical curettage (ECC) after conisation in patients treated for adenocarcinoma in situ (AIS) of the uterine cervix. MATERIALS AND METHODS: Patients with AIS diagnosed between 1990 and 2010 and with a minimum of 1.5 years of follow-up were retrospectively identified using computerised clinical files. RESULTS: The authors identified 195 patients (median age 32 years) with a median follow-up of 6.4 years. ECC was performed in 165 patients. In 144 (87%) the initial ECC was normal. In 129 no recurrence was observed during follow-up (90%). A positive ECC was observed in 21. Thirteen patients had hysterectomies; six hysterectomies were normal. Eight patients treated conservatively developed no recurrent disease. Two patients with a positive ECC did not have a hysterectomy and developed recurrent disease. In patients with affected margins, 17% developed recurrent disease. CONCLUSION: ECC performed during initial conisation is a prognostic tool for the treatment ofAIS. Close follow-up is recommended in patients treated conservatively. PMID- 25556276 TI - Propofol induces apoptosis of epithelial ovarian cancer cells by upregulation of microRNA let-7i expression. AB - OBJECTIVE: Propofol is one of the extensively and commonly used intravenous anaesthetic agents. The aims of the current study were to evaluate effects of propofol on the behavior of human epithelial ovarian cancer (EOC) cells and role of miR-let-7i in these effects. MATERIALS AND METHODS: The effects of propofol on cell proliferation and apoptosis were detected by MTT assays and flow cytometry. Real-time polymerase chain reaction (PCR) was used to assess miR-let-7i expression in human EOC cells OVCAR-3 with or without propofol treatment. Finally, the authors evaluated the effect ofmiR-let-7i on propofol-induced anti tumor activity using anti-miR-let-7i. RESULTS: Propofol inhibited the proliferation of OVCAR-3 cells in a dose- and time-dependent manner. After exposure to propofol for 24 hours, OVCAR-3 cells showed increased apoptosis and increased expression of miR-let-7i. Finally, anti-miR-let-7i reversed the effect of propofol on cell proliferation and apoptosis. CONCLUSIONS: Propofol can effectively inhibit proliferation and induce apoptosis of EOC cells and modulation of miR-let-7i possibly contributes to the anti-tumor action of propofol. PMID- 25556277 TI - Borderline epithelial ovarian tumors: a single center experience. AB - AIM: To evaluate the clinical outcomes of the patients treated for borderline ovarian tumor (BOT). MATERIALS AND METHODS: In this retrospective study, records of the patients between November 2001 and December 2012 who underwent surgery and whose final pathological diagnosis were BOT were retrieved. RESULTS: During the study period, 78 patients were diagnosed as BOT. The patho- logical diagnoses of the tumors were serous in 26 (33.3%) and mucinous in 52 patients (66.6 %), respectively. Accuracy of frozen section diagnosis was observed in 63 of 89 patients (70.7%). Sixty-eight women (87.1%) underwent complete staging procedure. According to final pathological diagnoses, Stage IA, IB, and IC were found in 52 (67%), five (6.5%), and seven (9%) patients, respectively. FIGO Stages IIC and IIIC were found in one case in each (1.25%). Remaining 12 patients were classified as unstaged (15%). The median follow-up time was 63 months. The authors observed only one recurrence (1.3%) and that patient died of disease. CONCLUSION: The survival rate in patients with BOTs confined to the ovary is excellent. Surgical staging procedure can be omitted in the patients with grossly apparent Stage I mucinous tumors. PMID- 25556278 TI - Heterogeneous nuclear ribonucleoproteins (hnRNPs) and human transformer-2-beta1 (hTra2-beta1)-regulated estrogen receptor-alpha improves prognosis of endometrial cancer. AB - PURPOSE OF INVESTIGATION: Heterogeneous nuclear ribonucleoprotein (hnRNP) family possesses decreasing effect towards endometrial cancer (EC) and human transformer 2-betal (hTra2-betal) performs an intimate relationship with EC, either. Recent study shows that hnRNPs and hTra2-betal regulate the genetic expression, which is concerned with estrogen receptor (ER). MATERIALS AND METHODS: The present study was designed to investigate the link between ER and hnRNPs or hTra2-betal in the prognosis of EC patients by Real-time PCR and immunohistochemisty (IHC). RESULTS: Results showed that ER protein expression presented a significant change in the recurrence and outcome of EC patients, and the nucleus hTra2-betal protein expression was also increased in the recurrent patients, indicating that the three might be important in ER expression in the prognosis therapy of EC patients. CONCLUSION: The present findings provide an insight of pharmaceutical targeting therapy and prognosis of EC. PMID- 25556280 TI - Curcumin promotes the apoptosis of human endometrial carcinoma cells by downregulating the expression of androgen receptor through Wnt signal pathway. AB - OBJECTIVE: The current study aimed to explore the effect ofcurcumin on androgen receptor (AR) expression in endometrial carcinoma cells, as well as the underlying mechanisms. MATERIALS AND METHODS: Endometrial carcinoma cells were treated with curcumin (10, 50, and 100 micromol/l) for 12, 24, and 48 hours. Their growth curves were drawn using MTT assays and their apoptotic rates were determined using flow cytometry. The mRNA and protein expression of AR was detected using PCR and that of the Wnt signal related nucleopro- tein beta cantenin was observed using western blot analysis. The influence of beta-cantenin on the action of curcumin was observed. RESULTS: Curcumin downregulated the proliferation and apoptosis of human endometrial carcinoma cells in concentration and time-dependent manners. It downregulated the expression of AR and beta cantenin in the cells. rWnt3a partially cancelled the effects of curcumin on the proliferation and apoptosis of human endometrial carcinoma cells as well as the AR expression-downregulating effect of curcumin. CONCLUSION: Curcumin inhibits the proliferation and apoptosis of human endometrial carcinoma cells by downregulating their AR expression through the Wnt signal pathway. PMID- 25556279 TI - High risk HPV in situ hybridization, p16 INK 4A, and survivin expressions in cervical carcinomas and intraepithelial neoplasms: evaluation of prognostic factors. AB - BACKGROUND: Cervical carcinoma (CC) is one of the most important health problems of adult women in developing countries. CC is the second most common carcinoma of the women worldwide. Efficient screening and early therapeutic programmes are vital because of the higher burden of the disease. MATERIALS AND METHODS: The authors included a total of 53 cases in this study. Distribution of diagnoses among cases was as follows: cervical intraepithelial neoplasm (CIN) (n=44), squamous cell carcinoma (SCC) (n=7), adenocarcinoma in situ (n=1), and condyloma accuminatum (n=l). Presence, density, and nuclear identification form of human papilloma virus (HPV) DNA in relation with host cell DNA were evaluated by in situ hybridization (ISH) and p16 and survivin by immunohistochem- ical methods (IHC). RESULTS: The authors determined that the presence, density, and nuclear identification form of high risk HPV DNA had diagnostic and prognostic importance in CC and CIN (p < 0.05). p16 and survivin also had diagnostic significance. Since p16 and survivin expressions signalled progressive oncogenic events, p16 and survivin were persistent HPV markers (for p16, p < 0.001, for survivin p < 0.01). The authors determined that expressions, density, and prevalence of all three markers showed correlation with increasing CIN grade (for p 16, p < 0.001, for survivin, p < 0.01, for HPV, p = 0.002). The episomal pattern which is the independent visit of Hr HPV DNA to host cell DNA, signalled early HPV infection (p = 0.001). When it is integrated into host cell DNA, especially if HPV DNA signal intensity and prevalence increases, then this signal signifies persistent HPV infection (p = 0.001). CONCLUSION: With the aid of these findings, the authors determined that HPV is infectious in CIN I and proliferative (neoplastic) in CIN II-CIN III lesions. PMID- 25556281 TI - Comparison of two kinds of orthotopic xenograft models for human ovarian cancer. AB - OBJECTIVE: The aim of this study was to compare the characteristics of two orthotopic xenograft models established with human epithelial ovarian cancer solid tumor tissue slices and human ovarian carcinoma cell line OVCAR-3. MATERIALS AND METHODS: Tumor tissues and cell line OVCAR3 of human epithelial ovarian cancer were grown in subcutaneous tissue and the subcutaneous tumor source was fetched and inoculated in ovarian capsule of nude mice under microscope to establish the orthotopic implantation model. At four and eight weeks after modeling, the orthotopic tumor formation rate, tumor diameter, metastasis rate outside the ovary, incidence rate of ascites, and CA125 levels in the two models were observed. RESULTS: The orthotopic tumor formation rate in the solid tumor slices group (60.0%) was significantly lower than that in the cell line group (85.0%, p < 0.05). However, the tumor diameter, metastasis rate outside the ovary, incidence rate of ascites, and CA125 levels in the solid tumor slices group (2.4 +/- 0.61 cm, 75.0%, 50.0%, and 80.13 +/- 11.26 U/ml, respectively) were remarkably higher than those in the cell line group (1.6 +/- 0.53 cm, 52.9%, 29.4%, and 36.5 +/- 6.71 U/ml, respectively) (p < 0.05, respectively). CONCLUSION: There are differences between the two orthotopic xenograft models established with human epithelial ovarian cancer solid tumor tissue slices and human ovarian carcinoma cell line OVCAR-3. The biological characteristics of the solid tumor slices model are more similar to human ovarian cancer. PMID- 25556282 TI - Paraneoplastic arthritis mimicking rheumatoid arthritis in cervical cancer. AB - Paraneoplastic arthritis, a subcategory ofparaneoplastic syndrome, presents in a similar manner to rheumatic disorder and usually precedes the detection of the primary tumor by years. Herein, the authors report a case of a patient who was diagnosed with parane- oplastic rheumatoid arthritis (RA)-like arthritis with synchronous cervical cancer. A 38-year-old nulligravida woman was admitted to the gynecology department with a three-month history of irregular vaginal spotting accompanied by severe multiple joint pain. She had a one-year history of RA, for which she had been receiving treatment. During the early stage of treatment, her symptoms were slightly improved by RA treatment; however, after eight months of treatment, she showed absolute resistance to RA treatments and complained of a profuse vaginal discharge with severe foul odor. After colposcopy-directed punch biopsy, she was diagnosed with Stage IIA2 squamous cell carcinoma of the cervix. She underwent radical hysterectomy with lymphadenectomy without complications. After treatment, the multiple joint pain associated with paraneoplastic arthritis spontaneously disappeared. There was no evidence of malignancy according to the follow-up cervical cytology report, magnetic resonance imaging, and positron emission tomography-computed tomography. PMID- 25556283 TI - Uterine endometrioid carcinoma with focal area of choriocarcinomatous differentiation: case report. AB - PURPOSE OF INVESTIGATION: An endometrioid carcinoma coexisting with choriocarcinomatous differentiation is an uncommon event with an aggressive clinical course and a poor prognosis. MATERIALS AND METHODS: The authors describe an endometrioid carcinoma of the endometrium provided with a focus of choriocarcinoma-like cells in a 50-year-old menstruated woman with a history of abnormal uterine bleeding. A total bilateral hystero-annessectomy was performed. RESULTS: Histopathologic study showed endometrioid adenocarcinoma limited to the endometrium with a single microinvasive (< one mm) choriocarcinomatous focus. Immunohistochemistry established intense reactivity of tumor cells for CK 7 and AE1/AE3, for beta-human chorionic gonadotropin (beta-hCG), and for HER2 confirming the diagnosis. During the clinical course and follow-up, serum levels of beta-hCG were always negative. Up to date the patient is still alive with no evidence of disease. CONCLUSION: Even if endometrioid carcinoma with choriocarcinomatous differentiation is considered highly malignant, occasionally it may have a good prognosis, especially when a non-invasive behaviour is detected together with negative serum beta-hCG levels. PMID- 25556284 TI - Meigs' syndrome with elevated serum CA 125 level in a case of ovarian fibrothecoma. AB - Meigs' syndrome is the association of benign ovarian tumor, pleural effusion, and ascites. Meigs' syndrome with marked elevated CA 125 is a rare clinical entity and only 42 cases have been reported. Although there is difficulty in discerning the diagnosis of Meigs' syndrome from that of an ovarian malignancy, it should be considered in the differential diagnosis in postmenopausal patients with an ovarian mass, hydrothorax, ascites, and elevated CA 125. In this report, the authors present the case of a 52-year-old postmenopausal woman with ovarian fibrothecoma, pleural effusion, ascites, and elevated CA 125 (319.2 IU/ml). Exploratory laparotomy with total hysterectomy and bilateral salpingo oophorectomy was performed, and the pathologic diagnosis was ovarian fibrothecoma. After the surgery, the pleural effusion disappeared spontaneously and the CA 125 became normal. The authors also summarized other cases of Meigs' syndrome with elevated CA 125, and reviewed the mechanism of elevation of CA 125, ascites, and pleural effusion. PMID- 25556285 TI - Ovarian yolk sac tumor associated with pregnancy: a case report and review of the literature. AB - BACKGROUND: Ovarian yolk sac tumor (YST) that is diagnosed during pregnancy is extremely rare. CLINICAL CASE: A 22-year-old pregnant woman diagnosed with Stage IIIc YST at 17 weeks of gestation is presented. A 20-cm multilocular cystic tumor containing solid components with massive ascites was detected. Subsequently she underwent left salpingo-oophorectomy and cytoreductive surgery for peritoneal dissemination at 18 weeks of gestation, and the tumors were diagnosed as YST. After vaginal termination at 20 weeks of gestation, she received five cycles of combination therapy with bleomycin, etoposide, and cisplatin. There was no evidence of recurrence at 85 months after primary treatment. CONCLUSION: Considering the rarity, treatment strategy for advanced-staged YST should be further investigated in international collaborative studies. PMID- 25556286 TI - Paratubal cancer found at the time of laparoscopic surgery for adnexal torsion: a case report and literature review. AB - INTRODUCTION: Paratubal cysts are common incidental finding, but malignant paratubal cancers have rare occurrence and have not been sufficiently described and discussed in previous studies. CASE REPORT: This report describes a case of a 70-year-old female who underwent emergent laparoscopy for adnexal torsion. A serous cystadenocarcinoma arising in a paratubal cyst and accompanied by tubal torsion was revealed by frozen section and successfully treated with laparoscopic cytoreductive surgery and adjuvant chemotherapy. CONCLUSION: This report is the first case of paratubal cancer with bilateral tubal torsion which was diagnosed and treated with laparoscopic surgery, and the third report describing serous cystadenocarcinoma arising in a paratubal cyst. In the laparoscopic surgery for the paratubal cyst clinically presumed as accompanied with tubal torsion, surgeons should not ignore the possibility of malignancy in spite of the rare incidence of paratubal cancers and the preconception that adnexal malignancies are seldom accompanied by tubal torsion. PMID- 25556287 TI - Primary clear cell adenocarcinoma of the peritoneum presents as Sister Mary Joseph's nodule: a case report and literature review. AB - BACKGROUND: Sister Mary Joseph's nodule (SMJN) is a raised nodule around the umbilicus and is often a clinical sign of metastatic malignancy with poor prognosis. Primary clear cell adenocarcinoma of the peritoneum is rare. Herein the authors describe a case of primary peritoneal clear cell adenocarcinoma presenting with SMJN as an initial sign. CASE: A 59-year-old woman was admitted into the present hospital complaining of an enlarged, painful umbilical nodule, and increasing abdominal distention. After the biopsy of the peritoneal nodule, primary clear cell adenocarcinoma of the peritoneum was diagnosed. The patient underwent multiple courses of aggressive chemotherapy combined with radiotherapy and surgery and has survived for more than four years. CONCLUSION: Considering that SMJN is a rare sign of visceral malignancies, clinicians should be aware of this rare clinical sign when determining the differential diagnosis. Umbilical metastasis is usually indicates a poor prognosis. However, the present case suggests that long-term survival is possible. PMID- 25556288 TI - Chiral and achiral basket-handle porphyrins: short synthesis and stereostructures of these versatile building blocks. AB - Both, chiral and achiral basket-handle porphyrins were synthesized via a short, reliable, and efficient route in multigram quantities. Standard synthetic protocols such as metalation of the macrocycle, halogenation, and borylation of the porphyrin core or alkyl- and arylation with lithium organyls were successfully adapted. The planar-chiral representatives were resolved into their enantiomers, whose absolute configurations were determined by comparison of experimental CD spectra with TDCAM-B3LYP calculated ones. PMID- 25556289 TI - Lethal laryngopyocele. AB - A 44-year-old man collapsed after complaining of difficulty breathing. Layer dissection of the neck at autopsy revealed a large mixed internal and external laryngopyocele occluding the upper airway. It contained 30 mls of yellow-gray pus. Mechanisms of death in laryngoceles involve obstruction of the opening into the larynx resulting in accumulation of mucus or air within the sac causing airway occlusion. Once infection supervenes, deaths in laryngopyocoeles result either from accumulated pus causing airway occlusion from a mass effect (as in the current case) or the discharge of pus into the airway causing death from aspiration. Sudden death in laryngopyoceles is a very rare event that requires careful dissection at autopsy to demonstrate the characteristics of the underlying lesion and the possible mechanism of death. Laryngopyocele should be considered in the differential diagnosis of natural conditions causing acute, potentially lethal, upper airway obstruction. PMID- 25556290 TI - Oxygen inhibition layer of composite resins: effects of layer thickness and surface layer treatment on the interlayer bond strength. AB - An oxygen inhibition layer develops on surfaces exposed to air during polymerization of particulate filling composite. This study assessed the thickness of the oxygen inhibition layer of short-fiber-reinforced composite in comparison with conventional particulate filling composites. The effect of an oxygen inhibition layer on the shear bond strength of incrementally placed particulate filling composite layers was also evaluated. Four different restorative composites were selected: everX Posterior (a short-fiber-reinforced composite), Z250, SupremeXT, and Silorane. All composites were evaluated regarding the thickness of the oxygen inhibition layer and for shear bond strength. An equal amount of each composite was polymerized in air between two glass plates and the thickness of the oxygen inhibition layer was measured using a stereomicroscope. Cylindrical-shaped specimens were prepared for measurement of shear bond strength by placing incrementally two layers of the same composite material. Before applying the second composite layer, the first increment's bonding site was treated as follows: grinding with 1,000-grit silicon-carbide (SiC) abrasive paper, or treatment with ethanol or with water-spray. The inhibition depth was lowest (11.6 MUm) for water-sprayed Silorane and greatest (22.9 MUm) for the water-sprayed short-fiber-reinforced composite. The shear bond strength ranged from 5.8 MPa (ground Silorane) to 36.4 MPa (water-sprayed SupremeXT). The presence of an oxygen inhibition layer enhanced the interlayer shear bond strength of all investigated materials, but its absence resulted in cohesive and mixed failures only with the short-fiber-reinforced composite. Thus, more durable adhesion with short-fiber-reinforced composite is expected. PMID- 25556291 TI - Diffuse reflectance spectroscopy: toward real-time quantification of steatosis in liver. AB - Assessment of fatty liver grafts during orthotopic liver transplantation is a challenge due to the lack of real-time analysis options during surgery. Diffuse reflectance spectroscopy (DRS) could be a new diagnostic tool to quickly assess steatosis. Eight hundred and seventy-eight optical measurements were performed in vivo in 17 patients in liver tissue during surgery and ex vivo on liver resection specimens from 41 patients. Liver steatosis was quantified from the collected optical spectra and compared with the histology analysis from the measurement location by three independent pathologists. Twenty two patients were diagnosed with <5% steatosis, 15 patients had mild steatosis, and four had moderate steatosis. Severe steatosis was not identified. Intraclass correlation between the pathologists analysis was 0.949. A correlation of 0.854 was found between the histology and DRS analyses of liver steatosis ex vivo. For the same liver tissue, a correlation of 0.925 was demonstrated between in vivo and ex vivo DRS analysis for steatosis quantification. DRS can quantify steatosis in liver tissue both in vivo and ex vivo with good agreement compared to histopathology analysis. This analysis can be performed real time and may therefore be useful for fast objective assessment of liver steatosis in liver surgery. PMID- 25556292 TI - Urinary endometriosis: MR imaging appearance with surgical and histological correlations. AB - OBJECTIVES: The goals of the study were to describe the MR imaging features of endometriosis of the urinary tract and identify those that suggest intrinsic involvement of ureteric wall. MATERIALS AND METHODS: Thirty-five women with proven urinary tract endometriosis and who had preoperative MR imaging between 2001 and 2011 were included retrospectively. MR images were intrepreted by one junior and one senior radiologists. To characterize the intrinsic parietal involvement, the ureteric circumference involved by the lesion of endometriosis was noted. RESULTS: Thirty-eight ureteric and 13 bladder lesions were analyzed. They were found in association in nine women. Ureteric lesions were bilateral in seven women. Of the 38 ureteric lesions, 27 were extrinsic and 11 intrinsic at histopathological analysis. Sixteen women with extrinsic lesions and 10 with intrinsic ones were correctly identified on MR imaging. When the ureter was included less than 360 degrees in the lesion, extrinsic involvement was confirmed in 80% of cases. CONCLUSION: MR imaging appears to be more sensitive (91%vs 82%) but less specific (59% vs 67%) than surgery for the diagnosis of intrinsic form of ureteric location. PMID- 25556294 TI - The role of maternal behavior and offspring development in the survival of mountain goat kids. AB - Studies on juvenile survival have mainly focused on the effects of environmental conditions and maternal traits. However, growing evidence indicates that the ability of parents to care for their young and the offspring developmental behaviors could be key determinants of their survival. We examined the relative influence of (1) environmental conditions, (2) offspring traits, (3) maternal traits, (4) maternal care behaviors, and (5) offspring developmental behaviors on kid survival to weaning and to 1 year old in mountain goats (Oreamnos americanus). Offspring development and maternal care directly affected offspring survival, and this more importantly than did environmental conditions and maternal traits. Frequency of play strongly increased survival before weaning. Greater maternal care increased offspring survival during winter, directly and indirectly through kid mass. Kid mass was also a major determinant of both summer and winter survival. Environmental conditions mainly influenced summer survival while maternal characteristics indirectly affected winter survival through an effect on kid mass. Behavioral adaptations of maternal care and offspring development to local selective pressures can lead to local adaptations and have greater implications in population dynamic studies than previously believed. PMID- 25556295 TI - Morphological variation and different branch modularity across contrasting flow conditions in dominant Pocillopora reef-building corals. AB - Pocillopora corals, the dominant reef-builders in the Eastern Tropical Pacific, exhibit a high level of phenotypic plasticity, making the interpretation of morphological variation and the identification of species challenging. To test the hypothesis that different coral morphospecies represent phenotypes that develop in different flow conditions, we compared branch characters in three Pocillopora morphospecies (P. damicornis, P. verrucosa, and P. meandrina) from two communities in the Gulf of California exposed to contrasting flow conditions. Morphological variation and branch modularity (i.e., the tendency of different sets of branch traits to vary in a coordinated way) were assessed in colonies classified as Pocillopora type 1 according to two mitochondrial regions. Our results can be summarized as follows. (1) Pocillopora type 1 morphospecies corresponded to a pattern of morphological variation in the Gulf of California. Overall, P. damicornis had the thinnest branches and its colonies the highest branch density, followed by P. verrucosa, and then by P. meandrina, which had the thickest branches and its colonies the lowest branch density. (2) The differentiation among morphospecies was promoted by different levels of modularity of traits. P. verrucosa had the highest coordination of traits, followed by P. damicornis, and P. meandrina. (3) The variation and modularity of branch traits were related to water flow condition. Morphology under the high flow condition was more similar among morphospecies than under the low-flow condition and seemed to be related to mechanisms for coping with these conditions. Our results provide the first evidence that in scleractinian corals different levels of modularity can be promoted by different environmental conditions. PMID- 25556296 TI - Simple functionalization strategies for enhancing nanoparticle separation and recovery with asymmetric flow field flow fractionation. AB - Due to the increasing use of engineered nanomaterials in consumer products, regulatory agencies and other research organizations have determined that the development of robust, reliable, and accurate methodologies to characterize nanoparticles in complex matrices is a top priority. Of particular interest are methods that can separate and determine the size of nanomaterials in samples that contain polydisperse and/or multimodal nanoparticle populations. Asymmetric-flow field flow fractionation (AF4) has shown promise for the separation of nanoparticles with wide size range distributions; however, low analyte recoveries and decreased membrane lifetimes, due to membrane fouling, have limited its application. Herein, we report straightforward strategies to minimize membrane fouling and improve nanoparticle recovery by functionalizing the surface of the nanoparticles, as well as that of the AF4 membranes. Gold nanoparticles (AuNP) were stabilized through functionalization with a phosphine molecule, whereas the surface of the membranes was coated with a negatively charged polystyrenesulfonate polymer. Improved nanoparticle separation, recoveries of 99.1 (+/-0.5) %, and a detection limit of 6 MUg/kg were demonstrated by analyzing AuNP reference materials of different sizes (e.g., 10, 30, and 60 nm), obtained from the National Institute of Standards and Technology (NIST). Furthermore, the stability of the polymer coating and its specificity toward minimizing membrane fouling were demonstrated. PMID- 25556297 TI - Gargantuan left atrium: a sequela of mitral regurgitation and mitral stenosis. AB - Cardiac magnetic resonance imaging and echocardiography revealed a gargantuan left atrium measuring 18.9 cm * 15.7 cm * 11.3 cm in a 56-year-old patient diagnosed with severe rheumatic mitral stenosis, severe pulmonary hypertension, and permanent atrial fibrillation. A chest x-ray also revealed a cardiothoracic ratio approaching 1.0 and a transthoracic echocardiogram measured diameters as large as 19.2 cm. The patient then underwent mitral valve replacement and left atrial reduction surgery and has had no further admissions or complications. PMID- 25556298 TI - Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory. AB - Recent evidence has placed the unfolded protein response (UPR) at the centre of pathological processes leading to neurodegenerative disease. The translational repression caused by UPR activation starves neurons of the essential proteins they need to function and survive. Restoration of protein synthesis, via genetic or pharmacological means, is neuroprotective in animal models, prolonging survival. This is of great interest due to the observation of UPR activation in the post mortem brains of patients with Alzheimer's, Parkinson's, tauopathies and prion diseases. Protein synthesis is also an essential step in the formation of new memories. Restoring translation in disease or increasing protein synthesis from basal levels has been shown to improve memory in numerous models. As neurodegenerative diseases often present with memory impairments, targeting the UPR to both provide neuroprotection and enhance memory provides an extremely exciting novel therapeutic target. PMID- 25556299 TI - Porphyrin conjugated SiC/SiOx nanowires for X-ray-excited photodynamic therapy. AB - The development of innovative nanosystems opens new perspectives for multidisciplinary applications at the frontier between materials science and nanomedicine. Here we present a novel hybrid nanosystem based on cytocompatible inorganic SiC/SiOx core/shell nanowires conjugated via click-chemistry procedures with an organic photosensitizer, a tetracarboxyphenyl porphyrin derivative. We show that this nanosystem is an efficient source of singlet oxygen for cell oxidative stress when irradiated with 6 MV X-Rays at low doses (0.4-2 Gy). The in vitro clonogenic survival assay on lung adenocarcinoma cells shows that 12 days after irradiation at a dose of 2 Gy, the cell population is reduced by about 75% with respect to control cells. These results demonstrate that our approach is very efficient to enhance radiation therapy effects for cancer treatments. PMID- 25556301 TI - One session of partial-body cryotherapy (-110 degrees C) improves muscle damage recovery. AB - To evaluate the effects of a single session of partial-body cryotherapy (PBC) on muscle recovery, 26 young men performed a muscle-damaging protocol that consisted of five sets of 20 drop jumps with 2-min rest intervals between sets. After the exercise, the PBC group (n = 13) was exposed to 3 min of PBC at -110 degrees C, and the control group (n = 13) was exposed to 3 min at 21 degrees C. Anterior thigh muscle thickness, isometric peak torque, and muscle soreness of knee extensors were measured pre, post, 24, 48, 72, and 96 h following exercise. Peak torque did not return to baseline in control group (P < 0.05), whereas the PBC group recovered peak torques 96 h post exercise (P > 0.05). Peak torque was also higher after PBC at 72 and 96 h compared with control group (P < 0.05). Muscle thickness increased after 24 h in the control group (P < 0.05) and was significantly higher compared with the PBC group at 24 and 96 h (P < 0.05). Muscle soreness returned to baseline for the PBC group at 72 h compared with 96 h for controls. These results indicate that PBC after strenuous exercise may enhance recovery from muscle damage. PMID- 25556302 TI - Infrared spectroscopy of phenol-triethylsilane dihydrogen-bonded cluster and its cationic analogues: intrinsic strength of the Si-H...H-O dihydrogen bond. AB - Spectroscopic and theoretical investigations have been carried out for neutral phenol-triethylsilane clusters to reveal an intrinsic nature of the Si-H...H-O type dihydrogen bond. On the basis of the laser-induced fluorescence and infrared spectra, four isomers are identified. Three of them have a structure in which the dihydrogen bond and the dispersion interaction are competing in the stabilization of the cluster. However, the other isomer is found to have a distinct structure in which the dihydrogen bond is much stronger than the other isomers. In addition to the neutral clusters, cationic phenol(+)-diethylmethylsilane and phenol(+) triethylsilane clusters are investigated by infrared photodissociation spectroscopy. It is found that the dihydrogen bond is the dominant intermolecular interaction in these clusters. On the basis of the red shifts of the OH stretching bands, it is revealed that the strength of the Si-H...H-O dihydrogen bond is stronger than that of the pi-type hydrogen bond. The proton affinities of triethylsilane and diethylmethylsilane estimated by the theoretical calculation are larger than those of benzene and ethylene. These results are consistent with our experimental observations. PMID- 25556303 TI - Frailty in nursing homes: the FRAIL-NH Scale. PMID- 25556304 TI - Are we making the grade? Practices and reported efficacy measures of primate conservation education programs. AB - Conservation education is often employed alongside primate conservation efforts with the aim of changing knowledge, attitudes, and behaviors toward non-human primates. Recommended best-use practices include longevity, use of program incentives, collaboration among educators, and adaptive program assessment, among others. This study surveys primate conservation education programs (PCEPs) to assess the frequency of suggested best-use practices, and to investigate impacts on program efficacy. Online surveys were collected from PCEPs in 2013-2014 (N = 43). The majority of programs reported lengths of 5-10 years, with participant involvement ranging widely from a day to several years. Non-economic and economic incentives were distributed by approximately half of all programs, with programs that provided economic incentives reporting positive participant attitude changes more frequently than those that did not (P = 0.03). While >70% of PCEPs consulted with community leaders, local teachers, and research scientists, only 45.9% collaborated with other conservation educators and only 27% collaborated with cultural experts such as cultural anthropologists. Programs that collaborated with other conservation educators were more likely to report reductions in threats to primates, specifically to bushmeat hunting and capture of primates for the pet trade (P = 0.07). Formal program evaluations were employed by 72.1% of all programs, with the majority of programs using surveys to assess changes to participant attitudes and knowledge. Formal evaluations of participant behavior, community attitudes and behaviors, and threats to primate populations were less common. While results indicate that PCEPs follow many suggested best-use practices, program impacts may be enhanced by greater discussion of economic incentivization, increased collaboration between conservation educators, and improved commitment to adaptive evaluation of changes to behaviors in addition to attitudes and knowledge. PMID- 25556305 TI - Indoxyl sulfate upregulates prorenin expression via nuclear factor-kappaB p65, signal transducer and activator of transcription 3, and reactive oxygen species in proximal tubular cells. AB - We have recently found that indoxyl sulfate induces prorenin expression in proximal tubular cells. The present study aimed to determine whether nuclear factor-kappaB (NF-kappaB) p65, signal transducer and activator of transcription 3 (Stat3), and reactive oxygen species are involved in indoxyl sulfate-induced prorenin expression in cultured human proximal tubular cells (HK-2 cells). Effects of indoxyl sulfate on prorenin expression were determined using HK-2 cells with small interfering RNAs (siRNAs) specific to NF-kappaB p65 and Stat3, N acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase. Indoxyl sulfate increased prorenin expression in HK-2 cells. siRNAs specific to NF-kappaB p65 and Stat3 inhibited indoxyl sulfate-induced prorenin expression. Both N-acetylcysteine and diphenyleneiodonium suppressed indoxyl sulfate-induced prorenin expression. Indoxyl sulfate upregulates the expression of prorenin via NF-kappaB p65, Stat3, and reactive oxygen species in proximal tubular cells. PMID- 25556306 TI - Timing of dialysis initiation: when to start? Which treatment? AB - During the late 1990s early initiation of dialysis was introduced on a large scale and between 1996 and 2008, the percentage of patients with an estimated glomerular filtration rate (eGFR) above 10 mL/minute starting dialysis rose from 25% to 54% in the United States. However, several subsequent studies showed no survival benefit for patients commencing dialysis earlier. One possible explanation for the negative results could be that eGFR may be a flawed index; s creatinine is lower in patients with muscle wasting or fluid overload and these vulnerable patients with high comorbidity burden often start "early", i.e., at higher eGFR. Another explanation could be that dialysis is in fact harmful; dialysis initiation with conventional thrice weekly in-center hemodialysis clearly associates with increased initial mortality risk especially when using temporary dialysis catheters. Interestingly, patients starting on peritoneal dialysis (PD) appear to have better initial outcomes. More attention should be given to finding new objective mortality-predictive markers of uremia, reducing the use of temporary hemodialysis catheters, and increasing the use of PD as initial dialysis modality. PD may not only provide better initial dialysis outcomes but may also preserve renal function and vessels for vascular access for the benefit of better long-term outcomes. PMID- 25556307 TI - Bioimpedance can solve problems of fluid overload. AB - Bioimpedance (BI) techniques for measuring normal hydration status (NHS) can be generally classified as (1) by frequency as single frequency at 50 kHz, BI analysis, and multifrequency BI spectroscopy and (2) by method as whole body (wrist to ankle) measurement and calf BI spectroscopy. The aim of this article was to review current BI methods for clinical practice in patients with end-stage of kidney disease. BI vector analysis using whole-body single-frequency BI at 50 kHz may be useful for population studies to indicate a range of degree of fluid loading and of nutritional status. Whole body multifrequency BI spectroscopy is used to estimate extracellular (ECV), intracellular fluid volume, and total body water in dialysis patients. The whole-body BI model is used in the body composition monitor (BCM). The whole-body BI model is established with ECV, intracellular fluid volume, and body weight based on parameters from regression analysis in healthy subjects to calculate fluid overload in dialysis patients. Calf BI methods have been developed to measure NHS by 2 ways: (1) continuous measurement of the intradialytic resistance curve until flattening occurs; (2) calf normalized resistivity in the range of healthy subjects (18.5 * 10(-2) Omega m(3)/kg in male and 19.1 * 10(-2) Omega m(3)/kg in female). In general, for population studies, BI vector analysis or ECV/total body water may be useful; BCM is a commercially available device that can certainly guide volume reduction safely over time. For more exact measure of fluid overload, calf BI methods appear to be most accurate, but these are at present research tools. BI techniques are not only useful in assessing NHS but also in the study of nutrition and body composition. PMID- 25556308 TI - Cardiorenal syndrome: role of protein-bound uremic toxins. AB - Renal impairment is a strong independent risk factor associated with poor prognosis in cardiovascular disease patients. Renal dysfunction is likely contributed by progressive renal structural damage. Accurate detection of kidney injury in a timely manner as well as increased knowledge of the pathophysiology and mechanisms underlying this injury is of great importance in developing therapeutic interventions for combating renal complications at an early stage. Regarding the role of uremic solutes in the pathophysiology of cardiorenal syndrome, a number of further studies are warranted. There may be uremic solutes discovered from proteomics not yet chemically identified or tested for biological activity. Beyond Protein-bound uremic toxins, uremic solutes in other classes (according to the European Uraemic Toxin Work Group classification) may have adverse cardiorenal effects. Although most small water-soluble solutes and middle molecules can be satisfactorily removed by either conventional or newly developed dialysis strategies, targeting uremic toxins with cardiorenal toxicity at predialysis stage of chronic kidney disease may retard or prevent incident dialysis as well as the initiation/progression of cardiorenal syndrome. PMID- 25556309 TI - Endocrine and metabolic changes affecting cardiovascular disease in dialysis patients. AB - Protein-energy wasting plays an important role in the increased risk of mortality from cardiovascular disease in people with end-stage renal disease. Because protein-energy wasting is a condition of imbalance between anabolism and catabolism, endocrine and metabolic alterations that regulate such balance should be the possible target of intervention. Subjects with end-stage renal disease exhibit various changes in thyroid function, gonadal hormones, adrenal androgen, glucose metabolism, dyslipidemia, fatty acid composition, cholesterol absorption, and vitamin D. In this article, we briefly review the association of these alterations with mortality and cardiovascular disease in hemodialysis patients. Although some of them may be the adaptive response to the catabolic condition, these observational data are useful for risk stratification of patients and also for providing new ideas for possible prevention. PMID- 25556310 TI - Recent advances in understanding the pathogenesis of atherosclerosis in CKD patients. AB - A need exists for developing new therapies to improve cardiovascular outcomes in end-stage kidney disease. Three new areas that address novel pathophysiological mechanisms and/or therapeutic approaches toward cardiovascular events in chronic kidney disease patients include the use of an anti-inflammatory agent, the role of catalytic iron, and protein carbamylation. In preliminary studies, hydroxychloroquine, which has multiple anti-inflammatory properties, preserved vascular compliance for the aorta and major vessels, as well as reduced the extent of severity of atherosclerosis in ApoE-/- mice. The ability of iron to rapidly and reversibly cycle between 2 oxidation states makes iron potentially hazardous by enabling it to participate in the generation of powerful oxidant species. We have shown that high catalytic iron in the general population is associated with a 4-fold increase in prevalent cardiovascular disease (CVD), even after accounting for traditional risk factors. In addition, the highest levels of catalytic iron are present in dialysis patients and, more specifically, patients with prevalent CVD have several-fold higher catalytic iron levels compared with controls without CVD. These data suggest the utility of iron chelators for preventing and treating CVD in patients with chronic kidney disease and should be further investigated. Carbamylation of proteins results from nonenzymatic chemical modification by isocyanic acid derived from urea and an alternative route, the myeloperoxidase-catalyzed oxidation of thiocyanate. We have shown carbamylated low-density lipoprotein to have all the major biological effects relevant to atherosclerosis including endothelial cell injury, increased expression of cell adhesion molecules, and vascular smooth muscle cell proliferation. In 2 separate clinical studies, plasma levels of carbamylated protein independently predicted an increased risk of CVD and death. PMID- 25556311 TI - Inside and outside the pituitary: comparative analysis of Gnrhr expression provides insight into the mechanisms underlying the evolution of gene expression. AB - DNA cis-acting elements involved in gene regulation may actively contribute to adaptation processes because they are submitted to lower evolutionary constraints than coding DNA. In this regard, comparisons of the mechanisms underlying basal and regulated Gnrhr expression have revealed some features that promote stable and consistent Gnrhr expression in pituitary gonadotroph cells in different species. The presence of two divergent SF1 (NR5A1) response elements in all analysed mammalian Gnrhr promoters probably comprises one of the features that ensures reliable expression in the pituitary. By contrast, in other tissues, such as the hippocampus and testis, our analyses revealed dissimilar levels of Gnrhr expression among species. Indeed, Gnrhr was consistently expressed after birth in the rat but not the mouse hippocampus. Similar discrepancies were observed in foetal and adult testes. The ability of the rat promoter to drive reporter gene expression in the hippocampus and testis of transgenic mice just as it naturally directs the expression of the endogenous Gnrhr in rats strongly suggests that regulatory DNA sequences contained species-specific instructions prevailing over other controls. The major conclusion emerging from these studies is that Gnrhr promoter sequences are mainly responsible for directing transcriptional programmes and play a predominant role over the species-specific cell environment. PMID- 25556312 TI - The role of corticosterone and toxicity in the antipredator behavior of the Rough skinned Newt (Taricha granulosa). AB - A variety of mechanisms are responsible for enabling an organism to escape a predatory attack, including behavioral changes, alterations in hormone levels, and production and/or secretion of toxins. However, these mechanisms are rarely studied in conjunction with each other. The Rough-skinned Newt (Taricha granulosa) is an ideal organism to examine the relationships between these mechanisms because its behavioral displays and toxin secretion during a predator attack are well documented and readily characterized. While we found no direct relationship between antipredator behavior and endogenous levels of corticosterone (CORT), antipredator behavior was inhibited when exogenous CORT and adrenocorticotropic hormone (ACTH) were administered, resulting in high circulating concentrations of CORT, indicating that CORT may play a role in mediating the behavior. There was no correlation between the animal's toxicity and either CORT or behavior. The results of this study provide evidence that CORT plays an important, yet complex, role in the antipredator response of these amphibians. PMID- 25556313 TI - Dense breast tissue notification: impact on women's perceived risk, anxiety, and intentions for future breast cancer screening. AB - PURPOSE: The aim of this study was to explore how women respond to the wording of dense breast tissue notifications, which are increasingly required by state law after mammography. The specific aims were to (1) determine whether perceived lifetime risk for breast cancer and intentions to undergo mammography increase after reviewing a sample notification, (2) explore individual difference variables (eg, minority status, insurance coverage) that may influence intentions for additional ultrasound screening, and (3) assess whether anxiety mediates the relationship between perceived risk and screening intentions. METHODS: A total of 184 women aged >40 years in the United States were recruited from Amazon Mechanical Turk to respond to a dense breast tissue notification as if they had personally received it. RESULTS: After reviewing a notification, women reported greater perceived risk (d = 0.67) and intentions to undergo mammography (d = 0.25) than before. Most women intended to undergo additional ultrasound screening, although to a lesser extent when ultrasound was covered by insurance than when it was not (d = 1.03). All screening intentions were lower in women with ambiguity aversion, a tendency to avoid tests without medical consensus, and those who preferred an active decision-making role. Anxiety mediated the relationship between perceived breast cancer risk and all screening intentions. CONCLUSIONS: Women who receive dense breast tissue notifications may generally increase their breast cancer screening intentions; however, intention strength varies depending on internal (eg, ambiguity aversion) and external (eg, insurance for ultrasound) factors. Although perceived risk increases after notification, it is anxiety that drives women's intentions for future screening. PMID- 25556314 TI - Efficacy and Safety of Plasmakinetic Resection of the Prostate in Patients with a Prostate Gland Larger than 80 cc: 30-Month Follow-Up Results. AB - PURPOSE: This study aimed to evaluate the efficacy and safety of transurethral plasmakinetic resection of the prostate (PKRP) for the treatment of patients with benign prostatic hyperplasia (BPH) in men with prostate volume >80 cc. PATIENTS AND METHODS: From January 2010 to December 2011, 120 patients were included in our study; among these patients, 66 had prostate sizes of 80 cc to 100 cc and 54 had prostate sizes >100 cc. Pre-, peri- and postoperative evaluations were performed. RESULTS: The mean operative duration of PKRP was 112 minutes, and the mean resected tissue weight was 60.01 g. Hemoglobin level decreased by 0.65+/ 0.52 g/dL, and serum sodium content decreased by 0.06+/-2.62 mmol/L. The mean catheterization time was 83.05 hours, and the mean hospital stay was 12.47 days. The short follow-up time (30 months) demonstrated significant improvement in International Prostate Symptom Score, quality of life, and postvoid residual volume compared with preoperative characteristics. One patient underwent reoperation because of a blood clot in the bladder. Twelve patients complained of retrograde ejaculation. No patient experienced urinary incontinence. CONCLUSIONS: PKRP is safe and efficacious for men with BPH who have a large prostate (volume >80 cc). PMID- 25556315 TI - The bitter side of the nightshades: Genomics drives discovery in Solanaceae steroidal alkaloid metabolism. AB - Steroidal alkaloids (SAs) and their glycosylated forms (SGAs) are toxic compounds largely produced by members of the Solanaceae and Liliaceae plant families. This class of specialized metabolites serves as a chemical barrier against a broad range of pest and pathogens. In humans and animals, SAs are considered anti nutritional factors because they affect the digestion and absorption of nutrients from food and might even cause poisoning. In spite of the first report on SAs nearly 200 years ago, much of the molecular basis of their biosynthesis and regulation remains unknown. Aspects concerning chemical structures and biological activities of SAs have been reviewed extensively elsewhere; therefore, in this review the latest insights to the elucidation of the SAs biosynthetic pathway are highlighted. Recently, co-expression analysis combined with metabolic profiling revealed metabolic gene clusters in tomato and potato that contain core genes required for production of the prominent SGAs in these two species. Elaborating the knowledge regarding the SAs biosynthetic pathway, the subcellular transport of these molecules, as well as the identification of regulatory and signaling factors associated with SA metabolism will likely advance understanding of chemical defense mechanisms in Solanaceae and Liliaceae plants. It will also provide the means to develop, through classical breeding or genetic engineering, crops with modified levels of anti-nutritional SAs. PMID- 25556316 TI - Expression and membrane-targeting of an active plant cytochrome P450 in the chloroplast of the green alga Chlamydomonas reinhardtii. AB - The unicellular green alga Chlamydomonas reinhardtii has potential as a cell factory for the production of recombinant proteins and other compounds, but mainstream adoption has been hindered by a scarcity of genetic tools and a need to identify products that can be generated in a cost-effective manner. A promising strategy is to use algal chloroplasts as a site for synthesis of high value bioactive compounds such as diterpenoids since these are derived from metabolic building blocks that occur naturally within the organelle. However, synthesis of these complex plant metabolites requires the introduction of membrane-associated enzymes including cytochrome P450 enzymes (P450s). Here, we show that a gene (CYP79A1) encoding a model P450 can be introduced into the C. reinhardtii chloroplast genome using a simple transformation system. The gene is stably expressed and the P450 is efficiently targeted into chloroplast membranes by means of its endogenous N-terminal anchor domain, where it is active and accounts for 0.4% of total cell protein. These results provide proof of concept for the introduction of diterpenoid synthesis pathways into the chloroplast of C. reinhardtii. PMID- 25556318 TI - Extensive metazoan reefs from the Ediacaran Nama Group, Namibia: the rise of benthic suspension feeding. AB - We describe new, ecologically complex reef types from the Ediacaran Nama Group, Namibia, dated at ~548 million years ago (Ma), where the earliest known skeletal metazoans, Cloudina riemkeae and Namacalathus, formed extensive reefs up to 20 m in height and width. C. riemkeae formed densely aggregating assemblages associated with microbialite and thrombolite, each from 30 to 100 mm high, which successively colonised former generations to create stacked laminar or columnar reef frameworks. C. riemkeae individuals show budding, multiple, radiating attachment sites and cementation between individuals. Isolated Namacalathus either intergrew with C. riemkeae or formed dense, monospecific aggregations succeeding C. riemkeae frameworks, providing a potential example of environmentally mediated ecological succession. Cloudina and Namacalathus also grow cryptically, either as pendent aggregations from laminar crypt ceilings in microbial framework reefs or as clusters associated with thrombolite attached to neptunian dyke walls. These reefs are notable for their size, exceeding that of the succeeding Lower Cambrian archaeocyath-microbial communities. The repeated colonisation shown by C. riemkeae of former assemblages implies philopatric larval aggregation to colonise limited favourable substrates. As such, not only were skeletal metazoans more important contributors to reef building in the Ediacaran, but there were also more variable reef types with more complex ecologies, than previously thought. Such an abundance of inferred suspension feeders with biomineralised skeletons indicates the efficient exploitation of new resources, more active carbon removal with a strengthened energy flow between planktic and benthic realms, and the rise of biological control over benthic carbonate production. These mark the prelude to the Cambrian Explosion and the modernisation of the global carbon cycle. PMID- 25556317 TI - The effects of geometry and stability of solid-state nanopores on detecting single DNA molecules. AB - In this work we use a combination of 3D-TEM tomography, energy filtered TEM, single molecule DNA translocation experiments, and numerical modeling to show a more precise relationship between nanopore shape and ionic conductance and show that changes in geometry while in solution can account for most deviations between predicted and measured conductance. We compare the structural stability of ion beam sculpted (IBS), IBS-annealed, and TEM drilled nanopores. We demonstrate that annealing can significantly improve the stability of IBS made pores. Furthermore, the methods developed in this work can be used to predict pore conductance and current drop amplitudes of DNA translocation events for a wide variety of pore geometries. We discuss that chemical dissolution is one mechanism of the geometry change for SiNx nanopores and show that small modification in fabrication procedure can significantly increase the stability of IBS nanopores. PMID- 25556319 TI - Differential abundance of sarcoplasmic proteome explains animal effect on beef Longissimus lumborum color stability. AB - The sarcoplasmic proteome of beef Longissimus lumborum demonstrating animal-to animal variation in color stability was examined to correlate proteome profile with color. Longissimus lumborum (36 h post-mortem) muscles were obtained from 73 beef carcasses, aged for 13 days, and fabricated to 2.5-cm steaks. One steak was allotted to retail display, and another was immediately vacuum packaged and frozen at -80 degrees C. Aerobically packaged steaks were stored under display, and color was evaluated on days 0 and 11. The steaks were ranked based on redness and color stability on day 11, and ten color-stable and ten color-labile carcasses were identified. Sarcoplasmic proteome of frozen steaks from the selected carcasses was analyzed. Nine proteins were differentially abundant in color-stable and color-labile steaks. Three glycolytic enzymes (phosphoglucomutase-1, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase M2) were over-abundant in color-stable steaks and positively correlated (P<0.05) to redness and color stability. These results indicated that animal variations in proteome contribute to differences in beef color. PMID- 25556321 TI - Loss of oligophrenin1 leads to uncontrolled Rho activation and increased thrombus formation in mice. AB - BACKGROUND: Platelet cytoskeletal reorganization is essential for platelet adhesion and thrombus formation in hemostasis and thrombosis. The Rho GTPases RhoA, Rac1 and Cdc42 are the main players in cytoskeletal dynamics of platelets and induce filopodia and lamellipodia formation and actin polymerization to strongly increase the platelet surface upon activation. Moreover, they are important for platelet secretion, integrin activation and arterial thrombus formation. OBJECTIVES: Rho GTPases are regulated by GTPase-activating proteins (GAPs) that stimulate their GTPase activity to terminate Rho signaling. The regulation of Rho GTPase activity in platelets is not well defined. Recently, we identified oligophrenin1 (OPHN1), a RhoGAP in platelets that exhibits strong GTPase-stimulating activity towards RhoA, Cdc42 and Rac1. RESULTS: In the present study we show for the first time, that deficiency of OPHN1 led to abnormal Rho activation and increased platelet cytoskeletal reorganization, including cell adhesion and lamellipodia formation on fibrinogen. Furthermore, platelets from ophn1(-/-) mice showed enhanced susceptibility to platelet activation with alterations in actin distribution and early release of granules. Platelet activation was enhanced following GPVI and PAR4 stimulation. This translated into elevated platelet thrombus formation and promoted arterial thrombosis under low shear conditions with altered hemostasis, as detected by tail bleeding time. CONCLUSIONS: The results of the present study identified OPHN1 as an important regulator of platelet cytoskeletal reorganization and demonstrate that abnormal regulation of Rho proteins leads to increased platelet adhesion and thrombus formation under low shear conditions in vitro and in vivo, suggesting a prothrombotic phenotype of mice critical for acute thrombotic occlusions. PMID- 25556320 TI - Stereological study of pyramidal neurons in the human superior temporal gyrus from childhood to adulthood. AB - The association cortex of the superior temporal gyrus (STG) is implicated in complex social and linguistic functions. Thus, reliable methods for quantifying cellular variation in this region could greatly benefit researchers interested in addressing the cellular correlates of typical and atypical function associated with these critical cognitive abilities. To facilitate this task, we first present a general set of cytoarchitectonic criteria targeted specifically toward stereological analyses of thick, Nissl-stained sections for the homotypical cortex of the STG, referred to here as BA22/TA. Second, we use the optical fractionator to estimate pyramidal neuron number and the nucleator for pyramidal somal and nuclear volume. We also investigated the influence of age and sex on these parameters, as well as set a typically developing baseline for future comparisons. In 11 typically developing cases aged 4-48 years, the most distinguishing features of BA22/TA were the presence of distinct granular layers, a prominent, jagged layer IIIc, and a distinctly staining VIa. The average number of neurons was 91 +/- 15 million, the volume of pyramidal soma 1,512 um(3) , and the nuclear volume 348 um(3) . We found no correlation with age and neuron number. In contrast, pyramidal somal and nuclear volume were both negatively correlated and linearly associated with age in regression analyses. We found no significant sex differences. Overall, the data support the idea that postnatal neuron numbers are relatively stable through development but also suggest that neuronal volume may be subject to important developmental variation. Both measures are critical variables in the study of developmental neuropathology. PMID- 25556322 TI - Correlation between SPARC (Osteonectin) expression with immunophenotypical and invasion characteristics of pituitary adenomas. AB - Pituitary adenomas are the third most common intracranial tumors. Invasive adenomas account for only 0.1-0.2% of pituitary tumors. SPARC is a matrix glycoprotein that plays a role in progression and invasiveness of neoplasms. In this study, we examined the potential role of SPARC in invasive pituitary adenomas. Forty pituitary adenomas have been examined with histopathological and immunohistochemical techniques. The cohort has been classified into two groups as invasive (n = 25) and non-invasive (n = 15) utilizing the Hardy classification. Formalin fixed tissues have been stained with hematoxylin eosin. Ki-67, p53, and SPARC monoclonal antibodies have been used. We did not detect any significant difference on Ki-67, SPARC, and p53 expression patterns correlating with the pathological subtype or invasiveness. Only 24% of invasive adenomas had Ki-67 levels over 1%. A total of 67.7% non-invasive adenomas had Ki-67 levels below 1%. We did not detect any relation between SPARC levels and invasiveness of pituitary adenomas. Absence of significant SPARC expression in tumor progression, sellar dilatation, erosion and destruction suggest that SPARC scores are not related with invasiveness or progressiveness of pituitary adenomas. PMID- 25556323 TI - Hutchinson-Gilford progeria syndrome caused by an LMNA mutation: a case report. AB - Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity. PMID- 25556324 TI - Sarcopenia is an independent predictor of complications following pancreatectomy for adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: Sarcopenia, which is subclinical loss of skeletal muscle mass, is commonly observed in patients with malignancy. The objective of this study is to determine the correlation between sarcopenia and operative complications following pancreatectomy for cancer. METHODS: A retrospective review of a pancreatectomy database was performed. The Hounsfield Unit Average Calculation (HUAC) of the psoas muscle, a marker of muscle density and fatty infiltration, was measured from preoperative CT scans. Complications were graded and multivariate logistic regression analysis was performed. RESULTS: One hundred eighteen patients met criteria for analysis; the overall morbidity rate was 78.8% (n = 93). There were 31 (26.3%) patients who met criteria for sarcopenia using the HUAC. When analyzed as a continuous variable, sarcopenia was an independent predictor of major grade III complications, length of stay, intensive care unit admission, delayed gastric emptying, and infectious, gastrointestinal, pulmonary, and cardiac complications. CONCLUSIONS: These data suggest that sarcopenia as measured with the HUAC, a value that can be obtained from a preoperative CT scan, is a significant independent predictor of surgical outcome and can be used to improve patient selection and informed consent prior to pancreatectomy in patients with cancer. PMID- 25556325 TI - The Atopic Dermatitis Antecubital Severity score: validity, reliability, and sensitivity to change in patients with atopic dermatitis. AB - BACKGROUND: The Atopic Dermatitis Antecubital Severity (ADAS) score is a new objective scale for the assessment of the severity of atopic dermatitis (AD). It is calculated by multiplying the intensity of inflammatory signs by the size of an antecubital eczema lesion. AIM: To test the validity, reliability, and sensitivity to changes of the ADAS score compared with those of the Eczema Area and Severity Index (EASI) score. METHODS: Forty patients with AD were enrolled and treated with a moisturizer. At baseline, and in weeks 1 and 2, two independent evaluators measured the ADAS score, the EASI score, and the investigator's global assessment score rated on a six-point scale. RESULTS: The ADAS score showed a higher validity than the EASI score. The superiority of the ADAS to the EASI was prominent in mild AD. Inter-evaluator reliability was excellent in both the ADAS score and the EASI. The sensitivity to changes was higher in the ADAS score than in the EASI score. CONCLUSIONS: The ADAS score may be used as a simple scoring system with good validity, reliability, and sensitivity to changes, especially in patients with mild-to-moderate AD. PMID- 25556326 TI - Dehydrated amnion/chorion membrane and venous leg ulcers. PMID- 25556327 TI - Effects of dietary enrichment with a marine oil-based n-3 LCPUFA supplement in sows with predicted birth weight phenotypes on growth performance and carcass quality of offspring. AB - Effects of a marine oil-based n-3 LCPUFA supplement (mLCPUFA) fed from weaning until the end of the next lactation to sows with a predicted low litter birth weight (LBW) phenotype on growth performance and carcass quality of litters born to these sows were studied, based on the hypothesis that LBW litters would benefit most from mLCPUFA supplementation. Sows were allocated to be fed either standard corn/soybean meal-based gestation and lactation diets (CON), or the same diets enriched with 0.5% of the mLCPUFA supplement at the expense of corn. The growth performance from birth until slaughter of the litters with the lowest average birth weight in each treatment (n=24 per treatment) is reported in this paper. At weaning, each litter was split between two nursery pens with three to six pigs per pen. At the end of the 5-week nursery period, two barrows and two gilts from each litter that had individual birth weights closest to their litter average birth weight, were moved to experimental grow-finish pens (barn A), where they were housed as two pigs per pen, sorted by sex within litter. Remaining pigs in each litter were moved to another grow-finish barn (barn B) and kept in mixed sex pens of up to 10 littermates. After 8 weeks, one of the two pigs in each pen in barn A was relocated to the pens holding their respective littermates in barn B. The remaining barrows and gilts were individually housed in the pens in barn A until slaughter. Maternal mLCPUFA supplementation increased docosahexaenoic acid (DHA) concentration in the brain, liver and Semitendinosus muscle of stillborn pigs (P<0.01), did not affect eicosapentaenoic acid and DHA concentrations in sow serum at the end of lactation, and did not affect average daily gain, average daily feed intake or feed utilization efficiency of the offspring. BW was higher (P<0.01) in the second half of the grow-finish phase in pigs from mLCPUFA sows compared with controls in barn A, where space and competition for feed was minimal, but not barn B. Carcass quality was not affected by treatment for pigs from barn A, but maternal mLCPUFA supplementation negatively affected carcass quality in pigs from barn B. Collectively, these results suggest that nutritional supplementation of sows can have lasting effects on litter development, but that feeding mLCPUFA to sows during gestation and lactation was not effective in improving growth rates or carcass quality of LBW litters. PMID- 25556328 TI - Different behaviours of promoters in Mycobacterium tuberculosis H37Rv and H37Ra. AB - Mycobacterium tuberculosis H37Rv and H37Ra are two closely-related bacterial strains in which the former is virulent whereas the latter is not. Although the genetic differences between these strains are known, our understanding of how they control the difference in virulence characteristics is incomplete. In this work, we tested the activities of different mycobacterium gene promoters in the two strains using a gfp reporter gene. The promoter activities were compared between growth in vitro and growth of bacteria residing in U937 cells (a macrophage-like cell line). The promoters tested included M. tuberculosis isocitrate lyase (icl), alpha crystalline homolog (hspX) and moeZ, and the M. avium macrophage-induced gene (mig) promoter. Two hspX constructs with different lengths of the promoter sequence were tested. All promoters except the shorter hspX construct were active in the H37Ra strain in both liquid culture and in U937 cells. In the H37Rv strain, the shorter hspX and icl constructs were induced in infected U937 cells relative to liquid culture, whereas the mig construct was active in both conditions. In conclusion, the inducible properties of the shorter hspX and the icl promoters evident in H37Rv appeared to be lost in the H37Ra strain. Furthermore, sequence further upstream of the hspX gene appears to modulate the inducible property of the hspX promoter in a strain-dependent manner. PMID- 25556329 TI - Real-time ventilation and perfusion distributions by electrical impedance tomography during one-lung ventilation with capnothorax. AB - BACKGROUND: Carbon dioxide insufflation into the pleural cavity, capnothorax, with one-lung ventilation (OLV) may entail respiratory and hemodynamic impairments. We investigated the online physiological effects of OLV/capnothorax by electrical impedance tomography (EIT) in a porcine model mimicking the clinical setting. METHODS: Five anesthetized, muscle-relaxed piglets were subjected to first right and then left capnothorax with an intra-pleural pressure of 19 cm H2 O. The contra-lateral lung was mechanically ventilated with a double lumen tube at positive end-expiratory pressure 5 and subsequently 10 cm H2 O. Regional lung perfusion and ventilation were assessed by EIT. Hemodynamics, cerebral tissue oxygenation and lung gas exchange were also measured. RESULTS: During right-sided capnothorax, mixed venous oxygen saturation (P = 0.018), as well as a tissue oxygenation index (P = 0.038) decreased. There was also an increase in central venous pressure (P = 0.006), and a decrease in mean arterial pressure (P = 0.045) and cardiac output (P = 0.017). During the left-sided capnothorax, the hemodynamic impairment was less than during the right side. EIT revealed that during the first period of OLV/capnothorax, no or very minor ventilation on the right side could be seen (3 +/- 3% vs. 97 +/- 3%, right vs. left, P = 0.007), perfusion decreased in the non-ventilated and increased in the ventilated lung (18 +/- 2% vs. 82 +/- 2%, right vs. left, P = 0.03). During the second OLV/capnothorax period, a similar distribution of perfusion was seen in the animals with successful separation (84 +/- 4% vs. 16 +/- 4%, right vs. left). CONCLUSION: EIT detected in real-time dynamic changes in pulmonary ventilation and perfusion distributions. OLV to the left lung with right-sided capnothorax caused a decrease in cardiac output, arterial oxygenation and mixed venous saturation. PMID- 25556330 TI - A case report of sudden-onset upper and lower extremity weakness. AB - Thyrotoxic hypokalemic periodic paralysis is characterized by acute attacks of muscle paralysis, hypokalemia, and thyrotoxicosis. It is a medical emergency, as fatal and life-threatening ventricular arrhythmia associated with hypokalemia has been reported. A 24-year-old man presented with severe lower extremity weakness, which progressed to his trunk and arms. He denied any associated symptoms and had no history of a similar episode or predisposing condition. The physical examination was significant for bilateral extremity weakness, more severe in the lower as compared to the upper extremities. The rest of the neurologic exam was normal. A small, smooth, nontender goiter was palpated. Laboratory data was significant for a potassium level of 2.0 mEq/L. Final lab data revealed a thyroid panel consistent with hyperthyroidism. Once the patient's potassium level normalized after repletion, he recovered his strength and was able to walk again. He was diagnosed with thyrotoxic hypokalemic periodic paralysis, a potentially lethal complication of hyperthyroidism. Because it is reversible with treatment of hyperthyroidism, it is imperative that this condition be considered, recognized and managed appropriately. PMID- 25556332 TI - A solvated zinc analogue of the calomel-dication. AB - The synthesis and characterisation of the solvent-stabilized salt [Zn2(THF)6](2+)[BAr4(F)]2(-) (1) is presented, which features the dizinc dication [Zn2](2+) as an analogue of the calomel dication [Hg2](2+). The labile tetrahydrofuran (THF) solvate molecules of 1 can be readily substituted by other ligands. Reaction with the strong donor ligand PMe3 (Me = CH3) leads to the Zn(ii) complex [Zn(PMe3)4](2+)[BAr4(F)]2(-) by disproportionation, while the pi acceptor-ligand phenylisocyanide (PhNC) gives the substitution product [Zn2(PhNC)6](2+)[BAr4(F)]2(-) (2) with an intact Zn-Zn bond. PMID- 25556331 TI - Routine storage of red blood cell (RBC) units in additive solution-3: a comprehensive investigation of the RBC metabolome. AB - BACKGROUND: In most countries, red blood cells (RBCs) can be stored up to 42 days before transfusion. However, observational studies have suggested that storage duration might be associated with increased morbidity and mortality. While clinical trials are under way, impaired metabolism has been documented in RBCs stored in several additive solutions (ASs). Here we hypothesize that, despite reported beneficial effects, storage in AS-3 results in metabolic impairment weeks before the end of the unit shelf life. STUDY DESIGN AND METHODS: Five leukofiltered AS-3 RBC units were sampled before, during, and after leukoreduction Day 0 and then assayed on a weekly basis from storage Day 1 through Day 42. RBC extracts and supernatants were assayed using a ultra-high performance liquid chromatography separations coupled online with mass spectrometry detection metabolomics workflow. RESULTS: Blood bank storage significantly affects metabolic profiles of RBC extracts and supernatants by Day 14. In addition to energy and redox metabolism impairment, intra- and extracellular accumulation of amino acids was observed proportionally to storage duration, suggesting a role for glutamine and serine metabolism in aging RBCs. CONCLUSION: Metabolomics of stored RBCs could drive the introduction of alternative ASs to address some of the storage-dependent metabolic lesions herein reported, thereby increasing the quality of transfused RBCs and minimizing potential links to patient morbidity. PMID- 25556333 TI - Contraceptive methods and ovarian cancer risk among Chinese women: A report from the Shanghai Women's Health Study. AB - Oral contraceptive use is associated with reduced ovarian cancer risk; however, associations with other contraceptive methods, such as intrauterine device (IUD) and tubal ligation, are less clear. Women in China differ from western women in regard to mechanisms and duration of use of contraception. This study was undertaken to evaluate associations between contraceptive methods and ovarian cancer risk using data from the prospective Shanghai Women's Health Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. A total of 174 epithelial ovarian cancer cases were found to occur among 70,259 women who were followed-up for a total of 888,258 person-years. The majority of women had ever used any contraception (77.0%), including IUD (55.6%), oral contraceptive (20.4%), tubal ligation (14.7%) or contraceptive shots (2.6%). Ever use of any contraception was associated with a nonsignificant reduction in ovarian cancer risk (HR: 0.86, 95% CI: 0.60-1.24). Longer duration of IUD use was associated with lower ovarian cancer risk (p-value for trend = 0.04). Compared with never users, women with durations of IUD use longer than the median (20 years) were 38% less likely to develop ovarian cancer (HR: 0.62, 95% CI: 0.40-0.97). Based on the high prevalence and long duration of IUD use among Chinese women, we estimate a preventive fraction of 9.3%, corresponding to approximately 16 ovarian cancer cases. High prevalence of long-term IUD use may, therefore, contribute to the low incidence of ovarian cancer observed in China. PMID- 25556334 TI - pH-Responsive Capsules Engineered from Metal-Phenolic Networks for Anticancer Drug Delivery. AB - A new class of pH-responsive capsules based on metal-phenolic networks (MPNs) for anticancer drug loading, delivery and release is reported. The fabrication of drug-loaded MPN capsules, which is based on the formation of coordination complexes between natural polyphenols and metal ions over a drug-coated template, represents a rapid strategy to engineer robust and versatile drug delivery carriers. PMID- 25556335 TI - Parental attitude toward deviance as a predictor of delinquency: making the connection via perception and cognition. AB - This study tested a core postulate of social cognitive theory: i.e., that perception precedes cognition in the development of behavior. Using data from four of the first five waves of the 1725-member (918 males, 807 females) National Youth Survey (NYS), youth perception of parental attitude toward deviance and youth attitude toward deviance at Waves 2 and 3 were tested as possible mediators of the relationship between Wave 1 parental attitude toward deviance and self reported delinquency at Wave 5. The target chain was both significant and significantly stronger than the reverse chain and there was no evidence that age, race, or sex moderated this mediated relationship. These results support the presence of a chaining process in which proximal social, perceptual, and cognitive events link to distal behavioral outcomes like delinquency. PMID- 25556336 TI - Rational design of a humanized glucagon-like peptide-1 receptor agonist antibody. AB - Bovine antibody BLV1H12 possesses a unique "stalk-knob" architecture in its ultralong heavy chain CDR3, allowing substitutions of the "knob" domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon-like peptide-1 (GLP-1) receptor agonist antibody by first introducing a coiled-coil "stalk" into CDR3H of the antibody herceptin. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex-4 to allow release of the N-terminus of the fused peptide. The resulting clipped herceptin-Ex-4 fusion protein is more potent in vitro in activating GLP-1 receptors than the Ex-4 peptide. The clipped herceptin-Ex-4 has an extended plasma half-life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics. PMID- 25556337 TI - Sense of coherence is significantly associated with both metabolic syndrome and lifestyle in Japanese computer software office workers. AB - OBJECTIVES: Sense of coherence (SOC) is an individual characteristic related to a positive life orientation, leading to effective coping. Little is known about the relationship between SOC and metabolic syndrome (MetS). This cross-sectional study aimed at testing the hypothesis that workers with a strong SOC have fewer atherosclerotic risk factors, including MetS, and healthier lifestyle behaviors. MATERIAL AND METHODS: One hundred and sixty-seven computer software workers aged 20-64 years underwent a periodical health examination including assessment of body mass index, waist circumference, blood pressure, blood lipid levels, fasting blood sugar (FBS) levels and lifestyle behaviors (walking duration, smoking status, nutrition, alcohol consumption, and sleep duration). During this period, the participants also completed a 29-item questionnaire of SOC and the Brief Job Stress Questionnaire to assess job stressors such as job strain and workplace social support. RESULTS: Our results showed that the participants with a stronger SOC were likely to walk for at least 1 h a day, to eat slowly or at a moderate speed, and to sleep for at least 6 h. Compared with the participants with the weakest SOC, those with the strongest SOC had a significantly lower odds ratio (OR) for being overweight (OR = 0.31; 95% confidence interval (CI): 0.11-0.81), and having higher FBS levels (OR = 0.11; 95% CI: 0.02-0.54), dyslipidemia (OR = 0.29; 95% CI: 0.09-0.84), and MetS (OR = 0.12; 95% CI: 0.02-0.63), even after adjusting for age, gender and job stressors. CONCLUSIONS: High SOC is associated with a healthy lifestyle and fewer atherosclerotic risk factors, including MetS. PMID- 25556338 TI - Greater deciduous shrub abundance extends tundra peak season and increases modeled net CO2 uptake. AB - Satellite studies of the terrestrial Arctic report increased summer greening and longer overall growing and peak seasons since the 1980s, which increases productivity and the period of carbon uptake. These trends are attributed to increasing air temperatures and reduced snow cover duration in spring and fall. Concurrently, deciduous shrubs are becoming increasingly abundant in tundra landscapes, which may also impact canopy phenology and productivity. Our aim was to determine the influence of greater deciduous shrub abundance on tundra canopy phenology and subsequent impacts on net ecosystem carbon exchange (NEE) during the growing and peak seasons in the arctic foothills region of Alaska. We compared deciduous shrub-dominated and evergreen/graminoid-dominated community level canopy phenology throughout the growing season using the normalized difference vegetation index (NDVI). We used a tundra plant-community-specific leaf area index (LAI) model to estimate LAI throughout the green season and a tundra-specific NEE model to estimate the impact of greater deciduous shrub abundance and associated shifts in both leaf area and canopy phenology on tundra carbon flux. We found that deciduous shrub canopies reached the onset of peak greenness 13 days earlier and the onset of senescence 3 days earlier compared to evergreen/graminoid canopies, resulting in a 10-day extension of the peak season. The combined effect of the longer peak season and greater leaf area of deciduous shrub canopies almost tripled the modeled net carbon uptake of deciduous shrub communities compared to evergreen/graminoid communities, while the longer peak season alone resulted in 84% greater carbon uptake in deciduous shrub communities. These results suggest that greater deciduous shrub abundance increases carbon uptake not only due to greater leaf area, but also due to an extension of the period of peak greenness, which extends the period of maximum carbon uptake. PMID- 25556339 TI - False discovery rates for rare variants from sequenced data. AB - The detection of rare deleterious variants is the preeminent current technical challenge in statistical genetics. Sorting the deleterious from neutral variants at a disease locus is challenging because of the sparseness of the evidence for each individual variant. Hierarchical modeling and Bayesian model uncertainty are two techniques that have been shown to be promising in pinpointing individual rare variants that may be driving the association. Interpreting the results from these techniques from the perspective of multiple testing is a challenge and the goal of this article is to better understand their false discovery properties. Using simulations, we conclude that accurate false discovery control cannot be achieved in this framework unless the magnitude of the variants' risk is large and the hierarchical characteristics have high accuracy in distinguishing deleterious from neutral variants. PMID- 25556340 TI - Growth, crystalline perfection, spectral and optical characterization of a novel optical material: l-tryptophan p-nitrophenol trisolvate single crystal. AB - l-tryptophan p-nitrophenol trisolvate (LTPN), an organic nonlinear optical material was synthesized using ethanol-water mixed solvent and the crystals were grown by a slow solvent evaporation method. The crystal structure and morphology were studied by single crystal X-ray diffraction analysis. The crystalline perfection of the LTPN crystal was analyzed by high-resolution X-ray diffraction study. The molecular structure of the crystal was confirmed by observing the various characteristic functional groups of the material using vibrational spectroscopy. The cut-off wavelength, optical transmission, refractive index and band gap energy were determined using UV-visible data. The variation of refractive index with wavelength shows the normal behavior. The second harmonic generation of the crystal was confirmed and the efficiency was measured using Kurtz Perry powder method. Single and multiple shot methods were employed to measure surface laser damage of the crystal. The photoluminescence spectral study revealed that the emission may be associated with the radiative recombination of trapped electrons and holes. Microhardness measurements revealed that LTPN belongs to a soft material category. PMID- 25556341 TI - Conformation and NH stretching of 1,1-dihalogenoheptan-1-amines [CH3(CH2)5CX2NH2; X=F, Cl or Br]: halogen and solvent effects. AB - The effects of halogen and solvent on the conformation and NH stretching of 1,1 dihalogeno-heptan-1-amines [CH3(CH2)5CX2NH2; X=F, Cl or Br] were investigated using the density functional theory method. The functional used was B3LYP employing the 6-31++G(d,p) basis set for all atoms. Computations were carried out for ten possible conformational isomers of the compounds, in the gas phase and both in a non-polar solvent (benzene) and in a polar solvent (methanol). This research work indicates that both the halogen and the medium affect conformational preference, geometrical parameters and NH vibrational frequency. The findings of this work can be useful to those systems involving changes in the conformations analogous to the compounds studied. PMID- 25556342 TI - Normal co-ordinate analysis, molecular structural, non-linear optical, second order perturbation studies of Tizanidine by density functional theory. AB - The spectroscopic techniques and semi-empirical molecular calculations have been utilized to analyze the drug Tizanidine (5CDIBTA). The solid phase Fourier Transform Infrared (FTIR) and Fourier Transform Raman (FTR) spectral analysis of 5CDIBTA is carried out along with density functional theory (DFT) calculations (B3LYP) with the 6-311++G(d,p) basis set. Detailed interpretation of the vibrational spectra of the compound has been made on the basis of the calculated potential energy distribution (PED). The individual atomic charges by NPA using B3LYP method is studied. A study on the Mulliken atomic charges, frontier molecular orbitals (HOMO-LUMO), molecular electrostatic potential (MEP) and thermodynamic properties were performed. The electric dipole moment (MU) and the first hyperpolarizability (alpha) values of the investigated molecule were also computed. PMID- 25556344 TI - One of the ongoing challenges in the management of CRS is determining the optimal diagnostic method. PMID- 25556343 TI - Cross-linked human serum albumin dimer has the potential for use as a plasma retaining agent for the fatty acid-conjugated antidiabetic drugs. AB - OBJECTIVES: The half-life of fatty acid-conjugated antidiabetic drugs are prolonged through binding to albumin, but this may not occur in diabetic patients with nephropathy complicated with hypoalbuminemia. We previously showed that human serum albumin (HSA) dimerized at the protein's Cys34 by 1,6 bis(maleimido)hexane has longer half-life than the monomer under high permeability conditions. The aim of this study was to investigate the superior ability of this HSA dimer as a plasma-retaining agent for fatty acid conjugated antidiabetic drugs. METHODS: The diabetic nephropathy rat model was prepared by administering a single injection of streptozotocin (STZ) intravenously, and the pharmacokinetic properties of HSA monomer and dimer were evaluated. Site-specific fluorescent probe displacement experiments were performed using warfarin and dansylsarcosine as site I and site II specific fluorescent probes, respectively. KEY FINDINGS: The half-life of the HSA dimer in STZ-induced diabetic nephropathy model rats was 1.5 times longer than the HSA monomer. The fluorescent probe displacement experiment results for HSA monomer and dimer were similar, where fatty acid-conjugated antidiabetic drugs displaced dansylsarcosine but not warfarin in a concentration-dependent manner. CONCLUSIONS: The HSA dimer shows potential for use as a plasma-retaining agent for antidiabetic drugs due to its favourable pharmacokinetic properties. PMID- 25556345 TI - Hippocampal sclerosis: the missing link of cysticercosis epileptogenesis? PMID- 25556346 TI - Ligand-modulated interactions between charged monolayer-protected Au144(SR)60 gold nanoparticles in physiological saline. AB - In order to determine how functionalized gold nanoparticles (AuNPs) interact in a near-physiological environment, we performed all-atom molecular dynamics simulations on the icosahedral Au144 nanoparticles each coated with a homogeneous set of 60 thiolates selected from one of these five (5) types: 11-mercapto-1 undecanesulfonate -SC11H22(SO3(-)), 5-mercapto-1-pentanesulfonate -SC5H10(SO3( )), 5-mercapto-1-pentaneamine -SC5H10(NH3(+)), 4-mercapto-benzoate -SPh(COO(-)), or 4-mercapto-benzamide -SPh(CONH3(+)). These thiolates were selected to elucidate how the aggregation behavior of AuNPs depends on ligand parameters, including the charge of the terminal group (anionic vs. cationic), and its length and conformational flexibility. For this purpose, each functionalized AuNP was paired with a copy of itself, placed in an aqueous cell, neutralized by 120 Na(+)/Cl(-) counter-ions and salinated with a 150 mM concentration of NaCl, to form five (5) systems of like-charged AuNPs pairs in a saline. We computed the potential of mean force (the reversible work of separation) as a function of the intra-pair distance and, based on which, the aggregation affinities. We found that the AuNPs coated with negatively charged, short ligands have very high affinities. Structurally, a significant number of Na(+) counter-ions reside on a plane between the AuNPs, mediating the interaction. Each such ion forms a "salt bridge" (or "ionic bonds") to both of the AuNPs when they are separated by its diameter plus 0.2-0.3 nm. The positively charged AuNPs have much weaker affinities, as Cl(-) counter-ions form fewer and weaker salt bridges between the AuNPs. In the case of Au144(SC11H22(SO3(-)))60 pair, the flexible ligands fluctuate much more than the other four cases. The large fluctuations disfavor the forming of salt bridges between two AuNPs, but enable hydrophobic contact between the exposed hydrocarbon chains of the two AuNPs, which are subject to an effective attraction at a separation much greater than the AuNP diameter and involve a higher concentration of counter ions in the inter-pair space. PMID- 25556347 TI - Standardization of a human organ culture model of intestinal inflammation and its application for drug testing. AB - Targeting early molecular events in intestinal inflammation may represent a useful therapeutic strategy for maintaining remission in inflammatory bowel disease. Recently, we established an intestinal organ culture model (LEL model), which allows to study the initiation of an intestinal inflammatory response in human tissue. In this model, EDTA-mediated depletion of epithelial cells of colonic mucosa results in an instantaneous inflammatory response in resident lamina propria cells, which shows features of intestinal inflammation in vivo. Furthermore, activated immune cells emigrate from the lamina propria onto the luminal side of the basement membrane. Here, we standardize the LEL model and explore its suitability for drug testing. To this end, human mucosal punches of defined surface area were prepared, depleted of epithelial cells, and cultured at an optimized ratio of medium volume/punch area. The intra-assay variability of measurements of inflammatory parameters ranged from 13% for cell migration to 19% for secretion and 30% for tissue gene expression, respectively, of the inflammatory mediators IL-8 and IL-6. Importantly, known suppressive effects of dexamethasone, a drug employed for the treatment of inflammatory bowel diseases, on leucocyte migration, IL8, IL6, and TNF-alpha production as well as CD86 surface expression by myeloid cells were observed in this model. In conclusion, the present results suggest that the LEL model may represent a useful human experimental system not only for studying initial activation mechanisms in intestinal inflammation but also for evaluating drug compounds for the treatment of mucosal inflammation. PMID- 25556348 TI - Spin switching in electronic devices based on 2D assemblies of spin-crossover nanoparticles. AB - Two-dimensional assemblies of triazole-based spin-crossover nanoparticles (SCO NPs) presenting different morphologies are prepared and electrically characterized. The thermal hysteresis loop in the electrical conductance near room temperature correlates with the NP morphologies and their 2D organization. The unprecedentedly large difference - up to two orders of magnitude - in the electrical conductance of the two spin states is of interest for applications. PMID- 25556349 TI - Alleviating gastro-intestinal symptoms and concerns by integrating patient tailored complementary medicine in supportive cancer care. AB - BACKGROUND & AIMS: Chemotherapy-induced gastrointestinal (GI) toxicities often impair quality-of-life (QOL) and require reduction of the chemotherapy dose intensity. We explored the effects of a complementary integrative medicine (CIM) therapeutic process, administered in conjunction with conventional supportive care, on GI-related symptoms and concerns in patients undergoing chemotherapy. PATIENTS AND METHODS: We conducted a prospective, pragmatic study among patients undergoing chemotherapy referred by their healthcare providers to a CIM-trained integrative physician (IP) for consultation, followed by CIM treatments. Symptom severity and patient concerns were assessed at baseline and at an IP follow-up visit at 6-12 weeks, using the Edmonton Symptom Assessment Scale (ESAS) and the Measure Yourself Concerns and Wellbeing (MYCAW) questionnaires. Adherence to the integrative care (AIC) program was defined as attendance of >=4 CIM treatments, with <=30 days between sessions. RESULTS: Of the 308 patients referred to the IP consultation, 275 (89.3%) expressed GI symptoms and concerns, 189 of whom attended the follow-up IP assessment. Of these, 144 (46%) were found to be adherent to the treatment plan (AIC group). Repeated measure analysis indicated a statistical interaction between baseline and follow-up scores, for ESAS (appetite, p = 0.005; drowsiness, p = 0.027; shortness of breath, p = 0.027; and sleep, p = 0.034) and for MYCAW outcomes. This when comparing the AIC to the non AIC group responses. Reduction of GI concerns (p = 0.024) was greater among patients in the AIC group (MYCAW questionnaire), with significantly less chemotherapy-related hospitalizations found in this group (p = 0.008). The participation of a registered dietitian during CIM treatments led to greater reduction in nausea (from 4.24 to 1.85 vs. 2.73 to 1.36, respectively; p = 0.017). CONCLUSIONS: Integration of CIM with standard supportive care, especially in patients adhering to the CIM treatment regimen, may help reduce chemotherapy induced GI symptoms and concerns, as well as QOL-related non-GI symptoms. Further research is needed in order to explore the effects of specific CIM modalities on GI symptoms and concerns during chemotherapy. PMID- 25556350 TI - The effect of 2 mMol glutamine supplementation on HSP70 and TNF-alpha release by LPS stimulated blood from healthy children. AB - OBJECTIVE: Glutamine has been shown to promote heat shock protein 70 (HSP70) release both within experimental in vitro models of sepsis (2-10 mM) and in adults post trauma (0.5 g/kg), although the efficacy varies and is dependent on the model used. The effect of glutamine supplementation on HSP70 release in children is less clear. Therefore, the aim of this study was to investigate the effect of 2 mM glutamine added to incubation media on HSP70 and inflammatory mediator release in an in vitro model of paediatric sepsis using whole blood from healthy paediatric volunteers. METHODS: An in vitro whole blood endotoxin stimulation model using 1 MUg/ml lipopolysaccharide (LPS) over a 24 h time period was used to investigate the effects of 2 mM glutamine on HSP70 and inflammatory mediator release in healthy children. RESULTS: The addition of 2 mM glutamine to the incubation media significantly increased HSP70 release over time (p < 0.05). This was associated with an early pro-inflammatory effect on TNF-alpha release at 4 h (p < 0.005) which was not seen at 24 h. There was a non significant trend towards higher levels of IL-6 and IL-10 following the addition of 2 mM glutamine, which appears to differ from the response reported in adult and animal models. CONCLUSION: Glutamine supplementation of incubation media promotes HSP70 and early TNF- alpha release in an in vitro model using blood samples from healthy children. PMID- 25556351 TI - Validation of the patient advocacy engagement scale for health professionals. AB - Codes of ethics of nursing, social work, and medicine, as well as Joint Commission Accreditation Standards, require members of these professions to engage in advocacy on behalf of patients. With use of expert panels, seven categories of patient problems in the healthcare milieu were identified: ethical rights, quality care, preventive care, culturally competent care, affordable/accessible care, mental health care, and care linked to patients' homes and communities. To measure the frequency with which healthcare professionals engage in patient advocacy related to these specific problems, the Patient Advocacy Engagement Scale (Patient-AES) scale was developed and validated through analysis of responses of 297 professionals (94 social workers, 97 nurses, and 104 medical residents) recruited from the personnel rosters of eight acute care hospitals in Los Angeles County. Hospitals included public, not-for-profit, HMO, and church-affiliated hospitals that served general hospital populations, veterans, cancer patients, and children. Results supported the validity of both the concept and the instrument. Construct validity was supported by testing the hypothesized seven-factor solution through confirmatory factor analysis; 26 items loaded onto seven components. Pearson correlations for the overall scale and seven subscales in two administrations supported their test-retest stability. Cronbach alpha ranged from .55 to .94 for the seven subscales and .95 for the overall Patient-AES. The Patient-AES is, to our knowledge, the first scale that measures patient advocacy engagement by healthcare professionals in acute-care settings related to a broad range of specific patient problems. (c) 2014 Wiley Periodicals, Inc. PMID- 25556352 TI - Influence of using different bonding systems and composites on the margin integrity and the mechanical properties of selectively excavated teeth in vitro. AB - OBJECTIVES: Selective (incomplete) caries excavation reduces the risk of pulpal complications, but might compromise the properties of teeth or restorations. Different restorative approaches might be required after selective instead of complete excavation. We compared margin integrity, micro-leakage and fracture resistance of selectively excavated and differently restored premolars in vitro. METHODS: In 72 extracted human premolars, artificial residual lesions were induced on pulpo-axial walls of standardized cavities. Teeth were restored using one of three bonding systems (OptiBond FL, Clearfil SE Bond, G-aenial Bond) and a fibre-enforced (EverX) or standard hybrid composite resin (Filtek Z250). After thermo-mechanical cycling, groups (n = 12) were compared regarding their gingivo cervical margin integrity (proportion of acceptable margins), microleakage depth, and fracture resistance, with statistical evaluation using generalized linear modelling. RESULTS: Margin integrity was significantly influenced by the bonding system (p < 0.001), but not by the composite (p = 0.105). Proportions of acceptable margins were increased in teeth restored with OptiBond FL (median [25th/75th percentiles]: 93 [78/100%]) or Clearfil SE (82 [60/94]%) compared with G-aenial Bond (43 [15/74%]; p < 0.05). Neither bonding systems nor composites significantly influenced leakage depth in enamel (p = 0.749/0.569) or dentine (p = 0.112/0.909). Fracture resistance was significantly influenced by bonding system (p = 0.008) and composite (p = 0.001), and was higher in teeth restored using OptiBond FL (mean [SD]: 1210 [336]N) compared with Clearfil SE (1007 [208]N) or G-aenial Bond (1023 [281]N, p < 0.05), and using EverX (1182 [314]N) instead of Filtek Z250 (979 [228]N; p < 0.01). CONCLUSIONS: Bonding systems which perform well in completely excavated teeth also yielded good results for selectively excavated teeth in vitro. Using fibre-enforced composites to restore selectively teeth increased fracture resistance. CLINICAL SIGNIFICANCE: Bonding systems which perform well in completely excavated teeth are also suitable for restoring selectively excavated teeth. Using fibre-enforced composites seems suitable for increasing the fracture resistance of selectively excavated teeth and their restorations. PMID- 25556353 TI - Cluster formation and drag reduction-proposed mechanism of particle recirculation within the partition column of the bottom spray fluid-bed coater. AB - Bottom spray fluid-bed coating is a common technique for coating multiparticulates. Under the quality-by-design framework, particle recirculation within the partition column is one of the main variability sources affecting particle coating and coat uniformity. However, the occurrence and mechanism of particle recirculation within the partition column of the coater are not well understood. The purpose of this study was to visualize and define particle recirculation within the partition column. Based on different combinations of partition gap setting, air accelerator insert diameter, and particle size fraction, particle movements within the partition column were captured using a high-speed video camera. The particle recirculation probability and voidage information were mapped using a visiometric process analyzer. High-speed images showed that particles contributing to the recirculation phenomenon were behaving as clustered colonies. Fluid dynamics analysis indicated that particle recirculation within the partition column may be attributed to the combined effect of cluster formation and drag reduction. Both visiometric process analysis and particle coating experiments showed that smaller particles had greater propensity toward cluster formation than larger particles. The influence of cluster formation on coating performance and possible solutions to cluster formation were further discussed. PMID- 25556354 TI - History of oral contraceptive use in breast cancer patients: impact on prognosis and endocrine treatment response. AB - The purpose was to study oral contraceptive (OC) use in relation to breast cancer events and endocrine treatment response in a prospective population-based cohort, because it is unclear whether history of OC use impacts on prognosis in breast cancer patients. Between 2002 and 2011, 994 primary breast cancer patients without preoperative treatment were enrolled in Lund, Sweden and followed until December 2012. History of OC use was obtained from preoperative questionnaires. Tumor characteristics, clinical data, and date of death were obtained from pathology reports, patient charts, and population registries. Among the 948 patients with invasive cancer and no metastasis detected on the post-operative screen, 74 % had ever used OCs. Patients were followed for up to nine years (median follow-up 3 years), and 100 breast cancer events were recorded. Ever OC use was not associated with prognosis, irrespective of duration. However, any OC use before age 20 was associated with a threefold increased risk for breast cancer events in patients <50 years but not in patients >=50 years (P interaction = 0.009). In patients >=50 years with estrogen receptor positive tumors, previous OC use at any age was associated with a significantly decreased risk of breast cancer events among patients who received aromatase inhibitors compared to patients who never used OCs (adjusted HR 0.37: 95 % CI 0.15-0.87). OC use was not associated with tamoxifen-response. If confirmed, history of OC use may yield valuable prognostic and treatment predictive information in addition to currently used criteria. PMID- 25556355 TI - Thyroid function alters during neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01). AB - This side study investigated the effect of chemotherapy on thyroid function and the extent to which it can predict pathological complete response (pCR) in patients with early breast cancer taking part in NEOZOTAC phase III trial, randomizing between neoadjuvant chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on toxicity. Serum samples of 38 patients were available for analyses. Free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were compared between baseline and before the 6th cycle and between subjects with and without pCR. The relation between toxicity and the variation in fT4 and TSH levels during chemotherapy was tested. Samples at baseline and before the 6th cycle were available for 31 and 21 patients, respectively. The mean baseline fT4 level was 16.0 pmol/L and TSH level 1.11 mU/L, and these did not differ between both arms at each time point. During six cycles of chemotherapy, fT4 levels decreased (p = 0.0001), and TSH levels increased significantly (p = 0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting, or neuropathy, than in patients with those side effects (p = 0.037, p = 0.043, and p = 0.050, respectively). Baseline TSH levels tended to be higher in patients with pCR (p = 0.035 univariate analysis and p = 0.074 multivariate analysis). Chemotherapy blunts thyroid function, which was associated with less side effects. These data urge further evaluation of the effects of thyroid function on toxicity and outcome of breast cancer therapy. PMID- 25556356 TI - Epstein-Barr virus-positive plasmacytoma in immunocompetent patients. AB - AIMS: Extramedullary plasmacytomas are often localized, clinically indolent neoplasms, and affected patients usually respond to radiation therapy or limited cycles of chemotherapy. In contrast, plasmablastic lymphomas are clinically aggressive neoplasms composed of immunoblastic or plasmablastic cells and associated with more mature plasma cells in some cases. Patients with plasmablastic lymphoma usually have a poor prognosis despite aggressive chemotherapy. Evidence of Epstein-Barr virus (EBV) infection is uncommon in plasmacytoma, but common in plasmablastic lymphoma, and is therefore helpful in differential diagnosis. The aim of this study is to describe four cases of plasmacytoma arising in immunocompetent individuals that were diffusely positive for Epstein-Barr virus-encoded small RNA as shown by in-situ hybridization. METHODS AND RESULTS: We describe the clinicopathological and immunophenotypic findings of four EBV-positive plasmacytomas arising in immunocompetent patients. These tumours were characterized by diffuse proliferation of mature-appearing plasma cells intermixed with a briskly reactive, CD8-positive, TIA-1-positive cytotoxic T-cell infiltrate. Long-term follow-up was available for all patients, and all were alive and free of disease at last follow-up (median 43.4 months). CONCLUSIONS: We suggest the term EBV-positive plasmacytoma in immunocompetent patients for these lesions. It is essential to distinguish these tumours from plasmablastic lymphoma, as the latter diagnosis is associated with a much poorer prognosis, and patients require much more aggressive therapy. PMID- 25556357 TI - Hope thinking and past trauma mediate the relationships of body mass index with perceived mental health treatment need and mental health treatment use. AB - Greater body mass is associated with a greater risk of mental health conditions and more frequent mental health treatment use. However, factors that might influence perceived mental health treatment need and mental health treatment use among those of greater weight, including hope thinking, trauma history and perceived mental health treatment stigma, are not well understood. OBJECTIVE: The objective of this study was to determine if hope thinking, trauma history and/or perceived mental health treatment stigma mediate the relationships of body mass index [BMI] with perceived mental health treatment need and mental health treatment use. METHOD: Primary care clinic patients in the Midwest United States (N = 196; BMI range = 18.5 to 47.0, mean = 29.26 +/- 6.61, median = 27.90) were recruited to complete a battery of self-report measures that assessed perceived mental health treatment need, mental health treatment use, hope thinking (Trait Hope Scale), trauma history (a single-item traumatic event history screen from the posttraumatic stress disorder module of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and perceived mental health treatment stigma (Stigma Scale for Receiving Psychological Help). RESULTS: Reduced hope thinking and a greater incidence of past trauma accounted for greater perceived mental health treatment need and greater mental health treatment use among those of greater BMI. BMI was not related to perceived unmet mental health treatment need. CONCLUSION: Increased perceived mental health treatment need and mental health treatment use among those of greater BMI may be explained by lower hope thinking and a greater incidence of trauma in this population. Heavier patients may benefit from interventions designed to augment hope and address traumatic histories. PMID- 25556358 TI - Influence of culture conditions and extracellular matrix alignment on human mesenchymal stem cells invasion into decellularized engineered tissues. AB - The variables that influence the in vitro recellularization potential of decellularized engineered tissues, such as cell culture conditions and scaffold alignment, have yet to be explored. The goal of this work was to explore the influence of insulin and ascorbic acid and extracellular matrix (ECM) alignment on the recellularization of decellularized engineered tissue by human mesenchymal stem cells (hMSCs). Aligned and non-aligned tissues were created by specifying the geometry and associated mechanical constraints to fibroblast-mediated fibrin gel contraction and remodelling using circular and C-shaped moulds. Decellularized tissues (matrices) of the same alignment were created by decellularization with detergents. Ascorbic acid promoted the invasion of hMSCs into the matrices due to a stimulated increase in motility and proliferation. Invasion correlated with hyaluronic acid secretion, alpha-smooth muscle actin expression and decreased matrix thickness. Furthermore, hMSCs invasion into aligned and non-aligned matrices was not different, although there was a difference in cell orientation. Finally, we show that hMSCs on the matrix surface appear to differentiate toward a smooth muscle cell or myofibroblast phenotype with ascorbic acid treatment. These results inform the strategy of recellularizing decellularized engineered tissue with hMSCs. PMID- 25556360 TI - Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. AB - Highly sensitive and specific non-invasive molecular imaging methods are particularly desirable for the early detection of cancers. Here we report a near infrared optical imaging probe highly specific to the hypoxic tumour microenvironment to detect tumour and cancer cells with the sensitivity to a few thousands cancer cells. This oxygen-sensitive, near-infrared emitting and water soluble phosphorescent macromolecular probe can not only report the hypoxic tumour environment of various cancer models, including metastatic tumours in vivo, but can also detect a small amount of cancer cells before the formation of the tumour based on the increased oxygen consumption during cancer cell proliferation. Thus, the reported hypoxia-sensitive probe may offer an imaging tool for characterizing the tumour microenvironment in vivo, detecting cancer cells at a very early stage of tumour development and lymph node metastasis. PMID- 25556359 TI - Longitudinal differences in aerobic capacity between children with sickle cell anemia and matched controls. AB - BACKGROUND: The purpose of this study was to compare longitudinal trajectories of maximal aerobic capacity in children with sickle cell anemia (SCA) and matched healthy controls, and explore whether these trajectories were associated with selected physiologic variables. PROCEDURE: Children with SCA (n = 33) and healthy controls (n = 30) matched at baseline for race, sex, Tanner stage, height, and weight completed three consecutive annual fitness assessments (VO2peak ). Data were compared between the groups at each time point and within groups over time. Change in VO2peak between the two groups over time was assessed using a linear mixed model with age, sex, fat-free mass (FFM), Tanner stage, and hemoglobin (Hgb) concentration as covariates. RESULTS: At baseline, children with SCA had significantly lower Hgb concentration (8.9 vs. 13.7 g/dL, P < 0.001) and relative VO2peak (24.2 vs. 27.9 ml/kg/min, P = 0.006) than healthy controls. Over time, children with SCA had smaller increases than healthy controls in VO2peak (-0.1 and +4.9 ml/kg/min, P < 0.001), Tanner stage at year 2 (15% and 66% Tanner 4, P < 0.001), and FFM (+4.0 and +6.8 kg, P = 0.02). Changes in Hgb concentration did not differ between groups (+0.03 and +0.09 g/dL, P = 1.0). After adjusting for age, sex, Tanner stage, FFM, and Hgb concentration the differences in change in VO2peak over time remained significant (P < 0.001). CONCLUSION: Children with SCA demonstrate lower relative VO2peak compared to healthy children and the difference increases over time. The difference in VO2peak trajectories between the two groups during puberty remains significant after adjusting for age, sex, FFM, Tanner stage, and Hgb concentration. PMID- 25556361 TI - Effects of mesenchymal stem cell therapy, in association with pharmacologically active microcarriers releasing VEGF, in an ischaemic stroke model in the rat. AB - Few effective therapeutic interventions are available to limit brain damage and functional deficits after ischaemic stroke. Within this context, mesenchymal stem cell (MSC) therapy carries minimal risks while remaining efficacious through the secretion of trophic, protective, neurogenic and angiogenic factors. The limited survival rate of MSCs restricts their beneficial effects. The usefulness of a three-dimensional support, such as a pharmacologically active microcarrier (PAM), on the survival of MSCs during hypoxia has been shown in vitro, especially when the PAMs were loaded with vascular endothelial growth factor (VEGF). In the present study, the effect of MSCs attached to laminin-PAMs (LM-PAMs), releasing VEGF or not, was evaluated in vivo in a model of transient stroke. The parameters assessed were infarct volume, functional recovery and endogenous cellular reactions. LM-PAMs induced the expression of neuronal markers by MSCs both in vitro and in vivo. Moreover, the prolonged release of VEGF increased angiogenesis around the site of implantation of the LM-PAMs and facilitated the migration of immature neurons towards the ischaemic tissue. Nonetheless, MSCs/LM-PAMs-VEGF failed to improve sensorimotor functions. The use of LM-PAMs to convey MSCs and to deliver growth factors could be an effective strategy to repair the brain damage caused by a stroke. PMID- 25556362 TI - Clinical manifestation of pediatric granulomatosis with polyangiitis - the experience of two regions in Poland. AB - BACKGROUND: The purpose of this study was to describe clinical manifestations, laboratory findings and outcome of granulomatosis with polyangiitis (GPA) in pediatric patients living in two regions (Southern and Central) of Poland. METHODS: Retrospective analysis of patient hospital records from four large hospitals during a period from 1995 to 2013. Patients with confirmed diagnosis of GPA according to American College of Rheumatology (ACR) and EULAR/PRINTO/PRES criteria for GPA were analyzed. All patients were subjected to clinical, laboratory, radiological and immunological assessment. RESULTS: During this 18 year period only 9 children with confirmed diagnosis of GPA (6 girls, 3 boys) were identified. The average age of the disease onset was 12 years (range: 8-16 years). Average delay between first symptoms and diagnosis was approx. 20 months (range: 0-84 months). Organ system involvement at presentation included: kidneys 88.8% (8/9), lungs 77.7% (7/9), ear/nose/ throat 55.5% (5/9), gastrointestinal tract 55.5% (5/9), skin 44.4% (4/9), joints 22.2% (2/9), eyes 11.1% (1/9) and nervous system 11.1% (1/9). In 5 children disease course was progressive (constant progression of sinusitis in one case, end-stage renal disease in two, chronic kidney disease stage IV in one and one child died due to alveolar hemorrhage). CONCLUSION: The majority of our patients were females. Clinical features of pediatric GPA were similar to those described in adults. None of our patients developed subglottic stenosis and in only 2 children saddle-nose deformity was observed. Although GPA was treated according to contemporary standards care, disease progression was observed in more than a half of children. PMID- 25556363 TI - Variations of the anterior communicating artery complex and occurrence of anterior communicating artery aneurysm: A2 segment consideration. AB - INTRODUCTION: The anterior communicating artery (ACoA) is the most frequent site of intracranial aneurysm location. Despite many studies the frequency of aneurysm occurrence with anatomical anomalies is still poorly described. Moreover the significance of the A2 segment of anterior cerebral artery anomalies has been neglected. The aim of this study was to determine the frequency and types of variations of the anterior cerebral circulation in patients with ACoA aneurysms and to analyze their relation to aneurysm occurrence in the Polish population. MATERIALS AND METHODS: We studied 50 patients with an established radiological diagnosis of ACoA aneurysm and 100 healthy age- and sex-matched controls using Computed Tomgraphy Angio- graphy. Maximum Intensity and Volume Rendering Projections were used to examine the cerebral arterial circulation. Univariate logistic regression was used to determine the statistical association between ACoA complex anomalies and aneurysm occurrence. RESULTS: Patients in the study group had a significantly higher incidence of hypoplastic A1 seg- ment of the anterior cerebral artery (24% vs. 7%; p <0.01) and aplastic A1 segment of the anterior cerebral artery (12% vs. 3%; p = 0.03). The frequency of A1 segment hypoplasia or aplasia in the study group was 36%. There was a statistical trend regarding A2 segment aplasia/hypoplasia as a potential predictor of ACoA aneurysm (6% vs. 1%; p = 0.07). CONCLUSION: Occurrence of an ACoA aneurysm is associated with hypoplasia or aplasia of the A1 segment of the anterior cerebral artery. A2 segment anomalies may potentially be associated with aneurysm formation. PMID- 25556364 TI - Structured-light 3D scanner in use to assess the human body posture in physical therapy - a pilot study. AB - AIM: The main goal of this study was to asses the possibility of using mass production structured-light 3d scanner to asses human body posture. MATERIALS AND METHODS: The study was conducted on a healthy 23 year old volunteer and a lay figure. The experiment consisted of 28 3D scans, divided into three separate tests. RESULTS: The largest deviation observed in the first two trials was 24.42 mm. While the largest deviation observed in the third trial was 49.91 mm. CONCLUSIONS: Data obtained with the mass production structured-light 3d scanner may have comparable or better performance than commercially available systems for the assessment of BP. PMID- 25556365 TI - Enhanced generation of reactive oxygen intermediates by suppressor T cell-derived exosome-treated macrophages. AB - Macrophages (Mphi) as efficient phagocytes able to present the antigen and playing an effector role induce and orchestrate the immune response also through the release of soluble factors. Recently described T CD8+ cell-derived suppressive exosomes carrying miRNA-150, that act antigen-specifically, seem to inhibit murine contact sensitivity reaction indirectly by affecting antigen presenting cells, especially Mphi. Present studies investigated the influence of suppressive exosomes on secretory activity of Mphi assessed as their ability to generate reactive oxygen intermediates (ROIs), nitric oxide, cytokines as well as their viability and expression of antigen phagocytosis and presentation markers. Interestingly, in vivo and in vitro treatment of Mphi with assayed hapten specific exosomes affected only ROIs generation, significantly enhancing their production. Current results suggest that ROIs may participate in antigen-specific tolerance mechanism mediated by suppressive T lymphocyte-derived exosome influenced Mphi, by inhibition of effector T cell proliferation and induction of T regulatory lymphocytes. PMID- 25556366 TI - Serum potassium, sodium and calcium levels in healthy individuals - literature review and data analysis. AB - PURPOSE: The human body is known to be composed of 24 elements, among which potassium, sodium and calcium are considered to be essential. These necessary components play a significant physiological role which includes regulation of the electrical and mechanical action of the heart. Abnormal concentration of the above-mentioned ions, i.e. water-electrolyte imbalance, may result in cardiac arrhythmias, muscle contraction disorders, disturbances of neuronal activity and influences the drugs activity. METHODS: The study aimed at gathering and analyzing results of publicly available research which reported serum concentration of these ions. This information, together with an additional collection of data (gender, age, height, weight, measurement method), is presented in table form attached as supplementary material. RESULTS: The serum ions concentrations means weighted by the study-specific sample sizes indicated statistically significant differences between males and females for all ions - K+ 4.21 and 4.09, Na+ 140.1 and 138.17, Ca2+ 2.42 and 2.31 respectively). CONCLUSIONS: Obtained results correspond with the current laboratory reference values. As potassium, sodium and calcium follow the circadian rhythm, publications reporting serum concentration values were also collected and presented. Further studies are planned to describe such phenomenon in a form of the statistical model. PMID- 25556367 TI - Number and distribution of interstitial cells of Cajal in human gallbladder. AB - Based on the review of current literature and on their own studies authors postulate that decreased number of interstitial cells in the wall of gallbladder may be pathognomonic for gallstone disease (cholelithiasis). PMID- 25556368 TI - The level of negative emotions, coping with stress and social support for parents of children suffering from epilepsy. AB - INTRODUCTION: Child epilepsy can be source of negative emotions and stress in pa- rents. Social support is an external personal resource coupled with the process of coping with difficult situations. AIM: The aim of the study evaluation the severity of negative emotions and ways of dealing with the stress of parents of children with epilepsy in relation to the received social support. MATERIALS AND METHODS: The study was conducted in one of the children's hospitals in Malopolska, on 213 parents (148 women and 65 men) aged 21 to 66 years. The study used: HADS-M (Hospital Anxiety and Depression Scale Modified HADS-M, BSSS (Berlin Social Suport Scale), Inventory for Measurement Coping Mini-COPE and the author's questionnaire. Statistical analysis used Pearson and Spearman's correlation and Mann-Whitney test and t-test. Calculations were performed using IBM SPSS Statistics 20 Statistical significance was p <=0.05. RESULTS: The dominant emotion that accompanied the parents was anxiety. Parents have used more strategies based on active coping, and seeking emotional support or instrumental. It has been shown there is a correlation between the level of intensity of negative emotions and social support, and also correlation between social support and ways of coping with stress. CONCLUSION: Parents expressed negative emotions but not of high severity which may be related to the choice of active coping strategies. Steps should be taken not only to assess the prevalence of negative emotions in a group of parents, but also to reduce the level of their intensity by exposing the importance of social support. PMID- 25556370 TI - Antiangiogenic activity of the lipophilic antimicrobial peptides from an endophytic bacterial strain isolated from red pepper leaf. AB - The induction of angiogenesis is a crucial step in tumor progression, and therefore, efficient inhibition of angiogenesis is considered a powerful strategy for the treatment of cancer. In the present study, we report that the lipophilic antimicrobial peptides from EML-CAP3, a new endophytic bacterial strain isolated from red pepper leaf (Capsicum annuum L.), exhibit potent antiangiogenic activity both in vitro and in vivo. The newly obtained antimicrobial peptides effectively inhibited the proliferation of human umbilical vein endothelial cells at subtoxic doses. Furthermore, the peptides suppressed the in vitro characteristics of angiogenesis such as endothelial cell invasion and tube formation stimulated by vascular endothelial growth factor, as well as neovascularization of the chorioallantoic membrane of growing chick embryos in vivo without showing cytotoxicity. Notably, the angiostatic peptides blocked tumor cell-induced angiogenesis by suppressing the expression levels of hypoxia-inducible factor 1alpha and its target gene, vascular endothelial growth factor (VEGF). To our knowledge, our findings demonstrate for the first time that the antimicrobial peptides from EML-CAP3 possess antiangiogenic potential and may thus be used for the treatment of hypervascularized tumors. PMID- 25556372 TI - MicroRNA-576-3p inhibits proliferation in bladder cancer cells by targeting cyclin D1. AB - MicroRNAs (miRNAs) are small, endogenous RNAs that play important gene-regulatory roles by binding to the imperfectly complementary sequences at the 3'-UTR of mRNAs and directing their gene expression. Here, we first discovered that miR-576 3p was down-regulated in human bladder cancer cell lines compared with the non malignant cell line. To better characterize the role of miR-576-3p in bladder cancer cells, we over-expressed or down-regulated miR-576-3p in bladder cancer cells by transfecting with chemically synthesized mimic or inhibitor. The overexpression of miR-576-3p remarkably inhibited cell proliferation via G1-phase arrest, and decreased both mRNA and protein levels of cyclin D1 which played a key role in G1/S phase transition. The knock-down of miR-576-3p significantly promoted the proliferation of bladder cancer cells by accelerating the progression of cell cycle and increased the expression of cyclin D1. Moreover, the dual-luciferase reporter assays indicated that miR-576-3p could directly target cyclin D1 through binding its 3'-UTR. All the results demonstrated that miR-576-3p might be a novel suppressor of bladder cancer cell proliferation through targeting cyclin D1. PMID- 25556373 TI - A validated method for simultaneous determination of codeine, codeine-6 glucuronide, norcodeine, morphine, morphine-3-glucuronide and morphine-6 glucuronide in post-mortem blood, vitreous fluid, muscle, fat and brain tissue by LC-MS. AB - The toxicodynamics and, to a lesser degree, toxicokinetics of the widely used opiate codeine remain a matter of controversy. To address this issue, analytical methods capable of providing reliable quantification of codeine metabolites alongside codeine concentrations are required. This article presents a validated method for simultaneous determination of codeine, codeine metabolites codeine-6 glucuronide (C6G), norcodeine and morphine, and morphine metabolites morphine-3 glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem whole blood, vitreous fluid, muscle, fat and brain tissue by high-performance liquid chromatography mass spectrometry. Samples were prepared by solid-phase extraction. The validated ranges were 1.5-300 ng/mL for codeine, norcodeine and morphine, and 23-4,600 ng/mL for C6G, M3G and M6G, with exceptions for norcodeine in muscle (3-300 ng/mL), morphine in muscle, fat and brain (3-300 ng/mL) and M6G in fat (46-4,600 ng/mL). Within-run and between-run accuracy (88.1-114.1%) and precision (CV 0.6-12.7%), matrix effects (CV 0.3-13.5%) and recovery (57.8-94.1%) were validated at two concentration levels; 3 and 150 ng/mL for codeine, norcodeine and morphine, and 46 and 2,300 ng/mL for C6G, M3G and M6G. Freeze-thaw and long-term stability (6 months at -80 degrees C) was assessed, showing no significant changes in analyte concentrations (-12 to +8%). The method was applied in two authentic forensic autopsy cases implicating codeine in both therapeutic and presumably lethal concentration levels. PMID- 25556371 TI - Tristetraprolin inhibits the growth of human glioma cells through downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor mRNAs. AB - Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) play a major role in the infiltrative growth of glioblastoma. Downregulatoion of the uPA and uPAR has been reported to inhibit the growth glioblastoma. Here, we demonstrate that tristetraprolin (TTP) inhibits the growth of U87MG human glioma cells through downregulation of uPA and uPAR. Our results show that expression level of TTP is inversely correlated with those of uPA and uPAR in human glioma cells and tissues. TTP binds to the AU-rich elements within the 3' untranslated regions of uPA and uPAR and overexpression of TTP decreased the expression of uPA and uPAR through enhancing the degradation of their mRNAs. In addition, overexpression of TTP inhibited the growth and invasion of U87MG cells. Our findings implicate that TTP can be used as a promising therapeutic target to treat human glioma. PMID- 25556375 TI - Carbon nanotube network varactor. AB - Microelectromechanical system (MEMS) varactors based on a freestanding layer of single-walled carbon nanotube (SWCNT) films were designed, fabricated and tested. The freestanding SWCNT film was employed as a movable upper patch in the parallel plate capacitor of the MEMS. The measurements of the SWCNT varactors show very high tunability, nearly 100%, of the capacitance with a low actuation voltage of 10 V. The functionality of the varactor is improved by implementing a flexible nanocellulose aerogel filling. PMID- 25556374 TI - Risk factors for HIV infection among circumcised men in Uganda: a case-control study. AB - INTRODUCTION: Male circumcision (MC) reduces the risk of HIV infection. However, the risk reduction effect of MC can be modified by type of circumcision (medical, traditional and religious) and sexual risk behaviours post-circumcision. Understanding the risk behaviours associated with HIV infection among circumcised men (regardless of form of circumcision) is critical to the design of comprehensive risk reduction interventions. This study assessed risk factors for HIV infection among men circumcised through various circumcision approaches. METHODS: This was a case-control study which enrolled 155 cases (HIV-infected) and 155 controls (HIV-uninfected), all of whom were men aged 18-35 years presenting at the AIDS Information Center for HIV testing and care. The outcome variable was HIV sero-status. Using SPSS version 17, multivariable logistic regression was performed to identify factors independently associated with HIV infection. RESULTS: Overall, 83.9% among cases and 56.8% among controls were traditionally circumcised; 7.7% of cases and 21.3% of controls were religiously circumcised while 8.4% of cases and 21.9% of controls were medically circumcised. A higher proportion of cases than controls reported resuming sexual intercourse before complete wound healing (36.9% vs. 14.1%; p<0.01). Risk factors for HIV infection prior to circumcision were:being in a polygamous marriage (AOR: 6.6, CI: 2.3-18.8) and belonging to the Bagisu ethnic group (AOR: 6.1, CI: 2.6-14.0). After circumcision, HIV infection was associated with: being circumcised at >18 years (AOR: 5.0, CI: 2.4-10.2); resuming sexual intercourse before wound healing (AOR: 3.4, CI: 1.6-7.3); inconsistent use of condoms (AOR: 2.7, CI: 1.5-5.1); and having sexual intercourse under the influence of peers (AOR: 2.9, CI: 1.5-5.5). Men who had religious circumcision were less likely to have HIV infection (AOR: 0.4, 95% CI: 0.2-0.9) than the traditionally circumcised but there was no statistically significant difference between those who were traditionally circumcised and those who were medically circumcised (AOR: 0.40, 95% CI: 0.1 1.1). CONCLUSIONS: Being circumcised at adulthood, resumption of sexual intercourse before wound healing, inconsistent condom use and having sex under the influence of peers were significant risk factors for HIV infection. Risk reduction messages should address these risk factors, especially among traditionally circumcised men. PMID- 25556376 TI - Excited-state proton transfer of weak photoacids adsorbed on biomaterials: proton transfer to glucosamine of chitosan. AB - UV-vis steady-state and time-resolved techniques were employed to study the excited-state proton-transfer process from two weak photoacids positioned next to the surface of chitosan and cellulose. Both chitosan and cellulose are linear polysaccharides; chitosan is composed mainly of d-glucosamine units. In order to overcome the problem of the high basicity of the glucosamine, we chose 2-naphthol (pKa* ~ 2.7) and 2-naphthol-6-sulfonate (pKa* ~ 1.7) as the proton emitters because of their ground state pKa (~9). Next to the 1:1 cellulose:water weight ratio, the ESPT rate of these photoacids is comparable to that of bulk water. We found that the ESPT rate of 2-naphthol (2NP) and 2-naphthol-6-sulfonate (2N6S) next to chitosan in water (1:1) weight ratio samples is higher than in bulk water by a factor of about 5 and 2, respectively. We also found an efficient ESPT process that takes place from these photoacids in the methanol environment next to the chitosan scaffold, whereas ESPT is not observed in methanolic bulk solutions of these photoacids. We therefore conclude that ESPT occurs from these photoacids to the d-glucosamine units that make up chitosan. PMID- 25556377 TI - Three-dimensional mesoporous graphene aerogel-supported SnO2 nanocrystals for high-performance NO2 gas sensing at low temperature. AB - A facile and cost-efficient hydrothermal and lyophilization two-step strategy has been developed to prepare three-dimensional (3D) SnO2/rGO composites as NO2 gas sensor. In the present study, two different metal salt precursors (Sn(2+) and Sn(4+)) were used to prepare the 3D porous composites. It was found that the products prepared from different tin salts exhibited different sensing performance for NO2 detection. The scanning electron microscopy and transmission electron microscopy characterizations clearly show the macroporous 3D hybrids, nanoporous structure of reduce graphene oxide (rGO), and the supported SnO2 nanocrystals with an average size of 2-7 nm. The specific surface area and porosity properties of the 3D mesoporous composites were analyzed by Braunauer Emmett-Teller method. The results showed that the SnO2/rGO composite synthesized from Sn(4+) precursor (SnO2/rGO-4) has large surface area (441.9 m(2)/g), which is beneficial for its application as a gas sensing material. The gas sensing platform fabricated from the SnO2/rGO-4 composite exhibited a good linearity for NO2 detection, and the limit of detection was calculated to be as low as about 2 ppm at low temperature. The present work demonstrates that the 3D mesoporous SnO2/rGO composites with extremely large surface area and stable nanostructure are excellent candidate materials for gas sensing. PMID- 25556378 TI - Fertility behaviour of Iranian women: a community-based, cross-sectional study. AB - BACKGROUND: The fertility behavior of Iranian women and their reproductive needs is changing and consequently, for providing good services, it is critical to monitor their reproductive behavior at a national level. METHODS: This study was carried out by Avicenna Research Institute in the urban and rural parts of Iran between 2010 and 2011. Using cluster sampling, the reproductive history of 17,187 married women aged 20 - 40 years were recorded. The statistical analysis of the data was performed using SPSS software (Version 11.5), and P < 0.05 was considered significant. RESULTS: The common methods of contraception at the time of interview were natural methods (29.8%). The first pregnancy was unwanted in 20.6% of the women. The average number of childbirth per 35 - 40 years woman was 2.4. The mean age of women at marriage date and the mean age at the first childbirth both have increased with time (p< 0.001). CONCLUSION: Although the fertility rate has declined in Iran, the most important reproductive issues like unwanted pregnancy and use of non-reliable methods of contraception are not resolved yet. Increased mean age at first Childbirth and elevated numbers of couples with no childbirth, because of voluntarily childlessness or Infertility should be noticed more by policy makers. Then allocating enough resources for reproductive health services is vital in new family planning policies. PMID- 25556379 TI - A follow-up study on acute respiratory distress syndrome survivors after extracorporeal membrane oxygenation by pulmonary high-resolution CT. AB - OBJECTIVE: This study aims to identify morphological changes in the lung parenchyma of acute respiratory distress syndrome (ARDS) survivors after extracorporeal membrane oxygenation (ECMO) by high-resolution computed tomography (HRCT) follow-up. Factors influencing these changes are also examined. METHODS: Information and lung HRCT scans were collected and studied 1, 3, 6, and 12 months after the withdrawal of severe ARDS survivors rescued by ECMO in the Respiratory Care Unit of Beijing Chaoyang Hospital from November 2009 to August 2012. The observation endpoint was set as the time when the lung lesions were basically absorbed or 12 months after withdrawal. RESULTS: Among nine survivors, one survivor was lost to follow-up. The lesions of two patients, which were attributed to bacterial pneumonia and pneumocystis pneumonia, were basically absorbed 1 month after surgery. Six patients completed the 12 month follow-up. Although initial morphological changes varied, different degrees of absorption improvement were observed in later stages of treatment. Lung HRCT analysis on the sixth month indicated that the degree of involvement of the ventral region was greater than that of the dorsal area. No significant difference was observed in patients in terms of ECMO support time, pre-ECMO Murray score, and APACHE II score, among others. CONCLUSION: Lung HRCT of severe ARDS survivors after ECMO treatment showed various degrees of morphological changes in the lung parenchyma. The severity of these changes may be associated with the disease duration. PMID- 25556380 TI - Insight into the serum kisspeptin levels in infertile males. AB - BACKGROUND: Regulation of reproduction is now considered to be carried out by the kisspeptin and its receptor, GPR54 or Kiss1r. Mutations of either Kiss1 or Kiss1r in humans and mice result in profound hypogonadotropic hypogonadism. The present study was aimed to determine whether the levels of kisspeptin are associated with male infertility. METHODOLOGY: The study involved 176 male subjects aged 18 - 50 years including 26 fertile and 150 infertile. Infertile subjects were further subdivided according to WHO guidelines of semen analysis into 22 asthenozoospermia, 08 asthenoteratozoospermia, 18 azoospermia, 58 normozoospermia, 06 oligozoospermia, 12 oligoasthenozoospermia and 26 oligoasthenoteratozoospermia. Thorough clinical examinations excluded those suffering from chronic health problems. Serum kisspeptin levels were measured by enzyme immunoassay (EIA) and follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were estimated by chemiluminescence assay (CLIA). RESULTS: The results of the present study have revealed that kisspeptin levels were significantly lower in all infertile males as compared to the fertile males. Significantly low LH and testosterone levels were observed in all infertile groups as compared to fertile group. FSH levels were significantly lower in normozoospermic and azoospermic as compared to fertile males, while no significant difference was observed between the other infertile and fertile group. CONCLUSION: The study revealed that serum kisspeptin levels were observed significantly lower in the infertile as compared to fertile males, indicating that the kisspeptin might be associated with the fertility problems in males. PMID- 25556381 TI - Chemoprotection of MNNG-initiated gastric cancer in rats using Iranian propolis. AB - BACKGROUND: Iranian propolis is a natural product of honeybees that has significant and varied anti-cancer benefits. The present study was designed to investigate the protective effects of Iranian propolis on gastric tissue carcinogenesis in an animal model. METHODS: Propolis samples were collected from Hamadan and Taleghan districts of Iran, followed by ultra performance liquid chromatography mass spectrometry analysis. Fifty-five rats were divided into three groups; control, Taleghan propolis and Hamadan propolis. All the animals received N-methyl-N-nitro-N-nitrosoguanidine (MNNG, 100 MUg/ml) in drinking water ad libitum for 34 weeks. In the treated groups, nutrition with propolis was started two weeks before MNNG administration. At the end of the study, the entire gastrointestinal tract was scrutinized for tumors, and the rest of the body was assessed for metastatic deposits. RESULTS: Results indicated that the incidence and number of tumors were significantly decreased by propolis in comparison with the control group (P < 0.05). The nuclear/cytoplasmic ratio, epithelial stratification, nuclear dispolarity, structural abnormality, and Beta-catenin and Bcl-2 proteins expression were significantly reduced in the propolis group compared to the control group (P < 0.05). In addition, Bax protein expression was significantly increased in the propolis group in comparison with the control group (P < 0.05). CONCLUSION: The present study demonstrated the potential chemoprotective effects of the Iranian propolis against gastric cancer in a typical animal model. The results provide evidence for the hypothesis that Iranian propolis may exert a chemoprotective effect on MNNG-initiated gastric cancer through inhibition of cell proliferation and apoptosis induction. PMID- 25556382 TI - Innovation of a new silicone prosthesis for inguinal hernioplasty: new method for silicone prosthesis production, a preliminary study. AB - PURPOSE: The main strategy in inguinal hernia repair is mesh hernioplasty (specially prolene mesh). Pain in anterior femoral, inguinal and scrotal areas, mainly due to sensory nerve injury in the very regions and vas deferen injury are the main complications reported following repairing inguinal hernia. In this study we decided to use semiliquid silicone in order to form it in an in-vivo prosthesis production method to perform hernioplasty. METHODS: In this technique, silicone was produced through Room Temperature Vulcanization (RTV) technique, which is feasible in the room temperature. The produced semiliquid polymer was shaped in the inguinal canal in six cadavers. RESULT: While the prostheses adequately covered all the anatomic area of the canal with an acceptable thickness in all of the cases, a satisfactory shape was developed in four cases. While 15 - 20 cc of silicone was needed to cover all anatomic areas properly, the hardness equal to 15 was achieved after curing process. CONCLUSION: New silicone prosthesis forms satisfyingly in the inguinal canal and can protect it by encapsulation mechanism. It is soft with no risk of damage to the nerves or vas. It is inert and has no toxicity to the adjacent tissue. This technique of silicone remodeling can also be used in other fields of surgery such as plastic or vascular surgery. PMID- 25556383 TI - The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. AB - OBJECTIVE: Preclinical studies and early pilot clinical investigations have suggested that N-acetylcysteine (NAC) may be useful in treatment of methamphetamine (METH) dependence. The present study evaluated whether NAC would suppress craving to the METH. METHODS: In a double-blind, controlled crossover clinical trial, 32 METH-dependent volunteers were chosen to receive either NAC (1200 mg/day) or placebo, randomly. They were intervened in two four-week sessions. During first session they received either 1200 mg/day of NAC (group A) or placebo (group B). After three days of washout period, next session started with the crossover intervention of the previous regimen. During these eight weeks, all participants received standardized, and Matrix Model of treatment. Craving was assessed using the Cocaine Craving Questionnaire-Brief (CCQ-Brief). The data were analyzed using SPSS version 20.0 (SPSS Inc. Chicago, Illinois, USA). RESULTS: In 23 subjects who completed the study, the mean score of CCQ Brief reduced in four consecutive weeks with NAC treatment. The mean (SD) scores of carving in group A and B were 3.38 (1.16) and 5.96 (1.03), at the end of first session; and 4.57 (1.88) and 3.2 (0.86), at the end of the second session, respectively. Our findings indicate that the main effect was significant for NAC (P < 0.001). Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects who reported side effects did not differ. CONCLUSION: The NAC showed good efficacy in suppressing METH craving, and may be a useful pharmacological treatment for METH dependency. PMID- 25556384 TI - Seroprevalence of hepatitis B before marriage: a study on marriage candidates in the Southeast of Iran; is it worthy of consideration? AB - OBJECTIVES: Hepatitis B virus infection is one of the most common causes of acute and chronic hepatitis worldwide. Furthermore, since most people with hepatitis B virus are asymptomatic, timely diagnosis is important for prevention. This study has evaluated the prevalence of Hepatitis B seromarkers in marriage candidates. DESIGN: In this Cross-sectional study, 370 marriage volunteers selected by the simple sampling method were investigated in 2011 - 2012. RESULTS: A total of 185 men and 185 women were investigated. Mean Age of participants was 24.7 years. The prevalence rates of hepatitis B surface antigen (HBsAg), anti hepatitis B surface antibody (anti-HBs) and anti-hepatitis B core antibody (anti-HBc) were 1.1%, 47.6% and 8.9% respectively. Frequency of HBsAg was 0.5% and 1.6% in men and women respectively. The prevalence of anti-HBs was 43.8% in men and 51.45% in women. Anti-HBs was more common in young people and those with higher levels of education and positive history of vaccination. The prevalence of anti-HBc was 8.1% and 9.7% in men and women respectively. CONCLUSION: Although Kerman is a low endemic area, due to the high risk of transmission to the spouse and offspring, screening for HBV study before marriage is recommended. PMID- 25556385 TI - Completed suicide and associated risk factors: a six-year population based survey. AB - INTRODUCTION: The investigations on suicide conducted within low- and middle income countries are limited. This study evaluated the trend of suicide and its associated risk factors in the west of Iran. METHODS: This six-year population based survey was conducted in Kermanshah Province, in 2012. The data on suicide was extracted from the suicide database of the Provincial Health Center, which was collected for six successive years. Multivariate logistic regression analysis was performed and odds ratio (OR) as well as its 95% confidence intervals (CI) was reported. RESULTS: During the study period, 13,810 attempted suicides occurred of which 1,564 (11.33%) were completed. The incidence rate of suicide has increased in recent years. Based on logistic regression analysis, OR estimate of completed suicide increased 1.46 (95% CI: 1.36, 1.56) fold for every 10-year increase in age. Moreover, OR estimate of completed suicide was 2.53 (95% CI: 1.94, 3.31) in men compared to women. Compared to married people, the OR estimate of completed suicide was 1.41 (95% CI: 1.15, 1.72) in single people, 1.92 (95% CI: 1.15, 3.23) in widowed people, and 1.97 (1.32, 2.95) in divorced people. The lower the educational level, the higher the risk of completed suicide. Compared to school/college students, the risk of completed suicide was higher among housewives, employed people or employees, and retirees. A majority of the suicides (90.05%) occurred at home. Taking medications was the most common way (69.13%) of a suicide attempt. CONCLUSION: We indicated that associated factors with completed suicide vary in Iran compared to other developed and developing countries and that factors associated with attempted suicide are different from that of completed suicide. PMID- 25556386 TI - Evaluation of different primers for detection of Brucella in human and animal serum samples by using PCR method. AB - BACKGROUND: The Polymerase Chain Reaction (PCR) method can overcome the limitations of conventional methodology. The aim of this study is to evaluate three primer pairs broadly used B4/B5, F4/R2 and JPF/JPR, for detection of Brucella by PCR, in human and animal serum samples and to determine analytic sensitivity of primers. METHODS: Total of 68 serum samples were collected during the acute phase of brucellosis. 10-fold serial dilutions were prepared from bacterial suspension and serum suspension using Brucella abortus S19. DNA was isolated using boiling. The best dilution from DNA was determined for PCR with three primer pairs. PCR was performed using primer pairs on all bacterial dilutions, serum dilutions, 1/200 dilutions and serum samples. Comparison of sensitivity between three primer pairs was performed with statistical analysis. RESULTS: The best DNA dilution was 1/200. From 68 serum samples, 54 cases (79.41%), 44 cases (64.70%) and 35 cases (51.47%), were positive by PCR with B4/B5, F4/R2 and JPF/JPR respectively. B4/B5, F4/R2 and JPF/JPR were able to identify 9 * 10(2), 9 and 9 * 10(5) bacteria in 1 ml of bacterial suspension and 9 * 10(4), 9 * 10(5) and 9 * 10(7) bacteria in 1 ml of dilution 1/200 of Serum dilutions respectively. The differences between primers by statistical analysis were significant for human, animal and total samples. CONCLUSION: No band was observed in dilutions one of DNA isolated from serum. Therefore, to decrease the effects of inhibitors, DNA was diluted. When DNA isolation is boiling, F4/R2 and B4/B5 have the greatest sensitivity for purified bacteria and serum in the detection of Brucella respectively. DNA isolation by boiling can decrease the PCR costs. PMID- 25556388 TI - Ulnar tunnel syndrome due to an aberrant muscle. AB - This report presents a case of dynamic ulnar tunnel syndrome due to an additional origin of abductor digiti minimi muscle (ADMM) from the palmaris longus tendon. Patient's symptoms resolved after excision of the aberrant muscle. PMID- 25556387 TI - Nutrition and physical activity educational intervention on CHD risk factors: a systematic review study. AB - INTRODUCTION: Fast growing epidemic of chronic diseases causes many health challenges over the world. Regarding reported pros and cons, the aim of the current study is to review the effect of nutrition and physical educational intervention in decreasing cardiovascular risk factors. METHODS & MATERIALS: In this review study, searching has done through the English and Persian databases. Articles with other languages, lack of important information, and score 3 or less in the JADAD standard checklist were exluded from the study. FINDINGS: In the primary search, 194 articles have been found.Through four stages of secondary search and further evaluation, 43 articles were selected. These articles were published between 1989 to 2013. CONCLUSION: According to these findings, the majority of articles showed a positive effect of nutrition and physical activity educational interventions on cardiovascular risk factors- blood cholesterol, systolic and diastolic blood pressure, as well as smoking cigarette in high risk patients. These results, suggest the necessity of continiuting nutrition and physical educational intervention for individuals with cardiovascular risk factors. PMID- 25556389 TI - Report of a patient with limb-girdle muscular dystrophy, ptosis and ophthalmoparesis caused by plectinopathy. AB - Mutations in plectin, a widely expressed giant cytolinker protein can lead to different diseases mostly with signs of muscular dystrophy (MD) and skin blistering. The only report of plectin-related disease without skin involvement is limb-girdle muscular dystrophy type 2Q (LGMD2Q) phenotype, showing early-onset limb-girdle muscular dystrophy symptoms with progressive manner and no cranial muscle involvement. Here, we report a non-consanguineous Iranian family with two affected sisters showing progressive limb and ocular muscle weakness. Whole Exome Sequencing (WES) led to identification of a compound heterozygous mutations, p.Gln1022Ter (c.3064C>T) and p.Gly3835Ser (c.11503G>A), in PLEC gene. To the best of our knowledge, this would be the first report of a patient with LGMD and myasthenic symptoms without any skin involvement, caused by plectinopathy. This observation extends the phenotypic spectrum of PLEC related diseases and suggests a variable expression of the PLEC- related symptoms. PMID- 25556390 TI - Diseases at the crossroads: chronic myelogenous leukemia and tuberculosis. AB - Chronic myelogenous leukemia (CML) and tuberculosis (TB) are diseases with effective available therapy. Treating patients who are afflicted simultaneously with both of these conditions is challenging due to significant drug interactions and the requirement of strict adherence to the multi-agent treatment regimen. Here, we report a case of peritoneal tuberculosis which was successfully treated with a non-rifampin based regimen in tandem with ongoing administration of a tyrosine kinase inhibitor, dasatinib, for CML. We discuss treatment challenges and the strategy on how to circumvent them. As prevalence of CML increases worldwide, patients with concomitant CML and TB will be seen more often by physicians in all continents, and development of guidelines on simultaneous management of these conditions is imperative. PMID- 25556391 TI - Colostrum production in ewes: a review of regulation mechanisms and of energy supply. AB - In sheep production systems based on extensive grazing, neonatal mortality often reaches 15% to 20% of lambs born, and the mortality rate can be doubled in the case of multiple births. An important contributing factor is the nutrition of the mother because it affects the amount of colostrum available at birth. Ewes carrying multiple lambs have higher energy requirements than ewes carrying a single lamb and this problem is compounded by limitations to voluntary feed intake as the gravid uterus compresses the rumen. This combination of factors means that the nutritional requirements of the ewe carrying multiple lambs can rarely be met by the supply of pasture alone. This problem can overcome by supplementation with energy during the last week of pregnancy, a treatment that increases colostrum production and also reduces colostrum viscosity, making it easier for the neonatal lamb to suck. In addition, litter size and nutrition both accelerate the decline in concentration of circulating progesterone that, in turn, triggers the onsets of both birth and lactogenesis, and thus ensures the synchrony of these two events. Furthermore, the presence of colostrum in the gut of the lamb increases its ability to recognize its mother, and thus improves mother-young bonding. Most cereal grains that are rich in energy in the form of starch, when used as supplements in late pregnancy will increase colostrum production by 90% to 185% above control (unsupplemented) values. Variation among types of cereal grain in the response they induce may be due to differences in the amount of starch digested post-ruminally. As a percentage of grain dry matter intake, the amount of starch entering the lower digestive tract is 14% for maize, 8.5% for barley and 2% for oats. Supplements of high quality protein from legumes and oleiferous seeds can also increase colostrum production but they are less effective than cereal grains. In conclusion, short-term supplementation before parturition, particularly with energy-rich concentrates, can improve colostrum production, help meet the energy and immunological requirements for new-born lambs, and improve lamb survival. PMID- 25556392 TI - Exogenous lipoid pneumonia as a contributory factor in a drug-related death. AB - Postmortem investigation often reveals various conditions, which may or may not have played a part in the death of the individual. The case of a 32-year-old woman is reported, with a long history of drug addiction. She was found dead in her bed. The autopsy revealed diffuse pulmonary edema with congestion of the lungs, brain, liver, and spleen. Microscopic examination of the lungs showed multiple intra-alveolar and interstitial foamy macrophages and extracellular fat droplets surrounded by polynuclear giant cells. Death was attributed to acute polydrug intoxication. As microscopic examination had revealed severe pulmonary lesions, lipoid pneumonia was considered as a contributing factor to death. Lipoid pneumonia is an uncommon entity with the characteristic radiograph features and histologic findings of alveoli filled with vacuolated, lipid-laden histiocytes. It can be either exogenous or endogenous in cause, based on the source of the lipid. Exogenous lipoid pneumonia usually results from aspiration or inhalation of fat-like material, such as mineral oil or petroleum-based lubricants and decongestants, resulting in pulmonary inflammatory reactions. PMID- 25556393 TI - Detection and characterization of a bacteriocin, putadicin T01, produced by Pseudomonas putida isolated from hot spring water. AB - Pseudomonas strains isolated from hot spring water were tested for bacteriocin like substance (BLS) production using a target panel of closely related microorganisms and other Gram-positive and Gram-negative bacteria. Molecular identification was carried out through specific PCR and 16S RNA sequence analysis. Isolates were identified as Brevundimonas diminuta and Pseudomonas putida, the latter exhibited antimicrobial activity. Pseudomonas putida strains produce an inhibitory substance against other Pseudomonas strains and other species including food-borne pathogens. The BLS was sensitive to the proteolytic action of proteinase K, pronase E and trypsin but resistant to alpha-amylase, RNase and lipase C, reflecting its proteinaceous nature. The BLS was stable at 100 degrees C and also after thermal treatment at 121 degrees C for 15 min. Additionally, it was stable within a wide range of pH (2-10). The substance from P. putida T01 strain was bactericidal to Escherichia coli. SDS-PAGE analysis of the partial purified supernatant of strain T01 revealed a BLS with an approximate molecular mass of 8 kDa. Therefore, the results of this study show that P. putida strain T01 produces a BLS with a higher activity spectrum, which may find application in human medicine and in minimally processed food preservation. PMID- 25556394 TI - Transesophageal Echocardiography for the Evaluation of Aorto-Left Ventricular Tunnel in Adults, with Follow-ups. AB - OBJECTIVE: This study aims to compare the diagnostic accuracy of combined two dimensional (2D) and real time three-dimensional (RT3D) transesophageal echocardiogram (TEE) imaging with the anatomic findings during surgery in adults with aorto-left ventricular tunnel (ALVT). BACKGROUND: ALVT has typically been reported in infants rather than in adults. TEE appears to be a promising method of recognizing the spatial relationship of intracardiac structures. METHODS: Patients underwent comprehensive 2D and RT3DTEE within 1 week preoperative and intraoperative. The TEE images were compared with the surgical findings. RESULTS: Nine patients diagnosed with ALVT using TEE were selected. The operations were successfully performed in 8 patients. The origin of the tunnels diagnosed by TEE was superior to the right coronary sinus (RCS) in 3 patients, superior to the commissure of the left coronary sinus (LCS) and the RCS in 3 patients, inferior to the junction of the LCS and noncoronary sinus (NCS) in 2 patients, and superior to the NCS in 1 patient. The surgical findings confirmed ALVT in 8 patients. The average diameter of the tunnel orifices in the LV or in the aorta measured by TEE versus surgery was 6.15 +/- 3.21 mm versus 6.80 +/- 3.91 mm (correlation displayed as r = 0.99, P < 0.0001). Seven (78%) patients had mild to severe aortic regurgitation, and 6 (67%) patients had mitral regurgitation. CONCLUSIONS: A combination of 2D and RT3DTEE imaging modalities would be needed to optimally define the anatomy and functional consequences of ALVT in adults. PMID- 25556395 TI - Investigation of Abeta phosphorylated at serine 8 (pAbeta) in Alzheimer's disease, dementia with Lewy bodies and vascular dementia. AB - AIMS: Deposition of amyloid beta (Abeta) in the brain is one of the defining abnormalities of Alzheimer's disease (AD). Phosphorylation of Abeta at serine 8 (pAbeta) has been implicated in its aggregation in vitro and pAbeta level has been shown to be significantly elevated in AD. We aimed to assess the specificity of pAbeta for AD and have investigated associations of pAbeta with parenchymal and cerebrovascular accumulation of Abeta, disease progression, angiotensin converting enzyme activity and APOE genotype. METHODS: The distribution of pAbeta was studied by immunohistochemistry in sporadic and familial AD, pure dementia with Lewy bodies (DLB), pure vascular dementia (VaD) and age-matched controls. Soluble and insoluble (guanidine-extractable) pAbeta level was measured by enzyme linked immunosorbent assay (ELISA) in the midfrontal and parahippocampal cortex in sporadic AD (n = 20, 10 with Braak tangle stages of III-IV and 10 of stages V VI), DLB (n = 10), VaD (n = 10) and age-matched controls (n = 20). RESULTS: We found pAbeta to be associated with only a subset of Abeta plaques and vascular deposits in sporadic and familial AD, with absent or minimal immunohistochemically detectable pAbeta in control, DLB and VaD brains. In both brain regions, insoluble pAbeta level was significantly elevated only in advanced AD (Braak tangle stage of V or VI) and in the parahippocampus soluble and insoluble pAbeta level increased with the number of APOE epsilon4 alleles. CONCLUSIONS: These results indicate that pAbeta accumulation in the parenchyma and vasculature is largely restricted to late-stage AD (Braak tangle stage V-VI). PMID- 25556396 TI - ACL injury risk in elite female youth soccer: Changes in neuromuscular control of the knee following soccer-specific fatigue. AB - Fatigue is known to influence dynamic knee joint stability from a neuromuscular perspective, and electromechanical delay (EMD) plays an important role as the feedback activation mechanism that stabilizes the joint. The aim of this study was to investigate the influence of soccer-specific fatigue on EMD in U13-, U15-, and U17-year-old female soccer players. Thirty-six youth soccer players performed eccentric actions of the hamstrings in a prone position at 60, 120, and 180 degrees /s before and after a soccer-specific fatigue trial. Surface electromyography was used to determine EMD from the semitendinosus, biceps femoris and gastrocnemius. A time * age * muscle * velocity repeated measures analysis of variance was used to explore the influence of fatigue on EMD. A significant main effect for time (P = 0.001) indicated that EMD was significantly longer post- compared with pre-fatigue (58.4% increase). A significant time * group interaction effect (P = 0.046) indicated EMD was significantly longer in the U13 age group compared with the U15 (P = 0.011) and U17 (P = 0.021) groups and greater post-fatigue. Soccer-specific fatigue compromised neuromuscular feedback mechanisms and the age-related effects may represent a more compliant muscle-tendon system in younger compared with older girls, increasing risk of injury. PMID- 25556397 TI - Short-term hybridisation activates Tnt1 and Tto1 Copia retrotransposons in wild tuber-bearing Solanum species. AB - Interspecific hybridisation in tuber-bearing species of Solanum is a common phenomenon and represents an important source of variability, crucial for adaptation and speciation of potato species. In this regard, the effects of interspecific hybridisation on retrotransposon families present in the genomes, and their consequent effects on generation of genetic variability in wild tuber bearing Solanum species, are poorly characterised. The aim of this study was to analyse the activity of retrotransposons in inter- and intraspecific hybrids between S. kurtzianum and S. microdontum, obtained by controlled crosses, and the effects on morphological, genetic and epigenetic variability. For genetic and epigenetic analysis, S-SAP (sequence-specific amplification polymorphism) and TMD (transposon methylation display) techniques were used, respectively, with specific primers for Tnt1 and Tto1 retrotransposon families (Order LTR, Superfamily Copia). The results indicate that at morphological level, interspecific hybrid genotypes differ from their parental species, whereas derived intraspecific hybrids do not. In both cases, we observed significant reductions in pollen grain viability, and a negative correlation with Tnt1 mobility. Both retrotransposons, Tto1 and Tnt1, were mobilised in the genotypes analysed, with mobility ranging from 0 to 7.8%. Furthermore, at the epigenetic level, demethylation was detected in the vicinity of Tnt1 and Tto1 in the hybrids compared with the parental genotypes. These patterns were positively correlated with the activity of the retrotransposons. The results suggest a possible mechanism through which hybridisation events generate genetic variability in tuber-bearing species of Solanum through retrotranposon activation. PMID- 25556398 TI - Exposed: the elusive alphaC regions in fibrinogen, fibrin protofibrils and fibers. PMID- 25556399 TI - Simulation-based training for emergency medicine residents in sterile technique during central venous catheterization: impact on performance, policy, and outcomes. AB - OBJECTIVES: Central line-associated bloodstream infection (CLABSI) is a preventable nosocomial infection. Simulation-based training in sterile technique during central venous catheter (CVC) placement for emergency medicine (EM) residents, and its effect on changing the medical intensive care unit (MICU) practice of routine replacement of CVCs placed under sterile technique in the emergency department (ED), has not been evaluated. METHODS: Emergency medicine residents received simulation-based sterile technique training during CVC placement between May 2008 and September 2010. Between June 2008 and January 2011, the authors reviewed records of patients who had CVCs placed in the ED under sterile technique by EM residents and were admitted to the MICU (group 1) and CVCs placed in the MICU under sterile technique by internal medicine (IM) residents (group 2). IM residents completed similar simulation-based training before May 2008. Changes in EM residents' sterile technique performance scores were compared, as well as CLABSI rates in both groups. EM residents' CVC procedural skills were not assessed. RESULTS: Seventy-six EM residents completed simulation-based training with significant improvement in performance (median scores 13 out of 24 before training, 24 out of 24 after training; p < 0.001). CLABSI rates per 1,000 catheter-days were 1.02 in group 1 and 1.02 in group 2 (p = 0.99). Both groups had similar demographics, acuity, and mortality (p > 0.5). CONCLUSIONS: Routine replacement of CVCs placed in the ED under sterile technique after simulation-based training would appear to be unnecessary. These findings demonstrate patient-centered outcomes that are comparable for CVCs in ED-admitted MICU patients, regardless of whether the CVC was placed in the ED or MICU. PMID- 25556400 TI - Mineralization of Alvinella polychaete tubes at hydrothermal vents. AB - Alvinellid polychaete worms form multilayered organic tubes in the hottest and most rapidly growing areas of deep-sea hydrothermal vent chimneys. Over short periods of time, these tubes can become entirely mineralized within this environment. Documenting the nature of this process in terms of the stages of mineralization, as well as the mineral textures and end products that result, is essential for our understanding of the fossilization of polychaetes at hydrothermal vents. Here, we report in detail the full mineralization of Alvinella spp. tubes collected from the East Pacific Rise, determined through the use of a wide range of imaging and analytical techniques. We propose a new model for tube mineralization, whereby mineralization begins as templating of tube layer and sublayer surfaces and results in fully mineralized tubes comprised of multiple concentric, colloform, pyrite bands. Silica appeared to preserve organic tube layers in some samples. Fine-scale features such as protein fibres, extracellular polymeric substances and two types of filamentous microbial colonies were also found to be well preserved within a subset of the tubes. The fully mineralized Alvinella spp. tubes do not closely resemble known ancient hydrothermal vent tube fossils, corroborating molecular evidence suggesting that the alvinellids are a relatively recent polychaete lineage. We also compare pyrite and silica preservation of organic tissues within hydrothermal vents to soft tissue preservation in sediments and hot springs. PMID- 25556401 TI - Temporal and spatial characteristics of high frequency oscillations as a new biomarker in epilepsy. AB - OBJECTIVE: Interictal high frequency oscillations (HFOs) are a promising candidate as a biomarker in epilepsy as well as for defining the seizure-onset zone as for the prediction of the surgical outcome after epilepsy surgery. The purpose of the study is to investigate properties of HFOs in long-term recordings with respect to the sleep-wake cycle and anatomic regions to verify previous results based on observations from short intervals and patients mainly with temporal lobe epilepsy to the analysis of hours of recordings and focal epilepsies with extratemporal origin. METHODS: Automatic HFO detection using a radial basis function neural network detector was performed in long-term recordings of 15 presurgical patients investigated with subdural strip, grid, and depth contacts. Periods with visual marked sleep stages based on parallel scalp recordings from two consecutive nights were compared to awake intervals. Statistical analysis was based on the Kruskal-Wallis test, Mann-Whitney U-test and Spearman's rank correlations. RESULTS: HFO rates in seizure-onset contacts differed from other brain regions independent of the sleep-wake cycle. For temporal contacts, the HFO rate increased significantly with sleep stage. In addition, contacts covering the parietal lobe, including rolandic cortex, showed a significant increase of HFO rates during sleep. However, no significant HFO rate changes depending on the sleep-wake cycle were found for frontal contacts. SIGNIFICANCE: The rate of interictal HFOs predicted the SOZ with statistical significance at the group level, but properties other than the HFO rate may need to be considered to improve the diagnostic utility of HFOs. This study gives evidence that the modulation of HFO rates by states of the sleep-wake cycle has particular characteristics within different neocortical regions and in mesiotemporal structures, and contributes to the establishment of HFOs as a biomarker in epilepsy. PMID- 25556402 TI - Endoscopic findings for predicting gastric acid secretion status. AB - BACKGROUND AND AIM: Gastric acidic abnormalities are related to various types of diseases in Helicobacter pylori (H. pylori) infection status. However, no studies have shown correlations between many tiny endoscopic findings and the acid secretion level simultaneously. In the present study, we investigated predictive tiny endoscopic findings of hyperchlorhydria and hypochlorhydria. METHODS: A total of 223 subjects without organic diseases who underwent esophagogastroduodenoscopy and endoscopic gastrin test (EGT) for estimating gastrin-stimulated gastric acid secretory response between 1999 and 2012 at our institution were retrospectively analyzed. Two blinded expert endoscopists reviewed the images independently and recorded the endoscopic findings. RESULTS: According to the EGT values, the enrolled subjects were categorized into hyperchlorhydria, normal acid secretion, and hypochlorhydria groups. In all subjects, hematin (odds ratio [95% confidence interval] = 3.32 [1.40-7.84]) and antral erosion(2.88 [1.24-6.70]) were the predictive endoscopic findings for hyperchlorhydria, and swelling of areae gastricae (14.4 [5.74-36.1]) and open type atrophy (15.1 [7.35-31.1]) were those for hypochlorhydria. In addition, the predictive endoscopic findings for hyperchlorhydria differed according to the H. pylori infection status, hematin in H. pylori-positive subjects and antral erosion in H. pylori-negative subjects, in contrast to those for hypochlorhydria, which were the same irrespective of the H. pylori infection status. CONCLUSIONS: We could predict the acid secretion status based on the endoscopic findings regardless of H. pylori infection status, which would be of some help for evaluating the risk for acid-related diseases. PMID- 25556403 TI - Developing accurate models of the human airways. AB - OBJECTIVES: Particle delivery to the airways is an attractive prospect for many potential therapeutics, including vaccines. Developing strategies for inhalation of particles provides a targeted, controlled and non-invasive delivery route but, as with all novel therapeutics, in vitro and in vivo testing are needed prior to clinical use. Whilst advanced vaccine testing demands the use of animal models to address safety issues, the production of robust in vitro cellular models would take account of the ethical framework known as the 3Rs (Replacement, Reduction and Refinement of animal use), by permitting initial screening of potential candidates prior to animal use. There is thus a need for relevant, realistic in vitro models of the human airways. KEY FINDINGS: Our laboratory has designed and characterised a multi-cellular model of human airways that takes account of the conditions in the airways and recapitulates many salient features, including the epithelial barrier and mucus secretion. SUMMARY: Our human pulmonary models recreate many of the obstacles to successful pulmonary delivery of particles and therefore represent a valid test platform for screening compounds and delivery systems. PMID- 25556404 TI - Origins and environmental mobility of antibiotic resistance genes, virulence factors and bacteria in a tidal creek's watershed. AB - AIMS: To compare bacterial compositions of watershed run-offs released by a human settlement and a forested area, and to evaluate their role as carriers of antibiotic resistance and virulence genes. METHODS AND RESULTS: Run-offs from a forested area and a small settlement in a tidal creek' s watershed were compared for bacterial composition and profiles of 16 tetracycline resistance (TRG), eight virulence (VG) and integrase1 and 2 genes. Integrase 1 gene was detected only once. No integrase 2 gene was observed. VGs were detected only in settlement's run-offs, and TRG incidence frequency there was twice as high as in the forest's run-offs. Gene incidences revealed a positive correspondence to the rainfall, and weak correlations to water parameters. Metagenomic, Principle Coordinates and Shannon analyses together revealed distinctive bacterial compositions of the forest's and settlement's run-offs. Passage of the latter through a salt marsh resulted in the elimination of TRGs and three-fold decrease in VG incidence, and their bacterial composition was shifted towards that of the tidal creek. CONCLUSIONS: The settlement was a major source of TRGs and VGs in the watershed, but these contaminants were mitigated by a salt marsh system. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data revealed the role of small settlements in biological contamination of the coastal waters. They also indicated that salt marshes are capable of reducing not only chemical but also biological contamination of run-offs. PMID- 25556406 TI - Diagnosing and predicting outcome in leptospirosis: the need for clinically relevant basic sciences research. PMID- 25556407 TI - Outcome of patients with ST segment elevation myocardial infarction (STEMI) following percutaneous transluminal coronary angioplasty: a retrospective study. AB - OBJECTIVES: To study the characteristics and long term outcome of patients who had segment elevation myocardial infarction (STEMI) and treated with PTCA in a fee levying hospital in Sri Lanka. METHODS: A retrospective study was conducted among patients diagnosed with STEMI and treated with PTCA in a fee levying private hospital in Colombo from 1st January 2009 to 1st November 2012. Details of patients were obtained from medical records and the survival status, cause of death and date of death where relevant, were obtained from records, patients or close relatives. RESULTS: 197 patients (153 men; 77.7%) were included. More than 50% had a history of diabetes, dyslipidaemia or hypertension. The three year survival was 82.7% (95% CI: 77.9%-90.5%). Based on the Cox's Proportional Hazards model, site of arterial occlusion (proximal vs distal segment of left anterior descending artery [LAD] was significantly associated with mortality due to all causes [HR 10.98; 95% CI: 1.09-110.20]. Low ejection fraction, not on regular medication and delay of more than 3 hours between onset to door time were associated with death due to cardiovascular causes in patients whose right coronary artery or left circumflex artery was the culprit artery. CONCLUSIONS: The three year survival of patients with STEMI and who had PTCA was 83%. Patients with proximal LAD occlusion were 11 times more likely to die within 3 years of PTCA as compared to those who had a distal LAD occlusion. PMID- 25556408 TI - Outcome of retrograde ureteric stenting as a urinary drainage procedure in ureteric obstruction related to malignant lesions. AB - OBJECTIVES: We investigated the outcome of endoscopic retrograde ureteric stenting (RUS) in patients with ureteric obstruction related to malignant lesions. METHODS: Data were prospectively collected from patients with ureteric obstruction related to malignant lesions treated at a single urology unit from 1 January 2011 to 30 April 2014. All patients had radiologically significant hydronephrosis by ultrasonography and CT scanning. First choice of urinary drainage was placing a retrograde ureteric stent cystoscopically. Outcome of patients who had stenting were recorded after following them until death or removal of stents. RESULTS: Eighty two patients with ureteric obstruction related to malignant lesions had complete data. In 33 (25%) patients, retrograde ureteric stenting was possible. Fifteen of them had recurrent tumour in the pelvis at the time of stenting and 13 (87%) were dead within 3 months of stenting. Four of the five patients who did not have pelvic tumour recurrence were alive at the end of the study. All eight patients who underwent stenting before surgery as a prophylactic measure and three of the five patients who had retroperitoneal tumour mass and underwent RUS were alive. Stenting was not possible in 42 patients. Thirty eight of them had pelvic tumour recurrences and two were having retroperitoneal tumour masses. Only one did not have tumour in the pelvis.CT evidence of tumour recurrence in the pelvis (OR 12.7; 95% CI 1.3-117.6; p=0.026) and high serum creatinine (OR 4.3; 95% CI 1.6-11.7; p=0.004) were associated with failure to ureteric stenting. CONCLUSIONS: Chances of successful RUS were low in patients with ureteric obstruction in the presence of tumour recurrences or elevated serum creatinine. Even if ureteric stenting was successful, their life expectancy was short. PMID- 25556409 TI - An observational study of alopecia areata in Sri Lankan adult patients. AB - OBJECTIVES: The objectives were to assess the demographical pattern, clinical presentation and therapeutic response in a cohort of patients with alopecia areata (AA) in Sri Lanka. METHODS: Hospital-based observational study of 290 adults aged 18 years or above. RESULTS: Alopecia areata was commoner in men (M:F=1.3:1). Age of onset was between 20-35 years (median 31 years) in 61%. Those with juvenile-onset AA (<= 17 years, n=5) showed severe disease with many relapses and resistance to therapy. Late-onset AA (<50 years, n=12) was commoner among females and had mild disease activity. Alopecia areata was the commonest clinical type (93.7%), followed by alopecia universalis (n=10), ophiasis pattern (n=3), alopecia totalis (n=3), and reverse ophiasis pattern (n=1). Mild disease (>10% scalp area) was the commonest (82%). Alopecia was total, universal or extensive (>10% scalp area) in 18%. Sites involved were scalp (71%), beard only (20.5%) and multiple sites (8.7%). Nail changes were associated with severe disease. Associated autoimmune diseases were vitiligo 6 (2%), thyroid disease 5 (1.7%) and rheumatoid arthritis 1 (0.3%). Atopy (21%) was not associated with younger age of onset or severity of disease. Patients with a family history among first degree relatives had earlier onset of disease. Most (61%) were cured after 1-2 intralesional steroid injections. Oral dexamethasone mini pulse with or without topical 5% minoxidil lotion for 12 months or more were used in 28%. CONCLUSIONS: In Sri Lanka AA is a disease of the young. Extensive disease, juvenile onset, and associated nail changes were poor prognostic factors. PMID- 25556410 TI - Pattern of clinically recognisable congenital malformations in babies born in a tertiary referral centre in Sri Lanka. AB - OBJECTIVES: To record incidence, pattern and prevalence of risk factors of congenital malformations (CM) in live new born babies at a Teaching Hospital in Sri Lanka. METHODS: All newborn babies delivered over a period of six months at the Teaching Hospital, Mahamodara were included in this cross sectional study and they were subjected to thorough medical examination to detect any CM. An interviewer administered questionnaire was used to collect information on socio demographics and risk factors associated with CM. RESULTS: Overall prevalence of CM in the study group was 4.3%. Occurrence was higher in males (61.4%) than females (36.9%). Highest frequency of CM was in the musculoskeletal system. Parents' age, previous history of abortions or stillbirths, consanguinity and pre conceptual folic acid deficiency were the most prevalent risk factors related to CM. CONCLUSIONS: Prevalence of CM in the study group is high compared to other countries in the region. Emphasis on preventing CM is recommended and public health actions is required in improving well-being of affected babies. PMID- 25556411 TI - Head circumference during infancy in a birth cohort of Sri Lankan children: are we using the correct chart? AB - INTRODUCTION: Measuring head circumference and plotting it in centile charts is a routine practice in paediatrics. However if wrong charts are used, serious misinterpretations can ensue. OBJECTIVES: This study was carried out to ascertain the appropriateness of charts used in Sri Lanka. Out of a birth cohort of 2215 children, 250 from each sex were invited for a follow up study. Head circumference was measured at 2, 4, 6, 9 and 12 months. Statistical characteristics of head circumference for each sex, at each age were calculated. RESULTS: At the first follow up 244 boys and 241 girls were assessed. Out of this, 85% of boys and 86% of girls completed the follow up. CONCLUSIONS: Head circumference of both sexes deviated significantly at all ages from the charts available in the Child Health Developmental Record (CHDR). Head circumference charts available in the CHDR are inappropriate for use in Sri Lankan children. PMID- 25556412 TI - Pringle manoeuvre versus selective hepatic vascular exclusion: outcome of a case series in a tertiary referral centre. AB - A retrospective comparative study was done to compare the outcome of intermittent Pringle manoeuvre (IPM) and selective hepatic vascular exclusion (SHVE) in 19 major hepatectomies in non-cirrhotic patients that were done from October 2003 to June 2009. Intra-operative blood loss (IBL), total operative time (TOT) and immediate outcome were assessed in the two groups. Thirteen underwent IPM and the others underwent SHVE. The mean age was 50 years (SHVE) and 39.2 years (IPM). Mean IBL was 641 ml and 802 ml in the SHVE and IPM groups respectively (p > .05). TOT was 4.7 hours in both groups. There was one mortality from myocardial infarction in the IPM group and no morbidities in both groups. The results obtained from this study shows that IPM is equivalent to SHVE, with regards to IBL, TOT and immediate outcome in major hepatectomies in non-cirrhotic patients. PMID- 25556413 TI - Malnutrition and anaemia among hospitalised children in Vavuniya. AB - We conducted a cross sectional descriptive study to describe the factors associated with the degree of malnutrition among hospitalised malnourished children in General Hospital, Vavuniya. All hospitalised children from January to June 2012 (n=1210) were screened and the nutritional status assessed using WHO growth standards for weight for height/length. A total of 179 children with moderate acute malnutrition (MAM) (14.8%) and 105 children with severe acute malnutrition (SAM) (8.7%) were detected during this period. Having SAM (compared to MAM) was associated with lower maternal education (p<0.001), lower paternal education (p<0.001), low family income (p=0.022) and mother being a housewife (p=0.009). Prevalence of anaemia among 284 malnourished children was mild 32.4% (n=92), moderate 22.2% (n=63) and severe 0.7% (n=2). Anaemia was highest among infants and prevalence decreased with increasing age. Social determinants played an important role in degree of malnutrition and anaemia among malnourished children admitted to the General Hospital, Vavuniya. PMID- 25556414 TI - An unusual presentation of Behcet's disease. PMID- 25556415 TI - Transplacental transfer of dengue. PMID- 25556416 TI - Perineal groove leading to a suspicion of child sexual abuse. PMID- 25556417 TI - Superficial cerebral hemosiderosis in a patient treated with warfarin. PMID- 25556418 TI - Progressive blindness in a child with neurofibromatosis type 1. PMID- 25556419 TI - Antenatally diagnosed lung malformations: a plea for long-term outcome studies. AB - There is a wide variation in the management of infants with antenatally diagnosed lung malformations, with many paediatric surgeons and respiratory paediatricians recommending early investigations for all infants and a surgical excision for the majority of lesions, while others favour a conservative management for all asymptomatic infants. The benefits and risks of a surgical intervention have to be compared with the natural history of the untreated malformation and cohort studies from foetal diagnosis to adult life are required to provide the relevant evidence. Careful and repeated surveillance of identified foetuses is essential as recent advances in foetal medicine and surgery have improved the outcomes for the small minority, who are at risk of developing hydrops. PMID- 25556420 TI - Autologous graft-versus-host disease in a child with stage IV neuroblastoma. AB - Graft-versus-host disease (GVHD) is an underappreciated complication of autologous hematopoietic stem cell transplantation (AHSCT) that can affect the skin, gastrointestinal tract, and liver. The development of this rare condition is probably due to an impairment of immunologic tolerance that can occur spontaneously through T-cell dysregulation, possibly from intensive conditioning chemotherapy regimens, or intentionally through administration of cyclosporine in the hopes of promoting an antitumor response. We present the case of a 2-year-old boy with metastatic neuroblastoma who spontaneously developed autologous GVHD after AHSCT. Severe pruritus and an inability to taper his oral steroids without a disease flare marked his disease. Eventually partial relief was achieved with initiation of cyclosporine and a strict soak and smear protocol using topical triamcinolone 0.1% ointment. PMID- 25556422 TI - A case of Kindler syndrome with severe esophageal stenosis. PMID- 25556423 TI - Aprepitant in the prevention of vomiting induced by moderately and highly emetogenic chemotherapy. AB - Chemotherapy is a major therapeutic approach for malignant neoplasms; however, due to the most common adverse events of nausea and vomiting, scheduled chemotherapeutic programs may be impeded or even interrupted, which severely impairs the efficacy. Aprepitants, 5-HT3 antagonists and dexamethasone are primary drugs used to prevent chemotherapy-induced nausea and vomiting (CINV). These drugs have excellent efficacy for control of acute vomiting but are relatively ineffective for delayed vomiting. Aprepitant may remedy this deficiency. Substance P was discovered in the 1930s and its association with vomiting was confirmed in the 1950s. This was followed by a period of non-peptide neurokinin-1 (NK-1) receptor antagonist synthesis and investigation in preclinical studies and clinical trials (phases I, II and III). The FDA granted permission for the clinical chemotherapeutic use of aprepitant in 2003. At present, the combined use of aprepitant, 5-HT3 antagonists and dexamethasone satisfactorily controls vomiting but not nausea. Therefore, new therapeutic approaches and drugs are still needed. PMID- 25556424 TI - Innovations in HPV vaccination and roles of nurses in cervical cancer prevention. AB - The human papilloma virus (HPV) is the main aetiological agent for cervical cancer, one of the most frequent cancers observed in women throughout the world. There are effective programs for reducing the incidence of cervical cancer with HPV vaccination. The objective of this study was to discuss the applicability of the HPV vaccination and the role of nurses in prevention of cervical cancer. Use of bivalent and quadrivalent vaccines has been initiated against the types of HPV which are the primary cause of cancer. The quadrivalent HPV vaccination has entered into the routine vaccination schedule in many European countries for use in children and adolescents between 9-15 years of age and for women between 16-26 years of age, whereas it has been proposed that the bivalent vaccination should be given to girls between 9-18 years of age. While cervical cancer is among the cancers that can be prevented, it is essential to continue screening tests while introducing vaccination in a systematic manner for protection. On this subject, among the most important roles of nurses is to implement the screening programs by fulfilling the caregiving, training and consultancy roles for the society and especially, for high risk groups and to increase the awareness of the people. PMID- 25556425 TI - 18FDG synthesis and supply: a journey from existing centralized to future decentralized models. AB - Positron emission tomography (PET) as the functional component of current hybrid imaging (like PET/ CT or PET/MRI) seems to dominate the horizon of medical imaging in coming decades. 18Flourodeoxyglucose (18FDG) is the most commonly used probe in oncology and also in cardiology and neurology around the globe. However, the major capital cost and exorbitant running expenditure of low to medium energy cyclotrons (about 20 MeV) and radiochemistry units are the seminal reasons of low number of cyclotrons but mushroom growth pattern of PET scanners. This fact and longer half-life of 18F (110 minutes) have paved the path of a centralized model in which 18FDG is produced by commercial PET radiopharmacies and the finished product (multi-dose vial with tungsten shielding) is dispensed to customers having only PET scanners. This indeed reduced the cost but has limitations of dependence upon timely arrival of daily shipments as delay caused by any reason results in cancellation or rescheduling of the PET procedures. In recent years, industry and academia have taken a step forward by producing low energy, table top cyclotrons with compact and automated radiochemistry units (Lab- on-Chip). This decentralized strategy enables the users to produce on-demand doses of PET probe themselves at reasonably low cost using an automated and user-friendly technology. This technological development would indeed provide a real impetus to the availability of complete set up of PET based molecular imaging at an affordable cost to the developing countries. PMID- 25556421 TI - Treating severe malaria in pregnancy: a review of the evidence. AB - Severe malaria in pregnancy is a large contributor to maternal morbidity and mortality. Intravenous quinine has traditionally been the treatment drug of choice for severe malaria in pregnancy. However, recent randomized clinical trials (RCTs) indicate that intravenous artesunate is more efficacious for treating severe malaria, resulting in changes to the World Health Organization (WHO) treatment guidelines. Artemisinins, including artesunate, are embryo-lethal in animal studies and there is limited experience with their use in the first trimester. This review summarizes the current literature supporting 2010 WHO treatment guidelines for severe malaria in pregnancy and the efficacy, pharmacokinetics, and adverse event data for currently used antimalarials available for severe malaria in pregnancy. We identified ten studies on the treatment of severe malaria in pregnancy that reported clinical outcomes. In two studies comparing intravenous quinine with intravenous artesunate, intravenous artesunate was more efficacious and safe for use in pregnant women. No studies detected an increased risk of miscarriage, stillbirth, or congenital anomalies associated with first trimester exposure to artesunate. Although the WHO recommends using either quinine or artesunate for the treatment of severe malaria in first trimester pregnancies, our findings suggest that artesunate should be the preferred treatment option for severe malaria in all trimesters. PMID- 25556427 TI - Antiproliferative effect of metformin on the endometrium--a clinical trial. AB - BACKGROUND: Unopposed estrogen has a central role in development of endometrial benign, premalignant and malignant lesions. The aim of this study was to evaluate the anti-estrogenic effect of metformin on endometrial histology in comparison with progesterone. MATERIALS AND METHODS: A total of 43 patients who were referred to our center for abnormal uterine bleeding and had a histologic diagnosis were disordered proliferative endometrium or simple endometrial hyperplasia were included and randomly distributed in two groups treated with metformin (500mg Bid) or megestrol (40mg daily), respectively, for three months. After this period the patients were evaluated by another endometrial biopsy to assess the impact of the two drugs in restoring normal endometrial histology. RESULTS: Our findings revealed that metformin could induce endometrial atrophy in 21 out of 22 patients (95.5%) while this positive response was achieved in only 13 out of 21 patients (61.9%) in the megstrol group. In addition two low grade endometrial carcinomas in the metformin group responded very well. CONCLUSIONS: We conclude that metformin could be used as an effective antiestrogenic agent in control of abnormal endometrial proliferative disorders. PMID- 25556426 TI - Human papillomavirus genotypes among females in Mexico: a study from the Mexican institute for social security. AB - BACKGROUND: The aetiological relationship between human papillomavirus (HPV) infection and cervical cancer (CC) is widely accepted. Our goal was to determine the prevalence of HPV types in Mexican women attending at the Mexican Institute for Social Security from different areas of Mexico. MATERIALS AND METHODS: DNAs from 2,956 cervical samples were subjected to HPV genotyping: 1,020 samples with normal cytology, 931 with low-grade squamous intraepithelial lesions (LGSIL), 481 with high grade HGSIL and 524 CC. RESULTS: Overall HPV prevalence was 67.1%. A total of 40 HPV types were found; HPV16 was detected in 39.4% of the HPV-positive samples followed by HPV18 at 7.5%, HPV31 at 7.1%, HPV59 at 4.9%, and HPV58 at 3.2%. HPV16 presented the highest prevalence both in women with altered or normal cytology and HPV 18 presented a minor prevalence as reported worldwide. The prevalence ratio (PR) was calculated for the HPV types. The analysis of PR showed that HPV16 presents the highest association with CC, HPV 31, -33, -45, -52 and 58 also demonstrating a high association. CONCLUSIONS: The most prevalent HPV types in cervical cancer samples were -16, -18, -31, but it is important to note that we obtained a minor prevalence of HPV18 as reported worldwide, and that HPV58 and -52 also were genotypes with an important prevalence in CC samples. Determination of HPV genotypes is very important in order to evaluate the impact of vaccine introduction and future cervical cancer prevention strategies. PMID- 25556428 TI - Challenges of providing cervical cancer prevention programs in Iran: a qualitative study. AB - BACKGROUND: Cervical cancer has become a major public health problem worldwide. Iran, like other developing countries, is facing a number of challenges in managing the disease. This qualitative study documents challenges encountered in cervical cancer preventing programs in Iran. MATERIALS AND METHODS: In-depth interviews were conducted with 28 participants including eleven patients with cervical cancer, three gynecologic oncologists, five specialists in Obstetrics and Gynecology, five midwives, three health care managers and one epidemiologist in Mashhad Iran, between May and December of 2012. The sample was selected purposively until data saturation was achieved. Data credibility verified via allocated sufficient time for data collection, using member checking and peer debriefing. Data analysis was carried out using conventional content analysis approach with ATLAS. ti software. RESULTS: Findings from data analysis demonstrated 2 major themes and 6 categories about challenges of providing cervical cancer prevention programs including: individual and social challenges (cognitive/behavioral challenges and socio/cultural challenges) and health system challenges (stewardship, financing, competency of health care providers and access to services). Each category included some subcategories. CONCLUSIONS: Managing the cervical cancer prevention programs need to include the consideration of individuals, health care providers and health system challenges. Addressing the low level of knowledge, negative attitudes, socio cultural challenges, Poor intersectional collaboration and coordination and intra sectional management, financing and competency of health care providers are essential steps toward significantly reducing the burdens of cervical cancer. PMID- 25556429 TI - New therapeutic schedule for prostatic cancer-3 cells with ET-1 RNAi and Endostar. AB - BACKGROUND: Endothelin-1 and Endostar are both significant for the progression, proliferation, metastasis and invasion of cancer. In this paper, we studied the effect of ET-1 RNAi and Endostar in PC-3 prostatic cancer cells. MATERIALS AND METHODS: The lentiviral vector was used in the establishment of ET-1 knockdown PC 3 cells. Progression and apoptosis were assessed by CKK-8 and flow cytometry, respectively. Transwell assay was used to estimate invasion and signaling pathways were studied by Western blotting. RESULTS: ET-1 mRNA and protein in ET-1 knockdown PC-3 cells were reduced to 26.4% and 22.4% compared with control group, respectively. ET-1 RNAi and Endostar both were effective for the suppression of progression and invasion of PC-3 cells. From Western blotting results, the effects of ET-1 regulation and Endostar on PC-3 cells were at least related to some signaling pathways involving PI3K/Akt/Caspase-3, Erk1/2/Bcl-2/Caspase-3 and MMPs (MMP-2 and MMP-9). Furthermore, combined treatment of ET-1RNAi and Endostar was found to be more effective than single treatment. CONCLUSIONS: Both ET-1 RNAi and Endostar can inhibit the progression and invasion of PC-3 cells, but combined treatment might be a better therapeutic schedule. PMID- 25556430 TI - Induction of apoptosis by IGFBP3 overexpression in hepatocellular carcinoma cells. AB - BACKGROUND: The insulin-like growth factor (IGF) system comprises a group of proteins that play key roles in regulating cell growth, differentiation, and apoptosis in a variety of cellular systems. The aim of this study was to investigate the role of insulin-like growth factor binding protein 3 (IGFBP3) in hepatocellular carcinoma. MATERIALS AND METHODS: Expression of IGF2, IGFBP3, and PTEN was analyzed by qRT-PCR. Lentivirus vectors were used to overexpress IGFBP3 in hepatocellular carcinoma cell (HCC) lines. The effect of IGFBP3 on proliferation was investigated by MTT and colony formation assays. RESULTS: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells. CONCLUSIONS: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/ trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells. PMID- 25556431 TI - Description of deaths on Easter Island, 2000-2012 period. AB - Easter Island is a small island of 180 km2, located 3,800 km from the Chilean coast and one of the most isolated inhabited places in the world. Since the mid twentieth century, it has been undergoing an epidemiological transition in relation to the causes of death, from a predominance of infectious to non communicable diseases (NCDs) such as cardiovascular ailments and cancer. The aim of this study is to describe the causes of death to Easter Island between 2000 and 2012, so the statistical records of Hanga Roa Hospital and death certificates were reviewed. The period under review of 13 years there was a total of 252 deaths, an average to 19.3 deaths per year. The most frequent causes of death found in the general population of Easter Island were cardiovascular diseases (25.4%), followed by neoplasms (23.4%), accidents (18.6%). Related to Rapa Nui people, cardiovascular and neoplastic diseases (both 26.7%) predominate, while in the population without belonging to the ethnic group the main causes were traumatic (25%) and cardiovascular (22.2%). Comparing the leading causes of death of Easter Island with mainland Chile, it can be seen how they resemble. Taking the island death profile, it is necessary to work on public health strategies aimed to this, considering that some of the causes are completely preventable. PMID- 25556432 TI - Knowledge, attitude and practices of technicians working at hospitals towards testicular cancer and self-examination of testicles in Turkey. AB - BACKGROUND: The present study was conducted to determine knowledge level of technicians working in hospitals about testicular cancer (TC) and self examination of testicles (TSE) and to determine levels of consciousness and implementation status about TSE. MATERIALS AND METHODS: This cross-sectional study was conducted with technicians working in hospitals (n=243) between 2nd January-31st May 2012 at private and governmental hospitals in urban Kayseri. Healthy control subjects (n=235) who were similar to technicians in terms of age, education level and income status were also included to the study. Chi-square test was used in comparison of categorical variables. RESULTS: Technicians were significantly more aware of TC than controls, but the latter were found to have significantly more information about TSE. There was no significant difference between the two groups in terms of knowing how to do TSE and 80% of both groups were unaware this exam. Of technicians, 19.8% and of controls, 25.5% did TSE, the difference being statistically insignificant. First reason for not doing TSE was "not-knowing" among technicians (48.1%) while it was "ignorance" among controls (66.8%). Of technicians doing TSE, 37.5% did as it came to their mind while 51.7% of controls performed TSE several times in the previous year. Technicians were significantly more afraid of getting TC than controls (p=0.037). CONCLUSIONS: It was determined in the present study that rates of TSE were similar between technicians and controls. However compliance with the recommended frequency and right method was low. Consequently, public health educationshould be planned and applied in order to increase the knowledge of TC and TSE. PMID- 25556433 TI - Intrinsic motivation factors based on the self-determinant theory for regular breast cancer screening. AB - The purpose of this study was to identify factors of intrinsic motivation that affect regular breast cancer screening and contribute to development of a program for strategies to improve effective breast cancer screening. Subjects were residing in South Korea Gangwon-Province and were female over 40 and under 69 years of age. For the investigation, the Intrinsic Motivation Inventory (IMI) was modified to the situation of cancer screening and was used to survey 905 inhabitants. Multinominal logistic regression analyses were conducted for regular breast cancer screening (RS), one-time breast cancer screening (OS) and non breast cancer screening (NS). For statistical analysis, IBM SPSS 20.0 was utilized. The determinant factors between RS and NS were "perceived effort and choice" and "stress and strain" - internal motivations related to regular breast cancer screening. Also, determinant factors between RS and OS are "age" and "perceived effort and choice" for internal motivation related to cancer screening. To increase regular screening, strategies that address individual perceived effort and choice are recommended. PMID- 25556434 TI - Association of a pre-miR-27a polymorphism with cancer risk: an updated meta analysis. AB - MicroRNA-27a is highly expressed in cancers and has been identified as an oncogenic microRNA. A genetic variant in pre-miR-27a (rs895819) with a transition of A to G has been demonstrated to be associated with cancer risk; however, the results of these studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis to derive a more precise estimation. Through searching PubMed or other databases up to March 2014 using the following MeSH terms and keywords, "miR-27a", "polymorphism" and "cancer", seventeen case-control studies were identified in this meta-analysis, including 7,813 cases and 9,602. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to investigate the association strength between rs895819 and the susceptibility of cancer. The results of the overall meta-analysis did not suggest any association between rs895819 polymorphism and cancer susceptibility, and this remained in Asians as a sub- group. In Caucasians, however, the rs895819 was associated with a reduced cancer risk in heterozygous (OR, 0.83; 95%CI, 0.75 0.93) and dominant models (OR, 0.84; 95%CI, 0.76-0.93), and the [G] allele of rs895819 showed a protective effect (OR, 0.90, 95%CI, 0.84-0.97). Further studies showed a significant association between the [G] allele of rs895819 and decreased risk of breast cancer (0.91; 95%CI, 0.85-0.98), and stratified analyses indicated a protective effect of the [G] allele in Caucasians (OR, 0.89; 95%CI, 0.82-0.98), younger breast cancer cases (OR, 0.87; 95%CI, 0.79-0.96), and in the group of unilateral breast cancer patients (OR, 0.90; 95%CI, 0.83-0.97). These findings suggest an association between pre-miR-27a polymorphism rs895819 and cancer risk in Caucasians. The protective effect of rs895819 [G] allele in younger breast cancer and in the group of unilateral breast cancer patients await further confirmation since the included studies in this meta-analysis were limited. PMID- 25556435 TI - IGF-1 from adipose-derived mesenchymal stem cells promotes radioresistance of breast cancer cells. AB - PURPOSE: The aim of this study was to investigate effects of adipose-derived mesenchymal stem cells (AMSCs) on radioresistance of breast cancer cells. MATERIALS AND METHODS: MTT assays were used to detect any influence of AMSC supernatants on proliferation of breast cancer cells; cell migration assays were used to determine the effect of breast cancer cells on the recruitment of AMSCs; the cell survival fraction post-irradiation was assessed by clonogenic survival assay; gamma-H2AX foci number post-irradiation was determined via fluorescence microscopy; and expression of IGF-1R was detected by Western blotting. RESULTS: AMSC supernatants promoted proliferation and radioresistance of breast cancer cells. Breast cancer cells could recruit AMSCs, especially after irradiation. IGF 1 derived from AMSCs might be responsible for the radioresistance of breast cancer cells. CONCLUSIONS: Our results suggest that AMSCs in the tumor microenvironment may affect the outcome of radiotherapy for breast cancer in vitro. PMID- 25556436 TI - Psychometric properties of the Persian version of satisfaction with care EORTC-in patsat32 questionnaire among Iranian cancer patients. AB - BACKGROUND: Cancers impose an increasing burden on health of the populations and individuals, but little is known about cancer patient satisfaction with care. The aim of this study was to assess the psychometric properties of the Persian version of European Organisation for Research and Treatment of Cancer (EORTC) In Patsat32, as a recently developed questionnaire to assess cancer patient satisfaction with care and information provided during hospital admission. MATERIALS AND METHODS: Complying with EORTC protocols, the Persian version of Inpatsat32 was translated and piloted in a small group of patients, then applied to 380 cancer patients admitted to different oncology wards in Tehran. Validity (convergent, discriminant, and divergent) and reliability of the tool was assessed through using multitrait analysis, factor analysis, intraclass correlations, Chronbach's alpha and test-retest (on a sample of 70 patients). RESULTS: Good acceptance and high sensitivity of the questionnaire with low floor and ceiling effects were recognized, indicating power of the instrument to detect differences between groups with heterogeneous levels of satisfaction. Multitrait scaling analyses supported the convergent validity of the majority of scales (correlation coefficient >0.4) and favorable discriminant validity (item own scale correlation >0.8). There was no correlation between In-patsat32 scales and the EORTC-C30, which measures different concepts, confirming divergent validity of the tool. Internal consistency for all domains was high (alpha>0.70) except for the hospital access score and the test-retest reliability was excellent (r=0.86-0.96). There was a weak responsiveness to change except for nurses technical skills. Principle component analysis confirmed five domains with much improved internal consistency (alpha>0.9). CONCLUSIONS: The Persian version of the EORTC-in-patsat32 module is a reliable and valid instrument to measure cancer patient satisfaction with care received during their hospitalization period and can be utilized in clinical cancer research. PMID- 25556437 TI - Knowledge, attitude and practice of tobacco use and its impact on oral health status of 12 and 15 year-old school children of Chhattisgarh, India. AB - BACKGROUND: Tobacco is a leading preventable cause of deaths worldwide; the situation is particularly serious in the developing countries. Tobacco use amongst the children and adolescents is already a pandemic and they are vulnerable targets of tobacco industry. This is also the case in India. OBJECTIVES: 1) Document and monitor the prevalence of tobacco use including smoked, smokeless and other forms of tobacco; 2) Understand studentknowledge and attitudes related to tobacco use and its health impact; 3) Assess the impact of tobacco on the oral health status of school-going children in India. MATERIALS AND METHODS: The sample was 1,500 school children of the age group 12-15 years age. A pretested, close ended questionnaire was administered in the form of extensive face to face interview to understand student knowledge, attitudes and behavior related to tobacco use and its health impact and to assess the prevalence of tobacco use including smoked, smokeless and other forms of tobacco. Oral health status was assessed using the Community Periodontal Index (CPI). Frequency distribution, Chi-square tests and Odd's ratio was calculated. RESULTS: Prevalence of tobacco usage amongst the prevalence was 20.4%: 9.2% reported smoking, 15.8% used tobacco in the chewable form and 25.3% children were involved in consuming betel nut/areca nuts. The OR (Odd's ratio) for calculus formation was highest for guthka chewers (OR=14.322), paan masala chewers had the highest odds of developing bleeding on probing when compared to the others. CONCLUSIONS: There is an urgent need to launch school-based tobacco prevention programs for community awareness of children and the public, as preventing the initiation of a habit is far easier than stopping it. PMID- 25556438 TI - An in silico appraisal to identify high affinity anti-apoptotic synthetic tetrapeptide inhibitors targeting the mammalian caspase 3 enzyme. AB - Apoptosis is a general phenomenon of all multicellular organisms and caspases form a group of important proteins central to suicide of cells. Pathologies like cancer, Myocardial infarction, Stroke, Sepsis, Alzheimer's, Psoriasis, Parkinson and Huntington diseases are often associated with change in caspase 3 mediated apoptosis and therefore, caspases may serve as potential inhibitory targets for drug development. In the present study, two series of synthetic acetylated tetrapeptides containing aldehyde and fluromethyl keto groups respectively at the C terminus were proposed. All these compounds were evaluated for binding affinity against caspase 3 structure. In series 1 compound Ac-DEHD-CHO demonstrated appreciable and high binding affinity (Rerank Score: -138.899) against caspase 3. While in series 2 it was Ac-WEVD-FMK which showed higher binding affinity (Rerank Score: -139.317). Further these two compounds met ADMET properties and demonstrated to be non- toxic. PMID- 25556439 TI - Prevalence of human papillomavirus 16 in esophageal cancer among the Chinese population: a systematic review and meta-analysis. AB - BACKGROUND AND AIM: No firm evidence of HPV infection in esophageal cancer has been established to date. The aim of this meta-analysis was to investigate the prevalence of HPV 16 in esophageal cancer in China, which had a high burden of the disease. MATERIALS AND METHODS: Studies on HPV infection and esophageal cancer were identified and a random-effects model was used to pool the summary prevalence and corresponding 95% confidence intervals (CIs). RESULTS: A total of 3,429 esophageal cancer cases were evaluated from 26 eligible studies in this meta-analysis. The summary estimate for HPV16 prevalence was 0.381 (95% CI: 0.283, 0.479). The prevalence varied by geographical areas of the study, publication year, HPV detection method and types of specimen. In sensitivity analysis, HPV 16 prevalence ranged from 0.368 (95% CI: 0.276, 0.460) to 0.397 (95% CI: 0.286, 0.508). CONCLUSIONS: The results indicate a relatively high level of HPV 16 prevalence in esophageal cancer among Chinese population, although there was variation between different variables. Further studies are needed to elucidate the role of HPV in esophageal carcinogenesis with careful consideration of study design and laboratory detection method, providing more accurate assessment of the HPV status in esophageal cancer. PMID- 25556440 TI - 4-Hydroxynonenal promotes growth and angiogenesis of breast cancer cells through HIF-1alpha stabilization. AB - 4-Hydroxynonenal (4-HNE) is a stable end product of lipid peroxidation, which has been shown to play an important role in cell signal transduction, while increasing cell growth and differentiation. 4-HNE could inhibit phosphatase and tensin homolog (PTEN) activity in hepatocytes and increased levels have been found in human invasive breast cancer. Here we report that 4-HNE increased the cell growth of breast cancer cells as revealed by colony formation assay. Moreover, vascular endothelial growth factor (VEGF) expression was elevated, while protein levels of hypoxia inducible factor 1 alpha (HIF-1alpha) were up regulated. Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, is reported to destabilize HIF-1alpha. Here, 4-HNE could inhibit the deacetylase activity of SIRT3 by thiol-specific modification. We further demonstrated that the regulation by 4-HNE of levels of HIF-1alpha and VEGF depends on SIRT3. Consistent with this, 4-HNE could not increase the cell growth in SIRT3 knockdown breast cancer cells. Additionally, 4-HNE promoted angiogenesis and invasion of breast cancer cells in a SIRT3-dependent manner. In conclusion, we propose that 4 HNE promotes growth, invasion and angiogenesis of breast cancer cells through the SIRT3-HIF-1alpha-VEGF axis. PMID- 25556441 TI - Factors that influence awareness of breast cancer screening among Arab women in Qatar: results from a cross sectional survey. AB - BACKGROUND: Breast cancer is the most common cancer among women in the State of Qatar. Due to low participation in breast cancer screening (BCS) activities, women in Qatar are often diagnosed with breast cancer at advanced stages of the disease. Findings indicate that low participation rates in BCS activities are significantly related to women's low level of awareness of breast cancer screening. The objectives of this study were to: (1) determine the factors that influence Qatari women's awareness of breast cancer and its screening activities: and (2) to find ways to effectively promote breast cancer screening activities among Arabic speaking women in Qatar. MATERIALS AND METHODS: A multicenter, cross sectional quantitative survey of 1,063 (87.5% response rate) female Qatari citizens and non-Qatari Arabic-speaking residents, 35 years of age or older, was conducted in Qatar from March 2011 to July 2011. Outcome measures included participant awareness levels of the most recent national recommended guidelines of BCS, participation rates in BCS activities, and factors related to awareness of BCS activities. RESULTS: While most participants (90.7%) were aware of breast cancer, less than half had awareness of BCS practices (28.9% were aware of breast self-examination and 41.8% of clinical breast exams, while 26.4% knew that mammography was recommended by national screening guidelines. Only 7.6% had knowledge of all three BCS activities). Regarding BCS practice, less than one third practiced BCS appropriately (13.9% of participants performed breast self examination (BSE) monthly, 31.3% had a clinical breast exam (CBE) once a year or once every two years, and 26.9% of women 40 years of age or older had a mammogram once every year or two years). Awareness of BCS was significantly related to BCS practice, education level, and receipt of information about breast cancer and/or BCS from a variety of sources, particularly doctors and the media. CONCLUSIONS: The low levels of participation rates in BCS among Arab women in this study indicate a strong need to increase awareness of the importance of breast cancer screening in Qatari women. Without this awareness, compliance with the most recent breast cancer screening recommendations in Qatar will remain low. An increased effort to implement mass media and public health campaigns regarding the impact of breast cancer on women's health and the benefits of early detection of breast cancer must be coupled with an enhanced participation of health care providers in delivering this message to Qatar population. PMID- 25556442 TI - Can megestrol acetate induce thrombosis in advanced oncology patients receiving chemotherapy? AB - BACKGROUND: Megestrol acetate (MA) is a steroid origin medicine often used for control of cachexia in oncologic palliative care. Thrombosis is a common problem in oncology patients. One question is whether MA can cause thrombosis. This retrospective, registry-based analysis was therefore conducted to assess thrombotic processes in oncology patients using MA concurrent with chemotherapy. MATERIALS AND METHODS: Data on oncology patients at the metastatic stage using MA were obtained from the archives of our center. Outcomes of patients were evaluated for thromboembolic events (VTEs) during treatment. RESULTS: Ninety seven oncology patients with a median age of 62 (33-84) years were included. During the median follow-up of 17 months, 58 (59.8%) died leaving 39 (31.2%) still alive. Median overall survival (OS) was 19 months (6-180). Mean time of MA use was 8.69 months(+/-3.53), with a median dose of 160mg (range 160-480mg). Eleven VTEs were detected after MA use, 4 of these in pancreatic cancer cases. The patients with thrombosis non-significantly had worse OS, than those without thrombosis (p=0.106). CONCLUSIONS: This trial revealed that the 11.3% of all patients developed thrombosis,who had been treated with MA and chemotherapy concomittantly. There was no statistically significant difference regarding to occurrence of thrombotic process, among the patients receiving different chemotherapy regimens with MA concomittantly. Pancreatic cancer seemed to be related to thrombosis rather than MA use. PMID- 25556443 TI - Differences in the prognostic significance of the SUVmax between patients with resected pulmonary Adenocarcinoma and squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to determine the prognostic significance of the maximum standardized uptake value (SUVmax) on F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) in patients undergoing surgical treatment for non-small cell lung cancer. MATERIALS AND METHODS: Seventy-eight consecutive patients (58 with adenocarcinomas, 20 with squamous cell carcinomas) treated with potentially curative surgery were retrospectively reviewed. RESULTS: The SUVmax was significantly higher in the patients with recurrent than with non-recurrent adenocarcinoma (p<0.01). However, among the patients with squamous cell carcinoma, there were no differences with or without recurrence (p=0.69). Multivariate analysis indicated that the SUVmax of adenocarcinoma lesions was a significant predictor of disease-free survival (p=0.04). In addition, an SUVmax of 6.19, the cut-off point based on ROC curve analysis of the patients with pathological IB or more advanced stage adenocarcinomas, was found to be a significant predictor of disease-free survival (p<0.01). CONCLUSIONS: SUVmax is a useful predictor of disease-free survival in patients with resected adenocarcinoma, but not squamous cell carcinoma. Patients with adenocarcinoma exhibiting an SUVmax above 6.19 are candidates for more intensive adjuvant therapy. PMID- 25556444 TI - The RTEL1 rs6010620 polymorphism and glioma risk: a meta-analysis based on 12 case-control studies. AB - BACKGROUND: The association between the RTEL1 rs6010620 single nucleotide polymorphism (SNP) and glioma risk has been extensively studied. However, the results remain inconclusive. To further examine this association, we performed a meta-analysis. MATERIALS AND METHODS: A computerized search of the PubMed and Embase databases for publications regarding the RTEL1 rs6010620 polymorphism and glioma cancer risk was performed. Genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analyses, tests of heterogeneity, cumulative meta analyses, and assessments of bias were performed in our meta-analysis. RESULTS: Our meta-analysis confirmed that risk with allele A is lower than with allele G for glioma. The A allele of rs6010620 in RTEL1 decreased the risk of developing glioma in the 12 case-control studies for all genetic models: the allele model (OR=0.752, 95%CI: 0.715-0.792), the dominant model (OR=0.729, 95%CI: 0.685 0.776), the recessive model (OR=0.647, 95%CI: 0.569-0.734), the homozygote comparison (OR=0.528, 95%CI: 0.456-0.612), and the heterozygote comparison (OR=0.761, 95%CI: 0.713-0.812). CONCLUSIONS: In all genetic models, the association between the RTEL1 rs6010620 polymorphism and glioma risk was significant. This meta-analysis suggests that the RTEL1 rs6010620 polymorphism may be a risk factor for glioma. Further functional studies evaluating this polymorphism and glioma risk are warranted. PMID- 25556445 TI - MiR-323-5p acts as a tumor suppressor by targeting the insulin-like growth factor 1 receptor in human glioma cells. AB - BACKGROUND: MicroRNAs, small noncoding RNA molecules, can regulate mammalian cell growth, apoptosis and differentiation by controlling the expression of target genes. The aim of this study was to investigate the function of miR-323-5p in the glioma cell line, U251. MATERIALS AND METHODS: After over-expression of miR-323- 5p using miR-323-5p mimics, cell growth, apoptosis and migration were tested by MTT, flow cytometry and cell wound healing assay, respectively. We also assessed the influence of miR-323-5p on the mRNA expression of IGF- 1R by quantitative real-time reverse transcriptase PCR (qRT-PCR), and on the protein levels by Western blot analysi. In addition, dual-luciferase reporter assays were performed to determine the target site of miR-323-5p to IGF-1R 3'UTR. RESULTS: Our findings showed that over-expression of miR-323-5p could promote apoptosis of U251 and inhibit the proliferation and migration of the glioma cells. CONCLUSIONS: This study demonstrated that increased expression of miR-323-5p might be related to glioma progression, which indicates a potential role of miR-323-5p for clinical therapy. PMID- 25556446 TI - Association of CYP39A1, RUNX2 and oxidized alpha-1 antitrypsin expression in relation to cholangiocarcinoma progression. AB - Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs. PMID- 25556447 TI - Demographic survey of four thousand patients with 10 common cancers in North Eastern Iran over the past three decades. AB - BACKGROUND: Cancer is a major cause of mortality in developing countries and correct and valid information about the epidemiology of this disease is the first step in the planning of health care in each region. The aim of this study was to determine the relative frequency, mean age and sex ratio of the most 10 common non-skin cancers in the world and Iran, among patients referred to an oncology clinic. MATERIALS AND METHODS: This descriptive study was conducted in Mashhad, north east of Iran. The data obtained from the records of patients referred to the private oncology center between the years of 1985-2012." According to the latest report of GLOBOCAN study commonest malignancies included were lung, breast, colorectal, prostate, stomach, liver, cervix, esophageal, bladder cancers and Non-Hodgkin lymphoma. RESULTS: A total of 4,606 cases were analyzed. The mean age was 55.5+/-13.8years (male: 59.5+/-13.9, female: 52.6+/-12.9). Overall, breast cancer (1,264 cases, relative frequency of 27.4%) was the most prevalent cancer; however the mean ages of diagnosis were not significantly different between 5-year time period divisions (p=0.290). The most common cancer in men was esophageal cancer (26.3%).The lowest mean age was related to women diagnosed with breast cancer (48.5+/-11.8) and men with non-Hodgkins lymphoma (48.4+/-17.8). There were statistically significant differences between the mean age of men and women with gastric (p=0.003) and esophageal cancers (p<0.001). Male to female sex ratios in our study for bladder, lung and stomach cancers were 6.57, 2.60 and 2.50 respectively. CONCLUSIONS: The results showed that breast cancer tends to be found in younger female patients and bladder cancer appears more often in men. Screening in target population in addition to early diagnosis may reduce death and disability. PMID- 25556448 TI - Developing a scale for the assessment of fatigue in pediatric oncology patients aged 7-12 for children and parents. AB - BACKGROUND: This study was planned in an attempt to develop scales for the assessment of fatigue in pediatric oncology patients aged 7-12 as well as for their parents. MATERIALS AND METHODS: In collecting the study data, we used the Child and Parent Information Form, Visual Fatigue Scale, Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 7-12 and the Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 7-12 for Parents. We also used Pearson correlation analysis, the Cronbach Alpha coefficient, Factor Analysis and ROC Analysis for the study data. RESULTS: In this study, the total Cronbach alpha value of the parent form was 0.95, the total factor load was 0.52 0.95 and the total variance being explained was 85.7%. The cutoff point of the parent form was 82 points. The total Cronbach alpha value of the child form was 0.98, the total factor load was 0.71-0.94 and the total variance being explained was 84.7%. The cutoff point of the child form was 75 points. CONCLUSIONS: This study suggests that our scales for the assessment of fatigue in pediatric oncology patients aged 7-12 and their parents are valid and reliable instruments. PMID- 25556449 TI - Independent and additive interaction between tumor necrosis factor beta +252 polymorphisms and chronic hepatitis B and C virus infection on risk and prognosis of hepatocellular carcinoma: a case-control study. AB - To assess the contribution of tumor necrosis factor (TNF)beta +252 polymorphisms to risk and prognosis of hepatocellular carcinoma (HCC), we enrolled 150 pairs of sex- and age-matched patients with HCC, patients with cirrhosis alone, and unrelated healthy controls. TNFbeta +252 genotypes were determined by polymerase chain reaction with restriction fragment length polymorphism. Multivariate analysis indicated that TNFbeta G/G genotype [odds ratio (OR), 3.64; 95%CI, 1.49 8.91], hepatitis B surface antigen (OR, 16.38; 95%CI, 8.30-32.33), and antibodies to hepatitis C virus (HCV) (OR, 39.11; 95%CI, 14.83-103.14) were independent risk factors for HCC. There was an additive interaction between TNFbeta G/G genotype and chronic hepatitis B virus (HBV)/HCV infection (synergy index=1.15). Multivariate analysis indicated that factors associated with TNFbeta G/G genotype included cirrhosis with Child-Pugh C (OR, 4.06; 95%CI, 1.34-12.29), thrombocytopenia (OR, 6.55; 95%CI, 1.46-29.43), and higher serum alpha fetoprotein concentration (OR, 2.53; 95%CI, 1.14-5.62). Patients with TNFbeta G/G genotype had poor cumulative survival (p=0.005). Cox proportional hazard model indicated that TNFbeta G/G genotype was a biomarker for poor HCC survival (hazard ratio, 1.70; 95%CI, 1.07-2.69). In conclusion, there are independent and additive effects between TNFbeta G/G genotype and chronic HBV/HCV infection on risk for HCC. It is a biomarker for poor HCC survival. Carriage of this genotype correlates with disease severity and advanced hepatic fibrosis, which may contribute to a higher risk and poor survival of HCC. Chronic HBV/HCV infected subjects with this genotype should receive more intensive surveillance for early detection of HCC. PMID- 25556450 TI - ST6Gal-I predicts postoperative clinical outcome for patients with localized clear-cell renal cell carcinoma. AB - Hyperactivated alpha2-6-sialylation on N-glycans due to overexpression of the Golgi enzyme beta-galactoside: alpha2-6- sialyltransferase (ST6Gal-I) often correlates with cancer progression, metastasis, and poor prognosis. This study was aimed to determine the association between ST6Gal-I expression and the risk of recurrence and survival of patients with localized clear-cell renal cell carcinoma (ccRCC) following surgery. We retrospectively enrolled 391 patients (265 in training cohort and 126 in validation cohort) with localized ccRCC underwent nephrectomy at a single center. Tissue microarrays were constructed for immunostaining of ST6Gal-I. Prognostic value and clinical outcomes were evaluated. High ST6Gal-I expression was associated with Fuhrman grade (p<0.001 and p=0.016, respectively) and the University of California Los-Angeles Integrated Staging System (UISS) score (p=0.004 and p=0.017, respectively) in both cohorts. Patients with high ST6Gal-I expression had significantly worse overall survival (OS) (p<0.001 and p<0.001, respectively) and recurrence free survival (RFS) (p<0.001 and p=0.002, respectively) than those with low expression in both cohorts. On multivariate analysis, ST6Gal-I expression remained associated with OS and RFS even after adjusting for the UISS score. Stratified analysis suggested that the association is more pronounced among patients with low and intermediate-risk disease defined by the UISS score. High ST6Gal-I expression is a potential independent adverse predictor of survival and recurrence in ccRCC patients, and the prognostic value is most prominent in those with low and intermediate-risk disease defined by the UISS score. PMID- 25556451 TI - Correlation between selected XRCC2, XRCC3 and RAD51 gene polymorphisms and primary breast cancer in women in Pakistan. AB - Genetic polymorphisms in homologous recombination repair genes cause an abnormal development of cancerous cells. In the present study we evaluated the possibility of breast cancer association with single nucleotide polymorphisms of RAD51, XRCC2 and XRCC3 genes. Polymorphisms selected in this study were RAD51 135G/C, XRCC2 Arg188His; and XRCC3 Thr241Met. Each polymorphism was genotyped using Polymerase chain reaction-restriction fragment length polymorphism in study cohort of 306 females (156 breast cancer patients and 150 controls). We observed that heterozygous variant genotype (GC) of RAD51 135 G/C polymorphism was associated with a significantly (OR=2.70; 95%CI (0.63-1.79); p<0.03) increased risk of breast cancer. In case of the XRCC3 gene we observed that frequency of heterozygous (OR=2.88; 95%CI (1.02-8.14); p<0.02) and homozygous (OR=1.46; 95%CI (0.89-2.40); p<0.04) genotype of Thr241Met polymorphism were significantly higher in breast cancer patients. For the Arg188His polymorphism of XRCC2, ~2fold increase in breast cancer risk (OR=1.6, 95%CI = 0.73-3.50) was associated with GA genotype with a p value for trend of 0.03. Our results suggest that the 135G/C polymorphism of the RAD51, Thr241Met polymorphism of XRCC3 and Arg188His polymorphism of XRCC2 can be independent markers of breast cancer risk in Pakistan. PMID- 25556452 TI - Preoperative thrombocytosis and poor prognostic factors in endometrial cancer. AB - This study aimed to evaluate the prevalence of preoperative thrombocytosis and its prognostic significance in Thai patients with endometrial cancer. We retrospectively reviewed the medical records of 238 cases who had undergone surgical staging procedures between January 2005 and December 2008. Associations between clinicopathological variables and preoperative platelet counts were analyzed using Pearson's chi square or two- tailed Fisher's exact tests. Survival analysis was performed with Kaplan-Meier estimates. Univariate and Cox- regression models were used to evaluate the prognostic impact of various factors including platelet count in terms of disease-free survival and overall survival. The mean preoperative platelet count was 315,437/MUL (SD 100,167/ MUL). Patients who had advanced stage, adnexal involvement, lymph node metastasis, and positive peritoneal cytology had significantly higher mean preoperative platelet counts when compared with those who had not. We found thrombocytosis (platelet count greater than 400,000/MUL) in 18.1% of our patients with endometrial cancer. These had significant higher rates of advanced stage, cervical involvement, adnexal involvement, positive peritoneal cytology, and lymph node involvement than patients with a normal pretreatment platelet count. The 5-year disease-free survival and overall survival were significantly lower in patients who had thrombocytosis compared with those who had not (67.4% vs. 85.1%, p=0.001 and 86.0% vs. 94.9%, p=0.034, respectively). Thrombocytosis was shown to be a prognostic factor in the univariate but not the multivariate analysis. In conclusion, presence of thrombocytosis is not uncommon in endometrial cancer and may reflect unfavorable prognostic factors but its prognostic impact on survival needs to be clarified in further studies. PMID- 25556453 TI - Risk factors of prostate cancer: a case-control study in Faisalabad, Pakistan. AB - BACKGROUND: Prostate cancer is the third most commonly diagnosed cancer among males in Pakistan but very little is known about risk factors among the Pakistani population. Therefore a hospital-based, case-control study was carried out in Faisalabad to identify potential risk factors. MATERIALS AND METHODS: This study was based on 140 prostate cancer cases and 280 normal controls. Logistic regression was used to estimate odds ratios and 95% confidence intervals for odds ratios to assess the relationship between prostate cancer and different risk factors. RESULTS: Family history of prostate cancer, age, smoking, obesity, consumption of red meat and frequent use of fat items significantly increased the prostate cancer risk (odds ratios and 95% confidence intervals of: 7.32; 1.79 29.8; 16.9, 5.60-50.8; 2.47, 1.17-5.18; 5.79, 2.66-12.6; 2.71, 1.07-6.91; and 3.39, 1.47-7.83, respectively. On the other hand, more consumption of fruit, fluid intake and better lifestyle (physical activity) significantly reduced the risk of developing prostate cancer with odd ratios and corresponding 95% confidence intervals of: 0.27, 0.11-0.61; 0.05, 0.02-0.12; and 0.28, 0.13- 0.58. CONCLUSIONS: The results of the present study suggested that age, family history of prostate cancer, smoking, obesity, fluid intake, frequent use of fat items, consumption of fruits and better lifestyle might be associated with prostate cancer among Pakistani males. PMID- 25556454 TI - Efficacy of Bifidobacterium tetragenous viable bacteria tablets for cancer patients with functional constipation. AB - OBJECTIVE: To investigate the efficacy and side effects of Bifidobacterium tetragenous viable bacteria tablets in treating cancer patients with functional constipation during chemotherapy. METHODS: A consecutive cohort of 100 cancer patients with functional constipation were divided into two equal groups: patients in the experimental group were given Bifidobacterium tetragenous viable bacteria tablets combined with chemotherapy, while patients in the control group received chemotherapy alone. After 4 weeks, the efficacy and side effects in treating functional constipation were evaluated. RESULTS: Constipation in 48 patients in experimental group was controlled (9 returned to normal), with a total response rate of 96%, and 1 patient reported diarrhea (2%). In contrast only 16 patients in the control group demonstrated improvement and 34 were still constipated after chemotherapy, with a response rate of 32%. The difference in response rate was statistically significant (P <0.05). CONCLUSION: This study suggested that Bifidobacterium tetragenous viable bacteria tablets are effective and safe in treating cancer patients with functional constipation during chemotherapy. PMID- 25556455 TI - Dexamethasone disrupts cytoskeleton organization and migration of T47D Human breast cancer cells by modulating the AKT/mTOR/RhoA pathway. AB - BACKGROUND: Glucocorticoids are commonly co-administered with chemotherapy to prevent drug-induced allergic reactions, nausea, and vomiting, and have anti tumor functions clinically; however, the distinct effects of GC on subtypes of tumor cells, especially in breast cancer cells, are still not well understood. In this study, we aimed to clarify the effect of GC on subtypes of T47D breast cancer cells by focusing on apoptosis, cell organization and migration, and underluing molecular mechanisms. MATERIALS AND METHODS: The cell scratch test was performed to observe the cell migration rate in T47D cells treated with dexamethasone (Dex). Hoechst and MTT assays were conducted to detect cell survival and rhodamine-labeled phalloidin staining to observe cytoskeleton dynamics. Related factors in the AKT/mTOR pathway were determined by Western blotting. RESULTS: Dex treatment could effectively inhibit T47D breast cancer cell migration with disruption of the cytoskeletal dynamic organization. Moreover, the effect of Dex on cell migration and cytoskeleton may be mediated by AKT/ mTOR/RhoA pathway. Although Dex inhibited T47D cell migration, it alone may not induce cell apoptosis in T47D cells. CONCLUSIONS: Dex in T47D human breast cancer cells could effectively inhibit cell migration by disrupting the cytoskeletal dynamic organization, which may be mediated by the AKT/mTOR/RhoA pathway. Our work suggests that glucocorticoid/Dex clinical use may prove helpful for the treatment of breast cancer metastasis. PMID- 25556456 TI - Risk awareness on uterine cancer among Australian women. AB - Uterine cancer is the most common invasive gynaecological cancer in Australia. Early detection is a key predictive factor achieved by increasing public awareness and participation in screening. This observational study measures awareness of gynaecological malignancies, particularly uterine, among women in two rural areas of New South Wales, Australia. Patients presenting to gynaecology clinics in January to March 2014 were invited to complete a structured questionnaire. Women with a history of cancer and incomplete questionnaires were excluded. Of the 382 patients invited to participate, 329 (86%) responded with complete feedback. Most respondents were younger than than 50 years (66%) and married with at least 2 children (74%). The majority (94%) of participants had no awareness of uterine cancer and many (46%) were unable to identify common risk factors including obesity, diabetes and hypertension. The ability to identify risk factors was correlated to age, marital status and obesity. The study identifies poor awareness on uterine malignancies in two typical areas of rural Australia. Although external validity is limited by sociological factors, poor awareness of uterine cancer among rural patients in this study represents a valid public health concern. It is imperative to improve awareness of uterine cancer and available screening programs to facilitate early detection and cure. PMID- 25556457 TI - Polymorphisms and functional analysis of the intact human papillomavirus16 e2 gene. AB - High risk human papillomavirus (HR-HPV) E2 proteins play roles in transcriptional regulation and are commonly functionally disrupted when the HPV genome integrates into host chromosomes. Some 15-40% of cancer cases, however, contain an intact E2 gene or episomal HPV. In these cases, polymorphism of the E2 gene might be involved. This study aimed to determine polymorphisms of the E2 gene in episomal HPV16 detected in high grade squamous intraepithelial lesions and squamous cell carcinomas and altered functions compared to the E2 prototype. The E2 gene was amplified and sequenced. Two expression vectors containing E2 gene polymorphisms were constructed and transfected in SiHa and C33A cells, then E6 gene as well as Il- 10 and TNF-alpha expression was determined by quantitative RT-PCR. Expression vectors and reporter vectors containing the HPV16 long control region (LCR) were co-transfected and transcriptional activity was determined. The results showed that a total of 32 nucleotides and 23 amino acids were changed in all 20 cases of study, found in the transactivation (TA) domain, hinge (H) region and DNA binding (DB) domain with 14, 5 and 13 nucleotide positions. They mostly caused amino acid change. The expressing vectors containing different E2 gene polymorphisms showed E6 mRNA suppression, TNF-alpha mRNA suppression and IL-10 induction but no statistically significant differences when compared to the E2 prototype. Moreover, promoter activity in HPV16 LCR was not affected by E2 protein with different gene polymorphisms, in contrast to nucleotide variations in LCR that showed an effect on transcription activity. These results demonstrated that E2 gene polymorphisms of episomal HPV16 did not affect transcriptional regulation and suggested that nucleotide variation as well as epigenetic modification of the LCR might play a role in inducing malignant transformation of cells containing episomal HPV16. PMID- 25556458 TI - Risk of treatment related death and febrile neutropaenia with first line palliative chemotherapy for de novo metastatic breast cancer in clinical practice in a middle resource country. AB - BACKGROUND: The risk of febrile neutropaenia (FN) and treatment related death (TRD) with first line palliative chemotherapy for de novo metastatic breast cancer (MBC) remains unknown outside of a clinical trial setting despite its widespread usage. This study aimed to determine rates in a large cohort of patients treated in the University of Malaya Medical Centre (UMMC). MATERIALS AND METHODS: Patients who were treated with first line palliative chemotherapy for de novo MBC from 2002-2011 in UMMC were identified from the UMMC Breast Cancer Registry. Information collected included patient demographics, histopathological features, treatment received, including the different chemotherapy regimens, and presence of FN and TRD. FN was defined as an oral temperature >38.5 degrees or two consecutive readings of >38.0 degrees for 2 hours and an absolute neutrophil count <0.5x109/L, or expected to fall below 0.5x109/L (de Naurois et al, 2010). TRD was defined as death occurring during or within 30 days of the last chemotherapy treatment, as a consequence of the chemotherapy treatment. Statistical analysis was performed using the SPSS version 18.0 software. Survival probabilities were estimated using the Kaplan-Meier method and differences in survival compared using log-rank test. RESULTS: Between 1st January 2002 and 31st December 2011, 424 patients with MBC were treated in UMMC. A total of 186 out of 221 patients with de novo MBC who received first line palliative chemotherapy were analyzed. The mean age of patients in this study was 49.5 years (range 24 to 74 years). Biologically, ER status was negative in 54.4% of patients and Her-2 status was positive in 31.1%. A 5-flourouracil, epirubicin and cyclophosphamide (FEC) chemotherapy regimen was chosen for 86.6% of the cases. Most patients had multiple metastatic sites (58.6%). The main result of this study showed a FN rate of 5.9% and TRD rate of 3.2%. The median survival (MS) for the entire cohort was 19 months. For those with multiple metastatic sites, liver only, lung only, bone only and brain only metastatic sites, the MS was 18, 24, 19, 24 and 8 months respectively (p-value= 0.319). CONCLUSIONS: In conclusion, we surmise that FEC is a safe regimen with acceptable FN and TRD rates for de novo MBC. PMID- 25556459 TI - Tumor markers for diagnosis, monitoring of recurrence and prognosis in patients with upper gastrointestinal tract cancer. AB - To evaluate the value of combined detection of serum CEA, CA19-9, CA24-2, AFP, CA72-4, SCC, TPA and TPS for the clinical diagnosis of upper gastrointestinal tract (GIT) cancer and to analyze the efficacy of these tumor markers (TMs) in evaluating curative effects and prognosis. A total of 573 patients with upper GIT cancer between January 2004 and December 2007 were enrolled in this study. Serum levels of CEA, CA19-9, CA24-2, AFP, CA72-4, SCC, TPA and TPS were examined preoperatively and every 3 months postoperatively by ELISA. The sensitivity of CEA, CA19-9, CA24-2, AFP, CA72-4, SCC, TPA and TPS were 26.8%, 36.2%, 42.9%, 2.84%, 25.4%, 34.6%, 34.2% and 30.9%, respectively. The combined detection of CEA+CA199+CA242+CA724 had higher sensitivity and specificity in gastric cancer (GC) and cardiac cancer, while CEA+CA199+CA242+SCC was the best combination of diagnosis for esophageal cancer (EC). Elevation of preoperative CEA, CA19-9 and CA24-2, SCC and CA72-4 was significantly associated with pathological types (p<0.05) and TNM staging (p<0.05). Correlation analysis showed that CA24-2 was significantly correlated with CA19-9 (r=0.810, p<0.001). The levels of CEA, CA19 9, CA24-2, CA72-4 and SCC decreased obviously 3 months after operations. When metastasis and recurrence occurred, the levels of TMs significantly increased. On multivariate analysis, high preoperative CA72-4, CA24-2 and SCC served as prognostic factors for cardiac carcinoma, GC and EC, respectively. combined detection of CEA+CA199+CA242+SCC proved to be the most economic and practical strategy in diagnosis of EC; CEA+CA199+CA242+CA724 proved to be a better evaluation indicator for cardiac cancer and GC. CEA and CA19-9, CA24-2, CA72-4 and SCC, examined postoperatively during follow-up, were useful to find early tumor recurrence and metastasis, and evaluate prognosis. AFP, TPA and TPS have no significant value in diagnosis of patients with upper GIT cancer. PMID- 25556461 TI - Correlation between Ki67 and histological grade in breast cancer patients treated with preoperative chemotherapy. AB - BACKGROUND AND AIM: Breast cancer (BC) is a heterogeneous disease and cell proliferation markers may help to identify subtypes of clinical interest. We here analyzed the correlation between cell proliferation determined by Ki67 and HG in BC patients undergoing preoperative chemotherapy (PCT). MATERIALS AND METHODS: We obtained clinical/pathological data from patients with invasive BC treated at our institution from 1999 until 2012. Expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor type 2 (HER2) and Ki67 were determined by immuno-histochemistry (IHC). Clinicopathological subtypes were defined as: Luminal A, ER and/or PR positive, HER2 negative, HG 1 or 2; Luminal B, ER and/or PR positive, HER2 negative or positive and/or HG 3; triple negative (TN), ER, PR and HER2 negative independent of HG; HER2 positive, ER, PR negative and HER2 positive, independent of HG. By using Ki67, a value of 14% separated Luminal A and B tumors, independently of the histological grade. We analyzed correlations between Ki67 and HG, to define BC subtypes and their predictive value for response to PCT. RESULTS: 1,560 BC patients were treated in the period, 147 receiving PCT (9.5%). Some 57 had sufficient clinicopathological information to be included in the study. Median age was 52 years (26-72), with 87.7% invasive ductal carcinomas (n=50). We performed IHC for Ki67 in 40 core biopsies and 50 surgical biopsies, 37 paired samples with Ki67 before and after chemotherapy being available. There was no significant correlation between Ki67 and HG (p=0.237), both categorizing patients into different subtypes. In most cases Ki67 decreased after PCT (65.8%). Only 3 patients had pathologic complete response (cPR). CONCLUSIONS: In our experience we did not find associations between Ki67 and HG. Determination of clinicopathological luminal subtypes differs by using Ki67 or HG. PMID- 25556460 TI - Clinical study of nimotuzumab combined with chemotherapy in the treatment of late stage gastric cancer. AB - OBJECTIVE: To explore the clinical effects of nimotuzumab combined with chemotherapy in the treatment of late gastric cancer. METHODS: A total of 34 reoccurrence or metastatic patients with late stage gastric cancer who were confirmed by histopathology and/or cytology were selected and randomly divided into observational and control groups, of 17 cases each. Patients in the control group were treated with the standard DCF plan, while patients in observational group additionally received nimotuzumab. The short-term and long-term efficacy and adverse reactions in the 2 groups were followed. RESULTS: The objective response rate (ORR) and disease control rate (DCR) were 64.7% (11/17) and 82.4% (14/17) in observational group and 25.0%(4/16) and 37.5%(6/16) in the control group(ORR and DCR between 2 groups, chi2=5.2412, P=0.0221 and chi2=6.9453, P=0.0084). The median progression-free survival (PFS) time and median overall survival (OS) time were 6.50 months and 12.50 months in observational group and 4.50 months and 8.25 months in the control group (P=0.0212; P=0.0255). The main toxic and side effects in the 2 groups were reduced leukocytes and hemoglobin, gastrointestinal reactions and hair loss and these were relieved after symptomatic treatment and nutrition support therapy. There were no differences in the occurrence of toxic and side effects between the 2 groups. CONCLUSIONS: Nimotuzumab combined with DCF plan is effective in treating late stage gastric cancer. A larger scale study is now warranted for confirmation of the findings. PMID- 25556462 TI - Synthesis, characterization and in vitro anti-tumoral evaluation of Erlotinib PCEC nanoparticles. AB - BACKGROUND: Development of a nanosized polymeric delivery system for erlotinib was the main objective of this research. MATERIALS AND METHODS: Poly caprolactone polyethylene glycol-polycaprolactone (PCEC) copolymers with different compositions were synthesized via ring opening polymerization. Formation of triblock copolymers was confirmed by HNMR as well as FT-IR. Erlotinib loaded nanoparticles were prepared by means of synthesized copolymers with solvent displacement method. RESULTS: Physicochemical properties of obtained polymeric nanoparticles were dependent on composition of used copolymers. Size of particles was decreased with decreasing the PCL/PEG molar ratio in used copolymers. Encapsulation efficiency of prepared formulations was declined by decreasing their particle size. Drug release behavior from the prepared nanoparticles exhibited a sustained pattern without a burst release. From the release profiles, it can be found that erlotinib release rate from polymeric nanoparticles is decreased by increase of CL/PEG molar ratio of prepared block copolymers. Based on MTT assay results, cell growth inhibition of erlotinib has a dose and time dependent pattern. After 72 hours of exposure, the 50% inhibitory concentration (IC50) of erlotinib hydrochloride was appeared to be 14.8 MUM. CONCLUSIONS: From the obtained results, it can be concluded that the prepared PCEC nanoparticles in this study might have the potential to be considered as delivery system for erlotinib. PMID- 25556463 TI - Significance of p16 positive expression in oropharyngeal cancers. AB - BACKGROUND: The involvement of HPV in oral and oropharyngeal carcinogenesis was first proposed in 2004, based on epithelial HPV tropism and detection of HPV genotypes in oral squamous cell carcinoma samples. While 60-70% of oropharynx tumors may be HPV-positive, only 10 to 19% of tumors of the oral cavity, larynx and hypopharynx appear to have HPV infection. The aim of the study was to evaluate HPV infection associated with oropharyngeal cancer. MATERIALS AND METHODS: Seventy-eight cases were selected for p16 immunoexpression reactions, and demographic data were collected for comparisons. RESULTS: Most patients were over 60 years old, and 64.1% were smokers. Immunohistochemistry results showed that 86.3% of cases stained positive for p16 protein. CONCLUSION: The oropharyngeal cancer profile at Erasto Gaertner Hospital presented a high index of smokers over 60 years as well a high number of p16+ tumors, for what we can not determinate the main etiologic factor, but can be aware of the number of patients that presented HPV infection. Since prevention is still the best way to deal with cancer disease, it is important to analyze the interaction of these two etiologic factors and how to detect lesions at an early stage. PMID- 25556464 TI - No effect of energy intake overall on risk of endometrial cancers: a meta analysis. AB - BACKGROUND: Previous epidemiologic studies on the association between energy intake and endometrial cancer risk have only generated contradictory results. The role of energy intake in endometrial carcinogenesis thus remains unclear. To quantitatively assess the potential association between energy intake and endometrial cancer, a meta-analysis of case-control and cohort studies was here conducted. MATERIALS AND METHODS: Eligible studies were retrieved via both computerized searches and review of references. Fixed-or random-effect models were used to summarize the estimates of OR with 95%CIs. Stratified analyses on study design, region and macronutrients' calorie were performed. RESULTS: Sixteen studies met the inclusion criteria of the meta-analysis. No association between total energy intake and endometrial cancer was observed in either overall group (OR=1.11, 95%CI 0.92-1.30) or subgroups stratified by study design and region. In the specific macronutrients' calorie analysis, higher fat energy intake was found to be associated with increased endometrial risk (OR=1.72, 95%CI 1.12- 2.32) while energy from carbohydrate and protein was not related to endometrial cancer risk. CONCLUSIONS: Our analysis did not support that total energy intake is related to endometrial cancer risk, in contrast to fat energy. PMID- 25556465 TI - Epigenetic changes within the promoter regions of antigen processing machinery family genes in Kazakh primary esophageal squamous cell carcinoma. AB - The esophageal squamous cell carcinoma (ESCC) is thought to develop through a multi-stage process. Epigenetic gene silencing constitutes an alternative or complementary mechanism to mutational events in tumorigenesis. Posttranscriptional regulation of human leukocyte antigen class I (HLA-I) and antigen processing machinery (APM) proteins expression may be associated with novel epigenetic modifications in cancer development. In the present study, we determined the expression levels of HLA-I antigen and APM components by immunohistochemistry. Then by a bisulfite-sequencing PCR (BSP) approach, we identified target CpG islands methylated at the gene promoter region of APM family genes in a ESCC cell line (ECa109), and further quantitative analysis of CpG site specific methylation of these genes in cases of Kazakh primary ESCCs with corresponding non-cancerous esophageal tissues using the Sequenom MassARRAY platform. Here we showed that the development of ESCCs was accompanied by partial or total loss of protein expression of HLA-B, TAP2, LMP7, tapasin and ERp57. The results demonstrated that although no statistical significance was found of global target CpG fragment methylation level sof HLA-B, TAP2, tapasin and ERp57 genes between ESCC and corresponding non-cancerous esophageal tissues, there was significant differences in the methylation level of several single sites between the two groups. Of thesse only the global methylation level of LMP7 gene target fragments was statistically higher (0.0517+/-0.0357) in Kazakh esophageal cancer than in neighboring normal tissues (0.0380+/-0.0214, p<0.05). Our results suggest that multiple CpG sites, but not methylation of every site leads to down regulation or deletion of gene expression. Only some of them result in genetic transcription, and silencing of HLA-B, ERp57, and LMP7 expression through hypermethylation of the promoters or other mechanisms may contribute to mechanisms of tumor escape from immune surveillance in Kazakh esophageal carcinogenesis. PMID- 25556466 TI - Thyroid nodules with atypia or follicular lesions of undetermined significance (AUS/FLUS): analysis of variables associated with outcome. AB - BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology is one of the main classification systems for thyroid nodules. It expects that 7% of all fine needle aspiration biopsies will be reported as atypia or follicular lesions of undetermined significance, and 5-15% of these undetermined nodules are malignant. Our study is a retrospective analysis of variables that may be associated with outcome in patients with indeterminate thyroid nodules. MATERIALS AND METHODS: Patients who underwent thyroidectomy in our institution between 2010 and 2014 were retrieved from the institutional records database. Patient demographics and medical histories were recorded. All ultrasonography reports were examined for nodule features and biochemical blood levels, hormone levels and complete blood counts were recorded. RESULTS: A total of 103 patient cytopathology reports were regarded as belonging to the undetermined category. Some 35% of patients had malignant nodules. Median preoperative red cell distribution width (RDW) level was 13.6 inthe benign group, while it was 14.3 in patients with malignancy, demonstrating a significant correlation (p=0.003). Only calcification presence was significantly different between benign and malignant groups on ultrasonography (p=0.034). CONCLUSIONS: Ultrasonography is one of the primary tools for this matter. RDW levels may become another promising tool to predict malignancy. PMID- 25556467 TI - Years of potential life lost due to breast and cervical cancer: a challenge for Brazilian public policy. AB - BACKGROUND: The purpose of the article was to analyze the years of potential life lost (YPLL) of women who died from breast and cervical cancer in the State of Parana, Southern Brazil. This was a temporal trend study (2000 to 2010) about the coefficients of mortality and the years of potential life lost in women aged 20 to 70 years. MATERIALS AND METHODS: Data were obtained through the database of the Department of the Unified Health System (DATASUS) and the National Mortality Information System. RESULTS: There was a loss of 125.075 YPLL due to breast cancer, with an average of 11.370 YPLL. Regarding cervical cancer, the figure obtained was 91.625 YPLL from 2000 to 2010, with an average of 8.329 YPLL. Increased risk of death from breast cancer was observed for women aged 50 to 59 years, with a significant increase among those in the age group from 40 to 49 years. There was an increased rate of cervical cancer among women 40 to 69 years. CONCLUSIONS: The risk of death grows with increasing age, being higher from 40 years. Prevention is paramount for both cancers. Thus, preventive measures are required and a reassessment of political strategies should be adopted. PMID- 25556468 TI - Clinicopathological findings and five year survival rates for patients with central nervous system tumors in Yazd, Iran. AB - BACKGROUND: The incidence rate of brain tumors has increased more than 40% in the past 20 years, especially in adults. We aimed to study the clinical and pathological findings of central nervous system (CNS) tumor patients and to evaluate their 5 year survival rates. MATERIALS AND METHODS: The archives of all patients with CNS tumors in 6 health care centers in Yazd, Iran, from 2006 to 2013, were studied. Patients data were extracted using a checklist which included age, sex, date of reference and diagnosis, date of death, clinical signs, radiography findings, pathology report, size and location of tumor, patient treatment and grade of tumor. RESULTS: A total of 306 patient records were studied in the 8 year period. The most prevalent type of tumor was astrocytoma (n=113, 36.9%). The frequency of almost all tumor types was statistically higher in male patients (p=0.025). In most cases surgery with radiotherapy was the treatment of choice (49.3%). The most frequent symptom reported was headache (in 60.8% of patients) followed by convulsions (15.7%). Most of the tumors were located in the right hemisphere (46.1%) and the frontal and parietal lobe (26% and 12%, respectively). Radiography findings displayed edema with a nonhomogeneous lesion in majority of the patients (87%). The survival fraction of the patients with malignant tumors decreased over time (0.807 in the first year and 0.358 at the end of the 5th year). CONCLUSIONS: Astrocytoma was the more common CNS tumor with male predominance. Overall survival rates of malignant tumors decreased over time and this was in relation with tumor grade. PMID- 25556469 TI - Association of RASSF1A promoter methylation with lung cancer risk: a meta analysis. AB - RASSF1A, regarded as a candidate tumor suppressor, is frequently silenced and inactivated by methylation of its promoter region in many human tumors. However, the association between RASSF1A promoter methylation and lung cancer risk remains unclear. To provide a more reliable estimate we conducted a meta-analysis of cohort studies to evaluate the potential role of RASSF1A promoter methylation in lung carcinogenesis. Relevant studies were identified by searches of PubMed, Web of Science, ProQest and Medline databasesusing the following key words: 'lung cancer or lung neoplasm or lung carcinoma', 'RASSF1A methylation' or 'RASSF1A hypermethylation'. According to the selection standard, 15 articles were identified and analysised by STATA 12.0 software. Combined odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association between RASSF1A promoter methylation and lung cancer risk. A chi-square-based Q test and sensitivity analyses were performed to test between-study heterogeneity and the contributions of single studies to the final results, respectively. Funnel plots were carried out to evaluate publication bias. Overall, a significant relationship between RASSF1A promoter methylation and lung cancer risk (OR, 16.12; 95%CI, 11.40-22.81; p<0.001) with no between-study heterogeneity. In subgroup analyses, increased risk of RASSF1A methylation in cases than controls was found for the NSCLC group (OR, 13.66, 95%CI, 9.529- 19.57) and in the SCLC group (OR, 314.85, 95%CI, 48.93-2026.2). PMID- 25556470 TI - Lack of influence of an XRCC3 gene polymorphism on oral cancer susceptibility: meta-analysis. AB - BACKGROUND: To systematically summarize the association between the X-ray repair cross complementing 3 (XRCC3) gene polymorphism and oral cancer susceptibility by meta-analysis. MATERIALS AND METHODS: Databases including PubMed, EMbase, CNKI, VIP and WanFang Data were searched to identify case-control studies concerning the association between an XRCC3 gene polymorphism and the risk of oral cancer from the inception to June 2014. Two reviewers independently screened the literature according to the criteria, extracted the data and assessed the quality. Then meta-analysis was performed using Stata 11.0 software. RESULTS: Seven published case-control studies including 775 patients with oral cancer and 1922 controls were selected. Associations between the rs861539 polymorphism and overall oral cancer risk were not statistically significant in all kinds of comparison models (CT vs CC: OR=0.94, 95%CI=0.74-1.18; TT vs CC: OR=0.94, 95%CI=0.64- 1.38; dominant model: OR=0.95, 95%CI=0.76-1.18; recessive model: OR=0.94, 95%CI=0.69-1.29; allele T vs C: OR=0.97, 95%CI=0.84-1.11). In the stratified analysis by ethnicity, no significant associations were found among Asians and Caucasians. On stratification by tumor type, no significant associations were found for cancer and oral premalignant lesions. CONCLUSIONS: The XRCC3 gene polymorphism was not found to be associated with the risk of oral cancer. Considering the limited quality of the included case-control studies, more high quality studies with large sample size are needed to verify the above conclusion. PMID- 25556471 TI - Identifying high-risk clusters of gastric cancer incidence in Iran, 2004 - 2009. AB - BACKGROUND: Gastric cancer is considered as the second most prevalent cancer in Iran. The present research sought to identify high risk clusters of gastric cancer with mapping using space-time scan statistics. MATERIALS AND METHODS: The present research is of descriptive type. The required data were gathered from the registered cancer reports of Cancer Control Office in the Center for Non Communicable Disease of the Ministry of Health (MOH). The data were extracted at province level in the time span of 2004-9. Sat-Scan software was used to analyse the data and to identify high risk clusters. ArcGIS10 was utilized to map the distribution of gastric cancer and to demonstrate high risk clusters. RESULTS: The most likely clusters were found in Ardabil, Gilan, Zanjan, East-Azerbaijan, Qazvin, West-Azerbaijan, Kurdistan, Hamadan, Tehran and Mazandaran between 2007 and 2009. It was statistically significant at the p-value below 0.05. CONCLUSIONS: High risk regions included Northern, West-North and central provinces, particularly Ardabil, Kurdistan, Mazandaran and Gilan. More screening tests are suggested to be conducted in high risk regions along with more frequent epidemiological studies to enact gastric cancer prevention programs. PMID- 25556472 TI - Dopamine receptor gene (DRD1-DRD5) expression changes as stress factors associated with breast cancer. AB - Breast cancer is the most common cancer among females worldwide and a most prevalent malignancy in Iranian women. Chronic stress may make an important contribution to cancer, especially in the breast. Numerous studies showed roles of neurotransmitters in the occurrence and progression of cancers which are mediated by their various types of receptors. This study was conducted to evaluate alterations in the expression profile of dopamine receptor genes in peripheral blood mononuclear cells (PBMC) as stress factors in breast cancer patients and the human breast cancer cell line (MCF-7). Peripheral blood samples were obtained from 30 patients and 30 healthy individuals. Total mRNA was extracted from PBMC and MCF-7 cells and RT-PCR was performed to confirm the presence of five dopamine receptors (DRD1-DRD5). Expression changes of dopamine receptor genes were evaluated by real time PCR. We observed that DRD2-DRD4 in PBMCs of breast cancer patients were increased compared to healthy individuals. In addition, all dopamine receptor subtypes but DRD1 were expressed in MCF-7 cells. Therefore, alterations of these receptors as stress factorsshould be assessed for selecting appropriate drugs such as D2-like agonists for treatment of breast cancer after performing complimentary tests. Determining the expression profile of dopamine receptor genes thus seems promising. PMID- 25556473 TI - Identification of anti-cancer targets of eco-friendly waste Punica granatum peel by dual reverse virtual screening and binding analysis. AB - BACKGROUND: Punica granatum (family: Lythraceae) is mainly found in Iran, which is considered to be its primary centre of origin. Studies on pomegranate peel have revealed antioxidant, anti-inflammatory, anti- angiogenesis activities, with prevention of premature aging and reducing inflammation. In addition to this it is also useful in treating various diseases like diabetes, maintaining blood pressure and treatment of neoplasms such as prostate and breast cancer. OBJECTIVES: In this study we identified anti-cancer targets of active compounds like corilagin (tannins), quercetin (flavonoids) and pseudopelletierine (alkaloids) present in pomegranate peel by employing dual reverse screening and binding analysis. MATERIALS AND METHODS: The potent targets of the pomegranate peel were annotated by the PharmMapper and ReverseScreen 3D, then compared with targets identified from different Bioassay databases (NPACT and HIT's). Docking was then further employed using AutoDock pyrx and validated through discovery studio for studying molecular interactions. RESULTS: A number of potent anti cancerous targets were attained from the PharmMapper server according to their fit score and from ReverseScreen 3D server according to decreasing 3D scores. CONCLUSION: The identified targets now need to be further validated through in vitro and in vivo studies. PMID- 25556474 TI - Inhibition of metastasis and invasion of ovarian cancer cells by crude polysaccharides from rosa roxburghii tratt in vitro. AB - BACKGROUND: Rosa Roxburghii Tratt is a promising wild fruit crop in Southwest China. Its extracts have been used as traditional Chinese medicine, which benefit immune responses and cure various health disorders. However, whether Rosa Roxburghii Tratt polysaccharides could inhibit metastasis and invasion of ovarian cancer cells remains unknown. MATERIALS AND METHODS: Effects of crude polysaccharides from Rosa Roxburghii Tratt on the viability of ovarian cancer A2780 cells were detected by MTT assay. Ovarian carcinoma cell migration and invasion after exposure to Rosa Roxburghii Tratt polysaccharides were quantified by wound healing and Transwell assays, respectively. Western blotting was applied to assess protein levels of MMP-9. RESULTS: The results indicated that Rosa Roxburghii Tratt polysaccharides significantly reduced wound closure rate of A2780 cells, inhibited their migration and invasion, and suppressed the expression of MMP-9. CONCLUSIONS: Our findings indicated that Rosa Roxburghii Tratt polysaccharides have potential for develop as anti-metastatic cancer drug preparations for ovarian cancer patients. PMID- 25556475 TI - Systematical analysis of cutaneous squamous cell carcinoma network of microRNAs, transcription factors, and target and host genes. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules found in multicellular eukaryotes which are implicated in development of cancer, including cutaneous squamous cell carcinoma (cSCC). Expression is controlled by transcription factors (TFs) that bind to specific DNA sequences, thereby controlling the flow (or transcription) of genetic information from DNA to messenger RNA. Interactions result in biological signal control networks. MATERIALS AND METHODS: Molecular components involved in cSCC were here assembled at abnormally expressed, related and global levels. Networks at these three levels were constructed with corresponding biological factors in term of interactions between miRNAs and target genes, TFs and miRNAs, and host genes and miRNAs. Up/down regulation or mutation of the factors were considered in the context of the regulation and significant patterns were extracted. RESULTS: Participants of the networks were evaluated based on their expression and regulation of other factors. Sub-networks with two core TFs, TP53 and EIF2C2, as the centers are identified. These share self-adapt feedback regulation in which a mutual restraint exists. Up or down regulation of certain genes and miRNAs are discussed. Some, for example the expression of MMP13, were in line with expectation while others, including FGFR3, need further investigation of their unexpected behavior. CONCLUSIONS: The present research suggests that dozens of components, miRNAs, TFs, target genes and host genes included, unite as networks through their regulation to function systematically in human cSCC. Networks built under the currently available sources provide critical signal controlling pathways and frequent patterns. Inappropriate controlling signal flow from abnormal expression of key TFs may push the system into an incontrollable situation and therefore contributes to cSCC development. PMID- 25556476 TI - Diagnostic and prognostic importance of the neutrophil lymphocyte ratio in breast cancer. AB - BACKGROUND: The aim of this study was to determine diagnostic and prognostic roles of the neutrophil to lymphocyte ratio (NLR) in breast cancer patients. To date, data are limited on associations of primary breast carcinoma (PBC) and benign proliferative breast disease (BPBD) with preoperative NLR values. MATERIALS AND METHODS: Our study covered of 120 female patients with PBC and 50 with BPBD. Diagnostic values of NLR were estimated using sensitivity, specificity and areas under receiver operating characteristic curves (AUC). RESULTS: NLR values were significantly higher in the PBC patients than in those with BPBD, with an AUC of 0.668 in the PBC case. The optimal cut-off for NLR was 2.96 and this was validated in the testing set, giving a sensitivity and a specificity of 79.7% and 76.2%, respectively, in PBC patients. CONCLUSIONS: Preoperative high NLR is a significant diagnostic predictor of distinction of breast cancer from BPBD and elevated NLR is also an important prognostic marker for primary invasive breast cancer. PMID- 25556477 TI - Development of a family nursing model for prevention of cancer and other noncommunicable diseases through an appreciative inquiry. AB - BACKGROUND: Cancer and non-communicable diseases are a major issue not only for the developed but also developing countries. Public health and primary care nursing offer great potential for primary and secondary prevention of these diseases through community and family-based approaches. Within Thailand there are related established educational curricula but less is known about how graduate practitioners enact ideas in practice and how these can influence policy at local levels. AIM: The aim of this inquiry was to develop family nursing practice in primary care settings in the Isaan region or Northeastern Thailand and to distill what worked well into a nursing model to guide practice. MATERIALS AND METHODS: An appreciative inquiry approach involving analysis of written reports, focus group discussions and individual interviews was used to synthesize what worked well for fourteen family nurses involved in primary care delivery and to build the related model. RESULTS: Three main strategies were seen to offer a basis for optimal care delivery, namely: enacting a participatory action approach mobilizing families' social capital; using family nursing process; and implementing action strategies within communities. These were distilled into a new conceptual model. CONCLUSIONS: The model has some features in common with related community partnership models and the World Health Organization Europe Family Health Nurse model, but highlights practical strategies for family nursing enactment. The model offers a basis not only for planning and implementing family care to help prevent cancer and other diseases but also for education of nurses and health care providers working in communities. This articulation of what works in this culture also offers possible transference to different contexts internationally, with related potential to inform health and social care policies, and international development of care models. PMID- 25556478 TI - XELOX plus bevacizumab vs. FOLFIRI plus bevacizumab treatment for first-line chemotherapy in metastatic colon cancer: a retrospective study of the Anatolian Society of Medical Oncology. AB - BACKGROUND: XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev) treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this study was to compare efficacy of first line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC. MATERIALS AND METHODS: A total of 409 patients with mCRC who received chemotherapy were included and divided into 2 groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made in terms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity. RESULTS: Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in 29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%) and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively. Median OS was 25 months (range 2-57 months, 95%CI; 22.2 27.7) for Group 1 and 20 months (range 1-67 months, 95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) for Group 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4% in Group 1 and 26.1% in Group 2 (p<0.001). CONCLUSIONS: First-line XELOX-Bev is more effective with a better response rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev. PMID- 25556479 TI - A sphingosine kinase-1 inhibitor, SKI-II, induces growth inhibition and apoptosis in human gastric cancer cells. AB - SKI-II has been reported as an inhibitor of sphingosine kinase 1 and has been extensively used to prove the involvement of sphingosine kinase and sphingosine-1 phosphate (Sphk1) in cellular processes. In the current study, we investigated the effects of SKI-II and its potential mechanisms in human gastric cancer SGC7901 cells. After treatment with SKI-II, cell growth, cell cycle distribution, apoptosis, expression of Sphk1, NF-kappaB, Bcl-2, Bax and p27 were assessed by MTT assay, flow cytometry, electron microscopy, immunocytochemistry and Western blot assay, respectively. Our results showed that SKI-II markedly inhibited SGC7901 cell survival in a dose-dependent manner, reduced cell proliferation with accumulation of cells in the G0/G1 phase and induced apoptosis in the tumor cells. Furthermore, Western blotting and immunocytochemistry showed that the expression of p27 and Bax was increased significantly, but the expression of NF kappaB, Bcl-2 and Sphk1 decreased by different degrees. These results indicate that SKI-II induced cell growth arrest and apoptosis. The increased apoptotic sensitivity of SGC7901 was correlated with NF-kappaB or Bcl-2/Bax activation. PMID- 25556480 TI - Association between a p73 gene polymorphism and genetic susceptibility to non small cell lung cancer in the South of China. AB - BACKGROUND: This study aimed to identify any association between the p73 gene G4C14-to-A4T14 polymorphism and risk of non-small cell lung cancer (NSCLC) in the south of China. MATERIALS AND METHODS: We genotyped the p73 gene polymorphism of peripheral blood DNA from 168 patients with NSCLC and 195 normal controls using HRM (high resolution melting) and PCR-CTPP (polymerase chain reaction with confronting two-pair primers). RESULTS: The results of genotyping by HRM and PCR CTPP were consistent with direct sequencing, the p73 genotype distribution in 168 lung cancer patients being as follows: GC/GC 101 cases (60.1%), GC/ AT 59 cases (35.1%), AT/AT 8 cases (4.8%). The carriers of AT/AT genotype had a significantly reduced risk of NSCLC (OR=0.370; 95%CI: 0.170-0.806; p=0.010) as compared with non-carriers. However, we found no relations between p73 genotypes and histological type (p=0.798, x2=0.452), tumor stage (p=0.806, x2=0.806), or lymph node metastasis (p=0.578, x2=1.098). CONCLUSIONS: Our findings suggest that the p73 G4C14-to-A4T14 polymorphism may be a modifier of NSCLC susceptibility in the Chinese population. PMID- 25556481 TI - The polymorphism of hypoxia-inducible factor-1a gene in endometrial cancer. AB - BACKGROUND: Endometral carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in women after breast, colorectal and lung cancers Hypoxia-inducible factor -1 (HIF-1) is a key transcription factor that regulates cellular response to hypoxia HIF-1 plays important roles in the development and progression of cancer through activation of various genes that are involved in crucial aspects of cancer biology, including angiogenesis, energy metabolism, vasomotor function, erythropoiesis, and cell survival. In this study, we aimed to investigate the association between HIF-1 1772 C/T polymorphisms and endometrial cancer. MATERIALS AND METHODS: 75 patients with endometrial carcinoma and 75 patients whose underwent hysterectomy for non tumoral indication selected for evaluation of HIF-1 1772 C/T polymorphisms by PCR RFLP and sequencing. RESULTS: For the 1772 C/T polymorphism, the analysis showed that the T allele and genotype TT were significantly associated with endometrial cancer risk. CONCLUSIONS: Our results suggest that the C1772T polymorphism of the HIF-1a may be associated with endometrial cancers. PMID- 25556482 TI - Stigmalactam from Orophea enterocarpa induces human cancer cell apoptosis via a mitochondrial pathway. AB - Stigmalactam, an aristolactam-type alkaloid extracted from Orophea enterocarpa, exerts cytotoxicity against several human and murine cancer cell lines, but the molecular mechanisms remain elusive. The aims of this study were to identify the mode and mechanisms of human cancer cell death induced by stigmalactam employing human hepatocellular carcinoma HepG2 and human invasive breast cancer MDA-MB-231 cells as models, compared to normal murine fibroblasts. It was found that stigmalactam was toxic to HepG2 and MDA-MB-231 cells with IC50 levels of 23.0+/ 2.67 MUM and 33.2+/-4.54 MUM, respectively, using MTT assays. At the same time the IC50 level towards murine normal fibroblast NIH3T3 cells was 24.4+/-6.75 MUM. Reactive oxygen species (ROS) production was reduced in stigmalactam-treated cells dose dependently after 4 h of incubation, indicating antioxidant activity, measured by using 2',7',-dichlorohydrofluorescein diacetate and flow cytometry. Caspase-3 and caspase-9 activities were increased in a dose response manner, while stigmalactam decreased the mitochondrial transmembrane potential dose dependently in HepG2 cells, using 3,3'-dihexyloxacarbocyanine iodide and flow cytometry, indicating mitochondrial pathway-mediated apoptosis. In conclusion, stigmalactam from O. enterocarpa was toxic to both HepG2 and MDA-MB-231 cells and induced human cancer HepG2 cells to undergo apoptosis via the intrinsic (mitochondrial) pathway. PMID- 25556483 TI - Can recurrence and progression be predicted by HYAL-1 expression in primary T1 bladder cancer? AB - BACKGROUND: Molecular prognostic markers have been under investigation for the last decade and no validated marker to date has been proven to be used in daily clinical practice for urinary bladder cancers. The aim of the present study is to evaluate the significance of HYAL-1 expression in prediction of recurrence and progression in pT1 urothelial carcinomas. MATERIALS AND METHODS: Eighty-nine urothelial carcinoma cases staged as T1 according to 2004 WHO classification were studied. Representative sections from every case were stained immunohistochemically for HYAL-1 and scored between 0 and +3, according to staining density, and graded as low and high for the scores 0-1 and 2-3, respectively. RESULTS: Of the 89 pT1 bladder cancer patients, HYAL-1 expression was high in 92.1% (82 patients; 72 patients +3 and 10 patients +2) and low in 7.9% (only 7 patients; 6 patients +1 and 1 patient 0) of the cases. Of the 89 patients, 38 (42.7%) had recurrence and 22 (24.7%) showed progression. HYAL-1 staining did not show significant characteristics for tumor grade, accompanying CIS, multiplicity, tumor size, age and sex. HYAL-1 expression did not have any prognostic value in estimating recurrence or progression. CONCLUSIONS: HYAL-1 expression was found to be high, but did not have any prognostic importance in T1 bladder urothelial carcinomas. PMID- 25556484 TI - beta-elemene induces caspase-dependent apoptosis in human glioma cells in vitro through the upregulation of Bax and Fas/ FasL and downregulation of Bcl-2. AB - BACKGROUND: beta-elemene, extracted from herb medicine Curcuma wenyujin has potent anti-tumor effects in various cancer cell lines. However, the activity of beta-elemene against glioma cells remains unclear. In the present study, we assessed effects of beta-elemene on human glioma cells and explored the underlying mechanism. MATERIALS AND METHODS: Human glioma U87 cells were used. Cell proliferation was determined with MTT assay and colony formation assay to detect the effect of beta-elemene at different doses and times. Fluorescence microscopy was used to observe cell apoptosis with Hoechst 33258 staining and change of glioma apoptosis and cell cycling were analyzed by flow cytometry. Real time quantitative PCR and Western-blotting assay were performed to investigated the influence of beta-elemene on expression levels of Fas/FasL, caspase-3, Bcl-2 and Bax. The experiment was divided into two groups: the blank control group and beta-elemne treatment group. RESULTS: With increase in the concentration of beta elemene, cytotoxic effects were enhanced in the glioma cell line and the concentration of inhibited cell viability (IC50) was 48.5 MUg/mL for 24h. beta elemene could induce cell cycle arrest in the G0/G1 phase. With Hoechst 33258 staining, apoptotic nuclear morphological changes were observed. Activation of caspase-3,-8 and -9 was increased and the pro-apoptotic factors Fas/FasL and Bax were upregulated, while the anti-apoptotic Bcl-2 was downregulated after treatment with beta-elemene at both mRNA and protein levels. Furthermore, proliferation and colony formation by U87 cells were inhibited by beta-elemene in a time and does- dependent manner. CONCLUSIONS: Our results indicate that beta elemene inhibits growth and induces apoptosis of human glioma cells in vitro. The induction of apoptosis appears to be related with the upregulation of Fas/FasL and Bax, activation of caspase-3,-8 and -9 and downregulation of Bcl-2, which then trigger major apoptotic cascades. PMID- 25556485 TI - Protective effect of astragalus polysaccharides on liver injury induced by several different chemotherapeutics in mice. AB - Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place. The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) against the hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel (DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups (DTXL, CTXL, EPIL or DTXH, CTXH, EPIH), and low or high dose chemotherapeutics+APS groups (DTXL+APS, CTXL+APS, EPIL+APS or DTXH+APS, CTXH+APS, EPIH+APS). Controls were treated with equivalent normal saline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or high doses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group were separately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS (100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructure morphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points. With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and AST were significantly increased. Sections of liver tissue showed massive hepatotoxicity in CTXH group compared to the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis in hepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatin aggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that the protein levels of caspase-3 increased in CTXH group. The low dose groups exhibited trivial hepatotoxicity. More interestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities (low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes and the protein levels of caspase-3 (CTXH+APS group). In conclusion, DTX, CTX and EPI induce liver damage in a dose dependent manner, whereas APS exerted protective effects. PMID- 25556486 TI - Red meat intake and risk of non-Hodgkin lymphoma: a meta-analysis. AB - BACKGROUND: While the incidence of non-Hodgkins lymphoma (NHL) has been rising worldwide, the reasons remain undefined. Recent research has focused on effect of red andf processed meat intake as a risk factor, but with inconclusive results. We therefore conducted a meta-analysis of data published to date, to ascertain the overall association between intake and NHL. MATERIALS AND METHODS: A published literature search was performed through Pubmed, Cochrane Library, Medline, and Science Citation Index Expanded databases for articles published in English. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using random or fixed effects models. Heterogeneity was assessed using Chi-square and I2 statistics. Dissemination bias was evaluated by funnel plot analysis.We performed a formal meta-analysis using summary measures from these studies. RESULTS: In total, 11 published studies were included in the final analysis. The combined analysis revealed that there was significant association between the red meat and NHL risk (OR=1.10, 95%CI: 1.02 to 1.19, p=0.01). Additionally, there was showed significance association between processed red meat and NHL risk (OR=1.17, 95%CI: 1.06 to 1.29, p=0.001). In subgroup analysis, a statistical significant association was noted between diffuse large B-cell lymphoma (DLBCL) (OR=1.20, 95%CI: 1.04 to 2.37, P=0.01) and red meat intake. CONCLUSIONS: In this meta-Analysis, there was evidence for association between consumption of red meat, or processed meat and risk of NHL, particularly with the DLBCL subtype in the red meat case. PMID- 25556487 TI - Oral potentially malignant disorders among dental patients: a pilot study in Jordan. AB - BACKGROUND: To determine the prevalence, types, and risk factors of oral potentially malignant disorders (OPMDs) among a group of Arab Jordanian dental patients, and to evaluate their awareness and attitudes toward early diagnosis and treatment. MATERIALS AND METHODS: A total of 1,041 patients attending a University Hospital for dental care were examined for the presence of OPMDs. Histopathological examination was performed on all cases clinically diagnosed and patients were directly interviewed to evaluate their knowledge and attitudes toward early detection and treatment of oral cancer. RESULTS: The prevalence of OPMDs overall was 2.8%. Lichen planus/lichenoid lesions were the most common lesions (1.8%) followed by leukoplakias (0.48%), chronic hyperplastic candidiosis (0.38%), and erythroplakia (0.096%). Smoking, alcohol, and age (>40 years) were the main identifiable risk factors. Patients with OPMDs displayed a general lack of awareness and negative attitudes towards early diagnosis and treatment. CONCLUSIONS: OPMDs among Arab dental patients are relatively uncommon and awareness about oral cancer among Jordanian dental patients is low. Interventions to improve public knowledge about oral cancer and attitudes toward early diagnosis and treatment are urgently indicated. PMID- 25556488 TI - New haplotypes of the ATP synthase subunit 6 gene of mitochondrial DNA are associated with acute lymphoblastic leukemia in Saudi Arabia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among those younger than 15 years of age. AIM AND OBJECTIVES: This study investigated substitutions in the ATP synthase subunit 6 gene of mitochondrial DNA (mtDNA) as a potential diagnostic biomarker for early detection and diagnosis of acute lymphoblastic leukemia. Based on mtDNA from 23 subjects diagnosed with acute lymphoblastic leukemia, approximately 465 bp of the ATP synthase subunit 6 gene were amplified and sequenced. RESULTS: The sequencing revealed thirty-one mutations at 14 locations in ATP synthase subunit 6 of mtDNA in the ALL subjects. All were identified as single nucleotide polymorphisms (SNPs) with a homoplasmic pattern. The mutations were distributed between males and females. Novel haplotypes were identified in this investigation: haplotype (G) was recorded in 34% in diagnosed subjects; the second haplotype was (C) with frequency of 13% in ALL subjects. Neither of these were observed in control samples. CONCLUSIONS: These haplotypes were identified for the first time in acute lymphoblastic leukemia patients. Five mutations able to change amino acid synthesis for the ATP synthase subunit 6 were associated with acute lymphoblastic leukemia. This investigation could be used to provide an overview of incidence frequency of acute lyphoblastic leukemia (ALL) in Saudi patients based on molecular events. PMID- 25556490 TI - Clinical study on fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain. AB - OBJECTIVE: To observe treatment effects and safety of fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain. METHODS: Patients confirmed pathologically with cancer and complicated with moderate to severe pain, were divided into control and experimental groups. Oxycodone prolonged-release tablets, with or without fluvoxamine, were administrated to all study patients until pain relief. Degree of pain relief, dose of oxycodone prolonged-release tablets, side effects and quality of life were compared before and after treatment. RESULTS: In total, 120 patients were recruited. No statistically significant difference was detected regarding age, gender, types of cancer, KPS between two groups of patients (P> 0.05). Baseline pain score of patients with moderate pain in treatment and control group was 4.9+/-0.8 and 5.1+/-0.8, respectively; and decreased to 1.8+/ 1.1 and 1.2+/-1.1 after treatment, respectively. Pain intensity was significantly reduced in the treatment group (P =0.028). Average daily consumption of oxycodone prolonged- release tablets was (54.0+/-19.6) mg and (44.7+/- 18.7) mg respectively, which is lower in treatment grpup than in control group, but the difference was not statistically significant (P=0.065). Baseline pain score of patients with severe pain in treatment and control groups were 8.3+/-1.1 and 8.3+/-1.1, respectively; and pain intensity after treatment decreased to 2.9+/ 1.0 and 2.3+/-1.0. Pain intensity was significantly reduced in the treatment group, with statistical significance (P =0.026). Average daily consumption of oxycodone prolonged-release tablets was (132.0+/-42.2) mg and (110.7+/-33.9) mg, respectively, which is lower in treatment group than in control group, and the difference was statistically significant (P=0.035). In terms of quality of life, patients in treatment group had better performance status, daily activity, mood, and sleep than that in control group (P < 0.05). Patients in two groups had similar side effects, eg., constipation, nausea/vomiting, lethargy, dizziness, itchy skin, dysuria, and ataxia. Lower incidence of nausea/vomiting, lethargy, was obtained from patients in treatment than in control group, while significant low constipation was observed in treatment than in control group (35.0% vs 49.2%, P=0.026). CONCLUSION: Fluvoxamine combined with oxycodone prolonged-release tablets could be more effective in treating patients with cancer pain, and could reduce the dosage of oxycodone prolonged-release tablets and thus be associated with lower side effects, and improved quality of life. PMID- 25556489 TI - miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. AB - Many chemotherapeutic agents have been successfully used to treat hepatocellular carcinoma (HCC); however, the development of chemoresistance in liver cancer cells usually results in a relapse and worsening of prognosis. It has been demonstrated that DNA methylation and histone modification play crucial roles in chemotherapy resistance. Currently, extensive research has shown that there is another potential mechanism of gene expression control, which is mediated through the function of short noncoding RNAs, especially for microRNAs (miRNAs), but little is known about their roles in cancer cell drug resistance. In present study, by taking advantage of miRNA effects on the resistance of human hepatocellular carcinoma cells line to cisplatin, it has been demonstrated that miR-340 were significantly downregulated whereas Nrf2 was upregulated in HepG2/ CDDP (cisplatin) cells, compared with parental HepG2 cells. Bioinformatics analysis and luciferase assays of Nrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR- 340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/ CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitors reactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively, the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistance in hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway. PMID- 25556491 TI - A retrospective multicenter evaluation of cutaneous melanomas in Turkey. AB - BACKGROUND: We defined melanoma distribution in a large series of Turkish patients and evaluated the prognostic parameters of melanomas. MATERIALS AND METHODS: A total of 1574 patients' data was retrospectively collected at 18 centers in Turkey. Demographic characteristics were questioned and noted. Prognostic parametres were evaluated based on sentinel lymph node involvement. RESULTS: Mean age was 56.7 (4-99) years. While 844 (53.6%) cases were male, 730 (46.4%) cases were female. One thousand four hundred forty-seven (92%) cases were invasive melanoma and 127 (8%) cases were in-situ melanoma. The most common histopathological form was the superficial spreading melanoma (SSM) which was found in 549 patients (37.9%). It was followed by nodular melanoma in 379 (26.2%), acral lentiginous melanoma (ALM) in 191 (13.2%) and lentigo maligna melanoma in 132 (9.1%), respectively. On univariate analysis, lymphovascular invasion (p<0.001), tumor thickness (p<0.001), histopathological subtype (p<0.001), Clark level (p=0.001), ulceration (p<0.001), >=6/mm2 mitosis (p=0.005), satellite formation (p=0.001) and gender (p=0.03) were found to be associated with sentinel lymph node positivity. Regression was associated with sentinel lymph node negativity (p=0.017). According to multivariate analysis, lymphovascular invasion and tumor thickness were significant independent predictive factors of SLN positivity. Patient age, tumor localization, precursor lesions, lymphocytic infiltration and neurotropism were not related with sentinel lymph node involvement. CONCLUSIONS: In this retrospective analysis, it was found that the prevalence of SSM is at a lower rate while the prevalence of ALM is at a higher rate when compared to western countries. According to Breslow index; most of the melanoma lesions' thickness were greater than 2 mm, corresponding Clark IV. Vascular invasion and tumor thickness are the most important factors for sentinel lymph node involvement. PMID- 25556492 TI - Association of RAD 51 135 G/C, 172 G/T and XRCC3 Thr241Met gene polymorphisms with increased risk of head and neck cancer. AB - Homologous recombination repair (HRR) plays an important role in protection against carcinogenic factors. Genes regulating the HRR mechanisms may impair their functions and consequently result in increased cancer susceptibility. RAD 51 and XRCC3 are key regulators of the HRR pathway and genetic variability in these may contribute to the appearance and progression of various cancers including head and neck cancer (HNC). The aim of the present study was to compare the distribution of genotypes of RAD51 (135G/C, 172 G/T) and XRCC3 (Thr241Met) polymorphisms between HNC patients and controls. Each polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymerase (PCR RFLP) technique in 200 pathologically confirmed HNC patients along with 150 blood samples from normal, disease free healthy individuals. We observed that homozygous variant CC genotype of RAD51 135G/C was associated with a 2.5 fold increased HNC risk (OR=2.5; 95%CI=0.69-9.53; p<0.02), while second polymorphism of RAD 51 172 G/T, heterozygous variant GT genotype was associated with a 1.68 fold (OR=1.68; 95%CI=1.08-2.61; p<0.02) elevation when compared with controls. In the case of the Thr241Met polymorphism of XRCC3, we observed a 16 fold (OR=16; 95% CI= 3.78-69.67; p<0.0002) increased HNC risk in patients compared to controls. These results further suggested that RAD51 (135G/C, 172 G/T) and XRCC3 (Thr241Met) polymorphisms may be effective biomarkers for genetic susceptibility to HNC. Larger studies are needed to confirm our findings and identify the underlying mechanisms. PMID- 25556493 TI - Opisthorchis viverrini infection activates the PI3K/ AKT/PTEN and Wnt/beta catenin signaling pathways in a Cholangiocarcinogenesis model. AB - Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and Wnt/beta- catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/ AKT/PTEN and Wnt/beta-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the p85alpha-regulatory and p110alpha-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of Wnt/beta-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and beta-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of beta-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and Wnt/beta-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA. PMID- 25556494 TI - Solanum Nigrum polysaccharide (SNL) extract effects in transplanted tumor-bearing mice--erythrocyte membrane fluidity and blocking of functions. AB - BACKGROUND: Solanum nigrum L. has been used in traditional Chinese medicine because of its diuretic and antipyretic effects. The present research concerned effects of crude polysaccharides isolated from Solanum nigrum L. on erythrocyte membranes of tumor-bearing S180 and H22 in mice. MATERIALS AND METHODS: Fluorescence- labeled red blood cell membranes were used with DPH fluorescence spectrophotometry to examine erythrocyte membrane fluidity, and colorimetry to determine degree of erythrocyte surface membrane blocking. Extent of reaction by tumor-bearing mice with the enzyme erythrocyte membrane bubble shadow detection of red cell membrane variation in the degree of closure before and after administration. RESULTS: Solanum nigrum polysaccharide could significantly improve the S180 and H22 tumor-bearing mice erythrocyte membrane fluidity, compared with the control group, the difference was significant (p<0.01), SNL can significantly improve the red blood cell membrane and then S180 tumor-bearing mice sealing ability, compared with the negative control group, the difference was significant(p<0.05, p<0.01). H22 tumor-bearing mice can increase red cell membrane and then sealing ability, the difference was significant (p<0.05). Solanum nigrum polysaccharide degree of fluidity and blocking two transplanted tumors in mice restored the ability to raise the red cell membrane has a significant effect. CONCLUSIONS: Solanum nigrum L.-type mice transplanted tumor can affect the red blood cell membrane fluidity and re-closed, through the red cell membrane of red blood cells to enhance the immune function of the possibility of erythrocyte immunity against tumor formation garland provide experimental basis. PMID- 25556495 TI - Comprehensive expression analysis suggests functional overlapping of human FOX transcription factors in cancer. AB - Forkhead-box (FOX) transcription factors comprise a large gene family that contains more than 50 members in man. Extensive studies have revealed that they not only have functions in control of growth and development, but also play important roles in different diseases, especially in cancer. However, biological functions for most of the members in the FOX family remain unknown. In the present study, the expression of 39 FOX genes in 48 kinds of cancer was mined from the Gene Expression Atlas database of European Bioinformatics Institute. The analysis results showed that some FOX genes demonstrate overlapping expression in various cancers, which suggests particular biological functions. The pleiotropic features of the FOX genes make them excellent candidates in efforts aimed to give medical treatment for cancers at the genetic level. The results also indicated that different FOX genes may have the synergy or antagonistics effects in the same cancers. The study provides clues for further functional analysis of FOX genes, especially for the pleiotropic biological functions and crosstalk of FOX genes in human cancers. PMID- 25556496 TI - Heptaphylline induces apoptosis in human colon adenocarcinoma cells through bid and Akt/NF-kappaB (p65) pathways. AB - Heptaphylline derivatives are carbazoles in Clausena harmandiana, a medicinal plant that is utilized for headache, stomach ache, and other treatments of illness. The present study examined the effects of heptaphylline and 7 methoxyheptaphylline on apoptosis of human colon adenocarcinoma cells (HT-29 cell line). Quantification of cell viability was performed using cell proliferation assay (MTT assay) and of protein expression through immunoblotting. The results showed that only heptaphylline, but not 7-methoxyheptaphylline, significantly significantly activated cleaved of caspase-3 and poly (ADP-ribose) polymerase (PARP-1) which resulted in HT-29 cell death. We found that heptaphylline activated BH3 interacting-domain death agonist (Bid) and Bak, proapoptotic proteins. In contrast, it suppressed X-linked inhibitor-of-apoptosis protein (XIAP), Bcl-xL and survivin, inhibitors of apoptosis. In addition, heptaphylline inhibited activation of NF-kappaB/p65 (rel), a regulator of apoptotic regulating proteins by suppressing the activation of Akt and IKKalpha, upstream regulators of p65. The findings suggested that heptaphylline induces apoptosis in human colon adenocarcinoma cells . PMID- 25556497 TI - Profiles of Epstein-Barr virus associated gastric carcinomas in Brunei Darussalam. AB - BACKGROUND: Gastric cancer is the second most common gastrointestinal cancer and is largely attributed to Helicobacter pylori (H. pylori) infection. In addition, studies have also shown association with Epstein-Barr virus (EBV) in 10% of gastric cancers. This study assessed the characteristics of EBV associated gastric cancers (EBVaGC) in Brunei Darussalam. MATERIALS AND METHODS: This study included gastric cancers diagnosed between 2008 and 2012, registered with the Department of Pathology RIPAS Hospital, Brunei Darussalam. Clinical case notes were systematically reviewed. Histology specimens were all stained for EBV and also assessed for intestinal metaplasia and H. pylori. RESULTS: There were a total of 81 patients (54 male and 27 females) with a mean age of 65.8+/-14.8 years included in the study. Intestinal metaplasia and active H. pylori infection were detected in 40.7% and 30.9% respectively. A majority of the tumors were proximally located (55.6%), most poorly differentiated (well differentiated 16%, moderately differentiated 30.9% and poorly differentiated 53.1%) and the stages at diagnosis were; stage I (44.4%), stage II (23.5%), stage III (8.6%) and stage IV (23.5%). EBV positivity (EBVaGC) was seen in 30.9%. Between EBVaGC and EBV negative gastric cancers, there were no significant differences (age, gender, ethnic group, presence of Intestinal metaplasia, tumor locations, stages of disease and degree of tumor differentiation). CONCLUSIONS: This study showed that a third of gastric cancers in Brunei Darussalam were positive for EBV, higher than what have been reported in the literature. However, there were no significant differences between EBVaGC and EBV negative gastric cancers. This suggests that the role of EBV in gastric cancer may be mostly incidental rather than any causal relation. However, further studies are required. PMID- 25556498 TI - Bufalin induces mitochondrial pathway-mediated apoptosis in lung adenocarcinoma cells. AB - BACKGROUND: To evaluate the effects of bufalin in A549 human lung adenocarcinoma epithelial cells in vitro and assess the underlying mechanisms. MATERIALS AND METHODS: Human A549 non-small cell lung cancer (NSCLC) cells were treated with various concentrations of bufalin. Cell proliferation was measured by CCK-8 assay, apoptotic cell percentage was calculated by flow cytometry and morphological change was observed by inverted phase contrast microscopy/transmission electron microscopy. In addition, the membrane potential of mitochondria was detected by JC-1 fluorescence microscopy assay, and the related protein expression of cytochrome C and caspase-3 was analyzed by Western blotting. RESULTS: Bufalin could inhibit the proliferation of A549 cells via induction of apoptosis, with the evidence of characteristic morphological changes in the nucleus and mitochondria. Furthermore, bufalin decreased the mitochondrial membrane potential with up-regulation of cytochrome C in the cytosol, and activation of caspase-3. CONCLUSIONS: Bufalin inhibits the proliferation of A549 cells and triggers mitochondria-dependent apoptosis, pointing to therapeutic application for NSCLC. PMID- 25556499 TI - Elevated mean platelet volume is associated with presence of colon cancer. AB - BACKGROUND: Colon cancer is the second most common cancer in developed countries. Activated platelets play a key role in inflammation and atherothrombosis, with mean platelet volume (MPV) is an early marker of platelet activation. The aim of the study was to clarify the relevance of MPV in patients with colon cancer. MATERIALS AND METHODS: We measured MPV levels in 128 patients with colon cancer before and after surgery, and 128 controls matched for age, gender, body mass index (BMI) and smoking status. The odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer were calculated using multivariate logistic regression analyses across MPV quartiles. RESULTS: Patients with colon cancer had higher MPV compared with controls. Surgical tumor resection resulted in a significant decrease in MPV levels (11.4 fL vs 10.7 fL; p<0.001). A positive correlation between MPV and tumor-nodule-metastases (TNM) stage was found. Furthermore, after adjusting for other risk factors, the ORs (95%CIs) for colon cancer according to MPV quartiles were 1.000, 2.238 (1.014-4.943), 3.410 (1.528 7.613), and 5.379 (2.372-12.198), respectively. CONCLUSIONS: The findings show that patients with colon cancer have higher MPV levels compared with controls, and these are reduced after surgery. In addition, MPV was found to be independently associated with the presence of colon cancer. Further studies are warranted to assess the utility of MPV as a novel diagnostic screening tool for colon cancer. PMID- 25556500 TI - Survival time and molecular subtypes of breast cancer after radiotherapy in Thailand. AB - BACKGROUND: Breast cancer is an important cause of death among women. One way of classifying different forms of breast cancer is by molecular features, usually in terms of the four subtypes: luminal A, luminal B, HER2-enriched, and triple negative. OBJECTIVES: This study aimed to investigate the association between molecular subtypes and survival among breast cancer patients treated with radiotherapy. MATERIALS AND METHODS: A retrospective cohort study was conducted. The subjects were 272 breast cancer patients who had received treatment in the radiotherapy unit at Srinagarind Hospital, Thailand, between 1 January, 1999, and 31 May, 2009. The end of the study was 1 June, 2014. Overall survival was defined as the time elapsing between initial registration at the radiotherapy unit and death or the end of the study. Survival curves were estimated by the Kaplan-Meier method, and a multivariate analysis was performed using Cox's proportional hazard regression model. RESULTS: The patient mean age was 47.5+/-10.4 at the time of diagnosis. Of the 272 patients, 146 (53.7%) were classified as luminal A, 12 (4.4%) as luminal B, 30 (11.0%) as HER2-enriched, and 84 (30.9%) as triple negative. The overall survival rates at 1, 3 and 5 years were 87.1%, 68.4% and 59.2%, respectively. According to molecular subtypes, HER2-enriched patients had the lowest 5-year survival rate (30.0 %, 95%CI: 15.02-46.55). The median follow up time was 8.37 years. In the Cox model analysis a higher risk of death was found for patients with HER2-enriched (HRadj=3.34, 95%CI:1.96-5.67), triple negative (HRadj=2.17, 95%CI: 1.44-3.27), and stage IIlB (HRadj=2.20, 95%CI: 1.16 4.17) cancers. CONCLUSIONS: The worst survival rates were among patients classified as HER2-enriched, triple negative and at stage IIIB. Early detection and an advanced treatment modality are needed to help these patients. PMID- 25556501 TI - Differential diagnosis of CT images in children with neuroblastomas and ganglioneuroblastomas. AB - OBJECTIVE: To investigate the differential features of CT images in children with neuroblastomas (N) and ganglioneuroblastomas (G). MATERIALS AND METHODS: Clinical data of 12 children in group G and 15 in group N undergoing CT examination and definitely diagnosed by pathology were retrospectively analyzed. The focal conditions were observed and compared in the two groups, including location, size, boundaries, morphology, enhanced degree and mode, abdominal vascular involvement, presence or absence of spanning the midline, infiltration of peripheral organs, angiography manifestations in tumors or surroundings, presence or absence of calcification and vascular tumor emboli as well as metastases of distal organs and lymph nodes. RESULTS: In group N, the incidence of tumors in the adrenal area was conspicuously higher than in group G (P<0.05), while that of tumors with regular morphology and clear boundaries was significantly lower than in group G (P<0.01); Angiography manifestation rate and incidences of vascular embedding, lymph node metastasis, infiltration and organic metastasis in group N were all markedly higher than in group G (P<0.05). There was no statistical significance between the two groups in terms of focal size, presence or absence of calcification and spanning the midline, and enhanced degree and mode, as well as vascular tumor emboli (P>0.05). CONCLUSIONS: Mostly located in adrenal areas and with vascular embedding as a primary manifestation, the neuroblastoma extremely readily metastases to lymph nodes and other organs as well as infiltrating local tissues, with dilation on angiography frequent in or around the tumors. With vascular displacement as a primary manifestation, ganglioneuroblastoma has a regular morphology and clear boundaries. PMID- 25556502 TI - Long non-coding RNAs are differentially expressed in hepatocellular carcinoma cell lines with differing metastatic potential. AB - BACKGROUND: Metastasis is a major reason for poor prognosis in patients with cancer, including hepatocellular carcinoma (HCC). A salient feature is the ability of cancer cells to colonize different organs. Long non-coding RNAs (lncRNAs) play important roles in numerous cellular processes, including metastasis. MATERIALS AND METHODS: In this study, the lncRNA expression profiles of two HCC cell lines, one with high potential for metastasis to the lung (HCCLM3) and the other to lymph nodes (HCCLYM-H2) were assessed using the Arraystar Human LncRNA Array v2.0, which contains 33,045 lncRNAs and 30,215 mRNAs. Coding-non-coding gene co-expression (CNC) networks were constructed and gene set enrichment analysis (GSEA) was performed to identify lncRNAs with potential functions in organ-specific metastasis. Levels of two representative lncRNAs and one representative mRNA, RP5-1014O16.1, lincRNA-TSPAN8 and TSPAN8, were further detected in HCC cell lines with differing metastasis potential by qRT-PCR. RESULTS: Using microarray data, we identified 1,482 lncRNAs and 1,629 mRNAs that were differentially expressed (>=1.5 fold-change) between the two HCC cell lines. The most upregulated lncRNAs in H2 were RP11-672F9.1, RP5-1014O16.1, and RP11-501G6.1, while the most downregulated ones were lincRNA-TSPAN8, lincRNA CALCA, C14orf132, NCRNA00173, and CR613944. The most upregulated mRNAs in H2 were C15orf48, PSG2, and PSG8, while the most downregulated ones were CALCB, CD81, CD24, TSPAN8, and SOST. Among them, lincRNA-TSPAN8 and TSPAN8 were found highly expressed in high lung metastatic potential HCC cells, while lowly expressed in no or low lung metastatic potential HCC cells. RP5- 1014O16.1 was highly expressed in high lymphatic metastatic potential HCC cell lines, while lowly expressed in no lymphatic metastatic potential HCC cell lines. CONCLUSIONS: We provide the first detailed description of lncRNA expression profiles related to organ-specific metastasis in HCC. We demonstrated that a large number of lncRNAs may play important roles in driving HCC cells to metastasize to different sites; these lncRNAs may provide novel molecular biomarkers and offer a new basis for combating metastasis in HCC cases. PMID- 25556503 TI - Impact of perceived cancer risk on the cancer screening rate in the general Korean population: results from the Korean health panel survey data. AB - OBJECTIVE: To investigate the relationship between the perception of cancer risk and likelihood of having undergone cancer screening. MATERIALS AND METHODS: We used data from the Korean Health Panel Survey from December 2011 onward. Of 3,390 patients who visited a hospital during the previous year, we included data from 2,466 individuals; 924 samples were excluded due to missing data. Logistic regression analysis and the chi square test were used to investigate the association between perceived cancer risk and the likelihood of having undergone cancer screening. RESULTS: For patients who perceived their risk of developing cancer during the next 10 years to be 30-40%, the odds ratio was increased 1.65 fold (95%CI: 1.223, 2.234) compared with those who perceived their risk to be almost zero. Although the difference was not statistically significant, perceiving cancer risk as either extremely low or extremely high appears to be associated with a reduced likelihood of having undergone cancer screening, resulting in an inverted U-shaped relationship. CONCLUSIONS: Physicians and researchers should be aware of the importance of the affective component of risk perception. Policies addressing the influence of cancer risk perception should be implemented in South Korea and worldwide. PMID- 25556504 TI - Influence of offspring on quality of life among cancer patients and survivors: results from the Korean longitudinal study of aging (KLoSA), 2008-2011. AB - BACKGROUND: To examine whether offspring improve or reduce quality of life (QOL) among cancer patients and survivors. MATERIALS AND METHODS: We used data from the Korean Longitudinal Study of Aging (KLoSA) from 2008 to 2011. There were 490 research subjects in our study: 245 cancer patients and survivors and 245 controls matched using propensity scores. RESULTS: For cancer patients and survivors with no offspring, the QOL estimate was -2.831 lower (SE: 5.508, p value: 0.623) than that of those with two offspring, while for those with five or more offspring, the QOL estimate was 7.336 higher (SE: 2.840, p-value: 0.036). For non-cancer patients and survivors with one child, the QOL estimate was 11.258 lower (SE: 2.430, p-value: 0.002) than that of those with two offspring, while for those with five or more offspring, the QOL estimate was -4.881 lower (SE: 2.484, p-value: 0.090). CONCLUSIONS: This article provides evidence for a beneficial effect of offspring upon QOL in cancer patients and survivors, indicating that offspring are important for them. PMID- 25556505 TI - Lung cancer risk prediction method based on feature selection and artificial neural network. AB - A method to predict the risk of lung cancer is proposed, based on two feature selection algorithms: Fisher and ReliefF, and BP Neural Networks. An appropriate quantity of risk factors was chosen for lung cancer risk prediction. The process featured two steps, firstly choosing the risk factors by combining two feature selection algorithms, then providing the predictive value by neural network. Based on the method framework, an algorithm LCRP (lung cancer risk prediction) is presented, to reduce the amount of risk factors collected in practical applications. The proposed method is suitable for health monitoring and self testing. Experiments showed it can actually provide satisfactory accuracy under low dimensions of risk factors. PMID- 25556506 TI - Blood supply of human uterine cervix - a SEM study. AB - AIM: The main goal of this study was assessment of vascular structure of human uterine cervix. MATERIALS AND METHODS: The study was carried out on 25 human uteri of females aged 25-45, collected upon autopsy. Vessels were injected with synthetic resin, next corroded and coated with gold, finally observed using scanning electron microscope. RESULTS: On a sagittal section we have distinguished several zones in the vascular picture of the uterine cervix consisted of differently arranged veins, arteries, arterioles and capillaries. Due to technical reasons we were unable to receive a picture of vascular composition of cervical uterine canal on transverse section. CONCLUSIONS: Scanning elector microscopy is a method which might be applied to study the structure of human uterine cervix. PMID- 25556507 TI - Ossification of the ligamentum flavum of the lumbosacral spine in the Polish hospitalized population - a prospective cohort study. AB - AIM: The aim of this study was to assess the prevalence, clinical features and distribution of lumbosacral ossifications of the ligamentum flavum (OLF), using MRI, CT and microCT, in hospitalized Polish patients. METHODS: Patients were recruited prospectively between January 2011 and January 2013. Patients were further qualified to the study group only if CT or MRI of the lumbosacral region detected OLF. Level of OLF excision was determined by the localization of spinal stenosis. After excision the LF fragments containing OLF were stored in a 4% solution of formaldehyde until microCT assessment. RESULTS: A total of 184 agreed to take part in the study. In 50 patients (27.2%) OLF were found. Thus, the study group consisted of 17 women (34%) and 33 men, with a mean age of 55.4 +/- 17.2 years. OLF occurred more often in men (66%) than in women (34%) (p = 0.0014). The most common site for the localization of OLF in women, as well as in men was the L5/S1 level (60% and 53.3% respectively). The mean volume of OLF was 3.87 +/- 5.27 mm3 (4.66 +/- 5.71 mm3 vs. 1.27 +/- 2.19 mm3, in men and women respectively; p = 0.023). The LF were thickened in 21 (42%) patients. The mean volume of OLF in patients with normal LF was 4.78 +/- 5.95 mm3 and in patients with thickened LF 5.33 +/- 6.10 mm3 (p = 0.75). CONCLUSIONS: The prevalence of lumbosacral OLF in the Polish hospitalized population is very high. The most common site of their localization is the L5/S1 level. LF thickening is not associated with OLF formation. PMID- 25556508 TI - Imaging of the Wormian bones using microcomputed tomography. AB - Wormian bones are irregular ossicles of small size and reveal fractal pattern of their edges. Their anatomy was visualized in volumetric reconstructions obtained from a series of micro-CT scans. In visual evaluation Wormian bones showed typical anatomy for the calvarial bones. They revealed three-layer composition: the outer and the inner table of the compact bone intervening with the table of the spongy bone. Microcomputed tomography captured all details of the interdigitation of the edge being incorporated into the lambdoid suture and interlocked between opposing edges of the occipital and parietal bones. This modality provided accurate images which allowed delineating morphological differences between the compact bone and the diploe, including vascular channels. PMID- 25556509 TI - Mandible - clinically revisited. AB - Based on the current literature authors revised anatomical and clinical datas considering the mandible. PMID- 25556510 TI - Median nerve (anatomical variations) and carpal tunel syndrome - revisited. AB - Carpal tunnel syndrome belongs to the most common causative factors of surgical interventions in the wrist region. Anatomy of carpal tunnel and median nerve is a subject of current revision. Authors paid attention to etiology of the syndrome based on review of literature and their own anatomical studies. They remind basic knowledge on the median nerve and indicate that only based on number of dissections a good orthopedic surgeon may acquire experience necessary to perform procedures in a most appropriate way. PMID- 25556511 TI - Does bile protect or damage interstitial Cajal-like cells in the human gallbladder? AB - the etiology of gallstone disease is considered to be multifactorial, including biliary cholesterol hypersecretion, supersaturation and crystallization, stone formation, bile stasis and mucus hypersecretion and gel formation. Gallbladder hypomotility seems to be a key process that triggers the precipitation of cholesterol microcrystals from supersaturated lithogenic bile. the purpose of the current study was to determine whether ICLCs in the gallbladder were influenced by lithogenic bile. Gallbladder specimens were collected from 30 patients (8 males and 22 females) who underwent elective laparoscopic cholecystectomy for symptomatic gallstone disease. The control group consisted of 25 consecutive patients (11 males and 14 females) who received elective treatment for pancreatic head tumors. ICLCs were visualized in paraffin sections of gallbladders using double immunofluorescence protocol with monoclonal c-kit antibodies and mast cell tryptase. Cholesterol, phospholipid and bile acid concentrations were measured in bile samples obtained by needle aspiration from the gallbladder at the time of surgery. The number of ICLCs in the gallbladder wall was significantly lower in the study group than in the control group (3.35 +/- 1.23 vs. 7.06 +/- 1.82 cell/FOV in the muscularis propria, P < 0.001) and correlated with a significant increase in the cholesterol saturation index. The glycocholic and taurocholic acid levels were significantly elevated in the control subjects compared with the study group. The results suggest that bile composition may play an important role in the reduction of ICLC density in the gallbladder. PMID- 25556512 TI - Controversies on the position of the mandibular foramen - review of the literature. AB - Foramen of mandible is the most important point considering the Halsted anesthesia. Position of this foramen seems to be stable, however there are lots of controversies regarded to its position. Based on the current literature authors revised datas from literature considering the location of the mandibular foramen. PMID- 25556513 TI - Do leukoreduction filters passively reduce the transmission risk of human granulocytic anaplasmosis? AB - BACKGROUND: Human granulocytic anaplasmosis, caused by Anaplasma phagocytophilum, poses an increasing public health risk in the United States. Since 2000, case reports have increased annually; 2782 cases were reported in 2013. Despite the increasing frequency of clinical cases, only eight cases of transfusion transmitted anaplasmosis (TTA) have been reported. We investigated if current leukoreduction practices impact transfusion risk. STUDY DESIGN AND METHODS: Whole blood units (WBUs) with integral red blood cell (RBC) leukoreduction filters were collected and spiked with A. phagocytophilum-infected HL-60 cells equivalent to 0.01, 1, or 5% of total neutrophils. After 24 hours at 4 degrees C WBUs were processed into plasma and RBCs, the latter subsequently leukoreduced (LR RBCs). To evaluate the removal of A. phagocytophilum by filtration, pre- and postfiltration samples were compared by culture and polymerase chain reaction (PCR). RESULTS: Compared to Day 0 or Day 1 positive controls, LR RBCs demonstrated reduced levels of A. phagocytophilum by culture and PCR. At 0.01% infection levels LR RBCs yielded no positive cultures and a log reduction of 2.5 by PCR. Similarly, at 1 and 5% infections levels, LR RBCs produced only 44% (4/9) and 56% (5/9) positive cultures, respectively. PCR results were comparable, 3.0 log reduction for 1% and 3.3 log reduction for 5% infection levels. CONCLUSIONS: The recent increase in TTA suggests that A. phagocytophilum may represent an emerging blood safety issue. However, the current study indicates that the widespread practice of leukoreduction might passively reduce, but not eliminate, TTA risk. In the absence of viable testing or pathogen inactivation and/or reduction options, leukoreduction may offer some protection from transmission risk. PMID- 25556514 TI - Robotic Intracorporeal Continent Cutaneous Urinary Diversion: Primary Description. AB - The purpose is to present the first report and describe our novel technique for intracorporeal continent cutaneous diversion after robotic cystectomy. After completion of robot-assisted cystectomy using a standard six-port transperitoneal technique, three additional ports are placed, and the robot is redocked laterally over the patient's right side in the modified lateral position. Our technique replicates step-by-step the principles of the open approach. Ileocolonic anastomosis, ureteroenteral anastomoses, and construction of a hand-sewn right colonic pouch are all performed intracorporeally. Tapering of efferent ileal limb and reinforcement of the ileocecal valve are performed via the extraction site, while the stoma is matured through a prospective port site. Successful robotic intracorporeal creation of a modified Indiana pouch was achieved. Operative time for diversion was 3 hours, with negligible blood loss, and without any intraoperative complications. No major (Clavien III-V) 90-day complications were observed. At a follow-up of 1 year, the patient continues to catheterize without difficulty. We demonstrate the first description of robotic intracorporeal continent cutaneous urinary diversion after robot-assisted cystectomy. We present a systematic minimally invasive approach, replicating the principles of open surgery, which is technically feasible and safe with a good functional result. PMID- 25556515 TI - Diffuse and strong cyclin D1 immunoreactivity in clear cell sarcoma of the kidney. AB - AIMS: Distinguishing clear cell sarcoma of the kidney (CCSK) from other paediatric malignancies, particularly blastema-rich Wilms tumour (WT) and congenital mesoblastic nephroma (CMN), is challenging. Specific immunohistochemistry for CCSK does not exist, and diagnosis rests upon histopa thology. Recently, the YWHAE-FAM22 rearrange ment, identical to that in endometrial stromal sarcoma (ESS), has been identified in CCSKs. As this fusion results in overexpression of cyclin D1 in ESS, we postulated that overexpression would also occur in CCSK; cyclin D1 immunohistochemistry could then be used to differentiate CCSK from other tumours. The goal of this study was therefore to evaluate the utility of cyclin D1 immunohistochemistry in identifying CCSK and helping to differentiate it from its mimics. METHODS AND RESULTS: Cyclin D1 expression was evaluated in 59 renal tumours-CCSK (14), WT (25), rhabdoid tumour (four), Ewing sarcoma (five), and CMN (11)-and four neuroblastomas. All 14 CCSKs showed diffuse and strong reactivity. In contrast, the blastematous component of most WTs showed only rare positive nuclei, that of rhabdoid tumours showed rare to focal immunoreactivity, and that of more than half of CMNs showed weak or focal immunoreactivity. Most Ewing sarcomas and all neuroblastomas showed diffuse moderate to strong staining. CONCLUSIONS: Cyclin D1 is most helpful in distinguishing CCSK from WT, rhabdoid tumour, and some CMNs, but not from neuroblastoma or Ewing sarcomas. PMID- 25556516 TI - Long-term clinical outcomes in women with breast pain in the absence of additional clinical findings: mammography remains indicated. AB - The purpose of the study was to determine the long-term clinical outcomes of women with breast pain in the absence of additional symptoms or signs (isolated breast pain), and the utility of mammography in their work-up. IRB approved, HIPAA compliant study retrospectively reviewed 1,386 patients referred for breast imaging with ICD-9 code for breast pain between 1/1/2006 and 12/31/2007. Of these, 617 consecutive women (mean age, 49 years) with isolated breast pain, mammogram, and follow-up (mean, 51 months) constituted the study group. Clinical data, mammographic and sonographic BI-RADS assessments, and geographic relationship between the site of cancer and pain were evaluated. The frequency of malignancies and of specific benign outcomes, both at and subsequent to the time of presentation, was determined. Breast cancer and specific benign outcomes were diagnosed in the painful breast of 11/617 (1.8 %) and 63/617 (10.2 %) women, respectively. Majority of the cancers (9/11, 81.8 %) were diagnosed subsequent (5 52 months) to initial imaging evaluation, whereas the majority of benign outcomes (52/63, 82.5 %) were diagnosed at initial presentation. Diagnostic mammography at initial presentation had a negative predictive value of 99.8 % (95 % CI 99.1 %, 100 %), specificity of 98.5 % (95 % CI 97.2 %, 99.3 %), and sensitivity of 66.7 % (95 % CI 11.6 %, 94.5 %). Three cancers were subsequently diagnosed in the contralateral (non-painful) breast. Eleven of 14 (78.6 %) cancers were in the symptomatic breast, of which 9 (81.8 %) geographically corresponded to the same area of focal pain. Thus, infrequently, breast cancer may clinically present as or be preceded by isolated breast pain and diagnostic mammography is useful for assessment. PMID- 25556517 TI - Atypical plasma cells with coexpression of myeloid markers and bundles of Auer rod-like inclusions. PMID- 25556519 TI - Regioselective C(sp2)-H dual functionalization of indoles using hypervalent iodine(III): bromo-amination via 1,3-migration of imides on indolyl(phenyl)iodonium imides. AB - A regioselective C(sp(2))-H dual functionalization of indoles, which underlies bromo-amination via the 1,3-migration of imide groups on indolyl(phenyl)iodonium imides as novel imide-combined hypervalent iodines(III), has been developed to provide 2-bis(sulfonyl)amino-3-bromo-indoles under the metal-free conditions. PMID- 25556518 TI - Silent cerebral events/lesions related to atrial fibrillation ablation: a clinical review. AB - Brain magnetic resonance imaging (MRI) has identified a high incidence of cerebral ischemia in asymptomatic patients after atrial fibrillation (AF) ablation (silent). Detection of cerebral ischemic events on MRI is based on acute hyperintense lesions on diffusion-weighted imaging. In the literature, the incidence is related to specifications of MRI and depends on the definition applied. In comparative studies, silent cerebral events (SCE, diffusion-weighted MRI [DWI] positive only) appear to be approximately 3 times more common compared to using a definition of silent cerebral lesions (SCL; without fluid attenuated inverse recovery sequence [FLAIR] positivity). Whereas the FLAIR sequence may turn positive within days after the ischemic event, SCE definition is highly sensitive for early phases of ischemic brain damage. SCE/SCL appear to represent cerebral ischemic infarcts and determine the "embolic fingerprint" of a specific ablation technology and strategy used. The optimum time point for detecting SCE is early after AF ablation (24-72 hours), whereas detection of SCL can only be performed within the first 2-7 days (due to delay of FLAIR positivity). Different technology-, procedure-, and patient-related parameters have been identified to play a role in the multifactorial genesis of SCE/SCL. In recent years, evidence has been gathered that there may be differences of SCE/SCL rates depending upon the ablation technology used, but small patient numbers and a large number of potential confounders hamper all studies. As major findings of recent studies, mode of periprocedural and intraprocedural anticoagulation has been identified as a major predictor for incidences of SCE/SCL. Whereas procedural characteristics related to higher SCE/SCL-rates may be modified, unchangeable patient-related factors should be taken into account for future individualized risk assessment. Novel ablation devices introduced into the market should be tested for their potential embolic fingerprint and refinements of ablation procedures to reduce their embolic potential should be prompted. The knowledge of "best practice" in terms of low SCE/SCL rates has prompted changes in work-flow, which have been implemented into ablation procedures using novel ablation devices. So far, no study has linked SCE/SCL to neuropsychological decline and the low number of AF ablation-associated events needs to be weighted against the multitude of preexisting asymptomatic MRI-detected brain lesions related to the course of AF itself. Future studies are needed to evaluate if more white matter hyperintensities due to AF may be prevented by AF ablation (producing only a small number of SCE/SCL). PMID- 25556520 TI - Correlation between microsatellite instability-high phenotype and occult lymph node metastasis in gastric carcinoma. AB - The aim of this study is to investigate the association of microsatellite instability (MSI) status with nodal status in gastric carcinoma (GC). MSI status was investigated in 623 consecutively resected GCs. To detect occult lymph node (LN) metastasis, immunohistochemistry (IHC) using antibodies against pan cytokeratin was performed in 391 node-negative cases by initial histologic examination. MSI-high (MSI-H) phenotype was found in 68 GC cases (10.9%) and was significantly associated with increased patient age, antral location, intestinal type, absence of venous/perineural invasion, and expanding growth type (p < 0.05). When the nodal status was evaluated, the number of metastatic LNs of MSI-H tumors tended to be lower than that of microsatellite stable/MSI-low (MSS/L) tumors (1.49 +/- 3.15 vs 4.37 +/- 9.81; p = 0.052), but the MSI-H phenotype was associated with the presence of lymphatic invasion (p = 0.036) and IHC-positive occult LN metastasis (p = 0.007). By multivariate analysis, MSI-H phenotype was significantly associated with IHC-positive occult LN metastasis (Odds ratio, 2.654; p = 0.044). MSI status and occult LN metastasis were not prognostic factors by survival analysis. Our findings suggest that the relationship between MSI status and regional LN metastasis may have some clinical and biologic implications to be elucidated. PMID- 25556521 TI - Long-range Cooper pair splitter with high entanglement production rate. AB - Cooper pairs in the superconductor are a natural source of spin entanglement. The existing proposals of the Cooper pair splitter can only realize a low efficiency of entanglement production, and its size is constrained by the superconducting coherence length. Here we show that a long-range Cooper pair splitter can be implemented in a normal metal-superconductor-normal metal (NSN) junction by driving a supercurrent in the S. The supercurrent results in a band gap modification of the S, which significantly enhances the crossed Andreev reflection (CAR) of the NSN junction and simultaneously quenches its elastic cotunneling. Therefore, a high entanglement production rate close to its saturation value can be achieved by the inverse CAR. Interestingly, in addition to the conventional entangled electron states between opposite energy levels, novel entangled states with equal energy can also be induced in our proposal. PMID- 25556522 TI - Seeding atomic layer deposition of alumina on graphene with yttria. AB - Integrating graphene into nanoelectronic device structure requires interfacing graphene with high-kappa dielectric materials. However, the dewetting and thermal instability of dielectric layers on top of graphene makes fabricating a pinhole free, uniform, and conformal graphene/dielectric interface challenging. Here, we demonstrate that an ultrathin layer of high-kappa dielectric material Y2O3 acts as an effective seeding layer for atomic layer deposition of Al2O3 on graphene. Whereas identical Al2O3 depositions lead to discontinuous film on bare graphene, the Y2O3 seeding layer yields uniform and conformal films. The morphology of the Al2O3 film is characterized by atomic force microscopy and transmission electron microscopy. C-1s X-ray photoemission spectroscopy indicates that the underlying graphene remains intact following Y2O3 seed and Al2O3 deposition. Finally, photoemission measurements of the graphene/SiO2/Si, Y2O3/graphene/SiO2, and Al2O3/Y2O3/graphene/SiO2 interfaces indicate n-type doping of graphene with different doping levels due to charge transfer at the interfaces. PMID- 25556523 TI - Perceived competency towards preventive dentistry among dental graduates: the need for curriculum change. AB - BACKGROUND: A previous study has shown that dental practitioners in Benghazi believed that the less prevention-oriented education system is one of the barriers to applying preventive dentistry. OBJECTIVE: To assess attitudes and perceived competence of the dental graduates in Benghazi towards prevention and early management of dental caries. METHODS: A cross-sectional, questionnaire based survey was conducted among internship students attending the Department of Community and Preventive Dentistry in Faculty of Dentistry, Benghazi, Libya. The participants were asked to provide demographic information, to respond to statements about their attitudes towards preventive dentistry, and to answer questions regarding their perceived competence in applying preventive dentistry procedures. RESULTS: Data from 108 Libyan dental graduates were analysed for this study, of which 64% of them were females and 42.1% of them passed their final year with grade: acceptable. The most acknowledged aspects of preventive dentistry were being useful and essential to the community (95.4 and 90.8%, respectively). The percentage of participants expressing a proficiency in providing oral hygiene instructions was the highest (95.4%). There were differences between study subgroups in their perceived competence of preventive dental practices by gender and academic performance (p<=0.05). CONCLUSION: This study highlighted that the currently implemented undergraduate education programme in Benghazi dental school does not provide dentists with the required attitude and skills to fulfil their role in providing preventive-oriented health services. PMID- 25556524 TI - Computer simulation and image guidance for individualised dynamic spinal stabilization. AB - PURPOSE: Dynamic implants for the human spine are used to re-establish regular segmental motion. However, the results have often been unsatisfactory and complications such as screw loosening are common. Individualisation of appliances and precision implantation are needed to improve the outcome of this procedure. Computer simulation, virtual implant optimisation and image guidance were used to improve the technique. METHODS: A human lumbar spine computer model was developed using multi-body simulation software. The model simulates spinal motion under load and degenerative changes. After virtual degeneration of a L4/5 segment, virtual pedicle screw-based implants were introduced. The implants' positions and properties were iteratively optimised. The resulting implant positions were used as operative plan for image guidance and finally implemented in a physical spine model. RESULTS: In the simulation, the introduction and optimisation of virtually designed dynamic implants could partly compensate for the effects of virtual lumbar segment degeneration. The optimised operative plan was exported to two different image-guidance systems for transfer to a physical spine model. CONCLUSION: Three-dimensional computer graphic simulation is a feasible means to develop operative plans for dynamic spinal stabilization. These operative plans can be transferred to commercially available image-guidance systems for use in implantation of physical implants in a spine model. This concept has important potential in the design of operative plans and implants for individualised dynamic spine stabilization surgery. PMID- 25556525 TI - Multimodality liver registration of Open-MR and CT scans. AB - PURPOSE: Multimodality registration of liver CT and MRI scans is challenging due to large initial misalignment, non-uniform MR signal intensity in the liver parenchyma, incomplete liver shapes in Open-MR scans and non-rigid deformations of the organ. An automated method was developed to register liver CT and open-MRI scans. METHODS: A hybrid registration algorithm was developed which incorporates both rigid and non-rigid methods. First, large misalignment of input CT and Open MR images was compensated by intensity-based registration. Maximum intensity projections (MIPs) of CT and MR data were registered in 2D, and the corresponding rigid transform parameters were used to align 3D images in axial, coronal and sagittal planes. Use of MIP projections compensates for intensity inhomogeneities inherent in the Open-MR data. A bounding box of MIP images defines an ROI which removes outliers and copes with incomplete MR data. Next, principal components analysis (PCA) was used to align MR and CT data datasets. The corresponding translation and rotation parameters were then used to increase the global registration accuracy. A modified TPS-RPM point-based non-rigid algorithm was used to accommodate local liver deformations. Surface points on the liver and branching points of the portal veins were input as landmarks to TPS-RPM method. Incorporating vascular branching points improves registration since tumors are usually found near vessels, so greater weight was given to branching points compared with surface points. RESULTS: The automated registration algorithm was compared with both rigid and non-rigid methods. Quantitative evaluation was performed using modified Hausdorff distance and overlap measure. The mean modified Hausdorff distances of liver and tumor were decreased from 23.53 and 40.03 mm to 9.38 and 8.88 mm, respectively. The mean overlap measures of liver and tumor were increased from 39 and 0 % to 78 and 27 %, respectively. Statistical analysis of the outcomes resulted in a p value less than 5 %. CONCLUSION: MIP-PCA-based rigid multimodality CT-MRI registration of liver scans compensates for large misalignment of input images even when the data are incomplete. A modified TPS-RPM algorithm, in which vascular points are emphasized over surface points, successfully handled local deformations. PMID- 25556526 TI - An analysis of tracking error in image-guided neurosurgery. AB - PURPOSE: This study quantifies some of the technical and physical factors that contribute to error in image-guided interventions. Errors associated with tracking, tool calibration and registration between a physical object and its corresponding image were investigated and compared with theoretical descriptions of these errors. METHODS: A precision milled linear testing apparatus was constructed to perform the measurements. RESULTS: The tracking error was shown to increase in linear fashion with distance normal to the camera, and the tracking error ranged between 0.15 and 0.6 mm. The tool calibration error increased as a function of distance from the camera and the reference tool (0.2-0.8 mm). The fiducial registration error was shown to improve when more points were used up until a plateau value was reached which corresponded to the total fiducial localization error ([Formula: see text]0.8 mm). The target registration error distributions followed a [Formula: see text] distribution with the largest error and variation around fiducial points. CONCLUSIONS: To minimize errors, tools should be calibrated as close as possible to the reference tool and camera, and tools should be used as close to the front edge of the camera throughout the intervention, with the camera pointed in the direction where accuracy is least needed during surgery. PMID- 25556527 TI - Metal-assisted exfoliation (MAE): green, roll-to-roll compatible method for transferring graphene to flexible substrates. AB - Graphene is expected to play a significant role in future technologies that span a range from consumer electronics, to devices for the conversion and storage of energy, to conformable biomedical devices for healthcare. To realize these applications, however, a low-cost method of synthesizing large areas of high quality graphene is required. Currently, the only method to generate large-area single-layer graphene that is compatible with roll-to-roll manufacturing destroys approximately 300 kg of copper foil (thickness = 25 MUm) for every 1 g of graphene produced. This paper describes a new environmentally benign and scalable process of transferring graphene to flexible substrates. The process is based on the preferential adhesion of certain thin metallic films to graphene; separation of the graphene from the catalytic copper foil is followed by lamination to a flexible target substrate in a process that is compatible with roll-to-roll manufacturing. The copper substrate is indefinitely reusable and the method is substantially greener than the current process that uses relatively large amounts of corrosive etchants to remove the copper. The sheet resistance of the graphene produced by this new process is unoptimized but should be comparable in principle to that produced by the standard method, given the defects observable by Raman spectroscopy and the presence of process-induced cracks. With further improvements, this green, inexpensive synthesis of single-layer graphene could enable applications in flexible, stretchable, and disposable electronics, low profile and lightweight barrier materials, and in large-area displays and photovoltaic modules. PMID- 25556528 TI - Al20(+) does melt, albeit above the bulk melting temperature of aluminium. AB - Employing first principles parallel tempering molecular dynamics in the microcanonical ensemble, we report the presence of a clear solid-liquid-like melting transition in Al20(+) clusters, not found in experiments. The phase transition temperature obtained from the multiple histogram method is 993 K, 60 K above the melting point of aluminium. Root mean squared bond length fluctuation, the velocity auto-correlation function and the corresponding power spectrum further confirm the phase transition from a solid-like to liquid-like phase. Atoms-In-Molecules analysis shows a strong charge segregation between the internal and surface atoms, with negatively charged internal atoms and positive charge at the surface. Analysis of the calculated diffusion coefficients indicates different mobilities of the internal and surface atoms in the solid like phase, and the differences between the environment of the internal atoms in these clusters with that of the bulk atoms suggest a physical picture for the origin of greater-than-bulk melting temperatures. PMID- 25556529 TI - Localizing and extracting filament distributions from microscopy images. AB - Detailed quantitative measurements of biological filament networks represent a crucial step in understanding architecture and structure of cells and tissues, which in turn explain important biological events such as wound healing and cancer metastases. Microscopic images of biological specimens marked for different structural proteins constitute an important source for observing and measuring meaningful parameters of biological networks. Unfortunately, current efforts at quantitative estimation of architecture and orientation of biological filament networks from microscopy images are predominantly limited to visual estimation and indirect experimental inference. Here, we describe a new method for localizing and extracting filament distributions from 2D microscopy images of different modalities. The method combines a filter-based detection of pixels likely to contain a filament with a constrained reverse diffusion-based approach for localizing the filaments centrelines. We show with qualitative and quantitative experiments, using both simulated and real data, that the new method can provide more accurate centreline estimates of filament in comparison to other approaches currently available. In addition, we show the algorithm is more robust with respect to variations in the initial filter-based filament detection step often used. We demonstrate the application of the method in extracting quantitative parameters from confocal microscopy images of actin filaments and atomic force microscopy images of DNA fragments. PMID- 25556530 TI - Senescence in breeding success of female Alpine chamois (Rupicapra rupicapra): the role of female quality and age. AB - Although numerous studies have reported reproductive senescence in wild animal populations, we still know very little on inter-individual differences in rates of ageing and on the factors accounting for these differences. To investigate age related variation in breeding success in a natural population of Alpine chamois (Rupicapra rupicapra), we used 15 years of data obtained by monitoring individual ear-tagged females. Analyses at the population level confirmed the occurrence of a decline in female breeding success, which is most noticeable from 9 years of age onward. Using an age-reverse approach, we showed that senescence in female breeding success occurs at the same age, since only very old individuals (older than 16 years) showed a decline in breeding success in the years preceding death. Interestingly, we also found evidence that 'success comes from success', as females that gave birth in a given year were more likely to procreate again in the following year. Moreover, results showed that discrepancies between successful and unsuccessful individuals tend to become more relevant in the oldest age classes. There was no evidence of a terminal allocation. These results emphasize the importance of age-dependent effects and individual quality in shaping reproductive senescence in a wild long-lived ungulate. PMID- 25556532 TI - Effects of sequential feeding with low- and high-protein diets on growth performances and plasma metabolite levels in geese. AB - This study was conducted by two trials to investigate effects of sequential feeding with low- and high-protein diets on growth traits and plasma metabolites in geese. In Trial I, the effect of sequential feeding under time-restricted feeding system was investigated. Seventy-two White Roman goslings were randomly allotted into either sequential feeding (S1) or control feeding (C1) group. All goslings were fed for 1 h at morning and at evening, respectively, from 2 to 8 weeks of age. S1 group was offered 13% CP diet at morning and 19% CP diet at evening. C1 group was offered the same diet (16% CP; mixed equally with the two diets mentioned above) at both morning and evening. Blood samples were hourly collected for 4 h after feeding at both morning and evening for the determination of the postprandial plasma levels of glucose, triacylglycerol and uric acid at the end of experiment. Results showed that BW, average daily gain (ADG), and daily feed intake (FI) were not different between groups, but the feed efficiency (FE) in S1 group was significantly higher than that in C1 group (P<0.05). The areas under curve (AUC) of plasma postprandial levels of glucose, triacylglycerol and uric acid were not affected by treatment, but the AUC of triacylglycerol and uric acid in morning were lower than those in evening (P<0.05). In Trial II, the effect of sequential feeding under ad libitum feeding system was investigated. Twenty-four goslings were randomly allotted into either sequential feeding (S2) or control feeding (C2) group. Diets were altered at 0600 and 1800 h, respectively, and geese were fed ad libitum from 4 to 8 weeks of age. S2 group was offered 14% CP diet at morning and 20% CP diet at evening. C2 group was supplied the same diet (mixed with the two diets according to the ratio of diets consumed by S2 group on the preceded day) at both morning and evening. Results showed that the ADG in S2 group was higher than those in C2 group (P<0.05). Summarized data from both trials showed that sequential feeding improves daily gain and FE in growing geese. PMID- 25556533 TI - Contraction velocity influence the magnitude and etiology of neuromuscular fatigue during repeated maximal contractions. AB - This study aimed to compare the magnitude and etiology of neuromuscular fatigue during maximal repeated contractions performed in two contraction modes (concentric vs isometric) and at two contraction velocities (30/s vs 240 degrees /s). Eleven lower limb-trained males performed 20 sets of maximal contractions at three different angular velocities: 0 degrees /s (KE0), 30/s (KE30), and 240 degrees /s (KE240). Cumulated work, number of contraction, duty cycle, and contraction time were controlled. Torque, superimposed and resting twitches, as well as gas exchange, were analyzed. Increasing contraction velocity was associated with greater maximal voluntary torque loss (KE0: -9.8 +/- 3.9%; KE30: 16.4 +/- 8.5%; KE240: -32.6 +/- 6.3%; P < 0.05). Interestingly, the torque decrease was similar for a given cumulated work. Compared with KE0, KE240 generated a greater evoked torque loss (Db100: -24.3 +/- 5.3% vs -5.9 +/- 6.9%; P < 0.001), a higher O2 consumption (23.7 +/- 6.4 mL/min/kg vs 15.7 +/- 3.8 mL/min/kg; P < 0.001), but a lower voluntary activation (VA) loss (-4.3 +/- 1.6% vs -11.2 +/- 4.9%; P < 0.001). The neuromuscular perturbations were intermediate for KE30 (Db100: -10.0 +/- 6.8%; VA: -7.2 +/- 2.8%). Although the amount of mechanical work cumulated strongly determined the magnitude of torque decrease, the contraction velocity and mode influenced the origin of the neuromuscular fatigue. The metabolic stress and peripheral fatigue increased but reduction of VA is attenuated when the contraction velocity increased from 0 degrees /s to 240 degrees /s. PMID- 25556531 TI - An acetylation switch controls TDP-43 function and aggregation propensity. AB - TDP-43 pathology is a disease hallmark that characterizes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Although a critical role for TDP-43 as an RNA-binding protein has emerged, the regulation of TDP-43 function is poorly understood. Here, we identify lysine acetylation as a novel post-translational modification controlling TDP-43 function and aggregation. We provide evidence that TDP-43 acetylation impairs RNA binding and promotes accumulation of insoluble, hyper-phosphorylated TDP-43 species that largely resemble pathological inclusions in ALS and FTLD-TDP. Moreover, biochemical and cell-based assays identify oxidative stress as a signalling cue that promotes acetylated TDP-43 aggregates that are readily engaged by the cellular defense machinery. Importantly, acetylated TDP-43 lesions are found in ALS patient spinal cord, indicating that aberrant TDP-43 acetylation and loss of RNA binding are linked to TDP-43 proteinopathy. Thus, modulating TDP-43 acetylation represents a plausible strategy to fine-tune TDP-43 activity, which could provide new therapeutic avenues for TDP-43 proteinopathies. PMID- 25556534 TI - Survival from uveal melanoma in Western Australia 1981-2005. AB - BACKGROUND: The survival rates for patients diagnosed with uveal melanoma in Australia are unknown. Few long-term studies of uveal melanoma are available, and it is unclear whether their results are applicable to the Australian population. DESIGN: Retrospective population-based study. PARTICIPANTS: Patients diagnosed with uveal melanoma between 1981 and 2005 in Western Australia. METHODS: Three hundred eight cases were included. Relative survival and Cox regression were performed. Variables tested for their predictive ability included patient age and sex, tumour-specific variables, and treatment modality. MAIN OUTCOME MEASURES: All-cause survival rates and relative survival rates of patients with diagnosed uveal melanoma. RESULTS: Relative survival rates for the entire cohort were 88.2%, 81.4% and 71.4% at 3, 5 and 10 years, respectively. Predictors of worse survival included mixed-cell tumour morphology (hazard ratio [HR] = 2.1; P-value = 0.002), tumour location at the ciliary body (HR = 1.7; P-value = 0.029) and tumour apical height more than 5 mm (HR 1.9, P-value = 0.026). Of all patients who underwent enucleation, those diagnosed in 1998-2005 died twice as fast (HR = 2.3; P-value = 0.004). In the 17 patients with metastasis, the median survival time from date of diagnosis of metastasis was 3.1 months. CONCLUSIONS: These survival estimates are comparable to those reported for the USA, and more optimistic than those reported for most European-based studies. Tumour apical height, tumour site, tumour morphology and having an enucleation in certain calendar periods of diagnosis were independent predictors of survival. Survival prognosis for patients with diagnosed metastatic uveal melanoma is very poor. PMID- 25556535 TI - Prognostic Value of Stress Echocardiography in Patients Presenting with Syncope. AB - BACKGROUND: Evaluation for ischemia is appropriate in patients at risk for or with a history of coronary artery disease presenting with syncope. The aim of this study is to determine the prognostic value of stress echocardiography in patients presenting with syncope. METHODS: We examined our database of all patients undergoing stress echocardiography at our institution. Patients referred due to syncope were grouped as high risk based on any of the following: (1) known history of coronary artery disease, (2) left ventricular ejection fraction <50%, (3) moderate or severe mitral or aortic valve regurgitation, and (4) moderate mitral or aortic valve stenosis. The main outcomes were the presence of ischemia on stress imaging and all-cause mortality using the social security death index. RESULTS: A total of 225 patients were identified; mean age was 64.3 +/- 14.5 years, the mean follow-up duration was 29.2 +/- 13.8 months. There were 163 patients in the low-risk group and 62 patients in the high-risk group. On imaging, 7% of the overall cohort had ischemia. The low-risk group had 5 (3%) patients with ischemia and the high-risk group had 10 patients (16%) with ischemia (P < 0.01). The mortality rate was significantly higher in the high-risk group (3.99%/year vs. 1.02%/year; P = 0.02); this difference was not affected by the presence of ischemia. CONCLUSIONS: High-risk patients with syncope as defined by appropriateness criteria and existing evidence carry a higher risk of ischemia and all-cause mortality. The presence of ischemia may not be predictive of long term outcome in this group. PMID- 25556537 TI - Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders. AB - BACKGROUND: Inherited platelet function disorders (PFDs) are heterogeneous, and identification of the underlying genetic defects is difficult when based solely on phenotypic and clinical features of the patient. OBJECTIVE: To analyze 329 genes regulating platelet function, number, and size in order to identify candidate gene defects in patients with PFDs. PATIENTS/METHODS: Targeted analysis of candidate PFD genes was undertaken after next-generation sequencing of exomic DNA from 18 unrelated index cases with PFDs who were recruited into the UK Genotyping and Phenotyping of Platelets (GAPP) study and diagnosed with platelet abnormalities affecting either Gi signaling (n = 12) or secretion (n = 6). The potential pathogenicity of candidate gene defects was assessed using computational predictive algorithms. RESULTS: Analysis of the 329 candidate PFD genes identified 63 candidate defects, affecting 40 genes, among index cases with Gi signaling abnormalities, while 53 defects, within 49 genes, were identified among patients with secretion abnormalities. Homozygous gene defects were more commonly associated with secretion abnormalities. Functional annotation analysis identified distinct gene clusters in the two patient subgroups. Thirteen genes with significant annotation enrichment for 'intracellular signaling' harbored 16 of the candidate gene defects identified in nine index cases with Gi signaling abnormalities. Four gene clusters, representing 14 genes, with significantly associated gene ontology annotations were identified among the cases with secretion abnormalities, the most significant association being with 'establishment of protein localization.' CONCLUSION: Our findings demonstrate the genetic complexity of PFDs and highlight plausible candidate genes for targeted analysis in patients with platelet secretion and Gi signaling abnormalities. PMID- 25556538 TI - Comparison of the Glasgow-Blatchford and AIMS65 scoring systems for risk stratification in upper gastrointestinal bleeding in the emergency department. AB - OBJECTIVES: The aim of this study was to compare the performance of the Glasgow Blatchford and the AIMS65 scoring systems as early risk assessment tools for accurately identifying patients with upper gastrointestinal (GI) bleeding who are at a low risk of requiring clinical interventions, including emergency endoscopy. The secondary objective was to compare their performance regarding relevant clinical outcomes. METHODS: Data were collected prospectively over a 2-year period in the emergency department of a university hospital. Adult patients with upper GI bleeding from either variceal or nonvariceal sources were included. Composite clinical outcomes consisted of a need for surgical or endoscopic intervention, rebleeding, intensive care unit admission, or in-hospital mortality. Patients who required blood transfusions or suffered composite clinical outcomes were considered high-risk patients. Glasgow-Blatchford score (GBS) and AIMS65 score were calculated for each patient. The sensitivity and specificity of the scoring systems were calculated. The areas under the receiver operating characteristic curve (AUC) of the scores were compared. RESULTS: There were 254 patients in the study, of whom 163 (64.2%) were men. The median age was 61 years (interquartile range = 45 to 72 years). Among the patients, 211 (83.1%) underwent endoscopy, of whom 49 (19.3%) required endoscopic intervention to achieve hemostasis. Five (2%) patients required surgical intervention. Rebleeding was observed in 33 (13%) patients. A total of 143 (56.3%) patients received blood transfusions. A total of 152 (59.8%) were defined as high risk. Eighty-one (31.9%) experienced at least one component of the composite clinical outcomes, 18 (7.1%) of whom suffered in-hospital mortality. A GBS of 0 was observed in 16 patients (6.3%) in the study group. Two of these were high-risk patients. A total of 101 (39.8%) patients had AIMS65 scores of 0. Thirty-four of these were high risk patients. A GBS of 0 had higher sensitivity than an AIMS65 score of 0 (98.68% vs. 77.6%). The negative predictive values of the GBS and AIMS65 of 0 were 87.5 and 66.3%, respectively. The GBS and AIMS65 were similar with regard to the composite outcome prediction, with AUCs of 0.795 (95% confidence interval [CI] = 0.74 to 0.843) and 0.746 (95% CI = 0.688 to 0.798), respectively (p = 0.137). The scores were also similar with respect to predicting in-hospital mortality (AUCs of 0.85 vs. 0.81; p = 0.342). The GBS was superior to the AIMS65 in identifying high-risk patients, with AUCs of 0.896 (95% CI = 0.85 to 0.93) and 0.771 (95% CI = 0.714 to 0.821; p < 0.001), respectively. The GBS was also more accurate than the AIM65 in predicting the need for blood transfusions (AUCs of 0.904 vs. 0.796; p < 0.001) and interventions (AUCs of 0.727 vs. 0.647; p = 0.05). CONCLUSIONS: These results suggest that the GBS has superior sensitivity relative to the AIMS65 in identifying patients who were not likely to require interventions, including emergency endoscopy. Additional work to determine the use in real-time decision making may be warranted and helpful in providing guidance to clinicians. PMID- 25556539 TI - Analgesic effect of ultrasound-guided transversus abdominis plane block after total abdominal hysterectomy: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To assess the effect of bilateral ultrasound-guided transversus abdominis plane block with ropivacaine compared with placebo as part of a multimodal analgesic regimen. DESIGN: A randomized, double-blind, placebo controlled trial following the CONSORT criteria. SETTING: Hvidovre University Hospital. PATIENTS: Forty-six women scheduled for total abdominal hysterectomy. INTERVENTION: Women received either ropivacaine 0.75%, 20 mL (n = 24) or 0.9% saline, 20 mL (n = 24) in the transversus abdominis plane on each side. MAIN OUTCOME MEASURES: Primary outcome was the 24-h postoperative morphine consumption. Secondary outcomes were pain scores at rest and during coughing, postoperative nausea and vomiting at 1, 2, 4, 6, 8, and 24 h, and time to first mobilization. RESULTS: There was no difference in the mean 24-h postoperative morphine consumption between the two groups (p = 0.733). The ropivacaine group had significantly lower median pain scores at 1 h (p = 0.008) and 2 h (p = 0.027) postoperatively at rest and at 8 h (p = 0.028) during coughing. There was no significant difference in other secondary outcomes. CONCLUSION: There was no reduction in 24-h morphine consumption when using an ultrasound-guided transversus abdominis plane block in women undergoing total abdominal hysterectomy. As part of a multimodal regimen the transversus abdominis plane block showed some effect on pain scores at rest only in the early postoperative period. PMID- 25556536 TI - Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. AB - Hereditary frontotemporal dementia associated with mutations in the microtubule associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms. PMID- 25556541 TI - Cord serum dipeptidyl-peptidase 4 activity in gestational diabetes. AB - BACKGROUND: Tissue-specific dipeptidyl-peptidase 4 (DPP4) dysregulation has been described in adults with diabetes mellitus. The DPP4 -incretin system has not been studied in foetal life. In this study, DPP4 activity and glucagon-like peptide-1 (GLP-1) levels were assessed in cord blood of neonates born to women with gestational diabetes mellitus (GDM) and nondiabetic controls. MATERIAL AND METHODS: This study has been conducted in two Hungarian and one Austrian centres. PATIENTS: A total of 568 pregnant women were enrolled in the study after their OGTT between the 24th and 28th gestational week. Cord blood samplings with DPP4 activity and GLP-1 level measurements were possible in 270 (DPP4: 159 control, 111 GDM) and 112 (GLP-1: 72 control, 40 GDM) cases. OGTT (24-28th gestational week) and cord blood sampling at delivery were performed. Cord serum DPP4 activity was determined in a continuous monitoring microplate-based kinetic assay, and cord plasma GLP-1 was measured using a fluorescence ELISA method. RESULTS: Cord serum DPP4 activity was lower in GDM [mean (95% CI): 28.07 U/L (26.32-29.82 U/L)] than in controls [31.61 U/L (29.93-33.29 U/L), MWU P = 0.0015]. Cord plasma active GLP-1 levels were close to the lower detection limit and were not altered in GDM (control: mean = 3.43 pM, 95% CI: 3.04-3.82 pM, GDM: mean = 3.61 pM, 95% CI: 2.96-4.28 pM - MWU test P = 0.6). CONCLUSIONS: Decreased cord serum DPP4 activity in gestational diabetes mellitus might be the result of an adaptive foetal response or an early dysregulation in the entero-insular axis with consequences beyond the incretin system. Cord plasma GLP-1 levels may reflect the missing oral intake with a limited glucose sensing of L cells via the circulation in foetal life. PMID- 25556540 TI - Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy. AB - BACKGROUND & AIMS: Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort. METHODS: We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results. RESULTS: We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication. CONCLUSION: These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection. PMID- 25556542 TI - Advanced technology for the improvement of adenoma and polyp detection during colonoscopy. AB - Early detection and removal of adenomatous polyps reduces colorectal cancer death. However, many studies have reported that up to 20% of adenomas can be missed during colonoscopy. To improve visualization and reduce the blind spot of the colonic mucosa for an increase in the adenoma detection rate, many endoscopic techniques and technologies have been developed. The benefit of the high definition endoscope for improving adenoma and polyp detection is marginal. Wide angle colonoscope has failed to improve adenoma detection compared to standard colonoscopy. Although the cap-assisted colonoscope can reduce cecal intubation times, it does not seem to improve adenoma and polyp detection. The diagnostic accuracy of the colon capsule endoscope is low compared to the conventional colonoscope. Third Eye((r)) retroscope((r)) , which provides additional retrograde viewing, has revealed significant improvement in adenoma and polyp detection compared to standard colonoscopy. However, this device increases procedural times. Recently developed full-spectrum endoscopy colonoscope and extra-wide-angle-view colonoscope have demonstrated a significantly lower miss rate of polyps. However, clinical trials are mandatory to determine the efficacy of these novel technologies for cancer screening. In addition, education and training for these novel techniques and technologies should seriously be considered to improve adenoma and polyp detection. PMID- 25556543 TI - A decade of theory of mind research on Cayo Santiago: Insights into rhesus macaque social cognition. AB - Over the past several decades, researchers have become increasingly interested in understanding how primates understand the behavior of others. One open question concerns whether nonhuman primates think about others' behavior in psychological terms, that is, whether they have a theory of mind. Over the last ten years, experiments conducted on the free-ranging rhesus monkeys (Macaca mulatta) living on Cayo Santiago have provided important insights into this question. In this review, we highlight what we think are some of the most exciting results of this body of work. Specifically we describe experiments suggesting that rhesus monkeys may understand some psychological states, such as what others see, hear, and know, but that they fail to demonstrate an understanding of others' beliefs. Thus, while some aspects of theory of mind may be shared between humans and other primates, others capacities are likely to be uniquely human. We also discuss some of the broader debates surrounding comparative theory of mind research, as well as what we think may be productive lines for future research with the rhesus macaques of Cayo Santiago. PMID- 25556544 TI - Cartilage tissue engineering on macroporous scaffolds using human tooth germ stem cells. AB - The main objective was to study cartilage regeneration through differentiation of human tooth germ stem cells (HTGSCs) into chondrocytes on different three dimensional (3D) scaffolds (PCL, PLLA and PCL-PLLA). Scaffold topographies were studied by scanning electron microscopy and it was found that the scaffolds had interconnected macroporous structures. HTGSCs were isolated from impacted third molar tooth germs of young adult patients and grown for 3 weeks on the scaffolds in chondrogenic differentiation medium. Cell proliferation on the scaffolds was determined by MTS assay and it was observed that all scaffolds supported cell proliferation. Immunostaining was carried out for morphological and differentiation analyses. Immunohistochemical analyses revealed that the cells attached onto the scaffolds and deposited cartilage-specific extracellular matrix (ECM). Real-time PCR was performed to determine the expression levels of cartilage-specific genes. After 21 days of incubation in cartilage differentiation medium, expression of collagen type II increased only in the cells seeded onto PCL-PLLA blend scaffolds. Similarly, aggrecan expression was the highest on PCL-PLLA scaffolds after 3 weeks. These results suggest that all the scaffolds, and especially PCL-PLLA, were suitable for chondrogenic differentiation of HTGSCs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25556545 TI - Evidence for limited D1 and D2 receptor coexpression and colocalization within the dorsal striatum of the neonatal mouse. AB - The striatum is the major input nucleus of the basal ganglia involved in reward processing, goal-directed behaviors, habit learning, and motor control. The striatum projects to the basal ganglia output nuclei via the "direct" and "indirect" pathways, which can be distinguished by their projection fields and their opposing effects on behavior. In adult animals, the functional opposition is modulated by the differential actions of D1 and D2 dopamine receptors (D1R, D2R), the expression of which is largely separated between these pathways. To determine whether a similar degree of separation exists earlier in development, we used dual-label immunohistochemistry to map dorsal-striatal D1R and D2R expression at the promoter level in postnatal day 0 (PD0) Drd1a-tdTomato/Drd2-GFP BAC transgenic mice, and at the receptor level by costaining for native D1R and D2R in wildtype (WT) PD0 animals. To assess for potential molecular interactions between D1R and D2R we also employed a recently developed proximity-ligation assay (PLA). Limited coexpression and colocalization of the D1R and D2R proteins was found in clusters of neurons endemic to the "patch" compartment as identified by costaining with tyrosine hydroxylase, but not outside these clusters. Moreover, in contrast to our recent findings where we failed to detect a D1R-D2R PLA signal in the adult striatum, in PD0 striatum we did identify a clear PLA signal for this pair of receptors. This colocalization at close proximity points to a possible role for D1R/D2R-mediated crosstalk in early striatal ontogeny. PMID- 25556546 TI - Visualization and quantification of transmembrane ion transport into giant unilamellar vesicles. AB - Transmembrane ion transporters (ionophores) are widely investigated as supramolecular agents with potential for biological activity. Tests are usually performed in synthetic membranes that are assembled into large unilamellar vesicles (LUVs). However transport must be followed through bulk properties of the vesicle suspension, because LUVs are too small for individual study. An alternative approach is described whereby ion transport can be revealed and quantified through direct observation. The method employs giant unilamellar vesicles (GUVs), which are 20-60 MUm in diameter and readily imaged by light microscopy. This allows characterization of individual GUVs containing transporter molecules, followed by studies of transport through fluorescence emission from encapsulated indicators. The method provides new levels of certainty and relevance, given that the GUVs are similar in size to living cells. It has been demonstrated using a highly active anion carrier, and should aid the development of compounds for treating channelopathies such as cystic fibrosis. PMID- 25556548 TI - Role of radiation therapy for non-extremity soft tissue sarcomas. AB - BACKGROUND: Negative surgical margins are uncommon for non-extremity soft tissue sarcomas. Radiation therapy is usually recommended to improve local control; however, appropriate RT dosing is challenging due to nearby dose-limiting normal structures. MATERIAL AND METHODS: Comprehensive literature search using PubMed (March 2014). RESULTS: Data suggest radiation therapy is an important modality in maximizing local tumor control in non-extremity sarcomas. CONCLUSION: The literature supports the use of RT to improve local control for non-extremity soft tissue sarcomas. PMID- 25556547 TI - Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence. AB - Bladder cancer is the fourth most common cancer among men in the United States and more than half of patients experience recurrences within 5 years after initial diagnosis. Additional clinically informative and actionable biomarkers of the recurrent bladder cancer phenotypes are needed to improve screening and molecular therapeutic approaches for recurrence prevention. MicroRNA-34a (miR 34a) is a short noncoding regulatory RNA with tumor suppressive attributes. We leveraged our unique, large, population-based prognostic study of bladder cancer in New Hampshire, United States to evaluate miR-34a expression levels in individual tumor cells to assess prognostic value. We collected detailed exposure and medical history data, as well as tumor tissue specimens from bladder patients and followed them long-term for recurrence, progression and survival. Fluorescence-based in situ hybridization assays were performed on urothelial carcinoma tissue specimens (n = 229). A larger proportion of the nonmuscle invasive tumors had high levels of miR-34a within the carcinoma cells compared to those tumors that were muscle invasive. Patients with high miR-34a levels in their baseline nonmuscle invasive tumors experienced lower risks of recurrence (adjusted hazard ratio 0.57, 95% confidence interval 0.34-0.93). Consistent with these observations, we demonstrated a functional tumor suppressive role for miR 34a in cultured urothelial cells, including reduced matrigel invasion and growth in soft agar. Our results highlight the need for further clinical studies of miR 34a as a guide for recurrence screening and as a possible candidate therapeutic target in the bladder. PMID- 25556549 TI - Nonword repetition errors of children with and without specific language impairments (SLI). AB - BACKGROUND: Two ubiquitous findings from the literature are that (1) children with specific language impairments (SLI) repeat nonwords less accurately than peers with typical language development (TLD), and (2) all children repeat nonwords with frequent phonotactic patterns more accurately than low-probability nonwords. Many studies have examined repetition accuracy, but little work has examined children's errors. AIMS: To examine nonword repetition errors from a previously published study in terms of phonotactic probability. METHODS & PROCEDURES: Eighteen children with SLI (mean age = 9;2) and 18 age-matched controls (mean age = 8;11) repeated three- and four-syllable nonwords. Substitutions were analysed in terms of phoneme frequency and phonotactic probability of the syllable containing the substitution. OUTCOMES & RESULTS: Results for all children show that phoneme substitutions generally involved replacement with more frequently occurring phonemes. Also, the resulting phonotactic probability within syllables containing substitutions was greater than the probability of the targets. This trend did not differ by group. CONCLUSIONS & IMPLICATIONS: These results suggest that both children with SLI and children with TLD substitute less frequent phonemes with more frequent ones, and less probabilistic syllables with higher probability ones. PMID- 25556550 TI - Synthesis and pharmacological evaluations of 4-hydroxycoumarin derivatives as a new class of anti-Staphylococcus aureus agents. AB - OBJECTIVES: Due to the increasing prevalence of drug-resistant Staphylococcus aureus infection, we develop novel 4-hydroxycoumarin derivatives as antimicrobials. METHODS: The antibacterial activity of 4-hydroxycoumarin derivatives against drug-susceptive S. aureus (ATCC 29213) and methicillin resistant S. aureus (MRSA) were evaluated using minimal inhibitory concentration (MIC) assay; the activity of favourable compound was further observed using bacterial growth curves assay and in the MRSA infection mice. KEY FINDINGS: Compared with dihydropyran derivatives, compound 1 as one of biscoumarins showed most potent activity with MIC values of 4-8 MUg/ml and apparently inhibited the growth rate of S. aureus ATCC 29213 and USA300 strain in concentrations of both 16 and 32 mg/ml. In the mice infected with MRSA USA300, administration of 5 mg/kg compound 1 improved the animal survival rate to 66.7%, and improved the pathological change in lung tissue compared with the infection model animals. No significant cytotoxicity of compound 1 was observed on the umbilical vein endothelial cells (HUVECs) under the concentration of 800 MUg/ml. CONCLUSION: Compared with the dihydropyran derivatives, biscoumarins exhibited more promising activity against both drug-sensitive and drug-resistant S. aureus, and it is efficacious in treating MRSA infections in mouse models with a favourable safety in human cells. PMID- 25556551 TI - Legg-Calve-Perthes disease produces chronic hip synovitis and elevation of interleukin-6 in the synovial fluid. AB - Legg-Calve-Perthes disease (LCPD) is a childhood hip disorder of ischemic osteonecrosis of the femoral head. Hip joint synovitis is a common feature of LCPD, but the nature and pathophysiology of the synovitis remain unknown. The purpose of this study was to determine the chronicity of the synovitis and the inflammatory cytokines present in the synovial fluid at an active stage of LCPD. Serial MRI was performed on 28 patients. T2-weighted and gadolinium-enhanced MR images were used to assess synovial effusion and synovial enhancement (hyperemia) over time. A multiple-cytokine assay was used to determine the levels of 27 inflammatory cytokines and related factors present in the synovial fluid from 13 patients. MRI analysis showed fold increases of 5.0 +/- 3.3 and 3.1 +/- 2.1 in the synovial fluid volume in the affected hip compared to the unaffected hip at the initial and the last follow-up MRI, respectively. The mean duration between the initial and the last MRI was 17.7 +/- 8.3 months. The volume of enhanced synovium on the contrast MRI was increased 16.5 +/- 8.5 fold and 6.3 +/- 5.6 fold in the affected hip compared to the unaffected hip at the initial MRI and the last follow-up MRI, respectively. In the synovial fluid of the affected hips, IL 6 protein levels were significantly increased (LCPD: 509 +/- 519 pg/mL, non-LCPD: 19 +/- 22 pg/mL; p = 0.0005) on the multi-cytokine assay. Interestingly, IL-1beta and TNF-alpha levels were not elevated. In the active stage of LCPD, chronic hip synovitis and significant elevation of IL-6 are produced in the synovial fluid. Further studies are warranted to investigate the role of IL-6 on the pathophysiology of synovitis in LCPD and how it affects bone healing. PMID- 25556552 TI - Toward a new generation of electrically controllable hygromorphic soft actuators. AB - An innovative processing strategy for fabricating soft structures that possess electric- and humidity-driven active/passive actuation capabilities along with touch- and humidity-sensing properties is reported. The intrinsically multifunctional material comprises an active thin layer of poly(3,4 ethylenedioxythiophene):poly-(styrene sulfonate) in a double-layered structure with a silicone elastomer and provides an opportunity toward developing a new class of smart structures for soft robotics. PMID- 25556553 TI - Impact of saline irrigation and topical corticosteroids on the postsurgical sinonasal microbiota. AB - BACKGROUND: Topical treatments with nasal saline irrigation, topical steroid sprays, or corticosteroid rinses can improve sinonasal symptoms in chronic rhinosinusitis (CRS). However, the impact of these therapies on commensals (Corynebacterium) and on biofilm pathogens associated with CRS (Staphylococcus aureus and Pseudomonas) is not well characterized. METHODS: Paired nasal and sinus swabs were collected endoscopically from 28 controls and 14 CRS patients with nasal polyposis (CRSwNP) who had not received systemic antibiotics or corticosteroids in the previous 8 weeks. Total DNA from swab eluents were extracted and analyzed by 16S rRNA gene-based pyrosequencing. A total of 359,077 reads were obtained and classified taxonomically. The association of use of topical therapies with sinonasal microbiota composition was assessed by factor/vector-fitting. The proportional abundances of sinonasal bacteria between topical therapy users and nonusers were further compared by 2-tailed Kolmogorov Smirnov test among controls and among CRSwNP participants. RESULTS: Nasal saline irrigation, with or without added budesonide, was not associated with significantly distinct sinonasal microbiota composition or significantly decreased Pseudomonas or S. aureus abundances among either controls or CRSwNP participants. Corynebacterium was slightly lower in controls that reported using saline irrigation than those who did not. No significant association was found between nasal saline irrigation and the proportional abundances of Pseudomonas, S. aureus, and Corynebacterium in CRSwNP participants. However, male CRSwNP patients were noted to have significantly higher Corynebacterium proportional abundances than their female counterparts. The use of topical steroid sprays was associated with a distinct microbiota in control subjects, characterized by higher proportional abundances of Dolosigranulum and Simonsiella and a lower proportional abundance of Campylobacter. CONCLUSION: Nasal saline irrigation is not associated with a distinct alteration in the proportional abundance of commensal bacteria or biofilm-forming pathogens in CRSwNP patients. However, use of topical intranasal corticosteroid sprays in control subjects is associated with a distinct sinonasal microbiota. PMID- 25556554 TI - Isolation and characterisation of a Sphingomonas strain able to degrade the fungicide ortho-phenylphenol. AB - BACKGROUND: Ortho-phenylphenol (OPP) is a fungicide used in fruit packaging plants for the control of fungal infestations during storage. Its application leads to the production of large wastewater volumes which according to the European legislation should be treated on site. In spite of this, no efficient treatment systems are currently available, and the development of biological systems based on tailored-made pesticide-degrading inocula for the treatment of these wastewaters is an appealing solution. RESULTS: Enrichment cultures from a soil collected from a wastewater disposal site resulted in the isolation of a pure Sphingomonas haloaromaticamans strain P3 able to degrade rapidly OPP and use it as an energy source. Its degrading capacity was dependent on the external supply of amino acids or on the presence of other bacteria that did not contribute to fungicide degradation. The isolated S. haloaromaticamans strain was able to metabolise up to 150 mg L(-1) of OPP within 7 days, in a wide range of pH (4.5-9) and temperatures (4-37 degrees C), and in the presence of other pesticides (thiabendazole and diphenylamine) co-used in the fruit packaging industry. CONCLUSION: Overall, the OPP-degrading bacterium isolated showed high potential for use in future biodepuration treatment systems and bioremediation strategies. PMID- 25556555 TI - The abiotic and biotic factors limiting establishment of predatory fishes at their expanding northern range boundaries in Ontario, Canada. AB - There is a poor understanding of the importance of biotic interactions in determining species distributions with climate change. Theory from invasion biology suggests that the success of species introductions outside of their historical ranges may be either positively (biotic acceptance) or negatively (biotic resistance) related to native biodiversity. Using data on fish community composition from two survey periods separated by approximately 28 years during which climate was warming, we examined the factors influencing the establishment of three predatory centrarchids: Smallmouth Bass (Micropterus dolomieu), Largemouth Bass (M. salmoides), and Rock Bass (Ambloplites rupestris) in lakes at their expanding northern range boundaries in Ontario. Variance partitioning demonstrated that, at a regional scale, abiotic factors play a stronger role in determining the establishment of these species than biotic factors. Pairing lakes within watersheds where each species had established with lakes sharing similar abiotic conditions where the species had not established revealed both positive and negative relationships between the establishment of centrarchids and the historical presence of other predatory species. The establishment of these species near their northern range boundaries is primarily determined by abiotic factors at a regional scale; however, biotic factors become important at the lake to-lake scale. Studies of exotic species invasions have previously highlighted how spatial scale mediates the importance of abiotic vs. biotic factors on species establishment. Our study demonstrates how concepts from invasion biology can inform our understanding of the factors controlling species distributions with changing climate. PMID- 25556556 TI - Critical hypercalcemia following discontinuation of denosumab therapy for metastatic giant cell tumor of bone. AB - We report a 14 year-old female with Giant Cell Tumor of Bone, successfully treated with denosumab, who developed critical hypercalcemia after completion of therapy. Five months after her last denosumab treatment, serum calcium rose to 16.5 mg/dL (normal 8.7-10.8 mg/dL), nearly double her prior level of 8.4 mg/dL while receiving denosumab. She required emergent intervention to treat her hypercalcemia, which was attributed to rebound osteoclast activity and osteopetrotic bone. Denosumab is widely used in adults and increasingly in pediatric oncology populations and our experience demonstrates the need for close monitoring for electrolyte derangements following discontinuation. PMID- 25556558 TI - A new p-metal-n structure AgBr-Ag-BiOBr with superior visible-light-responsive catalytic performance. AB - A novel visible-light-driven AgBr-Ag-BiOBr photocatalyst was synthesized by a facile hydrothermal method. Taking advantage of both p-n heterojunctions and localized surface plasmon resonance, the p-metal-n structure exhibited a superior performance concerning degradation of methyl orange under visible-light irradiation (lambda>420 nm). A possible photodegradation mechanism in the presence of AgBr-Ag-BiOBr composites was proposed, and the radical species involved in the degradation reaction were investigated. HO2(?)/(?)O2(-) played the same important role as (?)OH in the AgBr-Ag-BiOBr photocatalytic system, and both the electron and hole were fully used for degradation of organic pollutants. A dual role of metallic Ag in the photocatalysis was proposed, one being surface plasmon resonance and the other being an electron-hole bridge. Due to the distinctive p-metal-n structure, the visible-light absorption, the separation of photogenerated carriers and the photocatalysis efficiency were greatly enhanced. PMID- 25556557 TI - Evaluating the validity of the Braden scale using longitudinal electronic medical records. AB - In this study, we evaluated the validity of the Braden scale in assessing the risk of pressure ulcers. Longitudinal clinical data including weekly Braden scale scores for 1,138 patients admitted to a university hospital who developed pressure ulcers during the hospital stay and 4,794 who did not develop pressure ulcers were extracted from the hospital's electronic medical record system. Braden scale scores at three points during hospitalization were analyzed: the initial score at admission, the last score recorded before diagnosis (for pressure ulcer patients) or before discharge (for those without pressure ulcers), and the minimum (highest-risk) score recorded. Using these data, the predictive validity of the scale was evaluated using a cut-off score of 18, followed by an evaluation of the relative advantages and disadvantages of cut-off scores from 12 to 19. Among patients in the general units, the minimum score had the greatest sensitivity (0.85), negative predictive value (NPV; 0.98), and Youden index (0.73). Among patients in the intensive care units, the last score had the best NPV (0.65), Youden index (0.53), and area under the receiver operating characteristic curve (0.78), while the minimum score had the highest sensitivity (0.88). The optimal cut-off score for patients in the general units was 19 and for those in the intensive care units was 18. These results support a higher cut off score than previously recommended, particularly for severely ill patients who are more prone to developing pressure ulcers. PMID- 25556559 TI - Effect of Age at Diagnosis on Chronic Quality of Life and Long-Term Outcomes of Individuals with Psoriasis. AB - Psoriasis is a skin disorder that frequently begins in the pediatric and young adult population but imposes physical and psychosocial burdens over a lifetime. The objective of this retrospective cohort study was to evaluate the effect of age at diagnosis on the lifetime outcomes of psoriasis patients. Individuals with psoriasis (N = 114) completed a questionnaire regarding disabilities, relationships, education, finances, and medical outcomes. Responses were compared among quartiles of age at diagnosis and regression analyses were performed. Those diagnosed at a younger age were more likely to have a greater lifetime Dermatology Life Quality Index (LT DLQI) (p < 0.001), have felt depressed (p = 0.003), believe that psoriasis had caused their depression (p < 0.001), experience lifetime sleep problems (p = 0.004), use recreational drugs (p < 0.001), hide their psoriasis over their lifetime (p < 0.001), and experience more severe lifetime discrimination in social settings (p = 0.002). Early onset psoriasis is associated with depression, social discrimination, and greater LT DLQI. PMID- 25556560 TI - Population pharmacokinetics of pomalidomide. AB - A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed based on data from 6 clinical trials of pomalidomide (dose range, 0.5-10 mg) in healthy participants (n = 96) and patients with multiple myeloma (MM; n = 144). PPK data described herein suggest that systemic clearance of pomalidomide is comparable between healthy study participants and patients with MM. However, apparent peripheral volume of distribution and apparent intercompartmental clearance between central and peripheral compartments were 8- and 3.7-fold higher in patients with MM vs. healthy subjects, suggesting drug exposure is higher in peripheral compartments of patients with MM vs. healthy subjects. Covariate analysis suggested pomalidomide clearance is not affected by demographic factors except for gender, and it is unlikely this factor is clinically relevant. In addition, renal function as measured by creatinine clearance or renal impairment (RI) does not significantly affect clearance of pomalidomide. In conclusion, pomalidomide has robust pharmacokinetic exposure, not affected by demographic factors or renal impairment. Pomalidomide is preferentially taken up by tumors over healthy tissues in patients with MM. PMID- 25556561 TI - Opalescence in monoclonal antibody solutions and its correlation with intermolecular interactions in dilute and concentrated solutions. AB - Opalescence indicates physical instability of a formulation because of the presence of aggregates or liquid-liquid phase separation in solution and has been reported for monoclonal antibody (mAb) formulations. Increased solution opalescence can be attributed to attractive protein-protein interactions (PPIs). Techniques including light scattering, AUC, or membrane osmometry are routinely employed to measure PPIs in dilute solutions, whereas opalescence is seen at relatively higher concentrations, where both long- and short-range forces contribute to overall PPIs. The mAb molecule studied here shows a unique property of high opalescence because of liquid-liquid phase separation. In this study, opalescence measurements are correlated to PPIs measured in diluted and concentrated solutions using light scattering (kD ) and high-frequency rheology (G'), respectively. Charges on the molecules were calculated using zeta potential measurements. Results indicate that high opalescence and phase separation are a result of the attractive interactions in solution; however, the presence of attractive interactions do not always imply phase separation. Temperature dependence of opalescence suggests that thermodynamic contribution to opalescence is significant and Tcloud can be utilized as a potential tool to assess attractive interactions in solution. PMID- 25556562 TI - Delirium symptoms during hospitalization predict long-term mortality in patients with severe pneumonia. AB - INTRODUCTION: Delirium is common in critically ill patients and impact in hospital mortality in patients with pneumonia. The aim of the study was to evaluate the prevalence of delirium symptoms during hospitalization in patients with severe pneumonia and their impact on one-year mortality. METHODS: This was an observational, retrospective, cohort study of consecutive patients admitted to the respiratory high dependency unit of the San Gerardo University Hospital, Monza, Italy, between January 2009 and December 2012 with a diagnosis of severe pneumonia. A search through the charts looking for ten key words associated with delirium (confusion, disorientation, altered mental status, delirium, agitation, inappropriate behavior, mental status change, inattention, hallucination, lethargy) was performed by a multidisciplinary team. The primary endpoint was mortality at one-year follow-up. Secondary endpoint was in-hospital mortality. RESULTS: A total of 172 patients were enrolled (78 % males; median age 75 years). At least one delirium symptom was detected in 53 patients (31 %) during hospitalization. The prevalence of delirium symptoms was higher among those who died during hospitalization vs. those who survived (44 vs. 27 %, p = 0.049, respectively). Seventy-one patients (46 %) died during the one-year follow-up. The prevalence of at least one delirium symptom was higher among those who died than those who survived during the one-year follow-up (39 vs. 21 %, p = 0.014, respectively). At the multivariable logistic regression analysis, after adjustment for age, comorbidities and severe sepsis, the presence of at least one delirium symptom during hospitalization was an independent predictor of one-year mortality (OR 2.35; 95 % CI 1.13-4.90; p = 0.023). CONCLUSIONS: Delirium symptoms are independent predictors of one-year mortality in hospitalized patients with severe pneumonia. Further studies should confirm our results using prospective methods of collecting data. PMID- 25556564 TI - Proceedings of the Eleventh International Society of Sports Nutrition (ISSN) Conference and Expo. PMID- 25556563 TI - Metastatic calcification of floor of the mouth secondary to chronic renal failure report of a rare case with atypical presentation. AB - Soft-tissue calcification is always pathological. Metastatic calcification is calcification of soft tissues owing to hyperphosphataemia with or without hypercalcaemia. Metastatic calcification of oral cavity is extremely rare. A case report of metastatic calcification of the floor of the mouth with atypical radiologic and clinical picture is presented here along with a review of earlier reports. A chance finding of the granular oral mucosa on palpation led to a radiographic examination revealing granular calcifications of the floor of the mouth. Blood chemistry and hormone analysis revealed chronic renal failure and hyperparathyroidism. A diagnosis of metastatic calcification secondary to renal failure was made and the treatment was aimed at correcting the renal failure without any intervention for the asymptomatic calcifications. Key differences between the present case and other cases reported in the literature are outlined. PMID- 25556565 TI - Controlled release of C-type natriuretic peptide by microencapsulation dampens proinflammatory effects induced by IL-1beta in cartilage explants. AB - C-type natriuretic peptide (CNP) exhibits potent anti-inflammatory effects in chondrocytes that have the potential to repair cartilage damage observed in osteoarthritis (OA). However, treatments for OA have been challenging due to poor targeting and delivery of therapeutics. The present study fabricated polyelectrolyte microcapsules loaded with CNP and examined whether the layer-by layer (LbL) approach could have protective effects in cartilage explants treated with the pro-inflammatory cytokine, interleukin-1beta (IL-1beta). SEM showed uniform, 2 to 3 MUm spherical microcapsules with morphological characteristic similar to templates loaded with or without CNP. The protein was localized around the external surface of the microcapsules with encapsulation efficiencies >82.9%. CNP release profiles were broadly similar following 9 days of culture. The presence of CNP microcapsules did not significantly affect cell viability (80%) with DNA values that remained stable throughout the culture conditions. Confocal imaging showed clustering of microcapsules in chondrocytes to natriuretic peptide receptor (Npr) 2 and 3. Treatment of cartilage explants with CNP microcapsules led to concentration-dependent inhibition of NO release in response to IL-1beta and restoration of matrix synthesis. In summary, we demonstrate controlled delivery of CNP to dampen pro-inflammatory effects induced by IL-1beta in cartilage explants. The LbL approach has the potential to promote cartilage repair in vivo. PMID- 25556566 TI - Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. AB - Direct cell reprogramming enables direct conversion of fibroblasts into functional neurons and oligodendrocytes using a minimal set of cell-lineage specific transcription factors. This approach is rapid and simple, generating the cell types of interest in one step. However, it remains unknown whether this technology can be applied to convert fibroblasts into astrocytes, the third neural lineage. Astrocytes play crucial roles in neuronal homeostasis, and their dysfunctions contribute to the origin and progression of multiple human diseases. Herein, we carried out a screening using several transcription factors involved in defining the astroglial cell fate and identified NFIA, NFIB, and SOX9 to be sufficient to convert with high efficiency embryonic and postnatal mouse fibroblasts into astrocytes (iAstrocytes). We proved both by gene-expression profiling and functional tests that iAstrocytes are comparable to native brain astrocytes. This protocol can be then employed to generate functional iAstrocytes for a wide range of experimental applications. PMID- 25556567 TI - Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia. AB - To understand how haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSCs) from patients carrying the GRN(IVS1+5G > C) mutation (FTD-iPSCs). FTD-iPSCs were fated to cortical neurons, the cells most affected in FTD. Although generation of neuroprogenitors was unaffected, their further differentiation into CTIP2-, FOXP2 , or TBR1-TUJ1 double-positive cortical neurons, but not motorneurons, was significantly decreased in FTD-neural progeny. Zinc finger nuclease-mediated introduction of GRN cDNA into the AAVS1 locus corrected defects in cortical neurogenesis, demonstrating that PGRN haploinsufficiency causes inefficient cortical neuron generation. RNA sequencing analysis confirmed reversal of the altered gene expression profile following genetic correction. We identified the Wnt signaling pathway as one of the top defective pathways in FTD-iPSC-derived neurons, which was reversed following genetic correction. Differentiation of FTD iPSCs in the presence of a WNT inhibitor mitigated defective corticogenesis. Therefore, we demonstrate that PGRN haploinsufficiency hampers corticogenesis in vitro. PMID- 25556568 TI - Successful reprogramming of epiblast stem cells by blocking nuclear localization of beta-catenin. AB - Epiblast stem cells (EpiSCs) in mice and rats are primed pluripotent stem cells (PSCs). They barely contribute to chimeric embryos when injected into blastocysts. Reprogramming of EpiSCs to embryonic stem cell (ESC)-like cells (rESCs) may occur in response to LIF-STAT3 signaling; however, low reprogramming efficiency hampers potential use of rESCs in generating chimeras. Here, we describe dramatic improvement of conversion efficiency from primed to naive-like PSCs through upregulation of E-cadherin in the presence of the cytokine LIF. Analysis revealed that blocking nuclear localization of beta-CATENIN with small molecule inhibitors significantly enhances reprogramming efficiency of mouse EpiSCs. Although activation of Wnt/beta-catenin signals has been thought desirable for maintenance of naive PSCs, this study provides the evidence that inhibition of nuclear translocation of beta-CATENIN enhances conversion of mouse EpiSCs to naive-like PSCs (rESCs). This affords better understanding of gene regulatory circuits underlying pluripotency and reprogramming of PSCs. PMID- 25556569 TI - Prevalence of symptoms of depression and anxiety in adults with cystic fibrosis based on the PHQ-9 and GAD-7 screening questionnaires. AB - OBJECTIVE: To examine the prevalence of symptoms of depression and anxiety among patients with cystic fibrosis (CF) who were followed up at the University of Washington Adult CF clinic and to identify sociodemographic and clinical factors associated with symptoms. METHODS: A total of 178 adults with CF were asked to complete the Patient Health Questionnaire-9 for depression and General Anxiety Disorder-7 for anxiety when clinically stable. Clinically significant symptoms of depression and anxiety were defined in the following 2 ways: (1) symptom definition-presence of moderate-to-severe symptoms based on the questionnaires and (2) composite definition-symptom definition or the use of psychiatric medications to manage symptoms. Associations between Patient Health Questionnaire 9 and General Anxiety Disorder-7 scores with sociodemographic (gender, age, age of CF diagnosis, vocation, and spousal status) and clinical factors (forced expiratory volume in 1 second, body mass index, and CF-related diabetes on insulin) were examined. RESULTS: Of 178 patients, 153 (85%) completed the screening questionnaires. Based on the symptom definition, 7% of patients had symptoms of depression and 5% had symptoms of anxiety. Using the composite definition, 22% of patients had symptoms of depression and 10% had symptoms of anxiety. Based on the Patient Health Questionnaire-9, 5% of patients reported suicidal thoughts. In multiple linear regression analysis, only forced expiratory volume in 1 second % predicted was independently associated with Patient Health Questionnaire-9 depression scores, and no sociodemographic or clinical factors were associated with General Anxiety Disorder-7 anxiety scores. CONCLUSIONS: We conclude that all adults with CF should be screened for symptoms of depression and anxiety given the difficulty in identifying strong clinical risk factors and the unexpected high rates of suicidal ideation. PMID- 25556570 TI - Ready, set, relax: biofeedback-assisted relaxation training (BART) in a pediatric psychiatry consultation service. AB - BACKGROUND: Biofeedback-assisted relaxation training (BART) can treat several common pediatric presentations, including chronic pain and anxiety. Its effectiveness, applicability to a variety of conditions, and equipment portability make it an ideal treatment approach for use in an inpatient pediatric consultation-liaison service. OBJECTIVE: Since there is a paucity of published research on the utility of BART in this setting, we studied pediatric patients (>=8y), medically-admitted to Boston Children's Hospital, and referred to the Psychiatry Consultation Service for assistance in managing pain, anxiety or both. METHODS: The patients received at least 1 session of BART. In addition to heart rate variability and skin temperature data collection, participants completed the Wong-Baker FACES Pain Rating Scale and a brief mood/affective state rating scale (Youth Feelings Scale) before and after the BART sessions. RESULTS: A total of 152 sessions were conducted with 66 patients across 11 referring services. BART was successfully used 61% of the time on the medical floor with common barriers involving patient unavailability or refusal. The patients completed an average of 1.57 sessions per admission. The post-BART session pain and mood ratings significantly improved over the presession ratings. Patients with both pain and anxiety reported the greatest changes across sessions in comparison with those with only pain or anxiety. Higher heart rate variability was observed in the "pain-only" group. CONCLUSIONS: The use of BART in a consultation-liaison setting demonstrates promising utility in working with patients with pain, anxiety, or a combination of symptoms. BART was well-received by patients with subjective reports of benefit across sessions. PMID- 25556572 TI - Ping-pong gaze in a patient with bilateral hemispheric ischemic stroke: case report and video. AB - Ping-pong gaze (PPG) is a rare eye movement abnormality consisting of conjugate smooth rhythmical horizontal eye deviations between the 2 extreme positions. PPG is encountered in cases of severe bilateral hemispheric or posterior fossa brain damage with intact brain stem and more rarely during drug toxicity. In this brief video case report, we present a 91-year-old woman with PPG after sustaining bilateral hemispheric ischemic stroke. We also present the neuroanatomic substrates of PPG along with its main saccadic variant, and we coin the hypothesis that PPG actually represents the paralysis of eye saccades. PMID- 25556571 TI - The association of co-morbid symptoms of depression and anxiety with all-cause mortality and cardiac rehospitalization in patients with heart failure. AB - BACKGROUND: Patients with heart failure (HF) experience multiple psychologic symptoms. Depression and anxiety are independently associated with survival. Whether co-morbid symptoms of anxiety and depression are associated with outcomes in patients with HF is unknown. OBJECTIVE: To determine whether co-morbid symptoms of depression and anxiety are associated with all-cause mortality or rehospitalization for cardiac causes in patients with HF. METHOD: A total of 1260 patients with HF participated in this study. Cox regression analysis was used to determine whether co-morbid symptoms of depression and anxiety independently predicted all-cause mortality and cardiac rehospitalization. Anxiety and depression were treated first as continuous-level variables, then as categorical variables using standard published cut points. Patients were then divided into 4 groups based on the presence of anxiety and depression symptoms. RESULTS: When entered as a continuous variable, the interaction between anxiety and depression (hazard ratio = 1.02; 95% CI: 1.01-1.03; p = 0.002) was a significant predictor of all-cause mortality in patients with HF. When entered as a categorical variable, co-morbid symptoms of depression and anxiety (vs no symptoms or symptoms of anxiety or depression alone) independently predicted all-cause mortality (hazard ratio = 2.59; 95% CI: 1.49-4.49; p = 0.001). None of the psychologic variables was a predictor of cardiac rehospitalization in patients with HF whether using the continuous or categorical level of measurement. CONCLUSION: To improve mortality outcomes in patients with HF, attention must be paid by health care providers to the assessment and management of co-morbid symptoms of depression and anxiety. PMID- 25556573 TI - National Institutes of Health Stroke Scale (NIHSS) as An Early Predictor of Poststroke Dysphagia. AB - BACKGROUND: Despite the availability of multiple comprehensive screening methods to detect dysphagia during acute stroke care, consensus is lacking as to the best practice. Our previous study demonstrated favorable sensitivity of the Functional Independence Measure (FIM) compared with a bedside 3-sip test. However, the FIM is challenging to administer during acute stroke care. The National Institutes of Health Stroke Scale (NIHSS) is administered routinely in the emergency department. OBJECTIVE: To evaluate the utility of the NIHSS as a predictor of clinically relevant poststroke dysphagia compared with FIM data in the same cohort. DESIGN: Retrospective analysis. SETTING: Academic medical center. PATIENTS: Individuals with acute stroke who were admitted for acute care and later transferred to acute rehabilitation within the same institution. METHODS: Clinically relevant dysphagia was defined as aspiration on modified barium swallow or laryngeal penetration on modified barium swallow requiring diet change, or aspiration pneumonia. NIHSS and FIM scores were compiled for all patients. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for NIHSS and FIM. Sensitivity and specificity of different values of NIHSS and FIM were analyzed via receiver operator characteristic curves. RESULTS: Of 290 patients admitted to acute stroke rehabilitation, 88 (30%) manifested clinically relevant dysphagia during their rehabilitation stay. Sensitivity analyses suggested cut off values for the NIHSS and the FIM of >9 and <55, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for the NIHSS were 75%, 62%, 46%, and 85%, respectively. For the FIM, these parameters were 80%, 72%, 55%, and 92%, respectively. CONCLUSIONS: The NIHSS >9 and FIM <55 are moderately predictive of clinically relevant dysphagia. Although the NIHSS clinical test characteristics are not as favorable as the FIM, NIHSS appears to be more sensitive than some other reported methods such as a 3-sip water test. Further study into development of paradigms that incorporate NIHSS into initial assessment of dysphagia risk may be appropriate. PMID- 25556574 TI - Hematologic effects and complications of snake envenoming. AB - Hematologic abnormalities are the most common effects of snake envenoming globally. Venom-induced consumption coagulopathy (VICC) is the commonest and most important. Other hematologic abnormalities are an anticoagulant coagulopathy and thrombotic microangiopathy. Venom-induced consumption coagulopathy is a venom induced activation of the clotting pathway by procoagulant toxins, resulting in clotting factor consumption and coagulopathy. The type of procoagulant toxin differs between snakes and can activate prothrombin, factor X, and factor V or consume fibrinogen. The most useful investigation in VICC is a prothrombin time/international normalized ratio. The d-dimer may assist in early diagnosis, but fibrinogen levels often add little in the clinical setting. Bedside investigations would be ideal, but point-of-care testing international normalized ratio and whole blood clotting tests have been shown to be unreliable in VICC. The major complication of VICC is hemorrhage, including intracranial hemorrhage which is often fatal. The role of antivenom in VICC is controversial and may only be beneficial for some types of snakes including Echis spp where the duration of abnormal clotting is reduced from more than a week to 24 to 48 hours. In contrast, antivenom does not appear to speed the recovery of VICC in Australian snake envenoming. Other treatments for VICC include factor replacement, observation and prevention of trauma, and heparin. An Australian study showed that fresh-frozen plasma speeds recovery of VICC, but early use may increase consumption. There is no evidence to support heparin. PMID- 25556575 TI - Red blood cell Thomsen-Friedenreich antigen expression and galectin-3 plasma concentrations in Streptococcus pneumoniae-associated hemolytic uremic syndrome and hemolytic anemia. AB - BACKGROUND: Pneumococcal hemolytic uremic syndrome (P-HUS) is a rare but severe complication of invasive pneumococcal disease (IPD) in young children. Consensual biologic diagnosis criteria are currently lacking. STUDY DESIGN AND METHODS: A prospective study was conducted on 10 children with culture-confirmed IPD. Five presented with full-blown P-HUS, three had an incomplete form with hemolytic anemia and mild or no uremia (P-HA), and two had neither HUS nor HA. Thomsen Friedenreich (T), Th, and Tk cryptantigens and sialic acid expression were determined on red blood cells (RBCs) with peanut (PNA), Glycine soja (SBA), Bandeiraea simplicifolia II, and Maackia amurensis lectins. Plasma concentrations of the major endogenous T-antigen-binding protein, galectin-3 (Gal-3), were analyzed. RESULTS: We found that RBCs strongly reacted with PNA and SBA lectins in all P-HUS and P-HA patients. Three P-HUS and three P-HA patients showed also concomitant Tk activation. Direct antiglobulin test (DAT) was positive in three P HUS (one with anti-C3d and two with anti-IgG) and two P-HA patients (one with anti-C3d and one with anti-IgG). RBCs derived from the two uncomplicated IPD patients reacted with PNA but not with SBA lectin. Gal-3 plasma concentrations were increased in all P-HUS patients. CONCLUSIONS: The results indicate high levels of neuraminidase activity and desialylation in both P-HUS and P-HA patients. T-antigen activation is more sensitive than DAT for P-HUS diagnosis. Combining PNA and SBA lectins is needed to improve the specificity of T-antigen activation. High concentrations of Gal-3 in P-HUS patients suggest that Gal-3 may contribute to the pathogenesis of P-HUS. PMID- 25556576 TI - Adaptive functioning in pediatric epilepsy: contributions of seizure-related variables and parental anxiety. AB - Young people with epilepsy are less likely to achieve the level of independence attained by their peers. We examined the seizure-related variables that placed a group of 97 pediatric patients with intractable seizures at risk for poor adaptive functioning. Analyses evaluated both the direct effects of the medical variables and indirect effects that were mediated through increased parental anxiety about their child's epilepsy. Higher numbers of anticonvulsants, presence of seizures that secondarily generalize, longer duration of seizure disorder, and younger age at onset were all identified as risk factors for poor adaptive functioning. Depending on the specific behavioral domain of adaptive functioning, the effects were sometimes direct and sometimes indirect. Lower levels of parental education and positive family history of seizures were associated with higher levels of parental anxiety. Interventions that target parental anxiety about seizures may mitigate the deleterious effects of epilepsy on social development. PMID- 25556577 TI - Letter by Bassareo regarding the article of Fouzas et al. "Heterogeneity of ventricular repolarization in newborns with intrauterine growth restriction". PMID- 25556578 TI - Associations between developmental trajectories of movement variety and visual attention in fullterm and preterm infants during the first six months postterm. AB - BACKGROUND: During early infancy major developmental changes, both in the variety of body movements and in visual attention, help the infant to explore its surroundings. Both behaviours depend on a gradual shift from subcortical to cortical functioning. AIMS: First, to determine whether preterms reach mature levels of movement variety (the number of different movement patterns) and visual attention earlier than fullterms. Second, to determine whether individual developmental trajectories of movement variety and visual attention were associated. Finally, we compared the associations of developmental trajectories between fullterm and preterm infants. STUDY DESIGN: In this longitudinal study, 20 fullterm and 9 low-risk preterm infants performed a visual disengagement task every four weeks from six weeks until six months postterm. For each infant we drew up developmental trajectories for movement variety, and for frequencies and latencies of looks. We analyzed the developmental trajectories by means of general linear model (GLM) repeated measures and Monte Carlo analyses. RESULTS: In comparison to fullterms, preterm infants showed a similar increase in movement variety over time (F(4,108)=0.27; partial eta(2)=0.01; P=.90). Visual attention reached mature levels four weeks earlier than movement variety. This effect was stronger in fullterm infants. Neither in fullterm nor in preterm infants did we find an association between the developmental trajectories of movement variety and visual attention. P values ranged from .37 to .99. CONCLUSIONS: During the first 6 months postterm, movement variety and visual attention developed independently. Temporarily, preterm exposure to the extrauterine environment led to shorter latencies of looks but it did not affect developmental trajectories of frequencies of looks and movement variety. PMID- 25556579 TI - Radiofrequency ablation versus partial nephrectomy for clinical T1a renal-cell carcinoma: long-term clinical and oncologic outcomes based on a propensity score analysis. AB - PURPOSE: To compare outcomes in patients treated with radiofrequency ablation (RFA) and partial nephrectomy (PN) for clinical T1a renal-cell carcinoma (RCC) in a propensity-score matched cohort. METHODS: We conducted a retrospective review of the records of all patients who underwent RFA or nephrectomy between February 2005 and December 2009 in our institution. The Kaplan-Meier method was used to generate the survival curves that were compared with the log-rank test. Univariable and multivariable regression analyses were performed to determine predictors of survival. RESULTS: A total of 90 patients were included in the final study after being matched by propensity scores (RFA 45; PN 45). The 5-year overall survival (95% confidence interval [CI]) was 90.2% (78.6-98.8) vs 93.2% (85.8-98.9); 5-year cancer-specific survival (95% CI) was 95.6% (89.5-98.1) vs 97.7% (93.4-99.3); 5-year disease-free survival (95% CI) was 86.7% (89.5-96.7) and 88.5% (79.1-97.9); 5-year recurrence-free survival (95% CI) was 95.4% (89.3 98.1) vs 97.7% (93.3-99.2); and 5-year metastasis-free survival (95% CI) was 95.5% (89.4-98.0) vs 95.5% (89.4-98.0). Age was the only factor that could predict the disease-free survival (P=0.044). The percentage decrease in the glomerular filtration rate was significantly lower in the RFA group at the time of last follow-up (P=0.001). CONCLUSIONS: In the propensity-score matched cohort of patients with clinical T1a RCC, we observed that RFA was an effective treatment option that provided comparable 5-year oncologic outcomes and better preservation of renal function than PN. PMID- 25556581 TI - Passive samplers and community science in regional air quality measurement, education and communication. AB - Charlotte, in Mecklenburg County, North Carolina, was ranked in the top ten cities with the worst air quality for ozone in the United States by the American Lung Association from 2009 to 2011. Nearby counties that may experience similar air quality do not have state or county monitors. This study utilized NOx and ozone Ogawa passive samplers and community scientists to monitor air quality in five counties surrounding Charlotte and increase public engagement in air quality issues. Community scientists deployed samplers weekly at a residential site within each county. Samples were analyzed using spectrophotometry and ion chromatography. Elevated NOx concentrations were observed in four of the five counties relative to those with existing monitors. Ozone concentrations showed little county to county variation, except Iredell and Cabarrus which had higher concentrations than Rowan. Community involvement in this work led to an increase in local dissemination of the results, thus increasing air quality awareness. PMID- 25556580 TI - Prophylaxis of acute graft-versus-host disease by CCR5 blockade combined with cyclosporine A in a murine model. AB - OBJECTIVE: One characteristic feature of graft-versus-host disease (GVHD) is lymphocytes' trafficking and recruitment to target tissues, and CCR5 plays a key role in the process. Thus, blockade of lymphocytes' chemotaxis may attenuate GVHD. METHODS: We tested the effects of CCR5 blockade using an established murine model. The mean survival time, body weight change, and clinical GVHD scores were assessed. Concentrations of cytokines and chemokines, the CCR5, CXCR3, and CCR7 expressions on T lymphocytes, and histological changes of visceral organs were also evaluated. Additionally, we assessed the immunophenotype of infiltration cells in liver and intestine. RESULTS: Mice undergoing total body irradiation and allogenic hematopoietic stem cell transplantation (allo-HSCT) developed typical GVHD. MVC increased CCR5 expression whereas CCR7 and CXCR3 expression were unaffected. MVC also increased plasma levels of the ligands of CCR5. A combination of MVC with CsA significantly alleviated the degree of visceral injuries and prolonged survival time. CONCLUSION: MVC has a synergistic effect with CsA. It can attenuate the severity of GVHD and increase survival rate of mice in our murine model. This may offer a novel therapeutic perspective for clinical GVHD after allo-HSCT. PMID- 25556582 TI - Inducible nitric oxide synthase promoter polymorphism: a molecular susceptibility marker for vitiligo in Egyptians. AB - BACKGROUND: Vitiligo is a depigmentary disease characterized by loss of melanocytes from the skin and mucous membranes. The pathomechanism of vitiligo is still obscure. Inducible nitric oxide synthase (iNOS) produces very large amounts of nitric oxide (NO). Promotor polymorphisms within iNOS gene have been reported to be associated with overproduction of NO, which may induce melanocyte destruction. AIM: The current study aimed at investigating the possible association between iNOS gene polymorphism (-954 G/C and Ex 16+14 C/T) and susceptibility to non-segmental vitiligo in a cohort of Egyptians. METHODS: The study was conducted on 200 participants: 100 patients with vitiligo and 100 aged matched healthy controls. Polymerase chain reaction using restriction fragment length polymorphism method (PCR-RFLP) was used to identify the genotypes. RESULTS: Our results showed that iNOS -954 G/C heteromutant genotype (GC) was associated with increased risk of vitiligo (OR = 3.35, 95% CI = 1.77-6.33), and the risk increased when confined to females (OR = 7.4, 95% CI = 2.80-19.40). iNOS Ex 16 + 14 C/T heteromutant genotype (CT) conferred two folds increased risk of vitiligo (OR = 2.47, 95% CI = 1.39-4.37). Furthermore, the risk of vitiligo increased when the heteromutant genotype of iNOS -954 G/C (GC) was co-inherited with the wild genotype of iNOS Ex16+14 C/T (CC) (OR = 23.2, 95% CI = 3.04 177.21). CONCLUSIONS: Inducible nitric oxide synthase -954 G/C and Ex 16+14 C/T might be considered as genetic susceptibility markers for non-segmental vitiligo among Egyptians. PMID- 25556584 TI - How does the serrated polyp pathway alter CRC screening and surveillance? AB - Screening and surveillance for colorectal cancer (CRC) reduces mortality through the detection of early-stage adenocarcinoma, and more importantly the detection and removal of premalignant polyps. While adenomas have historically been considered the most common and screening-relevant precursor lesions, there is accumulating evidence showing that the serrated pathway is an important contributor to CRC, and a disproportionate contributor to interval or postcolonoscopy CRC, particularly in the proximal colon. The serrated pathway is characterized by mutations in the BRAF gene, high levels of methylation of promoter CpG islands (CIMP-high), and the sessile serrated adenoma/polyp (SSA/P) is the most important precursor lesion. The study of serrated polyps has been complicated by evolving nomenclature, substantial variation among pathologists in the identification of SSA/Ps, high variability in endoscopic detection rates, and uncertainty regarding the relation to synchronous and metachronous colonic neoplasia. This paper presents an overview of the serrated polyp pathway and discusses its clinical implications including its impact on CRC screening. PMID- 25556583 TI - Cancer chemoprevention: Much has been done, but there is still much to do. State of the art and possible new approaches. AB - Over the past three decades great efforts have been made in search of cancer chemoprevention strategies. The increase in knowledge of the long process from normal to cancer cell has enabled interventions in terms of lifestyle modifications, natural compounds or drugs to block or reverse the process. Great successes have been achieved, especially for breast and colorectal cancer. However, these strategies have yet to find clinical application on a large scale. In this article we identify the achievements, the pitfalls and the next steps to be taken to improve the efficacy and applicability of chemoprevention strategies. Among the crucial key points to be implemented are educational activities for physicians to appropriately disseminate the aim and indeed the culture of chemoprevention. It is essential to improve the risk-benefit balance, seeking the minimal active doses, intermittent schedules, a better characterization of the risk categories via a more personalized intervention based on individual characteristics, and ensure the containment of costs of public and private health prevention programs. PMID- 25556585 TI - Complementary and Alternative Medicine Use Is Prevalent Among Patients with Gastrointestinal Diseases. AB - INTRODUCTION: Complementary and alternative medicine (CAM) use is reported to be higher among patients with irritable bowel syndrome and inflammatory bowel disease; however, demographic predictors and reasons for utilization for all GI conditions are less clear. AIM: To determine prevalence, predictors, and reasons for CAM use among all patients attending a gastrointestinal (GI) clinic in a single academic center. METHODS: Adults attending outpatient GI clinics at Beth Israel Deaconess Medical Center completed a questionnaire to assess CAM utilization as well as perceived benefits, harms, and costs of CAM therapy. Fisher's exact test was used to compare statistical differences between CAM and non-CAM users. RESULTS: Survey questionnaires were completed by 269 patients. Prevalence of CAM use was 44 % (95 % CI 38-50). Users were more likely to be female (81 vs. 56 %, p < 0.01) and dissatisfied with conventional treatment (22 vs. 8 %, p < 0.01). There was no significant difference in age, race, education, income, GI diagnosis, and duration of symptoms between the two groups. Users reported "wish to feel generally better" as main reason for utilization, and a majority of patients (62 %) experienced improved GI symptoms. Among patients who did not discuss CAM with their physicians (30 %), they cited physician failure to ask about CAM as the major reason (82 %). CONCLUSION: CAM is prevalent among patients attending a GI clinic, particularly among women and those who are dissatisfied with conventional therapies and "wish to feel better." Greater awareness and understanding of CAM among GI physicians is necessary. PMID- 25556586 TI - Re: Editorial 'Keep your hands on the chest'. PMID- 25556587 TI - Reply to letter: "re: editorial 'keep your hands on the chest"'. PMID- 25556588 TI - Confirmation of the depth of the endotracheal tube: where should the cuff be? PMID- 25556589 TI - Inaccurate treatment decisions of automated external defibrillators used by emergency medical services personnel: incidence, cause and impact on outcome. AB - BACKGROUND: The rhythm analysis algorithm (RAA) of automated external defibrillators (AEDs) may be deceived by many factors. In this observational study we assessed RAA accuracy in prehospital interventions. For every rhythm analysis judged to be inaccurate, we looked for causal factors and estimated the impact on outcome. METHODS: In 135 consecutive patients, two physicians reviewed 837 rhythm analyses independently. When they disagreed, a third physician made the final decision. RESULTS: Among 148 shockable episodes, 23 (16%) were not recognized by the RAA due to external artifacts (n=7), fine ventricular fibrillation (VF; n=7), RAA error without external artifacts (n=4) or a combination of factors (n=5). In six cases the omitted/delayed shock was judged to be of clinical relevance: survival with some neurological deficit (n=4), death without regaining consciousness (n=1) and no restoration of spontaneous circulation (n=1). In 689 non-shockable episodes, the RAA decided "shockable" 25 times (4%). This wrongful decision was due to external artifacts (n=9), a concurrent shock of an internal cardioverter defibrillator (n=1), RAA error without external artifacts (n=13) or a combination of factors (n=2). Fifteen spurious shocks were delivered. As these non-shockable rhythms did not deteriorate after the shock, we assumed that no significant harm was done. CONCLUSIONS: Up to 16% of shockable rhythms were not detected and 4% of non shockable rhythms were interpreted as shockable. Therefore, all AED interventions should be reviewed. Feedback to caregivers may avoid future deleterious interactions with the AED, whereas AED manufacturers may use this information to improve RAA accuracy. This approach may improve the outcome of some VF patients. PMID- 25556591 TI - The diverse nematicidal properties and biocontrol efficacy of Bacillus thuringiensis Cry6A against the root-knot nematode Meloidogyne hapla. AB - Cry6A toxin from Bacillus thuringiensis is a representative nematicidal crystal protein with a variety of nematicidal properties to free-living nematode Caenorhabditis elegans. Cry6A shares very low homology and different structure with Cry5B, another representative nematicidal crystal protein, and probably acts in a distinct pathway. All these strongly indicate that Cry6A toxin is likely a potent candidate for nematicide. The present study dealt with global investigation to determine the detrimental impacts of Cry6Aa2 toxin on Meloidogyne hapla, a root-knot nematode, and evaluated its biocontrol efficacy in pot experiment. Obtained results indicated that Cry6Aa2 toxin exhibits obvious toxicity to second-stage juvenile of M. hapla, and significantly inhibits egg hatch, motility, and penetration to host plant. Pot experiment suggested that soil drenching with spore-crystal mixture of Cry6Aa2 can clearly lighten the disease of root-knot nematode, including reduction of galling index and egg masses on host plant root, decreasing final population of nematode in soil. Moreover, application of Cry6Aa2 can obviously promote plant growth. These results demonstrated that Cry6Aa2 toxin is a promising nematicidal agent, and possesses great potential in plant-parasitic nematode management and construction of transgenic crop with constant resistance to nematode. PMID- 25556590 TI - Decreased expression of thymus-specific proteasome subunit beta5t in Down syndrome patients. AB - AIMS: The majority of patients with Down syndrome (DS), trisomy 21, have morphologically abnormal thymuses and present with intrinsic immunological abnormalities affecting mainly the cellular immune response. The aim of this study was to examine whether the expression of functionally important molecules is altered in thymic stromal cells in patients with DS. METHODS AND RESULTS: We analysed thymic tissues from patients with trisomy 13 (n = 4), trisomy 18 (n = 14) and trisomy 21 (n = 13) for histological alterations, and for the expression of functionally important molecules such as beta5t, a thymoproteasome subunit, and cathepsins L and S. In patients with trisomy 13 and trisomy 18, the thymus was morphologically normal or showed only mild depletion of cortical thymocytes. In contrast, the thymus showed variable histological changes in patients with trisomy 21; six of 13 cases showed severe depletion of thymocytes accompanied by the disappearance of thymic lobular architecture. In such thymuses, spindle shaped keratin-positive cells were densely distributed, and expression of beta5t, but not of cathepsin L, was markedly decreased. CONCLUSIONS: The present study suggests that abnormal thymic architecture and decreased expression of functionally important molecules in thymic stromal cells may be involved in immunological abnormalities in DS patients. PMID- 25556592 TI - Interventions to increase influenza vaccination rates in children with high-risk conditions--a systematic review. AB - BACKGROUND: Influenza is a common cause of morbidity and mortality, especially among the elderly and those with certain chronic diseases. Annual influenza vaccination is recommended for individuals in at-risk groups, but rates of vaccination are particularly low in children with high-risk conditions (HRCs). OBJECTIVE: To conduct a systematic review of studies that have examined interventions aimed at improving influenza vaccination in children with HRCs. METHODS: Two databases - PubMed and SCOPUS - were searched (with no time or language restrictions) using a combination of keywords - Influenza AND vaccination OR immunization OR children AND asthma OR malignancy OR high-risk AND reminder. Duplicates were removed, and abstracts of relevant articles were screened using specific inclusion/exclusion criteria. Thirteen articles were selected, and five additional studies were identified following a review of the reference lists of the initial thirteen articles, bringing the total number to eighteen. RESULTS: Most studies were conducted in the United States. Among the 18 studies, there was one systematic review of a specific intervention in asthmatic children, seven randomized controlled trials (RCTs), six before-and-after studies, one non-randomized controlled trial, one retrospective cohort study, one quasi-experimental post-test study, and one letter to editors. Interventions reported include multi-component strategies, letter reminders, telephone recall, letters plus telephone calls, an asthma education tool and year-round scheduling for influenza vaccination, amongst others. CONCLUSION: There is good evidence that reminder letters will improve influenza vaccination uptake in children with HRCs, but the evidence that telephone recall or a combination of letter reminder and telephone recall will improve uptake is weak. It is not known if multiple reminder letters are more effective than single letters or if multi-component strategies are more effective than single or dual component strategies. There is a need for further research of these interventions, possibly outside the United States. PMID- 25556594 TI - Response to letter from Dr Hoffmann. PMID- 25556593 TI - Prolonged bilateral reactive miosis as a symptom of severe insulin intoxication. AB - BACKGROUND: Miosis occurs following exposure to toxins that decrease the sympathomimetic tone, increase the cholinergic tone, or exert sedative-hypnotic effects, but has not been reported in insulin poisoning. CASE REPORT: A 64-year- old woman without co-morbidities was found unconscious next to an empty insulin pen. Her Glasgow Coma Scale was 3 with absent reflexes, bilateral reactive miosis, and injection marks across the abdominal wall. The patient was endotracheally intubated, mechanically ventilated, and transferred to this hospital. At admission, the blood glucose level was 34 mg/dL. Glasgow Coma Scale remained at 3, with persistent bilateral reactive miosis. The toxicology screening was negative for ethanol, barbiturates, tricyclic antidepressants, phenothiazines, amphetamines, cannabinoids, salicylates, acetaminophen, and cocaine. Cranial computed tomography with angiography and magnetic resonance imaging (MRI) did not show any structural brain lesions. Intravenous glucose was continued at 6-14 g/h for 3 days. On repeated neurological examinations, the patient remained deeply comatose, with partial loss of cranial nerve function. Bilateral reactive miosis persisted for 4 days. From day 5 on, the patient awoke progressively. At discharge, the patient was fully alert and orientated, without a focal neurological deficit. CONCLUSIONS: Prolonged bilateral reactive miosis can be a clinical symptom accompanying metabolic encephalopathy in severe insulin poisoning. Functional impairment of the pons due to relative hypoperfusion during hypoglycemia may serve as a reasonable pathophysiologic explanation for this phenomenon. PMID- 25556595 TI - Glutathione-coordinated [2Fe-2S] cluster: a viable physiological substrate for mitochondrial ABCB7 transport. AB - The glutathione-coordinated [2Fe-2S] cluster is demonstrated to be a viable and likely substrate for physiological iron-sulfur cluster transport by Atm1p, a mitochondrial ABC export protein. Flow cytometry and colorimetric assays demonstrate a quantitative methodology for study of metal translocation proteins and their proteoliposome products. PMID- 25556597 TI - Gastric cancer in young vs old Romanian patients: immunoprofile with emphasis on maspin and mena protein reactivity. AB - Increasing number of early-onset gastric carcinomas (GCs) and controversial results regarding the differences among young and older patients with this type of cancer are the reasons why correlation of clinicopathological factors with molecular markers is necessary. The aim of our study was to compare the demographic, clinical and immunohistochemical (IHC) aspects in Romanian patients with GC diagnosed below and above 45 years old. In 191 samples provided from patients with GC, the clinicopathological parameters were correlated with a panel of 15 antibodies: E-cadherin, HER-2, VEGF, CD31, CD105, COX-2, maspin, bax, bcl 2, p53, Ki67, MLH-1, MSH-2, mena protein and vimentin. Compared to the conventional cases, GCs diagnosed below 45 years old were more frequently located at the gastroesophageal junction and presented a higher percentage of lymph node metastases. The diffuse type E-cadherin/mena/p53/Ki67/bax-negative cases that displayed nuclear maspin positivity were also more frequently in younger patients. The intestinal type early-onset GCs were the most angiogenic ones, the apoptotic rate being lower than in the intestinal type GCs of the aged. Compared to the conventional cases, in the early-onset GCs the nuclear maspin-mediated antiproliferative activity is more intense in diffuse type while the mena dependent tumor cell proliferation is more characteristic for intestinal type GCs. PMID- 25556598 TI - A significant improvement in the electrocatalytic stability of N-doped graphene nanosheets used as a counter electrode for [Co(bpy)3](3+/2+) based porphyrin sensitized solar cells. AB - A significant improvement in efficiency is achieved for porphyrin (YD2-o-C8) based dye-sensitized solar cells, coupled with [Co(bpy)3](3+/2+) mediator electrolyte. However, the poison of the counter electrode (CE) by the [Co(bpy)3](3+/2+) mediator remains a significant barrier to producing a reliable high-performance device. In this paper, nitrogen-doped graphene nanosheets (NG) are produced using a low-cost solution-based process and are used as the CE for [Co(bpy)3](3+/2+) based porphyrin-sensitized solar cells. These produce significantly better electrocatalytic activity than the commonly used Pt CE. The superior performance is a result of the increased number of catalytic sites and the wettable surface that is caused by the substitution of pyridinic and pyrrolic N into the carbon-conjugated lattice. To the authors' best knowledge, the significantly improved cycling stability (>1000 times) of NG CE for [Co(bpy)3](3+/2+) redox complexes is demonstrated for the first time. PMID- 25556596 TI - NLRP1 L155H Polymorphism is a Risk Factor for Preeclampsia Development. AB - PROBLEM: Augmented levels of IL-1beta have been pointed out as an important pathogenic factor for preeclampsia development. Inflammasome is the cytoplasmic complex responsible for pro-IL1beta cleavage and IL-1beta secretion. Aim of the study was to evaluate the association between polymorphisms in inflammasome' genes and preeclampsia. METHOD OF STUDY: Selected polymorphisms in inflammasome genes (NLRP1, NLRP3, CARD8, and IL1B) were analyzed in 286 Brazilian women with and 309 without preeclampsia. RESULTS AND CONLCLUSIONS: The NLRP1 variant rs12150220 (L155H) was associated with the development of preeclampsia (OR = 1.58), suggesting a role of this inflammasome receptor in the pathogenesis of this multifactorial disorder. PMID- 25556599 TI - Physiotherapy students' conceptions of skill at the beginning of their Bachelor studies. AB - Skills have recently received widespread attention in education policy documents and discussions. This article reports the results of research on Bachelor's degree physiotherapy students' conceptions of skill at the beginning of their studies. The aim of the present study was to examine how beginning students understand skill, and the focus was on conceptions of skill in general rather than on any particular skills. The participants of the study were 35 physiotherapy students. The data were gathered within the first two weeks of their university studies. Specifically, requested essays written by the students were analyzed using the phenomenographic approach. The data-driven analysis yielded four descriptive categories which reflect the students' conceptions of skill: (1) Talents; (2) Skills requiring individual practice; (3) Skills requiring social practice; and (4) Competence requiring collaboration. The categories form a hierarchy. The differences between the categories are described along seven themes of variation. The themes were named: (1) Acquisition; (2) Emotions; (3) Motivation; (4) Reflection; (5) Evaluation; (6) Agency; and (7) Social Environment. This hierarchical system of categories sheds new light on students' understanding of the skill. The findings can be used as a basis for planning physiotherapy curricula, especially for designing skills education and training, and for supporting students along their educational path, especially in offering opportunities for students to reflect on their skill conceptions. Ultimately, physiotherapy students' awareness of different skill conceptions and developing their skills to advise and treat will benefit patients. PMID- 25556600 TI - Chronic obstructive pulmonary disease- a growing cause of death and disability worldwide. PMID- 25556601 TI - Endoscopic volume reduction in COPD- a critical review. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is common in Germany, with a prevalence of 13.2%. The available treatments are exclusively symptomatic, except for lung transplantation, from which no more than a few patients can benefit. Over the past decade, endoscopic lung volume reduction (ELVR) has broadened the therapeutic spectrum for patients with advanced pulmonary emphysema. METHODS: We review pertinent publications that were retrieved from Pubmed using the search terms "endoscopic lung volume reduction," "endobronchial valves," "endobronchial coil," and "bronchoscopic thermal vapor ablation," along with current data from the annual meeting of the German Respiratory Society (Deutsche Gesellschaft fur Pneumologie). RESULTS: ELVR is now performed with three different techniques. Endoscopic valve implantation has been studied in three randomized controlled trials (RCTs) and several noncontrolled trials, which have shown a benefit from valve therapy particularly for patients who have only a small amount of interlobar collateral ventilation or none at all. A reduction of lobar lung volume by 56-80% was found, in association with a significant improvement of lung function (a 16-26% increase of forced expiratory volume in one second [FEV1]). The main complication of valve therapy is pneumothorax, which arises in up to 23% of cases. Coil implantation has been studied to date in only a single RCT, which revealed a significant improvement in quality of life as the primary endpoint (St. George's Respiratory Questionnaire [SGRQ]: -8 points). Bronchoscopic thermoablation has been studied only in noncontrolled intervention trials; in patients with emphysema mainly affecting the upper lobes, it has been found to reduce lobar volume by an average of 48%. CONCLUSION: Endoscopic lung volume reduction has broadened the therapeutic spectrum for selected patients with advanced pulmonary emphysema. Further prospective trials are needed to evaluate the benefits, risks, and long-term effects of the available techniques for ELVR. PMID- 25556604 TI - All carbon coaxial supercapacitors based on hollow carbon nanotube sleeve structure. AB - All carbon coaxial supercapacitors based on hollow carbon nanotube (CNT) sleeve structure are assembled and tested. The key advantage of the structure is that the inner core electrode is variable from CNT sleeve sponges, to CNT fibers, reduced graphene oxide fibers, and graphene woven fabrics. By changing core electrodes from sleeve sponges to CNT fibers, the electrochemical performance has been significantly enhanced. The capacitance based on sleeve sponge + CNT fiber double the capacitances of double-sleeve sponge supercapacitors thanks to reduction of the series and internal resistances. Besides, the coaxial sleeve structure possesses many other features, including high rate capacitance, long cycle life, and good flexibility. PMID- 25556602 TI - The diagnosis of chronic obstructive pulmonary disease. AB - BACKGROUND: Estimates of the prevalence of chronic obstructive pulmonary disease (COPD) in Germany range from 1.9% to 13.2%, depending on the population studied and the investigative methods used. About 30% of all patients already have severe airway obstruction by the time the condition is diagnosed. METHODS: Review of pertinent literature retrieved by a selective search, including current guidelines and textbooks. RESULTS: Smoking is the main risk factor for COPD. The diagnosis is based on characteristic symptoms that patients at risk should be actively asked about-cough, dyspnea, diminished physical reserve, and frequent airway infections-together with abnormal pulmonary function tests. Spirometry usually suffices to document impaired air flow. The clinical evaluation and the treatment strategy are based on the severity of airway obstruction and dyspnea, and the frequency of exacerbations. According to a European study, dyspnea is present in 73% of persons with severe COPD, expectoration in 64%, cough in 59%, and wheezing in 42%. Asthma, congestive heart failure, and interstitial lung disease are the main differential diagnoses. CONCLUSION: COPD may begin with symptoms that are only mild at first even in a longstanding smoker. The available diagnostic techniques need better prospective validation with respect to relevant endpoints, including mortality, symptom progression, quality of life, and frequency of exacerbations. PMID- 25556603 TI - A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. AB - Circulating microRNAs (miRNAs) are emerging as clinically useful tools for cancer detection; however, little is known about their early diagnostic impact on RCC. The levels of 754 serum miRNAs were initially determined using a TaqMan Low Density Array in two pooled samples from 25 RCC and 25 noncancer controls. Markedly dysregulated miRNAs in RCC cases were subsequently validated individually by qRT-PCR in another 107 patients and 107 controls arranged in two sets. The serum levels of miR-193a-3p, miR-362 and miR-572 were significantly increased whereas the levels of miR-28-5p and miR-378 were markedly decreased in patients with RCC, even in those with stage I disease, compared with the noncancer controls (P < 0.01). The areas under the ROC curve (AUCs) for the 5 combined miRNAs were 0.807 (95% CI, 0.687-0.928) and 0.796 (95% CI, 0.724-0.867) for the training set and the validation set, respectively. Furthermore, the panel enabled the differentiation of stage I RCC from controls with AUC of 0.807 (95% CI, 0.731-0.871), a sensitivity of 80% and a specificity of 71%. This panel of 5 serum miRNA may have the potential to be used clinically as an auxiliary diagnostic tool for the early detection of RCC. PMID- 25556605 TI - Diffusion-weighted MRI in a case of nonsuppressing rebound thymic hyperplasia on chemical-shift MRI. AB - Rebound thymic hyperplasia (RTH) generally retains the quadrilateral or triangular shape typical of the normal thymus. Nevertheless, RTH may rarely appear as a focal mass, a condition that mimics tumors if reveals soft tissue attenuation at computed tomography (CT). In such cases, chemical-shift magnetic resonance imaging (MRI) can demonstrate microscopic fat within tissue, that would be indistinct at CT, by showing signal suppression on opposed-phase images relative to in-phase images, although two cases of nonsuppressing thymus have been described in early adulthood, both of them with minimally fat amount at histology, but none with RTH. Albeit diffusion-weighted MRI could be helpful in cases of nonsuppressing RTH at chemical-shift MRI, considering its capability in differentiating benign from malignant lesions, currently, no data are available on its use in such cases. Hereby, we report a case of atypical RTH at CT with no signal suppression on chemical-shift MRI, arose after corticosteroid treatment for mixed cryoglobulinemia in a 60-year-old woman. Diffusion-weighted MRI demonstrated unrestricted diffusion, as generally seen for benign tissue with no cellular atypia, and thus was helpful to differentiate RTH from malignant mediastinal tumors, especially from B cell lymphoma related to type II cryoglobulinemia. PMID- 25556606 TI - Porosity imaged by a vector projection algorithm correlates with fractal dimension measured on 3D models obtained by microCT. AB - Porosity is an important factor to consider in a large variety of materials. Porosity can be visualized in bone or 3D synthetic biomaterials by microcomputed tomography (microCT). Blocks of porous poly(2-hydroxyethyl methacrylate) were prepared with polystyrene beads of different diameter (500, 850, 1160 and 1560 MUm) and analysed by microCT. On each 2D binarized microCT section, pixels of the pores which belong to the same image column received the same pseudo-colour according to a look up table. The same colour was applied on the same column of a frontal plane image which was constructed line by line from all images of the microCT stack. The fractal dimension Df of the frontal plane image was measured as well as the descriptors of the 3D models (porosity, 3D fractal dimension D3D, thickness, density and separation of material walls. Porosity, thickness Df and D3D increased with the size of the porogen beads. A linear correlation was observed between Df and D3D. This method provides quantitative and qualitative analysis of porosity on a single frontal plane image of a porous object. PMID- 25556607 TI - Reducing optical losses in organic solar cells using microlens arrays: theoretical and experimental investigation of microlens dimensions. AB - The performance of organic photovoltaic devices is improving steadily and efficiencies have now exceeded 10%. However, the incident solar spectrum still largely remains poorly absorbed. To reduce optical losses, we employed a microlens array (MLA) layer on the side of the glass substrate facing the incident light; this approach does not interfere with the processing of the active-layer. We observed up to 10% enhancement in the short circuit current of poly({4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl}{3-fluoro 2-[(2-ethylhexyl)carbonyl] thieno[3,4-b]thiophenediyl}):(6,6)-phenyl C71-butyric acid methyl ester (PTB7:PC71BM) OPV cells. Theoretically and experimentally investigating several MLA dimensions, we found that photocurrent increases with the ratio of the height to the pitch size of MLA. Simulations reveal the enhancement mechanisms: MLA focuses light, and also increases the light path within the active-layer by diffraction. Photocurrent enhancements increase for a polymer system with thinner active-layers, as demonstrated in poly[N-9' heptadecanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3' benzothiadiazole)] (PCDTBT):PC71BM OPVs with 17% improvement in short circuit current. PMID- 25556608 TI - Characteristics and prognosis of colorectal cancer associated with rheumatic disease. AB - It is well known that host immunity plays an important role in the defense against colorectal cancer (CRC) progression. The effects of autoimmune diseases, such as rheumatic disease (RD) in which the immune system is deregulated, on this immunity have not been fully investigated. The medical records of 1299 consecutive patients diagnosed with primary colorectal cancer who underwent surgical resection were retrospectively reviewed. The clinicopathologic factors of 28 subjects with RD (RD group) were compared with those of 1271 patients without RD (non-RD group). Compared to the non-RD group, the RD group was typified by a predominance of females (P < 0.01), older age (P < 0.01), and a lower incidence of rectal cancer (P = 0.02). Although no difference was observed between the groups in terms of TNM classification, disease-free and overall survival were significantly poorer in the RD group in both univariate and multivariate analyses. Subjects who had RD for more than 10 years tended to have a higher frequency of lymph node metastasis (P = 0.06) and a significantly higher incidence of synchronous distant metastasis (P = 0.035) at the time of cancer diagnosis. RD was associated with a significantly poorer prognosis of colorectal cancer, suggesting that deregulation of the immune system by autoimmune diseases may adversely affect the host immune defense against colorectal cancer progression. PMID- 25556609 TI - Design, development, and feasibility of a spanish-language cancer survivor support group. AB - PURPOSE: Latino cancer survivors experience lower psychosocial well-being compared to non-Latino Whites. This study describes the development of a culturally appropriate support group and reports on feasibility of implementation and preliminary outcomes. METHODS: Promotores (lay health workers) conducted all aspects of data collection and program implementation. Participants were 29 Spanish-speaking Latino cancer survivors (n = 12 men, 17 women) who took part in one of three study phases. Phase 1 included one-on-one interviews and focus groups (n = 14) to investigate psychosocial needs of survivors. During phase 2, a 10-week program was developed that integrated data from phase 1 and culturally relevant concepts. Session topics included stress, nutrition, physical activity, body image, sexuality, medical advocacy, and social support. In phase 3, the program was implemented within gender-specific groups (n = 15). Within-group pre post comparisons of distress (distress thermometer, salivary cortisol) and quality of life (FACIT) were conducted. Follow-up focus groups assessed participant experience RESULTS: Phase 1 activities identified survivor needs and interests (e.g., isolation, family and spirituality, supporting other Latinos with cancer). Evidence of program feasibility was demonstrated (e.g., 90-100% attendance, 100% data completion). While interpretation of significance is limited due to sample size, improvements in quality of life [functional (p = 0.05), social (p = 0.02), and meaning/purpose (p = 0.05)] were observed among women but not men. Qualitative follow-up revealed high satisfaction with group participation, but discomfort with the topic of sexuality in women. CONCLUSIONS: This project demonstrates development and feasibility outcomes for providing culturally appropriate psychosocial support to Latino cancer survivors. Limitations, including lack of control group, and future directions are discussed. PMID- 25556610 TI - Mortality, length of stay, and health care costs of febrile neutropenia-related hospitalizations among patients with breast cancer in the United States. AB - PURPOSE: Febrile neutropenia is a potentially life threatening complication of breast cancer chemotherapy associated with a significant amount of morbidity, mortality, and health care resource utilization. Recent data on the national estimates of mortality rate, length of stay, and health care costs among the subpopulation of febrile neutropenia admissions with breast cancer are lacking. METHODS: We used the Nationwide Inpatient Sample database to identify patients with breast cancer hospitalized for febrile neutropenia from 2009 to 2011. We derived data on inhospital mortality rate, length of stay, and mean health care costs and compared it with previous studies. RESULTS: The average inhospital mortality rate during 2009-2011 was 2.6 % (n = 685). Advanced age (>= 65 years) was found to be significantly associated with a higher odds of mortality (4.4 vs 1.7 %, OR 2.7, 95 % CI 2.3-3.1, p < 0.01). The mean length of stay was 5.7 days (95 % CI 5.5-5.9 days), whereas the mean cost of hospitalization was $37,087 (95 % CI $34,009-$40,165). CONCLUSION: Febrile neutropenia-related hospitalizations continue to account for significant morbidity, mortality, and health care resource utilization among patients with breast cancer. Further efforts should be focused on curtailing the rising health care costs without compromising the quality of care. PMID- 25556611 TI - Improved patient functioning after treatment of breakthrough cancer pain: an open label study of fentanyl buccal tablet in patients with cancer pain. AB - PURPOSE: This open-label study evaluated the effects of fentanyl buccal tablet (FBT) on functioning and mood in cancer patients with breakthrough cancer pain (BTcP). METHODS: Opioid-tolerant patients in seven European countries with up to four BTcP episodes/day received FBT doses (100-800 MUg) identified during open label titration to treat up to eight BTcP episodes during an open-label treatment period. In countries where FBT was not commercially available, patients could enter an open-label continuation phase. Functionality and satisfaction assessments included change from baseline to the end of the treatment period in the modified Brief Pain Inventory (BPI-7S) seven-item interference subscale, patient's global assessment of satisfaction and ease of use, and Patient's Global Impression of Change (PGIC). Safety was also assessed. RESULTS: Of 330 randomized patients, 218 completed the treatment period and 88 entered the continuation phase. Median background pain intensity was 4.0 (mild) throughout the study. After the treatment period, mean (SD) global modified BPI-7S score improved from 39.7 (15.9) at baseline to 31.6 (16.8) for a mean change of -8.6 (95% confidence interval CI -10.5, -6.7; P < 0.0001), and 74.5% of patients reported improvement in overall status (PGIC) compared with 25.5% who reported no change or worsening (P < 0.001). Treatment-related adverse events (>=2 patients) during the continuation phase were application site erythema (6.9%), application site swelling (4.6%), and vertigo (4.6%). CONCLUSIONS: FBT may improve patient functioning, mood, and overall satisfaction in the management of BTcP. Long-term data did not indicate new safety concerns with FBT doses up to 800 MUg. PMID- 25556612 TI - Filopodia-based Wnt transport during vertebrate tissue patterning. AB - Paracrine Wnt/beta-catenin signalling is important during developmental processes, tissue regeneration and stem cell regulation. Wnt proteins are morphogens, which form concentration gradients across responsive tissues. Little is known about the transport mechanism for these lipid-modified signalling proteins in vertebrates. Here we show that Wnt8a is transported on actin-based filopodia to contact responding cells and activate signalling during neural plate formation in zebrafish. Cdc42/N-Wasp regulates the formation of these Wnt positive filopodia. Enhanced formation of filopodia increases the effective signalling range of Wnt by facilitating spreading. Consistently, reduction in filopodia leads to a restricted distribution of the ligand and a limited signalling range. Using a simulation, we provide evidence that such a short-range transport system for Wnt has a long-range signalling function. Indeed, we show that a filopodia-based transport system for Wnt8a controls anteroposterior patterning of the neural plate during vertebrate gastrulation. PMID- 25556613 TI - Ovarian cancer: a molecularly insidious disease. AB - In this issue of the Chinese Journal of Cancer, European, American, and Chinese experts review the current management and future perspectives of epithelial ovarian cancer (EOC), the leading cause of gynecological cancer deaths. Although major advances have been made in understanding the cellular and molecular biology of this highly heterogeneous malignancy, the survival rate of women with EOC has changed little since the introduction of platinum-based treatment as a front-line therapy. The papers describe the progress in deciphering the molecular complexity of this disease and the newly available molecular-driven therapies, which have been applied by shifting trial designs toward restricting eligibility to specific subgroups of patients rather than testing agents in unselected populations. These new trial designs provide potential opportunities for improved efficacy in targeted populations. Given the molecular complexity of this disease, patient survival may be increased by searching for new molecular prognostic/predictive signatures as well as by translating the recent insight of microRNA involvement in EOC progression into new, targeted therapies. Particular attention has been given to the issue of fertility sparing for women affected by curable diseases. PMID- 25556614 TI - The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. AB - The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed. PMID- 25556615 TI - Ovarian cancer standard of care: are there real alternatives? AB - Ovarian cancer remains a major issue for gynecological oncologists, and most patients are diagnosed when the disease is already advanced with a poor chance of survival. Debulking surgery followed by platinum-taxane chemotherapy is the current standard of care, but based on several different strategies currently under evaluation, some encouraging data have been published in the last 4 to 5 years. This review provides a state-of-the-art overview of the available alternatives to conventional treatment and the most promising new combinations. For example, neoadjuvant chemotherapy does not seem to be inferior to primary debulking. Despite its outcome improvements, intraperitoneal chemotherapy struggles for acceptance due to the heavy toxicity. Dose-dense chemotherapy, after showing an impressive efficacy in Asian populations, has not produced equal results in a European cohort, and the results of alternative platinum doublets are not superior to those of carboplatin and paclitaxel. In this setting, adherence to a maintenance therapy after first-line treatment and multiple (primarily antiangiogenic) agents appears to be effective. Although many questions, including the duration of maintenance treatment and the use of bevacizumab beyond progression, remain unanswered, new biologic agents, such as poly(ADP-ribose) polymerase (PARP) inhibitors, nintedanib, and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, have emerged as potential therapeutic options in the very near future. Based on the multiplicity of available strategies, the histological and molecular features of the tumor, in addition to patient's clinical condition and disease state, continue to gain importance in guiding treatment choices. PMID- 25556617 TI - Trabectedin therapy as an emerging treatment strategy for recurrent platinum sensitive ovarian cancer. AB - Epithelial ovarian cancer (OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. Despite the high response rate to primary therapy, approximately 85% of patients will develop recurrent ovarian cancer (ROC). This review identifies the clinical use of trabectedin in the treatment algorithm for ROC, with specific emphasis on platinum-sensitive ROC, for which trabectedin in combination with pegylated liposomal doxorubicin has been approved as a treatment protocol. The main mechanisms of action of trabectedin at the cellular level and in the tumor microenvironment is also discussed as bases for identifying biomarkers for selecting patients who may largely benefit from trabectedin-based therapies. PMID- 25556618 TI - Pathobiology of ovarian carcinomas. AB - Ovarian tumors comprise a heterogeneous group of lesions, displaying distinct tumor pathology and oncogenic potentiel. These tumors are subdivided into three main categories: epithelial, germ cell, and sex-cord stromal tumors. We report herein the newly described molecular abnormalities in epithelial ovarian cancers (carcinomas). Immunohistochemistry and molecular testing help pathologists to decipher the significant heterogeneity of this disease. Our better understanding of the molecular basis of ovarian carcinomas represents the first step in the development of targeted therapies in the near future. PMID- 25556619 TI - Fertility preservation in female cancer patients: a single center experience. AB - Advances in cancer treatment allow women to be cured and live longer. However, the necessary chemotherapy and radiotherapy regimens have a negative impact on future fertility. Oncofertility has emerged as a new interdisciplinary field to address the issue of gonadotoxicity associated with cancer treatment and to facilitate fertility preservation, including oocyte and ovarian tissue cryopreservation. These fertility issues are often inadequately addressed, and referral rates to oncofertility centers are low. The aim of this study was to report the 3-year experience of the San Raffaele Oncofertility Unit. A total of 96 patients were referred to the Oncofertility Unit for evaluation after the diagnosis of cancer and before gonadotoxic treatment between April 2011 and June 2014. Of the 96 patients, 30 (31.2%) were affected by breast cancers, 20 (20.8%) by sarcomas, 28 (29.2%) by hematologic malignancies, 13 (13.5%) by central nervous system cancers, 3 (3.1%) by bowel tumors, 1 (1.0%) by Wilms' tumor, and 1 (1.0%) by a thyroid tumor; 47 (49.0%) were referred for oocyte cryopreservation before starting chemotherapy, 20 (20.8%) were referred for ovarian tissue cryopreservation, and 29 (30.2%) were not recruited. The mean time between the patients' counseling and oocyte retrieval was 15 days (range, 2-37 days). The mean time between the laparoscopic surgery and the beginning of treatment was 4 days (range, 2-10 days). The number of patients who were referred increased over time, whereas the rate of patients who were not recruited decreased, showing an improvement in referrals to the Oncofertility Unit and in the patients' counseling and understanding. Our results indicate that an effective multidisciplinary oncofertility team is necessary for prompt referrals and treatment. PMID- 25556616 TI - Key nodes of a microRNA network associated with the integrated mesenchymal subtype of high-grade serous ovarian cancer. AB - Metastasis is the main cause of cancer mortality. One of the initiating events of cancer metastasis of epithelial tumors is epithelial-to-mesenchymal transition (EMT), during which cells dedifferentiate from a relatively rigid cell structure/morphology to a flexible and changeable structure/morphology often associated with mesenchymal cells. The presence of EMT in human epithelial tumors is reflected by the increased expression of genes and levels of proteins that are preferentially present in mesenchymal cells. The combined presence of these genes forms the basis of mesenchymal gene signatures, which are the foundation for classifying a mesenchymal subtype of tumors. Indeed, tumor classification schemes that use clustering analysis of large genomic characterizations, like The Cancer Genome Atlas (TCGA), have defined mesenchymal subtype in a number of cancer types, such as high-grade serous ovarian cancer and glioblastoma. However, recent analyses have shown that gene expression-based classifications of mesenchymal subtypes often do not associate with poor survival. This "paradox" can be ameliorated using integrated analysis that combines multiple data types. We recently found that integrating mRNA and microRNA (miRNA) data revealed an integrated mesenchymal subtype that is consistently associated with poor survival in multiple cohorts of patients with serous ovarian cancer. This network consists of 8 major miRNAs and 214 mRNAs. Among the 8 miRNAs, 4 are known to be regulators of EMT. This review provides a summary of these 8 miRNAs, which were associated with the integrated mesenchymal subtype of serous ovarian cancer. PMID- 25556620 TI - Erythropoietin does not reduce plasma lactate, H+, and K+ during intense exercise. AB - It is investigated if recombinant human erythropoietin (rHuEPO) treatment for 15 weeks (n = 8) reduces extracellular accumulation of metabolic stress markers such as lactate, H(+) , and K(+) during incremental exhaustive exercise. After rHuEPO treatment, normalization of blood volume and composition by hemodilution preceded an additional incremental test. Group averages were calculated for an exercise intensity ~80% of pre-rHuEPO peak power output. After rHuEPO treatment, leg lactate release to the plasma compartment was similar to before (4.3 +/- 1.6 vs 3.9 +/- 2.5 mmol/min) and remained similar after hemodilution. Venous lactate concentration was higher (P < 0.05) after rHuEPO treatment (7.1 +/- 1.6 vs 5.2 +/ 2.1 mM). Leg H(+) release to the plasma compartment after rHuEPO was similar to before (19.6 +/- 5.4 vs 17.6 +/- 6.0 mmol/min) and remained similar after hemodilution. Nevertheless, venous pH was lower (P < 0.05) after rHuEPO treatment (7.18 +/- 0.04 vs 7.22 +/- 0.05). Leg K(+) release to the plasma compartment after rHuEPO treatment was similar to before (0.8 +/- 0.5 vs 0.7 +/- 0.7 mmol/min) and remained similar after hemodilution. Additionally, venous K(+) concentrations were similar after vs before rHuEPO (5.3 +/- 0.3 vs 5.1 +/- 0.4 mM). In conclusion, rHuEPO does not reduce plasma accumulation of lactate, H(+) , and K(+) at work rates corresponding to ~80% of peak power output. PMID- 25556621 TI - Peer support for parents of disabled children part 2: how organizational and process factors influenced shared experience in a one-to-one service, a qualitative study. AB - BACKGROUND: Parents of disabled children often seek support from their peers. The shared experience between parents appears to be a crucial mediating factor. Understanding how a sense of shared experience is fostered can help to design and evaluate services that seek to provide peer support. METHODS: We carried out a qualitative study involving semi-structured interviews and focus groups. Participants were 12 parents and 23 befrienders who had contact with the Face2Face one-to-one befriending service in Devon and Cornwall during a 12-month period, and 10 professionals from health, social care and education. FINDINGS: Formal structures and processes in place such as training and ongoing supervision and support were highly valued as was the highly personalized, confidential, flexible, one-to-one at-home nature of the service. Crucial to establishing rapport was putting the right people together and ensuring a good match between befrienders and parents. Clearly, the befriending parent has to be emotionally prepared to provide help. However, if the parent being offered support was not ready to accept help at the time it was offered or the type of support was not right for them, they are less likely to engage with the service. CONCLUSION: Organizational and process factors as well as characteristics of the parents offering and receiving support contribute to the sense of shared experience in one-to-one peer support. These factors interact to influence whether peer support is effective and should be explicitly considered when designing and evaluating services. PMID- 25556622 TI - Early recognition of apical ballooning syndrome by global longitudinal strain using speckle tracking imaging--the evil eye pattern, a case series. AB - We report 4 cases of patients diagnosed with stress-induced cardiomyopathy and the pattern of typical apical ballooning syndrome (ABS), who presented to our institution with chest pain, mildly elevated cardiac enzymes and ischemic electrocardiographic changes, found to have severe hypokinesis or akinesis of the mid to apical segments with dynamic basal segments on two-dimensional (2D) echocardiography along with a global longitudinal strain (GLS) pattern markedly different from the typical left anterior descending artery (LAD) myocardial infarction pattern. All of them had a similar GLS pattern on presentation, which was easy to recognize on the polar map the day of the event. Three of the patients underwent left heart catheterization and found to have nonobstructive coronary artery disease (CAD). We discuss the usefulness of early recognition of ABS using GLS images. PMID- 25556623 TI - Cutaneous lesions from lymphangioma circumscriptum. PMID- 25556624 TI - Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses. AB - BACKGROUND: The plasmin(ogen) and complement systems are simultaneously activated at sites of tissue injury, participating in hemostasis, wound healing, inflammation and immune surveillance. In particular, the C3 proteolytic fragment, iC3b, and its degradation product C3dg, which is generated by cleavage by factor I (FI) and the cofactor complement receptor CR1, are important in bridging innate and adaptive immunity. Via a thioester (TE) bond, iC3b and C3dg covalently tag pathogens, modulating phagocytosis and adaptive immune responses. OBJECTIVE: To examine plasmin-mediated proteolysis of iC3b, and to evaluate the functional consequences, comparing the effects with products generated by FI/CR1 cleavage of iC3b. METHODS: Dose-dependent and time-dependent plasmin-mediated cleavage of iC3b were characterized by analytical gel electrophoresis. The properties of the resultant TE bond-containing fragments on phagocytosis and induction of pro inflammatory cytokines were measured in cell culture systems. RESULTS: At low concentrations, plasmin effectively cleaves iC3b, but at numerous previously undescribed sites, giving rise to novel C3c-like and C3dg-like moieties, the latter of which retain the TE bond. When attached to zymosan or erythrocytes and exposed to THP-1 macrophages, the C3dg-like proteins behave almost identically to the bona fide C3dg, yielding less phagocytosis as compared with the opsonin iC3b, and more macrophage secretion of the pro-inflammatory cytokine, IL-12. CONCLUSION: Plasmin cleavage of iC3b provides a complement regulatory pathway that is as efficient as FI/CR1 but does not require a cellular cofactor. PMID- 25556625 TI - Eligibility and safety of the first interferon-free therapy against hepatitis C in a real-world setting. AB - BACKGROUND & AIMS: Several real world data demonstrated that eligibility for and tolerability of triple therapy against hepatitis C virus (HCV) infection with a first-wave protease inhibitor is limited. With the approval of sofosbuvir (SOF) effective treatment with and without pegylated interferon (PEG-IFN) has become available for most genotypes. However, no data are available regarding the added benefit of an interferon-free treatment concerning eligibility and tolerability in a real-world scenario. We aimed to assess the eligibility and safety of SOF based therapies in patients with primarily advanced cirrhosis, including decompensated cirrhosis, in a real-world setting. RESULTS: In total, 207 patients were evaluated for a SOF based treatment with and without PEG-IFN. Twenty-six patients did not receive treatment because of safety reasons. Common causes were severe concomitant cardiac disease and advanced renal disease. Autoimmune disease, thrombopaenia, anaemia or hepatic dysfunction did not preclude treatment. Eighty-four patients started treatment, 15 with decompensated cirrhosis. During the first 12 weeks hospitalization occurred in 11 patients most frequently because of typical complications of advanced liver disease. Risk factors for hospitalization were low platelet count and deteriorated liver function. Overall, 982 of 1008 planned treatment weeks (97%) were successfully completed within the first 12 weeks of therapy. CONCLUSION: With the better safety profile of interferon-free therapies, eligibility for HCV treatment will expand broadly, including patients with decompensated cirrhosis. Current limitations are renal failure and concomitant cardiac disease. Patients with advanced cirrhosis still have a high risk for hospitalization even with interferon-free therapies, but can continue HCV treatment in most cases. PMID- 25556626 TI - Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy: influence of gonadotropin-releasing hormone. PMID- 25556627 TI - A slow or modulatory role of astrocytes in neurovascular coupling. AB - Astrocytes are thought to play an important role in NVC, a process that allows the brain to locally control blood flow in response to changes in activity. However, there is an ongoing debate as to when, and under what conditions astrocyte activity is required. In the following review we set forth the hypotheses that astrocytes: (i) act to modulate but not initiate functional hyperemia and (ii) help set the basal tone state of the brain microvasculature by the tonic release of vaso-active messengers. Through these actions astrocytes could help match metabolic demand with supply over a spectrum of activity timescales. PMID- 25556628 TI - Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. AB - The prevalence of carbapenem-resistant Gram-negative bacilli is on the rise worldwide, posing a major public health threat. Previously, this was mostly a problem in Pseudomonas and Acinetobacter, but during the last decade, carbapenem resistance has escalated in medically important species such as Klebsiella pneumoniae and Escherichia coli. In particular, the rising trend in E. coli is of concern, as this may lead to almost untreatable community-acquired infections. Resistance is conferred by carbapenemases, which are beta-lactamases that can breakdown essentially all beta-lactams. Moreover, bacteria carrying these resistance determinants are often resistant to other treatment options, due to the frequent co-acquisition of non-beta-lactam resistance genes located on the same mobile genetic elements. The detection of carbapenemase-producing Enterobacteriaceae (CPE) is a challenge, because some carbapenemases produce relatively discrete levels of carbapenem resistance. Current clinical evidence for treatment guidance is limited and based on retrospective observational studies and case reports. Existing data support the use of combination therapy for treatment of severe infections caused by CPE. Combination regimens including colistin, carbapenems, tigecycline, aminoglycosides and fosfomycin have been used. Randomized controlled studies of combination regimens are ongoing and may help to determine the optimal therapy. Novel beta-lactamase inhibitors may also have a role in future treatment of these infections. Strict infection control measures including isolation or cohort care of affected patients as well as contact tracing and active screening are needed to curb the spread of CPE. In this review, we provide a clinical perspective on the management of patients infected or colonized with CPE. PMID- 25556630 TI - Diagnostic potential of endoscopic ultrasonography-elastography for gastric submucosal tumors. PMID- 25556629 TI - The transradial approach during transcatheter structural heart disease interventions: a review. AB - AIMS: To review the safety and feasibility of a transradial (TR) approach during transcatheter structural or congenital heart disease interventions when utilized as either as a primary or secondary arterial access site. METHODS AND RESULTS: Studies and case reports published between 2002 and 2014 utilizing the TR access during transcatheter structural and congenital heart disease interventions during alcohol septal ablation (ASA), ventricular septal defect (VSD), renal denervation (RD), paravalvular leak (PVL) closure, transcatheter aortic valve implantation (TAVI, secondary access) and endovascular repair of aortic coarctation (ERAC, secondary access) were evaluated. Access-site (femoral vs. TR) vascular and bleeding complications were assessed. Femoral access complications ranged from 0.16% to 40%, with an overall incidence of 2.2% (56/2521). There were 18 reports or studies specifically evaluating the utility of TR access in the context of transcatheter structural heart disease interventions (ASA: 3; VSD: 1; RD: 3; PVL closure: 1; TAVI: 7, ERAC: 3). The use of TR access either as primary or secondary access site was feasible and allowed the completion of the procedure in all cases. The overall incidence of access-site complications following a TR approach was 0.5% (2/406 patients), with no major vascular or bleeding complications. CONCLUSIONS: A TR approach during transcatheter structural heart disease interventions appears to be a safe, effective means of delivering high procedural success accompanied by lower bleeding complications compared with the transfemoral approach. PMID- 25556631 TI - Differential coexpression of FoxP1, FoxP2, and FoxP4 in the Zebra Finch (Taeniopygia guttata) song system. AB - Heterozygous disruptions of the Forkhead transcription factor FoxP2 impair acquisition of speech and language. Experimental downregulation in brain region Area X of the avian ortholog FoxP2 disrupts song learning in juvenile male zebra finches. In vitro, transcriptional activity of FoxP2 requires dimerization with itself or with paralogs FoxP1 and FoxP4. Whether this is the case in vivo is unknown. To provide the means for future functional studies we cloned FoxP4 from zebra finches and compared regional and cellular coexpression of FoxP1, FoxP2, and FoxP4 mRNA and protein in brains of juvenile and adult male zebra finches. In the telencephalic song nuclei HVC, RA, and Area X, the three investigated FoxPs were either expressed alone or occurred in specific combinations with each other, as shown by double in situ hybridization and triple immunohistochemistry. FoxP1 and FoxP4 but not FoxP2 were expressed in RA and in the HVCRA and HVCX projection neurons. In Area X and the surrounding striatum the density of neurons expressing all three FoxPs together or FoxP1 and FoxP4 together was significantly higher than the density of neurons expressing other combinations. Interestingly, the proportions of Area X neurons expressing particular combinations of FoxPs remained constant at all ages. In addition, FoxP-expressing neurons in adult Area X express dopamine receptors 1A, 1B, and 2. Together, these data provide the first evidence that Area X neurons can coexpress all avian FoxP subfamily members, thus allowing for a variety of regulatory possibilities via heterodimerization that could impact song behavior in zebra finches. PMID- 25556632 TI - Poly-3-hydroxybutyrate strips seeded with regenerative cells are effective promoters of peripheral nerve repair. AB - Peripheral nerve injuries are often associated with loss of nerve tissue and require a graft to bridge the gap. Autologous nerve grafts are still the 'gold standard' in reconstructive surgery but have several disadvantages, such as sacrifice of a functional nerve, neuroma formation and loss of sensation at the donor site. Bioengineered grafts represent a promising approach to address this problem. In this study, poly-3-hydroxybutyrate (PHB) strips were used to bridge a 10 mm rat sciatic nerve gap and their effects on long-term (12 weeks) nerve regeneration were compared. PHB strips were seeded with different cell types, either primary Schwann cells (SCs) or SC-like differentiated adipose-derived stem cells (dASCs) suspended in a fibrin glue matrix. The control group was PHB and fibrin matrix without cells. Functional and morphological properties of the regenerated nerve were assessed using walking track analysis, EMGs, muscle weight ratios and muscle and nerve histology. The animals treated with PHB strips seeded with SCs or dASCs showed significantly better functional ability than the control group. This correlated with less muscle atrophy and greater axon myelination in the cell groups. These findings suggest that the PHB strip seeded with cells provides a beneficial environment for nerve regeneration. Furthermore, dASCs, which are abundant and easily accessible, constitute an attractive cell source for future applications of cell therapy for the clinical repair of traumatic nerve injuries. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25556633 TI - Primate extirpation from rainforest fragments does not appear to influence seedling recruitment. AB - Primates are important seed dispersers, especially of large-seeded tree species, but the impact that these animals have on seedling recruitment is unclear. Evidence suggests that forest regeneration might be disrupted in forest fragments in which primates were extirpated. We tested this hypothesis by assessing seedling recruitment in 3 forest fragments occupied (OF) by primates, 3 fragments unoccupied (UF) by primates, and 3 areas within a continuous forest (CF) in the Lacandona rainforest, Mexico. Species and stem densities of tree, palm and liana seedlings were recorded over 16 months. Individuals were classified according to dispersal mode: large-seeded animal-dispersed (LS), small- and medium-seeded animal-dispersed (SS), and abiotically-dispersed species (AD). We assessed the influence of primate presence, adult tree assemblage, and fragment spatial metrics (size, age, distance to nearest fragment, and distance to continuous forest) on seedling assemblages. We recorded 6879 seedlings belonging to 90 species, and 59 genera in 405 1-m(2) plots. Both seedlings and adults showed similar differences in species and stem densities of LS, SS and AD species among forest types, suggesting that seedling assemblages were strongly influenced by the adult assemblages. The recruitment of each LS species varied among study sites, but evidence supporting higher recruitment enhancement of these species in continuous forest and occupied fragments was weak. Distance to continuous forest was the unique fragment spatial metric related (negatively) to the recruitment of LS species. Thus, primate extirpation does not appear to disrupt seedling assemblages in the Lancandona rainforest. Nevertheless, we cannot reject the hypothesis that certain LS species such as Spondias radlkoferi may be affected by the extirpation of primates. PMID- 25556634 TI - Significance of diabetes on morbidity and mortality following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND AND OBJECTIVES: Patients with diabetes suffering from peritoneal surface disease represent a challenge to treat due to the effects of both processes on multiple organ systems. We sought to define the impact of diabetes on outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: A retrospective analysis of a prospective database of 1065 CRS/HIPEC procedures was conducted. Patient demographics, comorbidities, and tumor characteristics were reviewed. RESULTS: CRS/HIPEC was performed in 91 diabetic and 844 non-diabetic patients with peritoneal surface disease from 1991 to 2013. Diabetics and non-diabetics spent 6.8 and 3.1 (P = 0.009) days in the ICU, respectively. Diabetics were more likely to suffer major complications (P < 0.001) including infectious (P < 0.001) and thrombotic (P = 0.05) complications, arrhythmias (P = 0.007), renal insufficiency (P = 0.002) and respiratory failure (P = 0.002) than non-diabetics. Mortality was significantly worse for diabetic patients at 30-days (8.8% vs. 2.7%, P = 0.007) and at 90-days (13.2% vs. 5.2%, P = 0.008). Even after adjusting for other significant predictors of morbidity, diabetes predicted more major complications and increased mortality following CRS/HIPEC. CONCLUSIONS: Diabetes predicts major complications and specific complication patterns associated with increased ICU stay and worse mortality in patients undergoing CRS/HIPEC. Diabetic patients deemed to be appropriate candidates for CRS/HIPEC should be treated with caution. PMID- 25556635 TI - Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA. AB - The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence. PMID- 25556636 TI - Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia. AB - The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days * 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors. PMID- 25556637 TI - Structural basis for acceptor-substrate recognition of UDP-glucose: anthocyanidin 3-O-glucosyltransferase from Clitoria ternatea. AB - UDP-glucose: anthocyanidin 3-O-glucosyltransferase (UGT78K6) from Clitoria ternatea catalyzes the transfer of glucose from UDP-glucose to anthocyanidins such as delphinidin. After the acylation of the 3-O-glucosyl residue, the 3'- and 5'-hydroxyl groups of the product are further glucosylated by a glucosyltransferase in the biosynthesis of ternatins, which are anthocyanin pigments. To understand the acceptor-recognition scheme of UGT78K6, the crystal structure of UGT78K6 and its complex forms with anthocyanidin delphinidin and petunidin, and flavonol kaempferol were determined to resolutions of 1.85 A, 2.55 A, 2.70 A, and 1.75 A, respectively. The enzyme recognition of unstable anthocyanidin aglycones was initially observed in this structural determination. The anthocyanidin- and flavonol-acceptor binding details are almost identical in each complex structure, although the glucosylation activities against each acceptor were significantly different. The 3-hydroxyl groups of the acceptor substrates were located at hydrogen-bonding distances to the Nepsilon2 atom of the His17 catalytic residue, supporting a role for glucosyl transfer to the 3 hydroxyl groups of anthocyanidins and flavonols. However, the molecular orientations of these three acceptors are different from those of the known flavonoid glycosyltransferases, VvGT1 and UGT78G1. The acceptor substrates in UGT78K6 are reversely bound to its binding site by a 180 degrees rotation about the O1-O3 axis of the flavonoid backbones observed in VvGT1 and UGT78G1; consequently, the 5- and 7-hydroxyl groups are protected from glucosylation. These substrate recognition schemes are useful to understand the unique reaction mechanism of UGT78K6 for the ternatin biosynthesis, and suggest the potential for controlled synthesis of natural pigments. PMID- 25556638 TI - Recombinant protein subunit vaccine synthesis in microbes: a role for yeast? AB - OBJECTIVES: Recombinant protein subunit vaccines are formulated using protein antigens that have been synthesized in heterologous host cells. Several host cells are available for this purpose, ranging from Escherichia coli to mammalian cell lines. This article highlights the benefits of using yeast as the recombinant host. KEY FINDINGS: The yeast species, Saccharomyces cerevisiae and Pichia pastoris, have been used to optimize the functional yields of potential antigens for the development of subunit vaccines against a wide range of diseases caused by bacteria and viruses. Saccharomyces cerevisiae has also been used in the manufacture of 11 approved vaccines against hepatitis B virus and one against human papillomavirus; in both cases, the recombinant protein forms highly immunogenic virus-like particles. SUMMARY: Advances in our understanding of how a yeast cell responds to the metabolic load of producing recombinant proteins will allow us to identify host strains that have improved yield properties and enable the synthesis of more challenging antigens that cannot be produced in other systems. Yeasts therefore have the potential to become important host organisms for the production of recombinant antigens that can be used in the manufacture of subunit vaccines or in new vaccine development. PMID- 25556639 TI - Inhibition of DMBA-induced Oral Squamous Cells Carcinoma Growth by Brazilian Red Propolis in Rodent Model. AB - We investigated the effect of oral administration of hydroalcoholic extract of Brazilian red propolis (HERP) on DMBA-induced oral squamous cell carcinomas (OSCC) in rodents. The chemical components of the HERP were assessed by high performance liquid chromatography (HPLC). Carcinogenesis was topically induced in the lower lip of 25 rats using 9,10-dimethyl-1,2-benzanthracene (DMBA); the tumour was treated with saline (TUM1) and Tween 80 (TUM2) as well as HERP at 10, 50 and 100 mg/kg (HERP10, HERP50 and HERP100, respectively) for 20 weeks. Topical application of saline and oral administration of 100 mg/kg HERP was used in five rats as a control group (CTR). After 26 weeks, the histological malignancy grading and immunohistochemical expression of Ki-67 and p16(INK4A) were assessed in the tumours/tissue samples. The compounds identified were propyl gallate, daidzein, catechin, epicatechin, formononetin and biochanin A. Formononetin, daidzein and biochanin A showed concentration of 23.29, 0.38 and 0.67 mg/g of HERP, respectively. HERP at doses of 50 and 100 mg/kg inhibited 40% of OSCC growth and promoted a 3-week delay in development of clinically detectable tumours. Epithelial dysplasia was observed in all samples with no clinical tumour, except in CTR. No significant difference in the immunoexpression of Ki-67 and p16(INK4A) was observed between HERP-treated and saline/Tween 80-treated groups (p > 0.05). Our results suggest that HERP exerts chemopreventive activity on the progression of DMBA-induced epithelial dysplasia to OSCC in an experimental model of labial carcinogenesis; however, this effect is not associated with Ki-67 and p16(INK4A) immunoexpression. PMID- 25556640 TI - Early language impairments and developmental pathways of emotional problems across childhood. AB - BACKGROUND: Language impairments are associated with an increased likelihood of emotional difficulties later in childhood or adolescence, but little is known about the impact of LI on the growth of emotional problems. AIMS: To examine the link between early language status (language impaired (LI), typical language (TL)) and the pattern and predictors of growth in emotional difficulties from school entry to the start of high school in a large cohort of Australian children. METHODS & PROCEDURES: Unconditional latent growth curves of emotional difficulties were modelled across four waves (ages 4-5, 6-7, 8-9 and 10-11) using data from 1627 boys (280 LI, 1347 TL) and 1609 girls (159 LI, 1450 TL). Conditional latent growth curves estimated the main effects of LI on the severity and slope of growth in emotional problems. Simultaneous multiple regression tested the interaction between language status and the other predictors of the development of emotional symptoms. OUTCOMES & RESULTS: LI predicted a significant persistent elevation in severity of emotional difficulties across childhood among boys (d = 0.33-0.57) and girls (d = 0.25-0.39) but was not associated with their growth. LI moderated the association between hostile parenting and the severity of emotional symptoms for boys and the effect of socioeconomic status (SES) and temperamental sociability on the linear and quadratic growth of emotional problems for girls but had no impact on the influence of other predictors. CONCLUSIONS & IMPLICATIONS: There is no effect of LI on the characteristic rate and shape of growth in emotional symptoms across childhood although LI children maintain elevated severities of emotional difficulties. The associations between child reactivity, peer problems, prosocial behaviours, maternal distress and parental warmth and the development of emotional difficulties were the same for LI and TL children. LI enhanced the influence of hostile parenting on a higher severity of emotional symptoms for boys and of lower SES on a faster rate of development of emotional symptoms for girls. LI offset the usual protective effect of higher sociability and the usual vulnerability of higher social avoidance to a faster increase in emotional symptoms with age. PMID- 25556641 TI - Secondary cutaneous lymphoma: comparative clinical features and survival outcome analysis of 106 cases according to lymphoma cell lineage. AB - BACKGROUND: The relative frequency, clinical features and survival outcomes of secondary cutaneous lymphoma remain poorly understood. OBJECTIVES: To determine the clinical characteristics and survival outcomes of secondary cutaneous lymphoma. MATERIALS AND METHODS: The present retrospective cohort study included all 106 patients who presented with secondary cutaneous lymphoma. Patient medical records were reviewed to determine the clinical features, survival outcomes and prognostic factors. Survival outcomes were analysed by using the Kaplan-Meier method and comparisons between lymphoma cell lineages [T or natural killer (T /NK)-cell vs. B-cell lymphoma] were performed using the log-rank test. RESULTS: Secondary cutaneous lymphomas consisted of mature T-/NK-cell lymphomas (56%), mature B-cell lymphomas (35%), immature haematopoietic malignancies (8%) and Hodgkin lymphoma (1%). The T-/NK-cell lineage lymphoma cases were more likely to have multiple and disseminated skin lesions than the B-cell lineage lymphoma cases. The lymphoma cell lineage did not significantly influence survival outcomes. Patients who showed cutaneous involvement within 6 months of the initial diagnosis of primary disease had a poorer overall survival (OS) outcome than patients who developed cutaneous dissemination 6 or more months after the initial diagnosis (P < 0.001). Patients with disseminated skin lesions had a poorer OS than patients with localized skin lesions (P = 0.028). The two lymphoma cell lineages differed in terms of prognostic factors that influenced survival. CONCLUSIONS: Skin lesion characteristics such as time point of appearance and extent affect the survival outcomes of secondary cutaneous lymphoma. Cell lineage did not influence survival outcomes but the two lineages are associated with different prognostic factors. PMID- 25556642 TI - Measurements of nanomaterials in environmentally relevant water matrices using liquid nebulization/differential mobility analysis. AB - A liquid nebulization-differential mobility analysis methodology was evaluated for the measurement of the size distribution and quantitative mass concentration of nanomaterials in environmentally relevant aqueous media. The analysis time is 8 min, and the method requires little routine sample preparation and less than 8 mL of sample. The method can be used for rapid, direct analysis of nanomaterials in aqueous media with a particular application to dose verification in ecotoxicology studies, analysis of manufacturing process waste streams, and raw material analysis. Twelve reference materials having a diameter traceable to the National Institute of Standards and Technology were spiked into 6 different aqueous matrices that included drinking water, groundwater, industrial wastewater, as well as the algae and daphnia media used in ecotoxicology testing. Measurement of the diameter of a reference material was within the expected range for the reference material. Individual response factors for each reference material were determined in each medium and the accuracy and precision of the concentration measurements evaluated. In ecotoxicology test media, measurements of the concentration of nanoparticles having diameter >= 30 nm, had corresponding accuracies and precisions of 103% and 7%, respectively. Over 28 d 86% of the samples had concentrations within 20% of the initial concentration. The method limit of quantification depended primarily on matrix complexity and particle diameter; the limit of quantification ranged from 0.01 mg/L to 3 g/L. PMID- 25556647 TI - Coping with catastrophe: the value of endoscopic vascular injury training. AB - BACKGROUND: Inadvertent injury to the internal carotid artery (ICA), if poorly managed, not only presents a risk of exsanguination but can also result in significant long-term morbidity. Through the implementation of a novel animal model of endoscopic carotid artery injury (CAI), effective techniques to manage this scenario have been developed. The Vascular Injuries Workshop has trained over 110 surgeons in these techniques. This study reviews events of major arterial hemorrhage managed by surgeons who completed this vascular injury workshop training. METHODS: We report a retrospective multicenter case series of patients who required endoscopic management of intranasal major arterial hemorrhage. Delegates who had attended the course were contacted by e-mail and surveyed with regard to instances of major arterial bleeding and the management undertaken. Patient demographics, tumor type, factors influencing injury, management technique, and outcomes were reviewed. RESULTS: The cases reported herein are characterized as follows: 9 cases are reported in total, 3 male, 6 female; age range 37 to 82 years; 1 basilar artery, and 8 ICA injuries. Each case was successfully managed endoscopically with intraoperative muscle patch application. There were no deaths, 1 case of pseudoaneurysm with successful endovascular treatment, 2 cases of impaired carotid flow, and 1 carotid dissection was conservatively managed. There were no permanent neurological sequelae or other permanent morbidity. CONCLUSION: The Vascular Injuries Workshop arms surgeons with a structured approach to managing the surgical field and provides effective hemostatic techniques in the face of impending catastrophe. In comparison to the existing literature on ICA rupture, our results show trained surgeons are well equipped to achieve safe outcomes for their patients. PMID- 25556648 TI - Liver sharing and organ procurement organization performance. AB - Whether the liver allocation system shifts organs from better performing organ procurement organizations (OPOs) to poorer performing OPOs has been debated for many years. Models of OPO performance from the Scientific Registry of Transplant Recipients make it possible to study this question in a data-driven manner. We investigated whether each OPO's net liver import was correlated with 2 performance metrics [observed to expected (O:E) liver yield and liver donor conversion ratio] as well as 2 alternative explanations [eligible deaths and incident listings above a Model for End-Stage Liver Disease (MELD) score of 15]. We found no evidence to support the hypothesis that the allocation system transfers livers from better performing OPOs to centers with poorer performing OPOs. Also, having fewer eligible deaths was not associated with a net import. However, having more incident listings was strongly correlated with the net import, both before and after Share 35. Most importantly, the magnitude of the variation in OPO performance was much lower than the variation in demand: although the poorest performing OPOs differed from the best ones by less than 2 fold in the O:E liver yield, incident listings above a MELD score of 15 varied nearly 14-fold. Although it is imperative that all OPOs achieve the best possible results, the flow of livers is not explained by OPO performance metrics, and instead, it appears to be strongly related to differences in demand. PMID- 25556649 TI - RECQL4 Regulates p53 Function In Vivo During Skeletogenesis. AB - RECQ DNA helicases play critical roles in maintaining genomic stability, but their role in development has been less well studied. Rothmund-Thomson syndrome, RAPADILINO, and Baller-Gerold syndrome are rare genetic disorders caused by mutations in the RECQL4 gene. These patients have significant skeletal developmental abnormalities including radial ray, limb and craniofacial defects. To investigate the role of Recql4 in the developing skeletal system, we generated Recql4 conditional knockout mice targeting the skeletal lineage. Inactivation of Recql4 using the Prx1-Cre transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human RECQL4 patients. These Prx1-Cre(+) ;Recql4(fl/fl) mice as well as Col2a1-Cre(+) ;Recql4(fl/fl) mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of Trp53 in these Recql4 mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between Recql4 and Trp53, and p53 activation as an underlying mechanism for the developmental bone abnormalities in RECQL4 disorders. Our findings show that RECQL4 is critical for skeletal development by modulating p53 activity in vivo. PMID- 25556650 TI - Academic outcomes of very low birth weight infants: the influence of mother-child relationships. AB - It is commonly accepted that parent-child interactions are bidirectional and complex and are influenced by many different factors. The current study examined the academic and behavioral skills in the early elementary years of preterm infants and the influence of their early mother-child interactions on these skills. Using a sample of 21 premature infants and their mothers, this study found that positive early interactions during feeding were related to later mutual enjoyment during a teaching task at school age, but early maternal depression was not. Early risk factors of premature infants, specifically the number of days spent on a ventilator, were positively related to maternal perceptions of hassle associated with feeding and negatively related to maternal sensitivity during feeding. Finally, mutual enjoyment was strongly associated with language, cognitive, and behavioral skills at school age. These results suggest that it is not only the infant risk factors following a premature birth that influence later development but also the parent-child relationship and emphasize the importance of understanding and promoting these early positive parent-child interactions for premature infants. PMID- 25556651 TI - Induced expression of FcgammaRIIIa (CD16a) on CD4+ T cells triggers generation of IFN-gammahigh subset. AB - Whether or not CD4(+) T-cells express low affinity receptor FcgammaRIIIa (CD16a) in disease pathology has not been examined in great detail. In this study, we show that a subset of activated CD4(+) T-cells in humans express FcgammaRIIIa. The ligation of FcgammaRIIIa by immune complexes (ICs) in human CD4(+) T-cells produced co-stimulatory signal like CD28 that triggered IFN-gamma production. The induced expression of FcgammaRIIIa on CD4(+) helper T-cells is an important finding since these receptors via ITAM contribute to intracellular signaling. The induced expression of FcgammaRIIIa on CD4(+) T helper cells and their ability to co-stimulate T-cell activation are important and novel findings that may reveal new pathways to regulate adaptive immune responses during inflammation and in autoimmunity. PMID- 25556653 TI - Naphthalimide-based triptycenes: synthesis and optoelectronic properties. AB - In the past decades, the naphthalimide structure has found application in many areas of chemistry due to its unique photophysical properties. Naphthalimide has two isomers, 1,8-naphthalimide containing a six-membered imide ring and 2,3 naphthalimide containing a five-membered imide ring. The former has been widely investigated while studies on the latter are considerably more rare. On the other hand, naphthalimide can also be regarded as a building block to construct polycyclic aromatic hydrocarbons (PAHs), which have found wide applications in optical materials. Here we report the synthesis and optoelectronic properties of three 2,3-naphthalimide-based triptycenes. These three triptycene derivatives enrich the family of triptycenes. PMID- 25556652 TI - Structure-function analysis of CCL28 in the development of post-viral asthma. AB - CCL28 is a human chemokine constitutively expressed by epithelial cells in diverse mucosal tissues and is known to attract a variety of immune cell types including T-cell subsets and eosinophils. Elevated levels of CCL28 have been found in the airways of individuals with asthma, and previous studies have indicated that CCL28 plays a vital role in the acute development of post-viral asthma. Our study builds on this, demonstrating that CCL28 is also important in the chronic post-viral asthma phenotype. In the absence of a viral infection, we also demonstrate that CCL28 is both necessary and sufficient for induction of asthma pathology. Additionally, we present the first effort aimed at elucidating the structural features of CCL28. Chemokines are defined by a conserved tertiary structure composed of a three-stranded beta-sheet and a C-terminal alpha-helix constrained by two disulfide bonds. In addition to the four disulfide bond forming cysteine residues that define the traditional chemokine fold, CCL28 possesses two additional cysteine residues that form a third disulfide bond. If all disulfide bonds are disrupted, recombinant human CCL28 is no longer able to drive mouse CD4+ T-cell chemotaxis or in vivo airway hyper-reactivity, indicating that the conserved chemokine fold is necessary for its biologic activity. Due to the intimate relationship between CCL28 and asthma pathology, it is clear that CCL28 presents a novel target for the development of alternative asthma therapeutics. PMID- 25556654 TI - Adams-Oliver syndrome: a case report. AB - We report the case of an infant with Adams-Oliver syndrome, a rare disorder characterized by aplasia cutis congenita, defects of the limbs and extremities, and cutis marmorata telangiectatica. Other associated anomalies have been reported, such as facial dysmorphism, heart defects, and disorders of the central nervous system. PMID- 25556655 TI - Porous membrane culture method for expansion of human pluripotent stem cells. AB - For the clinical application of human pluripotent stem cells (hPSCs), it is critical to develop novel culture techniques that completely exclude the use of animal feeder cells and enzyme treatments used in conventional hPSC culture systems. Here, we describe a novel culture method using a porous membrane that allows to maintain stable attachment and expansion of hPSCs, obviates the need for enzyme treatment, and also reduces feeder layer contamination. PMID- 25556656 TI - Ultrasound characterization of medial gastrocnemius tissue composition in children with spastic cerebral palsy. AB - INTRODUCTION: In this study we aimed to characterize muscle composition of the medial gastrocnemius in children with spastic cerebral palsy (SCP) using quantitative ultrasound. METHODS: Forty children with SCP, aged 4-14 years, participated in this study. Children were grouped according to the gross motor function classification system (GMFCS I-V) and compared with a cohort of age- and gender-matched, typically developing children (TD; n = 12). Ultrasound scans were taken of the medial gastrocnemius. Images were then characterized using grayscale statistics to determine mean echo intensity (EI) and the size and number of spatially connected homogeneous regions (i.e., blobs). RESULTS: Significant differences in skeletal muscle composition were found between children with SCP and their TD peers. Children classified as GMFCS III consistently exhibited the highest EI and blob area. CONCLUSIONS: This study demonstrates altered tissue composition in children with SCP visualized using ultrasound. Further work is required to determine the pathophysiology contributing to these alterations in SCP. PMID- 25556657 TI - How far are we from the clinical use of placental-derived mesenchymal stem cells? AB - In recent years, multiple studies have investigated the biology and clinical applications of mesenchymal stem cells (MSCs), trying to define their markers, and elucidate their effects in animal models. MSCs are available from different tissues, and the use of placental-derived MSCs (PMSCs) for treating a variety of disorders is on the forefront. Herein, we discuss the most recent findings regarding the standardization of their isolation procedure and phenotype, along with advantages and limitations of their use. We also discuss the safety of the placental cell products, including the issue of senescence and mutagenesis of PMSCs, and efficacy from preclinical studies. PMID- 25556658 TI - Dynamic phosphorylation of CENP-A at Ser68 orchestrates its cell-cycle-dependent deposition at centromeres. AB - The H3 histone variant CENP-A is an epigenetic marker critical for the centromere identity and function. However, the precise regulation of the spatiotemporal deposition and propagation of CENP-A at centromeres during the cell cycle is still poorly understood. Here, we show that CENP-A is phosphorylated at Ser68 during early mitosis by Cdk1. Our results demonstrate that phosphorylation of Ser68 eliminates the binding of CENP-A to the assembly factor HJURP, thus preventing the premature loading of CENP-A to the centromere prior to mitotic exit. Because Cdk1 activity is at its minimum at the mitotic exit, the ratio of Cdk1/PP1alpha activity changes in favor of Ser68 dephosphorylation, thus making CENP-A available for centromeric deposition by HJURP. Thus, we reveal that dynamic phosphorylation of CENP-A Ser68 orchestrates the spatiotemporal assembly of newly synthesized CENP-A at active centromeres during the cell cycle. PMID- 25556660 TI - Recommendations for fracture management in patients with osteopetrosis: case report. AB - INTRODUCTION: Osteopetrosis is caused by general increase in bone density and obliteration of the medullary canal. Fractures are a frequent complication and their management is considered a challenge due to increased resistance to reaming and screw positioning; reduction maneuvers have to be done more carefully to avoid intraoperative fractures, and there is an increased risk of drill breakage. There is also a higher risk of infection and malunion, which increases the incidence of surgical revisions in this population. CASE REPORT: 55-year-old male with osteopetrosis and a history of two previous proximal femur fractures, who sustained an oblique supracondylar fracture of the left humerus and a simple, intra-articular, rotated fragment with capitelum involvement, as well as a fracture in the base of the coronoid process was admitted in our hospital. We performed an open reduction and internal fixation (ORIF) and 12 months after surgery, the patient's bone has healed and he recovered flexion (110) and extension (-10) without complications. DISCUSSION: During ORIF, two drill bits were broken and screw fixation was challenging due to the strength required. Bone overheating was also present during drilling, evidenced by smoke production and increased temperature of both bone and drill bits. Recommendations to avoid these problems include continuous cold saline irrigation, frequent drill bit changing, and spaced cycles with low-speed drilling. Additionally, high-resistance and high speed electric drill bits can also be effective. Finally, patients should be closely followed postoperatively due to the high incidence of refracture, infection and malunion. CONCLUSIONS: Fracture fixation in patients with osteopetrosis requires strategies to overcome the technical difficulties found during the procedure. Preoperative planning must include the availability of multiple metal drill bits, electric drills, and bone substitutes, having in mind drilling techniques, drilling speed, and temperature control. Patients should be closely followed to evidence any complications such as infections and malunions. PMID- 25556661 TI - Minimal invasive posterior total hip arthroplasty: are 6 weeks of hip precautions really necessary? AB - INTRODUCTION: Postoperative hip dislocations have been reported in 0.5 to 10.6 % of patients after primary posterolateral total hip arthroplasty (THA). Hip precautions are currently recommended for 6 weeks postoperatively to reduce early dislocation and facilitate healing of the posterior soft tissue repair. MATERIALS AND METHODS: To determine the impact of a modified 4-week precaution protocol on the dislocation rate, 698 consecutive patients (797 hips) operated by a single surgeon between September 2008 and December 2012 were retrospectively evaluated. All patients had a standard THA using a minimal invasive posterior approach with posterior soft tissue repair and 28-36-mm head size. 98.7 % of the patients were available for follow-up. RESULTS: There were eight (1 %) dislocations in 797 hips in the first 12 months after surgery with 4 weeks of hip precautions. The average time to dislocation was 7.5 weeks after surgery (range 1.0-16.9 weeks); two dislocations (25 %) took place in the first 4 weeks. CONCLUSIONS: Shortening the time of posterolateral hip precautions from 6 to 4 weeks after surgery does not increase the risk of postoperative dislocation. PMID- 25556659 TI - Ankrd11 is a chromatin regulator involved in autism that is essential for neural development. AB - Ankrd11 is a potential chromatin regulator implicated in neural development and autism spectrum disorder (ASD) with no known function in the brain. Here, we show that knockdown of Ankrd11 in developing murine or human cortical neural precursors caused decreased proliferation, reduced neurogenesis, and aberrant neuronal positioning. Similar cellular phenotypes and aberrant ASD-like behaviors were observed in Yoda mice carrying a point mutation in the Ankrd11 HDAC-binding domain. Consistent with a role for Ankrd11 in histone acetylation, Ankrd11 was associated with chromatin and colocalized with HDAC3, and expression and histone acetylation of Ankrd11 target genes were altered in Yoda neural precursors. Moreover, the Ankrd11 knockdown-mediated decrease in precursor proliferation was rescued by inhibiting histone acetyltransferase activity or expressing HDAC3. Thus, Ankrd11 is a crucial chromatin regulator that controls histone acetylation and gene expression during neural development, thereby providing a likely explanation for its association with cognitive dysfunction and ASD. PMID- 25556662 TI - Low preoperative Constant score is a negative predictive factor for postoperative proprioception after total shoulder arthroplasty in osteoarthritis. AB - BACKGROUND: Shoulder proprioception in patients with glenohumeral osteoarthritis and the effect of total shoulder arthroplasty (TSA) on proprioception have been evaluated previously. Measuring proprioception with an active angle reproduction (AAR) test, proprioception remained unchanged or deteriorated in a short follow up period after shoulder replacement. Therefore, the purpose of this prospective study was to evaluate the influence of the preoperative Constant score (CS) on postoperative proprioceptive outcome after TSA in patients with primary osteoarthritis to address the question of whether the preoperative state of shoulder function influences postoperative proprioceptive outcome. METHODS: Twenty-four patients who received total shoulder arthroplasty (TSA) (n = 24) for primary osteoarthritis of the shoulder were enrolled. After retrospectively analyzing the preoperative CS for 120 patients with primary osteoarthritis of the shoulder who received TSA, the patient group was divided into three subgroups according to preoperative functional assessment of the shoulder using the CS. Group one consisted of patients with CS < 20, group two patients with CS 20-30, and group three patients with the best preoperative CS (>30). In all patients proprioception was examined 1 day before the operation and 3 months after surgery by 3D motion analysis with an AAR test and also CS. RESULTS: Postoperatively, proprioception in group one (CS < 20) deteriorated significantly from 5.2 degrees (SD 2.2) to 8.1 degrees (SD 1.8); p = 0.018. In group two, there were no significant changes from preoperative to postoperative status [8.7 degrees (SD 2.1) vs. 9.3 degrees (SD 2.7) (p = 0.554)], likewise in group three [6.3 degrees (SD 2.3) preoperatively vs. 6.9 degrees (SD 3.3) postoperatively (p = 0.617)]. Comparing the postoperative results, the best proprioception [6.9 degrees (SD 3.3)] was found in the group that had the best preoperative CS (group three, CS > 30). CONCLUSION: In conclusion, a low preoperative CS is a negative predictive factor for postoperative proprioception after TSA. We should keep that in mind when determining the best timepoint for shoulder replacement in patients with glenohumeral osteoarthritis. PMID- 25556663 TI - Nanosized titanium dioxide reduces copper toxicity--the role of organic material and the crystalline phase. AB - Titanium dioxide nanoparticles (nTiO2) are expected to interact with natural substances and other chemicals in the environment, however little is known about their combined effects. Therefore, this study assessed the toxicity of copper (Cu) in combination with varying crystalline phases (anatase, rutile, and the mixture) of nTiO2 and differing organic materials on Daphnia magna. The nanoparticles reduced the Cu-toxicity depending on the product (0.3- to 2-fold higher 48-h EC50). This decrease in toxicity coincided with a lowered Cu concentration in the water column, which was driven by the adsorption of Cu to nTiO2-depending on available surface area and structure-and their subsequent sedimentation. In the presence of organic material and nTiO2, the Cu-toxicity was further reduced (up to 7-fold higher 48-h EC50). This observation can be explained by a reduced Cu-bioavailability as a result of complexation and adsorption by the organic material and nTiO2, respectively. Thus, the crystalline phase composition, which is determining the surface area and structure of nTiO2, seems to be of major importance for the toxicity reduction of heavy metals, while the influence of the organic materials was mainly driven by the quantity and quality of humic substances. PMID- 25556664 TI - Synthesis and cell-selective antitumor properties of amino acid conjugated tumor associated carbohydrate antigen-coated gold nanoparticles. AB - The Thomsen Friedenreich antigen (TFag) disaccharide is a tumor-associated carbohydrate antigen (TACA) found primarily on carcinoma cells and rarely expressed in normal tissue. The TFag has been shown to interact with Galectin-3 (Gal-3), one in a family of beta-galactoside binding proteins. Galectins have a variety of cellular functions, and Gal-3 has been shown to be the sole galectin with anti-apoptotic activity. We have previously prepared gold nanoparticles (AuNP) coated with the TFag in various presentations as potential anti-adhesive therapeutic tools or antitumor vaccine platforms. Here we describe the synthesis of TFag-glycoamino acid conjugates attached to gold nanoparticles through a combined alkane/PEG linker, where the TFag was attached to either a serine or threonine amino acid. Particles were fully characterized by a host of biophysical techniques, and along with a control particle carrying hydroxyl-terminated linker units, were evaluated in both Gal-3 positive and negative cell lines. We show that the particles bearing the saccharides selectively inhibited tumor cell growth of the Gal-3 positive cells significantly more than the Gal-3 negative cells. In addition, the threonine-attached TF particles were more potent than the serine-attached constructs. These results support the use of AuNP as antitumor therapeutic platforms, targeted against cell lines that express specific lectins that interact with TFag. PMID- 25556666 TI - Correlation between cationic lipid-based transfection and cell division. AB - We evaluate the temporal relation between protein expression by cationic lipid mediated transfection and cell division using time lapse fluorescence microscopy. Detailed image analysis provides new insights on the single cell level while simultaneously achieving appropriate statistics. Earlier evidence by less direct methods such as flow cytometry indicates a primary route for transfection involving nuclear envelope breakdown, but also suggests the existence of a pathway independent of mitosis. We confirm and quantify both mechanisms. We found the timing for successful transfection to be unexpectedly flexible, contrary to assertions of a narrow time window. Specifically, cells dividing more than 24h after exposure to the transfection medium express the probed protein at a comparable level to cells in a mitotic state during or shortly after transfection. This finding can have a profound impact on the guidance and development of non-viral gene delivery materials. PMID- 25556667 TI - Impact of increasing sample volume from 4 ml to 8 ml on bacterial detection rates in apheresis platelets: a meta-analysis. AB - Some blood centres have increased sample volume of in-process cultures to improve detection of bacterial contamination when screening apheresis platelet units. We performed a meta-analysis to evaluate extant published North American data comparing apheresis platelet bacterial contamination rates from 4 ml and 8 ml sample volume. Pooled results indicate an 8 ml sample volume yields higher true positive rates than 4 ml resulting in a significant increase in the detection rate and interdiction of contaminated units, which should contribute to reduced risk of adverse transfusion outcomes. PMID- 25556665 TI - Inability to maintain GSH pool in G6PD-deficient red cells causes futile AMPK activation and irreversible metabolic disturbance. AB - AIMS: Glucose 6-phosphate dehydrogenase (G6PD) is essential for maintenance of nicotinamide dinucleotide hydrogen phosphate (NADPH) levels and redox homeostasis. A number of drugs, such as antimalarial drugs, act to induce reactive oxygen species and hemolytic crisis in G6PD-deficient patients. We used diamide (DIA) to mimic drug-induced oxidative stress and studied how these drugs affect cellular metabolism using a metabolomic approach. RESULTS: There are a few differences in metabolome between red blood cells (RBCs) from normal and G6PD deficient individuals. DIA causes modest changes in normal RBC metabolism. In contrast, there are significant changes in various biochemical pathways, namely glutathione (GSH) metabolism, purine metabolism, and glycolysis, in G6PD deficient cells. GSH depletion is concomitant with a shift in energy metabolism. Adenosine monophosphate (AMP) and adenosine diphosphate (ADP) accumulation activates AMP protein kinase (AMPK) and increases entry of glucose into glycolysis. However, inhibition of pyruvate kinase (PK) reduces the efficacy of energy production. Metabolic changes and protein oxidation occurs to a greater extent in G6PD-deficient RBCs than in normal cells, leading to severe irreversible loss of deformability of the former. INNOVATION AND CONCLUSION: Normal and G6PD-deficient RBCs differ in their responses to oxidants. Normal cells have adequate NADPH regeneration for maintenance of GSH pool. In contrast, G6PD-deficient cells are unable to regenerate enough NADPH under a stressful situation, and switch to biosynthetic pathway for GSH supply. Rapid GSH exhaustion causes energy crisis and futile AMPK activation. Our findings suggest that drug-induced oxidative stress differentially affects metabolism and metabolite signaling in normal and G6PD-deficient cells. It also provides an insight into the pathophysiology of acute hemolytic anemia in G6PD-deficient patients. PMID- 25556668 TI - Febuxostat for the treatment of gout. AB - INTRODUCTION: Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues. The xanthine oxidase inhibitor, allopurinol, has historically been the principle agent utilized for reducing elevated uric acid levels and treating underlying cause of gout symptoms; the availability of febuxostat, a newer non purine selective xanthine oxidase inhibitor, represents an alternative therapy for those patients with contraindications or intolerance to allopurinol. AREAS COVERED: This article reviews the published literature on the pharmacologic characteristics and clinical safety and efficacy data on the use of febuxostat in the treatment of gout. A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-November 2014) was conducted utilizing the key words 'febuxostat', 'allopurinol', and 'gout'. All published articles regarding febuxostat were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. EXPERT OPINION: Febuxostat has shown benefit with respect to symptomatic relief and uric acid level reduction. The safety profile of this agent makes it an ideal alternative in those patients with contraindications to or who are intolerant of allopurinol. PMID- 25556669 TI - Functional significance of a novel 7-factor model of DSM-5 PTSD symptoms: results from the National Health and Resilience in Veterans study. AB - BACKGROUND: While posttraumatic stress disorder (PTSD) symptoms in the recently published Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) are clustered into four factors, emerging confirmatory factor analytic studies suggest that this disorder is best characterized by seven symptom clusters, including re-experiencing, avoidance, negative affect, anhedonia, externalizing behaviors, and anxious and dysphoric arousal symptoms. To date, however, data are lacking regarding the relation between this novel model of DSM 5 PTSD symptoms and measures of clinical significance in this population (e.g., functioning). METHODS: Using data from the National Health and Resilience in Veterans Study (NHRVS), a contemporary, nationally representative sample of 1484 U.S. veterans, we evaluated clinical and functional correlates of a novel 7 factor model of DSM-5 PTSD symptoms. RESULTS: Differential patterns of associations were observed between DSM-5 PTSD symptom clusters, and psychiatric comorbidities, suicidal ideation, hostility, and functioning and quality of life. Anhedonia symptoms, in particular, were strongly related to current depression, as well as reduced mental functioning and quality of life. Externalizing behaviors were most strongly related to hostility, supporting the convergent validity of this construct. LIMITATIONS: Cross-sectional design and employment of self-report measures. CONCLUSIONS: These results suggest that a more refined 7 factor model of DSM-5 PTSD symptoms may provide greater specificity in understanding associations with comorbid psychopathology, suicidal ideation, and functioning and quality of life in U.S. veterans. They further suggest that prevention and treatment efforts that target distinct aspects of the PTSD phenotype may be more effective in mitigating key clinical and functional outcomes in this population. PMID- 25556670 TI - Association of resting-state network dysfunction with their dynamics of inter network interactions in depression. AB - BACKGROUND: Network-level brain analysis on resting state has demonstrated that depression is not only associated with intra-network dysfunction, but relates to the disturbed interplay between the networks. However, the underlying associations between the intra-network dysfunction and the disturbed inter network interactions remain unexplored. This study was aimed to explore the association of resting-state networks dysfunction with their dynamics of inter network interactions in depression. METHODS: Resting-state functional magnetic resonance imaging (fMRI) data were collected from 20 depressed patients and 20 matched healthy controls. We evaluated the Hurst exponents of the time series from resting-state networks, and employed multivariate pattern analysis to capture depression-associated networks with increased or decreased Hurst values. Granger causalities between these networks were explored to undertake an intensive study of the dynamic inter-network interactions. RESULTS: The default mode network (DMN) exhibited decreased Hurst value, indicative of more irregular oscillation within the DMN implicated in depressive symptoms. The ventromedial prefrontal network (vmPFN) and salience network (SN) with increased Hurst values, as compensatory mechanisms, continually enhanced the interactions to the DMN for trying hard to impel the DMN to function synchronously. On the other side, the DMN exerted frequently enhanced causality on the left fronto-parietal network with elevated Hurst exponent, accompanied by imbalance between the fronto parietal network and DMN circuits in depression. LIMITATIONS: This study suffers from small sample size and is confined to large-scale networks. CONCLUSIONS: Our preliminary findings mainly revealed the DMN-related dynamic interactions with the vmPFN, SN and the fronto-parietal network in depression, which might offer useful information for discovering the neuropathological mechanisms underlying the depressive symptoms. PMID- 25556671 TI - Prevalence and predictors of bipolar disorders in patients with a major depressive episode: the Japanese epidemiological trial with latest measure of bipolar disorder (JET-LMBP). AB - BACKGROUND: For patients with a major depressive episode, early differential diagnosis of bipolar disorder and subsequent appropriate treatment are critical. This study, conducted in clinical settings in Japan, examined patients with a major depressive episode to investigate the prevalence and predictors of bipolar disorders. METHODS: A total of 448 patients with a major depressive episode were interviewed using the Mini-International Neuropsychiatric Interview to determine the presence of mood episodes and psychiatric comorbidities. The diagnosis of bipolar disorder was based on the collected information according to the DSM-IV TR. RESULTS: Of the 448 patients with a major depressive episode, 114 patients (25.4%) were diagnosed with bipolar disorder. Multivariate logistic regression identified five predictors that were significantly correlated with bipolar disorder: antidepressant-related switch to mania/hypomania, mixed depression, two or more previous mood episodes within the past year, early age at the onset of a major depressive episode (<25 years), and a history of suicide attempts. The area under the curve of receiver operating characteristic analysis based on the multivariate logistic regression of the five predictors was 0.849. LIMITATIONS: The diagnosis of bipolar disorder in patients was already conclusively confirmed by long illness observations but was not confirmed by a prospective study. CONCLUSIONS: In patients with a major depressive episode, the differential diagnosis of bipolar disorder and major depressive disorder, which exhibit similar depressive symptoms, is essential. Several predictors identified in the present study may be useful in supporting a differential diagnosis of these disorders in routine clinical practice. PMID- 25556672 TI - Microstructural abnormalities in anterior callosal fibers and their relationship with cognitive function in major depressive disorder and bipolar disorder: a tract-specific analysis study. AB - BACKGROUND: The corpus callosum modulates interhemispheric communication and cognitive processes. It has been suggested that white matter abnormalities in the corpus callosum are related to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study was to examine microstructural abnormalities in callosal fibers separated by their connection to functional brain regions and determine the relationship of these abnormalities with cognitive function in MDD and BD. METHODS: The subjects were 18 patients with MDD, 20 patients with BD, and 21 healthy controls. The callosal fibers were divided into 6 segments based on their cortical projection using tract-specific analysis of diffusion tensor imaging. We examined differences in the fractional anisotropy (FA) of callosal fibers in six segments among the three subject groups and examined the correlation between the FA in each segment and cognitive performance in the 3 groups. RESULTS: The FA of anterior callosal fibers were reduced significantly in the MDD and BD groups compared to those in the HC group, and the FA of anterior callosal fibers correlated significantly with the raw scores of the digit sequencing task and symbol coding in the MDD group. LIMITATIONS: The patients were medicated at the time of scanning, and the MDD and BD groups were not matched for symptom severity. CONCLUSIONS: Our results suggest that MDD and BD have similar microstructural abnormalities in anterior callosal fibers connecting bilateral frontal cortices, and these abnormalities may be related to impairment of working memory and attention in MDD. PMID- 25556673 TI - Premature termination from psychotherapy and internalizing psychopathology: the role of demoralization. AB - BACKGROUND: Some research suggests that higher levels of depression and anxiety related symptoms at intake are associated with premature termination from psychotherapy, but findings are mixed. However, theoretical and measurement considerations - introduced by a common mood factor - might complicate literature synthesis. Tellegen (1985) demonstrated that demoralization causes multicollinearity between measures of depression and anxiety, and other lines of research have converged to indicate that this construct is an important non specific factor to consider when assessing mood pathology. METHODS: We utilized a sample of 557 community mental health center outpatients (188 males, 265 females; 80% Caucasian) with an average age of 32.2 years (SD=10.2). We used self-report indicators to model latent low positive emotionality and negative emotionality constructs, which are temperament markers of core depressive and anxiety symptoms. We further specified a latent demoralization bifactor from these indicators. RESULTS: As hypothesized, the bifactor model yielded significantly better fit than competing one-factor and two-factor models. Furthermore, the bifactor was substantially correlated with a demoralization measure (r=.96). As expected, low positive emotionality and negative emotionality were significant predictors of therapist ratings of premature termination. Though demoralization was a non-significant predictor, the structural paths from the other two internalizing constructs markedly increased in the bifactor model relative to the two-factor model. LIMITATIONS: Replications with other, more diverse clinical populations using multi-method indicators of premature termination are needed. CONCLUSIONS: This research indicates that after accounting for demoralization patients presenting with core mood disorder symptoms are at substantially increased risk for premature termination. PMID- 25556674 TI - Trends in psychological distress, depressive episodes and mental health treatment seeking in the United States: 2001-2012. AB - BACKGROUND: There has been an increase in the use of mental health services in a number of industrialized countries over the past two decades with little impact on mental health status of the populations. Few studies, however, have examined recent trends in mental health status in the US. METHODS: Using data from three large general annual population surveys in the US-the National Health Interview Survey, Behavioral Risk Factor Surveillance System, and National Survey on Drug Use and Health-we examined temporal trends in non-specific psychological distress, depressive episodes and mental health treatment seeking over the 2001 2012 period. RESULTS: Prevalence of past-month significant psychological distress and past-year depressive symptoms changed little over time. However, a larger percentage of participants reported poor mental health for >=15 days or 30 days in the past month in 2011-2012 (8.7% and 5.7%, respectively) than in 2001-2002 (6.6% and 4.6%). A larger percentage of participants in the later period also reported receiving mental health treatments. LIMITATIONS: Possible changes in mental health status may have been missed due to the limited scope of assessments or the small magnitude of changes. Potential reciprocal influences between service use and mental health status could not be investigated because of cross sectional data. CONCLUSIONS: Despite increasing use of mental health treatments in the US in the first decade of this century, there is no evidence of decrease in prevalence of psychological distress or depression. Poor match between need for treatment and actual treatments received in usual care settings may partly explain the findings. PMID- 25556676 TI - A thermochromic silver nanocluster exhibiting dual emission character. AB - A Ag12(SCH2C10H7)6(CF3CO2)6(CH3CN)6 (1) nanocluster modified using naphthalen-2 yl-methanethiol was synthesized and structurally characterized by single crystal X-ray analysis. The targeted luminescent nanocluster displays dual emission with the property of reversible thermochromism spanning from red to bright yellow. PMID- 25556677 TI - Localized lymphomatoid papulosis. PMID- 25556675 TI - Trends in education gradients of 'preventable' mortality: a test of fundamental cause theory. AB - Fundamental cause theory explains persisting associations between socioeconomic status and mortality in terms of personal resources such as knowledge, money, power, prestige, and social connections, as well as disparate social contexts related to these resources. We review evidence concerning fundamental cause theory and test three central claims using the National Health Interview Survey Linked Mortality Files 1986-2004. We then examine cohort-based variation in the associations between a fundamental social cause of disease, educational attainment, and mortality rates from heart disease, other "preventable" causes of death, and less preventable causes of death. We further explore race/ethnic and gender variation in these associations. Overall, findings are consistent with nearly all features of fundamental cause theory. Results show, first, larger education gradients in mortality risk for causes of death that are under greater human control than for less preventable causes of death, and, second, that these gradients grew more rapidly across successive cohorts than gradients for less preventable causes. Results also show that relative sizes and cohort-based changes in the education gradients vary substantially by race/ethnicity and gender. PMID- 25556678 TI - Microsurgical knee reconstruction in a type IA tibial hemimelia. PMID- 25556681 TI - Tumour-to-tumour metastasis from papillary thyroid carcinoma with BRAF mutation to lung adenocarcinoma with EGFR mutation: the utility of mutation-specific antibodies. AB - AIMS: Tumour-to-tumour metastasis is a rare event. The aim of this study is to demonstrate the utility of mutation-specific antibodies to prove the occurrence of metastatic papillary thyroid cancer donor into lung adenocarcinoma recipient. METHODS AND RESULTS: We report the case of an 80-year-old woman who had a papillary thyroid carcinoma with a v-raf murine sarcoma viral oncogene homologue B1 mutation that metastasized into a lung adenocarcinoma with an epidermal growth factor receptor mutation. Immunohistochemical analysis with mutation-specific antibodies not only clearly revealed two components, but also revealed their gene mutation statuses. CONCLUSIONS: As a component of multimodal diagnostic tools, immunohistochemistry can avoid some pitfalls involved in the molecular diagnosis of complicated cases (such as our own) and can help to ensure that patients receive optimal treatments. PMID- 25556680 TI - Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer. AB - BACKGROUND: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. METHODS: Adult men with chemotherapy-naive mCRPC, serum prostate-specific antigen (PSA) >=5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m(2) every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. RESULTS: In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23% of patients achieved >=30, >=50, and >=90% PSA reductions, respectively; median best PSA response was -77%. Seven of 10 (70%) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78%), alopecia (61%), diarrhea (48%), nausea (43%), dysgeusia (39%), and neutropenia (39%). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. CONCLUSIONS: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses. PMID- 25556679 TI - Metabolic insights from zebrafish genetics, physiology, and chemical biology. AB - Metabolic diseases-atherosclerotic cardiovascular disease, type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease--have reached pandemic proportions. Across gene, cell, organ, organism, and social-environmental scales, fundamental discoveries of the derangements that occur in these diseases are required to develop effective new treatments. Here we will review genetic, physiological, pathological and chemical biological discoveries in the emerging zebrafish model for studying metabolism and metabolic diseases. We present a synthesis of recent studies using forward and reverse genetic tools to make new contributions to our understanding of lipid trafficking, diabetes pathogenesis and complications, and to beta-cell biology. The technical and physiological advantages and the pharmacological potential of this organism for discovery and validation of metabolic disease targets are stressed by our summary of recent findings. We conclude by arguing that metabolic research using zebrafish will benefit from adoption of conventional blood and tissue metabolite measurements, employment of modern imaging techniques, and development of more rigorous metabolic flux methods. PMID- 25556682 TI - The role of early stages of cortical visual processing in size and distance judgment: a transcranial direct current stimulation study. AB - Recent research suggests that V1 plays an active role in the judgment of size and distance. Nevertheless, no research has been performed using direct brain stimulation to address this issue. We used transcranial direct-current stimulation (tDCS) to directly modulate the early stages of cortical visual processing while measuring size and distance perception with a psychophysical scaling method of magnitude estimation in a repeated-measures design. The subjects randomly received anodal, cathodal, and sham tDCS in separate sessions starting with size or distance judgment tasks. Power functions were fit to the size judgment data, whereas logarithmic functions were fit to distance judgment data. Slopes and R(2) were compared with separate repeated-measures analyses of variance with two factors: task (size vs. distance) and tDCS (anodal vs. cathodal vs. sham). Anodal tDCS significantly decreased slopes, apparently interfering with size perception. No effects were found for distance perception. Consistent with previous studies, the results of the size task appeared to reflect a prothetic continuum, whereas the results of the distance task seemed to reflect a metathetic continuum. The differential effects of tDCS on these tasks may support the hypothesis that different physiological mechanisms underlie judgments on these two continua. The results further suggest the complex involvement of the early visual cortex in size judgment tasks that go beyond the simple representation of low-level stimulus properties. This supports predictive coding models and experimental findings that suggest that higher-order visual areas may inhibit incoming information from the early visual cortex through feedback connections when complex tasks are performed. PMID- 25556683 TI - Acupuncture improves locomotor function by enhancing GABA receptor expression in transient focal cerebral ischemia rats. AB - Stroke is the major cause of long-term disability among adults. Recent studies have found that GABAergic inhibitory neurotransmission plays a vital role in ameliorate locomotor damage after ischemic injury. Acupuncture has been widely used to improve locomotor function. However, the underlying mechanisms remain unclear. The present study is designed to investigate whether GABA and GABA receptors are involved in the mechanism underlying acupuncture treatment in rats with middle cerebral artery occlusion (MCAO). One week after acupuncture at JiaJi acupoint, the locomotor function and infarct volumes were tested. Then level of GABA and the expressions of GABAAgamma2 and GABABR2 were assessed by high performance liquid chromatography, immunofluorescence and immunohistochemistry, respectively. Compared with normal group, GABAAgamma2 and GABABR2 expressions were decreased in striatum and spinal cord of the MCAO group. After acupuncture, the expressions of the two receptors were increased, but levels of GABA and trafficking protein, kinesin binding 1 (TRAK1), which plays a role in the intracellular transport of GABA receptors, were unchanged. The present study suggests that acupuncture could reverse locomotor function by modulating the expressions of GABA receptors in MCAO rats. PMID- 25556685 TI - Painful peripheral neuropathy and sodium channel mutations. AB - Peripheral neuropathy can lead to neuropathic pain in a subset of patients. Painful peripheral neuropathy is a debilitating disorder, reflected by a reduced quality of life. Therapeutic strategies are limited and often disappointing, as in most cases targeted treatment is not available. Elucidating pathogenetic factors for pain might provide a target for optimal treatment. Voltage-gated sodium channels NaV1.7-NaV1.9 are expressed in the small-diameter dorsal root ganglion neurons and their axons. By a targeted gene approach, missense gain-of function mutations of NaV1.7-NaV1.9 have been demonstrated in painful peripheral neuropathy. Functional analyses have shown that these mutations produce a spectrum of pro-excitatory changes in channel biophysics, with the shared outcome at the cellular level of dorsal root ganglion hyperexcitability. Reduced neurite outgrowth may be another consequence of sodium channel mutations, and possible therapeutic strategies include blockade of sodium channels or block of reverse operation of the sodium-calcium exchanger. Increased understanding of the pathophysiology of painful peripheral neuropathy offers new targets that may provide a basis for more effective treatment. PMID- 25556684 TI - 17-DMAG induces Hsp70 and protects the auditory hair cells from kanamycin ototoxicity in vitro. AB - Heat shock protein 70 (Hsp70) has been known to be able to play a protective role in the cochlea. The aim of this study was to investigate whether geldanamycin hydrosoluble derivative 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17 DMAG) has the ability to induce Hsp70 up-regulation to protect hair cells from kanamycin-induced ototoxicity in vitro. The organ of Corti (OC) explants were isolated from mice at postnatal day 3-5. Then, the explants were exposed to kanamycin with or without pre-incubation with 17-DMAG. The expression of Hsp70 was assessed by reverse transcription-quantitative polymerase chain reaction, ELISA, and immunofluorescent staining. The surviving hair cells were examined by phalloidin labeling and were counted. We found that Hsp70 expression in the explants after pre-incubation with 17-DMAG was significantly increased at both mRNA and protein levels. Immunofluorescent staining showed that Hsp70 was mainly located in the auditory hair cells. Compared with kanamycin group, the loss of hair cells was inhibited significantly in 17-DMAG+kanamycin group. Our study demonstrated that 17-DMAG induces Hsp70 in the hair cells, and has a significant protective effect against kanamycin ototoxicity in vitro. 17-DMAG has the possibility to be a safe and effective anti-ototoxic drug. PMID- 25556686 TI - Serum deprivation alters lipid profile in HN9.10e embryonic hippocampal cells. AB - The understanding of the mechanism of apoptosis is important to improve the use of stem cells for the treatment of neurodegenerative disorders. Sphingolipids are bioactive molecules involved in the regulation of cell fate. In HN9.10e embryonic hippocampal cells, serum deprivation induces apoptosis preceded by sphingomyelinase activation and raise of ceramide levels. Increasing evidence indicates that individual ceramide species regulated by specific pathways in distinct subcellular compartments might carry out distinct cellular functions, but the ceramides species involved in embryonic hippocampal cell death induced by growth factor deprivation are unknown. In the present paper, by using the UFLC MS/MS methodology, we have investigated the effect of serum deprivation on the lipid profile in HN9.10e cells. At 48h of serum deprivation, we detected a decrease in cholesterol and increase in sphingosine-1-phoshate 18:1, phosphatidylcholine 18:1 18:0, sphingomyelin 18:1 16:0 and in ceramides 18:1 16:0; we also found an increase in saturated/unsaturated fatty acid ratio in sphingomyelin. We hypothesize that the rearrangement of sphingo- and glycerolipids with increase of saturated fatty acids in serum-deprivated, neural cells might represent a cellular response aimed at holding cholesterol inside the cells. PMID- 25556687 TI - Integrating models to investigate critical phenological overlaps in complex ecological interactions: the mountain pine beetle-fungus symbiosis. AB - The fates of individual species are often tied to synchronization of phenology, however, few methods have been developed for integrating phenological models involving linked species. In this paper, we focus on mountain pine beetle (MPB, Dendroctonus ponderosae) and its two obligate mutualistic fungi, Grosmannia clavigera and Ophiostoma montium. Growth rates of all three partners are driven by temperature, and their idiosyncratic responses affect interactions at important life stage junctures. One critical phase for MPB-fungus symbiosis occurs just before dispersal of teneral (new) adult beetles, when fungi are acquired and transported in specialized structures (mycangia). Before dispersal, fungi must capture sufficient spatial resources within the tree to ensure contact with teneral adults and get packed into mycangia. Mycangial packing occurs at an unknown time during teneral feeding. We adapt thermal models predicting fungal growth and beetle development to predict overlap between the competing fungi and MPB teneral adult feeding windows and emergence. We consider a spectrum of mycangial packing strategies and describe them in terms of explicit functions with unknown parameters. Rates of growth are fixed by laboratory data, the unknown parameters describing various packing strategies, as well as the degree to which mycangial growth is slowed in woody tissues as compared to agar, are determined by maximum likelihood and two years of field observations. At the field location used, the most likely fungus acquisition strategy for MPB was packing mycangia just prior to emergence. Estimated model parameters suggested large differences in the relative growth rates of the two fungi in trees at the study site, with the most likely model estimating that G. clavigera grew approximately twenty-five times faster than O. montium under the bark, which is completely unexpected in comparison with observed fungal growth on agar. PMID- 25556688 TI - Functional response and population dynamics for fighting predator, based on activity distribution. AB - The classical Holling type II functional response, describing the per capita predation as a function of prey density, was modified by Beddington and de Angelis to include interference of predators that increases with predator density and decreases the number of killed prey. In the present paper we further generalize the Beddington-de Angelis functional response, considering that all predator activities (searching and handling prey, fight and recovery) have time duration, the probabilities of predator activities depend on the encounter probabilities, and hence on the prey and predator abundance, too. Under these conditions, the aim of the study is to introduce a functional response for fighting the predator and to analyse the corresponding dynamics, when predator predator-prey encounters also occur. From this general approach, the Holling type functional responses can also be obtained as particular cases. In terms of the activity distribution, we give biologically interpretable sufficient conditions for stable coexistence. We consider two-individual (predator-prey) and three individual (predator-predator-prey) encounters. In the three-individual encounter model there is a relatively higher fighting rate and a lower killing rate. Using numerical simulation, we surprisingly found that when the intrinsic prey growth rate and the conversion rate are small enough, the equilibrium predator abundance is higher in the three-individual encounter case. The above means that, when the equilibrium abundance of the predator is small, coexistence appears first in the three-individual encounter model. PMID- 25556689 TI - Animal rights activists: misconceived proposals. PMID- 25556690 TI - Screening of hemolysis in whole-blood specimens. PMID- 25556691 TI - Chemical design enables the control of conformational polymorphism in functional 2,3-thieno(bis)imide-ended materials. AB - We report a successful chemical design strategy based on the even-odd alkyl end tailoring, which allows us to promote and control conformational polymorphism in single crystal and thin deposits of thienoimide-based molecular semiconductors (Cx-NT4N). PMID- 25556692 TI - Light-induced efficient molecular oxygen activation on a Cu(II)-grafted TiO2/graphene photocatalyst for phenol degradation. AB - An efficient photocatalytic process involves two closely related steps: charge separation and the subsequent surface redox reaction. Herein, a ternary hybrid photocatalytic system was designed and fabricated by anchoring Cu(II) clusters onto a TiO2/reduced graphene oxide (RGO) composite. Microscopic and spectroscopic characterization revealed that both TiO2 nanoparticles and Cu(II) clusters were highly dispersed on a graphene sheet with intimate interfacial contact. Compared with pristine TiO2, the TiO2/RGO/Cu(II) composite yielded an almost 3-fold enhancement in the photodegradation rate toward phenol degradation under UV irradiation. Electron spin resonance (ESR) spectra and electrochemical measurements demonstrated that the improved photocatalytic activity of this ternary system benefitted from the synergetic effect between RGO and Cu(II), which facilitates the interfacial charge transfer and simultaneously achieves in situ generation of H2O2 via two-electron reduction of O2. These results highlight the importance to harmonize the charge separation and surface reaction process in achieving high photocatalytic efficiency for practical application. PMID- 25556693 TI - Towards hybrid biocompatible magnetic rHuman serum albumin-based nanoparticles: use of ultra-small (CeLn)3/4+ cation-doped maghemite nanoparticles as functional shell. AB - Human serum albumin (HSA) is a protein found in human blood. Over the last decade, HSA has been evaluated as a promising drug carrier. However, not being magnetic, HSA cannot be used for biomedical applications such as magnetic resonance imaging (MRI) and magnetic drug targeting. Therefore, subsequent composites building on iron oxide nanoparticles that are already used clinically as MRI contrast agents are extensively studied. Recently and in this context, innovative fully hydrophilic ultra-small CAN-stabilized maghemite ((CeLn)(3/4+) gamma-Fe2O3) nanoparticles have been readily fabricated. The present study discusses the design, fabrication, and characterization of a dual phase hybrid core (rHSA)-shell ((CeLn)(3/4+)-gamma-Fe2O3 NPs) nanosystem. Quite importantly and in contrast to widely used encapsulation strategies, rHSA NP surface-attached (CeLn)(3/4+)-gamma-Fe2O3 NPs enabled to exploit both rHSA (protein functionalities) and (CeLn)(3/4+)-gamma-Fe2O3 NP surface functionalities (COOH and ligand L coordinative exchange) in addition to very effective MRI contrast capability due to optimal accessibility of H2O molecules with the outer magnetic phase. Resulting hybrid nanoparticles might be used as a platform modular system for therapeutic (drug delivery system) and MR diagnostic purposes. PMID- 25556694 TI - Clostridium difficile infection among kidney transplant recipients: frequency, clinical presentation, and outcome. AB - The objective of this study was to evaluate the frequency of Clostridium Difficile Infection (CDI) among kidney transplant recipients and describe the clinical picture in correlation with the presence of certain risk factors. We included kidney transplant recipients with a functioning graft, who were admitted during the period 1/2012-12/2013, and patients with ESRD who were admitted to undergo Kidney Transplantation (KTx) from a deceased or a living donor in the same period. Patients were screened following clinical indication of gastrointestinal infection. CDI diagnosis was based on a positive stool sample for CD toxins and stool culture. Within the period 2012-2013, we recorded 24 cases of CDI in 19 patients, accounting for a frequency of 5.4% of CDI in our population. In addition to diarrhea, 63.15% of the patients presented with fever, 31.25% with anorexia, while abdominal pain was a rare symptom (0.53%). None of the patients had ileus, bowel obstruction or megacolon. Fourteen patients (73.7%) had a history of recent exposure (15 days) to antimicrobial agents prior to the evolution of CDI symptoms. A relapse of the CDI infection was identified in five cases. CDI infection is a significant factor of morbidity in patients with KTx and should be considered in the clinical setting of diarrhea, even in cases with no exposure to antibiotic agents. PMID- 25556695 TI - A Convenient and Efficient Method to Enrich and Maintain Highly Proliferative Human Fetal Liver Stem Cells. AB - Pluripotent human hepatic stem cells have broad research and clinical applications, which are, however, restricted by both limited resources and technical difficulties with respect to isolation of stem cells from the adult or fetal liver. In this study, we developed a convenient and efficient method involving a two-step in situ collagenase perfusion, gravity sedimentation, and Percoll density gradient centrifugation to enrich and maintain highly proliferative human fetal liver stem cells (hFLSCs). Using this method, the isolated hFLSCs entered into the exponential growth phase within 10 days and maintained sufficient proliferative activity to permit subculture for at least 20 passages without differentiation. Immunocytochemistry, immunofluorescence, and flow cytometry results showed that these cells expressed stem cell markers, such as c-kit, CD44, epithelial cell adhesion molecule (EpCAM), oval cell marker-6 (OV 6), epithelial marker cytokeratin 18 (CK18), biliary ductal marker CK19, and alpha-fetoprotein (AFP). Gene expression analysis showed that these cells had stable mRNA expression of c-Kit, EpCAM, neural cell adhesion molecule (NCAM), CK19, CK18, AFP, and claudin 3 (CLDN-3) throughout each passage while maintaining low levels of ALB, but with complete absence of cytochrome P450 3A4 (C3A4), phosphoenolpyruvate carboxykinase (PEPCK), telomeric repeat binding factor (TRF), and connexin 26 (CX26) expression. When grown in appropriate medium, these isolated liver stem cells could differentiate into hepatocytes, cholangiocytes, osteoblasts, adipocytes, or endothelial cells. Thus, we have demonstrated a more economical and efficient method to isolate hFLSCs than magnetic-activated cell sorting (MACS). This novel approach may provide an excellent tool to isolate highly proliferative hFLSCs for tissue engineering and regenerative therapies. PMID- 25556697 TI - Cave spiders choose optimal environmental factors with respect to the generated entropy when laying their cocoon. AB - The choice of a suitable area to spiders where to lay eggs is promoted in terms of Darwinian fitness. Despite its importance, the underlying factors behind this key decision are generally poorly understood. Here, we designed a multidisciplinary study based both on in-field data and laboratory experiments focusing on the European cave spider Meta menardi (Araneae, Tetragnathidae) and aiming at understanding the selective forces driving the female in the choice of the depositional area. Our in-field data analysis demonstrated a major role of air velocity and distance from the cave entrance within a particular cave in driving the female choice. This has been interpreted using a model based on the Entropy Generation Minimization - EGM - method, without invoking best fit parameters and thanks to independent lab experiments, thus demonstrating that the female chooses the depositional area according to minimal level of thermo-fluid dynamic irreversibility. This methodology may pave the way to a novel approach in understanding evolutionary strategies for other living organisms. PMID- 25556696 TI - Advancement in genetic variants conferring obesity susceptibility from genome wide association studies. AB - Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed. PMID- 25556698 TI - Enzyme promiscuity in enolase superfamily. Theoretical study of o succinylbenzoate synthase using QM/MM methods. AB - The promiscuous activity of the enzyme o-succinylbenzoate synthase (OSBS) from the actinobacteria Amycolatopsis is investigated by means of QM/MM methods, using both density functional theory and semiempirical Hamiltonians. This enzyme catalyzes not only the dehydration of 2-succinyl-6R-hydroxy-2,4-cyclohexadiene-1R carboxylate but also catalyzes racemization of different acylamino acids, with N succinyl-R-phenylglycine being the best substrate. We investigated the molecular mechanisms for both reactions exploring the potential energy surface. Then, molecular dynamics simulations were performed to obtain the free energy profiles and the averaged interaction energies of enzymatic residues with the reacting system. Our results confirm the plausibility of the reaction mechanisms proposed in the literature, with a good agreement between theoretical and experimentally derived activation free energies. Our simulations unravel the role played by the different residues in each of the two possible reactions. The presence of flexible loops in the active site and the selection of structural modifications in the substrate seem to be key elements to promote the promiscuity of this enzyme. PMID- 25556701 TI - Rotational dynamics of bases in the gene coding interferon alpha 17 (IFNA17). AB - In the present work, rotational oscillations of nitrogenous bases in the DNA with the sequence of the gene coding interferon alpha 17 (IFNA17), are investigated. As a mathematical model simulating oscillations of the bases, we use a system of two coupled nonlinear partial differential equations that takes into account effects of dissipation, action of external fields and dependence of the equation coefficients on the sequence of bases. We apply the methods of the theory of oscillations to solve the equations in the linear approach and to construct the dispersive curves determining the dependence of the frequency of the plane waves (omega) on the wave vector (q). In the nonlinear case, the solutions in the form of kink are considered, and the main characteristics of the kink: the rest energy (E0), the rest mass (m0), the size (d) and sound velocity (C0), are calculated. With the help of the energetic method, the kink velocity (upsilon), the path (S), and the lifetime (tau) are also obtained. PMID- 25556699 TI - Interplay between population firing stability and single neuron dynamics in hippocampal networks. AB - Neuronal circuits' ability to maintain the delicate balance between stability and flexibility in changing environments is critical for normal neuronal functioning. However, to what extent individual neurons and neuronal populations maintain internal firing properties remains largely unknown. In this study, we show that distributions of spontaneous population firing rates and synchrony are subject to accurate homeostatic control following increase of synaptic inhibition in cultured hippocampal networks. Reduction in firing rate triggered synaptic and intrinsic adaptive responses operating as global homeostatic mechanisms to maintain firing macro-stability, without achieving local homeostasis at the single-neuron level. Adaptive mechanisms, while stabilizing population firing properties, reduced short-term facilitation essential for synaptic discrimination of input patterns. Thus, invariant ongoing population dynamics emerge from intrinsically unstable activity patterns of individual neurons and synapses. The observed differences in the precision of homeostatic control at different spatial scales challenge cell-autonomous theory of network homeostasis and suggest the existence of network-wide regulation rules. PMID- 25556702 TI - Changes in microstructure and physical properties of skutterudites after severe plastic deformation. AB - The best p-type skutterudites with ZT > 1.1 so far are didymium (DD) filled, Fe/Co substituted, Sb-based skutterudites. DD0.68Fe3CoSb12 was prepared using an annealing-reacting-melting-quenching technique followed by ball milling and hot pressing. After severe plastic deformation via high-pressure torsion (HPT), no phase changes but particular structural variations were achieved, leading to modified transport properties with higher ZT values. Although after measurement induced heating some of the HPT induced defects were annealed out, a still attractive ZT-value was preserved. In this paper we focus on explanations for these changes via TEM investigations, Raman spectroscopy and texture measurements. The grain sizes and dislocation densities, evaluated from TEM images, showed that (i) the majority of cracks generated during high-pressure torsion are healed during annealing, leaving only small pores, that (ii) the grains have grown, and that (iii) the dislocation density is decreased. While Raman spectra indicate that after HPT processing and annealing the vibration modes related to the shorter Sb-Sb bonds in the Sb4 rings are more affected than those related to the longer Sb-Sb bonds, almost no visible changes were observed in the pole intensity and/or orientation. PMID- 25556700 TI - miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6. AB - miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Borjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability. PMID- 25556703 TI - Variation in fatigue among 6011 (long-term) cancer survivors and a normative population: a study from the population-based PROFILES registry. AB - PURPOSE: Cancer survivors commonly experience fatigue, related to disease and its treatment. This study aimed to compare fatigue severity among survivors of different cancer types with a normative population and also to identify variations in fatigue among cancer survivors according to clinical and demographic variables. METHODS: We used cancer survivorship data from the population-based PROFILES registry. We included survivors of endometrial (EC, n = 741) or colorectal cancer (CRC, n = 3878) (1998-2007), thyroid cancer (TC, n = 306) (1990-2008), Hodgkin (HL, n = 150) or non-Hodgkin lymphoma (NHL, n = 716), or multiple myeloma (MM, n = 120) (1999-2008). A representative Dutch normative population (n = 2040) was also assessed. Participants completed the Fatigue Assessment Scale. RESULTS: Cancer survivors were more often classified as fatigued (EC/CRC 39%, HL 40%, NHL 43%, MM 51%, TC 44%) compared with the normative population (21 %; p < 0.001). MM survivors were more often classified as fatigued than all other cancer groups, except NHL (overall p = 0.02). Shorter times since diagnosis (<5 years, 41 versus 38%; p < 0.05), younger age (<=65 years, 42 versus 39%; p < 0.01), being female (43 versus 36%; p < 0.01), chemotherapy treatment (43 versus 39%; p < 0.01), comorbidity (no (27%) versus 1 (35%) versus >=2 (52%); p < 0.01), educational level (low (44%) versus medium (41%) versus high (32%); p < 0.01), and absence of a partner (47 versus 38%; p < 0.01) were associated with fatigue. CONCLUSIONS: Fatigue levels are substantial in (long-term) cancer survivors and vary depending on cancer type, time since diagnosis, age, gender, treatment with chemotherapy, number of comorbid conditions, educational level, and partnership. Since significantly more cancer survivors feel fatigued in comparison with the normative population, appropriate information, assessment, and interventions for fatigue are needed during or after oncologic treatment. Furthermore, focus on better control or management of comorbid conditions of cancer survivors is recommended. PMID- 25556705 TI - Dirac leaky-wave antennas for continuous beam scanning from photonic crystals. AB - Leaky-Wave Antennas (LWAs) enable directive and scannable radiation patterns, which are highly desirable attributes at terahertz, infrared and optical frequencies. However, a LWA is generally incapable of continuous beam scanning through broadside, due to an open stopband in its dispersion characteristic. This issue is yet to be addressed at frequencies beyond microwaves, mainly as existing microwave solutions (for example, transmission line metamaterials) are unavailable at these higher frequencies. Here we report leaky-wave radiation from the interface of a photonic crystal (PC) with a Dirac-type dispersion and air. The resulting Dirac LWA (DLWA) can radiate at broadside, chiefly owing to the closed Gamma-point bandgap of the Dirac PC. Thus, the DLWA can continuously scan a directive beam over a wide range of angles by varying the frequency. These DLWAs can be designed at microwave as well as terahertz to optical frequencies, with feasible dimensions and low losses. PMID- 25556706 TI - Self-assembly of metal atoms (Na, K, Ca) on graphene. AB - A thorough search of the distribution pattern of Na, K, and Ca atoms on graphene surface, carried out using a synergistic combination of density functional theory and particle swarm optimization algorithm, yielded some unusual results. The equilibrium distribution is concentration and metal dependent; the metal atoms distribute uniformly when their coverage ratio M : C (M = Na, K, Ca) is 1 : 6, but Na and Ca atoms self-assemble to form parallel quasi-one-dimensional chains when their coverage is reduced to 1 : 8. At the higher concentration (M : C = 1 : 6), electron-phonon coupling calculations further show that the NaC6 is a superconductor with critical temperature of 5.8 K, which is the highest value among all the stable alkali or alkaline-earth metal decorated monolayer graphene systems studied to-date. At the lower concentration (M : C = 1 : 8) and depending on metal species, well-aligned atomic metal chains interact with graphene with varying intensity, making it possible to achieve either rigid or non-rigid band doping in graphene. PMID- 25556704 TI - Quality of life in Arab Muslim cancer survivors following hematopoietic stem cell transplantation: comparison with matched healthy group. AB - PURPOSE: The aims of this study were to determine if quality of life (QOL) among Arab Muslim hematopoietic stem cell transplantation (HSCT) survivors differs from that of a healthy matched comparison group and to examine the relationships of demographic and medical variables and perceived social support with post-HSCT QOL. METHODS: HSCT survivors (n = 63) were recruited from the King Hussein Cancer Center outpatient clinic. A matched (age, gender, education), healthy comparison group (n = 63) was recruited through public advertisements. Participants completed the EORTC-30 QOL scale and the Medical Outcomes Study Social Support Survey. RESULTS: Differences were found between the Arab Muslim HSCT survivor and healthy comparison groups for physical functioning (p < .0001), role functioning (p < .01), social functioning (p < .0001) QOL domains, and an overall symptom score (p = .003) with the HSCT group reporting poorer status than the healthy comparison group. Effect sizes for the three QOL domains ranged from .50 (role functioning) to 1.20 (social functioning). No significant difference was noted between the Arab Muslim HSCT and comparison groups in emotional and cognitive QOL domains. Higher overall symptom scores were significantly associated with poorer QOL across all QOL domains. CONCLUSION: Similar to prior research with HSCT survivors, results suggest that HSCT has a significant negative impact on QOL. However, despite this general similarity, results suggest that the needs and experience of Muslim Arab HSCT survivors might differ from those of Western HSCT survivors in the social and emotional QOL domains. Given growing numbers of Arab and Muslim cancer survivors in the USA and other Western countries, future research is warranted. PMID- 25556707 TI - Nutritional supplement and doping use in sport: Possible underlying social cognitive processes. AB - There is growing evidence suggesting that nutritional supplement (NS) use is strongly associated to doping use in elite and amateur sports. However, there is a paucity of research on the psychological processes that underlie this association. The present study investigated the cognitive and behavioral components of the association between NS use and doping among adolescent sub elite athletes. Six hundred and fifty adolescent athletes completed a questionnaire including measures of doping intentions, attitudes, norms, and beliefs about NS use. The results showed that NS users who did not report doping use had significantly stronger doping intentions and more positive attitudes and favorable beliefs toward doping use, as compared with athletes who did not use NS. In support of the "shared mental representations" hypothesis, the present findings show that NS use is associated with biased reasoning patterns in favor of doping use. This mechanism may explain why some NS users decide to engage in doping. PMID- 25556708 TI - Implementation of the WHO-6-step method in the medical curriculum to improve pharmacology knowledge and pharmacotherapy skills. AB - AIM: The only validated tool for pharmacotherapy education for medical students is the 6-step method of the World Health Organization. It has proven effective in experimental studies with short term interventions. The generalizability of this effect after implementation in a contextual-rich medical curriculum was investigated. METHODS: The pharmacology knowledge and pharmacotherapy skills of cohorts of students, from years before, during and after implementation of a WHO 6-step-based integrated learning programme were tested using a standardized assessment containing 50 items covering knowledge of basic (n = 25) and clinical (n = 24) pharmacology, and pharmacotherapy skills (n = 1 open question). All scores are expressed as a percentage of the maximum score possible per (sub)domain. RESULTS: In total, 1652 students were included between September 2010 and July 2014 (participation rate 89%). The WHO-6-step-based learning programme improved students' knowledge of basic pharmacology (mean score +/- SD, 60.6 +/- 10.5% vs. 63.4 +/- 10.9%, P < 0.01) and clinical or applied pharmacology (63.7 +/- 10.4% vs. 67.4 +/- 10.3%, P < 0.01), and improved their pharmacotherapy skills (68.8 +/- 26.1% vs. 74.6% +/- 22.9%, P 0.02). Moreover, satisfaction with education increased (5.7 +/- 1.3 vs. 6.3 +/- 1.0 on a 10-point scale, P < 0.01) and as did students' confidence in daily practice (from -0.81 +/- 0.72 to -0.50 +/- 0.79 on a -2 to +2 scale, P < 0.01). CONCLUSIONS: The WHO-6-step method was successfully implemented in a medical curriculum. In this observational study, the integrated learning programme had positive effects on students' knowledge of basic and applied pharmacology, improved their pharmacotherapy skills, and increased satisfaction with education and self-confidence in prescribing. Whether this training method leads to better patient care remains to be established. PMID- 25556709 TI - Transrectal ultrasound-guided biopsy sepsis and the rise in carbapenem antibiotic use. AB - BACKGROUND: This study sought to determine the number of hospital admissions for sepsis following transrectal ultrasound-guided (TRUS) biopsy, and the rate of both prophylactic and therapeutic use of carbapenem antibiotics for TRUS biopsy, at a single institution. METHODS: A retrospective review of prospectively collected data from the medical records electronic database of Cabrini Health, a private metropolitan hospital, was queried for coding of admissions under any admitting urologist for sepsis and prostate-related infections from 2009 to 2012. Records were examined for whether a TRUS biopsy had been performed within 14 days prior and if a therapeutic carbapenem was required. The database also queried the use of carbapenems as prophylaxis in patients undergoing TRUS biopsy. RESULTS: Of the 63 admissions for TRUS biopsy sepsis, multi-drug-resistant organisms were isolated from 26 (41%). Twenty-three admissions were from the 1937 patients who underwent a TRUS biopsy at Cabrini (a sepsis rate of 1.2%) and 40 were following TRUS biopsies at other centres. Thirty-seven (58.7%) patients received therapeutic carbapenems either empirically, or after culture results. Of the 1937 Cabrini TRUS biopsy patients, 154 (8%) were given a carbapenem as prophylaxis, with a rapid increase in prophylactic use over the 4 years studied from 0.25% to 13%. CONCLUSION: This study did not show evidence of an increasing rate of hospital admissions for TRUS biopsy sepsis at this institution. However, there was a dramatic uptake in prophylactic administration of carbapenems. Increasing carbapenem use may contribute to development of carbapenem-resistant bacteria. Alternative methods of prostate biopsy that avoid sepsis should be considered. PMID- 25556710 TI - Exploring Noninvasive Tricuspid dP/dt as a Marker of Right Ventricular Function. AB - BACKGROUND: Right ventricular (RV) function assumes prognostic significance in various disease states, but RV geometry is not amenable to volumetric assessment by two-dimensional echocardiography. Intra-ventricular pressure rate of rise (dP/dt) predicts myocardial contractility and adjusting for the maximal regurgitant velocity (Vmax) corrects for preload. We examined the relationship of noninvasive tricuspid dP/dt and dP/dt/Vmax with RV ejection fraction (RVEF) by cardiac magnetic resonance imaging (CMR) as a measure of RV function. METHODS: Fifty CMRs and echocardiograms performed within 30 days were included. Tricuspid regurgitation (TR) spectral Doppler trace was analyzed offline. TR dP/dt was calculated using simplified Bernoulli equation (dP/dt between 1 and 2 m/sec). dP/dt/Vmax was calculated as a ratio of dP/dt and TR Vmax . RV end-diastolic (EDV) and end-systolic volumes (ESV) were obtained from contouring of steady state-free precession axial stack CMR images; RVEF was calculated as [(RVEDV - RVESV)/RVEDV] * 100. RVEF >42% was considered normal. RESULTS: Majority of studies were suitable for analysis. Median age was 48 years (IQR = 36-63); 56.4% were female (n = 22/39). There was correlation between dP/dt and RVEF (r(2) = 0.51, P < 0.01) which improved with dP/dt/Vmax (r(2) = 0.59, P < 0.01). dP/dt >400 mmHg/sec had a positive predictive value of 91%, sensitivity and specificity of 74% and 84% respectively for normal RVEF. Inter-observer agreement and repeatability analysis showed no significant difference. CONCLUSION: Tricuspid dP/dt correlates well with CMR RVEF. A dP/dt of more than 400 mmHg/sec strongly predicts normal RVEF. Adjusting for preload (dP/dt/Vmax) further improves this correlation. PMID- 25556711 TI - Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. PMID- 25556712 TI - Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation. AB - The histone modification H3K27me3 regulates transcription negatively, and Jmjd3 and Ezh2 demethylate and methylate H3K27me3 and H3K27, respectively. We demonstrated previously that Jmjd3 plays pivotal roles in the differentiation of subsets of bipolar (BP) cells by regulating H3K27me3 levels at the Bhlhb4 and Vsx1 loci, both of which are transcription factors essential for the maturation of BP cell subsets. In this study, we examined the role of Ezh2 in retinal development using retina-specific Ezh2 conditional knockout mice (Ezh2-CKO). The eyes of the Ezh2-CKO mice were microphthalemic, and the proliferation of retinal cells was diminished postnatally in Ezh2-CKO. Differentiation of all examined retinal subsets was observed with higher proportion of BP cell subsets, which was determined by immunostaining using specific retinal markers. The onsets of Muller glia and rod photoreceptor differentiation were accelerated. The expression of Bhlhb4 was increased in postnatal retinas, which was accompanied by the loss of H3K27me3 modifications at these genetic loci. Decreased expression of proneural genes in postnatal stage was observed. As reported previously in other Ezh2-KO tissues, increased expression of Arf/Ink4a was observed in the Ezh2-CKO retinas. The ectopic expression of Arf or Ink4a in the retina suppressed proliferation and increased apoptosis. In addition, earlier onset of Muller glia differentiation was observed in Ink4a-expressing cells. These results support an important role for histone H3K27me3 modification in regulating the proliferation and maturation of certain subsets of interneurons in the retina. PMID- 25556713 TI - Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with LiraglutideTM. AB - OBJECTIVE: Cerebral microvascular impairments occurring in AD may reduce Abeta peptide clearance and impact upon circulatory ultrastructure and function. We hypothesized that microvascular pathologies occur in organs responsible for systemic Abeta peptide clearance in a model of AD and that Liraglutide (Victoza((r))) improves vessel architecture. METHODS: Seven-month-old APP/PS1 and age-matched wild-type mice received once-daily intraperitoneal injections of either Liraglutide or saline (n = 4 per group) for eight weeks. Casts of cerebral, splenic, hepatic, and renal microanatomy were analyzed using SEM. RESULTS: Casts from wild-type mice showed regularly spaced microvasculature with smooth lumenal profiles, whereas APP/PS1 mice revealed evidence of microangiopathies including cerebral microanuerysms, intracerebral microvascular leakage, extravasation from renal glomerular microvessels, and significant reductions in both splenic sinus density (p = 0.0286) and intussusceptive microvascular pillars (p = 0.0412). Quantification of hepatic vascular ultrastructure in APP/PS1 mice revealed that vessel parameters (width, length, branching points, intussusceptive pillars and microaneurysms) were not significantly different from wild-type mice. Systemic administration of Liraglutide reduced the incidence of cerebral microanuerysms and leakage, restored renal microvascular architecture and significantly increased both splenic venous sinus number (p = 0.0286) and intussusceptive pillar formation (p = 0.0129). CONCLUSION: Liraglutide restores cerebral, splenic, and renal architecture in APP/PS1 mice. PMID- 25556715 TI - Treatment of multidrug-resistant pseudomonas aeruginosa using extended-infusion antimicrobial regimens. AB - In the management of multidrug-resistant infections in critically ill patients with multiorgan dysfunction, consideration must be given to the pharmacokinetics and pharmacodynamics of an antimicrobial agent to optimize dosing. We describe a 25-year-old woman who was undergoing thrice-weekly hemodialysis and developed multidrug-resistant Pseudomonas aeruginosa bacteremia secondary to infected left and right ventricular assist devices. After multiple courses of antibiotics, her blood cultures revealed that the infecting organism was becoming progressively more resistant to antibiotic options. Cefepime 2 g administered over 3 hours/day (in combination with colistimethate) provided adequate drug levels for multidrug resistant, cefepime-intermediate P. aeruginosa bacteremia in this patient. We present the clinical case of this patient, followed by a discussion of possible therapeutic approaches to be considered, including illustration of the principles of using extended-infusion antimicrobial regimens, and present the patient's resulting clinical course. PMID- 25556714 TI - Forns index predicts recurrence and death in patients with hepatitis B-related hepatocellular carcinoma after curative resection. AB - BACKGROUND & AIMS: Advanced liver fibrosis is associated with recurrence after curative resection of hepatocellular carcinoma (HCC). This study aimed to investigate whether noninvasive fibrosis indices could predict intrahepatic recurrence and death after curative resection of HCC. METHODS: Patients who underwent curative resection for hepatitis B virus (HBV)-related HCC between 2006 and 2010 at a single tertiary hospital were included. This study analysed the association of noninvasive fibrosis indices with recurrence and overall survival. RESULTS: A total of 303 patients were included. During a median follow-up period of 56.0 (interquartile range, 42.0-70.0) months, 151 (49.8%) patients experienced HCC recurrence and 54 (17.8%) died. Based on multivariate analysis, Forns index [hazard ratio (HR), 1.238; 95% confidence interval (CI), 1.097-1.398; P = 0.001] was independently associated with tumour recurrence after adjustment for anti-HBe positivity, histological cirrhosis, tumour size and number. Patients with Forns index <6.9 had a significantly longer recurrence-free survival rate than patients with Forns index >=6.9 (P < 0.001 by log-rank test). Forns index (HR, 1.246; 95% CI, 1.034-1.501; P = 0.02) could also predict overall survival after adjustment for tumour size and number. Forns index detected cirrhosis with an AUROC of 0.700 (95% CI, 0.641-0.758). Aspartate aminotransferase-to-platelet ratio index, cirrhosis discriminant score, FIB-4 index, P2/MS and Lok index detected cirrhosis comparably to Forns index, but were not associated with tumour recurrence or death. CONCLUSIONS: Our data suggest that Forns index could be a useful predictor of recurrence and overall survival after curative resection of HBV-related HCC. PMID- 25556716 TI - Antitumor activity of an anti-CD98 antibody. AB - CD98 is expressed on several tissue types and specifically upregulated on fast cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors. PMID- 25556717 TI - IgE+ B cells are scarce, but allergen-specific B cells with a memory phenotype circulate in patients with allergic rhinitis. AB - BACKGROUND: Despite the critical role of immunoglobulin E (IgE) in allergy, circulating IgE+ B cells are scarce. Here, we describe in patients with allergic rhinitis B cells with a memory phenotype responding to a prototypic aeroallergen. METHODS: Fifteen allergic rhinitis patients with grass pollen allergy and 13 control subjects were examined. Blood mononuclear cells stained with carboxyfluorescein diacetate succinimidyl ester (CFSE) were cultured with Bahia grass pollen. Proliferation and phenotype were assessed by multicolour flow cytometry. RESULTS: In blood of allergic rhinitis patients with high serum IgE to grass pollen, most IgE(hi) cells were CD123+ HLA-DR(-) basophils, with IgE for the major pollen allergen (Pas n 1). Both B and T cells from pollen-allergic donors showed higher proliferation to grass pollen than nonallergic donors (P = 0.002, and 0.010, respectively), whereas responses to vaccine antigens and mitogen did not differ between groups. Allergen-driven B cells that divided rapidly (CD19(mid) CD3(-) CFSE(lo) ) showed higher CD27 (P = 0.008) and lower CD19 (P = 0.004) and CD20 (P = 0.004) expression than B cells that were slow to respond to allergen (CD19(hi) CD3(-) CFSE(mid) ). Moreover, rapidly dividing allergen-driven B cells (CD19(mid) CFSE(lo) CD27(hi) ) showed higher expression of the plasmablast marker CD38 compared with B cells (CD19(hi) CFSE(mid) CD27(lo) ) that were slow to divide. CONCLUSION: Patients with pollen allergy but not control donors have a population of circulating allergen-specific B cells with the phenotype and functional properties of adaptive memory B-cell responses. These cells could provide precursors for allergen-specific IgE production upon allergen re-exposure. PMID- 25556718 TI - Biological heterogeneity of obsessive-compulsive disorder: A voxel-based morphometric study based on dimensional assessment. AB - AIM: Although many neuroimaging studies of obsessive-compulsive disorder (OCD) have reported broad abnormalities in gray matter (GM), their results remain inconsistent. One reason for this inconsistency could be the heterogeneity of OCD. In the present study, we aimed to classify alterations in brain anatomy by OCD subtype. METHODS: Magnetic resonance imaging examinations of 37 OCD patients and 37 matched healthy controls were conducted using a 3.0-Tesla scanner. In the voxel-based morphometric procedure, preprocessed GM structural images were used to compare the two groups, and multiple regression analysis was used to investigate the correlation between regional GM volume in OCD patients and the OCD symptom dimension type assessed by using the Dimensional Yale-Brown Obsessive Compulsive Scale. RESULTS: We found significant reductions in GM volume in broad areas of the left prefrontal, right orbitofrontal, right parietal, right temporal, and right posterior cingulate cortex in the OCD patients compared to healthy controls. In addition, we found specific negative correlations between symptomatic dimension scores and regional GM volumes, mainly as decreased right cerebellum in 'aggression/checking' and decreased right insula in 'contamination/washing'. CONCLUSION: The pathophysiology of OCD may involve widely distributed neural systems. Moreover, there are distinct correlations among symptomatic dimensions and structural abnormalities. PMID- 25556719 TI - Why is impaired sexual function distressing to women? The primacy of pleasure in female sexual dysfunction. AB - INTRODUCTION: Recent research has highlighted a complex association between female sexual function and subjective distress regarding sexual activity. These findings are difficult to explain given limited knowledge as to the mechanisms through which impaired sexual function causes distress. AIM: The current study assessed whether a number of specific consequences of impaired sexual function, including decreased physical pleasure, disruption of sexual activity, and negative partner responses, mediated the association between sexual function and distress. METHODS: Eighty-seven women in sexually active relationships reporting impairments in sexual function completed validated self-report measures and daily online assessments of sexual experiences. MAIN OUTCOME MEASURES: Participants completed the Sexual Satisfaction Scale for Women, the Female Sexual Function Index, and the Measure of Sexual Consequences. RESULTS: Results suggested that decreased physical pleasure and disruption of sexual activity, but not partner responses, statistically mediated the association between sexual function and distress. CONCLUSION: Sexual consequences represent potential maintaining factors of sexual dysfunction that are highly distressing to women. Results are discussed in the context of theoretical models of sexual dysfunction and related treatments. PMID- 25556720 TI - Epicardial fat accumulation, cardiometabolic profile and cardiovascular events in patients with stages 3-5 chronic kidney disease. AB - BACKGROUND: It has been hypothesized that epicardial adipose tissue (EAT) exerts pathogenic effects on cardiac structures. We analysed the associations between EAT and both cardiovascular (CV) disease risk factors and CV events in patients with chronic kidney disease (CKD). PATIENTS AND METHODS: We included 277 nondialysed patients [median age 61, interquartile range (IQR) 53-68 years; 63% men] with stages 3-5 CKD in this cross-sectional evaluation. EAT and abdominal visceral adipose tissue (VAT) were assessed by computed tomography. Patients were followed for median 32 (IQR 20-39) months, and the composite of fatal and nonfatal CV events was recorded. RESULTS: With increasing EAT quartiles, patients were older, had higher glomerular filtration rate, body mass index, waist, VAT and coronary calcification, higher levels of haemoglobin, triglycerides, albumin, C-reactive protein and leptin and higher prevalence of left ventricular hypertrophy and myocardial ischaemia; total and high-density lipoprotein cholesterol, 25-hydroxy-vitamin D and 1, 25-dihydroxy-vitamin D progressively decreased. Associations between EAT and cardiac alterations were not independent of VAT. During follow-up, 58 CV events occurred. A 1-SD higher EAT volume was associated with an increased risk of CV events in crude [hazard ratio (HR) 1.41, 95% confidence interval (CI) (1.12-1.78) and adjusted (HR 1.55, 95% CI 1.21-1.99) Cox models. However, adding EAT to a standard CV disease risk prediction model did not result in a clinically relevant improvement in prediction. CONCLUSION: Epicardial adipose tissue accumulation in patients with CKD increases the risk of CV events independent of general adiposity. This is consistent with the notion of a local pathogenic effect of EAT on the heart or heart vessels, or both. However, EAT adds negligible explanatory power to standard CV disease risk factors. PMID- 25556721 TI - A high-temperature molecular ferroelectric Zn/Dy complex exhibiting single-ion magnet behavior and lanthanide luminescence. AB - Multifunctional molecular ferroelectrics are exciting materials synthesized using molecular chemistry concepts, which may combine a spontaneous electrical polarization, switched upon applying an electric field, with another physical property. A high-temperature ferroelectric material is presented that is based on a chiral Zn(2+) /Dy(3+) complex exhibiting Dy(3+) luminescence, optical activity, and magnetism. We investigate the correlations between the electric polarization and the crystal structure as well as between the low-temperature magnetic slow relaxation and the optical properties. PMID- 25556722 TI - Diagnostic efficacy of a brand-new endoscopic ultrasound processor for early stage chronic pancreatitis. PMID- 25556723 TI - Is there a place for community treatment orders after the OCTET study? PMID- 25556724 TI - A case of metastatic pancreatic adenocarcinoma with prolonged survival after combination of neoadjuvant FOLFIRINOX therapy and synchronous distal pancreatectomy and hepatectomy. AB - In this case report we detail the treatment of a patient with pancreatic ductal adenocarcinoma and a solitary liver metastasis who received nine cycles of FOLFIRINOX therapy with favourable response. The patient subsequently underwent synchronous distal pancreatectomy and hepatectomy with an R0 resection followed by three further cycles of FOLFIRINOX. At the last follow-up, 2 years from operation and 28 months from the diagnosis of metastatic pancreatic adenocarcinoma the patient remains disease free. PMID- 25556725 TI - Research advances in artificial musk. AB - Based on the milestone events in the research and development of artificial musk,this artilce elucidates the applications of the musk as traditional Chinese medicine,the protection of the musk deer,the research and development principles and strategies of artificial musk. Artificial musk is a major breakthrough in research on substitutes for medicinal raw materials derived from rare animals. PMID- 25556726 TI - Research, Development, and industrialization of artificial musk: an overview. AB - Four key problems need to be addressed during the research and development of artificial musk. The past two decades have witnessed the remarkable industrialization of artificial musk in China. PMID- 25556727 TI - Effect of artificial musk aqueous extract on the expressions of inflammatory mediators released from lipopolysaccharide-stimulated RAW264.7 cells. AB - OBJECTIVE: To identify the anti-inflammatory effects of artificial musk aqueous extract(AME)on lipopolysaccharide-stimulated cytokines secreted or released by RAW264.7 cells. METHODS: Cytokines including interleukin(IL)-6,IL-10,and tumor necrosis factor Alpha were determined using cytokine enzyme-linked immunosorbent assay kits. RESULT: Compared with model group,the levels of major cytokines such as tumor necrosis factor Alpha,IL-6,and IL-10 significantly decreased in different AME groups in a dose-dependent manner. CONCLUSION: In lipopolysaccharide-stimulated RAW264.7 macrophages,AME can remarkably inhibit the release of inflammatory cytokines and thus exerts its anti-inflammatory effects. PMID- 25556728 TI - High performance liquid chromatography characteristic spectrum of artificial musk. AB - OBJECTIVE: To determine the high performance liquid chromatography(HPLC)characteristic spectrum of artificial musk. METHODS: HPLC was performed on a HiQ Sil C18 analytical column(4.6 mm*250 mm)with the mobile phase of methanol/water(90:10 v/v);the detection wavelength was 254 nm and the column temperature was maintained at 25 C. The similarities among 10 batches of artificial musk samples were anlysised in accordance with the System for Evaluating the Similarities among the Chromatographic Fingerprints of Traditional Chinese Drugs,which is recommended by Chinese Pharmacopoeia Commission. RESULT: The similarities among these 10 batches of artificial musk ranged between 0.999 and 1.000. CONCLUSION: HPLC is a convenient,accurate and reliable technique for establishing the specific spectum of artificial musk and therefore can be used for the quality control of this product. PMID- 25556729 TI - Detection of artificial musk in Xihuangwan by gas chromatography-mass spectrometery. AB - OBJECTIVE: To control the quality of Xihuangwan by improving the qualitative detection of artificial musk inside this pill. METHOD: The qualitative detection of artificial musk was carried out by gas chromatography-mass spectrometery(GC MS). RESULT: The established GC-MS successfully detected artificial musk in Xihuangwan. CONCLUSION: GC-MS is reliable,accurate,and practical in the identification of artificial must inside Xihuangwan. PMID- 25556730 TI - Determination of the content of residual solvents in Haikesu I by head-space gas chromatography. AB - OBJECTIVE: To explore the usefulness of head-space gas chromatography for the determination of methanol and ethanol in Haikesu I,a raw material of artificial musk. METHODS: The determination was performed on HP-5(30 m*0.53 mm,5 MUm)capillary column with an hydrogen flame ionization detector. The solvent was dimethyl sulfoxide and the internal standard was acetone. The injector temperature and the detector temperature were controlled at 180 C and 250 C,respectively. The carrier gas was nitrogen. The containers of head-space injector were preheated at 90 C for 15 minutes. The column temperature was programmed raised,which achieved baseline separation of the components. RESULTS: The results showed a good linear relationship for methanol and ethanol in their linearity range;and the limit of detection was 0.8 and 1.0 MUg/ml,respectively. The precision and average recoveries were satisfactory. CONCLUSION: The head space gas chromatography is simple,rapid,and precise technique for the measurement of residual solvents in Haikesu I. PMID- 25556731 TI - Determination of the content of residual solvents in Haikesu 2 by head-space gas chromatography. AB - OBJECTIVE: To determine ethylacetate and petroleum ether(60-90 C)in Haikesu 2,which is one of the raw materials of artificial musk,using the head-space gas chromatography. METHODS: The determination was performed on HP-5(30 m*0.53 mm,5 MUm)capillary column with an hydrogen flame ionization detector. The solvent was dimethyl sulfoxide and the internal standard was methanol. The injector temperature and the detector temperature were controlled at 180 C and 250 C,respectively. The carrier gas was nitrogen. The containers of head-space injector were preheated at 90 C for 15 minutes. The column temperature was programmed raised,which achieved baseline separation of the components. RESULTS: The results showed a good linear relationship for ethylacetate and petroleum ether(60-90 C)in their linearity range;and the limit of detection was 0.7 and 0.3 MUg/ml,respectively. The good precision and good average recoveries were satisfactory. CONCLUSION: The head-space gas chromatography is simple,rapid,and precise technique for the measurement of residual solvents in Haikesu 2. PMID- 25556732 TI - Determination of the content of residual solvents in muscone by head-space gas chromatography. AB - OBJECTIVE: To explore the usefulness of a head-space gas chromatography in the determination of residual solvents including methanol,ethanol,ethyl ether,and petroleum ether in muscone in artificial musk. METHODS: The head-space gas chromatography was performed on HP-5(30 m*0.53 mm,5 MUm)capillary column with a hydrogen flame ionization detector. The carrier gas was nitrogen and the solvent was dimethyl sulfoxide. The injector temperature and the detector temperature were controlled at 180 C and 250 C,respectively. The containers of head-space injector were preheated at 80 C for 15 minutes. The column temperature was programmed raised,which achieved baseline separation of the components. RESULTS: The results showed a good linear relationship for methanol,ethanol,ethyl ether,and petroleum ether(60-90 C)in the range of each consistency; and the limit of detection was 0.8,1.0,0.1,and 0.3 MUg/ml,respectively. The precision and average recoveries were satisfactory. CONCLUSION: The head-space gas chromatography is simple,rapid,and precise technique for measuring residual solvents in muscone. PMID- 25556733 TI - Determination of the contents of five heavy metals in artificial musk. AB - OBJECTIVE: To evaluate the safety of artificial musk by determining its content of five hazard heavy metals. METHOD: The contents of Pb, Cd,As,Hg,and Cu in artificial musk were detected using inductively coupled plasma-mass spectrometry. RESULT: The contents of Pb,Cd,As,Hg,and Cu was less than 0.35,0.05,0.30,0.20,and 4.50 mg/kg in artificial musk. CONCLUSION: Artificial musk has low contents of heavy metals and therefore meets the safety and quality requirments. PMID- 25556734 TI - Effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in mice. AB - OBJECTIVE: To investigate the effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in C57BL/6 mice. METHODS: Four-week-old C57BL/6 mice were allocated into normal diet group,high-fat diet group,and high-glucose diet group according to the random number table until 20 weeks old. Body weight,epididymal adipose tissue weight,blood leptin,fat infiltration in liver,M1/M2 macrophage subtypes,and monocyte chemoattractant protein-1 mRNA in epididymal adipose tissues were measured. RESULTS: Compared with normal diet group,body weight,epididymal adipose tissue weight,and leptin concentration in high fat diet group at 20 weeks were significantly increased (P < 0.05),and oil red O staining showed more prominent adipocyte infiltration in liver in high-fat diet group than those in normal diet and high-glucose diet group. However,no apparent differences were seen in high-glucose diet group at 20 weeks in terms of body weight,epididymal adipose tissue weight and leptin concentration. In high fat diet group,the macrophages infiltration in epididymal adipose tissue increased with time and the percentage of M2 macrophage decreased in high-fat diet group than that in high-glucose diet group(P<0.05). Compared with normal diet group,monocyte chemoattractant protein-1 mRNA expression increased significantly in high-fat diet group(P<0.05). In high-glucose group,however,no significant differences were discerned (P > 0.05). CONCLUSION: High-fat diet,rather than 60% high glucose diet,will lead to obesity and macrophage infiltration in adipose tissues. PMID- 25556735 TI - Impact of cuff pressure on airway leak pressure in laryngeal mask airway supreme and flexible. AB - OBJECTIVE: To investigate the impact of cuff pressure on airway leak pressure in laryngeal mask airway(LMA)Supreme and Flexible. METHODS: Patients about to have elective breast surgery were divided into Supreme group(35 cases)and Flexible group(33 cases). After general induction of anesthesia,LMA Supreme or Flexible was inserted by one anesthesiologist. We confirmed the LMA location,adjusted the cuff pressure,and recorded the peak airway leak pressures under different cuff pressures(10,20,30,40,and 50 cmH2O). RESULTS: In Supreme group,peak airway leak pressures [(24.46+/-5.43),(25.11+/-5.51),(25.86+/-5.57),(26.17+/-5.72)cmH2O] under 20,30,40,and 50 cmH2O cuff pressure showed no significant difference(P>0.05)between each other,but significantly higher than that under 10 cmH2O cuff pressure(20.80+/-4.63)cmH2O(P<0.05). And in the Flexible group,peak airway leak pressures [(20.09+/-2.98),(20.70+/-3.08),(21.21+/-3.15)cmH2O] under 30,40,50 cmH2O cuff pressure also showed no significant difference(P>0.05)between each other,but significantly higher than those under 10 or 20 cmH2O cuff pressure [(17.52+/-2.39),(18.61+/-2.42)cmH2O]. Mean peak airway leak pressure [(25.40+/ 5.52) cmH2O] of LMA Supreme was significantly higher than that of LMA Flexible(20.67+/-3.06)cmH2O(P<0.05). CONCLUSIONS: Mean airway leak pressure of LMA Supreme is higher than LMA Flexible. The lowest cuff pressure to meet the tightness requirement with LMA Supreme is 20 cmH2O,which is lower than Flexible(30 cmH2O). PMID- 25556736 TI - Comparison of endovascular aortic repair and open surgical repair for ruptured abdominal aortic aneurysm. AB - OBJECTIVE: To compare the clinical efficacies of endovascular aortic repair(EVAR)and open surgical repair(OSR)for ruptured abdominal aortic aneurysm(rAAA). METHODS: The clinical data of 28 rAAA patients undergoing emergent treatment between February 2002 and February 2013 in PUMC Hospital were retrospectively reviewed. Among them 13 cases were treated by EVAR and 15 cases by OSR. RESULTS: Before the surgery,the general conditions,comorbidities,and hemodynamics were not significantly different between these two groups(all P>0.05),although the EVAR group had significantly higher mean age than OSR group(P=0.041). In the perioperative period,the EVAR group showed significantly lower 30-day mortality(P=0.044),less blood loss(P=0.005),less blood transfusion(P=0.003),less infusion quantity(P=0.000),shorter length of procedure(P=0.001),and shorter hospital stay(P=0.020). Also,the EVAR group had no severe perioperative complications and showed superior 1-year follow up survival(P<0.05). CONCLUSIONS: EVAR is an effective treatment for rAAA and can improve the clinical outcomes. EVAR may be adopted as the first-line treatment for rAAA,especially for the aged. PMID- 25556737 TI - Relationship between cardiovascular responses and coping styles among recruits under the stress. AB - OBJECTIVE: To explore the relationship between the cardiovascular responses and coping styles among recruits in psychological stress. METHODS: Using random cluster sampling method,we chose 406 army recruits in Xinjiang from October 2013 to November 2013,and the questionnaire survey combined with laboratory test was applied. The questionnaire used in this study was the simplified coping style questionnaire. Systolic blood pressure(SPB),diastolic blood pressure(DPB),and heart rate(HR)were recorded. The relationship between cardiovascular responses and coping methods was analyzed using descriptive statistics,correlations,and regression analysis. RESULTS: There were statistically significant differences in changes of the indicators of cardiovascular responses(P=0.000). The positive coping styles were significantly associated with age(P=0.008)and father's education degree(P=0.010). The negative coping styles were associated with the mother's educational degree(P=0.046). The positive coping styles were associated with the SBP in recall task period(P=0.039)and with the HR in calculating task period(P=0.025). The negative coping styles were significantly associated with the SBP difference between the baseline and calculating task period(P=0.034). Stepwise regression analysis showed that age and father's education degree(P=0.008,P=0.041)had a positive effect on the positive coping styles,and the SPB difference between the baseline and calculating task period had a negative effect on the positive coping styles(P=0.034). CONCLUSIONS: Age and father's education degree can affect the positive coping style of the recruits. Increased psychological stress has a negative impact on the negative coping styles of the recruits. PMID- 25556738 TI - Safety and efficacy of microscope-assisted insertion of screws into fused C1 occipital condyle complex for occipital cervical fixation in atlantal cervical nonsegmentation patients. AB - OBJECTIVE: To explore the safety and efficacy of the insertion of screws into fused C1-occipital condyle(CC)complex without image guidance in atlantal-cervical nonsegmentation patients. METHODS: The occipital condyle junction was fixed posteriorly in 10 basilar invagination patients with atlantal-cervical nonsegmentation using polyaxial titanium screws(3.5 mm)inserted unicortically into the CC complex and C2 pedicles,followed by fixation to a 3 mm rod. Drilling was guided by anatomic landmarks. The entry point was at the center of posterior surface of the CC complex. The angle of medicalization was 10-15 degrees. In the sagittal plane,the angle for maximal superior screw angulation was also 10-15 degrees. The screw length to obtain unicortical purchase was 16 to 22 mm. CT scans were obtained before and after the surgery. The length,width,and height of CC complex were measured on computed tomography(CT)preoperatively. The position of screws and the condition of fixation were analyzed on postoperative CT scan. Postoperative complications were recorded. The mean follow-up was(30.2+/ 4.38)months(range: 24-36 months). RESULTS: The width,length,height of left side CC complex were(7.96+/-2.23)mm,(16.06+/-2.73)mm,and(13.76+/-2.06)mm,and the width,length,height of right side CC complex were(7.84+/-1.38)mm,(16.66+/ 2.58)mm,and(12.81+/-2.62)mm. No fracture was identified. There was no screw malposition or neurovascular complication related to screw insertion. No screw loosening or construct failure was observed during the follow-up. CONCLUSIONS: In patients with atlantal cervical nonsegmentation,the CC complex screws can be safely inserted assisted by microscope without image guidance. Occipital condyle junction fixation using polyaxial CC complex screws is feasible and can be a good alternative where other fixation techniques are not satisfactory. PMID- 25556739 TI - Clinical features of 30 patients with cryoglobulinemia. AB - OBJECTIVE: To summarize the clinical features of cryoglobulinemia. METHOD: We retrospectively analyzed the clinical data of 30 patients admitted to Peking Union Medical College Hospital from January 2003 to March 2013 due to cryoglobulinemia. RESULTS: The average age was(53.8+/-11.9)years in these 30 patients(12 men and 18 women),among whom 22 patient(73.3%)developed infectious diseases including hepatitis B(n=11)and hepatitis C(n=11);in addition,3 hepatitis B patients and 1 hepatitis C patient also had malignancies. Four patients(13.3%)were accompanied with malignant lymphocytic proliferation diseases,and three(10.0%)with connective tissue diseases. The cause of disease was unclear in 5 patients(16.7%). The clinical manifestations varied due to the primary diseases;notably,20 patients(66.7%)had an onset of purpura rash,22(73.3%)and 19(63.3%)were accompanied with hypertension and chronic renal insufficiency,respectively. The severity of renal involvement was relevant with the increase of C reactive protein,erythrocytes,sedimentation rate,and IgM and the decrease of complements. Treatment should be directed at the primary diseases. Glucocorticoid and immunosuppressants were good choices for relieving renal involvement. Elderly, type 1 cryoglobulinemia,and poor renal function were associated with the poor prognosis. CONCLUSIONS: Cryoglobulinemia is mainly seen in middle and elderly patients. It can often affect multiple systems,in particular the kidney. Inflammatory markers,IgM,and complements is related with the disease severity. Age,primary disease,and renal function are related with prognosis. PMID- 25556740 TI - Characteristics of serum lipid metabolism in patients with autoimmune pulmonary alveolar proteinosis. AB - OBJECTIVE: To study the serum lipid panels in consecutive autoimmune pulmonary alveolar proteinosis(APAP)patients and analyze their relationship with anti granulocyte macrophage-colony stimulating factor(GM-CSF)antibody and other markers. METHODS: Thirty-two non-diabetic APAP patients were enrolled in the study. Serum lipids of these patients and 100 healthy volunteers were tested after an overnight fasting. Anti-GM-CSF antibody levels were measured with enzyme linked immunosorbent assay. The correlation of serum lipids with lactate dehydrogenase,carcinoembryonic antigen,pulmonary function,and artery blood gas parameters were analyzed. RESULTS: Total cholesterol and low-density lipoprotein cholesterol levels [(5.54+/-0.99)and(3.73+/-0.83)mmol/L respectively] were significantly higher in APAP patients than in healthy volunteers [(5.05+/ 0.97)and(3.17+/-0.89)mmol/L respectively](all P<0.05). High-density lipoprotein cholesterol(HDL-C)level of the APAP group [(1.10+/-0.18)mmol/L ]was significantly lower than that of the healthy group(P<0.05). Low-density lipoprotein/HDL and total cholesterol/HDL ratios in the APAP group(3.47+/-0.90 and 5.14+/-1.12 respectively)were significantly higher than those in the healthy group[(2.63+/ 0.87)and(4.18+/-1.12)](all P<0.05). There was no significant difference in triglyceride level between the two groups(P>0.05). HDL-C level was negatively correlated with alveolar-arterial oxygen pressure difference(r=-0.436,P<0.05)and positively correlated with arterial oxygen saturation(r=0.459,P<0.05). None of the lipid markers correlated with serum anti-GM-CSF antibody levels(all P>0.05). CONCLUSIONS: APAP patients were likely to suffer from disturbed lipid metabolism,which was correlated with disease severity to some degree. Lipid markers deserved more attention in the management of APAP patients. PMID- 25556741 TI - Expression of vascular endothelial growth factor in deep second-degree scald wounds in rats. AB - OBJECTIVE: To observe the expression of vascular endothelial growth factor(VEGF)in deep second-degree scald wounds,with an attempt to further explore the role of VEGF in burn wound healing. METHODS: Totally 36 adult Wistar rats were randomized into two groups: the scald group(30 rats)and the control group(6 rats). In the scald group,rat models of deep second-degree scald wounds were established. Full-thickness tissues of the wounds were collected respectively 1,3,7,14,and 21 days after the modeling. The expressions of the VEGF mRNA and protein were detected with real-time quantitative PCR and Western blot,respectively. In the control group,the same procedures were performed but without modeling. RESULTS: Compared with the control group,the expressions of VEGF mRNA and proteins were significantly higher in the scald group(P<0.05). The expression levels reached the peak on day 1,gradually decreased on day 3,reached the lowest points on day 14,but increased again on day 21. CONCLUSIONS: VEGF is involved in the healing of scald burns. The expression of VEGF during the wound healing is closely correlated with the wound angiogenesis. PMID- 25556742 TI - Effect of bone morphogenetic protein 7 on differentiation of adipose derived mesenchymal stem cells into brown adipocytes in rats. AB - OBJECTIVE: To evaluate the effect of bone morphogenetic protein(BMP7)on the differentiation of adipose derived mesenchymal stem cells(AD-MSCs)isolated from different adipose tissues into brown adipocytes in rats. METHODS: Primary AD-MSCs were isolated from rate interscapular brown adipose tissue(iBAT),inguinal subcutaneous white adipose tissue(sWAT),and epididymal white adipose tissue(eWAT),respectively,and then cultivated in vitro. Differentiation of AD MSCs into brown adipocytes was induced by BMP7. The characteristics of brown adipocytes were detected by immunofluorescence staining and oil red staining of cells. The expression levels of brown adipocyte-related genes were detected by polymerase chain reaction. RESULTS: AD-MSCs from iBAT and sWAT were differentiated into cluster multilocular cells,which were stained red by oil red "O"staining and showed uncoupling protein 1-positive by immunofluorescent staining method. AD-MSCs from eWAT had a small number of scattered multilocular cells and showed uncoupling protein 1-negative. The results of reverse transcription-polymerase chain reaction showed that the uncoupling protein 1 gene was highly expressed in the iBAT group and sWAT group but was negative in the eWAT group. CONCLUSION: AD-MSCs isolated from different adipose tissues in rats have different gene expression profiles and differentiation potentials. PMID- 25556743 TI - Effect of sinusoidal electromagnetic field on bone mineral density and histomorphometry of rats at different time points. AB - OBJECTIVE: To investigate the effect of 50 Hz 0.1 mT sinusoidal electromagnetic field at different time points on bone mineral density(BMD)and histomorphometry in rats. METHODS: Totally 50 6-week-old female SD rats were equally randomized into 5 groups: control group,45-minute group,90-minute group,180-minute group,and 270-minute group. Except for the control group,the other four groups were given magnetic intervention in the 50-Hz 0.1-mT sinusoidal electromagnetic field for 45 minutes,90 minutes,180 minutes,or 270 minutes,respectively,on a daily basis. After 8 weeks,the total body BMD,femur BMD,and vertebral BMD were measured by dual-energy X-ray absorptiometry. The left tibia and the fifth lumbar vertebrae were separated for bone tissue static and dynamic analyses. RESULTS: Compared with control group,the 90-minute group and the 180-minute group had significantly different total body BMD(P<0.01,P<0.05),while no such significant difference was seen in the 45-minute group and 270-minute group (P>0.05). The femur,vertebral BMD,serum biochemical markers,and the static parameters of the fifth lumbar vertebrae tissue showed significant differences in the 90-minute group,180-minute group,and 270-minute group(P<0.01),but not in the 45-minute group (P>0.05). As shown by double fluorescent labeling,the distance was sorted in an order of 90 minute group>180-minutes group>270-minute group>45-minutes group>control group. CONCLUSION: The 50-Hz 0.1-mT sinusoidal electromagnetic field can effectively increase bone mineral density and improve bone morphology;however,the intervention effectiveness differs at different time points,with the best effectiveness seen at 90 minutes. PMID- 25556744 TI - Advances in the medical imaging of multiple myeloma and related clinical significance. AB - Multiple myeloma is an incurable malignancy developed in the bone marrow plasma cell system. It usually consists of focal lesions of the bone,soft tissue lesions,and diffuse bone marrow infiltration. Currently,the diagnosis and follow up of multiple myeloma are highly dependent on various medical imaging techniques. PMID- 25556745 TI - Recent progress of adult orthodontic treatment. AB - With the improvement of living standards and oral health awareness in people and with the development of the techniques in orthodontic therapy,the number of adult patients in orthodontics is gradually increasing. Due to adults' social occupations,psychological factors,complicated intraoral status,these factors make adult patients differences from adolescents. In this paper,the problems related with adult orthodontic treatment were reviewed. PMID- 25556746 TI - Research advances in the application of methylprednisolone in the treatment of acute spinal cord injury. AB - Acute spinal cord injury(ASCI),mainly caused by traffic accidents and fall injuries,is a catastrophic event that can profoundly affect the trajectory of a patient's life. Debate continues over the medical management of ASCI,in particular the usefulness,dosage,and potential risks of methylprednisolone(MP). Although the results of American National Acute Spinal Cord Injury Study 2 and 3 trials led to the wide adoption of a high-dose MP regimen for ASCI patients,the reliabilities of their study methods and data were still questionable. Based on the currently available literature,we conclude that high-dose MP is no longer a recommended therapy for ASCI;however,due to the lack of effective treatment,it remains a useful option for this condition. PMID- 25556747 TI - Role of p66Shc gene in human longevity. AB - The p66Shc gene has emerged as a novel gerontogene affecting health and life during aging. In murine models of aging,a genetic deficiency of the p66Shc gene,which encodes a phosphotyrosine signal adapter protein,extends life span by 30%. p66Shc is a crucial regulator of reactive oxygen species levels and is involved in age-related dysfunctions. UP to now,oxidative stress has been recognized to be involved in human diseases such as high cholesterol,diabetes,and cardiovascular diseases. Further study on the role of p66Shc will facilitate the research of novel disease-targetted drugs and slow down or cure age-related pathologies. PMID- 25556748 TI - Roles of non-coding RNA in pancreatic islet development and functioning. AB - Non-coding RNA is a kind of non-coding protein RNA which is widely present in most of the organisms. Non-coding RNA plays key roles in the embryonic development,cell fate determination,and growth control in the living organisms. MicroRNA and long non-coding RNA involve in differentiation of endocrine cell,insulin gene expression and secretion,and insulin resistance,which are closely associated with diabetes. PMID- 25556749 TI - Regulatory effect of caffeine on the acute and the chronic pain and its possible mechanisms. AB - Caffeine,as an important component of refreshment beverage,has been used for a long history. In recent years,its effect on pain relief has been widely explored. As one of nonselective adenosine receptor blockers,caffeine plays different roles in the central and peripheral pain. This review explores the roles of caffeine in acute and chronic pain and the potential mechanisms. PMID- 25556750 TI - The effect of reactive oxygen species on motility parameters, DNA integrity, tyrosine phosphorylation and phosphatase activity of common carp (Cyprinus carpio L.) spermatozoa. AB - The effect of reactive oxygen species production on the motility parameters, DNA integrity, acid phosphatase activity, and protein tyrosine phosphorylation in spermatozoa of the common carp (Cyprinus carpio) was investigated. Spermatozoa were exposed to different concentrations of xanthine and xanthine oxidase (X-XO) either in the presence or absence of antioxidants for 15 and 60 min. A dose- and time-dependent reduction in spermatozoa motility and velocity was observed. Comet assays showed a dramatic increase in DNA fragmentation after 15 min. Changes in tyrosine phosphorylation of spermatozoa proteins were observed by Western blotting with anti-phosphotyrosine antibodies, and proteins of interest were identified by mass spectrometry. After a 60 min exposure to X-XO, O-linked N acetylglucosamine transferase, isoform 4 was phosphorylated and septin-8-A was dephosphorylated. Acid phosphatase activity also decreased in a dose-dependent manner after a 60 min exposure to oxidative stress. The results demonstrate that oxidative stress impaired functional variables (sperm motility, velocity, DNA integrity) of carp spermatozoa, and altered intracellular signalling pathways through changes in tyrosine phosphorylation and acid phosphatase activity. PMID- 25556751 TI - Reviews 2015. PMID- 25556756 TI - Long-term follow-up of pediatric trachyonychia. AB - Pediatric trachyonychia is an acquired nail disease that can cause distress to families. It is a poorly understood disease, and long-term follow-up data are lacking. We present an institutional review of 11 children with isolated pediatric trachyonychia followed over time. Children with the diagnosis of pediatric trachyonychia were identified and invited to participate. Pictures were taken on follow-up and a questionnaire was answered. Exclusion criteria include having another diagnosis at the initial visit that causes nail dystrophy. Eleven patients with the diagnosis of pediatric trachyonychia were available for follow up. The mean age of appearance was 2.7 years (range 2-7 yrs) and the average follow-up was 66 months (range 10-126 mos). Nine patients were treated with potent topical corticosteroids, one used only petrolatum, and one took vitamin supplements. One patient was found to have an additional skin and hair diagnosis of alopecia areata on follow-up. On follow-up, 82% noted improvement of the nails, whereas 18% noted no change. A majority of cases of pediatric trachyonychia are isolated and improve with time, regardless of treatment. PMID- 25556757 TI - Worse outcome in women with STEMI: a systematic review of prognostic studies. AB - BACKGROUND: Treatment of ST elevation myocardial infarction (STEMI) has improved enormously since the introduction of primary percutaneous coronary intervention (pPCI). It remains unclear whether differences in survival between women and men treated with pPCI exist and whether these potential differences can be explained by gender or by differences in baseline- or procedural characteristics. Therefore we systematically reviewed the available evidence. MATERIALS AND METHODS: On 10 May 2013 PubMed, Embase and Cochrane were searched for studies comprising original data on STEMI patients treated with pPCI. A separate gender analysis including > 100 women was a requirement. Data were extracted and pooled whenever possible. RESULTS: 21 studies were included from 2001 to 2013 comprising 47.439 men and 16.927 women. Women were older, had more diabetes (women 24%, men 15%) and hypertension (women 58%, men 45%), and were less current smokers (women 30%, men 54%). The procedural characteristics were comparable except for a longer symptom-to-balloon time (women 266 min, men 240 min) and less use of GP IIb/IIIa inhibitors in women (women 51%, men 57%). Crude short- and long-term mortality was higher in women. Although we could not pool adjusted mortality proportions due to heterogeneity, generally the difference in mortality disappeared after adjustment for baseline- and procedural characteristics. CONCLUSION: Mortality is higher in women with STEMI and can be explained by their unfavourable risk profile and longer symptom-to-balloon time. PMID- 25556758 TI - Effectiveness of clinical supervision of physiotherapists: a survey. AB - OBJECTIVES: Limited literature exists on the practice of clinical supervision (CS) of professional physiotherapists despite current Australian safety and quality health standards stating that CS is to be provided to all physiotherapists. The aim of the present study was to evaluate the effectiveness of CS of physiotherapists working in an Australian public health service. METHODS: CS was measured using the allied health-specific 26-item modified Manchester Clinical Supervision Scale (MCSS-26). Subscales of the MCSS-26 were summed for three domain scores (normative, restorative and formative) and a total score was calculated, which was compared with the reported threshold score of 73 for effective supervision. Sixty registered physiotherapists (response rate 92%), working for a large metropolitan public health service, with six different site locations, completed the survey. RESULTS: The mean (+/- s.d.) total MCSS-26 score was 71.0 +/- 14.3 (95% confidence interval (CI) 67.4-74.6). Hospital site was the only variable that had a significant effect on total MCSS-26 score (P=0.005); there was no effect for supervisor or supervisee experience, or hospital setting (acute vs subacute). Physiotherapists scored a significantly lower mean percentage MCSS-26 score on the normative domain compared with the restorative domain (mean difference 7.8%; 95% CI 2.9-12.7; P=0.002) and the formative domain (mean difference 9.6%; 95% CI 6.3-13.0; P<0.001). Of the two subscales that form the normative domain, 'finding time' had a significantly lower mean percentage MCSS-26 score than 'importance/value of CS' (mean difference 35.4%; 95% CI 31.3 39.4; P<0.001). CONCLUSIONS: Within this publicly funded physiotherapy department there was uncertainty about the effectiveness of CS, with more than half the physiotherapists rating their supervision as less than effective, suggesting there is opportunity for improvement in the practice of physiotherapy CS. Physiotherapists scored lowest in the normative domain, indicating that they found it difficult to find time for CS. PMID- 25556759 TI - Human rhinovirus serotypes in the nasal washes and mucosa of patients with chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) can be aggravated by viral upper respiratory infections. We aimed to investigate whether any specific human rhinovirus (HRV) serotype is more common in the mucosa of CRS patients, and to find any defining clinical characteristics, according to the various HRV serotypes. METHODS: A prospective case-control study was conducted to determine HRV serotypes in 111 CRS patients and 51 non-CRS controls. No participant had a history of upper respiratory infection over a 4-week period. Nasal lavage fluids and turbinate epithelial cells were collected prospectively. When HRV was detected with multiplex polymerase chain reaction (PCR), strains were further characterized by sequencing the VP4/VP2 region of the HRV genome. RESULTS: HRV was detected in 40 CRS subjects (36%) and 11 non-CRS controls (21%). The overall detection rates of HRV in CRS patients were higher than in non-CRS controls (p < 0.05). Of the 8 serotypes detected in CRS patients, 5 belonged to HRV-A and 3 belonged to HRV-B; HRV-C was not detected. In non-CRS controls, only HRV-A was identified, with only 2 serotypes detected (HRV-A13 and HRV-A16). HRV-B and C were not detected. CONCLUSION: The high prevalence of HRV in CRS patients was confirmed in our study. However, we were unable to determine whether certain HRV serotypes are more predominant in CRS patients than non-CRS controls. HRV-A13 was the most common serotype in both CRS patients and non-CRS controls. We could not find any differences in the clinical characteristics according to the HRV serotypes in CRS patients. PMID- 25556760 TI - Wnt Acts as a Prosurvival Signal to Enhance Dentin Regeneration. AB - Wnt proteins are lipid-modified, short-range signals that control stem cell self renewal and tissue regeneration. We identified a population of Wnt responsive cells in the pulp cavity, characterized their function, and then created a pulp injury. The repair response was evaluated over time using molecular, cellular, and quantitative assays. We tested how healing was impacted by wound environments in which Wnt signaling was amplified. We found that a Wnt-amplified environment was associated with superior pulp healing. Although cell death was still rampant, the number of cells undergoing apoptosis was significantly reduced. This resulted in significantly better survival of injured pulp cells, and resulted in the formation of more tertiary dentin. We engineered a liposome-reconstituted form of WNT3A then tested whether this biomimetic compound could activate cells in the injured tooth pulp and stimulate dentin regeneration. Pulp cells responded to the elevated Wnt stimulus by differentiating into secretory odontoblasts. Thus, transiently amplifying the body's natural Wnt response resulted in improved pulp vitality. These data have direct clinical implications for treating dental caries, the most prevalent disease affecting mankind. PMID- 25556761 TI - Electrochemical properties of substituted 2-methyl-1,4-naphthoquinones: redox behavior predictions. AB - In the context of the investigation of drug-induced oxidative stress in parasitic cells, electrochemical properties of a focused library of polysubstituted menadione derivatives were studied by cyclic voltammetry. These values were used, together with compatible measurements from literature (quinones and related compounds), to build and evaluate a predictive structure-redox potential model (quantitative structure-property relationship, QSPR). Able to provide an online evaluation (through Web interface) of the oxidant character of quinones, the model is aimed to help chemists targeting their synthetic efforts towards analogues of desired redox properties. PMID- 25556762 TI - Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: a comprehensive review. AB - Potential genotoxic impurities in pharmaceuticals at trace levels are of increasing concern to both pharmaceutical industries and regulatory agencies due to their possibility for human carcinogenesis. Molecular functional groups that render starting materials and synthetic intermediates as reactive building blocks for small molecules may also be responsible for their genotoxicity. Determination of these genotoxic impurities at trace levels requires highly sensitive and selective analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical research and development. Experimental guidance for the analytical determination of some important classes of genotoxic impurities is still unavailable in the literature. Therefore, the present review explores the structural alerts of commonly encountered potential genotoxic impurities, draft guidance of various regulatory authorities in order to control the level of impurities in drug substances and to assess their toxicity. This review also describes the analytical considerations for the determination of potential genotoxic impurities at trace levels and finally few case studies are also discussed for the determination of some important classes of potential genotoxic impurities. It is the authors' intention to provide a complete strategy that helps analytical scientists for the analysis of such potential genotoxic impurities in pharmaceuticals. PMID- 25556763 TI - Low concentrations of dibromoacetic acid and N-nitrosodimethylamine induce several stimulatory effects in the invertebrate model Caenorhabditis elegans. AB - Dibromoacetic acid (DBAA) and N-nitrosodimethylamine (NDMA) have natural and anthropogenic sources and are ubiquitously distributed in the environment. They are classified as toxic and carcinogenetic and various studies have addressed their effects on vertebrates. Furthermore, there is no information about the whole-organism effects at low concentrations or about their impact on invertebrates. Therefore, these compounds were studied with the model invertebrate Caenorhabditis elegans (C. elegans) at relatively low concentrations. Biological tests (life span, reproduction, body size, thermal stress resistance) as well as biochemical (pro- and antioxidative capacity and lipid peroxidation) and biomolecular assays (transcription of stress genes) were performed. None of the applied concentrations showed a toxic potential. Instead, they extended life span and increased the body length. Both xenobiotics did not cause oxidative stress or DNA damages, or acted as endocrine disruptors. The stimulatory effects on C. elegans were most likely not a result of an induced protective stress response. Instead, an 'energy saving mode', indicated by the reduced transcription of many stress response genes, could have provided additional resources for longevity and growth. Although both substances are potentially toxic at higher doses, the present study underlines the importance of testing lower concentrations and their impact on invertebrates. PMID- 25556765 TI - Aging attenuates acquired heat tolerance and hypothalamic neurogenesis in rats. AB - This study investigated age-dependent changes in heat exposure-induced hypothalamic neurogenesis and acquired heat tolerance in rats. We previously reported that neuronal progenitor cell proliferation and neural differentiation are enhanced in the hypothalamus of long-term heat-acclimated (HA) rats. Male Wistar rats, 5 weeks (Young), 10-11 months (Adult), or 22-25 months (Old) old, were subjected to an ambient temperature of 32 degrees C for 40-50 days (HA rats). Rats underwent a heat tolerance test. In HA rats, increases in abdominal temperature (Tab ) in the the Young, Adult, and Old groups were significantly smaller than those in their respective controls. However, the increase in Tab of HA rats became greater with advancing age. The number of hypothalamic bromodeoxyuridine (BrdU)-immunopositive cells double stained with a mature neuron marker, neuronal nuclei (NeuN), of HA rats was significantly higher in the Young group than that in the control group. In Young HA, BrdU/NeuN-immunopositive cells of the preoptic area/anterior hypothalamus appeared to be the highest among regions examined. Large numbers of newborn neurons were also located in the ventromedial and dorsomedial nuclei, as well as the posterior hypothalamic area, whereas heat exposure did not increase such numbers in the Adult and Old groups. Aging may interfere with heat exposure-induced hypothalamic neurogenesis and acquired heat tolerance in rats. PMID- 25556766 TI - Zeyheria montana Mart. (Bignoniaceae) as source of antioxidant and immunomodulatory compounds with beneficial effects on intestinal inflammation. AB - OBJECTIVES: Zeyheria montana is a medicinal plant used in Brazilian folk medicine for treating skin affections, ulcers, inflammation and diarrhoea, and as an antisyphilitic and antiblenorrhagic agent, but little is known about its mechanisms of action. Herein, a bio-guided assay was carried out to further evaluate its antioxidant and immunomodulatory effects, and the possible benefits on experimental intestinal inflammation. METHODS: Extracts, partitions, fractions and isolated compounds were tested for inhibition of lipid peroxidation. Isolated compounds were tested in vitro for its antioxidant and immunomodulatory action prior to in-vivo evaluation in trinitrobenzenesulfonic acid-induced rat colitis. KEY FINDINGS: Two major compounds were identified in the leaf dichloromethane extract: 3'-hydroxy-5,7,4'-trimethoxyflavone and 6-hydroxy-5,7-dimethoxyflavone, which exhibited an antioxidant activity. The compounds protected the colonic glutathione levels in more than 90% despite the absence of protection against the gross macroscopic colonic damage. In addition, the compounds inhibited IL-1beta secretion by macrophages in 91.5% and 72.7% respectively, whereas both reduced IL 6 secretion in about 44.5%. CONCLUSIONS: The major active compounds from Z. montana leaves exerted antioxidant and immunomodulatory effects, endorsing the use of Z. montana in folk medicine as an anti-inflammatory agent. However, further investigation is still needed regarding medicinal plants and the identification of candidate compounds for the treatment of the inflammatory bowel diseases. PMID- 25556767 TI - Hereditary benign telangiectasia in monozygotic twins with no family history. PMID- 25556764 TI - 12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction. AB - To understand the mechanisms of 15(S)-HETE-induced endothelial cell (EC) barrier dysfunction, we examined the role of xanthine oxidase (XO). 15(S)-HETE induced junction adhesion molecule A (JamA) phosphorylation on Y164, Y218, and Y280 involving XO-mediated reactive oxygen species production and Src and Pyk2 activation, resulting in its dissociation from occludin, thereby causing tight junction (TJ) disruption, increased vascular permeability, and enhanced leukocyte and monocyte transmigration in vitro using EC monolayer and ex vivo using arteries as models. The phosphorylation of JamA on Y164, Y218, and Y280 appears to be critical for its role in 15(S)-HETE-induced EC barrier dysfunction, as mutation of any one of these amino acid residues prevented its dissociation from occludin and restored TJ integrity and barrier function. In response to high-fat diet (HFD) feeding, WT, but not 12/15-lipoxygenase (LO)(-/-), mice showed enhanced XO expression and its activity in the artery, which was correlated with increased aortic TJ disruption and barrier permeability with enhanced leukocyte adhesion and these responses were inhibited by allopurinol. These observations provide novel insights on the role of XO in 12/15-LO-induced JamA tyrosine phosphorylation and TJ disruption leading to increased vascular permeability in response to HFD. PMID- 25556768 TI - Fulminant lipid storage myopathy due to multiple acyl-coenzyme a dehydrogenase deficiency. AB - INTRODUCTION: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. METHODS: We describe a rapidly progressive myopathy in a previously healthy 33-year-old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. RESULTS: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. CONCLUSIONS: This report illustrates a late-onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy. PMID- 25556769 TI - Galvanic deposition of Rh and Ru on randomly structured Ti felts for the electrochemical NH3 synthesis. AB - Nowadays NH3 is exclusively synthesized by the Haber process. Unfortunately, the energy demand and the CO2 emissions due to H2 production are high. Hydrogen production utilizes precious carbon sources such as coal and natural gas. In the past we proposed an alternative process concept using a membrane electrode assembly in an electrochemical membrane reactor (ecMR). At the anode H2O is oxidized at an IrMMO catalyst to form protons. By applying an external potential to the ecMR N2 is reduced to NH3 at the cathode. Just recently Rh and Ru were identified as possible cathodic electrocatalysts by DFT calculations. We present an easy and highly efficient method for galvanic coatings of Rh and Ru on randomly structured Ti felts to be used in a membrane electrode assembly. Linear sweep voltammetry measurements give a slightly higher activity of Ru for the liquid phase electrochemical NH3 synthesis. The NH4(+) concentration reached is 8 times higher for Ru than for Rh. From an economical point of view, Ru is also more feasible for an electrochemical NH3 synthesis process. Such electrodes can now be evaluated in an ecMR in comparison to recently demonstrated Ti-based electrodes. PMID- 25556770 TI - Differential Improvements in Student Fruit and Vegetable Selection and Consumption in Response to the New National School Lunch Program Regulations: A Pilot Study. AB - OBJECTIVE: To investigate changes in student food selection and consumption in response to the new National School Lunch Program meal patterns during fall 2011. DESIGN: Eight elementary and four intermediate schools in one Houston area school district were matched on free/reduced-price meal eligibility and randomized into control or intervention conditions. INTERVENTION: Both intervention and control school cafeterias served the same menu. The intervention school cafeterias posted the new meal pattern daily; students could select one fruit and two vegetable servings per reimbursable meal. Control school students could only select the previous meal pattern: a total of two fruit and vegetable servings per meal. MAIN OUTCOME MEASURES: Students were observed during lunch: student sex and foods selected/consumed were recorded. Diet analysis software was used to calculate energy/food groups selected/consumed. STATISTICAL ANALYSES PERFORMED: Cochran Mantel-Haenszel chi2 tests examined differences in the percent of students selecting each meal component by condition, controlling for sex, grade, and school free/reduced-price meal eligibility. Analysis of covariance assessed differences in amount of energy/food groups selected and consumed, and differences in percent of food groups consumed. RESULTS: Observations were conducted for 1,149 elementary and 427 intermediate students. Compared with students in the control schools, significantly more intervention elementary and intermediate school students selected total (P<0.001, P<0.05) and starchy vegetables (P<0.001, P<0.01); more intervention intermediate school students selected fruit (P<0.001), legumes (P<0.05), and protein foods (P<0.01). There were significantly greater amounts of these foods selected and consumed, but no differences in the proportion of the foods consumed by condition. Fewer calories were consumed by elementary and intermediate school intervention students. CONCLUSIONS: More intervention students selected fruit and vegetables at lunch and consumed them compared with control condition students. Future studies with larger and more diverse student populations are warranted. PMID- 25556771 TI - MLST-based inference of genetic diversity and population structure of clinical Klebsiella pneumoniae, China. AB - Multilocus sequence typing was applied to a collection of 327 clinical isolates of Klebsiella pneumoniae from China, which was proven to be a good representative of the global diversity of K. pneumoniae. Three lineages L1 to L3 are presented in the population with limited genetic flow across different lineages. However, extremely high levels of recombination can be observed within lineages to the extent at which the alleles are associated almost randomly. Lineages L2 and L3 most likely represent highly specific subgroups of less-virulent K. pneumoniae with modified metabolic networks, while lineage L1 contains not only hypervirulent clones with massive acquisition of virulent genes but also 'primitive and intermediate forms' during evolution of hypervirulent K. pneumoniae. PMID- 25556772 TI - Reflections on the role of opioids in the treatment of chronic pain: a shared solution for prescription opioid abuse and pain. PMID- 25556774 TI - Development of a novel approach for breast cancer prediction and early detection using minimally invasive procedures and molecular analysis: how cytomorphology became a breast cancer risk predictor. AB - With enhanced public awareness, advances in breast imaging, and emphasis on early breast cancer detection and prevention, more women are seeking consultation to assess the status of their breast health. Risk assessment has become an integral part of established multi-disciplinary breast care, and breast cancer risk reduction interventions have received a great deal of attention. Similarly, interest in identification of high-risk individuals has increased significantly. Atypical proliferative changes in breast epithelial cells are ranked high among various known breast cancer risk factors and, in recent years, have been the subject of several investigations. Breast tissue and fluid in the ductal system provide a rich source of cells and biomarkers that have the potential to aid in the assessment of short-term risk of breast cancer development, and assess responses to interventional prevention efforts. There are three minimally invasive procedures currently being utilized to sample breast tissue in asymptomatic high-risk individuals. These procedures are: fine-needle aspiration biopsy, nipple aspiration fluid, and ductal lavage. In this review article, the merits and limitations of each procedure are presented, and the contribution of cytomorphology and molecular analysis in breast cancer prediction is highlighted. In addition, the role of Masood Cytology Index as a surrogate endpoint biomarker in chemopreventative trials is discussed. PMID- 25556775 TI - Prevalence of psychological problems and associated transplant-related variables at different time periods after liver transplantation. AB - After liver transplantation, recipients often experience psychological problems that are influenced by demographic, personal, and transplant-related variables. However, because previous studies have mostly reported on psychological problems and their influencing factors in the first years after transplantation, less is known about their prevalence and influence in the long run. The aims of this study were to examine point-prevalence rates of symptoms of anxiety, depression, and posttraumatic stress (PTS) at different time periods after transplantation and to examine the transplant-related variables associated with these problems. A cross-sectional survey was performed among 373 liver transplant recipients who received transplants between 1979 and 2009 at our center. Five clinically relevant time periods were identified: 0.5 to <2 years, 2 to <5 years, 5 to <10 years, 10 to <15 years, and >=15 years after transplantation. The response rate was 75% (n=281). Overall, 33.4% of the respondents experienced clinically relevant symptom levels of anxiety (28.7%), depression (16.5%), or PTS (10.0%). Symptoms of anxiety and depression were more prevalent in the first 2 years and in the long term after transplantation. PTS symptoms were more prevalent in the first 5 years after transplantation. However, the prevalence rates did not differ significantly between time periods. Viral hepatitis and the number of side effects of the immunosuppressive (IS) medication were found to be associated with all psychological problems. Alcoholic liver disease was associated with anxiety and depression in the short term after transplantation. In conclusion, a significant subset of transplant recipients experience psychological problems, both shortly after transplantation and in the long run. These problems are often associated with side effects from the IS medication. Therefore, the monitoring of psychological problems, the offering of psychological counseling, and the management of the medication's side effects should be part of the routine care of transplant recipients. PMID- 25556776 TI - Help-seeking amongst women survivors of domestic violence: a qualitative study of pathways towards formal and informal support. AB - BACKGROUND: Informal and formal support for women experiencing domestic violence and abuse (DVA) can improve safety and health outcomes. There has been little qualitative work on the role of both pathways to support and women's experiences of disclosing their experience of DVA in different contexts. OBJECTIVE AND STUDY DESIGN: This qualitative study used repeat interviews with women survivors of DVA to explore their pathways to support and their experiences of barriers and facilitators to disclosure and help-seeking. SETTING AND PARTICIPANTS: Thirty-one women seeking help from specialist DVA agencies in the UK were interviewed twice over 5 months. RESULTS: Women recounted long journeys of ambivalence, often only disclosing abuse after leaving the perpetrator. Access to specialist support rarely came via general practitioners, despite high levels of consulting for anxious and depressed feelings, and was more often facilitated by police or housing agencies following a crisis such as assault. Informal disclosure only led to specialist help if the family member or friend themselves had experience or knowledge of DVA. DISCUSSION AND CONCLUSIONS: Women experiencing DVA need earlier access to specialized DVA services. Many women needed an 'enabler' to facilitate access, but once this contact was made, disclosure to other professionals or to family and friends was legitimized in the eyes of the women. Safely accessible publicity about DVA services and an appropriate response from social and health care professionals should be promoted, including support for women disclosing DVA to take action on the information they receive about services. PMID- 25556777 TI - Efficacy and safety of calcium channel blocker/diuretics combination therapy in hypertensive patients: a meta-analysis. AB - Although recent guidelines recommend the combination of calcium channel blockers (CCBs) and thiazide (-like) diuretics, this combination is not widely used in clinical practice. The aim of this meta-analysis was to assess the efficacy and safety of this combination regarding the following endpoints: all-cause and cardiovascular mortality, myocardial infarction, and stroke. Four studies with a total of 30,791 of patients met the inclusion criteria. The combination CCB/thiazide (-like) diuretic was associated with a significant risk reduction for myocardial infarction (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.73-0.95) and stroke (RR, 0.77; CI, 0.64-0.92) compared with other combinations, whereas it was similarly effective compared with other combinations in reducing the risk of all-cause (RR, 0.89; CI, 0.75-1.06) and cardiovascular (RR, 0.89; CI 0.71-1.10) mortality. Elderly patients with isolated systolic hypertension may particularly benefit from such a combination, since both drug classes have been shown to confer cerebrovascular protection. PMID- 25556778 TI - Self-retaining contact lens simplifies intravitreal injection course in rats. AB - BACKGROUND: The aim of this study was to design a self-retaining rat contact lens to simplify intravitreous injection in rats. MATERIAL/METHODS: A self-retaining, plane-concave prism contact lens customized for rats was designed. Forty diabetic rats were randomly divided into 2 groups and received the intravitreous injection of 10 MUl of a cell suspension containing bone marrow-derived stroma cell (BMSC). Group A: used a microsyringe and a rat contact lens (n=20). Group B: used the same microsyringe and a traditional cover-slip (n=20).The duration of the intravitreous injection course and the success rate of intravitreous injection were observed. RESULTS: With the use of a self-retaining rat contact lens, a clear and stable view of the rat fundus was provided and the intravitreous injection course of rats quickly achieved, averaging 4.65+/-0.53 min in Group A and 12.33+/-2.79 min in Group B. The difference was statistically significant, and the time saved averaged 7.68 min. None of the Group A rats had retinal bleeding or lens injury; whereas 2 of 20 Group B rats had bleeding and 1 of 20 had lens injury. There was no significant difference between the rats in Group A and Group B. CONCLUSIONS: A self-retaining rat contact lens is a potentially powerful instrument that allows high-quality observation of the rat fundus and simplifies the course of intravitreal injection. PMID- 25556780 TI - Demand response, behind-the-meter generation and air quality. AB - We investigated the implications of behind-the-meter (BTM) generation participating in demand response (DR) programs. Specifically, we evaluated the impacts of NOx emissions from BTM generators enrolled in the New York Independent System Operator (NYISO)'s reliability-based DR programs. Through analyzing the DR program enrollment data, DR event records, ozone air quality monitoring data, and emission characteristics of the generators, we found that the emissions from BTM generators very likely contribute to exceedingly high ozone concentrations in the Northeast Corridor region, and very likely account for a substantial fraction of total NOx emissions from electricity generation. In addition, a companion study showed that the emissions from BTM generators could also form near-source particulate matter (PM) hotspots. The important policy implications are that the absence of up-to-date regulations on BTM generators may offset the current efforts to reduce the emissions from peaking power plants, and that there is a need to quantify the environmental impacts of DR programs in designing sound policies related to demand-side resources. Furthermore, we proposed the concept of "Green" DR resources, referring to those that not only provide power systems reliability services, but also have verifiable environmental benefits or minimal negative environmental impacts. We argue that Green DR resources that are able to maintain resource adequacy and reduce emissions at the same time are key to achieving the cobenefits of power system reliability and protecting public health during periods with peak electricity demand. PMID- 25556779 TI - Bone remodeling after a mean of 10 years in diaphyseal cortical defects repaired with femoral revision using bypass fixation of extensively porous-coated stems with high stiffness. AB - INTRODUCTION: Femoral component revisions with extensively porous-coated stems have shown promising clinical results, although there are still concerns over stress-shielding. MATERIALS AND METHODS: We retrospectively reviewed data for 18 patients undergoing femoral component revisions with extensively porous-coated stems with high stiffness. The average length of follow-up was 10 years (range 6 13.7 years). RESULTS: Radiographic evidence of a bone-ingrown stem was present in 94 % of the hips, and stable fibrous fixation was present in only one hip, but no hips were considered unstable. There was mild stress-shielding in 15 hips, moderate stress-shielding in one hip, and severe stress-shielding in two hips. In one of the latter two hips, stress-shielding was progressive even 8 years after revision surgery. In 12 (92 %) of the 13 hips in which bypass fixation for diaphyseal cortical defects was used, there was good remodeling. CONCLUSIONS: We suggest that femoral component revision using extensive porous-coated stems is a useful option that may allow for healing of diaphyseal cortical defects. PMID- 25556781 TI - Laser-assisted sample preparation of silicon for high-resolution transmission electron microscopy. AB - A sample-polishing technique was developed to provide a well-defined thin foil of Si with a clean surface down to atomic dimensions. The resulting samples permit high-resolution transmission electron microscope (HRTEM) imaging unobstructed by artifacts originating from a damaged sample. Samples were not polished by dynamic momentum transfer via accelerated ions like in ion milling; instead, valence electron excitation by photon absorption was used. HRTEM inspection showed that the foils prepared by this method were free from extrinsic lattice defects and had smooth surfaces down to atomic dimensions. PMID- 25556782 TI - Alarming evidence: high fat diet alters brainstem circuits prior to the development of obesity. PMID- 25556784 TI - Ionotropic glutamate receptors: alive and kicking. PMID- 25556785 TI - Structure and gating of tetrameric glutamate receptors. AB - Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that open their ion-conducting pores in response to the binding of agonist glutamate. In recent years, significant progress has been achieved in studies of iGluRs by determining numerous structures of isolated water-soluble ligand-binding and amino-terminal domains, as well as solving the first crystal structure of the full-length AMPA receptor in the closed, antagonist-bound state. These structural data combined with electrophysiological and fluorescence recordings, biochemical experiments, mutagenesis and molecular dynamics simulations have greatly improved our understanding of iGluR assembly, activation and desensitization processes. This article reviews the recent structural and functional advances in the iGluR field and summarizes them in a simplified model of full-length iGluR gating. PMID- 25556783 TI - Facing the challenge of mammalian neural microcircuits: taking a few breaths may help. AB - Breathing in mammals is a seemingly straightforward behaviour controlled by the brain. A brainstem nucleus called the preBotzinger Complex sits at the core of the neural circuit generating respiratory rhythm. Despite the discovery of this microcircuit almost 25 years ago, the mechanisms controlling breathing remain elusive. Given the apparent simplicity and well-defined nature of regulatory breathing behaviour, the identification of much of the circuitry, and the ability to study breathing in vitro as well as in vivo, many neuroscientists and physiologists are surprised that respiratory rhythm generation is still not well understood. Our view is that conventional rhythmogenic mechanisms involving pacemakers, inhibition or bursting are problematic and that simplifying assumptions commonly made for many vertebrate neural circuits ignore consequential detail. We propose that novel emergent mechanisms govern the generation of respiratory rhythm. That a mammalian function as basic as rhythm generation arises from complex and dynamic molecular, synaptic and neuronal interactions within a diverse neural microcircuit highlights the challenges in understanding neural control of mammalian behaviours, many (considerably) more elaborate than breathing. We suggest that the neural circuit controlling breathing is inimitably tractable and may inspire general strategies for elucidating other neural microcircuits. PMID- 25556786 TI - Assembly of AMPA receptors: mechanisms and regulation. AB - AMPA receptors (AMPARs) play a critical role in excitatory glutamatergic neurotransmission. The number and subunit composition of AMPARs at synapses determines the dynamics of fast glutamatergic signalling. Functional AMPARs on the cell surface are tetramers. Thus tetrameric assembly of AMPARs represents a promising target for modulating AMPAR-mediated signalling in health and disease. Multiple structural domains within the receptor influence AMPAR assembly. In a proposed model for AMPAR assembly, the amino-terminal domain underlies the formation of a dimer pool. The transmembrane domain facilitates the formation and enhances the stability of the tetramer. The ligand-binding domain influences assembly through a process referred to as 'domain swapping'. We propose that this core AMPAR assembly process could be regulated by neuronal signals and speculate on possible mechanisms for such regulation. PMID- 25556787 TI - Glutamate receptor pores. AB - Glutamate receptors are ligand-gated ion channels that mediate fast excitatory synaptic transmission throughout the central nervous system. Functional receptors are homo- or heteromeric tetramers with each subunit contributing a re-entrant pore loop that dips into the membrane from the cytoplasmic side. The pore loops form a narrow constriction near their apex with a wide vestibule toward the cytoplasm and an aqueous central cavity facing the extracellular solution. This article focuses on the pore region, reviewing how structural differences among glutamate receptor subtypes determine their distinct functional properties. PMID- 25556788 TI - Modulation of non-NMDA receptor gating by auxiliary subunits. AB - During the past decade, considerable evidence has accumulated that non-NMDA glutamate receptors (both AMPA and kainate subtypes) are modulated by the association of the core tetrameric receptor with auxiliary proteins that are integral components of native receptor assemblies. This short review focuses on the effect of two types of auxiliary subunits on the biophysical properties and kinetic behaviour of AMPA and kainate receptors at the level of single receptor molecules. Type I transmembrane AMPA receptor proteins increase the number of AMPA receptor openings that result from a single receptor activation as well as the proportion of openings to conductance levels above 30 pS, resulting in larger peak ensemble currents that decay more slowly and bi-exponentially. Co-expression of Neto1 and 2 with pore-forming kainate receptor subunits also increases the duration of bursts and destabilizes desensitized states, resulting in a rapid component of recovery and clusters of bursts that produce a slow component in desensitization decays. The distinct gating seen in the presence of auxiliary subunits reflects slow switching between gating modes with different single channel kinetics and open probability. At any given time, the relative proportions of receptors in each gating mode determine both the shape and the amplitude of synaptic currents. PMID- 25556789 TI - The multifaceted subunit interfaces of ionotropic glutamate receptors. AB - The past fifteen years has seen a revolution in our understanding of ionotropic glutamate receptor (iGluR) structure, starting with the first view of the ligand binding domain (LBD) published in 1998, and in many ways culminating in the publication of the full-length structure of GluA2 in 2009. These reports have revealed not only the central role played by subunit interfaces in iGluR function, but also myriad binding sites within interfaces for endogenous and exogenous factors. Changes in the conformation of inter-subunit interfaces are central to transmission of ligand gating into pore opening (itself a rearrangement of interfaces), and subsequent closure through desensitization. With the exception of the agonist binding site, which is located entirely within individual subunits, almost all modulatory factors affecting iGluRs appear to bind to sites in subunit interfaces. This review seeks to summarize what we currently understand about the diverse roles interfaces play in iGluR function, and to highlight questions for future research. PMID- 25556790 TI - Molecular bases of NMDA receptor subtype-dependent properties. AB - NMDA receptors (NMDARs) are a class of ionotropic glutamate receptors (iGluRs) that are essential for neuronal development, synaptic plasticity, learning and cell survival. Several features distinguish NMDARs from other iGluRs and underlie the crucial roles NMDARs play in nervous system physiology. NMDARs display slow deactivation kinetics, are highly Ca(2+) permeable, and require depolarization to relieve channel block by external Mg(2+) ions, thereby making them effective coincidence detectors. These properties and others differ among NMDAR subtypes, which are defined by the subunits that compose the receptor. NMDARs, which are heterotetrameric, commonly are composed of two GluN1 subunits and two GluN2 subunits, of which there are four types, GluN2A-D. 'Diheteromeric' NMDARs contain two identical GluN2 subunits. Gating and ligand-binding properties (e.g. deactivation kinetics) and channel properties (e.g. channel block by Mg(2+)) depend strongly on the GluN2 subunit contained in diheteromeric NMDARs. Recent work shows that two distinct regions of GluN2 subunits control most diheteromeric NMDAR subtype-dependent properties: the N-terminal domain is responsible for most subtype dependence of gating and ligand-binding properties; a single residue difference between GluN2 subunits at a site termed the GluN2 S/L site is responsible for most subtype dependence of channel properties. Thus, two structurally and functionally distinct regions underlie the majority of subtype dependence of NMDAR properties. This topical review highlights recent studies of recombinant diheteromeric NMDARs that uncovered the involvement of the N-terminal domain and of the GluN2 S/L site in the subtype dependence of NMDAR properties. PMID- 25556791 TI - Retour aux sources: defining the structural basis of glutamate receptor activation. AB - Ionotropic glutamate receptors (iGluRs) are the major excitatory neurotransmitter receptor in the vertebrate CNS and, as a result, their activation properties lie at the heart of much of the neuronal network activity observed in the developing and adult brain. iGluRs have also been implicated in many nervous system disorders associated with postnatal development (e.g. autism, schizophrenia), cerebral insult (e.g. stroke, epilepsy), and disorders of the ageing brain (e.g. Alzheimer's disease, Parkinsonism). In view of this, an emphasis has been placed on understanding how iGluRs activate and desensitize in functional and structural terms. Early structural models of iGluRs suggested that the strength of the agonist response was primarily governed by the degree of closure induced in the ligand-binding domain (LBD). However, recent studies have suggested a more nuanced role for the LBD with current evidence identifying the iGluR LBD interface as a "hotspot" regulating agonist behaviour. Such ideas remain to be consolidated with recently solved structures of full-length iGluRs to account for the global changes that underlie channel activation and desensitization. PMID- 25556792 TI - Differential phospholipase C-dependent modulation of TASK and TREK two-pore domain K+ channels in rat thalamocortical relay neurons. AB - KEY POINTS: During the behavioural states of sleep and wakefulness thalamocortical relay neurons fire action potentials in high frequency bursts or tonic sequences, respectively. The modulation of specific K(+) channel types, termed TASK and TREK, allows these neurons to switch between the two modes of activity. In this study we show that the signalling lipids phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG), which are components of their membrane environment, switch on and shut off TREK and TASK channels, respectively. These channel modulations contribute to a better understanding of the molecular basis of the effects of neurotransmitters such as ACh which are released by the brainstem arousal system. The present report introduces PIP2 and DAG as new elements of signal transduction in the thalamus. The activity of two pore domain potassium channels (K2P ) regulates the excitability and firing modes of thalamocortical (TC) neurons. In particular, the inhibition of two-pore domain weakly inwardly rectifying K(+) channel (TWIK)-related acid-sensitive K(+) (TASK) channels and TWIK-related K(+) (TREK) channels, as a consequence of the stimulation of muscarinic ACh receptors (MAChRs) which are coupled to phosphoinositide-specific phospholipase C (PLCbeta), induces a shift from burst to tonic firing. By using a whole cell patch-clamp approach, the contribution of the membrane-bound second messenger molecules phosphatidylinositol 4,5 bisphosphate (PIP2 ) and diacylglycerol (DAG) acting downstream of PLCbeta was probed. The standing outward current (ISO ) was used to monitor the current through TASK and TREK channels in TC neurons. By exploiting different manoeuvres to change the intracellular PIP2 level in TC neurons, we here show that the scavenging of PIP2 (by neomycin) results in an increased muscarinic effect on ISO whereas increased availability of PIP2 (inclusion to the patch pipette; histone based carrier) decreased muscarinic signalling. The degree of muscarinic inhibition specifically depends on phosphatidylinositol phosphate (PIP) and PIP2 but no other phospholipids (phosphatidic acid, phosphatidylserine). The use of specific blockers revealed that PIP2 is targeting TREK but not TASK channels. Furthermore, we demonstrate that the inhibition of TASK channels is induced by the application of the DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG). Under current clamp conditions the activation of MAChRs and PLCbeta as well as the application of OAG resulted in membrane depolarization, while PIP2 application via histone carrier induced a hyperpolarization. These results demonstrate a differential role of PIP2 and DAG in K2P channel modulation in native neurons which allows a fine-tuned inhibition of TREK (via PIP2 depletion) and TASK (via DAG) channels following MAChR stimulation. PMID- 25556793 TI - alpha-Synuclein forms non-selective cation channels and stimulates ATP-sensitive potassium channels in hippocampal neurons. AB - KEY POINTS: In Parkinson's disease, the protein alpha-synuclein (alphaS) is produced within neurons and also appears in the extracellular fluid. In this study in hippocampal neurons, alphaS formed non-selective cation channels with multiple levels of conductance and rectification depending on their insertion site. alphaS channels induced local spontaneous increases in intracellular Na(+) and Ca(2+), depolarized neurons, augmented bursting activity and stimulated the opening of ATP-sensitive K(+) channels. Non-selective channels were also observed in neurons transfected with either wild-type or mutant A53T alphaS, and after extracellular application of these proteins. The properties of alphaS channels in neuronal membranes suggest that extracellular alphaS is more toxic than alphaS produced within neurons. In Parkinson's disease and several other neurodegenerative diseases, the protein alpha-synuclein (alphaS) is produced within neurons and accumulates in the extracellular fluid. Several mechanisms of alphaS action are proposed, one of which is the formation of cation-permeable pores that may mediate toxicity. alphaS induces non-selective cation channels in lipid bilayers, but whether this occurs in living neurons and which properties the channels possess have not yet been examined. In this study the properties of alphaS channels in dissociated hippocampal neurons are documented. In cell attached recordings the incorporation of alphaS into membranes was driven by applied negative potentials. These channels exhibited multiple levels of conductance (30, 70 and 120 pS at -100 mV) and inward rectification. The persistent activity of alphaS channels induced local changes in intracellular Na(+) and Ca(2+), depolarized neurons and augmented bursting activity. alphaS channels formed by adding alphaS to the intracellular membrane in inside-out patches exhibited outward rectification. alphaS channels were equally permeable to Na(+), K(+) and Ca(2+). These channels were also observed in neurons transfected with wild-type or mutant A53T alphaS, and after extracellular application of wild-type or mutant A53T alphaS proteins. Opening of alphaS channels stimulated opening of ATP-sensitive K(+) (KATP ) channels and did not interfere with the activity of delayed rectifier K(+) channels. The properties of alphaS channels in neuronal membranes suggest stronger toxicity of extracellularly applied alphaS than intracellular alphaS. Enhancement of neuronal excitability and distortions in ion homeostasis may underlie the toxic effects of alphaS that can be dampened by KATP channels. PMID- 25556794 TI - GABAB receptor-mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram-treated rats. AB - KEY POINTS: Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain and play important roles in regulating many brain functions. LC neurons are subject to tonic inhibition mediated by GABAB receptors (GABAB Rs) and that the extent of the effect varies with ambient GABA levels. GABAB R-mediated tonic inhibition can effectively tune the spontaneous firing rate (SFR) of LC neurons; it is developmentally regulated and is responsible for maintaining a constant SFR of LC neurons during development. In male, but not female rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, results in downregulation of GABAB R-mediated tonic inhibition of LC neurons that partially accounts for increased SFR in male, but not female, rats receiving such treatment. Our results show that GABAB R-mediated tonic inhibition could be an important player in the development of normal and abnormal behaviours/brain functions associated with the LC-NA system. Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain. Their activity is believed to be a key factor regulating the wakefulness/arousal level of the brain. In this study, we found that the activity of NA-releasing neurons in the LC (LC neurons) was subject to gamma-aminobutyric acid (GABA) tonic inhibition through GABAB receptors (GABAB Rs), but not GABAA receptors. The intensity of GABAB R tonic inhibition was found to depend on ambient GABA levels, as it was dramatically increased by blockade of GABA reuptake. It also varied with the function of GABAB Rs. The GABAB R activity on LC neurons was found to increase with postnatal age up to postnatal days 8-10, resulting in increased tonic inhibition. Interestingly, there was no significant difference in the spontaneous activity of LC neurons at different postnatal ages unless GABAB R tonic inhibition was blocked. These results show that, during postnatal development, there is a continuous increase in GABAB R tonic inhibition that maintains the activity of LC neurons at a proper level. In male, but not female, rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, reduced GABAB R activity and tonic inhibition, which might result in the significantly higher spontaneous activity of LC neurons seen in these animals. In conclusion, our results show that GABAB R-mediated tonic inhibition has a direct impact on the spontaneous activity of LC neurons and that the extent of the effect varies with ambient GABA levels and functionality of GABAB R signalling. PMID- 25556795 TI - KV 10.1 opposes activity-dependent increase in Ca2+ influx into the presynaptic terminal of the parallel fibre-Purkinje cell synapse. AB - KEY POINTS: Voltage-gated KV 10.1 potassium channels are widely expressed in the mammalian brain but their function remains poorly understood. We report that KV 10.1 is enriched in the presynaptic terminals and does not take part in somatic action potentials. In parallel fibre synapses in the cerebellar cortex, we find that KV 10.1 regulates Ca(2+) influx and neurotransmitter release during repetitive high-frequency activity. Our results describe the physiological role of mammalian KV 10.1 for the first time and help understand the fine-tuning of synaptic transmission. The voltage-gated potassium channel KV 10.1 (Eag1) is widely expressed in the mammalian brain, but its physiological function is not yet understood. Previous studies revealed highest expression levels in hippocampus and cerebellum and suggested a synaptic localization of the channel. The distinct activation kinetics of KV 10.1 indicate a role during repetitive activity of the cell. Here, we confirm the synaptic localization of KV 10.1 both biochemically and functionally and that the channel is sufficiently fast at physiological temperature to take part in repolarization of the action potential (AP). We studied the role of the channel in cerebellar physiology using patch clamp and two-photon Ca(2+) imaging in KV 10.1-deficient and wild-type mice. The excitability and action potential waveform recorded at granule cell somata was unchanged, while Ca(2+) influx into axonal boutons was enhanced in mutants in response to stimulation with three APs, but not after a single AP. Furthermore, mutants exhibited a frequency-dependent increase in facilitation at the parallel fibre-Purkinje cell synapse at high firing rates. We propose that KV 10.1 acts as a modulator of local AP shape specifically during high-frequency burst firing when other potassium channels suffer cumulative inactivation. PMID- 25556796 TI - Activation of muscarinic receptors by ACh release in hippocampal CA1 depolarizes VIP but has varying effects on parvalbumin-expressing basket cells. AB - KEY POINTS: Optogenetically released acetylcholine (ACh) from medial septal afferents activates muscarinic receptors on both vasoactive intestinal peptide expressing (VIP) and parvalbumin-expressing (PV) basket cells (BCs) in mouse hippocampal CA1. ACh release depolarized VIP BCs whereas PV BCs depolarized, hyperpolarized or produced biphasic responses. Depolarizing responses in VIP or PV BCs resulted in increased amplitudes and frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. The instantaneous frequency of sIPSCs that result from excitation of VIP or PV BCs primarily occurred within the low gamma frequency band (25-50 Hz). We investigated the effect of acetylcholine release on mouse hippocampal CA1 perisomatically projecting interneurons. Acetylcholine was optogenetically released in hippocampal slices by expressing the excitatory optogenetic protein oChIEF tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated virally mediated transfection. The effect of optogenetically released acetylcholine was assessed on interneurons expressing Cre recombinase in vasoactive intestinal peptide (VIP) or parvalbumin (PV) interneurons using whole cell patch clamp methods. Acetylcholine released onto VIP interneurons that innervate pyramidal neuron perisomatic regions (basket cells, BCs) were depolarized by muscarinic receptors. Although PV BCs were also excited by muscarinic receptor activation, they more frequently responded with hyperpolarizing or biphasic responses. Muscarinic receptor activation resulting from ACh release increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in downstream hippocampal CA1 pyramidal neurons with peak instantaneous frequencies occurring in both the gamma and theta bandwidths. Both PV and VIP BCs contributed to the increased sIPSC frequency in pyramidal neurons and optogenetic suppression of PV or VIP BCs inhibited sIPSCs occurring in the gamma range. Therefore, we propose acetylcholine release in CA1 has a complex effect on CA1 pyramidal neuron output through varying effects on perisomatically projecting interneurons. PMID- 25556797 TI - GABAergic transmission and enhanced modulation by opioids and endocannabinoids in adult rat rostral ventromedial medulla. AB - KEY POINTS: Electrical stimulation of the rostral ventromedial medulla (RVM) facilitates pain behaviours in neonates but inhibits these behaviours in adults. The cellular mechanisms underlying these changes in RVM modulation of pain behaviours are not known. We optimized whole-cell patch-clamp recordings for RVM neurons in animals older than postnatal day 30 and compared the results to postnatal day 10-21 animals. Our results demonstrate that the gamma-aminobutyric acid (GABA) release is lower and opioid effects are more evident in adult rats compared to early postnatal rats. A cannabinoid receptor antagonist significantly increased GABA release in mature but not in immature RVM neurons suggesting the presence of local endocannabinoid tone in mature RVM. Neurons in the rostral ventromedial medulla (RVM) play critical and complex roles in pain modulation. Recent studies have shown that electrical stimulation of the RVM produces pain facilitation in young animals (postnatal (PN) day < 21) but predominantly inhibits pain behaviours in adults. The cellular mechanisms underlying these changes in RVM modulation of pain behaviours are not known. This is in part because whole-cell patch-clamp studies in RVM to date have been in young (PN day < 18) animals because the organization and abundance of myelinated fibres in this region make the RVM a challenging area for whole-cell patch-clamp recording in adults. Several neurotransmitter systems, including GABAergic neurotransmission, undergo developmental changes that mature by PN day 21. Thus, we focused on optimizing whole-cell patch-clamp recordings for RVM neurons in animals older than PN day 30 and compared the results to animals at PN day 10-21. Our results demonstrate that the probability of GABA release is lower and that opioid and endocannabinoid effects are more evident in adult rats (mature) compared to early postnatal (immature) rats. Differences in these properties of RVM neurons may contribute to the developmental changes in descending control of pain from the RVM to the spinal cord. PMID- 25556798 TI - Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice. AB - KEY POINTS: The cerebrospinal fluid contains numerous neuromodulators at ambient levels but whether, and how, they affect the activity of central neurons is unknown. This study provides experimental evidence that human cerebrospinal fluid (hCSF) increases the excitability of hippocampal and neocortical pyramidal neurons. Hippocampal CA1 pyramidal neurons in hCSF displayed lowered firing thresholds, depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The excitability increasing effect of hCSF on CA1 pyramidal neurons was entirely occluded by intracellular application of GTPgammaS, suggesting that neuromodulatory effects were mediated by G-protein coupled receptors. These results indicate that the CSF promotes spontaneous excitatory neuronal activity, and may help to explain observed differences in the activity of pyramidal neurons recorded in vivo and in vitro. The composition of brain extracellular fluid is shaped by a continuous exchange of substances between the cerebrospinal fluid (CSF) and interstitial fluid. The CSF is known to contain a wide range of endogenous neuromodulatory substances, but their collective influence on neuronal activity has been poorly investigated. We show here that replacing artificial CSF (aCSF), routinely used for perfusion of brain slices in vitro, with human CSF (hCSF) powerfully boosts spontaneous firing of CA1, CA3 and layer 5 pyramidal neurons in the rat brain slice. CA1 pyramidal neurons in hCSF display lowered firing thresholds, more depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The increased excitability of CA1 pyramidal neurons was completely occluded by intracellular application of GTPgammaS, suggesting that endogenous neuromodulators in hCSF act on G-protein coupled receptors to enhance excitability. We found no increase in spontaneous inhibitory synaptic transmission by hCSF, indicating a differential effect on glutamatergic and GABAergic neurons. Our findings highlight a previously unknown function of the CSF in promoting spontaneous excitatory activity, and may help to explain differences observed in the activity of pyramidal neurons recorded in vivo and in vitro. PMID- 25556799 TI - Loss of beta2-laminin alters calcium sensitivity and voltage-gated calcium channel maturation of neurotransmission at the neuromuscular junction. AB - KEY POINTS: Neuromuscular junctions from beta2-laminin-deficient mice exhibit lower levels of calcium sensitivity. Loss of beta2-laminin leads to a failure in switching from N- to P/Q-type voltage-gated calcium channel (VGCC)-mediated transmitter release that normally occurs with neuromuscular junction maturation. The motor nerve terminals from beta2-laminin-deficient mice fail to up-regulate the expression of P/Q-type VGCCs clusters and down-regulate N-type VGCCs clusters, as they mature. There is decreased co-localisation of presynaptic specialisations in beta2-laminin-deficient neuromuscular junctions as a consequence of lesser P/Q-type VGCC expression. These findings support the idea that beta2-laminin is critical in the organisation and maintenance of active zones at the neuromuscular junction via its interaction with P/Q-type VGCCs, which aid in stabilisation of the synapse. beta2-laminin is a key mediator in the differentiation and formation of the skeletal neuromuscular junction. Loss of beta2-laminin results in significant structural and functional aberrations such as decreased number of active zones and reduced spontaneous release of transmitter. In vitro beta2-laminin has been shown to bind directly to the pore forming subunit of P/Q-type voltage-gated calcium channels (VGCCs). Neurotransmission is initially mediated by N-type VGCCs, but by postnatal day 18 switches to P/Q-type VGCC dominance. The present study investigated the changes in neurotransmission during the switch from N- to P/Q-type VGCC-mediated transmitter release at beta2-laminin-deficient junctions. Analysis of the relationship between quantal content and extracellular calcium concentrations demonstrated a decrease in the calcium sensitivity, but no change in calcium dependence at beta2-laminin-deficient junctions. Electrophysiological studies on VGCC sub-types involved in transmitter release indicate N-type VGCCs remain the primary mediator of transmitter release at matured beta2-laminin-deficient junctions. Immunohistochemical analyses displayed irregularly shaped and immature beta2-laminin-deficient neuromuscular junctions when compared to matured wild type junctions. beta2-laminin-deficient junctions also maintained the presence of N-type VGCC clustering within the presynaptic membrane, which supported the functional findings of the present study. We conclude that beta2-laminin is a key regulator in development of the NMJ, with its loss resulting in reduced transmitter release due to decreased calcium sensitivity stemming from a failure to switch from N- to P/Q-type VGCC-mediated synaptic transmission. PMID- 25556801 TI - Exposure to a high fat diet during the perinatal period alters vagal motoneurone excitability, even in the absence of obesity. AB - KEY POINTS: Obesity is recognized as being multifactorial in origin, involving both genetic and environmental factors. The perinatal period is known to be critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes. Diet-induced obesity alters the biophysical, pharmacological and morphological properties of vagal neurocircuits regulating upper gastrointestinal tract functions, including satiety. Less information is available, however, regarding the effects of a high fat diet (HFD) itself on the properties of vagal neurocircuits. The present study was designed to test the hypothesis that exposure to a HFD during the perinatal period alters the electrophysiological, pharmacological and morphological properties of vagal efferent motoneurones innervating the stomach. Our data indicate that perinatal HFD decreases the excitability of gastric-projecting dorsal motor nucleus neurones and dysregulates neurotransmitter release from synaptic inputs and that these alterations occur prior to the development of obesity. These findings represent the first direct evidence that exposure to a HFD modulates the processing of central vagal neurocircuits even in the absence of obesity. The perinatal period is critically important to the development of autonomic neural circuits responsible for energy homeostasis. Vagal neurocircuits are vital to the regulation of upper gastrointestinal functions, including satiety. Diet-induced obesity modulates the excitability and responsiveness of both peripheral vagal afferents and central vagal efferents but less information is available regarding the effects of diet per se on vagal neurocircuit functions. The aims of this study were to investigate whether perinatal exposure to a high fat diet (HFD) dysregulated dorsal motor nucleus of the vagus (DMV) neurones, prior to the development of obesity. Whole cell patch clamp recordings were made from gastric-projecting DMV neurones in thin brainstem slices from rats that were exposed to either a control diet or HFD from pregnancy day 13. Our data demonstrate that following perinatal HFD: (i) DMV neurones had decreased excitability and input resistance with a reduced ability to fire action potentials; (ii) the proportion of DMV neurones excited by cholecystokinin (CCK) was unaltered but the proportion of neurones in which CCK increased excitatory glutamatergic synaptic inputs was reduced; (iii) the tonic activation of presynaptic group II metabotropic glutamate receptors on inhibitory nerve terminals was attenuated, allowing modulation of GABAergic synaptic transmission; and (iv) the size and dendritic arborization of gastric-projecting DMV neurones was increased. These results suggest that perinatal HFD exposure compromises the excitability and responsiveness of gastric-projecting DMV neurones, even in the absence of obesity, suggesting that attenuation of vago-vagal reflex signalling may precede the development of obesity. PMID- 25556800 TI - Developmentally regulated neurosteroid synthesis enhances GABAergic neurotransmission in mouse thalamocortical neurones. AB - KEY POINTS: During neuronal development synaptic events mediated by GABAA receptors are progressively reduced in their duration, allowing for rapid and precise network function. Here we focused on ventrobasal thalamocortical neurones, which contribute to behaviourally relevant oscillations between thalamus and cortex. We demonstrate that the developmental decrease in the duration of inhibitory phasic events results predominantly from a precisely timed loss of locally produced neurosteroids, which act as positive allosteric modulators of the GABAA receptor. The mature thalamus retains the ability to synthesise neurosteroids, thus preserving the capacity to enhance both phasic and tonic inhibition, mediated by synaptic and extrasynaptic GABAA receptors, respectively, in physiological and pathophysiological scenarios associated with perturbed neurosteroid levels. Our data establish a potent, endogenous mechanism to locally regulate the GABAA receptor function and thereby influence thalamocortical activity. During brain development the duration of miniature inhibitory postsynaptic currents (mIPSCs) mediated by GABAA receptors (GABAA Rs) progressively reduces, to accommodate the temporal demands required for precise network activity. Conventionally, this synaptic plasticity results from GABAA R subunit reorganisation. In particular, in certain developing neurones synaptic alpha2-GABAA Rs are replaced by alpha1-GABAA Rs. However, in thalamocortical neurones of the mouse ventrobasal (VB) thalamus, the major alteration to mIPSC kinetics occurs on postnatal (P) day 10, some days prior to the GABAA R isoform change. Here, whole-cell voltage-clamp recordings from VB neurones of mouse thalamic slices revealed that early in postnatal development (P7-P8), the mIPSC duration is prolonged by local neurosteroids acting in a paracrine or autocrine manner to enhance GABAA R function. However, by P10, this neurosteroid 'tone' rapidly dissipates, thereby producing brief mIPSCs. This plasticity results from a lack of steroid substrate as pre-treatment of mature thalamic slices (P20-24) with the GABAA R-inactive precursor 5alpha-dihydroprogesterone (5alpha-DHP) resulted in markedly prolonged mIPSCs and a greatly enhanced tonic conductance, mediated by synaptic and extrasynaptic GABAA Rs, respectively. In summary, endogenous neurosteroids profoundly influence GABAergic neurotransmission in developing VB neurones and govern a transition from slow to fast phasic synaptic events. Furthermore, the retained capacity for steroidogenesis in the mature thalamus raises the prospect that certain physiological or pathophysiological conditions may trigger neurosteroid neosynthesis, thereby providing a local mechanism for fine-tuning neuronal excitability. PMID- 25556802 TI - Prostaglandin E2 differentially modulates the central control of eupnoea, sighs and gasping in mice. AB - Prostaglandin E2 (PGE2) augments distinct inspiratory motor patterns, generated within the preBotzinger complex (preBotC), in a dose-dependent way. The frequency of sighs and gasping are stimulated at low concentrations, while the frequency of eupnoea increases only at high concentrations. We used in vivo microinjections into the preBotC and in vitro isolated brainstem slice preparations to investigate the dose-dependent effects of PGE2 on the preBotC activity. Synaptic measurements in whole cell voltage clamp recordings of inspiratory neurons revealed no changes in inhibitory or excitatory synaptic transmission in response to PGE2 exposure. In current clamp recordings obtained from inspiratory neurons of the preBotC, we found an increase in the frequency and amplitude of bursting activity in neurons with intrinsic bursting properties after exposure to PGE2. Riluzole, a blocker of the persistent sodium current, abolished the effect of PGE2 on sigh activity, while flufenamic acid, a blocker of the calcium-activated non-selective cation conductance, abolished the effect on eupnoeic activity caused by PGE2. Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E2 (PGE2) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBotzinger complex (preBotC), a medullary area that is critical for breathing. Low concentrations of PGE2 (100 300 nm) increased the sigh frequency, while higher concentrations (1-2 MUm) were required to increase the eupnoeic frequency. The concentration-dependent effects were similarly observed in the isolated preBotC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current (INap), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium-activated non-selective cation conductance (ICAN ) abolished the effect of PGE2 on fictive eupnoea at higher concentrations. At the cellular level PGE2 significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE2 affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE2 differentially modulates sigh, gasping and eupnoeic activity by differentially increasing INap and ICAN currents in preBotC neurons. PMID- 25556803 TI - In vivo properties of cerebellar interneurons in the macaque caudal vestibular vermis. AB - KEY POINTS: We quantify both spontaneous and stimulus-driven responses of interneurons in lobules X (nodulus) and IXc,d (ventral uvula) of the caudal vermis during vestibular stimulation. Based on baseline firing, at least three types of neuronal populations could be distinguished. First, there was a group of very regular firing neurons with high mean discharge rates. Second, there was a group of low firing neurons with a range of discharge regularity. Third, we also encountered putative interneurons with discharge regularity and mean firing rates that were indistinguishable from those of physiologically identified Purkinje cells. The vestibular responses of putative interneurons were generally similar to those of Purkinje cells, thus encoding tilt, translation or mixtures of these signals. Mossy fibres showed unprocessed, otolith afferent-like properties. The cerebellar cortex is among the brain's most well-studied circuits and includes distinct classes of excitatory and inhibitory interneurons. Several studies have attempted to characterize the in vivo properties of cerebellar interneurons, yet little is currently known about their stimulus-driven properties. Here we quantify both spontaneous and stimulus-driven responses of interneurons in lobules X (nodulus) and IXc,d (ventral uvula) of the macaque caudal vermis during vestibular stimulation. Interneurons were identified as cells located >100 MUm from the Purkinje cell layer that did not exhibit complex spikes. Based on baseline firing, three types of interneurons could be distinguished. First, there was a group of very regular firing interneurons with high mean discharge rates, which consistently encoded tilt, rather than translational head movements. Second, there was a group of low firing interneurons with a range of discharge regularity. This group had more diverse vestibular properties, where most were translation-selective and a few tilt- or gravitoinertial acceleration-selective. Third, we also encountered interneurons that were similar to Purkinje cells in terms of discharge regularity and mean firing rate. This group also encoded mixtures of tilt and translation signals. A few mossy fibres showed unprocessed, otolith afferent-like properties, encoding the gravitoinertial acceleration. We conclude that tilt- and translation-selective signals, which reflect neural computations transforming vestibular afferent information, are not only encountered in Purkinje cell responses. Instead, upstream interneurons within the cerebellar cortex are also characterized by similar properties, thus implying a widespread network computation. PMID- 25556805 TI - Self-assessed and radiographic outcomes of humeral head replacement with nonprosthetic glenoid arthroplasty. AB - BACKGROUND: Active and young patients who place frequent demands on their shoulder present a treatment dilemma when glenohumeral arthritis progresses to a point at which surgical intervention is considered. Humeral head replacement with nonprosthetic glenoid arthroplasty ("ream-and-run") has been proposed to address the limitations of total shoulder arthroplasty and hemiarthroplasty in this population. Several reports from a single institution have shown substantial improvement in self-assessed comfort and function after this procedure. However, to the best of our knowledge, no clinical results pertaining to this technique have been reported from other institutions. METHODS: Hemiarthroplasty with nonprosthetic glenoid arthroplasty was performed in 17 patients with a minimum 2 year follow-up. Patients were clinically evaluated preoperatively and postoperatively with physical examination, Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons score, visual analog scale, and standardized radiographs. Preoperative radiographs and patient demographics were assessed for correlation with outcome measures. RESULTS: Improvement of >30% of preoperative SST score was noted in 14 of 17 patients at a mean follow-up of 3.9 years (range, 2.0-6.8 years). SST score improved from mean 3.2 +/- 3.1 preoperatively to 10.0 +/- 2.6 at latest follow-up (P < .0001). American Shoulder and Elbow Surgeons score improved from mean 42 +/- 23 to 90 +/- 13 (P < .0001). Male patients had higher SST scores (P = .03) and greater external rotation (P = .03) at latest follow-up. CONCLUSIONS: Nonprosthetic glenoid arthroplasty demonstrated results that correlate with prior data published by the center at which the procedure was initially described. Patients with concentric glenoid morphology preoperatively did not demonstrate results superior to those of patients with eccentric glenoids. PMID- 25556804 TI - Functional changes in deep dorsal horn interneurons following spinal cord injury are enhanced with different durations of exercise training. AB - KEY POINTS: Exercise training after spinal cord injury (SCI) enhances collateral sprouting from axons near the injury and is thought to promote intraspinal circuit reorganisation that effectively bridges the SCI. The effects of exercise training, and its duration, on interneurons in these de novo intraspinal circuits are poorly understood. In an adult mouse hemisection model of SCI, we used whole cell patch-clamp electrophysiology to examine changes in the intrinsic and synaptic properties of deep dorsal horn interneurons in the vicinity of a SCI in response to the injury, and after 3 and 6 weeks of treadmill exercise training. SCI alone exerted powerful effects on the intrinsic and synaptic properties of interneurons near the lesion. Importantly, synaptic activity, both local and descending, was preferentially enhanced by exercise training, suggesting that exercise promotes synaptic plasticity in spinal cord interneurons that are ideally placed to form new intraspinal circuits after SCI. Following incomplete spinal cord injury (SCI), collaterals sprout from intact and injured axons in the vicinity of the lesion. These sprouts are thought to form new synaptic contacts that effectively bypass the lesion epicentre and contribute to improved functional recovery. Such anatomical changes are known to be enhanced by exercise training; however, the mechanisms underlying exercise-mediated plasticity are poorly understood. Specifically, we do not know how SCI alone or SCI combined with exercise alters the intrinsic and synaptic properties of interneurons in the vicinity of a SCI. Here we use a hemisection model of incomplete SCI in adult mice and whole-cell patch-clamp recording in a horizontal spinal cord slice preparation to examine the functional properties of deep dorsal horn (DDH) interneurons located in the vicinity of a SCI following 3 or 6 weeks of treadmill exercise training. We examined the functional properties of local and descending excitatory synaptic connections by recording spontaneous excitatory postsynaptic currents (sEPSCs) and responses to dorsal column stimulation, respectively. We find that SCI in untrained animals exerts powerful effects on intrinsic, and especially, synaptic properties of DDH interneurons. Plasticity in intrinsic properties was most prominent at 3 weeks post SCI, whereas synaptic plasticity was greatest at 6 weeks post injury. Exercise training did not markedly affect intrinsic membrane properties; however, local and descending excitatory synaptic drive were enhanced by 3 and 6 weeks of training. These results suggest exercise promotes synaptic plasticity in spinal cord interneurons that are ideally placed to form new intraspinal circuits after SCI. PMID- 25556806 TI - The effect of trunk rotation during shoulder exercises on the activity of the scapular muscle and scapular kinematics. AB - BACKGROUND: In patients with shoulder disease, kinetic chain exercises including hip or trunk movement are recommended. However, the actual muscle activation and scapular kinematics of these exercises are not known. The purpose of this study was to examine the effect of trunk rotation on shoulder exercises that are devised to improve scapular function. METHODS: Thirteen healthy young men participated in this study. Scaption, external rotation in the first and second positions, and prone scapular retraction at 45 degrees , 90 degrees , and 145 degrees of shoulder abduction were performed with and without trunk rotation. Electromyography was used to assess the scapular muscle activity of the upper trapezius (UT), middle trapezius (MT), lower trapezius (LT), and serratus anterior (SA), and electromagnetic motion capture was used to assess scapular motion. The muscle activity ratio, which is the activity of the UT to the MT, LT, and SA, was calculated. These data were compared between 2 conditions (with and without trunk rotation) for each exercise. RESULTS: Adding trunk rotation to scaption, the first external rotation, and the second external rotation significantly increased scapular external rotation and posterior tilt, and all 3 exercises increased LT activation. In addition, trunk rotation with scapular retraction at 90 degrees and 145 degrees of shoulder abduction significantly decreased the UT/LT ratio. CONCLUSIONS: Our findings suggest that shoulder exercises with trunk rotation in this study may be effective in patients who have difficulty in enhancing LT activity and suppressing excessive activation of the UT or in cases in which a decreased scapular external rotation or posterior tilt is observed. PMID- 25556808 TI - Pectoralis major ruptures: a review of current management. AB - BACKGROUND: Rupture of the pectoralis major tendon is increasing in incidence, with a spike in the number of reported cases in the last decade. This is commonly attributed to an increased interest in health, fitness, and weight training combined occasionally with concomitant use of anabolic steroids. It is essential for the diagnosis to be recognized and for the patient to be referred to a surgeon with expertise in dealing with these injuries so that appropriate and informed care can be implemented. METHODS: Based on a comprehensive review of the literature and expert opinion, we present a review of pectoralis major ruptures, including information pertaining to the anatomy and biomechanics of the musculotendinous unit and how this relates to the injury pattern and management; the clinical diagnosis and indications for additional imaging; and the indications for nonoperative and operative management along with the authors' preferred technique. A summary of outcomes is presented. CONCLUSION: The combination of patient demographics and clinical features frequently yields an accurate diagnosis, but further imaging is helpful. Magnetic resonance imaging with dedicated sequencing is the investigation of choice and can aid in diagnosis, surgical planning, and providing important information about prognosis and outcome. Early surgery is preferable, but good outcomes in the chronic setting are achievable. With a detailed understanding of the anatomy, direct repair to bone is possible with either transosseous or anchor repair techniques in acute and the majority of chronic cases. In chronic cases in which direct repair is not achievable, autograft and allograft reconstruction should be considered. PMID- 25556807 TI - Comparing conventional and computer-assisted surgery baseplate and screw placement in reverse shoulder arthroplasty. AB - BACKGROUND: Preoperative planning and intraoperative navigation technologies have each been shown separately to be beneficial for optimizing screw and baseplate positioning in reverse shoulder arthroplasty (RSA) but to date have not been combined. This study describes development of a system for performing computer assisted RSA glenoid baseplate and screw placement, including preoperative planning, intraoperative navigation, and postoperative evaluation, and compares this system with a conventional approach. MATERIALS AND METHODS: We used a custom designed system allowing computed tomography (CT)-based preoperative planning, intraoperative navigation, and postoperative evaluation. Five orthopedic surgeons defined common preoperative plans on 3-dimensional CT reconstructed cadaveric shoulders. Each surgeon performed 3 computer-assisted and 3 conventional simulated procedures. The 3-dimensional CT reconstructed postoperative units were digitally matched to the preoperative model for evaluation of entry points, end points, and angulations of screws and baseplate. Values were used to find accuracy and precision of the 2 groups with respect to the defined placement. Statistical analysis was performed by t tests (alpha = .05). RESULTS: Comparison of the groups revealed no difference in accuracy or precision of screws or baseplate entry points (P > .05). Accuracy and precision were improved with use of navigation for end points and angulations of 3 screws (P < .05). Accuracy of the inferior screw showed a trend of improvement with navigation (P > .05). Navigated baseplate end point precision was improved (P < .05), with a trend toward improved accuracy (P > .05). CONCLUSION: We conclude that CT-based preoperative planning and intraoperative navigation allow improved accuracy and precision for screw placement and precision for baseplate positioning with respect to a predefined placement compared with conventional techniques in RSA. PMID- 25556809 TI - Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. AB - Tardive dyskinesia is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking psychotropic drugs. The pathophysiology of tardive dyskinesia is complex, multifactorial and still not fully understood. A number of drugs were tried for the management of this motor disturbance, yet until now no effective and standard treatment has been found. It is very disappointing to realize that the introduction of antipsychotics from the second generation has not significantly decreased the prevalence and incidence of tardive dyskinesia. Therefore, the management of this motor disturbance remains an actual topic as well as a challenge for clinicians. This review summarizes recent relevant publications concerning the treatment of tardive dyskinesia. PMID- 25556810 TI - The Pekin duck programmed death-ligand 1: cDNA cloning, genomic structure, molecular characterization and mRNA expression analysis. AB - Programmed death ligand-1 (PD-L1) plays an important role in the attenuation of adaptive immune responses in higher vertebrates. Here, we describe the identification of the Pekin duck PD-L1 orthologue (duPD-L1) and its gene structure. The duPD-L1 cDNA encodes a 311-amino acid protein that has an amino acid identity of 78% and 42% with chicken and human PD-L1, respectively. Mapping of the duPD-L1 cDNA with duck genomic sequences revealed an exonic structure of its coding sequence similar to those of other vertebrates but lacked a noncoding exon 1. Homology modelling of the duPD-L1 extracellular domain was compatible with the tandem IgV-like and IgC-like IgSF domain structure of human PD-L1 (PDB ID: 3BIS). Residues known to be important for receptor binding of human PD-L1 were mostly conserved in duPD-L1 within the N-terminus and the G sheet, and partially conserved within the F sheet but not within sheets C and C'. DuPD-L1 mRNA was constitutively expressed in all tissues examined with highest expression levels in lung and spleen and very low levels of expression in muscle, kidney and brain. Mitogen stimulation of duck peripheral blood mononuclear cells transiently increased duPD-L1 mRNA expression. Our observations demonstrate evolutionary conservation of the exonic structure of its coding sequence, the extracellular domain structure and residues implicated in receptor binding, but the role of the longer cytoplasmic tail in avian PD-L1 proteins remains to be determined. PMID- 25556812 TI - Modulation of selective attention by polarity-specific tDCS effects. AB - Selective attention relies on working memory to maintain an attention set of task priorities. Consequently, selective attention is more efficient when working memory resources are not depleted. However, there is some evidence that distractors are processed even when working memory load is low. We used tDCS to assess whether boosting the activity of the Dorsolateral Prefrontal Cortex (DLPFC), involved in selective attention and working memory, would reduce interference from emotional distractors. Findings showed that anodal tDCS over the DLPFC was not sufficient to reduce interference from angry distractors. In contrast, cathodal tDCS over the DLPFC reduced interference from happy distractors. These findings show that altering the DLPFC activity is not sufficient to establish top-down control and increase selective attention efficiency. Although, when the neural signal in the DLPFC is altered by cathodal tDCS, interference from emotional distractors is reduced, leading to an improved performance. PMID- 25556811 TI - The impact of different aetiologies on the cognitive performance of frontal patients. AB - Neuropsychological group study methodology is considered one of the primary methods to further understanding of the organisation of frontal 'executive' functions. Typically, patients with frontal lesions caused by stroke or tumours have been grouped together to obtain sufficient power. However, it has been debated whether it is methodologically appropriate to group together patients with neurological lesions of different aetiologies. Despite this debate, very few studies have directly compared the performance of patients with different neurological aetiologies on neuropsychological measures. The few that did included patients with both anterior and posterior lesions. We present the first comprehensive retrospective comparison of the impact of lesions of different aetiologies on neuropsychological performance in a large number of patients whose lesion solely affects the frontal cortex. We investigated patients who had a cerebrovascular accident (CVA), high (HGT) or low grade (LGT) tumour, or meningioma, all at the post-operative stage. The same frontal 'executive' (Raven's Advanced Progressive Matrices, Stroop Colour-Word Test, Letter Fluency S; Trail Making Test Part B) and nominal (Graded Naming Test) tasks were compared. Patients' performance was compared across aetiologies controlling for age and NART IQ scores. Assessments of focal frontal lesion location, lesion volume, global brain atrophy and non-specific white matter (WM) changes were undertaken and compared across the four aetiology. We found no significant difference in performance between the four aetiology subgroups on the 'frontal' executive and nominal tasks. However, we found strong effects of premorbid IQ on all cognitive tasks and robust effects of age only on the frontal tasks. We also compared specific aetiology subgroups directly, as previously reported in the literature. Overall we found no significant differences in the performance of CVA and tumour patients, or LGT and HGT patients or LGT, HGT and meningioma's on our four frontal tests. No difference was found with respect to the location of frontal lesions, lesion volume, global brain atrophy and non-specific WM changes between the subgroups. Our results suggest that the grouping of frontal patients caused by different aetiologies is a pragmatic, justified methodological approach that can help to further understanding of the organisation of frontal executive functions. PMID- 25556813 TI - Modulation of executive control in dual tasks with transcranial direct current stimulation (tDCS). AB - Executive processing in dual tasks is primarily associated with activation of the lateral prefrontal cortex (lPFC), which is demonstrated in functional imaging studies (e.g., Szameitat et al., 2006). However, a causal relation between lPFC activity and executive functions in dual tasks has not been demonstrated so far. Here, we used anodal transcranial direct current stimulation (atDCS [1 mA, 20 min] vs. sham stimulation [1 mA, 30s]) over the left inferior frontal junction under conditions of random and fixed task order in dual tasks as well as in single tasks in healthy young individuals (Experiment 1). We found that atDCS, if administered simultaneously to the task, improved performance in random-order dual tasks, but not in fixed-order dual tasks and single tasks. Moreover, dual task performance under random-order conditions did not improve if atDCS was applied prior to the task performance. The identical procedure in Experiment 2 showed no difference in dual-task performance under random-task order conditions when we compared cathodal tDCS (ctDCS) with sham stimulation. Our findings suggest that dual-task performance is causally related to lPFC activation under conditions that require task-order decisions and high demands on executive functioning. Subsequent studies may now explore if atDCS leads to sustained improvements parallel to the training of dual tasks. PMID- 25556814 TI - Thermal spring water drinking attenuates dextran-sulfate-sodium-induced colitis in mice. AB - INTRODUCTION: The present study investigates the effect of oral consumption of hydrogen sulfide-containing Harkany thermal spring water, as well as sodium hydrogen sulfide (NaHS) solution on experimental colitis. METHODS: Colitis was induced by 2% dextran sulfate sodium (DSS) in the drinking water of C57BL/6 mice for 7 days. Some animal groups drank Harkany thermal spring water or water supplemented with 21.68 mg/L NaHS. General signs of colitis, myeloperoxidase (MPO) enzyme activity of colon samples, histological features of colitis and function of the enteric nervous system were assessed. RESULTS: Oral administration of Harkany thermal spring water significantly attenuated general signs of colitis, MPO enzyme activity of colon samples and detrimental effect of colitis on the function of the enteric nervous system, but not histological signs of colitis. These findings could be reproduced using NaHS solution with additional significantly diminished histological damage. CONCLUSIONS: We conclude that oral treatment with Harkany thermal spring water relieves various aspects of DSS-evoked colitis in mice. This effect is most likely to be mediated by hydrogen sulfide content of the Harkany water. Our data might promote complementary utilization of sulfurous thermal spring water in the therapy of inflammatory bowel disease. PMID- 25556815 TI - Planktonic and biofilm-grown nitrogen-cycling bacteria exhibit different susceptibilities to copper nanoparticles. AB - Proper characterization of nanoparticle (NP) interactions with environmentally relevant bacteria under representative conditions is necessary to enable their sustainable manufacture, use, and disposal. Previous nanotoxicology research based on planktonic growth has not adequately explored biofilms, which serve as the predominant mode of bacterial growth in natural and engineered environments. Copper nanoparticle (Cu-NP) impacts on biofilms were compared with respective planktonic cultures of the ammonium-oxidizing Nitrosomonas europaea, nitrogen fixing Azotobacter vinelandii, and denitrifying Paracoccus denitrificans using a suite of independent toxicity diagnostics. Median inhibitory concentration (IC50) values derived from adenosine triphosphate (ATP) for Cu-NPs were lower in N. europaea biofilms (19.6 +/- 15.3 mg/L) than in planktonic cells (49.0 +/- 8.0 mg/L). However, in absorbance-based growth assays, compared with unexposed controls, N. europaea growth rates in biofilms were twice as resilient to inhibition than those in planktonic cultures. Similarly, relative to unexposed controls, growth rates and yields of P. denitrificans in biofilms exposed to Cu NPs were 40-fold to 50-fold less inhibited than those in planktonic cells. Physiological evaluation of ammonium oxidation and nitrate reduction suggested that biofilms were also less inhibited by Cu-NPs than planktonic cells. Furthermore, functional gene expression for ammonium oxidation (amoA) and nitrite reduction (nirK) showed lower inhibition by NPs in biofilms relative to planktonic-grown cells. These results suggest that biofilms mitigate NP impacts, and that nitrogen-cycling bacteria in wastewater, wetlands, and soils might be more resilient to NPs than planktonic-based assessments suggest. PMID- 25556816 TI - Two main metabolites of gentiopicroside detected in rat plasma by LC-TOF-MS following 2,4-dinitrophenylhydrazine derivatization. AB - The metabolism of gentiopicroside in vivo was studied by LC/MS following 2,4 dinitrophenylhydrazine derivatization for the first time. The ionization efficiency of the major metabolites erythrocentaurin and gentiopicral were greatly enhanced by the new analytical method developed, and they were successfully detected in rat plasma after oral administration of gentiopicroside. Methyl 4-formylbenzoate was used as the internal standard to quantify erythrocentaurin and gentiopicral in rat plasma in negative mode by UPLC-TOF-MS. It was found that erythrocentaurin reached the maximum plasma concentration of 625.2+/-246.3 ng/mL at about 2 h and gentiopicral reached the maximum plasma concentration of 157.6+/-86.6 ng/mL at about 4 h after oral administration of gentiopicroside at a dose of 200 mg/kg. The metabolic pathway of gentiopicroside to erythrocentaurin and gentiopicral was proposed. The monoterpene compound gentiopicroside was found to be metabolized to dihydroisocoumarin in vivo which may be responsible for the pharmacological effect of gentiopicroside. The results may shed light on clinical efficacy of gentiopicroside and the new analytical method developed may assist in studies for the metabolism of other natural iridoids and secoiridoids in vivo. PMID- 25556817 TI - Glucose-fructose likely improves gastrointestinal comfort and endurance running performance relative to glucose-only. AB - This study aimed to determine whether glucose-fructose (GF) ingestion, relative to glucose-only, would alter performance, metabolism, gastrointestinal (GI) symptoms, and psychological affect during prolonged running. On two occasions, 20 runners (14 men) completed a 120-min submaximal run followed by a 4-mile time trial (TT). Participants consumed glucose-only (G) or GF (1.2:1 ratio) beverages, which supplied ~ 1.3 g/min of carbohydrate. Substrate use, blood lactate, psychological affect [Feeling Scale (FS)], and GI distress were measured. Differences between conditions were assessed using magnitude-based inferential statistics. Participants completed the TT 1.9% (-1.9; -4.2, 0.4) faster with GF, representing a likely benefit. FS ratings were possibly higher and GI symptoms were possibly-to-likely lower with GF during the submaximal period and TT. Effect sizes for GI distress and FS ratings were relatively small (Cohen's d = ~0.2 to 0.4). GF resulted in possibly higher fat oxidation during the submaximal period. No clear differences in lactate were observed. In conclusion, GF ingestion - compared with glucose-only - likely improves TT performance after 2 h of submaximal running, and GI distress and psychological affect are likely mechanisms. These results apply to runners consuming fluid at 500-600 mL/h and carbohydrate at 1.0-1.3 g/min during running at 60-70% VO2peak . PMID- 25556818 TI - Fluorescence imaging of metal ions implicated in diseases. AB - Metal ions play an important role in various biological processes, their abnormal homeostasis in cells is related to many diseases, such as neurodegenerative disease, cancer and diabetes. Fluorescent imaging offers a unique route to detect metal ions in cells via a contactless and damage-free way with high spatial and temporal fidelity. Consequently, it represents a promising method to advance the understanding of physiological and pathological functions of metal ions in cell biology. In this highlight article, we will discuss recent advances in fluorescent imaging of metal ions by small-molecule sensors for understanding the role of metals in related diseases. We will also discuss challenges and opportunities for the design of small-molecule sensors for fluorescent detection of cellular metal ions as a potential method for disease diagnosis. PMID- 25556819 TI - Seemingly Harmless Racial Communications Are Not So Harmless: Racial Microaggressions Lead to Suicidal Ideation by Way of Depression Symptoms. AB - Racial microaggressions, a contemporary form of subtle discrimination that occurs in everyday interactions, are associated with a variety of negative mental health outcomes. Research has not extended the connection between racial microaggressions and negative mental health to include suicide risk. Given the well-known association between negative mental health outcomes and suicide risk, the current study examined whether racial microaggressions predicted suicidal ideation through depression symptoms among 405 young adults of color. Depression symptoms mediated the relationship between racial microaggressions and suicidal ideation. This is the first study to associate racial microaggressions to suicide risk. Societal and clinical implications are discussed. PMID- 25556820 TI - Demographics and discharge outcomes of dysvascular and non-vascular lower limb amputees at a subacute rehabilitation unit: a 7-year series. AB - OBJECTIVE: To examine personal and social demographics, and rehabilitation discharge outcomes of dysvascular and non-vascular lower limb amputees. METHODS: In total, 425 lower limb amputation inpatient rehabilitation admissions (335 individuals) from 2005 to 2011 were examined. Admission and discharge descriptive statistics (frequency, percentages) were calculated and compared by aetiology. RESULTS: Participants were male (74%), aged 65 years (s.d. 14), born in Australia (72%), had predominantly dysvascular aetiology (80%) and a median length of stay 48 days (interquartile range (IQR): 25-76). Following amputation, 56% received prostheses for mobility, 21% (n = 89) changed residence and 28% (n = 116) required community services. Dysvascular amputees were older (mean 67 years, s.d. 12 vs 54 years, s.d. 16; P < 0.001) and recorded lower functional independence measure--motor scores at admission (z = 3.61, P < 0.001) and discharge (z = 4.52, P < 0.001). More non-vascular amputees worked before amputation (43% vs 11%; P < 0.001), were prescribed a prosthesis by discharge (73% vs 52%; P < 0.001) and had a shorter length of stay (7 days, 95% confidence interval: -3 to 17), although this was not statistically significant. CONCLUSIONS: Differences exist in social and demographic outcomes between dysvascular and non-vascular lower limb amputees. PMID- 25556822 TI - Description of a Rat Palatal Acrylic Plate That Can Be Relined. AB - PURPOSE: The objective of this article is to describe a method to construct an intraoral acrylic device that permits a reline material to be added to the inner surface of the palatal plate. MATERIALS AND METHODS: Fifteen 60-day-old adult female rats (Rattus Norvegicus Albinus Wistar), weighing 150 to 250 g were used for this study and allocated to three groups (n = 5): G1, animals wearing a heat polymerized acrylic resin palatal plate (Lucitone 550) for 14 days; G2, animals wearing a heat-polymerized acrylic resin palatal plate (Lucitone 550) relined with Tokuyama Rebase II for 14 days; and G3, animals maintained under the same conditions as the experimental groups, without wearing palatal plates for 14 days. The manipulation of the animals followed the guidelines of the Brazilian College of Animal Experimentation, under the approval of the animal ethics committee of the State University of Ponta Grossa. The palatal plates covered the whole palate, were fixed in the molar region with light-cured resin, and were kept there for 14 days. The animals received a paste diet and water ad libitum. Before and after the trial period, the rats were weighed individually on a precision scale. Statistical analysis was performed using a two-way analysis of variance (alpha = 0.05) test for comparison of the animals' weight (g) at time 0 and after 14 days of using the palatal plate. RESULTS: No statistical differences were observed regarding the weight of the animals among the experimental groups in the study. CONCLUSIONS: The individual master impressions, the molar teeth coverage, and the method of cementation with nonadhesive composite resin provided good stability for the palatal plate showed in this study, not disturbing the eating habits and nutrition of the animals. This model seems reproducible, offering adequate histopathological evaluation. Differences in tissue morphology exist between the animals that used the palatal plate and the animals that did not use this device. Use of these palatal plates could clarify how prostheses bring changes in the palatal mucosa of users. PMID- 25556823 TI - The novel GJB3 mutation p.Thr202Asn in the M4 transmembrane domain underlies erythrokeratodermia variabilis. PMID- 25556821 TI - A controllable on-off strategy for the reproductive containment of fish. AB - A major impediment to the commercialization and cultivation of transgenic fish is the potential ecological risks they pose to natural environments: a problem that could be solved by the production of sterile transgenic fish. Here, we have developed an on-off reproductive containment strategy for fish that renders the offspring sterile but leaves their parents fertile. TG1 (Tol2-CMV-GFP-pA-CMV-gal4 pA-Tol2) and TG2 (Tol2-CMV-RFP-pA-5 * UAS-as/dnd-pA-Tol2) zebrafish lines were established using a GAL4/UAS system. While the parental lines remained fertile, in the hybrid offspring, GAL4 induced 5 * UAS to drive the transcription of antisense dnd, which significantly down-regulated endogenous dnd expression. This disrupted the migration of primordial germ cells (PGCs), led to their apoptosis, and resulted in few or no PGCs migrating to the genital ridge. This process induced sterility or reduced fertility in adult fish. This on-off strategy is a potentially effective means of generating sterile fish for commercialization while retaining fertility in brood stocks, and offers a novel method to mitigate the ecological risks of fish introductions. PMID- 25556824 TI - Circumventing resistance to anti-infective agents. PMID- 25556825 TI - A novel mutation in the COL7A1 gene results in a unique phenotype of epidermolysis bullosa pruriginosa. PMID- 25556826 TI - Erratum: using isothermal titration calorimetry to determine thermodynamic parameters of protein-glycosaminoglycan interactions. PMID- 25556827 TI - Bronchopleural fistula arising after commencement of pazopanib for progressive sarcoma. PMID- 25556828 TI - Outpatient use of oral propranolol and topical timolol for infantile hemangiomas: survey results and comparison with propranolol consensus statement guidelines. AB - Oral and topical beta-blockers are used to treat infantile hemangiomas (IHs). Although a recent consensus report provided guidelines for the treatment of IH with propranolol, there are no standard guidelines for the use of topical timolol. The objectives of this study were to determine the current use of oral propranolol and topical timolol by pediatric dermatologists in an outpatient setting and to compare current propranolol use with published propranolol consensus guidelines. An electronic survey was sent to pediatric dermatologists in May and June 2013. One hundred forty-nine pediatric dermatologists responded to the survey, a 79% response rate. Of the respondents, 96% prescribed oral propranolol, but 75% did not follow consensus guidelines exactly; recommended history, physical examination, initial dose, and frequency varied. The dose of propranolol was usually titrated up to goal dose as recommended (89%). Fifty-six percent monitored vital signs in patients after the initial dose and 49% continued to monitor vital signs in their clinic after each dose escalation, which did not meet consensus guideline recommendations. Ninety-one percent reported using topical timolol for the treatment of IH and 66% responded they had used topical timolol in conjunction with oral propranolol to treat IH. The most common indication was superficial hemangiomas (97%). Most practitioners (74%) did not routinely monitor heart rate or blood pressure in infants treated with topical timolol. This study highlights the variability in prescribing and monitoring practices of physicians using propranolol for the treatment of IHs and demonstrates that topical timolol is commonly used alone and in conjunction with oral propranolol to treat IHs. PMID- 25556829 TI - Adipose-derived stem cells in veterinary medicine: characterization and therapeutic applications. AB - Mesenchymal stem cells, considered one of the most promising cell types for therapeutic applications due to their capacity to secrete regenerative bioactive molecules, are present in all tissues. Stem cells derived from the adipose tissue have been increasingly used for cell therapy in humans and animals, both as freshly isolated, stromal vascular fraction (SVF) cells, or as cultivated adipose derived stem cells (ASCs). ASCs have been characterized in different animal species for proliferation, differentiation potential, immunophenotype, gene expression, and potential for tissue engineering. Whereas canine and equine ASCs are well studied, feline cells are still poorly known. Many companies around the world offer ASC therapy for dogs, cats, and horses, although in most countries these activities are not yet controlled by regulatory agencies. This is the first study to review the characterization and clinical use of SVF and ASCs in spontaneously occurring diseases in veterinary patients. Although a relatively large number of studies investigating ASC therapy in induced lesions are available in the literature, a surprisingly small number of reports describe ASC therapy for naturally affected dogs, cats, and horses. A total of seven studies were found with dogs, only two studies in cats, and four in horses. Taken as a whole, the results do not allow a conclusion on the effect of this therapy, due to the generally small number of patients included, diversity of cell populations used, and lack of adequate controls. Further controlled studies are clearly needed to establish the real potential of ASC in veterinary medicine. PMID- 25556830 TI - The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells. AB - Baclofen is used clinically as a drug that treats spasticity, which is a syndrome characterized by excessive contraction of the muscles and hyperflexia in the central nervous system (CNS), by activating GABA(B) receptors (GABA(B)Rs). Baclofen was recently reported to desensitize chemokine receptors and to suppress inflammation through the activation of GABA(B)Rs. GABA(B)Rs are expressed in various immune cells, but the functions of these receptors in autoimmune diseases remain largely unknown. In this study, we investigated the effects of baclofen in murine collagen-induced arthritis (CIA). Oral administration of baclofen alleviated the clinical development of CIA, with a reduced number of IL-17 producing T helper 17 (T(H)17) cells. In addition, baclofen treatment suppressed dendritic cell (DC)-primed T(H)17 cell differentiation by reducing the production of IL-6 by DCs in vitro. Furthermore, the pharmacological and genetic blockade of GABA(B)Rs in DCs weakened the effects of baclofen, indicating that GABA(B)Rs are the molecular targets of baclofen on DCs. Thus, our findings revealed a potential role for baclofen in the treatment of CIA, as well as a previously unknown signaling pathway that regulates DC function. PMID- 25556831 TI - Recombinant T-cell receptor ligand RTL1000 limits inflammation and decreases infarct size after experimental ischemic stroke in middle-aged mice. AB - We have previously demonstrated that recombinant T-cell receptor ligand 1000 (RTL1000) reduces infarct size and improves long-term functional recovery after experimental stroke in young transgenic mice expressing human leukocyte antigen DR2 (DR2-Tg). In this study, we determined the effect of RTL1000 on infarct size in 12-month-old middle-aged DR2-Tg mice, and investigated its mechanism of action. Twelve-month-old male DR2-Tg mice underwent 60min of intraluminal reversible middle cerebral artery occlusion (MCAO). Vehicle or RTL1000 was injected 4, 24, 48 and 72h after MCAO. Cortical, striatal and total hemispheric infarcts were measured 96h after stroke. Spleen and brain tissues were collected 96h after stroke for immunological analysis. Our data showed that RTL1000 significantly reduced infarct size 96h after MCAO in middle-aged male DR2-Tg mice. RTL1000 decreased the number of activated monocytes/microglia cells (CD11b(+)CD45(hi)) and CD3(+) T cells in the ischemic hemisphere. RTL1000 also reduced the percentage of total T cells and inflammatory neutrophils in the spleen. These findings suggest that RTL1000 protects against ischemic stroke in middle-aged male mice by limiting post-ischemic inflammation. PMID- 25556832 TI - Transition of pattern generation: the phenomenon of post-scratching locomotion. AB - A fundamental problem in neurophysiology is the understanding of neuronal mechanisms by which the central nervous system produces a sequence of voluntary or involuntary motor acts from a diverse repertory of movements. These kinds of transitions between motor acts are extremely complex; however, they could be analyzed in a more simple form in decerebrate animals in the context of spinal central pattern generation. Here, we present for the first time a physiological phenomenon of post-scratching locomotion in which decerebrate cats exhibit a compulsory locomotor activity after an episode of scratching. We found flexor, extensor and intermediate single interneurons rhythmically firing in the same phase during both scratching and the subsequent post-scratching locomotion. Because no changes in phase of these neurons from scratching to post-scratching locomotion were found, we suggest that in the lumbar spinal cord there are neurons associated with both motor tasks. Moreover, because of its high reproducibility we suggest that the study of post-scratching fictive locomotion, together with the unitary recording of neurons, could become a useful tool to study neuronal mechanisms underlying transitions from one rhythmic motor task to another, and to study in more detail the central pattern generator circuitry in the spinal cord. PMID- 25556833 TI - DeCoN: genome-wide analysis of in vivo transcriptional dynamics during pyramidal neuron fate selection in neocortex. AB - Neuronal development requires a complex choreography of transcriptional decisions to obtain specific cellular identities. Realizing the ultimate goal of identifying genome-wide signatures that define and drive specific neuronal fates has been hampered by enormous complexity in both time and space during development. Here, we have paired high-throughput purification of pyramidal neuron subclasses with deep profiling of spatiotemporal transcriptional dynamics during corticogenesis to resolve lineage choice decisions. We identified numerous features ranging from spatial and temporal usage of alternative mRNA isoforms and promoters to a host of mRNA genes modulated during fate specification. Notably, we uncovered numerous long noncoding RNAs with restricted temporal and cell-type specific expression. To facilitate future exploration, we provide an interactive online database to enable multidimensional data mining and dissemination. This multifaceted study generates a powerful resource and informs understanding of the transcriptional regulation underlying pyramidal neuron diversity in the neocortex. VIDEO ABSTRACT: PMID- 25556834 TI - Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. AB - Huntington's disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is early and robust vulnerability in striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in HD brain and show that introducing the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, impaired dopamine signaling, and increases autophagy. We also find that the expression of Rhes, a striatum-enriched mTOR activator, is reduced in HD patient and mouse brain and that exogenous addition of Rhes alleviates motor deficits and improves brain pathology in HD mice. Our combined work indicates that impaired Rhes/mTORC1 activity in HD brain may underlie the notable striatal susceptibility and thus presents a promising therapeutic target for HD therapy. PMID- 25556836 TI - Visual areas exert feedforward and feedback influences through distinct frequency channels. AB - Visual cortical areas subserve cognitive functions by interacting in both feedforward and feedback directions. While feedforward influences convey sensory signals, feedback influences modulate feedforward signaling according to the current behavioral context. We investigated whether these interareal influences are subserved differentially by rhythmic synchronization. We correlated frequency specific directed influences among 28 pairs of visual areas with anatomical metrics of the feedforward or feedback character of the respective interareal projections. This revealed that in the primate visual system, feedforward influences are carried by theta-band (~ 4 Hz) and gamma-band (~ 60-80 Hz) synchronization, and feedback influences by beta-band (~ 14-18 Hz) synchronization. The functional directed influences constrain a functional hierarchy similar to the anatomical hierarchy, but exhibiting task-dependent dynamic changes in particular with regard to the hierarchical positions of frontal areas. Our results demonstrate that feedforward and feedback signaling use distinct frequency channels, suggesting that they subserve differential communication requirements. PMID- 25556835 TI - Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. AB - Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain. Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain. PMID- 25556838 TI - An unusual mass of tricuspid valve in an adult patient: blood-filled cyst. AB - Blood-filled cysts (BFC) within the heart are common findings at postmortem examinations of fetuses and infants. However, such cysts are very rare entities in adolescents and adults. We report here an adult case of BFC attached to the posterior leaflet of the tricuspid valve, demonstrating the importance of multimodal diagnostic imaging combining both echocardiography and magnetic resonance imaging. PMID- 25556839 TI - Communicating in context: a priority for gene therapy researchers. AB - History shows that public opinion of emerging biotechnologies has the potential to impact the research process through mechanisms such as funding and advocacy. It is critical, therefore, to consider public attitudes towards modern biotechnology such as gene therapy and more specifically towards the ethics of gene therapy, alongside advances in basic and clinical research. Research conducted through social media recently assessed how online users view the ethics of gene therapy and showed that while acceptability is high, significant ethical concerns remain. To address these concerns, the development of effective and evidence-based communication strategies that engage a wide range of stakeholders should be a priority for researchers. PMID- 25556837 TI - Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity. AB - AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 +/- 8.1 years old, 63.1 +/- 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients. PMID- 25556840 TI - The challenge of linear (E)-enones in the Rh-catalyzed, asymmetric 1,4-addition reaction of phenylboronic acid: a DFT computational analysis. AB - Why are linear (E)-enones such challenging substrates in the Rh-catalyzed asymmetric arylation with boronic acids, which is one of the most important asymmetric catalysis methods? DFT computations show that these substrates adopt a specific conformation in which the largest substituent is antiperiplanar to Rh(I) pi-complexed with the C = C bond within the enantioselectivity-determining carborhodation transition state. Additionally, for such structures, there is a strong, but not exclusive, preference for s-cis enone conformation. This folding minimizes steric interactions between the substrate and the ligand, and hence reduces the enantioselectivity. This idea is further confirmed by investigating three computation-only substrate "probes", one of which is capable of double asymmetric induction, and a recent computationally designed 1,5-diene ligand. On average, excellent agreement between predicted and experimental enantioselectivity was attained by a three-pronged approach: 1) thorough conformational search within ligand and substrate subunits to locate the most preferred carborhodation transition state; 2) including dispersion interaction and long-range corrections by SMD/omegaB97xD/DGDZVP level of theory; and 3) full substrate and ligand modeling. Based on the results, a theory-enhanced enantioselectivity model that is applicable to both chiral diene and diphosphane ligands is proposed. PMID- 25556841 TI - Mental Health in Offspring of Traumatized Refugees with and without Post traumatic Stress Disorder. AB - Intergenerational transmission of psychological trauma and the impact of parental post-traumatic stress disorder (PTSD) on offspring are controversially discussed. We studied 50 offspring (36 women and 14 men, mean age 42.1 years) of refugees who were severely traumatized as children at the end of World War II. From these, 25 of the refugees currently suffered from chronic PTSD, and 25 had no PTSD. Parental PTSD status did not significantly influence mental health [as per the Symptom Checklist (SCL)-90-R] or quality of life (assessed by the 36-item Short form Health Survey) in their children. In the entire sample, frequency of talking with the mother about the flight correlated with phobic anxiety (r = 0.67, p = 0.03). Interestingly, the stated burden of having a parent with a history of flight significantly (p < 0.05) correlated with almost all subscales of the SCL 90-R. These results in a non-clinical sample do not support a specific role of parental PTSD in intergenerational trauma transmission. Our other remarkable, but preliminary, results need to be studied in larger samples using more subtle interaction or schema analyses. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25556842 TI - A computational model of the effect of symplastic growth on cell mechanics in a linear leaf blade. AB - The epidermis of a linear leaf, as in Poaceae, is established by parallel files of cells originating from the leaf base. Their feature is symplastic growth where neighboring cell walls adhere and do not slide along each other. We developed a simple mechanical cell-based model for symplastic growth of linear leaf blade. The challenge is to determine what restrictions on cell size symplastic growth creates compared to the free growing cells. We assume an unidirectional growing cell ensemble starting from a meristem-like layer of generative cells and then generating parallel cell rows from every cell of the initial layer. Each cell is characterized by its growth function, and growth of the whole leaf blade is accompanied by mutual adjustment between all the cells. Cells divide once they have reached a threshold area. A mathematical model and its implementation are proposed for computational simulation of 1D symplastic growth of tissues. The question analyzed is how a cell grows in a plant tissue if there is a mechanism for regulating the growth of an isolated growing cell and the behavior of the cell wall matter is elastoplastic. The results of the simulation of linear leaf blade growth are compared to those for a free-growing cell population. PMID- 25556843 TI - Research on the immunosuppressive activity of ingredients contained in sunscreens. AB - The immunosuppressive properties of Benzophenone-4, an UV-filter and three ingredients, Allantoin, Bisabolol and Enoxolon used in sunscreen formulation, previously characterized as anti-inflammatory compounds, are studied. The results of this study demonstrate that four tested molecules have effects on DCs and T cells which are the most important cells of the immune system. The impact is also visible on keratinocyte cells which are in the direct contact with skin sunscreens. Each ingredient should be used with caution at reduced doses or even removed from some cosmetic preparations, such as sunscreens. PMID- 25556844 TI - ParaHydrogen Induced Polarization of 13C carboxylate resonance in acetate and pyruvate. AB - The advent of nuclear spins hyperpolarization techniques represents a breakthrough in the field of medical diagnoses by magnetic resonance imaging. Dynamic nuclear polarization (DNP) is the most widely used method, and hyperpolarized metabolites such as [1-(13)C]-pyruvate are shown to report on status of tumours. Parahydrogen-induced polarization (PHIP) is a chemistry-based technique, easier to handle and much less expensive in respect to DNP, with significantly shorter polarization times. Its main limitation is the availability of unsaturated precursors for the target substrates; for instance, acetate and pyruvate cannot be obtained by direct incorporation of the parahydrogen molecule. Herein we report a method that allows us to achieve hyperpolarization in this kind of molecule by means of a tailored precursor containing a hydrogenable functionality that, after polarization transfer to the target (13)C moiety, is cleaved to obtain the metabolite of interest. The reported procedure can be extended to a number of other biologically relevant substrates. PMID- 25556845 TI - Ion Transport through Ultrathin Electrolyte under Applied Voltages. AB - The influence of the Coulomb transport (CT) effect on ion transport in electrolytes is evaluated through two prototypical systems: the [IrCl6](2-/3-) redox couple in aqueous solution and Mg(2+) (with TFSI(-) counterions) in acetonitrile solution. In the first system, transport of the [IrCl6](2-/3-) anions is inhibited, and ions are trapped near the positive electrode due to the unscreened electric field. With larger applied voltage, the inhibition is stronger. This effect can be weakened, however, by adding supporting charges, which screen the electric field of the electrodes. In the second system, the unscreened electric field provides a means of separating [Mgx(TFSI)y]((2x-y)+) clusters in the electrolyte. This effect enhances charge transport by providing a larger number of faster-moving (smaller) ions. Considered together, these systems provide examples of how the CT effect may increase or decrease charge transport and how one might attempt to modulate this effect in order to enhance electrochemical cell conduction. PMID- 25556846 TI - Ancient DNA and the human settlement of the Pacific: a review. AB - The Pacific region provides unique opportunities to study human evolution including through analyses of ancient DNA. While some of the earliest studies involving ancient DNA from skeletal remains focused on Pacific samples, in the following 25 years, several factors meant that little aDNA research, particularly research focused on human populations, has emerged. This paper briefly presents the genetic evidence for population origins, reviews what ancient DNA work has been undertaken to address human history and evolution in the Pacific region, and argues that the future is bright but research requires a collaborative approach between academic disciplines but also with local communities. PMID- 25556847 TI - High-performance semitransparent perovskite solar cells with solution-processed silver nanowires as top electrodes. AB - In this work, we report efficient semitransparent perovskite solar cells using solution-processed silver nanowires (AgNWs) as top electrodes. A thin layer of zinc oxide nanoparticles is introduced beneath the AgNWs, which fulfills two essential functionalities: it ensures ohmic contact between the PC60BM and the AgNWs and it serves as a physical foundation that enables the solution-deposition of AgNWs without causing damage to the underlying perovskite. The as-fabricated semitransparent perovskite cells show a high fill factor of 66.8%, Voc = 0.964 V, Jsc = 13.18 mA cm(-2), yielding an overall efficiency of 8.49% which corresponds to 80% of the reference devices with reflective opaque electrodes. PMID- 25556848 TI - Involvement of the human midbrain and thalamus in auditory deviance detection. AB - Prompt detection of unexpected changes in the sensory environment is critical for survival. In the auditory domain, the occurrence of a rare stimulus triggers a cascade of neurophysiological events spanning over multiple time-scales. Besides the role of the mismatch negativity (MMN), whose cortical generators are located in supratemporal areas, cumulative evidence suggests that violations of auditory regularities can be detected earlier and lower in the auditory hierarchy. Recent human scalp recordings have shown signatures of auditory mismatch responses at shorter latencies than those of the MMN. Moreover, animal single-unit recordings have demonstrated that rare stimulus changes cause a release from stimulus specific adaptation in neurons of the primary auditory cortex, the medial geniculate body (MGB), and the inferior colliculus (IC). Although these data suggest that change detection is a pervasive property of the auditory system which may reside upstream cortical sites, direct evidence for the involvement of subcortical stages in the human auditory novelty system is lacking. Using event related functional magnetic resonance imaging during a frequency oddball paradigm, we here report that auditory deviance detection occurs in the MGB and the IC of healthy human participants. By implementing a random condition controlling for neural refractoriness effects, we show that auditory change detection in these subcortical stations involves the encoding of statistical regularities from the acoustic input. These results provide the first direct evidence of the existence of multiple mismatch detectors nested at different levels along the human ascending auditory pathway. PMID- 25556849 TI - A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro. AB - The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Abeta) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Abeta production were used. EHT 5372 inhibits DYRK1A induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Abeta-induced Tau phosphorylation and DYRK1A-stimulated Abeta production. DYRK1A is thus as a key element of Abeta mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Abeta production and Abeta effects on phospho-Tau, including Tau aggregation. PMID- 25556850 TI - Programmable engineering of a biosensing interface with tetrahedral DNA nanostructures for ultrasensitive DNA detection. AB - Self-assembled DNA nanostructures with precise sizes allow a programmable "soft lithography" approach to engineer the interface of electrochemical DNA sensors. By using millimeter-sized gold electrodes modified with several types of tetrahedral DNA nanostructures (TDNs) of different sizes, both the kinetics and thermodynamics of DNA hybridization were profoundly affected. Because each DNA probe is anchored on an individual TDN, its lateral spacing and interactions are finely tuned by the TDN size. By simply varying the size of the TDNs, the hybridization time was decreased and the hybridization efficiency was increased. More significantly, the detection limit for DNA detection was tuned over four orders of magnitude with differentially nanostructured electrodes, and achieved attomolar sensitivity with polymeric enzyme amplification. PMID- 25556852 TI - Total synthesis of (-)-dolastatrienol. AB - The first asymmetric total synthesis of the tricyclic diterpenoid natural product (-)-dolastatrienol has been accomplished using a rhodium(II)-catalyzed carbene cyclization cycloaddition cascade reaction as the key step to construct the [5.4.0]carbobicyclic core. An intramolecular Heck reaction furnished the tricyclic skeleton and a challenging methylenation completed the synthesis of the target. PMID- 25556851 TI - Di-macrocyclic terephthalamide ligands as chelators for the PET radionuclide zirconium-89. AB - The development of bifunctional chelators (BFCs) which can stably chelate zirconium-89 ((89)Zr) while being conjugated to targeting molecules is an area of active research. Herein we report the first octadentate terephthalamide ligands, which are easily radiolabeled with (89)Zr and are highly stable in vitro. They represent a novel class of chelators, which are worthy of further development as BFCs for (89)Zr. PMID- 25556853 TI - Activation of the Canonical Wnt Signaling Pathway Induces Cementum Regeneration. AB - Canonical Wnt signaling is important in tooth development but it is unclear whether it can induce cementogenesis and promote the regeneration of periodontal tissues lost because of disease. Therefore, the aim of this study is to investigate the influence of canonical Wnt signaling enhancers on human periodontal ligament cell (hPDLCs) cementogenic differentiation in vitro and cementum repair in a rat periodontal defect model. Canonical Wnt signaling was induced by (1) local injection of lithium chloride; (2) local injection of sclerostin antibody; and (3) local injection of a lentiviral construct overexpressing beta-catenin. The results showed that the local activation of canonical Wnt signaling resulted in significant new cellular cementum deposition and the formation of well-organized periodontal ligament fibers, which was absent in the control group. In vitro experiments using hPDLCs showed that the Wnt signaling pathway activators significantly increased mineralization, alkaline phosphatase (ALP) activity, and gene and protein expression of the bone and cementum markers osteocalcin (OCN), osteopontin (OPN), cementum protein 1 (CEMP1), and cementum attachment protein (CAP). Our results show that the activation of the canonical Wnt signaling pathway can induce in vivo cementum regeneration and in vitro cementogenic differentiation of hPDLCs. PMID- 25556854 TI - Comparison of longer-term outcomes after kidney transplantation between Hispanic and non-Hispanic whites in the United States. AB - Little is known about the longer-term kidney transplant outcomes in the rapidly growing Hispanic population. Using the United States Renal Data System, we identified 105 250 Caucasian patients who received a first kidney transplant between January 1, 1996 and December 31, 2010. We tested for differences between Hispanic and non-Hispanic patients in the outcomes of (1) mortality, (2) all cause graft failure, and (3) graft failure excluding death with a functioning graft. We used Cox regression to estimate (with 95% confidence intervals) multivariable-adjusted cause-specific hazard ratios (aHRCS ) for mortality and all-cause graft failure and subdistribution hazard ratios (aHRSD ) accounting for death as a competing risk for graft failure excluding death with a functioning graft. Both mortality [aHRCS = 0.69 (0.65-0.73)] and all-cause graft failure [aHRCS = 0.79 (0.75-0.83)] were lower in Hispanics. The association between Hispanic ethnicity and graft failure excluding death was modified by age (p < 0.003). Compared with non-Hispanic whites, graft failure excluding death with a functioning graft did not differ in Hispanics aged 18-39 years [aHRSD = 0.96 (0.89-1.05)] or aged 40-59 years [aHRSD = 1.08 (1.00-1.16)], but was 13% lower in those aged >=60 years [aHRSD = 0.87 (0.78-0.98)]. In conclusion, once accounting for differences in overall survival, better graft survival was found in older Hispanic patients, but among not those aged <60 years. PMID- 25556855 TI - Novel nanometer-level uniform amorphous carbon coating for boron powders by direct pyrolysis of coronene without solvent. AB - A 3 nm coronene coating and a 4 nm amorphous carbon coating with a uniform shell core encapsulation structure for nanosized boron (B) powders are formed by a simple process in which coronene is directly mixed with boron particles without a solvent and heated at 520 degrees C for 1 h or at 630 degrees C for 3 h in a vacuum-sealed silica tube. Coronene has a melting point lower than its decomposition temperature, which enables liquid coronene to cover B particles by liquid diffusion and penetration without the need for a solvent. The diffusion and penetration of coronene can extend to the boundaries of particles and to inside the agglomerated nanoparticles to form a complete shell-core encapsulated structure. As the temperature is increased, thermal decomposition of coronene on the B particles results in the formation of a uniform amorphous carbon coating layer. This novel and simple nanometer-level uniform amorphous carbon coating method can possibly be applied to many other powders; thus, it has potential applications in many fields at low cost. PMID- 25556856 TI - Social support and responsiveness in online patient communities: impact on service quality perceptions. AB - BACKGROUND: Hospitals frequently evaluate their service quality based on the care and services provided to patients by their clinical and non-clinical staff.(1,2) However, such evaluations do not take into consideration the many interactions that patients have in online patient communities with the health-care organization (HCO) as well as with peer patients. Patients' interactions in these online communities could impact their perceptions regarding the HCO's service quality. PURPOSES: The objective of this pilot study was to evaluate the impact of social support and responsiveness that patients experience in an HCO's online community on patients' perceptions regarding the HCO's service quality. METHOD: The study data are collected from CHESS, a health-care programme (Comprehensive Health Enhancement Support System) run by the Centre for Health Enhancement System Studies at the University of Wisconsin-Madison. FINDINGS: Findings show that the social support and the responsiveness received from peer patients in the online patient communities will impact patients' perceptions regarding the service quality of the HCO even when the organizational members themselves do not participate in the online discussions. PRACTICE IMPLICATIONS: The results indicate that interactions in such HCO-provided online patient communities should not be ignored as they could translate into patients' perceptions regarding HCOs' service quality. Ways to improve responsiveness and social support in an HCO's online patient community are discussed. PMID- 25556857 TI - CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion. AB - AIMS: The inability of pancreatic beta-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in beta-cells on beta-cell function and glucose homeostasis. RESULTS: Silencing of Nrf1 in beta cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 beta-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from beta-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. INNOVATION: Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in beta cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. CONCLUSION: Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting beta-cells. PMID- 25556860 TI - Re: does the experience level of the radiologist, assessment in consensus, or the addition of the abduction and external rotation view improve the diagnostic reproducibility and accuracy of MRA of the shoulder? PMID- 25556858 TI - Comprehensive expression map of transcription regulators in the adult zebrafish telencephalon reveals distinct neurogenic niches. AB - The zebrafish has become a model to study adult vertebrate neurogenesis. In particular, the adult telencephalon has been an intensely studied structure in the zebrafish brain. Differential expression of transcriptional regulators (TRs) is a key feature of development and tissue homeostasis. Here we report an expression map of 1,202 TR genes in the telencephalon of adult zebrafish. Our results are summarized in a database with search and clustering functions to identify genes expressed in particular regions of the telencephalon. We classified 562 genes into 13 distinct patterns, including genes expressed in the proliferative zone. The remaining 640 genes displayed unique and complex patterns of expression and could thus not be grouped into distinct classes. The neurogenic ventricular regions express overlapping but distinct sets of TR genes, suggesting regional differences in the neurogenic niches in the telencephalon. In summary, the small telencephalon of the zebrafish shows a remarkable complexity in TR gene expression. The adult zebrafish telencephalon has become a model to study neurogenesis. We established the expression pattern of more than 1200 transcription regulators (TR) in the adult telencephalon. The neurogenic regions express overlapping but distinct sets of TR genes suggesting regional differences in the neurogenic potential. PMID- 25556861 TI - Antioxidant activity of Tween-20 and Tween-80 evaluated through different in vitro tests. AB - OBJECTIVES: This study aimed to evaluate the possible antioxidant activity of Tween-20 and Tween-80, two amphipathic nonionic surfactants commonly used as solubilizers and stabilizers, whose pharmacological effects have been ignored to a large degree. METHODS: Antioxidant activity was investigated in vitro measuring the scavenging activity on the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH(?) ), the production of reactive oxygen species (ROS) in activated human neutrophils using flow cytometry and the myeloperoxidase (MPO) inhibitory activity. KEY FINDINGS: Tween-20 and Tween-80 did not show scavenging activity on DPPH(?) , while produced a decrease of the ROS production in human neutrophils, being Tween-20 more active than Tween-80. Moreover, Tween-80 and Tween-20 were found to significantly stimulate MPO enzymatic activity. CONCLUSIONS: Our findings raise concerns with regard to the indiscriminate use of Tween-20 and Tween-80 in clinical and laboratory testing, since they could influence the results that are assigned to the tested substance. PMID- 25556859 TI - Cdc48-independent proteasomal degradation coincides with a reduced need for ubiquitylation. AB - Ubiquitin fusion degradation (UFD) substrates are delivered at the proteasome by a handover mechanism involving the ubiquitin-selective chaperone Cdc48 and the ubiquitin shuttle factor Rad23. Here, we show that introduction of a 20 amino acid peptide extension not only rendered degradation independent of Cdc48, in line with the model that this chaperone is involved in early unfolding events of tightly folded substrates, but at the same time relieved the need for efficient polyubiquitylation and the ubiquitin shuttle factor Rad23. Removal of the ubiquitylation sites in the N-terminal UFD signal made the degradation of this substrate strictly dependent on the peptide extension and also on Cdc48 and, importantly the presence of a functional ubiquitylation machinery. This suggests that the extension in the absence of N-terminal ubiquitylation sites is not properly positioned to engage the unfoldase machinery of the proteasome. Thus the need for efficient ubiquitylation and Cdc48 in facilitating proteasomal degradation are tightly linked but can be bypassed in the context of UFD substrates by the introduction of an unstructured extension. Our data suggest that polyubiquitin-binding complexes acting upstream of the proteasome, rather than the proteasome itself, can be primary determinants for the level of ubiquitylation required for protein degradation. PMID- 25556862 TI - Intraoperative graft assessment during coronary artery bypass surgery. AB - Coronary artery bypass grafting (CABG) is an established revascularization method for treating multivessel coronary artery disease. The goal of CABG is to achieve complete revascularization with a durable, patent graft without reintervention. However, early graft failure, including that associated with technical errors, has been reported. This makes intraoperative verification of graft patency one of the most important ways in which surgeons can reduce the rate of early graft failure. Conventional angiography is considered the gold standard for graft assessment. However, because it is invasive and inconvenient, several alternatives to intraoperative graft assessment have become available that help reduce early graft failure by allowing revision of the anastomosis intraoperatively. The aim of this article is to review the advantages and disadvantages of several intraoperative graft assessment methods for CABG. PMID- 25556863 TI - Comparison of sinoatrial conduction time measured by Holter method and premature stimulation method. AB - BACKGROUND: The reliability of noninvasive Holter method for the calculation of sinoatrial conduction time (SACT) has not been confirmed by results of invasive electrophysiological studies of sinus nodal function. The aim of this study was to compare the values of SACT obtained by Holter method with values estimated by premature atrial stimulation method. METHODS: The study population consisted of 61 patients, in whom the 24-hour ambulatory ECG monitoring had shown the occurrence of atrial premature beats. All these subjects were undergoing electrophysiological study including programmed atrial and ventricular stimulation. The measurements of SACT were obtained using spontaneous atrial premature beats (Holter method) and high right atrial stimulation (Strauss method). RESULTS: There was a good correlation between measurements of SACT by Holter method and Strauss method (r = 0.79; P < 0.001). There was no significant difference between values of SACT estimated by two compared methods. However, in certain patients, there were appreciable differences and SACT measured using spontaneous premature beats was shorter in 34 and longer in 23 patients than that estimated by the Strauss method. The values of SACT calculated by Holter method and Strauss method were significantly (P < 0.001) higher in patients with sick sinus syndrome than in those without evidence of sinus node dysfunction. CONCLUSIONS: Good correlation between values of SACT obtained by two compared methods suggests that single measurement performed using Holter method may be adequate for reliable calculation of SACT. PMID- 25556864 TI - Ureteral stent insertion for gynecologic interstitial high-dose-rate brachytherapy. AB - PURPOSE: To determine the utility of ureteral stents in interstitial gynecological brachytherapy. METHODS AND MATERIALS: We reviewed 289 patients with cervix cancer treated with high-dose-rate interstitial brachytherapy who did not have pretreatment hydronephrosis to determine the relative incidence of benign ureteral strictures after treatment. We also did comparative dosimetry analysis in five cases of high-dose-rate brachytherapy. Bilateral ureteral stents were placed during the procedure. Three dosimetry plans were created to determine the impact of modifying clinical target volume (CTV) and applying ureteral dose constraints. In Plan 1, the ureters were contoured and excluded from the CTV and 120% dose constraints were applied. In Plan 2, the ureters were contoured and excluded, but no dose constraints were applied to the ureter. In Plan 3, the CTV was created as if the location of the ureters was unknown and then ureteral dose was determined. RESULTS: There were 11 ureteral strictures observed in 255 nonstented cases and 0 ureteral strictures in 34 stented cases. Plan 1 reduced the ureter dose (D(0.1cc)) by a median 22% (7.0-53.8%) compared with Plan 2 and by a median of 30.9% (12.3-65%). compared with Plan 3. CONCLUSIONS: Placement of stents and ureteral dose constraints facilitates dosimetry and reduces the dose to ureters. Temporary ureteral stents prevent obstruction during interstitial gynecologic brachytherapy and allows the ureters to be addressed as an organ at risk. PMID- 25556865 TI - Outpatient-based high-dose-rate interstitial brachytherapy for gynecologic malignancies. AB - PURPOSE: To evaluate outpatient-based high-dose-rate (HDR) interstitial brachytherapy (ISBT) in the treatment of gynecologic malignancies. METHODS AND MATERIALS: Between December 2006 and July 2012, 50 patients were treated with twice-daily outpatient-based HDR iridium-192 ISBT at our institution. Thirty-two patients had vaginal cancers, 13 vulvar, 3 urethral, and 2 cervical cancers. The most common histologies were squamous cell carcinoma (58%) and endometrioid adenocarcinoma (26%). Twenty-six patients were treated with definitive radiation therapy with or without platinum-based chemotherapy, 16 were treated for recurrent disease, 5 were treated in the postoperative setting, and 3 were treated palliatively. Forty patients received external beam radiation therapy before ISBT. RESULTS: Median followup was 13.7 months. Median interstitial dose was 18 Gy in 2.25 Gy twice-daily fractions prescribed to the implant volume. Median external beam dose was 50.4 Gy in 1.8 Gy daily fractions prescribed to the primary disease site. Eight patients (16%) were seen in the emergency room or were admitted to the hospital during treatment. Six patients (17%) experienced significant complications after treatment (3 ulcerations at the primary site, 1 vaginal necrosis, 1 vaginal abscess, and 1 patient with urinary obstruction). Larger volume encompassing 100% of the prescribed dose was correlated with significant complications on multivariate analysis (p = 0.039). Actuarial local control at 1 year was 72%, with univariate analysis demonstrating worse local control for nonendometrioid adenocarcinoma compared with squamous cell carcinoma (20% vs. 84%, p = 0.044). CONCLUSIONS: Outpatient-based HDR ISBT is feasible and safe, with toxicity and local control rates consistent with historical outcomes. PMID- 25556866 TI - Identification and characterization of genes, encoding the 3-hydroxybutyrate dehydrogenase and a putative lipase, in an avirulent spontaneous Legionella pneumophila serogroup 6 mutant. AB - Legionella pneumophila is a pathogen widespread in aquatic environment, able to multiply both within amoebae and human macrophages. The aim of this study was to identify genes differently expressed in a spontaneous avirulent Legionella pneumophila serogroup 6 mutant, named Vir-, respect the parental strain (Vir+), and to determine their role in the loss of virulence. Protein profiles revealed some differences in Vir- proteomic maps, and among the identified proteins the undetectable 3-hydroxybutyrate dehydrogenase (BdhA) and a down-produced lipase. Both Legionella enzymes were studied before and were here further characterized at genetic level. A significant down-regulation of both genes was observed in Vir at the transcriptional level, but the use of defined mutants demonstrated that they did not affect the intracellular multiplication. A mutant (MS1) showed an accumulation of poly-3-hydroxybutyrate (PHB) granules suggesting a role of bdhA gene in its degradation process. The lipase deduced amino acid sequence revealed a catalytic triad, typical of the 'lipase box' characteristic of PHB de polymerase enzymes, that let us suppose a possible involvement of lipase in the PHB granule degradation process. Our results revealed unexpected alterations in secondary metabolic pathways possibly linking the loss of virulence to Legionella lack of energy sources. PMID- 25556867 TI - Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. AB - STUDY OBJECTIVE: To assess the short-term efficacy and safety of an accelerated intravenous iron regimen in hospitalized patients with heart failure and iron deficiency. DESIGN: Prospective, single-arm, open-label study. SETTING: Large tertiary care medical center. PATIENTS: Thirteen patients with New York Heart Association class III-IV heart failure, anemia (hemoglobin level <= 12.0 g/dl), and iron deficiency (ferritin level < 100 ng/ml, or ferritin level of 100-300 ng/ml with transferrin saturation < 20%) hospitalized between April 2011 and December 2013. INTERVENTION: All patients received sodium ferric gluconate 250 mg in 100 ml of normal saline intravenously over 2 hours twice/day until the iron deficit was corrected or the patient was discharged. MEASUREMENTS AND MAIN RESULTS: Changes in hematologic parameters were assessed at 1-4 weeks after therapy. Patients received a mean +/- standard deviation (SD) total iron dose of 1269 +/- 207 mg over 3.4 +/- 1.0 days. After a mean +/- SD follow-up of 13.1 +/- 5.6 days, intravenous iron increased hemoglobin level by 1.2 g/dl (95% confidence interval [CI] 0.45-1.9, p=0.005), ferritin level by 364.2 ng/ml (95% CI 129.7 598.7, p=0.007), and transferrin saturation by 10.5% (95% CI 6.5-14.6%, p<0.001). Changes in hemoglobin level did not correlate with volume status, as determined by differences in body weight. No significant changes in blood pressure or heart rate were observed. Adverse events were few and minor in severity (e.g., nausea, constipation, and abdominal discomfort). CONCLUSION: An accelerated intravenous iron regimen improved hematologic parameters and was well tolerated in hospitalized patients with advanced heart failure. A randomized multicenter trial comparing this regimen with placebo is warranted. PMID- 25556868 TI - Management considerations to minimize environmental impacts of arsenic following monosodium methylarsenate (MSMA) applications to turfgrass. AB - Monosodium methylarsenate (MSMA) is an organic arsenical herbicide currently utilized in turfgrass and cotton systems. In recent years, concerns over adverse impacts of arsenic (As) from MSMA applications have emerged; however, little research has been conducted in controlled field experiments using typical management practices. To address this knowledge gap, a field lysimeter experiment was conducted during 2012-2013 to determine the fate of As following MSMA applications to a bareground and an established turfgrass system. Arsenic concentrations in soil, porewater, and aboveground vegetation, were measured through one yr after treatment. Aboveground vegetation As concentration was increased compared to nontreated through 120 d after initial treatment (DAIT). In both systems, increased soil As concentrations were observed at 0-4 cm at 30 and 120 DAIT and 0-8 cm at 60 and 365 DAIT, suggesting that As was bound in shallow soil depths. Porewater As concentrations in MSMA-treated lysimeters from a 30-cm depth (22.0-83.8 MUg L(-1)) were greater than those at 76-cm depth (0.4-5.1 MUg L(-1)). These results were combined with previous research to devise management considerations in systems where MSMA is utilized. MSMA should not be applied if rainfall is forecasted within 7 DAIT and/or in areas with shallow water tables. Further, disposing of MSMA-treated turfgrass aboveground vegetation in a confined area - a common management practice for turfgrass clippings - may be of concern due to As release to surface water or groundwater as the vegetation decomposes. Finally, long-term MSMA use may cause soil As accumulation and thus downward migration of As over time; therefore, MSMA should be used in rotation with other herbicides. PMID- 25556869 TI - A new approach to macroalgal bloom control in eutrophic, shallow-water, coastal areas. AB - In summer 2012, an experiment was conducted in a shallow eutrophic lagoon with poor water exchange to determine the consequences of harvesting algae on the algal mat itself, which was traversed and repeatedly disturbed by large harvester boats. Four areas with high macroalgal density, measuring half a hectare each, were selected. Two were subjected to frequent disturbance of the algal mat and sediment (12 two-hour operations over a 38-day period) and the other two were left undisturbed as control. The following variables were determined: 1) water column physical chemistry and nutrients; 2) redox potential, nutrients and organic load in sediments; 3) C, N and P content of algal thalli; 4) macroalgal biomass. In 2013, a further experiment was conducted on a larger scale. Biomass was estimated in a high-density mat measuring 235 ha, where macroalgae were harvested and stirred up by four harvesting boats, and in two high-density mats measuring 150 and 120 ha, left undisturbed as control (9.15, 9.92 and 3.68 kg/m(2), respectively). In the first experiment, no significant changes were observed in the water column. In sediment the main variation was a significant reduction in labile organic matter in the disturbed areas and a significant increase mainly in refractory organic matter in the undisturbed areas. Biomass showed a significant drastic reduction in disturbed areas and substantial stability in undisturbed areas. In the large-scale experiment, the biomass of the disturbed mat declined by about 63%, only 6.5% of which was due to harvesting. On the other hand, the undisturbed mat with higher density underwent a natural decline in biomass of about 23% and the other increased by about 50%. These results demonstrate that disturbance of high-density mat in shallow water by boats can cause decay of the mat. PMID- 25556870 TI - Rapid degradation of endosulfan by zero-valent zinc in water and soil. AB - Endosulfan has been included in the list of persistent organic pollutants (POPs) in 2011. The degradation of endosulfan by zero-valent zinc in water and soil was first investigated. The results showed that >90% endosulfan could be degraded in 180 min. The degradation was accelerated under acidic conditions with the absence of dissolved oxygen, while the nature of the soil only exhibited a negligible effect. The half-life was decreased from 130.75 min to 41.75 min with the increment of Zn(0) from 0.1 g to 1 g in soil. The use of Zn(0) was more effective than Fe(0) for the degradation of endosulfan with a half-life of 110 min and 330 min. The cationic surfactant was more effective at enhancing the degradation of endosulfan than anionic and nonionic surfactant. The degradation pathway was speculated, and four chlorine of endosulfan were proposed to be reduced. The method exhibited obvious advantages over traditional endosulfan treatments, and the research results will lay a foundation for practical application of the method. PMID- 25556875 TI - Organoamine-functionalized graphene oxide as a bifunctional carbocatalyst with remarkable acceleration in a one-pot multistep reaction. AB - In this work, we reported the synthesis of bifunctional carbocatalyst with acid base dual-activation mechanism by introducing organoamines on the basal planes of graphene oxide (GO). Interestingly, GO-supported primary amine (AP-GO) exclusively promoted one-pot Henry-Michael reactions with excellent activity to give synthetically valuable multifunctionalized nitroalkanes. Notably, it also exhibited significantly higher activity than those using propylamine, activated carbon-supported primary amine, and mesoporous silica-supported primary amine as the catalysts. This superior catalytic performance originated from the unique properties of AP-GO, which provided the acid-base cooperative effect by the appropriate positioning of primary amines on their basal planes and carboxyl acids along their edges and the decreased diffusion resistance of the reactants and the intermediates during the multistep catalytic cycles because of its open two-dimensional sheet-like structure. Moreover, it could be readily recycled by simple filtration and subsequently reused without significant loss of its catalytic activity in a six times run test. PMID- 25556871 TI - Mechanism insights into enhanced trichloroethylene removal using xanthan gum modified microscale zero-valent iron particles. AB - This report focuses on the enhancement in trichloroethylene (TCE) removal from contaminated groundwater using xanthan gum (XG)-modified, microscale, zero-valent iron (mZVI). Compared with bare mZVI, XG-coated mZVI increased the TCE removal efficiency by 30.37% over a 480-h experimental period. Because the TCE removal is attributed to both sorption and reduction processes, the contributions from sorption and reduction were separately investigated to determine the mechanism of XG on TCE removal using mZVI. The results showed that the TCE sorption capacity of mZVI was lower in the presence of XG, whereas the TCE reduction capacity was significantly increased. The FTIR spectra confirmed that XG, which is rich in hydrophilic functional groups, was adsorbed onto the iron surface through intermolecular hydrogen bonds, which competitively repelled the sorption and mass transfer of TCE toward reactive sites. The variations in the pH, Eh, and Fe(2+) concentration as functions of the reaction time were recorded and indicated that XG buffered the solution pH, inhibited surface passivation, and promoted TCE reduction by mZVI. Overall, the XG-modified mZVI was considered to be potentially effective for the in-situ remediation of TCE contaminated groundwater due to its high stability and dechlorination reactivity. PMID- 25556877 TI - Erratum to: Enduring inequality: educational disparities in health among the oldest old in Sweden 1992-2011. PMID- 25556876 TI - Beauty in the eyes of the beholders: colour vision is tuned to mate preference in the Trinidadian guppy (Poecilia reticulata). AB - A broad range of animals use visual signals to assess potential mates, and the theory of sensory exploitation suggests variation in visual systems drives mate preference variation due to sensory bias. Trinidadian guppies (Poecilia reticulata), a classic system for studies of the evolution of female mate choice, provide a unique opportunity to test this theory by looking for covariation in visual tuning, light environment and mate preferences. Female preference co evolves with male coloration, such that guppy females from 'low-predation' environments have stronger preferences for males with more orange/red coloration than do females from 'high-predation' environments. Here, we show that colour vision also varies across populations, with 'low'-predation guppies investing more of their colour vision to detect red/orange coloration. In independently colonized watersheds, guppies expressed higher levels of both LWS-1 and LWS-3 (the most abundant LWS opsins) in 'low-predation' populations than 'high predation' populations at a time that corresponds to differences in cone cell abundance. We also observed that the frequency of a coding polymorphism differed between high- and low-predation populations. Together, this shows that the variation underlying preference could be explained by simple changes in expression and coding of opsins, providing important candidate genes to investigate the genetic basis of female preference variation in this model system. PMID- 25556878 TI - Repeatability of transient-evoked otoacoustic emissions in young adults. AB - BACKGROUND: The aim of this study was to evaluate the repeatability and variability of TEOAE characteristics in hearing screening tests performed under practical conditions on normal subjects. MATERIAL/METHODS: A group of 11 young, normal-hearing subjects aged 19-24 years was tested. They were examined otologically and audiologically prior to the tests and no ear pathologies were found. Responses were acquired with a commercially available instrument (Integrity, Vivosonic Inc.) using a standardized OAE protocol. The TEOAE tests were repeated 3 times in each subject at random intervals within 24 h. The analyzed parameters of interest were: (i) whole wave reproducibility (WWR) and; (ii) signal-to-noise ratio (SNR). RESULTS: WWR and SNR did not differ significantly among the 3 measurement sessions. In most cases the differences in WWR among measurements were around 1-2% and for SNRs they were 1-4 dB SNRs and were highest in the 1-2 kHz range. TEOAE-based tests can be useful tools for hearing screening. CONCLUSIONS: The tests can give reliable results provided that adequate procedures are used and low-noise conditions are ensured. The tests are best complemented with other examinations to widen the range of ear pathologies able to be detected. PMID- 25556879 TI - Detection of physiological activities of G protein-coupled receptor-acting pharmaceuticals in wastewater. AB - Although pharmaceuticals are generally found at very low levels in aquatic environments, concern about their potential risks to humans and aquatic species has been raised because they are designed to be biologically active. To resolve this concern, we must know whether the biological activity of pharmaceuticals can be detected in waters. Nearly half of all marketed pharmaceuticals act by binding to the G protein-coupled receptors (GPCRs). In this study, we measured the physiological activity of pharmaceuticals in wastewater. We applied the in vitro transforming growth factor-alpha (TGFalpha) shedding assay, which accurately and sensitively detect GPCR activation, to investigate the agonistic/antagonistic activities of wastewater extracts against receptors for angiotensin (AT1), dopamine (D2, D4), adrenergic family members (alpha1B, alpha2A, beta1, beta3), acetylcholine (M1, M3), cannabinoid (CB1), vasopressin (V1A, V2), histamine (H1, H2, H3), 5-hydroxytryptamine (5-HT1A, 5-HT2C), prostanoid (EP3), and leukotriene (BLT1). As a result, antagonistic activity against AT1, D2, alpha1B, beta1, M1, M3, H1, and V2 receptors was detected at up to several MUg/L for the first time. Agonistic activity against alpha2A receptor was also detected. The TGFalpha shedding assay is useful for measuring the physiological activity of GPCR-acting pharmaceuticals in the aquatic environment. PMID- 25556880 TI - Eosinophilic annular erythema: complete clinical response with dapsone. PMID- 25556881 TI - Synthetic polyglycomer short-term absorbable sutures vs. polydioxanone long-term absorbable sutures for preventing incisional hernia and wound dehiscence after abdominal wall closure: a comparative randomized study of patients treated for gastric or colon cancer. AB - PURPOSE: To compare the results of abdominal wall closure using interrupted synthetic short-term vs. long-term tensile strength-retaining absorbable sutures. METHODS: The subjects were 55 patients undergoing elective laparotomy through a midline vertical incision for gastric or colon cancer surgery between November 2008 and August 2010, at our hospital. After providing informed consent, the patients were randomized for suturing with Polysorb((r)), which provides short term tensile strength, or with PDS((r))II, which provides long-term strength. The primary outcome analyzed was the incidence of incisional hernia or wound dehiscence. RESULT: There were 28 patients allocated to the Polysorb group and 27 to the PDS II group. Postoperative wound dehiscence was noted in two patients (3.6%). Five of 51 patients (9.8%) suffered incisional hernia within 1 year after surgery, 6 of 41 patients (14.6%) within 2 years, and 6 of 35 patients (17.1%) within 3 years. There was no significant per year difference in the incidence of incisional hernia or wound dehiscence between the groups. CONCLUSION: Outcomes were favorable in both groups and not inferior to reported outcomes of larger scale studies. Verification of the equivalence between the two types of suture material necessitates larger-scale studies that adopt the same suture methods. PMID- 25556882 TI - Segregated growth kinetics of Escherichia coli DH5alpha-NH36 in exponential-fed perfusion culture for pDNA vaccine production. AB - The clinical demand of plasmid DNA (pDNA) has been increasing constantly. An exponential-fed perfusion (EFP) culture is a new mode for plasmid production for clinical trials and commercialization. However, the culture conditions may lead to cell filamentation and growth cessation. In this study, the variation of the physiological state and the plasmid contents of Escherichia coli DH5alpha hosting pVAX1-NH36 in an EFP culture for application as a Leishmaniasis vaccine was investigated. The culture performance was monitored using flow cytometry (FC) and real-time quantitative PCR. The FC studies showed a high viability of cell population and a constant distribution of complexity and size. A high homogeneity of pDNA (>95 % of supercoiled) was obtained, which might be attributed to a better culture environment. The obtained plasmid specific and volumetric yields of 1.8 mg/g dcw and 36.5 mg/L represent typical values for laboratory-scale plasmid production in a defined medium. A segregated kinetic model of the perfusion system was developed and fitted to the experimental data (R(2) > 0.96). A practical conclusion of this work is that a space-time yield analysis of a bioprocess requires a viability evaluation. This new strategy of culture operation might help in the efficient production of pDNA for therapeutic use. PMID- 25556883 TI - Syk mediates airway contractility independent of leukocyte function. AB - BACKGROUND: Syk, an immune regulatory tyrosine kinase, plays a role in inflammatory disease processes. We recently reported a role for epithelial expression of Syk in the airways hyper-responsiveness in response to air pollution in a mouse model of asthma. The aim of this study was to further investigate the role of Syk in airway contractility in response to methacholine (MCh) and particulate matter (PM) air pollutants, in the absence of underlying inflammation. METHODS: We used Syk(flox/flox) //rosa26CreER(T) (2) conditional Syk knockout mice to evaluate respiratory mechanics and MCh responsiveness following PM exposure in vivo using the ventilator-based flexiVent system. RESULTS: While total and differential cell counts in bronchoalveolar lavage fluid were similar between the Syk(flox/flox) and Syk(del/del) mice, central airways respiratory resistance (RN ) to MCh was significantly augmented following PM exposure between Syk-intact (Syk(flox/flox) ) and Syk-deficient (Syk(del/del) ) mice (RN (max) : 2.06 +/- 0.29 vs. 1.29 +/- 0.10, respectively; p < 0.05, n = 8 10/group). We employed live videomicroscopy to investigate changes in airway luminal diameter using ex vivo lung slices, which were devoid of circulating leukocytes. MCh reduced the airway luminal area of Syk(flox/flox) mice to 81.1 +/ 1.4% of baseline, which was virtually abrogated in Syk(del/del) mice (luminal area = 93.2 +/- 0.5%, n = 5/group, p < 0.05). In response to PM exposure, Syk(flox/flox) airways contracted to 73.8 +/- 2.7% of baseline luminal diameter, whereas Syk(del/del) airways exhibited minimal contractility to PM and MCh (90.0 +/- 1.3% of baseline, n = 5/group, p < 0.05). CONCLUSIONS: These observations suggest that Syk mediates airway contractility in the normal and allergic airways, independent of its role and function in leukocytes, and supports a paracrine role for airway epithelial Syk in modulating airway smooth muscle activity. PMID- 25556884 TI - Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy. AB - BACKGROUND: Diabetic autonomic neuropathy (DAN) results in increased morbidity and mortality. The early diagnosis of DAN can be difficult and is commonly evaluated using cardiac autonomic function tests as a surrogate. However, they are not widely available, have limited sensitivity and specificity, and can be confounded by concomitant cardiovascular disease and medications. METHODS: The diagnostic utility of corneal confocal microscopy for diagnosis of DAN was assessed. Thirty-four diabetic patients without [Composite Autonomic Scoring Scale (CASS)<=2] vs with (CASS>2) DAN and 18 healthy control subjects (HC) underwent detailed assessment of somatic and autonomic neuropathy, Composite Autonomic Symptom Scale (COMPASS), (CASS), and Corneal Confocal Microscopy (CCM). RESULTS: Corneal nerve fiber density, branch density, and length showed a progressive and significant reduction in patients with DAN vs HC and those without DAN. CCM correlated highly significantly with COMPASS and CASS, and corneal nerve fiber parameters demonstrated a high sensitivity and specificity for diagnosis of DAN. CONCLUSIONS: This study demonstrates that corneal nerve damage detected using CCM can be deployed to diagnose subclinical and overt DAN. It therefore represents a rapid, non-invasive, highly sensitive and specific diagnostic test for DAN. PMID- 25556886 TI - Diffusion weighted images of metastatic as compared with nonmetastatic axillary lymph nodes in patients with newly diagnosed breast cancer. AB - BACKGROUND: To investigate the ability of diffusion weighted images (DWI) to differentiate between metastatic and nonmetastatic axillary lymph nodes (LNs) in patients with newly diagnosed breast cancer. METHODS: From January 2010 to February 2012, DWI was performed at b values of 0 and 800 for 16 metastatic LNs from 16 patients with breast cancer, and 20 nonmetastatic LNs from 20 women without breast cancer. The metastatic LNs were proven by ultrasound (US) guided core biopsy and the same LNs were identified on MRI by comparing the US images with MR images. Nonmetastatic LNs were verified by the stability in size and shape for at least 2 years on MRI. The apparent diffusion coefficient (ADC) value of the metastatic and nonmetastatic axillary LNs was compared. Receiver-operating characteristics (ROC) analysis was performed to evaluate the diagnostic performance of the ADC value in differentiating between metastatic and nonmetastatic axillary LNs. RESULTS: The mean ADC value was 0.746 * 10(-3) for metastatic LNs and 1.033 * 10(-3) for nonmetastatic LNs (P < 0.001). The area under the ROC curve was 0.884. The sensitivity and specificity for differentiating metastatic from nonmetastatic axillary LNs using a cutoff ADC value of 0.852 were 85% and 81%, respectively. CONCLUSION: There is a statistically significant difference between the ADC values of pathologically proven metastatic LNs and nonmetastatic LNs. DWI and ADC values are a useful tool for differentiating metastatic from nonmetastatic axillary LNs. PMID- 25556885 TI - The dynamics of the G protein-coupled neuropeptide Y2 receptor in monounsaturated membranes investigated by solid-state NMR spectroscopy. AB - In contrast to the static snapshots provided by protein crystallography, G protein-coupled receptors constitute a group of proteins with highly dynamic properties, which are required in the receptors' function as signaling molecule. Here, the human neuropeptide Y2 receptor was reconstituted into a model membrane composed of monounsaturated phospholipids and solid-state NMR was used to characterize its dynamics. Qualitative static (15)N NMR spectra and quantitative determination of (1)H-(13)C order parameters through measurement of the (1)H (13)C dipolar couplings of the CH, CH2 and CH3 groups revealed axially symmetric motions of the whole molecule in the membrane and molecular fluctuations of varying amplitude from all molecular segments. The molecular order parameters (S(backbone) = 0.59-0.67, S(CH2) = 0.41-0.51 and S(CH3) = 0.22) obtained in directly polarized (13)C NMR experiments demonstrate that the Y2 receptor is highly mobile in the native-like membrane. Interestingly, according to these results the receptor was found to be slightly more rigid in the membranes formed by the monounsaturated phospholipids than by saturated phospholipids as investigated previously. This could be caused by an increased chain length of the monounsaturated lipids, which may result in a higher helical content of the receptor. Furthermore, the incorporation of cholesterol, phosphatidylethanolamine, or negatively charged phosphatidylserine into the membrane did not have a significant influence on the molecular mobility of the Y2 receptor. PMID- 25556887 TI - Topical monobenzyl ether of hydroquinone is an effective and safe treatment for depigmentation of extensive vitiligo in the medium term: a retrospective cohort study of 53 cases. PMID- 25556888 TI - Effects of hamstring-emphasized neuromuscular training on strength and sprinting mechanics in football players. AB - The objective of this study was to examine the effects of a neuromuscular training program combining eccentric hamstring muscle strength, plyometrics, and free/resisted sprinting exercises on knee extensor/flexor muscle strength, sprinting performance, and horizontal mechanical properties of sprint running in football (soccer) players. Sixty footballers were randomly assigned to an experimental group (EG) or a control group (CG). Twenty-seven players completed the EG and 24 players the CG. Both groups performed regular football training while the EG performed also a neuromuscular training during a 7-week period. The EG showed a small increases in concentric quadriceps strength (ES = 0.38/0.58), a moderate to large increase in concentric (ES = 0.70/0.74) and eccentric (ES = 0.66/0.87) hamstring strength, and a small improvement in 5-m sprint performance (ES = 0.32). By contrast, the CG presented lower magnitude changes in quadriceps (ES = 0.04/0.29) and hamstring (ES = 0.27/0.34) concentric muscle strength and no changes in hamstring eccentric muscle strength (ES = -0.02/0.11). Thus, in contrast to the CG (ES = -0.27/0.14), the EG showed an almost certain increase in the hamstring/quadriceps strength functional ratio (ES = 0.32/0.75). Moreover, the CG showed small magnitude impairments in sprinting performance (ES = -0.35/ 0.11). Horizontal mechanical properties of sprint running remained typically unchanged in both groups. These results indicate that a neuromuscular training program can induce positive hamstring strength and maintain sprinting performance, which might help in preventing hamstring strains in football players. PMID- 25556889 TI - Evaluation of the appropriateness of frozen plasma usage after introduction of prothrombin complex concentrates: a retrospective study. AB - BACKGROUND: Prothrombin complex concentrates (PCCs) can be used instead of frozen plasma (FP) transfusion to reverse the effect of warfarin. Audits have demonstrated over usage of FP transfusions even before the introduction of PCC. The objective of this study was to determine the appropriateness of current FP transfusion practice in the current era since the introduction of PCCs. METHODS: A retrospective cohort study of consecutive patients receiving FP over 3 months was carried out. Each episode of FP use over a 24-h period was adjudicated independently by two reviewers as appropriate (consistent with Canadian/AABB guidelines), appropriate but inconsistent with guidelines or inappropriate. Discrepancies were resolved by a third reviewer. Use of FP to reverse warfarin was considered inappropriate. FP usage from previous years was assessed as baseline. RESULTS: During the study period, 111 FP transfusions were administered. 74.8% of FP usage occurred in the ICU. The proportion of FP transfusions that were deemed appropriate, inconsistent yet appropriate or inappropriate were 33/89 (37.1%), 16/89 (18.0%) and 40/89 (44.9%), respectively, when use of FP for therapeutic plasma exchange was excluded. The most common reasons for inappropriate use were the absence of bleeding with an increased INR or warfarin reversal. CONCLUSION: Our study is the first to audit FP transfusions in the post-PCC era in Canada. FP usage remains inappropriately high in INR prolongation without another indication or to reverse warfarin. Targeted interventions to reduce FP usage in the future should focus on the ICU and on education about warfarin reversal. PMID- 25556890 TI - Diagnostic opportunities for evaluation of the exposure of dairy cows to the mycotoxins deoxynivalenol (DON) and zearalenone (ZEN): reliability of blood plasma, bile and follicular fluid as indicators. AB - To investigate the usefulness of follicular fluid (FF) in relation to blood plasma and bile as indicators of exposure of dairy cows to ZEN, DON and their metabolites, a dose-response study was performed with 30 dairy cows. The cows, 10 in each group (named CON; FUS-50, FUS-100), received a diet with three different concentrations of Fusarium toxin-contaminated maize. Thereby, the following dietary concentration were reached: CON (0.02 mg ZEN and 0.07 mg DON, per kg dry matter, DM), FUS-50 (0.33 mg ZEN and 2.62 mg DON, per kg DM) and FUS-100 (0.66 mg ZEN and 5.24 mg DON, per kg DM). ZEN, DON and de-epoxy-DON (de-DON) were detected in FF. Based on the linear regression between toxin concentration in plasma and FF, it seems that about 50% (m = 0.5) of ZEN present in plasma is present in FF while an increase of 1 ng/ml DON or de-DON in plasma is paralleled by an increase of 1.5 ng/ml DON or 1.1 ng/ml de-DON in FF. ZEN, DON and their metabolites, except zearalenone (ZAN), were also detected in bile. Contrary to DON and de-DON, ZEN and its metabolites were accumulated in bile so that the concentration of ZEN and metabolites was much higher than for DON and de-DON. The main compound was beta-zearalenol (beta-ZEL). The biliary ZEN, alpha-zearalenol (alpha-ZEL) and beta-ZEL concentration correlated linearly with each other with an uncertainty of <15% (r(2) >= 0.86), whereas the ratio between ZEN: alpha-ZEL: beta-ZEL was about 1.5:1:11. With the help of established linear relationship between toxin intake and toxin concentration, bile could be used as diagnostic indicator to assess the exposure of cows. PMID- 25556891 TI - Following the north star: radial marker lines help preserve anatomic landmarks after local injection of anesthetic. AB - Injection of local anesthetic can result in distortion of local anatomic architecture. "Following the North Star" is a technique that uses radial markings to aid in better preservation of surgical landmarks. PMID- 25556892 TI - First insights into the giant panda (Ailuropoda melanoleuca) blood transcriptome: a resource for novel gene loci and immunogenetics. AB - The giant panda (Ailuropoda melanoleuca) is one of the most famous flagship species for conservation, and its draft genome has recently been assembled. However, the transcriptome is not yet available. In this study, the blood transcriptomes of three pandas were characterized and about 160 million sequencing reads were generated using Illumina HiSeq 2000 paired-end sequencing technology. The assembly yielded 92 598 transcripts with an average length of 1626 bp and N50 length of 2842 bp. Based on a sequence similarity search against nonredundant (nr) protein database, a total of 38 522 (41.6%) transcripts were annotated. Of these annotated transcripts, 25 142 and 8272 transcripts were assigned to gene ontology terms and clusters of orthologous group, respectively. A search against the Kyoto Encyclopedia of Genes and Genomes Pathway database (KEGG) indicated that 9098 (9.83%) transcripts mapped to 324 KEGG pathways, and the best represented functional categories of pathways were signal transduction and immune system. We have also identified 23 460 microsatellites, 43 560 SNPs as well as 21 456 alternative splicing events in the assembly. Additionally, a total of 24 341 complete open reading frames (ORFs) were detected from the assembly where 1492 ORFs were found to be novel gene loci as these have not been annotated so far in any public database. PMID- 25556894 TI - Funding issues and options for pharmacists providing sessional services to rural hospitals in Australia. AB - OBJECTIVE: Many of Australia' s rural hospitals operate without an on-site pharmacist. In some, community pharmacists have sessional contracts to provide medication management services to inpatients. This paper discusses the funding arrangements of identified sessional employment models to raise awareness of options for other rural hospitals. METHODS: Semistructured one-on-one interviews were conducted with rural pharmacists with experience in a sessional employment role (n =8) or who were seeking sessional arrangements (n = 4). Participants were identified via publicity and referrals. Interviews were conducted via telephone or Skype for ~40-55 min each, recorded and analysed descriptively. RESULTS: A shortage of state funding and reliance on federal funding was reported. Pharmacists accredited to provide medication reviews claimed remuneration via these federal schemes; however, restrictive criteria limited their scope of services. Funds pooling to subsidise remuneration for the pharmacists was evident and arrangements with local community pharmacies provided business frameworks to support sessional services. CONCLUSION: Participants were unaware of each other's models of practice, highlighting the need to share information and these findings. Several similarities existed, namely, pooling funds and use of federal medication review remuneration. Findings highlighted the need for a stable remuneration pathway and business model to enable wider implementation of sessional pharmacist models. PMID- 25556893 TI - Altered intracellular region of MUC1 and disrupted correlation of polarity related molecules in breast cancer subtypes. AB - MUC1 glycoprotein is overexpressed and its intracellular localization altered during breast carcinoma tumorigenesis. The present study aimed to clarify the relationship of cytoplasmic localization of MUC1 with the breast cancer subtype and the correlation of 10 molecules associated with cell polarity in breast cancer subtypes. We immunostained 131 formalin-fixed and paraffin-embedded breast cancer specimens with an anti-MUC1 antibody (MUC1/CORE). For 48 of the 131 tumor specimens, laser-assisted microdissection and real-time quantitative RT-PCR were performed to analyze mRNA levels of MUC1 and 10 molecules, beta-catenin, E cadherin, claudin 3, claudin 4, claudin 7, RhoA, cdc42, Rac1, Par3 and Par6. Localization of MUC1 protein varied among breast cancer subtypes, that is, both the apical domain and cytoplasm in luminal A-like tumors (P < 0.01) and both the cytoplasm and cell membrane in luminal B-like (growth factor receptor 2 [HER2]+) tumors (P < 0.05), and no expression was found in triple negative tumors (P < 0.001). Estrogen receptor (ER)+ breast cancers showed higher MUC1 mRNA levels than ER- breast cancers (P < 0.01). The incidence of mutual correlations of expression levels between two of the 10 molecules (55 combinations) was 54.5% in normal breast tissue and 38.2% in luminal A-like specimens, 16.4% in luminal B like (HER2+), 3.6% in HER2 and 18.2% in triple negative specimens. In conclusion, each breast cancer subtype has characteristic cytoplasmic localization patterns of MUC1 and different degrees of disrupted correlation of the expression levels between the 10 examined molecules in comparison with normal breast tissue. PMID- 25556895 TI - Who do you refer to? How young students with mild intellectual disability confront anaphoric ambiguities in texts and sentences. AB - Along 2 experiments we tested the anaphoric pronoun resolution abilities of readers with intellectual disability in comparison with chronological and reading age-matched groups. In Experiment 1, the anaphor test of Elosua, Carriedo, and Garcia-Madruga (2009) confirmed that readers with intellectual disability (ID) are slower than control readers resolving clitic anaphoric pronouns, especially when the use of morphological cues (e.g. gender) is necessary. In order to test if the poor performance could be due to low levels of metacognitive skills during reading, an inconsistency detection task combined with eye tracking was designed in Experiment 2. Participants read short texts with an anaphoric pronoun in the fifth sentence, either morphologically (gender) consistent or not with the information provided in the second sentence. The scores in the anaphor comprehension questions presented after the text confirmed that readers with ID are affected by the gender inconsistency but they are unable to explicitly report it and recover from it, as the number of re-fixations after reading the critical sentence suggests. As their answers to the explicit detection questions showed, the adults control group did not show any preference for morphosyntax or semantics in spite of being aware of the inconsistency. In sum, both groups of readers with and without ID are affected by inconsistencies, but ID readers do not have appropriate metacognitive skills to explicitly identify the source of the inconsistency and fix it. PMID- 25556896 TI - Percutaneous closure of patent foramen ovale: safe and effective but underutilized. AB - With three recently published randomized trials on patent foramen ovale (PFO) closure, the concept of PFO closure to reduce recurrent strokes has been proven; however, PFO closure is currently only considered for secondary prevention. Given the potential devastating consequences of a PFO-related event, we advocate screening for and closure of a PFO for primary prevention in high-risk populations. Such populations include patients who are suffering from a disease that is associated with PFO (e.g., migraine) or patients with high-risk hobbies/professions (e.g., weight-lifters, frequent-flyers, and deep sea divers). Looking at young people with a remaining average life expectancy of 50 years, we have to close 2.4 PFOs to prevent one stroke. This should support a more proactive attitude toward PFO screening and closure. PMID- 25556897 TI - Avoiding Anomalous Tendon Harvest at the Pes Anserinus Insertion. AB - The purpose of this study was to identify the frequency and characteristics of anomalous pes anserinus tendon morphology in an adolescent population undergoing knee anterior cruciate ligament (ACL) reconstruction surgery. The records of all children who underwent ACL reconstruction surgery at our tertiary care children's hospital from June 2008 through February 2012 were reviewed. Operative reports were reviewed for any indication that an anomaly existed in the pes anserinus or that there was difficulty harvesting the required tendons. Magnetic resonance imaging (MRI) studies were then reviewed for these patients looking for evidence of any anomaly within the pes anserinus structures. Retrospective review was performed on 123 children (mean age, 16.1 years). Three girls (mean age, 16.2 years) were identified as having a low-lying muscle belly and accessory tendon when attempting to harvest the gracilis tendon. Proximal exploration of this short tendon conjoining the gracilis insertion revealed a muscle belly approximately 5 cm from its insertion in the pes anserinus. This anomaly was present in 2.4% of the cases. Based on previous literature, the anomalous muscle present in our cohort could be sartorius or semimembranosus. MRI analysis suggests that the accessory muscle and tendon could be an aberrant strip of the semimembranosus tendon, an anomalous tendon and muscle belly of the gracilis, or a thickening and separation of the sartorius tendon. Anomalous pes anserinus tendons were found to exist in 2.4% of our adolescent study population. At the time of surgery, if a tendon is harvested with a very low-lying muscle belly (with less than 6 cm of tendon), then the presence of an aberrant tendon should be considered. Preoperative MRI may provide evidence of an anomalous tendon if that information is sought. PMID- 25556898 TI - Sperm displacement in the Drosophila bipectinata species complex: evidence for interspecific variations. AB - We studied sperm displacement in two members of the Drosophila bipectinata species complex i.e., Drosophila parabipectinata and Drosophila malerkotliana by employing mutant and wild type strains. We found a significant increase in the productivity of remated females than that of once mated ones in all the crosses of the two species. The P2' values range from 0.67 to 0.70 in D. malerkotliana and 0.52 to 0.56 in D. parabipectinata. These results were compared with that of our earlier finding in D. bipectinata belonging to the same complex. We found that though the three species exhibit differences in the degree of sperm displacement, the pattern is somewhat similar in the three species. However, as far as its genetic variability and population size maintenance is considered, D. malerkotliana and D. bipectinata (P2' is 0.60-0.67) are at the forefront. Our finding is also supported by the fact that D. parabipectinata is derived from D. bipectinata and has not diverged much since its emergence as a separate species. The differences in the pattern of sperm displacement may be attributed to differences in remating latency, duration of copulation in first mating and sperm usage pattern among the members of this complex. PMID- 25556899 TI - Do particle size and surface functionality affect uptake and depuration of gold nanoparticles by aquatic invertebrates? AB - Because of the widespread use of engineered nanoparticles (ENPs) in consumer and industrial products, it is inevitable that these materials will enter the environment. It is often stated that the uptake of ENPs into organisms in the environment is related to the particle size and surface functionality. To test this assumption, the present study investigated the uptake and depuration of gold nanoparticle (Au NPs) coated with either citrate (Au-citrate NPs), mercaptoundecanoic acid (Au-MUDA NPs), amino polyethylene glycol (PEG) thiol (Au NH2 NPs), or PEG (Au-PEG NP) by the aquatic invertebrate Gammarus pulex. The studies were performed using a range of standard ecotoxicity media and natural waters, resulting in varying degrees of aggregation of the different NPs. Uptake of gold by G. pulex varied depending on the surface coatings, with Au-MUDA and Au citrate NPs being taken up to a greater extent than Au-NH2 and Au-PEG NPs in all test media and natural waters. In all test media evaluated, higher amounts of amino and PEG-coated ENPs were eliminated compared with MUDA- and citrate-coated ENPs. No obvious relationships were seen between the aggregation state of the different Au NPs in treatment and uptake, suggesting that the widely accepted assumption that Au NP uptake is related to particle size does not hold for the range of aggregation states studied (67.1-178.8 nm). Positive correlations between particle number concentration in the media and uptake were observed, indicating that this factor might partly explain the differences in uptake of a particle from different media types. PMID- 25556900 TI - Generation of tumor-specific cytotoxic T-lymphocytes from the peripheral blood of colorectal cancer patients for adoptive T-cell transfer. AB - This study designs a strategy for an adoptive cellular therapy (ACT) protocol based on the ex-vivo selection of autologous peripheral blood-derived CD8 enriched T-cells, stimulated with dendritic cells (DCs) that had been pulsed with apoptotic tumor cells to generate cytotoxic T lymphocytes (CTLs) with anti-tumor activity. Seventy-eight colorectal cancer (CRC) patients were enrolled in this study. Tumor tissues and peripheral blood (PB) were obtained at surgery. Tissues were mechanically dissociated and cultured to obtain a primary tumor cell line from each patient. DCs were derived from peripheral blood mononuclear cells (PBMCs) using magnetic positive selection of CD14+ monocytes. Anti-tumor CTLs were elicited in co-/micro-cultures using DCs as antigen-presenting cells, autologous apoptotic tumor cells as a source of antigens, and CD8+ T lymphocytes as effectors. Interferon-gamma (IFN-gamma) secretion was assessed by ELISpot assays to evaluate the activation of the CTLs against the autologous tumor cells. Primary tumor cell lines were obtained from 20 of 78 patients (25.6%). DCs were generated from 26 patients, and of them, corresponding tumor cell lines were derived from six patients. ELISpot results showed that significant IFN-gamma secretion was detected after different numbers of stimulations for two patients, whereas weak secretion was observed for three patients. Despite difficulties due to contamination of several primary tumor cell lines with gut intestinal flora, the results suggest that the generation of tumor-specific CTLs is feasible from patients with CRC, and could be useful for supporting an ACT approach in CRC. PMID- 25556902 TI - Glyconanosynthons as powerful scaffolds and building blocks for the rapid construction of multifaceted, dense and chiral dendrimers. AB - This review represents the first of its kind in that it is mainly devoted to the use of carbohydrates as both scaffolds and building blocks for the construction of a wide range of novel, dense, and chiral dendrimers. It deviates from several previous reviews describing solely carbohydrates as functional surface groups, mostly devoted to biological applications. A brief overview of the most recent synthetic strategies in dendrimer design will be presented for the purpose of comparing their differences, similitudes, and advantages. A particular emphasis will be devoted to the general family of core molecules or scaffolds possessing a large number of functional groups from which, carbohydrates clearly emanate for their wide structural diversities, abundant chiral centers, and the relative ease with which their functional groups can be selectively manipulated. This beneficial characteristic relies on the fact that carbohydrates exist in enantiomeric states, several conformations, anomeric configurations, range of functional groups, and as three to seven carbon units. PMID- 25556901 TI - Causal Networks or Causal Islands? The Representation of Mechanisms and the Transitivity of Causal Judgment. AB - Knowledge of mechanisms is critical for causal reasoning. We contrasted two possible organizations of causal knowledge-an interconnected causal network, where events are causally connected without any boundaries delineating discrete mechanisms; or a set of disparate mechanisms-causal islands-such that events in different mechanisms are not thought to be related even when they belong to the same causal chain. To distinguish these possibilities, we tested whether people make transitive judgments about causal chains by inferring, given A causes B and B causes C, that A causes C. Specifically, causal chains schematized as one chunk or mechanism in semantic memory (e.g., exercising, becoming thirsty, drinking water) led to transitive causal judgments. On the other hand, chains schematized as multiple chunks (e.g., having sex, becoming pregnant, becoming nauseous) led to intransitive judgments despite strong intermediate links ((Experiments 1-3). Normative accounts of causal intransitivity could not explain these intransitive judgments (Experiments 4 and 5). PMID- 25556903 TI - Accurate characterization of delay discounting: a multiple model approach using approximate Bayesian model selection and a unified discounting measure. AB - The study of delay discounting, or valuation of future rewards as a function of delay, has contributed to understanding the behavioral economics of addiction. Accurate characterization of discounting can be furthered by statistical model selection given that many functions have been proposed to measure future valuation of rewards. The present study provides a convenient Bayesian model selection algorithm that selects the most probable discounting model among a set of candidate models chosen by the researcher. The approach assigns the most probable model for each individual subject. Importantly, effective delay 50 (ED50) functions as a suitable unifying measure that is computable for and comparable between a number of popular functions, including both one- and two parameter models. The combined model selection/ED50 approach is illustrated using empirical discounting data collected from a sample of 111 undergraduate students with models proposed by Laibson (1997); Mazur (1987); Myerson & Green (1995); Rachlin (2006); and Samuelson (1937). Computer simulation suggests that the proposed Bayesian model selection approach outperforms the single model approach when data truly arise from multiple models. When a single model underlies all participant data, the simulation suggests that the proposed approach fares no worse than the single model approach. PMID- 25556904 TI - Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. AB - Rituximab is a B cell depleting monoclonal antibody used to treat lymphoma and autoimmune disease. Hypogammaglobulinemia has occurred after rituximab for lymphoma and rheumatoid arthritis but data are scarce for other autoimmune indications. This study describes the incidence and severity of hypogammaglobulinemia in patients receiving rituximab for small vessel vasculitis and other multi-system autoimmune diseases. Predictors for and clinical outcomes of hypogammaglobulinemia were explored. We conducted a retrospective study in a tertiary referral specialist clinic. The severity of hypogammaglobulinemia was categorized by the nadir serum IgG concentration measured during clinical care. We identified 288 patients who received rituximab; 243 were eligible for inclusion with median follow up of 42 months. 26% were IgG hypogammaglobulinemic at the time that rituximab was initiated and 56% had IgG hypogammaglobulinemia during follow-up (5-6.9 g/L in 30%, 3-4.9 g/L in 22% and <3 g/L in 4%); IgM <=0.3 g/L in 58%. The nadir IgG was non-sustained in 50% of cases with moderate/severe hypogammaglobulinemia. A weak association was noted between prior cyclophosphamide exposure and nadir IgG concentration, but not cumulative rituximab dose. IgG concentrations prior to and at the time of rituximab correlated with the nadir IgG post rituximab. IgG replacement was initiated because of recurrent infection in 12 (4.2%) patients and a lower IgG increased the odds ratio of receiving IgG replacement. Rituximab is associated with an increased risk of hypogammaglobulinemia but recovery of IgG level can occur. IgG monitoring may be useful for patients receiving rituximab. PMID- 25556905 TI - Investigation of the Relationship between Increased Vertical Overlap with Minimum Horizontal Overlap and the Signs of Temporomandibular Disorders. AB - PURPOSE: The purpose of this study was to test the null hypothesis that there was no relationship between increased vertical overlap (vertical overlap >=4 mm) with minimal horizontal overlap (horizontal overlap <=2 mm) and the signs of temporomandibular disorders. MATERIALS AND METHODS: Thirty participants (20 women, aged 20 to 45 years) with increased vertical overlap and minimal horizontal overlap, and 30 participants (20 women, aged 20 to 45 years) with no contact between the anterior teeth (control group) were examined. Diagnoses, psychological status (depression and nonspesific physical symptoms), and chronic pain severity were judged according to the Research Diagnostic Criteria for Temporomandibular Disorders and then compared. For statistical analysis of quantitative data, along with the descriptive statistical methods (mean, standard deviation, frequency), Student's t-test was used to compare parameters that reflected a normal distribution. Comparison of qualitative data between groups was performed using Chi-square and Fisher's exact tests. The level of significance was set at p < 0.05. RESULTS: In this study, deviation upon maximum opening was found significantly more frequently in the increased vertical overlap group than in the control group (p < 0.05). Tenderness upon palpation of lateral pterygoid muscles was observed more often in the increased vertical overlap group compared with the control group (p < 0.05). Opening-closing joint sounds occurred significantly more often in the increased vertical overlap group than in the control group (p = 0.050). CONCLUSION: Within the limitations of this study, deviation upon maximum opening, tenderness of lateral pterygoid muscles (upon palpation), and opening-closing joint sounds occurred more often in the increased vertical overlap occlusions with minimum horizontal overlap compared to the control groups. These results indicated that clinicians should pay special attention to the tempormandibuar joint status of patients with significant vertical overlap anteriorly and position of the incisors when performing dental treatments that require reestablishment of incisor relationships. PMID- 25556906 TI - Novel Echocardiographic Indices as Predictors of Immediate Recurrence after Undersized Ring Annuloplasty for Ischemic Mitral Regurgitation. AB - BACKGROUND AND AIM: Ischemic mitral regurgitation (IMR) is among the most serious complications of myocardial infarction which doubles the late mortality; mainly treated by undersizing ring annuloplasty. To find some preoperative echocardiographic indices that predict immediate failure of mitral valve annuloplasty (MVA), we designed the present study with more focusing on some novel parameters. METHOD: Transthoracic echocardiography (TTE) indices of consecutive patients referred with 3+ or 4+ IMR were registered 24 hours before surgery. Thirty days later, a second TTE was performed. According to the results, the patients were categorized as the "successful" group (with 1+ or less mitral regurgitation) and the "unsuccessful" group (with 2+ or higher MR). Preoperative TTE indices were compared among the two groups using suitable statistical tests. RESULTS: Of the total of 126 cases, 68 had successful and 58 had unsuccessful MVA. Statistically significant differences were found between the two groups for left ventricular ejection fraction (LVEF) (P = 0.007), left ventricular end systolic volume (LVESV) (P = 0.044), and basal-interpapillary muscle distance (IPMD) diastolic-to-systolic ratio (DSR) (P = 0.008). Receiver Operating Characteristic analysis demonstrated 37.5%, 3.85 cm(3) , and 1.25, as the best cutoff points for LVEF (P = 0.03, sensitivity: 81%, specificity: 69%), LVESV (P = 0.023, sensitivity: 83%, specificity: 57%), and basal-IPMD DSR (P = 0.001, sensitivity: 100%, specificity: 95%), respectively. CONCLUSION: Among all TTE indices, LVEF, LVESV, and basal-IPMD DSR were helpful to differentiate between the successful and unsuccessful MVA results. We believe the basal-IPMD DSR as a novel index could be targeted in the future studies. PMID- 25556907 TI - Advances in software for faster procedure and lower radiotracer dose myocardial perfusion imaging. AB - The American Society of Nuclear Cardiology has recently published documents that encourage laboratories to take all the appropriate steps to greatly decrease patient radiation dose and has set the goal of 50% of all myocardial perfusion studies performed with an associated radiation exposure of 9mSv by 2014. In the present work, a description of the major software techniques readily available to shorten procedure time and decrease injected activity is presented. Particularly new reconstruction methods and their ability to include means for resolution recovery and noise regularization are described. The use of these improved reconstruction algorithms results in a consistent reduction in acquisition time, injected activity and consequently in the radiation dose absorbed by the patient. The clinical implications to the use of these techniques are also described in terms of maintained and even improved study quality, accuracy and sensitivity for the detection of heart disease. PMID- 25556910 TI - Mass spectrometric characterization of methylaluminoxane-activated metallocene complexes. AB - Electrospray-ionization mass spectrometric studies of poly(methylaluminoxane) (MAO) in the presence of [Cp2 ZrMe2 ], [Cp2 ZrMe(Cl)], and [Cp2 ZrCl2 ] in fluorobenzene (PhF) solution are reported. The results demonstrate that alkylation and ionization are separate events that occur at competitive rates in a polar solvent. Furthermore, there are significant differences in ion-pair speciation that result from the use of metallocene dichloride complexes in comparison to alkylated precursors at otherwise identical Al/Zr ratios. Finally, the counter anions that form are dependent on the choice of precursor and Al/Zr ratio; halogenated aluminoxane anions [(MeAlO)x (Me3 Al)y-z (Me2 AlCl)z Me](-) (z=1, 2, 3...?) are observed using metal chloride complexes and under some conditions may predominate over their non-halogenated precursors [(MeAlO)x (Me3 Al)y Me](-) . Specifically, this halogenation process appears selective for the anions that form in comparison to the neutral components of MAO. Only at very high Al/Zr ratios is the same "native" anion distribution observed when using [Cp2 ZrCl2 ] when compared with [Cp2 ZrMe2 ]. Together, the results suggest that the need for a large excess of MAO when using metallocene dichloride complexes is a reflection of competitive alkylation vs. ionization, the persistence of unreactive, homodinuclear ion pairs in the case of [Cp2 ZrCl2 ], as well as a change in ion pairing resulting from modification of the anions formed at lower Al/Zr ratios. Models for neutral precursors and anions are examined computationally. PMID- 25556908 TI - Diversity and distribution of unicellular opisthokonts along the European coast analysed using high-throughput sequencing. AB - The opisthokonts are one of the major super groups of eukaryotes. It comprises two major clades: (i) the Metazoa and their unicellular relatives and (ii) the Fungi and their unicellular relatives. There is, however, little knowledge of the role of opisthokont microbes in many natural environments, especially among non metazoan and non-fungal opisthokonts. Here, we begin to address this gap by analysing high-throughput 18S rDNA and 18S rRNA sequencing data from different European coastal sites, sampled at different size fractions and depths. In particular, we analyse the diversity and abundance of choanoflagellates, filastereans, ichthyosporeans, nucleariids, corallochytreans and their related lineages. Our results show the great diversity of choanoflagellates in coastal waters as well as a relevant representation of the ichthyosporeans and the uncultured marine opisthokonts (MAOP). Furthermore, we describe a new lineage of marine fonticulids (MAFO) that appears to be abundant in sediments. Taken together, our work points to a greater potential ecological role for unicellular opisthokonts than previously appreciated in marine environments, both in water column and sediments, and also provides evidence of novel opisthokont phylogenetic lineages. This study highlights the importance of high-throughput sequencing approaches to unravel the diversity and distribution of both known and novel eukaryotic lineages. PMID- 25556909 TI - Indications of newer and older anti-epileptic drug use: findings from a southern Italian general practice setting from 2005-2011. AB - AIMS: The aim of the study was to analyze the prescribing pattern of both newer and older AEDs. METHODS: A population of almost 150 000 individuals registered with 123 general practitioners was included in this study. Patients who received at least one AED prescription over 2005-2011 were identified. The 1 year prevalence and cumulative incidence of AED use, by drug class and individual drug, were calculated over the study period. Potential predictors of starting therapy with newer AEDs were also investigated. RESULTS: The prevalence of use per 1000 inhabitants of older AEDs increased from 10.7 (95% CI10.1, 11.2) in 2005 to 13.0 (95% CI12.4, 13.6) in 2011, while the incidence remained stable. Newer AED incidence decreased from 9.4 (95% CI 8.9, 9.9) in 2005 to 7.0 (95% CI 6.6, 7.5) in 2011, with a peak of 15.5 (95% CI 14.8, 16.1) in 2006. Phenobarbital and valproic acid were the most commonly prescribed AEDs as starting therapy for epilepsy. Gabapentin and pregabalin accounted for most new pain-related prescriptions, while valproic acid and lamotrigine were increasingly used for mood disorders. Female gender (OR 1.36, 95% CI 1.20, 1.53), age ranging between 45-54 years (OR 1.39, 95% CI 1.16, 1.66) and pain as an indication (OR 16.7, 95% CI, 13.1, 21.2) were associated with newer AEDs starting therapy. CONCLUSIONS: Older AEDs were mainly used for epileptic and mood disorders, while newer drugs were preferred for neuropathic pain. Gender, age, indication of use and year of starting therapy influenced the choice of AED type. The decrease of newer AED use during 2007 is probably related to the restricted reimbursement criteria for gabapentin and pregabalin. PMID- 25556911 TI - Social life cycle assessment and participatory approaches: A methodological proposal applied to citrus farming in Southern Italy. AB - Recently, Social Life Cycle Assessment (S-LCA) has been developed under the methodological framework of Life Cycle Thinking (LCT) to evaluate the social impacts that emerge during the overall life cycle of a product or service. There is not yet a standardized methodology for S-LCA as there is for environmental LCA (eLCA), due to the nature of social impacts that do not depend only on the processes themselves, but also on the behavior and context of actors (manufactures, consumers, local community members, etc.). One of the most critical steps in the application of S-LCA concerns the choice of criteria for selecting affected actors, impact categories, subcategories, and the taxonomic relation among them. Moreover, the importance (in terms of weight) of these impacts may be felt differently by affected actors, confirming the importance of the context within which impacts arise. In this sense, the integration of participatory tools can be useful in making the S-LCA more locally relevant. The aim of the present study is twofold. First, we will outline a methodology that combines S-LCA with two research tools. The first is the focus group, adopted from qualitative research. The second is the Analytic Hierarchy Process (AHP), adopted from operational research, which belongs to the framework of Multicriteria Decision Analysis (MCDA). These have been used to make the S-LCA more locally relevant and to legitimate the criteria used. Second, we will test this methodology by applying it to a specific field, i.e., 3 production areas and 3 different crop systems of citrus growing in the Calabria region in Southern Italy. Citrus growing is one of the most important agricultural sectors at regional level, and it is also well known for issues of social concern, particularly in relation to immigrant workers. The results show a number of differences between cases and could offer useful insights to both local decision makers, such as agricultural entrepreneurs, and to those public decision makers that design and implement territorial planning strategies. Results have allowed the authors to rank the social performance of each case and to reflect on the most critical steps in conducting an S-LCA. KEY FINDINGS: The integration of qualitative techniques and a multicriteria in sLCA allows catching local specificities by involving local experts and stakeholders Results highlighted that impact categories mostly contributed to performance differences Public deciders can be supported in deciding which farming practices should be encouraged, which social domains must be paid more attention, and where social problems mostly occur The methodological application allowed the authors also to foresee the feasibility of the integration of LCA and LCC results as inputs in sLCA to conduct a Life Cycle Sustainability Assessment (LCSA). PMID- 25556913 TI - The influence of activity on axon pathfinding in the optic tectum. AB - The relative importance of neural activity versus activity-independent cues in shaping the initial wiring of the brain is still largely an open question. While activity is clearly critical for circuit rearrangements after initial connections have been made, whether it also plays a role in initial axon pathfinding remains to be determined. Here, we investigated this question using the guidance of zebrafish retinal ganglion cell axons to their targets in the tectum as a model. Recent results have implicated biased branching as a key feature of pathfinding in the zebrafish tectum. Using tetrodotoxin to silence neural activity globally, we found a decrease in the area covered by axon branches during pathfinding. After reaching the target, there were dynamic differences in axon length, area and the number of branches between conditions. However, other aspects of pathfinding were unaffected by silencing, including the ratio of branches directed toward the target, length, and number of branches, as well as turning angle, velocity, and number of growth cones per axon. These results challenge the hypothesis that neural connections develop in sequential stages of molecularly guided pathfinding and activity-based refinement. Despite a maintenance of overall guidance, axon pathfinding dynamics can nevertheless be altered by activity loss. PMID- 25556912 TI - Social and spatial heterogeneity in psychosis proneness in a multilevel case prodrome-control study. AB - OBJECTIVE: To test whether spatial and social neighbourhood patterning of people at ultra-high risk (UHR) of psychosis differs from first-episode psychosis (FEP) participants or controls and to determine whether exposure to different social environments is evident before disorder onset. METHOD: We tested differences in the spatial distributions of representative samples of FEP, UHR and control participants and fitted two-level multinomial logistic regression models, adjusted for individual-level covariates, to examine group differences in neighbourhood-level characteristics. RESULTS: The spatial distribution of controls (n = 41) differed from UHR (n = 48; P = 0.04) and FEP participants (n = 159; P = 0.01), whose distribution was similar (P = 0.17). Risk in FEP and UHR groups was associated with the same neighbourhood-level exposures: proportion of single-parent households [FEP adjusted odds ratio (aOR): 1.56 95% CI: 1.00-2.45; UHR aOR: 1.59; 95% CI: 0.99-2.57], ethnic diversity (FEP aOR: 1.27; 95% CI: 1.02 1.58; UHR aOR: 1.28; 95% CI: 1.00-1.63) and multiple deprivation (FEP aOR: 0.88; 95% CI: 0.78-1.00; UHR aOR: 0.86; 95% CI: 0.76-0.99). CONCLUSION: Similar neighbourhood-level exposures predicted UHR and FEP risk, whose residential patterning was closer to each other's than controls. Adverse social environments are associated with psychosis before FEP onset. PMID- 25556914 TI - A controlled study of internalizing symptoms in older adolescents with sickle cell disease. AB - BACKGROUND: Due to the ongoing medical challenges we hypothesized that older adolescents with sickle cell disease (SCD) would report greater rates of internalizing symptoms and diagnoses. This study is a follow-up to a previous study [1] that found few differences between the emotional well-being of children ages 8-15 with SCD and comparison peers. Our aim is to re-assess internalizing symptoms of youth with SCD and comparison peers at age 18. PROCEDURE: At follow up, trained staff members administered semi-structured psychiatric interviews and widely use behavioral health questionnaires to adolescents with SCD (n = 48), their comparison peers (COMP; n = 51) and a caregiver. Mood, internalizing symptoms and diagnoses, were evaluated cross-sectionally at the follow-up (age 18). RESULTS: Psychiatric interview data showed that COMP reported more phobias relative to adolescents with SCD; no significant differences were reported for any other current symptoms (depression, anxiety, or mania). Questionnaire data showed all scores in the normal range with two significant differences: older adolescents with SCD reported more symptoms of tension-anxiety and fatigue inertia. Both groups reported significant rates of internalizing disorders with 31% of youth with SCD and 35% of COMP having a DSM-IV diagnosis. CONCLUSIONS: Psychiatric interview data for both groups of older adolescents suggested considerable psychopathology; questionnaire data for both groups were in the normal range. We report few significant differences-more phobias in comparisons peers; more tension-anxiety and fatigue-inertia reported by youth with SCD. The overall findings suggest considerable resilience for youth with SCD, but both groups of adolescents report significant rates of psychopathology similar to national rates. PMID- 25556915 TI - Isolation and identification of stem cells in different subtype of cartilage tissue. AB - BACKGROUND: Cartilage tissue engineering provided a promising therapy for the repair of cartilage defects, and seeding cells play a vital role in cartilage regeneration. Chondrocytes and bone marrow-derived mesenchymal stem cells (BMSCs) were reported to be the ideal seeding cells, but 'dedifferentiation' and 'unstable phenotype' of tissue-engineered cartilage constructed by the two cell type hamper their clinical application. Recently, cartilage tissue was reported to possess a stem cell population, which may be a more superior cell source in cartilage tissue engineering. METHODS: In current study, we isolated a cell population from different subtype of cartilage tissue via a differential adhesion assay to fibronectin. RESULTS: Flow cytometry analysis demonstrates the cell lines expressed mesenchyme stem cell positive surface marker such as CD29 and CD90. Meanwhile, the cells are highly proliferative and multipotent. Reverse transcription-PCR detection showed the cell population expressed osteogenic and adipogenic differentiation under different induction conditions. More interesting, monolayer cells underwent chondrogenic differentiation in the presence of dexamethasone and insulin-like growth factor 1. In addition, the expression of chondrogenic genes in cartilage-derived stem cells (CSCs) was higher than those in BMSCs. CONCLUSION: CSC may become an ideal seeding cell in cartilage tissue engineering, owing to its stemness and chondrogenic characteristics. PMID- 25556917 TI - Alternative splicing can lead to chaos. AB - Alternative splicing is a widespread phenomenon in higher eukaryotes, where it serves as a mechanism to increase the functional diversity of proteins. This phenomenon has been described for different classes of proteins, including transcription regulatory proteins. We demonstrated that in the simplest genetic system model the formation of the alternatively spliced isoforms with opposite functions (activators and repressors) could be a cause of transition to chaotic dynamics. Under the simplest genetic system we understand a system consisting of a single gene encoding the structure of a transcription regulatory protein whose expression is regulated by a feedback mechanism. As demonstrated by numerical analysis of the models, if the synthesized isoforms regulate the expression of their own gene acting through different sites and independently of each other, for the generation of chaotic dynamics it is sufficient that the regulatory proteins have a dimeric structure. If regulatory proteins act through one site, the chaotic dynamics is generated in the system only when the repressor protein is either a tetrameric or a higher-dimensional multimer. In this case the activator can be a dimer. It was also demonstrated that if the transcription factor isoforms exhibit either activating or inhibiting activity and are lower dimensional multimers (< 4), independently of the regulation type the model demonstrates either cyclic or stationary trajectories. PMID- 25556916 TI - Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute. AB - This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m(2) , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand-foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer. PMID- 25556919 TI - Cardiovascular risk assessment in rheumatoid arthritis and other inflammatory arthritides. PMID- 25556918 TI - Optical focusing deep inside dynamic scattering media with near-infrared time reversed ultrasonically encoded (TRUE) light. AB - Focusing light deep inside living tissue has not been achieved despite its promise to play a central role in biomedical imaging, optical manipulation and therapy. To address this challenge, internal-guide-star-based wavefront engineering techniques--for example, time-reversed ultrasonically encoded (TRUE) optical focusing--were developed. The speeds of these techniques, however, were limited to no greater than 1 Hz, preventing them from in vivo applications. Here we improve the speed of optical focusing deep inside scattering media by two orders of magnitude, and focus diffuse light inside a dynamic scattering medium having a speckle correlation time as short as 5.6 ms, typical of living tissue. By imaging a target, we demonstrate the first focusing of diffuse light inside a dynamic scattering medium containing living tissue. Since the achieved focusing speed approaches the tissue decorrelation rate, this work is an important step towards in vivo deep tissue noninvasive optical imaging, optogenetics and photodynamic therapy. PMID- 25556921 TI - Comparison of immunohistochemistry and DNA sequencing for the detection of IDH1 mutations in gliomas. PMID- 25556922 TI - Separation and enrichment of six indicator polychlorinated biphenyls from real waters using a novel magnetic multiwalled carbon nanotube composite absorbent. AB - A novel and effective magnetic multiwalled carbon nanotube composite for the separation and enrichment of polychlorinated biphenyls was developed. Fe3 O4 @SiO2 core-shell structured nanoparticles were first synthesized, then the poly(sodium 4-styrenesulfonate) was laid on its surface to prepare the polyanionic magnetic nanoparticles. The above materials were then grafted with polycationic multiwalled carbon nanotubes, which were modified by polydiallyl dimethyl ammonium chloride through the layer-by-layer self-assembly approach. Its performance was tested by magnetic solid-phase extraction and gas chromatography with mass spectrometry for the determination of six kinds of indicator polychlorinated biphenyls in water samples. Under optimal conditions, the spiked recoveries of several real samples for six kinds of polychlorinated biphenyls (PCB28, PCB52, PCB101, PCB138, PCB153, PCB180) were in the range of 73.4-99.5% with relative standard deviations varying from 1.5 to 8.4%. All target compounds showed good linearities in the tested range with correlation coefficients higher than 0.9993. The limits of quantification for six kinds of indicator polychlorinated biphenyls were between 0.018 and 0.039 ng/mL. The proposed method was successfully applied to analyze polychlorinated biphenyls in real water samples. Satisfactory results were obtained using the effective magnetic absorbent. PMID- 25556920 TI - Biopsy versus partial versus gross total resection in older patients with high grade glioma: a systematic review and meta-analysis. AB - BACKGROUND: Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection. METHODS: We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (>=60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling. RESULTS: A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14-5.62, P < .001), postoperative KPS (MD 10.4, 95% CI: 6.58-14.22, P < .001), PFS (MD 2.44 mo, 95% CI: 1.45-3.43, P < .001), mortality (RR = 0.27, 95% CI: 0.12-0.61, P = .002), and morbidity (RR = 0.82, 95% CI: 0.46 1.46, P = .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26-5.29, P < .001), postoperative KPS (MD 4.91, 95% CI: 0.91-8.92, P = .016), and PFS (MD 2.21 mo, 95% CI: 1.13-3.3, P < .001) with no difference in mortality (RR = 0.53, 95% CI: 0.05-5.71, P = .600) or morbidity (RR = 0.52, 95% CI: 0.18-1.49, P = .223). CONCLUSIONS: Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established safety measures when managing elderly patients harboring HGGs. PMID- 25556923 TI - Associations between body mass index, ambulatory blood pressure findings, and changes in cardiac structure: relevance of pulse and nighttime pressures. AB - Ambulatory blood pressure monitoring (ABPM) is central in the management of hypertension. Factors related to BP, such as body mass index (BMI), may differently affect particular aspects of 24-hour ABPM profiles. However, the relevance of BMI, the most used index of adiposity, has been underappreciated in the determination of specific aspects of 24-hour ABPM profiles in hypertension. The authors evaluated the association between BMI and aspects of ABPM together with their associations with cardiac remodeling in 1841 patients. A positive association of BMI with 24-hour, daytime, and nighttime pulse pressure in untreated normal weight and overweight/obese hypertensive patients and a positive association of BMI with nocturnal BP parameters in treated overweight/obese hypertensive patients was observed. The clinical relevance of these findings was supported by the positive significant correlations of BMI-related BPs with left ventricular mass and atrial diameter. PMID- 25556924 TI - Geophysical and Hydrologic Studies of Lake Seepage Variability. AB - Variations in lake seepage were studied along a 130 m shoreline of Mirror Lake NH. Seepage was downward from the lake to groundwater; rates measured from 28 seepage meters varied from 0 to -282 cm/d. Causes of this variation were investigated using electrical resistivity surveys and lakebed sediment characterization. Two-dimensional (2D) resistivity surveys showed a transition in lakebed sediments from outwash to till that correlated with high- and low-seepage zones, respectively. However, the 2D survey was not able to predict smaller scale variations within these facies. In the outwash, fast seepage was associated with permeability variations in a thin (2 cm) layer of sediments at the top of the lakebed. In the till, where seepage was slower than that in the outwash, a three dimensional resistivity survey mapped a point of high seepage associated with heterogeneity (lower resistivity and likely higher permeability). Points of focused flow across the sediment-water interface are difficult to detect and can transmit a large percentage of total exchange. Using a series of electrical resistivity geophysical methods in combination with hydrologic data to locate heterogeneities that affect seepage rates can help guide seepage meter placement. Improving our understanding of the causes and types of heterogeneity in lake seepage will provide better data for lake budgets and prediction of mass transfer of solutes or contaminants between lakes and groundwater. PMID- 25556925 TI - Renal function and klotho gene polymorphisms among Uygur and Kazak populations in Xinjiang, China. AB - BACKGROUND: The association of genetic polymorphisms of klotho gene with aging has not been thoroughly examined. Previous studies showed that longevity in the Uygurs was considerably greater than in Kazaks in Xinjiang. This study aimed to investigate the difference of renal function and Klotho gene polymorphisms between Kazak and Uygur normal populations in Xinjiang, China. MATERIAL/METHODS: A total of 249 Uygur and 386 Kazak clinically normal subjects were included in this study. Four single-nucleotide polymorphisms (rs1207568, rs564481, rs9527025, and rs9536314) of the klotho gene were genotyped using the ABI SNaPshot method. Estimated glomerular filtration rate (eGFR) was calculated according to the Chinese simplified MDRD equation. RESULTS: There were significant differences between Kazak and Uygur healthy populations in both allele frequencies and genotype distributions in rs9527025 and rs9536314 (P<0.05, respectively). When the subjects were divided into 2 groups according to the genotypes of the klotho gene polymorphism, in the GA+AA genotype distributions of the rs1207568, the differences I serum creatinine and estimated glomerular filtration rate between the Kazak and Uygur groups were statistically significant (P<0.05, respectively). In CC genotype of rs564481, serum creatinine was significantly higher in Kazaks compared with Uygurs (P<0.05). In GG genotype of rs9527025, serum creatinine was significantly higher in the Kazak group compared with the Uygur group (P<0.05), as well as in CG+CC genotype of rs9527025 (P<0.05). Serum creatinine was significantly higher in the Kazak group compared with the Uygur group in TT genotype of rs9536314 (P<0.05), as was GT+GG genotype of rs9536314. Haplotype analysis indicated that the frequencies of ACGT, GTGT, and GCCG haplotypes were significantly different between Kazak and Uygur healthy populations (P=0.04, P=0.018, P=0.000, respectively). CONCLUSIONS: Significant differences in klotho gene rs9527025 and rs9536314 polymorphisms were found between the Uygur and Kazak populations. PMID- 25556927 TI - Hydrothermal synthesis and characterization of aluminum-free Mn-beta zeolite: a catalyst for phenol hydroxylation. AB - Zeolite beta, especially heteroatomic zeolite beta, has been widely used in the industries of fine chemicals and petroleum refining because of its outstanding thermal stability, acid resistance, and unique 3-D open-frame structure. In this paper, aluminum-free Mn-beta zeolite was hydrothermally synthesized in the SiO2 MnO2-(TEA)2O-NaF-H2O system. The effect of the chemical composition of the precursor mixture to the crystallization of the Al-free Mn-beta zeolite was investigated. The synthesized Al-free Mn-beta zeolite was characterized by inductively coupled plasma (ICP), XRD, thermogravimetric/differential thermal analysis (TG/DTA), N2 adsorption-desorption, FT-IR, UV-vis, X-ray photoelectron spectroscopy (XPS), and scanning electron microscope (SEM). The results show that the synthesized zeolite has a structure of beta zeolite with good crystallinity and Mn ions present in the framework of the zeolite. The synthesized Al-free Mn beta zeolite shows great catalytic activity toward the phenol hydroxylation reaction using H2O2 as the oxidant. Approximately 35% of phenol conversion and ~98% of dihydroxybenzene selectivity can be obtained under the optimal conditions. PMID- 25556926 TI - Cinnamic aldehyde treatment alleviates chronic unexpected stress-induced depressive-like behaviors via targeting cyclooxygenase-2 in mid-aged rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: COX-2 has been considered as a potent molecular target for prevention and therapy of depression. However, a recent study showed that COX-2 inhibitor does not improve depressive symptoms in persons aged 70 and over. Therefore, whether treatments targeting COX-2 have a clinical efficacy in depression, especially elderly individuals, remains unclear. Cinnamic aldehyde is a major constituent of Cinnamomum cassia, which has exhibited excellent anti inflammatory activities as a COX-2 inhibitor. To investigate the potential antidepressant effect of cinnamic aldehyde in mid-aged rats. MATERIALS AND METHODS: The depressive-like behaviors were measured after the rats exposed to chronic unexpected mild stress (CUMS). Cinnamic aldehyde was administrated by oral gavage to stressed rats (22.5, 45, 90 mg/kg, respectively) for 21 days. The mRNA, protein expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E2 (PGE2) levels were measured in the frontal cortex and hippocampus of stressed animals. RESULTS: We found that CUMS procedure not only decreased the sucrose preference, but also elevated the COX-2 activity, mRNA and protein levels, and increased PGE2 concentration in rat brain regions. Treatment with high doses of cinnamic aldehyde (45, 90 mg/kg) reversed the behavioral abnormalities, and decreased the COX-2 protein and activity (but not COX-2 mRNA expression) and PGE2 concentration in frontal cortex and hippocampus of stressed rats. CONCLUSION: Cinnamic aldehyde exerted antidepressant-like effects in stressed mid-aged rats, and its mechanism of action appears to decrease COX-2 protein and activity. The current findings suggest that targeting COX-2 system might be benefit to the depression, especially elderly individuals and cinnamic aldehyde might be a promising medicine to treat the subjects in the depression. PMID- 25556928 TI - Vibrational shape tracking of atomic force microscopy cantilevers for improved sensitivity and accuracy of nanomechanical measurements. AB - Contact resonance atomic force microscopy (CR-AFM) methods currently utilize the eigenvalues, or resonant frequencies, of an AFM cantilever in contact with a surface to quantify local mechanical properties. However, the cantilever eigenmodes, or vibrational shapes, also depend strongly on tip-sample contact stiffness. In this paper, we evaluate the potential of eigenmode measurements for improved accuracy and sensitivity of CR-AFM. We apply a recently developed, in situ laser scanning method to experimentally measure changes in cantilever eigenmodes as a function of tip-sample stiffness. Regions of maximum sensitivity for eigenvalues and eigenmodes are compared and found to occur at different values of contact stiffness. The results allow the development of practical guidelines for CR-AFM experiments, such as optimum laser spot positioning for different experimental conditions. These experiments provide insight into the complex system dynamics that can affect CR-AFM and lay a foundation for enhanced nanomechanical measurements with CR-AFM. PMID- 25556929 TI - Can EGFR mutation status be reliably determined in pre-operative needle biopsies from adenocarcinomas of the lung? AB - The identification of EGFR mutations in non-small-cell lung cancer is important for selecting patients, who may benefit from treatment with EGFR tyrosine kinase inhibitors. The analysis is usually performed on cytological aspirates and/or histological needle biopsies, representing a small fraction of the tumour volume. The aim of the present investigation was to evaluate the diagnostic performance of this molecular test. We retrospectively included 201 patients with primary adenocarcinoma of the lung. EGFR mutation status (exon 19 deletions and exon 21 L858R point mutation) was evaluated on both pre-operative biopsies (131 histological and 70 cytological) and on the surgical specimens, using PCR. Samples with low tumour cell fraction were assigned to laser micro-dissection (LMD). We found nine (4.5%) patients with EGFR mutation in the lung tumour resections, but failed to identify mutation in one of the corresponding pre operative, cytological specimens. Several (18.4%) analyses of the pre-operative biopsies were inconclusive, especially in case of biopsies undergoing LMD and regarding exon 21 analysis. Discrepancy of mutation status in one patient may reflect intra-tumoural heterogeneity or technical issues. Moreover, several inconclusive results in the diagnostic biopsies reveal that attention must be paid on the suitability of pre-operative biopsies for EGFR mutation analysis. PMID- 25556930 TI - Development and validation of a 48-target analytical method for high-throughput monitoring of genetically modified organisms. AB - The rapid increase in the number of genetically modified (GM) varieties has led to a demand for high-throughput methods to detect genetically modified organisms (GMOs). We describe a new dynamic array-based high throughput method to simultaneously detect 48 targets in 48 samples on a Fludigm system. The test targets included species-specific genes, common screening elements, most of the Chinese-approved GM events, and several unapproved events. The 48 TaqMan assays successfully amplified products from both single-event samples and complex samples with a GMO DNA amount of 0.05 ng, and displayed high specificity. To improve the sensitivity of detection, a preamplification step for 48 pooled targets was added to enrich the amount of template before performing dynamic chip assays. This dynamic chip-based method allowed the synchronous high-throughput detection of multiple targets in multiple samples. Thus, it represents an efficient, qualitative method for GMO multi-detection. PMID- 25556931 TI - Identification and genetic mapping of the putative Thinopyrum intermedium-derived dominant powdery mildew resistance gene PmL962 on wheat chromosome arm 2BS. AB - KEY MESSAGE: Powdery resistance putatively derived from Thinopyrum intermedium in the wheat line L962 is controlled by a single dominant gene designated PmL962 and mapped to chromosome arm 2BS. Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a destructive disease affecting the production of wheat (Triticum aestivum). Powdery mildew resistance was putatively transferred from Thinopyrum intermedium to the common wheat line L962, which conferred resistance to multiple Chinese Bgt isolates. Genetic analysis of the powdery mildew response was conducted by crossing the resistant line L962 with the susceptible line L983. Disease assessments of the F1, F2, and F2:3 populations from the cross L983/L962 indicated that resistance was controlled by a single dominant gene. A total of 373 F2:3 lines and 781 pairs of genomic simple sequence repeat (SSR) primers were employed to determine the chromosomal location of the resistance gene. The gene was linked to four publicly available and recently developed wheat genomic SSR markers and seven EST-STS markers. The resistance gene was mapped to chromosome arm 2BS based on the locations of the linked markers. Pedigree, molecular marker and resistance response data indicated that the powdery mildew resistance gene in L962 is novel. It was temporarily designated PmL962. It is flanked by Xwmc314 and BE443737at genetic distances of 2.09 and 3.74 cM, respectively, and located in a 20.77 cM interval that is co-linear with a 269.4 kb genomic region on chromosome 5 in Brachypodium distachyon and a 223.5 kb genomic region on rice (Oryza sativa) chromosome 4. The markers that are closely linked to this gene have potential applications in marker-assisted breeding. PMID- 25556932 TI - Photocatalytic hydrogenolysis of epoxides using alcohols as reducing agents on TiO2 loaded with Pt nanoparticles. AB - Photoexcitation (lambda > 300 nm) of TiO2 loaded with Pt particles promotes selective hydrogenolysis of epoxides using alcohols as reducing agents. PMID- 25556933 TI - A negative association between lithium in drinking water and the incidences of homicides, in Greece. AB - The purpose of the present study was to evaluate the association between lithium levels in the public water supply and incidences of homicide in Greece. A total of 149 samples of drinking water were collected from 34 out of 52 prefectures, and data for homicides were taken from National Statistic Service of Greece (Hellenic Statistical Authority - EL.STAT). The average lithium level was 11.10 MUg/l (SD = 21.16). The results indicate that there is a tendency for lower mean number of homicides in the prefectures with high levels of lithium in drinking water (R(2) = 0.054, beta = -0.38, p = .004). Considering the results of our previous study, which showed an inverse association between the lithium levels in drinking water and the incidence of suicide, homicide, rape, and drug abuse, we suggest that natural lithium level intake may influence impulsiveness, a factor that mediate to the manifestation of both suicidality and aggressiveness. PMID- 25556934 TI - NE strengthens the immunosuppression induced by AlCl3 through beta2-AR/cAMP pathway in cultured rat peritoneal macrophages. AB - To investigate the effect of noradrenaline (NE) on the immunosuppression induced by aluminum trichloride (AlCl3), the peritoneal macrophages were cultured with RPMI-1640 medium containing 0.97 mM AlCl3 (1/10 IC50). NE was added to the medium at the final concentrations of 0 (control group, N-C), 0.1 (low-dose group, N-L), 1 (mid-dose group, N-M), and 10 (high-dose group, N-H) nM, respectively. No addition of both AlCl3 and NE serviced as blank group (D-C). Chemotaxis, adhesion, phagocytosis, tumor necrosis factor alpha (TNF-alpha) secretion, cyclic adenosine monophosphate (cAMP) content, beta2 adrenergic receptors (beta2-AR) density, and messenger RNA (mRNA) expression of macrophages were detected. The results showed that AlCl3 reduced the chemotaxis, adhesion, phagocytosis, and TNF alpha secretion and increased the cAMP content, beta2-AR density, and mRNA expression of peritoneal macrophages. Meanwhile, the chemotaxis, adhesion, phagocytosis, TNF-alpha secretion, beta2-AR density, and mRNA expression were reduced while the cAMP content was increased in NE-treated groups than those in N C group. The results indicated that NE strengthens the immunosuppression induced by AlCl3 in cultured rat peritoneal macrophages through the beta2-AR/cAMP pathway. PMID- 25556936 TI - Comparison of pediatric perioperative risk assessment by ASA physical status and by NARCO-SS (neurological, airway, respiratory, cardiovascular, other-surgical severity) scores. AB - BACKGROUND: ASA-PS is a widely used perioperative health assessment method, but with poor reproducibility. A novel objective, pediatric-specific risk classification system based on Neurological, Airway, Respiratory, Cardiovascular, Other categories and Surgical Severity (NARCO-SS) has been validated in only one US center. OBJECTIVE: Independent external validation of the NARCO-SS and comparison with the ASA-PS in predicting perioperative outcomes. METHODS: Preoperative ASA-PS and NARCO-SS scores were assigned to 387 children by pediatric anesthesia consultants at a tertiary care center in India and predefined perioperative adverse events and escalation of care recorded. Spearman's correlations determined the relationship between outcomes and scores and kappa statistics for interobserver reliability. The predictive performance of the ASA-PS and NARCO-SS was evaluated by the area under the receiver operating characteristics curves (AUC-ROC) for discrimination and Pearson's chi-square for calibration. RESULTS: NARCO-SS and ASA scores had significant Spearman's correlation coefficients with perioperative outcomes and moderate interobserver reliability. The NARCO-SS showed greater discrimination than the ASA-PS (AUC-ROC 0.778 vs 0.710 for escalation of care and 0.822 vs 0.724 for adverse events, P < 0.01). However, both scores had poor calibration (Pearson's chi-square, P < 0.0001). Individual NARCO-SS categories for neurological and airway lacked statistically significant Spearman's correlations. CONCLUSIONS: NARCO-SS is a valid risk stratification tool that is better than the ASA-PS in discriminating children with adverse perioperative outcomes. The poor calibration of both scores suggests neither can reliably predict perioperative outcomes in individual patients. Modification of neurological and airway categories may improve the predictive accuracy of the NARCO-SS. PMID- 25556935 TI - Regulation of mitochondrial biogenesis and its intersection with inflammatory responses. AB - SIGNIFICANCE: Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. RECENT ADVANCES: Early-phase inflammatory mediator proteins interact with PRRs to activate NF-kappaB-, MAPK-, and PKB/Akt dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1alpha, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1alpha, participating in Nfe2l2 mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. CRITICAL ISSUES: Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-kappaB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. FUTURE DIRECTIONS: Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation. PMID- 25556937 TI - Opportunistic testing versus organized prostate-specific antigen screening: outcome after 18 years in the Goteborg randomized population-based prostate cancer screening trial. AB - BACKGROUND: It has been shown that organized screening decreases prostate cancer (PC) mortality, but the effect of opportunistic screening is largely unknown. OBJECTIVE: To compare the ability to reduce PC mortality and the risk of overdiagnosis between organized and opportunistic screening. DESIGN, SETTING, AND PARTICIPANTS: The Goteborg screening study invited 10 000 randomly selected men for prostate-specific antigen (PSA) testing every 2 yr since 1995, with a prostate biopsy recommended for men with PSA >=2.5 ng/ml. The control group of 10 000 men not invited has been exposed to a previously reported increased rate of opportunistic PSA testing. Both groups were followed until December 31, 2012. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Observed cumulative PC incidence and mortality rates in both groups were calculated using the actuarial method. Using historical data from 1990-1994 (pre-PSA era), we calculated expected PC incidence and mortality rates in the absence of any PSA testing. The number needed to invite (NNI) and the number needed to diagnose (NND) were calculated by comparing the expected versus observed incidence and mortality rates. RESULTS AND LIMITATIONS: At 18 yr, 1396 men were diagnosed with PC and 79 men died of PC in the screening group, compared to 962 and 122, respectively, in the control group. In the screening group, the observed cumulative PC incidence/mortality was 16%/0.98% compared to expected values of 6.8%/1.7%. The corresponding values for the control group were 11%/1.5% and 6.9%/1.7%. Organized screening was associated with an absolute PC-specific mortality reduction of 0.72% (95% confidence interval [CI] 0.50-0.94%) and relative risk reduction of 42% (95% CI 28-54%). There was an absolute reduction in PC deaths of 0.20% (95% CI -0.06% to 0.47%) and a relative risk reduction of 12% (95% CI -5 to 26%) associated with opportunistic PSA testing. NNI and NND were 139 (95% CI 107-200) and 13 for organized biennial screening and 493 (95% CI 213- -1563) and 23 for opportunistic screening. The extent of opportunistic screening could not be measured; incidence trends were used as a proxy. CONCLUSIONS: Organized screening reduces PC mortality but is associated with overdiagnosis. Opportunistic PSA testing had little if any effect on PC mortality and resulted in more overdiagnosis, with almost twice the number of men needed to be diagnosed to save one man from dying from PC compared to men offered an organized biennial screening program. PATIENT SUMMARY: Prostate-specific antigen (PSA) screening within the framework of an organized program seems more effective than unorganized screening. PMID- 25556938 TI - Using cavity microelectrodes for electrochemical noise studies of oxygen-evolving catalysts. AB - Cavity microelectrodes were used as a binder-free platform to evaluate oxygen evolution reaction (OER) electrocatalysts with respect to gas bubble formation and departure. Electrochemical noise measurements were performed by using RuO2 as a benchmark catalyst and the perovskite La0.58 Sr0.4 Fe0.8 Co0.2 O3 as a non noble metal OER catalyst with lower intrinsic conductivity. Changes in the current during the OER originate from variations in electrolyte resistance during the formation of the gas phase and partial coverage of the active area. Fluctuations observed in current and conductance transients were used to establish the contribution from the ohmic overpotential and to determine the characteristic frequency of oxygen evolution. The proposed quantitative determination of gas bubble growth and departure opens up the route for a rational interface design by considering gas bubble growth and departure as a main contributing factor to the overall electrocatalytic activity at high current densities. PMID- 25556939 TI - BioGPS: navigating biological space to predict polypharmacology, off-targeting, and selectivity. AB - The structural comparison of protein binding sites is increasingly important in drug design; identifying structurally similar sites can be useful for techniques such as drug repurposing, and also in a polypharmacological approach to deliberately affect multiple targets in a disease pathway, or to explain unwanted off-target effects. Once similar sites are identified, identifying local differences can aid in the design of selectivity. Such an approach moves away from the classical "one target one drug" approach and toward a wider systems biology paradigm. Here, we report a semiautomated approach, called BioGPS, that is based on the software FLAP which combines GRID Molecular Interactions Fields (MIFs) and pharmacophoric fingerprints. BioGPS comprises the automatic preparation of protein structure data, identification of binding sites, and subsequent comparison by aligning the sites and directly comparing the MIFs. Chemometric approaches are included to reduce the complexity of the resulting data on large datasets, enabling focus on the most relevant information. Individual site similarities can be analyzed in terms of their Pharmacophoric Interaction Field (PIF) similarity, and importantly the differences in their PIFs can be extracted. Here we describe the BioGPS approach, and demonstrate its applicability to rationalize off-target effects (ERalpha and SERCA), to classify protein families and explain polypharmacology (ABL1 kinase and NQO2), and to rationalize selectivity between subfamilies (MAP kinases p38alpha/ERK2 and PPARdelta/PPARgamma). The examples shown demonstrate a significant validation of the method and illustrate the effectiveness of the approach. PMID- 25556940 TI - Cortical and thalamic projections to cytoarchitectural areas 6Va and 8C of the marmoset monkey: connectionally distinct subdivisions of the lateral premotor cortex. AB - We studied the afferent connections of two cytoarchitectural subdivisions of the caudolateral frontal cortex, areas 6Va and 8C, in marmoset monkeys. These areas received connections from the same set of thalamic nuclei, including main inputs from the ventral lateral and ventral anterior complexes, but differed in their patterns of corticocortical connections. Areas 8C and 6Va had reciprocal interconnections, and received similar proportions of afferents from premotor areas 6M and 6DC, and from the prefrontal cortex. However, area 8C received stronger inputs from frontal areas that have been implicated in oculomotor functions, whereas area 6Va received stronger projections from the primary motor area. Somatosensory projections to area 6Va were generally stronger than those to area 8C, and originated from several areas; in contrast, only the second somatosensory area (S2) sent major inputs to area 8C. Finally, although both 6Va and 8C received major inputs from the rostral posterior parietal cortex (putative homologs of areas PE, PF, and PFG), area 8C also received a variety of smaller connections from posterior midline, caudal posterior parietal, and extrastriate areas. Statistical analyses revealed that the pattern of connections of area 8C is more akin to that characterizing a premotor area, rather than a prefrontal area. We conclude that cytoarchitectural area 6Va in the marmoset is similar to ventral premotor areas identified in other simian primates, and that area 8C corresponds to a specialized subdivision of the caudal premotor complex where visual information for the guidance of movements is likely to be emphasized. PMID- 25556941 TI - Serious psychological distress as a barrier to dental care in community-dwelling adults in the United States. AB - OBJECTIVES: To examine whether serious psychological distress (SPD), a nonspecific indicator of past year mental health problems, was associated with subsequent dental care utilization, dental expenditures, and unmet dental needs. METHODS: We analyzed data from panel 13 thru 15 of the Medical Expenditure Panel Survey -Household Component (n=31,056). SPD was defined as a score of 13 or higher on the Kessler Psychological Distress Scale (K6). Logistic regression, zero-inflated negative binomial model, and generalized linear model (GLM) with a gamma distribution were used to test the study hypotheses. RESULTS: Adults with SPD had, in the subsequent year, 35 percent lower odds of adhering to annual dental checkups and a twofold increase in the odds of having unmet dental needs. Although adults with SPD did not have significantly more dental visits than those without SPD, they spent 20 percent more on dental care. CONCLUSIONS: SPD was a modest independent risk factor for lack of subsequent preventive dental care, greater unmet dental needs, and greater dental expenditures. In addition to expanding adult dental coverage, it is important to develop and evaluate interventions to increase the utilization of dental care particularly preventive dental services among people with mental illness in order to improve oral health and reduce dental expenditures among this vulnerable population. PMID- 25556943 TI - Protein kinase d inhibitors uncouple phosphorylation from activity by promoting agonist-dependent activation loop phosphorylation. AB - Protein kinase D (PKD) is acutely activated by two tightly coupled events: binding to the second messenger diacylglycerol (DAG) followed by novel protein kinase C (nPKC) phosphorylation at the activation loop and autophosphorylation at the C terminus. Thus, phosphorylation serves as a widely accepted measure of PKD activity. Here we show that treatment of cells with PKD inhibitors paradoxically promotes agonist-dependent activation loop phosphorylation, thus uncoupling phosphorylation from activation. This inhibitor-induced enhancement of phosphorylation differs mechanistically from that previously reported for PKC and Akt, for which active-site inhibitors stabilize a phosphatase-resistant conformation. Rather, a conformational reporter reveals that inhibitor binding induces a conformational change, resulting in relocalization of PKD to basal DAG pools, where it is more readily phosphorylated by nPKCs. These findings illustrate the diverse conformational effects that small molecules exert on their target proteins, underscoring the importance of using caution when interpreting kinase activity from phosphorylation state. PMID- 25556942 TI - Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis. AB - Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts. PMID- 25556944 TI - Probes to monitor activity of the paracaspase MALT1. AB - The human paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) plays a central role in nuclear factor-kappaB (NF-kappaB) signaling as both a protease and scaffolding protein. Knocking out MALT1 leads to impaired NF-kappaB signaling and failure to mount an effective immune response. However, it is unclear to which degree it is the scaffolding function versus the proteolytic activity of MALT1 that is essential. Previous work involving a MALT1 inhibitor with low selectivity suggests that the enzymatic function plays an important role in different cell lines. To help elucidate this proteolytic role of MALT1, we have designed activity-based probes that inhibit its proteolytic activity. The probes selectively label active enzyme and can be used to inhibit MALT1 and trace its activity profile, helping to create a better picture of the significance of the proteolytic function of MALT1. PMID- 25556945 TI - Activity-based probes for detection of active MALT1 paracaspase in immune cells and lymphomas. AB - MALT1 paracaspase is activated upon antigen receptor stimulation to promote lymphocyte activation. In addition, deregulated MALT1 protease activity drives survival of distinct lymphomas such as the activated B cell type of diffuse large B cell lymphoma (ABC-DLBCL). Here, we designed fluorophore or biotin-coupled activity based-probes (ABP) that covalently modify the active center of MALT1. MALT1-ABPs are exclusively labeling an active modified full length form of MALT1 upon T cell stimulation. Further, despite the CARMA1 requirement for initial MALT1 activation, the MALT1-ABPs show that protease activity is not confined to the high-molecular CARMA1-BCL10-MALT1 (CBM) complex. Using biotin-coupled ABPs, we developed a robust assay for sensitive and selective detection of active MALT1 in cell lines, primary lymphocytes, and DLBCL tumor biopsies. Taken together, MALT1-ABPs represent powerful chemical tools to measure cellular MALT1 activation, determine efficacy of small molecule inhibitors, and classify lymphomas based on MALT1 activity status. PMID- 25556949 TI - Ectopic sebaceous glands: a rare cause of vaginal swelling. PMID- 25556946 TI - Comparison of the deleterious effects of binge drinking-like alcohol exposure in adolescent and adult mice. AB - A major cause of alcohol toxicity is the production of reactive oxygen species generated during ethanol metabolism. The aim of this study was to compare the effect of binge drinking-like alcohol exposure on a panel of genes implicated in oxidative mechanisms in adolescent and adult mice. In adolescent animals, alcohol decreased the expression of genes involved in the repair and protection of oxidative DNA damage such as atr, gpx7, or nudt15 and increased the expression of proapoptotic genes such as casp3. In contrast, in the adult brain, genes activated by alcohol were mainly associated with protective mechanisms that prevent cells from oxidative damage. Whatever the age, iterative binge-like episodes provoked the same deleterious effects as those observed after a single binge episode. In adolescent mice, multiple binge ethanol exposure substantially reduced neurogenesis in the dentate gyrus and impaired short-term memory in the novel object and passive avoidance tests. Taken together, our results indicate that alcohol causes deleterious effects in the adolescent brain which are distinct from those observed in adults. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity. The effects of alcohol exposure were investigated on genes involved in oxidative mechanisms. In adolescent animals, alcohol decreased the expression of genes involved in DNA repair, a potential cause of the observed decrease of neurogenesis. In contrast, in the adult brain, alcohol increased the expression of genes associated with antioxidant mechanisms. Apoptosis was increase in all groups and converged with other biochemical alterations to enhance short-term memory impairment in the adolescent brain. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity. PMID- 25556951 TI - Liver transplantation with aged donors in patients with hepatitis C virus. PMID- 25556950 TI - Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies. AB - Frontotemporal lobar degeneration with tau pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick's disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8% of non-diseased controls, we found grains, coiled bodies, and/or tau-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau. PMID- 25556952 TI - Self esteem, dependency, self-efficacy and self-criticism in social anxiety disorder. AB - BACKGROUND: Social anxiety disorder (SAD) is characterized by fear and avoidance in social situations where one perceives being in danger of scrutiny by others. Low self-esteem, low self-efficacy, high self-criticism and high dependency are additional potential features of SAD, and thus their examination is warranted, as is the elucidation of their inter-relationship. METHOD: Thirty-two SAD subjects diagnosed with the Mini-International Neuropsychiatric Interview and 30 healthy controls, were administered the Liebowitz Social Anxiety Scale (LSAS), the Rosenberg Self Esteem Scale, the Depressive Experiences Questionnaire (DEQ) that assesses self-criticism, dependency and self-efficacy, and a socio-demographic questionnaire. We hypothesized that the SAD group would present higher scores of dependency and self-criticism and lower self-esteem and self-efficacy. We also hypothesized that low self-esteem, low self-efficacy, high self-criticism and high dependency will predict the severity of SAD. RESULTS: In line with the hypotheses, SAD patients had higher scores of self-criticism and dependency and lower scores of self-esteem. The social anxiety score correlated negatively with self-esteem and self-efficacy, and positively with dependency and self-criticism. Self-criticism, but not the other measures, predicted the total LSAS score. CONCLUSIONS: Self-esteem, self-criticism, dependency and self-efficacy are related to SAD and their relations should be examined in future studies that will employ larger samples. It is suggested to search for ways to affect these factors through cognitive-behavioral interventions and additional psychotherapeutic treatments. Research should also focus on the specific role of self-criticism in SAD. PMID- 25556953 TI - Erratum to: Existing Challenges Associated with Offering Prenatal Genetic Diagnosis in an Arab Society in the Sultanate of Oman. PMID- 25556955 TI - @InorgChem. PMID- 25556954 TI - Long-term immunoglobulin therapy for chronic inflammatory demyelinating polyradiculoneuropathy. AB - Immunoglobulins are an effective but expensive treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although the goal is to improve function, use of functional scales to monitor therapy is not widespread. Limited recent evidence suggests that doses lower than those used traditionally may be as effective. There are no proven correlations of effective dose with weight, disease severity, or duration. The clinical course of CIDP is heterogeneous and includes monophasic forms and complete remissions. Careful monitoring of immunoglobulin use is necessary to avoid overtreatment. Definitive evidence for immunoglobulin superiority over steroids is lacking. Although latest trial evidence favors immunoglobulins over steroids, the latter may result in higher remission rates and longer remission periods. This article addresses the appropriateness of first-line, high-dose immunoglobulin treatment for CIDP and reviews important clinical questions regarding the need for long-term therapy protocols, adequate monitoring, treatment withdrawal, and consideration of corticosteroids as an alternative to immunoglobulin therapy. PMID- 25556956 TI - Selection by phage display of nanobodies directed against hypoxia inducible factor-1alpha (HIF-1alpha). AB - Hypoxia, which promotes tumor invasion and metastasis, is a common phenomenon in solid tumors. Hypoxia generally leads to a higher expression level of hypoxia inducible factor-1 (HIF-1) in tumors (cells) relative to normal tissues (cells). Given the unique expression of HIF-1alpha in human cancers and its vital importance in mediating hypoxic adaptation, we have identified 20 different HIF 1alpha-specific nanobodies by using a llama-derived nonimmune phage display library. PAS-B domain of HIF-1alpha (HIF-1alpha-PAS-B) has been used as an antigen. Nanobody (VHH16) was selected from these 20 nanobodies by phage enzyme linked immunosorbent assay. The preliminary analysis of biological activity demonstrates that VHH16 can specifically bind to HIF-1alpha with high affinity. VHH16 is the first nanobody that specifically binds to HIF-1alpha-PAS-B as well. We suggest here that VHH16 is useful in disease diagnosis and also has potential in medical applications. PMID- 25556957 TI - Does a cleansing enema improve image quality of 3T surface coil multiparametric prostate MRI? AB - PURPOSE: To assesses the utility of a preparatory enema in the interpretation of prostate multiparametric (MP) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Under a waiver from the Institutional Review Board (IRB), 32 patients without bowel preparation and 28 patients who underwent a self-administered enema were imaged consecutively with 3T MP-MRI over 6 months. Two blinded radiologists independently assessed image quality on T2 -weighted (T2 W), trace b 1000 mm(2) /sec echo-planar (EPI) and apparent-diffusion coefficient (ADC) and assessed for motion/blur on T2 W and distortion/blur on EPI and ADC. Radiologists also quantified rectal stool and gas. A third blinded radiologist generated contrast curves from dynamic contrast-enhanced (DCE) data at six locations and measured the number of corrupted data points, defined as >10% aberrant signal intensity change. Subjective scores were compared using Wilcoxon sign rank test. Rectal contents were correlated to artifact using Spearman correlation. Contrast curves were evaluated with independent t-tests. RESULTS: There was no difference in image quality on T2 W (P = 0.66-0.74), EPI (P = 0.13-0.36) or ADC (P = 0.49 0.59). There was less rectal stool in the enema group (P = 0.004) and amount of stool correlated with motion artifact on T2 W (r = 0.23, P = 0.02); however, there was no difference in motion artifact between groups (P = 0.47-0.94). Only a minority of patients in the non-enema group had moderate or large amounts of stool (16%) and none of these patients had severe or extensive artifact on T2 . There was less rectal gas in the enema group (P = 0.002); however, amount of gas did not correlate with distortion artifact on EPI or ADC (P = 0.17-0.41) and there was no difference in blur (P = 0.41-0.91) or distortion (P = 0.31-0.99) on EPI or ADC between groups. There was no difference in corrupted data points on DCE (P = 0.46). CONCLUSION: In this study the use of a preparatory enema did not improve image quality or reduce artifact in prostate MP-MRI. PMID- 25556958 TI - Satellite lesions accompanying herpes zoster: a new prognostic sign for high-risk zoster. AB - BACKGROUND: The incidence, clinical relevance and pathogenesis of single, isolated, varicella-like skin lesions occurring far beyond the primary herpes zoster (HZ)-affected dermatome remain unclear. OBJECTIVES: To search prospectively for these satellite lesions in 120 patients with HZ and to correlate their presence with a series of clinical, histological and virological data. METHODS: Relevant clinical data were recorded from 109 patients with proven HZ using immunohistochemistry on Tzanck smears. Furthermore, skin biopsies and blood samples were obtained from a subgroup of patients presenting with primary HZ with and without satellite lesions for histology, immunohistology, serology and real-time polymerase chain reaction. RESULTS: This study identified satellite lesions in 21.1% of the patients with HZ. Their presence conveyed a statistically significant relative risk (RR) for severe (RR 3.27, P < 0.001), multidermatomal (RR 10.6, P < 0.001) and multistage HZ (RR 3.30, P < 0.001); systemic signs (RR 2.08, P = 0.0031); immunosuppression (RR 2.38, P = 0.0014) and hospitalization (RR 2.94, P < 0.001). Varicella zoster virus (VZV) viraemia was higher (mean 4075 copies mL(-1) ) in patients with HZ with satellite lesions than in those without (mean 1466 copies mL(-1) ). In contrast to HZ lesions, satellite lesions often presented positive VZV immunostaining in endothelial cells, suggesting a similar pathogenesis to varicella. A limitation of this study is the centre-linked overrepresentation of immunocompromised patients. CONCLUSIONS: Total-body examination searching for satellite lesions is a rapid, simple and reliable tool for identifying patients with high-risk HZ. PMID- 25556959 TI - Unraveling the intrinsic color of chlorophyll. AB - The exact color of light absorbed by chlorophyll (Chl) pigments, the light harvesters in photosynthesis, is tuned by the protein microenvironment, but without knowledge of the intrinsic color of Chl it remains unclear how large this effect is. Experimental first absorption energies of Chl a and b isolated in vacuo and tagged with quaternary ammonium cations are reported. The energies are largely insensitive to details of the tag structure, a finding supported by first principles calculations using time-dependent density functional theory. Absorption is significantly blue-shifted compared to that of Chl-containing proteins (by 30-70 nm). A single red-shifting perturbation, such as axial ligation or the protein medium, is insufficient to account even for the smallest shift; the largest requires pigment-pigment interactions. PMID- 25556960 TI - Therapeutic drug monitoring of continuous-infusion acylovir for disseminated herpes simplex virus infection in a neonate receiving concurrent extracorporeal life support and continuous renal replacement therapy. AB - Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity that yields high mortality. Acyclovir is the primary antiviral agent used to treat life-threatening HSV infections in neonates; however, even though the agent has reduced morbidity overall from these infections, mortality with disseminated disease remains high. Currently, to our knowledge, no data exist regarding therapeutic drug monitoring of acyclovir in the setting of extracorporeal life support (ECLS) or continuous renal replacement therapy (CRRT) coupled with ECLS. We describe the case of a 14-day-old female with disseminated HSV-1 infection that progressed to fulminant hepatic and renal failure, necessitating the use of ECLS for hemodynamic support and CRRT as a treatment modality for hepatic and renal failure. The standard dosage of acyclovir 20 mg/kg/dose intravenously every 8 hours had been initiated, but after conversion to ECLS and CRRT, the patient's dosage was increased to 30 mg/kg/dose every 8 hours. After a repeat viral load remained unchanged from the initial viral load at 1 * 10(8) copies/ml, the patient was transitioned from intermittent dosing to a continuous infusion of acyclovir added to the dialysate solution for CRRT at a concentration of 5.5 mg/L. To provide an optimal outcome, dosing was designed to maintain acyclovir plasma concentrations of at least 3 mg/L in order to maintain an acyclovir concentration of at least 1 mg/L in the cerebrospinal fluid. The patient's acyclovir serum concentrations measured at 24 and 72 hours after starting continuous-infusion acyclovir via the dialysate were 8.8 and 5.3 mg/L, respectively, allowing for a continuous serum concentration above 3 mg/L. Unfortunately, before a repeat viral load could be obtained to assess the efficacy of the continuous infusion acyclovir, the patient experienced an intracerebral hemorrhage as a complication related to ECLS after which technological support was withdrawn. This is the first report to describe the pharmacokinetics of continuous-infusion acyclovir in a neonate receiving ECLS with concurrent CRRT. These data suggest that adding acyclovir to the dialysate fluid during CRRT is effective in achieving therapeutic drug concentrations despite the complications of adding ECLS and CRRT circuits to a small patient. PMID- 25556961 TI - Anaphylactic bronchospasm during general anesthesia is not related to asthma. AB - In the general population, a history of asthma (HA) is associated with a higher risk of mortality of anaphylactic shock (AS), but it is unknown whether this association remains valid for intra-operative AS. The goal of this retrospective study was to investigate whether a HA was associated with a higher risk of bronchospasm during intra-operative AS. We analyzed 106 patients (January 2009 December 2012) with intra-operative AS: 57% of them had a confirmed IgE-mediated reaction and 27% had a HA. On logistic regression, the only factor statistically associated with bronchospasm was a neuromuscular blocking drug, with both IgE- or non-IgE-mediated reactions. These results suggest that the mechanisms of bronchospasm in AS may be different from those of asthma and that, in the presence of bronchospasm during anesthesia, AS should be considered to be the most likely cause. PMID- 25556962 TI - Effects of psychological priming, video, and music on anaerobic exercise performance. AB - Peak performance videos accompanied by music can help athletes to optimize their pre-competition mindset and are often used. Priming techniques can be incorporated into such videos to influence athletes' motivational state. There has been limited empirical work investigating the combined effects of such stimuli on anaerobic performance. The present study examined the psychological and psychophysiological effects of video, music, and priming when used as a pre performance intervention for an anaerobic endurance task. Psychological measures included the main axes of the circumplex model of affect and liking scores taken pre-task, and the Exercise-induced Feeling Inventory, which was administered post task. Physiological measures comprised heart rate variability and heart rate recorded pre-task. Fifteen males (age = 26.3 +/- 2.8 years) were exposed to four conditions prior to performing the Wingate Anaerobic Test: music-only, video and music, video with music and motivational primes, and a no-video/no-music control. Results indicate that the combined video, music, and primes condition was the most effective in terms of influencing participants' pre-task affect and subsequent anaerobic performance; this was followed by the music-only condition. The findings indicate the utility of such stimuli as a pre-performance technique to enhance athletes' or exercisers' psychological states. PMID- 25556963 TI - Detection of granulocyte-reactive antibodies: a comparison of different methods. AB - BACKGROUND AND OBJECTIVES: Granulocyte-reactive antibodies can cause autoimmune and neonatal immune neutropenias as well as transfusion-related acute lung injury. The classical antibody-detection methods granulocyte aggregation test (GAT), granulocyte immunofluorescence test (GIFT) and monoclonal antibody specific immobilization of granulocyte antigens (MAIGA) are time-consuming and technically challenging. In recent years, flow cytometric white blood cell immunofluorescence test (Flow-WIFT) and the microbeads assay LabScreen(r) Multi have emerged and are still subject of evaluation. These serological tests were compared on a screening and specification level. MATERIALS AND METHODS: For screening, the combination of GAT/GIFT was compared to Flow-WIFT testing 333 samples. Positive samples were further analysed with MAIGA and LabScreen(r) Multi. RESULTS: Granulocyte aggregation test/GIFT detected 77 positive samples, Flow-WIFT found 108 granulocyte-reactive samples. Six Samples were only positive in GAT/GIFT, and 37 samples were only positive in Flow-WIFT (kappa = 0.682). Antibody specification with MAIGA and the microbeads assay confirmed granulocyte reactivity in 83 cases with 70 matching results (kappa = 0.742). However, out of six detected human neutrophil antigen (HNA) reactivities only two specificities matched in both assays. CONCLUSION: Flow-WIFT may be a valuable addition to GIFT for granulocyte-reactive antibody screening. MAIGA remains the most reliable laboratory method for antibody specification. PMID- 25556964 TI - Thread epilation: a less traumatic technique for patients undergoing isotretinoin therapy. AB - Skin fragility is a well-established complication of isotretinoin therapy for severe or resistant acne and presents a challenge to traditional modes of epilation such as waxing. As such, other less traumatic hair removal methods are desired. Herein we present the threading technique as an alternative form of epilation for patients in whom waxing is contraindicated secondary to concerns over skin fragility. PMID- 25556965 TI - Is viscotrabeculotomy superior to conventional trabeculotomy in the management of Egyptian infants with congenital glaucoma? AB - PURPOSE: The aim of this study was to assess the efficacy of viscotrabeculotomy in the management of congenital glaucoma as compared to conventional trabeculotomy, in Egyptian infants. METHODS: This is a prospective interventional randomized comparative study in which patients with primary congenital glaucoma were randomly allocated to either group A or B; viscotrabeculotomy (VT); and trabeculotomy (T), respectively. Patients were followed up regarding intra-ocular pressure (IOP), cup/disc (C/D) ratio and horizontal corneal diameter (HCD) for 6 months. A probability value (p value) <0.05 was considered significant. RESULTS: Twenty-one eyes in group A and 20 eyes in group B were enrolled in the study. The mean preoperative IOP was 23.5 and 24.3 mmHg in the VT and T groups, respectively. Postoperatively, IOP dropped at six months to 14.7 and 17 mmHg in the VT and T groups, respectively. That was significant in either group when compared to preoperative IOP, but not significant between both groups at the same point of comparison. CONCLUSIONS: Both techniques were equally effective in the reduction in IOP in the management of congenital glaucoma, but viscotrabeculotomy did not appear to add more benefit to the surgical outcome than classic trabeculotomy. PMID- 25556966 TI - Synthesis and Biological Evaluation of New Eugenol Mannich Bases as Promising Antifungal Agents. AB - New Mannich base-type eugenol derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 4-allyl-2-methoxy-6-(morpholin-4-ylmethyl) phenyl benzoate (7) and 4-{5-allyl-2-[(4-chlorobenzoyl)oxy]-3-methoxybenzyl}morpholin-4-ium chloride (8) were found to be the most effective antifungal compounds with low IC50 values, some of them well below those of reference drug fluconazole. The most significant IC50 values were those of 7 against C. glabrata (1.23 MUm), C. albicans and C. krusei (both 0.63 MUm). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on human mononuclear cells. As result, the cytotoxic activity of eugenol in eukaryotic cells decreased with the introduction of the morpholinyl group. Given these findings, we point out compounds 7 and 8 as the most promising derivatives because they showed potency values greater than those of eugenol and fluconazole and they also presented high selectivity indexes. PMID- 25556967 TI - Implementing antimicrobial stewardship in the Australian private hospital system: a qualitative study. AB - OBJECTIVE: To explore organisational factors and barriers contributing to limited uptake of antimicrobial stewardship (AMS) in Australian private hospitals and to determine solutions for AMS implementation. METHODS: A qualitative study using a series of focus group discussions was conducted in a large private hospital making use of a semistructured interview guide to facilitate discussion among clinical and non-clinical stakeholders. A thematic analysis using five sequential components that mapped and interpreted emergent themes surrounding AMS implementation was undertaken by a multidisciplinary team of researchers. RESULTS: Analysis revealed that autonomy of consultant specialists was perceived as being of greater significance in private hospitals compared with public hospitals. Use of an expert team providing antimicrobial prescribing advice and education without intruding on existing patient-specialist relationships was proposed by participants as an acceptable method of introducing AMS in private hospitals. There was more opportunity for nursing and pharmacist involvement, as well as empowering patients. Opportunities were identified for the hospital executive to market an AMS service as a feature that promoted excellence in patient care. CONCLUSIONS: Provision of advice from experts, championing by clinical leaders, marketing by hospital executives and involving nurses, pharmacists and patients should be considered during implementation of AMS in private hospitals. PMID- 25556968 TI - Important differences in the diagnostic spectrum of primary immunodeficiency in adults versus children. AB - Primary immunodeficiency disorders (PIDs) constitute a heterogeneous group of genetic disorders caused by defects in immunity, leading to recurrent infections, autoimmunity, lymphoproliferation and malignancies. Early diagnosis of PIDs is crucial for improving the quality of life in patients with PIDs while a delay in diagnosis, or inadequate treatment, results in an increased mortality and morbidity in affected individuals. Although most cases of PIDs present in children with recurrent and/or severe acute infections, some of the primary immune disorders are diagnosed during adulthood. Some common clues, both in children and adults, help physicians to diagnose PIDs; however, there are some specific clues to the diagnosis of PIDs for each group. This article reviews the important differences in the diagnostic spectrum of PIDs in adults versus children. PMID- 25556969 TI - Global transcriptomic profiling of Schizosaccharomyces pombe in response to nitrosative stress. AB - Excess production of nitric oxide (NO) and reactive nitrogen intermediates (RNIs) cause nitrosative stress on cells. Schizosaccharomyces pombe was used as a model to study nitrosative stress response. This is the first report on the global gene expression profile in response to NO in S. pombe using microarray. Among the 4824 genes reported for S. pombe, 818 were differentially expressed by at least 2-fold upon NO donor treatment. We previously showed that Pap1, the Activator Protein 1 transcription factor is required to combat nitrosative stress. In this study, the transcriptional response to NO in a null mutant for pap1 identified 45 genes that seem to be controlled by Pap1. Surprisingly, Pap1 regulated genes in S. pombe were distinctly different under nitrosative stress than those reported under oxidative stress. Genes of the pathway meiosis, cell cycle, spliceosome and oxidative phosphorylation were mostly affected under nitrosative stress in the fission yeast. PMID- 25556970 TI - Community wide interventions for increasing physical activity. AB - BACKGROUND: Multi-strategic community wide interventions for physical activity are increasingly popular but their ability to achieve population level improvements is unknown. OBJECTIVES: To evaluate the effects of community wide, multi-strategic interventions upon population levels of physical activity. SEARCH METHODS: We searched the Cochrane Public Health Group Segment of the Cochrane Register of Studies,The Cochrane Library, MEDLINE, MEDLINE in Process, EMBASE, CINAHL, LILACS, PsycINFO, ASSIA, the British Nursing Index, Chinese CNKI databases, EPPI Centre (DoPHER, TRoPHI), ERIC, HMIC, Sociological Abstracts, SPORT Discus, Transport Database and Web of Science (Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index). We also scanned websites of the EU Platform on Diet, Physical Activity and Health; Health Evidence.org; the International Union for Health Promotion and Education; the NIHR Coordinating Centre for Health Technology (NCCHTA); the US Centre for Disease Control and Prevention (CDC) and NICE and SIGN guidelines. Reference lists of all relevant systematic reviews, guidelines and primary studies were searched and we contacted experts in the field. The searches were updated to 16 January 2014, unrestricted by language or publication status. SELECTION CRITERIA: Cluster randomised controlled trials, randomised controlled trials, quasi experimental designs which used a control population for comparison, interrupted time-series studies, and prospective controlled cohort studies were included. Only studies with a minimum six-month follow up from the start of the intervention to measurement of outcomes were included. Community wide interventions had to comprise at least two broad strategies aimed at physical activity for the whole population. Studies which randomised individuals from the same community were excluded. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted the data and assessed the risk of bias. Each study was assessed for the setting, the number of included components and their intensity. The primary outcome measures were grouped according to whether they were dichotomous (per cent physically active, per cent physically active during leisure time, and per cent physically inactive) or continuous (leisure time physical activity time (time spent)), walking (time spent), energy expenditure (as metabolic equivalents or METS)). For dichotomous measures we calculated the unadjusted and adjusted risk difference, and the unadjusted and adjusted relative risk. For continuous measures we calculated percentage change from baseline, unadjusted and adjusted. MAIN RESULTS: After the selection process had been completed, 33 studies were included. A total of 267 communities were included in the review (populations between 500 and 1.9 million). Of the included studies, 25 were set in high income countries and eight were in low income countries. The interventions varied by the number of strategies included and their intensity. Almost all of the interventions included a component of building partnerships with local governments or non-governmental organisations (NGOs) (29 studies). None of the studies provided results by socio-economic disadvantage or other markers of equity. However, of those included studies undertaken in high income countries, 14 studies were described as being provided to deprived, disadvantaged or low socio-economic communities. Nineteen studies were identified as having a high risk of bias, 10 studies were unclear, and four studies had a low risk of bias. Selection bias was a major concern with these studies, with only five studies using randomisation to allocate communities. Four studies were judged as being at low risk of selection bias although 19 studies were considered to have an unclear risk of bias. Twelve studies had a high risk of detection bias, 13 an unclear risk and four a low risk of bias. Generally, the better designed studies showed no improvement in the primary outcome measure of physical activity at a population level.All four of the newly included, and judged to be at low risk of bias, studies (conducted in Japan, United Kingdom and USA) used randomisation to allocate the intervention to the communities. Three studies used a cluster randomised design and one study used a stepped wedge design. The approach to measuring the primary outcome of physical activity was better in these four studies than in many of the earlier studies. One study obtained objective population representative measurements of physical activity by accelerometers, while the remaining three low-risk studies used validated self-reported measures. The study using accelerometry, conducted in low income, high crime communities of USA, emphasised social marketing, partnership with police and environmental improvements. No change in the seven-day average daily minutes of moderate to vigorous physical activity was observed during the two years of operation. Some program level effect was observed with more people walking in the intervention community, however this result was not evident in the whole community. Similarly, the two studies conducted in the United Kingdom (one in rural villages and the other in urban London; both using communication, partnership and environmental strategies) found no improvement in the mean levels of energy expenditure per person per week, measured from one to four years from baseline. None of the three low risk studies reporting a dichotomous outcome of physical activity found improvements associated with the intervention.Overall, there was a noticeable absence of reporting of benefit in physical activity for community wide interventions in the included studies. However, as a group, the interventions undertaken in China appeared to have the greatest possibility of success with high participation rates reported. Reporting bias was evident with two studies failing to report physical activity measured at follow up. No adverse events were reported.The data pertaining to cost and sustainability of the interventions were limited and varied. AUTHORS' CONCLUSIONS: Although numerous studies have been undertaken, there is a noticeable inconsistency of the findings in the available studies and this is confounded by serious methodological issues within the included studies. The body of evidence in this review does not support the hypothesis that the multi-component community wide interventions studied effectively increased physical activity for the population, although some studies with environmental components observed more people walking. PMID- 25556971 TI - Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. AB - Genetic testing for hereditary breast and/or ovarian cancer mostly relies on laborious molecular tools that use Sanger sequencing to scan for mutations in the BRCA1 and BRCA2 genes. We explored a more efficient genetic screening strategy based on next-generation sequencing of the BRCA1 and BRCA2 genes in 210 hereditary breast and/or ovarian cancer patients. We first validated this approach in a cohort of 115 samples with previously known BRCA1 and BRCA2 mutations and polymorphisms. Genomic DNA was amplified using the Ion AmpliSeq BRCA1 and BRCA2 panel. The DNA Libraries were pooled, barcoded, and sequenced using an Ion Torrent Personal Genome Machine sequencer. The combination of different robust bioinformatics tools allowed detection of all previously known pathogenic mutations and polymorphisms in the 115 samples, without detecting spurious pathogenic calls. We then used the same assay in a discovery cohort of 95 uncharacterized hereditary breast and/or ovarian cancer patients for BRCA1 and BRCA2. In addition, we describe the allelic frequencies across 210 hereditary breast and/or ovarian cancer patients of 74 unique definitely and likely pathogenic and uncertain BRCA1 and BRCA2 variants, some of which have not been previously annotated in the public databases. Targeted next-generation sequencing is ready to substitute classic molecular methods to perform genetic testing on the BRCA1 and BRCA2 genes and provides a greater opportunity for more comprehensive testing of at-risk patients. PMID- 25556972 TI - Development and application of a multimetal multibiotic ligand model for assessing aquatic toxicity of metal mixtures. AB - A multimetal, multiple binding site version of the biotic ligand model (mBLM) has been developed for predicting and explaining the bioavailability and toxicity of mixtures of metals to aquatic organisms. The mBLM was constructed by combining information from single-metal BLMs to preserve compatibility between the single metal and multiple-metal approaches. The toxicities from individual metals were predicted by assuming additivity of the individual responses. Mixture toxicity was predicted based on both dissolved metal and mBLM-normalized bioavailable metal. Comparison of the 2 prediction methods indicates that metal mixtures frequently appear to have greater toxicity than an additive estimation of individual effects on a dissolved metal basis. However, on an mBLM-normalized basis, mixtures of metals appear to be additive or less than additive. This difference results from interactions between metals and ligands in solutions including natural organic matter, processes that are accounted for in the mBLM. As part of the mBLM approach, a technique for considering variability was developed to calculate confidence bounds (called response envelopes) around the central concentration-response relationship. Predictions using the mBLM and response envelope were compared with observed toxicity for a number of invertebrate and fish species. The results show that the mBLM is a useful tool for considering bioavailability when assessing the toxicity of metal mixtures. PMID- 25556974 TI - Abstracts of the 14th Annual Congress of the French Speaking Society of Transplantation, 2-5 december, 2014, Caen, France. PMID- 25556975 TI - A strategy to enhance the efficiency of dye-sensitized solar cells by the highly efficient TiO2/ZnS photoanode. AB - In dye-sensitized solar cells (DSSCs), the TiO2 photoanode film plays an important role in increasing the power conversion efficiency. In this work, TiO2 nanoparticles were first coated on fluorine-doped tin oxide by the doctor-blade method, and then a thin film of zinc sulfide (ZnS) was successfully fabricated on the surface of the TiO2 nanoparticles using the successive ionic layer adsorption and reaction method. The performance of the DSSCs was examined in detail using a cobalt sulfide counter electrode and I(-)/I3(-) electrolyte. X-ray diffraction and energy dispersive X-ray spectroscopy measurements were used to find the composition of the films. Characterization with electrochemical impedance spectroscopy indicated that the recombination rate decreased drastically during the electron transportation. The DSSCs based on ZnS coated TiO2 photoanode achieved a power conversion efficiency of 5.90% under 1 sunlight illumination, which is higher than that of the bare TiO2 photoanode (4.43%). This suggests that the promising ZnS-coated TiO2 nanoparticles accumulate a large number of photo injected electrons in the conduction band of the photoanode and the N719 dye lowers the recombination of photo-injected electrons with the redox electrolyte. PMID- 25556973 TI - Angiotensin receptor I stimulates osteoprogenitor proliferation through TGFbeta mediated signaling. AB - Clinical studies of large human populations and pharmacological interventions in rodent models have recently suggested that anti-hypertensive drugs that target angiotensin II (Ang II) activity may also reduce loss of bone mineral density. Here, we identified in a genetic screening the Ang II type I receptor (AT1R) as a potential determinant of osteogenic differentiation and, implicitly, bone formation. Silencing of AT1R expression by RNA interference severely impaired the maturation of a multipotent mesenchymal cell line (W20-17) along the osteoblastic lineage. The same effect was also observed after the addition of the AT1R antagonist losartan but not the AT2R inhibitor PD123,319. Additional cell culture assays traced the time of greatest losartan action to the early stages of W20-17 differentiation, namely during cell proliferation. Indeed, addition of Ang II increased proliferation of differentiating W20-17 and primary mesenchymal stem cells and this stimulation was reversed by losartan treatment. Cells treated with losartan also displayed an appreciable decrease of activated (phosphorylated) Smad2/3 proteins. Moreover, Ang II treatment elevated endogenous transforming growth factor beta (TGFbeta) expression considerably and in an AT1R-dependent manner. Finally, exogenous TGFbeta was able to restore high proliferative activity to W20-17 cells that were treated with both Ang II and losartan. Collectively, these results suggest a novel mechanism of Ang II action in bone metabolism that is mediated by TGFbeta and targets proliferation of osteoblast progenitors. PMID- 25556976 TI - Efficacy and safety of aripiprazole once-monthly in Asian patients with schizophrenia: a multicenter, randomized, double-blind, non-inferiority study versus oral aripiprazole. AB - OBJECTIVE: This study was designed to evaluate efficacy and safety of aripiprazole once-monthly (AOM) by verifying non-inferiority of AOM to oral aripiprazole in Asian patients with schizophrenia. METHOD: The study consisted of a screening phase and three phases: an oral conversion phase (<=12weeks), an oral stabilization phase (<=12weeks) and a 52-week double-blind phase. Patients meeting stabilization criteria for 4weeks during the oral stabilization phase were randomly assigned (1:1) to AOM (400mg) or oral aripiprazole (6-24mg/day). The primary endpoint was Kaplan-Meier estimated rate of non-exacerbation of psychotic symptoms/non-relapse at Week 26. RESULTS: A total of 724 patients were screened, and 502 patients entered the oral stabilization phase. Of 455 patients randomized in the double-blind phase, 228 received AOM and 227 received oral aripiprazole. The non-exacerbation of psychotic symptoms/non-relapse rates at Week 26 were 95.0% (AOM) and 94.7% (oral aripiprazole) and the difference was 0.3% (95% CI: -3.9,4.5), thus non-inferiority of AOM compared to oral aripiprazole with respect to non-exacerbation of psychotic symptoms/non-relapse rate was shown with a margin of -3.9% which is well above the pre-defined non inferiority limit (-15%). The proportions of patients meeting exacerbation of psychotic symptoms/relapse criteria and stabilization of psychotic symptoms/maintenance criteria were 6.6% and 92.5% in both groups. Discontinuation rates due to all reasons were 25.9% (AOM) and 33.5% (oral aripiprazole). AOM was well tolerated as well as oral aripiprazole. CONCLUSIONS: Non-inferiority of AOM to oral aripiprazole was established. AOM is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole. CLINICAL TRIALS REGISTRATION: JapicCTI-101175. PMID- 25556977 TI - Position of Occlusal Plane in Dentate Patients with Reference to the Ala-Tragal Line Using a Custom-Made Occlusal Plane Analyzer. AB - PURPOSE: The purpose of this study was to determine which of the three positions on the tragus, (superior, middle, inferior) when joined with the ala of the nose for the ala-tragal line was most parallel to the natural occlusal plane in dentate patients. MATERIAL AND METHODS: This study was carried out on 500 individuals, selected randomly and who agreed to participate in the study. A custom-made occlusal plane analyzer was used to check the parallelism between the ala-tragal line and the occlusal plane. The tragus was divided into three parts: superior, middle, and inferior. The instrument was placed in the participant's mouth, and the posterior points on the tragus were determined. RESULTS: For the 500 dentate participants in this study, the most common location of the posterior point on the tragus was the inferior part of the tragus (50.8%). The second most common location of the tragus was the middle part (24.7%), followed by the superior location (12.1%). CONCLUSION: The results of this study indicated that the occlusal plane was found parallel to a line joining the ala of the nose and the inferior part of the tragus in a slight majority of the participants. PMID- 25556978 TI - Acute stress and working memory in older people. AB - Several studies have shown that acute stress affects working memory (WM) in young adults, but the effect in older people is understudied. As observed in other types of memory, older people may be less sensitive to acute effects of stress on WM. We performed two independent studies with healthy older men and women (from 55 to 77 years old) to investigate the effects of acute stress (Trier Social Stress Test; TSST) and cortisol on WM. In study 1 (n = 63), after the TSST women (but not men) improved their performance on Digit Span Forward (a measure of the memory span component of WM) but not on Digit Span Backward (a measure of both memory span and the executive component of WM). Furthermore, in women, cortisol levels at the moment of memory testing showed a positive association with the memory span component of WM before and after the TSST, and with the executive component of WM only before the stress task. In study 2 (n = 76), although participants showed a cortisol and salivary alpha-amylase (sAA) response to the TSST, stress did not affect performance on Letter-Number Sequencing (LNS; a task that places a high demand on the executive component of WM). Cortisol and sAA were not associated with WM. The results indicate that circulating cortisol levels at the moment of memory testing, and not the stress response, affect memory span in older women, and that stress and the increase in cortisol levels after stress do not affect the executive component of WM in older men and women. This study provides further evidence that older people may be less sensitive to stress and stress-induced cortisol response effects on memory processes. PMID- 25556979 TI - Long-term changes in the CA3 associative network of fear-conditioned mice. AB - The CA3 associative network plays a critical role in the generation of network activity patterns related to emotional state and fear memory. We investigated long-term changes in the corticosterone (CORT)-sensitive function of this network following fear conditioning and fear memory reactivation. In acute slice preparations from mice trained in either condition, the ratio of orthodromic population spike (PS) to antidromic PS was reduced compared to unconditioned animals, indicating a decrease in efficacy of neuronal coupling within the associative CA3 network. However, spontaneous sharp wave-ripples (SW-R), which are thought to arise from this network, remained unaltered. Following CORT application, we observed an increase in orthodromic PS and a normalization to control levels of their ratio to antidromic PS, while SW-R increased in slices of fear conditioned and fear reactivated mice, but not in slices of unconditioned controls. Together with our previous observations of altered hippocampal gamma activity under these learning paradigms, these data suggest that fear conditioning and fear reactivation lastingly alters the CORT-sensitive configuration of different network activity patterns generated by the CA3 associational network. Observed changes in the mRNA expression of receptors for glutamate, GABA and cannabinoids in the stratum pyramidale of area CA3 may provide a molecular mechanism for these adaptive changes. PMID- 25556981 TI - Work-related stress is associated with impaired neuropsychological test performance: a clinical cross-sectional study. AB - Patients on sick leave due to work-related stress often complain about impaired concentration and memory. However, it is undetermined how widespread these impairments are, and which cognitive domains are most long-term stress sensitive. Previous studies show inconsistent results and are difficult to synthesize. The primary aim of this study was to examine whether patients with work-related stress complaints have cognitive impairments compared to a matched control group without stress. Our secondary aim was to examine whether the level of self reported perceived stress is associated with neuropsychological test performance. We used a broad neuropsychological test battery to assess 59 outpatients with work-related stress complaints (without major depression) and 59 healthy controls. We matched the patients and controls pairwise by sex, age and educational level. Compared to controls, patients generally showed mildly reduced performance across all the measured domains of the neuropsychological test battery. However, only three comparisons reached statistical significance (p < 0.05). Effect sizes (Cohen's d) were generally small to medium. The most pronounced differences between patients and controls were seen on tests of prospective memory, speed and complex working memory. There were no statistical significant associations between self-reported perceived stress level and neuropsychological test performance. In conclusion, we recommend that cognitive functions should be considered when evaluating patients with work-related stress complaints, especially when given advice regarding return to work. Since this study had a cross-sectional design, it is still uncertain whether the impairments are permanent. Further study is required to establish causal links between work related stress and cognitive deficits. PMID- 25556980 TI - Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis. AB - Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. ADX rats received corticosterone (CORT) replacement in the drinking water (25 MUg/mL), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 MUL, 0.25 MUL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40-min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 min after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5 to 2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame. PMID- 25556982 TI - Memory Without Consolidation: Temporal Distinctiveness Explains Retroactive Interference. AB - Is consolidation needed to account for retroactive interference in free recall? Interfering mental activity during the retention interval of a memory task impairs performance, in particular if the interference occurs in temporal proximity to the encoding of the to-be-remembered (TBR) information. There are at least two rival theoretical accounts of this temporal gradient of retroactive interference. The cognitive neuroscience literature has suggested neural consolidation is a pivotal factor determining item recall. According to this account, interfering activity interrupts consolidation processes that would otherwise stabilize the memory representations of TBR items post-encoding. Temporal distinctiveness theory, by contrast, proposes that the retrievability of items depends on their isolation in psychological time. According to this theory, information processed after the encoding of TBR material will reduce the temporal distinctiveness of the TBR information. To test between these accounts, implementations of consolidation were added to the SIMPLE model of memory and learning. We report data from two experiments utilizing a two-list free recall paradigm. Modeling results imply that SIMPLE was able to model the data and did not benefit from the addition of consolidation. It is concluded that the temporal gradient of retroactive interference cannot be taken as evidence for memory consolidation. PMID- 25556983 TI - A holistic view of polyhydroxyalkanoate metabolism in Pseudomonas putida. AB - Polyhydroxyalkanoate (PHA) metabolism has been traditionally considered as a futile cycle involved in carbon and energy storage. The use of cutting-edge technologies linked to systems biology has improved our understanding of the interaction between bacterial physiology, PHA metabolism and other cell functions in model bacteria such as Pseudomonas putida KT2440. PHA granules or carbonosomes are supramolecular complexes of biopolyester and proteins that are essential for granule segregation during cell division, and for the functioning of the PHA metabolic route as a continuous cycle. The simultaneous activities of PHA synthase and depolymerase ensure the carbon flow to the transient demand for metabolic intermediates to balance the storage and use of carbon and energy. PHA cycle also determines the number and size of bacterial cells. The importance of PHAs as nutrients for members of the microbial community different to those that produce them is illustrated here via examples of bacterial predators such as Bdellovibrio bacteriovorus that prey on PHA producers and produces specific extra cellular depolymerases. PHA hydrolysis confers Bdellovibrio ecological advantages in terms of motility and predation efficiency, demonstrating the importance of PHA producers predation in population dynamics. Metabolic modulation strategies for broadening the portfolio of PHAs are summarized and their properties are compiled. PMID- 25556984 TI - Discovery of a novel isoxazoline derivative of prednisolone endowed with a robust anti-inflammatory profile and suitable for topical pulmonary administration. AB - A novel glucocorticoids series of (GCs), 6alpha,9alpha-di-Fluoro 3-substituted C 16,17-isoxazolines was designed, synthesised and their structure-activity relationship was evaluated with glucocorticoid receptor (GR) binding studies together with GR nuclear translocation cell-based assays. This strategy, coupled with in silico modelling analysis, allowed for the identification of Cpd #15, an isoxazoline showing a sub-nanomolar inhibitory potency (IC50=0.84 nM) against TNFalpha-evoked IL-8 release in primary human airways smooth muscle cells. In Raw264.7 mouse macrophages, Cpd #15 inhibited LPS-induced NO release with a potency (IC50=6 nM)>10-fold higher with respect to Dexamethasone. Upon intratracheal (i.t.) administration, Cpd #15, at 0.1 MUmol/kg significantly inhibited and at 1 MUmol/kg fully counteracted eosinophilic infiltration in a model of allergen-induced pulmonary inflammation in rats. Moreover, Cpd #15 proved to be suitable for pulmonary topical administration given its sustained lung retention (t1/2=6.5h) and high pulmonary levels (>100-fold higher than plasma levels) upon intratracheal administration in rats. In summary, Cpd #15 displays a pharmacokinetic and pharmacodynamic profile suitable for topical treatment of conditions associated with pulmonary inflammation such as asthma and COPD. PMID- 25556986 TI - Interactive effects of climate change with nutrients, mercury, and freshwater acidification on key taxa in the North Atlantic Landscape Conservation Cooperative region. AB - The North Atlantic Landscape Conservation Cooperative LCC (NA LCC) is a public private partnership that provides information to support conservation decisions that may be affected by global climate change (GCC) and other threats. The NA LCC region extends from southeast Virginia to the Canadian Maritime Provinces. Within this region, the US National Climate Assessment documented increases in air temperature, total precipitation, frequency of heavy precipitation events, and rising sea level, and predicted more drastic changes. Here, we synthesize literature on the effects of GCC interacting with selected contaminant, nutrient, and environmental processes to adversely affect natural resources within this region. Using a case study approach, we focused on 3 stressors with sufficient NA LCC region-specific information for an informed discussion. We describe GCC interactions with a contaminant (Hg) and 2 complex environmental phenomena freshwater acidification and eutrophication. We also prepared taxa case studies on GCC- and GCC-contaminant/nutrient/process effects on amphibians and freshwater mussels. Several avian species of high conservation concern have blood Hg concentrations that have been associated with reduced nesting success. Freshwater acidification has adversely affected terrestrial and aquatic ecosystems in the Adirondacks and other areas of the region that are slowly recovering due to decreased emissions of N and sulfur oxides. Eutrophication in many estuaries within the region is projected to increase from greater storm runoff and less denitrification in riparian wetlands. Estuarine hypoxia may be exacerbated by increased stratification. Elevated water temperature favors algal species that produce harmful algal blooms (HABs). In several of the region's estuaries, HABs have been associated with bird die-offs. In the NA LCC region, amphibian populations appear to be declining. Some species may be adversely affected by GCC through higher temperatures and more frequent droughts. GCC may affect freshwater mussel populations via altered stream temperatures and increased sediment loading during heavy storms. Freshwater mussels are sensitive to un-ionized ammonia that more toxic at higher temperatures. We recommend studying the interactive effects of GCC on generation and bioavailability of methylmercury and how GCC-driven shifts in bird species distributions will affect avian exposure to methylmercury. Research is needed on how decreases in acid deposition concurrent with GCC will alter the structure and function of sensitive watersheds and surface waters. Studies are needed to determine how GCC will affect HABs and avian disease, and how more severe and extensive hypoxia will affect fish and shellfish populations. Regarding amphibians, we suggest research on 1) thermal tolerance and moisture requirements of species of concern, 2) effects of multiple stressors (temperature, desiccation, contaminants, nutrients), and 3) approaches to mitigate impacts of increased temperature and seasonal drought. We recommend studies to assess which mussel species and populations are vulnerable and which are resilient to rising stream temperatures, hydrological shifts, and ionic pollutants, all of which are influenced by GCC. PMID- 25556985 TI - Single-sweep spectral analysis of contact heat evoked potentials: a novel approach to identify altered cortical processing after morphine treatment. AB - AIMS: The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (CHEPs) may be altered by morphine. However, previous studies have averaged CHEPs over multiple stimuli, which are confounded by jitter between sweeps. Thus, the aim was to assess single-sweep characteristics to identify alterations induced by morphine. METHODS: In a crossover study 15 single sweep CHEPs were analyzed from 62 electroencephalography electrodes in 26 healthy volunteers before and after administration of morphine or placebo. Each sweep was decomposed by a continuous wavelet transform to obtain normalized spectral indices in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-80 Hz) bands. The average distribution over all sweeps and channels was calculated for the four recordings for each volunteer, and the two recordings before treatments were assessed for reproducibility. Baseline corrected spectral indices after morphine and placebo treatments were compared to identify alterations induced by morphine. RESULTS: Reproducibility between baseline CHEPs was demonstrated. As compared with placebo, morphine decreased the spectral indices in the delta and theta bands by 13% (P = 0.04) and 9% (P = 0.007), while the beta and gamma bands were increased by 10% (P = 0.006) and 24% (P = 0.04). CONCLUSION: The decreases in the delta and theta band are suggested to represent a decrease in the pain specific morphology of the CHEPs, which indicates a diminished pain response after morphine administration. Hence, assessment of spectral indices in single-sweep CHEPs can be used to study cortical mechanisms induced by morphine treatment. PMID- 25556987 TI - Self-nano-emulsifying drug delivery systems: an update of the biopharmaceutical aspects. AB - INTRODUCTION: Thirty percent of top marketed drugs in the USA and 70% of all new drug candidates are lipophilic and exhibit poor water solubility. With such physicochemical properties, the oral bioavailability of these compounds lacks dose proportionality, is very limited and extremely erratic. Different lipid based formulations have been explored in the past few decades to improve the oral delivery of such compounds. In recent years, the most popular approach is their incorporation into self-emulsifying drug delivery systems (SEDDS), with particular emphasis on self-nano-emulsifying drug delivery systems (SNEDDS). AREAS COVERED: This review offers an updated overview of SNEDDS application from the biopharmaceutical point of view. The focus of this review deals with the potential of SNEDDS utilization to overcome absorption barriers following oral administration of lipophilic drugs. This includes a comprehensive description of the primary mechanisms by which lipids and lipophilic excipients, used to formulate SNEDDS, could affect drug absorption, bioavailability and disposition following oral administration. EXPERT OPINION: The utilization of SNEDDS to augment the oral bioavailability of poorly water-soluble drugs goes beyond improvement in drug's solubility, as was initially presumed. In fact, SNEDDS have a potential to increase oral bioavailability by multi-concerted mechanisms such as reduced intra-enterocyte metabolism by CYP P450 enzymes, reduced P glycoprotein (P-gp) efflux activity and hepatic first-pass metabolism bypass via lymphatic absorption. This unique biopharmaceutical point of view, presented in this review, contributes to the understanding of proper drug candidate selection and of the approach in SNEDDS formulation design. PMID- 25556989 TI - A genomic region encompassing a newly identified exon provides enhancing activity sufficient for normal myo7aa expression in zebrafish sensory hair cells. AB - MYO7A is an unconventional myosin involved in the structural organization of hair bundles at the apex of sensory hair cells (SHCs) where it serves mechanotransduction in the process of hearing and balance. Mutations of MYO7A are responsible for abnormal shaping of hair bundles, resulting in human deafness and murine deafness/circling behavior. Myo7aa, expressed in SHCs of the inner ear and lateral line of zebrafish, causes circling behavior and abnormal hair cell function when deficient in mariner mutant. This work identifies a new hair cell specific enhancer, highly conserved between species, located within Intron 2-3 of zebrafish myosin 7a (myo7aa) gene. This enhancer is contained within a 761-bp DNA fragment that encompasses a newly identified Exon of myo7aa and whose activity does not depend on orientation. Compensation of mariner mutation by expression of mCherry-Myo7aa fusion protein under the control of this 761-bp DNA fragment results in recovery of balance, normal hair bundle shape and restored hair cell function. Two smaller adjacent fragments (344-bp and 431-bp), extracted from the 761-bp fragment, both show hair cell-specific enhancing activity, with apparently reduced intensity and coverage. These data should help understand the role of Myo7aa in sensory hair cell differentiation and function. They provide tools to decipher how myo7aa gene is expressed and regulated in SHCs by allowing the identification of potential transcription factors involved in this process. The discovered enhancer could represent a new target for the identification of deafness-causing mutations affecting human MYO7A. PMID- 25556988 TI - Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors. AB - BACKGROUND: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. PROCEDURE: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60 mg/m(2) /dose), and DL2 (80 mg/m(2) /dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. RESULTS: Nine patients received 1-15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. CONCLUSIONS: The MTD of oral satraplatin in children with solid tumors was 60 mg/m(2) /dose daily *5 days every 28 days, which is lower than the adult recommended dose of 80-120 mg/m(2) /dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed. PMID- 25556991 TI - Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells. AB - Breast cancer is one of the leading cancer-related causes of death worldwide. Treatment of triple-negative breast cancer (TNBC) is complex and challenging, especially when metastasis has developed. In this study, we applied infrared radiation as an alternative approach for the treatment of TNBC. We used middle infrared (MIR) with a wavelength range of 3-5 MUm to irradiate breast cancer cells. MIR significantly inhibited cell proliferation in several breast cancer cells but did not affect the growth of normal breast epithelial cells. We performed iTRAQ-coupled LC-MS/MS analysis to investigate the MIR-triggered molecular mechanisms in breast cancer cells. A total of 1749 proteins were identified, quantified, and subjected to functional enrichment analysis. From the constructed functionally enriched network, we confirmed that MIR caused G2/M cell cycle arrest, remodeled the microtubule network to an astral pole arrangement, altered the actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability. Our results reveal the coordinative effects of MIR-regulated physiological responses in concentrated networks, demonstrating the potential implementation of infrared radiation in breast cancer therapy. PMID- 25556990 TI - Quality of life in children with CF: Psychometrics and relations with stress and mealtime behaviors. AB - BACKGROUND: The purpose of this study was to evaluate the utility of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) with toddlers and preschool-aged children. Clinically relevant relations between health-related quality of life (HRQOL), stress, and mealtime behaviors have not been examined. It was hypothesized that problematic mealtime behaviors and increased stress would be negatively associated with HRQOL. METHODS: Parents of 73 children (2-6 years) with CF completed questionnaires assessing their children's generic (PedsQL) and CF specific HRQOL, parenting and CF-specific stress, and mealtime behaviors. RESULTS: CFQ-R Physical, Eating, and Respiratory HRQOL subscales had acceptable to strong reliability (alphas = 0.73-0.86); other scales approached acceptable reliability. Lower CF-specific stress was associated with higher CFQ-R Eating HRQOL (B = -0.84; P < 0.05) scores. Fewer eating problems were associated with higher CFQ-R Eating (B = -1.17; P < 0.0001) and Weight HRQOL (B = -0.78; P < 0.01) scores. CONCLUSIONS: As hypothesized, problematic eating and higher CF specific stress was associated with lower CF-specific HRQOL. The CFQ-R has promise for use in young children with CF, but will need to be modified to exchange items not relevant to preschoolers with items that are more relevant to this age group. PMID- 25556992 TI - Insight into the mechanism of hydrogenation of amino acids to amino alcohols catalyzed by a heterogeneous MoO(x) -modified Rh catalyst. AB - Hydrogenation of amino acids to amino alcohols is a promising utilization of natural amino acids. We found that MoOx -modified Rh/SiO2 (Rh-MoOx /SiO2 ) is an efficient heterogeneous catalyst for the reaction at low temperature (323 K) and the addition of a small amount of MoOx drastically increases the activity and selectivity. Here, we report the catalytic potential of Rh-MoOx /SiO2 and the results of kinetic and spectroscopic studies to elucidate the reaction mechanism of Rh-MoOx /SiO2 catalyzed hydrogenation of amino acids to amino alcohols. Rh MoOx /SiO2 is superior to previously reported catalysts in terms of activity and substrate scope. This reaction proceeds by direct formation of an aldehyde intermediate from the carboxylic acid moiety, which is different from the reported reaction mechanism. This mechanism can be attributed to the reactive hydride species and substrate adsorption caused by MoOx modification of Rh metal, which results in high activity, selectivity, and enantioselectivity. PMID- 25556993 TI - The Pittsburgh Fatigability scale for older adults: development and validation. AB - OBJECTIVES: To describe the development of the Pittsburgh Fatigability Scale (PFS) and establish its reliability and concurrent and convergent validity against performance measures. DESIGN: Cross-sectional. SETTING: University of Pittsburgh, Pittsburgh, Pennsylvania. PARTICIPANTS: Scale development sample: 1,013 individuals aged 60 and older from two registries; validation sample: 483 adults aged 60 and older from the Baltimore Longitudinal Study of Aging (BLSA). MEASUREMENTS: The scale development sample and BLSA participants self administered an initial 26-item perceived fatigability scale. BLSA participants also completed measures of performance fatigability (perceived exertion from a standard treadmill task and performance deterioration from a fast-paced long distance corridor walk), a 6-m usual-paced corridor walk, and five timed chair stands. RESULTS: Principal components analysis with varimax rotation reduced the 26-item scale to the 10-item PFS. The PFS showed strong internal consistency (Cronbach's alpha 0.88) and excellent test-retest reliability (intraclass correlation 0.86). In the validation sample, PFS scores, adjusted for age, sex, and race, were greater for those with high performance fatigability, slow gait speed, worse physical function, and lower fitness, with differences between high and low fatigability ranging from 3.2 to 5.1 points (P < .001). CONCLUSION: The 10-item PFS physical fatigability score is a valid and reliable measure of perceived fatigability in older adults and can serve as an adjunct to performance based fatigability measures for identifying older adults at risk of mobility limitation in clinical and research settings. PMID- 25556995 TI - Revisiting the role of histo-blood group antigens in rotavirus host-cell invasion. AB - Histo-blood group antigens (HBGAs) have been proposed as rotavirus receptors. H type-1 and Lewis(b) antigens have been reported to bind VP8* from major human rotavirus genotypes P[4], P[6] and P[8], while VP8* from a rarer P[14] rotavirus recognizes A-type HBGAs. However, the role and significance of HBGA receptors in rotavirus pathogenesis remains uncertain. Here we report that P[14] rotavirus HAL1166 and the related P[9] human rotavirus K8 bind to A-type HBGAs, although neither virus engages the HBGA-specific alpha1,2-linked fucose moiety. Notably, human rotaviruses DS-1 (P[4]) and RV-3 (P[6]) also use A-type HBGAs for infection, with fucose involvement. However, human P[8] rotavirus Wa does not recognize A-type HBGAs. Furthermore, the common human rotaviruses that we have investigated do not use Lewis(b) and H type-1 antigens. Our results indicate that A-type HBGAs are receptors for human rotaviruses, although rotavirus strains vary in their ability to recognize these antigens. PMID- 25556996 TI - Endothelial, but not smooth muscle, peroxisome proliferator-activated receptor beta/delta regulates vascular permeability and anaphylaxis. AB - BACKGROUND: Remodeling of quiescent vessels with increases in permeability, vasodilatation, and edema are hallmarks of inflammatory disorders. Factors involved in this type of remodeling represent potential therapeutic targets. OBJECTIVES: We investigated whether the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) beta/delta, a regulator of metabolism, fibrosis, and skin homeostasis, is involved in regulation of this type of remodeling. METHODS: Wild-type and various Pparb/d mutant mice were used to monitor dermal acute vascular hyperpermeability (AVH) and passive systemic anaphylaxis-induced hypothermia and edema. PPARbeta/delta-dependent kinase activation and remodeling of endothelial cell-cell junctions were addressed by using human endothelial cells. RESULTS: AVH and dilatation of dermal microvessels stimulated by vascular endothelial growth factor A, histamine, and thrombin are severely compromised in PPARbeta/delta-deficient mice. Selective deletion of the Pparb/d-encoding gene in endothelial cells in vivo similarly limits dermal AVH and vasodilatation, providing evidence that endothelial PPARbeta/delta is the major player in regulating acute dermal microvessel remodeling. Furthermore, endothelial PPARbeta/delta regulatory functions are not restricted to the skin vasculature because its deletion in the endothelium, but not in smooth muscle cells, also leads to reduced systemic anaphylaxis, the most severe form of allergic reaction, in which an acute vascular response plays a key role. PPARbeta/delta-dependent AVH activation likely involves the activation of mitogen activated protein kinase and Akt pathways and leads to downstream destabilization of endothelial cell-cell junctions. CONCLUSION: These results unveil not only a novel function of PPARbeta/delta as a direct regulator of acute vessel permeability and dilatation but also provide evidence that antagonizing PPARbeta/delta represents an important strategy to consider for moderating diseases with altered endothelial integrity, such as acute inflammatory and allergic disorders. PMID- 25556997 TI - 3,3'-Diamino-N-methyldipropylamine as a versatile affinity ligand. AB - Currently, in biomedicine and biotechnology fields, there is a growing need to develop and produce biomolecules with a high degree of purity. To accomplish this goal, new purification methods are being developed looking for higher performance, efficiency, selectivity, and cost-effectiveness. Affinity chromatography is considered one of the most highly selective methods for biomolecules purification. The purpose of this work is to explore a new type of a structurally simple ligand immobilized onto an agarose matrix to be used in affinity chromatography. The ligand in this study, 3,3'-diamino-N methyldipropylamine has shown low toxicity and low cost of preparation. Moreover, the ability of the ligand to be used in affinity chromatography to purify proteins and nucleic acids was verified. An increasing sodium chloride gradient, using salt concentrations up to 500 mM, was suitable to accomplish the purification of these biomolecules, meaning that the new support allows the recovery of target biomolecules under mild conditions. Thus, the 3,3'-diamino-N methyldipropylamine ligand is shown to be a useful and versatile tool in chromatographic experiments, with very good results either for proteins or supercoiled plasmid isoform purification. PMID- 25556998 TI - A case of long term survival with skeletal only metastatic breast cancer. AB - INTRODUCTION: The prognosis of patients with metastatic breast cancer is very poor. Because of this, treatment of skeletal metastasis is often palliative with limited goals rather than cure. However, there are those patients, such as presented here, who survive for an extended time. PRESENTATION OF CASE: This thirty-six year old female presented with lytic lesions to one ulna and rib five years after mastectomy for breast cancer. Despite radiation and chemotherapy, the ulnar lesion expanded and resulted in an elbow dislocation. The rib lesion was resected and the arm amputated above the elbow. She developed local recurrence in both her above elbow amputation stump and chest wall and a more proximal below shoulder amputation was performed with resection of chest wall lesion. Even though she had locally aggressive disease, she has survived for 31 years after diagnosis without any evidence of disease. DISCUSSION: Reports of metastatic breast cancer survival indicate the five year survival to be 15%. There have been few reports indicating that those patients with skeletal only or oligometastatic disease have improved prognosis. It is not clear what biological properties of these tumors results in the improved survival. CONCLUSION: This case highlights the challenges of giving patients the optimal treatment in the light of limited ability to predict prognosis. It also highlights the need to further investigate the phenotypes of breast cancer that can, despite metastatic disease and with modern treatment go on to long survival. In addition this case demonstrates the importance of long term followup. PMID- 25556999 TI - Liver transplantation with aged donors in patients with hepatitis C virus: authors' reply. PMID- 25557000 TI - Comment on 'Anaphylaxis caused by in-season switchover of sublingual immunotherapy formulation'. PMID- 25557001 TI - Urinary sodium excretion and ambulatory blood pressure findings in patients with hypertension. AB - Use of ambulatory blood pressure (BP) monitoring (ABPM) allows for identification of dipping, nondipping, extreme dipping, and reverse dipping of BP. Using office BP and ABPM, hypertension subtypes can be identified: sustained normotension (SNT), white-coat hypertension, masked hypertension, and sustained hypertension. The comparison of hemodynamic parameters and salt intake has not been investigated among these patient groups. Office BP, ABPM, augmentation index (AIx), pulse wave velocity (PWV), cardiac output (CO), and total peripheral resistance (TPR) were automatically measured. Estimation of salt intake was assessed by 24-hour urinary sodium excretion. Urinary sodium excretion was not different among groups. AIx, PWV, CO, and TPR were lowest in patients with SNT. CO was lowest while AIx adjusted for a heart rate of 75 beats per minute, PWV, and TPR were highest in the extreme dipper group. No relationship was detected between hypertension subtypes and urinary sodium excretion. PMID- 25557002 TI - Induction of salt tolerance and up-regulation of aquaporin genes in tropical corn by rhizobacterium Pantoea agglomerans. AB - Bacteria were isolated from surface disinfected seeds of eight modern corn types and an ancestor of corn, 'teosinte' and identified using 16S rDNA sequences. From each of the modern corn types we obtained Bacillus spp. (including, Bacillus amyloliquefaciens and Bacillus subtilis); while from teosinte we obtained only Pantoea agglomerans and Agrobacterium species. Of these bacteria, only P. agglomerans could actively grow under hypersaline conditions and increase salt tolerance of tropical corn seedlings. In laboratory and greenhouse experiments where plants were watered with a 0.2 mol l(-1) NaCl solution, P. agglomerans was found to enhance the capacity of tropical corn to grow compared to uninoculated controls. The total dry biomass was significantly higher in P. agglomerans treated plants compared to controls under saline water. Gene expression analysis showed the up-regulation of the aquaporin gene family especially plasma membrane integral protein (ZmPIP) genes in P. agglomerans-treated plants. The plasma membrane integral protein type 2 (PIP2-1) gene in tropical corn seedlings was highly up-regulated by P. agglomerans treatment under salt stress conditions. Microscopic examination of P. agglomerans inoculated seedlings revealed that the bacterium colonized root meristems densely, and as roots developed, the bacterium became sparsely located in cell junctions. SIGNIFICANCE AND IMPACT OF THE STUDY: The enhancement of salt tolerance capacity in tropical corn, an important food crop, has the capacity to increase its cultivation area and yield in saline soils. The application of rhizobacteria to improve salt tolerance of tropical corn is ecofriendly and cost effective. We show that P. agglomerans isolated from teosinte (an ancestor of corn) induces salt tolerance in tropical corn and up regulation of aquaporin genes. This study shows that microbes that increase salt tolerance may be used to enhance crop growth in saline soils. PMID- 25557003 TI - Swallowing outcome after TORS for sleep apnea: short- and long-term evaluation. AB - The aim of this study was to evaluate outcomes related to swallowing function in patients who underwent transoral robotic surgery (TORS) for sleep apnea on both short- and long-term scales. 78 patients who underwent TORS for sleep apnea between 2011 and 2014 were followed up for an average period of 20 +/- 7.12 months (range 7-32 months), then swallowing outcomes determined by MD Anderson Dysphagia Inventory (MDADI) questionnaire, gastrografin fluoroscopy imaging results, nasogastric tube dependence and subjectively by recording the patients' complaints were analyzed and reported. Minimal insignificant short-term impact on swallowing function (4.58 +/- 7.03 preoperative MDADI score versus 5.18 +/- 8.32 post-operative) (p = 0.56) was registered. Mean time for start of oral feeding was 1.05 +/- 0.25 days (average, 1-3). In no case nasogastric tube feeding was required. Only five patients (6 %) showed significant aspiration on gastrografin fluoroscopy examination after 1 week; there was no significant correlation between the volume of tissue removed from both tongue base and epiglottis to the incidence of aspiration as shown by gastrografin fluoroscopy examination (p = 0.72). No long-term swallowing complaint was registered. Patients who underwent TORS tongue base reduction and supraglottoplasty for sleep apnea proved to have a reasonable short-term swallowing outcomes with no long-term sequelae. PMID- 25557004 TI - Endoscopic prelacrimal recess approach adjunct with vestibular sulcus incision: case report of a minimally invasive access to remove infratemporal fossa tumor. AB - To remove tumor located at anterolateral-inferior of infratemporal fossa (ITF) with purely transnasal approach is still a great challenge because of the over lateral angulation. The aim of this study is to present our initial experience- endoscopic prelacrimal recess approach adjunct with vestibular sulcus incision as a simple and minimally invasive approach to remove tumor in this area. Tumor in anterolateral ITF can be well explored via endoscopic prelacrimal recess approach; a simple vestibular sulcus incision provides a second access for two surgeon co-operation, so tumor can be removed conveniently with minimal invasion. It is a viable alternative to endoscopic extended medial maxillectomy approach or open approaches to this area. PMID- 25557006 TI - Comparison of the accuracy of a 3-dimensional virtual method and the conventional method for transferring the maxillary cast to a virtual articulator. AB - STATEMENT OF PROBLEM: The currently available virtual articulators fail to locate the digitized maxillary cast at the exact position in the virtual environment. Some locate the casts on a mechanical articulator with a facebow, and this position is then digitized for the virtual environment. PURPOSE: The purpose of this study was to compare the location of the maxillary cast on an articulator by using 2 different procedures: the conventional method and a virtual method. MATERIAL AND METHODS: With the conventional procedure, the kinematic axis of the participant was determined with an axiograph. The location of the maxillary cast in reference to this axis was then physically transferred to a Panadent mechanical articulator. By a virtual procedure, the same kinematic axis and the maxillary cast were transferred directly from the participant to the Panadent virtual articulator by means of reverse engineering devices. The locations obtained with both procedures were compared in a virtual environment with an optical scanner. By calculating the deviation at every point of the occlusal surface, the results obtained with this procedure were then compared with those of the conventional method. RESULTS: The mean deviation on the occlusal surface was 0.752 mm, and the standard deviation was 0.456 mm. CONCLUSIONS: The deviation between the procedures was sufficiently small to allow the methodology for orthodontic purposes. However, the accuracy of the virtual procedure should be improved so as to extend its use to other fields, such as orthognathic surgery or dental restorations, in which the clinical technique requires an articulator. PMID- 25557005 TI - Population-based cohort studies of type 2 diabetes and stomach cancer risk in Chinese men and women. AB - Although positive associations have been found for diabetes and a number of cancer sites, investigations of stomach cancer are limited and the results lack consistency. In this prospective study we investigated the relationship between type 2 diabetes mellitus (T2DM) and stomach cancer risk in mainland China. We assessed the associations among T2DM, T2DM duration, and stomach cancer risk in two prospective population-based cohorts, the Shanghai Women's Health Study and the Shanghai Men's Health Study. Included in the study were 61 480 men and 74 941 women. Stomach cancer cases were identified through annual record linkage to the Shanghai Cancer Registry, and verified through home visits and review of medical charts. After a median follow-up of 7.5 years for the Shanghai Men's Health Study and 13.2 years for the Shanghai Women's Health Study, a total of 755 incident cases of stomach cancer (376 men and 379 women) were identified through to September 2013. Overall, we did not find any evidence that T2DM was associated with an increased risk of stomach cancer either in men (multi-adjusted hazard ratio = 0.83, 95% confidence interval, 0.59-1.16) or in women (multi-adjusted hazard ratio = 0.92, 95% confidence interval, 0.68-1.25). Our findings from two large prospective population-based cohorts suggest that T2DM was not associated with stomach cancer risk. PMID- 25557007 TI - Immune cell dynamics in the CNS: Learning from the zebrafish. AB - A major question in research on immune responses in the brain is how the timing and nature of these responses influence physiology, pathogenesis or recovery from pathogenic processes. Proper understanding of the immune regulation of the human brain requires a detailed description of the function and activities of the immune cells in the brain. Zebrafish larvae allow long-term, noninvasive imaging inside the brain at high-spatiotemporal resolution using fluorescent transgenic reporters labeling specific cell populations. Together with recent additional technical advances this allows an unprecedented versatility and scope of future studies. Modeling of human physiology and pathology in zebrafish has already yielded relevant insights into cellular dynamics and function that can be translated to the human clinical situation. For instance, in vivo studies in the zebrafish have provided new insight into immune cell dynamics in granuloma formation in tuberculosis and the mechanisms involving treatment resistance. In this review, we highlight recent findings and novel tools paving the way for basic neuroimmunology research in the zebrafish. GLIA 2015;63:719-735. PMID- 25557009 TI - News & announcements: American Society for Laser Medicine & Surgery, inc. PMID- 25557008 TI - In vivo laser cartilage reshaping with carbon dioxide spray cooling in a rabbit ear model: a pilot study. AB - BACKGROUND/OBJECTIVES: Similar to conventional cryogen spray cooling, carbon dioxide (CO2) spray may be used in combination with laser cartilage reshaping (LCR) to produce cartilage shape change while minimizing cutaneous thermal injury. Recent ex vivo evaluation of LCR with CO2 cooling in a rabbit model has identified a promising initial parameter space for in vivo safety and efficacy evaluation. This pilot study aimed to evaluate shape change and cutaneous injury following LCR with CO2 cooling in 5 live rabbits. STUDY DESIGN/MATERIALS AND METHODS: The midportion of live rabbit ears were irradiated with a 1.45 um wavelength diode laser (12 J/cm(2)) with simultaneous CO2 spray cooling (85 millisecond duration, 4 alternating heating/cooling cycles per site, 5 to 6 irradiation sites per row for 3 rows per ear). Experimental and control ears (no LCR) were splinted in the flexed position for 30 days following exposure. A total of 5 ears each were allocated to the experimental and control groups. RESULTS: Shape change was observed in all irradiated ears (mean 70 +/- 3 degrees ), which was statistically different from control (mean 37 +/- 11 degrees , P = 0.009). No significant thermal cutaneous injury was observed, with preservation of the full thickness of skin, microvasculature, and adnexal structures. Confocal microscopy and histology demonstrated an intact and viable chondrocyte population surrounding irradiated sites. CONCLUSIONS: LCR with CO2 spray cooling can produce clinically significant shape change in the rabbit auricle while minimizing thermal cutaneous and cartilaginous injury and frostbite. This pilot study lends support for the potential use of CO2 spray as an adjunct to existing thermal based cartilage reshaping modalities. An in vivo systematic evaluation of optimal laser dosimetry and cooling parameters is required. PMID- 25557010 TI - Bench-top testing of suction forces generated through endoscopic ultrasound guided aspiration needles. AB - BACKGROUND: Adequate needle size and tissue acquisition techniques for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) need further elucidation. Moreover, the actual negative pressure and suction forces of FNA needles remain unknown. We evaluated the suction forces of 19-gauge, 22-gauge, and 25-gauge conventional FNA needles and side hole aspiration needles using conventional negative pressure and the slow pull technique. METHODS: Using a manometer, we determined the mean (SD) negative pressure and suction force for needle gauge, aspiration volume, and aspiration technique. We also evaluated the time to reach the maximum negative pressure. RESULTS: Suction force was comparatively higher in the 19-gauge needle when 50 ml of negative pressure was applied. Suction force using the slow pull method was very weak at 5% of pressure found with conventional methods. With the use of a 20-ml syringe, the time to reach the maximum negative pressure was 4 s in the 19-gauge needle, 11 s in the 22-gauge needle, and 80 s in the 25-gauge needle. CONCLUSIONS: Bench-top testing showed that suction force increases with a larger gauge needle and larger aspiration volume. The slow pull method produces a very weak suction force. The time to reach the maximum negative pressure was longest in the 25-gauge needle. PMID- 25557011 TI - Correction: Myoglobin-catalyzed intermolecular carbene N-H insertion with arylamine substrates. AB - Correction for 'Myoglobin-catalyzed intermolecular carbene N-H insertion with arylamine substrates' by Gopeekrishnan Sreenilayam et al., Chem. Commun., 2015, DOI: . PMID- 25557012 TI - Glutathione peroxidase 8 is transcriptionally regulated by HIFalpha and modulates growth factor signaling in HeLa cells. AB - GPx8 is a mammalian Cys-glutathione peroxidase of the endoplasmic reticulum membrane, involved in protein folding. Its regulation is mostly unknown. We addressed both the functionality of two hypoxia-response elements (HREs) within the promoter, GPx8 HRE1 and GPx8 HRE2, and the GPx8 physiological role. In HeLa cells, treatment with HIFalpha stabilizers, such as diethyl succinate (DES) or 2 2'-bipyridyl (BP), induces GPx8 expression at both mRNA and protein level. Luciferase activity of pGL3(GPx8wt), containing a fragment of the GPx8 promoter including the two HREs, is also induced by DES/BP or by overexpressing either individual HIFalpha subunit. Mutating GPx8 HRE1 within pGL3(GPx8wt) resulted in a significantly higher inhibition of luciferase activity than mutating GPx8 HRE2. Electrophoretic mobility-shift assay showed that both HREs exhibit enhanced binding to a nuclear extract from DES/BP-treated cells, with stronger binding by GPx8 HRE1. In DES-treated cells transfected with pGL3(GPx8wt) or mutants thereof, silencing of HIF2alpha, but not HIF1alpha, abolishes luciferase activity. Thus GPx8 is a novel HIF target preferentially responding to HIF2alpha binding at its two novel functional GPx8 HREs, with GPx8 HRE1 playing the major role. Fibroblast growth factor (FGF) treatment increases GPx8 mRNA expression, and reporter gene experiments indicate that induction occurs via HIF. Comparing the effects of depleting GPx8 on the downstream effectors of FGF or insulin signaling revealed that absence of GPx8 results in a 16- or 12-fold increase in phosphorylated ERK1/2 by FGF or insulin treatment, respectively. Furthermore, in GPx8-depleted cells, phosphorylation of AKT by insulin treatment increases 2.5-fold. We suggest that induction of GPx8 expression by HIF slows down proliferative signaling during hypoxia and/or growth stimulation through receptor tyrosine kinases. PMID- 25557013 TI - High thermal performance of SnO2:F thin transparent heaters with scattered metal nanodots. AB - Facile production and novel transparent heaters consisting of fluorine-doped tin oxide (SnO2:F or FTO) thin films covered with three different scattered metal nanodots (Cr-nd, NiCr-nd and Ni-nd) prepared by plasma-enhanced sputtering system and electron cyclotron resonance-metal organic chemical vapor deposition are investigated. The heaters exhibit excellent optical transmittances of over 85% and superior saturated temperatures of more than 80 degrees C when a relatively low 12 V DC is supplied. The scattered metal nanodots FTO heaters successfully improve the specific power of bare FTO heater by 21, 15, and 12% for NiCr-nd FTO, Cr-nd FTO, and Ni-nd FTO, respectively. These results reveal that the FTO transparent heaters with scattered metal nanodots are the suitable heating materials that can be applied for various functional devices. PMID- 25557014 TI - A pilot study to determine whether visually evoked hemodynamic responses are preserved in children during inhalational anesthesia. AB - BACKGROUND: Anesthetic depth is an important parameter to monitor during surgery, yet remains difficult to quantify, particularly in young children where developmental changes influence the electroencephalogram. A more fundamental physiological response to stimulation is the increase in cerebral blood flow secondary to increased metabolic demand, referred to as flow-metabolism coupling (FMC) and measurable using near-infrared spectroscopy (NIRS). Little is known about the effect of anesthesia on FMC; therefore, we studied visually evoked hemodynamic responses (VEHRs) using NIRS in children undergoing general anesthesia for minor surgical procedures. METHOD: We recruited 23 children (aged 2-5 years), undergoing surgery requiring general anesthesia. VEHRs were measured for 30 min using NIRS, including 5 min of baseline recording after anesthetic induction. Parameters recorded using NIRS included the concentrations of oxygenated (oxy), deoxygenated (deoxy), and total hemoglobin (Hb), which were separated into epochs for evoked response analysis after filtration of motion artifact and baseline drift. Goodness-of-fit statistics and classification rules were used to determine the existence of evoked responses, and a modified Gaussian equation was used to model each evoked response. RESULTS: Near-infrared spectroscopy data were recorded in 20/23 children, of whom nine showed a VEHR. No responses were seen in the baseline control data. When examining the relationship between VEHR and anesthetic agents, we noted that for 8/10 patients in whom preoperative or intraoperative fentanyl were administered and VEHRs were absent. CONCLUSION: We have shown that VEHRs can be detected using NIRS in some anesthetized children. Administration of fentanyl was associated with an absence of VEHRs. The mechanism underlying this association is unclear. PMID- 25557015 TI - Long-lasting anti-diabetic efficacy of PEGylated FGF-21 and liraglutide in treatment of type 2 diabetic mice. AB - Fibroblast growth factor-21 (FGF-21) is a new member of the FGF family and potential drug candidate for the treatment of type 2 diabetes mellitus. However, FGF-21 protein has short half-life in vivo, which severely affects its clinical application. In the present study, PEGylated FGF-21 was prepared by modifying the N-terminus of hFGF-21 with 20 kDa mPEG-ALD. The long-acting hypoglycemic effect of PEGylated FGF-21 and liraglutide was compared on type 2 diabetic db/db mice. The pharmacological efficacy of the compounds was evaluated by blood glucose levels, body weight, glycosylated hemoglobin levels, insulin levels, oral glucose tolerance test, lipid levels, and liver function parameters. We noticed that both PEGylated FGF-21 and liraglutide could significantly decrease plasma glucose in db/db mice. However, comparing to liraglutide treatments, PEGylated FGF-21 therapy resulted in more significant effect in lowering blood glucose levels and glycosylated hemoglobin levels, alleviating insulin resistance, improving lipid profile, liver function, and glucose control of the experimental mice. Our results suggest that PEGylated FGF-21 appears more beneficial anti-diabetic effect in type 2 diabetic mice than liraglutide, which holds significant promise as an ideal candidate for the treatment of type 2 diabetic patients. PMID- 25557016 TI - Maternal position and development of hypotension in patients undergoing cesarean section under combined spinal-epidural anesthesia of intrathecal hyperbaric ropivacaine. AB - BACKGROUND: Spinal anesthesia (SA) is usually associated with hypotension in pregnant women. We sought to assess the influence of various maternal positions on SA-induced hypotension MATERIAL/METHODS: The study population comprised 99 women at full-term gestation scheduled for elective cesarean section. They were randomized into 3 equal groups: the LL group, in which the patient was placed in the full left-lateral position until the start of surgery with the Whitacre needle bevel oriented laterally; the LS group, in which the patient was placed in the full left-lateral position initially and then shifted to the left-tilt supine position with the needle bevel oriented laterally; and the CS group, in which the patient was initially placed in the full left-lateral position and then shifted to the left-tilt supine position with the needle oriented in the cephalad direction. RESULTS: The incidences of hypotension in the LL, LS, and CS groups were 9.7%, 54.8%, and 56.3%, respectively. Ephedrine requirements were lower in the LL group than in the LS group (P<0.01). CONCLUSIONS: The maternal position during the induction of anesthesia played an important role in the development of hypotension during cesarean delivery. PMID- 25557017 TI - Impact of myasthenia gravis on family planning: How do women with myasthenia gravis decide and why? AB - INTRODUCTION: We analyzed the impact of myasthenia gravis (MG) on decision-making in family planning by women with the disease. METHODS: In a cross-sectional, anonymous survey, a standardized questionnaire was sent or handed out to 1,637 women with MG. RESULTS: In total, 801 questionnaires were eligible for analysis. Over fifty percent of the patients had abstained from having children due to MG. The concern mentioned most often was the possible influence of MG medication on the unborn child (87.1%). Spouses/partners (91.8%) and MG treating physicians (82.9%) were the most important persons involved in the decision-making process. Higher age and personal experience of intensive-care treatment for MG were independently associated with the decision to abstain from having children. Lower level of knowledge was independently associated with the probability of discouraging other MG patients from having children. CONCLUSIONS: Women with MG need specific guidance about family planning issues, which may lead to lower rates of voluntary childlessness. On the basis of our data, more specific hypotheses can be generated that require prospective investigation. PMID- 25557018 TI - Pseudofolliculitis barbae in women: a clinical perspective. PMID- 25557019 TI - Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria. AB - 3-hydroxy-3-methylglutaric aciduria (HMGA; OMIM 246450) is a rare autosomal recessive disorder, caused by the deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (4.1.3.4), which results in the accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Recent in vivo and in vitro animal studies have demonstrated that the accumulation of these metabolites can disturb the cellular redox homeostasis, which can contribute to the neurological manifestations presented by the patients. So, in the present work, we investigated oxidative stress parameters in plasma and urine samples from HMGA patients, obtained at the moment of diagnosis of this disorder and during therapy with low-protein diet and L-carnitine supplementation. It was verified that untreated HMGA patients presented higher levels of urinary di-tyrosine and plasma thiobarbituric acid reactive substances (TBA-RS), which are markers of protein and lipid oxidative damage, respectively, as well as a reduction of the urinary antioxidant capacity. Treated HMGA patients also presented an increased protein oxidative damage, as demonstrated by their higher concentrations of plasma protein carbonyl groups and urinary di-tyrosine, as well as by the reduction of total sulfhydryl groups in plasma, in relation to controls. On the other hand, HMGA patients under therapy presented normal levels of TBA-RS and urinary antioxidant capacity, which can be related, at least in part, to the antioxidant and antiperoxidative effects exerted by L-carnitine. The results of this work are the first report showing that a redox imbalance occurs in patients with HMGA what reinforces the importance of the antioxidant therapy in this disorder. PMID- 25557020 TI - Synthesis and characterization of water-soluble polythiophene derivatives for cell imaging. AB - In this work, four water-soluble polythiophene derivatives (PT, PT-DDA, PT-ADA, and PT-ADA-PPR) with different pendant moieties were synthesized via oxidative copolymerization by FeCl3. By increasing the hydrophobic ability of side chain moieties, there is a gradually blue shift for the maximum absorption wavelength and red shift for the maximum emission wavelength, a reducing trend for fluorescence quantum yields, a growing trend for Stokes shift, and an increasing trend for the mean sizes in the order of PT, PT-ADA, and PT-DDA. All the synthesized polymers show low toxicity and good photostability and accumulate in the lysosomes of A549 cells. Furthermore, the introduction of porphyrin group to PT-ADA side chain (PT-ADA-PPR) broadens the absorption and emission ranges of PT ADA. PT-ADA-PPR could be excited at two different excitation wavelengths (488 nm and 559 nm) and exhibits two emission pathways, and dual-color fluorescence images (orange and red) of PT-ADA-PPR accumulated in A549 cells are observed. Thus, PT-ADA-PPR could be used as an excellent dual-color fluorescent and lysosome-specific imaging material. PMID- 25557021 TI - Multiple origins and chromosomal novelty in the allotetraploid Tragopogon castellanus (Asteraceae). AB - Tragopogon includes two classic examples of recently formed allopolyploid species in North America: T. mirus and T. miscellus. Older Tragopogon allotetraploids from Eurasia offer ideal taxa for comparing the longer term outcomes of allopolyploidy. To help resolve the ancestry of one of these older polyploids, phylogenetic analyses of multiple populations of the allotetraploid T. castellanus (2n = 24) and its putative diploid parents, T. crocifolius and T. lamottei, were conducted using sequences from nuclear (internal transcribed spacer, ITS; and alcohol dehydrogenase 1A, Adh) and plastid (trnT-trnL spacer, trnL intron, trnL-trnF spacer and rpl16 intron) loci. Fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) were used to investigate the chromosomal constitution of T. castellanus. Our data confirm that the widely distributed T. crocifolius and the Iberian endemic, T. lamottei, are the diploid parents of T. castellanus, and that this polyploid formed at least three times. One group of populations of T. castellanus is distinct in exhibiting two pairs of rearranged chromosomes. These data suggest that some of the chromosomal variants that originate in young polyploids (here, an intergenomic translocation) may become fixed in populations, contributing to novelty in older polyploid lineages. The geographical distributions of the allopolyploids and parents are also complex, with allotetraploid populations being disjunct from one or both of the most closely related diploid parental populations. PMID- 25557023 TI - Seasonal variability in the biophysical properties of forehead skin in women in Guangzhou City, China. AB - BACKGROUND: Skin appearance is influenced by biophysical parameters. Seasonal changes affect the condition of normal skin and may trigger cutaneous disorders. OBJECTIVES: This study was undertaken to measure the effects of seasonal changes on biophysical parameters in the skin of female subjects living in Guangzhou City in southern China. METHODS: A cross-sectional study was conducted in 178 healthy, adult Chinese women in whom forehead skin was examined in all four seasons between March 2007 and February 2008. Commercially available, non-invasive devices were used to measure skin hydration, sebum content, pH, and transepidermal water loss (TEWL) in a closed environment under controlled and constant conditions of temperature and humidity. Correlations between skin parameters and climate conditions were investigated. RESULTS: There were significant seasonal changes in TEWL and pH (autumn and winter > spring and summer), skin hydration (spring and summer > autumn and winter), and sebum content (spring and summer > autumn and winter). Skin hydration was correlated with average temperature and humidity. Skin TEWL and skin pH were correlated with average temperature, humidity, and ultraviolet (UV) radiation levels. Skin sebum content was correlated with average humidity. CONCLUSIONS: Facial skin physiology showed seasonal variations in China. The reasons for the changes may refer to seasonal changes in temperature, humidity, and UV radiation. PMID- 25557022 TI - Substantially elevating the levels of alphaB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation. AB - There has been great interest in enhancing endogenous protein maintenance pathways such as the heat-shock chaperone response, as it is postulated that enhancing clearance of misfolded proteins could have beneficial disease modifying effects in amyotrophic lateral sclerosis and other neurodegenerative disorders. In cultured cell models of mutant SOD1 aggregation, co-expression of alphaB crystallin (alphaB-crys) has been shown to inhibit the formation of detergent insoluble forms of mutant protein. Here, we describe the generation of a new line of transgenic mice that express alphaB-crys at > 6-fold the normal level in spinal cord, with robust increases in immunoreactivity throughout the spinal cord grey matter and, specifically, in spinal motor neurons. Surprisingly, spinal cords of mice expressing alphaB-crys alone contained 20% more motor neurons per section than littermate controls. Raising alphaB-crys by these levels in mice transgenic for either G93A or L126Z mutant SOD1 had no effect on the age at which paralysis developed. In the G93A mice, which showed the most robust degree of motor neuron loss, the number of these cells declined by the same proportion as in mice expressing the mutant SOD1 alone. In paralyzed bigenic mice, the levels of detergent-insoluble, misfolded, mutant SOD1 were similar to those of mice expressing mutant SOD1 alone. These findings indicate that raising the levels of alphaB-crys in spinal motor neurons by 6-fold does not produce the therapeutic effects predicted by cell culture models of mutant SOD1 aggregation. Enhancing the protein chaperone function may present a therapeutic approach to amyotrophic lateral sclerosis caused by mutations in SOD1, and other neurodegenerative disorders characterized by cytosolic protein aggregation. Previous studies in cell models suggested that the chaperone known as alphaB-crystallin (alphaB-crys) can prevent mutant SOD1 aggregation. We report that transgenic expression of alphaB-crys at > 6-fold the normal level in spinal cords of mice expressing mutant SOD1 produces no therapeutic benefit. PMID- 25557025 TI - Efficiently screening heart failure in patients with type 2 diabetes. AB - AIMS: Our aim was to develop a screening tool for heart failure in patients with type 2 diabetes. METHODS AND RESULTS: A total of 581 consecutive patients from 21 primary care practices in The Netherlands with type 2 diabetes, in whom the diagnosis of heart failure (HF) was not known, underwent an extensive diagnostic assessment, including medical history taking, physical examination, ECG, and echocardiography. The presence or absence of HF was established by a panel of two cardiologists and one general practitioner following the guidelines on HF of the European Society of Cardiology. In 161 patients, HF was considered present. A model based on the medical history and symptoms had a good discriminative value for detecting or excluding HF [C-statistic after bootstrapping 0.80; 95% confidence interval (CI) 0.76-0.83]. Adding signs improved the C-statistic to 0.82 (95% CI 0.79-0.86). A diagnostic screening score based on the clinical model had good discriminative properties applying a cut-off of 3 points (24.7% risk of HF) with sensitivity 70.8%, specificity 79.0%, negative predictive value 87.6%, and positive predictive value 56.4%. ECG and natriuretic peptides both had independent added value beyond the clinical model and increased the C-statistic to 0.86 (95% CI 0.83- 0.89). With a 20% threshold, the net reclassification of adding ECG and NT-proBNP to the clinical model was only 0.06. CONCLUSIONS: A decision aid based on items from the clinical assessment is useful for screening HF in older patients with type 2 diabetes and to pre-select for echocardiography. TRIAL REGISTRATION: NL2271704108. PMID- 25557024 TI - Disorders without borders: current and future directions in the meta-structure of mental disorders. AB - PURPOSE: Classification is the cornerstone of clinical diagnostic practice and research. However, the extant psychiatric classification systems are not well supported by research evidence. In particular, extensive comorbidity among putatively distinct disorders flags an urgent need for fundamental changes in how we conceptualize psychopathology. Over the past decade, research has coalesced on an empirically based model that suggests many common mental disorders are structured according to two correlated latent dimensions: internalizing and externalizing. METHODS: We review and discuss the development of a dimensional spectrum model which organizes mental disorders in an empirically based manner. We also touch upon changes in the DSM-5 and put forward recommendations for future research endeavors. RESULTS: Our review highlights substantial empirical support for the empirically based internalizing-externalizing model of psychopathology, which provides a parsimonious means of addressing comorbidity. CONCLUSIONS: As future research goals, we suggest that the field would benefit from: expanding the meta-structure of psychopathology to include additional disorders, development of empirically based thresholds, inclusion of a developmental perspective, and intertwining genomic and neuroscience dimensions with the empirical structure of psychopathology. PMID- 25557026 TI - Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism. AB - BACKGROUND/OBJECTIVES: Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecular cause. We aimed to document the molecular basis of growth retardation in a Moroccan cohort. DESIGN/PATIENTS: 80 index cases [54 with isolated growth hormone deficiency (IGHD), 26 with combined pituitary hormone deficiency (CPHD)] were screened for molecular defects in GH1 (including LCR-GH1), GHRHR, GHSR, GHRH, PROP1, POU1F1, HESX1, LHX3, LHX4 and SOX3. RESULTS: Five different deleterious mutations were identified in 14 patients from eight families. In the IGHD group, three genes were found to be involved: GH1, GHRHR and GHSR. In the CPHD group, PROP1 was the only mutated gene. In addition, two heterozygous variations whose deleterious effect remains to be demonstrated were identified (in GH1 and LHX4), and two polymorphisms (missense variations) were detected (in LHX3 and in GHSR). The prevalence of mutations in this Moroccan GHD cohort was 10% (8/80), 11.1% (6/54) in the IGHD group and 7.7% (2/26) in the CPHD group. CONCLUSION: This is the first molecular screening of congenital GHD in a Moroccan population and, like other studies, mutations were preferentially identified in familial cases (75%); mutations in genes such as POU1F1, HESX1, SOX3, LHX3 and LHX4 are extremely rare. The p.R73C PROP1 mutation was the most frequent mutation in CPHD; this should be the first one to screen in this population. Our results should contribute to a better diagnosis and management of this heterogeneous disease condition. PMID- 25557027 TI - Control of charging energy in chemically assembled nanoparticle single-electron transistors. AB - We show the control of a charging energy in chemically assembled nanoparticle single-electron transistors (SETs) by altering the core diameter of Au nanoparticles. The charging energy is a fundamental parameter that decides the operating temperature of SETs. Practical application of SETs requires us to regulate the value of the charging energy by tuning the diameter of quantum dots. In this study, we used 3.0, 5.0 and 6.2 nm diameter synthesized Au nanoparticles as a quantum dot in the SETs. The total capacitances and charging energy of the SETs were evaluated from the rhombic Coulomb diamonds attributed to a single Coulomb island. The capacitance and charging energy matched with a concentric sphere model much better than with a simple sphere model. The operating temperatures of the SETs suggested that a charging energy 2.2 times greater than the thermal energy was required for stable operation, in theory. These results will help us to select an appropriate core diameter for the Au nanoparticles in practical SETs. PMID- 25557028 TI - Biological evaluation and molecular docking of baicalin and scutellarin as Helicobacter pylori urease inhibitors. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Baicalin and scutellarin are the principal bioactive components of Scutellaria baicalensis Georgi which has extensively been incorporated into heat-clearing and detoxification formulas for the treatment of Helicobacter pylori-related gastrointestinal disorders in traditional Chinese medicine. However, the mechanism of action remained to be defined. AIM OF THE STUDY: To explore the inhibitory effect, kinetics and mechanism of Helicobacter pylori urease (the vital pathogenetic factor for Helicobacter pylori infection) inhibition by baicalin and scutellarin, for their therapeutic potential. MATERIALS AND METHODS: The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of baicalin and scutellarin was characterized with IC50 values, compared to acetohydroxamic acid (AHA), a well known Helicobacter pylori urease inhibitor. Lineweaver-Burk and Dixon plots for the Helicobacter pylori urease inhibition of baicalin and scutellarin was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni(2+) binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode. Moreover, cytotoxicity experiment using Gastric Epithelial Cells (GES-1) was evaluated. RESULTS: Baicalin and scutellarin effectively suppressed Helicobacter pylori urease in dose-dependent and time-independent manner with IC50 of 0.82+/-0.07 mM and 0.47+/-0.04 mM, respectively, compared to AHA (IC50=0.14+/-0.05 mM). Structure-activity relationship disclosed 4'-hydroxyl gave flavones an advantage to binding with Helicobacter pylori urease. Kinetic analysis revealed that the types of inhibition were non-competitive and reversible with inhibition constant Ki of 0.14+/-0.01 mM and 0.18+/-0.02 mM for baicalin and scutellarin, respectively. The mechanism of urease inhibition was considered to be blockage of the SH groups of Helicobacter pylori urease, since thiol reagents (L,D-dithiothreitol, L-cysteine and glutathione) abolished the inhibitory action and competitive active site Ni(2+) binding inhibitors (boric acid and sodium fluoride) carried invalid effect. Molecular docking study further supported the structure-activity analysis and indicated that baicalin and scutellarin interacted with the key residues Cys321 located on the mobile flap through S-H.pi interaction, but did not interact with active site Ni(2+). Moreover, Baicalin (at 0.59-1.05 mM concentrations) and scutellarin (at 0.23-0.71 mM concentrations) did not exhibit significant cytotoxicity to GES-1. CONCLUSIONS: Baicalin and scutellarin were non-competitive inhibitors targeting sulfhydryl groups especially Cys321 around the active site of Helicobacter pylori urease, representing potential to be good candidate for future research as urease inhibitor for treatment of Helicobacter pylori infection. Furthermore, our work gave additional scientific support to the use of Scutellaria baicalensis in traditional Chinese medicine (TCM) to treat gastrointestinal disorders. PMID- 25557029 TI - In vitro evaluation of dual agonists for PPARgamma/beta from the flower of Edgeworthia gardneri (wall.) Meisn. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Tibet, the flower of Edgeworthia gardneri (Wall.) Meisn., locally named "Lvluohua, [symbols: see text]", has been traditionally used to treat diabetes mellitus for many years. AIM OF THIS STUDY: To evaluate the activity of dual agonists for PPARgamma/beta from the flower of E.gardneri in vitro. MATERIALS AND METHODS: HeLa cells were transiently co transfected with the re-constructed plasmids of pBIND-PPARgamma-LBD or pBIND PPARbeta-LBD and rL4.35. The activities of crude extracts, secondary fractions and compounds from the flower of E.gardneri were evaluated with the transfected cells. Rosiglitazone (at 0.5 MUg/mL) and L-165041 (at 0.5 MUg/mL) were used as the positive controls for PPARgamma and PPARbeta respectively. RESULTS: The results demonstrated that n-hexane, ethyl acetate and n-butanol extracts from the flower of E.gardneri were able to significantly activate PPARgamma and PPARbeta respectively, and the activity of ethyl acetate extract was much better. We further observed that, among the 11 secondary fractions of ethyl acetate extract, the fr. 9 could activate PPARgamma and PPARbeta significantly. Moreover, umbelliferone (from fr.9) and pentadecanoic acid could activate PPARgamma and PPARbeta at the same time. CONCLUSIONS: The extracts from the flower of E.gardneri could significantly activate PPARgamma and PPARbeta. Besides, umbelliferone and pentadecanoic acid isolated from the flower of E.gardneri were the new agonists for PPARgamma and PPARbeta. PMID- 25557030 TI - A protective mechanism of licorice (Glycyrrhiza uralensis): isoliquiritigenin stimulates detoxification system via Nrf2 activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhizae radix), the root of Glycyrrhiza uralensis Fisch. (Leguminosae), is mainly used to moderate the characteristics of toxic herbs in Traditional Chinese Medicine, which could be partly interpreted as detoxification. However, the underlying mechanism is still not fully elucidated. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the protection against toxic xenobiotics. In our previous research, we have identified that extracts from Glycyrrhiza uralensis induced the expression of Nrf2 nuclear protein and its downstream genes. This research aims to screen the most potent Nrf2 inducer isolated from Glycyrrhiza uralensis and examine its effect on Nrf2 signaling pathway and detoxification system. MATERIALS AND METHODS: Four compounds derived from Glycyrrhiza uralensis (glycyrrhetinic acid, liquiritigenin, isoliquiritigenin and liquiritin) were screened by ARE luciferase reporter. The most potent ARE-luciferase inducer was chosen to further examine its effect on Nrf2 and detoxification genes in HepG2 cells. The role of Nrf2-dependent mechanism was tested by using Nrf2 knockout mice (Nrf2 KO) and Nrf2 wild-type mice (Nrf2 WT). RESULTS: ARE-luciferase reporter assay showed these four compounds were all potent Nrf2 inducers, and isoliquiritigenin was the most potent inducer. Isoliquiritigenin significantly up-regulated the expression of Nrf2 and its downstream detoxification genes UDP-glucuronosyltransferase 1A1 (UGT1A1), glutamate cysteine ligase (GCL), multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) in vitro and in vivo. Additionally, isoliquiritigenin showed Nrf2-dependent transactivation of UGT1A1, GCLC and MRP2. CONCLUSIONS: Isoliquiritigenin, isolated from Glycyrrhiza uralensis, stimulates detoxification system via Nrf2 activation, which could be a potential protective mechanism of licorice. PMID- 25557031 TI - In vivo evaluation of the antitussive, expectorant and bronchodilating effects of extract and fractions from aerial parts of Peganum harmala linn. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Peganum harmala Linn (APP) is used as traditional medical herb in Uighur medicine in China, and it is traditionally used for treatment of cough and asthma.The aim of the present study is to evaluate the antitussive, expectorant and bronchodilating effects of extract and fractions (alkaloids and flavonoids) from APP, and to support its folk use with scientific evidence, and lay a foundation for its further researches. MATERIALS AND METHODS: APP was extracted with 50% ethanol by reflux, extracts were concentrated in vacuum to afford total extract of APP (EXT). EXT was separated to provide alkaloid fraction (ALK) and flavonoid fraction (FLA) by macroporous resin. Antitussive evaluations were carried out with cough models in mice and guinea pigs induced by ammonia liquor, capsaicin, and citric acid. Phenol red secretion experiments in mice were performed to evaluate the expectorant activity. Bronchodilating activities were evaluated with a bronchoconstrictive challenge induced by acetylcholine chloride and histamine in guinea pigs. RESULTS: In all the three antitussive tests, the EXT and ALK could significantly inhibit the frequency of cough, and prolong the cough latent period in animals. High dose of EXT (1650 mg/kg) and ALK (90 mg/kg) in mice and in guinea pigs created therapeutic activities as good as that of codeine phosphate (30 mg/kg). EXT could significantly increase phenol red secretion in mice for 0.64, 1.08 and 1.29 fold averagely at dosages of 183, 550, and 1650 mg/kg, ALK for 0.63, 0.96, 1.06 fold averagely at dosages of 10, 30, and 90 mg/kg, and ammonium chloride (1500 mg/kg, standard expectorant drug) for 0.97 fold, comparing with control group. Aminophylline could dramatically prolong the preconvulsive time for 162.28% in guinea pigs, EXT for 67.34%, 101.96% and 138.00% at dosages of 183, 550, and 1650 mg/kg, ALK for 55.47%, 97.74% and 126.77% at dosages of 10, 30, and 90 mg/kg, and FLA for 84.69%, 95.94% and 154.52% at dosages of 10, 30, and 90 mg/kg, comparing with pretreatment. CONCLUSIONS: APP is an effective traditional folk medicine for the treatment of cough with potent antitussive, expectorant and bronchodilating activities. The alkaloid fraction is proved to be the most effective components of APP. The alkaloids from APP may be valuable lead compounds for drug development of respiratory diseases. PMID- 25557032 TI - Active components alignment of Gegenqinlian decoction protects ulcerative colitis by attenuating inflammatory and oxidative stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gegenqinlian Decoction (GQD) has been used as a folk remedy for gastrointestinal diseases in China over thousands of years. It has significant treatment efficacy for patients with inflammatory bowel disease (IBD). We analyzed and showed that the active components alignment of Gegenqinlian Decoction (ACAG) possesses broad pharmacological effects including analgesic, antipyretic, anti-inflammatory, antibacterial, antiviral and antidiarrhea, as well as the effect of adjusting gastrointestinal function in our preliminary experiments. However, the exact molecular mechanisms on how ACAG exerts these pharmacological effects still remain elusive. In the present study, the plausible pharmacological effects of ACAG on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were investigated. MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats with TNBS/ethanol-induced colitis were used. The colonic wet weight, macroscopic and histological colon injury, superoxide dismutase (SOD), malonyldialdehyde (MDA), and inducible nitric oxide synthase (iNOS) activity were observed. Pro-inflammation cytokines were determined by ELISA methods, semi-quantitative RT-PCR and Immuno-histochemistry. RESULTS: We showed administration of ACAG was able to improve colitis. This was manifested by a decreased in the score of macroscopic and histological colonic injury, by lowered colonic wet weight, accompanied by significant increased of SOD activity, and decreased of MDA and iNOS activities. The treatment also significantly reduced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in colon and serum as well as the colonic mRNA levels for several inflammatory cytokines such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX 2), macrophage inflammatory protein-2 (MIP-2), intercellular adhesion molecule-1 (ICAM-1) and toll-like receptor 2, 4 (TLR2, TLR4). In addition, we also showed that ACAG was able to inhibit the activation and translocation of transcription factors, nuclear factor kappaBp65 (NF-kappaBp65) in colon. CONCLUSIONS: Our results suggest that ACAG exhibits protective effect in TNBS-induced ulcerative colitis. We postulate that this might be due to its modulation of oxidant/anti oxidant balance, downregulation of productions, expressions of pro-inflammatory cytokines and inhibition of NF-kappaBp65 signal transduction pathways. PMID- 25557033 TI - Manufacturing risk: reframing the discourse of safety of commodified potent substances. AB - ETHNOPHARMALOGICAL RELEVANCE: The rapid commodification of plant-based medicines has led to the development of regulatory guidelines and standards by the World Health Organization to ensure the safety of these products. However, these standards have been identified to be selectively implemented, if implemented at all, in many contexts. A primary concern for proving the safety of intrinsic factors of plant-based medicines, may result in less attention paid to the often more problematic extrinsic factors of mass production. This article critically examines the normative global discourse of safety concerning plant-based medicines and problematises many of the assumptions identified in this discourse. MATERIALS AND METHODS: This qualitative research was conducted in the Traditional Medicine Unit of the Western Pacific Regional Office of the World Health Organization (WHO) and in field work in the rural Philippines. Data was collected through archival research, analysis of WHO data sets, semi-structured and structured interviews and surveys, participant observation concerning local plant based medicine use in the Philippines and participant observation in WHO meetings regarding future strategies for traditional Asian medicines. RESULTS: Although informants reported concerns of safety for every aspect of the production, marketing and sales of plant-based medicines, this research has identified that the implementation (WHO guidelines) has been uneven and inconsistent over the past ten years in the Western Pacific Region of the WHO. Differences in local contexts that are not consistent with global guidelines and standards were reported by informants. Issues have also been identified in the inconsistent regulation of plant-based medicines as pharmaceuticals within only certain, rather than all, processes of production. CONCLUSIONS: It is imperative to understand plant-based medicines as the potent substances they are, whose rapid global commodification may affect both their potency and safety. The WHO discourse of the need for safety in the use of plant-based medicines has justified the need for biomedical oversight through processes of commodification. Yet, it is often through these very processes of commodification and mass production that safety may be compromised. This research suggests that the discourse concerning the safety of the plant-based medicines needs to be reframed from a primary focus on the intrinsic factors of plant-based medicines to a greater focus on the extrinsic factors of global commodification. PMID- 25557034 TI - An UHPLC-MS/MS method for simultaneous quantification of gallic acid and protocatechuic acid in rat plasma after oral administration of Polygonum capitatum extract and its application to pharmacokinetics. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum capitatum Buch.-Ham. ex D. Don has been traditionally used by Hmong for the treatments of urinary tract infections and pyelonephritis. Gallic acid (GA) and protocatechuic acid (PCA) are regarded as two of the main bioactive compounds in the herb. MATERIALS AND METHODS: A rapid, selective and sensitive UHPLC-ESI-MS/MS method was established and validated for the quantification of GA and PCA in rat plasma after oral administration of P. capitatum extract. Concentrations of GA and PCA were determined at different time points after dosing 20 mg/kg (equivalent to 4 mg/kg of GA and 0.3 mg/kg of PCA), 60 mg/kg and 120 mg/kg of P. capitatum extract. The main pharmacokinetic parameters of GA and PCA were obtained based on the analysis of the plasma sample by non-compartmental analysis. RESULTS: After oral administration of P. capitatum extract, GA and PCA were quickly absorbed and showed a dose-dependent profile. Pharmacokinetic parameters for GA and PCA following oral administration of the extract were respectively: Cmax 246.24-806.27 and 15.73-30.72 ng/mL; Tmax 40-100 and 20-40 min. In the rats treated with P. capitatum t1/2 and Tmax of GA were prolonged by comparing with that of its pure form. CONCLUSION: Other compounds in P. capitatum extract may be metabolized to GA, which affected the pharmacokinetic profiles of GA. This pharmacokinetic study seems to be useful for a further clinical study of P. capitatum extract. PMID- 25557035 TI - Ethnomedicinal knowledge among Karens of Andaman & Nicobar Islands, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study documents the use of medicinal plants by Karens of Middle Andaman, of the Andaman and Nicobar Islands. In spite of the availability of modern medicines, Karens preferred herbal remedies provided by the Traditional Knowledge Practitioners (TKPs), who served as their healers. Hence, the aim of this study was to collect information from TKPs and determine the significance of plants utilized for medicinal purposes. The informant consensus factor (ICF) in relation to medicinal plants used was also estimated and analysed. MATERIALS AND METHODS: Field research was conducted in three villages of Middle Andaman, inhabited by Karens, during October 2010 - February 2013. TKPs were interviewed with a questionnaire-guided ethno-medical survey protocol. The data obtained were analysed using the informant consensus factor (ICF) and use value (UV). Voucher specimens of all the cited plants were deposited at Regional Medical Research Centre (ICMR), Port Blair. RESULTS: Use of 78 medicinal plant species belonging to 71 genera encompassing 48 families was recorded during the survey. These plants were used to treat 38 different ailments, and divided into ten categories of use. The highest ICF value (0.79) was observed for infections and infestations. The Zingiberaceae and Fabaceae families exhibited the highest number of species, and the plants with the highest use values were Typha angustifolia L., Millingtonia hortensis L. f. and Piper betle L. The most common growth form observed were herbs (42%). Among the several plant parts used, leaves were mostly preferred for preparation of medicines. Water was the main excipient used for mixing the herbs. CONCLUSIONS: This study documents the use of medicinal plants by Karens of the Andaman and Nicobar Islands. Phytochemical and pharmacological aspects of these plants need to be studied, to confirm their efficacy and safety, and determine their potential use in modern medicine. PMID- 25557036 TI - Hepatotoxic assessment of Polygoni Multiflori Radix extract and toxicokinetic study of stilbene glucoside and anthraquinones in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygoni Multiflori Radix (PMR) has been traditionally used as a tonic and an anti-aging remedy for centuries; however, hepatic lesions linked to PMR have been frequently reported. AIM OF THE STUDY: This work attempted to investigate the hepatotoxic potential of PMR extract and the toxicokinetics of stilbene glucoside and anthraquinones in PMR extract following repeated administration. MATERIALS AND METHODS: Histopathological and biochemical tests were performed to assess the hepatotoxicity of PMR extract. A rapid and sensitive liquid chromatography-mass spectrometry (LC-MS) assay was developed for toxicokinetic analysis of the main constituents of PMR extract, including 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), emodin-8-O beta-D-glucoside and emodin. RESULTS: The histopathological and biochemical tests indicated that repeated administration of high-dose PMR extract (20 g/kg) for 3 weeks could cause hepatic lesions, while the low-dose treatment (1 g/kg) was safe. Necrosis and steatosis of hepatic cells, inflammatory cell infiltration and mild fibrosis were the main toxicity symptoms caused by high-dose PMR extract in rat liver. The aspartate aminotransferase (AST) levels increased by approximately 17%, from 110.80+/-0.84 to 129.75+/-10.83 IU/L, in the high-dose group compared with the control group. The proposed LC-MS method was proven to be suitable for the simultaneous quantification of these three constituents by affording desirable linearity (r(2)>0.998) and satisfactory precision (error less than 10%). The toxicokinetic study showed that emodin could not be detected in the low dose group, but the AUC and Cmax of emodin displayed a gradual increase with repeated treatments in the high-dose group. The toxicokinetics of TSG in the low- and high-dose groups exhibited similar trends after repeated administration. CONCLUSIONS: Consideration needs to be given to the rational application of PMR in the clinic to balance its benefits and risks. The increased emodin exposure in vivo provided a putative explanation for the observed hepatic lesions induced by PMR extract, although further studies to confirm the potentially causal link between emodin exposure and hepatic lesions are still necessary. PMID- 25557038 TI - Flow-Through Stream Modeling with MODFLOW and MT3D: Certainties and Limitations. AB - This paper aims to assess MODFLOW and MT3D capabilities for simulating the spread of contaminants from a river exhibiting an unusual relationship with an alluvial aquifer, with the groundwater head higher than the river head on one side and lower on the other (flow-through stream). A series of simulation tests is conducted using a simple hypothetical model so as to characterize and quantify these limitations. Simulation results show that the expected contaminant spread could be achieved with a specific configuration composed of two sets of parameters: (1) modeled object parameters (hydraulic groundwater gradient, hydraulic conductivity values of aquifer and streambed), and (2) modeling parameters (vertical discretization of aquifer, horizontal refinement of stream modeled with River [RIV] package). The influence of these various parameters on simulation results is investigated, and potential complications and errors are identified. Contaminant spread from stream to aquifer is not always reproduced by MT3D due to the RIV package's inability to simulate lateral exchange fluxes between stream and aquifer. This paper identifies the need for a MODFLOW streamflow package allowing lateral stream-aquifer interactions and streamflow routine calculations. Such developments could be of particular interest for modeling contaminated flow-through streams. PMID- 25557037 TI - Exploration of molecular pathways mediating electric field-directed Schwann cell migration by RNA-seq. AB - In peripheral nervous systems, Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. Following spinal cord injury, Schwann cells regenerate and migrate to the lesion and are involved in the spinal cord regeneration process. Transplantation of Schwann cells into injured neural tissue results in enhanced spinal axonal regeneration. Effective directional migration of Schwann cells is critical in the neural regeneration process. In this study, we report that Schwann cells migrate anodally in an applied electric field (EF). The directedness and displacement of anodal migration increased significantly when the strength of the EF increased from 50 mV/mm to 200 mV/mm. The EF did not significantly affect the cell migration speed. To explore the genes and signaling pathways that regulate cell migration in EFs, we performed a comparative analysis of differential gene expression between cells stimulated with an EF (100 mV/mm) and those without using next-generation RNA sequencing, verified by RT-qPCR. Based on the cut-off criteria (FC > 1.2, q < 0.05), we identified 1,045 up regulated and 1,636 down-regulated genes in control cells versus EF-stimulated cells. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found that compared to the control group, 21 pathways are down-regulated, while 10 pathways are up-regulated. Differentially expressed genes participate in multiple cellular signaling pathways involved in the regulation of cell migration, including pathways of regulation of actin cytoskeleton, focal adhesion, and PI3K Akt. PMID- 25557040 TI - Liver transplantation for neonatal hemochromatosis: analysis of the UNOS database. AB - NH is the most common identifiable cause of ALF in the neonate. LT is the definitive treatment for neonates with NH who have failed medical therapy. Our aim was to determine the outcomes of LT in infants with NH. Patients (less than one yr of age) with NH who were listed for LT and patients who underwent LT between 1994 and 2013 were identified from the UNOS database for analysis. Risk factors for death and graft loss were analyzed by multivariate logistic regression. Thirty-eight infants with NH with a total of 43 transplants were identified. One- and five-yr patient and graft survival were 84.2%, 81.6%, 71.1%, and 68.4%, respectively. The outcomes for NH were not significantly different when compared to the same age-matched recipients with other causes of ALF. There were no statistically significant risk factors identified for graft loss or death. Ninety infants with NH were listed for LT. Reasons for removal included transplanted (49%), death (27%), too sick to transplant (7%), and improved status (13%). LT for infants with NH has a high rate of graft loss and death; however, outcomes are comparable to the same age-matched recipients with other causes of ALF. PMID- 25557039 TI - Hemoconcentration induced by exercise: Revisiting the Dill and Costill equation. AB - The Dill and Costill equation is used to estimate the exercise-induced hemoconcentration. However, this calculation requires drawing an extra whole blood sample, which cannot be frozen and has to be analyzed with dedicate instrumentation in a relative short time. The aim of the present study was to explore the usefulness of some serum biochemical parameters to estimate hemoconcentration induced by exhaustive exercise. Fourteen healthy male subjects (19-34 years) performed a15-min running test at 110% of anaerobic threshold speed. Hemoglobin, hematocrit, brain natriuretic peptide (BNP), creatinine, gamma glutamyltransferase (GGT), total-proteins, albumin, total calcium (Ca), K(+), Na(+), and Cl(-) were determined in blood samples taken before, after exercise, and after a 30-min recovery period. Plasma volume loss (DeltaPV) was calculated by Dill and Costill equation. At post-exercise and after recovery, the percentage increments of total-proteins, albumin, GGT and Ca correlated significantly with DeltaPV. Bland-Altman analyses showed that correcting BNP, creatinine, and K(+) concentration by Ca percentage increments yield biases and limits of agreement that are acceptable when compared with Dill and Costill equation correction. Ca concentration may be used as a hemoconcentration biomarker in high-intensity exercise, which would allow scientists and physicians avoid extra costs, facilitate in-field research, and delayed estimation of hemoconcentration using stored serum samples. PMID- 25557042 TI - IL-37 requires IL-18Ralpha and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice. AB - BACKGROUND: Interleukin (IL) 37 has been described as a negative regulator of innate immunity, as it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma. METHODS: Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48 h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wild type, IL-18Ralpha-deficient ((-/-) ), and SIGIRR(-/-) C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined. RESULTS: IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Ralpha or SIGIRR/IL-1R8. CONCLUSIONS: This study demonstrates that IL-37 is able to ablate a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Ralpha as well as the orphan receptor SIGIRR/IL-1R8. PMID- 25557041 TI - Therapeutic targeting of tumor suppressor genes. AB - Carcinogenesis is a multistep process attributable to both gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. Currently, most molecular targeted therapies are inhibitors of oncogenes, because inactivated tumor suppressor genes have proven harder to "drug." Nevertheless, in cancers, tumor suppressor genes undergo alteration more frequently than do oncogenes. In recent years, several promising strategies directed at tumor suppressor genes, or the pathways controlled by these genes, have emerged. Here, we describe advances in a number of different methodologies aimed at therapeutically targeting tumors driven by inactivated tumor suppressor genes. PMID- 25557044 TI - Synthesis of single and multipatch particles by dip-coating method and self assembly thereof. AB - We report a simple strategy to produce single and multipatch particles via the conventional dip-coating process. In this method, a close-packed monolayer of micron-sized silica particles is first formed at air-polymer solution interface, followed by dip coating of particles on a glass substrate. The simultaneous deposition of both polymer and particles on the substrate gives rise to a thin polymer layer and a monolayer of silica particles. Sonication of the substrate leads to the formation of a polymeric patch on one side of the particles. The patch shape depends on the aging of the polymer film prior to sonication. With aging time the patch evolves from ring-like to disk-like. This technique allows easy control of patch width by varying the concentration of polymer in the solution. We further show that the number of patches on the particle can be increased by controlling the concentration of silica particles at the interface such that surface coverage is less than that required for the formation of a close-packed monolayer. The single and multipatch particles are characterized by scanning electron and optical microscopy for the patch size, shape, and number distribution. The as-synthesized particles are used as a model to study self assembly of colloids with electrostatic repulsion and patchy hydrophobic attractions due to polymeric patches. We find the formation of doublets and finite-sized clusters due to patchy interactions. Dip coating can be automated to produce large quantities of patchy particles, which is one of the major limitations of other methods of producing patchy particles. PMID- 25557043 TI - The sigma1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control. AB - AIMS: The in vivo pharmacology of the sigma 1 receptor (sigma1R) is certainly complex; however, sigma1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the sigma1R is involved in the negative control that glutamate N-methyl-d-aspartate acid receptors (NMDARs) exert on opioid antinociception. RESULTS: The MOR C terminus carries the histidine triad nucleotide-binding protein 1 (HINT1) coupled to the regulator of G-protein signaling RGSZ2-neural nitric oxide synthase assembly. Activated MORs stimulate the production of nitric oxide (NO), and the redox zinc switch RGSZ2 converts this signal into free zinc ions that are required to recruit the redox sensor PKCgamma to HINT1 proteins. Then, PKCgamma impairs HINT1-RGSZ2 association and enables sigma1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of sigma1Rs prevents HINT1 PKCgamma interaction, and MOR-NMDAR cross-regulation fails. The sigma1R antagonists transitorily remove the binding of sigma1Rs to NR1 subunits, facilitate the entrance of negative regulators of NMDARs, likely Ca(2+)-CaM, and prevent NR1 interaction with HINT1, thereby impairing the negative feedback of glutamate on opioid analgesia. INNOVATION: A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the sigma1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit. CONCLUSION: The sigma1R antagonists enhance opioid analgesia in naive mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, sigma1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs. PMID- 25557045 TI - Erosion of a dual-chamber pacemaker system. PMID- 25557046 TI - Labeling of Cellular DNA with a Cyclosal Phosphotriester Pronucleotide Analog of 5-ethynyl-2'-deoxyuridine. AB - DNA synthesis is a fundamental biological process central to all proliferating cells, and the design of small molecule probes that allow detection of this DNA is important for many applications. 5-Ethynyl-2'-deoxyuridine, known as EdU, has become a workhorse for metabolic labeling of DNA in mammalian cells, followed by bioconjugation to a small molecule fluorescent azide using copper-catalyzed azide alkyne cycloaddition (CuAAC), click chemistry, to allow detection. In this study, we demonstrate that a cyclosal phosphotriester pronucleotide analog of EdU is suitable for metabolic incorporation into DNA of proliferating cells and subsequent labeling by CuAAC. This analog has two advantages over EdU; first, by delivering EdU with a preinstalled 5'-monophosphate moiety, it bypasses the need for thymidine kinase processing, and second, the increased lipophilicity compared to EdU may enable passive diffusion across the cell membrane and may circumvent the reliance on nucleoside active transport mechanisms for cellular uptake. These advantages pave the way for the development of additional novel pronucleotides to widen experimental opportunities for future bioconjugation applications involving cellular DNA. PMID- 25557047 TI - Effects of dietary quercetin on female fertility in mice: implication of transglutaminase 2. AB - Use of the dietary supplement quercetin is on the rise. Because previous studies imply an inhibitory effect of quercetin on male fertility, we explored the effects of this flavonoid on fertility in female mice. Birth outcomes, and ovarian morphology in 4-week-old offspring, were assessed in mice receiving dietary quercetin (5mgkg-1day-1) for 9 months during two breeding periods: from 2 to 6 months (prime reproductive age) and 8 to11 months of age. Quercetin increased birth spacing, leading to a 60% reduction in the number of litters, but enhanced folliculogenesis in ovaries of female offspring. While in young females quercetin caused an almost 70% increase in litter size, in older animals this effect was reversed. Consistent with the inhibitory activity of quercetin on the enzyme transglutaminase 2 (TG2), genetic ablation of TG2 in mice mirrors the effects of quercetin on birth outcomes and follicular development. Further, TG2 null mice lack responsiveness to quercetin ingestion. Our study shows for the first time that dietary quercetin can cause reduced reproductive potential in female mice and implies that TG2 may regulate ovarian ageing. PMID- 25557048 TI - The cytoplasmic localization of the catalytic site of CSLF6 supports a channeling model for the biosynthesis of mixed-linkage glucan. AB - Mixed-linkage glucan (MLG) is a significant cell wall carbohydrate in grasses and an important carbon source for human consumption and biofuel production. MLG biosynthesis depends on the biochemical activity of membrane spanning glucan synthases encoded by the CSLH and CSLF cellulose synthase-like gene families. CSLF proteins are the best characterized to date but relatively little information is known about their topology with respect to the biosynthetic membranes. In this study, we report on the topology of CSLF6 protein derived from the model grass species Brachypodium distachyon (BdCSLF6) when it is expressed in heterologous systems. Using live cell imaging and immuno-electron microscopy analyses of tobacco epidermal cells expressing BdCSLF6, we demonstrate that a functional yellow fluorescent protein (YFP) fusion of BdCSLF6 is localized to the Golgi apparatus and that the Golgi localization of BdCSLF6 is sufficient for MLG biosynthesis. By implementing protease protection assays of BdCSLF6 expressed in the yeast Pichia pastoris, we also demonstrate that the catalytic domain, the N terminus and the C- terminus of the protein are exposed in the cytosol. Furthermore, we found that BdCSLF6 is capable of producing MLG not only in tobacco cells but also in Pichia, which generally does not produce MLG. Together, these results support the conclusion that BdCSLF6 can produce both of the linkages present in the (1,3;1,4)-beta-d-glucan chain of MLG and that the product is channelled at the Golgi into the secretory pathway for deposition into the cell wall. PMID- 25557049 TI - Crosslinkable hydrogels derived from cartilage, meniscus, and tendon tissue. AB - Decellularized tissues have proven to be versatile matrices for the engineering of tissues and organs. These matrices usually consist of collagens, matrix specific proteins, and a set of largely undefined growth factors and signaling molecules. Although several decellularized tissues have found their way to clinical applications, their use in the engineering of cartilage tissue has only been explored to a limited extent. We set out to generate hydrogels from several tissue-derived matrices, as hydrogels are the current preferred cell carriers for cartilage repair. Equine cartilage, meniscus, and tendon tissue was harvested, decellularized, enzymatically digested, and functionalized with methacrylamide groups. After photo-cross-linking, these tissue digests were mechanically characterized. Next, gelatin methacrylamide (GelMA) hydrogel was functionalized with these methacrylated tissue digests. Equine chondrocytes and mesenchymal stromal cells (MSCs) (both from three donors) were encapsulated and cultured in vitro up to 6 weeks. Gene expression (COL1A1, COL2A1, ACAN, MMP-3, MMP-13, and MMP-14), cartilage-specific matrix formation, and hydrogel stiffness were analyzed after culture. The cartilage, meniscus, and tendon digests were successfully photo-cross-linked into hydrogels. The addition of the tissue derived matrices to GelMA affected chondrogenic differentiation of MSCs, although no consequent improvement was demonstrated. For chondrocytes, the tissue-derived matrix gels performed worse compared to GelMA alone. This work demonstrates for the first time that native tissues can be processed into crosslinkable hydrogels for the engineering of tissues. Moreover, the differentiation of encapsulated cells can be influenced in these stable, decellularized matrix hydrogels. PMID- 25557050 TI - The many faces of interferon tau. AB - Interferon tau (IFNT) was discovered as the pregnancy recognition signal in ruminants, but is now known to have a plethora of physiological functions in the mammalian uterus. The mammalian uterus includes, from the outer surface to the lumen, the serosa, myometrium and endometrium. The endometrium consists of the luminal, superficial glandular, and glandular epithelia, each with a unique phenotype, stromal cells, vascular elements, nerves and immune cells. The uterine epithelia secrete or selectively transport molecules into the uterine lumen that are collectively known as histotroph. Histotroph is required for growth and development of the conceptus (embryo and its associated extra-embryonic membranes) and includes nutrients such as amino acids and glucose, enzymes, growth factors, cytokines, lymphokines, transport proteins for vitamins and minerals and extracellular matrix molecules. Interferon tau and progesterone stimulate transport of amino acids in histotroph, particularly arginine. Arginine stimulates the mechanistic target of rapamycin pathway to induce proliferation, migration and protein synthesis by cells of the conceptus, and arginine is the substrate for synthesis of nitric oxide and polyamines required for growth and development of the conceptus. In ruminants, IFNT also acts in concert with progesterone from the corpus luteum to increase expression of genes for transport of nutrients into the uterine lumen, as well as proteases, protease inhibitors, growth factors for hematopoiesis and angiogenesis and other molecules critical for implantation and placentation. Collectively, the pleiotropic effects of IFNT contribute to survival, growth and development of the ruminant conceptus. PMID- 25557051 TI - Tc-99m-labeled RGD-conjugated alpha-melanocyte stimulating hormone hybrid peptides with reduced renal uptake. AB - The purpose of this study was to examine whether the replacement of the positively-charged Lys or Arg linker with a neutral linker could reduce the renal uptake of Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (alpha-MSH) hybrid peptide. The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), D-Phe(7), Arg(11)]alpha-MSH3-13 {(Arg(11))CCMSH} through the neutral betaAla or Ahx {aminohexanoic acid} linker (replacing the Lys or Arg linker) to generate novel RGD-betaAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH hybrid peptides. The receptor-binding affinity and cytotoxicity of RGD-betaAla (Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH were determined in B16/F1 melanoma cells. The melanoma targeting and imaging properties of (99m)Tc-RGD-betaAla (Arg(11))CCMSH and (99m)Tc-RGD-Ahx-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The replacement of the Lys or Arg linker with the betaAla or Ahx linker retained nanomolar receptor-binding affinities and remarkable cytotoxicity of RGD-betaAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH. The receptor-binding affinities of RGD-betaAla-(Arg(11))CCMSH and RGD-Ahx (Arg(11))CCMSH were 0.8 +/- 0.05 and 1.3 +/- 0.1 nM. Three-hour incubation with 0.1 uM of RGD-betaAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH decreased the survival percentages of B16/F1 cells by 71 and 67 % as compared to the untreated control cells 5 days post the treatment. The replacement of the Arg linker with the betaAla or Ahx linker reduced the non-specific renal uptake of (99m)Tc-RGD betaAla-(Arg(11))CCMSH and (99m)Tc-RGD-Ahx-(Arg(11))CCMSH by 62 and 61 % at 2 h post-injection. (99m)Tc-RGD-betaAla-(Arg(11))CCMSH displayed higher melanoma uptake than (99m)Tc-RGD-Ahx-(Arg(11))CCMSH at 0.5, 2, 4, and 24 h post-injection. Enhanced tumor to kidney uptake ratio of (99m)Tc-RGD-betaAla-(Arg(11))CCMSH warranted the further evaluation of (188)Re-labeled RGD-betaAla-(Arg(11))CCMSH as a novel MC1 receptor-targeting therapeutic peptide for melanoma treatment in the future. PMID- 25557052 TI - Effect of grapefruit juice on the bioactivation of prasugrel. AB - AIMS: The P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of grapefruit juice on prasugrel. METHODS: In a randomized crossover study, seven healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 4 days. On day 3, they ingested a single 10 mg dose of prasugrel with an additional 200 ml of grapefruit juice or water. Plasma concentrations of prasugrel metabolites and the antiplatelet effect were measured. RESULTS: Grapefruit juice increased the geometric mean area under the plasma concentration-time curve (AUC(0-infinity)) of the primary, inactive metabolite of prasugrel to 164% of the control value (95% confidence interval 122 220%, P = 0.008), without a significant effect on its peak plasma concentration (C(max)). The C(max) and AUC(0-infinity) of the secondary, active metabolite were decreased to 51% (95% confidence interval 32-84%, P = 0.017) and 74% of the control value (95% confidence interval 60-91%, P = 0.014) by grapefruit juice (P < 0.05). The average platelet inhibition, assessed with the VerifyNow(r) method at 0-24 h after prasugrel intake, was 5 percentage points (95% confidence interval 1-10 percentage points) lower in the grapefruit juice phase than in the water phase (P = 0.034). CONCLUSIONS: Grapefruit juice reduces the bioactivation of prasugrel, but this has only a limited effect on the antiplatelet effect of prasugrel. PMID- 25557053 TI - Renal involvement in Chinese patients with Behcet's disease: a report of 16 cases. AB - AIM: To investigate the clinical and pathological characteristics of renal involvement in Behcet's disease (BD). METHODS: A retrospective analysis was carried out in BD patients complicated with renal damage who were hospitalized in Peking Union Medical College Hospital from June 1998 to July 2012. RESULTS: There were 16 BD patients with renal involvement, accounted for 2.6% of all the 618 hospitalized BD patients. The presentation of renal disease was chronic glomerulonephritis in six patients (including one with nephritic syndrome), renal tubular acidosis in one patient, renal artery stenosis in eight patients and renal vein thrombosis in one patient. Renal biopsy was performed in five patients, three of whom revealed to have minor glomerular lesions, mild mesangial proliferative glomerulonephritis and chronic tubular-interstitial nephropathy, respectively. The other two patients underwent a second biopsy, the one with minor glomerular lesion in the first biopsy was transformed into grade III immunoglobulin A (IgA) nephropathy on Lee's glomerular grading system 6 years later, and the other one who had IgA nephropathy of grade II in the first biopsy was progressed to grade IV 2 years later. Among the nine patients with renal vascular involvement, two underwent surgery, and several received anticoagulant therapy. During the follow-up of 13 patients, the urine protein quantifications were reduced, and renal function remained relatively stable. CONCLUSIONS: Renal damage is relatively uncommon in BD patients. There are various clinical presentations of renal involvement in BD. Routine screening with urinalysis, serum creatinine and imaging studies should be carried out for the early diagnosis of renal involvement in BD. PMID- 25557054 TI - Minimal Clinically Important Difference of Grip and Pinch Strength in Women With Thumb Carpometacarpal Osteoarthritis When Compared to Healthy Subjects. AB - PURPOSE: The primary objective of this study was to compare grip and pinch strength between women with carpometacarpal (CMC) osteoarthritis (OA) between affected and unaffected sides of the body in patients or dominant and nondominant sides in healthy subjects. The secondary aim was to establish the cutoff value scores for the minimal clinically important difference (MCID) for grip strength, tip, and tripod pinch. DESIGN: A prospective case-control study. METHODS: One hundred ten women participated in the study. The CMC OA group consisted of 57 patients, and the control group consisted of 53 healthy subjects. Grip strength, tip, and tripod pinch were assessed bilaterally. The two-way analysis of variance (ANOVA) was conducted to determine the differences between sides of the body and between the groups. FINDINGS: The post hoc analysis indicated that the patients in the CMC OA group indicated statistically significant lower scores on the grip and pinch strength (all, p < .001). The MCID from baseline score in this patient population was 0.84 kg for grip, 0.33 kg for tip, and 0.35 kg for tripod pinch for the affected right arm and 1.12 kg for grip, 0.23 kg for tip, and 0.30 kg for tripod pinch for the unaffected left side. CONCLUSIONS: Women with CMC OA have significantly decreased grip strength, tip, and tripod pinch as compared to their healthy counterparts and may experience functional consequences because of this limitation. CLINICAL RELEVANCE: Our study established the MCID for grip and pinch strength for individuals with CMC OA and their healthy counterparts. PMID- 25557056 TI - Information Density and Syntactic Repetition. AB - In noun phrase (NP) coordinate constructions (e.g., NP and NP), there is a strong tendency for the syntactic structure of the second conjunct to match that of the first; the second conjunct in such constructions is therefore low in syntactic information. The theory of uniform information density predicts that low information syntactic constructions will be counterbalanced by high information in other aspects of that part of the sentence, and high-information constructions will be counterbalanced by other low-information components. Three predictions follow: (a) lexical probabilities (measured by N-gram probabilities and head dependent probabilities) will be lower in second conjuncts than first conjuncts; (b) lexical probabilities will be lower in matching second conjuncts (those whose syntactic expansions match the first conjunct) than nonmatching ones; and (c) syntactic repetition should be especially common for low-frequency NP expansions. Corpus analysis provides support for all three of these predictions. PMID- 25557055 TI - The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. AB - Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5'-epsilon region of HBV pregenomic RNA. In addition, RIG-I could also counteract the interaction of HBV polymerase (P protein) with the 5'-epsilon region in an RNA-binding dependent manner, which consistently suppressed viral replication. Liposome-mediated delivery and vector based expression of this epsilon region-derived RNA in liver abolished the HBV replication in human hepatocyte-chimeric mice. These findings identify an innate recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes. PMID- 25557057 TI - Nevus comedonicus: a case series. AB - Twelve previously unreported cases of nevus comedonicus are presented. Characteristic closely grouped dilated follicular openings with horny plugs that mimic comedones led to the diagnosis. One patient had nevus comedonicus syndrome and there were cases with atypical locations and unusual complications of this condition. We also highlight clinical associations and therapeutic options. PMID- 25557058 TI - Implications of in vitro bioaccessibility differences for the assessment of risks of metals to bats. AB - Food chain modeling is often used to assess the risks of chemical contaminants to wildlife. In modeling efforts, bioaccessibility from different dietary components is assumed to be similar. The present study explored potential differences in the in vitro bioaccessibility of metals from a range of insect orders, which are common components of the diet of insectivorous bats, and assessed the implications of this for environmental exposure assessment. Bioaccessibility of metals was assessed using an in vitro gastric model simulating gastric and intestinal conditions of insectivorous bats. In vitro-derived metal bioaccessibility was found to differ significantly across insect orders. Bioaccessibility was found to be greatest in Coleoptera, followed by Lepidoptera and Diptera. To establish the implications for risk assessment, a spatially explicit risk model was employed that included and excluded in vitro bioaccessibility data; to examine the daily oral exposure of metals to 14 bat species. The results show that when bioaccessibility data are included in the model, metal exposure predictions across species are changed and that the ranking of bat species, in terms of metal exposure, are altered. The authors recommend that in vitro bioaccessibility data begin to be employed when establishing the risks of contaminants to wildlife species. PMID- 25557060 TI - A novel mutation of the GATA site in the erythroid cell-specific regulatory element of the ABO gene in a blood donor with the Am B phenotype. AB - The Am and Bm phenotypes are characterized by weak expression of the A or B antigens, respectively, by red blood cells with a normal expression by the saliva of secretors. Deletion of the regulatory element in the first intron of the ABO gene and disruption of the GATA motif in the element were found to be responsible. In this study, we identified a novel mutation within the GATA motif (G>C substitution at position c.28 + 5830) in the regulatory element of the A allele that might diminish transcription activity causing the generation of the Am B phenotype. PMID- 25557059 TI - Low circulating levels of bisphenol-A induce cognitive deficits and loss of asymmetric spine synapses in dorsolateral prefrontal cortex and hippocampus of adult male monkeys. AB - Bisphenol-A (BPA) is widely used in the manufacture of plastics, epoxy resins, and certain paper products. A majority of the population in the developed world is routinely exposed to BPA from multiple sources and has significant circulating levels of BPA. Although BPA is categorized as an endocrine disruptor with a growing literature on adverse effects, it is uncertain whether cognitive dysfunction is induced in humans by exposure to BPA. The present study examined the impact of BPA in primate brain by exposing adult male vervet monkeys for 4 weeks continuously to circulating levels of BPA that were in the range measured in studies of humans environmentally exposed to BPA. This regimen of exposure to BPA decreased both working memory accuracy and the number of excitatory synaptic inputs on dendritic spines of pyramidal neurons in two brain regions that are necessary for working memory (prefrontal cortex and hippocampus). These observed behavioral and synaptic effects were ameliorated following withdrawal from BPA. As Old World monkeys (e.g., vervets) and humans share some uniquely primate morphological, endocrine, and cognitive traits, this study indicates the potential for significant cognitive disruption following exposure of humans to BPA. PMID- 25557061 TI - A site-specific ecological risk assessment for corn-associated insecticides. AB - A site-specific ecological risk assessment (ERA) was conducted to examine the simultaneous use of genetically modified corn (Bt corn) with a neonicotinoid seed coating, clothianidin, and use of a granular insecticide, tefluthrin, to protect crops from pest damage. A field study was conducted on site, and exposure data from the literature were summarized to determine the matrices and exposure concentrations that nontarget species could typically experience within an agricultural ecosystem. To determine ecological effects on nontarget species, acute toxicity bioassays were conducted on earthworms (Eisenia fetida), amphipods (Hyalella azteca), and Elmid riffle beetle larvae (Ancyronyx spp.) in which the test species were exposed to single insecticides as well as the mixture of the 3 insecticides. In the risk characterization section of the ERA, stressor-response profiles for each species tested were compared with field distributions of the insecticides, and a margin of safety at the 10th percentile (MOS10) was calculated to estimate risk. No acute toxicity was observed in any of the 3 nontarget species after exposure to senescent Bt corn leaf tissue. Large MOS10 values were calculated for clothianidin to the nontarget species. When bioassays were compared with tefluthrin field distributions, very low MOS10 values were calculated for earthworms (0.06) and H. azteca (0.08) because the environmental concentrations often exceeded the stressor-response profile. No increased toxicity was observed when nontarget species were exposed to a mixture of the 3 insecticides. In summary, the genetically modified corn insecticidal proteins and clothianidin were not found at environmental concentrations exceeding benchmark values for ecological effects, but tefluthrin was consistently detected in the environment at levels that could be causing toxicity to nontarget species, especially if this pyrethroid is able to travel off site. PMID- 25557062 TI - Structural and functional correlates of hypnotic depth and suggestibility. AB - This study explores whether self-reported depth of hypnosis and hypnotic suggestibility are associated with individual differences in neuroanatomy and/or levels of functional connectivity. Twenty-nine people varying in suggestibility were recruited and underwent structural, and after a hypnotic induction, functional magnetic resonance imaging at rest. We used voxel-based morphometry to assess the correlation of grey matter (GM) and white matter (WM) against the independent variables: depth of hypnosis, level of relaxation and hypnotic suggestibility. Functional networks identified with independent components analysis were regressed with the independent variables. Hypnotic depth ratings were positively correlated with GM volume in the frontal cortex and the anterior cingulate cortex (ACC). Hypnotic suggestibility was positively correlated with GM volume in the left temporal-occipital cortex. Relaxation ratings did not correlate significantly with GM volume and none of the independent variables correlated with regional WM volume measures. Self-reported deeper levels of hypnosis were associated with less connectivity within the anterior default mode network. Taken together, the results suggest that the greater GM volume in the medial frontal cortex and ACC, and lower connectivity in the DMN during hypnosis facilitate experiences of greater hypnotic depth. The patterns of results suggest that hypnotic depth and hypnotic suggestibility should not be considered synonyms. PMID- 25557064 TI - Histone deacetylase inhibitor for NUT midline carcinoma. AB - NUT Midline carcinoma (NMC) is a rare and invariably fatal poorly differentiated carcinoma characterized by chromosomal rearrangement involving the nuclear protein of the testis (NUT) gene. Current approaches do not provide durable response. We report a case of widely metastatic NMC in a 17-year-old female who, following an initial response to combination chemotherapy developed rapid disease progression. Treatment with vorinostat, a histone deacetylase inhibitor (HDACi) resulted in an objective response, yet she died in less than one year from initial diagnosis. This report shows a potentially promising activity of HDACi in the treatment of NMC that needs further exploration. PMID- 25557065 TI - Ureteric reconstruction for the management of transplant ureteric stricture: a decade of experience from a single centre. AB - This study was conducted to review the outcomes of patients who had undergone surgical repair of a ureteric stricture following renal transplantation. All patients who developed a ureteric stricture and underwent ureteric reconstruction following renal transplantation, between December 2003 and November 2013, were reviewed. One thousand five hundred and sixty renal transplants were performed during the study period. Forty patients required surgical repair of a ureteric stricture (2.5%, 25 male, median age 48 [14-78]). The median time to stricture was 3 [1-149] months. 19 patients were reconstructed by reimplantation to the bladder, 18 utilized a Boari flap, two were a pre-existing ileal conduit and one was an anastomosis to a native ureter. In one patient, reconstruction was impossible and consequently an extra-anatomic stent was used. Two patients required re-operation for restricture and kinking. Median serum creatinine at 12 months following surgery was 148 [84-508] MUmol/l. There was no 90-day mortality. Eleven grafts were lost at the time of this study, a median time of 11 [1-103] months after reconstruction. The incidence of ureteric stricture following renal transplant is low. Surgical reconstruction of the transplant ureter is the optimal treatment and is successful in the majority of patients. PMID- 25557063 TI - Clinical high risk and first episode schizophrenia: auditory event-related potentials. AB - The clinical high risk (CHR) period is a phase denoting a risk for overt psychosis during which subacute symptoms often appear, and cognitive functions may deteriorate. To compare biological indices during this phase with those during first episode schizophrenia, we cross-sectionally examined sex- and age matched clinical high risk (CHR, n=21), first episode schizophrenia patients (FESZ, n=20) and matched healthy controls (HC, n=25) on oddball and novelty paradigms and assessed the N100, P200, P3a and P3b as indices of perceptual, attentional and working memory processes. To our knowledge, this is the only such comparison using all of these event-related potentials (ERPs) in two paradigms. We hypothesized that the ERPs would differentiate between the three groups and allow prediction of a diagnostic group. The majority of ERPs were significantly affected in CHR and FESZ compared with controls, with similar effect sizes. Nonetheless, in logistic regression, only the P3a and N100 distinguished CHR and FESZ from healthy controls, suggesting that ERPs not associated with an overt task might be more sensitive to prediction of group membership. PMID- 25557066 TI - Nebulization as a delivery method for mAbs in respiratory diseases. AB - INTRODUCTION: The pulmonary route is not invasive and can be used to target drugs directly to the lungs, limiting the exposure of secondary organs. It is, thus, an attractive alternative to the intravenous route, for the delivery of mAbs, which display limited transfer from blood into the lungs. AREAS COVERED: This review provides an overview of the pharmacological properties of antibody-based treatments, describes those for respiratory diseases and discusses preclinical/clinical results of aerosolized antibody-based therapeutics. The advantages and limitations of aerosol devices and the formulation for the administration of aerosolized mAbs are also detailed. EXPERT OPINION: Overall, the inhalation of mAbs for therapeutic purposes is both appropriate and feasible. The size and structure of the biotherapeutic molecule are important properties to be taken into account when trying to achieve long-term retention. Mesh nebulizers currently appear to be the most appropriate devices for the safe delivery of large amounts of active mAb into the lungs. mAbs should be formulated so as to prevent their degradation and possible immunogenicity. General guidelines can be given for mAb aerosolization, but the formulation and device combination should be adapted for each therapeutic and clinical application. PMID- 25557067 TI - Photoinduced interactions of two dirhodium complexes with d(GTCGAC)2 probed by 2D NOESY. AB - The interactions between the 6-mer duplex oligonucleotide d(GTCGAC)2 and the photoactive dirhodium complexes cis-H,H-[Rh2(HNOCCH3)2(L)(CH3CN)4](2+), where L represents bpy (1, 2,2'-bipyridine) and dppz (2, dipyrido[3,2-a:2',3' c]phenazine), were probed using 2D (1)H-(1)H NOESY NMR spectroscopy. Complex does not interact with the duplex in the dark, but binds covalently to the terminal guanine following irradiation with visible light. Similar behavior was observed for 2, but in addition to the photoinduced covalent DNA binding, the planar dppz ligand of the complex shields the terminal cytosine protons after irradiation. The results are consistent with photoinduced guanine coordination and end-capping of the duplex through pi-stacking interactions with the terminal GC base pair. These data show that in the presence of the 6-mer duplex oligonucleotide, 1 and 2 exhibit photoinduced covalent binding to DNA. In addition, the pi-stacking interactions of 2 with the duplex are enhanced upon irradiation. PMID- 25557068 TI - Micro-CT Detection and Characterization of Porosity in Luting Cements. AB - PURPOSE: To evaluate porosity volume and localization in luting cements under fixed dental prostheses after cementation using micro-computed tomography (CT). MATERIALS AND METHODS: Seventy-seven sound molars were circumferentially prepared to receive all-ceramic crowns, and IPS e.max ceramic copings were fabricated according to the manufacturer's instructions. For this study, different dental luting cements were used: eight resin-based cements (Variolink II, RelyX ARC, Clearfil Esthetic, BisCem, RelyX U100, Panavia EX, Super Bond C&B, and Multilink Automix), one resin-modified glass ionomer (Ketac Cem Plus), one glass ionomer (Ketac Cem), and one polycarboxylate (Durelon). Specimens were scanned with a micro-CT (SkyScan) for detection and comparison of the cements' porosities. Statistical analyses were performed using Kruskal-Wallis one-way ANOVA and Bonferroni's adjusted Mann-Whitney U tests. RESULTS: Multilink Automix (Volume = 0.11 +/- 0.08 mm3 ; Surface Area = 1.63 +/- 1.31 mm2 ), Ketac Cem Plus (Volume = 0.22 +/- 0.21 mm3 ; Surface Area = 4.32 +/- 3.71 mm2 ), and Variolink II (Volume = 0.34 +/- 0.38 mm3 ; Surface Area = 6.47 +/- 5.10 mm2 ) contained less porosity (p < 0.001) than all other cements. All other cements were not significantly different from one another (p > 0.05); however, the volume and surface area of the porosity found in the other tested luting cements were significantly greater than those of the Multilink Automix, Ketac Cem Plus, and Variolink II (p < 0.001), all of which demonstrated no significant differences (p > 0.05). CONCLUSION: The liquid and powder forms prepared by manually mixing the cements were found to cause greater porosity. PMID- 25557069 TI - Self-reported walking difficulty predicts late-life mortality in Finnish war veterans: results from the Veteran 1992 Project Survey. AB - OBJECTIVES: To determine risk factors and their combinations that predict late life mortality. DESIGN: Postal questionnaire. SETTING: Veteran 1992 Project Survey. PARTICIPANTS: Finnish Second World War veterans living in Finland (177,989 men, 48,745 women), with a participation rate of 93%. MEASUREMENTS: Main outcomes were total, cardiovascular disease (CVD), and accident and violence (AAV) mortality. Absolute 10-year mortality risks for total mortality with combinations of different risk factors were calculated. RESULTS: The strongest predictor of total mortality was self-reported walking difficulty (hazard ratio (HR) = 1.74, 95% confidence interval (CI) = 1.71-1.76 in men without disability, HR = 1.62, 95% CI = 1.58-1.67 in men with disability, HR = 1.61, 95% CI = 1.57 1.65 in women). The highest HRs of CVD mortality were for self-reported walking difficulty among men without disability (HR = 1.98, 95% CI = 1.95-2.02) and among men with disability (HR = 1.88, 95% CI = 1.82-1.94). In women, the highest HR for CVD mortality was for multimorbidity (HR = 1.87, 95% CI = 1.79-1.96). For AAV mortality, the highest HRs were for falls in men and age in women. A combination of walking difficulty and multimorbidity had the highest absolute 10-year mortality risk for total mortality (0.730 in men without disability, 0.729 in men with disability, 0.487 in women). CONCLUSION: Self-reported walking difficulty was the most important predictor of total mortality in all veteran groups and for CVD mortality in men. The study demonstrates the importance of self-reported walking difficulty and multimorbidity as markers of high mortality risk in Finnish war veterans. PMID- 25557070 TI - ZnCl2 -promoted asymmetric hydrogenation of beta-secondary-amino ketones catalyzed by a P-chiral Rh-bisphosphine complex. AB - A new catalytic system has been developed for the asymmetric hydrogenation of beta-secondary-amino ketones using a highly efficient P-chiral bisphosphine rhodium complex in combination with ZnCl2 as the activator of the catalyst. The chiral gamma-secondary-amino alcohols were obtained in 90-94 % yields, 90-99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl2 on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine, in high yields and with excellent enantioselectivities. PMID- 25557071 TI - First identification of tetrodotoxin (TTX) in the flatworm Stylochoplana sp.; a source of TTX for the sea slug Pleurobranchaea maculata. AB - High concentrations of the neurotoxin tetrodotoxin (TTX) were detected by liquid chromatography-mass spectrometry (LC-MS) in the Platyhelminthes Stylochoplana sp. from Pilot Bay (Tauranga, New Zealand). This is the first detection of TTX in this genus. Concentrations were monitored from March to November (2013) and found to significantly decrease from a peak in July (avg. 551 mg kg(-1)) to November (avg. 140 mg kg(-1)). Stylochoplana sp. co-occurred with TTX-containing Pleurobranchaea maculata (Opisthobranchia). A Stylochoplana sp.-specific real time PCR assay was developed targeting the mitochondrial cytochrome c oxidase subunit I gene to determine if P. maculata consumed Stylochoplana sp. Positive Stylochoplana sp. signals were obtained for 7 of 19 P. maculata tested. Mass calculations indicate Stylochoplana sp. could supply Pilot Bay P. maculata with the TTX required to account for the concentrations reported in previous studies (ca. 1.04 mg TTX per individual) based on an ingestion rate of one individual every 2-3 days throughout their lifetime. However, due to the lack of Stylochoplana sp. in areas with dense P. maculata populations, and high concentration (ca. 1400 mg kg(-1)) of TTX detected in some individuals, it is unlikely that Stylochoplana sp. represent the sole source of TTX in P. maculata. PMID- 25557073 TI - Cytologic diagnostic approach to poorly differentiated thyroid carcinoma: a single-institution study. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) is a well-established technique for the preoperative evaluation of thyroid nodules because it is minimally invasive, cost-effective, quick, efficient, and safe. Various articles have discussed differences in the cytomorphology of different types of thyroid cancer. However, review articles on the cytologic diagnosis of poorly differentiated thyroid carcinoma (PDTC) are scarce as PDTC are rare tumors. Although the histologic diagnostic criteria are well standardized, the cytologic diagnostic criteria are not yet standardized. This prompted us to study the cytomorphological features of PDTC and assess features of distinction from differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). METHODS: This was a retrospective study of thyroid FNAC smears from 44 PDTC cases retrieved from the database of a single tertiary cancer institute (2009-2013). Papanicolaou and Giemsa smears were evaluated for 21 cytomorphologic features. Immunocytochemistry was available for 6 cases only. RESULTS: The frequencies of cytomorphologic features in the 44 cases were as follows: hypercellularity, 84.1%; insular pattern, 79.5%; small cell size, 93.2%; high nuclear-cytoplasmic ratio, 93.2%; granular chromatin pattern, 95.45%; nuclear overlapping, 88.64%; mild pleomorphism, 86.36%; grooves/inclusions, 22.7%; binucleation/multinucleation, 9.1%; abrupt nucleomegaly, 34.1%; apoptosis, 45%; mitosis, 25%; necrosis, 34.1%; and colloid, 22.7%. CONCLUSION: A high index of suspicion is necessary for an upfront diagnosis of PDTC on FNAC. Although PDTC, DTC, and MTC have overlapping features, there are distinguishing features also. The cytologic diagnostic criteria for PDTC need to be standardized by collaborative efforts among tertiary cancer centers. A prompt diagnosis is the key feature for planning multimodality treatment. PMID- 25557072 TI - Quantification of myocardial blood flow with dynamic perfusion 3.0 Tesla MRI: Validation with (15) O-water PET. AB - BACKGROUND: To develop and validate a method for quantifying myocardial blood flow (MBF) using dynamic perfusion magnetic resonance imaging (MBFMRI ) at 3.0 Tesla (T) and compare the findings with those of (15) O-water positron emission tomography (MBFPET ). METHODS: Twenty healthy male volunteers underwent magnetic resonance imaging (MRI) and (15) O-water positron emission tomography (PET) at rest and during adenosine triphosphate infusion. The single-tissue compartment model was used to estimate the inflow rate constant (K1). We estimated the extraction fraction of Gd-DTPA using K1 and MBF values obtained from (15) O-water PET for the first 10 subjects. For validation, we calculated MBFMRI values for the remaining 10 subjects and compared them with the MBFPET values. In addition, we compared MBFMRI values of 10 patients with coronary artery disease with those of healthy subjects. RESULTS: The mean resting and stress MBFMRI values were 0.76 +/- 0.10 and 3.04 +/- 0.82 mL/min/g, respectively, and showed excellent correlation with the mean MBFPET values (r = 0.96, P < 0.01). The mean stress MBFMRI value was significantly lower for the patients (1.92 +/- 0.37) than for the healthy subjects (P < 0.001). CONCLUSION: The use of dynamic perfusion MRI at 3T is useful for estimating MBF and can be applied for patients with coronary artery disease. PMID- 25557074 TI - The evaluation of a national interprofessional palliative care workshop. AB - The purpose of this study was to evaluate the impact of a palliative/end-of-life care workshop on students' perceptions of professional identity, team understanding, and their readiness for interprofessional education (IPE). A before-and-after design was used combining both qualitative and quantitative methods. A survey was completed by 25 undergraduate students from a variety of health care professional schools across Canada, both before and after they attended the five-day workshop. There was a significant increase in students' readiness for IPE, perceptions of professional identity, and team understanding after they attended the palliative care workshop. Students stated that learning about other professionals' backgrounds and becoming more sensitive to other team members and their scopes of practice helped change the way they would practice. The findings from this study will contribute to our understanding of student attitudes around IPE and palliative care. PMID- 25557075 TI - Blood pressure profiles 5 to 10 years after transplant in pediatric solid organ recipients. AB - Arterial hypertension is a major risk factor for cardiovascular disease after solid organ transplantation, emphasizing the need for blood pressure (BP) monitoring. The authors studied 24-hour ambulatory BP monitoring (ABPM) parameters (index, load, dipping) and their predictive value with regard to hypertension as well as correlations with graft function and metabolic parameters such as obesity and dyslipidemias. The ABPM profiles of 111 renal, 29 heart, and 13 liver transplant recipients were retrospectively analyzed 5 to 10 years after transplant (median 5.1 years). The BP profiles among the different transplant groups were similar. The BP index and load were abnormal especially at nighttime and the nocturnal BP dipping was often blunted (in 49% to 83% of the patients). The BP variables were found to be equally valued when assessing hypertension. BP load of 50% instead of 25% seems to be a more adequate cutoff value. The BP variables correlated poorly with the metabolic parameters and kidney function. Antihypertensive medication did not notably change the ABPM profile in renal transplant recipients. Hypertension, including nocturnal hypertension, is present in children receiving solid organ transplant, underlining the importance of use of ABPM in the follow-up of these patients. PMID- 25557076 TI - Synthesis of pyrrolidine derivatives by a platinum/bronsted acid relay catalytic cascade reaction. AB - A new catalytic reaction for the synthesis of pyrrolidine derivatives is presented. The method implies the coupling of N-Boc-protected alkynamine derivatives and appropriate alkenes or alkynes in a process catalysed by a platinum/triflic acid catalytic binary system. This reaction is believed to proceed through a cascade process implying an initial platinum-catalysed cycloisomerization of the alkynamine derivative followed by a triflic acid promoted nucleophilic addition of the alkene or alkyne and trapping of the cationic species formed by the Boc group. Not only simple alkenes and alkynes were used in this reaction but also allyltrimethylsilane and propargyltrimethylsilane. Particularly, when allyltrimethylsilane is used as the alkene counterpart interesting bicyclic compounds containing a trimethylsilane group are obtained. However, when propargyltrimethylsilane is used in the presence of water we observed the formation of a related bicyclic compound lacking the trimethylsilane group and containing an exocyclic carbon-carbon bond. PMID- 25557078 TI - Subcellular trafficking of FGF controls tracheal invasion of Drosophila flight muscle. AB - To meet the extreme oxygen demand of insect flight muscle, tracheal (respiratory) tubes ramify not only on its surface, as in other tissues, but also within T tubules and ultimately surrounding every mitochondrion. Although this remarkable physiological specialization has long been recognized, its cellular and molecular basis is unknown. Here, we show that Drosophila tracheoles invade flight muscle T tubules through transient surface openings. Like other tracheal branching events, invasion requires the Branchless FGF pathway. However, localization of the FGF chemoattractant changes from all muscle membranes to T-tubules as invasion begins. Core regulators of epithelial basolateral membrane identity localize to T tubules, and knockdown of AP-1gamma, required for basolateral trafficking, redirects FGF from T-tubules to surface, increasing tracheal surface ramification and preventing invasion. We propose that tracheal invasion is controlled by an AP 1-dependent switch in FGF trafficking. Thus, subcellular targeting of a chemoattractant can direct outgrowth to specific domains, including inside the cell. PMID- 25557077 TI - The cell biology of malaria infection of mosquito: advances and opportunities. AB - Recent reviews (Feachem et al.; Alonso et al.) have concluded that in order to have a sustainable impact on the global burden of malaria, it is essential that we knowingly reduce the global incidence of infected persons. To achieve this we must reduce the basic reproductive rate of the parasites to < 1 in diverse epidemiological settings. This can be achieved by impacting combinations of the following parameters: the number of mosquitoes relative to the number of persons, the mosquito/human biting rate, the proportion of mosquitoes carrying infectious sporozoites, the daily survival rate of the infectious mosquito and the ability of malaria-infected persons to infect mosquito vectors. This paper focuses on our understanding of parasite biology underpinning the last of these terms: infection of the mosquito. The article attempts to highlight central issues that require further study to assist in the discovery of useful transmission-blocking measures. PMID- 25557081 TI - Onset of psoriatic arthritis during ustekinumab treatment for psoriasis: a case series of seven patients. PMID- 25557082 TI - Evaluation of new silica-based humic acid stationary phase for the separation of tocopherols in cold-pressed oils by normal-phase high-performance liquid chromatography. AB - A new humic acid stationary phase was prepared by immobilizing humic acid onto aminopropyl silica via an amide linkage formation and used, for the first time, for the separation and quantification of the tocopherol compounds in cold-pressed oil samples under normal-phase high-performance liquid chromatography conditions. Parameters affecting the chromatographic separation such as mobile phase composition and flow rate were optimized. By evaluating the calculations of capacity factor, asymmetry factor, resolution, selectivity factor, and theoretical plate number, the best separation was obtained with isocratic elution of n-hexane and isopropyl alcohol (99:1% v/v) at a flow rate of 1.0 mL/min. The effluent was monitored by a fluorescence detector set at excitation and emission wavelengths 295 and 330 nm, respectively. All compounds were separated in 20 min. The method was validated according to international guidelines and found to be linear in a wide concentration range, also the mean recovery of the compounds ranged from 97.9 to 99.2%, with a CV less than 2.7% in all cases. The results showed that the developed stationary phase is suitable for the separation and quantification of the tocopherol compounds in real oil samples. PMID- 25557079 TI - Low affinity binding site clusters confer hox specificity and regulatory robustness. AB - In animals, Hox transcription factors define regional identity in distinct anatomical domains. How Hox genes encode this specificity is a paradox, because different Hox proteins bind with high affinity in vitro to similar DNA sequences. Here, we demonstrate that the Hox protein Ultrabithorax (Ubx) in complex with its cofactor Extradenticle (Exd) bound specifically to clusters of very low affinity sites in enhancers of the shavenbaby gene of Drosophila. These low affinity sites conferred specificity for Ubx binding in vivo, but multiple clustered sites were required for robust expression when embryos developed in variable environments. Although most individual Ubx binding sites are not evolutionarily conserved, the overall enhancer architecture-clusters of low affinity binding sites-is maintained and required for enhancer function. Natural selection therefore works at the level of the enhancer, requiring a particular density of low affinity Ubx sites to confer both specific and robust expression. PMID- 25557083 TI - Visible red light enhances physiological anagen entry in vivo and has direct and indirect stimulative effects in vitro. AB - BACKGROUND AND OBJECTIVES: Hair follicles are located at the interface of the external and internal environments and their cycling has been shown to be regulated by intra- and extra-follicular factors. The aim of this study is to examine whether or how hair follicles respond to visible light. STUDY DESIGN/MATERIALS AND METHODS: We examined the effect of 3 mW red (630 nm, 1 J/cm(2)), 2 mW green (522 nm, 1 J/cm(2)), and 2 mW blue light (463 nm, 1 J/cm(2)) on telogen in mice for 3 weeks. The photobiologic effects of red light on cell proliferation of outer root sheath keratinocytes and dermal papilla cells were studied in vitro. RESULTS: We found that red light accelerated anagen entry faster than green and blue light in mice. Red light irradiation stimulated the proliferation of both outer root sheath keratinocytes and dermal papilla cells in a dose-dependent manner by promoting cell cycle progression. This stimulative effect was mediated via extracellular signal-regulated kinase phosphorylation in both cells. In a co-culture condition, dermal papilla cells irradiated by red light further enhanced keratinocyte proliferation, suggesting enhanced epithelial mesenchymal interaction. In search for factors that mediated this paracrine effect, we found fibroblast growth factor 7 was upregulated in both mRNA and protein levels. The stimulative paracrine effect on keratinocytes was significantly inhibited by neutralizing antibody against fibroblast growth factor 7. CONCLUSIONS: These results suggest that hair follicles respond to visible light in vivo. Red light may promote physiological telogen to anagen transition by directly stimulating outer root sheath keratinocytes and indirectly by enhancing epithelial-mesenchymal interaction in vitro. PMID- 25557080 TI - Organoid models of human and mouse ductal pancreatic cancer. AB - Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy. PMID- 25557085 TI - Endoscopic cutting technique using scissors forceps after temporary endoscopic naso-gallbladder drainage for acute cholecystitis (with videos). PMID- 25557084 TI - Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures. AB - PURPOSE: The bone changes of vitamin D deficiency rickets have been invoked as an alternate explanation for child-abuse related fractures identified through medical imaging. The lack of modern histopathologic comparisons between these two entities limits the abilities of the forensic pathologist to address this differential diagnosis, both in their autopsy reports and on the witness stand. METHODS: We report a comparison of the histologic appearance of the bones in a two year old child with vitamin D deficiency rickets with fractures occurring in three young children with child abuse. RESULTS: In the case of rickets, there was marked architectural disorganization of endochondral ossification at the costochondral junctions and growth plates of long bones. The child abuse-related fractures showed osteochondral callus at different stages of healing, either centered on a discrete fracture line or at metaphyses (e.g. classical metaphyseal lesions). In many instances, the healing fractures disrupted the line of endochondral ossification. In none of the child abuse-related fractures was there any similarity to the histologic appearance of rickets. CONCLUSION: The maturation disturbance in the growth plate that occurs in rickets is a distinctive entity that cannot be confused histologically with healing fractures, including the classical metaphyseal lesion. PMID- 25557086 TI - Intracranial fat migration: A newly described complication of autologous fat repair of a cerebrospinal fluid leak following supracerebellar infratentorial approach. AB - INTRODUCTION: Intracranial fat migration following autologous fat graft and placement of a lumbar drain for cerebrospinal fluid leak after pineal cyst resection surgery has not been previously reported. CASE PRESENTATION: The authors present a case of a 39-year-old male with a history of headaches who presented for removal of a pineal cyst from the pineal region. He subsequently experienced cerebrospinal fluid leak and postoperative Escherichia coli (E. Coli) wound infection, and meningitis, which were treated initially with wound washout and antibiotics in addition to bone removal and primary repair with primary suture-closure of the durotomy. A lumbar drain was left in place. The cerebrospinal fluid leak returned two weeks following removal of the lumbar drain; therefore, autologous fat graft repair and lumbar drain placement were performed. Three days later, the patient began experiencing right homonymous hemianopia and was found via computed tomography and magnetic resonance imaging to have autologous fat in the infra- and supratentorial space, including intraparenchymal and subarachnoid spread. Symptoms began to resolve with supportive care over 48 hours and had almost fully resolved within one week. DISCUSSION: This is the first known report of a patient with an autologous fat graft entering the subarachnoid space, intraparenchymal space, and ventricles following fat graft and lumbar drainage. CONCLUSION: This case highlights the importance of monitoring for complications of lumbar drain placement. PMID- 25557087 TI - Successful three-year outcome in a patient with allogenous sternal bone graft in the treatment of massive post-sternotomy defects. AB - INTRODUCTION: Deep sternal wound infection is a life-threatening complication of longitudinal median sternotomy with extensive loss of sternal bone tissue and adjacent ribs. Wound dehiscence cases with no loss of bone tissue can be resolved via osteosynthesis using titanium plates. Unfortunately, this cannot be used in cases of massive bone tissue loss defects due to insufficient support for fixing the plate material caused by missing bone surface which increasing the risk of osteosynthesis failure. We describe the treatment outcome of sternal dehiscence with massive bone tissue loss defects using an allogenous sternal bone graft. CASE PRESENTATION: A 62 year old diabetic female was operated for serious sternotomy dehiscence after surgery for aortic valve replacement. There was bone tissue loss and complications. We used allogenous sternal bone graft to close the wound. To monitor the healing of the graft, we performed SPECT/CT examinations of anterior chest wall. We describe the successful healing of the graft with the reduction of defects in osteoblastic activity by 42% 21 months after the graft implantation. The wound was found to be healed on all examinations, The chest wall is stable and the patient reports a good life quality. DISCUSSION: An allogenous bone transplant contains no vital bone marrow cells, which eliminates immuno-genetic graft rejection by the patient. Significant osteoblastic activity was thus registered, especially in places where crushed spongy bone had been applied. CONCLUSIONS: Transplantation of allogenous bone graft sternum in our experience is the best option for treating extensive post-sternotomy defects. PMID- 25557088 TI - Rhinitis in the first 18 months of life: exploring the role of respiratory viruses. AB - BACKGROUND: Rhinitis is common in early childhood, but allergic rhinitis is considered a later manifestation of the atopic march. This study aimed to evaluate rhinitis (allergic and non-allergic) in the first 18 months of life, its link with other atopic manifestations and the role of respiratory viruses. METHODS: Subjects (n = 1237) of the Singapore GUSTO birth cohort were followed up quarterly until 18 months of age with questionnaires to screen for rhinitis symptoms lasting at least 2 wk and with monthly calls to positive subjects to detect prolonged/recurrent rhinitis symptoms (total duration >= 4 wk). Anterior nasal swabbing for molecular-based virus detection was conducted during these visits and near (within a month) rhinitis episodes. Skin prick testing to common environmental and food allergens was conducted at the 18 month visit. RESULTS: Prolonged/recurrent rhinitis was significantly associated with history of parental atopy (mother: aOR = 2.17; father: aOR = 1.82) and atopic comorbidities of eczema (aOR = 2.53) and wheeze (aOR = 4.63) (p < 0.05), though not with allergen sensitization. Although the frequency of nasal respiratory virus detection during scheduled quarterly visits did not differ between prolonged/recurrent rhinitis and matched controls (p > 0.05), virus detection was higher in swabs obtained within a month following rhinitis episodes in prolonged/recurrent rhinitis subjects compared with scheduled visits (adjusted p = 0.04). CONCLUSIONS: Based on the duration of rhinitis symptoms, this study defined a subset of early childhood rhinitis which was associated with atopic predisposition and comorbidities. Persistent respiratory viral shedding may contribute to the symptomatology. Whether this entity is a precursor of subsequent childhood allergic rhinitis will require longer follow-up. PMID- 25557089 TI - Characterization of two CENH3 genes and their roles in wheat evolution. AB - Wheat evolution is complex as a result of successive rounds of allopolyploidization and continuous selection during domestication. Diploid and tetraploid wheat species (Triticum spp.) were used as model systems in which to study the role of centromere-specific histone H3 variant (CENH3) in wheat evolution. We characterized two types of CENH3 genes, named alphaCENH3 and betaCENH3, each of which has three slightly different copies derived from the AA, BB and DD genomes. Specific antibodies were raised against the two CENH3 proteins and were co-localized to centromeres with subtle differences. In most tetraploid wheat species, CENH3 genes are more highly expressed from the AA genome. In wild tetraploids, betaCENH3 has a much lower expression level than alphaCENH3, while in cultivated tetraploids betaCENH3 transcripts are enhanced to near alphaCENH3 levels. Comparison of the CENH3 proteins in wild and cultivated tetraploids revealed that the histone folding domain (HFD) of only betaCENH3 is under positive selection, especially in the region responsible for targeting of CENH3 to the centromere. Taken together, positive selection of betaCENH3 and its increased expression in tetraploid cultivars are indicative of adaptive evolution. Furthermore, the differences in localization between alphaCENH3 and betaCENH3 observed using fiber fluorescence in situ hybridization (FISH) and immunodetection and in developmental phenotypes resulting from virus-reduced gene silencing imply their functional diversification during wheat evolution. PMID- 25557090 TI - Imaging with a small number of photons. AB - Low-light-level imaging techniques have application in many diverse fields, ranging from biological sciences to security. A high-quality digital camera based on a multi-megapixel array will typically record an image by collecting of order 10(5) photons per pixel, but by how much could this photon flux be reduced? In this work we demonstrate a single-photon imaging system based on a time-gated intensified camera from which the image of an object can be inferred from very few detected photons. We show that a ghost-imaging configuration, where the image is obtained from photons that have never interacted with the object, is a useful approach for obtaining images with high signal-to-noise ratios. The use of heralded single photons ensures that the background counts can be virtually eliminated from the recorded images. By applying principles of image compression and associated image reconstruction, we obtain high-quality images of objects from raw data formed from an average of fewer than one detected photon per image pixel. PMID- 25557091 TI - A plasmapheresis protocol for refractory pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of proteinaceous material within the lungs. While typically managed with whole lung lavage (WLL), more recent PAP therapies aimed at reducing granulocyte-macrophage colony stimulating factor autoantibodies (anti-GM-CSF) have reduced symptoms and improved lung function. We present a patient with PAP refractory to WLL, exogenous GM-CSF and rituximab who underwent a novel plasmapheresis protocol as a therapeutic trial. While previously reported regimens have utilized plasmapheresis sessions distributed over months, our patient underwent five consecutive days of plasmapheresis, followed by rituximab. Anti-GM-CSF levels decreased from 24.8 to 2.7 mcg/mL post-plasmapheresis. This reduction of autoantibody correlated with reduction in WLL frequency, increase in diffusing capacity for carbon monoxide, and subjective improvement in dyspnea. Our case suggests that five consecutive days of plasmapharesis results in increased clearance of anti-GM-CSF and may be potentially efficacious in cases of refractory PAP. PMID- 25557092 TI - A pliable electroporation patch (ep-Patch) for efficient delivery of nucleic acid molecules into animal tissues with irregular surface shapes. AB - Delivery of nucleic acids into animal tissues by electroporation is an appealing approach for various types of gene therapy, but efficiency of existing methodsis not satisfactory. Here we present the validation of novel electroporation patch (ep-Patch) for efficient delivery of DNA and siRNA into mouse tissues. Using micromachining technology, closely spaced gold electrodes were made on the pliable parylene substrate to form a patch-like electroporation metrics. It enabled large coverage of the target tissues and close surface contact between the tissues and electrodes, thus providing a uniform electric field to deliver nucleic acids into tissues, even beneath intact skin. Using this ep-Patch for efficiently delivery of both DNA and siRNA, non-invasive electroporation of healthy mouse muscle tissue was successfully achieved. Delivery of these nucleic acids was performed to intact tumors with satisfactory results. Silencing of tumor genes using the ep-Patch was also demonstrated on mice. This pliable electroporation patch method constitutes a novel way of in vivo delivery of siRNA and DNA to certain tissues or organs to circumvent the disadvantages of existing methodologies for in vivo delivery of nucleic acid molecules. PMID- 25557094 TI - Experimental research on safety impacts of the inside shoulder based on driving simulation. AB - Statistical data shows that single-vehicle crashes account for half of all traffic crashes on expressways in China, and previous research has indicated that main contributing factors were related to whether and how the inside shoulder was paved. The inside shoulder provides space for drivers to make evasive maneuvers and accommodate driver errors. However, lower-cost construction solutions in China have resulted in the design of numerous urban expressway segments that lack inside shoulders. This paper has two objectives. The first is to reveal the safety impacts of inside shoulders on urban expressways by driving simulator experiment. The second objective is to propose optimal range and recommended value of inside shoulder width for designing inside shoulders of urban expressways. The empirical data, including subjects' eye movement data, heart rate (HR) and the lateral position of vehicles, were collected in a driving simulator. The data were analyzed to evaluate the safety impacts of the inside shoulder. The results have revealed that the inside shoulder has an impact on drivers' visual perception, behaviors, and psychology; in particular, it has a significant effect on vehicle operations. In addition, this paper recommends the desired and optimal inside shoulder widths for eight-lane, two-way divided expressways. PMID- 25557095 TI - [Molecular biology in pediatric neurosurgery:update]. PMID- 25557096 TI - [Current treatment of acromegaly]. PMID- 25557093 TI - Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes. AB - Abnormal structure and function of astrocytes have been observed within the lamina cribrosa region of the optic nerve head (ONH) in glaucomatous neurodegeneration. Glutamate excitotoxicity-mediated mitochondrial alteration has been implicated in experimental glaucoma. However, the relationships among glutamate excitotoxicity, mitochondrial alteration and ONH astrocytes in the pathogenesis of glaucoma remain unknown. We found that functional N-methyl-d aspartate (NMDA) receptors (NRs) are present in human ONH astrocytes and that glaucomatous human ONH astrocytes have increased expression levels of NRs and the glutamate aspartate transporter. Glaucomatous human ONH astrocytes exhibit mitochondrial fission that is linked to increased expression of dynamin-related protein 1 and its phosphorylation at Serine 616. In BAC ALDH1L1 eGFP or Thy1-CFP transgenic mice, NMDA treatment induced axon loss as well as hypertrophic morphology and mitochondrial fission in astrocytes of the glial lamina. In human ONH astrocytes, NMDA treatment in vitro triggered mitochondrial fission by decreasing mitochondrial length and number, thereby reducing mitochondrial volume density. However, blocking excitotoxicity by memantine (MEM) prevented these alterations by increasing mitochondrial length, number and volume density. In glaucomatous DBA/2J (D2) mice, blocking excitotoxicity by MEM inhibited the morphological alteration as well as increased mitochondrial number and volume density in astrocytes of the glial lamina. However, blocking excitotoxicity decreased autophagosome/autolysosome volume density in both astrocytes and axons in the glial lamina of glaucomatous D2 mice. These findings provide evidence that blocking excitotoxicity prevents ONH astrocyte dysfunction in glaucomatous neurodegeneration by increasing mitochondrial fission, increasing mitochondrial volume density and length, and decreasing autophagosome/autolysosome formation. GLIA 2015;63:736-753. PMID- 25557097 TI - [Application of brain diffusion-weighted imaging performed using readout segmentation of long variable echo trains]. AB - We report the preliminary use of the readout segmentation of long variable echo trains(RESOLVE)sequence, a novel magnetic resonance(MR)scanning technique based on a readout segmented echo planar imaging(EPI)strategy. RESOLVE enables high resolution diffusion-weighted imaging(DWI)by minimizing susceptibility distortions and T2* blurring. The software for this sequence was provided by Siemens AG, Germany. Previously, we determined appropriate sequence parameters to obtain sufficiently high-resolution images through phantom studies. Then, we applied the sequence to some clinical cases with neurological disorders and analyzed the RESOLVE-DWI data with diffusion tensor imaging(DTI)techniques. In this article, we report clinical application of the RESOLVE sequence in two cases, one with cerebellar infarction and one with an intracranial epidermoid cyst. In both cases, RESOLVE-DWI clearly exposed structures that were obscured or severely distorted by artifacts on usual single-shot EPI-DWI. DTI analyses for RESOLVE-DWI data provided detailed information about fiber tracts and cranial nerves. PMID- 25557098 TI - [Pre-surgical simulation of microvascular decompression for hemifacial spasm using 3D-models]. AB - We have been performing pre-surgical simulations using custom-built patient specific 3D-models. Here we report the advantageous use of 3D-models for simulating microvascular decompression(MVD)for hemifacial spasms. Seven cases of MVD surgery were performed. Two types of 3D-printers were used to fabricate the 3D-models:one using plaster as the modeling material(Z Printer(r)450, 3D systems, Rock Hill, SC, USA)and the other using acrylonitrile butadiene styrene(ABS)(UP! Plus 3D printer(r), Beijing Tiertime Technology, Beijing). We tested three types of models. Type 1 was a plaster model of the brainstem, cerebellum, facial nerve, and the artery compressing the root exit zone of the facial nerve. Part of the cerebellum was digitally trimmed off to observe "the compressing point" from the same angle as that used during actual surgery. Type 2 was a modified Type 1 in which part of the skull was opened digitally to mimic a craniectomy. Type 3 was a combined model in which the cerebellum and the artery of the Type 2 model were replaced by a soft retractable cerebellum and an elastic artery. The cerebellum was made from polyurethane and cast from a plaster prototype. To fabricate elastic arteries, liquid silicone was painted onto the surface of an ABS artery and the inner ABS model was dissolved away using solvent. In all cases, the 3D models were very useful. Although each type has advantages, the Type-3 model was judged extremely useful for training junior surgeons in microsurgical approaches. PMID- 25557099 TI - [Cervical spinal dural arteriovenous fistula with rapidly progressive brainstem dysfunction due to venous congestion: a case report]. AB - Spinal dural arteriovenous fistulas(S-dAVFs)are rare vascular malformations of the spine. We experienced a case that presented with rapidly progressive brainstem dysfunction due to venous congestion of cervical dAVFs. A 56-year-old man diagnosed with cervical dAVF four years prior presented with gait disturbance and abnormal thermal nociception on his right side. In addition to the high intensity lesion from the lower pons to the medulla oblongata on T2-weighted magnetic resonance imaging, diffusion-weighted imaging demonstrated cerebral infarction of the left ventrolateral medulla oblongata. Left vertebral angiography revealed that a feeding artery supplied by the radicular artery at the C4 level formed a fistula with the dilated ascending anterior perimedullary vein. We made a diagnosis of venous congestion due to cervical dAVFs. Numbness on the left upper limb occurred five days after the first symptom. Subsequently, hemiparesis on the left upper limb and swallowing disturbance occurred two weeks after the first symptom. The patient underwent surgical ligation of the dilated abnormal vein, with gradual improvement of his symptoms. Myelopathy due to venous congestion of S-dAVFs usually progresses slowly for several years. However, this case report warns about the possibility that some cases of S-dAVF with rapidly exacerbated symptoms may require prompt therapy. PMID- 25557100 TI - [A case of cerebellar hemangioblastoma complicated by pregnancy and concerns about the surgical period]. AB - We report herein a case of cerebellar hemangioblastoma complicated by pregnancy and concerns about the period in which surgery could be performed successfully. A 19-year-old woman, who was also 35 weeks pregnant, was admitted to our hospital with headache, nausea, and general fatigue. Neurological examination on admission revealed disturbed consciousness, and the patient's general condition was poor. Computed tomography and magnetic resonance imaging showed a large tumor in the cerebellar vermis along with an obstructive hydrocephalus. Computed tomographic angiography with three-dimensional reconstruction revealed feeding arteries and a draining vein in this tumor. Based on the clinical features, hemangioblastoma was suspected, and surgical excision and extraction of the fetus were scheduled. However, because of rapid neurological deterioration due to tumor progression, an emergency cesarean section was performed under general anesthesia. After extracting the fetus, the level of consciousness improved, so a tumor resection was planned after the patient's general condition improved. However, the neurological state deteriorated again due to the worsening hydrocephalus, which was suspected to be caused by the increased cerebral blood flow following uterine contraction. Emergency surgery for the brain tumor was performed two days after delivery. The tumor was resected completely and histopathological examination confirmed a diagnosis of hemangioblastoma. The postoperative course was uneventful, and the patient and newborn were discharged with no neurological deficits three weeks after the operation. This case suggested that if we encounter patients with brain tumors complicated by pregnancy, not only is earlier diagnosis from clinical features important, but also persistent additional treatment should be carried out without delay to effectively control intracranial pressure. PMID- 25557101 TI - [Functional mapping using subdural electrodes combined with monitoring during awake craniotomy enabled preservation of function and extensive resection of a glioma adjacent to the parietal lobe language sites: a case report]. AB - INTRODUCTION: Surgical resection of gliomas located in the dominant parietal lobe is difficult because this lesion is surrounded by multiple functional areas. Although functional mapping during awake craniotomy is very useful for resection of gliomas adjacent to eloquent areas, the limited time available makes it difficult to sufficiently evaluate multiple functions, such as language, calculative ability, distinction of right and left sides, and finger recognition. Here, we report a case of anaplastic oligodendroglioma, which was successfully treated with a combination of functional mapping using subdural electrodes and monitoring under awake craniotomy for glioma. CASE PRESENTATION: A 32-year-old man presented with generalized seizure. Magnetic resonance imaging revealed a non enhanced tumor in the left angular and supramarginal gyri. In addition, the tumor showed high accumulation on 11C-methionine positron emission tomography(PET)(tumor/normal brain tissue ratio=3.20). Preparatory mapping using subdural electrodes showed absence of brain function on the tumor lesion. Surgical removal was performed using cortical mapping during awake craniotomy with an updated navigation system using intraoperative magnetic resonance imaging(MRI). The tumor was resected until aphasia was detected by functional monitoring, and the extent of tumor resection was 93%. The patient showed transient transcortical aphasia and Gerstmann's syndrome after surgery but eventually recovered. The pathological diagnosis was anaplastic oligodendroglioma, and the patient was administered chemo-radiotherapy. The patient has been progression free for more than 2 years. CONCLUSION: The combination of subdural electrode mapping and monitoring during awake craniotomy is useful in order to achieve preservation of function and extensive resection for gliomas in the dominant parietal lobe. PMID- 25557102 TI - [A case of acute intracranial epidural hematoma caused by chronic nasal sinusitis]. AB - Non-traumatic intracranial acute epidural hematoma(EDH)is rare. It is mostly caused by coagulation disorders, dural metastasis, or vascular malformations of the dura. We report a case of non-traumatic acute EDH caused by chronic nasal sinusitis and review the literature comprising 10 cases of acute EDH caused by chronic nasal sinusitis. A 16-year-old boy visited our outpatient clinic with a 2 day history of severe headache. He did not have fever or neurological abnormalities and showed no evidence of head trauma. Cranial computed tomography(CT)revealed sphenoid sinusitis and a small amount of epidural air in the middle fossa, but no other intracranial abnormalities. After eight days with no subsequent history of trauma, radiological exams showed a massive acute epidural hematoma in the left middle fossa and temporal convexity without any vascular lesion or skull fracture. The patient underwent a hematoma evacuation that revealed neither a skull fracture nor a vascular abnormality. In this adolescent, chronic nasal sinusitis caused fragility of the meningeal artery wall, an air collection in the epidural space, and the detachment of the dura mater from the inner surface of the skull, thereby resulting in a non-traumatic acute EDH. PMID- 25557103 TI - [Unruptured cerebral aneurysm associated with fenestration of the anterior cerebral artery successfully treated with coil embolization using an intracranial stent: a case report]. AB - Recent sporadic reports have described successful endovascular treatment of cerebral aneurysms associated with fenestration. We experienced an unruptured cerebral aneurysm case, with fenestration of the horizontal portion of the anterior cerebral artery that was successfully treated with coil embolization using an intracranial stent. An 80-year-old man presented with a chief complaint of gait disorder. Magnetic resonance imaging showed an incidental unruptured aneurysm. Three-dimensional digital subtraction angiography revealed a cerebral aneurysm associated with fenestration of the horizontal portion of the anterior cerebral artery. Endovascular surgery was performed at the patient's request. Conservation of the fenestrated vessels and perforators is important in the treatment of cerebral aneurysm associated with fenestration. Intracranial stents are reportedly useful for conserving not only parent vessels but also their perforators. In the present case, no postoperative perforator damage occurred. An endovascular approach is a potential treatment option with full evaluation of the relationship between the aneurysm and fenestrated vessels. PMID- 25557104 TI - [Intracerebral hemorrhage]. PMID- 25557105 TI - Does behaviour play a role in house fly resistance to imidacloprid-containing baits? AB - The objective of this research was to examine the role and type of behavioural mechanisms that function in house fly, Musca domestica L. (Diptera: Muscidae), resistance to an imidacloprid-containing commercial fly bait, QuickBayt((r)) , using an insecticide-susceptible and an imidacloprid-resistant strain. Mortality and feeding behaviour were observed through choice bioassays of three post imidacloprid selected house fly generations to determine whether flies would consume the bait in the presence of an alternative food source. Mortality rates in choice containers progressively decreased in post-selection flies as QuickBayt((r)) no-choice selections proceeded. There were no differences between the proportions of flies observed contacting QuickBayt((r)) and sugar, respectively, a finding that eliminates repellency as a mechanism of stimulus dependent behavioural resistance. However, differences in QuickBayt((r)) consumption and subsequent mortality between choice and no-choice containers provided strong support for the evolution of consumption irritancy- or taste aversion-related behavioural resistance. The results of this study support the responsible rotation of insecticide bait formulations for house fly control. PMID- 25557106 TI - Feasibility of fluorescence-guided resection of recurrent gliomas using five aminolevulinic acid: retrospective analysis of surgical and neurological outcome in 58 patients. AB - Five-aminolevulinic-acid (5-ALA) is known for its benefits in surgery of primary gliomas, but has only been cautiously used in recurrent gliomas dreading over resection, insufficient or false-positive fluorescence in adjuvantly treated tumors. We evaluated intraoperative fluorescence based on tumor pathology, pretreatment as well as surgical and neurological outcome in patients with recurrent gliomas. Patients who underwent fluorescence-guided surgery for recurrent gliomas between 6/2010 and 2/2014 at our institution were retrospectively selected. Degree of surgical resection, neurological status, pathology results, intraoperative fluorescence and follow up status were analyzed. Patients who underwent repeat surgery without 5-ALA were selected as controls. 58 patients with high grade gliomas ( degrees III and degrees IV) were included. 10 of 63 tumors (15.9 %) failed to fluoresce intraoperatively of which nine (90 %) had been adjuvantly treated prior to recurrence, as were 46 of the 53 fluorescing tumors (86.8 %). Non-fluorescing tumors were IDH mutated significantly more often (p = 0.005). 30 tumors (47.6 %) were located eloquently. 51 (80.9 %) patients showed no new neurologic deficits postoperatively. 13 patients (20.6 %) showed no signs of recurrence at their latest follow up. Eight patients were lost to follow up. Overall survival was significantly longer in the 5-ALA group (p = 0.025). Fluorescence-guided surgery in recurrent gliomas is safe and allows for a good surgical and neurological outcome in a difficult surgical environment, especially when used in combination with neuronavigation and intraoperative ultrasound to prevent over-resection. Adjuvant therapy did not significantly influence fluorescing properties. PMID- 25557108 TI - Evidence of high mortality in long term survivors of childhood medulloblastoma. AB - The diagnosis of pediatric medulloblastoma now carries a much improved overall survival; however as outcomes advance, late mortality, from causes such as disease recurrence and subsequent malignancies, are of increasing concern for these patients. Using the Surveillance, Epidemiology, and End Results database, the causes of late mortality in long term survivors of medulloblastoma were evaluated. Patients diagnosed with a medulloblastoma between the ages of 0-19 years who survived at least 5 years after diagnosis were included. Using U.S. population data, standardized mortality ratios (SMRs) were calculated. Cumulative incidence estimates and standardized incidence ratios (SIRs) of subsequent malignancies were calculated. A total of 455 patients were included in the analysis. All patients received radiation as part of therapy. Median age at diagnosis was 7 years, and mean follow-up was 16 years. By the time of last follow-up, 20.4 % of patients had died, representing an SMR of 24.0 (95 % CI 19.3 29.4). Overall survival at 30 years was 65.5 %. Primary recurrence accounted for 59 % of late deaths, while subsequent malignancy accounted for 11.8 %. SIR for subsequent malignancy in these patients was 10.4 (95 % CI 6.9-15.1). The most common secondary tumor was another brain tumor (32 %), followed by thyroid cancer (21 %). These data demonstrate that late mortality remains a significant problem in these patients. The causes of death are largely attributable to disease recurrence and secondary malignancies. Efforts to improve risk stratification and tailor therapy will help in reducing late mortality in this population. PMID- 25557107 TI - HDAC4, a prognostic and chromosomal instability marker, refines the predictive value of MGMT promoter methylation. AB - Chromosomal instability is a hallmark of human cancers and is closely linked to tumorigenesis. The prognostic value of molecular signatures of chromosomal instability (CIN) has been validated in various cancers. However, few studies have examined the relationship between CIN and glioma. Histone deacetylases (HDACs) regulate chromosome structure and are linked to the loss of genomic integrity in cancer cells. In this study, the prognostic value of HDAC4 expression and its association with markers of CIN were investigated by analyzing data from our own and four other large sample databases. The results showed that HDAC4 expression is downregulated in high- as compared to low-grade glioma and is associated with a favorable clinical outcome. HDAC4 expression and CIN were closely related in glioma from both functional and statistical standpoints. Moreover, the predictive value of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status-a widely used glioma marker-was refined by HDAC4 expression level, which was significantly related to CIN in our study. In conclusion, we propose that HDAC4 expression, a prognostic and CIN marker, enhances the predictive value of MGMT promoter methylation status for identifying patients who will most benefit from radiochemotherapy. PMID- 25557109 TI - Li/Ag ratio dependent structure and upconversion photoluminescence of Li(x)Ag(1 x)Yb(0.99)(MoO4)(2):0.01Er(3+) phosphors. AB - A series of double molybdate scheelite-type phosphors LixAg1 xYb0.99(MoO4)2:0.01Er(3+) (x = 0, 0.1, 0.3, 0.5, 0.7, 0.9, 1.0) were synthesized by the solid state reaction method, and their crystal structures and upconversion (UC) luminescence properties were investigated in detail. The phase structure evolution of this series samples was discussed and the selected Li0.5Ag0.5Yb0.99(MoO4)2:0.01Er(3+) was analyzed based on the Rietveld refinement. The UC emission properties and the related UC mechanism were also studied. With an increasing Li/Ag ratio in this host, the UC emission intensities of LixAg1 xYb0.99(MoO4)2:0.01Er(3+) increased obviously, and the enhancement could be attributed to the coupling effect and the nonradiative transition between two energy levels of LixAg1-xYb(MoO4)2 matrices and the activator Er(3+), which have also been analyzed based on the results of the ultraviolet-visible diffuse reflection spectroscopy (UV-vis DRS) and Raman spectroscopy. PMID- 25557110 TI - The early-career consultation psychiatrist: administrative innovations in psychosomatic medicine. PMID- 25557111 TI - Capacity evaluations in late-stage pregnancy. PMID- 25557113 TI - Prevalence of atrial fibrillation and association of previous antithrombotic treatment in patients with cerebral microbleeds. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are associated with an increased risk of intracerebral hemorrhage. The impact of oral anticoagulation (OAC) on CMBs is not well characterized. Our aim was to assess the prevalence of CMBs in stroke and transient ischaemic attack (TIA) patients with atrial fibrillation (AF) and to analyze the implications of previous treatment with OAC. METHODS: In this retrospective analysis on data from a prospectively recruiting stroke registry, patients with ischaemic stroke or TIA with brain magnetic resonance imaging including susceptibility weighted imaging were consecutively enrolled during a 3-year period. For each patient cardiovascular risk factors, AF history and recent diagnosis of AF, present use of OAC and antiplatelets, the National Institute of Health Stroke Scale and the premorbid modified Rankin Scale score were recorded. Two independent raters identified CMBs according to consensus criteria. CMB location was classified as lobar, deep or in the posterior fossa. RESULTS: In all, 785 patients (mean age 63.9 +/- 14.2 years) were included. At least one CMB was detected in 186 (23.7%) patients. CMBs were significantly more frequent in patients with AF (30.5% vs. 22.4%). Patients with previous OAC treatment were more likely to have CMBs (36.7% vs. 22.8%, P = 0.03) and abundant CMBs (n > 10) were more frequent in anticoagulated patients even after adjustment for age. However, age was the only independent factor predicting CMBs (P = 0.001). CONCLUSIONS: Cerebral microbleeds are common in elderly AF patients with acute ischaemic stroke. Previous OAC is associated with a higher number of CMBs predominantly in the lobar location. Establishing a causal relationship requires prospective longitudinal investigation. PMID- 25557114 TI - Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1. AB - AIM: Forkhead box M1 (FoxM1) is a transcription factor that plays important roles in the pathogenesis and progression of human cancers, including hepatocellular carcinoma (HCC). The aim of this study was to examine the involvement of FoxM1 in the anti-cancer action of sorafenib, a multikinase inhibitor, in human HCC cells. METHODS: HCC cell lines HepG2 and HuH-7 were tested. Cell viability was examined using MTT assay and cell invasion was determined with Transwell migration assay. The relevant mRNA expression was determined with RT-PCR, and the proteins were detected using Western blotting and immunofluorescence assays. RNA interference was used to modify the expression of p53 and FoxM1. HuH-7 cell line xenograft mice were used for in vivo study, which were treated with sorafenib (40 mg/kg, po) daily for 3 weeks. RESULTS: Sorafenib (2-20 MUmol/L) inhibited the proliferation of the cells in dose- and time-dependent manners with an IC50 value of nearly 6 MUmol/L at 48 h. Sorafenib (6 MUmol/L) markedly suppressed the cell invasion. Furthermore, sorafenib (2-6 MUmol/L) dose-dependently decreased the expression of FoxM1, MMP-2, and Ki-67, and up-regulated that of p53 in the cells. Silencing p53 abolished the decrease of FoxM1 and increase of p53 in sorafenib treated cells. Silencing FoxM1 significantly reduced the expression of MMP-2 and Ki-67, and enhanced the anti-proliferation action of sorafenib in the cells, whereas overexpression of FoxM1 increased the expression of MMP-2 and Ki-67, and abrogated the anti-proliferation action of sorafenib. In the xenograft mice, sorafenib administration decreased the tumor growth by 40%, and markedly increased the expression of p53, and decreased the expression of FoxM1, MMP-2, and Ki-67 in tumor tissues. CONCLUSION: Sorafenib inhibits HCC proliferation and invasion by inhibiting MMP-2 and Ki-67 expression due to up-regulation of P53 and suppressing FoxM1. PMID- 25557116 TI - Electrical conduction mechanism of an individual polypyrrole nanowire at low temperatures. AB - Conducting polypyrrole (PPY) nanowires doped with p-toluene sulfonamide (PTSA) were synthesized by a template-free self-assembly method. Electrical transport characteristics, i.e. current-voltage (I-V) behavior, of an individual PPY/PTSA nanowire have been explored in a wide temperature range from 300 down to 40 K. The fitting results of I-V curves indicated that the electrical conduction mechanism can be explained by the space-charge-limited current (SCLC) theory from 300 down to 100 K. In this temperature range, traps play an important role for this non-crystalline system. The corresponding trap energy and trap concentration have also been calculated based on the SCLC theory. Interestingly, there is no trap at 160 K, different from other temperatures. The obtained carrier mobility for the polymer nanowires is 0.964 cm(2) V(-1) s(-1) on the basis of trap free SCLC theory. In the temperature range of 80-40 K, little current can flow through the nanowire especially at lower voltages, however, the current follows the equation I infinity (V/Vt-1)(zeta) at higher bias, which could be attributed to Coulomb blockade effect. Additionally, the differential conductance dI/dV curves also show some clear Coulomb oscillations. PMID- 25557115 TI - The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non small cell lung cancer. AB - Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. PMID- 25557117 TI - Recalcitrant psoriatic uveitis and anti-tumor necrosis factor-alpha monoclonal antibodies: experience from a psoriasis referral center. AB - BACKGROUND: The incidence of non-infectious uveitis on a background of psoriasis is estimated to be 7-20%. The use of tumor necrosis factor-alpha (TNF-alpha) inhibitors as a treatment for refractory uveitis is emerging. METHODS: The psoriasis outpatient database at our referral center was searched for patients with concurrent diagnoses of psoriasis and uveitis. The medical records of the patients identified were reviewed for the use of TNF-alpha inhibitors. RESULTS: Five patients (three women and two men) were identified. All of them suffered moderate to severe psoriasis and chronic, bilateral uveitis. The patient with the most severe ocular inflammation was the only patient positive for human leukocyte antigen B27 (HLA-B27) and the only one to suffer from psoriatic arthritis. All patients had received treatment with adalimumab and had been evaluated at three and six months. Their psoriasis had responded excellently, and in four patients, uveitis had shown the complete remission of inflammation at six months. The fifth patient (HLA-B27+) exhibited improved uveitis activity but not complete remission at six months. CONCLUSIONS: Uveitis is an entity that should be considered when evaluating psoriasis patients with ocular complaints, even in the absence of arthritis. Anti-TNF-alpha monoclonal antibodies and adalimumab in particular seem to represent a promising therapeutic avenue for the treatment of refractory psoriatic uveitis. Larger randomized clinical trials are needed to confirm our conclusions. PMID- 25557118 TI - Lipocalin-2 enhances angiogenesis in rat brain endothelial cells via reactive oxygen species and iron-dependent mechanisms. AB - Inflammation is a key part of central nervous system pathophysiology. However, inflammatory factors are now thought to have both beneficial and deleterious effects. Here, we examine the hypothesis that lipocalin-2 (LCN2), an inflammatory molecule that can be up-regulated in the distressed central nervous system, may enhance angiogenesis in brain endothelial cells. Adding LCN2 (0.5-2.0 MUg/mL) to RBE (Rat brain endothelial cells). 4 rat brain endothelial cells significantly increased matrigel tube formation and scratch migration, and also elevated levels of iron and reactive oxygen species. Co-treatment with a radical scavenger (U83836E), a Nox inhibitor (apocynin) and an iron chelating agent (deferiprone) significantly dampened the ability of LCN2 to enhance tube formation and scratch migration in brain endothelial cells. These findings provide in vitro proof of the concept that LCN2 can promote angiogenesis via iron- and reactive oxygen species-related pathways, and support the idea that LCN2 may contribute to the neurovascular recovery aspects of inflammation. Angiogenesis is an important part of stroke recovery. In the present study, we examined the hypothesis that lipocalin-2 (LCN2) may enhance angiogenesis in brain endothelial cells. LCN2 promoted tube formation and migration via iron and ROS-related pathways in rat brain endothelial cells. ROS scavengers, Nox inhibitors and iron chelators all dampened the ability of LCN2 to enhance in vitro angiogenesis. These findings support the idea that LCN2 that is released by damaged neurons may act as a 'help me' signal that promotes neurovascular recovery after stroke and brain injury. PMID- 25557120 TI - Fluorene-based sensitizers with a phenothiazine donor: effect of mode of donor tethering on the performance of dye-sensitized solar cells. AB - Two types of fluorene-based organic dyes featuring T-shape/rod-shape molecular configuration with phenothiazine donor and cyanoacrylic acid acceptor have been synthesized and characterized as sensitizers for dye-sensitized solar cells. Phenothiazine is functionalized at either nitrogen (N10) or carbon (C3) to obtain T-shape and rod-like organic dyes, respectively. The effect of structural alternation on the optical, electrochemical, and the photovoltaic properties is investigated. The crystal structure determination of the dye containing phenyl linker revealed cofacial slip-stack columnar packing of the molecules. The trends in the optical properties of the dyes are interpreted using time-dependent density functional theory (TDDFT) computations. The rod-shaped dyes exhibited longer wavelength absorption and low oxidation potentials when compared to the corresponding T-shaped dyes attributable to the favorable electronic overlap between the phenothiazine unit and the rest of the molecule in the former dyes. However, the T-shaped dyes showed better photovoltaic properties due to the lowest unoccupied molecular orbital (LUMO) energy level favorable for electron injection into the conduction band of TiO2 and appropriate orientation of the phenothiazine unit rendering effective surface blocking to suppress the recombination of electrons between the electrolyte I3(-) and TiO2. The electrochemical impedance spectroscopy investigations provide further support for the variations in the electron injection and transfer kinetics due to the structural modifications. PMID- 25557121 TI - Why is heart failure so important in the 21st century? PMID- 25557119 TI - Nucleolar protein PES1 is a marker of neuroblastoma outcome and is associated with neuroblastoma differentiation. AB - Neuroblastoma (NB) is a childhood malignant tumor that arises from precursor cells of the sympathetic nervous system. Spontaneous regression is a phenomenon unique to NBs and is caused by differentiation of tumor cells. PES1 is a multifunctional protein with roles in both neural development and ribosome biogenesis. Various kinds of models have revealed the significance of PES1 in neurodevelopment. However, the roles of PES1 in NB tumorigenesis and differentiation have remained unknown. Here we show that NB cases with MYCN amplification and clinically unfavorable stage (INSS stage 4) express higher levels of PES1. High PES1 expression was associated with worse overall and relapse-free survival. In NB cell lines, PES1 knockdown suppressed tumor cell growth and induced apoptosis. This growth inhibition was associated with the expression of NB differentiation markers. However, when the differentiation of NB cell lines was induced by the use of all-trans retinoic acid, there was a corresponding decrease in PES1 expression. Pes1 expression of tumorspheres originated from MYCN transgenic mice also diminished after the induction of differentiation with growth factors. We also reanalyzed the distribution of PES1 in the nucleolus. PES1 was localized in the dense fibrillar component, but not in the granular component of nucleoli. After treatment with the DNA-damaging agent camptothecin, this distribution was dramatically changed to diffuse nucleoplasmic. These data suggest that PES1 is a marker of NB outcome, that it regulates NB cell proliferation, and is associated with NB differentiation. PMID- 25557122 TI - Clinical experience of seropositive ganglionic acetylcholine receptor antibody in a tertiary neurology referral center. AB - INTRODUCTION: Antibody against the acetylcholine receptor of autonomic ganglia (gAChR-Ab) is implicated in the pathogenesis of autoimmune autonomic ganglionopathy (AAG) and several other disorders. METHODS: This study was a retrospective evaluation of 95 patients positive for gAChR-Ab. RESULTS: Twenty one (22%) patients had AAG, with a greater median gAChR-Ab level (0.21 nmol/L) and higher percentage (57%) of antibody levels >0.20 nmol/L when compared with the remaining 74 patients without autonomic manifestations (non-AAG group, 0.10 nmol/L and 15%, respectively). Only 2 new cases of malignancy were diagnosed after gAChR-Ab detection. The non-AAG group was associated with high frequencies of neurological and non-neurological autoimmunity, but also included 23 (31%) patients with mostly degenerative disorders. CONCLUSION: Detection of gAChR-Ab, especially at a higher level, is helpful for the diagnosis of AAG in patients with corresponding autonomic symptoms. However, its value is limited for predicting cancer risk and for diagnosis and management of patients without autonomic symptoms. PMID- 25557123 TI - Is cognitive impairment in cirrhotic patients due to increased peroxynitrite and oxidative stress? AB - Cirrhotic patients may suffer minimal hepatic encephalopathy (MHE), with mild cognitive impairment. 3-Nitro-tyrosine levels are a good biomarker for diagnosis of the cognitive impairment and MHE in cirrhotic patients. This suggests that oxidative stress could be involved in the induction of cognitive and motor alterations in MHE. We have observed that patients with MHE show increased oxidative stress in blood compared with cirrhotic patients without MHE, with increased lipid peroxidation, DNA oxidation, protein carbonylation, 3 nitrotyrosine, oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio, and GSH levels. The activities of antioxidant enzymes are enhanced in erythrocytes and mononuclear cells from patients with and without MHE compared with control subjects. Only glutathione peroxidase activity was increased in MHE patients compared with patients without MHE. Oxidative stress markers in blood, especially GSSG/GSH ratio, GSH, malondialdehyde, and 3-nitrotyrosine, correlate with deficits in attention and motor coordination. The increase in antioxidant activities in patients would be an adaptive mechanism to cope with enhanced oxidative stress, although it is not effective enough to normalize it. Our observations lead to the hypothesis that oxidative stress and increased peroxynitrite formation would mediate the synergistic effects of hyperammonemia and inflammation on cognitive and motor impairment in MHE. PMID- 25557124 TI - Thyroid-stimulating hormone acutely increases levels of circulating pro-coagulant microparticles. PMID- 25557125 TI - Propofol-ketamine or propofol-remifentanil for deep sedation and analgesia in pediatric patients undergoing burn dressing changes: a randomized clinical trial. AB - OBJECTIVE: In this study, we compared the propofol-ketamine and propofol remifentanil combinations for deep sedation and analgesia during pediatric burn wound dressing changes. METHODS: Fifty pediatric patients aged 12-36 months, undergoing burn wound dressing changes, were randomly assigned to receive propofol-remifentanil (group PR) or propofol-ketamine (group PK) for deep sedation and analgesia. Patients in the group PR received 2 mg.kg(-1) propofol and 0.1 MUg.kg(-1) remifentanil, and 0.05 MUg.kg(-1) .min(-1) remifentanil was infused continuously until the end of the procedure. Patients in the group PK received 2 mg.kg(-1) propofol and 1 mg.kg(-1) ketamine, and the same volume of isotonic saline was infused continuously until the end of the procedure. Additional propofol with remifentanil or ketamine was administered when required. Hemodynamic variables, drug requirements, occurrence of patient movement, surgeon's satisfaction score, recovery time, and the incidence of adverse events were recorded throughout the procedure and recovery. RESULTS: Recovery time was significantly shorter in the group PR compared to that in the group PK (10.3 [9.1 11.5] min vs 22.5 [20.3-25.6] min, median [interquartile range], respectively; P < 0.001). No significant hypotension or bradycardia occurred throughout the procedure. No significant differences were observed in terms of drug requirements, occurrence of patient movement, surgeon's satisfaction, incidence of respiratory depression, hypoxia, or nausea and vomiting CONCLUSIONS: The combinations of propofol-ketamine and propofol-remifentanil were effective for sedation and analgesia in pediatric patients undergoing burn dressing changes, but the propofol-remifentanil combination provided faster recovery compared to the propofol-ketamine combination. PMID- 25557126 TI - Multislice algorithms revisited: solving the Schrodinger equation numerically for imaging with electrons. AB - For a long time, the high-energy approximation was sufficient for any image simulation in electron microscopy. This changed with the advent of aberration correctors that allow high-resolution imaging at low electron energies. To deal with this fact, we present a numerical solution of the exact Schrodinger equation that is novel in the field of electron microscopy. Furthermore, we investigate systematically the advantages and problems of several multislice algorithms, especially the real-space algorithms. PMID- 25557127 TI - Persistent infections with infectious pancreatic necrosis virus (IPNV) of different virulence in Atlantic salmon, Salmo salar L. AB - Infectious pancreatic necrosis virus (IPNV) is a prevalent pathogen in fish worldwide. The virus causes substantial mortality in Atlantic salmon juveniles and smolts when transferred to sea water and persistent infection in surviving fish after disease outbreaks. Here, we have investigated the occurrence of the virus as well as the innate immune marker Mx in the head kidney (HK) of Atlantic salmon throughout an experimental challenge covering both a fresh and a seawater phase. The fish were challenged with a high (HV) and low virulence (LV) IPNV. Both isolates caused mortality due to reactivation of the virus after transfer to sea water. In the freshwater phase, higher levels of virus transcripts were detected in the HK of fish infected with LV IPNV compared to HV, suggesting that the HV isolate is able to limit its own replication to a level where the innate immune system is not alerted. Further, ex vivoHK leucocytes derived from fish infected with the two isolates were stimulated with CpG DNA. Significantly, higher IFN levels were found in the LV compared to the HV group in the freshwater phase. This suggests that the viruses attenuate the antiviral host immune response at different levels which may contribute to the observed differences in disease outcome. PMID- 25557129 TI - Thermal Influence of an Alpine Deep Hydrothermal Fault on the Surrounding Rocks. AB - Major fault zones in mountain areas are often associated with cold-water circulations and hydrothermal pathways. Compared with the massif as a whole, the deep groundwater flows in these high hydraulic-conductivity zones modify the thermal state of the surrounding rock. This paper examines the thermal effects of groundwater flow in the area around the steeply dipping La Lechere deep fault zone (LFZ, French Alps) and associated shallow decompressed zone. We used a 3D numerical model drawn up from groundwater circulation data to investigate the La Lechere hydrothermal system and the thermal state of the rock in the valley sides. Hydrothermal simulations showed that convective flow into the LFZ cools the valley sides and creates a thermal upwelling under the valley floor. An unsteady thermal regime that continues for about 10,000 years is also needed to obtain the temperatures currently found under the valley floor in the LFZ. Temperature-depth profiles around the LFZ show disturbances in the thermal gradients in the valley sides and the valley floor. Convective heat transfer into the LFZ and the decompressed zone, and conductive heat transfer in the surrounding rocks produce an unsteady, asymmetric thermal state in the rock on both sides of the LFZ. PMID- 25557128 TI - Effect of warning statements in e-cigarette advertisements: an experiment with young adults in the United States. AB - BACKGROUND AND AIMS: This on-line experiment examined whether the addition of ingredient- or industry-themed warning statements in television advertisements for e-cigarettes would affect young adults' craving for and risk perceptions of e cigarettes and combustible cigarettes, as well as intent to purchase e cigarettes. DESIGN: Advertisements for two leading e-cigarette brands were edited to contain a warning statement about product ingredients or about the tobacco industry. Participants were assigned randomly to one of eight treatments or one of two brand-specific control conditions without any warning statement. PARTICIPANTS: Young adults (n=900, aged 18-34 years) in a web panel were recruited from three groups: recent e-cigarette users, current smokers who used combustible cigarettes exclusively and non-users of either product. MEASUREMENTS: Craving and risk perceptions (addictiveness, harmful to health in general, harmful to others) were measured separately for e-cigarettes and combustible cigarettes. The Juster scale measured intention to purchase e-cigarettes. FINDINGS: Exposure to both types of warnings was associated with lower craving for e-cigarettes among e-cigarette users and smokers who experienced any craving (P<0.01) and lower intention to purchase among all participants (P<0.001). Only exposure to ingredient-themed warnings was associated with lower craving for combustible cigarettes (P<0.05). Participants who saw industry-themed warnings reported greater perceptions of general harm (P<0.001), but also rated e cigarettes as less addictive than the control conditions (P<0.05). CONCLUSION: The addition of ingredient- or industry-themed warning statements to e-cigarette television advertising similarly reduces craving and purchase intent for e cigarettes, but has inconsistent effects on perceived risks. PMID- 25557130 TI - Association of previous injury and speed with running style and stride-to-stride fluctuations. AB - Running-related injuries remain problematic among recreational runners. We evaluated the association between having sustained a recent running-related injury and speed, and the strike index (a measure of footstrike pattern, SI) and spatiotemporal parameters of running. Forty-four previously injured and 46 previously uninjured runners underwent treadmill running at 80%, 90%, 100%, 110%, and 120% of their preferred running speed. Participants wore a pressure insole device to measure SI, temporal parameters, and stride length (S(length)) and stride frequency (S(frequency)) over 2-min intervals. Coefficient of variation and detrended fluctuation analysis provided information on stride-to-stride variability and correlative patterns. Linear mixed models were used to compare differences between groups and changes with speed. Previously injured runners displayed significantly higher stride-to-stride correlations of SI than controls (P = 0.046). As speed increased, SI, contact time (T(contact)), stride time (T(stride)), and duty factor (DF) decreased (P < 0.001), whereas flight time (T(flight)), S(length), and S(frequency) increased (P < 0.001). Stride-to-stride variability decreased significantly for SI, T(contact), T(flight), and DF (P <= 0.005), as did correlative patterns for T(contact), T(stride), DF, S(length), and S(frequency) (P <= 0.044). Previous running-related injury was associated with less stride-to-stride randomness of footstrike pattern. Overall, runners became more pronounced rearfoot strikers as running speed increased. PMID- 25557131 TI - Immunological effects of a tumor necrosis factor alpha-armed oncolytic adenovirus. AB - For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24 hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy. PMID- 25557132 TI - Difficult decision: what should we do when a VAD-supported child experiences a severe stroke? PMID- 25557133 TI - Impaired expression of HIF-2alpha induces compensatory expression of HIF-1alpha for the recovery from anemia. AB - Erythropoiesis is strongly influenced by the interactions between stromal cells and erythroid progenitors, as well as by a key regulatory factor, erythropoietin (EPO). We previously generated mice with a knockdown mutation of Hif-2alpha (referred to as kd/kd) and found that these kd/kd mice exhibited normocytic anemia, even though the EPO expression was not severely affected. However, the VCAM-1 expression in spleen endothelial cells (EC), which is regulated by HIF 2alpha, was impaired, resulting in defective erythroid maturation. A deficiency of HIF-2alpha clearly led to pancytopenia. However, the critical level of HIF 2alpha required for erythropoiesis has not yet been elucidated. In this study, we generated HIF-2alpha knockdown/knockout heterozygous mice (kd/null). Strikingly, anemia was observed in the kd/null mice, but the red blood cell indices were significantly improved compared to those of kd/kd mice. In the spleens of kd/null mice, higher HIF-1alpha activity and expansion of the red pulp area were observed compared to those of kd/kd mice. Importantly, EC isolated from kd/null spleens showed high expression of VEGF receptors, FLK-1 and FLT-1, which are regulated by HIF-1alpha instead of HIF-2alpha under hypoxic conditions. We also found higher expression of phosphorylated ERK and higher proliferative activity in the EC isolated from kd/null mice compared to those from kd/kd mice. While the HIF 2alpha expression was diminished, HIF-1alpha bound to the HRE region in the promoters of genes that are normally regulated by HIF-2alpha. These results suggest that there is a compensatory pathway involving HIF-1alpha that regulates the expression of some HIF-2alpha target genes. PMID- 25557135 TI - Alkane metathesis with the tantalum methylidene [(=SiO)Ta(?CH2)Me2]/[(=SiO)2Ta(?CH2)Me] generated from well-defined surface organometallic complex [(=SiO)Ta(V)Me4]. AB - By grafting TaMe5 on Aerosil700, a stable, well-defined, silica-supported tetramethyl tantalum(V) complex, [(=SiO)TaMe4], is obtained on the silica surface. After thermal treatment at 150 degrees C, the complex is transformed into two surface tantalum methylidenes, [(=SiO)2Ta(?CH2)Me] and [(=SiO)Ta(?CH2)Me2], which are active in alkane metathesis and comparable to the previously reported [(=SiO)2TaHx]. Here we present the first experimental study to isolate and identify a surface tantalum carbene as the intermediate in alkane metathesis. A systematic experimental study reveals a new reasonable pathway for this reaction. PMID- 25557134 TI - Conditional survival in pediatric malignancies: analysis of data from the Childhood Cancer Survivor Study and the Surveillance, Epidemiology, and End Results Program. AB - BACKGROUND: Long-term survivors of pediatric cancer are at risk of life threatening late effects of their cancer. Previous studies have shown excesses in long-term mortality within high-risk groups defined by demographic and treatment characteristics. METHODS: To investigate conditional survival in a pediatric cancer population, the authors performed an analysis of conditional survival in the original Childhood Cancer Survivor Study (CCSS) cohort and the Surveillance, Epidemiology, and End Results (SEER) database registry. The overall probability of death for patients at 5 years and 10 years after they survived 5, 10, 15, and 20 years since cancer diagnosis and cause-specific death in 10 years for 5-year survivors were estimated using the cumulative incidence method. RESULTS: Among patients in the CCSS and SEER cohorts who were alive 5 years after their cancer diagnosis, within each diagnosis group at least 92% were alive in the subsequent 5 years, except for patients with leukemia, of whom only 88% of 5-year survivors remained alive in the subsequent 5 years. The probability of all-cause mortality in the next 10 years among patients who survived at least 5 years after diagnosis was 8.8% in CCSS and 10.6% in SEER, approximately 75% of which was due to neoplasms as the cause of death. CONCLUSIONS: The risk of death among survivors of pediatric cancer in 10 years can vary between diagnosis groups by at most 12%, even up to 20 years after diagnosis. This information is clinically significant when counseling patients regarding their conditional survival, particularly when survivors are seen in long-term follow-up. PMID- 25557136 TI - Surgical management of major intrathoracic hemorrhage resulting from high-risk transvenous pacemaker/defibrillator lead extraction. AB - A method, based on well-established trauma principles, is described for surgical management of serious intrathoracic bleeding complications that can occur during the extraction of pacemaker or defibrillator leads. Using this method, four patients who experienced rapid hemodynamic deterioration due to traumatic injury of the superior vena cava and its tributaries during defibrillator lead extraction underwent successful surgical repair. Perioperative preparation for high-risk lead extractions, management of major bleeding complications, and surgical repair techniques are discussed. Major bleeding complications can be managed effectively with this strategy leading to excellent overall success rates for extractions without mortality. PMID- 25557137 TI - Actin crosslinking protein filamin A during early pregnancy in the rat uterus. AB - During early pregnancy the endometrium undergoes a major transformation in order for it to become receptive to blastocyst implantation. The actin cytoskeleton and plasma membrane of luminal uterine epithelial cells (UECs) and the underlying stromal cells undergo dramatic remodelling to facilitate these changes. Filamin A (FLNA), a protein that crosslinks actin filaments and also mediates the anchorage of membrane proteins to the actin cytoskeleton, was investigated in the rat uterus at fertilisation (Day 1) and implantation (Day 6) to determine the role of FLNA in actin cytoskeletal remodelling of UECs and decidua during early pregnancy. Localisation of FLNA in UECs at the time of fertilisation was cytoplasmic, whilst at implantation it was distributed apically; its localisation is under the influence of progesterone. FLNA was also concentrated to the first two to three stromal cell layers at the time of fertilisation and shifted to the primary decidualisation zone at the time of implantation. This shift in localisation was found to be dependent on the decidualisation reaction. Protein abundance of the FLNA 280-kDa monomer and calpain-cleaved fragment (240kDa) did not change during early pregnancy in UECs. Since major actin cytoskeletal remodelling occurs during early pregnancy in UECs and in decidual cells, the changing localisation of FLNA suggests that it may be an important regulator of cytoskeletal remodelling of these cells to allow uterine receptivity and decidualisation necessary for implantation in the rat. PMID- 25557139 TI - The "kidney-liver" multiorgan ex vivo perfused model improves the circuit's biochemical milieu during perfusion compared to the "liver-kidney" counterpart. AB - The multiorgan ex vivo perfused liver-kidney model allows studying the hepatic pathophysiology and purifying waste products. We tested if the addition of the kidney first followed by the liver (KL circuit) produces better results compared to the classic liver-first approach (LK). Intact livers and kidneys were obtained post mortem from ten female domestic white pigs, five experiments were conducted with the KL circuit and five with the LK. Bile, urine production, arterial blood gases, glucose, renal and liver tests were collected hourly during the perfusions. The KL circuit had values more close to physiological ranges, more stable over time and showed less variability compared to the LK circuit for urine production, glucose, PH, anion gap, lactate, urea, sodium, potassium and Alanine Transaminase (ANOVA test for repeated measures p < 0.05). The KL circuit produced a more physiological and reliable biochemical milieu. PMID- 25557140 TI - Recombination products suggest the frequent occurrence of aberrant gene replacement in the moss Physcomitrella patens. AB - In gene replacement, a variant of gene targeting, transformed DNA integrates into the genome by homologous recombination (HR) to replace resident sequences. Gene replacement in the moss Physcomitrella patens is extremely efficient, but often large amounts of additional DNA are integrated at the target locus. A detailed analysis of recombination junctions of PpCOL2 gene knockout mutants shows that the integrated DNA can be highly rearranged. Our data suggest that the replaced sequences were excised by HR and became integrated back into the genome by non homologous end-joining (NHEJ). RAD51-mediated strand-invasion and subsequent strand-exchange is central to the two-end invasion pathway, the major gene replacement pathway in yeast. In this pathway, integration is initiated by the free ends of a single replacement vector-derived donor molecule which then integrates as an entity. Gene replacement in P. patens is entirely RAD51 dependent suggesting the existence of a pathway mechanistically similar to two end invasion. However, invasion of the two ends does not seem to be stringently coordinated in P. patens. Actually, often only one fragment end became integrated by HR, or one-sided integration of two independent donor fragments occurred simultaneously leading to a double-strand break that is subsequently sealed by NHEJ and thus causes the observed rearrangements. PMID- 25557138 TI - Long-term outcome of loss-of-function mutations in thyrotropin receptor gene. AB - BACKGROUND: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations. METHODS: The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH. RESULTS: Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time. CONCLUSION: SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended. PMID- 25557142 TI - Thermal stability of gold nanoparticles embedded within metal oxide frameworks fabricated by hybrid modifications onto sacrificial textile templates. AB - The stability and spatial separation of nanoparticles (NP's) is essential for employing their advantageous nanoscale properties. This work demonstrates the entrapment of gold NP's embedded in a porous inorganic matrix. Initially, gold NP's are decorated on fibrous nylon-6, which is used as an inexpensive sacrificial template. This is followed by inorganic modification using a novel single exposure cycle vapor phase technique resulting in distributed NP's embedded within a hybrid organic-inorganic matrix. The processing is extended to the synthesis of porous nanoflakes after calcination of the modified nylon-6 yielding a porous metal oxide framework surrounding the disconnected NP's with a surface area of 250 m(2)/g. A unique feature of this work is the use of a transmission electron microscope (TEM) equipped with an in situ annealing sample holder. The apparatus affords the opportunity to explore the underlying nanoscopic stability of NP's embedded in these frameworks in a single step. TEM analysis indicates thermal stability up to 670 degrees C and agglomeration characteristics thereafter. The vapor phase processes developed in this work will facilitate new complex NP/oxide materials useful for catalytic platforms. PMID- 25557141 TI - Population pharmacokinetic model of free and total ropivacaine after transversus abdominis plane nerve block in patients undergoing liver resection. AB - AIMS: The aim of this study was to develop a pharmacokinetic model in order to characterize the free and total ropivacaine concentrations after transversus abdominis plane block in a population of patients undergoing liver resection surgery. In particular, we evaluated the impact of the size of liver resection on ropivacaine pharmacokinetics. METHODS: This work is based on a single-centre, double-blinded, randomized, placebo-controlled study. Among the 39 patients included, 19 patients were randomized to the ropivacaine group. The free and total ropivacaine concentrations were measured in nine or 10 blood samples per patient. A pharmacokinetic model was built using a nonlinear mixed-effect modelling approach. RESULTS: The free ropivacaine concentrations remained under the previously published toxic threshold. A one-compartment model, including protein binding site with a first-order absorption, best described the data. The protein binding site concentration was considered as a latent variable. Bodyweight, the number of resected liver segments and postoperative fibrinogen evolution were, respectively, included in the calculation of the volume of distribution, clearance and binding site production rate. The resection of three or more liver segments was associated with a 53% decrease in the free ropivacaine clearance. CONCLUSIONS: Although large liver resections were associated with lower free ropivacaine clearance, the ropivacaine pharmacokinetic profile remained within the safe range after this type of surgery. PMID- 25557143 TI - Next-generation training: publishing student scientists' research. AB - Too often, young students fail to translate their childhood curiosity into a passion for scientific discovery. The Journal of Emerging Investigators (JEI) aims to stimulate scientific curiosity in middle and high school students by providing them with an opportunity to publish their science projects in an open access, peer-reviewed journal. PMID- 25557144 TI - Risk of tuberculosis in patients treated with anti-tumor necrosis factor therapy: a nationwide study in South Korea, a country with an intermediate tuberculosis burden. AB - AIM: The aim of this study was to investigate the incidence of tuberculosis (TB) following anti-tumor necrosis factor (TNF) therapy in an intermediate TB burden area and to compare the risk between drugs and diseases. METHODS: The data were obtained from a nationwide database maintained by the Health Insurance Review and Assessment Service. The study population comprised of patients who were prescribed with TNF inhibitors from 2005 to 2009. TB cases were selected based on prescription of anti-TB medications. RESULTS: Of 8421 patients in the study population, 1729 patients with latent TB prophylaxis were identified and 102 patients developed TB. The incidence of TB was 1017 per 100 000 person-years. When divided into four groups according to the main diagnosis and using an ankylosing spondylitis group as a reference, the incidence of TB was highest in patients with inflammatory bowel disease (IBD) (incidence rate ratio [IRR] 5.97, 95% confidence interval [CI] 3.34-10.66), followed by patients with rheumatoid arthritis (IRR 1.02, 95% CI 0.57-1.83) and those with psoriatic arthritis (IRR 1.00, 95% CI 0.14-7.30). Comparison between drugs showed a significantly lower incidence of TB in patients treated with etanercept (reference), highest incidence in those treated with infliximab (IRR 6.8, 95% CI 3.74-12.37) and an intermediate incidence in patients treated with adalimumab (IRR 3.45, 95% CI 1.82 6.55). CONCLUSIONS: The difference in TB risk between TNF inhibitors was similar with countries of low TB burden. This study suggests that particular attention is required for patients treated with TNF monoclonal antibodies. PMID- 25557145 TI - Perceived Exercise Self-Efficacy, Benefits and Barriers, and Commitment to a Plan for Exercise among Jordanians with Chronic Illnesses. AB - PURPOSE: To explore Jordanian chronic illnesses patients' perceived exercise self efficacy, benefits and barriers, and commitment to exercise planning, and to assess the relationship between those variables. DESIGN: Descriptive cross sectional design. METHODS: Data were collected from a convenience sample of 402 outpatient Jordanians with chronic illnesses, using Exercise Self-Efficacy Scale, Exercise Benefits and Barriers Scale, and Commitment to a Plan for Exercise Scale. FINDINGS: The average BMI was 28.3, and exercise period 3.2 hours/ week. Participants reported moderate perceived self-efficacy (M= 47.5%, SD= 11.7), commitment to exercise planning (M=2.0/3, SD=0.3), exercise barriers (M=2.4/4, SD=0.3), and benefits (M=2.3/4, SD=0.3). Commitment to exercise planning had a significant correlation with barriers (r=0.11) and benefits (r=0.10). Self efficacy was not found to correlate with other variables. CONCLUSIONS: Even though participants reported higher perceived self-efficacy and commitment to exercise plan than that reported in literature, they were found to be overweight and inactive, which indicates the importance of such study. Exercise education programs are needed taking into considerations patients' individual differences. However, the broad grouping of diseases may not produce a homogenous sample, for which disease categories are recommended in future studies. CLINICAL RELEVANCE: Patients with chronic illness need more encouragement to engage themselves in exercise practices. Exercise educational program for patients with chronic illnesses should consider patients' reported exercise benefits and barriers. PMID- 25557146 TI - Irreversible electroporation of the porcine kidney: Temperature development and distribution. AB - OBJECTIVE: Although tissue ablation by irreversible electroporation (IRE) has been characterized as nonthermal, the application of frequent repetitive high intensity electric pulses has the potential of substantially heating the targeted tissue and causing thermal damage. This study evaluates the risk of possible thermal damage by measuring temperature development and distribution during IRE of porcine kidney tissue. METHODS: The animal procedures were conducted following an approved Institutional Animal Ethics Committee protocol. IRE ablation was performed in 8 porcine kidneys. Of them, 4 kidneys were treated with a 3-needle configuration and the remaining 4 with a 4-needle configuration. All IRE ablations consisted of 70 pulses with a length 90 us. The pulse frequency was set at 90 pulses/min, and the pulse intensity at 1,500 V/cm with a spacing of 15 mm between the needles. The temperature was measured internally using 4 fiber-optic temperature probes and at the surface using a thermal camera. RESULTS: For the 3 needle configuration, a peak temperature of 57 degrees C (mean = 49 +/- 10 degrees C, n = 3) was measured in the core of the ablation zone and 40 degrees C (mean = 36 +/- 3 degrees C, n = 3) at 1cm outside of the ablation zone, from a baseline temperature of 33 +/- 1 degrees C. For the 4-needle configuration, a peak temperature of 79 degrees C (mean = 62 +/- 16 degrees C, n = 3) was measured in the core of the ablation zone and 42 degrees C (mean = 39 +/- 3 degrees C, n = 3) at 1cm outside of the ablation zone, from a baseline of 35 +/- 1 degrees C. The thermal camera recorded the peak surface temperatures in the center of the ablation zone, reaching 31 degrees C and 35 degrees C for the 3- and 4-needle configuration IRE (baseline 22 degrees C). CONCLUSIONS: The application of repetitive high-intensity electric pulses during IRE ablation in porcine kidney causes a lethal rise in temperature within the ablation zone. Temperature monitoring should be considered when performing IRE ablation near vital structures. PMID- 25557147 TI - Combinations of Hd2 and Hd4 genes determine rice adaptability to Heilongjiang Province, northern limit of China. AB - Heading date is a key trait in rice domestication and adaption, and a number of quantitative trait loci (QTLs) have been identified. The rice (Oryza sativa L.) cultivars in the Heilongjiang Province, the northernmost region of China, have to flower extremely early to fulfill their life cycle. However, the critical genes or different gene combinations controlling early flowering in this region have not been determined. QTL and candidate gene analysis revealed that Hd2/Ghd7.1/OsPRR37 plays a major role in controlling rice distribution in Heilongjiang. Further association analysis with a collection of rice cultivars demonstrated that another three major QTL genes (Hd4/Ghd7, Hd5/DTH8/Ghd8, and Hd1) also participate in regulating heading date under natural long day (LD) conditions. Hd2/Ghd7.1/OsPRR37 and Hd4/Ghd7 are two major QTLs and function additively. With the northward rice cultivation, the Hd2/Ghd7.1/OsPRR37 and Hd4/Ghd7 haplotypes became non-functional alleles. Hd1 might be non-functional in most Heilongjiang rice varieties, implying that recessive hd1 were selected during local rice breeding. Non-functional Hd5/DTH8/Ghd8 is very rare, but constitutes a potential target for breeding extremely early flowering cultivars. Our results indicated that diverse genetic combinations of Hd1, Hd2, Hd4, and Hd5 determined the different distribution of rice varieties in this northernmost province of China. PMID- 25557148 TI - Lethal and sublethal effects of selected PPCPs on the freshwater rotifer, Plationus patulus. AB - Pharmaceuticals and personal care products (PPCPs) have been reported in surface waters around the world. The continuous input of these pollutants into freshwaters and their potential effects on aquatic life are of increasing concern. The rotifer Plationus patulus, a basal member of riverine food webs, was used to test acute and chronic toxicity of 4 PPCPs (acetamidophenol, caffeine, fluoxetine, triclosan). A population from a remote site in Mexico (reference population) and one from an urbanized stretch of the Rio Grande were exposed. Acute toxicity tests show that both populations were more sensitive to fluoxetine. Chronic exposure to acetamidophenol (10 mg/L, 15 mg/L, and 20 mg/L) inhibited reference population growth, whereas Rio Grande population growth was inhibited only at 15 mg/L and 20 mg/L. Population growth was inhibited at 200 mg/L and 300 mg/L of caffeine for both populations. Chronic exposure to fluoxetine (0.020 mg/L) significantly inhibited population growth for the Rio Grande population only. Triclosan (0.05 mg/L, 0.075 mg/L, 0.10 mg/L) had the most deleterious effects, significantly reducing both populations' growth rates. Sublethal effects of chronic exposure to PPCPs included decreased egg production and increased egg detachment. A mixed exposure (6 PPCPs, environmentally relevant concentrations) did not affect population growth in either population. However, the continuous introduction of a broad suite of PPCPs to aquatic ecosystems still may present a risk to aquatic communities. Environ Toxicol Chem 2015;34:913-922. (c) 2014 SETAC. PMID- 25557149 TI - Successful treatment of pearly penile papules with carbon dioxide laser resurfacing after local anesthesia in an adolescent patient. AB - Pearly penile papules (PPP) can cause significant psychological morbidity. Herein we report the successful use of a macrofractionated carbon dioxide laser at full field ablative density settings for the treatment of PPP in a 17-year-old boy using local anesthetic alone. Our experience leads us to believe that PPP can be successfully treated in the pediatric and adolescent populations using this novel and relatively noninvasive technique. PMID- 25557150 TI - Topographic organization and possible function of the posterior optic tubercles in the brain of the desert locust Schistocerca gregaria. AB - Migrating desert locusts, Schistocerca gregaria, are able to use the skylight polarization pattern for navigation. They detect polarized light with a specialized dorsal rim area in their compound eye. After multistage processing, polarization signals are transferred to the central complex, a midline-spanning brain area involved in locomotor control. Polarization-sensitive tangential neurons (TB-neurons) of the protocerebral bridge, a part of the central complex, give rise to a topographic arrangement of preferred polarization angles in the bridge, suggesting that the central complex acts as an internal sky compass. TB neurons connect the protocerebral bridge with two adjacent brain areas, the posterior optic tubercles. To analyze the polarotopic organization of the central complex further, we investigated the number and morphologies of TB-neurons and the presence and colocalization of three neuroactive substances in these neurons. Triple immunostaining with antisera against Diploptera punctata allatostatin (Dip AST), Manduca sexta allatotropin (Mas-AT), and serotonin (5HT) raised in the same host species revealed three spatially distinct TB-neuron clusters, each consisting of 10 neurons per hemisphere: cluster 1 and 3 showed Dip-AST/5HT immunostaining, whereas cluster 2 showed Dip-AST/Mas-AT immunostaining. Five subtypes of TB-neuron could be distinguished based on ramification patterns. Corresponding to ramification domains in the protocerebral bridge, the neurons invaded distinct but overlapping layers within the posterior optic tubercle. Similarly, neurons interconnecting the tubercles of the two hemispheres also targeted distinct layers of these neuropils. From these data we propose a neuronal circuit that may be suited to stabilize the internal sky compass in the central complex of the locust. PMID- 25557151 TI - Presence of medication taken by blood donors in plasma for transfusion. AB - BACKGROUND AND OBJECTIVES: The TRIP national hemovigilance and biovigilance office receives reports on side-effects and incidents associated with transfusion of labile blood products. Anaphylactic reactions accounted for the largest number of serious transfusion reactions in the period 2008-2012. In most cases, no cause is found for these reactions. TRIP data show that anaphylactic reactions occur relatively frequently with transfusion of plasma or platelet concentrates. Data from blood services show that 10% or more of plasma donors regularly use medication which is permitted under donation guidelines. It is conceivable that medication taken by the donor in plasma for transfusion could cause an anaphylactic transfusion reaction in the recipient. This exploratory study investigated the presence of drugs or drug metabolites in donor plasma. MATERIALS AND METHODS: Samples (5 ml) were taken from thawed, quarantine fresh frozen plasma units (FFP) which had to be rejected for transfusion because of leaks or length of time after thawing. The samples were analysed for approximately 1000 drugs and drug metabolites using a toxicological screening method. RESULTS: Eighty-seven samples were analysed. Toxicological screening was positive in fourteen samples (16%). In eleven samples, one substance was found, and in three samples, the presence of two or three drugs was detected. CONCLUSION: After freezing, storage and thawing of fresh FFP, it is possible to detect medication taken by the donor. Further investigation is recommended to analyse whether donors' medication in plasma can be implicated in some cases of allergic or anaphylactic reactions in transfusion recipients. PMID- 25557152 TI - Beyond the throwaway society: A life cycle-based assessment of the environmental benefit of reuse. AB - In the context of a circular economy, sustainable consumption is often seen as the antithesis of current consumption patterns, which have led to the definition of the so-called throwaway society. Reuse may provide a preferred alternative to other waste management options, because it promotes resource efficiency and may significantly reduce environmental impacts. To appraise the environmental benefits related to reuse of goods, a methodology adopting life cycle assessment (LCA) has been developed. A standardized procedure has been developed, identifying reference products within product category subject to reuse, and collecting reliable inventory data as a basis for calculating environmental impact through LCA. A case study on a second-hand shop is presented, and the avoided impacts are quantified. Inventory data were taken both from the literature and directly from sales and surveys submitted to customers. The results are presented, highlighting: 1) for each product category, the average avoided impacts for 1 unit of reused product considered; and 2) for the overall activities of the second-hand shop, the cumulative avoided impacts in 1 yr. In the case study, the higher contribution to avoided impacts comes from the apparel sector, due to the high amount of items sold, followed by the furniture sector, because of the high amount of environmental impacts avoided by the reuse of each single item. PMID- 25557153 TI - Modified expansive open-door laminoplasty technique improved postoperative neck pain and cervical range of motion. AB - BACKGROUND/PURPOSE: Expansive open-door laminoplasty (EOLP) is a useful technique for multiple-level cervical spondylotic myelopathy. The common postoperative complications of EOLP include moderate to severe neck pain, loss of cervical lordosis, decrease of cervical range of motion, and C5 palsy. We modified the surgical technique to lessen these complications. This study is aimed to elucidate the efficacy of modified techniques to lessen the complications of traditional procedures. METHODS: We collected data from 126 consecutive patients treated at our institution between August 2008 and December 2012. Of these, 66 patients underwent conventional EOLP (CEOLP) and the other 60 patients underwent modified EOLP (MEOLP). The demographic and preoperative data, axial pain visual analog scale scores at 2 weeks and 3 months postoperatively, clinical outcomes evaluated using Nurick score and Japanese Orthopedic Association recovery rate at 12 months postoperatively, and radiographic results assessed using plain films at 3 months and 12 months postoperatively for both groups were compared and analyzed. RESULTS: There were no significant differences regarding the preoperative condition between the CEOLP and MEOLP groups (p > 0.05). The Japanese Orthopedic Association recovery rate of the MEOLP group was 70.3%, comparable to the result of the other group (70.2%). Postoperative axial neck pain, loss of range of motion, and loss of lordosis of cervical curvature decreased significantly in the MEOLP group (p < 0.05). The complications of temporary C5 nerve palsy found in the CEOLP group did not exist in the MEOLP group. CONCLUSION: MEOLP is a minimally invasive surgical method to treat multiple-level cervical spondylotic myelopathy, which decreases postoperative complications effectively. PMID- 25557154 TI - Significant association of deficiencies of hemoglobin, iron, folic acid, and vitamin B12 and high homocysteine level with oral lichen planus. AB - BACKGROUND/PURPOSE: A portion of patients with oral lichen planus (OLP) may have nutritional deficiency. This study evaluated whether there was an intimate association of the deficiencies of hemoglobin (Hb), iron, vitamin B12, and folic acid and high blood homocysteine level with OLP. METHODS: The blood Hb, iron, vitamin B12, folic acid, and homocysteine concentrations in 352 OLP patients were measured and compared with the corresponding levels in 352 age- and sex-matched healthy control participants. RESULTS: We found that 77 (21.9%) OLP patients, 48 (13.6%) OLP patients, 25 (7.1%) OLP patients, and one (0.3%) OLP patient had deficiencies of Hb (men < 13 g/dL, women < 12 g/dL), iron (< 60 MUg/dL), vitamin B12 (< 200 pg/mL), and folic acid (< 4 ng/mL), respectively. Moreover, 52 (14.8%) OLP patients had abnormally high blood homocysteine level. OLP patients had a significantly higher frequency of Hb, iron, or vitamin B12 deficiency and of abnormally elevated blood homocysteine level than healthy control participants (all p < 0.001). Upon further dividing OLP patients into those with major erosive OLP (MjEOLP; n = 67), minor erosive OLP (n = 202), and nonerosive OLP (NEOLP; n = 83), we found that MjEOLP patients had a significantly higher mean homocysteine level than NEOLP patients (p = 0.035). CONCLUSION: We conclude that there is a significant association of deficiencies of Hb, iron, folic acid, and vitamin B12 and abnormally high blood homocysteine level with OLP. There may be a close relation of high blood homocysteine level to severity of OLP. PMID- 25557155 TI - A survey of infectious disease clinical practices among pediatric blood and marrow transplant programs in the United States. AB - We assessed clinical practice standards for infectious complications among pediatric blood and marrow transplant (PBMT) recipients. An anonymous online survey was sent to all 64 pediatric program directors (PD) of PBMT centers in the United States, which are accredited by the Foundation for the Accreditation of Cellular Therapy (FACT). The overall response rate was 56% (CI: 44-68%); variations in clinical practices were noted regarding (i) surveillance for late onset cytomegalovirus (CMV) infection and (ii) pharmacokinetic/therapeutic drug monitoring of antimicrobials. Prospective studies among PBMT recipients to address infectious complications among this population and variations in clinical practice may be required. PMID- 25557156 TI - Safety of inhaled corticosteroids for treating chronic obstructive pulmonary disease. AB - INTRODUCTION: The frequent use of inhaled corticosteroids (ICSs), especially at higher doses, has been accompanied by concern about both systemic and local side effects. Patients suffering from chronic obstructive pulmonary disease (COPD) are more at risk from side effects, likely because of the use of higher doses of ICS in COPD to overcome corticosteroid unresponsiveness. AREAS COVERED: There is considerable concern about increased incidence of pneumonia, osteoporosis and hyperglycemia in diabetic patients and cataracts. The local side effects of ICSs, such as hoarseness and pharyngeal discomfort, oral and oropharyngeal candidiasis, cough during inhalation, and a sensation of thirst, are not usually serious but are of clinical importance because they may lead to patients discontinuing therapy. EXPERT OPINION: The possibility that ICSs induce adverse side effects should not lead us to avoid their use in patients in whom clinical evidence suggests that they may be helpful. However, clinicians should balance the potential benefits of ICSs in COPD against their potential side effects and always consider using the lowest possible dose to achieve the best possible management. PMID- 25557157 TI - Effect of Incorporation of Nano-Oxides on Color Stability of Maxillofacial Silicone Elastomer Subjected to Outdoor Weathering. AB - PURPOSE: The aim of this study was to evaluate the effect of incorporation of two compositions of nano-oxides on color stability of intrinsically colored maxillofacial silicone elastomer subjected to outdoor weathering. MATERIALS AND METHODS: Ninety Cosmesil M511 silicone elastomer specimens were fabricated. The control group was incorporated with intrinsic coloring agents (umber, brown, yellow), group A was incorporated with intrinsic coloring agents and nanosized titanium oxide (TiO2 ), and group B was incorporated with intrinsic coloring agents and nanosized zinc oxide (ZnO). For outdoor weathering, specimens were mounted on a treated plywood rack, and the assembly was weathered for 6 months. A GretagMacbeth Spectrolino spectrophotometer was used to determine the CIELAB (L*a*b*) parameter before and after weathering of each specimen, and the values were noted. The color change (?E) values were analyzed by one-way ANOVA, Tukey's post hoc test, and paired t-test. RESULTS: The color change (DeltaE*) for groups were control group > group A > group B. The control group (0.76 +/- 0.32) and group A (0.47 +/- 0.19) showed significant difference in the color change before and after weathering (p < 0.00001). Group B (0.03 +/- 0.05) showed no significant difference in color change before and after weathering (p = 0.08). CONCLUSIONS: The present findings suggest that incorporation of nano-oxides improved the color stability of Cosmesil M511 silicone elastomer and also acted as an opacifier. ZnO incorporated Cosmesil M511 specimens showed minimal or no color change and proved to be most color stable after being subjected to outdoor weathering. PMID- 25557158 TI - Psychosocial and physical outcome following kidney donation-a retrospective analysis. AB - Living renal donation is of benefit to the allograft recipient. Careful analysis of the donor outcome is necessary with respect to the medical condition, socioeconomic status, and health-related quality of life. All living kidney donors of the Transplant Center at Heidelberg were included. Renal function and comorbidities were assessed. HRQoL and fatigue symptoms were determined by self reporting validated test systems [Short-Form 36 (SF-36), Multidimensional Fatigue Inventory (MFI-20), Patient Health Questionnaire (PHQ)]. In total, 430 of 519 living renal donors were eligible to participate: 295 living donors (68.6%) provided informed consent (age at donation 49 +/- 11 years) with a median time after donation of 77 (24-484) months. Renal function was lower compared with predonation (66 +/- 15 ml/min vs. 88 +/- 14 ml/min). Blood pressure remained stable (128 +/- 14 mmHg vs. 129 +/- 15 mmHg) with an increase of 56 donors receiving antihypertensive treatment (27.1% vs. 19%). The SF-36 physical component summary score was significantly better for both genders compared with the general population; the SF-36 mental component summary score was lower for female donors, caused by a reduced role functioning. Prevalence of fatigue was increased in female donors between the ages of 40 and 59 years. Renal function and blood pressure were as expected from previous studies. Concerning the psychosocial outcome, female donors might be at risk of impairments postdonation. Future evaluations will confirm and specify whether these results are necessary. PMID- 25557159 TI - Reductive lithium insertion into B-cation deficient niobium perovskite oxides. AB - Reaction between LiH and the A(n)B(n-1)O(3n) cation deficient perovskite phases Ba(5)Nb(4)O(15), Ba(6)TiNb(4)O(18) and Ba(3)LaNb(3)O(12) proceeds by reductive lithium insertion, leading to the formation of Ba(5)LiNb(4)O(15), Ba(6)LiTiNb(4)O(18) and Ba(3)LaLiNb(3)O(12) respectively. During lithium insertion into Ba(5)Nb(4)O(15) and Ba(6)TiNb(4)O(18) the respective ccchh and cccchh stacking sequences are converted into entirely cubic stacking sequences, while the B-cation vacancy order of the two phases is faithfully converted into Li-Nb or Li-Nb/Ti cation order in the lithiated products. In contrast lithium insertion into Ba(3)LaNb(3)O(12) leads to no gross change in structure, with the inserted lithium cations displacing some of the niobium cations leading to a cation disordered material. Transport measurements indicate semiconducting behaviour consistent with variable range hopping for Ba(5)LiNb(4)O(15) and insulating behaviour for Ba(6)LiTiNb(4)O(18) and Ba(3)LaLiNb(3)O(12). Detailed analysis of the crystal structure of Ba(6)LiTiNb(4)O(18) suggests crystallographic charge ordering in this phase. PMID- 25557161 TI - Comment on: Addictive disorders after Roux-en-Y gastric bypass. PMID- 25557160 TI - Slight chronic elevation of C-reactive protein is associated with lower aerobic fitness but does not impair meal-induced stimulation of muscle protein metabolism in healthy old men. AB - Ageing impairs the muscle anabolic effect of food intake, which may explain muscle loss and an increased risk of sarcopenia. Ageing is also associated with low grade inflammation (LGI), which has been negatively correlated with muscle mass and strength. In rodents, the muscle anabolic resistance observed during ageing and sarcopenia has been ascribed to the development of the LGI. We aimed to investigate this relationship in humans. We studied protein metabolism and physical fitness in healthy elderly volunteers with slight chronic C-reactive protein. Two groups of healthy elderly volunteers were selected on the presence (or not) of a chronic, slight, elevation of CRP (Control: <1; CRP+: >2 mg l(-1) and <10 mg l(-1) , for 2 months). Body composition, short performance battery test, aerobic fitness and muscle strength were assessed. Whole body and muscle protein metabolism and the splanchnic extraction of amino acids were assessed using [(13) C]leucine and [(2) H]leucine infusion. The anabolic effect of food intake was measured by studying the volunteers both at the post-absorptive and post-prandial states. Slight chronic CRP elevation resulted in neither an alteration of whole body, nor skeletal muscle protein metabolism at both the post absorptive and the post-prandial states. However, CRP+ presented a reduction of physical fitness, increased abdominal fat mass and post-prandial insulin resistance. Plasma cytokines (interleukin-1, interleukin-6, tumour necrosis factor alpha) and markers of endothelial inflammation (intercellular adhesion molecule, vascular cell adhesion molecule, selectins) were similar between groups. An isolated elevated CRP in healthy older population does not indicate an impaired skeletal muscle anabolism after food intake, nor an increased risk of skeletal muscle wasting. We propose that a broader picture of LGI (notably with elevated pro-inflammatory cytokines) is required to impact muscle metabolism and mass. However, an isolated chronic CRP elevation could predict a decrease in aerobic fitness and insulin resistance installation in elderly individuals. PMID- 25557162 TI - Cytomorphological features of ALK-positive lung adenocarcinomas: psammoma bodies and signet ring cells. AB - BACKGROUND: Correlation between histology and genotype has been described in lung adenocarcinomas. For example, studies have demonstrated that adenocarcinomas with an anaplastic lymphoma kinase (ALK) gene rearrangement may have mucinous features. The objective of the current study was to determine whether a similar association can be identified in cytological specimens. METHODS: A retrospective search for ALK-rearranged cytopathology (CP) and surgical pathology (SP) lung carcinomas was conducted. Additional ALK-negative (-) lung adenocarcinomas served as controls. For CP and SP cases, the clinical data (i.e., age, sex, and smoking history), architecture, nuclear features, presence of mucin-containing cells (including signet ring cells), and any additional salient characteristics were evaluated. RESULTS: The search yielded 20 ALK-positive (+) adenocarcinomas. Compared with patients with ALK(-) lung adenocarcinomas (33 patients; 12 with epidermal growth factor receptor [EGFR]-mutation, 11 with Kristen rat sarcoma [KRAS]-mutation, and 10 wild-type adenocarcinomas), patients with ALK(+) adenocarcinoma presented at a younger age; and there was no correlation noted with sex or smoking status. The most common histological pattern in SP was papillary/micropapillary. Mucinous features were associated with ALK rearrangement in SP specimens. Signet ring cells and psammoma bodies were evident in and significantly associated with ALK(+) SP and CP specimens. However, psammoma bodies were observed in rare adenocarcinomas with an EGFR mutation. Both the ALK(+) and ALK(-) groups had mostly high nuclear grade. CONCLUSIONS: Salient features, including signet ring cells and psammoma bodies, were found to be significantly associated with ALK(+) lung adenocarcinomas and are identifiable on CP specimens. Recognizing these may be especially helpful in the molecular triage of scant CP samples. PMID- 25557163 TI - Distractions during critical phases of anaesthesia for caesarean section: an observational study. AB - Aviation's 'sterile cockpit' rule holds that distractions on the flight deck should be kept at a minimum during critical phases of flight. To assess current practice at comparable points during obstetric regional anaesthesia, we measured ambient noise and distracting events during 30 caesarean sections in three phases: during establishment of regional anaesthesia; during testing of regional blockade; and after delivery of the fetal head. Mean (SD) noise levels were 62.5 (3.9) dB during establishment of blockade, 63.9 (4.1) dB during testing and 66.8 (5.0) dB after delivery (p < 0.001). The median rates of sudden, loud (> 70 dB) noises, non-clinical conversations and numbers of staff present in the operating theatre increased during each of the three phases. Conversely, entrances into, and exits from, theatre per minute were highest during establishment of regional anaesthesia and decreased over the subsequent two time periods (p < 0.001). PMID- 25557164 TI - A beta-hairpin-binding protein for three different disease-related amyloidogenic proteins. AB - Amyloidogenic proteins share a propensity to convert to the beta-structure-rich amyloid state that is associated with the progression of several protein misfolding disorders. Here we show that a single engineered beta-hairpin-binding protein, the beta-wrapin AS10, binds monomers of three different amyloidogenic proteins, that is, amyloid-beta peptide, alpha-synuclein, and islet amyloid polypeptide, with sub-micromolar affinity. AS10 binding inhibits the aggregation and toxicity of all three proteins. The results demonstrate common conformational preferences and related binding sites in a subset of the amyloidogenic proteins. These commonalities enable the generation of multispecific monomer-binding agents. PMID- 25557165 TI - Fatigue in psoriasis: a phenomenon to be explored. AB - Fatigue is a prevalent and substantial phenomenon in many patients with chronic inflammatory diseases, often rated by patients as the most troublesome symptom and aspect of their disease. It frequently interferes with physical and social functions and may lead to social withdrawal, long-standing sick leave and disability. Although psychological and somatic factors such as depression, sleep disorders, pain and anaemia influence fatigue, the underlying pathophysiological mechanisms by which fatigue is generated and regulated are largely unknown. Increasing evidence points towards a genetic and molecular basis for fatigue as part of the innate immune system and cellular stress responses. Few studies have focused on fatigue in dermatological diseases. Most of these studies describe fatigue as a phenomenon related to psoriatic arthritis and describe the beneficial effects of biological agents on fatigue observed in clinical studies. It is therefore possible that this problem has been underestimated and deserves more attention in the dermatological community. In this review, we provide a definition and explanation for chronic fatigue, describe some commonly used instruments for measuring fatigue, and present hypothetical biological mechanisms with an emphasis on activation of the innate immune system and oxidative stress. An overview of relevant clinical studies covering the theme 'psoriasis and fatigue' is given. PMID- 25557166 TI - Gold(I)-catalyzed cycloisomerizations and alkoxycyclizations of ortho (alkynyl)styrenes. AB - Indenes and related polycyclic structures have been efficiently synthesized by gold(I)-catalyzed cycloisomerizations of appropriate ortho-(alkynyl)styrenes. Disubstitution at the terminal position of the olefin was demonstrated to be essential to obtain products originating from a formal 5-endo-dig cyclization. Interestingly, a complete switch in the selectivity of the cyclization of o (alkynyl)-alpha-methylstyrenes from 6-endo to 5-endo was observed by adding an alcohol to the reaction media. This allowed the synthesis of interesting indenes bearing an all-carbon quaternary center at C1. Moreover, dihydrobenzo[a]fluorenes can be obtained from substrates bearing a secondary alkyl group at the beta position of the styrene moiety by a tandem cycloisomerization/1,2-hydride migration process. In addition, diverse polycyclic compounds were obtained by an intramolecular gold-catalyzed alkoxycyclization of o-(alkynyl)styrenes bearing a nucleophile in their structure. Finally, the use of a chiral gold complex allowed access to elusive chiral 1H-indenes in good enantioselectivities. PMID- 25557167 TI - B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells. AB - In the treatment of metastatic melanoma, a highly therapy-refractory cancer, alkylating agents are used and, for the subgroup of BRAFV600E cancers, the B-Raf inhibitor vemurafenib. Although vemurafenib is initially beneficial, development of drug resistance occurs leading to tumor relapse, which necessitates the requirement for combined or sequential therapy with other drugs, including genotoxic alkylating agents. This leads to the question whether vemurafenib and alkylating agents act synergistically and whether chronic vemurafenib treatment alters the melanoma cell response to alkylating agents. Here we show that a) BRAFV600E melanoma cells are killed by vemurafenib, driving apoptosis, b) BRAFV600E melanoma cells are neither more resistant nor sensitive to temozolomide/fotemustine than non-mutant cells, c) combined treatment with vemurafenib plus temozolomide or fotemustine has an additive effect on cell kill, d) acquired vemurafenib resistance of BRAFV600E melanoma cells does not affect MGMT, MSH2, MSH6, PMS2 and MLH1, nor does it affect the resistance to temozolomide and fotemustine, e) metastatic melanoma biopsies obtained from patients prior to and after vemurafenib treatment did not show a change in the MGMT promoter methylation status and MGMT expression level. The data suggest that consecutive treatment with vemurafenib and alkylating drugs is a reasonable strategy for metastatic melanoma treatment. PMID- 25557168 TI - Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide due its resistance to chemotherapy and aggressive tumor growth. Polo like kinase 1 (PLK1) is a serine-threonine protein kinase which is overexpressed in cancer cells, and plays a major role in regulating tumor growth. A number of PLK1 inhibitors are in clinical trial; however, poor tumor bioavailability and off-target effects limit their efficacy. Short-interfering-RNA (siRNA) holds promise as a class of therapeutics, which can selectively silence disease-causing genes. However, siRNA cannot enter cells without a delivery vehicle. Herein, we investigated whether RNAi-interfering nanoparticles could deliver siRNA to NSCLC cells and silence PLK1 expression in vitro and in vivo. iNOP-7 was non-toxic, and delivered siRNA with high efficiency to NSCLC cells. iNOP-7-PLK1 siRNA silenced PLK1 expression and reduced NSCLC growth in vitro. Notably, iNOP-7 delivered siRNA to orthotopic lung tumors in mice, and administration of iNOP-7-PLK1 siRNA reduced lung tumor burden. These novel data show that iNOP-7 can deliver siRNA against PLK1 to NSCLC cells, and decrease cell proliferation both in vitro and in vivo. iNOP-7-PLK1 siRNA may provide a novel therapeutic strategy for the treatment of NSCLC as well as other cancers which aberrantly express this gene. PMID- 25557169 TI - Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS. AB - High-grade serous ovarian cancers (HGSOC) are genomically complex, heterogeneous cancers with a high mortality rate, due to acquired chemoresistance and lack of targeted therapy options. Cyclin-dependent kinase inhibitors (CDKi) target the retinoblastoma (RB) signaling network, and have been successfully incorporated into treatment regimens for breast and other cancers. Here, we have compared mechanisms of response and resistance to three CDKi that target either CDK4/6 or CDK2 and abrogate E2F target gene expression. We identify CCNE1 gain and RB1 loss as mechanisms of resistance to CDK4/6 inhibition, whereas receptor tyrosine kinase (RTK) and RAS signaling is associated with CDK2 inhibitor resistance. Mechanistically, we show that ETS factors are mediators of RTK/RAS signaling that cooperate with E2F in cell cycle progression. Consequently, CDK2 inhibition sensitizes cyclin E1-driven but not RAS-driven ovarian cancer cells to platinum based chemotherapy. In summary, this study outlines a rational approach for incorporating CDKi into treatment regimens for HGSOC. PMID- 25557170 TI - Overexpression of Nodal induces a metastatic phenotype in pancreatic cancer cells via the Smad2/3 pathway. AB - Metastasis is the major cause for the high mortality rate of pancreatic cancer. Human embryonic stem cell (hESC) associated genes frequently correlate with malignant disease progression. Recent studies have demonstrated that the embryonic protein Nodal, which plays a critical role during embryonic development, is re-expressed in several types of tumors and promotes cancers progression. However, little is known about the role of Nodal in pancreatic cancer. Here, we show that Nodal expression is upregulated in human pancreatic cancer tissues. Moreover, Nodal expression levels correlate well with the grade of pancreatic cancer differentiation. In addition, we present clear evidence that Nodal induces signal transduction through the Smad2/3-dependent pathway in vitro. Furthermore, we show that Nodal promotes pancreatic cancer cell migration and invasion, induces epithelial-mesenchymal transition (EMT) and enhances the expression of matrix metalloproteinase-2 (MMP2) and CXC chemokine receptor 4 (CXCR4). Using an in vivo liver metastasis model of pancreatic cancer, we observed that blocking Nodal signaling activity with the small-molecule inhibitor SB431542 decreases the number and size of liver metastases. Taken together, our results suggest that Nodal overexpression induces a metastatic phenotype in pancreatic cancer cells, and that targeting Nodal signaling may be a promising therapeutic strategy for pancreatic cancer. PMID- 25557171 TI - Targeting of TGF-beta-activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer. AB - TGF-beta-activated protein kinase 1 (TAK1) is a critical mediator in inflammation, immune response and cancer development. Our previous study demonstrated that activation of TAK1 increases the expression of chemokine (C-C motif) receptor 7 (CCR7) and promotes lymphatic invasion ability of breast cancer cells. However, the expression and association of activated TAK1 and CCR7 in breast tumor tissues is unknown and the therapeutic effect by targeting TAK1 is also unclear. We showed that activated TAK1 (as indicated by phospho-TAK1) and its binding protein TAB1 are strongly expressed in breast tumor tissues (77% and 74% respectively). In addition, increase of phospho-TAK1 or TAB1 is strongly associated with overexpression of CCR7. TAK1 inhibitor 5Z-7-Oxozeaenol (5Z-O) inhibited TAK1 activity, suppressed downstream signaling pathways including p38, IkappaB kinase (IKK) and c-Jun N-terminal kinase (JNK) and reduced CCR7 expression in metastatic MDA-MB-231 cells. In addition, 5Z-O repressed NF-kappaB- and c-JUN-mediated transcription of CCR7 gene. Knockdown of TAB1 attenuated CCR7 expression and tumor growth in an orthotopic animal study. More importantly, lymphatic invasion and lung metastasis were suppressed. Collectively, our results demonstrate that constitutive activation of TAK1 is frequently found in human breast cancer and this kinase is a potential therapeutic target for this cancer. PMID- 25557172 TI - GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers. AB - Identification of a single molecular trait that is determinant of common malignancies may serve as a powerful diagnostic supplement to cancer type specific markers. Here, we report a DNA methylation mark that is characteristic of seven studied malignancies, namely cancers of lung, breast, prostate, pancreas, colorectum, glioblastoma and B cell chronic lymphocytic leukaemia (CLL) (n = 137). This mark was defined by substantial hypermethylation at the promoter and first exon of growth hormone secretagouge receptor (GHSR) through bisulfite pyrosequencing. The degree of aberrant methylation was capable of accurate discrimination between cancer and control samples. The highest sensitivity and specificity of cancer detection was achieved for cancers of pancreas, lung, breast and CLL yielding the area under the curve (AUC) values of 1.0000, 0.9952, 0.9800 and 0.9400, respectively. Narrowing to a single CpG site within the gene's promoter or four consecutive CpG units of the highest methylation levels within the first exon improved the detection power. GHSR hypermethylation was detected already at the early stage tumors. The accurate performance of this marker was further replicated in an independent set of pancreatic cancer and control samples (n = 78). These findings support the candidature of GHSR methylation as a highly accurate pan-cancer marker. PMID- 25557173 TI - Lateral inhibition of Notch signaling in neoplastic cells. AB - During normal development, heterogeneous expression of Notch ligands can result in pathway suppression in the signal-sending cell, a process known as lateral inhibition. It is unclear if an analogous phenomenon occurs in malignant cells. We observed significant induction of Notch ligands in glioblastoma neurospheres and pancreatic carcinoma cells cultured in low oxygen, suggesting that this phenomenon could occur around hypoxic regions. To model lateral inhibition in these tumors, the ligand Jagged1 was overexpressed in glioblastoma and pancreatic carcinoma cells, resulting in overall induction of pathway targets. However, when ligand high and ligand low cells from a single line were co-cultured and then separated, we noted suppression of Notch pathway targets in the former and induction in the latter, suggesting that neoplastic lateral inhibition can occur. We also found that repression of Notch pathway targets in signal-sending cells may occur through the activity of a Notch ligand intracellular domain, which translocates into the nucleus. Understanding how this neoplastic lateral inhibition process functions in cancer cells may be important in targeting ligand driven Notch signaling in solid tumors. PMID- 25557174 TI - Novel receptor tyrosine kinase targeted combination therapies for imatinib resistant gastrointestinal stromal tumors (GIST). AB - BACKGROUND: c-Kit/alpha-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance. METHODS: RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting. RESULTS: Immunohistochemistry pre-/post-IM demonstrated continued expression of c Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST 882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 uM to IM respectively. GIST48 have an IC50 0.66 uM to IM, 0.91 uM to amuvatinib [AMU] and 0.67 uM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63). CONCLUSION: Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST. PMID- 25557175 TI - Emotional distress in parents of long-term survivors of childhood acute lymphoblastic leukemia. AB - OBJECTIVE: The current study investigated the occurrence of emotional distress in parents of long-term survivors of childhood acute lymphoblastic leukemia (ALL) and identified factors associated with parent emotional distress symptoms. METHODS: Parents of 127 long-term survivors of childhood ALL treated on a chemotherapy-only protocol at St. Jude Children's Research Hospital participated in the study. Parents completed standard ratings of emotional distress, caregiver strain, and child physical, emotional, and psychosocial functioning. Multivariable hierarchical linear regression analyses were used to examine associations between symptoms of caregiver strain, survivor functioning, and parent emotional distress. Covariates included parent education, survivor age, survivor sex, and time since childhood cancer diagnosis. RESULTS: On average, few parents reported significant symptoms of emotional distress. Clinically significant levels of anxiety and depression were reported by 7.1% and 3.1% of parents, respectively. Only 3.9% of parents endorsed significant symptoms of posttraumatic stress. Perceived caregiver strain was significantly associated with symptoms of parent anxiety, depression, and posttraumatic stress. Parent report of child emotional functioning was significantly associated with symptoms of parent anxiety. CONCLUSIONS: Most parents of long-term survivors of ALL exhibit low levels of emotional distress in the context of rates observed in the general population. Perceived caregiver strain was significantly associated with parent emotional distress. Further research is required to examine specific sources of caregiver strain, as well as other risk and protective factors associated with parent emotional distress symptoms. PMID- 25557176 TI - The economic implications of switching to rivaroxaban from enoxaparin plus vitamin K antagonist in the treatment of venous thromboembolism. AB - OBJECTIVE: Venous thromboembolism (VTE) impacts ~900,000 individuals annually in the US, causing up to 100,000 deaths. Patients experiencing VTE have heightened risk of recurrence. Initial parenteral anti-coagulation is standard therapy for acute VTE followed by >=3 months of warfarin, which introduces the risk of major bleeding. Balancing increased risks of bleeding and recurrent VTE remains challenging. Recent clinical trials suggest that rivaroxaban, an oral direct inhibitor of factor Xa, provides an effective, safe, simplified approach to treatment. This study considers the economic implications of these data. METHODS: This study modeled inpatient, acute, and 1-year VTE costs for a hypothetical commercial plan with 1 million members. At baseline, all VTE patients receive standard therapy. Alternatively, 25% are instead treated with rivaroxaban. Model inputs are trial- and literature-based. RESULTS: Standard therapy for VTE consumes 9474 inpatient days ($31.6 million). Added to that is treatment for 74 recurrences ($1.4 million); major and non-major bleed events ($1 million); and direct costs of anti-coagulation ($5.3 million). Alternatively, a 25% shift to oral anti-coagulation with rivaroxaban reduces inpatient days (by 5%); associated acute-care costs (by 2%); recurrences and costs (by 6%). Four major bleeding events are prevented, at the cost of one additional non-major bleeding event, which, taken together, reduce net utilization by 9%. Direct costs of anti coagulation increase by 5%. CONCLUSION: The reduction in inpatient utilization, recurrences, and major bleeding resulting from a 25% shift from standard therapy to rivaroxaban following acute VTE would conserve ~$860,475 for every 1 million commercial health plan enrollees. PMID- 25557177 TI - Acute Liver Failure in Infants and Young Children in a Specialized Pediatric Liver Centre in India. AB - OBJECTIVE: To study the etiological spectrum of acute liver failure in infants and young children and to identify clinical and biochemical markers for metabolic liver disease (MLD). METHODS: This study was conducted at Department of Pediatric Hepatology, in a tertiary care specialized centre for liver diseases. All children less than 3 y of age, with liver dysfunction and INR >=2 were included in the study. They were managed as per the departmental protocol. Included children were divided based on the etiology into 2 groups: MLD and non MLD group. Comparison analysis (MLD vs. non MLD) of the clinical and biochemical parameters was done. RESULTS: There were 30 children under 3 y of age with acute liver failure (ALF) with median age of 12.5 mo. Fifteen children were less than 12 mo. MLD (33 %) and hemophagocytic lymphohistiocytosis (HLH) (17 %) together accounted for half of the cases of ALF in children below 3 y of age. The other common etiologies were drug induced liver injury and acute viral hepatitis A. Etiology remained indeterminate in 3 cases (10 %). Comparative analysis of the clinical and biochemical parameters between MLD and non MLD group showed significant difference between the two groups in the median values of age (p = 0.014), bilirubin (p = 0.017), jaundice to encephalopathy (JE) interval (p = 0.039) and blood sugar (p = 0.001). Suggestive family history (OR 3.73, 95 %CI 1.67-8.30), developmental delay (OR 4.4 95 %CI 2.03-9.51), presence of diarrhea/vomiting (OR 3.28, 95 %CI 1.32-8.13) in the history and presence of urinary non glucose reducing substance (NGRS) (OR 15.5, 95 %CI 2.26-106.87) were also significantly associated with MLD group. Only 40 % children survived with native liver. CONCLUSIONS: MLD and HLH account for majority of ALF in infants. About 10 % of cases remain indeterminate. Viral hepatitis is more common in young children. Apart from clinical indicators, young age, high bilirubin, synthetic dysfunction, low sugar and NGRS in urine indicate MLD as a cause. Survival with native liver is low. PMID- 25557179 TI - The effect of spatial frequency on peripheral collinear facilitation. AB - The detection of a Gabor patch (target) can be decreased or improved by the presence of co-oriented Gabor patches (flankers) having the same spatial frequency as the target. These phenomena are thought to be mediated by lateral interactions. Depending on the distance between target and flankers, commonly defined as a multiple of the wavelength (lambda) of the carrier, flankers can increase or decrease a target's detectability. Studies with foveal presentation showed that for target-to-flankers distances<2lambda contrast thresholds for the central target increase, while for target-to-flankers distances>3lambda contrast thresholds decrease. Earlier studies on collinear facilitation at the near periphery of the visual field (4 degrees of eccentricity) showed inconsistent facilitation (Shani & Sagi, 2005, Vision Research, 45, 2009-2024) whereas more recent studies showed consistent facilitation for larger separations (7-8lambda) (Maniglia et al., 2011, PLoS ONE, 6, e25568; Lev & Polat, 2011, Vision Research, 51, 2488-2498). However, all of these studies used medium-to-high spatial frequencies (3-8 cpd). In this study we tested lower spatial frequencies (1, 2, and 3 cpd) with different target-to-flankers distances. The rationale was that near-peripheral vision is tuned for lower spatial frequencies and this could be reflected in collinear facilitation. Results show consistent collinear facilitation at 8lambda for all the spatial frequencies tested, but also show collinear facilitation at shorter target-to-flanker distance (6lambda) for the lowest spatial frequencies tested (1 cpd). Additionally, collinear facilitation decreases as spatial frequency increases; opposite to the findings of Polat (2009, Spatial Vision, 22, 179-193) in the fovea, indicating a different spatial frequency tuning between foveal and peripheral lateral interactions. PMID- 25557178 TI - Advances in pediatric neuroimaging. AB - Conventional MRI protocols are an integral part of routine clinical imaging in pediatric patients. The advent of several newer MRI techniques provides crucial insight into the structural integrity and functional aspects of the developing brain, especially with the introduction of 3T MRI systems in clinical practice. The field of pediatric neuroimaging continues to evolve, with greater emphasis on high spatial resolution, faster scan time, as well as a quest for visualization of the functional aspects of the human brain. MR vendors are increasingly focusing on optimizing MR technology to make it suitable for children, in whom as compared to adults the head size is usually smaller and demonstrates inherent neuroanatomical differences relating to brain development. The eventual goal of these advances would be to evolve as potential biomarkers for predicting neurodevelopment outcomes and prognostication, in addition to their utility in routine diagnostic and therapeutic decision-making. Advanced MR techniques like diffusion tensor imaging, functional MRI, MR perfusion, spectroscopy, volumetric imaging and arterial spin labeling add to our understanding of normal brain development and pathophysiology of various neurological disease processes. This review is primarily focused on outlining advanced MR techniques and their current and potential pediatric neuroimaging applications as well as providing a brief overview of advances in hardware and machine design. PMID- 25557180 TI - Prose memory impairment in amyotrophic lateral sclerosis patients is related to hippocampus volume. AB - BACKGROUND AND PURPOSE: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. METHODS: Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1- and T2 weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. RESULTS: Immediate and delayed story recall scores were abnormal in 23% of ALS patients and correlated to bilateral hippocampus grey matter volume (r = 0.52 for both memory tests; P < 0.05; corrected for age, gender and total grey matter volume). This correlation was not found in healthy controls with similar age, education, anxiety and depression levels and white matter changes. CONCLUSIONS: Prose memory impairment is a frequent finding in this cohort and is associated with hippocampus volume in ALS patients without dementia. These findings complement previous hippocampus changes in imaging studies in ALS and suggest involvement of the hippocampus in cognitive dysfunction of ALS. PMID- 25557181 TI - Topological solitons as addressable phase bits in a driven laser. AB - Optical localized states are usually defined as self-localized bistable packets of light, which exist as independently controllable optical intensity pulses either in the longitudinal or transverse dimension of nonlinear optical systems. Here we demonstrate experimentally and analytically the existence of longitudinal localized states that exist fundamentally in the phase of laser light. These robust and versatile phase bits can be individually nucleated and canceled in an injection-locked semiconductor laser operated in a neuron-like excitable regime and submitted to delayed feedback. The demonstration of their control opens the way to their use as phase information units in next-generation coherent communication systems. We analyse our observations in terms of a generic model, which confirms the topological nature of the phase bits and discloses their formal but profound analogy with Sine-Gordon solitons. PMID- 25557182 TI - Arginase promotes endothelial dysfunction and hypertension in obese rats. AB - OBJECTIVE: This study investigated whether arginase contributes to endothelial dysfunction and hypertension in obese rats. METHODS: Endothelial function and arginase expression were examined in skeletal muscle arterioles from lean and obese Zucker rats (ZRs). Arginase activity, arginine bioavailability, and blood pressure were measured in lean and obese animals. RESULTS: Arginase activity and expression was increased while global arginine bioavailability decreased in obese ZRs. Acetylcholine or luminal flow caused dilation of isolated skeletal muscle arterioles, but this was reduced or absent in vessels from obese ZRs. Treatment of arterioles with a nitric oxide synthase inhibitor blocked dilation in lean arterioles and eliminated differences among lean and obese vessels. In contrast, arginase inhibitors or l-arginine enhanced vasodilation in obese ZRs and abolished differences between lean and obese animals, while d-arginine had no effect. Finally, mean arterial blood pressure was significantly increased in obese ZRs. However, administration of l-arginine or arginase inhibitors lowered blood pressure in obese but not lean animals, and this was associated with an improvement in systemic arginine bioavailability. CONCLUSIONS: Arginase promotes endothelial dysfunction and hypertension in obesity by reducing arginine bioavailability. Therapeutic approaches targeting arginase represent a promising approach in treating obesity-related vascular disease. PMID- 25557183 TI - Relatedness is a poor predictor of negative plant-soil feedbacks. AB - Understanding the mechanisms underlying negative plant-soil feedbacks remains a critical challenge in plant ecology. If closely related species are more similar, then phylogeny could be used as a predictor for plant species interactions, simplifying our understanding of how plant-soil feedbacks structure plant communities, underlie invasive species dynamics, or reduce agricultural productivity. Here, we test the utility of phylogeny for predicting plant-soil feedbacks by undertaking a hierarchical Bayesian meta-analysis on all available pairwise plant-soil feedback experiments conducted over the last two decades, including 133 plant species in 329 pairwise interactions. We found that the sign and magnitude of plant-soil feedback effects were not explained by the phylogenetic distance separating interacting species. This result was consistent across different life forms, life cycles, provenances, and phylogenetic scales. Our analysis shows that, contrary to widespread assumption, relatedness is a poor predictor of plant-soil feedback effects. PMID- 25557184 TI - Detection of shiga-toxin producing E. coli (STEC) in leafy greens sold at local retail markets in Alexandria, Egypt. AB - Leafy green vegetables, a popular and an indispensable ingredient of the daily menus of Egyptians' diets, currently presents a great concern in terms of microbiological hazards. To the best of our knowledge, this is the first report that provides scientific evidence for prevalence of shiga-toxigenic Escherichia coli (STEC) in leafy greens sold at open air local retail markets and superstores in the Egyptian environment. A total of 486 conventional and organic leafy green samples that are eaten raw were collected from different areas in Alexandria, evaluated for total E. coli counts (ECCs), and screened for E. coli O157:H7 using conventional and molecular methods. Recovery of E. coli (>=10(2)CFU/g) from all studied types of leafy greens was indicative of fecal contamination. Total ECCs in conventional samples ranged from 5.47 to 2.56 log CFU/g. Based on their inability to ferment sorbitol on CT-SMAC media, 26 presumptive E. coli O157 isolates were detected in 71.4% (270/378) of the studied conventional samples. From all studied organic samples, only 2 types (organic cabbage and parsley, 16.7%) were contaminated with presumptive E. coli O157. All 28 isolates were further serotyped as E. coli O157 by latex agglutination test, and biochemically confirmed as E. coli. Multiplex PCR assays confirmed the ability of 21.4% (6/28) of the E. coli O157 strains to produce shiga-toxins (Stxs), and their virulence markers were as follows: stx1, 66.6% (4/6); stx2, 50% (3/6); stx1/stx2, 16.7% (1/6); eaeA, 83.3% (5/6); and hlyA, 16.7% (1/6). Only 2 strains recovered from conventional and organic parsley could possibly be classified as E. coli O157:H7 based on the presence of stx-genes (either stx1 or stx2 or both). Results of the present research highlight that high E. coli loads, together with recovery of STEC O157 isolates could pose serious health risks to the produce consumers. This emphasizes the urgent need for health authorities to value and utilize the existing knowledge to identify strategies that reduce microbiological risks due to fecal contamination of agricultural products, and implement control measures at all stages of the food chain to specifically eliminate the presence of STEC O157 on the leafy green category. PMID- 25557185 TI - Distinctive proteolytic activity of cell envelope proteinase of Lactobacillus helveticus isolated from airag, a traditional Mongolian fermented mare's milk. AB - Airag is a traditional fermented milk of Mongolia that is usually made from raw mare's milk. Lactobacillus helveticus is one of the lactic acid bacteria most frequently isolated from airag. In this study, we investigated the genetic and physiological characteristics of L. helveticus strains isolated from airag and clarified their significance in airag by comparing them with strains from different sources. Six strains of L. helveticus were isolated from five home-made airag samples collected from different regions of Mongolia. The optimal temperature for acidification in skim milk was 30 to 35 degrees C for all the Mongolian strains, which is lower than those for the reference strains (JCM 1554 and JCM 1120(T)) isolated from European cheeses. All of the strains had a prtH1 like gene encoding a variant type of cell envelope proteinase (CEP). The CEP amino acid sequence in Snow Brand Typeculture (SBT) 11087 isolated from airag shared 71% identity with PrtH of L. helveticus CNRZ32 (AAD50643.1) but 98% identity with PrtH of Lactobacillus kefiranofaciens ZW3 (AEG40278.1) isolated from a traditional fermented milk in Tibet. The proteolytic activities of the CEP from SBT11087 on artificial substrate (N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide) and pure casein were measured using an intact-cell degradation assay. The activity of the CEP from SBT11087 was observed to be weak and exhibited a lower optimal temperature (40 degrees C) than those from the reference strains (45-50 degrees C). The specificity of the SBT11087 CEP for alphaS1-casein was typical of the CEPs previously reported in L. helveticus, as determined through the degradation profiles obtained through gel electrophoresis and mass spectrometry analyses. In contrast, the degradation profile of beta-casein revealed that the CEP of SBT11087 primarily hydrolyzes its C-terminal domain and hydrolyzed nine of the 16 cleavage sites shared among the CEPs of other L. helveticus strains. Thus, the CEP of SBT11087 is distinct from those from previously reported L. helveticus strains in terms of its optimal temperature and its degradation of beta-casein. Therefore, the Mongolian L. helveticus strains differ from other strains of the species in different collections and are specifically suited for the natural lactic acid bacterial population in airag. PMID- 25557186 TI - The World Hypertension League: a look back and a vision forward. PMID- 25557187 TI - Changes in blood testosterone concentrations after surgical and chemical sterilization of male free-roaming dogs in southern Chile. AB - There is a growing interest in chemical sterilization as an alternative to surgical castration in large-scale sterilization campaigns to control canine populations. An important step toward understanding the short-term and long-term effects of chemical sterilants is to determine their impact on blood testosterone concentrations, particularly as these could influence dog behavior after treatment. A field trial was conducted with 118 free-roaming male dogs in the Chilean Patagonia, where 36 dogs were chemically sterilized using EsterilSol, 39 dogs were surgically castrated, and 43 dogs remained intact as controls. Blood testosterone levels were determined at four time periods: on enrollment 6 months before treatment (t-6m), at the time of treatment (t0, within one hour after surgical castration or chemical sterilization and during a concurrent 2-week period for the control group), four (t+4m), and six (t+6m) months after treatment. Intrinsic and temporal factors were evaluated; age was significantly associated with testosterone, where dogs 2- to 4-year-old had the highest testosterone concentrations (P = 0.036), whereas body weight and body condition scores were not associated with testosterone; testosterone concentration was not influenced by time of day, month, or season. After treatment (t+4m and t+6m), all of the surgically castrated dogs had testosterone concentrations below 1.0 ng/mL. On the basis of this cut point (<1 ng/mL), testosterone remained unchanged in 66% of the chemically sterilized dogs at both t+4m and t+6m; it remained low for 22% of dogs at both t+4m and t+6m; it was unchanged at t+4m but low at t+6m in 9% of dogs; and, it was low at t+4m but reverted back to unchanged at t+6m in one dog (3%). Incidentally, testosterone in chemically sterilized dogs increased dramatically within 1 hour of treatment (t0), more than doubling (131%) the concentration of control dogs at the time of treatment (t0), likely because of severe necrosis of interstitial cells. The use of EsterilSol as a method of sterilizing dogs had a variable effect on blood testosterone concentrations. Approximately, 30% of chemically sterilized dogs had a reduced testosterone concentration (actual maximum, 1 ng/mL) after 6 months, similar to that of surgically castrated dogs. Most chemically sterilized dogs, however, showed no long-term changes in blood testosterone concentrations. PMID- 25557188 TI - Cellular and molecular mechanisms of pentoxifylline's beneficial effects in experimental polycystic ovary. AB - Chronic low-grade inflammation and oxidative stress (OS) appear to be two main pathways involved in the pathogenesis of polycystic ovary (PCO) syndrome. Therefore, targeting these pathways by means of anticytokine and antioxidant agents might be a therapeutic alternative approach to the current treatments of PCO syndrome. In this study, we investigated the protective effects of pentoxifylline (PTX), a drug with antioxidant and anti-tumor necrosis factor alpha (TNF-alpha) properties, in hyperandrogenism-induced PCO rats. The inflammatory and OS responses and their connections with ovarian functionality in induced PCO rats were investigated through ovarian histopathologic examination and a series of biochemical measurements including serum estradiol, progesterone, testosterone, insulin, and TNF-alpha, ovarian and serum lipid peroxidation, total antioxidant power, and reactive oxygen species. Experimental PCO was induced in rats by oral administration of letrozole (1 mg/kg body weight) for 21 consecutive days. In a different group, PTX was administrated orally (50 mg/kg/d) for 21 days simultaneous with letrozole to assess its potential protective effects. The letrozole-induced PCOs were characterized by irregular cycles, high incidence of subcapsular ovarian cysts with diminished or scant granulosa cell layers, increased number of atretic preantral and antral follicles, and absence of CL. In addition, the letrozole-induced PCO rats exhibited notable increase in lipid peroxidation and reactive oxygen species of serum and ovary, serum testosterone, insulin, and TNF-alpha and significant decline in total antioxidant power, serum estradiol, and serum progesterone. Our results indicated that all the identified pathologic parameters and biochemical characteristics in letrozole-induced PCO rats in this study were preserved close to normal levels by simultaneous PTX treatments. Present results demonstrate that there is a direct connection between ovarian dysfunction and increased OS and inflammation in PCO. For the first time, the beneficial effects of PTX as a powerful antioxidant and TNF-alpha blocker in hyperandrogenism-induced PCO are reported. PMID- 25557189 TI - Stress-induced modulation of NF-kappaB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men. AB - Acute psychosocial stress stimulates transient increases in circulating pro inflammatory plasma cytokines, but little is known about stress effects on anti inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-kappaB (NF kappaB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF kappaB, its inhibitor IkappaBalpha, and of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1beta, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-kappaB-BA and delayed increases in plasma IL-6 and mRNA of IL-1beta, IL-6, and IkappaBalpha (p's<.045). In the stress group, significant increases over time were also observed for NF-kappaB mRNA and plasma IL-1beta and IL-10 (p's<.055). NF-kappaB BA correlated significantly with mRNA of IL-1beta (r=.52, p=.002), NF-kappaB (r=.48, p=.004), and IkappaBalpha (r=.42, p=.013), and marginally with IL-6 mRNA (r=.31, p=.11). Plasma cytokines did not relate to NF-kappaB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF kappaB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells. PMID- 25557190 TI - A strategy for fabricating porous PdNi@Pt core-shell nanostructures and their enhanced activity and durability for the methanol electrooxidation. AB - Three-dimensionally (3D) porous morphology of nanostructures can effectively improve their electrocatalytic activity and durability for various electrochemical reactions owing to big surface area and interconnected structure. Cyanogel, a jelly-like inorganic polymer, can be used to synthesize various three dimensionally (3D) porous alloy nanomaterials owing to its double-metal property and particular 3D backbone. Here, 3D porous PdNi@Pt core-shell nanostructures (CSNSs) are facilely synthesized by first preparing the Pd-Ni alloy networks (Pd Ni ANWs) core via cyanogel-reduction method followed by a galvanic displacement reaction to generate the Pt-rich shell. The as-synthesized PdNi@Pt CSNSs exhibit a much improved catalytic activity and durability for the methanol oxidation reaction (MOR) in the acidic media compared to the commercial used Pt black because of their specific structural characteristics. The facile and mild method described herein is highly attractive for the synthisis of 3D porous core-shell nanostructures. PMID- 25557191 TI - Fullerene-like boron clusters stabilized by an endohedrally doped iron atom: B(n)Fe with n = 14, 16, 18 and 20. AB - Stabilized fullerene and tubular forms can be produced in boron clusters Bn in small sizes from n~ 14 to 20 upon doping by transition metal atoms. B14Fe and B16Fe are stable tubes whereas B18Fe and B20Fe are stable fullerenes. Their formation and stability suggest the use of dopants to induce different growth paths leading to larger cages, fullerenes and tubes of boron. PMID- 25557192 TI - Behavioural responses of stable flies to cattle manure slurry associated odourants. AB - Stable flies (Stomoxys calcitrans [Diptera: Muscidae] L.) are blood-feeding synanthropic pests, which cause significant economic losses in livestock. Stable fly antennae contain olfactory sensilla responsive to host and host environment associated odours. Field observation indicated that the abundance of stable flies increased significantly in grasslands or crop fields when cattle manure slurry was applied. Major volatile compounds emanating from manure slurry were collected and identified. Behavioural responses of stable flies to those compounds were investigated in laboratory bioassays and field-trapping studies. Results from olfactometer assays revealed that phenol, p-cresol and m-cresol were attractive to adult stable flies. When tested individually, attraction was higher with lower dosages. Stable flies were most attracted to blends of phenol and m-cresol or p cresol. Traps with binary blend lures caught more stable flies in field trials as well. PMID- 25557193 TI - Proteomics into its third decade. PMID- 25557199 TI - An automated lung segmentation approach using bidirectional chain codes to improve nodule detection accuracy. AB - Computer-aided detection and diagnosis (CAD) has been widely investigated to improve radiologists' diagnostic accuracy in detecting and characterizing lung disease, as well as to assist with the processing of increasingly sizable volumes of imaging. Lung segmentation is a requisite preprocessing step for most CAD schemes. This paper proposes a parameter-free lung segmentation algorithm with the aim of improving lung nodule detection accuracy, focusing on juxtapleural nodules. A bidirectional chain coding method combined with a support vector machine (SVM) classifier is used to selectively smooth the lung border while minimizing the over-segmentation of adjacent regions. This automated method was tested on 233 computed tomography (CT) studies from the lung imaging database consortium (LIDC), representing 403 juxtapleural nodules. The approach obtained a 92.6% re-inclusion rate. Segmentation accuracy was further validated on 10 randomly selected CT series, finding a 0.3% average over-segmentation ratio and 2.4% under-segmentation rate when compared to manually segmented reference standards done by an expert. PMID- 25557200 TI - Discontinuous Galerkin finite element method for solving population density functions of cortical pyramidal and thalamic neuronal populations. AB - Compared with the Monte Carlo method, the population density method is efficient for modeling collective dynamics of neuronal populations in human brain. In this method, a population density function describes the probabilistic distribution of states of all neurons in the population and it is governed by a hyperbolic partial differential equation. In the past, the problem was mainly solved by using the finite difference method. In a previous study, a continuous Galerkin finite element method was found better than the finite difference method for solving the hyperbolic partial differential equation; however, the population density function often has discontinuity and both methods suffer from a numerical stability problem. The goal of this study is to improve the numerical stability of the solution using discontinuous Galerkin finite element method. To test the performance of the new approach, interaction of a population of cortical pyramidal neurons and a population of thalamic neurons was simulated. The numerical results showed good agreement between results of discontinuous Galerkin finite element and Monte Carlo methods. The convergence and accuracy of the solutions are excellent. The numerical stability problem could be resolved using the discontinuous Galerkin finite element method which has total-variation diminishing property. The efficient approach will be employed to simulate the electroencephalogram or dynamics of thalamocortical network which involves three populations, namely, thalamic reticular neurons, thalamocortical neurons and cortical pyramidal neurons. PMID- 25557201 TI - Mathematical modelling of thermoregulation processes for premature infants in closed convectively heated incubators. AB - The low-weight newborns and especially the premature infants have difficulty in maintaining their temperature in the range considered to be normal. Several studies revealed the importance of thermal environment and moisture to increase the survival rate of newborns. This work models the process of heat exchange and energy balance in premature newborns during the first hours of life in a closed incubator. In addition, a control problem was proposed and solved in order to maintain thermal stability of premature newborns to increase their rate of survival and weight. For this purpose, we propose an algorithm to control the temperature inside the incubator. It takes into account the measurements of the body temperature of a premature newborn which are recorded continuously. We show that using this model the temperature of a premature newborn inside the incubator can be kept in a thermal stability range. PMID- 25557202 TI - Go with the flow: how the consideration of joy versus pride influences automaticity. AB - Recently, we have shown that the consideration of joy, without the actual experience of the emotion, impaired performance on the antisaccade task (Katzir, Eyal, Meiran, & Kessler, 2010). We interpreted this finding as indicating inhibitory control failure. However, impaired antisaccade performance may result from either the weakening of inhibitory control, the potentiation of the competing automatic response, or both. In the current research we used a task switching paradigm, which allowed us to assess cognitive control more directly, using Backward Inhibition, Competitor Rule Suppression, and Competitor Rule Priming as cognitive-control indices as well as assessing the Task Rule Congruency Effect (TRCE) which, like the antisaccade, is influenced by both control and automaticity. We found that considering joy compared to pride did not influence any of the cognitive control indices but increased the TRCE. We interpret this finding as evidence that joy consideration leads to increased reliance on automatic tendencies, such as short-term desires. PMID- 25557203 TI - Effectiveness of an electronic tool for medication reconciliation in a general surgery department. AB - BACKGROUND: Medication reconciliation is a key tool in the prevention of adverse drug events. OBJECTIVE: To assess the impact of an electronic reconciliation tool in decreasing unintended discrepancies between medications prescribed after surgery and the patient's usual treatment. SETTING: General Surgery Department of Gregorio Maranon's University General Hospital, Madrid. METHOD: A pre-post intervention study with no equivalent control group was carried out between June 2009 and December 2010. Patients hospitalized in the General Surgery Department for 24 h or more, and whose prescriptions prior to admission included three or more drugs were included in the study. Patients were interviewed to gather information about their usual treatment drugs. Discrepancies between the latter and the drugs prescribed after surgery were assessed before and after the medication reconciliation electronic tool was implemented. MAIN OUTCOME MEASURE: Proportion of patients with at least one unintended discrepancy. RESULTS: A total of 107 patients in the pre-intervention phase and 84 patients in the post intervention phase were included. We detected 1,678 discrepancies, 167 were found to be unintended. The number of patients with at least one unintended discrepancy was 43 (40.2 %) in the pre-intervention phase, and 38 (38.1 %) in the post intervention phase, p = 0.885. The percentage of unintended discrepancies over the total amount of drugs reconciled was lower in the post-intervention phase than in the pre-intervention phase (6.6 vs. 10.6 %), p = 0.002. Regarding unintended discrepancies 79.2 % were grade C severity (the error reached the patient but caused no harm), 13.6 % grade D (the error reached the patient and required monitoring or intervention to preclude harm) and 7.1 % grade E (the error may have contributed to or resulted in temporary harm to the patient and required intervention). CONCLUSION: Implementation of an electronic tool facilitated the process of medication reconciliation in a general surgery unit. The proportion of unintended discrepancies over the total amount of drugs reconciled was reduced after the implementation of the reconciliation programme. However, we could not demonstrate a more significant impact due to some methodological limitations. PMID- 25557204 TI - IL-17A activates ERK1/2 and enhances differentiation of oligodendrocyte progenitor cells. AB - Inflammatory signals present in demyelinated multiple sclerosis lesions affect the reparative remyelination process conducted by oligodendrocyte progenitor cells (OPCs). Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF alpha), and interleukin (IL)-6 have differing effects on the viability and growth of OPCs, however the effects of IL-17A are largely unknown. Primary murine OPCs were stimulated with IL-17A and their viability, proliferation, and maturation were assessed in culture. IL-17A-stimulated OPCs exited the cell cycle and differentiated with no loss in viability. Expression of the myelin-specific protein, proteolipid protein, increased in a cerebellar slice culture assay in the presence of IL-17A. Downstream, IL-17A activated ERK1/2 within 15 min and induced chemokine expression in 2 days. These results demonstrate that IL-17A exposure stimulates OPCs to mature and participate in the inflammatory response. PMID- 25557206 TI - Predictors of early menopause in HIV-infected women: a prospective cohort study. AB - OBJECTIVE: This study sought to investigate the age at natural menopause and its predictors in a cohort of human immunodeficiency virus (HIV)-infected women in Rio de Janeiro, Brazil. STUDY DESIGN: HIV-infected women >=30 years of age were included. Menopause was defined as having >=1 year since the last menstrual period. Early age at natural menopause was defined as the onset of menopause at <=45 years of age. Multivariate Cox proportional hazards analysis was applied. RESULTS: A total of 667 women were included, and the median age at baseline was 34.9 years (interquartile range, 30.9-40.5 years). In all, 507 (76%) women were premenopausal, and 160 (24%) reached menopause during the observational period; of these, 36 of 160 (27%) had early menopause. The median age at natural menopause was 48 years (interquartile range, 45-50 years). Menarche at <11 years of age (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.23-3.37), cigarette smoking during the observational period (HR, 1.59; 95% CI, 1.08-2.33), chronic hepatitis C virus (HCV) infection (HR, 2.53; 95% CI, 1.27-5.07), and CD4 count <50 cells/mm(3) (HR, 3.07; 95% CI, 1.07-8.80) were significantly associated with an earlier age at natural menopause. The magnitudes of the effects of menarche at <11 years of age (HR, 2.7; 95% CI, 1.23-5.94), cigarette smoking during the observational period (HR, 3.00; 95% CI, 1.39-6.45), chronic HCV infection (HR, 6.26; 95% CI, 2.12-18.52), and CD4 count <50 cells/mm(3) (HR, 6.64; 95% CI, 1.91-23.20) were much higher and significantly associated with early natural menopause. CONCLUSION: Early natural menopause was frequent among the HIV-infected women. In addition to menarche and cigarette smoking, which are menopausal factors among women in general, HIV-related immunodeficiency and chronic HCV were additional predictors for an earlier age at natural menopause. Adequate management of HIV in women is critical, as early onset of menopause has been associated with increased morbidity and mortality. PMID- 25557205 TI - Evidence for pelvic organ prolapse predisposition genes on chromosomes 10 and 17. AB - OBJECTIVE: We conducted a genomewide linkage analysis to identify pelvic organ prolapse (POP) predisposition genes using a resource of high-risk POP pedigrees. STUDY DESIGN: Cases are defined as women who reported bothersome symptoms of POP based on standardized symptom questions (Pelvic Floor Distress Inventory, moderately or quite bothered), and/or received treatment for POP documented in medical records. Our complete pedigree resource contains 299 familial POP cases in 83 high-risk pedigrees. Genotype data were obtained from Illumina HumanHap550, 610Q, the Human1M-Duo, Human Omni1-Quad, or the Human Omni 2.5 platforms. A set of single nucleotide polymorphism markers common to all platforms was identified and markers in high linkage disequilibrium were removed. We performed a genomewide linkage analysis under general dominant and recessive models using a Markov chain, Monte Carlo linkage analysis method implemented in MCLINK (University of Utah) software. Because 70 individuals in 32 pedigrees were used in a previously published linkage analysis for a phenotype of POP requiring treatment/surgery, we also performed linkage only including the 225 newly recruited and genotyped cases in 61 pedigrees. RESULTS: Linkage analysis using our complete pedigree resource for the loosened criteria of bothersome POP showed evidence for significant genomewide linkage on chromosome 10q24-26 (recessive model, maximum heterogeneity logarithm of odds 3.4); suggestive evidence was identified on chromosomes 6 and 17, and an additional region on chromosome 10. In the subset of only the newly recruited familial POP cases, significant evidence for genomewide linkage was observed on chromosome 17q25 (recessive model, maximum heterogeneity logarithm of odds 3.3), and suggestive evidence for linkage was observed on chromosomes 10 and 11. Neither analysis duplicated the previously published linkage evidence for the POP requiring treatment/surgery phenotype observed on chromosome 9. CONCLUSION: While the etiology of this common condition is unknown, this study provides evidence that loci on chromosomes 10q and 17q may contribute to POP etiology. PMID- 25557207 TI - Reply: To PMID 24881821. PMID- 25557208 TI - Subtotal versus total abdominal hysterectomy: randomized clinical trial with 14 year questionnaire follow-up. AB - OBJECTIVE: The objective of the study was to compare long-term results of subtotal vs total abdominal hysterectomy for benign uterine diseases 14 years after hysterectomy, with urinary incontinence as the primary outcome measure. STUDY DESIGN: This was a long-term follow-up of a multicenter, randomized clinical trial without blinding. Eleven gynecological departments in Denmark contributed participants to the trial. Women referred for benign uterine diseases who did not have contraindications to subtotal abdominal hysterectomy were randomized to subtotal (n = 161) vs total (n = 158) abdominal hysterectomy. All women enrolled in the trial from 1996 to 2000 who were still alive and living in Denmark (n = 304) were invited to answer the validated questionnaire used in prior 1 and 5 year follow-ups. Hospital contacts possibly related to hysterectomy from 5 to 14 years postoperatively were registered from discharge summaries from all public hospitals in Denmark. The results were analyzed as intention to treat and per protocol. Possible bias caused by missing data was handled by multiple imputation. The primary outcome was urinary incontinence; the secondary outcomes were pelvic organ prolapse, constipation, pain, sexuality, quality of life (Short Form-36 questionnaire), hospital contacts, and vaginal bleeding. RESULTS: The questionnaire was answered by 197 of 304 women (64.8%) (subtotal hysterectomy [n = 97] [63.4%]; total hysterectomy [n = 100] [66.2%]). Mean follow-up time was 14 years and mean age at follow-up was 60.1 years. After subtotal abdominal hysterectomy, 32 of 97 women (33%) complained of urinary incontinence compared with 20 of 100 women (20%) after total abdominal hysterectomy 14 years after hysterectomy (relative risk, 1.67; 95% confidence interval, 1.02-2.70; P = .035). After a multiple imputation analysis, this difference disappeared (relative risk, 1.36; 95% confidence interval, 0.86-2.13; P = .19). No differences were seen in any of the secondary outcomes. CONCLUSION: Subtotal abdominal hysterectomy was not superior to total abdominal hysterectomy on any outcomes. More women seem to have subjective urinary incontinence 14 years after subtotal abdominal hysterectomy. This result was not confirmed by multiple imputation analysis and should be interpreted cautiously. PMID- 25557209 TI - Association of trimester-specific gestational weight gain with fetal growth, offspring obesity, and cardiometabolic traits in early childhood. AB - OBJECTIVE: The purpose of this study was to investigate the association of trimester-specific gestational weight gain with offspring fetal growth, obesity risk, and cardiometabolic health outcomes from birth to 4 years of age. STUDY DESIGN: We conducted the present study with 977 mother-child pairs of the pregnancy cohort "Rhea" study in Crete, Greece. We measured birthweight, body mass index from 6 months to 4 years of age, waist circumference, skinfold thickness, blood pressure, and blood levels of lipids, C-reactive protein, and adipose tissue hormones at 4 years of age. We used multiple linear and log Poisson regression models to examine the association of exposure with continuous or binary outcomes, respectively. RESULTS: Greater rate of gestational weight gain in the first trimester of pregnancy (per 200 g/wk) was associated with increased risk of overweight/obesity from 2 years (relative risk [RR], 1.25; 95% confidence interval [CI], 1.09-1.42) to 4 years of age (RR, 1.15; 95% CI, 1.05 1.25), but not with birth size. Each 200 g/wk of weight gain in the first trimester of pregnancy was also associated with greater risk of high waist circumference (RR, 1.13; 95% CI, 1.04-1.23), high sum of skinfold thickness (RR, 1.15; 95% CI, 1.02-1.29), and higher diastolic blood pressure at 4 years of age (beta, 0.43 mm Hg; 95% CI, 0.00-0.86). Greater rate of gestational weight gain during the second and third trimesters of pregnancy (per 200 g/wk) was associated with greater risk of large-for-gestational-age neonates (RR, 1.22; 95% CI, 1.02, 1.45) and higher levels of cord blood leptin (ratio of geometric means, 1.08; 95% CI, 1.00-1.17), but not with child anthropometry at later ages. CONCLUSION: Timing of gestational weight gain may influence childhood cardiometabolic outcomes differentially. PMID- 25557212 TI - Designing environmental research for impact. AB - Transdisciplinary research, involving close collaboration between researchers and the users of research, has been a feature of environmental problem solving for several decades, often spurred by the need to find negotiated outcomes to intractable problems. In 2005, the Australian government allocated funding to its environment portfolio for public good research, which resulted in consecutive four-year programmes (Commonwealth Environmental Research Facilities, National Environmental Research Program). In April 2014, representatives of the funders, researchers and research users associated with these programmes met to reflect on eight years of experience with these collaborative research models. This structured reflection concluded that successful multi-institutional transdisciplinary research is necessarily a joint enterprise between funding agencies, researchers and the end users of research. The design and governance of research programmes need to explicitly recognise shared accountabilities among the participants, while respecting the different perspectives of each group. Experience shows that traditional incentive systems for academic researchers, current trends in public sector management, and loose organisation of many end users, work against sustained transdisciplinary research on intractable problems, which require continuity and adaptive learning by all three parties. The likelihood of research influencing and improving environmental policy and management is maximised when researchers, funders and research users have shared goals; there is sufficient continuity of personnel to build trust and sustain dialogue throughout the research process from issue scoping to application of findings; and there is sufficient flexibility in the funding, structure and operation of transdisciplinary research initiatives to enable the enterprise to assimilate and respond to new knowledge and situations. PMID- 25557210 TI - The preterm placental microbiome varies in association with excess maternal gestational weight gain. AB - OBJECTIVE: Although a higher maternal body mass index is associated with preterm birth, it is unclear whether excess gestational weight gain (GWG) or obesity drives increased risk. We and others have shown that the placenta harbors microbiota, which is significantly different among preterm births. Our aim in this study was to investigate whether the preterm placental microbiome varies by virtue of obesity or alternately by excess GWG. STUDY DESIGN: Placentas (n=320) were collected from term and preterm pregnancies. Genomic DNA was extracted and subjected to metagenomic sequencing. Data were analyzed by clinical covariates that included the 2009 Institute of Medicine's GWG guideline and obesity. RESULTS: Analysis of 16S recombinant RNA-based metagenomics revealed no clustering of the microbiome by virtue of obesity (P=.161). Among women who spontaneously delivered preterm, there was again no clustering by obesity (P=.480), but there was significant clustering by excess GWG (P=.022). Moreover, among preterm births, detailed analysis identified microbial genera (family and genus level) and bacterial metabolic gene pathways that varied among pregnancies with excess GWG. Notably, excess GWG was associated with decreased microbial folate biosynthesis pathways and decreased butanoate metabolism (linear discriminate analysis, >3.0-fold). CONCLUSION: Although there were no significant alterations in the microbiome by virtue of obesity per se, excess GWG was associated with an altered microbiome and its metabolic profile among those women who experienced a preterm birth. PMID- 25557214 TI - The electric field strength in orifice-like nanopores of ultrathin membranes. AB - Here we show that the electric field inside an ultrathin membrane is weaker than conventional theory would predict, and that the reduced field is predictive of measured electroosmotic flow rates. Our theoretical analysis shows that the electric field inside a charged nanopore is affected by end effects and dependent on the Dukhin number Du when the pore length-to-diameter aspect ratio lambda is less than 80 for Du ? 1 or 300 for Du ? 1. The electric field follows an unconventional scaling law; it no longer scales uniformly with the thickness of membrane, but with the local value of lambda for each nanopore. PMID- 25557211 TI - Pimecrolimus in atopic dermatitis: consensus on safety and the need to allow use in infants. AB - Atopic dermatitis (AD) is a distressing dermatological disease, which is highly prevalent during infancy, can persist into later life and requires long-term management with anti-inflammatory compounds. The introduction of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, more than 10 yr ago was a major breakthrough for the topical anti-inflammatory treatment of AD. Pimecrolimus 1% is approved for second-line use in children (>=2 yr old) and adults with mild-to-moderate AD. The age restriction was emphasized in a boxed warning added by the FDA in January 2006, which also highlights the lack of long term safety data and the theoretical risk of skin malignancy and lymphoma. Since then, pimecrolimus has been extensively investigated in short- and long-term studies including over 4000 infants (<2 yr old). These studies showed that pimecrolimus effectively treats AD in infants, with sustained improvement with long-term intermittent use. Unlike topical corticosteroids, long-term TCI use does not carry the risks of skin atrophy, impaired epidermal barrier function or enhanced percutaneous absorption, and so is suitable for AD treatment especially in sensitive skin areas. Most importantly, the studies of pimecrolimus in infants provided no evidence for systemic immunosuppression, and a comprehensive body of evidence from clinical studies, post-marketing surveillance and epidemiological investigations does not support potential safety concerns. In conclusion, the authors consider that the labelling restrictions regarding the use of pimecrolimus in infants are no longer justified and recommend that the validity of the boxed warning for TCIs should be reconsidered. PMID- 25557213 TI - Entamoeba infections in different populations of dogs in an endemic area of Lahore, Pakistan. AB - Entamoeba histolytica, a protozoan parasite that affects humans and other primates all over the world. It is a common waterborne pathogen in endemic areas that have fecal oral transmission cycle. The aim of the present study was to examine the prevalence of E. histolytica and other Entamoeba species cysts in three different dog populations. Fecal samples from 600 dogs were collected and processed to detect Entamoeba cysts using the triple fecal test (light microscopy) and fecal antigens of E. histolytica were detected using a fecal antigen ELISA (TechLab E. histolytica II). Because it is impossible to differentiate E. histolytica from Entamoeba dispar and E. moshkovskii, using light microscopy we referred to all cysts morphologically consistent with E. histolytica as E. histolytica/dispar/moskovskii to reflect this uncertainty. Samples from 197 household dogs without clinical signs, 122 samples from household dogs exhibiting clinical signs of diarrhea, dysentery and vomiting and 281 stray dogs with no specific clinical signs were examined. Entamoeba histolytica-like cysts were observed in 94 (15.6%, 95% CI=+/-3.88) by triple fecal test microscopy and E. histolytica antigens were demonstrated in 66 (11%, 95% CI=+/-4.41) by fecal antigen ELISA in 600 fecal samples. Significant differences (P<=0.05) in prevalence were found between the three populations. Twenty (10.1%, 95% CI=+/-7.86) and 11 (5.6%, 95% CI=+/-7.70) of 197 fecal samples from household dogs without clinical signs were positive by microscopy and by antigen ELISA, respectively. Twenty-nine (23.8%, 95% CI=+/-6.58) and 23 (18.8%, 95% CI=+/-7.81) of 122 the fecal samples from household dogs with clinical signs were positive by microscopy and by antigen ELISA, respectively. Forty-five (16.01%, 95% CI=+/-5.62) and 32 (11.3%, 95% CI=+/-6.38) of 281 fecal samples from stray dogs were positive by microscopy and by fecal antigen ELISA, respectively. Dogs from the youngest age group (6 months to 1 year) were more likely to be E. histolytica antigen positive than were dogs from the other two older age groups, with a significant difference (P<=0.05) between all age groups. Statistically, no significant (P>=0.05) difference of prevalence was seen in male and female dogs. The local dogs had the highest prevalence rate of E. histolytica antigens (36 of 246, 14.2%, 95% CI=+/-6.32) followed by imported breeds (11 of 115, 9.5%, 95% CI=+/-10.4) and crossbred (19 of 239, 8.3%, 95% CI=+/-7.47), indicating a significant (P<=0.05) trend of positivity between various breeds of dogs. These findings suggest that dogs may play an important role in the epidemiology of this pathogen. PMID- 25557215 TI - Family reunion of nuclear hormone receptors: structures, diseases, and drug discovery. PMID- 25557216 TI - Metastatic phaeochromocytoma in a 23-year-old woman with an unclassified variant in the von Hippel Lindau disease gene: how can the pathogenicity of this variant be determined? AB - A 23-year-old woman with metastatic phaeochromocytoma was found to have a previously unclassified variant in the von Hippel Lindau disease gene (c.361G>C). We use this case to highlight the issue of unclassified single nucleotide variants and the approaches to help predict whether they are disease causing or neutral. With increasing use of genetic testing, and widespread clinical use of next-generation sequencing around the corner, this issue is likely to become more prominent. PMID- 25557217 TI - Three-tesla magnetic resonance neurography of the brachial plexus in cervical radiculopathy. AB - INTRODUCTION: There have been no reports of the use of 3-Tesla magnetic resonance neurography (3T MRN) to characterize cervical radiculopathy. In particular, there are no reports of MRN of brachial plexus involvement in patients with cervical radiculopathy. METHODS: We reviewed retrospectively 12 consecutive patients with cervical radiculopathy who underwent 3T MRN. RESULTS: The median age was 54.5 years. Eleven of 12 patients were men. The distribution of nerve-root signal abnormality was correlated with intervertebral foraminal stenosis and the presence of muscles that exhibited weakness and/or signs of denervation on electromyography. MRN abnormalities were found to extend into the distal part of the brachial plexus in 10 patients. CONCLUSION: This study demonstrates that MRN is potentially useful for diagnosis in patients with suspected cervical radiculopathy. Moreover, the finding of brachial plexus involvement on MRN may indicate a possible pathophysiological relationship between cervical radiculopathy and brachial plexopathy. PMID- 25557219 TI - Solitary erythematous crusted plaque on the neck. PMID- 25557218 TI - Isolevuglandin adducts in disease. AB - SIGNIFICANCE: A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences. CRITICAL ISSUES: IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo. RECENT ADVANCES: The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Abeta1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells. FUTURE DIRECTIONS: Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein protein and DNA-protein cross-link formation, and its biological consequences. PMID- 25557220 TI - Defining the interaction between exercise and arrhythmogenic right ventricular cardiomyopathy. PMID- 25557221 TI - No difference in clinical outcome between patella eversion and lateral retraction in total knee arthroplasty: a systemic review and meta-analysis. AB - PURPOSE: Surgical exposure during total knee arthroplasty (TKA) requires mobilization technique of the patella. Proponents of minimally invasive TKA claim that lateral retraction, rather than eversion, of the patella may be beneficial. Many randomized controlled studies attempt to identify this issue; however, no final conclusion arrives. With this systemic review and meta-analysis, we intended to test whether patella eversion during TKA had deleterious effects. METHODS: A comprehensive literature search was performed in PubMed, MEDLINE, EMBASE and other internet database. We retrieved all the relevant studies designed to interpret this issue. The searching time frame was from the establishing of these databases until July 2014. RESULTS: Six randomized controlled trials assessing a total of 414 patients and 451 knees were included. The duration of surgery was much shorter (p = 0.003), and the length of skin incision was much longer (p < 0.00001). No significant difference was found on other measurements, including length of hospital stay, quadriceps strength, complications, straight leg raise, Visual Analogue Scale score and functional scores. CONCLUSIONS: Patella eversion could decrease the duration of the surgery; nevertheless, the length of skin incision was longer; no significant difference was found on other measurements, especially the quadriceps strength and complications which were concerned. Patella eversion and patella lateral retraction could achieve similar clinical outcomes. LEVEL OF EVIDENCE: Systematic review and meta-analysis, Level I. PMID- 25557224 TI - Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome. AB - BACKGROUND: Altered pain anticipation likely contributes to disturbed central pain processing in chronic pain conditions like irritable bowel syndrome (IBS), but the learning processes shaping the expectation of pain remain poorly understood. We assessed the neural circuitry mediating the formation, extinction, and reactivation of abdominal pain-related memories in IBS patients compared to healthy controls (HC) in a differential fear conditioning paradigm. METHODS: During fear acquisition, predictive visual cues (CS(+)) were paired with rectal distensions (US), while control cues (CS(-)) were presented unpaired. During extinction, only CSs were presented. Subsequently, memory reactivation was assessed with a reinstatement procedure involving unexpected USs. Using functional magnetic resonance imaging, group differences in neural activation to CS(+) vs CS(-) were analyzed, along with skin conductance responses (SCR), CS valence, CS-US contingency, state anxiety, salivary cortisol, and alpha-amylase activity. The contribution of anxiety symptoms was addressed in covariance analyses. KEY RESULTS: Fear acquisition was altered in IBS, as indicated by more accurate contingency awareness, greater CS-related valence change, and enhanced CS(+)-induced differential activation of prefrontal cortex and amygdala. IBS patients further revealed enhanced differential cingulate activation during extinction and greater differential hippocampal activation during reinstatement. Anxiety affected neural responses during memory formation and reinstatement. CONCLUSIONS & INFERENCES: Abdominal pain-related fear learning and memory processes are altered in IBS, mediated by amygdala, cingulate cortex, prefrontal areas, and hippocampus. Enhanced reinstatement may contribute to hypervigilance and central pain amplification, especially in anxious patients. Preventing a 'relapse' of learned fear utilizing extinction-based interventions may be a promising treatment goal in IBS. PMID- 25557223 TI - Corticotrophin-releasing factor 1 activation in the central amygdale and visceral hyperalgesia. AB - Corticotropin-releasing factor (CRF)-CRF1 receptor in the brain plays a key role in stress-related alterations of behavior including anxiety/depression, and autonomic and visceral functions. In particular, CRF1 signaling mediates hypersensitivity to colorectal distension (CRD) in various models (early life adverse events, repeated psychological stress, chronic high anxiety, postcolonic inflammation, or repeated nociceptive CRD). So far, knowledge of brain sites involved is limited. A recent article demonstrates in rats that CRF microinjected into the central amygdala (CeA) induces a hyperalgesic response to CRD and enhances the noradrenaline and dopamine levels at this site. The visceral and noradrenaline, unlike dopamine, responses were blocked by a CRF1 antagonist injected into the CeA. Here, we review the emerging role that CRF-CRF1 signaling plays in the CeA to induce visceral hypersensitivity. In the somatic pain field, CRF in the CeA was shown to induce pain sensitization. This is mediated by the activation of postsynaptic CRF1 receptors and protein kinase A signaling that increases N-methyl-d-aspartate receptor neurotransmission. In addition, the activation of tetraethylamonium-sensitive ion channels such as Kv3 accelerates repolarization and firing rate. Whether facilitation of pain transmission underlies CRF action in the CeA-induced visceral hypersensitivity will need to be delineated. CRF1 signaling in the CeA is also an important component of the neuronal circuitry inducing anxiety-like behavior and positioned at the interphase of the reciprocal relationship between pain and affective state. The hyperactivity of this system may represent the neuroanatomical and biochemical substrate contributing to the coexpression of hypersensitivity to CRD and mood disorders in subsets of irritable bowel syndrome patients. PMID- 25557225 TI - ERK and p38MAPK pathways regulate myosin light chain phosphatase and contribute to Ca2+ sensitization of intestinal smooth muscle contraction. AB - BACKGROUND: Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinase (ERK) and p38MAPK, are known regulators of smooth muscle contractility. The contraction of smooth muscle is mainly regulated by the phosphorylation of regulatory light chains of myosin II (LC20), which is driven by the balance between myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP). We hypothesized that one possible mechanism for MAPK dependent modulation of intestinal smooth muscle contractility is via the regulation of MLCP activity. METHODS: Contractile responses to carbachol (CCh) and effects of MAPK inhibitors on CCh-induced contractions were assessed with isolated rat ileal longitudinal smooth muscle strips. Biochemical assessments of MLCP activity and myosin phosphatse targeting subunit (MYPT1) and CPI-17 phosphorylations were completed. KEY RESULTS: Treatment of ileal smooth muscle with PD98059 (10 MUM; MEK inhibitor) or SB203580 (10 MUM; p38MAPK inhibitor) significantly inhibited CCh-induced contractile force. Decreased MLCP activity was observed during sustained contractions induced by CCh; the MLCP activity was recovered by treatment with PD98059 and SB203580. However, MYPT1 (Thr697 and Thr855) and CPI-17 (Thr38) phosphorylations were not affected. Application of ML 7 (MLCK inhibitor) during CCh-induced sustained contraction elicited an MLCP dependent relaxation, the rate of which was accelerated by application of PD98059 and SB203580 with proportional changes in LC20 phosphorylation levels but not MYPT1 phosphorylation (Thr697 or Thr855). CONCLUSIONS & INFERENCES: ERK and p38MAPK contribute to CCh-induced sustained contraction in a LC20 phosphorylation dependent manner. Moreover, both kinases inhibit MLCP activity possibly by a novel mechanism. PMID- 25557222 TI - Magnetic resonance imaging criteria for the assessment of the rotator cuff after repair: a systematic review. AB - PURPOSE: The purpose of this systematic review was to detect the reliability of the currently available magnetic resonance imaging measurements used in the evaluation of repaired rotator cuff. METHODS: Search was performed using major electronic databases from their inception to February 2014. All studies reporting post-operative magnetic resonance assessment after rotator cuff repair were included. After the identification of available magnetic resonance criteria, reliability studies were further analysed. Descriptive statistics were used to summarize findings. Methodological quality was assessed using the Quality Appraisal of Reliability Studies checklist. RESULTS: One hundred and twenty studies were included in the review. Twenty-six different criteria were identified. Ten studies reported inter-observer reliability, and only two assessed intra-observer reliability of some of the identified criteria. Structural integrity was the most investigated criterion. The dichotomized Sugaya's classification showed the highest reliability (k = 0.80-0.91). All other criteria showed moderate to low inter-observer reliability. Tendon signal intensity and footprint coverage showed a complete discordance. Intra-observer reliability was high for the presence of structural integrity, and moderate to low for all other criteria. Methodological quality was high only for one study and moderate for three studies. CONCLUSIONS: Twenty-six different criteria described by multiple classification systems have been identified for the magnetic resonance assessment of rotator cuff after repair. Reliability of most of them has not been analysed yet. With the data available, only the presence of structural integrity showed good intra- and inter-observer agreement. LEVEL OF EVIDENCE: Systematic review of descriptive and qualitative studies, Level IV. PMID- 25557226 TI - Characterization of ghrelin-sensitive neurons in the lumbosacral defecation center in rats. AB - BACKGROUND: Ghrelin is involved in the regulation of somatic growth, feeding behavior and energy homeostasis. Ghrelin stimulates neuropeptide Y (NPY) neurons and activates intracellular AMP-activated protein kinase (AMPK) in the hypothalamus. These NPY neurons also express the leptin receptor and leptin inhibits ghrelin-induced activation of NPY neurons. In the spinal cord, we have demonstrated colokinetic action of ghrelin. However, the precise characteristics of the ghrelin-sensitive neurons remain to be clarified. The aim of this study was firstly to confirm that the action of ghrelin is mediated via a neurogenic pathway in the spinal cord, and secondly to characterize the ghrelin-sensitive neurons by comparing with hypothalamic ghrelin-sensitive neurons. METHODS: Rats were anesthetised with alpha-chloralose and ketamine, and colorectal intraluminal pressure and expelled volume were recorded in vivo. Drugs were applied intrathecally. KEY RESULTS: Ghrelin caused enhancement of propulsive contractions. Tetrodotoxin completely blocked the colokinetic effect of ghrelin. An AMPK activator, aminoimidazole carboxamide ribonucleotide, failed to mimic the ghrelin effect. Leptin had no effect on the spontaneous contractions and did not exert a suppressive effect on the ghrelin-enhanced colorectal motility. An NPY Y1 receptor antagonist did not affect the action of ghrelin. NPY had no effect on the colorectal motility. CONCLUSIONS & INFERENCES: This study showed that intrathecal injection of ghrelin stimulates colorectal motility by acting on ghrelin-sensitive neurons in the lumbosacral defecation center. The characteristics of ghrelin-sensitive neurons in the spinal cord are quite different from those of ghrelin-sensitive neurons in the hypothalamus. PMID- 25557227 TI - Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells. AB - To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research. PMID- 25557228 TI - Prophylactic methylprednisolone to reduce inflammation and improve outcomes from one lung ventilation in children: a randomized clinical trial. AB - BACKGROUND: One lung ventilation (OLV) results in inflammatory and mechanical injury, leading to intraoperative and postoperative complications in children. No interventions have been studied in children to minimize such injury. OBJECTIVE: We hypothesized that a single 2-mg.kg(-1) dose of methylprednisolone given 45-60 min prior to lung collapse would minimize injury from OLV and improve physiological stability. METHODS: Twenty-eight children scheduled to undergo OLV were randomly assigned to receive 2 mg.kg(-1) methylprednisolone (MP) or normal saline (placebo group) prior to OLV. Anesthetic management was standardized, and data were collected for physiological stability (bronchospasm, respiratory resistance, and compliance). Plasma was assayed for inflammatory markers related to lung injury at timed intervals related to administration of methylprednisolone. RESULTS: Three children in the placebo group experienced clinically significant intraoperative and postoperative respiratory complications. Respiratory resistance was lower (P = 0.04) in the methylprednisolone group. Pro-inflammatory cytokine IL-6 was lower (P = 0.01), and anti-inflammatory cytokine IL-10 was higher (P = 0.001) in the methylprednisolone group. Tryptase, measured before and after OLV, was lower (P = 0.03) in the methylprednisolone group while increased levels of tryptase were seen in placebo group after OLV (did not achieve significance). There were no side effects observed that could be attributed to methylprednisolone in this study. CONCLUSIONS: Methylprednisolone at 2 mg.kg(-1) given as a single dose prior to OLV provides physiological stability to children undergoing OLV. In addition, methylprednisolone results in lower pro-inflammatory markers and higher anti-inflammatory markers in the children's plasma. PMID- 25557229 TI - Mood repair via attention refocusing or recall of positive autobiographical memories by adolescents with pediatric-onset major depression. AB - BACKGROUND: Impaired emotion regulation is increasingly recognized as a core feature of depressive disorders. Indeed, currently and previously depressed adults both report greater problems in attenuating sadness (mood repair) in daily life than healthy controls. In contrast, studies of various strategies to attenuate sad affect have mostly found that currently or previously depressed adults and controls were similarly successful at mood repair in the laboratory. But few studies have examined mood repair among depression-prone youths or the effects of trait characteristics on mood repair outcomes in the laboratory. METHODS: Adolescents, whose first episode of major depressive disorder (MDD) had onset at age 9, on average (probands), and were either in remission or depressed, and control peers, watched a sad film clip. Then, they were instructed to engage in refocusing attention (distraction) or recalling happy memories. Using affect ratings provided by the youths, we tested two developmentally informed hypotheses about whether the subject groups would be similarly able to attenuate sadness via the two mood repair strategies. We also explored if self-reported habitual (trait) mood repair influenced laboratory performance. RESULTS: Contrary to expectations, attention refocusing and recall of happy memories led to comparable mood benefits across subjects. Control adolescents reported significantly greater reductions in sadness than did depressed (Cohen's d = .48) or remitted (Cohen's d = .32) probands, regardless of mood repair strategy, while currently depressed probands remained the saddest after mood repair. Habitual mood repair styles moderated the effects of instructed (state) mood repair in the laboratory. CONCLUSIONS: Whether depressed or in remission, adolescents with MDD histories are not as efficient at mood repair in the laboratory as controls. But proband control group differences in mood repair outcomes were modest in scope, suggesting that the abilities that subserve affect regulation have been preserved in probands to some degree. Further information about the nature of mood repair problems among youths with depression histories would help to better understand the clinical course of MDD and to design personalized interventions for depression. PMID- 25557231 TI - Baicalein Decreases Hydrogen Peroxide-Induced Damage to NG108-15 Cells via Upregulation of Nrf2. AB - Baicalein is a flavonoid inhibitor of 12-lipoxygenase. Here, we investigated its effect on hydrogen peroxide-induced damage to NG108-15 cells. Hydrogen peroxide activated the mitochondrial apoptotic pathway, decreased Nrf2 expression, increased reactive oxygen species (ROS) levels, reduced viability, and increased cell death after 2-24 h treatment of NG108-15 cells. Co-treatment with hydrogen peroxide and baicalein completely suppressed the activation of mitochondrial apoptotic pathway by upregulating Nrf2 expression and reducing ROS stress and partially inhibited the effects on cell viability and cell death. Silencing of 12 lipoxygenase had a similar protective effect to baicalein on hydrogen peroxide induced damage by blocking the hydrogen peroxide-induced decrease in Nrf2 expression and increase in ROS levels. Neither protective effect was altered by addition of 12-hydroxyeicosatetraenoic acid, the product of 12-lipoxygenase, suggesting that hydrogen peroxide induced damage via 12-lipoxygenase by another, as yet unknown, mechanism, rather than activating it. Co-treatment of cells with hydrogen peroxide and N-acetylcysteine or the Nrf2 inducer sulforaphane reduced hydrogen peroxide-induced damage in a similar fashion to baicalein, while the Nrf2 inhibitor retinoic acid blocked the protective effect of baicalein. Silencing Nrf2 also inhibited the protective effects of baicalein, sulforaphane, and N-acetylcysteine and resulted in high ROS levels, suggesting ROS elimination was mediated by Nrf2. Taken together our results suggest that baicalein protects cells from hydrogen peroxide-induced activation of the mitochondrial apoptotic pathway by upregulating Nrf2 and inhibiting 12-lipoxygenase to block the increase in ROS levels. Hydrogen peroxide also activates a second mitochondrial dysfunction independent death pathway which is resistant to baicalein. PMID- 25557232 TI - Novel KRT83 and KRT86 mutations associated with monilethrix. AB - Monilethrix is an autosomal dominant hair disorder caused by mutations in the hard keratins KRT81, KRT83 and KRT86. The affected hairs are fragile and break easily, leading to scarring alopecia. Follicular hyperkeratosis in the neck and on extensor sides of extremities is a frequently associated finding. The disorder is rare, but probably underreported because its manifestations may be mild. Mutations in KRT81 and KRT86 are the most common. Here, we report new cases from Venezuela, the Netherlands, Belgium and France. The Venezuelan kindred is special for having patients with digenic novel nucleotide changes, a KRT86 mutation associated with monilethrix and a KRT81 variant of unknown clinical significance. In the French and Dutch patients, we found novel KRT86 and KRT83 mutations. Our findings expand the mutational spectrum associated with monilethrix. PMID- 25557233 TI - The challenges of immunological scores to predict the risk of infection after transplant. PMID- 25557235 TI - Coarctation with a calcified aneurysm of the descending thoracic aorta. PMID- 25557236 TI - The reliability of medial and lateral plantar nerve recordings in healthy elderly individuals. AB - The aim of this study was to investigate the reliability of medial plantar (MP) and lateral plantar (LP) nerve conduction studies (NCS) in healthy individuals aged >65 years, and to obtain reference values for this age group. The study included 81 healthy subjects. MP response was absent in only 2 subjects, but LP response could not be obtained bilaterally in 43 of the 81 subjects. Regression analysis showed that MP NCS could be reliably performed in those aged <= 72 years and normal values for MP nerve in individuals aged 66-72 years would be strongly against a large-fiber neuropathy. However, LP response was absent in 53.1 % of the healthy elderly subjects; therefore, we think it is unreliable to study the LP nerve in this age group. PMID- 25557237 TI - Anti-GAD antibody-positive myoclonic leg jerks. PMID- 25557238 TI - Analysis of the CYC/TB1 class of TCP transcription factors in basal angiosperms and magnoliids. AB - Flower monosymmetry contributes to specialized interactions between plants and their insect pollinators. In the magnoliids, flower monosymmetry is exhibited only in the Aristolochiaceae (Piperales). Aristolochia flowers develop a calyx derived monosymmetric perianth that enhances pollination success by a flytrap mechanism. Aristolochia arborea forms additionally a special perianth outgrowth that mimics a mushroom to attract flies, the mushroom mimicry structure (MMS). In core eudicots, members of the CYC2 clade of TCP transcription factors are key regulators of corolla monosymmetry establishment. The CYC2 clade arose via core eudicot-specific duplications from ancestral CYC/TB1 genes. CYC/TB1 genes are also thought to affect monosymmetry formation in early diverging eudicot and monocot species. Here, we demonstrate that CYC/TB1 genes, named CYC-like genes (CYCL) are present in basal angiosperms and magnoliids. Expression analyses in A. arborea indicate that CYCL genes participate in perianth and MMS differentiation processes and do not support a CYCL gene function in initial flower monosymmetry formation. Heterologous CYCL and CYC2 gene overexpression studies in Arabidopsis show that Aristolochia CYCL proteins only perform a CYC2-like function when the CYCL TCP domain is replaced by a CYC2 domain. Comparative TCP domain analyses revealed that an LxxLL motif, known to mediate protein-protein interactions, evolved in the second helix of the TCP domain in the CYC2 lineage and contributes to CYC2-related functions. Our data imply that divergent evolution of the CYC/TB1 lineages caused significant changes in their coding regions, which together with cis-regulatory changes established the key CYC2 function in regulating eudicot flower monosymmetry. PMID- 25557234 TI - Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer. AB - BACKGROUND: Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs. METHODS: In total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed. RESULTS: The average +/- standard deviation methylation in LS (9% +/- 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% +/- 17%; P < .001) and in MSI BRAF wild-type CRC (25% +/- 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses. CONCLUSIONS: Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS. PMID- 25557239 TI - Creation of DNA aptamers against recombinant bone morphogenetic protein 15. AB - The oocyte-derived growth factor bone morphogenetic protein (BMP) 15 plays important roles in fertility, but its mechanism of action differs between species. Generation of BMP15-binding molecules, as an essential investigation tool, would be helpful to provide valuable insight into the underlying biological features of BMP15. The BMP15-binding molecules could be antibodies or aptamers. Aptamers have many advantages over antibodies as macromolecular ligands for target proteins. DNA aptamers can be obtained by a method of Systematic Evolution of Ligands by EXponential enrichment (SELEX) beginning with a pool of random sequences. However, the success of this technique cannot be guaranteed if the initial pool lacks candidate sequences. Herein, we report on the creation of DNA aptamers by means of modified SELEX. The modification included enhanced mutation and progressive selection during an in vitro evolutionary process. As a proof-of principle, we started from a single sequence instead of a multiple-sequence pool. Functional aptamers against the recombinant BMP15 were successfully created and identified. PMID- 25557240 TI - Increased protein oxidation and decreased expression of nuclear factor E2-related factor 2 protein in skin tissue of patients with diabetes. AB - BACKGROUND: Reactive oxygen species (ROS) contribute to the cell dysfunction and tissue damage that result from glucolipotoxicity in diabetes. ROS formation in cells causes oxidative stress, thereby activating oxidative damage-inducing genes. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to play an essential role in the vital defence mechanisms that help cells cope with oxidative stress. AIM: To compare Nrf2 protein expression in nondiabetic skin tissue with that in diabetic skin tissue. METHODS: Nrf2 expression was evaluated by Western blotting, reverse transcription (RT)-PCR, and immunohistochemical staining in diabetic and nondiabetic skin tissues. Dinitrophenylhydrazone derivatives of protein carbonyls in the oxidized proteins were measured by oxyblotting analysis. Cytoplasmic and nuclear Nrf2 protein expression was determined to identify the activity and level of Nrf2. RESULTS: Protein oxidation, a marker of oxidative stress, was found to be increased in diabetic skin tissue. In subcellular fraction analysis, Nrf2 protein was detected in the nuclei and cytoplasm of nondiabetic skin tissues, and the Nrf2 protein band was identified from among the multiple bands detected, using small interfering RNA mediated Nrf2 gene silencing. Compared with nondiabetic tissue, diabetic skin tissue showed simultaneous downregulation of Nrf2 at both the mRNA and protein levels. Nuclear condensation, loss of nuclei, and vacuolization were seen in some parts of the specimen by haematoxylin and eosin staining of diabetic skin tissue. Immunohistochemical staining of Nrf2 confirmed the RT-PCR and Western blotting results. CONCLUSIONS: Collectively, our data show that expression of Nrf2 is clearly downregulated in diabetic skin tissue, and suggest that Nrf2 may be necessary for protection against glucose-induced oxidative stress. PMID- 25557241 TI - Outcomes of preimplantation genetic diagnosis in neurofibromatosis type 1. AB - OBJECTIVE: To examine the effect of patient and facility level factors on the success of preimplantation genetic diagnosis (PGD) in patients with neurofibromatosis 1 (NF1). DESIGN: Retrospective review. SETTING: Large PGD reference laboratory. PATIENT(S): All patients with NF1 referred from June 2004 to May 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryos' NF1 mutation status and live birth rates. RESULT(S): Seventy-seven couples underwent 156 PGD cycles during the study period. The average maternal age at the time of embryo biopsy was 33.2 years. The majority of embryos had a day 3 single blastomere biopsy without aneuploidy screening. A diagnosis was obtained for 80% of biopsied embryos; 20% of biopsies were nondiagnostic due to technical failures. Diagnosis was more often obtained for embryos of parents with familial disease and for embryos biopsied at centers that referred multiple NF1 cases. Among diagnosed embryos, 483/1,060 (46%) were unaffected by the parental NF1 mutation. Twenty-two (14%) of the 156 cycles had a confirmed live birth; if the observed success rate is applied to cycles with unknown outcomes, 33/156 (21%) cycles are expected to have resulted in live birth. In multivariate logistic regression, having a live birth was significantly associated with having more unaffected embryos available for transfer (odds ratio 1.33 per additional embryo, 95% confidence interval 1.02-1.72). CONCLUSION(S): Advances in biopsy and diagnostic techniques which increase the number of unaffected embryos identified may improve live birth rates for patients with NF1. Clinicians should counsel patients about their fertility and reproductive options early, with the use of disease-specific data, to set appropriate expectations for the PGD process. PMID- 25557243 TI - Increased blastomere number in cleavage-stage embryos is associated with higher aneuploidy. AB - OBJECTIVE: To evaluate the relationship between blastomere number and aneuploidy. DESIGN: Historical cohort study. SETTING: In vitro fertilization clinic. PATIENT(S): Two hundred fifty-nine patients undergoing in vitro fertilization (IVF) in combination with comprehensive chromosomal screening of embryos. INTERVENTION(S): A total of 1,915 embryos were biopsied on day 3 and underwent comprehensive chromosomal screening with microarray-based comparative genomic hybridization. MAIN OUTCOME MEASURE(S): Relationship between day 3 blastomere number, aneuploidy rate, and progression to the blastocyst stage. RESULT(S): A number of day 3 blastomeres >9 was associated with significantly increased aneuploidy rates. Rapidly developing embryos were significantly more likely to blastulate regardless of their chromosomal status. Number of embryos per patient greater than 13 was independently associated with lower aneuploidy rates after controlling for maternal age. This trend was not significant with the use of a more clinically relevant threshold of greater than six embryos per patient. CONCLUSION(S): Embryos with 6-9 cells at the cleavage stage should be considered for transfer over embryos with >9 cells. Day 3 blastomere number may be used in conjunction with extended culture to improve selection of euploid embryos, especially when supernumerary embryos are available. Further studies are needed to show if these selection criteria improve clinical outcomes. PMID- 25557242 TI - Lapse in embryo transfer training does not negatively affect clinical pregnancy rates for reproductive endocrinology and infertility fellows. AB - OBJECTIVE: To compare rates of clinical pregnancy (CPR) and live birth (LBR) following embryo transfer (ET) performed by reproductive endocrinology and infertility (REI) fellows before and after a prolonged lapse in clinical training due to an 18-month research rotation. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): All women undergoing in vitro fertilization (IVF) and IVF-intracytoplasmic sperm injection (ICSI) cycles with ET performed by REI fellows from August 2003 to July 2012. INTERVENTION: Eighteen-month lapse in clinical training of REI fellows. MAIN OUTCOME MEASURE(S): CPR and LBR before and after the lapse in clinical training were calculated and compared per fellow and as a composite group. Alternating logistic regression models were used to calculate the odds of clinical pregnancy and live birth following transfers performed before and after the lapse in training. RESULT(S): Unadjusted odds of clinical pregnancy and live birth were similar between the two time periods both for individual fellows and for the composite group. Alternate logistic regression analysis revealed no significant difference in CPR (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.83-1.07) or LBR (OR 1.05, 95% CI 0.94-1.18) after the lapse in training compared with before. CONCLUSION(S): A research rotation is common in REI fellowship training programs. This prolonged departure from clinical training does not appear to negatively affect pregnancy outcome following fellow ET. PMID- 25557244 TI - Economic evaluation of elective single-embryo transfer with subsequent single frozen embryo transfer in an in vitro fertilization/intracytoplasmic sperm injection program. AB - OBJECTIVE: To analyze the cost-effectiveness of IVF-ICSI cycles with elective single-embryo transfer (eSET), plus elective single frozen embryo transfer (eSFET) if pregnancy is not achieved, compared with double-embryo transfer (DET). DESIGN: Cost-effectiveness analysis. SETTING: Public hospital. PATIENT(S): A population of 121 women (<38 years old), undergoing their first or second IVF cycles. INTERVENTION(S): We conducted a cost-effectiveness analysis using the results of a prospective clinical trial. The women in group 1 received eSET plus eSFET, and those in group 2 received DET. A probabilistic sensitivity analysis was performed. MAIN OUTCOME MEASURE(S): Live birth delivery rate. RESULT(S): The cumulative live birth delivery rate was 38.60% in the eSET+eSFET group versus 42.19% in the DET group. The mean costs per patient were ?5,614.11 in the eSET+eSFET group and ?5,562.29 in the DET group. These differences were not statistically significant. The rate of multiple gestation was significantly lower in the eSET group than in the DET group (0 vs. 25.9%). CONCLUSION(S): This study does not show that eSET is superior to DET in terms of effectiveness or of costs. The lack of superiority of the results for the eSET+eSFET and the DET groups corroborates that the choice of strategy to be adopted should be determined by the context of the health care system and the individual prognosis. PMID- 25557245 TI - Relevance of lymphocyte subsets to B cell-targeted therapy in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with heterogeneous clinical manifestations, and pathologically characterized by activation of autoreactive T cells and overproduction of autoantibodies by B cells. Although corticosteroids and immunosuppressants are widely used for the treatment, safer and more effective therapies are needed. B cells play a pivotal role in the pathogenesis of SLE not only by producing pathogenic autoantibodies but also by modulating immune responses via production of cytokines and chemokines. The potential efficacy of B-cell depletion therapy has been reported in SLE. Treatment with rituximab, an anti-CD20 antibody, results in reconstitution of B cells in the periphery, thereby inhibiting T cell activation and differentiation, which in turn leads to long-term remission of SLE. However, we have reported SLE recurrence driven by B cell- or T cell-memory activation after long-term remission, demonstrating pathological heterogeneity in SLE. Ideally, differential targeting therapies should be considered according to relevant lymphocyte subsets. Therefore, evaluation of peripheral blood lymphocyte subsets could be valuable for predicting the response to B cell-targeted therapy. A better understanding of B cell pathology should contribute to the development of novel specific therapies for SLE. PMID- 25557246 TI - Ultrathin films of TiO2 nanoparticles at interfaces. AB - The properties of a material change remarkably as a result of the scaling dimensions. The Langmuir-Blodgett (LB) film deposition technique is known to offer precise control over the film thickness and the interparticle separation. To form a well-ordered LB film, it is essential to form a stable Langmuir film at the air-water interface. Here, we report our studies on ultrathin films of TiO2 nanoparticles at air-water and air-solid interfaces. The Langmuir film of TiO2 nanoparticles at the air-water interface was found to be very stable, and it exhibits loose-packing and close-packing phases. The LB films were transferred onto solid substrates for characterization and application. The surface morphology of the LB film was obtained by a field emission scanning electron microscope. The optical and electronic properties of the LB films of TiO2 nanoparticles were studied using UV-vis spectroscopy and current-voltage measurements, respectively. The LB film of TiO2 nanoparticles was employed for ethanol gas sensing, and the sensing performance was compared to that of bulk material. Because of the enormous gain in the surface to volume ratio and the increase in crystalline defect density in the ultrathin LB film of TiO2 nanoparticles, the LB film is found to be a potential functional layer for ethanol sensing as compared to the bulk material. PMID- 25557248 TI - Paraneoplastic pemphigus: two cases of intra-abdominal malignancy presenting solely as treatment refractory oral ulceration. AB - Two patients with initial diagnoses of oral lichen planus and pemphigus vulgaris presented with refractory oral mucosal blistering. Subsequent positive serology results for paraneoplastic pemphigus led to the discovery of occult intra abdominal malignancies in both, unicentric Castleman's and non-Hodgkin's lymphoma. The diagnosis of paraneoplastic pemphigus should be considered in patients with recalcitrant oral ulceration, even in the absence of clinical features of malignancy. PMID- 25557247 TI - PINK1 phosphorylates transglutaminase 2 and blocks its proteasomal degradation. AB - Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss and the formation of abnormal protein aggregates, referred to as Lewy bodies (LBs). PINK1 is a serine/threonine protein kinase that protects cells from stress induced mitochondrial dysfunction. PINK1 gene mutations cause one form of autosomal recessive early-onset PD. Transglutaminase 2 (TG2) is an intracellular protein cross-linking enzyme that has an important role in LB formation during PD pathogenesis. This study identifies PINK1 as a novel TG2 binding partner and shows that PINK1 stabilizes the half-life of TG2 via inhibition of TG2 ubiquitination and subsequent proteasomal degradation. PINK1 affects TG2 stability in a kinase-dependent manner. In addition, PINK1 directly phosphorylates TG2 in carbonyl cyanide m-chlorophenyl hydrazine-induced mitochondrial damaged states, thereby enhancing TG2 accumulation and intracellular protein cross-linking products. This study further confirms the functional link between upstream PINK1 and downstream TG2 in Drosophila melanogaster. These data suggest that PINK1 positively regulates TG2 activity, which may be closely associated with aggresome formation in neuronal cells. PMID- 25557249 TI - Quality of life and social isolation in Greek adolescents with primary focal hyperhidrosis treated with botulinum toxin type A: a case series. AB - Primary hyperhidrosis, although extensively documented in adults, typically has onset that dates back to early childhood. It is an unpleasant and socially disabling problem for the affected child, but little attention has been paid to the disease in adolescents. The objective of the current study was to evaluate the effectiveness of botulinum toxin type A (BTXA) in adolescents with primary palmar and axillary hyperhidrosis and to determine its effect on quality of life and social isolation. Thirty-five individuals (17 girls, 18 boys) with moderate to severe palmar and axillary hyperhidrosis were treated with BTXA (onabotulinum). Patients were examined at baseline and 6 months after treatment. The Hyperhidrosis Disease Severity Scale (HDSS) was used to evaluate disease severity and the Children's Dermatology Life Quality Index (CDLQI) was used to assess quality of life. The University of California at Los Angeles loneliness scale (UCLA version 3) was used to assess personal perception of loneliness and social isolation. The median age of the participants was 14 years, and 48.6% were female. Twenty-one had palmar hyperhidrosis, and 14 had axillary hyperhidrosis. Total CDLQI and social isolation scores decreased significantly after treatment with BTXA (both p < 0.001). There was a significant difference between pre- and post-treatment levels of severity of hyperhidrosis. No statistically significant difference was documented for CDLQI and UCLA scores between boys and girls. Treatment of hyperhidrosis with BTXA resulted in improvement in quality of life, social skills, and activities. PMID- 25557250 TI - Riboflavin and amotosalen photochemical treatments of platelet concentrates reduce thrombus formation kinetics in vitro. AB - BACKGROUND: Photochemical treatment (PCT) of platelet concentrates using photosensitizers and ultraviolet light illumination reduces the proliferation potential of pathogens by damaging biomolecules. MATERIALS AND METHODS: The impact of riboflavin (RF-PRT)- and amotosalen (AS-PCT)-based pathogen inactivation on platelets was studied using microfluidic flow chambers on immobilized collagen using standard platelet concentrates prepared from buffy coats in additive solution. Flow cytometry, metabolic parameters and light transmission aggregometry with thrombin-related peptide, collagen and ristocetin were determined concurrently. RESULTS: Both PCTs significantly decreased the platelet surface coverage kinetics in flow chambers over the course of the 7-day study. Platelet aggregation was affected following RF-PRT in response to all agonists, while AS-PCT mainly impacted low-dose ristocetin agglutination. RF-PRT induces premature platelet activation because integrin alphaII b beta3 was spontaneously activated, and alpha-degranulation, phosphatidylserine/ ethanolamine exposure and anaerobic metabolism significantly increased following treatment, which was not the case for AS-PCT. On the other hand, AS-PCT significantly diminished thrombus growth onto von Willebrand factor under shear flow. This defect was caused by fewer integrin alphaII b beta3 interactions, not by defective GPIbalpha-VWF binding as shown by adhesion experiments in the presence of tirofiban. Moreover, integrin alphaII b beta3 activation was also affected following the activation of platelets via GPVI-FcgammaRIIa or PAR1. Finally, amotosalen illumination as such is sufficient to induce platelet damage, with no additional measurable effect of the chemical adsorption step. Gamma irradiation caused no significant difference compared to controls on any time point or for any parameter. CONCLUSION: Both PCTs significantly reduce thrombus formation rate but by different biochemical mechanisms. PMID- 25557251 TI - Characterization of a halophilic heterotrophic nitrification-aerobic denitrification bacterium and its application on treatment of saline wastewater. AB - A novel halophilic bacterium capable of heterotrophic nitrification-aerobic denitrification was isolated from marine sediments and identified as Vibrio diabolicus SF16. It had ability to remove 91.82% of NH4(+)-N (119.77 mg/L) and 99.71% of NO3(-)-N (136.43 mg/L). The nitrogen balance showed that 35.83% of initial NH4(+)-N (119.77 mg/L) was changed to intracellular nitrogen, and 53.98% of the initial NH4(+)-N was converted to gaseous denitrification products. The existence of napA gene further proved the aerobic denitrification ability of strain SF16. The optimum culture conditions were salinity 1-5%, sodium acetate as carbon source, C/N 10, and pH 7.5-9.5. When an aerated biological filter system inoculated with strain SF16 was employed to treat saline wastewater, the average removal efficiency of NH4(+)-N and TN reached 97.14% and 73.92%, respectively, indicating great potential of strain SF16 for future full-scale applications. PMID- 25557252 TI - Effective collection of peripheral blood stem cells in children weighing 20 kilogram or less in a single large-volume apheresis procedure. AB - INTRODUCTION: Peripheral blood stem cell (PBSC) transplantation has become a routine procedure in pediatric oncology. A special group of PBSC donors are children weighing 20 kg or less. Limited vascular access and low blood volume puts them at a higher risk. Central line placement and a priming apheresis machine are recommended to avoid these complications. PATIENTS AND METHODS: PBSC collections performed from July 2006 to May 2013 in children weighing less than 20 kg were included. All donors had a central venous catheter (CVC). An apheresis machine was primed with packet red blood cells. RESULTS: Twenty-seven PBSC collections were performed in 22 children weighing 20 kg or less, 14 for allogeneic and 8 for autologous transplantation, in order to collect at least 2 * 10(6) CD34+ cells/kg. In the allogeneic group, median age and weight were 3 years (0.8-7) and 15.5 kg (8-20). In the autologous group, median age and weight were 3 years (2-7) and 15.35 kg (12.5-19.5). A single large-volume apheresis was sufficient to obtain the CD34+ cells needed in 78.5% and 75% of the allogeneic and autologous groups, respectively, with a median 11.84 * 10(6) and 5.79 * 10(6) CD34+ cells collected per kilogram of weight of the recipient. No serious complications related to the apheresis procedure or CVC placement occurred. CONCLUSION: PBSC collection in a single large-volume apheresis for allogeneic and autologous transplants in children weighing 20 kg or less is a safe and effective procedure when based on standardized protocols. PMID- 25557253 TI - Genome-wide identification, expression analysis of auxin-responsive GH3 family genes in maize (Zea mays L.) under abiotic stresses. AB - Auxin is involved in different aspects of plant growth and development by regulating the expression of auxin-responsive family genes. As one of the three major auxin-responsive families, GH3 (Gretchen Hagen3) genes participate in auxin homeostasis by catalyzing auxin conjugation and bounding free indole-3-acetic acid (IAA) to amino acids. However, how GH3 genes function in responses to abiotic stresses and various hormones in maize is largely unknown. Here, the latest updated maize (Zea mays L.) reference genome sequence was used to characterize and analyze the ZmGH3 family genes from maize. The results showed that 13 ZmGH3 genes were mapped on five maize chromosomes (total 10 chromosomes). Highly diversified gene structures and tissue-specific expression patterns suggested the possibility of function diversification for these genes in response to environmental stresses and hormone stimuli. The expression patterns of ZmGH3 genes are responsive to several abiotic stresses (salt, drought and cadmium) and major stress-related hormones (abscisic acid, salicylic acid and jasmonic acid). Various environmental factors suppress auxin free IAA contents in maize roots suggesting that these abiotic stresses and hormones might alter GH3-mediated auxin levels. The responsiveness of ZmGH3 genes to a wide range of abiotic stresses and stress-related hormones suggested that ZmGH3s are involved in maize tolerance to environmental stresses. PMID- 25557255 TI - Protective Effect of Aronia Melanocarpa Polyphenols on Cadmium Accumulation in the Body: A Study in a Rat Model of Human Exposure to this Metal. AB - Recently a growing attention has been paid to the possibility of using biologically active compounds, including polyphenols, for the prevention of unfavourable effects of exposure to xenobiotics. The study was aimed to investigate, in a female rat model, whether consumption of Aronia melanocarpa polyphenols (AMP) under chronic exposure to cadmium (Cd) decreases the gastrointestinal absorption and body burden of this heavy metal. For this purpose, Cd turnover (apparent absorption, retention in the body, concentration in the blood, soft tissues and bone tissue, total pool in internal organs, faecal and urinary excretion) was evaluated in the female Wistar rats who were administered only a 0.1% aqueous extract of AMP (prepared from the powdered extract containing 65.74% of polyphenols) as drinking fluid or/and Cd in diet (1 and 5 mg/kg) for up to 24 months. AMP administration under the low Cd treatment (1 mg/kg diet) had only a very slight protective impact against this metal accumulation in the organism, whereas polyphenols application under moderate exposure (5 mg Cd/kg diet) significantly decreased apparent absorption and retention in the body, and increased urinary concentration of this xenobiotic, resulting in its lower concentration in the blood and lower accumulation in soft tissues (mainly in the liver and kidneys) and bone tissue. Based on the study, it can be concluded that consumption of polyphenol- rich products may prevent Cd absorption from the diet polluted by this metal and its accumulation in the females' body, and thus also prevent its toxic action. PMID- 25557256 TI - OPA1 in Cardiovascular Health and Disease. AB - Mitochondria are known to play crucial roles in normal cellular physiology and in more recent years they have been implicated in a wide range of pathologies. Central to both these roles is their ability to alter their shape interchangeably between two different morphologies: an elongated interconnected network and a fragmented discrete phenotype - processes which are under the regulation of the mitochondrial fusion and fission proteins, respectively. In this review article, we focus on the mitochondrial fusion protein optic atrophy protein 1 (OPA1) in cardiovascular health and disease and we explore its role as a potential therapeutic target for treating cardiovascular and metabolic disease. PMID- 25557254 TI - 22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXRalpha. AB - Chronic ethanol consumption causes hepatic steatosis and inflammation, which are associated with liver hypoxia. Monocyte chemoattractant protein-1 (MCP-1) is a hypoxia response factor that determines recruitment and activation of monocytes to the site of tissue injury. The level of MCP-1 is elevated in the serum and liver of patients with alcoholic liver disease (ALD); however, the molecular details regarding the regulation of MCP-1 expression are not yet understood completely. Here, we show the role of liver X receptor alpha (LXRalpha) in the regulation of MCP-1 expression during the development of ethanol-induced fatty liver injury, using an antagonist, 22-S-hydroxycholesterol (22-S-HC). First, administration of 22-S-HC attenuated the signs of liver injury with decreased levels of MCP-1 and its receptor CCR2 in ethanol-fed mice. Second, hypoxic conditions or treatment with the LXRalpha agonist GW3965 significantly induced the expression of MCP-1, which was completely blocked by treatment with 22-S-HC or infection by shLXRalpha lentivirus in the primary hepatocytes. Third, over expression of LXRalpha or GW3965 treatment increased MCP-1 promoter activity by increasing the binding of hypoxia-inducible factor-1alpha to the hypoxia response elements, together with LXRalpha. Finally, treatment with recombinant MCP-1 increased the level of expression of LXRalpha and LXRalpha-dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXRalpha and its ligand-induced up-regulation of MCP-1 and MCP-1-induced LXRalpha dependent lipogenesis play a key role in the autocrine and paracrine activation of MCP-1 in the pathogenesis of alcoholic fatty liver disease, and that this activation may provide a promising new target for ALD therapy. PMID- 25557257 TI - Novel Approaches for Potential Therapy of Cystic Fibrosis. AB - Cystic fibrosis (CF) is a lethal autosomal recessive disease that causes severe damage to the respiratory and digestive systems. It results from a dysfunctional CF Transmembrane Conductance Regulator (CFTR) protein, which is a cAMP- regulated epithelial chloride channel. CFTR is also a subtype of the ABC-transporter superfamily, and is expressed primarily in the apical membrane of epithelial cells in the airways, pancreas, and intestines. A single amino acid deletion of phenylalanine (Phe) is the most common mutation in CF patients known as F508del CFTR. Normally, wild-type CFTR is largely degraded before reaching the cell membrane and F508del-CFTR virtually never reaches the cell surface. Ultimately, our goal is to correct dysfunctional CFTR proteins in CF patients. Via high throughput screening techniques, several novel compounds for potential drugs effective in reversing the molecular CF defect and prohibiting further progression of CF have recently been discovered. S-nitrosothiols (SNOs) are small, naturally occurring endogenous cell signaling compounds, which have potential relevance to human lung diseases, including CF. Remarkably, researchers have found that the level of SNOs are reduced in the CF airway. It was previously reported that different types of SNOs, such as GSNO and S-nitrosoglutathione diethyl ester will increase CFTR maturation and function at the plasma membrane in human airway epithelial cells. The mechanisms by which SNOs improve CFTR maturation remain elusive. Currently, clinical trials are still investigating the effectiveness and safety of novel corrector and potentiator drugs for F508del- CFTR. This review article offers a summary of our knowledge on the most up-to date CF therapies. PMID- 25557258 TI - Recent Advances in Optical Molecular Imaging and its Applications in Targeted Drug Delivery. AB - Optical molecular imaging has been frequently used in many preclinical researches including cancer detection, tumor mechanism study, drug efficacy evaluation and targeted drug delivery. Among optical molecular imaging modalities, bioluminescence imaging and fluorescence imaging have acquired certain degree of development and attracted more and more attention in recent years for their high sensitivity and low cost. With the development of optical technology and probe technology, two-photon microscopy imaging and Raman imaging have been widely used in drug evaluation and tumor studies through cell and tissue imaging. This paper focuses on the occurrence and development of optical molecular imaging especially for its imaging method imaging system and its application in target drug delivery. Finally, the existing challenges and brand new applications of optical imaging techniques in drug delivery research are discussed. PMID- 25557260 TI - Clinicopathologic analysis of spindle cell/sclerosing rhabdomyosarcoma. AB - BACKGROUND: Clinical characteristics and optimal treatment strategies for spindle cell/sclerosing rhabdomyosarcoma (ssRMS) have not been well established because of its rarity. PROCEDURE: Retrospective re-evaluation of sarcoma specimens (1997 2014) identified 16 ssRMSs (median age 20 years, range 7-39 years). Clinicopathological features, clinical course, and outcome were analyzed. RESULTS: Primary disease sites were the head and neck (10 cases) and other regions (6 cases). Nine cases were at Intergroup Rhabdomyosarcoma Study preoperative stage 3. The primary tumors were >5 cm in 13 cases. Two patients had lymph node metastases, but none had distant metastases at presentation. At follow up (median period 39 months, range 4.6-201), seven patients were alive without disease. Among nine patients treated with the vincristine, actinomycin, and cyclophosphamide (VAC) regimen, five responded well, with four surviving free of disease. Among ten patients with recurrent or progressive disease, three experienced local recurrence, four had distant metastases, and three had both. None exhibited bone marrow invasion. Eight of the ten patients died in median time from relapse to death of 18 months (range 11-56). CONCLUSIONS: Although most ssRMSs present as a bulky tumor, nodal or distant metastases are rare at presentation. ssRMSs initially show good response to VAC, but >50% of tumors recur or progress; these data suggest a worse prognosis of ssRMS compared to the pediatric embryonal variant. As relapse typically occurs as local or distant solitary lesion without bone marrow invasion, localized treatment combined with chemotherapy would contribute to improve the prognosis of recurrent ssRMS. PMID- 25557259 TI - PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. AB - Somatic activating mutations in the phosphatidylinositol-3-kinase/AKT/mTOR pathway underlie heterogeneous segmental overgrowth phenotypes. Because of the extreme differences among patients, we sought to characterize the phenotypic spectrum associated with different genotypes and mutation burdens, including a better understanding of associated complications and natural history. Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose hyperplasia or Overgrowth (FAO), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly syndromes, Megalencephaly-Capillary Malformation (MCAP or M-CM) and Dysplastic Megalencephaly (DMEG). A workshop was convened at the National Institutes of Health (NIH) to discuss and develop a consensus document regarding diagnosis and treatment of patients with PIK3CA-associated somatic overgrowth disorders. Participants in the workshop included a group of researchers from several institutions who have been studying these disorders and have published their findings, as well as representatives from patient-advocacy and support groups. The umbrella term of "PIK3CA-Related Overgrowth Spectrum (PROS)" was agreed upon to encompass both the known and emerging clinical entities associated with somatic PIK3CA mutations including, macrodactyly, FAO, HHML, CLOVES, and related megalencephaly conditions. Key clinical diagnostic features and criteria for testing were proposed, and testing approaches summarized. Preliminary recommendations for a uniform approach to assessment of overgrowth and molecular diagnostic testing were determined. Future areas to address include the surgical management of overgrowth tissue and vascular anomalies, the optimal approach to thrombosis risk, and the testing of potential pharmacologic therapies. PMID- 25557261 TI - Active and passive surveillance of enoxaparin generics: a case study relevant to biosimilars. AB - OBJECTIVE: This retrospective analysis assessed the capability of active and passive safety surveillance systems to track product-specific safety events in the USA for branded and generic enoxaparin, a complex injectable subject to immune-related and other adverse events (AEs). METHODS: Analysis of heparin induced thrombocytopenia (HIT) incidence was performed on benefit claims for commercial and Medicare supplemental-insured individuals newly treated with enoxaparin under pharmacy benefit (1 January 2009 - 30 June 2012). Additionally, spontaneous reports from the FDA AE Reporting System were reviewed to identify incidence and attribution of enoxaparin-related reports to specific manufacturers. RESULTS: Specific, dispensed products were identifiable from National Drug Codes only in pharmacy-benefit databases, permitting sensitive comparison of HIT incidence in nearly a third of patients treated with brand or generic enoxaparin. After originator medicine's loss of exclusivity, only 5% of spontaneous reports were processed by generic manufacturers; reports attributable to specific generics were approximately ninefold lower than expected based on market share. CONCLUSIONS: Claims data were useful for active surveillance of enoxaparin generics dispensed under pharmacy benefits but not for products administered under medical benefits. These findings suggest that the current spontaneous reporting system will not distinguish product-specific safety signals for products distributed by multiple manufacturers, including biosimilars. PMID- 25557262 TI - Fracture and Fatigue Resistance of Cemented versus Fused CAD-on Veneers over Customized Zirconia Implant Abutments. AB - PURPOSE: To evaluate the fracture mechanics of cemented versus fused CAD-on veneers on customized zirconia implant abutments. MATERIALS AND METHODS: Forty five identical customized CAD/CAM zirconia implant abutments (0.5 mm thick) were prepared and seated on short titanium implant abutments (Ti base). A second scan was made to fabricate 45 CAD-on veneers (IPS Empress CAD, A2). Fifteen CAD-on veneers were cemented on the zirconia abutments (Panavia F2.0). Another 15 were fused to the zirconia abutments using low-fusing glass, while manually layered veneers served as control (n = 15). The restorations were subjected to artificial aging (3.2 million cycles between 5 and 10 kg in a water bath at 37 degrees C) before being axially loaded to failure. Fractured specimens were examined using scanning electron microscopy to detect fracture origin, location, and size of critical crack. Stress at failure was calculated using fractography principles (alpha = 0.05). RESULTS: Cemented CAD-on restorations demonstrated significantly higher (F = 72, p < 0.001) fracture load compared to fused CAD-on and manually layered restorations. Fractographic analysis of fractured specimens indicated that cemented CAD-on veneers failed due to radial cracks originating from the veneer/resin interface. Branching of the critical crack was observed in the bulk of the veneer. Fused CAD-on veneers demonstrated cohesive fracture originating at the thickest part of the veneer ceramic, while manually layered veneers failed due to interfacial fracture at the zirconia/veneer interface. CONCLUSIONS: Within the limitations of this study, cemented CAD-on veneers on customized zirconia implant abutments demonstrated higher fracture than fused and manually layered veneers. PMID- 25557263 TI - Early kidney transplantation improves neurocognitive outcome in patients with severe congenital chronic kidney disease. AB - Renal replacement therapy has become available for the majority of patients suffering from severe congenital chronic kidney disease (CKD). Data on the long term neurocognitive outcome and the impact of early kidney transplantation (KTx) in this setting is unclear. Neurocognitive outcomes in 15 patients (11 male) with isolated congenital CKD (stage 3-5) requiring KTx at a mean age of 2.8 +/- 1.3 were assessed at a mean age of 8.3 +/- 1.4 years. Patients underwent neurological examination and testing for neuromotor and neurocognitive function using three independent tests. Pre-emptive KTx was performed in six patients, and nine patients were dialyzed prior to KTx for a mean period of 11.1 +/- 8.6 months. Neuromotor function was abnormal in 8/15 patients. HAWIK-III showed a global intelligence quotient (IQ) of 93.5 +/- 11.4 (P = 0.05) due to a significantly reduced performance IQ of 89.1 +/- 11.3 (P < 0.01). In three patients, the global IQ was clinically significantly reduced by >1 SD to <85. In patients with neuromotor dysfunction, performance IQ was lower than in patients with normal neuromotor function (83.8 +/- 10.2 vs. 96.2 +/- 9.0, P = 0.04). Time on dialysis was inversely correlated to verbal IQ (r = 0.78, P = 0.02). Pre-emptive KTx and duration of dialysis treatment <3 months was associated with superior neurocognitive outcome. Early (pre-emptive) KTx results in superior long-term neurocognitive outcome in children with severe congenital CKD. PMID- 25557264 TI - Assembly of silver alkynyl compounds with various nuclearities. AB - A convenient method for the synthesis of silver alkynyl compounds containing different nuclearities has been developed. The reaction of AgC[triple bond, length as m-dash]CBu(t) and AgX (X = CF3CO2(-), C2F5CO2(-)) in the presence of auxiliary ligands L (L = bipyridine, bipy; 1,10-phenanthroline, phen; 2 (diphenylphosphino)pyridine, dppy) under different conditions afforded a family of new silver alkynyl compounds, namely, [Ag3(bipy)(C[triple bond, length as m dash]CBu(t))(CF3CO2)2]n (), [Ag4(bipy)2(C[triple bond, length as m dash]CBu(t))(CF3CO2)3]n (), [Ag6(phen)3(C[triple bond, length as m dash]CBu(t))2(C2F5CO2)4(MeOH)(EtOH)] (), [Ag8L4(C[triple bond, length as m dash]CBu(t))2(C2F5CO2)6] (L = bipy, ; L = phen, ), [Ag10(dppy)2(C[triple bond, length as m-dash]CBu(t))6X4] (X = CF3CO2(-), ; X = C2F5CO2(-), ), [Ag12(bipy)2(C[triple bond, length as m-dash]CBu(t))8(C2F5CO2)4] () and [Ag12(phen)4(C[triple bond, length as m-dash]CBu(t))6(CF3CO2)6].2EtOH (). Single crystal X-ray analysis revealed that compounds and display infinite-chain structures, while the other seven compounds are discrete molecules containing silver nuclearities varying from 6 to 12. The formation of various structural motifs depends on the reactant ratios and the ligands/anions with different nature. PMID- 25557265 TI - Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans. AB - An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions. PMID- 25557266 TI - Intermittent Chemotherapy as a Platform for Testing Novel Agents in Patients With Metastatic Castration-Resistant Prostate Cancer: A Department of Defense Prostate Cancer Clinical Trials Consortium Randomized Phase II Trial of Intermittent Docetaxel With Prednisone With or Without Maintenance GM-CSF. AB - BACKGROUND: Immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), an agent that previously demonstrated antitumor activity, was evaluated within an intermittent chemotherapy framework of docetaxel with prednisone (D+P) in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: mCRPC patients with >= 50% prostate-specific antigen (PSA) decline after 6 cycles of D+P were randomized to either GM-CSF or observation (Obs). At disease progression (PD), D+P was reinitiated for 6 cycles followed by the same "off chemotherapy" regimen in patients eligible for chemotherapy interruption. The sequence was repeated until PD during chemotherapy, lack of PSA response to chemotherapy, or unacceptable toxicity. The primary end point was time to chemotherapy resistance (TTCR). RESULTS: Of 125 patients enrolled, 52 (42%) experienced >= 50% PSA decline on induction D+P and were randomized to GM-CSF (n = 27) or Obs (n = 25). The median time to PD was 3.3 months (95% confidence interval [CI], 2.4-3.5) and 1.5 months (95% CI, 1.5-2.4) during the initial course of GM-CSF and Obs, respectively. Twelve of 26 (46%) patients responded to a second course of D+P. Eleven randomized patients (21%) experienced PD during chemotherapy, precluding accurate assessment of TTCR. The remaining 41 randomized patients discontinued study for lack of PSA response to chemotherapy (n = 8), patient choice to not restart chemotherapy with PSA PD (n = 13), toxicity (n = 7), or study withdrawal (n = 13). CONCLUSION: Conducting a prospective study in mCRPC with maintenance immunotherapy within the framework of intermittent chemotherapy was feasible. The use of PSA instead of radiographic end points limited the number of evaluable patients. This study provides important insight into designing contemporary intermittent chemotherapy trials with maintenance immunotherapy in patients with advanced prostate cancer. PMID- 25557267 TI - Combination of p16(INK4a) /Ki67 immunocytology and HPV polymerase chain reaction for the noninvasive analysis of HPV involvement in head and neck cancer. AB - BACKGROUND: High-risk human papillomavirus (HPV) infection has been identified as a relevant risk for the development of head and neck squamous cell carcinomas (HNSCCs). As HPV status has also gained a role as a prognostic and predictive biomarker for this entity, there is a growing demand for valid HPV testing in HNSCC patients METHODS: Liquid-based cytological smears from 45 HNSCC and 20 control patients were collected and used for simultaneous immunocytochemical p16(INK4a) /Ki67 staining using a CINtec PLUS kit after the presence of tumor cells was verified in a Papanicolaou-stained slide. The same cytological suspension was used for the detection of HPV DNA by specific polymerase chain reaction (PCR). RESULTS: Tumor cells were detected in the swab material of 44 HNSCC patients corresponding to a sensitivity of 98% (44 of 45). PCR analysis revealed the presence of HPV DNA in the cytological suspension of 13 patients (13 of 65, 20%) with simultaneous p16(INK4a) /Ki67 expression by the tumor cells in 11 of these HPV DNA-positive samples (11 of 13, 85%) - a staining pattern that is strongly associated with a carcinogenic HPV infection. CONCLUSIONS: A simultaneous immunocytochemical detection of p16(INK4a) and Ki67 can reliably be performed on liquid-based cytological smears from HNSCC patients using a CINtec PLUS kit. In addition, the same cytological material can be used for the detection of HPV DNA by specific PCR. The combined results of both techniques enable better discrimination between latent and carcinogenic HPV infections as well as HPV-negative cases and thus can provide information on the prognosis of HNSCC patients and facilitate therapeutic decisions. PMID- 25557269 TI - BODIPY-based fluorescent thermometer as a lysosome-targetable probe: how the oligo(ethylene glycols) compete photoinduced electron transfer. AB - A novel BODIPY-based fluorescent thermometer, which shows a lysosome-targeting property, was successfully prepared. Due to the electron-donating ability of the oligo(ethylene glycols), the photoinduced electron-transfer pathway from morpholine to BODIPY dye is blocked. The fluorescence of the thermometer quenched by intramolecular rotation at room temperature was progressively enhanced during heating due to the increased microviscosity around the fluorophore. PMID- 25557268 TI - Androgen deprivation therapy prevents bladder cancer recurrence. AB - Although accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development, its clinical relevance remains unclear. We aimed to evaluate the predictive role of androgen deprivation therapy (ADT) in BC recurrence in prostate cancer (PC) patients. We retrospectively reviewed 20,328 patients with PC diagnosed during 1991-2013 and identified 239 (1.2%) men having primary BC. After excluding ineligible patients, 162 patients made up a final cohort. With a median follow-up of 62 months, 38 (50%) of 76 control patients without ADT experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT for their PC showed a significantly lower risk of BC recurrence (5-year actuarial recurrence free survival: 76% v 40%; P < 0.001) and also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001), compared to the control patients. A multivariable analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17 0.49) for BC recurrence. This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence. PMID- 25557270 TI - Quantitative metabolic parameters measured on F-18 FDG PET/CT predict survival after relapse in patients with relapsed epithelial ovarian cancer. AB - OBJECTIVE: This study aimed to evaluate the prognostic value of quantitative metabolic parameters measured on F-18 FDG PET/CT (FDG PET/CT) at the time of the first relapse in patients with relapsed epithelial ovarian cancer (EOC). METHODS: Fifty-six relapsed EOC patients were retrospectively included. Quantitative metabolic parameters including maximum standardized uptake value (SUVmax), whole body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) were measured on FDG PET/CT at the time of the first relapse. Post relapse survival (PRS) was calculated from the date of diagnosis of relapsed disease to the date of death or last follow-up. Univariate and multivariate analyses for PRS were performed using clinical and quantitative metabolic parameters. RESULTS: Thirty-two patients died from the disease during the follow up period (median: 46.2 months). On univariate and multivariate analyses, the platinum-free interval, type of second-line treatment, WBMTV, and WBTLG were all significant prognostic factors for PRS. The subgroup of patients who were platinum-sensitive with low WBMTV and low WBTLG showed better prognosis, when compared with other subgroups (log-rank test, p<0.001). Patients treated with secondary cytoreductive surgery (SCS) followed by second-line chemotherapy showed significantly longer duration of PRS than patients treated with second-line chemotherapy only (mean PRS=61 vs. 36 months, chi(2)=8.68, p=0.032). CONCLUSION: Our results suggest that quantitative metabolic parameters measured on FDG PET/CT at the time of the first relapse have significant predictive values for PRS. Incorporating quantitative metabolic parameters and conventional clinical parameters has a superior prognostic discrimination compared with conventional clinical parameters alone. PMID- 25557272 TI - Sleep in cluster headache - beyond a temporal rapid eye movement relationship? AB - BACKGROUND AND PURPOSE: Cluster headache (CH) is a primary headache disorder characterized by severe attacks of unilateral pain following a chronobiological pattern. There is a close connection with sleep as most attacks occur during sleep. Hypothalamic involvement and a particular association with rapid eye movement (REM) sleep have been suggested. Sleep in a large, well-characterized population of CH patients was investigated. METHODS: Polysomnography (PSG) was performed on two nights in 40 CH patients during active bout and one night in 25 age, sex and body mass index matched controls in hospital. Macrostructure and other features of sleep were analyzed and related to phenotype. Clinical headache characterization was obtained by semi-structured interview. RESULTS: Ninety-nine nights of PSG were analyzed. Findings included a reduced percentage of REM sleep (17.3% vs. 23.0%, P = 0.0037), longer REM latency (2.0 vs. 1.2 h, P = 0.0012) and fewer arousals (7.34 vs. 14.1, P = 0.003) in CH patients. There was no difference in prevalence of sleep apnea between patients (38%) and matched controls (32%, P = 0.64) although the apnea index in patients was numerically higher (mean apnea hypopnea index 10.75 vs. 4.93). No temporal association between nocturnal attacks (n = 45) and particular sleep stages was observed. CONCLUSIONS: To date, this is the largest study of sleep in CH. It is demonstrated that REM sleep is affected which is in line with our current understanding of CH and hypothalamic involvement in the regulation of this sleep stage. Further, fewer arousals were found in CH patients but no association between apnea events or specific sleep stages. The findings support a central role of the hypothalamus and arousal systems in CH. PMID- 25557271 TI - Central and Eastern European experience with sunitinib in metastatic renal cell carcinoma: a sub-analysis of the global expanded-access trial. AB - A global, open-label, expanded-access trial (EAT) provided sunitinib treatment on a compassionate-use basis to patients with metastatic renal cell carcinoma (mRCC) between 2005 and 2011. This retrospective analysis examines outcomes in patients from Central and East European (CEE) countries participating in the global EAT. Sunitinib (starting dose 50 mg orally once daily, with dose reduction for toxicity) was administered in repeated 6-week cycles (4 weeks on and 2 weeks off) until occurrence of disease progression or unacceptable toxicity. Tumor assessments were guided by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but were performed according to local standards of care. In total, 401 CEE patients received sunitinib (median treatment duration 9.6 months), of whom 378 were evaluable for tumor response. The most frequent grade >=3 toxicities were fatigue (7.5 %), hypertension (7.0 %), thrombocytopenia (6.5 %), diarrhea (4.2 %), nausea and hand-foot syndrome (both 3.7 %) and neutropenia (3.0 %). Median overall survival was 30.7 months (95 % CI 23.3, - months). Overall survival tended to be longer in cytokine-naive than cytokine-experienced patients (median 60.8 vs. 27.5 months; P = 0.1324). Among patients with evaluable tumors, 4.0 % achieved a complete and 14.6 % a partial response [objective response rate (ORR) 18.5 % (95 % CI 14.7, 22.8 %)]. Median progression-free survival was 11.6 months (95 % CI 10.3, 12.8 months). Sunitinib demonstrates safety and effectiveness in real-world mRCC patients in CEE countries. Expanded-access program patients showed a lower tumor response rate but similar survival outcomes to patients in the pivotal Phase III clinical trial of sunitinib in mRCC. PMID- 25557273 TI - Dislocation-mediated relaxation in nanograined columnar palladium films revealed by on-chip time-resolved HRTEM testing. AB - The high-rate sensitivity of nanostructured metallic materials demonstrated in the recent literature is related to the predominance of thermally activated deformation mechanisms favoured by a large density of internal interfaces. Here we report time-resolved high-resolution electron transmission microscopy creep tests on thin nanograined films using on-chip nanomechanical testing. Tests are performed on palladium, which exhibited unexpectedly large creep rates at room temperature. Despite the small 30-nm grain size, relaxation is found to be mediated by dislocation mechanisms. The dislocations interact with the growth nanotwins present in the grains, leading to a loss of coherency of twin boundaries. The density of stored dislocations first increases with applied deformation, and then decreases with time to drive additional deformation while no grain boundary mechanism is observed. This fast relaxation constitutes a key issue in the development of various micro- and nanotechnologies such as palladium membranes for hydrogen applications. PMID- 25557274 TI - Late effects of sleep restriction: Potentiating weight gain and insulin resistance arising from a high-fat diet in mice. AB - OBJECTIVE: Epidemiological studies show the association of sleep restriction (SR) with obesity and insulin resistance. Experimental studies are limited to the concurrent or short-term effects of SR. Here, we examined the late effects of SR regarding weight gain and metabolic alterations induced by a high-fat diet (HFD). METHODS: C57BL/6 mice were subjected to a multiple platform method of SR for 15 days, 21 h daily, followed by 6 weeks of a 30% HFD. RESULTS: Just after SR, serum insulin and resistin concentrations were increased and glycerol content decreased. In addition, resistin, TNF-alpha, and IL-6 mRNA expression were notably increased in epididymal fat. At the end of the HFD period, mice previously submitted to SR gained more weight (32.3 +/- 1.0 vs. 29.4 +/- 0.7 g) with increased subcutaneous fat mass, had increments in the expression of the adipogenic genes PPARgamma, C/EBPalpha, and C/EBPbeta, and had macrophage infiltration in the epididymal adipose tissue. Furthermore, enhanced glucose tolerance and insulin resistance were also observed. CONCLUSIONS: The consequences of SR may last for a long period, characterizing SR as a predisposing factor for weight gain and insulin resistance. Metabolic changes during SR seem to prime adipose tissue, aggravating the harmful effects of diet induced obesity. PMID- 25557275 TI - A continental view of pine-associated ectomycorrhizal fungal spore banks: a quiescent functional guild with a strong biogeographic pattern. AB - Ecologists have long acknowledged the importance of seed banks; yet, despite the fact that many plants rely on mycorrhizal fungi for survival and growth, the structure of ectomycorrhizal (ECM) fungal spore banks remains poorly understood. The primary goal of this study was to assess the geographic structure in pine associated ECM fungal spore banks across the North American continent. Soils were collected from 19 plots in forests across North America. Fresh soils were pyrosequenced for fungal internal transcribed spacer (ITS) amplicons. Adjacent soil cores were dried and bioassayed with pine seedlings, and colonized roots were pyrosequenced to detect resistant propagules of ECM fungi. The results showed that ECM spore banks correlated strongly with biogeographic location, but not with the identity of congeneric plant hosts. Minimal community overlap was found between resident ECM fungi vs those in spore banks, and spore bank assemblages were relatively simple and dominated by Rhizopogon, Wilcoxina, Cenococcum, Thelephora, Tuber, Laccaria and Suillus. Similar to plant seed banks, ECM fungal spore banks are, in general, depauperate, and represent a small and rare subset of the mature forest soil fungal community. Yet, they may be extremely important in fungal colonization after large-scale disturbances such as clear cuts and forest fires. PMID- 25557276 TI - Hypertension criterion for stroke prevention--to strengthen the principle of individualization in guidelines. AB - The diagnosis of hypertension, as recommended by most guidelines, is determined by systolic blood pressure >=140 mm Hg and/or diastolic blood pressure >=90 mm Hg. A threshold-based definition of hypertension, however, ignores sex and age, pathophysiology, and disparities in patient-specific conditions. Moreover, the harmful effects of hypertension-induced target organ damage cannot be ignored. Although the principle of individualization for hypertension management is recommended, especially for stroke prevention, how to practice it in a clinical setting has not been clearly elaborated. Therefore, we put forward a proposal for individualized hypertension management incorporating target organ damage, the main harmful effect of hypertension. We propose that hypertension should be diagnosed when an individual's blood pressure exceeds some difference from their own baseline in young adulthood, accompanied by any hypertension-induced target organ damage, confirmed by various detection methods. Application of this proposal to stroke prevention will hopefully strengthen the principle of individualized hypertension management. PMID- 25557277 TI - Contact fatigue of veneer feldspathic porcelain on dental zirconia. AB - OBJECTIVES: To understand the resistance to cyclic and static contact loading of feldspathic porcelain on dental zirconia (3Y-TZP), in order to understand the partial failure of porcelain (chipping or cracking). METHODS: Hertzian contact techniques were used to evaluate the appearance of damage as a ring crack in terms of applied load and number of cycles in air and simulated saliva. RESULTS: Static contact loading showed the presence of stress corrosion cracking in the porcelain; the environmental crack growth in air was determined from the results of time to damage under static load. There was also a contribution of fatigue effects due to the interactions of the crack with the microstructure. From the obtained results, a time to failure was estimated depending on the material counterpart. Cracking can occur on porcelain coatings if the contact counterpart is teeth or porcelain in a time interval of a few years, consistent with clinical studies. SIGNIFICANCE: Contact loading, particularly against teeth or other ceramic materials can be a significant cause of failure and chipping of feldspathic porcelain on zirconia, especially if the patient suffers from bruxism. Protection, by e.g. a guard, against repetitive contact against the porcelain can increase the lifetime of the veneer. PMID- 25557279 TI - IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice. AB - Cardiac hypertrophy, a risk factor for heart failure, is associated with enhanced oxidative stress in the mitochondria, resulting from high levels of reactive oxygen species (ROS). The balance between ROS generation and ROS detoxification dictates ROS levels. As such, disruption of these processes results in either increased or decreased levels of ROS. In previous publications, we have demonstrated that one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) is to control the mitochondrial redox balance, and thereby mediate the cellular defense against oxidative damage, via the production of NADPH. To explore the association between IDH2 expression and cardiac function, we measured myocardial hypertrophy, apoptosis, and contractile dysfunction in IDH2 knockout (idh2(-/-)) and wild-type (idh2(+/+)) mice. As expected, mitochondria from the hearts of knockout mice lacked IDH2 activity and the hearts of IDH2-deficient mice developed accelerated heart failure, increased levels of apoptosis and hypertrophy, and exhibited mitochondrial dysfunction, which was associated with a loss of redox homeostasis. Our results suggest that IDH2 plays an important role in maintaining both baseline mitochondrial function and cardiac contractile function following pressure-overload hypertrophy, by preventing oxidative stress. PMID- 25557278 TI - Peroxisome proliferator-activated receptor gamma depletion stimulates Nox4 expression and human pulmonary artery smooth muscle cell proliferation. AB - Hypoxia stimulates pulmonary hypertension (PH) in part by increasing the proliferation of pulmonary vascular wall cells. Recent evidence suggests that signaling events involved in hypoxia-induced cell proliferation include sustained nuclear factor-kappaB (NF-kappaB) activation, increased NADPH oxidase 4 (Nox4) expression, and downregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) levels. To further understand the role of reduced PPARgamma levels associated with PH pathobiology, siRNA was employed to reduce PPARgamma levels in human pulmonary artery smooth muscle cells (HPASMC) in vitro under normoxic conditions. PPARgamma protein levels were reduced to levels comparable to those observed under hypoxic conditions. Depletion of PPARgamma for 24-72 h activated mitogen-activated protein kinase, ERK 1/2, and NF-kappaB. Inhibition of ERK 1/2 prevented NF-kappaB activation caused by PPARgamma depletion, indicating that ERK 1/2 lies upstream of NF-kappaB activation. Depletion of PPARgamma for 72 h increased NF-kappaB-dependent Nox4 expression and H2O2 production. Inhibition of NF-kappaB or Nox4 attenuated PPARgamma depletion-induced HPASMC proliferation. Degradation of PPARgamma depletion-induced H2O2 by PEG-catalase prevented HPASMC proliferation and also ERK 1/2 and NF-kappaB activation and Nox4 expression, indicating that H2O2 participates in feed-forward activation of the above signaling events. Contrary to the effects of PPARgamma depletion, HPASMC PPARgamma overexpression reduced ERK 1/2 and NF-kappaB activation, Nox4 expression, and cell proliferation. Taken together these findings provide novel evidence that PPARgamma plays a central role in the regulation of the ERK1/2-NF kappaB-Nox4-H2O2 signaling axis in HPASMC. These results indicate that reductions in PPARgamma caused by pathophysiological stimuli such as prolonged hypoxia exposure are sufficient to promote the proliferation of pulmonary vascular smooth muscle cells observed in PH pathobiology. PMID- 25557280 TI - Diagnostic yield of external loop recording in patients with acute ischemic stroke or TIA. AB - Atrial fibrillation (AF) is a strong risk factor for first-ever stroke and stroke recurrence. The detection rate is low and detection is often costly and time consuming. We evaluated the diagnostic yield of an external loop recorder (ELR) in patients with acute ischemic stroke or TIA, and assessed factors that are associated with AF detection. We prospectively studied patients admitted to the stroke unit with ischemic stroke or TIA, without a history of AF, and no AF on routine-ECG and 24-h telemetry. Patients received an ELR for another 24-h registration. Rhythm registration with an ELR was performed in 94 patients. AF was identified in 5 patients (5 %). AF was associated with cryptogenic stroke and cortical or subcortical involvement. If ELR was limited to patients with cryptogenic stroke in combination with cortical or subcortical involvement, the detection rate increased to 17 %. Automated recording with ELR was easy to use in the acute setting of ischemic stroke or TIA and seems promising to detect AF or atrial flutter, in particular in patients with cryptogenic stroke in combination with cortical or subcortical symptoms. PMID- 25557281 TI - Transcranial midbrain sonography and depressive symptoms in patients with Parkinson's disease. AB - Transcranial sonography (TCS) appeared to be a promising marker associated with depression: hypo/anechogenicity of the brainstem raphe (BR) was found in 50-70 % of patients with unipolar depression, in 40-60 % of depressed patients with Parkinson's disease (PD), but also in 8-28 % of healthy controls. Our study included 120 consecutive PD outpatients. Abnormal BR echogenicity was found in 51 (43 %), while normal findings were present in 67 PD patients (57 %). Patients with abnormal BR echogenicity had higher scores on the Montgomery-Asberg Depression Rating Scale (MADRS) items of apparent sadness (p = 0.03), reported sadness (p = 0.01), and pessimistic thoughts (p = 0.049), when compared to those with normal BR. In the second part of the study, previously suggested cut-off value at 14/15 on the MADRS was used to dichotomize patients into depressed (dPD) (46 patients; 39 %) and non-depressed PD patients (ndPD) (72 patients; 61 %). Abnormal TCS BR findings were obtained in 27 dPD (58.7 %) and in only 24 ndPD patients (33.3 %) (p = 0.007): the risk that PD patients with the TCS BR abnormality would display depressive symptoms was about 3.5 times higher when compared to PD patients with intact BR, controlling for the effect of motor difficulties (cross-odds ratio; OR = 3.48). Therefore, at least in a subgroup of dPD patients, TCS of the midbrain midline structure may potentially be a useful tool for depressive symptoms prediction. PMID- 25557282 TI - Outcomes of a 5-day physiotherapy programme for functional (psychogenic) motor disorders. AB - Patients with functional motor disorder (FMD) are commonly seen by physiotherapists and there is growing evidence to support a physical rehabilitation approach. There are, however, few descriptions in the literature of the content of successful physiotherapy treatment. This prospective cohort study reports the practicalities and outcomes of a pilot 5-day physiotherapy programme. Patients were referred from a specialist movement disorders clinic. The treatment consisted of education and movement retraining, with a long-term self-management focus. Education and movement retraining was based on a pathophysiological model for FMD that stresses the importance of self-focussed attention and illness belief. Patients were assessed at baseline, end of treatment and 3-month follow-up. 47 patients completed the programme, mean symptom duration was 5.5 years, 64 % were unemployed due to ill health. At the end of treatment, 65 % rated their symptoms as "very much improved" or "much improved", this reduced to 55 % at 3 months. At follow-up, there was a significant improvement in physical domains of the SF-36, Berg Balance Scale and 10 Metre Timed Walk. Measures of mental health did not change. This prospective cohort study adds to the growing evidence that supports the use of specialist physiotherapy treatment for FMD. Improvements here were made despite the cohort having characteristics associated with poor prognosis. We argue that specific treatment techniques are important and have the potential to improve physical function, quality of life and may prove to be a cost-effective treatment for selected patients with FMD. PMID- 25557283 TI - Inhibitory effect of double atmospheric pressure argon cold plasma on spores and mycotoxin production of Aspergillus niger contaminating date palm fruits. AB - BACKGROUND: Aspergillus niger has been reported as a potentially dangerous pathogen of date-palm fruits in Saudi Arabia due to the production of fumonisin B2 (FB2 ) and ochratoxin A (OTA). In a trial to disinfect this product, a double atmospheric pressure argon cold plasma (DAPACP) jet system was set up and evaluated against spore germination and mycotoxin production of the pathogen. RESULTS: The plasma jets were characterised photographically, electrically and spectroscopically. DAPACP jet length increases with the increase of argon flow rate, with optimum rate at 3.5 L min(-1) . The viability of A. niger spores, inoculated onto sterilised date palm fruit discs, progressively decreases with extension of the exposure time of DAPACP due to the more quantitative amount of OH and O radicals interacting with the examined samples. There was a progressive reduction of the amount of FB2 and OTA detected in date palm discs on extension of the exposure time of the plasma-treated inoculums at flow rate of 3.5 L min( 1) . FB2 was not detected in the discs inoculated with 6-min plasma-treated A. niger, while OTA was completely absent when the fungus was treated for 7.5 min. CONCLUSION: DAPACP showed promising results in dry fruit decontamination and in inhibition of mycotoxin release by A. niger contaminating the fruits. The progress in the commercial application of cold plasma needs further investigation concerning the ideal width of the plasma output to enable it to cover wider surfaces of the sample and consequently inducing greater plasma performance. PMID- 25557285 TI - Effect of the borax mass and pre-spray medium temperature on droplet size and velocity vector distributions of intermittently sprayed starchy solutions. AB - Spray coating technology has demonstrated great potential in the slow release fertilizers industry. The better understanding of the key spray parameters benefits both the environment and low cost coating processes. The use of starch based materials to coat the slow release fertilizers is a new development. However, the hydraulic spray jet breakup of the non-Newtonian starchy solutions is a complex phenomenon and very little known. The aim of this research was to study the axial and radial distributions of the Sauter Mean Diameter (SMD) and velocity vectors in pulsing spray patterns of native and modified tapioca starch solutions. To meet the objective, high speed imaging and Phase Doppler Anemometry (PDA) techniques were employed to characterize the four compositions of the starch-urea-borax complex namely S0, S1, S2 and S3. The unheated solutions exhibited very high viscosities ranging from 2035 to 3030 cP. No jet breakup was seen at any stage of the nozzle operation at an injection pressure of 1-5 bar. However, at 80 degrees C temperature and 5 bar pressure, the viscosity was reduced to 455 to 638 cP and dense spray patterns emerged from the nozzle obscuring the PDA signals. The axial size distribution revealed a significant decrease in SMD along the spray centreline. The smallest axial SMD (51 to 79 MUm) was noticed in S0 spray followed by S1, S2 and S3. Unlikely, the radial SMD in S0 spray did not vary significantly at any stage of the spray injection. This trend was attributed to the continuous growth of the surface wave instabilities on the native starch sheet. However, SMD obtained with S1, S2 and S3 varied appreciably along the radial direction. The mean velocity vector profiles followed the non Gaussian distribution. The constant vector distributions were seen in the near nozzle regions, where the spray was in the phase of development. In far regions, the velocity vectors were poly-dispersed and a series of ups and downs were seen in the respective radial distributions. PMID- 25557284 TI - Dielectric tube waveguides with absorptive cladding for broadband, low-dispersion and low loss THz guiding. AB - Research on terahertz waveguides is experiencing a tremendous growth due to their importance for compact and robust THz systems. However, designing compact, broadband, mechanically stable and environmentally shielded THz waveguides is still a challenge due to high losses of both metals and dielectrics in this frequency range. Here we report on a novel twist on the classical tube waveguide where we deliberately introduce a thick and highly lossy cladding layer. By this we attenuate the field in the cladding and thus prevent interference with the core field. This mechanism breaks the well-known ARROW guiding mechanism, and as a result, extremely broad bandwidth and low dispersion can be achieved with a very simple design. Since the main part of the field propagates inside the air core, the propagation loss is still kept at a very low level. Simulations, analytical modelling and experiments verify our findings. The proposed THz waveguide is robust, insensitive to external perturbation and easy to handle, and thus the design represents a significant advance of the field of THz dielectric waveguides suitable for the 0.3-1 THz band which in the future will be important for ultrafast wireless communication systems. PMID- 25557286 TI - One-step synthesis of biofunctional carbon quantum dots for bacterial labeling. AB - In this study, we used a simple one-step dry heating method to synthesize mannose modified fluorescent carbon quantum dots (Man-CQDs) from solid ammonium citrate and mannose, and successfully applied for labeling Escherichia coli. The highly soluble Man-CQDs had an average particle diameter of 3.1+/-1.2 nm and exhibited a quantum yield of 9.8% at excitation and emission wavelengths of 365 and 450 nm, respectively. The fluorescent Man-CQDs could selectively bind to the FimH lectin unit in the flagella of the wild-type 1 E. coli K12 strain. We optimized the labeling efficiency of the Man-CQDs by controlling the ratio of ammonium citrate to mannose during their synthesis. The specific binding of the mannose units to E. coli allowed quantitative detection of the bacteria at levels down to 450 colony forming units mL(-1) in lab samples, and facilitate the application of the Man-CQDs for bacterial analyses of real samples (tap water, apple juice, human urine). The synthesis of our Man-CQDs, their labeling, and their use in the detection of bacteria were all simple, inexpensive and efficient processes. PMID- 25557287 TI - Feasibility assessment of shear wave elastography to rotator cuff muscle. AB - Pre-surgical measurement of supraspinatus muscle extensibility is important for rotator cuff repair. The purpose of the present study was to explore the potential feasibility of a shear wave ultrasound elastography (SWE)-based method, combined with B-mode ultrasound, to measure the in vivo stiffness of the supraspinatus muscle non-invasively and thus obtain key information about supraspinatus muscle extensibility. Our investigation comprised two steps. First, we determined the orientation of the supraspinatus muscle fibers in cadaveric shoulders without rotator cuff tear in order to optimize the ultrasound probe positions for SWE imaging. Second, we investigated the feasibility of quantifying the stiffness of the normal supraspinatus muscle by SWE in vivo. The supraspinatus muscle was divided into four anatomical regions: anterior superficial (AS), posterior superficial (PS), anterior deep (AD), and posterior deep (PD). Each region was examined by SWE. The SWE stiffnesses of AD, AS, PD, and PS were 40.0 +/- 12.4, 34.0 +/- 9.9, 32.7 +/- 12.7, 39.1 +/- 15.7 kPa, respectively. SWE combined with B-Mode ultrasound imaging could be a feasible method for quantifying the local stiffness of the rotator cuff muscles. PMID- 25557288 TI - Multi-modal management of acromegaly: a value perspective. AB - PURPOSE: The Acromegaly Consensus Group recently released updated guidelines for medical management of acromegaly patients. We subjected these guidelines to a cost analysis. METHODS: We conducted a cost analysis of the recommendations based on published efficacy rates as well as publicly available cost data. The results were compared to findings from a previously reported comparative effectiveness analysis of acromegaly treatments. Using decision tree software, two models were created based on the Acromegaly Consensus Group's recommendations and the comparative effectiveness analysis. The decision tree for the Consensus Group's recommendations was subjected to multi-way tornado analysis to identify variables that most impacted the value analysis of the decision tree. RESULTS: The value analysis confirmed the Consensus Group's recommendations of somatostatin analogs as first line therapy for medical management. Our model also demonstrated significant value in using dopamine agonist agents as upfront therapy as well. Sensitivity analysis identified the cost of somatostatin analogs and growth hormone receptor antagonists as having the most significant impact on the cost effectiveness of medical therapies. CONCLUSION: Our analysis confirmed the value of surgery as first-line therapy for patients with surgically accessible lesions. Surgery provides the greatest value for management of patients with acromegaly. However, in accordance with the Acromegaly Consensus Group's recent recommendations, somatostatin analogs provide the greatest value and should be used as first-line therapy for patients who cannot be managed surgically. At present, the substantial cost is the most significant negative factor in the value of medical therapies for acromegaly. PMID- 25557290 TI - Identification of high-risk Dukes B colorectal cancer by microRNA expression profiling: a preliminary study. AB - AIM: MicroRNAs (miRNAs) from tumour tissue and common gene mutations were studied to determine whether they predict the development of metastasis in patients with Dukes B colorectal cancer. METHOD: Patients who underwent curative resection for Dukes B colorectal cancer who subsequently developed distant metastatic disease at some stage in the following 5 years ('high-risk B') were compared with case matched controls of Dukes A, Dukes B (no metastases, 'low-risk B') and Dukes C patients without any detectable metastasis at 5 years of follow-up. MiRNAs from tumour and adjacent normal tissue and common gene mutations (KRAS, BRAF, PIK3CA) in primary cancer tissue were analysed to identify prognostic tissue markers for the development of metastasis in patients with Dukes B colorectal cancer. RESULTS: Expression of miR-15b and miR-135b was significantly downregulated (P < 0.001) in 'high-risk B' tumours compared with Dukes A, 'low-risk B' and C without metastasis. No significant differences were noted for mutation status and the development of metastasis. CONCLUSION: The study suggests that the development of metastasis in Dukes B tumours may be predictable based on the miRNA expression of miR-15b and miR-135b. This requires further study on a much larger cohort. PMID- 25557289 TI - Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells. AB - INTRODUCTION: Transgenic mice overexpressing the high mobility group A (HMGA) genes, Hmga1 or Hmga2 develop pituitary tumours and their overexpression is also a frequent finding in human pituitary adenomas. In some cases, increased expression of HMGA2 but not that of HMGA1 is consequent to genetic perturbations. However, recent studies show that down-regulation of microRNA (miRNA), that contemporaneously target the HMGA1 and HMGA2 transcripts, are associated with their overexpression. RESULTS: In a cohort of primary pituitary adenoma we determine the impact of epigenetic modifications on the expression of HMGA targeting miRNA. For these miRNAs, chromatin immunoprecipitations showed that transcript down-regulation is correlated with histone tail modifications associated with condensed silenced genes. The functional impact of epigenetic modification on miRNA expression was determined in the rodent pituitary cell line, GH3. In these cells, histone tail, miRNA-associated, modifications were similar to those apparent in human adenoma and likely account for their repression. Indeed, challenge of GH3 cells with the epidrugs, zebularine and TSA, led to enrichment of the histone modification, H3K9Ac, associated with active genes, and depletion of the modification, H3K27me3, associated with silent genes and re-expression of HMGA-targeting miRNA. Moreover, epidrugs challenges were also associated with a concomitant decrease in hmga1 transcript and protein levels and concurrent increase in bmp-4 expression. CONCLUSIONS: These findings show that the inverse relationship between HMGA expression and targeting miRNA is reversible through epidrug interventions. In addition to showing a mechanistic link between epigenetic modifications and miRNA expression these findings underscore their potential as therapeutic targets in this and other diseases. PMID- 25557291 TI - Surgery for high-risk prostate cancer and metastatic prostate cancer. PMID- 25557292 TI - Epidemiology of advanced prostate cancer: overview of known and less explored disparities in prostate cancer prognosis. PMID- 25557294 TI - Influenza A infection attenuates relaxation responses of mouse tracheal smooth muscle evoked by acrolein. AB - The airway epithelium is an important source of relaxant mediators, and damage to the epithelium caused by respiratory tract viruses may contribute to airway hyperreactivity. The aim of this study was to determine whether influenza A induced epithelial damage would modulate relaxation responses evoked by acrolein, a toxic and prevalent component of smoke. Male BALB/c mice were inoculated intranasally with influenza A/PR-8/34 (VIRUS-infected) or allantoic fluid (SHAM infected). On day 4 post-inoculation, isometric tension recording studies were conducted on carbachol pre-contracted tracheal segments isolated from VIRUS and SHAM mice. Relaxant responses to acrolein (30 MUM) were markedly smaller in VIRUS segments compared to SHAM segments (2 +/- 1% relaxation vs. 28 +/- 5%, n=14, p<0.01). Similarly, relaxation responses of VIRUS segments to the neuropeptide substance P (SP) were greatly attenuated (1 +/- 1% vs. 47 +/- 6% evoked by 1 nM SP, n=14, p<0.001). Consistent with epithelial damage, PGE2 release in response to both acrolein and SP were reduced in VIRUS segments (>35% reduction, n=6, p<0.01), as determined using ELISA. In contrast, exogenous PGE2 was 2.8-fold more potent in VIRUS relative to SHAM segments (-log EC50 7.82 +/- 0.14 vs. 7.38 +/- 0.05, n=7, p<0.01) whilst responses of VIRUS segments to the beta-adrenoceptor agonist isoprenaline were similar to SHAM segments. In conclusion, relaxation responses evoked by acrolein were profoundly diminished in tracheal segments isolated from influenza A-infected mice. The mechanism through which influenza A infection attenuates this response appears to involve reduced production of PGE2 in response to SP due to epithelial cell loss, and may provide insight into the airway hyperreactivity observed with influenza A infection. PMID- 25557293 TI - Disulfiram-induced cytotoxicity and endo-lysosomal sequestration of zinc in breast cancer cells. AB - Disulfiram, a clinically used alcohol-deterrent has gained prominence as a potential anti-cancer agent due to its impact on copper-dependent processes. Few studies have investigated zinc effects on disulfiram action, despite it having high affinity for this metal. Here we studied the cytotoxic effects of disulfiram in breast cancer cells, and its relationship with both intra and extracellular zinc. MCF-7 and BT474 cancer cell lines gave a striking time-dependent biphasic cytotoxic response between 0.01 and 10 MUM disulfiram. Co-incubation of disulfiram with low-level zinc removed this effect, suggesting that availability of extracellular zinc significantly influences disulfiram efficacy. Live-cell confocal microscopy using fluorescent endocytic probes and the zinc dye Fluozin-3 revealed that disulfiram selectively and rapidly increased zinc levels in endo lysosomes. Disulfiram also caused spatial disorganization of late endosomes and lysosomes, suggesting they are novel targets for this drug. This relationship between disulfiram toxicity and ionophore activity was consolidated via synthesis of a new disulfiram analog and overall we demonstrate a novel mechanism of disulfiram-cytotoxicity with significant clinical implications for future use as a cancer therapeutic. PMID- 25557295 TI - The naturally born fusariotoxin enniatin B and sorafenib exert synergistic activity against cervical cancer in vitro and in vivo. AB - During the last decades substantial progress has been made in developing systemic cancer therapy. However, tumors are frequently intrinsically resistant against structurally and mechanistically unrelated drugs. Thus, it is of predominant interest to overcome drug resistance and to encourage the research for novel chemotherapeutic approaches. Recently, we have introduced enniatins, naturally occurring cyclohexadepsipeptides produced by filamentous fungi of the genus Fusarium, as potential anticancer drugs. Here, we expend this approach by demonstrating antiangiogenic properties for enniatin B (Enn B) indicated by a strong inhibition of human endothelial cell migration and tube formation. Moreover, combination of Enn B with the clinically approved multi-kinase inhibitor sorafenib (Sora) displayed profound synergistic in vitro and in vivo anticancer effects against cervical cancer. Subsequent studies showed that this strong synergism is accompanied by a marked increase in mitochondrial injury and apoptosis induction reflected by mitochondrial membrane depolarization, caspase-7 activation, and subsequent cleavage of PARP. Additionally, cells were shown to stop DNA synthesis and accumulate in S and G2/M phase of the cell cycle. The multifaceted characteristics underlying this strong synergism were suggested to be based on interference with the p38 MAPK as well as the ERK signaling pathways. Finally, also in vivo studies revealed that the combination treatment is distinctly superior to single drug treatments against the KB-3-1 cervix carcinoma xenograft model. Taken together, our data confirm the anticancer benefits of the naturally occurring fusariotoxin Enn B and further present Enn B/Sora as a novel combination strategy especially for the treatment of cervical cancer. PMID- 25557297 TI - Does salivary protein(s) act an ovulation indicator for women? A hypothesis. AB - Ovulation is an important physiological process in human, and its effect may reflect in body fluids via secretion of biomolecules such as proteins, amino acids, antioxidants, antimicrobial peptides and so on. Recently, the non-invasive sampling approaches are used to diagnose disease status and access health condition of human. Saliva comprises various proteins which are secreted through salivary glands. The proteins present in the saliva may vary in their expression according to the hormonal level and physiological nature of the body which are said to be hormone receptors, stress proteins and antimicrobial peptides. Therefore, it is postulated that saliva can be used in the detection of ovulation time in human using specific protein(s) expression and which can be considered as a best non-invasive method. The identification of these proteins by adopting LC MS/MS followed by Western blot analysis are possible to identify a promising biomarker for ovulation detection in human. PMID- 25557296 TI - A labdane diterpene exerts ex vivo and in vivo cardioprotection against post ischemic injury: involvement of AKT-dependent mechanisms. AB - Therapeutic approaches to protect the heart from ischemia/reperfusion (I/R) injury are an area of intense research, as myocardial infarction is a major cause of mortality and morbidity. Diterpenes are bioactive natural products with great therapeutic potential. In the present study, we have investigated the in vivo cardioprotective effects of a labdane diterpene (DT1) against cardiac I/R injury and the molecular mechanisms involved. DT1 attenuates post-ischemic injury via an AKT-dependent activation of HIF-1alpha, survival pathways and inhibition of NF kappaB signaling. Myocardial infarction (MI) was induced in Wistar rats occluding the left coronary artery (LCA) for 30min followed by 72h reperfusion. DT1 (5mg/kg) was intravenously administered at reperfusion. In addition, we investigated the mechanisms of cardioprotection in the Langendorff-perfused model. Cardioprotection was observed when DT1 was administered after myocardial injury. The molecular mechanisms involved the activation of the survival pathway PDK-1, AKT and AMPK, a reduced phosphorylation of PKD1/2 and sustained HIF-1alpha activity, leading to increased expression of anti-apoptotic proteins and decreased caspase-3 activation. Pharmacological inhibition of AKT following MI and prior to DT1 challenge significantly decreased the cardioprotection afforded by DT1 therapy at reperfusion. Cardiac function after MI was significantly improved after DT1-treatment, as evidenced by hemodynamic recovery and decreased myocardial infarct size. These findings demonstrate an efficient in vivo cardioprotection by diterpene DT1 against I/R when administered at reperfusion, opening new therapeutic strategies as adjunctive therapy for the pharmacological management of I/R injury. PMID- 25557298 TI - Preparation and evaluation of a novel biodegradable long-acting intravitreal implant containing ligustrazine for the treatment of proliferative vitreoretinopathy. AB - OBJECTIVES: It is challenging to deliver the therapeutic drug effectively to the posterior ocular disease location with optimized exposure and long-term effects when treating proliferative vitreoretinopathy (PVR). The objective of this study is to develop a novel biodegradable and long-acting ocular implant for PVR therapy with ligustrazine as the active ingredient. METHODS: The ligustrazine implants were prepared with poly(DL-lactide-co-glycolide) using a hot-melting extrusion. The physicochemical properties of the implants were characterized. The effectiveness of the selected ligustrazine implants was evaluated in a PVR rabbit model. Furthermore, the in-vitro drug release profile and pharmacokinetics were compared, and in-vitro/in-vivo correlations were evaluated. KEY FINDINGS: The optimal implants had an ideal zero-order in-vitro drug release profile, which was correlated with the in-vivo drug absorption fraction in the vitreous bodies of the rabbits. The sustained-release ligustrazine implants significantly reduced the development of PVR in the animal model. CONCLUSIONS: Ligustrazine implants can be used to treat posterior ocular disease in rabbit animal models, and it provides more choices for medical research on posterior ocular disease. PMID- 25557299 TI - Are they dermatological lesions, bottle top burns or bite mark injuries? AB - Bite marks can be considered as a patterned injury where identification of the causative tool will lead to the identification of the perpetrator. When patterned injuries resembling bite marks are seen on the victim or an assailant of a potential crime, all efforts must be made to carry out an immediate and proper investigation. The classical human bite mark pattern will appear as an oval or circular injury. However there are several dermatological lesions which can be misinterpreted or confused with bite marks. Similarly scars left as a result of contact with hot objects can sometimes bear a resemblance to bite marks. To the untrained eye, identification of bite mark injuries is not an easy task. Since bite marks are common in cases of child abuse and neglect, it is recommended that dental surgeons with forensic background become members of the child abuse and neglect management teams. During investigation of bite marks in alleged cases of child abuse and neglect, it is imperative to compare the injury with dentition of all the persons who have direct access to the child including siblings and playmates. Information revealed through the forensic analysis of bite marks not only helps in the criminal investigation but also in the clinical management of the persons concern. PMID- 25557300 TI - The impact of tooth avulsion on daily life performance using the Brazilian OIDP index in children and young adults. AB - INTRODUCTION: The evaluation of orofacial damage is an emerging branch in the forensic sciences, specifically in forensic odontology and medicine. One of the major limitations during the evaluation of forensic orofacial damages is establishing the consolidation date of acquired lesions. The consolidation date is defined as the moment from which orofacial damages are considered irreversible. AIM: To stress the relevance of knowing the consolidation date in children who underwent orofacial trauma, and to enhance forensic expertise on the evaluation of dentomaxillofacial damages. MATERIAL AND METHODS: Ninety-six patients, aged between 11 and 31 years old, treated at the dental clinics of the Federal University of Minas Gerais, Brazil, were selected for forensic orofacial evaluation. All the patients presented at least one traumatically avulsed tooth and a temporary partial denture. RESULTS: The mean age for the traumatic avulsion was 10,3 years old. The mean time for the placement of a prosthesis was 2,9 years after the initial consultation. The mean time for the use of prosthesis was 2,2 years. No significant differences were observed regarding orofacial damage outcomes between patients younger or older than 18 years of age. It was observed that patients using temporary removable partial dentures presented a 3,6-fold greater possibility of developing socially significant sequels if compared with patients using temporary fixed partial dentures. CONCLUSION: Knowing the consolidation date of orofacial damageenables the prediction of the potential development of social sequels in children and adolescents who isaster victim identification (DVI) is an intensive and demanding task involving specialists from various disciplines. The forensic dentist is one of the key persons who underwent traumatic dental avulsion. PMID- 25557301 TI - Estimation of stature in a young adult indian population using the Carrea's index. AB - The stature or height of an individual is useful for assisting in forensic identifications. Teeth can act as a valuable tool for stature estimation when only the skull is available. Carrea's index estimates the stature of a person from the dimensions of lower anterior teeth. The aim of this study was to assess the reliability of the Carrea's index in an Indian population. Data was collected from plaster models of 125 undergraduate students for examination. Each hemiarch was considered separately equaling 250 inferior hemi-arches, which were divided according to the dental alignment into normal, crowded and diastema and the measurements (Arch and Chord) were made with a 'divider caliper'. A statistically significant difference between the types of dental arch was obtained for both males and females with regards to the different dental alignments; where normal dentition (94.03%) obtained the highest success rates for males and crowded dentition (87.87%) for females. Statistically significant differences were also found between the types of arches for both right and left side (p < 0.001; p=0.004). The presence of diastema reduced the success rates when compared in terms of both sex and side of the arch. It was concluded that the Carrea s index is a reliable method for height estimation in arches with normal and crowded dentitions, useful for both sexes, and for both right and left side of the arch. However, the method was not reliable for hemiarches with a diastema. PMID- 25557303 TI - The effect of hyperglycaemia on haemostasis testing--a volunteer study. AB - We investigated whether the contamination of samples with glucose subsequently tested for haemostasis affected the results, including prothrombin time, activated partial thromboplastin time and fibrinogen concentration. Venous blood was collected from 12 healthy subjects and divided into four aliquots, which were subjected to different degrees of contamination with standard glucose solution (0%, 5%, 10%, 20%). With increasing glucose contamination, prothrombin time increased from mean (SD) 11.0 (0.7) s to 11.2 (0.7) s, 11.5 (0.7) s and 12.2 (0.8) s, all p < 0.001. Activated partial thromboplastin time decreased from 32.3 (0.9) s to 30.9 (0.8) s, 30.8 (0.8) s, and 29.7 (0.7) s, all p < 0.001. Fibrinogen concentration decreased from 3.8 (0.7) g.l(-1) to 3.7 (0.6) g.l(-1), 3.6 (0.6) g.l(-1), and 3.4 (0.6) g.l(-1), all p < 0.001. Bias was clinically meaningful from 5% contamination for activated partial thromboplastin time, 10% contamination for prothrombin time and 20% contamination for fibrinogen concentration. We conclude that if glucose contamination of haemostasis samples is suspected or has occurred, the specimens should not be analysed. PMID- 25557305 TI - How do I know what I can do? Anticipating expectancy of success regarding novel academic tasks. AB - BACKGROUND: After graduation from secondary school, academic tasks (i.e., learning contents) are no longer structured in terms of school subjects (i.e., English, mathematics). Therefore, learners lack past performance and mastery experience to inform their expectancy of success (i.e., ability beliefs) regarding novel tasks. AIMS: In this paper, we investigate how individuals establish expectancy of success regarding novel academic tasks. We hypothesize that individuals draw on ability beliefs regarding known tasks that are deemed similar to novel tasks to estimate expectancy of success (generalization hypothesis). SAMPLE(S): Participants were first-year students (n = 354) in the field of business administration (Study 1), and (Study 2) psychology students predominantly (n = 174). METHODS: In Study 1, we analysed relations between ability beliefs (i.e., academic self-concepts of ability) regarding four school subjects and four fields of study varying in similarity. In Study 2, we assessed mastery experience regarding two school subjects and expectancy of success (i.e., self-efficacy) regarding a fictitious course manipulating participants' similarity judgement. We analysed the data using mainly structural equation modelling. RESULTS: Results support the generalization hypothesis regarding both indicators of expectancy of success (i.e., self-concept and self-efficacy). Subject-specific self-concepts of ability predict study-related self-concepts of ability according to individuals' similarity judgements. Subject-specific mastery experience predicts expectancy of success only if the respective school subject is emphasized in the course description. CONCLUSION: Individuals apparently draw on established ability beliefs regarding known tasks to inform their expectancy of success regarding novel tasks. Findings further our understanding of the development of motivation to learn in adulthood. PMID- 25557304 TI - Optimizing the high-resolution manometry (HRM) study protocol. AB - BACKGROUND: Intolerance of the esophageal manometry catheter may prolong high resolution manometry (HRM) studies and increase patient distress. We assessed the impact of obtaining the landmark phase at the end of the study when the patient has acclimatized to the HRM catheter. METHODS: 366 patients (mean age 55.4 +/- 0.8 years, 62.0% female) undergoing esophageal HRM over a 1-year period were studied. The standard protocol consisted of the landmark phase, 10 5 mL water swallows 20-30 s apart, and multiple rapid swallows where 4-6 2 mL swallows were administered in rapid succession. The modified protocol consisted of the landmark phase at the end of the study after test swallows. Study duration, technical characteristics, indications, and motor findings were compared between standard and modified protocols. KEY RESULTS: Of the 366 patients, 89.6% underwent the standard protocol (study duration 12.9 +/- 0.3 min). In 10.4% with poor catheter tolerance undergoing the modified protocol, study duration was significantly longer (15.6 +/- 1.0 min, p = 0.004) despite similar duration of study maneuvers. Only elevated upper esophageal sphincter basal pressures at the beginning of the study segregated modified protocol patients. The 95th percentile time to landmark phase in the standard protocol patients was 6.1 min; as many as 31.4% of modified protocol patients could not obtain their first study maneuver within this period (p = 0.0003). Interpretation was not impacted by shifting the landmark phase to the end of the study. CONCLUSIONS & INFERENCES: Modification of the HRM study protocol with the landmark phase obtained at the end of the study optimizes study duration without compromising quality. PMID- 25557302 TI - Beyond mitophagy: cytosolic PINK1 as a messenger of mitochondrial health. AB - SIGNIFICANCE: Disruptions in mitochondrial homeostasis are implicated in human diseases across the lifespan. Recessive mutations in PINK1, which encodes the mitochondrially targeted PTEN-induced putative kinase 1 (PINK1), cause an autosomal recessive form of Parkinson's disease. As with all kinases, PINK1 participates in multiple functional pathways, and its dysregulation has been implicated in a growing number of diseases. RECENT ADVANCES: In addition to its heavily studied role in mitophagy, PINK1 regulates mitochondrial respiratory function, reactive oxygen species generation, and mitochondrial transport. Moreover, recent studies implicate processed PINK1 in cytosolic signaling cascades that promote cell survival and neuron differentiation. Cytosolic PINK1 is also capable of suppressing autophagy and mitophagy. We propose a working hypothesis that PINK1 is released by functional mitochondria as a signal to coordinate cell growth and differentiation in response to mitochondrial status. CRITICAL ISSUES: PINK1 biology needs to be better understood in primary neurons, as the stability and subcellular localization of PINK1 is differentially regulated in different cell types. Delineating factors that regulate its mitochondrial import/export, processing by different peptidases, kinase activity, subcellular localization, and degradation will be important for defining relevant downstream kinase targets. FUTURE DIRECTIONS: It is becoming clear that different subcellular pools of PINK1 mediate distinct functions. Future studies will undoubtedly expand on the spectrum of cellular functions regulated by PINK1. Continued study of cytosolic PINK1 may offer novel insights into how functional mitochondria communicate their status with the rest of the cell. PMID- 25557307 TI - A bright year for physical chemistry. PMID- 25557306 TI - Reliability of the log-transformed EMG amplitude-power output relationship for incremental knee-extensor ergometry. AB - INTRODUCTION: The purpose of this investigation was to determine the reproducibility of the log-transformed model for electromyography (EMG) amplitude during incremental single-leg knee-extensor exercise. METHODS: Eight healthy college-aged men performed 3 incremental tests on separate occasions on a knee extensor ergometer. EMG amplitude was analyzed for each participant on each occasion for the rectus femoris and vastus medialis muscles at 4 different exercise power outputs (30%, 50%, 70%, and 90%) corresponding to each participant's maximal power output. Intraclass correlation coefficients (ICC) were determined for the slope and y-intercept terms derived from the log transformed EMG amplitude-power output relationship for each muscle. RESULTS: The ICC values for the rectus femoris (slope = 0.779; y-intercept = 0.787) and vastus medialis (slope = 0.756; y-intercept = 0.763) muscles were high. CONCLUSIONS: The log-transformed EMG amplitude-power output relationship is a reliable index for measuring motor unit activation. PMID- 25557313 TI - 50 years ago ... PMID- 25557311 TI - Mucocutaneous leishmaniasis caused by Leishmania donovani infection in an Indian man. AB - BACKGROUND: Leishmaniasis is a protozoal disease caused by species of Leishmania. Mucocutaneous leishmaniasis (MCL) involves the skin and mucosa. India is endemic for species such as Leishmania donovani and Leishmania major, which are responsible for visceral and cutaneous leishmaniasis, respectively. Although MCL has been reported from India previously, the implicated pathogen was identified as L. donovani in only one case. CASE REPORT: A 55-year-old man presented with a nasal ulcer of four years' duration. He had been treated for borderline lepromatous (BL) leprosy 25 years earlier. Differential diagnoses of MCL, lupus vulgaris, and subcutaneous mycosis were considered. Leishman-Donovan bodies were seen on tissue imprints, and histopathology showed epidermal thinning with loss of appendages and dense pandermal infiltrate. Polymerase chain reaction was positive for L. donovani-specific DNA amplification. A diagnosis of MCL with treated BL leprosy was made. The patient was treated with sodium stibogluconate and achieved complete healing of the ulcer. CONCLUSIONS: The coexistence of manifestations of disease from opposite ends of the spectrum (a hyperergic form of leishmaniasis with an anergic form of leprosy) is difficult to explain. However, the development of MCL after the cure of BL leprosy may reflect the loss of the inhibitory effect of Mycobacterium leprae antigen on interferon-gamma production, and delayed persistence and the gradual clearance of the antigen from the body may account for the 20-year time lag. Further research centered on the immunological interactions between leishmaniasis and leprosy is warranted, particularly with respect to different Leishmania species. PMID- 25557316 TI - Vitamin D supplementation and testosterone concentrations in male human subjects. AB - OBJECTIVE: A possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DESIGN: To investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non Western immigrants in the Netherlands (study 3). METHODS: In study 1, 92 subjects were randomized to either vitamin D (2000 IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6 weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600 IU daily) or placebo. Blood was drawn at baseline, after 8 and 16 weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200 IU daily) or placebo. Blood was drawn at baseline, after 8 and 16 weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. RESULTS: Serum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36 nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 0.5 and 0 nmol/l in studies 1, 2 and 3, respectively). CONCLUSIONS: In this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations. PMID- 25557317 TI - Metacognition and mentalizing in the psychotherapy of patients with psychosis and personality disorders. AB - Many adults with significant forms of mental illness, including psychosis and personality disorders, experience deficits in metacognition that are reflected in a limited ability to describe and think about their own mental states and those of others. Above and beyond experiencing symptoms specific to their disorder, they may be unaware of their own emotions, unable to see their own thoughts as subjective and fallible, and struggle to form complex self-representations of themselves as unique beings in the world. Similarly, they have difficulties grasping the thoughts, feelings, and intentions underlying the behavior of others. Moreover, these patients may be relatively unable to use knowledge about themselves and others to respond to psychological and interpersonal challenges. In this introduction to this JCLP: In Session issue on metacognition and mentalizing, we detail different ways to understand these deficits and discuss three unique challenges these present to treating clinicians. PMID- 25557318 TI - A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) has been used to evaluate the long-term consequences of early exposure to neurotoxic agents. fMRI shows that different patterns of brain activation occur in ethanol-exposed subjects performing a go/no-go response inhibition task. Pharmacologically, ethanol and general anesthetics have similar receptor-level activity in the brain. This study utilizes fMRI to examine brain activation patterns in children exposed to general anesthesia and surgery during early brain development. METHODS: After obtaining Nationwide Children's Hospital IRB approval, a surgical database was utilized to identify children aged 10-17 years with a history of at least 1 h of exposure to general anesthetics and surgery when they were between 0 and 24 months of age. Age- and gender-matched children without anesthesia exposure were recruited as a control group. All subjects were scanned while being presented with a go/no-go response inhibition task. Reaction time and accuracy data were acquired, and the blood-oxygen-level-dependent (BOLD) fMRI signal was measured as a biomarker for regional neuronal activity. RESULTS: There were no differences in terms of performance accuracy and response time. The analysis did not reveal any significant activation differences in the primary region of interest (prefrontal cortex and caudate nucleus); however, activation differences were seen in other structures, including the cerebellum, cingulate gyrus, and paracentral lobule. CONCLUSIONS: Early anesthetic exposure and surgery did not affect accuracy, response time, or activation patterns in the primary region of interest during performance of the task. Intergroup differences in activation patterns in other areas of the brain were observed, and the significance of these findings is unknown. fMRI appears to be a useful tool in evaluating the long-term effects of early exposure to general anesthesia. PMID- 25557319 TI - Characterization of the cross-linked enzyme aggregates of a novel beta galactosidase, a potential catalyst for the synthesis of galacto oligosaccharides. AB - A novel beta-galactosidase (Bgal1-3) was isolated from a marine metagenomic library and then its cross-linked enzyme aggregates (CLEAs) were prepared. The enzymatic properties of Bgal1-3-CLEAs were studied and compared with that of the free enzyme. The thermostability and storage stability of Bgal1-3 were significantly improved after it was immobilized as CLEAs. The galactose-tolerance of the enzyme was also enhanced after the immobilization, which could relieve the inhibitory effect and then tends to be beneficial for the galacto oligosaccharides (GOS) synthesis. Moreover, higher GOS yield was achieved (59.4 +/- 1.5%) by Bgal1-3-CLEAs compared to the free counterpart (57.1 +/- 1.7%) in an organic-aqueous biphasic system. The GOS content and composition of the syrups synthesized by the free enzyme and Bgal1-3-CLEAs were similar and they both contained at least seven different oligosaccharides with the degree of polymerization (DP) ranging between 3 and 9. Furthermore, Bgal1-3-CLEAs maintained 82.1 +/- 2.1% activity after ten cycles of reuse; the GOS yield of the tenth batch was 52.3 +/- 0.3%, which was still higher than that of the most former reports. To the best of our knowledge, this is the first report on the GOS synthesis using CLEAs of beta-galactosidase in an organic-aqueous biphasic system. The study not only further expands the application scope of CLEA, but also provides a potential catalyst for the synthesis of GOS with low cost. PMID- 25557321 TI - Differential transcriptome analysis between Populus and its synthesized allotriploids driven by second-division restitution. AB - In this report, we compared transcriptomic differences between a synthetic Populus section Tacamahaca triploid driven by second-division restitution and its parents using a high-throughput RNA-seq method. A total of 4,080 genes were differentially expressed between the high-growth vigor allotriploids (SDR-H) and their parents, and 719 genes were non-additively expressed in SDR-H. Differences in gene expression between the allotriploid and male parent were more significant than those between the allotriploid and female parent, which may be caused by maternal effects. We observed 3,559 differentially expressed genes (DEGs) between the SDR-H and male parent. Notably, the genes were mainly involved in metabolic process, cell proliferation, DNA methylation, cell division, and meristem and developmental growth. Among the 1,056 DEGs between SDR-H and female parent, many genes were associated with metabolic process and carbon utilization. In addition, 1,789 DEGs between high- and low-growth vigor allotriploid were mainly associated with metabolic process, auxin poplar transport, and regulation of meristem growth. Our results indicated that the higher poplar ploidy level can generate extensive transcriptomic diversity compared with its parents. Overall, these results increased our understanding of the driving force for phenotypic variation and adaptation in allopolyploids driven by second-division restitution. PMID- 25557322 TI - Do infant vocabulary skills predict school-age language and literacy outcomes? AB - BACKGROUND: Strong associations between infant vocabulary and school-age language and literacy skills would have important practical and theoretical implications: Preschool assessment of vocabulary skills could be used to identify children at risk of reading and language difficulties, and vocabulary could be viewed as a cognitive foundation for reading. However, evidence to date suggests predictive ability from infant vocabulary to later language and literacy is low. This study provides an investigation into, and interpretation of, the magnitude of such infant to school-age relationships. METHODS: Three hundred British infants whose vocabularies were assessed by parent report in the 2nd year of life (between 16 and 24 months) were followed up on average 5 years later (ages ranged from 4 to 9 years), when their vocabulary, phonological and reading skills were measured. RESULTS: Structural equation modelling of age-regressed scores was used to assess the strength of longitudinal relationships. Infant vocabulary (a latent factor of receptive and expressive vocabulary) was a statistically significant predictor of later vocabulary, phonological awareness, reading accuracy and reading comprehension (accounting for between 4% and 18% of variance). Family risk for language or literacy difficulties explained additional variance in reading (approximately 10%) but not language outcomes. CONCLUSIONS: Significant longitudinal relationships between preliteracy vocabulary knowledge and subsequent reading support the theory that vocabulary is a cognitive foundation of both reading accuracy and reading comprehension. Importantly however, the stability of vocabulary skills from infancy to later childhood is too low to be sufficiently predictive of language outcomes at an individual level - a finding that fits well with the observation that the majority of 'late talkers' resolve their early language difficulties. For reading outcomes, prediction of future difficulties is likely to be improved when considering family history of language/literacy difficulties alongside infant vocabulary levels. PMID- 25557323 TI - Lotus hosts delimit the mutualism-parasitism continuum of Bradyrhizobium. AB - Symbioses are modelled as evolutionarily and ecologically variable with fitness outcomes for hosts shifting on a continuum from mutualism to parasitism. In a classic example, rhizobia fix atmospheric nitrogen for legume hosts in exchange for photosynthetic carbon. Rhizobial infection often enhances legume growth, but hosts also incur interaction costs because of root tissues and or metabolites needed to support symbionts in planta. Rhizobia exhibit genetic variation in symbiotic effectiveness, and ecological changes in light or mineral nitrogen availability can also alter the benefits of rhizobial infection for hosts. The net effects of symbiosis thus can range from mutualistic to parasitic in a context-dependent manner. We tested the extent of the mutualism-parasitism continuum in the legume-rhizobium symbiosis and the degree to which host investment can shape its limits. We infected Lotus strigosus with sympatric Bradyrhizobium genotypes that vary in symbiotic effectiveness. Inoculations occurred under different mineral nitrogen and light regimes spanning ecologically relevant ranges. Net growth benefits of Bradyrhizobium infection varied for Lotus and were reduced or eliminated dependent on Bradyrhizobium genotype, mineral nitrogen and light availability. But we did not detect parasitism. Lotus proportionally reduced investment in Bradyrhizobium as net benefit from infection decreased. Lotus control occurred primarily after infection, via fine-scale modulation of nodule growth, as opposed to control over initial nodulation. Our results show how divestment of symbiosis by Lotus can prevent shifts to parasitism. PMID- 25557324 TI - Improving our understanding of the use of traditional complementary/alternative medicine in children with cancer. AB - BACKGROUND: Children with cancer in high-income and low-income countries often use traditional complementary/alternative medicine (TCAM). With efforts by the World Health Organization and international twinning programs improving access to conventional care for patients with childhood cancer, understanding the global use of TCAM is important because reliance on TCAM may affect time to presentation, adherence, and abandonment of care. In the current study, the authors describe the process and validation of an international survey documenting the use of TCAM among children with cancer. METHODS: The survey was designed to collect information on TCAM use and associated factors through both open-ended and close-ended questions. During the period between June 2012 and December 2013, the survey was administered to 300 children and adolescents (or their parents) who were undergoing treatment for cancer at a collaborating institution located in Mexico, Uruguay, and Nicaragua. RESULTS: For the majority of constructs, the survey demonstrated strong test-retest reliability as evidenced by an intraclass correlation of at least >=0.79 in each of the participating countries. The survey demonstrated good internal consistency and reliability across countries (alpha range from. 77 to. 85 for the belief scale; and an alpha range from. 60 to. 86 for the cause scale) and convergent validity between TCAM beliefs and behavior constructs (adjusted correlation range, 0.35 0.60). CONCLUSIONS: The results of the current study demonstrate the successful development of a cross-cultural survey that produced results that were reliable and valid. These findings will aid investigators in providing guidelines concerning TCAM, support the development of education and research priorities, and identify variables associated with TCAM that are region-specific. PMID- 25557325 TI - Treatment modalities for Maori and New Zealand European men with localised prostate cancer. AB - OBJECTIVES: To examine diagnostic and treatment pathways for Maori (the indigenous people of New Zealand [NZ]) and NZ European men with prostate cancer in order to identify causes of higher mortality rates for Maori men. METHODS: All Maori men (150) diagnosed with prostate cancer in the Midland Cancer Network region between 2007 and 2010 were identified from the NZ Cancer Registry and frequency age-matched with three randomly sampled NZ European men. Clinical records of these men were searched for information on clinical stage at diagnosis, comorbidities, and type of treatment for localised disease. RESULTS: The final cohort included 136 Maori and 400 NZ European men, of whom 97 Maori and 311 NZ European were diagnosed with localised prostate cancer. Maori men were twice as likely to be diagnosed with distant metastases compared with NZ European men (19.1 vs 9.8 %). Maori men with localised disease were less likely to be treated with radical prostatectomy compared with NZ European men [RR 0.66 (95 % CI 0.48, 0.90)]. Multivariate regression analysis adjusted for age, D'Amico risk strata, comorbidities, and socioeconomic deprivation showed that Maori men were more likely to be managed expectantly [RR 1.74 (95 % CI 1.06, 2.57)]. CONCLUSION: Differences between Maori and NZ European men observed in the management of localised prostate cancer cannot be readily explained by patient characteristics, such as comorbidities or risk assessment at diagnosis. Poorer outcomes for Maori men may not only be related to later stage at diagnosis but differences in treatment modalities may also be a factor. PMID- 25557326 TI - Restorative effect of hair follicular dermal cells on injured human hair follicles in a mouse model. AB - No model is available for examining whether in vivo-damaged human hair follicles (hu-HFs) are rescued by transplanting cultured hu-HF dermal cells (dermal papilla and dermal sheath cells). Such a model might be valuable for examining whether in vivo-damaged hu-HFs such as miniaturized hu-HFs in androgenic alopecia are improvable by auto-transplanting hu-HF dermal cells. In this study, we first developed mice with humanized skin composed of hu-keratinocytes and hu-dermal fibroblasts. Then, a 'humanized scalp model mouse' was generated by transplanting hu-scalp HFs into the humanized skin. To demonstrate the usability of the model, the lower halves of the hu-HFs in the model were amputated in situ, and cultured hu-HF dermal cells were injected around the amputated area. The results demonstrated that the transplanted cells contributed to the restoration of the damaged HFs. This model could be used to explore clinically effective technologies for hair restoration therapy by autologous cell transplantation. PMID- 25557327 TI - Accumulation of the NON-YELLOW COLORING 1 protein of the chlorophyll cycle requires chlorophyll b in Arabidopsis thaliana. AB - Chlorophyll a and chlorophyll b are interconverted in the chlorophyll cycle. The initial step in the conversion of chlorophyll b to chlorophyll a is catalyzed by the chlorophyll b reductases NON-YELLOW COLORING 1 (NYC1) and NYC1-like (NOL), which convert chlorophyll b to 7-hydroxymethyl chlorophyll a. This step is also the first stage in the degradation of the light-harvesting chlorophyll a/b protein complex (LHC). In this study, we examined the effect of chlorophyll b on the level of NYC1. NYC1 mRNA and NYC1 protein were in low abundance in green leaves, but their levels increased in response to dark-induced senescence. When the level of chlorophyll b was enhanced by the introduction of a truncated chlorophyllide a oxygenase gene and the leaves were incubated in the dark, the amount of NYC1 was greatly increased compared with that of the wild type; however, the amount of NYC1 mRNA was the same as in the wild type. In contrast, NYC1 did not accumulate in the mutant without chlorophyll b, even though the NYC1 mRNA level was high after incubation in the dark. Quantification of the LHC protein showed no strong correlation between the levels of NYC1 and LHC proteins. However, the level of chlorophyll fluorescence of the dark adapted plant (Fo ) was closely related to the accumulation of NYC1, suggesting that the NYC1 level is related to the energetically uncoupled LHC. These results and previous reports on the degradation of chlorophyllide a oxygenase suggest that the a feedforward and feedback network is included in chlorophyll cycle. PMID- 25557328 TI - Rehabilitation of Danish veterans with spinal cord injuries during international missions. AB - INTRODUCTION: In the past decades, Danish soldiers have participated more frequently in combat which has resulted in an increased number of severe injuries. The aim of this study was to describe the initial treatment and rehabilitation as well as the level of function, employment, social relations, participation in leisure time activities, health, quality of life (QoL) and late complications at a follow-up in six veterans who sustained a spinal cord injury (SCI) during international military missions. METHODS: Medical records were retrieved regarding the initial treatment and rehabilitation. Questionnaires based on international experience related to SCI were used. RESULTS: The six male veterans were generally satisfied with their rehabilitation and found that they had influenced its course. All veterans had consultation with psychologists during hospitalisation, and two were advised to attend further consultations with military psychologists following discharge. The length of hospitalisation corresponded to the mean hospitalisation period for SCI patients in Denmark. At discharge, the veterans were independent with regard to clothing, toileting and mobility. All resumed work after discharge, five in the military. Satisfaction with their current work was related to whether their work skills corresponded to the work tasks at hand. Four found that their QoL was very good, one that it was satisfactory, another that it was unsatisfactory. CONCLUSION: Danish veterans with SCI were generally satisfied with their initial rehabilitation. They regained independence, and all returned to work. FUNDING: government funding via the Veteran's policy programme. TRIAL REGISTRATION: GLO-2012-10. PMID- 25557329 TI - Acceptable effect of multimodal analgesic treatment after a Bascom cleft lift operation. AB - INTRODUCTION: Information on multimodal analgesic efficacy in patients undergoing a Bascom cleft lift operation is limited. The aim of this prospective consecutive study was to evaluate early post-operative pain in patients receiving a standardised multimodal analgesic regimen. METHODS: A total of 48 patients undergoing a Bascom cleft lift operation were included over an 8-month period in a day-case set-up. The operation was performed under saddle block. In addition, patients received a standardised multi-modal analgesic regimen consisting of gabapentin, ketorolac, dexamethasone, acetaminophen (paracetamol) and ibuprofen. The intensity of pain was registered preoperatively and at 2, 24, 48 h, and 30 days post-operatively. Nausea, vomiting, dizziness, ability to void, morphine consumption and post-anaesthesia care unit (PACU) time were registered. RESULTS: Thirty patients were available for analysis. Post-operative visual analogue scale pain scores were low (at 2, 24, and 48 h (median values: 0 (range: 0-40), 25 (0 70), and 30 (0-60), respectively), but changed significantly over time (p < 0.001). The median overall morphine consumption was 0 (range: 0-30). None of the patients experienced vomiting or dizziness. Only two patients reported mild nausea during the stay in the PACU. CONCLUSION: This study suggests that the Bascom cleft lift operation is feasible with minimal post-operative pain when using a multimodal analgesic regimen together with saddle block. FUNDING: not relevant. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02196727. Regional Ethics Committee Reg. no.: H-3-2013-073. Danish Data Protection Agency Reg. no.: HVH 2013-031, with I-Suite no.: 02408. PMID- 25557330 TI - A follow-up urine sample has limited value after treatment for urinary tract infection in children. AB - INTRODUCTION: A routine follow-up urine sample (FUS) in the form of a midstream urine sample (MSU) is recommended after treatment for urinary tract infection (UTI) according to the Danish Paediatric Society (DPS) and "Laegehandbogen" published by Danish Regions. We studied the effect of FUS with a focus on patients without symptoms at the time of FUS. METHODS: Consecutive patients below 16.0 years treated for upper or lower UTI from 1 January 2009 to 31 December 2009 at Hvidovre Hospital in accordance with the guidelines of the department and the DPS. All patients were asked to provide a FUS within 21 days. RESULTS: A total of 87 patients were treated for upper UTI: 59 girls and 28 boys, the median age was 1.1 year (range: 0.1-15.6 years); and 42 girls were treated for lower UTI, their median age was 8.2 years (range: 2.5-15.3 years). After treatment, the risk of a UTI was 0% (0/87) after upper UTI versus 19% (8/42) after lower UTI (Fisher's exact test (FE), p < 0.0001). Among those without symptoms at FUS, the risk of a UTI was 0% (0/75) (95% confidence interval (CI): 0-4.9%) after upper UTI versus 4% (1/26) (95% CI: 0.1-19.6%) after lower UTI (FE, p = 0.2754). The cost of requesting a FUS in patients without symptoms was 166 euro after treatment for upper UTI and 66 euro after treatment of lower UTI. CONCLUSION: We do not recommend a FUS after treatment for UTI as the 95% CI of risk of missing UTI after treatment for upper UTI was below 5%. This strategy will save the patients/families and the health-care system. However, if a child has symptoms after treatment for UTI, it must be examined. FUNDING: not relevant. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (J. no. 2007-58-0015). PMID- 25557331 TI - Epidemiology of cerebral palsy in Southern Denmark. AB - INTRODUCTION: The aim of this study was to describe the prevalence, subtypes, severity and neuroimaging findings of cerebral palsy (CP) in a cohort of children born in Southern Denmark. Risk factors were analysed and aetiology considered. METHODS: A population-based cohort study covering 17,580 live births from 2003 to 2008. RESULTS: The study included 43 children diagnosed with CP. The overall prevalence of CP was 2.4 per 1,000 live births (95% confidence interval (CI): 1.8 3.2). The gestational age (GA)-specific prevalence ranged from 63.5 per 1,000 live births for GA < 32 weeks to 1.3 for GA >= 37 weeks. Almost half of the children were born preterm and 28% were from multiple pregnancies. The prevalence of CP was 1.8 per 1,000 in singletons and 15.4 per 1,000 in multiples. Low GA and birth weight were risk factors for CP, also after stratification for multiple births. Spastic CP was the predominating subtype of CP, and 24 children (56%) were able to walk independently. White-matter lesions were the most common magnetic resonance imaging finding, and the aetiology of CP was known in 37% of cases. CONCLUSION: The overall prevalence of CP was slightly higher than that found in other Scandinavian studies due to its higher prevalence in the preterm group. Possible explanations include the high rate of multiple births in the background population. Neuroimaging findings were abnormal in the majority of children with CP, but aetiology could only be established in one third of the children. Primary prevention of CP is possible if the numbers of preterm births and multiple pregnancies can be reduced. FUNDING: The Danish Cerebral Palsy Follow-up Programme is supported by the foundation "Ludvig og Sara Elsass Fond". TRIAL REGISTRATION: 2008-58-0034. PMID- 25557332 TI - Watchful waiting versus colorectal resection after polypectomy for malignant colorectal polyps. AB - INTRODUCTION: Unexpected malignancy in removed colorectal polyps is reported in up to 9% of cases. The introduction of screening for colorectal cancer will inevitably increase the number of removed colorectal polyps and therefore also the incidence of malignant polyps. The treatment strategy is either watchful waiting or subsequent colorectal resection. The aim of this study was to perform a preliminary evaluation of the oncological results of polypectomy for malignant polyps with or without subsequent resection, including the patients' long-term survival. METHODS: This was a retrospective analysis of prospectively collected data on 50 patients with unexpected malignancy after a polypectomy treated between January 2003 and January 2008. A total of 27 patients (54%) were treated with watchful waiting, and 23 (46%) underwent subsequent surgery. The Mann Whitney U-test and chi-square test were used to compare the results between the two groups. RESULTS: There were more patients in the surgery group with positive resection margins after the polypectomy (p = 0.002). No difference was found regarding tumour differentiation grade, lymphovascular invasion, local recurrence or distant metastasis. Intraoperative complications occurred in three patients (13%, 95% confidence interval: 0-28%). In all, 16 of the 23 operated patients had no residual tumour. Overall long-term survival was higher among the operated patients (p = 0.005), but there was no difference in cancer-free survival (p = 0.071). CONCLUSION: Overtreatment of patients with malignant colorectal polyps seems to occur. Which patients benefit from further surgery has yet to be determined. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25557333 TI - Low success rate of salvage surgery for testicular torsion in newborns. AB - INTRODUCTION: Testicular torsion within the first 30 days of life is rare. The treatment is controversial, and the prognosis for testis viability varies from 0 to 40% in the literature. The aim of this study was to review our institutional results for surgery for testicular torsion in the neonatal period with a special focus on salvage surgery. METHODS: Patient records were reviewed for all children in the age up to 30 days who were operated for testicular torsion at our hospital during the past 20 years. RESULTS: A total of 13 patients were included, two with bilateral affection. Emergency surgery was performed in eight cases and delayed surgery in five cases. Out of our 15 affected testes, 12 (85%) were non-viable at the time of surgery and were removed, one was fibrotic and left in place and two were salvageable. CONCLUSION: The overall frequency of salvageable testis was low, and testis was only salvaged in cases with urgent surgery at symptom recognition. Cases that presented within the first day of life resulted in a non salvageable testis despite emergency surgery. The reason may be prenatal torsion. Doctor's delay was common for this rare disease. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25557334 TI - Positive experience with intrathecal baclofen treatment in children with severe cerebral palsy. AB - INTRODUCTION: Treatment of severe spasticity and dystonia with intrathecal baclofen (ITB) in children has been shown to be effective and has therefore been employed in the Region of Southern Denmark. The aim of this retrospective study was to analyse the efficacy and adverse events since ITB was introduced in 2003. METHODS: A total of 46 children who had a baclofen pump from April 2003 to January 2013 were included. The children's medical records were reviewed and clinical characteristics, efficacy and adverse events were registered. The efficacy of treatment experienced by parents was ascertained by telephone interviews, and data were rated on a Likert scale ranging from one to five, where one was no effect and five was marked improvement. RESULTS: After ITB, spasticity was reduced from a median of four to two in the upper extremities and from a median of four to one in the lower extremities. Baclofen infusion was 105.1-2,000 micrograms/day (mean 494.9 micrograms/day). Oral baclofen was reduced from 27.3 to 17.7 mg/day after ITB (p < 0.01). The parents' assessment of improvement in well-being, function and ease of care of their child had a mean score of 3.7, 2.2 and 3.4, respectively. 87.1% of parents stated that ITB had been worthwhile, and 90.3% would recommend it to other parents. Most infectious and mechanical adverse events were experienced during the first 200 days after pump implantation. The total complication rate was 0.40 per pump year. CONCLUSION: ITB resulted in reduced spasticity in children with severe spasticity and dystonia, and ITB could be considered safe. Parents' satisfaction with ITB was rated as good and most parents would recommend ITB to others. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25557335 TI - Development, validation and implementation of an in vitro model for the study of metabolic and immune function in normal and inflamed human colonic epithelium. AB - Ulcerative colitis (UC) and Crohn's disease (CD), collectively referred to as inflammatory bowel disease (IBD), are chronic immune disorders affecting the gastrointestinal tract. The aetiology of IBD remains an enigma, but increasing evidence suggests that the development of IBD may be triggered by a disturbance in the balance between gut commensal bacteria and host response in the intestinal mucosa. It is now known that epithelial cells have the capacity to secrete and respond to a range of immunological mediators and this suggests that these cells play a prominent role in the pathogenesis of IBD. Current knowledge about the intestinal epithelium has mainly been obtained using models based on animal cells, transformed human intestinal cell lines and isolated cells from resected colonic bowel segments. Species difference, malignant origin and confounders related to surgery, obviously make these cell models however less applicable for patophysiological studies. Consequently, there was a clear need for models of representative intestinal epithelial cells that would allow functional and dynamic studies of the differentiated human colonic epithelium in vitro. The primary purpose of this thesis was to explore and validate the optimal conditions for establishing a model based on short-term cultures of human colonic epithelial cells obtained from endoscopical biopsies. The cell cultures were accordingly used to describe the interplay between proinflammatory cytokines and colonic epithelium, with focus on alterations in viability, butyrate metabolism and secretion of a chemokine and metalloproteinases (MMP). Finally, the model was used to characterize expression and activation of receptors like toll like receptor (TLR)9 and peroxisome activated proliferators (PPAR)- known to be important players in regulation of innate and adaptive immune responses in human colonic epithelium. The results showed that it is possible to establish short term cultures of representative, viable human colonic epithelial cells from endoscopic mucosal biopsies of patients with IBD. Short-time isolation by EGTA/EDTA from colonic biopsies allowed establishment of small scale cultures of epithelial cells which were viable and metabolic active for up to 48 hours in vitro. The cell model preserved important cellular metabolic and immunological functions of the human colonic epithelium, including the ability to oxidate butyrate, detoxificate phenolic compounds and secrete the chemokine interleukin (IL)-8 in vitro. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma are pro-inflammatory cytokines, which are present in increased amounts in inflamed colonic mucosa. The precise mechanisms of cytokine-mediated mucosal injury are unknown, but one might be that TNF-alpha and IFN-gamma directly impair epithelial cell function similar to effects seen on distinct target cells in other autoimmune diseases. Using the model, both cytokines were found directly to impair the viability of colonic epithelial cells and to induce secretion of IL-8 in vitro. Interestingly, the cells from inflamed IBD mucosa were less sensitive to cytokine-induced damage, which suggests that an intrinsic defense mechanism is triggered in these cells, perhaps as a result of exposure to toxic luminal factors or high local cytokine levels in vivo. TNF-alpha and IFN-gamma may also be involved in regulation of intestinal inflammation through stimulation of MMP expression and proteolytic activity. We found that colonic epithelial cells express a range of MMPs and moreover that expression of distinct MMPs is increased in cells from inflamed IBD mucosa. Using a functional peptide cleavage assay it was shown that epithelial cells secreted proteolytic active enzymes and that the functional MMP activity was increased in inflamed IBD mucosa. This suggests that colonic epithelial cells, like myofibroblasts and immune cells, may contribute to local intestinal mucosal damage, through secretion of active MMPs. Disturbance of recognition and discrimination of potentially harmful pathogens from commensals in the intestinal mucosa have increasingly been implicated in the pathogenesis of IBD. Our results revealed that colonic epithelial cells express TLR9, a key pattern recognition receptor. Interestingly, the differentiated epithelial cells, which have been exposed to the luminal bacterial flora in vivo, were unresponsive to TLR9 ligand stimulation, contrasting findings in the epithelial cell line HT-29 that is cultured continuously in bacteria free environment. These findings suggest, theoretically, that colonic epithelium may regulate immune responses to microbial antigens including commensal bacterial DNA through modulation of the TLR9 pathway. Currently, the results are in line with the emerging view, that the epithelium represents an important frontline cellular component of the innate immune system in the gut. PPARgamma is a nuclear receptor involved in the regulation of lipid and carbonhydrate metabolism. Recent studies in rodent colitis models suggest that PPARgamma also is involved in modulation of inflammatory processes in the colon. Using the model, we characterise expression and activity of PPARs in human colonic epithelium and, additionally, evaluated the functional significance of a possible imbalanced PPARgamma regulation in relation to inflammation. Our experiments showed that colonic epithelial cells express PPARgamma and furthermore that PPARgamma signalling was impaired in inflamed UC epithelium. It was possible to restore PPARgamma signalling in the cell cultures by stimulation with rosiglitazone (a synthetic PPARgamma ligand) in vitro. Hence, these experiments prompted us to design a small controlled, clinical study exploring the possible stimulatory effects of rosiglitazone (a PPAR ligand) in vivo. Interestingly, it was found that topical application of rosiglitazone in patients with active distal UC reduced clinical activity and mucosal inflammation similar to the effects measured in patients treated with mesalazine enemas. Moreover, rectal application of rosiglitazone induced PPARgamma signalling in the epithelium in vivo, supporting the view that activation of PPARgamma may be a new potential therapeutic target in the treatment of UC. Overall, the in vitro model of representative human colonic epithelial cells has shown to be a useful technique for detailed studies of metabolic and immunological functions that are important for homeostasis of the colonic epithelium. Currently, the findings support the view that intestinal epithelial cells actively participate in immunological processes in the colonic mucosa. Additionally, the model seems to be applicable for generating and evaluating new therapeutic approaches from laboratory bench to bed line as illustrated by the PPARgamma study. It is therefore probable, that studies in models of representative colonic epithelial cells, as the one described here, could contribute with important knowledge about the pathogenesis of human inflammatory colonic diseases also in the future. PMID- 25557336 TI - Colonoscopy surveillance for dysplasia and colorectal cancer in patients with inflammatory bowel disease. AB - The risk of colorectal cancer (CRC) and dysplasia in patients with inflammatory bowel disease (IBD) has been highly debated as risk estimates from different studies vary greatly. The present national Danish guideline on colonoscopy surveillance for dysplasia and colorectal cancer in patients with IBD is based on a thorough review of existing literature with particular focus on recent studies from Denmark revealing a lower risk of CRC than previously assumed. The overall risk of CRC in the Danish IBD population does not appear to be different from that of the background population; however, in some subgroups of patients the risk is increased. These subgroups of patients, who should be offered colonoscopy surveillance, include patients with ulcerative colitis having extensive disease and a long disease duration (10-13 years); early age at onset (less than 19 years of age) of ulcerative colitis; and patients with ulcerative colitis as well as Crohn's disease with a concomitant diagnosis of primary sclerosing cholangitis. A colonoscopy surveillance program is recommended in these subgroups with intervals ranging from every 3-6 months to every 5 years, using chromoendoscopy with targeted biopsies of the lesion and adjacent mucosa, instead of conventional colonoscopy with random biopsies. Preferably, the colonoscopy should be performed during clinical remission. If a lesion is detected the endoscopical resectability together with the pathology of the lesion and the adjacent mucosa determine how the lesion should be treated. PMID- 25557337 TI - Reduction in tissue plasmin: a new mechanism of action of narrowband ultraviolet B in psoriasis. AB - BACKGROUND: Plasmin (PL) is a potent inflammatory cell activator, and ultraviolet (UV)B has immunomodulatory effects on cutaneous inflammatory responses. There are no previous studies comparing the effect of narrowband (NB)-UVB on tissue PL levels in psoriasis. AIM: To estimate the possible role of PL in the pathogenesis of psoriasis, and to evaluate the effect of NB-UVB on tissue PL in psoriasis. METHODS: This case-control study enrolled 21 patients with psoriasis and 20 clinically healthy volunteers matched for age and sex. Patients underwent 24 sessions of NB-UVB radiation. Biopsy samples using a 4 mm punch were taken from all patients before and after treatment and from the controls for estimation of tissue PL level by ELISA. RESULTS: Tissue PL was significantly upregulated in psoriasis before treatment (mean +/- SD 1.73 +/- 1.23 ng/mg protein) compared with controls (0.21 +/- 0.15 ng/mg protein) (P < 0.001). A statistically significant positive correlation (P = 0.02) was found between the tissue PL before treatment and the Psoriasis Area and Severity Index. Patients received 24 sessions of NB-UVB, with a mean cumulative dose of 23.25 +/- 8.14 mJ/cm(2) . Tissue PL levels were reduced by a mean of 30.3% post-treatment compared with baseline (P < 0.001). The reduction in Pl levels was significantly correlated with the cumulative dose of NB-UVB, and with the percentage reduction in PASI (P < 0.001). CONCLUSIONS: Our study highlights the possible role played by tissue PL level in the pathogenesis of psoriasis. PL level appears to reflect disease severity, and is a possible marker of therapeutic efficacy of NB-UVB on psoriatic skin. PMID- 25557338 TI - Surface properties of nanocrystalline PbS films deposited at the water-oil interface: a study of atmospheric aging. AB - Nanocrystalline thin films of PbS are obtained in a straightforward reaction by precipitation at the interface between toluene (containing a Pb precursor) and water (containing Na2S). Lead thiobiuret [Pb(SON(CN(i)Pr2)2)2] and lead diethyldithiocarbamate [Pb(S2CNEt2)2] precursors are used. The films are characterized by X-ray diffraction and electron microscopy, revealing typical particle sizes of 10-40 nm and preferred (200) orientation. Synchrotron-excited depth-profiling X-ray photoelectron spectroscopy (XPS) is used to determine the depth-dependent chemical composition as a function of surface aging in air for periods of up to 9 months. The as-synthesized films show a 1:1 Pb/S composition. Initial degradation occurs to form lead hydroxide and small quantities of surface adsorbed -SH species. A lead-deficient Pb1-xS phase is produced as the aging proceeds. Oxidation of the sulfur occurs later to form sulfite and sulfate products that are highly localized at the surface layers of the nanocrystals. These species show logarithmic growth kinetics, demonstrating that the sulfite/sulfate layer acts to passivate the nanocrystals. Our results demonstrate that the initial reaction of the PbS nanocrystals (forming lead hydroxide) is incongruent. The results are discussed in the context of the use of PbS nanocrystals as light-harvesting elements in next-generation solar technology. PMID- 25557340 TI - Changes in The Ocular Surface through technology and time. PMID- 25557339 TI - Neural systemic impairment from whole-body vibration. AB - Insidious brain microinjury from motor vehicle-induced whole-body vibration (WBV) has not yet been investigated. For a long time we have believed that WBV would cause cumulative brain microinjury and impair cerebral function, which suggests an important risk factor for motor vehicle accidents and secondary cerebral vascular diseases. Fifty-six Sprague-Dawley rats were divided into seven groups (n = 8): 1) 2-week normal control group, 2) 2-week sham control group (restrained in the tube without vibration), 3) 2-week vibration group (exposed to whole-body vibration at 30 Hz and 0.5g acceleration for 4 hr/day, 5 days/week, for 2 weeks), 4) 4-week sham control group, 5) 4-week vibration group, 6) 8-week sham control group, and 7) 8-week vibration group. At the end point, all rats were evaluated in behavior, physiological, and brain histopathological studies. The cerebral injury from WBV is a cumulative process starting with vasospasm squeezing of the endothelial cells, followed by constriction of the cerebral arteries. After the 4 week vibration, brain neuron apoptosis started. After the 8-week vibration, vacuoles increased further in the brain arteries. Brain capillary walls thickened, mean neuron size was obviously reduced, neuron necrosis became prominent, and wide-ranging chronic cerebral edema was seen. These pathological findings are strongly correlated with neural functional impairments. PMID- 25557341 TI - Impressions on The Ocular Surface: the entity and the journal. PMID- 25557342 TI - Window cross and Placido disc. PMID- 25557343 TI - Biochemical properties and aggregation propensity of transforming growth factor induced protein (TGFBIp) and the amyloid forming mutants. AB - TGFBI-associated corneal dystrophies are characterized by accumulation of insoluble deposits of the mutant protein transforming growth factor beta-induced protein (TGFBIp) in the cornea. Depending on the nature of mutation, the lesions appear as granular (non-amyloid) or lattice lines (amyloid) in the Bowman's layer or in the stroma. This review article emphasizes the structural biology aspects of TGFBIp. We discuss the tinctorial properties and ultrastructure of deposits observed in granular and lattice corneal dystrophic mutants with amyloid and non amyloid forms of other human protein deposition diseases and review the biochemical and putative functional role of the protein. Using bioinformatics tools, we identify intrinsic aggregation propensity and discuss the possible protective role of gatekeepers close to the "aggregation-prone" regions of native TGFBIp. We describe the relative aggregation rates of lattice corneal dystrophy (LCD) and granular corneal dystrophy (GCD2) mutants using the three-parameter model, which is based on intrinsic properties of polypeptide chains. The predictive power of this model is compared with two other algorithms. We conclude that the model is able to predict the aggregation rate of mutants which do not alter overall net charge of the protein. The need to understand the mechanism of corneal dystrophies from the structural biology viewpoint is emphasized. PMID- 25557344 TI - The presence and significance of polar meibum and tear lipids. AB - The ocular tear film is a complex structure composed of a number of elements. While all of these components serve valuable functional and structural roles, the external lipid layer has been a focus because it is known to play a critical role in dry eye. Traditionally, meibomian gland phospholipids have been considered to be the vital amphiphilic molecules needed to create an interphase between the outer nonpolar lipid layer and inner aqueous layers, yet recent work has called this theory into question. The purpose of this review is to clarify the current understanding of the origins, identity, and significance of polar tear lipids. Studies indicate that both phospholipids and omega-hydroxy fatty acids likely play a critical role in tear film stability. Studies also indicate that polar lipids likely originate from multiple sources and that they are integrally involved in ocular surface disease. Additional studies are needed to fully understand the origins and significance of polar tear lipids, because to date only correlational evidence has described their hypothesized origins and functions. PMID- 25557345 TI - Monitoring corneal hydration with a mid-infrared (IR) laser. AB - A mid-infrared (IR) source at ~ 3 MUm radiation is used as a probe to measure hydration in porcine cornea. Since the Er(3+):YAG emission targets vibrational modes (around 3300 cm(-1)) in the H2O molecule, it is highly sensitive to changes in water content in the first ~ 10 MUm of the corneal tissue. PMID- 25557347 TI - Abdominal breathing increases tear secretion in healthy women. AB - PURPOSE: To determine the relationship between abdominal breathing and tear meniscus volume in healthy women, we investigated the change in tear meniscus volume in two groups: normal breathing and abdominal breathing. METHODS: We used a crossover experimental model and examined 20 healthy women aged 20-54 years (mean +/- SD, 32.7 +/- 11.1 years). The participants were randomly assigned to one of two groups. During the first visit, the normal breathing group was subjected to normal breathing for 3 min, whereas the abdominal breathing group was subjected to abdominal breathing (4-second inhalation and 6-second exhalation) for 3 min. During the second visit, the protocols were swapped between the two groups. We estimated the R wave to R wave (R-R) interval, tear meniscus volume, salivary amylase activity, pulse, and blood pressure before and immediately after, 15 min after, and 30 min after completion of the breathing activity. RESULTS: After abdominal breathing, compared to that before breathing, the tear meniscus volume increased significantly 15 min after breathing (P<.01). Furthermore, systolic blood pressure showed a significant decrease immediately after abdominal breathing (P<0.05). No significant difference was found in the test parameters in the normal breathing group. CONCLUSION: Abdominal breathing for 3 minutes increases the tear meniscus volume in healthy women. Consequently, abdominal breathing may be considered in the treatment of dry eye disease. PMID- 25557348 TI - The right to try. PMID- 25557346 TI - Potentially pathogenic immune cells and networks in apparently healthy lacrimal glands. AB - Lacrimal glands of people over 40 years old frequently contain lymphocytic infiltrates. Relationships between histopathological presentation and physiological dysfunction are not straightforward. Data from rabbit studies have suggested that at least two immune cell networks form in healthy lacrimal glands, one responding to environmental dryness, the other to high temperatures. New findings indicate that mRNAs for several chemokines and cytokines are expressed primarily in epithelial cells; certain others are expressed in both epithelial cells and immune cells. Transcript abundances vary substantially across glands from animals that have experienced the same conditions, allowing for correlation analyses, which detect clusters that map to various cell types and to networks of coordinately functioning cells. A core network--expressing mRNAs including IL 1alpha, IL-6, IL-17A, and IL-10--expands adaptively with exposure to dryness, suppressing IFN-gamma, but potentially causing physiological dysfunction. High temperature elicits concurrent increases of mRNAs for prolactin (PRL), CCL21, and IL-18. PRL is associated with crosstalk to IFN-gamma, BAFF, and IL-4. The core network reacts to the resulting PRL-BAFF-IL-4 network, creating a profile reminiscent of Sjogren's disease. In a warmer, moderately dry setting, PRL associated increases of IFN-gamma are associated with suppression of IL-10 and augmentations of IL-1alpha and IL-17, creating a profile reminiscent of severe chronic inflammation. PMID- 25557349 TI - Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations. AB - BACKGROUND: Recent studies have shown that recessive mutations in the TBC1D24 gene cause a variety of epilepsy syndromes, DOORS syndrome and nonsyndromic deafness. METHODS/RESULTS: We report on two siblings with hypotonia, early-onset epileptic encephalopathy, and severe developmental delay. The patients presented with clonic and myoclonic jerks within 1 h after birth. The seizures were resistant to treatment. Audiologic examination showed bilateral sensorineural hearing loss in both siblings. Genetic analysis revealed compound heterozygous mutations in the TBC1D24 gene: a novel missense mutation c.32A > G (p.Asp11Gly) in exon 2 and a frameshift mutation c.1008delT (p.His336Glnfs*12) in exon 4. CONCLUSION: This report supports previous observations that mutations in TBC1D24 cause diverse phenotypes. In fact, early-onset epileptic encephalopathy with sensorineural hearing loss is an additional phenotype observed in patients with recessive TBC1D24 mutations. PMID- 25557350 TI - Climate Variability and the Occurrence of Human Puumala Hantavirus Infections in Europe: A Systematic Review. AB - Hantaviruses are distributed worldwide and are transmitted by rodents. In Europe, the infection usually manifests as a mild form of haemorrhagic fever with renal syndrome (HFRS) known as nephropathia epidemica (NE), which is triggered by the virus species Puumala. Its host is the bank vole (Myodes glareolus). In the context of climate change, interest in the role of climatic factors for the disease has increased. A systematic review was conducted to investigate the association between climate variability and the occurrence of human Puumala hantavirus infections in Europe. We performed a literature search in the databases MEDLINE, EMBASE and Web of Science. Studies that investigated Puumala virus infection and climatic factors in any European country with a minimum collection period of 2 years were included. The selection of abstracts and the evaluation of included studies were performed by two independent reviewers. A total of 434 titles were identified in the databases, of which nine studies fulfilled the inclusion criteria. The majority of studies were conducted in central Europe (Belgium, France and Germany), while only two came from the north (Sweden) and one from the south (Bosnia). Strong evidence was found for a positive association between temperature and NE incidence in central Europe, while the evidence for northern Europe so far appears insufficient. Results regarding precipitation were contradictory. Overall, the complex relationships between climate and hantavirus infections need further exploration to identify specific health risks and initiate appropriate intervention measures in the context of climate change. PMID- 25557351 TI - Growth hormone treatment of Prader-Willi syndrome has long-term, positive effects on body composition. AB - AIM: Growth hormone (GH) treatment is a relatively new concept in adults, and the knowledge of its long-term effects is limited. We studied ten men with Prader Willi Syndrome (PWS) after more than 5 years of GH treatment. METHODS: Study participants underwent a detailed physical examination, including blood tests. Five had received GH as childhood and five had started GH as adults. RESULTS: The total duration of GH treatment was 16 +/- 4 years in the childhood PWS group and 15 +/- 1 years in the adulthood PWS group. Their respective mean ages were 27 +/- 4 years and 44 +/- 4 years, mean heights were 178 +/- 11 cm and 156 +/- 5 cm, and mean body mass indexes were 32.4 +/- 10.3 kg/m(2) and 28.9 +/- 4.6 kg/m(2) . There were no differences in body composition between the groups and all lipids and insulin-like growth factor 1 were normal or close to normal. Four had well controlled type 2 diabetes. The GH doses in the childhood and adulthood groups were 0.4 mg and 0.3 mg, respectively. CONCLUSION: Men with PWS who received GH treatment displayed positive effects on body composition independent of when the GH treatment had started. Only patients who gained weight developed diabetes. The duration of GH treatment should balance the benefits and observed side effects. PMID- 25557352 TI - Random skin biopsy of patients with intravascular large B-cell lymphoma associated with thrombocytopenia and coagulation abnormalities: proposal of a modified biopsy method. AB - Intravascular large B-cell lymphoma (IVLBCL) is classified as a rare type of non Hodgkin's B-cell lymphoma by the World Health Organization. It is characterized by the presence of lymphoma cells in the lumens of the small vessels of several organs, most notably the skin. Diagnosis of IVLBCL is difficult because of the lack of lymphadenopathy and because lesions need to be histologically confirmed via a biopsy of the affected organs. Random skin biopsy (RSB) of normal-appearing skin is a useful and apparently safe means of evaluating IVLBCL. However, patients with IVLBCL often exhibit thrombocytopenia, and we describe a case in which a patient with thrombocytopenia experienced hemorrhagic shock and died shortly after RSB. For this reason, we reviewed cases of RSB performed at our hospital and found that the middle adipose tissue contained a higher percentage of atypical lymphoid cells than other layers of the skin. On the basis of our findings, we propose a strategy for the safer performance of RSB in IVLBCL patients with thrombocytopenia and coagulation abnormalities. PMID- 25557353 TI - Staphylococcus lugdunensis abscesses complicating molluscum contagiosum in two children. AB - We report the occurrence of Staphylococcus lugdunensis abscesses in two girls with molluscum contagiosum who both required surgical intervention under general anaesthesia. S. lugdunensis is a coagulase-negative Staphylococcus recently recognized as an emerging human pathogen. Because of its ubiquitous nature and the high prevalence of molluscum contagiosum in children, it is likely that this as yet unreported association may be underestimated, thus raising the question as to whether bacterial culture of superinfected mollusca should be obtained more often. PMID- 25557354 TI - Pathogen inactivation of double-dose buffy-coat platelet concentrates photochemically treated with amotosalen and UVA light: preservation of in vitro function. AB - BACKGROUND: The INTERCEPT Blood System for Platelets (PLT) utilizes amotosalen (S 59) in combination with ultraviolet A (UVA) light to inactivate viruses, bacteria, protozoa and leucocytes that may contaminate PLT concentrates. However, limited data are available on the quality of INTERCEPT-treated double-dose (DD) buffy-coat (BC) PLT units allowing a single treatment procedure to produce two pathogen-inactivated PLT units for transfusion. STUDY DESIGN AND METHODS: The objective of this study was to evaluate potential in vitro effects of the INTERCEPT treatment on pools of 7 BCs as compared to untreated units. Functional, phenotypic and mitochondrial properties of DD BC PLTs during storage over 7 days were studied. RESULTS: For some parameters measured, small yet significant differences were observed including PLT count (P < 0.05), pH, pCO2 and glucose concentration. Throughout storage, no significant differences were observed in ATP levels, ESC, HSR reactivity and CD62P expression. Similarly, no differences were observed in the expression of PAC-1, CD42b and PECAM-1 at any time-points. The mitochondrial membrane potential (MMP) determined by JC-1-labelling was well maintained until day 7 in all treated and untreated units (>90%). The release of sCD40L increased over time (P < 0.01) in all units but without any significant differences between treated and untreated PLTs. CONCLUSION: Our data demonstrate that photochemical pathogen inactivation of DD-BC PLT concentrates with the INTERCEPT Blood System had no influence on the PLT in vitro quality over the 7 day of storage. However, whether in vivo efficacy of INTERCEPT-treated PLTs is affected may require clinical evaluation. PMID- 25557355 TI - Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the CDKN1A (p21(WAF1) (/) (CIP1) ) and SIRT1 genes. AB - Oncogene-induced senescence is an important tumour-suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX (NR2E1) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene-induced senescence. We determined that TLX exhibited an increased expression in high-grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo, whereas its over-expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin-induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene-induced senescence induced either by activated oncogene H-Ras(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of CDKN1A and transactivation of SIRT1. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene-induced senescence, and also suggests that targeting the senescence-regulatory TLX is of potential therapeutic significance in prostate cancer. PMID- 25557357 TI - RNA SHAPE chemistry with aromatic acylating reagents. AB - As chemical methods for RNA secondary structure determination, SHAPE chemistry (selective 2'-hydroxyl acylation analyzed by primer extension) has been developed to specifically target flexible nucleotides (often unpaired nucleotides) independently to their purine or pyrimidine nature. In order to improve the specificity of acylating reagents towards unpaired nucleotides, we have explored the reactivity of symmetric anhydrides, acyl fluorides, active esters like succinimidyl ester and cyanomethyl esters for 2'-O-acylation reaction. Among the tested compounds, only the acyl fluoride 4 showed a low reactivity (compared to NMIA). However, this study is the first to show that nucleophilic catalysts like DMAP greatly improved the selective 2'-hydroxyl acylation by symmetric anhydrides, acyl fluorides and succinimidyl ester, with the 2-fluorobenzoic anhydride 5 being the most reactive. PMID- 25557356 TI - Maintenance plasma exchange treatment for muscle specific kinase antibody positive myasthenia gravis patients. AB - BACKGROUND: Anti-muscle specific kinase antibody positive myasthenia gravis (MuSK MG) is often characterized by a relatively severe and progressive course, refractoriness to standard myasthenia gravis (MG) medications, and an increased risk of myasthenic crisis. We report here successful management of three MuSK MG patients using maintenance therapeutic plasma exchange (TPE) treatment for up to 4.5 years. MATERIALS: The study was a 5-year retrospective review of all MG patients treated with TPE between 2008 and 2013 at University of Michigan. Inclusion criteria of MuSK MG were positive for anti-MuSK antibodies and a diagnosis of MuSK MG by staff neurologists. Patient data included age, gender, diagnostic testing results, medications, and the dates and response to TPE treatments. RESULTS: A total of 153 MG patients underwent at least one course of TPE between 2008 and 2013. A total of 12 patients (7.8%) were positive for anti MuSK antibodies. Patients were predominantly female (83.3%) and a median age of onset was 46-years old. Three MuSK MG patients were successfully managed with maintenance TPE. CONCLUSION: Maintenance TPE may be an effective option for MuSK MG patients. The key of successful maintenance treatment at our institution has been to tailor the TPE frequency for each individual, and to modify the treatment interval in conjunction with medical management. PMID- 25557358 TI - Flow cytometry immunophenotypic analysis of Philadelphia-negative myeloproliferative neoplasms: Correlation with histopathologic features. AB - BACKGROUND: Compared with the proven utility of flow cytometry immunophenotyping (FCI) analysis in the workup of myelodysplastic syndromes (MDS), immunophenotypic alterations in myeloproliferative neoplasms (MPN) have been less studied and the potential utility of FCI is not defined. METHODS: Bone marrow (BM) samples of 83 Philadelphia-negative MPN patients were assessed by multicolor FCI including 27 with essential thrombocythemia (ET); 17 polycythemia vera (PV); 33 primary myelofibrosis (PMF) and 6 MPN-unclassifiable (MPN-U). The time interval from initial diagnosis of MPN to FCI analysis was 18 months (0-370). Ninety-five age matched MDS patients with a similar BM blast count were included for comparison. RESULTS: Immunophenotypic alterations, either in CD34(+) cells or myelomonocytic cells, were detected in 82 of 83 (99%) MPN cases. FCI abnormalities were more frequently observed in cases with substantial myelofibrosis but not different between PMF and fibrotic stage of ET/PV. Furthermore, FCI abnormalities were more frequent in cases with >=5% BM blasts and/or circulating blasts (P = 0.006); as well as cases with an abnormal karyotype (P = 0.036); but not associated with morphologic dysplasia or JAK2 mutation status. Comparing with MDS, FCI abnormalities were overall less pronounced in MPN cases (P = 0.001). CONCLUSIONS: MPNs exhibit frequent immunophenotypic alterations, more pronounced in cases with adverse histopathologic features. These findings illustrate that immunophenotypic alterations are a part of constellational findings in MPN, and correlate progressively with disease stage. The study results also suggest a role of FCI in diagnosis of MPN and monitoring disease over time and after therapy. PMID- 25557359 TI - Solabegron: a potential future addition to the beta-3 adrenoceptor agonist armamentarium for the management of overactive bladder. AB - INTRODUCTION: Overactive bladder (OAB) affects many women and men worldwide and has a significant adverse effect on a person's quality of life. Historically, behavioral therapy and anti-muscarinic agents have been the primary therapies used in the management of OAB. However, persistence with anti-muscarinic therapy has been limited. The role of beta-3 agonists is established in the management of OAB with the first beta-3 agonist recently approved by the FDA. Solabegron is one such selective beta-3 agonist currently under investigation. AREAS COVERED: In this review, the authors discuss animal studies, in vitro human bladder strip and Phase II studies, which suggest a role for solabegron in the management of OAB. The authors also discuss its potential role in combination therapy. EXPERT OPINION: Phase II studies with solabegron support its potential future role in the management of OAB. However, further studies are needed to establish its efficacy and safety as well as to allow its clinical comparison with current therapies. PMID- 25557361 TI - Prosthetic Management for a Palatal Perforation from Cocaine Abuse. AB - The intranasal inhalation of cocaine predisposes the user to a wider range of local and systemic complications. This article describes the history of a 31-year old woman with a palatal perforation produced by the chronic use of cocaine. In view of the doubts about abstinence from cocaine abuse, prosthetic management was chosen. The obturator comprised a metal framework for dental retention and to prevent displacement and a resin obturator to block the defect. In addition, acrylic resin facilitated adjustments due to the fact that it is easy to adapt to changes in the size of the palatal defect. PMID- 25557360 TI - Factors affecting response to everolimus therapy for subependymal giant cell astrocytomas associated with tuberous sclerosis. AB - BACKGROUND: The aim of the study was to investigate factors affecting response to everolimus, a mammalian-target-of-rapamycin (mTOR) inhibitor, of subependymal giant cell astrocytomas (SEGA) in patients with tuberous sclerosis complex (TSC). METHODS: The study group consisted of 15 children with a diagnosis of TSC-related SEGA. Median therapy duration was 13 months. Age, sex, previous neurosurgical or mTOR inhibitor treatment, everolimus blood concentration and anticonvulsant therapy were analyzed as potential factors affecting reduction of SEGA tumor volume. RESULTS: Significant reductions in SEGA volumes were noted at 3 and 6 months (median tumor volume 0.97 cm(3) and 0.70 cm(3) , respectively, versus 2.70 cm(3) at baseline, P = 0.001). Responses were observed in 11/15 (73.3%) and 10/12 (83.3%) patients at 3 and 6 months, respectively. The most rapid reduction of SEGA volume (58.6%) was found during the initial 3 months of treatment. There was no statistical difference in the extent of SEGA volume reduction between patients with everolimus trough levels <5 ng/ml and >=5 ng/ml. Patients treated with <=1 anticonvulsant had greater tumor reduction after 6 months of treatment. CONCLUSIONS: Everolimus is an effective and safe treatment option for TSC-related SEGA. Drug dose titration according to blood concentration did not appear to be crucial to achieve clinical efficacy; however, concomitant anticonvulsant therapy may affect response to mTOR inhibitors. PMID- 25557362 TI - The Latin American population in Spain and organ donation. Attitude toward deceased organ donation and organ donation rates. AB - The Latin American (LA) population has similarities with the Spanish population which makes its integration into Spanish society easier. OBJECTIVE: to analyze the attitude toward organ donation among Latin American citizens residing in Spain, to determine the psychosocial variables which affect this attitude, and to examine the correlation between donation rates of LA citizens in Spain and in their countries of origin. A random sample of LA residents in Spain was taken and stratified according to the respondent's nationality (n = 1.314), in the year 2010. Attitude was assessed using a validated questionnaire (PCID-DTO Dr Rios). The survey was self-administered and completed anonymously. STATISTICAL ANALYSIS: Student's t-test, the chi(2) test, and logistic regression analysis. There was a 94% completion rate (n = 1.237). Attitude toward donation was favorable in 60% of cases (n = 745), 12% (n = 145) were against, and 28% (n = 347) were undecided. The following variables were associated with attitude toward donation: sex (P = 0.038), level of formal education (P < 0.001), country of origin (P = 0.002), attitude toward the donation of a family member's organs (P < 0.001), having discussed donation with the family (P < 0.001), carrying out prosocial activities (P = 0.025), attitude toward cremation of the body (P < 0.001), attitude toward burial of the body (P < 0.001), attitude toward having an autopsy carried out (P < 0.001), previous experience of the organ donation and transplantation process (P < 0.001), fear of mutilation after donation (P < 0.001), knowledge that the Church has a positive attitude toward organ donation and transplantation (P < 0.001), knowledge of one's partner's attitude toward organ donation (P < 0.001), and a belief that one might need a transplant in the future (P < 0.001). The donation rates in this population group in Spain are higher than those recorded in their countries of origin (55.76 vs. <10 pmp; P < 0.001). The attitude toward organ donation among LA citizens residing in Spain is slightly worse than that reported in the native Spanish population and is determined by many psychosocial factors. The donation rates of LA citizens in Spain are higher than those in their countries of origin. PMID- 25557363 TI - Modulating glyoxalase I metal selectivity by deletional mutagenesis: underlying structural factors contributing to nickel activation profiles. AB - Metabolically produced methylglyoxal is a cytotoxic compound that can lead to covalent modification of cellular DNA, RNA and protein. One pathway to detoxify this compound is via the glyoxalase enzyme system. The first enzyme of this detoxification system, glyoxalase I (GlxI), can be divided into two classes according to its metal activation profile, a Zn(2+)-activated class and a Ni(2+) activated class. In order to elucidate some of the key structural features required for selective metal activation by these two classes of GlxI, deletional mutagenesis was utilized to remove, in a step-wise fashion, a key alpha-helix (residues 73-87) and two small loop regions (residues 99-103 and 111-114) from the Zn(2+)-activated Pseudomonas aeruginosa GlxI (GloA3) in order to mimic the smaller Ni(2+)-activated GlxI (GloA2) from the same organism. This approach was observed to clearly shift the metal activation profile of a Zn(2+)-activated class GlxI into a Ni(2+)-activated class GlxI enzyme. The alpha-helix structural component was found to contribute significantly toward GlxI metal specificity, while the two small loop regions were observed to play a more crucial role in the magnitude of the enzymatic activity. The current study should provide additional information on the fundamental relationship of protein structure to metal selectivity in these metalloenzymes. PMID- 25557364 TI - ARID1A is a useful marker of malignancy in peritoneal washings for endometrial carcinoma. AB - BACKGROUND: ARID1A (AT-rich interactive domain 1A gene) has recently been identified as a novel tumor suppressor gene and one of the driver genes in endometrial carcinogenesis. Approximately 30% to 40% of endometrial carcinomas harbor mutations in the ARID1A gene, which results in complete loss of ARID1A protein expression. Although ARID1A aberrations are not restricted to endometrial cancer, the authors hypothesized that it might be a useful marker of malignancy in peritoneal washings for patients with endometrial cancer. METHODS: The cytology archive of Brigham and Women's Hospital was searched to identify cell blocks from peritoneal washings that contained malignant or benign endometrial epithelium. From 2006 through 2013, 17 cases of endometrial carcinoma (EMCA) and 16 cases of endometriosis were identified. Surgical pathology reports and follow up data were used to confirm the diagnoses. Immunohistochemistry for ARID1A was performed, and slides were scored as 0 (complete loss of staining) or 1 (retained staining) by 2 independent pathologists. The discordant cases were resolved by consensus. The two-tailed Fisher exact probability test was used to calculate statistical significance. RESULTS: Complete loss of ARID1A expression was found in 8 of 17 EMCA cases (47%) and none of the 16 endometriosis cases (0%) (P = .024). The concordance among the pathologists on first review was high (96.7%). CONCLUSIONS: The results of the current study demonstrated that ARID1A can be used in peritoneal washings to confirm malignancy in patients with EMCA. Complete loss of ARID1A expression by immunohistochemistry is highly specific for carcinoma, but retained expression is not informative. PMID- 25557365 TI - Utility of RAPD marker for genetic diversity analysis in gamma rays and ethyl methane sulphonate (EMS)-treated Jatropha curcas plants. AB - The presence of important chemical and physical properties in Jatropha curcas makes it a valuable raw material for numerous industrial applications, including the production of biofuel. Hence, the researcher's interest is diversified to develop more and better varieties with outstanding agronomic characteristics using conventional breeding. Among these, mutation breeding is one of the best approaches to bring genetic changes in plant species. The aim of this study is to evaluate the diversity and genetic relationship among J. curcas mutants, which were obtained from different doses of gamma rays (control, 5 Kr, 10 Kr, 15 Kr, 20 Kr and 25 Kr) and EMS (1%, 2%, 3% and 4%), using RAPD marker. Among the 21 random primers, 20 produced polymorphic bands. The primers, OPM-14 and OPAW-13, produced a minimum number of bands (3) each across the ten mutants, while the primer OPF 13 produced the maximum number of bands (10), followed by the primers OPU-13, OPAM-06, OPAW-09 and OPD-05, which produced 9 bands each. The number of amplicons varied from 3 to 10, with an average of 7 bands, out of which 4.57 were polymorphic. The percentage of polymorphism ranged from 0.00 to 100 with an average of 57%. In the present study, RAPD markers were found most polymorphic, with an average polymorphism information content (PIC) value of 0.347, effective multiplex ratio (EMR) of 35.14, marker index (MI) of 14.19, resolution power (Rp) of 11.19, effective marker index (EMI) of 8.21 and genotype index (GI) of 0.36, indicating that random primers are useful in studies of genetic characterization in J. curcas mutant plants. In a dendrogram constructed based on Jaccard's similarity coefficients, the mutants were grouped into three main clusters viz., (a) control, 10 Kr, 15 Kr, 20 Kr, 2% EMS, and 3% EMS, (b) 5 Kr and 1% EMS, and (c) 25 Kr and 4% EMS mutants. Based on the attributes of the random primers and polymorphism studied, it is concluded that RAPD analysis offers a useful molecular marker for the identification of the mutants in gamma rays and EMS treated plants. PMID- 25557366 TI - Microarray hybridization analysis of light-dependent gene expression in Penicillium chrysogenum identifies bZIP transcription factor PcAtfA. AB - The fungal velvet complex is a light-dependent master regulator of secondary metabolism and development in the major penicillin producer, Penicillium chrysogenum. However, the light-dependent mechanism is unclear. To identify velvet-dependent transcriptional regulators that show light-regulated expression, we performed microarray hybridizations with RNA isolated from P. chrysogenum DeltaPcku70 cultures grown under 13 different long-term, light-dependent growth conditions. We compared these expression data to data from two velvet complex deletion mutants; one lacked a subunit of the velvet complex (DeltaPcvelA), and the other lacked a velvet-associated protein (DeltaPclaeA). We sought to identify genes that were up-regulated in light, but down-regulated in DeltaPcvelA and DeltaPclaeA. We identified 148 co-regulated genes that displayed this regulatory pattern. In silico analyses of the co-regulated genes identified six proteins with fungal-specific transcription factor domains. Among these, we selected the bZIP transcription factor, PcAtfA, for functional characterization in deletion and complementation strains. Our data clearly indicates that PcAtfA governs spore germination. This comparative analysis of different microarray hybridization data sets provided results that may be useful for identifying genes for future functional analyses. PMID- 25557367 TI - Mechanistic aspects of the gas-phase reactions of halobenzenes with bare lanthanide cations: a combined experimental/theoretical investigation. AB - The gas-phase reactions of chlorobenzene with all atomic lanthanide cations Ln(+) (except Pm(+) ) have been investigated by using Fourier transform ion cyclotron resonance mass spectrometry in conjunction with density functional theory calculations. According to the latter, a direct chlorine transfer to the lanthanide cation, which has been observed previously for fluorine abstraction from fluorobenzene, is not operative for the C6 H5 Cl/Ln(+) couples; rather, chlorine transfer proceeds through an initial coordination of the lanthanide cation to the aromatic ring of the substrate. Both, the product distribution and the chlorine abstraction efficiencies are affected by the bond dissociation energy (BDE(Ln(+) ?Cl)) as well as the promotion energies of Ln(+) to attain a 4f(n) 5d(1) 6s(1) configuration. In addition, mechanistic aspects of some C?H and C?C bond activations are presented. Where appropriate, comparison with the previously studied C6 H5 F/Ln(+) systems is made. PMID- 25557368 TI - Chitosan cocrystals embedded alginate beads for enhancing the solubility and bioavailability of aceclofenac. AB - Enhanced oral bioavailability of aceclofenac has been achieved using chitosan cocrystals of aceclofenac and its entrapment into alginate matrix a super saturated drug delivery system (SDDS). Prepared SDDS were evaluated by various physiochemical and pharmacological methods. The result revealed that the primary cocrystals enhanced the solubility of the drug and the thick gelled polymer matrix that formed from swelling of calcium alginate beads makes it to release the drug in continuous and sustained manner by supersaturated drug diffusion. The Cmax, Tmax and relative bioavailability for aceclofenac cocrystal and aceclofenac SDDS were 2.06+/-0.42 MUg/ml, 1 h, 159.72+/-10.84 and 2.01 MUg/ml, 1 h, 352.76+/ 12.91, respectively. Anti-inflammatory activity of aceclofenac was significantly improved with the SDDS. With respect to the results, it revealed that the SDDS described herein might be a promising tool for the oral sustained release of aceclofenac and likely for that of various other poorly soluble drugs. PMID- 25557369 TI - AtPHT4;4 is a chloroplast-localized ascorbate transporter in Arabidopsis. AB - Ascorbate is an antioxidant and coenzyme for various metabolic reactions in vivo. In plant chloroplasts, high ascorbate levels are required to overcome photoinhibition caused by strong light. However, ascorbate is synthesized in the mitochondria and the molecular mechanisms underlying ascorbate transport into chloroplasts are unknown. Here we show that AtPHT4;4, a member of the phosphate transporter 4 family of Arabidopsis thaliana, functions as an ascorbate transporter. In vitro analysis shows that proteoliposomes containing the purified AtPHT4;4 protein exhibit membrane potential- and Cl(-)-dependent ascorbate uptake. The AtPHT4;4 protein is abundantly expressed in the chloroplast envelope membrane. Knockout of AtPHT4;4 results in decreased levels of the reduced form of ascorbate in the leaves and the heat dissipation process of excessive energy during photosynthesis is compromised. Taken together, these observations indicate that the AtPHT4;4 protein is an ascorbate transporter at the chloroplast envelope membrane, which may be required for tolerance to strong light stress. PMID- 25557370 TI - The bacterial signal transduction protein GlnB regulates the committed step in fatty acid biosynthesis by acting as a dissociable regulatory subunit of acetyl CoA carboxylase. AB - Biosynthesis of fatty acids is one of the most fundamental biochemical pathways in nature. In bacteria and plant chloroplasts, the committed and rate-limiting step in fatty acid biosynthesis is catalyzed by a multi-subunit form of the acetyl-CoA carboxylase enzyme (ACC). This enzyme carboxylates acetyl-CoA to produce malonyl-CoA, which in turn acts as the building block for fatty acid elongation. In Escherichia coli, ACC is comprised of three functional modules: the biotin carboxylase (BC), the biotin carboxyl carrier protein (BCCP) and the carboxyl transferase (CT). Previous data showed that both bacterial and plant BCCP interact with signal transduction proteins belonging to the PII family. Here we show that the GlnB paralogues of the PII proteins from E. coli and Azospirillum brasiliense, but not the GlnK paralogues, can specifically form a ternary complex with the BC-BCCP components of ACC. This interaction results in ACC inhibition by decreasing the enzyme turnover number. Both the BC-BCCP-GlnB interaction and ACC inhibition were relieved by 2-oxoglutarate and by GlnB uridylylation. We propose that the GlnB protein acts as a 2-oxoglutarate sensitive dissociable regulatory subunit of ACC in Bacteria. PMID- 25557371 TI - Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), demonstrated efficacy and safety in relapsing-remitting multiple sclerosis in the 2-year, randomized, placebo-controlled, phase 3 DEFINE and CONFIRM trials. A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF. METHODS: Eligible patients were randomized to receive placebo, DMF 240 mg twice (BID) or three times (TID) daily or glatiramer acetate (GA; reference comparator; CONFIRM only) for up to 96 weeks. Patients in the GA group were excluded from this analysis. RESULTS: A total of 2301 patients were randomized and received treatment with placebo (n = 771) or DMF BID (n = 769) or TID (n = 761). DMF significantly reduced the annualized relapse rate beginning in weeks 0-12 (BID, P = 0.0159; TID, P = 0.0314); the proportion of patients relapsed beginning at week 10 (BID, P = 0.0427) and week 12 (TID, P = 0.0451); and the proportion of patients with 12-week confirmed disability progression beginning at week 62 (BID, P = 0.0454) and week 72 (TID, P = 0.0399), compared with placebo. These effects were sustained throughout the 2-year study period. DMF significantly reduced the odds of having a higher number of gadolinium-enhancing lesions by 88% (BID) and 75% (TID) and the mean number of new or enlarging T2 lesions by 72% (BID) and 67% (TID), from the first post baseline magnetic resonance imaging assessment at 24 weeks (all P < 0.0001 versus placebo). CONCLUSIONS: In phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing-remitting multiple sclerosis. PMID- 25557372 TI - Telmisartan promotes potential glucose homeostasis in stroke-resistant spontaneously hypertensive rats via peroxisome proliferator-activated receptor gamma activation. AB - An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-gamma, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-gamma and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-gamma activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR gamma in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-gamma activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis. PMID- 25557373 TI - Factor VIII levels are associated with ischemic stroke, stroke subtypes and neurological worsening. AB - The role played by hemostasis in the pathogenesis of ischemic stroke is still controversial. In the present study, we looked for a possible association of ischemic stroke with the high clotting activity of factor VIII (FVIII). The study population consisted of 116 patients with acute ischemic stroke who had been admitted between September 2013 and September 2014 to the Department of Neurology, Chiayi Chang Gung Memorial Hospital, and 76 control subjects with no history of stroke. FVIII levels were higher in stroke patients as compared to controls (127.5 +/- 52.5 vs. 108.4 +/- 49.0 IU/dL; P = 0.012). In a univariate risk analysis, FVIII at levels above 150 IU/dL was associated with an odds ratio (OR) for ischemic stroke of up to 2.55 (95% CI, 1.20-5.42, P = 0.013). In a multivariate analysis using a logistic regression model including age, hypertension, low density lipoprotein cholesterol level, estimated glomerular filtration rate, and high FVIII (< 150 IU/dL), high FVIII was still found to significantly add to the risk of ischemic stroke (OR = 3.26 with 95% CI, 1.38 7.68, P = 0.007). As for the stroke subtypes, mean FVIII level was significantly higher in patients with cardioembolic stroke than patients with noncardioembolic stroke (156.0 +/- 51.5 IU/dL vs. 124.3 +/- 51.9 IU/dL). High levels of FVIII were also associated significantly with neurological worsening (OR = 3.66 with 95% CI, 1.24-10.82, P = 0.019). A high plasma level of FVIII is a prevalent and independent risk factor for ischemic stroke and neurological worsening after acute stroke. PMID- 25557374 TI - HspB8 is neuroprotective during oxygen glucose deprivation and reperfusion. AB - Heat shock protein B8 (HspB8) is a chaperone protein that is highly and constitutively expressed in the brain, cardiac tissue and many other organs. Recently, it has been shown that HspB8 can enhance cardiac function and render cardioprotection. However, the potential benefits of HspB8 action on ischemic stroke and the underlying mechanism(s) are largely unknown. To investigate whether HspB8 exerts protective effects on in vitro ischemia/ reperfusion (I/R) injury, mouse neuroblastoma cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R). At first, we investigated and described the HspB8 expression and distribution in N2A cells exposed to OGD/R. Expressions of HspB8 were upregulated in mouse N2A cells after OGD/R, both at mRNA and protein levels. The level of HspB8 began increased after the OGD/R and peaked at 12 hour (12h) after the reperfusion, then declined at 24-hour time points, however, the level of HspB8 was still significantly increased compared to controls. Immunofluorescence analysis revealed that the expressed HspB8 was constitutively localized in the cytoplasm and at the periphery of the nucleus. Nuclear HspB8 levels increased after OGD/R compared with levels in the control, beginning as early as 4h reperfusion, the most conspicuous nuclear HspB8 staining was observed after 24h of reperfusion. Furthermore, overexpression of HspB8 reduced OGD/R induced apoptosis by reducing the release of cytochrome c from mitochondria to cytosol. In conclusion, our data demonstrated that increased HspB8 expression and its nuclear shift in mouse N2A neuroblastoma cells protected against I/R injury, resulting in reduced apoptosis with the decrease of the release of cytochrome c from mitochondria to cytosol. Therefore, HspB8 might play a fundamental role in opposing and alleviating I/R injury in primary myocardial cells, and it may constitute a new therapeutic target for cerebral ischemic diseases. PMID- 25557375 TI - Melatonin leads to axonal regeneration, reduction in oxidative stress, and improved functional recovery following sciatic nerve injury. AB - Despite recent advances in microsurgical techniques and equipments, recovery of function following repair of transected nerves often remains suboptimal. Contrary to traumatic injuries vascular damage that causes peripheral nerve injury has not been well-documented in the literature. In the present study a total of 40 female rats were randomly divided into four groups: Group 1: intact controls (n: 10), Group 2: sham-operated (n: 10), Group 3: vehicle-treated (n: 10), Group 4: melatonin-treated (n: 10). Sciatic nerve damage was created by stripping of the epineurial vessels around the nerve. 50 mg/kg Melatonin was injected intraperitoneally immediately after epineurial stripping in Group 4 in the course of 4 postoperative weeks. We found that melatonin administration after stripping of the epineurial vessels exerted a beneficial effect on axonal regeneration and functional recovery was confirmed by functional (sensory-motor, biochemical, and electrophysiological analyses) and morphological (light microscopic and ultrastructural analyses) data. In the light of these results we concluded that melatonin in a model of sciatic nerve injury leads to axonal regeneration, reducing in oxidative stress, and improved functional recovery. PMID- 25557377 TI - Significant correlation between cystatin C, cerebral infarction, and potential biomarker for increased risk of stroke. AB - This study investigated the correlation of serum cystatin C levels with cerebral infarction (CI) and different subtypes of CI, the severity of CI and the risk of recurrent CI. Totally 1017 patients with CI and 534 healthy controls were included, with clinical and biochemical characteristics documented and analyzed. The results showed serum cystatin C were 0.93 +/- 0.21 mg/l and 1.19 +/- 0.5 mg/l in control and CI, respectively (p < 0.001). The significant risk factors for CI were age (p < 0.001, OR = 1.048), presence of diabetes (p = 0.007, OR = 2.397), cystatin C (p = 0.001, OR = 1.021), uric acid (p = 0.017, OR = 4.226), and systolic blood pressure (p = 0.021, OR = 1.003). The risk of CI increased with cystatin C levels. Also, cystatin C levels were associated with different subtypes of CI, with large-artery atherosclerosis (LAA) subtype having the highest level of cystatin C. Moreover, cystatin C levels were significantly and positively correlated with Essen Stroke Risk Score (ESRS). The higher level of cystatin C the higher risk of recurrent stroke. In contrast, correlation between cystatin C levels and National Institute of Health stroke scale (NIHSS) score was not significant. In conclusion, cystatin C was an independent risk factor for CI. LAA subtype of CI was more closely related to increased cystatin C level. Furthermore, cystatin C levels predict risk of recurrent CI but not the severity of CI. PMID- 25557376 TI - Low baseline urine creatinine excretion rate predicts poor outcomes among critically ill acute stroke patients. AB - Urinary creatinine excretion rate (CER) is an established marker of muscle mass. Low CER has been linked to poor coronary artery disease outcomes, but a link between CER and acute stroke prognosis has not been previously explored. We prospectively collected data from patients with acute stroke (ischemic or hemorrhagic) within 24 hours from symptom onset in a Neurological and Neurosurgery Intensive Care Unit in Taiwan. Baseline CER (mg/d) was calculated by urine creatinine concentration in morning spot urine multiplies 24-hour urine volume on the second day of admission. Patients were divided into 3 tertiles with highest, middle, and lowest CER. Primary endpoint was poor outcome defined as modified Rankin Scale 3-6 at 6 months. Among 156 critically ill acute stroke patients meeting study entry criteria, average age was 67.9 years, and 83 (53.2%) patients had ischemic stroke. Patients with lowest CER (vs. highest CER) had a high risk of poor outcome at 6-month after adjustment (odds ratio 4.96, 95% confidence interval 1.22 to 20.15, p value = 0.025). In conclusion, low baseline CER, a marker of muscle mass, was independently associated with poor 6-month outcome among critically ill acute stroke patients. We speculate that preservation of muscle mass through exercise or protein-energy supplement might be helpful for improving prognosis in severe stroke patients. PMID- 25557378 TI - Carbon monoxide and iron modulate plasmatic coagulation in Alzheimer's disease. AB - Alzheimer's disease (AD) is a significant source of morbidity and mortality for millions of people worldwide, and multiple potential etiologies have been postulated to contribute to AD. Among these, spontaneous cerebral emboli and increased cerebral and circulating heme oxygenase (Hmox) activity in AD patients are of particular interest, as two of the products of Hmox activity, carbon monoxide (CO) and iron enhance plasmatic coagulation and modify the ultrastructure of thrombi. We hypothesized that patients afflicted with AD would have coagulation kinetics modulated by CO and iron. Using viscoelastic assessments of coagulation, it was determined with a small cohort (n=11) of AD patients that all had enhancement of coagulation by CO, iron, or both. In a complementary fashion, it was determined that a separate cohort (n=12) of AD patients had thrombi with ultrastructural features consistent with iron and CO exposure as assessed with scanning electron microscopy. Further, when stratified by normal or abnormally increased serum ferritin concentrations (which can be increased by Hmox), the AD patients with abnormal ferritin concentrations had significantly thinner fibrin fiber diameters, not unlike that noted when normal plasma is mixed with iron or CO. In sum, AD patients were noted to have plasmatic coagulation kinetic and thrombus ultrastructural changes consistent with exposure to CO and iron. Future investigation of CO and iron in the pathogenesis of Alzheimer's disease is warranted. PMID- 25557379 TI - Thromboxane A2 receptor polymorphism in association with cerebral infarction and its regulation on platelet function. AB - Binding of thromboxane A2 (TXA2) to its receptor TXA2R modulates thrombosis/hemostasis and plays a vital role in the pathogenesis of cerebral infarction (CI). In this study, we investigated the relationship between TXA2R polymorphisms and CI in Chinese Han population and the effect on platelet function by these polymorphisms. Polymerase chain reaction and ligase detection reaction (PCR-LDR) was performed in 230 CI patients and 143 healthy volunteers to examine four single nucleotide polymorphisms (SNPs) in human TXA2R gene (C795T, T924C and G1686A in the exon region, and rs768963 in the promoter region). We found that rs768963 polymorphism was significantly more frequent in the CI group than in the non-CI group and the T-T-G-T haplotype of C795T-T924C-G1686A-rs768963 was significantly less frequent in the CI subjects (0.238 versus 0.339; OR 0.617 [95%CI 0.444-0.856]). In the meantime, we constructed wild-type and mutant (C795T, G910A and T924C) eukaryotic expression plasmids, and transfected these plasmids into human embryonic kidney (HEK) 293T cells or Chinese hamster ovary (CHO) cells stably expressing human TXA2R (GPb/a- CHO). C795T and T924C variants of TXA2R led to increased ligand binding-induced intracellular calcium influx and fibrinogen-integrin conjugation, while dominant negative mutant G910A abolished the signal enhancement. Together these data show that TXA2R polymorphisms may affect platelet function and the risk of developing cerebral ischemia. PMID- 25557381 TI - Reconciling functions and evolution of isoprene emission in higher plants. AB - Compilation and analysis of existing inventories reveal that isoprene is emitted by c. 20% of the perennial vegetation of tropical and temperate regions of the world. Isoprene emitters are found across different plant families without any clear phylogenetic thread. However, by critically appraising information in inventories, several ecological patterns of isoprene emission can be highlighted, including absence of emission from C4 and annual plants, and widespread emission from perennial and deciduous plants of temperate environments. Based on this analysis, and on available information on biochemistry, ecology and functional roles of isoprene, it is suggested that isoprene may not have evolved to help plants face heavy or prolonged stresses, but rather assists C3 plants to run efficient photosynthesis and to overcome transient and mild stresses, especially during periods of active plant growth in warm seasons. When the stress status persists, or when evergreen leaves cope with multiple and repeated stresses, isoprene biosynthesis is replaced by the synthesis of less volatile secondary compounds, in part produced by the same biochemical pathway, thus indicating causal determinism in the evolution of isoprene-emitting plants in response to the environment. PMID- 25557380 TI - Platelets in the Alzheimer's disease brain: do they play a role in cerebral amyloid angiopathy? AB - Alzheimer's disease (AD) is characterized by extracellular beta-amyloid plaques and intracellular tau tangles. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis. Platelets circulate along the vessel wall responding immediately to vascular injury. The aim of the present study was to explore the presence and migration of platelets (thrombocytes) to sites of small vascular bleedings and/or to beta-amyloid plaques in the brain. We infused fluorescently labeled red PKH26 mouse platelets into transgenic Alzheimer mice overexpressing APP with Swedish/Dutch/Iowa mutations (APP_SDI) and explored if platelets migrate into the brain. Further we studied whether platelets accumulate in the vicinity of beta-amyloid plaques. Our animal data shows that infused platelets are found in the liver and partly in the lung, while in the brain platelets were visible to a minor degree. In mice, we did not observe a significant association of platelets with beta-amyloid plaques or vessels. In the brain of Alzheimer postmortem patients platelets could be detected by immunohistochemistry for CD41 and CD62P, but the majority was found in vessels with or without beta-amyloid load, and only a few single platelets migrated deeper into the brain. Our findings suggest that platelets do not migrate into the brains of Alzheimer disease but are concentrated in brain vessels. PMID- 25557383 TI - Effect of garlic on blood pressure: a meta-analysis. AB - Garlic supplements are thought to reduce blood pressure (BP). The authors performed a meta-analysis to investigate garlic's effect on BP. Ovid Medline, Cochrane Library, and PubMed (1946 to November 2013) were used to search for randomized controlled trials. Seventeen trials were included. Pooled analysis showed that garlic intake caused a 3.75-mm Hg reduction (95% confidence interval [CI], -5.04 to -2.45, I(2) =30.7%; P<.001) in systolic BP and a 3.39-mm Hg reduction (95% CI, -4.14 to -2.65, I(2) =67%; P<.001) in diastolic BP compared with controls. Meta-analysis of subgroups showed a significant reduction in systolic BP in hypertensive (-4.4 mm Hg; 95% CI, -7.37 to -1.42, I(2) =0.0%; P=.004) but not normotensive patients. No significant reduction in diastolic BP was seen. After sensitivity analysis, heterogeneity disappeared and significant diastolic BP reduction (-2.68 mm Hg, 95% CI, -4.93 to -0.42, I(2) =0.0%; P=.020) was shown in hypertensive patients. This meta-analysis suggests that garlic supplements are superior to controls (placebo in most trails) in reducing BP, especially in hypertensive patients. PMID- 25557382 TI - Cannabis use in relation to obesity and insulin resistance in the Inuit population. AB - OBJECTIVE: To ascertain the relationship between cannabis use, obesity, and insulin resistance. METHODS: Data on 786 Inuit adults from the Nunavik Inuit Health Survey (2004) were analyzed. Information on cannabis use was obtained from a self-completed, confidential questionnaire. Fasting blood glucose and insulin and homeostasis model assessment of insulin resistance (HOMA-IR) served as surrogate markers of insulin resistance. Analysis of covariance and multivariate logistic regression ascertained relationships between cannabis use and outcomes. RESULTS: Cannabis use was highly prevalent in the study population (57.4%) and was statistically associated with lower body mass index (BMI) (P < 0.001), lower % fat mass (P < 0.001), lower fasting insulin (P = 0.04), and lower HOMA-IR (P = 0.01), after adjusting for numerous confounding variables. Further adjustment for BMI rendered fasting insulin and HOMA-IR differences statistically nonsignificant between past-year cannabis users and nonusers. Mediation analysis showed that the effect of cannabis use on insulin resistance was indirect, through BMI. In multivariate analysis, past-year cannabis use was associated with 0.56 lower likelihood of obesity (95% confidence interval 0.37-0.84). CONCLUSIONS: Cannabis use was associated with lower BMI, and such an association did not occur through the glucose metabolic process or related inflammatory markers. The association between cannabis use and insulin resistance was mediated through its influence on weight. PMID- 25557384 TI - Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line. AB - The Forkhead box protein M1 (FoxM1) is an important transcription factor having significant roles in various cellular events. FoxM1 overexpression has been reported to be related with many types of cancer. However, it is not known whether it contributes to oncogenesis of acute lymphoblastic leukemia. Siomycin A, a thiazol antibiotic, is known to inhibit FoxM1 transcriptional activity. In this study, we aimed to determine gene expression levels of FoxM1 in Jurkat cells (T-cell acute lymphoblastic leukemia cell line) and therapeutic potential of targeting FoxM1 by siomycin A alone and in combination with dexamethasone which improves the survival of children with T-cell acute lymphoblastic leukemia (ALL). We also examined the molecular mechanisms of siomycin A and dexamethasone-induced cell death in Jurkat cells. We demonstrated that FoxM1 mRNA is highly expressed in Jurkat cells. Dexamethasone and siomycin A caused a significant reduction in gene expression levels of FoxM1 in Jurkat cells. Targeting FoxM1 by siomycin A and dexamethasone caused a significant decrease in T-ALL cell line proliferation through induction of G1 cell cycle arrest. All these findings suggest a possible role of FoxM1 in T-cell ALL pathogenesis and represent FoxM1 as an attractive target for T-cell ALL therapy. PMID- 25557385 TI - Hypoglycaemic effects of functional tri-peptides from silk in differentiated adipocytes and streptozotocin-induced diabetic mice. AB - BACKGROUND: In this study, the tri-peptides Gly-Glu-Tyr (GEY) and Gly-Tyr-Gly (GYG), identified previously as active compounds from the silk peptide E5K6, significantly stimulated basal and insulin-mediated glucose uptake by 3T3-L1 fibroblasts in a dose-dependent manner. RESULTS: Synthetic GEY and GYG peptides at a concentration of 500 umol L(-1) significantly increased glucose transporter type 4 expression by 157% and 239%, respectively. Differentiation of 3T3-L1 cells into adipocytes leads to accumulation of intracellular fat droplets, and GEY and GYG at a concentration of 250 umol L(-1) suppressed this effect by 72% and 75%, respectively. GYG improved glucose tolerance in steptozotocin (STZ)-induced diabetic mice in a dose-dependent manner. CONCLUSION: These results suggest that GYG isolated from E5K6 has anti-diabetic potential and silk waste products containing bioactive peptides could be used to the developments of treatments to lower blood glucose. PMID- 25557386 TI - Fitness level impacts salivary antimicrobial protein responses to a single bout of cycling exercise. AB - PURPOSE: Salivary antimicrobial proteins (sAMPs) protect the upper respiratory tract (URTI) from invading microorganisms and have been linked with URTI infection risk in athletes. While high training volume is associated with increased URTI risk, it is not known if fitness affects the sAMP response to acute exercise. This study compared the sAMP responses to various exercising workloads of highly fit experienced cyclists with those who were less fit. METHODS: Seventeen experienced cyclists (nine highly fit; eight less fit) completed three 30-min exercise trials at workloads corresponding to -5, +5 and +15 % of the individual blood lactate threshold. Saliva samples were collected pre- and post-exercise to determine the concentration and secretion of alpha amylase, human neutrophil proteins 1-3 (HNP1-3) lactoferrin, LL-37, lysozyme, and salivary SIgA. RESULTS: The concentration and/or secretion of all sAMPs increased post-exercise, but only alpha-amylase was sensitive to exercise workload. Highly fit cyclists had lower baseline concentrations of alpha-amylase, HNP1-3, and lactoferrin, although secretion rates did not differ between the groups. Highly fit cyclists did, however, exhibit greater post-exercise increases in the concentration and/or secretion of a majority of measured sAMPs (percentage difference between highly fit and less fit in parentheses), including alpha amylase concentration (+107 %) and secretion (+148 %), HNP1-3 concentration (+97 %) and secretion (+158 %), salivary SIgA concentration (+181 %), lactoferrin secretion (+209 %) and LL-37 secretion (+138 %). CONCLUSION: We show for the first time that fitness level is a major determinant of exercise-induced changes in sAMPs. This might be due to training-induced alterations in parasympathetic and sympathetic nervous system activation. PMID- 25557388 TI - Pacing strategies during the swim, cycle and run disciplines of sprint, Olympic and half-Ironman triathlons. AB - PURPOSE: This study investigated the influence of distance on self-selected pacing during the swim, cycle and run disciplines of sprint, Olympic and half Ironman (HIM) distance triathlon races. METHOD: Eight trained male triathletes performed the three individual races in <2 months. Participants' bikes were fitted with Schoberer Rad Mebetatechnik to monitor speed, power output and heart rate during the cycle discipline. Global positioning system was worn to determine speed and heart rate during the swim and run disciplines. RESULT: An even swim pacing strategy was adopted across all distances. A more stochastic pacing was observed during the HIM cycle [standard deviation of exposure variation analysis (EVASD) = 3.21 +/- 0.61] when compared with the sprint cycle discipline (EVASD = 3.84 +/- 0.44, p = 0.018). Only 20.9 +/- 4.1 % of the cycling time was spent more than 10 % above the mean power output in the HIM, compared with 43.8 +/- 2.9 % (p = 0.002) and 37.7 +/- 11.1 % (p = 0.039) during the sprint and Olympic distance triathlons, respectively. Conversely, 13.6 +/- 5.1 % of the cycling time was spent 5-10 % below the mean power output during the HIM, compared with 5.9 +/- 1.2 % (p = 0.034) and 8.0 +/- 5.1 % (p = 0.045) during the sprint and Olympic distance triathlons, respectively. A negative pacing strategy was adopted during the sprint distance run, compared with positive pacing strategy during the Olympic and HIM. CONCLUSION: Results of this study suggest that pacing strategies during triathlon are highly influenced by distance and discipline, and highlight the importance of developing pacing strategies based on distance, strengths and individual fitness. PMID- 25557387 TI - Effect of balance training on neuromuscular function at rest and during isometric maximum voluntary contraction. AB - PURPOSE: This study was directed to investigate the neuromuscular function of the plantar flexors and tibialis anterior (TA) before and after 8 weeks of balance training. METHODS: Twenty-six young adult subjects were randomly assigned to an intervention group and a control group. During neuromuscular testing, rate of torque development (RTD), isometric maximum voluntary torque (iMVT) and muscle activation were measured. Triceps surae muscle activation and TA muscle co activation were assessed by normalized root mean square of the EMG signal during the initial phase of contraction (0-100, 0-200 ms) and maximum voluntary contraction (MVC) of the plantar flexors. Furthermore, evoked spinal reflex responses of the soleus muscle (H-reflex evoked at rest and during MVC, V-wave), peak twitch torques induced by electrical stimulation at rest and balance performance were evaluated. RESULTS: We found a significant difference between groups in RTD of the plantar flexors during MVC in the time interval 0-100 ms [37.0 N m s(-1) (4.2-69.9 N m s(-1), P = 0.029)]. This change was accompanied by reduced antagonistic muscle co-activity. The normalized H-reflex of the soleus muscle at rest as well as the sway of the center of pressure during balance performance assessment were significantly lower for the intervention group compared with controls. The training intervention had no effect on iMVT, normalized muscle activity of the plantar flexors, normalized muscle activity of TA, normalized V-wave and normalized H-reflex evoked during MVC. CONCLUSION: Data suggest that balance training reduced antagonistic muscle co-activity at the onset of triceps surae contraction and, in turn, increased isometric explosive voluntary strength of the plantar flexors. PMID- 25557389 TI - Treatment in vitro with PPARalpha and PPARgamma ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice. AB - Trypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-alpha, IL-1beta and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARgamma, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARgamma, PPARalpha is also involved in the in vitro polarization of macrophages isolated from T. cruzi infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-beta. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation. PMID- 25557392 TI - Electrochemical oxidation stability of anions for modern battery electrolytes: a CBS and DFT study. AB - The electrochemical stability vs. oxidation is a crucial property of anions in order to be suitable as components in lithium-ion batteries. Here the applicability of a number of computational approaches and methods to assess this property, employing a wide selection of DFT functionals, has been studied using the CCSD(T)/CBS method as the reference. In all, the vertical anion oxidation potential, DeltaEv, is a fair way to calculate the stability vs. oxidation, however, a functional of at least hybrid quality is recommended. In addition, the chemical hardness, eta, is identified as a novel approach to calculate the stability vs. oxidation. PMID- 25557391 TI - Born in 1949 in postwar Japan. AB - In this article, I would like to look back at my life as a researcher of photosynthesis. I was born in 1949, and grew up and was educated in postwar Japan in the 1950s and 1960s. I have studied photosynthesis, in particular Photosystem II, after research experiences in the USA and UK. My study of Photosystem II has continued over 43 years until now. Through the present retrospection, I would like to suggest that all photosynthesis researchers, including the members of the "49ers", many other established scientists, and young students as well, should not simply stay in the lab working hard on their studies and writing papers; but should also do something for the public. People want to learn from us about many critical social issues such as the environment, food, energy and, most importantly, peace. I believe that our knowledge must form an important basis for people to take action to create a peaceful and harmonious human society. PMID- 25557393 TI - Impression cytology: a novel sampling technique for conjunctival cytology of the feline eye. AB - OBJECTIVE: Impression cytology is a noninvasive investigation of the ocular surface. It uses the adhesive features of different filter papers to collect a monolayer of epithelial cells from the cornea and/or conjunctiva. Samples obtained by impression cytology exhibit all characteristics of an ideal cytology specimen. The aim of this study was to test the feasibility of impression cytology and determine the most appropriate filter paper to achieve maximum diagnostic value of the feline eye. ANIMALS STUDIED: Ten healthy cats. PROCEDURES: The study was conducted in two phases. In the first phase, eight different filter papers (FPs) with various pore sizes were tested: 3.0-, 1.2-, 0.8-, 0.45-, 0.22-, 0.05- and 0.025-MUm cellulose acetate papers and a 0.4-MUm Biopore membrane (BM). Samples were obtained from the superior bulbar and from the inferior palpebral conjunctiva. In the second phase, three different sampling methods - with and without topical anesthesia, and with topical anesthesia and drying of the conjunctiva - were compared employing the BM encased in the intended BM device (BMD). Samples were evaluated for cellularity and quality of cells. RESULTS: In the first phase, samples obtained from the superior bulbar conjunctiva with the BM had the most sufficient cellularity and quality. In the second phase, BMD with topical anesthesia and additional drying of the conjunctiva was the most ideal method. CONCLUSION: The BMD may prove to be a suitable diagnostic tool for clinicians. Sampling is quick, processing is simple, and a large area of intact cells can be harvested. PMID- 25557390 TI - The ITM2B (BRI2) gene is a target of BCL6 repression: Implications for lymphomas and neurodegenerative diseases. AB - The human BCL6 gene encodes a transcriptional repressor that is crucial for germinal center B cell development and T follicular helper cell differentiation. It is involved in the pathogenesis of certain human lymphomas. In an effort to identify targets of BCL6 repression, we used a previously described cell system in which BCL6 repressive effects are inhibited, followed by subtractive hybridization, and identified the integral membrane 2B gene (ITM2B, formerly BRI2) as a potential target. Here we show that BCL6 can bind to its preferential consensus binding site within the first intron of ITM2B and represses its transcription. Knockdown of endogenous BCL6 in a human B cell lymphoma line increases ITM2B expression. Further, there is an inverse relationship between the expression levels of BCL6 and ITM2B proteins in 16 human B- and T-cell lymphomas studied by immunohistochemistry. Both the BCL6 and ITM2B proteins are expressed ubiquitously. Similar to some other targets of BCL6, a short form of the ITM2B protein generated by alternative splicing induces apoptosis in hematopoietic cell lines. Molecular alterations in the ITM2B gene are associated with two neurodegenerative diseases, Familial British and Familial Danish dementia. ITM2B dysfunction also may be relevant for the development of Alzheimer's disease. Our data confirm ITM2B as a target of BCL6 repression in lymphoma. A further understanding of the genes that function as regulators of the ITM2B protein may provide insights for the development of new molecular tools not only for targeted lymphoma therapy but also for the treatment of these dementias. PMID- 25557394 TI - Thymoquinone treatment for inner-ear acoustic trauma in rats. AB - OBJECTIVE: To investigate whether thymoquinone has any eliminative effects against inner-ear damage caused by acoustic trauma. METHODS: Thirty-two male rats were divided into four groups. Group 1 was only exposed to acoustic trauma. Group 2 was given thymoquinone 24 hours before acoustic trauma and continued to receive it for 10 days after the trauma. Group 3 was only treated with thymoquinone, for 10 days. Group 4, the control group, suffered no trauma and received saline instead of thymoquinone. Groups 1 and 2 were exposed to acoustic trauma using 105 dB SPL white noise for 4 hours. RESULTS: There was a significant decrease in distortion product otoacoustic emission values and an increase in auditory brainstem response thresholds in group 1 on days 1, 5 and 10, compared with baseline measurements. In group 2, a decrease in distortion product otoacoustic emission values and an increase in auditory brainstem response threshold were observed on day 1 after acoustic trauma, but measurements were comparable to baseline values on days 5 and 10. In group 3, thymoquinone had no detrimental effects on hearing. Similarly, the control group showed stable results. CONCLUSION: Thymoquinone was demonstrated to be a reparative rather than preventive treatment that could be used to relieve acoustic trauma. PMID- 25557395 TI - Mechanisms of change in an emotion regulation group therapy for deliberate self harm among women with borderline personality disorder. AB - Despite growing evidence for the efficacy of Gratz and colleagues' emotion regulation group therapy (ERGT) for deliberate self-harm (DSH) among women with borderline personality disorder (BPD), the proposed mechanism of change in this treatment (i.e., emotion regulation) remains largely unexamined. This study examined change in emotion dysregulation as a mediator of the effects of this ERGT on DSH and BPD symptoms, as well as the extent to which change in emotion dysregulation during treatment predicts further improvements in DSH during a 9 month follow-up. Participants included 61 female outpatients with BPD and recent DSH who were randomly assigned to receive this ERGT in addition to their ongoing outpatient therapy immediately (n = 31) or after 14 weeks (n = 30). Measures of emotion dysregulation, DSH, and BPD symptoms were administered pre- and post treatment or -waitlist, and at 9-months post-treatment (for participants in both conditions who received ERGT). Results from a series of mediation analyses provide further support for emotion regulation as a mechanism of change in this treatment. Specifically, results revealed that improvements in emotion dysregulation over the course of treatment mediated the observed reductions in BPD cognitive and affective symptoms during treatment and predicted further improvements in DSH during follow-up. PMID- 25557396 TI - From efficacy to effectiveness: comparing outcomes for youth with anorexia nervosa treated in research trials versus clinical care. AB - This study examined outcomes for 84 youth with anorexia nervosa (AN) who received family-based treatment (FBT) in a research trial (randomized trial care [RTC]: n = 32) compared to fee-for-service care (specialty clinical care [SCC]: n = 52) at an outpatient eating disorder clinic. Weight was collected up to 12 months post baseline. Survival curves were used to examine time to weight restoration as predicted by type of care, baseline demographic and clinical characteristics, and their interaction. There was not a significant main effect for type of care, but its interaction with initial %EBW was significant (p = .005), indicating that weight restoration was achieved faster in RTC compared to SCC for youth with a lower initial %EBW (i.e., <=81), while rates of weight restoration were comparable for those with a higher initial %EBW (i.e., >81). These data suggest that FBT is as effective as it is efficacious, except for youth with lower initial body weights. Therefore, clinicians may need to be particularly active in encouraging early weight gain for this subset of patients. Nevertheless, this study suggests that FBT is appropriate as a first-line treatment for youth with AN who present for clinical care. PMID- 25557397 TI - The Per Case and Total Annual Costs of Foodborne Illness in the United States. AB - We present an economic welfare-based method to estimate the health costs associated with foodborne illness caused by known viruses, bacteria, parasites, allergens, two marine biotoxins, and unspecified agents. The method generates health costs measured in both quality-adjusted life years and in dollars. We calculate the reduction in quality-adjusted life days caused by the illness and add reductions in quality-adjusted life years from any secondary effects that are estimated to occur. For fatal cases, we calculate the life years lost due to premature death. We add direct medical expenses to the monetary costs as derived from estimates of willingness to pay to reduce health risks. In total, we estimate that foodborne illness represents an annual burden to society of approximately $36 billion, with an average identified illness estimated to reduce quality-adjusted life days by 0.84, which is monetized and included in the average cost burden per illness of $3,630. PMID- 25557398 TI - Predicting learning plateau of working memory from whole-brain intrinsic network connectivity patterns. AB - Individual learning performance of cognitive function is related to functional connections within 'task-activated' regions where activities increase during the corresponding cognitive tasks. On the other hand, since any brain region is connected with other regions and brain-wide networks, learning is characterized by modulations in connectivity between networks with different functions. Therefore, we hypothesized that learning performance is determined by functional connections among intrinsic networks that include both task-activated and less activated networks. Subjects underwent resting-state functional MRI and a short period of training (80-90 min) in a working memory task on separate days. We calculated functional connectivity patterns of whole-brain intrinsic networks and examined whether a sparse linear regression model predicts a performance plateau from the individual patterns. The model resulted in highly accurate predictions (R(2) = 0.73, p = 0.003). Positive connections within task-activated networks, including the left fronto-parietal network, accounted for nearly half (48%) of the contribution ratio to the prediction. Moreover, consistent with our hypothesis, connections of the task-activated networks with less-activated networks showed a comparable contribution (44%). Our findings suggest that learning performance is potentially constrained by system-level interactions within task-activated networks as well as those between task-activated and less activated networks. PMID- 25557399 TI - Structural determination of Cu and Fe-Citrate complexes: theoretical investigation and analysis by ESI-MS. AB - The combined use of ESI-MS (electrospray ionization-mass spectrometry) and theoretical calculations for the determination of citrate:metal (metal=Cu and Fe) structures are reported. Mass spectrometry allowed to determine the stoichiometry 1:1 and 2:1 of the complexes, corroborating the theoretical calculations. The species found in the ratio 2:1 had their calculated structures readjusted, from what was originally simulated, since the deprotonation of citric acid differed from what was before simulated. The thermodynamic stability (DeltaH(aq.)(0)) of the complexes optimized at the B3LYP/LANL2DZ level was more exoenergetic than for the complexes found by the PM6 semi-empirical method. PMID- 25557401 TI - Top-down controlled and bottom-up triggered orienting of auditory attention to pitch activate overlapping brain networks. AB - A number of previous studies have suggested segregated networks of brain areas for top-down controlled and bottom-up triggered orienting of visual attention. However, the corresponding networks involved in auditory attention remain less studied. Our participants attended selectively to a tone stream with either a lower pitch or higher pitch in order to respond to infrequent changes in duration of attended tones. The participants were also required to shift their attention from one stream to the other when guided by a visual arrow cue. In addition to these top-down controlled cued attention shifts, infrequent task-irrelevant louder tones occurred in both streams to trigger attention in a bottom-up manner. Both cued shifts and louder tones were associated with enhanced activity in the superior temporal gyrus and sulcus, temporo-parietal junction, superior parietal lobule, inferior and middle frontal gyri, frontal eye field, supplementary motor area, and anterior cingulate gyrus. Thus, the present findings suggest that in the auditory modality, unlike in vision, top-down controlled and bottom-up triggered attention activate largely the same cortical networks. Comparison of the present results with our previous results from a similar experiment on spatial auditory attention suggests that fronto-parietal networks of attention to location or pitch overlap substantially. However, the auditory areas in the anterior superior temporal cortex might have a more important role in attention to the pitch than location of sounds. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25557403 TI - Brain and memory: Old arguments and new perspectives. PMID- 25557400 TI - Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. AB - The promise of 'personalized cancer care' with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized heterogeneity within any given tumor-type from patient to patient (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) as demonstrated by molecular evolution through space (primary tumor to metastasis) and time (after therapy). These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents. Classic trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic 'oncogenic driver' aberrations with adequate power. Usual accrual difficulties to clinical trials are exacerbated by low frequencies of any given molecular driver. To address these challenges, there is need for innovative clinical trial designs and strategies implementing novel diagnostic biomarker technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for pre-defined treatment priority algorithms given numerous aberrations commonly observed within any one individual sample. Access to multiple available therapeutic agents simultaneously is crucial. Finally intra patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression. This report discusses various 'next generation' biomarker-driven trial designs and their potentials and limitations to tackle these recognized molecular heterogeneity challenges. Regulatory hurdles, with respect to drug and companion diagnostic development and approval, are considered. Focus is on the 'Expansion Platform Design Types I and II', the latter demonstrated with a first example, 'PANGEA: Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma'. Applying integral medium-throughput genomic and proteomic assays along with a practical biomarker assessment and treatment algorithm, 'PANGEA' attempts to address the problem of heterogeneity towards successful implementation of molecularly targeted therapies. PMID- 25557402 TI - Blockade of ENaCs by amiloride induces c-Fos activation of the area postrema. AB - Epithelial sodium channels (ENaCs) are strongly expressed in the circumventricular organs (CVOs), and these structures may play an important role in sensing plasma sodium levels. Here, the potent ENaC blocker amiloride was injected intraperitoneally in rats and 2h later, the c-Fos activation pattern in the CVOs was studied. Amiloride elicited dose-related activation in the area postrema (AP) but only ~10% of the rats showed c-Fos activity in the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO). Tyrosine hydroxylase-immunoreactive (catecholamine) AP neurons were activated, but tryptophan hydroxylase-immunoreactive (serotonin) neurons were unaffected. The AP projects to FoxP2-expressing neurons in the dorsolateral pons which include the pre-locus coeruleus nucleus and external lateral part of the parabrachial nucleus; both cell groups were c-Fos activated following systemic injections of amiloride. In contrast, another AP projection target--the aldosterone-sensitive neurons of the nucleus tractus solitarius which express the enzyme 11-beta hydroxysteriod dehydrogenase type 2 (HSD2) were not activated. As shown here, plasma concentrations of amiloride used in these experiments were near or below the IC50 level for ENaCs. Amiloride did not induce changes in blood pressure, heart rate, or regional vascular resistance, so sensory feedback from the cardiovascular system was probably not a causal factor for the c-Fos activity seen in the CVOs. In summary, amiloride may have a dual effect on sodium homeostasis causing a loss of sodium via the kidney and inhibiting sodium appetite by activating the central satiety pathway arising from the AP. PMID- 25557404 TI - Ultra-high spatial resolution basal and evoked cerebral blood flow MRI of the rat brain. AB - Cerebral blood flow (CBF) is tightly coupled to metabolism and neural activity under normal physiological conditions, and is often perturbed in disease states. The goals of this study were to implement a high-resolution (up to 50*38MUm(2)) CBF MRI protocol of the rat brain, create a digital CBF atlas, report CBF values for 30+ brain structures based on the atlas, and explore applications of high resolution CBF fMRI of forepaw stimulation. Excellent blood-flow contrasts were observed among different cortical and subcortical structures. CBF MRI showed column-like alternating bright and dark bands in the neocortices, reflecting the layout of descending arterioles and ascending venules, respectively. CBF MRI also showed lamina-like alternating bright and dark layers across the cortical thicknesses, consistent with the underlying vascular density. CBF profiles across the cortical thickness showed two peaks in layers IV and VI and a shallow trough in layer V. Whole-brain CBF was about 0.89ml/g/min, with the highest CBF values found amongst the neocortical structures (1ml/g/min, range: 0.89-1.16ml/g/min) and the lowest CBF values in the corpus callosum (0.32ml/g/min), yielding a gray:white matter CBF ratio of 3.1. CBF fMRI responses peaked across layers IV-V, whereas the BOLD fMRI responses showed a peak in the superficial layers II-III. High-resolution basal CBF MRI, evoked CBF fMRI, and CBF brain atlas can be used to study neurological disorders (such as ischemic stroke). PMID- 25557405 TI - Involvement of decreased neuroglobin protein level in cognitive dysfunction induced by 1-bromopropane in rats. AB - 1-Bromopropane (1-BP) is used as a substitute for ozone-depleting solvents (ODS) in industrial applications. 1-BP could display central nervous system (CNS) neurotoxicity manifested by cognitive dysfunction. Neuroglobin (Ngb) is an endogenous neuroprotectant and is predominantly expressed in the nervous system. The present study aimed to investigate Ngb involvement in CNS neurotoxicity induced by 1-BP in rats. Male Wistar rats were randomly divided into 5 groups (n=14) and treated with 0, 100, 200, 400 and 800 mg/kg bw 1-BP, respectively, by gavage for consecutive 12 days. Rats displayed cognitive dysfunction dose dependently through Morris water maze (MWM) test. Significant neuron loss in layer 5 of the prelimbic cortex (PL) was observed. Moreover, 1-BP decreased Ngb protein level in cerebral cortex and Ngb decrease was significantly positively correlated with cognitive dysfunction. Glutathione (GSH) content, GSH/oxidized glutathione (GSSG) ratio and glutamate cysteine ligase (GCL) activity decreased in cerebral cortex, coupled with the increase in GSSG content. GSH and GSH/GSSG ratio decrease were significantly positively correlated with cortical Ngb decrease. Additionally, levels of N-epsilon-hexanoyl-lysine (HEL) and 4-hydroxy-2 nonenal (4-HNE) modified proteins in cerebral cortex of 1-BP-treated rats increased significantly. In conclusion, it was suggested that 1-BP resulted in decreased endogenous neuroprotectant Ngb in cerebral cortex, which might play an important role in CNS neurotoxicity induced by 1-BP and that 1-BP-induced oxidative stress in cerebral cortex might partly be responsible for Ngb decrease. PMID- 25557406 TI - The participation of oxytocin in the abirritation of lateral habenular nucleus on normal adult rats. AB - This paper probes into the participation of different concentrations of oxytocin in the pain regulation of lateral habenular nucleus on normal adult rats. The detailed experiment steps are as follows: microinject 1.25, 2.5, and 5nmol of oxytocin to three adult rats' lateral habenular nucleus, and measure the hind paw withdrawal latency (HWL) after 5, 10, 15, 20, 30, 45 and 60min with hot plate and pressure plate test as the indicator of algesia. At the same time, another group of adult rats were injected with normal saline as a control to observe the participation of oxytocin in the pain regulation of lateral habenular nucleus. Through the oxytocin microinjection, the HWL of rats was significantly prolonged, compared with the control group. According to the experimental results, the HWL of thermo stimulation on the left paw of the rats between OT group and the control group (injected with normal saline) showed no difference (p>0.05) after a microinjection of 1.25nmol in LHb, while the HWL of thermo stimulation on the left paw of the rats showed significant difference (p<0.01; p<0.01) after a microinjection of 2.5 and 5nmol in LHb; The HWL of thermo stimulation on the right paw of the rats between OT group and the control group (injected with normal saline) showed significant difference, slight difference and significant difference (p<0.01; p<0.05; p<0.01) after a microinjection of 1.25, 2.5 and 5.0nmol in LHb; The HWL of mechanical stimulation both on the left paw of the rats after a microinjection of 2.5nmol and on the right paw of the rats after a microinjection of 5nmol showed significant differences (p<0.01; p<0.01), and all the rest showed extremely significant differences (p<0.001). This experiment shows that oxytocin has significant abirritational effect on the lateral habenular nucleus of adult rats, which is dose dependent, especially after OT was injected for 15min. PMID- 25557408 TI - Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. AB - SIGNIFICANCE: In all cells, the endoplasmic reticulum (ER) and mitochondria are physically connected to form junctions termed mitochondria-associated membranes (MAMs). This subcellular compartment is under intense investigation because it represents a "hot spot" for the intracellular signaling of important pathways, including the synthesis of cholesterol and phospholipids, calcium homeostasis, and reactive oxygen species (ROS) generation and activity. RECENT ADVANCES: The advanced methods currently used to study this fascinating intracellular microdomain in detail have enabled the identification of the molecular composition of MAMs and their involvement within different physiopathological contexts. CRITICAL ISSUES: Here, we review the knowledge regarding (i) MAMs composition in terms of protein composition, (ii) the relationship between MAMs and ROS, (iii) the involvement of MAMs in cell death programs with particular emphasis within the tumor context, (iv) the emerging role of MAMs during inflammation, and (v) the key role of MAMs alterations in selected neurological disorders. FUTURE DIRECTIONS: Whether alterations in MAMs represent a response to the disease pathogenesis or directly contribute to the disease has not yet been unequivocally established. In any case, the signaling at the MAMs represents a promising pharmacological target for several important human diseases. PMID- 25557407 TI - The effects of human immunodeficiency virus infection on the expression of the drug efflux proteins P-glycoprotein and breast cancer resistance protein in a human intestine model. AB - OBJECTIVES: In human immunodeficiency virus (HIV) infection, decreased penetration of antiretroviral drugs is postulated to contribute to HIV persistence within lymphoid-rich regions of the gastrointestinal (GI) tract. However, mechanistic explanations for this phenomenon remain unclear. Specifically, investigations of HIV effects on drug efflux proteins within intestinal models are minimal. METHODS: Using an in-vitro co-culture model of the GI tract, the effects of HIV infection on drug efflux proteins, P-glycoprotein and breast cancer resistance protein (BCRP) were evaluated. The influence of the HIV-1 protein, Tat, and oxidative stress on P-glycoprotein and BCRP was also evaluated. KEY FINDINGS: P-glycoprotein expression demonstrated an HIV-induced upregulation in Caco-2 cells over time for cells grown in co-culture with resting lymphocytes. BCRP overall expression increased with HIV exposure in activated primary human lymphocytes co-cultured with Caco-2 cells. Tat treatment resulted in no significant alterations in P-glycoprotein (43% increase), BCRP expression, or oxidative stress. CONCLUSIONS: HIV exposure within an in-vitro intestinal model resulted in increases in P-glycoprotein and BCRP in a cell-specific manner. Additionally, observed changes were not mediated by Tat. Collectively, these results suggest that alterations in BCRP and P-glycoprotein may contribute, in part, to decreased antiretroviral concentrations within the gut-associated lymphoid tissue of the GI tract in HIV infection. PMID- 25557409 TI - Human trafficking: Role of oral health care providers. AB - Trafficking in human beings is a modern form of slavery and is a well-known phenomenon throughout the European Union and beyond. After drug dealing and the weapons industry, human trafficking is the second largest criminal activity in the world today and it is a growing crime. The aim of governmental and non governmental agencies, which are either directly or indirectly involved in combating trafficking in human beings, is the identification and referral of victims of trafficking and also to encourage self-referrals. Identification is the most important step to provide protection and assistance to victims of trafficking. Victims often have a variety of physical and mental health needs, including psychological trauma, injuries from violence, head and neck trauma, sexually transmitted infections and other gynaecological problems, dental/oral problems and have poor nutrition. The author's experience in the field of community dentistry in presented within. Volunteer dental services are offered to non-European Union patients held in a centre for asylum seekers in Bari (Italy). Dental professionals can, in fact, contribute to the identification, assistance and protection of trafficked persons, as well as offering forensic services to assist the police investigation in order to identify crimes and find the criminal organizations behind them. As for domestic violence and child abuse cases, there are ethical concerns involved in the identification and protection of the trafficked persons, as well as the need for interdisciplinary work and awareness. Adequate training in behavioural science and intercultural learning is paramount in order to avoid misunderstandings and increase sensitivity. PMID- 25557410 TI - An Australian government dental scheme: Doctor-dentist-patient tensions in the triangle. AB - Autonomy of participants is challenged when legislation to provide a public health service is weakly designed and implemented. BACKGROUND: Australia's Chronic Disease Dental Scheme was instigated to provide a government subsidy for private dental treatment for people suffering chronic illness impacting their oral health or vice versa. They were allocated AUD$4250 towards comprehensive treatment over 2 years with their eligibility determined by their general medical doctor. RESEARCH: A qualitative research study was conducted to explore the experiences from the perspectives of the patient, medical and dental practitioner. One of the research outcomes identified a frequently reported level of discomfort in the patient/doctor/dentist triangle. Doctors and dentists reported feeling forced by patients into positions that compromised their autonomy in obeying the intent (if not the law) of the scheme. Additionally, dentists felt under pressure from doctors and patients to provide subsidized treatment to those eligible. In turn, the patients reported difficulties in gaining access to the scheme and in some cases, experiencing full or partially unmet oral health needs. REASON FOR CONFLICT: Poor inter-professional communication and lack of understanding about profession-unique patient-driven pressures, ultimately contributed to dissonance. Ill-defined eligibility guidelines rendered the doctor's ability to gate-keep challenging. OUTCOME OF CONFLICT: Inefficient gate-keeping led to exponential increase in referrals, resulting in unprecedented cost blow-outs. Ensuing government-led audits caused political tensions and contributed to the media-induced vilification of dentists. In December 2013, government financing of dental treatment through Chronic Disease Dental Scheme was discontinued, leaving many Australians without a viable alternative. RECOMMENDATIONS: There is a need for qualitative research methods to help identify social issues that affect public health policy process. In order to succeed, new health policies should respect, consider and attempt to understand the autonomy of key participants, prior to and throughout. PMID- 25557411 TI - Informed consent in community-based oral health research. AB - The ethical principle of respect for persons presents multiple dimensions to stimulate debate around issues related to informed consent for participation, data management, confidentiality and privacy. The informed consent process is built on a continuum involving a comprehensive explanation of the proposed study; and the declaration of consent (the right to withdraw from at anytime from the study without any negative consequences). All research involving human participants carry a certain level of risk (physical or informational) and it is not possible for the researcher to know all the consequences of participation before a study commences. This presentation will focus around the key issues of information, consent' and competence in relation to community-based oral health research and outlines some of debates in the informed consent process. PMID- 25557412 TI - Professional consequence for dentists involved in unethical decision-making in South Africa. AB - The previously gullible and apathetic South African public, generally speaking, is lately becoming increasingly rights-based sophisticated. Patients are no longer accepting inferior quality work and have become more knowledgeable especially regarding the expected skills and professional conduct of dentists. The present study examined archival material as published between 2007 and 2013 of penalties against ethical misconduct. It was found that the majority of ethical transgressions took place in urban settings and the most predominant transgression was charging for services not performed and submitting these claims to medical aids as well as performing sub-optimal interventions. Legally a practitioner who performs such acts may be held liable for the damage or injury suffered by the patient as a consequence of these acts, on the basis of negligence. Penalties imposed by the Health Professions Council of South Africa vary between 5,000 Rand and 15,000 Rand, as well as suspensions of between 9 to 12 months. It is doubtful that transgressors would change their behaviour in the light of the present Continuous Professional Development programmes where attendance is really the only prerequisite and not moral reflection. This study recommends that the Health Professions Council of South Africa need to re evaluate the effectiveness of their ethical training programmes and adapt the model to incorporate more inclusive learning. PMID- 25557413 TI - Limited rights of minors in the Dutch healthcare. AB - In many countries, if not all, the autonomy of minors is limited. Especially in countries with comprehensive legislation in the field of health law the (lack of) autonomy of minors may create challenges. These problems become more complex if the costs of treatment are not paid by the government or covered by insurance. Some challenges are: At what age is a minor able to decide about his health? As not every treatment is the same, how should the system take this into account? The Netherlands has a long history of very comprehensive health care legislation. This legislation includes a section about the treatment of minors that addresses the questions of the conditions in which the autonomy of minors is limited. Though this legislation is limited to the Netherlands other countries face the same challenges. PMID- 25557415 TI - Pd-catalyzed benzylic C-H oxidation of cyclotriveratrylene--product diversity. AB - The inner-rim functionalization of CTV has been examined by employing Pd catalyzed benzylic oxidation. The outcome of the oxidation depends upon the solvent and co-oxidants employed. An interesting array of CTV derivatives has been synthesized with a simple change in the conditions. PMID- 25557414 TI - Can autonomy be limited--an ethical and legal perspective in a South African context? AB - The principle of autonomy acknowledges the positive duty on a health care practitioner to respect the decisions of a patient. The principle of respect for autonomy is codified in the International Bill of Rights, the African Charter, The South African Constitution (108 of 1996) and the Patients' Right Charter. The common notion is to protect a person's liberty, privacy and integrity. Health care practitioners should honour the rights of patients to self-determination or to make their own informed choices. Patients have the right to live their lives by their own beliefs, values and preferences. This implies that a healthcare practitioner should respect the wishes of a patient when a patient makes an autonomous decision. The principle of respect for autonomy takes into consideration a patient's choice based on informed consent and the protection of confidentiality of the patient. Informed consent is a process whereby information is shared with a patient to enable an informed decision. It is therefore important for a patient to be well informed to give effect to the notion of making an informed decision. The relationship between the healthcare practitioner and the patient is based on trust and communication. Full disclosure to a patient will empower a patient to make a true informed decision. It is of particular importance for a health care practitioner to acknowledge and respect the decisions and choice made by a patient so as not to violate a patient's autonomy. Can autonomy be limited? It can, if legally required and duly justified. Section 36 of the South African Constitution (Act 108 of 1996) limits rights in the Bill of Rights by application of a general law. PMID- 25557416 TI - Mal de Meleda in Indonesia: Mutations in the SLURP1 gene appear to be ubiquitous. AB - Mal de Meleda is a rare autosomal recessive genodermatosis caused by mutations in the ARS B (SLURP1) gene, with possible founder effects in the Mediterranean and Adriatic regions. We report an affected individual from Indonesia without known consanguinity in the family, suggesting that SLURP1 gene mutations are ubiquitous. Recognition of the phenotype can be confirmed by genetic testing, thus facilitating genetic counselling. PMID- 25557418 TI - Luminescence enhancement after adding organic salts to nanohybrid under aqueous condition. AB - Lanthanide-based organic-inorganic hybrid materials (LnOIH) are of immense importance for various applications nowadays, while it still remains a significant challenge to achieve high luminescence efficiency in aqueous environment. Herein we present a simple and environmentally friendly two-step strategy to prepare strongly red-light emitting nano-LnOIH by first in situ forming Eu(3+)-beta-dikeonate complexes on Laponite platelets and subsequently increasing the coordination number of the complexes via the modification with a silane-functionalized imidazolium salt, which can fully protect Eu(3+) ions from the water molecule quenching. The mechanism of how the imidazolium salt favors the formation of Eu(3+)-beta-dikeonate complex with large coordination number was elucidated. The result is that the removal of the abundant protons on the Laponite platelets through a mechanism of synergic effect of ion exchange and neutralization drives the formation of Eu(3+)-beta-diketonate complexes with high coordination number. The high efficiency of the resulting luminescent nano-LnOIH in water endows the nanohybrid with good aqueous solution processability and opens the possibility of using them under complicated aqueous conditions for biorelated applications. PMID- 25557417 TI - Gastric emptying scintigraphy results in children are affected by age, anthropometric factors, and study duration. AB - BACKGROUND: A standardized 4-h adult-based gastric emptying scintigraphy (GES) protocol is increasingly being used in children to evaluate for gastroparesis. We sought to determine the effect of age, anthropometrics, and study duration on GES results using this protocol in children. METHODS: Retrospective review of children who underwent a 4-h solid-meal GES study at a tertiary care center. GES results and anthropometric data (e.g., weight, stature, body surface area [BSA]) were systematically captured. KEY RESULTS: Of 216 children, 188 (87%) were able to complete the study meal. Children unable to complete the meal were younger and smaller. In multivariate analysis, only increasing BSA was identified as being positively associated with ability to complete the meal (odds ratio: 19.7; p < 0.001). Of those completing the meal, 48 (26%) had delayed emptying (4-h retention value >10%). These children were significantly younger and smaller than those with normal emptying. In multivariate analysis of those completing the meal, only increasing BSA (odds ratio: 0.26; p = 0.006) was identified as being negatively associated with delayed emptying. There was a progressive increase in the positive predictive value for identification of delayed gastric emptying as the duration of the study increased (0.25, 0.60, and 0.71 at 1, 2, and 3 h, respectively) using the 4-hr value as a comparator. CONCLUSIONS & INFERENCES: Young children have more difficulty completing the GES meal. Childhood gastric retention is affected by age and anthropometric factors, primarily BSA. The standardized 4-h GES protocol may need to take these factors into account in children. PMID- 25557420 TI - Gas-phase infrared spectra of three compounds of astrochemical interest: vinyl, allenyl, and propargyl isocyanides. AB - Isocyanides, isomers of the cyanides detected in the interstellar medium, are also possible components of this medium. The infrared spectra (5000-500 cm(-1) ) of gaseous vinyl isocyanide, allenyl isocyanide, and propargyl isocyanide have been recorded at 0.1 cm(-1) resolution. When prepared on a gram scale to produce a partial pressure of 10 mbar after evaporation in the cell, these three isocyanides, which have previously been reported to be kinetically unstable, do not display any sign of decomposition when recording the spectra. Geometry optimizations and harmonic and anharmonic vibrational frequencies were calculated using the LCCSD(T) method with the cc-pVTZ basis set. Anharmonic frequencies of fundamental, overtone, and combination transitions were calculated using a variational approach implemented in the P Anhar.v2.0 code, to assign the experimental data for each compound. These results improve our knowledge of these under-investigated compounds and pave the way for other physicochemical studies on functionalized isocyanides. PMID- 25557419 TI - Demographic and clinical features of inclusion body myositis in North America. AB - INTRODUCTION: Few studies of the demographics, natural history, and clinical management of inclusion body myositis (IBM) have been performed in a large patient population. To more accurately define these characteristics, we developed and distributed a questionnaire to patients with IBM. METHODS: A cross-sectional, self-reporting survey was conducted. RESULTS: The mean age of the 916 participants was 70.4 years, the male-to-female ratio was 2:1, and the majority reported difficulty with ambulation and activities of daily living. The earliest symptoms included impaired use and weakness of arms and legs. The mean time from first symptoms to diagnosis was 4.7 years. Half reported that IBM was their initial diagnosis. A composite functional index negatively associated with age and disease duration, and positively associated with participation in exercise. CONCLUSIONS: These data are valuable for informing patients how IBM manifestations are expected to impair daily living and indicate that self reporting could be used to establish outcome measures in clinical trials. PMID- 25557421 TI - New alpha-papillomavirus 4 isolate in a verruca vulgaris with multicentric superficial basal cell carcinoma. PMID- 25557422 TI - Fasting but not changes of plasma metabolome during oral glucose tolerance tests improves the diagnosis of severe coronary arterial stenosis. AB - BACKGROUND: Noninvasive stress tests for the diagnosis of significant coronary arterial stenosis requiring intervention are not perfect. We investigated whether plasma metabolome during the oral glucose tolerance test (OGTT) can improve the diagnosis. METHODS: A total of 117 subjects with positive stress test results who received coronary angiography were recruited. After excluding subjects with a history of myocardial infarction and subjects who did not receive OGTT, the 18 subjects without significant stenosis were selected as controls. Another 18 age- and sex-matched subjects with significant stenosis were selected as cases. Plasma metabolome from samples obtained in fasting, 30 and 120 min after OGTT was measured using liquid chromatography combined with time-of-flight mass spectrometry. RESULTS: We found five metabolites which can identify patients with significant stenosis independent to clinical risk factors, including diabetes, hypertension, hypercholesterolaemia, smoking and history of percutaneous coronary intervention (all P < 0.05). The area under the receiver operating characteristic (AUROC) curve of these metabolites was 0.799-0.818 at fasting and 30 min after OGTT. The addition of metabolites to clinical factors increases the AUROC (0.616, 95%CI 0.429-0.803 for model with clinical factors only; 0.824, 95%CI 0.689-0.959 for model with four metabolites and clinical factors). The changes of plasma metabolite levels during OGTT did not significantly improve the diagnostic performance. CONCLUSIONS: Fasting plasma metabolome, but not change of plasma metabolome during OGTT, can improve the diagnosis of significant stenosis in patients with positive noninvasive stress test results. PMID- 25557424 TI - Applying population genetics for authentication of marine fish: the case of saithe (Pollachius virens). AB - The number of fishery products with a quite detailed description of the origin is increasing. This trend is driven by the interest of consumers and the fight against illegal unregulated and unreported fisheries. Unfortunately, there is a lack of methods to prove this information experimentally besides the document based traceability assessments. For marine fish population genetics is a promising strategy, but research is concentrated only on a few species. Saithe is a commercially important fish species, despite the fact that genetic knowledge is scarce regarding the specification of populations. For a comparative study cost- and time-effective strategies were tested: We found RAPD-PCR to be a useful method for low-budget research or prestudies. Adoption of microsatellites from closely related species turned out to be possible with limited success quota. Our results suggest a clustered structure of populations within the Northeast Atlantic, probably overlapping in the northern North Sea. PMID- 25557423 TI - Influence of ligand architecture on oxidation reactions by high-valent nonheme manganese oxo complexes using water as a source of oxygen. AB - Mononuclear nonheme Mn(IV)=O complexes with two isomers of a bispidine ligand have been synthesized and characterized by various spectroscopies and density functional theory (DFT). The Mn(IV)=O complexes show reactivity in oxidation reactions (hydrogen-atom abstraction and sulfoxidation). Interestingly, one of the isomers (L(1) ) is significantly more reactive than the other (L(2) ), while in the corresponding Fe(IV)=O based oxidation reactions the L(2) -based system was previously found to be more reactive than the L(1) -based catalyst. This inversion of reactivities is discussed on the basis of DFT and molecular mechanics (MM) model calculations, which indicate that the order of reactivities are primarily due to a switch of reaction channels (sigma versus pi) and concomitant steric effects. PMID- 25557426 TI - Diet and feeding behaviour of longnosed skate Dipturus oxyrinchus. AB - A total of 255 longnosed skate Dipturus oxyrinchus caught in Sardinian waters (central-western Mediterranean Sea), was analysed with respect to fish total length (LT ), season and depth, in order to provide information on diet and feeding behaviour. Specimens ranging from 93 to 1153 mm LT , were collected at depths between 121 and 671 m, during experimental trawl surveys carried out from 2005 to 2010. The diet comprised crustaceans [prey specific index of relative importance (%IPSRI ) = 72.69], teleosts (%IPSRI = 10.28) and molluscs (%IPSRI = 10.94). Levins' index (Bi ) showed a narrow niche breadth (Bi = 0.35). The mean +/- s.e. trophic level (TL ) was 3.63 +/- 0.50. The analysis showed major ontogenetic changes in the feeding behaviour. Early life stages were characterized by a benthic diet, which changed to benthopelagic during growth. Mysids, particularly Lophogaster typicus (%IPSRI = 34.51), were the main prey items of immature individuals, replaced by euphausiids, mainly Meganyctiphanes norvegica (%IPSRI = 13.19), in maturing fish. Crustaceans became less important in mature specimens, being replaced by molluscs (%IPSRI = 28.99) and teleosts (%IPSRI = 24.56). A concomitant increase of the TL was recorded (mean +/- s.e. = 3.41 +/- 0.44, 3.75 +/- 0.54 and 4.28 +/- 0.61 for immature, maturing and mature individuals). These feeding patterns ensured low levels of intraspecific competition. This study provides new information about the role that the D. oxyrinchus plays in the marine food chain and data now essential to formulate new and effective management plans for this species. PMID- 25557425 TI - Metacognitive reflective and insight therapy for people in early phase of a schizophrenia spectrum disorder. AB - Schizophrenia often involves a loss of metacognitive capacity, the ability to form complex and integrated representations of self and others. Independent of symptoms and neurocognition, deficits in synthetic metacognition are related to difficulties of engaging in goal-directed activities in social and vocational settings. Within this backdrop, we provide a case report of the effects of Metacognitive Reflective Insight Therapy (MERIT) that assisted a patient suffering from first episode schizophrenia during 2 years of individual psychotherapy. A total of 8 elements of MERIT that stimulate and promote metacognitive capacity are presented. As illustrated in this report, these procedures helped the patient move from a state in which he had virtually no complex ideas about himself or others to one in which he had developed integrated and realistic ideas about his own identity and the identity of others. He then could use these representations to understand and effectively respond to life challenges. PMID- 25557427 TI - Ovarian cavity fluid of the viviparous surfperch Neoditrema ransonnetii suppresses the spontaneous cytotoxic activity of head-kidney leucocytes against xenogeneic targets. AB - In this study, the effect of ovarian cavity fluid (OCF) from a surfperch Neoditrema ransonnetii on the cytotoxic activity of leucocytes was investigated. In an assay targeting RTG-2, a cell line derived from rainbow trout Oncorhynchus mykiss gonads, leucocytes from both the spleen and head kidney showed spontaneous killing activity. Pre-incubation with OCF significantly suppressed the cytotoxic activity of head-kidney leucocytes towards RTG-2. This suppressive activity was due to the presence of low molecular-mass materials. These results suggest that OCF plays significant roles in pregnancy by its ability to modulate cytotoxicity with maternal leucocytes. PMID- 25557428 TI - Measures of immune system status in young-of-the-year winter flounder Pseudopleuronectes americanus. AB - The immune status of young-of-the-year (YOY) winter flounder Pseudopleuronectes americanus was evaluated in fish collected from six areas around Long Island, NY, U.S.A. representing more urban areas with high population density in the west, to less densely populated more rural areas in to the east. Gene expression markers for innate immunity (pleurocidin) and contaminant exposure (cytochrome P4501A; cyp1a) were measured in liver and fin of fish collected at each site. Expression of pleurocidin was significantly higher in fin than liver, but was highly variable among individuals. Some statistically significant differences in pleurocidin expression among sites were observed, although elevated levels were not associated with degree of urbanization. Expression was related in part to fish size: a positive correlation between expression and total length (LT ) of fish was observed with the largest LT class (>125 mm) exhibiting significantly elevated pleurocidin expression as compared with fish in the smaller LT class. This indicates that immune competency may increase with age. No site-specific differences in cyp1a expression were observed. These data suggest that exposure to aromatic hydrocarbon contaminants is fairly widespread throughout the study area and that any differences in pleurocidin expression in YOY P. americanus are probably due to other factors. Antimicrobial activity was also measured as a functional indicator of immune response. Activity was highly variable, showing no significant site-specific differences, and no significant correlation to pleurocidin expression. The lack of correlation between pleurocidin expression and antimicrobial activity indicates that other antimicrobial peptides may be active against the bacteria tested or that other factors are influencing antimicrobial activity. This is the first quantitative evaluation of pleurocidin expression in YOY P. americanus from an urban area. Further work is needed to characterize factors controlling pleurocidin expression, as well as other indicators of immune response in young fish. PMID- 25557429 TI - Spawning aggregations of three protogynous groupers in the southern Gulf of Mexico. AB - Spawning aggregations of red hind Epinephelus guttatus, tiger grouper Mycteroperca tigris and yellowfin grouper Mycteroperca venenosa were identified at two coral-reef systems: Arrecife Alacranes (emergent bank reef) and Bajos del Norte (submerged bank reef) on the continental shelf of the Yucatan Peninsula (Campeche Bank), Mexico. At both reefs, E. guttatus forms large spawning aggregations between February and March. At Bajos del Norte, M. tigris reproduces in a small, low-density aggregation in May, while M. venenosa aggregates at high densities for spawning between March and May. Multi-species use of an aggregation site by E. guttatus and M. venenosa was observed at Bajos del Norte. The identified spawning aggregations are apparently stable in location over time, and all three species were commonly observed to spawn within 1 week following the full moon. Development and survival of the larvae spawned in these aggregations are probably aided by a seasonal (spring-summer) upwelling in the north-east Campeche Bank. A permanent area closure at Bajos del Norte, currently outside any specific fisheries management area or regulations, would provide protection needed for the spawning aggregations of these three species. PMID- 25557430 TI - Hypoxic refuges, predator-prey interactions and habitat selection by fishes. AB - Localized hypoxic habitats were created in Delta Marsh, Manitoba, Canada to determine the potential of regions of moderate hypoxia to act as refuges for forage fishes from piscine predators. Minnow traps and giving-up density (GUD) plates (plexiglas plates covered with trout crumble and fine gravel) were used to assess habitat use and perceived habitat quality for forage fishes, respectively, while passive integrated transponder tags provided data on habitat use by predator species to assess the level of predation risk. Data were collected both before and after a hypoxia manipulation (2-3 mg l(-1) dissolved oxygen, DO) to create a before-after control-effect style experiment. Fathead minnows Pimephales promelas were more abundant and consumed more food from GUD plates in hypoxic bays after the DO manipulation, indicating hypoxic locations were perceived as higher quality, lower-risk habitats. The frequency of predator visits was not consistently affected. The duration of visits, and therefore the total time spent in these habitats, however, was significantly shorter. These predator data, combined with the prey information, are consistent with the hypothesis that hypoxic regions function as predator refuges. The refuge effect is not the result of predator exclusion, however; instead predators are rendered less capable of foraging and pose less of a threat in hypoxic locations. PMID- 25557431 TI - Age, growth and maturity of the pelagic thresher Alopias pelagicus and the scalloped hammerhead Sphyrna lewini. AB - Indonesia has the greatest reported chondrichthyan catches worldwide, with c.110,000 t caught annually. The pelagic thresher (Alopias pelagicus) and scalloped hammerhead (Sphryna lewini) together comprise about 25% of the total catches of sharks landed in Indonesia. Age and growth parameters were estimated for A. pelagicus and S. lewini from growth-band counts of thin-cut vertebral sections. Alopias pelagicus (n = 158) and S. lewini (n = 157) vertebrae were collected from three Indonesian fish markets over a 5 year period. A multi-model analysis was used to estimate growth parameters for both species. The models of best fit for males and females for A. pelagicus was the three-parameter logistic (Linfinity = 3169 mm LT , k = 0.2) and the two-parameter von Bertalanffy models (Linfinity = 3281 mm LT , k = 0.12). Age at maturity was calculated to be 10.4 and 13.2 years for males and females, respectively, and these are the oldest estimated for this species. The samples of S. lewini were heavily biased towards females, and the model of best fit for males and females was the three-parameter Gompertz (Linfinity = 2598 mm LT , k = 0.15) and the two-parameter Gompertz (Linfinity = 2896 mm LT , k= 0.16). Age at maturity was calculated to be 8.9 and 13.2 years for males and females, respectively. Although numerous age and growth studies have previously been undertaken on S. lewini, few studies have been able to obtain adequate samples from all components of the population because adult females, adult males and juveniles often reside in different areas. For the first time, sex bias in this study was towards sexually mature females, which are commonly lacking in previous biological studies on S. lewini. Additionally, some of the oldest aged specimens and highest age at maturity for both species were observed in this study. Both species exhibit slow rates of growth and late age at maturity, highlighting the need for a re-assessment of the relative resilience of these two globally threatened sharks at current high levels of fishing mortality throughout the eastern Indian Ocean. PMID- 25557432 TI - Does the abundance of girellids and kyphosids correlate with cover of the palatable green algae, Ulva spp.? A test on temperate rocky intertidal reefs. AB - This study assessed whether the abundance of girellids and kyphosids was related to cover of the palatable green algae, Ulva australis and Ulva compressa, on rocky intertidal reefs in Jervis Bay, New South Wales, Australia. No relationship was found between Ulva spp. cover and abundance of Girella tricuspidata, Girella elevata and Kyphosus sydneyanus during a period of relatively low Ulva spp. cover (i.e. February 2011 to March 2011), but during a period of significantly higher Ulva spp. cover (i.e. October 2011 to November 2011) there was a strong correlation between Ulva spp. cover and G. tricuspidata abundance. Spatial analysis indicated that the abundance of G. tricuspidata was consistent across time, suggesting G. tricuspidata were not moving between reefs in response to variation in Ulva spp. cover between periods but rather that large schools of G. tricuspidata resided on reefs that had relatively higher Ulva spp. cover at certain times of the year. PMID- 25557433 TI - Squamate hatchling size and the evolutionary causes of negative offspring size allometry. AB - Although fecundity selection is ubiquitous, in an overwhelming majority of animal lineages, small species produce smaller number of offspring per clutch. In this context, egg, hatchling and neonate sizes are absolutely larger, but smaller relative to adult body size in larger species. The evolutionary causes of this widespread phenomenon are not fully explored. The negative offspring size allometry can result from processes limiting maximal egg/offspring size forcing larger species to produce relatively smaller offspring ('upper limit'), or from a limit on minimal egg/offspring size forcing smaller species to produce relatively larger offspring ('lower limit'). Several reptile lineages have invariant clutch sizes, where females always lay either one or two eggs per clutch. These lineages offer an interesting perspective on the general evolutionary forces driving negative offspring size allometry, because an important selective factor, fecundity selection in a single clutch, is eliminated here. Under the upper limit hypotheses, large offspring should be selected against in lineages with invariant clutch sizes as well, and these lineages should therefore exhibit the same, or shallower, offspring size allometry as lineages with variable clutch size. On the other hand, the lower limit hypotheses would allow lineages with invariant clutch sizes to have steeper offspring size allometries. Using an extensive data set on the hatchling and female sizes of > 1800 species of squamates, we document that negative offspring size allometry is widespread in lizards and snakes with variable clutch sizes and that some lineages with invariant clutch sizes have unusually steep offspring size allometries. These findings suggest that the negative offspring size allometry is driven by a constraint on minimal offspring size, which scales with a negative allometry. PMID- 25557434 TI - Tumor thickness as a prognostic factor in extramammary Paget's disease. AB - Extramammary Paget's disease (EMPD) is a rare tumor and a widely accepted classification system specific for the disease has not been established. To elucidate prognostic factors of EMPD, we conducted a retrospective review of 145 patients with 155 EMPD lesions and investigated clinicopathological factors using univariate and multivariate analyses. We also explored tumor thickness and metastatic lymph nodes using detection analysis to determine cut-off points for survival. All patients were Japanese (88 men and 57 women), with EMPD in the genital (82.8%), perianal (3.4%) and axillary regions (1.4%). In the remaining cases (12.4%), there were lesions at two or more regions. Univariate analysis revealed the following prognostic factors: perianal location, presence of nodules, invasion depth, tumor thickness, number of metastatic nodes and serum carcinoembryonic antigen level. Both tumor thickness and perianal location retained statistical significance in multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 1.12-1.72; P = 0.0024; hazard ratio, 50.72; 95% confidence interval, 4.20-612.63; P = 0.0020; respectively). The signal detection analysis indicated tumor thickness of more than 3 mm and three or more metastatic lymph nodes as cut-off points for survival. In conclusion, tumor thickness and the number of metastatic lymph nodes closely correlated with patient outcome and these factors could be suitable for the tumor and node classification. PMID- 25557435 TI - H1 -Antihistamines and itch in atopic dermatitis. PMID- 25557436 TI - Calmodulin mutations causing catecholaminergic polymorphic ventricular tachycardia confer opposing functional and biophysical molecular changes. AB - Calmodulin (CaM) is the central mediator of intracellular Ca(2+) signalling in cardiomyocytes, where it conveys the intricate Ca(2+) transients to the proteins controlling cardiac contraction. We recently linked two separate mutations in CaM (N53I and N97S) to dominantly inherited catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmic disorder in which exercise or acute emotion can lead to syncope and sudden cardiac death. Given the ubiquitous presence of CaM in all eukaryote cells, it is particular intriguing that carriers of either mutation show no additional symptoms. Here, we investigated the effects of the CaM CPVT mutations in a zebrafish animal model. Three-day-old embryos injected with either CaM mRNA showed no detectable pathologies or developmental abnormalities. However, embryos injected with CPVT CaM mRNA displayed increased heart rate compared to wild-type CaM mRNA under beta-adrenergic stimulation, demonstrating a conserved dominant cardiac specific effect between zebrafish and human carriers of these mutations. Motivated by the highly similar physiological phenotypes, we compared the effects of the N53I and N97S mutations on the biophysical and functional properties of CaM. Surprisingly, the mutations have opposing effects on CaM C-lobe Ca(2+) binding affinity and kinetics, and changes to the CaM N-lobe Ca(2+) binding are minor and specific to the N53I mutation. Furthermore, both mutations induce differential perturbations to structure and stability towards unfolding. Our results suggest different molecular disease mechanisms for the CPVT (N53I and N97S mutations) and strongly support that cardiac contraction is the physiological process most sensitive to CaM integrity. PMID- 25557437 TI - Does phase 1 trial enrollment preclude quality end-of-life care? Phase 1 trial enrollment and end-of-life care characteristics in children with cancer. AB - BACKGROUND: End-of-life care (EOLC) discussions and treatment-related decisions, including phase 1 trial enrollment, in patients with incurable disease are complex and can influence the quality of EOLC received. The current study was conducted in pediatric oncology patients to determine whether end-of-life characteristics differed between those who were and were not enrolled in a phase 1 trial. METHODS: The authors reviewed the medical records of 380 pediatric oncology patients (aged <22 years at the time of death) who died during a 3.5 year period. Of these, 103 patients with hematologic malignancies were excluded. A total of 277 patients with a diagnosis of a brain tumor or other solid tumor malignancy were divided into 2 groups based on phase 1 trial enrollment: a phase 1 cohort (PIC; 120 patients) and a non-phase 1 cohort (NPIC; 157 patients). The EOLC characteristics of these 2 cohorts were compared using regression analysis and chi-square testing. RESULTS: A comparison of patients in the PIC and NPIC revealed no significant differences in either demographic characteristics (including sex, race, religious affiliation, referral origin, diagnosis, or age at diagnosis, with the exception of age at the time of death [P =.03]) or in EOLC indices (such as use or timing of do not attempt resuscitation orders, hospice use or length of stay, forgoing life-sustaining therapies, location of death, time from first EOLC discussion to death, and total number of EOLC discussions). CONCLUSIONS: The results of the current study of a large cohort of deceased pediatric cancer patients indicate that enrollment on a phase 1 trial does not affect EOLC characteristics, suggesting that quality EOLC can be delivered regardless of phase 1 trial participation. PMID- 25557438 TI - Life is physics and chemistry and communication. AB - Manfred Eigen extended Erwin Schroedinger's concept of "life is physics and chemistry" through the introduction of information theory and cybernetic systems theory into "life is physics and chemistry and information." Based on this assumption, Eigen developed the concepts of quasispecies and hypercycles, which have been dominant in molecular biology and virology ever since. He insisted that the genetic code is not just used metaphorically: it represents a real natural language. However, the basics of scientific knowledge changed dramatically within the second half of the 20th century. Unfortunately, Eigen ignored the results of the philosophy of science discourse on essential features of natural languages and codes: a natural language or code emerges from populations of living agents that communicate. This contribution will look at some of the highlights of this historical development and the results relevant for biological theories about life. PMID- 25557439 TI - Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses. AB - BACKGROUND: The gangliosidoses (Tay-Sachs disease, Sandhoff disease, and GM1 gangliosidosis) are progressive neurodegenerative diseases caused by lysosomal enzyme activity deficiencies and consequent accumulation of gangliosides in the central nervous system (CNS). The infantile forms are distinguished from the juvenile forms by age of onset, rate of disease progression, and age of death. There are no approved treatments for the gangliosidoses. In search of potential biomarkers of disease, we quantified 188 analytes in CSF and serum from living human patients with longitudinal (serial) measurements. Notably, several associated with inflammation were elevated in the CSF of infantile gangliosidosis patients, and less so in more slowly progressing forms of juvenile gangliosidosis, but not in MPS disease. Thirteen CSF and two serum biomarker candidates were identified. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1alpha, MIP-1beta, and TNFR2. Correspondence of abnormal elevation with other variables of disease-i.e., severity of clinical phenotype, differentiation from changes in serum, and lack of abnormality in other neurodegenerative lysosomal diseases-identifies these analytes as biomarkers of neuropathology specific to the gangliosidosis diseases. PMID- 25557441 TI - Rapid divergence and high diversity of miRNAs and miRNA targets in the Camelineae. AB - MicroRNAs (miRNAs) are short RNAs involved in gene regulation through translational inhibition and transcript cleavage. After processing from imperfect fold-back structures, miRNAs are incorporated into RNA-induced silencing complexes (RISCs) before targeting transcripts with varying degrees of complementarity. Some miRNAs are evolutionarily deep-rooted, and sequence complementarity with their targets is maintained through purifying selection. Both Arabidopsis and Capsella belong to the tribe Camelineae in the Brassicaceae, with Capsella rubella serving as an outgroup to the genus Arabidopsis. The genome sequence of C. rubella has recently been released, which allows characterization of its miRNA complement in comparison with Arabidopsis thaliana and Arabidopsis lyrata. Through next-generation sequencing, we identify high-confidence miRNA candidates specific to the C. rubella lineage. Only a few lineage-specific miRNAs have been studied for evolutionary constraints, and there have been no systematic studies of miRNA target diversity within or divergence between closely related plant species. Therefore we contrast sequence variation in miRNAs and their targets within A. thaliana, and between A. thaliana, A. lyrata and C. rubella. We document a surprising amount of small-scale variation in miRNA-target pairs, where many miRNAs are predicted to have species-specific targets in addition to ones that are shared between species. Our results emphasize that the transitive nature of many miRNA-target pairs can be observed even on a relatively short evolutionary time-scale, with non-random occurrences of differences in miRNAs and their complements in the miRNA precursors, the miRNA* sequences. PMID- 25557443 TI - [Should hyperthyroidism in pregnancy be treated and if so with what medicine?]. PMID- 25557442 TI - Pouch-related fistula and intraoperative tricks to prevent it. PMID- 25557444 TI - [What are the causes of recurrent abdominal pain?]. PMID- 25557445 TI - [Induction of labor for post-term pregnancy saves lives]. PMID- 25557446 TI - [A three-year old girl with bruises on several places on the body]. PMID- 25557447 TI - [Spontaneous cerebrospinal fluid leak may cause intracranial hypotension]. AB - Spontaneous intracranial hypotension (SIH) is often misinterpreted as migraine or tension headache. This type of headache is, however, orthostatic and resolves in supine position. CT scan/MRI of the brain has characteristic findings, enhancement of the pachymeninges and bilateral hygroma. An extreme situation of a 70-year-old woman with sagging midbrain is described in this case report. Although this type of headache may be caused by a dural fistula with spinal fluid leak it is not necessary to locate the lesion with myelografi/MR. Timely treatment with an epidural blood patch at any lumbal level could prevent potentially life-threatening complications and the headache resolved within hours/few days. PMID- 25557448 TI - [Chronic exertional compartment syndrome in the lower leg]. AB - Chronic exertional compartment syndrome (CECS) commonly occurs in young adult runners. The mechanism of pain is unknown. CECS is a clinical diagnosis and is confirmed by intracompartmental pressure testing (IPT). The evidence-based guidance for IPT is sparse. Instead of Pedowitz et al's criteria we recommend one minute after pain triggered exercise IPT >= 36 mmHg as diagnostic value. At the moment fasciotomy is the treatment of choice for athletes who would like to maintain the same level of activity, but injection with botulinum toxin type A could be a new useful alternative. PMID- 25557449 TI - [Frostbite injuries causing compromised airway after inhalation of propane]. AB - We describe a case report of a 23-year-old man with acute pharyngeal injuries due to frostbite subsequent to inhalation of propane. He was fiber-optically intubated on admission to hospital since his airways were considered acutely compromised. He was subsequently kept intubated for 11 days due to persistent pharyngeal oedema and frostbite injuries. The latter is caused by low temperature of propane upon release from a pressurized container. Injuries caused by frostbite often gradually progress and thus caution should be exerted in regards to airway management. PMID- 25557450 TI - [Crowdsourcing is a new method for generating data for scientific research]. AB - Crowdsourcing (CS) is a rapidly emerging method in scientific research. In CS, large groups of people generate new data or try to find solutions to specific research questions, mainly by online collaboration. Examples of the current use of CS in medicine include disease surveillance as well as diagnosis of rare conditions. CS techniques are rapid, low cost and geographically independent - traits lacking in traditional types of study design. However, CS as a method has not yet found its place in the evidence rating scale and a standard for conducting and reporting CS studies does not yet exist. PMID- 25557451 TI - [Post-transplant lymphoproliferative disorder is a rare cause of spinal cord compression]. AB - A 74-year-old man presented with sensory deficits and lower limb weakness four years after a renal transplant. MRI showed an intramedullary mass at the T5 level. Following surgical excision the diagnosis post-transplant lymphoproliferative disorder (PTLD) was made. Although the frequency of PTLD is low in kidney transplant recipients (<= 1%), it is an important differential diagnosis in a patient with new-onset neurological deficits following solid-organ transplantation. PMID- 25557452 TI - A prospective study of mastectomy patients with and without delayed breast reconstruction: long-term psychosocial functioning in the breast cancer survivorship period. AB - INTRODUCTION: For women who have mastectomy, breast reconstruction is an option which may improve psychosocial functioning. The purpose of this study was to evaluate changes in psychosocial functioning over a long follow-up period after mastectomy, specifically examining the differences between those with mastectomy alone and those who underwent postmastectomy delayed breast reconstruction (DBR). METHODS: This was a prospective longitudinal survey study of women with mastectomy in which a repeated measures design was used to compare psychosocial function scores over 3 timepoints: 1) pre-mastectomy; 2) one year post mastectomy; and 3) long-term post-mastectomy (mean 6.3 years). In addition, psychosocial functioning was compared between the mastectomy alone group and the group who elected for DBR. RESULTS: 67 women who completed questionnaires at all three time points were included. The long-term follow-up time post-mastectomy was 75.2 months (6.3 years). Twenty-eight women (41.8%) underwent DBR in the study period. For the entire cohort, between one-year and long-term post-mastectomy, there were significant improvements in scores for body concerns (P = 0.03), cancer-related distress (P = 0.01), and total distress (P = 0.04). At long-term follow-up, women with DBR had significantly higher levels of total distress (P = 0.01), obsessiveness (P = 0.03), and cancer-related distress (P = 0.02) compared to those with mastectomy alone. There were no differences in quality of life between the two groups at any time point. CONCLUSIONS: Psychosocial functioning improves over time in patients treated with mastectomy in the long-term breast cancer survivorship period, which may be related to the effect of time post treatment, rather than an effect of choice for or against DBR. PMID- 25557453 TI - Donor organ distribution according to urgency of need or outcome maximization in liver transplantation. A questionnaire survey among patients and medical staff. AB - Low donor rates in Germany cause a trade-off between equity in the distribution of chances for survival and efficiency in dead-donor liver transplantation. Public attitudes concerning the principles that should govern organ allocation are of interest. We performed a questionnaire-based study among patients and medical staff. 1826 of 2200 questionnaires were returned. 79.2%, 67.1%, and 24.4% patients wanted to accept liver transplantation for themselves if expected 1-year survival was 80%, 50%, and 20%, respectively. 57.7% affirmed 'averting immediate risk of death (urgency) is a more important criterion for organ allocation than expected long-term success' (P = 0.002 against indifference). The majority of medical staff took the opposite decision. 20.7%, 8.8%, and 21.2% of patients chose 50%, 33%, and 10% as lowest acceptable 5-year survival, respectively. 49.3% accepted a survival of <10%. Variables associated with preferring urgency over efficiency as criterion for allocation were age (OR 1.009; 95% CI: 1.000-1.017; female gender (OR 1.331; 95%CI 0.992-1.784); higher education (OR 0.881; 95%CI 0.801-0.969); and refusal of transplantation for oneself (OR 1.719; 95%CI 1.272 2.324). Most patients supported urgency-based liver allocation. Patients and medical staff would accept lower survival rates than the transplant community. PMID- 25557454 TI - Neural tube dysraphism: review of cutaneous markers and imaging. AB - Neural tube dysraphisms are congenital anomalies resulting from impaired formation of structures along the craniospinal axis during central nervous system development. When these malformations are large or lack a skin covering, they are easily recognized, whereas smaller or skin-covered malformations may not be readily apparent. Due to the intimate embryologic origin of the skin and nervous system, these occult malformations are often heralded by associated cutaneous abnormalities. In this article, the common clinical presentations and cutaneous markers of craniospinal dysraphism are reviewed, along with the recommended imaging modalities. PMID- 25557455 TI - Morphological and functional response to injury to the external urethral sphincter - similarities and differences between male and female rats. AB - AIMS: The objective of this study was to evaluate the similarities and differences of the urethral morphological and functional changes following external urethral sphincter EUS injury in male and female rats. METHODS: 30 female and 30 male age-matched Wistar rats were used in the experiments. Half of them underwent electrocauterization of the surrounding tissues lateral to the urethra at the level of the (EUS) and the others, a sham operation. At 2, 6, and 16 weeks after surgeries they underwent anesthetized cystometry, measurement of leak point pressure (LPP) and their urethras were harvested for morphological analyses. RESULTS: There were no differences in cystometric parameters between sex-time-matched animals, ensuring normal bladder function in the manipulated animals. The mean LPP in male and female rats was lower compared with sham animals. Age-time-matched sham operated male rats exhibited a higher LPP compared with female rats. The reduction in LPP comparing electrocauterized and sham time matched animals was more pronounced in male rats than in female rats. Electrocauterization produced urethral collagen deposition and nerve damage in both male and female animals. Muscle atrophy and disruption also occurred, being more evident in female rats. CONCLUSIONS: The urethras of male and female rats exhibited a similar morphological and functional response to electrocauterization. The time-course evaluation revealed that the male animal model is as reliable, reproducible and long-lasting as the female model. Intact males had a higher LPP than female rats and the nerve injury led to a more drastic impairment of this mechanism. PMID- 25557456 TI - Dynamics and evolution of highly pathogenic porcine reproductive and respiratory syndrome virus following its introduction into a herd concurrently infected with both types 1 and 2. AB - Since its first emergence in Thailand in late 2010, highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has caused sporadic outbreaks on Thai swine farms. The objective of this study was to investigate the dynamics and evolution of PRRSV in a herd experiencing an HP-PRRSV outbreak. Following its introduction, HP-PRRSV caused severe outbreaks and subsequently established persistent infection in the herd, resulting in the emergence of a novel cluster of type 2 (North American, NA) isolates. HP-PRRSV co-existed with type 1 (European, EU) isolates without influencing their development. In contrast, HP-PRRSV influenced the evolution of the type 2 (NA) isolates by increasing diversity through the addition of a novel cluster and influencing the evolution of other viral clusters previously existing in the herd. Recombination between the endemic and emerging isolates was observed. The recombinants, however, disappeared and were not able to survive in the herd. The results of this study suggest that the introduction of HP-PRRSV to a herd results in an increased diversity of genetically related isolates and persistent HP-PRRSV infection. PMID- 25557457 TI - Discontinued anxiolytic drugs (2009 - 2014). AB - INTRODUCTION: Anxiety is a complex psychiatric disorder with an unknown aetiology and involving several neurotransmitter systems. These constraints have meant that researchers have looked to develop drugs, which target a variety of molecular targets, with the aim of creating safer and more effective anxiolytic drugs. Apart from the 'traditional' GABAergic and serotonergic systems, the endocannabinoid, opioidergic, glutamatergic, neurokinin, and even cholinergic systems have been (and are being) considered as preferred targets for prospective new drugs. AREAS COVERED: This review presents candidate drugs that were investigated for the treatment of anxiety-spectrum disorders and then discontinued between the 2009 and 2014 period. EXPERT OPINION: Despite the large variety of molecular targets, and the considerable financial and R&D resources dedicated to finding treatment solutions for anxiety-spectrum disorders, a great number of candidates have failed to reach the market. Indeed, there is still an unmet need for more effective anxiolytics that give patients a better quality of life. Although there are inherent problems with psychiatric drug development, it is thought that repurposed drugs may provide some benefit in the future. PMID- 25557458 TI - From strength to strength: a new journal launched this year. PMID- 25557460 TI - Pillar[5,6]arene-functionalized silicon dioxide: synthesis, characterization, and adsorption of herbicide. AB - A layer of synthetic supramolecular macrocycles, that is, perhydroxyl pillar[5]arene and perhydroxyl-pillar[6]arene, has been covalently attached to hydrophilic silica supports through Si-O-Si linkages with a coverage of up to 250 MUmol pillar[5,6]arenes/g to form novel absorbent hybrid materials. Their adsorption toward a typical herbicide, namely, paraquat, from its aqueous solution has been investigated. Kinetic studies disclosed that paraquat adsorption fits a first-order kinetic model. Equilibrium adsorption data could be explained very well by the Langmuir equation. The pillar[6]arene-modified materials showed more obvious adsorption as compared with pillar[5]arene-modified ones and the saturation adsorption quantity reached about 0.20 mmol of paraquat per gram of materials. The entire process of adsorption was endothermic, and significantly an elevated temperature led to an increase in the adsorption quantity. This new type of pillarene-based adsorbent materials can be considered as a potential adsorbent for harmful substances removal from wastewaters. PMID- 25557459 TI - Increasing survival of the graft: the way forward in ovarian tissue transplantation. PMID- 25557461 TI - Bioactive, nanostructured Si-substituted hydroxyapatite coatings on titanium prepared by pulsed laser deposition. AB - AIMS: The aim of this work was to deposit silicon-substituted hydroxyapatite (Si HAp) coatings on titanium for biomedical applications, since it is known that Si HAp is able to promote osteoblastic cells activity, resulting in the enhanced bone ingrowth. MATERIALS AND METHODS: Pulsed laser deposition (PLD) method was used for coatings preparation. For depositions, Si-HAp targets (1.4 wt % of Si), made up from nanopowders synthesized by wet method, were used. RESULTS: Microstructural and mechanical properties of the produced coatings, as a function of substrate temperature, were investigated by scanning electron and atomic force microscopies, X-ray diffraction, Fourier transform infrared spectroscopy, and Vickers microhardness. In the temperature range of 400-600 degrees C, 1.4-1.5 um thick Si-HAp films, presenting composition similar to that of the used target, were deposited. The prepared coatings were dense, crystalline, and nanostructured, characterized by nanotopography of surface and enhanced hardness. Whereas the substrate temperature of 750 degrees C was too high and led to the HAp decomposition. Moreover, the bioactivity of coatings was evaluated by in vitro tests in an osteoblastic/osteoclastic culture medium (alpha-Modified Eagle's Medium). CONCLUSIONS: The prepared bioactive Si-HAp coatings could be considered for applications in orthopedics and dentistry to improve the osteointegration of bone implants. PMID- 25557462 TI - Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect. AB - Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes. PMID- 25557464 TI - The TOC159 mutant of Arabidopsis thaliana accumulates altered levels of saturated and polyunsaturated fatty acids. AB - We evaluated whether the TOC159 mutant of Arabidopsis called plastid protein import 2-2 (ppi2-2) accumulates normal levels of fatty acids, and transcripts of fatty acid desaturases and galactolipid synthesis enzymes. The ppi2-2 mutant accumulates decreased pigments and total fatty acid content. The MGD1 gene was downregulated and the mutant accumulates decreased levels of monogalactosyldiacylglycerol (MGDG) and 16:3, which suggests that the prokaryotic pathway was impaired in the mutant. The HY5 gene, which encodes long hypocotyl5 transcription factor, was upregulated in the mutant. The DGD1 gene, an HY5 target was marginally increased and the mutant accumulates digalactosyldiacylglycerol at the control level. The mutant had increased expression of 3-ketoacyl-ACP synthase II gene, which encodes a plastid enzyme that elongates 16:0 to 18:0. Interestingly, glycerolipids in the mutant accumulate increased levels of 18:0. A gene that encodes stearoyl-ACP desaturase (SAD) was expressed at the control level and 18:1 was increased, which suggest that SAD may be strongly regulated at the posttranscriptional level. The molar ratio of MGDG to bilayer forming plastid lipids was decreased in the cold-acclimated wild type but not in the ppi2-2 mutant. This indicates that the mutant was unresponsive to cold-stress, and is consistent with increased levels of 18:0, and decreased 16:3 and 18:3 in the ppi2 2 mutant. Overall, these data indicate that a defective Toc159 receptor impaired the synthesis of MGDG, and affected desaturation of 16 and 18-carbon fatty acids. We conclude that expression of the MGD1 gene and synthesis of MGDG are tightly linked to plastid biogenesis. PMID- 25557465 TI - Next-generation sequencing and the cytopathologist. PMID- 25557463 TI - Autophagic vacuolar pathology in desminopathies. AB - Autophagic vacuolar myopathies are an emerging group of muscle diseases with common pathologic features. These include autophagic vacuoles containing both lysosomal and autophagosomal proteins sometimes lined with sarcolemmal proteins such as dystrophin. These features have been most clearly described in patients with Danon's disease due to LAMP2 deficiency and X-linked myopathy with excessive autophagy (XMEA) due to mutations in VMA21. Disruptions of these proteins lead to lysosomal dysfunction and subsequent autophagic vacuolar pathology. We performed whole exome sequencing on two families with autosomal dominantly inherited myopathies with autophagic vacuolar pathology and surprisingly identified a p.R454W tail domain mutation and a novel p.S6W head domain mutation in desmin, DES. In addition, re-evaluation of muscle tissue from another family with a novel p.I402N missense DES mutation also identified autophagic vacuoles. We suggest that autophagic vacuoles may be an underappreciated pathology present in desminopathy patient muscle. Moreover, autophagic vacuolar pathology can be due to genetic etiologies unrelated to primary defects in the lysosomes or autophagic machinery. Specifically, cytoskeletal derangement and the accumulation of aggregated proteins such as desmin may activate the autophagic system leading to the pathologic features of an autophagic vacuolar myopathy. PMID- 25557466 TI - Myocardial iron load and fibrosis in long term survivors of childhood leukemia. AB - BACKGROUND: We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function. PROCEDURE: Fifty-eight (33 males) adult survivors, aged 24.5 +/- 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 +/- 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging. RESULTS: None of the survivors had significant myocardial iron overload (T2*<20 msec). The prevalence of LV and RV fibrosis was 9% (5/58) and 38% (22/58), respectively. Left ventricular EF was subnormal (EF 45-<55%) in 9% (5/58), while RV EF was abnormal (EF <45%) in 12% (7/58) and subnormal in 34% (20/58) of survivors. Patients with LV fibrosis had significantly lower mitral annular early diastolic velocity (P = 0.01) and smaller LV end-systolic volume (P = 0.02), while those with RV fibrosis had significantly lower tricuspid late diastolic annular velocity (P = 0.02) and early to late diastolic annular velocity ratio (P = 0.02) compared to those without. Cumulative anthracycline dose correlated with early diastolic mitral (r = -0.28, P = 0.038) and tricuspid (r = -0.40, P = 0.002) annular velocities, but not LV and RV EF or fibrosis (all P > 0.05). CONCLUSION: Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload. PMID- 25557467 TI - Using induced pluripotent stem cell-derived conditional medium to attenuate the light-induced photodamaged retina of rats. AB - BACKGROUND: Light injury to photoreceptor cells and retinal pigment epithelium may lead to oxidative stress and irreversible degeneration of retina, especially degeneration of the high energy-demanded macula. The model of retinal photodamage could be applied to age-related macular degeneration and other degenerative retinal diseases for exploring new treatments. Based on broadly investigated induced pluripotent stem cells (iPSC) in the field of retinal degeneration, we aimed to clarify further how the interaction progresses between iPSC-conditional medium (CM) and light-damaged retina. METHODS: iPSCs were generated from murine embryonic fibroblasts of C57/B6 mice by retroviral transfection of three factors: Oct4, Sox2, and Klf4. Cytokine array was performed to analyze the components of CM. Sprague-Dawley rats receiving white light exposure to retina were viewed as an animal model of light injury. The rats were divided into four subgroups: light injured rats receiving intravitreal injection of iPSC-CM, apoptotic iPSC-CM, or sodium phosphate buffer (PBS); and a control group without light damage. The electroretinography and thickness of outer nuclear layer were measured to document the therapeutic effects in each condition. Apoptosis arrays for detecting annexin V and caspase 3 were performed in the retinal tissues from each group. RESULTS: Murine embryonic fibroblasts were induced into iPSCs and expressed the marker genes similar to embryonic stem cells. These iPSCs can differentiate into Embryoid bodies (EBs), three germ layers in vitro and develop teratoma in severe combined immunodeficiency mice. The quantitative polymerase chain reaction of our iPSC-CM showed significantly elevated fibroblast growth factor-2, glial cell-derived neurotrophic factor, and insulin-like growth factor binding proteins-1, -2, and -3. Compared to rats without photodamage, the light injured rats receiving iPSC-CM had less reduction of outer nuclear layer thickness on Day 21 than other groups treated with either PBS or apoptotic iPSC CM. In the same animal model, both a- and b-waves of electroretinography measurement in the group treated with iPSC-CM were significantly maintained compared to the control group and others with apoptotic iPSC-CM or PBS treatment. The apoptosis assay also demonstrated lower levels of annexin V and caspase 3 in the group with iPSC-CM treatment than in other groups presenting increasing apoptotic markers. CONCLUSION: The conditional medium of iPSCs contains plenty of cytoprotective, immune-modulative and rescue chemicals, contributing to the maintenance of neuronal function and retinal layers in light-damaged retina compared with apoptotic iPSC-CM and PBS. The antiapoptotic effect of iPSC-CM also shows promise in restoring damaged neurons. This result demonstrates that iPSC-CM may serve as an alternative to cell therapy alone to treat retinal light damage and maintain functional and structural integrity of the retina. PMID- 25557468 TI - To evaluate the treatment response of locally advanced esophageal cancer after preoperative chemoradiotherapy by FDG-PET/CT scan. AB - BACKGROUND: This study was designed to gauge the effectiveness of evaluation of tumor response and prognosis by positron emission tomography with 18F fluorodeoxyglucose-positron emission tomography (FDG-PET) before and after preoperative chemoradiotherapy in patients with esophageal cancer. METHODS: Forty nine patients from October 2008 to September 2012 with locally advanced stage esophageal carcinoma, clinical stage T2-4N0-3M0, who underwent preoperative chemoradiotherapy (pre-CRT) followed by esophagectomy were enrolled in our study. All patients underwent two FDG-PET scans to compare those results with the pathologic results. Metabolic response of the primary tumor by the percentage change of the SUVmax/1 hour (DeltaSUV) before and after pre-CRT (DeltaSUV was calculated as the difference between pre-CRT SUVmax/1 hour and post-CRT SUVmax/1 hour divided by pre-CRT SUVmax/1 hour at esophageal tumor) was evaluated for overall survival (OS), disease free survival (DFS), local recurrence rate, and distant failure free survival (DFFS). Prognostic factors such as age, different regimen of chemotherapy, pathologic stage, FDG-PET stage, endoscopic esophageal tumor length, and DeltaSUV were analyzed. The number of highly suspect malignant lymph nodes was calculated by PET when SUVmax/1 hour >=2.5 and by surgical removal. Sensitivity and specificity of regional lymph node detection by PET were also recorded. RESULTS: Upon univariate analysis, overall survival rate was related to DeltaSUV >60% (p = 0.045), pathological N stage (p = 0.001), and endoscopic total length of esophageal tumor (p = 0.005). The result of FDG-PET scan after pre-CRT had high specificity (96.7%) but low sensitivity (45.8%) in predicting the residual malignant lymph node numbers. The positive and the negative prediction rates were 44% and 96%, respectively. The result of the FDG PET after pre-CRT showed upstaged in 16 patients (32.6%), downstaged in nine patients (18.3%), and the same stage in 24 patients (48.9%) when compared with the pathologic stage [corrected]. CONCLUSION: The change of SUVmax can be a tool for evaluating tumor response after pre-CRT. There is also a trend of good prognosis in overall survival rate when DeltaSUV value is >60%. PMID- 25557469 TI - A Survey of the Management of Patients with Temporomandibular Disorders by General Dental Practitioners in Southern Brazil. AB - PURPOSE: Temporomandibular disorders (TMD) are recognized as one of the most controversial topics in dentistry, despite the fact that both basic science and clinical researchers have currently reached some degree of consensus. This study aimed to conduct a questionnaire-based survey about the management of TMD patients by general dental practitioners (GDPs). MATERIALS AND METHODS: One hundred fifty-one GDPs with a private practice in a city of southern Brazil were included, independent of school of origin, gender, graduation year, and curriculum content. All participants were administered a questionnaire about the management of patients with TMD, and the responses were analyzed by binomial and chi-square tests (alpha = 0.05). RESULTS: Of the GDPs, 88.7% received TMD patients, who were primarily diagnosed on the basis of medical history (36.6%) or physical examination (30.4%). Of these, 65.4% referred the patients elsewhere, primarily to specialists in occlusion (36.1%) or orthodontics (29.7%). Occlusal splinting was the most commonly used management modality (20.8%), followed by occlusal adjustment (18.1%) and pharmacotherapy (16.6%). Splints were fabricated in maximum habitual intercuspation or centric relation depending on individual patient (54.8%). The hard stabilization form was the most common type of appliance used (35.0%). Moreover, 73.8% of the GDPs did not employ semi adjustable articulators, and 69.5% adjusted the appliances at the time of fixing. The duration of splint use and the frequency of follow-up were considered patient dependent by 62.1% and 72.8%, respectively. GDPs considered the two major TMD etiologic categories as multifactorial (20.8%) and occlusion (19.9%). Multidisciplinary medical and dental treatment was considered necessary by 97.9%. CONCLUSIONS: The evaluated general dental practitioners manage TMD patients according to international guidelines. PMID- 25557470 TI - The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment. AB - Iron refractory iron deficiency anemia (IRIDA) is a rare hereditary disease caused by mutations in TMPRSS6 gene encoding Matriptase-2, a negative regulator of hepcidin transcription. Up to now, 53 IRIDA patients from 35 families with different ethnic origins have been reported and 41 TMPRSS6 mutations have been identified. TMPRSS6 polymorphisms are more frequent than mutations, and have been associated with variation in iron and hematologic parameters. Our study evaluated their presence in 113 subjects with iron deficiency anemia (IDA) partially responsive to oral iron therapy and in 50 healthy blood donors. Thalassemic trait was diagnosed in 38 patients. Sequencing analysis of TMPRSS6 gene revealed that the frequency of several polymorphisms was markedly different between IDA subjects and controls. In particular, the V736A TMPRSS6 polymorphism was associated to moderately lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin levels, and in thalassemia carriers with marked anemia and microcytosis. A new variant-H448R- and two uncommon polymorphisms -A719T and V795I- were also identified. These results indicate that TMPRSS6 polymorphisms are more frequent in subjects with persistent IDA than in healthy controls, and in thalassemia carriers V736A variant may account for lower hemoglobin and MCV levels. Further studies in larger court of patients are necessary to identify potential haplotypes and polymorphisms responsible for low response to oral iron treatment and may be useful for planning a correct iron supplementation. PMID- 25557471 TI - Idiopathic facial aseptic granuloma. AB - Idiopathic facial aseptic granuloma (IFAG) is a condition that is commonly encountered in clinical practice, but is rarely reported. It appears in childhood and its pathogenesis is still unknown. It has a benign course with resolution within a few months without aggressive treatment. Microbiological tests are negative and histological findings are nonspecific. It is possible that this condition is part of the spectrum of granulomatous rosacea in childhood. We present two cases in which diagnosis of IFAG was established and resolved without sequelae following topical antibiotic treatment. PMID- 25557472 TI - Characterization of new Myoviridae bacteriophage WZ1 against multi-drug resistant (MDR) Shigella dysenteriae. AB - Shigella dysenteriae is a normal inhabitant of the human gastrointestinal tract, but sometimes it causes severe infection known as shigellosis (bacillary dysentery). Bacteriophages are considered very safe and effective agents for controlling bacterial infections and contaminations. In this study, we describe the isolation and characterization of bacteriophage WZ1, isolated from waste water which inhibits the growth of S. dysenteriae. Phage WZ1 showed maximum stability at 37 degrees C and was stable up to 65 degrees C but was totally inactive at 70 degrees C. The pH stability increased from low to high and was totally inactive at pH 3 while maximum stability was observed at optimal pH 7. Phage WZ1 adsorption rate to the host bacterium was significantly enhanced by the addition of CaCl2 . It has a latent time and burst time of 24 min and about 430 virions/cell, respectively. Transmission electron microscopy of phage WZ1 revealed a head width of 10 +/- 0.5 nm and length of 10 +/- 0.2 nm with a contractile tail of 128 +/- 25 nm long and 21 +/- 0.5 nm wide and belongs to family Myoviridae of order Caudovirales. Twelve structural proteins ranging from 22 to 150 kDa were detected by Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE). The genome was found to be double stranded DNA with an approximate size of 38 kb. It has a very good reduction potential for S. dysenteriae by lowering abruptly the optical density of the planktonic S. dysenteriae culture. Phage WZ1 is a very promising candidate for phage therapy and other applications such as phage typing. PMID- 25557473 TI - Cu-promoted sydnone cycloadditions of alkynes: scope and mechanism studies. AB - Cu salts have been found to promote the cycloaddition reaction of sydnones and terminal alkynes, providing significant reduction in reaction times. Specifically, the use of Cu(OTf)2 is found to provide 1,3-disubstituted pyrazoles, whereas simply switching the promoter system to Cu(OAc)2 allows the corresponding 1,4-isomers to be produced. The mechanism of the Cu-effect in each case has been investigated by experimental and theoretical studies, and they suggest that Cu(OTf)2 functions by Lewis acid activation of the sydnone, whereas Cu(OAc)2 promotes formation of reactive Cu(I) acetylides. PMID- 25557474 TI - A workshop report on the development of the Cow's Milk-related Symptom Score awareness tool for young children. AB - Clinicians with expertise in managing children with gastrointestinal problems and/or atopic diseases attended a workshop in Brussels in September 2014 to review the literature and determine whether a clinical score derived from symptoms associated with the ingestion of cow's milk proteins could help primary healthcare providers. The Cow's Milk-related Symptom Score (CoMiSS), which considers general manifestations, dermatological, gastrointestinal and respiratory symptoms, was developed as an awareness tool for cow's milk-related symptoms. It can also be used to evaluate and quantify the evolution of symptoms during therapeutic interventions, but does not diagnose cow's milk protein allergy and does not replace a food challenge. Its usefulness needs to be evaluated by a prospective randomised study. CONCLUSION: The CoMiSS provides primary healthcare clinicians with a simple, fast and easy-to-use awareness tool for cow's milk-related symptoms. PMID- 25557475 TI - Loop-mediated isothermal amplification (LAMP): principle, features, and future prospects. AB - Loop-mediated isothermal amplification (LAMP), a newly developed gene amplification method, combines rapidity, simplicity, and high specificity. Several tests have been developed based on this method, and simplicity is maintained throughout all steps, from extraction of nucleic acids to detection of amplification. In the LAMP reaction, samples are amplified at a fixed temperature through a repetition of two types of elongation reactions occurring at the loop regions: self-elongation of templates from the stem loop structure formed at the 3'-terminal and the binding and elongation of new primers to the loop region. The LAMP reaction has a wide range of possible applications, including point-of-care testing, genetic testing in resource-poor settings (such as in developing countries), and rapid testing of food products and environmental samples. PMID- 25557476 TI - Description of Pseudomonas asuensis sp. nov. from biological soil crusts in the Colorado plateau, United States of America. AB - A Gram-negative, aerobic, non spore-forming, non-motile, rod-shaped, yellow pigmented bacterium CP155-2(T) was isolated from a biological soil crusts sample collected in the Colorado plateau, USA and subjected to polyphasic taxonomic characterization. Strain CP155-2(T) contained summed feature 3 (C(16:1)omega5c/C(16:1)omega7c) and C(18:1)omega7c as major fatty acids and diphosphatidylglycerol (DPG) along with phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) as major polar lipids. Based on these characteristics CP155-2(T) was assigned to the genus Pseudomonas. Phylogenetic analysis based on 16S rRNA gene sequence further confirmed the affiliation of CP155-2(T) to the genus Pseudomonas and showed a 16S rRNA gene sequence similarity of less than 98.7% with already described species of the genus. Pseudomonas luteola, Pseudomonas zeshuii, and Pseudomonas duriflava were identified as the closest species of the genus Pseudomonas with 16S rRNA gene sequence similarities of 98.7%, 98.6%, and 96.9%, respectively. The values for DNACDNA relatedness between CP155-2(T) and Pseudomonas luteola and Pseudomonas zeshuii were 23% and 14% respectively a value below the 70% threshold value, indicating that strain CP155 2(T) belongs to a novel taxon of the genus Pseudomonas lineage. The novel taxon status was strengthened by a number of phenotypic differences wherein CP155-2(T) was positive for oxidase, negative for gelatin hydrolysis, could utilize D cellobiose, D-raffinose, L-rhamnose, D-sorbitol but not L-aspartic acid and L glutamic acid. Based on the collective differences strain CP155-2(T) exhibited, it was identified as a novel species and the name Pseudomonas asuensis sp. nov. was proposed. The type strain of Pseudomonas asuensis sp. nov. is CP155-2(T) (DSM 17866(T) =ATCC BAA-1264(T) =JCM13501(T) =KCTC 32484(T)). PMID- 25557477 TI - Genetic diversity of Clavispora lusitaniae isolated from Agave fourcroydes Lem, as revealed by DNA fingerprinting. AB - This study characterized Clavispora lusitaniae strains isolated from different stages of the processing and early fermentation of a henequen (Agave fourcroydes) spirit produced in Yucatan, Mexico using a molecular technique. Sixteen strains identified based on morphological features, obtained from different substrates, were typed molecularly. Nine different versions of the divergent D1/D2 domain of the large-subunit ribosomal DNA sequence were identified among the C. lusitaniae strains. The greatest degree of polymorphism was found in the 90-bp structural motif of the D2 domain. The MSP-PCR technique was able to differentiate 100% of the isolates. This study provides significant insight into the genetic diversity of the mycobiota present during the henequen fermentation process, especially that of C. lusitaniae, for which only a few studies in plants have been published. The applied MSP-PCR markers were very efficient in revealing olymorphisms between isolates of this species. PMID- 25557478 TI - Characterization of NpgA, a 4'-phosphopantetheinyl transferase of Aspergillus nidulans, and evidence of its involvement in fungal growth and formation of conidia and cleistothecia for development. AB - The null pigmentation mutant (npgA1) in Aspergillus nidulans results in a phenotype with colorless organs, decreased branching growth, delayed of asexual spore development, and aberrant cell wall structure. The npgA gene was isolated from A. nidulans to investigate these pleiomorphic phenomena of npgA1 mutant. Sequencing analysis of the complementing gene indicated that it contained a 4' phosphopantetheinyl transferase (PPTase) superfamily domain. Enzymatic assay of the PPTase, encoded by the npgA gene, was implemented in vivo and in vitro. Loss of-function of LYS5, which encoded a PPTase in Saccharomyces cerevisiae, was functionally complemented by NpgA, and Escherichia coli-derived NpgA revealed phosphopantetheinylation activity with the elaboration of 3'5'-ADP. Deletion of the npgA gene caused perfectly a lethal phenotype and the absence of asexual/sexual sporulation and secondary metabolites such as pigments in A. nidulans. However, a cross feeding effect with A. nidulans wild type allowed recovery from deletion defects, and phased-culture filtrate from the wild type were used to verify that the npgA gene was essential for formation of metabolites needed for development as well as growth. In addition, forced expression of npgA promoted the formation of conidia and cleistothecia as well as growth. These results indicate that the npgA gene is involved in the phosphopantetheinylation required for primary biological processes such as growth, asexual/sexual development, and the synthesis of secondary metabolites in A. nidulans. PMID- 25557479 TI - Performance of a real-time PCR assay for the rapid identification of Mycobacterium species. AB - Mycobacteria cause a variety of illnesses that differ in severity and public health implications. The differentiation of Mycobacterium tuberculosis (MTB) from nontuberculous mycobacteria (NTM) is of primary importance for infection control and choice of antimicrobial therapy. The diagnosis of diseases caused by NTM is difficult because NTM species are prevalent in the environment and because they have fastidious properties. In the present study, we evaluated 279 clinical isolates grown in liquid culture provided by The Catholic University of Korea, St. Vincent's Hospital using real-time PCR based on mycobacterial rpoB gene sequences. The positive rate of real-time PCR assay accurately discriminated 100% (195/195) and 100% (84/84) between MTB and NTM species. Comparison of isolates identified using the MolecuTech REBA Myco-ID((r)) and Real Myco-ID(r) were completely concordant except for two samples. Two cases that were identified as mixed infection (M. intracellulare-M. massiliense and M. avium-M. massiliense co infection) by PCRREBA assay were only detected using M. abscessus-specific probes by Real Myco-ID((r)). Among a total of 84 cases, the most frequently identified NTM species were M. intracellulare (n=38, 45.2%), M. avium (n=18, 23.7%), M. massiliense (n=10, 13.2%), M. fortuitum (n=5, 6%), M. abscessus (n=3, 3.9%), M. gordonae (n=3, 3.9%), M. kansasii (n=2, 2.4%), M. mucogenicum (n=2, 2.4%), and M. chelonae (n= 1, 1.2%). Real Myco-ID((r)) is an efficient tool for the rapid detection of NTM species as well as MTB and sensitive and specific and comparable to conventional methods. PMID- 25557480 TI - Effect of carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on killing Acinetobacter baumannii by colistin. AB - We investigated the effect of cyanide 3-chlorophenylhydrazone (CCCP) and other efflux pump inhibitors (EPIs) on the colistin susceptibility in Acinetobacter baumannii. While minimum inhibitory concentrations (MICs) of colistin in all colistin-resistant strains decreased significantly with 25 MUM of CCCP and 2,4 dinitrophenol (DNP), phenyl-arginine-beta-naphthylamide (PAbetaN), and reserpine did not decrease the colistin MICs. However, CCCP and DNP as well as PAbetaN and reserpine did not have a significant effect on the MICs of the other agents. Efflux pump gene expressions in colistin-resistant strains were not increased compared with those in colistin-susceptible strains. When only 5X MIC of colistin (5 mg/L) was provided to a colistin-susceptible A. baumannii strain, the bacterial cell number was reduced by 9 h after exposure to colistin, but regrowth was observed. When CCCP was added to colistin, bacterial cells were completely killed after 24 to 48 h of incubation, which was not due to the toxicity of CCCP itself. Colistin resistance in A. baumannii may not be due to efflux pumps. Our present study suggests that bacterial cells with reduced metabolic activity by CCCP are more susceptible to colistin in A. baumannii. It may show the possibility that combined therapy with colistin and other antimicrobial agents could effective against A. baumannii infections. PMID- 25557481 TI - Improved pipeline for reducing erroneous identification by 16S rRNA sequences using the Illumina MiSeq platform. AB - The cost of DNA sequencing has decreased due to advancements in Next Generation Sequencing. The number of sequences obtained from the Illumina platform is large, use of this platform can reduce costs more than the 454 pyrosequencer. However, the Illumina platform has other challenges, including bioinformatics analysis of large numbers of sequences and the need to reduce erroneous nucleotides generated at the 3'-ends of the sequences. These erroneous sequences can lead to errors in analysis of microbial communities. Therefore, correction of these erroneous sequences is necessary for accurate taxonomic identification. Several studies that have used the Illumina platform to perform metagenomic analyses proposed curating pipelines to increase accuracy. In this study, we evaluated the likelihood of obtaining an erroneous microbial composition using the MiSeq 250 bp paired sequence platform and improved the pipeline to reduce erroneous identifications. We compared different sequencing conditions by varying the percentage of control phiX added, the concentration of the sequencing library, and the 16S rRNA gene target region using a mock community sample composed of known sequences. Our recommended method corrected erroneous nucleotides and improved identification accuracy. Overall, 99.5% of the total reads shared 95% similarity with the corresponding template sequences and 93.6% of the total reads shared over 97% similarity. This indicated that the MiSeq platform can be used to analyze microbial communities at the genus level with high accuracy. The improved analysis method recommended in this study can be applied to amplicon studies in various environments using high-throughput reads generated on the MiSeq platform. PMID- 25557482 TI - Hypermethylation of the interferon regulatory factor 5 promoter in Epstein-Barr virus-associated gastric carcinoma. AB - Interferon regulatory factor-5 (IRF-5), a member of the mammalian IRF transcription factor family, is regulated by p53, type I interferon and virus infection. IRF-5 participates in virus-induced TLR-mediated innate immune responses and may play a role as a tumor suppressor. It was suppressed in various EBV-infected transformed cells, thus it is valuable to identify the suppression mechanism. We focused on a promoter CpG islands methylation, a kind of epigenetic regulation in EBV-associated Burkitt's lymphomas (BLs) and gastric carcinomas. IRF-5 is not detected in most of EBV-infected BL cell lines due to hypermethylation of IRF-5 distal promoter (promoter-A), which was restored by a demethylating agent, 5-aza-2'-deoxycytidine. Hypomethylation of CpG islands in promoter-A was observed only in EBV type III latent infected BL cell lines (LCL and Mutu III). Similarly, during EBV infection to Akata-4E3 cells, IRF-5 was observed at early time periods (2 days to 8 weeks), concomitant unmethylation of promoter-A, but suppressed in later infection periods as observed in latency I BL cell lines. Moreover, hypermethylation in IRF-5 promoter-A region was also observed in EBV-associated gastric carcinoma (EBVaGC) cell lines or primary gastric carcinoma tissues, which show type I latent infection. In summary, IRF-5 is suppressed by hypermethylation of its promoter-A in most of EBV-infected transformed cells, especially BLs and EBVaGC. EBV-induced carcinogenesis takes an advantage of proliferative effects of TLR signaling, while limiting IRF-5 mediated negative effects in the establishment of EBVaGCs. PMID- 25557484 TI - Erratum to: Protective role of gut commensal microbes against intestinal infections. PMID- 25557483 TI - Extended stability of cyclin D1 contributes to limited cell cycle arrest at G1 phase in BHK-21 cells with Japanese encephalitis virus persistent infection. AB - There is increasing evidence that many RNA viruses manipulate cell cycle control to achieve favorable cellular environments for their efficient replication during infection. Although virus-induced G0/G1 arrest often delays early apoptosis temporarily, a prolonged replication of the infected virus leads host cells to eventual death. In contrast, most mammalian cells with RNA virus persistent infection often escape cytolysis in the presence of productive viral replication. In this study, we demonstrated that the extended endurance of cyclin D1 was clearly associated with the suppression of glycogen synthase kinase-3beta (GSK 3beta) expression in BHK-21 cells that are persistently infected with Japanese encephalitis virus (JEV). The G0/G1 arrest of these cells turned much loose compared to the normal BHK-21 cells with JEV acute infection. After cycloheximide treatment, cyclin D1 in the persistently infected cells lasted several hours longer than those in acutely infected cells. Furthermore, both p21(Cip1) and p27(Kip1), positive regulators for cyclin D1 accumulation in the nucleus, were suppressed in their expression, which contrasts with those in JEV acute infection. Inhibition of the GSK-3beta by lithium chloride treatment rescued a significant number of cells from cytolysis in JEV acute infection, which coincided with the levels of cyclin D1 that escaped from proteolysis. Therefore, the limitation of G1/S arrest in the BHK-21 cells with JEV persistent infection is associated with the suppression of GSK-3beta expression, resulting in the extended duration of cyclin D1. PMID- 25557486 TI - Attention: Tuning sensory selection. PMID- 25557485 TI - Transcriptomic correlates of organ failure extent in sepsis. AB - OBJECTIVES: Sepsis is characterised by the frequent presence of organ failure and marked immunologic alterations. We studied the association between the extent of organ failure and the transcriptomic response of septic patients. METHODS: Gene expression profiles in the blood of 74 surgical patients with sepsis were compared with those of 30 surgical patients with no sepsis. Differentially expressed genes were assessed for their correlation with the sequential organ failure (SOFA) score. RESULTS: The expression levels of a group of genes participating in the cell cycle (HIST1H1C, CKS2, CCNA2, CDK1, CCNB2, CIT, CCNB1, AURKA, RAD51), neutrophil protease activity (ELANE, ADORA3, MPO, MMP8, CTSG), IL 1R and IL-18R response correlated directly with SOFA and mortality. Genes involved in T cell (LCK, CD3G, CD3D, ZAP70, ICOS, CD3E, CD28, IL2RB, CD8B, CD8A, CD40LG, IL23A, CCL5, SH2D1A, ITK, CD247, TBX21, GATA3, CCR7, LEF1, STAT4) and NK cell immunity (CD244, KLRK1, KLRD1) were inversely associated with SOFA and mortality. CONCLUSIONS: The extent of organ failure in sepsis correlates directly with the existence of imbalanced innate and adaptive responses at the transcriptomic level. Quantification of the expression levels of the genes identified here could contribute to the simultaneous assessment of disease severity and immunological alterations in sepsis. PMID- 25557487 TI - Lineage-specific activities of a multipotent mitochondrion of trypanosomatid flagellates. AB - Trypanosomatids are a very diverse group composed of monoxenous and dixenous parasites belonging to the excavate class Kinetoplastea. Here we studied the respiration of five monoxenous species (Blechomonas ayalai, Herpetomonas muscarum, H. samuelpessoai, Leptomonas pyrrhocoris and Sergeia podlipaevi) introduced into culture, each representing a novel yet globally distributed and/or species-rich clade, and compare them with well-studied flagellates Trypanosoma brucei, Phytomonas serpens, Crithidia fasciculata and Leishmania tarentolae. Differences in structure and activities of respiratory chain complexes, respiration and other biochemical parameters recorded under laboratory conditions reveal their substantial diversity, likely a reflection of different host environments. Phylogenetic relationships of the analysed trypanosomatids do not correlate with their biochemical parameters, with the differences within clades by far exceeding those among clades. As the S. podlipaevi canonical respiratory chain complexes have very low activities, we believe that its mitochondrion is utilised for purposes other than oxidative phosphorylation. Hence, the single reticulated mitochondrion of diverse trypanosomatids seems to retain multipotency, with the capacity to activate its individual components based on the host environment. PMID- 25557488 TI - Should we start evaluating intrathecal IgM production clinically? PMID- 25557489 TI - Exposure of barley plants to low Pi leads to rapid changes in root respiration that correlate with specific alterations in amino acid substrates. AB - The majority of inorganic phosphate (Pi ) stress studies in plants have focused on the response after growth has been retarded. Evidence from transcript analysis, however, shows that a Pi -stress specific response is initiated within minutes of transfer to low Pi and in crop plants precedes the expression of Pi transporters and depletion of vacuolar Pi reserves by days. In order to investigate the physiological and metabolic events during early exposure to low Pi in grain crops, we monitored the response of whole barley plants during the first hours following Pi withdrawal. Lowering the concentration of Pi led to rapid changes in root respiration and leaf gas exchange throughout the early phase of the light course. Combining amino and organic acid analysis with (15) N labelling we show a root-specific effect on nitrogen metabolism linked to specific substrates of respiration as soon as 1 h following Pi withdrawal; this explains the respiratory responses observed and was confirmed by stimulation of respiration by exogenous addition of these respiratory substrates to roots. The rapid adjustment of substrates for respiration in roots during short-term Pi stress is highlighted and this could help guide roots towards Pi -rich soil patches without compromising biomass accumulation of the plant. PMID- 25557491 TI - Remembering Dr Marvin Moser. PMID- 25557490 TI - Covariation of change in bioavailable testosterone and adiposity in midlife women. AB - OBJECTIVE: To determine whether menopause-related changes in reproductive hormones were associated with change in adiposity and whether these relationships were independent of important covariates. METHODS: Annual assessments of adiposity measures [computed tomography-assessed visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) and dual-energy X-ray absorptiometry-assessed total body fat (TBF)] over 4 years from an ancillary study at the Chicago site of the Study of Women's Health Across the Nation (SWAN) were paired with reproductive hormones collected by SWAN. Included were 243 women (44% African American, 56% Caucasian) who were eligible participants in a population-based cohort with a 72% participation rate. RESULTS: VAT increased by 3.8% annually, and SAT increased by 1.8% per year. Change in bioavailable testosterone was significantly positively associated with changes both in VAT and in SAT but was not related to change in total body fat. The associations were independent of age, race, physical activity, smoking, baseline TBF, baseline bioavailable testosterone, and change in TBF. Change in estradiol was unrelated to changes in any adiposity measure. CONCLUSIONS: Bioavailable testosterone may play an important role in menopause-related redistribution of visceral and subcutaneous fat in the central abdominal region. PMID- 25557492 TI - Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents. AB - A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of alpha- and beta-tubulin that is occupied by colchicine, and were stabilized by van der Waals' interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs. PMID- 25557493 TI - Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia. AB - We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2 propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1 (phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits. PMID- 25557494 TI - Computed tomography for preoperative evaluation of need for sternotomy in surgery for retrosternal goitre. AB - PURPOSE: The purposes of this study are to evaluate the usefulness of available CT classifications of retrosternal goitre (RSG) to identify patients needing sternotomy and to examine the effect of neck extension on goitre position. METHODS: From the Scandinavian Quality Register for Thyroid and Parathyroid Surgery, all patients treated for RSG at Sahlgrenska (January 2005 through August 2012) were identified. Medical records and preoperative CT scans were retrospectively reviewed. Paired CT (normal position/neck extension) was done in three patients. RESULTS: Of 1698 patients undergoing thyroid surgery, 158 (9.3 %) were registered as having RSG, of these 38 were excluded (no preoperative CT n = 27, no RSG at preoperative CT n = 11). Of 120 included patients (71 % females, median age 67 years, rate of malignancy 14 %), 104 were managed with a cervical approach only, 16 (13.3 %) needed sternotomy, of these 13/16 had growth below the aortic arch concavity. Predictors for sternotomy were goitre extension below the aortic arch concavity (positive/negative predictive value (PPV/NPV) 54/97 %, sensitivity/specificity 81/89 %, odds ratio (OR) 36.6, p < 0.001); main mass of RSG to the right of the midline (PPV/NPV 21/95 %, sensitivity/specificity 81/53 %, OR 4.9, p < 0.008); and main mass of RSG retrotracheal (PPV/NPV 31/92 %, sensitivity/specificity 50/83 %, OR 4.8, p < 0.005). The goitre was displaced cranially a mean 11 mm with neck extension, but the relationship to the aortic arch was unchanged. CONCLUSIONS: RSG extension below the aortic arch concavity was confirmed as a significant risk factor for sternotomy, with a NPV for sternotomy of 97 % for less extensive goitres. CT in neck extension provided no additional clinically relevant information. PMID- 25557497 TI - Use of a "silver bullet" to resolve crystal lattice dislocation disorder: a cobalamin complex of Delta1-pyrroline-5-carboxylate dehydrogenase from Mycobacterium tuberculosis. AB - The use of small molecules as "silver bullets" that can bind to generate crosslinks between protein molecules has been advanced as a powerful means of enhancing success in protein crystallization (McPherson and Cudney, 2006). We have explored this approach in attempts to overcome an order-disorder phenomenon that complicated the structural analysis of the enzyme Delta(1)-pyrroline-5 carboxylate dehydrogenase from Mycobacterium tuberculosis (P5CDH, Mtb-PruA). Using the Silver Bullets Bio screen, we obtained new crystal packing using cobalamin as a co-crystallization agent. This crystal form did not display the order-disorder phenomenon previously encountered. Solution of the crystal structure showed that cobalamin molecules are present in the crystal contacts. Although the cobalamin binding probably does not have physiological relevance, it reflects similarities in the nucleotide-binding region of Mtb-PruA, with the nucleotide loop of cobalamin sharing the binding site for the adenine moiety of NAD(+). PMID- 25557496 TI - The Patient Activation Measure: a validation study in a neurological population. AB - PURPOSE: To assess the validity of the Patient Activation Measure (PAM13) of patient activation in persons with neurological conditions. METHODS: "The Everyday Experience of Living with and Managing a Neurological Condition" (The LINC study) surveyed 948 adults with neurological conditions residing in Canada in 2011 and 2012. Using data for 722 respondents who met coding requirements for the PAM-13, we examined the properties of the measure using principle components analysis, inter-item correlations and Cronbach's alpha to assess unidimensionality and internal consistency. Rasch modeling was used to assess item performance and scaling. Construct validity was assessed by calculating associations between the PAM and known correlates. RESULTS: PAM-13 provides a suitably reliable and valid instrument for research in patients with neurological conditions, but scaling problems may yield measurement error and biases for those with low levels of activation. This is of particular importance when used in clinical settings or for individual client care. Our study also suggests that measurement of activation may benefit from tailoring items and scaling to specific diagnostic groups such as people with neurological conditions, thus allowing the PAM-13 to recognize unique attributes and management challenges in those conditions. CONCLUSIONS: The PAM-13 is an internally reliable and valid tool for research purposes. The use of categorical activation "level" in clinical settings should be done with caution. PMID- 25557495 TI - Grape seed extract targets mitochondrial electron transport chain complex III and induces oxidative and metabolic stress leading to cytoprotective autophagy and apoptotic death in human head and neck cancer cells. AB - Head and neck squamous cell carcinoma (HNSCC) is a major killer worldwide and innovative measures are urgently warranted to lower the morbidity and mortality caused by this malignancy. Aberrant redox and metabolic status in HNSCC cells offer a unique opportunity to specifically target cancer cells. Therefore, we investigated the efficacy of grape seed extract (GSE) to target the redox and bioenergetic alterations in HNSCC cells. GSE treatment decreased the mitochondrial electron transport chain complex III activity, increased the mitochondrial superoxide levels and depleted the levels of cellular antioxidant (glutathione), thus resulting in the loss of mitochondrial membrane potential in human HNSCC Detroit 562 and FaDu cells. Polyethylene glycol-SOD addition reversed the GSE-mediated apoptosis without restoring complex III activity. Along with redox changes, GSE inhibited the extracellular acidification rate (representing glycolysis) and oxygen consumption rate (indicating oxidative phosphorylation) leading to metabolic stress in HNSCC cells. Molecular studies revealed that GSE activated AMP-activated protein kinase (AMPK), and suppressed Akt/mTOR/4E-BP1/S6K signaling in both Detroit 562 and FaDu cells. Interestingly, GSE increased the autophagic load specifically in FaDu cells, and autophagy inhibition significantly augmented the apoptosis in these cells. Consistent with in vitro results, in vivo analyses also showed that GSE feeding in nude mice activated AMPK and induced-autophagy in FaDu xenograft tumor tissues. Overall, these findings are innovative as we for the first time showed that GSE targets ETC complex III and induces oxidative and metabolic stress, thereby, causing autophagy and apoptotic death in HNSCC cells. PMID- 25557499 TI - Large area sub-micron chemical imaging of magnesium in sea urchin teeth. AB - The heterogeneous and site-specific incorporation of inorganic ions can profoundly influence the local mechanical properties of damage tolerant biological composites. Using the sea urchin tooth as a research model, we describe a multi-technique approach to spatially map the distribution of magnesium in this complex multiphase system. Through the combined use of 16-bit backscattered scanning electron microscopy, multi-channel energy dispersive spectroscopy elemental mapping, and diffraction-limited confocal Raman spectroscopy, we demonstrate a new set of high throughput, multi-spectral, high resolution methods for the large scale characterization of mineralized biological materials. In addition, instrument hardware and data collection protocols can be modified such that several of these measurements can be performed on irregularly shaped samples with complex surface geometries and without the need for extensive sample preparation. Using these approaches, in conjunction with whole animal micro-computed tomography studies, we have been able to spatially resolve micron and sub-micron structural features across macroscopic length scales on entire urchin tooth cross-sections and correlate these complex morphological features with local variability in elemental composition. PMID- 25557501 TI - A quantitative prediction of the viscosity of ionic liquids using S(sigma profile) molecular descriptors. AB - In this study, two novel QSPR models have been developed to predict the viscosity of ionic liquids (ILs) using multiple linear regression (MLR) and support vector machine (SVM) algorithms based on Conductor-like Screening Model for Real Solvents (COSMO-RS) molecular descriptors (Ssigma-profile). A total data set of 1502 experimental viscosity data points under a wide range of temperatures and pressures for 89 ILs, is employed to train and verify the models. The Average Absolute Relative Deviation (AARD) values of the total data set of the MLR and SVM are 10.68% and 6.58%, respectively. The results show that both the MLR and SVM models can predict the viscosity of ILs, and the performance of the nonlinear model developed using the SVM is superior to the linear model (MLR). Furthermore, the derived models also can throw some light onto structural characteristics that are related to the viscosity of ILs. PMID- 25557498 TI - An N-terminal extension to the hepatitis B virus core protein forms a poorly ordered trimeric spike in assembled virus-like particles. AB - Virus-like particles composed of the core antigen of hepatitis B virus (HBcAg) have been shown to be an effective platform for the display of foreign epitopes in vaccine development. Heterologous sequences have been successfully inserted at both amino and carboxy termini as well as internally at the major immunodominant epitope. We used cryogenic electron microscopy (CryoEM) and three-dimensional image reconstruction to investigate the structure of VLPs assembled from an N terminal extended HBcAg that contained a polyhistidine tag. The insert was seen to form a trimeric spike on the capsid surface that was poorly resolved, most likely owing to it being flexible. We hypothesise that the capacity of N-terminal inserts to form trimers may have application in the development of multivalent vaccines to trimeric antigens. Our analysis also highlights the value of tools for local resolution assessment in studies of partially disordered macromolecular assemblies by cryoEM. PMID- 25557500 TI - Tough, in-situ thermogelling, injectable hydrogels for biomedical applications. AB - Injectable hydrogels are extensively used in drug delivery and tissue engineering to administer drugs, genes, growth factors and live cells. We report a method to produce tough, in-situ thermogelling, non-toxic, injectable hydrogels made of chitosan and hyaluronic acid co-crosslinked with beta-glycerophophate and genipin. The gels are highly homogeneous and form within 32 min, i.e., faster than gels crosslinked with either genipin or beta-glycerophophate. The shear strength of co-crosslinked hydrogels is 3.5 kPa, higher than any chitosan-based gel reported. Chondrocytes and nucleus pulposus cells thrive inside the gels and produce large amounts of collagen II. Injection in rats shows that the gels form in-vivo within a short time and remain well localized for more than one week while the rats remain healthy and active. The excellent mechanical properties, fast in-situ gelation, good biocompatibility and the ability to encapsulate live cells at physiological conditions make these hydrogels ideal for tissue engineering, especially cartilage regeneration. PMID- 25557502 TI - Validity of aqueocentesis as a component of anterior uveitis investigation in dogs and cats. AB - OBJECTIVE: To describe aqueocentesis cytopathology results from dogs and cats presenting for uveitis investigation and to determine whether this is a useful and safe procedure. ANIMAL STUDIED: Dogs and cats presenting for investigation of anterior uveitis (April 2008-December 2013). PROCEDURES: Aqueous was collected via limbal entry under sedation/general anesthesia, for cytopathology and occasionally bacterial culture or polymerase chain reaction (PCR) testing. Further workup included blood testing (hematology, biochemistry, and serology), diagnostic imaging, nonocular cytopathology, and available histopathology. RESULTS: Fifty-six dogs and 39 cats were included in the study. An aqueous cytopathologic diagnosis of lymphoma (or discrete cell neoplasia) was made in six dogs and seven cats, and a diagnosis of large cell carcinoma made in one dog. This diagnosis of lymphoma was confirmed by ocular histopathology in two dogs and one cat; nonocular cytopathology corroborated lymphoma in another three dogs and five cats. Lymphoma was not evident on aqueous cytopathology but confirmed on nonocular histopathology in two dogs and by cytopathology in one cat. Additionally, aqueous cytopathology in three cats suggested, but was not considered diagnostic of, lymphoma; one of these cats had a confirmatory diagnosis of lymphoma on subsequent clinical investigation. Aqueous humor cytopathology alone was not diagnostic in non-neoplastic anterior uveitis cases, but supplemented the clinical picture with other systemic diagnostic tests. No clinically important complications were reported in association with aqueocentesis. CONCLUSIONS: Aqueocentesis is performed readily with minimal risk. The results were primarily useful in aiding a diagnosis of lymphoma in both dogs and cats. PMID- 25557504 TI - Simulation of the ground states of spin rings with cavity-assisted neutral atoms. AB - Quantum phase transitions occur when the ground state of a Hamiltonian undergoes qualitative changes with a control parameter changing. In this paper we consider a particular system--an Isng-type spin ring with competing many-body interactions. Depending on the relative strength interactions, the ground state of the system is either a product state or entangled state. We implement the system in a cavity-assisted neutral atomic simulator and study the non-locality and entanglement of the simulated ground state of an Ising-type three-spin ring with the control parameter changing. The simplicity of the setup and its robustness to noise give it a great practicality within the framework of current experimental technology. PMID- 25557506 TI - Call for special issue of midwifery on risk in childbirth. PMID- 25557503 TI - Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3). AB - Microglia are the main innate immune cells in the central nervous system that are actively involved in maintaining brain homeostasis and diseases. T cell Ig and mucin domain protein 3 (Tim-3) plays critical roles in both the adaptive and the innate immune system and is an emerging therapeutic target for treatment of various disorders. In the brain Tim-3 is specifically expressed on microglia but its functional role is unclear. Here, we showed that Tim-3 was up-regulated on microglia by ATP or LPS stimulation. Tim-3 activation with antibodies increased microglia expression of TGF-beta, TNF-alpha and IL-1beta. Blocking of Tim-3 with antibodies decreased the microglial phagocytosis of apoptotic neurons. Tim-3 blocking alleviated the detrimental effect of microglia on neurons and promoted NG2 cell differentiation in co-cultures. Finally, MAPKs namely ERK1/2 and JNK proteins were phosphorylated upon Tim-3 activation in microglia. Data indicated that Tim-3 modulates microglia activity and regulates the interaction of microglia-neural cells. PMID- 25557507 TI - Encapsulation of carvacrol, a monoterpene present in the essential oil of oregano, with beta-cyclodextrin, improves the pharmacological response on cancer pain experimental protocols. AB - Cancer pain is a major public health problem worldwide due to the strong impact on the quality of life of patients and side effects of the existing therapeutic options. Monoterpenes, as carvacrol (CARV), have been extensively studied about their therapeutic properties, especially their importance in the control of painful conditions and inflammation, which can be improved through the use of inclusion complexes of beta-cyclodextrin (beta-CD). We evaluated the effect of encapsulation of CARV in beta-CD (CARV/beta-CD) on the nociception induced by tumor cells (Sarcoma 180) in rodents. Inclusion complexes were prepared in two different procedures and characterized through thermal analysis and scanning electron microscopy. CARV/beta-CD complex was administered (50 mg/kg, p.o.) in mice with tumor on the hind paw and was able to reduce the hyperalgesia (von Frey) during 24 h, unlike the free CARV (100 mg/kg, p.o.), which promoted effects until 9 h. Administration on alternate days of complex of CARV/beta-CD (12.5-50 mg/kg, p.o.) reduced hyperalgesia, as well as spontaneous and palpation-induced nociception. However, pure CARV (50 mg/kg) did not cause significant changes in nociceptive responses. Together, these results produced evidence that the encapsulation of carvacrol in beta-cyclodextrin can be useful for the development of new options for pain management. PMID- 25557508 TI - Apigenin attenuates heart injury in lipopolysaccharide-induced endotoxemic model by suppressing sphingosine kinase 1/sphingosine 1-phosphate signaling pathway. AB - Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. This study is to investigate the effects of apigenin on heart injury in lipopolysaccharide-induced endotoxemic rat model. Normal Wistar rats were randomly divided into four groups: control group, LPS group (15 mg/kg), LPS plus apigenin groups with different apigenin doses (50 mg/kg, 100 mg/kg). Serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta (IL-1beta) were measured after the rats were sacrificed. SphK1/S1P signaling pathway proteins, cleaved caspase-3, cleaved caspase-9, Bax and Bcl-2 in heart were measured by Western blot. In vitro, we evaluated the protective effect of apigenin on rat embryonic heart-derived myogenic cell line H9c2 induced by LPS. Apigenin decreased serum levels of CK-MB, LDH, TNF-alpha, IL-6, IL-1beta. SphK1/S1P signaling pathway proteins, cleaved caspase-3, cleaved caspase-9, Bax in heart were found inhibited and Bcl-2 increased in the apigenin groups in vivo. In addition, apigenin inhibited intracellular calcium, the MAPK pathway and SphK1/S1P signaling pathway in vitro. Apigenin exerts pronounced cardioprotection in rats subjected to LPS likely through suppressing myocardial apoptosis and inflammation by inhibiting the SphK1/S1P signaling pathway. PMID- 25557509 TI - A novel carbohydrate derived compound FCP5 causes DNA strand breaks and oxidative modifications of DNA bases in cancer cells. AB - 1,5-Anhydro-6-deoxy-methane-sulfamido-D-glucitol (FCP5) is a functionalized carbohydrate containing functional groups that render it potentially therapeutically useful. According to our concept of 'functional carb pharmacophores' (FCPs) incorporation of the methanesulfonamido pharmacophore to 1,5 glucitol could create a therapeutically useful compound. Our previous studies revealed that FCP5 was cytotoxic to cancer cells. Therefore, in this work we assessed the cytotoxic mechanisms of FCP5 in four cancer cell lines - HeLa, LoVo, A549 and MCF-7, with particular focus on DNA damage and repair. A broad spectrum of methods, including comet assay with modifications, DNA repair enzyme assay, plasmid relaxation assay, and DNA fragmentation assay, were used. We also checked the potential for FCP5 to induce apoptosis. The results show that FCP5 can induce DNA strand breaks as well as oxidative modifications of DNA bases. DNA lesions induced by FCP5 were not entirely repaired in HeLa cells and DNA repair kinetics differs from other cell lines. Results from molecular docking and plasmid relaxation assay suggest that FCP5 binds to the major groove of DNA with a preference for adenosine-thymine base pair sequences and directly induces DNA strand breaks. Thus, FCP5 may represent a novel lead for the design of new major groove-binding compounds. The results also confirmed the validity of functional carb-pharmacophores as a new source of innovative drugs. PMID- 25557510 TI - Hypervascular mediastinal masses: action points for radiologists. AB - Hypervascular mediastinal masses are a distinct group of rare diseases that include a subset of benign and malignant entities. Characteristic features and known association with syndromes and genetic mutations assist in achieving a diagnosis. Imaging allows an understanding of the vascularity of the lesion and should alert the radiologist and clinician to potential hemorrhagic complications and avoid percutaneous CT guided biopsies. In such cases, pre-procedure embolization and surgical biopsy maybe considered for better control of post procedure hemorrhage. The purpose of this article is to describe and illustrate the clinical features and radiologic spectrum of hypervascular mediastinal masses, and discuss the associated clinical and genetic syndromes. We will present an imaging algorithm to determine further evaluation and subsequently guide treatment. PMID- 25557511 TI - Lemnalol attenuates mast cell activation and osteoclast activity in a gouty arthritis model. AB - OBJECTIVES: In this study, we investigated the effects of a soft coral-derived anti-inflammatory compound, lemnalol, on mast cell (MC) function and osteoclast activity in rats with monosodium urate (MSU) crystal-induced gouty arthritis. METHODS: In this study, we examined the therapeutic effects of lemnalol on intra articular injection of MSU induces gouty arthritis with the measurement of ankle oedema. Toluidine blue staining were used to analyse the infiltration and the percentage degranulation MCs. Immunohistochemical analysis showed CD117, transforming growth factor beta 1 (TGF-beta1), matrix metalloproteinase 9 (MMP 9), the osteoclast markers cathepsin K and tartrate-resistant acid phosphatase (TRAP) protein expression in ankle tissue. KEY FINDINGS: We found that both infiltration and degranulation of MCs increased at 24 h after MSU injection in the ankle joint. Immunohistochemical analysis showed that MSU induced upregulation of TGF-beta1, MMP-9, the osteoclast markers cathepsin K and TRAP in ankle tissues. Administration of lemnalol ameliorated MSU-induced TGF-beta1, MMP 9, cathepsin K and TRAP protein expression. CONCLUSIONS: Taken together, our results show that MSU-induced gouty arthritis is accompanied by osteoclast related protein upregulation and that lemnalol treatment may be beneficial for the attenuation of MC infiltration and degranulation and for suppressing osteoclast activation in gouty arthritis. PMID- 25557512 TI - Hypersensitive response-like lesions 1 codes for AtPPT1 and regulates accumulation of ROS and defense against bacterial pathogen Pseudomonas syringae in Arabidopsis thaliana. AB - AIMS: Plants employ both basal and resistance gene (R gene)-mediated defenses in response to pathogens. Reactive oxygen species (ROS) are widely reported to play a central role in both basal and R gene-mediated defense; however, the nature of ROS has been less well established for basal defense. In addition, spatial distribution of redox moieties and mechanisms of plant responses during basal defense are poorly understood. We investigated redox signaling in Arabidopsis thaliana in response to virulent bacterial pathogen, focusing on the role of the mitochondria in balancing energy demands against generation of physiologically relevant ROS. RESULTS: Positional cloning of an Arabidopsis lesion mimic mutant identified a polyprenyl transferase involved in the biosynthesis of Coenzyme Q10 (CoQ), which leads to novel insights into physiological ROS levels and their role in basal resistance. Gain- and loss-of-function studies identified Coenzyme Q10 redox state to be a key determinant of ROS levels. These Coenzyme Q10 redox state mediated ROS levels had a direct bearing on both response against pathogen and ability to thrive in high oxidative stress environments. INNOVATION: We demonstrate that Coenzyme Q10 redox state generates an ROS threshold for a successful basal resistance response. Perturbation of the Coenzyme Q10 redox state has the potential to disrupt plant defense responses against bacterial pathogens. CONCLUSIONS: Coenzyme Q10 redox state is a key regulator of Arabidopsis basal resistance against bacterial pathogens. PMID- 25557513 TI - Casebooks in early modern England: medicine, astrology, and written records. AB - Casebooks are the richest sources that we have for encounters between early modern medical practitioners and their patients. This article compares astrological and medical records across two centuries, focused on England, and charts developments in the ways in which practitioners kept records and reflected on their practices. Astrologers had a long history of working from particular moments, stellar configurations, and events to general rules. These practices required systematic notation. Physicians increasingly modeled themselves on Hippocrates, recording details of cases as the basis for reasoned expositions of the histories of disease. Medical records, as other scholars have demonstrated, shaped the production of medical knowledge. Instead, this article focuses on the nature of casebooks as artifacts of the medical encounter. It establishes that casebooks were serial records of practice, akin to diaries, testimonials, and registers; identifies extant English casebooks and the practices that led to their production and preservation; and concludes that the processes of writing, ordering, and preserving medical records are as important for understanding the medical encounter as the records themselves. PMID- 25557514 TI - Setting scientific standards: publishing in medical societies in nineteenth century Belgium. AB - This article examines the publishing procedures of nineteenth-century medical societies, using the Medical Society of Ghent (Belgium) as a case study. It argues, more precisely, that the introduction of formalized review procedures in medical societies can be considered part of the emergence of a professional scientific culture in the first half of the nineteenth century. First, by participating in these procedures physicians took on different stylized roles, for example of the contributing author, the righteous judge, or the punctual secretary, and articulated new professional values such as contributing to science. Second, the publishing procedures of medical societies also provide insight into the mechanisms of reaching consensus in nineteenth-century medicine. By developing new scientific genres, such as the published meeting report, medical societies aimed to extend the community of peers beyond the group of society members and establish trust and agreement throughout the medical community. PMID- 25557515 TI - Targeting the American market for medicines, ca. 1950s-1970s: ICI and Rhone Poulenc compared. AB - The forces that have shaped American medicine include a wide set of interrelated changes, among them the changing research, development, and marketing practices of the pharmaceutical industry. This article compares the research and development (R&D) and marketing strategies of the British group Imperial Chemical Industries (ICI, whose Pharmaceutical Division was spun off and merged with the Swedish company Astra to form AstraZeneca) and its French counterpart Rhone Poulenc (now part of Sanofi-Aventis) in dealing with the American medical market. It examines how, in the process, the relationship between R&D and marketing was altered, and the firms themselves were transformed. The article also questions the extent to which their approaches to this market, one of the most significant markets for drugs in general, and for anticancer drugs in particular, became standardized in the period of "scientific marketing." PMID- 25557516 TI - Autopsy issues in German Federal Republic transplantation legislation until 1997. AB - This article analyzes the relevance of autopsy issues for German Federal Republic transplantation legislation until 1997 against the background of legal traditions and the distribution of constitutional legislative powers. It is based on Federal Ministry of Justice records and German Parliament documents on transplantation legislation. Transplantation and autopsy legislation started with close ties in the 1970s. Viewing transplantation legislation as relevant for future autopsy regulation contributed to the decision to stall transplantation legislation, because the interests of the federal government and the medical profession converged to avoid subsequent restrictions on the practice of conducting autopsies and procuring tissues for transplantation. Sublegal norms were insufficient for the prosecution of the organ trade and area-wide transplantation regulation after the reunification of Germany. In contrast to autopsy issues, legislative power for transplantation issues was extended to the federal level by an amendment to the constitution, allowing decision making for Germany as a whole. PMID- 25557518 TI - The history of medicine in the digital age. PMID- 25557519 TI - HIV/AIDS histories: community service organizations and the direct-action AIDS movement in documentary film. PMID- 25557523 TI - A new look at the antibiotic amphotericin B effect on Candida albicans plasma membrane permeability and cell viability functions. AB - Amphotericin B (AmB) is an antifungal polyene for which the most accepted mode of action is formation of protein-like ion channels in the cell membrane. Patch clamp research on Candida albicans protoplasts carried out in the outside-out configuration showed that application of 0.05 and 0.1 MUM AmB caused a decrease in seal resistance. Such a phenomenon can be correlated with a decrease in membrane tightness. AmB applied at a 0.05 MUM concentration also caused a decrease in the number of active TOK1 (two-pore outward rectifiers) potassium channels, but did not significantly change their open probability. The results indicate that in C. albicans protoplast AmB causes a decrease in cell membrane integrity by interaction with its lipid phase but not with ion channels. Fluorescence microscopy techniques showed that AmB treatment, in clinical concentrations, had no effect on the percentage of PI-positive protoplasts. AmB treatment in the concentrations tested did not cause a rapid reduction of the number of C. albicans protoplasts. However, there was a significant loss of replication competency and numerous morphological and physiological disorders, including cytoplasm shrinking, abnormal morphology of the nucleus and mitochondria, a sudden decrease in the MTT reduction level and oxidative stress. Our results show that the induction of yeast cell death by AmB, at therapeutic doses, is a multistage and long-term process involving multiple intracellular pathways. PMID- 25557524 TI - Measurement of pulp blood flow rates in maxillary anterior teeth using ultrasound Doppler flowmetry. AB - AIM: To measure pulp blood flow rates of clinically normal maxillary anterior teeth of healthy adults using ultrasound Doppler flowmetry (UDF). METHODOLOGY: A total of 359 anterior teeth from 63 patients (mean age, 29.8 years; range, 22-52 years; 26 females and 36 males) were included. The data were collected according to tooth type (three groups: central incisors, lateral incisors and canines). An MM-D-K (Minimax, Moscow, Russia) ultrasound Doppler imaging instrument was used to measure pulp blood flow. Differences between the tooth types were analysed with one-way anova and a Bonferroni correction at the 95% confidence level. RESULTS: The mean average linear velocities during the systolic period (Vams) of the central incisors, lateral incisors and canines were 0.58, 0.58 and 0.52 cm s( 1) , respectively. There were no significant differences in the mean Vams between the tooth types (P > 0.05). CONCLUSIONS: Within the limitations of this study, the pulp blood velocities of clinically normal, maxillary anterior teeth of healthy adults were between 0.5 and 0.6 cm s(-1) . There were no significant differences in mean blood flow rates between maxillary central incisors, lateral incisors and canines. PMID- 25557525 TI - Normal esophageal pressure topography metrics for data derived from the Sandhill Unisensor high-resolution manometry assembly in supine and sitting positions. AB - BACKGROUND: Normal values of the esophageal motor function parameters for high resolution manometry (HRM-EPT) adopted by the Chicago classification were established using the proprietary system of Given Imaging. It is conceivable that normal values of a system do not apply to data from others. Most studies using HRM were based on supine swallows, whereas deglutition occurs mostly in the upright position. We wished to establish normal values for HRM-EPT parameters obtained with the Sandhill's HRM-EPT system and compare the results in supine and sitting positions. METHODS: Sixty-nine healthy volunteers, 38 females, median age 27 years, were included in this study. All underwent supine HRM, and 34 of them underwent sitting HRM, with at least 10 single 5-mL swallows for analysis obtained in each position. KEY RESULTS: The normal range (5-95th percentiles) for the following parameters was calculated: distal contractile integral (DCI), 606 4998 mmHg.s.cm; contractile front velocity (CFV), 2.0-6.5 cm/s; distal latency (DL), 5.1-8.8 s; intrabolus pressure (IBP), 1.9-17.6 mmHg; upper esophageal sphincter (UES) pressure, 45.2-186.9 mmHg; esophagogastric junction (EGJ) length, 1.8-4 cm; EGJ resting pressure, 8.1-61.6 mmHg, and integrated relaxation pressure (IRP) 2.5-23.5 mmHg. Normal values of EGJ resting pressure, IRP, DCI, and IBP but not CFV, DL, and UES resting pressure were significantly lower in the sitting posture. CONCLUSIONS & INFERENCES: Studies performed with Sandhill's HRM-EPT system should use its own specific normal data. Normal values should be established for different study. PMID- 25557526 TI - Multiple clustered dermatofibroma presenting in a segmental distribution. AB - Multiple dermatofibromas is a rare entity consisting of more than fifteen lesions. Multiple clustered dermatofibroma is a distinct variant of multiple dermatofibromas and is defined as a well-demarcated plaque composed of individual dermatofibromas. We report a 16-year-old boy with multiple clustered dermatofibroma in a segmental distribution, which has previously not been reported in the literature. PMID- 25557527 TI - Methods to determine the pressure dependence of the molecular order parameter in (bio)macromolecular fibres. AB - The experimental realization and an algorithm for analysing the pressure dependence of the molecular order parameter of specific structural moieties in (bio)macromolecular fibres are described. By employing a diamond anvil cell (DAC) the polarization-dependent IR-transmission and in parallel, using an integrated microscope, the macroscopic orientation of the fibres is determined. This enables one to separate between order and disorder at macroscopic and microscopic scales. Using the example of spider silk the pressure dependence of the molecular order parameter of alanine groups being located within nano-crystalline building blocks is deduced and found to decrease reversibly by 0.01 GPa(-1) when varying the external hydrostatic pressure between 0 and 3 GPa. PMID- 25557528 TI - Follicular T helper cells and humoral reactivity in kidney transplant patients. AB - Memory B cells play a pivotal role in alloreactivity in kidney transplantation. Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients, therefore we investigated the absolute numbers and function of peripheral Tfh cells (CD4(POS) CXCR5(POS) T cells) in patients before and after transplantation. In addition, we studied their relationship with the presence of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA), and the presence of Tfh cells in rejection biopsies. After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor antagonist. After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA. In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures. Our data on Tfh cells in kidney transplantation demonstrate that Tfh cells may mediate humoral alloreactivity, which is also seen in the immunosuppressed milieu. PMID- 25557529 TI - Tumour suppressors and cellular senescence. AB - Cellular senescence is a stable cell cycle arrest that normal cells undergo in response to a variety of intrinsic and extrinsic stimuli, including progressive telomere shortening, changes in telomeric structure or other forms of genotoxic as well nongenotoxic stress. Senescence is thought to have originated as a remodelling program that is active in embryonic development and acts as a key tumour suppressor mechanism during the reproductive stage in early adult life, by leading to the removal of potentially cancerous cells. However, in later adult life, it promotes organismal aging by compromising tissue repair and regeneration due to the accumulation of senescent cells, depletion of stem/progenitor cells and secretion of an array of inflammatory cytokines, chemokines and matrix metalloproteases. Whilst suppressing tumour formation in the senescent cells, these inflammatory cytokines, chemokines and metalloproteases can promote tumour progression and metastasis in the neighbouring cells. Herein, we review the molecular pathways that underlie cellular senescence and how it contributes towards tumour suppression. PMID- 25557530 TI - Amyloid polyneuropathy caused by wild-type transthyretin. AB - INTRODUCTION: Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene. METHODS: We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. RESULTS: The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly patients with cardiomyopathy, but a few cases of polyneuropathy have been reported. CONCLUSIONS: This entity is especially noteworthy in light of emerging treatment options for hereditary transthyretin amyloidosis, which are likely to also be beneficial in wild-type disease. PMID- 25557531 TI - Feasibility study of colestipol as an oral phosphate binder in hemodialysis patients. AB - BACKGROUND: Currently available calcium- and aluminium-based phosphate binders are dose limited because of potential toxicity, and newer proprietary phosphate binders are expensive. We examined phosphate-binding effects of the bile acid sequestrant colestipol, a non-proprietary drug that is in the same class as sevelamer. METHODS: The trial was an 8 week prospective feasibility study in stable hemodialysis patients using colestipol as the only phosphate binder, preceded and followed by a washout phase of all other phosphate binders. The primary study endpoint was weekly measurements of serum phosphate. Secondary endpoints were serum calcium, lipids and coagulation status. Analyses used random effects mixed models. RESULTS: Thirty patients were screened for participation of which 26 met criteria for treatment. At a mean dose of 8.8 g/24 h of colestipol by study end, serum phosphate dropped from 2.24 to 1.96 mmol/L (P < 0.001). Three patients required calcium supplementation. LDL cholesterol dropped from 1.75 to 1.2 mmol/L (P < 0.001). Three patients dropped out because of side effects or intolerance of the required dose. CONCLUSION: The results support the feasibility of a larger trial to determine the efficacy of colestipol as a phosphate binder and that other non-proprietary anion-exchange resins may also warrant investigation. PMID- 25557532 TI - Prevalence of parathyroid carcinoma in 348 patients with multiple endocrine neoplasia type 1 - case report and review of the literature. AB - OBJECTIVE: To report the prevalence of parathyroid carcinoma (PC) in patients with multiple endocrine neoplasia type 1 (MEN1) and review of the literature. BACKGROUND: Primary hyperparathyroidism (PHP) is the most common manifestation of MEN1. The occurrence of PC in patients with MEN1 is rare and the literature regarding the clinical manifestations - including the prevalence of the disease - is scarce. CONTEXT: Single tertiary care centre experience from 1977 to 2013. DESIGN: Electronic search of the medical records to identify a cohort of patients with MEN1. Literature review based on current case reports. PATIENTS: Single case of PC in a cohort of 348 patients with MEN1. Ten cases of PC in patients with MEN1 reported in the literature. MEASUREMENT: Clinical features of PC in patients with MEN1. RESULTS: The prevalence of PC in 348 patients with MEN1 was found to be 0.28% (95% CI, 0-1.4%). Based on the current published cases of PC in patients with MEN1, 54.5% were women, mean age at diagnosis was 48.3 years, and the serum PTH concentrations at least four times the upper limit of the reference range in 73% of the cases. CONCLUSION: PC in patients with MEN 1 is rare with a prevalence of 0.28%, and the clinical features are similar to PC in patients without MEN1. PMID- 25557533 TI - Enhancing electrochemical water-splitting kinetics by polarization-driven formation of near-surface iron(0): an in situ XPS study on perovskite-type electrodes. AB - In the search for optimized cathode materials for high-temperature electrolysis, mixed conducting oxides are highly promising candidates. This study deals with fundamentally novel insights into the relation between surface chemistry and electrocatalytic activity of lanthanum ferrite based electrolysis cathodes. For this means, near-ambient-pressure X-ray photoelectron spectroscopy (NAP-XPS) and impedance spectroscopy experiments were performed simultaneously on electrochemically polarized La0.6 Sr0.4 FeO3-delta (LSF) thin film electrodes. Under cathodic polarization the formation of Fe(0) on the LSF surface could be observed, which was accompanied by a strong improvement of the electrochemical water splitting activity of the electrodes. This correlation suggests a fundamentally different water splitting mechanism in presence of the metallic iron species and may open novel paths in the search for electrodes with increased water splitting activity. PMID- 25557534 TI - Nicolau syndrome after benzathine penicillin treated with hyperbaric oxygen therapy. PMID- 25557535 TI - Preparation and characterization of debranched-starch/phosphatidylcholine inclusion complexes. AB - In this study, debranched-starch/phosphatidylcholine inclusion complexes were prepared. The effect of reaction parameters such as reaction temperature, reaction time, and addition amount of phosphatidylcholine on the phosphatidylcholine payload and inclusion rate was investigated. The phosphatidylcholine payload and inclusion rate prepared under the optimal conditions were 106 mg/g and 84.8%, respectively. The formation of debranched starch/phosphatidylcholine inclusion complexes was confirmed by the results of XRD and FT-IR. Furthermore, the molecular, cluster, and fractal structures of the complexes were investigated using (13)C CP/MAS NMR and SAXS. The results indicated that the inclusion complexes were formed by hydrophobic interactions between alkyl chain of phosphatidylcholine and debranched-starch helix cavity. The complexes possessed a mass fractal structure, and a semicrystalline structure with a Bragg distance of 19.04 nm formed. After complexation, the stability of phosphatidylcholine was significantly improved, and phosphatidylcholine of the complexes can be gradually released with pancreatin treatment. This study revealed that debranched-starch can be used as an effective carrier of phosphatidylcholine for the purpose of improving its stability. PMID- 25557536 TI - Predicting recurrence after chronic subdural haematoma drainage. AB - BACKGROUND: Recurrence of chronic subdural haematomas (CSDHs) after surgical drainage is a significant problem with rates up to 20%. This study focuses on determining factors predictive of haematoma recurrence and presents a scoring system stratifying recurrence risk for individual patients. METHODS: Between the years 2005 and 2009, 331 consecutive patients with CSDHs treated with surgery were included in this study. Univariate and multivariate analyses were performed searching for risk factors of increased post-operative haematoma volume and haematoma recurrence requiring repeat drainage. RESULTS: We found a 12% reoperation rate. CSDH septation (seen on computed tomogram scan) was found to be an independent risk factor for recurrence requiring reoperation (p=0.04). Larger post-operative subdural haematoma volume was also significantly associated with requiring a second drainage procedure (p<0.001). Independent risk factors of larger post-operative haematoma volume included septations within a CSDH (p<0.01), increased pre-operative haematoma volume (p<0.01), and a greater amount of parenchymal atrophy (p=0.04). A simple scoring system for quantifying recurrence risk was created and validated based on patient age (< or >= 80 years), haematoma volume (< or >= 160 cc), and presence of septations within the subdural collection (yes or no). CONCLUSION: Septations within CSDHs are associated with larger post-operative residual haematoma collections requiring repeat drainage. When septations are clearly visible within a CSDH, craniotomy might be more suitable as a primary procedure as it allows greater access to a septated subdural collection. Our proposed scoring system combining haematoma volume, age, and presence of septations might be useful in identifying patients at higher risk for recurrence. PMID- 25557537 TI - A mentalization-based approach to the development of the therapeutic alliance in the treatment of schizophrenia. AB - This article presents a clinical illustration of a mentalization-based approach to the development of a therapeutic alliance in the treatment of schizophrenia. A clinically focused overview of the attachment-based understanding of mentalization central to the mentalization-based treatment model is first provided. This is followed by a brief summary of the theory and evidence supporting the possible link between attachment disturbances and deficits of mental state understanding in schizophrenia. A case presentation then illustrates the application of core mentalization-based principles and interventions to enhance the therapeutic alliance by addressing disruptions of mentalization and reducing paranoia in the treatment of a patient with early course schizophrenia. PMID- 25557538 TI - Relationship between pharmacokinetics and pharmacodynamics of calcineurin inhibitors in renal transplant patients. AB - The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs, which are typically employed in the field of organ transplantation. Both drugs have narrow therapeutic indices, highly variable pharmacokinetics, and are associated with severe adverse effects. In current clinical routine, the dose finding of CNIs is based on the measurement of their blood concentrations. However, this method is limited in its ability to determine the biological impact of the drug. Alternative monitoring strategies, focusing on the pharmacodynamics of CNIs, could help to personalize drug dosing and optimize the treatment with CNIs. Therefore, we analyzed the relationship between pharmacokinetic and pharmacodynamic of the CNIs CsA (n = 9) and Tac (n = 8) in stable renal transplant patients during a 12-h dosing period. We observed a significant decrease in the drug-blood concentration during the course of the day and in parallel a significant recovery of T cell function. In addition, our data document that analysis of intracellular interleukin (IL)-2 production and determination of the IL-2 release are accurate parameters for monitoring the pharmacodynamics of CNIs. PMID- 25557540 TI - Abundance of Cottus poecilopus is influenced by O2 saturation, food density and Salmo trutta in three tributaries of the Roznovska Becva River, Czech Republic. AB - The distribution patterns of alpine bullhead Cottus poecilopus in three tributary streams of the Roznovska Becva River (Danube basin) were studied with respect to temperature, oxygen concentration and saturation, shading, current, conductivity, total organic carbon (TOC), nitrates and phosphates, biochemical oxygen demand (BOD5 ), pH, redox potential, bottom grain structure, density of macroinvertebrates and the abundance of brown trout Salmo trutta. Sites with lower abundance per hectare of C. poecilopus differed significantly in dissolved oxygen saturation, density of macroinvertebrates during the autumn period (positive correlation with C. poecilopus) and in abundance per hectare of S. trutta (negative correlation). These results indicate that these factors significantly influence the distribution of this endangered species in the studied catchment and that stocking of S. trutta will impair its recovery. PMID- 25557539 TI - Immune complex negatively regulates Toll-like receptor 9-mediated immune responses in B cells through the inhibitory Fc-gamma receptor IIb. AB - Because inappropriate activation of Toll-like receptor 9 (TLR9) may induce pathological damage, negative regulation of the TLR9-triggered immune response has attracted considerable attention. Nonpathogenic immune complex (IC) has been demonstrated to have beneficial therapeutic effects in some kinds of autoimmune diseases. However, the role of IC in the regulation of TLR9-triggered immune responses and the underlying mechanisms remain unclear. In this study, it was demonstrated that IC stimulation of B cells not only suppresses CpG oligodeoxynucleotide (CpG-ODN)-induced pro-inflammatory IL-6 and IgM kappa production, but also attenuates CD40 and CD80 expression. Furthermore, our results suggest that the receptor for the Fc portion of IgG (FcgammaR) IIb is involved in the suppressive effect of IC on TLR9-mediated CD40, CD80 and IL-6 expression. Finally, it was found that IC down-regulates TLR9 expression in CpG ODN activated B cells. Our results provide an outline of a new pathway for the negative regulation of TLR9-triggered immune responses in B cells via FcgammaRIIb. A new mechanistic explanation of the therapeutic effect of nonpathogenic IC on inflammatory and autoimmune diseases is also provided. PMID- 25557541 TI - Regenerative metamorphosis in hairs and feathers: follicle as a programmable biological printer. PMID- 25557542 TI - Communication between nurses and physicians: strategies to surviving in the emergency department trenches. AB - The emergency department (ED) is a challenging and stressful work environment where communication lapses can lead to negative health outcomes. This article offers strategies to Emergency Medicine residents, nurses and staff physicians on how to improve communication to optimize patient care. PMID- 25557543 TI - Bevacizumab-induced hypertension is a predictive marker for improved outcomes in patients with recurrent glioblastoma treated with bevacizumab. AB - BACKGROUND: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor and is approved for the treatment of patients with recurrent glioblastoma (GBM). Previous authors have reported differential response to bevacizumab on an individual basis. Bevacizumab-induced hypertension is a well documented side effect, and some reports have suggested this occurrence to be related to treatment outcome in other cancers. In the current study, the authors analyzed patients with recurrent GBM who were treated with bevacizumab based on whether the patients developed drug-induced hypertension. METHODS: All patients with GBM treated within the Emory Healthcare system from 2007 through 2012 were reviewed. A total of 82 patients were identified who received bevacizumab for the treatment of recurrent GBM and were included in the current study. Patients were classified as normotensive or hypertensive depending on whether hypertension developed that was attributable to therapy. Progression-free survival (PFS) and overall survival (OS) were graphed by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards method. RESULTS: The median follow-up was 19.7 months. Of the 82 patients with recurrent GBM who were treated with bevacizumab, 30 developed drug-induced hypertension. The median time to the development of hypertension was 21 days. The median PFS for the normotensive and hypertensive groups were 2.5 months (95% confidence interval [95% CI], 1.6-3.0 months) and 6.7 months (95% CI, 4.6-10.0 months), respectively (P<.001). The median OS times for the normotensive and hypertensive groups were 4.9 months (95% CI, 4.4-6.8 months) and 11.7 months (95% CI, 9.0-20.5 months), respectively (P<.001). CONCLUSIONS: Patients with recurrent GBM who developed bevacizumab-induced hypertension demonstrated significantly better PFS and OS compared with normotensive individuals. Bevacizumab-induced hypertension may be a physiologic marker of outcome in patients with recurrent GBM. PMID- 25557544 TI - Refreshing memory traces: thinking of an item improves retrieval from visual working memory. AB - This article provides evidence that refreshing, a hypothetical attention-based process operating in working memory (WM), improves the accessibility of visual representations for recall. "Thinking of", one of several concurrently active representations, is assumed to refresh its trace in WM, protecting the representation from being forgotten. The link between refreshing and WM performance, however, has only been tenuously supported by empirical evidence. Here, we controlled which and how often individual items were refreshed in a color reconstruction task by presenting cues prompting participants to think of specific WM items during the retention interval. We show that the frequency with which an item is refreshed improves recall of this item from visual WM. Our study establishes a role of refreshing in recall from visual WM and provides a new method for studying the impact of refreshing on the amount of information we can keep accessible for ongoing cognition. PMID- 25557545 TI - Atg27 tyrosine sorting motif is important for its trafficking and Atg9 localization. AB - During autophagy, the transmembrane protein Atg27 facilitates transport of the major autophagy membrane protein Atg9 to the preautophagosomal structure (PAS). To better understand the function of Atg27 and its relationship with Atg9, Atg27 trafficking and localization were examined. Atg27 localized to endosomes and the vacuolar membrane, in addition to previously described PAS, Golgi and Atg9 positive structures. Atg27 vacuolar membrane localization was dependent on the adaptor AP-3, which mediates direct transport from the trans-Golgi to the vacuole. The four C-terminal amino acids (YSAV) of Atg27 comprise a tyrosine sorting motif. Mutation of the YSAV abrogated Atg27 transport to the vacuolar membrane and affected its distribution in TGN/endosomal compartments, while PAS localization was normal. Also, in atg27(DeltaYSAV) or AP-3 mutants, accumulation of Atg9 in the vacuolar lumen was observed upon autophagy induction. Nevertheless, PAS localization of Atg9 was normal in atg27(DeltaYSAV) cells. The vacuole lumen localization of Atg9 was dependent on transport through the multivesicular body, as Atg9 accumulated in the class E compartment and vacuole membrane in atg27(DeltaYSAV) vps4Delta but not in ATG27 vps4Delta cells. We suggest that Atg27 has an additional role to retain Atg9 in endosomal reservoirs that can be mobilized during autophagy. PMID- 25557546 TI - Ubiquitin-SUMO circuitry controls activated fanconi anemia ID complex dosage in response to DNA damage. AB - We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase core complex, and the SUMO E3 ligases PIAS1/PIAS4 and is antagonized by the SUMO protease SENP6. SUMOylation of the ID complex drives substrate selectivity by triggering its polyubiquitylation by the SUMO-targeted ubiquitin ligase RNF4 to promote its removal from sites of DNA damage via the DVC1-p97 ubiquitin segregase complex. Deregulation of ID complex SUMOylation compromises cell survival following replication stress. Our results uncover a regulatory role for SUMOylation in the FA pathway, and we propose that ubiquitin-SUMO signaling circuitry is a mechanism that contributes to the balance of activated ID complex dosage at sites of DNA damage. PMID- 25557547 TI - Molecular basis for SMC rod formation and its dissolution upon DNA binding. AB - SMC condensin complexes are central modulators of chromosome superstructure in all branches of life. Their SMC subunits form a long intramolecular coiled coil, which connects a constitutive "hinge" dimerization domain with an ATP-regulated "head" dimerization module. Here, we address the structural arrangement of the long coiled coils in SMC complexes. We unequivocally show that prokaryotic Smc ScpAB, eukaryotic condensin, and possibly also cohesin form rod-like structures, with their coiled coils being closely juxtaposed and accurately anchored to the hinge. Upon ATP-induced binding of DNA to the hinge, however, Smc switches to a more open configuration. Our data suggest that a long-distance structural transition is transmitted from the Smc head domains to regulate Smc-ScpAB's association with DNA. These findings uncover a conserved architectural theme in SMC complexes, provide a mechanistic basis for Smc's dynamic engagement with chromosomes, and offer a molecular explanation for defects in Cornelia de Lange syndrome. PMID- 25557548 TI - Interaction of Chk1 with Treslin negatively regulates the initiation of chromosomal DNA replication. AB - Treslin helps to trigger the initiation of DNA replication by promoting integration of Cdc45 into the replicative helicase. Treslin is a key positive regulatory target of cell-cycle control mechanisms; activation of Treslin by cyclin-dependent kinase is essential for the initiation of replication. Here we demonstrate that Treslin is also a critical locus for negative regulatory mechanisms that suppress initiation. We found that the checkpoint-regulatory kinase Chk1 associates specifically with a C-terminal domain of Treslin (designated TRCT). Mutations in the TRCT domain abolish binding of Chk1 to Treslin and thereby eliminate Chk1-catalyzed phosphorylation of Treslin. Significantly, abolition of the Treslin-Chk1 interaction results in elevated initiation of chromosomal DNA replication during an unperturbed cell cycle, which reveals a function for Chk1 during a normal S phase. This increase is due to enhanced loading of Cdc45 onto potential replication origins. These studies provide important insights into how vertebrate cells orchestrate proper initiation of replication. PMID- 25557549 TI - Global analysis of the RNA-protein interaction and RNA secondary structure landscapes of the Arabidopsis nucleus. AB - Posttranscriptional regulation in eukaryotes requires cis- and trans-acting features and factors including RNA secondary structure and RNA-binding proteins (RBPs). However, a comprehensive view of the structural and RBP interaction landscape of nuclear RNAs has yet to be compiled for any organism. Here, we use our ribonuclease-mediated structure and RBP-binding site mapping approaches to globally profile these features in Arabidopsis seedling nuclei in vivo. We reveal anticorrelated patterns of secondary structure and RBP binding throughout nuclear mRNAs that demarcate sites of alternative splicing and polyadenylation. We also uncover a collection of protein-bound sequence motifs, and identify their structural contexts, co-occurrences in transcripts encoding functionally related proteins, and interactions with putative RBPs. Finally, using these motifs, we find that the chloroplast RBP CP29A also interacts with nuclear mRNAs. In total, we provide a simultaneous view of the RNA secondary structure and RBP interaction landscapes in a eukaryotic nucleus. PMID- 25557553 TI - The public health crisis of child sexual abuse in low and middle income countries: an integrative review of the literature. AB - PURPOSE: Theoretical and empirical studies conducted to ascertain the incidence and characteristics of child sexual abuse (CSA) in developing countries around the world are inconsistent and poorly synthesized. In order to prevent and respond to these heinous acts, clinicians and policymakers require a substantive body of evidence on which to base interventions and treatment programs. The purpose of this study is to conduct an integrative review of the literature concerning CSA in non-industrialized nations. Ultimately, this evidence could be used to drive research and policy implementation in this area. METHODS: An integrative literature review of publications identified through a comprehensive search of five relevant databases (PubMed, CINAHL, EMBase, PsycINFO, and Web of Science) regarding the incidence and characteristics of all forms of child sexual assault in low and middle-income countries (LMICs) since 1980. Independent and collective thematic assessment and analysis was utilized to identify major concepts of the phenomenon. FINDINGS: Forty-four articles were identified. These represented 32 separate low or middle-income countries. More studies were identified in low-income countries, and there was a disproportional distribution of studies conducted on regions of the world. CSA has been identified at all levels of society in nearly every region and continent of the world. It is being falsely perceived as a new phenomenon in some developing countries, most likely as a result of increases in CSA reporting. Researching and discussing CSA is difficult because of the sensitive and taboo nature of the topic. Four major themes emerged including difficulty of accurate measurement, barriers to reporting, barriers to justice, and the false perception of CSA as a new phenomenon. Themes of early marriage, human trafficking, sexual coercion and forced first sex, and males as victims have been identified as characteristics and topics placing individuals at risk for CSA. Poverty and its resultant social or family strain are exacerbating factors to CSA. CONCLUSIONS: There is inadequate representation of CSA research in LMICs, and an increasing awareness that sexual abuse of children is an endemic threat to the health and safety of children worldwide. This review lays the foundation for an array of further areas of analysis to explore the expanse of unanswered questions that remain regarding the phenomena of CSA in low and middle-income countries. CLINICAL RELEVANCE: Healthcare workers hold a unique position and responsibility for identifying and responding to CSA. PMID- 25557551 TI - CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases. AB - DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles in various biological processes. The TET dioxygenases catalyze iterative oxidation of 5mC, leading to eventual demethylation. Inactivation of TET enzymes causes multistage developmental defects, impaired cell reprogramming, and hematopoietic malignancies. However, little is known about how TET activity is regulated. Here we show that all three TET proteins bind to VprBP and are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4(VprBP)) on a highly conserved lysine residue. Deletion of VprBP in oocytes abrogated paternal DNA hydroxymethylation in zygotes. VprBP-mediated monoubiquitylation promotes TET binding to chromatin. Multiple recurrent TET2 inactivating mutations derived from leukemia target either the monoubiquitylation site (K1299) or residues essential for VprBP binding. Cumulatively, our data demonstrate that CRL4(VprBP) is a critical regulator of TET dioxygenases during development and in tumor suppression. PMID- 25557550 TI - Dicer-TRBP complex formation ensures accurate mammalian microRNA biogenesis. AB - RNA-mediated gene silencing in human cells requires the accurate generation of ~22 nt microRNAs (miRNAs) from double-stranded RNA substrates by the endonuclease Dicer. Although the phylogenetically conserved RNA-binding proteins TRBP and PACT are known to contribute to this process, their mode of Dicer binding and their genome-wide effects on miRNA processing have not been determined. We solved the crystal structure of the human Dicer-TRBP interface, revealing the structural basis of the interaction. Interface residues conserved between TRBP and PACT show that the proteins bind to Dicer in a similar manner and by mutual exclusion. Based on the structure, a catalytically active Dicer that cannot bind TRBP or PACT was designed and introduced into Dicer-deficient mammalian cells, revealing selective defects in guide strand selection. These results demonstrate the role of Dicer-associated RNA binding proteins in maintenance of gene silencing fidelity. PMID- 25557554 TI - Systematic review of health-related quality of life issues in locally recurrent rectal cancer. AB - The standardization of surgical techniques supplemented with appropriate neoadjuvant chemoradiation has led to the decline in local recurrence rates of rectal cancer (LRRC) from 25-50% to 5-10%. The outcomes reported for surgical intervention in LRRC is encouraging, however, a number of controversies exist especially in the ultra-advanced and palliative setting. Incorporating health related quality of life (HRQoL) outcomes in this field could supplement traditional clinical endpoints in assessing the effectiveness of surgical intervention in this cohort. This review aimed to identify the HRQOL themes that might be relevant to patients with LRRC. A systematic review was undertaken to identify all studies reporting HRQoL in LRRC. Each study was evaluated with regards to its design and statistical methodology. A meta-synthesis of qualitative and quantitative studies was undertaken to identify relevant HRQoL themes. A total of 14 studies were identified, with 501 patients, with 80% of patients undergoing surgery. HRQoL was the primary endpoint in eight studies. Eight themes were identified: physical, psychological and social impact, symptoms, financial and occupational impact, relationships with others, communication with healthcare professionals and sexual function. The impact on HRQoL is multifactorial and wide ranging, with a number of issues identified that are not included in current measures. These issues must be incorporated into the assessment of HRQoL in LRRC through the development of a validated, disease specific tool. PMID- 25557555 TI - A cost-benefit analysis of the immunisation of children against respiratory syncytial virus (RSV) using the English Hospital Episode Statistics (HES) data set. AB - Respiratory syncytial virus (RSV) is a common cause of respiratory infection that is highly prevalent in infants, particularly those with underlying medical conditions. Severe cases of RSV require hospitalisation as well as admission to intensive care and may even result in death. The objective of the study was to measure the net benefits that could arise from an immunisation programme of infants that may well eradicate RSV to a high degree and save the direct and indirect medical care costs from hospitalisation, morbidity and the gain from potential life-time earnings by reducing the probability of mortality. In this context, the majority of existing empirical investigations are based on data from clinical trials, and where relevant facts are not available, a series of strong assumptions is derived from the published literature, whereas in this study, for the first time, the hospital episode statistics database is used to calculate the cost-benefit ratios. The methodology of the analysis adopts a cost-benefit approach to assess the impact of the immunisation and whether it is beneficial to society. The underlying assumptions of the basic model are assessed by adopting a sensitivity analysis. The results show that a number of categories are cost effective with the use of the passive drug, which means benefits by raising the life expectancy and quality as well as reducing the resource burden on society. PMID- 25557556 TI - Meta-analysis of Duct-to-duct versus Roux-en-Y biliary reconstruction following liver transplantation for primary sclerosing cholangitis. AB - This meta-analysis aimed to compare outcomes following bile duct reconstruction in patients with primary sclerosing cholangitis (PSC) undergoing liver transplantation depending on whether duct-to-duct or Roux-en-Y anastomosis was utilized. An electronic search was performed of the MEDLINE, EMBASE, PubMed databases using both subject headings (MeSH) and truncated word searches. Pooled risk ratios and mean difference were calculated using the fixed-effects and random-effects models for meta-analysis. Ten studies including 910 patients met the inclusion criteria. There was no difference in the overall incidence of biliary strictures between the two groups [odds ratio (OR) 1.06 (0.68, 1.66); (P = 0.80)]. The anastomotic stricture rate was similar, [OR 1.18 (0.56, 2.50); (P = 0.67)]. Ascending cholangitis was higher in the Roux-en-Y group [OR 2.91 (1.17, 7.23); (P = 0.02)]. Anastomotic bile leak rates, graft survival, PSC recurrence and number of patients diagnosed with cholangiocarcinoma following transplantation were comparable between both groups. Duct-to-duct and Roux-en-Y reconstruction had comparable outcomes. Both techniques are associated with similar incidence of biliary stricture. The bilioenteric reconstruction was associated with a higher risk of cholangitis. The incidence of de novo cholangiocarcinoma was similar in both groups. Duct-to-duct reconstruction should be considered when feasible in patients with PSC. PMID- 25557557 TI - Evaluation of Treatments for Pruritus in Epidermolysis Bullosa. AB - Pruritus is a common complication in patients with epidermolysis bullosa (EB). There is limited published data about the treatments that individuals with EB use for pruritus. The objective of the current study was to determine quantitatively which treatments individuals with EB have used for pruritus and to evaluate the perceived effectiveness of these treatments in pruritus relief. A questionnaire was developed to evaluate the treatments and therapies used for pruritus in patients of all ages and for all types of EB. Questions about bathing products, moisturizers, topical products, oral medications, dressings, and alternative therapies were included. A 5-point Likert scale (-2 = relieves itch a lot, -1 = relieves itch a little, 0 = no change, 1 = increases itch a little, 2 = increases itch a lot) was used to evaluate perceived effectiveness. Patients from seven North American EB centers were invited to participate. Greasy ointments (53.4%), lotions (45.2%), creams (40.4%), and oral hydroxyzine (39.0%) were the most frequently used treatments for pruritus. Treatments that were used frequently and perceived to be the most effective included creams (mean = -1.1), topical prescription corticosteroids (mean = -1.0), oils (mean = -0.9), oral hydroxyzine (mean = -0.9), topical diphenhydramine (mean = -0.9), and vaporizing rub (menthol, camphor, eucalyptus) (mean = -0.9). Systemic opioids (mean = 0.3), adherent bandages (mean = 0.3), and bleach baths (mean = 0.2) slightly increased pruritus. Randomized controlled trials of therapies will be necessary to develop evidence-based recommendations for control of pruritus in individuals with EB. PMID- 25557558 TI - The inflammatory cytokine IL-1beta is involved in bladder remodeling after bladder outlet obstruction in mice. AB - AIMS: We investigated the relationship between IL-1beta and morphological and functional changes following partial bladder outlet obstruction (pBOO). METHODS: Female wild-type C57/BL6 mice (WT) and IL-1beta-/- mice (KO) were used. Animals were sacrificed either 1 or 3 weeks after pBOO or sham surgery, and their bladders were harvested to determine bladder weight, for RT-PCR to measure interleukin-1beta (IL-1beta), insulin growth factor-1 (IGF-1), and transforming growth factor-beta (TGF-beta) levels, and for histological analysis with Hematoxylin-Eosin (HE) staining. Cystometry was performed on conscious animals 3 weeks after surgery to evaluate urodynamic parameters. IGF-1 was also administered intraperitoneally to KO with pBOO, and bladder weight was then investigated. RESULTS: IL-1beta-mRNA levels were significantly higher in WT-pBOO than in WT-sham. IGF-1-mRNA and TGF-beta-mRNA levels were also significantly higher in WT-pBOO than in WT-sham; however, these increases were smaller in KO pBOO than in WT-pBOO. Bladder weight was significantly higher in WT-pBOO than in WT-sham, while increases in bladder weight were significantly suppressed in KO pBOO. HE staining revealed the thickened bladder wall in WT-pBOO, and this phenomenon was less in KO-pBOO than in WT-pBOO. Regarding the urodynamic parameters examined, micturition pressure and bladder capacity were significantly higher in WT-pBOO than in WT-sham, but remained unchanged in KO-pBOO. The administration of IGF-1 to KO-pBOO led to similar increases in bladder weight and the thickened bladder wall as those observed in WT-pBOO. CONCLUSION: IL-1beta has the potential to induce bladder remodeling and deteriorate urodynamic parameters in pBOO. PMID- 25557559 TI - Emerging drugs for squamous cell lung cancer. AB - INTRODUCTION: The management of advanced NSCLC has been shifted by histology driven treatment and molecularly targeted therapy, especially in lung adenocarcinoma. However, as the second most common histology in NSCLC, the treatment options for squamous cell lung cancer (SQCLC) remain very limited. AREAS COVERED: The review first discusses the role of histology in management of NSCLC and new cytotoxic agents in SQCLC, and then addresses genomic characterization and potential molecular targets in SQCLC. The article then provides an overview for several major categories of novel molecularly targeted therapies and immune-based strategies with particular attention to ongoing SQCLC trials. EXPERT OPINION: The key challenges in drug development are to uncover novel actionable targets and to identify predictive biomarkers. Progress in genomic analysis has identified some promising targetable genes and oncogenic pathways in SQCLC with a wave of targeted agents being tested in clinical trials. Immunotherapy has also raised great interest in management of SQCLC, especially agents targeting immune check points, cytotoxic T-lymphocyte antigen-4, programmed death-1 receptor and its ligands. Better understanding of tumor biology and development of novel targeted therapies will help to facilitate more effective personalized therapy for patients with this devastating illness. PMID- 25557560 TI - Gene delivery in tissue engineering and regenerative medicine. AB - As a promising strategy to aid or replace tissue/organ transplantation, gene delivery has been used for regenerative medicine applications to create or restore normal function at the cell and tissue levels. Gene delivery has been successfully performed ex vivo and in vivo in these applications. Excellent proliferation capabilities and differentiation potentials render certain cells as excellent candidates for ex vivo gene delivery for regenerative medicine applications, which is why multipotent and pluripotent cells have been intensely studied in this vein. In this review, gene delivery is discussed in detail, along with its applications to tissue engineering and regenerative medicine. A definition of a stem cell is compared to a definition of a stem property, and both provide the foundation for an in-depth look at gene delivery investigations from a germ lineage angle. PMID- 25557561 TI - Update to an evaluation of ICD-11 PTSD and complex PTSD criteria in a sample of adult survivors of childhood institutional abuse by Knefel & Lueger-Schuster (2013): a latent profile analysis. AB - BACKGROUND: The World Health Organization (WHO) International Classification of Diseases, 11th version (ICD-11), has proposed a trauma-related diagnosis of complex posttraumatic stress disorder (CPTSD) separate and distinct from posttraumatic stress disorder (PTSD). OBJECTIVE: To determine whether the symptoms endorsed by individuals who had experienced childhood institutional abuse form classes that are consistent with diagnostic criteria for ICD-11 CPTSD as distinct from PTSD. METHODS: A latent profile analysis (LPA) was conducted on 229 adult survivors of institutional abuse using the Brief Symptom Inventory and the PTSD Checklist-Civilian Version to assess current psychopathological symptoms. RESULTS: The LPA revealed four classes of individuals: (1) a class with elevated symptoms of CPTSD (PTSD symptoms and disturbances in self-organization); (2) a class with elevated symptoms of PTSD and low disturbances in self organization; (3) a class with elevated disturbances in self-organization symptoms and some elevated PTSD symptoms; and (4) a class with low symptoms. CONCLUSIONS: The results support the existence of a distinct group in our sample, that could be described by the proposed diagnostic category termed CPTSD more precisely than by normal PTSD. In addition, there seems to be a group of persons that do not fulfill the criteria for a trauma-related disorder but yet suffer from psychopathological symptoms. PMID- 25557562 TI - Fixing the doc fix. PMID- 25557563 TI - Ring in the new. PMID- 25557564 TI - Business intelligence, data mining, and future trends. PMID- 25557565 TI - How to code tomosynthesis. PMID- 25557566 TI - Introduction to rethinking the patient experience. PMID- 25557567 TI - The pursuit of excellence: from hotels to hospitals. PMID- 25557568 TI - ACR Appropriateness Criteria Dementia and Movement Disorders. AB - Neurodegenerative disease, including dementia, extrapyramidal degeneration, and motor system degeneration, is a growing public health concern and is quickly becoming one of the top health care priorities of developed nations. The primary function of anatomic neuroimaging studies in evaluating patients with dementia or movement disorders is to rule out structural causes that may be reversible. Lack of sensitivity and specificity of many neuroimaging techniques applied to a variety of neurodegenerative disorders has limited the role of neuroimaging in differentiating types of neurodegenerative disorders encountered in everyday practice. Nevertheless, neuroimaging is a valuable research tool and has provided insight into the structure and function of the brain in patients with neurodegenerative disorders. Advanced imaging techniques, such as functional neuroimaging with MRI and MR spectroscopy, hold exciting investigative potential for better understanding of neurodegenerative disorders, but they are not considered routine clinical practice at this time. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25557569 TI - The impact of the Patient Protection and Affordable Care Act on radiology: beyond reimbursement. AB - The 2014 ACR Forum focused on the noneconomic implications of the Affordable Care Act on the field of radiology, with specific attention to the importance of the patient experience, the role of radiology in public and population health, and radiology's role in the effort to lower overall health care costs. The recommendations generated from the Forum seek to inform ACR leadership on the best strategies to pursue to best prepare the radiology community for the rapidly evolving health care landscape. PMID- 25557570 TI - International collaboration on clinical imaging guidelines: many hands make light work. PMID- 25557571 TI - Incidental findings on CT for suspected renal colic in emergency department patients: prevalence and types in 5,383 consecutive examinations. AB - PURPOSE: This study aimed to determine the prevalence, importance, and types of incidental findings (IF) in non-enhanced CT scans performed for suspected renal colic, based on ACR white papers and other accepted radiographic recommendations. METHODS: Retrospective review of 5,383 consecutive finalized reports of nonenhanced CT using renal colic protocol performed on adult patients at 2 emergency departments over a 5.5-year period. IF were defined as those unrelated to symptoms (as opposed to alternate causes of symptoms) and were categorized as "important" if follow-up was recommended based on recently published consensus recommendations. Subsets of reports of those with important IF were blindly re reviewed to calculate inter-rater variability for presence and categorization of important IF. RESULTS: Important IF were identified in 12.7% (95% confidence interval [CI]: 11.8%-13.6%) of scans. Prevalence of important IF increased with age: important IF in individuals age >80 years were 4 times more common than for those aged 18-30 years: 28.9% (95% CI: 22.4%-36.4%) versus 6.9% (95% CI: 5.5% 8.6%), respectively, P <= .05. Women had a higher prevalence of important IF compared with men: 13.4% (95% CI: 12.2%-14.7%) versus 11.9% (95% CI: 10.7% 13.2%), but the difference was not statically significant (P = .09). There was substantial inter-rater agreement (kappa >= 0.69) regarding presence and classification of important IFs using published guidelines. CONCLUSIONS: Important IF occurred in 12.7% of non-enhanced CT scans performed for suspected renal colic in the emergency department and are more common in older individuals. Prospective studies that use radiographic recommendations to characterize IF and examine the outcome and cost of their workup are encouraged. PMID- 25557572 TI - Effect of computerized physician order entry on imaging study indication. AB - PURPOSE: The effect of computerized physician order entry (CPOE) on imaging indication quality had only been measured in one institution's emergency department using a homegrown electronic health record with faculty physicians, and only with one instrument. To better understand how many US hospitals' recent CPOE implementations had affected indication quality, we measured its effect in a generalizable inpatient setting, using one existing and one novel instrument. METHODS: We retrospectively analyzed the indications for 100 randomly selected inpatient abdominal CT studies during 2 calendar months immediately prior to a 3/3/2012 CPOE implementation (1/1/2012-2/29/2012) and during 2 subsequent calendar months (5/1/2012-6/30/2012). We excluded 2 intervening months to avoid behaviors associated with adoption. We measured indication quality using a published 8-point explicit scoring scale and our own, novel, implicit 7-point Likert scale. RESULTS: Explicit scores increased 93% from a pre-CPOE mean +/- 95% confidence interval of 1.4 +/- 0.2 to a CPOE mean of 2.7 +/- 0.3 (P < .01). Implicit scores increased 26% from a pre-CPOE mean of 4.3 +/- 0.3 to a CPOE mean of 5.4 +/- 0.2 (P < .05). When presented with a statement that an indication was "extremely helpful," and choices ranging from "strongly disagree" = 1 to "strongly agree" = 7, implicit scores of 4 and 5 signified "undecided" and "somewhat agree," respectively. CONCLUSIONS: In an inpatient setting with strong external validity to other US hospitals, CPOE implementation increased indication quality, as measured by 2 independent scoring systems (one pre-existing explicit system and one novel, intuitive implicit system). CPOE thus appears to enhance communication from ordering clinicians to radiologists. PMID- 25557573 TI - Radiology resident preliminary reporting in an independent call environment: multiyear assessment of volume, timeliness, and accuracy. AB - PURPOSE: The objective of this paper is to assess the volume, accuracy, and timeliness of radiology resident preliminary reports as part of an independent call system. This study seeks to understand the relationship between resident year in training, study modality, and discrepancy rate. METHODS: Resident preliminary interpretations on radiographs, ultrasound, CT, and MRI from October 2009 through December 2013 were prospectively scored by faculty on a modified RADPEER scoring system. Discrepancy rates were evaluated based on postgraduate year of the resident and the study modality. Turnaround times for reports were also reviewed. Differences between groups were compared with a chi-square test with a significance level of 0.05. Institutional review board approval was waived as only deidentified data were used in the study. RESULTS: A total of 416,413 studies were reported by 93 residents, yielding 135,902 resident scores. The rate of major resident-faculty assessment discrepancies was 1.7%. Discrepancy rates improved with increasing experience, both overall (PGY-3: 1.8%, PGY-4: 1.7%, PGY 5: 1.5%) and for each individual modality. Discrepancy rates were highest for MR (3.7%), followed by CT (2.4%), radiographs (1.4%), and ultrasound (0.6%). Emergency department report turnaround time averaged 31.7 min. The average graduating resident has been scored on 2,746 +/- 267 reports during residency. CONCLUSIONS: Resident preliminary reports have a low rate of major discrepancies, which improves over 3 years of call-taking experience. Although more complex cross-sectional studies have slightly higher discrepancy rates, discrepancies were still within the range of faculty report variation. PMID- 25557574 TI - Is a picture worth a thousand words? The effect of viewing patient photographs on radiologist interpretation of CT studies. PMID- 25557575 TI - Is CT perfusion ready for liver cancer treatment evaluation? PMID- 25557576 TI - Bundling of abdomen/pelvis CT codes and change in ionizing radiation exposure. PMID- 25557577 TI - Breast biopsy Current Procedural Terminology code bundling and the impact on reimbursement. PMID- 25557578 TI - Authors' reply. PMID- 25557579 TI - Diversity matters: historical lessons. PMID- 25557581 TI - Clinical relevance of normal and tumour cell radiosensitivity in BRCA1/BRCA2 mutation carriers: a review. AB - Women harbouring BRCA1/2 mutations are known to be at higher lifetime risk of developing breast cancer than non-carriers. Compared to mastectomy, conservative surgery is also associated, in this patient population, with a higher probability to developing recurrent ipsilateral breast cancer following primary treatment. To reduce these risks, the management of BRCA1/2 - associated cancers has therefore focused on optimal prophylactic and therapeutic interventions at the time of diagnosis. In a recent past, comparative analyses of radiosensitivity levels have been carried out in murine embryos harbouring BRCA1/2 gene mutation and in non carriers. The fact that a number of these experimental data are in favour of higher radiosensitivity levels in carriers of germline mutations leads to concern regarding the potential consequences of exposure to radiation, especially in terms of excessive toxicity in normal tissues and radiation-induced malignancies. The objective of this review is to determine whether or not the potentially higher radiosensitivity of normal and tumour cells has a clinical relevance in BRCA1/2 mutations carriers in terms of disease control, acute and late adverse events, and tumourigenesis. PMID- 25557582 TI - A meta-analysis of the educational effectiveness of three-dimensional visualization technologies in teaching anatomy. AB - Many medical graduates are deficient in anatomy knowledge and perhaps below the standards for safe medical practice. Three-dimensional visualization technology (3DVT) has been advanced as a promising tool to enhance anatomy knowledge. The purpose of this review is to conduct a meta-analysis of the effectiveness of 3DVT in teaching and learning anatomy compared to all teaching methods. The primary outcomes were scores of anatomy knowledge tests expressed as factual or spatial knowledge percentage means. Secondary outcomes were perception scores of the learners. Thirty-six studies met the inclusion criteria including 28 (78%) randomized studies. Based on 2,226 participants including 2,128 from studies with comparison groups, 3DVTs (1) resulted in higher (d = 0.30, 95%CI: 0.02-0.62) factual knowledge, (2) yielded significant better results (d = 0.50, 95%CI: 0.20 0.80) in spatial knowledge acquisition, and (3) produced significant increase in user satisfaction (d = 0.28, 95%CI = 0.12-0.44) and in learners' perception of the effectiveness of the learning tool (d = 0.28, 95%CI = 0.14-0.43). The total mean scores (out of five) and +/-SDs for QUESTS's Quality and Strength dimensions were 4.38 (+/-SD 1.3) and 3.3 (+/-SD 1.7), respectively. The results have high internal validity, for the improved outcomes of 3DVTs compared to other methods of anatomy teaching. Given that anatomy teaching and learning in the modern medical school appears to be approaching a crisis, 3DVT can be a potential solution to the problem of inadequate anatomy pedagogy. PMID- 25557580 TI - Micelle-like nanoparticles as carriers for DNA and siRNA. AB - Gene therapy represents a potential efficient approach of disease prevention and therapy. However, due to their poor in vivo stability, gene molecules need to be associated with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. Cationic polymeric nanoparticles are popular carriers for small interfering RNA (siRNA) and DNA-based therapeutics for which efficient and safe delivery are important factors that need to be optimized. Micelle-like nanoparticles (MNP) (half micelles, half polymeric nanoparticles) can overcome some of the disadvantages of such cationic carriers by unifying in one single carrier the best of both delivery systems. In this review, we will discuss how the unique properties of MNP including self-assembly, condensation and protection of nucleic acids, improved cell association and gene transfection, and low toxicity may contribute to the successful application of siRNA- and DNA-based therapeutics into the clinic. Recent developments of MNP involving the addition of stimulus-sensitive functions to respond specifically to pathological or externally applied "triggers" (e.g., temperature, pH or enzymatic catalysis, light, or magnetic fields) will be discussed. Finally, we will overview the use of MNP as two-in-one carriers for the simultaneous delivery of different agents (small molecules, imaging agents) and nucleic acid combinations. PMID- 25557583 TI - Identifying causes of variability in outcomes in children with acute lymphoblastic leukemia treated in a resource-rich developing country. AB - BACKGROUND: The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions. PROCEDURE: We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children's Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases. RESULTS: Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 +/- 2.4%, 77.0 +/- 2.9%, and 81.4 +/- 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time. CONCLUSIONS: Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions. PMID- 25557584 TI - Is Irish set dancing feasible for people with Parkinson's disease in Ireland? AB - OBJECTIVE: To investigate if community-based Irish set dancing is feasible in Irish adults with Parkinson's disease. METHODS: Over an eight week period, ten participants attended one set dancing class per week and completed a home programme in parallel. Feasibility was assessed by monitoring adverse effects, participants' verbal feedback, compliance rates and feedback from an exit questionnaire. Participants were assessed using the Berg balance scale, 6-min walk test, UPDRS-3 and PDQ-39, before and after the intervention. RESULTS: No adverse effects were detected. Attendance at classes was 86%. Compliance with the home programme was 67%. Findings from the exit questionnaire showed participants enjoyed participating and reported improvements in aspects of health including balance. Quality of life improved with the dance programme and there was a trend toward improvement on the UPDRS-3. CONCLUSION: These findings suggest community based Irish set dancing is a feasible form of exercise that can positively influence quality of life. PMID- 25557585 TI - The Digital One-Abutment/One-Time Concept. A Clinical Report. AB - The digital fabrication of dental restorations on implants has become a standard procedure during the last decade. Avoiding changing abutments during prosthetic treatment has been shown to be superior to the traditional protocol. The presented concept for implant-supported single crowns describes a digital approach without a physical model from implant placement to final delivery in two appointments. A 54-year-old man was provided with a single-tooth implant on his left mandibular first molar. Before wound closure, the implant position was captured digitally with an intraoral scanning device. After bone healing at the time of second-stage surgery the final screw-retained crown fabricated without a physical model was inserted. Soft tissue healing took place at the definitive restoration, avoiding abutment changes or changes of the healing cap. These led to stable soft tissues with a minimum of surgery. The benefits of digital fabrication and the unique way to scan the implant right after placement give an additional value that would not be achieved by analog techniques. In addition to financial benefits it represents a biologically advantageous, one-abutment/one time approach with customized screw-retained, full-contour crowns or cemented crowns on custom abutments. PMID- 25557586 TI - Need for an improved vaccination rate in primary immune thrombocytopenia patients exposed to rituximab or splenectomy. A nationwide population-based study in France. AB - International guidelines on immune thrombocytopenia (ITP) management recommend vaccination against Streptococcus pneumoniae (S.p.), Haemophilus influenza b (Hib) and Neisseiria meningitidis (N.m.) before splenectomy. French guidelines also recommend these vaccinations before rituximab. The aim of this study was to assess the application of these recommendations. The French Adult ITP: a French pHarmacoepidemiological study (FAITH, n degrees ENCEPP 4574) is aimed at following in the French national health insurance system database (SNIIRAM) the cohort of all incident and persistent or chronic primary ITP adults treated in France. We assessed vaccine exposure in the 1,106 patients who entered the FAITH cohort between 2009 and 2011. Vaccination was said "recommended" if performed at least 2 weeks before rituximab or splenectomy accordingly with French guidelines. Among the 423 non-splenectomized patients exposed to rituximab, vaccination rates against S.p., Hib and N.m. were respectively 32.4%, 18.9%, and 3.8%. It was recommended in 12.8%, 6.6%, and 1.2% of the patients, respectively. Among the 178 splenectomized patients, vaccination rates were 70.2%, 47.0%, and 11.9%, respectively (recommended: 60.1%, 35.7%, and 9.5%). Among the splenectomized patients previously exposed to rituximab (n = 67), 53.3% of the vaccinations occurred during the semester following a rituximab infusion that is during the maximal B-cell depletion period. In multivariate analyses, a disease duration exceeding 3 months was the sole factor associated to recommended vaccination in rituximab-treated patients as well as in splenectomized patients. This study stresses the need of better and earlier vaccination of ITP patients. PMID- 25557587 TI - Prophylactic and therapeutic efficacy of pyridoxine supplements in the management of hand-foot syndrome during chemotherapy: a meta-analysis. AB - BACKGROUND: Hand-foot syndrome (HFS) is a common cutaneous side effect of certain systemic chemotherapeutic agents. AIM: To assess the efficacy of pyridoxine supplements in the management of HFS. METHODS: We searched PubMed, EMBASE and the Cochrane Central Register of Controlled Trials for studies reporting the efficacy of pyridoxine supplements to manage HFS. We performed a meta-analysis using HFS incidence and improvement rates to measure the preventive and treatment efficacy of pyridoxine supplementation. RESULTS: We assessed eight studies [two retrospective studies, two prospective comparative trials and four randomized controlled trials (RCTs)] for preventive efficacy and three studies (one RCT and two non-RCTs) for treatment efficacy. A random-effects meta-analysis did not find any significant association between prophylactic pyridoxine supplementation and HFS development [relative risk (RR) = 0.95; 95% CI 0.87-1.05) or any significant preventive efficacy against HFS in subgroup meta-analyses of study design, chemotherapeutic agents, pyridoxine dose, HFS severity, publication year or observation period. However, pyridoxine did show significant efficacy in treating HFS (RR = 1.75; 95% CI 1.09-2.80), but did not show efficacy in the only RCT (RR = 1.12; 95% CI 0.58-2.14). CONCLUSIONS: We found no clinical evidence to support the use of pyridoxine supplements to prevent HFS during chemotherapy. PMID- 25557588 TI - Decompressive craniectomy reduces white matter injury after controlled cortical impact in mice. AB - Reduction and avoidance of increases in intracranial pressure (ICP) after severe traumatic brain injury (TBI) continue to be the mainstays of treatment. Traumatic axonal injury is a major contributor to morbidity after TBI, but it remains unclear whether elevations in ICP influence axonal injury. Here we tested the hypothesis that reduction in elevations in ICP after experimental TBI would result in decreased axonal injury and white matter atrophy in mice. Six-week-old male mice (C57BL/6J) underwent either moderate controlled cortical impact (CCI) (n=48) or Sham surgery (Sham, n=12). Immediately after CCI, injured animals were randomized to a loose fitting plastic cap (Open) or replacement of the previously removed bone flap (Closed). Elevated ICP was observed in Closed animals compared with Open and Sham at 15 min (21.4+/-4.2 vs. 12.3+/-2.9 and 8.8+/-1.8 mm Hg, p<0.0001) and 1 day (17.8+/-3.7 vs. 10.6+/-2.0 and 8.9+/-1.9 mm Hg, p<0.0001) after injury. Beta amyloid precursor protein staining in the corpus callosum and ipsilateral external capsule revealed reduced axonal swellings and bulbs in Open compared with Closed animals (32% decrease, p<0.01 and 40% decrease, p<0.001 at 1 and 7 days post-injury, respectively). Open animals were also found to have decreased neurofilament-200 stained axonal swellings at 7 days post-injury compared with Open animals (32% decrease, p<0.001). At 4 weeks post-injury, Open animals had an 18% reduction in white matter volume compared with 34% in Closed animals (p<0.01). Thus, our results indicate that CCI with decompressive craniectomy was associated with reductions in ICP and reduced pericontusional axonal injury and white matter atrophy. If similar in humans, therapeutic interventions that ameliorate intracranial hypertension may positively influence white matter injury severity. PMID- 25557590 TI - Association efficiency of three ionic forms of oxytetracycline to cationic and anionic oil-in-water nanoemulsions analyzed by diafiltration. AB - The association efficiency of oxytetracycline (OTC) to pharmaceutical available, ionic oil-in-water nanoemulsions is studied. Theoretical mathematical developments allowed us to differentiate by diafiltration (DF) between thermodynamically and kinetically controlled binding of the drug to the nanoemulsions, and relate these important magnitudes to the association efficiency. The nanoemulsions have been prepared by the solvent displacement technique in the presence of cationic and anionic surfactants. The resulting nanoemulsions were stable at 4 degrees C and 25 degrees C for 60 days, have a size of ~ 200 nm, showing polydispersity indexes ranging between 0.11 and 0.23, and present zeta potentials ranging between -90 and +60 mV, depending on the charge of the surfactants used. The zeta potential of the nanoemulsions influenced the interaction with OTC, having three ionic forms at different pH, namely, cationic, zwitterionic, and anionic. DF proved to be a powerful tool for the quantification of the drug association efficiency, achieving values up to 84%. Furthermore, this technique allowed obtaining different values of the drug fractions reversibly bound (11%-57%) and irreversibly bound (10%-40%) to the nanoemulsions depending on the surfactants used and pH. These findings may be useful for the development of new drug delivery systems, and as routine assays in academia and pharmaceutical industries. PMID- 25557589 TI - MAPping the Ndc80 loop in cancer: A possible link between Ndc80/Hec1 overproduction and cancer formation. AB - Mis-regulation (e.g. overproduction) of the human Ndc80/Hec1 outer kinetochore protein has been associated with aneuploidy and tumourigenesis, but the genetic basis and underlying mechanisms of this phenomenon remain poorly understood. Recent studies have identified the ubiquitous Ndc80 internal loop as a protein protein interaction platform. Binding partners include the Ska complex, the replication licensing factor Cdt1, the Dam1 complex, TACC-TOG microtubule associated proteins (MAPs) and kinesin motors. We review the field and propose that the overproduction of Ndc80 may unfavourably absorb these interactors through the internal loop domain and lead to a change in the equilibrium of MAPs and motors in the cells. This sequestration will disrupt microtubule dynamics and the proper segregation of chromosomes in mitosis, leading to aneuploid formation. Further investigation of Ndc80 internal loop-MAPs interactions will bring new insights into their roles in kinetochore-microtubule attachment and tumourigenesis. PMID- 25557594 TI - WGS and targetted sequencing in acute lymphoblastic leukemia identifies putative enhancer mutation associated with over-expression of a growth factor. PMID- 25557591 TI - Current research suggests that the future looks brighter for cerebral oxygenation monitoring in preterm infants. AB - Brain injuries remain a significant problem for preterm infants, despite extensive physiological monitoring. Near infrared spectroscopy (NIRS) monitoring in the neonatal intensive care unit has to date remained limited to research activities. CONCLUSION: This review highlights the increasing clinical application of NIRS in delivery suites and neonatal units. Four randomised controlled trials incorporating NIRS monitoring suggest that the future may indeed be brighter for this technology in the care of very preterm infants. PMID- 25557595 TI - Regulation of body and brain size: role of MAP4 and other centrosomal proteins. PMID- 25557597 TI - Weaning of nasal CPAP in preterm infants: who, when and how? a systematic review of the literature. AB - BACKGROUND: There is increased use of early nasal continuous positive airway pressure (NCPAP) to manage respiratory distress in preterm infants but optimal methods and factors associated with successful wean are not well defined. A systematic review was performed to define the corrected gestational age (CGA), weight to wean NCPAP and the methods associated with successful weaning of the NCPAP among preterm infants, along with factors affecting it. METHODS: Searches were made of PubMed using the keywords-NCPAP, CPAP, weaning, withdrawal, preterm, and infants from its inception to January 1st, 2014, for studies in all languages but limited to humans. Previous reviews (including cross references) were also searched. We included all randomized and quasi-randomized controlled trials where preterm neonates were randomized to different NCPAP weaning strategies. Details of CGA, weight and methods used for weaning NCPAP were extracted along with factors which affect its withdrawal. RESULTS: Seven studies met the search criteria. The successful wean was at 32 to 33 weeks CGA and at 1600 g. Three different methods were used for weaning were sudden, gradual pressure wean and gradual graded time off wean. Criteria for readiness, success and failure to wean were defined. Factors affecting successful weaning were intubation, anemia, infection and gastro-esophageal reflux. CONCLUSIONS: The successful wean was at 32 to 33 weeks CGA and 1600 g. Criteria for readiness, success and failure to wean are well defined. Sudden weaning may be associated with a shorter weaning time. Future trials are needed comparing weaning methods using defined criteria for readiness and success of NCPAP wean and stratify the results by gestational age and birth weight. PMID- 25557596 TI - Henoch-Schonlein purpura nephritis in children: incidence, pathogenesis and management. AB - BACKGROUND: Henoch-Schonlein purpura (HSP) is one of the most common vasculitides in children. It is manifested by skin purpura, arthritis, abdominal pain, renal involvement, etc. Typically, HSP is considered to be self-limiting, although renal involvement (HSP purpura nephritis, HSPN) is the principal cause of morbidity from this disease. For this reason, it is important to clarify the mechanism of onset and clinical manifestations of HSPN and to ascertain the most appropriate treatment for HSPN. In this article, we review the updated pathophysiology and treatment strategies for HSPN. DATA SOURCES: We searched databases including PubMed, Elsevier and Wanfang for the following key words: Henoch-Schonlein purpura, nephritis, mechanism and treatment, and we selected those publications written in English that we judged to be relevant to the topic of this review. RESULTS: Based on the data present in the literature, we reviewed the following topics: 1) the possible pathogenesis of HSPN: several studies suggest that immunoglobulin A immune complexes deposit in the mesangium and induce renal injury; 2) multiple-drug treatment for HSPN: although there have been few evidence-based treatment strategies for HSPN, several studies have suggested that immunosuppressive drugs and multiple drug combination therapy were effective in ameliorating proteinuria and histological severity. CONCLUSIONS: HSPN is a severe disease of childhood. To better understand this disease, detailed investigations into the pathogenesis of HSPN and prospective randomized controlled treatment studies on children with severe HSPN are needed. PMID- 25557599 TI - The start of the European Journal of Neuroscience. PMID- 25557598 TI - Update on the management of ovarian torsion in children and adolescents. AB - BACKGROUND: Ovarian torsion is commonly seen in young girls. Unfortunately it is often misdiagnosed because of its non-specific symptoms and lack of diagnostic modalities. This article focuses on the diagnostic challenge and also the changes in the management of ovarian torsion. DATA SOURCES: We reviewed original reports on the management of ovarian torsion in young girls published from 1984 till 2014. A literature search was conducted by electronic scanning of five electronic database: MEDLINE, EMBASE, SCI, SSCI and CINAHL. In addition, relevant papers and review articles were hand-searched. The search was limited to English language and human studies. The search was conducted by combining the textwords "ovarian torsion", "adnexal torsion", "adolescents" and "oophoropexy". RESULTS: There are no specific symptoms that can be identified as a pathognomonic feature of ovarian torsion. Ultrasound is a useful diagnostic tool, but it is not always reliable in absence of an enlarged ovary. Laparoscopic detorsion is recognized as the mainstay of treatment regardless the condition of the ovaries. Reports have shown favorable ovarian function after detorsion. The role of oopheropexy remains controversial. CONCLUSIONS: Clinicians should be aware of ovarian torsion in girls presenting with abdominal pain. A timely management in this young population can help preserve their ovaries and fertility. PMID- 25557600 TI - Taking up the reins. PMID- 25557601 TI - Pre-steady state kinetic analysis of HIV-1 reverse transcriptase for non canonical ribonucleoside triphosphate incorporation and DNA synthesis from ribonucleoside-containing DNA template. AB - Non-dividing macrophages maintain extremely low cellular deoxyribonucleotide triphosphate (dNTP) levels, but high ribonucleotide triphosphate (rNTP) concentrations. The disparate nucleotide pools kinetically forces Human Immunodeficiency Virus 1 (HIV-1) reverse transcriptase (RT) to incorporate non canonical rNTPs during reverse transcription. HIV-1 RT pauses near ribonucleoside monophosphates (rNMPs) embedded in the template DNA, which has previously been shown to enhance mismatch extension. Here, pre-steady state kinetic analysis shows rNTP binding affinity (Kd) of HIV-1 RT for non-canonical rNTPs was 1.4- to 43-fold lower, and the rNTP rate of incorporation (kpol) was 15- to 1551-fold slower than for dNTPs. This suggests that RT is more selective for incorporation of dNTPs rather than rNTPs. HIV-1 RT selectivity for dNTP versus rNTP is the lowest for ATP, implying that HIV-1 RT preferentially incorporates ATP when dATP concentration is limited. We observed that incorporation of a dNTP occurring one nucleotide before an embedded rNMP in the template had a 29-fold greater Kd and a 20-fold slower kpol as compared to the same template containing dNMP. This reduced the overall dNTP incorporation efficiency of HIV-1 RT by 581-fold. Finally, the RT mutant Y115F displayed lower discrimination against rNTPs due to its increase in binding affinity for non-canonical rNTPs. Overall, these kinetic results demonstrate that HIV-1 RT utilizes both substrate binding and a conformational change during: (1) enzymatic discrimination of non-canonical rNTPs from dNTPs and (2) during dNTP primer extension with DNA templates containing embedded rNMP. PMID- 25557603 TI - Men and women with fibromyalgia: Relation between attentional function and clinical symptoms. AB - OBJECTIVES: This study was the first to explore whether individuals with fibromyalgia (FM) have different cognitive alterations (i.e., in alertness, orienting, and executive control) depending on their sex. We also analysed possible gender differences in the relationships between cognitive functioning and some of the main symptoms of FM. DESIGN: Cross-sectional study. METHODS: Two clinical groups with FM (n = 58 women and n = 20 men) and two healthy control groups (n = 21 women and n = 27 men) aged between 30 and 60 years old participated in this study. Pain intensity, sleep disturbance, depression, anxiety, pain catastrophizing, and daily functioning were evaluated with self report measures. Attentional function was assessed with the ANT-I task (Attentional Network Test-Interactions). RESULTS: Mixed ANOVAs showed impairment in vigilance and executive control in both male and female patients with FM compared with controls. Control men were faster than control women, but FM eliminated sex differences. In addition, attention deficit was associated with worse daily functioning in women but not in men with FM. Emotional distress and sleep disruption seemed to contribute differently to these cognitive alterations in both sexes. CONCLUSIONS: Therapy strategies aimed at reducing emotional distress and sleep disruption are likely to improve cognitive function by enhancing vigilance. Therapies aimed at reducing emotional distress seem to improve attentional function more in women than in men; those aimed at improving sleep quality are likely to reduce a vigilance/alertness deficit in women and executive problems in men. PMID- 25557602 TI - Natural compounds isolated from Brazilian plants are potent inhibitors of hepatitis C virus replication in vitro. AB - Compounds extracted from plants can provide an alternative approach to new therapies. They present characteristics such as high chemical diversity, lower cost of production and milder or inexistent side effects compared with conventional treatment. The Brazilian flora represents a vast, largely untapped, resource of potential antiviral compounds. In this study, we investigate the antiviral effects of a panel of natural compounds isolated from Brazilian plants species on hepatitis C virus (HCV) genome replication. To do this we used firefly luciferase-based HCV sub-genomic replicons of genotypes 2a (JFH-1), 1b and 3a and the compounds were assessed for their effects on both HCV replication and cellular toxicity. Initial screening of compounds was performed using the maximum non-toxic concentration and 4 compounds that exhibited a useful therapeutic index (favourable ratio of cytotoxicity to antiviral potency) were selected for extra analysis. The compounds APS (EC50=2.3MUM), a natural alkaloid isolated from Maytrenus ilicifolia, and the lignans 3(*)43 (EC50=4.0MUM), 3(*)20 (EC50=8.2MUM) and 5(*)362 (EC50=38.9MUM) from Peperomia blanda dramatically inhibited HCV replication as judged by reductions in luciferase activity and HCV protein expression in both the subgenomic and infectious systems. We further show that these compounds are active against a daclatasvir resistance mutant subgenomic replicon. Consistent with inhibition of genome replication, production of infectious JFH-1 virus was significantly reduced by all 4 compounds. These data are the first description of Brazilian natural compounds possessing anti-HCV activity and further analyses are being performed in order to investigate the mode of action of those compounds. PMID- 25557604 TI - The association of common polymorphisms in miR-196a2 with waist to hip ratio and miR-1908 with serum lipid and glucose. AB - OBJECTIVE: MicroRNAs (miRNAs) have been implicated in the regulation of cardiometabolic disorders. Given the crucial role of miRNAs in gene expression, genetic variation within miRNA genes is expected to affect miRNA function and substantially contribute to disease risk. METHODS: 2,320 variants in miRNA encoding sequences were systematically retrieved, and their associations with 17 cardiometabolic traits/diseases were investigated, using genome-wide association studies (GWAS) on glycemic indices, anthropometric measures, lipid traits, blood pressure, coronary artery disease, and type 2 diabetes. Next, target genes of the identified miRNAs that may mediate their effect on the phenotypes were examined. Furthermore, trans- expression quantitative trait loci analysis and luciferase reporter assay to provide functional evidence for our findings were performed. RESULTS: rs11614913:C/T in miR-196a2 was associated with waist to hip ratio (P value=1.7 * 10(-5) , beta = 0.023). Two target genes, SFMBT1 and HOXC8, which may mediate this association were identfied, and they were shown experimentally as direct targets of miR-196a2. Moreover, rs174561:C/T in miR-1908 was found to be associated with total cholesterol (P-value=6.5 * 10(-16) , beta=0.044), LDL cholesterol (P-value=4.3 * 10(-18) , beta=0.049), HDL-cholesterol (P-value=1.7 * 10(-6) , beta=0.026), triglyceride (P-value=7.8 * 10(-14) , beta=0.038), and fasting glucose (P-value=4.3 * 10(-10) , beta=0.02). In addition, a number of miR 1908 target genes were highlighted as potential mediators. CONCLUSIONS: The results indicated miRNA-dependent regulation of fat distribution by miR-196a2 and of lipid metabolism by miR-1908. PMID- 25557606 TI - Acute stress increases voluntary consumption of alcohol in undergraduates. AB - AIMS: The primary aim of this study was to assess whether an acute stressor directly increases alcohol intake among undergraduates. A secondary aim was to examine whether individual differences in state anxiety predict alcohol intake. METHOD: Following random assignment, undergraduate students (n = 75; 47% males; mean age = 20.1 +/- 2.8) completed the Trier Social Stress Test or no-stress protocol, and then engaged in a 30-min free-drinking session (alcohol, placebo, or non-alcoholic beverage). The State-Trait Anxiety Inventory was completed upon arrival, post-stressor, and after drinking. RESULTS: Planned comparisons demonstrated that psychosocial stress increased voluntary intake of alcohol, but not placebo or non-alcoholic beverages. In linear regression analyses, individual differences in anxiety did not predict voluntary alcohol consumption. CONCLUSION: A proximal relationship exists between acute stress and single-session alcohol intake in undergraduates, which may explain the relationship between life stressors and increased drinking in this group. These findings demonstrate that stress management is an important target for reducing heavy episodic drinking on university campuses. PMID- 25557605 TI - Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S vaccine. AB - Efficacy and safety of recombinant yeast-derived hepatitis B vaccines for prevention of hepatitis B have been demonstrated unequivocally worldwide as reflected in reduction in HBsAg carrier rates and hepatocellular carcinoma. A new generation of recombinant HBV vaccines expressed in mammalian cells containing Pre-S/S epitopes has been developed in several countries. Such vaccines are useful in special risk groups, i.e., in non-responders to conventional HBV vaccines including older adults, obese people, health care workers, patients with renal failure and on dialysis, transplant patients, patients with HIV as well as travelers on short notice to HBV endemic regions. The future of such vaccines depends on their enhanced immunogenicity and cost profile. Sci-B-VacTM is a mammalian cell-derived recombinant Pre-S1/Pre-S2/S hepatitis B vaccine which has been shown to be highly immunogenic, inducing faster and higher seroprotection rates against HBV with higher anti-HBs levels at lower HBsAg doses as compared to conventional yeast-derived vaccines. Recently, it has been suggested that such Pre-S/S vaccines against HBV might be efficacious not only for prevention but also for intervention in persistent HBV infection. Data obtained in a recent clinical trial conducted in Vietnam in patients with chronic hepatitis B suggest that repeated monthly i.m. injections of the Sci-B-VacTM co-administered with daily oral lamivudine treatment can suppress HBV replication and lead to anti-HBs seroconversion in ~50 % of treated patients. Optimization of protocols and efficacy of such an intervention, intended to bypass T cell exhaustion and immune tolerance to HBV remains to be explored. PMID- 25557608 TI - Adolescent alcohol use and binge drinking: an 18-year trend study of prevalence and correlates. AB - AIMS: Several studies suggest a rapid decrease of alcohol use among adolescents after the turn of the century. With decreasing prevalence rates of smokers, a so called hardening may have taken place, implying that remaining smokers are characterized by more psychosocial problems. Are similar processes witnessed among remaining adolescent alcohol users as well? METHODS: In 1992, 2002 and 2010 we used identical procedures to collect data from three population-based samples of 16- and 17-year-old Norwegians (n = 9207). We collected data on alcohol consumption, binge drinking, parental factors, use of other substances, conduct problems, depressive symptoms, social integration, sexual behaviour and loneliness. RESULTS: There was a steep increase in all measures of alcohol consumption from 1992 to 2002, followed by a similar decline until 2010. Most correlates remained stable over the time span. CONCLUSION: Alcohol use was consistently related to psychosocial problems; on the other hand, alcohol users reported higher levels of social acceptance and social integration than did non users. There were no signs of 'hardening' as seen for tobacco use. PMID- 25557607 TI - Assessing and treating alcohol relapse risk in liver transplantation candidates. AB - In Europe between 30 and 50% of all liver transplantations (LTX) are done within the context of chronic end-stage alcoholic liver disease (ALD). However, post operatively 20-25% of these patients lapse or relapse into heavy alcohol use. Thus, assessment of alcohol relapse risk before enlisting and therapeutic follow up during and after LTX is of utmost importance. However, as yet there are enormous differences between European countries and between transplant centers, with regard to the assessment methods and criteria and the implementation of therapeutic follow-up. Only the so-called '6-month abstinence' rule is widely used. However, there are not much scientific data validating its use in predicting relapse. Thus, there is a clear need of a more homogeneous approach, which was the focus of a symposium of the European Federation of Addiction Societies during the 14th conference of the European Society for Biomedical Research on Alcoholism, 2013 (ESBRA), entitled 'Liver transplantation: A European perspective'. In a follow-up on this symposium, the authors aim to sum up the evidence of psychiatric assessment criteria and psychiatric treatment interventions relevant in the context of patient selection and patient follow-up within ALD transplantation procedures. Based upon these findings, we propose elements of a procedure that can serve as a first step toward a model of good practice regarding addiction-specialist input within the pre- and post transplantation period. PMID- 25557609 TI - Hair as an indicator of the body content of polonium in humans: preliminary results from study of five male volunteers. AB - The radionuclide (210)Po is of importance from a radiation protection view and has properties that cause special problems when attempting to determine the body content in humans. Estimates have traditionally been made from either urine and/or fecal samples, which require a time-consuming radiochemical preparation before alpha spectrometric determination. In order to find a more simple and less labor intensive method hair has been used as a bioindicator and investigated in this study. The relationship between intake and excretion in hair has been estimated in five volunteers who ingested radioactive polonium ((209)Po as a bio tracer for (210)Po) in well determined quantities. Four of the volunteers were given 5-10 Bq (209)Po in a single intake (acute intake) and one volunteer has ingested a daily intake of 58.7 mBq (209)Po for a period of 180 d. Human hair was found to reflect the daily clearance of ingested polonium peaking at 0.001-0.01% d(-1) of the ingested amount, thereafter decreasing mono-exponentially, corresponding to a biological half-time of 10-20 days. For the case of protracted intake a mono-exponential build-up was observed with a half-time of 40 +/- 5 d. In addition, after cessation of intake, a short-term component (74%) with a biological half-time of 16 +/- 4 d, and a long-term component (26%) with a half time of 93 +/- 53 d were observed. It is concluded that hair can be used to detect not only the amount of ingested polonium but also whether the intake was protracted or acute. PMID- 25557610 TI - The update of anthocyanins on obesity and type 2 diabetes: experimental evidence and clinical perspectives. AB - With the dramatically increasing prevalence of obesity and type 2 diabetes mellitus (T2DM) worldwide, there is an urgent need for new strategies to combat the growing epidemic of these metabolic diseases. Diet is an essential factor affecting the development of and risk for obesity and T2DM and it can either help or hurt. In searching for preventative and therapeutic strategies, it is therefore advantageous to consider the potential of certain foods and their bioactive compounds to reverse or prevent the pathogenic processes associated with metabolic disease. Anthocyanins are naturally occurring polyphenolic compounds abundant in dark-colored fruits, vegetables and grains. Epidemiological studies suggest that increased consumption of anthocyanins lowers the risk of T2DM. Many in vitro and in vivo studies also reveal an array of mechanisms through which anthocyanins could prevent or reverse obesity- and T2DM-related pathologies including promotion of antioxidant and anti-inflammatory activities, improvement of insulin resistance, and hypolipidemic and hypoglycemic actions. Here, we summarize the data on anthocyanin-mediated protection against obesity and T2DM and the underlying mechanisms. Further population-based and long-term human intervention studies are necessary to ultimately evaluate the use of anthocyanins for protection/prevention against the development of obesity and T2DM. PMID- 25557612 TI - Arachidonoyl-ethanolamide activates endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase-2 and novel J-series prostamides. AB - Non-melanoma skin cancer and other epithelial tumors overexpress cyclooxygenase-2 (COX-2), differentiating them from normal cells. COX-2 metabolizes arachidonic acid to prostaglandins including, the J-series prostaglandins, which induce apoptosis by mechanisms including endoplasmic reticulum (ER) stress. Arachidonoyl ethanolamide (AEA) is a cannabinoid that causes apoptosis in diverse tumor types. Previous studies from our group demonstrated that AEA was metabolized by COX-2 to J-series prostaglandins. Thus, the current study examines the role of COX-2, J series prostaglandins, and ER stress in AEA-induced apoptosis. In tumorigenic keratinocytes that overexpress COX-2, AEA activated the PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE1), and activating transcription factor-6 (ATF6) ER stress pathways and the ER stress apoptosis-associated proteins, C/EBP homologous protein-10 (CHOP10), caspase-12, and caspase-3. Using an ER stress inhibitor, it was determined that ER stress was required for AEA-induced apoptosis. To evaluate the role of COX-2 in ER stress-apoptosis, HaCaT keratinocytes with low endogenous COX-2 expression were transfected with COX-2 cDNA or an empty vector and AEA-induced ER stress-apoptosis occurred only in the presence of COX-2. Moreover, LC-MS analysis showed that the novel prostaglandins, 15-deoxyDelta(12,14) PGJ2 -EA and Delta(12) PGJ2 /PGJ2-EA, were synthesized from AEA. These findings suggest that AEA will be selectively toxic in tumor cells that overexpress COX-2 due to the metabolism of AEA by COX-2 to J-series prostaglandin-ethanolamides (prostamides). Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX-2. PMID- 25557611 TI - RANKL/OPG; Critical role in bone physiology. AB - After it was proposed that the osteoblast lineage controlled the formation of osteoclasts, cell culture methods were developed that established this to be the case. Evidence was obtained that cytokines and hormones that promote osteoclast formation act first on osteoblast lineage cells to promote the production of a membrane-bound regulator of osteoclastogenesis. This proved to be receptor activator of NF-kB ligand (RANKL) a member of the tumor necrosis factor ligand family that acts upon its receptor RANK in the hematopoietic lineage, with interaction restricted by a decoy soluble receptor osteoprotegerin (OPG), also a product of the osteoblast lineage. The physiological roles of these factors were established through genetic and pharmacological studies, have led to a new physiology of bone, with complete revision of older ideas over the last 15 years, ultimately leading to the development of new pharmaceutical agents for bone disease. PMID- 25557614 TI - High-sensitivity strain sensor based on in-fiber rectangular air bubble. AB - We demonstrated a unique rectangular air bubble by means of splicing two sections of standard single mode fibers together and tapering the splicing joint. Such an air bubble can be used to develop a promising high-sensitivity strain sensor based on Fabry-Perot interference. The sensitivity of the strain sensor with a cavity length of about 61 MUm and a wall thickness of about 1 MUm was measured to be up to 43.0 pm/MUepsilon and is the highest strain sensitivity among the in fiber FPI-based strain sensors with air cavities reported so far. Moreover, our strain sensor has a very low temperature sensitivity of about 2.0 pm/ degrees C. Thus, the temperature-induced strain measurement error is less than 0.046 MUepsilon/ degrees C. PMID- 25557613 TI - Volatile sulphur compound measurement with OralChroma(TM): a methodological improvement. AB - The instrumental measurement of volatile sulphur compounds is a common practice to assess halitosis. One of the most widespread devices for that purpose is OralChroma(TM), a combination of a semiconductor gas sensor and a compact gas chromatograph (GC) system. Several lines of evidence indicate that although the hardware of OralChroma(TM) is fit for the precise measurement of volatile sulphur compounds (VSCs), its software needs revision to allow that precision. In this study we sought to develop software to solve this problem, and to test the utility of the new software in a population of patients and controls. The results were also compared with VSC measurements performed with Halimeter((r)), another widespread device, so as to assess the correlation. A set of measurements involving volunteers (21 controls and 14 oral cancer patients) were conducted. The analysis of the chromatograms recorded by OralChroma(TM) indicated that the majority of the studied breath samples contained significant amounts of isoprene (the peak was around 100 s) and acetaldehyde (the peak was around 350 s), therefore OralChroma(TM) was also calibrated for both isoprene and acetaldehyde. A linear relationship was found between the concentration (in the range of 80 1400 ppbv for acetaldehyde and 40-560 ppbv for isoprene) and the area under the corresponding peak. In numerous cases the concentrations of VSCs calculated by the software of OralChroma(TM) required revision. In the new software, the concentrations of the VSCs, isoprene and acetaldehyde were determined by fitting the chromatograms with the sum of six Gaussian functions. Based on the findings of the present study we conclude that our new software allows an improved and instantaneous evaluation of OralChroma(TM) chromatograms with the additional possibility of determining the isoprene and acetaldehyde concentrations from breath samples. PMID- 25557615 TI - Characterization and preparation of bio-tubular scaffolds for fabricating artificial vascular grafts by combining electrospinning and a 3D printing system. AB - The last decade has seen artificial blood vessels composed of natural polymer nanofibers grafted into human bodies to facilitate the recovery of damaged blood vessels. However, electrospun nanofibers (ENs) of biocompatible materials such as chitosan (CTS) suffer from poor mechanical properties. This study describes the design and fabrication of artificial blood vessels composed of a blend of CTS and PCL ENs and coated with PCL strands using rapid prototyping technology. The resulting tubular vessels exhibited excellent mechanical properties and showed that this process may be useful for vascular reconstruction. PMID- 25557616 TI - Agarose-assisted micro-contact printing for high-quality biomolecular micro patterns. AB - Micro-contact printing has been developed to print biomolecules, such as cell adhesive molecules, proteins, or DNAs, on a substrate, which can serve as experimental platforms for investigating biological issues and engineering biosensors. Despite the popularity of this method, it has been technically challenging to use a conventional stamp made of a hydrophobic polydimethoxysilane (PDMS) elastomer that often requires surface treatments to facilitate the inking and stamping of biomolecules. In this work, we proposed a new surface modification method for a PDMS stamp using agarose hydrogel and demonstrated the applications to the design of micro-patterned substrates with biomolecules. By using a simple bench-top dip-coating method with a commercial syringe pump to steadily pull out the stamp from boiled agarose solution, we coated an agarose layer on the stamp. It consequentially enhanced the transferability of ink molecules to the target substrate and the uniformity of printed patterns compared to the traditional methods for treating stamp surface such as surfactant coating and temporary oxidation with air plasma. In addition, this microstamping method was also used to produce patterns of proteins with the preservation of bioactivity, which could guide neuronal growth. Thus, we demonstrated the applicability to the interface designs of biochips and biosensors. PMID- 25557617 TI - Educational attainment and adult health: under what conditions is the association causal? PMID- 25557618 TI - Face inversion and acquired prosopagnosia reduce the size of the perceptual field of view. AB - Using a gaze-contingent morphing approach, we asked human observers to choose one of two faces that best matched the identity of a target face: one face corresponded to the reference face's fixated part only (e.g., one eye), the other corresponded to the unfixated area of the reference face. The face corresponding to the fixated part was selected significantly more frequently in the inverted than in the upright orientation. This observation provides evidence that face inversion reduces an observer's perceptual field of view, even when both upright and inverted faces are displayed at full view and there is no performance difference between these conditions. It rules out an account of the drop of performance for inverted faces--one of the most robust effects in experimental psychology--in terms of a mere difference in local processing efficiency. A brain damaged patient with pure prosopagnosia, viewing only upright faces, systematically selected the face corresponding to the fixated part, as if her perceptual field was reduced relative to normal observers. Altogether, these observations indicate that the absence of visual knowledge reduces the perceptual field of view, supporting an indirect view of visual perception. PMID- 25557619 TI - A requirement for Gch1 and tetrahydrobiopterin in embryonic development. AB - INTRODUCTION: GTP cyclohydrolase I (GTPCH) catalyses the first and rate-limiting reaction in the synthesis of the enzymatic cofactor, tetrahydrobiopterin (BH4). Loss of function mutations in the GCH1 gene lead to congenital neurological diseases such as DOPA-responsive dystonia and hyperphenylalaninemia. However, little is known about how GTPCH and BH4 affects embryonic development in utero, and in particular whether metabolic replacement or supplementation in pregnancy is sufficient to rescue genetic GTPCH deficiency in the developing embryo. METHODS AND RESULTS: Gch1 deficient mice were generated by the insertion of loxP sites flanking exons 2-3 of the Gch1 gene. Gch1(fl/fl) mice were bred with Sox2cre mice to generate mice with global Gch1 deficiency. Genetic ablation of Gch1 caused embryonic lethality by E13.5. Despite loss of Gch1 mRNA and GTPCH enzymatic activity, whole embryo BH4 levels were maintained until E11.5, indicating sufficient maternal transfer of BH4 to reach this stage of development. After E11.5, Gch1(-/-) embryos were deficient in BH4, but an unbiased metabolomic screen indicated that the lethality was not due to a gross disturbance in metabolic profile. Embryonic lethality in Gch1(-/-) embryos was not caused by structural abnormalities, but was associated with significant bradycardia at E11.5. Embryonic lethality was not rescued by maternal supplementation of BH4, but was partially rescued, up to E15.5, by maternal supplementation of BH4 and l-DOPA. CONCLUSION: These findings demonstrate a requirement for Gch1 in embryonic development and have important implications for the understanding of pathogenesis and treatment of genetic BH4 deficiencies, as well as the identification of new potential roles for BH4. PMID- 25557620 TI - A dual epimorphic and compensatory mode of heart regeneration in zebrafish. AB - Zebrafish heart regeneration relies on the capacity of cardiomyocytes to proliferate upon injury. To understand the principles of this process after cryoinjury-induced myocardial infarction, we established a spatio-temporal map of mitotic cardiomyocytes and their differentiation dynamics. Immunodetection of phosphohistone H3 and embryonic ventricular heavy chain myosin highlighted two distinct regenerative processes during the early phase of regeneration. The injury-abutting zone comprises a population of cardiac cells that reactivates the expression of embryo-specific sarcomeric proteins and it displays a 10-fold higher mitotic activity in comparison to the injury-remote zone. The undifferentiated cardiomyocytes resemble a blastema-like structure between the original and wound tissues. They integrate with the fibrotic tissue through the fibronectin-tenascin C extracellular matrix, and with the mature cardiomyocytes through upregulation of the tight junction marker, connexin 43. During the advanced regenerative phase, the population of undifferentiated cardiomyocytes disperses within the regenerating myocardium and it is not detected after the termination of regeneration. Although the blastema represents a transient landmark of the regenerating ventricle, the remaining mature myocardium also displays an enhanced mitotic index when compared to uninjured hearts. This suggests an unexpected contribution of a global proliferative activity to restore the impaired cardiac function. Based on these findings, we propose a new model of zebrafish heart regeneration that involves a combination of blastema-dependent epimorphosis and a compensatory organ-wide response. PMID- 25557622 TI - Oocyte glycoproteins regulate the form and function of the follicle basal lamina and theca cells. AB - Maintaining follicle integrity during development, whereby each follicle is a functional unit containing a single oocyte, is essential for the generation of healthy oocytes. However, the mechanisms that regulate this critical function have not been determined. In this paper we investigate the role of the oocyte in maintaining follicle development. To investigate this role, we use a mouse model with oocyte-specific deletion of C1galt1 which is required for the generation of core 1-derived O-glycans. The loss of oocyte-generated O-glycans results in the joining of follicles and the generation of Multiple-Oocyte Follicles (MOFs). The aim was to determine how Mutant follicle development is modified thus enabling follicles to join. Extracellular matrix and follicle permeability were studied using histology, immunohistochemistry and electron microscopy (EM). In ovaries containing Mutant Oocytes, the Follicle basal lamina (FBL) is altered both functionally and structurally from the primary stage onwards with Mutant follicles possessing unexpectedly thicker FBL. In Mutant ovaries, the theca cell layer is also modified with intermingling of theca between adjacent follicles. MOF function was analysed but despite increased numbers of preantral MOFs in Mutants, these do not reach the preovulatory stage after gonadotrophin stimulation. We propose a model describing how oocyte initiated changes in FBL and theca cells result in follicles joining. These data reveal new and important roles for the oocyte in follicle development and follicle integrity. PMID- 25557624 TI - Genotypic and phenotypic characteristics of aminoglycoside-resistant Mycobacterium tuberculosis isolates in Latvia. AB - Mutations causing resistance to aminoglycosides, such as kanamycin (KAN), amikacin (AMK), and streptomycin, are not completely understood. In this study, polymorphisms of aminoglycoside resistance influencing genes such as rrs, eis, rpsL, and gidB in 41 drug-resistant and 17 pan-sensitive Mycobacterium tuberculosis clinical isolates in Latvia were analyzed. Mutation A1400G in rrs gene was detected in 92% isolates with high resistance level to KAN and diverse MIC level to AMK. Mutations in promoter region of eis were detected in 80% isolates with low-level MIC of KAN. The association of K43R mutation in rpsL gene, a mutation in the rrs gene at position 513, and various polymorphisms in gidB gene with distinct genetic lineages of M. tuberculosis was observed. The results of this study suggest that association of different controversial mutations of M. tuberculosis genes to the drug resistance phenotype should be done in respect to genetic lineages. PMID- 25557621 TI - Sox4 regulates choroid fissure closure by limiting Hedgehog signaling during ocular morphogenesis. AB - SoxC transcription factors play critical roles in many developmental processes, including neurogenesis, cardiac formation, and skeletal differentiation. In vitro and in vivo loss-of-function studies have suggested that SoxC genes are required for oculogenesis; however the mechanism was poorly understood. Here, we have explored the function of the SoxC factor Sox4 during zebrafish eye development. We show that sox4a and sox4b are expressed in the forebrain and periocular mesenchyme adjacent to the optic stalk during early eye development. Knockdown of sox4 in zebrafish resulted in coloboma, a structural malformation of the eye that is a significant cause of pediatric visual impairment in humans, in which the choroid fissure fails to close. Sox4 morphants displayed altered proximo-distal patterning of the optic vesicle, including expanded pax2 expression in the optic stalk, as well as ectopic cell proliferation in the retina. We show that the abnormal ocular morphogenesis observed in Sox4-deficient zebrafish is caused by elevated Hedgehog (Hh) signaling, and this is due to increased expression of the Hh pathway ligand Indian Hedgehog b (ihhb). Consistent with these results, coloboma in sox4 morphants could be rescued by pharmacological treatment with the Hh inhibitor cyclopamine, or by co-knockdown of ihhb. Conversely, overexpression of sox4 reduced Hh signaling and ihhb expression, resulting in cyclopia. Finally, we demonstrate that sox4 and sox11 have overlapping, but not completely redundant, functions in regulating ocular morphogenesis. Taken together, our data demonstrate that Sox4 is required to limit the extent of Hh signaling during eye development, and suggest that mutations in SoxC factors could contribute to the development of coloboma. PMID- 25557625 TI - MicroRNA regulatory networks in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal scarring lung disease of unknown etiology, characterized by changes in microRNA expression. Activation of transforming growth factor (TGF-beta) is a key event in the development of IPF. Recent reports have also identified epigenetic modification as an important player in the pathogenesis of IPF. In this review, we summarize the main results of studies that address the role of microRNAs in IPF and highlight the synergistic actions of these microRNAs in regulating TGF beta, the primary fibrogenic mediator. We outline epigenetic regulation of microRNAs by methylation. Functional studies identify microRNAs that alter proliferative and migratory properties of fibroblasts, and induce phenotypic changes in epithelial cells consistent with epithelial-mesenchymal transition. Though these studies were performed in isolation, we identify multiple co operative actions after assembling the results into a network. Construction of such networks will help identify disease-propelling hubs that can be targeted for therapeutic purposes. PMID- 25557623 TI - Hybrid nonviral/viral vector systems for improved piggyBac DNA transposon in vivo delivery. AB - The DNA transposon piggyBac is a potential therapeutic agent for multiple genetic diseases such as cystic fibrosis (CF). Recombinant piggyBac transposon and transposase are typically codelivered by plasmid transfection; however, plasmid delivery is inefficient in somatic cells in vivo and is a barrier to the therapeutic application of transposon-based vector systems. Here, we investigate the potential for hybrid piggyBac/viral vectors to transduce cells and support transposase-mediated genomic integration of the transposon. We tested both adenovirus (Ad) and adeno-associated virus (AAV) as transposon delivery vehicles. An Ad vector expressing hyperactive insect piggyBac transposase (iPB7) was codelivered. We show transposase-dependent transposition activity and mapped integrations in mammalian cells in vitro and in vivo from each viral vector platform. We also demonstrate efficient and persistent transgene expression following nasal delivery of piggyBac/viral vectors to mice. Furthermore, using piggyBac/Ad expressing Cystic Fibrosis transmembrane Conductance Regulator (CFTR), we show persistent correction of chloride current in well-differentiated primary cultures of human airway epithelial cells derived from CF patients. Combining the emerging technologies of DNA transposon-based vectors with well studied adenoviral and AAV delivery provides new tools for in vivo gene transfer and presents an exciting opportunity to increase the delivery efficiency for therapeutic genes such as CFTR. PMID- 25557626 TI - Dissolution of mesalazine modified release tablets under standard and bio relevant test conditions. AB - OBJECTIVES: For the treatment of inflammatory bowel disease, the development of pH responsive modified release dosage forms is one of the most common approaches to achieve targeted drug delivery. In this study, the dissolution behaviour of eight different modified release (MR) products containing 800 mg mesalazine was investigated. METHODS: The performance of the products was compared under simulated fasted state conditions using the paddle apparatus as well as the dissolution stress test device mimicking mechanical stress events of bio-relevant intensity. KEY FINDINGS: The dissolution behaviour of the eight tested different pH-responsive MR tablets containing 800 mg mesalazine was dependent on the test conditions. Phases of mechanical stress with physiological intensity influenced the dissolution characteristics and caused in some cases accelerated drug release indicating possible dose dumping. CONCLUSION: The study demonstrates that besides the investigation of the pH dependency of drug release, the characterisation of the mechanical robustness of the dosage forms is an essential factor determining the dissolution characteristics of such pH-dependent targeted modified release tablets. The susceptibility of 800 mg mesalazine MR tablets towards mechanical stress may be one reason for undesired drug delivery in vivo. PMID- 25557627 TI - Nonquaternary poly(diallylammonium) polymers with different amine structure and their biocidal effect on Mycobacterium tuberculosis and Mycobacterium smegmatis. AB - Mycobacteria, especially Mycobacterium tuberculosis, are one of the most dangerous types of microorganisms to cause diseases and mortality. Due to the known distinctive structure of their cell wall, mycobacteria are resistant to majority of antibiotics and common chemical disinfectants, including quaternized low molecular weight and polymer biocides. In this work, nonquaternary protonated polydiallylamines (PDAAs) based on protonated monomers of the diallylamine (DAA) series have been synthesized, secondary s-PDAA and tertiary t-Me-PDAA and t-Et PDAA (with Me and Et N-substituents). The antimicrobial actions of PDAAs on M. tuberculosis and Mycobacterium smegmatis have been studied, namely, dependences of the activity on the amine structure, length of alkyl N-substituents, M w of polymers, treatment time, and cell concentration. All PDAAs examined at different conditions have been found to exhibit strong bactericidal effect on M. smegmatis and M. tuberculosis, including "nonculturable" dormant M. tuberculosis cells. The quaternary counterpart poly(diallyldimethylammonium chloride) (PDADMAC) and current antibiotics rifampicin and ciprofloxacin have been also tested and shown to be significantly less efficient or inactive at all (at the maximum tested concentration of 500 MUg mL(-1)). s-PDAA appeared to be the most effective or exhibited similar activity to t-Me-PDAA, while t-Et-PDAA appeared to be less active, especially against M. tuberculosis. The results obtained indicate a key role of the nonquaternary ammonium groups in the mycobactericidal action of PDAAs. Examination under an optical microscope in the epifluorescence mode has evidenced damage of the inner membrane permeability of M. smegmatis cells under the impact of PDAAs after 20 min. Studies on electrophoretic mobility (zeta potential) of M. smegmatis cells and some model liposomes in the presence of PDAAs have revealed a small negative charge of mycobacteria outer surface and recharge in the presence of PDAAs. A conclusion was made that bactericidal activity of PDAAs is related to the disturbance of the integrity of the mycobacterial cell wall followed by damage of the inner membrane permeability. PMID- 25557628 TI - Bead-based suspension array for simultaneous differential detection of five major swine viruses. AB - A novel multiplex detection array based on Luminex xMAP technology was developed and validated for simultaneous detection of five major viruses causing swine reproductive diseases. By combining one-step asymmetric multiplex reverse transcription polymerase chain reaction (RT-PCR) with xMAP bead-based hybridization and flow cytometry analysis, the resulting multiplex assay was capable of detecting single and mixed infections of PRRSV, PCV-2, PRV, CSFV, and PPV in a single reaction. The assay accurately detected and differentiated 23 viral strains used in this study. The low detection limit was determined as 2.2 22 copies/MUL (corresponding to 0.5-6.8 fg/MUL DNA template) on plasmid constructs containing viral fragments. The intra-assay and inter-assay variances (CV%) were low that ranged from 2.5 to 5.4 % and 4.1 to 7.6 %, respectively. The assay was applied to test field samples and detected single and mixed viral infections. The detection rate was higher than that of uniplex conventional PCR and RT-PCR methods. The detection of PRRSV by the bead-based multiplex assay was comparable with a commercially available real time RT-PCR kit. The test procedure on purified DNA or RNA samples could be completed within 2 h. In conclusion, the bead-based suspension array presented here proved to be a high-throughput practical tool that provided highly specific and sensitive identification of single and multiple infections of five major viruses in pigs and boar semen. PMID- 25557629 TI - Effects of constant pH and unsteady pH at different free ammonia concentrations on shortcut nitrification for landfill leachate treatment. AB - On the basis of achieving shortcut nitrification in a lab-scale SBR, the effects of constant pH and unsteady pH at different free ammonia concentrations on shortcut nitrification for landfill leachate treatment was investigated. The results indicate that under the condition of DO of 0.5 +/- 0.2 mg/L and temperature of 30 +/- 2 degrees C, the absolute value of nitrite accumulation increased significantly with the increase in free ammonia (FA) concentration from 5.30 to 48.67 mg/L; however, the nitrite accumulation rate remained almost constant at a constant pH of 8.0 +/- 0.1. Ammonia oxidation and the nitrite accumulation become slow with the pH decreased from 8.0 +/- 0.1 to 7.5 +/- 0.2, and the activities of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) were severely inhibited when the pH further decreased to 6.5. More importantly, this study confirmed that the pH decrease from 8.0 to 6.5 within a short time exhibited significant negative effect on the ammonia oxidation rather than the FA concentration. PMID- 25557630 TI - Colonic motor abnormalities in slow transit constipation defined by high resolution, fibre-optic manometry. AB - BACKGROUND: Slow transit constipation (STC) is associated with colonic motor abnormalities. The underlying cause(s) of the abnormalities remain poorly defined. In health, utilizing high resolution fiber-optic manometry, we have described a distal colonic propagating motor pattern with a slow wave frequency of 2-6 cycles per minute (cpm). A high calorie meal caused a rapid and significant increase in this activity, suggesting the intrinsic slow wave activity could be mediated by extrinsic neural input. Utilizing the same protocol our aim was to characterize colonic meal response STC patients. METHODS: A fiber optic manometry catheter (72 sensors at 1 cm intervals) was colonoscopically placed with the tip clipped at the ascending or transverse colon, in 14 patients with scintigraphically confirmed STC. Manometric recordings were taken, for 2 h pre and post a 700 kCal meal. Data were compared to 12 healthy adults. KEY RESULTS: Prior to and/or after the meal the cyclic propagating motor pattern was identified in 13 of 14 patients. However, the meal, did not increase the cyclic motor pattern (preprandial 7.4 +/- 7.6 vs postprandial 8.3 +/- 4.5 per/2 h), this is in contrast to the dramatic increase observed in health (8.3 +/- 13.3 vs 59.1 +/- 89.0 per/2 h; p < 0.001). CONCLUSIONS & INFERENCES: In patients with STC a meal fails to induce the normal increase in the distal colonic cyclic propagating motor patterns. We propose that these data may indicate that the normal extrinsic parasympathetic inputs to the colon are attenuated in these patients. PMID- 25557631 TI - Evaluation of apically extruded debris during root canal retreatment with several NiTi systems. AB - AIM: To compare the amount of debris extruded apically during root canal retreatment using ProTaper, Mtwo and Reciproc instruments with hand H-files. METHODOLOGY: In total, 60 freshly extracted human mandibular incisor teeth were used. All root canals were prepared with a Reciproc R25 file than filled with Gutta-percha and AH Plus sealer using cold lateral condensation before being assigned randomly to four groups (n = 15 each). In group 1, root fillings were removed with the Protaper Universal retreatment system; ProTaper Universal F3 and F4 instruments were used for the final preparation. In group 2, root fillings were removed with the Mtwo retreatment system; Mtwo size 30, .06 taper, size 35, .06 taper and size 40, .06 taper files were used for the final preparation. In group 3, root fillings were removed with Reciproc R25 instruments; Reciproc R40 instruments were used for the final preparation. In group 4, the root fillings were removed with Gates Glidden burs and sizes 35, 30 and 25 H-files; for final preparation, a size 40 H-file was used. Glass vials were used for debris collection. The vials were weighed before and after Gutta-percha removal. Additionally, the times required for the retreatment procedures were recorded. Data were analysed statistically using one-way analysis of variance. RESULTS: The Reciproc system produced significantly smaller amounts of apical extruded debris than the other groups (P < 0.05). There was no significant difference between the Mtwo, H-file and ProTaper groups. The ProTaper and Reciproc groups required significantly less time than the Mtwo and H-file groups (P < 0.001). CONCLUSIONS: Use of the reciprocating single file system resulted in the extrusion of significantly less debris compared with the full-sequence rotary NiTi instruments and hand filing. Use of the ProTaper and Reciproc instruments required less time for retreatment procedures than use of the Mtwo or H-file. PMID- 25557632 TI - Mycophenolic acid in dermatology a century after its discovery. AB - Mycophenolic acid was first discovered in 1913 and first used clinically in the 1970s as an immunosuppressant to prevent organ transplantation rejection. It was later used in the treatment of psoriasis. However due to its side-effect profile and fears over its carcinogenic potential it was abandoned. From the late 1990s a prodrug, mycophenolate mofetil (MMF), was developed and more recently, enteric coated mycophenolate sodium (EC-MPS), both of which have gained increasing use in the field of dermatology for a variety of skin conditions. This review discusses the pharmacology, mechanisms of action, side-effects and current clinical applications in dermatology of MMF and EC-MPS. PMID- 25557633 TI - Novel kynurenic acid analogues in the treatment of migraine and neurodegenerative disorders: preclinical studies and pharmaceutical design. AB - Though migraine and neurodegenerative disorders have a high socioeconomic impact, their therapeutic management has not been fully addressed. Their pathomechanisms are not completely understood, but glutamateinduced excitotoxicity, mitochondrial disturbances and oxidative stress all seem to play crucial roles. The overactivation of glutamate receptors contributes to the hyperexcitability observed in migraine and also to the neurodegenerative process. The kynurenine pathway of the tryptophan metabolism produces the only known endogenous Nmethyl- D-aspartate receptor antagonist, kynurenic acid, which has been proven in different preclinical studies to exert a neuroprotective effect. Influencing the kynurenine pathway might be beneficial in migraine and neurodegenerative diseases, and in the normalization of glutamatergic neurotransmission and the prevention of excitotoxic neuronal damage. The synthesis of kynurenic acid analogues may offer a valuable tool for drug development. PMID- 25557635 TI - Phenylbutyric Acid: simple structure - multiple effects. AB - Phenylbutyrate (PBA) is an aromatic short-chain fatty acid which is a chemical derivative of butyric acid naturally produced by colonic bacteria fermentation. At the intestinal level butyrate exerts a multitude of activities including amelioration of mucosal inflammation, regulation of transepithelial fluid transport, improvement in oxidative status and colon cancer prevention. Moreover, increasing number of studies report the beneficial role of butyric acid in prevention or inhibition of other types of malignancies, leading to cancer cell growth arrest and apoptosis. Similarly, phenylbutyrate displays potentially favorable effects on many pathologies including cancer, genetic metabolic syndromes, neuropathies, diabetes, hemoglobinopathies, and urea cycle disorders. The mechanisms by which PBA exerts these effects are different. Some of them are connected with the regulation of gene expression, playing the role of a histone deacetylase inhibitor, while others contribute to the ability of rescuing conformational abnormalities of proteins, serving as chemical chaperone, and some are dedicated to its metabolic characteristic enabling excretion of toxic ammonia, thus acting as ammonia scavenger. Phenylbutyrate may exert variable effects depending on the cell type, thus the term "butyrate paradox" has been proposed. These data indicate a broad spectrum of beneficial effects evoked by PBA with a high potential in therapy. In this review, we focus on cellular and systemic effects of PBA treatment with special attention to the three main branches of its molecular activity: ammonia scavenging, chaperoning and histone deacetylase inhibiting, and describe its particular role in various human diseases. PMID- 25557634 TI - 25OH-Vitamin D3 Levels in Obesity and Metabolic Syndrome-Unaltered in Young and not Correlated to Carotid IMT in All Ages. AB - Contradictory results exist for levels of vitamin D measured in patients with cardiovascular disease (CVD), obesity and metabolic syndrome (MetS). To clarify this, we investigated 527 participants of the STYJOBS/ EDECTA cohort (NCT00482924), with ages between 10 and 65 years. A cross-sectional analysis of anthropometry, carotid intima media thickness (IMT), and laboratory measurements for 25OH-Vitamin D3 (vitD), glucose metabolism, ultra-sensitive C-reactive protein (US-CRP), interleukin-6 (IL-6), lipids, liver-, renal-parameters, and kynurenine to tryptophan ratio were made for a selection of persons who were either obese or of normal weight. The homeostasis model assessment insulin resistance (HOMA) was also measured. As compared to the normal weight controls, significantly decreased blood levels of vitD were found in overweight/obese adults, which were not observed in the juveniles. Nevertheless, both overweight/obese juveniles and adults had significantly increased US-CRP, IL-6, HOMA, triglyceride, and LDL-cholesterol levels, and significantly decreased HDL cholesterol levels. Juveniles with MetS displayed unchanged levels of vitD as compared to overweight/obese juveniles without MetS. Although IMT was significantly increased in both juvenile and adult overweight/obese subjects, vitD and IMT levels were not correlated. Assuming a minimum threshold of 20 ng/ml for the establishment of "low" or "normal" vitD levels, no significant alteration in IMT, metabolic, and inflammatory markers was observed in juveniles with a low vitD-status . In conclusion, although metabolic and inflammatory symptoms of obesity are displayed in juveniles, their vitD levels are unaffected. This, together with the complete lack of association with carotid IMT in both juveniles and adults, argues against a causative role of vitD in obesity-associated vascular pathology. PMID- 25557636 TI - CXCR4 and CXCL12 Expression in Rectal Tumors of Stage IV Patients Before and After Local Radiotherapy and Systemic Neoadjuvant Treatment. AB - Metastatic rectal cancer patients could benefit from novel therapeutic approaches. The signaling network formed by chemokines and their receptors can promote metastasis and resistance to current anticancer treatments. This study assessed the expression of chemokine receptor 4 (CXCR4) and its ligand CXCL12 immuhistochemically in stage IV rectal tumors. Paraffin-embedded primary tumor collected before and after local radiotherapy and systemic treatment with bevacizumab, oxaliplatin and capecitabine was analyzed. Receptor and ligand expression was assessed in the cytoplasm and nucleus of tumor, stromal and normal rectal crypt cells. Baseline expression of CXCR4 and CXCL12 was correlated with patients' pathologic response to treatment. At diagnosis (n=46), 89% of the rectal tumors expressed cytoplasmic CXCR4 and 81% CXCL12. Nuclear CXCR4 expression in tumor cells was present in 30% and nuclear CXCL12 expression in 35% of the tumors. After radiochemotherapy and administration of bevacizumab, nuclear CXCL12 expression was observed in 79% of residual tumors, as compared to 31% of the paired tumor samples expressing nuclear CXCL12 before treatment (P=0.001). There were no differences in CXCR4 or CXCL12 expression at baseline between the patients who had (n=9) and did not have (n=30) a pathologic complete response. Our results show that CXCR4 and CXCL12 are extensively expressed in primary rectal tumors of patients presenting with metastatic disease, while radiochemotherapy and bevacizumab further upregulate CXCL12 expression. These data indicate the importance of the CXCR4/CXCL12 axis in rectal tumor biology, and may suggest the CXCR4/CXCL12 receptor-ligand pair as a potential therapeutic target in metastatic rectal cancer. PMID- 25557637 TI - Evaluation of the in vivo safety profiles of Rictor inhibition using a zebrafish model. AB - The mammalian target of rapamycin (mTOR), which assembles into two distinct multiprotein complexes, called mTORC1 and mTORC2, is known as a central regulator of cellular proliferation and maturation. Rictor is one of the key components of mTORC2 and acts as a scaffolding protein to maintain and stabilize mTORC2. Currently, mTORC2 and/or Rictor are increasingly being recognized as attractive targets for novel modalities of anti-cancer therapy. Unfortunately, the safety profile of Rictor- or mTORC2-targeting strategies has been poorly understood due to the lack of an ideal animal model. In the present study, we used zebrafish as an in vivo model system to evaluate the safety of Rictor inhibition. Our data showed that the Rictor of zebrafish was identified to have high sequence homology with mouse Rictor and human Rictor, which validates the rationale of using zebrafish as a research model. Rictor was dispensable in neonatal hematopoiesis and angiogenesis and was not required for vasculogenesis and other organs. These data are consistent with those of previous observations of using tissue-specific Rictor knockout mice model and have potentially important clinical implications. Our findings highlight a good in vivo safety profile for Rictor- or mTORC2 targeting therapy and point to the feasibility and advantages of using the zebrafish model to evaluate the safety of the therapeutic target. PMID- 25557638 TI - Quantitative muscle ultrasonography in the follow-up of juvenile dermatomyositis. AB - INTRODUCTION: We explored the use of quantitative muscle ultrasonography (QMUS) for follow-up of juvenile dermatomyositis (JDM). METHODS: Seven JDM patients were evaluated at diagnosis and 1, 3, 6, 12, and 24 months using the Childhood Myositis Assessment Scale (CMAS) and QMUS. Muscle thickness (MT) and quantitative muscle echo intensity (EI) were assessed with QMUS in 4 muscles. RESULTS: Six patients experienced a monocyclic course. At diagnosis EI was slightly increased, and MT was relatively normal. After start of treatment MT first decreased and EI increased, with normalization of EI within 6-12 months (n = 4). One patient had higher EIs at diagnosis and slower normalization, indicating fibrosis, despite early normalization of CMAS. One patient experienced a chronic course, with high EIs and atrophy during follow-up. CONCLUSIONS: QMUS can provide additional information for follow-up of JDM regarding disease severity and residual muscle damage, particularly after normalization of CMAS. PMID- 25557639 TI - Phthalate metabolites in urine samples from Beijing children and correlations with phthalate levels in their handwipes. AB - Little attention has been paid to dermal absorption of phthalates even though modeling suggests that this pathway may contribute meaningfully to total uptake. We have concurrently collected handwipe and urine samples from 39 Beijing children (5-9 years) for the purpose of measuring levels of five phthalates in handwipes, corresponding concentrations of eight of their metabolites in urine, and to subsequently assess the contribution of dermal absorption to total uptake. In summer sampling, DEHP was the most abundant phthalate in handwipes (median: 1130 MUg/m(2) ), while MnBP was the most abundant metabolite in urine (median: 232 ng/ml). We found significant associations between the parent phthalate in handwipes and its monoester metabolite in urine for DiBP (r = 0.41, P = 0.01), DnBP (r = 0.50, P = 0.002), BBzP (r = 0.48, P = 0.003), and DEHP (r = 0.36, P = 0.03). Assuming that no dermal uptake occurred under clothing-covered skin, we estimate that dermal absorption of DiBP, DnBP, BBzP, and DEHP contributed 6.9%, 4.6%, 6.9%, and 3.3%, respectively, to total uptake. Assuming that somewhat attenuated dermal uptake occurred under clothing-covered skin, these estimates increase to 19%, 14%, 17%, and 10%. The results indicate that absorption from skin surfaces makes a meaningful contribution to total phthalate uptake for children and should be considered in future risk assessments. PRACTICAL IMPLICATIONS: This study indicates that children's hands acquire substantial amounts of various phthalates. The levels measured in handwipes, although higher, are somewhat representative of levels on other body locations. Via dermal absorption, as well as hand-to-mouth activity, phthalates on hands and other body locations contribute to the overall body burden of these compounds. Dermal absorption from air and contact transfer from surfaces is expected to occur for many SVOCs commonly found indoors (e.g. bisphenols, synthetic musks, organophosphates). However, the dermal pathway has often been neglected in exposure assessments of indoor pollutants. Knowledge regarding phthalates and other SVOCs in handwipes can facilitate our understanding of risks and aid in the mitigation of adverse health effects resulting from indoor exposures. To make progress toward these goals, further studies are necessary, including investigations of phthalate level variability in skinwipes collected at different locations on the body and the impact of clothing on dermal absorption from air. PMID- 25557641 TI - Effect of length and rigidity of microtubules on the size of ring-shaped assemblies obtained through active self-organization. AB - The microtubule (MT)-kinesin biomolecular motor system has attracted considerable attention due to its possible applications in artificial biomachines. Recently, an active self-organization (AcSO) method has been established to integrate MT filaments into highly organized assembled structures. The ring-shaped MT assembly, one of the structures derived from the AcSO of MTs, can convert the translational motion of MTs into rotational motion. Due to this attractive feature, the ring-shaped MT assembly appears to be a promising candidate for developing artificial devices and for future nanotechnological applications. In this work, we have investigated the effect of length and rigidity of the MT filaments on the size of the ring-shaped MT assembly in the AcSO process. We show that the size of the ring-shaped MT assembly can be controlled by tuning the length and rigidity of MT filaments employed in the AcSO. Longer and stiffer MT filaments led to larger ring-shaped assemblies through AcSO, whereas AcSO of shorter and less stiff MT filaments produced smaller ring-shaped assemblies. This work might be important for the development of biomolecular motor based artificial biomachines, especially where size control of ring-shaped MT assembly will play an important role. PMID- 25557640 TI - Interaction between pancreatic cancer cells and tumor-associated macrophages promotes the invasion of pancreatic cancer cells and the differentiation and migration of macrophages. AB - In this study, the impact of pancreatic cancer cell interaction with macrophages on the differentiation and function of macrophages and the behaviors of pancreatic cancer cells in vitro is evaluated. The expression of immunocompetent cell-associated markers in 22 pancreatic cancer specimens was characterized by immunohistochemistry. The impact of pancreatic cancer cells (PANC-1 and BxPC-3) on the differentiation and migration of human U937 monocytes and the effect of U937-derived macrophages on the proliferation and invasion of PANC-1 and BxPC-3 were determined by transwell assays. The potential effect on U937-derived macrophages or on the behaviors of pancreatic cancer cells following coculture in a transwell system was analyzed by quantitative real-time polymerase chain reaction. The high levels of macrophage-related CD68 and CD163 expression were detected in the pancreatic cancer specimens. Pancreatic cancer cells promoted the differentiation of U937 cells and migration of U937-derived macrophages, but decreased the mRNA transcripts of macrophage polarization-related genes of interleukin (IL)-10, IL-12p40, inducible nitric oxide synthase (iNOS), and CD163, particularly for iNOS. Furthermore, U937-derived M2 macrophages inhibited the proliferation of pancreatic cancer cells, but promoted their invasion. Coculture of pancreatic cancer cells with U937-derived macrophages upregulated the mRNA expression of genes associated with the epithelial-mesenchymal transition process, angiogenesis, and stemness of pancreatic cancer, but downregulated the expression of E-cadherin in pancreatic cancer cells. The interaction between pancreatic cancer cells and tumor-associated macrophages may play a pivotal role in the progression of pancreatic cancer. PMID- 25557642 TI - Hemangioma Activity and Severity Index (HASI), an instrument for evaluating infantile hemangioma: development and preliminary validation. AB - BACKGROUND: Infantile hemangiomas (IHs) are the most common benign vascular tumors of infancy. Their evaluation is important and requires the use of a unified scoring system. OBJECTIVES: We designed a novel scoring index, the Hemangioma Activity and Severity Index (HASI), for the clinical evaluation of IHs. The purpose of this pilot study was to validate the HASI. METHODS: The HASI was evaluated for validity by an external panel of experts. The reliability study included 59 children with superficial and mixed hemangiomas. Patients attended an assessment visit and a subsequent visit three days later for a second scoring. They were then followed up monthly for six months and scored at each visit by two investigators separately. RESULTS: Interclass correlation coefficients (ICCs) for inter-rater reliability were 0.82 (95% confidence interval [CI] 0.75-0.88) for IH activity and 0.94 (95% CI 0.91-0.96) for IH severity. Intra-rater reliability was high, with negligible mean differences of 0.3 and 0.4 points between the two ratings. The average time required to complete the scoring was 2.5 minutes. CONCLUSIONS: Our preliminary studies on the HASI show promising results in terms of its clinical utility and applicability in practice. It could be used by physicians as an objective instrument for the scoring of IHs. PMID- 25557643 TI - Carnosine and vitamin E--a promising pair in the combat against testicular oxidative stress in aged rats. AB - Oxidative stress is considered to play a key role in ageing. Carnosine alone or together with vitamin E may prove to be helpful in dealing with problems of ageing through its antioxidant activity. Testis, by producing steroids and possessing a poor antioxidant system may become a strong target for the chronic oxidative stress generated during ageing. Therefore we investigated the in vivo effect of carnosine alone or together with vitamin E on testicular oxidative stress in aged rats. In this study, young (5 months) and aged (22 months) Wistar rats were used. Carnosine (250 mg kg(-1); i.p.; 5 days per week) and vitamin E (200 mg kg(-1); i.m.; twice per week) were given to aged rats for 2 months. Increased testicular lipid peroxidation and superoxide dismutase activity in aged rats were declined to the levels of young ones by both treatments. Decreased glutathione peroxidase and glutathione transferase activities returned to the level of young's only by carnosine plus vitamin E treatment. Histopathological evaluation described by Johnsen's score, also showed significant improvement with preserved spermatogenesis. Carnosine plus vitamin E treatment appears to stage a powerful performance by attenuating testicular oxidative stress and sparing the antioxidant system. PMID- 25557644 TI - Metacognitive interpersonal therapy for co-occurrent avoidant personality disorder and substance abuse. AB - Many patients with substance abuse problems present with co-occurrent cluster C personality disorders. Focusing on both disorders disrupts the maintenance mechanisms and the vicious cycle between the 2 conditions; however, treatment teams often neglect this issue. In this work, we describe the features of metacognitive interpersonal therapy as applied to a man with avoidant and depressive personality disorders and heroin, cocaine, and alcohol abuse. Psychotherapy proceeded through the following steps: (a) conducting drug therapy to deal with symptoms of abstinence from heroin; (b) forming a therapeutic bond to overcome the patient's severe emotional withdrawal; (c) fostering basic metacognitive capacities such as awareness of emotions and their triggers; (d) sharing formulations of maladaptive interpersonal schemas and descriptions of the associated states of mind; (e) conveying an understanding of the link between interpersonal events (recent ones and traumatic memories) and substance abuse; (f) facilitating the acquisition of critical distance from maladaptive schemas; and (g) promoting the use of adaptive coping skills instead of resorting to substance abuse. Implications for generalizing these procedures to the treatment of other patients with co-occurrent personality disorders and substance abuse are described. PMID- 25557646 TI - Skin diseases in Nigeria: the Calabar experience. AB - BACKGROUND: This paper reports on a 6-year study (April 2006 to April 2012) and a follow-up of a 9-month baseline survey of the pattern of dermatoses in Calabar, the capital of Cross River State in southern Nigeria. Prior to the time of this study, this region had not benefited from the services of a resident dermatologist for over a century. METHODS: Data on the age, gender, and diagnoses of 1307 consecutive new patients attending the relatively new dermatology clinic at the University of Calabar Teaching Hospital during the study period were obtained and analyzed. Most diagnoses were based on clinical findings but were supported by relevant laboratory investigations and histopathologic examinations when necessary. RESULTS: The male : female ratio of patients was 1 : 1.5. The mean +/- standard deviation age of the patients was 27.7 +/- 17.2 years (range: 4 weeks to 84 years). A total of 1459 diagnoses were recorded; 143 patients had more than one dermatosis. Diagnoses were broadly divided into 10 groups. Allergic/hypersensitivity diseases represented the most common group (30.4%), followed by infections/infestations (28.9%). A comparison of this study with others from various geopolitical zones of Nigeria revealed some similarities. Dermatophytosis and acne were consistent reasons for visits to dermatologists in all zones. CONCLUSIONS: Despite the wide spectrum of dermatoses observed, a small number of diseases account for a sizeable percentage of diagnoses. The pattern of dermatoses in Calabar is similar to that in other parts of the country. Climate and socioeconomic factors are synergistic in causing dermatoses that remain a major cause of morbidity in all age groups and both genders across Nigeria. PMID- 25557647 TI - The Okuda papers: an extraordinary--but unfortunately unrecognized--piece of work that could have changed the history of hair transplantation. PMID- 25557645 TI - Pocketome of human kinases: prioritizing the ATP binding sites of (yet) untapped protein kinases for drug discovery. AB - Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. Although the development of new kinase inhibitors is a major focus in pharmaceutical research, a large number of kinases remained so far unexplored in drug discovery projects. The selection and assessment of targets is an essential but challenging area. Today, a few thousands of experimentally determined kinase structures are available, covering about half of the human kinome. This large structural source allows guiding the target selection via structure-based druggability prediction approaches such as DoGSiteScorer. Here, a thorough analysis of the ATP pockets of the entire human kinome in the DFG-in state is presented in order to prioritize novel kinase structures for drug discovery projects. For this, all human kinase X-ray structures available in the PDB were collected, and homology models were generated for the missing part of the kinome. DoGSiteScorer was used to calculate geometrical and physicochemical properties of the ATP pockets and to predict the potential of each kinase to be druggable. The results indicate that about 75% of the kinome are in principle druggable. Top ranking structures comprise kinases that are primary targets of known approved drugs but additionally point to so far less explored kinases. The presented analysis provides new insights into the druggability of ATP binding pockets of the entire kinome. We anticipate this comprehensive druggability assessment of protein kinases to be helpful for the community to prioritize so far untapped kinases for drug discovery efforts. PMID- 25557648 TI - Liver transplantation arrests and reverses muscle wasting. AB - Muscle wasting, sarcopenia, is common in advanced cirrhosis and predicts adverse outcomes while awaiting and following liver transplantation. Frequent post transplant worsening of sarcopenia has attracted recent interest. It is unknown whether this serious problem is an expected metabolic consequence of transplantation or results from confounding conditions such as recurrent allograft liver disease or avoidable post-transplant complications. To clarify this question, we studied pre- and post-transplant muscle mass in a retrospective cohort of 40 patients transplanted for three diseases - alcoholic cirrhosis, non alcoholic steatohepatitis cirrhosis, and primary sclerosing cholangitis cirrhosis - in whom allograft disease recurrence was monitored and excluded, and who lacked common post-transplant muscle wasting complications such as sepsis, renal failure, ischemia, and cholestasis. We measured skeletal muscle index (SMI) using computed tomography before and 12-48 months after transplant. SMI as a categorical variable significantly improved, from 18 patients above the normal cutoff pre-transplant to 28 post-transplant (p = 0.008). SMI increases were greatest in patients with the lowest pre-transplant SMI (p < 0.01). As a continuous variable, mean SMI remained stable, with a non-significant trend toward improvement. We conclude that after liver transplantation sarcopenia does not progress but is arrested and frequently improves in the absence of confounding conditions. PMID- 25557650 TI - Effect of UV radiation on habitat selection by Girella laevifrons and Graus nigra (Kyphosidae). AB - The effect of UV radiation on habitat use of two species of intertidal fishes that inhabit the same pools but exhibit different activity levels and diets was measured: the highly active omnivorous Girella laevifrons and the cryptic carnivorous Graus nigra. Individuals of each species were acclimated to a tank divided in three sections with different illumination; no light (NL), ultraviolet light (UV) and white light (WL), and the time spent and number of visits to each section were recorded. Although both species preferred the NL section, G. laevifrons spent more time in UV and less time in WL compared with G. nigra; G. laevifrons also displayed higher number of visits to UV, suggesting a different tendency in space use in response to UV exposure in intertidal fishes. PMID- 25557649 TI - ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model. AB - The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy. PMID- 25557651 TI - Conquering depression. PMID- 25557652 TI - Can novel methods be useful for pain assessment of castrated piglets? AB - Given that surgical castration is a painful practice performed on millions of pigs every year, a need to identify novel reliable pain assessment tools exists in order to test anaesthetic and analgesic protocols that may reduce related pain. Two treatments were considered: handling (H) and surgical castration (C). Physiological (cortisol, lactate, glycaemia, rectal and eye temperature) and behavioural variables (latency to move after treatment and alterations in posture and walking) were analysed. Cortisol showed the greatest level in C piglets within 20 min after the surgical procedure and a positive correlation with glucose concentration. Eye temperature was higher in C piglets, and the same difference was detected for rectal temperature 3 h after castration. Behavioural parameters revealed that C piglets had longer latency to move and a higher percentage of them showed alterations in posture and walking. Results of this study showed that, in castrated piglets behavioural and physiological alterations occur mainly in the first 3 h from treatment. Latency to move, alterations in posture and walking, and eye temperature appear to give additional and useful information in piglet pain assessment. However, differently from the behavioural parameters considered, eye temperature involves several manipulations of the animals and a long process to acquire the data. PMID- 25557653 TI - Delayed presentation of major complications in patients undergoing cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy following hospital discharge. AB - INTRODUCTION: Peritoneal surface malignancy is increasingly treated with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC). This is associated with potentially high morbidity. We analyzed the incidence of delayed major complications following CRS plus HIPEC. METHODS: Delayed events were chosen as those which occurred after discharge from the hospital following CRS plus HIPEC and prior to 90 days. Major complications included any adverse event requiring intervention or intensive care unit admission. RESULTS: One hundred thirty six patients underwent 140 procedures. Eight patients (5.7%) developed delayed major complications. Complications were pancreatic pseudocyst/pancreatitis (n = 3), abdominal wall dehiscence (n = 2), gastric perforation (n = 1), and ureteral stricture with associated hydronephrosis (n = 2). All of the patients had undergone multivisceral resections. Seven patients achieved complete cytoreduction (cc <= 1). Mean peritoneal carcinomatosis index (PCI) was 15.25 +/- 5.33 (6-22). Standard of care was met for the management of all the complications and all patients recovered following intervention without any further morbidity or mortality. CONCLUSION: There is a lack of report of the delayed major complications in patients undergoing CRS plus HIPEC in the literature. Awareness should be raised among health care providers regarding possible occurrence of such late complications given that many patients undergo CRS plus HIPEC remotely from their localities. PMID- 25557654 TI - Increased CD11b(+) Gr-1(+) cell population in the placenta after infection with Toxoplasma gondii. AB - Toxoplasma gondii is an obligate intracellular protozoan pathogen that can cross the placenta, resulting in congenital toxoplasmosis with severe fetal brain abnormalities. The molecular mechanisms of immune responses against T. gondii infection in the placenta have largely remained unclear. An analytical method for characterizing phenotypes of immune cells in the placenta by flow cytometry was established and it was found that numbers of CD11b(+) Gr-1(+) cells in the placenta increased significantly after T. gondii infection. These results suggest that innate immune responses play an important role in immunity against T. gondii infection via the feto-maternal interface. PMID- 25557655 TI - Synthesis of mixed silylene-carbene chelate ligands from N-heterocyclic silylcarbenes mediated by nickel. AB - The Ni(II) -mediated tautomerization of the N-heterocyclic hydrosilylcarbene L(2) Si(H)(CH2 )NHC 1, where L(2) =CH(C?CH2 )(CMe)(NAr)2 , Ar=2,6-iPr2 C6 H3 ; NHC=3,4,5-trimethylimidazol-2-yliden-6-yl, leads to the first N-heterocyclic silylene (NHSi)-carbene (NHC) chelate ligand in the dibromo nickel(II) complex [L(1) Si:(CH2 )(NHC)NiBr2 ] 2 (L(1) =CH(MeC?NAr)2 ). Reduction of 2 with KC8 in the presence of PMe3 as an auxiliary ligand afforded, depending on the reaction time, the N-heterocyclic silyl-NHC bromo Ni(II) complex [L(2) Si(CH2 )NHCNiBr(PMe3 )] 3 and the unique Ni(0) complex [eta(2) (Si-H){L(2) Si(H)(CH2 )NHC}Ni(PMe3 )2 ] 4 featuring an agostic Si?H->Ni bonding interaction. When 1,2 bis(dimethylphosphino)ethane (DMPE) was employed as an exogenous ligand, the first NHSi-NHC chelate-ligand-stabilized Ni(0) complex [L(1) Si:(CH2 )NHCNi(dmpe)] 5 could be isolated. Moreover, the dicarbonyl Ni(0) complex 6, [L(1) Si:(CH2 )NHCNi(CO)2 ], is easily accessible by the reduction of 2 with K(BHEt3 ) under a CO atmosphere. The complexes were spectroscopically and structurally characterized. Furthermore, complex 2 can serve as an efficient precatalyst for Kumada-Corriu-type cross-coupling reactions. PMID- 25557656 TI - Quantifying dynamic and postural balance difficulty during gait perturbations using stabilizing/destabilizing forces. AB - Intensity of balance exercises used to reduce fall risk is often poorly quantified. The study aimed to test whether balance difficulty can be rated during gait perturbations against balance difficulty during gait without perturbation, using the stabilizing/destabilizing forces. These forces represent the difficulty to maintain balance as the theoretical forces necessary to cancel body velocity and to set the body into an unstable posture, respectively. Ten healthy subjects walked on a split-belt treadmill, that also generated perturbations. Kinetic and kinematic data were collected during gait at comfortable and fast speeds without perturbation, and in five trials at comfortable speed with perturbations. Perturbations consisted of increasing or decreasing the speed of one belt to three different levels in each direction in a random order during the stance phase of 12 random steps per trial. The difficulty of maintaining balance was measured during the perturbation and the three following recovery steps. Compared to comfortable speed, higher stabilizing and lower destabilizing forces indicated higher balance difficulty during the perturbation step for faster-belt perturbations, and recovery steps for slower belt perturbations. This was also associated with the center of mass shifted forward, and moving faster, and with the center of pressure closer to the forward limit of the base of support. Difficulty increased proportionally with the intensity of perturbation and was significantly higher for the more intense perturbations than at fast speed. Thus, the stabilizing/destabilizing forces seem adequate to evaluate balance difficulty during gait perturbations and could be used to determine the optimal difficulty for balance rehabilitation. PMID- 25557657 TI - Sirt-1 activity in PBMC from patients with spondyloarthritis. PMID- 25557659 TI - Systemic sclerosis: Recent insights. AB - Systemic sclerosis is an orphan connective tissue disease characterized by alterations of the microvasculature, disturbances of the immune system and massive deposition of collagen and other matrix substances in the skin and internal organs. A major achievement of the recent years has been the validation of new classification criteria, allowing earlier diagnosis and earlier treatment of systemic sclerosis, before irreversible fibrosis and organ damage appeared ("window of opportunity"). Raynaud's phenomenon is usually the first sign of the disease and is considered as the main sentinel sign for the identification of very early systemic sclerosis. Systemic sclerosis is clinically heterogeneous and disease course remains unpredictable. Its prognosis depends on cardiopulmonary involvement and recent studies aim to identify serum or genetic biomarkers predictive of severe organ involvement. Moreover, the prospective follow-up of large cohorts has provided and will offer critical material to identify strong prognostic factors. Whereas the outcomes of vascular manifestations of the disease has been recently improved due to targeted therapy, recent data have highlighted that mortality has not changed over the past 40 years. This reflects the absence of efficacy of current available drugs to counteract the fibrotic process. Nevertheless, several targeted immunity therapies, commonly with proven efficacy in other immune diseases, are about to be investigated in systemic sclerosis. Indeed, promising results in small and open studies have been reported. This article deals with recent insights into classification criteria, pathogenesis, organ involvements, outcome and current and possible future therapeutic options in systemic sclerosis. PMID- 25557658 TI - The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone remodeling markers in patients with rheumatoid arthritis. AB - Previous studies showed that the control of inflammation by biological therapies has a positive effect on bone in inflammatory diseases. The objective of this study was to assess the effects on bone mineral density (BMD) and bone remodeling of an anti-IL-6 monoclonal antibody (tocilizumab (TCZ)) in patients with rheumatoid arthritis (RA). METHODS: One hundred and three patients (75% women, 52+/-12years) with active RA were treated with TCZ 8mg/kg + methotrexate (MTX) every 4 weeks during 48 weeks. Hip and lumbar spine BMDs were measured at baseline and after 48 weeks by dual energy X-ray absorptiometry (DXA). Pro collagen serum type I N-terminal propeptide (PINP), serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), and serum levels of total Dickkopf-1 (Dkk 1) and sclerostin were assessed at baseline, 12 and 48 weeks. RESULTS: BMD was available for 76 patients at baseline and at the end of the study. There was no change in lumbar spine and hip BMD over 48 weeks. Serum PINP increased from baseline by 22% (P<=0.001) and 19% (P<=0.001) at week 12 and week 48, whereas serum CTX-I remained stable. Serum DKK-1 significantly decreased from baseline by -31% (P<=0.001) and -25% (P=0.025) at week 12 and 48. Similar results were observed in the patients receiving low doses of oral corticosteroids. CONCLUSION: In this 1-year prospective open study, patients with active RA receiving TCZ and MTX had no change in BMD, a decrease in serum DKK-1 and an increase in bone formation marker. PMID- 25557660 TI - Spontaneous resorption of extensive cervicothoracic pneumorrhachis. PMID- 25557661 TI - Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry. AB - A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed. PMID- 25557662 TI - A novel protein, ubiquitous in marine phytoplankton, concentrates iron at the cell surface and facilitates uptake. AB - Numerous cellular functions including respiration require iron. Plants and phytoplankton must also maintain the iron-rich photosynthetic electron transport chain, which most likely evolved in the iron-replete reducing environments of the Proterozoic ocean [1]. Iron bioavailability has drastically decreased in the contemporary ocean [1], most likely selecting for the evolution of efficient iron acquisition mechanisms among modern phytoplankton. Mesoscale iron fertilization experiments often result in blooms dominated by diatoms [2], indicating that diatoms have adaptations that allow survival in iron-limited waters and rapid multiplication when iron becomes available. Yet the genetic and molecular bases are unclear, as very few iron uptake genes have been functionally characterized from marine eukaryotic phytoplankton, and large portions of diatom iron starvation transcriptomes are genes encoding unknown functions [3-5]. Here we show that the marine diatom Phaeodactylum tricornutum utilizes ISIP2a to concentrate Fe(III) at the cell surface as part of a novel, copper-independent and thermodynamically controlled iron uptake system. ISIP2a is expressed in response to iron limitation several days prior to the induction of ferrireductase activity, and it facilitates significant Fe(III) uptake during the initial response to Fe limitation. ISIP2a is able to directly bind Fe(III) and increase iron uptake when heterologously expressed, whereas knockdown of ISIP2a in P. tricornutum decreases iron uptake, resulting in impaired growth and chlorosis during iron limitation. ISIP2a is expressed by diverse marine phytoplankton, indicating that it is an ecologically significant adaptation to the unique nutrient composition of marine environments. PMID- 25557663 TI - ELF3 controls thermoresponsive growth in Arabidopsis. AB - Plant development is highly responsive to ambient temperature, and this trait has been linked to the ability of plants to adapt to climate change. The mechanisms by which natural populations modulate their thermoresponsiveness are not known. To address this, we surveyed Arabidopsis accessions for variation in thermal responsiveness of elongation growth and mapped the corresponding loci. We find that the transcriptional regulator EARLY FLOWERING3 (ELF3) controls elongation growth in response to temperature. Through a combination of modeling and experiments, we show that high temperature relieves the gating of growth at night, highlighting the importance of temperature-dependent repressors of growth. ELF3 gating of transcriptional targets responds rapidly and reversibly to changes in temperature. We show that the binding of ELF3 to target promoters is temperature dependent, suggesting a mechanism where temperature directly controls ELF3 activity. PMID- 25557664 TI - Pavarotti/MKLP1 regulates microtubule sliding and neurite outgrowth in Drosophila neurons. AB - Recently, we demonstrated that kinesin-1 can slide microtubules against each other, providing the mechanical force required for initial neurite extension in Drosophila neurons. This sliding is only observed in young neurons actively forming neurites and is dramatically downregulated in older neurons. The downregulation is not caused by the global shutdown of kinesin-1, as the ability of kinesin-1 to transport membrane organelles is not diminished in mature neurons, suggesting that microtubule sliding is regulated by a dedicated mechanism. Here, we have identified the "mitotic" kinesin-6 Pavarotti (Pav-KLP) as an inhibitor of kinesin-1-driven microtubule sliding. Depletion of Pav-KLP in neurons strongly stimulated the sliding of long microtubules and neurite outgrowth, while its ectopic overexpression in the cytoplasm blocked both of these processes. Furthermore, postmitotic depletion of Pav-KLP in Drosophila neurons in vivo reduced embryonic and larval viability, with only a few animals surviving to the third instar larval stage. A detailed examination of motor neurons in the surviving larvae revealed the overextension of axons and mistargeting of neuromuscular junctions, resulting in uncoordinated locomotion. Taken together, our results identify a new role for Pav-KLP as a negative regulator of kinesin-1-driven neurite formation. These data suggest an important parallel between long microtubule-microtubule sliding in anaphase B and sliding of interphase microtubules during neurite formation. PMID- 25557665 TI - COPII coat composition is actively regulated by luminal cargo maturation. AB - BACKGROUND: Export from the ER is an essential process driven by the COPII coat, which forms vesicles at ER exit sites (ERESs) to transport mature secretory proteins to the Golgi. Although the basic mechanism of COPII assembly is known, how COPII machinery is regulated to meet varying cellular secretory demands is unclear. RESULTS: Here, we report a specialized COPII system that is actively recruited by luminal cargo maturation. Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are luminal secretory proteins anchored to the membrane by the glycolipid GPI. After protein attachment in the ER lumen, lipid and glycan parts of the GPI anchor are remodeled. In yeast, GPI-lipid remodeling concentrates GPI APs into specific ERESs. We found that GPI-glycan remodeling induces subsequent recruitment of the specialized ER export machinery that enables vesicle formation from these specific ERESs. First, the transmembrane cargo receptor p24 complex binds GPI-APs as a lectin by recognizing the remodeled GPI-glycan. Binding of remodeled cargo induces the p24 complex to recruit the COPII subtype Lst1p, specifically required for GPI-AP ER export. CONCLUSIONS: Our results show that COPII coat recruitment by cargo receptors is not constitutive but instead is actively regulated by binding of mature ligands. Therefore, we reveal a novel functional link between luminal cargo maturation and COPII vesicle budding, providing a mechanism to adjust specialized COPII vesicle production to the amount and quality of their luminal cargos that are ready for ER exit. This helps to understand how the ER export machinery adapts to different needs for luminal cargo secretion. PMID- 25557667 TI - ELF3-PIF4 interaction regulates plant growth independently of the Evening Complex. AB - The circadian clock plays a pivotal role in the control of Arabidopsis hypocotyl elongation by regulating rhythmic expression of the bHLH factors PHYTOCHROME INTERACTING FACTOR 4 and 5 (PIF4 and 5). Coincidence of increased PIF4/PIF5 transcript levels with the dark period allows nuclear accumulation of these factors, and in short days it phases maximal hypocotyl growth at dawn. During early night, PIF4 and PIF5 transcription is repressed by the Evening Complex (EC) proteins EARLY FLOWERING3 (ELF3), EARLY FLOWERING4 (ELF4), and LUX ARRHYTHMO (LUX). While ELF3 has an essential role in EC complex assembly, several lines of evidence indicate that this protein controls plant growth via other mechanisms that are presently unknown. Here, we show that the ELF3 and PIF4 proteins interact in an EC-independent manner, and that this interaction prevents PIF4 from activating its transcriptional targets. We also show that PIF4 overexpression leads to ELF3 protein destabilization, and that this effect is mediated indirectly by negative feedback regulation of photoactive PHYTOCHROME B (phyB). Physical interaction of the phyB photoreceptor with ELF3 has been reported, but its functional relevance remains poorly understood. Our findings establish that phyB is needed for ELF3 accumulation in the light, most likely by competing for CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1)-mediated ubiquitination and the proteasomal degradation of ELF3. Our results explain the short hypocotyl phenotype of ELF3 overexpressors, despite their normal clock function, and provide a molecular framework for understanding how warm temperatures promote hypocotyl elongation and affect the endogenous clock. PMID- 25557666 TI - Neuronal serotonin release triggers the heat shock response in C. elegans in the absence of temperature increase. AB - BACKGROUND: Cellular mechanisms aimed at repairing protein damage and maintaining homeostasis, widely understood to be triggered by the damage itself, have recently been shown to be under cell nonautonomous control in the metazoan C. elegans. The heat shock response (HSR) is one such conserved mechanism, activated by cells upon exposure to proteotoxic conditions such as heat. Previously, we had shown that this conserved cytoprotective response is regulated by the thermosensory neuronal circuitry of C. elegans. Here, we investigate the mechanisms and physiological relevance of neuronal control. RESULTS: By combining optogenetic methods with live visualization of the dynamics of the heat shock transcription factor (HSF1), we show that excitation of the AFD thermosensory neurons is sufficient to activate HSF1 in another cell, even in the absence of temperature increase. Excitation of the AFD thermosensory neurons enhances serotonin release. Serotonin release elicited by direct optogenetic stimulation of serotonergic neurons activates HSF1 and upregulates molecular chaperones through the metabotropic serotonin receptor SER-1. Consequently, excitation of serotonergic neurons alone can suppress protein misfolding in C. elegans peripheral tissue. CONCLUSIONS: These studies imply that thermosensory activity coupled to serotonergic signaling is sufficient to activate the protective HSR prior to frank proteotoxic damage. The ability of neurosensory release of serotonin to control cellular stress responses and activate HSF1 has powerful implications for the treatment of protein conformation diseases. PMID- 25557669 TI - Pharmaceuticals in the environment: expected and unexpected effects on aquatic fauna. AB - A growing database reports that human and veterinary pharmaceutical residues are present in aquatic and terrestrial environments worldwide. Evidence indicates that nontarget organisms may be chronically exposed to low (ng/L to MUg/L range) concentrations of a variety of pharmaceuticals, but that even these concentrations may result in significant biological effects. Here are briefly summarized well-documented examples demonstrating how pharmaceuticals behave differently from conventional pollutants, which suggests that they must be considered when risk to ecosystems and human health is assessed. In particular, examples are presented of expected effects related to the therapeutic mode of action, unwanted/side effects mainly related to oxidative stress, and unexpected effects induced by environmental concentrations of pharmaceuticals in aquatic animals. A list of the most relevant reviews on the subject is also provided to provide a more complete perspective on the effects of environmental pharmaceuticals in nontarget species. PMID- 25557668 TI - Potential implications of research on genetic or heritable contributions to pedophilia for the objectives of criminal law. AB - In recent years, there has been increasing scientific research on possible genetic or heritable influences to the etiology of pedophilia, driven by national and public concerns about better understanding the disorder in order to reduce children's vulnerabilities to pedophilic and child sex offenders. This research has corresponded to growing academic dialogue on how advances in genetic research, especially concerning the causes and development of particular mental disorders or behaviors, may affect traditional practices of criminal law and how the justice system views, manages, and adjudicates different types of criminal behavior and offenders. This paper strives to supplement this dialogue by exploring several of the many possible effects and implications of research surrounding genetic or heritable contributions to pedophilia for the five widely accepted objectives that enforce and regulate the punishment of criminal law. These include retribution, incapacitation, deterrence, rehabilitation, and restoration. Although still currently in early stages, genetic and heritability research on the etiology of pedophilia may have the potential moving forward to influence the current and established punitive methods and strategies of how the justice system perceives, adjudicates, regulates, and punishes pedophilic and sex offenders, as well as how to best prevent sexual offending against children by pedophilic offenders in the future. PMID- 25557670 TI - Characterization of dietary energy in Swine feed and feed ingredients: a review of recent research results. AB - Feed is single most expensive input in commercial pork production representing more than 50% of the total cost of production. The greatest proportion of this cost is associated with the energy component, thus making energy the most important dietary in terms of cost. For efficient pork production, it is imperative that diets are formulated to accurately match dietary energy supply to requirements for maintenance and productive functions. To achieve this goal, it is critical that the energy value of feeds is precisely determined and that the energy system that best meets the energy needs of a pig is used. Therefore, the present review focuses on dietary supply and needs for pigs and the available energy systems for formulating swine diets with particular emphasis on the net energy system. In addition to providing a more accurate estimate of the energy available to the animal in an ingredient and the subsequent diet, diets formulated using the this system are typically lower in crude protein, which leads to additional benefits in terms of reduced nitrogen excretion and consequent environmental pollution. Furthermore, using the net energy system may reduce diet cost as it allows for increased use of feedstuffs containing fibre in place of feedstuffs containing starch. A brief review of the use of distiller dried grains with solubles in swine diets as an energy source is included. PMID- 25557671 TI - Genetic diversity and population structure in native chicken populations from myanmar, Thailand and laos by using 102 indels markers. AB - The genetic diversity of native chicken populations from Myanmar, Thailand, and Laos was examined by using 102 insertion and/or deletion (indels) markers. Most of the indels loci were polymorphic (71% to 96%), and the genetic variability was similar in all populations. The average observed heterozygosities (H O ) and expected heterozygosities (H E ) ranged from 0.205 to 0.263 and 0.239 to 0.381, respectively. The coefficients of genetic differentiation (Gst) for all cumulated populations was 0.125, and the Thai native chickens showed higher Gst (0.088) than Myanmar (0.041) and Laotian (0.024) populations. The pairwise Fst distances ranged from 0.144 to 0.308 among populations. A neighbor-joining (NJ) tree, using Nei's genetic distance, revealed that Thai and Laotian native chicken populations were genetically close, while Myanmar native chickens were distant from the others. The native chickens from these three countries were thought to be descended from three different origins (K = 3) from STRUCTURE analysis. Genetic admixture was observed in Thai and Laotian native chickens, while admixture was absent in Myanmar native chickens. PMID- 25557672 TI - Molecular Characterization and Expression Analysis of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein-1 Genes in Qinghai-Tibet Plateau Bos grunniens and Lowland Bos taurus. AB - Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) play a pivotal role in regulating cellular hypoxic response. In this study, we cloned and characterized the genes encoding IGF-1 and IGFBP-1 to improve the current knowledge on their roles in highland Bos grunniens (Yak). We also compared their expression levels in the liver and kidney tissues between yaks and lowland cattle. We obtained full-length 465 bp IGF-1 and 792 bp IGFBP-1, encoding 154 amino acids (AA) IGF-1, and 263 AA IGFBP-1 protein, respectively using reverse transcriptase-polyerase chain reaction (RT-PCR) technology. Analysis of their corresponding amino acid sequences showed a high identity between B. grunniens and lowland mammals. Moreover, the two genes were proved to be widely distributed in the examined tissues through expression pattern analysis. Real-time PCR results revealed that IGF-1 expression was higher in the liver and kidney tissues in B. grunniens than in Bos taurus (p<0.05). The IGFBP-1 gene was expressed at a higher level in the liver (p<0.05) of B. taurus than B. grunniens, but it has a similar expression level in the kidneys of the two species. These results indicated that upregulated IGF-1 and downregulated IGFBP-1 are associated with hypoxia adaptive response in B. grunniens. PMID- 25557673 TI - Evaluation of inbreeding and genetic variability of five pig breeds in czech republic. AB - The complex analysis of the pedigree records of Czech Landrace (CLA), Czech Large White-dam line (CLWd), Czech Large White-sire line (CLWs), Duroc (DC), and Pietrain (PN) was performed to determine trends of genetic diversity (GD), and to find the main sources of the GD loss. The total size of the pedigree was 132,365, 391,151, 32,913, 13,299, and 7,160 animals in CLA, CLWd, CLWs, DC, and PN, respectively. Animals born in the years 2011 through 2013 were assumed as the reference population. The average pedigree completeness index for one generation back was 95.9%, 97.4%, 91.2%, 89.8%, and 94.2% for appropriate breeds. Number of ancestors explaining 100% of gene pool was 186, 373, 125, 157, and 37 in CLA, CLWd, CLWs, DC, and PN, respectively. The relative proportion of inbred animals (58%, 58%, 54%, 47%, and 25%), the average inbreeding (2.7%, 1.4%, 2.5%, 3.6%, and 1.3%) and the average co-ancestry (3.1%, 1.6%, 3.3%, 4.2%, and 3.3%) were found over the past decade in analysed breeds. The expected inbreeding under random mating increased during the last 10 years in CLWs and PN and varied from 1.27% to 3.2%. The effective population size computed on the basis of inbreeding was 76, 74, 50, 35, and 83 in 2012 in CLA, CLWd, CLWs, DC, and PN, respectively. The shortest generation interval (1.45) was observed for CLWd in sire to son selection pathway. The longest generation interval obtained PN (1.95) in sire to daughter pathway. The average relative GD loss within last generation interval was 7.05%, 4.70%, 9.81%, 7.47%, and 10.46%, respectively. The relative proportion of GD loss due to genetic drift on total GD loss was 85.04%, 84.51%, 89.46%, 86.19%, and 83.68% in CLA, CLWd, CLWs, DC, and PN, respectively. All breeds were characterized by a high proportion of inbred animals, but the average inbreeding was low. The most vulnerable breeds to loss of GD are DC and PN. Therefore, a breeding program should be more oriented to prevent the increase of GD loss in these breeds. PMID- 25557674 TI - Mineral Metabolism in Singleton and Twin-pregnant Dairy Goats. AB - During pregnancy, the maternal body undergoes significant physiological changes. The present study assessed the changes on calcium (Ca), phosphorus (P), magnesium (Mg), sodium (Na) and potassium (K) metabolism in singleton and twin-pregnant dairy goats. The 42 goats used (49.5 kg+/-7.6 body weight [BW]) were assigned at random to treatments that were factorially arranged to account for 2 breeds (Oberhasli and Saanen), 2 pregnancy types (singleton and twin) and 3 gestation periods (80, 110, and 140 days). Digestibility trials were performed at 80, 110, and 140 days of gestation. Mineral retention during pregnancy was determined in the maternal body, femur, uterus, mammary gland, fetus and fetal fluid. Blood samples were taken during pregnancy before and after a meal, and Ca, P, Mg, Na, K ions and alkaline phosphatase activity determined in serum. Bone mineral density was determined in the right femur. Statistical analyses were performed using the SAS MIXED procedure. Dry matter intake decreased linearly up to 140 days of gestation. Maternal BW gain, and Ca, P, and Mg retention (g/kg) decreased linearly with the advance of gestation days. Macromineral retention in maternal body (g/kg) was greater in Oberhasli than Saanen goats, and their fetuses had higher Ca, P, and Mg deposition (mg/g). Mineral retention (mg/g) increased in fetuses according to pregnancy development, with no differences between singleton and twin pregnancy. In the mammary gland, the retention of all minerals (g) increased with the days of pregnancy. In conclusion, related to Ca, P, and Mg metabolism can be divided into two stages. Up to 80 days of gestation, was characterized by the preparation of the maternal body reserves for future mineral demands. From 80 days of gestation onward, was characterized by the transfer of maternal body reserves for fetal development and colostrum production. Na and K supply was provided by adjustments in endogenous excretion and an increase in intestinal absorption. Finally, mineral metabolism was specific to each genotype and, except for Na, was not affected by the number of fetuses. PMID- 25557675 TI - Effect of Soybean Meal and Soluble Starch on Biogenic Amine Production and Microbial Diversity Using In vitro Rumen Fermentation. AB - This study was conducted to investigate the effect of soybean meal (SM) and soluble starch (SS) on biogenic amine production and microbial diversity using in vitro ruminal fermentation. Treatments comprised of incubation of 2 g of mixture (expressed as 10 parts) containing different ratios of SM to SS as: 0:0, 10:0, 7:3, 5:5, 3:7, or 0:10. In vitro ruminal fermentation parameters were determined at 0, 12, 24, and 48 h of incubation while the biogenic amine and microbial diversity were determined at 48 h of incubation. Treatment with highest proportion of SM had higher (p<0.05) gas production than those with higher proportions of SS. Samples with higher proportion of SS resulted in lower pH than those with higher proportion of SM after 48 h of incubation. The largest change in NH3-N concentration from 0 to 48 h was observed on all SM while the smallest was observed on exclusive SS. Similarly, exclusive SS had the lowest NH3-N concentration among all groups after 24 h of incubation. Increasing methane (CH4) concentrations were observed with time, and CH4 concentrations were higher (p<0.05) with greater proportions of SM than SS. Balanced proportion of SM and SS had the highest (p<0.05) total volatile fatty acid (TVFA) while propionate was found highest in higher proportion of SS. Moreover, biogenic amine (BA) was higher (p<0.05) in samples containing greater proportions of SM. Histamines, amine index and total amines were highest in exclusive SM followed in sequence mixtures with increasing proportion of SS (and lowered proportion of SM) at 48 h of incubation. Nine dominant bands were identified by denaturing gradient gel electrophoresis (DGGE) and their identity ranged from 87% to 100% which were mostly isolated from rumen and feces. Bands R2 (uncultured bacterium clone RB 5E1) and R4 (uncultured rumen bacterium clone L7A_C10) bands were found in samples with higher proportions of SM while R3 (uncultured Firmicutes bacterium clone NI_52), R7 (Selenomonas sp. MCB2), R8 (Selenomonas ruminantium gene) and R9 (Selenomonas ruminantium strain LongY6) were found in samples with higher proportions of SS. Different feed ratios affect rumen fermentation in terms of pH, NH3-N, CH4, BA, volatile fatty acid and other metabolite concentrations and microbial diversity. Balanced protein and carbohydrate ratios are needed for rumen fermentation. PMID- 25557677 TI - Effect of heifer frame score on growth, fertility, and economics. AB - A non-traditional forage-based protocol was employed to evaluate replacement heifer growth, fertility, and economics between small frame (SF, 3.50; n = 50) and large frame (LF, 5.56; n = 50) heifers using three increasing gain growth phases. Preceding an 85 d growing-breeding period (Phase 3; P3) the heifers were managed as a common group for Phases 1 and 2 (P1 and P2). During P1, heifers grazed common fields of unharvested corn and corn residue (total digestible nutrients [TDN] 56%) with supplemental hay. For P2, heifers grazed early spring crested wheatgrass pasture (CWG; TDN 62%) that was followed by the final P3 drylot growing and breeding period (TDN 68%). Small frame heifers were lighter at the end of P1 in May and at the start of P3 breeding in August (p = 0.0002). Percent of mature body weight (BW) at the end of P1 (209 d) was 48.7% and 46.8%, respectively, for the SF and LF heifers and the percent pubertal was lower for SF than for LF heifers (18.0% vs 40.0%; p = 0.02). At breeding initiation (P3), the percentage of mature BW was 57.8 and 57.2 and the percentage pubertal was 90.0 and 96.0 (p = 0.07) for the SF and LF heifers, respectively; a 5-fold increase for SF heifers. Breeding cycle pregnancy on days 21, 42, and 63, and total percent pregnant did not differ (p>0.10). In drylot, SF heifer dry matter intake (DMI) was 20.1% less (p = 0.001) and feed cost/d was 20.3% lower (p = 0.001), but feed cost/kg of gain did not differ between SF and LF heifers (p = 0.41). Economically important live animal measurements for muscling were measured in May and at the end of the study in October. SF heifers had greater L. dorsi muscle area per unit of BW than LF heifers (p = 0.03). Small frame heifer value was lower at weaning (p = 0.005) and the non-pregnant ending heifer value was lower for SF heifers than for the LF heifers (p = 0.005). However, the total development cost was lower for SF heifers (p = 0.001) and the net cost per pregnant heifer, after accounting for the sale of non-pregnant heifers, was lower for SF heifers (p = 0.004). These data suggest that high breeding efficiency can be attained among March-April born SF and LF virgin heifers when transitioned to a more favorable May-June calving period through the strategic use of grazed and harvested forages resulting in a lower net cost per pregnant SF heifer. PMID- 25557676 TI - Changes of Serum Calcium Concentration, Frequency of Ruminal Contraction and Feed Intake Soon after Parturition of Dairy Cows Fed Difructose Anhydride III. AB - Requirements to control the large decrease in serum calcium (Ca) due to parturition and to increase the feed intake soon after parturition have been well accepted in dairy cows. This study was aimed to investigate the feed intake affected by serum Ca concentration with difructose anhydride (DFA) III supplement in dairy cows soon after parturition. Fourteen transition Holstein cows were divided into DFA and control (CONT) groups within 1 to 5 parity variations in each group. Measurement schedule for an individual cow was from 14 d before parturition to 7 d following parturition. The cows in DFA group were supplied 0.2 kg/head/d of DFA III feed containing 40 g of pure DFA III while the cows in CONT group received no DFA III. Other feeding procedures were the same for all cows in both groups. At parturition (d 0), serum Ca concentration sharply declined in both groups (p<0.05). Time interval for recovery from decreased serum Ca to its normal range (>9.0 mg/dL) tended to be faster in DFA group (12 h) than in the CONT group (48 h), but the differences were not significant. Active ruminal contraction was observed in DFA group at following parturition of d 1 (p<0.05), d 3 (p<0.05), and d 5 (p<0.01). Dry matter (DM) intake did not differ between the groups. However, positive correlations were observed between serum Ca concentration and ruminal contraction (p<0.001), and between ruminal contraction and DM intake (p<0.001) during following parturition. According to multiple regression analysis (R(2) = 0.824, p<0.001), the DM intake was positively affected by serum Ca concentration and ruminal contraction. These results suggest that feed intake soon after parturition in dairy cows can be increased by improvement of serum Ca concentration and active ruminal contraction, but DFA III supplementation in this study did not improve the lower serum Ca concentration due to parturition. PMID- 25557678 TI - Antioxidant Enzyme Activity and Meat Quality of Meat Type Ducks Fed with Dried Oregano (Origanum vulgare L.) Powder. AB - One-day-old Cherry valley meat-strain ducks were used to investigate the effect of supplemental dried oregano powder (DOP) in feed on the productivity, antioxidant enzyme activity, and breast meat quality. One hundred sixty five ducks were assigned to 5 dietary treatments for 42 days. The dietary treatment groups were control group (CON; no antibiotic, no DOP), antibiotic group (ANT; CON+0.1% Patrol), 0.1% DOP (CON+0.1% DOP), 0.5% DOP (CON+0.5% DOP), and 1.0% DOP (CON+1.0% DOP). Upon feeding, 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activity of oregano extracts was higher than that of tocopherol, although it was less than that of ascorbic acid. As a result of in vivo study, DOP in the diet showed no effects on final body weight, feed intake, or feed conversion ratio. However, dietary 0.5% and 1% DOP supplementation caused a significant increase in the serum enzyme activity of superoxide dismutase (SOD) compared with CON and ANT, while glutathione peroxidase (GPx) in tissue was increased as compared to ANT (p<0.05). Cooking loss from ducks fed with DOP decreased compared with the control ducks. Thiobarbituric acid reactive substance (TBARS) values of duck breast meat at 5 d post slaughter was found to be significantly reduced in ducks whose diets were supplemented with 0.5% and 1% DOP (p<0.05). These results suggest that diets containing 0.5% and 1% DOP may beneficially affect antioxidant enzyme activity of GPx and SOD, improve meat cooking loss, and reduce TBARS values in breast meat at 5 d of storage in ducks. PMID- 25557679 TI - Determination and prediction of the amino Acid digestibility of sunflower seed meals in growing pigs. AB - This experiment was conducted to evaluate the chemical composition and amino acid (AA) digestibility of sunflower seed meal (SFSM) and to use this data to develop prediction equations for estimating AA digestibility for growing pigs. Ten SFSM were collected from five provinces in China. Twelve barrows (38.8+/-4.6 kg), fitted with ileal T-cannula were allotted into two 6*6 Latin square designs. Each of six experimental periods comprised a 5-d adaption period followed by a 2-d collection of ileal digesta. The ten test diets contained 50% SFSM as the sole source of AA. Another nitrogen-free diet was used to measure the basal endogenous losses of crude protein (CP) and AA. Chromic oxide (0.3%) was used as an inert marker in each diet. There was considerable variation (CV>10%) among the ten SFSM in chemical composition (dry matter [DM]). The concentration of CP and ether extract (EE) ranged from 29.33% to 39.09% and 0.88% to 11.33%, respectively. Crude fibre (CF), neutral detergent fibre and acid detergent fibre ranged from 21.46% to 36.42%, 38.15% to 55.40%, and 24.59% to 37.34%, respectively. There was variation among the ten SFSM in apparent ileal digestibility (AID) and standardized ileal digestibility (SID) for lysine and threonine, which ranged from 63.16 to 79.21 and 55.19% to 72.04% for AID and 67.03% to 82.07% and 61.97% to 77.01% for SID, respectively. The variation in CP and methionine ranged from 60.13% to 74.72% and 74.79% to 88.60% for AID and 66.70% to 79.31% and 77.16% to 90.27% for SID, respectively. Methionine was a good indicator to predict AA digestibility. These results indicate that conventional chemical composition of SFSM was variable (CV>10%) among the ten SFSM (DM). The results of AID, SID and prediction equations could be used to evaluate the digestibility of SFSM in growing pigs. PMID- 25557680 TI - Effects of Dietary Fermented Chlorella vulgaris (CBT((r))) on Growth Performance, Relative Organ Weights, Cecal Microflora, Tibia Bone Characteristics, and Meat Qualities in Pekin Ducks. AB - Fermented Chlorella vulgaris was examined for its effects on growth performance, cecal microflora, tibia bone strength, and meat qualities in commercial Pekin ducks. A total of three hundred, day-old male Pekin ducks were divided into three groups with five replicates (n = 20 ducklings per replicate) and offered diets supplemented with commercial fermented C. vulgaris (CBT((r))) at the level of 0, 1,000 or 2,000 mg/kg, respectively for 6 wks. The final body weight was linearly (p = 0.001) increased as the addition of fermented C. vulgaris into diets increased. Similarly, dietary C. vulgaris linearly increased body weight gain (p = 0.001) and feed intake (p = 0.001) especially at the later days of the feeding trial. However, there was no C. vulgaris effect on feed efficiency. Relative weights of liver were significantly lowered by dietary fermented C. vulgaris (linear effect at p = 0.044). Dietary fermented C. vulgaris did not affect total microbes, lactic acid bacteria, and coliforms in cecal contents. Finally, meat quality parameters such as meat color (i.e., yellowness), shear force, pH, or water holding capacity were altered by adding fermented C. vulgaris into the diet. In our knowledge, this is the first report to show that dietary fermented C. vulgaris enhanced meat qualities of duck meats. In conclusion, our study indicates that dietary fermented C. vulgaris exerted benefits on productivity and can be employed as a novel, nutrition-based strategy to produce value-added duck meats. PMID- 25557681 TI - Effect of different inclusion level of condensed distillers solubles ratios and oil content on amino Acid digestibility of corn distillers dried grains with solubles in growing pigs. AB - The purpose of this experiment was to determine and compare the digestibility of crude protein (CP) and amino acids (AA) in full-oil (no oil extracted) and de oiled (oil extracted) corn distillers dried grains with solubles (DDGS) with different condensed distillers solubles (CDS) ratios. Six barrows (29.6+/-2.3 kg) fitted with ileal T-cannula were allotted into a 6*6 Latin square design. Each period was comprised of a 5-d adaption period followed by a 2-d collection of ileal digesta. The five test diets contained 62% DDGS as the sole source of AA. A nitrogen-free diet was used to measure the basal endogenous losses of CP and AA. Chromic oxide (0.3%) was used as an index in each diet. The results showed that CP and AA were very similar in 5 DDGS, but the standardized ileal digestibility (SID) of lysine (from 56.16% to 71.15%) and tryptophan (from 54.90% to 68.38%) had the lowest values and largest variation within the essential AA, which suggests reduced availability of AA and different levels of Maillard reactions in the five DDGS. The apparent ileal digestibility and SID of CP and most of AA in full-oil DDGS (sources 1 and 2) were greater (p<0.05) than de-oiled DDGS (sources 3, 4, and 5). Comparing the AA SID in the 5 DDGS, full-oil with low CDS ratio DDGS (source 1) had non-significantly higher values (p >0.05) than full-oil with high CDS ratio DDGS (source 2); however, the SID of most AA of de-oiled with low CDS ratios DDGS (source 3) were non-significantly lower (p>0.05) than de-oiled with high CDS ratio DDGS (source 4); and the de-oiled DDGS with middle CDS ratio (source 5) but with different drying processing had the lowest SID AA values. In conclusion, de-oiled DDGS had lower SID of CP and AA than full-oil DDGS; a higher CDS ratio tended to decrease the SID of AA in full-oil DDGS but not in de-oiled DDGS; and compared with CDS ratio, processing, especially drying, may have more of an effect on AA digestibility of DDGS. PMID- 25557682 TI - Optimal Incorporation Level of Dietary Alternative Phosphate (MgHPO4) and Requirement for Phosphorus in Juvenile Far Eastern Catfish (Silurus asotus). AB - A growth trial was conducted to determine the optimal incorporation level of dietary magnesium hydrogen phosphate (MHP, MgHPO4), which was manufactured from swine manure and phosphorus (P), required by juvenile far eastern catfish (Silurus asotus). Graded MHP of 0.5%, 1.0%, 1.5%, and 2.0%, and 2.0% monocalcium phosphate (MCP) each was added to the basal diet (control) in lieu of cellulose to become the range of available P (AP) from 0.4% to 0.8% of which diets were designated as control, MHP0.5, MHP1.0, MHP1.5, MHP2.0, and MCP, respectively. Control diet contained fish meal (20%), soybean meal (40%), wheat flour (27%), corn gluten meal (5%), fish oil (2%) and soy oil (2%) as main ingredients. Following a 24 h fasting, 540 fish with a mean body weight of 11.8 g were randomly allotted to 6 groups in triplicate, whereby 18 tanks (0.4*0.6*0.36 cm, water volume of 66 L) were prepared. The feeding experiment lasted for 8 weeks. Fish group fed the control diet showed the lowest weight gain (WG) and feed efficiency (FE) among treatments. The WG was, however, not significantly different (p>0.05) from that of fish group fed MHP0.5. Fish group fed MHP2.0 showed the highest WG and FE of which values were not significantly different from those of fish groups fed diets MHP1.0 and MHP1.5 as well as MCP (p>0.05) except fish groups fed control and MHP0.5. Aspartate aminotransferase was significantly decreased with an increase in available P, while alanine aminotransferase did not show a significant difference among treatment. The highest inorganic P in plasma was observed in fish fed MHP2.0. From the present results, a second-order regression analysis revealed that the optimal dietary MHP level and the AP requirement were found to be 1.62% and 0.7%, respectively. PMID- 25557683 TI - Physicochemical and Sensory Properties of Red Ginseng Extracts or Red Ginseng Hydrolyzates-added Asiago Cheese during Ripening. AB - This study was carried out to investigate physicochemical properties of different concentrations (0.1%, 0.3%, and 0.5%) of red ginseng hydrolyzates (RGH)- or red ginseng extract (RGE)-added Asiago cheeses (AC) during ripening at 14 degrees C for 4 months. The moisture content significantly increased with increasing concentrations of both RGH- and RGE- added AC (p<0.05). While RGHAC and RGEAC were more yellow and darker with increasing concentrations than that of control (p<0.05), the color was not influenced from the hydrolysis. In texture analysis, hardness, cohesiveness, and chewiness of RGHAC and RGEAC significantly decreased compared to the control during the ripening (p<0.05). In sensory analysis, bitterness and ginseng flavor and taste scores increased significantly with increasing the concentrations of RGH and RGE during ripening (p<0.05). In conclusion, the addition of RGH and RGE into cheese slightly influenced the properties of Asiago cheese, and similarities were observed between RGHAC and RGEAC. Thus, the lower concentrations (0.1% to 0.3%) of RGH and RGE added to AC were preferred for color, texture, and sensory during the ripening, therefore, these cheeses would be worth developing commercially. PMID- 25557684 TI - Effects of castration on expression of lipid metabolism genes in the liver of korean cattle. AB - Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001) hepatic lipids contents and higher (p<0.01) mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3 phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration. PMID- 25557685 TI - Immune Responses in Broiler Chicks Fed Propolis Extraction Residue-supplemented Diets. AB - This study was conducted to evaluate the effect of inclusion of propolis extraction residue in the feed of broilers from 1 to 21 d of age on phagocytic activity of macrophages, cutaneous basophil hypersensitivity response to phytohemagglutinin, antibody production against Newcastle disease, lymphoid organ weight and hematological profile and to determine the optimal level of inclusion. 120 chicks, reared in metabolism cages until 21 days of age, were distributed in a completely randomized design, with five treatments (0%, 1%, 2%, 3%, and 4% of propolis residue) and six replications. The relative weight of thymus and monocyte percentage were affected by propolis residue, with a quadratic response (p<0.05) and lowest values estimated at 2.38% and 2.49%, respectively. Changes in relative weight of cloacal bursa and spleen, percentage of lymphocyte, heterophil, basophil, eosinophil, and heterophil:lymphocyte ratio, antibody production against Newcastle disease, phagocytic activity of macrophages and the average number of phagocytosed erythrocytes were not observed. The nitric oxide production with regard to positive control (macrophages+erythrocytes) decreased linearly (p<0.05) with increased doses of propolis residue. The remaining variables of nitric oxide production (negative control - macrophages, and difference between the controls) were not affected by propolis residue. The cutaneous basophil hypersensitivity response to phytohemagglutinin as determined by the increase in interdigital skin thickness exhibited a quadratic response (p<0.05), which predicted a lower reaction response at a dose of 2.60% of propolis residue and highest reaction response after 43.05 hours of phytohemagglutinin injection. The inclusion of 1% to 4% of propolis extraction residue in broiler diets from 1 to 21 days of age was not able to improve the immune parameters, despite the modest changes in the relative weight in thymus, blood monocyte percentage, nitric oxide concentration, and interdigital reaction to phytohemagglutinin. PMID- 25557686 TI - Effects of bedding material composition in deep litter systems on bedding characteristics and growth performance of limousin calves. AB - The objective of this study was to evaluate the effects of different litter mixture compositions on bedding system temperature, pH and volatile fatty acid and ammonia-N (NH3-N) content, and the serum physico-chemical parameters and growth indices of calves. Thirty-two Limousin calves (280+/-20 kg) were randomly assigned to four groups (n = 8 for each group) according to the bedding system used: i) control with soil only (CTR); ii) mixture with 50% paddy hulls (PH), 30% saw dusts (SD), 10% peat moss (PM) and 10% corn cobs (CC) (TRT1); iii) mixture with 15% PH, 15% SD, 10% PM, 40% CC, and 20% corn stover (CS) (TRT2); iv) mixture with 30% PH, 10% PM, 40% CC, and 20% CS (TRT3). The litter material combinations of different treatments were based on the cost of bedding system materials in China. The cost of four treatments from low to high: Control 0.05). This is in contrast to previously published results from healthy adults. However, the counterregulatory responses to hypoglycaemia during normoxia were not impaired in carotid body-resected patients when compared with control subjects (main effect of group, P > 0.05). Our data provide further corroborative evidence that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, relatively normal counterregulatory responses to hypoglycaemia in carotid body-resected patients highlight the importance of redundant mechanisms in mediating hypoglycaemia counterregulation. PMID- 25557732 TI - The claudin-16 channel gene is transcriptionally inhibited by 1,25 dihydroxyvitamin D. AB - NEW FINDINGS: What is the central question of this study? In the kidney, the bulk of the filtered Mg(2+) is reabsorbed in the thick ascending limb by paracellular conductance, mediated by the tight junction protein, claudin-16, which is encoded by the gene CLDN16. The role of 1,25-dihydroxyvitamin D [1,25(OH)2 VitD] in renal Mg(2+) handling is unclear. We aimed to explore the molecular mechanisms underlying the effect of 1,25(OH)2 VitD on claudin-16-mediated Mg(2+) transport. What is the main finding and its importance? Paracellular, claudin-16-mediated Mg(2+) transport is transcriptionally repressed by 1,25(OH)2 VitD, probably via a Ca(2+)-sensing receptor-dependent mechanism. This renal effect of 1,25(OH)2 VitD may serve as an adaptive mechanism to the 1,25(OH)2 VitD-induced enteric hyperabsorption of dietary Mg(2+). Magnesium is reabsorbed in the thick ascending limb by paracellular conductance, mediated by the CLDN16-encoded tight junction protein, claudin-16. However, the role of 1,25-dihydroxyvitamin D [1,25(OH)2 VitD] in renal Mg(2+) handling is unclear. We have shown that Mg(2+) depletion increases and 1,25(OH)2 VitD inhibits CLDN16 transcription. We have now explored further the molecular mechanisms underlying the effect of 1,25(OH)2 VitD on claudin-16-mediated Mg(2+) transport. Adult mice received parenteral 1,25(OH)2 VitD or 1,25(OH)2 VitD combined with either high-Mg(2+) or low-Mg(2+) diets. Administration of 1,25(OH)2 VitD enhanced urinary excretion of Mg(2+) and Ca(2+). The 1,25(OH)2 VitD also increased renal Ca(2+)-sensing receptor (CaSR) mRNA and decreased renal claudin-16 and claudin-19 mRNA and claudin-16 protein, but did not affect renal claudin-2 mRNA. The 1,25(OH)2 VitD reversed the expected increase in claudin-16 mRNA in Mg(2+)-depleted animals. Comparably treated HEK 293 cells showed similar changes in claudin-16 mRNA, but 1,25(OH)2 VitD did not alter mRNA of the TRPM6 Mg(2+) channel. A luciferase reporter vector containing 2.5 kb of 5'-flanking DNA sequence from human CLDN16 (hCLDN16) was transfected into HEK 293 and OK cells. The hCLDN16 promoter activity was modestly decreased by 1,25(OH)2 VitD, but markedly inhibited in HEK 293 cells coexpressing CaSR. Coexpression in OK cells of dominant-negative CaSR completely abolished inhibition of hCLDN16 promoter activity by 1,25(OH)2 VitD. The 1,25(OH)2 VitD induced decrease in hCLDN16 promoter activity was attenuated in Mg(2+)-depleted HEK 293 cells. In conclusion, 1,25(OH)2 VitD transcriptionally inhibits claudin 16 expression by a mechanism sensitive to CaSR and Mg(2+). This renal effect of 1,25(OH)2 VitD may serve as an adaptive response to the 1,25(OH)2 VitD-induced increase in intestinal Mg(2+) absorption. PMID- 25557733 TI - Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells. AB - NEW FINDINGS: What is the central question of this study? Why do different doses of sphingosine-1-phosphate (S1P) induce distinct biological effects in endothelial cells? What is the main finding and its importance? S1P at physiological concentrations preserved endothelial barrier function by binding to S1P receptor 1, then triggering Ca(2+) release from endoplasmic reticulum through phosphoinositide phospholipase C and inositol triphosphate, and consequently strengthening tight junction and F-actin assembly through Rac1 activation. Excessive S1P induced endothelial malfunction by activating S1P receptor 2 and RhoA/ROCK pathway, causing F-actin and tight junction disorganisation. Extracellular Ca(2+) influx was involved in this process. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid in plasma, and its plasma concentration can be adjusted through a complex metabolic process. The alterations in S1P levels and the activation of receptors collaboratively regulate distinct biological effects. This study was performed to investigate comparatively the effect of different concentrations of S1P on endothelial barrier function and to explore the roles of S1P receptors (S1PRs), Rho GTPases and calcium in S1P-induced endothelial responses. Endothelial barrier function was studied using transendothelial electric resistance and a resistance meter in human umbilical vein endothelial cells. Specific agonists or antagonists were applied to control the activation of S1P receptors and the release of calcium from different cellular compartments. The results indicated that at physiological concentrations, S1P preserved endothelial barrier function by binding with S1PR1. The activation of S1PR1 triggered the release of intracellular Ca(2+) from the endoplasmic reticulum through the PI-phospholipase C and inositol trisphosphate pathways. Consequently, the Rho GTPase Rac1 was activated, strengthening the assembly of tight junction proteins and F-actin. However, excessive S1P induced endothelial barrier dysfunction by activating S1PR2 followed by the RhoA/RhoA kinase pathway, causing the disorganization of F-actin and the disassembly of the tight junction protein ZO-1. An influx of extracellular Ca(2+) was involved in this process. These data suggest that physiological and excessive amounts of S1P induce different responses in human umbilical vein endothelial cells; the activation of the 1PR1 PLC-IP3 R-Ca(2+) -Rac1 pathway governs the low-dose S1P-enhanced endothelial barrier integrity, and the activation of S1PR2-calcium influx-RhoA/ROCK dominates the high-dose S1P-induced endothelial monolayer hyperpermeability response. PMID- 25557735 TI - An investigation into the prevalence of exploratory behavior in captive cheetahs (Acinonyx jubatus). AB - Exploratory behavior in the wild is fundamentally linked to an animal's survival and natural life history. The ability to gather information about their environment, establish territories, assert dominance, communicate information regarding reproductive status and locate mates are closely associated with a range of exploratory behaviors. Understanding how these behaviors are performed within the captive setting is crucial in order to create a captive environment in which these behaviors can be expressed, and their function conserved. The objective of this research was to highlight the factors of captive husbandry and management that influence the occurrence of exploratory behaviour of cheetahs (Acinonyx jubatus) in captivity. One hundred and twelve cheetahs in 88 enclosures across nine zoological institutions in five countries were the subjects of this study. The presence of raised areas, number of movements between enclosures, group composition, sex and an interaction between group composition and the ability to view cheetahs in adjacent enclosures, all significantly influenced the prevalence of exploratory behavior in captive cheetahs. The presence of raised areas and an increasing number of movements between enclosures significantly increased the probability of observing exploratory behaviour, while this probability was significantly decreased for female cheetahs, when cheetahs were able to view conspecifics in adjacent enclosures, and were maintained in groups. A number of recommendations are discussed in relation to promoting exploratory behavior in captive cheetahs. PMID- 25557736 TI - Effects of floor type, stocking density, slaughter age and gender on productive and qualitative traits of rabbits reared in collective pens. AB - At 34 days of age, 376 crossbred rabbits of both sexes were housed in 16 open-top collective pens (1.68 m2) according to a 2*2*2 factorial arrangement with two types of pen floor (plastic v. wooden slatted), two stocking densities (12 v. 16 animals/m2) and two slaughter ages (76 v. 83 days). The rabbits were examined for growth performance, slaughter results and meat quality. The effect of gender was also examined. The percentage of rabbits with wounds due to aggression varied with stocking density (8.2% v. 26.2% for 12 v. 16 animals/m2; P?0.001), slaughter age (15.0% v. 22.0% at 76 v. 83 days; P?0.10) and gender (11.3% v. 25.8% for females v. males; P?0.001). Rearing rabbits on a plastic rather than a wooden slatted floor promoted slaughter weight (2795 v. 2567 g; P?0.001), dressing percentage (61.4% v. 60.9%; P?0.01), dissectible fat (2.4% v. 2.0%; P?0.01) and hind leg muscle-to-bone ratio (5.81 v. 5.35; P?0.001). Increased stocking density impaired daily growth (38.5 v. 35.9 g/day; P?0.05) and feed intake (140 v. 134 g/day; P?0.01) during the second period (55 days to slaughter) and decreased slaughter weight (2725 v. 2637 g; P?0.01). At the older slaughter age, the feed conversion ratio was impaired (2.98 v. 3.18; P?0.001); the slaughter weight (2574 g v. 2788 g; P?0.001), dissectible fat (2.0% v. 2.4%; P?0.01) and hind leg muscle to-bone ratio (5.41 v. 5.75; P?0.01) increased; meat thawing losses, cooking losses and shear force decreased (P?0.05). The main differences between the females and males were found in the slaughter for transport losses (2.6% v. 2.2%; P?0.01) and longissimus lumborum proportions (13.0% v. 12.4%; P?0.01). In conclusion, the growth performance of pen-housed rabbits was largely determined by the type of floor and less affected by stocking density. The meat quality depended on ontogenetic factors, such as slaughter age and gender, and not on housing conditions. The differences in the percentages of wounded animals owing to experimental factors deserve further investigation from the perspective of animal welfare issues. PMID- 25557738 TI - Isolation of autophagosome subpopulations after induction of autophagy by calcium. AB - Autophagy is a dynamic process accomplished by the generation and maturation of autophagosomes. Isolation of autophagosomes and subsequent compositional analysis can provide information about their biogenesis mechanism. In this article, HEK293 cells expressing GFP-LC3 were treated by calcium phosphate precipitates (CPP) to induce autophagy. The autophaogomes induced by CPP were tubular and vesicular structures, extensively formed in the cytosol. After all membranes in the cell lysate were fractionated by differential centrifugation, autophagosomes from light and heavy membranes were isolated by immuno-precipitation, using antibodies against GFP-LC3 and Atg5. We found that GFP-LC3 and Atg5 positive autophagosomes represented distinctive subpopulations. Judged from the molecular markers associated, including organelle markers and Atg proteins, GFP-LC3 positive autophagosomes were overall at the later biogenetic stage. Furthermore, both GFP LC3 and Atg5 positive autophagosomes from light membranes were less mature than those from heavy membranes. We have established a method to isolate subpopulations of autophagsomes for further characterization. PMID- 25557737 TI - Direct fungal fermentation of lignocellulosic biomass into itaconic, fumaric, and malic acids: current and future prospects. AB - Various economic and environmental sustainability concerns as well as consumer preference for bio-based products from natural sources have paved the way for the development and expansion of biorefining technologies. These involve the conversion of renewable biomass feedstock to fuels and chemicals using biological systems as alternatives to petroleum-based products. Filamentous fungi possess an expansive portfolio of products including the multifunctional organic acids itaconic, fumaric, and malic acids that have wide-ranging current applications and potentially addressable markets as platform chemicals. However, current bioprocessing technologies for the production of these compounds are mostly based on submerged fermentation, which necessitates physicochemical pretreatment and hydrolysis of lignocellulose biomass to soluble fermentable sugars in liquid media. This review will focus on current research work on fungal production of itaconic, fumaric, and malic acids and perspectives on the potential application of solid-state fungal cultivation techniques for the consolidated hydrolysis and organic acid fermentation of lignocellulosic biomass. PMID- 25557739 TI - Necrotizing and sarcoidal granulomas in the skin and synovial membrane, associated with common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia, T-cell abnormalities and recurrent bacterial infections. Patients with CVID can present granulomatous lesions on both the skin and other organs. When these lesions are the first sign of the disease, the diagnosis can be very challenging. We report the case of a patient with undiagnosed CVID, who presented with necrotizing and sarcoidal granulomas on the skin and synovial membrane as the first appearance of immunodeficiency. PMID- 25557740 TI - Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study. AB - This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (>=39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management. PMID- 25557741 TI - Caregivers' treatment-seeking behaviour for children under age five in malaria endemic areas of rural Myanmar: a cross-sectional study. AB - BACKGROUND: A community-based malaria intervention was introduced through fixed and mobile clinics in rural Myanmar. This study attempted to identify treatment seeking behaviour of caregivers for children under five and the determinants of appropriate treatment-seeking behaviour in mobile clinic villages (MV) and non mobile clinic villages (NMV) in malaria-endemic rural areas in Myanmar. METHODS: A cross-sectional study was conducted in 23 MV and 25 NMV in Ingapu Township, Myanmar. Appropriate treatment-seeking behaviour was operationally defined as seeking treatment from trained personnel or at a health facility within 24 hours after the onset of fever. Multiple logistic regression analyses were conducted to identify the determinants of appropriate treatment-seeking behaviour. RESULTS: Among the 597 participants in both types of villages, 166 (35.3%) caregivers sought appropriate treatment. No significant difference in appropriate treatment seeking behaviour was found between the two types of villages (adjusted odds ratio (AOR), 0.80; 95% confidence interval (CI), 0.51-1.24). Determinants of behaviour include proximity to public health facilities (AOR, 5.86; 95% CI, 3.43 10.02), knowledge of malaria (AOR, 1.90; 95% CI, 1.14-3.17), malaria prevention behaviour (AOR, 1.76; 95% CI, 1.13-2.76), treatment at home (AOR, 0.26; 95% CI, 0.15-0.45), and treatment and transportation costs (AOR, 0.52; 95% CI, 0.33 0.83). CONCLUSIONS: Caregivers' treatment-seeking behaviour was poor for fever cases among children under age five, and did not differ significantly between MV and NMV. It is necessary to educate caregivers, particularly for early treatment seeking and appropriate use of health care options for fever, and catering to their medical needs. These findings can help promote awareness and prevention, and improve the quality of interventions at the community level. PMID- 25557742 TI - Purified type I collagen wound matrix improves chronic wound healing in patients with recessive dystrophic epidermolysis bullosa. AB - Recessive dystrophic epidermolysis bullosa is a severe genetic blistering skin condition resulting in chronic wounds. Nonhealing wounds were treated over 8 weeks using a reconstituted natural purified type I collagen skin substitute. Chronic wounds were defined as nonhealing wounds present for longer than 6 months. For each patient, two chronic wounds were identified and randomized into a control or treatment group. Both groups received standard-of-care wound dressings. The treatment group received an additional type I collagen skin substitute. Wound size was measured at baseline and weeks 1, 4, and 8. Pain, pruritus, and burning and stinging were assessed. Wound cultures were obtained at baseline and thereafter as was considered clinically relevant. Ten subjects were enrolled; seven completed the study. Six subjects showed a positive response to the type I collagen skin substitute. Three subjects demonstrated full wound reepithelialization. Wounds treated using the collagen skin substitute showed statistically significantly greater improvement. Average scores for pruritus and pain decreased significantly. Reconstituted natural purified type I collagen skin substitutes improved the healing of chronic wounds and may be a valuable addition to the epidermolysis bullosa wound care arsenal. PMID- 25557743 TI - Shining light in dark corners: diagnosis and management of late-onset fetal growth restriction. AB - Fetal growth restriction (FGR) is the single biggest risk factor for stillbirth. In the absence of any effective treatment for fetal growth restriction, the mainstay of management is close surveillance and timely delivery. While such statements are almost self-evident, the daily clinical challenge of late-onset fetal growth restriction remains; the competing priorities of minimising stillbirth risk, while avoiding excessive obstetric intervention and the neonatal sequelae of iatrogenic preterm birth. This dilemma is made harder because the tools for late-onset FGR diagnosis and surveillance compare poorly to those used in early-onset FGR; screening tests in early pregnancy have limited predictive value; most cases escape clinical detection, a phenomenon set to worsen given the obesity epidemic; there is a failure of consensus on the definition of small for gestational age, and ancillary tools, such as umbilical artery Doppler--of value in identification of preterm FGR--are less useful in the late-preterm period and at term. Most importantly, the problem is common; 96% of all births occur after 32 weeks. This means a poor noise/signal ratio of any test or management algorithm will inevitably have large clinical consequences. Into such a dark corner, we cast some light; a summary on diagnostic criteria, new developments to improve the diagnosis of late-onset FGR and a suggested approach to management. PMID- 25557744 TI - A re-assessment of species diversity within the 'revolutum' group of Echinostoma Rudolphi, 1809 (Digenea: Echinostomatidae) in Europe. AB - Species of Echinostoma Rudolphi, 1809 (Digenea: Echinostomatidae) belonging to the 'revolutum' species complex were re-examined based on material gathered in an extensive sampling programme in eight countries in Europe. The morphology of the life-cycle stages was studied in naturally and experimentally infected snail and bird hosts. A review, with an updated synonymy, is presented for six European species, including one new to science, i.e. Echinostoma revolutum (Frolich, 1802) (sensu stricto) (type-species), E. bolschewense (Kotova, 1939), E. miyagawai Ishii, 1932, E. nasincovae n. sp., E. paraulum Dietz, 1909 and Echinostoma sp. IG), and keys to the identification of their cercariae and adults are provided. PMID- 25557745 TI - Description of two new species of Hymenolepis Weinland, 1858 (Cestoda: Hymenolepididae) from rodents on Luzon Island, Philippines. AB - Our helminthological examination of murid rodents on Luzon Island, Philippines, revealed a remarkable diversity of Hymenolepis Weinland, 1858. Here we describe two new species based on specimens from murid rodents Rattus everetti (Gunther) and Apomys datae (Meyer) collected from Luzon Island. Hymenolepis alterna n. sp. differs from all known species of Hymenolepis in having irregularly alternating genital pores. This feature has not been reported from any previously known member of Hymenolepis. Additionally, Hymenolepis alterna n. sp. also differs from other Hymenolepis spp. in the relative position of both poral and antiporal dorsal osmoregulatory canals which are shifted towards the middle of the proglottis in relation to the ventral canals on both sides of the proglottides, and in having curved or twisted external seminal vesicle, covered externally by a dense layer of intensely stained cells. Hymenolepis bilaterala n. sp. differs from all known species of Hymenolepis in the relative position of both poral and antiporal dorsal osmoregulatory canals, which are shifted bilaterally towards the margins of proglottides in relation to the ventral canals, and in possession of testes situated in a triangle and eggs with very thin outer coat. A total of seven species of Hymenolepis are known from the Philippine archipelago. This total includes the cosmopolitan species Hymenolepis diminuta (Rudolphi, 1819), which was likely introduced to the island with invasive rats. Strikingly, all seven known species occur on the island of Luzon alone. By comparison, only six Hymenolepis spp. are known from the whole Palaearctic and seven from the Nearctic despite a much better level of knowledge of rodent helminths in these zoogeographical regions, as well as vast territories, diverse landscapes and very rich rodent fauna. This suggests that Hymenolepis spp. may have undergone an unusually active radiation in the Philippines. Possible explanations of this phenomenon are discussed. PMID- 25557746 TI - Prosthenystera oonastica n. sp. (Digenea: Callodistomidae) from ictalurid catfishes in southeastern United States and molecular evidence differentiating species in the genus across Americas. AB - Prosthenhystera oonastica n. sp. is described as a cryptic species from the gall bladder of three ictalurid catfishes, Ictalurus punctatus (Rafinesque), Ictalurus furcatus (Valenciennes), and Pylodictis olivaris (Rafinesque), in rivers in the southeastern United States. The species was originally named by Wilmer A. Rogers in 1979 but never formally described. Material used for the description consists of two specimens of Roger's original material and ten new specimens. We found no significant morphological features that are useful for discriminating between the new species and its closest relative Prosthenhystera obesa (Diesing, 1850) Travassos, 1922 that occurs in the gall bladders of freshwater characiform, perciform and siluriform fishes, ranging from South America to southern Mexico. However, we found substantial differences in the large subunit ribosomal DNA (partial 28S rRNA gene) between the two species justifying the naming of the new species. Prosthenhystera oonastica n. sp. is readily differentiated from Prosthenhystera caballeroi Jimenez-Guzman, 1973 that occurs in the gall bladders of characid fishes in Central America and Mexico, by having a relatively straight or bent rather than highly convoluted oesophagus, a relatively smaller ovary, smaller and less coalesced vitelline follicles, narrower caeca and smaller eggs. Comparison of ribosomal DNA (partial ITS1, 5.8S, ITS2, and partial 28S gene) between P. oonastica n. sp. and P. caballeroi revealed large differences between the two species. Phylogenetic analysis based on partial 28S rRNA gene sequences from the three studied species of Prosthenhystera Travassos, 1922 and related digenean taxa revealed a closer relationship between P. oonastica n. sp. and P. obesa than either has had with P. caballeroi. PMID- 25557747 TI - Redescription and phylogenetic relationships of Euparyphium capitaneum Dietz, 1909, the type-species of Euparyphium Dietz, 1909 (Digenea: Echinostomatidae). AB - Euparyphium capitaneum Dietz, 1909, the type-species of the genus Euparyphium Dietz, 1909, is described on the basis of material collected from the type-host Anhinga anhinga (L.) from Pascagoula River, which drains into the northern coast of the Gulf of Mexico. Combination of light and scanning electron microscopy observations of freshly collected and properly fixed specimens in our study has allowed us to provide novel information on the morphology and topology of the reproductive systems and other morphological features of the species. A Bayesian inference analysis based on the newly-obtained partial sequence of the nuclear 28S rRNA gene for E. capitaneum and 24 previously published sequences from the superfamily Echinostomatoidea Looss, 1899 provided evidence supporting the distinct status of the genera Euparyphium and Isthmiophora Luhe, 1909. PMID- 25557749 TI - Two new species of Ergasilus Nordmann, 1832 (Copepoda: Ergasilidae) and a redescription of Ergasilus salmini Thatcher & Brazil-Sato, 2008 from Salminus brasiliensis Cuvier and S. franciscanus Lima & Britsky (Teleostei: Characidae) in Brazil. AB - Three species of Ergasilus Nordmann, 1832 are reported from the gills of Salminus spp. in Brazil. Ergasilus salmini Thatcher & Brazil-Sato, 2008 from Salminus brasiliensis Cuvier is redescribed, based on examination of paratypes. The study revealed morphological differences from the original description, especially in the morphology of the cephalothorax and the ornamentation of antenna, antennule and legs. Ergasilus lacusauratus n. sp. described from S. brasiliensis in lake Lagoa Dourada (Parana) differs from the only known species from this host group, E. salmini, in the shape and size of the cephalothorax and the general morphology of the egg-sacs. Ergasilus sinefalcatus n. sp. from S. franciscanus Lima & Britsky in River Sao Francisco (Minas Gerais) closely resembles E. pitalicus, E. coatiarus and E. leporinidis in the lack of a pectinate seta on the first exopodal segment, a feature common in species of Ergasilus in the Neotropics. Ergasilus sinefalcatus n. sp. differs from these species in the presence of a spiniform process on the coxae of legs 2, 3 and 4, an ornament never reported from freshwater species of Ergasilus in South America. PMID- 25557748 TI - Molecular analysis of the genera Hapalotrema Looss, 1899 and Learedius Price, 1934 (Digenea: Spirorchiidae) reveals potential cryptic species, with comments on the validity of the genus Learedius. AB - Adult blood flukes of the genera Hapalotrema Looss, 1899 and Learedius Price, 1934 were collected from turtles off Queensland and the Hawaiian Islands. Specimens were identified as Hapalotrema pambanensis Mehrotra, 1973, H. synorchis Luhman, 1935, H. postorchis Rao, 1976 and Learedius learedi Price, 1934 on the basis of morphology. No major morphological differences were found between specimens from this study and previously published descriptions. DNA was also extracted and sequences obtained using custom spirorchiid-specific primers for the ITS2 and 28S rDNA regions, in order to confirm species identification and investigate phylogenetic relationships. Intraspecific genetic variation was generally low. However the ITS2 region of H. postorchis and to a lesser extent that of L. learedi showed considerable variation between specimens from the Pacific and Atlantic oceans. Further studies will be required to determine whether this variation should be considered inter- or intra-specific. Maximum likelihood phylogenetic analyses were completed for both sequenced genes. Learedius learedi was unequivocally nested among species of Hapalotrema, suggesting that the status of the genus Learedius may need to be reassessed. PMID- 25557750 TI - New species of the feather mite genus Promegninia Gaud & Atyeo (Acari: Avenzoariidae) from petrels and shearwaters (Procellariiformes: Procellariidae). AB - Two new species of the feather mite genus Promegninia Gaud & Atyeo, 1967 (Avenzoariidae: Bonnetellinae) are described from procellariids in the northeasterm Atlantic Ocean: Promegninia bulweriae n. sp. from the Bulwer's petrel Bulweria bulwerii (Jardine & Selby) and P. calonectris n. sp. from the Cory's shearwater Calonectris borealis (Cory) (Procellariiformes: Procellariidae). Males of P bulweriae n. sp. are most clearly distinguished from the other known species in the genus by having short legs III extending only to the level of lobar apices and short conical tarsi III with lanceolate ventral seta w; females of this species are characterised by the absence of additional sclerites at postero-lateral angles of the prodorsal shield. Males of P. calonectris differ from the other known species in having bidentate terminal lamellae on the lobar apices and the entire adanal shield; females of this species are distinguished by having well-developed pygidial shields and a hysteronotal shield encompassing the bases of setae c2. Sequence data of the mitochondrial cytochrome c oxidase subunit I gene fragment (COI) are also obtained for the new species. An updated diagnosis of Promegninia and a key to the known species are provided. PMID- 25557751 TI - Stammerinema hyalinum n. comb. for Filaria hyalina von Linstow, 1890 and its recognition as a senior synonym of Stammerinema rhopalocephalum (Soltys, 1952) (Spirurida: Acuariidae), a parasite of shrews. AB - Based on a re-examination of type-specimens of Filaria hyalina von Linstow, 1890 from Sorex araneus L. (Mammalia: Soricidae) and morphological studies (light and scanning electron microscopy) of specimens collected from the same host species in Bulgaria and previously identified as Stammerinema rhopalocephalum (Soltys, 1952), both these forms are considered to be conspecific. Accordingly, F. hyalina is transferred to the genus Stammerinema Osche, 1955 as Stammerinema hyalinum n. comb. and the species originally described as Synhimantus rhopalocephalus Soltys, 1952 is considered its junior synonym. PMID- 25557752 TI - Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. AB - CONTEXT: The effects of testosterone treatment on glucose metabolism and other outcomes in men with type 2 diabetes (T2D) and/or the metabolic syndrome are controversial. OBJECTIVE: To perform a systematic review and meta-analysis of placebo-controlled double-blind randomized controlled clinical trials (RCT) of testosterone treatment in men with T2D and/or the metabolic syndrome. DATA SOURCES: A systematic search of RCTs was conducted using Medline, Embase and the Cochrane Register of controlled trials from inception to July 2014 followed by a manual review of the literature. STUDY SELECTION: Eligible studies were published placebo-controlled double-blind RCTs published in English. DATA EXTRACTION: Two reviewers independently selected studies, determined study quality and extracted outcome and descriptive data. DATA SYNTHESIS: Of the 112 identified studies, seven RCTs including 833 men were eligible for the meta-analysis. In studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance (HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) -1.58 [-2.25, 0.91], P < 0.001. The treatment effect was nonsignificant for RCTs using a more stringent computer-based equation (HOMA2), MD -0.19 [-0.86, 0.49], P = 0.58). Testosterone treatment did not improve glycaemic (HbA1c) control, MD -0.15 [ 0.39, 0.10], P = 0.25, or constitutional symptoms, Aging Male Symptom score, MD 2.49 [-5.81, 0.83], P = 0.14). CONCLUSIONS: This meta-analysis does not support the routine use of testosterone treatment in men with T2D and/or the metabolic syndrome without classical hypogonadism. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome. PMID- 25557753 TI - The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate-specific Antigen era. AB - Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential. PMID- 25557754 TI - Effects of weight loss via high fat vs. low fat alternate day fasting diets on free fatty acid profiles. AB - Cardiovascular disease risk is associated with excess body weight and elevated plasma free fatty acid (FFA) concentrations. This study examines how an alternate day fasting (ADF) diet high (HF) or low (LF) in fat affects plasma FFA profiles in the context of weight loss, and changes in body composition and lipid profiles. After a 2-week weight maintenance period, 29 women (BMI 30-39.9 kg/m(2)) 25-65 years old were randomized to an 8-week ADF-HF (45% fat) diet or an ADF-LF (25% fat) diet with 25% energy intake on fast days and ad libitum intake on feed days. Body weight, BMI and waist circumference were assessed weekly and body composition was measured using dual x-ray absorptiometry (DXA). Total and individual FFA and plasma lipid concentrations were measured before and after weight loss. Body weight, BMI, fat mass, total cholesterol, LDL-C and triglyceride concentrations decreased (P < 0.05) in both groups. Total FFA concentrations also decreased (P < 0.001). In the ADF-LF group, decreases were found in several more FFAs than in the ADF-HF group. In the ADF-HF group, FFA concentrations were positively correlated with waist circumference. Depending on the macronutrient composition of a diet, weight loss with an ADF diet decreases FFA concentrations through potentially different mechanisms. PMID- 25557755 TI - Risk Factors for Early Hemorrhagic Progression after Traumatic Brain Injury: A Focus on Lipid Profile. AB - The purpose of this study was to identify the risk factors related to the hemorrhagic progression (HP) of brain contusion in patients after traumatic brain injury (TBI). Recently, many studies have reported abnormal lipid levels associated with hemorrhagic stroke. Unlike hemorrhage stroke, however, the lipid profiles in patients with TBI have not been examined. Therefore, we evaluated the risk factors of HP in patients with TBI and focused on lipid profiles. Fifty-six patients with TBI with mild to moderate injuries (Glasgow Coma Scale >=9) who initially did not need surgical intervention were enrolled in this study. Patients underwent repeated computed tomography (CT) scans at 4 h and 24 h after injury. Magnetic resonance imaging (MRI) was performed 7 days after the initial injury. In each noncontrast CT scan, the hemorrhage volume was quantified using the ABC/2 technique. Clinical features, previous medical history, initial CT, and microbleeding on follow-up MRI were analyzed retrospectively. There were 31 (55%) patients in whom significant HP developed (volume >30%). Current smoking (p=0.034), higher initial systolic blood pressure (p=0.035), and lower triglyceride levels (p=0.039) were significantly associated with HP. Current smoking and a triglyceride (TG) level <150 mg/dL were the only statistically significant predictors of HP in the multivariate analysis (p=0.019, p=0.021, respectively). HP with TBI is common in patients who currently smoke and have lower TG levels (150 mg/dL). These patients should be monitored closely, and surgery may be considered before deterioration occurs. PMID- 25557756 TI - Introducing Choosing Wisely(r): Next steps in improving healthcare value. PMID- 25557757 TI - Emerging hormonal treatments for menopausal symptoms. AB - INTRODUCTION: The majority of women experience bothersome symptoms postmenopause (e.g., hot flushes, vaginal symptoms). Estrogen receptor agonists remain the most effective options for ameliorating menopausal symptoms. However, use of hormonal therapies has declined in the wake of issues raised by the Women's Health Initiative trials. As a result, there is a need for new safe and effective alternatives to estrogen-progestogen hormone therapy. AREAS COVERED: We review the efficacy and safety profile of hormonal menopausal therapies that are in Phase III clinical trials or recently approved. Investigational treatments discussed include two new vaginal estrogen products (TX-004HR, WC-3011); the first combination of estradiol and progesterone, and a novel combination of dehydroepiandrosterone and acolbifene. We also review a new selective estrogen receptor modulator (SERM), ospemifene, recently approved for treatment of dyspareunia related to menopause, and conjugated estrogens plus bazedoxifene, an estrogens/SERM combination, recently approved for moderate-to-severe vasomotor symptoms and prevention of osteoporosis. EXPERT OPINION: New and emerging hormonal treatments for managing menopausal symptoms may have improved safety and efficacy profiles compared with traditional estrogen-progestogen therapy; however, long-term safety data will be needed. PMID- 25557758 TI - The effect of intra-articular Tenoxicam on knee effusion after arthroscopy. AB - PURPOSE: NSAIDs and analgesic drugs are used intra-articularly after knee arthroscopy for pain relief. However, synovial effusion is still a common cause of delayed physical therapy. The aim of this study was to demonstrate the beneficial effect of intra-articular injection of Tenoxicam on knee effusion after arthroscopy. METHOD: This was a prospective non-randomized study on 134 patients with a mean age of 36.7 years. Knee arthroscopy on a day-case basis was performed; normal saline was used for irrigation. At the end of the procedure, fluid was aspirated from the knee joint and 20 ml of Tenoxicam diluted with 20 ml of 0.9% normal saline was injected into the knee five minutes before deflation of limb tourniquet. The same surgeon performed clinical examination for knee effusion 14 days postoperatively. RESULTS: Encountered pathologies included meniscal injury, degenerative arthropathy, synovial plica and ACL rupture. Knee effusion developed in 15.7% of the patients, particularly in those with degenerative arthropathy (p = 0.006) and meniscal lesions (p = 0.06). CONCLUSION: Intra-articular Tenoxicam is a simple method for the prevention of postoperative knee effusion. Degenerative arthropathy and meniscal lesions are major risk factors for post arthroscopy knee effusion. PMID- 25557761 TI - Tuning transport selectivity of ionic species by phosphoric acid gradient in positively charged nanochannel membranes. AB - The transport of ionic species through a nanochannel plays important roles in fundamental research and practical applications of the nanofluidic device. Here, we demonstrated that ionic transport selectivity of a positively charged nanochannel membrane can be tuned under a phosphoric acid gradient. When phosphoric acid solution and analyte solution were connected by the positively charged nanochannel membrane, the faster-moving analyte through the positively charged nanochannel membrane was the positively charged dye (methylviologen, MV(2+)) instead of the negatively charged dye (1,5-naphthalene disulfonate, NDS(2 )). In other words, a reversed ion selectivity of the nanochannel membranes can be found. It can be explained as a result of the combination of diffusion, induced electroosmosis, and induced electrophoresis. In addition, the influencing factors of transport selectivity, including concentration of phosphoric acid, penetration time, and volume of feed solution, were also investigated. The results showed that the transport selectivity can further be tuned by adjusting these factors. As a method of tuning ionic transport selectivity by establishing phosphoric acid gradient, it will be conducive to improving the separation of ionic species. PMID- 25557759 TI - Dislocation of bipolar hip hemiarthroplasty through a postero-lateral approach for femoral neck fractures: A cohort study. AB - PURPOSE: To analyze postoperative global femoral offset (FO), leg length discrepancy (LLD) and Wiberg angle as risk factors for prosthetic dislocation after treatment with bipolar hemiarthoplasty (HA) through a postero-lateral approach for femoral neck fracture (FNF). METHODS: Three hundred and seventy three patients treated with a cemented bipolar HA through a postero-lateral approach between January 2006 and December 2013 were included in a cohort study with a follow-up time ranging from 6 months to 7 years. Radiographs and all surgical records were reviewed regarding Global FO, LLD and Wiberg angle. We compared stable hips without dislocation to those with either a single dislocation and those with recurrent instability. RESULTS: Three hundred and twenty eight hips fulfilled the inclusion criteria and were analyzed in the study. The incidence of prosthetic dislocation was 10.7% (36/373). The mean time from surgery to first dislocation was 3.9 months (0-47) and 62.5% had recurrent dislocations. Patients with dislocation had a statistically significantly decreased postoperative global FO (-6.4 mm vs. -2.8 mm, p = 0.04), LLD (-2 vs. 1.5 mm, p = 0.03) and smaller Wiberg angle (40 degrees vs. 46 degrees , p = 0.01) on the operated side compared with the rest of cohort. In comparison to age and sex-matched control groups from the cohort, the difference in the radiographic parameters were significant in patients with recurrent dislocations but not in patients with a single dislocation. CONCLUSION: Patients with recurrent dislocations had a decreased postoperative global FO, shorter leg and shallower acetabulum on the operated side compared with their controls. These factors might decrease the soft-tissue tension around the operated hip and predispose to dislocation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25557762 TI - Induction therapy: clinical and quality of life outcomes in aged renal transplant recipients. AB - BACKGROUND: One primary purpose of transplant is to improve quality of life (QOL) in renal transplant recipients (RTRs) >= 50 yr of age, where death with a functioning graft limits life years gained. We aimed to determine the impact of induction therapy, with its subsequent effects on rejection, infection, and readmissions, on QOL. METHODS: Subanalysis of patients >= 50 yr of age that participated in a single-center, prospective, risk-stratified, randomized, open label study. Two hundred RTRs >= 50 yr of age. INTERVENTIONS: All patients received either rabbit antithymocyte globulin (rATG) or interleukin 2 receptor antagonists (IL-2RA) in addition to tacrolimus (FK), mycophenolate mofetil (MMF), and corticosteroids in a randomized fashion. Outcome analyses included safety, efficacy, and QOL. RESULTS: Results reported 1 yr post-transplant. Of 111 patients >= 50 yr old, 48 received IL-2RA and 63 received rATG. Baseline characteristics were similar between groups. Patients that received rATG had a trend toward lower acute rejection rates, fewer readmissions, and fewer supratherapeutic tacrolimus troughs, with similar rates of infections. QOL analysis demonstrated patients that received rATG were significantly more likely to have improvements in physical and social functioning after transplant. CONCLUSIONS: Contrary to the common practice, T-cell depletion in recipients >= 50 yr of age may be beneficial. PMID- 25557763 TI - Effects of metabolites of the analgesic agent dipyrone (metamizol) on rostral ventromedial medulla cell activity in mice. AB - The molecular mechanism of action of dipyrone, a widely used antipyretic and non opioid analgesic drug, is still not fully understood. Actions upon peripheral inflamed tissues as well as the central nervous system, especially upon the PAG RVM axis, have been suggested. Dipyrone is a prodrug and its activity is due to its immediate conversion to its active metabolites. We tested the effect of two recently discovered metabolites of dipyrone, the arachidonoyl amides of 4 methylaminoantipyrine and 4-aminoantipyrine, on the neurons of the rostral ventromedial medulla (RVM), which are part of the descending pathway of antinociception. These compounds reduced the activity of ON-cells and increased the activity of OFF-cells. Both CB1 and TRPV1 blockade reversed these effects, suggesting that the endocannabinoid/endovanilloid system takes part in the analgesic effects of dipyrone. PMID- 25557766 TI - Binding body and self in visuo-vestibular conflicts. AB - Maintenance of the bodily self relies on the accurate integration of multisensory inputs in which visuo-vestibular cue integration is thought to play an essential role. Here, we tested in healthy volunteers how conflicting visuo-vestibular bodily input might impact on body self-coherence in a full body illusion set-up. Natural passive vestibular stimulation was provided on a motion platform, while visual input was manipulated using virtual reality equipment. Explicit (questionnaire) and implicit (skin temperature) measures were employed to assess illusory self-identification with either a mannequin or a control object. Questionnaire results pointed to a relatively small illusion, but hand skin temperature, plausibly an index of illusory body ownership, showed the predicted drop specifically in the condition when participants saw the mannequin moving in congruence with them. We argue that this implicit measure was accessible to visuo vestibular modulation of the sense of self, possibly mediated by shared neural processes in the insula involved in vestibular and interoceptive signalling, thermoregulation and multisensory integration. PMID- 25557767 TI - Structural heterogeneity and dynamics of dyes on TiO2: implications for charge transfer across organic-inorganic interfaces. AB - Charge transfer across organic-inorganic interfaces plays a vital role in many important applications. Dye-semiconductor systems are the prototypical such interface and provide an excellent platform for exploring the underlying molecular-level factors that affect charge transfer dynamics and efficiency. Experiments often show multi-exponential electron injection kinetics from adsorbed dyes to a semiconductor substrate, suggesting the presence of interfacial heterogeneity. Nonetheless, both the diversity of interfacial structures and the associated implications for electronic dynamics are poorly understood. In the present work, we examine the effect of structural heterogeneity and dynamics on charge injection (as measured by dye-semiconductor electronic coupling) from plane wave density functional theory and ab initio molecular dynamics calculations on model dye-semiconductor systems. We demonstrate that dye binding motif, conformation, solvation, and corresponding thermal fluctuations significantly affect charge injection kinetics. We suggest that the experimentally observed multi-exponential kinetics likely result not only from an intrinsic heterogeneous distribution of electronic coupling strengths, but also from the conformational or solvent dynamics that in turn modulate the coupling strength and/or band alignment. PMID- 25557764 TI - Aspirin may influence cellular energy status. AB - In our previous findings, we have demonstrated that aspirin/acetyl salicylic acid (ASA) might induce sirtuins via aryl hydrocarbon receptor (Ah receptor). Induction effects included an increase in cellular paraoxonase 1 (PON1) activity and apolipoprotein A1 (ApoA1) gene expression. As predicted, ASA and salicylic acid (SA) treatment resulted in generation of H2O2, which is known to be an inducer of mitochondrial gene Sirt4 and other downstream target genes of Sirt1. Our current mass spectroscopic studies further confirm the metabolism of the drugs ASA and SA. Our studies show that HepG2 cells readily converted ASA to SA, which was then metabolized to 2,3-DHBA. HepG2 cells transfected with aryl hydrocarbon receptor siRNA upon treatment with SA showed the absence of a DHBA peak as measured by LC-MS/MS. MS studies for Sirt1 action also showed a peak at 180.9 m/z for the deacetylated and chlorinated product formed from N-acetyl lepsilon-lysine. Thus an increase in Sirt4, Nrf2, Tfam, UCP1, eNOS, HO1 and STAT3 genes could profoundly affect mitochondrial function, cholesterol homeostasis, and fatty acid oxidation, suggesting that ASA could be beneficial beyond simply its ability to inhibit cyclooxygenase. PMID- 25557765 TI - Regulation of T-type calcium channel expression by sodium butyrate in prostate cancer cells. AB - Several cellular mechanisms contribute to the neuroendocrine differentiation of prostate cancer cells, including exposure to sodium butyrate (NaBu), a naturally occurring salt of the short chain fatty acid n-butyric acid. NaBu belongs to a class of histone deacetylase inhibitors with potential anticancer function. T type calcium channel expression constitutes an important route for calcium influx in tumor cells that may trigger changes in cell proliferation and differentiation. In this work we investigated the role NaBu on the differentiation of lymph node carcinoma of the prostate (LNCaP) cells and its effect on T-type Ca(2+) channel expression. NaBu stimulates the morphological and molecular differentiation of LNCaP cells. Stimulation of LNCaP cells with NaBu evokes a significant increase in the expression of the Cav3.2 T-type channel subunits. Furthermore, the increased Cav3.2 expression promotes membrane insertion of T-type Ca(2+) channels capable of generating fast inactivating Ca(2+) currents, sensitive to 100MUM Ni(2+) ions. Inhibition of T-type Ca(2+) channel function reduces the outgrowth of neurite-like processes in LNCaP cells. NaBu-evoked expression of T-type Ca(2+) channels is also involved in the regulation of cell viability. Inhibition of T-type Ca(2+) channels causes a significant reduction in the viability of LNCaP cells treated with 1mM NaBu, suggesting that Ca(2+) influx via T-type channels can promote cell proliferation. However, increased expression of T-type Ca(2+) channels enhanced the cytotoxic effect of thapsigargin and paclitaxel on cell proliferation. These findings demonstrate that NaBu stimulates T-type Ca(2+) channel expression, thereby regulating both the morphological differentiation and growth of prostate cancer cells. PMID- 25557768 TI - Recombination of strain O segments to HCpro-encoding sequence of strain N of Potato virus Y modulates necrosis induced in tobacco and in potatoes carrying resistance genes Ny or Nc. AB - Hypersensitive resistance (HR) to strains O and C of Potato virus Y (PVY, genus Potyvirus) is conferred by potato genes Ny(tbr) and Nc(tbr), respectively; however, PVY N strains overcome these resistance genes. The viral helper component proteinases (HCpro, 456 amino acids) from PVY(N) and PVY(O) are distinguished by an eight-amino-acid signature sequence, causing HCpro to fold into alternative conformations. Substitution of only two residues (K269R and R270K) of the eight-amino-acid signature in PVY(N) HCpro was needed to convert the three-dimensional (3D) model of PVY(N) HCpro to a PVY(O) -like conformation and render PVY(N) avirulent in the presence of Ny(tbr), whereas four amino acid substitutions were necessary to change PVY(O) HCpro to a PVY(N) -like conformation. Hence, the HCpro conformation rather than other features ascribed to the sequence were essential for recognition by Ny(tbr). The 3D model of PVY(C) HCpro closely resembled PVY(O), but differed from PVY(N) HCpro. HCpro of all strains was structurally similar to beta-catenin. Sixteen PVY(N) 605-based chimeras were inoculated to potato cv. Pentland Crown (Ny(tbr)), King Edward (Nc(tbr)) and Pentland Ivory (Ny(tbr)/Nc(tbr)). Eleven chimeras induced necrotic local lesions and caused no systemic infection, and thus differed from both parental viruses that infected King Edward systemically, and from PVY(N) 605 that infected Pentland Crown and Pentland Ivory systemically. These 11 chimeras triggered both Ny(tbr) and Nc(tbr) and, in addition, six induced veinal necrosis in tobacco. Further, specific amino acid residues were found to have an additive impact on necrosis. These results shed new light on the causes of PVY-related necrotic symptoms in potato. PMID- 25557770 TI - An outbreak of Burkholderia cepacia complex pseudobacteremia associated with intrinsically contaminated commercial 0.5% chlorhexidine solution. AB - BACKGROUND: Burkholderia cepacia complex (Bcc) is well-known for intrinsic resistance to certain antiseptics. We experienced a sudden rise in Bcc bloodstream infections in a 786-bed hospital. An investigation was conducted to identify the source and to intervene in the ongoing infections. METHODS: The cases were defined as patients with positive blood cultures for Bcc from October 10, 2013-December 16, 2013. We reviewed medical records, interviewed health care workers, and audited the clinical laboratory. A microbiologic culture for a suspected antiseptic was performed, and interventions were instituted. RESULTS: During the outbreak period, Bcc were isolated from 46 blood cultures from 40 patients. The temporal and spatial distributions did not reveal common factors. The clinical features of the case patients suggested pseudobacteremia. A 0.5% chlorhexidine solution product was found to be contaminated with Bcc and had been misused as a skin antiseptic during blood culture. After withdrawal of the product and staff education, the outbreak was terminated. CONCLUSION: The pseudobacteremia was caused by contaminated 0.5% chlorhexidine from a single company. This contamination was permitted by multiple breaches of infection control principles that could have caused significant outbreaks of true infections. Regulatory actions at the government level are needed to ensure the sterility of antiseptics. PMID- 25557769 TI - Estimating retrospective exposure of household humidifier disinfectants. AB - We conducted a comprehensive humidifier disinfectant exposure characterization for 374 subjects with lung disease who presumed their disease was related to humidifier disinfectant use (patient group) and for 303 of their family members (family group) for an ongoing epidemiological study. We visited the homes of the registered patients to investigate disinfectant use characteristics. Probability of exposure to disinfectants was determined from the questionnaire and supporting evidence from photographs demonstrating the use of humidifier disinfectant, disinfectant purchase receipts, any residual disinfectant, and the consistency of their statements. Exposure duration was estimated as cumulative disinfectant use hours from the questionnaire. Airborne disinfectant exposure intensity (MUg/m(3)) was estimated based on the disinfectant volume (ml) and frequency added to the humidifier per day, disinfectant bulk level (MUg/ml), the volume of the room (m(3)) with humidifier disinfectant, and the degree of ventilation. Overall, the distribution patterns of the intensity, duration, and cumulative exposure to humidifier disinfectants for the patient group were higher than those of the family group, especially for pregnant women and patients <=6 years old. Further study is underway to evaluate the association between the disinfectant exposures estimated here with clinically diagnosed lung disease. PRACTICAL IMPLICATIONS: Retrospective exposure to household humidifier disinfectant as estimated here can be used to evaluate associations with clinically diagnosed lung disease due to the use of humidifier disinfectant in Korea. The framework, with modifications to account for dispersion and use patterns, can also be potentially adapted to assessment of other household chemical exposures. PMID- 25557771 TI - Seek and you shall find: prevalence of Clostridium difficile in Wuhan, China. AB - Clostridium difficile infection (CDI) is one of the leading health care acquired infections in the United States, but much of the epidemiology and burden of disease is unknown in China. The aim of this study was to determine the prevalence and possible risk factors of CDI among hospitalized patients with diarrhea in Wuhan, China. The overall prevalence of CDI was 28% (31/111). The findings of this study suggest the prevalence of CDI in hospitalized patients with diarrhea is higher then what has been previously reported in the current literature. PMID- 25557772 TI - Use of portable electronic devices in a hospital setting and their potential for bacterial colonization. AB - Portable electronic devices are increasingly being used in the hospital setting. As with other fomites, these devices represent a potential reservoir for the transmission of pathogens. We conducted a convenience sampling of devices in 2 large medical centers to identify bacterial colonization rates and potential risk factors. PMID- 25557773 TI - Open extensor tendon injuries. AB - The extensor tendons in the dorsum of the hand lie relatively superficially, making open injuries to the extensor mechanism a common source of morbidity. These injuries can range from simple clean lacerations to complex open injuries associated with severe skin and soft tissue loss. Although many advances in the treatment of tendon injuries focused on the flexor tendon, the extensor tendon has begun to receive more attention in recent literature. Knowledge of modern repair techniques and rehabilitation protocols may improve patient outcomes. This Current Concepts article summarizes the treatment of open extensor tendon injuries with a focus on the recent literature. PMID- 25557774 TI - Evidence-based hand and upper extremity surgery. PMID- 25557775 TI - Management of rotator cuff tears. AB - Every year approximately 18 million Americans report shoulder pain, a large percentage of which are a result of rotator cuff disease. Rotator cuff tear progression can be difficult to predict. Factors associated with tear enlargement include increasing symptoms, advanced age, involvement of 2 or more tendons, and rotator cable lesion. Nonsurgical treatment can be effective for patients with full-thickness tears. When conservative treatment fails, surgical repair provides a reliable treatment alternative. Recurrent tears after surgery can compromise outcomes, particularly for younger patients with physically demanding occupations. Revision surgery provides satisfactory results for those with symptomatic re-tears. If the tear is deemed irreparable, addressing concomitant biceps pathology or performing partial repairs can reliably improve pain and potentially reverse pseudoparalysis. The reverse shoulder arthroplasty has limited indications in the setting of rotator cuff tears and should be reserved for patients with painful pseudoparalysis and associated arthropathy. PMID- 25557776 TI - Biofeedback relaxation for pain associated with continuous passive motion in Taiwanese patients after total knee arthroplasty. AB - Effective pain management is crucial for patient recovery after total knee arthroplasty (TKA). Biofeedback therapy, which encourages relaxation and helps alleviate various conditions associated with stress, may help to decrease postoperative pain in patients undergoing TKA. A quasi- experimental design was used to investigate the efficacy of a biofeedback relaxation intervention in reducing pain associated with postoperative continuous passive motion (CPM) therapy. Sixty-six patients admitted to a general hospital in Taiwan for TKA were recruited and randomly assigned to the intervention or control group. The intervention group received biofeedback training twice daily for 5 days, concurrent with CPM therapy, whereas the control group did not receive the biofeedback intervention. Pain was measured using a numeric rating scale before and after each CPM therapy session on postoperative days 1 through 5. The CPM elicited pain score was calculated by subtracting the pre-CPM pain score from the post-CPM pain score. Results of repeated-measures analysis of variance showed intervention group reported significantly less pain caused by CPM than did the control group (f = 29.70, p < 0.001). The study results provide preliminary support for biofeedback relaxation, a non-invasive and non-pharmacological intervention, as a complementary treatment option for pain management in this population. PMID- 25557778 TI - Excluded-volume effects in living cells. AB - Biomolecules evolve and function in densely crowded and highly heterogeneous cellular environments. Such conditions are often mimicked in the test tube by the addition of artificial macromolecular crowding agents. Still, it is unclear if such cosolutes indeed reflect the physicochemical properties of the cellular environment as the in-cell crowding effect has not yet been quantified. We have developed a macromolecular crowding sensor based on a FRET-labeled polymer to probe the macromolecular crowding effect inside single living cells. Surprisingly, we find that excluded-volume effects, although observed in the presence of artificial crowding agents, do not lead to a compression of the sensor in the cell. The average conformation of the sensor is similar to that in aqueous buffer solution and cell lysate. However, the in-cell crowding effect is distributed heterogeneously and changes significantly upon cell stress. We present a tool to systematically study the in-cell crowding effect as a modulator of biomolecular reactions. PMID- 25557777 TI - Amygdala subnuclei connectivity in response to violence reveals unique influences of individual differences in psychopathic traits in a nonforensic sample. AB - Atypical amygdala function and connectivity have reliably been associated with psychopathy. However, the amygdala is not a unitary structure. To examine how psychopathic traits in a nonforensic sample are linked to amygdala response to violence, this study used probabilistic tractography to classify amygdala subnuclei based on anatomical projections to and from amygdala subnuclei in a group of 43 male participants. The segmentation identified the basolateral complex (BLA; lateral, basal, and accessory basal subnuclei) and the central subnucleus (CE), which were used as seeds in a functional connectivity analysis to identify differences in neuronal coupling specific to observed violence. While a full amygdala seed showed significant connectivity only to right middle occipital gyrus, subnuclei seeds revealed unique connectivity patterns. BLA showed enhanced coupling with anterior cingulate and prefrontal regions, while CE showed increased connectivity with the brainstem, but reduced connectivity with superior parietal and precentral gyrus. Further, psychopathic personality factors were related to specific patterns of connectivity. Fearless Dominance scores on the psychopathic personality inventory predicted increased coupling between the BLA seed and sensory integration cortices, and increased connectivity between the CE seed and posterior insula. Conversely, Self-Centered Impulsivity scores were negatively correlated with coupling between BLA and ventrolateral prefrontal cortex, and Coldheartedness scores predicted increased functional connectivity between BLA and dorsal anterior cingulate cortex. Taken together, these findings demonstrate how subnuclei segmentations reveal important functional connectivity differences that are otherwise inaccessible. Such an approach yields a better understanding of amygdala dysfunction in psychopathy. PMID- 25557779 TI - Defects of CRB2 cause steroid-resistant nephrotic syndrome. AB - Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS. PMID- 25557780 TI - CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. AB - We report five fetuses and a child from three families who shared a phenotype comprising cerebral ventriculomegaly and echogenic kidneys with histopathological findings of congenital nephrosis. The presenting features were greatly elevated maternal serum alpha-fetoprotein (MSAFP) or amniotic fluid alpha-fetoprotein (AFAFP) levels or abnormalities visualized on ultrasound scan during the second trimester of pregnancy. Exome sequencing revealed deleterious sequence variants in Crumbs, Drosophila, Homolog of, 2 (CRB2) consistent with autosomal-recessive inheritance. Two fetuses with cerebral ventriculomegaly and renal microcysts were compound heterozygotes for p.Asn800Lys and p.Trp759Ter, one fetus with renal microcysts was a compound heterozygote for p.Glu643Ala and p.Asn800Lys, and one child with cerebral ventriculomegaly, periventricular heterotopias, echogenic kidneys, and renal failure was homozygous for p.Arg633Trp in CRB2. Examination of the kidneys in one fetus showed tubular cysts at the corticomedullary junction and diffuse effacement of the epithelial foot processes and microvillous transformation of the renal podocytes, findings that were similar to those reported in congenital nephrotic syndrome, Finnish type, that is caused by mutations in nephrin (NPHS1). Loss of function for crb2b and nphs1 in Danio rerio were previously shown to result in loss of the slit diaphragms of the podocytes, leading to the hypothesis that nephrosis develops from an inability to develop a functional glomerular barrier. We conclude that the phenotype associated with CRB2 mutations is pleiotropic and that the condition is an important consideration in the evaluation of high MSAFP/AFAFP where a renal cause is suspected. PMID- 25557781 TI - MAT2A mutations predispose individuals to thoracic aortic aneurysms. AB - Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIalpha). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Ialpha are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIalpha enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIalpha function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease. PMID- 25557782 TI - Uncovering the genetic history of the present-day Greenlandic population. AB - Because of past limitations in samples and genotyping technologies, important questions about the history of the present-day Greenlandic population remain unanswered. In an effort to answer these questions and in general investigate the genetic history of the Greenlandic population, we analyzed ~200,000 SNPs from more than 10% of the adult Greenlandic population (n = 4,674). We found that recent gene flow from Europe has had a substantial impact on the population: more than 80% of the Greenlanders have some European ancestry (on average ~25% of their genome). However, we also found that the amount of recent European gene flow varies across Greenland and is far smaller in the more historically isolated areas in the north and east and in the small villages in the south. Furthermore, we found that there is substantial population structure in the Inuit genetic component of the Greenlanders and that individuals from the east, west, and north can be distinguished from each other. Moreover, the genetic differences in the Inuit ancestry are consistent with a single colonization wave of the island from north to west to south to east. Although it has been speculated that there has been historical admixture between the Norse Vikings who lived in Greenland for a limited period ~600-1,000 years ago and the Inuit, we found no evidence supporting this hypothesis. Similarly, we found no evidence supporting a previously hypothesized admixture event between the Inuit in East Greenland and the Dorset people, who lived in Greenland before the Inuit. PMID- 25557783 TI - Biased allelic expression in human primary fibroblast single cells. AB - The study of gene expression in mammalian single cells via genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblasts over 133,633 unique heterozygous single-nucleotide variants (hetSNVs). We observed that at the snapshot of analyses, each cell contained mostly transcripts from one allele from the majority of genes; indeed, 76.4% of the hetSNVs displayed stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibited a haplotype consistent allelic ratio; in contrast, distant sites located in two different genes were independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in the majority of the single cells at a given time point were rare and enriched with highly expressed genes. The relative abundance of each allele in a cell was controlled by some regulatory mechanisms given that we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability. PMID- 25557785 TI - Improvement of SMN2 pre-mRNA processing mediated by exon-specific U1 small nuclear RNA. AB - Exon-specific U1 snRNAs (ExSpe U1s) are modified U1 snRNAs that interact with intronic sequences downstream of the 5' splice site (ss) by complementarity. This process restores exon skipping caused by different types of mutation. We have investigated the molecular mechanism and activity of these molecules in spinal muscular atrophy (SMA), a genetic neuromuscular disease where a silent exonic transition on the survival motor neuron 2 (SMN2) leads to exon 7 (E7) skipping. By using different cellular models, we show that a single chromosome-integrated copy of ExSpe U1 induced a significant correction of endogenous SMN2 E7 splicing and resulted in the restoration of the corresponding SMN protein levels. Interestingly, the analysis of pre-mRNA transcript abundance and decay showed that ExSpe U1s promote E7 inclusion and stabilizes the SMN pre-mRNA intermediate. This selective effect on pre-mRNA stability resulted in higher levels of SMN mRNAs in comparison with those after treatment with an antisense oligonucleotide (AON) that targets corresponding intronic sequences. In mice harboring the SMN2 transgene, AAV-mediated delivery of ExSpe U1 increased E7 inclusion in brain, heart, liver, kidney, and skeletal muscle. The positive effect of ExSpe U1s on SMN pre-mRNA processing highlights their therapeutic potential in SMA and in other pathologies caused by exon-skipping mutations. PMID- 25557786 TI - Combinatorial screening for specific drug solubilizers with switchable release profiles. AB - Polymer-block-peptide conjugates are tailored to render hydrophobic small molecule drugs water soluble. The combinatorial strategy selects for bioconjugates that exhibit sequence-specific solubilization and switchable release profiles of the cargo through incorporation of a disulfide linker moiety into the peptide-library design. While the study focused on the photosensitizer m THPC and reductive carrier cleavage, the approach is generic and might be expanded toward a broad range of poorly soluble small-molecule drugs and other selective cleavage mechanisms to disassemble a peptide binding domain of the bioconjugate-based solubilizer. PMID- 25557784 TI - DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. AB - Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits beta-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC. PMID- 25557787 TI - Acetone-butanol-ethanol production from substandard and surplus dates by Egyptian native Clostridium strains. AB - One hundred and seven mesophilic isolates of Clostridium were isolated from agricultural soils cultivated with different plants in Assuit Governorate, Egypt. Eighty isolates (out of 107) showed the ability to produce ABE (Acetone, butanol and ethanol) on T6 medium ranging from 0.036 to 31.89 g/L. The highest numbers of ABE producing isolates were obtained from soil samples of potato contributing 27 isolates, followed by 18 isolates from wheat and 10 isolates from onion. On the other hand, there were three native isolates that produced ABE more than those produced by the reference isolate Clostridium acetobutylicum ATCC 824 (11.543 g/L). The three isolates were identified based on phenotypic and gene encoding 16S rRNA as Clostridium beijerinckii ASU10 (KF372577), Clostridium chauvoei ASU55 (KF372580) and Clostridium roseum ASU58 (KF372581). The highest ABE level from substandard and surplus dates was produced by C. beijerinckii ASU10 (24.07 g/L) comprising butanol 67.15% (16.16 g/L), acetone 30.73% (7.4 g/L) and ethanol 2.12% (0.51 g/L), while C. roseum ASU58 and C. chauvoei ASU55 produced ABE contributing 20.20 and 13.79 g/L, respectively. ABE production by C. acetobutylicum ATCC 824 was 15.01 g/L. This study proved that the native strains C. beijerinckii ASU10 and C. roseum ASU58 have high competitive efficacy on ABE production from economical substrate as substandard and surplus date fruits. Additionally, using this substrate without any nutritional components is considered to be a commercial substrate for desired ABE production. PMID- 25557788 TI - MD-miniRNA could be a more accurate biomarker for prostate cancer screening compared with serum prostate-specific antigen level. AB - Prostate cancer and prostatic hyperplasia detection remains a great challenge, lacking of effective non-invasive and specific diagnostic biomarkers. In the current study, we aimed to identify the relative expression of plasma MD-miniRNA and its diagnostic performance in differentiating prostate cancer and prostatic hyperplasia patients from healthy controls, compared with serum prostate-specific antigen (PSA) level. All of the clinical participants (63 prostate cancer patients, 32 prostatic hyperplasia patients, and 50 healthy controls) were obtained from the Third Affiliated Hospital of Suzhou University in China between January 2013 and April 2014. Clinical characteristics were well matched. Plasma samples were extracted to test the relative expression of MD-miniRNA using the method of qRT-PCR. SPSS 22.0 statistical software package was used to analyze the data and GraphPad Prism 6.0 was used to generate the graphs. Relativity expression of plasma MD-miniRNA was significantly upregulated in prostate cancer, compared with prostatic hyperplasia patients and healthy controls. Serum PSA level revealed similar differences among these groups. MD-miniRNA presented a relatively high diagnostic accuracy with AUC of 0.86 (95 % CI 0.80-0.93) in differentiating prostate cancer patients from healthy controls. Simultaneously, MD-miniRNA was able to discriminate prostate cancer patients from prostatic hyperplasia controls with AUC of 0.79 (95 % CI 0.70-0.88). In addition, MD miniRNA displayed a better diagnostic performance than PSA level. However, the panel of these two biomarkers revealed the best diagnostic performance, compared with either single biomarker. Results of this study showed that plasma MD-miniRNA could serve as a promising and noninvasive biomarker for diagnosing prostate cancer. Further large-scale studies are needed to confirm its clinical diagnosis accuracy. PMID- 25557789 TI - Proapoptotic CD95L levels in normal human serum and sera of breast cancer patients. AB - The CD95 pathway is a critical apoptotic pathway used by immune cells to avoid cancer development. CD95 ligand (CD95L) is found in several forms, as a cell membrane-associated form, a soluble metalloprotease-cleaved form, and a soluble but membrane-bound CD95L released on cell-derived exosomes. In this study, we used a cell-based assay to evaluate the activity of proapoptotic CD95L in sera from healthy individuals and breast cancer patients. We confirmed that our cell based assay using Jurkat cells was sensitive to the presence of proapoptotic CD95L in serum, and apoptosis induction by mechanisms other than CD95 was discriminated using apoptosis-resistant Jurkat subclones. Our results indicated a proapoptotic potential of normal serum that involved CD95L. Sera from breast cancer patients exhibited significantly decreased apoptosis induction, due to increased CD95 receptor levels compared with healthy women. Apoptotic potential tended to decrease as the Breast Imaging Reporting and Data System grade increased, and we observed restoration of proapoptotic potential after tumor removal. The CD95L in serum responsible for apoptotic induction was associated with high-molecular-weight particles, perhaps with exosomes. The sera of healthy individuals generally contain a proapoptotic environment, and this property is mainly maintained by the presence of CD95L. Furthermore, measurement of CD95L mediated apoptosis induction by sera could be a useful parameter to be evaluated during cancer development and therapeutic response. PMID- 25557790 TI - An exon variant in insulin receptor gene is associated with susceptibility to colorectal cancer in women. AB - Given the role of insulin resistance in colorectal cancer (CRC), we explored whether genetic variants in insulin (INS), insulin receptor (INSR), insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), insulin-like growth factor 1 (IGF1), and insulin-like growth factor binding protein 3 (IGFBP3) genes were associated with CRC risk. A total of 600 subjects, including 261 cases with CRC and 339 controls, were enrolled in this case-control study. Six polymorphisms in INS (rs689), INSR (rs1799817), IRS1 (rs1801278), IRS2 (rs1805097), IGF1 (rs5742612), and IGFBP3 (rs2854744) genes were genotyped using PCR-RFLP method. No significant difference was observed for INS, INSR, IRS1, IRS2, IGF1, and IGFBP3 genes between the cases and controls. However, the INSR rs1799817 "TT + CT" genotype and "CT" genotype compared with "CC" genotype occurred more frequently in the women with CRC than women controls (P = 0.007; OR = 1.93, 95 %CI = 1.20-3.11 and P = 0.002, OR = 2.15, 95 %CI = 1.31-3.53, respectively), and the difference remained significant after adjustment for confounding factors including age, BMI, smoking status, NSAID use, and family history of CRC (P = 0.018; OR = 1.86, 95 %CI = 1.11-3.10 and P = 0.004, OR = 2.18, 95 %CI = 1.28-3.71, respectively). In conclusion, to our knowledge, this study indicated for the first time that the INSR rs1799817 TT + CT genotype and CT genotype compared with the CC genotype had 1.86-fold and 2.18-fold increased risks for CRC among women, respectively. Furthermore, this finding is in line with previous studies which found significant associations between other variants of the INSR gene and CRC risk. Nevertheless, further studies are required to confirm our findings. PMID- 25557792 TI - Ultrasound mediated, iodine catalyzed green synthesis of novel 2-amino-3-cyano-4H pyran derivatives. AB - An efficient synthesis of a novel series of twelve substituted 2-amino-3-cyano-4H pyran derivatives was achieved by a one-pot three-component cyclocondensation reaction of heteroaryl aldehydes, malononitrile and active methylene compounds catalyzed by iodine in aqueous medium under ultrasound irradiation. In comparison with conventional methods, our protocol is convenient and offers several advantages, such as shorter reaction time, higher yields, milder conditions and environmental friendliness. We have herein successfully demonstrated the synergistic outcome of multi-component reaction (MCR) and sonication to offer a facile route for the design of these derivatives. PMID- 25557791 TI - Role of EHD2 in migration and invasion of human breast cancer cells. AB - Eps15 homology domain-containing 2 (EHD2) is a tumor suppressor gene, overexpressed in several solid tumors, including ovarian cancer and esophageal squamous cell carcinoma. The current study examined the expression and the role of EHD2 in human breast cancer. EHD2 expression was determined by Western blot and immunohistochemistry (IHC) in 80 breast cancer and paired noncancerous breast tissues. Correlations between clinicopathologic variables, overall survival, and EHD2 expression were analyzed. We investigated the role of EHD2 in breast cancer migration and invasion by wound healing assay and trans-well invasion assays. A notably lower level of EHD2 expression was found in breast cancer tissues. EHD2 expression was associated with histological grade, lymph node metastasis, and tumor size. Expression of EHD2 was found to be an independent prognostic factor in breast cancer patients. Furthermore, overexpression of EHD2 suppressed, while elimination of EHD2 promoted, the migration and invasion of breast cancer cells. Molecular data showed that EHD2 inhibited breast cancer migration and invasion probably by dampening the expression of Ras-related C3 botulinum toxin substrate 1 (Rac1). Downregulation of EHD2 was associated with migration and invasion by abrogating the expression of Rac1 in breast cancer patients. EHD2 may serve as a prognostic marker in breast cancer. PMID- 25557793 TI - Ultrastructural assessment of granulomas in the liver of perch (Perca fluviatilis) Infected by tapeworm. AB - Granulomas caused by migration of larvae of a helminth parasite, Triaenophorus nodulosus, within the liver of perch (Perca fluviatilis) from Rimov Dam Lake (Czech Republic) were assessed by transmission electron microscopy. Lesions were found in the liver of 29 out of 34 perch examined (85.2%) and there were between 1 and 15 T. nodulosus larvae identified per host. Pathological changes were more severe in livers containing more granulomas. Within the granulomas, there were three concentric regions: an outer layer of fibrous connective tissue, a middle clear epithelioid layer and a central dark spindle cell layer. The outer layer contained mast cells, fibroblasts, thick collagen bundles and epithelioid cells. The granulomas contained few lymphocytes and macrophages. Hepatocytes adjacent to the granulomas showed pronounced degeneration (ranging from vacuolar degeneration to acute cellular swelling). PMID- 25557795 TI - Transpositional shuffling and quality control in male germ cells to enhance evolution of complex organisms. AB - Complex organisms, particularly mammals, have long generation times and produce small numbers of progeny that undergo increasingly entangled developmental programs. This reduces the ability of such organisms to explore evolutionary space, and, consequently, strategies that mitigate this problem likely have a strategic advantage. Here, we suggest that animals exploit the controlled shuffling of transposons to enhance genomic variability in conjunction with a molecular screening mechanism to exclude deleterious events. Accordingly, the removal of repressive DNA-methylation marks during male germ cell development is an evolved function that exploits the mutagenic potential of transposable elements. A wave of transcription during the meiotic phase of spermatogenesis produces the most complex transcriptome of all mammalian cells, including genic and noncoding sense-antisense RNA pairs that enable a genome-wide quality-control mechanism. Cells that fail the genomic quality test are excluded from further development, eventually resulting in a positively selected mature sperm population. We suggest that these processes, enhanced variability and stringent molecular quality control, compensate for the apparent reduced potential of complex animals to adapt and evolve. PMID- 25557794 TI - Tumour cell-derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth. AB - The contributions of mesenchymal stem cells (MSCs) to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs). We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell-derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell-derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can "educate" MSCs to induce local microenvironmental changes that enhance tumour cell growth. PMID- 25557796 TI - Coherent neocortical gamma oscillations decrease during REM sleep in the rat. AB - Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the high frequency band (30-100 Hz) of the electroencephalogram (EEG), that have been postulated to be a product of this interaction, are involved in the binding of spatially separated but temporally correlated neural events, which results in a unified perceptual experience. The extent of this functional connectivity can be examined by means of the mathematical algorithm called "coherence", which is correlated with the "strength" of functional interactions between cortical areas. As a continuation of previous studies in the cat [6,7], the present study was conducted to analyze EEG coherence in the gamma band of the rat during wakefulness (W), non-REM (NREM) sleep and REM sleep. Rats were implanted with electrodes in different cortical areas to record EEG activity, and the magnitude squared coherence values within the gamma frequency band of EEG (30-48 and 52-100 Hz) were determined. Coherence between all cortical regions in the low and high gamma frequency bands was greater during W compared with sleep. Remarkably, EEG coherence in the low and high gamma bands was smallest during REM sleep. We conclude that high frequency interactions between cortical areas are radically different during sleep and wakefulness in the rat. Since this feature is conserved in other mammals, including humans, we suggest that the uncoupling of gamma frequency activity during REM sleep is a defining trait of REM sleep in mammals. PMID- 25557797 TI - Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid. AB - Autism is a severe neurodevelopmental disorder with a population prevalence of 1 in 68, and dramatically increasing. While no single pharmacologic intervention has successfully targeted the core symptoms of autism, emerging evidence suggests that postnatal environmental manipulations may offer greater therapeutic efficacy. Massage therapy, or tactile stimulation (TS), early in life has repeatedly been shown to be an effective, low-cost, therapeutic approach in ameliorating the cognitive, social, and emotional symptoms of autism. While early TS treatment attenuates many of the behavioral aberrations among children with autism, the neuroanatomical correlates driving such changes are unknown. The present study assessed the therapeutic effects of early TS treatment on behavior and neuroanatomy using the valproic acid (VPA) rodent model of autism. Rats were prenatally exposed to VPA on gestational day 12.5 and received TS shortly following birth. Whereas TS reversed almost all the VPA-induced alterations in neuroanatomy, it failed to do so behaviorally. The TS VPA animals, when compared to VPA animals, did not exhibit altered or improved behavior in the delayed non match-to-sample T-maze, Whishaw tray reaching, activity box, or elevated plus maze tasks. Anatomically, however, there were significant increases in dendritic branching and spine density in the medial prefrontal cortex, orbital frontal cortex, and amygdala in VPA animals following early TS treatment, suggesting a complete reversal or remediation of the VPA-induced effects in these regions. The results suggest that postnatal TS, during a critical period in development, acts as a powerful reorganization tool that can ameliorate the neuroanatomical consequences of prenatal VPA exposure. PMID- 25557798 TI - Adenosine A1 receptor activation modulates N-methyl-d-aspartate (NMDA) preconditioning phenotype in the brain. AB - N-methyl-d-aspartate (NMDA) preconditioning is induced by subtoxic doses of NMDA and it promotes a transient state of resistance against subsequent lethal insults. Interestingly, this mechanism of neuroprotection depends on adenosine A1 receptors (A1R), since blockade of A1R precludes this phenomenon. In this study we evaluated the consequences of NMDA preconditioning on the hippocampal A1R biology (i.e. expression, binding properties and functionality). Accordingly, we measured A1R expression in NMDA preconditioned mice (75mg/kg, i.p.; 24h) and showed that neither the total amount of receptor, nor the A1R levels in the synaptic fraction was altered. In addition, the A1R binding affinity to the antagonist [(3)H] DPCPX was slightly increased in total membrane extracts of hippocampus from preconditioned mice. Next, we evaluated the impact of NMDA preconditioning on A1R functioning by measuring the A1R-mediated regulation of glutamate uptake into hippocampal slices and on behavioral responses in the open field and hot plate tests. NMDA preconditioning increased glutamate uptake into hippocampal slices without altering the expression of glutamate transporter GLT 1. Interestingly, NMDA preconditioning also induced antinociception in the hot plate test and both effects were reversed by post-activation of A1R with the agonist CCPA (0.2mg/kg, i.p.). NMDA preconditioning or A1R modulation did not alter locomotor activity in the open field. Overall, the results described herein provide new evidence that post-activation of A1R modulates NMDA preconditioning mediated responses, pointing to the importance of the cross-talk between glutamatergic and adenosinergic systems to neuroprotection. PMID- 25557800 TI - Acute and chronic alcohol administration: effects on performance of zebrafish in a latent learning task. AB - Alcohol abuse is a major medical problem. Zebrafish have been proposed to model alcohol related human disorders. Alcohol impairs learning and memory. Here, we analyze the effects of alcohol on performance of zebrafish in a recently developed latent learning paradigm. We employ a 2*3*2 experimental design (chronic*acute alcohol treatment*path blocked). The latent learning task had two phases: one, 30min long exploration trials (16 days, 1 trial/day) with left or right path of a complex maze blocked, and two, a subsequent probe trial with all paths open leading to a goal box that now contained stimulus fish. During the 16 days each fish received one of two chronic treatments: freshwater or 0.50% (v/v%) alcohol. Subsequently, fish were immersed for 1h in one of the following solutions: 0.00 (freshwater), 0.50% or 1.00% alcohol, the acute challenge. Behavior of fish was recorded during the probe trial that commenced immediately after the acute treatment. Path choices, latency to leave the start box and to enter the goal box, time spent in the goal box, distance traveled, and duration of freezing were quantified. We found that acute exposure to 1.00% alcohol after chronic freshwater disrupted learning performance, so did exposure to freshwater after chronic alcohol treatment (withdrawal). We also found exposure to chronic alcohol to diminish the effect of subsequent acute alcohol suggesting development of tolerance. Our results demonstrate that analysis of learning performance of zebrafish allows detection of alcohol-induced functional changes. The simplicity and scalability of the employed task also imply the utility of the zebrafish in high throughput drug screens. PMID- 25557799 TI - Sex differences in sensitivity to the social consequences of acute ethanol and social drinking during adolescence. AB - In human adolescents, sociable males frequently drink to enhance positive emotional states, whereas anxious females often drink to avoid negative affective states. This study used a rat model of adolescence to provide information regarding possible sex differences in contributors to social drinking. The effects of ethanol (0, 0.5, and 0.75g/kg) on play fighting and social preference were assessed on P30, P32, and P34 using a within-subject design. Then animals were tested in a social drinking paradigm (P37-P40), with this testing revealing high drinkers and low drinkers. Sex differences in sensitivity to ethanol emerged among high and low drinkers. High socially drinking males, but not females, when tested prior to drinking sessions, showed significant increases in play fighting at both doses. In low drinking males, play fighting was increased by 0.5g/kg ethanol, whereas the higher dose of 0.75g/kg produced significant decreases in play fighting. High drinking females initially showed low levels of social preference than high drinking males and low drinking females and were extremely sensitive to ethanol-induced enhancement of this social measure. Low social drinkers, both males and females, were more sensitive to the suppressing effects of ethanol on social preference following 0.75g/kg ethanol. These findings indicate that during adolescence enhanced sensitivity to the facilitating effects of ethanol on play fighting is associated with heavy drinking among males, whereas low social preference together with high sensitivity to ethanol-induced enhancement of social preference is related to high social drinking in females. PMID- 25557802 TI - Calcineurin inhibitor-sparing regimens based on mycophenolic acid after kidney transplantation. AB - The use of calcineurin inhibitors (CNIs) has dramatically reduced the number of acute rejections and improved kidney allograft survival. However, CNIs can also cause kidney damage and several adverse events. This has prompted transplant physicians to use CNI-sparing regimens. CNI withdrawal, minimization, or avoidance protocols have been conducted using mycophenolic acid (MPA), and/or mammalian-target-of-rapamycin inhibitors, and/or belatacept. Herein, we review the outcomes of minimizing, withdrawing, or avoiding CNIs when giving mycophenolic acid to de novo and maintenance kidney transplant patients. Protocols on CNI withdrawal, when based on MPA without mammalian-target-of rapamycin inhibitors (mTORi) or belatacept, in de novo and maintenance kidney transplant patients, are associated with an increased risk of acute rejection. Consequently, these strategies have been abandoned and are not recommended. Protocols on CNI minimization show a beneficial impact of kidney function and acceptable acute rejection rates mainly in patients who have been recipients of a graft for >3-5 years. However, no significant improvement to graft survival has been observed. PMID- 25557804 TI - The effects of salinity on swimming performance of two estuarine fishes, Fundulus heteroclitus and Fundulus majalis. AB - Prolonged and high-speed swimming performance measurements were used to explore the swimming abilities of two species of estuarine fishes, the mummichog Fundulus heteroclitus and the striped killifish Fundulus majalis, under different salinities. Critical swimming performance was significantly higher for F. majalis in high salinity than in low salinity, but no difference was observed in brief constant acceleration swimming trials in this species; however, the swimming performance of F. heteroclitus was not significantly affected by salinity changes, indicating that this species is well adapted to regular estuarine salinity oscillations. Fundulus majalis displayed higher swimming speeds than F. heteroclitus in both high and low salinities, and while this cannot be explained by their respective salinity preferences, the specific habitat preferences of F. majalis for sandy subtidal habitats and F. heteroclitus for vegetated marshes could explain the better swimming performance of F. majalis. PMID- 25557801 TI - Bidirectional amygdaloid control of neuropathic hypersensitivity mediated by descending serotonergic pathways acting on spinal 5-HT3 and 5-HT1A receptors. AB - Amygdala is involved in processing of primary emotions and particularly its central nucleus (CeA) also in pain control. Here we studied mechanisms mediating the descending control of mechanical hypersensitivity by the CeA in rats with a peripheral neuropathy in the left hind limb. For drug administrations, the animals had a guide cannula in the right CeA and an intrathecal catheter or another guide cannula in the medullary raphe. Hypersensitivity was tested with monofilaments. Glutamate administration in the CeA produced a bidirectional effect on hypersensitivity that varied from an increase at a low-dose (9MUg) to a reduction at high doses (30-100MUg). The increase but not the reduction of hypersensitivity was prevented by blocking the amygdaloid NMDA receptor with a dose of MK-801 that alone had no effects. The glutamate-induced increase in hypersensitivity was reversed by blocking the spinal 5-HT3 receptor with ondansetron, whereas the reduction in hypersensitivity was reversed by blocking the spinal 5-HT1A receptor with WAY-100635. Both the increase and decrease of hypersensitivity induced by amygdaloid glutamate treatment were reversed by medullary administration of a 5-HT1A agonist, 8-OH-DPAT, that presumably produced autoinhibition of serotonergic cell bodies in the medullary raphe. The results indicate that depending on the dose, glutamate in the CeA has a descending facilitatory or inhibitory effect on neuropathic pain hypersensitivity. Serotoninergic raphe neurons are involved in mediating both of these effects. Spinally, the 5-HT3 receptor contributes to the increase and the 5-HT1A receptor to the decrease of neuropathic hypersensitivity induced by amygdaloid glutamate. PMID- 25557805 TI - Paediatric infectious diseases: the last 50 years. AB - Many advances and challenges have occurred in the field of paediatric infectious diseases during the past 50 years. It is impossible to cover all of these in a short review, but a few highlights and lowlights will be covered. These include virtual disappearance of some infectious diseases, emergence of new ones, infections in the immunocompromised, antimicrobial resistance, development of new and improved antimicrobials, improved diagnostic tests and the Human Microbiome Project. PMID- 25557806 TI - Body composition parameters and adipokines levels in relation to bone mineral density in patients with malignant bone tumors after treatment. AB - BACKGROUND: Recent data support the concept that adipokines, which are secreted by fat cells, are important modulators of bone metabolism. The aim of this study was to assess the relationships between body composition parameters, adipokines (leptin, adiponectin) and bone mineral density (BMD) in patients with malignant bone tumors after anticancer therapy. PROCEDURE: The study included 35 patients (median age 14.8 years) with diagnosed malignant bone tumors treated according to obligatory protocols. Total fat mass, lean mass, bone mineral content (BMC) and BMD measurements were performed after treatment completion by dual energy-ray absorptiometry (DXA). Serum concentrations of leptin, leptin receptor and adiponectin were determined using immunoenzymatic assays. The control group consisted of 28 healthy children (median age 14.3 years). RESULTS: Patients with bone tumor after chemotherapy had significantly higher fat mass (P < 0.01), increased ratio of fat mass/lean mass (P < 0.001), and a decrease (P < 0.001) in total body and lumbar spine BMD compared with controls. We observed higher serum leptin concentration (P < 0.01) and lower soluble leptin receptor (P < 0.001) and adiponectin (P = 0.01) in patients than in controls. The ratios of leptin/leptin receptor and leptin/adiponectin were about three-fold higher in patients compared with the control group (P = 0.001). We found a significant positive correlation between BMD and body composition and a negative correlation between BMD and adiponectin in the patients group. CONCLUSIONS: Changes in body composition parameters coexisting with disturbed adipokine levels, especially higher levels of leptin and lower levels of adiponectin, might be associated with bone status in patients treated for malignant bone tumors. PMID- 25557807 TI - Willingness to pay for continued delivery of a lifestyle-based weight loss program: The Hopkins POWER trial. AB - OBJECTIVE: In behavioral studies of weight loss programs, participants typically receive interventions free of charge. Understanding an individual's willingness to pay (WTP) for weight loss programs could be helpful when evaluating potential funding models. This study assessed WTP for the continuation of a weight loss program at the end of a weight loss study. METHODS: WTP was assessed with monthly coaching contacts at the end of the two-year Hopkins POWER trial. Interview administered questionnaires determined the amount participants were willing to pay for continued intervention. Estimated maximum payment was calculated among those willing to pay and was based on quantile regression adjusted for age, body mass index, race, sex, household income, treatment condition, and weight change at 24 months. RESULTS: Among the participants (N=234), 95% were willing to pay for continued weight loss intervention; the adjusted median payment was $45 per month. Blacks had a higher adjusted median WTP ($65/month) compared to Non-Blacks ($45/month), P=0.021. CONCLUSIONS: A majority of participants were willing to pay for a continued weight loss intervention with a median monthly amount that was similar to the cost of commercial weight loss programs. PMID- 25557808 TI - Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: a review. AB - OBJECTIVES: In this paper, we focused on essential oils and their constituents as skin penetration enhancers for transdermal drug delivery, mechanism of their action as well as their possible toxicity. KEY FINDINGS: Essential oils and their volatile constituents can penetrate through the skin as well as enhance penetration of different drug from topical formulation into the lower skin layers using different mechanisms of action based on (1) disintegration of the highly ordered intercellular lipid structure between corneocytes in stratum corneum, (2) interaction with intercellular domain of protein, which induces their conformational modification, (3) increase the partitioning of a drug. After application to the skin, essential oils and their components are rapidly metabolized, not accumulated in the organism and fast excreted what strongly suggest that they can be successfully use as safe penetration enhancers. SUMMARY: Essential oils and their constituents may be preferred over the traditionally used synthetics materials as safe and suitable permeation enhancers to promote the percutaneous absorption of hydrophilic and lipophilic drugs from topical formulation into the lower skin layers. PMID- 25557809 TI - A Candidate Single Nucleotide Polymorphism in the 3' Untranslated Region of Stearoyl-CoA Desaturase Gene for Fatness Quality and the Gene Expression in Berkshire Pigs. AB - Fatness qualities in pigs measured by the amount of fat deposition and composition of fatty acids (FAs) in pork have considerable effect on current breeding goals. The stearoyl-CoA desaturase (SCD) gene plays a crucial role in the conversion of saturated FAs into monounsaturated FAs (MUFAs), and hence, is among the candidate genes responsible for pig fatness traits. Here, we identified a single nucleotide polymorphism (SNP, c.*2041T>C) in the 3' untranslated region by direct sequencing focused on coding and regulatory regions of porcine SCD. According to the association analysis using a hundred of Berkshire pigs, the SNP was significantly associated with FA composition (MUFAs and polyunsaturated FAs [PUFAs]), polyunsaturated to saturated (P:S) FA ratio, n-6:n-3 FA ratio, and extent of fat deposition such as intramuscular fat and marbling (p<0.05). In addition, the SNP showed a significant effect on the SCD mRNA expression levels (p = 0.041). Based on our results, we suggest that the SCD c.*2041T>C SNP plays a role in the gene regulation and affects the fatness qualities in Berkshire pigs. PMID- 25557810 TI - Sequencing and Characterization of Divergent Marbling Levels in the Beef Cattle (Longissimus dorsi Muscle) Transcriptome. AB - Marbling is an important trait regarding the quality of beef. Analysis of beef cattle transcriptome and its expression profile data are essential to extend the genetic information resources and would support further studies on beef cattle. RNA sequencing was performed in beef cattle using the Illumina High-Seq2000 platform. Approximately 251.58 million clean reads were generated from a high marbling (H) group and low marbling (L) group. Approximately 80.12% of the 19,994 bovine genes (protein coding) were detected in all samples, and 749 genes exhibited differential expression between the H and L groups based on fold change (>1.5-fold, p<0.05). Multiple gene ontology terms and biological pathways were found significantly enriched among the differentially expressed genes. The transcriptome data will facilitate future functional studies on marbling formation in beef cattle and may be applied to improve breeding programs for cattle and closely related mammals. PMID- 25557811 TI - Bovine Genome-wide Association Study for Genetic Elements to Resist the Infection of Foot-and-mouth Disease in the Field. AB - Foot-and-mouth disease (FMD) is a highly contagious disease affecting cloven hoofed animals and causes severe economic loss and devastating effect on international trade of animal or animal products. Since FMD outbreaks have recently occurred in some Asian countries, it is important to understand the relationship between diverse immunogenomic structures of host animals and the immunity to foot-and-mouth disease virus (FMDV). We performed genome wide association study based on high-density bovine single nucleotide polymorphism (SNP) chip for identifying FMD resistant loci in Holstein cattle. Among 624532 SNP after quality control, we found that 11 SNPs on 3 chromosomes (chr17, 22, and 15) were significantly associated with the trait at the p.adjust <0.05 after PERMORY test. Most significantly associated SNPs were located on chromosome 17, around the genes Myosin XVIIIB and Seizure related 6 homolog (mouse)-like, which were associated with lung cancer. Based on the known function of the genes nearby the significant SNPs, the FMD resistant animals might have ability to improve their innate immune response to FMDV infection. PMID- 25557812 TI - Zearalenone Altered the Serum Hormones, Morphologic and Apoptotic Measurements of Genital Organs in Post-weaning Gilts. AB - The present study was aimed at investigating the adverse effects of dietary zearalenone (ZEA) (1.1 to 3.2 mg/kg diet) on serum hormones, morphologic and apoptotic measurements of genital organs in post-weaning gilts. A total of twenty gilts (Landrace*Yorkshire*Duroc) weaned at 21 d with an average body weight of 10.36+/-1.21 kg were used in the study. Gilts were fed a basal diet with an addition of 0, 1.1, 2.0, or 3.2 mg/kg purified ZEA for 18 d ad libitum. Results showed that 3.2 mg/kg ZEA challenged gilts decreased (p<0.05) the serum levels of luteinizing hormone, however, serum levels of prolactin in gilts fed the diet containing 2.0 mg/kg ZEA or more were increased (p<0.05) compared to those in the control. Linear effects on all tested serum hormones except progesterone were observed as dietary ZEA levels increased (p<0.05). Gilts fed ZEA-contaminated diet showed increase (p<0.05) in genital organs size, hyperplasia of submucosal smooth muscles in the corpus uteri in a dose-dependent manner. However, the decreased numbers of follicles in the cortex and apoptotic cells in the ovarian were observed in gilts treated with ZEA in a dose-dependent manner. Degeneration and structural abnormalities of genital organs tissues were also observed in the gilts fed diet containing 1.1 mg/kg ZEA or more. Results suggested that dietary ZEA at 1.1 to 3.2 mg/kg can induce endocrine disturbance and damage genital organs in post-weaning gilts. PMID- 25557813 TI - Effect of By-product Feed-based Silage Feeding on the Performance, Blood Metabolites, and Carcass Characteristics of Hanwoo Steers (a Field Study). AB - This study was conducted to determine the effects of feeding by-product feed (BF) based silage on the performance, blood metabolite parameters, and carcass characteristics of Hanwoo steers. The BF-based silage was composed of 50% spent mushroom substrate, 21% recycled poultry bedding, 15% cut ryegrass straw, 10.8% rice bran, 2% molasses, 0.6% bentonite, and 0.6% microbial additive (on a wet basis), and ensiled for over 5 d. Fifteen steers were allocated to three diets during the growing and fattening periods (3.1 and 9.8 months, respectively): a control diet (concentrate mix and free access to rice straw), a 50% BF-based silage diet (control diet+50% of maximum BF-based silage intake), and a 100% BF based silage diet (the same amount of concentrate mix and ad libitum BF-based silage). The BF-based silage was fed during the growing and fattening periods, and was replaced with larger particles of rice straw during the finishing period. After 19.6 months of the whole period all the steers were slaughtered. Compared with feeding rice straw, feeding BF-based silage tended (p = 0.10) to increase the average daily gain (27%) and feed efficiency (18%) of the growing steers, caused by increased voluntary feed intake. Feeding BF-based silage had little effect on serum constituents, electrolytes, enzymes, or the blood cell profiles of fattening steers, except for low serum Ca and high blood urea concentrations (p<0.05). Feeding BF-based silage did not affect cold carcass weight, yield traits such as back fat thickness, longissimus muscle area, yield index or yield grade, or quality traits such as meat color, fat color, texture, maturity, marbling score, or quality grade. However, it improved good quality grade (1(+) and 1(++)) appearance rates (60% for the control group vs 100% for the BF-based silage-fed groups). In conclusion, cheap BF-based silage could be successfully used as a good quality roughage source for beef cattle. PMID- 25557814 TI - Effect of Tannin and Species Variation on In vitro Digestibility, Gas, and Methane Production of Tropical Browse Plants. AB - Nineteen tanniferous browse plants were collected from South Africa to investigate their digestibility, gas production (GP) characteristics and methane production. Fresh samples were collected, dried in forced oven, and ground and analyzed for nutrient composition. In vitro GP and in vitro organic matter digestibility (IVOMD) were determined using rumen fluid collected, strained and anaerobically prepared. A semi- automated system was used to measure GP by incubating the sample in a shaking incubator at 39 degrees C. There was significant (p<0.05) variation in chemical composition of studied browses. Crude protein (CP) content of the species ranged from 86.9 to 305.0 g/kg dry matter (DM). The neutral detergent fiber (NDF) ranged from 292.8 to 517.5 g/kg DM while acid detergent fiber (ADF) ranged from 273.3 to 495.1 g/kg DM. The ash, ether extract, non-fibrous carbohydrate, neutral detergent insoluble nitrogen, and acid detergent insoluble nitrogen and CP were negatively correlated with methane production. Methane production was positively correlated with NDF, ADF, cellulose and hemi-cellulose. Tannin decreased GP, IVOMD, total volatile fatty acid and methane production. The observed low methanogenic potential and substantial ammonia generation of some of the browses might be potentially useful as rumen manipulating agents. However, a systematic evaluation is needed to determine optimum levels of supplementation in a mixed diet in order to attain a maximal depressing effect on enteric CH4 production with a minimal detrimental effect on rumen fermentation of poor quality roughage based diet. PMID- 25557816 TI - Effect of High Dietary Carbohydrate on the Growth Performance, Blood Chemistry, Hepatic Enzyme Activities and Growth Hormone Gene Expression of Wuchang Bream (Megalobrama amblycephala) at Two Temperatures. AB - The effects of high carbohydrate diet on growth, serum physiological response, and hepatic heat shock protein 70 expression in Wuchang bream were determined at 25 degrees C and 30 degrees C. At each temperature, the fish fed the control diet (31% CHO) had significantly higher weight gain, specific growth rate, protein efficiency ratio and hepatic glucose-6-phosphatase activities, lower feed conversion ratio and hepatosomatic index (HSI), whole crude lipid, serum glucose, hepatic glucokinase (GK) activity than those fed the high-carbohydrate diet (47% CHO) (p<0.05). The fish reared at 25 degrees C had significantly higher whole body crude protein and ash, serum cholesterol and triglyceride, hepatic G-6-Pase activity, lower glycogen content and relative levels of hepatic growth hormone (GH) gene expression than those reared at 30 degrees C (p<0.05). Significant interaction between temperature and diet was found for HSI, condition factor, hepatic GK activity and the relative levels of hepatic GH gene expression (p<0.05). PMID- 25557815 TI - Responses of blood glucose, insulin, glucagon, and Fatty acids to intraruminal infusion of propionate in hanwoo. AB - This study was carried out to investigate the effects of intraruminal infusion of propionate on ruminal fermentation characteristics and blood hormones and metabolites in Hanwoo (Korean cattle) steers. Four Hanwoo steers (average body wt. 270 kg, 13 month of age) equipped with rumen cannula were infused into rumens with 0.0 M (Water, C), 0.5 M (37 g/L, T1), 1.0 M (74 g/L, T2) and 1.5 M (111 g/L, T3) of propionate for 1 hour per day and allotted by 4*4 Latin square design. On the 5th day of infusion, samples of rumen and blood were collected at 0, 60, 120, 180, and 300 min after intraruminal infusion of propionate. The concentrations of serum glucose and plasma glucagon were not affected (p>0.05) by intraruminal infusion of propionate. The serum insulin concentration at 60 min after infusion was significantly (p<0.05) higher in T3 than in C, while the concentration of non esterified fatty acid (NEFA) at 60 and 180 min after infusion was significantly (p<0.05) lower in the propionate treatments than in C. Hence, intraruminal infusion of propionate stimulates the secretion of insulin, and decreases serum NEFA concentration rather than the change of serum glucose concentration. PMID- 25557817 TI - Addition of a worm leachate as source of humic substances in the drinking water of broiler chickens. AB - The objective of this research was to evaluate the growth performance, the apparent ileal digestibility of nitrogen and energy, the retention of nutrients and the apparent metabolizable energy corrected to zero nitrogen retention (AMEn) in broiler chickens supplemented with increasing doses of a worm leachate (WL) as a source of humic substances (HS) in the drinking water. In Exp. 1, 140 male broilers were penned individually and assigned to four WL levels (0%, 10%, 20%, and 30%) mixed in the drinking water from 21 to 49 days of age. Water was offered in plastic bottles tied to the cage. In Exp. 2, 600 male broilers from 21 to 49 days of age housed in floor pens were assigned to three levels of WL (0%, 10%, and 20%) mixed in the drinking water. The WL was mixed with tap water in plastic containers connected by plastic tubing to bell drinkers. The results of both experiments were subjected to analysis of variance and polynomial contrasts. In Exp. 1, the daily water consumption was similar among treatments but the consumption of humic, fulvic, and total humic acids increased linearly (p<0.01) as the WL increased in the drinking water. The feed conversion (p<0.01) and the ileal digestibility of energy, the excretion of dry matter and energy, the retention of dry matter, ash and nitrogen and the AMEn showed quadratic responses (p<0.05) relative to the WL levels in drinking water. In Exp. 2, the increasing level of WL in the drinking water had quadratic effects on the final body weight, daily weight gain and feed conversion ratio (p<0.05). The addition of WL as a source of HS in the drinking water had beneficial effects on the growth performance, ileal digestibility of energy, the retention of nutrients as well on the AMEn in broiler chickens; the best results were observed when the WL was mixed at levels of 20% to 30% in the drinking water. PMID- 25557818 TI - Effects of Dietary Coconut Oil as a Medium-chain Fatty Acid Source on Performance, Carcass Composition and Serum Lipids in Male Broilers. AB - This study was conducted to investigate the effects of dietary coconut oil as a medium-chain fatty acid (MCFA) source on performance, carcass composition and serum lipids in male broilers. A total of 540, one-day-old, male Arbor Acres broilers were randomly allotted to 1 of 5 treatments with each treatment being applied to 6 replicates of 18 chicks. The basal diet (i.e., R0) was based on corn and soybean meal and was supplemented with 1.5% soybean oil during the starter phase (d 0 to 21) and 3.0% soybean oil during the grower phase (d 22 to 42). Four experimental diets were formulated by replacing 25%, 50%, 75%, or 100% of the soybean oil with coconut oil (i.e., R25, R50, R75, and R100). Soybean oil and coconut oil were used as sources of long-chain fatty acid and MCFA, respectively. The feeding trial showed that dietary coconut oil had no effect on weight gain, feed intake or feed conversion. On d 42, serum levels of total cholesterol, low density lipoprotein cholesterol, and low-density lipoprotein/high-density lipoprotein cholesterol were linearly decreased as the coconut oil level increased (p<0.01). Lipoprotein lipase, hepatic lipase, and total lipase activities were linearly increased as the coconut oil level increased (p<0.01). Abdominal fat weight/eviscerated weight (p = 0.05), intermuscular fat width (p<0.01) and subcutaneous fat thickness (p<0.01) showed a significant quadratic relationship, with the lowest value at R75. These results indicated that replacement of 75% of the soybean oil in diets with coconut oil is the optimum level to reduce fat deposition and favorably affect lipid profiles without impairing performance in broilers. PMID- 25557819 TI - Nutritional Value of Rice Bran Fermented by Bacillus amyloliquefaciens and Humic Substances and Its Utilization as a Feed Ingredient for Broiler Chickens. AB - An experiment was conducted to increase the quality of rice bran by fermentation using Bacillus amyloliquefaciens and humic substances and its utilization as a feed ingredient for broiler chickens. The experiment was carried out in two steps. First, the fermentation process was done using a completely randomized design in factorial with 16 treatments: i) Dosage of B. amyloliquefaciens (2.10(8) cfu/g), 10 and 20 g/kg; ii) Graded levels of humic substances, 0, 100, 200, and 400 ppm; iii) Length of fermentation, three and five days. The results showed that the fermentation significantly (p<0.05) reduced crude fiber content. The recommended conditions for fermentation of rice bran: 20 g/kg dosage of inoculums B. amyloliquefaciens, 100 ppm level of humic substances and three days fermentation period. The second step was a feeding trial to evaluate the fermented rice bran (FRB) as a feed ingredient for broiler chickens. Three hundred and seventy-five one-day-old broiler chicks were randomly assigned into five treatment diets. Arrangement of the diets as follows: 0%, 5%, 10%, 15%, and 20% level of FRB and the diets formulation based on equal amounts of energy and protein. The results showed that 15% inclusion of FRB in the diet provided the best bodyweight gain and feed conversion ratio (FCR) values. In conclusion, the nutrient content of rice bran improved after fermentation and the utilization of FRB as a feed ingredient for broiler chickens could be included up to 15% of the broiler diet. PMID- 25557820 TI - Effect of Bacillus amyloliquefaciens-based Direct-fed Microbial on Performance, Nutrient Utilization, Intestinal Morphology and Cecal Microflora in Broiler Chickens. AB - The present study was conducted to evaluate the effect of the dietary supplementation of Bacillus amyloliquefaciens-based direct-fed microbial (DFM) on growth performance, nutrient utilization, intestinal morphology and cecal microflora in broiler chickens. A total of two hundred and eighty eight 1-d-old Arbor Acres male broilers were randomly allocated to one of four experimental treatments in a completely randomized design. Each treatment was fed to eight replicate cages, with nine birds per cage. Dietary treatments were composed of an antibiotic-free basal diet (control), and the basal diet supplemented with either 15 mg/kg of virginiamycin as antibiotic growth promoter (AGP), 30 mg/kg of Bacillus amyloliquefaciens-based DFM (DFM 30) or 60 mg/kg of Bacillus amyloliquefaciens-based DFM (DFM 60). Experimental diets were fed in two phases: starter (d 1 to 21) and finisher (d 22 to 42). Growth performance, nutrient utilization, morphological parameters of the small intestine and cecal microbial populations were measured at the end of the starter (d 21) and finisher (d 42) phases. During the starter phase, DFM and virginiamycin supplementation improved the feed conversion ratio (FCR; p<0.01) compared with the control group. For the finisher phase and the overall experiment (d 1 to 42) broilers fed diets with the DFM had better body weight gain (BWG) and FCR than that of control (p<0.05). Supplementation of virginiamycin and DFM significantly increased the total tract apparent digestibility of crude protein (CP), dry matter (DM) and gross energy during both starter and finisher phases (p<0.05) compared with the control group. On d 21, villus height, crypt depth and villus height to crypt depth ratio of duodenum, jejunum, and ileum were significantly increased for the birds fed with the DFM diets as compared with the control group (p<0.05). The DFM 30, DFM 60, and AGP groups decreased the Escherichia coli population in cecum at d 21 and d 42 compared with control group (p<0.01). In addition, the population of Lactobacillus was increased in DFM 30 and DFM 60 groups as compared with control and AGP groups (p<0.01). It can be concluded that Bacillus amyloliquefaciens based DFM could be an alternative to the use of AGPs in broilers diets based on plant protein. PMID- 25557821 TI - Effects of onion extracts on growth performance, carcass characteristics and blood profiles of white mini broilers. AB - This experiment was carried out to investigate effects of onion extract on growth performance, meat quality and blood profiles of White mini broilers. Total of 600 one-d-old male White mini broiler chicks were divided into four groups and fed control diets (non-medicated commercial diet or antibiotics medicated) or experimental diets (non-medicated diets containing 0.3% or 0.5% onion extract) for 5 wks. The final body weight (BW) and weight gain of the group fed non medicated control diet were lower than those of medicated control group (p<0.01). The chicks fed diet with 0.3% or 0.5% onion extract showed a similar BW to that of medicated control group. The relative weight of various organs, such as liver, spleen, bursa of Fabricius, abdominal fat, and the activities of serum enzymes were not affected by dietary treatments. There were no significant differences in meat color among groups. Whereas, groups fed diets containing onion extract had slightly lower cooking loss and higher shear force value, but not significantly. The concentrations of serum free cholesterol and triacylglycerol in groups fed diet containing onion extract were significantly decreased compared with those of controls (p<0.01). In conclusion, the onion extracts exerted a growth-promoting effect when added in White mini broiler diets, reflecting potential alternative substances to replace antibiotics. PMID- 25557822 TI - Efficacy of Sweet Potato Powder and Added Water as Fat Replacer on the Quality Attributes of Low-fat Pork Patties. AB - The present study was conducted to investigate the efficacy of sweet potato powder (SPP) and water as a fat replacer in low-fat pork patties. Low-fat pork patties were developed by replacing the added fat with combinations of SPP and chilled water. Three different levels of SPP/chilled water viz. 0.5/9.5% (T-1), 1.0/9.0% (T-2), and 1.5/8.5% (T-3) were compared with a control containing 10% animal fat. The quality of low-fat pork patties was evaluated for physico chemical (pH, emulsion stability, cooking yield, aw), proximate, instrumental colour and textural profile, and sensory attributes. The cooking yield and emulsion stability improved (p<0.05) in all treatments over the control and were highest in T-2. Instrumental texture profile attributes and hardness decreased, whereas cohesiveness increased compared with control, irrespective of SPP level. Dimensional parameters (% gain in height and % decrease in diameter) were better maintained during cooking in the low-fat product than control. The sensory quality attributes juiciness, texture and overall acceptability of T-2 and T-3 were (p<0.05) higher than control. Results concluded that low-fat pork patties with acceptable sensory attributes, improved cooking yield and textural attributes can be successfully developed with the incorporation of a combination of 1.0% SPP and 9.0% chilled water. PMID- 25557823 TI - Effect of different tumbling marination treatments on the quality characteristics of prepared pork chops. AB - The effect of different tumbling marination treatments (control group, CG; conventional static marination, SM; vacuum continuous tumbling marination, CT; vacuum intermittent tumbling marination, IT) on the quality characteristics of prepared pork chops was investigated under simulated commercial conditions. The CT treatment increased (p<0.05) the pH value, b* value, product yield, tenderness, overall flavor, sensory juiciness and overall acceptability in comparison to other treatments for prepared boneless pork chops. The CT treatment decreased (p<0.05) cooking loss, shear force value, hardness, gumminess and chewiness compared with other treatments. In addition, CT treatment effectively improved springiness and sensory color more than other treatments. However, IT treatment achieved the numerically highest (p<0.05) L* and a* values. These results suggested that CT treatment obtained the best quality characteristics of prepared pork chops and should be adopted as the optimal commercial processing method for this prepared boneless pork chops. PMID- 25557824 TI - Comparison of milk yield and animal health in Turkish farms with differing stall types and resting surfaces. AB - The current study was carried out to determine the influence of different resting surfaces and stall types on milk yield and animal health. Study was carried out in Bursa that is one of the most important cities of Turkey in terms of dairy production. Effects of resting surfaces and stall types on milk yield were found to be important. Also influence of different resting surfaces and stall types on lactation length was examined and found that rubber mats were different from the two other options. Relationships between different resting surfaces or stall types and health problems were examined and connection between stall type and repeat breeding (RB), dystocia, retained placenta and a connection between resting surface types and RB and clinical mastitis were found to be important. Considering their economic reflections, it can be said that results are quite important to the Turkish dairy industry. PMID- 25557825 TI - Interaction between Leptospiral Lipopolysaccharide and Toll-like Receptor 2 in Pig Fibroblast Cell Line, and Inhibitory Effect of Antibody against Leptospiral Lipopolysaccharide on Interaction. AB - Leptospiral lipopolysaccharide (L-LPS) has shown potency in activating toll-like receptor 2 (TLR2) in pig fibroblasts (PEFs_NCC1), and causes the expression of proinflammatory cytokines. However, the stimulation by L-LPS was weak eliciting the function of TLR2 sufficiently in pig innate immunity responses during Leptospira infection. In this study, the immune response of pig embryonic fibroblast cell line (PEFs_SV40) was investigated and was found to be the high immune response, thus TLR2 is the predominate receptor of L-LPS in pig cells. Further, we found a strategy using the antibody against L-LPS, to prevent L-LPS interaction with TLR2 in pig cells which could impact on immune activation. PMID- 25557826 TI - Biogas production from vietnamese animal manure, plant residues and organic waste: influence of biomass composition on methane yield. AB - Anaerobic digestion is an efficient and renewable energy technology that can produce biogas from a variety of biomasses such as animal manure, food waste and plant residues. In developing countries this technology is widely used for the production of biogas using local biomasses, but there is little information about the value of these biomasses for energy production. This study was therefore carried out with the objective of estimating the biogas production potential of typical Vietnamese biomasses such as animal manure, slaughterhouse waste and plant residues, and developing a model that relates methane (CH4) production to the chemical characteristics of the biomass. The biochemical methane potential (BMP) and biomass characteristics were measured. Results showed that piglet manure produced the highest CH4 yield of 443 normal litter (NL) CH4 kg(-1) volatile solids (VS) compared to 222 from cows, 177 from sows, 172 from rabbits, 169 from goats and 153 from buffaloes. Methane production from duckweed (Spirodela polyrrhiza) was higher than from lawn grass and water spinach at 340, 220, and 110.6 NL CH4 kg(-1) VS, respectively. The BMP experiment also demonstrated that the CH4 production was inhibited with chicken manure, slaughterhouse waste, cassava residue and shoe-making waste. Statistical analysis showed that lipid and lignin are the most significant predictors of BMP. The model was developed from knowledge that the BMP was related to biomass content of lipid, lignin and protein from manure and plant residues as a percentage of VS with coefficient of determination (R-square) at 0.95. This model was applied to calculate the CH4 yield for a household with 17 fattening pigs in the highlands and lowlands of northern Vietnam. PMID- 25557827 TI - Nanotechnology in meat processing and packaging: potential applications - a review. AB - Growing demand for sustainable production, increasing competition and consideration of health concerns have led the meat industries on a path to innovation. Meat industries across the world are focusing on the development of novel meat products and processes to meet consumer demand. Hence, a process innovation, like nanotechnology, can have a significant impact on the meat processing industry through the development of not only novel functional meat products, but also novel packaging for the products. The potential benefits of utilizing nanomaterials in food are improved bioavailability, antimicrobial effects, enhanced sensory acceptance and targeted delivery of bioactive compounds. However, challenges exist in the application of nanomaterials due to knowledge gaps in the production of ingredients such as nanopowders, stability of delivery systems in meat products and health risks caused by the same properties which also offer the benefits. For the success of nanotechnology in meat products, challenges in public acceptance, economics and the regulation of food processed with nanomaterials which may have the potential to persist, accumulate and lead to toxicity need to be addressed. So far, the most promising area for nanotechnology application seems to be in meat packaging, but the long term effects on human health and environment due to migration of the nanomaterials from the packaging needs to be studied further. The future of nanotechnology in meat products depends on the roles played by governments, regulatory agencies and manufacturers in addressing the challenges related to the application of nanomaterials in food. PMID- 25557828 TI - Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial. AB - BACKGROUND: The CURRENT-OASIS-7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin. OBJECTIVE: To explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite (AM) levels. METHODS: In part 1, using a 2 * 2 factorial design, we randomized patients to clopidogrel 600 mg loading dose (LD) followed by 150 mg day(-1) for 6 days and 75 mg day(-1) thereafter, or clopidogrel 300 mg LD followed by 75 mg day(-1) thereafter, and compared aspirin at 325 mg or 81 mg day(-1) . In part 2, patients were given a 600-mg clopidogrel LD, and were randomly allocated to aspirin 325 mg or 81 mg day(-1) . We combine the data from the two parts. Blood samples were collected 1 h after administration of the study drug. RESULTS: We randomized 302 patients (mean age 60.4 +/- 9.9 years). Clopidogrel AM levels were similar in patients randomized to aspirin 325 or 81 mg (geometric mean, 12.70 ng mL(-1) ; 95% CI, 10.96-14.72 ng mL(-1) ; and geometric mean, 12.55 ng mL(-1) ; 95% CI, 10.80-14.58 ng mL(-1) ; P = 0.91). Blood levels of clopidogrel were lower in CYP2C19*2 loss of-function (LOF) carriers compared with non-carriers (10.72 ng mL(-1) ; 95% CI, 8.83-13.01 ng mL(-1) ; and 15.21 ng mL(-1) ; 95% CI, 13.30-17.40 ng mL(-1) , respectively; P = 0.003) whereas levels in gain of function carriers and non carriers were similar (13.31 ng mL(-1) ; 95% CI, 11.53-15.35 ng mL(-1) ; and 14.07 ng mL(-1) ; 95% CI, 11.74-16.87 ng mL(-1) , respectively; P = 0.4). Independent baseline predictors of clopidogrel AM levels were LOF genotype, body mass index, diabetes, proton pump inhibitor use and creatinine clearance, but accounted for only 20% of the variability in levels. CONCLUSION: Aspirin dose does not predict clopidogrel AM levels 1 h post-LD. Most of the variability in clopidogrel AM levels is not explained by patient characteristics or CYP2C19 metabolizer status. PMID- 25557829 TI - Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats. AB - Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque-Dawley rats with common bile duct ligation induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6-cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice-weekly for 8 weeks)-induced cirrhotic rats. Caffeine down-regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho-VEGFR2, and phospho-Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. CONCLUSIONS: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH-related complications in cirrhosis. PMID- 25557830 TI - Identification of a subnuclear body involved in sequence-specific cytokine RNA processing. AB - Processing of interleukin RNAs must be tightly controlled during the immune response. Here we report that a subnuclear body called the interleukin-6 and -10 splicing activating compartment (InSAC) is a nuclear site of cytokine RNA production and stability. Tat-activating regulatory DNA-binding protein-43 (TDP 43) acts as an InSAC scaffold that selectively associates with IL-6 and IL-10 RNAs in a sequence-specific manner. TDP-43 also recruits key spliceosomal components from Cajal bodies. LPS induces posttranslational modifications of TDP 43; in particular, TDP-43 ubiquitination provides a driving force for InSAC formation. As a consequence, in vivo depletion of TDP-43 leads to a dramatic reduction in the RNA processing and the protein levels of IL-6 in serum. Collectively, our findings highlight the importance of TDP-43-mediated InSAC biogenesis in immune regulation. PMID- 25557831 TI - Identification of a major metabolite of danshensu in rat urine and simultaneous determination of danshensu and its metabolite in plasma: application to a pharmacokinetic study in rats. AB - Danshensu, as the effective component of Salvia miltiorrhiza (Danshen), has been widely used in clinical studies for treatment of cardiovascular diseases in China. A new metabolite, 4-hydroxy-3-methoxyphenyllactic acid was isolated from the urine of rats, and its chemical structure was identified by ultraviolet (UV), Infrared Spectroscopy (IR), mass spectrometry (MS) and nuclear magnetic resonance (NMR). Furthermore, a selective and sensitive high performance liquid chromatography-tandem mass spectrometric (HPLC-MS/MS) method was developed for the simultaneous quantification of danshensu and its major metabolite, 4-hydroxy 3-methoxyphenyllactic acid, in rat plasma after oral and intravenous administration of danshensu. The separation was performed on a Hypersil Gold C18 column (150 * 2.1 mm i.d., 3.0 um, Thermo, San jose CA, USA) with gradient elution using a mobile phase composed of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. Linear detection responses were obtained for danshensu and 4-hydroxy-3-methoxyphenyllactic acid ranging from 5 to 10000 ng/mL and 5 to 4000 ng/mL, respectively. The lower limits of quantification (LLOQs) for the two compounds were both 5 ng/mL. The intra-and inter-day precision (R.S.D %) were within 5.61% for the two analytes. The average recoveries of the analytes were greater than 72.43%. The method was proved to be stable during all sample storage, preparation and analytic procedures. This method was successfully applied to the pharmacokinetic studies of danshensu and 4 hydroxy-3-methoxyphenyllactic acid after oral and intravenous administration of danshensu in rats. PMID- 25557832 TI - C60/collapsed carbon nanotube hybrids: a variant of peapods. AB - We examine a variant of so-called carbon nanotube peapods by packing C60 molecules inside the open edge ducts of collapsed carbon nanotubes. C60 insertion is accomplished through a facile single-step solution-based process. Theoretical modeling is used to evaluate favorable low-energy structural configurations. Overfilling of the collapsed tubes allows infiltration of C60 over the full cross section of the tubes and consequent partial or complete reinflation, yielding few wall, large diameter cylindrical nanotubes packed with crystalline C60 solid cores. PMID- 25557833 TI - Clinical significance of DNA methylation mRNA levels of TET family members in colorectal cancer. AB - PURPOSE: Ten eleven translocation (TET) enzyme activity is essential for active DNA demethylation in biological processes, and their altered expression has been observed in various malignancies. Therefore, we investigated DNA methylation and mRNA levels of all TETs in colorectal cancer (CRC) patients. METHODS: TET mRNA levels were evaluated using quantitative RT-PCR in primary cancerous and histopathologically unchanged colorectal tissues from patients who underwent radical surgical colon resection (n = 113). DNA methylation levels of the TET CpG island were assessed using bisulfite DNA sequencing and high-resolution melting analysis. RESULTS: We found reduced transcript levels of TET1, TET2 and TET3 in cancerous tissue compared with their histopathologically unchanged counterparts (p = 0.000011; p = 0.000001; p = 0.00031, respectively). Importantly, multivariate Cox regression analysis revealed favorable overall survival (OS) and disease-free survival (DFS) outcomes for patients with high TET2 mRNA levels in histopathologically unchanged tissue (HR(OS) = 0.091, 95 % CI 0.011-0.77, p = 0.028; HR(DFS) = 0.21, 95 % CI 0.04-1.06, p = 0.059). Moreover, we found no DNA methylation in the TET2 and TET3 promoter regions in cancerous and histopathologically unchanged tissue. In contrast, we reported TET1 DNA hypermethylation in a small fraction of patients (n = 12/113). CONCLUSION: To best of our knowledge, our study is the first to investigate TET mRNA levels in a cohort of CRC patients and correlate them with patients' prognosis. Present study provides the evidence that TET2 mRNA expression may be an independent prognostic factor for disease recurrence and outcome. Additionally, our findings initially indicate the importance of DNA methylation in regulating TET1 expression. PMID- 25557834 TI - Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption. AB - The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24 h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-) baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature. PMID- 25557835 TI - Ethanol withdrawal increases oxidative stress and reduces nitric oxide bioavailability in the vasculature of rats. AB - We analyzed the effects of ethanol withdrawal on the vascular and systemic renin angiotensin system (RAS) and vascular oxidative stress. Male Wistar rats were treated with ethanol 3-9% (v/v) for a period of 21 days. Ethanol withdrawal was induced by abrupt discontinuation of the treatment. Experiments were performed 48 h after ethanol discontinuation. Rats from the ethanol withdrawal group showed decreased exploration of the open arms of the elevated-plus maze (EPM) and increased plasma corticosterone levels. Ethanol withdrawal significantly increased systolic blood pressure and plasma angiotensin II (ANG II) levels without an effect on plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, or plasma angiotensin I (ANG I) levels. No differences in vascular ANG I, ANG II levels, and ACE activity/expression and AT1 and AT2 receptor expression were detected among the experimental groups. Plasma osmolality, as well as plasma sodium, potassium, and glucose levels were not affected by ethanol withdrawal. Ethanol withdrawal induced systemic and vascular oxidative stress, as evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels and the vascular generation of superoxide anion. Ethanol withdrawal significantly decreased plasma and vascular nitrate/nitrite levels. Major new findings of the present study are that ethanol withdrawal induces vascular oxidative stress and reduces nitric oxide (NO) levels in the vasculature. Additionally, our study provides novel evidence that ethanol withdrawal does not affect the vascular ANG II generating system while stimulating systemic RAS. These responses could predispose individuals to the development of cardiovascular diseases. PMID- 25557836 TI - Evaluation of orange-brown precipitate formed in root canals after irrigation with chlorhexidine and QMix and spectroscopic analysis of precipitates produced by a mixture of chlorhexidine/NaOCl and QMix/NaOCl. AB - AIMS: (i) To compare chlorhexidine and QMix(TM) in terms of orange-brown precipitate generation in root canals and (ii) to analyse the precipitate produced by mixing chlorhexidine and QMix(TM) with NaOCl to determine whether para-chloroaniline was produced. METHODOLOGY: The root canals of 57 single-rooted anterior teeth were prepared using ProTaper Universal rotary instruments up to size F4. Two millilitres of 2.5% NaOCl was used between each instrument change. The specimens were then divided randomly into three groups (n = 19) and irrigated as follows: group 1, 5 mL of distilled water (control group) for 60 s; group 2, 5 mL of 2% chlorhexidine for 60 s; and group 3, 5 mL of QMix for 60 s. The roots were split longitudinally, and one of the halves was photographed using a stereomicroscope. The amount of orange-brown precipitate was evaluated using a four-grade scoring system. The data were analysed statistically using the Kruskal Wallis and Mann-Whitney U-tests (P = 0.05). To evaluate whether the precipitates included para-chloroaniline, 5 mL of 2% chlorhexidine and 5 mL QMix were separately mixed with 5 mL of 2.5% NaOCl in two flasks. After centrifugation, precipitates were obtained and analysed using (1) H NMR spectra. The data were subjected to statistical analysis using the Kruskal-Wallis and Mann-Whitney tests at a 95% confidence level (P = 0.05). RESULTS: Chlorhexidine had significantly higher scores than QMix(TM) in terms of orange-brown precipitate formed in the root canals (P < 0.001). According to the 1H NMR spectra, para-chloroaniline was present in the mixture of chlorhexidine and NaOCl. However, the mixture of QMix(TM) and NaOCl did not result in para-chloroaniline formation. CONCLUSION: QMix(TM) does not form para-chloroaniline when associated with NaOCl. PMID- 25557837 TI - Limb-bud and Heart (LBH) functions as a tumor suppressor of nasopharyngeal carcinoma by inducing G1/S cell cycle arrest. AB - Epstein-Barr virus-encoded latent membrane protein-1 (LMP1) plays a fundamental role in the malignant transformation of nasopharyngeal carcinoma (NPC), although the mechanism is not well understood. Here, we showed that Limb-bud and Heart (LBH) is considerably downregulated in patient NPC tissues. The expression of LBH in biopsies of 40 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines was also analyzed, and we found the LBH expression level was correlated with some of clinicopathological features, disease-specific survival (DSS), distant metastasis-free survival (DMFS). We further determined that LBH normally induces NPC cell cycle arrest at the G1/S transition, and LBH can suppress the growth of transplanted NPC tumors in vivo by downregulating LMP1-mediated NF-kappaB transcriptional activity. Transforming growth factor-beta 1 (TGF-beta1) normally protects against tumor development by suppressing cell proliferation, but NPC cells acquire resistance to TGF-beta1-mediated inhibition. We found that TGF-beta1 inhibits NF-kappaB transcriptional activity and nasopharyngeal epithelial cell proliferation through upregulating LBH expression. These data reveal a previously unknown NPC transformation mechanism and provide a new concept and treatment strategy for LMP1-driven oncogenesis in NPC. PMID- 25557838 TI - Zanamivir versus trivalent split virus influenza vaccine: a pilot randomized trial. AB - BACKGROUND: Healthcare workers may be exposed to people with respiratory viral infections more often than other working adults. Understanding the risk and the effectiveness of different preventive measures is of great importance. OBJECTIVES: To estimate adherence to prophylactic antiviral medication for a full influenza season, to the compare efficacy of antiviral prophylaxis to that of the seasonal influenza vaccine and to identify exposures that increase risk of acute respiratory illnesses (ARI) in healthy adults. METHODS: Participants were randomized 1:2 to receive the 2008-2009 influenza vaccine or daily prophylaxis with 10 mg of zanamivir during the season. Web-based questionnaires collected information on demographics, symptoms, exposures, medication use and side effects. RESULTS: Sixty-four healthy adults were recruited in November 2008. Three of 40 active participants discontinued zanamivir due to side effects; the remaining 37 took >85% of scheduled doses for a median of 121 days. Symptomatic, laboratory-confirmed influenza was detected in one person randomized to zanamivir (2.5%) and 2/20 (10%) who received the vaccine (P = 0.25). Forty-seven participants reported 109 episodes of ARI. Factors associated with an ARI were exposure to a spouse (OR 7.2), child (OR 2.4) or patient (OR 2.0) with symptoms of an ARI in the previous 7 days. CONCLUSIONS: Breakthrough influenza infection occurred in both vaccinated participants and those receiving antiviral prophylaxis. Most adults were willing and able to comply with season-long prophylaxis. Report of recent exposure to family members and patients with an ARI increased the risk of developing an ARI in healthy adults. PMID- 25557839 TI - Dopant titrating ion mobility spectrometry for trace exhaled nitric oxide detection. AB - Ion mobility spectrometry (IMS) is a promising non-invasive tool for the analysis of exhaled gas and exhaled nitric oxide (NO), a biomarker for diagnosis of respiratory diseases. However, the high moisture in exhaled gas always brings about extra overlapping ion peaks and results in poor identification ability. In this paper, p-benzoquinone (PBQ) was introduced into IMS to eliminate the interference of overlapping ion peaks and realize the selective identification of NO. The overlapping ions caused by moisture were titrated by PBQ and then converted to hydrated PBQ anions (C6H4[Formula: see text](H2O)n). The NO concentration could be determined by quantifying gas phase hydrated nitrite anions (N[Formula: see text](H2O)n), product ions of NO. Under optimized conditions, a limit of detection (LOD) of about 1.4 ppbv and a linear range of 10 200 ppbv were obtained for NO even in 100% relative humidity (RH) purified air. Furthermore, this established method was applied to measure hourly the exhaled NO of eight healthy volunteers, and real-time monitoring the exhaled NO of an esophageal carcinoma patient during radical surgery. These results revealed the potential of the current dopant titrating IMS method in the measurement of exhaled NO for medical disease diagnosis. PMID- 25557840 TI - Neutrophil to lymphocyte ratio predicts pattern of recurrence in patients undergoing liver resection for colorectal liver metastasis and thus the overall survival. AB - OBJECTIVE: We investigate the neutrophil to lymphocyte ratio (NLR) as a potential prognostic factor for patients undergoing curative liver resection for colorectal liver metastasis (CRLM). METHODS: We identified patients who underwent liver resection, via our prospectively accumulated surgical database at the Royal Marsden Hospital and The London Clinic, by two liver surgeons (SM and AZK) between January 2005 and December 2012 and patients included had liver resection for CRLM and received preoperative chemotherapy with an NLR > 2.5 considered elevated. NLR's role in disease-free, post-recurrence and overall survival was determined by univariate and multivariate Cox regression models. RESULTS: One hundred and sixty nine patients were enrolled. Seventy-one patients (42%) demonstrated NLR > 2.5. Elevated NLR was associated with decreased OS in univariate and multivariate analysis (HR 2.12; 95% CI, 1.18-3.82; P = 0.012) but not with DFS. Analyzed as continuous variable, higher NLR was associated with decreased OS(HR 1.17; 95% CI, 1.03-132; P = 0.011) and associated with increased risk of extrahepatic/multifocal recurrence (P = 0.007), linked in this way with a decreased post-recurrence survival (HR 1.24, 95% CI, 1.02-1.52; P = 0.032). CONCLUSIONS: Elevated NLR in patients who undergo hepatectomy following neoadjuvant chemotherapy for CRLM increases risk of extrahepatic/multifocal recurrence and is an independent predictor of overall survival. PMID- 25557841 TI - Morusin inhibits glioblastoma stem cell growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction. AB - Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are responsible for the progression and recurrence of GBM after conventional therapy. Morusin possesses anti-cancer activity in vitro. The purpose of this study is to confirm the growth inhibition effect of morusin on human GSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. Human GSCs were enriched under nonadhesive culture system, and characterized through neurosphere formation, toluidine blue staining, immunofluorescence staining, Western blotting analysis of stemness markers of CD133, nestin, Sox2 and Oct4, and tumorigenecity in vivo; the growth inhibition effect of morusin on human GSCs in vitro and in vivo were tested by cell cytotoxicity, neurosphere formation inhibition, adipogenic differentiation, apoptosis induction, and tumor growth inhibition in vivo assays. The potential molecular mechanisms underlying the growth inhibition effect of morusin on GSCs in vitro and in vivo were investigated with Western blotting evaluation of stemness, adipogenic, and apoptotic proteins in morusin treated GSCs and tumor tissues. GSCs enriched under nonadhesive culture system possess stemness characterstics; Morusin inhibited GSCs growth in vitro and in vivo, it reduced stemness of GSCs, induced them adipocyte-like transdifferention and apoptosis. Morusin has the potential to inhibit human GSCs growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction. PMID- 25557842 TI - Attenuation of morphine-induced dependence and tolerance by ceftriaxone and amitriptyline in mice. AB - INTRODUCTION: Tolerance to and dependence on the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration. OBJECTIVE: The aim of this study was to evaluate the protective effects of ceftriaxone and amitriptyline on the development of morphine-induced tolerance and dependence. METHODS: In this study, 18 groups (9 groups each for tolerance and dependency tests) of mice (n = 8) received saline [10 mL/kg, intraperitoneally (i.p.)], morphine (50 mg/kg, i.p.), ceftriaxone (50 mg/kg, i.p., 100 mg/kg, i.p., and 200 mg/kg, i.p.), amitriptyline (5 mg/kg, i.p., 10 mg/kg, i.p., and 15 mg/kg, i.p.), or a combination of ceftriaxone (50 mg/kg, i.p.) and amitriptyline (5 mg/kg, i.p.) once per day for 4 days for investigation and comparison of the effects of ceftriaxone and amitriptyline on the prevention of dependency and tolerance to morphine. Tolerance was assessed with administration of morphine (9 mg/kg, i.p.) and using the hot plate test on the 5(th) day. In dependency tests, withdrawal symptoms were assessed on the 4(th) day for each animal 30 minutes after the administration of naloxone (4 mg/kg, i.p.; 2 hours after the last dose of morphine). RESULTS: It was found that treatment with ceftriaxone or amitriptyline attenuated the development of tolerance to the antinociceptive effect of morphine and also reduced naloxone precipitated withdrawal jumping and standing on feet. Furthermore, coadministration of ceftriaxone and amitriptyline at low doses (50 mg/kg, i.p. and 5 mg/kg, i.p., respectively) prior to morphine injection also decreased both morphine-induced tolerance and dependence. CONCLUSION: Results indicate that the treatment with ceftriaxone and amitriptyline, alone or in combination, could attenuate the development of morphine-induced tolerance and dependence. PMID- 25557843 TI - Ushering in a new dawn in obstetrics and gynecology: the industry of cell-free DNA testing. PMID- 25557844 TI - A flawed challenge but valid recommendation: a response to Takoudes and Hamar. PMID- 25557845 TI - The influence of vascularization of transplanted processed allograft nerve on return of motor function in rats. AB - Processed nerve allografts have become an alternative to repair segmental nerve defects, with results comparable with autografts regarding sensory recovery; however, they have failed to reproduce comparable motor recovery. The purpose of this study was to determine how revascularizaton of processed nerve allograft would affect motor recovery. Eighty-eight rats were divided in four groups of 22 animals each. A unilateral 10-mm sciatic nerve defect was repaired with allograft (group I), allograft wrapped with silicone conduit (group II), allograft augmented with vascular endothelial growth factor (group III), or autograft (group IV). Eight animals from each group were sacrificed at 3 days, and the remaining animals at 16 weeks. Revascularization was evaluated by measuring the graft capillary density at 3 days and 16 weeks. Measurements of ankle contracture, compound muscle action potential, tibialis anterior muscle weight and force, and nerve histomorphometry were performed at 16 weeks. All results were normalized to the contralateral side. The results of capillary density at 3 days were 0.99% +/- 1.3% for group I, 0.33% +/- 0.6% for group II, 0.05% +/- 0.1% for group III, and 75.6% +/- 45.7% for group IV. At 16 weeks, the results were 69.9% +/- 22.4% for group I, 37.0% +/- 16.6% for group II, 84.6% +/- 46.6% for group III, and 108.3% +/- 46.8% for group IV. The results of muscle force were 47.5% +/- 14.4% for group I, 21.7% +/- 13.5% for group II, 47.1% +/- 7.9% for group III, and 54.4% +/- 10.6% for group IV. The use of vascular endothelial growth factor in the fashion used in this study improved neither the nerve allograft short-term revascularization nor the functional motor recovery after 16 weeks. Blocking allograft vascularization from surrounding tissues was detrimental for motor recovery. The processed nerve allografts used in this study showed similar functional motor recovery compared with that of the autograft. PMID- 25557846 TI - Resting-State Functional Connectivity of the Sensorimotor Network in Individuals with Nonspecific Low Back Pain and the Association with the Sit-to-Stand-to-Sit Task. AB - Individuals with nonspecific low back pain (NSLBP) show a decreased sit-to-stand to-sit (STSTS) performance. This dynamic sensorimotor task requires integration of sensory and motor information in the brain. Therefore, a better understanding of the underlying central mechanisms of impaired sensorimotor performance and the presence of NSLBP is needed. The aims of this study were to characterize differences in sensorimotor functional connectivity in individuals with NSLBP and to investigate whether the patterns of sensorimotor functional connectivity underlie the impaired STSTS performance. Seventeen individuals with NSLBP and 17 healthy controls were instructed to perform five consecutive STSTS movements as fast as possible. Based on the center of pressure displacement, the total duration of the STSTS task was determined. In addition, resting-state functional connectivity images were acquired and analyzed on a multivariate level using both functional connectivity density mapping and independent component analysis. Individuals with NSLBP needed significantly more time to perform the STSTS task compared to healthy controls. In addition, decreased resting-state functional connectivity of brain areas related to the integration of sensory and/or motor information was shown in the individuals with NSLBP. Moreover, the decreased functional connectivity at rest of the left precentral gyrus and lobule IV and V of the left cerebellum was associated with a longer duration of the STSTS task in both individuals with NSLBP and healthy controls. In summary, individuals with NSLBP showed a reorganization of the sensorimotor network at rest, and the functional connectivity of specific sensorimotor areas was associated with the performance of a dynamic sensorimotor task. PMID- 25557847 TI - Elevation of serum KL-6 in patients with psoriasis treated with anti-tumour necrosis factor-alpha therapy. AB - We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)-6 increased during therapy with anti-tumour necrosis factor (TNF)-alpha. A diagnosis of early-phase or subclinical interstitial pneumonia was made in two patients, and their KL-6 level decreased after anti-TNF-alpha discontinuation. The rise in KL-6 in the other patient was attributed to methotrexate. We propose that serum KL-6 should be monitored routinely in patients treated with anti-TNF agents. PMID- 25557848 TI - Enzyme dehydration using MicroglassificationTM preserves the protein's structure and function. AB - Controlled enzyme dehydration using a new processing technique of MicroglassificationTM has been investigated. Aqueous solution microdroplets of lysozyme, alpha-chymotrypsin, catalase, and horseradish peroxidase were dehydrated in n-pentanol, n-octanol, n-decanol, triacetin, or butyl lactate, and changes in their structure and function were analyzed upon rehydration. Water solubility and microdroplet dissolution rate in each solvent decreased in the order: butyl lactate > n-pentanol > triacetin > n-octanol > n-decanol. Enzymes MicroglassifiedTM in n-pentanol retained higher activity (93%-98%) than n-octanol (78%-85%) or n-decanol (75%-89%), whereas those MicroglassifiedTM in triacetin (36%-75%) and butyl lactate (48%-79%) retained markedly lower activity. FTIR spectroscopy analyses showed alpha-helix to beta-sheet transformation for all enzymes upon MicroglassificationTM, reflecting a loss of bound water in the dried state; however, the enzymes reverted to native-like conformation upon rehydration. Accelerated stressed-storage tests using MicroglassifiedTM lysozyme showed a significant (p < 0.01) decrease in enzymatic activity from 46,560 +/- 2736 to 31,060 +/- 4327 units/mg after 3 months of incubation; however, it was comparable to the activity of the lyophilized formulation throughout the test period. These results establish MicroglassificationTM as a viable technique for enzyme preservation without affecting its structure or function. PMID- 25557849 TI - Analysis and characterization of the head kidney transcriptome from the Antarctic fish Trematomus bernacchii (Teleostea, Notothenioidea): a source for immune relevant genes. AB - In this study we describe the de novo assembled head kidney transcriptome of the Antarctic notothenioid fish Trematomus bernacchii, an important model species for biochemical, environmental and immunological studies. RNA-seq data was generated using Illumina paired-end sequencing, obtaining ~7 Gbp of sequence data, which were assembled into 96,641 contigs and annotated with the Trinotate pipeline. Since this sequence collection is expected to contain a relevant number of immunity-related transcripts, it will be used as a reference for future immunological studies in this species. PMID- 25557850 TI - Socioeconomic gradient in consumption of whole fruit and 100% fruit juice among US children and adults. AB - BACKGROUND: The consumption of fruit is generally associated with better health, but also higher socioeconomic status (SES). Most previous studies evaluating consumption of fruits have not separated 100% fruit juice and whole fruit, which may conceal interesting patterns in consumption. OBJECTIVE: To estimate demographic and socioeconomic correlates of whole fruit versus 100% juice consumption among children and adults in the United States. DESIGN: Secondary analyses of two cycles of the nationally representative National Health and Nutrition Examination Survey (NHANES) from 2007-2010, by gender, age group, race/ethnicity and SES among 16,628 children and adults. RESULTS: Total fruit consumption (population average of 1.06 cup equivalents/d) fell far short of national goals. Overall, whole fruit provided about 65% of total fruit, while 100% juice provided the remainder. Whereas 100% juice consumption was highest among children and declined sharply with age, whole fruit consumption was highest among older adults. Total fruit and whole fruit consumption was generally higher among those with higher incomes or more education. By contrast, the highest 100% juice consumption was found among children, racial/ethnic minorities and lower income groups. CONCLUSIONS: Consumption patterns for whole fruit versus 100% fruit juice showed different gradients by race/ethnicity, education, and income. The advice to replace 100% juice with whole fruit may pose a challenge for the economically disadvantaged and some minority groups, whose fruit consumption falls short of national goals. PMID- 25557851 TI - Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of beta-thalassemia intermedia. AB - beta-thalassemias result from diminished beta-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of beta-thalassemia intermedia. To further interrogate the efficacy of an RNAi therapeutic downregulating Tmprss6, beta-thalassemic Hbb(th3/+) animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb(th3/+) animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in beta-thalassemia intermedia. PMID- 25557852 TI - Phakomatous choristoma in a 10-week-old boy: a case report and review of the literature. AB - Phakomatous choristoma (PC) is a rare benign congenital lesion of lenticular anlage. It presents in young patients as a firm subcutaneous mass in the medial eyelid or orbit and may raise clinical concern for neoplasms such as rhabdomyosarcoma, but its histopathology is distinct, consisting of dense collagenous stroma and eosinophilic cuboidal epithelial cells forming nests, tubules, cords, or pseudoglands. We present a case of PC in a 10-week-old boy to illustrate the unique clinical, histopathologic, and immunophenotypic features of this condition and to reaffirm that familiarity with this rare entity aids accurate diagnosis. PMID- 25557853 TI - Duloxetine, dual serotonin and norepinephrine reuptake inhibitor, versus paroxetine, selective serotonin reuptake inhibitor, in the treatment for premature ejaculation. AB - PURPOSE: In the current analysis due to the mechanism of effect, we evaluated the treatment benefit of duloxetine 40 mg comparing with paroxetine 20 mg, based on its effects on personal distress and interpersonal difficulty related to ejaculation, perceived control over ejaculation, and satisfaction with sexual intercourse, as well as the patient-reported global impression of change in premature ejaculation (PE) and the effect on intravaginal ejaculatory latency times (IELT) in men with premature ejaculation. MATERIALS AND METHODS: The study included 80 married male patients diagnosed with lifelong PE. A total of 80 patients were randomly distributed into two groups of 40 patients each. Group 1 patients received 40 mg duloxetine once a day for a month. Group 2 patients received 20 mg paroxetine once a day for a month. International index of erectile function questionnaire (IIEF) and IELT and PE profile were recorded before and after treatment. RESULTS: Comparing the groups' mean treatment IELT, there was no difference between groups. The IELT increase from baseline to treatment was 117 % in the duloxetine group (P < 0.001) and 126 % in the paroxetine group (P < 0.001). There was no statistical difference between two groups in terms of IELT increase (P > 0.05). Also, there was no statistically significant difference between two groups at baseline IIEF to treatment IIEF scores. All PEP measures improved significantly with duloxetine and paroxetine groups (P < 0.001). CONCLUSION: We think that duloxetine is safe and effective for the treatment for premature ejaculation. PMID- 25557854 TI - Occupation and risk of oesophageal adenocarcinoma and squamous-cell carcinoma: The Nordic Occupational Cancer Study. AB - To assess associations between occupation and risk of oesophageal adenocarcinoma (AC) and squamous-cell carcinoma (SCC), data from the Nordic Occupational Cancer Study, a large population-based cohort with long-term follow-up, was used. The Nordic Occupational Cancer Study includes 12.9 million individuals aged 30-64 years who participated in national censuses in Finland, Iceland, Norway and Sweden in 1960-1990. Individuals were assigned to one of the 54 occupational categories, and individuals with oesophageal cancer were identified through nationwide cancer registries with follow-up through 2005. Country-specific standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated. During follow-up, 4,722 ACs and 14,496 SCCs were observed. Among men, increased risks of AC and SCC were observed among waiters (SIR = 2.58, 95% CI 1.41-4.32 and SIR = 3.22, 95% CI 2.30-4.38 for AC and SCC, respectively), cooks and stewards (1.72, 1.04-2.69 and 2.53, 1.94-3.25), seamen (1.52, 1.16-1.95 and 1.77, 1.53-2.05), food workers (1.51, 1.18-1.90 and 1.21, 1.03-1.42), miscellaneous construction workers (1.24, 1.04-1.48 and 1.39, 1.25-1.54) and drivers (1.16, 1.01-1.33 and 1.23, 1.13-1.34). Decreased risks of AC and SCC were observed among technical workers, physicians, teachers, religious workers and gardeners. The SIR for AC was significantly different from that for SCC in six occupational categories. Among women, increased risks among food workers and waiters and decreased risks among teachers, nurses and assistant nurses were observed for SCC only. In both sexes, increased risks were observed among waiters and food workers, and decreased risks were observed among teachers. This large cohort study indicates that the risk of oesophageal cancer varies by occupation, but not by histological type in most occupational categories. PMID- 25557855 TI - Clinical treatment and prognosis of equine odontoclastic tooth resorption and hypercementosis. AB - REASONS FOR PERFORMING STUDY: Equine odontoclastic tooth resorption and hypercementosis is an infrequent and underdiagnosed form of severe dental disease in horses that can affect quality of life. The study was performed to compare the clinical, radiographic, histological and prognostic findings specific to equine odontoclastic tooth resorption and hypercementosis in horses. Removal of affected teeth is currently the best treatment. OBJECTIVES: The goals are to report salient clinical and histological features of the disease and its management in a case series describing an under-reported syndrome in horses and the long-term prognosis. STUDY DESIGN: Retrospective case series. METHODS: Medical records from New Bolton Center, University of Pennsylvania from January 2000 to December 2012 were reviewed from horses that had a diagnosis of 'cementoma' or 'hypercementosis' and any associated dental-related diagnosis affecting the teeth and oral cavity. Radiographic, surgical and histological reports were collated and the clinical cases compared and tabulated to provide a better description of the equine disease. RESULTS: A total of 18 cases were identified, 17 of which were geldings and one of which was a nonbreeding stallion; no mares had the disease. The mean age at diagnosis was 24 years, with a range of 17-29 years. There was no breed predilection, and varied clinical signs relating to the mouth were found. Some teeth involved had only radiographic changes of disease and not gross clinical evidence. The mandibular incisors were generally affected earlier than the maxillary incisors, but the disease is progressive, and eventually, all of the incisors and sometimes the canines are involved. No premolars or molars were affected in this case series. CONCLUSIONS: Based on this case series, all teeth, and particularly the incisors, should be examined for signs of gingivitis and hypercementosis and subsequently radiographed for an early diagnosis and management. When compared with our hospital population, older geldings were more likely to be affected with cementoma formation and its accompanying resorptive process. Removal of clinically and radiographically affected teeth carries a good prognosis for improved quality of life. PMID- 25557856 TI - Glycopyrrolate-induced respiratory arrest: an unusual side effect. AB - A descriptive case report of a 22-year-old woman, scheduled for elective laparotomy who had a respiratory arrest after premedication with inj glycopyrrolate and ondansetron. Respiratory arrest is an uncommon side effect of glycopyrrolate with very few published reports. Ondansteron can also cause respiratory arrest, however is most often associated with bradycardia. This patient had tachycardia and respiratory arrest and is suggestive of glycopyrrolate-induced respiratory arrest. This case report highlights the importance of strict vigilance by the anaesthesiologist even during premedication. PMID- 25557858 TI - Antenatal care provider's advice is the key determinant of influenza vaccination uptake in pregnant women. AB - BACKGROUND: Although influenza vaccination is an important component of antenatal care and is recommended and funded by the Australian government, vaccination uptake has been low. AIMS: This study compared seasonal influenza vaccination uptake among pregnant Western Australian (WA) women and identified factors associated with vaccination uptake. MATERIALS AND METHODS: Adult women who were pregnant during the 2012 and 2013 influenza vaccination seasons were selected at random and invited to complete a computer-assisted telephone interview survey about whether they received influenza vaccination during pregnancy. Data analyses were weighted to the age distribution of women of reproductive age in WA. Multivariate logistic regression was used to identify factors associated with vaccination uptake. RESULTS: Between 2012 and 2013, the proportion of WA women whose antenatal care provider recommended influenza vaccination increased from 37.6 to 62.1% and vaccination uptake increased from 23.0 to 36.5%. The antenatal care provider's advice to have influenza vaccine was the single most important factor associated with vaccination (OR 11.1, 95% CI 7.9-15.5). Most women (63.7%) were vaccinated in general practice, 18.8% in a public hospital antenatal clinic and 11.0% at their workplace. Wanting to protect their infant from infection (91.2%) and having the vaccine recommended by their GP (60.0%) or obstetrician (51.0%) were commonly reported reasons for vaccination; worrying about side effects was a common reason for nonvaccination. CONCLUSIONS: To optimise maternal and infant health outcomes, Australian antenatal care providers and services need to incorporate both the recommendation and delivery of influenza vaccination into routine antenatal care. PMID- 25557857 TI - Interlayer water regulates the bio-nano interface of a beta-sheet protein stacking on graphene. AB - Using molecular dynamics simulations, we investigated an integrated bio-nano interface consisting of a beta-sheet protein stacked onto graphene. We found that the stacking assembly of the model protein on graphene could be controlled by water molecules. The interlayer water filled within interstices of the bio-nano interface could suppress the molecular vibration of surface groups on protein, and could impair the CH...pi interaction driving the attraction of the protein and graphene. The intermolecular coupling of interlayer water would be relaxed by the relative motion of protein upon graphene due to the interaction between water and protein surface. This effect reduced the hindrance of the interlayer water against the assembly of protein on graphene, resulting an appropriate adsorption status of protein on graphene with a deep free energy trap. Thereby, the confinement and the relative sliding between protein and graphene, the coupling of protein and water, and the interaction between graphene and water all have involved in the modulation of behaviors of water molecules within the bio-nano interface, governing the hindrance of interlayer water against the protein assembly on hydrophobic graphene. These results provide a deep insight into the fundamental mechanism of protein adsorption onto graphene surface in water. PMID- 25557859 TI - Multi-Band-SWIFT. AB - A useful extension to SWIFT (SWeep Imaging with Fourier Transformation) utilizing sidebands of the excitation pulse is introduced. This MRI method, called Multi Band-SWIFT, achieves much higher bandwidth than standard SWIFT by using multiple segmented excitations (bands) of the field of view. A description of the general idea and variants of the pulse sequence are presented. From simulations and semi phenomenological theory, estimations of power deposition and signal-to-noise ratio are made. MB-SWIFT and ZTE (zero-TE) sequences are compared based on images of a phantom and human mandible. Multi-Band-SWIFT provides a bridge between SWIFT and ZTE sequences and allows greatly increased excitation and acquisition bandwidths relative to standard SWIFT for the same hardware switching parameters and requires less peak amplitude of the radiofrequency field (or greater flip angle at same peak amplitude) as compared to ZTE. Multi-Band-SWIFT appears to be an attractive extension of SWIFT for certain musculoskeletal and other medical imaging applications, as well as for imaging materials. PMID- 25557860 TI - High resolution in-operando microimaging of solar cells with pulsed electrically detected magnetic resonance. AB - The in-operando detection and high resolution spatial imaging of paramagnetic defects, impurities, and states becomes increasingly important for understanding loss mechanisms in solid-state electronic devices. Electron spin resonance (ESR), commonly employed for observing these species, cannot meet this challenge since it suffers from limited sensitivity and spatial resolution. An alternative and much more sensitive method, called electrically-detected magnetic resonance (EDMR), detects the species through their magnetic fingerprint, which can be traced in the device's electrical current. However, until now it could not obtain high resolution images in operating electronic devices. In this work, the first spatially-resolved electrically-detected magnetic resonance images (EDMRI) of paramagnetic states in an operating real-world electronic device are provided. The presented method is based on a novel microwave pulse sequence allowing for the coherent electrical detection of spin echoes in combination with powerful pulsed magnetic-field gradients. The applicability of the method is demonstrated on a device-grade 1-MUm-thick amorphous silicon (a-Si:H) solar cell and an identical device that was degraded locally by an electron beam. The degraded areas with increased concentrations of paramagnetic defects lead to a local increase in recombination that is mapped by EDMRI with ~20-MUm-scale pixel resolution. The novel approach presented here can be widely used in the nondestructive in-operando three-dimensional characterization of solid-state electronic devices with a resolution potential of less than 100 nm. PMID- 25557862 TI - Feasibility of high-resolution one-dimensional relaxation imaging at low magnetic field using a single-sided NMR scanner applied to articular cartilage. AB - Low field Nuclear Magnetic Resonance increases the contrast of the longitudinal relaxation rate in many biological tissues; one prominent example is hyaline articular cartilage. In order to take advantage of this increased contrast and to profile the depth-dependent variations, high resolution parameter measurements are carried out which can be of critical importance in an early diagnosis of cartilage diseases such as osteoarthritis. However, the maximum achievable spatial resolution of parameter profiles is limited by factors such as sensor geometry, sample curvature, and diffusion limitation. In this work, we report on high-resolution single-sided NMR scanner measurements with a commercial device, and quantify these limitations. The highest achievable spatial resolution on the used profiler, and the lateral dimension of the sensitive volume were determined. Since articular cartilage samples are usually bent, we also focus on averaging effects inside the horizontally aligned sensitive volume and their impact on the relaxation profiles. Taking these critical parameters into consideration, depth dependent relaxation time profiles with the maximum achievable vertical resolution of 20 MUm are discussed, and are correlated with diffusion coefficient profiles in hyaline articular cartilage in order to reconstruct T(2) maps from the diffusion-weighted CPMG decays of apparent relaxation rates. PMID- 25557861 TI - Observation of 1H-13C and 1H-1H proximities in a paramagnetic solid by NMR at high magnetic field under ultra-fast MAS. AB - The assignment of NMR signals in paramagnetic solids is often challenging since: (i) the large paramagnetic shifts often mask the diamagnetic shifts specific to the local chemical environment, and (ii) the hyperfine interactions with unpaired electrons broaden the NMR spectra and decrease the coherence lifetime, thus reducing the efficiency of usual homo- and hetero-nuclear NMR correlation experiments. Here we show that the assignment of (1)H and (13)C signals in isotopically unmodified paramagnetic compounds with moderate hyperfine interactions can be facilitated by the use of two two-dimensional (2D) experiments: (i) (1)H-(13)C correlations with (1)H detection and (ii) (1)H-(1)H double-quantum<->single-quantum correlations. These methods are experimentally demonstrated on isotopically unmodified copper (II) complex of l-alanine at high magnetic field (18.8 T) and ultra-fast Magic Angle Spinning (MAS) frequency of 62.5 kHz. Compared to (13)C detection, we show that (1)H detection leads to a 3 fold enhancement in sensitivity for (1)H-(13)C 2D correlation experiments. By combining (1)H-(13)C and (1)H-(1)H 2D correlation experiments with the analysis of (13)C longitudinal relaxation times, we have been able to assign the (1)H and (13)C signals of each l-alanine ligand. PMID- 25557863 TI - Two heteronuclear dipolar results at the price of one: quantifying Na/P contacts in phosphosilicate glasses and biomimetic hydroxy-apatite. AB - The analysis of S{I} recoupling experiments applied to amorphous solids yields a heteronuclear second moment M(2)(S-I) that represents the effective through-space dipolar interaction between the detected S spins and the neighboring I-spin species. We show that both M(2)(S-I) and M(2)(I-S) values are readily accessible from a sole S{I} or I{S} experiment, which may involve either S or I detection, and is naturally selected as the most favorable option under the given experimental conditions. For the common case where I has half-integer spin, an I{S} REDOR implementation is preferred to the S{I} REAPDOR counterpart. We verify the procedure by (23)Na{(31)P} REDOR and (31)P{(23)Na} REAPDOR NMR applied to Na(2)O-CaO-SiO(2)-P(2)O(5) glasses and biomimetic hydroxyapatite, where the M(2)(P-Na) values directly determined by REAPDOR agree very well with those derived from the corresponding M(2)(Na-P) results measured by REDOR. Moreover, we show that dipolar second moments are readily extracted from the REAPDOR NMR protocol by a straightforward numerical fitting of the initial dephasing data, in direct analogy with the well-established procedure to determine M(2)(S-I) values from REDOR NMR experiments applied to amorphous materials; this avoids the problems with time-consuming numerically exact simulations whose accuracy is limited for describing the dynamics of a priori unknown multi-spin systems in disordered structures. PMID- 25557865 TI - Changes to inpatient versus outpatient hospitalization: Medicare's 2-midnight rule. AB - Outpatient versus inpatient status determinations for hospitalized patients impact how hospitals bill Medicare for hospital services. Medicare policies related to status determinations and the Recovery Audit Contractor (RAC) program charged with postpayment review of such determinations are of increasing concern to hospitals and physicians. We present an overview and discussion of these policies, including the recent 2-midnight rule, the effect on status determinations by the RAC program, and other recent and pertinent legislative and regulatory activity. Finally, we discuss the future direction of Medicare status determination policies and the RAC program, so that physicians and other healthcare providers caring for hospitalized Medicare beneficiaries may better understand these important and dynamic topics. PMID- 25557864 TI - Associated factors of drug-drug interactions of highly active antiretroviral therapy: report from a referral center. AB - OBJECTIVE: To assess different aspects of potential drug-drug interactions (DDIs) including incidence, severity, level of evidence and probable associated factors in Iranian HIV-infected individuals receiving antiretroviral therapy. METHODS: All adult HIV-infected patients under highly active antiretroviral therapy regimen attending a referral HIV clinic during 1 year were screened retrospectively for potential moderate or severe DDIs by the Lexi-Interact On Desktop software. RESULTS: Near seventy percent (69.89%) of detected DDIs in our population were major. The three most common detected potential DDIs were efavirenz + methadone (11 cases), lopinavir-ritonavir + sulfamethoxazole trimethoprim, (10 cases) and lamivudine + ribavirin (7 cases). Lopinavir ritonavir (27.96%) and citalopram (23.66%) were the most common offending antiretroviral and non-antiretroviral agents, respectively. CONCLUSION: Performing multicenter and prospective studies is warranted to assess the real clinical as well as economic impacts of DDIs on HIV-infected patients receiving antiretroviral agents in our population and also to develop efficient preventive strategies. PMID- 25557866 TI - Excisional treatments of the cervix and effect on subsequent fertility: a retrospective cohort study. AB - OBJECTIVE: Concerns exist regarding the impact of excisional treatments for cervical intraepithelial neoplasia (CIN) on subsequent pregnancy outcome yet few studies have addressed fertility following surgery. STUDY DESIGN: Retrospective cohort study. Set in the colposcopy service of National Maternity Hospital. A postal questionnaire was sent to 3590 women of reproductive age who attended colposcopy from 2001 to 2007; 1795 of these had at least one excisional treatment (surgical group) and 1795 had no treatment (non-surgical group). Records were reviewed to confirm the clinical details and volume of tissue excised. The main outcome measures were pregnancy and fertility rates as well as time to conception correlated with volume of tissue excised. Students' t-test, Mann-Whitney U-test, spearman correlation and Kruskal-Wallis tests were used during the analysis. RESULTS: 1355 Women (37.7%) responded. 537 Women had no treatment and 818 had at least one excision. A subsequent pregnancy was reported in 730 women (434 surgical and 296 non-surgical groups). No difference was detected between the groups in the reported pregnancy rates (p=0.56), the time to conception (p=0.37) or fertility problems (p=0.89). The volume of the excision did not affect fertility rates or time to conception. There were fewer pregnancies in women following a cold knife cone or more than one LLETZ treatment-significant surgery, (p=0.004) but no difference in their reported time to conception (p=0.54). CONCLUSIONS: One excisional treatment for CIN does not appear to affect subsequent fertility. Our study showed no delay in conception and no increased risk of problems conceiving in this group, even when controlling for the volume and depth of tissue removed. Women should be reassured by these results. Further work is required to evaluate the effect of cold knife cone biopsy and repeated LLETZ procedures on subsequent fertility. PMID- 25557869 TI - Spectral domain optical coherence tomography and auto-fluorescence findings in adult-onset vitelliform dystrophy. PMID- 25557868 TI - Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing. AB - PURPOSE: To characterize the determinants of variability for oxaliplatin pharmacokinetics including age, renal function, and hepatic function in children and adults. METHODS: Oxaliplatin pharmacokinetic data were combined from phase I and II clinical trials: three pediatric trials (Peds1-3) and two adult NCI organ dysfunction studies (Hepatic and Renal). A population pharmacokinetic model was developed utilizing platinum ultrafiltrate concentrations to characterize changes in oxaliplatin disposition with age and organ dysfunction along with other potential sources of oxaliplatin pharmacokinetic variability. RESULTS: A total of 1,508 concentrations from 186 children and adults were used in the study. The data were well described by a three-compartment model. Serum creatinine (SCR) was an independent predictor of clearance (CL) while age was an independent predictor of volume of distribution. Although age was a significant covariate on CL in the univariate analysis, age effects on CL were entirely accounted for by SCR. Gender, hepatic function, and race had no effect on CL or volume of distribution. Median CL values were 0.58 (Hepatic), 0.34 (Renal), 0.78 (Peds1), 0.74 (Peds2), and 0.81 (Peds3) (L/h/kg(0.75)). Monte Carlo simulations of the final model with 130 mg/m(2) yielded median AUC values of: 14.2 (2-6 years), 16.8 (6-12 years), 16.5 (12-18 years), and 17.3 (>18 years) (ug h/mL). CONCLUSIONS: Renal function had the greatest effect on CL with a small age effect seen on the distribution of oxaliplatin. Young pediatric patients had higher CL values than adults as a result of better renal function. PMID- 25557870 TI - Label-free photoelectrochemical immunosensor for neutrophil gelatinase-associated lipocalin based on the use of nanobodies. AB - Acute renal failure (ARF) represents a very important and potentially devastating disorder in clinical nephrology. Neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for ARF in a wide range of different disease processes, which is frequently detected in clinical diagnosis. Herein, we present a label-free and sensitive photoelectrochemical (PEC) immunosensor for NGAL by utilizing a biotinylated anti-NGAL Nanobody (Nb) orientedly immobilized to streptavidin-coated cobalt 2,9,16,23-tetraaminophthalocyanine (CoPc)-sensitized TiO2 electrode. The Nb was biotinylated at the C-terminus, which is situated at the opposite site of the antigen binding region. Using highly oriented Nb as receptor molecules, a label-free PEC immunosensor for NGAL was developed by monitoring the changes in the photocurrent signals of the electrode resulting from immunoreaction. Immobilization of Nb to streptavidin-coated CoPc-sensitized TiO2 electrode surface provides high binding capacity to NGAL; thus, it can lead to a high sensitivity. The limit of detection (LOD) of the proposed immunosensor has been significantly lowered to 0.6 pg mL(-1). This proposed immunosensor reveals high specificity to detect NGAL, with acceptable intra-assay precision and excellent stability. In addition, the present work provides a new approach to design Nb-based PEC immunosensor and increases versatility of Nbs. PMID- 25557871 TI - Non-classical mechanism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine. AB - Antidepressants have many targets in the central nervous system. A growing body of data demonstrates the influence of antidepressants on glutamatergic neurotransmission. In the present work, we studied the inhibition of native Ca(2+)-permeable and Ca(2+)-impermeable alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca(2+)-impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC50 value for the inhibition of Ca(2+)-permeable AMPA receptors in giant striatal interneurons was 43 +/- 7 MUM. The inhibition of Ca(2+)-permeable AMPA receptors was voltage dependent, suggesting deep binding in the pore. However, the use dependence of fluoxetine action differed markedly from that of classical AMPA receptor open-channel blockers. Moreover, fluoxetine did not compete with other channel blockers. In contrast to fluoxetine, its membrane impermeant quaternary analog demonstrated all of the features of channel inhibition typical for open-channel blockers. It is suggested that fluoxetine reaches the binding site through a hydrophobic access pathway. Such a mechanism of block is described for ligands of sodium and calcium channels, but was never found in AMPA receptors. Molecular modeling suggests binding of fluoxetine in the subunit interface; analogous binding was proposed for local anesthetics in closed sodium channels and for benzothiazepines in calcium channels. PMID- 25557872 TI - Moderate band-gap-broadening induced high separation of electron-hole pairs in Br substituted BiOI: a combined experimental and theoretical investigation. AB - We, for the first time, demonstrate band-gap-broadening as a new approach to remarkably enhance the photocatalytic activity of Br(-) substituted BiOI photocatalysts, which were fabricated via a facile chemical precipitation route. The successful incorporation of Br(-) ions into the crystal lattice of BiOI was confirmed by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and high-resolution transmission electron microscopy (HRTEM). The photocatalytic experiments demonstrated that all of the Br-BiOI samples exhibited highly improved photocatalytic performances pertaining to rhodamine B (RhB) and phenol degradation under visible light (lambda > 420 nm). The active species trapping and electron spin resonance (ESR) experiments also suggested that more superoxide radicals (O2(-)), serving as the main active species, were generated over Br-BiOI than pristine BiOI in the photooxidation process. Based on the results from experiments and theoretical calculations, the enhancement of photocatalytic activity should be attributed to the lowered valence band (VB) potential and enlarged band gap induced by the Br(-) replacement, which greatly facilitated the high separation of photoinduced electron-hole pairs, as verified by the photoluminescence (PL) experiments, electrochemical impedance spectra (EIS) and Bode-phase spectra. This work sheds light on a new method to improve the photocatalytic performance of photocatalysts. PMID- 25557873 TI - Differentially expressed proteins in human MCF-7 breast cancer cells sensitive and resistant to paclitaxel. AB - Resistance of cancer cells to chemotherapeutic agents is one of the main causes of treatment failure. In order to detect proteins potentially involved in the mechanism of resistance to taxanes, we assessed differences in protein expression in MCF-7 breast cancer cells that are sensitive to paclitaxel and in the same cells with acquired resistance to paclitaxel (established in our lab). Proteins were separated using two-dimensional electrophoresis. Changes in their expression were determined and proteins with altered expression were identified using mass spectrometry. Changes in their expression were confirmed using western blot analysis. With these techniques, we found three proteins expressed differently in resistant MCF-7 cells, i.e., thyroid hormone-interacting protein 6 (TRIP6; upregulated to 650%), heat shock protein 27 (HSP27; downregulated to 50%) and cathepsin D (downregulated to 28%). Silencing of TRIP6 expression by specific siRNA leads to decreased number of grown resistant MCF-7 cells. In the present study we have pointed at some new directions in the studies of the mechanism of resistance to paclitaxel in breast cancer cells. PMID- 25557874 TI - Overexpression of activin-A and -B in malignant mesothelioma - attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth. AB - Activin-A and activin-B, members of the TGF-beta superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth. PMID- 25557875 TI - Factors circulating in the blood of type 2 diabetes mellitus patients affect osteoblast maturation - description of a novel in vitro model. AB - Type 2 diabetes mellitus (T2DM) is one of the most frequent metabolic disorders in industrialized countries. Among other complications, T2DM patients have an increased fracture risk and delayed fracture healing. We have demonstrated that supraphysiological glucose and insulin levels inhibit primary human osteoblasts' maturation. We aimed at developing a more physiologically relevant in vitro model to analyze T2DM-mediated osteoblast changes. Therefore, SCP-1-immortalized pre osteoblasts were differentiated with T2DM or control (non-obese and obese) sera. Between both control groups, no significant changes were observed. Proliferation was significantly increased (1.69-fold), while AP activity and matrix mineralization was significantly reduced in the T2DM group. Expression levels of osteogenic marker genes and transcription factors were altered, e.g. down regulation of RUNX2 and SP-7 or up-regulation of STAT1, in the T2DM group. Active TGF-beta levels were significantly increased (1.46-fold) in T2DM patients' sera. SCP-1 cells treated with these sera showed significantly increased TGF-beta signaling (2.47-fold). Signaling inhibition effectively restored osteoblast maturation in the T2DM group. Summarizing our data, SCP-1 cells differentiated in the presence of T2DM patients' serum exhibit reduced osteoblast function. Thus, this model has a high physiological impact, as it can identify circulating factors in T2DM patients' blood that may affect bone function, e.g. TGF-beta. PMID- 25557876 TI - CYP2S1 depletion enhances colorectal cell proliferation is associated with PGE2 mediated activation of beta-catenin signaling. AB - Colorectal epithelial cancer is one of the most common cancers in the world and its 5-year survival rate is still relatively low. Cytochrome P450 (CYP) enzymes in epithelial cells lining the alimentary tract play an important role in the oxidative metabolism of a wide range of xenobiotics, including (pro-)carcinogens and endogenous compounds. Although CYP2S1, a member of CYP family, strongly expressed in many extrahepatic tissues, the role of CYP2S1 in cancer remains unclear. To investigate whether CYP2S1 involves in colorectal carcinogenesis, cell proliferation was analyzed in HCT116 cells depleted of CYP2S1 using small hairpin interfering RNA. Our data show that CYP2S1 knockdown promotes cell proliferation through increasing the level of endogenous prostaglandin E2(PGE2). PGE2, in turn, reduces phosphorylation of beta-catenin and activates beta-catenin signaling, which contributes to the cell proliferation. Furthermore, CYP2S1 knockdown increase tumor growth in xenograft mouse model. In brief, these results demonstrate that CYP2S1 regulates colorectal cancer growth through associated with PGE2-mediated activation of beta-catenin signaling. PMID- 25557878 TI - Immediate vs. delayed loading in the posterior mandible: a split-mouth study with up to 15 years of follow-up. AB - PURPOSE: The aim of this study was to evaluate the long-term clinical and radiographic outcomes of implants that were immediately loaded in a prospective, randomized, split-mouth clinical trial in the posterior mandible. MATERIALS AND METHODS: Patients with alveolar ridges that were bilaterally edentulous distal to the canines were enrolled to participate. On one randomly selected side of each patient's jaw, three implants (control group) with platform switching and a progressive thread design were placed, allowed to heal for 3 months, uncovered, and loaded occlusally using resin-splinted crowns, which then were replaced 6 weeks later by final prostheses. Three additional implants (test group) of the same size and design were placed on the contralateral side of each patient in symmetrical locations. The test implants were connected to their final abutments immediately after placement and immediately loaded. Periodontal indices and bone loss were evaluated at regular intervals. RESULTS: After a mean loading period of 12.14 (+/-0.89) years for the test group and 12.40 (+/-0.89) years for controls, differences between the immediately and delayed loaded implants were not statistically significant (P > 0.05). The crestal bone loss was (mesial) 0.70 (+/ 1.09) mm (test group) and 1.17 (+/-1.27) mm (control group) and the distal bone loss was 0.43 (+/-1.02) mm (test group) and 1.06 (+/-1.33) mm (control group) (P > 0.05). The maximum crestal bone loss was 3.12 mm for the test group and 3.78 mm for the controls after 10.125/10.397 years, respectively. CONCLUSION: Immediate loading does not negatively influence the long-term prognosis of dental implants in the posterior mandible, improves the implant stability, and is associated with minimal crestal bone loss when platform switching and a one-abutment concept with a Morse-tapered connection are used. PMID- 25557877 TI - Overexpression of patatin-related phospholipase AIIIdelta altered plant growth and increased seed oil content in camelina. AB - Camelina sativa is a Brassicaceae oilseed species being explored as a biofuel and industrial oil crop. A growing number of studies have indicated that the turnover of phosphatidylcholine plays an important role in the synthesis and modification of triacylglycerols. This study manipulated the expression of a patatin-related phospholipase AIIIdelta (pPLAIIIdelta) in camelina to determine its effect on seed oil content and plant growth. Constitutive overexpression of pPLAIIIdelta under the control of the constitutive cauliflower mosaic 35S promoter resulted in a significant increase in seed oil content and a decrease in cellulose content. In addition, the content of major membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine, in 35S::pPLAIIIdelta plants was increased. However, these changes in 35S::pPLAIIIdelta camelina were associated with shorter cell length, leaves, stems, and seed pods and a decrease in overall seed production. When pPLAIIIdelta was expressed under the control of the seed specific, beta conglycinin promoter, the seed oil content was increased without compromising plant growth. The results suggest that pPLAIIIdelta alters the carbon partitioning by decreasing cellulose content and increasing oil content in camelina. PMID- 25557879 TI - Three-dimensional effect of pitch, roll, and yaw rotations on maxillomandibular complex movement. AB - OBJECTIVES: The purpose of this study was to evaluate the 3-dimensional (3D) effect of pitch, roll, and yaw rotations on maxillomandibular complex (MMC) movements in skeletal Class III surgical patients using 3D cone-beam computed tomography (CBCT) data and mathematical calculations. MATERIALS AND METHODS: Preoperative CBCT data of 152 skeletal Class III surgical patients was obtained. The subjects were divided into four groups: group 1, non-extraction with a normal/short face; group 2, non-extraction with a long face; group 3, extraction with a normal/short face; and group 4, extraction with a long face. The maxillary and mandibular landmarks were digitized on the reconstructed 3D models, and the movements of their standardized coordinates by pitch, roll, and yaw rotations were calculated using a transformation matrix. RESULTS: The rotations resulted in significantly different amounts of MMC movement among the groups, which generally increased from groups 1 to 4. While roll rotation greatly affected the lateral movement of the menton and the vertical movement of the gonion, yaw rotation primarily affected the lateral and anteroposterior movement of the gonion. Combined pitch and roll rotations were required for unilateral impaction of the maxillary first molar. CONCLUSION: The 3D surgical treatment objectives (STO) method was valuable for accurate prediction of MMC movements by pitch, roll, and yaw rotations, which are frequently required in orthognathic surgery patients. PMID- 25557880 TI - Design of antimicrobial peptide arenicin analogs with improved therapeutic indices. AB - beta-Hairpin antimicrobial peptides are among the most potent peptide antibiotics of animal origin. Arenicins, isolated earlier from marine polychaeta lugworm Arenicola marina, belong to a family of beta-hairpin antimicrobial peptides and display a broad spectrum of biological activities. However, despite being potent antimicrobials, arenicins are partially unapplicable as therapeutics as a result of their relatively high cytotoxicity against mammalian cells. In this study, a template-based approach was used to create therapeutically valuable analogs of arenicin-1 and identify amino acid residues important for antibacterial and cytotoxic activities of the peptide. The plasmids encoding recombinant analogs were constructed by mutagenesis technique based on inverse PCR amplification of the whole arenicin-1 expression plasmid. The analogs were produced as a part of the fusion proteins in Escherichia coli. It was shown that an obvious reduction in hemolytic activity without lose of antimicrobial activity can be achieved by a single amino acid substitution in the non-polar face of the molecule with hydrophilic residues such as serine and arginine. As the result, the selective analog with 50-fold improved therapeutic index was developed. The circular dichroism spectra demonstrated that the secondary structure of the analog was similar to the natural arenicin-1 in water solution and sodium dodecyl sulfate micelles but significantly differed in the presence of dodecylphosphocholine micelles mimicking mammalian membranes. Similarly to arenicin-1, the designed analog killed bacteria via induction of the membrane damage, assessed using the fluorescent dye SYTOX Green uptake. Our results afford molecular insight into mechanism of antimicrobial action of the designed arenicin analogs and their possible clinical application. PMID- 25557882 TI - Generation of a genetically encoded, photoactivatable intein for the controlled production of cyclic peptides. AB - Cyclic peptides are important natural products and hold great promise for the identification of new bioactive molecules. The split-intein-mediated SICLOPPS technology provides a generic access to fully genetically encoded head-to-tail cyclized peptides and large libraries thereof (SICLOPPS=split-intein circular ligation of peptides and proteins). However, owing to the spontaneous protein splicing reaction, product formation occurs inside cells, making peptide isolation inconvenient and precluding traditional in vitro assays for inhibitor discovery. The design of a genetically encoded, light-dependent intein using the photocaged tyrosine derivative ortho-nitrobenzyltyrosine incorporated at an internal, non-catalytic position is now reported. Stable intein precursors were purified from the E.coli expression host and subsequently subjected to light activation in vitro for both the regular protein splicing format and cyclic peptide production, including the natural product segetalin H as an example. The activity of the intein could also be triggered in living cells. PMID- 25557881 TI - Differences in caregiver-reported health problems and health care use in maltreated adolescents and a comparison group from the same urban environment. AB - Maltreated youth have a high prevalence of acute and chronic mental and physical health problems, but it is not clear whether these problems are related to maltreatment or to a disadvantaged environment. To compare health status and health care use of maltreated youth who had an open case with child protective services to comparison youth living in the same community, we conducted a secondary analysis of caregiver reports for 207 maltreated adolescents (mean age 11.9 years) and 142 comparison adolescents (mean age 12.3 years) living in urban Los Angeles, using questionnaire data from a larger longitudinal study framed in a socio-ecological model. Caregivers included biological parents, relatives, and unrelated caregivers. Analyses included t-test, MANOVA, chi-square, and multivariable logistic regression. Caregivers reported similar rates of physical health problems but more mental health problems and psychotropic medicine use in maltreated youth than in the comparison youth, suggesting that maltreated youths' higher rates of mental health problems could not be attributed to the disadvantaged environment. Although there were no differences in health insurance coverage, maltreated youth received preventive medical care more often than comparison youth. For all youth, having Medicaid improved their odds of receiving preventive health and dental care. Attention to mental health issues in maltreated adolescents remains important. Acceptance of Medicaid by neighborhood based and/or school-based services in low-income communities may reduce barriers to preventive care. PMID- 25557883 TI - Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. AB - OBJECTIVE: Nonimmune hydrops is the presence of >=2 abnormal fetal fluid collections in the absence of red cell alloimmunization. The most common etiologies include cardiovascular, chromosomal, and hematologic abnormalities, followed by structural fetal anomalies, complications of monochorionic twinning, infection, and placental abnormalities. We sought to provide evidence-based guidelines for the evaluation and management of nonimmune hydrops fetalis. METHODS: A systematic literature review was performed using MEDLINE, PubMed, EMBASE, and Cochrane Library. The search was restricted to English-language articles published from 1966 through June 2014. Priority was given to articles reporting original research, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Evidence reports and guidelines published by organizations or institutions such as the National Institutes of Health, Agency for Health Research and Quality, American Congress of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. Grading of Recommendations Assessment, Development, and Evaluation methodology was employed for defining strength of recommendations and rating quality of evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence. RESULTS AND RECOMMENDATIONS: Evaluation of hydrops begins with an antibody screen (indirect Coombs test) to determine if it is nonimmune, detailed sonography of the fetus(es) and placenta, including echocardiography and assessment for fetal arrhythmia, and middle cerebral artery Doppler evaluation for anemia, as well as fetal karyotype and/or chromosomal microarray analysis, regardless of whether a structural fetal anomaly is identified. Recommended treatment depends on the underlying etiology and gestational age; preterm delivery is recommended only for obstetric indications including development of mirror syndrome. Candidates for corticosteroids and antepartum surveillance include those with an idiopathic etiology, an etiology amenable to prenatal or postnatal treatment, and those in whom intervention is planned if fetal deterioration occurs. Such pregnancies should be delivered at a facility with the capability to stabilize and treat critically ill newborns. The prognosis depends on etiology, response to therapy if treatable, and the gestational age at detection and delivery. Aneuploidy confers a poor prognosis, and even in the absence of aneuploidy, neonatal survival is often <50%. Mirror syndrome is a form of severe preeclampsia that may develop in association with fetal hydrops and in most cases necessitates delivery. PMID- 25557884 TI - Amphiphilic PEO-b-PBLG diblock and PBLG-b-PEO-b-PBLG triblock copolymer based nanoparticles: doxorubicin loading and in vitro evaluation. AB - Huisgen's 1,3-dipolar cycloaddition ("Click Chemestry") has been used to prepare amphiphilic PEO-b-PBLG diblock and PBLG-b-PEO-b-PBLG triblock copolymers as potential carriers of anticancer drugs. Spherical and flower shaped micelles (D ~ 100 nm) were obtained from diblock and triblock copolymers respectively. DOX was effectively encapsulated up to 18 wt.% and 50-60% of it was steadily released from the micelles over a period of 7 d. Flow cytometry and fluorescence microscopy confirmed the effective intracellular uptake as well as the sustained release of DOX from micelles. These results suggest that the diblock as well as triblock copolymers are promising carriers for intra-cellular drug delivery. PMID- 25557885 TI - Clustering clinical models from local electronic health records based on semantic similarity. AB - BACKGROUND: Clinical models in electronic health records are typically expressed as templates which support the multiple clinical workflows in which the system is used. The templates are often designed using local rather than standard information models and terminology, which hinders semantic interoperability. Semantic challenges can be solved by harmonizing and standardizing clinical models. However, methods supporting harmonization based on existing clinical models are lacking. One approach is to explore semantic similarity estimation as a basis of an analytical framework. Therefore, the aim of this study is to develop and apply methods for intrinsic similarity-estimation based analysis that can compare and give an overview of multiple clinical models. METHOD: For a similarity estimate to be intrinsic it should be based on an established ontology, for which SNOMED CT was chosen. In this study, Lin similarity estimates and Sokal and Sneath similarity estimates were used together with two aggregation techniques (average and best-match-average respectively) resulting in a total of four methods. The similarity estimations are used to hierarchically cluster templates. The test material consists of templates from Danish and Swedish EHR systems. The test material was used to evaluate how the four different methods perform. RESULT AND DISCUSSION: The best-match-average aggregation technique performed better in terms of clustering similar templates than the average aggregation technique. No difference could be seen in terms of the choice of similarity estimate in this study, but the finding may be different for other datasets. The dendrograms resulting from the hierarchical clustering gave an overview of the templates and a basis of further analysis. CONCLUSION: Hierarchical clustering of templates based on SNOMED CT and semantic similarity estimation with best-match-average aggregation technique can be used for comparison and summarization of multiple templates. Consequently, it can provide a valuable tool for harmonization and standardization of clinical models. PMID- 25557886 TI - Pathologic and imunohistochemical characterization of tumoral inflammatory cell infiltrate in invasive penile squamous cell carcinomas: Fox-P3 expression is an independent predictor of recurrence. AB - Penile carcinomas (PeCa) are relatively rare, but devastating neoplasms, more frequent among people of underprivileged socioeconomic status. There is mounting evidence that immune cells may trigger various mechanisms that enhance tumor growth and metastasis, but no data on the peritumoral inflammation is available for PeCa. The objectives of the present study are to evaluate the immunohistomorphology of tumoral inflammation in PeCa, and to correlate it with clinicopathological parameters, which could contribute to the prognostic evaluation. One hundred and twenty-two patients with the diagnosis of usual-type squamous cell penile carcinoma were included. Paraffin-embedded tissue was submitted to immunohistochemical evaluation of p16 protein, CD3, CD4, CD8, CD20, CD68, CD138, granzyme B, and Fox-P3. The Fisher's exact test was employed for comparison between histological variables and parameters, and the Kaplan-Meier method for the analysis of survival. Improved 5-year overall survival was significantly associated to age <=60 years, stage I + II, tumor size T1 + T2, lymph node status N0, and absent perineural invasion. In a multivariate analysis age >=60 years, presence of lymph node metastasis, urethral invasion, and high histologic grade retained a significantly more unfavorable outcome. Improved 5 year failure free survival was associated to stage of the disease I + II, lymph node status N0, absence of perineural, vascular, and urethral invasion, and Fox P3 expression. In a multivariate analysis, presence of lymph node metastasis, perineural and vascular invasion, and of Fox-P3-positive lymphocytes together with low inflammatory infiltrate retained a significantly more unfavorable outcome. These results support the prognostic value of determining the levels of Fox-P3-positive lymphocytes by immunohistochemistry in PeCa, as this parameter adds value to the traditional clinicopathological features. PMID- 25557887 TI - Antimicrobial peptide m2163 or m2386 identified from Lactobacillus casei ATCC 334 can trigger apoptosis in the human colorectal cancer cell line SW480. AB - Ribosomal synthesized antimicrobial peptides (AMPs) are widely distributed in nature and are toxic to certain microorganisms. Some of these AMPs are found to exhibit cytotoxic activity against the growth of cancer cells and thus have obvious anticancer potential. Here, we have studied the antiproliferation on the human colorectal cancer cell line SW480 of two AMPs, namely m2163 and m2386, identified by us from a lactic acid bacterium Lactobacillus casei ATCC 334 previously. A half maximal inhibitory concentration (IC50) of 40 MUg/ml is determined first using the MTT (3-(4, 5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay for either peptide m2163 or m2386. The apoptosis in treated SW480 cells by either peptide m2163 or m2386 is analyzed using flow cytometry with annexin V-fluorescein isothiocyanate (FITC) and propidium iodide double staining. These analyses show that a substantial population of treated SW480 cells can undergo apoptosis by either peptide m2163 or m2386. The real-time quantitative polymerase chain reaction (qPCR) and Western blot analyses are subsequently used to study how the apoptosis is induced in the treated SW480 cells by either peptide m2163 or m2386. While m2163 is found to induce the expression of Fas and TRAILR1, the expression of Fas, TNFR1, and TRAILR1 death receptors on the cell surface of treated SW480 cells is found to be induced by m2386. Further, the expression of some mitochondria-related apoptosis proteins such as Smac is found to be also induced, suggesting that either peptide m2163 or m2386 can trigger both the extrinsic and intrinsic apoptosis pathways. The cell membrane permeability is greatly enhanced upon treatment with either peptide m2163 or m2386 as analyzed by the flow cytometry using both FITC-labeled peptides. The flow cytometry is also used to analyze the fluorescence intensity given by FITC-m2163 in either the mitochondria or cytoplasm fraction of the treated and fractionated SW480 cells. It is found that the detected fluorescence intensity of the mitochondria fraction is much weaker than that of the cytoplasm one, suggesting that most of the FITC-m2163 peptides are located in the cytoplasm rather than the mitochondria. This is further confirmed by a confocal microscopy study that either peptide m2163 or m2386 can localize on the cell membrane for a substantial length of time and then penetrate into the cell cytoplasm to induce the apoptosis. PMID- 25557888 TI - Anxiety in Parkinson's disease: Symptom dimensions and overlap with depression and autonomic failure. AB - INTRODUCTION: Anxiety disorders are highly prevalent in patients with Parkinson's disease (PD) and have a major impact on wellbeing. They nevertheless receive limited scientific attention. This study aimed to establish the symptom dimensions of anxiety in PD, and their relationship with depression, autonomic failure and motor symptoms. METHODS: In this cross-sectional observational study, symptoms of anxiety were measured with the Beck Anxiety Inventory (BAI) in 294 PD patients. Symptom dimensions of anxiety in PD were explored through principal component analysis (PCA) of BAI items. The relationship between anxiety and depressive, autonomic and motor symptoms was assessed through PCA and regression analyses. RESULTS: Clinically relevant symptoms of anxiety were present in 45% of patients. PCA of the BAI resulted in five subscales, corresponding to a single affective and four somatic symptom dimensions (thermoregulation, hypotension, hyperventilation and trembling) of anxiety. Symptoms of anxiety and depression displayed a large overlap. All somatic BAI subscales were significantly influenced by motor and autonomic symptoms, while the affective subscale was not. CONCLUSION: Anxiety in PD comprises affective and somatic symptom dimensions. The affective subscale of the BAI is not influenced by motor or autonomic symptoms, and may therefore prove useful for future research. Scores on the somatic subscales of the BAI were associated with autonomic failure and motor impairment, demonstrating a strong interplay between motor and non-motor symptoms in PD. These results stress the importance of a holistic approach of anxiety in PD. PMID- 25557889 TI - Are E-cigarettes a safe and good alternative to cigarette smoking? AB - Electronic cigarettes (E-cigarettes) are devices that can vaporize a nicotine solution combined with liquid flavors instead of burning tobacco leaves. Since their emergence in 2004, E-cigarettes have become widely available, and their use has increased exponentially worldwide. E-cigarettes are aggressively advertised as a smoking cessation aid; as healthier, cheaper, and more socially acceptable than conventional cigarettes. In recent years, these claims have been evaluated in numerous studies. This review explores the development of the current E cigarette and its market, prevalence of awareness, and use. The review also explores the beneficial and adverse effects of E-cigarettes in various aspects in accordance with recent research. The discussed aspects include smoking cessation or reduction and the health risks, social impact, and environmental consequences of E-cigarettes. PMID- 25557890 TI - The faster the better: anastomosis time influences patient survival after deceased donor kidney transplantation. AB - Despite a continuously growing knowledge of the impact of factors on kidney graft function, such as donor age, body mass index, and cold ischemia time, few data are available regarding anastomosis time (AT) and its impact on long-term results. We investigated whether surgical AT correlates with patient and graft survival after kidney transplantation performing a retrospective analysis of 1245 consecutive deceased donor kidney transplantations between 01/2000 and 12/2010 at Innsbruck Medical University. Kaplan-Meier and log-rank analyses were carried out for 1- and 5-year patient and graft survival. AT was defined as time from anastomosis start until reperfusion. Median AT was 30 min. Five-year survival of allografts with an AT >30 min was 76.6% compared with 80.6% in the group with AT <30 min (P = 0.027). Patient survival in the group with higher AT similarly was inferior with 85.7% after 5 years compared with 89.6% (P < 0.0001) [Correction added on February 18, 2015, after first online publication: the percentage value for patient survival was previously incorrect and have now been changed to 89.6%]. Cox regression analysis revealed AT as an independent significant factor for patient survival (HR 1.021 per minute; 95% CI 1.006-1.037; P = 0.006). As longer AT closely correlates with inferior long-term patient survival, it has to be considered as a major risk factor for inferior long-term results after deceased donor kidney transplantation. PMID- 25557891 TI - Preference mapping of dulce de leche commercialized in Brazilian markets. AB - Dulce de leche samples available in the Brazilian market were submitted to sensory profiling by quantitative descriptive analysis and acceptance test, as well sensory evaluation using the just-about-right scale and purchase intent. External preference mapping and the ideal sensory characteristics of dulce de leche were determined. The results were also evaluated by principal component analysis, hierarchical cluster analysis, partial least squares regression, artificial neural networks, and logistic regression. Overall, significant product acceptance was related to intermediate scores of the sensory attributes in the descriptive test, and this trend was observed even after consumer segmentation. The results obtained by sensometric techniques showed that optimizing an ideal dulce de leche from the sensory standpoint is a multidimensional process, with necessary adjustments on the appearance, aroma, taste, and texture attributes of the product for better consumer acceptance and purchase. The optimum dulce de leche was characterized by high scores for the attributes sweet taste, caramel taste, brightness, color, and caramel aroma in accordance with the preference mapping findings. In industrial terms, this means changing the parameters used in the thermal treatment and quantitative changes in the ingredients used in formulations. PMID- 25557892 TI - Effect of condensed corn distillers solubles concentration on lactation performance of Holstein cows. AB - Forty-eight Holstein cows (32 multiparous and 16 primiparous) in mid to late lactation averaging 219+/-71 days in milk and 30.5+/-6.6 kg/d of 3.5% fat corrected milk were used in a 56-d completely randomized design experiment to evaluate condensed corn distillers solubles (CCDS) inclusion in high-fiber total mixed rations (TMR). Inclusion rates evaluated were 0, 6.6, 13.2, and 19.8% CCDS as a percentage of dry matter (DM). Distiller solubles substituted for soybean meal, corn grain, and whole cottonseed such that diets were similar in protein (16.6%) and fat (4.50%). Water was added to 0, 6.6, and 13.2% CCDS treatments so that final TMR DM concentrations (47.8%) were similar across diets. The forage portion of the diet was kept constant at 19.6% annual ryegrass hay and 26.0% sorghum baleage. Diet in vitro true digestibility tended to increase as CCDS addition increased, but neutral detergent fiber digestibility trended lower in CCDS diets. Percent P (0.39, 0.55, 0.69, and 0.73%) and S (0.32, 0.35, 0.39, and 0.42%) in TMR increased as CCDS concentration increased. Milk yield (23.5, 24.7, 25.5, and 24.8 kg/d of 3.5% fat-corrected milk) was similar for control and CCDS diets. Milk fat (3.88, 3.73, 3.78, and 3.68%), protein (3.28, 3.27, 3.31, and 3.31%), and lactose (4.61, 4.66, 4.69, and 4.77) percentages were similar across diets. Milk urea nitrogen (16.60, 15.58, 15.43, and 14.75 mg/dL) declined with increasing CCDS addition. Animal activity, body weight, body condition scores, and locomotion scores were not influenced by CCDS. Day 28 poststudy locomotion scores were similar across diets. Ruminal acetate concentrations did not differ among diets, but propionate and butyrate concentrations were elevated in rumen fluid of cows receiving 19.6% CCDS. Although rumen fluid pH values were similar (6.5, 6.4, 6.3, and 6.2), the two highest CCDS diets exhibited depressed acetate:propionate ratios relative to controls. The results from this study indicate that CCDS may be included in high-fiber TMR for lactating dairy cows at up to nearly 20% of diet DM; however, caution is recommended because high CCDS P concentrations may create Ca:P imbalances and excess P may be introduced into the environment. PMID- 25557893 TI - Differences in leukocyte profile, gene expression, and metabolite status of dairy cows with or without sole ulcers. AB - Sole ulcers are one of the most severe pathologies causing lameness in dairy cows and are associated with abnormal behavior and impaired production performance. However, little is known about how or whether lameness caused by sole ulcers affects the cow systemically. This study compared hematology profile, leukocyte gene expression, and physiological responses [metabolite, cortisol, the endogenous steroid hormone dehydroepiandrosterone (DHEA), and haptoglobin concentrations] of cows with sole ulcers and healthy cows. Twelve clinically lame cows (lame) were identified as having at least one sole ulcer and no other disorder, and matched with a cow that had good locomotion and no disorders (sound), using days in milk, liveweight, body condition score, and diet. Blood samples were taken from all 24 cows within 24h of sole ulcer diagnosis. Leukocyte counts were obtained using an automated cell counter, cortisol and DHEA concentration by ELISA, and plasma haptoglobin, urea, total protein, creatine kinase, and glucose were analyzed on an Olympus analyzer. Expression of 16 genes associated with lameness or stress were estimated using reverse transcription PCR. Data were analyzed using the MIXED procedure in SAS software (version 9.3; SAS Institute Inc., Cary, NC). Lame cows had a higher neutrophil percentage, a numerically lower lymphocyte percentage, and tended to have a higher neutrophil:lymphocyte ratio than sound cows. Serum cortisol and DHEA concentrations were higher in lame than in sound cows. Lame cows also tended to have higher haptoglobin and glucose levels than sound, as well as higher protein yet lower urea levels. Sound cows tended to have higher relative expression of the gene coding for colony-stimulating factor 2 than lame, but in all other cases where differences were detected in cytokine gene expression (IL-1alpha, IL-1beta, CXCL8, and IL-10), relative gene expression in sound cows tended to be, or was, lower than in lame. Relative expression of MMP-13, GR-alpha, Fas, haptoglobin, and CD62L were, or tended to be, higher in lame than sound cows. A high neutrophil:lymphocyte ratio in combination with higher cortisol levels in cows with ulcers is indicative of physiological stress. Moreover, increased DHEA and a higher cortisol:DHEA ratio, as well as a tendency for higher haptoglobin levels and increased haptoglobin mRNA expression, are indicative of systemic inflammation. Increased cytokine mRNA expression indicates activation of the immune system compared with healthy cows. Increased expression of MMP-13 mRNA has been found in cows with impaired locomotion and thus could be implicated in development of claw horn disorders. PMID- 25557894 TI - Technical note: Rapid calculation of genomic evaluations for new animals. AB - A method was developed to calculate preliminary genomic evaluations daily or weekly before the release of official monthly evaluations by processing only newly genotyped animals using estimates of single nucleotide polymorphism effects from the previous official evaluation. To minimize computing time, reliabilities and genomic inbreeding are not calculated, and fixed weights are used to combine genomic and traditional information. Correlations of preliminary and September official monthly evaluations for animals with genotypes that became usable after the extraction of genotypes for August 2014 evaluations were >0.99 for most Holstein traits. Correlations were lower for breeds with smaller population size. Earlier access to genomic evaluations benefits producers by enabling earlier culling decisions and genotyping laboratories by making workloads more uniform across the month. PMID- 25557895 TI - The effect of dietary cation-anion difference concentration and cation source on milk production and feed efficiency in lactating dairy cows. AB - Feed costs currently account for 55% or more of the total cost of milk production in US dairy herds, and dairy producers are looking for strategies to improve feed efficiency [FE; 3.5% fat-corrected milk (FCM) per dry matter (DM) intake]. Increasing dietary cation-anion difference [DCAD; Na+K-Cl (mEq/kg of DM)] has been shown to increase milk production, FCM, and FE. However, the optimal DCAD concentration for maximal FE has yet to be determined. The objectives of this research were to test the effects of DCAD concentration and cation source on dairy FE. Sixty Holstein dairy cows (20 cows per experiment) were used in three 4*4 Latin square design experiments with 3-wk experimental periods. In experiments 1 and 2, we tested the effect of DCAD concentration: cows were fed a basal diet containing ~250 mEq/kg of DM DCAD that was supplemented with potassium carbonate at 0, 50, 100, and 150 mEq/kg of DM or 0, 125, 250, and 375 mEq/kg of DM in experiments 1 and 2, respectively. In experiment 3, we tested the effect of cation source: sodium sesquicarbonate replaced 0, 33, 67, and 100% of the supplemental potassium carbonate (150 mEq/kg of DM DCAD). The DCAD concentration had no effect on milk production, milk protein concentration, or milk protein yield in experiments 1 and 2. Dry matter intake was not affected by DCAD concentration in experiment 1 or by cation source in experiment 3. However, DMI increased linearly with increasing DCAD in experiment 2. We detected a linear increase in milk fat concentration and yield with increasing DCAD in experiments 1 and 2 and by substituting sodium sesquicarbonate for potassium carbonate in experiment 3. Increased milk fat concentration with increasing DCAD led to increases in 3.5% FCM in experiments 1 and 2. Maximal dairy FE was achieved at a DCAD concentration of 426 mEq/kg of DM in experiments 1 and 2 and by substituting Na for K in experiment 3. The results of these experiments suggest that both DCAD concentration and the cation source used to alter DCAD concentration have effects on milk fat content and yield and dairy FE. PMID- 25557896 TI - Partial suckling of lambs reduced the linoleic and conjugated linoleic acid contents of marketable milk in Chios ewes. AB - The objective of this work was to investigate the effect of weaning systems applied in a commercial dairy sheep farm on the fatty acid (FA) composition of marketable milk produced. Forty second parity, purebred Chios ewes were allocated to the following weaning treatments: (a) ewes were weaned from their lambs at 48 h after birth and machine milked twice daily [no lambs (NL) group, n=20]; or, (b) starting 48 h postpartum, ewes were separated from their lambs for 12h during the evening, machine milked once daily the following morning, and lambs were allowed to suckle for 12 h during the day for the first 5 wk of lactation [partial suckling (PS) group, n=20]. After weaning of the PS lambs at wk 6 of age, all ewes were machine milked twice daily. Commercial milk yield and milk composition was recorded weekly (fat, protein, FA content) or fortnightly (somatic cell counts) throughout the first 10 wk of lactation. The PS ewes compared with NL group produced commercial milk lower in milk yield, milk fat, and somatic cell counts, but not in protein content during the first 5-wk period. Such differences were not observed after weaning of the PS lambs. The FA profile of commercial milk was also affected by partial suckling during the preweaning period. Total polyunsaturated FA were higher in NL compared with PS ewe milk at wk 1, 2, 4, and 5 (on average, 21% higher), whereas no differences were detected between NL and PS ewe milk from wk 6 to 10 of lactation. From the polyunsaturated FA, linoleic acid (C18:2 cis-9,cis-12) and conjugated linoleic acid (C18:2 cis-9,trans-11; rumenic acid) were particularly affected, showing on average a reduction of 18 and 38%, respectively. From the monounsaturated FA, vaccenic acid (C18:1 trans 11) was affected during wk 1 and 2 of the treatment period, with the PS ewe milk having reduced content compared with the NL milk. Other unsaturated FA, such as oleic acid and alpha-linolenic acid, or saturated FA were not found to be affected by the weaning treatment. The results indicate that partial suckling of lambs during the first 5 wk of lactation adversely affected both the total fat content of milk obtained by machine milking of their dams and the unsaturation content of the milk fat. Particularly affected were the linoleic acid and cis 9,trans-11 conjugated linoleic acid content of ewe milk. PMID- 25557897 TI - Fatty acid profile differs between organic and conventionally produced cow milk independent of season or milking time. AB - Differing amounts of fresh forage and concentrates fed, and level of input contributes to the differences reported in fatty acid (FA) composition of organic and conventionally produced cow milk. In many previous studies designed to investigate this phenomenon, comparisons were made between grazed organic cows and housed conventional cows. In the present study, we have investigated differences between organic and conventional milk produced using year-round pasture grazing, as practiced in New Zealand. The FA composition was determined in milk sampled at morning and evening milking in both spring and autumn. Samples were taken from 45 cows from the Massey University organic herd and compared with 50 cows from the corresponding conventional herd grazed and managed similarly at the same location. Forty-three out of 51 analyzed FA were influenced by season, whereas 28 were different between production systems. In addition, one-half were also different due to time of milking. Levels of linoleic acid and alpha linolenic acid were higher in organic milk, whereas conjugated linoleic acid (CLA) and vaccenic acid were higher in conventional milk. The first 3 FA (linoleic acid, alpha-linolenic acid, and CLA) were more abundant in milk harvested during autumn, and the CLA concentration was also significantly influenced by time of milking. Our results confirm reports that the FA profile is affected by season and time of milking, and we also showed an effect due to the production system, when both sets of cows were kept continuously on pasture, even after taking milking time and seasonal effect into account. PMID- 25557900 TI - The effect of education on regional brain metabolism and its functional connectivity in an aged population utilizing positron emission tomography. AB - Education involves learning new information and acquiring cognitive skills. These require various cognitive processes including learning, memory, and language. Since cognitive processes activate associated brain areas, we proposed that the brains of elderly people with longer education periods would show traces of repeated activation as increased synaptic connectivity and capillary in brain areas involved in learning, memory, and language. Utilizing positron emission topography (PET), this study examined the effect of education in the human brain utilizing the regional cerebral glucose metabolism rates (rCMRglcs). 26 elderly women with high-level education (HEG) and 26 with low-level education (LEG) were compared with regard to their regional brain activation and association between the regions. Further, graphical theoretical analysis using rCMRglcs was applied to examine differences in the functional network properties of the brain. The results showed that the HEG had higher rCMRglc in the ventral cerebral regions that are mainly involved in memory, language, and neurogenesis, while the LEG had higher rCMRglc in apical areas of the cerebrum mainly involved in motor and somatosensory functions. Functional connectivity investigated with graph theoretical analysis illustrated that the brain of the HEG compared to those of the LEG were overall more efficient, more resilient, and characterized by small worldness. This may be one of the brain's mechanisms mediating the reserve effects found in people with higher education. PMID- 25557899 TI - Synthesis and biological activities of some new isonicotinic acid 2-(2-hydroxy-8 substituted-tricyclo[7.3.1.0(2.7)]tridec-13-ylidene)-hydrazides. AB - A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8 substituted-tricyclo[7.3.1.0(2.7)]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.0(2.7)]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6. It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3, but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT 8 cell lines. The expression level of CYP3A4 was increased by compounds 1, 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co administration with new compounds in slow acetylators. PMID- 25557901 TI - Brainstem-sparing craniospinal irradiation delivered with pencil beam scanning proton therapy. AB - Delivery of craniospinal irradiation (CSI) is a curative approach to recurrent ependymoma, but is associated with risks from re-irradiation, particularly of the brainstem. Pencil beam scanning proton therapy allows delivery of CSI with sparing of normal tissues. Here, we describe a case of brainstem-sparing CSI that resulted in excellent coverage of the craniospinal axis with minimal radiation to brainstem. This is a novel concept that compares favorably to previously described methods using x-rays that may result in underdosing of surrounding tissues in effort to spare brainstem. PMID- 25557902 TI - Clifton A. Baile, Ph.D. (1940-2014). PMID- 25557903 TI - Omega-3 fatty acid profile of eggs from laying hens fed diets supplemented with chia, fish oil, and flaxseed. AB - The aim of this study was to investigate the effect of diets supplemented with fish oil, flaxseed, and chia seed on the omega-3 fatty acid composition and sensory properties of hens' eggs. No significant difference in yolk fat content was found between treatments. The fatty acid composition of egg yolk was significantly affected by the dietary treatments. Inclusion of chia at 300 g/kg into the diet produced eggs with the highest concentration of omega-3 fatty acid. Eicosapentaenoic acid and docosahexaenoic acid were only detected in eggs from laying hens fed the diet supplemented with fish oil. Diet had a significant effect on color, flavor and overall acceptability of eggs. Types and levels of omega-3 fatty acids in feed influence the level of yolk omega-3 fatty acids in egg yolk. Inclusion of chia into the hens' diet significantly increased the concentration of yolk omega-3 fatty acid without significant change in sensory properties. PMID- 25557904 TI - The quest for tailored treatments: a meta-discussion of six social cognitive therapies. AB - In this commentary on the 6 articles comprising this In Session issue on metacognition and mentalizing in the psychotherapeutic treatment of severe mental disorders, we strive to contextualize and bring together salient issues reflected in these articles. In the foreground of our discussion is the point that the commonalities of these and related social cognitive treatments far outweigh their differences. We attempt to pinpoint some of the more specific tailored treatment elements described by the authors and relate these to empirical findings and theoretical and practical problems. Among the key issues addressed in this commentary are conceptual fallacies, therapist transparency, personality disorder and self-harm in adolescence, therapeutic alliance, and a metacognitive-informed group psychotherapy practice for patients with avoidant personality disorder or alexithymia. PMID- 25557905 TI - Procedural failure of chronic total occlusion percutaneous coronary intervention: Insights from a multicenter US registry. AB - BACKGROUND: The hybrid approach to chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has significantly increased procedural success rates, yet some cases still fail. We sought to evaluate the causes of failure in a contemporary CTO PCI registry. METHODS: We examined 380 consecutive patients who underwent CTO-PCI at 4 high volume CTO PCI centers in the United States using the "hybrid" approach. Clinical, angiographic, complication, and efficiency outcomes were compared between successful and failed cases. Failed cases were individually reviewed by an independent reviewer to determine the cause of failure. RESULTS: Procedural success was 91.3%. Compared with patients in whom CTO PCI was successful, those in whom CTO PCI failed had similar baseline clinical characteristics, but were more likely to have longer occlusion length, more tortuosity, more proximal cap ambiguity and blunt stump, and higher mean J-CTO scores (2.8 +/- 1.1 vs. 3.5 +/- 1.0, P < 0.001), and less likely to have collaterals suitable for the retrograde approach (66% vs. 45%, P = 0.021). Failure was due to a complication in 10 cases (30%). In the remaining 23 cases (70%) failure was due to inability to wire the lesion (n = 21, 4 of which were CTOs due to in-stent restenosis), or poor antegrade flow after PCI (n = 5). CONCLUSIONS: Compared with successful cases, failed CTO-PCI cases are more likely to have higher J-CTO scores, longer occlusion length, ambiguous proximal cap and no appropriate collaterals for retrograde crossing. Development of novel CTO crossing techniques is needed to further increase CTO PCI success rates. PMID- 25557906 TI - Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. AB - Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is associated with accelerated progression of liver disease, frequently leading to graft loss and early death. Existing treatment options for severe recurrent HCV infection are limited by suboptimal efficacy, poor tolerability, and numerous drug interactions. We provided sofosbuvir (SOF) and ribavirin (RBV) on a compassionate-use basis to patients with severe recurrent hepatitis C, including those with fibrosing cholestatic hepatitis (FCH) and decompensated cirrhosis who had a life expectancy of 1 year or less. All patients were to receive 24-48 weeks of SOF plus RBV. Investigators could add pegylated interferon to the regimen at their discretion. Data from the first 104 patients who completed or prematurely discontinued treatment by January 1, 2014 are presented. Of the 104 patients analyzed, 52 had an early severe recurrence (diagnosed <12 months after LT) and 52 had cirrhosis (diagnosed >12 months after LT). Twelve patients who underwent retransplantation were excluded from our efficacy analysis. Of the 92 patients assessed, 54 (59%) achieved sustained virological response (SVR) at 12 weeks after the end of treatment, with a higher rate (73%; 35 of 48) in patients with early severe recurrence. Of the 103 patients assessed for clinical outcome, 59 (57%) reported clinical improvement at the last study visit, 23 (22%) were unchanged, 3 (3%) had a worsened clinical status, and 13 (13%) died. Overall, 123 serious adverse events (SAEs) occurred in 49 patients (47%). SAEs associated with hepatic decompensation were the most frequent, with 26 SAEs occurring in 19 patients (18%). CONCLUSION: SOF and RBV provide high rates of SVR in patients with severe recurrent HCV, including patients with early severe recurrence, FCH, and cirrhosis. PMID- 25557907 TI - Effects of cigarette smoking on erectile dysfunction. AB - Cigarette smoking is a leading cause of preventable morbidity and mortality in the United States. Although public policies have resulted in a decreased number of new smokers, smoking rates remain stubbornly high in certain demographics with 20% of all American middle-aged men smoking. In addition to the well-established harmful effects of smoking (i.e. coronary artery disease and lung cancer), the past three decades have led to a compendium of evidence being compiled into the development of a relationship between cigarette smoking and erectile dysfunction. The main physiologic mechanism that appears to be affected includes the nitric oxide signal transduction pathway. This review details the recent literature linking cigarette smoking to erectile dysfunction, epidemiological associations, dose dependency and the effects of smoking cessation on improving erectile quality. PMID- 25557908 TI - Tinea capitis in schoolchildren in a rural area in southern Ethiopia. AB - OBJECTIVES: Skin diseases, especially tinea capitis, represent some of the most frequent causes of morbidity in developing countries. The aim of this study was to examine the prevalences of fungal infections in schoolchildren in a primary school located in a rural area in southern Ethiopia and to perform an analysis of the risk factors associated with tinea capitis. METHODS: This school-based, prospective cross-sectional study was conducted in October 2012 in Gambo School, Kore, West Arsi, Oromya Region, Ethiopia. Detailed interviews and dermatological examinations were performed. No laboratory examinations were conducted. RESULTS: A total of 647 students were interviewed and examined. The mean age of these children was 10 years (range: 4-14 years). Of the children examined, 236 had some type of dermatophytosis (prevalence: 36.5%, 95% confidence interval [CI] 32.8 40.3), which represented the most frequent type of skin problem. The prevalence of dermatophytoses was more common in males than in females (42.2% and 30.5%, respectively; P = 0.002), and among pupils aged 5-7 years (46.9%; P < 0.001). A total of 159 (prevalence: 24.6%, 95% CI 21.3-28.1) children had tinea capitis, 56 (8.7%) had tinea pedis, 50 (7.7%) had tinea corporis, and six (0.9%) had tinea unguium. In multivariate analysis, the risk factors for tinea capitis were: age (odds ratio [OR] 0.75, 95% CI 0.69-0.84; P < 0.001), and male gender (OR 2.56, 95% CI 1.69-13.39; P = 0.002). CONCLUSIONS: Fungal dermatoses, especially tinea capitis, are common in primary schoolchildren in rural areas of southern Ethiopia, especially in young boys. PMID- 25557909 TI - Iatrogenic anemia/Twenty-five million liters of blood into the sewer: comment. PMID- 25557910 TI - Composition of mineralizing incisor enamel in cystic fibrosis transmembrane conductance regulator-deficient mice. AB - Formation of crystals in the enamel space releases protons that need to be buffered to sustain mineral accretion. We hypothesized that apical cystic fibrosis transmembrane conductance regulator (CFTR) in maturation ameloblasts transduces chloride into forming enamel as a critical step to secrete bicarbonates. We tested this by determining the calcium, chloride, and fluoride levels in developing enamel of Cftr-null mice by quantitative electron probe microanalysis. Maturation-stage enamel from Cftr-null mice contained less chloride and calcium than did wild-type enamel, was more acidic when stained with pH dyes ex vivo, and formed no fluorescent modulation bands after in vivo injection of the mice with calcein. To acidify the enamel further we exposed Cftr null mice to fluoride in drinking water to stimulate proton release during formation of hypermineralized lines. In Cftr-deficient mice, fluoride further lowered enamel calcium without further reducing chloride levels. The data support the view that apical CFTR in maturation ameloblasts tranduces chloride into developing enamel as part of the machinery to buffer protons released during mineral accretion. PMID- 25557912 TI - Erythema nodosum leprosum on glans penis: unusual manifestation of common disease. AB - BACKGROUND: Erythema nodosum leprosum (ENL) classically presents as tender evanescent skin nodules involving extremities, trunk, and face but may appear at any site. Mucosal involvement in ENL is uncommon, and its occurrence over glans is extremely rare. METHOD: We describe two interesting cases of ENL involving the glans penis and prepuce with different presentations. RESULT: The first case had lepromatous leprosy with ENL with involvement of the glans penis in the form of a painful ulcer with necrotic slough. The second case had borderline lepromatous leprosy with ENL with involvement of glans in the form of a single painful nodule. Histopathology showed features of ENL, and Ziehl-Neelsen staining showed numerous acid fast bacilli. CONCLUSION: We should be aware of genital involvement of ENL, which is a rare presentation and needs to be differentiated from other conditions requiring a different management approach. PMID- 25557911 TI - Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control. AB - Cells respond to DNA damage by activating cell cycle checkpoints to delay proliferation and facilitate DNA repair. Here, to uncover new checkpoint regulators, we perform RNA interference screening targeting genes involved in ubiquitylation processes. We show that the F-box protein cyclin F plays an important role in checkpoint control following ionizing radiation. Cyclin F depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein cyclin F with suppression of the B-Myb/cyclin A pathway to ensure a DNA damage-induced checkpoint response in G2. PMID- 25557913 TI - The usefulness of biomarkers of alcohol abuse in hair and serum carbohydrate deficient transferrin: a case report. AB - The detection of carbohydrate-deficient transferrin (CDT) in serum is widely accepted to identify chronic alcohol consumption over the previous two weeks, but minor ethanol metabolites detected in hair often complete the information obtained. In particular, ethylglucuronide and cocaethylene (a marker of simultaneous intake of cocaine and alcohol) allow correct interpretation of data obtained in forensic cases. We refer to a negative CDT value obtained from a serum sample collected during hospitalization of a man admitted for cardiac arrest who died about 14 h later. Clinical analysis performed on admission showed a high ethanol level and a positive urinary screening for cocaine. The toxicological analyses of post-mortem samples found cocaine metabolites in his urine and blood. The negative CDT level suggested the ethanol concentration at admission to be an acute episode. Cocaine and cocaethylene well above the cut-off suggested by the literature were found in hair analyzed for the entire length (about 1 cm). Ethylglucuronide detected on the same hair sample confirmed chronic abuse of ethanol in the previous month, at least. The present report suggests caution in the interpretation of biomarkers of alcohol abuse, encouraging the detection of more than one marker to avoid misinterpretation. PMID- 25557914 TI - Identification of a novel compound heterozygous mutation in PTPRQ in a DFNB84 family with prelingual sensorineural hearing impairment. AB - With a prevalence of 0.1 %, hearing loss is among the most common sensory impairments and affects several million people around the world. Identification of deafness-related genes or loci may facilitate basic research and clinical translational research of the disorder. The PTPRQ gene encodes protein tyrosine phosphatase receptor Q, which is required for the formation of shaft connectors and the normal maturation and development of hair bundles in the mammalian cochlea. Here, we present the genetic and molecular characteristics of a Kazakh family with an autosomal recessive non-syndromic hearing impairment, DFNB84. Using whole-exome sequencing, we identified two mutations that together form a novel compound heterozygous mutation in PTPRQ. Sanger sequencing confirmed that the affected members inherited both the c.16_17insT (L8fsX18) and c.2714delA (E909fsX922) mutations. Both mutations lead to a frameshift and a truncated form of the protein. The novel compound heterozygous mutation co-segregated with hearing loss in this family, and neither of the two mutations was found in 200 healthy Kazakh controls or in any of the public databases. In the study, we identified novel mutations in PTPRQ responsible for DFNB84. This is the third report of PTPRQ mutations involved in deafness and the first report of familial deafness in China. The identification of novel mutations in PTPRQ presented here further confirms the essential role of PTPRQ in hearing development and auditory function. Our data provide additional molecular information for establishing a better genotype-phenotype understanding of DFNB84. PMID- 25557916 TI - Crk and CrkL are required for cell transformation by v-fos and v-ras. AB - Crk and CrkL are SH2- and SH3-containing cytosolic adaptor proteins that can induce anchorage-independent growth of fibroblasts. Crk and CrkL play key roles in maintaining cytoskeletal integrity, cell motility and migration. We investigated the role of these two proteins in oncogenic transformation induced by v-fos and v-ras oncogenes using cell lines and fibroblasts carrying conditional alleles of Crk or CrkL. Transformation was assessed by cell morphology, saturation density and anchorage-independent growth in soft agar. We found that cell lines expressing v-fos or v-ras in the absence of Crk or CrkL displayed no evident morphological alterations and reduced anchorage-independent growth compared to those retaining Crk and CrkL. Similarly, overexpression of v fos in mouse embryonic fibroblasts conferred a growth advantage and induced morphological changes, both of which were abrogated in the absence of either Crk or CrkL. In contrast, Crk, but not CrkL, contributed to v-ras-induced transformation of embryonic fibroblasts. These results suggest that both Crk and CrkL are required for the acquisition of cellular transformation by v-fos, whereas Crk plays a more prominent role than CrkL in v-ras-induced transformation. PMID- 25557915 TI - Low level light therapy modulates inflammatory mediators secreted by human annulus fibrosus cells during intervertebral disc degeneration in vitro. AB - Intervertebral disc degeneration (IVD) is one of the important causes of low back pain and is associated with inflammation induced by interaction between macrophages and the human annulus fibrosus (AF) cells. Low-level light therapy (LLLT) has been widely known to regulate inflammatory reaction. However, the effect of LLLT on macrophage-mediated inflammation in the AF cells has not been studied till date. The aim of this study is to mimic the inflammatory microenvironment and to investigate the anti-inflammatory effect of LLLT at a range of wavelengths (405, 532 and 650 nm) on the AF treated with macrophage-like THP-1 cells conditioned medium (MCM) containing proinflammatory cytokines and chemokines (interleukin-1beta, tumor necrosis factor-alpha, interleukin-6 and 8). We observed that AF cells exposed to MCM secrete significantly higher concentrations of IL-6, IL-8, IL-1beta and TNF-alpha. LLLT markedly inhibited secretion of IL-6 at 405 nm in a time-dependent manner. Level of IL-8 was significantly decreased at all wavelengths in a time-dependent manner. We showed that MCM can induce the inflammatory microenvironment in AF cells and LLLT selectively suppressed IL-6 and 8 levels. The results indicate that LLLT is a potential method of IVD treatment and provide insights into further investigation of its anti-inflammation effect on IVD. PMID- 25557917 TI - Breath analysis for in vivo detection of pathogens related to ventilator associated pneumonia in intensive care patients: a prospective pilot study. AB - Existing methods for the early detection of infections in mechanically ventilated (MV) patients at intensive care units (ICUs) are unsatisfactory. Here we present an exploratory study assessing the feasibility of breath VOC analyses for the non invasive detection of pathogens in the lower respiratory tract of ventilated patients. An open uncontrolled clinical pilot study was performed by enrolling 28 mechanically ventilated (MV) patients with severe intracranial disease, being at risk for the development of or already with confirmed ventilation-associated pneumonia (VAP). The recently developed sampling technique enabled the collection of breath gas with a maximized contribution of alveolar air directly from the respiratory circuit under continuous capnography control, adsorptive preconcentration and final analysis by means of gas chromatography-mass spectrometry (GC-MS).VAP was confirmed in 22/28 preselected patients (78%). The most common microorganisms were Staphylococcus aureus (5/22 VAP patients), Escherichia coli (5/22 VAP patients) and Candida spp. (5/22 VAP patients). 12/32 metabolites released by S. aureus in our previous in vitro studies were also detected in the end-tidal air of VAP patients infected with this pathogen. A similar overlap was seen in Candida albicans infections (8/29 VOCs). Moreover, the concentration profile of selected compounds correlated with the course of the infection.This prospective pilot study provides proof of the concept that the appearance and the concentration profile of pathogen-derived metabolites (elucidated from in vitro experiments) in the breath of ventilated patients during clinically confirmed VAP correlates with the presence of a particular pathogen. PMID- 25557918 TI - Hamstring Tendon Regeneration After Harvest for Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - PURPOSE: To assess whether the portions of the semitendinosus and gracilis tendons harvested for anterior cruciate ligament reconstruction have the potential to regenerate and, if so, to evaluate the histologic properties and actual function of this newly formed tissue. METHODS: We performed a comprehensive search of CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase, Medline, the Cochrane Central Registry of Controlled Trials, and SPORTDiscus from inception of the databases to July 2014, using various combinations of keywords. Studies focusing on hamstring tendon and muscle regeneration through imaging and histology, as well as on the related functional outcomes, were selected. We included studies assessing evidence of tissue regeneration with imaging (magnetic resonance imaging, 3-dimensional computed tomography, ultrasonography) or with histologic examination of biopsy samples (or a combination thereof). RESULTS: Nineteen articles were included in this review, with a total of 400 patients observed. The overall rate of tissue regeneration was 86.0%, with similar values shown in most studies regardless of the methodology of the assessment. Biopsy confirmed that the tissue found at the site in 74% of the cases showed typical histologic features of the tendon. The mean modified Coleman Methodology Score of the studies included was 52.7 points, showing a modest methodologic quality for the studies published to date. CONCLUSIONS: In over 85% of the cases analyzed, regeneration signs of the harvested tendon were found through different imaging and histologic methodologies. A torque deficit in deep knee flexion is always present postoperatively, but the cause for this is still unclear. There is a need for better-designed trials featuring a higher level of evidence to further investigate this matter, and the effects of postoperative care and the surgical approach used on the regeneration process should be analyzed in the future. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV studies. PMID- 25557919 TI - Bioabsorbable versus metallic interference screws in anterior cruciate ligament reconstruction: a systematic review of overlapping meta-analyses. AB - PURPOSE: Multiple meta-analyses of randomized controlled trials have been conducted to compare clinical and functional outcomes after anterior cruciate ligament (ACL) reconstruction using metallic interference screw (MIS) versus bioabsorbable interference screw (BIS) fixation, but discrepancies in their findings have prevented a consensus conclusion. The purposes of this study were (1) to conduct a systematic review of meta-analyses comparing MISs and BISs in ACL reconstruction, (2) to provide surgical treatment recommendations for ACL graft fixation based on the highest available evidence, and (3) to propose future research avenues in areas of practice lacking high-level evidence. METHODS: The literature was systematically reviewed to identify meta-analyses comparing MISs and BISs in ACL reconstruction. Data were extracted for clinical and functional outcomes, and methodologic quality was assessed using the validated Quality of Reporting of Meta-analyses and Oxman-Guyatt systems. To determine which meta analyses provided the current best available evidence, the Jadad decision algorithm was used. RESULTS: One Level I and 2 Level II meta-analyses were included. None showed differences between BISs and MISs in validated outcome scores, pivot-shift testing, KT arthrometry (MEDmetric, San Diego, CA), or loss of knee motion. Subgroup analyses found no differences in clinical outcomes or knee stability across biomaterials. All meta-analyses were of high quality according to the Quality of Reporting of Meta-analyses and Oxman-Guyatt systems. Two meta-analyses were determined by the Jadad algorithm to represent the current best available evidence. Both studies showed prolonged knee effusion with BIS use, with 1 also showing an increased incidence of femoral tunnel widening and screw breakage with BIS use. CONCLUSIONS: Whereas clinical and functional outcomes are similar with MISs and BISs, prolonged knee effusion, femoral tunnel widening, and screw breakage are more common with BIS use. Future cost effectiveness analyses may help weigh the known advantages of BISs against their costs and adverse-event profile. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies. PMID- 25557921 TI - What's in this issue? PMID- 25557920 TI - Influenza vaccination coverage and effectiveness in young children in Thailand, 2011-2013. AB - BACKGROUND: Since 2009, Thailand has recommended influenza vaccine for children aged 6 months through 2 years, but no estimates of influenza vaccine coverage or effectiveness are available for this target group. METHODS: During August 2011 May 2013, high-risk and healthy children aged <=36 months were enrolled in a 2 year prospective cohort study. Parents were contacted weekly about acute respiratory illness (ARI) in their child. Ill children had combined nasal and throat swabs tested for influenza viruses by real-time reverse transcription polymerase chain reaction. Influenza vaccination status was verified with vaccination cards. The Cox proportional hazards approach was used to estimate hazard ratios. Vaccine effectiveness (VE) was estimated as 100% x (1-hazard ratio). RESULTS: During 2011-2013, 968 children were enrolled (median age, 10.3 months); 948 (97.9%) had a vaccination record and were included. Of these, 394 (41.6%) had >=1 medical conditions. Vaccination coverage for the 2011-2012 and 2012-2013 seasons was 29.3% (93/317) and 30.0% (197/656), respectively. In 2011 2012, there were 213 ARI episodes, of which 10 (4.6%) were influenza positive (2.3 per 1000 vaccinated and 3.8 per 1000 unvaccinated child-weeks). The VE was 55% (95% confidence interval [CI], -72, 88). In 2012-2013, there were 846 ARIs, of which 52 (6.2%) were influenza positive (1.8 per 1000 vaccinated and 4.5 per 1000 unvaccinated child-weeks). The VE was 64% (CI, 13%, 85%). CONCLUSION: Influenza vaccination coverage among young children in Thailand was low, although vaccination was moderately effective. Continued efforts are needed to increase influenza vaccination coverage and evaluate VE among young children in Thailand. PMID- 25557922 TI - Effect of low doses of herbicide paraquat on antioxidant defense in Drosophila. AB - Despite a high toxicity, paraquat is one of the most widely used herbicides in the world. Our study evaluated the effect of paraquat exposure on antioxidant response and locomotion activity in Drosophila melanogaster. We examined the enzymatic activity of superoxide dismutase (SOD) and catalase, and the transcript levels of both enzymes. Flies were exposed to a wide range of paraquat concentrations (0.25 MUM to 25 mM) for 12 h. SOD, at both transcript and enzymatic levels, revealed a biphasic dose-response curve with the peak at 2.5 MUM paraquat. A similar dose-response curve was observed at transcript levels of catalase. Males revealed higher susceptibility to paraquat exposure, displaying higher lethality, increased levels of SOD activity, and increased peroxide levels than in females. We found that the exposure of females to 2.5 MUM paraquat leads to an increase in locomotion activity. Because susceptibility to paraquat was enhanced by mating, the study supports the hypothesis of elevation of stress sensitivity as a physiological cost of reproduction. PMID- 25557923 TI - New insights into the lymphovascular microanatomy of the colon and the risk of metastases in pT1 colorectal cancer obtained with quantitative methods and three dimensional digital reconstruction. AB - AIMS: UK faecal occult blood test screening has tripled the proportion of pT1 colorectal cancers. The risk of metastasis is predicted by depth of invasion, suggesting that access to deep lymphovascular vessels is important. The aim of this study was to quantify the distribution and size of the submucosal vasculature, and generate a novel three-dimensional (3D) model to validate the findings. METHODS AND RESULTS: Thirty samples of normal large bowel wall were immunostained with CD31, a vascular endothelium marker, to identify blood vessels, which were quantified and digitally analysed for their number, circumference, area and diameter in the deep mucosa and submucosa (Sm1, Sm2, and Sm3). The model required serial sections, a double immunostain (using CD31 and D2 40), and 3D reconstruction. Significant differences were shown between submucosal layers in the number, circumference and area of vessels (P < 0.001). Blood vessels were most numerous in the mucosa (11.79 vessels/0.2 mm(2)) but smaller [median area of 247 MUm(2) , interquartile range (IQR) 162-373 MUm(2)] than in Sm2, where they were fewer in number (6.92 vessels/0.2 mm(2)) but considerably larger (2086 MUm(2), IQR 1007-4784 MUm(2)). The 3D model generated novel observations on lymphovascular structures. CONCLUSIONS: The number and size of blood vessels do not increase with depth of submucosa, as hypothesized. The distribution of vessels suggests that we should investigate the area or volume of submucosal invasion rather than the depth. PMID- 25557925 TI - Functional Connectivity in Frequency-Tagged Cortical Networks During Active Harm Avoidance. AB - Many behavioral and cognitive processes are grounded in widespread and dynamic communication between brain regions. Thus, the quantification of functional connectivity with high temporal resolution is highly desirable for capturing in vivo brain function. However, many of the commonly used measures of functional connectivity capture only linear signal dependence and are based entirely on relatively simple quantitative measures such as mean and variance. In this study, the authors used a recently developed algorithm, the generalized measure of association (GMA), to quantify dynamic changes in cortical connectivity using steady-state visual evoked potentials (ssVEPs) measured in the context of a conditioned behavioral avoidance task. GMA uses a nonparametric estimator of statistical dependence based on ranks that are efficient and capable of providing temporal precision roughly corresponding to the timing of cognitive acts (~ 100 200 msec). Participants viewed simple gratings predicting the presence/absence of an aversive loud noise, co-occurring with peripheral cues indicating whether the loud noise could be avoided by means of a key press (active) or not (passive). For active compared with passive trials, heightened connectivity between visual and central areas was observed in time segments preceding and surrounding the avoidance cue. Viewing of the threat stimuli also led to greater initial connectivity between occipital and central regions, followed by heightened local coupling among visual regions surrounding the motor response. Local neural coupling within extended visual regions was sustained throughout major parts of the viewing epoch. These findings are discussed in a framework of flexible synchronization between cortical networks as a function of experience and active sensorimotor coupling. PMID- 25557924 TI - Outcomes of microwave ablation for colorectal cancer liver metastases: a single center experience. AB - BACKGROUND AND OBJECTIVES: Surgical management of colorectal cancer liver metastases continues to evolve to optimize oncologic outcomes while maximizing parenchymal preservation. Long-term data after intraoperative microwave ablation are limited. This study investigates outcomes and patterns of recurrence in patients who underwent intraoperative microwave ablation. METHODS: A retrospective analysis of 33 patients who underwent intraoperative microwave ablation of colorectal cancer liver metastases from 2009 to 2013 at our institution was performed. Perioperative and long-term data were reviewed to determine outcomes and patterns of recurrence. RESULTS: A total of 49 tumors were treated, ranging 0.5-5.5 cm in size. Median Clavien-Dindo classification was one. Median follow-up was 531 days, with 13 (39.4%) patients presenting with a recurrence. Median time to first recurrence was 364 days. In those patients, 1 (7.8%) presented with an isolated local recurrence in the liver. Only 1 of 7 ablated tumors greater than 3 cm recurred (14.3%). Overall survival was 35.2% at 4 years, with a 19.3% disease-free survival at 3.5 years. No perioperative variables predicted systemic or local recurrence. CONCLUSION: Intraoperative microwave ablation is a safe and effective modality for use in the treatment of colorectal cancer liver metastases in tumors as large as 5.5 cm in size. PMID- 25557926 TI - Evolution of intracranial atherosclerotic disease under modern medical therapy. AB - OBJECTIVE: Understanding how symptomatic intracranial atherosclerotic disease (ICAD) evolves with current medical therapy may inform secondary stroke prevention. METHODS: In a prospective academic-initiated study, we recruited 50 patients (mean age = 63.4 +/- 9.0 years) with acute strokes attributed to high grade (>=70%) intracranial atherosclerotic stenosis for 3-dimensional rotational angiograms before and after intensive medical therapy for 12 months. Treatment targets included low-density lipoprotein <= 70mg/dl, glycosylated hemoglobin (HbA1c) <= 6.5%, and systolic blood pressure <= 140 mmHg. We analyzed infarct topography and monitored microembolic signal in recurrent strokes. The reference group was a published cohort of 143 ICAD patients. RESULTS: Overall, the stenoses regressed from 79% at baseline (interquartile range [IQR] = 71-87%) to 63% (IQR = 54-74%) in 1 year (p < 0.001). Specifically, the qualifying lesions (n = 49) regressed (stenosis reduced >10%) in 24 patients (49%), remained quiescent (stenosis same or +/-10%) in 21 patients (43%), and progressed (stenosis increased >10%) in 4 patients (8%). There was no difference in intensity of risk factor control between groups of diverging clinical or angiographic outcomes. Higher HbA1c at baseline predicted plaque regression at 1 year (odds ratio = 4.4, 95% confidence interval = 1.4-14.5, p = 0.006). Among the 6 patients with recurrent strokes pertaining to the qualifying stenosis, 5 patients had solitary or rosarylike acute infarcts along the internal or anterior border zones, and 2 patients showed microembolic signals in transcranial Doppler ultrasound. INTERPRETATION: A majority of symptomatic high-grade intracranial plaques had regressed or remained quiescent by 12 months under intensive medical therapy. Artery-to-artery thromboembolism with impaired washout at border zones was a common mechanism in stroke recurrence. PMID- 25557927 TI - A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. AB - Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-beta receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9 induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology. PMID- 25557928 TI - Comparative analysis of selected innate immune-related genes following infection of immortal DF-1 cells with highly pathogenic (H5N1) and low pathogenic (H9N2) avian influenza viruses. AB - H5N1 and H9N2 viruses are important causes of avian influenza in China. H5N1 is typically associated with severe to fatal disease in poultry, while H9N2 is usually associated with mild disease. Differences in viral virulence prompted us to investigate whether innate immune responses would be differentially regulated following infection by H5N1 and H9N2 viruses. To address this hypothesis, expression of a panel of innate immune-related genes including IFN-alpha, IFN beta, Mx1, OASL, ISG12, IFIT5, IRF7, USP18, SST, and KHSRP in immortal DF-1 cells following H5N1 and H9N2 infection was analyzed and compared by real-time quantitative RT-PCR. Cells infected by either virus overall exhibited a similar expression profile for four ISGs (Mx1, OASL, ISG12, and IFIT5), IFN-alpha, IFN beta, and SST gene. However, two immune-regulatory genes (IRF7 and KHSRP) were not responsive to highly pathogenic H5N1 infection but were strongly up-regulated in DF-1 cells infected with low pathogenic H9N2 infection. The subtype-dependent host response observed in this study offers new insights into the potential roles of IRF7 and KHSRP in control and modulation of the replication and virulence of different subtypes or strains of avian influenza A virus. PMID- 25557929 TI - Complete genome of Chinese sacbrood virus from Apis cerana and analysis of the 3C like cysteine protease. AB - The complete genome sequence of Chinese sacbrood virus (CSBV), isolated from diseased larvae of Apis cerana in Fujian province, China was analyzed. The viral genome consisted of 8,800 nucleotides, encoding 2,848 amino acids. A phylogenetic tree analysis showed the sacbrood virus (SBV) segregated into three distinct groups. The isolates originated from A. c. indica and were the first distinct evolutionary group. The AcSBV-SBM2 isolate, from A. c. cerana, belonged to the second distinct group. The remaining SBV isolates formed the third group. The phylogenetic relationships of SBV isolates suggest that they are derived from similar honeybee species or geographic origins. The 3C-like cysteine protease protein plays an important role in viral replication. The 3C-like cysteine protease protein of CSBV-FZ was predicted to contain a transmembrane domain. The subcellular localization of 3C-like cysteine protease was distributed as discrete punctate inclusions and co-localized with VP1 of CSBV. These results suggest that the non-structural protein 3C-like cysteine protease might be involved in viral replication. Insect cell cultures can further advance our understanding of picorna-like virus replication. PMID- 25557930 TI - Genetic characterization of a rare H12N3 avian influenza virus isolated from a green-winged teal in Japan. AB - This study reports on the genetic characterization of an avian influenza virus, subtype H12N3, isolated from an Eurasian green-winged teal (Anas crecca) in Japan in 2009. The entire genome sequence of the isolate was analyzed, and phylogenetic analyses were conducted to characterize the evolutionary history of the isolate. Phylogenetic analysis of the hemagglutinin and neuraminidase genes indicated that the virus belonged to the Eurasian-like avian lineage. Molecular dating indicated that this H12 virus is likely a multiple reassortant influenza A virus. This is the first reported characterization of influenza A virus subtype H12N3 isolated in Japan and these data contribute to the accumulation of knowledge on the genetic diversity and generation of novel influenza A viruses. PMID- 25557931 TI - Capillary-venous malformation in the upper limb. AB - We present a group of patients with regional capillary malformations of the upper limbs and few additional findings other than prominent veins. We believe that this entity is the upper extremity equivalent of capillary-venous malformation of the lower limb and, likewise, belongs at the minor end of the spectrum of vascular disorders with overgrowth. PMID- 25557933 TI - Intraosseous and intravenous administration of antibiotics yields comparable plasma concentrations during experimental septic shock. AB - BACKGROUND: We aimed to investigate whether comparable antibiotic concentrations could be reached with intraosseous and intravenous administration during septic shock. METHODS: In this randomized, prospective experimental study conducted at an animal research laboratory at the University Hospital of Uppsala, eight anesthetized pigs, weighing 21.2 to 29.1 kg (mean: 25.2 +/- 2.3 kg), received endotoxin infusion at 4 MUg/kg/h for 6 h. At the onset of clinical shock, alternatively after 3 h of endotoxemia, they received 75 mg/kg of cefotaxime and 7 mg/kg of gentamicin either in a proximal tibial intraosseous catheter or in a peripheral intravenous catheter. Mixed venous samples were taken after 5, 15, 30, 60, 120 and 180 min and analyzed for antibiotic concentrations. RESULTS: For both antibiotics, plasma concentrations after intraosseous and intravenous administration followed similar curves throughout the observation period, and peak concentrations were comparable. Mean concentration area under the curve (AUC mg * h/l) for cefotaxime was 108.1 +/- 19.5 after intraosseous and 116.5 +/- 11.1 after intravenous administration; ratio 0.93, (95% CI 0.71-1.19). Mean AUC for gentamicin was 28.1 +/- 6.8 for intraosseous and 32.2 +/- 3.5 for intravenous administration; ratio 0.87 (95% CI 0.62-1.19). CONCLUSIONS: In this porcine septic shock model, intraosseous and intravenous administration of gentamicin and cefotaxime yielded comparable concentrations. In an emergency, intraosseous administration of these antibiotics may be considered in severe infections when venous access is difficult. PMID- 25557934 TI - Comparative analyses of tooth wear in free-ranging and captive wild equids. AB - REASONS FOR PERFORMING STUDY: Captive breeding has played a crucial role in the conservation of threatened equid species. Grazing ruminants and rhinoceros in captivity have less abrasion-dominated tooth wear than their free-ranging conspecifics, with potential negative consequences for their health. However, a similar study on wild equids in captivity is missing. OBJECTIVES: The aim was to establish if different tooth wear patterns are exhibited by free-ranging and captive equids. STUDY DESIGN: Cross-sectional study of museum specimens comparing free-ranging and captive equids. METHODS: Dental casts of maxillary cheek teeth of 228 museum specimens (122 from free-ranging and 106 from captive individuals) of 7 wild equid species were analysed using the extended mesowear method. Although teeth showing specific abnormalities were not scored, the presence of focal overgrowths (hooks) of the rostral premolars (106, 206) was recorded. RESULTS: Captive Equus ferus przewalskii, E. grevyi, E. hemionus, E. quagga boehmi and E. zebra hartmannae have less abrasion-dominated tooth wear on their premolars than their free-ranging conspecifics (P<0.001). Fewer differences were exhibited between populations in the molars. No differences were exhibited in the distal cusp of the molars (110, 210) between populations, except in a small sample of E. kiang. Captive equids exhibited more homogeneous wear along the tooth row whereas free-ranging equids exhibited a tooth wear gradient, with more abrasion on premolars than molars. There were more rostral hooks on the premolars (106, 206) in the captive than the free-ranging population (P = 0.02). CONCLUSIONS: Captive equids did experience less abrasion-dominated tooth wear than their free-ranging conspecifics, but the differences in tooth wear were less pronounced than those between captive and free-ranging wild ruminant and rhinoceros species. This indicates that feeding regimes for captive equids deviate less from natural diets than those for captive ruminants and rhinoceros but that factors leading to hook formation, in particular feeding height, should receive special attention. The Summary is available in Chinese - see Supporting information. PMID- 25557932 TI - Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study. AB - Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC. PMID- 25557935 TI - Ultra-low percolation threshold in ferrite-metal cofired ceramics brings both high permeability and high permittivity. AB - High permeability and high permittivity are hard to be achieved simultaneously, either in single-phased materials or in composite materials, such as ferrite ferroelectric ceramic composites and ferrite-metal percolative composites. In this work, ultra-low percolation threshold is achieved in NiZnCu ferrite-Ag cofired ceramics, which endows the composite with both high permeability and high permittivity by minimizing the negative effect of nonmagnetic conductive fillers on magnetic properties. The percolation threshold is controlled by the temperature matching between ferrite densification and Ag melting. A thin and long percolative net forms between large ferrite grains under a proper cofiring process, which brings a low percolation threshold of 1.21vol%, more than one order of magnitude lower than the theoretical value of 16vol%. Near the ultra-low threshold, the composite exhibits a high permeability of 585 and a high permittivity of 78. PMID- 25557936 TI - Prospective evaluation of complications of the usage of buffering lidocaine for secondary intention healing. AB - BACKGROUND: Circular excision by secondary-intention healing is useful for small skin defects (diameter <10 mm). But the injection pain as the local anesthesia is administered one of the patients' biggest concerns. Buffered lidocaine can effectively relieve the injection pain, but it might increase the potential complications. This study examined the effect of buffered lidocaine on wound healing. METHODS: Patients undergoing circular excision by secondary-intention healing were divided into 2 groups and were administered buffered or unbuffered lidocaine as the local anesthesia. Comparative parameters included injection pain, postoperative pain, complication rate, scar width, and scar quality at 6 months. Statistical differences between the 2 agents were assessed. RESULTS: The patients in the buffered group experienced 0.9 fewer scaled injection pain units than did the patients in the unbuffered group (p = 0.009). Complication rates and scar appearance did not show any statistical difference between the 2 groups. CONCLUSION: Buffered lidocaine is useful to relieve the injection pain during the secondary-intention healing, and it is safe to use if it is applied properly. PMID- 25557937 TI - Introducing a Novel In Vitro Model to Characterize Hydrodynamic Effects of Percutaneous Nephrolithotomy Systems. AB - PURPOSE: To widen the understanding of the fluid mechanics during percutaneous nephrolithotomy (PCNL), a new in vitro model for empiric studies was developed. Our first aim was to characterize common PCNL systems with regard to their intrapyelocaliceal pressure and their irrigation flow volume as possible parameters of hydrodynamic invasiveness. MATERIALS AND METHODS: The model is based on a watertight cylindrical cast. Low pressure miniaturized PCNL (miniPCNL) systems and conventional PCNL systems were tested. Intrapelvic pressure and the total of irrigation flow volume per minute were measured for each PCNL system at 10 predefined levels of irrigation pressure between 40 and 130 cm H2O. RESULTS: Linear regression showed a linear relation between irrigation pressure and intrapelvic pressure. Compared with miniPCNL systems, conventional PCNL sheaths with closed Rutner sidearm generate significantly higher intrapelvic pressures. Opening the Rutner sidearm leads to a decrease in intrapelvic pressure to the level of the open mini PCNL systems. Polynomal regression revealed a square root relation between irrigation pressure and irrigation flow volume. CONCLUSIONS: Our in vitro model is suitable for obtaining reliable and valid data of intrapelvic pressure and irrigation flow volume of commonly used PCNL systems. Conventional PCNL sheaths with opened Rutner sidearm provide intrapelvic pressure and irrigation volume similar to miniPCNL. Consequently, a relevant difference of the hydrodynamic impact between conventional and miniPCNL systems are not necessarily to be assumed. Regression analysis revealed a new starting point for further empiric research of fluid mechanics during PCNL. PMID- 25557938 TI - Outcomes associated with a mandatory gastroenterology consultation to improve the quality of care of patients hospitalized with decompensated cirrhosis. AB - BACKGROUND AND AIMS: Patients with decompensated cirrhosis (DC) have significant morbidity and resource utilization. In a cohort of patients with DC undergoing usual care (UC) in 2009, we demonstrated that quality indicators (QI) were met <50% of the time. We established a gastroenterology mandatory consultation (MC) to improve the care of patients with DC. We sought to evaluate the impact of the MC intervention on adherence to QI, and compared outcomes to UC. METHODS: This was a prospective cohort study with historic control examining all admissions in a year for DC at an academic medical center. All admissions were seen by a gastroenterologist encouraged to implement QIs (MC). Scores were calculated for each group per admission as the proportion of QIs met versus QIs for which the patient was eligible. QI scores were examined as a function of group assignment multivariable fractional logit regression. We evaluated the impact of the intervention on compliance with QIs, length of stay (LOS), 30-day readmission, and inpatient death. RESULTS: Three hundred three patients were observed in 695 hospitalizations (149 patients in 379 admissions [UC]; 154 patients in 316 admissions [MC]). The QI score was significantly higher in the MC group than the UC group (77.0% vs 46.0%, P < 0.001), reflecting better management of ascites and documentation of transplant evaluation. The management of variceal bleeding improved also but did not reach statistical significance. CONCLUSION: The MC intervention was associated with greater adherence to recommended care but was not powered to detect difference in LOS, readmission, or mortality rates. PMID- 25557939 TI - Effect of pre-heating on the chemical oxidation efficiency: implications for the PAH availability measurement in contaminated soils. AB - Three chemical oxidation treatments (KMnO4, H2O2 and Fenton-like) were applied on three PAH-contaminated soils presenting different properties to determine the potential use of these treatments to evaluate the available PAH fraction. In order to increase the available fraction, a pre-heating (100 degrees C under N2 for one week) was also applied on the samples prior oxidant addition. PAH and extractable organic matter contents were determined before and after treatment applications. KMnO4 was efficient to degrade PAHs in all the soil samples and the pre-heating slightly improved its efficiency. H2O2 and Fenton-like treatments presented low efficiency to degrade PAH in the soil presenting poor PAH availability, however, the PAH degradation rates were improved with the pre heating. Consequently H2O2-based treatments (including Fenton-like) are highly sensitive to contaminant availability and seem to be valid methods to estimate the available PAH fraction in contaminated soils. PMID- 25557940 TI - Porous p-NiO/n-Nb2O5 nanocomposites prepared by an EISA route with enhanced photocatalytic activity in simultaneous Cr(VI) reduction and methyl orange decolorization under visible light irradiation. AB - Porous NiO/Nb2O5 nanocomposites with Ni/Nb molar ratio of 0.4, 0.8 and 1.2 have been obtained via the EISA route using P123 copolymer as organic template, and are assigned as NiNb0.4, NiNb0.8 and NiNb1.2, respectively. For comparison, pure Nb2O5 sample assigned as NiNb0.0 was also synthesized by the same method. Structural and textural features of the as prepared samples were investigated by XRD, FTIR, FE-SEM, EDX, UV-vis DRS and BET techniques. The results indicated that the porous p-NiO/n-Nb2O5 junction nanocomposites were formed and coupling of NiO with Nb2O5 resulted a remarkable red shift in the optical response of the nanocomposite samples. The photocatalytic properties of the nanocomposite samples, and also synthesized pure Nb2O5 (NiNb0.0) and commercial Nb2O5 as reference catalysts were evaluated for the first time by simultaneous Cr(VI) reduction and MO decolorization in aqueous suspension under visible light irradiation at pH 2. NiNb0.4 was found to be the most active photocatalyst, which might be attributed to the extended absorption in the visible light region and the effective photogenerated electron-hole separation by the photosynergistic effects of the p-NiO/n-Nb2O5 composite powder. The photocatalytic efficiency of the most active photocatalyst, NiNb0.4, was found to be rather low for either single Cr(VI) solution or single MO solution. However, the photocatalytic reduction of Cr(VI) and photocatalytic decolorization of MO proceed more rapidly for the coexistence system of Cr(VI) and MO than for the single process, showing synergetic effect between the reduction and decolorization reactions. The effects of initial concentration of Cr(VI), MO and the initial pH value on the rate of simultaneous photoreactions over NiNb0.4 sample, were also investigated. The Cr(VI) and MO removal rates were further enhanced by increasing MO and Cr (VI) concentration to an optimal value, respectively, and/or decreasing solution pH. PMID- 25557942 TI - Amniotic membrane: new concepts for an old dressing. PMID- 25557943 TI - Physical activity and body mass index as predictors of prostate cancer risk. AB - PURPOSE: Physical activity and body mass index (BMI) are involved in prostate cancer etiology; possible biologic mechanisms include their effects on hormonal levels. Our aim was to investigate the relationship between physical activity, obesity, and prostate cancer. METHODS: We followed a cohort of 13,109 Swedish men for 13 years and investigated the association of self-reported physical activity and BMI at baseline with prostate cancer incidence. We further analyzed whether BMI could modulate effects of physical activity. Occupational, recreational, and total physical activity were analyzed in relation to overall, localized, and advanced prostate cancer. RESULTS: During the study follow-up, we observed a total of 904 cases of prostate cancer (429 localized, 407 advanced, and 68 unclassified). High levels of occupational physical activity were associated with a nonsignificantly decreased risk of overall (HR 0.81, 95 % CI 0.61-1.07), localized (HR 0.75, 95 % CI 0.51-1.12), and advanced (HR 0.85, 95 % CI 0.55-1.31) prostate cancer. We found no association between high BMI and risk of prostate cancer incidence: We observed, however, a significant interaction between BMI and leisure physical activity. CONCLUSION: No association was confirmed between total physical activity and localized or advanced prostate cancer. The highest, relative to the lowest, level of occupational physical activity tended to be linked to a lower risk of prostate cancer, with a suggested dose-response relationship. We found no association between high BMI and risk of prostate cancer incidence; however, our analyses suggested an interaction between BMI and physical activity during recreational time that merits further investigation in future studies. PMID- 25557944 TI - Is in vivo analysis of urinary stone composition feasible? Evaluation of an experimental setup of a Raman system coupled to commercial lithotripsy laser fibers. AB - PURPOSE: Raman spectroscopy allows immediate analysis of stone composition. In vivo stone analysis during endoscopic treatment may offer advantages concerning surgical strategy and metaphylaxis. Urinary stone components were evaluated utilizing an experimental setup of a Raman system coupled to commercial laser fibers. METHODS: Samples of paracetamol (acetaminophen) and human urinary stones with known Raman spectra were analyzed using an experimental Raman system coupled to common commercial lithotripsy laser fibers (200 and 940 um). Two different excitation lasers were used at wavelengths of 532 and 785 nm. Numerical aperture of the fibers, proportion of reflected light reaching the CCD chip, and integration times were calculated. Mathematical signal correction was performed. RESULTS: Both the laser beam profile and the quality of light reflected by the specimens were impaired significantly when used with commercial fibers. Acquired spectra could no longer be assigned to a specific stone composition. Subsequent measurements revealed a strong intrinsic fluorescence of the fibers and poor light acquisition properties leading to a significant decrease in the Raman signal in comparison with a free-beam setup. This was true for both investigated fiber diameters and both wavelengths. Microscopic examination showed highly irregular fiber tip surfaces (both new and used fibers). CONCLUSIONS: Our results propose that laser excitation and light acquisition properties of commercial lithotripsy fibers impair detectable Raman signals significantly in a fiber coupled setting. This study provides essential physical and technological information for the development of an advanced fiber-coupled system able to be used for immediate stone analysis during endoscopic stone therapy. PMID- 25557945 TI - TEAD2, a Hippo pathway gene, is somatically mutated in gastric and colorectal cancers with high microsatellite instability. PMID- 25557946 TI - Rigid gas-permeable contact lens related life quality in keratoconic patients with different grades of severity. AB - PURPOSE: The aim was to compare the impact of rigid gas-permeable (RGP) contact lenses on vision-related quality of life (VR-QOL) in keratoconic patients with different grades of severity. METHODS: This comparative study was conducted from December 2012 to September 2013 on 46 patients with bilateral keratoconus. Patients were divided into three groups according to the average of the steep keratometry (K) readings in the two eyes of each patient. Main outcome measures included binocular visual acuity (VA), lens wearing time, the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), foreign body (FB) sensation, comfort and overall satisfaction. RESULTS: Patients with severe keratoconus showed significantly reduced wearing time compared with the other two groups (4.8 +/- 2.5 hours per day). Regarding the subjective criteria, there was no significant difference on NEI-VFQ-25 scores, foreign body sensation, comfort and overall satisfaction between mild and moderate keratoconus groups but scores in the group with severe keratoconus were significantly lower than the other two groups. Binocular VA strongly correlated with NEI-VFQ-25 scores; however, NEI-VFQ 25 scores had no significant correlations with different disease severities. CONCLUSIONS: Appropriate correction with RGP lenses contributes to good VR-QOL for keratoconic patients; however, as the disease progresses to a steep keratometric value of more than 52 dioptres (6.50 mm), RGP lenses did not guarantee a relatively good VR-QOL. Other lens options with new designs might bring better life quality for these patients with severe keratoconus. PMID- 25557948 TI - Oxygen-participated electrochemistry of new lithium-rich layered oxides Li3MRuO5 (M = Mn, Fe). AB - We describe the synthesis, crystal structure and lithium deinsertion-insertion electrochemistry of two new lithium-rich layered oxides, Li3MRuO5 (M = Mn, Fe), related to rock salt based Li2MnO3 and LiCoO2. The Li3MnRuO5 oxide adopts a structure related to Li2MnO3 (C2/m) where Li and (Li0.2Mn0.4Ru0.4) layers alternate along the c-axis, while the Li3FeRuO5 oxide adopts a near-perfect LiCoO2 (R3[combining macron]m) structure where Li and (Li0.2Fe0.4Ru0.4) layers are stacked alternately. Magnetic measurements indicate for Li3MnRuO5 the presence of Mn(3+) and low spin configuration for Ru(4+) where the itinerant electrons occupy a pi*-band. The onset of a net maximum in the chi vs. T plot at 9.5 K and the negative value of the Weiss constant (theta) of -31.4 K indicate the presence of antiferromagnetic superexchange interactions according to different pathways. Lithium electrochemistry shows a similar behaviour for both oxides and related to the typical behaviour of Li-rich layered oxides where participation of oxide ions in the electrochemical processes is usually found. A long first charge process with capacities of 240 mA h g(-1) (2.3 Li per f.u.) and 144 mA h g(-1) (1.38 Li per f.u.) is observed for Li3MnRuO5 and Li3FeRuO5, respectively. An initial sloping region (OCV to ca. 4.1 V) is followed by a long plateau (ca. 4.3 V). Further discharge-charge cycling points to partial reversibility (ca. 160 mA h g(-1) and 45 mA h g(-1) for Mn and Fe, respectively). Nevertheless, just after a few cycles, cell failure is observed. X-ray photoelectron spectroscopy (XPS) characterisation of both pristine and electrochemically oxidized Li3MRuO5 reveals that in the Li3MnRuO5 oxide, Mn(3+) and Ru(4+) are partially oxidized to Mn(4+) and Ru(5+) in the sloping region at low voltage, while in the long plateau, O(2-) is also oxidized. Oxygen release likely occurs which may be the cause for failure of cells upon cycling. Interestingly, some other Li-rich layered oxides have been reported to cycle acceptably even with the participation of the O(2-) ligand in the reversible redox processes. In the Li3FeRuO5 oxide, the oxidation process appears to affect only Ru (4+ to 5+ in the sloping region) and O(2-) (plateau) while Fe seems to retain its 3+ state. PMID- 25557947 TI - Hormonal regulation of steroid receptor coactivator-1 mRNA in the male and female green anole brain. AB - Green anole lizards are seasonal breeders, with male sexual behaviour primarily regulated by an annual increase in testosterone. Morphological, biochemical and behavioural changes associated with reproduction are activated by testosterone, generally with a greater effect in the breeding season (BS) than in the nonbreeding season (NBS). The present study investigates the possibility that differences in a steroid receptor coactivator may regulate this seasonal difference in responsiveness to testosterone. In situ hybridisation was used to examine the expression of steroid receptor coactivator-1 (SRC-1) in the brains of gonadally intact male and female green anoles across breeding states. A second experiment examined gonadectomised animals with and without testosterone treatment. Gonadally intact males had more SRC-1 expressing cells in the preoptic area and larger volumes of this region as defined by these cells than females. Main effects of both sex and season (males > females and BS > NBS) were present in cell number and volume of the ventromedial hypothalamus. An interaction between sex and season suggested that high expression in BS males was driving these effects. In hormone-manipulated animals, testosterone treatment increased both the number of SRC-1 expressing cells in and volumes of the preoptic area and amygdala. These results suggest that testosterone selectively regulates SRC-1, and that this coactivator may play a role in facilitating reproductive behaviours across both sexes. However, changes in SRC-1 expression are not likely responsible for the seasonal change in responsiveness to testosterone. PMID- 25557949 TI - Target-driven triple-binder assembly of MNAzyme for amplified electrochemical immunosensing of protein biomarker. AB - A simple electrochemical immunosensing method is presented for highly sensitive and selective detection of protein biomarker. This method uses a newly designed assembly of Mg(2+)-dependent MNAzyme via target-driven triple-binder proximity hybridization to catalyze the cleavage of methylene blue (MB)-labeled hairpin, which leads to the departure of MB from the electrode surface and thus an amplified decrease of electrochemical signal for immunoassay of the target protein. The MNAzyme assembly is achieved by the simultaneous recognition of target protein with three DNA-labeled antibodies in the presence of Mg(2+), which greatly improves the detection sensitivity and selectivity. As a proof of concept, this strategy can detect carcinoembryonic antigen (CEA) ranging from 0.002 to 500 ng mL(-1) with a detection limit of 1.5 pg mL(-1). The whole assay including the target-driven MNAzyme formation and subsequent cleavage of hairpin can be completed with one step in 40 min. The immunosensor, prepared with a hairpin DNA, possesses good extensibility for large protein biomarkers as CEA by using corresponding antibodies, though the protein target size dependence was not investigated in this work. The proposed immunoassay method shows the advantages of easy operation, high sensitivity, wide concentration range, good selectivity, and excellent versatility, displaying potential application for protein analysis. PMID- 25557951 TI - Endoscopic ultrasonography-guided jejunojejunostomy to facilitate endoscopic retrograde cholangiopancreatography: a minimally invasive option. PMID- 25557950 TI - Identification of risk loci for Crohn's disease phenotypes using a genome-wide association study. AB - BACKGROUND & AIMS: Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. METHODS: We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes (P < 2 * 10(-4)) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. RESULTS: We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 * 10(-8)), disease location (Pcombined = 1.3 * 10(-6)), mild disease course (Pcombined = 5.94 * 10(-7)), and erythema nodosum (Pcombined = 2.27 * 10(-6)), respectively. CONCLUSIONS: In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease. PMID- 25557952 TI - The combination of simeprevir and sofosbuvir is more effective than that of peginterferon, ribavirin, and sofosbuvir for patients with hepatitis C-related Child's class A cirrhosis. AB - BACKGROUND & AIMS: The efficacy and safety of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infections require further evaluation and comparison with those of interferon-containing regimens. We compared a regimen of peginterferon, ribavirin, and sofosbuvir with a regimen of simeprevir and sofosbuvir in patients with HCV infection and unfavorable treatment features. METHODS: We performed a prospective open-label study of 82 patients with chronic HCV genotype 1a infection and Child's grade A cirrhosis enrolled from 2 clinics at a single center in Atlanta, Georgia, from December 2013 through January 2014. Fifty patients (61%) had not responded to treatment with peginterferon and ribavirin (null responders), and 32 (39%) were therapy naive; 39 (48%) were African American. Subjects were assigned randomly to groups given simeprevir (150 mg/day) and sofosbuvir (400 mg/day) (n = 58 in the final analysis) or peginterferon alfa 2b (1.5 mcg/kg/wk), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day) (n = 24 in the final analysis). Both regimens were given for 12 weeks. The primary trial end point was the proportion of patients with undetectable HCV-RNA levels 12 weeks after therapy completion (SVR12). RESULTS: A significantly greater percentage of patients (93%) given simeprevir and sofosbuvir achieved an SVR12 than those given the interferon-containing regimen (75%) (P = .02). Patients given the interferon-containing regimen had a significantly higher rate of virologic relapse than patients given simeprevir and sofosbuvir (P = .009), as well as worse self-reported outcomes and more side effects. Quality-of-life scores were higher in patients with SVR12 than those without, regardless of treatment regimen. CONCLUSIONS: In a prospective study of patients with chronic HCV genotype 1a infection and cirrhosis (48% African American and 61% prior null responders), a 12-week regimen of simeprevir and sofosbuvir produced a significantly higher rate of SVR12 and was better tolerated, with a lower viral relapse rate, than a 12-week regimen of peginterferon, ribavirin, and sofosbuvir. Clinicaltrials.gov no: NCT021683615. PMID- 25557954 TI - A review of competencies needed for health librarians--a comparison of Irish and international practice. AB - OBJECTIVES: The purpose of this review was to uncover areas of competence which may lead to a baseline of skills for health librarians. A baseline could inform personal development plans for health librarians, criteria for job descriptions and curriculum for library and information science (LIS) courses. METHODS: This research outlines existing competencies for librarians working in health care as defined by library associations, recent job descriptions and a mapping review of the library and information science literature. This is performed in the context of librarians working in the Irish health system with examples of practice drawn from the Irish experience. RESULTS: Ten areas of competence were found to be common to three of five library associations, which were also common to recent job descriptions. The literature reveals an ever changing working environment for librarians working in health with opportunities for new and evolving roles. CONCLUSIONS: The challenge for librarians moving into these roles will be to stay relevant and to keep skills updated in a rapidly moving health and information environment. PMID- 25557953 TI - Unique genomic profile of fibrolamellar hepatocellular carcinoma. AB - BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. METHODS: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. RESULTS: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. CONCLUSIONS: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time. PMID- 25557957 TI - Discoveries in peripartum cardiomyopathy. AB - The past decade has seen remarkable gains for outcomes in peripartum cardiomyopathy (PPCM), one of the leading causes of maternal mortality and morbidity in the USA and many other countries, including the high-incidence areas of Haiti and South Africa. This review article emphasizes the importance of continuing the process of increasing awareness of PPCM and presents details of this evolving picture, including important discoveries that point the way to full recovery for almost all PPCM subjects. In addition, new interventions will be highlighted, which may facilitate recovery. Numerous studies have demonstrated that when the diagnosis of PPCM is made with LVEF > 0.30, the probability is that recovery to LVEF >= 0.50 will occur in the overwhelming majority of subjects. PPCM patients diagnosed with severely depressed systolic function (LVEF < 0.30) and a remodeled left ventricle with greater dilatation (LVEDd >= 60mm) are least likely to reach the outcome recovery goals. These are the patients with the greatest need for newer interventional strategies. PMID- 25557958 TI - The twisted structure of the human Achilles tendon. AB - The Achilles tendon (AT) consists of fascicles that originate from the medial head of the gastrocnemius (MG), lateral head of the gastrocnemius (LG), and soleus muscle (Sol). These fascicles are reported to have a twisted structure. However, there is no consensus as to the degree of torsion. The purpose of this study was to investigate the twisted structure of the AT at the level of fascicles that originate from the MG, LG, and Sol, and elucidate the morphological characteristics. Gross anatomical study of 60 Japanese cadavers (111 legs) was used. The AT fascicles originated from the MG, LG, and Sol were fused while twisting among themselves. There were three classification types depending on the degree of torsion. Further fine separation of each fascicle revealed MG ran fairly parallel in all types, whereas LG and Sol, particularly of the extreme type, were inserted onto the calcaneal tuberosity with strong torsion. In addition, the sites of Sol torsion were 3-5 cm proximal to the calcaneal insertion of the AT. These findings provide promising basic data to elucidate the functional role of the twisted structure and mechanisms for the occurrence of AT injury and other conditions. PMID- 25557959 TI - Role of copper and the copper-related protein CUTA in mediating APP processing and Abeta generation. AB - One major pathologic hallmark and trigger of Alzheimer's disease (AD) is overproduction and accumulation of beta-amyloid (Abeta) species in the brain. Abeta is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases. Abnormal copper homeostasis also contributes to AD pathogenesis. Recently, we find that a copper-related protein, CutA divalent cation tolerance homolog of Escherichia coli (CUTA), interacts with the beta-secretase beta-site APP cleaving enzyme 1 (BACE1) and inhibits APP beta processing and Abeta generation. Herein, we further found that overexpression of CUTA increases intracellular copper level, whereas copper treatments promote CUTA expression. We also confirmed that copper treatments promote APP expression and Abeta secretion. In addition, copper treatments promoted the increase of Abeta secretion induced by CUTA downregulation but had no effect on CUTA-beta-site APP cleaving enzyme 1 interaction. On the other hand, CUTA overexpression ameliorated copper-induced Abeta secretion but had no effect on APP expression. Moreover, we found that Abeta treatments can reduce both CUTA and copper levels in mouse primary neurons. Consistently, both CUTA and copper levels were decreased in the hippocampus of APP/PS1 AD mouse brain. Together, our results reveal a reciprocal modulation of copper and CUTA and suggest that both regulate Abeta generation through different mechanisms, although Abeta mutually affects copper and CUTA levels. PMID- 25557961 TI - Synthesis of peptides containing 2-oxohistidine residues and their characterization by liquid chromatography-tandem mass spectrometry. AB - Protein oxidation by reactive oxygen species has been associated with aging and neurodegenerative disorders, and histidine is one of the major oxidation targets due to its metal-chelating property and susceptibility to metal-catalyzed oxidation. 2-Oxohistidine, the major product of histidine oxidation, has been recently identified as a stable marker of oxidative damage in biological systems, but its biophysical and biochemical properties are understudied, partly because of difficulties in its chemical synthesis. We developed an efficient method to generate a 2-oxohistidine side chain using metal-catalyzed oxidation, applicable to both monomers and peptides. By optimizing reagent ratios and pH buffering in Cu(2+) /ascorbate/O2 reaction system, we improved the yield more than tenfold compared to reported conditions, which allowed us to obtain homogeneously modified 2-oxohisidine peptides for further studies. Analysis of 2-oxohistidine containing model peptides by liquid chromatography-tandem mass spectrometry demonstrated increased retention time in reverse-phase chromatography and general stability of 2-oxohistidine under electrospray ionization and collision-induced dissociation. Thus, large-scale analysis of 2-oxohistidine-modified proteome should be feasible using shotgun protein mass spectrometry, and we were able to observe such peptides in proteomics datasets. The feasibility of acquiring purified peptide probes and peptide antigens containing 2-oxohistidine will help advance the study of this non-enzymatic posttranslational modification. PMID- 25557960 TI - Spatial relationship between fast and slow components of ictal activities and interictal epileptiform discharges in epileptic spasms. AB - OBJECTIVE: We analyzed the spatial distribution and concordance of fast (>10Hz) and slow (<5Hz) electroencephalogram (EEG) components of ictal activities and interictal epileptiform discharges (IIED) recorded by intracranial video EEG (IVEEG) in children with epileptic spasms (ES). METHODS: We studied eight children with ES, who underwent IVEEG before resective surgery for epilepsy. We quantified the root-mean-square (RMS) amplitude of the fast and slow components of ictal activities during ES and IIED. We compared the concordance between the spatial distributions of the fast and slow components of ES and IIED. RESULTS: There was a larger concordance between the spatial distributions of the fast and slow components in IIED than in ES (p=0.0206 and 0.0401). CONCLUSIONS: The spatial concordance between the fast and slow EEG components was significantly different between ES and IIED. SIGNIFICANCE: The mechanisms underlying the generation of slow EEG components may differ between ES and IIED. The slow EEG components of ES might indicate an extensive epileptic network involving remote symptomatic zones for ES in either the cortical or subcortical areas. The high spatial concordance between the fast and slow components of IIED suggests the involvement of a local inhibitory process within the epileptic cortex. PMID- 25557955 TI - Frontotemporal dementia: a bridge between dementia and neuromuscular disease. AB - The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD-ALS cases and the understanding that repeat containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD. PMID- 25557962 TI - Impact of single nucleotide polymorphisms of cytarabine metabolic genes on drug toxicity in childhood acute lymphoblastic leukemia. AB - BACKGROUND: Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL. PROCEDURE: We studied 8 SNPs in the CDA, DCK, DCTD, SLC28A3, and SLC29A1 genes in 144 patients with childhood acute lymphoblastic leukemia treated according to ALLIC BFM 1990, 1995 and 2002 protocols. RESULTS: DCK rs12648166 and DCK rs4694362 SNPs were associated with hematologic toxicity (OR = 2.63, CI 95% = 1.37-5.04, P = 0.0036 and OR = 2.53, CI 95% = 1.34-4.80, P = 0.0044, respectively). CONCLUSIONS: Our results indicate that DCK polymorphisms might be important genetic risk factors for hematologic toxicity during ALL treatment with ara-C. Individualized chemotherapy based on genetic profiling may help to optimize ara-C dosing, leading to improvements in clinical outcome and reduced toxicity. PMID- 25557963 TI - The relation of peripubertal and pubertal growth to final adult height in children with classic congenital adrenal hyperplasia. AB - OBJECTIVES: To determine the relationships between peripubertal and pubertal timing and growth, along with glucocorticoid exposure, to the reduced final adult height seen in patients with congenital adrenal hyperplasia (CAH). STUDY DESIGN: Chart review of 104 children with classic CAH (41 males: 28 salt-wasting, 13 simple-virilizing; 63 females: 38 salt-wasting, 25 simple-virilizing) were selected from a cohort from 3 medical institutions in Minnesota. Triple logistic modeling of longitudinal data was performed to determine patterns of peripubertal and pubertal growth. RESULTS: Hydrocortisone dose was similar between subtypes and during all growth periods. Simple-virilizing boys (P < .01) and girls (P < .01) were diagnosed later than their salt-wasting counterparts. Height at take off SDS was reduced for patients with salt-wasting (boys: P < .01; girls: P < .01), and bone age at take-off SDS was more advanced for patients with simple virilizing (boys: P < .01; girls: P = .05). Bone age at pubertal onset SDS was advanced for all patients, but more so for boys and girls with simple-virilizing. Although all patients had reduced final adult height SDS, this was more pronounced in patients with salt-wasting. CONCLUSION: Reduced final adult height SDS in patients with salt-wasting vs simple-virilizing may be attributable in part to a later age of diagnosis and resultant less prolonged exposure to hydrocortisone. This finding suggests that duration of hydrocortisone treatment in the peripubertal period, independent of the hydrocortisone dose, may affect final adult height in patients with CAH. PMID- 25557964 TI - The role of pre-primary classes on school-age cognition in rural Nepal. AB - OBJECTIVES: In rural Nepal, we assessed the factors associated with pre-primary school attendance and its relationship to cognitive testing and school progress. STUDY DESIGN: Sociodemographic, household, and schooling data were collected among 1466 children age 7-9 years from Sarlahi, Nepal. We performed the Universal Nonverbal Intelligence Test, backward digit span, go/no-go test, Movement Assessment Battery for Children, finger-tapping test, and Stroop numbers test. We conducted adjusted regression analyses to determine the association of pre primary school attendance with test results and school progress. RESULTS: We found that pre-primary class enrollment was lower among children of female sex, Madheshi ethnicity, and low socioeconomic status. In adjusted analyses, pre primary school enrollment was associated with beneficial scores on all cognitive tests. In addition, children who attended pre-primary school were less likely to repeat grade 1 (prevalence ratio 0.15, 95% CI 0.08-0.30, P < .001) or ever fail a grade (prevalence ratio 0.48, 95% CI 0.26-0.90, P = .02). CONCLUSIONS: In rural Nepal, there continue to be disparities in pre-primary school attendance; however, independent of these factors, pre-primary school attendance was associated with benefits in multiple cognitive domains and early school performance. PMID- 25557965 TI - Are we doing right by dying children? PMID- 25557966 TI - Universal screening programs for gestational exposures. PMID- 25557967 TI - Prevalence of functional gastrointestinal disorders in infants and toddlers. AB - OBJECTIVES: To determine the prevalence of gastrointestinal symptoms suggestive of an infant/toddler functional gastrointestinal disorder (FGID) as reported by parents in a representative community sample. STUDY DESIGN: Mothers (n = 320) of children aged 0-3 years old were recruited in the US and completed a questionnaire about their child's and their own gastrointestinal symptoms. RESULTS: By Rome criteria, 27% of infants/toddlers qualified for FGIDs. Infant regurgitation was the most common disorder in infants and functional constipation in toddlers. No age, sex, or race differences were found in FGID diagnoses. Compared with those who did not meet Rome criteria, toddlers with FGID had lower quality of life (M = 80.1 vs M = 90.3, P < .001), increased medical visits (M = 0.38 vs 0.14; P < .05), mental health visits (M = 0.29 vs 0.06; P < .05), and hospital stays (M = 0.35 vs 0.06; P < .01). A child was more likely to suffer from hard stools if the parent also reported hard stools (P = .02), but similar association was not found with loose stools. CONCLUSIONS: FGIDs are common in infants and toddlers and can be identified in the general population. They do not vary with sex and race. Quality of life is reduced in those with FGIDs. More research is needed into these largely neglected conditions as it may improve the lives of a significant number of young children. PMID- 25557968 TI - A brain and heart connection: X-linked periventricular heterotopia. PMID- 25557969 TI - Rapid deterioration of insulin secretion in obese adolescents preceding the onset of type 2 diabetes. AB - OBJECTIVE: To identify pathophysiologic changes that lead to the onset of type 2 diabetes (T2DM) in adolescents. STUDY DESIGN: Obese adolescents with normal glucose tolerance (n = 41) were studied longitudinally over the course of 4 years with serial measure of the acute insulin response to glucose (AIRg) as well as proinsulin (PI) concentrations. Insulin resistance was estimated with the homeostatic model assessment of insulin resistance (HOMA-IR), the disposition index (DI) computed as AIRg * 1/HOMA-IR, and intravenous glucose tolerance estimated as the glucose disappearance constant. RESULTS: Four adolescents developed diabetes mellitus (DM) during the study, and the rest of the cohort remained nondiabetic. Baseline PI exceeded the IQR of the nondiabetic group in 3 of 4 subjects with DM, and all had >85% reduction from baseline AIRg, and DI, within 6 months of diagnosis. All the subjects with DM gained weight over the course of the study, but these changes paralleled those for the nondiabetic group. HOMA-IR increased substantially in 1 of the subjects with DM at the time of diagnosis but was comparable with baseline in the other 3. The DI and glucose disappearance constant of the subjects with DM was less than the 10th percentile of the nondiabetic group before and after diagnosis. CONCLUSION: Conversion from normal glucose tolerance to T2DM in adolescents can occur rapidly, and the onset of T2DM is heralded by a substantial decrease in AIRg and DI, as well as increased release of PI. These results support loss of beta-cell function as the proximate step in the development of T2DM in this age group. PMID- 25557970 TI - The impact of operative timing on outcomes of appendicitis: a National Surgical Quality Improvement Project analysis. AB - BACKGROUND: Surgery is indicated for acute uncomplicated appendicitis but the optimal timing is controversial. Recent literature is conflicting on the effect of time to intervention. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Project dataset for patients undergoing laparoscopic and open appendectomy between 2007 and 2012. Logistic regression was used to evaluate 30-day morbidity and mortality of intervention at different time periods, adjusting for preoperative risk factors. RESULTS: A total of 69,926 patients undergoing appendectomy were identified. Groups were divided by time to intervention: group 1, less than 24 hours (n = 55,839; 79.9%); group 2, 24 to 48 hours (n = 13,409; 18.6%); and group 3, greater than 48 hours (n = 1,038; 1.5%). After adjustment, the risk of complication remained increased for group 3 versus group 1 or 2 (odds ratio 1.66, 95% confidence interval 1.34 to 2.07). CONCLUSIONS: These data demonstrate equivalent outcomes between time to appendectomy of less than 24 and 24 to 48 hours. There was a 2-fold increase in complication rate for patients delayed longer than 48 hours. PMID- 25557971 TI - Experience with a simple clamp-crush technique devoid of other devices for liver resections in a surgical oncology practice. AB - BACKGROUND: Parenchyma transection techniques during liver resection (LR) are linked to intraoperative blood loss and postoperative morbidity, with a recent increased use of energy devices over traditional clamp-crush hepatotomy (CCH). METHODS: Prospectively collected data from 191 consecutive patients undergoing LR with exclusive CCH by a single surgeon were examined. RESULTS: There were 94 men and 97 women, with 25% primary and 59% secondary malignancies or other conditions (16%). Forty-nine percent of LRs were major, 65% anatomic, and 32% included extrahepatic components. Median Pringle time was 23 minutes (9 to 76), blood loss 300 mL (20 to 5,000), and red blood cell transfusion rate 14%. Morbidity rate was 27% with 6 deaths. Significant relationships were observed for blood loss with complex resections, transfusions, major morbidity, and length of stay, but not between Pringle time and any outcomes. CONCLUSION: A CCH technique as employed in this LR experience without any use of additional devices can yield good postoperative results. PMID- 25557972 TI - Preoperative simultaneous fractionated cisplatin and radiation therapy in the treatment of advanced operable stage III and IV squamous cell carcinoma of the head and neck. AB - BACKGROUND: In Stage III/IV head and neck squamous cell carcinoma of the head and neck, multidisciplinary treatment is not standardized. This study evaluated preoperative simultaneous radiation therapy and Cisplatin 20 mg/M(2)/4 days during weeks 1, 4, and 7 of irradiation (CTRT). METHODS: Records of 143 CTRT and 48 patients treated with other surgery/radiation/chemotherapy regimens (CONTROL) were reviewed. Chi-square, analysis of variance, and Kaplan-Meier statistical analysis were performed. RESULTS: CTRT improved outcomes in Grade 2 to 5 toxicity (76% CONTROL vs 45% CTRT, P < .0001), complete clinical response (68% CTRT vs 36% CONTROL, P < .003), histologic complete response (67% in CTRT vs 28% in CONTROL, P = .0002), recurrence (33% in CTRT vs 66% in CONTROL, P = .0007), and distant metastases (2% CTRT vs 37% CONTROL, P = .0003); Kaplan-Meier disease-free survival was 65% CTRT versus 34% CONTROL. CONCLUSIONS: CTRT increases complete clinical response, histologic complete response, organ preservation, and survival, with lower recurrence and reduced toxicity and rare recurrence. CTRT may be the first treatment for Stage III/IV head and neck squamous cell carcinoma of the head and neck. PMID- 25557973 TI - How reliable are parenchymal tissues for the evaluation of carbon monoxide poisoning? A pilot study. AB - Dealing with burnt bodies, the forensic pathologist must first of all answer the question whether the victim was alive at the moment of the fire. This study aims at clarifying whether some human solid tissues may be reliably used for the forensic diagnosis of Co poisoning on burnt bodies providing no collectable blood during the autopsy. From 34 selected cases, both cardiac blood and parenchymal samples were collected to perform CO-oxymeter, spectrophotometry, and gas chromatography tests: blood CO estimations (blood COHb% and blood[CO]) and parenchymal[CO] values have been compared with special focus on R values. The solid tissues having the best correlations with blood CO amount turned out to be the lung (R 0.84), the liver (R 0.83), the kidney (R 0.79), and the spleen (R 0.92). PMID- 25557974 TI - Total synthesis of (-)-lundurine A and determination of its absolute configuration. AB - A 15-step total synthesis of (-)-lundurine A (1) from easily accessible (S) pyrrolidinone 18 is reported. A Simmons-Smith reaction allows the efficient, simultaneous assembly of the cyclopropyl C ring, the six-membered D ring, the seven-membered E ring, and the quaternary carbon stereocenters at C2 and C7. The absolute configuration of natural (-)-lundurine A was deduced to be 2R,7R,20R based on the stepwise construction of the stereocenters during the total synthesis. PMID- 25557976 TI - Effects of permeability and living space on cell fate and neo-tissue development in hydrogel-based scaffolds: a study with cartilaginous model. AB - One bottleneck in tissue regeneration with hydrogel scaffolds is the limited understanding of the crucial factors for controlling hydrogel's physical microenvironments to regulate cell fate. Here, the effects of permeability and living space of hydrogels on encapsulated cells' behavior were evaluated, respectively. Three model hydrogel-based constructs are fabricated by using photo crosslinkable hyaluronic acid as precursor and chondrocytes as model cell type. The better permeable hydrogels facilitate better cell viability and rapid proliferation, which lead to increased production of extracellular matrix (ECM), e.g. collagen, glycosaminoglycan. By prolonged culture, nano-sized hydrogel networks inhibit neo-tissue development, and the presence of macro-porous living spaces significantly enhance ECM deposition via forming larger cell clusters and eventually induce formation of scaffold-free neo-tissue islets. The results of this work demonstrate that the manipulation and optimization of hydrogel microenvironments, namely permeability and living space, are crucial to direct cell fate and neo-tissue formation. PMID- 25557975 TI - Ubiquitin-specific protease 7 accelerates p14(ARF) degradation by deubiquitinating thyroid hormone receptor-interacting protein 12 and promotes hepatocellular carcinoma progression. AB - The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that expression of deubiquitylase ubiquitin-specific protease 7 (USP7) is higher in human HCC tissues than in matched peritumoral tissues. Ectopic USP7 expression promotes growth of HCC cells in vivo and in vitro. Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing thyroid hormone receptor-interacting protein 12 (TRIP12), which induces constitutive p14(ARF) ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated alpha fetoprotein, and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates of HCC. CONCLUSION: USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14(ARF) and promoting HCC progression. This represents a novel marker for predicting prognosis and a potential therapeutic target for HCC. PMID- 25557977 TI - Proteolytic processing of the porcine reproductive and respiratory syndrome virus replicase. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) replicase polyproteins pp1a and pp1ab are proteolytically processed by four proteases encoded in ORF1a. In this study, a large set of PRRSV replicase cleavage products were identified and pp1a cleavage sites were verified by using a combination of bioinformatics, proteomics, immunoprecipitation, and site-directed mutagenesis. For genotype 1 PRRSV (isolate SD01-08), proteomic analysis identified H180/S181, G385/A386, and G1446/A1447 as the cleavage sites separating nsp1alpha/1beta, nsp1beta/nsp2, and nsp2/nsp3, respectively. Transient expression of nsp2-8, nsp3 8, nsp4-8, nsp5-8 (using the recombinant vaccinia virus/T7 RNA polymerase system) and immunoprecipitation identified the cleavage end products nsp2, nsp3, nsp4, nsp7alpha and nsp7beta, and various processing intermediates. Our studies also revealed the existence of alternative proteolytic processing pathways for the processing of the nsp3-8 region, depending on the presence or absence of nsp2 as a co-factor. The identity of most cleavage products was further corroborated by site-directed mutagenesis of individual cleavage sites in constructs expressing nsp3-8 or nsp4-8. This study constitutes the first in-depth experimental analysis of PRRSV replicase processing and the data are discussed against the background of the processing scheme previously derived for the arterivirus prototype, the distantly related equine arteritis virus (EAV). Despite several differences between the two viruses, of which the functional significance remains to be studied, our study demonstrates the general conservation of the replicase pp1a processing scheme between EAV and PRRSV, and likely also the other members of the arterivirus family. PMID- 25557979 TI - Evaluation of occupational and patient radiation doses in orthopedic surgery. AB - This study intends to measure the radiation dose to patients and staff during (i) Dynamic Hip Screw (DHS) and (ii) Dynamic Cannula Screw (DCS) and to evaluate entrance surface Air kerma (ESAK) dose and organ doses and effective doses. Calibrated Thermoluminescence dosimeters (TLD-GR200A) were used. The mean patients' doses were 0.46mGy and 0.07mGy for DHS and DCS procedures, respectively. The mean staff doses at the thyroid and chest were 4.69mGy and 1.21mGy per procedure. The mean organ and effective dose for patients and staff were higher in DHS compared to DCS. Orthopedic surgeons were exposed to unnecessary radiation doses due to the lack of protection measures. The radiation dose per hip procedure is within the safety limit and less than the previous studies. PMID- 25557978 TI - Life course body mass index and adolescent self-esteem: Evidence from Hong Kong's "Children of 1997" Birth Cohort. AB - OBJECTIVE: Self-esteem is an important determinant of adolescent mental health. Prior adiposity may be a factor in the development of self-esteem. However, the association of adiposity with self-esteem is inconsistent, perhaps because adiposity and self-esteem tend to be socially patterned, making it unclear whether observed associations are biologically based or contextually specific. METHODS: Multivariable partial least squares regression was used to assess the adjusted association of birth weight and childhood body mass index (BMI) z-score at 3 and 9 months and at 3, 7, 9 and 11 years and changes in BMI z-score with self-esteem at ~11 years, assessed from the self-reported Culture Free Self Esteem Inventory in a population-representative Chinese birth cohort, which has little social patterning of adiposity. Whether the associations varied by sex also was assessed. RESULTS: Self-esteem score was available for 6,520 girls and boys (78.5% follow-up). Birth weight z-score, BMI z-scores at 3 and 9 months and at 3, 7, 9, and 11 years, and successive BMI z-score changes had little association with self-esteem at ~11 years, adjusted for socio-economic position. CONCLUSIONS: In a developed, non-Western setting, life course BMI does not appear to be a factor in the development of self-esteem in early adolescence, suggesting that observed associations to date may be contextually specific rather than biologically based. PMID- 25557980 TI - Prolonged Tpeak-end and Tpeak-end/QT ratio as predictors of malignant ventricular arrhythmias in the acute phase of ST-segment elevation myocardial infarction: a prospective case-control study. AB - BACKGROUND: Prolonged Tpeak-end (the interval from the peak of the T wave to the end of the T wave) and Tpeak-end/QT ratio have been shown to be markers of arrhythmogenesis in various cardiac disorders. OBJECTIVES: The purpose of this study was to evaluate the utility of Tpeak-end and Tpeak-end/QT ratio at admission in patients with acute ST-segment elevation myocardial infarction (STEMI) in predicting malignant ventricular arrhythmias. METHODS: The study group included 50 patients presenting with STEMI, in whom Tpeak-end and Tpeak-end/QT ratio were measured at admission; these patients were monitored for arrhythmias with a continuous electrocardiogram in the intensive care unit for 48 hours, and 50 healthy individuals acted as controls. RESULTS: The Tpeak-end (0.11 +/- 0.04 seconds vs 0.08 +/- 0.006 seconds; P < .0010) and Tpeak-end/QT ratio (0.30 +/- 0.06 vs 0.21 +/- 0.02; P < .001) were prolonged in patients with STEMI. Three patients with STEMI who sustained ventricular fibrillation (VF) within 24 hours of admission had prolonged corrected QT interval (0.39 +/- 0.04 seconds vs 0.46 +/- 0.13 seconds; P = .019), Tpeak-end (0.10 +/- 0.02 seconds vs 0.20 +/- 0.11 seconds; P < .001), and Tpeak-end/QT ratio (0.26 +/- 0.05 vs 0.41 +/- 0.09; P < .001) as compared with patients with STEMI without VF. Tpeak-end > 0.1 seconds and Tpeak-end/QT ratio > 0.3 predicted VF with a sensitivity of 100%. However, the Tpeak-end/QT ratio had a higher specificity (82.9% for Tpeak-end/QT ratio vs 44.7% for Tpeak-end) and accuracy (84% for Tpeak-end/QT ratio vs 48% for Tpeak end). CONCLUSION: Tpeak-end and Tpeak-end/QT ratio are prolonged in patients with STEMI compared with healthy individuals, and Tpeak-end > 0.1 and Tpeak-end/QT ratio > 0.3 predict malignant ventricular arrhythmias within 24 hours of STEMI. PMID- 25557981 TI - What is left unsaid: an interpretive description of the information needs of parents of children with asthma. AB - Parents of children with asthma provide the vast majority of day-to-day asthma care. Understanding their information needs is an essential step to provide meaningful and effective family-centered asthma education. To gain insight into the information needs and information deficits of parents of children with asthma, we conducted an interpretive descriptive study to capture the perspectives of 21 parents from diverse backgrounds whose 23 children with asthma had a range of illness trajectories and management scenarios. Parents were purposively sampled from two asthma clinics and one pediatric emergency department in a large urban center in North America. Semi-structured interviews were conducted in 2011-2012. In data analysis, parents' self-identified information needs were distinguished from analysts' interpretations of information deficits. Participants' knowledge did not always reflect time since diagnosis, and information needs and deficits persisted for years. Parents often reported receiving little or no little or no education about asthma and its management. An asthma management information hierarchy was identified, starting with the most foundational, recognizing severity; followed by acute management; prevention versus crisis orientation; and knowing "about" asthma. In the absence of adequate and accurate education, parents' beliefs about the nature of asthma as an acute rather than chronic condition shaped their asthma management decisions and information-seeking behaviors. Information deficits were affected by interactions with health care providers. These parents' pervasive unmet information needs and deficits highlight the need for comprehensive, problem oriented asthma education. PMID- 25557983 TI - 3D printed models for planning endovascular stenting in transverse aortic arch hypoplasia. AB - OBJECTIVES: To evaluate whether three-dimensional (3D) printed models can be used to improve interventional simulation and planning in patients with aortic arch hypoplasia. BACKGROUND: Stenting of a hypoplastic transverse arch is technically challenging, and complications such as stent migration and partial obstruction of the origin of the head and neck vessels are highly dependent on operator skills and expertise. METHODS: Using magnetic resonance imaging (MRI) data, a 3D model of a repaired aortic coarctation of a 15-year-old boy with hypoplastic aortic arch was printed. Simulation of the endovascular stenting of the hypoplastic arch was carried out under fluoroscopic guidance in the 3D printed model, and subsequently in the patient. A Bland-Altman analysis was used to evaluate the agreement between measurements of aortic diameter in the 3D printed model and the patient's MRI and X-ray angiography. RESULTS: The 3D printed model proved to be radio-opaque and allowed simulation of the stenting intervention. The assessment of optimal stent position, size, and length was found to be useful for the actual intervention in the patient. There was excellent agreement between the 3D printed model and both MRI and X-ray angiographic images (mean bias and standard deviation of 0.36 +/- 0.45 mm). CONCLUSIONS: 3D printed models accurately replicate patients' anatomy and are helpful in planning endovascular stenting in transverse arch hypoplasia. This opens a door for potential simulation applications of 3D models in the field of catheterization and cardiovascular interventions. PMID- 25557982 TI - Control strategies for active lower extremity prosthetics and orthotics: a review. AB - : Technological advancements have led to the development of numerous wearable robotic devices for the physical assistance and restoration of human locomotion. While many challenges remain with respect to the mechanical design of such devices, it is at least equally challenging and important to develop strategies to control them in concert with the intentions of the user.This work reviews the state-of-the-art techniques for controlling portable active lower limb prosthetic and orthotic (P/O) devices in the context of locomotive activities of daily living (ADL), and considers how these can be interfaced with the user's sensory motor control system. This review underscores the practical challenges and opportunities associated with P/O control, which can be used to accelerate future developments in this field. Furthermore, this work provides a classification scheme for the comparison of the various control strategies.As a novel contribution, a general framework for the control of portable gait-assistance devices is proposed. This framework accounts for the physical and informatic interactions between the controller, the user, the environment, and the mechanical device itself. Such a treatment of P/Os--not as independent devices, but as actors within an ecosystem--is suggested to be necessary to structure the next generation of intelligent and multifunctional controllers.Each element of the proposed framework is discussed with respect to the role that it plays in the assistance of locomotion, along with how its states can be sensed as inputs to the controller. The reviewed controllers are shown to fit within different levels of a hierarchical scheme, which loosely resembles the structure and functionality of the nominal human central nervous system (CNS). Active and passive safety mechanisms are considered to be central aspects underlying all of P/O design and control, and are shown to be critical for regulatory approval of such devices for real-world use.The works discussed herein provide evidence that, while we are getting ever closer, significant challenges still exist for the development of controllers for portable powered P/O devices that can seamlessly integrate with the user's neuromusculoskeletal system and are practical for use in locomotive ADL. PMID- 25557984 TI - Recombinant PAI-1 therapy restores myoendothelial junctions and erectile function in PAI-1-deficient mice. AB - Myoendothelial junctions are specialised projections of cell : cell contact through the internal elastic lamina between endothelial cells and vascular smooth muscle cells. These junctions allow for endothelial cells and vascular smooth muscle cells to make direct membrane apposition and are involved in cell : cell communication. In this study, we evaluated for the presence of myoendothelial junctions in murine corporal tissue and used plasminogen activator inhibitor (PAI)-1-deficient mice, which lack myoendothelial junctions, to determine whether myoendothelial junctions affect erectile function. Transmission electron microscopy demonstrated the presence of myoendothelial junctions in the corporal tissue of wild-type mice and confirmed the decreased junction numbers in the tissue of PAI-1(-/-) mice. A potential role for myoendothelial junctions in tumescence was established; in that, PAI-1(-/-) mice demonstrated a significantly longer time to achieve maximal intracavernous pressure. Treatment of PAI-1(-/-) mice with recombinant PAI-1 restored the number of myoendothelial junctions in the corporal tissue and also induced a significant decrease in time to maximal corporal pressures. Myoendothelial junctions were similarly identified in the human corporal tissue. These results suggest a critical role for myoendothelial junctions in erectile pathophysiology and therapies aimed at restoring myoendothelial junction numbers in the corporal tissue may provide a novel therapy for erectile dysfunction. PMID- 25557985 TI - Motor endplate-targeted botulinum toxin injections of the gracilis muscle in children with cerebral palsy. AB - AIM: Intramuscular botulinum toxin-A (BoNT-A) injections reduce spasticity by blocking neurotransmission at the motor endplate (MEP). The goal of this study was to assess the reduction in spasticity achieved by injecting BoNT-A at different sites of the gracilis muscle. METHOD: Thirty-four gracilis muscles, in 27 children (10 females and 17 males, mean age of 8.6y [SD 2.5y]) with spastic cerebral palsy (unilateral and bilateral, Gross Motor Function Classification System [GMFCS] levels I-IV), were randomly assigned to one of two groups. In one group BoNT-A was injected proximally (at a site 25% of the distance from the pubic tubercle and the medial epicondyle) and in the other it was injected at the MEP zones (half of the dose was administered at 30% of this distance and half at 60%). Spasticity was assessed before and after BoNT-A injection using simultaneous measurements of surface electromyography (sEMG) and angular velocity during passive muscle stretch applied at different velocities. The primary outcome measure included the velocity-dependent change in average root mean square electromyography (RMS-EMG). Secondary outcome was assessed with the Modified Ashworth Scale (MAS) and Modified Tardieu Scale (MTS). RESULTS: Spasticity decreased more in MEP-targeted muscles than in proximally injected muscles, as demonstrated by a larger reduction in average RMS-EMG values (p=0.04), though this difference was not found with the MAS or MTS. INTERPRETATION: The results suggest that BoNT-A injection of the gracilis at sites with a high concentration of MEPs is effective at reducing spasticity. These preliminary findings should be confirmed by larger studies. In the case of long muscles, such as the gracilis, the injection site is important. PMID- 25557986 TI - The forgotten ones: challenges and needs of children living with disabling parental chronic pain. AB - A qualitative study explored the challenges and needs of children living with parental chronic pain. Young adult children (n=30) of parents with chronic pain were interviewed. Parents (n=20) with chronic pain participated in four focus groups. Content analysis yielded five categories of child challenges: (a) understanding the big picture; (b) enduring hardships; (c) grieving losses; (d) communicating with parent, and; (e) isolating self from peers. Three categories of child needs emerged: (a) knowledge; (b) skills, and; (c) supervised interaction. Understanding these challenges and needs is a vital step in the process of developing evidence-based interventions for this at-risk group. PMID- 25557987 TI - Impact of dental caries on quality of life among preschool children: emphasis on the type of tooth and stages of progression. AB - The aim of this cross-sectional study was to evaluate the impact of dental caries on the quality of life of preschool children and their parents/caretakers, with an emphasis on the type of tooth and stage of progression. A randomly selected sample of preschool children, 3-5 yrs of age, underwent an oral examination for the assessment of dental caries using the International Caries Detection and Assessment System II (ICDAS II) criteria. Parents/caretakers answered two questionnaires, one on the oral health-related quality of life (OHRQoL) of the child [the Early Childhood Oral Health Impact Scale (ECOHIS)], and the other on the socio-economic characteristics of the family. Statistical analyses were performed using the chi-square test, Kruskal-Wallis test, Mann-Whitney U-test, and Poisson regression. A total of 451 preschool children participated in the study. The majority of carious lesions exhibited severe decay (60.6%) and were found in both anterior (incisors/canines) and posterior (molars) teeth. The final Poisson model revealed negative impacts on quality of life from more advanced stages of dental caries, both in incisors/canines and molars. Child's age and household income were also associated with impact on quality of life. Carious lesions in more advanced stages of progression in anterior and posterior teeth were associated with a negative impact on the quality of life of preschool children. PMID- 25557993 TI - Advanced journals - open for innovation. PMID- 25557988 TI - Regulation of the formin Cappuccino is critical for polarity of Drosophila oocytes. AB - The Drosophila formin Cappuccino (Capu) creates an actin mesh-like structure that traverses the oocyte during midoogenesis. This mesh is thought to prevent premature onset of fast cytoplasmic streaming which normally happens during late oogenesis. Proper cytoskeletal organization and cytoplasmic streaming are crucial for localization of polarity determinants such as osk, grk, bcd, and nanos mRNAs. Capu mutants disrupt these events, leading to female sterility. Capu is regulated by another nucleator, Spire, as well as by autoinhibition in vitro. Studies in vivo confirm that Spire modulates Capu's function in oocytes; however, how autoinhibition contributes is still unclear. To study the role of autoinhibition in flies, we expressed a Capu construct that is missing the Capu Inhibitory Domain, CapuDeltaN. Consistent with a gain of activity due to loss of autoinhibition, the actin mesh was denser in CapuDeltaN oocytes. Further, cytoplasmic streaming was delayed and fertility levels decreased. Localization of osk mRNA in early stages, and bcd and nanos in late stages, were disrupted in CapuDeltaN-expressing oocytes. Finally, evidence that these phenotypes were due to a loss of autoinhibition comes from coexpression of the N-terminal half of Capu with CapuDeltaN, which suppressed the defects in actin, cytoplasmic streaming and fertility. From these results, we conclude that Capu can be autoinhibited during Drosophila oocyte development. PMID- 25557989 TI - Co-migration of colon cancer cells and CAFs induced by TGFbeta1 enhances liver metastasis. AB - Colorectal cancer (CRC) cells often metastatize to the liver. Cancer-associated fibroblasts (CAFs) enhance metastasis by providing cytokines that create a favorable microenvironment and by inducing co-dissemination with tumor cells. However, the mechanisms of co-metastatization remain elusive. The aim of this study is to assess the role of TGFbeta1 in CRC cell-CAFs attachment and its impact on liver metastasis. CAFs were obtained after xenotransplantation of Mc38 cells into EGFP-C57BL/6 mice. Attachment experiments with CRC cells and CAFs (with or without TGFbeta1 and the inhibitory peptide P17) were carried out, as well as in vivo liver metastasis assays. TGFbeta1 induced adhesion of CRC cells to CAFs, whereas exposure to P17 abrogated this effect. Co-injection of Mc38 cells with CAFs intrasplenically increased liver metastasis, as compared to injection of tumor cells alone. Pretreatment of Mc38 cells with TGFbeta1 enhanced the metastatic burden, in comparison to untreated Mc38 + CAFs. TGFbeta1 pretreated Mc38 cells co-metastatized with CAFs to the liver in a highly efficient way. Importantly, the metastatic burden was significantly reduced (p < 0.001) when P17 was administered in mice. The number of PCNA+ and CD-31+ cells was also reduced by P17 in these animals, indicating a decrease in proliferation and angiogenesis upon TGFbeta1 signaling blockade. Through microarray analysis, we identified potential TGFbeta1-regulated genes that may mediate cancer cell stroma interactions to increase metastasis. In conclusion, TGFbeta1 promotes co travelling of CRC cells and CAFs to the liver to enhance metastasis. Our results strongly support the use of TGFbeta1 targeted drugs as a novel strategy to reduce liver metastasis in CRC patients. PMID- 25557998 TI - Drug-drug interactions related to altered absorption and plasma protein binding: theoretical and regulatory considerations, and an industry perspective. AB - Drug-drug interactions (DDIs) related to altered drug absorption and plasma protein binding have received much less attention from regulatory agencies relative to DDIs mediated via drug metabolizing enzymes and transporters. In this review, a number of theoretical bases and regulatory framework are presented for these DDI aspects. Also presented is an industry perspective on how to approach these issues in support of drug development. Overall, with the exception of highly permeable and highly soluble (BCS 1) drugs, DDIs related to drug-induced changes in gastrointestinal (GI) physiology can be substantial, thus warranting more attentions. For a better understanding of absorption-associated DDI potential in a clinical setting, mechanistic studies should be conducted based on holistic integration of the pharmaceutical profiles (e.g., pH-dependent solubility) and pharmacological properties (e.g., GI physiology and therapeutic margin) of drug candidates. Although majority of DDI events related to altered plasma protein binding are not expected to be of clinical significance, exceptions exist for a subset of compounds with certain pharmacokinetic and pharmacological properties. Knowledge of the identity of binding proteins and the binding extent in various clinical setting (including disease states) can be valuable in aiding clinical DDI data interpretations, and ensuring safe and effective use of new drugs. PMID- 25557999 TI - Developing a prognostic model for localized Ewing sarcoma family of tumors: A single institutional experience of 224 cases treated with uniform chemotherapy protocol. AB - BACKGROUND: Data on patients with localized Ewing sarcoma family of tumors (ESFT) who have received a uniform chemotherapy protocol are minimal. METHODS: This is a single institutional review of patients with ESFT treated between June 2003 and November 2011. RESULTS: 224/374 (60%) patients with ESFT presented with localized disease; median age was 15 years (range: 0.1-55). Ninety-nine patients underwent surgery of which 50 received adjuvant radiotherapy; 80 patients received radical radiotherapy following neoadjuvant chemotherapy. At median follow-up of 40.2 months (range: 1.3-129), 5-year EFS, OS, and local-control-rate, were 36.8 +/- 3.6%, 52.4 +/- 4.3%, and 63 +/- 4.3%, respectively. In multivariate analysis, tumor diameter > 8 cm (P = 0.03), symptom duration > 4 months (P = 0.04), and WBC > 11 * 10(9) /L (P = 0.003) predicted inferior EFS; spine/abdomino-pelvic primary (P = 0.009) and WBC > 11 * 10(9) /L (P = 0.003) predicted inferior OS. Tumor size > 8 cm (P = 0.03) and radical radiotherapy as local treatment (P = 0.01) predicted inferior local-control-rate. CONCLUSION: Prognostic hazard models for EFS and OS based on significant prognostic factors suggested that patients with combination of ESFT of spine/abdomino-pelvic region and baseline WBC > 11 * 10(9) /L had inferior OS (hazard ratio 4.44, P < 0.001) while patients with combination of ESFT with symptom duration > 4 months, tumor diameter > 8 m and baseline WBC > 11 * 10(9) /L had inferior EFS (hazard ratio 3.89, P = 0.002). PMID- 25558001 TI - A lithium-ion sulfur battery using a polymer, polysulfide-added membrane. AB - In this paper we report the performances of a lithium-ion sulfur battery characterized by a polymer configuration. The cell, based on a sulfur-carbon cathode, a Li-Sn-C nanostructured anode and a PEO-based, polysulfide-added electrolyte, shows very good electrochemical performances in terms of stability and delivered capacity. The remarkable cell performances are ascribed to the mitigation of the cathode dissolution process due to the buffer action ensured by the polysulfide added to the polymer electrolyte. This electrolyte configuration allows the achievement of a stable capacity ranging from 500 to 1500 mAh gS(-1), depending on the cycling rate. The use of a polymer electrolyte and the replacement of the lithium metal with a Li-Sn-C nanostructured alloy are expected to guarantee high safety content, thus suggesting the battery here studied as advanced energy storage system. PMID- 25558002 TI - A new 2-micrometer continuous wave laser method for management of the distal ureter in retroperitoneal laparoscopic nephroureterectomy. AB - BACKGROUND AND PURPOSE: Retroperitoneal laparoscopic nephroureterectomy (LNU) is a classic technique for the treatment of patients with urothelial cancer of the upper urinary tract. Management of the distal ureter in patients undergoing this procedure remains controversial, however. We evaluated a new method involving cystoscopic sleeve resection of the distal ureter using a 2-MUm continuous wave laser before LNU. PATIENTS AND METHODS: LNU was performed in 38 patients at our hospital between January 2008 and January 2012. The distal end of the ureter was managed by using a 2-MUm continuous wave laser to evaporate and excise the ureteral orifice and bladder cuff. A standard technique was applied to keep the ureter intact. The ureter was dissected to the entrance of the bladder, and the distal ureter was easily detached from the bladder. RESULTS: The distal ureter was excised completely in all cases using this new technique. The average operative time was 2.4 hours, and the average blood loss was 69.4 mL. At 1 year after surgery, the cause-specific survival rate of the patients was 100%, the bladder recurrence-free rate was 89%, and the extravesical recurrence-free rate was 100%. CONCLUSIONS: For managing the distal ureter during LNU, the new technique described proved to be a simple, safe, and minimally invasive method. PMID- 25558000 TI - Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism. AB - Tissue inhibitor of metalloproteinases-3 (TIMP3) is a tumor suppressor and a potent inhibitor of angiogenesis. TIMP3 exerts its anti-angiogenic effect via a direct interaction with vascular endothelial growth factor (VEGF) receptor-2 (KDR) and inhibition of proliferation, migration and tube formation of endothelial cells (ECs). TIMP3 has also been shown to induce apoptosis in some cancer cells and vascular smooth muscle cells via MMP inhibition and caspase dependent mechanisms. In this study, we examined the molecular mechanisms of TIMP3-mediated apoptosis in endothelial cells. We have previously demonstrated that mice developed smaller tumors with decreased vascularity when injected with breast carcinoma cells overexpressing TIMP3, than with control breast carcinoma cells. TIMP3 overexpression resulted in increased apoptosis in human breast carcinoma (MDA-MB435) in vivo but not in vitro. However, TIMP3 could induce apoptosis in ECs in vitro. The apoptotic activity of TIMP3 in ECs appears to be independent of MMP inhibitory activity. Furthermore, the equivalent expression of functional TIMP3 promoted apoptosis and caspase activation in ECs expressing KDR (PAE/KDR), but not in ECs expressing PDGF beta-receptor (PAE/beta-R). Surprisingly, the apoptotic activity of TIMP3 appears to be independent of caspases. TIMP3 inhibited matrix-induced focal adhesion kinase (FAK) tyrosine phosphorylation and association with paxillin and disrupted the incorporation of beta3 integrin, FAK and paxillin into focal adhesion contacts on the matrix, which were not affected by caspase inhibitors. Thus, TIMP3 may induce apoptosis in ECs by triggering a caspase-independent cell death pathway and targeting a FAK dependent survival pathway. PMID- 25558004 TI - Scoping dietary supplements versus botanical medicines. PMID- 25558005 TI - Is resveratrol an imposter? PMID- 25558009 TI - Particle size dependence of the surface-enhanced Raman scattering properties of densely arranged two-dimensional assemblies of Au(core)-Ag(shell) nanospheres. AB - We investigated the dependence of the surface-enhanced Raman scattering (SERS) activity of densely arranged two-dimensional assemblies of spherical Au(core) Ag(shell) nanoparticles (Au/AgNSs) on the nanoparticle diameter. The size controlled Au/AgNSs were synthesized using the Au nanosphere seed-mediated growth method without any bulky stabilizers. The diameters of the Au/AgNSs were 38, 53, and 90 nm and the ratio of the total diameter to the Au core diameter was adjusted to ca. 2.0. Extinction spectra of the colloidal solutions of these nanoparticles exhibited the prominent peak of the localized surface plasmon resonance (LSPR) of Ag and therefore the Au/AgNSs exhibited LSPR properties almost the same as Ag nanospheres. It was confirmed from SEM observation that the organic solvent-mediated liquid-liquid interface assembly technique easily generated densely arranged two-dimensional assemblies of the nanospheres. The extinction spectra of all the assemblies exhibited a prominent broad peak ranging from 500 nm to the near-infrared region, which is assigned to the longitudinal LSPR mode of the coupling nanospheres. The extinction intensity increased with increasing nanosphere diameter. The SERS activities of these assemblies were investigated using p-aminothiophenol as a probe molecule. The result revealed that the enhancement factor (EF) of the Raman signal dramatically increased upon increasing the particle diameter. The maximum EF obtained with a laser excitation wavelength of 785 nm was 1.90 * 10(6) for a nanosphere diameter of 90 nm. This renders the two-dimensional assemblies of the plasmonic Au/AgNSs promising for the development of highly sensitive SERS sensor platforms due to their strong electromagnetic effect. PMID- 25558011 TI - Response to a recently published Letter to the Editor in The Lancet. PMID- 25558010 TI - Molecular characterization of insulin-like androgenic gland hormone-binding protein gene from the oriental river prawn Macrobrachium nipponense and investigation of its transcriptional relationship with the insulin-like androgenic gland hormone gene. AB - Insulin-like androgenic gland hormone-binding protein (IAGBP) has been investigated in crustaceans in vitro. However, the relationship between IAGBP and its putative binding protein partner insulin-like androgenic gland hormone (IAG) has not been studied at the transcriptional level in vivo. In the current study, we cloned the full-length cDNA of IAGBP from the oriental river prawn Macrobrachium nipponense (Mn-IAGBP) and investigated the transcriptional patterns of Mn-IAGBP and the M. nipponense IAG gene (Mn-IAG) at different developmental stages and in different tissues. Mn-IAGBP mRNA was detected in all examined tissues from adult male prawns, with the highest transcriptional levels in the testis. Mn-IAG mRNA was detected in the androgenic gland and hepatopancreas. The genomic sequences of Mn-IAGBP and Mn-IAG were isolated by genome walking and two gene copies were found in both Mn-IAGBP and Mn-IAG. The relationship between Mn IAGBP and Mn-IAG at the transcriptional level was studied by RNA interference. Injection of Mn-IAGBP double-stranded RNA (dsRNA) significantly reduced the transcription of Mn-IAG, while injection of Mn-IAG dsRNA significantly reduced the transcription of Mn-IAGBP in testis, muscle, androgenic gland, and hepatopancreas. These results demonstrate the involvement of the IAGBP gene in IAG signaling in M. nipponense. PMID- 25558012 TI - Weighing the benefits and risks of diabetes drugs: a call for a unified global approach. PMID- 25558013 TI - Clinical categorization of psychogenic blepharospasm. PMID- 25558014 TI - Analogues of deltorphin I containing conformationally restricted amino acids in position 2: structure and opioid activity. AB - New analogues of deltorphin I (DT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 ), with the D-Ala residue in position 2 replaced by alpha-methyl-beta-azido(amino, 1 pyrrolidinyl, 1-piperidinyl or 4-morpholinyl)alanine, were synthesized by a combination of solid-phase and solution methods. All ten new analogues were tested for receptor affinity and selectivity to MU- and delta-opioid receptors. The affinity of analogues containing (R) or (S)-alpha-methyl-beta-azidoalanine in position 2 to delta-receptors strongly depended on the chirality of the alpha,alpha-disubstituted residue. Peptide II, containing (S)-alpha-methyl-beta azidoalanine in position 2, displayed excellent delta-receptor selectivity with its delta-receptor affinity being only three times lower than that of DT I. PMID- 25558015 TI - Screening for thyroid cancer according to French recommendations with thyroid ultrasound in newly diagnosed Graves' disease without palpable nodule is not useful. AB - OBJECTIVE: The aim of the study was to evaluate systematic thyroid ultrasonography (US) relevance in newly diagnosed Graves' disease among patients presenting without palpable nodules. SUBJECTS AND METHODS: We consecutively recruited 208 cases of Graves' disease without palpable nodule. All patients were screened for thyroid antibodies and underwent a thyroid US. Ultrasonically guided biopsy was proposed for the assessment of all nodules upper or equal to 10mm in diameter. RESULTS: Two third of patients had an abnormal thyroid at palpation requiring an US. One third of patients had a normal thyroid at palpation and US was consequently unwarranted. Among all patients, US detected non-palpable nodules in 26% of cases. We found no smears suspected to be cancerous. CONCLUSIONS: In newly diagnosed Graves' disease, the US relevance is only questionable in patients without abnormal thyroid at palpation. Ultrasonography detected non-palpable nodules and none was suspected to be cancerous. These data suggest that US is not useful in patients without abnormal thyroid at palpation. Nevertheless, the recent Thyroid Imaging-Reporting And Data System classification (TI-RADS) might change our conclusions. The TI-RADS classification indeed improves the selection of nodules lower than 10mm in diameter requiring a biopsy. Nodules lower than 10mm in diameter were not biopsied in the present study. The other US data presented herein (echogenicity, vascularisation) provide no further relevance for systematic US in newly diagnosed patients. PMID- 25558016 TI - Secondary nocturnal enuresis related to central diabetes insipidus as an early manifestation of intracranial germinomatous germ cell tumors in a series of male youngsters. AB - Nocturnal enuresis is a common symptom in children. It is usually attributed to benign causes and diagnostic evaluation is not carried out. We report three male young patients initially presenting with short stature and nocturnal enuresis, related to diabetes insipidus, caused by intracranial germinomatous germ cell tumors. In all three cases, water deprivation tests confirmed diabetes insipidus. Extensive endocrinological investigation also showed further hormone deficiencies. Magnetic resonance imaging of the brain revealed the presence of a central nervous system lesion and histology confirmed the final diagnosis. Surgery, radiation with or without chemotherapy was conducted and the patients were treated with hormone replacement therapies. The patients after a long follow up were free of disease. We present these cases to alert clinicians to bear in mind that the presence of an intracranial germinomatous germ cell tumor should at least be considered in a child presenting with bed wetting, especially if additional symptoms and signs, including late onset puberty and growth delay or morning hypernatremia, may coexist. PMID- 25558017 TI - The phosphinoboration reaction. AB - The synthesis of phosphinoboronate esters containing a single P-B bond is reported, together with preliminary reactivity studies towards a range of organic substrates. These compounds add readily to aldehydes, ketones, aldimines, and alpha,beta-unsaturated enones to give primarily the corresponding 1,2-addition products containing a new P-C bond. The first examples of transition-metal catalyzed phosphinoborations of C-C multiple bonds in which P-C and B-C bonds are formed in a single step are also disclosed; allenes react by a highly regioselective 1,2-addition whereas terminal alkynes undergo a formal 1,1 addition. PMID- 25558018 TI - Effects of starvation and hormones on DNA synthesis in silk gland cells of the silkworm, Bombyx mori. AB - Silk gland cells of silkworm larvae undergo multiple cycles of endomitosis for the synthesis of silk proteins during the spinning phase. In this paper, we analyzed the endomitotic DNA synthesis of silk gland cells during larval development, and found that it was a periodic fluctuation, increasing during the vigorous feeding phase and being gradually inhibited in the next molting phase. That means it might be activated by a self-regulating process after molting. The expression levels of cyclin E, cdt1 and pcna were consistent with these developmental changes. Moreover, we further examined whether these changes in endomitotic DNA synthesis resulted from feeding or hormonal stimulation. The results showed that DNA synthesis could be inhibited by starvation and re activated by re-feeding, and therefore appears to be dependent on nutrition. DNA synthesis was suppressed by in vivo treatment with 20-hydroxyecdysone (20E). However, there was no effect on DNA synthesis by in vitro 20E treatment or by either in vivo or in vitro juvenile hormone treatment. The levels of Akt and 4E BP phosphorylation in the silk glands were also reduced by starvation and in vivo treatment with 20E. These results indicate that the activation of endomitotic DNA synthesis during the intermolt stages is related to feeding and DNA synthesis is inhibited indirectly by 20E. PMID- 25558020 TI - Distribution of polychlorinated biphenyl residues in sediments and blue mussels (Mytilus galloprovincialis) from Port Elizabeth Harbour, South Africa. AB - Sediment and Mytilus galloprovincialis samples collected from the Port Elizabeth Harbour were analysed for six indicator PCB congeners to assess their contamination status. The concentrations of total PCBs in sediments and M. galloprovincialis ranged from 0.56 to 2.35 ng/g dry weight and 14.48 to 21.37 ng/g wet weight, respectively. Congeners 138 and 153 were dominant and accounted for an average of 29% and 24% of total PCBs in M. galloprovincialis; 32% and 30% in sediments, respectively. Sediments are home to a wide variety of aquatic life. None of the sediments analysed exceeded the PCB limits recommended the Canadian interim sediment quality guideline and the South African recommended sediment guidelines (21.6 ng/g). Both humans and aquatic life are sensitive to the toxic effects of PCBs. PMID- 25558019 TI - A macroalgal germling bioassay to assess biocide concentrations in marine waters. AB - A bioassay method using the early life stages (germlings) of macroalgae was developed to detect toxicity of anti-fouling paint biocides. A laboratory based bioassay using Ulva intestinalis and Fucus spiralis germlings was performed with 4 common anti-fouling biocides (tributyltin (TBT), Irgarol 1051, Diuron and zinc sulphate), over a range of environmentally relevant concentrations (0.0033-10 MUg l(-1)). Comparison between the two species showed that germlings of U. intestinalis were better adapted for in-situ monitoring, as germlings of F. spiralis appeared to be too robust to display sufficient growth differences. The response of U. intestinalis germling growth appeared to reflect environmental biocide concentrations. Overall the developed method showed potential for the assessment of the sub-lethal effects of anti-fouling biocides on the early developmental stages of U. intestinalis. PMID- 25558021 TI - The amount and accumulation rate of plastic debris on marshes and beaches on the Georgia coast. AB - The amount and accumulation rate of plastic debris at 20 sites along the Georgia coast were prepared using data reported by a number of volunteer organizations. The amount of plastic debris at highly visited barrier island beaches and estuarine marshes ranged from 300 to >1000 kg. Relatively large amount of plastics (180-500 kg) were found on less visited barrier island beaches, i.e. Blackbeard, Ossabaw and Cumberland Islands. A follow up monthly or quarterly collection study was carried out on two of the sites, a barrier beach and estuarine marsh, to determine accumulation rate in 8000 m(2) areas. Accumulation rates ranged from 0.18 to 1.28 kg/30 days-8000 m(2) on the barrier island beach and from 0.6 to 1.61 kg/30 days-8000 m(2) at the estuarine marsh site. The major type of plastics, e.g. bottles, food wrappers, plastic fragments, was highly variable at different seasons and sites. The authors recommend consideration of a standardization in reporting plastic debris, with respect to quantitation of debris and sample area. PMID- 25558023 TI - High satiety expectations of a first course promote selection of less energy in a main course picture task. AB - One of the factors determining meal size is the expectation one has about satiating properties of foods. Foods eliciting low satiety expectations are often chosen in larger portions. We investigated whether satiety expectations of one food lead to a different portion size selection of other foods, using an online picture task. One hundred and twenty-six subjects (64 unrestrained, 62 restrained) participated in three conditions (within-subject). In two conditions subjects were asked to imagine they consumed soup as a first course. They were shown pictures of soups differing in terms of visual attributes, e.g. colour intensity, ingredients variety, etc. that conveyed a high or low expected satiety. In the control condition, no picture was shown. After viewing either a soup picture or no picture, subjects chose an ideal menu and portion size out of several other foods (meat, side dishes and vegetables) via an online choice task, specifically developed for this experiment. The energy (kcal) and weight (grams) selected for the main course was measured. More energy was chosen in the low satiety compared with the high satiety soup picture condition, but this effect was only significant for restrained eaters. This study shows that satiety expectations of a first course 'carry over' to the rest of the menu in people who carefully watch their diet, i.e. restrained eaters make satiety estimations for an entire menu. Our online choice task was able to capture these estimations in an implicit manner. PMID- 25558022 TI - The Satter Eating Competence Inventory for Low-income persons is a valid measure of eating competence for persons of higher socioeconomic position. AB - Eating competence is an important behavioral construct, shown to be associated with healthful lifestyle practices, including dietary quality, weight management, physical activity, and sleep duration. A 16-item instrument to measure eating competence, the Satter Eating Competence Inventory was previously validated in a general sample and subsequently, a 16-item instrument was developed to address specific concerns of low-income persons; 12 items were common to both instruments. The purpose of this study was to determine if the low-income version could be applied to a general audience, simplifying intervention evaluation and facilitating cross-study comparison. Both surveys were fully completed by 127 parents (89% white; 35.8 +/- 5.3 y; 86% college graduates; 51% eating competent) of preschool-age children; 96 of whom were not considered low-income. Cognitive interviews with 14 parents of varying eating competence levels clarified and confirmed findings. Scores were highly correlated (r = .98) and only 2 of the 96 were not congruently classified for eating competence. Mean difference between the two versions was .24 +/- 1.55. The general audience version explained 95% of the variance in the low-income version score. Findings support the low-income version of the Satter Eating Competence Inventory for general audience use as the Satter Eating Competence Inventory 2.0. PMID- 25558024 TI - Eww she sneezed! Contamination context affects children's food preferences and consumption. AB - Does contextual information about disgust influence children's food consumption and subjective experience of taste? Three- to eight-year-old children (N = 60) were presented with two identical foods, yet children were led to believe that one food had been contaminated by sneezing and licking, while the other was clean. When given the opportunity to eat the foods, 5- to 8-year-old children consumed more clean food and rated the clean food's taste more positively; younger children did not distinguish between the foods. The relation between contamination and subjective taste held even among children who ate both foods and had direct evidence that they were identical. These data indicate that children's consumption behavior and food preferences are influenced by information external to foods themselves. PMID- 25558025 TI - Associations between eating occasions and places of consumption among adults. AB - The objective of this study was to determine whether places of consumption are associated with types of eating occasions. Data on dietary behaviors of 226 adults in five U.S. cities were collected in food diaries for one week. Types of eating occasions and places of consumption were recorded. Eating occasions were defined as occurrences of meal, snack, beverage, and non-fruit dessert consumption. Nearly one-third of eating occasions occurred at non-designated eating places. Repeated measure generalized linear models were used to assess the associations between types of eating occasions and places where food was consumed. Snacking on low-nutrient foods were more likely to occur in non designated eating places. Snacking was more likely at work than at home, and sugar sweetened beverage consumption was more likely at food service outlets than at home. The finding that places of consumption were associated with different types of eating occasions suggests that contextual characteristics of a place are important in individual eating behaviors. Policies and programs aiming to promote healthy eating should leverage contextual characteristics of eating environments. PMID- 25558026 TI - Impact of readiness to change behavior on the effects of a multidisciplinary intervention in obese Brazilian children and adolescents. AB - The obesity epidemic is a global challenge that requires evidence-based intervention to slow the emergence of weight-related illness in children and adolescents. Thus, effective treatments are urgently needed. This study aimed to analyze whether there is relationship between the initial stage of readiness for behavior change (SRBC) and the results obtained through participation in a multidisciplinary program of obesity treatment (MPOT). The study included 113 overweight or obese children and adolescents who participated in an intervention for 16 weeks, in which the categorical variable was the SRBC. The dependent variables included: anthropometric measures of body composition, hemodynamic parameters (e.g., blood pressure values), and health-related physical fitness. Although stages 1 and 2 had greater improvements in flexibility than those in stage 5, and stage 1 had greater percentage changes in abdominal strength than those in stage 5, children and adolescents in the highest stage had greater percentage changes for anthropometric, hemodynamic and cardiorespiratory fitness, suggesting an impact of the stage of change on the effects of a MPOT. This study suggests that SRBC plays a role in obesity treatment in Brazilian children and adolescents and warrants consideration when enrolling patients to intervention. PMID- 25558027 TI - Associations among pericolonic fat, visceral fat, and colorectal polyps on CT colonography. AB - OBJECTIVE: To determine the association between pericolonic fat and colorectal polyps using CT colonography (CTC). METHODS: A total of 1169 patients who underwent CTC and optical colonoscopy on the same day were assessed. Pericolonic fat was measured on CTC in a band surrounding the colon. Visceral adipose tissue volume was measured at the L2-L3 levels. Student's t-tests, odds ratio, logistic regression, binomial statistics, and weighted kappa were performed to ascertain associations with the incidence of colorectal polyps. RESULTS: Pericolonic fat volume fractions (PFVF) were 61.5 +/- 11.0% versus 58.1 +/- 11.5%, 61.6 +/- 11.1% versus 58.7 +/- 11.5%, and 62.4 +/- 10.6% versus 58.8 +/- 11.5% for patients with and without any polyps, adenomatous polyps, and hyperplastic polyps, respectively (P<0.0001). Similar trends were observed when examining visceral fat volume fractions (VFVF). When patients were ordered by quintiles of PFVF or VFVF, there were 2.49-, 2.19-, and 2.39-fold increases in odds ratio for the presence of any polyp, adenomatous polyps, or hyperplastic polyps from the first to the fifth quintile for PFVF and 1.92-, 2.00-, and 1.71-fold increases in odds ratio for VFVF. Polyps tended to occur more commonly in parts of the colon that had more PFVF than the spatially adjusted average for patients in the highest quintile of VFVF. CONCLUSIONS: Pericolonic fat accumulations, like visceral fat, are correlated with an increased risk of adenomatous and hyperplastic polyps. PMID- 25558028 TI - Geographical sequence variation in the Leishmania major virulence factor P46. AB - Cutaneous leishmaniasis as caused by Leishmania major is a zoonotic infection with wide epidemiological impact. The L. major P46 virulence gene was shown to boost the parasite's virulence and extends its range of experimental hosts. Here we show that P46 is subject to significant geographical sequence variations that may reflect the adaption to different reservoir hosts. This view is supported by the results of passage experiments using P46 variants in different experimental hosts. Conversely, loss of P46 expression leads to attenuation both in vitro and in BALB/c mice. Although part of the L. major exosomal protein payload, P46 is not required for exosome-mediated immune modulation. PMID- 25558029 TI - Multilocus sequence typing approach for a broader range of species of Leishmania genus: describing parasite diversity in Argentina. AB - Leishmaniasis is a vector-borne protozoan infection affecting over 350 million people around the world. In Argentina cutaneous leishmaniasis is endemic in nine provinces and visceral leishmaniasis is spreading from autochthonous transmission foci in seven provinces. However, there is limited information about the diversity of the parasite in this country. Implementation of molecular strategies for parasite typing, particularly multilocus sequence typing (MLST), represents an improved approach for genetic variability and population dynamics analyses. We selected six loci as candidates implemented in reference strains and Argentinean isolates. Phylogenetic analysis showed high correlation with taxonomic classification of the parasite. Autochthonous Leishmania (Viannia) braziliensis showed higher genetic diversity than L. (Leishmania) infantum but low support was obtained for intra-L. braziliensis complex variants suggesting the need of new loci that contribute to phylogenetic resolution for an improved MLST or nested MLST scheme. This study represents the first characterization of genetic variability of Leishmania spp. in Argentina. PMID- 25558030 TI - The effect of abdominal massage in reducing malignant ascites symptoms. AB - As many as 50% of end-stage cancer patients will develop ascites and associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, loss of appetite, dyspnea, perceived abdominal bloating, and immobility. Abdominal massage may stimulate lymph return to the venous system and reduce ascites-related symptoms. The purpose of this study was to test the effect of abdominal massage in reducing these symptoms and reducing ascites itself as reflected in body weight. For a randomized controlled design using repeated measures, a sample of 80 patients with malignant ascites was recruited from gastroenterology and oncology units of a medical center in northern Taiwan and randomly assigned to the intervention or the control group. A 15-minute gentle abdominal massage, using straight rubbing, point rubbing, and kneading, was administered twice daily for 3 days. The control group received a twice-daily 15 minute social interaction contact with the same nurse. Symptoms and body weight were measured in the morning for 4 consecutive days from pre- to post-test. In generalized estimation equation modeling, a significant group-by-time interaction on depression, anxiety, poor wellbeing, and perceived abdominal bloating, indicated that abdominal massage improved these four symptoms, with the greatest effect on perceived bloating. The intervention had no effect on pain, tiredness, nausea, drowsiness, poor appetite, shortness of breath, mobility limitation, or body weight. Abdominal massage appears useful for managing selected symptoms of malignant ascites. PMID- 25558031 TI - Feasibility and cost of a medical student proxy-based mobile teledermatology consult service with Kisoro, Uganda, and Lake Atitlan, Guatemala. AB - BACKGROUND: The expansion of mobile technology and coverage has unveiled new means for delivering medical care to isolated and resource-poor communities. Teledermatology, or dermatology consultation from a distance using technology, is gaining greater acceptance among physicians and patients. OBJECTIVES: To evaluate feasibility and cost of a smartphone-based teledermatology consult service utilizing a designated medical student proxy to facilitate all consults on site, and to evaluate the service's effect upon diagnosis and management. METHODS: An IRB-approved smartphone-based teledermatology consult service was established to serve two rural communities in the developing world: Kisoro, Uganda, and Lake Atitlan, Guatemala. Fourth-year medical students were recruited as proxies for each site, responding to consults by local doctors and transmitting photographs and clinical information via a smartphone application to a dermatology resident and attending in the USA over an encrypted website. At the Ugandan site, when indicated, the medical student performed skin biopsies under supervision, and rotating Montefiore residents transported specimens back to the USA. RESULTS: From October 2011 to August 2012, 93 cases were evaluated by the consult service (57 from Uganda and 36 from Guatemala). Initial diagnoses changed completely in 55.9% (52 of 93) of cases, and management changes were recommended in 89.2% (83 of 93) of cases. The estimated total cost of supplies and technology was 42.01 USD per consult and 64.24 USD per biopsy (including processing). Given fixed upfront costs, the cost per consult decreased with each additional case. CONCLUSION: Smartphone-based systems for teledermatology consultation using a medical student proxy are feasible for delivery of care in the developing world at relatively little cost. Optimization and sustainability of this system requires and deserves further investigation in larger studies. PMID- 25558032 TI - Arterial stiffness in diabetes mellitus. AB - Arterial stiffness is an age-related process that is a shared consequence of numerous diseases including diabetes mellitus (DM), and is an independent predictor of mortality both in this population and in the general population. While much has been published about arterial stiffness in patients with DM, a thorough review of the current literature is lacking. Using a systematic literature search strategy, we aimed to summarize our current understanding related to arterial stiffness in DM. We review key studies demonstrating that, among patients with established DM, arterial stiffness is closely related to the progression of complications of DM, including nephropathy, retinopathy, and neuropathy. It is also becoming clear that arterial stiffness can be increased even in pre-diabetic populations with impaired glucose tolerance, and in those with the metabolic syndrome (METS), well before the onset of overt DM. Some data suggests that arterial stiffness can predict the onset of DM. However, future work is needed to further clarify whether large artery stiffness and the pulsatile hemodynamic changes that accompany it are involved in the pathogenesis of DM, and whether interventions targeting arterial stiffness are associated with improved clinical outcomes in DM. We also review of the potential mechanisms of arterial stiffness in DM, with particular emphasis on the role of advanced glycation endproducts (AGEs) and nitric oxide dysregulation, and address potential future directions for research. PMID- 25558033 TI - Effects of combined vitamin D--calcium supplements on the cardiovascular system: should we be cautious? AB - Despite the growing body of evidence on the potential effects of calcium and vitamin D as monotherapies on different cardiovascular (CV) parameters, the combined supplementation with calcium and vitamin D (CaD), which is most frequently encountered in clinical practice, has not received the attention it deserves. A literature search was conducted via EMBASE and Medline and identified 14 randomised controlled trials (RCTs) and 2 meta-analyses reporting on effects of combined supplementation with CaD on CV events, CV death, blood pressure, lipids, glucose metabolism and weight. Overall, the existing evidence does not support beneficial properties of supplementation with CaD on the CV system, nor does it suggest that a re-appraisal of the use of CaD is necessary due to adverse effects, although increased risk of CV events has been reported by some authors. The guidelines for the use of CaD supplementation need not change until well conducted RCTs that have CV effects as primary outcomes and adjust for major confounders indicate otherwise. PMID- 25558034 TI - Acute effects of interval versus continuous endurance training on pulse wave reflection in healthy young men. AB - AIM: Our aim was to investigate the acute and 24-hour (h) effects of high intensity interval training (HIIT) and moderate continuous training (MCT) on arterial pulse wave reflection, an established marker of arterial stiffness and cardiovascular risk. METHODS: In a randomized cross-over design, 21 young healthy male participants performed a HIIT or a MCT on separate visits. Before and 5 (t5), 20 (t20), 35 (t35), and 50 (t50) minutes after the acute exercise bouts, the crude augmentation index (AIx) and the AIx at a set heart rate (AIx@75) were analysed by applanation tonometry. Starting 1 h post-exercise, both indices were captured over 24-h with an oscillometric monitoring device. RESULTS: AIx did not change significantly after MCT but declined progressively after HIIT, reaching significantly lower values compared to MCT at t35 (P = 0.045) and t50 (P = 0.008). AIx@75 increased after both acute exercise types but was higher after HIIT at t5 (P < 0.001), t20 (P < 0.001) and t35 (P = 0.009) compared to MCT. The 24-h follow-up revealed a significant decline in AIx@75 after HIIT (P = 0.007) but not after MCT (P = 0.813). CONCLUSIONS: Exercise intensity affects pulse wave reflection, with different time courses for AIx and AIx@75 post-exercise. Although initially higher after HIIT, AIx@75 declines in the 24-h recovery period indicating more favourable effects on pulse wave reflection compared to MCT. This may result in substantial positive chronic training effects on arterial stiffness in health and cardiovascular disease. PMID- 25558035 TI - International atherosclerosis research school (iARS) 2014 in Hamburg, Germany. PMID- 25558037 TI - Endogenous ochronosis in dermal melanocytic nevi: diagnosis of alkaptonuria by skin biopsy. PMID- 25558036 TI - Sleep, cardiac autonomic function, and carotid atherosclerosis in patients with cardiovascular risks: HSCAA study. AB - OBJECTIVES: Behavioral and psychosocial factors have been gaining increased attention in regard to cardiovascular diseases. We evaluated sleep conditions, cardiac autonomic function, and carotid atherosclerosis in subjects who participated in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study. METHODS: This cross-sectional study included 330 serial patients registered in the HSCAA study who were free from past cardiovascular diseases, and prescribing alpha- or beta-blockers. In addition to clinical background and classical cardiovascular risk factors, sleep efficiency, apnea hypopnea index (AHI), awake physical activity, heart rate variability (HRV), carotid intima-media thickness (IMT), presence of plaque and plaque score were determined. RESULTS: Sleep efficiency (r = -0.183) and all HRV parameters (SDNN: r = -0.202; rMSSD: r = 0.234; pNN50: r = -0.277) were significantly (p < 0.01) and negatively associated with IMT, while AHI (r = 0.220, p < 0.001) was positively associated with IMT. Similarly, sleep efficiency (r = -0.129), HRV parameters (SDNN: r = -0.170; rMSSD: r = -0.217; pNN50: r = -0.260) and AHI (r = 0.184) were also significantly (p < 0.05) associated with plaque scores. Multivariate logistic regression analyses showed that rMSSD, but not sleep efficiency or AHI, was significantly associated with carotid plaque (OR 0.74, 95% CI 0.56-0.98, p = 0.037), independent of classical risk factors. The association of rMSSD with carotid plaque remained significant even after adjustment for sleep efficiency or AHI. A comparison of risk factors in specific subgroups showed that the association of lower HRV with carotid plaque was more prominent in patients with cardiovascular risk factors including male gender, hypertension, dyslipidemia and diabetes mellitus. CONCLUSION: Cardiac autonomic nervous dysfunction was independently associated with carotid atherosclerosis, independent of sleep condition. Moreover, that association was more prominent in specific subgroups with cardiovascular risk factors. PMID- 25558038 TI - Atypical intraepidermal keratinocytic lesions falling short of carcinoma in situ (Bowen disease) on routine staining: the utility of p16 immunostaining. PMID- 25558040 TI - Modulation of Gestural-verbal Semantic Integration by tDCS. AB - BACKGROUND: Understanding actions based on either language or observation of gestures is presumed to involve the motor system, and reflect the engagement of an embodied conceptual network. The role of the left inferior frontal gyrus (IFG) in language tasks is well established, but the role of the right hemisphere is unclear with some imaging evidence suggesting right IFG activation when gestures mismatch speech. OBJECTIVE: Using transcranial direct current stimulation (tDCS), we explored the hemispheric asymmetries in the assumed cognitive embodiment required for gestural-verbal integration. METHODS: Symbolic gestures served as primes for verbal targets. Primes were clips of symbolic gestures taken from a rich set of emblems and pantomimes. Participants responded by performing a semantic relatedness-judgment under 3 stimulation conditions - anodal tDCS (atDCS) over the left IFG, atDCS over the right IFG, and sham. There was also a non-semantic control task of attentional load. RESULTS: AtDCS of the right IFG generated faster responses to symbolic gestures than atDCS over the left IFG or sham stimulation. For the attentional load task, no differences were observed across the three stimulation conditions. These results support a right lateralization bias of the human mirror neuron system in processing gestural verbal stimuli. CONCLUSION: Gesture comprehension may be enhanced by improved gesture and language integration. PMID- 25558042 TI - Vertebrate pest management: diverse solutions for diverse problems. PMID- 25558041 TI - Enhancement of Neurotrophic Factors in Astrocyte for Neuroprotective Effects in Brain Disorders Using Low-intensity Pulsed Ultrasound Stimulation. AB - BACKGROUND: Astrocytes play an important role in the growth and survival of developing neurons by secreting neurotrophic factors. OBJECTIVE: The goal of this study was to investigate how low-intensity pulsed ultrasound (LIPUS) stimulation directly affects brain astrocyte function. METHODS: Here, we report that LIPUS stimulation increased protein levels of BDNF, GDNF, VEGF, and GLUT1 in rat brain astrocytes as measured by western blot analysis. Histological outcomes including demyelination and apoptosis were examined in rats after administration of aluminum chloride (AlCl3). RESULTS: At the mechanistic level, integrin inhibitor (RGD peptide) attenuated the LIPUS-induced neurotrophic factor expression. The data suggest that neurotrophic factor protein levels may be promoted by LIPUS through activation of integrin receptor signaling. In addition, LIPUS stimulation protected cells against aluminum toxicity as demonstrated by an increase in the median lethal dose for AlCl3 from 3.77 to 6.25 mM. In in vivo histological evaluations, LIPUS significantly reduced cerebral damages in terms of myelin loss and apoptosis induced by AlCl3. CONCLUSIONS: The results of this study demonstrate that transcranial LIPUS is capable of enhancing the protein levels of neurotrophic factors, which could have neuroprotective effects against neurodegenerative diseases. PMID- 25558043 TI - Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification. AB - Inherited disorders of gamma-aminobutyric acid (GABA) metabolism include succinic semialdehyde dehydrogenase (SSADH) and gamma-aminobutyric acid transaminase (GABA T) deficiencies. The clinical features, pathophysiology, diagnosis, and management of both, and an updated list of mutations in the ALDH5A1 gene, which cause SSADH deficiency, are discussed. A database of 112 individuals (71 children and adolescents, and 41 adults) indicates that developmental delay and hypotonia are the most common symptoms arising from SSADH deficiency. Furthermore, epilepsy is present in two-thirds of SSADH-deficient individuals by adulthood. Research with murine genetic models and human participants, using [11 C] flumazenil positron emission tomography (FMZ-PET) and transcranial magnetic stimulation, have led to therapeutic trials, and the identification of additional disruptions to GABA metabolism. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy, with enhanced activation of the mammalian target of rapamycin (mTOR) pathway. Details of known pathogenic mutations in the ALDH5A1 gene, three of which have not previously been reported, are summarized here. Investigations into disorders of GABA metabolism provide fundamental insights into the mechanisms underlying epilepsy, and support the importance of developing biomarkers and clinical trials. Comprehensive definition of phenotypes arising as a result of deficiencies in both SSADH and GABA-T may increase our understanding of the neurophysiological consequences of a hyper-GABAergic state. PMID- 25558045 TI - Phospholipid vesicle-based permeation assay and EpiSkin(r) in assessment of drug therapies destined for skin administration. AB - Cost-effective and efficient methods for permeability screening are crucial during early development of drugs, drug formulations, and cosmeceuticals. Alternatives to animal experiments are impelled for both economical and ethical reasons. The aim of this study was to determine the ability of the phospholipid vesicle-based permeation assay (PVPA) to assess the effect of different formulations on drug permeability and thus establish its utility in formulation development. Three model drugs were tested in solutions and as liposomal formulations. The permeability results for the PVPA models were compared with the results for the reconstructed human skin model, EpiSkin((r)). The drugs were ranked based on their estimated penetration potentials, and the results were in accordance with what was expected considering the physicochemical properties of the drugs. PVPAs (E-80, ceramide, cholesterol, cholesteryl sulfate, and palmitic acid) was able to distinguish between drug solutions and liposomal formulations; however, EpiSkin((r)) detected only small differences between the drugs in solution and formulations. In contrast with EpiSkin((r)), which is limited by a 3 day testing window, PVPA barriers can be stored frozen for up to 2 weeks or even up to 16 months, depending on their compositions. The PVPA models are thus more cost effective and efficient than the EpiSkin((r)) model for permeability screening during early drug development. PMID- 25558046 TI - Pathway-based association study of multiple candidate genes and multiple traits using structural equation models. AB - There is increasing interest in the joint analysis of multiple genetic variants from multiple genes and multiple correlated quantitative traits in association studies. The classical approach involves testing univariate associations between genotypes and phenotypes and correcting for multiple testing that results in loss of power to detect associations. In this paper, we propose modeling complex relationships between genetic variants in candidate genes and measured correlated traits using structural equation models (SEM), taking advantage of prior knowledge on clinical and genetic pathways. We adopt generalized structured component analysis (GSCA) as an approach to SEM and develop a single association test between multiple genetic variants in a gene and a set of correlated traits, taking into account all available data from other genes and other traits. The performance of this test is investigated by simulations. We apply the proposed method to the Quebec Child and Adolescent Health and Social Survey (1999) data to investigate genetic associations with cardiovascular disease-related traits. PMID- 25558044 TI - Chlamydomonas axonemal dynein assembly locus ODA8 encodes a conserved flagellar protein needed for cytoplasmic maturation of outer dynein arm complexes. AB - The Chlamydomonas reinhardtii oda8 mutation blocks assembly of flagellar outer dynein arms (ODAs), and interacts genetically with ODA5 and ODA10, which encode axonemal proteins thought to aid dynein binding onto axonemal docking sites. We positionally cloned ODA8 and identified the gene product as the algal homolog of vertebrate LRRC56. Its flagellar localization depends on ODA5 and ODA10, consistent with genetic interaction studies, but phylogenomics suggests that LRRC56 homologs play a role in intraflagellar transport (IFT)-dependent assembly of outer row dynein arms, not axonemal docking. ODA8 distribution between cytoplasm and flagella is similar to that of IFT proteins and about half of flagellar ODA8 is in the soluble matrix fraction. Dynein extracted in vitro from wild type axonemes will rebind efficiently to oda8 mutant axonemes, without re binding of ODA8, further supporting a role in dynein assembly or transport, not axonemal binding. Assays comparing preassembled ODA complexes from the cytoplasm of wild type and mutant strains show that dynein in oda8 mutant cytoplasm has not properly preassembled and cannot bind normally onto oda axonemes. We conclude that ODA8 plays an important role in formation and transport of mature dynein complexes during flagellar assembly. PMID- 25558055 TI - Characterisation of the secretome of the clam parasite, QPX. AB - Secreted and cell surface-associated molecules play a major role in disease development processes and host-pathogen interactions, and usually determine the virulence of invading organisms. In this study, we investigated proteins secreted by quahog parasite unknown, a thraustochytrid protist that infects the hard clam, Mercenaria mercenaria. In silico analysis of quahog parasite unknown transcripts predicted over 1200 proteins to possess an amino-terminal signal peptide which directs proteins into the classical eukaryotic secretory pathway. Proteomic analysis using LC/MS technology identified 56 proteins present in the extracellular secretion of quahog parasite unknown cells grown in vitro, including six mucin-like molecules, four glycosyl hydrolases and eight peptidases. Transcription levels of 19 quahog parasite unknown extracellular proteins were investigated in clam tissue lesions (in vivo) using quantitative PCR. The overexpression of six of these extracellular proteins in clam tissues compared with in vitro cultures suggests that they are involved in interaction with the clam host. PMID- 25558057 TI - Integrating physiological threshold experiments with climate modeling to project mangrove species' range expansion. AB - Predictions of climate-related shifts in species ranges have largely been based on correlative models. Due to limitations of these models, there is a need for more integration of experimental approaches when studying impacts of climate change on species distributions. Here, we used controlled experiments to identify physiological thresholds that control poleward range limits of three species of mangroves found in North America. We found that all three species exhibited a threshold response to extreme cold, but freeze tolerance thresholds varied among species. From these experiments, we developed a climate metric, freeze degree days (FDD), which incorporates both the intensity and the frequency of freezes. When included in distribution models, FDD accurately predicted mangrove presence/absence. Using 28 years of satellite imagery, we linked FDD to observed changes in mangrove abundance in Florida, further exemplifying the importance of extreme cold. We then used downscaled climate projections of FDD to project that these range limits will move northward by 2.2-3.2 km yr(-1) over the next 50 years. PMID- 25558058 TI - [Pharmaceutical involvement in academic clinical trials: Quality assessment of pharmaceutical manufacturing operations]. AB - INTRODUCTION: For academic clinical trials, the hospital pharmacy may be required to perform the specific activity of preparing investigational drugs. MATERIAL AND METHODS: With regards to such activity, and in light of the recent changes in the regulatory environment, the main objective of this study was to evaluate whether quality levels and traceability were in compliance with the applicable regulatory standards. In order to do so, two internal audits have been conducted, the first on the compliance of operations with existing regulatory standards and the second on the quality of traceability of the operations. RESULTS: The proportion of academic clinical trials is constantly growing and currently represents 41% of the total clinical trials in the establishment. An average of 29,000 therapeutic units of investigational drugs are prepared each year (84% under the form of capsules). An overall conformity level of 75% and 88% has been identified in the aforementioned audits, respectively. Such audits have also allowed for the identification of weaknesses in current practices as well as potential improvement areas to achieve better compliance. DISCUSSION: The hospital pharmacy can provide expertise for the preparation of specific dosage or drugs that are not available on the market. It also can be involved for the conception of appropriated packaging function of the study design. CONCLUSION: Results of audits encourage us to continue this activity with a satisfactory level of quality in accordance with the necessary requirements to ensure the safety of patients and the quality of clinical trials conducted. PMID- 25558059 TI - An autotrophic H2 -oxidizing, nitrate-respiring, Tc(VII)-reducing Acidovorax sp. isolated from a subsurface oxic-anoxic transition zone. AB - Increasing concentrations of H2 with depth were observed across a geologic unconformity and associated redox transition zone in the subsurface at the Hanford Site in south-central Washington, USA. An opposing gradient characterized by decreasing O2 and nitrate concentrations was consistent with microbial catalysed biogeochemical processes. Sterile sand was incubated in situ within a multilevel sampler placed across the redox transition zone to evaluate the potential for Tc(VII) reduction and for enrichment of H2 -oxidizing denitrifiers capable of reducing Tc(VII). H2 -driven TcO4 (-) reduction was detected in sand incubated at all depths but was strongest in material from a depth of 17.1 m. Acidovorax spp. were isolated from H2 -nitrate enrichments from colonized sand from 15.1 m, with one representative, strain JHL-9, subsequently characterized. JHL-9 grew on acetate with either O2 or nitrate as electron acceptor (data not shown) and on medium with bicarbonate, H2 and nitrate. JHL-9 also reduced pertechnetate (TcO4 (-) ) under denitrifying conditions with H2 as the electron donor. H2 -oxidizing Acidovorax spp. in the subsurface at Hanford and other locations may contribute to the maintenance of subsurface redox gradients and offer the potential for Tc(VII) reduction. PMID- 25558056 TI - The cytochrome P450 family in the parasitic nematode Haemonchus contortus. AB - Haemonchus contortus, a highly pathogenic and economically important parasitic nematode of sheep, is particularly adept at developing resistance to the anthelmintic drugs used in its treatment and control. The basis of anthelmintic resistance is poorly understood for many commonly used drugs with most research being focused on mechanisms involving drug targets or drug efflux. Altered or increased drug metabolism is a possible mechanism that has yet to receive much attention despite the clear role of xenobiotic metabolism in pesticide resistance in insects. The cytochrome P450s (CYPs) are a large family of drug-metabolising enzymes present in almost all living organisms, but for many years thought to be absent from parasitic nematodes. In this paper, we describe the CYP sequences encoded in the H. contortus genome and compare their expression in different parasite life-stages, sexes and tissues. We developed a novel real-time PCR approach based on partially assembled CYP sequences "tags" and confirmed findings in the subsequent draft genome with RNA-seq. Constitutive expression was highest in larval stages for the majority of CYPs, although higher expression was detected in the adult male or female for a small subset of genes. Many CYPs were expressed in the worm intestine. A number of H. contortus genes share high identity with Caenorhabditis elegans CYPs and the similarity in their expression profiles supports their classification as putative orthologues. Notably, H. contortus appears to lack the dramatic CYP subfamily expansions seen in C. elegans and other species, which are typical of CYPs with exogenous roles. However, a small group of H. contortus genes cluster with the C. elegans CYP34 and CYP35 subfamilies and may represent candidate xenobiotic metabolising genes in the parasite. PMID- 25558060 TI - Relationship between lethal toxicity in oral administration and injection to mice: effect of exposure routes. AB - The lethal toxicity (LD50) in oral administration, intravenous, intraperitoneal, intramuscular and subcutaneous injections were used to investigate relationships of log 1/LD50 from different exposure routes. Regression analysis showed that log 1/LD50 in oral route was related to the toxicity in injection route. This relationship in lethality between the two routes is apparently due to the same mechanisms of the compounds to the same species. However, the scatter in the correlation curve indicates that exposure route is an important factor that influences the relationship. Some compounds with low intestinal absorption exhibit much less toxicity in oral administration than that in the injection route. A systemic bias of log 1/LD50 between oral and injection routes indicates that tissue distribution of compounds between blood and target site is a very rapid process, leading to log 1/LD50 in injection greater than those in oral administration. Although compounds can be metabolized in the body both from oral and injection routes, first-pass metabolism occurs in oral route but not in injection route. This will result in decrease of toxicity in oral route for most compounds as compared with injection route. In addition, experimental uncertainty, differences in gender, and species can also affect relationships of log1/LD50 between exposure routes. PMID- 25558061 TI - Heterosynaptic structural plasticity on local dendritic segments of hippocampal CA1 neurons. AB - Competition between synapses contributes to activity-dependent refinement of the nervous system during development. Does local competition between neighboring synapses drive circuit remodeling during experience-dependent plasticity in the cerebral cortex? Here, we examined the role of activity-mediated competitive interactions in regulating dendritic spine structure and function on hippocampal CA1 neurons. We found that high-frequency glutamatergic stimulation at individual spines, which leads to input-specific synaptic potentiation, induces shrinkage and weakening of nearby unstimulated synapses. This heterosynaptic plasticity requires potentiation of multiple neighboring spines, suggesting that a local threshold of neural activity exists beyond which inactive synapses are punished. Notably, inhibition of calcineurin, IP3Rs, or group I metabotropic glutamate receptors (mGluRs) blocked heterosynaptic shrinkage without blocking structural potentiation, and inhibition of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) blocked structural potentiation without blocking heterosynaptic shrinkage. Our results support a model in which activity-induced shrinkage signal, and not competition for limited structural resources, drives heterosynaptic structural and functional depression during neural circuit refinement. PMID- 25558062 TI - GPR124 functions as a WNT7-specific coactivator of canonical beta-catenin signaling. AB - G protein-coupled receptor 124 (GPR124) is an orphan receptor in the adhesion family of GPCRs, and previous global or endothelial-specific disruption of Gpr124 in mice led to defective CNS angiogenesis and blood-brain barriergenesis. Similar developmental defects were observed following dual deletion of Wnt7a/Wnt7b or deletion of beta-catenin in endothelial cells, suggesting a possible relationship between GPR124 and canonical WNT signaling. Here, we show using in vitro reporter assays, mutation analysis, and genetic interaction studies in vivo that GPR124 functions as a WNT7A/WNT7B-specific costimulator of beta-catenin signaling in brain endothelium. WNT7-stimulated beta-catenin signaling was dependent upon GPR124's intracellular PDZ binding motif and a set of leucine-rich repeats in its extracellular domain. This study reveals a vital role for GPR124 in potentiation of WNT7-induced canonical beta-catenin signaling with important implications for understanding and manipulating CNS-specific angiogenesis and blood-brain barrier genesis. PMID- 25558063 TI - Mapping social behavior-induced brain activation at cellular resolution in the mouse. AB - Understanding how brain activation mediates behaviors is a central goal of systems neuroscience. Here, we apply an automated method for mapping brain activation in the mouse in order to probe how sex-specific social behaviors are represented in the male brain. Our method uses the immediate-early-gene c-fos, a marker of neuronal activation, visualized by serial two-photon tomography: the c fos-GFP+ neurons are computationally detected, their distribution is registered to a reference brain and a brain atlas, and their numbers are analyzed by statistical tests. Our results reveal distinct and shared female and male interaction-evoked patterns of male brain activation representing sex discrimination and social recognition. We also identify brain regions whose degree of activity correlates to specific features of social behaviors and estimate the total numbers and the densities of activated neurons per brain areas. Our study opens the door to automated screening of behavior-evoked brain activation in the mouse. PMID- 25558064 TI - Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. AB - The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases. PMID- 25558066 TI - Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. AB - Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, it is important to understand circRNA biogenesis. Besides human ALU repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified circRNAs in C. elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched in comparison to linear controls. By scoring the presence of reverse complementary sequences in human introns, we predicted and experimentally validated circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyperediting events. Knockdown of the double-strand RNA-editing enzyme ADAR1 significantly and specifically upregulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA-RNA interactions of introns form larger structures that promote circularization of embedded exons, whereas ADAR1 antagonizes circRNA expression by melting stems within these interactions. PMID- 25558065 TI - Accelerating novel candidate gene discovery in neurogenetic disorders via whole exome sequencing of prescreened multiplex consanguineous families. AB - Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function. PMID- 25558067 TI - Respective functions of two distinct Siwi complexes assembled during PIWI interacting RNA biogenesis in Bombyx germ cells. AB - PIWI-interacting RNA (piRNA) biogenesis consists of two sequential steps: primary piRNA processing and the ping-pong cycle that depends on reciprocal Slicer mediated RNA cleavage by PIWI proteins. However, the molecular functions of the factors involved remain elusive. Here, we show that RNAs cleaved by a Bombyx mori PIWI, Siwi, remain bound to the protein upon cleavage but are released by a DEAD box protein BmVasa. BmVasa copurifies with Siwi but not another PIWI BmAgo3. A lack of BmVasa does not affect primary piRNA processing but abolishes the ping pong cycle. Siwi also forms a complex with BmSpn-E and BmQin. This complex is physically separable from the Siwi/BmVasa complex. BmSpn-E, unlike BmVasa, is necessary for primary piRNA production. We propose a model for piRNA biogenesis, where the BmSpn-E/BmQin dimer binds Siwi to function in primary piRNA processing, whereas BmVasa, by associating with Siwi, ensures target RNA release upon cleavage to facilitate the ping-pong cycle. PMID- 25558068 TI - Beta-catenin-dependent control of positional information along the AP body axis in planarians involves a teashirt family member. AB - Wnt/beta-catenin signaling regulates tissue homeostasis and regeneration in metazoans. In planarians-flatworms with high regenerative potential-Wnt ligands are thought to control tissue polarity by shaping a beta-catenin activity gradient along the anterior-posterior axis, yet the downstream mechanisms are poorly understood. We performed an RNA sequencing (RNA-seq)-based screen and identified hundreds of beta-catenin-dependent transcripts, of which several were expressed in muscle tissue and stem cells in a graded fashion. In particular, a teashirt (tsh) ortholog was induced in a beta-catenin-dependent manner during regeneration in planarians and zebrafish, and RNAi resulted in two-headed planarians. Strikingly, intact planarians depleted of tsh induced anterior markers and slowly transformed their tail into a head, reminiscent of beta catenin RNAi phenotypes. Given that beta-catenin RNAi enhanced the formation of muscle cells expressing anterior determinants in tail regions, our study suggests that this pathway controls tissue polarity through regulating the identity of differentiating cells during homeostasis and regeneration. PMID- 25558069 TI - Effect of the morphology of synthetic kaolinites on their sorption properties. AB - Natural kaolinites often have a permanent charge due to mineralogical impurities preventing to link directly the morphology of the kaolinite particle to a selectivity coefficient between two cations for edge sites. In this study, kaolinites with no permanent charge were hydrothermally synthesized under different physicochemical conditions to obtain various morphologies (hexagon shaped, more or less anisotropic). Na(+) and H(+) were chosen as the sorbed cations due to their ubiquitous presence in natural waters. For synthetic kaolinites for which no swelling layer was detected, an experimental sorption isotherm between Na(+) and H(+) was obtained. Data were interpreted using a surface complexation model, containing no electrostatic term, by considering the specific surfaces of lateral sites and sorption site density identified by crystallography for the different faces presented in the samples ((010), (110), (1-10)). Selectivity coefficients between Na(+) and H(+) for all lateral sites characterizing a given morphology were calculated and validated in the [4-10] pH range, corresponding to the pH range for which dissolution can be considered negligible. The results showed that the Na(+)/H(+) selectivity coefficient depends strongly on the particle morphology and that the sorption properties of kaolinites cannot be obtained with good accuracy without a fine knowledge of the morphology of the particles. PMID- 25558070 TI - Obtaining antibiotics without prescription in Spain in 2014: even easier now than 6 years ago. PMID- 25558072 TI - Failure of combination therapy with daptomycin and synergistic ceftriaxone for enterococcal endocarditis-authors' response. PMID- 25558071 TI - Dynamics of MDR Enterobacter cloacae outbreaks in a neonatal unit in Nepal: insights using wider sampling frames and next-generation sequencing. AB - OBJECTIVES: There are limited data on Enterobacter cloacae outbreaks and fewer describing these in association with NDM-1. With whole-genome sequencing, we tested the hypothesis that a cluster of 16 E. cloacae bacteraemia cases in a Nepali neonatal unit represented a single clonal outbreak, using a wider set of epidemiologically unrelated clinical E. cloacae isolates for comparison. METHODS: Forty-three isolates were analysed, including 23 E. cloacae and 3 Citrobacter sp. isolates obtained from blood cultures from 16 neonates over a 3 month period. These were compared with two contemporaneous community-associated drug-resistant isolates from adults, a unit soap dispenser isolate and a set of historical invasive isolates (n=14) from the same geographical locality. RESULTS: There were two clear neonatal outbreaks and one isolated case in the unit. One outbreak was associated with an NDM-1 plasmid also identified in a historical community associated strain. The smaller, second outbreak was likely associated with a contaminated soap dispenser. The two community-acquired adult cases and three sets of historical hospital-associated neonatal isolates represented four additional genetic clusters. CONCLUSIONS: E. cloacae infections in this context represent several different transmission networks, operating at the community/hospital and host strain/plasmid levels. Wide sampling frames and high resolution typing methods are needed to describe the complex molecular epidemiology of E. cloacae outbreaks, which is not appropriately reflected by routine susceptibility phenotypes. Soap dispensers may represent a reservoir for E. cloacae and bacterial strains and plasmids may persist in hospitals and in the community for long periods, sporadically being involved in outbreaks of disease. PMID- 25558073 TI - Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort. AB - OBJECTIVES: The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD. METHODS: As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured. RESULTS: The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%). CONCLUSIONS: Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required. PMID- 25558074 TI - How is income generated by outpatient parenteral antibiotic treatment (OPAT) in the UK? Analysis of payment tariffs for cellulitis. AB - OBJECTIVES: We determined the available mechanisms to generate income from outpatient parenteral antimicrobial therapy (OPAT) in the UK and calculated the revenue generated from treatment of an episode of cellulitis. METHODS: Revenue was calculated for patients receiving treatment for cellulitis as an inpatient and for patients receiving OPAT by a series of different payment pathways. Selected established OPAT services in Northern Ireland, Scotland and Wales, where Payment-by-Results (PbR) does not operate, were contacted to determine individual national funding arrangements. RESULTS: In England, a traditional inpatient episode for uncomplicated cellulitis requiring 7 days of treatment generated L1361 of revenue, while OPAT generated revenue ranging from L773 to L2084 for the same length of treatment depending on the payment pathway used. Treatment using OPAT to avoid admission entirely generated L2084, inpatient admission followed by transfer to a virtual OPAT ward at day 2 generated L1361 and inpatient admission followed by discharge from hospital to OPAT at day 2 generated L773. In Northern Ireland, Scotland and Wales block contracts were used and no income was calculable for an individual episode of cellulitis. CONCLUSIONS: No single funding mechanism supports OPAT across the UK. In England, revenue generated by OPAT providers from treatment of cellulitis varied with the OPAT payment pathway used, but equalled or exceeded the income generated from equivalent inpatient care. Cost savings for OPAT and reuse of released inpatient beds will increase revenue further. A single OPAT tariff is proposed. PMID- 25558075 TI - Association of guideline-based antimicrobial therapy and outcomes in healthcare associated pneumonia. AB - OBJECTIVES: Guidelines for treatment of healthcare-associated pneumonia (HCAP) recommend empirical therapy with broad-spectrum antimicrobials. Our objective was to examine the association between guideline-based therapy (GBT) and outcomes for patients with HCAP. PATIENTS AND METHODS: We conducted a pharmacoepidemiological cohort study at 346 US hospitals. We included adults hospitalized between July 2007 and June 2010 for HCAP, defined as patients admitted from a nursing home, with end-stage renal disease or immunosuppression, or discharged from a hospital in the previous 90 days. Outcome measures included in-hospital mortality, length of stay and costs. RESULTS: Of 85 097 patients at 346 hospitals, 31 949 (37.5%) received GBT (one agent against MRSA and at least one against Pseudomonas). Compared with patients who received non-GBT, those who received GBT had a heavier burden of chronic disease and more severe pneumonia. GBT was associated with higher mortality (17.1% versus 7.7%, P < 0.001). Adjustment for demographics, comorbidities, propensity for treatment with GBT and initial severity of disease decreased, but did not eliminate, the association (OR 1.39, 95% CI 1.32-1.47). Using an adaptation of an instrumental variable analysis, GBT was not associated with higher mortality (OR 0.93, 95% CI 0.75-1.16). Adjusted length of stay and costs were also higher with GBT. CONCLUSIONS: Among patients who met HCAP criteria, GBT was not associated with lower adjusted mortality, length of stay or costs in any analyses. Better criteria are needed to identify patients at risk for MDR infections who might benefit from broad-spectrum antimicrobial coverage. PMID- 25558076 TI - Antifungal activity of compounds targeting the Hsp90-calcineurin pathway against various mould species. AB - OBJECTIVES: Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90 calcineurin axis against different mould species. METHODS: The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-MU was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.) RESULTS: FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-MU exhibited little antifungal activity. CONCLUSIONS: Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds. PMID- 25558078 TI - In vitro antifungal activity and in vivo antibiofilm activity of cerium nitrate against Candida species. AB - OBJECTIVES: The objective of this study was to clarify the antifungal properties of cerium, a lanthanide member, against Candida species. A comprehensive study with planktonic and sessile cells was performed. The ability of cerium nitrate (CN) to impair in vitro and in vivo biofilm formation was evaluated and its potential use in biofilm treatment was also evaluated. METHODS: Forty-eight clinical isolates of different Candida species and the type strain ATCC 90028 were tested according to the protocol M27-A3. The MICs and minimum lethal concentrations were determined. A time-kill assay was performed and a cytometric kinetic study was performed using live/dead markers. Biofilm inhibition and biofilm susceptibility in the presence of cerium was evaluated by quantification of the biofilm metabolic activity and total biomass with XTT and crystal violet assays, respectively. CN in vivo efficacy as a coating for medical indwelling devices was evaluated for the first time for Candida parapsilosis, using a mouse subcutaneous foreign body model using polyurethane catheter segments. Scanning electron microscopy was used to assess biofilm architecture after CN treatment. RESULTS: The MICs for planktonic cells correlated with severe cellular metabolic activity impairment and membrane damage after 3 h of incubation. Moreover, CN efficiently prevented biofilm formation both in vitro and in vivo in segments of polyurethane catheters. At higher concentrations, it was also able to disorganize and almost eradicate preformed biofilms. CONCLUSIONS: Our results strongly suggest that CN application in the clinical setting might be effective in preventing the formation of biofilm-associated infections, namely through catheter coating and ultimately as an antimicrobial lock therapy. PMID- 25558079 TI - Clinical characteristics and treatment outcomes of patients with candidaemia due to Candida parapsilosis sensu lato species at a medical centre in Taiwan, 2000 12. AB - OBJECTIVES: To investigate the clinical characteristics and treatment outcomes of adult patients with Candida parapsilosis sensu lato candidaemia. METHODS: We evaluated data in the mycology database of the National Taiwan University Hospital and on patients diagnosed with candidaemia due to C. parapsilosis sensu lato species from 2000 to 2012. Isolates were identified to the species level by conventional identification methods, MALDI-TOF and gene sequencing analysis. RESULTS: A total of 323 adult patients with candidaemia caused by C. parapsilosis sensu lato species were evaluated, including 256 (79.3%) patients with C. parapsilosis sensu stricto, 34 (10.5%) with Candida orthopsilosis and 33 (10.2%) with Candida metapsilosis. There were 222 men and 101 women and the median age was 60 years (range 18-103 years). Among them, 178 (55%) had an underlying diagnosis of cancer. The overall 30 day mortality rate was 25% (n = 80). Multivariate analysis revealed that shock (P < 0.001), antifungal therapy (P = 0.002), central catheter removal (P = 0.02) and abdominal surgery (P = 0.043) were independent prognostic factors for patients with candidaemia due to C. parapsilosis sensu lato species. There were no significant differences in 30 day mortality rate among patients with candidaemia caused by the three different species (P = 0.770). All isolates of C. metapsilosis, C. orthopsilosis and C. parapsilosis sensu stricto were susceptible to voriconazole. WT isolates were susceptible to itraconazole, posaconazole and amphotericin B. CONCLUSIONS: There were no significant differences in 30 day mortality among patients with candidaemia caused by C. parapsilosis sensu stricto, C. metapsilosis or C. orthopsilosis. The currently used antifungal agents exhibited good in vitro activities against C. parapsilosis sensu lato species isolates. PMID- 25558080 TI - Evidence for intra-sexual selection in wild female baboons. AB - Because female reproductive success in social mammals is determined largely by parental rather than mating effort, intra-sexual competition among females has typically been assumed to occur primarily over food. Recently, however, renewed attention has been paid to the importance of other sources of variation in female fitness, with a concomitant focus on a broader definition of intra-sexual selection that encompasses both competition for resources and competition for mates and social partners. We present behavioural and demographic data gathered over 15 years on a group of wild chacma baboons (Papio hamadryas ursinus) which show that females incur several costs when living in groups with many females and comparatively few males: increased intra-sexual aggression, less stable bonds with female partners, and increased mortality. Female-female aggression was higher in years when the adult sex ratio was more highly skewed toward females, with low-ranking female exhibiting particularly high rates of aggression toward other females. Females' social bonds with other females also became less stable in years when the group contained many females. Finally, female mortality rates were highest in years when the group contained comparatively more females and fewer males. The negative correlation between the number of males and female mortality suggests that the increase in mortality was due to increased predation rather than food competition. Results indicate that intra-sexual competition for social partners, mates, paternal investment, and perhaps also male protection occurs even in species where females exhibit low reproductive skew. PMID- 25558081 TI - A Simple Capacitive Charge-Division Readout for Position-Sensitive Solid-State Photomultiplier Arrays. AB - A capacitive charge-division readout method for reading out a 2 * 2 array of 5 mm * 5 mm position-sensitive solid-state photomultipliers (PS-SSPM) was designed and evaluated. Using this analog multiplexing method, the 20 signals (16 position, 4 timing) from the PS-SSPM array are reduced to 5 signals (4 position, 1 timing), allowing the PS-SSPM array to be treated as an individual large-area PS-SSPM module. A global positioning approach can now be used, instead of individual positioning for each PS-SSPM in the array, ensuring that the entire light signal is utilized. The signal-to-noise ratio (SNR) and flood histogram quality at different bias voltages (27.5 V to 32.0 V at 0.5 V intervals) and a fixed temperature of 0 degrees C were evaluated by coupling a 6 * 6 array of 1.3 mm * 1.3 mm * 20 mm polished LSO crystals to the center of the PS-SSPM array. The timing resolution was measured at a fixed bias voltage of 31.0 V and a fixed temperature of 0 degrees C. All the measurements were evaluated and compared using capacitors with different values and tolerances. Capacitor values ranged from 0.051 nf to 10 nf, and the capacitance tolerance ranged from 1% to 20%. The results show that better performance was achieved using capacitors with smaller values and better capacitance tolerance. Using 0.2 nf capacitors, the SNR, energy resolution and timing resolution were 24.3, 18.2% and 8.8 ns at a bias voltage 31.0 V, respectively. The flood histogram quality was also evaluated by using a 10 * 10 array of 1 mm * 1 mm * 10 mm polished LSO crystals and a 10 * 10 array of 0.7 mm * 0.7 mm * 20 mm unpolished LSO crystals to determine the smallest crystal size resolvable. These studies showed that the high spatial resolution of the PS SSPM was preserved allowing for 0.7 mm crystals to be identified. These results show that the capacitive charge-division analog signal processing method can significantly reduce the number of electronic channels, from 20 to 5, while retaining the excellent performance of the detector. PMID- 25558077 TI - Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients. AB - OBJECTIVES: The objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir). PATIENTS AND METHODS: Data were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23). RESULTS: Among the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P < 0.001) and low genotypic sensitivity score of the associated treatment with raltegravir (P < 0.001) were associated with the presence of raltegravir-associated mutations at failure. Q148 mutations were selected more frequently in B subtypes versus non-B subtypes (P = 0.004). CONCLUSIONS: This study shows that a high proportion of viruses remain susceptible to dolutegravir in the case of failure on a raltegravir-containing regimen. PMID- 25558082 TI - Modelling the spatial spread of a homing endonuclease gene in a mosquito population. AB - SUMMARY: Homing endonuclease genes (HEGs) exist naturally in many single-celled organisms and can show extremely strong genetic drive allowing them to spread through populations into which they are introduced. They are being investigated as tools to manipulate the populations of important vectors of human disease, in particular the mosquitoes that transmit malaria. Before HEGs can be deployed, it is important to study their spatial spread in order to design efficient release strategies.A spatially explicit model is developed to study the spread of a HEG through a landscape whose structure is defined by the distribution of mosquito breeding and feeding sites. The model is motivated by the biology of the major vectors of malaria in Africa. The conditions for spread, fixation and loss of two major types of HEG are explored in different landscapes.In landscapes where mosquito resources are abundant, the conditions for spread are well approximated by a mean-field model. Where a HEG imposes a genetic load, it can cause population extinction, though spatial models more often predict population suppression.In certain types of landscapes where mosquito resources are rare, an introduced HEG may be prevented from moving between local mosquito populations and so a simple release strategy is unlikely to be effective, yet if the HEG succeeds in spreading population extinction is a feasible outcome. Increasing the number of release sites at the expense of releasing fewer mosquitoes per site reduces the probability that a HEG will fail.Synthesis and applications. The model presented asks for the first time how the spatial structure of mosquito populations will influence the effectiveness of a technology that is being rapidly developed for vector control. If homing endonuclease genes (HEGs) are to be used in this way, we have qualified the importance of accounting for landscape characteristics in both the execution and the expectation of their application. The next stage is to use the model to study the spread of HEGs through real landscapes where releases may take place, something that will be facilitated by the results of the present study. PMID- 25558083 TI - Ecological feedbacks can reduce population-level efficacy of wildlife fertility control. AB - Anthropogenic stress on natural systems, particularly the fragmentation of landscapes and the extirpation of predators from food webs, has intensified the need to regulate abundance of wildlife populations with management. Controlling population growth using fertility control has been considered for almost four decades, but nearly all research has focused on understanding effects of fertility control agents on individual animals. Questions about the efficacy of fertility control as a way to control populations remain largely unanswered.Collateral consequences of contraception can produce unexpected changes in birth rates, survival, immigration and emigration that may reduce the effectiveness of regulating animal abundance. The magnitude and frequency of such effects vary with species-specific social and reproductive systems, as well as connectivity of populations. Developing models that incorporate static demographic parameters from populations not controlled by contraception may bias predictions of fertility control efficacy.Many population-level studies demonstrate that changes in survival and immigration induced by fertility control can compensate for the reduction in births caused by contraception. The most successful cases of regulating populations using fertility control come from applications of contraceptives to small, closed populations of gregarious and easily accessed species.Fertility control can result in artificial selection pressures on the population and may lead to long-term unintentional genetic consequences. The magnitude of such selection is dependent on individual heritability and behavioural traits, as well as environmental variation.Synthesis and applications. Understanding species' life-history strategies, biology, behavioural ecology and ecological context is critical to developing realistic expectations of regulating populations using fertility control. Before time, effort and funding are invested in wildlife contraception, managers may need to consider the possibility that many species and populations can compensate for reduction in fecundity, and this could minimize any reduction in population growth rate. PMID- 25558084 TI - China's transboundary waters: new paradigms for water and ecological security through applied ecology. AB - China is Asia's most important upstream riparian country, sharing 110 rivers and lakes with 18 downstream countries. Consequently, China's management of transboundary water resources must consider both environmental and geopolitical risks.The major threats to and conflicts over international rivers in China revolve around biotic homogenisation due to the installation of transport links, water allocation, water pollution, alteration of natural flow patterns and disruption of fisheries due to the installation of hydropower dams, and droughts and floods exacerbated by climate change. Because these problems have an international component, they fall under China's Peaceful Rise strategy, mandating that transboundary conflicts be resolved amicably as part of the overarching goal of increasing regional economic growth with as little conflict as possible.Science-backed policy is more likely to result in long term, mutually agreeable solutions; the results of applied ecological research have already resulted in a number of mitigation measures, including setting operational thresholds to reduce the downstream impact of dams, designating protected areas along key river stretches where dams cannot be installed (one dam in a critical location has been cancelled), and the installation of terrestrial protected-area networks.Synthesis and applications. Applied ecology will continue to play an important role in the diagnosis and resolution of environmental threats to China's transboundary waters. More importantly, applied ecology can inform the development of a transboundary environmental compensation mechanism and regional consultative mechanisms that support informed, cooperative decision-making for China and its riparian neighbours. PMID- 25558085 TI - The role of predation and food limitation on claims for compensation, reindeer demography and population dynamics. AB - A major challenge in biodiversity conservation is to facilitate viable populations of large apex predators in ecosystems where they were recently driven to ecological extinction due to resource conflict with humans.Monetary compensation for losses of livestock due to predation is currently a key instrument to encourage human-carnivore coexistence. However, a lack of quantitative estimates of livestock losses due to predation leads to disagreement over the practice of compensation payments. This disagreement sustains the human carnivore conflict.The level of depredation on year-round, free-ranging, semi domestic reindeer by large carnivores in Fennoscandia has been widely debated over several decades. In Norway, the reindeer herders claim that lynx and wolverine cause losses of tens of thousands of animals annually and cause negative population growth in herds. Conversely, previous research has suggested that monetary predator compensation can result in positive population growth in the husbandry, with cascading negative effects of high grazer densities on the biodiversity in tundra ecosystems.We utilized a long-term, large-scale data set to estimate the relative importance of lynx and wolverine predation and density dependent and climatic food limitation on claims for losses, recruitment and population growth rates in Norwegian reindeer husbandry.Claims of losses increased with increasing predator densities, but with no detectable effect on population growth rates. Density-dependent and climatic effects on claims of losses, recruitment and population growth rates were much stronger than the effects of variation in lynx and wolverine densities.Synthesis and applications. Our analysis provides a quantitative basis for predator compensation and estimation of the costs of reintroducing lynx and wolverine in areas with free ranging semi-domestic reindeer. We outline a potential path for conflict management which involves adaptive monitoring programmes, open access to data, herder involvement and development of management strategy evaluation (MSE) models to disentangle complex responses including multiple stakeholders and individual harvester decisions. PMID- 25558086 TI - Agriculture modifies the seasonal decline of breeding success in a tropical wild bird population. AB - Habitat conversion for agriculture is a major driver of biodiversity loss, but our understanding of the demographic processes involved remains poor. We typically investigate the impacts of agriculture in isolation even though populations are likely to experience multiple, concurrent changes in the environment (e.g. land and climate change). Drivers of environmental change may interact to affect demography, but the mechanisms have yet to be explored fully in wild populations.Here, we investigate the mechanisms linking agricultural land use with breeding success using long-term data for the formerly Critically Endangered Mauritius kestrel Falco punctatus, a tropical forest specialist that also occupies agricultural habitats. We specifically focused on the relationship between breeding success, agriculture and the timing of breeding because the latter is sensitive to changes in climatic conditions (spring rainfall) and enables us to explore the interactive effects of different (land and climate) drivers of environmental change.Breeding success, measured as egg survival to fledging, declines seasonally in this population, but we found that the rate of this decline became increasingly rapid as the area of agriculture around a nest site increased. If the relationship between breeding success and agriculture was used in isolation to estimate the demographic impact of agriculture, it would significantly under-estimate breeding success in dry (early) springs and over estimate breeding success in wet (late) springs.Analysis of prey delivered to nests suggests that the relationship between breeding success and agriculture might be due, in part, to spatial variation in the availability of native, arboreal geckos.Synthesis and applications. Agriculture modifies the seasonal decline in breeding success in this population. As springs are becoming wetter in our study area and since the kestrels breed later in wetter springs, the impact of agriculture on breeding success will become worse over time. Our results suggest that forest restoration designed to reduce the detrimental impacts of agriculture on breeding may also help reduce the detrimental effects of breeding late due to wetter springs. Our results therefore highlight the importance of considering the interactive effects of environmental change when managing wild populations. PMID- 25558087 TI - FORUM: Ecological networks: the missing links in biomonitoring science. AB - Monitoring anthropogenic impacts is essential for managing and conserving ecosystems, yet current biomonitoring approaches lack the tools required to deal with the effects of stressors on species and their interactions in complex natural systems.Ecological networks (trophic or mutualistic) can offer new insights into ecosystem degradation, adding value to current taxonomically constrained schemes. We highlight some examples to show how new network approaches can be used to interpret ecological responses.Synthesis and applications. Augmenting routine biomonitoring data with interaction data derived from the literature, complemented with ground-truthed data from direct observations where feasible, allows us to begin to characterise large numbers of ecological networks across environmental gradients. This process can be accelerated by adopting emerging technologies and novel analytical approaches, enabling biomonitoring to move beyond simple pass/fail schemes and to address the many ecological responses that can only be understood from a network-based perspective. PMID- 25558088 TI - Thiol-norbornene photo-click hydrogels for tissue engineering applications. AB - Thiol-norbornene (thiol-ene) photo-click hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are cross linked through light mediated orthogonal reactions between multi-functional norbornene-modified macromers (e.g., poly(ethylene glycol), hyaluronic acid, gelatin) and sulfhydryl-containing linkers (e.g., dithiothreitol, PEG-dithiol, bis-cysteine peptides) using low concentration of photoinitiator. The gelation of thiol-norbornene hydrogels can be initiated by long-wave UV light or visible light without additional co-initiator or co-monomer. The cross-linking and degradation behaviors of thiol-norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned owing to the orthogonal reactivity between norbornene and thiol moieties. Uniquely, the cross-linking of step-growth thiol-norbornene hydrogels is not oxygen-inhibited, therefore the gelation is much faster and highly cytocompatible compared with chain-growth polymerized hydrogels using similar gelation conditions. These hydrogels have been prepared as tunable substrates for 2D cell culture, as microgels or bulk gels for affinity based or protease-sensitive drug delivery, and as scaffolds for 3D cell culture. Reports from different laboratories have demonstrated the broad utility of thiol norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas-related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, as well as cancer cell biology. This article provides an up-to-date overview on thiol-norbornene hydrogel cross-linking and degradation mechanisms, tunable material properties, as well as the use of thiol-norbornene hydrogels in drug delivery and tissue engineering applications. PMID- 25558089 TI - How exotic plants integrate into pollination networks. AB - SUMMARY: There is increasing world-wide concern about the impact of the introduction of exotic species on ecological communities. Since many exotic plants depend on native pollinators to successfully establish, it is of paramount importance that we understand precisely how exotic species integrate into existing plant-pollinator communities. In this manuscript, we have studied a global data base of empirical pollination networks to determine whether community, network, species or interaction characteristics can help identify invaded communities. We found that a limited number of community and network properties showed significant differences across the empirical data sets - namely networks with exotic plants present are characterized by greater total, plant and pollinator richness, as well as higher values of relative nestedness.We also observed significant differences in terms of the pollinators that interact with the exotic plants. In particular, we found that specialist pollinators that are also weak contributors to community nestedness are far more likely to interact with exotic plants than would be expected by chance alone.Synthesis. By virtue of their interactions, it appears that exotic plants may provide a key service to a community's specialist pollinators as well as fill otherwise vacant 'coevolutionary niches'. PMID- 25558090 TI - Evidence for shifts to faster growth strategies in the new ranges of invasive alien plants. AB - SUMMARY: Understanding the processes underlying the transition from introduction to naturalization and spread is an important goal of invasion ecology. Release from pests and pathogens in association with capacity for rapid growth is thought to confer an advantage for species in novel regions.We assessed leaf herbivory and leaf-level traits associated with growth strategy in the native and exotic ranges of 13 invasive plant species from 256 populations. Species were native to either the Western Cape region of South Africa, south-western Australia or south eastern Australia and had been introduced to at least one of the other regions or to New Zealand. We tested for evidence of herbivore release and shifts in leaf traits between native and exotic ranges of the 13 species.Across all species, leaf herbivory, specific leaf area and leaf area were significantly different between native and exotic ranges while there were no significant differences across the 13 species found for leaf mass, assimilation rate, dark respiration or foliar nitrogen.Analysis at the species- and region-level showed that eight out of 13 species had reduced leaf herbivory in at least one exotic region compared to its native range.Six out of 13 species had significantly larger specific leaf area (SLA) in at least one exotic range region and five of those six species experienced reduced leaf herbivory. Increases in SLA were underpinned by increases in leaf area rather than reductions in leaf mass.No species showed differences in the direction of trait shifts from the native range between different exotic regions. This suggests that the driver of selection on these traits in the exotic range is consistent across regions and hence is most likely to be associated with factors linked with introduction to a novel environment, such as release from leaf herbivory, rather than with particular environmental conditions.Synthesis. These results provide evidence that introduction of a plant species into a novel environment commonly results in a reduction in the top-down constraint imposed by herbivores on growth, allowing plants to shift towards a faster growth strategy which may result in an increase in population size and spread and consequently to invasive success. PMID- 25558091 TI - Conditions favouring hard seededness as a dispersal and predator escape strategy. AB - SUMMERY: The water-impermeable seed coat of 'hard' seeds is commonly considered a dormancy trait. Seed smell is, however, strongly correlated with seed water content, and hard seeds are therefore olfactionally cryptic to foraging rodents. This is the rationale for the crypsis hypothesis, which proposes that the primary functions of hard seeds are to reduce seed predation and promote rodent seed dispersal. We use a mechanistic model to describe seed survival success of plants with different dimorphic soft and hard seed strategies. The model is based on established empirical-ecological relationships of moisture requirements for germination and benefits of seed dispersal, and on experimentally demonstrated relationships between seed volatile emission, predation and predator escape. We find that water-impermeable seed coats can reduce seed predation under a wide range of natural humidity conditions. Plants with rodent dispersed seeds benefit from producing dimorphic soft and hard seeds at ratios where the anti-predator advantages of hard seeds are balanced by the dispersal benefits gained by producing some soft seeds. The seed pathway predicted from the model is similar to those of experimental seed-tracking studies. This validates the relevance and realism of the ecological mechanisms and relationships incorporated in the model. Synthesis. Rodent seed predators are often also important seed dispersers and have the potential to exert strong selective pressures on seeds to evolve methods of avoiding detection, and hard seeds seem to do just that. This work suggests that water-impermeable hard seeds may evolve in the absence of a dormancy function and that optimal seed survival in many environments with rodent seed predators is obtained by plants having a dimorphic soft and hard seed strategy. PMID- 25558093 TI - Barred owls and landscape attributes influence territory occupancy of northern spotted owls. AB - We used multi-season occupancy analyses to model 2 fates of northern spotted owl territories in relation to habitat amount, habitat fragmentation, and the presence of barred owls in Washington State, USA, 1989-2005. Local colonization is the probability a territory unoccupied by a spotted owl in year i would be occupied in year i + 1, and local extinction is the probability a territory that was occupied by a spotted owl in year i would be unoccupied in year i + 1. We found a negative relationship between local extinction probability and amount of late-seral forest edge. We found a negative relationship between colonization probability and the number of late-seral forest patches (higher fragmentation), and a negative relationship between colonization probability and the amount of non-habitat within 600 m of a spotted owl territory center (Akaike weight = 0.59). The presence of barred owls was positively related to extinction probability and negatively related to detection probability of spotted owls. The negative relationship between presence of barred owls and detectability of spotted owls indicated that spotted owls could be modifying their calling behavior in the presence of barred owls. The positive relationship between barred owl detections and local extinction probability suggests that because of competition with barred owls, spotted owls are being displaced. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 25558094 TI - The Role of Repeated Exposure to Multimodal Input in Incidental Acquisition of Foreign Language Vocabulary. AB - Prior research has reported incidental vocabulary acquisition with complete beginners in a foreign language (FL), within 8 exposures to auditory and written FL word forms presented with a picture depicting their meaning. However, important questions remain about whether acquisition occurs with fewer exposures to FL words in a multimodal situation and whether there is a repeated exposure effect. Here we report a study where the number of exposures to FL words in an incidental learning phase varied between 2, 4, 6, and 8 exposures. Following the incidental learning phase, participants completed an explicit learning task where they learned to recognize written translation equivalents of auditory FL word forms, half of which had occurred in the incidental learning phase. The results showed that participants performed better on the words they had previously been exposed to, and that this incidental learning effect occurred from as little as 2 exposures to the multimodal stimuli. In addition, repeated exposure to the stimuli was found to have a larger impact on learning during the first few exposures and decrease thereafter, suggesting that the effects of repeated exposure on vocabulary acquisition are not necessarily constant. PMID- 25558092 TI - Tree diversity and the role of non-host neighbour tree species in reducing fungal pathogen infestation. AB - The degree to which plant pathogen infestation occurs in a host plant is expected to be strongly influenced by the level of species diversity among neighbouring host and non-host plant species. Since pathogen infestation can negatively affect host plant performance, it can mediate the effects of local biodiversity on ecosystem functioning.We tested the effects of tree diversity and the proportion of neighbouring host and non-host species with respect to the foliar fungal pathogens of Tilia cordata and Quercus petraea in the Kreinitz tree diversity experiment in Germany. We hypothesized that fungal pathogen richness increases while infestation decreases with increasing local tree diversity. In addition, we tested whether fungal pathogen richness and infestation are dependent on the proportion of host plant species present or on the proportion of particular non host neighbouring tree species.Leaves of the two target species were sampled across three consecutive years with visible foliar fungal pathogens on the leaf surface being identified macro- and microscopically. Effects of diversity among neighbouring trees were analysed: (i) for total fungal species richness and fungal infestation on host trees and (ii) for infestation by individual fungal species.We detected four and five fungal species on T. cordata and Q. petraea, respectively. High local tree diversity reduced (i) total fungal species richness and infestation of T. cordata and fungal infestation of Q. petraea and (ii) infestation by three host-specialized fungal pathogen species. These effects were brought about by local tree diversity and were independent of host species proportion. In general, host species proportion had almost no effect on fungal species richness and infestation. Strong effects associated with the proportion of particular non-host neighbouring tree species on fungal species richness and infestation were, however, recorded.Synthesis. For the first time, we experimentally demonstrated that for two common forestry tree species, foliar fungal pathogen richness and infestation depend on local biodiversity. Thus, local tree diversity can have positive impacts on ecosystem functioning in managed forests by decreasing the level of fungal pathogen infestation. PMID- 25558095 TI - Using the Bollen-Stine Bootstrapping Method for Evaluating Approximate Fit Indices. AB - Accepting that a model will not exactly fit any empirical data, global approximate fit indices quantify the degree of misfit. Recent research (Chen et al., 2008) has shown that using fixed conventional cut-points for approximate fit indices can lead to decision errors. Instead of using fixed cut-points for evaluating approximate fit indices, this study focuses on the meaning of approximate fit and introduces a new method to evaluate approximate fit indices. Millsap (2012) introduced a simulation-based method to evaluate approximate fit indices. A limitation of Millsap's work was that a rather strong assumption of multivariate normality was implied in generating simulation data. In this study, the Bollen-Stine bootstrapping procedure (Bollen & Stine, 1993) is proposed to supplement the former study. When data are non-normal, the conclusions derived from Millsap's (2012) simulation method and the Bollen-Stine method can differ. Examples are given to illustrate the use of the Bollen-Stine bootstrapping procedure for evaluating RMSEA. Comparisons are made with the simulation method. The results are discussed, and suggestions are given for the use of proposed method. PMID- 25558097 TI - The Ebola epidemic: a transformative moment for global health. PMID- 25558098 TI - Reversing a global health workforce crisis. PMID- 25558099 TI - Expensive medicines: ensuring objective appraisal and equitable access. PMID- 25558100 TI - Public health round-up. PMID- 25558101 TI - The race against time. PMID- 25558102 TI - Noncommunicable diseases: stepping up the fight. PMID- 25558103 TI - Responses to donor proliferation in Ghana's health sector: a qualitative case study. AB - OBJECTIVE: To investigate how donors and government agencies responded to a proliferation of donors providing aid to Ghana's health sector between 1995 and 2012. METHODS: We interviewed 39 key informants from donor agencies, central government and nongovernmental organizations in Accra. These respondents were purposively selected to provide local and international views from the three types of institutions. Data collected from the respondents were compared with relevant documentary materials - e.g. reports and media articles - collected during interviews and through online research. FINDINGS: Ghana's response to donor proliferation included creation of a sector-wide approach, a shift to sector budget support, the institutionalization of a Health Sector Working Group and anticipation of donor withdrawal following the country's change from low income to lower-middle income status. Key themes included the importance of leadership and political support, the internalization of norms for harmonization, alignment and ownership, tension between the different methods used to improve aid effectiveness, and a shift to a unidirectional accountability paradigm for health-sector performance. CONCLUSION: In 1995-2012, the country's central government and donors responded to donor proliferation in health-sector aid by promoting harmonization and alignment. This response was motivated by Ghana's need for foreign aid, constraints on the capacity of governmental human resources and inefficiencies created by donor proliferation. Although this decreased the government's transaction costs, it also increased the donors' coordination costs and reduced the government's negotiation options. Harmonization and alignment measures may have prompted donors to return to stand-alone projects to increase accountability and identification with beneficial impacts of projects. PMID- 25558104 TI - Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013. AB - OBJECTIVE: To estimate cause-of-death distributions in the early (0-6 days of age) and late (7-27 days of age) neonatal periods, for 194 countries between 2000 and 2013. METHODS: For 65 countries with high-quality vital registration, we used each country's observed early and late neonatal proportional cause distributions. For the remaining 129 countries, we used multinomial logistic models to estimate these distributions. For countries with low child mortality we used vital registration data as inputs and for countries with high child mortality we used neonatal cause-of-death distribution data from studies in similar settings. We applied cause-specific proportions to neonatal death estimates from the United Nations Inter-agency Group for Child Mortality Estimation, by country and year, to estimate cause-specific risks and numbers of deaths. FINDINGS: Over time, neonatal deaths decreased for most causes. Of the 2.8 million neonatal deaths in 2013, 0.99 million deaths (uncertainty range: 0.70-1.31) were estimated to be caused by preterm birth complications, 0.64 million (uncertainty range: 0.46 0.84) by intrapartum complications and 0.43 million (uncertainty range: 0.22 0.66) by sepsis and other severe infections. Preterm birth (40.8%) and intrapartum complications (27.0%) accounted for most early neonatal deaths while infections caused nearly half of late neonatal deaths. Preterm birth complications were the leading cause of death in all regions of the world. CONCLUSION: The neonatal cause-of-death distribution differs between the early and late periods and varies with neonatal mortality rate level. To reduce neonatal deaths, effective interventions to address these causes must be incorporated into policy decisions. PMID- 25558105 TI - Association between antiretroviral therapy adherence and employment status: systematic review and meta-analysis. AB - OBJECTIVE: To assess the association between the employment status of human immunodeficiency virus (HIV)-infected individuals and adherence to antiretroviral therapy (ART). METHODS: We searched the Medline, Embase and Cochrane Central Register of Controlled Trials databases for studies reporting ART adherence and employment status published between January 1980 and September 2014. Information from a wide range of other sources, including the grey literature, was also analysed. Two independent reviewers extracted data on treatment adherence and study characteristics. Study data on the association between being employed and adhering to ART were pooled using a random-effects model. Between-study heterogeneity and sources of bias were evaluated. FINDINGS: The meta-analysis included 28 studies published between 1996 and 2014 that together involved 8743 HIV-infected individuals from 14 countries. The overall pooled odds ratio (OR) for the association between being employed and adhering to ART was 1.27 (95% confidence interval, CI: 1.04-1.55). The association was significant for studies from low-income countries (OR: 1.85, 95% CI: 1.58-2.18) and high-income countries (OR: 1.33, 95% CI: 1.02-1.74) but not middle-income countries (OR: 0.94, 95% CI: 0.62-1.42). In addition, studies published after 2011 and larger studies showed less association between employment and adherence than earlier and small studies, respectively. CONCLUSION: Employed HIV-infected individuals, particularly those in low- and high-income countries, were more likely to adhere to ART than unemployed individuals. Further research is needed on the mechanisms by which employment and ART adherence affect each other and on whether employment-creation interventions can positively influence ART adherence, HIV disease progression and quality of life. PMID- 25558106 TI - Ensuring accurate testing for human immunodeficiency virus in Myanmar. AB - PROBLEM: Until 2005, the quality of rapid diagnostic human immunodeficiency virus (HIV) testing was not monitored and no regular technical support was provided to hospital laboratories in Myanmar. APPROACH: The national reference laboratory introduced a national external quality assessment scheme. The scheme involved (i) training laboratory technicians in HIV testing and in the requirements of the quality assessment system; (ii) implementing a biannual proficiency panel testing programme; (iii) on-site assessments of poorly-performing laboratories to improve testing procedures; and (iv) development of national guidelines. LOCAL SETTING: In 2011, a total of 422 public hospitals in Myanmar had laboratories providing HIV tests. In addition, private laboratories supported by nongovernmental organizations (NGOs) conducted HIV testing. RELEVANT CHANGES: The scheme was started in 65 public laboratories in 2005. In 2012, it had expanded nationwide to 347 laboratories, including 33 NGO laboratories. During the expansion of the scheme, laboratory response rates were greater than 90% and the proportion of laboratories reporting at least one aberrant result improved from 9.2% (6/65) in 2005 to 5.4% (17/316) in 2012. LESSONS LEARNT: National testing guidelines and a reference laboratory are needed to successfully implement quality assurance of HIV testing services. On-site assessments are crucial for all participating laboratories and the only source for insight on the causes of aberrant results; lessons that the reference laboratory can share nationally. Proficiency testing helps laboratory technicians to maintain HIV testing skills by ensuring that they regularly encountered HIV-positive samples. PMID- 25558107 TI - Informing evidence-based policies for ageing and health in Ghana. AB - PROBLEM: Ghana's population is ageing. In 2011, the Government of Ghana requested technical support from the World Health Organization (WHO) to help revise national policies on ageing and health. APPROACH: We applied WHO's knowledge translation framework on ageing and health to assist evidence based policy-making in Ghana. First, we defined priority problems and health system responses by performing a country assessment of epidemiologic data, policy review, site visits and interviews of key informants. Second, we gathered evidence on effective health systems interventions in low- middle- and high-income countries. Third, key stakeholders were engaged in a policy dialogue. Fourth, policy briefs were developed and presented to the Ghana Health Services. LOCAL SETTING: Ghana has a well-structured health system that can adapt to meet the health care needs of older people. RELEVANT CHANGES: Six problems were selected as priorities, however after the policy dialogue, only five were agreed as priorities by the stakeholders. The key stakeholders drafted evidence-based policy recommendations that were used to develop policy briefs. The briefs were presented to the Ghana Health Service in 2014. LESSONS LEARNT: The framework can be used to build local capacity on evidence-informed policy-making. However, knowledge translation tools need further development to be used in low-income countries and in the field of ageing. The terms and language of the tools need to be adapted to local contexts. Evidence for health system interventions on ageing populations is very limited, particularly for low- and middle-income settings. PMID- 25558109 TI - Financing health care for adolescents: a necessary part of universal health coverage. PMID- 25558108 TI - Integrated prevention of mother-to-child transmission for human immunodeficiency virus, syphilis and hepatitis B virus in China. AB - PROBLEM: China continues to face challenges in eliminating mother-to-child transmission of human immunodeficiency virus (HIV), syphilis and hepatitis B virus (HBV). APPROACH: In 2010, a programme that integrated and standardized prevention of mother-to-child transmission (PMTCT) efforts for HIV, syphilis and HBV was implemented in 1156 counties. At participating antenatal care clinics, pregnant women were offered all three tests concurrently and free of charge. Further interventions such as free treatment, prophylaxis and testing for mothers and their children were provided for HIV and syphilis. LOCAL SETTING: China's national PMTCT HIV programme started in 2003, at which time there were no national programmes for perinatal syphilis and HBV. In 2009, the rate of maternal to-child transmission of HIV was 8.1% (57/702). Reported congenital syphilis was 60.8 per 100,000 live births. HBV infection was 7.2% of the overall population infected. RELEVANT CHANGES: Between 2010 and 2013 the number of pregnant women attending antenatal care clinics with integrated PMTCT services increased from 5.5 million to 13.1 million. In 2013, 12.7 million pregnant women were tested for HIV, 12.6 million for syphilis and 12.7 million for HBV. Mother-to-child transmission of HIV fell to 6.7% in 2013. Data on syphilis transmission are not yet available. LESSONS LEARNT: Integrated PMTCT services proved to be feasible and effective, and they are now part of the routine maternal and child health services provided to infected women. The services are provided through a collaboration between maternal and child health clinics, the national and local Centers for Disease Control and Prevention, and general hospitals. PMID- 25558110 TI - Measuring the incidence and prevalence of obstetric fistula: approaches, needs and recommendations. PMID- 25558112 TI - Nebraska's groundwater legacy: Nitrate contamination beneath irrigated cropland. AB - A 31 year record of ~44,000 nitrate analyses in ~11,500 irrigation wells was utilized to depict the decadal expansion of groundwater nitrate contamination (N >= 10 mg/L) in the irrigated corn-growing areas of eastern and central Nebraska and analyze long-term nitrate concentration trends in 17 management areas (MAs) subject to N fertilizer and budgeting requirements. The 1.3 M contaminated hectares were characterized by irrigation method, soil drainage, and vadose zone thickness and lithology. The areal extent and growth of contaminated groundwater in two predominately sprinkler-irrigated areas was only ~20% smaller beneath well drained silt loams with thick clayey-silt unsaturated layers and unsaturated thicknesses >15 m (400,000 ha and 15,000 ha/yr) than beneath well and excessively well-drained soils with very sandy vadose zones (511,000 ha and 18,600 ha/yr). Much slower expansion (3700 ha/yr) occurred in the 220,000 contaminated hectares in the central Platte valley characterized by predominately gravity irrigation on thick, well-drained silt loams above a thin (~5.3 m), sandy unsaturated zone. The only reversals in long-term concentration trends occurred in two MAs (120,500 ha) within this contaminated area. Concentrations declined 0.14 and 0.20 mg N/L/yr (p < 0.02) to ~18.3 and 18.8 mg N/L, respectively, during >20 years of management. Average annual concentrations in 10 MAs are increasing (p < 0.05) and indicate that average nitrate concentrations in leachates below the root zone and groundwater concentrations have not yet reached steady state. While management practices likely have slowed increases in groundwater nitrate concentrations, irrigation and nutrient applications must be more effectively controlled to retain nitrate in the root zone. PMID- 25558113 TI - Principal Component Geostatistical Approach for large-dimensional inverse problems. AB - The quasi-linear geostatistical approach is for weakly nonlinear underdetermined inverse problems, such as Hydraulic Tomography and Electrical Resistivity Tomography. It provides best estimates as well as measures for uncertainty quantification. However, for its textbook implementation, the approach involves iterations, to reach an optimum, and requires the determination of the Jacobian matrix, i.e., the derivative of the observation function with respect to the unknown. Although there are elegant methods for the determination of the Jacobian, the cost is high when the number of unknowns, m, and the number of observations, n, is high. It is also wasteful to compute the Jacobian for points away from the optimum. Irrespective of the issue of computing derivatives, the computational cost of implementing the method is generally of the order of m2n, though there are methods to reduce the computational cost. In this work, we present an implementation that utilizes a matrix free in terms of the Jacobian matrix Gauss-Newton method and improves the scalability of the geostatistical inverse problem. For each iteration, it is required to perform K runs of the forward problem, where K is not just much smaller than m but can be smaller that n. The computational and storage cost of implementation of the inverse procedure scales roughly linearly with m instead of m2 as in the textbook approach. For problems of very large m, this implementation constitutes a dramatic reduction in computational cost compared to the textbook approach. Results illustrate the validity of the approach and provide insight in the conditions under which this method perform best. PMID- 25558114 TI - Extrapolating active layer thickness measurements across Arctic polygonal terrain using LiDAR and NDVI data sets. AB - Landscape attributes that vary with microtopography, such as active layer thickness (ALT), are labor intensive and difficult to document effectively through in situ methods at kilometer spatial extents, thus rendering remotely sensed methods desirable. Spatially explicit estimates of ALT can provide critically needed data for parameterization, initialization, and evaluation of Arctic terrestrial models. In this work, we demonstrate a new approach using high resolution remotely sensed data for estimating centimeter-scale ALT in a 5 km2 area of ice-wedge polygon terrain in Barrow, Alaska. We use a simple regression based, machine learning data-fusion algorithm that uses topographic and spectral metrics derived from multisensor data (LiDAR and WorldView-2) to estimate ALT (2 m spatial resolution) across the study area. Comparison of the ALT estimates with ground-based measurements, indicates the accuracy (r2 = 0.76, RMSE +/-4.4 cm) of the approach. While it is generally accepted that broad climatic variability associated with increasing air temperature will govern the regional averages of ALT, consistent with prior studies, our findings using high-resolution LiDAR and WorldView-2 data, show that smaller-scale variability in ALT is controlled by local eco-hydro-geomorphic factors. This work demonstrates a path forward for mapping ALT at high spatial resolution and across sufficiently large regions for improved understanding and predictions of coupled dynamics among permafrost, hydrology, and land-surface processes from readily available remote sensing data. PMID- 25558115 TI - Stochastic reduced order models for inverse problems under uncertainty. AB - This work presents a novel methodology for solving inverse problems under uncertainty using stochastic reduced order models (SROMs). Given statistical information about an observed state variable in a system, unknown parameters are estimated probabilistically through the solution of a model-constrained, stochastic optimization problem. The point of departure and crux of the proposed framework is the representation of a random quantity using a SROM - a low dimensional, discrete approximation to a continuous random element that permits e cient and non-intrusive stochastic computations. Characterizing the uncertainties with SROMs transforms the stochastic optimization problem into a deterministic one. The non-intrusive nature of SROMs facilitates e cient gradient computations for random vector unknowns and relies entirely on calls to existing deterministic solvers. Furthermore, the method is naturally extended to handle multiple sources of uncertainty in cases where state variable data, system parameters, and boundary conditions are all considered random. The new and widely-applicable SROM framework is formulated for a general stochastic optimization problem in terms of an abstract objective function and constraining model. For demonstration purposes, however, we study its performance in the specific case of inverse identification of random material parameters in elastodynamics. We demonstrate the ability to efficiently recover random shear moduli given material displacement statistics as input data. We also show that the approach remains effective for the case where the loading in the problem is random as well. PMID- 25558116 TI - The foundation of the child's right to an open future. PMID- 25558117 TI - Health Shocks and Natural Resource Management: Evidence from Western Kenya. AB - Poverty and altered planning horizons brought on by the HIV/AIDS epidemic can change individual discount rates, altering incentives to conserve natural resources. Using longitudinal household survey data from western Kenya, we estimate the effects of health status on investments in soil quality, as indicated by households' agricultural land fallowing decisions. We first show that this effect is theoretically ambiguous: while health improvements lower discount rates and thus increase incentives to conserve natural resources, they also increase labor productivity and make it more likely that households can engage in labor-intensive resource extraction activities. We find that household size and composition are predictors of whether the effect of health improvements on discount rates dominates the productivity effect, or vice-versa. Since households with more and younger members are better able to reallocate labor to cope with productivity shocks, the discount rate effect dominates for these households and health improvements lead to greater levels of conservation. In smaller families with less substitutable labor, the productivity effect dominates and health improvements lead to greater environmental degradation. PMID- 25558118 TI - Evolutionary Design of Gene Networks: Forced Evolution by Genomic Parasites. AB - The co-evolution of species with their genomic parasites (transposons) is thought to be one of the primary ways of rewiring gene regulatory networks (GRNs). We develop a framework for conducting evolutionary computations (EC) using the transposon mechanism. We find that the selective pressure of transposons can speed evolutionary searches for solutions and lead to outgrowth of GRNs (through co-option of new genes to acquire insensitivity to the attacking transposons). We test the approach by finding GRNs which can solve a fundamental problem in developmental biology: how GRNs in early embryo development can robustly read maternal signaling gradients, despite continued attacks on the genome by transposons. We observed co-evolutionary oscillations in the abundance of particular GRNs and their transposons, reminiscent of predator-prey or host parasite dynamics. PMID- 25558120 TI - Multiview stereo and silhouette fusion via minimizing generalized reprojection error. AB - Accurate reconstruction of 3D geometrical shape from a set of calibrated 2D multiview images is an active yet challenging task in computer vision. The existing multiview stereo methods usually perform poorly in recovering deeply concave and thinly protruding structures, and suffer from several common problems like slow convergence, sensitivity to initial conditions, and high memory requirements. To address these issues, we propose a two-phase optimization method for generalized reprojection error minimization (TwGREM), where a generalized framework of reprojection error is proposed to integrate stereo and silhouette cues into a unified energy function. For the minimization of the function, we first introduce a convex relaxation on 3D volumetric grids which can be efficiently solved using variable splitting and Chambolle projection. Then, the resulting surface is parameterized as a triangle mesh and refined using surface evolution to obtain a high-quality 3D reconstruction. Our comparative experiments with several state-of-the-art methods show that the performance of TwGREM based 3D reconstruction is among the highest with respect to accuracy and efficiency, especially for data with smooth texture and sparsely sampled viewpoints. PMID- 25558119 TI - Transition Metals Catalyzed Element-Cyano Bonds Activations. AB - Cyano group as a versatile functionalized intermediate has been explored for several decades, as it readily transfers to many useful functionalization groups such as amine, amide, acid, etc., which make it possess high popularization and use value in organic synthesis. Reactions involved with element-cyano bond cleavage can provide not only a new cyano group but also a freshly functionalized skeleton in one-pot, consequently making it of high importance. The highlights reviewed herein include H-CN, Si-CN, C-CN, B-CN, Sn-CN, Ge-CN, S-CN, Halo-CN, N CN, and O-CN bonds cleavages and will summarize progress in such an important research area. This review article will focus on transition metal catalyzed reactions involving element-cyano bond activation. PMID- 25558121 TI - Iron ochre - a pre-catalyst for the cracking of methane. AB - BACKGROUND: Iron ochres are gelatinous sludges that can cause problems in terms of water management. In this work, the application of iron ochre obtained from a river has been applied to catalytically crack methane - another potential waste product - into two useful products, hydrogen and a magnetic carbon-containing composite. RESULTS: The powder X-ray diffraction (XRD) pattern of the iron ochre was found to be consistent with the expected 2-line ferrihydrite, and energy dispersive X-ray (EDX) analysis showed Fe to be a major component although some Si and Ca were present. The sample was observed to contain a fraction with a tubular morphology consistent with the presence of extra-cellular biogenic iron oxide formed by leptothrix. Upon exposure to methane at elevated temperatures, the material was found to transform into an active catalyst for hydrogen production yielding a magnetic carbon-containing composite material comprising filamentous carbon and encapsulating graphite. CONCLUSION: The application of two waste products - iron ochre and methane - to generate two useful products - hydrogen and a magnetic carbon-containing composite - has been demonstrated. Furthermore, the ochre has been shown to comprise tubular morphology extra cellular biogenic iron oxide which may be of interest in terms of other applications. (c) 2014 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 25558122 TI - Optimization approaches to ameliorate humidity and vibration related issues using the microAeth black carbon monitor for personal exposure measurement. AB - Exposure to ambient black carbon (BC) is associated with adverse health effects. Black carbon levels display large spatial and temporal variability in many settings, such as cities and rural households where fossil fuel and biomass, respectively, are commonly burned for transportation, heat and cooking. This paper addresses the optimization of the miniaturized personal BC monitor, the microAeth(r) for use in epidemiology studies. To address false positive and negative peaks in real time BC concentrations resulting from changes in temperature and humidity, an inlet with a diffusion drier was developed. In addition, we developed data cleaning algorithms to address occasional false positive and negative fluctuations in BC readings related to physical vibration, due in part to both dirt accumulations in the optical inserts and degraded components. These methods were successfully used to process real-time BC data generated from a cohort of 9-10 year old children (N= 54) in NYC, who wore 1 or 2 microAeth units for six 24hr time periods. Two hour and daily BC averages after data cleaning were consistent with averaged raw data (slopes near 1 with R =0.99, p<0.001; R= 0.95, p<0.001, respectively), strongly suggesting that the false positive and negative excursions balance each other out when averaged for at least 2 hrs. Data cleaning of identified suspect events allows more confidence in the interpretation of the real-time personal monitoring data generated in environmental exposure studies, with mean percent difference <10% for 19 duplicate deployments. PMID- 25558123 TI - Don't tell on me: Experimental evidence of asymmetric information in transnational households. AB - Although most theoretical models of household decision making assume perfect information, empirical studies suggest that information asymmetries can have large impacts on resource allocation. I demonstrate the importance of these asymmetries in transnational households, where physical distance between family members can make information barriers especially acute. I implement an experiment among migrants in Washington, DC, and their families in El Salvador that examines how information asymmetries can have strategic and inadvertent impacts on remittance decisions. Migrants make an incentivized decision over how much of a cash windfall to remit, and recipients decide how they will spend a remittance. Migrants strategically send home less when their choice is not revealed to recipients. Recipients make spending choices closer to migrants' preferences when the migrants' preferences are shared, regardless of whether or not the spending choices are revealed to the migrants, suggesting that recipients' choices are inadvertently affected by imperfect information. PMID- 25558124 TI - Exact Statistical Tests for Heterogeneity of Frequencies Based on Extreme Values. AB - Sophisticated statistical analyses of incidence frequencies are often required for various epidemiologic and biomedical applications. Among the most commonly applied methods is Pearson's chi2 test, which is structured to detect non specific anomalous patterns of frequencies and is useful for testing the significance for incidence heterogeneity. However, the Pearson's chi2 test is not efficient for assessing the significance of frequency in a particular cell (or class) to be attributed to chance alone. We recently developed statistical tests for detecting temporal anomalies of disease cases based on maximum and minimum frequencies; these tests are actually designed to test of significance for a particular high or low frequency. We show that our proposed methods are more sensitive and powerful for testing extreme cell counts than is the Pearson's chi2 test. We elucidated and illustrated the differences in sensitivity among our tests and the Pearson's chi2 test by analyzing a data set of Langerhans cell histiocytosis cases and its hypothetical sets. We also computed and compared the statistical power of these methods using various sets of cell numbers and alternative frequencies. Our study will provide investigators with useful guidelines for selecting the appropriate tests for their studies. PMID- 25558125 TI - Corporate Diversity Programs and Gender Inequality in the Oil and Gas Industry. AB - Since the 1980s, major U.S. corporations have embraced diversity as a management strategy to increase the number of women in top jobs. Diversity management programs include targeted recruitment, hiring, and promotions policies; mentoring programs; affinity groups; and diversity training. Few of these programs have proven effective in achieving gender diversity in the corporate world, despite their widespread popularity. To explore the reasons for this, the authors investigate the experiences of women scientists in the oil and gas industry who are targeted by these programs. In-depth interviews reveal possible reasons why these programs fail to achieve their intended goals. The authors find that these programs can paradoxically reinforce gender inequality and male dominance in the industry. The authors discuss alternative approaches for addressing gender inequality in work organizations and conclude with implications of their findings for corporate approaches to promoting diversity and for future research. PMID- 25558126 TI - Optimal Design of Non-equilibrium Experiments for Genetic Network Interrogation. AB - Many experimental systems in biology, especially synthetic gene networks, are amenable to perturbations that are controlled by the experimenter. We developed an optimal design algorithm that calculates optimal observation times in conjunction with optimal experimental perturbations in order to maximize the amount of information gained from longitudinal data derived from such experiments. We applied the algorithm to a validated model of a synthetic Brome Mosaic Virus (BMV) gene network and found that optimizing experimental perturbations may substantially decrease uncertainty in estimating BMV model parameters. PMID- 25558127 TI - Entrainment and coherence in biology. PMID- 25558128 TI - Effectiveness of Iyengar yoga in treating spinal (back and neck) pain: A systematic review. AB - Considerable amount of money spent in health care is used for treatments of lifestyle related, chronic health conditions, which come from behaviors that contribute to morbidity and mortality of the population. Back and neck pain are two of the most common musculoskeletal problems in modern society that have significant cost in health care. Yoga, as a branch of complementary alternative medicine, has emerged and is showing to be an effective treatment against nonspecific spinal pain. Recent studies have shown positive outcome of yoga in general on reducing pain and functional disability of the spine. The objective of this study is to conduct a systematic review of the existing research within Iyengar yoga method and its effectiveness on relieving back and neck pain (defined as spinal pain). Database research form the following sources (Cochrane library, NCBI PubMed, the Clinical Trial Registry of the Indian Council of Medical Research, Google Scholar, EMBASE, CINAHL, and PsychINFO) demonstrated inclusion and exclusion criteria that selected only Iyengar yoga interventions, which in turn, identified six randomized control trials dedicated to compare the effectiveness of yoga for back and neck pain versus other care. The difference between the groups on the postintervention pain or functional disability intensity assessment was, in all six studies, favoring the yoga group, which projected a decrease in back and neck pain. Overall six studies with 570 patients showed, that Iyengar yoga is an effective means for both back and neck pain in comparison to control groups. This systematic review found strong evidence for short-term effectiveness, but little evidence for long-term effectiveness of yoga for chronic spine pain in the patient-centered outcomes. PMID- 25558129 TI - Effects of suryanamaskar on relaxation among college students with high stress in Pune, India. AB - CONTEXT: Suryanamaskar is a yogic practice widely practiced across India. Along with the available studies on physiology, there is a need to study its psychological effects. AIMS: This research aims at studying the effects of suryanamaskar on relaxation dispositions (R-dispositions) among college students with high stress in Pune, India. SETTINGS AND DESIGN: The present study was conducted in a college setting and used a randomized control group design. MATERIALS AND METHODS: A group of 419 college students (age 17-22 years) were assessed on stress symptoms using the ABC relaxation theory. A total of 124 out of 419 students who were identified as high on stress were randomly assigned to an experimental and control group. And 40 participants each in both the group completed the program and were assessed on R-dispositions and stress dispositions before and after the suryanamaskar program. STATISTICAL ANALYSIS USED: Analysis of covariance (ANCOVA) was used to study the differences in R-dispositions and stress dispositions between the experimental and control groups. RESULTS: The experimental group was found to be higher on the R-dispositions of physical relaxation, mental quiet, at ease/peace, rested and refreshed, strength and awareness and joy and lower on sleepiness, and stress dispositions-somatic stress, worry, and negative emotion compared with the control group. CONCLUSIONS: It was concluded that suryanamaskar is effective in leading to R-Dispositions like physical relaxation, mental quiet, at ease/peace, rested and refreshed, strength and awareness and joy and reduces sleepiness, somatic stress, worry and negative emotion at a dispositional level. PMID- 25558130 TI - Comparative effect of 12 weeks of slow and fast pranayama training on pulmonary function in young, healthy volunteers: A randomized controlled trial. AB - CONTEXT: Pranayamas are breathing techniques that exert profound physiological effects on pulmonary, cardiovascular, and mental functions. Previous studies demonstrate that different types of pranayamas produce divergent effects. AIM: The aim was to compare the effect of 12 weeks of slow and fast pranayama training on pulmonary function in young, healthy volunteers. SETTINGS AND DESIGN: This study was carried out in Departments of Physiology and ACYTER, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry in 2011. SUBJECTS AND METHODS: Ninety one healthy volunteers were randomized into slow pranayama group (SPG), n =29, fast pranayama group (FPG), n = 32 and control groups (CG) (n = 30). Supervised pranayama training (SPG: Nadisodhana, Pranav pranayama and Savitri pranayama; FPG: Kapalabhati, Bhastrika and Kukkriya pranayama) was given for 30 min/day, thrice/week for 12 weeks by certified yoga instructors. Pulmonary function parameters (PFT) such as forced vital capacity (FVC), forced expiratory volume in first second (FEV1), ratio between FEV1 and FVC (FEV1 /FVC), peak expiratory flow rate (PEFR), maximum voluntary ventilation (MVV), and forced expiratory flow25-75 (FEF25-75), were recorded at baseline and after 12 weeks of pranayama training using the computerized spirometer (Micro laboratory V1.32, England). RESULTS: In SPG, PEFR, and FEF25-75 improved significantly (P < 0.05) while other parameters (FVC, FEV1, FEV1 /FVC, and MVV) showed only marginal improvements. In FPG, FEV1 /FVC, PEFR, and FEF25-75 parameters improved significantly (P < 0.05), while FVC, FEV1, and MVV did not show significant (P > 0.05) change. No significant change was observed in CG. CONCLUSION: Twelve weeks of pranayama training in young subjects showed improvement in the commonly measured PFT. This indicates that pranayama training improved pulmonary function and that this was more pronounced in the FPG. PMID- 25558131 TI - Suryanamaskar: An equivalent approach towards management of physical fitness in obese females. AB - BACKGROUND: In India, obesity is highly prevalent in women as compared to men. As the obesity epidemic spreads, there are growing concerns about efficient obesity management. AIMS: To compare between circuit training (CT), treadmill (TM) walking and suryanamaskar (SN) training in weight management and physical fitness enhancement in obese females. SETTINGS AND DESIGNS: Comparative controlled study conducted in a community setting. MATERIALS AND METHODS: 119 females of age between 20 and 40 years of body mass index (BMI) between 25.1 and 34.9 kg/m(2). 87 participants completed the study. Group 1: CT; group 2: TM walking; group 3: Modified SN; group 4: Control. OUTCOME MEASURES: Body composition, cardio respiratory and muscle endurance, flexibility. STATISTICAL ANALYSIS: Within-group data was analyzed with the paired t-test. P =0.05. Analysis between the groups was done using one way ANOVA test. Analysis between the groups was done using ANCOVA test controlling for baseline differences only for those variables that have significant differences at baseline. For those which do not have significant difference at baseline, RMANOVA was done at end of 8 weeks. RESULTS: Reducation in mean body weight in CT group (2.2%), TM (1.7%) and SN (1.6%), (P < 0.05), BMI in all the three groups (P < 0.01), total body fat % in the CT (5%) and SN (3.7%), (P < 0.01), metabolic age with CT (2%) and TM (2%), (P = 0.001). Improvement in muscle mass in CT (4%, P = 0.009), VO2max in CT group by 17.2%, SN (14%), TM group (8%) (P < 0.05). Upper limb Muscle endurance in CT (51.3%), SN group (51.24%) and in TM group (40%), (P = 0.05), in lower limb TM (21.2%) and SN (24.5%) (P = 0.05), flexibility in SN (12.4%, P = 0.0001). CONCLUSIONS: All three methods were effective in weight and physical fitness management. CT and SN were more effective in improving cardio-respiratory fitness and upper limb muscle endurance while only SN was effective in improving body flexibility. PMID- 25558132 TI - Age related differences of selected Hatha yoga practices on anthropometric characteristics, muscular strength and flexibility of healthy individuals. AB - BACKGROUND: Physiological benefits of yoga on volunteers of a particular age group are available. However, reports on efficacy of a specific yoga package on the populace of different age groups from similar occupational background is still very limited. Therefore, the present study was conducted to appraise the effect of a specific Hatha yoga package on anthropometric characteristics, flexibility and muscular strength of healthy individuals of different age groups from similar occupational trade. MATERIALS AND METHODS: A total of 71 participants (Group All) from Indian Air Force ground personnel volunteered and age wise divided into 3 groups - (i) Group I (Gr. - I) (n1 = 27, 20-29 years), (ii) Group II (Gr. - II) (n2 = 21, 30-39 years) and (iii) Group III (Gr. - III) (n3 = 23, 40-49 years). All the participants undergone selected Hatha yoga training for 1 h daily for a period of 12 weeks. Parameters were recorded before and after the training. Pre and post training differences were assessed by Student's t-test. RESULTS: Body weight (All, Gr. - II and Gr. - III [all P < 0.05]), body mass index (Gr. - II and Gr. - III [both P < 0.01]) and fat% (Gr. - II and III [both P < 0.05]) were decreased significantly. Neck circumference was increased significantly in Gr. - I (P < 0.05) but decreased significantly in Gr. III (P < 0.05). Chest circumference (All (P < 0.001), in Gr. - I and II [both P < 0.05]), grip strength (All [left: P < 0.01 and right: P < 0.05], in Gr. - I [left: P < 0.05 and right: P < 0.01], in Gr. - II [right: P < 0.05] and in Gr. - III [left: P < 0.05 and right: P < 0.01]), back leg strength (group wise P < 0.001, P < 0.05, P < 0.01 and P < 0.05 respectively) and flexibility (all P < 0.001) were increased significantly. SUMMARY AND CONCLUSION: Hatha yoga can improve anthropometric characteristics, muscular strength and flexibility among volunteers of different age group and can also be helpful in preventing and attenuating age related deterioration of these parameters. PMID- 25558133 TI - Effectiveness of pranayama on cancer-related fatigue in breast cancer patients undergoing radiation therapy: A randomized controlled trial. AB - CONTEXT: Incidence of breast cancer is very high among women around the world. Breast cancer patients experience cancer-related fatigue at some points during the treatment for breast cancer. Since cancer-related fatigue is of multifactorial origin, there are no evidence-based treatment strategies for fatigue. This study tested the effectiveness of certain pranayama techniques in reducing cancer-related fatigue among breast cancer patients undergoing radiation therapy. AIMS: The objective of this study was to determine the effectiveness of pranayama on cancer-related fatigue among breast cancer patients undergoing radiation therapy as measured by cancer fatigue scale. SETTINGS AND DESIGN: Shirdi Sai Baba Cancer Hospital and Research Center, Kasturba Hospital Manipal. MATERIALS AND METHODS: Study was a randomized controlled trial done among breast cancer patients receiving radiation therapy. STATISTICAL ANALYSIS USED: Demographic characteristics of the participants are presented as frequency and percentage. Comparison of means of cancer-related fatigue between the two groups is done by Mann-Whitney U-test and comparison of pre- and pos t-test means of cancer-related fatigue among the experimental group is done by Wilcoxon sign rank test. RESULTS: There was a significant difference between the two groups with regard to the scores of cancer-related fatigue. The experimental group of patients who performed pranayama along with radiation therapy experienced less fatigue. CONCLUSIONS: Pranayama can be used as a supportive therapy for breast cancer patients undergoing radiation therapy. PMID- 25558134 TI - Yoga for correction of lymphedema's impairment of gait as an adjunct to lymphatic drainage: A pilot observational study. AB - INTRODUCTION: Yoga used as a major component of integrative treatment protocol in 14 Indian village camps improved quality-of-life in 425 lymphatic filariasis patients. They experienced better mobility and reduced disability. This paper documents the gait abnormalities observed in lower limb lymphedema patients and the locomotor changes following integrative treatment. MATERIALS AND METHODS: Yoga postures were performed as explained by traditional yoga practice in two sessions: Before ayurvedic oil massage without compression bandages and after the massage with compression bandages. Each yoga posture lasted for 5 min and the whole session ended in 45 min. Throughout each session, we advised patients to do long, diaphragmatic breathing, concentrating on each breath. The flexion of joints was coordinated with exhalation and extension with inhalation. We educated the patients to do longer expiration than inspiration. RESULTS AND DISCUSSION: A total of 98 patients (133 limbs) attending the 6(th) month follow-up were evaluated. The most common gait abnormality was antalgic gait. Structural and functional abnormalities were observed in hip, knee and ankle joints. We found that yoga as an adjunct to other components in integrative treatment improved the gait problems. Long standing lymphedema caused altered gait and joint deformities. This was mostly due to inactivity causing muscle weakness and edema within and around the muscles. Both large and small limbs have shown significant volume reduction (P < 0.01) during follow-up after 6 months. CONCLUSION: There can be a mixed etiology for gait related problems in lymphedema patients. Further studies are recommended to understand the causes of deformities in lymphedema patients and an exact role of yoga. PMID- 25558135 TI - Effect of yoga regimen on lung functions including diffusion capacity in coronary artery disease patients: A randomized controlled study. AB - BACKGROUND: Lung functions are found to be impaired in coronary artery disease (CAD), congestive heart failure, left ventricular dysfunction, and after cardiac surgery. Diffusion capacity progressively worsens as the severity of CAD increases due to reduction in lung tissue participating in gas exchange. AIMS AND OBJECTIVES: Pranayama breathing exercises and yogic postures may play an impressive role in improving cardio-respiratory efficiency and facilitating gas diffusion at the alveolo-capillary membrane. This study was done to see the effect of yoga regimen on lung functions particularly diffusion capacity in CAD patients. MATERIALS AND METHODS: A total of 80 stable CAD patients below 65 years of age of both sexes were selected and randomized into two groups of 40 each. Group I CAD patients were given yoga regimen for 3 months which consisted of yogic postures, pranayama breathing exercises, dietary modification, and holistic teaching along with their conventional medicine while Group II CAD patients were put only on conventional medicine. Lung functions including diffusion capacity were recorded thrice in both the groups: 0 day as baseline, 22(nd) day and on 90(th) day by using computerized MS medisoft Cardio-respiratory Instrument, HYP'AIR Compact model of cardio-respiratory testing machine was manufactured by P K Morgan, India. The recorded parameters were statistically analyzed by repeated measures ANOVA followed by Tukey's test in both the groups. Cardiovascular parameters were also compared before and after intervention in both the groups. RESULTS: Statistically significant improvements were seen in slow vital capacity, forced vital capacity, peak expiratory flow rate, maximum voluntary ventilation, and diffusion factor/ transfer factor of lung for carbon monoxide after 3 months of yoga regimen in Group I. Forced expiratory volume in 1(st) sec (FEV1), and FEV1 % also showed a trend toward improvement although not statistically significant. HR, SBP and DBP also showed significant improvement in Group-I patients who followed yoga regimen. CONCLUSIONS: Yoga regimen was found to improve lung functions and diffusion capacity in CAD patients besides improving cardiovascular functions. Thus, it can be used as a complimentary or adjunct therapy along with the conventional medicine for their treatment and rehabilitation. PMID- 25558136 TI - Effect of yoga regimen on lung functions including diffusion capacity in coronary artery disease patients. PMID- 25558137 TI - Immediate effect of mind sound resonance technique on state anxiety and cognitive functions in patients suffering from generalized anxiety disorder: A self controlled pilot study. AB - OBJECTIVES: To compare the immediate effect of mind sound resonance technique (MSRT) with supine rest (SR) on state anxiety and psychomotor performance in 15 (eight male and seven female) right-handed generalized anxiety disorder patients (GAD) with an age range of 34.8 +/- 12.8 years. MATERIALS AND METHODS: Self as control design was followed. Diagnosis of GAD was made by a psychiatrist using sections of the Mini International Neuropsychiatric Interview (MINI). Participants practiced MSRT or SR (as control intervention) for 30 min at the same time for two consecutive days. The sequence of intervention was assigned randomly to the participants. State anxiety was assessed using state trait anxiety inventory (STAI; Form X1). Digit letter substitution task (DLST) was used to assess psychomotor performance, which involves visual scanning, mental flexibility, sustained attention, psychomotor speed and speed of information processing. Intervention was given in a quiet dark room on an empty stomach. Subjects received a training of MSRT and SR for 1 week before the data were taken. A pre-recorded audiotape was used to administer the technique of MSRT. Difference in scores after baseline and intervention was used to check normality, and was found to be normally distributed by the Kolmogrov-Smirnov test. The changes in STAI, DLST and difference in scores before and after two interventions (MSRT and SR) were compared using the paired samples t test. RESULTS: As compared with baseline, STAI scores reduced and DLST scores increased significantly (STAI; P < 0.01; DLST; P < 0.01) after MSRT. After SR, there was a significant reduction in STAI scores from baseline (STAI; P < 0.05), but there was no significant change in the DLST scores (P = 0.26). Comparison of the difference in scores for DLST and STAI before and after the two interventions (MSRT and SR) showed a significantly higher score for DLST (P < 0.05) and a significantly lower score for STAI (P < 0.01) for MSRT as compared with SR. CONCLUSION: This pilot study suggests that MSRT may have a potential role in reducing state anxiety and enhancing psychomotor performance in patients suffering from GAD immediately after the practice. These findings need confirmation from studies with a larger sample size and randomized controlled design, which are implicated in the future. PMID- 25558138 TI - A randomized controlled pilot study of the therapeutic effects of yoga in people with Parkinson's disease. AB - BACKGROUND: Exercise can be beneficial for cardiopulmonary, musculoskeletal or neurological systems, and other factors including mood, and may be beneficial in reducing fall risks, dementia and variables associated with quality of life (QOL). Parkinson's disease (PD) produces progressive motor and cognitive deterioration that may leave those inflicted unable to participate in standard exercise programs. Alternative forms of exercise such as yoga may be successful in improving physical function, QOL and physiological variables for overall well being. AIM: This randomized controlled pilot study investigated the effectiveness of yoga intervention on physiological and health-related QOL measures in people with PD. METHODS AND MATERIALS: Thirteen people with stage 1-2 PD were randomized to either a yoga (n = 8) or a control group (n = 5). The yoga group participated in twice-weekly yoga sessions for 12 weeks. Participants were tested at baseline, and at 6 and 12 weeks using the Unified Parkinson's Disease Rating Scale (UPDRS), clinical measures of health-related QOL and physiological measures. RESULTS: Significant improvement in UPDRS scores (P = .006), diastolic blood pressure (P = 0.036) and average forced vital capacity (P = 0.03) was noted in the yoga group over time. Changes between groups were also noted in two SF-36 subscales. Positive trends of improvement were noted in depression scores (P = 0.056), body weight (P = 0.056) and forced expiratory volume (P = 0.059). Yoga participants reported more positive symptom changes including immediate tremor reduction. CONCLUSIONS: The results suggest that yoga may improve aspects of QOL and physiological functions in stages 1-2 PD. Future larger studies are needed to confirm and extend our findings of the effects of yoga in PD. PMID- 25558139 TI - Need for revised protocol of heart rate variability for sequential evaluation of physiological changes in yoga. PMID- 25558140 TI - Trataka and cognitive function. PMID- 25558141 TI - Response to "trataka and cognitive function". PMID- 25558142 TI - Not neural deformation or compression but instability is the cause of symptoms in degenerative spinal disease. PMID- 25558143 TI - The music of movement - in health - n - disease. PMID- 25558144 TI - Describing a new syndrome in L5-S1 disc herniation: Sexual and sphincter dysfunction without pain and muscle weakness. AB - CONTEXT: Little seems to be known about the sexual dysfunction (SD) in lumbar intervertebral disc herniation. AIMS: Investigation of sexual and sphincter dysfunction in patient with lumbar disc hernitions. SETTINGS AND DESIGN: A retrospective analysis. MATERIALS AND METHODS: Sexual and sphincter dysfunction in patients admitted with lumbar disc herniations between September 2012-March 2014. STATISTICAL ANALYSIS USED: Statistical analysis was performed using the Predictive Analytics SoftWare (PASW) Statistics 18.0 for Windows (Statistical Package for the Social Sciences, SPSS Inc., Chicago, Illinois). The statistical significance was set at P < 0.05. The Wilcoxon signed ranks test was used to evaluate the difference between patients. RESULTS: Four patients with sexual and sphincter dysfunction were found, including two women and two men, aged between 20 and 52 years. All of them admitted without low back pain. In addition, on neurological examination, reflex and motor deficit were not found. However, almost all patients had perianal sensory deficit and sexual and sphincter dysfunction. Magnetic resonance imaging (MRI) of three patients displayed a large extruded disc fragment at L5-S1 level on the left side. In fourth patient, there were not prominent disc herniations. There was not statistically significant difference between pre-operative and post-operative sexual function, anal urethral sphincter function, and perianal sensation score. A syndrome in L5-S1 disc herniation with sexual and sphincter dysfunction without pain and muscle weakness was noted. We think that it is crucial for neurosurgeons to early realise that paralysis of the sphincter and sexual dysfunction are possible in patients with lumbar L5-S1 disc disease. CONCLUSION: A syndrome with perianal sensory deficit, paralysis of the sphincter, and sexual dysfunction may occur in patients with lumbar L5-S1 disc disease. The improvement of perianal sensory deficit after surgery was counteracted by a trend toward disturbed sexual function. Further researches are needed to explore the extent of this problem. PMID- 25558145 TI - Optimal measurement for "posterolateral protrusion" of the vertebral artery at the craniovertebral junction using computed tomography angiography. AB - PURPOSE: Among extraosseous abnormalities of the vertebral artery (VA) at the craniovertebral junction (CVJ), available evidence regarding "posterolateral protrusion," the VA running distant from the groove over the superior surface of the posterior arch of the atlas, is limited. The purpose of this study was to determine the optimal measurement to indicate posterolateral protrusion of the VA. MATERIALS AND METHODS: Computed tomography angiography (CTA) images of 40 consecutive patients with cervical disease were reviewed. Ultimately, 66 arteries were included in this study. Five parameters predicted to indicate posterolateral protrusion of the VA were defined (A-E) and measured by two surgeons twice over a 2-week interval. Intraclass correlation coefficients (ICC) were used to examine intra-observer reproducibility and inter-observer reliability. Receiver operating characteristic (ROC) curve analysis was performed to determine the most optimal parameter to predict posterolateral protrusion of the VA. RESULTS: Excellent inter-observer reliability and intra-observer reproducibility were obtained for all parameters (ICC = 0.87-0.99). Among them, parameter A, defined as the maximal length from the outer surface of the VA to the outer surface of the posterior arch of the atlas, was most accurately described posterolateral protrusion of the VA. The optimal cut-off value of parameter A obtained with ROC curves was 8.3 mm (sensitivity 97.5%, specificity 100%). CONCLUSIONS: The measurement in this study can quantitatively evaluate the posterolateral protrusion of the VA. Before posterior surgery at the CVJ, pre-operative CTA can help surgeons detect anomalous VA and reduce the risk of intra-operative VA injury. PMID- 25558146 TI - Quantitative morphometric analysis of the lumbar vertebral facets and evaluation of feasibility of lumbar spinal nerve root and spinal canal decompression using the Goel intraarticular facetal spacer distraction technique: A lumbar/cervical facet comparison. AB - OBJECTIVE: The authors evaluate the anatomic subtleties of lumbar facets and assess the feasibility and effectiveness of use of 'Goel facet spacer' in the treatment of degenerative spinal canal stenosis. MATERIALS AND METHODS: Twenty five lumbar vertebral cadaveric dried bones were used for the purpose. A number of morphometric parameters were evaluated both before and after the introduction of Goel facet spacers within the confines of the facet joint. RESULTS: The spacers achieved distraction of facets that was more pronounced in the vertical perspective. Introduction of spacers on both sides resulted in an increase in the intervertebral foraminal height and a circumferential increase in the spinal canal dimensions. Additionally, there was an increase in the disc space or intervertebral body height. The lumbar facets are more vertically and anteroposteriorly oriented when compared to cervical facets that are obliquely and transversely oriented. CONCLUSIONS: Understanding the anatomical peculiarities of the lumbar and cervical facets can lead to an optimum utilization of the potential of Goel facet distraction arthrodesis technique in the treatment of spinal degenerative canal stenosis. PMID- 25558147 TI - Traumatic atlantoaxial rotatory fixation associated with C2 articular facet fracture in adult patient: Case report. AB - Traumatic atlantoaxial rotatory fixation is a very rare injury in adults which is often misdiagnosed initially. Its combination with C2 fractures is predominated by dens lesions. Therapeutic management is challenging because of the difficulty to achieve optimal reduction and permanent stability. We report a rare case of traumatic atlantoaxial rotatory fixation in a 56-year-old women associated with C2 articular facet fracture successfully treated by conservative means after patient-awake manual reduction with optimal functional and radiographic outcome. PMID- 25558148 TI - Radiculopathy due to spontaneous facetal cyst hemorrhage. AB - Facetal cysts are usually encountered as incidental radiological findings in spinal imaging studies. Only rarely can neurological symptoms be attributed to them. These cysts are lined by vascularized synovial tissue. There are few reports in literature of hemorrhagic transformation in these cysts with sudden increase in size precipitating symptoms acutely. We report one such case where the existence of a hitherto undiagnosed cyst was unmasked by the haemorrhage. There is a need to be aware of this complication in patients with untreated or incidentally diagnosed cysts so that any sudden neurological deterioration can be dealt with promptly. PMID- 25558149 TI - Occipitalized os odontoideum: A case report. AB - We report on a 36-year-old man presenting with a sudden onset of motor weakness and numbness in the upper extremities following a fall from a truck bed. Radiological findings demonstrated an os odontoideum and osseous continuity between the occiput and an ossicle, termed an "occipitalized os odontoideum." The occipitalized ossicle and atlas moved as a functional unit from the body of the axis. He underwent atlantoasxial stabilization with an atlas lateral mass screw and axis pedicle screw. Eighteen months later, he remained free of symptoms and showed solid bone fusion. Atlantoaxial stabilization resulted in an excellent clinical outcome for this condition. Our report provides useful knowledge regarding treatment of extremely rare osseous anomalies in the craniovertebral junction. PMID- 25558150 TI - Lumbosacral actinomycosis in an immunocompetent individual: An extremely rare case. AB - Actinomycosis is a gram positive commensal bacteria. In predisposed individuals like immunocompromised patients, it can cause myriad lesions involving virtually any organ of the body. Involvement of spinal cord with its compression is rare though. We are reporting here a case of 30-year-old immunocompetent male who presented with weakness of left lower limb. Radiologically differential diagnosis was tuberculosis or lymphoma of spinal cord. Histopathology showed actinomycotic colonies that were periodic Schiff (PAS) positive and revealed gram positive filamentous bacteria. PMID- 25558151 TI - Complete absence of the posterior arch of C1: Case report. AB - Posterior atlas arch anomalies are relatively common, but have a variety of presentations ranging from partial clefts to complete agenesis of the posterior arch. Partial clefts are prevalent in 4% of patients and are generally asymptomatic. However, complete agenesis of the posterior arch is extremely rare. We report the case of a 46-year-old man who presented with upper cervical spine and occipital pain as well as left sided headaches. Imaging revealed congenital complete absence of the posterior arch of C1 (Type E) without any radiographic evidence of instability. We discuss our case in light of other reported cases and detail its management. PMID- 25558152 TI - Credential evidences of Ayurvedic cardio-vascular herbs. PMID- 25558153 TI - Natural medicaments in dentistry. AB - The major objective in root canal treatment is to disinfect the entire root canal system. Cleaning, shaping, and use of antimicrobial medicaments are effective in reducing the bacterial load to some extent, but some bacteria do remain behind and multiply, causing reinfection. Taking into consideration the ineffectiveness, potential side-effects and safety concerns of synthetic drugs, the herbal alternatives for endodontic usage might prove to be advantageous. Over the past decade, interest in drugs derived from medicinal plants has markedly increased. Phytomedicine has been used in dentistry as anti-inflammatory, antibiotic, analgesic, sedative and also as endodontic irrigant. Herbal preparations can be derived from the root, leaves, seeds, stem, and flowers. The PubMed database search revealed that the reference list for natural medicaments featured 1480 articles and in dentistry 173 articles. A forward search was undertaken on the selected articles and author names. This review focuses on various natural drugs and products as well as their therapeutic applications when used as phytomedicine in dentistry. PMID- 25558154 TI - Some basic aspects of statistical methods and sample size determination in health science research. AB - A health science researcher may sometimes wonder "why statistical methods are so important in research?" Simple answer is that, statistical methods are used throughout a study that includes planning, designing, collecting data, analyzing and drawing meaningful interpretation and report the findings. Hence, it is important that a researcher knows the concepts of at least basic statistical methods used at various stages of a research study. This helps the researcher in the conduct of an appropriately well-designed study leading to valid and reliable results that can be generalized to the population. A well-designed study possesses fewer biases, which intern gives precise, valid and reliable results. There are many statistical methods and tests that are used at various stages of a research. In this communication, we discuss the overall importance of statistical considerations in medical research with the main emphasis on estimating minimum sample size for different study objectives. PMID- 25558155 TI - Consequences of excessive use of Amlarasa (sour taste): A case-control study. AB - BACKGROUND: Palatability is an important factor for choice of food by an individual. Amlarasa (sour taste) is one of the main organoleptic entities in foods of present day, which always tempts the consumer to take it now and then. According to classical Ayurvedic texts, balanced intake of Amlarasa in diet helps to maintain physiological health, but its excessive intake produces some signs and symptoms such as dentine hypersensitivity, stomatitis, halitosis, heartburn, urticaria, papule and joint inflammation. AIM: To establish the relationship between excessive use of sour predominant diets and signs/symptoms produced by it. MATERIALS AND METHODS: A case-control survey study was designed wherein total of 178 volunteers were interviewed personally. Subjects with particular symptoms consider as a cases while healthy volunteers as controls. To measure the excessive intake of Amlarasa, quantity and frequency of common food articles such as mango, tomato, lime, butter milk, tamarind, curd, fermented items etc., are taken into consideration. Data was arranged in to 2 * 2 table and odd ratio was calculated for each symptom. RESULTS: Odds ratio for dentine hypersensitivity, stomatitis, halitosis, heartburn, urticaria, papule and joint inflammation with 95% confidence interval were found 1.95 (0.97-3.93), 2.45 (1.12-5.40), 2.76 (0.96 7.98), 2.21 (1.09-4.53), 0.86 (0.32-2.32), 2.28 (1.02-5.05) and 4.85 (1.09-10.24) respectively. CONCLUSION: Study reveals that Amlarasa is a risk factor for joint inflammation, dentine hypersensitivity, stomatitis, halitosis, heartburn and papules. Study supports the Ayurvedic classical claim regarding Atiyoga of Amlarasa. PMID- 25558156 TI - An observational pilot study on the effect of Gomutra Haritaki, diet control and exercise in the management of Sthaulya (obesity). AB - BACKGROUND: India is currently witnessing rising numbers of people in the middle class who are obese. A lot of the Indian population has started relying on processed foods that contain a huge percentage of trans-fat, sugars, and other unhealthy and artificial ingredients. Obesity is considered the core of many diseases. Increased weight carries significant health risks for some cancers, diabetes, heart diseases and strokes. Junk food, alcohol and sedentary lifestyle are leading us to silent self destruction, making one in every five Indian men and women either obese or overweight. AIM: To determine the effect of Gomutra Haritaki on Sthaulya. MATERIALS AND METHODS: An observational pilot study on the effect of Gomutra Haritaki, diet control and exercise in the management of Sthaulya (obesity) was conducted on 21 patients. Enrolled patients were screened on the basis of clinical findings and allocated into two groups. Trial group received Gomutra Haritaki (6 g/day in three divided doses) while control group received placebo capsules in the same dose for 8 weeks. RESULT: Statistically highly significant relief was found in weight reduction (P < 0.001), and body mass index (BMI) (P < 0.01) in both groups. Control group has shown better results against trial group. CONCLUSION: These results prove the impact of diet and exercise in the management of Sthaulya. PMID- 25558157 TI - A clinical study on the efficacy of Panchavalkala cream in Vrana Shodhana w.s.r to its action on microbial load and wound infection. AB - BACKGROUND: The science of wound healing is advancing rapidly, particularly as a result of new therapeutic approaches. The wound healing effect of different herbal ointments have been enormous and are in wide practice these days. AIM: To evaluate the efficacy of Panchavalkala cream over wound debridement (wound infection and microbial load). MATERIALS AND METHODS: Ghanasatwa (water extract) of the individual drugs of Panchavalkala was prepared and the extract formulated as herbal ointment. This was used to treat patients of infected chronic non healing wounds. The signs and symptoms of infection were graded before and during the course of treatment. Tissue biopsy to estimate the microbial load prior to and during the course of treatment was done. RESULTS: The clinical symptoms like Slough, swelling, redness, pain, discharge, tenderness, and malodor in wounds showed statistically significant reduction following treatment. The microbial load of the wounds was also reduced significantly. CONCLUSION: In most of the cases, there was a progressive reduction in the microbial load with time, during the course of treatment indicating the efficacy of the formulation in reducing the microbial load and thus controlling infection, facilitating wound healing. PMID- 25558158 TI - Comparative study of Ksharasutra suturing and Lord's anal dilatation in the management of Parikartika (chronic fissure-in-ano). AB - BACKGROUND: Parikartika resembles fissure-in-ano which is very common among all ano-rectal disorders. In Ayurvedic texts, Parikartika is described as a complication of Vamana and Virechana as well as complication of Atisara. Ksharasutra was proved successful in the management of fistula-in-ano, piles, and there is a need to try its efficacy in fissure-in-ano. AIM: To evaluate the role of Ksharasutra suturing (KSS) in fissure bed in chronic fissure-in-ano. MATERIALS AND METHODS: Total 100 patients of chronic fissure-in-ano were selected and randomly divided into two groups (50 in each group). In group-A, patients were undergone by KSS; while in patients of Group-B Lord's anal dilatation followed by KSS was done under spinal anesthesia. The KSS was done once and after slough out of Ksharasutra, the wound was treated for 4 weeks and assessment of the result was done on the basis of gradation adopted. RESULTS: The pain relief on 14(th) day in Group-A was 86% while in Group-B 100% was observed. As on 7(th) day in Group-A, oozing was stopped in 68% patients, while in Group-B, oozing was stopped in 82% patients. On 21(st) day, Group-B showed more healing (85%) as compared to Group-A (69%). In this study 68% of patients were cured. CONCLUSION: In Group-B (KSS with Lord's anal dilatation) patients were cured early as compared to patients of Group-A (KSS alone). PMID- 25558159 TI - Effect of anuvasana basti with ksheerabala taila in sandhigata vata (osteoarthritis). AB - BACKGROUND: Osteoarthritis (OA) is the most common joint disorder. In Ayurveda the disease Sandhigata Vata resembles with OA, which is described under Vatavyadhi. Treatment provides symptomatic relief, but the underlying pathology remains unchecked due to the absence of effective drugs. In the management of Sandhigata Vata, all the Acharyas have described the employment of Bahya Snehan, Swedana, Abhyantara Tikta Snehapana, Basti treatment and Guggulu Prayoga. AIM: To evaluate the effect of Ksheerbala Taila Anuvasana Basti in Sandhigata Vata. MATERIALS AND METHODS: In the present study, 30 patients of Sandhigata Vata were given Anuvasana Basti with Ksheerabala Taila. Subjective assessment of pain by visual analog scale and swelling, tenderness, crepitus and walking velocity were graded according to their severity. RESULTS: Significant results (P < 0.05) were found in all the cardinal symptoms - Pain (Sandhiruja), Swelling (Shotha), tenderness, crepitus and walking velocity. Radiological findings showed no significant changes. CONCLUSION: Anuvasana Basti with Ksheerabala Taila was significant in the subjective symptoms of Sandhigata Vata. PMID- 25558160 TI - A comparative clinical study of Asanadi Ghanavati and Gomutra Haritaki in Kapha Medo Margavarana (dyslipidemia). AB - BACKGROUND: Dyslipidemia is a disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency and it can be understood in the parlance of the closest conditions in Ayurveda, viz. Kapha Medo Margavarana (dyslipidemia), Atisthaulya (obesity) or Meda Roga and Prameha. Asanadi Ghanavati (AG) is a modified presentation of Asanadi Gana drugs referred in Ashtanga Hridaya and Gomutra Haritaki (GH) is described in Charaka Samhita under Shotha Chikitsa and Ashtanga Hridaya in Arsha Chikitsa. AIM: To evaluate and compare the clinical effect of AG and GH in Kapha Medo Margavarana. MATERIALS AND METHODS: Patients with the high lipid profile were selected and randomly divided into two groups. In Group A (n = 30), patients were administered with tablet of AG 1 g (500 mg each) thrice a day for 8 weeks and in Group B (n = 30), tablet of GH in similar dose and duration. Effect of therapy was assessed by body circumference, Body Mass Index (BMI), cardinal symptoms like Anga-Gaurava, Bharavriddhi, etc., and lipid profile parameters. RESULT: AG decreased the serum cholesterol by 7.12%, Serum Triglyceride (S. TG) by 7.72%, Serum Low Density Lipoprotein (S. LDL) by 11.68%, Serum Very Low Density Lipoprotein (S. VLDL) by 7.73%, and had increased Serum High Density Lipoprotein (S. HDL) by 9.52%, with moderate improvement in 14.81% and mild improvement in 70.37% of patients. The GH decreased the serum cholesterol by 6.31%, S. TG by 9.61%, S. LDL by 12.55%, serum VLDL by 8.99%, and increased S. HDL by 10.52% with moderate improvement in 3.70%, and mild improvement in 74.07% patients. CONCLUSION: AG and GH are suggested to be used in Kleda Bahul Samprapti Janya Vyadhi and Ama Bahul Samprapti Janya Vyadhi respectively. PMID- 25558161 TI - Low resource screening method of pre-cancerous lesions and its reversal by Triphala in teen-age Indian population. AB - BACKGROUND: Cancer screening is the main weapon for early detection at a pre invasive or premalignant stage. It has been reported that over 12 million people use some form of tobacco, which is one of the high risk factors and has hence become an alarming world-wide problem. AIM: To evaluate the effective diagnostic screening of disease in its early stage by inexpensive method and also to evaluate the effect of indigenous mouthrinse on reversal of pre-cancerous lesions. MATERIALS AND METHODS: The screening for teenagers belonging to low socio-economic status was carried out. Suspected subjects were evaluated for the reversal of the lesions by use of Ayurvedic preparation as a mouthwash. From 13 to19 years working-child population of North India was selected for the study. Screening was performed by new method-visual inspection with acetic acid. The positive subjects were further investigated by pap smear and biopsy was done as a confirmatory histopathological report. In second phase, the subjects showing positive lesions were advised indigenous anti-cancer mouth rinse and its effect was evaluated after 6 month and 9 month of prescribing the rinse. RESULTS: The total 1095 children were screened (831 boys and 264 girls). Out of total 34 teenager boys were diagnosed, as acetowhite positive lesion. All the acetowhite positive lesions were found exclusively in males. Histological findings after 9 month use of Triphala mouth rinse revealed no changes in cells in 23 (85.2%), hyperkeratinization in 2 (7.4%), hyperkeratinization and spongiosis was evident in 1 (3.7%), mild pleomorphism in 1 (3.7%) patient. Comparative evaluation from 0 9 month showed statistically highly significant test (P < 0.01). CONCLUSION: Use of different forms of tobacco and betel nut showed convincing relationship between developments of oral pre-cancerous lesions. Triphala was found to have great potential for reversal of these lesions. PMID- 25558163 TI - Topical application of Katupila (Securinega leucopyrus) in Dushta Vrana (chronic wound) showing excellent healing effect: A case study. AB - Securinega leucopyrus (Willd.) Muell. is known as Humari in India, Katupila in Sri Lanka and Spinous fluggea in English. It is a desert climatic plant used topically in paste form for healing of chronic and non-healing wounds. Application of Katupila Kalka (paste) is used commonly in the management of acute as well as chronic wounds in Sri Lanka as a folklore medicine. The aim of this study is to evaluate the role of herbal paste of Katupila in the treatment of Dushta Vrana (chronic wound). It is a single observational innovative case study. A female aged 40 years presented with a non-healing infected wound on her right buttock with a history of 2 months. On examination, there was a rounded wound having black color necrosed tissue and slough with foul smelling, measuring about 3 inch * 3 inch * 1 inch in diameter caused by pyogenic local infection. The routine laboratory investigations were within normal limit except hemoglobin and the swab culture test of the wound bed was reported infection of Staphylococcus aureus. This case study showed effective wound healing by topical application of Katupila paste and sesame oil. PMID- 25558162 TI - Efficacy of Varunadi Ghritha (polyherbal compound) in treated head and neck cancer cases as a biological response modifier. AB - BACKGROUND: Persistent immune suppression is reported in Head and Neck Cancers (HNC) even after treatment and a higher recurrence rate was observed in patients with poor CD3 count. Loco regional recurrences and second primary tumours are the common forms of failure in head and neck cancers. Several agents have been tried to overcome this problem without much benefit. In Ayurveda, several plant based products have been reported to have anti-tumour and immunomodulatory properties. AIM: To test the role of Varunadi Ghritha, as an immunomodulator in apparently healthy, treated and controlled HNC patients and to evaluate its effectiveness in preventing locoregional relapses and development of second primary tumours. MATERIALS AND METHODS: Total 78 patients of treated head and neck cancers were randomly selected for intervention and control group. Patients in the intervention group (n = 38) received Varunadi Ghritha, 5gms twice daily for one year and followed up to two years. Patients in the control group (n = 40) were followed up at regular intervals. Immune parameters were assessed in the peripheral blood at base line and at the end of administration of the study compound. RESULTS: In the intervention group, mean percentage increase in CD3, CD19 and CD16 positive cells were significantly higher after the administration of the study compound compared to the control group indicating an immunomodulatory effect of the study compound. A non-significant improvement in disease control was observed in patients with advanced stage of disease in the intervention group. CONCLUSION: Administration of Varunadi Ghritha resulted in an increase in T cell counts in patients with treated HNC. PMID- 25558164 TI - Role of thin-layer chromatography in ascertaining Kashaya Rasa (astringent taste) in medicinal plants on the concept of Samana and Vichitra Pratyayarabdha principles of Ayurveda. AB - BACKGROUND: Pharmacodynamics, in Ayurveda has been described in terms of Rasadipanchaka. Rasa, on one side indicates the Bhautika composition of the drug and on the other side predicts the action. Different analytical techniques, pharmaceutical processes are being used in Ayurveda for the purpose of standardization of raw drugs. AIM: In this study an attempt has been made to apply chromatographic technique in determination of Kashaya (astringent) Rasa (taste). MATERIALS AND METHODS: Two important Kashaya dominant drugs Kulattha (Dolichos biflorus Linn.) and Kanchanara (Bauhinia variegata Linn.), falling under Vichitra and Samana Pratyayarabdha category respectively, were subjected to physicochemical parameters and qualitative tests followed by High-Performance Thin-Layer Chromatography (HPTLC). In light of chromatographic fingerprinting; sample preparation protocol is modified to incorporate taste threshold in correlation. Column chromatography is used for first-level discrimination technique followed by HPTLC. Kashaya Rasa Dominant Zone (KsRDZ) was separated and subjected to TLC fingerprinting. The KsRDZ fraction was designated as Botanical Reference Material (BRM) in further analysis. RESULTS: Ash value, Alcohol and water soluble extract value were more in B variegata as compared to D biflorus. Presence of tannin in both the samples was confirmed through qualitative test. The KsRDZ fraction separated at Rf 0.46 and 0.48 for Kulattha and Kanchanara respectively. CONCLUSION: The results showed that the planner chromatography technique seems very useful when BRM hypothesis was adjunct to method that explains the categorization according to traditional Rasa domain classification method. PMID- 25558165 TI - Shelf-life evaluation of Rasayana Churna: A preliminary study. AB - BACKGROUND: Concept of Saviryta Avadhi (shelf-life) of Ayurvedic dosage forms is well-defined in classics of Ayurveda. Information on this is scattered in initial classics of Ayurveda like Charaka Samhita, but focused well after 13(th) Century AD in texts such as Vangasena Samhita, Sharangadhara Samhita and Yogaratnakara. Though the concepts have a strong background; considering the pharmaceutical development, a need is felt to re-evaluate the age old concepts by following current norms. AIM: To evaluate shelf-life of two samples of Rasayana Churna. MATERIALS AND METHODS: Raw material was procured from The Pharmacy, Gujarat Ayurved University and authenticated at Pharmacognosy Laboratory. Individual drugs were powdered and blended in specified ratio to obtain Rasayana Churna (RC). RC was levigated with decoction of Amalaki, Guduchi and Gokshura to prepare Bhavita Rasayana Churna (BRC). Both the samples were subjected to accelerated stability studies by following standard guidelines. RESULTS: Both the samples are bitter and astringent with characteristic odor. RC is creamish brown in colour, while BRC is dark blackish brown. These Organoleptic characters were unchanged till the 6(th) month of study. On comparision, BRC is found to be more stable than RC. CONCLUSION: This signifies that, Bhavana not only incorporates additional therapeutic attributes, but also helpful in increasing shelf-life. PMID- 25558166 TI - Hypoglycemic and antihyperglycemic activity of Saptarangyadi Ghanavati: An Ayurvedic compound formulation. AB - BACKGROUND: Diabetes mellitus is a persistent health problem that requires innovative strategies to improve health and needs a multifactorial approach for the treatment. Saptarangyadi Ghanavati, a formulated Ayurvedic compound consists of herbs with anti-diabetic potential. AIM: To evaluate the hypoglycemic and antihyperglycemic activities of Saptarangydi Ghanavati. MATERIALS AND METHODS: For hypoglycemic activity 18 Swiss albino mice were divided into three groups (6 in each). First group served as normal control, second group is the test drug and third is the standard control group. For antihyperglycemic activity 24 Swiss albino mice were divided into four groups (6 in each). First group served as water control, second negative control, third test drug and fourth as standard control group. Test drug Saptarangydi Ghanavati was suspended in water and administered to animals at the dose of 400 mg/kg. Glibenclamide was used as reference standard in both the models at the dose of 0.65 mg/kg. RESULTS: Saptarangyadi Ghanavati showed mild reduction in Blood Sugar Level (BSL) at all the time intervals in normoglycemic mice; however, the observed decrease of BSL was found to be statistically non significant. In antihyperglycemic activity, even though the drug failed to cease the hyperglycemia in the first hour after the glucose overload, it attenuated the same in later hours in nonsignificant extent. CONCLUSION: The study reveals that Saptarangydi Ghanavati has moderate hypoglycemic and antihyperglycemic effect. PMID- 25558167 TI - The evaluation of anti-ulcerogenic effect of rhizome starch of two source plants of Tugaksheeree (Curcuma angustifolia Roxb. and Maranta arundinacea Linn.) on pyloric ligated rats. AB - BACKGROUND: In the present era, because of the life-style, the disorders such as hyperacidity and gastric ulcers are found very frequently. Satwa (starch) obtained from the rhizomes of two plants namely Curcuma angustifolia Roxb. and Maranta arundinacea Linn. are used in folklore practice for the treatment of above complaints under the name Tugaksheeree. AIM: To compare the anti ulcerogenic activity of the above two drugs in pyloric ligation induced gastric ulcer in albino rats. MATERIALS AND METHODS: A total of 18 Wistar strain albino rats of both sexes grouped into three groups. Group C served as pyloric ligated control group, Group I received starch of C. angustifolia suspension and Group II received starch of M. arundinacea for seven days. On 8(th) day pylorus was ligated. After ligation the animals were deprived of food and water and sacrificed at the end of 14 h. The collected gastric contents were used for biochemical estimation and ulcer index was calculated from excised stomach. RESULTS: Both the test drugs showed statistically significant decrease in the volume, increase in the pH, reduced the free acidity of gastric juice and decreased the peptic activity. The starch of C. angustifolia reduced a total acidity non-significantly while M. arundinacea reduced it significantly. Among the two drugs the M. arundinacea has effectively reduced the peptic activity, which is statistically significant. M. arundinacea shown statistically significant increase of total carbohydrates. CONCLUSION: Both the test drugs proved anti-ulcer activity and prevents the chance of gastric ulcer. Among these two M. arundinacea is more effective. PMID- 25558168 TI - Evaluation of a topical herbal drug for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis. AB - BACKGROUND: Antibiotics have been in use in the treatment of bovine mastitis since decades; however, their use is associated with cost issues and human health concern. Use of herbal drugs does not generally carry these disadvantages. Many plants/herbs have been evaluated in the treatment of bovine mastitis with additional property of immunomodulation in affected mammary gland. AIM: To evaluate a topical herbal drug in two breeds of cattle for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis. MATERIALS AND METHODS: The response to treatment was evaluated by enumerating somatic cell count (SCC), determining total bacterial load, and studying the expression of different cytokines (interleukin [IL]-6, IL 8, IL-12, granulocyte macrophage-colony stimulating factor, interferon (IFN) gamma and tumor necrosis factor [TNF]-alpha). RESULTS: The pre- and post treatment SCC in mastitic quarters statistically did not differ significantly, however, total bacterial load declined significantly from day 0 onwards in both the breeds. Highly significant differences (P < 0.01) were observed in all the cytokines on day 0, 5, and 21 postlast treatment in both the breeds. The expression level of all the cytokines showed a significant increase on day 5, while a decrease was noticed on day 21 in both the breeds of cattle. The comparison of cytokine expression profiles between crossbred and Gir cattle revealed a significant difference in expression of IL-6 and TNF-alpha. However, other cytokines exhibited a similar pattern of expression in both breeds, which was non-significant. CONCLUSION: The topical herbal drug exhibited antibacterial and immunomodulatory activities in subclinical mastitis and thus the work supports its use as alternative herbal therapy against subclinical udder infection in bovines. PMID- 25558169 TI - Microbial evaluation of Limnophila rugosa Roth. (Merr) leaf. AB - BACKGROUND: Limphonia rugosa Roth. (Merr.), family-Scrophulariaceae is considered as a botanical source of classical Ayurvedic drug Bhringaraja by the traditional practitioners of Odisha and is being used for the management of various disorders. AIM: To study the antimicrobial activity of leaf of L. rugosa. MATERIALS AND METHODS: Methanol extract of L. rugosa leaf (LRLM) has been studied, at various (5, 25, 50, 100, 250 MUg/ml) dilutions, against medically important human pathogenic bacteria (two Gram-positive Staphylococcus aureus, Streptococcus pyogenes and two Gram-negative-Escherichia coli, Pseudomonas aeruginosa) and two fungal strains (Aspergillus niger, A. clavatus, Candida albicans) by using the agar disc diffusion method. A zone of inhibition of extract was compared with that of different standards such as ampicillin, ciprofloxacin, norfloxacin and chloramphenicol for antibacterial activity and nystatin and griseofulvin for antifungal activity. RESULTS: The antibacterial and antifungal activities of the LRLM increased linear with the increase in concentration of extracts. When compared with standard drugs, the results revealed that, for bacterial activity S. pyogenes and S. aureus were more sensitive and in fungal activity C. albicans was more inhibited. The range of growth inhibition zone for all the sensitive bacteria was 11-20 mm and 13-19 mm for fungal strains. CONCLUSION: Methanolic extract of L. rugosa leaf is having antibacterial and antifungal activities. PMID- 25558170 TI - Therapeutic potency of saponin rich aqueous extract of Scoparia dulcis L. in alloxan induced diabetes in rats. AB - BACKGROUND: Diabetes mellitus is major metabolic disorders of carbohydrate metabolism. This leads to alter the multiple organ system. AIMS: To investigate the antidiabetic and antioxidant effects of the saponin rich aqueous extract of Scoparia dulcis (SRE-SD) using alloxan-induced hyperglycemic rat model. MATERIAL AND METHODS: The single dose of alloxan was injected for the induction of diabetes in rats. The SRE-SD and glibenclamide were administered for 15 consecutive days from the 3(rd) day of alloxan administration. Quantity of food and water intake was measured at day 0, and 18. Further, body weight was recorded and blood samples were collected at different time intervals that is, day 0, 3, 8, 13, and 18. The oxidative biomarkers (i.e. thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and nitrite (NO(2-)) levels were also estimated in the serum sample. RESULTS: The SRE-SD showed a remarkable dose and time-dependent changes in alloxan-induced rise in the level of food consumption and water intake, serum glucose level, TBARS, NO(2-) and fall in the level of GSH. Further, significant attenuation was observed at 20 and 30 mg/kg of SRE-SD treated group. CONCLUSIONS: These findings demonstrate that SRE-SD has both antidiabetic and antioxidant effects on the experimental model of diabetes in rat. PMID- 25558171 TI - An improvement of the 2^(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. AB - BACKGROUND: The 2-DeltaDeltaCT method has been extensively used as a relative quantification strategy for quantitative real-time polymerase chain reaction (qPCR) data analysis. This method is a convenient way to calculate relative gene expression levels between different samples in that it directly uses the threshold cycles (CTs) generated by the qPCR system for calculation. However, this approach relies heavily on an invalid assumption of 100% PCR amplification efficiency across all samples. In addition, the 2-DeltaDeltaCT method is applied to data with automatic removal of background fluorescence by the qPCR software. Since the background fluorescence is unknown, subtracting an inaccurate background can lead to distortion of the results. To address these problems, we present an improved method, the individual efficiency corrected calculation. RESULTS: Our method takes into account the PCR efficiency of each individual sample. In addition, it eliminates the need for background fluorescence estimation or subtraction because the background can be cancelled out using the differencing strategy. The DNA amount for a certain gene and the relative DNA amount among different samples estimated using our method were closer to the true values compared to the results of the 2-DeltaDeltaCT method. CONCLUSIONS: The improved method, the individual efficiency corrected calculation, produces more accurate estimates in relative gene expression than the 2-DeltaDeltaCT method and is thus a better way to calculate relative gene expression. PMID- 25558172 TI - Pharmacogenetic associations with long-term response to anti-vascular endothelial growth factor treatment in neovascular AMD patients. AB - PURPOSE: To investigate the pharmacogenetic associations between the genetic risk variants of age-related macular degeneration (AMD) and long-term outcome after intravitreal anti-vascular endothelial growth factor (VEGF) treatment in Korean neovascular AMD patients. METHODS: This prospective study included 394 treatment naive patients (394 eyes) that underwent intravitreal anti-VEGF treatment for neovascular AMD for at least 12 months. Patients were genotyped for 17 single nucleotide polymorphisms within 13 AMD-relevant genes. Initially, patients underwent three monthly injections of intravitreal ranibizumab and were retreated as needed with ranibizumab or bevacizumab. For each candidate polymorphism, genotypic associations with treatment outcome measures at months 12 and 24, including mean change in best-corrected visual acuity (BCVA) from baseline, visual gain of >=15 letters, mean change in central subfield macular thickness (CSMT) from baseline on spectral domain optical coherence tomography (OCT), presence of fluid on OCT, and mean number of injections, were investigated using logistic or linear regression models with adjustment for non-genetic covariates. RESULTS: At month 24, BCVA improved by 4.5 +/- 22.5 letters and CSMT decreased by 69.4 +/- 112.6 um from baseline. Regression analysis with Bonferroni correction showed that the TT genotype for VEGFA rs3025039 was associated with a significantly higher chance of a visual gain of >=15 letters at month 24 than other genotypes (odds ratio, 4.57; 95% confidence interval, 1.89 - 11.1; corrected p = 0.0434). As for tomographic outcome, the minor allele homozygotes for ARMS2 rs10490924 and HTRA1 rs1100638 (GG genotype for both) were associated with a larger CSMT reduction at month 12 than other genotypes, with borderline significance after Bonferroni correction (118.6 +/- 132.7 um versus 62.7 +/- 89.7 um, corrected p = 0.0656 for rs10490924; 115.7 +/- 131.7 um versus 63.6 +/- 89.8 um, corrected p = 0.0528 for rs11200638). No polymorphism showed a significant association with the number of injections. CONCLUSIONS: In this Korean neovascular AMD cohort, treatment outcome after anti-VEGF was found to differ by the genotypes of VEGFA rs3025039, ARMS2 rs10490924, and HTRA1 rs11200638. Given more evidence of pharmacogenetic associations with the anti-VEGF agent, individualized therapeutic approaches based on genetic background could lead to optimal treatment in neovascular AMD. PMID- 25558173 TI - Disease progression in iridocorneal angle tissues of BMP2-induced ocular hypertensive mice with optical coherence tomography. AB - PURPOSE: The goal of the present study was to test for the first time whether glaucomatous-like disease progression in a mouse can be assessed morphologically and functionally with spectral domain optical coherence tomography (SD-OCT). METHODS: We monitored progressive changes in conventional outflow tissues of living mice overexpressing human bone morphogenetic protein 2 (BMP2), a model for glaucoma. Intraocular pressure (IOP) and outflow tissue morphology/Young's modulus were followed in mice for 36 days with rebound tonometry and SD-OCT, respectively. Results were compared to standard histological methods. Outflow facility was calculated from flow measurements with direct cannulation of anterior chambers subjected to three sequential pressure steps. RESULTS: Overexpression of BMP2 significantly elevated IOP in a biphasic manner over time compared to mice that overexpressed green fluorescent protein in outflow cells and naive controls. SD-OCT revealed changes in outflow tissues overexpressing BMP2 that corresponded with the timing of the IOP phases and decreased outflow facility. In the first phase, the angle was open, but the trabecular meshwork and the cornea were thickened. OCT detected increased trabecular meshwork stiffness after provocative IOP challenges of the BMP2 eyes, which corresponded to increased collagen deposition with transmission electron microscopy. In contrast, the angle was closed in the second phase. IOP elevation over 36 days due to BMP2 overexpression resulted in significant retinal ganglion cell and axon loss. CONCLUSIONS: Although not a feasible open-angle glaucoma model, the BMP2 mice were useful for demonstrating the utility of SD-OCT in following disease progression and differentiating between two forms of ocular pathology over time that resulted in ocular hypertension. PMID- 25558174 TI - Resolvin E1 analog RX-10045 0.1% reduces corneal stromal haze in rabbits when applied topically after PRK. AB - PURPOSE: To perform a masked study to determine whether resolvin E1 (RvE1), a lipid-derived immunomodulator, could regulate the development of corneal haze and opacity-related myofibroblasts after opacity-generating high correction photorefractive keratectomy (PRK) in rabbits. METHODS: Three groups of eight rabbits each were included in the study. Nine diopter (D) PRK for myopia was performed in each test cornea, and the eyes were treated with 30 ul of topical solution every 4 h (six times a day) for 5 days starting immediately after PRK. Group 1 was treated with 0.1% RX-10045, a prodrug of an RvE1 analog; group 2 was treated with 0.01% RX-10045; and group 3 was treated with vehicle control solution. At 1 month after PRK, haze was graded at the slit-lamp by a masked observer. Immunohistochemistry for alpha-smooth muscle actin (SMA) was performed on the central cornea of each test eye to determine the anterior stromal myofibroblast density. RESULTS: Corneal opacity was significantly lower in the 0.1% RX-10045 group, but not the 0.01% RX-10045 group, compared to the vehicle control group (p=0.029), at 1 month after -9.0D PRK. At 1 month after -9.0D PRK, SMA+ myofibroblast densities in the anterior stroma were not statistically significantly different among the three groups, although a trend toward lower myofibroblast generation was noted in the 0.1% RX-10045 group. CONCLUSIONS: Topical 0.1% RX-10045, a prodrug of an RvE1 analog, reduces corneal opacity after haze-generating PRK in rabbits. Further studies are needed to determine the precise points at which RvE1 decreases corneal opacity after injury. PMID- 25558175 TI - MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome. AB - PURPOSE: To analyze the spectrum of sequence variants in the MYO7A and USH2A genes in a group of Italian patients affected by Usher syndrome (USH). METHODS: Thirty-six Italian patients with a diagnosis of USH were recruited. They received a standard ophthalmologic examination, visual field testing, optical coherence tomography (OCT) scan, and electrophysiological tests. Fluorescein angiography and fundus autofluorescence imaging were performed in selected cases. All the patients underwent an audiologic examination for the 0.25-8,000 Hz frequencies. Vestibular function was evaluated with specific tests. DNA samples were analyzed for sequence variants of the MYO7A gene (for USH1) and the USH2A gene (for USH2) with direct sequencing techniques. A few patients were analyzed for both genes. RESULTS: In the MYO7A gene, ten missense variants were found; three patients were compound heterozygous, and two were homozygous. Thirty-four USH2A gene variants were detected, including eight missense variants, nine nonsense variants, six splicing variants, and 11 duplications/deletions; 19 patients were compound heterozygous, and three were homozygous. Four MYO7A and 17 USH2A variants have already been described in the literature. Among the novel mutations there are four USH2A large deletions, detected with multiplex ligation dependent probe amplification (MLPA) technology. Two potentially pathogenic variants were found in 27 patients (75%). Affected patients showed variable clinical pictures without a clear genotype-phenotype correlation. CONCLUSIONS: Ten variants in the MYO7A gene and 34 variants in the USH2A gene were detected in Italian patients with USH at a high detection rate. A selective analysis of these genes may be valuable for molecular analysis, combining diagnostic efficiency with little time wastage and less resource consumption. PMID- 25558176 TI - Five novel CNGB3 gene mutations in Polish patients with achromatopsia. AB - PURPOSE: To identify the genetic basis of achromatopsia (ACHM) in four patients from four unrelated Polish families. METHODS: In this study, we investigated probands with a clinical diagnosis of ACHM. Ophthalmologic examinations, including visual acuity testing, color vision testing, and full-field electroretinography (ERG), were performed in all patients (with the exception of patient p4, who had no ERG). Direct DNA sequencing encompassing the entire coding region of the CNGB3 gene, eight exons of the GNAT2 gene, and exons 5-7 of the CNGA3 gene was performed. Segregation analysis for the presence and independent inheritance of two mutant alleles was performed in the three families available for study. RESULTS: All patients showed typical achromatopsia signs and symptoms. Sequencing helped detect causative changes in the CNGB3 gene in all probands. Eight different mutations were detected in the CNGB3 gene, including five novel mutations: two splice site mutations (c.1579-1G>A and c.494-2A>T), one nonsense substitution (c.1194T>G), and two frame-shift mutations (c.393_394delGCinsTCCTGGTGA and c.1366delC). We also found three mutations: one splice site (c.1578+1G>A) and two frame-shift deletions that had been previously described (c.819_826del and c.1148delC). All respective parents were shown to be heterozygous carriers for the mutation detected in their children. CONCLUSIONS: The present study reports five novel mutations in the CNGB3 gene, and thus broadens the spectrum of probably pathogenic mutations associated with ACHM. Together with molecular data, we provide a brief clinical description of the affected individuals. PMID- 25558178 TI - Graphic tobacco warning labels - an improper solution? PMID- 25558177 TI - Subconjunctivally applied naive Tregs support corneal graft survival in baby rats. AB - PURPOSE: Corneal transplantation is the most frequent and successful form of tissue transplantation in adults (<10% rejection). In young children, any corneal opacity should be corrected as early as possible to prevent lifelong visual impairment. However, the corneal graft rejection rate is dramatically increased in infants younger than 12 months of age (up to 85% rejection), and immunosuppressive therapy is particularly challenging in this age group. Regulatory T cells (Tregs) are a well-characterized T cell subpopulation with the potential to prevent autoimmune disorders or transplant rejection. Antigen specific Tregs were shown to inhibit graft rejection in adult stem cell transplantation. Less is known about the role of naive Tregs.The purpose of the present study was to elucidate the relevance of naive Tregs in juvenile corneal transplantation in a baby rat keratoplasty model that reproduces the accelerated rejection in young patients. METHODS: Counts and inhibitory potential of Tregs were studied in spleens of 3- and 10-week-old rats. Unprimed Tregs (CD4+CD25+) were isolated from the spleens of 10-week-old Lewis rats and systemically or subconjunctivally administered in vivo in allogenic keratoplasty in 3- and 10 week-old Lewis recipient rats. In subconjunctival tissue, transcription was analyzed for induction of transforming-growth-factor beta (TGF-beta). RESULTS: In 3-week-old rats, CD4 T cell counts, but not FoxP3 T cell counts were lower than in 10-week-old rats. The Tregs of both age groups had the potential to inhibit T cell activation in vitro. No significant delay in rejection was observed when Tregs were applied systemically before keratoplasty. However, subconjunctival application of Tregs abrogated rejection in 66.7% and 33.3% of the 3- and 10-week old recipients, respectively. Analysis of the conjunctival tissue revealed a transplantation-induced increase in TGF-beta transcription in the 3-week-old rats. CONCLUSIONS: Our data suggest that local application of unprimed regulatory T cells may be a therapeutic strategy for preventing corneal graft rejection in young recipients. PMID- 25558179 TI - Oral administration of fermented probiotics improves the condition of feces in adult horses. AB - The effects of probiotics on horses are still controversial. The present study was a randomized, double-blinded, placebo-controlled crossover study designed to evaluate the ability of probiotics to improve intestinal conditions in adult horses. Fermented probiotics were administered to 10 healthy adult geldings for 28 days. The clinical condition of the horses was monitored daily, and the blood and feces were biochemically analyzed every 14 days. In the probiotic-treated group, the concentration of carboxylic acids in the feces was increased at days 14 and 28. In contrast to the fecal pH in the control group, which increased at days 14 and 28, the fecal pH in the probiotic-treated group did not increase. Additionally, the relative amounts of enteropathogenic bacterial DNA were diminished in the probiotic-treated group. These results suggest that probiotic bacteria proliferated in the equine intestine. No instances of abnormal clinical conditions or abnormal values in blood tests were observed throughout the study. Oral administration of fermented probiotics may have the ability to improve the intestinal environment biochemically and microbiologically without the risk of adverse effects. PMID- 25558180 TI - The Effects of Inclination (Up and Down) of the Treadmill on the Electromyogram Activities of the Forelimb and Hind limb Muscles at a Walk and a Trot in Thoroughbred Horses. AB - It is important to know the effects of the inclination of a slope on the activity of each muscle, because training by running on a sloped track is commonly used for Thoroughbred racehorses. The effects of incline (from -6 to +6%) on the forelimbs and hind limbs during walking and trotting on a treadmill were evaluated by an integrated electromyogram (iEMG). The muscle activities in the forelimbs (5 horses) and hind limbs (4 horses) were measured separately. Two stainless steel wires were inserted into each of the brachiocephalicus (Bc), biceps brachii (BB), splenius (Sp), and pectoralis descendens (PD) in the forelimb experiment and into the longissimus dorsi (LD), vastus lateralis (VL), gluteus medius (GM), and biceps femoris (BF) in the hind limb experiment. The EMG recordings were taken at a sampling rate of 1,000 Hz. At a walk, the iEMG values for the forelimb were not significantly different under any of the inclinations. In the hind limb, the iEMG values for the GM and BF significantly decreased as the inclination decreased. At a trot, the iEMG values for the Bc in the forelimb significantly decreased as the inclination of the treadmill decreased. In the hind limb, the iEMG values for the LD, GM, and BF significantly decreased as the inclination decreased. Uphill exercise increased the iEMG values for the Bc, LD, GM, and BF, while downhill exercise resulted in little increase in the iEMG values. It was concluded that the effects of inclination on the muscle activities were larger for the uphill exercises, and for the hind limb muscles compared with the forelimb muscles. PMID- 25558181 TI - Comparison of the Occurrence of Transportation-associated Fever in 2 Years Old Thoroughbreds before and after Introduction of Prophylactic Marbofloxacin Administration. AB - In order to reveal the preventive effect of marbofloxacin (MRFX) administration just before transportation, we compared the occurrence of transportation associated fever before and after introduction of MRFX administration. After the introduction of prophylactic MRFX administration, the rectal temperatures of horses after transportation were significantly lower than before the introduction of MRFX administration (P<0.01) and the number of febrile horses was significantly lower than before the introduction of MRFX administration (P<0.01). In conclusion, these results show that prophylactic MRFX administration just before transportation is clinically effective at preventing transportation associated fever. PMID- 25558182 TI - Semiparametric tests for sufficient cause interaction. AB - A sufficient cause interaction between two exposures signals the presence of individuals for whom the outcome would occur only under certain values of the two exposures. When the outcome is dichotomous and all exposures are categorical, then under certain no confounding assumptions, empirical conditions for sufficient cause interactions can be constructed based on the sign of linear contrasts of conditional outcome probabilities between differently exposed subgroups, given confounders. It is argued that logistic regression models are unsatisfactory for evaluating such contrasts, and that Bernoulli regression models with linear link are prone to misspecification. We therefore develop semiparametric tests for sufficient cause interactions under models which postulate probability contrasts in terms of a finite-dimensional parameter, but which are otherwise unspecified. Estimation is often not feasible in these models because it would require nonparametric estimation of auxiliary conditional expectations given high-dimensional variables. We therefore develop 'multiply robust tests' under a union model that assumes at least one of several working submodels holds. In the special case of a randomized experiment or a family-based genetic study in which the joint exposure distribution is known by design or Mendelian inheritance, the procedure leads to asymptotically distribution-free tests of the null hypothesis of no sufficient cause interaction. PMID- 25558183 TI - The Racial Residential Segregation of Black Single Adults Living Alone. AB - While many studies have examined the intersection of race and class with residential segregation and residential preferences, very little is known about the role played by household composition in shaping residential patterns. This paper focuses on the residential patterns of a particular kind of household: those consisting of persons single and living alone (SALA). We compare the residential segregation of black SALA households-an important subset of non family households and a rapidly growing segment of the population-from white SALA households and both white and black married-couple households. We examine how group and metropolitan characteristics influence segregation levels for these household types. Using data from the 2000 census, we find that black SALA households are less segregated from white SALA households than from white married couple households. Multivariate analyses show that smaller income differences across SALA households account for these segregation patterns, indicating the importance of economic resources in influencing residential patterns. Nevertheless, race continues to play an important role, as black SALA household segregation from both kinds of white households is high in absolute terms and relative to their segregation from black married-couple households. PMID- 25558184 TI - Realigning the Crooked Room: Spelman Claims a Space for African American Women in STEM. PMID- 25558185 TI - Virtual Constraint Control of a Powered Prosthetic Leg: From Simulation to Experiments with Transfemoral Amputees. AB - Recent powered (or robotic) prosthetic legs independently control different joints and time periods of the gait cycle, resulting in control parameters and switching rules that can be difficult to tune by clinicians. This challenge might be addressed by a unifying control model used by recent bipedal robots, in which virtual constraints define joint patterns as functions of a monotonic variable that continuously represents the gait cycle phase. In the first application of virtual constraints to amputee locomotion, this paper derives exact and approximate control laws for a partial feedback linearization to enforce virtual constraints on a prosthetic leg. We then encode a human-inspired invariance property called effective shape into virtual constraints for the stance period. After simulating the robustness of the partial feedback linearization to clinically meaningful conditions, we experimentally implement this control strategy on a powered transfemoral leg. We report the results of three amputee subjects walking overground and at variable cadences on a treadmill, demonstrating the clinical viability of this novel control approach. PMID- 25558186 TI - Analysis of Partially Incomplete Tables of Breast Cancer Characteristics with an Ordinal Variable. AB - Our goal is to model the joint distribution of a series of 4*2*2*2 contingency tables for which some of the data are partially collapsed (i.e., aggregated in as few as two dimensions). More specifically, the joint distribution of 4 clinical characteristics in breast cancer patients is estimated. These characteristics include estrogen receptor status (positive/negative), nodal involvement (positive/negative), HER2-neu expression (positive/negative), and stage of disease (I, II, III, IV). The joint distribution of the first three characteristics is estimated conditional on stage of disease and we propose a dynamic model for the conditional probabilities that let them evolve as the stage of disease progresses. The dynamic model is based on a series of Dirichlet distributions whose parameters are related by a Markov prior structure (called dynamic Dirichlet prior). This model makes use of information across disease stage (known as "borrowing strength") and provides a way of estimating the distribution of patients with particular tumor characteristics. In addition, since some of the data sources are aggregated, a data augmentation technique is proposed to carry out a meta-analysis of the different datasets. PMID- 25558188 TI - Polymeric Multilayers that contain Silver Nanoparticles can be Stamped onto Biological Tissues to Provide Antibacterial Activity. AB - We report the design of polyelectrolyte multilayers (PEMs) that can be prefabricated on an elastomeric stamp and mechanically transferred onto biomedically-relevant soft materials, including medical-grade silicone elastomers (E'~450-1500 kPa; E'-elastic modulus) and the dermis of cadaver-skin (E'~200-600 kPa). Whereas initial attempts to stamp PEMs formed from poly(allylamine hydrochloride) and poly(acrylic acid) resulted in minimal transfer onto soft materials, we report that integration of micrometer-sized beads into the PEMs (thicknesses of 6-160 nm) led to their quantitative transfer within 30 seconds of contact at a pressure of ~196 kPa. To demonstrate the utility of this approach, PEMs were impregnated with a range of loadings of silver-nanoparticles and stamped onto the dermis of human cadaver-skin (a wound-simulant) that was subsequently incubated with bacterial cultures. Skin-dermis stamped with PEMs that released 0.25+/-0.01 MUg cm-2 of silver ions caused a 6 log10 reduction in colony forming units of Staphylococcus epidermidis and Pseudomonas aeruginosa within 12 h. Significantly, this level of silver release is below that which is cytotoxic to NIH 3T3 mouse fibroblast cells. Overall, this study describes a general and facile approach for the functionalization of biomaterial surfaces without subjecting them to potentially deleterious processing conditions. PMID- 25558189 TI - Labor pain relief for parturients: We can do better. PMID- 25558191 TI - Effect of single oral dose of tramadol on gastric secretions pH. AB - BACKGROUND: Tramadol is an atypical analgesic agent. It has been shown that intramuscular or intravenous injection tramadol is able to inhibit M3 muscarinic receptors. Tramadol is able to mediate smooth muscles contraction and glandular secretions. We have evaluated the effects of single oral dose of tramadol given preoperatively on gastric juices pH in patients electively scheduled for laparoscopic cholecystectomy. MATERIALS AND METHODS: Sixty adult, American Society of Anesthesiologist I and II patients scheduled for laparoscopic cholecystectomy were included in the study. Patients were randomly assigned to receive either placebo (n = 30) or oral tramadol 50 mg (n = 30). General anesthesia was induced using propofol, fentanyl and cisatracurium. After induction of anesthesia 5 ml of gastric fluid was aspirated through orogastric tube. The gastric fluid pH was measured using pH meter. RESULT: There was no significant difference in the pH between the groups. Gastric pH of the placebo and tramadol groups was 1.97 versus 1.98 (P = 0.092) respectively. CONCLUSION: Preoperatively single oral dose of tramadol was unable to elevate the desired level of gastric acid secretions pH (>2.5). This may be due to pharmacokinetic disparity between the analgesic and pH elevating properties of tramadol. PMID- 25558187 TI - Role of Endothelial Cells in Myocardial Ischemia-Reperfusion Injury. AB - Minimizing myocardial ischemia-reperfusion injury has broad clinical implications and is a critical mediator of cardiac surgical outcomes. "Ischemic injury" results from a restriction in blood supply leading to a mismatch between oxygen supply and demand of a sufficient intensity and/or duration that leads to cell necrosis, whereas ischemia-reperfusion injury occurs when blood supply is restored after a period of ischemia and is usually associated with apoptosis (i.e. programmed cell death). Compared to vascular endothelial cells, cardiac myocytes are more sensitive to ischemic injury and have received the most attention in preventing myocardial ischemia-reperfusion injury. Many comprehensive reviews exist on various aspects of myocardial ischemia-reperfusion injury. The purpose of this review is to examine the role of vascular endothelial cells in myocardial ischemia-reperfusion injury, and to stimulate further research in this exciting and clinically relevant area. Two specific areas that are addressed include: 1) data suggesting that coronary endothelial cells are critical mediators of myocardial dysfunction after ischemia-reperfusion injury; and 2) the involvement of the mitochondrial permeability transition pore in endothelial cell death as a result of an ischemia-reperfusion insult. Elucidating the cellular signaling pathway(s) that leads to endothelial cell injury and/or death in response to ischemia-reperfusion is a key component to developing clinically applicable strategies that might minimize myocardial ischemia reperfusion injury. PMID- 25558190 TI - 0.5% levobupivacaine versus 0.5% ropivacaine: Are they different in ultrasound guided sciatic block? AB - CONTEXT AND AIMS: Little is known about onset and duration of sciatic block after 0.5% levobupivacaine (Levo) versus 0.5% ropivacaine (Ropi) for ultrasound-guided technique. We assessed these parameters in the ultrasound-guided block, to know for the practice. SETTING AND DESIGN: A comparative randomized double-blind study was conducted in the University Hospital. MATERIALS AND METHODS: Were included 35 adults of ASA I-II, scheduled for foot surgery, presenting clear imaging of their sciatic nerve at mid-thigh. A volume of 20 mL of either 0.5% Levo or 0.5% Ropi were injected around the sciatic nerve at mid-thigh using ultrasound guidance (out of the plane) followed by placement of a catheter to use, if necessary, for perioperative analgesia. A femoral single shot block was systematically performed to block the saphenous nerve. The onset times until complete foot block (primary outcome) and the sensory and motor block duration (secondary outcome) were assessed using Wilcoxon test. Values were expressed as medians (1(st)-3(rd) quartile). RESULTS: Except for two delayed sciatic blocks in each group, the onset time otherwise was 35 min (20-60) in Ropi versus 40 min (30-60) in Levo, P = 0.5. Sensory block lasted longer in Levo, 17 h (14-27) compared with 15 h (10 17) in Ropi, P = 0.04. No significant between-group difference was found with motor block durations, 15 h (12-18) in Levo and 15 h (12-16) in Ropi, P = 0.3. CONCLUSION: No difference of onset times was found in ultrasound-guided sciatic block whether using Levo or Ropi. Levo induced a longer-lasting sensory block. PMID- 25558192 TI - Neurodevelopmental outcome after cardiac surgery utilizing cardiopulmonary bypass in children. AB - INTRODUCTION: Modulating the stress response and perioperative factors can have a paramount impact on the neurodevelopmental outcome of infants who undergo cardiac surgery utilizing cardiopulmonary bypass. MATERIALS AND METHODS: In this single center prospective follow-up study, we evaluated the impact of three different anesthetic techniques on the neurodevelopmental outcomes of 19 children who previously underwent congenital cardiac surgery within their 1(st) year of life. Cases were done from May 2011 to December 2013. Children were assessed using the Stanford-Binet Intelligence Scales (5(th) edition). Multiple regression analysis was used to test different parental and perioperative factors that could significantly predict the different neurodevelopmental outcomes in the entire cohort of patients. RESULTS: When comparing the three groups regarding the major cognitive scores, a high-dose fentanyl (HDF) patients scored significantly higher than the low-dose fentanyl (LDF) + dexmedetomidine (DEX) (LDF + DEX) group in the quantitative reasoning scores (106 +/- 22 vs. 82 +/- 15 P = 0.046). The bispectral index (BIS) value at the end of surgery for the -LDF group was significantly higher than that in LDF + DEX group (P = 0.011). For the entire cohort, a strong correlation was seen between the standard verbal intelligence quotient (IQ) score and the baseline adrenocorticotropic hormone level, the interleukin-6 level at the end of surgery and the BIS value at the end of the procedure with an R(2) value of 0.67 and P < 0.04. There was an inverse correlation between the cardiac Intensive Care Unit length of stay and the full scale IQ score (R = 0.4675 and P 0.027). CONCLUSIONS: Patients in the HDF group demonstrated overall higher neurodevelopmental scores, although it did not reach statistical significance except in fluid reasoning scores. Our results may point to a possible correlation between blunting the stress response and improvement of the neurodevelopmental outcome. PMID- 25558193 TI - Modified sevoflurane-based sedation technique versus propofol sedation technique: A randomized-controlled study. AB - BACKGROUND: The aim of this study was to evaluate the safety and efficacy of sevoflurane-based sedation technique for colonoscopy in geriatric patients as compared with that using propofol. MATERIALS AND METHODS: Sixty elderly patients, who were scheduled for colonoscopy, participated in this controlled prospective study and were randomly allocated into two groups; P and S. The patients were sedated using either propofol in P group or sevoflurane in S group. Complications (including apnea, the need for airway intervention, occurrence of general anesthesia [GA], hemodynamic instability and others), the fentanyl requirement and the times of the procedure, recovery, and discharge were recorded in both groups. RESULTS: The patients in P group had more frequent apnea attacks, need for airway intervention and occurrence of GA compared to the patients in S group. However, both groups were comparable regarding the other measured variables. CONCLUSION: For geriatric colonoscopy, sevoflurane can provide safe and effective sedation alternative to propofol. PMID- 25558194 TI - Frequency of Intensive Care Unit admission after elective interventional neuroradiological procedures under general anesthesia in a tertiary care hospital. AB - BACKGROUND: The aim of this study was to determine the frequency of patients admitted to Intensive Care Unit (ICU) after elective interventional neuroradiology (INR) procedures under general anesthesia. MATERIALS AND METHODS: We retrospectively evaluated 121 patients underwent INR procedures performed with general anesthesia within a 5-year period. Information including demographics, aneurysm/arteriovenous malformations pathology (ruptured or un-ruptured), preoperative neurological status, co-morbidities, complications during procedure and postoperative admission in ICU were recorded on a predesigned form. RESULTS: Elective INR procedure for both ruptured (n = 29, 24%) and un-ruptured (n = 85, 70.25%) aneurysms was performed. Rate of postoperative admission in ICU was significantly high in patients with preoperative ruptured aneurysm (P < 0.01). High rate of neurological deficit, sub-arachnoid hemorrhage (SAH) and hypertension in patients were significant factors of postoperative admission in ICU (P < 0.05). Out of 24 patients, 12 were admitted to ICU postoperatively because of procedure-related complications and 11 were sent due to preexisting significant co-morbidities with added complication of SAH. CONCLUSION: The authors conclude that patients without major co-morbidities, intraoperative complications, or complex aneurysm morphology can be safely observed in a regular ward rather than being admitted to the ICU. PMID- 25558195 TI - Effective dose 50 of desflurane for laryngeal mask airway removal in anaesthetized children in cataract surgeries with subtenon block. AB - BACKGROUND: Quantification of the depth of desflurane anesthesia required for laryngeal mask airway (LMA) removal in children has been done with the use of intravenous fentanyl or caudal anesthesia. This study aimed to determine the end tidal concentration of desflurane required for LMA removal in children without the use of caudal or opioid analgesia in children undergoing elective cataract surgery. MATERIALS AND METHODS: Our study enrolled 25 American Society of Anesthesiologists I and II children aged 2-10 years, undergoing elective cataract surgery. Anesthesia was induced with sevoflurane and oxygen/nitrous oxide using face mask and a size 2 LMA inserted. A subtenon block was administered in all children before surgical incision. Desflurane was used for maintenance of anesthesia. Predetermined end tidal concentration of desflurane was maintained for 10 min at the end of surgery before LMA removal was attempted. End tidal concentrations were increased/decreased using the Dixon up-down method (with 0.5% as a step size) in the next patient depending on the previous patient's response. Patient responses to LMA removal were classified as "movement" or "no movement." RESULTS: 50% effective dose (ED50) for successful removal of the LMA with desflurane in the presence of subtenon block was 3.6% (3.20-3.97%) and that the 95% ED95 was 4.648% (4.15-6.47%). CONCLUSION: Laryngeal mask airway removal can be successfully accomplished in 50% and 95% anesthetized children at 3.6% and 4.65% end-tidal desflurane concentration. PMID- 25558196 TI - Effectiveness of gaseous and intravenous inductions on children's anxiety and distress during extraction of teeth under general anesthesia. AB - CONTEXT: Anxiety and distress regarding dental treatment is a major issue for dental patients and can be exaggerated in pediatric dental patients. AIMS: The aim was to investigate how different methods of induction for general anesthesia affect children's distress for dental procedures such as extraction of teeth. SUBJECTS AND METHODS: This was an observational clinical study conducted at Manchester University Dental Hospital. The induction of anesthesia in children was achieved with either intravenous (I.V.) or a gaseous induction. The Modified Child Smiley Faces Scales were completed for children at various times intervals. STATISTICAL ANALYSIS USED: There were statistically significant differences between the mean distress scores for the I.V. and inhalation groups (P values from independent t-test: P < 0.001) was applied. RESULTS: In gaseous induction group, the number of children who scored severe and very severe distress was greater than those who were in I.V. group. Gaseous induction was used for 23 children. Preoperatively, 56.5% children were in very severe distress, 17.4% in severe distress, 13% in moderate distress, 8.7% in mild distress and only one (4.3%) showed no distress. For I.V. induction, 11.2% children were in very severe distress, 9% in severe distress, and 9.6% in moderate distress, 24.2% in mild distress and 46.1% showed no distress. CONCLUSIONS: Gaseous induction anesthesia for extractions of teeth does produce high levels of distress than I.V. induction in children for dental extractions. There was no significant difference between both induction methods in terms of distress levels at the time of recovery and 15 min postoperatively. PMID- 25558197 TI - A comparison of fiberoptical guided tracheal intubation via laryngeal mask and laryngeal tube. AB - BACKGROUND: Fiberoptical assisted intubation via a placed laryngeal mask airway (LMA) has been described as save and easy procedure to manage a difficult airway. The laryngeal tube (LT) is a promising alternative to the LMA as supraglottic airway device. Fiberoptical assisted intubation via LT is possible, however considered more difficult. The aim of this study was to compare the fiberoptical assisted intubation via LT and LMA. MATERIALS AND METHODS: A total of 22 anesthesiologists with different levels of experience participated in the study performed on an adult airway model. Primarily the supraglottic device was placed and correct position was confirmed by successful ventilation. A 5 mm internal diameter tracheal tube was loaded onto a flexible 3.6 mm fiberscope and the so prepared device was inserted into the proximal lumen of the LMA or the LT. The glottis was passed under visual control and the tube advanced into the trachea. After removal of the fiberscope, ventilation was examined clinically by inspection. Success rates, procedure time and observed complications of LMA versus LT were compared (U-test; P < 0.05). RESULTS: Placement of the endotracheal tube was successful in all attempts using both the LMA and LT. There was no difference in the time needed for the placement procedure (33 [26-38] s LMA; 35 [32-38] s LT). Only minor technical complications were observed in both groups. CONCLUSION: A fiberoptical assisted intubation via LT can be considered as a relevant alternative in advanced airway management. PMID- 25558198 TI - Effect of low dose tranexamic acid on intra-operative blood loss in neurosurgical patients. AB - BACKGROUND: Blood loss is often a major complication in neurosurgery that requires transfusion of multiple units of blood. The purpose of this study was to assess the effect of tranexamic acid (TXA) on intraoperative blood loss and the need for blood transfusion in patients undergoing craniotomy for tumor excision. MATERIALS AND METHODS: A total of 100 patients aged 18-60 years, with American Society of Anesthesiologists physical Status 1 and 2 scheduled to undergo elective craniotomy for tumor excision were enrolled. Patients received 10 mg/kg bolus about 20 min before skin incision followed by 1 mg/kg/h infusion of either TXA or saline. Hemodynamic variables, intravenous fluid transfused, amount of blood loss and blood given were measured every 2 h. Laboratory parameters such as serum electrolytes and fibrinogen values were measured every 3 h. On the 5(th) postoperative day hemoglobin (POD Hb5), Hb estimation was done and the estimated blood loss (EBL) calculated. Patients were also monitored for any complications. RESULTS: The Mean heart rate in TXA group was significantly lower compared with the saline group. Mean arterial pressure and fibrinogen levels were higher in TXA group. The mean total blood loss in the TXA group was less than in the saline group. Blood transfusion requirements were comparable in two groups. The EBL and POD5 Hb were comparable in two groups. CONCLUSION: Even though, there is a significant reduction in the total amount of blood loss in TXA group. However, there was no reduction in intraoperative transfusion requirement. PMID- 25558199 TI - Is the World Health Organization-recommended dose of pralidoxime effective in the treatment of organophosphorus poisoning? A randomized, double-blinded and placebo controlled trial. AB - BACKGROUND: Organophosphorus poisoning (OPP) is a major global public health problem. Pralidoxime has been used in a complimentary role to atropine for the management of OPP. World Health Organization (WHO) recommends use of pralidoxime but studies regarding its role have been inconclusive, ranging from being ineffective to harmful or beneficial. MATERIALS AND METHODS: The present study was undertaken to evaluate the effectiveness of pralidoxime. Eddleston's study was the most compelling factor for our study, as he showed worst outcomes using pralidoxime. Our practice of continuous use of pralidoxime was based on the WHO guidelines and the study by Pawar (2006), which showed better outcome with higher doses of pralidoxime. These conflicting results suggested that a re-evaluation of its use in our clinical practice was indicated. RESULTS: There was no difference in mortality rates, hemodynamic parameters and atropine requirements between the AP and A groups. Mean duration of ventilation (3.6 +/- 4.6 in AP group vs. 3.6 +/ 4.4 in A group) and Intensive Care Unit stay (7.1 +/- 5.4 in AP group vs. 6.8 +/ 4.7 in A group) was comparable. Serum sodium concentrations showed a correlation with mortality, with lower concentrations associated with better outcomes. CONCLUSION: The study suggests that add-on WHO-recommended pralidoxime therapy does not provide any benefit over atropine monotherapy. Adding pralidoxime does not seem to be beneficial and at the same time does not result in increased mortality rates. Our practice changed after completion of this study, and it has proven to be of significant benefit to patients who had to bear the expense of treatment. PMID- 25558200 TI - Comparison of efficacy of three subanesthetic doses of ketamine in allaying procedural discomfort during establishment of subarachnoid block: A randomized double-blind trial. AB - BACKGROUND: Procedural discomfort is experienced by patients during the establishment of subarachnoid block even after good preoperative counseling and adequate premedication. To enhance comfort, procedural sedation that would provide good analgesia, faster recovery, and amnesia is necessary. MATERIALS AND METHODS: Patients with American Society of Anesthesiologists Status I and II posted for elective surgeries under subarachnoid block were premedicated with injection midazolam 0.05 mg/kg and preloaded with 10 ml/kg ringer lactate solution. They were randomized into three groups of 30 each. Group K0.3 received ketamine 0.3 mg/kg, Group K0.4 received ketamine 0.4 mg/kg and Group K0.5 received ketamine 0.5 mg/kg intravenously. University of Michigan sedation score, ease of positioning, prick response, verbal response, hallucinations, recall of procedure, and patient satisfaction were evaluated. RESULTS: There was statistically significant difference in sedation among the three groups. Increased dose necessitated help of two persons to position the patient, which showed statistically significant difference. Verbal response was seen early in Group K0.3 (4.67 +/- 2.84 min). There was no recall of experience of subarachnoid block procedure in any of the groups in spite of back muscle contraction or patient movement. Hence, all patients in all three groups were satisfied and were willing to undergo subarachnoid block, if the situation arises. CONCLUSION: Ketamine in the dose of 0.3 mg/kg provided sufficient sedation for allaying procedural discomfort due to less sedation, less positional difficulty, early verbal response, no hallucinations, no recall of performance of procedure, and good patient satisfaction. PMID- 25558201 TI - Morphometry of stylomastoid foramen and its clinical application in facial nerve block. AB - BACKGROUND: Stylomastoid foramen is an important site for Nadbath facial nerve block. Exact localization of foramen holds the key to success, thus decreasing the complications. Wide racial variation exists in position of stylomastoid foramen in different population groups. AIM: The aim was to study the morphometry of stylomastoid foramen and its location with respect to nearby anatomical landmarks. MATERIALS AND METHODS: A total of 100 dry skulls (60 male and 40 female) were studied to locate the position of center of stylomastoid foramen (CSMF) with respect to tip and anterior border of the mastoid process and jugular foramen (JF). Along with this angle between antero-posterior line passing through the tip of the mastoid process and line joining the tip with stylomastoid foramen was also measured. RESULT: In 83.51% sides of skulls, the most common position of foramen was found to be anterior to the line passing through anterior border of the mastoid process. The mean distance of center of foramen from the tip of the mastoid process was 15.26 +/- 1.4 mm on right and 14.32 +/- 1.8 on the left side (P < 0.001) and from JF was 12.28 +/- 1.9 mm and 12.96 +/- 2.1 mm on the right and left sides, respectively (P < 0.01). The position of CSMF was found at an angle of 66.57 degrees +/- 2.6 degrees and 65.96 degrees +/- 1.8 degrees on the right and left sides, respectively from the tip of the mastoid process. CONCLUSION: This study makes possible the identification of the exact position of stylomastoid foramen and its application in facial nerve block. PMID- 25558202 TI - Status of problem based learning in postgraduate anesthesia teaching: A cross sectional survey. AB - BACKGROUND: Anesthesia is a specialized branch of medicine with a very narrow margin of error. Incorporation of problem-based learning (PBL) in anesthesia post graduate (PG) teaching enhances the critical thinking and problem-solving skills. It also helps in developing a broader prospective of clinical case scenarios. Case based discussions (CBD) are most widely practiced out of all PBL methods in anesthesia PG teaching. MATERIALS AND METHODS: We conducted an anonymous questionnaire based, cross-sectional survey among 62 anesthesia residents from various medical institutions in a city of Delhi, India. We aimed to assess the current status of PBL by assessing the student satisfaction with CBD in anesthesia PG teaching, educational objectives accomplished with CBD and effectiveness of teaching curriculum in PG teaching with suggested modifications, if any. RESULT AND CONCLUSION: We observed that CBD is lacking in many important key areas of PBL e.g., formulation of objectives, communication on the content and direction of PBL, facilitation skills, supplementation of inadequacies of CBD. However, CBD seems to be a valid method of PBL in terms of the educational objectives accomplished with it but increased motivation for learning is required. Majority of the students felt that PG teaching curriculum should be centralized, with increased emphasis on open interactive sessions regarding its effectiveness. PMID- 25558204 TI - Anesthesia for hemicolectomy in a known porphyric with cecal malignancy. AB - Intraoperative management of a known acute intermittent porphyria patient is a challenge requiring awareness of factors, which trigger an acute crisis, clinical features of a porphyric attack, knowledge of safe pharmacologic intervention, and preparedness for reintubation and ventilatory support. The classical signs of a porphyric crisis such as pain abdomen, vomiting and neuropsychiatric symptoms are masked under general anesthesia and can be confused with postoperative pain and vomiting and postoperative cognitive dysfunction, especially for intra-abdominal surgeries. Eternal vigilance for onset of an acute crisis is imperative. After a crisis of acute intermittent porphyria, residual paresis may persist for years in the absence of further attacks. PMID- 25558205 TI - Anesthesia management in a child with laryngeal papilloma causing near complete airway obstruction. AB - Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease of viral etiology affecting most commonly larynx. A 5-year-old child with stridor was posted for microlaryngoscopic excision of laryngeal papilloma. We discuss the perioperative management of case with the various ventilation strategies. In child with stridor intubation remains the safest option. It is suggested to maintain spontaneous ventilation until intubation as mask ventilation could be difficult. PMID- 25558203 TI - The evolution of spinal/epidural neostigmine in clinical application: Thoughts after two decades. AB - Since the first clinical application of analgesia following spinal anticholinesterase by 1940's, several clinical double-blind studies have been conducted to date, where intrathecal doses of neostigmine in humans ranged from 750 to 1 MUg, due to side-effects. Conversely, epidural neostigmine has been evaluated in proportionally higher doses and represents an alternative, but still deserves more investigation concerning both acute and chronic pain, as it seems devoid of important side-effects. PMID- 25558206 TI - Anesthetic management of a case of armored brain. AB - Armored brain is condition, which occurs due to calcification in a chronic subdural hematoma (SDH). Here, we are reporting a case of armored brain due to chronic SDH as a complication of vetriculoperitoneal shunt (VP shunt). Patient had undergone major surgery for removal of calcified hematoma. VP shunt is a simple surgery, but can lead to catastrophic complications like this. In this report, we had described this condition and its aspects. PMID- 25558207 TI - Anesthetic management of patient with systemic lupus erythematosus and antiphospholipid antibodies syndrome for laparoscopic nephrectomy and cholecystectomy. AB - We report a case of a female having systemic lupus erythematosus and antiphospholipid antibodies syndrome, who was on immunosuppressant therapy. We discussed the preoperative evaluation and perioperative management who underwent nephrectomy and cholecystectomy. PMID- 25558208 TI - An unusual cause of high peak airway pressure: Interpretation of displayed alarms. AB - Airway pressure monitoring is critical in modern day anesthesia ventilators to detect and warn high or low pressure conditions in the breathing system. We report a scenario leading to unexpectedly very high peak inspiratory pressure in the intraoperative period and describe the mechanism for high priority alarm activation. We also discuss the role of a blocked bacterial filter in causing sustained display of increased airway pressure. This scenario is a very good example for understanding the unique safety feature present in the Drager ventilators and the attending anesthesiologist must have an adequate knowledge of the functioning and safety feature of the ventilators they are using to interpret the alarms in the perioperative to prevent unnecessary anxiety and intervention. PMID- 25558209 TI - Pediatric fiberoptic intubation: Another challenge... another approach!! PMID- 25558210 TI - Safe anesthesia management protocol of a child with congenital long QT syndrome and deafness (Jervell and lange-nielsen syndrome) for cochlear implant surgery. PMID- 25558211 TI - Successful awake nasal fiberoptic intubation in a patient with restricted mouth opening due to a large tongue flap. PMID- 25558212 TI - Cardiopulmonary bypass with deep hypothermic circulatory arrest for liver abscess with inferior vena cava thrombus: An anesthetic challenge. PMID- 25558213 TI - Prevention and treatment of sevoflurane emergence agitation and delirium in children with dexmedetomidine. PMID- 25558214 TI - Dexmedetomidine during carotid endarterectomy: A review or a commentary? PMID- 25558215 TI - Genetic heterogenicity of Angelman syndrome and its significance to the anesthesiologist. PMID- 25558216 TI - Novel technique of inhalational induction of an infant with a large nasal mass. PMID- 25558217 TI - Self-expanding metal stents for esophageal perforation with nasogastric tube insertion in esophageal carcinoma. PMID- 25558218 TI - Is there a role for therapeutic bronchoscopy in acute severe asthma? PMID- 25558219 TI - A proposal for a new approach in the prevention of laryngospasm in children. PMID- 25558220 TI - Neuroprotective effects of the immunomodulatory drug Setarud on cerebral ischemia in male rats. AB - Anti-inflammatory and anti-oxidant agents can alleviate ischemic cerebral injury. The immunomodulary drug Setarud, which is composed of herbal extracts including Rosa canina, Urtica dioica and Tanacetum vulgare, supplemented with selenium exhibits anti-inflammatory and anti-oxidant properties. Therefore, we hypothesized that Setarud will have a neuroprotective effect against ischemic cerebral injury. To validate this hypothesis, rats were intraperitoneally administered with 0.66 mL/kg Setarud for 30 minutes after middle cerebral artery occlusion. Triphenyltetrazolium chloride staining showed that Setarud could reduce cerebral infarct volume of rats subjected to cerebral ischemia. Transmission electron microscopy and hematoxylin-eosin staining results showed that Setarud could alleviate the degenerative changes in cortical neurons of rats with cerebral ischemia. The inclined plate test and prehensile test showed that Setarud could significantly improve the motor function of rats with cerebral ischemia. These findings suggest that Setarud shows neuroprotective effects against ischemic brain injury. PMID- 25558221 TI - Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson's disease rats. AB - Previous studies found that iron accumulates in the substantia nigra of Parkinson's disease patients. However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone induced Parkinson's disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons. PMID- 25558222 TI - Effects of Chinese herbal monomers on oxidative phosphorylation and membrane potential in cerebral mitochondria isolated from hypoxia-exposed rats in vitro. AB - Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia. Some Chinese herbal monomers may exert anti hypoxic effects through enhancing the efficiency of oxidative phosphorylation. In this study, effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia exposed rats in vitro were investigated to screen anti-hypoxic drugs. Rats were exposed to a low-pressure environment of 405.35 mm Hg (54.04 kPa) for 3 days to establish high-altitude hypoxic models. Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers (sinomenine, silymarin, glycyrrhizic acid, baicalin, quercetin, ginkgolide B, saffron, piperine, ginsenoside Rg1 and oxymatrine) for 5 minutes in vitro. Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method, respectively. Hypoxic exposure significantly decreased the state 3 respiratory rate, respiratory control rate and mitochondrial membrane potential, and significantly increased the state 4 respiratory rate. Treatment with saffron, ginsenoside Rg1 and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro, while ginsenoside Rg1, piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats. The Chinese herbal monomers saffron, ginsenoside Rg1, piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro. PMID- 25558223 TI - Zhichan powder regulates nigrostriatal dopamine synthesis and metabolism in Parkinson's disease rats. AB - In this study, rat models of Parkinson's disease induced by substantia nigra injection of 6-hydroxy-dopamine were intragastrically administered Zhichan powder daily for 50 days. Reverse transcription PCR results showed that tyrosine hydroxylase mRNA expression in the rat substantia nigra was significantly increased, while monoamine oxidase B mRNA expression was significantly decreased in the Zhichan powder group, compared with the model group. In addition, the levels of striatal dopamine and homovanillic acid, the ratio of dopamine to homovanillic acid, and the activity of blood superoxide dismutase were all higher in the Zhichan powder group than in the model group, but the content of malondialdehyde in blood was lower. Our experimental findings indicate that Zhichan powder has an antioxidant effect, it can regulate the expression of monoamine oxidase B and tyrosine hydroxylase in the substantia nigra of Parkinson's disease rats, and it can facilitate the secretion of striatal dopamine and its metabolite homovanillic acid. PMID- 25558224 TI - Effects of Zhichan powder on signal transduction and apoptosis-associated gene expression in the substantia nigra of Parkinson's disease rats. AB - Previous studies have shown that Zhichan powder elevated immunity and suppressed oxidation in mice. Rat models of Parkinson's disease were induced by stereotaxically injecting 6-hydroxydopamine into the substantia nigra. The rat models were intragastrically treated with Zhichan powder, which is composed of milkvetch root, ginseng, bunge swallowwort root, himalayan teasel root, Magnolia officinalis, Ligustrum lucidum Ait. and szechwan lovage rhizome. Immunohistochemistry and reverse transcription-PCR results demonstrated that mRNA and protein expression of tumor necrosis factor receptor 1, Fas, caspase-8, cytochrome C, Bax, caspase-3, and p53 significantly increased, but Bcl-2 expression significantly decreased in the substantia nigra of rats with Parkinson's disease. Following Zhichan powder administration, mRNA and protein expression of tumor necrosis factor receptor 1, Fas, caspase-8, cytochrome C, Bax, caspase-3, and p53 diminished, but Bcl-2 expression increased in the rat substantia nigra. These results indicate that Zhichan powder regulates signal transduction protein expression, inhibits apoptosis, and exerts therapeutic effects on Parkinson's disease. PMID- 25558225 TI - Improvement in quality of life in depressed patients following verum acupuncture or electroacupuncture plus paroxetine: A randomized controlled study of 157 cases. AB - Depressed patients with scores of 17 or more on the 17 items of the Hamilton Depression Rating Scale were treated with the antidepressant drug paroxetine. They also underwent verum acupuncture or electroacupuncture at Baihui (GV20) and Yintang (GV29). The World Health Organization Quality of Life Scale Brief Version showed a significant increase in the total scores of patients who underwent verum acupuncture and electroacupuncture for 6 weeks compared with those who were given paroxetine only; significantly increased physical domain and social relationship scores in verum acupuncture patients compared with paroxetine only; and significantly elevated psychological domain scores with electroacupuncture compared with paroxetine only. These results indicate that both verum acupuncture and electroacupuncture can improve quality of life in depressed patients undergoing paroxetine treatment. PMID- 25558226 TI - Electroacupuncture upregulated platelet derived growth factor expression in spared dorsal root ganglion of cats. AB - A bilateral spared dorsal root ganglion model was established in healthy adult cats by bilateral resection of L1-5 and L7-S2 dorsal root ganglia. L6 dorsal root ganglia were spared. Zusanli (ST36) and Xuanzhong (BL39) or Futu (ST32) and Sanyinjiao (SP6) were alternatively electro-stimulated on the right leg. Immunohistochemical staining of anti-serum platelet-derived growth factor demonstrated that the number of total neurons and medium-small sized platelet derived growth factor positive neurons was significantly decreased on the 7(th) day following injury. After 7 days of acupuncture, the total number of positive and large neurons staining for platelet-derived growth factor on the acupuncture side significantly increased compared to the non-acupuncture side. After acupuncture for 14 days, the total positive and medium-small sized neurons significantly increased compared with the non-acupuncture side. Results indicate that acupuncture promoted the synthesis of platelet-derived growth factor in spared dorsal root ganglia. PMID- 25558227 TI - Neurochemical mechanism of the gastrointestinal interdigestive migrating motor complex in rats with acute inflammatory stomach ache. AB - The normal gastrointestinal interdigestive migrating motor complex cycle was interrupted, and paroxysmal contraction appeared after formaldehyde-induced stomach ache. Activities of nitric oxide synthase, acetylcholinesterase and vasoactive intestinal peptide neurons were significantly reduced, whereas activities of calcitonin gene-related peptide neurons were significantly increased in the pyloric sphincter muscular layer, myenteric nerve plexus and submucous nerve plexus. Electroacupuncture at Zusanli (ST36) suppressed paroxysmal contraction in rats with formaldehyde-induced stomach ache, and neurons in the enteric nervous system were normal. These results indicated that nitrergic neurons, cholinergic neurons, vasoactive intestinal peptide neurons and calcitonin gene-related peptide neurons in the enteric nervous system may be involved in changes to the gastrointestinal interdigestive migrating motor complex following stomach ache, and that electroacupuncture can regulate this process. PMID- 25558228 TI - Construction of a recombinant lentivirus containing human microRNA-7-3 and its inhibitory effects on glioma proliferation. AB - In the present study, we constructed a lentivirus, FIV-CMV-GFP-miR-7-3, containing the microRNA-7-3 gene and the green fluorescent protein gene, and used it to transfect human glioma U251 cells. Fluorescence microscopy showed that 80% of U251 cells expressed green fluorescence. Real-time reverse transcription PCR showed that microRNA-7-3 RNA expression in U251 cells was significantly increased. Proliferation was slowed in transfected U251 cells, and most cells were in the G1 phase of the cell cycle. In addition, the expression of the serine/threonine protein kinase 2 was decreased. Results suggested that transfection with a lentivirus carrying microRNA-7-3 can effectively suppress epidermal growth factor receptor pathway activity in U251 cells, arrest cell cycle transition from G1 phase to S phase and inhibit glioma cell growth. PMID- 25558229 TI - Quantification of Tc-99m-ethyl cysteinate dimer brain single photon emission computed tomography images using statistical probabilistic brain atlas in depressive end-stage renal disease patients: Correlation with disease severity and symptom factors. AB - This study adapted a statistical probabilistic anatomical map of the brain for single photon emission computed tomography images of depressive end-stage renal disease patients. This research aimed to investigate the relationship between symptom clusters, disease severity, and cerebral blood flow. Twenty-seven patients (16 males, 11 females) with stages 4 and 5 end-stage renal disease were enrolled, along with 25 healthy controls. All patients underwent depressive mood assessment and brain single photon emission computed tomography. The statistical probabilistic anatomical map images were used to calculate the brain single photon emission computed tomography counts. Asymmetric index was acquired and Pearson correlation analysis was performed to analyze the correlation between symptom factors, severity, and regional cerebral blood flow. The depression factors of the Hamilton Depression Rating Scale showed a negative correlation with cerebral blood flow in the left amygdale. The insomnia factor showed negative correlations with cerebral blood flow in the left amygdala, right superior frontal gyrus, right middle frontal gyrus, and left middle frontal gyrus. The anxiety factor showed a positive correlation with cerebral glucose metabolism in the cerebellar vermis and a negative correlation with cerebral glucose metabolism in the left globus pallidus, right inferior frontal gyrus, both temporal poles, and left parahippocampus. The overall depression severity (total scores of Hamilton Depression Rating Scale) was negatively correlated with the statistical probabilistic anatomical map results in the left amygdala and right inferior frontal gyrus. In conclusion, our results demonstrated that the disease severity and extent of cerebral blood flow quantified by a probabilistic brain atlas was related to various brain areas in terms of the overall severity and symptom factors in end-stage renal disease patients. PMID- 25558230 TI - Effects of low level laser treatment on the survival of axotomized retinal ganglion cells in adult Hamsters. AB - Injury to axons close to the neuronal bodies in the mammalian central nervous system causes a large proportion of parenting neurons to degenerate. It is known that optic nerve transection close to the eye in rodents leads to a loss of about half of retinal ganglion cells in 1 week and about 90% in 2 weeks. Using low level laser treatment in the present study, we demonstrated that treatment with helium-neon (660 nm) laser with 15 mW power could delay retinal ganglion cell death after optic nerve axotomy in adult hamsters. The effect was most apparent in the first week with a short period of treatment time (5 minutes) in which 65 66% of retinal ganglion cells survived the optic nerve axotomy whereas 45-47% of retinal ganglion cells did so in optic nerve axotomy controls. We also found that single dose and early commencement of laser irradiation were important in protecting retinal ganglion cells following optic nerve axotomy. These findings thus convincingly show that appropriate laser treatment may be neuroprotective to retinal ganglion cells. PMID- 25558232 TI - Reactive astrocytes promote axonal remodeling and neurological recovery after stroke. PMID- 25558231 TI - New drug treatments show neuroprotective effects in Alzheimer's and Parkinson's diseases. AB - Type 2 diabetes is a risk factor for Alzheimer's disease and Parkinson's disease. Insulin signaling in the brains of people with Alzheimer's disease or Parkinson's disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alzheimer's disease and Parkinson's disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer's disease and Parkinson's disease. On the basis of these promising findings, several clinical trials are ongoing with the first encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer's disease and Parkinson's disease that are currently unavailable. PMID- 25558233 TI - Membrane resealing as a promising strategy for early treatment of neurotrauma. PMID- 25558234 TI - GluN2B-NMDA receptors in Alzheimer's disease: beyond synapse loss and cell death. PMID- 25558235 TI - Neuroactive alkaloids that modulate the neuronal nicotinic receptor and provide neuroprotection in an Alzheimer's disease model: the case of Teline monspessulana. PMID- 25558236 TI - Sigma-1 receptor: a potential new target for Parkinson's disease? PMID- 25558237 TI - Syringaldehyde exerts neuroprotective effect on cerebral ischemia injury in rats through anti-oxidative and anti-apoptotic properties. AB - There are few studies on the neuroprotective effects of syringaldehyde in a rat model of cerebral ischemia. The study aimed to elucidate the mechanisms underlying the neuroprotective effects of syringaldehyde on ischemic brain cells. Rat models of cerebral ischemia were intraperitoneally administered syringaldehyde. At 6 and 24 hours after syringaldehyde administration, cell damage in the brain of cerebral ischemia rats was obviously reduced, superoxide dismutase activity and nuclear respiratory factor 1 expression in the brain tissue were markedly increased, malondiadehyde level was obviously decreased, apoptosis-related cysteine peptidase caspase-3 and -9 immunoreactivity was obviously decreased, and neurological function was markedly improved. These findings suggest that syringaldehyde exerts neuroprotective effects on cerebral ischemia injury through anti-oxidation and anti-apoptosis. PMID- 25558238 TI - Does progesterone show neuroprotective effects on traumatic brain injury through increasing phosphorylation of Akt in the hippocampus? AB - There are currently no federally approved neuroprotective agents to treat traumatic brain injury. Progesterone, a hydrophobic steroid hormone, has been shown in recent studies to exhibit neuroprotective effects in controlled cortical impact rat models. Akt is a protein kinase known to play a role in cell signaling pathways that reduce edema, inflammation, apoptosis, and promote cell growth in the brain. This study aims to determine if progesterone modulates the phosphorylation of Akt via its threonine 308 phosphorylation site. Phosphorylation at the threonine 308 site is one of several sites responsible for activating Akt and enabling the protein kinase to carry out its neuroprotective effects. To assess the effects of progesterone on Akt phosphorylation, C57BL/6 mice were treated with progesterone (8 mg/kg) at 1 (intraperitonally), 6, 24, and 48 hours (subcutaneously) post closed-skull traumatic brain injury. The hippocampus was harvested at 72 hours post injury and prepared for western blot analysis. Traumatic brain injury caused a significant decrease in Akt phosphorylation compared to sham operation. However, mice treated with progesterone following traumatic brain injury had an increase in phosphorylation of Akt compared to traumatic brain injury vehicle. Our findings suggest that progesterone is a viable treatment option for activating neuroprotective pathways after traumatic brain injury. PMID- 25558239 TI - Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury. AB - The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after fluid percussion injury. Diazepam can inhibit the hyperexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment significantly increased the slope of input-output curves in rat neurons after fluid percussion injury. Diazepam significantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 MUmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the fluid percussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area. PMID- 25558240 TI - The occurrence of diffuse axonal injury in the brain: associated with the accumulation and clearance of myelin debris. AB - The accumulation of myelin debris may be a major contributor to the inflammatory response after diffuse axonal injury. In this study, we examined the accumulation and clearance of myelin debris in a rat model of diffuse axonal injury. Oil Red O staining was performed on sections from the cerebral cortex, hippocampus and brain stem to identify the myelin debris. Seven days after diffuse axonal injury, many Oil Red O-stained particles were observed in the cerebral cortex, hippocampus and brain stem. In the cerebral cortex and hippocampus, the amount of myelin debris peaked at 14 days after injury, and decreased significantly at 28 days. In the brain stem, the amount of myelin debris peaked at 7 days after injury, and decreased significantly at 14 and 28 days. In the cortex and hippocampus, some myelin debris could still be observed at 28 days after diffuse axonal injury. Our findings suggest that myelin debris may persist in the rat central nervous system after diffuse axonal injury, which would hinder recovery. PMID- 25558241 TI - Adult neurogenesis in the four-striped mice (Rhabdomys pumilio). AB - In this study, we investigated non-captive four-striped mice (Rhabdomys pumilio) for evidence that adult neurogenesis occurs in the adult brain of animal models in natural environment. Ki-67 (a marker for cell proliferation) and doublecortin (a marker for immature neurons) immunostaining confirmed that adult neurogenesis occurs in the active sites of subventricular zone of the lateral ventricle with the migratory stream to the olfactory bulb, and the subgranular zone of the dentate gyrus of the hippocampus. No Ki-67 proliferating cells were observed in the striatum substantia nigra, amygdala, cerebral cortex or dorsal vagal complex. Doublecortin-immunoreactive cells were observed in the striatum, third ventricle, cerebral cortex, amygdala, olfactory bulb and along the rostral migratory stream but absent in the substantia nigra and dorsal vagal complex. The potential neurogenic sites in the four-striped mouse species could invariably lead to increased neural plasticity. PMID- 25558242 TI - Reversible lesions in the brain parenchyma in Wilson's disease confirmed by magnetic resonance imaging: earlier administration of chelating therapy can reduce the damage to the brain. AB - The aim of this study was to evaluate the resolution of brain lesions in patients with Wilson's disease during the long-term chelating therapy using magnetic resonance imaging and a possible significance of the time latency between the initial symptoms of the disease and the introduction of this therapy. Initial magnetic resonance examination was performed in 37 patients with proven neurological form of Wilson's disease with cerebellar, parkinsonian and dystonic presentation. Magnetic resonance reexamination was done 5.7 +/- 1.3 years later in 14 patients. Patients were divided into: group A, where chelating therapy was initiated < 24 months from the first symptoms and group B, where the therapy started >= 24 months after the initial symptoms. Symmetry of the lesions was seen in 100% of patients. There was a significant difference between groups A and B regarding complete resolution of brain stem and putaminal lesions (P = 0.005 and P = 0.024, respectively). If the correct diagnosis and adequate treatment are not established less than 24 months after onset of the symptoms, irreversible lesions in the brain parenchyma could be expected. Signal abnormalities on magnetic resonance imaging might therefore, at least in the early stages, represent reversible myelinolisis or cytotoxic edema associated with copper toxicity. PMID- 25558243 TI - Inhibition of Sirtuin 2 exerts neuroprotection in aging rats with increased neonatal iron intake. AB - Impaired iron homeostasis may cause damage to dopaminergic neurons and is critically involved in the pathogenesis of Parkinson's disease. At present, very little is understood about the effect of neonatal iron intake on behavior in aging animals. Therefore, we hypothesized that increased neonatal iron intake would result in significant behavior abnormalities and striatal dopamine depletion during aging, and Sirtuin 2 contributes to the age-related neurotoxicity. In the present study, we observed that neonatal iron intake (120 MUg/g per day) during postnatal days 10-17 resulted in significant behavior abnormalities and striatal dopamine depletion in aging rats. Furthermore, after AK-7 (a selective Sirtuin 2 inhibitor) was injected into the substantia nigra at postnatal 540 days and 570 days (5 MUg/side per day), striatal dopamine depletion was significantly diminished and behavior abnormality was improved in aging rats with neonatal iron intake. Experimental findings suggest that increased neonatal iron intake may result in Parkinson's disease-like neurochemical and behavioral deficits with aging, and inhibition of Sirtuin 2 expression may be a neuroprotective measure in Parkinson's disease. PMID- 25558244 TI - Amyloid precursor-like protein 2 C-terminal fragments upregulate S100A9 gene and protein expression in BV2 cells. AB - The murine microglial cell line BV2 has neuroprotective effects, but is toxic to neurons by secreting inflammatory cytokines, and is an important target in the treatment of nerve inflammation and neurodegenerative diseases. In the present study, we observed the effects of transfecting three amyloid precursor-like protein 2 (APLP2) C-terminal fragments (CTFs; C57, C50 and C31) in the pEGFP-N1 vector on S100A9 expression in BV2 cells. Reverse transcription-PCR, western blot assay and immunocytochemistry revealed that S100A9 protein and mRNA expression was greater in BV2 cells after CTF transfection than after mock transfection with an empty vector. Furthermore, transfection of full-length APLP2-751 resulted in low levels of S100A9 protein expression. Our results show that APLP2-CTFs upregulate S100A9 protein and mRNA expression in BV2 cells, and identify a novel pathway involved in neuronal injury and apoptosis, and repair and protection in Alzheimer's disease. PMID- 25558245 TI - Recovery of cerebellar peduncle injury in a patient with a cerebellar tumor: validation by diffusion tensor tractography. PMID- 25558246 TI - Hot spots and future directions of research on the neuroprotective effects of nimodipine. AB - Calcium antagonists are widely used in the clinical treatment of ischemic cerebrovascular disease because of their vascular and neuroprotective effects. Nimodipine, a typical calcium antagonist, can cross the blood-brain barrier and act selectively at neurons and blood vessels of target tissues, thus exerting neuroprotective effects. The aim of the present study was to explore the hot spots and future trends of research on the neuroprotective effects of nimodipine. We retrieved 425 articles on the neuroprotective effects of nimodipine that were indexed in the Web of the Science database between 2000 and 2014. The retrieved articles were analyzed using document analysis reporting and the derived information function in the Web of Science, and the information visualization software CiteSpace III. The reference co-citation network was plotted, and the high frequency key words in these publications were used to analyze the research fronts and development trends for nimodipine neuroprotection. According to these co-citation clusters, the research front of nimodipine neuroprotection is the use of randomized controlled trials to study nimodipine intervention of subarachnoid hemorrhage. Using time zone view analysis on hot spots labeled with a key word, the areas of interest in the field of nimodipine neuroprotection are nimodipine pharmacology and therapeutics, blood-brain barrier, trials, and anti-angiospasm. PMID- 25558248 TI - Effect of applying cold gel pack on the pain associated with deep breathing and coughing after open heart surgery. AB - BACKGROUND: Coughing and deep breathing after sternotomy causes severe pain. This study was conducted to assess the effect of cold therapy on the pain in patients undergoing open heart surgery. MATERIALS AND METHODS: In a randomized controlled trial (RCT) with crossover design, 50 eligible and consenting patients were recruited and randomly allocated to gel pack and non-gel pack groups on the first postoperative day. All patients performed four episodes of deep breathing and coughing (DB and C) every 2 h. Pain intesity was measured and compared at rest and after DB and C in both groups. At the end of the study, all patients were asked about their preferences for the cold gel pack application prior to DB and C. The study hypotheses were analyzed using repeated measures analysis of variance (RM-ANOVA). RESULTS: Data analysis showed significant reduction in pain scores (P < 0.001) after cold gel application. Forty-five (90%) patients were inclined to reapply the gel pack in the future. CONCLUSION: Cold gel pack can reduce the pain associated with DB and C in cardiac surgery patients. PMID- 25558249 TI - Experiences of adult smokers from the concepts of smoking: A content analysis. AB - BACKGROUND: Smoking cigarettes is a risk factor for many physical and mental diseases. About five million people die of smoking every year. Understanding the concept of cigarette smoking can help people develop their knowledge with regard to smoking. A qualitative research seems essential to detect these concepts. Therefore, the present study aims to take into account the experience of adult smokers with regard to the concept of smoking. MATERIALS AND METHODS: This is a qualitative content analysis study conducted on 12 smokers in four selected cities in Iran. Data were collected by in-depth, semi-structured interviews, transcribed verbatim, and simultaneously coded. Subsequently, they were analyzed using the content analysis method. RESULTS: In the present study, eight concepts (themes), 22 subcategories, and 81 codes have emerged. The obtained concepts are physics of a cigarette, addiction and dependency, habit, feel the need, pleasure, seeking peace, mental involvement, and self-induction. CONCLUSIONS: The participants' experiences with regard to cigarette smoking can affect their understanding of the concepts of smoking. The understanding of these concepts by nurses and smokers can enhance their knowledge about the existing facts of smoking, which can act as a foundation for designing preventive methods and smoking cessation programs. PMID- 25558247 TI - Modeling murine yolk sac hematopoiesis with embryonic stem cell culture systems. AB - The onset of hematopoiesis in mammals is defined by generation of primitive erythrocytes and macrophage progenitors in embryonic yolk sac. Laboratories have met the challenge of transient and swiftly changing specification events from ventral mesoderm through multipotent progenitors and maturing lineage-restricted hematopoietic subtypes, by developing powerful in vitro experimental models to interrogate hematopoietic ontogeny. Most importantly, studies of differentiating embryonic stem cell derivatives in embryoid body and stromal coculture systems have identified crucial roles for transcription factor networks (e.g. Gata1, Runx1, Scl) and signaling pathways (e.g. BMP, VEGF, WNT) in controlling stem and progenitor cell output. These and other relevant pathways have pleiotropic biological effects, and are often associated with early embryonic lethality in knockout mice. Further refinement in subsequent studies has allowed conditional expression of key regulatory genes, and isolation of progenitors via cell surface markers (e.g. FLK1) and reporter-tagged constructs, with the purpose of measuring their primitive and definitive hematopoietic potential. These observations continue to inform attempts to direct the differentiation, and augment the expansion, of progenitors in human cell culture systems that may prove useful in cell replacement therapies for hematopoietic deficiencies. The purpose of this review is to survey the extant literature on the use of differentiating murine embryonic stem cells in culture to model the developmental process of yolk sac hematopoiesis. PMID- 25558250 TI - Effects of needs-assessment-based psycho-education of schizophrenic patients' families on the severity of symptoms and relapse rate of patients. AB - BACKGROUND: Family psycho-education is one of the most effective interventions for preventing relapse in patients with schizophrenia. We evaluated the efficacy of a needs-assessment-based educational program in comparison with a current program (textbook based) in the treatment of schizophrenia. MATERIALS AND METHODS: Patients with schizophrenia and their families (N = 60) were allocated to needs-assessment-based education (treatment) and textbook-based (control) programs; both included 10 sessions of education within about 6 months. Symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) prior to intervention and every 3 months for a total of 18 months. A 25% decrease or increase in total PANSS score was considered as response or relapse, respectively. RESULTS: Forty-two cases completed the study. The total PANSS score was significantly decreased in both groups with more reduction in the treatment group. Positive and negative scale scores were reduced in the treatment group, but not significantly in the control group. Response rate was higher in the treatment group and relapse rate was lower (15% vs. 27.2%, P = 0.279). In logistic regression analysis, needs-assessment-based psycho-education was associated with more treatment response. CONCLUSIONS: Needs-assessment-based psycho-education is more effective than textbook-based education for treating schizophrenia. We recommend psychiatric care centers to conduct needs-assessment and develop their own program for family psycho-education. PMID- 25558251 TI - Effect of subcutaneous Enoxaparin injection duration on bruising size in acute coronary syndrome patients. AB - BACKGROUND: Bruising is an unpleasant result of subcutaneous injection of Enoxaparin, which causes physical discomfort, limitation of injection site, patient's refusal of treatment, and distrust in nurses' ability. The application of techniques which reduce patients' fear, anxiety, and physical damage is one of the tasks of nurses. This clinical trial investigated the effect of duration of subcutaneous Enoxaparin injection on the bruising size in acute coronary syndrome patients. MATERIALS AND METHODS: Seventy 35-75-year-old acute coronary syndrome patients hospitalized in Coronary Care Units were selected randomly. Each subject received 10- and 30-sec duration of injections by a single researcher on both sides of the abdomen in 12-h intervals. The bruising size was measured using a transparent millimeter measuring paper, 24 and 48 h after each injection. Data were gathered by a data recording form (demographic and measurements data) and analyzed by descriptive statistics and non-parametric tests through SPSS. RESULTS: Results showed that the mean bruising sizes at 24 h after 10- and 30-sec injection were 33.26 mm(2) (72.77) and 48.96 mm(2) (99.91), respectively, and at 48 h were 15.61 mm(2) (142.02) and 52.48 mm(2) (143), respectively. There was no significant relationship between the two techniques (P > 0.05), although the effect of age on bruising size was significant (P = 0.01). CONCLUSION: According to the findings of the present study, length of Enoxaparin subcutaneous injection has no effect on the bruising size. PMID- 25558252 TI - Risk of early menopausal symptoms in clinical workers. AB - BACKGROUND: Workplace exposures as in clinical work can cause disorders. Some organ systems are at risk. This work may be a risk factor for early symptoms of menopause. The objective of this study was to compare the early symptoms of menopause between hospital personnel who work in clinical and office settings. MATERIALS AND METHODS: This was a historical cohort study conducted on clinical and office workers of hospitals. The study was conducted using a flexible interview conducted with a questionnaire among personnel of age 40 years and above. According to their menopausal status, they were divided into three phases: premenopause, perimenopause, and postmenopause. Symptoms in 10 items were assessed and scored from 1 to 10, and were compared. Data were analyzed with SPSS 16, t-test, and Chi-square tests and were calculated considering P < 0.05 as the significant level. Odds ratios were calculated along with 95% confidence interval. RESULTS: Frequency of menopausal symptoms was higher in the clinical group than in the office group. In the clinical group, the odds ratio for menopausal symptoms like flashing and sweating was 1.879 (1.457-2.423) and in the office personnel, it was 0.192 (0.030-1.238). In the clinical group, the odds ratio for anxiety and irritability was 2.029 (1.660-2.481) and in the office personnel, it was 0.116 (0.017-0.779). CONCLUSIONS: Clinical personnel had higher risk for early menopausal symptoms such as flashing, sweating, anxiety, and irritability. Assessing the health of these personnel may help to improve their reproductive health. The person with reproductive risk factors is not suitable for clinical work. PMID- 25558253 TI - The effect of lavender essential oil on anxiety level in patients undergoing coronary artery bypass graft surgery: A double-blinded randomized clinical trial. AB - BACKGROUND: Open heart surgery can cause high levels of anxiety in patients. Nowadays, lavender essential oil is widely used in medical research. This study was conducted with an aim to investigate the effects of lavender essential oil to reduce the anxiety of patients after coronary artery bypass surgery. MATERIALS AND METHODS: This research is double-blinded randomized controlled trial on 60 patients who had undergone coronary artery bypass surgery in a 2-day intervention targeting reduction of anxiety. This study was conducted in Ekbatan Therapeutic and Educational Center, Hamadan city, Iran, in 2013. The patients in the inhalation aromatherapy group inhaled two drops of 2% lavender essential oil and those in the control group inhaled two drops of distilled water as placebo for 20 min on the 2(nd) and 3(rd) days after surgery. The level of anxiety was evaluated by Spielberger's State Anxiety questionnaire before and after intervention and the vital signs were documented as well. Data were analyzed using Stata 11 (Stata Corp., College Station, TX, USA) by independent t-test for continuous variables and Chi-square test for categorical variables. RESULTS: The mean score of anxiety in the aromatherapy group was 48.73 +/- 5.08 and in the control group was 48 +/- 6.98 before the intervention (P = 0.64), which reduced after the intervention to 42.6 +/- 5.44 and 42.73 +/- 7.30, respectively. On the 3(rd) day after surgery, the mean score of anxiety in the aromatherapy group was 46.76 +/- 4.07 and in the control group was 46.53 +/- 7.05 before the intervention, which reduced to 41.33 +/- 3.65 and 41.56 +/- 6.18, respectively, after the intervention. However, there was no statistically significant difference in the mean scores of anxiety between the aromatherapy and control groups. CONCLUSIONS: Lavender essential oil has no significant effect on anxiety in patients after coronary artery bypass surgery, although it decreased the level of anxiety in the patients. PMID- 25558254 TI - Comparative evaluation of the efficacy of herbal drugs (fennelin and vitagnus) and mefenamic acid in the treatment of primary dysmenorrhea. AB - BACKGROUND: Different therapeutic methods have been applied for the treatment of dysmenorrhea and the method with the lesser side effects is preferred. The aim of this study was to compare the effects of herbal products (fennelin and vitagnus) and mefenamic acid in the treatment of primary dysmenorrhea. MATERIALS AND METHODS: This ouble-blind clinical trial was carried out in 105 students with mild and moderate dysmenorrhea. The students were randomly divided into four groups which received the extracts of fennelin and vitagnus, mefenamic acid, and placebo, respectively. Severity of pain was detected by the Visual Analog Scale (VAS) during one cycle before and two cycles after the intervention. Data were analyzed by SPSS version 16 and (P < 0.05 was considered significant. RESULTS: Demographic characteristics of the students were similar in the four groups. There was no significant difference in the mean of severity of dysmenorrhea during one cycle before the intervention between the four groups, but the difference was significant during two cycles after the intervention. Fennelin had similar effects as vitagnus on dysmenorrhea. Mefenamic acid had less effect than both the drugs (P <0.05). CONCLUSION: Fennelin and vitagnus had higher effect than mefenamic acid. Use of these products is suggested for dysmenorrhea. PMID- 25558255 TI - Iranian nurses' experience of essential technical competences in disaster response: A qualitative content analysis study. AB - BACKGROUND: Today disasters are a part of many people's lives. Iran has a long history of disaster events and nurses are one of the most significant groups within the Iranian disaster relief operations, providing immediate and long-term care for those affected by the disaster. However, the technical competence of Iranian nurses and their training for this work has received little attention. This article presents the results of a study that aims to explore this context. MATERIALS AND METHODS: A qualitative study was conducted using in-depth interviews to collect data from 30 nurses, who were deliberately selected from the health centers affiliated to the Isfahan University of Medical Sciences. Themes were identified using the conventional qualitative content analysis. The trustworthiness of the study was supported by considering the auditability, neutrality, consistency, and transferability. The study lasted from 2011 to 2012. RESULTS: Data analysis undertaken for the qualitative study resulted in the identification of five main themes, which included: (1) Management competences, (2) ethical and legal competences, (3) team working, and (4) personal abilities and the specific technical competences presented in this report. CONCLUSIONS: This report presents an overview of the nursing technical capabilities required for Iranian nurses during disaster relief. It is argued that additional competencies are required for nurses who care in high-risk situations, including disasters. Nurses need to prepare themselves more effectively to be responsible and effective in nursing care. PMID- 25558256 TI - Quality of life in multiple sclerosis (MS) and role of fatigue, depression, anxiety, and stress: A bicenter study from north of Iran. AB - BACKGROUND: Although studies have demonstrated significant negative relationships between quality of life (QOL), fatigue, and the most common psychological symptoms (depression, anxiety, stress), the main ambiguity of previous studies on QOL is in the relative importance of these predictors. Also, there is lack of adequate knowledge about the actual contribution of each of them in the prediction of QOL dimensions. Thus, the main objective of this study is to assess the role of fatigue, depression, anxiety, and stress in relation to QOL of multiple sclerosis (MS) patients. MATERIALS AND METHODS: One hundred and sixty two MS patients completed the questionnaire on demographic variables, and then they were evaluated by the Persian versions of Short-Form Health Survey Questionnaire (SF-36), Fatigue Survey Scale (FSS), and Depression, Anxiety, Stress Scale-21 (DASS-21). Data were analyzed by Pearson correlation coefficient and hierarchical regression. RESULTS: Correlation analysis showed a significant relationship between QOL elements in SF-36 (physical component summary and mental component summary) and depression, fatigue, stress, and anxiety (P < 0.01). Hierarchical regression analysis indicated that among the predictor variables in the final step, fatigue, depression, and anxiety were identified as the physical component summary predictor variables. Anxiety was found to be the most powerful predictor variable amongst all (beta = -0.46, P < 0.001). Furthermore, results have shown depression as the only significant mental component summary predictor variable (beta = -0.39, P < 0.001). CONCLUSIONS: This study has highlighted the role of anxiety, fatigue, and depression in physical dimensions and the role of depression in psychological dimensions of the lives of MS patients. In addition, the findings of this study indirectly suggest that psychological interventions for reducing fatigue, depression, and anxiety can lead to improved QOL of MS patients. PMID- 25558257 TI - "Parents a dead end life": The main experiences of parents of children with leukemia. AB - BACKGROUND: The quantitative studies show that due to the widespread prevalence, high death rate, high treatment expenses, and long hospital stay, leukemia influences the families and their children to a great extent. In this regard, no qualitative study has been conducted in Iran. So, this study was conducted in Arak in 2011 with the aim of expressing the experiences of the parents whose children suffered from leukemia. MATERIALS AND METHODS: Using qualitative research approach, by applying content analysis method, 22 participants were interviewed in two educational hospitals during 2 months. The study was started by purposive sampling and continued by theoretical one. The data were analyzed based on the content analysis method. RESLUTS: Data analysis showed that insolvency, knapsack problems, cancer secrecy, trust on God, self-sacrifice, adaptation, medical malpractice, and hospital facilities were the level 3 codes of parents' experiences and "parents a dead end life" was the main theme of this study. CONCLUSION: In this study, the experiences of the parents whose children suffered from cancer were studied deeply by the use of qualitative method, especially by the use of resources syncretism rather than studying quantitatively. Parents a dead end life emerged as the main theme of this study, emphasizing the necessity of paying further attention to the parents. On the other hand, making more use of parents' experiences and encouraging them helps make the treatment more effective. It is suggested that these experiences be shared with parents in the form of pamphlets distributed right at the beginning of the treatment process. PMID- 25558258 TI - The effect of progressive muscle relaxation method on test anxiety in nursing students. AB - BACKGROUND: Concerning the prevalence of test anxiety among nursing students and presence of stress in nursing education years, this study was conducted to determine the effect of progressive muscle relaxation method on test anxiety among nursing students of Isfahan University of Medical Sciences in 2013. MATERIALS AND METHODS: This was a quasi-experimental study conducted in three stages on 49 male and female nursing students divided into two groups (study and control). In the pre-test stage, demographic data and Sarason anxiety questionnaires were filled by 94 students (of terms 3 and 4). Then, in the intervention stage, the students having test anxiety were assigned to two groups (study and control), and the progressive muscle relaxation method was performed in the experiment group in four sessions. Then, the students did this method two times a day until final exams, immediately following which they filled the self reported checklists. On the first day of the final exams, test anxiety questionnaire was filled by the two groups again. The collected data were analyzed by the statistical tests, i.e. chi(2), paired t-test, independent sample t-test, Mann-Whitney and Wilcoxon tests, using SPSS 18. RESULTS: Independent t test showed a significant difference in the mean scores of test anxiety after intervention between the two groups of study and control (P = 0.00), but this difference was not significant before intervention (P = 0.76). Also, in the study group, there was a significant difference in the mean scores of test anxiety before and after intervention (P = 0.00), but this difference was not significant in the control group (P = 0.09). Mann-Whitney test showed no significant difference in categorization of test anxiety scores before intervention in the study and control groups (P = 0.60), but the difference was significant after intervention (P = 0.00). Wilcoxon test showed a significant difference in categorization of test anxiety scores in the study group before and after intervention (P = 0.00), but the difference was not significant in the control group (P = 0.083). CONCLUSIONS: Generally, the results showed that performing progressive muscle relaxation method was effective in reducing test anxiety among nursing students. It is suggested to conduct educational programs concerning this method in the faculties of nursing to decrease the test anxiety of nursing students. PMID- 25558259 TI - The utilization rate of antenatal care after health sector reform implementation in rural areas of Islamic Republic of Iran. AB - BACKGROUND: Improving the utilization rate of antenatal care is a critical strategy for achieving the reproductive health goals in Iran. The aim of this study was to assess the utilization rate of antenatal care (ANC) by women after health sector reform (HSR) interventions in rural areas of Islamic Republic of Iran (IR Iran). MATERIALS AND METHODS: This is a retrospective cross-sectional study. The data were gathered by cluster sampling from 400 motherhood records of mothers whose last pregnancies had been terminated in the first 3 months of 2013. Data were collected from 21 rural health centers of Isfahan district during the year 2013. The utilization rate of ANC by mothers was assessed by the number of visits they had, the time of the first ANC visit, the occurrence of pregnancy- or delivery-related complications, and the number of postpartum visits. RESULTS: The mean time of the first ANC was 9 +/- 5.23(th) week of gestational age. For 69.3% of pregnant women, the first ANC was before the 12(th) week. Overall, the frequency of ANC visits ranged from 2 to 21, with the average of 10.6 +/- 3.23 visits. 93.8% of the utilized ANC visits were adequate. 99.8% of the deliveries took place in the hospital. 99% of mothers had at least one visit in the postpartum period. 4% of the mothers had suffered from pregnancy-related complications. CONCLUSION: It seems that IR Iran has achieved to one of the important objectives by its reform in health care access, that is, more ANC for pregnant women. PMID- 25558260 TI - The evaluation of reproductive health PhD program in Iran: The input indicators analysis. AB - BACKGROUND: Appropriate quality achievement of a PhD program requires frequent assessment and discovering the shortcomings in the program. Inputs, which are important elements of the curriculum, are frequently missed in evaluations. The purpose of this study was to evaluate the input indicators of reproductive health PhD program in Iran based on the Context, Input, Process, and Product (CIPP) evaluation model. MATERIALS AND METHODS: This is a descriptive and evaluative study based on the CIPP evaluation model. It was conducted in 2013 in four Iranian schools of nursing and midwifery of medical sciences universities. Statistical population consisted of four groups: heads of departments (n = 5), faculty members (n = 18), graduates (n = 12), and PhD students of reproductive health (n = 54). Data collection tools were five separate questionnaires including 37 indicators that were developed by the researcher. Content and face validity were evaluated based on the experts' indications. The Cronbach's alpha coefficient was calculated in order to obtain the reliability of the questionnaires. Collected data were analyzed by SPSS software. Data were analyzed by descriptive statistics (mean, frequency, percentage, and standard deviation), and one-way analysis of variance (ANOVA) and least significant difference (LSD) post hoc tests to compare means between groups. RESULTS: The results of the study indicated that the highest percentage of the heads of departments (80%), graduates (66.7%), and students (68.5%) evaluated the status of input indicators of reproductive health PhD program as relatively appropriate, while most of the faculties (66.7%) evaluated that as appropriate. CONCLUSIONS: It is suggested to explore the reasons for relatively appropriate evaluation of input indicators by further academic researches and improve the reproductive health PhD program accordingly. PMID- 25558261 TI - The effect of a family need-based program on burden of caregivers of leukemia patients in Isfahan in 2013-2014. AB - BACKGROUND: The family of cancer patients experience burden of care because of their caring role. Therefore, appropriate and effective interventions are essential in order to decrease burden. The goal of the present research was to determine the effect of a family need-based program on the burden of care in caregivers of leukemia patients. MATERIALS AND METHODS: In this clinical research, 70 caregivers of leukemia patients who referred to Sayed Al-Shohada Medical Center in Isfahan, Iran were chosen and divided, through convenient sampling method and using table of random numbers, into two groups, experimental and control. Caregivers of the experimental group attended five training sessions. The data collection tool of this study was the Zarit Burden Scale. It was completed by members of both groups before, immediately after, and 1 month after the intervention. The data obtained were analyzed with SPSS software. RESULTS: During the study period, burden slowly decreased in the experimental group and increased in the control group. Mean burden of care score before, immediately after, and 1 month after the intervention was 63.6, 30.4, and 23.03, respectively, in the experimental group and 62.5, 67.3, and 68.8, respectively, in the control group. In addition, the mean burden score in the experimental group significantly decreased in comparison with the control group (P < 0.001). CONCLUSION: This family need-based program can decrease burden in caregivers of leukemia patients and may potentially improve the quality of life of both patients and caregivers. PMID- 25558262 TI - Sources of hope: Perception of Iranian family members of patients in the Intensive Care Unit. AB - BACKGROUND: Admission to an Intensive Care Unit (ICU) is recognized as a situation with emotional strain, uncertainty, and fear of losing the patient. In such stressful situations, it is hope that can promote psychological stability in the patient's family members. Related literature revealed that sources of hope in this situation have still not been discussed well in studies. The purpose of this qualitative study was to explore the sources of hope from the perspective of families of ICU patients in Iran. MATERIALS AND METHODS: In this qualitative study that was carried out adopting the conventional qualitative content analysis approach, 19 family members of 13 patients hospitalized in the ICU from three teaching hospitals were selected, through purposive sampling. Semi-structured interviews were used for data collection. The interviews were transcribed verbatim and analyzed using conventional content analysis, through the process of data reduction and condensation, coding, and also generating categories and subcategories. RESULTS: Analysis of the data revealed sources of hope in families of ICU patients. These sources appeared as two main categories- internal sources and external sources. The internal sources had two subcategories consisting of 'religious-spirituality beliefs' and 'positive attitude'. The external sources had four subcategories consisting of healthcare professionals' interactions, empathy of families and friends, patient's condition, and participation in care. CONCLUSIONS: The results of this study showed the sources of hope in the families of the patients in the ICU. These sources, as moderating factors, could reduce physical and psychological damages caused to the families. In the present study, the categorizations of the participants' in-depth experience could develop a new horizon for healthcare professionals, especially nurses, on the sources of hope, based on culture. PMID- 25558263 TI - Effect of using static ultrasound technique on peripherally inserted central catheters' insertion success rate in neonates in a neonatal intensive care unit. AB - BACKGROUND: Peripheral insertion of central catheters can be difficult in neonates. We compared the success rates of peripherally inserted central catheters by two methods of using static ultrasound and traditional technique (vein visualization and palpation) in neonates. MATERIALS AND METHODS: In a prospective randomized, controlled trial, 52 neonates with birth weight lower than 1500 g in a level 3 neonatal intensive care unit were enrolled. Neonates were randomized to undergo peripherally inserted central catheter placement using a traditional technique (n = 27) versus static ultrasound-guided technique (n = 25). In the ultrasound group, vein localization was performed and the skin overlying the target vessel was marked. Insertion of catheter was then immediately performed. We recorded and compared success rates in the groups. RESULTS: Success rate after the first attempt was 68% in ultrasound group and 60% in traditional group. These rates for the second attempt were 50% and 40%, respectively. The overall success rates after two attempts were 84% and 76% in ultrasound and traditional groups, retrospectively (P = 0.24). CONCLUSIONS: There was no significant difference between the two groups regarding PICC success rates, probably because in the present study, most of the subjects were premature neonates whose vasculature was visually detectable. PMID- 25558264 TI - Investigating the effect of an education plan based on the health belief model on the physical activity of women who are at risk for hypertension. AB - BACKGROUND: Hypertension is the main risk factor of many diseases and the main reason of death all over the world. Because the signs of hypertension are not clear, people do not feel its dangers and do not believe they are at risk. This problem makes preventing hypertension a great challenge for the health system. One factor that is related to lifestyle and is effective in preventing hypertension is increasing exercise. The aim of this study is investigate the effect of an education plan based on the health belief model on the physical activity of women who are at risk for hypertension. MATERIALS AND METHODS: This is a field experimental study. Field of study was two health care centers in Isfahan, which were selected through simple random sampling. Ninety-two females who were at risk for hypertension were the subjects of study. Subjects were selected through systematic sampling. Beck questionnaire was used to evaluate the physical activity of both experimental and control group subjects before and 2 months after the intervention. The intervention plan was three education sections that were conducted in 4 weeks. The data were analyzed by descriptive statistical tests and inferential tests of repetitive variance analysis and t-test through SPSS. RESULTS: The results showed that the average of physical activity increased significantly in the intervention group 2 months after education (P = 0.03). CONCLUSIONS: The findings of the study confirm the efficiency of education plan based on the health belief model on the physical activity of women who are at risk for hypertension. PMID- 25558265 TI - Comparison of childbirth training workshop effects on knowledge, attitude, and delivery method between mothers and couples groups referring to Isfahan health centers in Iran. AB - BACKGROUND: The World Health Organization announced the acceptable level of cesarean section (CS) as 10-15%. In recent years, the rate of CS has been increasing irregularly. Lack of appropriate knowledge and attitude among couples plays a major role in this regard. This study tried to compare the effects of a childbirth training workshop on knowledge, attitude, and delivery method. MATERIALS AND METHODS: The present study is a randomized clinical trial conducted in four stages on 180 subjects referring to Isfahan health care centers in three groups of mothers (alone), couples (mothers and their respective partners), and control. After sampling, a pre-test and intervention in the form of an educational workshop were conducted. Then, post-test was conducted immediately after, 1 month later, and in puerperium in all three groups. Data were analyzed by SPSS version 15. RESULTS: The analysis showed that the knowledge mean was statically significant in mothers (P < 0.0001), couples (P < 0.0001), and control group (P < 0.0001) before and after intervention. Also, the attitude mean was statically significant in mothers (P < 0.0001), couples (P < 0.0001), and control groups (P < 0.0001) before and after intervention. Analysis of delivery method showed that in mothers, couples, and control groups, normal vaginal delivery was the most preferred method in that order, w hich was significant (P = 0.017). CONCLUSIONS: Workshop education of pregnant women and their spouses was effective on encouraging them to natural delivery. Therefore, designing educational and counseling programs through collaborative methods for mothers and their spouses is suggested to reduce the rate of cesarean deliveries. PMID- 25558266 TI - Several food items and multiple sclerosis: A case-control study in Ahvaz (Iran). AB - BACKGROUND: Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system. Despite extensive research, its exact cause is unknown. One of the roles of nurses is discovery and prevention of factors related to the disease. This study aimed to investigate several food items concerning the etiology of MS in a population of Ahvaz (Iran). MATERIALS AND METHODS: This case control study was conducted on 113 MS patients and 113 healthy women. Food information was collected through interviews using a standard designed questionnaire. Statistical analysis was performed by adopting descriptive tests (mean, frequency, standard deviation) and inferential tests (Chi-square test, Fisher's exact test, logistic regression, and multivariate conditional logistic regression with a significance level of 0.05 and 95% confidence interval) through SPSS version 19. RESULTS: Univariate regression analysis showed a significant association between MS and consumption of solid vegetable oil (P = 0.004), fruits (P = 0.002), vegetables (P = 0.016), dates (P = 0.02), and low-fat dairy (P = 0.009) more than five times a week. According to multivariate conditional logistic regression analysis, consumption of fruits (P = 0.03) and low-fat dairy (P = 0.04) more than five times a week had a protective role and solid vegetable oil consumption was significantly associated with a risk for MS (P = 0.01). CONCLUSIONS: This study suggests a protective role of consumption of fruits and low-fat dairy in MS and an increased risk of MS with solid vegetable oil consumption in Ahvaz (Iran). PMID- 25558267 TI - Comparison of the effect of aromatherapy with Jasminum officinale and Salvia officinale on pain severity and labor outcome in nulliparous women. AB - BACKGROUND: Using non-pharmacological pain relief methods for reducing labor pain has always been one of the major concerns in obstetrics and gynecology. OBJECTIVE: Comparing the effects of aromatherapy with jasmine and salvia on pain severity and labor outcome in nulliparous women. MATERIALS AND METHODS: In this randomized clinical trial, 156 nulliparous women in labor were randomly selected and divided into salvia, jasmine, and control groups (52 in each group). The study duration was 6 months (from October 2009 to March 2010). Each group underwent aromatherapy using an incense mask for 15 min (distilled water for the control group). Pain severity was measured before and 30 and 60 min after the incense aromatherapy. Also, duration of the first and second stages of labor, first- and fifth-minute APGAR scores of the baby, and the frequency of labor type were measured and recorded in each group. RESULTS: In comparison to the other groups, pain severity and duration of the first and second stages of labor were significantly lower in the aromatherapy group of salvia 30 min after the intervention (P = 0.001). However, no significant difference was found among the three groups regarding pain severity 60 min after the aromatherapy, first- and fifth-minute APGAR scores of the baby, and the frequency of labor type. CONCLUSIONS: The results of the present study indicated that aromatherapy with saliva had beneficial effects on pain relief, shortened the labor stages, and had no negative impact on the baby's APGAR score. PMID- 25558268 TI - The effect of earplugs and eye mask on patients' perceived sleep quality in intensive care unit. AB - BACKGROUND: Sleep is one of the basic human needs and sleep deprivation causes numerous undesirable effects on the human body and mind, especially in the intensive care unit (ICU) patients. It seems that noise and light are important environmental factors interrupting sleep in these patients. This study was carried out to determine the effect of earplugs and eye mask on Iranian patients' sleep quality in ICU. MATERIALS AND METHODS: In this cross-over clinical trial, 50 patients in the ICUs of Al-zahra Medical Center in Isfahan in 2012 were selected by convenient sampling method and randomly assigned to two groups. In group A, patients wore earplugs and eye mask in the first night during their sleep and slept without earplugs and eye mask in the second night, and the intervention was conversely conducted in group B. Verran and Snyder-Halpern Sleep Scales were used to measure the patients' sleep quality. The data were analyzed by paired t-test, independent t-test, one-sample t-test, and one-way analysis of variance (ANOVA) through SPSS version 18. RESULTS: Effect of the intervention on sleep effectiveness was positive, and there were significant differences (P < 0.001) between treatment night and control night, and also within each group (P < 0.001). Effect of the interventions on sleep disturbance was positive, and there was a significant difference at treatment night compared to the control night between groups and within each group (P < 0.001). Also, the mean scores for sleep supplementation were measured after the second night, and the results showed the scores significantly increased in the intervention group compared to the control group (P < 0.001, ER = 47, F = 22.1). In addition, carryover effects for sleep efficiency and sleep disturbance were positive, but periodic effects for sleep efficiency and sleep disturbance were negative and positive, respectively. CONCLUSIONS: : Although wearing earplugs and eye mask is a cost-effective and safe method and can improve perceived sleep quality in ICU patients, further research is needed to demonstrate the effect of this method. PMID- 25558269 TI - Nursing handover: Are its principles taught in universities during bachelor's degree? PMID- 25558270 TI - From a Cell's Viewpoint: Targeting Mitochondria in Alzheimer's disease. AB - Mitochondria are well-known cellular organelles widely studied in relation to a variety of disease states, including Alzheimer's disease. With roles in several metabolic processes, numerous signal transduction pathways, and overall cell maintenance and survival, mitochondria are essential to understanding the inner workings of cells. As mitochondria are able to be utilized by diverse illnesses to increase the likelihood of disease progression, targeting specific processes in these organelles could provide beneficial therapeutic options. PMID- 25558271 TI - Utility of endoscopic ultrasound-guided transbronchial fine-needle cytology in the diagnosis of sarcoidosis: A Saudi experience. AB - BACKGROUND: Endoscopic ultrasound-guided transbronchial fine-needle aspiration (EBUS-TFNA) is a minimally invasive technique for diagnosis of mediastinal masses/lesions. Although most studies have reported the utility of EBUS-TFNA in malignancy, its use has been extended to the benign conditions as well. OBJECTIVE: The present study focused on utility of EBUS in contributing to reach the final diagnosis of sarcoidosis. DESIGN: From May 2010 to December 2013, 19 of 80 patients who underwent EBUS-TFNA at one center for radiologically suspicious lesions for sarcoidosis, and with no definite histological diagnosis, were included in this retrospective study. RESULTS: When the histological diagnosis was taken as the gold standard, the sensitivity of EBUS-TFNA was 84.2% and specificity 100% with the positive predictive value of 100. The combined diagnostic sensitivity of EBUS-TFNA and transbronchial lung biopsy was 100%. CONCLUSION: EBUS is a valuable, minimally invasive diagnostic modality to support the diagnosis of sarcoidosis in appropriate clinical setting, after conventional work-up - particularly if patients have suspicious radiological findings. This minimally invasive procedure helps in providing a final diagnosis without exposing the patient to the risk of complications from more invasive procedures. PMID- 25558272 TI - Diagnostic accuracy of bronchial brush cytology and the added value of immunohistochemistry and fluorescence in situ hybridization of pulmonary neuroendocrine tumors. AB - BACKGROUND: Bronchial brush (BB) cytology carries low sensitivity for detecting neuroendocrine carcinomas (NECs), including typical carcinoid (TC) tumors of the lung. We aimed to investigate the detection of neuroendocrine tumors including TC through BB routine cytology cell block (CB), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH). MATERIALS AND METHODS: A SNOMED search showed 187 lung biopsy or resection specimens from 2008 through 2011 containing neuroendocrine or carcinoid in the diagnosis. Residual BB specimens retained in PreservCyt were used to prepare a ThinPrep slide for FISH analysis. CBs were stained with H and E and IHC for chromogranin and synaptophysin. RESULTS: Of the 187 cases, 16 had residual BB material available within 1 year of diagnosis and were used in CB preparation for IHC and FISH slides. Cytologic evaluation determined 1 case positive for malignancy (small cell lung carcinoma [SCLC]), 1 suspicious for adenocarcinoma, and 14 negative for malignancy. On the basis of histologic diagnosis, FISH was performed. SCLC showed polysomy (86% abnormal cells); 2 TC tumors showed a gain of 7p12 (15% abnormal cells) and a gain of 5q15 (72% abnormal cells), respectively. Two cases had CBs with positive immunoreactivity for chromogranin and synaptophysin. The sensitivity for detection of NEC was 18.8%, 15.4%, and 25% for cytologic evaluation, CB, and FISH, respectively. CONCLUSION: Neuroendocrine tumors, including TC are difficult to detect with BB cytologic evaluation, most likely because tumor cells lack in the specimen. Assessment of further studies is needed to explore the role of cytology and ancillary methods for detection of these tumors. PMID- 25558273 TI - Developmental dynamics of myogenesis in the shipworm Lyrodus pedicellatus (Mollusca: Bivalvia). AB - BACKGROUND: The shipworm Lyrodus pedicellatus is a wood-boring bivalve with an unusual vermiform body. Although its larvae are brooded, they retain the general appearance of a typical bivalve veliger-type larva. Here, we describe myogenesis of L. pedicellatus revealed by filamentous actin labelling and discuss the data in a comparative framework in order to test for homologous structures that might be part of the bivalve (larval) muscular ground pattern. RESULTS: Five major muscle systems were identified: a velum retractor, foot retractor, larval retractor, a distinct mantle musculature and an adductor system. For a short period of larval life, an additional ventral larval retractor is present. Early in development, a velum muscle ring and an oral velum musculature emerge. In late stages the lateral and dorsal mantle musculature, paired finger-shaped muscles, an accessory adductor and a pedal plexus are formed. Similar to other bivalve larvae, L. pedicellatus exhibits three velum retractor muscles, but in contrast to other species, one of them disappears in early stages of L. pedicellatus. The remaining two velum retractors are considerably remodelled during late larval development and are most likely incorporated into the elaborate mantle musculature of the adult. CONCLUSIONS: To our knowledge, this is the first account of any larval retractor system that might contribute to the adult bodyplan of a (conchiferan) mollusk. A comparative analysis shows that a pedal plexus, adductors, a larval velum ring, velum retractors and a ventral larval retractor are commonly found among bivalve larvae, and thus most likely belong to the ground pattern of the bivalve larval musculature. PMID- 25558274 TI - Ultrasharp nonlinear photothermal and photoacoustic resonances and holes beyond the spectral limit. AB - High-resolution nonlinear laser spectroscopy based on absorption saturation, Lamb dip and spectral hole-burning phenomena have contributed much to basic and applied photonics. Here, a laser spectroscopy based on nonlinear photothermal and photoacoustic phenomena is presented. It shows ultrasharp resonances and dips up to a few nanometres wide in broad plasmonic spectra of nanoparticles. It also demonstrates narrowing of absorption spectra of dyes and chromophores, as well as an increase in the sensitivity and resolution of the spectral hole-burning technique. This approach can permit the study of laser-nanoparticle interactions at a level of resolution beyond the spectral limits, identification of weakly absorbing spectral holes, spectral optimization of photothermal nanotherapy, measurements of tiny red and blue plasmon resonance shifts, multispectral imaging and multicolour cytometry. PMID- 25558275 TI - Protective effects of acacetin isolated from Ziziphora clinopodioides Lam. (Xintahua) on neonatal rat cardiomyocytes. AB - BACKGROUND: The total flavonoids from ethanol extract of the aerial part of Ziziphora clinopodioides Lam. (Lamlaceae) (Xintahua) showed protective activities against rat acute myocardial ischemia in rats. This study aims to isolate acacetin, a flavonoid, from the aerial part of Z. clinopodioides, to develop an HPLC method for its detection, and to evaluate its protective effects on neonatal rat cardiomyocytes. METHODS: Sephadex LH-20 silicagel and pillar layer chromatography silica gel were applied for the isolation and purification of acacetin and its structure was elucidated on the basis of (1)H and (13)C NMR spectroscopy. The content of acacetin in Z. clinopodioides collected from three different origins was determined by HPLC. The neonatal rat cardiomyocytes were isolated and cultured in vitro to establish a hypoxia/reoxygenation injury model. The viability of cardiomyocytes was measured by the MTT method. Changes of malondialdehyde (MDA) content in the medium were also determined. RESULTS: The acacetin content in various batches of Z. clinopodioides ranged from 45.50 to 47.41 MUg/g. Acacetin of 25, 10, 5 MUg/mL significantly decreased the MDA content in a model of hypoxia/reoxygenation injury (P < 0.001, P < 0.001 and P = 0.033, respectively). CONCLUSIONS: Acacetin protects neonatal cardiomyocytes from the damage induced by hypoxia/reoxygenation stress through reduction of lipid peroxidation and enhancement of the antioxidant activity. PMID- 25558276 TI - Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD. AB - Several lines of evidence implicate dysfunction of the serotonin (5-HT) system in autism spectrum disorder (ASD). Specifically, the serotonin transporter (5-HTT, SERT) has been scrutinized as an ASD candidate risk gene. SERT plays key roles in the development of circuits that underlie sensory function, particularly in the somatosensory system. One previous study in ASD found association of a rare, hyperfunctional SERT variant with sensory aversion, but studies of common SERT variants have never examined sensory symptoms in ASD. Using standardized caregiver assessments of sensory function in children, we evaluated patterns of sensory responsiveness in 47 children with ASD and 38 typically developing (TD) children. Study participants were genotyped for the functional SERT promoter polymorphisms, 5-HTTLPR and rs25531, to test the hypothesis that the higher expressing genotypes would be associated with hyperresponsiveness to touch, a common sensory aversion in ASD. All measures of sensory hypo- and hyperresponsiveness were increased in children with ASD, with hyporesponsive sensory patterns negatively correlated to age and hyperresponsive sensory patterns positively correlated to repetitive behavior. Strikingly, high expressing SERT genotypes were associated with increased tactile hyperresponsiveness in the ASD group. Our findings indicate genetic variation that increases SERT function may specifically impact somatosensory processing in ASD. PMID- 25558277 TI - Evolutionary Applications research highlights for issue 9: the ever-evolving field of agriculture. PMID- 25558279 TI - Does human-induced hybridization have long-term genetic effects? Empirical testing with domesticated, wild and hybridized fish populations. AB - Current conservation practices exclude human-generated hybridized populations from protection, as the genetic effects of hybridization in the wild have been observed to be long-lasting based on neutral genetic markers and are considered potentially irreversible. Theory, however, predicts otherwise for genes under selection. We transplanted combinations of wild, domesticated and hybridized populations of a fish species to new environments. We then compared survival, phenotypic variation and plasticity to determine whether hybridization affects adaptive potential after multiple generations of selection in the wild. Although the fitness of our hybridized populations at the onset of hybridization cannot be assessed, our results suggest that within five to eleven generations, selection can remove introduced foreign genes from wild populations that have hybridized with domesticated conspecifics. The end result is hybridized populations that, in terms of survival, phenotypic plasticity, mean trait expression and overall general responses to environmental change, closely resemble neighbouring wild populations. These results have important implications for considering the potential conservation value of hybridized populations and illustrate the effectiveness of selection in a local environment. PMID- 25558278 TI - Evolutionary rescue: linking theory for conservation and medicine. AB - Evolutionary responses that rescue populations from extinction when drastic environmental changes occur can be friend or foe. The field of conservation biology is concerned with the survival of species in deteriorating global habitats. In medicine, in contrast, infected patients are treated with chemotherapeutic interventions, but drug resistance can compromise eradication of pathogens. These contrasting biological systems and goals have created two quite separate research communities, despite addressing the same central question of whether populations will decline to extinction or be rescued through evolution. We argue that closer integration of the two fields, especially of theoretical understanding, would yield new insights and accelerate progress on these applied problems. Here, we overview and link mathematical modelling approaches in these fields, suggest specific areas with potential for fruitful exchange, and discuss common ideas and issues for empirical testing and prediction. PMID- 25558281 TI - Hybridization facilitates evolutionary rescue. AB - The resilience of populations to rapid environmental degradation is a major concern for biodiversity conservation. When environments deteriorate to lethal levels, species must evolve to adapt to the new conditions to avoid extinction. Here, we test the hypothesis that evolutionary rescue may be enabled by hybridization, because hybridization increases genetic variability. Using experimental evolution, we show that interspecific hybrid populations of Saccharomyces yeast adapt to grow in more highly degraded environments than intraspecific and parental crosses, resulting in survival rates far exceeding those of their ancestors. We conclude that hybridization can increase evolutionary responsiveness and that taxa able to exchange genes with distant relatives may better survive rapid environmental change. PMID- 25558280 TI - Genes predict long distance migration and large body size in a migratory fish, Pacific lamprey. AB - Elucidation of genetic mechanisms underpinning migratory behavior could help predict how changes in genetic diversity may affect future spatiotemporal distribution of a migratory species. This ability would benefit conservation of one such declining species, anadromous Pacific lamprey (Entosphenus tridentatus). Nonphilopatric migration of adult Pacific lamprey has homogenized population level neutral variation but has maintained adaptive variation that differentiates groups based on geography, run-timing and adult body form. To investigate causes for this adaptive divergence, we examined 647 adult lamprey sampled at a fixed location on the Columbia River and radiotracked during their subsequent upstream migration. We tested whether genetic variation [94 neutral and adaptive single nucleotide polymorphisms (SNPs) previously identified from a genomewide association study] was associated with phenotypes of migration distance, migration timing, or morphology. Three adaptive markers were strongly associated with morphology, and one marker also correlated with upstream migration distance and timing. Genes physically linked with these markers plausibly influence differences in body size, which is also consistently associated with migration distance in Pacific lamprey. Pacific lamprey conservation implications include the potential to predict an individual's upstream destination based on its genotype. More broadly, the results suggest a genetic basis for intrapopulation variation in migration distance in migratory species. PMID- 25558282 TI - Fundamental population-productivity relationships can be modified through density dependent feedbacks of life-history evolution. AB - The evolution of life histories over contemporary time scales will almost certainly affect population demography. One important pathway for such eco evolutionary interactions is the density-dependent regulation of population dynamics. Here, we investigate how fisheries-induced evolution (FIE) might alter density-dependent population-productivity relationships. To this end, we simulate the eco-evolutionary dynamics of an Atlantic cod (Gadus morhua) population under fishing, followed by a period of recovery in the absence of fishing. FIE is associated with increases in juvenile production, the ratio of juveniles to mature population biomass, and the ratio of the mature population biomass relative to the total population biomass. In contrast, net reproductive rate (R 0 ) and per capita population growth rate (r) decline concomitantly with evolution. Our findings suggest that FIE can substantially modify the fundamental population productivity relationships that underlie density-dependent population regulation and that form the primary population-dynamical basis for fisheries stock assessment projections. From a conservation and fisheries-rebuilding perspective, we find that FIE reduces R 0 and r, the two fundamental correlates of population recovery ability and inversely extinction probability. PMID- 25558283 TI - Increased temperature, but not acidification, enhances fertilization and development in a tropical urchin: potential for adaptation to a tropicalized eastern Australia. AB - To predict the effects of global change on marine populations, it is important to measure the effects of climate stressors on performance and potential for adaptation. Adaptation depends on heritable genetic variance for stress tolerance being present in populations. We determined the effects of near-future ocean conditions on fertilization success of the sea urchin Pseudoboletia indiana. In 16 multiple dam-sire crosses, we quantified genetic variation in tolerance of warming (+3 degrees C) and acidification (-0.3 to 0.5 pH units) at the gastrulation stage. Ocean acidification decreased fertilization across all dam sire combinations with effects of pH significantly differing among the pairings. Decreased pH reduced the percentage of normal gastrulae with negative effects alleviated by increased temperature. Significant sire by environment interactions indicated the presence of heritable variation in tolerance of stressors at gastrulation and thus the potential for selection of resistant genotypes, which may enhance population persistence. A low genetic correlation indicated that genotypes that performed well at gastrulation in low pH did not necessarily perform well at higher temperatures. Furthermore, performance at fertilization was not necessarily a good predictor of performance at the later stage of gastrulation. Southern range edge populations of Pseudoboletia indiana may benefit from future warming with potential for extension of their distribution in south-east Australia. PMID- 25558284 TI - Antipathogen genes and the replacement of disease-vectoring mosquito populations: a model-based evaluation. AB - Recently, genetic strategies aimed at controlling populations of disease vectoring mosquitoes have received considerable attention as alternatives to traditional measures. Theoretical studies have shown that female-killing (FK), antipathogen (AP), and reduce and replace (R&R) strategies can each decrease the number competent vectors. In this study, we utilize a mathematical model to evaluate impacts on competent Aedes aegypti populations of FK, AP, and R&R releases as well as hybrid strategies that result from combinations of these three approaches. We show that while the ordering of efficacy of these strategies depends upon population life history parameters, sex ratio of releases, and switch time in combination strategies, AP-only and R&R/AP releases typically lead to the greatest long-term reduction in competent vectors. R&R-only releases are often less effective at long-term reduction of competent vectors than AP-only releases or R&R/AP releases. Furthermore, the reduction in competent vectors caused by AP-only releases is easier to maintain than that caused by FK-only or R&R-only releases even when the AP gene confers a fitness cost. We discuss the roles that density dependence and inclusion of females play in the order of efficacy of the strategies. We anticipate that our results will provide added impetus to continue developing AP strategies. PMID- 25558285 TI - Human-caused habitat fragmentation can drive rapid divergence of male genitalia. AB - The aim of this study rests on three premises: (i) humans are altering ecosystems worldwide, (ii) environmental variation often influences the strength and nature of sexual selection, and (iii) sexual selection is largely responsible for rapid and divergent evolution of male genitalia. While each of these assertions has strong empirical support, no study has yet investigated their logical conclusion that human impacts on the environment might commonly drive rapid diversification of male genital morphology. We tested whether anthropogenic habitat fragmentation has resulted in rapid changes in the size, allometry, shape, and meristics of male genitalia in three native species of livebearing fishes (genus: Gambusia) inhabiting tidal creeks across six Bahamian islands. We found that genital shape and allometry consistently and repeatedly diverged in fragmented systems across all species and islands. Using a model selection framework, we identified three ecological consequences of fragmentation that apparently underlie observed morphological patterns: decreased predatory fish density, increased conspecific density, and reduced salinity. Our results demonstrate that human modifications to the environment can drive rapid and predictable divergence in male genitalia. Given the ubiquity of anthropogenic impacts on the environment, future research should evaluate the generality of our findings and potential consequences for reproductive isolation. PMID- 25558287 TI - Consensus-based recommendations of Australian podiatrists for the prescription of foot orthoses for symptomatic flexible pes planus in adults. AB - BACKGROUND: Foot orthoses are commonly used for symptomatic flexible pes planus in adults. However, there are no clinical guidelines for the prescription of customised foot orthoses that are specific to this population. The aim of this study was to investigate prescription habits of Australian podiatrists for customised foot orthoses for symptomatic flexible pes planus in adults and to develop consensus-based practice recommendations for the prescription of these foot orthoses. METHODS: A four round Delphi survey was undertaken with 24 podiatric experts to establish current use and rationale for individual prescription variables of customised foot orthoses for symptomatic flexible pes planus in adults. Round one determined prescription use (consensus) and rounds two, three and four determined the rationale for use (agreement) of prescription variables across the rearfoot, midfoot, forefoot, as well as accommodation and materials used. For consensus and agreement to be accepted, 70% of the respondents were required to use or agree on the rationale for use of individual prescription variables. RESULTS: Consensus was reached in round one for two variables, choice of shell material (polyolefin) and when to prescribe a forefoot post balanced to perpendicular. In rounds two, three and four, agreement was reached for 52 statements related to the rationale for use of individual prescription variables, including when to prescribe: an inverted cast pour [heel in an inverted position], an inverted rearfoot post, a medial heel (Kirby) skive, minimal/maximum arch fill, a medial flange, a forefoot post and common orthotic accommodations. CONCLUSION: This study found consensus or agreement for the use of several prescription variables for customised foot orthoses for symptomatic flexible pes planus in adults. The findings were used to develop the Foot orthosis Prescription Recommendations for symptOmatic flexible Pes planus in adults (FootPROP) proforma, to guide clinicians and researchers in the prescription of customised foot orthoses for this population. PMID- 25558288 TI - Foot posture as a risk factor for lower limb overuse injury: a systematic review and meta-analysis. AB - BACKGROUND: Static measures of foot posture are regularly used as part of a clinical examination to determine the need for foot level interventions. This is based on the premise that pronated and supinated foot postures may be risk factors for or associated with lower limb injury. This systematic review and meta analysis investigates foot posture (measured statically) as a potential risk factor for lower limb overuse injuries. METHODS: A systematic search was performed using Medline, CINAHL, Embase, SportDiscus in April 2014, to identify prospective cohort studies that investigated foot posture and function as a risk factor for lower limb overuse injury. Eligible studies were classified based on the method of foot assessment: (i) static foot posture assessment; and/or (ii) dynamic foot function assessment. This review presents studies evaluating static foot posture. The methodological quality of included studies was evaluated by two independent reviewers, using an adapted version of the Epidemiological Appraisal Instrument (EAI). Where possible, effects were expressed as standardised mean differences (SMD) for continuous scaled data, and risk ratios (RR) for nominal scaled data. Meta-analysis was performed where injuries and outcomes were considered homogenous. RESULTS: Twenty-one studies were included (total n = 6,228; EAI 0.8 to 1.7 out of 2.0). There was strong evidence that a pronated foot posture was a risk factor for medial tibial stress syndrome (MTSS) development and very limited evidence that a pronated foot posture was a risk factor for patellofemoral pain development, although associated effect sizes were small (0.28 to 0.33). No relationship was identified between a pronated foot posture and any other evaluated pathology (i.e. foot/ankle injury, bone stress reactions and non-specific lower limb overuse injury). CONCLUSION: This systematic review identified strong and very limited evidence of small effect that a pronated foot posture is a risk factor for MTSS and patellofemoral pain respectively. Evaluation of static foot posture should be included in a multifactorial assessment for both MTSS and patellofemoral pain, although only as a part of the potential injury risk profile. Whilst the included measures are clinically applicable, further studies are required to determine their relationship with dynamic foot function. PMID- 25558289 TI - Modifying the Rizzoli foot model to improve the diagnosis of pes-planus: application to kinematics of feet in teenagers. AB - BACKGROUND: A number of multi-segment foot protocols have been proposed to obtain measurements of clinical value. In the clinical assessment of foot pathologies and deformities, such as in the pes-planus, the frontal-plane alignment of the calcaneus and the dynamic properties of the medial longitudinal arch are critical parameters though often neglected by the majority of foot protocols. The aim of the present work is to modify an established foot protocol to obtain static and kinematic measures more consistent with corresponding clinical observations. Moreover, while many papers have reported kinematic data from varying populations, few investigations have focussed on young participants from same-age cohorts. METHODS: A 6-camera motion capture system was employed to track the shank, rear-, mid- and fore-foot segments in the left and right leg of 10 children (13.1 +/- 0.8 years) during gait. Three markers were attached to each segment thus allowing for triplanar motion of five joints to be described according to the Rizzoli Foot Model. An additional marker was attached to the posterior bottom of the calcaneus to enhance measurement of frontal-plane orientation. Description of the medial longitudinal arch angle was redefined to be more consistent with rearfoot orientation and to common clinical assessments. A novel 3-marker description of the hallux segment was implemented to improve robustness in calculating 1(st) metatarso-phalangeal joint rotations. RESULTS: Foot segments kinematics showed good inter- participant repeatability and overall consistency with previous similar reports. 15 out of 20 feet showed neutral or slightly valgus orientation of the calcaneus. Relatively large medial longitudinal arch angles (mean 186 +/- 16 deg) were found in the present young population. Both measurements were reasonably in accordance with the relevant clinical observations of these feet. CONCLUSIONS: Modifications to a widely used multisegmental foot kinematic model were implemented to improve robustness and consistency with relevant clinical observations. A detailed description of foot joints motion during barefoot walking in a population of 13-year old children with apparent flat feet has been presented, which may provide useful information to investigate the development of gait in children and the diagnosis of flexible flat foot. PMID- 25558290 TI - Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization. AB - BACKGROUND: Fatty acid vesicles are an important part of protocell models currently studied. As protocells can be considered as pre-biological precursors of cells, the models try to contribute to a better understanding of the (cellular) origin of life and emphasize on 2 major aspects: compartmentalization and replication. It has been demonstrated that lipid-based membranes are amenable to growth and division (shell replication). Furthermore compartmentalization creates a unique micro-environment in which biomolecules can accumulate and reactions can occur. Pioneering research by Sugawara, Deamer, Luisi, Szostak and Rasmussen gave more insight in obtaining autocatalytic, self-replicating vesicles capable of containing and reproducing nucleic acid sequences (core replication). Linking both core and shell replication is a challenging feat requiring thorough understanding of membrane dynamics and (auto)catalytic systems. A possible solution may lie in a class of compounds called nucleolipids, who combine a nucleoside, nucleotide or nucleobase with a lipophilic moiety. Early contributions by the group of Yanagawa mentions the prebiotic significance (as a primitive helical template) arising from the supramolecular organization of these compounds. Further contributions, exploring the supramolecular scope regarding phospoliponucleosides (e.g. 5'-dioleylphosphatidyl derivatives of adenosine, uridine and cytidine) can be accounted to Baglioni, Luisi and Berti. This emerging field of amphiphiles is being investigated for surface behavior, supramolecular assembly and even drug ability. RESULTS: A series of alpha/beta hydroxy fatty acids and alpha-amino fatty acids, covalently bound to nucleoside 5'-monophosphates via a hydroxyl or amino group on the fatty acid was examined for spontaneous self-assembly in spherical aggregates and their stability towards intramolecular cleavage. Staining the resulting hydrophobic aggregates with BODIPY-dyes followed by fluorescent microscopy gave several distinct images of vesicles varying from small, isolated spheres to higher order aggregates and large, multimicrometer sized particles. Other observations include rod-like vesicle precursors. NMR was used to assess the stability of a representative sample of nucleolipids. 1D 31P NMR revealed that beta-hydroxy fatty acids containing nucleotides were pH-stable while the alpha-analogs are acid labile. Degradation products identified by [1H-31P] heteroTOCSY revealed that phosphoesters are cleaved between sugar and phosphate, while phosphoramidates are also cleaved at the lipid-phosphate bond. For the latter compounds, the ratio between both degradation pathways is influenced by the nucleobase moiety. However no oligomerization of nucleotides was observed; nor the formation of 3'-5'-cyclic nucleotides, possible intermediates for oligonucleotide synthesis. CONCLUSIONS: The nucleolipids with a deoxyribose sugar moiety form small or large vesicles, rod-like structures, vesicle aggregates or large vesicles. Some of these aggregates can be considered as intermediate forms in vesicle formation or division. However, we could not observe nucleotide polymerization or cyclic nucleotide function of these nucleolipids, regardless of the sugar moiety that is investigated (deoxyribose, ribose, xylose). To unravel this observation, the chemical stability of the constructs was studied. While the nucleolipids containing beta-hydroxy fatty acids are stable as well in base as in acid circumstances, others degraded in acidic conditions. Phosphoramidate nucleolipids hydrolyzed by P-N as well as P-O bond cleavage where the ratio between both pathways depends on the nucleobase. Diester constructs with an alpha-hydroxy stearic acid degraded exclusively by hydrolysis of the 5'-O-nucleoside ester bond. As the compounds are too stable and harsh conditions would destruct the material itself, more reactive species such as lipid imidazolates of nucleotides need to be synthesized to further analyze the potential polymerization process. Graphical AbstractVesicle information of a nucleolipid consisting of a nucleoside 5'-monophosphate and a alpha-hydroxy fatty acid. PMID- 25558291 TI - Fast Screening of Polycyclic Aromatic Hydrocarbons using Trapped Ion Mobility Spectrometry - Mass Spectrometry. AB - In the present paper, we showed the advantages of trapped ion mobility spectrometry coupled too mass spectrometry (TIMS-MS) combined with theoretical calculations for fast identification (millisecond timescale) of polycyclic aromatic hydrocarbons (PAH) compounds from complex mixtures. Accurate PAH collision cross sections (CCS, in nitrogen as a bath gas) are reported for the most commonly encountered PAH compounds and the ability to separate PAH geometric isomers is shown for three isobaric pairs with mobility resolution exceeding 150 (3-5 times higher than conventional IMS devices). Theoretical candidate structures (optimized at the DFT/B3LYP level) are proposed for the most commonly encountered PAH compounds showing good agreement with the experimental CCS values (<5%). The potential of TIMS-MS for the separation and identification of PAH compounds from complex mixtures without the need of lengthy pre-separation steps is illustrated for the case of a complex soil mixture. PMID- 25558292 TI - Individualized Survival and Treatment Response Predictions in Breast Cancer Patients: Involvements of Phospho-EGFR and Phospho-Her2/neu Proteins. AB - Our robust prediction system for individual breast cancer patients combines three well-known machine-learning classifiers to provide stable and accurate clinical outcome prediction (N=269). The average performance of the selected classifiers is used as the evaluation criterion in breast cancer outcome predictions. A profile (incorporating histology, lymph node status, tumor grade, tumor stage, ER, PR, Her2/neu, patient's age and smoking status) generated over 95% accuracy in individualized disease-free survival and treatment response predictions. Furthermore, our analysis demonstrated that the measurement of phospho-EGFR and phospho-Her2/neu is more powerful in breast cancer survival prediction than that of total EGFR and total Her2/neu (p < 0.05). The incorporation of hormone receptor status, Her2/neu, patient's age and smoking status into the traditional pathologic markers creates a powerful standard to perform individualized survival and treatment outcome predictions for breast cancer patients. PMID- 25558294 TI - Automating Content Analysis of Open-Ended Responses: Wordscores and Affective Intonation. AB - This study presents automated methods for predicting valence and quantifying valenced thoughts of a text. First, it examines whether Wordscores, developed by Laver, Benoit, and Garry (2003), can be adapted to reliably predict the valence of open-ended responses in a survey about bioethical issues in genetics research, and then tests a complementary and novel technique for coding the number of valenced thoughts in open-ended responses, termed Affective Intonation. Results show that Wordscores successfully predicts the valence of brief and grammatically imperfect open-ended responses, and Affective Intonation achieves comparable performance to human coders when estimating number of valenced thoughts. Both Wordscores and Affective Intonation have promise as reliable, effective, and efficient methods when researchers content-analyze large amounts of textual data systematically. PMID- 25558293 TI - Salutary effect of pre-treatment with an Nrf2 inducer on ischemia reperfusion injury in the rat liver. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is a common phenomenon occurring during liver surgery, transplantation, and trauma. IRI causes oxidative stress which plays a critical role in causing organ damage. The Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Nrf2 dysfunction has been implicated in the pathogenesis of several inflammatory disorders, cancer, and aging. This study was undertaken to investigate the effect of Nrf2 pathway activator (dh404) on warm liver IRI in a rodent model. METHODS: Ten Sprague-Dawley rats were treated with dh404 or vehicle. Dh404 was dissolved in sesame oil and was given orally (1.5mg/kg) the night before and 5 hours before procedures. Rat livers were subjected to 60 minutes of 70% ischemia followed by 3 hours of reperfusion. Serum ALT and Malondialdehyde (MDA) were determined and liver tissue was processed for histological examination, and determination of apoptosis, myeloperoxidase (MPO) activity, ADP/ATP ratio, and expressions of Nrf2, eNOS, anti-oxidant enzymes, and inflammatory mediators. RESULTS: Serum ALT and MDA levels and tissue MPO activity were significantly lower, expression of the anti-oxidant enzyme, glutamate cysteine ligase were significantly higher, whereas expression of NFkB and COX-2 was unchanged in the dh404-treated group. Although the total Suzuki histology score did not differ significantly, the extent of sinusoidal congestion, vacuolization, and apoptosis was significantly reduced in the dh404 treated compared to the untreated group (P<0.01). CONCLUSIONS: Pre-treatment with dh404 resulted in partial attenuation of hepatic ischemia reperfusion injury in rats. PMID- 25558295 TI - Local Tests for Identifying Anisotropic Diffusion Areas in Human Brain with DTI. AB - Diffusion tensor imaging (DTI) plays a key role in analyzing the physical structures of biological tissues, particularly in reconstructing fiber tracts of the human brain in vivo. On the one hand, eigenvalues of diffusion tensors (DTs) estimated from diffusion weighted imaging (DWI) data usually contain systematic bias, which subsequently biases the diffusivity measurements popularly adopted in fiber tracking algorithms. On the other hand, correctly accounting for the spatial information is important in the construction of these diffusivity measurements since the fiber tracts are typically spatially structured. This paper aims to establish test-based approaches to identify anisotropic water diffusion areas in the human brain. These areas in turn indicate the areas passed by fiber tracts. Our proposed test statistic not only takes into account the bias components in eigenvalue estimates, but also incorporates the spatial information of neighboring voxels. Under mild regularity conditions, we demonstrate that the proposed test statistic asymptotically follows a chi2 distribution under the null hypothesis. Simulation and real DTI data examples are provided to illustrate the efficacy of our proposed methods. PMID- 25558296 TI - Comments: Should Principal Stratification Be Used to Study Mediational Processes? PMID- 25558297 TI - The graphical lasso: New insights and alternatives. AB - The graphical lasso [5] is an algorithm for learning the structure in an undirected Gaussian graphical model, using l1 regularization to control the number of zeros in the precision matrix Theta = Sigma-1 [2, 11]. The R package GLASSO [5] is popular, fast, and allows one to efficiently build a path of models for different values of the tuning parameter. Convergence of GLASSO can be tricky; the converged precision matrix might not be the inverse of the estimated covariance, and occasionally it fails to converge with warm starts. In this paper we explain this behavior, and propose new algorithms that appear to outperform GLASSO. By studying the "normal equations" we see that, GLASSO is solving the dual of the graphical lasso penalized likelihood, by block coordinate ascent; a result which can also be found in [2]. In this dual, the target of estimation is Sigma, the covariance matrix, rather than the precision matrix Theta. We propose similar primal algorithms P-GLASSO and DP-GLASSO, that also operate by block coordinate descent, where Theta is the optimization target. We study all of these algorithms, and in particular different approaches to solving their coordinate sub-problems. We conclude that DP-GLASSO is superior from several points of view. PMID- 25558299 TI - Primary non-hyperlipidemia xanthoma of bone: a case report with review of the literature. AB - Primary xanthoma of bone is very rare. And its clinical, pathological and radiological presentation is different from other position. It is generally known that xanthoma of bone are usually are associated with lipid disorders. Non hyperlipidemia xanthoma of bone are exceedingly unusual. In this report, we describe a rare case of primary bone xanthoma without hyperlipidemia and reviews the literature on primary bone xanthomas, focusing on those without hyperlipidemia. The difference of age between non-hyperlipidemia xanthoma of bone and other xanthoma of bone did not existed. But male patients outnumber female in non-hyperlipidemia xanthoma of bone. It often involve the irregular flat bones than the long bones. Inflammatory cells, cholesterol clefts and hemosiderin are rare compared with xanthoma with lipid disorders. At the same time, imaging manifestations is not steady, except for osteolytic sign. So the diagnosis usually depend on a pathological biopsy. Therefore we suggested that non hyperlipidemia xanthoma of bone was a kind of independent disease. It should be belong to bone tumors of undefined neoplastic nature. Its etiology need more data collection and further analysis. PMID- 25558298 TI - ADHD, Multimodal Treatment, and Longitudinal Outcome: Evidence, Paradox, and Challenge. AB - Given major increases in the diagnosis of attention-deficit hyperactivity disorder (ADHD) and in rates of medication for this condition, we carefully examine evidence for effects of single versus multimodal (i.e., combined medication and psychosocial/behavioral) interventions for ADHD. Our primary data source is the Multimodal Treatment Study of Children with ADHD (MTA), a 14-month, randomized clinical trial in which intensive behavioral, medication, and multimodal treatment arms were contrasted with one another and with community intervention (treatment-as-usual), regarding outcome domains of ADHD symptoms, comorbidities, and core functional impairments. Although initial reports emphasized the superiority of well-monitored medication for symptomatic improvement, reanalyses and reappraisals have highlighted (a) the superiority of combination treatment for composite outcomes and for domains of functional impairment (e.g., academic achievement, social skills, parenting practices); (b) the importance of considering moderator and mediator processes underlying differential patterns of outcome, including comorbid subgroups and improvements in family discipline style during the intervention period; (c) the emergence of side effects (e.g., mild growth suppression) in youth treated with long-term medication; and (d) the diminution of medication's initial superiority once the randomly assigned treatment phase turned into naturalistic follow-up. The key paradox is that whereas ADHD clearly responds to medication and behavioral treatment in the short term, evidence for long-term effectiveness remains elusive. We close with discussion of future directions and a call for greater understanding of relevant developmental processes in the attempt to promote optimal, generalized, and lasting treatments for this important and impairing neurodevelopmental disorder. PMID- 25558300 TI - A different kind of merger. PMID- 25558301 TI - Cardiovascular events and safety outcomes associated with azithromycin therapy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Azithromycin has been used for many years for the treatment of patients with various types of bacterial infections, as well as for the secondary prevention of coronary events. There is a growing concern, however, that azithromycin may be associated with an increased cardiovascular (CV) risk and may lead to CV-related death in high-risk patients. OBJECTIVE: This systematic review of randomized controlled trials was conducted to analyze and describe the CV risk and safety outcomes associated with azithromycin therapy. METHODS: A meta analysis was conducted based on the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases from 1990 through September 2013. Specific medical search terms in the English language included "azithromycin," "macrolide," "antibiotic," "cardiovascular diseases," and "cardiovascular events" and were used to identify relevant randomized clinical trials that assessed the risk for CV events in patients receiving azithromycin therapy or placebo. The randomized clinical trials that were selected included patients who received azithromycin or placebo for the treatment of infection or for the secondary prevention of coronary events. Major health outcome measures included mortality, hospitalization, and coronary intervention. Meta-analyses were performed using a random effects model. RESULTS: A total of 12 randomized clinical trials included 15,588 patients. Patients were divided into 2 groups, either to azithromycin therapy or to placebo. Compared with patients who had not received azithromycin, patients who had received azithromycin had an overall risk ratio (RR) of death of 0.877 (95% confidence interval [CI], 0.752-1.024; P = .097). No heterogeneity was observed (I(2) = 0%). Similarly, no differences were found in the pooled RRs for hospitalization or for clinical intervention for CV events (RR, 1.005; 95% CI, 0.922-1.094; P = .915; I(2) = 0% and RR, 0.999; 95% CI, 0.896-1.125; P = .984; I(2) = 0%, respectively). CONCLUSION: No increased risks for mortality or for CV events associated with azithromycin therapy compared with placebo were found among patients included in the 12 randomized clinical trials reviewed in this analysis. PMID- 25558302 TI - Healthcare costs among patients with excessive sleepiness associated with obstructive sleep apnea, shift work disorder, or narcolepsy. AB - BACKGROUND: Excessive daytime sleepiness affects nearly 20% of the general population and is associated with many medical conditions, including shift work disorder (SWD), obstructive sleep apnea (OSA), and narcolepsy. Excessive sleepiness imposes a significant clinical, quality-of-life, safety, and economic burden on society. OBJECTIVE: To compare healthcare costs for patients receiving initial therapy with armodafinil or with modafinil for the treatment of excessive sleepiness associated with OSA, SWD, or narcolepsy. METHODS: A retrospective cohort analysis of medical and pharmacy claims was conducted using the IMS LifeLink Health Plan Claims Database. Patients aged >=18 years who had a pharmacy claim for armodafinil or for modafinil between June 1, 2009, and February 28, 2012, and had 6 months of continuous eligibility before the index prescription date, as well as International Classification of Diseases, Ninth Revision diagnosis for either OSA (327.23), SWD (327.36), or narcolepsy (347.0x) were included in the study. Patients were placed into 1 of 2 treatment cohorts based on their index prescription and followed for 1 month minimum and 34 months maximum. The annualized all-cause costs were calculated by multiplying the average per-month medical and pharmacy costs for each patient by 12 months. The daily average consumption (DACON) for armodafinil or for modafinil was calculated by dividing the total units dispensed of either drug by the prescription days supply. RESULTS: A total of 5693 patients receiving armodafinil and 9212 patients receiving modafinil were included in this study. A lower DACON was observed for armodafinil (1.04) compared with modafinil (1.47). The postindex mean medical costs were significantly lower for the armodafinil cohort compared with the modafinil cohort after adjusting for baseline differences ($11,363 vs $13,775, respectively; P = .005). The mean monthly drug-specific pharmacy costs were lower for the armodafinil cohort compared with the modafinil cohort ($166 vs $326, respectively; P <.001). In addition, lower total healthcare costs were observed for the armodafinil cohort compared with the modafinil cohort after correcting for baseline differences ($18,309 vs $23,530, respectively; P <.001). CONCLUSION: As shown in this analysis, armodafinil may have real-world DACON advantages and may be associated with lower overall healthcare costs compared with modafinil. PMID- 25558303 TI - Effects of medicare part d on disparity implications of medication therapy management eligibility criteria. AB - BACKGROUND: Previous studies have shown that there were greater racial and ethnic disparities among individuals who were ineligible for medication therapy management (MTM) services than among MTM-eligible individuals before the implementation of Medicare Part D in 2006. OBJECTIVE: To determine whether the implementation of Medicare Part D in 2006 correlates to changes in racial and ethnic disparities among MTM-ineligible and MTM-eligible beneficiaries. METHODS: Data from the Medicare Current Beneficiary Survey were analyzed in this retrospective observational analysis. To examine potential racial and ethnic disparities, non-Hispanic whites were compared with non-Hispanic blacks and Hispanics. Three aspects of disparities were analyzed, including health status, health services utilization and costs, and medication utilization patterns. A generalized difference-in-differences analysis was used to examine the changes in difference in disparities between MTM-ineligible and MTM-eligible individuals from 2004-2005 to 2007-2008 relative to changes from 2001-2002 and 2004-2005. Various multivariate regressions were used based on the types of dependent variables. A main analysis and several sensitivity analyses were conducted to represent the ranges of MTM eligibility thresholds used by Medicare Part D plans in 2010. RESULTS: The main analysis showed that Part D implementation was not associated with reductions in greater racial and ethnic disparities among MTM ineligible than MTM-eligible Medicare beneficiaries. The main analysis suggests that after Part D implementation, Medicare MTM eligibility criteria may not consistently improve the existing racial and ethnic disparities in health status, health services utilization and costs, and medication utilization. By contrast, several sensitivity analyses showed that Part D implementation did correlate with a significant reduction in greater racial disparities among the MTM-ineligible group than the MTM-eligible group in activities of daily living and in instrumental activities of daily living. Part D implementation may be also associated with a reduction in greater ethnic disparities among the MTM ineligible group than the MTM-eligible groups in the costs of physician visits. CONCLUSION: Part D implementation was not associated with consistent reductions in the disparity implications of the Medicare MTM eligibility criteria. The main analysis showed that Part D implementation was not associated with a reduction in disparities associated with MTM eligibility, although several sensitivity analyses did show reductions in disparities in specific aspects. Future research should explore alternative Medicare MTM eligibility criteria to eliminate racial and ethnic disparities among the Medicare population. PMID- 25558304 TI - Read all about it. PMID- 25558305 TI - Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting. AB - BACKGROUND: In November 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) together issued new guidelines for the treatment of patients with high cholesterol, providing a new paradigm for the management of cholesterol in the primary and secondary prevention of coronary artery disease. OBJECTIVE: To examine the impact of the 2013 ACC/AHA cholesterol treatment guidelines on pharmacy utilization of cholesterol-lowering drugs in a real-world managed care setting. METHODS: Pharmacy claims from OptumRx, a national pharmacy benefit management provider, for the period between January 1, 2013, and December 31, 2013 (baseline period), were used to identify candidates for cholesterol lowering therapy and to estimate the number of potential patients who will be starting or intensifying statin therapy based on the updated cholesterol treatment guidelines. Potential candidates for cholesterol-lowering treatments included patients with diabetes or hypertension aged 40 to 75 years who were not already receiving a cholesterol-lowering medication, as well as patients receiving cholesterol-lowering therapies during the baseline period. The baseline cholesterol-lowering medication market share was used to project changes in pharmacy utilization over the next 3 years. RESULTS: Based on the 2013 ACC/AHA cholesterol treatment guidelines, there will be a 25% increase in the proportion of the overall population that is treated with statins over the next 3 years, increasing from 3,909,407 (27.7%) patients to 4,892,668 (34.7%) patients. The largest proportion of the increase in statin utilization is projected to be for primary prevention in patients aged 40 to 75 years who were not receiving any cholesterol-lowering treatment at baseline. These projected changes will increase the overall number of statin prescriptions by 25% and will decrease the number of nonstatin cholesterol-lowering medication prescriptions by 68% during the next 3 years. CONCLUSION: The new 2013 ACC/AHA cholesterol treatment guidelines are projected to have a significant impact on the utilization of cholesterol-lowering drugs by increasing the overall proportion of the population receiving statin therapy and by decreasing the utilization of nonstatin cholesterol-lowering medications. PMID- 25558306 TI - Utilization of parenteral anticoagulants and warfarin: impact on the risk of venous thromboembolism recurrence in the outpatient setting. AB - BACKGROUND: Clinical guidelines recommend parenteral anticoagulation therapy with an early initiation of warfarin therapy for the treatment of patients with acute venous thromboembolism (VTE) and the prevention of recurrence. OBJECTIVES: To evaluate the outpatient utilization of parenteral anticoagulant therapy and warfarin among patients with VTE, and to examine the effects of parenteral anticoagulant use and the time to warfarin initiation from VTE diagnosis on the risk for VTE recurrence. METHODS: The Truven Health MarketScan Commercial Claims Database was used to identify patients aged 18 to 64 years who had an outpatient claim for deep-vein thrombosis or pulmonary embolism between January 2010 and December 2011 (ie, index date) and had no VTE diagnosis or treatment during the 12 months before the index date, had no hospital or emergency department VTE claim within 7 days after the index outpatient VTE claim, and had received warfarin <30 days after the index date. A recurrent VTE event was defined as a VTE-related emergency department visit or hospitalization within 8 to 365 days after the index date. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) associated with VTE recurrence risk related to parenteral anticoagulant use and warfarin initiation timing. RESULTS: A total of 5820 patients were included in the study (mean age, 50.5 years); of these, 45% were female. A total of 75.7% (4403) of the patients receiving warfarin also received a parenteral anticoagulant, and the median time from VTE diagnosis to warfarin initiation was 5 days for parenteral anticoagulant users compared with 11 days for nonusers. Parenteral anticoagulant use was associated with a 49% recurrent VTE risk reduction (HR, 0.51; 95% confidence interval [CI], 0.43-0.60; P <.001). Each day of delayed warfarin initiation from the diagnosis of acute VTE was associated with a 1% increase in the risk for VTE recurrence (HR, 1.01; 95% CI, 1.01-1.02; P = .003). CONCLUSIONS: Overall, 1 in 4 patients with VTE who had received warfarin in the outpatient setting did not receive parenteral anticoagulation therapy. Among those who received warfarin, its initiation was not always timely, despite its positive effects on reducing VTE recurrence. These findings highlight the potential quality-of-care concerns associated with the failure to use or the delayed implementation of guideline-recommended VTE treatment, and the need to improve compliance with clinical guidelines in the treatment of patients with VTE. PMID- 25558307 TI - New and emerging drugs and targets for type 2 diabetes: reviewing the evidence. AB - BACKGROUND: Diabetes is a deadly and costly disease. The number of adults in the United States with newly diagnosed diabetes has nearly tripled from 1980 to 2011. At the current pace, 1 in 3 US adults will have diabetes in their lifetime. Currently, 14 classes of drugs are available to treat type 2 diabetes mellitus, but only 36% of patients with type 2 diabetes achieve glycemic control with the currently available therapies. Therefore, new treatment options are desperately needed. DISCUSSION: Despite the availability of many pharmacotherapies, in 2011 an estimated 3.1 million (14.9%) patients with type 2 diabetes still reported not taking medications to treat their diabetes. Patient compliance is a major obstacle facing practicing clinicians on a daily basis. New treatment options are desperately needed, but efficacy and tolerability are no longer the only criteria contributing to the success of a drug. Ease of administration, convenient dosing frequency, being weight control friendly, and having a low risk for hypoglycemia are important factors for the survival of a new drug in the US healthcare system. The present review is focused on important new drugs and drug classes in the pipeline, as well as on recently approved drugs, including sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 agents, and new insulin therapies, as well as on the technologic improvements in the delivery and dosing frequency of some of the currently available drugs. CONCLUSIONS: In the United States, diabetes can be expected to continue to wreak significant human and financial tolls. The associated complications will continue to climb if they are not controlled and stopped. New therapies for diabetes are clearly needed that will better address these unmet needs. The common threads among the emerging therapies are their convenience of administration and dosing frequency, which are important to the improvement of patient adherence. PMID- 25558308 TI - Complex Mental Health Sequelae of Psychological Trauma Among Women in Prenatal Care. AB - Pregnancy is a critical time to identify and address maternal mental health problems, for the health of both mother and child. Pregnant women with histories of exposure to interpersonal psychological trauma may experience a range of mental health problems including but not limited to posttraumatic stress disorder (PTSD). In a community sample of 1,581 pregnant women, 25% reported symptoms consistent with at least one of six syndromes, including PTSD, major depressive disorder (MDD), generalized anxiety disorder (GAD), or clinically significant dissociation, somatization, or affect dysregulation. Six sub-groups with distinct mental health problem profiles were identified by cluster analysis. Controlling for sociodemographic risk factors, women with histories of interpersonal trauma were over-represented in four sub-groups characterized by: (1) PTSD comorbid with depression (childhood sexual abuse), (2) PTSD comorbid with affect/interpersonal dysregulation (childhood physical or emotional abuse), (3) somatization (adult abuse), and (4) GAD (foster/adoptive placement). Findings suggest risk relationships warranting further study between different types of interpersonal trauma exposure and psychiatric outcomes in pregnant women, including PTSD with two types of comorbidity. PMID- 25558309 TI - Self-Construal as a Predictor of Korean American Women's Intention to Vaccinate Daughters against Human Papillomavirus. AB - Korean Americans represent one of the fastest growing Asian subpopulations in the United States. Despite a dramatic reduction in incidence nationwide, cervical cancer remains a major threat for Korean American women. By preventing the strains of the Human Papillomavirus (HPV) known to cause cervical cancer, the HPV vaccines appear to be a promising solution to reduce the persistent disparities in cervical cancer among not only Korean Americans, but also other racial and ethnic minorities more generally. However, current literature lacks a better understanding of how cultural and behavioral factors influence Korean American women's intention to vaccinate their adolescent daughters against HPV. This manuscript presents the results of testing the mechanisms through which interdependent self-construal (an orientation of self in which individuals define themselves primarily through their relationships with others), attitudes, and subjective norms impact Korean American mothers' intention to vaccinate their daughters. Our findings suggest that self-construal holds promise for health communication research to not only uncover the rich variance of health-related beliefs among individuals of shared cultural descent, but also to understand the context in which these beliefs are embedded. PMID- 25558310 TI - Assessing Acculturation Over Time: A Four-year Prospective Study of Asian American Young Adults. AB - Acculturation is commonly defined as a dynamic and multidimensional process in which individuals and groups change over time when coming into contact with another culture. Despite the emphasis on acculturation as a process of change over time, few researchers have directly assessed this hypothesis. The current study first identifies and then examines "stable" and "dynamic" dimensions of acculturation within a 4-year prospective study of 433 first- and second generation Chinese- and Korean-American college students. Separate growth model analyses revealed significant linear change for first-generation students toward greater U.S. acculturation. In comparison, tests of linear and quadratic change for second-generation students were not significant. When stratifying by gender, acculturation increased for women but there was no significant change in acculturation for men. While all students reported increases in alcohol consumption over the study period, changes in acculturation predicted changes in alcohol consumption only for women. Chinese men showed greater increases in alcohol consumption than Korean men but there was no effect for ethnicity among women. There was significant individual variability in the models, which underscores the importance of examining change prospectively through within and between person analyses. The findings highlight the importance of examining acculturation changes over time for different migrant groups with implications for further development of acculturation measures, research methodologies, and health interventions. More prospective research designs of acculturation are needed to examine changes in health behavior and overall adaptation across migrant groups at varying stages of development. PMID- 25558311 TI - Coccygectomy as a surgical option in the treatment of chronic traumatic coccygodynia: a single-center experience and literature review. AB - STUDY DESIGN: Retrospective cohort study. PURPOSE: Trauma is the most common cause for chronic coccygodynia. The present study aims at presenting our results after complete removal of the coccyx for refractory traumatic coccygodynia in terms of pain level, complication rates, and patients' overall satisfaction. OVERVIEW OF LITERATURE: There is limited extant literature describing the success rate and complications in refractory isolated traumatic coccygodynia. METHODS: From January 2011 to January 2012, 10 consecutive patients with posttraumatic coccygodynia (six males and four females; mean age, 42 years) were enrolled in our study. Conservative treatment of the condition had failed in all patients. The same surgeon performed a complete coccygectomy on all patients. Postoperative outcomes included measurements of pain relief and degree of patient satisfaction with the procedure's results. RESULTS: In our selected cohort, all patients indicated complete pain relief or significant pain improvement in follow up-care and would recommend this procedure. One patient developed a subcutaneous hematoma that required surgical intervention. CONCLUSIONS: Our results suggest that complete removal of the coccyx relieves pain in patients with refractory chronic traumatic coccygodyniaand is therefore a reasonable treatment option after conservative treatment failure. PMID- 25558312 TI - The Extended Posterior Circumferential Decompression Technique in the Management of Tubercular Spondylitis with and without Paraplegia. AB - STUDY DESIGN: Retrospective clinical series. PURPOSE: To study the clinical, functional and radiological results of patients with tuberculous spondylitis with and without paraplegia, treated surgically using the "Extended Posterior Circumferential Decompression (EPCD)" technique. OVERVIEW OF LITERATURE: With the increasing possibility of addressing all three columns by a single approach, posterior and posterolateral approaches are gaining acceptance. A single exposure for cases with neurological deficit and kyphotic deformity requiring circumferential decompression, anterior column reconstruction and posterior instrumentation is helpful. METHODS: Forty-one patients with dorsal/dorsolumbar/lumbar tubercular spondylitis who were operated using the EPCD approach between 2006 to 2009 were included. Postoperatively, patients were started on nine-month anti-tuberculous treatment. They were serially followed up to thirty-six months and both clinical measures (including pain, neurological status and ambulatory status) and radiological measures (including kyphotic angle correction, loss of correction and healing status) were used for assessment. RESULTS: Disease-healing with bony fusion (interbody fusion) was seen in 97.5% of cases. Average deformity (kyphosis) correction was 54.6% in dorsal spine and 207.3% in lumbar spine. Corresponding loss of correction was 3.6 degrees in dorsal spine and 1.9 degrees in the lumbar spine. Neurological recovery in Frankel B and C paraplegia was 85.7% and 62.5%, respectively. CONCLUSIONS: The EPCD approach permits all the advantages of a single or dual session anterior and posterior surgery, with significant benefits in terms of decreased operative time, reduced hospital stay and better kyphotic angle correction. PMID- 25558313 TI - Adjacent segment pathology following anterior decompression and fusion using cage and plate for the treatment of degenerative cervical spinal diseases. AB - STUDY DESIGN: Retrospective study. PURPOSE: To analyze the incidence and prevalence of clinical adjacent segment pathology (CASP) following anterior decompression and fusion with cage and plate augmentation for degenerative cervical diseases. OVERVIEW OF LITERATURE: No long-term data on the use of cage and plate augmentation have been reported. METHODS: The study population consisted of 231 patients who underwent anterior cervical discectomy and fusion (ACDF) with cage and plate for degenerative cervical spinal disease. The incidence and prevalence of CASP was determined by using the Kaplan-Meier survival analysis. To analyze the factors that influence CASP, data on preoperative and postoperative sagittal alignment, spinal canal diameter, the distance between the plate and adjacent disc, extent of fusion level, and the presence or absence of adjacent segment degenerative changes by imaging studies were evaluated. RESULTS: CASP occurred in 15 of the cases, of which 9 required additional surgery. At 8-year follow-up, the average yearly incidence was 1.1%. The rate of disease-free survival based on Kaplan-Meier survival analysis was 93.6% at 5 years and 90.2% at 8 years. No statistically significant differences in CASP incidence based on radiological analysis were observed. Significantly high incidence of CASP was observed in the presence of increased adjacent segment degenerative changes (p<0.001). CONCLUSIONS: ACDF with cage and plate for the treatment of degenerative cervical disease is associated with a lower incidence in CSAP by 1.1% per year, and the extent of preoperative adjacent segment degenerative changes has been shown as a risk factor for CASP. PMID- 25558314 TI - How many high risk korean patients with osteopenia could overlook treatment eligibility? AB - STUDY DESIGN: Retrospective study. PURPOSE: To determine the prevalence of high risk patient with osteopenia requiring pharmacologic treatment and investigate the difference of 10-year fracture probability whether bone mineral density (BMD) include or not in Korean FRAX model. OVERVIEW OF LITERATURE: Many people with the fracture have osteopenia rather than osteoporosis, and BMD alone could be considered as a chance to prevent fracture. METHODS: Three hundred sixty-nine patients who was diagnosed as osteopenia were divided into two groups according to age (group 1, under 65 years; group 2, over 65 years), and 10-year fracture probabilities were calculated by FRAX algorithm with and without femur neck T score. RESULTS: The high risk patients of the fracture who had above 3% of 10 year hip fracture probability were 15 cases in group 1 and 121 cases in group 2. In 193 patients of group 1, the mean 10-year fracture probability with BMD was significantly higher than the results without BMD (hip fracture: p=0.04, major osteoporotic fracture: p=0.01). Unlike the results of the group 1, the mean 10 year fracture probability without BMD was significantly higher than the results with BMD in 176 patients of group 2 (hip fracture: p=0.01, major osteoporotic fracture: p=0.01). CONCLUSIONS: Total of 136 cases (36.8%) as a high risk of the fracture with osteopenia could be overlooked treatment eligibility in Korean. The Korean FRAX model without BMD could be effective in predicting fracture risk especially in the individuals who were over 65 years. PMID- 25558315 TI - C1-C3 Lateral Mass Screw-Rod Fixation and Fusion for C2 Pathologies and Hangman's Fractures. AB - STUDY DESIGN: Retrospective clinical study. PURPOSE: We report our experience of eight patients treated with C1-C3 lateral mass rod-screw stabilization and fusion in the treatment of Hangman's fracture and other axis pathologies. OVERVIEW OF LITERATURE: Different surgical approaches, both anterior and posterior, have been described for treating Hangman's fracture and other pathologies where surgery is indicated. METHODS: All patients who underwent surgical treatment for Hangman's fracture and axial pathology where C1-C3 lateral mass screw-rod stabilization and fusion done, following reduction of the fracture or removal of the pathology were included in this series. The recorded patient management data was retrospectively studied. RESULTS: There were 8 cases in total. All were male, with an average age of 40.75 years. Hangman's fracture occurred in 6 cases (75%), one with metastatic squamous cell carcinoma and the remaining with plasmocytoma. Among the Hangman's fractures 4 (66.66%) had no neuro-deficit. Reduction and bilateral C1-C3 lateral mass screw and rod fixation with posterior fusion by bone graft was performed in all cases. In 2 cases, a C2 body tumor was removed transorally. All patients with neuro-deficit fully recovered, except one who expired in the early post-operative period. Rest of all patients were leading a normal life till last follow up. CONCLUSIONS: Although the number of cases was very small with a relatively short follow up period, C1 and C3 lateral mass screw-rod fixation followed by fusion showed promise as an effective and biomechanically sound way for the treatment of properly selected Hangman's fracture cases, and may also be suitable in other axial pathologies. PMID- 25558316 TI - Kinematic analysis of the cervical cord and cervical canal by dynamic neck motion. AB - STUDY DESIGN: Normal cervical sagittal length patterns were measured by magnetic resonance imaging (MRI). PURPOSE: The aim of this study was to evaluate the relationship of sagittal length patterns between the cervical cord and the cervical canal in flexion-extension kinematics. OVERVIEW OF LITERATURE: Cervical dynamic factors sometimes cause a cervical spondylotic myelopathy in elderly subjects and an overstretching myelopathy in juvenile subjects. Previous studies showed the length changing of the cervical cord in flexion and extension. However, there is no detailed literature about the relationship between cervical vertebral motion and cord distortion yet. METHODS: Sixty-two normal subjects (28 male and 34 female, 42.1+/-8.5 years old) without neck motion disturbances and abnormalities on cervical X-ray and MRI were enrolled in this study. RESULTS: The cervical cord length was significantly longer in flexion and significantly shorter in extension in all cervical cord sagittal lines. The cervical canal length pattern was also the same as the cervical cord. The elongation of the cervical cord and canal was the largest at the site of the posterior cervical canal and the shortest at the anterior canal site. The positions of the cerebellar tonsils were verified at each neck position. CONCLUSIONS: The posterior elements of the cervical canal were most affected by neck motion. Movement directions of the upper cervical cord were verified among the various neck positions. PMID- 25558317 TI - Effect of cryotherapy after spine surgery. AB - STUDY DESIGN: Historical controlled trial. PURPOSE: To clarify the usefulness of cryotherapy after spine surgery. OVERVIEW OF LITERATURE: Cryotherapy has generally been performed subsequent to surgery on joints and in this application its clinical effects are well understood. However, cryotherapy has yet to be used following spine surgery. Its clinical efficacy in this context is unknown. METHODS: Thirty six patients had undergone one level microendoscopic surgery. Sixteen were enrolled into the cooling group, with the remaining 20 making up the no postoperative cryotherapy control group. Cryotherapy was performed at 5C using an icing system. A silicone balloon catheter with a thermo sensor on the tip was placed in the surgical wound. The temperature in the wound was recorded every 30 minutes until the next morning. The relationship between the depth of the sensor and the temperature in the wound were investigated using simple linear regression analysis. Laboratory data, visual analogue scale (VAS) for wound pain and postoperative bleeding were investigated. RESULTS: The mean temperature in the surgical wound was 37.0 in the control group and 35.0C in the cooling group (p<0.001). There was a positive correlation between the depth of the thermo sensor and the temperature in the wound in the cooling group (y=0.91x+30.2, r=0.67, p=0.004). There were no significant differences between the groups in terms of laboratory data, VAS or postoperative bleeding. CONCLUSIONS: The temperature in the wound was decreased significantly by spinal surgery cryotherapy. PMID- 25558318 TI - Mid-term results of computer-assisted cervical pedicle screw fixation. AB - STUDY DESIGN: A retrospective study. PURPOSE: The present study aimed to evaluate mid-term results of cervical pedicle screw (CPS) fixation for cervical instability. OVERVIEW OF LITERATURE: CPS fixation has widely used in the treatment of cervical spinal instability from various causes; however, there are few reports on mid-term surgical results of CPS fixation. METHODS: Record of 19 patients who underwent cervical and/or upper thoracic (C2-T1) pedicle screw fixation for cervical instability was reviewed. The mean observation period was 90.2 months. Evaluated items included Japanese Orthopaedic Association (JOA) score and C2-7 lordotic angle before surgery and at 5 years after surgery. Postoperative computerized tomography was used to determine the accuracy of screw placement. Visual analog scale (VAS) for neck pain and radiological evidence of adjacent segment degeneration (ASD) at the 5-year follow-up were also evaluated. RESULTS: Mean JOA score was significantly improved from 9.0 points before surgery to 12.8 at 5 years after surgery (p=0.001). The C2-7 lordotic angle of the neutral position improved from 6.4 degrees to 7.8 degrees at 5 years after surgery, but this was not significant. The major perforation rate was 5.0%. There were no clinically significant complications such as vertebral artery injury, spinal cord injury, or nerve root injury caused by any screw perforation. Mean VAS for neck pain was 49.4 at 5 years after surgery. The rate of ASD was 21.1%. CONCLUSIONS: Our mid-term results showed that CPS fixation was useful for treating cervical instability. Severe complications were prevented with the assistance of a computed tomography-based navigation system. PMID- 25558319 TI - Comparison of Spinous Process-Splitting Laminectomy versus Conventional Laminectomy for Lumbar Spinal Stenosis. AB - STUDY DESIGN: Seventy-five patients who had been treated for lumbar spinal stenosis (LSS) were reviewed retrospectively. PURPOSE: Invasion into the paravertebral muscle can cause major problems after laminectomy for LSS. To address these problems, we performed spinous process-splitting laminectomy. We present a comparative study of decompression of LSS using 2 approaches. OVERVIEW OF LITERATURE: There are no other study has investigated the lumbar spinal instability after spinous process-splitting laminectomy. METHODS: This study included 75 patients who underwent laminectomy for the treatment of LSS and who were observed through follow-ups for more than 2 years. Fifty-five patients underwent spinous process-splitting laminectomy (splitting group) and 20 patients underwent conventional laminectomy (conventional group). We evaluated the clinical and radiographic results of each surgical procedure. RESULTS: Japanese Orthopaedic Association score improved significantly in both groups two years postoperatively. The following values were all significantly lower, as shown with p-values, in the splitting group compared to the conventional group: average operating time (p=0.002), postoperative C-reactive protein level (p=0.006), the mean postoperative number of days until returning to normal body temperature (p=0.047), and the mean change in angulation 2 years postoperatively (p=0.007). The adjacent segment degeneration occurred in 6 patients (10.9%) in the splitting group and 11 patients (55.0%) in the conventional group. CONCLUSIONS: In this study, the spinous process-splitting laminectomy was shown to be less invasive and more stable for patients with LSS, compared to the conventional laminectomy. PMID- 25558321 TI - Study of Vertebral Body Replacement with Reconstruction Spinal Cages in Dorsolumbar Traumatic and Koch's Spine. AB - STUDY DESIGN: Retrospective and prospective case series. PURPOSE: The aim of this study was to assess the results of reconstruction of anterior column, fusion and complications related to cages. OVERVIEW OF LITERATURE: Literature shows that corpectomy has become a common surgical procedure for spinal infection, trauma, deformity, instability and metastasis. Also the use of reconstructive spinal cages is common after corpectomy. METHODS: Study was carried out in patients with dorsolumbar traumatic and Koch's spine. We assessed 25 patients (13 traumatic/12 tuberculous) who were treated with cages with/without any other instrumentation. Radiographs were obtained before and after the surgery. A preoperative magnetic resonance imaging was obtained in every patient. RESULTS: Fourteen patients underwent 1 level of corpectomy, 9 patients underwent 2 levels and 2 patients underwent 3 levels of corpectomy. Anterior reconstruction alone was performed in 8 patients; 360 degrees reconstruction was performed in 17 patients and 2 of them underwent reconstruction through single posterior approach only. The mean kyphotic angulation improved from 21.2 degrees preoperatively to 9.3 degrees postoperatively and to 12 degrees at final follow up. 8 patients with neurological deficits had improvement by at least one or more Frankel grade. No migration/displacement of cage was seen in any patients. CONCLUSIONS: The present study demonstrates that the vertebral body replacement after corpectomy by reconstructive cages provides a reconstruction of the anterior column, good correction of the mean kyphotic angle, and a correction maintained with cage without any cage related complication at long term follow up. The fusion can be achieved with reconstructive cage plus bone graft with or without posterior instrumentation. PMID- 25558320 TI - Comparison between Bilateral C2 Pedicle Screwing and Unilateral C2 Pedicle Screwing, Combined with Contralateral C2 Laminar Screwing, for Atlantoaxial Posterior Fixation. AB - STUDY DESIGN: A retrospective study. PURPOSE: To compare clinical and radiological outcomes between bilateral C2 pedicle screwing (C2PS) and unilateral C2PS, combined with contralateral C2 laminar screwing (LS), for posterior atlantoaxial fixation. OVERVIEW OF LITERATURE: Posterior fixation with C1 lateral mass screwing (C1LMS) and C2PS (C1LMS-C2PS method) is an accepted procedure for rigid atlantoaxial stabilization. However, conventional bilateral C2PS is not always allowed in this method due to anatomical variations of C2 pedicles and/or asymmetry of the vertebral artery. Although unilateral C2PS plus contralateral LS (C2PS+LS) is an alternative in such cases, the efficacy of this procedure has not been evaluated in controlled studies (i.e., with bilateral C2PS as a control). METHODS: Clinical and radiological records of patients who underwent the C1LMS C2PS method, using unilateral C2PS+LS (n=9), and those treated using conventional bilateral C2PS (n=10) were compared, with a minimum two years follow-up. RESULTS: Postoperative complications related to the unilateral C2PS+LS technique included one case of spontaneous spinous process fracture of C2. A C1 anterior arch fracture occurred after a fall in one patient, who underwent bilateral C2PS and C1 laminectomy. No significant differences were seen between the groups in reduction of neck pain after surgery or improvement of neurological status, as evaluated using the Japanese Orthopaedic Association score. A delayed union occurred in one patient each of the groups, with the final fusion rate being 100% in both groups. CONCLUSIONS: Clinical and radiological outcomes of unilateral C2PS+LS were comparable with those of the bilateral C2PS fixation technique for the C1LMS-C2PS method. PMID- 25558322 TI - PainVision Apparatus Is Effective for Assessing Low Back Pain. AB - STUDY DESIGN: Case series. PURPOSE: To determine the utility of "PainVision" apparatus for the assessment of low back pain. OVERVIEW OF LITERATURE: A newly developed device, the PainVision PS-2100 (Nipro, Osaka, Japan), has been used to assess the perception of pain in a quantitative manner. In the current study, we aimed to evaluate the efficacy of PainVision for the assessment of low back pain. METHODS: We assessed 89 patients with low back pain. The numeric rating scale (NRS) score, McGill Pain Questionnaire (MPQ) score and the degree of pain calculated by PainVision were measured twice at 4-week intervals in each patient. An electrode was patched on the forearm surface of the patients and the degree of pain was automatically calculated (degree of pain=100*[current producing pain comparable with low back pain-current at perception threshold/current at perception threshold]). Correlations between NRS and MPQ scores and the degree of pain were determined using Spearman's rank correlation test. RESULTS: There was a strong correlation between the NRS and MPQ scores at each time point (rs =0.60, p<0.0001). The degree of pain also showed a moderate correlation with NRS and MPQ scores at each time point (rs =0.40, p<0.03). The change in the degree of pain over 4 weeks showed a moderate correlation with changes in the NRS and MPQ scores (rs =0.40, p<0.01). CONCLUSIONS: PainVision as self-reported questionnaires is a useful tool to assess low back pain. PMID- 25558323 TI - Quality of Life Comparison between Vertebroplasty and Kyphoplasty in Patients with Osteoporotic Vertebral Fractures. AB - STUDY DESIGN: Retrospective evaluation. PURPOSE: To compare quality of life in postmenopausal women with osteoporotic vertebral fractures (OVFs) who underwent vertebroplasty (VP) or kyphoplasty (KP). OVERVIEW OF LITERATURE: Patient with OVFs who do not respond to conservative treatment can be treated with VP or ballon KP for faster pain relief. There are controversies on which procedure is more effective. METHODS: Five hundred twenty-eight postmenopausal women in nationwide hospitals with age of 50 years or older who underwent VP of KP for OVFs were enrolled in this study. Health related quality of life was measured using the European Quality of Life 5 Domains (EQ-5D) and visual analogue scale (VAS). RESULTS: In the VP group, average EQ-5D dimension was 1.95 in mobility, 1.86 in self care, 2.02 in usual activity, 2.19 in pain, 1.69 in anxiety or depression. In the KP group, average EQ-5D dimension was 1.83 in mobility, 1.78 in self care, 1.98 in usual activity, 2.03 in pain, 1.55 in anxiety or depression. Quality of life of KP group was significantly better than that of the VP group in mobility (p=0.016), pain (p=0.001), and anxiety or depression (p=0.008). Average EQ-5D index of the VP and the KP group was 0.353 (+/-0.472) and 0.485 (+/-0.357), respectively. The EQ-5D index of the KP group was significantly (p<0.001) higher than that of the KP group. The difference of VAS between VP and KP group was not statistically significant (p=0.580). CONCLUSIONS: Quality of life in patient with OVFs who underwent KP was significantly better than that of patients who underwent VP. PMID- 25558324 TI - Determination of the distal fusion level in the management of thoracolumbar and lumbar adolescent idiopathic scoliosis using pedicle screw instrumentation. AB - STUDY DESIGN: A retrospective study. PURPOSE: To determine the exact distal fusion level in the management of thoracolumbar/lumbar adolescent idiopathic scoliosis (TL/L AIS) using pedicle screw instrumentation (PSI). OVERVIEW OF LITERATURE: The selection of distal fusion level remains controversial in TL/L AIS. METHODS: Radiographic parameters of 66 TL/L AIS patients were analyzed. The patients were grouped according to the distal fusion level; L3 group (fusion to L3, n=58) and L4 group (fusion to L4, n=8). The L3 group was subdivided into L3A (L3 crosses the mid-sacral line with rotation of less than grade II, n=33) and L3B (L3 does not cross the mid-sacral line or rotation is grade II or more, n=25) based on both bending radiographs. All of the patients in the L4 group had the same location and rotation of L3 in bending films as that of patients in the L3B group. An unsatisfactory result was defined as a lowest instrumented vertebral tilt (LIVT) of more than 10 degrees or coronal balance of more than 15 mm. RESULTS: Among the 3 groups, there was a significantly lesser correction in the TL/L curve and LIVT in the L3B group. Unsatisfactory results were obtained in 3 patients (9.1%) of the L3A group, in 15 patients (68.2%) of the L3B group, and in 1 patient (12.5%) of the L4 group with a significant difference. CONCLUSIONS: In TL/L AIS treatment with PSI, the curve can be fused to L3 with favorable radiographic outcomes when L3 crosses the mid-sacral line with rotation of less than grade II in bending films. Otherwise, fusion has to be extended to L4. PMID- 25558325 TI - Lumbosacral sagittal alignment in association to intervertebral disc diseases. AB - STUDY DESIGN: A cross-sectional case-control study was designed to compare the sagittal alignment of lumbosacral regions in two groups of patients suffering from low back pain, one with intervertebral disc pathologies and one without. PURPOSE: To evaluate the correlation between lumbosacral sagittal alignment and disc degeneration. OVERVIEW OF LITERATURE: Changes in lumbar lordosis and pelvic parameters in degenerative disc lesions have been assessed in few studies. Overall, patients with discopathy were shown to have lower lumbar lordosis and more vertical sacral profiles. METHODS: From patients with intractable low back pain undergoing lumbosacral magnetic resonance imaging, 50 subjects with disc degeneration and 50 controls with normal scans were consecutively enrolled. A method was defined with anterior tangent-lines going through anterior bodies of L1 and S1 to measure global lumbosacral angle, incorporating both lumbar lordosis and sacral slope. Global lumbosacral angle using the proposed method and lumbar lordosis using Cobb's method were measured in both groups. RESULTS: Lumbar lordosis based on Cobb's method was lower in group with discopathy (20 degrees 67 degrees ; mean, 40.48 degrees +/-9.89 degrees ) than control group (30 degrees -62 degrees ; mean, 44.96 degrees +/-7.68 degrees ), although it was not statistically significant. The proposed global lumbosacral angle in subject group (53 degrees -103 degrees ; mean, 76.5 degrees +/-11.018 degrees ) was less than control group (52 degrees -101 degrees ; mean, 80.18 degrees +/-9.95 degrees ), with the difference being statistically significant (p=0.002). CONCLUSIONS: Patients with intervertebral disc lesions seem to have more straightened lumbosacral profiles, but it has not been proven which comes first: disc degeneration or changes in sagittal alignment. Finding an answer to this dilemma demands more comprehensive long-term prospective studies. PMID- 25558326 TI - Operative technique for en bloc resection of upper cervical chordomas: extended transoral transmandibular approach and multilevel reconstruction. AB - Anterior exposure for cervical chordomas remains challenging because of the anatomical complexities and the restoration of the dimensional balance of the atlanto-axial region. In this report, we describe and analyze the transmandibular transoral approach and multilevel spinal reconstruction for upper cervical chordomas. We report two cases of cervical chordomas (C2 and C2-C4) that were treated by marginal en bloc resection with a transmandibular approach and anterior-posterior multilevel spinal reconstruction/fixation. Both patients showed clinical improvement. Postoperative imaging was negative for any residual tumor and revealed adequate reconstruction and stabilization. Marginal resection requires more extensive exposure to allow the surgeon access to the entire pathology, as an inadequate tumor margin is the main factor that negatively affects the prognosis. Anterior and posterior reconstruction provides a rigid reconstruction that protects the medulla and decreases axial pain by properly stabilizing the cervical spine. PMID- 25558327 TI - Negative pressure pulmonary edema associated with anterior cervical spine surgery. AB - We report a very rare case of negative pressure pulmonary edema (NPPE) that occurred immediately after anterior cervical discectomy and fusion (ACDF). The patient was a 25-year-old man who sustained a facet fracture-dislocation of C5 during a traffic accident. After ACDF, he developed NPPE and needed mechanical ventilation. Fortunately, he recovered fully within 24 hours. NPPE is a rare postoperative complication that may occur after cervical spine surgery. The aims of this report are to present information regarding the diagnosis and emergent treatment of NPPE, and to review the previous literature regarding this serious complication. PMID- 25558328 TI - Spinal cord ischemia secondary to hypovolemic shock. AB - A 44-year-old male presented with symptoms of spinal cord compression secondary to metastatic prostate cancer. An urgent decompression at the cervical-thoracic region was performed, and there were no complications intraoperatively. Three hours postoperatively, the patient developed acute bilateral lower-limb paralysis (motor grade 0). Clinically, he was in class 3 hypovolemic shock. An urgent magnetic resonance imaging (MRI) was performed, showing no epidural hematoma. He was managed aggressively with medical therapy to improve his spinal cord perfusion. The patient improved significantly, and after one week, he was able to regain most of his motor functions. Although not commonly reported, spinal cord ischemia post-surgery should be recognized early, especially in the presence of hypovolemic shock. MRI should be performed to exclude other potential causes of compression. Spinal cord ischemia needs to be managed aggressively with medical treatment to improve spinal cord perfusion. The prognosis depends on the severity of deficits, and is usually favorable. PMID- 25558329 TI - Progressive relapse of ligamentum flavum ossification following decompressive surgery. AB - Thoracic ossification of the ligamentum flavum (T-OLF) is a relatively rare spinal disorder that generally requires surgical intervention, due to its progressive nature and the poor response to conservative therapy. The prevalence of OLF has been reported at 3.8%-26%, which is similar to that of cervical ossification of the posterior longitudinal ligament (OPLL). The progression of OPLL after cervical laminoplasty for the treatment of OPLL is often shown in long term follow-up. However, there have been no reports on the progression of OLF following surgery. We report a case of thoracic myelopathy secondary to the progressive relapse of OLF following laminectomy. PMID- 25558330 TI - Cervical myelopathy caused by disc herniation at the segment of existing osteochondroma in a patient with hereditary multiple exostoses. AB - Hereditary multiple exostoses (HME) is a benign hereditary disorder characterized by multiple osteochondromas. Osteochondroma appears occasionally in the spinal column as a part of HME. A 37-year-old man presented with a history of HME and cervical compressive myelopathy caused by intraspinal osteochondroma arising from the lamina of the C5 and disc herniation at the C5-6. He was treated by open-door laminoplasty at the C5 and C6 with excision of the tumor. The neurological symptoms were immediately relieved after surgery. Magnetic resonance images demonstrated a sufficient decompression of the spinal cord with a spontaneous regression of the herniated disc at one year after surgery. There was no recurrence of the tumor and no appearance of kyphosis and segmental instability of the cervical spine on postoperative imaging studies for three years after surgery. The patient could be successfully treated by laminoplasty with excision of the tumor and without removal of the herniated disc. PMID- 25558331 TI - Myxopapillary ependymoma of the cauda equina in a 5-year-old boy. AB - Myxopapillary ependymoma in childhood typically occurs in the central nervous system. There are few surgical cases of myxopapillary ependymoma of the cauda equina in children. We report a case of myxopapillary ependymoma of the cauda equina in a 5-year-old boy, who presented with leg pain and abnormal gait. Subtotal resection surgery was performed. Following the subtotal tumor resection, follow-up magnetic resonance imaging evaluation showed a recurrent tumor. As a result, we performed a second subtotal tumor resection and followed with postoperative radiation therapy. No further evidence of the disease has been noted elsewhere in the patient in over ten years of follow-up. Myxopapillary ependymoma of the cauda equina in a young boy was improved by subtotal tumor resection and postoperative radiation therapy. PMID- 25558332 TI - Eleven levels of spinous process fractures in thoracolumbar spine. AB - Cases of over 5-level spinous process fractures are extremely rare. Thoracolumbar region of spine is superimposed on ribs; and as such additional studies such as computerized tomography are needed to diagnose fractures in this region. We report a case of 11 contiguous level thoracolumbar spinous process fractures, which has been treated conservatively. PMID- 25558334 TI - Letter to the editor: surgery-related complications and sequelae in management of tuberculosis of spine. PMID- 25558333 TI - Lumbar spondylolysis and spondylolytic spondylolisthesis: who should be have surgery? An algorithmic approach. AB - Lumbar spondylolysis and spondylolisthesis are common spinal disorders that most of the times are incidental findings or respond favorably to conservative treatment. In a small percentage of the patients, surgical intervention becomes necessary. Because too much attention has been paid to novel surgical techniques and new modern spinal implants, some of fundamental concepts have been forgotten. Identifying that small but important number of patients with lumbar spondylolysis or spondylolisthesis who would really benefit from lumbar surgery is one of those forgotten concepts. In this paper, we have developed an algorithmic approach to determine who is a good candidate for surgery due to lumbar spondylolysis or spondylolisthesis. PMID- 25558335 TI - Prevention of rocuronium injection pain. PMID- 25558336 TI - The efficacy of sevolflurane inhalation alone or its combination with intravenous remifentanil against withdrawal movements on rocuronium injection in children. AB - BACKGROUND: The aims of this study were to compare the efficacy of sevoflurane inhalation alone, intravenous remifentanil alone, and the combination of sevoflurane inhalation and remifentanil as pretreatment for the prevention of rocuronium-induced withdrawal movement in pediatric patients. METHODS: In this prospective, randomized study, 90 American Society of Anesthesiologists physical status I or II pediatric patients aged 3 to 10 years were randomly allocated to one of three treatment groups: The Group S comprising the patients receiving sevoflurane inhalation, the Group R comprising those doing intravenous remifentanil 0.5 ug/kg and the Group C comprising those doing sevoflurane inhalation+intravenous remifentanil 0.5 ug/kg. The response of the patients was graded based on a 4-point scale. RESULTS: The overall incidence of withdrawal movement on rocuronium injection was 54% (16/30) in the Group S, 57% (17/30) in the Group R and 17% (5/30) in the Group C. There was no significant difference in the incidence of withdrawal movements on rocuronium injection between the Group S and Group R. In addition, the incidence of withdrawal movements and generalized movement on rocuronium injection was significantly lower in the Group C as compared with the Group S and R (P < 0.05). CONCLUSIONS: Our results indicate not only that there was no significant difference in the degree of the effect in lowering the incidence of withdrawal movements on rocuronium injection between sevoflurane inhalation and intravenous remifentanil but also that it was significantly higher when combined with intravenous remifentanil as compared with the single use of sevoflurane inhalation or intravenous remifentanil. PMID- 25558337 TI - The correlation between the Trendelenburg position and the stroke volume variation. AB - BACKGROUND: The stroke volume variation (SVV), based on lung-heart interaction during mechanical ventilation, is a useful dynamic parameter for fluid responsiveness. However, it is affected by many factors. The aim of this study was to evaluate the effects of SVV on Trendelenburg (T) and reverse Trendelenburg (RT) position and to further elaborate on the patterns of the SVV with position. METHODS: Forty-two patients undergoing elective surgery were enrolled in this study. Fifteen minutes after standardized induction of anesthesia with propofol, fentanyl, and rocuronium with volume controlled ventilation (tidal volume of 8 ml/kg of ideal body weight, inspiration : expiration ratio of 1 : 2, and respiratory rate of 10-13 breaths/min), the patients underwent posture changes as follows: supine, T position at slopes of operating table of -5 degrees , -10 degrees , and -15 degrees , and RT position at slopes of operating table of 5 degrees , 10 degrees , and 15 degrees . At each point, SVV, cardiac output (CO), peak airway pressure (PAP), mean blood pressure, and heart rate (HR) were recorded. RESULTS: The SVV was significant decreased with decreased slopes of operating table in T position, and increased with increased slopes of operating table in RT position (P = 0.000). Schematically, it was increased by 1% when the slope of operating table was increased by 5 degrees . But, the CO and PAP were significant increased with decreased slopes of operating table in T position, and decreased with increased slopes of operating table in RT position (P = 0.045, 0.027). CONCLUSIONS: SVV is subjected to the posture, and we should take these findings into account on reading SVV for fluid therapy. PMID- 25558338 TI - The relationship between perioperative nausea and vomiting and serum serotonin concentrations in patients undergoing cesarean section under epidural anesthesia. AB - BACKGROUND: Serotonin-also known as 5-hydroxytryptamine or 5-HT-can induce nausea and vomiting (NV) by peripheral mechanisms via the activation of 5-HT3 receptors. In this study, we observed perioperative NV, including intraoperative NV, and changes in serum 5-HT concentrations. We evaluated the relationship between perioperative NV and serum 5-HT levels in patients undergoing cesarean section under epidural anesthesia, and carried out a pilot study to determine if further studies on a larger scale were justified. METHODS: Twenty-eight patients who were scheduled for cesarean section under epidural anesthesia were included in the study. Patients were assigned to 2 groups according to the occurrence of NV after induction, i.e., an NV-positive or an NV-negative group. Serum 5-HT concentrations were measured before induction, at the time that NV occurred (in the case of the NV-positive group) or 5 min after the umbilical cord clamping (in the case of the NV-negative group) during surgery, and at 2 h postoperatively. RESULTS: NV occurred in 10 of the 28 patients. No significant differences in serum 5-HT concentrations were found within or between the two groups. CONCLUSIONS: This study suggests that there is no correlation between serum 5-HT concentration and the occurrence of perioperative NV in patients undergoing cesarean section under epidural anesthesia, and the findings do not seem to support further investigations regarding a possible relationship between serum 5 HT concentration and perioperative NV. PMID- 25558339 TI - Comparison of the effects of on-pump and off-pump coronary artery bypass surgery on cerebral oxygen saturation using near-infrared spectroscopy. AB - BACKGROUND: Central nervous system complications are the most clinically important of those affecting mortality in patients undergoing coronary artery surgery. Newly developed sophisticated techniques and surgical interventions obviating the need for cardiopulmonary pumps have facilitated avoidance of these complications. In this study, we compared the impact of on-pump and off-pump coronary artery bypass surgery on cerebral oxygenation using near-infrared spectroscopy. METHODS: This study included 40 patients with no comorbidities who were scheduled for on-pump (n = 20) and off-pump (n = 20) cardiac surgery. Preoperative and postoperative Standardized Mini-Mental State Examination (SMMSE) scores, perioperative mean arterial blood pressure (MAP), hematocrit (Hct), peripheral oxygen saturation (SpO2), regional cerebral oximetry values (rSO2), body temperature, and partial pressure of carbon dioxide (PCO2) were recorded, for all patients. Intergroup and intragroup comparisons were then performed. RESULTS: The mean operative time was longer in the on-pump group. SMMSE scores were similar and relevant postoperative values were lower in both groups. Perioperative MAP, PCO2, and SpO2 were similar in both groups. SpO2 and PCO2 did not differ from baseline levels in either group, while the postextubation MAP at 2 h postoperatively remained low. Hct levels decreased during the perioperative and postoperative periods, while the body temperature declined perioperatively and to a greater degree in the on-pump group. The intraoperative and postoperative rSO2 decreased in both groups. In the on-pump group, the decrease in rSO2 was more prominent during the interval between the start and closure of the sternotomy. CONCLUSIONS: Physiological alterations that occur during coronary artery surgery affect cerebral oxygenation during and after the operation irrespective of the application of a cardiopulmonary pump. Cerebral oxygenation decreases to a greater extent during on-pump surgery; however, probably because of the neuroprotective effects of hypothermia, the postoperative changes resemble those of off-pump surgery. PMID- 25558340 TI - Is transverse abdominis plane block effective following local anesthetic infiltration in laparoscopic totally extraperitoneal hernia repair? AB - BACKGROUND: Transverse abdominis plane (TAP) block can be recommended as a multimodal method to reduce postoperative pain in laparoscopic abdominal surgery. However, it is unclear whether TAP block following local anesthetic infiltration is effective. We planned this study to evaluate the effectiveness of the latter technique in laparoscopic totally extraperitoneal hernia repair (TEP). METHODS: We randomly divided patients into two groups: the control group (n = 37) and TAP group (n = 37). Following the induction of general anesthesia, as a preemptive method, all of the patients were subjected to local anesthetic infiltration at the trocar sites, and the TAP group was subjected to ultrasound-guided bilateral TAP block with 30 ml of 0.375% ropivacaine in addition before TEP. Pain was assessed in the recovery room and post-surgery at 4, 8, and 24 h. Additionally, during the postoperative 24 h, the total injected dose of analgesics and incidence of nausea were recorded. RESULTS: On arrival in the recovery room, the pain score of the TAP group (4.33 +/- 1.83) was found to be significantly lower than that of the control group (5.73 +/- 2.04). However, the pain score was not significantly different between the TAP group and control group at 4, 8, and 24 h post-surgery. The total amounts of analgesics used in the TAP group were significantly less than in the control group. No significant difference was found in the incidence of nausea between the two groups. CONCLUSIONS: TAP block following local infiltration had a clinical advantage only in the recovery room. PMID- 25558341 TI - Mepivacaine-induced intracellular calcium increase appears to be mediated primarily by calcium influx in rat aorta without endothelium. AB - BACKGROUND: Mepivacaine induces contraction or decreased blood flow both in vivo and in vitro. Vasoconstriction is associated with an increase in the intracellular calcium concentration ([Ca(2+)]i). However, the mechanism responsible for the mepivacaine-evoked [Ca(2+)]i increase remains to be determined. Therefore, the objective of this in vitro study was to examine the mechanism responsible for the mepivacaine-evoked [Ca(2+)]i increment in isolated rat aorta. METHODS: Isometric tension was measured in isolated rat aorta without endothelium. In addition, fura-2 loaded aortic muscle strips were illuminated alternately (48 Hz) at two excitation wavelengths (340 and 380 nm). The ratio of F340 to F380 (F340/F380) was regarded as an amount of [Ca(2+)]i. We investigated the effects of nifedipine, 2-aminoethoxydiphenylborate (2-APB), gadolinium chloride hexahydrate (Gd(3+)), low calcium level and Krebs solution without calcium on the mepivacaine-evoked contraction in isolated rat aorta and on the mepivacaine-evoked [Ca(2+)]i increment in fura-2 loaded aortic strips. We assessed the effect of verapamil on the mepivacaine-evoked [Ca(2+)]i increment. RESULTS: Mepivacaine produced vasoconstriction and increased [Ca(2+)]i. Nifedipine, 2-APB and low calcium attenuated vasoconstriction and the [Ca(2+)]i increase evoked by mepivacaine. Verapamil attenuated the mepivacaine-induced [Ca(2+)]i increment. Calcium-free solution almost abolished mepivacaine-induced contraction and strongly attenuated the mepivacaineinduced [Ca(2+)]i increase. Gd(3+) had no effect on either vasoconstriction or the [Ca(2+)]i increment evoked by mepivacaine. CONCLUSIONS: The mepivacaine-evoked [Ca(2+)]i increment, which contributes to mepivacaine-evoked contraction, appears to be mediated mainly by calcium influx and partially by calcium released from the sarcoplasmic reticulum. PMID- 25558342 TI - Sudden cardiovascular collapse caused by severe anaphylaxis after cisatracurium use: a case report. AB - Kounis syndrome is an acute coronary syndrome concurrently occurs with allergic or hypersensitivity reactions. In patient with this syndrome, inflammatory mediators released due to an allergic reaction implicate to induce coronary artery spasm and atheromatous plaque rupture. We describe a patient with coronary artery disease who developed acute perioperative myocardial infarction leading to cardiac arrest after the anaphylactic reaction to cisatracurium, which led to a suspicion of Kounis syndrome. Anesthesiologists should be aware that anaphylaxis or allergic reactions can progress to acute coronary syndrome, thereby significantly change the course of the disease. PMID- 25558343 TI - Ventricular arrhythmia in patients with prolonged QT interval during liver transplantation: two cases report. AB - QT interval prolongation is associated with an increased risk of ventricular arrhythmia in various conditions. Cardiac electrophysiologic abnormalities including QT interval prolongation are well documented in patients with advanced liver cirrhosis. We report two cases of patients with QT interval prolongation on preoperative electrocardiography who exhibited repetitive ventricular arrhythmias with significant hemodynamic deterioration during liver transplantation. For the treatment and prevention of ventricular arrhythmias during the intraoperative period, we performed intravenous administration of lidocaine and isoproterenol, corrected imbalances of electrolytes including potassium and magnesium, and prepared a defibrillator. These cases emphasize that preoperative recognition of QT interval prolongation and adequate management to prevent fatal arrhythmias are important in patients undergoing liver transplantation. PMID- 25558344 TI - Sedation using 5% lidocaine patches, midazolam and propofol in a combative, obese adolescent with severe autistic disorder undergoing brain magnetic resonance imaging: a case report. AB - We present a 17-year-old man who underwent brain magnetic resonance imaging and laboratory exams for uncontrolled seizure. Patients with an autistic disorder require deep sedation or, occasionally, general anesthesia even for radiologic exams or simple procedures. The anesthetic management of an obese, violent patient with a severe autistic disorder and mental retardation can be challenging to anesthesiologists and requires a more careful approach in selecting adequate anesthetics and doses. This case emphasizes the importance of having a detailed plan to ensure the smooth process of premedication, anesthetic induction, maintenance, emergence and safe discharge of incorporated patients in the event of unexpected situations. A 5% lidocaine patch to relieve the pain from the intramuscular injection and intravenous cannulation, intramuscular midazolam as premedication, and propofol for the maintenance of sedation can be a good sedation protocol in incorporated patients. PMID- 25558345 TI - Paradoxical carbon dioxide embolism during laparoscopic cholecystectomy as a cause of cardiac arrest and neurologic sequelae: a case report. AB - An 81-year-old male patient was scheduled for a laparoscopic cholecystectomy due to acute cholecystitis. About 50 minutes into the operation, the arterial blood pressure suddenly decreased and ventricular fibrillation appeared on the electrocardiography. The patient received cardiopulmonary resuscitation and recovered a normal vital sign. We suspected a carbon dioxide embolism as the middle hepatic vein had been injured during the surgery. We performed a transesophageal echocardiography and were able to confirm the presence of multiple gas bubbles in all of the cardiac chambers. After the operation, the patient presented a stable hemodynamic state, but showed weaknesses in the left arm and leg. There were no acute lesions except for a chronic cerebral cortical atrophy and chronic microvascular encephalopathy on the postoperative brain computed tomography, 3D angiography and magnetic resonance image. Fortunately, three days after the operation, the patient's hemiparesis had entirely subsided and he was discharged without any neurologic sequelae. PMID- 25558346 TI - Persistent left superior vena cava: diagnosed by bedside echocardiography in a liver transplant patient: a case report. AB - In most cases, persistent left superior vena cava (PLSVC) is asymptomatic and discovered accidentally. This case involves a 43-year-old male who underwent an emergency cadaveric liver transplantation. Postoperatively, the left internal jugular vein was cannulated using a sono-guided Seldinger technique in the intensive care unit. But the chest X-ray showed that the catheter followed the left paramediastinal course instead of crossing midline to the right to enter the superior vena cava. In consideration of the patient's status, an intra-arterial or extra-vascular placement could be excluded. For a diagnosis, we performed a bed-side transthoracic echocardiography with an agitated saline micro-bubble test. When agitated saline was injected through the catheter, the coronary sinus was initially opacified, and then the right atrium followed. In conclusion, we were able to make a diagnosis of PLSVC by a bedside test without radiation exposure. PMID- 25558347 TI - Techniques for dental implant nanosurface modifications. AB - PURPOSE: Dental implant has gained clinical success over last decade with the major drawback related to osseointegration as properties of metal (Titanium) are different from human bone. Currently implant procedures include endosseous type of dental implants with nanoscale surface characteristics. The objective of this review article is to summarize the role of nanotopography on titanium dental implant surfaces in order to improve osseointegration and various techniques that can generate nanoscale topographic features to titanium implants. MATERIALS AND METHODS: A systematic electronic search of English language peer reviewed dental literature was performed for articles published between December 1987 to January 2012. Search was conducted in Medline, PubMed and Google scholar supplemented by hand searching of selected journals. 101 articles were assigned to full text analysis. Articles were selected according to inclusion and exclusion criterion. All articles were screened according to inclusion standard. 39 articles were included in the analysis. RESULTS: Out of 39 studies, seven studies demonstrated that bone implant contact increases with increase in surface roughness. Five studies showed comparative evaluation of techniques producing microtopography and nanotopography. Eight studies concluded that osteoblasts preferably adhere to nano structure as compared to smooth surface. Six studies illustrated that nanotopography modify implant surface and their properties. Thirteen studies described techniques to produce nano roughness. CONCLUSION: Modification of dental osseous implants at nanoscale level produced by various techniques can alter biological responses that may improve osseointegration and dental implant procedures. PMID- 25558348 TI - Focal epithelial hyperplasia arising after delivery of metal-ceramic fixed dental prosthesis. AB - Focal epithelial hyperplasia (FEH) is a human papillomavirus (HPV)-induced alteration of the oral mucosa that presents with a clinically distinct appearance. While other HPV-infected lesions such as squamous papilloma, verruca vulgaris, and condyloma acuminatum involve the skin, oral mucosa, and genital mucosa, FEH occurs only in the oral mucosa. The affected oral mucosa exhibits multiple papules and nodules with each papule/nodule being flat-topped or sessile. The affected region resembles the normal color of oral mucosa rather than appearing as a white color since the epithelial surface is not hyperkeratinized. Almost all cases present with multiple sites of occurrence. This rare, benign epithelial proliferation is related to low-risk HPV, especially HPV-13 and -32, and is not transformed into carcinoma. We report a case of FEH that arose on the attached gingiva of an East Asian male adult related to prosthesis without detection of any HPV subtype in HPV DNA chip and sequencing. PMID- 25558349 TI - Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation. AB - Protein palmitoylation describes the hydrophobic post-translational modification of cysteine residues in certain proteins, and is required for the spatial organization and composition of cellular membrane environments. Certain palmitoylated proteins are processed by acyl protein thioesterase (APT) enzymes, which catalyze thioester hydrolysis of palmitoylated cysteine residues. Inhibiting APT enzymes disrupts Ras trafficking and attenuates oncogenic growth signaling, highlighting these enzymes as potential therapeutic targets. As members of the serine hydrolase enzyme family, APT enzymes can be assayed by fluorophosphonate activity-based protein profiling (ABPP) methods, allowing rapid profiling of inhibitor selectivity and potency. In this review, we discuss recent progress in the development of potent and selective inhibitors to APT enzymes, including both competitive and non-competitive chemotypes. These examples highlight how ABPP methods integrate with medicinal chemistry for the discovery and optimization of inhibitors in complex proteomes. PMID- 25558351 TI - Why are pediatric primary care providers reluctant to prescribe antidepressants to teens? PMID- 25558350 TI - Copy number variation analysis based on AluScan sequences. AB - BACKGROUND: AluScan combines inter-Alu PCR using multiple Alu-based primers with opposite orientations and next-generation sequencing to capture a huge number of Alu-proximal genomic sequences for investigation. Its requirement of only sub microgram quantities of DNA facilitates the examination of large numbers of samples. However, the special features of AluScan data rendered difficult the calling of copy number variation (CNV) directly using the calling algorithms designed for whole genome sequencing (WGS) or exome sequencing. RESULTS: In this study, an AluScanCNV package has been assembled for efficient CNV calling from AluScan sequencing data employing a Geary-Hinkley transformation (GHT) of read depth ratios between either paired test-control samples, or between test samples and a reference template constructed from reference samples, to call the localized CNVs, followed by use of a GISTIC-like algorithm to identify recurrent CNVs and circular binary segmentation (CBS) to reveal large extended CNVs. To evaluate the utility of CNVs called from AluScan data, the AluScans from 23 non cancer and 38 cancer genomes were analyzed in this study. The glioma samples analyzed yielded the familiar extended copy-number losses on chromosomes 1p and 9. Also, the recurrent somatic CNVs identified from liver cancer samples were similar to those reported for liver cancer WGS with respect to a striking enrichment of copy-number gains in chromosomes 1q and 8q. When localized or recurrent CNV-features capable of distinguishing between liver and non-liver cancer samples were selected by correlation-based machine learning, a highly accurate separation of the liver and non-liver cancer classes was attained. CONCLUSIONS: The results obtained from non-cancer and cancerous tissues indicated that the AluScanCNV package can be employed to call localized, recurrent and extended CNVs from AluScan sequences. Moreover, both the localized and recurrent CNVs identified by this method could be subjected to machine-learning selection to yield distinguishing CNV-features that were capable of separating between liver cancers and other types of cancers. Since the method is applicable to any human DNA sample with or without the availability of a paired control, it can also be employed to analyze the constitutional CNVs of individuals. PMID- 25558352 TI - Preadaptation and post-introduction evolution facilitate the invasion of Phragmites australis in North America. AB - Compared with non-invasive species, invasive plant species may benefit from certain advantageous traits, for example, higher photosynthesis capacity and resource/energy-use efficiency. These traits can be preadapted prior to introduction, but can also be acquired through evolution following introduction to the new range. Disentangling the origins of these advantageous traits is a fundamental and emerging question in invasion ecology. We conducted a multiple comparative experiment under identical environmental condition with the invasive haplotype M lineage of the wetland grass Phragmites australis and compared the ecophysiological traits of this invasive haplotype M in North America with those of the European ancestor and the conspecific North American native haplotype E lineage, P. australis ssp. americanus. The invasive haplotype M differed significantly from the native North American conspecific haplotype E in several ecophysiological and morphological traits, and the European haplotype M had a more efficient photosynthetic apparatus than the native North American P. australis ssp. americanus. Within the haplotype M lineage, the introduced North American P. australis exhibited different biomass allocation patterns and resource/energy-use strategies compared to its European ancestor group. A discriminant analysis of principal components separated the haplotype M and the haplotype E lineages completely along the first canonical axis, highly related to photosynthetic gas-exchange parameters, photosynthetic energy-use efficiency and payback time. The second canonical axis, highly related to photosynthetic nitrogen use efficiency and construction costs, significantly separated the introduced P. australis in North America from its European ancestor. Synthesis. We conclude that the European P. australis lineage was preadapted to be invasive prior to its introduction, and that the invasion in North America is further stimulated by rapid post-introduction evolution in several advantageous traits. The multicomparison approach used in this study could be an effective approach for distinguishing preadaptation and post-introduction evolution of invasive species. Further research is needed to link the observed changes in invasive traits to the genetic variation and the interaction with the environment. PMID- 25558354 TI - Habitat heterogeneities versus spatial type frequency variances as driving forces of dispersal evolution. AB - Understanding the evolution of dispersal is essential for understanding and predicting the dynamics of natural populations. Two main factors are known to influence dispersal evolution: spatio-temporal variation in the environment and relatedness between individuals. However, the relation between these factors is still poorly understood, and they are usually treated separately. In this article, I present a theoretical framework that contains and connects effects of both environmental variation and relatedness, and reproduces and extends their known features. Spatial habitat variation selects for balanced dispersal strategies, whereby the population is kept at an ideal free distribution. Within this class of dispersal strategies, I explain how increased dispersal is promoted by perturbations to the dispersal type frequencies. An explicit formula shows the magnitude of the selective advantage of increased dispersal in terms of the spatial variability in the frequencies of the different dispersal strategies present. These variances are capable of capturing various sources of stochasticity and hence establish a common scale for their effects on the evolution of dispersal. The results furthermore indicate an alternative approach to identifying effects of relatedness on dispersal evolution. PMID- 25558353 TI - Step selection techniques uncover the environmental predictors of space use patterns in flocks of Amazonian birds. AB - Understanding the behavioral decisions behind animal movement and space use patterns is a key challenge for behavioral ecology. Tools to quantify these patterns from movement and animal-habitat interactions are vital for transforming ecology into a predictive science. This is particularly important in environments undergoing rapid anthropogenic changes, such as the Amazon rainforest, where animals face novel landscapes. Insectivorous bird flocks are key elements of avian biodiversity in the Amazonian ecosystem. Therefore, disentangling and quantifying the drivers behind their movement and space use patterns is of great importance for Amazonian conservation. We use a step selection function (SSF) approach to uncover environmental drivers behind movement choices. This is used to construct a mechanistic model, from which we derive predicted utilization distributions (home ranges) of flocks. We show that movement decisions are significantly influenced by canopy height and topography, but depletion and renewal of resources do not appear to affect movement significantly. We quantify the magnitude of these effects and demonstrate that they are helpful for understanding various heterogeneous aspects of space use. We compare our results to recent analytic derivations of space use, demonstrating that the analytic approximation is only accurate when assuming that there is no persistence in the animals' movement. Our model can be translated into other environments or hypothetical scenarios, such as those given by proposed future anthropogenic actions, to make predictions of spatial patterns in bird flocks. Furthermore, our approach is quite general, so could potentially be used to understand the drivers of movement and spatial patterns for a wide variety of animal communities. PMID- 25558355 TI - Seasonal flooding regime and ecological traits influence genetic structure of two small rodents. AB - Although codistributed species are affected by the same abiotic factors, such as rivers and seasonal flooding regimes, ecological traits, such as locomotion habits and habitat preferences, may also influence differences in levels of genetic diversity and differentiation. We examined population genetic structure and diversity of Hylaeamys megacephalus and Oecomys aff. roberti, two cricetid rodent species from the mid-Araguaia River in central Brazil, using mitochondrial DNA sequence data. Specifically, we aim to test whether the Araguaia River acts as a barrier to the gene flow of these two species and to assess how ecological traits, such as locomotion habits and habitat preferences, may influence differences in levels of genetic diversity and differentiation. As both species occur in flooded forests, neither showed genetic differences related to river banks. Oecomys aff. roberti showed stronger population structure that appears to be associated with isolation by distance. This arboreal species maintained stable populations in the Araguaia River, while the terrestrial H. megacephalus was more affected by seasonal floods, resulting in a genetic signature of population expansion. Our initial predictions were largely supported by our results given that locomotion habits and habitat preferences of each species appears to have played a role on the genetic structure of these two sympatric rodent species. PMID- 25558356 TI - Reconstruction of a windborne insect invasion using a particle dispersal model, historical wind data, and Bayesian analysis of genetic data. AB - Understanding how invasive species establish and spread is vital for developing effective management strategies for invaded areas and identifying new areas where the risk of invasion is highest. We investigated the explanatory power of dispersal histories reconstructed based on local-scale wind data and a regional scale wind-dispersed particle trajectory model for the invasive seed chalcid wasp Megastigmus schimitscheki (Hymenoptera: Torymidae) in France. The explanatory power was tested by: (1) survival analysis of empirical data on M. schimitscheki presence, absence and year of arrival at 52 stands of the wasp's obligate hosts, Cedrus (true cedar trees); and (2) Approximate Bayesian analysis of M. schimitscheki genetic data using a coalescence model. The Bayesian demographic modeling and traditional population genetic analysis suggested that initial invasion across the range was the result of long-distance dispersal from the longest established sites. The survival analyses of the windborne expansion patterns derived from a particle dispersal model indicated that there was an informative correlation between the M. schimitscheki presence/absence data from the annual surveys and the scenarios based on regional-scale wind data. These three very different analyses produced highly congruent results supporting our proposal that wind is the most probable vector for passive long-distance dispersal of this invasive seed wasp. This result confirms that long-distance dispersal from introduction areas is a likely driver of secondary expansion of alien invasive species. Based on our results, management programs for this and other windborne invasive species may consider (1) focusing effort at the longest established sites and (2) monitoring outlying populations remains critically important due to their influence on rates of spread. We also suggest that there is a distinct need for new analysis methods that have the capacity to combine empirical spatiotemporal field data, genetic data, and environmental data to investigate dispersal and invasion. PMID- 25558357 TI - Are all species necessary to reveal ecologically important patterns? AB - While studying ecological patterns at large scales, ecologists are often unable to identify all collections, forcing them to either omit these unidentified records entirely, without knowing the effect of this, or pursue very costly and time-consuming efforts for identifying them. These "indets" may be of critical importance, but as yet, their impact on the reliability of ecological analyses is poorly known. We investigated the consequence of omitting the unidentified records and provide an explanation for the results. We used three large-scale independent datasets, (Guyana/ Suriname, French Guiana, Ecuador) each consisting of records having been identified to a valid species name (identified morpho species - IMS) and a number of unidentified records (unidentified morpho-species UMS). A subset was created for each dataset containing only the IMS, which was compared with the complete dataset containing all morpho-species (AMS: = IMS + UMS) for the following analyses: species diversity (Fisher's alpha), similarity of species composition, Mantel test and ordination (NMDS). In addition, we also simulated an even larger number of unidentified records for all three datasets and analyzed the agreement between similarities again with these simulated datasets. For all analyses, results were extremely similar when using the complete datasets or the truncated subsets. IMS predicted >=91% of the variation in AMS in all tests/analyses. Even when simulating a larger fraction of UMS, IMS predicted the results for AMS rather well. Using only IMS also out-performed using higher taxon data (genus-level identification) for similarity analyses. Finding a high congruence for all analyses when using IMS rather than AMS suggests that patterns of similarity and composition are very robust. In other words, having a large number of unidentified species in a dataset may not affect our conclusions as much as is often thought. PMID- 25558358 TI - The risks of learning: confounding detection and demographic trend when using count-based indices for population monitoring. AB - Theory recognizes that a treatment of the detection process is required to avoid producing biased estimates of population rate of change. Still, one of three monitoring programmes on animal or plant populations is focused on simply counting individuals or other fixed visible structures, such as natal dens, nests, tree cavities. This type of monitoring design poses concerns about the possibility to respect the assumption of constant detection, as the information acquired in a given year about the spatial distribution of reproductive sites can provide a higher chance to detect the species in subsequent years. We developed an individual-based simulation model, which evaluates how the accumulation of knowledge about the spatial distribution of a population process can affect the accuracy of population growth rate estimates, when using simple count-based indices. Then, we assessed the relative importance of each parameter in affecting monitoring performance. We also present the case of wolverines (Gulo gulo) in southern Scandinavia as an example of a monitoring system with an intrinsic tendency to accumulate knowledge and increase detectability. When the occupation of a nest or den is temporally autocorrelated, the monitoring system is prone to increase its knowledge with time. This happens also when there is no intensification in monitoring effort and no change in the monitoring conditions. Such accumulated knowledge is likely to increase detection probability with time and can produce severe bias in the estimation of the rate and direction of population change over time. We recommend that a systematic sampling of the population process under study and an explicit treatment of the underlying detection process should be implemented whenever economic and logistical constraints permit, as failure to include detection probability in the estimation of population growth rate can lead to serious bias and severe consequences for management and conservation. PMID- 25558359 TI - High intraspecific variability in the functional niche of a predator is associated with ontogenetic shift and individual specialization. AB - Investigations on the functional niche of organisms have primarily focused on differences among species and tended to neglect the potential effects of intraspecific variability despite the fact that its potential ecological and evolutionary importance is now widely recognized. In this study, we measured the distribution of functional traits in an entire population of largemouth bass (Micropterus salmoides) to quantify the magnitude of intraspecific variability in functional traits and niche (size, position, and overlap) between age classes. Stable isotope analyses (delta (13)C and delta (15)N) were also used to determine the association between individual trophic ecology and intraspecific functional trait variability. We observed that functional traits were highly variable within the population (mean coefficient variation: 15.62% +/- 1.78% SE) and predominantly different between age classes. In addition, functional and trophic niche overlap between age classes was extremely low. Differences in functional niche between age classes were associated with strong changes in trophic niche occurring during ontogeny while, within age classes, differences among individuals were likely driven by trophic specialization. Each age class filled only a small portion of the total functional niche of the population and age classes occupied distinct portions in the functional space, indicating the existence of ontogenetic specialists with different functional roles within the population. The high amplitude of intraspecific variability in functional traits and differences in functional niche position among individuals reported here supports the recent claims for an individual-based approach in functional ecology. PMID- 25558360 TI - MODISTools - downloading and processing MODIS remotely sensed data in R. AB - Remotely sensed data - available at medium to high resolution across global spatial and temporal scales - are a valuable resource for ecologists. In particular, products from NASA's MODerate-resolution Imaging Spectroradiometer (MODIS), providing twice-daily global coverage, have been widely used for ecological applications. We present MODISTools, an R package designed to improve the accessing, downloading, and processing of remotely sensed MODIS data. MODISTools automates the process of data downloading and processing from any number of locations, time periods, and MODIS products. This automation reduces the risk of human error, and the researcher effort required compared to manual per-location downloads. The package will be particularly useful for ecological studies that include multiple sites, such as meta-analyses, observation networks, and globally distributed experiments. We give examples of the simple, reproducible workflow that MODISTools provides and of the checks that are carried out in the process. The end product is in a format that is amenable to statistical modeling. We analyzed the relationship between species richness across multiple higher taxa observed at 526 sites in temperate forests and vegetation indices, measures of aboveground net primary productivity. We downloaded MODIS derived vegetation index time series for each location where the species richness had been sampled, and summarized the data into three measures: maximum time-series value, temporal mean, and temporal variability. On average, species richness covaried positively with our vegetation index measures. Different higher taxa show different positive relationships with vegetation indices. Models had high R (2) values, suggesting higher taxon identity and a gradient of vegetation index together explain most of the variation in species richness in our data. MODISTools can be used on Windows, Mac, and Linux platforms, and is available from CRAN and GitHub (https://github.com/seantuck12/MODISTools). PMID- 25558361 TI - Extensive population admixture on drone congregation areas of the giant honeybee, Apis dorsata (Fabricius, 1793). AB - The giant honeybee Apis dorsata often forms dense colony aggregations which can include up to 200 often closely related nests in the same location, setting the stage for inbred matings. Yet, like in all other Apis species, A. dorsata queens mate in mid-air on lek like drone congregation areas (DCAs) where large numbers of males gather in flight. We here report how the drone composition of A. dorsata DCAs facilitates outbreeding, taking into the account both spatial (three DCAs) and temporal (subsequent sampling days) dynamics. We compared the drones' genotypes at ten microsatellite DNA markers with those of the queen genotypes of six drone-producing colonies located close to the DCAs (Tenom, Sabah, Malaysia). None of 430 sampled drones originated from any of these nearby colonies. Moreover, we estimated that 141 unidentified colonies were contributing to the three DCAs. Most of these colonies were participating multiple times in the different locations and/or during the consecutive days of sampling. The drones sampled in the DCAs could be attributed to six subpopulations. These were all admixed in all DCA samples, increasing the effective population size an order of magnitude and preventing matings between potentially related queens and drones. PMID- 25558362 TI - Seasonal changes in the body size of two rotifer species living in activated sludge follow the Temperature-Size Rule. AB - Temperature-Size Rule (TSR) is a phenotypic body size response of ectotherms to changing temperature. It is known from the laboratory studies, but seasonal patterns in the field were not studied so far. We examined the body size changes in time of rotifers inhabiting activated sludge. We hypothesize that temperature is the most influencing parameter in sludge environment, leading sludge rotifers to seasonally change their body size according to TSR, and that oxygen content also induces the size response. The presence of TSR in Lecane inermis rotifer was tested in a laboratory study with two temperature and two food-type treatments. The effect of interaction between temperature and food was significant; L. inermis followed TSR in one food type only. The seasonal variability in the body sizes of the rotifers L. inermis and Cephalodella gracilis was estimated by monthly sampling and analyzed by multiple regression, in relation to the sludge parameters selected as the most influential by multivariate analysis, and predicted to alter rotifer body size (temperature and oxygen). L. inermis varied significantly in size throughout the year, and this variability is explained by temperature as predicted by the TSR, but not by oxygen availability. C. gracilis also varied in size, though this variability was explained by both temperature and oxygen. We suggest that sludge age acts as a mortality factor in activated sludge. It may have a seasonal effect on the body size of L. inermis and modify a possible effect of oxygen. Activated sludge habitat is driven by both biological processes and human regulation, yet its resident organisms follow general evolutionary rule as they do in other biological systems. The interspecific response patterns differ, revealing the importance of taking species-specific properties into account. Our findings are applicable to sludge properties enhancement through optimizing the conditions for its biological component. PMID- 25558363 TI - Optimizing passive acoustic sampling of bats in forests. AB - Passive acoustic methods are increasingly used in biodiversity research and monitoring programs because they are cost-effective and permit the collection of large datasets. However, the accuracy of the results depends on the bioacoustic characteristics of the focal taxa and their habitat use. In particular, this applies to bats which exhibit distinct activity patterns in three-dimensionally structured habitats such as forests. We assessed the performance of 21 acoustic sampling schemes with three temporal sampling patterns and seven sampling designs. Acoustic sampling was performed in 32 forest plots, each containing three microhabitats: forest ground, canopy, and forest gap. We compared bat activity, species richness, and sampling effort using species accumulation curves fitted with the clench equation. In addition, we estimated the sampling costs to undertake the best sampling schemes. We recorded a total of 145,433 echolocation call sequences of 16 bat species. Our results indicated that to generate the best outcome, it was necessary to sample all three microhabitats of a given forest location simultaneously throughout the entire night. Sampling only the forest gaps and the forest ground simultaneously was the second best choice and proved to be a viable alternative when the number of available detectors is limited. When assessing bat species richness at the 1-km(2) scale, the implementation of these sampling schemes at three to four forest locations yielded highest labor cost-benefit ratios but increasing equipment costs. Our study illustrates that multiple passive acoustic sampling schemes require testing based on the target taxa and habitat complexity and should be performed with reference to cost benefit ratios. Choosing a standardized and replicated sampling scheme is particularly important to optimize the level of precision in inventories, especially when rare or elusive species are expected. PMID- 25558365 TI - Inferring the temperature dependence of population parameters: the effects of experimental design and inference algorithm. AB - Understanding and quantifying the temperature dependence of population parameters, such as intrinsic growth rate and carrying capacity, is critical for predicting the ecological responses to environmental change. Many studies provide empirical estimates of such temperature dependencies, but a thorough investigation of the methods used to infer them has not been performed yet. We created artificial population time series using a stochastic logistic model parameterized with the Arrhenius equation, so that activation energy drives the temperature dependence of population parameters. We simulated different experimental designs and used different inference methods, varying the likelihood functions and other aspects of the parameter estimation methods. Finally, we applied the best performing inference methods to real data for the species Paramecium caudatum. The relative error of the estimates of activation energy varied between 5% and 30%. The fraction of habitat sampled played the most important role in determining the relative error; sampling at least 1% of the habitat kept it below 50%. We found that methods that simultaneously use all time series data (direct methods) and methods that estimate population parameters separately for each temperature (indirect methods) are complementary. Indirect methods provide a clearer insight into the shape of the functional form describing the temperature dependence of population parameters; direct methods enable a more accurate estimation of the parameters of such functional forms. Using both methods, we found that growth rate and carrying capacity of Paramecium caudatum scale with temperature according to different activation energies. Our study shows how careful choice of experimental design and inference methods can increase the accuracy of the inferred relationships between temperature and population parameters. The comparison of estimation methods provided here can increase the accuracy of model predictions, with important implications in understanding and predicting the effects of temperature on the dynamics of populations. PMID- 25558366 TI - Maintaining microendemic primate species along an environmental gradient - parasites as drivers for species differentiation. AB - Understanding the drivers of species adaptations to changing environments on the one hand and the limits for hybridization on the other hand is among the hottest questions in evolutionary biology. Parasites represent one of the major selective forces driving host evolution and at least those with free-living stages are at the same time dependent on the ecological conditions of their host's habitat. Local immunological adaptations of host species to varying parasite pressure are therefore expected and might represent the genetic basis for ecological speciation and the maintenance of recently diverged species. Madagascar provides one of the rare examples where two partially sympatric primate species (Microcebus griseorufus, M. murinus) and their hybrids, as well as an allopatric species (M. cf rufus) live in close proximity along a very steep environmental gradient ranging from southern dry spiny bush to gallery forest to evergreen eastern humid rain forest, thus mimicking the situation encountered during extensions and retreats of vegetation formations under changing climatic conditions. This system was used to study parasite infection and immune gene (MHC) adaptations to varying parasite pressure that might provide selective advantages to pure species over hybrids. Parasite burdens increased with increasing humidity. M. griseorufus, M. murinus, and their hybrids but not M. rufus shared the same MHC alleles, indicating either retention of ancestral polymorphism or recent gene flow. The hybrids had much higher prevalence of intestinal parasites than either of the parent species living under identical environmental conditions. The different representation of parasites can indicate a handicap for hybrids that maintains species identities. PMID- 25558367 TI - Disturbance, neutral theory, and patterns of beta diversity in soil communities. AB - Beta diversity describes how local communities within an area or region differ in species composition/abundance. There have been attempts to use changes in beta diversity as a biotic indicator of disturbance, but lack of theory and methodological caveats have hampered progress. We here propose that the neutral theory of biodiversity plus the definition of beta diversity as the total variance of a community matrix provide a suitable, novel, starting point for ecological applications. Observed levels of beta diversity (BD) can be compared to neutral predictions with three possible outcomes: Observed BD equals neutral prediction or is larger (divergence) or smaller (convergence) than the neutral prediction. Disturbance might lead to either divergence or convergence, depending on type and strength. We here apply these ideas to datasets collected on oribatid mites (a key, very diverse soil taxon) under several regimes of disturbances. When disturbance is expected to increase the heterogeneity of soil spatial properties or the sampling strategy encompassed a range of diverging environmental conditions, we observed diverging assemblages. On the contrary, we observed patterns consistent with neutrality when disturbance could determine homogenization of soil properties in space or the sampling strategy encompassed fairly homogeneous areas. With our method, spatial and temporal changes in beta diversity can be directly and easily monitored to detect significant changes in community dynamics, although the method itself cannot inform on underlying mechanisms. However, human-driven disturbances and the spatial scales at which they operate are usually known. In this case, our approach allows the formulation of testable predictions in terms of expected changes in beta diversity, thereby offering a promising monitoring tool. PMID- 25558368 TI - The potential for arms race and Red Queen coevolution in a protist host-parasite system. AB - The dynamics and consequences of host-parasite coevolution depend on the nature of host genotype-by-parasite genotype interactions (G * G) for host and parasite fitness. G * G with crossing reaction norms can yield cyclic dynamics of allele frequencies ("Red Queen" dynamics) while G * G where the variance among host genotypes differs between parasite genotypes results in selective sweeps ("arms race" dynamics). Here, we investigate the relative potential for arms race and Red Queen coevolution in a protist host-parasite system, the dinoflagellate Alexandrium minutum and its parasite Parvilucifera sinerae. We challenged nine different clones of A. minutum with 10 clones of P. sinerae in a fully factorial design and measured infection success and host and parasite fitness. Each host genotype was successfully infected by four to ten of the parasite genotypes. There were strong G * Gs for infection success, as well as both host and parasite fitness. About three quarters of the G * G variance components for host and parasite fitness were due to crossing reaction norms. There were no general costs of resistance or infectivity. We conclude that there is high potential for Red Queen dynamics in this host-parasite system. PMID- 25558369 TI - Interaction effects between weather and space use on harvesting effort and patterns in red deer. AB - Most cervid populations in Europe and North America are managed through selective harvesting, often with age- and sex-specific quotas, with a large influence on the population growth rate. Less well understood is how prevailing weather affects harvesting selectivity and off-take indirectly through changes in individual animal and hunter behavior. The behavior and movement patterns of hunters and their prey are expected to be influenced by weather conditions. Furthermore, habitat characteristics like habitat openness are also known to affect movement patterns and harvesting vulnerability, but how much such processes affect harvest composition has not been quantified. We use harvest data from red deer (Cervus elaphus) to investigate how weather and habitat characteristics affect behavioral decisions of red deer and their hunters throughout the hunting season. More specifically, we look at how sex and age class, temperature, precipitation, moon phase, and day of week affect the probability of being harvested on farmland (open habitat), hunter effort, and the overall harvest numbers. Moon phase and day of week were the strongest predictors of hunter effort and harvest numbers, with higher effort during full moon and weekends, and higher numbers during full moon. In general, the effect of fall weather conditions and habitat characteristics on harvest effort and numbers varied through the season. Yearlings showed the highest variation in the probability of being harvested on farmland through the season, but there was no effect of sex. Our study is among the first to highlight that weather may affect harvesting patterns and off-take indirectly through animal and hunter behavior, but the interaction effects of weather and space use on hunter behavior are complicated, and seem less important than hunter preference and quotas in determining hunter selection and harvest off-take. The consideration of hunter behavior is therefore key when forming management rules for sustainable harvesting. PMID- 25558370 TI - A tool for simulating and communicating uncertainty when modelling species distributions under future climates. AB - Tools for exploring and communicating the impact of uncertainty on spatial prediction are urgently needed, particularly when projecting species distributions to future conditions.We provide a tool for simulating uncertainty, focusing on uncertainty due to data quality. We illustrate the use of the tool using a Tasmanian endemic species as a case study. Our simulations provide probabilistic, spatially explicit illustrations of the impact of uncertainty on model projections. We also illustrate differences in model projections using six different global climate models and two contrasting emissions scenarios.Our case study results illustrate how different sources of uncertainty have different impacts on model output and how the geographic distribution of uncertainty can vary.Synthesis and applications: We provide a conceptual framework for understanding sources of uncertainty based on a review of potential sources of uncertainty in species distribution modelling; a tool for simulating uncertainty in species distribution models; and protocols for dealing with uncertainty due to climate models and emissions scenarios. Our tool provides a step forward in understanding and communicating the impacts of uncertainty on species distribution models under future climates which will be particularly helpful for informing discussions between researchers, policy makers, and conservation practitioners. PMID- 25558372 TI - A novel delta current method for transport stoichiometry estimation. AB - BACKGROUND: The ion transport stoichiometry (q) of electrogenic transporters is an important determinant of their function. q can be determined by the reversal potential (Erev) if the transporter under study is the only electrogenic transport mechanism or a specific inhibitor is available. An alternative approach is to calculate delta reversal potential (DeltaErev) by altering the concentrations of the transported substrates. This approach is based on the hypothesis that the contributions of other channels and transporters on the membrane to Erev are additive. However, Erev is a complicated function of the sum of different conductances rather than being additive. RESULTS: We propose a new delta current (DeltaI) method based on a simplified model for electrogenic secondary active transport by Heinz (Electrical Potentials in Biological Membrane Transport, 1981). DeltaI is the difference between two currents obtained from altering the external concentration of a transported substrate thereby eliminating other currents without the need for a specific inhibitor. q is determined by the ratio of DeltaI at two different membrane voltages (V1 and V2) where q = 2RT/(F(V2 -V1))ln(DeltaI2/DeltaI1) + 1. We tested this DeltaI methodology in HEK-293 cells expressing the elctrogenic SLC4 sodium bicarbonate cotransporters NBCe2-C and NBCe1-A, the results were consistent with those obtained with the Erev inhibitor method. Furthermore, using computational simulations, we compared the estimates of q with the DeltaErev and DeltaI methods. The results showed that the DeltaErev method introduces significant error when other channels or electrogenic transporters are present on the membrane and that the DeltaI equation accurately calculates the stoichiometric ratio. CONCLUSIONS: We developed a DeltaI method for estimating transport stoichiometry of electrogenic transporters based on the Heinz model. This model reduces to the conventional reversal potential method when the transporter under study is the only electrogenic transport process in the membrane. When there are other electrogenic transport pathways, DeltaI method eliminates their contribution in estimating q. Computational simulations demonstrated that the DeltaErev method introduces significant error when other channels or electrogenic transporters are present and that the DeltaI equation accurately calculates the stoichiometric ratio. This new DeltaI method can be readily extended to the analysis of other electrogenic transporters in other tissues. PMID- 25558373 TI - Preservation of Capillary-beds in Rat Lung Tissue Using Optimized Chemical Decellularization. AB - Promoting regeneration using scaffolds created by decellularizing native tissue is becoming a popular technique applied to a variety of tissues. We demonstrate a method to decellularize highly vascular tissue keeping the vascular structure intact down to the capillary scale. Using vascular corrosion casting (VCC), we created a method for quantitatively assessing the functionality of vascular extracellular matrix (ECM) following decellularization. Murine lung tissue was decellularized using a number of techniques, then characterized using standard histological methods, as well as our quantitative VCC (qVCC) technique. Using an optimized acellular method, we successfully decellularized lung tissue while leaving behind a patent vascular network based on qualitative and quantitative histological methods. PMID- 25558374 TI - A comparative study of zwitterionic ligands-mediated mineralization and the potential of mineralized zwitterionic matrices for bone tissue engineering. AB - Cationic and anionic residues of the extracellular matrices (ECM) of bone play synergistic roles in recruiting precursor ions and templating the nucleation, growth and crystalline transformations of calcium apatite in natural biomineralization. We previously reported that zwitterionic sulfobetaine ligands can template extensive 3-dimensional (3-D) hydroxyapaptite (HA)-mineralization of photo-crosslinked polymethacrylatehydrogels. Here, we compared the potency of two other major zwitterionic ligands, phosphobetaine and carboxybetaine, with that of the sulfobetaine in mediating 3-D mineralization using the crosslinked polymethacrylate hydrogel platform. We confirmed that all three zwitterionic hydrogels were able to effectively template 3-D mineralization, supporting the general ability of zwitterions to mediate templated mineralization. Among them, however, sulfobetaine and phosphobetaine hydrogels templated denser 3-D mineralizationthan the carboxybetaine hydrogel, likely due to their higher free water fractions and better maintenance of zwitterionic nature throughout the pH changes during the in vitro mineralization process. We further demonstrated that the extensively mineralized zwitterionic hydrogels could be exploited for efficient retention (e.g. 99% retention after 24-h incubation in PBS) of osteogenic growth factor recombinant bone morphogenetic protein-2 (rhBMP-2) and subsequent sustained local release with retained bioactivity. Combined with the excellent cytocompatibility of all three zwitterionic hydrogels and the significantly improved cell adhesive properties of their mineralized matrices, these materials could find promising applications in bone tissue engineering. PMID- 25558375 TI - Human nail usage as a Bio-indicator in contamination monitoring of heavy metals in Dizajabaad, Zanjan province-Iran. AB - BACKGROUND: Due to pedogeochemical background and anthropogenic sources, heavy metal contamination of soil is a widespread problem in some parts of Zanjan province located in North West Iran. In this study an affected area located near National Iranian Lead and Zinc Company (NILZ) was selected for detailed study. METHODOLOGY: Thirty soil samples and eighteen leaf samples were collected and analyzed for heavy metal contamination by Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES). Both soil and plant samples were found to be basically polluted by Pb (72.60 and 97.11), Zn (546.47 and 166.61), and Cd (1.80 and 1.55) mg. kg(-1) respectively. High concentrations of these elements in soil and plant species signifies possible health risks to humans. The distribution maps drawn using Arc GIS (10) show high concentrations of these toxic metals around Dizajabaad village. To assess vulnerability and health risks of metal concentrations in human bodies' twenty nine fingernail samples were also collected from people living in this village. RESULTS AND DISCUSSION: Analysis for different heavy metal contents of nail samples reveals very high levels of the same toxic elements (Pb = 15.15, Cd = 1.18, As = 15.47, Zn = 68.46 and Ni = 18.22 mg. kg(-1)) compared with samples collected from an unaffected area and available values indicated in the literature. Further, high concentration of heavy metals in the nail samples suggests long term exposure of inhabitants to these toxic metals. PMID- 25558376 TI - The Midlife in the United States (MIDUS) Series: A National Longitudinal Study of Health and Well-being. AB - Midlife in the United States (MIDUS) is a national longitudinal study of health and well-being (http://midus.wisc.edu/). It was conceived by a multidisciplinary team of scholars interested in understanding aging as an integrated bio-psycho social process, and as such it includes data collected in a wide array of research protocols using a variety of survey and non-survey instruments. The data captured by these different protocols (comprising around 20,000 variables) represent survey measures, cognitive assessments, daily stress diaries, clinical, biomarker and neuroscience data which are contained in separate flat or stacked data files with a common ID system that allows easy data merges among them. All MIDUS datasets and documentation are archived at the ICPSR (http://www.icpsr.umich.edu/) repository at the University of Michigan and are publicly available in a variety of formats and statistical packages. Special attention is given to providing clear user-friendly documentation; the study has embraced the Data Documentation Initiative (DDI) metadata standard and produces DDI-Lifecycle compliant codebooks. Potential for secondary use of MIDUS is high and actively encouraged. The study has become very popular with the research public as measured by data downloads and citation counts (see Reuse Potential below). PMID- 25558377 TI - Bony abnormalities of the hip joint: a new comprehensive, reliable and radiation free measurement method using magnetic resonance imaging. AB - OBJECTIVES: To develop comprehensive and reliable radiation-free methods to quantify femoral and acetabular morphology using MRI. METHODS: 32 hips (16 subjects, 6 with intra-articular hip disorder (IAHD); 10 controls) were included. A 1.5T magnetic resonance system was used to obtain 3D fat suppressed gradient echo images at the pelvis and distal femora. After acquisition, pelvic images were post-processed to correct for coronal, axial and sagittal rotation. Measurements performed included acetabular version (AV), femoral version (FV), lateral center edge angle (LCEA), femoral neck angle (FNA) and alpha angle (AA) at 3, 2, 1 and 12 o'clock. Two experienced raters, a musculoskeletal radiologist and an orthopaedic physical therapist, and a novice rater, a research assistant, completed reliability testing. Raters measured all hips twice with minimum 2 weeks between sessions. Intraclass Correlation Coefficients were used to determine rater reliability; standard error of measurements was reported to estimate the reasonable limits of the expected error in the different raters' scores. RESULTS: Interrater reliability was good to excellent for all raters for AV, FV, FNA, and LCEA (ICCs: 0.82-0.98); good to excellent between experienced raters (ICCs: 0.78-0.86) and poor to good between novice and experienced raters (ICCs: 0.23-0.78) for AA. Intrarater reliability was good to excellent for all raters for AV, FV and FNA (ICCs: 0.93-0.99); for one experienced and novice rater for LCEA (ICCs: 0.84-0.89); moderate to excellent for the experienced raters for AA (ICCs: 0.72-0.89). Intrarater reliability was poor for the second experienced rater for LCEA (ICC: 0.56), due to a single measurement error and for the novice rater for AA (ICCs: 0.17-0.38). CONCLUSION: We described MRI methods to comprehensively assess femoral and acetabular morphology. Measurements such as AV, FV and FNA and the LCEA can be made reliably by both experienced and novice raters, however the AA measurement was reliable only among experienced raters. PMID- 25558364 TI - The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts. AB - Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015. PMID- 25558378 TI - Psychometric evaluation of the role strain scale: the persian version. AB - BACKGROUND: Nursing teachers have difficulties fulfilling multiple roles expectations and balancing the various dimensions of their roles that may lead to role strain. In order to lack of culturally and academically proper scale in Iran to measure role strain in nursing teachers, localizing a foreign scale in this field is necessary. OBJECTIVES: The objective of this study was psychometric evaluation of the Role Strain Scale (RSS) and confirming its structural model in an Iranian population. MATERIALS AND METHODS: The present cross- sectional study was conducted in 2012, comprising 302 nursing teachers from around the country who were selected using stratified- cluster sampling. Psychometric evaluation process of the RSS was carried out by Face, content and constructs validity (confirmatory and exploratory factor analysis). Reliability was examined using test-retest and Cronbach's alpha for internal consistency reliability. RESULTS: In the primary results, in spite of being approved by face and content validity, in Construct validity, fitness indices of original Role Strain Scale showed no satisfactory findings in Iranian data. Therefore, some items from the structural model of original version were extracted by exploratory factor analysis and a five-factor model with 33 items was obtained. These factors were role conflict, role ambiguity, role overload, role incompetence, and role incongruity. New model as Persian version of RSS was confirmed by calculating fitness indices such as GFI = 0.93, AGFI = 0.94, NFI = 0.91, RMSEA = 0.093. Internal consistency reliability for the total scale and subscales were respectively 0.92, and 0.71 0.84. Results from Pearson correlation test indicate a high degree of test-retest reliability (r = 0. 89). ICC was also 0.91. CONCLUSIONS: This reliable and valid scale is academically appropriate for nursing teachers to measure role strain and helps detect and predict a multiplicity of role problems and consequently make educational managers aware of nursing teachers' difficulties while facing with multiple roles and possible future challenges. PMID- 25558379 TI - Estimating the Annual Incidence of Abortions in Iran Applying a Network Scale-up Approach. AB - BACKGROUND: Abortions are of major public health concern in developing countries. In settings in which abortion is highly prohibited, the direct interview is not a reliable method to estimate the abortion rate. The indirect estimation methods to measure the rate of abortion might overcome this dilemma; They are practical methods to estimate the size of the hidden group who do not agree to participate in a direct interview. OBJECTIVES: The aim of this study was to explore the practicality of an indirect method for estimating the abortion rate , Known as Network Scale-up, and to provide an estimate about the episode of abortion with and without medical indications (AWMI+ and AWMI-) in Iran. MATERIALS AND METHODS: This cross-sectional study was conducted in 31 provinces of Iran in 2012. A random sample between 200 and 1000 was selected in each province by the multistage sampling method that 75% of the data were collected from the capital and 25% from one main city. We selected samples from urban people more than 18 years old (12960) and we asked them about the number of abortion in women they knew who had experienced the medical and non-medical abortions in the past year. A range for the transparency factor was estimated based on the expert opinion. RESULTS: The range of the transparency factors for AWMI+ and AWOMI- were 0.43 0.75 and 0.2-0.34, respectively. Regarding the AWMI+, our minimum and maximum estimations (per 1000 pregnancies) were 70.54 and 116.9, respectively. The corresponding figures for AWMI- were 93.18, and 148.7. CONCLUSIONS: The frequency rates for AWMI+ and AWMI- were relatively high. Therefore, the system has to address to this hidden problem using the appropriate preventive policies. PMID- 25558380 TI - Family and the risky behaviors of high school students. AB - BACKGROUND: Family plays an important role in helping adolescent acquiring skills or strengthening their characters. OBJECTIVES: We aimed to evaluate the influences of family factors, risky and protective, on adolescent health-risk behavior (HRB). PATIENTS AND METHODS: In this cross-sectional study, students of high schools in Kerman, Iran at all levels participated, during November 2011 till December 2011. The research sample included 1024 students (588 females and 436 males) aged 15 to 19 years. A CTC (Communities That Care Youth Survey) questionnaire was designed in order to collect the profile of the students' risky behaviors. Stratified cluster sampling method was used to collect the data. RESULTS: Using logistic regression, 7 variables enrolled; 4 of them were risk factors and 3 were protective factors. The risk factors were age, (linear effect, ORa = 1.20, P = 0.001), boys versus girls (ORa = 2.33, P = 0.001), family history of antisocial behavior (ORa = 2.29, P = 0.001), and parental attitudes favorable toward antisocial behavior (ORa = 1.72, P = 0.03). And, protective factors were family religiosity (ORa = 0.65, P = 0.001), father education (linear effect, ORa = 0.48, P = 0.001), and family attachment (ORa = 0.78, P = 0.001). CONCLUSIONS: Our findings showed that family has a very significant role in protecting students against risky behaviors. The education level of the father, family religiosity, and attachment were the most important factors. PMID- 25558381 TI - Staphylococcal enterotoxin C in synovial fluid of patients with rheumatoid arthritis. AB - BACKGROUND: In the previous studies using the commercial ELISA kit, the existence of staphylococcal superantigens has been reported in synovial fluid of patients with rheumatoid arthritis (RA). OBJECTIVES: This study aimed to design molecular methods to detect staphylococcal enterotoxin C in synovial fluid of patients with rheumatoid arthritis. MATERIALS AND METHODS: In this experimental study, Staphylococcus aureus strain producing enterotoxin C was used as the reference strain. The polymerase chain reaction (PCR) was set up by design a specific pair of primers. Besides bacterial culture, 50 synovial fluid samples of patients with rheumatoid arthritis were subjected to DNA extraction, and then PCR amplification was carried out according to the protocol. All samples were examined by ELISA method for enterotoxin C. The data were descriptively analyzed. RESULTS: The results of bacterial culture were negative for all samples. The results showed that 66% (33 cases) of samples contained entC gene and only 46% (23 cases) have also enterotoxin C. The interesting finding was that the results of ELISA and PCR were the same and have shown only 22 positive cases (44%samples) for staphylococcal enterotoxin C. CONCLUSIONS: Based on the findings of this study, S. aureus enterotoxin C (SEC) has been detected in synovial fluid of patients with rheumatoid arthritis by PCR and ELISA methods. These valuable findings may describe the exact etiology of the RA and as well as change the methods of its diagnosis and treatment. This is the first research, which has shown the staphylococcal entC gene in synovial fluid of RA patients. However, S. aureus strains can produce more than 20 types of enterotoxins. Therefore, its involvement on rheumatoid arthritis pathogenesis makes an important challenge in the future. In this regard, further investigation on the other enterotoxins is necessary. PMID- 25558382 TI - Comparing the Healing Effects of Arnebia euchroma Ointment With Petrolatum on the Ulcers Caused by Fractional CO2 Laser: A Single-Blinded Clinical Trial. AB - BACKGROUND: Arnebia euchroma ointment (AEO) has been used in Iranian traditional medicine for burn wound healing. OBJECTIVES: The aim of this study is to evaluate wound healing efficacy of AEO in burn wounds after fractional Co2 laser. PATIENTS AND METHODS: This split-face, single-blinded, single-center clinical study was performed in Shohada-e-Tajrish Hospital, Tehran, Iran. A total of 26 subjects with facial acne scar, who were to receive fractional CO2 laser resurfacing were recruited. After laser procedure, AEO was applied to one side of the face and petrolatum on the other side for wound healing. Digital photographs were taken from acne scar area before resurfacing and on each of the assessment sessions. Three researchers, who were unaware of the applied medications, assessed these digital photographs for erythema, edema, epithelial confluence, crusting/scabbing, and general wound appearance. Subject's irritations such as dryness and itching were evaluated on the second, fifth, and seventh days. RESULTS: Our study indicated higher epithelial confluence and general wound appearance scores (P = 0.045 for both) and less erythema and edema on fifth day in petrolatum (P = 0.009 and P = 0.034, respectively). The results showed less crusting and erythema (P = 0.016 and P = 0.035, respectively) and higher general wound appearance scores in petrolatum on the second day (P = 0.035 and P = 0.001, respectively). Dryness was the most common subjective complaint in both groups; however, it was more severe in AEO, especially on the second day (P = 0.023). CONCLUSIONS: Despite the healing effects of AEO in burn wounds, petrolatum was more effective than AEO in post-laser wound. PMID- 25558383 TI - The occupational safety of health professionals working at community and family health centers. AB - BACKGROUND: Healthcare professionals encounter many medical risks while providing healthcare services to individuals and the community. Thus, occupational safety studies are very important in health care organizations. They involve studies performed to establish legal, technical, and medical measures that must be taken to prevent employees from sustaining physical or mental damage because of work hazards. OBJECTIVES: This study was conducted to determine if the occupational safety of health personnel at community and family health centers (CHC and FHC) has been achieved. MARTIALS AND METHODS: The population of this cross-sectional study comprised 507 nurses, 199 physicians, and 237 other medical personnel working at a total of 18 family health centers (FHC) and community health centers (CHC) in Trabzon, Turkey. The sample consisted of a total of 418 nurses, 156 physicians, and 123 other medical personnel. Sampling method was not used, and the researchers tried to reach the whole population. Data were gathered with the Occupational Safety Scale (OSS) and a questionnaire regarding demographic characteristics and occupational safety. RESULTS: According to the evaluations of all the medical personnel, the mean +/- SD of total score of the OSS was 3.57 +/- 0.98; of the OSS's subscales, the mean +/- SD of the health screening and registry systems was 2.76 +/- 1.44, of occupational diseases and problems was 3.04 +/- 1.3 and critical fields control was 3.12 +/- 1.62. In addition, occupational safety was found more insufficient by nurses (F = 14.18; P < 0.001). CONCLUSIONS: All healthcare personnel, particularly nurses working in CHCs and FHCs found occupational safety to be insufficient as related to protective and supportive activities. PMID- 25558384 TI - The effects of insulin-like growth factor-1 gene therapy and cell transplantation on rat acute wound model. AB - BACKGROUND: Wound healing is a complex process. Different types of skin cells, extracellular matrix and variety of growth factors are involved in wound healing. The use of recombinant growth factors in researches and production of skin substitutes are still a challenge. OBJECTIVES: Much research has been done on the effects of gene therapy and cell therapy on wound healing. In this experimental study, the effect of insulin-like growth factor (IGF-1) gene transfer in fibroblast cells was assessed on acute dermal wound healing. MATERIALS AND METHODS: Fibroblasts were cultured and transfected with IGF-1. Lipofectamine 2000 was used as a reagent of transfection. Transgene expression levels were measured by the enzyme linked immunosorbent assay (ELISA). To study in vivo, rats (weighing 170-200 g) were randomly divided into three groups (five/group) and full-thickness wounds were created on the dorsum region. Suspensions of transfected fibroblast cells were injected into the wound and were compared with wounds treated with native fibroblast cells and normal saline. For the microscopic examination, biopsy was performed on day seven. RESULTS: In vitro, the maximum expression of IGF1 (96.95 pg/mL) in transfected fibroblast cells was 24 hours after gene transfer. In vivo, it was clear that IGF-1 gene therapy caused an increase in the number of keratinocyte cells during the wound healing process (mean of group A vs. group B with P value = 0.01, mean of group A vs. group C with P value = 0.000). Granulation of tissue formation in the transfected fibroblast group was more organized when compared with the normal saline group and native fibroblast cells. CONCLUSIONS: This study indicated that the optimization of gene transfer increases the expression of IGF-1. High concentrations of IGF-1, in combination with cell therapy, have a significant effect on wound healing. PMID- 25558385 TI - Efficacy of Myrtus communis L. and Descurainia sophia L. Versus Salicylic Acid for Wart Treatment. AB - BACKGROUND: Wart is a skin disease with circular appendages, which is called "suloul" in Iranian traditional medicine (ITM). According to ITM literature, warts have different types and causes. The most important mechanism is excretion of materials (Khelt) from body to skin and mucus; its causative material is often phlegm, black bile or a combination of them. To treat warts, it is necessary to consider the patient's life style, modify his dietary intake and moisturize his temperament. OBJECTIVES: This study aimed to compare Myrtus communis L. and Descurainia sophia L. as a method of ITM, versus salicylic acid in treatment of wart. PATIENTS AND METHODS: In this study, conducted in Yazd, Iran, 100 patients were selected and randomly divided into four groups. Group 1) salicylic acid, group 2) salicylic acid and D. sophia L. group 3) M. communis L. group 4) M. communis L. and D. sophia L. Numbers, sizes of lesions and symptoms, on days 0, 20, 40 and 90 were examined and analyzed. The relapse rate was investigated three months after. Changes of sizes and numbers of warts in each period of time in each group, compared to baseline, were assessed by Wilcoxon Signed Rank test. To compare these changes between the groups, Kruskal Wallis test was used. RESULTS: In this study 100 patients participated, 69% of which were female. Compared to baseline, mean +/- SD of changes for the number of warts in day 40 were 1.12 +/- 4.2, 0.96 +/- 2.5, 1.32 +/- 5.1 and 0.04 +/- 0.2 respectively in the four groups (P = 0.02). Mean +/- SD of changes for the number of warts in day 90 were 1.84 +/ 4.5, 1.56 +/- 2.8, 1.24 +/- 5.1 and 0.04 +/- 0.6 respectively in the four groups (P = 0.03). In addition mean +/- SD of changes for the size of warts in day 40 were 0.96 +/- 1.8, 1.03 +/- 2.4, 2.47 +/- 3.0 and 0.45 +/- 1.7 respectively in the four groups (P < 0.001). Mean +/- SD of changes for the size of warts in day 90 were 1.24 +/- 2.1, 1.3 +/- 2.3, 2.45 +/- 3.1 and 0.45 +/- 1.7 respectively in the four groups (P < 0.001). Relapse was not seen in any groups after three months. The frequency of side effects was similar after three months. CONCLUSIONS: M. communis L. can be used as a topical treatment for warts. It not only shows more rapid response than salicylic acid, but also has fewer side effects. It seems that D. sophia L. can modify the digestion process and patients can excrete large amounts of the substance that causes warts. Therefore, it is better to use it more than 40 days. According to our investigation, in ITM, considering the cause and mechanism of disease generation and the causing materials of the disease, different treatments should be applied for each patient. Although applying an appropriate treatment is necessary, a unique treatment for all the patients cannot be available. PMID- 25558386 TI - Effects of SP6 Acupuncture Point Stimulation on Labor Pain and Duration of Labor. AB - BACKGROUND: Acupressure has been used frequently to improve labor, manage labor pain, and shorten delivery time. However, there has been little research-based evidence to support the positive effects of acupressure in the obstetric area and obstetric nursing. OBJECTIVES: The aim of this study was to evaluate the effects of SP6 acupressure on labor pain and delivery time in primigravida women in labor. PATIENTS AND METHODS: The study was conducted at the Trabzon Maternity Hospital in Turkey. Its design was a randomized controlled clinical trial study using a single-blinded method. One hundred (100) primigravida women in labor were randomly assigned to either the SP6 acupressure (n = 50) or control group (n = 50). Acupressure was practiced 35 times in total on the SP6 point of both legs in the SP6 acupressure group; 15 times (during contraction) when cervical dilation was 2-3 cm, 10 times when cervical dilation was 5-6 cm and 10 times at 9-10 cm dilation, while the women in the control group received standard care. Labor pain was measured five times using a structured questionnaire of a subjective labor pain scale (visual analogue scale-VAS) when dilation was 2-3 cm (VAS 2), 5-6 cm (VAS 3) and 8-9 cm (VAS 4) before and after acupressure was applied to the SP6 point (VAS 1), and finally at the early postpartum period (VAS 5). The duration of labor in both groups was measured with a partograph and the length of delivery time was calculated in two stages: from 3 cm cervical dilation to full cervical dilation, and from full cervical dilation to delivery. RESULTS: There were significant differences between the groups in subjective labor pain scores (except VAS 4) (P < 0.001). The duration of the Phase one (3 cm dilatation to full dilatation) and Phase two (full dilatation to birth) in the acupressure group was shorter than the control group (Phase one, 225 min and 320 min, respectively; Phase two, 15 min and 20 min, respectively; both P < 0.001). CONCLUSIONS: It was determined that SP6 acupressure was effective in decreasing pain and duration of labor. PMID- 25558388 TI - A qualitative content analysis of knowledge storage in nursing education system. AB - BACKGROUND: The need for effective management of intellectual and academic assets is constantly growing. The nursing educational system should be considered as a storage of knowledge since it is deposited in the nursing educational system in the form of intellectual investment. OBJECTIVES: The purpose of the present study was to explore nursing knowledge storage in the nursing educational system. MATERIALS AND METHODS: The participants of this study consisted of eight nursing educators and five students. The inductive content analysis method was used in this research. Participants were interviewed through the semi-structured method. Data analysis was done by five stage framework approaches. The trustworthiness of the study was ensured through validity and acceptability criteria. RESULTS: Data analysis showed that nursing educators and students were involve in teaching and learning activities by storing knowledge in subjective and objective forms. Knowledge was gained through the different educational activities of the nursing educators and through contact with their peers. Moreover, the nursing students gained knowledge for better learning and a more knowledgeable and advanced performance with the help of the educators. CONCLUSIONS: This study revealed the main components of knowledge storage. An enhanced preservation of explicit knowledge is recommended in the nursing educational system so that in the future, students and educators can easily access the same knowledge from storage sources and not from individuals who might be carrying only a single experience of the subject. PMID- 25558387 TI - Moral distress in physicians practicing in hospitals affiliated to medical sciences universities. AB - BACKGROUND: Researchers have regarded moral distress as a major concern in the health care system. Symptoms associated with moral distress may manifest as frustration, dissatisfaction, and anxiety and may lead to burnout, job leaving, and finally, failure to provide safe and competent care to patients. Proper management of this phenomenon can be fulfilled through study of its causes at different levels of health services and taking necessary measures to solve them. OBJECTIVES: This study aimed to determine the status of moral distress in physicians practicing in hospitals affiliated to Medical Sciences Universities in Tehran. MATERIALS AND METHODS: This cross-sectional study was carried out using the Standard Hamric Scale to collect data after modification and evaluation of its reliability and validity. A total of 399 physicians responded to the scale. Data analysis was performed using descriptive and correlation statistics with respect to the variables. RESULTS: Results showed that the frequency of moral distress of physicians was 1.24 +/- 0.63 and the intensity of moral distress and composite score of moral distress were 2.14 +/- 0.80 and 2.94 +/- 2.38, respectively. A significant negative correlation existed between age and frequency and composite score (r = -0.15, P < 0.01 and r = -0.16, P < 0.01, respectively) as well as years of experience and composite score (r = -0.11, P = 0.04). Moral distress composite score in adults specialists was higher than pediatricians (P = 0.002), but lower in physicians participated in medical ethics training courses compared to those not participated. CONCLUSIONS: Physicians may encounter moral distress during their practice; therefore, the common causes of distress should be identified in order to prevent its occurrence. PMID- 25558389 TI - Occupational asthma in a cable manufacturing company. AB - BACKGROUND: During the past decade, incidence of asthma has increased, which might have been due to environmental exposures. OBJECTIVES: Considering the expansion of cable manufacturing industry in Iran, the present study was conducted to evaluate the prevalence of occupational asthma in a cable manufacturing company in Iran as well as its related factors. PATIENTS AND METHODS: This study was conducted on employees of a cable manufacturing company in Yazd, Iran, in 2012. The workers were divided into two groups of exposure (to toluene diisocyanate, polyvinyl chloride, polyethylene or polypropylene) and without exposure. Diagnosis of occupational asthma was made based on the subjects' medical history, spirometry and peak flowmetry, and its frequency was compared between the two groups. RESULTS: The overall prevalence of occupational asthma was 9.7%. This rate was 13.8% in the exposed group. Logistic regression analysis showed that even after adjustment for confounding factors, a significant correlation existed between the frequency of occupational asthma and exposure to the produced dust particles (P < 0.05). In addition, age, work experience, body mass index, cigarette smoking and shift work had significant correlations with the prevalence of occupational asthma (P < 0.05). CONCLUSIONS: Considering the high prevalence of occupational asthma among cable manufacturing company workers in Iran, this issue needs to be addressed immediately in addition to reduction of exposure among subjects. Reduction in work shift duration, implementation of tobacco control and cessation programs for the personnel, and performing spirometry tests and respiratory examinations in shorter periods may be among effective measures for reducing the incidence of occupational asthma in this industry. PMID- 25558390 TI - Efficacy and safety of different dosages of praziquantel for the treatment of schistosoma japonicum: a systematic review and meta-analysis. AB - BACKGROUND: Praziquantel, an antischistosomal compound, is used as first-line drug for chemotherapy of Schistosoma japonicum since 1984. In this article, we conducted a systematic review and mete-analysis to evaluate the efficacy and safety of different dosages of praziquantel (PZQ) for treatment of Schistosoma japonicum. EVIDENCE ACQUISITION: A number of six articles published in peer reviewed journals before December 2012 were selected for analysis after searching the following literature databases: PubMed/Medline, the Chinese WanFang Literature Database, China National Knowledge Infrastructure (1994-2012.12), and the Chinese Biomedical Literature (1978-2012.12). RESULTS: The meta-analyses showed that there is no statistically significant difference of the negative rate on the egg using 40 mg/kg compared to 60 mg/kg PZQ for S. japonicum treatment (RR 0.79, 95% CI 0.46 1.35; P < 0.39). The meta-analysis showed that there is no statistically significant difference of the side effects using 30 mg/kg compared with 40 mg/kg (RR 0.97, 95% CI 0.68 1.38; P = 0.87), 40 mg/kg compared with 60 mg/kg (RR 0.79, 95% CI 0.46 1.35; P = 0.39) and 50 mg/kg compared with 60 mg/kg (RR 0.89, 95% CI 0.56 1.42; P = 0.63). CONCLUSIONS: According to the results, there is no statistically significant difference in different doses of PZQ for treating S. japonicum. PMID- 25558392 TI - Regulation of the target protein (transgene) expression in the adenovirus vector using agonists of toll-like receptors. AB - Replication-defective adenoviral vectors are effective molecular tools for both gene therapy and gene vaccination. Using such vectors one can deliver and express target genes in different epithelial, liver, hematopoietic and immune system cells of animal and human origin. The success of gene therapy and gene vaccination depends on the production intensity of the target protein encoded by the transgene. In this work, we studied influence of Toll-like receptors (TLR) agonists on transduction and expression efficacy of adenoviral vectors in animal and human antigen-presenting cells. We found that agonists of TLR2, 4, 5, 7, 8 and 9 significantly enhance a production of the target protein in cells transduced with adenoviral vector having the target gene insert. The enhancement was observed in dendritic cells and macrophages expressing cytoplasmic (GFP), membrane (HA) or secretory (SEAP) proteins encoded by the respective rAd-vectors. Experiments in mice showed that enhancement of the transgene expression can be achieved in the organism of animals using a pharmaceutical-grade TLR4-agonist. In contrast to other TLR-agonists, the agonist of TLR3 substantially suppressed the expression of transgene in cells transduced with adenoviral vectors having insert of GFP or SEAP target genes. We propose that the enhancement of transgene expression is linked to the activation of MyD88-> NF-kB, while the inhibition of transgene expression depends on TRIF-> IRF signaling pathways. Both of these pathways jointly exploited by TLR4-agonists lead to the enhancement of transgene expression due to the dominant role of the MyD88-> NF-kB signaling. PMID- 25558391 TI - Mechanisms of activation of voltage-gated potassium channels. AB - Voltage-gated potassium ion channels (Kv) play an important role in a variety of cellular processes, including the functioning of excitable cells, regulation of apoptosis, cell growth and differentiation, the release of neurotransmitters and hormones, maintenance of cardiac activity, etc. Failure in the functioning of Kv channels leads to severe genetic disorders and the development of tumors, including malignant ones. Understanding the mechanisms underlying Kv channels functioning is a key factor in determining the cause of the diseases associated with mutations in the channels, and in the search for new drugs. The mechanism of activation of the channels is a topic of ongoing debate, and a consensus on the issue has not yet been reached. This review discusses the key stages in studying the mechanisms of functioning of Kv channels and describes the basic models of their activation known to date. PMID- 25558393 TI - STIM1 Protein Activates Store-Operated Calcium Channels in Cellular Model of Huntington's Disease. AB - We have shown that the expression of full-length mutated huntingtin in human neuroblastoma cells (SK-N-SH) leads to an abnormal increase in calcium entry through store-operated channels. In this paper, the expression of the N-terminal fragment of mutated huntingtin (Htt138Q-1exon) is shown to be enough to provide an actual model for Huntington's disease. We have shown that Htt138Q-1exon expression causes increased store-operated calcium entry, which is mediated by at least two types of channels in SK-N-SH cells with different reversal potentials. Calcium sensor, STIM1, is required for activation of store-operated calcium entry in these cells. The results provide grounds for considering the proteins responsible for the activation and maintenance of the store-operated calcium entry as promising targets for developing novel therapeutics for neurodegenerative diseases. PMID- 25558394 TI - Specific visualization of tumor cells using upconversion nanophosphors. AB - The development of targeted constructs on the basis of photoluminescent nanoparticles with a high photo- and chemical stability and absorption/emission spectra in the "transparency window" of biological tissues is an important focus area of present-day medical diagnostics. In this work, a targeted two-component construct on the basis of upconversion nanophosphors (UCNPs) and anti-tumor 4D5 scFv was developed for selective labeling of tumor cells overexpressing the HER2 tumor marker characteristic of a number of human malignant tumors. A high affinity barnase : barstar (Bn : Bs) protein pair, which exhibits high stability in a wide range of pH and temperatures, was exploited as a molecular adapter providing self-assembly of the two-component construct. High selectivity for the binding of the two-component 4D5 scFv-Bn : UCNP-Bs construct to human breast adenocarcinoma SK-BR-3 cells overexpressing HER2 was demonstrated. This approach provides an opportunity to produce similar constructs for the visualization of different specific markers in pathogenic tissues, including malignant tumors. PMID- 25558395 TI - Excessive Labeling Technique Provides a Highly Sensitive Fluorescent Probe for Real-time Monitoring of Biodegradation of Biopolymer Pharmaceuticals in vivo. AB - Recombinant proteins represent a large sector of the biopharma market. Determination of the main elimination pathways raises the opportunities to significantly increase their half-lives in vivo. However, evaluation of biodegradation of pharmaceutical biopolymers performed in the course of pre clinical studies is frequently complicated. Noninvasive pharmacokinetic and biodistribution studies in living organism are possible using proteins conjugated with near-infrared dyes. In the present study we designed a highly efficient probe based on fluorescent dye self-quenching for monitoring of in vivo biodegradation of recombinant human butyrylcholinesterase. The maximum enhancement of integral fluorescence in response to degradation of an intravenously administered enzyme was observed 6 h after injection. Importantly, excessive butyrylcholinesterase labeling with fluorescent dye results in significant changes in the pharmacokinetic properties of the obtained conjugate. This fact must be taken into consideration during future pharmacokinetic studies using in vivo bioimaging. PMID- 25558396 TI - Human SLURP-1 and SLURP-2 Proteins Acting on Nicotinic Acetylcholine Receptors Reduce Proliferation of Human Colorectal Adenocarcinoma HT-29 Cells. AB - Human secreted Ly-6/uPAR related proteins (SLURP-1 and SLURP-2) are produced by various cells, including the epithelium and immune system. These proteins act as autocrine/paracrine hormones regulating the growth and differentiation of keratinocytes and are also involved in the control of inflammation and malignant cell transformation. These effects are assumed to be mediated by the interactions of SLURP-1 and SLURP-2 with the alpha7 and alpha3beta2 subtypes of nicotinic acetylcholine receptors (nAChRs), respectively. Available knowledge about the molecular mechanism underling the SLURP-1 and SLURP-2 effects is very limited. SLURP-2 remains one of the most poorly studied proteins of the Ly-6/uPAR family. In this study, we designed for the first time a bacterial system for SLURP-2 expression and a protocol for refolding of the protein from cytoplasmic inclusion bodies. Milligram quantities of recombinant SLURP-2 and its 13C-15N-labeled analog were obtained. The recombinant protein was characterized by NMR spectroscopy, and a structural model was developed. A comparative study of the SLURP-1 and SLURP-2 effects on the epithelial cell growth was conducted using human colorectal adenocarcinoma HT-29 cells, which express only alpha7-nAChRs. A pronounced antiproliferative effect of both proteins was observed. Incubation of cells with 1 MUM SLURP-1 and 1 MUM SLURP-2 during 48 h led to a reduction in the cell number down to ~ 54 and 63% relative to the control, respectively. Fluorescent microscopy did not reveal either apoptotic or necrotic cell death. An analysis of the dose-response curve revealed the concentration-dependent mode of the SLURP-1 and SLURP-2 action with EC50 ~ 0.1 and 0.2 nM, respectively. These findings suggest that the alpha7-nAChR is the main receptor responsible for the antiproliferative effect of SLURP proteins in epithelial cells. PMID- 25558397 TI - Investigation of channel-forming activity of polyene macrolide antibiotics in planar lipid bilayers in the presence of dipole modifiers. AB - The role of membrane components, sterols, phospholipids and sphingolipids in the formation and functioning of ion-permeable nanopores formed by antifungal macrolide antibiotics, amphotericin B, nystatin and filipin in planar lipid bilayers was studied. Dipole modifiers, flavonoids and styryl dyes, were used as a tool to study the molecular mechanisms of polyene channel-forming activity. The introduction of dipole modifiers into the membrane bathing solutions was shown to change the conductance of single channels and the steadystate transmembrane current induced by polyene antibiotics in the sterol-containing phospholipid bilayers. The conductance of single amphotericin B channels was found to depend on the dipole potential of the membrane. The experiments with various phospholipids, sterols, and polyenes led to the assumption that the shape of a phospholipid molecule, the presence of double bonds at the positions 7 and 22 of a sterol molecule, the number of conjugated double bonds, and the presence of an amino sugar in the polyene antibiotic molecule are important factors impacting the stability of polyene-lipid complexes forming ion-permeable pores. Experimental and literature data presented in the paper suggest that the channel forming activity of polyene antibiotics is also affected by the physicochemical properties of polyene-enriched ordered membrane domains. PMID- 25558398 TI - A cytofluorometric study of membrane rafts in human monocyte subsets in atherosclerosis. AB - The peripheral blood monocytes of atherosclerotic patients are pre-activated and have some of the features of tissue macrophages. Their adhesion to the endothelium is 1.5 times higher than that of monocytes from healthy subjects, and they express a number of receptors and antigens typical of tissue macrophages. Additionally, earlier we showed that the biosynthesis of gangliosides, whose main function is the formation of membrane rafts, is significantly activated in blood monocytes from atherosclerotic patients, as well as during the in vitro differentiation of normal monocytes into macrophages. In this study, we investigated the expression of membrane rafts on various monocyte subsets from healthy subjects and atherosclerotic patients. Based on flow cytometry results, the monocytes in the examined atherosclerotic patients were found to differ from those in healthy subjects by a twofold increase in the proportion of the intermediate subset (CD14(++)/CD16(+)) and by enhancement in the expression of the fractalkine receptor CX3CR1 on the intermediate and non-classical subsets (CD14(++)/CD16(+) and CD14(+)/CD16(++)) (2.3 and 1.8 times, respectively). This suggests a pre-activated state of monocytes in atherosclerotic patients. At the same time, the expression of the membrane raft marker on the monocyte subsets was similar in both studied groups. However, a study of the in vitro differentiation of monocytes into macrophages showed that the membrane raft expression increased 2 times as early as on the 1st day of culturing and 3 times on the 7th day compared to that in freshly isolated monocytes. Therefore, it is suggested that monocytes in atherosclerosis accumulate gangliosides that are used to form membrane rafts during the macrophage differentiation after the migration of monocytes into the arterial intima. PMID- 25558399 TI - Hct-a is a new actinoporin family from the heteractis crispa sea anemone. AB - Several new actinoporin isoforms with molecular weights of 18995.5 to 19398.7 Da exhibiting a high hemolytic activity were isolated from the tropical sea anemone Heteractis crispa using a combination of liquid chromatography techniques. The actinoporins were demonstrated to occur as mono-, di-, and trimers in aqueous solutions. The sequences of the genes encoding actinoporins were identified, and the amino acid sequences of the new polypeptides belonging to the Hct-A actinoporin family were obtained. The new acinoporins differ in their isoelectric points, the number and localization of charged amino acid residues at the functionally important N-terminal fragment of the molecule, as well as in the charge of a tetrapeptide (amino acid residues 74-77) involved in an electrostatic interaction with the cytoplasmic membrane. A recombinant actinoporin, rHct-A2, with a molecular weight of 19141 Da, pI of 9.64, and hemolytic activity of 4.0 * 104 HU/mg, was obtained. The conductivity of the ion channels formed by rHct-A2 in the BLM was demonstrated to be similar to that of the native actinoporin from H. crispa. The obtained data expand knowledge on the structural and functional relationships of actinoporins and contribute to our understanding of the functioning mechanism of these molecules, which is the basis for the development of compounds with a high biomedical potential. Currently, they are considered as models for obtaining antitumor, antibacterial, and cardiac-stimulating agents. PMID- 25558400 TI - Acipensins - Novel Antimicrobial Peptides from Leukocytes of the Russian Sturgeon Acipenser gueldenstaedtii. AB - Antimicrobial peptides (AMPs) play an important role in the innate defense mechanisms in humans and animals. We have isolated and studied a set of antimicrobial peptides from leukocytes of the Russian sturgeon Acipenser gueldenstaedtii belonging to a subclass of chondrosteans, an ancient group of bony fish. Structural analysis of the isolated peptides, designated as acipensins (Ac), revealed in leukocytes of the Russian sturgeon six novel peptides with molecular masses of 5336.2 Da, 3803.0 Da, 5173.0 Da, 4777.5 Da, 5449.4 Da, and 2740.2 Da, designated as Ac1-Ac6, respectively. Complete primary structures of all the isolated peptides were determined, and the biological activities of three major components - Ac1, Ac2, and Ac6 - were examined. The peptides Ac1, Ac2, Ac3, Ac4, and Ac5 were found to be the N-terminal acetylated fragments 1-0, 1-5, 1-9, 1-4, and 1-1 of the histone H2A, respectively, while Ac6 was shown to be the 62-5 fragment of the histone H2A. The peptides Ac1 and Ac2 displayed potent antimicrobial activity towards Gram-negative and Gram-positive bacteria (Escherichia coli ML35p, Listeria monocytogenes EGD, MRSA ATCC 33591) and the fungus Candida albicans 820, while Ac6 proved effective only against Gram negative bacteria. The efficacy of Ac 1 and Ac2 towards the fungus and MRSA was reduced upon an increase in the ionic strength of the solution. Ac1, Ac2, and Ac6, at concentrations close to their minimum inhibitory concentrations, enhanced the permeability of the E.coli ML35p outer membrane to the chromogenic marker, but they did not affect appreciably the permeability of the bacterial inner membrane in comparison with a potent pore-forming peptide, protegrin 1. Ac1, Ac2, and Ac6 revealed no hemolytic activity against human erythrocytes at concentrations of 1 to 40 MUM and had no cytotoxic effect (1 to 20 MUM) on K-562 and U-937 cells in vitro. Our findings suggest that histone-derived peptides serve as important anti-infective host defense molecules. PMID- 25558401 TI - The mechanism of choline-mediated inhibition of acetylcholine release in mouse motor synapses. AB - The mechanism of action of tonically applied choline, the agonist of alpha7 nicotinic acetylcholine receptors (nAChRs), to the spontaneous and evoked release of a neurotransmitter in mouse motor synapses in diaphragm neuromuscular preparations using intracellular microelectrode recordings of miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs) was studied. Exogenous choline was shown to exhibit a presynaptic inhibitory effect on the amplitude and quantal content of EPPs for the activity of neuromuscular junction evoked by single and rhythmic stimuli. This effect was inhibited either by antagonists of alpha7-nAChRs, such as methyllycaconitine and alpha-cobratoxin, or by blocking SK type calcium-activated potassium (KCa) channels with apamin or blocking intraterminal ryanodine receptors with ryanodine. A hypothesis was put forward that choline in mouse motoneuron nerve terminals can activate presynaptic alpha7 nAChRs, followed by the release of the stored calcium through ryanodine receptors and activation of SK-type KCa channels, resulting in sustained decay of the quantal content of the evoked neurotransmitter release. PMID- 25558402 TI - Phosphoryl guanidines: a new type of nucleic Acid analogues. AB - A new type of nucleic acid analogues with a phosphoryl guanidine group is described. Oxidation of polymer-supported dinucleoside 2-cyanoethyl phosphite by iodine in the presence of 1,1,3,3-tetramethyl guanidine yields a dinucleotide with an internucleoside tetramethyl phosphoryl guanidine (Tmg) group as the main product. The Tmg group is stable under conditions of solid-phase DNA synthesis and subsequent cleavage and deprotection with ammonia. Oligonucleotides with one or more Tmg groups bind their complementary DNA or RNA with affinity similar to that of natural oligodeoxyribonucleotides. PMID- 25558403 TI - Improvement of Adult BTE Hearing Aid Wearers' Front/Back Localization Performance Using Digital Pinna-Cue Preserving Technologies: An Evidence-Based Review. AB - This systematic review evaluated the impact of using digital pinna-cue preserving technologies (PPT) on front/back sound localization for adult hearing aid users. Two peer-reviewed studies and two non-peer-reviewed studies were included. Lab based and self-report outcomes were both assessed. The overall findings suggested that PPT was superior to omni-directional and full directional settings in a relatively quiet, well-controlled laboratory environment but not in the real world. However, observed individual differences in self-report measures suggested that PPT was potentially beneficial to certain hearing aid users. PPT candidacy was discussed and the importance of a pre-fitting interview/consultation was emphasized to assist clinicians in making a solid evidence-based and cost effectiveness decision when prescribing hearing aids to adults with hearing impairment. PMID- 25558404 TI - Effects of ageing and hearing thresholds on speech perception in quiet and in noise perceived in different locations. AB - BACKGROUND AND OBJECTIVES: This study investigated the effect of ageing on speech perception in quiet and in noise, with noise directed from front, right and left. SUBJECTS AND METHODS: Sixty Malay native adults with normal or near normal hearing comprising of 20 young adults (21 to 39 years old), 20 middle aged (40 to 59 years old) and 20 older adults (60 to 74 years old) participated in this study. Their speech perception ability was measured using the Malay Hearing in Noise Test (HINT) in four test conditions; 1) in quiet (HINT Q), 2) with noise from front (HINT NF), 3) with noise from right (HINT NR), and 4) with noise from left (HINT NL). Reception thresholds for sentences (RTSs) were measured in each of the aforementioned conditions using an adaptive method. RESULTS: The results showed that, 1) genuine age-related decline was found in speech perception performance in HINT (NF), 2) hearing threshold was a major determinant differentiating speech perception performance for HINT (Q) and HINT (NL) conditions, and 3) speech perception performance for HINT (NR) was determined by both age and hearing threshold. CONCLUSIONS: This study suggests that, in older adults, while hearing thresholds affect speech perception in quiet, other factors such as central auditory processing and cognitive functions might be more important determinant factors for speech perception performance in noise. PMID- 25558405 TI - The effects of unilateral tinnitus on auditory temporal resolution: gaps-in-noise performance. AB - BACKGROUND AND OBJECTIVES: The Gaps-In-Noise (GIN) test is a measure to assess auditory temporal resolution, which is the ability to follow rapid changes in the envelope of a sound stimulus over time. We investigated whether unilateral tinnitus affects temporal resolution by the GIN performance. SUBJECTS AND METHODS: Hearing tests including the GIN test were performed in 120 ears of 60 patients with unilateral tinnitus who showed symmetric hearing within 20 dB HL difference up to 8 kHz (tinnitus-affected ears, 14.6+/-11.2 dB HL; non-tinnitus ears 15.1+/-11.5 dB HL) and 60 ears of 30 subjects with normal hearing. Comparisons were made between tinnitus and non-tinnitus side of patients and normal ears of controls. RESULTS: There was no significant difference of the mean GIN thresholds among tinnitus-affected ears (5.18+/-0.6 ms), non-tinnitus ears (4.98+/-0.6 ms) and normal ears (4.97+/-0.8 ms). The mean percentage of correct answers in tinnitus side (67.3+/-5.5%) was slightly less than that in non tinnitus side (70.0+/-5.5%) but it was not significantly different from that in normal ears (69.4+/-7.5%). Neither the GIN threshold nor the GIN perception level in tinnitus ears has relation to sex, frequency and loudness of tinnitus, and audiometric data. Age only showed a significant correlation with the GIN performance. CONCLUSIONS: We found no evidence which supported the influence of unilateral tinnitus on auditory temporal resolution. These results imply that tinnitus may not simply fill in the silent gaps in the background noise. PMID- 25558406 TI - Benign paroxysmal positional vertigo with simultaneous involvement of multiple semicircular canals. AB - BACKGROUND AND OBJECTIVES: Benign paroxysmal positional vertigo (BPPV) generally involves a single semicircular canal (single canal BPPV) but it has been reported that more than one semicircular canal on either the same or the opposite side can be involved in 6.8-20% of the cases (multiple canal BPPV). In this study, the clinical characteristics of multiple canal BPPV were analyzed and compared to those of single canal BPPV. MATERIALS AND METHODS: Retrospective analysis was performed on 1054 consecutive patients diagnosed with BPPV. Multiple canal BPPV was diagnosed when the combination of typical nystagmus was provoked by the Dix Hallpike and supine head roll tests. Canalith repositioning maneuver was performed sequentially starting with the semicircular canal causing more severe nystagmus or symptoms. Clinical characteristics and the treatment course were statistically compared between single canal BPPV and multiple canal BPPV. RESULTS: Among the 1054 patients, single canal BPPV was diagnosed in 1005 patients (95.4%) while multiple canal BPPV was diagnosed in 49 patients (4.6%). BPPV involving semicircular canals on the same side was more common (79.6%) than BPPV with bilateral involvement. The most common combination of the involved canals was ipsilateral posterior and horizontal semicircular canals (63.3%). Multiple canal BPPV was significantly more associated with underlying otologic diseases, especially labyrinthitis. Multiple canal BPPV required more treatment sessions and longer duration of treatment to achieve resolution of nystagmus and symptoms. CONCLUSIONS: As all cases of multiple canal BPPV were treated successfully although a longer duration of treatment and more treatment sessions were required compared to single canal BPPV, the results of our study could aid in making an accurate diagnosis and providing appropriate treatment of multiple canal BPPV. PMID- 25558407 TI - Association between Vestibular Function and Hearing Outcome in Idiopathic Sudden Sensorineural Hearing Loss. AB - BACKGROUND AND OBJECTIVES: To investigate whether different vestibular function tests such as cervical vestibular evoked myogenic potential (cVEMP) and caloric test were correlated with severity, pattern and prognosis in idiopathic sudden sensorineural hearing loss (ISSNHL). SUBJECTS AND METHODS: Ninety-two patients with unilateral ISSNHL were subjected to complete audiovestibular evaluation. cVEMP and caloric test results were compared with patients' initial and final audiogram. We classified patients in 4 groups as cochlear nerve (C) type, cochlear and superior vestibular nerve (C+S) type, cochlear and inferior vestibular nerve (C+I) type and cochlear, superior vestibular nerve, inferior vestibular nerve (C+S+I) type, for evaluation of the results. cVEMP and caloric tests were compared among the groups. RESULTS: Abnormal caloric test results and abnormal cVEMP results were found in 50% and 31.6% patients, respectively. Multivariate analysis showed that abnormal caloric result (canal paresis) is a significant negative prognostic factor. CONCLUSIONS: Initial vestibular function test can be valuable in predicting the final outcome in patients with ISSNHL. PMID- 25558408 TI - Transverse fracture of the stapes anterior crus caused by the blast pressure from a land mine explosion. AB - Stapes fractures without other ossicle problems are rare and ossicle problems due to explosion pressure are also rare. We describe a very rare case of stapes anterior crural fracture resulting from a land mine explosion. As this case suggests, a close examination of the ossicles is necessary during an exploration tympanotomy. PMID- 25558409 TI - Recurrent benign myoepithelioma of the auricle. AB - Myoepithelioma, a generally benign tumor comprised of myoepithlial cells, is an uncommon salivary gland tumor. Myoepithelioma originates primarily in the parotid gland, but several isolated cases have been described. Although myoepithelioma has a benign nature, but there is a potential risk of malignant change and recurrence in case of incomplete resection. We acknowledge that benign myoepithelioma originating from the auricle has not been reported in the English literature. We present a rare case of 27-year-old female who had recurrent benign myoepithelioma originating from the auricle and already had been given twice operations at the other clinic. PMID- 25558410 TI - Cochlear implantation using a suprameatal approach in a case of severely contracted mastoid cavity. AB - Although cochlear implantation using posterior tympanotomy has been performed worldwide, other alternative approaches might be more beneficial and convenient in some selected cases. Of these, suprameatal approach was reported to be one of useful options in cases with narrow facial recess, anteriorly located facial nerve and an ossified cochlea. We describe a case of cochlear implantation using the modified suprameatal approach in a severely contracted mastoid cavity and suggest another indication of this approach. PMID- 25558411 TI - A case of cochlear implantation targeting preserved cerebral cortex in severe traumatic brain injury. AB - Temporal bone fracture and blunt head trauma was once considered as contraindication for the surgery. Increasing numbers of successful cochlear implantation are being reported. However, the outcome of cochlear implantation in severe damaged brain is unclear. A multichannel cochlear implant was successfully implanted in a 33-year-old man who had both sensorineural deafness, left hemiplegia due to bilateral transverse temporal bone fractures and severe right brain damage after a traffic accident. PMID- 25558412 TI - Eccrine poroma of the auricle: a case report. AB - Eccrine poroma is described as a benign neoplasm originating from the intraepidermal eccrine duct of sweat glands. This tumor is known to arise in bare skin areas, but more rarely appeared in head and neck region. A 54-year-old female presented with a mass on the retroauricular aspect of the left auricle. There was a soft, protruding, and purple-colored, solitary mass of about 1.0*1.0 cm in size. After authors performed an excisional biopsy, eccrine poroma was confirmed histopathologically. Thus, we report a rare case of eccrine poroma of the ear with the review of literature. PMID- 25558413 TI - A case of labyrinthine fistula by cholesteatoma mimicking lateral canal benign paroxysmal positional vertigo. AB - Acute peripheral vestibulopathy, of which the chief complaint is positional vertigo, comprises benign paroxysmal positional vertigo (BPPV), labyrinthitis, labyrinthine fistula, and cerebellopontine angle tumors. Since the typical presentation of labyrinthine fistulas may be sensorineural hearing loss, positional vertigo, or disequilibrium, it is often difficult to distinguish from BPPV or Meniere's disease. Herein we report a 61-year-old female patient with typical symptoms and signs attributable to geotropic type variant of the lateral semicircular canal BPPV on the left side, who eventually was confirmed as having a labyrinthine fistula from chronic otitis media with cholesteatoma on the left side. This is another case where, even in the presence of isolated vertigo showing typical findings of acute peripheral vestibulopathy, other otologic symptoms and signs must not be overlooked. PMID- 25558414 TI - From assessment for new targets to comprehensive assessment. PMID- 25558416 TI - Influence of Panax ginseng on Alpha-Adrenergic Receptor of Benign Prostatic Hyperplasia. AB - PURPOSE: Benign prostatic hyperplasia (BPH) is the most common prostate problem in older men. The present study aimed to investigate the inhibitory effect of Panax ginseng C.A. Meyer (P. ginseng) on a rat model of testosterone-induced BPH. METHODS: The rats were divided into 3 groups (each group, n=10): control, testosterone-induced BPH (20 mg/kg, subcutaneous injection), and P. ginseng (200 mg/kg, orally) groups. After 4 weeks, all animals were sacrificed to examine the blood biochemical profiles, prostate volume, weight, histopathological changes, alpha-1D adrenergic receptor (Adra1d) mRNA expression, and epidermal growth factor receptor (EGFR) and B-cell CLL/lymphoma 2 (BCL2) protein expression. RESULTS: The group treated with P. ginseng showed significantly lesser prostate size and weight than the testosterone-induced BPH group. In addition, P. ginseng decreased the mRNA expression of Adra1d as well as the expression of EGFR and BCL2 in prostate tissue. CONCLUSIONS: These results suggest that P. ginseng may inhibit the alpha-1-adrenergic receptor to suppress the development of BPH. PMID- 25558417 TI - Factors influencing nonabsolute indications for surgery in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: analysis using causal bayesian networks. AB - PURPOSE: To identify the factors affecting the surgical decisions of experienced physicians when treating patients with lower urinary tract symptoms that are suggestive of benign prostatic hyperplasia (LUTS/BPH). METHODS: Patients with LUTS/BPH treated by two physicians between October 2004 and August 2013 were included in this study. The causal Bayesian network (CBN) model was used to analyze factors influencing the surgical decisions of physicians and the actual performance of surgery. The accuracies of the established CBN models were verified using linear regression (LR) analysis. RESULTS: A total of 1,108 patients with LUTS/BPH were analyzed. The mean age and total prostate volume (TPV) were 66.2 (+/-7.3, standard deviation) years and 47.3 (+/-25.4) mL, respectively. Of the total 1,108 patients, 603 (54.4%) were treated by physician A and 505 (45.6%) were treated by physician B. Although surgery was recommended to 699 patients (63.1%), 589 (53.2%) actually underwent surgery. Our CBN model showed that the TPV (R=0.432), treating physician (R=0.370), bladder outlet obstruction (BOO) on urodynamic study (UDS) (R=0.324), and International Prostate Symptom Score (IPSS) question 3 (intermittency; R=0.141) were the factors directly influencing the surgical decision. The transition zone volume (R=0.396), treating physician (R=0.340), and BOO (R=0.300) directly affected the performance of surgery. Compared to the LR model, the area under the receiver operating characteristic curve of the CBN surgical decision model was slightly compromised (0.803 vs. 0.847, P<0.001), whereas that of the actual performance of surgery model was similar (0.801 vs. 0.820, P=0.063) to the LR model. CONCLUSIONS: The TPV, treating physician, BOO on UDS, and the IPSS item of intermittency were factors that directly influenced decision-making in physicians treating patients with LUTS/BPH. PMID- 25558415 TI - Microtubule-Targeting Agents Enter the Central Nervous System (CNS): Double-edged Swords for Treating CNS Injury and Disease. AB - Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases. PMID- 25558418 TI - Do rotational shifts affect micturition patterns in real practice? A pilot study in healthy, young female nurses. AB - PURPOSE: Healthy, young individuals are known to exhibit circadian variation in urinary functions. However, the effects of chronic circadian disturbance on voiding functions are largely unknown. The present work compared the effects of rotational shifts on the micturition patterns of female nurses to that in female nurses with routine daytime shifts. METHODS: A total of 19 nurses without lower urinary tract symptoms who worked rotational shifts for an average duration of 2 years were recruited. A voiding diary was kept for 9 consecutive days, and the overactive bladder symptom score (OABSS) questionnaire was completed three times, starting 3 days before their night duties until 3 days after completion of their night duties. For comparison, seven nurses with regular shifts completed a 3-day voiding diary and the OABSS questionnaire. RESULTS: Female nurses working rotational shifts had lower overall urine production and had decreased urination frequency and nocturia than female nurses working regular shifts, even when the nurses who worked rotational shifts had a regular night's sleep for at least 7 days. Upon reinitiation of night duty, overall urine production increased significantly, with no significant changes in urgency and frequency. When these nurses returned to daytime duty, the volume of urine decreased but nocturnal urine production remained high, and the incidence of nocturia also increased significantly. However, the effects on OABSS score were not significant under the study design used. CONCLUSIONS: Long-term rotational shifts resulted in adaptive changes such as decreased urine production and frequency in healthy, young female nurses. In addition, their micturition patterns were significantly affected by abrupt changes in their work schedules. Although working in shifts did not increase urgency or frequency of urination in healthy, young female nurses working rotational shifts for an average 2 years, large-scale studies are needed to systematically analyze the influence of shift work timings on micturition in humans. PMID- 25558419 TI - Effect of combined systematized behavioral modification education program with desmopressin in patients with nocturia: a prospective, multicenter, randomized, and parallel study. AB - PURPOSE: The aims of this study were to investigate the efficacy of combining the systematized behavioral modification program (SBMP) with desmopressin therapy and to compare this with desmopressin monotherapy in the treatment of nocturnal polyuria (NPU). METHODS: Patients were randomized at 8 centers to receive desmopressin monotherapy (group A) or combination therapy, comprising desmopressin and the SBMP (group B). Nocturia was defined as an average of 2 or more nightly voids. The primary endpoint was a change in the mean number of nocturnal voids from baseline during the 3-month treatment period. The secondary endpoints were changes in the bladder diary parameters and questionnaires scores, and improvements in self-perception for nocturia. RESULTS: A total of 200 patients were screened and 76 were excluded from the study, because they failed the screening process. A total of 124 patients were randomized to receive treatment, with group A comprising 68 patients and group B comprising 56 patients. The patients' characteristics were similar between the groups. Nocturnal voids showed a greater decline in group B (-1.5) compared with group A (-1.2), a difference that was not statistically significant. Significant differences were observed between groups A and B with respect to the NPU index (0.37 vs. 0.29, P=0.028), the change in the maximal bladder capacity (-41.3 mL vs. 13.3 mL, P<0.001), and the rate of patients lost to follow up (10.3% [7/68] vs. 0% [0/56], P=0.016). Self-perception for nocturia significantly improved in both groups. CONCLUSIONS: Combination treatment did not have any additional benefits in relation to reducing nocturnal voids in patients with NPU; however, combination therapy is helpful because it increases the maximal bladder capacity and decreases the NPI. Furthermore, combination therapy increased the persistence of desmopressin in patients with NPU. PMID- 25558421 TI - Why I am concerned about the future of medicine. PMID- 25558420 TI - 4-aminopyridine improves lower urinary tract symptoms in a patient with benign prostatic hyperplasia and downbeat nystagmus syndrome. AB - Aminopyridines are potassium channel blockers that increase the excitability of nerve cells and axons; therefore, they are widely used to treat different neurological disorders. Here we present a patient with idiopathic downbeat nystagmus and lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia who was treated with the sustained-release form of 4-aminopyridine (4 AP). During treatment with 4-AP, the LUTS improved. This improvement was monitored by using uroflowmetry and the International Prostate Symptom Score. A significant improvement of symptoms was observed in relation to the voided volume. This included an improved emptying of the bladder without an increase in residual urine. In animal studies, both nonselective K(+) channel blockade and selective voltage-sensitive potassium blockade by 4-AP resulted in increased contraction on rat detrusor strips. To our knowledge, this is the first clinical observation of the mode of action of 4-AP in urological symptoms in humans. PMID- 25558422 TI - Surgical strategy for intracranial dermoid and epidermoid tumors: An experience with 33 Patients. AB - BACKGROUND: The aim of this paper is to report on our surgical strategy and technique and to identify the best management for intracranial dermoids and epidermoids tumors (IDETs). METHODS: We retrospectively reviewed 33 consecutive patients (14 males and 19 females; mean age at surgery, 37.9 years) with pathologically confirmed IDETs who underwent surgical resection, with mean follow up of 7.2 years. RESULTS: Gross total tumor removal was achieved in 24 cases (72.7%) with zero surgical mortality and a recurrence rate of 9%. CONCLUSIONS: The surgical strategies used in this group of patients enabled total removal of most tumors without surgical mortality and with low morbidity and recurrence rates, proving to be safe and effective. PMID- 25558423 TI - Spinal intradural subpial angiolipoma: Case report and review of literature. AB - BACKGROUND: Spinal angiolipomas are rare tumors consisting of mature adipose tissue and abnormal vascular elements. Intradural location is very rare, and till now, only seven cases have been reported in literature. Authors report a case of an intradural intramedullary (subpial) angiolipoma located in the thoracic cord. CASE DESCRIPTION: A 26-year-old patient presented with features of progressive myelopathy of relatively short duration. Imaging showed a heterogeneous fat containing intradural lesion at D5-D9 level, which enhanced on contrast enhanced fat saturation sequences. Subtotal excision was performed and patient had partial recovery of his neurological deficits. Histopathology was suggestive of angiolipoma. CONCLUSIONS: Intradural angiolipomas are very rare. Complete excision often leads to neurological deficits. Hence, safe maximal decompression would suffice leading to long-term recurrence-free periods. PMID- 25558424 TI - Intradural vertebral endarterectomy with nonautologous patch angioplasty for refractory vertebrobasilar ischemia: Case report and literature review. AB - BACKGROUND: The natural history of patients with symptomatic vertebrobasilar ischemic symptoms due to chronic bilateral vertebral artery occlusive disease is progressive, and poses significant challenges when refractory to medical therapy. Surgical treatment options depend largely on location and characteristics of the atheroma (s), and generally include percutaneous transluminal angioplasty (PTA) with or without stent placement, posterior circulation revascularization (bypass), extracranial vertebral artery reconstruction, or vertebral artery endarterectomy. CASE DESCRIPTION: We present the case of a 56-year-old male with progressive vertebrobasilar ischemia due to tandem lesions in the right vertebral artery at the origin and intracranially in the V4 segment. The contralateral vertebral artery was occluded to the level of posterior inferior cerebellar artery (PICA) and posterior communicating arteries were absent. Following PTA and stent placement at the right vertebral artery origin, the patient was successfully treated with intradural vertebral artery endarterectomy (V4EA) and patch angioplasty via the far lateral approach. Distal endovascular intervention at the V4 segment proved not technically feasible after multiple attempts. CONCLUSIONS: V4EA is an uncommonly performed procedure, but may be considered for carefully selected patients. The authors' techniques and indications are discussed. Historical outcomes, relevant anatomic considerations, and lessons learned are reviewed from the literature. PMID- 25558425 TI - Endovascular management of external ventricular drain-associated cerebrovascular injuries. AB - BACKGROUND: Placement of external ventricular drains (EVDs) is a common, life saving neurosurgical procedure indicated across a variety of settings. While advances have made the procedure quite safe, the potential for iatrogenic morbidity and mortality continues. We document our experience with the endovascular management of three pseudoaneurysms associated with EVD placement and discuss the endovascular treatment options for EVD-associated cerebrovascular injury. METHODS: We performed a retrospective analysis to identify all EVDs placed from 2008 through 2013 at our institution. In instances of EVD-associated cerebrovascular injury, all admission and subsequent radiographic studies were reviewed, including cerebral angiograms and computed tomography (CT) scans where available. Angiograms were reviewed to record the extent of vascular injury and outcomes after treatment. RESULTS: One female and two male patients (age range, 40-75 years) were found to have developed vascular injuries associated with EVD placement. Three pseudoaneurysms, of the posterior communicating artery (PCOM), pericallosal artery branch, and the middle meningeal artery, respectively, were treated by coil and/or glue embolization. CONCLUSIONS: Although EVD-associated cerebrovascular injury remains a rare phenomenon, such procedures are not entirely benign. Endovascular repair for such lesions proves a viable, effective option. PMID- 25558426 TI - Neurosurgery: A profession or a technical trade? AB - The American Association of Neurological Surgeons (AANS), 11 years ago converted its Internal Revenue Code (IRC) tax status from a 501 (c) (3) to a 501 (c) (6) entity. By doing so, the professional medical association, now a trade association, was able to more aggressively lobby, support political campaigns, and pursue business opportunities for its members. In the following decade, major changes were seen in the practice of neurosurgery, especially as it relates to spine surgery. With the majority of neurosurgeons limiting themselves to a spine practice, an increased number of spinal procedures, most noted in the Medicare population, was recorded. For example, a 15-fold increase in complex spinal fusions for spinal stenosis was seen between 2002 and 2007. While the basis for this increase was not readily apparent, it was associated with a reduction in reimbursement per case of about 50%, fueling the belief that the increase in complexity of surgery permitted recovery of fees in complex cases to off-set the loss of reimbursement for simpler cases. Considering the growth of spinal surgery within neurosurgery, and decrease funding for spine surgery, in the future there may be too many surgeons chasing too few dollars. There appears to be within neurosurgery a crisis developing where future manpower projections do not realistically match future anticipated specialty funding. PMID- 25558427 TI - The death of spine surgery, sequel - 2014. PMID- 25558428 TI - Ethics Standards (HRPP) and Public Partnership (PARTAKE) to Address Clinical Research Concerns in India: Moving Toward Ethical, Responsible, Culturally Sensitive, and Community-Engaging Clinical Research. AB - Like other emerging economies, India's quest for independent, evidence-based, and affordable healthcare has led to robust and promising growth in the clinical research sector, with a compound annual growth rate (CAGR) of 20.4% between 2005 and 2010. However, while the fundamental drivers and strengths are still strong, the past few years witnessed a declining trend (CAGR -16.7%) amid regulatory concerns, activist protests, and sponsor departure. And although India accounts for 17.5% of the world's population, it currently conducts only 1% of clinical trials. Indian and international experts and public stakeholders gathered for a 2 day conference in June 2013 in New Delhi to discuss the challenges facing clinical research in India and to explore solutions. The main themes discussed were ethical standards, regulatory oversight, and partnerships with public stakeholders. The meeting was a collaboration of AAHRPP (Association for the Accreditation of Human Research Protection Programs)-aimed at establishing responsible and ethical clinical research standards-and PARTAKE (Public Awareness of Research for Therapeutic Advancements through Knowledge and Empowerment)-aimed at informing and engaging the public in clinical research. The present article covers recent clinical research developments in India as well as associated expectations, challenges, and suggestions for future directions. AAHRPP and PARTAKE provide etiologically based solutions to protect, inform, and engage the public and medical research sponsors. PMID- 25558429 TI - Two Cases of Thyroid Metastasis from Head and Neck Squamous Cell Carcinoma Detected by FDG-PET/CT. AB - We present two cases of head and neck squamous cell carcinoma (SCC) metastasizing to the thyroid gland. This is the first report that shows (18) F fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) images of tonsillar and supraglottic SCCs invading the thyroid gland. Alcohol and tobacco use are the two most important risk factors for head and neck cancers, but recently human papilloma virus (HPV) infection has become a significant risk factor in the United States. FDG-PET/CT is very useful for SCC staging/restaging and follow-up. PMID- 25558430 TI - Blood Pool Contrast-enhanced Magnetic Resonance Angiography with Correlation to Digital Subtraction Angiography: A Pictorial Review. AB - Magnetic resonance angiography (MRA) provides noninvasive visualization of the vascular supply of soft tissue masses and vascular pathology, without harmful radiation. This is important for planning an endovascular intervention, and helps to evaluate the efficiency and effectiveness of the treatment. MRA with conventional extracellular contrast agents relies on accurate contrast bolus timing, limiting the imaging window to first-pass arterial phase. The recently introduced blood pool contrast agent (BPCA), gadofosveset trisodium, reversibly binds to human serum albumin, resulting in increased T1 relaxivity and prolonged intravascular retention time, permitting both first-pass and steady-state phase high-resolution imaging. In our practice, high-quality MRA serves as a detailed "roadmap" for the needed endovascular intervention. Cases of aortoiliac occlusive disease, inferior vena cava thrombus, pelvic congestion syndrome, and lower extremity arteriovenous malformation are discussed in this article. MRA was acquired at 1.5 T with an 8-channel phased array coil after intravenous administration of gadofosveset (0.03 mmol/kg body weight), at the first-pass phase. In the steady-state, serial T1-weighted 3D spoiled gradient echo images were obtained with high resolution. All patients underwent digital subtraction angiography (DSA) and endovascular treatment. MRA and DSA findings of vascular anatomy and pathology are discussed and correlated. BPCA-enhanced MRA provides high-quality first-pass and steady-state vascular imaging. This could increase the diagnostic accuracy and create a detailed map for pre-intervention planning. Understanding the pharmacokinetics of BPCA and being familiar with the indications and technique of MRA are important for diagnosis and endovascular intervention. PMID- 25558431 TI - Dedicated Breast CT: Feasibility for Monitoring Neoadjuvant Chemotherapy Treatment. AB - OBJECTIVES: In this prospective pilot study, the feasibility of non-contrast dedicated breast computed tomography (bCT) to determine primary tumor volume and monitor its changes during neoadjuvant chemotherapy (NAC) treatment was investigated. MATERIALS AND METHODS: Eleven women who underwent NAC were imaged with a clinical prototype dedicated bCT system at three time points - pre-, mid-, and post-treatment. The study radiologist marked the boundary of the primary tumor from which the tumor volume was quantified. An automated algorithm was developed to quantify the primary tumor volume for comparison with radiologist's segmentation. The correlation between pre-treatment tumor volumes from bCT and MRI, and the correlation and concordance in tumor size between post-treatment bCT and pathology were determined. RESULTS: Tumor volumes from automated and radiologist's segmentations were correlated (Pearson's r = 0.935, P < 0.001) and were not different over all time points [P = 0.808, repeated measures analysis of variance (ANOVA)]. Pre-treatment tumor volumes from MRI and bCT were correlated (r = 0.905, P < 0.001). Tumor size from post-treatment bCT was correlated with pathology (r = 0.987, P = 0.002) for invasive ductal carcinoma larger than 5 mm and the maximum difference in tumor size was 0.57 cm. The presence of biopsy clip (3 mm) limited the ability to accurately measure tumors smaller than 5 mm. All study participants were pathologically assessed to be responders, with three subjects experiencing complete pathologic response for invasive cancer and the reminder experiencing partial response. Compared to pre-treatment tumor volume, there was a statistically significant (P = 0.0003, paired t-test) reduction in tumor volume at mid-treatment observed with bCT, with an average tumor volume reduction of 47%. CONCLUSIONS: This pilot study suggests that dedicated non contrast bCT has the potential to serve as an expedient imaging tool for monitoring tumor volume changes during NAC. Larger studies are needed in future. PMID- 25558432 TI - Imaging of Unilateral Meningo-ophthalmic Artery Anomaly in a Patient with Bilateral Nasopharyngeal Angiofibroma. AB - A 12-year-old boy with epistaxis presented with a rare midline nasopharyngeal angiofibroma that extended lateral into the pterygoid and infratemporal fossae. Pre-operative angiography revealed bilateral prominent feeder arteries and two major anastomotic connections, and a rare left meningo-ophthalmic artery (M-OA) anomaly that was the sole path of supply to the eye. A literature search using Pubmed and Medline was conducted. For imaging, a six-vessel study (i.e. external and internal carotid and vertebral arteries on both sides) was selected. Embolization of prominent tumor feeder arteries was unsafe for tumor extirpation, but super-selective embolization of both sphenopalatine arteries was performed to control epistaxis. The M-OA anomaly that originated from the maxillary artery (MA) was marked by an ophthalmic artery (OA) variant with orbital and ocular divisions that coursed through the superior orbital fissure and optic foramen, respectively, each with distinct branching patterns, a middle meningeal artery (MMA) with normal branches (i.e. anterior and posterior branches), and two branch variations (i.e. lacrimal and meningeal branches) that originated from the anterior branch of the MMA. The lacrimal branch coursed through a cranio-orbital foramen, but the meningeal branch remained outside the orbit. The anatomy of the right OA was normal. The left M-OA anomaly was considered incidental and not tumor-related since the tumor was more prominent on the right side, and no intra orbital infiltrations occurred. Of clinical significance is that proximal embolization of MA or MMA carries a high risk of visual impairment in cases where M-OA anomalies are the sole mode of supply to the eye. PMID- 25558433 TI - A rare case of aneurysm of arc of riolan artery and gastroduodenal artery. AB - Arc of Riolan is a collateral channel that connects the proximal superior mesenteric artery (SMA) or its middle colic branch and the proximal inferior mesenteric artery or its left colic branch in case of stenosis of either of the arteries. A 65-year-old diabetic female presented with vague abdominal pain. Ultrasonography showed a large aneurysm within the abdomen in the left lumbar region. Computed tomography (CT) angiography done showed severe diffuse atherosclerotic calcification of the abdominal aorta with complete occlusion of the celiac trunk and mild stenosis of SMA origin. The arc of Riolan was seen between the middle colic artery and the ascending branch of the left colic artery, with a large saccular aneurysm in its mid section. No evidence of rupture or hematoma was visible. Another saccular aneurysm was also seen involving the gastro-duodenal and the pancreatico-duodenal collateral arcade. As far as we know, this is the first case of arc of Riolan artery aneurysm to be reported in English literature. PMID- 25558434 TI - Management of Bleeding Duodenal Varices with Combined TIPS Decompression and Trans-TIPS Transvenous Obliteration Utilizing 3% Sodium Tetradecyl Sulfate Foam Sclerosis. AB - OBJECTIVES: Endoscopic experience in the management of duodenal varices (DVs) is limited and challenging given the anatomic constraints and limited experience. The endovascular management of DVs is not yet established and the controversy of whether to manage them by decompression with a transjugular intrahepatic portosystemic shunt (TIPS) or by transvenous obliteration is unresolved. In the literature, the 6-12 month rebleeding rate of DVs after TIPS is 21-37% and after transvenous obliteration is 13%. The purpose of the study is to evaluate the clinical outcome of combined TIPS decompression and transvenous obliteration/sclerosis. MATERIALS AND METHODS: This is a retrospective study (case series) of two institutions, evaluating patients who underwent TIPS and/or transvenous obliteration/sclerosis for bleeding DVs (from January 2009 to June 2013). TIPS was performed according to a standard procedure using covered stents. Transvenous obliteration (variceal sclerosis) from the systemic and/or portal venous circulation was performed utilizing 3% sodium tetradecyl sulfate foam. Transvenous obliteration was commonly augmented with coils and/or vascular plugs. Technical (technical success of establishing TIPS and completely obliterating the DVs) and clinical outcomes (rebleeding rate and survival) were evaluated. RESULTS: Five patients with liver cirrhosis presenting with bleeding DVs were included in the study with all eventually (and coincidentally) receiving TIPS and transvenous obliteration. Two of the five patients underwent concomitant TIPS and transvenous obliteration in the same procedural setting. However, three patients underwent transvenous obliteration due to bleeding despite a patent TIPS that had been previously placed. The average time from TIPS placement to transvenous obliteration was 125 days (range: 3-324 days). After having both procedures, there was no rebleeding in the patients during a mean follow-up period of 22 months (6-50 months). Coils and/or metallic vascular plugs were used to augment the sclerosant obliteration in four of five patients. CONCLUSION: The combination of TIPS decompression and foam sclerosant transvenous obliteration appears to be effective in preventing rebleeding in this limited case series and compares favorably with the existing evidence for either approach [TIPS or balloon occluded retrograde transvenous obliteration (BRTO)] alone. PMID- 25558435 TI - Levoatriocardinal Vein: An Unusual Cause of Right-to-Left Shunting. AB - We present a case demonstrating an anomalous vessel connecting the left brachiocephalic vein and the left superior pulmonary vein, found incidentally on computed tomography (CT) imaging. This pulmonary-systemic venous connection, known as a levoatriocardinal vein, is a rare anomaly. In previous descriptions, this vessel has typically been associated with left-to-right shunt. Here, we describe the magnetic resonance imaging (MRI) and CT findings in a case with right-to-left shunting through the anomalous vessel likely secondary to elevated right cardiac pressure. PMID- 25558436 TI - Management of Mucoepidermoid Carcinoma of the Palate Utilizing (18)F-FDG PET/CT. AB - Salivary gland carcinomas are a clinically diverse group of neoplasms with histological patterns overlapping other tumors, thus complicating their diagnosis. Mucoepidermoid carcinoma (MEC), first described by Masson and Berger in 1924, is a well-recognized salivary gland neoplasm, accounting for 5-10% of all salivary gland tumors. MEC frequently involves the major salivary glands and is rarely seen involving the jaws. The biological behavior of MEC is usually more aggressive with higher nodal and metastatic status at the time of presentation, which notably reduces the survival rate. Hence, early and accurate diagnosis utilizing advanced imaging modalities can reduce its morbidity. The present case is a rare presentation of MEC involving the palate, where (18) F fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was utilized for diagnosis and treatment. PMID- 25558437 TI - Physician and Family Recommendations to Obtain a Mammogram and Mammography Intentions: The Moderating Effects of Perceived Seriousness and Risk of Breast Cancer. AB - A growing body of literature has demonstrated psychosocial factors enable mammography intentions and usage among Latinas. Although these factors (e.g., family recommendations, breast cancer perceptions) likely influence one another, little research has examined interactive effects. The current study assessed the moderating effect of perceived breast cancer seriousness and risk on associations between recommendations to obtain mammography and mammography intentions. This sample included 97 Latinas in rural Eastern Washington State. After adjusting for age, two significant interactions emerged: perceived seriousness * physician recommendation and perceived risk * family recommendation. This exploratory study provides important directions for future communication research and planning to improve screening disparities. PMID- 25558439 TI - Carrots, Sticks and False Carrots: How high should weight control wellness incentives be? Findings from a population-level experiment. AB - Employers are increasingly using wellness incentives, including penalties for unhealthy behavior. Survey data suggests that people are willing to accept the principle of penalizing those perceived to take health risks, but the equally relevant question of the magnitude of acceptable penalties is unclear. While the principle of penalizing overweight and obese people has some support, findings from a population-level experiment (n=1,000) suggest that the acceptable size of penalties is comparatively small, around $50: more than 10-fold below levels favored by advocates. Reward-based incentives are favored over penalty-based ones by a factor of 4. Of two different ways of framing penalty programs, poorer and higher weight groups appear to find the one that is more overtly penalizing less acceptable. Levels of incentives matter on effectiveness as well as on ethical grounds, as it cannot be assumed that it is equally easy for all to meet health targets to secure a benefit or avoid a penalty. Programs should be designed to engage, not to frustrate those most in need of health improvement. Employee involvement in determining incentive types and levels, and explicit justification for program design can help both employees and employers to reap benefits. PMID- 25558438 TI - Trends in Fall-Related Traumatic Brain Injury among Older Persons in Connecticut from 2000-2007. AB - BACKGROUND: Anecdotal evidence suggests a rising trend in the occurrence of fall related traumatic brain injuries (FR-TBI) among persons >= 70 years. To document this apparent trend on a more substantive basis, this report longitudinally describes overall and age-stratified rates of three outcomes attributed to FR-TBI among persons >= 70 years: emergency department visits (ED), hospitalizations, and terminal hospitalizations. METHODS: Eight years (2000-2007) of observational data from emergency departments and acute care hospitals serving a non-randomly selected, densely populated region in southern Connecticut, U.S. RESULTS: From 2000-2007 among persons 70 years and older, overall rates of FR-TBI visits to emergency departments more than doubled while corresponding rates of hospitalization and terminal hospitalization rose 58% each. The point estimate of growth in the rate of ED in the oldest stratum was nearly triple that of the younger stratum whereas point estimates of growth in rates of hospitalization and terminal hospitalization were nearly four times higher. Total Medicare costs for ED visits increased nearly four-fold while corresponding costs for hospitalizations and terminal hospitalizations rose by 64% and 76%. The most common discharge diagnoses for ED and hospitalization were unspecified head injury and intracranial hemorrhage. CONCLUSIONS: The rapid rise in rates of FR TBI and associated Medicare costs underscore the urgent need to prevent this burgeoning source of human suffering and health care utilization. We believe the rise in rates is at least partially due to a greater public awareness of the outcome that has been facilitated by increasing use of diagnostic imaging in the ED and hospital. PMID- 25558440 TI - Virtual issue: molecular sensors. PMID- 25558441 TI - Sterically Demanding Unsymmetrical Diaryl-lambda(3)-iodanes for Electrophilic Pentafluorophenylation and an Approach to alpha-Pentafluorophenyl Carbonyl Compounds with an All-Carbon Stereocenter. AB - A sterically demanding unsymmetrical pentafluorophenyl-triisopropylphenyl lambda(3)-iodane was developed as an effective reagent for the electrophilic pentafluorophenylation of various beta-keto esters and a beta-keto amide. 17 examples of alpha-pentafluorophenylated 1,3-dicarbonyl compounds 3 having a quaternary carbon center are provided. The resulting compounds were nicely transformed into chiral alpha-pentafluorophenyl ketones with an all-carbon stereogenic center in high yields and high enantioselectivities using asymmetric organocatalysis (up to 98 % ee) or asymmetric metal catalysis (up to 82 % ee). PMID- 25558443 TI - Mixed aggregates of 1-methoxyallenyllithium with lithium chloride. AB - A combined computational and (13)C NMR study was used to investigate the formation of mixed aggregates of 1-methoxyallenyllithium and lithium chloride in tetrahydrofuran (THF) solution. The observed and calculated chemical shifts, as well as the calculated free energies of mixed aggregate formation (MP2/6 31+G(d)), are consistent with the formation of a mixed dimer as the major species in solution. Free energies of mixed dimer, trimer, and tetramer formation were calculated by using the B3LYP and MP2 methods and the 6-31+G(d) basis set. The two methods generated different predictions of which mixed aggregates will be formed, with B3LYP/6-31+G(d) favoring mixed trimers and tetramers in THF solution, and MP2/6-31+G(d) favoring mixed dimers. Formation of the sterically unhindered mixed dimers is also consistent with the enhanced reactivity of these compounds in the presence of lithium chloride. The spectra are also consistent with some residual 1-methoxyallenyllithium tetramer, as well as small amounts of higher mixed aggregates. Although neither computational method is perfect, for this particular system, the calculated free energies derived using the MP2 method are in better agreement with experimental data than those derived using the B3LYP method. PMID- 25558444 TI - Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides. AB - The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol 5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1+/-0.5 MUm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers. PMID- 25558442 TI - Multifunctional Benzothiadiazole-Based Small Molecules Displaying Solvatochromism and Sensing Properties toward Nitroarenes, Anions, and Cations. AB - Aryl or heteroaryl 5-substituted imidazo-benzothiadiazole derivatives were synthesized and shown to display remarkable solvatofluorochromism and selectively sense mercury(II) cations, acetate anions, and nitroaromatic derivatives, with discrimination between p-nitrophenol and picric acid. These novel sensors are of importance these days, as the detection of explosives is a high priority in issues of national security and environmental protection. To determine the ion binding properties of the sensors, their absorption and fluorescence emission spectra upon binding different cations and anions were compared. Significant shifts in the spectra were only observed for mercury(II) and acetate. The binding of these two ions was further studied using (1)H NMR. The binding properties of different nitroaromatic compounds were also determined, and the results showed the importance of the presence of a phenol group in the guest molecule. Specifically, the two sensors were shown to discriminate between p-nitrophenol and picric acid. Finally, the mechanism of fluorescence quenching upon addition of nitrophenols was determined by computational methods. PMID- 25558445 TI - A Highly Selective and Sensitive Turn-On Fluorescent Chemosensor Based on Rhodamine 6G for Iron(III). AB - Recently, more and more rhodamine derivatives have been used as fluorophores to construct sensors due to their excellent spectroscopic properties. A rhodamine based fluorescent and colorimetric Fe(3+) chemosensor 3',6'-bis(ethylamino)-2 acetoxyl-2',7'-dimethyl-spiro[1H-isoindole-1,9'-[9H]xanthen]-3(2H)-one (RAE) was designed and synthesized. Upon the addition of Fe(3+), the dramatic enhancement of both fluorescence and absorbance intensity, as well as the color change of the solution, could be observed. The detection limit of RAE for Fe(3+) was around 7.98 ppb. Common coexistent metal ions showed little or no interference in the detection of Fe(3+). Moreover, the addition of CN(-) could quench the fluorescence of the acetonitrile solution of RAE and Fe(3+), indicating the regeneration of the chemosensor RAE. The robust nature of the sensor was shown by the detection of Fe(3+) even after repeated rounds of quenching. As iron is a ubiquitous metal in cells and plays vital roles in many biological processes, this chemosensor could be developed to have applications in biological studies. PMID- 25558446 TI - Mass spectrometry of synthetic polysiloxanes: from linear models to plasma polymer networks. PMID- 25558447 TI - Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. AB - BACKGROUND: Billions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown. METHODS & RESULTS: Using a newly developed fortilin ELISA system, we show here that fortilin exists in the normal human and mouse circulation. We further demonstrate that fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. In addition, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increased serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptosed and released fortilin into the medium before plasma membrane integrity was compromised. CONCLUSIONS: Taken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo. GENERAL SIGNIFICANCE: Fortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans. PMID- 25558448 TI - O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma. AB - BACKGROUND: CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti resistance therapies. METHODS: We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). RESULTS: Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P <= 0.001) and continuous (P <= 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P <= 0.005) and longer PFS (P <= 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P <= 0.005), and among unmethylated tumors with less than median activity (P <= 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs. CONCLUSIONS: Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas. GENERAL SIGNIFICANCE: MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status. PMID- 25558449 TI - Pathognomonic features of Angle's Class II division 2 malocclusion: A comparative cephalometric and arch width study. AB - BACKGROUND: A thorough knowledge of the salient features of malocclusion helps the clinician in arriving at a proper diagnosis and treatment plan, and also to predict the prognosis, prior to the onset of treatment process. Among the four classes of Angle's classification of malocclusion, Class II division 2 occurs with the least frequency. There is still continuing debate in the literature whether the Class II division 2 patients ascribe the pathognomonic skeletal and dental features. AIM OF THE STUDY: The aim of this study is to describe the unique features of Angle's Class II division 2 malocclusion to differentiate it from Angle's Class II division 1 malocclusion. MATERIALS AND METHODS: A total of 582 pre-treatment records (study models and cephalograms), with the age of patients ranging from 15 to 22 years, were obtained from the hospital records of Vishnu Dental College, Bhimavaram and Geetam's Dental College, Visakhapatnam. Out of these, 11 pre-treatment records were excluded because of lack of clarity. In the rest of the sample, 283 were Class II division 1 and 288 were Class II division 2. The lateral cephalograms were analyzed by using digiceph and the arch width analysis was done based on the anatomical points described by Staley et al. and Sergl et al. RESULTS: An intergroup evaluation was done by using unpaired Student's "t" test. The skeletal vertical parameters, dental parameters, and the maxillary arch width parameters revealed a statistically significant difference between the two groups of malocclusion. CONCLUSION: Angle's Class II division 2 malocclusion has a pronounced horizontal growth pattern with decreased lower anterior facial height, retroclined upper anteriors, and significantly increased maxillary arch width parameters. PMID- 25558450 TI - Assessment of effectiveness of smoking cessation intervention among male prisoners in India: A randomized controlled trial. AB - BACKGROUND: Tobacco smoking is an integral part of prison life and an established part of the culture. Little attention has been paid to prevention of smoking in prison. Approximately 70-80% of prisoners have been identified as current smokers. AIM: To assess the effectiveness of smoking cessation intervention among male prisoners at Central Jail, Bangalore city. AIM: To assess the effectiveness of smoking cessation intervention among male prisoners at Central Jail, Bangalore city. MATERIALS AND METHODS: A randomized controlled trial was planned among male prisoners in Central Jail, Bangalore city. There were 1600 convicted prisoners. A self-administered questionnaire was given to the prisoners to assess their smoking behavior by which prevalence of tobacco smoking was found. Exactly 1352 tobacco users were studied. Among them, there were 1252 smokers. Based on inclusion criteria and informed consent given by the prisoners, a sample of 600 was chosen for the study by systematic random sampling. Among the 600 prisoners, 300 were randomly selected for the study group and 300 for the control group. RESULTS: Prevalence of tobacco smoking among the prisoners was 92.60%. In the present study, after smoking cessation intervention, 17% showed no change in smoking, 21.66% reduced smoking, 16% stopped smoking, and 45.33% relapsed (P < 0.0001) at the end of 6-month follow-up in the study group. CONCLUSION: Tobacco use was high among the prisoners. Tobacco reduction is possible in the prison even if the living conditions are not favorable. Relatively high rate of relapse in our study indicates that some policies should be adopted to improve smokers' information on consequences of tobacco on health and motivational intervention should be added to prisoners. PMID- 25558451 TI - Effect of aqueous and alcoholic Stevia (Stevia rebaudiana) extracts against Streptococcus mutans and Lactobacillus acidophilus in comparison to chlorhexidine: An in vitro study. AB - INTRODUCTION: Stevia (S. rebaudiana) a herb which has medicinal value and was used in ancient times as a remedy for a great diversity of ailments and sweetener. Leaves of Stevia contain a high concentration of Stevioside and Rebaudioside which are supposed to be sweetening agents. AIM: To compare the efficacy of aqueous and alcoholic S. rebaudiana extract against Streptococcus mutans and Lactobacillus acidophilus in comparison to chlorhexidine. MATERIALS AND METHODS: In the first part of the study, various concentrations of aqueous and ethanolic Stevia extract were prepared in the laboratory of Pharmacy College. It was then subjected to microbiological assay to determine its zone of inhibition using Agar disk diffusion test and minimum inhibitory concentration (MIC) using serial broth dilution method against Streptococcus mutans and Lactobacillus acidophilus. Chlorhexidine was used as a positive control. One way Analysis of Variance (ANOVA) test was used for multiple group comparisons followed by Tukey post hoc for group wise comparisons. RESULTS: Minimum inhibitory concentration (MIC) of aqueous and ethnolic Stevia extract against Streptococcus mutans and Lactobacillus acidophilus were 25% and 12.5% respectively. Mean zone of inhibition of the aqueous and alcoholic Stevia extracts against Streptococcus mutans at 48 hours were 22.8 mm and 26.7 mm respectively. Mean zone of inhibition of the aqueous and alcoholic Stevia extracts against Lactobacillus acidophilus at 48 hours were 14.4 mm and 15.1 mm respectively. Mean zone of inhibition of the chlorhexidine against Streptococcus mutans and Lactobacillus acidophilus at 48 hours was 20.5 and 13.2 respectively. CONCLUSION: The inhibitory effect shown by alcoholic Stevia extract against Streptococcus mutans and Lactobacillus acidophilus was superior when compared with that of aqueous form and was inferior when compared with Chlorhexidine. PMID- 25558452 TI - Use of mid upper arm circumference for evaluation of nutritional status of OSMF patients. AB - BACKGROUND: Oral submucous fibrosis (OSMF) is always associated with juxtaepithelial inflammatory reaction followed by fibroblastic changes in lamina propria, with epithelial atrophy leading to stiffness of oral mucosa and causing trismus and inability to eat. Mid upper arm circumference (MUAC) is a useful tool for a fast assessment of the nutritional status. AIMS: The study was undertaken to evaluate the correlation of MUAC as a nutritional status indicator in OSMF patients. PATIENTS AND METHODS: The study group comprised 50 clinically diagnosed and histopathologically confirmed cases of OSMF. MUAC was recorded using a plastic measuring tape. The right upper arm was measured at the midpoint between the tip of the shoulder and the tip of the elbow (olecranon process and the acromium). RESULTS: Out of 50 subjects, 76% (38) were having MUAC value <23 cm, which shows an inverse relation between MUAC and clinical staging. The relation of MUAC with clinical staging was significant. CONCLUSION: The patient with OSMF becomes unable to eat due to burning, ulcers, and inability to open mouth, which affects the health of the individual. Thus, it is crucial to access the nutritional status to improve the survival rate of patients. PMID- 25558453 TI - Effects of herbal and non-herbal toothpastes on plaque and gingivitis: A clinical comparative study. AB - BACKGROUND: Presence of plaque may be the culprit for dental caries, gingivitis, periodontal problems, and halitosis. Many mechanical aids are practiced worldwide to remove or control plaque, including tooth brushes, dental floss, mouth rinses, and dentifrices. The objective of this clinical study was to investigate the effectiveness of herbal toothpaste (Dabur Red) in controlling plaque and gingivitis, as compared to conventional (non-herbal) dentifrice (Pepsodent). MATERIALS AND METHODS: In this study, 30 subjects aged 35-43 years with established gingivitis and at least 20 natural teeth, and having a probing depth <3 mm were investigated. After the washout period, plaque and gingival index (PI and GI, respectively) scores were assessed at days 0 and 30. Differences between groups were compared with Mann-Whitney U test and the mean scores of PI and GI by Wilcoxon test. Statistical difference between the weights of dentifrices tubes on days 0 and 30 was evaluated by Student's t-test. RESULTS: At the end of 30 days of the study, there was statistically significant difference between both the groups for plaque and gingival scores. CONCLUSION: After 30 days of trial, both test and control groups showed effective reduction of plaque and gingivitis, which was statistically significant. No adverse reactions to dentifrices products were observed during the trial. It was concluded that herbal dentifrice was as effective as non-herbal dentifrices in the control of plaque and gingivitis. PMID- 25558454 TI - Dental insurance: A systematic review. AB - To review uses of finance in dentistry. A search of 25 electronic databases and World Wide Web was conducted. Relevant journals were hand searched and further information was requested from authors. Inclusion criteria were a predefined hierarchy of evidence and objectives. Study validity was assessed with checklists. Two reviewers independently screened sources, extracted data, and assessed validity. Insurance has come of ages and has become the mainstay of payment in many developed countries. So much so that all the alternative forms of payment which originated as an alternative to fee for service now depend on insurance at one point or the other. Fee for service is still the major form of payment in many developing countries including India. It is preferred in many instances since the payment is made immediately. PMID- 25558455 TI - Biomimetic ceramics for periodontal regeneration in infrabony defects: A systematic review. AB - Biomimetic materials are widely used in the treatment of osseous defects as an alternative to autogenous bone graft. The aim of this article was to review the literature and compare the quality of published articles on biomimetic ceramic material used for periodontal regeneration in the treatment of infrabony defects and to discuss the future direction of research. The bibliographic databases PubMed, Ebsco, and Google Scholar were searched from January 2000 to March 2014 for randomized control trials in which biomimetic ceramic graft material was compared with open flap debridement or in combination with any other regenerative material. To avoid the variability of the search terms, the thesaurus Mesh was used. The primary outcome variable assessed was clinical attachment level (CAL). The screening of eligible studies, assessment of the methodological quality of the trials, and data extraction were performed by two observers independently. Twenty-six articles were identified and included in this systematic review. The primary outcome was CAL. Out of the 26 studies, 24 showed more than 2 mm of CAL gain. The difference in CAL change between test and control groups varied from 1.2 mm to 5.88 mm with respect to different biomaterials/biomimetic materials, which was clinically and statistically significant. Meta-analysis was not done due to heterogeneity in results between studies. Overall, biomaterials were found to be more effective than open flap debridement in improving the attachment levels in intraosseous defects. Future research should aim at increasing the osteoinductive capacity of these biomimetic graft materials. PMID- 25558456 TI - Preschool children's caregivers' attitudes and behavior regarding bottle feeding in Bangpakong, Chachoengsao. AB - OBJECTIVES: To study a group of preschool children's caregivers' attitudes and behavior regarding bottle feeding in Bangpakong, Chachoengsao. MATERIALS AND METHODS: The study sample comprised 320 caregivers of preschool children aged 3-6 years, who were attending the public preschools in Bangpakong, Chachoengsao, and they completed self-administered questionnaires. The questionnaires had information about demographic data, weaning status, the feeding practices for children who were still on a bottle, and the caregivers' attitudes on bottle feeding according to weaning status. RESULTS: Of these children, 38.4% were still on a bottle while 61.6% had been weaned. Mean age at the weaning time was 3.1 +/- 0.6 years. The most common reason that led caregivers of bottle feeding group to allow continuation of the habit was the child refused to wean. Of these caregivers, 56% lacked knowledge concerning the appropriate weaning time and that the use of bottles should be actively discouraged for children after 1 year of age. Attitudes between bottle feeding and weaned groups were significantly different (P < 0.05) in the following: a child should be introduced to drink from cup after 1 year of age, nursing bottle works best to stop a child from crying, early weaning results in poor mental health, and early weaning results in malnutrition. CONCLUSION: Prolonged bottle feeding beyond the recommended age was found in the majority of preschool children in this study. Dental professions should provide oral health promotion education program including feeding practice information to caregivers. PMID- 25558457 TI - The influence of finishing/polishing time and cooling system on surface roughness and microhardness of two different types of composite resin restorations. AB - OBJECTIVE: The aim of this study was to evaluate the effect of finishing time and polishing time on surface roughness and microhardness of nanofilled and hybrid resin composites. MATERIALS AND METHODS: Hundred disk composite specimens from micro hybrid composite and nanohybrid composite were prepared, 50 for each type of composite. The specimens were divided into five groups according to the time of finishing and polishing (immediate, 15 min, 24 h and dry). Composite under the Mylar strip without finishing and polishing was taken as the control group. Surface roughness was measured with environmental scanning electronic microscope (ESEM) and microhardness was determined using Vickers Microhardness Tester. Data collected were statistically analyzed by t-test and one-way analysis of variance (ANOVA) followed by Turkey's post hoc test. RESULTS: Smooth surface with low hardness was obtained for the group under Mylar strip without finishing and polishing. The highest roughness was recorded for delayed finishing and polishing for both composites. Immediate finishing and polishing increased the surface hardness more than that in the control group in both types of composites. Dry finishing reduced the hardness significantly for micro hybrid composite, but resulted in the highest surface hardness for nanofilled composite. CONCLUSION: Immediate finishing and polishing under coolant resulted in the best surface smoothness and hardness values in micro hybrid composite; however, immediate dry finishing and polishing gave the best smoothness and hardness values in nanohybrid composite. PMID- 25558458 TI - Theory of Mind Development is Impaired in 4-year-old Children with Prenatal Exposure to Maternal Tobacco Smoking. AB - AIMS: Theory of Mind (ToM) is an important component of social cognition. Deficits in ToM are found in various neurodevelopmental disorders and social and environmental factors have been found to influence ToM development. Little previous research has focused on effects of exposure to toxins; this report examines the impact of tobacco. PLACE OF STUDY: Department of Psychiatry, University of Colorado School of Medicine, between April 2006 - August 2012. METHODOLOGY: 101 children, 18 with prenatal exposure to tobacco, underwent ToM testing at 40 (n=89) and 48 (n=77) months of age. Test questions received dichotomous pass/fail scores and percentage of correct responses was utilized as the primary dependent variable. RESULTS: At 40 months of age children were rarely able to correctly answer false belief questions and there were no significant differences according to prenatal tobacco exposure. At 48 months of age, there was a significant effect of prenatal tobacco exposure with non-exposed 48-month olds correctly answering 45+/-40.6% of content false belief questions correctly, compared to 13.9+/-25.3% for 48-month-olds with prenatal tobacco exposure (F=4.79, df= 1,73, p=.032). CONCLUSION: ToM abilities are rapidly developing between 40 and 48 months of age. Prenatal exposure to tobacco is associated with impairment at 48 but not 40 months of age. This finding supports consideration of nicotinic mechanisms as contributors to early development of social cognition. PMID- 25558459 TI - In Six-month-old Infants, Prenatal Exposure to Maternal Anxiety is Associated with Less Developed Smooth Pursuit Eye Movements: An Initial Study. AB - AIMS: There are an increasing number of reports suggesting an association between maternal anxiety experienced during pregnancy and adverse outcomes of the offspring. However, exploration of the biological changes in the brain that mediate that relationship has been hampered by the lack of appropriate biomarkers. This report represents an initial step exploring whether a potential infant biomarker, smooth pursuit eye movements, may be associated with prenatal exposure to maternal anxiety. STUDY DESIGN: Blinded cross-sectional study. PLACE AND DURATION OF STUDY: Department of Psychiatry, University of Colorado School of Medicine. Data collected from July 2011 to May 2012. METHODOLOGY: Forty-three infants including 34 whose prenatal maternal anxiety status was identified (12 with a known maternal prenatal anxiety diagnosis and 22 without) had eye movements recorded during a smooth pursuit eye movement task at four and/or six months of age. RESULTS: At 6 months of age, infants with prenatal exposure to maternal anxiety, compared to infants without such exposure, spent a higher percentage of time utilizing smooth pursuit (t=2.7, df=24, P=.013), had longer duration of smooth pursuit uninterrupted by saccades (t=2.5, df=24, P=.019), and had decreased frequency of forward saccades (t=3.8, df=24, P=.001). No differences between groups were identified at 4 months of age. CONCLUSION: Smooth pursuit abnormalities may, at six months of age, be a potential biomarker for prenatal maternal anxiety exposure. PMID- 25558461 TI - Engraftment potential of dermal fibroblasts following in vivo myogenic conversion in immunocompetent dystrophic skeletal muscle. AB - Autologous dermal fibroblasts are promising candidates for enhancing muscle regeneration in Duchenne muscular dystrophy (DMD) due to their ease of isolation, immunological compatibility, and greater proliferative potential than DMD satellite cells. We previously showed that mouse fibroblasts, after MyoD-mediated myogenic reprogramming in vivo, engraft in skeletal muscle and supply dystrophin. Assessing the therapeutic utility of this system requires optimization of conversion and transplantation conditions and quantitation of engraftment so that these parameters can be correlated with possible functional improvements. Here we derived dermal fibroblasts from transgenic mice carrying mini-dystrophin, transduced them by lentivirus carrying tamoxifen-inducible MyoD, and characterized their myogenic and engraftment potential. After cell transplantation into muscles of immunocompetent dystrophic mdx4cv mice, tamoxifen treatment drove myogenic conversion and fusion into myofibers that expressed high levels of mini-dystrophin. Injecting 50,000 cells/microliter (1 * 106 total cells) resulted in a peak of ~600 mini-dystrophin positive myofibers in TA muscle single cross-sections. However, EDL muscles with up to 30% regional engraftment showed no functional improvements; similar limitations were obtained with whole muscle mononuclear cells. Despite the current lack of physiological improvement, this study suggests a viable initial strategy for using a patient-accessible dermal cell population to enhance skeletal muscle regeneration in DMD. PMID- 25558462 TI - Correspondence of electroencephalography and near-infrared spectroscopy sensitivities to the cerebral cortex using a high-density layout. AB - This study investigates the correspondence of the cortical sensitivity of electroencephalography (EEG) and near-infrared spectroscopy (NIRS). EEG forward model sensitivity to the cerebral cortex was calculated for 329 EEG electrodes following the 10-5 EEG positioning system using a segmented structural magnetic resonance imaging scan of a human subject. NIRS forward model sensitivity was calculated for the same subject using 156 NIRS source-detector pairs selected from 32 source and 32 detector optodes positioned on the scalp using a subset of the 10-5 EEG positioning system. Sensitivity correlations between colocalized NIRS source-detector pair groups and EEG channels yielded R = 0.46 +/- 0.08. Groups of NIRS source-detector pairs with maximum correlations to EEG electrode sensitivities are tabulated. The mean correlation between the point spread functions for EEG and NIRS regions of interest (ROI) was R = 0.43 +/- 0.07. Spherical ROIs with radii of 26 mm yielded the maximum correlation between EEG and NIRS averaged across all cortical mesh nodes. These sensitivity correlations between EEG and NIRS should be taken into account when designing multimodal studies of neurovascular coupling and when using NIRS as a statistical prior for EEG source localization. PMID- 25558460 TI - Development of Gene Transfer for Induction of Antigen-specific Tolerance. AB - Gene replacement therapies, like organ and cell transplantation are likely to introduce neo-antigens that elicit rejection via humoral and/or effector T cell immune responses. Nonetheless, thanks to an ever growing body of pre-clinical studies it is now well accepted that gene transfer protocols can be specifically designed and optimized for induction of antigen-specific immune tolerance. One approach is to specifically express a gene in a tissue with a tolerogenic microenvironment such as the liver or thymus. Another strategy is to transfer a particular gene into hematopoietic stem cells or immunological precursor cells thus educating the immune system to recognize the therapeutic protein as "self". In addition, expression of the therapeutic protein in pro-tolerogenic antigen presenting cells such as immature dendritic cells and B cells has proven to be promising. All three approaches have successfully prevented unwanted immune responses in pre-clinical studies aimed at the treatment of inherited protein deficiencies, e.g. lysosomal storage disorders and hemophilia, and of type I diabetes and multiple sclerosis. In this review we focus on current gene transfer protocols that induce tolerance, including gene delivery vehicles and target tissues, and discuss successes and obstacles in different disease models. PMID- 25558463 TI - Coregistering functional near-infrared spectroscopy with underlying cortical areas in infants. AB - Functional near-infrared spectroscopy (fNIRS) is becoming a popular tool in developmental neuroscience for mapping functional localized brain responses. However, as it cannot provide information about underlying anatomy, researchers have begun to conduct spatial registration of fNIRS channels to cortical anatomy in adults. The current work investigated this issue with infants by coregistering fNIRS and magnetic resonance imaging (MRI) data from 55 individuals. Our findings suggest that fNIRS channels can be reliably registered with regions in the frontal and temporal cortex of infants from 4 to 7 months of age. Although some macro-anatomical regions are difficult to consistently define, others are more stable and fNIRS channels on an age-appropriate MRI template are often consistent with individual infant MRIs. We have generated a standardized scalp surface map of fNIRS channel locators to reliably locate cortical regions for fNIRS developmental researchers. This new map can be used to identify the inferior frontal gyrus, superior temporal sulcus (STS) region [which includes the superior and middle temporal gyri (MTG) nearest to the STS], and MTG and temporal-parietal regions in 4- to 7-month-old infants. Future work will model data for the whole head, taking into account the properties of light transport in tissue, and expanding to different ages across development. PMID- 25558464 TI - Fast calcium sensor proteins for monitoring neural activity. AB - A major goal of the BRAIN Initiative is the development of technologies to monitor neuronal network activity during active information processing. Toward this goal, genetically encoded calcium indicator proteins have become widely used for reporting activity in preparations ranging from invertebrates to awake mammals. However, slow response times, the narrow sensitivity range of Ca2+ and in some cases, poor signal-to-noise ratio still limit their usefulness. Here, we review recent improvements in the field of neural activity-sensitive probe design with a focus on the GCaMP family of calcium indicator proteins. In this context, we present our newly developed Fast-GCaMPs, which have up to 4-fold accelerated off-responses compared with the next-fastest GCaMP, GCaMP6f. Fast-GCaMPs were designed by destabilizing the association of the hydrophobic pocket of calcium bound calmodulin with the RS20 binding domain, an intramolecular interaction that protects the green fluorescent protein chromophore. Fast-GCaMP6f-RS06 and Fast GCaMP6f-RS09 have rapid off-responses in stopped-flow fluorimetry, in neocortical brain slices, and in the intact cerebellum in vivo. Fast-GCaMP6f variants should be useful for tracking action potentials closely spaced in time, and for following neural activity in fast-changing compartments, such as axons and dendrites. Finally, we discuss strategies that may allow tracking of a wider range of neuronal firing rates and improve spike detection. PMID- 25558465 TI - Impact of family structure and common environment on heritability estimation for neuroimaging genetics studies using Sequential Oligogenic Linkage Analysis Routines. AB - Imaging genetics is an emerging methodological field that combines genetic information with medical imaging-derived metrics to understand how genetic factors impact observable phenotypes. In order for a trait to be a reasonable phenotype in an imaging genetics study, it must be heritable: at least some proportion of its variance must be due to genetic influences. The Sequential Oligogenic Linkage Analysis Routines (SOLAR) imaging genetics software can estimate the heritability of a trait in complex pedigrees. We investigate the ability of SOLAR to accurately estimate heritability and common environmental effects on simulated imaging phenotypes in various family structures. We found that heritability is reliably estimated with small family-based studies of 40 to 80 individuals, though subtle differences remain between the family structures. In an imaging application analysis, we found that with 80 subjects in any of the family structures, estimated heritability of white matter fractional anisotropy was biased by <10% for every region of interest. Results from these studies can be used when investigators are evaluating power in planning genetic analyzes. PMID- 25558466 TI - Evaluation of Multi-Atlas Label Fusion for In Vivo MRI Orbital Segmentation. AB - Multi-atlas methods have been successful for brain segmentation, but their application to smaller anatomies remains relatively unexplored. We evaluate 7 statistical and voting-based label fusion algorithms (and 6 additional variants) to segment the optic nerves, eye globes and chiasm. For non-local STAPLE, we evaluate different intensity similarity measures (including mean square difference, locally normalized cross correlation, and a hybrid approach). Each algorithm is evaluated in terms of the Dice overlap and symmetric surface distance metrics. Finally, we evaluate refinement of label fusion results using a learning based correction method for consistent bias correction and Markov random field regularization. The multi-atlas labeling pipelines were evaluated on a cohort of 35 subjects including both healthy controls and patients. Across all three structures, NLSS with a mixed weighting type provided the most consistent results; for the optic nerve NLSS resulted in a median Dice similarity coefficient of 0.81, mean surface distance of 0.41 mm and Hausdorff distance 2.18 mm for the optic nerves. Joint label fusion resulted in slightly superior median performance for the optic nerves (0.82, 0.39 mm and 2.15 mm), but slightly worse on the globes. The fully automated multi-atlas labeling approach provides robust segmentations of orbital structures on MRI even in patients for whom significant atrophy (optic nerve head drusen) or inflammation (multiple sclerosis) is present. PMID- 25558467 TI - Cold Climate Is a Risk Factor for Thyroid Cancer. AB - BACKGROUND: The incidence rates of differentiated thyroid cancers of all sizes increased between 1988 and 2005 in both men and women. Exposure to ionizing radiation is the best-established environmental risk factor for thyroid cancer. Nonionizing radiation from cell phones has also been implicated. A positive correlation between all-cancer incidence rates and latitude and an inverse correlation between all-cancer incidence rates and temperature have been reported. In the present study, we examined the relationship between thyroid cancer incidence and average temperature in 50 U.S. states. METHODS: The age adjusted incidence of thyroid cancer is from U.S. Cancer Statistics Working Group, United States Cancer Statistics: 1999-2010, Incidence and Mortality Web based Report (Atlanta: Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2013, available at: www.cdc.gov/uscs). Average temperature by state is from the National Climatic Data Center, National Oceanic and Atmospheric Administration (http://www.ncdc.noaa.gov). Information on high-impact exposure to nuclear radiation by state is from the National Radiation Exposure Screening and Education Program, U.S. Health Resources and Services Administration (http://www.hrsa.gov/gethealthcare/conditions/radiationexposure). Cell-phone subscriber data for 2007 is from the Governing State and Local Sourcebook (http://sourcebook.governing.com). Mean elevation and latitude of U.S. states is from "Elevations and Distances in the United States," Reston, VA: U.S. Geological Survey, April 29, 2005 (http://pubs.er.usgs.gov). RESULTS: There was a significant negative correlation between average temperature by state and the age adjusted incidence of all thyroid cancers (r2 = -0.212, P = 0.001). Because of the possible effects of ionizing radiation exposure from nuclear testing and nonionizing radiation exposure from cell phones, multiple linear regression analysis was performed. The analysis was done only for all thyroid cancers and for thyroid cancers in whites. The data from blacks and Hispanics were too fragmentary to analyze. In all thyroid cancers and thyroid cancers in whites, there was a significant negative correlation between average temperature and incidence that was unrelated to nuclear testing, cell-phone use, altitude, and latitude and was independent of the significant correlation of cell-phone subscriptions per population with thyroid cancer in whites. CONCLUSIONS: Living in a cold-climate state, such as Alaska, doubles the risk of thyroid cancer as compared with a warm state such as Texas. Because of climate change, a significantly raised risk of heat-related and cold-related mortality is expected in the years to come. The elderly will be most at risk. No doubt, incidence patterns of thyroid cancer and other cancers may be affected. PMID- 25558468 TI - Identifying pediatric cancer clusters in Florida using loglinear models and generalized lasso penalties. AB - We discuss the identification of pediatric cancer clusters in Florida between 2000 and 2010 using a penalized generalized linear model. More specifically, we introduce a Poisson model for the observed number of cases on each of Florida's ZIP Code Tabulation Areas (ZCTA) and regularize the associated disease rate estimates using a generalized Lasso penalty. Our analysis suggests the presence of a number of pediatric cancer clusters during the period over study, with the largest ones being located around the cities of Jacksonville, Miami, Cape Coral/Fort Meyers and Palm Beach. PMID- 25558469 TI - Multi-view optical resolution photoacoustic microscopy. AB - Optical resolution photoacoustic microscopy (OR-PAM), while providing high lateral resolution, has been limited by its relatively poor acoustically determined axial resolution. Although this limitation has been tackled in recent works by using either broadband acoustic detection or nonlinear photoacoustic effects, a flexible solution with three dimensional optical resolution in reflection mode remains desired. Herein we present a multi-view OR-PAM technique. By imaging the sample from multiple view angles and reconstructing the data using a multi-view deconvolution method, we have experimentally demonstrated an isotropic optical resolution in three dimensions. PMID- 25558471 TI - Cell survival is dicey without Dicer. AB - The cellular requirements of Dicer, an essential miRNA processing enzyme, and the consequences of altered levels of it on tumorigenesis are incompletely understood. We review the effects of Dicer loss in cells of different origin and whether loss of p53 permits cell survival and growth in the absence of Dicer. PMID- 25558472 TI - Learning to Rank the Severity of Unrepaired Cleft Lip Nasal Deformity on 3D Mesh Data. AB - Cleft lip is a birth defect that results in deformity of the upper lip and nose. Its severity is widely variable and the results of treatment are influenced by the initial deformity. Objective assessment of severity would help to guide prognosis and treatment. However, most assessments are subjective. The purpose of this study is to develop and test quantitative computer-based methods of measuring cleft lip severity. In this paper, a grid-patch based measurement of symmetry is introduced, with which a computer program learns to rank the severity of cleft lip on 3D meshes of human infant faces. Three computer-based methods to define the midfacial reference plane were compared to two manual methods. Four different symmetry features were calculated based upon these reference planes, and evaluated. The result shows that the rankings predicted by the proposed features were highly correlated with the ranking orders provided by experts that were used as the ground truth. PMID- 25558473 TI - Vocabulary Knowledge of Deaf and Hearing Postsecondary Students. AB - Deaf children generally are found to have smaller English vocabularies than hearing peers, although studies involving children with cochlear implants have suggested that the gap may decrease or disappear with age. Less is known about the vocabularies of deaf and hard-of-hearing (DHH) postsecondary students or how their vocabulary knowledge relates to other aspects of academic achievement. This study used the Peabody Picture Vocabulary Test to examine the vocabulary knowledge of DHH and hearing postsecondary students as well as their awareness (predictions) of that knowledge. Relationships between vocabulary knowledge and print exposure, communication backgrounds, and reading and verbal abilities also were examined. Consistent with studies of children, hearing college students demonstrated significantly larger vocabularies than DHH students both with and without cochlear implants. DHH students were more likely to overestimate their vocabulary knowledge. Vocabulary scores were positively related to reading and verbal abilities but negatively related to sign language abilities. Among DHH students they also were positively related to measures of spoken language ability. Results are discussed in terms of related cognitive abilities, language fluency, and academic achievement of DHH students and implications for postsecondary education. PMID- 25558474 TI - AptaCluster - A Method to Cluster HT-SELEX Aptamer Pools and Lessons from its Application. AB - Systematic Evolution of Ligands by EXponential Enrichment (SELEX) is a well established experimental procedure to identify aptamers - synthetic single stranded (ribo)nucleic molecules that bind to a given molecular target. Recently, new sequencing technologies have revolutionized the SELEX protocol by allowing for deep sequencing of the selection pools after each cycle. The emergence of High Throughput SELEX (HT-SELEX) has opened the field to new computational opportunities and challenges that are yet to be addressed. To aid the analysis of the results of HT-SELEX and to advance the understanding of the selection process itself, we developed AptaCluster. This algorithm allows for an efficient clustering of whole HT-SELEX aptamer pools; a task that could not be accomplished with traditional clustering algorithms due to the enormous size of such datasets. We performed HT-SELEX with Interleukin 10 receptor alpha chain (IL-10RA) as the target molecule and used AptaCluster to analyze the resulting sequences. AptaCluster allowed for the first survey of the relationships between sequences in different selection rounds and revealed previously not appreciated properties of the SELEX protocol. As the first tool of this kind, AptaCluster enables novel ways to analyze and to optimize the HT-SELEX procedure. Our AptaCluster algorithm is available as a very fast multiprocessor implementation upon request. PMID- 25558470 TI - Constructing the toolbox: Patient-specific genetic factors of altered fracture healing. AB - The multifaceted sequence of events that follow fracture repair can be further complicated when considering risk factors for impaired union, present in a large and growing percentage of the population. Risk factors such as diabetes, substance abuse, and poor nutrition affect both the young and old alike, and have been shown to dramatically impair the body's natural healing processes. To this end, biotherapeudic interventions such as ultrasound, electrical simulation, growth factor treatment (BMP-2, BMP-7, PDGF-BB, FGF-2) have been evaluated in preclinical models and in some cases are used widely for patients with established non-union or risk/indication or impaired healing (ie. ultrasound, BMP 2, etc.). Despite the promise of these interventions, they have been shown to be reliant on patient compliance and can produce adverse side-effects such as heterotopic ossification. Gene and cell therapy approaches have attempted to apply controlled regimens of these factors and have produced promising results. However, there are safety and efficacy concerns that may limit the translation of these approaches. In addition, none of the above mentioned approaches consider genetic variation between individual patients. Several clinical and preclinical studies have demonstrated a genetic component to fracture repair and that SNPs and genetic background variation play major roles in the determination of healing outcomes. Despite this, there is a need for preclinical data to dissect the mechanism underlying the influence of specific gene loci on the processes of fracture healing, which will be paramount in the future of patient-centered interventions for fracture repair. PMID- 25558476 TI - Multivariate statistical methodologies applied in biomedical Raman spectroscopy: assessing the validity of partial least squares regression using simulated model datasets. AB - Raman spectroscopy is fast becoming a valuable analytical tool in a number of biomedical scenarios, most notably disease diagnostics. Importantly, the technique has also shown increasing promise in the assessment of drug interactions on cellular and subcellular levels, particularly when coupled with multivariate statistical analysis. However, with respect to both Raman spectroscopy and the associated statistical methodologies, an important consideration is the accuracy of these techniques and more specifically, the sensitivities which can be achieved, and ultimately the limits of detection of the various methods. The purpose of this study is thus the construction of a model simulated dataset with the aim of testing the accuracy and sensitivity of the partial least squares regression (PLSR) approach to spectral analysis. The basis of the dataset is the experimental spectral profiles of a previously reported Raman spectroscopic analysis of the interaction of the cancer chemotherapeutic agent cisplatin in an adenocarcinomic human alveolar basal epithelial cell-line, in vitro, and is thus reflective of actual experimental data. The simulated spectroscopic data are constructed by adding known perturbations which are independently linear in drug doses as well as cytological responses experimentally determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) cytotoxicity assay. It is demonstrated that, through appropriate choice of dose range, PLSR against the respective targets can differentiate between the spectroscopic signatures of the direct chemical effect of the drug dose and the indirect cytological effect it produces. PMID- 25558477 TI - Intramolecular Schmidt reaction of acyl chlorides with alkyl azides: preparation of pyrrolizine by intramolecular capture of intermediates with alkenes or alkynes. AB - The preparation of substituted pyrrolizines through the Schmidt reaction of acyl chlorides with alkyl azides has been realized. Intramolecular capture of the isocyanate ion and N-acyliminium ion intermediates from the Schmidt process with alkene or alkyne units was achieved, and the efficiency of the conversion with respect to ring construction and bond formation was demonstrated. PMID- 25558478 TI - Aerobic C-N bond activation: a simple strategy to construct pyridines and quinolines. AB - Inspired by the autoxidation processes, a dioxygen induced C-N bond activation of primary alkyl amines was demonstrated toward the synthesis of pyridines and quinolines. The transition-metal free conditions with O2 as the sole oxidant make this transformation very attractive. Notably, the substrate applicability of different kinds of ketones is greatly broadened for this transformation. PMID- 25558479 TI - Tetrazine functionalized zirconium MOF as an optical sensor for oxidizing gases. AB - Dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate was introduced into the chemically stable UiO-66 structure by a postsynthetic linker exchange reaction to create an optical sensor material for the detection of oxidative agents such as nitrous gases. The incorporated tetrazine unit can be reversibly oxidized and reduced, which is accompanied by a drastic colour change from yellow to pink and vice versa. The high stability of the framework during redox reaction was proven by powder X-ray diffraction and nitrogen physisorption measurements. PMID- 25558480 TI - Engineering supramolecular organic frameworks (SOFs) of C-alkylpyrogallol[4]arene with bipyridine-based spacers. AB - Supramolecular organic frameworks (SOFs) based on pyrogallol[4]arene and 4,4' bipyridine-type spacer molecules have been investigated. The hydrogen bonding pattern and molecular arrangement in the crystal structures are engineered through the cocrystallization approach. The length of the spacer molecules and the C-alkyl tail length of the PgC macrocycle are tuned to influence the hydrogen bonding pattern and thus the overall architecture of the resultant SOFs. Combined solid-state thermal analysis and solution-phase (1)H NMR results indicate the amount of solvent loss and the stability of the SOFs in solution. PMID- 25558481 TI - Red luminescence and ferromagnetism in europium oxynitridosilicates with a beta K2SO4 structure. AB - The new compounds LaSrSiO3N and LaBaSiO3N activated with Eu(2+) are orange-red light-emitting luminescent materials under excitation in the UV-blue range. They represent the first examples of stoichiometric alkaline earth oxynitridosilicates with a beta-K2SO4 structure. The isostructural compound LaEuSiO3N is ferromagnetic with a Curie temperature of 3 K and also shows red luminescence (lambdamax = 705 nm) under excitation at 405 nm. PMID- 25558482 TI - Constructing a multicomponent junction for improved visible-light photocatalytic performance induced by Au nanoparticles. AB - Au induced visible-light photocatalytic performance is, for the first time, demonstrated to be effectively enhanced by a proper construction of a junction nanostructure. A study of the O2(-) and H2O2 radicals indicates the efficient electron transfer across the Au-SrTiO3-TiO2 composite facilitated by the junction effect is responsible for the enhancement, and ultimately promotes the photocatalytic process. PMID- 25558483 TI - Guanidinium iodide-catalyzed oxidative alpha-nitroalkylation of beta-ketoamides. AB - Oxidative nitroalkylation of beta-ketoamides and nitroalkanes, mediated by hypoiodide generated from tert-butyl hydrogen peroxide and a catalytic amount of guanidinium iodide, afforded the corresponding alpha-nitroalkyl-beta-ketoamides in up to 97% yield. PMID- 25558484 TI - Formation and in situ reactions of hypervalent iodonium alkynyl triflates to form cyanocarbenes. AB - The conversion of readily available silylalkynes, iodobenzene diacetate, and azide anions was utilized to form and react cyanocarbenes. A copper(II)-catalyzed reaction was found to react in a different manner. Both of these methods benefit from the formation and in situ reaction of hypervalent iodonium alkynyl triflates in O-H insertion reactions. PMID- 25558485 TI - A host-guest inclusion compound for reversible switching of quadratic nonlinear optical properties. AB - A host-guest inclusion compound [(DPA)(18-crown-6)]ClO4 (DPA = dipropylamine) undergoes a reversible phase transition at 214 K, which enables it to switch the NLO response between SHG-ON and SHG-OFF states associated with the order-disorder transition of the guest DPA cations and a slight tilting of the host 18-crown-6 molecules. PMID- 25558486 TI - Biocatalytic conversion of ethylene to ethylene oxide using an engineered toluene monooxygenase. AB - Mutants of toluene o-xylene monooxygenase are demonstrated to oxidize ethylene to ethylene oxide in vivo at yields of >99%. The best mutant increases ethylene oxidation activity by >5500-fold relative to the native enzyme. This is the first report of a recombinant enzyme capable of carrying out this industrially significant chemical conversion. PMID- 25558487 TI - Virus-like particles as virus substitutes to design artificial virus-recognition nanomaterials. AB - Functional recognition imprints of virus-like particles, at the surface of silica particles, were generated following a strategy based on protein-templated polycondensation of organosilanes. PMID- 25558488 TI - [Harry Strack Sullivan: a socioenvironmental view of psychopathology]. PMID- 25558489 TI - [No more songs to be heard]. PMID- 25558490 TI - Assessing the effects of medical marijuana laws on marijuana use: the devil is in the details. AB - This paper sheds light on previous inconsistencies identified in the literature regarding the relationship between medical marijuana laws (MMLs) and recreational marijuana use by closely examining the importance of policy dimensions (registration requirements, home cultivation, dispensaries) and the timing of when particular policy dimensions are enacted. Using data from our own legal analysis of state MMLs, we evaluate which features are associated with adult and youth recreational and heavy use by linking these policy variables to data from the Treatment Episode Data Set (TEDS) and National Longitudinal Survey of Youth (NLSY97). We employ differences-in-differences techniques, controlling for state and year fixed effects, allowing us to exploit within-state policy changes. We find that while simple dichotomous indicators of MML laws are not positively associated with marijuana use or abuse, such measures hide the positive influence legal dispensaries have on adult and youth use, particularly heavy use. Sensitivity analyses that help address issues of policy endogeneity and actual implementation of dispensaries support our main conclusion that not all MML laws are the same. Dimensions of these policies, in particular legal protection of dispensaries, can lead to greater recreational marijuana use and abuse among adults and those under the legal age of 21 relative to MMLs without this supply source. PMID- 25558492 TI - [DSM-5: lights and shadows]. PMID- 25558493 TI - [Integrated and coordinated measures to manage autistic spectrum disorders]. PMID- 25558491 TI - Early-life origins of life-cycle well-being: research and policy implications. AB - Mounting evidence across different disciplines suggests that early-life conditions can have consequences on individual outcomes throughout the life cycle. Relative to other developed countries, the United States fares poorly on standard indicators of early-life health, and this disadvantage may have profound consequences not only for population well-being, but also for economic growth and competitiveness in a global economy. In this paper, we first discuss the research on the strength of the link between early-life health and adult outcomes, and then provide an evidence-based review of the effectiveness of existing U.S. policies targeting the early-life environment. We conclude that there is a robust and economically meaningful relationship between early-life conditions and well being throughout the life cycle, as measured by adult health, educational attainment, labor market attachment, and other indicators of socioeconomic status. However, there is some variation in the degree to which current policies in the United States are effective in improving early-life conditions. Among existing programs, some of the most effective are the Special Supplemental Program for Women, Infants, and Children (WIC), home visiting with nurse practitioners, and high-quality, center-based early-childhood care and education. In contrast, the evidence on other policies such as prenatal care and family leave is more mixed and limited. PMID- 25558494 TI - [Interview with Debora Feimann]. PMID- 25558495 TI - [World psychiatric association (WPA)]. PMID- 25558496 TI - [Cystatin C serum concentration combined with renal artery resistance index determination for early diagnosis of hepatorenal syndrome value]. PMID- 25558497 TI - [Pegylated interferon alpha-2a and ribavirin antiviral therapy efficacy for treating chronic hepatitis C and its effects on psychological status of patients]. PMID- 25558498 TI - [Percutaneous transhepatic intrahepatic portosystemic shunt plus embolotherapy treatment of portal hypertension]. PMID- 25558499 TI - [Promotion of HBeAg seroconversion/loss in patients with chronic hepatitis B following the switch from nucleoside drugs to telbivudine and adefovir]. PMID- 25558500 TI - [Hypophosphatemic osteomalacia and renal Fanconi syndrome induced by adefovir in a patient with chronic hepatitis B]. PMID- 25558501 TI - [Recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals]. PMID- 25558502 TI - [Evaluation of liver fibrosis a review current technologies and clinical perspectives]. PMID- 25558503 TI - [Intestinal microbiota and enterohepatic diseases]. PMID- 25558504 TI - [Natural killer cells play an important role in hepatitis C infection]. PMID- 25558505 TI - [Medical insurance is gaining importance]. PMID- 25558506 TI - [Psychiatric disorders and their effects on mortality and morbidity]. AB - Psychiatric disorders themselves--and not only the known psychotropic agents- lead to enhanced psychic and somatic morbidity, and not only as a so-called psychic reaction. Psychiatric disorders such as depression, anxiety disorders and schizophrenia are diseases with a high prevalence and incidence in most countries, and they are life-threatening because they induce--besides suicidality -also many somatic diseases such as coronary arte- riosclerotic syndrome and diabetes. As a result, they have an--often indirect--effect on mortality. In the future, studies should give greater attention to the underlying neurobiological mechanisms. True "psychosomatic medicine" consists of determining the combined biological effect of psychic and somatic factors and their interactions in greater detail. PMID- 25558508 TI - [Bilateral loss of vision in temporal arteriitis--a preventable condition?]. AB - BACKGROUND: Bilateral loss of vision (BLV) is one of the most feared complications of temporal arteriitis (TA). AIM: Analysis of factors contributing to BLV. PATIENTS AND METHODS: Observational study in 301 TA patients in- cluding 23 (8%) suffering from BLV. RESULTS: Diagnosis of TA was unknown in all patients before BLV. Total blindness of both eyes occurred in 10 and in one eye in 5 patients. BLV evolved simultaneously in 7, sequentially in 12, and time latency remained undetermined in 4 patients. Loss of vision occurred during hospital treatment in 5 patients. Progressive loss of vision despite glucocorticoid treatment was observed in 2 patients with bilateral AION. Warning signs of TA were absent due to atypical manifestation of the disease in 11 patients, and transient visual disturbances preceded BLV only in 5 patients. Typical abnormalities of the temporal artery on palpation were lacking in 11 patients, and ESR was below 50 mm in 5 patients. Co-morbidities were present in all patients, including diseases mimicking TA, other vascular disease and dementia, as an obstacle to correct analysis of the course of the disease. Medical malpractice was claimed and recognised in 2 patients and could not be excluded in other patients. CONCLUSION: Prevention of BLV due to TA and ischemia of the anterior visual pathways is not pos- sible in all patients because it may occur suddenly and simultaneously without any preceding clinical warning signs. PMID- 25558507 TI - [The histological confirmation of diffuse axonal injury in severe brain injury survivors]. AB - Diffuse axonal injury (DAI) plays a major role after traumatic brain injury (TBI). Its imaging is based on computed tomography (CT) or magnetic resonance imaging (MRI). However, DAI is a histological diagnosis. Histopathological findings on survival after TBI are very rare. Hence, it is unclear whether the neuroradiological findings are of clinical relevance. Cerebral specimens were taken in 24 patients with TBI requiring surgery. The presence of histopathological evidence for DAI was evaluated. Specimens were taken from an extracranial brain prolapse (n = 2) and from peripheral parts of a brain contusion (n = 22). Histological findings were correlated to the clinical course and the neurological status. A clinical follow-up was carried out 6 months after the surgery using the Glasgow Outcome Score (GOS). The study was approved by the local ethics committee. Specimens taken were temporal (n = 11), frontal (n = 8), parietal (n = 4) and cerebellar (n = 1). The incidence of DAI within these specimens was 30% (7 with DAI, 17 without DAI). DAI was verifiable up to 3 days after trauma. There was no correlation between DAI and Marshall classification in CT. The period of coma was longer in subjects with DAI. There was no difference in GOS in the case of a verified DAI. These results enforce the prognostic and neuroradiologic relevance of DAI. However, it is debatable whether the pathomorphologic findings in CT or MRI represent the histological findings of DAI. We suggest a multicentre study for further clarification. PMID- 25558509 TI - [Evaluation and socio-economic relevance of an integrated osteoporosis health care network]. AB - During the last 6 to 7 years, integrated health care has become more and more important in Germany. In August 2005 we initiated a collaborative project involving two orthopaedic clinics in Hanover and one rehabilitation clinic in Bad Pyrmont specialising in the treatment of osteoporosis. Here, we report the results of 633 women (83 +/- 7 years) and 162 men (75 +/- 10 years) who participated in this programme between August 2005 and August 2012. All participants gave informed consent. All patients were supplemented with 1200 mg of calcium and 800 IU of vitamin D. Intravenous bisphosphonates were given to 91% and parathyroid hormone to 7% of the patients. Two per cent received miscellanous therapeutic agents. Follow-up visits were attended by 89% of the patients after one year and 78% after two years. During this time, a significant improvement was observed in vitamin D, parathyroid hormone and the bone marker desoxypyridinoline. DXA measurements were falsified by degenerative disease or fractures. In the men, however, a significant increase was observed in the total hip. Over the two-year period, 16 vertebral and 3 non-vertebral fractures occurred in the women. In the men, one non-vertebral and 5 vertebral fractures were noted. Among the women, 18 died and 6 were admitted to a nursing home. The corresponding figures among the men were 7 and 4, respectively. According to the figures provided by the central German institute for statistics, the death rates among the women were significantly lower than expected, whereas a tendency toward lower death rates was seen in the men. In addition, the number of new hip fractures in the women was lower than the epidemiological data suggest. This was also noted in the men. Even among the very old, a musculoskeletal rehabilitation programme combined with adequate pharmaceutical therapy may prove very successful when it comes to death rates and nursing home admissions. The latter in particular may be very expensive in the long run and our longitudinal follow-up study may demonstrate cost-effectiveness if the rehabilitation programme is commenced as early as possible. PMID- 25558510 TI - [The placebo-republic]. PMID- 25558511 TI - [Current concepts in the treatment of Traditional Chinese Medicine]. PMID- 25558512 TI - [Diagnosis and treatment of an alleged mercury and lead exposure with DMPS]. PMID- 25558513 TI - [The "Psychological clause" in private accident insurance]. PMID- 25558514 TI - [Letter to GM Ostendorf: osteopath --an independent health professional? In: Insurance Medicine 66 (2014), No. 2, pp 97th]. PMID- 25558515 TI - Erosion: a sign of the times. PMID- 25558516 TI - Never work another day. PMID- 25558517 TI - For what it's worth, happy 1998. PMID- 25558518 TI - Death of a profession: is modern medicine a profession in terminal agony? PMID- 25558519 TI - Payer accountability push to continue in 2015 session. PMID- 25558520 TI - Prescribing guidelines for pain management and patient safety. PMID- 25558521 TI - Ebola preparation eases concerns. PMID- 25558522 TI - Annual award to honor longtime Vanderbilt physician. PMID- 25558523 TI - Big data. Big changes. What's the big idea?. PMID- 25558524 TI - E-cigarettes, vaping, hookahs and patients. PMID- 25558525 TI - ICD-10 in 2015: a year of transition. PMID- 25558526 TI - Hospitals are still struggling with reducing readmissions. AB - More hospitals than ever before are being penalized by the Centers for Medicare & Medicaid Services for excess readmissions and insurers are starting to develop their own readmission reduction programs. According to experts: Case managers and hospitals have to look beyond the hospital walls and determine what happens to patients throughout the continuum. Improving communication with post-acute providers is a critical part of reducing readmissions. Recognize that family members or other caregivers are an important factor in a patient's success after discharge and involve them in creating the discharge plan. PMID- 25558527 TI - Five more ways to improve readmissions, according to the experts. PMID- 25558529 TI - What home health nurses want from you. PMID- 25558528 TI - Total joint replacement patients need care coordination, too. AB - Joint replacement surgery may seem routine, but patients are being readmitted to the hospital for a variety of reasons, including comorbidities, poor outcomes from therapy, and deep venous thrombosis. Experts recommend the following: Develop triggers for a medical consultation for patients who have chronic conditions and comorbidities or otherwise are at risk. Take all of the patient's conditions into consideration when developing a discharge plan. Make follow-up phone calls to patients to ensure that they have any prescribed equipment, are participating in physical therapy, have follow-up doctor's appointments, and are taking their medication. PMID- 25558530 TI - Team effort reduces readmission rate by 20% in two years. AB - A team effort at Holzer Health System helped reduce the rate of all-cause readmissions by 20%. The case management department was redesigned so care managers and social workers report to the same person, care managers are housed on the unit, and the care management team works weekends, holidays, and evenings. The goal is for at-risk patients to have at least one visit from a home health nurse. When patients are being transferred to a post-acute facility, the vice president for post-acute care services calls the director of nursing at the receiving facility with information on the patient. PMID- 25558531 TI - Hospitals, Council on Aging partner to reduce readmissions. AB - Carondelet Health Network and the Pima Council on Aging have partnered to provide follow-up care coordination for at-risk patients who are being discharged from the hospital. Carondelet nurses visit patients in the hospital to assess them for eligibility and make at least one home visit to conduct medication reconciliation, educate them on self-management, and reinforce discharge education on signs and symptoms that indicate they should call their doctor. Care coordinators/social workers from the Pima Council on Aging are called coaches and help patients access social services, visit them in their homes as often as needed, and provide support in following the treatment plan. The Transitional Care team developed patient education tools based on color-coded zones for each diagnosis to alert patients on what to do when their condition changes. PMID- 25558532 TI - Assessing patients' functional status to identify risks for readmission. PMID- 25558533 TI - Hospital case management. CM recognition is increasing--but salaries, not so much. PMID- 25558534 TI - Little change seen in salaries despite greater case volume, responsibility. PMID- 25558535 TI - Hybrid medical leadership turns competitors into collaborators. PMID- 25558536 TI - Study sheds new light on natural history of RSIs. PMID- 25558537 TI - Affordable Care Act prompts OR leaders to push the efficiency envelope. PMID- 25558539 TI - Prepare now for more stringent joint replacement documentation requirements. PMID- 25558538 TI - Consider a wider range of potential complications to improve patient safety. PMID- 25558540 TI - ASC survey respondents see more pluses than minuses in compensation. PMID- 25558541 TI - Cost control leads list of strategies related to healthcare reform. PMID- 25558542 TI - Controlling the rate of middle ear barotrauma: an editorial perspective. PMID- 25558543 TI - Idiopathic sudden sensorineural hearing loss: beyond the window and tinnitus, too? An editorial perspective. PMID- 25558544 TI - Management of sudden hearing loss with hyperbaric oxygen therapy. AB - Idiopathic sudden sensorineural hearing loss (ISSHL) is defined as the sensorineural hearing loss of a minimum of 30 dB in at least three frequencies for three days or more. This study aims to evaluate the clinical efficacy of hyperbaric oxygen therapy (HBO2) in the management of idiopathic sudden sensorineural hearing loss. MATERIAL-METHODS: Patients with ISSHL received treatment including oral corticosteroids and HBO2. HBO2 protocol included five phases of five sessions each. ISSHL was assessed by measuring the tonal audiogram before and after each phase. Tinnitus was assessed using a questionnaire and a visual analogue scale at the beginning and the end of the study. Secondary assessment points included changes in the intensity and the improvement of tinnitus. RESULTS: 56 patients were included in the study. All patients completed Phases I and II of HBO2, 43 completed Phase III, 13 completed Phase IV, and six completed all five phases. Overall, a significant improvement was noted between the initial and final audiogram after HBO2 (p < 0.001). Tinnitus evaluation score, intensity and related problems were also significantly reduced (p < 0.001). CONCLUSION: This study affirms previous findings that the use of HBO2 and vasodilators are efficacious in the treatment of ISSHL. Our findings also suggest benefit for the treatment of tinnitus. PMID- 25558545 TI - Nitrogen narcosis and tactile shape memory in low visibility. AB - OBJECTIVE: Commercial diving often occurs in low visibility, where divers are reliant on their tactile senses. This study examined the effect of nitrogen narcosis on tactile memory for shapes as well as the influence of psychological and biographical factors on this relationship. METHOD: This crossover study tested 139 commercial divers in a dry hyperbaric chamber at 101.325 and 607.95 kPa (1 and 6 atmospheres absolute/atm abs). Divers memorized shapes while blindfolded, using their tactile senses only. Delayed recall was measured at the surface after each dive. Psychological and biographical data were also collected. RESULTS: A significant effect of hyperbaric pressure on tactile memory was demonstrated, and a further effect of sequence of testing found. Thus, divers' delayed shape recall deteriorated by 8% after learning material at depth, compared to learning on the surface. There were also significant but small effects of psychological and biographical markers on tactile memory performance, with lower trait anxiety associated with better recall, and lower education associated with poorer recall. CONCLUSION: The findings emphasize the importance of utilizing other forms of recording of events or objects at depth, particularly in conditions of low visibility during deeper diving, to aid memory encoding and subsequent recall at the surface. PMID- 25558546 TI - Seizure incidence by treatment pressure in patients undergoing hyperbaric oxygen therapy. AB - INTRODUCTION: Hyperbaric oxygen (HBO2) therapy uses different maximum treatment pressures. A side effect of HBO2 is oxygen toxicity seizure. The purpose of this study was to determine the overall incidence of oxygen toxicity seizure and assess risk at different treatment pressures. METHOD: A retrospective chart review was performed on patients who underwent HBO2 at a university hospital and at an outpatient center. Statistical analysis was performed to determine overall incidence of seizure and identify risk factors including maximum treatment pressure. RESULTS: A total of 931 patients were identified representing a total of 23,328 treatments. The overall incidence of seizure was one in 2,121 treatments (five per 10,000). There were zero per 10,000 at 2.0 atmospheres absolute/atm abs (0/16,430), 15 per 10,000 at 2.4/2.5 atm abs (1/669) and 51 per 10,000 at 2.8 atm abs (1/197). There was a statistically significant difference for seizure between the different pressures (chi2 (2, 23,540) = 31.38, p < .001). DISCUSSION: The overall incidence of oxygen toxicity seizure in this study is consistent with recent reports. This study demonstrated a statistically significant increased risk of seizure with increasing treatment pressure. Treatment at higher pressure should be chosen based on demonstrable benefit with a clear understanding of increased risk with higher pressure. PMID- 25558547 TI - Oxygen and carbogen breathing following simulated submarine escape. AB - Escape from a disabled submarine exposes escapers to a high risk of decompression sickness (DCS). The initial bubble load is thought to emanate from the fast tissues; it is this load that should be lowered to reduce risk of serious neurological DCS. The breathing of oxygen or carbogen (5% CO2, 95% O2) post surfacing was investigated with regard to its ability to reduce the initial bubble load in comparison to air breathing. Thirty-two goats were subject to a dry simulated submarine escape profile to and from 240 meters (2.5 MPa). On surfacing, they breathed air (control), oxygen or carbogen for 30 minutes. Regular Doppler audio bubble grading was carried out, using the Kisman Masurel (KM) scale. One suspected case of DCS was noted. No oxygen toxicity or arterial gas embolism occurred. No significant difference was found between the groups in terms of the median peak KM grade or the period before the KM grade dropped below III. Time to disappearance of bubbles was significantly different between groups; oxygen showed faster bubble resolution than carbogen and air. This reduction in time to bubble resolution may be beneficial in reducing decompression stress, but probably does not affect the risk of fast-tissue DCS. PMID- 25558548 TI - Middle ear barotrauma in hyperbaric oxygen therapy. AB - INTRODUCTION: Middle ear barotrauma (MEB) is a common complication of hyperbaric oxygen (HBO2) therapy. The purpose of this study was to determine the overall incidence of MEB and evaluate for differences in the incidence of MEB at different rates of compression (ROC). The study also sought to identify other potential risk factors for MEB. METHODS: A retrospective chart review was performed on patients undergoing HBO2 at an academic regional level 1 trauma center. The MEB overall incidence as well as incidence at different ROC were determined. RESULTS: 236 patients representing 4,981 treatments were analyzed. The overall incidence of MEB was 43.2%. There was no statistically significant difference in the incidence of MEB at different ROC. There was a statistically significant higher incidence of TEED 4 MEB in intubated patients (p < 0.0001). The vast majority of MEB was minor when considering severity based on overall lower TEED scores of 1 or 2 (84%). DISCUSSION: The overall incidence of MEB in this study is consistent with those previously reported. It is important to note that a vast majority of MEB was minor. This supports HBO2 as a safe treatment modality with minimal overall risk. The current study supports standardization of most treatment protocols to a ROC of 2 psi/minute. PMID- 25558549 TI - Hyperbaric oxygen therapy (HBO2) as an adjunct in the treatment of idiopathic sudden sensorineural hearing loss (ISSHL)--a case report on two patients. AB - We report on two cases of idiopathic sensorineural sudden hearing loss (ISSHL) successfully treated at our center. The patients were referred to us by a neurotologist for adjunctive hyperbaric oxygen therapy and were treated using a standard 2.4 atmospheres absolute (atm abs) 90-minute protocol with two five- minute air breaks. During this period the referring physician administered injections of steroids at his offices. The outcome in both cases was positive and produced significantly improved scores in both speech reception and speech discrimination. In October 2011, the UHMS added ISSHL to its list of approved indications. Despite this and an increasing body of literature that supports the use of hyperbaric oxygen therapy as an adjunct in the treatment of ISSHL, it has not yet been accepted for reimbursement by CMS and, in our experience, commercial carriers. We believe it would be beneficial in developing the case for reimbursement in this indication if all facilities record and submit their results to a national database perhaps organized and managed by the UHMS. PMID- 25558550 TI - Facial baroparesis: a critical differential diagnosis for scuba diving accidents- case report. AB - Facial nerve baroparesis is a rare and potentially under-reported complication of scuba diving. A diver, after surfacing from a shallow dive, developed isolated left-sided facial palsy accompanied by pain and decreased hearing in the left ear. No other signs or symptoms attributable to a scuba diving accident were detected. Forty minutes later, he heard a "pop" in the affected ear, after which all symptoms quickly resolved. Repeat neurological and ear examinations were normal. He showed no residual or new symptoms 24 hours later. The differential diagnosis of facial neurological deficit after diving includes decompression sickness, cerebral air embolism due to pulmonary barotrauma, facial nerve barotrauma and common conditions such as stroke and Bell's palsy. It is important to recognize the condition since recompression treatment can further damage the facial nerve. PMID- 25558551 TI - Folate and homocysteine metabolisms and their roles in the biochemical basis of neuropsychiatry. AB - The term 'one-carbon metabolism' is commonly used to describe 3 separate metabolic processes: folate metabolism, the homocysteine remethylation cycle, and the transsulfuration pathway. Folate metabolism concerns the biochemical reactions in which endogenous and exogenous one-carbon units are transferred to tetrahydrofolates. The remethylation cycle is used for the synthesis of methionine from homocysteine with one-carbon units that come from folate. This methionine is thenfused for the synthesis of S-adenosyl methionine, which is a general donor of methyl groups for many biochemical reactions in the human body. In the transsulfuration pathway, some amino acids and polypeptides, such as cystathionine, cysteine, and glutathione, are synthesized from homocysteine. The kinetics of the enzymes in this pathway are regulated by the substrates of the remethylation cycle. The methylation process has been thought to have an important role in the biochemical basis of neuropsychiatry. An elevated homocysteine level is the most important marker of folate and vitamin B12 deficiencies, and also the most reliable biochemical sign of functional insufficiency. Some neurological and neuropsychiatric diseases, such as psychosis, Alzheimer's disease, and autism, have been found to be related to disorders of one-carbon metabolism. This review aims to summarize both one-carbon metabolism and its relationships with neuropsychiatric disorders. PMID- 25558552 TI - The obesity prevalence among students between the ages of 5 and 19 in Kutahya. AB - AIM: To determine the prevalence of obesity among students between the ages of 5 and 19 in Kutahya, and to determine the factors associated with obesity prevalence. MATERIALS AND METHODS: The population in the survey was formed of students between the ages of 5 and 19 in the schools of Kutahya. Within the scope of this survey, obesity was evaluated in accordance with the percentile values indicated in a study on the body weight and height, head circumference, and body mass index reference values of Turkish children that was published in 2008. RESULTS: It was determined that 6.5% of the students were obese, 7.8% of them were overweight, and 7.8% of them were underweight. When the variables of age, sex, and school district were controlled, it was seen that obesity prevalence among students studying at private schools was 2.03 times higher than among students studying at public schools (P < 0.001). CONCLUSION: It is seen that, in the efforts to reduce childhood obesity, private schools should be considered as a risk factor and the obesity prevalence at private schools should be analyzed in further studies. PMID- 25558553 TI - Serum amyloid A, fetuin-A, and pentraxin-3 levels in patients with ischemic stroke: novel prognostic biomarkers? AB - AIM: Inflammation plays an important role in acute ischemic stroke. In this study we aimed to investigate the relationship between acute ischemic stroke and serum amyloid A, fetuin-A, and pentraxin-3 which are inflammation markers. MATERIALS AND METHODS: We enrolled 52 patients with acute ischemic stroke and 30 sex matched control subjects in the study. The patients were followed for 3 months. We evaluated the common risk factors, laboratory variables, and neurological examination of stroke patients according to prognosis scales. RESULTS: The median serum amyloid A, fetuin-A, and pentraxin-3 levels in the stroke patients were higher than in control subjects (respectively, P = 0.000, P = 0.002, and P = 0.037). National Institutes of Health Stroke Scale scores, glucose, C-reactive protein, fibrinogen, and white blood cell count showed differences within the group in terms of the serum amyloid A tertiles statistically. CONCLUSION: Pentraxin-3, fetuin-A, and serum amyloid A all arise together as novel prognostic factors in a group of patients with ischemic stroke. Relationships between higher levels of inflammation markers, especially serum amyloid A, and the severity of acute ischemic stroke were shown. PMID- 25558554 TI - Attachment style and perceived social support as predictors of biopsychosocial adjustment to cancer. AB - BACKGROUND/AIM: Social support is associated with a decrease in psychological symptoms and a better quality of life in cancer patients. The aim of this study was to investigate the role of attachment dimensions on social and psychological adjustment to cancer and to explore the social and psychological adjustments, and medical adherence, among patients. MATERIALS AND METHODS: The study was conducted with 68 cancer patients, between 18 and 74 years of age. The measures taken were the Demographic Information Form, Multidimensional Scale of Perceived Social Support (MSPSS), Experiences in Close Relationships-Revised (ECR-R), and Psychosocial Adjustment to Illness Scale (PAIS-SR). RESULTS: The results showed that an avoidant attachment style was related to difficulties in social relationships and an increase in psychological distress following cancer diagnosis. People who perceive more social support orient to health care more easily than people who perceive less social availability. It was shown that a higher level of perceived social support has a positive impact in adjustment to family relationships and leads to experiencing less psychological distress than in people who perceived less social support. CONCLUSION: Considering the complicated nature of cancer, a multi-perspective approach should be applied during the treatment process, and it is important to determine the psychosocial factors, and the causal pathways by which they lead to a better adjustment, in developing effective interventions. PMID- 25558555 TI - What is the best radiological method to predict the actual weight of the prostate? AB - AIM: We compared the weight of the prostate specimen extracted after radical prostatectomy with preoperatively estimated weights of the prostate by different imaging techniques. MATERIALS AND METHODS: Prostate weights were estimated by transabdominal ultrasonography (TAUS), transrectal ultrasonography (TRUS), and computed tomography (CT) preoperatively before radical prostatectomy. Prostatectomy specimens were weighed postoperatively and the actual prostate weights were calculated. Statistical analyses were done using 95% confidence intervals with repeated measurement analysis of variance and intraclass correlation coefficients. RESULTS: Of the 163 patients enrolled in the study, the mean age was 64.2 +/- 6.4 (range: 45 to 76) years. The mean postoperative prostate weight was 54.7 +/- 27.9 g. Preoperative mean prostate volumes calculated by TAUS, TRUS, and CT were 50.2 +/- 24.1, 50.7 +/- 24.6, and 62.7 +/- 28.2 mL, respectively (P < 0.001). The actual prostate weight measured using an electronic scale was correlated with the estimated prostate weight in each of 3 methods, the best of which was that of TRUS. CONCLUSION: The actual prostate weight is best estimated by measurements done with TRUS. However, clinicians should consider that some errors and deviations may occur with these imaging techniques. PMID- 25558556 TI - Distal radius measurements and efficacy of fixed-angle locking volar plates. AB - AIM: For surgical treatment of unstable distal radius fractures, fixed-angled locking volar plate fixation is becoming popular nowadays because of some advantages over other surgical techniques. In this article, we discuss the fitting of fixed-angle locking volar plates to the distal radius in relation to the changes in the distal radial angles. MATERIALS AND METHODS: First, we took conventional radiography images of 18 dried radii and later we measured the palmar subchondral angle, dorsal subchondral angle, mid-subchondral angle, and palmar cortical angle using lateral radiography. RESULTS: According to the measurements, the volar subchondral angles (alpha) ranged from 10.2 degrees to 28.1 degrees, the middle subchondral angles ranged from 55.9 degrees to 93.2 degrees, the dorsal subchondral angles ranged from 77 degrees to 109.6 degrees, and the volar cortical angles ranged from 134.5 degrees to 158.4 degrees. CONCLUSION: Although fixed-angle locking volar plates are accepted as anatomical, our measurements showed that volar cortical angles and the subchondral angles are variable. Therefore, the term "anatomic distal radius volar plate" should be discussed. PMID- 25558557 TI - Protective roles of Cimin grape tissues on oxidative stress markers in the cellular system model. AB - AIM: To analyze the phenolic composition of the Cimin grape, which is 1 of 2 grape varieties with a protected geographical indication in Turkey and is used locally to treat the symptoms of some disorders such as impotence and cardiovascular diseases, and to investigate its antioxidant potency against oxidant mediators in the models of intra- and extracellular surroundings. MATERIALS AND METHODS: Cimin grape samples were classified into 5 groups according to the grape's tissues and the extraction solvents used. Free radical scavenging (DPPH) and antilipid peroxidation product [thiobarbituric acid reactive substance (TBARS) and conjugated diene (CD)] levels of the grape tissues were extrapolated from the measurement of total phenolic and individual monomeric flavanol contents in each extract. RESULTS: The seed methanolic extract had the highest total amount of flavanols, with the amount of catechin at 4.034 mM. The DPPH activities of the seed extracts were 2- to 10-fold higher than those of the other samples. The seed extract-treated erythrocyte and unfractionated human plasma also showed lower TBARS and CD values. In addition, regeneration of glutathione was more obvious in grape seed extracts than in the rest of the tissues. CONCLUSION: The underlying mechanism of these changes can be related mainly to increased antioxidant status. Cimin grape consumption may have beneficial effects on health maintenance. PMID- 25558558 TI - Prognostic value of neutrophil/lymphocyte ratio in patients with pulmonary embolism. AB - AIM: Preliminary evidence suggests that inflammation plays a role in the development and prognosis of pulmonary embolism (PE). We used the neutrophil/lymphocyte ratio (NLR) as a measure of systemic inflammation and investigated its association with PE. MATERIALS AND METHODS: A total of 266 patients who were diagnosed with PE and a control group of 124 age- and sex matched healthy subjects were included in this study. We further classified the PE patients into 2 groups: those who survived and those who died in the first 30 days. Baseline NLR was measured by dividing neutrophil count to lymphocyte count and was compared between the groups. RESULTS: Median NLR was significantly higher among patients with PE compared to the healthy control group (3.9 (interquartile range (IQR): 5.0) vs. 1.9 (IQR: 0.6), P < 0.001). Of the 266 patients with PE, 16 (6%) died within 1 month. Median NLR was significantly higher among PE patients who died compared to those who survived, as well (3.7 (IQR: 4.3) vs. 9.0 (IQR: 7.9), P < 0.001). The optimal cut-off values, sensitivities, and specificities of NLR for predicting PE and in-hospital mortality of PE were >2.565 and >5.465, 70.3% and 75.0%, and 92.7% and 67.6%, respectively. Multiple logistic regression analysis showed that NLR values of >5.465 could define those patients with a mortal clinical course independently (odds ratio: 13.446, 95% confidence interval: 3.141-57.566, P < 0.001). PMID- 25558559 TI - Choroidal thickness in healthy Turkish subjects. AB - AIM: To investigate choroidal thickness in healthy Turkish subjects. MATERIALS AND METHODS: Refraction, axial length (AXL) measurement, anterior chamber, and fundus examinations were performed. Eyes that had any retinal or choroidal pathology were excluded from the study. Enhanced-depth imaging optical coherence tomography was used to evaluate choroidal thickness. RESULTS: 139 eyes from 70 subjects were investigated. The mean age, AXL, spherical equivalent refractive error (SE), and subfoveal choroidal thickness (SCT) were 34.7 +/- 12.7 years, 23.31 +/- 0.91 mm, -0.15 +/- 1.64 diopters (D), and 326 +/- 60 microm, respectively. A negative correlation was found between SCT and AXL (P = 0.043). The mean age, SE, AXL, and SCT were 31.7 +/- 9.3 and 34.6 +/- 14.3 years, -0.27 +/- 1.45 and 0.02 +/- 1.89 D, 23.52 +/- 0.94 and 23.02 +/- 0.75 mm, and 324 +/- 69 and 329 +/- 40 mirom in male and female subjects, respectively (P = 0.14, P = 0.31, P = 0.001, and P = 0.58, respectively). Regression analysis showed that SCT decreased by 0.93 microm for each year of age. CONCLUSION: In healthy Turkish subjects, SCT decreased by 0.93 pm for each year of age and was thicker in men when the results were adjusted according to AXL measurements. PMID- 25558560 TI - The diagnostic value of ischemia-modified albumin in the diagnosis of aortic pathology. AB - AIM: To investigate the diagnostic value of ischemia-modified albumin (IMA) in the diagnosis oflpatients with aortic aneurysm. MATERIALS AND METHODS: The study group consisted of 98 patients who presented to our university hospital emergency department with aortic pathology and were definitively diagnosed using spiral tomography. The control group consisted of 101 healthy individuals with similar demographic characteristics. RESULTS: Mean IMA values were 0.89 +/- 0.21 absorbance units (ABSU) in the aortic aneurysm group (P < 0.001), 0.70 +/- 0.12 ABSU in the aortic dissection group (P < 0.001), 0.98 +/- 0.23 ABSU in the aneurysm and dissection group (P < 0.001), 0.84 + 0.16 ABSU in the aneurysm and rupture group (P < 0.001), and 0.87 +/- 0.27 ABSU in the aneurysm, dissection, and rupture group (P < 0.001). Mean IMA value for the subjects in the control group was 0.62 +/- 0.17 ABSU. All the differences between the aortic pathology groups' IMA values and those of the control group were statistically significant (P < 0.001). CONCLUSION: On the basis of the findings from this study, serum IMA levels are higher in patients with aortic pathology compared to healthy individuals. This finding suggests that IMA may help to diagnose aortic pathology, but it requires confirmation by additional clinical studies. PMID- 25558561 TI - Comparison of the effects of different percutaneous tracheotomy techniques on acute tracheal trauma. AB - AIM: As it can easily be performed at the bedside with minimal morbidity, percutaneous dilatational tracheotomy (PDT) is preferred over surgical tracheotomy. The aim of this study is to compare the effects of different PDT techniques on posterior tracheal wall injury. MATERIALS AND METHODS: The study was conducted at the Gazi University Laparoscopy Training Center after approval was granted by the ethics committee. After sedation with xylazine/ketamine, electrocardiography, peripheral oxygen saturation, and blood pressure were monitored. Propofol was used to achieve the desired level of sedation during the procedure. There were 16 pigs, randomly allocated into 4 groups. Multiple, single, forceps, and twist dilator techniques were performed in groups I, II, III, and IV, respectively. At the end of the course all pigs were sacrificed and tracheas were harvested for macroscopic and histopathological evaluation. RESULTS: Macroscopic evaluation revealed erythematous/hemorrhagic and ulcerative lesions on the posterior wall of all samples. Histopathological injury was observed in all samples and was similar in all groups. Procedural time was significantly longer in group I than in all other groups (P < 0.05). CONCLUSION: Although the results are conflicting, bronchoscopy-aided PDT is believed to reduce complications. In our study, PDTs were performed without bronchoscopy, and posterior wall injury was observed in all samples. Therefore, we suggest using bronchoscopy to reduce procedure-related complications and improve patient safety during PDT. PMID- 25558562 TI - Increasing resistance of nosocomial Acinetobacter baumannii: are we going to be defeated? AB - AIM: To investigate the change of the antibiotic resistance profiles of the nosocomial Acinetobacter baumannii isolates in intensive care units (ICUs) between the years 2008 and 2011. MATERIALS AND METHODS: A. baumannii isolates that were responsible for ICU-acquired nosocomial infections between 2008 and 2011 were included in the study. The susceptibility rates of the antibiotics that are mainly used in the treatment of Acinetobacter infections were compared by years. Clinical and Laboratory Standards Institute criteria were used to determine antimicrobial susceptibility. RESULTS: There were 252 infection episodes detected in 229 hospitalized patients in the ICU that were caused by A. baumannii. Imipenem resistance was found as 98.9% in 2011 whereas it was 54% in 2008. A significant increase was observed for meropenem resistance from 2008 (73.5%) to 2011 (98.9%). Colistin resistance, confirmed by E-test, was found in 4 strains. The resistance rates of other antimicrobial agents were as follows: ampicillin/sulbactam 95.7% and 93.5%, cefoperazone/sulbactam 45.7% and 90.3%, netilmicin 41.7% and 53%, gentamicin 96% and 87.2%, and trimethoprimsulfamethoxazole 91.7% and 72%, in 2008 and 2011, respectively. The resistance rate to tigecycline increased to 81.3% in 2011 from 12.5% in 2008. PMID- 25558563 TI - Single port thoracoscopic sympathectomy for primary palmar hyperhidrosis in adolescence. AB - AIM: Hyperhidrosis is defined as excessive sweating beyond the physiologic needs of a person. Palmar hyperhidrosis in the adolescent period may have an impact on school work and may cause psychological problems. In this study we aim to increase awareness of this disregarded problem. MATERIALS AND METHODS: We explicated the early outcomes of 7 consecutive adolescents, where single port video-assisted thoracoscopic sympathectomy was performed for primary palmar hyperhidrosis. Patients were evaluated for symptom resolution, which was defined as complete dryness, patient satisfaction, operative complications, and compensatory sweating. RESULTS: In total 13 thoracoscopic procedures were done in 7 adolescents, consisting of 4 girls and 3 boys (median age = 16 years). Thoracoscopic sympathectomy achieved immediate complete dryness and all were very satisfied with the outcome of the procedure. Compensatory sweating was defined as mild by 4 (57%) patients. CONCLUSION: Thoracoscopic sympathectomy is safe and effective for the treatment of primary palmar hyperhidrosis in the adolescent period without any major side effects. PMID- 25558564 TI - Incidental parathyroidectomy during thyroid surgery: risk factors, incidence, and outcomes. AB - AIM: Incidental removal of the parathyroid glands is common in some cases. In this trial, we investigated the risk factors, incidence, and outcomes associated with incidental excision of the parathyroid glands during thyroid surgery. MATERIALS AND METHODS: The records of patients who had undergone thyroid surgery in our department between January 2006 and December 2011 were retrospectively evaluated. RESULTS: A total of 801 patients were enrolled in the trial. The number of incidental parathyroidectomies was determined as 19 (2.3%). Statistical evaluation revealed that sex (P > 0.05) and type of surgical operation (P > 0.05) were not associated with a significant impact on incidental parathyroidectomies. However, the rate of incidental parathyroidectomies was determined to be statistically significantly high among patients with malignant conditions (P < 0.05). Hypocalcemia was observed to be statistically significant in patients with an incidental parathyroidectomy (P < 0.05). CONCLUSION: Incidental parathyroidectomy is a rare condition in centers specializing in endocrine surgery. Furthermore, the parathyroid glands should always be explored during dissection in patients with malignancies. The clinical manifestation of hypocalcemia is a common condition observed after incidental parathyroidectomy. PMID- 25558565 TI - PUVA phototherapy-induced secondary amyloidosis in patients with mycosis fungoides: a rare adverse effect of phototherapy. AB - AIM: Amyloidosis is a common disorder in adults. Secondary amyloidosis in patients with mycosis fungoides (MF) after photochemotherapy with 8 methoxypsoralen followed by ultraviolet A (PUVA) treatment has not been reported. Our aim is to describe the clinical and histological features of PUVA phototherapy-induced secondary amyloidosis. MATERIALS AND METHODS: Sixty-one patients with MF treated with PUVA phototherapy were analyzed clinically and pathologically and by staining with Congo red and crystal violet. RESULTS: Of 61 patients, 5 met the study criteria. Secondary amyloidosis was detected in 5 patients treated with PUVA. The secondary amyloidosis appeared after a mean of 56 exposures (range: 30--81) and a mean cumulative PUVA radiation dose of 131.7 J/cm2 (range: 31-305.5). The mean follow-up duration from the date of occurrence of the secondary amyloidosis was 18.2 weeks (range: 10-30). Histologically, vacuolar interface changes, colloid bodies, and melanophages were seen in all 5 patients. There were 4 patients who had perivascular lymphocytic infiltration and 1 patient had lichenoid lymphocytic infiltration. CONCLUSION: It should be noted that secondary amyloidosis can be present in patients who have been treated with PUVA therapy and it can be a result of the apoptotic effect of PUVA on the basal keratinocytes. PMID- 25558566 TI - Is perioperative examination of frozen sections necessary in nephron-sparing surgery? AB - AIM: To evaluate the role of perioperative freezing in the management of surgical procedures in patients with malignant renal masses. MATERIALS AND METHODS: The study group consisted of 17 patients diagnosed with renal masses who underwent nephron-sparing surgery. The group included 5 females and 12 males aged from 44 to 68 years (mean = 54.6). The mean mass size was 5.5 cm. Mass locations were as follows: 9 were in the lower pole, 4 were in the mid-pole, and 6 were in the upper pole. Perioperative freezing was not carried out. The patients were followed-up in a period ranging from 3 months to 7 years. RESULTS: Tumor pathology was reported as renal cell carcinoma in all cases, and surgical margins were negative in all of them. One patient died after 1 year because of tumor metastasis. In another patient, the tumor reoccurred in the same kidney and a radical nephrectomy was performed. Other patients were followed without recurrence. CONCLUSION: Imaging of the renal vascular system and freezing during surgery is not necessary for nephron-sparing surgery for renal cell carcinoma; however, we should be careful in terms of capsule invasion because of tumor recurrence. PMID- 25558567 TI - Acute Q fever among febrile patients in Zahedan, southeastern Iran. AB - AIM: So far, few studies have been conducted on Q fever in Iran. The objective of this study was to determine the frequency of acute Q fever in febrile patients admitted to Boo-Ali Hospital in Zahedan (southeastern Iran). MATERIALS AND METHODS: In this study, 105 febrile patients suspected ofhaving brucellosis were examined using indirect immunofluorescent assay kit for the detection of Coxiella burnetii IgM and IgG phase antibodies in their serum. Serum with a phase II IgG titer of > or =256 and a phase II IgM titer of > or =50 was predictive for acute Q fever. Additionally, a 4-fold rise in antibody titers was considered diagnostic of Q fever. Results were analyzed using SPSS 17.0 for Windows. RESULTS: Among 105 patients (male: 52, female: 53), 35.2% (37/105) febrile patients had a positive serology test for acute Q fever. The prevalence of acute Q fever in women and men was 17/37 (45.9%) and 20/37 (54%), respectively. There was serological evidence of past infection in 36 (34.3%) patients. CONCLUSION: According to the results of our study, acute Q fever is highly prevalent in this province. Thus, it is necessary to pay attention to this disease to prevent its transmission in this region. PMID- 25558568 TI - Factors associated with the pain catastrophizing scale and validation in a sample of the Turkish population. AB - AIM: The aim of this study was to validate the Pain Catastrophizing Scale (PCS) in the Turkish population and to investigate its correlation with the demographic and clinical characteristics of patients. MATERIALS AND METHODS: Volunteer patients, who were scheduled for elective surgery and who applied to the Outpatient Clinic of Anesthesiology for preoperative evaluation, were asked to complete a PCS form. The patient's age, sex, educational level, marital status, presence of chronic pain, and American Society of Anesthesiologists score were recorded, and PCS scores and demographic variables were compared statistically. RESULTS: Of the 257 patients enrolled in the study, 136 were male, 121 female, and the median age was 40. The 3 subscales in the Turkish version of the PCS consisted of rumination, magnification, and helplessness. Internal consistency of PCS was found to be congruent with Cronbach's alpha = 0.90. Significantly higher PCS scores were found in women with chronic pain. In addition, patients who graduated from primary school had statistically higher scores compared to those who graduated from high school. CONCLUSION: In accordance with the original scale, demographic specifications of the Turkish version of the PCS were found congruent. PCS scores in our population were found compatible with the literature review. PMID- 25558569 TI - Bone mineral density and vitamin D status in children and adolescents with congenital adrenal hyperplasia. AB - AIM: To determine the prevalence of and risk factors for decreased bone mineral density (BMD) and vitamin D deficiency in children and adolescents with congenital adrenal hyperplasia (CAH). MATERIALS AND METHODS: This study was conducted on 30 girls and 22 boys with CAH (age range = 5-20 years) with median age of 12.0 years. BMD values of lumbar vertebras (L1-L4), which were determined by dual-energy X-ray absorptiometry, were used to calculate z-scores according to chronological age. A serum 25-hydroxyvitamin D level of <15 ng/mL was considered as indicative of vitamin D deficiency. RESULTS: Mean vitamin D level was 14.8 ng/mL in the whole group. Twenty-seven (51.9%) children had vitamin D deficiency and it was more prevalent during pubertal ages. Vitamin D levels were found to be significantly lower in pubertal females. BMD z-score was below -1 standard deviation in 40.1% of cases with significantly higher mean age and lower vitamin D levels. CONCLUSION: Decreased BMD z-score and vitamin D deficiency were common in these children with CAH. Vitamin D levels were significantly lower in girls and pubertal children. Decreased BMD z-score was related to older age and lower levels of vitamin D. Periodical controls of vitamin D status and vitamin D supplementation were recommended in these cases, whenever required. PMID- 25558570 TI - Protective role of caffeic acid phenethyl ester on serum cholinesterase inhibition by acute exposure to diazinon in rats. AB - AIM: To evaluate whether caffeic acid phenethyl ester (CAPE), a flavonoid-like natural compound plentifully found in beeswax, has a protective effect on diazinon-induced serum cholinesterase (ChE) inhibition in rats. MATERIALS AND METHODS: Animals were divided into 4 groups. The first animal group was not treated with any substance. The second animal group was orally given a 200 mg/kg body weight (bw) sublethal dose of diazinon. The third animal group was injected intraperitoneally with 2.84 mg (10 micromol)/kg bw of CAPE 1 day prior to administration of 200 mg/kg bw of diazinon orally. The fourth animal group was intraperitoneally injected with 2.84 mg (10 tmol)/kg bw of CAPE 30 min after 200 mg/kg bw of diazinon was orally administered. RESULTS: Analysis of the animal blood samples obtained 48 h after diazinon administration revealed that diazinon decreased serum ChE activity by 75%, while CAPE administration 24 h prior to and 30 min following diazinon application improved serum ChE activity by 25%-32% as compared to levels with diazinon administration only. In silico studies suggest that CAPE prevents diazinon from binding to butyryl ChE due to a higher binding affinity than that of diazinon. CONCLUSION: Our laboratory findings suggest that CAPE plays a protective role against butyryl ChE inhibition by diazinon. PMID- 25558571 TI - Liver enzymes, mean platelet volume, and red cell distribution width in gestational diabetes. AB - AIM: To investigate the value of measuring liver enzymes, red cell distribution width (RDW), and mean platelet volume (MPV) in predicting the development of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: The medical records of all pregnant women followed by the obstetrics clinic between January 2010 and November 2012 were systematically evaluated, and patients with a diagnosis of GDM were identified. A total of 68 patients with GDM and 61 healthy controls were included in the study. Results of relevant laboratory parameters were recorded. RESULTS: Out of all the parameters evaluated, mean values for platelet distribution width (PDW) and mean activities of alanine transaminase (ALT) and gamma-glutamyl transferase (GGT) were significantly higher in the GDM group compared to healthy controls (P = 0.003, P = 0.015, and P = 0.021, respectively), whereas mean plateletcrit (PCT) levels were significantly lower in the GDM group (P = 0.002). No significant difference was observed between groups in terms of MPV, RDW, platelet count, and aspartate transaminase levels. CONCLUSION: Our study results suggest that ALT, GGT, PCT, and PDW may be useful as predictors of impending GDM. PMID- 25558572 TI - Detection of cagA and vacA genotypes of Helicobacter pylori isolates from a university hospital in Ankara region, Turkey. AB - AIM: The cagA and vacA profiles and their association with clinical findings show a distinct geographical distribution. In the present study, we aimed to determine the cagA status and vacA allelic subtypes in strains isolated from a university hospital in Ankara and to evaluate their associations with histopathological and endoscopic findings. MATERIALS AND METHODS: A total of 120 H. pylori strains from stock cultures positive for the ureA gene were randomly included in the present study. Of these strains, cagA and vacA allelic subtypes (s1a, s1b, s2, m1, m2) were examined by polymerase chain reaction. RESULTS: Of the 120 strains, 64 (53.3%) were cagA-positive. However, no significant relationship was found between clinical outcomes and cagA positivity. There were 38 (33.6%) strains that had vacA m1 and 74 (65.5%) that had vacA m2 region. Overall, 75 (70.1%) samples were classified as vacA sla, 3 (2.8%) as vacA slb, and 29 (27.1%) as vacA s2. There was no significant relationship between vacA genotypes and endoscopic findings. The predominant vacA genotypes were slam2 (35.6%) and slam1 (33.6%), with almost the same rates. Furthermore, cagA positivity was found to be significantly related with the vacA slam1 genotype. CONCLUSION: The cagA and vacA profiles of our study population are consistent with the Middle Eastern profile. PMID- 25558573 TI - Epistaxis in geriatric patients. AB - AIM: Epistaxis is a common emergency in otolaryngology. The aim of this study is to analyze the etiology, management, and accompanying disorders of epistaxis in geriatric patients by reviewing the literature MATERIALS AND METHODS: Data of 117 patients 65 years old and older who presented to the Department of Otorhinolaryngology with active epistaxis between 2004 and 2010 were retrospectively reviewed. Records were evaluated for age, sex, accompanying disorders, drug medication, detailed otorhinolaryngological findings, and management of epistaxis. RESULTS: There were 67 women (57.26%) and 50 men (42.74%) with a mean age of 73.51 years (range: 65-90). Ninety-four (80.34%) patients had accompanying disorders such as hypertension, diabetes mellitus, cerebrovascular disease, sinusitis, chronic obstructive lung disease, nasal polyp, and drug treatment. The bleeding site was anterior in 90 patients (76.92%) and posterior in 16 (13.67%). In 11 patients (9.4%), the bleeding site was not identified. Fifty-seven patients (48.71%) were treated with cauterization, 17 patients (14.52%) with nasal packing, 12 patients (10.25%) with medical treatment, 1 patient (0.85%) with mass excision and nasal packing, and 19 patients (16.23%) with more than 1 treatment method. Six patients (5.12%) were untreated because of the unidentified bleeding point. Bleeding control was performed under local anesthesia in 113 patients (96.58%) and under general anesthesia in 4 patients (3.41%). Twenty-one patients (17.94%) were hospitalized and 3 patients (2.56%) required a blood transfusion. CONCLUSION: Epistaxis is the most common otorhinolaryngological emergency. It must be evaluated carefully to avoid the potential complications resulting from both epistaxis and its associated disorders, especially in geriatric patients. PMID- 25558574 TI - Indoor air quality in primary schools in Kecioren, Ankara. AB - AIM: To increase the awareness of environmental risk factors by determining the indoor air quality status of primary schools. MATERIALS AND METHODS: Indoor air quality parameters in 172 classrooms of 31 primary schools in Kecioren, Ankara, were examined for the purpose of assessing the levels of air pollutants (CO, CO2, SO2, NO2, and formaldehyde) within primary schools. RESULTS: Schools near heavy traffic had a statistically significant mean average of CO and SO2 (P < 0.05). The classrooms that had more than 35 students had higher and statistically significant averages of CO2, SO2, NO2, and formaldehyde compared to classrooms that had fewer than 35 students (P < 0.05). Of all classrooms, 29% had 100 CFU/100 mL and higher concentrations of microorganisms, which were not pathogens. CONCLUSION: Indoor air quality management should continually be maintained in primary schools for the prevention and control of acute and chronic diseases, particularly considering biological and chemical pollution. PMID- 25558576 TI - Evaluation of outer hair cell function and medial olivocochlear efferent system in patients with type II diabetes mellitus. AB - AIM: This study was designed to investigate the function of outer hair cells and medial olivocochlear efferents in type II diabetes mellitus (DM). MATERIALS AND METHODS: There were 50 patients with type II DM and 51 age- and sex-matched healthy controls included in the study. Both groups were compared in terms of transient evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAEs), and contralateral suppression of TEOAE. RESULTS: Pure tone thresholds of the patients with type II DM were significantly higher than in the controls (P < 0.05). The TEOAE amplitudes at 1 kHz and at 1.5, 2, 3, 4, and 6 kHz signal-to-noise ratio amplitudes on DPOAE testing were significantly lower in the patients than controls (P < 0.05). There was no significant difference between the type II DM and control groups regarding contralateral suppression test results of TEOAEs. CONCLUSION: Type II DM seems to impact the auditory system at the cochlear level by affecting the functions of outer hair cells, and it results in elevation of the thresholds on audiometry and a decrease in the amplitudes of otoacoustic emissions. PMID- 25558575 TI - Urinary tract infection in patients with chronic kidney disease. AB - AIM: Chronic kidney disease (CKD) has become a burden of health care globally. However, data on epidemiology, clinical features, and outcomes of urinary tract infection (UTI) in this population are scarce. This study aims to retrospectively review such data. MATERIALS AND METHODS: A retrospective cohort study was conducted from 1 January 2005 to 31 December 2011 in patients with CKD requiring hospitalization. Patients who had upper and lower UTIs were compared for demography and clinical data. Logistic regressior was used to assess which variables were associated with upper UTI. RESULTS: A total of 276 bacteriuria patients were admitted to our ward with upper and lower UTIs. The average ages of the upper and lower UTI patients were 59.21 +/- 16.54 and 71.18 +/- 14.77 years, respectively. The results of logistic regression analysis showed that age (OR 0.946, P < 0.001), female sex (OR 4.695, P < 0.001), and renal stones (OR 8.232, P < 0.001) were independently associated with upper UTI. CONCLUSION: This study shows that patients with CKD and UTIs were elderly, and that females were prone to have more bacteriuria and upper UTIs than males. In addition, patients who had renal stones were more prone to have upper UTI than other bacteriuria patients Aggressive treatment of renal stones should be considered in these patients. PMID- 25558577 TI - Ocular surface culture changes in patients after septoplasty. AB - AIM: To investigate the interrelationships between pre- and postoperative microbiological changes by taking samples from both eyes of 40 patients who underwent septoplasty due to septal deviation. MATERIALS AND METHODS: Forty patients diagnosed with septal deviation who underwent a septoplasty operation under general anesthesia were enrolled in this study. The study was conducted on 40 patients who met the inclusion criteria and attended follow-up visits. One day before the operation and 48 h after the operation, cultures were taken individually from the conjunctivas and puncta of both eyes and sent to the microbiology laboratory. RESULTS: Patients who were candidates for nasal surgery due to their symptoms and clinical examination results were randomly selected and 40 of these completed the study. No statistically significant differences in bacterial growth were observed between the eyes before the operation (P > 0.05). There were, however, statistically significant differences between the eyes in terms of bacterial growth in the postoperative period (P < 0.05). Pathogenic bacterial cultures were grown in 47 eyes in the postoperative period, and this finding was statistically significant. In the eye cultures, the most commonly isolated pathogens were S. epidermidis, and S. aureus. CONCLUSION: Although the indicated microorganisms isolated from the patient groups were grown in cultures, there were neither clinical symptoms nor signs related to ocular infections. PMID- 25558578 TI - An investigation of pulmonary findings of Crimean-Congo haemorrhagic fever patients. AB - AIM: Crimean-Congo haemorrhagic fever (CCHF) generally affects many organs. In this study a retrospective evaluation of the pulmonary findings of CCHF patients was made. MATERIALS AND METHODS: The records of patients were retrospectively analysed. For each patient an evaluation was made of age, sex, occupation, place of residence, contact with ticks, smoking history, and pulmonary radiological and laboratory findings. A confirmed diagnosis of CCHF was made on determination by enzyme-linked immunosorbent assay or polymerase chain reaction. RESULTS: Of the 128 patients, 48.4% were female. Symptoms of coughing were determined in 18% of patients, sputum in 4.7%, chest pain in 3.9%, dyspnoea in 3.1%, and haemoptysis in 0.8%. The mortality rate was 7%. In terms of sex, place of residence, contact with ticks, smoking, findings of the respiratory system, and physical examination findings, no statistically significant difference was seen between the survivor and nonsurvivor groups (P > 0.05). The white blood cell count values of the survivors were determined to be significantly lower compared to those of the nonsurvivors and the alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine phosphokinase, and C-reactive protein values of the nonsurvivors were significantly higher compared to those of the survivors (P < 0.05). CONCLUSION: CCHF can be fatal for the respiratory system. An early diagnosis of CCHF and referral to a specialised centre is therefore important. PMID- 25558579 TI - Evaluation of malaria cases in individuals after traveling to endemic regions of the world. AB - AIM: This study evaluates types of malaria and treatment success in a series of identified cases among individuals who were presumed to have travelled to regions where malaria is endemic. MATERIALS AND METHODS: In Sema Hospital, 25 cases of malaria (5 in women, 20 in men) were diagnosed during the 6-year period between 2006 and 2012. The mean age of the patients was 34.5 years. Diagnoses were established with thick and thin peripheral blood smears that were parasite positive. These tests were then compared to the rapid diagnostic test based on Plasmodium falciparum histidine-rich protein 2. RESULTS: All cases demonstrated fever beginning with chills. Three patients had prophylaxis with doxycycline, but all stopped the prophylaxis early of their own volition. P. falciparum was the parasitic agent in all cases. A regimen of artemisinin and lumefantrine was administered in 18 of the 25 cases; quinine plus doxycycline was given in 3, and chloroquine was administered in the remaining 4. Usage of these regimens cured all cases of malaria without complications. CONCLUSION: The importance of prophylaxis of malaria was demonstrated. Malaria should also be included in the differential diagnosis of patients with fever that have a history of travel to endemic regions. PMID- 25558581 TI - [Toward the online submission]. PMID- 25558580 TI - Right-sided double-lumen tubes: need for design improvement and better insertion technique? PMID- 25558582 TI - [A 3-year-old boy showing an episode of epileptic status provoked by high fever]. PMID- 25558583 TI - [Histopathologic features of epileptogenic brain lesions in infants and children]. AB - I retrospectively reviewed the histopathologic features of surgical specimens taken consecutively from 600 patients with intractable epilepsy, and showed the scope of variation in lesions responsible for epileptogenesis. The patients were divided into three groups on the basis of age at seizure onset: 94 patients with infantile onset (before 1 year of age), 307 patients with juvenile onset (between 1 and 12 years of age), and 199 patients with adolescent/adult onset (at 13 years of age or beyond). In the infant group, seizure duration was significantly shorter than in the other groups, and malformations caused by abnormalities of cortical development, including focal cortical dysplasia (FCD) type II a/b, tuberous sclerosis, hemimegalencephaly, and polymicrogyria were predominant, whereas in the juvenile and adolescent/adult groups, other lesions such as hippocampal sclerosis (HS), tumors, FCD type I, and vascular lesions were frequently observed. FCD type III a was noted in nearly half of patient with HS in both juvenile and adolescent/adult groups. The causative tumors included dysembryoplastic neuroepithelial tumors, gangliogliomas, astrocytomas, and other glioneuronal and glial tumors. Thus, various histopathological entities and types, showing clear predominance depending on the age at seizure onset, were observed in patients with epilepsy. These features appear to provide information on the pathomechanisms of the lesions and their clinical relevance in affected patients. PMID- 25558584 TI - [Evaluation of six cases with hypothalamic hamartoma: the relationship between MRI findings and clinical features]. AB - OBJECTIVE: We evaluated the relationship between MRI findings and clinical features in patients with hypothalamic hamartoma (HH). METHODS: We retrospectively reviewed MRI and clinical data (mental retardation, precocious puberty, behavioral problems, and epilepsy) in six patients (3 males and 3 females, ages 12 to 26) with HH. Based on the MRI classification by Arita, HH was classified into two types: parahypothalamic (P) and intrahypothalamic (I). RESULTS: Only one patient was classified as having P-type HH and five were classified as having I-type HH. The patient with P-type HH (diameter 21 mm) showed precocious puberty and mild behavioral problems, but did not developed epilepsy. On the other hand, all patients with I-type HH (diameter 10-32 mm, median 17 mm) developed epilepsy and behavioral problems. Except for one patient, who had the smallest sized HH, I-type four patients developed mental retardation and precocious puberty. Among patients with I-type HH, the size of the tumor was inversely correlated with the age at epilepsy onset and with the degree of mental retardation (DQ/IQ). CONCLUSION: Our data suggested that the MRI classification by Arita, when combined with tumor size, might be helpful in predicting the clinical manifestations in patients with HH. PMID- 25558585 TI - [Relationship between magnocellular function and reading skills in children: a study using visual evoked potentials]. AB - OBJECTIVE: Developmental dyslexia (DD) is a neurodevelopmental disorder that is characterized by difficulties with accurate and/or fluent word recognition and by poor spelling and decoding abilities. The magnocellular deficit theory is one of several hypotheses that have been proposed to explain the pathophysiology of DD. In this study, we investigated magnocellular system dysfunction in Japanese dyslexic children. METHODS: Subjects were 19 dyslexic children (DD group) and 19 aged-matched healthy children (TD group). They were aged between 7 and 16 years. Reversed patterns of black and white sinusoidal gratings generated at a low spatial frequency, high reversal frequency of 7.5 Hz, and low contrasts were used specifically to stimulate the magnocellular system. We recorded visual evoked potentials (VEP) from the occipital area and examined their relationship with reading and naming tasks, such as the time to read hiragana characters, rapid automatized naming of pictured objects, and phonological manipulation. RESULTS: Compared to the TD group, the DD group showed a significantly lower peak amplitude of VEPs through the complex demodulation method. Structural equation modeling showed that VEP peak amplitudes were related to the rapid automatized naming of pictured objects, and better rapid automatized naming resulted in higher reading skills. There was no correlation between VEP findings and the capacity for phonological manipulation. CONCLUSIONS: VEPs in response to the magnocellular system are useful for understanding the pathophysiology of DD. Single phonological deficit may not be sufficient to cause DD. PMID- 25558586 TI - [An analysis of the developmental trajectory of children with autism spectrum disorders]. AB - OBJECTIVE: To investigate the factors that affect the developmental trajectory in autism spectrum disorders (ASD) by means of a questionnaire-based retrospective analysis. METHOD: This study included 292 consecutive Japanese children with ASD who visited the pediatric developmental clinic at the Osaka University Hospital. Questionnaires were completed by caregivers on their first visit and were used for obtaining demographic information as well as nurturing environment and history of supportive intervention. Caregivers also fulfilled out The Infant Behavior Checklist (revised, in Japanese), and The Children's Behavior Questionnaire (revised, in Japanese). The scores for autistic traits during infancy and at present were compared in order to evaluate the developmental trajectory. RESULTS: Early intervention may attenuate ASD symptoms, whereas unfavorable domestic conditions, any psychiatric or neurological disorder in a family member, and epilepsy as a co-morbidity may aggravate these symptoms. In addition, impaired social interaction among all other ASD symptoms was specifically improved by early intervention, even if such intervention was not tailored to ASD. CONCLUSION: Early intervention and family support are important for children with ASD to promote their social development. PMID- 25558587 TI - [Successful treatment of epilepsy and circadian rhythm disturbance with levetiracetam in a patient with dentatorubral-pallidoluysian atrophy (DRPLA)]. AB - We report a 21-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA) showing progressive myoclonus epilepsy (PME), who responded to levetiracetam (LEV) at an initial dose of 1,000 mg/day. The patient developed epilepsy at the age of 10 years, and also showed intellectual regression. Various antiepileptic drugs showed no effects on generalized tonic seizures, tonic-clonic seizures, and myoclonus. Addition of LEV (1,000 mg/day) led to the reduction of myoclonus and tonic-clonic seizures, and improved the EEG and sleep-wake rhythm. He had a better appetite and gain weight. It is suggested that LEV may improve quality of life in patients with DRPLA, in addition to reducing the frequency of epileptic seizures. PMID- 25558588 TI - [A case of acute encephalitis with refractory repetitive partial seizures successfully controlled by very-high-dose phenobarbital therapy found in a boy]. AB - We experienced a case of acute encephalitis with refractory, repetitive partial seizures (AERRPS) found in an 8-year-old boy. Convulsive status epilepticus developed at the onset, which was intractable to the treatment with intravenous thiopental sodium even at the maximum dose of 9 mg/kg/hr. Since the adverse effect developed, thiopental sodium was discontinued. Phenobarbital (PB) was administrated at a very high daily dose up to 80 mg/kg, reaching serum trough level of 250 MUg/ml, which was markedly effective to the treatment. Because seizures reappeared during tapering the dosage of PB, potassium bromide (KBr) at a daily dose of 80 mg/kg was additionally administrated. PB was successfully tapered into a daily dose of 20 mg/kg with a trough serum level around 80 MUg/ml. He recovered in motor functions, but had disturbance of memory and apneic seizures. A very-high-dose PB therapy in an early period may be helpful for the treatment of intractable convulsive status epilepticus. PMID- 25558589 TI - [A case of neonatal herpes simplex virus encephalitis with characteristic MRI features in the early period]. PMID- 25558590 TI - [Sleep-related breathing disorders in pregnancy--a predictor of pre-eclampsia?]. AB - Sleep disorders are common in pregnancy. Several hormonal and physiological changes have been shown to affect the quality of sleep. Sleep disorders have been related to various pregnancy complications, e.g. pre-eclampsia. In particular, sleep apnea is more common among women who develop hypertension in pregnancy or pre-eclampsia. Compared with control patients, snoring is similarly more often apparent in women who will have pre-eclampsia manifested. Hence, the relationship between sleep disorders and pre-eclampsia warrants investigation. CPAP treatment has been proven to be effective in sleep apnea, but also in lowering blood pressure. CPAP may be useful also in the prevention and treatment of pre eclampsia. PMID- 25558591 TI - [Reversible cerebral vasoconstriction syndrome]. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is increasingly recognized. The condition is characterized by multifocal vasoconstriction lesions in cerebral arteries. Headache is the central symptom, with an acute onset and paroxysmal occurrence. Some of the patients develop intracranial hemorrhage, ischemic disturbance of the cerebral circulation, hypertensive encephalopathy (PRES) or epileptic seizures as complications. The disease is most common in middle-aged women. Most patients have an underlying predisposing factor, most commonly vasoactive medications, drugs or puerperium. There is no evidence-based practice. PMID- 25558592 TI - [Lie, whacking lie and pseudologia phantastica--pathological lying in factitious disorder]. AB - Pseudologia phantastica refers to chronic pathological lying without a clear motive. It is a symptom in the factitious disorder in adults, Munchausen syndrome and an illness made up for or inflicted on a child. Child abuse is often involved. Patients making up or causing symptoms for themselves of their child may have been exposed to similar behavior as a child. Some of them have received care and attention only through an illness. Pseudologia phantastica may then in adulthood be directed to making up or causing illnesses for oneself or another person. PMID- 25558593 TI - [Medical emergency treatment is here to stay]. AB - Lifelessness in a hospital ward is usually due to an hours-long disturbance of vital functions. The earlier the worsening of the patient's condition is observed, the simpler will the therapeutic measures often be that are sufficient to correct the condition. The medical emergency team will be called to a critically ill patient. The personnel of the hospital ward must be able to recognize in time a patient who will benefit from intensifying the treatment. The most important link of the medical emergency treatment chain is in fact the same as outside the hospital--calling for help early enough. PMID- 25558594 TI - [Childhood and adolescent cancer was cured--how to support health in adulthood?]. AB - The number of long-term survivors after cancer therapy in childhood and young adulthood is increasing. Accordingly, life-long follow-up of significant health problems related to the given cancer therapy is needed as only one third of the survivors will remain free of any physical or psychosocial late effects. At present, national activity is needed to establish a uniform follow-up clinic service to support education, diagnostics, therapy and rehabilitation of these long-term adverse effects after cancer therapy at young age. PMID- 25558595 TI - [Apolipoprotein A-I and B in laboratory diagnostics of dyslipidemia--what benefits do we gain compared with cholesterol measurements?]. AB - Laboratory diagnostics of dyslipidemia has been based on serum total cholesterol, HDL- cholesterol, triglycerides, and calculated or direct LDL-cholesterol measurements. Apolipoprotein A-I (apoA-I) is the main protein in HDL particles, and apoB is the main protein in all other atherogenic lipoprotein particles. An increased number of apoB-containing lipoproteins with normal total and LDL cholesterol is a common feature associated with obesity, metabolic syndrome, or type 2 diabetes. If the risk assessment of cardiovascular disease in these cardiometabolic disturbances is primarily based on LDL-cholesterol levels, the actual risk may be underestimated. Instead of cholesterol measurements, ApoA-Iand apoB measurements could produce more specific information on dyslipidemia. PMID- 25558596 TI - [Type 2 diabetes--hereditary destiny or punishment of the affluent society?]. AB - The pandemic of type 2 diabetes is threatening the entire world population. The number of obese people in the world has quadrupled over the last 30 years. It is clear that the human genome has not undergone such a rapid change, and thus alone does not explain the increased obesity. In fact, the rapidly changing society seems to be on a collision course with the genome. Through gene research we may hopefully learn the mechanisms by which the genome of some people makes them susceptible to type 2 diabetes while simultaneously protecting against the effects of unfavorable environmental factors and diabetes. PMID- 25558597 TI - [Treatment of endometrial carcinoma]. AB - The mainstay of the initial treatment for endometrial carcinoma is surgery with total hysterectomy and bilateral salpingo-oophorectomy. Pelvic-aortic lymphadenectomy may be appropriate for patients having tumors with a high risk for extrauterine spread. Most importantly, these include carcinomas with deep (>= 50%) myometrial invasion, poor differentiation, or nonendometrioid histology, in which lymphadenectomy aids in prognostication and tailoring of adjuvant treatments. Vaginal cuff brachytherapy ensures vaginal control in stage I endometrioid carcinomas with high-risk features. For advanced carcinomas, chemotherapy is the adjuvant treatment of choice, combined with whole pelvic external beam radiotherapy in selected cases. PMID- 25558598 TI - [Update on current care guideline: hypertension]. AB - Diagnosis is based on four sitting duplicate blood pressure measurements and confirmed by self- measurements or ambulatory monitoring.To reduce the overall cardiovascular risk, lifestyle-guidance is delivered. Drug treatment is initiated, if 1) the systolic pressure is at least 140 or diastolic at least 90 mmHg, and 2) home-measured or daytime ambulatory systolic pressure is at least 135 or diastolic at least 85 mmHg. The general goal is systolic/diastolic pressure below 140/90 mmHg. The goal is higher for the elderly and lower for patients with diabetes, kidney disease and albuminuria. Combination drug treatment is often needed. PMID- 25558599 TI - [Future of gynecological exfoliative cytology specimen, the Pap test]. AB - Screenings of cervical cancer in Finland by using the Pap test have decreased the incidence of the disease by approx. 80%. Automation-assisted cytology and liquid based Pap test have improved the technical quality of cytological examination. The HPV test allows the prevention of more cancers and its negative predictive value is crucially better than that of the Pap test. Its problem is the modest specificity in young age groups. When the HPV-vaccinated age groups reach the screening age, the HPV test should be adopted as the first-line screening test in all age groups. The Pap test will continue to have an important role as a further investigation and diagnostic specimen. PMID- 25558600 TI - [Cytology is in pivotal role at screening and surveillance of PSC]. AB - Primary sclerosing cholangitis (PSC) is an autoimmune disease leading to biliary strictures and inflammation. The lifetime risk for cholangiocarcinoma (CCA) among PSC patients is 7-13%, and biliary dysplasia is thought to be a precursor lesion for CCA. The diagnosis of PSC is based on endoscopic retrogradic cholangiography (ERC). During ERC brush cytology samples are routinely taken in our unit to detect possible biliary dysplasia. With repeated cytological dysplasia, liver transplantation is considered. Aneuploidy in DNA flow cytometry may support the suspicion of dysplasia. PSC is the most common indication for liver transplantation in Finland, and half of transplantations are prophylactic. PMID- 25558601 TI - [Neck lump--fine-needle aspiration biopsy specimen in diagnostics and planning of therapy]. AB - In elucidating the cause of a non-tender neck lump, the age of the patient, location and finding on palpation of lumps, and clinical examination of ear, nose and throat disorders and possible other findings are crucial. Fine-needle aspiration biopsy specimen, most commonly obtained in connection with ultrasonic imaging, is a key method in diagnosing lumps of the neck and salivary gland region that are obviously noninflammatory. Ultrasonic imaging combined with a cytological specimen is primary in the case of otherwise normal clinical examination. PMID- 25558602 TI - [Solid tumors in children]. AB - A quarter of cancers diagnosed in those under 18 years of age are leukemias, another quarter being tumors of the central nervous system. The remaining cancers are solid tumors occurring elswehere in the body, most commonly lymphomas, soft tissue and bone sarcomas, neuroblastomas and Wilms tumors. In almost all cases, the treatment of these solid tumors consists of combinations of surgery, cytotoxic drugs and radiotherapy. Although the prognoses have improved, they exhibit variation even within tumor groups. New targeted therapies are being developed, but for the time being they do not have any significant role. PMID- 25558603 TI - [Irritant-induced asthma]. AB - Irritant-induced asthma is a rare disease, usually being caused by an accidental or other exceptionally strong exposure to substances irritating the respiratory passages. High-dose inhaled corticosteroid medication is immediately started at the emergency call service. If severe exposure is suspected, it is important to monitor the patient at least for a couple of days in hospital. Immediately after the acute stage diagnostic investigations are carried out, including a metacholine or histamine challenge test, since demonstration of airway hyperreactivity is of diagnostic and prognostic significance. The asthma may remain permanent. PMID- 25558605 TI - [Four years of simultaneous pancreas-kidney transplantations in Finland]. AB - The first simultaneous pancreas-kidney transplantation in Finland was performed in 2010. On a global scale, already more than 45,000 pancreatic transplantations have been performed. Pancreatic transplantation restores the blood glucose level to normal, but only at the cost of possible adverse effects due to surgery and anti-rejection drugs. Based on our experience with 24 patients, this operation has met the expectations and shown that simultaneous pancreas-kidney transplantation is a good alternative for selected type 1 diabetics instead of mere kidney transplantation. In the future we aim to conduct approximately 15 combined transplantations per year. PMID- 25558604 TI - [Neonatal virus infections]. AB - At birth the immune system of a neonate is immature and viruses can cause severe infections. Since the signs and symptoms of postnatal viral diseases can be identical to those in bacterial infections, viral diseases are often treated with antibiotics. Any infant with signs of serious infections, in whom no bacteria are found, should be suspected for a viral infection. Prevention of transmission of viruses and cohorting of infected infants should be practiced in NICUs. Since postnatal viral infections can have a long-term impact on the health in a child, all effective preventive and curative interventions should be utilized. PMID- 25558606 TI - [Renin-angiotensin system (RAS) in the bowel]. AB - The significance of the renin-angiotensin system (RAS) in blood pressure regulation is indisputable. In addition to the heart and circulatory system, its components have recently been shown to be expressed also in the digestive tract, pancreas, brain and eyes, raising the idea that the significance of RAS for the functions of the body may be much more complex than currently thought. Its effects in the digestive tract could involve regulation of smooth muscle of the blood vessels and bowel, changes in permeability of the gut mucosa, or functioning as a digestive enzyme. PMID- 25558607 TI - [Cost-effectiveness alone is not sufficient as basis for prioritization]. AB - Cost-effectiveness has been suggested as the sole ethical basis for prioritization systems. The methods of health economics per se may be beneficial in decision making situations of various types. The structure of Finnish healthcare system and value-based choices associated with the application of cost effectiveness make, however, utilizability more difficult than thought. Analysis of cost- effectiveness is worth using, but criteria and methods of decision making of health economics cannot be harnessed as tools for technocratic decision making. Value-based choices should be subjected to wide public debate. PMID- 25558608 TI - [Examination of neck pain in adults]. AB - An accurate diagnosis is not obtained for most patients suffering from neck symptoms. Benign nonspecific pain is most common. Knowledge of functional anatomy and neuroanatomy forms the basis of clinical examination. Anamnesis and clinical examination are utilized to explore the need for further investigation and therapy. No particular instrumental investigations are needed in the exploration of the pain, unless the symptoms and clinical findings indicate any severe or specific illness. In clinical work it is practical to divide neck pain into four groups: a severe or specific illness, nerve root entrapment, nonspecific neck pain and whiplash injury. PMID- 25558609 TI - [Transient hemorrhagic diathesis caused by prothrombin-binding antiphospholipid antibody in a child]. AB - We describe three previously healthy children who developed acute extensive bruises about two weeks after a mild stomach bug. Coagulation tests revealed a shortened thromboplastin time (TT), long PT time, low level of coagulation factor II, and positive lupus anticoagulant among the antiphospholipid antibodies. In one patient the clinical symptoms disappeared during a one-week course of prednisolone, another one received a prothrombin complex preparation as substitution therapy. In the third patient the symptoms were milder and vanished without any specific treatment. The levels of coagulation factor increased in all patients and the lupus anticoagulant disappeared within a couple of months. PMID- 25558613 TI - [Palindromic rheumatism or incipient rheumatoid arthritis--chances of drug therapy]. AB - A patient suffering from palindromic rheumatism has recurrent periods of pain and swelling of joints lasting for hours, days or maximally 1 to 2 weeks with an irregular pattern.The diagnosis can be made based on patient history and rheumatoid factor or anti-citrullinated peptide antibodies (positive in approx. 50 to 70%) or on the basis of patient history and objectively established joint swelling. Hydroxychloroquine and other ordinary antirheumatic drugs slow down or may even prevent the progression of palindromic rheumatism into chronic rheumatoid arthritis. PMID- 25558614 TI - [68Ga-DOTA-PET for neuroendocrine tumours]. AB - Neuroendocrine tumors (NET) are found in several organs and called NET tumors. They are relatively rare, most of them giving no symptoms and remaining undetected. Most NETs arise from the gut, stomach and bronchus. These tumors are diagnosed either by histology or by imaging. A typical feature of NETs is abundance of somatostatin receptors on the cell surface, which makes it possible to image the tumor by nuclear methods as well as estimate the response to treatment by somatostatin analogues ("theranostics"). In order to improve the diagnosis of NETs we started to produce 68Ga-DOTA peptides for PET. PMID- 25558615 TI - [The many causes of chronic pain in the groin]. AB - One or more causes may be revealed underlying chronic pain in the groin. Knowledge of the complex anatomy of the groin may provide hints about the cause of the pain. In addition to clinical studies, imaging studies are often needed, with X-ray, ultrasonography and in particular MR imaging of the pelvis being the most important ones. The latter provides the best information on the structures of the groin region and the surrounding soft tissues. We present two rare causes of pain in the groin, the diagnosis of which was delayed due to insufficient imaging. PMID- 25558616 TI - [Update on current care guideline: third molar]. AB - The aim of the guideline is to promote uniformity in the clinical decision making, improve the quality of care, and prevent health problems related to third molars. The main problem is partial eruption followed by local infection with symptoms concerning mainly young adults. Indications for extraction are symptoms, clinical or radiological pathology, other dental or general disease, and preventive removal. Antibiotics are useful in the prevention of postoperative infections. Prevention of nerve injuries of removals is emphasized, and several methods are presented from coronectomy to centralizing the difficult operations to experts. PMID- 25558617 TI - [Microenvironment directs the life of stem cells]. AB - The regeneration of human tissues requires actively dividing tissue-specific stem cells. These cells are maintained and functionally regulated by a specific microenvironment, the stem cell niche. The niche provides protection and produces signals that guide stem cell division and differentiation. As a consequence, the niche plays a significant role in maintaining the tissue throughout life, and thus impaired tissue regeneration associated with aging may be partly due to the non-functional stem cell niche. PMID- 25558618 TI - [Human stem cells in the treatment of pancreatic and hepatic diseases]. AB - The pancreas and the liver are developmentally closely connected with each other.The development of stem cell technology has enabled the production of functional pancreatic endocrine cells and hepatocytes from pluripotent human stem cells. The differentiation of cells takes place by mimicking the events of developmental biology on a cell culture dish. The research is aiming at the development of cell replacement therapy for diabetes and hepatic insufficiency. Transplantations of islet cells have proven the possibilities of this strategy as a replacement of insulin therapy. Although there are promising initial clinical observations on hepatocyte transplantation, the limited growth capacity of these cells restricts the efficiency of the treatment. PMID- 25558619 TI - [Stem cells in cancer]. AB - The adult body contains undifferentiated stem cells of various tissues which, when necessary, will divide and produce new differentiated cells to replace dying cells, for example. Malignant tumors contain also less common populations of cancerous cells having a higher capacity than other cancerous cells to produce progeny. Cell structure molecules and regulatory mechanisms similar to those observed on normal stem cells have been detected on these cancer stem cells. Production and self-regeneration of stem cell progeny are subjects, the regulation of which is hoped to reveal mechanisms providing a target for intervention to enable the control of the growth of cancer cells and healthy auxiliary tissue of the tumor. PMID- 25558620 TI - [Stem cell therapy of the eye]. AB - The structure of the eye and the currently available methods of ophthalmic surgery enable the development work on stem cell transplantations and their clinical implementation. For example the frequency of occurrence of age-related macular degeneration will increase significantly with the ageing population. Stem cell transplantations are therefore expected to be of considerable significance in the future treatment of ocular diseases. Clearly the farthest advance has been achieved with treatments developed for diseases of the cornea and the retina. Cell transplantations based on local stem cell transplantations are already in clinical use in some corneal diseases, and transplantations of retinal pigment epithelial cells differentiated from stem cells are being used in clinical studies. PMID- 25558621 TI - [Beating heart cells--targeted diagnostics, individual optimization of therapy and tailored cell therapies]. AB - Myocardial infarction causes scarring and loss of functional capacity of the heart, because the heart is itself unable to repair the damaged area. While the development of new forms of treatment for the repair of myocardial destruction has actually been investigated by introducing into the heart various stem cells present in an adult human, the efficacy of the treatments conducted in the studies has so far unfortunately been low. Embryonic stem cells and iPS cells are a highly significant research subject. Cardiomyocytes differentiated from stem cells are being studied also in drug testing, and they are expected to revolutionize drug development and safety tests of novel drugs as well as enable personalized medication in the future. PMID- 25558622 TI - [Bone to the chin from adipose-derived stem cells]. AB - Adipose-derived stem cells have already proven their effectivity, for instance in the experimental treatment of bone defects. Bone defects in the facial and cranial region are complicated, and finding a suitable autologous bone transplant for them is difficult. Stem cell treatments have already been carried out successfully, and preclinical experiments have aroused no concerns about safety. We describe means to prepare so-called personal replacements for bone defects from the patient's own stem cells isolated from the adipose tissue, and the course of experimental therapy of two stem cell patients. PMID- 25558623 TI - [New drugs for hepatitis C]. AB - Hepatitis C is an important risk factor of hepatocellular carcinoma and in Europe the most common cause of liver transplantation performed due to cirrhosis. Pharmacologic therapy of hepatitis C has long been based on the combination of pegylated interferon and ribavirin. Telaprevir and boseprevir improved the treatment options of relapse patients in particular, but their use has been limited by adverse effects, among other things. The second-generation virus specific drugs that are now becoming available revolutionize the treatment of hepatitis C. They are orally administrable and as combinations effective against all genotypes. The price of these drugs is, however, notably high. PMID- 25558624 TI - [Chronic cough: common problem, discontended patients]. AB - The prevalence of chronic cough is 10 to 15%. It has a strong negative impact on the patients' quality of life and it often causes depression. Many patients find medications unhelpful. Successful management of chronic cough requires the identification of the underlying condition like chronic rhinosinusitis, asthma, and asthma-like syndrome, and esophageal reflux disease. If the underlying condition cannot be identified or if the drug trials fail to help, the patient probably suffers from idiopathic chronic cough. A new paradigm has been introduced in which chronic cough is regarded as a primary condition. PMID- 25558625 TI - [Complications caused by lumbar puncture]. AB - Lumbar puncture is not a harmless procedure. Orthostatic headache is a common complication especially after diagnostic punctures. Increasing numbers of hemorrhages into the epidural or spinal space have been reported in recent times, most likely resulting from active thromboprophylaxis in connection with spinal and epidural anesthesia in surgical operations. All lumbar punctures are, however, associated with a risk for hemorrhage, particularly in those using anticoagulants such warfarin and low-molecular weight heparins as well as factor X and thrombin inhibitors. Neurologic complications caused directly during the puncture or from drug toxicity are mostly transient, persistent complications fortunately being rare. PMID- 25558626 TI - [Inevitable senile death]. AB - Many systems essential to ontogenesis become inappropriate in later life, leading to the ageing of cells and loss of regenerative capacity. Ageing tissues are thus increasingly susceptible to chronic diseases associated with ageing. Upon statistical analysis, the elimination of these diseases would bring about only approximately 15 additional years to the life expectancy. With developing therapies, the making of a precise disease diagnosis upon the eventual death will become increasingly difficult, whereby the term frailty syndrome is utilized. PMID- 25558627 TI - [Effectiveness of music in brain rehabilitation. A systematic review]. AB - There is no curative treatment for diseases causing brain injury. Music causes extensive activation of the brain, promoting the repair of neural systems. Addition of music listening to rehabilitation enhances the regulation or motor functions in Parkinson and stroke patients, accelerates the recovery of speech disorder and cognitive injuries after stroke, and decreases the behavioral disorders of dementia patients. Music enhances the ability to concentrate and decreases mental confusion. The effect of music can also be observed as structural and functional changes of the brain. The effect is based, among other things, on lessening of physiologic stress and depression and on activation of the dopaminergic mesolimbic system. PMID- 25558628 TI - [Excision of a naevus]. AB - Skin biopsy due to a changed appearance of a skin mole is a common cause for visiting a doctor. Skin biopsy is a surgical procedure involving the usual surgical complications that can be avoided with careful planning. Histological microscopic examination is the indication for skin biopsy. The main principle should be that if the patient or the physician is concerned about the skin tumor, it should be removed and referred for further analysis and definitive diagnosis. PMID- 25558629 TI - [von Hippel-Lindau disease]. AB - Von Hippel-Lindau disease is a rare autosomal dominant hereditary tumor syndrome. The most common manifestations of the disease include cerebellar and spinal hemangioblastomas, retinal angiomas, renal cysts and clear cell cancer, pheochromocytoma, tumors of the inner ear, pancreatic cysts and neuroendocrine tumors. Coordination of examinations and treatment as well as collaboration between specialties is important. Screening of family members is recommended, and those having VHL should be monitoried annually through the rest of their lives. PMID- 25558630 TI - [Cerebral oedema caused by sodium valproate]. AB - Sodium valproate is widely used as an antiepileptic drug. It has potential side effects and its overdosage is toxic. We present a case where a sodium valproate intoxication with severe cerebral oedema was managed in the intensive care unit with hemodialysis, levocarnitine and supportive care. PMID- 25558631 TI - [Update on current care guideline: resuscitation (newborn)]. AB - Every newborn has a right to efficient resuscitation on demand in all Finnish delivery units. All delivery units must have a round-the-clock readiness for emergency C-section and resuscitation of the newborn, and medical doctors capable of these must be immediately available. Every newborn should be evaluated for the need for resuscitation. When needed, resuscitation should be started without delay. Resuscitation of the newborn includes stimulation, ventilation, chest compressions and other hemodynamic support, ventilation being the most important of these. Regular training is required to maintain and improve the resuscitation skills of the personnel. PMID- 25558632 TI - Effects of the medial or basolateral amygdala upon social anxiety and social recognition in mice. AB - AIM: Though social anxiety and social recognition have been studied extensively, the roles of the medial or basolateral amygdala in the control of social anxiety and social recognition remain to be determined. This study investigated the effects of excitotoxic bilateral medial or basolateral amygdala lesions upon social anxiety and social recognition in-mice. MATERIALS AND METHODS: Animals at 9 weeks of age were given bilateral medial or basolateral amygdala lesions via infusion of N-methyl- D-aspartate and then were used for behavioral tests: anxiety-related tests (including open-field test, light-dark test, and elevated plus maze test), social behavior test in a novel environment, social recognition test, and flavor recognition test. RESULTS: Medial or basolateral amygdala lesioned mice showed lower levels of anxiety and increased social behaviors in a novel environment. Destruction of the medial or basolateral amygdala neurons impaired social recognition but not flavor recognition. CONCLUSION: The medial or basolateral amygdala is involved in the control of anxiety-related behavior (social anxiety and social behaviors) in mice. Moreover, both the medial and the basolateral amygdala are essential for social recognition but not flavor recognition in mice. PMID- 25558633 TI - Effects of intraabdominal pressure on mean platelet volume during laparoscopic cholecystectomy. AB - BACKGROUND/AIM: Intraabdominal hypertension is a common occurrence, especially in intensive care unit patients, and it has high mortality and morbidity rates. The onset is commonly insidious and the poor prognosis is attributed to the long delay in diagnosis. Unfortunately, diagnosis is often delayed until loss of function in the affected tissues has already occurred. The aim of this study was to determine the predictive value of mean platelet volume (MPV) in assessing the risk of intraabdominal hypertension. MATERIALS AND METHODS: Pneumoperitoneum during elective laparoscopic cholecystectomy was used as a model for intraabdominal hypertension. The study included 103 patients who met the inclusion criteria. MPV evaluations were made at 3 distinct times during laparoscopic cholecystectomy based on the actual intraabdominal pressure. RESULTS: MPV values during preinsufflation, insufflation, and desufflation were 8.483 fL (range: 6.7 to 11.1), 8.901 fL (range: 6.8 to 11.9), and 8.538 fl (range: 5.8 to 10.9), respectively. A statistically significant increase in MPV values was found during high intraabdominal pressures (P < 0.001). A significant decrease in MPV values was also detected with desufflation (P < 0.001). CONCLUSION: Increasing MPV values may reflect increased intraabdominal pressures, which may have a clinical implementation in intraabdominal hypertension. PMID- 25558634 TI - Neutrophil-lymphocyte ratio as a predictive factor for tumor staging in colorectal cancer. AB - BACKGROUND/AIM: In the preoperative period, simple methods to identify the tumor stage of colorectal cancer patients are needed. In recent years, the neutrophil lymphocyte ratio (NLR) has been used as a predictive parameter for systemic inflammatory response in many different clinical entities. This study aims to determine if the NLR predicts the tumor stage in colorectal cancer patients in the preoperative period. MATERIALS AND METHODS: A total of 206 patients diagnosed with colorectal cancer and admitted for surgical treatment over a 6-year period were identified from a retrospectively maintained database. NLR was calculated from preoperative full blood counts. NLRs were compared with the tumor stages as determined in histopathological reports and scanning tests to determine the extent of metastasis. RESULTS: We found NLRs to be statistically higher in patients with T3 and T4 tumors than in patients with T1 and T2 tumors (mean: 5.261 vs. 4.499, respectively, P = 0.010). Similarly, we found statistically higher NLR values in the N1 and N2 groups than in the NO group (mean: 6.597 vs. 4.501, respectively, P < 0.001). Additionally, NLRs were statistically higher in M1 patients than in MO patients (mean: 8.261 vs. 5.158, respectively, P = 0.004). CONCLUSION: In the preoperative period, NLR was found to be a valuable predictive parameter for tumor staging in patients with colorectal cancer, thus informing us as to the kind of tumor we will meet when we open the abdomen. PMID- 25558635 TI - Refeeding hypophosphatemia: a potentially fatal danger in the intensive care unit. AB - AIM: To determine the overall and comparative incidence of refeeding hypophosphatemia (RH) between enteral and parenteral nutrition in general adult intensive care unit (ICU) patients. MATERIALS AND METHODS: This study was performed as a retrospective analysis. A total of 117 patients who received enteral and parenteral nutrition were included in the study. Demographic characteristics, type of nutrition, daily energy intake, and serum phosphorus levels before and after the initiation of the nutrition were recorded for 7 days. RESULTS: The mean age of the patients was 65.8 +/- 16.7 years. RH was found in 61 patients (52.14%). There was no significant difference in RH with regard to nutrition type (P = 0.756). The duration of the ICU stay was longer in the patients with RH compared with the patients without RH [median: 12 (3-68) and 8.5 (3-41) days, respectively; P = 0.025]. The mortality rate was higher in patients with RH compared with patients without RH (P = 0.037). CONCLUSION: The incidence of RH was quite high in our medical ICU. The mortality rate and the duration of ICU stay were higher in the patients with RH than those without RH. PMID- 25558636 TI - Chronic moderate alcohol consumption induces iNOS expression in the penis: An immunohistochemical study. AB - AIM: To investigate the effect of moderate alcohol consumption on metabolic alterations, inducible nitric oxide synthase (iNOS), immunohistochemical distribution, and morphological damage to penile erectile tissue in rats. MATERIALS AND METHODS: Male Wistar albino rats were divided into 2 groups. Group 1 rats (control group, n = 8) received tap water ad libitum, and group 2 rats (n = 8) were fed with 20% ethanol. Increasing levels of alcohol were given to the rats over 12 weeks. Immunohistochemistry was then performed using the avidin biotin-peroxidase technique on 5-pm thickness tissue sections. Stained sections were examined by imaging microscope. RESULTS: Alcohol consumption resulted in a significant increase in iNOS immunoreactivity in the penile erectile tissue. Increased iNOS expression was determined in the tunica albuginea, cavernosal smooth muscle cells, trabeculae of connective tissue, arterioles, and the urethral epithelium. Moreover, chronic alcohol consumption resulted in decreasing serum testosterone and high density lipoprotein (HDL) levels with increasing cholesterol and triglyceride levels. CONCLUSION: Chronic moderate alcohol consumption can affect penile erectile tissue by increasing iNOS immunoreactivity and induce histopathological damage such as penile fibrosis. These abnormalities are also related to the defense mechanism against morphological damage. PMID- 25558637 TI - Protective effects of montelukast and Hypericum perforatum against intestinal ischemia-reperfusion injury in hamsters. AB - AIM: To evaluate the effects of montelukast and Hypericum perforatum against ischemia/reperfusion (I/R)-induced intestinal damage. MATERIALS AND METHODS: Twenty-eight hamsters were divided into 4 groups following midline abdominal laparotomy: control group (n = 7), I/R group (n = 7), montelukast and I/R (MIR) group (n = 7), and Hypericum perforatum and I/R (HPIR) group (n = 7). After 60 min of ischemia through obstruction of the superior mesenteric artery, 24 h of reperfusion was maintained. Ten minutes prior to the reperfusion period, the MIR group received 7 mg/kg of intraperitoneal montelukast and the HPIR group received 7 mg/kg of intraperitoneal Hypericum perforatum. Malondialdehyde, glutathione, myeloperoxidase, and cardiotrophin-1 levels were measured from blood samples. A semiquantitative histological evaluation was performed. RESULTS: Montelukast and Hypericum perforatum significantly reduced malondialdehyde levels and increased glutathione levels compared to the I/R group (P < 0.008). A statistically significant difference was also found between the I/R group and MIR and HPIR groups in terms of myelqperoxidase levels (P < 0.008). The MIR and HPIR groups showed increased cardiotrophin- 1 levels compared to the control and I/R groups (P < 0.008 for all). The MIR and HPIR groups showed significantly lower histological scores compared to the I/R group (P = 0.03 and P = 0.007, respectively). CONCLUSION: This study demonstrated the preventive effects of montelukast and Hypericum perforatum on I/R-induced intestinal injury. PMID- 25558638 TI - The McGrath Series 5 video laryngoscope versus the Macintosh laryngoscope: a randomized trial in obstetric patients. AB - BACKGROUND/AIM: Anesthesiologists have encountered various difficulties in securing the airway. Therefore, we compare the intubation times and hemodynamic changes between the McGrath Series 5 video laryngoscope and the Macintosh laryngoscope. MATERIALS AND METHODS: A total of 80 obstetric patients were divided into 2 groups, orotracheally intubated with either the McGrath video laryngoscope or the Macintosh laryngoscope. The intubation times, Cormack-Lehane grade, percentage of glottic opening, mean arterial blood pressure, and heart rates were compared among the groups. RESULTS: Intubation time in the McGrath video laryngoscope group was significantly longer than in the Macintosh laryngoscope group (P <0.01). The percentage of glottic opening was found to be higher in the McGrath video laryngoscope group (P = 0.002). CONCLUSION: The McGrath Series 5 video laryngoscope provides excellent views during orotracheal intubation in obstetric anesthesia with normal airways. PMID- 25558639 TI - The impact of antibiotic-impregnated catheters on ventriculoperitoneal shunt infection. AB - BACKGROUND/AIM: Ventriculoperitoneal shunt infections remain an important problem and result mainlyfrom perioperative colonization of shunt components by skin flora. Antibiotic-impregnated shunts have been designed to prevent such colonization. T'his study evaluates the incidence of shunt infection after the insertion of antibiotic-impregnated shunts in a population of children with hydrocephalus. MATERIALS AND METHODS: All pediatric patients who had undergone cerebrospinal fluid shunt insertion retrospectively were reviewed over a 6-year period between May 2004 and December 2010. The primary outcome measure was the rate of shunt infections. Patients were followed up with for an average of 26.2 months after shunt surgery, and shunt infections were evaluated. RESULTS: A total of 123 pediatric patients underwent 211 shunt placement procedures. Of these operations, 193 (91%) were performed with nonimpregnated catheters and 18 shunts (9%) were placed with antibiotic-impregnated shunt catheters. Of the patients with nonimpregnated catheters, 12 (6%) experienced shunt infection, whereas none of the patients with antibiotic-impregnated catheters experienced shunt infection within the 26.2-month follow-up period (P < 0.01). CONCLUSION: The antibiotic impregnated catheters significantly reduced the incidence of shunt infection in children with hydrocephalus during the postoperative period. Antibiotic impregnated catheters are effective devices to prevent perioperative colonization of shunt components. PMID- 25558640 TI - Gleason score at the margin can predict biochemical recurrence after radical prostatectomy, in addition to preoperative PSA and surgical margin status. AB - BACKGROUND/AIM: To evaluate the relation between biochemical recurrence (BCR) of prostate cancer and the extent of positive surgical margins (PSMs), Gleason score (GS) of the tumor at the margins, and preoperative prostate-specific antigen (PSA) levels. MATERIALS AND METHODS: A total of 94 patients who underwent radical prostatectomy were recruited for this study and received postoperative follow-up care for 2 years. All specimens were evaluated for surgical margin status, PSM length, GS at positive margin, size of tumor, multifocality, invasion of seminal vesicle, lymphovascular invasion, and perineural invasion. PSM was defined as a prostate tumor. RESULTS: Out of 94 patients, 34 patients (36.2%) had PSMs and 46 patients (48.9%) had BCR. A statistically significant relation between having a high risk of BCR of prostate cancer and having high preoperative PSA levels (P < 0.001), PSMs (P < 0.001), or a high GS at the surgical margin (P = 0.024) was found. CONCLUSION: High preoperative PSA levels, PSMs, and tumors with high GS at the margins have a poor prognostic impact, and they correlate with a higher rate of BCR. Close follow-up of patients with PSMs with high GS and high levels of preoperative PSA is recommended. PMID- 25558641 TI - Effects of whole-body vibration on plasma sclerostin level in healthy women. AB - BACKGROUND/AIM: To determine whether plasma sclerostin levels are affected by applying whole-body vibration treatments. MATERIALS AND METHODS: Following a pilot study, the pretsent prospective, randomized, controlled single-blind study was performed on 16 healthy volunteer women (ages 20 to 40 years). Subjects were randomly divided into 2 groups, and whole-body vibration was applied to the treatment group but not to the controls. The plasma sclerostin levels were measured before the treatment and at the 10th minute after whole-body vibration on the 1st, 2nd, and 5th days of application. RESULTS: The plasma sclerostin level measured at 10 min after the whole-body vibration treatment increased 91% (P = 0.024) on the 1st day and decreased 31.5% (P = 0.03) on the 5th day in the whole-body vibration group. In the control group, there was no change in the plasma sclerostin level at any time. A progressive increase in baseline plasma sclerostin levels during the 5 days of vibration sessions was also found. CONCLUSION: Our study demonstrated that whole-body vibration can change plasma sclerostin levels, and that this change is detectable 10 min after whole-body vibration treatments. PMID- 25558642 TI - The expression of EGFR, cerbB2, p16, and p53 and their relationship with conventional parameters in squamous cell carcinoma of the larynx. AB - BACKGROUND/AIM: To investigate the expression of epidermal growth factor receptor HER1 (EGFR), cerbB2 (HER2), p16, and p53, as well as the relationship of the expression of these genes with conventional parameters in squamous cell carcinoma (SCC) of the larynx. MATERIALS AND METHODS: Samples from 92 cases of diagnosed laryngeal SCC between 2001 and 2011 from the Pathology Department of Ministry of Health Ankara D1skapi Yildirinm Beyazit Teaching & Research Hospital were studied by immunohistochemistry using EGFR, cerbB2, p16, and p53 antibodies. RESULTS: An increase in the TNM stage and pathological tumor size status correlated with an increase in EGFR and cerbB2 expression. In the cases with lymphovascular invasion, the expression was detected at a higher ratio. Cases in which high levels ofpl6 and p53 expression were observed did not show any lymphovascular invasions. CONCLUSION: Expressions of p53 and p16 were considered to be most effective in early carcinogenesis stages of laryngeal SCC. In comparison with p53 and p16 expression levels, EGFR and cerbB2 expression levels were observed to be associated with poor prognostic parameters and were higher at later stages of laryngeal carcinogenesis development. PMID- 25558643 TI - Immunohistochemical investigation of galectin-3 in the skin of mice applied with Origanum hypericifolium essential oil and irradiated with ultraviolet B. AB - AIM: To demonstrate galectin-3-immunoreactivity in the undiluted essential oil of Origanum hypericifolium when applied to the ultraviolet B (UVB) irradiated skin of mice. MATERIALS AND METHODS: Female BALB/c mice were allocated to 4 groups, each comprising 6 mice (Group 1: control; Group 2: UVB irradiated control; Group 3: undiluted O. hypericifolium essential oil applied; Group 4: undiluted O. hypericifolium essential oil applied before UVB irradiation). One week prior to UVB irradiation, the undiluted O. hypericifolium essential oil was applied to, the shaved dorsal skin of mice 3 times a week. Subsequently, the mice were irradiated 3 times per week with UVB (week 1: 50 mJ/cm2, week 2: 70 mJ/cm2, and weeks 3 and 4: 80 mJ/cm2) for 4 weeks. At the end of this period, immunohistochemical staining for galectin-3 was performed on frozen sections of skin specimens, and then they were photographed. RESULTS: Numerous galectin-3 immunoreactive cells, whichwere considered to be immune system cells, were observed in the dermis of Group 3. CONCLUSION: It is suggested that undiluted O. hypericifolium essential oil may cause an increase in the galectin-3 immunoreactive cells. However, there is a need to research these findings with further molecular analyses. PMID- 25558644 TI - Relation of age and sex with carotid intima media thickness in healthy children. AB - BACKGROUND/AIM: To investigate the age- and sex-associated carotid intima media thickness (clMT) changes in healthy children to determine the age- and sex specific normal range of values for childhood. MATERIALS AND METHODS: This study examined 91 healthy school-age children aged 7-15 years prospectively. Standardized sonographic cIMT measurements and analyses were performed. Body mass index and blood pressure were obtained, and atherosclerotic risk factors were investigated. Age- and sex-specific cIMT measurements for different age groups were calculated and the relation with sex was investigated. RESULTS: Regarding the total study group, mean cIMT measurements for age groups 7-9, 10-12, and 13 15 years were 4.1 + 0.5 mm, 4.4 +/- 0.6 mm, and 4.6 +/- 0.4 mm, respectively. cIMT did not differ between boys and girls in the same age group. Age related analyses showed significant variations among the age groups with positive correlation between cIMT and age. CONCLUSION: Our results suggest that age related physiologic thickening of the carotid artery intima-media occurs not only in adults but also in children and that sex is not a factor for cIMT differences in childhood. PMID- 25558645 TI - Distribution of the hypoglossal nerve at the base of the tongue and its clinical importance in radiofrequency ablation therapy. AB - AIM: To identify the course of the hypoglossal nerve at the base of tongue and to determine a safe area for the placement ofradiofrequency ablation therapy (RAT) probes to protect the nerve trunk from any damage. MATERIALS AND METHODS: Anatomical structures located at the base of the tongue were investigated in 10 cadaveric human half-heads. On the base of our landmarks, which are clinically important sign points, measurements were made. RESULTS: The safe area was found to be: in the transverse plane, the 1/2 medial part of the half-tongue between the lateral edge and the foramen caecum of the tongue, and in the vertical plane, a 14.5-mm depth. Despite the presence of minor branches of the hypoglossal nerve in this area, we think that the trunk of the nerve would be preserved. CONCLUSION: We suggest that the landmarks that we determined to avoid motor deficit of the tongue will be helpful for clinicians during RAT to the tongue base. PMID- 25558646 TI - Is TrichoScan a new diagnostic method for diffuse hair loss? AB - AIM: In this study, we investigated the sensitivity of TrichoScan, a computer based phototrichogram, in the evaluation of diffuse hair loss in women and the relationship between iron deficiency anemia and hair loss. MATERIALS AND METHODS: We recruited 100 female patients with diffuse hair loss. In all of the patients, a 1-cm2 area of hair located in a temporoparietal region was shortened to 0.5 mm. The shaved scalp regions were stained with black dye. The subject then waited for 12 min. Subsequently, pictures of these regions were taken with a videodermoscope and analyzed with the TrichoScan software program. RESULTS: The ferritin levels were markedly low in these groups. The ratio of anagen was highest in the telogen effluvium (TE) mild group, followed by the TE severe group, and was lowest in the androgenetic alopecia (AGA) group (P <0.05). The ratio of telogen was markedly higher in the AGA group, and the difference was statistically significant when compared with the other 2 groups (P < 0.05). CONCLUSION: The hair analysis results with the TrichoScan software were satisfactory and the results were consistent with the clinical diagnosis. In particular, the use of TrichoScan was very successful in the differentiation between AGA and TE. PMID- 25558647 TI - Comparison of the efficacy of prednisolone, montelukast, and omalizumab in an experimental allergic rhinitis model. AB - AIM: To compare the efficacy ofprednisolone, montelukast, and omalizumab in reducing allergic symptoms and inflammation at tissue level in an experimental allergic rhinitis model. MATERIALS AND METHODS: Forty Sprague Dawley rats were randomized into 5 groups as naive (NS/NC), sensitized/challenged (S/C) by subcutaneous ovalbumin antigen injection, and montelukast-, prednisolone-, and omalizumab-treated groups. A nasal allergen challenge was performed every day from day 20 to day 26. The number of sneezes and nasal/eye rubbing movements, IL 4 and CysLT levels in serum, nasal and bronchoalveolar lavage fluids determined by ELISA, and histopathological findings of nasal mucosa, sinus, and lung tissues were compared. RESULTS: All of the treatments significantly controlled the allergic symptoms of sneezing and nasal/eye rubbing (P < 0.05). IL-4 and CysLT levels on days 20 and 26 were significantly higher in the S/C group compared to the NS/NC group (P < 0.05). Montelukast significantly decreased serum and nasal IL-4 and CysLT levels (P < 0.05), prednisolone decreased nasal lavage IL-4 and CysLT levels (P < 0.05), and omalizumab lowered nasal lavage CysLT levels (P < 0.05). CONCLUSION: Prednisolone, montelukast, and omalizumab were found to be effective in controlling the allergic symptoms of allergic rhinitis and upper/lower airway inflammation in an experimental allergic rhinitis model. PMID- 25558648 TI - Diastolic function of the right ventricle is impaired in experimental type 2 diabetic rat models. AB - AIM: To evaluate diastolic function alterations of the right ventricle (RV) by echocardiography in type 2 diabetic rat models. MATERIALS AND METHODS: Male Wistar rats were divided into 2 groups: a control group (n = 8) and a diabetic group (n = 16, with 11 remaining at the end of the experiment), which was fed a high-fat and high-calorie diet and injected with streptozotocin (STZ). RV diastolic functional alteration of rat models was studied by the tricuspid flow Doppler (Ep, Ap, and Ep/Ap) and tissue Doppler imaging (TDI) (Em, Am, and Em/Am) of the lateral tricuspid annulus. RV structural alteration of rat models was studied by standard 2D and M-mode echocardiography. RESULTS: Compared with-the control group rats, at the 12th week after STZ injection, the rats of the diabetic group developed RV diastolic dysfunction, lower Em, and lower ratios (Ep/Ap, Em/Am). At the end of the experiment, at the 16th week after STZ injection, the rats of the diabetic group showed further decreased Ep, Em, and ratios (Ep/Ap, Em/Am) and significantly higher RV diameters compared with the control group rats. CONCLUSION: We demonstrated that the diastolic dysfunction of the RV was the earliest complication observed in type 2 diabetic rat models, using TDI and tricuspid flow Doppler. TDI showed a high sensitivity in detecting changes of RV diastolic function. PMID- 25558649 TI - Neuropharmacological effects of methanolic extracts of Rubusfruticosus L. AB - AIM: To investigate methanol extracts of various parts of Rubus fruticosus L. (Rosaceae) for various neuropharmacological activities, such as anxiolytic, muscle relaxant, antidepressant, and sedative activities. MATERIALS AND METHODS: The extracts were administered to albino mice orally at doses of 100, 300, and 500 mg/kg. The antidepressant activity was determined by using the forced swimming test, while line crossing in a special box was used for assessment of locomotor activity. RESULTS: All extracts were found to be anxiolytic in nature, while no muscle relaxing activity or sedative effect was observed. The order of central nervous system (CNS) depressant effect for various parts of R.fruticosus was fruit > root > leaves > stem. CONCLUSION: Our results indicate that methanolic extract of various parts of R. fruticosus possess anxiolytic and CNS depressant effects but do not possess significant sedative or muscle relaxing potential. PMID- 25558650 TI - Detection of kinase amplifications in gastric adenocarcinomas. AB - AIM: To determine the incidences of copy number aberrations of receptor kinases and their relations in Turkish patients with gastric adenocarcinoma. MATERIALS AND METHODS: The prevalence of genomic copy number aberrations of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)/topoisomerase IIa (TOP2A), centrosome-associated kinase aurora A (AURK A), centrosome-associated kinase aurora B (AURK B), and mesenchymal-epithelial transition factor (MET) genes and polysomies of related chromosomes were analyzed by fluorescent in situ hybridization (FISH) in tumor samples from 35 patients with gastric cancer. RESULTS: There were 28.6%, 65.7%, 20.0%, 17.1%, 60.0%, and 45.7% cases considered FISH-positive for EGFR, MET, HER2, TOP2A, AURK A, and AURK B genes, respectively. Statistically significant associations were determined in detection of amplifications of 1) EGFR gene with chromosome 7 polysomy, 2) MET gene in nonpolysomic chromosome 7 nuclei, 3) HER2/TOP2A genes in nonpolysomic chromosome 17 nuclei, 4) coamplification of HER2/TOP2A in poorly differentiated carcinomas, and 5) AURK A gene in nonpolysomic chromosome 20 nuclei. Most of the aberrations were predominantly seen in poorly differentiated tumors, but a high rate of the amplified MET gene was also detected in moderately differentiated carcinomas. CONCLUSION: Chromosome 7 polysomy may be responsible for EGFR gene amplifications, and we concluded that MET and AURK A genes amplifications were commonly seen aberrations in gastric adenocarcinomas and may offer information about disease progression and administration of individualized treatment for gastric cancer patients. PMID- 25558651 TI - Protective effect of L-carnitine in a rat model of retinopathy of prematurity. AB - AIM: To investigate the effects of L-carnitine (LC) on rats with oxygen-induced retinopathy. MATERIALS AND METHODS: The study was conducted on 40 Sprague Dawley rat pups. The rat pups were randomly divided into 4 groups: group 1 (n = 10) the healthy control group with intraperitoneal 0.1 mL/day physiological saline injection; group 2 (n = 10), exposed to hyperoxygen, did not receive LC but received 0.1 mL/day physiological saline intraperitoneally; group 3 (n = 10), exposed to hyperoxygen and received 100 mg/kg/day LC intraperitoneally; group 4 (n = 10), exposed to hyperoxygen and received 200 mg/kg/ day LC intraperitoneally. After postnatal day 20, the rat pups were killed and an histological examination was performed on the eyes, in addition to the detection of plasma malondialdehyde (MDA) levels. RESULTS: The retinal and choroidal histopathological changes due to hyperoxygen were less in group 3 and minimal in group 4 compared with group 2. Compared with the healthy control group, the increase in the MDA levels in group 2 was significant (P <0.05). Compared with group 2 there was a significant (P < 0.05) decrease in the MDA levels in groups 3 and 4. CONCLUSION: LC has beneficial effects on oxygen-induced retinopathy in rats in terms of histopathological changes and MDA levels. PMID- 25558652 TI - Evaluation of patients with zygomycosis. AB - AIM: Zygomycosis is a severe angioinvasive infection caused by Zygomycetes. We retrospectively investigated 16 cases of zygomycosis. MATERIALS AND METHODS: The data of patients, who had been followed between 2004 and 2010 in 8 tertiary-care teaching hospitals, were reviewed. Demographic characteristics, underlying diseases, and clinical signs and symptoms of the patients, as well as diagnostic methods, data obtained by radiological imaging methods, and the therapies, were recorded. Therapeutic approaches, antifungal agents and duration of use, and the characteristics of the cases were identified. RESULTS: The study included 11 female and 5 male subjects. The most common symptoms and clinical signs were fever (n = 9) and retro- orbital pain (n = 7). Rhinocerebral zygomycosis was the most common form. The mean time elapsed for diagnosis was 14.26 + 13.96 (range: 2 52) days. Antifungal therapy was given to 15 patients (94%). In addition to antifungal therapy, 12 patients underwent surgical intervention 1 to 4 times. The mean duration of receiving antifungal therapy was 61.4 + 58.02 (range: 1-180) days. The median duration of treatment was 62.5 (range: 42-180) days in survivors. CONCLUSION: Zygomycosis is an infectious disease with high mortality despite antifungal therapy and surgical interventions. PMID- 25558653 TI - An anatomical study on the facial nerve trunk in fetus cadavers. AB - BACKGROUND/AIM: Facial nerve paralysis is the most worrying parotid surgery complication. Little attention has been paid to the facial nerve trunk, especially in children. Pathological variations, tumors, and anatomic variations of the facial nerve may cause parotid and facial nerve surgery difficulties. This study describes the facial nerve trunk. MATERIALS AND METHODS: We measured the facial nerve trunk from 8 female and 8 male fetus cadavers aged 21.0 to 35.5 gestational weeks. The locations and positions of the trunks were described. The length of the facial nerve trunk (K) was measured and bifurcation and trifurcation of the trunk was examined. Values were analyzed separately for right and left sides and for male and female fetuses. RESULTS: The most common facial nerve trunk type was bifurcation (81.25%), followed by trifurcation (18.75%). K was 11.59 + 2.80 mm in the total fetuses. There was no significant difference between K measurements. CONCLUSION: Facial nerve injury during parotid surgery is a main cause of pediatric facial paralysis. There are few previous descriptions of the facial trunk in children. K must be accurately known in any surgical procedure planned for the area. The main furcation of the facial nerve should also receive special attention. PMID- 25558654 TI - Early clinical predictors of intractable epilepsy in childhood. AB - AIM: In this retrospective study, we evaluated the clinical responses to antiepileptic drug (AED) therapy in pediatric epilepsy patients treated at a single center. MATERIALS AND METHODS: We identified 28 children with intractable epilepsy and 213 patients with drug-responsive epilepsy. RESULTS: Univariate analysis showed that age at onset, high (daily) initial seizure frequency, infantile spasm, history of neonatal seizures, abnormal neurodevelopmental status, neurological abnormalities, mental retardation, remote symptomatic etiology, and abnormal brain imaging results were significant risk factors for the development of intractable epilepsy (P < 0.05). Multivariate logistic regression analysis revealed that high (daily) initial seizure frequency and remote symptomatic etiology were significant and independent risk factors for intractable epilepsy (P < 0.05). CONCLUSION: Our study suggests that the risk of developing intractable epilepsy in childhood may be predicted, to some extent, by the early clinical course. Early identification of patients at high risk of developing intractable epilepsy will guide appropriate therapy and reduce exposure to ineffectual treatments. PMID- 25558655 TI - Resistin predicts ischemia in myocardial perfusion scintigraphy. AB - Aim: Resistin plays a role in the pathogenesis of coronary artery disease and is related to mortality and morbidity through a number of mechanisms. We hypothesize that plasma resistin levels are increased in the presence of ischemia, as measured by GATED single- photon emission computed tomography myocardial perfusion scintigraphy (SPECT MPS), in comparison with nonischemic subjects. MATERIALS AND METHODS: Fasting intravenous blood samples of patients were drawn before a stress test. An ELISA kit was used for the assays. All patients underwent a technetium 99m-sestamibi GATED SPECT MPS study with a 1-day stress rest protocol. Images were analyzed visually and patients were assessed as ischemic or nonischemic. Resistin levels were presented as medians (25th-75th percentiles) and were compared using the Mann-Whitney U test. RESULTS: Plasma resistin levels were higher in the ischemic group (n = 47) than in the nonischemic group (n = 67) [9.04 pmol/L (6.27-11.8 MUmol/L) vs. 3.56 MUmol/L (0.39-7.93 pnol/L), respectively; P < 0.001). We showed that plasma resistin levels (OR = 1.26, 95% CI: 1.13-1.41; P < 0.001) and METs (OR = 0.82, 95% CI: 0.70-0.92; P = 0.021) were independent predictors ofischemia. No linear correlation was found between plasma resistin levels and GATED SPECT or stress test parameters. CONCLUSION: Increased baseline resistin levels are independently related to presence of ischemia but are not related to the extent or severity of ischemia, or other functional parameters such as poststress ejection fraction, end systolic, and end diastolic volumes. PMID- 25558656 TI - The frequency of human papillomaviruses in colorectal cancer samples in Mashhad, northeastern Iran. AB - BACKGROUND/AIM: Infection with the human papillomaviruses (HPVs) is associated with the development of several cancers, including oral, esophageal, skin, lung, and cervical. However, the association of HPVs and colorectal cancers remains controversial. The aim of this study was to evaluate the association between HPV infection and paraffin-embedded colorectal tissue samples in Mashhad in the northeast of Iran. MATERIALS AND METHODS: Paraffin-embedded tissue specimens from 111 patients with colorectal cancer were subjected to DNA extraction. The quality of extracted DNA was confirmed by amplification of a P-globin fragment using polymerase chain reaction (PCR) and GH20/PCO4 primers. PCR with GP5+/GP6+ primers was then performed on positive samples to evaluate the sequence of HPVs. RESULTS: A total of 100 colorectal samples with positive results for the P-globin gene were analyzed. The age of patients ranged from 18 to 72 years (mean: 52). Sixty four patients (56.7%) were male and 47 patients (43.4%) were female. One (1%) out of 100 patients with colorectal cancer was found to be positive for HPV DNA. CONCLUSION: Results of the current study suggested that HPV infection is not common in patients with colorectal cancer in our population. We concluded that HPV types that are associated with malignant transformations do not meaningfully contribute to adenocarcinoma of the colon among our population. PMID- 25558657 TI - Comparison of cutaneous mastocytosis with onset in children and adults. AB - BACKGROUND/AIM: Mastocytosis is a heterogeneous group of diseases characterized by the abnormal infiltration of mast cells in the skin and sometimes other organs. This study aimed to compare the demographic, clinical, and histopathological findings of cutaneous mastocytosis with onset in children and in adults. MATERIALS AND METHODS: Patients diagnosed with cutaneous mastocytosis in 2 different dermatology clinics between 2007 and 2011 were included in the study. Demographic characteristics of the patients as well as localization and type of the cutaneous lesions, presence of symptoms, Darier's sign, family history, systemic involvement, and histopathological evaluations were retrospectively examined. RESULTS: Out of the 30 cases of cutaneous mastocytosis, 60% of patients were male (n = 18) and 40% were female (n = 12). Twenty-two patients had childhood-onset mastocytosis (<=15 years) and 8 patients had adult onset mastocytosis. The onset of the disease occurred before the age of 2 years in all cases of childhood onset. Patients with adult-onset mastocytosis had statistically significantly more systemic involvement than those with childhood onset mastocytosis (P < 0.05). CONCLUSION: Cutaneous mastocytosis is a benign disease in children without systemic involvement and is usually sporadic. PMID- 25558659 TI - Leiomyoma of the esophagus: open versus thoracoscopic enucleation. AB - BACKGROUND/AIM: To describe a novel, easy, and secure thoracoscopic surgical approach for esophageal leiomyomas. MATERIALS AND METHODS: We retrospectively analyzed 18 cases in which patients were treated at a single center between 1991 and 2011 for esophageal leiomyoma. We compared our results of patients who were treated by open surgery with those who were treated by the thoracoscopic approach, and we also compared our results with the results of resection of the leiomyoma of the esophagus in the literature. RESULTS: Eighteen patients were studied. Eight patients were treated with 3-port thoracoscopic surgery, 8 with open thoracotomy, 1 with surgical incision, and 1 with esophagectomy. The mean operating time was 167.5 min and 92.5 min in the thoracotomy and thoracoscopy groups, respectively (P = 0.0012). The average hospital stay was 9 days and 6 days for the thoracotomy and thoracoscopy groups, respectively (P = 0.016). Rupture of esophageal mucosa occurred preoperatively once in both groups and was repaired immediately, and postoperative esophageal leak was not seen in any patient. CONCLUSION: Thoracoscopic enucleation of esophageal leiomyomas is a safe and feasible procedure with decreased hospital stay and operating time. The 3 port technique that we used is a safe and effective procedure, as well. PMID- 25558658 TI - Prevalence of blaIMP, and blaVIM gene carriage in metallo-beta-lactamase producing burn isolates of Pseudomonas aeruginosa in Tehran. AB - BACKGROUND/AIM: To study the prevalence of blaVIM and blaIMP genes in metallo beta-lactamase (MBL)-producing burn isolates of Pseudomonas aeruginosa in relation with AmpC and extended-spectrum beta-lactamase (ESBL) production. MATERIALS AND METHODS: Thirty-two carbapenem-resistant MBL-producing P aeruginosa burn isolates from Shahid Motahari Burn Hospital in Tehran were employed. Antibiotic susceptibility was determined to 13 antibiotics including imipenem and meropenem by disk diffusion. AmpC and ESBL production was detected by the AmpC disk test and combined disk diffusion assay, respectively, blaIMP and blaVIM gene carriage was shown by polymerase chain reaction and type-specific primers. RESULTS: AmpC production was observed in 81% and ESBL production was detected in 12.5% of the isolates. blalMP carriage was observed in 56.25% and blaVIM gene in 46.8% of the isolates. Surprisingly, 43.5% of the isolates carried both blalMP and blaviM genes. CONCLUSION: We think that this is the first report on the cocarriage of blalMP and blavIM in P aeruginosa. There was also a strong association between MBL gene carriage and AmpC beta-lactamase production. PMID- 25558660 TI - What is the effect of radioiodine therapy on Helicobacterpylori infection? AB - BACKGROUND/AIM: Helicobacter pylori is an important human pathogen associated with gastric and duodenal ulcers, gastric mucosa- associated lymphoid tissue lymphoma, and adenocarcinoma. Radioiodine (RAI) treatment plays an important role in the management of differentiated thyroid cancer and primary hyperthyroidism. It is known that during RAI treatment, a considerable amount is absorbed by the stomach as well. In this study we aimed to reveal any therapeutic impact of RAI on H. pylori infections. MATERIALS AND METHODS: Eighty-seven patients who were hospitalized for RAI treatment were consecutively included in this study. Of those, 76 patients had differentiated thyroid cancer and 11 had primary hyperthyroidism. The urea breath test (UBT) was performed on the day before RAI, and the test was repeated after 2 months. RESULTS: The dose of RAI was 115 +/- 3.3 mCi (range: 100-150 mCi) in the patients with malignant disease and 22.7 +/- 1.4 mCi (range: 20-30 mCi) in the remaining patients. Among the patients with differentiated thyroid cancer, 44 (57%) had positive and 32 (43%) had negative UBT tests prior to RAI. Four (36%) patients with hyperthyroidism had pretreatment positive UBT tests and 7 (64%) had negative tests. The results of UBT conducted 2 months after RAI therapy were identical in every patient, which means that none of the patients with positive UBT became UBT-negative (P = 1). CONCLUSION: RAI does not have any therapeutic effect on H. Ovlori infection. PMID- 25558661 TI - Pulsatile ocular blood flow changes after panretinal photocoagulation treatment in patients with proliferative diabetic retinopathy. AB - BACKGROUND/AIM: To prospectively assess the effects of panretinal photocoagulation (PRP) treatment on pulsatile ocular blood flow (POBF) in patients with proliferative diabetic retinopathy (PDRP). MATERIALS AND METHODS: The study included 40 eyes with PDRP in 27 patients. The PRP treatments were completed in 3 sessions with 3-week intervals. The intraocular pressure (IOP), pulse amplitude (PA), pulse volume (PV), and POBF changes that arose during the sessions were recorded using a blood flow analyzer. RESULTS: The average age of the patients was 57.37 +/- 11.14 years. The pre-PRP basal IOP, PA, PV, and POBF values were 20.44 +/- 4.13 mmHg, 4.23 +/- 1.73 mmHg, 6.89 +/- 2.28 MUL, and 21.86 +/- 5.83 MUL/s, respectively. One month after the completion of the PRP sessions, the values were 18.49 +/- 4.44 mmHg, 2.78 +/- 1.13 mmHg, 5.27 +/- 2.08 MUL, and 15.89 +/- 5.05 MUL/s, respectively, and the differences were significant (P = 0.001, P < 0.0001, P < 0.0001, and P < 0.0001, respectively). CONCLUSION: PRP treatment reduces the choroidal blood flow and consequently causes significant decreases in IOP, PA, PV, and POBE . PMID- 25558662 TI - An unusual case of sclerosing angiomatoid nodular transformation: radiological and histopathological analyses. AB - Sclerosing angiomatoid nodular transformation (SANT) is a rare benign primary vascular lesion of the spleen. Its etiology is still debated. Radiological characteristics are less known, although there are some reports regarding histopathological features ofSANT. A 21-year-old male patient was admitted to our hospital with fatigue, weight loss, and abdominal pain for 4 months. Physical examination, complete blood count, andbiochemical parameters were unremarkable. Dynamic contrast-enhanced computed tomography (CT) of the abdomen was performed. A heterogeneous well-defined hyperdense nodular lesion 3 cm in diameter was detected during the arterial phase. The detected lesion was seen as isodense with the spleen parenchyma during the portal venous and late venous phases. Magnetic resonance imaging (MRI) showed an isointense-hypointense nodular lesion on T1- and T2-weighted images. Intraabdominal LAM or splenomegaly was not detected. Microscopically, it was composed of angiomatoid nodules separated by central stellate fibrous stroma and fibrous septa. The contrast enhancement pattern was described as centrally hypovascular, radially progressive centripetal vascular contrast enhancement, called a spoke-wheel pattern in previously reported cases. We present CT and MRI findings and their correlation with histopathological findings of a case of unusual symptomatic SANT. PMID- 25558663 TI - [Reproductive problems in women with PCOS, the impact of PAL-1 CARRIERS OF 4G PAI -1 polymorphism and BMI]. AB - Approximately 7-12% of women in reproductive age are affected by PCOS[2] and 40 to 70 percent of them are overweight contributing to the clinical picture of PCOS and increased reproductive and metabolic disorder. In order to investigate the role of PAl-1 as a possible risk factor for the development of PCOS a group of 67 women with polycystic ovarian disease and 70 healthy controls were investigated for levels of PAI-1 and carriage of the promoter polymorphism 675 4G/5G in gene of PAl-1. The results of the DNA analysis showed a high carriage of polymorphism 675 4G/4G in promoter of PAI-1 gene in women with PCOS but not as significant (OR = 1.6645, p = 0.141). Serum levels of PAI-1 were significantly higher in total group of patients compared to controls. The levels of PAI-1 is correlated with carriage of 675 4G/5G polymorphism in the gene for PAI-1 (R = 0.534, p = 0.03) as well as wih BMI, like correlation coefficients were higher in the group with PCOS (0.572, p = 0.04). Data from the disease history showed a higher percentage of women with reproductive problems: 61.5% (early pregnancy loss and infertility) significantly higher in the group with PCOS (70.1% compared to 54.1%). The carriers of polymorphism 4G are at greater risk for early pregnancy loss than those with 5G (61.45% as compared to 36.8%), which confirms that carriage of the polymorphism 4G/5G 675 gene PAI-1 has a specific in multifactorial pathogenesis and expression of PCOS. PMID- 25558664 TI - [Investigation of the role of tubal factor sterility in pelvic endometriosis]. AB - OBJECTIVE: To investigate frequency and characteristics of tubal factor in patients, diagnosed with endometriosis and sterility. MATERIAL AND METHODS: The invastigation includes 124 patients, diagnosed with endometriosis and history of sterility, who underwent diagnostic or operative laparoscopy for the period from 2008 to 2013. For each of the patients were registrated the results of chromopertubation, stage, according to rASRM, concomitant gynaecological diseases, sort and complexity grade of the operation. RESULTS AND DISCUSSION: According to the results, patients were divided in 3 groups, as each of them includes cases with similar prognosis and treatment models: 1. With maintained reproductive potentiality (75 patients); 2. With restricted reproductive potentiality, according to the uterine tubes (32 patients); 3. With absent reproductive potentiality, according to the uterine tubes (16 patients). CONCLUSION: The mini-invasive approach to women, suspicious for endometriosis and sterility, gives us the opportunity to make an accurate diagnosis and to determinate the severity of disease, to estimate the morphology and the presence of tubal occlusion, such as to accomplish the necessary range operative intervention of endometriosis lesions and other concomitant gynaecological diseases. PMID- 25558665 TI - [Laparoscopic myomectomy using bidirectional barbed suture: report of the new technique in 82 cases]. AB - Bidirectional barbed suture introduces a new paradigm in laparoscopic suturing. The aim of our study is to evaluate the efficacy and safety of using bidirectional barbed suture in laparoscopic myomectomy. It included 102 women, requiring a laparoscopic myomectomy for symptomatic uterine fibroids from June 2011 to May 2014. They are divided into two groups according to the thread used for closing the uterine incision. We used bidirectional barbed suture Quill and Vicryl in the control group. The mean operative time was shorter in the Quill group than in control group. Both intraoperative blood loss and drop of hemoglobin were significantly lower in the Quill group. The use of bidirectional barbed suture appears to be safe for closing the hysterotomy site during a laparoscopic myomectomy. PMID- 25558666 TI - [Sentinel lymph node dissection: preliminary results in vulvar cancer]. AB - AIM: The aim of the study was to investigate and assess sentinel lymph node dissection methods in squamous cell vulvar cancer in cases of individualized therapeutic approach. MATERIALS AND METHODS: In the period January 2000-2010, 113 patients with squamous cell vulvar carcinoma were diagnosed, treated and followed up at the Clinic of Gynecologic Oncology of University Hospital - Pleven. All patients underwent primary surgical treatment and were surgically staged. Groin dissection was performed on 77 (72.64%) patients with invasive carcinoma (deep stromal invasion > 1 mm). Sentinel lymph node dissection was performed on seven patients after preoperative application of subcutaneous peritumor infiltration of Blue V in four places. The sentinel lymph nodes were identified following skin incision parallel to the inguinal ligaments. The nodes were dissected and sent for prompt frozen section histological evaluation. All patients underwent inguinal lymph node dissection as indicated by findings. RESULTS AND DISCUSSION: In the seven patients, one to three lymph nodes were found and frozen sections were histologically analyzed. The analysis did not reveal metastases. Primary tumor diameters varied from 0.5 to 4 cm. During follow-up, no cancer recurrences were found in any of the seven patients. CONCLUSION: Sentinel lymph node dissection is a reliable method in early vulvar cancer when certain criteria are applied in patient selection. The method allows avoiding inguinofemoral lymphadenectomy in a group of carefully selected patients with vulvar cancer. PMID- 25558667 TI - [Anti-Mullerian hormone in the major phenotypes of polycystic ovary syndrome]. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and the leading cause of oligo/anovulatory infertility. The incidence of PCOS in the population is 5-10% depending on the phenotypic expression of the syndrome as use criteria for diagnosis Anti- Mullerian Hormone may be defined as a glycoprotein growth factor having autocrine and paracrine deystvie. Prodused in granulosa cells of the ovary and related to the growth and development of follicles. Studies devoted to the relationship between AMH and PCOS and hormone levels in the main phenotypes of PCOS are conflicting and few. OBJECTIVES: Comparison of the serum levels of Anti-Mullerian Hormone (AMH) in major phenotypes of polycystic ovarian syndrome (A, B, C, D). As to study of correlation between serum levels of anti-Mullerian Hormone (AMH) and the other hormonal parameters DESIGN: Prospective comparative study. MATERIAL AND METHODS: Material and Methods. This study was conducted in the Department of Obstetrics and Gynecology, University Hospital St. George, Plovdiv and Clinic of Endocrinology, University Hospital St. George - Plovdiv. We studied 100 women aged between 18-35 years with polycystic ovary syndrome (PCOS) have been selected according to the criteria of the American Society of Reproductive Medicine (ASRM) - Rotterdam, 2003. Distributed by phenotypic characterization into four groups: Phenotype A (OA, HA and PCOS)--42 women; Phenotype B (OA and H)--23 women; Phenotype C (OA and PCOS)--20 women; Phenotype D (PCOS and OA)--15 women. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, androstenedione, estradiol (E2) and the Anti-Mullerian Hormone (AMH) are measured during the early follicular phase (day 3-5) of spontaneous menstrual cycle or progestin--induced uterine bleeding. RESULTS: Record the difference in the values of AMH in the main phenotypes subject of the study. We found different in strength and direction of correlations between the levels of AMH and other hormonal parameters studied. CONCLUSION: These data on serum AMH levels in four major phenotypes of PCOS allow its use as an additional diagnostic criterion for diagnosis. Furthermore, differences in serum proven its level at the leading phenotypic expression may serve as a reliable tool to characterize the severity of the syndrome, monitoring and forecasting. PMID- 25558668 TI - [Socio-demographic characteristics and vitamin D status in women born before 32 weeks']. AB - Deficiency of vitamin D (25-OHD) is a health problem among prematurely born women and their newborns independently of the geographical location of the country. OBJECTIVES: To study serum levels of vitamin D in patients born before 32 weeks and their newborns at birth. To analyse the socio-demographic factors, complications of pregnancy and their relationship with vitamin D status of women. PATIENTS AND METHODS: The study has been carried out in the University hospital "Maichin dom" Sofia for the period August 2013-January 2014. 35 women who gave birth before 32 gestational week and their 41 newborns with birth weight < 1500g have been investigated. The serum level of vitamin D (25-OH D) in mother-infant pairs at birth and 8 weeks of age in infants has been investigated. The ECLIA method has been used. Serum levels of vit D (25-OHD) have been estimated as sufficient:(> 30 ng/ml), insufficient (21-29ng/ml) and deficient (< 20 ng/ml). RESULTS: At delivery according to their vit D (25- OHD) serum levels 63% of the mothers are defficient /12.61 +/- 4.8 ng/ml/, 28.5% are insufficient/26.66 +/- 2.59/and only 8.5%/40.4 +/- 8.48/sufficient with normal levels of vitamin D. For newborns data are respectively 32%/ 20.08 +/- 3.69/-deficient, 49%/27.39 +/- 2.70/- insufficient and 19 %- sufficient/41.6 + 10/ There is a positive correlation between mother's and children's serum levels of vitamin D (25- OHD). Statistical significant differences are observed in the levels of vitamin D and the presence of infection and preeclampsia in the mothers. During the period of the study there were no seasonal variations in vit D (25-OHD) serum levels of mother-baby pairs. All newborns received Vit D3 1334 IU/daily from 20th day of age. At eight weeks of age sufficient levels of vitamin D have 70% of the children, but 30% of the newborns remains with inadequate supplementation/27.09 ng/ml/. CONCLUSION: 91.5% of mothers are with insufficient serum levels of vitamin D (25OHD) at birth, and a deficit is present in 63% of all women. Only in 8.5% of the women had normal values. This implies more effective monitoring and vitamin D prophylaxis during pregnancy. PMID- 25558669 TI - [Use of cabergoline for prevention of ovarian hyperstimulation syndrome in assisted reproductive technologies]. AB - Presentation of seven cases of patients at risk for moderate or severe OHSS, treated with Cabergoline. PMID- 25558670 TI - [Gestational and non-gestational factors for perinatal programming of insulin resistance]. AB - Insulin resistance is well known problem in type 2 diabetes mellitus (T2DM). Various factors play roles in the mechanisms of prenatal programming of insulin resistance. Gestational or non-gestational factors are illustrated in the present paper. Adipocytes (fat cells) produce at least 50 proteins (adipokines; peptides, cytokines, etc.), and a large part of them are involved in prenatal development of insulin resistance. The role of pro-inflammatory cytokines as the tumor necrosis factor 1 (TNF alpha), interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) is documented. Leptin from adipocytes as well as from the placenta is involved in pathology of metabolism and plays a role as a gestational factor for the prenatal insulin resistance and the risk for T2DM. Epigenetic mechanisms as the methylation of DNA and histones, the acetylation of histones are documented for prenatal development of insulin resistance. Epigenetic modulations may explain the risk of T2DM for generations. New data indicated that the placenta does not produce adiponectin and it is also one of the important factors for the development of gestational diabetes and risk for the fetus. Taken together all factors documented in the present paper may predict the risk for prenatal T2DM. PMID- 25558671 TI - [Sentinel lymph node biopsy in endometrial cancer--a part of modern operative treatment]. AB - After brest cancer the endometrial cancer is the most common gynaecological malignancy. The lymphno destatus is with great prognostic value. There is no agreement for the therapeutic valuae and the contents of the lymph node desectionin early stages. That is why the sentinel lymph node biopsy is a part of modern operative treatment of endometrial cancer. PMID- 25558672 TI - [Case of intrauterine retardation and fetal death during labor]. AB - The case concerns to a 37 years old pregnant woman with a history of three miscarriages. Ultrasound biometry in early pregnancy corresponds to the term calculated according the last menstrual period (LMP). At 37 week of gestation was determined retardation of 5 weeks. Doppler velocimetry and quantity of amniotic fluid were in normal ranges and the pregnant refused hospitalization. She was admitted to the hospital three days after the appointed term without uterine contractions. The fetal ultrasound biometry meets 33 weeks and the Doppler examination of a. umbilicalis found resistance index (RI) of the upper limit of normal. The cardiotocography record shows: baseline fetal heart rate--143 beats/min, good variability and reactivity. There was one deceleration for 3 minutes, and then the recording returns to normal. Re-monitoring after 30 minutes establishes of a periodic decelerations and a tendency to bradycardia with reserved variability. At the start of the emergency Cesarean Section fetal heart beats are single. The delivered babe was with Apgar O. The reanimation was not successful and the fetus died. From the autopsy signs of severe asphyxia. In conclusion, it can be assumed that in strongly retarded fetuses, cardiotocography recording and Doppler velosimetry are not sufficiently reliable methods for continued monitoring. In late-onset and severe intrauterine growth retardation (IUGR) desirable delivery time is after reaching biological maturity at 36-37 week. PMID- 25558674 TI - [Perspective of use of agonists of adenosine and opioid receptors for prevention of reperfusion damages of heart. Analysis of experimental and clinical data]. AB - In Russia inhospital lethality after acute myocardial infarction is 16.5-16.7%. The part of patients perishes even after recanalisation of infarct-related coronary artery as a result of reperfusion cardiac injury. Experimental data indicate that adenosine receptor agonists and opioids can prevent reperfusion damages of heart that is mimic postconditioning phenomena. Data of clinical observation show that adenosine during intravenous infusion or intracoronary administration during thrombolysis or percutaneous coronary intervention exert infarct reducing effect and eliminate manifestation of of "no-reflow" phenomenon. Clinical data indicate that morphine is able to prevent cardiac reperfusion injury in human. Thus, analysis of published data testifies that adenosine and opioid receptor agonists can be prototype for development of drugs for prophylaxis of reperfusion heart injury. PMID- 25558673 TI - [Glanzmann thrombasthenia and pregnancy--report of a case and literature review]. AB - Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder which deficiency of the platelet glycoprotein IIb - III a. The disorder usually manifests as severe mucocutaneus bleeding in the chaildhood, menstrual patterns in pubertal--adolescent years, rarely life-threatening. Pregnancy and delivery in patients with TG are very rare and are associated with high risk for mother and fetus due to intra - and post-partum hemorrhage. We present a case 30, a patient with TG, emergency births by caesarean section, with intra- and postpartum haemorrhage managed through the use of recombinant factor VIIa, transfusion of packed red blood cells and platelets. PMID- 25558675 TI - [Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors]. AB - The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease. PMID- 25558676 TI - [Chemiluminescent and enzyme activity of neutrophils in patients with widespread purulent peritonitis depending on the outcome of disease]. AB - BACKGROUND: Aim was to study the chemiluminescent activity and the activity of NAD- and NADP-dependent dehydrogenases of neutrophils depending on the outcome of the widespread purulent peritonitis (WPP). PATIENTS AND METHODS: 51 patients with a mean age of RSE 54.2 +/- 19.2 years were observed. As a control 75 healthy people of similar age range were examined. Lucigenin- and luminol-dependent chemiluminescence activity and activity of NAD(P)-dependent dehydrogenases peripheral blood neutrophils were studied. RESULTS: In patients with a favorable outcome of WPP the maximum intensity increased and the magnitude of the activation index of lucigenine-dependent spontaneous chemiluminescence reduced. Regardless to the outcome of WPP in patients with increased activation index and maxima of the luminol-dependent spontaneous and zymosan-induced chemiluminescence. At the unfavorable outcome of the disease in neutrophils NAD- dependent isositrate dehydrogenase and anaerobic lactate dehydrogenase reaction activity increased. Regardless to the outcome WPP in patients neutrophils aerobic reaction of lactate dehydrogenase, glucose-6-phosphate dehydrogenase and NADP dependent glutamate dehydrogenase activity reduced but levels of NADH-dependent reaction of malate dehydrogenase, NADH-dependent glutamate dehydrogenase and NADP dependent isocitrate dehydrogenase activity increased. CONCLUSION: With the reduction of the intensity ofplastic processes and imbalances enzymatic activity in nitrogen metabolism in patients with WPP at unfavorable outcome of the disease increases the activity of enzymes that characterize the level of anaerobic and aerobic respiration. In the absence of marked changes in the activity of enzymes that characterize the level of energy processes in cells of patients with favorable outcome of the WPP, increases the intensity of spontaneous lucigenin dependent chemiluminescence and reduced neutrophil activation index. PMID- 25558677 TI - [Expression of apoptosis markers in adhesions in the abdominal cavity under the experimental conditions]. AB - BACKGROUND: Our aim was to study the expression of markers of caspase-dependent and caspase-independent apoptosis pathway activation in the process of repair in case of damage of the serous membrane of the abdominal cavity. MATERIALS AND METHODS: On the experimental model of adhesions in the abdominal cavity (male rats Wistar, n = 40) in dynamics from 2 hours to 30 days after injury to the peritoneum studied marker expression pro-apoptosis (Bcl-x) and anti-apoptosis (Bcl-2), and PARP-1. RESULTS: It was found that in the conditions of traumatic injury of the peritoneum apoptosis and anti-apoptosis occur in parallel. In the initial period of the anti-apoptosis mechanisms prevail, and in later periods dominated phenomena pro-apoptosis. PARP-1 activation indicates an increase in the frequency of DNA damage cells, and the duration of this process stimulates cell death by caspase-independent pathway. Together, these processes result in the elimination of a large number of cells, especially fibroblast of zone connective tissue formation in an aseptic area of inflammation in the peritoneal injury. We first established that in the case of peritoneal injury marker expression of anti apoptosis in the damage zone has the character of the two-wave with maximum expression at 1-third day of the pathological process with repetitive peak on the 14th day. CONCLUSION: Identifying key parts of apoptosis in the formation of adhesions in the abdominal cavity, which can be used for the development of drugs for the prevention of adhesions. PMID- 25558678 TI - [Morphological and functional features of circulatory system in retired and active elite athletes]. AB - Regular physical activity over a long period of time increases the output of the cardiovascular system. That leads to development of a normal (physiological) athlete's heart. Bradycardia, cardiac hypertrophy, and arterial hypotension are three major characteristics of a normal athlete's heart. Changes in parameters of cardiovascular system and features of heart remodeling are determined by type, frequency, and duration of a physical activity. Excessive levels of physical activity could result in development of a pathologic athlete's heart, negatively affect hearts metabolism, and increase the risk of both atherosclerosis and myocardial infarction. Autopsy studies have shown that atherosclerosis, which leads to development of an ischemic heart disease, is often found in both young and elderly athletes. 56% of sudden deaths in all athletes were due to cardiovascular problems. Reports of ischemic heart disease in athletes of all ages have increased over the past few years. Echocardiographic features and clinical outcomes of stable angina and myocardial infarction in retired professional athletes are not well studied. Further studies are needed to improve diagnosis, prevention, treatment, and rehabilitation in elite athletes with ischemic heart disease. PMID- 25558679 TI - [Genetic dependency of blood pressure and heart rate in patients with arterial hypertension and obesity]. AB - BACKGROUND: The aim of the study was to determine the effect of gene polymorphisms Arg389Gly ADRbeta1 gene and T393C gene GNAS1 on the level of heart rate (HR), systolic and diastolic blood pressure (SBP and DBP) in hypertensive patients according to body mass index (BMI). PATIENTS AND METHODS: The study involved 166 patients with hypertension and 90 healthy individuals. Patients of the main group was divided according to BMI into three subgroups: I subgroup- with normal body weight, II subgroup--overweight, II subgroup--obesity. Gene polymorphism is determined using polymerase chain reaction and subsequent analysis of restriction fragments. RESULTS: Patients from subgroups II and III, who had presence of genotypes Arg389Arg, Arg389Gly, had higher HR, SBP than in patients with genotype Gly389Gly (p = 0.010 and p = 0.001; p = 0.010 and p = 0.001, respectively). In the analysis of DBP, the dependence of its level of polymorphism Arg389Gly of ADRbeta1 gene was found only in I subgroup (p < 0.001). During the analysis of polymorphism T393C of GNAS1 gene only in patients from III subgroup was found a higher heart rate in patients with T393T genotype relatively to C393C genotype, but this difference was not statistically significant (p = 0.191). CONCLUSION: There is a direct correlation between HR and SBP in hypertensive patients with overweight and obesity from polymorphism Arg389Gly of ADRbeta1 gene, in hypertensive patients with normal body weight from this polymorphism depends DBP. Clinical manifestations of hypertension do not depend on polymorphism T393C of GNAS1 gene. PMID- 25558680 TI - [Outcomes after one-stage repair of coarctation of the aorta and combined intracardiac lesions in infants]. AB - BACKGROUND: The aim of the study was to compare the outcomes of hypothermic circulatory arrest (GCA) and selective cerebral perfusion (SCP). PATIENTS AND METHODS: Nine patients were treated at the Bakoulev Center for Cardiovascular Surgery. All congenital heart diseases were repaired simultaneously. Group 1 (n = 4) included infants who were treated using an HCA, and the patients who underwent repair with the use of SCP were in group 2 (n = 5). RESULTS: One patient (25%) in group 1 died in the period of thirty days after the repair. Moderate heart failure and respiratory failure occurred postoperatively with no significant difference between two groups. Recoarctation was a frequent (75%) complication after the "end to end" anastomosis creating. One patient (25%) was reoperated on day 3 after the primary repair. Two other patients (50%) were treated by balloon angioplasty. There was relatively high (75%) incidence of a prolonged open sternotomy in group 1. CONCLUSION: There were similar results in HCA and SCP groups. A tendency for frequent prolonged open sternotomy application after HCA surgery as well as occurrence of the recoarctation after "end to end" anastomosis creating was found. PMID- 25558681 TI - [Clinical polymorphisms and approaches of arrhythmias treatment in a family with deltaKPQ1505-1507 deletion in SCN5A gene]. AB - BACKGROUND: The aim of the study was to analyze spectrum of manifestation and treatment response in large family with rhythm disturbances caused by p.delKPQ1505-1507 mutation in SCN5A gene. PATIENTS AND METHODS: We had under our observation 18 members of large Iranian family with various combination of inherited arrhythmic syndromes. Careful cardiological examination, genetic councelling and venous blood sampling for molecular genetic study were performed for family members. Mutation screening in SCN5A gene was performed using bidirectional Sanger sequencing. RESULTS: Here by we show the observation of Iranian family with known mutation p.delKPQ 1505-1507 in SCN5A gene, who display not only LQ-TS phenotype but also some of the carriers of this mutation have had LQ-TS and Brugada syndrome (combine phenotype), interestingly. CONCLUSION: The overlapping phenotype associated with high risk of sudden cardiac death may require complex approaches to antiarrhythmic therapy, surgical treatment and prevention of sudden cardiac death in the family. PMID- 25558682 TI - [The role of alfa-2-beta-adrenoreceptor in development of ventricular conduction disturbance]. AB - BACKGROUND: The purpose of this study was to investigate association between the genetic polymorphism I/D of gene alpha2beta-adrenoreceptor (ADRA2B) and hereditary disorders of ventricular conduction. PATIENTS AND METHODS: In this study, 102 people with complete left bundle branch block (45.71 +/- 1.852 years)- 46 females and 56 males, and 86 people with complete right bundle branch block (34.59 +/- 1.86 years)--41 females and 45 males. The study was approved by Ethic Committee of the KrasSMU. All participants were included in the study after written informed consent form. Cardiological examination included clinical examination, electrocardiography, echocardiography, Holter monitoring, stress test, koronaroangiografy and radionuclide method of a myocardium and molecular and genetic researches. RESULTS: Statistically, significant prevalence of a homozygous genotype of DD on rare allele gene ADRA2B in both groups in comparison with group of control is established. The reliable dominance of the homozygous rare genotypes (D allele) of gene ADRA2B were detected in all groups. CONCLUSION: Polymorphism DD of a gene ADRA2B is a genetic predictor of predisposition to the blockade of the right and left bundle branch block. PMID- 25558683 TI - [Maintenance and health promotion of adolescent--pledge of sustainable development of society and state (current status of the issue)]. AB - The article presents submitted data of population dynamics of adolescent (10-17 years old) in Russian Federation over the period of 1995-2012 In the presence of reduction by 8.2 million of adolescent population the top-priority task of adolescent health and life maintenance was declared. The article deals with physical growth and development statistics of schoolchildren of 15-19 years old: as opposed to peers of 80-es increase of length, body weight and circumference of chest as well as reduction of muscle strength is observed. On the ground of the data analysis of authoritative statistical reporting the increase of morbidity rate by factor of 1.4 was detected over the last 10 years. It has been established that the true morbidity level is above the authoritative by the factor of 1.5. The number of adolescent at the age of 10-15 referred to 1st and 2nd health groups decreased almost on 20%, at the same time pathological processes become chronic. The reproductive and mental health of adolescent at the age of 15-17 years was analyzed over the last 10 years. The rate of mental health disorders in adolescent living in country is more than in the peers living in cities by the factor of 1.2-1.4. The rate of period disorders, salpingitis and oothecitis increased in girls under 10 years and ones at the age of 15-17. The rate and structure of child disability was analyzed. It was fixed that leading causes of adolescent disability are mental disorders, diseases of nervous system, congenital anomalies. The most commonly encountered seed of physical dysfunction is capacity to study. It is demonstrated that there is misreporting on both child disability in totally and adolescent disability in Russian Federation. After the analysis of particular provisions of legislation concerning medical and social issues of child disability the week points were detected. The morbidity rate of adolescent was studied: primary cause of death in adolescent is extrinsic factor (more than 70%), the leading one is suicide. Road traffic accidents and accidental poisoning comes then. The medical and social consequences of high morbidity, disability and mortality rates of adolescent were considered as labour, reproductive and military potential of society and state. Short-term and long-term plans focused on decrease of morbidity, disability and mortality rates of adolescent were formulated on the basis of submitted data. search for solution is supposed to be nationwide and local as well (public health service, education, social protection). PMID- 25558684 TI - [Peculiarities of physical growth and body composition of preterm infants, received different types of feeding, at the discharge from hospital]. AB - BACKGROUND: This article is devoted to a research and practice problem- optimization of feeding preterm infants. PATIENTS AND METHODS: 80 preterm infants of different GA with perinatal pathology were included in the study group. Anthropometric figures of weight and length z-scores and also BMI of preterm infants, received different types of feedings, at the discharge are presented. All patients' body composition (Fat free mass and Fat mass) was estimated by air plethysmography. RESULTS: Less mass and length at the discharge in preterm infants, received breast feeding (including fortified milk), in comparison with the infants, received mixed and formula feeding, were found out. At the same time, preterm infants received breast feeding had more optimal body composition (less fat mass), than the infants received formula feeding. CONCLUSION: Personalised approach to human milk fortifiers prescription is explained. Important practical value of methodology for estimating body composition by air plethysmography is established. PMID- 25558685 TI - [Clinical case of treatment of hepatic haemangioma by propranolol in the newborn]. AB - Clinical observation of conservative treatment of the left hemi-liver haemangioma by propranolol in the full-term newborn with initial symptoms of cardiac failure is presented. Extensive hepatic haemangioma was diagnosed prenataly on the 23 24th week of a gestation. After the birth the clinical diagnosis was confirmed by means of ultrasound investigation (the size--50 x 30 mm) and by the data of computer tomography. The starter dose of propranolol made 0.5 mg/kg per day with further increase to 1.5 mg/kg per day; the preparation was prescripted at the age of 2 days of life. Episodes of decrease in cardiac rate to 95 b/min are noted among side effects. The child was dismissed for out-patient observation at the age of 12 days of life in a stable state. The positive dynamics is registered during ultrasound investigation in 6 months after initiation of treatment: lesion was significantly decreased in the size, and there was a considerable decrease in a blood flow. Treatment by propranolol in a dose of 1.5 mg/kg per day was continued. Modern data on possible mechanisms of propranolol effect at haemangiomas in children, regimen, side effects and complications are provided in discussion. It is noted that this drug can be considered as the agent of choice in the treatment of infantile haemangiomas in children of difficult localization since the neonatality period. PMID- 25558686 TI - [Second-generation colon capsule in small bowel and colon disorders in pediatrics]. AB - BACKGROUND: Aim of the study was to assess the diagnostic yield of second generation colon capsule in pediatric gastrointestinal diseases. PATIENTS AND METHODS: Five patients with different symptoms of gastrointestinal diseases were included in the study. Among them were: suspicion on diffuse polyposis, intestinal bleeding, lymphangiectasia and inflammatory bowel disease. Image interpretation was made by experienced capsule users, previously trained on small bowel capsule and first generation colon capsule. Lesions or abnormal changes of the mucosa identified on capsule endoscopy served as indications for colonoscopy or esophagogastroduodenoscopy with biopsy or polypectomy if needed. RESULTS: Standard white light endoscopy was made in all children without any adverse events. Second-generation colon capsule allows diagnosing Crohn's disease in small intestine and colon, limphangiectasia of the ileum, single rectosigmoid polyp and diffuse polyposis of the colon. CONCLUSION: Second-generation colon capsule can be used as non-invasive screening method in children without serious complications, thus allowing to differentiate indications for traditional white light endoscopy, which is usually made under general anesthesia in pediatrics. PMID- 25558687 TI - [The influence of the bupivacaine epidural anesthesia on the rabbit myometrium contractile activity and the functional state of the fetuses in induced labor]. AB - BACKGROUND: The influence of bupivacaine (0.5% - 1 ml) epidural anesthesia (EA) on 15 pregnant rabbit females induced in labor by oxytocin on the 30th day of pregnancy in chronic experiment was conducted. MATERIALS AND METHODS: 26 pregnant rabbit females took part in the investigation. 11 females were included in the control group and 15--to the main group. Both groups retrospectively were divided in two on the fact of the delivery during the experiment. For each 5-minute interval the contractile activity of the myometrium (number of uterine contractions, duration and amplitude of the one uterine contraction), functional state of fetuses and female (ECG) were evaluated. Registration of the parameters was carried out simultaneously with the help of electrodes which were administrated in the myometrium, to the fetuses and females on the 28th day of pregnancy. RESULTS: It was shown that EA influence on the myometrium contractile activity and functional state of fetuses and female depends on the female delivery readiness. CONCLUSION: In the case of the optimal one short-term increase of the contractile activity (on the 15th minute after EA) with no significant fetal heart rate changes were observed. In the case of its absence no significant influence was revealed. Moderate female tachycardia in both groups under EA was registered more pronounced in delivery one group. PMID- 25558688 TI - [Psychological features of mothers bringing up disabled children]. AB - BACKGROUND: Research objective was to define psychological makers of mothers bringing up disabled children for scientific justification of the family psychotherapy branches. PATIENTS AND METHODS: 60 mothers bringing up children of early age with infantile cerebral palsy and 50 mothers of children with compensation of perinatal affections of the central nervous system by the 1 life year are surveyed. Personal characteristics, family orientations of mothers, child and mother relations, awareness of mothers on the children health state and the attitude to their rehabilitation were studied by means of psychological techniques. RESULTS: It is found out that the mothers bringing up disabled children more often have emotional disorders, negative attitude to divorce and give the leading role in a family to the husband less often they show hypoguardianship of the child than the mothers of children with compensation of perinatal affections of the central nervous system. Mothers are less satisfied with the child development, they are more often worried about disorders of development of movements, speech and mental development delay, small appetite of the child, they feel helplessness in rehabilitation more often, note the ambiguity of its prospects. They understand that their child needs the help of the qualified experts: neurologist, orthopaedist, logopedist, psychologist, but they aren't satisfied with communication with them more often, underestimate own role in rehabilitation. CONCLUSION: The revealed characteristics prove the necessity and define the main directions of family psychotherapy--correction of mother's emotional disorders, child and parental relations, increase of medical and psychological competence that allows to increase efficiency of rehabilitation. PMID- 25558689 TI - [Clinical management of disorders hemostasis-related with obstetric complications]. AB - BACKGROUND: The aim of the study was the reduction of adverse pregnancy outcomes in women with gestational and genetically determined changes in the hemostatic system. PATIENTS AND METHODS: The study group comprised 98 patients with obstetric complications on the background of changes in the parameters of coagulation screening. In 63 pregnant women, hemostatic disorders were not corrected, in 35 patients medical tactic defined clinical situation and the results of laboratory and instrumental studies of the hemostatic system. RESULTS: Hereditary thrombophilia detected in 85% of patients with obstetric complications. Carriage of the rare allele of MTHFR-677 2-fold increased risk of adverse pregnancy outcomes; heterozygous carriers of polymorphism PAI-1 - 1.5 times more. The prognostic parameters thrombelastographic (sensitivity 80%, specificity 82%) were higher than in laboratory tests. To determine the most predictive of adverse pregnancy outcome has a density of fibrin clot--the maximum amplitude. CONCLUSIONS: In women with obstetric complications associated with disturbances in the hemostatic system, medical diagnostic tactics using c thrombelastographic evaluates all stages of coagulation and fibrinolysis, allows you to select a reasonable pathogenetic anticoagulant therapy and reduce the number of adverse pregnancy outcomes. PMID- 25558690 TI - [Endothelial dysfunction indicators in patients with diabetic foot syndrome]. AB - BACKGROUND: In recent years, scientists have become increasingly interested in the role of the endothelium in the pathogenesis of vascular lesions of various origins, including diabetic patients. Therefore, the aim of the study was to investigate the expression of endothelial dysfunction in patients with diabetic foot syndrome (DFS), by examining the levels of nitric oxide, endothelin-1 levels in the serum, as well as lower limb microcirculation by laser doppler flowmetry. PATIENTS AND METHODS: It was examined 72 patients with diabetic foot syndrome with I-IV degree of lesion (by Meggit- Wagner classification). Neuropathic form was diagnosed in 32 people, ischemic--40 patients. The function of endothelium was studied on the basis of the determination of enzyme-linked immunosorbent NO and endothelin-1 in peripheral blood serum, as well as to assess the state of the microcirculation of the lower limbs by laser doppler flowmetry, using apparatus LACK-02 (Russia). RESULTS: Patients with DFS are marked with endothelial dysfunction, the severity of which depends on the type of diabetes, glycemic level and pathogenic forms of destruction. This is manifested by secretion reducing of vasodilators (NO) and increased synthesis of vasoconstrictors (endothelin-1), which leads to disruption of peripheral hemodynamic. Characteristic changes in the microcirculation are a dramatic violation of endothelium-dependent regulation mechanism, the redistribution of blood towards the nutritional circulation. Also it is showed a significant reduction in reserve capacity of the capillary bed in response to the sample and the occlusal restoration of blood flow during reactive hyperemia. CONCLUSION: Development of endothelial dysfunction and changes in peripheral hemodynamic in patients with DFS contributes to the emergence and prolongation of necrotic lesions, as well as violation of reparative processes. PMID- 25558691 TI - [Natural neurotropic autoantibodies in blood serum of epilepsy patients]. AB - BACKGROUND: The purpose of research was to determine the level of natural neurotropic autoantibodies in blood serum of patients with idiopathic and symptomatic epilepsies. PATIENTS AND METHODS: 43 epilepsy patients (27 males and 16 females) at the age of from 16 till 70 years (average age 43.1 +/- 1.02 years) were studied--11 patients with idiopathic epilepsy (group I) and 32 patients with symptomatic epilepsy (group II). By the method of immunoenzymatic analysis and original idiotype-antiidiotype test-system ELI-N-Test (Russia) in blood serum of the patients the levels of autoantibodies (aAB) to brain proteins-antigens (NF 200, GFAP, MBP and S100beta) and to receptors of neuromediators (glutamate, GABA, dopamine, serotonin and choline-receptors) we determined. RESULTS: All groups of epilepsy patients differed from control group by as individual levels, as degree of deviations of the studied immunological parameters. Serum levels of neurotropic aAB to NF-200, GFAP, MBP and S100beta, as well as to receptors of neuromediators (glutamate, GABA, dopamine, serotonin and choline-receptors) were noted to increase. The features of immune disturbances depended on the form and severity of epilepsy. CONCLUSION: Autoimmune processes have the certain place in the pathogenesis of epilepsy. The degree and duration of increase in the levels of neurotropic aAB have the prognostic significance for the evaluation severity degree of epilepsy course that could be an additional criterion in the integrated diagnosis and timely correction of treatment for epilepsy. PMID- 25558692 TI - [Evaluation of possibility of using new financial instruments for supporting biomedical projects]. AB - Analysis of selection criteria on projects of Russian medical research centers for funding in Russian scientific fund and Federal program "Research and innovations" was done. It was noted that a high degree of uncertainty of such concepts as "priority direction", "applied" and "search" research and "industrial partner" in regards to research of biomedical theme. Analysis of classified "Medicine and health care" "Forecast of scientific-technological development of Russian Federation till 2030 year" were completed. PMID- 25558693 TI - [Informatization of personalized adaptation medicine programs]. AB - State of art of personalized monitoring programs informatization and improvement of human adaptation abilities as one of the preferred direction of personalized (individualized, personalized) medicine which is focused on disclosure of potential and adaptive capabilities of human body and increase of life expectancy by means of directed patient-associated diagnostic and treatment effects on the basis of genetic influences of exogenous and regional factors are described. Biomedical concepts which are the background of monitoring and improvement of the implementation of human adaptation abilities that are designed by experts in the field of aerospace medicine and are the foundation of personalized non-drug medicine are defined: occupational health, preventive health changes cascade concept, concept of similar conditions, biological age, health-related quality of life concept, software risk-metric health information concept and telecommunication technologies for monitoring of human health information technology certification. The characteristics of the present stage of development of personalized non-drug medicine are issued. PMID- 25558694 TI - Protecting public health in the age of emerging infections. AB - Emerging and re-emerging infections cause huge concern among public health workers and international and national bodies such as the World Health Organization (WHO) and the U.S. National Institutes of Health (NIH). Indeed, scientists around the world express the view that despite the danger, research on these emerging virulent pathogens is crucial and must continue. While most of the studies underway are targeted at improving and protecting public health, some studies bear potentiallyserious risks resulting from misuse. These studies are defined as dual-use research of concern (DURC), where it is not evident that the benefits outweigh the risks. The H5N1 controversy has pushed various governments to institute new policies to govern such research. We describe the regulations that govern this emerging field of research in the United States and Israel, two countries that have taken leading stands on these issues. We suggest that the existing policies are able to mitigate many of the risks that this research encapsulates, yet more work is required--especially on the global level. PMID- 25558695 TI - An update of Gaucher mutations distribution in the Ashkenazi Jewish population: prevalence and country of origin of the mutation R496H. AB - BACKGROUND: Gaucher disease is the most prevalent inherited disorder among Ashkenazi Jews (carrier frequency of about 6%) and six mutations account for about 96% of their mutant alleles. Two mutations, N370S and R496H, have been reported only in mildly affected or asymptomatic patients. Due to the rarity of R496H, it was recommended that it be excluded from screening programs. OBJECTIVES: To verify the frequency and trace the origin of Gaucher mutations in screened individuals whose Ashkenazi ethnicity was confirmed by the birthplace of their grandparents. METHODS: We conducted a retrospective analysis of the screened results for the period 2006-2011. Mutations were identified by restriction analysis, Tag-It detection system, Pronto diagnostic kit and Nanogen technology (NanoChip 400). RESULTS: The heterozygote frequency of eight mutations was estimated in a cohort of 16,910 alleles. Two mutations, N370S and R496H, were the most frequent in our population. However, while the occurrence of N370S carriers was similar to other reports (1:19.4), that of R496H carriers was considerably elevated (1:207). Examination of the screened individuals' ethnicity showed a significant difference in the distribution pattern of the country of origin between the carriers of these two mutations. CONCLUSIONS: The origin pattern differences between the two groups of heterozygotes might reflect a separate geographic region of introduction for various mutations. As a result, secondary subgroups could be formed within the Ashkenazi population. This might clarify the dissimilarities in the occurrence of R496H mutation reported by various centers. PMID- 25558696 TI - Poisoning in Israel: annual report of the Israel Poison Information Center, 2012. AB - BACKGROUND: The Israel National Poison Information Center (IPIC), Rambam Health Care Campus, provides 24 hour telephone consultations in clinical toxicology as well as drug and teratogen information. It participates in research, teaching and regulatory activities, and also provides laboratory services. OBJECTIVES: To report data on the epidemiology of poisonings and poison exposures in Israel. METHODS: We made computerized queries and descriptive analyses of the medical records database of the IPIC during 2012. RESULTS: A total of 31,519 poison exposure cases were recorded, a 157.6% increase compared with 1995. Children < 6 years of age were involved in 43.1% of cases; 74.0% of calls were made by the public and 23.7% by physicians; 74.8% of exposures were unintentional and 9.1% intentional. Chemicals were involved in 35.8% of all cases (single and multiple substances), pharmaceuticals in 48.8%, bites and stings in 3.8%, and plants and mushrooms in 1.6%. Substances most frequently involved were analgesics, cleaning products and antimicrobials. Clinical severity was moderate/major in 3.4%. Substances most frequently involved in moderate/major exposures were corrosives, insecticides and snake venom. Four fatalities were recorded; all were intentional exposures in adults (corrosive, medications, energy drink). CONCLUSIONS: Poison exposures and poisonings have increased significantly and have contributed substantially to morbidity and mortality in Israel. The IPIC database is a valuable national resource for the collection and monitoring of poisoning exposure cases. It can be used as a real-time surveillance system for the benefit of public health. It is recommended that reporting to the IPIC become mandatory and its activities be adequately supported by national resources. PMID- 25558697 TI - Cephalometric evaluation of upper lip symmetry after functional unilateral cleft lip repair with the Kernahan and Bauer technique and primary cleft rhinoplasty. AB - BACKGROUND: Cleft lip repair with the Millard technique has undergone many modifications throughout the years, yet analysis of the successes of these various methods is still lacking. OBJECTIVES: To make a quantitative evaluation of the outcomes obtained after unilateral cleft lip surgical repair using the Kernahan and Bauer technique with primary rhinoplasty. METHODS: Five anatomical parameters for evaluating upper lip and nostril symmetry were compared between the cleft and the normal side at least 1 year post-surgery in 23 children who underwent unilateral cleft lip repair with this particular technique. RESULTS: Surgical success (defined as a 10% or less deviation between the cleft and contralateral side) was achieved for four of the five parameters: distance between oral commissure and peak of Cupid's bow, nasal sill width, distance between peak and lowest point of Cupid's bow, and vertical distance between the highest point of the philtral column and lowest point of the upper lip. Surgical success was not achieved for the last parameter: length of philtral column. CONCLUSIONS: Unilateral cleft lip repair using the Kernahan and Bauer technique with primary cleft rhinoplasty is mostly successful when aiming to achieve symmetry between the cleft and the normal side of the upper lip. Success was elusive in achieving symmetry between the philtral columns despite an overall average difference of only 1.2 mm. PMID- 25558698 TI - CA125 expression in the tissue of uterine leiomyosarcoma. AB - Background: Elevated serum levels of the epithelial marker CA125 are occasionally observed in leiomyosarcoma (LMS) patients. OBJECTIVES: To assess the immunohistochemical expression of this marker in the tissue of LMS. METHODS: The consecutive unselected records of all patients with LMS diagnosed during the period 1995-2012 were located and abstracted. After verification of the diagnosis, 4 MUm unstained slides were prepared from each case for immunohistochemical staining for CA125. Sections of ovarian carcinoma known to express CA125 were used as positive controls. RESULTS: We located 17 LMS patients from the period under study. Bleeding was the presenting symptom in 9 patients; the diagnosis was established prior to treatment in 11 patients. The tumor was in an advanced stage in 6 patients, and in 7 unstaged patients it was grossly confined to the uterus. Ten patients died within 14 months after the diagnosis. Serum CA125 levels prior to treatment were assessed in only 8 patients and were above normal limits (> 35 U/ml) in 3 of them. Two of the three with elevated serum levels were in stage III, and the third was an unstaged apparent stage I patient. None of the LMS tissue specimens demonstrated immunohistochemical expression of CA125. CONCLUSIONS: CA125 was not immunohistochemically expressed in the tissue of any LMS tumors examined by us. The origin of elevated serum CA125 in some of these tumors is therefore not in its tissue and remains unknown. PMID- 25558699 TI - C-Reactive protein levels in children with primary herpetic gingivostomatitis. AB - BACKGROUND: C-reactive protein (CRP) is often used to distinguish bacterial from viral infections. However, the CRP level does have implications, which depend on the clinical scenario and are still under research. OBJECTIVES: To evaluate the distribution of CRP levels in children with primary herpetic gingivostomatitis. METHODS: The electronic database of a tertiary pediatric medical center was searched for all inpatients with a diagnosis of primary herpetic gingivostomatitis without bacterial coinfection. Background and clinical information was collected and CRP levels were analyzed. RESULTS: The study group consisted of 66 patients aged 8 months to 7.1 years who met the study criteria. The average CRP was 7.4 mg/dl (normal 0.5 mg/dl). More than a third of the patients had a level higher than 7 mg/dl. CONCLUSIONS: High values of CRP are prevalent in patients with primary herpetic gingivostomatitis, similar to adenoviral infections and some bacterial infections. PMID- 25558700 TI - Comparison of knee SPECT and MRI in evaluating meniscus injuries in soldiers. AB - BACKGROUND: Medical evaluation of a suspected meniscus injury begins with a history-taking and physical examination. Suspected meniscus injuries not responding to treatment are usually sent for imaging to confirm the diagnosis before arthroscopy. Tc-MDP bone single photon emission computed tomography (SPECT) scan has been suggested as an alternative to magnetic resonance imaging (MRI) in evaluating suspected knee meniscus tears. OBJECTIVES: To examine the accuracy of knee SPECT as a tool to identify meniscus tears versus that of MRI as compared to the gold standard of arthroscopy. METHODS: The Israel Defense Forces database for 2005 through 2009 was searched using the key words: knee MRI, knee SPECT and knee arthroscopy. We identified 330 subjects who had undergone both a single knee SPECT and a single knee MRI prior to knee surgery. The medical files of 193 of the 330 subjects were randomly selected for review. A comparison was made between the preoperative SPECT and MRI studies and the arthroscopic finding. The sensitivity, specificity and accuracy were calculated. RESULTS: The subjects' age was 21.3 +/- 3.9. The agreement between SPECT and arthroscopy was 0.14 forthe medial meniscus and 0.29 for the lateral meniscus. The agreement between MRI and arthroscopy was 0.59 for the medial meniscus and 0.69 for the lateral meniscus. SPECT scan was found to be 61% sensitive, 54% specific and 58% accurate in detecting common knee pathology, whereas MRI was found to be 95% sensitive, 67% specific and 85% accurate. CONCLUSIONS: Knee SPECT has a lower sensitivity, specificity and accuracy than MRI in evaluating meniscal injuries and its use can result in increased unnecessary surgery. PMID- 25558702 TI - Assessment of surgical discharge summaries and evaluation of a new quality improvement model. AB - BACKGROUND: Discharge summaries after hospitalization provide the most reliable description and implications of the hospitalization. A concise discharge summary is crucial for maintaining continuity of care through the transition from inpatient to ambulatory care. Discharge summaries often lack information and are imprecise. Errors and insufficient recommendations regarding changes in the medical regimen may harm the patient's health and may result in readmission. OBJECTIVES: To evaluate a quality improvement model and training program for writing postoperative discharge summaries for three surgical procedures. METHODS: Medical records and surgical discharge summaries were reviewed and scored. Essential points for communication between surgeons and family physicians were included in automated forms. Staff was briefed twice regarding required summary contents with an interim evaluation. Changes in quality were evaluated. RESULTS: Summaries from 61 cholecystectomies, 42 hernioplasties and 45 colectomies were reviewed. The average quality score of all discharge summaries increased from 72.1 to 78.3 after the first intervention (P < 0.0005) to 81.0 following the second intervention. As the discharge summary's quality improved, its length decreased significantly. CONCLUSIONS: Discharge summaries lack important information and are too long. Developing a model for discharge summaries and instructing surgical staff regarding their contents resulted in measurable improvement. Frequent interventions and supervision are needed to maintain the quality of the surgical discharge summary. PMID- 25558701 TI - Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a familial disease with autosomal dominant inheritance and age-dependent penetrance, caused primarily by mutations of sarcomere genes. Because the clinical variability of HCM is related to its genetic heterogeneity, genetic studies may improve the diagnosis and prognostic evaluation in HCM. OBJECTIVES: To analyze the impact of genetic diagnosis on the clinical management of HCM. METHODS: Genetic studies were performed for either research or clinical reasons. Once the disease-causing mutation was identified, the management plan was reevaluated. Family members were invited to receive genetic counseling and encouraged to be tested for the mutation. RESULTS: Ten mutations in sarcomere protein genes were identified in 9 probands: 2 novel and 8 previously described. Advanced heart failure or sudden death in a young person prompted the genetic study in 8 of the 9 families. Of 98 relatives available for genotyping, only 53 (54%) agreed to be tested. The compliance was higher in families with sudden death and lower in what appeared to be sporadic HCM or elderly-onset disease. Among the healthy we identified 9 carriers and 19 non-carriers. In 6 individuals the test result resolved an uncertainty about "possible HCM." In several cases the genetic result was also used for family planning and played a role in decisions on cardioverter defibrillator implantation. CONCLUSIONS: Recurrence of a same mutation in different families created an opportunity to apply the information from the literature for risk stratification of individual patients. We suggest that the clinical context determines the indication for genetic testing and interpretation of the results. PMID- 25558703 TI - Comparison of the effectiveness of high flow nasal oxygen cannula vs. standard non-rebreather oxygen face mask in post-extubation intensive care unit patients. AB - BACKGROUND: Optimal oxygen supply is the cornerstone of the management of critically ill patients after extubation, especially in patients at high risk for extubation failure. In recent years, high flow oxygen system devices have offered an appropriate alternative to standard oxygen therapy devices such as conventional face masks and nasal prongs. OBJECTIVES: To assess the clinical effects of high flow nasal cannula (HFNC) compared with standard oxygen face masks in Intensive Care Unit (ICU) patients after extubation. METHODS: We retrospectively analyzed 67 consecutive ventilated critical care patients in the ICU over a period of 1 year. The patients were allocated to two treatment groups: HFNC (34 patients, group 1) and non-rebreathing oxygen face mask (NRB) (33 patients, group 2). Vital respiratory and hemodynamic parameters were assessed prior to extubation and 6 hours after extubation. The primary clinical outcomes measured were improvement in oxygenation, ventilation-free days, re-intubation, ICU length of stay, and mortality. RESULTS: The two groups demonstrated similar hemodynamic patterns before and after extubation. The respiratory rate was slightly elevated in both groups after extubation with no differences observed between groups. There were no statistically significant clinical differences in PaCO2. However, the use of HFNC resulted in improved PaO2/FiO2 post-extubation (P < 0.05). There were more ventilator-free days in the HFNC group (P< 0.05) and fewer patients required reintubation (1 vs. 6). There were no differences in ICU length of stay or mortality. CONCLUSION: This study demonstrated better oxygenation for patients treated with HFNC compared with NRB after extubation. HFNC may be more effective than standard oxygen supply devices for oxygenation in the post-extubation period. PMID- 25558704 TI - Screening for Gaucher disease: new challenges. PMID- 25558705 TI - Mixed connective tissue diseases: new aspects of clinical picture, prognosis and pathogenesis. PMID- 25558706 TI - Anti-glomerular basement membrane antibodies. AB - Basement membranes form an anatomic barrier that contains connective tissue. They are composed of type IV collagen, laminin and proteoglycans. Anti-basement membrane antibodies bind to the non-collagen site of the alpha3 chain of type IV collagen. A group of renal diseases, pulmonary diseases and perhaps others affecting different organs have long been associated with the presence of antibodies directed against glomerular basement membrane (GBM), alveolar basement membrane and tubular basement membrane. Goodpasture disease has a frequency of 0.5 to 1 case by million/year, and is responsible for up to 20% of crescentic glomerulonephritis in renal biopsy. It has been associated with genetic and immune abnormalities and there are usually environmental triggers preceding clinical onset. Renal disease can occur isolated or in association with pulmonary hemorrhage. In general, renal disease has a rapid progression that determines severe compromise, with rare spontaneous resolution. The diagnosis of Goodpasture disease requires the presence of the anti-GBM antibody, either in circulation or in renal tissue. The prognosis of non-treated patients is poor. The standard of care is plasma exchange combined with prednisone and cyclophosphamide. Anti-GBM antibody levels must be monitored frequently until their disappearance, and then every 6 months to confirm sustained remission in the absence of clinical signs of recurrence. Prognosis of the disease is strongly associated with its initial presentation. Survival rates are related to the degree of renal compromise at onset of the disease. Recurrence of the disease post-transplantation is low. PMID- 25558707 TI - Mixed connective tissue disease associated with autoimmune hepatitis and pulmonary fibrosis. PMID- 25558708 TI - Uterine leiomyoma in a man with persistent Mullerian duct syndrome and seminoma. PMID- 25558709 TI - The Lancet strikes again. PMID- 25558710 TI - [[The prevention of food wastage by restoring the value to food: reflections of an agroeconomist]. AB - Each year, about one trillion USD worth of food sales is lost or wasted. In addition to its economic impacts, food wastage has significant societal costs that are born indirectly by taxpayers. Should damage costs associated with food wastage be accounted for, this global wastage appears much higher. In fact, the monetization of environmental costs such as the impact of greenhouse gases, land erosion, water use and pollinators loss amnounts to another trillion USD. Furthermore, a valuation of social costs, such as health effects of pesticides, loss of livelihoods and conflicts over natural resources adds another trillion USD. Noteworthy is the fact that not all food wastage reduction strategies are equal in terms of environmental efficiency and reducing food wastage must be a priority over energy recovery fromn food wastage. As a case study, the Italian National Plan for Food Waste Prevention (PINPAS) aims at reducing food wastage upstream the food chain, will be considered. PINPAS also seeks to improve recovery measures of unsold food. As indicated in the Guidelines on the preparation of food waste prevention programmes by the European Commission, PINPAS engages all stakeholders of the agri-food chain, from policy makers to civil groups aid producers. The first action will be the reintroduction of food education at school. PMID- 25558711 TI - [Organization and technology in the grocery store sector]. AB - In Italy, grocery stores develop an annual turnover of 92 billion of , (data referred to 2013) and have 28.232 stores spread over a commercial area of 17.224.000 m2. The business involved are 252, linked with 30 important distribution leader companies. The total workforce is about 280.000 people. The grocery stores structure is composed by suppliers and producers warehouses and different kinds of stores (hypermarkets, supermarkets, shops and discounts). In the stores, the technological progress concerns fundamentally back-office operations; the improvement of information and computer science is the main renewal source. Other tasks as receiving goods and stocking shelves are still executed without specific inovations. In terms of organization, we observed a strong increase of part-time workers, the development of atypical contract and thie inclination to contract the easiest jobs (for example, stocking shelves). Also the warehouses often use to sub-contract the picking tasks. The increase of on-line shopping, also concerning the groceries, represents the most relevant evolution in tire near future. PMID- 25558712 TI - [Organization and technology in the catering sector]. AB - The catering industry is a service characterized by a contract between customer and supplier. In institutional catering industry, the customer is represented by public administration; in private catering industry, the customer is represented by privates. The annual catering trades size is about 6.74 billions of euros, equally distributed between health sector (hospitals, nursing homes), school sector and business sector (ivorkplace food service), with the participation of nearly 1.200 firms and 70.000 workers. Major services include off-premises catering (food prepared away from the location where it's served) and on-premises catering (meals prepared and served at the same place). Several tools and machineries are used during both warehousing and food refrigerating operations, and during preparation, cooking, packaging and transport of meals. In this sector, injuries, rarely resulting serious or deadly, show a downward trend in the last years. On the contrary, the number of occupational diseases shows an upward trend. About the near future, the firms should become global outsourcer, able to provide other services as cleaning, transport and maintenance. In addition, they should invest in innovation: from tools and machineries technology to work organization; from factory lay-out to safely and health in the workplaces. PMID- 25558713 TI - [Occupational risks in grocery stores]. AB - AIM: This work provides an overview of the spectrum of possible occupational risk factors in the retail grocery store/supermarket workplace. METHOD: Literature on this theme, obtained consulting PubMed database and Google Scholar, was checked. We also exjlore results from the National bInstitute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA). RESULTs: Contacts with objects, use of dangerous equipment (cutter, food slicer) and falls to the same level (slips, trips and falls) are the mainly described workplace hazards. Exposure to chemical (flour dust, components of detergents or disinfectants, volatile organic compounds and contact with nickel) and physical agents (cold exposure, nonionizing radiation and whole bpdy vibration) are reported by many authors. Relations between biomechanical and ergonomic risk factors and musculoskeletal disorders represent the main subjects of study. Few studies are found about biological agents (particularly among butchers). Data regarding psychosocial risks factors in this setting are still limited. CONCLUSIONS: Musculoskeletal disorders continue to be the most recurrent health problem between the grocery store workers (particularly low back pain and carpal tunnel syndrome among cashiers). Many technical documents and international Srecommendations are present to prevent these kinds of disorders. Psychosocial risk factors and risk of workplace violence should deserve further investigation. PMID- 25558714 TI - [Epidemiology of illnesses and musculoskeletal disorders in grocery stores and catering]. AB - Large scale retail industry and catering industry are characterized by the widespread presence of several risk factors of work-related musculoskeletal disorders (WMSD): repetitive movements, incongruous postures and manual handling tasks. We reviewed current epidemiological evidence related to musculoskeletal disorders within these two sectors, distinguishing between symptoms and clinically documented disorders. In retail industry cashier is the most investigated figure, regarding upper limbs disorders as a consequence of repetitive tasks. In the catering sector there are few studies, mostly focused only on the job as a cook. The majority of studies showed a high prevalence of WMSD and, to a lesser extent, a high frequency ofmusculoskeletal alterations; suggesting the presence of a not negligible risk. These findings, however, are affected by a number of methodological limitations: they derive from cross sectional studies, are based on voluntary self-selected workers, are focused on not unequivocally defined health outcomes, and are usually lacking a proper comparison. with the prevalence in less exposed/reference working groups. In order to achieve an effective control of the workers' risk, it is therefore necessary to design and conduct prospective studies that compare the risk of developing disorders and/or diseases in workers exposed to different levels of biomechanical load. It appears essential to involve occupational physicians in active health surveillance programs in order to identify critical areas and to develop effective preventive measures. PMID- 25558715 TI - [Risk assessment for food preparation, cooking and service]. AB - The restaurant and food preparation, cooking and distribution sector includes hotels, restaurants, catering, fast food, ecc. The restaurant and food preparation, cooking and distribution sector form a significant part of the Italian economy; they provide employment for a large number of people, both direct employees as well as part-time and contract staff. In this sector there are many hazards that can lead to a broad range of injuries and/or diseases to the workers. For the safety these hazards principally are slick floors, open flames, high temperature cooking surfaces, steam, knives and other cutting instruments and machineries. For the health: cleaning and disinfecting chemicals substances, cooking fumes and vapors, biological agents, heavy loads handling, thermal comfort, ecc. The paper presents an overview of the hazards in the sector and then make a focus on chemical risks identification and assessment to evaluate the workers' exposure (by skin adsorption and inhalation). PMID- 25558716 TI - [Focus: baker's asthma. Epidemiology, diagnosis and treatment of baker's asthma]. AB - Baker's asthma, though having been recognized and studied since long time, still stays one of the most common causes of occupational asthma. Moreover, our understanding of the causative agents, the pathophysiological mnechanisms, the usefulness of medical surveillance, the proper treatment and prevention of the disease is still scanty. This is due to either to its complex pathogenesis or to possible confoundings, besides the still inadequate quality and standardization of the tools available as far as the allergologic diagnosis is concerned. Proper medical surveillance, validated causal therapies, efficient primary prevention are still uncertain. Change of employment or relocation is often impossible, particularly among artisan workers. Various evidences have been critically revised and summarized. PMID- 25558717 TI - [Dermatoses in the grocery industry]. AB - Dermatological risks in supermarkets are largely comparable to those found in other workplaces such as food industry and trade in general Using two Pubmed search strings (one more specific, the other more sensitive) 11 papers were found (5 pertinent). The reasons for the little information may be the particular employment conditions that occur , in large-scale distribution. From this derives the difficulty in defining the epidemiology of skin diseases in the field and the need to refer to the literature on skin diseases in food handlers and cashiers. The most frequent dermatological disease in food handlers is irritant contact dermatitis, while the protein contact dermatitis seems to be more widespread than previously thought. Hand eczema together with nickel contact allergy is not rare in cashiers, but it can be difficult to assess if nickel allergy was occupationally acquired. PMID- 25558718 TI - [Methods of risk assessment and their validation]. AB - The review of the literature data shows several methods for the the risks assessment of biomnechanical overload of the musculoskeletal system in activities with repetitive strain of the upper limbs and manual material handling. The application of these methods should allow the quantification ofriskfor the working population, the identification of the preventive measures to reduce the risk and their effectiveness and thle design of a specific health surveillance scheme. In this paper we analyze the factors which must be taken into account in Occupational Medicine to implement a process of validation of these methods. In conclusion we believe it will necessary in the future the availability of new methods able to analyze and reduce the risk already in the design phase of the production process. PMID- 25558719 TI - [Risk assessment comparison of biomechanical overloading of the musculoskeletal system: 10 years' applied experience]. AB - Risk assessment for upper extremity work related muscoloskeletal disorders by applying six methods of ergonomic: a ten years experience. The objective of this research was to verify and validate the multiple step method suggested by SIMLII guidelines and to compare results obtained by use of these methods: Washington State Standard, OCRA, HAL, RULA, OREGE and STRAIN INDEX. METHODS: 598 workstations for a total of 1800 analysis by different methods were considered, by adopting the following multiple step procedure: prelinminary evaluation by Washington State method and OCRA checklist in all the working stations, RULA or HAL as first level evaluation, OREGE or SI as second level evaluation. RESULTS: The preliminary evaluation resulted negative (risk absent) in the 75% of examined work stations and by using checklist OCRA optimal-acceptable condition was found in 58% by HAL in 92% of analysis, by RULA in 100%, by OREGE in 64%; by SI in 70% of examined working positions. We observed similar evaluation of strain among methods and main differences have been observed in posture and frequency assessment. DISCUSSION AND CONCLUSION: The preliminary evaluation by State of Washington method appears to be an adequate instrument for identify the working condition at risk. All the adopted methods were in a good agreement in two estreme situations: high risk or absent risk, expecially in absent risk conditions. Level of accordance varied on the basis of their rationale and of the role of their different components so SIML indications about the critical use of biouzechanical methods and about the possible use of more than one of them (considering working chlaracteristics) have been confirmed. PMID- 25558720 TI - [Health surveillance and suitability: the role of the company physician in maintaining work ability]. AB - The ageing workforce is one of the major issues in Europe. Ageing has an important effect on work ability, especially in manual jobs where physical demand is high. Musculoskeletal disorders are the most common health problems among European workers and are able to affect work ability. In order to increase the employment rate of people aged 45-65, measures to sustain work ability and proper age management should be promoted: return to work strategies include adjustment of the job to the worker's health conditions and abilities. The contribution of health surveillance.programs in the management of workers affected by musculoskeletal disorders is discussed. PMID- 25558721 TI - [Management of the worker affected by shoulder pathology]. AB - Shoulder disorders due to overexertion include joint and soft tissues chronic conditions and are an important cause of disability. Shoulder pain is one of the most common musculoskeletal disorders and has been associated to manual handling of heavy loads, high repetition jobs, exposure to hand-arm vibration and to overhead activities. Diagnosis of shoulder disorders is primarily based on clinical examination; selected cases should be referred to an orthopedic specialist and to imaging. Return to normal activities should be encouraged. PMID- 25558722 TI - [Rheumatic diseases and work ability]. AB - Musculoskeletal diseases are tile most frequent cause of pain in the working population. Rheumatic diseases are chronic illnesses, cause of functional impairnment, relevant working disability and absence from work; however, affected patients maintain a significant functional ability. In this context, the "Fit for work" project, operating in Italy since 2012, promotes the management of chronic musculoskeletal conditions through the realization, also in our country, of a rheumatic medical assistance network in behalf of workers affected by rheumatic diseases and other musculoskeletal disabiliting conditions. PMID- 25558723 TI - [Role of occupational rehabilitation therapy in returning to work: experimental experience]. AB - The experimental experience is the result of combining cultural, clinical and scientific interest in rehabilitative, occupational and forensic mnedicine and in ergonomics. It deals with the rehabilitation and return at work of patients with physical disabilities caused by occupational trauma or disease. The programme described starts with a selection by INAIL and involves with an outpatient surgery inclusion. It is composed of: preliminary physical examination, functional assessment, the formulation of a rehabilitation plan and its successive implementation. At the end of the evaluation plan, there is a final assessment to identify outcome indicators and residual functional and work capacity. PMID- 25558724 TI - [Quality assurance systems and occupational medicine system: an history twenty years along]. AB - Along the last tventy years, in our country the quality assurance systems and the occupational medicine deeply interacted both in theoretical and practical fields of interest at three levels: (i) the need of preventive and therefore of occupational medicine in quality assurance systems; (ii) the need on reverse of quality in prevention and occupational mnedicine mainly in qualification and updating process; (iii) the evidence, proofs of efficacy or appropriateness of different preventive procedures and occupational physician activities; (iv) the connection with European and national legal directives and with technical or good practice norms. Finally we discuss about the role of occupational physician as the global consultant for enterprise, as a mandatory strategic technical figure in a typical multidisciplinary processes as the implementation of the quality systems. PMID- 25558725 TI - [Efficacy--appropriateness]. AB - I discuss the meaning and differences between the Appropriateness and Efficacy in the prevention of occupational risks and damage. It is argued that to be "appropriate" an intervention should be suitable, keeping with the circumstances, while the intervention that achieves the goal is "effective". In practice, the appropriateness is very used in the field of clinical medicine, with reference to the treatment, while in the prevention it is usual to use with greater frequency the term of effectiveness. PMID- 25558726 TI - [Competency evaluation of the company physician to improve prevention efficiency in the company]. AB - The activity of the occupational physician (OP) in the enterprise has as its purpose the protection of the health of workers and consists of two main areas: health surveillance and risk assessment. Every day thle OP have to take into account both the results of clinical diagnostic investigation and the outcomes of the estimation of occupational exposure to risk factors by making a right mix between what is proven by scientific evidence and professional experience. He also knows that its effectiveness is closely linked to the contribution of other figures ofprevention in the company. In the scientific literature, the authors are unanimous in considering the effective actions to reduce exposure to risk, risk behaviors, injuries, occupational illnesses, disability, absenteeism. The use of indicators of effectiveness and / or appropriateness for the enhancement of its contribution, especially as a consultant in the field ofprevention and health protection in the compmany and then with anmt active role in corporate governance of prevention, are a must and no longer postponed, as well as the development of tools that document in formal terms, its contributioni (annual health report, the definition of risk profiles). I, this paper, by analyzing the results of specific experiences in the surveillance of construction workers, drivers and bakers, the authors want to emmphasize the contribution of the OP. PMID- 25558727 TI - [Efficiency of health surveillance in occupational medicine]. AB - Medical surveillance is one of the primary instruments in occupational health activities and is considered essential to maintain employees' good health. However, the efficacy of medical surveillance has not been sufficiently tested. The aim of this review was to evaluate the usefulness of medical surveillance, using available literature on Pubmed for the period 2005 to 2014. Although on the basis of a small number of studies, our conclusion is that medical surveillance could be considered effective. Apart from the case of occupational asthma, it must be emphasised that the number of evaluation studies is small, especially in some areas, as well as the one of biomechanical overload. PMID- 25558728 TI - [Overdiagnosis and defensive medicine in occupational medicine]. AB - In clinical medicine since some years overdiagnosis is giving rise to growing attention and concern. Overdiagnosis is the diagnosis of a "disease" that will never cause symptoms or death during a patient's lifetime. It is a side effect of testing for early forms of disease which may turn people into patients unnecessarily and may lead to treatments that do no good and perhaps do harm. Overdiagnosis occurs when a disease is diagnosed correctly, but the diagnosis is irrelevant. A correct diagnosis may be irrelevant because treatment for the disease is not available, not needed, or not wanted. Four drivers engender overdiagnosis: 1) screening in non symptomatic subjects; 2) raised sensitivity of diagnostic tests; 3) incidental overdiagnosis; 4) broadening of diagnostic criteria for diseases. "Defensive medicine" can play a role. It begs the question of whether even in the context of Occupational Medicine overdiagnosis is possible. In relation to the double diagnostic evaluation peculiar to Occupational Medicine, the clinical and the causal, a dual phenomenon is possible: that of overdiagnosis properly said and what we could define the overattribution, in relation to the assessment of a causal relationship with work. Examples of occupational "diseases" that can represent cases of overdiagnosis, with the possible consequences of overtreatment, consisting of unnecessary and socially harmful limitations to fitness for work, are taken into consideration: pleural plaques, alterations of the intervertebral discs, "small airways disease", sub-clinical hearing impairment. In Italy the National Insurance for occupational diseases (INAIL) regularly recognizes less than 50% of the notified diseases; this might suggest overdiagnosis and possibly overattribution in reporting. Physicians dealing with the diagnosis of occupational diseases are obviously requested to perform a careful, up-to-date and active investigation. When applying to the diagnosis of occupational diseases, proper logical criteria should be even antecedent to a good diagnostic technique, due to social outcome for the worker. PMID- 25558729 TI - [The validity of proofs in demonstrating risk and in research into the causal connection of occupational diseases]. AB - The verification of the occupational origin of a disease is a forensic medical activity requiring: the confirmation of the existence and of the exact nosographic identification of the disease, as well as the type of work really performed, and the actual exposure to an effective occupational hazard during an adequate time, and finally a reconstruction of the causal relationship based on objective data. Checking the disease is essentially documentary, corroborated by direct survey by medical examination. The assessment of exposure to the occupational hazard must be scrupulous also, not being acceptable the medical history alone: that is, it does require documentary evidence. Finally, the logical process of recognition of causation requires the application of rigorous forensic medical methodology, with references to current scientific knowledge, and the application of legal criteriology from the legal field of law in which you are moving. Indeed, forensic medical methodology is not the same of epidemiological one: probability of occurrence of an event is not a proof, but only a circumstantial element. A forensic medical doctor organizes every evidence and circumstantial evidence in a unique decision-making process, as a result of a logical process, and probabilistic data can be among circumstantial evidence, but they must suit the case in details, in order to reach the so called "logic probability". But this doesn't mean that you have "proven" the occupational origin of a disease. In the "demonstration" of a fact you use the same forensic medical methodology (thus referring to classic criteria: temporality, biological gradient and plausibility, topographical, exclusion, and phenomenal continuity if suitable, too), and also the same general scientific references, nevertheless the law can be different in causality principles admitted (the principles governing the causal link are the same in Criminal Code and Civil law both, but they differ in private insurance), and besides there is a different rule of evidence, that is the "quantum of evidence" required (the amount of evidence needed) and, secondarily, also a different quality of proof required (how reliable such evidence should be considered, and which types of evidence admitted). Therefore in Civil law you can reach a "procedural truth" different from the one in Criminal law, and various from the one needed to prevail in litigation with social security insurance or with private insurance. PMID- 25558730 TI - [Musculoskeletal pathology in occupational risks and common degenerative disease: reflections on the intensity and duration of the risk]. AB - Nowadays, in Italy the reports of mnusculoskeletal diseases increase as confirmed in the last INAIL (national insurance for occupational diseases and injuries) annual report. The Emilia-Ronmagna is one of the region with the highest number of reports: 15.9% of the total in 2012. The decree no. 81/08 has partially simplified the medico-legal activities related to musculoskeletal diseases; however, the medico-legal physicians have still to deal with some issues such as risk assessment quality, economic crisis, and specific work environments (e.g. agriculture and many handicraft activities). Tire risk factors of musculoskeletal diseases and their assessments are quite well studied. The latency period of these diseases needs to be investigated, since it could be a relevant aspect for legal medical judgment, insurance protection and prevention. Based on literature data and INAIL experience, authors propose some considerations useful for a scientific debate. PMID- 25558731 TI - [160 activities analyzed by the risk of biomechanical overload on the upper limbs in small industry, handicrafts, services and agriculture]. AB - We analyzed 160 work activities in the sectors of small industries, handicrafts, services and agriculture to evaluate the risk of biomnechanical overload of the upper limbs with the OCRA Checklist. The aim was to provide a tool available for the risk assessment in activities generally underestimnated for this risk and typical of the Italian production. The information was provided in the form of cards containing easily accessible data, risk scenarios in different timing, along with some of the key prevention interventions that can be realized. PMID- 25558732 TI - [The role of coactivation of the trunk musculature in evaluating biomechanical risk]. AB - One of the mechanisms adopted by the central nervous system to stabilize the joints or the spine is muscle co-activation. Nevertheless during lifting tasks muscle co-activation increases spinal load. For co-activation assessment during 3 lifting tasks at increasing load levels we utilized a time-varying co-activation algorithm proposed by Rudolph in 2000. We found that Rudolph co-activation index grew with lifting index. The time-varying co-activation index gave a continuous measure of low back compression. A time-varying co-activation index could be of great interest in all conditions in which NIOSH equation is not applicable. PMID- 25558733 TI - [INAIL recourse in occupational diseases]. AB - The following paper examines the issue of the specific action of recourse brought by the National Insurance Accidents at work (INAIL) for occupational diseases by examining the regulatory framework and the diachronic evolution of the Court's legitimacy in the matter. The authors focus on the most frequent cases and highlight the orientation adopted by the administrative office in the matter. PMID- 25558734 TI - [MALPROF and the Plan for Prevention]. AB - The Inail data show that in the last years the complaints and acknowledgments of occupational diseases has been increasing, in contrast what happened previously. This growth is the expected and desired emergence of work- related diseases and it's also an alarm bell that the institutions can not ignore. In addition to the data provided by INAIL, the MalProf system gives an important contribution to tlhe understanding of occupational diseases. MalProf is a system for recording and analysis of reported occupational diseases using the source information provided by Service Prevention of ASL. The model used by the Surveillance System MALPROF, by combines the information in a consistent and standardized, assesses the relevance of a causal link between the disease and reports the activity carried out by the worker during his professional history. The two systems (INAIL database and MALPROF), although with some differences have largely confirmed the same data. The past decade has marked the final decline of the working traditional occupational diseases (respiratory toxic substance related diseases and by the accumulation of poisoning, skin, etc....); the hearing loss is still frequent but less important than it was in the past relevance. Tumors and, in particular, musculoskeletal disorders, have been emerging as one of the hidden problems before tumors but, above all, appeared on the scene and the group of musculoskeletal disorders. As indicated by the National Plan for the preventive actions should be directed in several directions: active surveillance, training of the subjects of prevention and other figures, the promotion of the quality of the risk assessment documents. PMID- 25558735 TI - [Active research, registration, and prevention of tumors of professional origin]. AB - Occupational cancer is an important public health concern in Italy and in many industrialized countries. The difficulties in monitoring and the complexity in retrieving occupational cancer cases have required the enrolment of a national epidemiologic sureveillance system at national scale with active search methods. A structured system for the registration of occupational cancer cases is normed by the Decree No. 81/2008, that accounts for the previous legislative procedures and experiences. Research activities and prevention of occupational cancer should be integrated with insurance policies to the purpose of an efficient protection of workers health. PMID- 25558736 TI - [Requirements of the system for registering occupational diseases: experience in comparison]. AB - The main characteristics of the OSH monitoring systems in use in Europe are described. We refer the results of a survey carried out in six different European countries using the ODIT tool for assessing the quality of these recordings. PMID- 25558737 TI - [The Health Surveillance database of a large hospital enterprise: a 20-year analysis]. AB - To evaluate the aging of the working population and its effects, a 20 years observational study was conducted on health surveillance data of a large healthcare company. The data showed a gradual increase in the mean age of workers, especially among subjects with restrictions/requirements regarding their job title. If no preventive/corrective measures are taken, the socio-economnic situation will get worse with economic and social damages. PMID- 25558738 TI - [The Information Flows System as an instrument for preventing technological illness]. AB - This paper describes the project "Information Flows", its contents of INAIL data about accidents and occupational diseases reported and recognized and its usefulness for programs of preventive initiatives undertaken by INAIL and by the responsible structures in the single italian regions. We propose some processings of data and suggest how their collection, according to criteria based on occupational medicine, industrial hygiene and epidemiology and a careful analysis and processing of data from more sources could lead to an extension of the workers protection, relatively to "unrecognized" occupational diseases, diseases caused by the "old" risks and the identification of occupational diseases caused by "new" risks. PMID- 25558739 TI - [The protection of health in law enforcement]. AB - Herein the question of health protection/safety and well being in the Law Enforcement is introduced and includes examples of some particular risk conditions that may be multiple and polymorphous. Not only the "traditional" sources are involved in these risks, like chemical, physical and biological agents, but other issues emerge in these "new scenarios" connected to risk factors involving organization and/or psychosocial elements. From this, we may deduce that there is a specific need for all the operators involved in prevention/care in this particular sector to be well versed on the highest possible updated specialized knowledge along with having a complete and thorough mastery of the best practices in Occupational Medicine to face this task in the correct manner: PMID- 25558740 TI - [Chemical, physical and biological risks in law enforcement]. AB - Chemical, physical and biological risks among public safety and security forces. Law enforcement personnel, involved in routine tasks and in emergency situations, are exposed to numerous and several occupational hazards (chemical, physical and biological) whith likely health and security consequences. These risks are particularly high when the organization and preparation are inadequate, there is a lacking or insufficient coordination, information, education and communication and safety and personal protective equipment are inadequate or insufficient. Despite the objective difficulties, caused by the actual special needs related to the service performed or the organizational peculiarities, the risk identification and assessment is essential for worker health and safety of personnel, as provided for by Legislative Decree no. 81/2008. Chemical risks include airborne pollutants due to vehicular traffic (carbon monoxide, ultrafine particles, benzene, polycyclic aromatic hydrocarbons, aldehydes, nitrogen and sulfur oxides, lead), toxic gases generated by combustion process following fires (aromatic hydrocarbons, PAHs, dioxins and furans, biphenyls, formaldehyde, metals and cyanides), substances emitted in case of chemical accidents (solvents, pesticides, toxic gases, caustics), drugs (methylamphetamine), riot control agents and self-defence spray, lead at firing ranges, and several materials and reagents used in forensic laboratory. The physical hazards are often caused by activities that induce biomechanical overload aid the onset of musculoskeletal disorders, the use of visual display terminals and work environments that may expose to heat stress and discomfort, high and low pressure, noise, vibrations, ionizing and non-ionizing radiation. The main biological risks are blood-borne diseases (viral hepatitis, AIDS), airborne diseases (eg, tuberculosis, meningitis, SARS, anthrax), MRSA, and vector-borne diseases. Many of these risk factors are unavoidable or are not predictable; so a proper risk assessment is very important, especially in case of emergencies, and also the necessary preventive measures, a careful analysis of alternative options for action and decision-making, implementation of security measures due to the provision of appropriate PPE and effective management of risk communication have great importance. Another important aspect is the education and training of staff, as in emergency situations should be able to take protective measures as quickly as possible. PMID- 25558741 TI - [24-hour work: the interaction of stress and changes in the sleep-wake cycle in the police force]. AB - Disruption in police officers. In recent years there has been a widespread growth in services, available regardless of time or day organization (24/7 service) and a diffuse increase in their use, both in work and private lives, generally ignoring the importance of a regular sleep organization. Police officers - often need to work extended shifts and long hours under highly stressful conditions, which results in reduced levels of safety and operational effectiveness. In numerous studies, perceived stress has been found to correlate with both subjective and objective disturbances in sleep. Consequently, excessive daytime sleepiness is one of the most frequent health and safety hazards that police officers have to deal with. Sleep deprivation affects performance outcomes through a wide range of cognitive domains. Sleepiness and fatigue, caused by sleep loss, extended work and wakefulness, circadian misalignment and sleep disorders are major causes of workplace human errors, incidents, and accidents. Therefore, prevention of sleep loss, high levels of stress and fatigue is a key factor to consider when assessing emergency intervention. In order to combat fatigue and sleepiness, a 30-90 minutes nap before night shift could be a viable option. PMID- 25558742 TI - [Risk factors in police activities: operational criticism in surveillance programs]. AB - The planning of specific health surveillance programs for police officers is extremely complex due to difficulty in predictability and variety of occupational hazards. Even in the case of conventional occupational risk factors clearly identified by current regulations, particular working conditions may require specific assessment to effectively identify and quantify the risk of occupational exposure. An extensive program of health surveillance, aimed at promoting overall health and effectiveness of the operators, would be really desirable, in order to help better address a number of risks that cannot be easily predicted. The progressive increase in the average age of the working population and the increasing prevalence of chronic degenerative diseases, may also suggest the need for health surveillance procedures designed to verify continued unqualified suitability to police service, providing for the identification of diversified suitability profiles in relation to age and state of health: accordingly, in regard to our field of interest, there is a close link between medico-legal eligibility and occupational medicine. PMID- 25558743 TI - [Evaluation methods in the work/stress correlations in law enforcement]. AB - Stress in police: assessment methods. INTRODUCTION: Police work is unanimously considered stressful. Prevention of stress in police is of the utmost importance, as a distressed officer could be hazardous for third parties. There is scientific evidence that the relationship between occupational stressors and their psychological and physical consequences can be described by Karasek's demand control-support (DCS) model and the effort / reward imbalance (ERI) model of Siegrist. METHOD: This study summarizes the results of surveys conducted using the DCS and ERI questionnaires.on police officers from the VI Mobile Unit of Genoa who were engaged in public order management at the G8 summit in L'Aquila in 2009. RESULTS: In spite of the high alert due to expected threats to public order during the G8 meeting, police officers were not affected by "distress". When the policemen were compared to other categories of workers, their stress levels were in the lowest range. In most cases, the personality profile of these workers did not differ substantially from that of the general population. There was an association between personality and stress response. The levels of perceived stress were significantly associated with absence from work. The prevalence of mental disorders in police officers was significantly lower than that of the general population. Occupational stress was associated with indicators of depression, anxiety and burnout. CONCLUSIONS: The DCS and ERI models yielded complementary results and proved to be effective in assessing the effects of stress in law enforcement. The extent of perceived stress does not directly depend on external events, but on the way in which these are handled: routine work may be more stressful than a single critical event. Special police forces are particularly resilient to stress, partly due to the characteristics and personality of individual officers, but mainly on account of their training. Occupational stress is associated with a lower level of psychological well-being and an increase in the frequency of absences from work. PMID- 25558744 TI - [Occupational risk factors and medical prevention in corrections officers]. AB - In Italy, the Law n. 395/1990 defines the tasks and attributions of prison officers. According to the article 25 of the Legislative Decree n. 81/2008, the occupational physician should participate to risk assessment, and carry out the sanitary surveillance. This report analyzes the various tasks of prison staff, identifies the risk factors, and discusses the preventive strategies, including workers formation and education. Biological agents and work-related stress are the main risk factors, as a consequence of prison overcrowding, personnel shortage and work organization complexity. In his preventive action, and particularly in formulating the judgment on work fitness, the occupational physician often clashes with inadequate ministerial funding. PMID- 25558745 TI - [The INSuLa Project: a knowledge survey among workers]. AB - The INSuLa project consisted of a national survey on health and safety at work involving all the relevant actors such as workers, employers, occupational physicians (MC), worker safety representatives (RLS), prevention and safety service in the workplace (SPSAL). The survey aimed, on one hand, at investigating workers' risk perceptions at the workplace and, on another hand, at exploring the general level of awareness about the enforcement of the Legislative Decree 81/2008 and subsequent amendments. The survey was conducted on a stratified sample of8000 workers representative of the national situation taking into consideration some of the most important socio-demographic and occupational variables, such as gender, geographic area, age, type of contract and sector of activity. The analysis of the results presented here and the subsequent secondary analyses will contribute to identify the needs and critical issues for implementing preventive interventions at the workplaces, also in consideration of the emerging risks and changes in the world of work. PMID- 25558746 TI - [The INSuLa Project: a knowledge survey of employers]. AB - In the framework of the INSuLa project, supported by Italian Ministry of Health, a national survey was conducted to evaluate the perceptions of employers about Occupational Safety and Health (OSH) activities. Main findings of this survey are presented in this paper. The survey was conducted on a sample of 1,010 employers weighted by economic activity sector, company size and geographic area. An ad hoc questionnaire was administered through Computer Assisted Telephone Interviewing methodology. Most of employers "mostly" or "completely" agree with the usefulness of OSH activities and the efficacy of specific prevention and protection measures. Around 37.7% of employers consider OSH management a shared responsibility with workers and 56.1% of them feel the OSH level to be increased following the implementation of Legislative Decree no. 81/08. The findings of this survey provide a picture of Italian employers' point of view about OSH and identify gaps and needs, thus contributing to choose proper actions for the improvement of OSH PMID- 25558747 TI - [The INSuLa Project: the knowledge survey of company physicians]. AB - The technological advancements, the occurrence of new emerging occupational risks and diseases, and the changes in the regulatory framework for occupational health and safety induce a constant evolution of occupational medicine. Consequently, the skills and training needs of the occupational physicians should be periodically revalued and upgraded in order to identify technical and operational issues and problems of this discipline. In this context, the aim of this national survey, carried out using a self-administered questionnaire submitted to a sample of 1,237 occupational physicians, has been to gain helpful information to ensure a continuous improvement of the quality and effectiveness of measures aimed at protecting the health and safety of workers. The questionnaire, that consists of 43 questions divided into 5 different areas (personal and professional information, training and updating needs of occupational physicians, professional activities and relationships with the corporate prevention system, relationships with the supervisory board of the Local Health Authority, relationships with the National Health Service), allowed to obtain personal and professional data, to assess the training needs and demands of occupational physicians and to evaluate their relationships with the other stakeholders of the Italian prevention system and with the National Health Service. The preliminary results of this survey appear extremely important. In fact, this findings, highlighting the current problems of occupational physician, constitute the starting point to identify, develop and implement management methodologies, operative procedures and training programs that are effective and modern. PMID- 25558748 TI - [The INSuLa Project: the survey of training needs in the SPSAL(Service for Prevention and Safety in the Work Environment)]. AB - According to Italian Legislative Decree 81/2008 and subsequent modifications the Regions and Autonomous Provinces have a innovative and complex role: 1) to regulate and coordinate the total prevention system and 2) to develop interventions/initiatives through regional/local occupational safety and health (OSH) department using not only inspections and controls but education, training and support. Recommendations also include consolidating the role of actors involved in preventing risks to occupational health throughout occupational safety and health education and training, keys for a successful process to improve prevention system. As result of changing world of work and OSH legislation the INSuLa project has creating a national survey involving of all Italian prevention system actors, in order to evaluate implementation and impact of the actual regulations. According to overall objective of the INSuLA project, for the first time in Italy, we studied about operators in regional/local OSH department. The purpose of this paper is to show and recognize the individual learning paths, the perception of adequacy education degree, the exploring criticalities andthe training needs. PMID- 25558749 TI - [Instituto de Investigaciones Clinicas "Dr. Americo Negrette": 55 years of excellent research versus global economic recession]. AB - The Instituto de Investigaciones Clinicas "Dr. Americo Negrette" belongs to the Faculty of Medicine at University of Zulia in Maracaibo, Zulia State, Venezuela. It was created on December 4, 1959 by Dr. Americo Negrette. Today, with 55 years of existence, the Institute seeks to fulfill the mission that characterizes it, based on the values instilled by its founder and maintained by subsequent generations, whose research projects are implemented through seven research sections: Biochemistry, Hematologic Research, Neuropharmacology and Neuroscience, Immunology and Cell Biology, Clinical Neurochemistry, Parasitology and Virology. The research originated in these laboratories have become national and international points of reference, despite the current economic situation with budget deficits that put at risk the quality and originality of their projects with negative consequences on the productivity and applications for health population, reasons of biomedical research. PMID- 25558750 TI - [A comparative study between the Vitek YBC and Microscan Walk Away RYID automated systems with conventional phenotypic methods for the identification of yeasts of clinical interest]. AB - The aim of this study was to compare the identification of clin- ically relevant yeasts by the Vitek YBC and Microscan Walk Away RYID automated methods with conventional phenotypic methods. One hundred and ninety three yeast strains isolated from clinical samples and five controls strains were used. All the yeasts were identified by the automated methods previously mentioned and conventional phenotypic methods such as carbohydrate assimilation, visualization of microscopic morphology on corn meal agar and the use of chromogenic agar. Variables were assessed by 2 x 2 contingency tables, McNemar's Chi square, the Kappa index, and concordance values were calculated, as well as major and minor errors for the automated methods. Yeasts were divided into two groups: (1) frequent isolation and (2) rare isolation. The Vitek YBC and Microscan Walk Away RYID systems were concordant in 88.4 and 85.9% respectively, when compared to conventional phenotypic methods. Although both automated systems can be used for yeasts identification, the presence of major and minor errors indicates the possibility of misidentifications; therefore, the operator of this equipment must use in parallel, phenotypic tests such as visualization of microscopic morphology on corn meal agar and chromogenic agar, especially against infrequently isolated yeasts. Automated systems are a valuable tool; however, the expertise and judgment of the microbiologist are an important strength to ensure the quality of the results. PMID- 25558751 TI - [Superficial mycoses in patients from Anzoategui state, Venezuela, period 2002 2012]. AB - Superficial fungal diseases that affect the skin and its appendages are frequently seen in basic triage and in dermatology services. These diseases are distributed in Venezuela with an incidence of 92.9%. The aim of this study was to determine the genera and species that cause dermatomycoses in residents of Anzoategui state, Venezuela, during the period 2002-2012. A total of 4257 patients with a presumptive diagnosis of superficial mycoses were studied, with ages from 7 months to 79 years. The overall prevalence was 30.9%. The most frequent were dermatophytosis (44.7%). M. canis produced 148 cases of tinea capitis. Three dermatophytic agents represented 95% of all cases, with a significant predominance of T. mentagrophytes with 50%. Candidosis occurred in 28.4%. C. albicans, and the C. parapsilosis complex, were responsible for 80% of the cases. The other species identified were C. tropicalis (n = 41, 11.0%), C. glabrata (n = 10, 2.7%), C. guilliermondii (n = 6, 1.6%), C. krusei (n = 4, 1.1%). Pityriasis versicolor occurred in 22.4% of the cases studied, and less frequently were present onychomycosis produced by a non dermatophytic mold: Fusarium oxysporum (n = 34, 65.4%), Aspergillus terreus (n=16, 30.8%) and Scytalidium dimidiatum (n=2; 3.8%). Rare cases of Trichosporon onychomycosis (0.5%) and one case of black tinea were also found. Health education in the population is recommended to promote measures to prevent transmission of these fungi and prevent the spread of this silent public health problem. PMID- 25558752 TI - [Natriuretic peptide in patients with Chagas disease: diagnostic utility in heart failure]. AB - The assessment of the type-B natriuretic peptide (BNP) has shown utility as a diagnostic and prognostic tool of heart failure. The aim of this study was to evaluate the BNP levels and to know its association within the systolic dysfunction level on Chagas disease. During the period 2010-2011, 64 patients were evaluated in the Chagas clinic of the Cardiopulmonary Unit of the University Hospital Dr. Luis Razetti, Barcelona-Anzoategui state, Venezuela. After confirming the seropositive state to antibodies anti-T. cruzi with three inmunoserological tests (ELISA, indirect inmunofluorescence and indirect hemaglutination), patients were classified into Groups I, II and III of cardiac disease, by the evaluation with electrocardiogram, echocardiogram and thorax radiography. Thirty three seronegative cardiological patients and eight healthy volunteers were included in the study as controls. BNP groups levels were as follow: Chagas I = 18.87 +/- 18.00 pg/mL (n=20), Chagas II = 99.88 +/- 171.52 pg/mL (n=24) y Chagas III = 365.80 +/- 280.54 pg/mL (n=20). The sensitivity and specificity of BNP were 85.0% and 93.2%, respectively, (p<0.0001; IC 95%), employing as parameter of reference the left ventricle fraction ejection (LVFE <40%), with a prognostic value of 89.0% (p=0.006). These results place the BNP in an equivalent position with the echocardiogram for the evaluation of cardiological patients, with the benefits of rapidity and simplicity, which makes the determination of this biochemical parameter a useful tool to perform field studies in endemic zones with limited access to the echocardiographic test. PMID- 25558753 TI - Mycobacterium tuberculosis population structure and molecular epidemiological analysis in Sucre municipality, Miranda state, Venezuela. AB - Sucre municipality is a large, densely populated marginal area in the eastern part of Caracas, Venezuela that consistently has more cases of tuberculosis than other municipalities in the country. To identify the neighborhoods in the municipality with the highest prevalence of tuberculosis, and determine whether the Mycobacterium tuberculosis strain distribution in this municipality is different from that previously found in the western part of Caracas and the rest of Venezuela, we collected data on all tuberculosis cases in the municipality diagnosed in 2005-6. We performed two separate molecular epidemiological studies, spoligotyping 44 strains in a first study, and spoligotyping 131 strains, followed by MIRU-VNTR 15 on 21 clustered isolates in the second. With spoligotyping, the most common patterns were Shared International Type SIT17 (21%); SIT42 (15%); SIT93 (11%); SIT20 (7%); SIT53 (6%), a distribution similar to other parts of Venezuela, except that SIT42 and SIT20 were more common. MIRU VNTR 15 showed that six of seven SIT17 strains examined belonged to a large cluster previously found circulating in Venezuela, but all of the SIT42 strains were related to a cluster centered in the neighborhoods of Union and Maca, with a MIRU-VNTR pattern not previously seen in Venezuela. It appears that a large percentage of the tuberculosis in the Sucre municipality is caused by the active transmission of two strain families centered within distinct neighborhoods, one reflecting communication with the rest of the country, and the other suggesting the insular, isolated nature of some sectors. PMID- 25558755 TI - Mutation c.1190-1delG/N in intron 8 and c.1708G>C/N in exon 12 not reported in the IDUA gene developed a clinical phenotype of Scheie syndrome. AB - Mucopolysaccharidoses are a group of lysosomal storage disorders caused by deficiency of enzymes catalyzing the degradation of glycosaminoglycans. Mucopoly saccharidosis I can present a wide range of phenotypic characteristics with three major recognized clinical entities: Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression. These are caused by the deficiency or absence of alpha-L-iduronidase, essential to the metabolism of both dermatan and heparan sulfate, and it is encoded by the lDUA gene. We report the case of a 34-year-old male patient with enzymatic deficiency of alpha-L-iduronidase, accumulation of its substrate and a previously unreported mutation in the IDUA gene that developed a phenotype of Scheie syndrome. PMID- 25558754 TI - Longterm melatonin administration alleviates paraquat mediated oxidative stress in Drosophila melanogaster. AB - We investigated the effect of melatonin (MEL) in the activities of cytosolic superoxide dismutase (SOD) and catalase as well as in the levels of H2O2 and mitochondrial malondialdehyde (MDA) in paraquat-intoxicated Drosophila melanogaster. Paraquat (40 mM) was administrated for 36 h. Three groups of flies intoxicated with paraquat were used: PQ (exposed during 36h to paraquat), PQ-MEL (exposed during 36h to paraquat and then treated with MEL [0.43 mM] for 12 days) and PQ-Control (maintained in standard corn meal for 12 days). Two additional groups without pre-intoxication with PQ were added: Control (maintained in standard corn meal) and MEL (treated with MEL for 12 days). Immediately after PQ intoxication the concentration of MDA (17.240 +/- 0.554 nmoles MDA/mg protein) and H2O2 (3.313 +/- 0.086 nmol hydrogen peroxide/mg protein) and the activities of SOD and catalase (419.667 + 0.731 and 0.216 +/- 0.009 Units/mg of protein, respectively) in the PQ group were significantly increased with respect to Control. After 12 days of intoxication with PQ, the PQ-Control flies showed in- creases in H2O2 (4.336 +/- 0.108) and MDA levels (8.620 +/- 0.156), and in the activities of SOD and catalase (692.570 +/- 0.433 and 0.327 +/- 0.003, respectively) as compared to PQ-MEL (p<0.001). Treatment with MEL extended the life span of the groups PQ-MEL and MEL when compared to their corresponding controls. Motor activity decreased significantly in PQ-Control and PQ-MEL flies, suggesting that the damage caused by PQ affected the nervous system of flies. Our findings showed that oxidative damage caused by paraquat was observed even after 12 days and that melatonin mitigates this damage. PMID- 25558756 TI - [Stem cells and cancer]. AB - Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Cancer stem cells are a subpopulation of the cells that form the tumor. The discovery of these human cancer cells opens a perspective for understanding tumor recurrence, drug resistance and metastasis; and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Therapeutic alternatives emerge from a better understanding of the biology and the environment of tumor stem cells. The present paper aims to summarize the characteristics and properties of cancer stem cells, the ongoing research, as well as the best strategies for prevention and control of the mechanisms of tumor recurrence. PMID- 25558758 TI - In the footsteps of nature. PMID- 25558757 TI - John of God: an enigma for the medical sciences. AB - Some cures carried out by Medium Joao Teixeira de Faria (John of God) are presented. He claims to channel spiritual entities (Drs. Augusto de Almeida, Oswaldo Cruz, and Jose Valdivino) that have instantaneous access to the physical, emotional and spiritual history of each patient who is then treated by physical or "spiritual" surgeries, herbs, meditation, prayers and the ingestion of "energized" water. People operated on have no pain during the interventions and infections have not been observed. The mechanisms responsible for the healings are unknown. PMID- 25558759 TI - Occlusion of artificial teeth in partial dentures in the "chewing center"--first exploratory population-based evaluations. AB - Occlusal performance is a substantial determinant of the quality of dental prosthetic restorations. In the follow-up (SHIP 1) to the Study of Health in Pomerania (SHIP), a representative population of 3300 subjects was studied in the first exploratory evaluation of the occlusion of artificial teeth in the chewing center (first molar region) of partial dentures. A digital analysis of interocclusal records of habitual intercuspation position (ICP) was performed using the Greifswald Digital Analyzing System (GEDAS), a software package that identifies contact points as transparent areas. 562 subjects (280 men aged 61.7 +/- 11.9 years and 282 women aged 60.7 +/- 10.7 years) had maxillary removable partial dentures (RPDs), and 619 (271 men aged 65.0 +/- 11.5 years and 348 women aged 62.4 +/- 10.6 years) had mandibular RPDs. Most RPDs were retained with either attachment retainers (11.7% maxilla, 11.7% mandible), cast clasps (38.4% maxilla, 40.7% mandible), telescopes with double crowns (15.7% maxilla, 19.1% mandible), or wrought wire clasps (16.4% maxilla, 8.2% mandible). Some had a combination of different retention elements. The mean number of artificial teeth was 7.8 +/- 2.9 in the maxilla and 7.5 +/- 3.0 in the mandible. Only the artificial teeth (first molars) in mandibular partial dentures showed differences in the frequency of occlusal contacts between groups (chi-square test). Of these, telescopic crown-retained RPDs had the highest frequency of occlusal contacts (74.4% at tooth 36 and 77.1% at tooth 46), and wrought wire-retained RPDs had the lowest (48.4% at tooth 36 and 45.2% at tooth 46). The results for RPDs with a free-end saddle were comparable and analogous; contact frequencies for those with an interdental saddle did not differ significantly. Notably, the overall frequency of occlusal contacts was greater for tooth 46 (62.9%) than for tooth 36. In conclusion, when replacing teeth in the chewing center, particularly in the mandible, telescopic crown-retained RPDs offer a distinct advantage in terms of occlusal contacts and thus provide better occlusal stability. PMID- 25558760 TI - Finite element analysis of the principles and loosening force of the conical telescopic crown: a computer-based study. AB - OBJECTIVES: The primary goal of the present finite element (FE) analysis of a special removable prosthesis, the conical telescopic crown (CTC), was to validate established results based on a rigid model of the CTC and to analyze its characteristic features as a function of the essential material and geometric parameters. Furthermore, the effectiveness of a new element, the composite stop (CS), was investigated. MATERIALS AND METHODS: The study used an axisymmetric FE model containing the inner and outer crown including resin or ceramic veneer, the CS, the cement layer between the interior crown and the tooth, and the upper part of the tooth itself. RESULTS: For a convergence angle (half-cone angle) alpha = 4 degrees and a moderate chewing force F = 150 N the loosening force decreased from - 50 N without to - 10 N with CS. Increasing alpha values yielded a decrease of the loosening force. Adherence between the inner (IC) and outer crown (OC) was achieved for all configurations (alpha = 2 degrees, 4 degrees, and 6 degrees), except for zirconium crowns with alpha = 6 degrees. In systems without CS, the maximum tensile stress in the veneer increased proportionally to F, but remained limited in those with CS. CONCLUSIONS: The angle a and the coefficient of static friction MU0 emerged as the decisive parameters of the CTC. The computed fitting/loosening behavior agreed well with results of a simple rigid-body model and experiments. The incorporation of a CS allows ceramic veneering of the outer crown. CLINICAL RELEVANCE: The optimal angle alpha of the CTC is ascribed to a number of customary material combinations for IC and OC. The CS limits the loosening forces of the CTC to values which guarantee non-traumatic removal of the prosthesis. PMID- 25558761 TI - Morphogenic designer--an efficient tool to digitally design tooth forms. AB - BACKGROUND AND PURPOSE: Different digital software tools are available today for the purpose of designing anatomically correct anterior and posterior restorations. The current concepts present weaknesses, which can be potentially addressed by more advanced modeling tools, such as the ones already available in professional CAD (Computer Aided Design) graphical software. AIM: This study describes the morphogenic designer (MGD) as an efficient and easy method for digitally designing tooth forms for the anterior and posterior dentition. MATERIALS AND METHOD: Anterior and posterior tooth forms were selected from a collection of digitalized natural teeth and subjectively assessed as "average". The models in the form of STL files were filtered, cleaned, idealized, and re meshed to match the specifications of the software used. The shapes were then imported as wavefront ".obj" model into Modo 701, software built for modeling, texturing, visualization, and animation. RESULTS: In order to create a parametric design system, intentional interactive deformations were performed on the average tooth shapes and then further defined as morph targets. By combining various such parameters, several tooth shapes were formed virtually and their images presented. CONCLUSION: MGD proved to be a versatile and powerful tool for the purpose of esthetic and functional digital crown designs. PMID- 25558762 TI - Provisional polymer-based CAD/CAM implant superstructures. AB - The prosthetic restoration of implants to obtain an esthetically balanced outcome is an extremely complex process--especially in terms of effective soft-tissue management. So-called hybrid abutment crowns, which can be made from polymer milling blocks in an uncomplicated process and used for immediate provisional restoration, represent an advance in the efficient production of superstructures. PMID- 25558763 TI - New Cerec software version 4.3 for Omnicam and Bluecam. AB - The introduction of the Cerec Omnicam acquisition unit in September 2012 presented Sirona with a challenge: con- figuring the existing software version 4 for both the exist- ing Bluecam, which uses still images, and the video-based Omnicam. Sirona has succeeded in making all the features introduced in version 4.2 (such as the virtual articulator or implant-supported single-tooth restorations, both monolithic and two-part designs) work with both camera types, without compromising the uniform, homogeneous look and feel of the software. The virtual articulator (Figs 1a to 1c) now has even more individual configuration options and allows the setting of almost all angles derived from the individual transfer bow based on precalculated average values. The new software version 4.3, presented in July 2014, fixes some minor bugs, such as the time-consuming "empty grinding" after necessary water changes during the grinding process, but also includes many features that noticeably ease the workflow. For example, the important scanning precision in the region of the anterior incisal edges has been improved, which makes the scanning process more reliable, faster, and far more comfortable. PMID- 25558765 TI - Surface photografting of acrylic acid on poly(dimethylsiloxane). Experimental and dissipative particle dynamics studies. AB - This work includes both experimental and theoretical studies of the wetting property changes of water on a surface of poly(dimethylsiloxane) (PDMS) modified with different amounts of acrylic acid (AA). The default surface properties of PDMS were changed from hydrophobic to hydrophilic behavior which was characterized with contact angle measurements by two approaches: (i) experimental tests of samples subjected to a photografting polymerization procedure to obtain a functionalized surface and (ii) DPD (dissipative particle dynamics) simulations which also involve the calculation of sets of repulsive parameters determined following two methods: the use of the "Blends" module in the Materials Studio software and the calculation of cohesive energy density with molecular simulations. Changes of contact angle values observed from both experimental and numerical simulation results provide qualitative and quantitative information on the wetting behavior of photografted surfaces. PMID- 25558766 TI - Organization of the MADS box from human SRF revealed by tyrosine perturbation. AB - MADS box family transcription factors are involved in signal transduction and development control through DNA specific sequence recognition. The DNA binding domain of these proteins contains a conservative 55-60 amino acid sequence which defines the membership of this large family. Here we present a thorough study of the MADS segment of serum response factor (MADS(SRF)). Fluorescence, UV absorption, and Raman spectroscopy studies were performed in order to disclose its behavior and basic functional properties in an aqueous environment. The secondary structure of MADS(SRF) estimated by analysis of Raman spectra and supported by CD has revealed only the C-terminal part as homologous with those of free core-SRF, while the N-terminal part has lost the stable alpha-helical structure found in both the free core-SRF and its specific complex with DNA. The three tyrosine residues of the MADS(SRF) were used as spectroscopic inner probes. The effect of environmental conditions, especially pH variations and addition of variously charged quenchers, on their spectra was examined. Two-component fluorescence quenching was revealed using factor analysis and corresponding Stern Volmer constants determined. Factor analysis of absorbance and fluorescence pH titration led to determination of three dissociation constants pKa1 = 6.4 +/- 0.2, pKa2 = 7.3 +/- 0.2, and pKa3 = 9.6 +/- 0.6. Critical comparison of all experiments identified the deprotonation of His193 hydrogen bonded to Tyr195 as a candidate for pKa1 (and that of Tyr158 as a candidate for pKa2). Within MADS(SRF), His193 is a key intermediary between the N-terminal primary DNA binding element and the hydrophobic C-terminal protein dimerization element. PMID- 25558767 TI - Keratin degradation by bacteria and fungi isolated from a poultry farm and plumage. AB - 1. Poultry processing generates a large quantity of feather waste. Feathers are a rich source of keratin and could be used as a feather meal in the feed industry if the keratin is degraded using suitable micro-organisms. 2. In this study, keratin-degrading micro-organisms were isolated from a poultry farm. The predominant organisms were identified as Bacillus subtilis, Aspergillus flavus, A. fumigatus and Trychophyton sp. 3. The isolates were inoculated into feather medium and observed for keratin degradation by measuring the protein content, free amino acids and change in pH. 4. During feather degradation by B. subtilis, the concentration of soluble protein released to the medium increased gradually and reached the maximum (433 ug/ml) during d 7 of incubation and the pH increased from the initial 6.9 to 8.4 on d 9 of incubation. Similarly, the maximum protein content of 414 ug/ml and pH of 8.5 was observed for A. fumigatus on d 21 of incubation. 5. B. subtilis and A. fumigatus showed almost the same level of keratinase activity. PMID- 25558768 TI - Illite spatial distribution patterns dictate Cr(VI) sorption macrocapacity and macrokinetics. AB - This work examines the largely unexplored role of illite spatial distribution patterns in dictating the sorption of Cr(VI), a ubiquitously occurring contaminant. Flow-through experiments were carried out at 0.6, 3.0, and 15.0 m/day using columns packed with the same illite and quartz mass however with different spatial patterns and permeability contrasts. Column-scale sorption macrocapacity and macrorates were found to decrease with transport connectivity, a quantitative measure of heterogeneity characteristics. At 0.6 and 3.0 m/day, well-connected low permeability illite zones oriented in the flow-parallel direction lead to diffusion-controlled mass transport limitation for accessing sorption sites. This results in up to 1.4 order of magnitude lower macrocapacity and macrorates compared to those in minimally connected columns with well-mixed illite and quartz. At 15.0 m/day, effects of spatial heterogeneities are less significant (up to a factor of 2.8) owing to the close to chemical kinetics controlled condition. Although the column-scale macrocapacity can reach full sorption capacity under low flow conditions, the macrorates are 10(-1) to 10(-3) of the microrates measured in well-mixed reactors. Insights gained here bridge gaps between laboratory observations and field applications and advance predictive understanding of reactive transport processes in the naturally heterogeneous subsurface. PMID- 25558770 TI - Solvent and ligand effects associated with the Rh(II)-catalyzed reactions of alpha-diazo-substituted amido esters. AB - We report a detailed investigation into the Rh(II)-catalyzed reactions of 2 alkynyl 2-diazo amido-substituted esters. The distribution of products was found to be dependent on the substituent group on the nitrogen atom, the ligand on the Rh(II) center, and the solvent used. The dominant product obtained from the reaction of 3-(trimethylsilyl)prop-2-ynyl-2-(dibenzylcarbamoyl)-2-diazoacetate (34) with Rh2(OAc)4 in hexane corresponds to an azetidinone derived by CH insertion of the carbenoid into the neighboring benzyl group. In contrast, the Rh2(esp)2-catalyzed reaction of 34 in CH2Cl2 afforded a 3-oxocyclohepta[c]pyrrole formed by cyclopropanation of the rhodium carbenoid across the aromatic pi-bond. Related systems were studied, and CH-insertion into an adjacent alkyl group was found to be the dominant or exclusive pathway. In none of the cases studied was it possible to detect products derived from a carbenoid/alkyne cascade sequence as had previously been found with a series of 2-alkynyl-2-diazo-3-oxobutanoates. PMID- 25558769 TI - Relying on procedural memory to enhance independence in daily living activities: Smartphone use in a case of semantic dementia. AB - Relying on procedural memory is a promising approach for interventions that address the cognitive difficulties found in semantic dementia. The aim of this study was to determine if procedural memory could be used to optimise learning of relevant smartphone functions in MH, a 55-year-old man with semantic dementia. The impact of learning to use specific smartphone applications, which display concepts and their semantic characteristics, on relearning useful significant concepts, was also explored in MH. This patient, who showed no deficits in procedural learning on a serial reaction time paradigm, was able to learn manipulations related to 15 smartphone functions although, because of his deficit in word comprehension, he generally needed verbal cues to clarify which functions he was asked to perform. Six months after the end of the intervention, he was still using 8 of the 15 functions regularly. However, repeated exposure to concepts through the use of two applications did not improve naming or retrieval of semantic attributes. This study showed the potential of relying on procedural memory to optimise learning of new technologies in the ecological rehabilitation of semantic dementia. PMID- 25558771 TI - Surface plasmon resonance (SPR) biosensors in pharmaceutical analysis. AB - This review aims to highlight the applications of one of the most prominent optical biosensor technologies, surface plasmon resonance (SPR), in the drug discovery process and quality analysis of pharmaceutical compounds and their particularities. SPR assay formats and experimental issues are used for pharmacokinetic drug profiling, ADMET studies, high-throughput screening, and fragment-based drug screening, the last with an emphasis on the detection of small (drug) molecules. The classical method strengths and some applications of localized SPR and SPR imaging that are of high interest in the drug discovery process are presented, as well as possible challenges. While similar works treat separately the steps of drug discovery or focus only on the detection of drug residues in food or health safety, this review presents in a compact format the results and the progress obtained in both areas (drug discovery and quality analysis) based on the application of SPR biosensors. PMID- 25558772 TI - The Kjeldahl method as a primary reference procedure for total protein in certified reference materials used in clinical chemistry. I. A review of Kjeldahl methods adopted by laboratory medicine. AB - We found previously that albumin-calibrated total protein in certified reference materials causes unacceptable positive bias in analysis of human sera. The simplest way to cure this defect is the use of human-based serum/plasma standards calibrated by the Kjeldahl method. Such standards, commutative with serum samples, will compensate for bias caused by lipids and bilirubin in most human sera. To find a suitable primary reference procedure for total protein in reference materials, we reviewed Kjeldahl methods adopted by laboratory medicine. We found two methods recommended for total protein in human samples: an indirect analysis based on total Kjeldahl nitrogen corrected for its nonprotein nitrogen and a direct analysis made on isolated protein precipitates. The methods found will be assessed in a subsequent article. PMID- 25558773 TI - The Kjeldahl method as a primary reference procedure for total protein in certified reference materials used in clinical chemistry. II. Selection of direct Kjeldahl analysis and its preliminary performance parameters. AB - To select a Kjeldahl procedure suitable for the determination of total protein in reference materials used in laboratory medicine, we reviewed in our previous article Kjeldahl methods adopted by clinical chemistry and found an indirect two step analysis by total Kjeldahl nitrogen corrected for its nonprotein nitrogen and a direct analysis made on isolated protein precipitates. In this article, we compare both procedures on various reference materials. An indirect Kjeldahl method gave falsely lower results than a direct analysis. Preliminary performance parameters qualify the direct Kjeldahl analysis as a suitable primary reference procedure for the certification of total protein in reference laboratories. PMID- 25558774 TI - Analytical procedure for the determination of zearalenone in environmental and biological samples. AB - The metabolism of zearalenone (ZEA) and analytical methods for determining the presence of ZEA and its metabolites are discussed in this study. Similar to phytoestrogens, solid metaloestrogens, pharmaceuticals, and selected pesticides, ZEA is a substance that displays endocrine activity. ZEA is accumulated in living organisms, and it is capable of contaminating all trophic levels of the food chain, from grain, maize, and other crop plants to human consumers. Zearalenone has a structure similar to that of estrogen (the presence of a macrocyclic lactone ring), it has an affinity for estrogen receptors, and it competes with 17beta-estradiol for binding the estrogen receptor in natural pathways. As endocrine disruptors, zearalenone and its metabolites can also contribute to carcinogenic mutations associated with female secondary sex characteristics. The determination of zearalenone and its metabolites in various matrices, first of all biological and environmental samples, poses significant problems. A variety ways of extracting and purifying zearalenone, including liquid-liquid extraction and solid-phase extraction, are described. Furthermore, it describes the possibility of applying a plurality of sensitive and specific instrumental methods, chromatographic techniques (TLC, HPLC, GC) as well as other methods (immunoaffinity chromatography). PMID- 25558775 TI - Environmentally oriented models and methods for the evaluation of drug * drug interaction effects. AB - This detailed review compares known and widely used methods for drug interaction estimation, some of which now have historical significance. Pharmaceutical application has been noted as far back as several thousand years ago. Relatively late in the 20th century, however, researchers became aware that their fate and metabolism, which still remain a great challenge for environmental analysts and risk assessors. For the patient's well-being, treatment based on the mixing of drugs has to be effective and should not cause any side effects (or side effects should not have a significant impact on health and mortality). Therefore, it is important to carefully examine drugs both individually and in combinations. It should be also stated that application form/way of entering the living organism is of great importance as well as the age and the place in the trophic system of the organism in order to eliminate harmful dosages in the case of infants' accidental intoxication. PMID- 25558776 TI - Applications of FT-IR spectrophotometry in cancer diagnostics. AB - This review provides a brief background to the application of infrared spectroscopy, including Fourier transform-infrared spectroscopy, in biological fluids. It is not meant to be complete or exhaustive but to provide the reader with sufficient background for selected applications in cancer diagnostics. Fourier transform-infrared spectroscopy (FT-IR) is a fast and nondestructive analytical method. The infrared spectrum of a mixture serves as the basis to quantitate its constituents, and a number of common clinical chemistry tests have proven to be feasible using this approach. This review focuses on biomedical FT IR applications, published in the period 2009-2013, used for early detection of cancer through qualitative and quantitative analysis. PMID- 25558777 TI - "Why not stoichiometry" versus "stoichiometry--why not?" Part I: General context. AB - The elementary concepts involved with stoichiometry are considered from different viewpoints. Some examples of approximate calculations made according to the stoichiometric scheme are indicated, and correct resolution of the problems involved is presented. The principles of balancing chemical equations, based on their apparent similarities with algebraic equations, are criticized. The review concerns some peculiarities inherent in chemical reaction notation and its use (and abuse) in stoichiometric calculations that provide inconsistent results for various reasons. This "conventional" approach to stoichiometry is put in context with the generalized approach to electrolytic systems (GATES) established by Michalowski. The article contains a number of proposals that could potentially be taken into account and included in the next edition of the Orange Book. Notation of ions used in this article is not, deliberately, in accordance with actual IUPAC requirements in this respect. This article is intended to be provocative with the hope that some critical debate around the important topics treated should be generated and creatively expanded in the scientific community. PMID- 25558778 TI - Robust superhydrophobic bridged silsesquioxane aerogels with tunable performances and their applications. AB - Aerogels are a family of highly porous materials whose applications are commonly restricted by poor mechanical properties. Herein, thiol-ene chemistry is employed to synthesize a series of novel bridged silsesquioxane (BSQ) precursors with various alkoxy groups. On the basis of the different hydrolyzing rates of the methoxy and ethoxy groups, robust superhydrophobic BSQ aerogels with tailorable morphology and mechanical performances have been prepared. The flexible thioether bridge contributes to the robustness of the as-formed aerogels, and the property can be tuned on the basis of the distinct combinations of alkoxy groups with the density of the aerogels almost unchanged. To the best of our knowledge, the lowest density among the ambient pressure dried aerogels is obtained. Further, potential application of the aerogels for oil/water separation and acoustic materials has also been presented. PMID- 25558780 TI - Intussusception in Australia: epidemiology prior to the introduction of rotavirus vaccine. AB - OBJECTIVES: To describe the incidence rate and clinical outcomes of intussusception in Australia in children aged <24 months prior to the use of rotavirus vaccines in Australia, and to explore associations between patient characteristics and outcomes in children with intussusception. METHODS: This study used Australian national hospital discharge data on intussusception from July 2000 to June 2006 for children aged <24 months and data from the Australian Bureau of Statistics (ABS) as a proxy for population numbers to estimate incidence. Logistic regression was used to examine associations between patient characteristics (age, sex, ethnicity) and outcomes (length of hospital stay >2 days and the need for surgical intervention). RESULTS: The overall incidence rate of intussusception was 5.4 per 10,000 child-years in children under 24 months (95%CI 5.17-5.70). There was a declining rate over the study period (p<0.001). Age at time of intussusception was strongly associated with length of hospital stay and surgery. CONCLUSIONS: This study provides an estimate of the pre rotavirus vaccine incidence of intussusception across Australia, which is important for monitoring the occurrence of intussusceptions post the introduction of rotavirus vaccine. PMID- 25558782 TI - The role of prior knowledge in error correction for younger and older adults. AB - Previous work has demonstrated that, when given feedback, younger adults are more likely to correct high-confidence errors compared with low-confidence errors, a finding termed the hypercorrection effect. Research examining the hypercorrection effect in both older and younger adults has demonstrated that the relationship between confidence and error correction was stronger for younger adults compared with older adults. Their results demonstrated that the relationship between confidence and error correction was stronger for younger adults compared with older adults. However, recent work suggests that error correction is largely related to prior knowledge, while confidence may primarily serve as a proxy for prior knowledge. Prior knowledge generally remains stable or increases with age; thus, the current experiment explored how both confidence and prior knowledge contributed to error correction in younger and older adults. Participants answered general knowledge questions, rated how confident they were that their response was correct, received correct answer feedback, and rated their prior knowledge of the correct response. Overall, confidence was related to error correction for younger adults, but this relationship was much smaller for older adults. However, prior knowledge was strongly related to error correction for both younger and older adults. Confidence alone played little unique role in error correction after controlling for the role of prior knowledge. These data demonstrate that prior knowledge largely predicts error correction and suggests that both older and younger adults can use their prior knowledge to effectively correct errors in memory. PMID- 25558779 TI - alphavbeta6 integrin is required for TGFbeta1-mediated matrix metalloproteinase2 expression. AB - Transforming growth factor (TGF) beta1 activity depends on a complex signalling cascade that controls expression of several genes. Among others, TGFbeta1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. In the present study, we demonstrate for the first time that the alphavbeta6 integrin interacts with TGFbeta receptor II (TbetaRII) through the beta6 cytoplasmic domain and promotes Smad3 activation in prostate cancer (PrCa) cells. Another related alphav integrin, alphavbeta5, as well as the alphavbeta6/3 integrin, which contains a chimeric form of beta6 with a beta3 cytoplasmic domain, do not associate with TbetaRII and fail to show similar responses. We provide evidence that alphavbeta6 is required for up-regulation of MMP2 by TGFbeta1 through a Smad3-mediated transcriptional programme in PrCa cells. The functional relevance of these results is underscored by the finding that alphavbeta6 modulates cell migration in an MMP2-dependent manner on an alphavbeta6-specific ligand, latency-associated peptide (LAP)-TGFbeta. Overall, these mechanistic studies establish that expression of a single integrin, alphavbeta6, is sufficient to promote activation of Smad3, regulation of MMP2 levels and consequent catalytic activity, as well as cell migration. Our study describes a new TGFbeta1-alphavbeta6-MMP2 signalling pathway that, given TGFbeta1 pro-metastatic activity, may have profound implications for PrCa therapy. PMID- 25558783 TI - Intestinal metastases as an unusual presentation of a burned-out testicular seminoma: PET/CT imaging. PMID- 25558784 TI - Managing and mitigating fatigue in the era of changing resident duty hours. AB - The medical establishment is grappling with the complex issue of duty hour regulations - an issue that is a natural consequence of the numerous changes in medical culture and practice that have occurred over the course of decades. Sleep deprivation resulting from long duty hours has a recognized impact on resident health and wellness. This paper will briefly outline the evolution of the concept of well-being in residency, review the specific theme of fatigue management within that context, and describe strategies that may be used to mitigate and manage fatigue, as well as approaches that may be taken to adapt to new scheduling models such as night float. Finally, the paper will call for a change in the culture in our workplaces and among our residents and faculty to one that promotes good health and ensures that we maintain a fit and sustainable medical workforce. PMID- 25558785 TI - Real-time modulation of visual feedback on human full-body movements in a virtual mirror: development and proof-of-concept. AB - BACKGROUND: Virtual reality (VR) provides interactive multimodal sensory stimuli and biofeedback, and can be a powerful tool for physical and cognitive rehabilitation. However, existing systems have generally not implemented realistic full-body avatars and/or a scaling of visual movement feedback. We developed a "virtual mirror" that displays a realistic full-body avatar that responds to full-body movements in all movement planes in real-time, and that allows for the scaling of visual feedback on movements in real-time. The primary objective of this proof-of-concept study was to assess the ability of healthy subjects to detect scaled feedback on trunk flexion movements. METHODS: The "virtual mirror" was developed by integrating motion capture, virtual reality and projection systems. A protocol was developed to provide both augmented and reduced feedback on trunk flexion movements while sitting and standing. The task required reliance on both visual and proprioceptive feedback. The ability to detect scaled feedback was assessed in healthy subjects (n = 10) using a two alternative forced choice paradigm. Additionally, immersion in the VR environment and task adherence (flexion angles, velocity, and fluency) were assessed. RESULTS: The ability to detect scaled feedback could be modelled using a sigmoid curve with a high goodness of fit (R2 range 89-98%). The point of subjective equivalence was not significantly different from 0 (i.e. not shifted), indicating an unbiased perception. The just noticeable difference was 0.035 +/- 0.007, indicating that subjects were able to discriminate different scaling levels consistently. VR immersion was reported to be good, despite some perceived delays between movements and VR projections. Movement kinematic analysis confirmed task adherence. CONCLUSIONS: The new "virtual mirror" extends existing VR systems for motor and pain rehabilitation by enabling the use of realistic full-body avatars and scaled feedback. Proof-of-concept was demonstrated for the assessment of body perception during active movement in healthy controls. The next step will be to apply this system to assessment of body perception disturbances in patients with chronic pain. PMID- 25558787 TI - Ultrasound-guided ablation for hepatocellular carcinoma: time for a reappraisal? AB - Ultrasound-guided techniques play a key role in the clinical management of hepatocellular carcinoma. Among these, percutaneous ethanol injection (PEI) was the first technique to be proposed for the treatment of nodular-type hepatocellular carcinoma: the role of PEI was first discussed during the European Association for the Study of the Liver conference held in Barcelona in 2000, 15 years ago. Since then, other techniques have been introduced and radiofrequency ablation now represents the most widely used percutaneous technique. PEI and radiofrequency ablation are widely used in clinical practice. However, only scant progresses in the application of these techniques have been performed over the past 15 years, and percutaneous approaches are often only marginally discussed and studied. Here, we discuss the most relevant clinical issues regarding PEI and radiofrequency ablation that have emerged in the past years. PMID- 25558786 TI - In vitro reconstitution of the catabolic reactions catalyzed by PcaHG, PcaB, and PcaL: the protocatechuate branch of the beta-ketoadipate pathway in Rhodococcus jostii RHA1. AB - The beta-ketoadipate pathway is a major pathway involved in the catabolism of the aromatic compounds in microbes. The recent progress in genome sequencing has led to a rapid accumulation of genes from the beta-ketoadipate pathway in the available genetic database, yet the functions of these genes remain uncharacterized. In this study, the protocatechuate branch of the beta ketoadipate pathway of Rhodococcus jostii was reconstituted in vitro. Analysis of the reaction products of PcaHG, PcaB, and PcaL was achieved by high-performance liquid chromatography. These reaction products, beta-ketoadipate enol-lactone, 3 carboxy-cis,cis-muconate, gamma-carboxymuconolactone, muconolactone, and beta ketoadipate, were further characterized using LC-MS and nuclear magnetic resonance. In addition, the in vitro reaction of PcaL, a bidomain protein consisting of gamma-carboxy-muconolactone decarboxylase and beta-ketoadipate enol lactone hydrolase activities, was demonstrated for the first time. This work provides a basis for analyzing the catalytic properties of enzymes involved in the growing number of beta-ketoadipate pathways deposited in the genetic database. PMID- 25558788 TI - An attribution theory perspective on emotional labour in nurse-patient encounters: a nested cross-sectional study in paediatric settings. AB - AIMS: To understand the role of patients' attributions under the attribution theory framework (locus, controllability, stability) in nurses' performance of surface or deep acting, as they unfold in interactions with different patients. BACKGROUND: Regulation of emotions at work, or emotional labour, has been conceptualized in terms of two main strategies: surface acting and deep acting. Most prior research tested for between-subject variation in the search for the factors evoking these strategies in nurses, assuming them to be trait-like characteristics. Only scant research has examined how nurses modify their emotional labour strategies in different patient-nurse encounters. DESIGN: A nested cross-sectional design (patients within nurses). METHODS: Data were collected during 2011-2012 through validated questionnaires from the nursing staff (N = 41) of two paediatric hospital wards and their randomly selected patients (N = 239). Questionnaires were administered to nurses multiple times after encounters with different patients. Analyses were conducted using mixed effects models. RESULTS: In accordance with attribution theory, different combinations of locus, controllability and stability attributions were related to the choice of surface or deep acting. Nurses' perceptions of patients' controllability were associated positively with surface acting and negatively with deep acting. Interaction terms of stability and locus and of controllability and stability, were distinctively associated with deep and surface acting. CONCLUSIONS: Findings innovatively introduce the attribution process as an explanatory perspective to nurses' emotional labour and highlight its situational nature, providing a potential tool for emotional labour strategy prediction. Raising nurses' awareness of how they perceive patients may increase control of the strategies employed. PMID- 25558789 TI - Choroidal metastasis response to crizotinib in a ROS1-rearranged NSCLC patient. AB - OBJECTIVES: Choroidal metastases are uncommon metastasis from non-small cell lung cancer (NSCLC). With improved survival from the use of targeted therapy against actionable driver mutation driven NSCLC, the incidence of choroidal metastases seems to be increasing. Recently, there are several case reports of choroidal metastases in patients with anaplastic lymphoma kinase (ALK)-driven NSCLC one of which the patient's choroidal metastases had responded to crizotinib, multi targeted tyrosine kinase inhibitor against ALK/ROS1/MET. Similarly ROS1 rearranged NSCLC has very similar clinicopathologic characteristics as ALK rearranged NSCLC and crizotinib has demonstrated significant clinical activity against ROS1-rearranged NSCLC. MATERIALS AND METHODS: Here in this report we presented a patient with ROS1-rearranged NSCLC that presented with choroidal metastases that did not respond to initial chemotherapy but had a rapid and complete response to crizotinib. CONCLUSIONS: Although likely to be exceeding rare, choroidal metastases from ROS1-rearranged NSCLC can be successfully treated with crizotinib similar to choroidal metastases from ALK-rearranged NSCLC can be successfully treated from another case report. PMID- 25558791 TI - The individualized choice of embryo transfer timing for patients with elevated serum progesterone level on the HCG day in IVF/ICSI cycles: a prospective randomized clinical study. AB - This study analyzed the clinical outcomes of patients with elevated progesterone level on the HCG day in IVF/ICSI cycles, with different timing of embryo transfer. A total of 123 patients were involved in this prospective randomized clinical study. Group 1: blastocyst transfer group, 38 cases; Group 2: frozen thawed embryo transfer group (first FET cycle), 42 cases; Group 3: fresh embryo transfer group, 43 cases. The basal FSH level was comparable among three groups (6.7 +/- 3 versus 7.0 +/- 2 versus 6.9 +/- 2.4, p = 0.897). The clinical pregnancy rate was highest in group 2, lowest in group 3, with significantly difference (31.6% versus 38.1% versus 13.9%, p = 0.037). The implantation rate and live birth rate were still lowest in group 3 (21.9% versus 19.8% versus 6.7%, p = 0.016 and 18.4% versus 31% versus 11.6%, p = 0.081). In conclusion, the elevated progesterone level will affect clinical pregnancy rate in fresh embryo transfer cycles. We suggest frozen-thawed embryo transfer for these patients. However, for those patients who expressed the wish to have fresh embryo transfer, they should be suggested fresh blastocyst transfer, if they have more than five good quality embryos. PMID- 25558790 TI - The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer. AB - OBJECTIVES: In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. However, this has not been investigated for rare EGFR mutations or their impact on treatment response and outcome to EGFR TKIs (primary objective) and chemotherapy (secondary objective). MATERIALS AND METHODS: In an observational prospective cohort, we analyzed 188 NSCLC patients from Mexico, Colombia and Costa Rica with EGFR mutations. As a first line of treatment, 66.5% received platinum-based chemotherapy. All patients received TKIs in first-line treatment or after progression to chemotherapy. The clinical-pathological characteristics as well as the f of common and rare EGFR mutations associated with treatment response were analyzed. RESULTS: Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinomas were associated with common EGFR mutations (p=0.010). Patients with common EGFR mutations had higher response rates to EGFR-TKIs than those who had rare EGFR mutations (63.8 vs 32.4%, p<0.001). Women had increased progression-free survival (PFS) to EGFR-TKIs than men (16.4 vs 9.5 months, p=0.02). The median PFS and overall survival (OS) were better in patients with common EGFR mutations (15.5 vs 3.9 months, p<0.001; and 37.3 vs 17.4 months, p<0.001) respectively. CONCLUSION: Our findings suggested that only patients with rare EGFR mutations could receive platinum-based chemotherapy as a first-line treatment, due to their low response rates and short PFS in response to EGFR-TKIs. Consequently, EGFR-TKIs could be reserved as a second- or third-line treatment. In patients with EGFR mutations, women have better PFS to EGFR-TKIs than men, and rare EGFR mutations are more frequent in high grade adenocarcinomas than in low grade tumors. PMID- 25558792 TI - Characterisation of Dyp-type peroxidases from Pseudomonas fluorescens Pf-5: Oxidation of Mn(II) and polymeric lignin by Dyp1B. AB - Members of the DyP family of peroxidases in Gram-positive bacteria have recently been shown to oxidise Mn(II) and lignin model compounds. Gram-negative pseudomonads, which also show activity for lignin oxidation, also contain dyp type peroxidase genes. Pseudomonas fluorescens Pf-5 contains three dyp-type peroxidases (35, 40 and 55kDa), each of which has been overexpressed in Escherichia coli, purified, and characterised. Each of the three enzymes shows activity for oxidation of phenol substrates, but the 35kDa Dyp1B enzyme also shows activity for oxidation of Mn(II) and Kraft lignin. Treatment of powdered lignocellulose with Dyp1B in the presence of Mn(II) and hydrogen peroxide leads to the release of a low molecular weight lignin fragment, which has been identified by mass spectrometry as a beta-aryl ether lignin dimer containing one G unit and one H unit bearing a benzylic ketone. A mechanism for release of this fragment from lignin oxidation is proposed. PMID- 25558793 TI - Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice. AB - Obesity is a serious chronic disease that increases the risk of numerous co morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. PMID- 25558794 TI - A lack of functional NK1 receptors explains most, but not all, abnormal behaviours of NK1R-/- mice(1). AB - Mice lacking functional neurokinin-1 receptors (NK1R-/-) display abnormal behaviours seen in Attention Deficit Hyperactivity Disorder (hyperactivity, impulsivity and inattentiveness). These abnormalities were evident when comparing the behaviour of separate (inbred: 'Hom') wildtype and NK1R-/- mouse strains. Here, we investigated whether the inbreeding protocol could influence their phenotype by comparing the behaviour of these mice with that of wildtype (NK1R+/+) and NK1R-/- progeny of heterozygous parents ('Het', derived from the same inbred strains). First, we recorded the spontaneous motor activity of the two colonies/genotypes, over 7 days. This continuous monitoring also enabled us to investigate whether the diurnal rhythm in motor activity differs in the two colonies/genotypes. NK1R-/- mice from both colonies were hyperactive compared with their wildtypes and their diurnal rhythm was also disrupted. Next, we evaluated the performance of the four groups of mice in the 5-Choice Serial Reaction-Time Task (5-CSRTT). During training, NK1R-/- mice from both colonies expressed more impulsive and perseverative behaviour than their wildtypes. During testing, only NK1R-/- mice from the Hom colony were more impulsive than their wildtypes, but NK1R-/- mice from both colonies were more perseverative. There were no colony differences in inattentiveness. Moreover, a genotype difference in this measure depended on time of day. We conclude that the hyperactivity, perseveration and, possibly, inattentiveness of NK1R-/- mice is a direct consequence of a lack of functional NK1R. However, the greater impulsivity of NK1R-/- mice depended on an interaction between a functional deficit of NK1R and other (possibly environmental and/or epigenetic) factors. PMID- 25558796 TI - The 8-item Morisky Medication Adherence Scale translated in German and validated against objective and subjective polypharmacy adherence measures in cardiovascular patients. AB - RATIONALE, AIMS AND OBJECTIVES: To translate in German the 8-item Morisky Medication Adherence Scale (MMAS-8D). To validate it against objective and subjective measures of adherence in cardiovascular patients with polypharmacy. METHODS: A standard forward-backward procedure was used to translate the MMAS-8 into German. Validation took place on a convenience sample of ambulatory patients on chronic antiplatelet therapy between June 2010 and June 2011. Objective adherence was obtained from electronically monitored multi-drug punch cards. Internal consistency was assessed using Cronbach's alpha coefficient, construct validity using exploratory factor analyses and correlations between MMAS-8D and related measures. Convergent validity was assessed with a subjective questionnaire about beliefs about medicines (BMQ Specific, two sub-scales). RESULTS: A total of 70 patients were included (mean age 65.7 +/- 9.9 years; 31.4% women). The mean score of the MMAS-8D was 7.5 (SD 0.8; range 4.5-8). Moderate internal consistency (alpha = 0.31) was observed due to multidimensionality of the scale. Factor analysis yielded four components that accounted for 71.7% of the total variance. Convergent validity was supported by significant correlations with BMQ Necessity (r = 0.31, P < 0.01), BMQ Concerns (r = -0.16, P < 0.05) and with electronic adherence reports (U-values 44 and 471, P < 0.05). Platelet aggregation values were within therapeutic range for 80% of the patients. Blood values of the antiplatelet agent within therapeutic range were associated with a higher MMAS-8D score (U-value 125, P < 0.05). CONCLUSIONS: The German MMAS-8 appears to be a reliable instrument to catch medication adherence in cardiovascular patients. It may be useful in patients with chronic therapy for detecting non-adherence. PMID- 25558795 TI - Hyaluronic acid prevents immunosuppressive drug-induced ovarian damage via up regulating PGRMC1 expression. AB - Chemotherapy treatment in women can frequently cause damage to the ovaries, which may lead to primary ovarian insufficiency (POI). In this study, we assessed the preventative effects of hyaluronic acid (HA) in immunosuppressive drug-induced POI-like rat models and investigated the possible mechanisms. We found that HA, which was reduced in primary and immunosuppressant-induced POI patients, could protect the immunosuppressant-induced damage to granulosa cells (GCs) in vitro. Then we found that HA blocked the tripterygium glycosides (TG) induced POI-like presentations in rats, including delayed or irregular estrous cycles, reduced 17 beta-estradiol(E2) concentration, decreased number of follicles, destruction of follicle structure, and damage of reproductive ability. Furthermore, we investigated the mechanisms of HA prevention effects on POI, which was associated with promotion of GC proliferation and PGRMC1 expression. In conclusion, HA prevents chemotherapy-induced ovarian damage by promoting PGRMC1 in GCs. This study may provide a new strategy for prevention and treatment of POI. PMID- 25558797 TI - Variability and predictors of urinary phthalate metabolites in Spanish pregnant women. AB - Developmental exposure to phthalates may be associated with adverse health outcomes but information on the variability and predictors of urinary phthalate metabolite concentrations during pregnancy is limited. We evaluated in Spanish pregnant women (n=391) the reproducibility of urinary phthalate metabolite concentrations and predictors of exposure. We measured mono-(4-methyl-7 hydroxyoctyl) phthalate (7-OHMMeOP), mono-(2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-carboxyhexyl) phthalate (MCMHP), mono-benzyl phthalate (MBzP), mono-ethyl phthalate (MEP), mono iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) in two spot urine samples collected in the first and third pregnancy trimesters. Questionnaires on predictors and food-frequency questionnaires were administered in the first and/or third pregnancy trimesters. Using creatinine-adjusted phthalate metabolite concentrations (log10-trasformed) we calculated intraclass correlation coefficients (ICCs). Linear mixed and regression models assessed the associations between predictors and phthalate metabolites. The ICCs ranged from 0.24 to 0.07 and were higher for MBzP, MEP, MiBP, and lower for MEOHP and MEHHP. Overweight, lower education and social class, and less frequent consumption of organic food were associated with higher levels of some phthalate metabolites. The use of household cleaning products (bleach, ammonia, glass cleaners, oven cleaning sprays and degreasing products) at least once per week during pregnancy was associated with 10-44% higher urinary phthalate metabolites. Bottled-water consumption, consumption of food groups usually stored in plastic containers or cans, use of plastic containers for heating food and cosmetic use were not associated with increased concentrations of phthalate metabolites. This large study with repeated phthalate measurements suggests that, in this Spanish setting, sociodemographic and lifestyle factors and household cleaning product use are better predictors of phthalate exposure levels in pregnant women than average water and food consumption and use of plastic containers and cosmetics. PMID- 25558798 TI - Predictors of quality of life in patients with relapsing-remitting multiple sclerosis: a 2-year longitudinal study. AB - INTRODUCTION: Knowledge of which factors are determinant of quality of life (QoL) in patients with multiple scleroris (MS) would assist clinicians in choosing the most appropriate interventions. The aim of this study was to determine the contribution of sociodemographic and clinical factors in the predicting QoL in a 2-year cohort of patients with relapsing-remitting MS (RR-MS). METHODS: The study had a multi-center, multi-regional, and longitudinal design. Main inclusion criteria were: patient with a RR-MS subtype (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score lower than 7.0. Sociodemographic (age, gender, education level, marital and employment status) and clinical (disability, disease duration, relapse) data were recorded. The QoL was assessed using the MusiQoL (disease-specific) and SF-36 (generic) questionnaires. Each patient was investigated at baseline and 24 months post-inclusion (ClinicalTrials.gov identifier: NCT00702065). RESULTS: Five hundred and twenty-six patients were enrolled in the present study. The 24-month MusiQoL index score was significantly inversely correlated with the disease duration. Baseline EDSS score impacted in both 'physical-like' and 'psychological-like' dimensions. At least one relapse during the follow-up period was associated with lower physical scores. Occupational status and marital status were associated with 24-month scores of MusiQoL and SF-36. CONCLUSION: After adjusting for disability and relapse occurrence, sociodemographics (age, marital status, and occupational status) and baseline QoL scores were also independent QoL predictors in MS patients. Special attention should be given to subgroups to ensure optimal management. PMID- 25558799 TI - [Ethical considerations for craniectomy in malignant cerebral infarct: Should we still deny our patients a life-saving procedure?]. PMID- 25558800 TI - [Improvement approaches in the hospital setting: From total quality management to Lean]. AB - Hospitals have to deal strong with economic constraints and increasing requirements in terms of quality and safety of care. To address these constraints, one solution could be the adoption of approaches from the industry sector. Following the decree of April 6, 2011 on the quality management of the medication use process, some of these approaches, such as risk management, are now part of the everyday work of healthcare professionals. However, other approaches, such as business process improvement, are still poorly developed in the hospital setting. In this general review, we discuss the main approaches of business process improvements that have been used in hospitals by focusing specifically on one of the newest and most currently used: Lean. PMID- 25558802 TI - Enhancement of photoluminescence intensity of erbium doped silica containing Ge nanocrystals: distance dependent interactions. AB - Photo-physical processes in Er-doped silica glass matrix containing Ge nanocrystals prepared by the sol-gel method are presented in this article. Strong photoluminescence at 1.54 MUm, important for fiber optics telecommunication systems, is observed from the different sol-gel derived glasses at room temperature. We demonstrate that Ge nanocrystals act as strong sensitizers for Er(3+) ions emission and the effective Er excitation cross section increases by almost four orders of magnitude with respect to the one without Ge nanocrystals. Rate equations are considered to demonstrate the sensitization of erbium luminescence by Ge nanocrystals. Analyzing the erbium effective excitation cross section, extracted from the flux dependent rise and decay times, a Dexter type of short range energy transfer from a Ge nanocrystal to erbium ion is established. PMID- 25558801 TI - [Pharmacist's interventions on outpatient prescriptions in a university hospital drugs sales service]. AB - For public health reasons, some drugs are only available in hospital drugs sales service. This activity takes place in a specific risk context of organization, patients and/or drugs. A systematic prescription analysis by pharmacist contributes to securise treatment dispensed. The aim of this paper is to present the main drugs problems in the analysis of outpatient prescriptions and pharmaceutical interventions in three units of hospital drugs sales service belong to university hospital. METHODS: Throughout the year 2013, drug problems detected were recorded prospectively and systematically. RESULTS: Of the 22,279 prescriptions analyzed, 247 pharmaceutical interventions (1.1%) were detected including 27.6% of problems concerning the dosages, 15.4% the unconformity, 6.9% contraindications. Regarding ATC drugs classes, we found 43.7% for anti infectives and 17.4% for antineoplatics. The overall acceptance rate is 81.8%. CONCLUSION: These results show the importance of the analysis of outpatient prescriptions before dispensing and the need to have all prescriptions, clinical and biological elements and to develop interprofessionality. The implementation of a platform for dematerialized data exchanges between professionals, including data from the pharmaceutical patient record should contribute to improving drug management of the patient. PMID- 25558803 TI - Novel Scaffold FingerPrint (SFP): applications in scaffold hopping and scaffold based selection of diverse compounds. AB - A novel 2D Scaffold FingerPrint (SFP) for mining ring fragments is presented. The rings are described not only by their topology, shape, and pharmacophoric features (hydrogen-bond acceptors and donors, their relative locations, sp3 carbons, and chirality) but also by the position and nature of their growing vectors because they play a critical role from the drug discovery perspective. SFP can be used (i) to identify alternative chemotypes to a reference ring either in a visual mode or by running quantitative similarity searches and (ii) in chemotype-based diversity selections. Two retrospective case studies focused on melanin concentrating hormone 1-receptor antagonists (MCH-R1) and phosphodiesterase-5 inhibitors (PDE5) demonstrate the capability of this method for identifying novel structurally different and synthetically accessible chemotypes. Good enrichment factor (155 and 219) and recall values (46% and 73%) are found within the first 100 ranked hits (0.3% of screened database). Our 2D SFP descriptor outperforms well-validated current gold-standard 2D fingerprints (ECFP_6) and 3D approaches based on shape and electrostatic similarity. Scaffold based selection of diverse compounds has a critical impact on corporate library design and compound acquisitions; thus, a novel strategy is introduced that uses diverse scaffold selections using this SFP descriptor combined with R-group selection at the different substitution sites. Both approaches are available as part of an interactive web-based application that requires minimal input and no computational knowledge by medicinal chemists. PMID- 25558804 TI - Development of a hazel cell culture-based paclitaxel and baccatin III production process on a benchtop scale. AB - The growing demand for the antitumorous agent paclitaxel and the difficulty in increasing its production by genetic engineering has prompted a search for new sources of taxanes. It has been reported that taxanes can be extracted from the angiosperm Corylus avellana L. Our aim was to improve taxane production by scaling up the process from mL-level to benchtop bioreactors, optimizing culture conditions and comparing the effect of two elicitors, 1 MUM coronatine (Cor) and 100 MUM methyl jasmonate (MeJA). Orbitally shaken flask cultures achieved a maximum fresh cell weight of 11.54 gDCW/L under control conditions, and MeJA- and Cor-treatment produced a statistically significant reduction in growth to 4.28 gDCW/L and 5.69 gDCW/L, while increasing the taxane content 3- and 27-fold, respectively. The enhancing effect of these elicitors on taxane production, despite affecting growth, was confirmed in orbitally shaken TubeSpin Bioreactors 50, where the highest taxane content (8583.3 MUg/L) was obtained when 1MUM Cor was used and elicitation took place at a packed cell volume of 50%. Two benchtop stirred bioreactors, BIOSTAT B plus and UniVessel SU, were compared, the latter providing a higher biomass of C. avellana cell suspension cultures. Transferring the established optimum culture conditions for taxane production to the UniVessel SU resulted in a total taxane content of 6246.1 MUg/L, a 10-fold increase compared with shake flask experiments. PMID- 25558805 TI - On the way to identify microorganisms in drinking water distribution networks via DNA analysis of the gut content of freshwater isopods. AB - Pure drinking water is the basis for a healthy society. In Germany the drinking water regulations demand for analysis of water via detection of certain microbiological parameters by cultivation only. However, not all prokaryotes can be detected by these standard methods. How to gain more and better information about the bacteria present in drinking water and its distribution systems? The biofilms in drinking water distribution systems are built by bacteria and therefore represent a valuable source of information about the species present. Unfortunately, these biofilms are badly accessible. We thus exploited the circumstance that a lot of metazoans graze the biofilms, so that the content of their guts partly reflects the respective biofilm biocenosis. Therefore, we collected omnivorous isopods, prepared their guts and examined and characterized their contents based on 16S und 18S rDNA analysis. These molecularbiological investigations provide a profound basis for the characterization of the biocenosis and thereby biologically assess the drinking water ecosystems. Combined with a thorough identification of the species and the knowledge of their habitats, this approach can provide useful indications for the assessment of drinking-water quality and the early detection of problems in the distribution system. PMID- 25558806 TI - Identification and characterization of a fatty acyl reductase from a Spodoptera littoralis female gland involved in pheromone biosynthesis. AB - Fatty acyl-CoA reductases (FARs), the enzymes that catalyse reduction of a fatty acyl-CoA to the corresponding alcohol in insect pheromone biosynthesis, are postulated to play an important role in determining the proportion of each component in the pheromone blend. For the first time, we have isolated and characterized from the Egyptian cotton leaf worm Spodoptera littoralis (Lepidoptera: Noctuidae) a FAR cDNA (Slit-FAR1), which appeared to be expressed only in the pheromone gland and was undetectable in other female tissues, such as fat body, ovaries, wings, legs or thorax. The encoded protein has been successfully expressed in a recombinant system, and the recombinant enzyme is able to produce the intermediate fatty acid alcohols of the pheromone biosynthesis of S. littoralis from the corresponding acyl-CoA precursors. The kinetic variables Km and Vmax, which have been calculated for each acyl-CoA pheromone precursor, suggest that in S. littoralis pheromone biosynthesis other biosynthetic enzymes (e.g. desaturases, acetyl transferase) should also contribute to the final ratio of components of the pheromone blend. In a phylogenetic analysis, Slit-FAR1 appeared grouped in a cluster of other FARs involved in the pheromone biosynthesis of other insects, with little or non specificity for the natural pheromone precursors. PMID- 25558808 TI - Female genital mutilation (FGM): Australian midwives' knowledge and attitudes. AB - Female genital mutilation (FGM) is a women's health and human rights issue attracting global interest. My purpose in this qualitative study was to report the knowledge and attitudes of Australian midwives toward FGM. Verbatim transcription and thematic analysis of semistructured interviews with 11 midwives resulted in these themes: knowledge of female genital mutilation and attitude toward female genital mutilation. Significant gaps in knowledge about FGM featured prominently. The midwives expressed anger toward FGM and empathy for affected women. Recommendations include increased information on FGM and associated legislation among midwives and other health providers in countries where FGM may be encountered. PMID- 25558809 TI - Photojunction field-effect transistor based on a colloidal quantum dot absorber channel layer. AB - The performance of photodetectors is judged via high responsivity, fast speed of response, and low background current. Many previously reported photodetectors based on size-tuned colloidal quantum dots (CQDs) have relied either on photodiodes, which, since they are primary photocarrier devices, lack gain; or photoconductors, which provide gain but at the expense of slow response (due to delayed charge carrier escape from sensitizing centers) and an inherent dark current vs responsivity trade-off. Here we report a photojunction field-effect transistor (photoJFET), which provides gain while breaking prior photoconductors' response/speed/dark current trade-off. This is achieved by ensuring that, in the dark, the channel is fully depleted due to a rectifying junction between a deep work-function transparent conductive top contact (MoO3) and a moderately n-type CQD film (iodine treated PbS CQDs). We characterize the rectifying behavior of the junction and the linearity of the channel characteristics under illumination, and we observe a 10 MUs rise time, a record for a gain-providing, low-dark current CQD photodetector. We prove, using an analytical model validated using experimental measurements, that for a given response time the device provides a two-orders-of-magnitude improvement in photocurrent-to-dark-current ratio compared to photoconductors. The photoJFET, which relies on a junction gate effect, enriches the growing family of CQD photosensitive transistors. PMID- 25558807 TI - The epidemiology of infections with Giardia species and genotypes in well cared for dogs and cats in Germany. AB - BACKGROUND: Giardia is now considered the most common enteric parasite in well cared for dogs and cats in developed countries. The ecology, epidemiology and clinical impact of infections with this parasite in such animals is still not fully understood due to variable results across different studies. METHODS: Faecal samples were collected between 2009 and 2012 from privately owned cats and dogs in Germany presented to local veterinarians for a variety of reasons. Giardia positive samples were identified by microscopy and coproantigen methods. Total faecal DNA was extracted from Giardia positive samples and multilocus genotyping methods (18S rDNA, beta-giardin, GDH) were applied. Relationships between host age, sex, and breed, season of presentation and the different species of Giardia detected were assessed. RESULTS: A total of 60 cat and 130 dog samples were identified as Giardia positive. Potentially zoonotic Giardia was identified in both animal species. Cats had a similarly high rate of infection with the G. duodenalis and G. cati. Cats less than 1 year were more likely to have G. duodenalis than cats older than 1 year. Pure breed cats demonstrated a greater proportion of zoonotic species than mixed breed cats. In samples from dogs, G. canis (C and D genotypes) were identified most commonly. Male dogs were more likely to have G. canis (genotype D) than female dogs. The 18S rDNA PCR protocol was the most successful followed by the beta-giardin and GDH (amplifying from 92%, 42% and 13% of samples respectively). CONCLUSIONS: The potentially zoonotic species G. duodenalis and G. enterica were found in cat and dog samples, with G. duodenalis found in greater numbers; however, this may be due to the detection techniques utilised. Cats appeared to show a relationship between G. duodenalis and G. cati with age and breed, which may be explained by different housing habitats for pure and mixed breed cats. The different success rates for the three loci utilised highlights the usefulness of the 18S locus as a screening tool, as well as the importance of using multiple loci for genotyping to fully determine the level of multiple infection of Giardia present. PMID- 25558810 TI - The superior turbinate straddling sphenoidotomy. PMID- 25558811 TI - The RIVUR trial: a factual interpretation of our data. AB - Vesicoureteral reflux (VUR) increases the risk of urinary tract infection (UTI) and renal scarring. Many prospective studies have evaluated the role of antimicrobial prophylaxis in the prevention of recurrent UTI and renal scarring in children with VUR. Of these, the RIVUR trial was the largest, randomized, placebo-controlled, double blind, multicenter study, involving 607 children aged 2-72 months with grade I-IV VUR and a first or second symptomatic UTI. The median age of children in the RIVUR trial was 12 months, 92% were female, 91% were randomized after a first UTI, 86% had a febrile index UTI, and 71 (56%) of 126 toilet-trained children had bladder bowel dysfunction. Trimethoprim/sulfamethoxazole reduced the risk of UTI recurrences by 50% (hazard ratio 0.50; 95% confidence interval 0.34-0.74) as compared to placebo. No significant difference was seen in renal scarring between the two groups. However, this does not invalidate the role of prophylaxis in preventing renal scars because RIVUR and other recent prospective studies were not designed to address renal scarring as a primary study endpoint. In view of the RIVUR Trial and other studies that showed similar results, albeit in selected groups of patients, the debate on antimicrobial prophylaxis should shift from "no prophylaxis" to "selective prophylaxis" in children with VUR. PMID- 25558813 TI - Standardized patient assessment of medical student empathy: ethnicity and gender effects in a multi-institutional study. AB - PURPOSE: To examine, primarily, the effects of ethnicity and gender, which could introduce bias into scoring, on standardized patient (SP) assessments of medical students and, secondarily, to examine medical students' self-reported empathy for ethnicity and gender effects so as to compare self-perception with the perceptions of SPs. METHOD: Participants were 577 students from four medical schools in 2012: 373 (65%) were white, 79 (14%) black/African American, and 125 (22%) Asian/Pacific Islander. These students were assessed by 84 SPs: 62 (74%) were white and 22 (26%) were black/African American. SPs completed the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE) and the Global Ratings of Empathy tool. Students completed the Jefferson Scale of Empathy and two Interpersonal Reactivity Index subscales. The investigators used 2,882 student-SP encounters in their analyses. RESULTS: Analyses of SPs' assessments of students' empathy indicated significant interaction effects of gender and ethnicity. Female students, regardless of ethnicity, obtained significantly higher mean JSPPPE scores than men. Female black/African American, female white, and female Asian/Pacific Islander students scored significantly higher on the JSPPPE than their respective male counterparts. Male black/African American students obtained the lowest SP assessment scores of empathy regardless of SP ethnicity. Black/African American students obtained the highest mean scores on self-reported empathy. CONCLUSIONS: The significant interaction effects of ethnicity and gender in clinical encounters, plus the inconsistencies observed between SPs' assessments of students' empathy and students' self-reported empathy, raise questions about possible ethnicity and gender biases in the SPs' assessments of medical students' clinical skills. PMID- 25558814 TI - Distribution and mixing of old and new nonstructural carbon in two temperate trees. AB - We know surprisingly little about whole-tree nonstructural carbon (NSC; primarily sugars and starch) budgets. Even less well understood is the mixing between recent photosynthetic assimilates (new NSC) and previously stored reserves. And, NSC turnover times are poorly constrained. We characterized the distribution of NSC in the stemwood, branches, and roots of two temperate trees, and we used the continuous label offered by the radiocarbon (carbon-14, (14) C) bomb spike to estimate the mean age of NSC in different tissues. NSC in branches and the outermost stemwood growth rings had the (14) C signature of the current growing season. However, NSC in older aboveground and belowground tissues was enriched in (14) C, indicating that it was produced from older assimilates. Radial patterns of (14) C in stemwood NSC showed strong mixing of NSC across the youngest growth rings, with limited 'mixing in' of younger NSC to older rings. Sugars in the outermost five growth rings, accounting for two-thirds of the stemwood pool, had a mean age < 1 yr, whereas sugars in older growth rings had a mean age > 5 yr. Our results are thus consistent with a previously-hypothesized two-pool ('fast' and 'slow' cycling NSC) model structure. These pools appear to be physically distinct. PMID- 25558815 TI - Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I. AB - Glutaric aciduria type I is an inherited defect in L-lysine, L-hydroxylysine and L-tryptophan degradation caused by deficiency of glutaryl-CoA dehydrogenase (GCDH). The majority of untreated patients presents with accumulation of neurotoxic metabolites - glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) - and striatal injury. Gcdh(-/-) mice display elevated levels of GA and 3-OH-GA but do not spontaneously develop striatal lesions. L-lysine-enriched diets (appr. 235 mg/d) were suggested to induce a neurological phenotype similar to affected patients. In our hands 93% of mice stressed according to the published protocol remained asymptomatic. To understand the underlying mechanism, we modified their genetic background (F1 C57BL6/Jx129/SvCrl) and increased the daily oral L-lysine supply (235-433 mg). We identified three modulating factors, (1) gender, (2) genetic background, and (3) amount of L-lysine. Male mice displayed higher vulnerability and inbreeding for more than two generations as well as elevating L lysine supply increased the diet-induced mortality rate (up to 89%). Onset of first symptoms leads to strongly reduced intake of food and, thus, L-lysine suggesting a threshold for toxic metabolite production to induce neurological disease. GA and 3-OH-GA tissue concentrations did not correlate with dietary L lysine supply but differed between symptomatic and asymptomatic mice. Cerebral activities of glyceraldehyde 3-phosphate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and aconitase were decreased. Symptomatic mice did not develop striatal lesions or intracerebral hemorrhages. We found severe spongiosis in the hippocampus of Gcdh(-/-) mice which was independent of dietary L-lysine supply. In conclusion, the L-lysine-induced pathology in Gcdh(-/-) mice depends on genetic and dietary parameters. PMID- 25558816 TI - Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines. AB - Alzheimer's disease is characterized by the accumulation of amyloid-beta (Abeta) and Tau in the brain. In mature neurons, Tau is concentrated in the axon and found at lower levels in the dendrite where it is required for targeting Fyn to the spines. Here Fyn mediates Abeta toxicity, which is vastly abrogated when Tau is either deleted or a truncated form of Tau (Tau(1-255)) is co-expressed. Interestingly, MAP2, a microtubule-binding protein with mainly dendritic localization that shares Fyn-binding motifs with Tau, does not mediate Abeta's synaptic toxicity in the absence of Tau. Here we show in hippocampal neurons that endogenous Tau enters the entire spine, albeit at low levels, whereas MAP2 only enters its neck or is restricted to the dendritic shaft. Based on an extensive mutagenesis study, we also reveal that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. When distinct phosphorylation sites (AT180-T231/S235, 12E8-S262/S356, PHF1-S396/S404) were pseudophosphorylated (with glutamic acid, using alanine replacements as controls), Tau targeting to spines was markedly increased, whereas the pseudophosphorylation of the late phospho-epitope S422 had no effect. In determining the role physiological Fyn has in the spine localization of Tau, we found that neither were endogenous Tau levels reduced in Fyn knockout compared with wild-type synaptosomal brain fractions nor was the spine localization of over-expressed pseudophosphorylated or P301L Tau. This demonstrates that although Fyn targeting to the spine is Tau dependent, elevated levels of phosphorylated Tau or P301L Tau can enter the spine in a Fyn-independent manner. PMID- 25558812 TI - Retinoic acid signaling and neuronal differentiation. AB - The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid (RA). The ability of RA to induce post-mitotic, neural phenotypes in various stem cells, in vitro, served as early evidence that RA is involved in the switch between proliferation and differentiation. In vivo studies have expanded this "opposing signal" model, and the number of primary neurons an embryo develops is now known to depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor (RAR) signaling (many of which are putative cell cycle regulators) remain largely unidentified. The molecular mechanisms underlying RA-induced primary neurogenesis in anamniote embryos are starting to be revealed; however, these data have been not been extended to amniote embryos. There is growing evidence that bona fide RARs are found in some mollusks and other invertebrates, but little is known about their necessity or functions in neurogenesis. One normal function of RA is to regulate the cell cycle to halt proliferation, and loss of RA signaling is associated with dedifferentiation and the development of cancer. Identifying the genes and pathways that mediate cell cycle exit downstream of RA will be critical for our understanding of how to target tumor differentiation. Overall, elucidating the molecular details of RAR-regulated neurogenesis will be decisive for developing and understanding neural proliferation-differentiation switches throughout development. PMID- 25558817 TI - Fibroblast growth factor and canonical WNT/beta-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage. AB - Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/beta-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/beta catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/beta catenin in suppression of chondrocyte differentiation. PMID- 25558818 TI - gamma-Glutamyl cysteine and gamma-glutamyl valine inhibit TNF-alpha signaling in intestinal epithelial cells and reduce inflammation in a mouse model of colitis via allosteric activation of the calcium-sensing receptor. AB - BACKGROUND: The extracellular calcium-sensing receptor (CaSR) is distributed throughout the gastrointestinal tract, and its activation has been shown to promote intestinal homeostasis, suggesting that CaSR may be a promising target for novel therapies to prevent chronic intestinal inflammation such as inflammatory bowel disease (IBD). The gamma-glutamyl dipeptides gamma-glutamyl cysteine (gamma-EC) and gamma-glutamyl valine (gamma-EV) are dietary flavor enhancing compounds, and have been shown to activate CaSR via allosteric ligand binding. The aim of this study was to examine the anti-inflammatory effects of gamma-EC and gamma-EV in vitro in intestinal epithelial cells and in a mouse model of intestinal inflammation. RESULTS: In vitro, treatment of Caco-2 cells with gamma-EC and gamma-EV resulted in the CaSR-mediated reduction of TNF-alpha stimulated pro-inflammatory cytokines and chemokines including IL-8, IL-6, and IL 1beta, and inhibited phosphorylation of JNK and IkappaBalpha, while increasing expression of IL-10. In vivo, using a mouse model of dextran sodium sulfate (DSS) induced colitis, gamma-EC and gamma-EV treatment ameliorated DSS-induced clinical signs, weight loss, colon shortening and histological damage. Moreover, gamma-EC and gamma-EV reduced the expression of TNF-alpha, IL-6, INF-gamma, IL-1beta, and IL-17, and increased the expression of IL-10 in the colon, in a CaSR-dependent manner. The CaSR-mediated anti-inflammatory effects of gamma-EC were abrogated in beta-arrestin2 knock-down Caco-2 cells, and involvement of beta-arrestin2 was found to inhibit TNF-alpha-dependent signaling via cross-talk with the TNF-alpha receptor (TNFR). CONCLUSIONS: Thus CaSR activation by gamma-EC and gamma-EV can aid in maintaining intestinal homeostasis and reducing inflammation in chronic inflammatory conditions such as IBD. PMID- 25558819 TI - Effect of Agrobacterium strain and plasmid copy number on transformation frequency, event quality and usable event quality in an elite maize cultivar. AB - KEY MESSAGE: Improving Agrobacterium -mediated transformation frequency and event quality by increasing binary plasmid copy number and appropriate strain selection is reported in an elite maize cultivar. Agrobacterium-mediated maize transformation is a well-established method for gene testing and for introducing useful traits in a commercial biotech product pipeline. To develop a highly efficient maize transformation system, we investigated the effect of two Agrobacterium tumefaciens strains and three different binary plasmid origins of replication (ORI) on transformation frequency, vector backbone insertion, single copy event frequency (percentage of events which are single copy for all transgenes), quality event frequency (percentage of single copy events with no vector backbone insertions among all events generated; QE) and usable event quality frequency (transformation frequency times QE frequency; UE) in an elite maize cultivar PHR03. Agrobacterium strain AGL0 gave a higher transformation frequency, but a reduced QE frequency than LBA4404 due to a higher number of vector backbone insertions. Higher binary plasmid copy number positively correlated with transformation frequency and usable event recovery. The above findings can be exploited to develop high-throughput transformation protocols, improve the quality of transgenic events in maize and other plants. PMID- 25558820 TI - Defining neurodegeneration on Guam by targeted genomic sequencing. AB - OBJECTIVE: Amyotrophic lateral sclerosis/parkinsonism-dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic. METHODS: In this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros. RESULTS: Genes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations. INTERPRETATION: The findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi-incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam. PMID- 25558821 TI - Membranous nephropathy: a review on the pathogenesis, diagnosis, and treatment. AB - In adults, membranous nephropathy (MN) is a major cause of nephrotic syndrome. However, the etiology of approximately 75% of MN cases is idiopathic. Secondary causes of MN are autoimmune diseases, infection, drugs, and malignancy. The pathogenesis of MN involves formation of immune complex in subepithelial sites, but the definite mechanism is still unknown. There are three hypotheses about the formation of immune complex, including preformed immune complex, in situ immune complex formation, and autoantibody against podocyte membrane antigen. The formation of immune complex initiates complement activation, which subsequently leads to glomerular damage. Recently, the antiphospholipase A2 receptor antibody was found to be associated with idiopathic MN. This finding may be useful in the diagnosis and prognosis of MN. The current treatment includes best supportive care, which consists of the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, lipid-lowering agents, and optimal control of blood pressure. Immunosuppressive agents should be used for patients who suffer from refractory proteinuria or complications associated with nephrotic syndrome. Existing evidence supports the use of a combination of steroid and alkylating agents. This article reviews the epidemiology, pathogenesis, diagnosis, and the treatment of MN. PMID- 25558822 TI - Reliability and validity of a wireless accelerometer for the assessment of postural sway. AB - Clinicians are in need of valid and objective measures of postural sway. Accelerometers have been shown to be suitable alternatives to expensive and stationary force plates. We evaluated the test-retest reliability and balance task discrimination capability of a new wireless triaxial accelerometer (YEI 3 Space Sensor). Four testing conditions (eyes open or closed, while on a firm or compliant surface) were used to progressively challenge the static balance of 20 healthy male (n = 8) and female (n = 12) older adults (mean age 81 +/- 4.3 y). Subjects completed 2 blocks of three 30-second trials per condition. The accelerometer was positioned on the lower back to acquire mediolateral (M-L) and anterior-posterior (A-P) accelerations. Intraclass correlation coefficients were all good to excellent, with values ranging from .736 to .972 for trial-to-trial and from .760 to .954 for block-to- block. A significant stepwise increase in center of mass acceleration root mean square values was found across the 4 balance conditions (F[1.49, 28.26] = 39.54, P < .001). The new accelerometer exhibited good to excellent trial-to-trial and block-to-block reliability and was sensitive to differences in visual and surface conditions and acceleration axes. PMID- 25558823 TI - BHBA influences bovine hepatic lipid metabolism via AMPK signaling pathway. AB - beta-hydroxybutyric acid (BHBA), an important metabolite in beta-oxidation, is involved in the development of ketosis in dairy cows. It is known that AMP activated protein kinase (AMPK) signaling pathway plays an important role in the regulation of lipid metabolism in hepatocytes. In the present study, bovine hepatocytes were treated with BHBA at variable concontrations and Compound C (Cpd C, an AMPK inhibitor) to investigate the effects of BHBA on the AMPK signaling pathway. The results showed that when the concentration of BHBA reached 1.2 mM, the AMPK signaling pathway was activated and the expression of sterol regulatory element binding protein-1c (SREBP-1c) as well as its target genes were significantly decreased. And these decreases were blocked by Cpd C. The binding activity and nucleus translocation of SREBP-1c showed a similar trend. The expression of peroxisome proliferator activated receptor-alpha (PPARalpha), carbohydrates response element binding protein (ChREBP) and their target genes were significantly increased while they were negatively suppressed by the Cpd C. The content of triglyceride (TG) had no obviously change in the BHBA and Cpd C treated groups. These results indicate that BHBA can activate AMPK signaling pathway and regulate lipid synthesis and lipid oxidation genes of AMPK but showed no effect on TG in bovine hepatocytes. PMID- 25558825 TI - Tuneable dynamics of a scandium nitride cluster inside an Ih-C80 cage. AB - The internal clusters in metallofullerenes usually exhibit certain motion that is potentially usable in molecular gyroscopes and nano-machines. Based on (45)Sc NMR, the motion of the scandium nitride cluster within the C80 cage was investigated via varying the temperature and modifying the cage, and by changing the cluster size. PMID- 25558824 TI - All in the Family: Barriers and Motivators to the Use of Cancer Family History Questionnaires and the Impact on Attendance Rates. AB - Data has demonstrated that family history questionnaires (FHQs) are an invaluable tool for assessing familial cancer risk and triaging patients for genetic counseling services. Despite their benefits, return rates of mailed FHQs from newly referred patients remain low, suggesting potential barriers to their use. To investigate this, a total of 461 participants, 239 who completed a FHQ (responders) and 222 who did not (non-responders), were surveyed at a subsequent appointment regarding potential barriers and motivators to using the FHQ. With respective rates of 51 and 56 %, there was no significant difference in the proportion of responders and non-responders who reported difficulty in completing the FHQ; however, for both groups factors related to family dynamics (large family size, lack of contact with relatives, and lack of knowledge of family history) were reported as major variables confounding completion of the FHQ. Responders were also significantly more likely to have a personal diagnosis of cancer (p = 0.02) and to report that their physician had discussed the reason for the appointment with them (p = 0.01). Overall, 19 % of non-responders returned their FHQ after being mailed an appointment letter and 67 % attended their scheduled genetic counseling appointment. These findings demonstrate that difficulty completing the FHQ is not inherent to its design but due to difficulty accessing one's family history, and that mailed appointment letters are a highly successful way to increase attendance rates in the non-responder population. Furthermore, these results demonstrate the important role that referring physicians play in the utilization of genetic counseling services. PMID- 25558826 TI - It is all about calcification. PMID- 25558827 TI - Regulation of zygotic genome activation and DNA damage checkpoint acquisition at the mid-blastula transition. AB - Following fertilization, oviparous embryos undergo rapid, mostly transcriptionally silent cleavage divisions until the mid-blastula transition (MBT), when large-scale developmental changes occur, including zygotic genome activation (ZGA) and cell cycle remodeling, via lengthening and checkpoint acquisition. Despite their concomitant appearance, whether these changes are co regulated is unclear. Three models have been proposed to account for the timing of (ZGA). One model implicates a threshold nuclear to cytoplasmic (N:C) ratio, another stresses the importance cell cycle elongation, while the third model invokes a timer mechanism. We show that precocious Chk1 activity in pre-MBT zebrafish embryos elongates cleavage cycles, thereby slowing the increase in the N:C ratio. We find that cell cycle elongation does not lead to transcriptional activation. Rather, ZGA slows in parallel with the N:C ratio. We show further that the DNA damage checkpoint program is maternally supplied and independent of ZGA. Although pre-MBT embryos detect damage and activate Chk2 after induction of DNA double-strand breaks, the Chk1 arm of the DNA damage response is not activated, and the checkpoint is nonfunctional. Our results are consistent with the N:C ratio model for ZGA. Moreover, the ability of precocious Chk1 activity to delay pre-MBT cell cycles indicate that lack of Chk1 activity limits checkpoint function during cleavage cycles. We propose that Chk1 gain-of-function at the MBT underlies cell cycle remodeling, whereas ZGA is regulated independently by the N:C ratio. PMID- 25558828 TI - A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells. AB - Overcoming chemoresistance of pancreatic cancer (PCa) cells should significantly extend patient survival. The current treatment modalities rely on a variety of DNA damaging agents including gemcitabine, FOLFIRINOX, and Abraxane that activate cell cycle checkpoints, which allows cells to survive these drug treaments. Indeed, these treatment regimens have only extended patient survival by a few months. The complex microenvironment of PCa tumors has been shown to complicate drug delivery thus decreasing the sensitivity of PCa tumors to chemotherapy. In this study, a genome-wide siRNA library was used to conduct a synthetic lethal screen of Panc1 cells that was treated with gemcitabine. A sublethal dose (50 nM) of the drug was used to model situations of limiting drug availability to PCa tumors in vivo. Twenty-seven validated sensitizer genes were identified from the screen including the Vitamin D receptor (VDR). Gemcitabine sensitivity was shown to be VDR dependent in multiple PCa cell lines in clonogenic survival assays. Sensitization was not achieved through checkpoint override but rather through disrupting DNA repair. VDR knockdown disrupted the cells' ability to form phospho gammaH2AX and Rad51 foci in response to gemcitabine treatment. Disruption of Rad51 foci formation, which compromises homologous recombination, was consistent with increased sensitivity of PCa cells to the PARP inhibitor Rucaparib. Thus inhibition of VDR in PCa cells provides a new way to enhance the efficacy of genotoxic drugs. PMID- 25558829 TI - Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4. AB - Barrett's esophagus (BE) is defined as an incomplete intestinal metaplasia characterized generally by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. BE is known as a precursor for esophageal adenocarcinoma. Currently, the cell of origin for human BE has yet to be clearly identified. Therefore, we investigated the role of Notch signaling in the initiation of BE metaplasia. Affymetrix gene expression microarray revealed that BE samples express decreased levels of Notch receptors (NOTCH2 and NOTCH3) and one of the the ligands (JAG1). Furthermore, BE tissue microarray showed decreased expression of NOTCH1 and its downstream target HES1. Therefore, Notch signaling was inhibited in human esophageal epithelial cells by expression of dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression. Cell transdifferentiation was then assessed by 3D organotypic culture and evaluation of BE-lineage specific gene expression. Notch inhibition promoted transdifferentiation of esophageal epithelial cells toward columnar-like cells as demonstrated by increased expression of columnar keratins (K8, K18, K19, K20) and glandular mucins (MUC2, MUC3B, MUC5B, MUC17) and decreased expression of squamous keratins (K5, K13, K14). In 3D culture, elongated cells were observed in the basal layer of the epithelium with Notch inhibition. Furthermore, we observed increased expression of KLF4, a potential driver of the changes observed by Notch inhibition. Interestingly, knockdown of KLF4 reversed the effects of Notch inhibition on BE-like metaplasia. Overall, Notch signaling inhibition promotes transdifferentiation of esophageal cells toward BE-like metaplasia in part via upregulation of KLF4. These results support a novel mechanism through which esophageal epithelial transdifferentiation promotes the evolution of BE. PMID- 25558830 TI - Kizuna is a novel mitotic substrate for CDC25B phosphatase. AB - CDC25 dual-specificity phosphatases play a central role in cell cycle control through the activation of Cyclin-Dependent Kinases (CDKs). Expression during mitosis of a stabilized CDC25B mutant (CDC25B-DDA), which cannot interact with the F-box protein betaTrCP for proteasome-dependent degradation, causes mitotic defects and chromosome segregation errors in mammalian cells. We found, using the same CDC25B mutant, that stabilization and failure to degrade CDC25B during mitosis lead to the appearance of multipolar spindle cells resulting from a fragmentation of pericentriolar material (PCM) and abolish mitotic Plk1-dependent phosphorylation of Kizuna (Kiz), which is essential for the function of Kiz in maintaining spindle pole integrity. Thus, in mitosis Kiz is a new substrate of CDC25B whose dephosphorylation following CDC25B stabilization leads to the formation of multipolar spindles. Furthermore, endogenous Kiz and CDC25B interact only in mitosis, suggesting that Kiz phosphorylation depends on a balance between CDC25B and Plk1 activities. Our data identify a novel mitotic substrate of CDC25B phosphatase that plays a key role in mitosis control. PMID- 25558831 TI - PITX1, a specificity determinant in the HIF-1alpha-mediated transcriptional response to hypoxia. AB - Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1alpha dependent target gene activation. Mechanistically, PITX1 associates with HIF-1beta and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1alpha-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1alpha dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers. PMID- 25558833 TI - Traction force during vacuum extraction: a prospective observational study. AB - OBJECTIVE: To investigate the traction force employed during vacuum extractions. DESIGN: Observational cross-sectional study. SETTING: Obstetric Department, Karolinska University Hospital, Sweden, and the Swedish National Congress of Obstetrics and Gynaecology, 2013. POPULATION: Two hundred women with vacuum extraction at term and 130 obstetricians participating in a simulated setting. METHODS: In a normal clinical setting, we used a specially adapted device to measure and record the force used to undertake vacuum extraction. In a subsequent part of the study, the force employed for vacuum extraction by a group of obstetricians in a fictive setting was estimated and objectively measured. MAIN OUTCOME MEASURES: Applied force during vacuum extraction in relation to the estimated level of difficulty in the delivery; perinatal diagnoses of asphyxia or head trauma; estimated force compared with objectively measured force employed in the fictive setting. RESULTS: The median (minimum-maximum) peak forces for minimum, average and excessive vacuum extraction in the clinical setting were 176 N (5-360 N), 225 N (115-436 N), and 241 N (164-452 N), respectively. In 34% of cases a force in excess of 216 N was employed. There was no correlation between the umbilical arterial pH at delivery and the traction force employed during extraction. Four cases of mild hypoxic ischaemic encephalopathy were observed, three of which were associated with a delivery whereby excessive traction force was employed during the vacuum extraction. In the fictive setting, the actual exerted force was twice the quantitative estimation. The measured forces in the clinical setting were four times higher than that estimated in the fictive setting. CONCLUSIONS: Higher than expected levels of traction force were used for vacuum extraction delivery. As obstetricians tend to underestimate the force applied during vacuum extraction, objective measurement with instantaneous feedback may be valuable in raising awareness. PMID- 25558832 TI - A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells. AB - The putative induction of adult beta-cell regeneration represents a promising approach for the treatment of type 1 diabetes. Toward this ultimate goal, it is essential to develop an inducible model mimicking the long-lasting disease progression. In the current study, we have established a novel beta-cell ablation mouse model, in which the beta-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the beta-cell specific genetic ablation of the transcription initiation factor 1A, TIF-IA, essential for RNA Polymerase I activity (TIF-IA(Delta/Delta)). Using this approach, we induced a slow apoptotic response that eventually leads to a protracted beta-cell death. In this model, we observed beta-cell regeneration that resulted in a complete recovery of the beta cell mass and normoglycemia. In addition, we showed that adaptive proliferation of remaining beta-cells is the prominent mechanism acting to compensate for the massive beta-cell loss in young but also aged mice. Interestingly, at any age, we also detected beta-like cells expressing the glucagon hormone, suggesting a transition between alpha- and beta-cell identities or vice versa. Taken together, the TIF-IA(Delta/Delta) mouse model can be used to investigate the potential therapeutic approaches for type 1 diabetes targeting beta-cell regeneration. PMID- 25558835 TI - Prostate cancer: Active surveillance comes of age. PMID- 25558834 TI - Use of three-compartment physiologically based pharmacokinetic modeling to predict hepatic blood levels of fluvoxamine relevant for drug-drug interactions. AB - Using a three-compartment physiologically based pharmacokinetic (PBPK) model and a tube model for hepatic extraction kinetics, equations for calculating blood drug levels (Cb s) and hepatic blood drug levels (Chb s, proportional to actual hepatic drug levels), were derived mathematically. Assuming the actual values for total body clearance (CLtot ), oral bioavailability (F), and steady-state distribution volume (Vdss ), Cb s, and Chb s after intravenous and oral administration of fluvoxamine (strong perpetrator in drug-drug interactions, DDIs), propranolol, imipramine, and tacrine were simulated. Values for Cb s corresponded to the actual values for all tested drugs, and mean Chb and maximal Chb -to-maximal Cb ratio predicted for oral fluvoxamine administration (50 mg twice-a-day administration) were nearly 100 nM and 2.3, respectively, which would be useful for the predictions of the DDIs caused by fluvoxamine. Fluvoxamine and tacrine are known to exhibit relatively large F values despite having CLtot similar to or larger than hepatic blood flow, which may be because of the high liver uptake (almost 0.6) upon intravenous administration. The present method is thus considered to be more predictive of the Chb for perpetrators of DDIs than other methods. PMID- 25558836 TI - Benign prostatic hyperplasia in 2014: Innovations in medical and surgical treatment. PMID- 25558837 TI - Kidney cancer: Resistance stems from tumour necrosis. PMID- 25558840 TI - Prostate cancer: Nerve-sparing surgery and risk of positive surgical margins. PMID- 25558839 TI - Surgery for postprostatectomy incontinence: which procedure for which patient? AB - Surgery remains the most effective treatment for postprostatectomy incontinence. Over the past two decades, this surgery has evolved with respect to both operative technique and sling design, and various devices are now available that have different mechanisms of action, such as the artificial urinary sphincter, retroluminal sling or quadratic sling. The choice of device, however, should be individualized according to the circumstances of each patient. The optimal surgical treatment depends on a variety of patient-related factors, including the degree of urine leakage as assessed by incontinence pad weight test results, bladder contractility, urethral compliance, history of radiation exposure or prior incontinence surgery, and patient preference--given the choice, most patients opt for a sling procedure over an artificial sphincter to avoid implantation of a mechanical device. Athorough urodynamic evaluation is, therefore, necessary for the majority of patients. An artificial urinary sphincter, retroluminal sling or quadratic sling might be the most appropriate choice for a particular patient, depending on their specific urodynamic findings. Progress in this field continues, and several new devices are in development. PMID- 25558841 TI - Bladder cancer in 2014: From the genomic frontier to immunotherapeutics. PMID- 25558845 TI - Virtual immersion for post-stroke hand rehabilitation therapy. AB - Stroke is the leading cause of serious, long-term disability in the United States. Impairment of upper extremity function is a common outcome following stroke, often to the detriment of lifestyle and employment opportunities. While the upper extremity is a natural target for therapy, treatment may be hampered by limitations in baseline capability as lack of success may discourage arm and hand use. We developeda virtual reality (VR) system in order to encourage repetitive task practice. This system combined an assistive glove with a novel VR environment. A set of exercises for this system was developed to encourage specific movements. Six stroke survivors with chronic upper extremity hemiparesis volunteered to participate in a pilot study in which they completed 18 one-hour training sessions with the VR system. Performance with the system was recorded across the 18 training sessions. Clinical evaluations of motor control were conducted at three time points: prior to initiation of training, following the end of training, and 1 month later. Subjects displayed significant improvement on performance of the virtual tasks over the course of the training, although for the clinical outcome measures only lateral pinch showed significant improvement. Future expansion to multi-user virtual environments may extend the benefits of this system for stroke survivors with hemiparesis by furthering engagement in the rehabilitation exercises. PMID- 25558846 TI - The effects of oxidative stress on the compressive damage thresholds of C2C12 mouse myoblasts: implications for deep tissue injury. AB - Deep tissue injury (DTI) is a severe kind of pressure ulcers formed by sustained deformation of muscle tissues over bony prominences. As a major clinical issue, DTI affects people with physical disabilities, and is obviously related to the load-bearing capacity of muscle cells in various in vivo conditions. It has been hypothesized that oxidative stress, either induced by reperfusion immediately following tissue unloading or in chronic inflammatory conditions, may affect the cellular capacity against subsequent mechanical damages. In this study, we measured the compressive damage threshold of C2C12 mouse myoblasts with or without pre-treatment of hydrogen peroxide as an oxidative agent to understand how changes in the oxidative environment may contribute to the development of DTI. Spherical indentation was applied onto a layer of agarose gel (3 mm thick) covering a monolayer of C2C12 myoblasts. Cell damage was recognized by using a cell membrane damage assay, propidium iodide. The spatial profile of the measured percentage cell damage was correlated with the radially varying stress field as determined by finite element analysis to estimate the compressive stress threshold for cell damage. Results supported the hypothesis that chronic exposure to high-dosage oxidative stress could compromise the capability of muscle cells to withstand compressive damages, while short exposure to low-dosage oxidative stress could enhance such capability. PMID- 25558847 TI - Synergy Between Intercellular Communication and Intracellular Ca(2+) Handling in Arrhythmogenesis. AB - Calcium is the primary signalling component of excitation-contraction coupling, the process linking electrical excitability of cardiac muscle cells to coordinated contraction of the heart. Understanding [Formula: see text] handling processes at the cellular level and the role of intercellular communication in the emergence of multicellular synchronization are key aspects in the study of arrhythmias. To probe these mechanisms, we have simulated cellular interactions on large scale arrays that mimic cardiac tissue, and where individual cells are represented by a mathematical model of intracellular [Formula: see text] dynamics. Theoretical predictions successfully reproduced experimental findings and provide novel insights on the action of two pharmacological agents (ionomycin and verapamil) that modulate [Formula: see text] signalling pathways via distinct mechanisms. Computational results have demonstrated how transitions between local synchronisation events and large scale wave formation are affected by these agents. Entrainment phenomena are shown to be linked to both intracellular [Formula: see text] and coupling-specific dynamics in a synergistic manner. The intrinsic variability of the cellular matrix is also shown to affect emergent patterns of rhythmicity, providing insights into the origins of arrhythmogenic [Formula: see text] perturbations in cardiac tissue in situ. PMID- 25558849 TI - Antihyperlipidaemic, antihypertrophic, and reducing effects of zingerone on experimentally induced myocardial infarcted rats. AB - The present study aims to evaluate the antihyperlipidaemic, antihypertrophic, and reducing effects of zingerone on isoproterenol-induced hyperlipidaemia and hypertrophy in rats. Rats were pretreated with zingerone (6 mg/kg body weight) daily for a period of 14 days and then induced myocardial infarction with isoproterenol (100 mg/kg body weight) on days 15 and 16. Isoproterenol increased serum creatine kinase and lactate dehydrogenase activities in the rats. Increased levels/concentrations of serum and heart cholesterol and triglycerides were observed in isoproterenol-induced myocardial infarcted rats. Isoproterenol also altered serum lipoproteins and the activity of liver 3-hydroxy-3-methyl glutaryl coenzyme-A-reductase in the rats. The in vitro study revealed a very convincing reducing power of zingerone. Pretreatment with zingerone prevented hyperlipidaemia and cardiac hypertrophy, by virtue of its antihyperlipidaemic, antihypertrophic, and reducing properties in isoproterenol-induced myocardial infarcted rats. PMID- 25558850 TI - Isothermal DNA origami folding: avoiding denaturing conditions for one-pot, hybrid-component annealing. AB - The DNA origami technique offers great potential for nanotechnology. Using biomolecular self-assembly, defined 2D and 3D nanoscale DNA structures can be realized. DNA origami allows the positioning of proteins, fluorophores or nanoparticles with an accuracy of a few nanometers and enables thereby novel nanoscale devices. Origami assembly usually includes a thermal denaturation step at 90 degrees C. Additional components used for nanoscale assembly (such as proteins) are often thermosensitive, and possibly damaged by such harsh conditions. They have therefore to be attached in an extra second step to avoid defects. To enable a streamlined one-step nanoscale synthesis - a so called one pot folding - an adaptation of the folding procedures is required. Here we present a thermal optimization of this process for a 2D DNA rectangle-shaped origami resulting in an isothermal assembly protocol below 60 degrees C without thermal denaturation. Moreover, a room temperature protocol is presented using the chemical additive betaine, which is biocompatible in contrast to chemical denaturing approaches reported previously. PMID- 25558851 TI - The value of clinical judgment in the detection of clinical deterioration. PMID- 25558848 TI - Cathepsins in Rotator Cuff Tendinopathy: Identification in Human Chronic Tears and Temporal Induction in a Rat Model. AB - While overuse of the supraspinatus tendon is a leading factor in rotator cuff injury, the underlying biochemical changes have not been fully elucidated. In this study, torn human rotator cuff (supraspinatus) tendon tissue was analyzed for the presence of active cathepsin proteases with multiplex cysteine cathepsin zymography. In addition, an overuse injury to supraspinatus tendons was induced through downhill running in an established rat model. Histological analysis demonstrated that structural damage occurred by 8 weeks of overuse compared to control rats in the region of tendon insertion into bone. In both 4- and 8-week overuse groups, via zymography, there was approximately a 180% increase in cathepsin L activity at the insertion region compared to the controls, while no difference was found in the midsubstance area. Additionally, an over 400% increase in cathepsin K activity was observed for the insertion region of the 4 week overused tendons. More cathepsin K and L immunostaining was observed at the insertion region of the overuse groups compared to controls. These results provide important information on a yet unexplored mechanism for tendon degeneration that may operate alone or in conjunction with other proteases to contribute to chronic tendinopathy. PMID- 25558852 TI - Ruthenium based nanostructures driven by morphological controls as efficient counter electrodes for dye-sensitized solar cells. AB - We introduce a facile approach to use ruthenium dioxide (RuO2) and ruthenium (Ru) nanostructures as effective counter electrodes instead of using platinum (Pt) for dye-sensitized solar cells (DSSCs). RuO2 and Ru nanostructure layers on the FTO glass can be readily prepared by a simple annealing process followed by the spin coating process of the mixture solution containing amorphous RuO2.xH2O precursor and poly(ethylene oxide) (PEO) as a dispersion matrix at low temperature in air. The Ru metal nanostructure layer prepared by the reduction of RuO2 with H2 shows the highest efficiency of 6.77% in DSSC operation, which is comparable to the efficiency of the Pt electrode (7.87%). PMID- 25558853 TI - Photoreduction of carbon dioxide to formic acid in aqueous suspension: a comparison between phthalocyanine/TiO2 and porphyrin/TiO2 catalysed processes. AB - Composite materials prepared by loading polycrystalline TiO2 powders with lipophilic highly branched Cu(II)- and metal-free phthalocyanines or porphyrins, which have been used in the past as photocatalysts for photodegradative processes, have been successfully tested for the efficient photoreduction of carbon dioxide in aqueous suspension affording significant amounts of formic acid. The results indicated that the presence of the sensitizers is beneficial for the photoactivity, confirming the important role of Cu(II) co-ordinated in the middle of the macrocycles. A comparison between Cu(II) phthalocyanines and Cu(II) porphyrins indicated that the Cu(II)- phthalocyanine sensitizer was more efficient in the photoreduction of CO2 to formic acid, probably due to its favorable reduction potential. PMID- 25558854 TI - Stem bark extract and fraction of Persea americana (Mill.) exhibits bactericidal activities against strains of bacillus cereus associated with food poisoning. AB - The study investigates the in vitro antibacterial potentials of stem bark extracts of Persea americana on strains of Bacillus cereus implicated in food poisoning. The crude stem bark extracts and butanolic fraction at a concentration of 25 mg/mL and 10 mg/mL, respectively, exhibited antibacterial activities against test isolates. The zones of inhibition exhibited by the crude extract and the fraction ranged between 10 mm and 26 mm, while the minimum inhibitory concentration values ranged between 0.78 and 5.00 mg/mL. The minimum bactericidal concentrations ranged between 3.12 mg/mL-12.5 mg/mL and 1.25-10 mg/mL for the extract and the fraction, respectively. The butanolic fraction killed 91.49% of the test isolates at a concentration of 2* MIC after 60 min of contact time, while a 100% killing was achieved after the test bacterial cells were exposed to the butanolic fraction at a concentration of 3* MIC after 90 min contact time. Intracellular protein and potassium ion leaked out of the test bacterial cells when exposed to certain concentrations of the fraction; this is an indication of bacterial cell wall disruptions by the extract's butanolic fraction and, thus, caused a biocidal effect on the cells, as evident in the killing rate test results. PMID- 25558855 TI - An effective vacuum assisted extraction method for the optimization of labdane diterpenoids from Andrographis paniculata by response surface methodology. AB - An effective vacuum assisted extraction (VAE) technique was proposed for the first time and applied to extract bioactive components from Andrographis paniculata. The process was carefully optimized by response surface methodology (RSM). Under the optimized experimental conditions, the best results were obtained using a boiling temperature of 65 degrees C, 50% ethanol concentration, 16 min of extraction time, one extraction cycles and a 12:1 liquid-solid ratio. Compared with conventional ultrasonic assisted extraction and heat reflux extraction, the VAE technique gave shorter extraction times and remarkable higher extraction efficiency, which indicated that a certain degree of vacuum gave the solvent a better penetration of the solvent into the pores and between the matrix particles, and enhanced the process of mass transfer. The present results demonstrated that VAE is an efficient, simple and fast method for extracting bioactive components from A. paniculata, which shows great potential for becoming an alternative technique for industrial scale-up applications. PMID- 25558856 TI - Lectins from edible mushrooms. AB - Mushrooms are famous for their nutritional and medicinal values and also for the diversity of bioactive compounds they contain including lectins. The present review is an attempt to summarize and discuss data available on molecular weights, structures, biological properties, N-terminal sequences and possible applications of lectins from edible mushrooms. It further aims to update and discuss/examine the recent advancements in the study of these lectins regarding their structures, functions, and exploitable properties. A detailed tabling of all the available data for N-terminal sequences of these lectins is also presented here. PMID- 25558857 TI - 4-[18F]Fluorophenylpiperazines by improved Hartwig-Buchwald N-arylation of 4 [18F]fluoroiodobenzene, formed via hypervalent lambda3-iodane precursors: application to build-up of the dopamine D4 ligand [18F]FAUC 316. AB - Substituted phenylpiperazines are often neuropharmacologically active compounds and in many cases are essential pharmacophores of neuroligands for different receptors such as D2-like dopaminergic, serotoninergic and other receptors. Nucleophilic, no-carrier-added (n.c.a.) 18F-labelling of these ligands in an aromatic position is desirable for studying receptors with in vivo molecular imaging. 1-(4-[18F]Fluorophenyl)piperazine was synthesized in two reaction steps starting by 18F-labelling of a iodobenzene-iodonium precursor, followed by Pd catalyzed N-arylation of the intermediate 4-[18F]fluoro-iodobenzene. Different palladium catalysts and solvents were tested with particular attention to the polar solvents dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Weak inorganic bases like potassium phosphate or cesium carbonate seem to be essential for the arylation step and lead to conversation rates above 70% in DMF which is comparable to those in typically used toluene. In DMSO even quantitative conversation was observed. Overall radiochemical yields of up to 40% and 60% in DMF and DMSO, respectively, were reached depending on the labelling yield of the first step. The fluorophenylpiperazine obtained was coupled in a third reaction step with 2-formyl-1H-indole-5-carbonitrile to yield the highly selective dopamine D4 ligand [18F]FAUC 316. PMID- 25558858 TI - Synthesis and X-ray structural studies of a substituted 2,3,4,5-tetrahydro-1H-3 benzazonine and a 1,2,3,5-tetrahydro-4,3-benzoxazonine. AB - Using a common 1-(1-phenylethenyl)-1,2,3,4-tetrahydroisoquinoline precursor to the required ylide or N-oxide intermediate, the Stevens [2,3] and analogous Meisenheimer [2,3] sigmatropic rearrangements have been applied to afford concise syntheses of phenyl -substituted representatives of each of the reduced 1H-3 benzazonine and 4,3-benzoxazonine systems, respectively. Single crystal X-ray structure determinations were employed to define the conformational characteristics for each ring type. PMID- 25558859 TI - A comparison of the environmental impact of different AOPs: risk indexes. AB - Today, environmental impact associated with pollution treatment is a matter of great concern. A method is proposed for evaluating environmental risk associated with Advanced Oxidation Processes (AOPs) applied to wastewater treatment. The method is based on the type of pollution (wastewater, solids, air or soil) and on materials and energy consumption. An Environmental Risk Index (E), constructed from numerical criteria provided, is presented for environmental comparison of processes and/or operations. The Operation Environmental Risk Index (EOi) for each of the unit operations involved in the process and the Aspects Environmental Risk Index (EAj) for process conditions were also estimated. Relative indexes were calculated to evaluate the risk of each operation (E/NOP) or aspect (E/NAS) involved in the process, and the percentage of the maximum achievable for each operation and aspect was found. A practical application of the method is presented for two AOPs: photo-Fenton and heterogeneous photocatalysis with suspended TiO2 in Solarbox. The results report the environmental risks associated with each process, so that AOPs tested and the operations involved with them can be compared. PMID- 25558860 TI - Learning categories via rules and similarity: comparing adults and children. AB - Two experiments explored the different strategies used by children and adults when learning new perceptual categories. Participants were asked to learn a set of categories for which both a single-feature rule and overall similarity would allow for perfect performance. Other rules allowed for suboptimal performance. Transfer stimuli (Experiments 1 and 2) and single features (Experiment 2) were presented after training to help determine how the categories were learned. In both experiments, we found that adults made significantly more optimal rule-based responses to the test stimuli than children. Children showed a variety of categorization styles, with a few relying on the optimal rules, many relying on suboptimal single-feature rules, and only a few relying on overall family resemblance. We interpret these results within a multiple systems framework, and we argue that children show the pattern they do because they lack the necessary cognitive resources to fully engage in hypothesis testing, rule selection, and verbally mediated category learning. PMID- 25558861 TI - Preschoolers' mutualistic conception of seeing is related to their knowledge of the pronoun "each other". AB - Previous research has shown that young children deny being able to see an agent whose eyes are covered. The current study explored this phenomenon further. In Experiment 1, 3-year-olds denied that they could "see," but affirmed that they could "look at," a doll whose eyes were covered--indicating that they demand mutuality for seeing another but not for looking at another. In Experiment 2, 3.5 year-olds drew the same distinction between "see" and "look at" when facing a doll or a human. A strong correlation between children's knowledge of the reciprocal pronoun "each other" and their adherence to the mutuality demand was found. The results are discussed with respect to children's bias for second personal encounters and children's relational concept of persons. PMID- 25558862 TI - Home uterine monitoring for detecting preterm labour. AB - BACKGROUND: To reduce the morbidity and mortality associated with preterm birth, home uterine activity monitoring aims for early detection of increased contraction frequency, and early intervention with tocolytic drugs to inhibit labour and prolong pregnancy. However, the effectiveness of such monitoring is disputed. OBJECTIVES: To determine whether home uterine activity monitoring is effective in improving the outcomes for women and their infants considered to be at high risk of preterm birth, when compared with conventional or other care packages that do not include home uterine monitoring. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014), CENTRAL (The Cochrane Library 2014, Issue 8), MEDLINE (1966 to 31 August 2014), EMBASE (1974 to 31 August 2014), CINAHL (1982 to 31 August 2014) and scanned reference lists of retrieved studies. SELECTION CRITERIA: Randomised control trials of home uterine activity monitoring, with or without patient education programmes, for women at risk for preterm birth, in comparison to the same care package without home uterine activity monitoring. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We did not attempt to contact authors to resolve queries. MAIN RESULTS: There were 15 included studies (total number of enrolled participants 6008); 13 studies contributed data. Women using home uterine monitoring were less likely to experience preterm birth at less than 34 weeks (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.62 to 0.99; three studies, n = 1596; fixed-effect analysis) (GRADE high). The significant difference was not evident when we carried out a sensitivity analysis, restricting the analysis to studies at low risk of bias based on study quality (RR 0.75; 95% CI 0.57 to 1.00, one study, 1292 women). There was no significant difference in the rate of perinatal mortality (RR 1.22; 95% CI 0.86 to 1.72; two studies, n = 2589) (GRADE low)There was no significant difference in the number of preterm births at less than 37 weeks (average RR 0.85; CI 0.72 to 1.01; eight studies, n = 4834; random-effects, T2 = 0.03, I2 = 68%) (GRADE very low). Infants born to women using home uterine monitoring were less likely to be admitted to neonatal intensive care unit (average RR 0.77; 95% CI 0.62 to 0.96; five studies, n = 2367; random-effects, T2 = 0.02, I2 = 32%) (GRADE moderate). The difference was not statistically significant when only high quality studies were included (RR 0.86; 95% CI 0.74 to 1.01; one study, n = 1292). Women using home uterine monitoring made more unscheduled antenatal visits (mean difference (MD) 0.49; 95% CI 0.39 to 0.62; two studies, n = 3707) (GRADE moderate). Women using home uterine monitoring were also more likely to have prophylactic tocolytic drug therapy (average RR 1.21; 95% CI 1.01 to 1.45; seven studies, n = 4316; random effects. T2 = 0.03, I2 = 62%) but this difference was no longer significant when the analysis was restricted to higher quality studies (average RR 1.22; 95% CI 0.90 to 1.65, three studies, n = 3749,random-effects, T2 = 0.05, I2 = 76%) (GRADE low). One small study reported that the home uterine monitoring group spent fewer days in hospital antenatally. No data on maternal anxiety or acceptability were found. AUTHORS' CONCLUSIONS: Home uterine monitoring may result in fewer admissions to a neonatal intensive care unit but more unscheduled antenatal visits and tocolytic treatment, but the level of evidence is generally low to moderate. Important group differences were not evident when sensitivity analysis was undertaken using only high quality trials. There is no impact on maternal and perinatal outcomes such as perinatal mortality or incidence of preterm birth. PMID- 25558863 TI - Erratum: Hyperosmolar and methotrexate therapy avoiding surgery in the acute presentation of primary central nervous system lymphoma: Erratum. AB - [This corrects the article on p. S175 in vol. 5, PMID: 25184099.]. PMID- 25558864 TI - Do corticosteroids have a role in treating Ebola virus disease? PMID- 25558865 TI - May early intervention with intravenous immunoglobulin pose a potentially successful treatment for Ebola virus infection? PMID- 25558866 TI - Lasting Prolonged-Release Tapentadol for Moderate/Severe Non-Cancer Musculoskeletal Chronic Pain. AB - INTRODUCTION: Despite opioids' recognized role in the treatment of moderate/severe musculoskeletal chronic pain, their long-term benefits need investigation. We explored the lasting analgesic efficacy, tolerability, influence on life quality, and chronicity stage of the novel prolonged release (PR) opioid, tapentadol, in 30 outpatients. METHODS: We evaluated patients' pain intensity and relief (Numerical Rating Scale; NRS), adverse effects, sleep quality, treatment satisfaction, health status (12-questions Health-Survey; SF 12), chronicity stage (Italian Mainz Pain-Staging System; I-MPSS) at 10, 30, 60, and 90 days after tapentadol prescription. RESULTS: At follow-ups, the investigated outcomes showed an overall statistically significant (Wilcoxon signed-rank test) improvement and remained stable over time, as did the health status and chronicity stage. Adverse effects were limited, transitory, and tolerable. CONCLUSIONS: Twelve weeks of PR tapentadol in outpatients with moderate/severe chronic musculoskeletal pain showed satisfactory analgesic efficacy and tolerability, and had a positive influence on life quality and chronicity stage. The results are robust enough to warrant a subsequent study with a larger sample and a longer observation period. PMID- 25558867 TI - Distributing a metabolic pathway among a microbial consortium enhances production of natural products. AB - Metabolic engineering of microorganisms such as Escherichia coli and Saccharomyces cerevisiae to produce high-value natural metabolites is often done through functional reconstitution of long metabolic pathways. Problems arise when parts of pathways require specialized environments or compartments for optimal function. Here we solve this problem through co-culture of engineered organisms, each of which contains the part of the pathway that it is best suited to hosting. In one example, we divided the synthetic pathway for the acetylated diol paclitaxel precursor into two modules, expressed in either S. cerevisiae or E. coli, neither of which can produce the paclitaxel precursor on their own. Stable co-culture in the same bioreactor was achieved by designing a mutualistic relationship between the two species in which a metabolic intermediate produced by E. coli was used and functionalized by yeast. This synthetic consortium produced 33 mg/L oxygenated taxanes, including a monoacetylated dioxygenated taxane. The same method was also used to produce tanshinone precursors and functionalized sesquiterpenes. PMID- 25558868 TI - Removal of aqueous cyanide with strongly basic ion-exchange resin. AB - The removal of cyanide (CN-) from aqueous solutions using a strongly basic ion exchange resin, Purolite A-250, was investigated. The effects of contact time, initial CN- concentration, pH, temperature, resin dosage, agitation speed, and particle size distribution on the removal of CN- were examined. The adsorption equilibrium data fitted the Langmuir isotherm very well. The maximum CN- adsorption capacity of Purolite A-250 was found to be 44 mg CN- g(-1) resin. More than 90% CN- adsorption was achieved for most CN- solutions (50, 100, and 200 mg CN- L(-1)) with a resin dose of 2 g L(-1). The equilibrium time was ~20 min, optimum pH was 10.0-10.5, and optimum agitation speed was 150 rpm. An increase in adsorption of CN- with increasing resin dosage was observed. Adsorption of CN- by the resin was marginally affected (maximum 4% variation) within an environmentally relevant temperature range of 20-50 degrees C. Fixed-bed column (20.5 mm internal diameters) experiments were performed to investigate the effects of resin bed depth and influent flow rate on breakthrough behaviour. Breakthrough occurred in 5 min for 0.60 cm bed depth while it was 340 min for 5.40 cm bed depth. Adsorption capacity was 25.5 mg CN- g(-1) for 5 mL min(-1) flow rate and 3.9 mg CN- g(-1) for 20 mL min(-1) flow rate. The research has established that the resin can be effectively used for CN- removal from aqueous solutions. PMID- 25558874 TI - Electrochemical biosensors for hormone analyses. AB - Electrochemical biosensors have a unique place in determination of hormones due to simplicity, sensitivity, portability and ease of operation. Unlike chromatographic techniques, electrochemical techniques used do not require pre treatment. Electrochemical biosensors are based on amperometric, potentiometric, impedimetric, and conductometric principle. Amperometric technique is a commonly used one. Although electrochemical biosensors offer a great selectivity and sensitivity for early clinical analysis, the poor reproducible results, difficult regeneration steps remain primary challenges to the commercialization of these biosensors. This review summarizes electrochemical (amperometric, potentiometric, impedimetric and conductometric) biosensors for hormone detection for the first time in the literature. After a brief description of the hormones, the immobilization steps and analytical performance of these biosensors are summarized. Linear ranges, LODs, reproducibilities, regenerations of developed biosensors are compared. Future outlooks in this area are also discussed. PMID- 25558869 TI - A low-cost and simple paper-based microfluidic device for simultaneous multiplex determination of different types of chemical contaminants in food. AB - It is difficult to carry out multiple detection of different type of chemicals because of the different chemical microenvironment requirements. Herein, a low cost and simple paper-based microfluidic device integrated with fluorescence labeled single-stranded DNA (ssDNA) functionalized graphene oxide sensor was developed for the multiplex determination of different types of chemical contaminants in food. In this work, Cy5 labeled corresponding functional ssDNA for different analytes associated with graphene oxide (ssDNA-GO) were employed as core detection sensors to sensitively report the presence of the different type of chemicals as well as enlarge the chemical compatibility, which made it possible to simultaneous detect multiple chemicals under a same chemical microenvironment. Paper microfluidic device can be easily fabricated and paper substrate also facilitated the integration of ssDNA-GO sensors via physical absorption. This device has been successfully applied in multiplex detection of heavy metal mercury (II) ion (Hg(2+)) and silver (I) ion (Ag(+)) and aminoglycoside antibiotics residues in food. It also provided enormous potential for applications of environmental monitoring and clinical diagnosis. PMID- 25558870 TI - A simple and sensitive fluorescent sensor for methyl parathion based on L tyrosine methyl ester functionalized carbon dots. AB - In this paper, a simple and sensitive fluorescent sensor for methyl parathion is developed based on L-tyrosine methyl ester functionalized carbon dots (Tyr-CDs) and tyrosinase system. The carbon dots are obtained by simple hydrothermal reaction using citric acid as carbon resource and L-tyrosine methyl ester as modification reagent. The carbon dots are characterized by transmission electron microscope, high resolution transmission electron microscopy, X-ray diffraction spectrum, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The carbon dots show strong and stable photoluminescence with a quantum yield of 3.8%. Tyrosinase can catalyze the oxidation of tyrosine methyl ester on the surface of carbon dots to corresponding quinone products, which can quench the fluorescence of carbon dots. When organophosphorus pesticides (OPs) are introduced in system, they can decrease the enzyme activity, thus decrease the fluorescence quenching rate. Methyl parathion, as a model of OPs, was detected. Experimental results show that the enzyme inhibition rate is proportional to the logarithm of the methyl parathion concentration in the range 1.0*10(-10)-1.0*10(-4) M with the detection limit (S/N=3) of 4.8*10(-11) M. This determination method shows a low detection limit, wide linear range, good selectivity and high reproducibility. This sensing system has been successfully used for the analysis of cabbage, milk and fruit juice samples. PMID- 25558871 TI - Carbon dot cluster as an efficient "off-on" fluorescent probe to detect Au(III) and glutathione. AB - In this paper, we reported for the first time that Au(III) decorated carbon dot cluster (Au(III)/CDC) was synthesized to detect glutathione through fluorescence "off-on" approach. The "off" process was realized by the introduction of Au(III) on luminescent carbon dots (CDs), which formed the complex of Au(III)/CDC and quenched the fluorescence of CDs efficiently. This "off" process was used to detect Au(III) with the selectivity among 21 metal ions and the limitation was 0.48 MUM (S/N=3). Au(III) could be removed from the complex by biothiol in the solution, which restored the fluorescence of CDC to achieve the "on" process. This process was selective for biothiols (especially for glutathione) among saccharides, dopamine and amino acids and the limit of detection was 2.02 MUM (S/N=3). Due to the dependence of the fluorescence restoration on the concentration of glutathione, Au(III)/CDC was applied as the fluorescence sensor for detection of glutathione in the solution and cellular cytosol. By referring to the fluorescence change in the solution, the intracellular glutathione with/without oxygen stress was evaluated. As compared with the commercial assay, our Au(III)/CDC based assay was simple, facile and low cost, which would be useful to measure intracellular glutathione at different cellular states. PMID- 25558876 TI - Peeling lead paint turns into poisonous dust. Guess where it ends up? A media campaign to prevent childhood lead poisoning in New York City. AB - Successful public health media campaigns promote messages, increase awareness, engage the public, and encourage behavior change. Between 2004 and 2006, the Lead Poisoning Prevention Program of the New York City Department of Health and Mental Hygiene conducted a media campaign grounded in social learning theory and the social marketing model to increase parents' awareness of childhood lead poisoning, ways to protect their children, and property owners' legal responsibility to fix peeling lead paint safely, and increase awareness of regulatory changes and encourage enforcement of New York City's Local Law 1 of 2004. Campaign materials were focus group tested and the campaign was refined annually. The campaign ran city-wide and in targeted high-risk neighborhoods. Neighborhoods and media venue (bus, train, kiosk, and store) changed annually, based on population risk factors and venue availability. Exposure to the campaign, campaign-related knowledge, and behavior were assessed using pre- and postcampaign street intercept surveys. Results showed that campaign reached the targeted population, and had an impact on knowledge of lead poisoning prevention measures as evidenced by increased knowledge of lead paint exposures sources in one year and increased knowledge of preventive behaviors in another year; these improvements were observed for both genders and most ethnic, primary language, educational attainment, and age groups in each year. Lessons learned indicate that well-targeted media campaigns, designed with audience participation, can reach parents through various venues, and improve key knowledge areas. Evaluation challenges faced include high levels of knowledge at baseline, competing media messages, and balancing between program needs and evaluation design. PMID- 25558880 TI - Molecular insights into the role of aqueous trehalose solution on temperature induced protein denaturation. AB - To investigate the underlying mechanism by which trehalose acts as a bioprotectant against thermal denaturation of protein in aqueous solution, we carry out classical molecular dynamics simulations at two different temperatures. Though it is widely accepted that trehalose acts as an antidote against such protein structural destabilization and numerous hypotheses have been proposed in regard to its mechanism of stabilization, there is still no definitive generally accepted answer to this question and it remains a subject of active research. In view of this, in this article we report the thermal denaturation process of a 15 residue S-peptide analogue at 360 K temperature and the counteracting ability of trehalose of varying concentrations at that temperature. In order to verify the conformational stability of the peptide at ambient temperature condition, we also carry out a separate simulation of peptide-water binary system at 300 K temperature. The goal is to provide a molecular level understanding of how trehalose protects protein at elevated temperature. The Calpha-rmsd calculation shows that in pure water, the peptide is stable at 300 K temperature and its unfolding is observed at 360 K. However, in peptide-water-trehalose ternary system, the value of Calpha-rmsd decreases as trehalose concentration is increased. Remarkably, at the highest trehalose concentration considered in this study, the value of Calpha-rmsd at 360 K is similar to that of water-peptide binary system at 300 K temperature. Further, the calculations of radius of gyration of Calpha-atoms and helical percentage of the peptide residues support the above observations. The total number of hydrogen bonds formed by the peptide with solution species (trehalose and water) remains constant, though the peptide water hydrogen bond decreases and peptide trehalose hydrogen bond increases with increasing trehalose concentration. This finding suggests replacement of water molecules by trehalose molecules and supports water replacement hypothesis. The calculations of preferential interaction parameter show that at the peptide surface, trehalose molecules are slightly more preferred over water and for the most concentrated solutions, a prominent exclusion of water and enrichment of trehalose molecules is observed. Also observed are (i) trehalose-induced second shell collapse of water structure, (ii) the growth of trehalose cluster as concentration is increased, and (iii) trehalose-induced slowing down of the translational motion of both water and trehalose, the effect being more pronounced for the latter. Implications of these results for counteracting mechanism of trehalose are discussed. PMID- 25558872 TI - A whole-cell electrochemical biosensing system based on bacterial inward electron flow for fumarate quantification. AB - Fumarate is of great importance as it is an oncometabolite as well as food spoilage indicator. However, cost-effective and fast quantification method for fumarate is lacking although it is urgently required. This work developed an electrochemical whole-cell biosensing system for fumarate quantification. A sensitive inwards electric output (electron flow from electrode into bacteria) responded to fumarate in Shewanella oneidensis MR-1 was characterized, and an electrochemical fumarate biosensing system was developed without genetic engineering. The biosensing system delivered symmetric current peak immediately upon fumarate addition, where the peak area increased in proportion to the increasing fumarate concentration with a wide range of 2 MUM-10 mM (R(2)=0.9997). The limit of detection (LOD) and the limit of quantification (LOQ) are 0.83 MUM and 1.2 MUM, respectively. This biosensing system displayed remarkable specificity to fumarate against other possible interferences. It was also successfully applied to samples of apple juice and kidney tissue. This study added new dimension to electrochemical biosensor design, and provide a simple, cost-effective, fast and robust tool for fumarate quantification. PMID- 25558884 TI - Formal synthesis of (+/-)-galanthamine and (+/-)-lycoramine using Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-ene-vinylcyclopropane and CO. AB - An efficient strategy using Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-ene vinylcyclopropane and CO as a key step to build the cis-hydrodibenzofuran skeleton has been developed and applied for the formal synthesis of (+/-) galanthamine and (+/-)-lycoramine. PMID- 25558878 TI - Myc-interacting zinc-finger protein 1 positively regulates Wnt signalling by protecting Dishevelled from Dapper1-mediated degradation. AB - Wnt signalling regulates embryonic development and tissue homoeostasis by modulating cell proliferation, differentiation and migration. Dapper1 (Dpr1) has been shown to be an important key negative regulator of Wnt signalling by promoting Dishevelled (Dvl) degradation. In the present study, we found that Myc interacting zinc-finger protein 1 (MIZ1) interacts with Dpr1 and this interaction attenuates the ability of Dpr1 to induce Dvl2 degradation, thus enhancing Wnt signalling. Mechanistically, MIZ1 is translocated from the nucleus to the cytoplasm upon Wnt3a stimulation or overexpression of Dpr1 and Dvl2, disrupting the interaction between Dpr1 and Dvl2. Furthermore, MIZ1 can promote the proliferation of breast cancer MDA-MB-231 and BT-549 cells through Wnt signalling and reverse the anti-proliferative effect of Dpr1 on colorectal cancer Caco-2. Together, our findings establish a novel layer of Wnt signalling regulation via the MIZ1-Dpr1-Dvl axis. PMID- 25558873 TI - Single electrode biosensor for simultaneous determination of interferon gamma and lysozyme. AB - Simultaneous detection of multiple biomarkers holds great promise for acute leukemia evaluation. Here, a novel biosensor is developed for simultaneous electrochemical detection of interferon gamma (IFN-gamma) and lysozyme (Lys) based on aptamer recognition by coupling "signal-on" and "signal-off" modes. On one Au electrode, two kinds of signaling probes labeled by the thiolated ferrocene (Fc)- and methy blue (MB)- were designed to hybridize with IFN-gamma and Lys aptamers respectively to form partial complementary DNA duplexes. In the presence of IFN-gamma and Lys, the target-aptamer interaction led to the release of aptamer from duplex DNA structure. The single-stranded signaling probes thus suffered from the conformation changes, which resulted in the decreased (or increased) oxidation peak current of Fc (or MB) according to the "signal-off (or signal-on)" mode. Electrodes were characterized using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Under the optimized conditions, the signal changes were quantified using square wave voltammetry (SWV). This proposed biosensor for IFN-gamma and Lys possessed linear detection range from 0.01 to 10 nM and 0.1 to 100 nM, with the detection limits of 1.14*10(-3) nM and 0.0164 nM, respectively. Moreover, this biosensor was readily regenerated and proved successful toward the practical analysis. The proposed strategy could provide more integrated and reliable information for acute leukemia evaluation. PMID- 25558883 TI - Measurement and modeling of CO2 solubility in natural and synthetic formation brines for CO2 sequestration. AB - CO2 solubility data in the natural formation brine, synthetic formation brine, and synthetic NaCl+CaCl2 brine were collected at the pressures from 100 to 200 bar, temperatures from 323 to 423 K. Experimental results demonstrate that the CO2 solubility in the synthetic formation brines can be reliably represented by that in the synthetic NaCl+CaCl2 brines. We extended our previously developed model (PSUCO2) to calculate CO2 solubility in aqueous mixed-salt solution by using the additivity rule of the Setschenow coefficients of the individual ions (Na(+), Ca(2+), Mg(2+), K(+), Cl(-), and SO4(2-)). Comparisons with previously published models against the experimental data reveal a clear improvement of the proposed PSUCO2 model. Additionally, the path of the maximum gradient of the CO2 solubility contours divides the P-T diagram into two distinct regions: in Region I, the CO2 solubility in the aqueous phase decreases monotonically in response to increased temperature; in region II, the behavior of the CO2 solubility is the opposite of that in Region I as the temperature increases. PMID- 25558875 TI - HyDA-Vista: towards optimal guided selection of k-mer size for sequence assembly. AB - MOTIVATION: Intimately tied to assembly quality is the complexity of the de Bruijn graph built by the assembler. Thus, there have been many paradigms developed to decrease the complexity of the de Bruijn graph. One obvious combinatorial paradigm for this is to allow the value of k to vary; having a larger value of k where the graph is more complex and a smaller value of k where the graph would likely contain fewer spurious edges and vertices. One open problem that affects the practicality of this method is how to predict the value of k prior to building the de Bruijn graph. We show that optimal values of k can be predicted prior to assembly by using the information contained in a phylogenetically-close genome and therefore, help make the use of multiple values of k practical for genome assembly. RESULTS: We present HyDA-Vista, which is a genome assembler that uses homology information to choose a value of k for each read prior to the de Bruijn graph construction. The chosen k is optimal if there are no sequencing errors and the coverage is sufficient. Fundamental to our method is the construction of the maximal sequence landscape, which is a data structure that stores for each position in the input string, the largest repeated substring containing that position. In particular, we show the maximal sequence landscape can be constructed in O(n+n log n)-time and O(n)-space. HyDA-Vista first constructs the maximal sequence landscape for a homologous genome. The reads are then aligned to this reference genome, and values of k are assigned to each read using the maximal sequence landscape and the alignments. Eventually, all the reads are assembled by an iterative de Bruijn graph construction method. Our results and comparison to other assemblers demonstrate that HyDA-Vista achieves the best assembly of E. coli before repeat resolution or scaffolding. AVAILABILITY: HyDA-Vista is freely available 1. The code for constructing the maximal sequence landscape and choosing the optimal value of k for each read is also separately available on the website and could be incorporated into any genome assembler. PMID- 25558888 TI - The experience of traumatic brain injury in Botswana. AB - Whilst the consequences of traumatic brain injury (TBI) are understood in Western countries, it is not known how cultural background and beliefs affect response and outcome following TBI in low and middle income countries. This study aimed to explore the experiences of TBI in Botswana. Participants included 21 individuals with moderate to severe TBI (68% males, mean age 35.2 years), 18 caregivers and 25 healthcare workers. Qualitative semi-structured interviews were transcribed, translated and thematically coded. Thematic analysis indicated several themes: Injury-related changes, attributions and beliefs about the cause of the injury, family reactions, attitudes, and resources. Participants described the common injury-related effects of TBI. Many participants attributed their injury to supernatural causes. Immediate family members of participants with TBI expressed a sense of love and devotion towards the injured person. Communication was characterised by inadequate information given to those injured and their caregivers. Provision of care was impeded by insufficient staff, limited supplies and lack of training of nurses. The current healthcare system would therefore appear to be ill-equipped to meet the needs of TBI survivors in Botswana. This study will improve understanding of cultural responses and approaches to brain injuries in Botswana which may, in turn, inform improved practice. PMID- 25558887 TI - A simple approach to the synthesis of BCN graphene with high capacitance. AB - Boron and nitrogen co-doped graphene (BCN graphene) was prepared through a simple thermal annealing approach in the presence of a single compound, melamine diborate. The as-prepared samples were characterized by scanning electron microscopy, transmission electron microscopy, x-ray photoelectron spectroscopy, Raman spectra and electrochemical techniques. The BCN graphene shows significantly enhanced specific capacitance due to boron and nitrogen co-doping, which permits higher overall doping levels. PMID- 25558882 TI - Molecular origin of enhanced proton conductivity in anhydrous ionic systems. AB - Ionic systems with enhanced proton conductivity are widely viewed as promising electrolytes in fuel cells and batteries. Nevertheless, a major challenge toward their commercial applications is determination of the factors controlling the fast proton hopping in anhydrous conditions. To address this issue, we have studied novel proton-conducting materials formed via a chemical reaction of lidocaine base with a series of acids characterized by a various number of proton active sites. From ambient and high pressure experimental data, we have found that there are fundamental differences in the conducting properties of the examined salts. On the other hand, DFT calculations revealed that the internal proton hopping within the cation structure strongly affects the pathways of mobility of the charge carrier. These findings offer a fresh look on the Grotthuss-type mechanism in protic ionic glasses as well as provide new ideas for the design of anhydrous materials with exceptionally high proton conductivity. PMID- 25558881 TI - Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles. AB - There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within N palmitoyl-N-methyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index. PMID- 25558886 TI - DataWarrior: an open-source program for chemistry aware data visualization and analysis. AB - Drug discovery projects in the pharmaceutical industry accumulate thousands of chemical structures and ten-thousands of data points from a dozen or more biological and pharmacological assays. A sufficient interpretation of the data requires understanding, which molecular families are present, which structural motifs correlate with measured properties, and which tiny structural changes cause large property changes. Data visualization and analysis software with sufficient chemical intelligence to support chemists in this task is rare. In an attempt to contribute to filling the gap, we released our in-house developed chemistry aware data analysis program DataWarrior for free public use. This paper gives an overview of DataWarrior's functionality and architecture. Exemplarily, a new unsupervised, 2-dimensional scaling algorithm is presented, which employs vector-based or nonvector-based descriptors to visualize the chemical or pharmacophore space of even large data sets. DataWarrior uses this method to interactively explore chemical space, activity landscapes, and activity cliffs. PMID- 25558885 TI - Novel poly(tetramethylene ether)glycol and poly(epsilon-caprolactone) based dynamic network via quadruple hydrogen bonding with triple-shape effect and self healing capacity. AB - A novel dynamic network was successfully prepared via self-complementary quadruple hydrogen bonding through Upy-telechelic poly(tetremethylene ether) glycol (PTMEG) and four-arm star-shaped poly(epsilon-caprolactone) ((4)PCL) precursors. The structure and the dynamic feature were identified by FT-IR and (1)H NMR. The differential scanning calorimetry (DSC) analysis indicated that the crystalline PCL and PTMEG segments show a separated melting peak, and the aggregation of Upy dimer was also observed. The dynamic mechanical analyzer (DMA) test reveals that the storage modulus of the network drops evidently across the thermal transition. These characteristics of the network ensure that it exhibits a triple-shape effect, and the composition of the network influences the performance of shape memory effect. The variation of the fixing ratio of the network in each deformation step is quite according to the crystallinity of the dominant segment. The reversibility of the quadruple hydrogen bonding between Upy dimer endues the network with self-healing capacity, and the damage and healing test of the network revealed that increasing the content of the PTMEG segment will be of benefit to self-healing performance. PMID- 25558879 TI - Tobacco may mask poorer episodic memory among young adult cannabis users. AB - OBJECTIVE: Co-occurring cannabis and tobacco use has become increasingly prevalent among young adults, but it is not clear how tobacco use may alter the neurocognitive profile typically observed among cannabis users. Although there is substantial evidence citing cannabis and tobacco's individual effect on episodic memory and related brain structures, few studies have examined the effect of combined cannabis and tobacco use on memory. METHOD: This investigation examined relationships between amount of past year cannabis and tobacco use on 4 different indices of episodic memory among a sample of young adults who identified cannabis as their drug of choice. RESULTS: Results indicated that more cannabis use was linked with poorer initial acquisition, total learning, and delayed recall on the Hopkins Verbal Learning Test-Revised, but only among cannabis users who sporadically smoked cigarettes in the past year. Conversely, the amount of past year cannabis use was not associated with episodic memory performance among individuals who more consistently smoked cigarettes in the past year. These differences could not be explained by several relevant potential confounds. CONCLUSIONS: These findings provide important insight into a potential mechanism (i.e., attenuation of cognitive decrements) that might reinforce use of both substances and hamper cessation attempts among cannabis users who also smoke cigarettes. Ongoing and future research will help to better understand how co-use of cannabis and tobacco affects memory during acute intoxication and abstinence and the stability of these associations over time. PMID- 25558891 TI - Electronic interaction between nitrogen atoms in doped graphene. AB - Many potential applications of graphene require either the possibility of tuning its electronic structure or the addition of reactive sites on its chemically inert basal plane. Among the various strategies proposed to reach these objectives, nitrogen doping, i.e., the incorporation of nitrogen atoms in the carbon lattice, leads in most cases to a globally n-doped material and to the presence of various types of point defects. In this context, the interactions between chemical dopants in graphene have important consequences on the electronic properties of the systems and cannot be neglected when interpreting spectroscopic data or setting up devices. In this report, the structural and electronic properties of complex doping sites in nitrogen-doped graphene have been investigated by means of scanning tunneling microscopy and spectroscopy, supported by density functional theory and tight-binding calculations. In particular, based on combined experimental and simulation works, we have systematically studied the electronic fingerprints of complex doping configurations made of pairs of substitutional nitrogen atoms. Localized bonding states are observed between the Dirac point and the Fermi level in contrast with the unoccupied state associated with single substitutional N atoms. For pyridinic nitrogen sites (i.e., the combination of N atoms with vacancies), a resonant state is observed close to the Dirac energy. This insight into the modifications of electronic structure induced by nitrogen doping in graphene provides us with a fair understanding of complex doping configurations in graphene, as it appears in real samples. PMID- 25558889 TI - Chickenpox infection during lactation. PMID- 25558893 TI - The international clinical practice guideline for prevention and treatment of pressure ulcers/injuries. PMID- 25558877 TI - Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease. AB - Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program. PMID- 25558894 TI - Radiological comparison of laser-microtextured and platform-switched implants in thin mucosal biotype. AB - OBJECTIVE: To compare how laser-microtextured implants and implants with platform switching maintain crestal bone stability in thin peri-implant tissues. MATERIAL AND METHODS: Thirty laser-microtextured implants of 4.6 mm diameter (Tapered Internal Laser-Lok, BioHorizons, Birmingham, AL, USA; Group 1) and 30 implants with platform switching of 5/4 mm diameter (Certain Prevail; Biomet/3i, Palm Beach Gardens, FL, USA; Group 2) were placed in 30 patients (12 males and 18 females, mean age 42.3 +/- 2.4) with thin mucosal tissues (<=2 mm). Implants were placed in posterior mandible in one-stage approach and after integration were restored with screw-retained metal-ceramic restorations. Radiographic examination was performed after implant placement, 2 months after healing, at prosthetic restoration delivery and after 1-year follow-up. Mean crestal bone loss was calculated, Mann-Whitney U-test was applied, and significance was set to 0.05. RESULTS: After 2 months of healing, the crestal bone loss was 0.71 +/- 0.25 mm SD (range, 0.25-1.6 mm) and 1.02 +/- 0.25 mm SD (range, 0.6-1.55 mm) in groups 1 and 2, respectively (P = 0.001). At restorations' delivery, the crestal bone loss was 1.10 +/- 0.30 mm SD (range, 0.65-1.85 mm) and 1.37 +/- 0.27 mm SD (range, 0.90 1.80 mm) in groups 1 and 2, respectively (P = 0.001). After 1-year follow-up, the crestal bone loss was 1.41 +/- 0.42 mm SD (range, +0.1-2.30 mm) and 1.43 +/- 0.23 mm SD (range, 1-1.80 mm) in groups 1 and 2, respectively (P = 0.976). CONCLUSIONS: Laser-microtexturing of implant collar or platform-switched implant/abutment connection did not eliminate crestal bone loss, if at the time of implant placement vertical soft tissue thickness was <=2 mm. However, laser microtextured implants may present less proximal bone loss than platform switching implants in the period before implant loading. PMID- 25558892 TI - Successive and cyclic oral contraceptive pill pretreatment improves IVF/ICSI outcomes of PCOS patients and ameliorates hyperandrogenism and antral follicle excess. AB - OBJECTIVES: To evaluate different oral contraceptive pill (OCP) pretreatment associated differential in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes of polycystic ovary syndrome (PCOS) patients and explore enhanced hormonal balance induced by the pretreatment. METHODS: This retrospective study included 500 PCOS women and 565 normal ovulating counterparts undergoing IVF/ICSI. The PCOS patients were divided into three groups based on the OCP pretreatment regimens: non-OCP (without OCP pretreatment), unsuccessive OCP (the period of successive pretreatment <=2 months) and successive OCP (the period of successive pretreatment >=3 months) groups. Comprehensive hormonal and ultra-sonographic assessments were performed before/after IVF pretreatment. Confounding factors affecting pregnancy outcomes were analyzed with logistic regression. RESULTS: PCOS patients with significant endocrine disorders had reduced implantation and pregnancy rates and increased miscarriage rate. Successive, not unsuccessive OCP pretreatment, significantly improved the implantation and pregnancy rates, and reduced the incidence of monotocous small for-gestational age infants, which was accompanied by remarkably decreased hyperandrogenism and antral follicles. CONCLUSION: PCOS is an independent risk factor for poor IVF outcome. Successive, not unsuccessive, OCP cyclical pretreatment could improve pregnancy outcome of PCOS patients, associated with reduction of hyperandrogenism and antral follicle excess. PMID- 25558897 TI - Contemporary multilevel analysis of the effectiveness of water fluoridation in Australia. AB - AIMS: Water fluoridation was extended in Queensland, Australia, across 2009-2011. A research program was commenced to inform the rationale for and the outcome of this program, to estimate the effectiveness of water fluoridation in preventing caries and to predict changes in caries experience as a result of the extension of fluoridation. METHODS: Queensland children were selected through a stratified random sample selection in 2010-2012. Oral epidemiological examinations provided individual-level outcomes for decayed, missing or filled primary or permanent tooth surfaces: dmfs (among 5-8-year-olds) and DMFS (9-14-year-olds). Explanatory factors at the individual-level, school-level and area-level fluoridation status were derived. Data were weighted to represent the population. Three-level multilevel multivariable models were sequentially specified for negative binomial distribution of dmfs/DMFS to estimate rate ratios (RR). The effectiveness of area level water fluoridation was evaluated in the full models controlling for other factors. RESULTS: Data from 2,214 5-8 year-olds and 3,186 9-14 year-olds from 207 schools in 16 areas were analysed. Queensland's average dmfs was 4.23 and DMFS 1.47. The lowest levels of dental caries were observed in long-term fluoridated Townsville. In the full models, Townsville children had significantly lower caries experience (RR for dmfs: 0.61 (95%CI: 0.44-0.82); RR for DMFS 0.60 (95%CI: 0.42-0.88)) compared with children in non-fluoridated areas. CONCLUSION: Comparison of caries experience of children at the time of the extension of water fluoridation supported the rationale for this population health measure. PMID- 25558900 TI - Effects of dietary electrolyte balance and addition of electrolyte-betaine supplements in feed or water on performance, acid-base balance and water retention in heat-stressed broilers. AB - The effects of dietary electrolyte balance (DEB) and electrolyte-betaine (El-Be) supplements on heat-stressed broiler performance, acid-base balance and water retention were evaluated during the period 31-40 d of age in a 2 * 3 factorial arrangement of treatments. A total of 240 broilers were assigned to 6 treatment groups each with 8 replicates of 5 birds per cage and were exposed to cyclic high temperature (32 - 24 +/- 1 degrees C). Birds were provided with diets having DEB of either 180 or 220 mEq/kg. El-Be supplements were either added to the diet, water or not added to either of them to complete the array of 6 treatment groups. An additional 80 birds were kept at thermoneutral temperature (20 +/- 1 degrees C) and were provided with tap water and diets with DEB of either 180 or 220 mEq/kg to serve as negative controls. Exposure to high temperature depressed growth performance, increased rectal temperature and decreased potassium (K(+)) retention. In high-temperature room, birds fed on diets with DEB of 220 mEq/kg tended to increase BW from 35-40 d of age. However, at thermoneutral temperature, broilers fed on diets with DEB of 220 mEq/kg increased K(+) retention. Adding El Be supplements in feed or water improved feed conversion ratio (FCR), enhanced water consumption and increased K(+) and sodium (Na(+)) retention. Interactions between DEB and El-Be supplements tended to affect body weight gain and FCR during the periods 35-40 and 31-40 d of age, respectively. It is suggested that when using a diet with DEB of 180 mEq/kg, adding the El-Be supplements in drinking water was more beneficial than in feed. Adding the supplements in feed or water was equally useful when using DEB of 220 mEq/kg. PMID- 25558895 TI - Sleep-like behavior and 24-h rhythm disruption in the Tc1 mouse model of Down syndrome. AB - Down syndrome is a common disorder associated with intellectual disability in humans. Among a variety of severe health problems, patients with Down syndrome exhibit disrupted sleep and abnormal 24-h rest/activity patterns. The transchromosomic mouse model of Down syndrome, Tc1, is a trans-species mouse model for Down syndrome, carrying most of human chromosome 21 in addition to the normal complement of mouse chromosomes and expresses many of the phenotypes characteristic of Down syndrome. To date, however, sleep and circadian rhythms have not been characterized in Tc1 mice. Using both circadian wheel-running analysis and video-based sleep scoring, we showed that these mice exhibited fragmented patterns of sleep-like behaviour during the light phase of a 12:12-h light/dark (LD) cycle with an extended period of continuous wakefulness at the beginning of the dark phase. Moreover, an acute light pulse during night-time was less effective in inducing sleep-like behaviour in Tc1 animals than in wild-type controls. In wheel-running analysis, free running in constant light (LL) or constant darkness (DD) showed no changes in the circadian period of Tc1 animals although they did express subtle behavioural differences including a reduction in total distance travelled on the wheel and differences in the acrophase of activity in LD and in DD. Our data confirm that Tc1 mice express sleep-related phenotypes that are comparable with those seen in Down syndrome patients with moderate disruptions in rest/activity patterns and hyperactive episodes, while circadian period under constant lighting conditions is essentially unaffected. PMID- 25558903 TI - Urinary incontinence in women comes and goes, and reasons remain elusive. PMID- 25558902 TI - Intermittent Pneumatic Compression and Bone Mineral Density: An Exploratory Study. AB - CONTEXT: Intermittent pneumatic compression (IPC) is a common therapeutic modality used to reduce swelling after trauma and prevent thrombosis due to postsurgical immobilization. Limited evidence suggests that IPC may decrease the time needed to rehabilitate skeletal fractures and increase bone remodeling. OBJECTIVE: To establish feasibility and explore the novel use of a common therapeutic modality, IPC, on bone mineral density (BMD) at the hip of noninjured volunteers. DESIGN: Within-subjects intervention. SETTING: University research laboratory. PARTICIPANTS: Noninjured participants (3 male, 6 female) completed IPC treatment on 1 leg 1 h/d, 5 d/wk for 10 wk. Pressure was set to 60 mm Hg when using the PresSsion and Flowtron Hydroven compression units. MAIN OUTCOME MEASURES: Dual-energy X-ray absorptiometry was used to assess BMD of the hip in treated and nontreated legs before and after the intervention. Anthropometrics, regular physical activity, and nutrient intake were also assessed. RESULTS: The average number of completed intervention sessions was 43.4 (+/- 3.8) at an average duration of 9.6 (+/- 0.8) wk. Repeated-measures analysis of variance indicated a significant time-by-treatment effect at the femoral neck (P = .023), trochanter (P = .027), and total hip (P = .008). On average, the treated hip increased 0.5-1.0%, while the nontreated hip displayed a 0.7-1.9% decrease, depending on the bone site. CONCLUSION: Results of this exploratory investigation suggest that IPC is a therapeutic modality that is safe and feasible for further investigation on its novel use in optimizing bone health. PMID- 25558898 TI - Evolution of phenotypic plasticity in colonizing species. AB - I elaborate an hypothesis to explain inconsistent empirical findings comparing phenotypic plasticity in colonizing populations or species with plasticity from their native or ancestral range. Quantitative genetic theory on the evolution of plasticity reveals that colonization of a novel environment can cause a transient increase in plasticity: a rapid initial increase in plasticity accelerates evolution of a new optimal phenotype, followed by slow genetic assimilation of the new phenotype and reduction of plasticity. An association of colonization with increased plasticity depends on the difference in the optimal phenotype between ancestral and colonized environments, the difference in mean, variance and predictability of the environment, the cost of plasticity, and the time elapsed since colonization. The relative importance of these parameters depends on whether a phenotypic character develops by one-shot plasticity to a constant adult phenotype or by labile plasticity involving continuous and reversible development throughout adult life. PMID- 25558899 TI - A national survey of defensive medicine among orthopaedic surgeons, trauma surgeons and radiologists in Austria: evaluation of prevalence and context. AB - RATIONALE, AIMS AND OBJECTIVES: Defensive medical practice represents an increasing concern in European countries and is reported to account for rising health care expenditures. Malpractice liability, current jurisdiction and the increasing claim for accountability appear to result in additional diagnostic requests with marginal clinical benefit. Investigations that evaluate the national Austrian prevalence and contextual principles and consequences of defensive medicine are lacking so far. METHOD: Orthopaedic and trauma surgeons as well as radiologists from public hospitals in Austria were invited to complete a study questionnaire retrieving personal estimation of the quantity of patient contacts and defensive requests in a typical month, subjective judgement of medico-legal climate, evolving defensive trends, working time usage for defensive considerations and prior confrontations with malpractice liability claims. RESULTS: The prevalence of defensive medicine was found to be 97.7%. The average orthopaedic or trauma surgeon requests 19.6 investigations per month for defensive reasons, which represents 28% of all diagnostic examinations. High quality imaging modalities and short-term admissions yield increasing defensive significance. Participants are confronted with 1.4 liability claims per month. During the treatment of high-risk patients, 81% of doctors request additional diagnostic procedures for defensive considerations. Expenditure of time for defensive practice amounts to 9.2 hours/month in radiology and to 17 and 18% of total working time, respectively, in orthopaedic and trauma surgery. CONCLUSION: Defensive medical practice represents a serious and common challenge in Austria. Our results indicate the urgent necessity for confrontation with and solution for the increasing effort of self-protection within the health care system. PMID- 25558896 TI - Gender-typing of leadership: evaluations of real and ideal managers. AB - This research focuses on female underrepresentation in managerial positions. Specifically, two studies examine gender-typing for managerial roles in Spain using ratings for real and ideal managers. In addition, we analyse the existence of same-gender bias on evaluations of the behavior of actual leaders. In the first study, 195 Spanish workers evaluate the extent to which gender stereotypical traits are important for becoming a successful middle manager in three conditions (female managers, male managers, and managers in general). In the second study, we explore the degree to which the behavior of real Spanish managers is gender-typed and the existence of same-gender bias on leadership styles - transformational, transactional and avoidant/passive - and on leadership outcomes - effectiveness, extra effort and satisfaction - from the perspective of subordinates (N = 605). Overall, the results demonstrate that masculine characteristics were rated as more important than feminine characteristics for managerial positions, and they were more often assigned to male managers than to female managers. Unexpectedly, this manager-male association is stronger among female participants than among male participants. Our findings also demonstrate that women subordinates evaluate their same-sex supervisors more favorably in transformational leadership, effectiveness, and extra effort. The negative consequences derived from gender-typing managerial positions are highlighted according to the role congruity theory of prejudice toward female leaders. The positive effects of in-group female bias on behavior ratings are also noted. The mixed implications of these results for women's advancement to leadership positions are discussed. PMID- 25558910 TI - Erratum to Significance of the lymph nodes in the 7th station in rational dissection for metastasis of distal gastric cancer with different T categories. AB - [This corrects the article on p. 423 in vol. 26, PMID: 25232215.]. PMID- 25558906 TI - Energy balance of triathletes during an ultra-endurance event. AB - The nutritional strategy during an ultra-endurance triathlon (UET) is one of the main concerns of athletes competing in such events. The purpose of this study is to provide a proper characterization of the energy and fluid intake during real competition in male triathletes during a complete UET and to estimate the energy expenditure (EE) and the fluid balance through the race. METHODS: Eleven triathletes performed a UET. All food and drinks ingested during the race were weighed and recorded in order to assess the energy intake (EI) during the race. The EE was estimated from heart rate (HR) recordings during the race, using the individual HR-oxygen uptake (Vo2) regressions developed from three incremental tests on the 50-m swimming pool, cycle ergometer, and running treadmill. Additionally, body mass (BM), total body water (TBW) and intracellular (ICW) and extracellular water (ECW) were assessed before and after the race using a multifrequency bioimpedance device (BIA). RESULTS: Mean competition time and HR was 755 +/- 69 min and 137 +/- 6 beats/min, respectively. Mean EI was 3643 +/- 1219 kcal and the estimated EE was 11,009 +/- 664 kcal. Consequently, athletes showed an energy deficit of 7365 +/- 1286 kcal (66.9% +/- 11.7%). BM decreased significantly after the race and significant losses of TBW were found. Such losses were more related to a reduction of extracellular fluids than intracellular fluids. CONCLUSIONS: Our results confirm the high energy demands of UET races, which are not compensated by nutrient and fluid intake, resulting in a large energy deficit. PMID- 25558904 TI - Piper and Vismia species from Colombian Amazonia differentially affect cell proliferation of hepatocarcinoma cells. AB - There is an increasing interest to identify plant-derived natural products with antitumor activities. In this work, we have studied the effects of aqueous leaf extracts from Amazonian Vismia and Piper species on human hepatocarcinoma cell toxicity. Results showed that, depending on the cell type, the plants displayed differential effects; thus, Vismia baccifera induced the selective killing of HepG2, while increasing cell growth of PLC-PRF and SK-HEP-1. In contrast, these two last cell lines were sensitive to the toxicity by Piper krukoffii and Piper putumayoense, while the Piperaceae did not affect HepG2 growth. All the extracts induced cytotoxicity to rat hepatoma McA-RH7777, but were innocuous (V. baccifera at concentrations < 75 ug/mL) or even protected cells from basal death (P. putumayoense) in primary cultures of rat hepatocytes. In every case, cytotoxicity was accompanied by an intracellular accumulation of reactive oxygen species (ROS). These results provide evidence for the anticancer activities of the studied plants on specific cell lines and suggest that cell killing could be mediated by ROS, thus involving mechanisms independent of the plants free radical scavenging activities. Results also support the use of these extracts of the Vismia and Piper genera with opposite effects as a model system to study the mechanisms of the antitumoral activity against different types of hepatocarcinoma. PMID- 25558909 TI - Evaluation of riboflavin intakes and status of 20-64-year-old adults in South Korea. AB - A recent Korea National Health and Nutrition Survey indicated inadequate riboflavin intake in Koreans, but there is limited research regarding riboflavin status in South Korea. The purpose of this study was to determine riboflavin intake and status of Korean adults. Three consecutive 24-h food recalls were collected from 412 (145 men and 267 women) healthy adults, aged 20-64 years, living in South Korea and urine samples were collected from 149 subjects of all subjects. The dietary and total (dietary plus supplemental) riboflavin intake was 1.33 +/- 0.34 and 2.87 +/- 6.29 mg/day, respectively. Approximately 28% of the subjects consumed total riboflavin less than the Estimated Average Requirement. Urinary riboflavin excretion was 205.1 +/- 190.1 MUg/g creatinine. Total riboflavin intake was significantly positively correlated to the urinary riboflavin excretion. (r = 0.17171, p = 0.0363). About 11% of the Korean adults had urinary riboflavin <27 MUg/g creatinine indicating a riboflavin deficiency and 21% had low status of riboflavin (27 MUg/g creatinine <= urinary riboflavin < 80 MUg/g creatinine). Thus, one-third of Korean adults in this study had inadequate riboflavin status. In some adults in Korea, consumption of riboflavin rich food sources should be encouraged. PMID- 25558912 TI - ClpB dynamics is driven by its ATPase cycle and regulated by the DnaK system and substrate proteins. AB - The hexameric AAA+ (ATPase associated with various cellular activities) chaperone ClpB reactivates protein aggregates in collaboration with the DnaK system. An intriguing aspect of ClpB function is that the active hexamer is unstable and therefore questions how this chaperone uses multiple rounds of ATP hydrolysis to translocate substrates through its central channel. In the present paper, we report the use of biochemical and fluorescence tools to explore ClpB dynamics under different experimental conditions. The analysis of the chaperone activity and the kinetics of subunit exchange between protein hexamers labelled at different protein domains indicates, in contrast with the current view, that (i) ATP favours assembly and ADP dissociation of the hexameric assembly, (ii) subunit exchange kinetics is at least one order of magnitude slower than the ATP hydrolysis rate, (iii) ClpB dynamics and activity are related processes, and (iv) DnaK and substrate proteins regulate the ATPase activity and dynamics of ClpB. These data suggest that ClpB hexamers remain associated during several ATP hydrolysis events required to partially or completely translocate substrates through the protein central channel, and that ClpB dynamics is tuned by DnaK and substrate proteins. PMID- 25558905 TI - Heart rate variability and cognitive function following a multi-vitamin and mineral supplementation with added guarana (Paullinia cupana). AB - The aim of this study was to assess cognitive performance and heart rate variability (HRV) following the ingestion of either a multi-vitamin-mineral preparation supplemented with 300 mg guarana (Ac); a caffeine supplement (C) or a placebo supplement (Pl). Fifty-six subjects took part in a randomized, double blind crossover design, consisting of three experimental sessions ran on a different day. Cognitive performance was assessed using a go/no-go task and a simple reaction time (SRT) task. HRV was assessed in the time domain (RMSSD) and in the frequency domain (HF) and cognitive tasks were performed before ingestion, 15 min after ingestion and then every 15 min over the course of 3 h. Responses were faster (without change in accuracy) when the go/no-go task was performed between 30 and 90 min after ingestion of Ac (4.6% +/- 0.8%, p < 0.05). No effect was observed on SRT task. A significant decrease in HRV was observed during the first hour under C and Pl, whereas HRV remained stable under Ac. The results suggest that the ingestion of a multi-vitamin-mineral with added guarana improves decision-making performance and is accompanied by a stable autonomic nervous system regulation during the first hour. PMID- 25558913 TI - Nondestructive in situ characterization of molecular structures at the surface and buried interface of silicon-supported low-k dielectric films. AB - As low-k dielectric/copper interconnects continue to scale down in size, the interfaces of low-k dielectric materials will increasingly determine the structure and properties of the materials. We report an in situ nondestructive characterization method to characterize the molecular structure at the surface and buried interface of silicon-supported low-k dielectric thin films using interface sensitive infrared-visible sum frequency generation vibrational spectroscopy (SFG). Film thickness-dependent reflected SFG signals were observed, which were explained by multiple reflections of the input and SFG beams within the low-k film. The effect of multiple reflections on the SFG signal was determined by incorporating thin-film interference into the local field factors at the low-k/air and Si/low-k interfaces. Simulated thickness-dependent SFG spectra were then used to deduce the relative contributions of the low-k/air and low-k/Si interfaces to the detected SFG signal. The nonlinear susceptibilities at each interface, which are directly related to the interfacial molecular structure, were then deduced from the isolated interfacial contributions to the detected SFG signal. The method developed here is general and demonstrates that SFG measurements can be integrated into other modern analytical and microfabrication methods that utilize silicon-based substrates. Therefore, the molecular structure at the surface and buried interface of thin polymer or organic films deposited on silicon substrates can be measured in the same experimental geometry used to measure many optical, electrical, and mechanical properties. PMID- 25558914 TI - Switching the charge state of individual surface atoms at Si(111)-?3 * ?3:B surfaces. AB - We show that each surface atom of heavily boron-doped, (111)-oriented silicon with a ?3 * ?3 reconstruction has electrically switchable two charge states due to the strong electron-lattice coupling at this surface. The structural and electronic properties of the two charge states as well as their energetics are uncovered by employing scanning tunneling microscopy measurements and density functional theory calculations, which reveals that one of the two is a two electron bound state or surface bipolaron. We also execute the single-atom bit operations on individual surface atoms by controlling their charge states while demonstrating implementation of the atomic scale memory at a silicon surface with an unprecedented recording density. PMID- 25558911 TI - Optimization of hydraulic shear parameters and reactor configuration in the aerobic granular sludge process. AB - The hydraulic shear acts as an important selection pressure in aerobic sludge granulation. The effects of the hydraulic shear rate and reactor configuration on structural characteristics of aerobic granule in view of the hydromechanics. The hydraulic shear analysis was proposed to overcome the limitation of using superficial gas velocity (SGV) to express the hydraulic shear stress. Results showed that the stronger hydraulic shear stress with SGV above 2.4 cm s(-1) promoted the microbial aggregation, and favoured the structural stability of the granular sludge. According to the hydraulic shear analysis, the total shear rate reached (0.56-2.31)*10(5) s(-1) in the granular reactor with a larger ratio of height to diameter (H/D), and was higher than that in the reactor with smaller H/D, where the sequencing airlift bioreactor with smaller H/D had a high total shear rate under the same SGV. Results demonstrated that the granular reactor could provide a stronger hydraulic shear stress which promotes the formation and structural stability of aerobic granules. PMID- 25558901 TI - Focus on Kir7.1: physiology and channelopathy. AB - Genetic studies have linked alterations in Kir7.1 channel to diverse pathologies. We summarize functional relevance of Kir7.1 channel in retinal pigment epithelium (RPE), regulation of channel function by various cytoplasmic metabolites, and mutations that cause channelopathies. At the apical membrane of RPE, K(+) channels contribute to subretinal K(+) homeostasis and support Na(+)/K(+) pump and Na(+)-K(+)-2Cl(-) cotransporter function by providing a pathway for K(+) secretion. Electrophysiological studies have established that barium- and cesium sensitive inwardly rectifying K(+) (Kir) channels make up a major component of the RPE apical membrane K(+) conductance. Native human RPE expresses transcripts for Kir1.1, Kir2.1, Kir2.2, Kir3.1, Kir3.4, Kir4.2, and Kir6.1, albeit at levels at least 50-fold lower than Kir7.1. Kir7.1 is structurally similar to other Kir channels, consisting of 2 trans-membrane domains, a pore-forming loop that contains the selectivity filter, and 2 cytoplasmic polar tails. Within the cytoplasmic structure, clusters of amino acid sequences form regulatory domains that interact with cellular metabolites and control the opening and closing of the channel. Recent evidence indicated that intrinsic sequence motifs present in Kir7.1 control surface expression. Mutant Kir7.1 channels are associated with inherited eye pathologies such as Snowflake Vitreoretinal Degeneration (SVD) and Lebers Congenital Amaurosis (LCA16). Based on the current evidence, mutations implicated in channelopathies have the potential to be used for genetic testing to diagnose blindness due to Kir7.1. PMID- 25558921 TI - Synthesis of uniform alpha-Si3N4 nanospheres by RF induction thermal plasma and their application in high thermal conductive nanocomposites. AB - In this paper, single-crystalline alpha-Si3N4 nanospheres with uniform size of ~50 nm are successfully synthesized by using a radio frequency (RF) thermal plasma system in a one-step and continuous way. All Si3N4 nanoparticles present nearly perfect spherical shape with a narrow size distribution, and the diameter is well-controlled by changing the feeding rate. Compact Si3N4/PR (PR = phenolic resin) composites with high thermal conductivity, excellent temperature stability, low dielectric loss tangent, and enhanced breakdown strength are obtained by incorporating the as-synthesized Si3N4 nanospheres. These enhanced properties are the results of good compatibility and strong interfacial adhesion between compact Si3N4 nanospheres and polymer matrix, as large amount of Si3N4 nanospheres can uniformly disperse in the polymer matrix and form thermal conductive networks for diffusion of heat flow. PMID- 25558920 TI - Pd-catalyzed direct C-H bond sulfonylation of azobenzenes with arylsulfonyl chlorides. AB - Pd(II)-catalyzed C-H sulfonylation of azobenzenes with arylsulfonyl chlorides has been developed. The sulfonylazobenzenes were obtained in moderate to excellent yields for 28 examples. This protocol features high efficiency, wide functional group tolerance, and atom economy. PMID- 25558918 TI - Enantiospecific cis-trans isomerization in chiral fulleropyrrolidines: hydrogen bonding assistance in the carbanion stabilization in H2O@C60. AB - The stereochemical outcome of cis-trans isomerization of optically pure [60], [70], and endohedral H2O@C60 fulleropyrrolidines reveals that the electronic nature of substituents, fullerene size, and surprisingly the incarcerated water molecule plays a crucial role in this rearrangement process. Theoretical DFT calculations are in very good agreement with the experimental findings. On the basis of the experimental results and computational calculations, a plausible reaction mechanism involving the hydrogen-bonding assistance of the inner water molecule in the carbanion stabilization of endofullerene is proposed. PMID- 25558919 TI - Temporal trends of polychlorinated biphenyls, polybrominated diphenyl ethers, and perfluorinated compounds in Chinese sturgeon (Acipenser sinensis) eggs (1984 2008). AB - Because investigation on the temporal trends of persistent halogenated compounds (PHCs) is necessary to predict their future impacts on the environment and human health and evaluate the effectiveness of regulations on their production and usage, it is of concern to investigate annual temporal trends of PHCs in biota samples. This study examined the temporal trends of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and perfluorinated compounds (PFCs) in Chinese sturgeon (Acipenser sinensis) eggs over a period of 25 years (1984-2008), and 62 PCBs (19.2-1030 ng/g dw for total PCBs), 16 PBDEs (4.7-572 ng/g dw for total PBDEs), and 14 PFCs (26-46 ng/g dw for total PFCs) were detected. Although a decreasing temporal trend was observed for total PCBs with annual reduction rate of 3.4% (rho = 0.005), a clear break point was observed around 1991, indicating their continuing emission in the 1980s in China. All major PBDEs showed increasing temporal trends, with annual change rates at 3.5 10.2% over the 25 years, but a sharp decreasing trend was observed after 2006, indicating a rapid response to the banning of PBDE usage in China in 2004. The greatest annual rate of increase was observed for BDE-28 (10.2%) followed by BDE 100 (7.7%), which would be due to metabolism input from higher brominated PBDEs. Significantly increasing temporal trends were observed for all PFCs, and the annual rates of increase were 7.9% and 5.9% for total perfluorinated carboxylic acids and perfluorooctanesulfonate (PFOS), respectively. A peak concentration for PFOS was observed in 1989, which may be related to the import history of PFCs in China. The present study is the first report of systematic temporal trends of PHCs in biota samples from China and shows that regulatory policy is needed to reduce their potential health and ecological risk in China considering the increasing temporal trends of PBDEs and PFCs. PMID- 25558907 TI - Hormonal and dietary characteristics in obese human subjects with and without food addiction. AB - The concept of food addiction (FA) is a potentially important contributing factor to the development of obesity in the general population; however, little is known about the hormonal and dietary differences between obesity with and without FA. Therefore, the aim of our study was to explore potential biomarkers, including various hormones and neuropeptides, which regulate appetite and metabolism, and dietary components that could potentially differentiate obesity with and without FA. Of the 737 adults recruited from the general Newfoundland population, 58 food addicted and non-food-addicted overweight/obese individuals (FAO, NFO) matched for age, sex, BMI and physical activity were selected. A total of 34 neuropeptides, gut hormones, pituitary polypeptide hormones and adipokines were measured in fasting serum. We found that the FAO group had lower levels of TSH, TNF-alpha and amylin, but higher levels of prolactin, as compared to NFO group. The total calorie intake (per kg body weight), the dietary intake of fat (per g/kg body weight, per BMI and per percentage of trunk fat) and the percent calorie intake from fat and carbohydrates (g/kg) was higher in the FAO group compared to the NFO group. The FAO subjects consumed more sugar, minerals (including sodium, potassium, calcium and selenium), fat and its components (such as saturated, monounsaturated and trans fat), omega 3 and 6, vitamin D and gamma tocopherol compared to the NFO group. To our knowledge, this is the first study indicating possible differences in hormonal levels and micro-nutrient intakes between obese individuals classified with and without food addiction. The findings provide insights into the mechanisms by which FA could contribute to obesity. PMID- 25558915 TI - Organizational interventions in response to duty hour reforms. AB - BACKGROUND: Changes in resident duty hours in Europe and North America have had a major impact on the internal organizational dynamics of health care organizations. This paper examines, and assesses the impact of, organizational interventions that were a direct response to these duty hour reforms. METHODS: The academic literature was searched through the SCOPUS database using the search terms "resident duty hours" and "European Working Time Directive," together with terms related to organizational factors. The search was limited to English language literature published between January 2003 and January 2012. Studies were included if they reported an organizational intervention and measured an organizational outcome. RESULTS: Twenty-five articles were included from the United States (n=18), the United Kingdom (n=5), Hong Kong (n=1), and Australia (n=1). They all described single-site projects; the majority used post intervention surveys (n=15) and audit techniques (n=4). The studies assessed organizational measures, including relationships among staff, work satisfaction, continuity of care, workflow, compliance, workload, and cost. Interventions included using new technologies to improve handovers and communications, changing staff mixes, and introducing new shift structures, all of which had varying effects on the organizational measures listed previously. CONCLUSIONS: Little research has assessed the organizational impact of duty hour reforms; however, the literature reviewed demonstrates that many organizations are using new technologies, new personnel, and revised and innovative shift structures to compensate for reduced resident coverage and to decrease the risk of limited continuity of care. Future research in this area should focus on both micro (e.g., use of technology, shift changes, staff mix) and macro (e.g., culture, leadership support) organizational aspects to aid in our understanding of how best to respond to these duty hour reforms. PMID- 25558917 TI - Predicting the effects of climate change on Schistosoma mansoni transmission in eastern Africa. AB - BACKGROUND: Survival and fitness attributes of free-living and sporocyst schistosome life-stages and their intermediate host snails are sensitive to water temperature. Climate change may alter the geographical distribution of schistosomiasis by affecting the suitability of freshwater bodies for hosting parasite and snail populations. METHODS: We have developed an agent-based model of the temperature-sensitive stages of the Schistosoma mansoni and intermediate host snail lifecycles. The model was run using low, moderate and high warming climate projections over eastern Africa. For each climate projection, eight model scenarios were used to determine the sensitivity of predictions to different relationships between air and water temperature, and different snail mortality rates. Maps were produced showing predicted changes in risk as a result of increasing temperatures over the next 20 and 50 years. RESULTS: Baseline model output compared to prevalence data indicates suitable temperatures are necessary but not sufficient for both S. mansoni transmission and high infection prevalences. All else being equal, infection risk may increase by up to 20% over most of eastern Africa over the next 20 and 50 years. Increases may be higher in Rwanda, Burundi, south-west Kenya and eastern Zambia, and S. mansoni may become newly endemic in some areas. Results for 20-year projections are robust to changes in simulated intermediate host snail habitat conditions. There is greater uncertainty about the effects of different habitats on changes in risk in 50 years' time. CONCLUSIONS: Temperatures are likely to become suitable for increased S. mansoni transmission over much of eastern Africa. This may reduce the impact of control and elimination programmes. S. mansoni may also spread to new areas outside existing control programmes. We call for increased surveillance in areas defined as potentially suitable for emergent transmission. PMID- 25558923 TI - Time to declare victory and unite pain and palliative medicine. AB - The value and importance of improved communication and collaboration among pain management and palliative care clinicians is presented. The commentator uses the case report in this issue of the journal on the use of indwelling catheters for continuous interscalene blocks in cancer pain management as an example of why these two medical subspecialties need improved collaboration and integration. PMID- 25558908 TI - Fucoidan supplementation improves exercise performance and exhibits anti-fatigue action in mice. AB - Fucoidan (FCD) is a well-known bioactive constituent of seaweed extract that possess a wide spectrum of activities in biological systems, including anti cancer, anti-inflammation and modulation of immune systems. However, evidence on the effects of FCD on exercise performance and physical fatigue is limited. Therefore, we investigated the potential beneficial effects of FCD on ergogenic and anti-fatigue functions following physiological challenge. Male ICR mice from three groups (n = 8 per group) were orally administered FCD for 21 days at 0, 310 and 620 mg/kg/day, which were, respectively, designated the vehicle, FCD-1X and FCD-2X groups. The results indicated that the FCD supplementations increased the grip strength (p = 0.0002) and endurance swimming time (p = 0.0195) in a dose depend manner. FCD treatments also produced dose-dependent decreases in serum levels of lactate (p < 0.0001) and ammonia (p = 0.0025), and also an increase in glucose level (p < 0.0001) after the 15-min swimming test. In addition, FCD supplementation had few subchronic toxic effects. Therefore, we suggest that long term supplementation with FCD can have a wide spectrum of bioactivities on health promotion, performance improvement and anti-fatigue. PMID- 25558922 TI - The emerging genomics and systems biology research lead to systems genomics studies. AB - Synergistically integrating multi-layer genomic data at systems level not only can lead to deeper insights into the molecular mechanisms related to disease initiation and progression, but also can guide pathway-based biomarker and drug target identification. With the advent of high-throughput next-generation sequencing technologies, sequencing both DNA and RNA has generated multi-layer genomic data that can provide DNA polymorphism, non-coding RNA, messenger RNA, gene expression, isoform and alternative splicing information. Systems biology on the other hand studies complex biological systems, particularly systematic study of complex molecular interactions within specific cells or organisms. Genomics and molecular systems biology can be merged into the study of genomic profiles and implicated biological functions at cellular or organism level. The prospectively emerging field can be referred to as systems genomics or genomic systems biology. The Mid-South Bioinformatics Centre (MBC) and Joint Bioinformatics Ph.D. Program of University of Arkansas at Little Rock and University of Arkansas for Medical Sciences are particularly interested in promoting education and research advancement in this prospectively emerging field. Based on past investigations and research outcomes, MBC is further utilizing differential gene and isoform/exon expression from RNA-seq and co regulation from the ChiP-seq specific for different phenotypes in combination with protein-protein interactions, and protein-DNA interactions to construct high level gene networks for an integrative genome-phoneme investigation at systems biology level. PMID- 25558924 TI - Myofascial pain syndrome: an overview. AB - Over the last few decades, advances have been made in the understanding of myofascial pain syndromes (MPSs). In spite of its high prevalence in the society, it is not a commonly established diagnosis. MPS is said to be the great imitator. This article puts some light on the various clinical presentations of the syndrome, on the various tools to reach to a diagnosis for commencing the treatment and on the treatment modalities that have been used so far. PMID- 25558916 TI - Protein kinase Cdelta mediates histamine-evoked itch and responses in pruriceptors. AB - BACKGROUND: Itch-producing compounds stimulate receptors expressed on small diameter fibers that innervate the skin. Many of the currently known pruritogen receptors are Gq Protein-Coupled Receptors (GqPCR), which activate Protein Kinase C (PKC). Specific isoforms of PKC have been previously shown to perform selective functions; however, the roles of PKC isoforms in regulating itch remain unclear. In this study, we investigated the novel PKC isoform PKCdelta as an intracellular modulator of itch signaling in response to histamine and the non-histaminergic pruritogens chloroquine and beta-alanine. RESULTS: Behavioral experiments indicate that PKCdelta knock-out (KO) mice have a 40% reduction in histamine induced scratching when compared to their wild type littermates. On the other hand, there were no differences between the two groups in scratching induced by the MRGPR agonists chloroquine or beta-alanine. PKCdelta was present in small diameter dorsal root ganglion (DRG) neurons. Of PKCdelta-expressing neurons, 55% also stained for the non-peptidergic marker IB4, while a smaller percentage (15%) expressed the peptidergic marker CGRP. Twenty-nine percent of PKCdelta-expressing neurons also expressed TRPV1. Calcium imaging studies of acutely dissociated DRG neurons from PKCdelta-KO mice show a 40% reduction in the total number of neurons responsive to histamine. In contrast, there was no difference in the number of capsaicin-responsive neurons between KO and WT animals. Acute pharmacological inhibition of PKCdelta with an isoform-specific peptide inhibitor (deltaV1-1) also significantly reduced the number of histamine-responsive sensory neurons. CONCLUSIONS: Our findings indicate that PKCdelta plays a role in mediating histamine-induced itch, but may be dispensable for chloroquine- and beta-alanine induced itch. PMID- 25558925 TI - Chronic opioid pain management for chronic kidney disease. AB - Questions from patients about pain conditions, pain treatment, and responses from authors are presented to help educate patients and make them effective self advocates. The topics addressed in this issue are renal or kidney failure and chronic pain management with opioids, morphine, and oxycodone effect in the body over a period of time. This includes process of absorption, distribution, localization in tissues, biotransformation and excretion in chronic kidney disease, expected side effects and recommendations. PMID- 25558929 TI - Message from the editors. PMID- 25558930 TI - Is there a future for metabotyping in clinical laboratories? PMID- 25558926 TI - Implications of bariatric surgery on chronic pain and opioid use. AB - Questions from patients about pain conditions, pain treatment, and responses from authors are presented to help educate patients and make them effective self advocates. The topics addressed in this report are implications of bariatric surgery or weight loss surgery on chronic pain and opioid use, what to expect with regards to pain control, and the need to change opioid dose after bariatric surgery. PMID- 25558940 TI - Engaging challenges in glycoproteomics: recent advances in MS-based glycopeptide analysis. AB - The proteomic analysis of glycosylation is uniquely challenging. The numerous and varied biological roles of protein-linked glycans have fueled a tremendous demand for technologies that enable rapid, in-depth structural examination of glycosylated proteins in complex biological systems. In turn, this demand has driven many innovations in wide ranging fields of bioanalytical science. This review will summarize key developments in glycoprotein separation and enrichment, glycoprotein proteolysis strategies, glycopeptide separation and enrichment, the role of mass measurement accuracy in glycopeptide detection, glycopeptide ion dissociation methods for MS/MS, and informatic tools for glycoproteomic analysis. In aggregate, this selection of topics serves to encapsulate the present status of MS-based analytical technologies for engaging the challenges of glycoproteomic analysis. PMID- 25558931 TI - Highlights from the 2014 Applied Pharmaceutical Analysis conference. AB - The 10th annual Applied Pharmaceutical Analysis (APA) conference was held from 8th to 10th September in Cambridge, MA, USA. This year's APA conference focused on three different 'workshops' over the 3 days: Regulated Bioanalysis, Biotransformation, and Discovery. There was a great amount of information discussed by a variety of experts over the 3 days. This included, among other things; speakers from the US FDA discussing statute changes and guidelines, leaders from academic laboratories discussing innovation in bioanalytical tools, and industry scientists discussing current trends in the industry. The conference afforded attendees the opportunity to learn from the speakers during their sessions. In addition, there was ample opportunity for attendees and speakers both to learn from each other through informal interactions. PMID- 25558933 TI - Detection limit enhancement of antiarrhythmic drugs in human plasma using capillary electrophoresis with dispersive liquid-liquid microextraction and field amplified sample stacking method. AB - BACKGROUND: A new capillary zone electrophoresis (CZE) with ultraviolet detection method has been developed and validated for the analysis of four antiarrhythmic drugs in human plasma samples. METHODS: In this study, a dispersive liquid-liquid microextraction (DLLME) coupled with field-amplified sample stacking (FASS) was employed for biological samples clean-up and sensitivity enhancement in CZE. RESULTS: Under optimum DLLME-FASS-CZE conditions, enhancement factors were in the range of 157-314. The method was validated over the concentration range of 20-800 ng/ml in human plasma. Inter- and intra-day precision and the accuracy were less than 20%; the detection limits ranged from 2.5 to 4.7 ng/ml. Furthermore, the validated method was successfully applied to the detection of studied drugs in patients' plasma samples. PMID- 25558944 TI - New Year's Greetings. PMID- 25558938 TI - MALDI-MS imaging for the study of tissue pharmacodynamics and toxicodynamics. AB - Pharmacodynamics and toxicodynamics are the study of the biochemical and physiological effects of therapeutic agents and toxicants and their mechanisms of action. MALDI-MS imaging offers great potential for the study of pharmaco/toxicodynamic responses in tissue owing is its ability to study multiple biomarkers simultaneously in a label-free manner. Here, existing examples of such studies examining anticancer drugs and topically applied treatments are described. Examination of the literature shows that the use of MS imaging in pharmaco/toxicodynamic studies is in fact quite low. The reasons for this are discussed and potential developments in the methodology that might lead to its further use are described. PMID- 25558937 TI - A microfluidic paper-based analytical device for the assay of albumin-corrected fructosamine values from whole blood samples. AB - BACKGROUND: A method for acquiring albumin-corrected fructosamine values from whole blood using a microfluidic paper-based analytical system that offers substantial improvement over previous methods is proposed. RESULTS: The time required to quantify both serum albumin and fructosamine is shortened to 10 min with detection limits of 0.50 g dl(-1) and 0.58 mM, respectively (S/N = 3). The proposed system also exhibited good within-run and run-to-run reproducibility. The results of the interference study revealed that the acceptable recoveries ranged from 95.1 to 106.2%. The system was compared with currently used large scale methods (n = 15), and the results demonstrated good agreement among the techniques. CONCLUSION: The microfluidic paper-based system has the potential to continuously monitor glycemic levels in low resource settings. PMID- 25558927 TI - Curcumin-incorporated albumin nanoparticles and its tumor image. AB - Albumin is an ideal carrier for hydrophobic drugs. This paper reports a facile route to develop human serum albumin (HSA)-curcumin (CCM) nanoparticles, in which beta-mercaptoethanol (beta-ME) acted as an inducer and CCM acted as a bridge. Fluorescence quenching and conformational changes in HSA-CCM nanoparticles occurred during assembly. Disulfide bonds and hydrophobic interactions may play a key role in assembly. HSA-CCM nanoparticles were about 130 nm in size, and the solubility of CCM increased by more than 500 times. The HSA-CCM nanoparticles could accumulate at the cytoplasm of tumor cells and target the tumor tissues. Therefore, HSA nanoparticles fabricated by beta-ME denaturation are promising nanocarriers for hydrophobic substances from chemotherapy drugs to imaging probes. PMID- 25558935 TI - High-sensitivity quantitation of a Nanobody(r) in plasma by single-cartridge multidimensional SPE and ultra-performance LC-MS/MS. AB - BACKGROUND: A major challenge in protein quantitation based on enzymatic digestion of complex biological samples and subsequent LC-MS/MS analysis of a signature peptide is dealing with the high complexity of the matrix after digestion, which can reduce sensitivity considerably. RESULTS: Using single cartridge multidimensional SPE, sufficient selectivity was introduced to allow quantitation in 50 ul of plasma down to 10.0 ng/ml (~0.3 nM). An inhouse prepared (18)O-labeled signature peptide was used as the internal standard. The procedure was validated for human and rabbit plasma. CONCLUSION: The developed SPE procedure allowed the sensitive and selective LC-MS/MS quantitation of the Nanobody((r)) without the use of antibodies. When appropriate precautions are taken, the (18)O-labeled peptide is a practical and economical alternative to custom synthesis. PMID- 25558928 TI - Localized RNAi therapeutics of chemoresistant grade IV glioma using hyaluronan grafted lipid-based nanoparticles. AB - Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP's surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM. PMID- 25558941 TI - Potential of mass spectrometry metabolomics for chemical food safety. AB - This review aims to describe the most significant applications of mass spectrometry-based metabolomics in the field of chemical food safety. A particular discussion of all the different analytical steps involved in the metabolomics workflow (sample preparation, mass spectrometry analytical platform and data processing) will be addressed. PMID- 25558945 TI - Preface to Journal of Dermatology special issue: pemphigus updates from around the world. PMID- 25558947 TI - Immune cellular regulation on autoantibody production in pemphigus. AB - Pemphigus is an autoantibody-mediated blistering disease in the skin and mucous membranes. The autoantibodies primarily target desmoglein (Dsg)1 or/and Dsg3, transmembrane glycoproteins of skin epidermal cells, leading to loss of desmosome adhesion and acantholysis through signaling dependent and independent pathways. Thus, the pemphigus autoantibodies themselves and immune processes, particularly cellular regulation of antibody production, remain as interesting topics in probing pemphigus pathogenesis. In this review, we focus on current advances regarding how the pemphigus antibody production is highly regulated by the key immune effectors including T cells, B cells and their secreted cytokines. Specifically targeting these immune effectors involved in the pemphigus autoantibody production should provide better therapeutic options for disease treatment of pemphigus. PMID- 25558939 TI - Validation of a two-step quality control approach for a large-scale human urine metabolomic study conducted in seven experimental batches with LC/QTOF-MS. AB - After his study of food science at the Rheinische Friedrich-Wilhelms University of Bonn, Tobias J Demetrowitsch obtained his doctoral degree in the research field of metabolomics at the Christian-Albrechts-University of Kiel. The present paper is part of his doctoral thesis and describes an extended strategy to evaluate and verify complex or large-scale experiments and data sets. Large-scale studies result in high sample numbers, requiring the analysis of samples in different batches. So far, the verification of such LC-MS-based metabolomics studies is difficult. Common approaches have not provided a reliable validation procedure to date. This article shows a novel verification process for a large scale human urine study (analyzed by a LC/QToF-MS system) using a two-step validation procedure. The first step comprises a targeted approach that aims to examine and exclude statistical outliers. The second step consists of a principle component analysis, with the aim of a tight cluster of all quality controls and a second for all volunteer samples. The applied study design provides a reliable two-step validation procedure for large-scale studies and additionally contains an inhouse verification procedure. PMID- 25558942 TI - Comprasion of ovarian stromal blood flow measured by color Doppler ultrasonography in polycystic ovary syndrome patients and healthy women with ultrasonographic evidence of polycystic. AB - OBJECTIVE: To compare ovarian stromal artery blood flows measured by Doppler ultrasonography of polycystic ovary syndrome (PCOS) patients and healthy women with polycystic ovarian image in ultrasonography. METHODS: Forty-two patients diagnosed with PCOS according to the criteria of 2003 Rotterdam Concencus Conferance on PCOS and 38 healthy volunteers with polycystic ovarian image in ultrasonography were included in the study. Ovarian volumes and ovarian stromal artery blood flows were measured by 3-dimensional (3-D) ultrasonography and Doppler ultrasonography in all patients. RESULTS: In patients with PCOS, ovarian stromal artery pulsatility index (PI) and resistivity index (RI) were found significantly different from healthy women with polycystic ovarian image in ultrasonography (p < 0.05). 3-D ovarian volumes were found significantly higher in patients with PCOS (p < 0.05), and a negative correlation was also obtained between ovarian volumes and ovarian stromal artery resistivity indices. CONCLUSION: Ovarian stromal artery Doppler examination could have an importance to explain the pathophysiology of PCOS, but there are few publications in the literature about PCOS and the details of ovarian stromal artery Doppler parameters in patients with polycystic ovarian image only. We conclude that Doppler ultrasonography findings of PCOS patients might be helpful in understanding the clinical follow-up and etiology of the disease. PMID- 25558932 TI - Significance of 'post bioanalysis phase' in bioanalysis: is GMP creeping into GLP? PMID- 25558943 TI - The potential of targeting Ras proteins in lung cancer. AB - The Ras pathway is a major driver in lung adenocarcinoma: over 75% of all cases harbor mutations that activate this pathway. While spectacular clinical successes have been achieved by targeting activated receptor tyrosine kinases in this pathway, little, if any, significant progress has been achieved targeting Ras proteins themselves or cancers driven by oncogenic Ras mutants. New approaches to drug discovery, new insights into Ras function, new ways of attacking undruggable proteins through RNA interference and new ways of harnessing the immune system could change this landscape in the relatively near future. PMID- 25558946 TI - Importance of serological tests in diagnosis of autoimmune blistering diseases. AB - Autoimmune blistering diseases are organ-specific autoimmune diseases characterized by autoantibodies against structural proteins that maintain cell cell (pemphigus diseases) and cell-matrix adhesions (pemphigoid diseases) in the skin and mucous membranes. Over the last few decades, identification of autoantigens and extensive characterization of autoantibodies have improved understanding of the pathogenesis of these diseases. In addition, the development of new sensitive and specific immunoassays enabled accurate diagnosis and proper evaluation of disease activity in autoimmune blistering diseases. In this review, we describe practical updates for molecular diagnostic tests for autoimmune blistering diseases and the basis for interpreting the results of the assays. PMID- 25558934 TI - Determination of thailandepsin B in rat plasma with a LC-MS/MS method. AB - BACKGROUND: Thailandepsin B (TDP-B) is a potent histone deacetylase inhibitor under development. A reliable bioanalytical method for the quantification of TDP B in plasma samples is required. RESULTS: The stabilizer mixture containing hydrochloric acid, formic acid and dichlorvos was applied to stabilize TDP-B in matrix samples. The method validation was conducted over the curve range of 1.00 to 1000 ng/ml. The intrabatch and interbatch precision and accuracy of the quality control samples showed <=10.9% relative standard deviation and -6.7% to 15.0% relative error. Moreover, a possible metabolite M of TDP-B was tentatively characterized. CONCLUSION: A reliable LC-MS/MS method was developed and validated for the quantification of TDP-B and was successfully applied to a rat pharmacokinetic study. PMID- 25558949 TI - Pemphigus in the Arab world. AB - The Arab world lies geographically between the Atlantic coasts of northern Africa and the Arabian Gulf. This area has wide latitudinal differences as well as variable environmental conditions ranging from deserts to forests. Approximately 370 million individuals who share the Arabic language live in this area. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are the main subtypes of the pemphigus disease. Both pemphigus subtypes are present in many Arab countries; however, there is variation in the predominant subtype among countries. PV is the most common subtype in Egypt, Sudan, Morocco, Syria, Kuwait, Saudi Arabia and Yemen. On the other hand, PF is more prevalent in Libya and is endemic in Tunisia. Interestingly, there is variation in the dominant subtype in some cities within Morocco. For example, PF is more common in Marrakech which is the second largest city. The presence of anti-desmoglein 1 antibodies in the sera of normal Tunisians and the presence of anti-desmoglein 3 in normal Egyptians' sera suggested that environmental factors played a role in the disease pathogenesis in those areas. Further researches detected that traditional cosmetics were among the risk factors in Tunisia. Moreover, farming was suggested as a risk factor in Egypt, Tunisia and Sudan. Because there is no consensus for pemphigus treatment among the Arab countries, there is diversity in their pemphigus treatment regimens. Studying the demographic characteristics and the environmental conditions which caused the variations in the prevailing clinical phenotype will help us fill the gaps to understand the pathogenesis of the pemphigus disease. PMID- 25558950 TI - Outcome measures for autoimmune blistering diseases. AB - Outcome measures are crucial in assessing an autoimmune blistering disease's (AIBD) severity as well as its impact on the patient's quality of life (QOL). The standardization of AIBD outcome measures is pivotal to accurately monitor the patient and to pool results from randomized controlled trials for meta-analysis, and thereby provide knowledge of the optimal AIBD therapies. In the past decade, several AIBD severity outcome measures have been developed and validated. For pemphigus severity, the Pemphigus Disease Area Index (PDAI) developed by the International Pemphigus Definitions Group was shown to be the most superior, followed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) by the German group. For bullous pemphigoid severity, the Bullous Pemphigoid Disease Area Index (BPDAI) was shown to be an accurate and valid measure. To quantify the burden of AIBD and its treatments on QOL, the Autoimmune Bullous Disease Quality of Life (ABQOL) and the Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) were also developed, validated, and are now being validated in multiple languages and cultures. PMID- 25558951 TI - Severe acute and reversible heart failure shortly after childbirth: systemic lupus erythematosus or peripartum cardiomyopathy? PMID- 25558936 TI - Bioanalytical method for in vitro metabolism study of repaglinide using 96-blade thin-film solid-phase microextraction and LC-MS/MS. AB - BACKGROUND: A high-throughput bioanalytical method using 96-blade thin film microextraction (TFME) and LC-MS/MS for the analysis of repaglinide (RPG) and two of its main metabolites was developed and used for an in vitro metabolism study. RESULTS: The target analytes were extracted from human microsomal medium by a 96 blade-TFME system employing the low-cost prototype 'SPME multi-sampler' using C18 coating. Method validation showed recoveries around 90% for all analytes and was linear over the concentration range of 2-1000 ng ml(-1) for RPG and of 2-500 ng ml(-1) for each RPG metabolite. CONCLUSION: The method was applied to an in vitro metabolism study of RPG employing human liver microsomes and proved to be very useful for this purpose. PMID- 25558948 TI - Update on fogo selvagem, an endemic form of pemphigus foliaceus. AB - Pemphigus are organ-specific autoimmune diseases, where autoantibodies (mainly immunoglobulin [Ig]G) directed against epidermal targets (glycoproteins of the desmosomal core) are detected. Endemic pemphigus foliaceus or fogo selvagem (FS) is one of the variants of pemphigus foliaceus pemphigus foliaceus that shares the same clinical and immunopathological features of the classic non-endemic pemphigus foliaceus form, including pathogenic IgG (mainly IgG4) autoantibodies directed against the ectodomain of desmoglein 1 (Dsg1), that lead to acantholysis. Pathogenesis of FS is complex, involving genetic, environmental and immunological factors. Human leukocyte antigen (HLA)-DRB1 alleles DRB1*0404, *1402, *1406 or *0102 have been previously identified as risk factors for FS (relative risk, >14). Individuals exposed to hematophagous insects are more susceptible to develop the disease. Non-pathogenic anti-Dsg1 antibodies of the IgG1 subclass, directed against the extracellular 5 domain of Dsg1, are detected in patients in the preclinical stage of the disease, and also in healthy controls living in endemic areas. In counterpart, patients with FS show pathogenic anti Dsg1 IgG4 autoantibodies that bind the pathogenic extracellular 1 and 2 domains of Dsg1, emphasizing the intramolecular epitope-spreading hypothesis. A possible explanation for the development of the autoimmune process would be antigenic mimicry, initiated by environmental stimuli in those genetically predisposed individuals. Characterization of the pathogenesis of FS will allow the development of specific therapeutic targets, and the elucidation of other autoimmune processes. PMID- 25558952 TI - Duty hour restrictions: organizational dynamics, systems issues, and the impact on faculty. AB - The potential impact of resident duty hour restrictions on faculty is likely significant; however, the extent of this impact has still not been well documented. We undertook a narrative review of the literature to determine the magnitude of that potential impact and the nature of the evolving discourse related to faculty members as individuals. The literature provides an inconsistent picture of the impact of duty hour restrictions on faculty. While some studies have reported a significant increase in faculty workload, others suggest that the impact of duty hour restrictions has been minimal. Some papers suggest that duty hour restrictions may fundamentally change the nature of resident-teacher interactions and, as a result, will necessitate significant changes to the way education is delivered. Overall, the majority of issues of concern relate to one of the following: volume and composition of work, impact on faculty career choice, evolving perceptions of residents as learners, and the need to find an appropriate balance between learning and the quality and quantity of patient care. In describing these themes we identify some potential solutions and future directions for reconciling duty hour restrictions with faculty perceptions, anxieties, and desired outcomes. PMID- 25558955 TI - Sleep apps and the quantified self: blessing or curse? PMID- 25558954 TI - Is the Predictability of New-Onset Postpartum Depression Better During Pregnancy or in the Early Postpartum Period? A Prospective Study in Croatian Women. AB - The researchers' aim was to examine whether it was better to predict new-onset postpartum depression (PPD) during pregnancy or immediately after childbirth. A prospective study conducted in Croatia followed women (N = 272) from the third trimester of pregnancy through the early postpartum period (within the first 3 postpartum days), to 6 weeks postpartum. Questionnaires on depression, anxiety, stress, coping, self-esteem, and social support were administered. Through regression analyses we showed that PPD symptoms could be equally predicted by variables from pregnancy (30.3%) and the early postpartum period (34.0%), with a small advantage of PPD prediction in the early postpartum period. PMID- 25558957 TI - Increased lipid peroxidation occurs during development in Japanese quail (Coturnix japonica) embryos. AB - The growth of the avian embryo is paralleled by an exponential increase in the rate of whole-embryonic oxygen consumption, which potentially increases oxidative damage. Age-related patterns of tissue lipid peroxidation were characterised in brain, liver and heart tissue of developing Japanese quail (Coturnix japonica) embryos between 9 and 15 d of age, over which embryo mass increased by a factor of 6. Lipid peroxidation was quantified in each tissue by spectrophotometric measurement of malondialdehyde using the thiobarbituric acid reactive substances assay. In all tissues, lipid peroxidation increased greatly as development proceeded. Concentrations of malondialdehyde increased in parallel with the cumulative amount of oxygen consumed by the developing embryo consistent with the hypothesis that oxidative stress results from the production of free radicals due to oxidative metabolism. This study describes in vivo oxidative stress in developing avian embryos and suggests that rates of embryonic growth, oxidative metabolism and oxidative damage likely vary in parallel. PMID- 25558958 TI - Higher prevalence of left ventricular hypertrophy in two Maori cohorts: findings from the Hauora Manawa/Community Heart Study. AB - OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of mortality in New Zealand with a disproportionate burden of disease in the Maori population. The Hauora Manawa Project investigated the prevalence of cardiovascular risk factors and CVD in randomly selected Maori and non-Maori participants. This paper reports the prevalence of structural changes in the heart. METHODS: A total of 252 rural Maori, 243 urban Maori; and 256 urban non-Maori underwent echocardiography to assess cardiac structure and function. Multivariable logistic regression was used to determine variables associated with heart size. RESULTS: Left ventricular (LV) mass measurements were largest in the rural Maori cohort (183.5,sd 61.4), intermediate in the urban Maori cohort (169.7,sd 57.1) and smallest in the non Maori cohort (152.6,sd 46.7; p<0.001). Similar patterns were observed for other measurements and indexation had no impact. One-third (32.3%) met the gender-based ASE criteria for LV hypertrophy (LVH) with higher prevalence in both Maori cohorts (highest in the rural cohort). There were three significant predictors of LVH: rural Maori (p=0.0001); age (p<0.0001); and gender (p=0.0048). CONCLUSION: Structural and functional heart abnormalities are more prevalent in Maori compared to non-Maori, and especially rural Maori. Early identification should lead to better management, ultimately improving life expectancy and quality of life. PMID- 25558960 TI - Athletes' use of mental skills during sport injury rehabilitation. AB - CONTEXT: Existing theoretical frameworks and empirical research support the applicability and usefulness of integrating mental skills throughout sport injury rehabilitation. OBJECTIVE: To determine what, if any, mental skills athletes use during injury rehabilitation, and by who these skills were taught. Cross-cultural differences were also examined. DESIGN: Cross-sectional design. SETTING: College athletes from 5 universities in the United States and a mixture of collegiate, professional, and recreational club athletes from the United Kingdom and Finland were recruited for this study. PARTICIPANTS: A total of 1283 athletes from the United States, United Kingdom, and Finland, who participated in diverse sports at varying competitive levels took part in this study. MAIN OUTCOME MEASURES: As part of a larger study on athletes' expectations of injury rehabilitation, participants were asked a series of open-ended and closed-ended questions concerning their use of mental skills during injury rehabilitation. RESULTS: Over half (64.0%) of the sample reported previous experience with athletic training, while 27.0% indicated that they used mental skills during injury rehabilitation. The top 3 mental skills reported were goal setting, positive self-talk/positive thoughts, and imagery. Of those athletes that used mental skills, 71.6% indicated that they felt mental skills helped them to rehabilitate faster. A greater proportion of athletes from the United States (33.4%) reported that they used mental skills during rehabilitation compared with athletes from the United Kingdom (23.4%) and Finland (20.3%). A small portion (27.6%) of the participants indicated that their sports medicine professional had taught them how to use mental skills; only 3% were taught mental skills by a sport psychologist. CONCLUSIONS: The low number of athletes who reported using mental skills during rehabilitation is discouraging, but not surprising given research findings that mental skills are underutilized by injured athletes in the 3 countries examined. More effort should be focused on educating and training athletes, coaches, and sports medicine professionals on the effectiveness of mental training in the injury rehabilitation context. PMID- 25558962 TI - Functions of nonsuicidal self-injury: exploratory and confirmatory factor analyses in a large community sample of adolescents. AB - Given that nonsuicidal self-injury (NSSI) is prevalent in adolescents, structured assessment is an essential tool to guide treatment interventions. The Functional Assessment of Self-Mutilation (FASM) is a self-report scale that assesses frequency, methods, and functions of NSSI. FASM was administered to 3,097 Swedish adolescents in a community sample. With the aim of examining the underlying factor structure of the functions of FASM in this sample, the adolescents with NSSI who completed all function items (n = 836) were randomly divided into 2 subsamples for cross-validation purposes. An exploratory factor analysis (EFA) was followed by a confirmatory factor analysis (CFA) using the mean and variance adjusted weighted least squares (WLSMV) estimator in the Mplus statistical modeling program. The results of the EFA suggested a 3-factor model (social influence, automatic functions, and nonconformist peer identification), which was supported by a good fit in the CFA. Factors differentiated between social/interpersonal and automatic/intrapersonal functions. Based on learning theory and the specific concepts of negative and positive reinforcement, the nonconformist peer identification factor was then split into 2 factors (peer identification and avoiding demands). The resulting 4-factor model showed an excellent fit. Dividing social functions into separate factors (social influence, peer identification, and avoiding demands) can be helpful in clinical practice, where the assessment of NSSI functions is an important tool with direct implications for treatment. PMID- 25558964 TI - Clinical assessment of organizational strategy: An examination of healthy adults. AB - During the assessment of patients with cognitive difficulties, clinicians often examine strategic processing, particularly the ability to use organization-based strategies to efficiently complete various tasks. Several commonly used neuropsychological tasks are currently thought to provide measures of organizational strategic processing, but empirical evidence for the construct validity of these strategic measures is needed before interpreting them as measuring the same underlying ability. This is particularly important for the assessment of organizational strategic processing because the measures span cognitive domains (e.g., memory strategy, language strategy) as well as types of organization. In the present study, 200 adults were administered cognitive tasks commonly used in clinical practice to assess organizational strategic processing. Factor analysis was used to examine whether these measures of organizational strategic processing, which involved different cognitive domains and types of organization, could be operationalized as measuring a unitary construct. A very good-fitting model of the data demonstrated no significant shared variance among any of the strategic variables from different tasks (root mean square error of approximation < .0001, standardized root-mean-square residual = .045, comparative fit index = 1.000). These findings suggest that organizational strategic processing is highly specific to the demands and goals of individual tasks even when tasks share commonalities such as involving the same cognitive domain. In the design of neuropsychological batteries involving the assessment of organizational strategic processing, it is recommended that various strategic measures across cognitive domains and types of organizational processing are selected as guided by each patient's individual cognitive difficulties. PMID- 25558967 TI - The Structured Assessment of Violence Risk in Youth in a large community sample of young adult males and females: The TRAILS study. AB - This study examined associations between the Structured Assessment of Violence Risk in Youth (SAVRY; Borum, Bartel, & Forth, 2002) risk and protective items, identified clusters of SAVRY items, and used these clusters to predict police contact and violence. SAVRY items were assessed in a community sample of adolescent boys and girls (N = 963, 46.5% boys) via self-, parent, and teacher reports at ages 11 and 13.5 as part of a longitudinal cohort study. Police contact and violence were assessed at age 19. Correlations between risk and protective items and police contact and violence were largely similar in boys and girls, though there were some differences with regard to outcome measure. Principal factor analysis on the SAVRY items yielded a 2-factor model, distinguishing between History of Violence/Dysregulation and Social Support factors. Follow-up analyses showed incremental validity of the Social Support factor over and beyond the History of Violence/Dysregulation factor and sex in the prediction of violence. The findings provide new insights into the SAVRY factor structure and show that the SAVRY was able to predict violence in a community sample of adolescents over a period of 4 to 7 years. PMID- 25558963 TI - Elaborating on the construct validity of the Minnesota Borderline Personality Disorder Scale (MBPD): a multi-sample, longitudinal examination. AB - Borderline personality disorder (BPD) is frequently conceptualized as an extreme variant of normal personality traits. A previous study successfully developed and validated a self-report BPD measure, the Minnesota Borderline Personality Disorder Scale (MBPD). We conducted 2 studies aimed at providing further validation for this measure. Results from Study 1 (clinical sample of substance users) indicated that the MBPD exhibited strong positive correlations with measures of convergent validity. In addition, the MBPD showed similar correlations with external correlates as those of the convergent validity measures as well as incremental utility in predicting these external correlates above and beyond negative affect and adult antisocial behavior. Also, a receiver operating characteristic curve analysis indicated that diagnostic accuracy of the MBPD was excellent for differentiation between BPD and non-BPD individuals. Likewise, Study 2 (nonclinical sample of undergraduate students followed over 6 months) showed strong correlations with an index of convergent validity, similar correlations with external correlates as that of the convergent validity index, and incremental predictive utility. Finally, in this study, the MBPD exhibited high rank-order stability. These data provide further evidence that the MBPD is a valid indicator of BPD. PMID- 25558965 TI - The shortened Person's Relating to Others Questionnaire (PROQ3): Comparison of the Internet-administered format with the standard-written one across four national samples. AB - The study aims to validate the shortened version of the Person's Relating to Others Questionnaire (PROQ3), a measure of negative and maladaptive relating to others, for data collection via the Internet across 4 national samples. The psychometric properties of the Internet-administered (IN) format of the PROQ3 in 4,802 participants (169 British; 360 Irish; 1,110 Dutch; and 3,163 Greek) were compared with that of the standard-written (SW) version in 1918 participants (338 British, 403 Irish, 204 Dutch, and 973 Greek), in respect of its measurement and structural equivalence. Internal consistency, as estimated by alpha coefficient and item-to-scale homogeneity, were consistently acceptable across nationality and modality. There was agreement in regard to the interscale correlations across nationality and modality. Lower mean scores for the British sample in the SW format, and lower mean scores for the Irish sample in the IN format were found. The structural equivalence across modality and nationality was also supported: A consistent 8-factor underlying structure, as supported by a multiple group factor analysis, and an octagonal higher order, as supported by a 3-way multidimensional scaling procedure, were found. It was concluded that the PROQ3 can be administered via the Internet with maintained psychometric properties for clinicians to screen people with interpersonal relating deficiencies and for researchers to collect data. PMID- 25558961 TI - Endothelial Piezo1: life depends on it. PMID- 25558956 TI - Impact of the Provider and Healthcare team Adherence to Treatment Guidelines (PHAT-G) intervention on adherence to national obesity clinical practice guidelines in a primary care centre. AB - RATIONALE, AIMS AND OBJECTIVES: Obesity is significantly underdiagnosed and undertreated in primary care settings. The purpose of this clinical practice change project was to increase provider adherence to national clinical practice guidelines for the diagnosis and treatment of obesity in adults. METHODS: Based upon the National Institutes of Health guidelines for the diagnosis and treatment of obesity, a clinical change project was implemented. Guided by the theory of planned behaviour, the Provider and Healthcare team Adherence to Treatment Guidelines (PHAT-G) intervention includes education sessions, additional provider resources for patient education, a provider reminder system and provider feedback. RESULTS: Primary care providers did not significantly increase on documentation of diagnosis and planned management of obesity for patients with body mass index (BMI) greater than or equal to 30. Medical assistants increased recording of height, weight and BMI in the patient record by 13%, which was significant. CONCLUSIONS: Documentation of accurate BMI should lead to diagnosis of appropriate weight category and subsequent care planning. Future studies will examine barriers to adherence to clinical practice guidelines for obesity. Interventions are needed that include inter-professional team members and may be more successful if delivered separately from routine primary care visits. PMID- 25558969 TI - The Protective Behavioral Strategies Scale-20: improved content validity of the Serious Harm Reduction subscale. AB - Excessive drinking in college leads to serious harms, but students who use protective behavioral strategies (PBS) avoid negative consequences by drinking in a safer manner. This study aimed to increase the content validity of the Serious Harm Reduction (SHR) subscale of the most widely used measure of PBS, the Protective Behavioral Strategies Scale (PBSS: Martens et al., 2005). An initial item pool was developed from literature on college student drinking, existing lists of drinking control strategies, and an online pilot survey of college students (N = 1,832). Items were also evaluated by focus groups of experts and members of the target population. Next, 1,376 students (57.9% women; Mage = 18.5 years; 86.3% White) completed questionnaires online. A subset (n = 170; 12.4%) completed a second survey 4-6 weeks later to examine test-retest reliability and criterion-related validity. The remaining students (n = 1,206) were divided into equal development and validation samples. Analyses included exploratory and confirmatory factor analysis of the development sample, factor structure replication, and gender invariance testing in the validity sample. Results of this process produced the PBSS-20, with an expanded SHR scale of eight items. The revised SHR scale demonstrated improved internal consistency and was associated with a broader range of alcohol-related negative consequences at follow-up. Given its focus on reducing serious harms, the SHR scale is arguably the most clinically relevant PBSS factor, and those who use this measure will benefit from the expanded breadth of SHR content and improved psychometric properties of the PBSS-20. PMID- 25558968 TI - A contemporary taxometric analysis of the latent structure of self-monitoring. AB - One of the most provocative findings in the personality psychology literature is evidence that the latent structure of self-monitoring is categorical. That is, individuals can be classified as either high or low self-monitors (Gangestad & Snyder, 1985). Surprisingly, in the three decades since its original publication, this study has never been replicated. Using the sample from the original study (N = 1,918) and a replication sample (N = 2,951), the latent structure of self monitoring was retested using contemporary taxometric procedures. Preliminary analyses indicated that the eight-item indicator set used in the original study lacked sufficient indicator validities for unambiguously detecting latent categorical structure. In addition, the Other-Directedness subscale, one of the three factor analytically derived subscale indicators used in the original investigation, was likewise found to be unsuitable, because of a combination of low validity and relative orthogonality vis-a-vis its fellow subscales. The 2 remaining subscales, Acting and Extraversion, had excellent properties as indicators, and were subsequently subjected to multiple taxometric procedures and consistency tests. Results failed to support the original taxonic claim; to the contrary, multiple comparison curves and a grand mean comparison curve fit index (CCFI) of .214 provided strong, convergent evidence that the latent structure of self-monitoring is dimensional rather than categorical. Dimensional findings indicate that the conventional model of self-monitoring may merit reexamination, and that theoretical models, measurement practices, and data analytic procedures that assume taxonicity should be replaced by dimensional conceptualizations and corresponding statistical procedures. Findings underscore the importance of replication in psychological science. PMID- 25558959 TI - Comparison of composted biosolid substrate for containerized turfgrass production. AB - Composts produced from composting municipal sewage sludge with bulking agent, namely hazelnut husk (HH), pine litter (PL), corn straw (CS) and sawdust (SW), were seeded with turfgrass mix and cultivated in a container to compare the suitability of composted substrates to produce turfgrass in greenhouse conditions. The performance of substrate was determined by both substrate properties compared to standard peat and by measuring plant growth parameters on each substrate during turfgrass sod establishment. In general, the physico chemical properties of all substrates were satisfactory for container substrates, but HH and PL substrates performed better in plant growth parameters than in SW and CS composts. The comprehensive growth index values obtained for plants growing in peat, HH and PL were 0.94, 0.87 and 0.84, respectively, which were higher than those in the CS and SW. Plant growth showed linear above-ground dry matter accumulation in all substrates, but was slower in SW and CS. HH and PL substrates appeared to be suitable for containerized sod production for natural soil and peat substitution. Biosolid proved to be an efficient component as a nutrient source ingredient of composted substrates for turfgrass. PMID- 25558953 TI - Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features. AB - The male sex chromosome disorder, 47,XYY syndrome (XYY), is associated with increased risk for social-emotional difficulties, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes. We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression and autistic behaviors (from questionnaires) in boys with XYY. The XYY cohort had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY vs. typically developing controls was increased twofold in the XYY group. Results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Males with XYY have social phenotypes that include increased risk for autism related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted. PMID- 25558966 TI - The Circumscribed Fear Measure: Development and initial validation of a trans stimulus phobia measure. AB - Extant stimulus-specific fear measures are limited to a small number of stimuli and contain significantly different content. This article describes 2 studies that develop a more flexible fear measure-the Circumscribed Fear Measure (CFM) and examine its psychometric properties. In Study 1, participants (N = 771) completed an initial item pool while considering their most feared stimulus. Results of factor analyses were used to propose a 25-item, 5-factor measure that would span the domain of specific phobia reactions, applicable to different stimuli. In Study 2, participants (N = 959) completed the 25-item CFM, extant phobia measures, and a measure of disability. The CFM exhibited a 5-scale structure that had an equivalent structure across different stimuli. It showed good factorial validity, reliability, and generally good convergent and discriminant validity. Criterion validity was commensurate with that of extant phobia measures. The use of the measure as an index of an individual's greatest fear is also discussed. The CFM shows promise and could have substantial research and clinical utility. PMID- 25558971 TI - Brief Moral Decision-Making Questionnaire: A Rasch-derived short form of the Greene dilemmas. AB - In this study, we developed the Brief Moral Decision-Making Questionnaire (BrMoD) as a standardized brief form of the dilemmas compiled by Greene and colleagues (Greene, Sommerville, Nystrom, Darley, & Cohen, 2001). An initial Rasch analysis was conducted over responses to 60 dilemmas to retain the most appropriate items. The psychometric properties of the 32-item brief instrument were determined in a community sample of 133 individuals using analyses from both the Rasch model and the classical test theory. The BrMoD scores showed appropriate reliability and construct validity. Differences between dilemma categories proposed by Greene et al. were observed in the BrMoD by measuring the difficulty of decisions and response times of the participants. In addition, there was no differential item functioning by the demographic variables. Therefore, the BrMoD is a good tool for assessing moral decision making in research or professional fields. PMID- 25558970 TI - The Internet Gaming Disorder Scale. AB - Recently, the American Psychiatric Association included Internet gaming disorder (IGD) in the appendix of the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The main aim of the current study was to test the reliability and validity of 4 survey instruments to measure IGD on the basis of the 9 criteria from the DSM-5: a long (27-item) and short (9-item) polytomous scale and a long (27-item) and short (9-item) dichotomous scale. The psychometric properties of these scales were tested among a representative sample of 2,444 Dutch adolescents and adults, ages 13-40 years. Confirmatory factor analyses demonstrated that the structural validity (i.e., the dimensional structure) of all scales was satisfactory. Both types of assessment (polytomous and dichotomous) were also reliable (i.e., internally consistent) and showed good criterion-related validity, as indicated by positive correlations with time spent playing games, loneliness, and aggression and negative correlations with self esteem, prosocial behavior, and life satisfaction. The dichotomous 9-item IGD scale showed solid psychometric properties and was the most practical scale for diagnostic purposes. Latent class analysis of this dichotomous scale indicated that 3 groups could be discerned: normal gamers, risky gamers, and disordered gamers. On the basis of the number of people in this last group, the prevalence of IGD among 13- through 40-year-olds in the Netherlands is approximately 4%. If the DSM-5 threshold for diagnosis (experiencing 5 or more criteria) is applied, the prevalence of disordered gamers is more than 5%. PMID- 25558974 TI - Tuning the spectroscopic properties of aryl carotenoids by slight changes in structure. AB - Two carotenoids with aryl rings were studied by femtosecond transient absorption spectroscopy and theoretical computational methods, and the results were compared with those obtained from their nonaryl counterpart, beta-carotene. Although isorenieratene has more conjugated C?C bonds than beta-carotene, its effective conjugation length, Neff, is shorter than of beta-carotene. This is evidenced by a longer S1 lifetime and higher S1 energy of isorenieratene compared to the values for beta-carotene. On the other hand, although isorenieratene and renierapurpurin have the same pi-electron conjugated chain structure, Neff is different for these two carotenoids. The S1 lifetime of renierapurpurin is shorter than that of isorenieratene, indicating a longer Neff for renierapurpurin. This conclusion is also consistent with a lower S1 energy of renierapurpurin compared to those of the other carotenoids. Density functional theory (DFT) was used to calculate equilibrium geometries of ground and excited states of all studied carotenoids. The terminal ring torsion in the ground state of isorenieratene (41 degrees ) is very close to that of beta-carotene (45 degrees ), but equilibration of the bond lengths within the aryl rings indicates that the each aryl ring forms its own conjugated system. This results in partial detachment of the aryl rings from the overall conjugation making Neff of isorenieratene shorter than that of beta-carotene. The different position of the methyl group at the aryl ring of renierapurpurin diminishes the aryl ring torsion to ~20 degrees . This planarization results in a longer Neff than that of isorenieratene, rationalizing the observed differences in spectroscopic properties. PMID- 25558975 TI - Derivation and validation phase for the development of clinical prediction rules for rehabilitation in chronic nonspecific low back pain patients: study protocol for a randomized controlled trial. AB - BACKGROUND: There is a consensus that exercise therapy should be used as a therapeutic approach in chronic low back pain (CLBP) but little consensus has been reached about the preferential type of therapy. Due to the heterogeneity of the population no clear effect of specific therapy interventions are found. Probably a specific subgroup of the investigated population will benefit from the intervention and another subgroup will not benefit, looking at the total investigated population no significant effects can be found. Therefore there is a need for the development of clinical prediction rules (CPRs). Objectives for this trial are first, the derivation of CPRs to predict treatment response to three forms of exercise therapy for patients with nonspecific CLBP. Secondly, we aim to validate a CPR for the three forms of exercise therapy for patients with nonspecific CLBP. METHODS/DESIGN: The study design is a randomized controlled trial. Patients with nonspecific CLBP of more than three months duration are recruited at the Antwerp University Hospital (Belgium) and Apra Rehabilitation Hospital. After examination, patients are randomly assigned to one of three intervention groups: motor control therapy, general active exercise therapy and isometric training therapy. All patients will undergo 18 treatment sessions during nine weeks. Measurements will be taken at baseline, nine weeks, six months and at one year. The primary outcome used is the Modified Oswestry Disability Questionnaire score. For each type of exercise therapy a CPR will be derived and validated. For validation, the CPR will be applied to divide each treatment group into two subgroups (matched and unmatched therapy) using the baseline measurements. We predict a better therapeutic effect for matched therapy. DISCUSSION: A randomized controlled trial has not previously been performed for the development of a CPR for exercise therapy in CLBP patients. Only one CPR was described in a single-arm design for motor control therapy in sub-acute non radicular LBP patients. In this study, a sufficiently large sample will be included in both the derivation and validation phase. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov on 10 February 2014, registration number: NCT02063503. PMID- 25558972 TI - Sterol metabolism controls T(H)17 differentiation by generating endogenous RORgamma agonists. AB - Retinoic acid receptor-related orphan receptor gamma (RORgammat) controls the differentiation of naive CD4(+) T cells into the TH17 lineage, which are critical cells in the pathogenesis of autoimmune diseases. Here we report that during TH17 differentiation, cholesterol biosynthesis and uptake programs are induced, whereas their metabolism and efflux programs are suppressed. These changes result in the accumulation of the cholesterol precursor, desmosterol, which functions as a potent endogenous RORgamma agonist. Generation of cholesterol precursors is essential for TH17 differentiation as blocking cholesterol synthesis with chemical inhibitors at steps before the formation of active precursors reduces differentiation. Upon activation, metabolic changes also lead to production of specific sterol-sulfate conjugates that favor activation of RORgamma over the TH17-inhibiting sterol receptor LXR. Thus, TH17 differentiation is orchestrated by coordinated sterol synthesis, mobilization and metabolism to selectively activate RORgamma. PMID- 25558981 TI - Erratum: An investigation on the association between students' knowledge and their tendency to take care of HIV patients among the students in nursing and midwifery school: Erratum. AB - [This corrects the article on p. 404 in vol. 19, PMID: 25183983.]. PMID- 25558978 TI - Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism. AB - Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using 'depletion of regulatory T-cell' (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)-GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF) beta1 inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4+CD25+CD127low Tregs and a relative increase in CD39+ cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy. PMID- 25558976 TI - Critical evaluation of root causes of the reduced compactability after roll compaction/dry granulation. AB - The influence of lubrication and particle size on the reduced compactability after dry granulation was investigated. Powder cellulose, lactose, magnesium carbonate, and two types of microcrystalline cellulose were roll compacted, granulated, and sieved into particle fractions. Particle fractions were compressed into tablets using internal and external lubrication. Internal lubrication resulted in an overlubrication of the granule material compared with the powder material. This resulted in extraordinary high reduction of compactability after dry granulation for lubricant-sensitive materials. The granule size can cause differences in strength, whereby the degree of this effect was material dependent. The loss in strength with increasing compaction force was comparable for different particles sizes of one material, suggesting a change in material properties independently of the size. Granule hardening could be one reason as for higher compaction forces the integrity of the granule structure survived the compression step. The results demonstrated that granule lubrication mainly influence the degree of the reduced compactability after dry granulation and must be considered for the evaluation of mechanism for this phenomenon. Hardening of the material as well as size enlargement will cause the loss in strength after recompression, but the influence of both depends strongly on the material. PMID- 25558988 TI - Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH). AB - From a research program aimed at the design of new chemical entities followed by extensive screening on various models of infectious diseases, an original series of 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidines endowed with notable antiviral properties were found. Using a whole cell measles virus replication assay, we describe here some aspects of the iterative process that, from 2-(4-benzyl-3 ethoxy-5-methyl-1H-pyrazol-1-yl)pyrimidine, led to 2-(4-(2,6-difluorophenoxy)-3 isopropoxy-5-methyl-1H-pyrazol-1-yl)-5-ethylpyrimidine and a 4000-fold improvement of antiviral activity with a subnanomolar level of inhibition. Moreover, recent precedents in the literature describing antiviral derivatives acting at the level of the de novo pyrimidine biosynthetic pathway led us to determine that the mode of action of this series is based on the inhibition of the cellular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this pathway. Biochemical studies with recombinant human DHODH led us to measure IC50 as low as 13 nM for the best example of this original series when using 2,3 dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone (coenzyme Q1) as a surrogate for coenzyme Q10, the cofactor of this enzyme. PMID- 25558973 TI - Opposing effects of folding and assembly chaperones on evolvability of Rubisco. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) catalyzes the fixation of CO2 in photosynthesis. Despite its pivotal role, Rubisco is an inefficient enzyme and thus is a key target for directed evolution. Rubisco biogenesis depends on auxiliary factors, including the GroEL/ES-type chaperonin for folding and the chaperone RbcX for assembly. Here we performed directed evolution of cyanobacterial form I Rubisco using a Rubisco-dependent Escherichia coli strain. Overexpression of GroEL/ES enhanced Rubisco solubility and tended to expand the range of permissible mutations. In contrast, the specific assembly chaperone RbcX had a negative effect on evolvability by preventing a subset of mutants from forming holoenzyme. Mutation F140I in the large Rubisco subunit, isolated in the absence of RbcX, increased carboxylation efficiency approximately threefold without reducing CO2 specificity. The F140I mutant resulted in a ~55% improved photosynthesis rate in Synechocystis PCC6803. The requirement of specific biogenesis factors downstream of chaperonin may have retarded the natural evolution of Rubisco. PMID- 25558987 TI - Recent trends in the prevalence of under- and overweight among adolescent girls in low- and middle-income countries. AB - BACKGROUND: Most studies of childhood malnutrition in low- and middle-income countries (LMICs) focus on children <5 years, with few focusing on adolescence, a critical stage in development. OBJECTIVE: This study aimed to evaluate recent trends in the prevalence of under- and overweight among girls (15-18 years) in LMICs. METHODS: Data are from Demographic and Health Surveys (53 countries) and national surveys conducted in Indonesia, China, Vietnam, Brazil and Mexico. The most recent surveys with sample sizes >=50 when stratified by rural-urban status were included: 46.6% of countries had a survey conducted in the past 5 years, while the most recent survey for 10.3% of countries was over 10 years old. The overall rural sample size was 94,857 and urban sample size was 81,025. Under- and overweight were defined using the International Obesity Task Force (IOTF) sex- and age-specific body mass index cut points. RESULTS: South Asia had the highest prevalence of underweight; nearly double that of East Asia and the Pacific and sub-Saharan Africa, and increasing annually by 0.66% in rural areas. Latin America and the Caribbean had the highest regional prevalence of overweight in both rural and urban settings, and this prevalence is increasing annually by about 0.50%. In urban areas, 38% of countries had both an under- and overweight prevalence >=10%. CONCLUSIONS: There is substantial variation across and within regions in the burden of under- and overweight, with increasing dual burdens in urban areas. Innovative public health interventions capable of addressing both ends of the malnutrition spectrum are urgently needed. PMID- 25558990 TI - Design and deployment of low-cost plastic optical fiber sensors for gas monitoring. AB - This paper describes an approach to develop and deploy low-cost plastic optical fiber sensors suitable for measuring low concentrations of pollutants in the atmosphere. The sensors are designed by depositing onto the exposed core of a plastic fiber thin films of sensitive compounds via either plasma sputtering or via plasma-enhanced chemical vapor deposition (PECVD). The interaction between the deposited layer and the gas alters the fiber's capability to transmit the light, so that the sensor can simply be realized with a few centimeters of fiber, an LED and a photodiode. Sensors arranged in this way exhibit several advantages in comparison to electrochemical and optical conventional sensors; in particular, they have an extremely low cost and can be easily designed to have an integral, i.e., cumulative, response. The paper describes the sensor design, the preparation procedure and two examples of sensor prototypes that exploit a cumulative response. One sensor is designed for monitoring indoor atmospheres for cultural heritage applications and the other for detecting the presence of particular gas species inside the RPC (resistive plate chamber) muon detector of the Compact Muon Solenoid (CMS) experiment at CERN in Geneva. PMID- 25558984 TI - CtIP tetramer assembly is required for DNA-end resection and repair. AB - Mammalian CtIP protein has major roles in DNA double-strand break (DSB) repair. Although it is well established that CtIP promotes DNA-end resection in preparation for homology-dependent DSB repair, the molecular basis for this function has remained unknown. Here we show by biophysical and X-ray crystallographic analyses that the N-terminal domain of human CtIP exists as a stable homotetramer. Tetramerization results from interlocking interactions between the N-terminal extensions of CtIP's coiled-coil region, which lead to a 'dimer-of-dimers' architecture. Through interrogation of the CtIP structure, we identify a point mutation that abolishes tetramerization of the N-terminal domain while preserving dimerization in vitro. Notably, we establish that this mutation abrogates CtIP oligomer assembly in cells, thus leading to strong defects in DNA end resection and gene conversion. These findings indicate that the CtIP tetramer architecture described here is essential for effective DSB repair by homologous recombination. PMID- 25558983 TI - A comparison of fentanyl with pethidine for pain relief during childbirth: a randomised controlled trial. AB - OBJECTIVE: To compare the efficacy of fentanyl administered via the subcutaneous (s.c.) or intranasal (i.n.) route with intramuscular (i.m.) pethidine in labouring women requesting analgesia. DESIGN: A randomised controlled trial three armed, parallel-design. SETTING: A regional hospital and the largest tertiary maternity centre in South Australia. SAMPLE: One hundred and fifty-six healthy parturients birthing at term. METHODS: Women were randomised to receive s.c. fentanyl (n = 53), i.n. fentanyl (n = 52), or i.m. pethidine (n = 51). The outcomes were analysed by intention-to-treat. MAIN OUTCOME MEASURES: Pain scores measured before and 30 minutes after opioid administration. RESULTS: All groups reported clinically significant reductions in pain scores (mean range 1.2-1.6; P < 0.001), with no significant differences between groups. Significantly more women in the fentanyl groups reported satisfaction with using the study drug again, compared with women receiving i.m. pethidine (82.9% i.n. fentanyl, 80.6% s.c. fentanyl, and 44.0% i.m. pethidine; P < 0.01). Women in the fentanyl groups experienced less sedation (i.n. fentanyl 7.3%, s.c. fentanyl 2.9%, i.m. pethidine 44%; P <= 0.03), shorter labours by at least 2 hours (P < 0.05), and fewer difficulties establishing breastfeeding (78.8% i.m. pethidine, 39.4% i.n. fentanyl, and 44.0% s.c. fentanyl; P < 0.01). Neonates in the pethidine group were more likely to require nursery admission (P < 0.02). CONCLUSIONS: Fentanyl administered by s.c. and i.n. routes is as efficacious in relieving labour pain as i.m. pethidine, but resulted in greater satisfaction, less sedation, shorter labour, fewer nursery admissions, and fewer difficulties in establishing breastfeeding. Fentanyl appears to be a suitable alternative to pethidine when providing parenteral pain relief to labouring women. PMID- 25558982 TI - Metal-free arylation of ethyl acetoacetate with hypervalent diaryliodonium salts: an immediate access to diverse 3-aryl-4(1H)-quinolones. AB - A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics, was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development. PMID- 25558985 TI - Charge-driven dynamics of nascent-chain movement through the SecYEG translocon. AB - On average, every fifth residue in secretory proteins carries either a positive or a negative charge. In a bacterium such as Escherichia coli, charged residues are exposed to an electric field as they transit through the inner membrane, and this should generate a fluctuating electric force on a translocating nascent chain. Here, we have used translational arrest peptides as in vivo force sensors to measure this electric force during cotranslational chain translocation through the SecYEG translocon. We find that charged residues experience a biphasic electric force as they move across the membrane, including an early component with a maximum when they are 47-49 residues away from the ribosomal P site, followed by a more slowly varying component. The early component is generated by the transmembrane electric potential, whereas the second may reflect interactions between charged residues and the periplasmic membrane surface. PMID- 25558997 TI - Analysis of discrimination techniques for low-cost narrow-band spectrofluorometers. AB - The need for covering large areas in oceanographic measurement campaigns and the general interest in reducing the observational costs open the necessity to develop new strategies towards this objective, fundamental to deal with current and future research projects. In this respect, the development of low-cost instruments becomes a key factor, but optimal signal-processing techniques must be used to balance their measurements with those obtained from accurate but expensive instruments. In this paper, a complete signal-processing chain to process the fluorescence spectra of marine organisms for taxonomic discrimination is proposed. It has been designed to deal with noisy, narrow-band and low resolution data obtained from low-cost sensors or instruments and to optimize its computational cost, and it consists of four separated blocks that denoise, normalize, transform and classify the samples. For each block, several techniques are tested and compared to find the best combination that optimizes the classification of the samples. The signal processing has been focused on the Chlorophyll-a fluorescence peak, since it presents the highest emission levels and it can be measured with sensors presenting poor sensitivity and signal-to noise ratios. The whole methodology has been successfully validated by means of the fluorescence spectra emitted by five different cultures. PMID- 25558998 TI - New system for measuring impact vibration on floor decking sheets. AB - Currently, there is a narrow range of materials that are used as attenuators of impact noise and building vibrations. Materials used in construction, such as elastic materials, must meet the requirement of having very low elastic modulus values. For the determination of the material's elastic modulus and the acoustic insulation of the same, costly and difficult to execute testing is required. The present paper exposes an alternative system that is simpler and more economic, consisting of a predefined striking device and a sensor able to determine, once the strike is produced, the energy absorbed by the plate. After the impact is produced, the plate undergoes a deformation, which absorbs part of the energy, the remaining part being transmitted to the slab and, at the same time, causing induced airborne noise in the adjoining room. The plate absorbs the power through its own deformation, which is measured with the help of a capacitive sensor. This way, it would be possible to properly define the geometry of the plates, after the execution of the test, and we will try to establish a relationship between the values proposed in this research and the acoustic behavior demanded by the Spanish standards. PMID- 25558992 TI - Development and characterization of a diamond-insulated graphitic multi electrode array realized with ion beam lithography. AB - The detection of quantal exocytic events from neurons and neuroendocrine cells is a challenging task in neuroscience. One of the most promising platforms for the development of a new generation of biosensors is diamond, due to its biocompatibility, transparency and chemical inertness. Moreover, the electrical properties of diamond can be turned from a perfect insulator into a conductive material (resistivity ~mOmega.cm) by exploiting the metastable nature of this allotropic form of carbon. A 16-channels MEA (Multi Electrode Array) suitable for cell culture growing has been fabricated by means of ion implantation. A focused 1.2 MeV He+ beam was scanned on a IIa single-crystal diamond sample (4.5 * 4.5 * 0.5 mm3) to cause highly damaged sub-superficial structures that were defined with micrometric spatial resolution. After implantation, the sample was annealed. This process provides the conversion of the sub-superficial highly damaged regions to a graphitic phase embedded in a highly insulating diamond matrix. Thanks to a three-dimensional masking technique, the endpoints of the sub superficial channels emerge in contact with the sample surface, therefore being available as sensing electrodes. Cyclic voltammetry and amperometry measurements of solutions with increasing concentrations of adrenaline were performed to characterize the biosensor sensitivity. The reported results demonstrate that this new type of biosensor is suitable for in vitro detection of catecholamine release. PMID- 25558986 TI - Role of the chemokine receptor CCR5-dependent host defense system in Neospora caninum infections. AB - BACKGROUND: Neospora caninum, a Toxoplasma gondii-like obligate intracellular parasite, causes abortion in cattle and neurological signs in canines. To understand neosporosis better, studies on host cell migration and host immune responses during the early phase of infection are important. Although the C-C chemokine receptor 5 (CCR5) plays a crucial role in immune cell migration, the role played by it in protective immunity against N. caninum is poorly understood. METHODS: CCR5(-/-) mice were used to investigate their sensitivity levels to N. caninum infection and their ability to activate immune cells against this parasite. RESULTS: Increased mortality and neurological impairment were observed in the N. caninum-infected CCR5(-/-) mice. In comparison with wild-type mice, CCR5(-/-) mice experienced poor migration of dendritic cells and natural killer T cells to the site of infection. Dendritic cells in an in vitro culture from CCR5( /-) mice could not be activated upon infection with N. caninum. Furthermore, higher levels of IFN-gamma and CCL5 expression, which are associated with brain tissue damage, were observed in the brain tissue of CCR5(-/-) mice during the acute phase of the infection, while there was no significant difference in the parasite load between the wild-type and CCR5(-/-) animals. Additionally, a primary microglia culture from CCR5(-/-) mice showed lower levels of IL-6 and IL 12 production against N. caninum parasites. CONCLUSIONS: Our findings show that migration and activation of immune cells via CCR5 is required for controlling N. caninum parasites during the early phase of the infection. PMID- 25558979 TI - Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: a systematic review and meta-analysis of observational studies. AB - The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes. PMID- 25558977 TI - Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain. AB - OBJECTIVE: Stroke is a leading cause of mortality and disability. The peptidyl prolyl cis/trans isomerase Pin1 regulates factors involved in cell growth. Recent evidence has shown that Pin1 plays a major role in apoptosis. However, the role of Pin1 in ischemic stroke remains to be investigated. METHODS: We used Pin1 overexpression and knockdown to manipulate Pin1 expression and explore the effects of Pin1 in cell death on ischemic stress in vitro and in a mouse stroke model. We also used Pin 1 inhibitor, gamma-secretase inhibitor, Notch1 intracellular domain (NICD1)-deleted mutant cells, and Pin1 mutant cells to investigate the underlying mechanisms of Pin1-NICD1-mediated cell death. RESULTS: Our findings indicate that Pin1 facilitates NICD1 stability and its proapoptotic function following ischemic stroke. Thus, overexpression of Pin1 increased NICD1 levels and enhanced its potentiation of neuronal death in simulated ischemia. By contrast, depletion or knockout of Pin1 reduced the NICD1 level, which in turn desensitized neurons to ischemic conditions. Pin1 interacted with NICD1 and increased its stability by inhibiting FBW7-induced polyubiquitination. We also demonstrate that Pin1 and NICD1 levels increase following stroke. Pin1 heterozygous (+/-) and knockout (-/-) mice, and also wild-type mice treated with an inhibitor of Pin1, each showed reduced brain damage and improved functional outcomes in a model of focal ischemic stroke. INTERPRETATION: These results suggest that Pin1 contributes to the pathogenesis of ischemic stroke by promoting Notch signaling, and that inhibition of Pin1 is a novel approach for treating ischemic stroke. PMID- 25558999 TI - Rapid elemental analysis and provenance study of Blumea balsamifera DC using laser-induced breakdown spectroscopy. AB - Laser-induced breakdown spectroscopy (LIBS) was applied to perform a rapid elemental analysis and provenance study of Blumea balsamifera DC. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were implemented to exploit the multivariate nature of the LIBS data. Scores and loadings of computed principal components visually illustrated the differing spectral data. The PLS-DA algorithm showed good classification performance. The PLS-DA model using complete spectra as input variables had similar discrimination performance to using selected spectral lines as input variables. The down selection of spectral lines was specifically focused on the major elements of B. balsamifera samples. Results indicated that LIBS could be used to rapidly analyze elements and to perform provenance study of B. balsamifera. PMID- 25558994 TI - Combining electrochemical sensors with miniaturized sample preparation for rapid detection in clinical samples. AB - Clinical analyses benefit world-wide from rapid and reliable diagnostics tests. New tests are sought with greatest demand not only for new analytes, but also to reduce costs, complexity and lengthy analysis times of current techniques. Among the myriad of possibilities available today to develop new test systems, amperometric biosensors are prominent players-best represented by the ubiquitous amperometric-based glucose sensors. Electrochemical approaches in general require little and often enough only simple hardware components, are rugged and yet provide low limits of detection. They thus offer many of the desirable attributes for point-of-care/point-of-need tests. This review focuses on investigating the important integration of sample preparation with (primarily electrochemical) biosensors. Sample clean up requirements, miniaturized sample preparation strategies, and their potential integration with sensors will be discussed, focusing on clinical sample analyses. PMID- 25558995 TI - Non-invasive UWB sensing of astronauts' breathing activity. AB - The use of a UWB system for sensing breathing activity of astronauts must account for many critical issues specific to the space environment. The aim of this paper is twofold. The first concerns the definition of design constraints about the pulse amplitude and waveform to transmit, as well as the immunity requirements of the receiver. The second issue concerns the assessment of the procedures and the characteristics of the algorithms to use for signal processing to retrieve the breathing frequency and respiration waveform. The algorithm has to work correctly in the presence of surrounding electromagnetic noise due to other sources in the environment. The highly reflecting walls increase the difficulty of the problem and the hostile scenario has to be accurately characterized. Examples of signal processing techniques able to recover breathing frequency in significant and realistic situations are shown and discussed. PMID- 25559000 TI - Pseudo optimization of e-nose data using region selection with feature feedback based on regularized linear discriminant analysis. AB - In this paper, we present a pseudo optimization method for electronic nose (e nose) data using region selection with feature feedback based on regularized linear discriminant analysis (R-LDA) to enhance the performance and cost functions of an e-nose system. To implement cost- and performance-effective e nose systems, the number of channels, sampling time and sensing time of the e nose must be considered. We propose a method to select both important channels and an important time-horizon by analyzing e-nose sensor data. By extending previous feature feedback results, we obtain a two-dimensional discriminant information map consisting of channels and time units by reverse mapping the feature space to the data space based on R-LDA. The discriminant information map enables optimal channels and time units to be heuristically selected to improve the performance and cost functions. The efficacy of the proposed method is demonstrated experimentally for different volatile organic compounds. In particular, our method is both cost and performance effective for the real implementation of e-nose systems. PMID- 25558980 TI - Novel associations between FAAH genetic variants and postoperative central opioid related adverse effects. AB - Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy. PMID- 25558993 TI - A fumonisins immunosensor based on polyanilino-carbon nanotubes doped with palladium telluride quantum dots. AB - An impedimetric immunosensor for fumonisins was developed based on poly(2,5 dimethoxyaniline)-multi-wall carbon nanotubes doped with palladium telluride quantum dots onto a glassy carbon surface. The composite was assembled by a layer by-layer method to form a multilayer film of quantum dots (QDs) and poly(2,5 dimethoxyaniline)-multi-wall carbon nanotubes (PDMA-MWCNT). Preparation of the electrochemical immunosensor for fumonisins involved drop-coating of fumonisins antibody onto the composite modified glassy carbon electrode. The electrochemical impedance spectroscopy response of the FB1 immunosensor (GCE/PT-PDMA-MWCNT/anti Fms-BSA) gave a linear range of 7 to 49 ng L-1 and the corresponding sensitivity and detection limits were 0.0162 kOmega L ng-1 and 0.46 pg L-1, respectively, hence the limit of detection of the GCE/PT-PDMA-MWCNT immunosensor for fumonisins in corn certified material was calculated to be 0.014 and 0.011 ppm for FB1, and FB2 and FB3, respectively. These results are lower than those obtained by ELISA, a provisional maximum tolerable daily intake (PMTDI) for fumonisins (the sum of FB1, FB2, and FB3) established by the Joint FAO/WHO expert committee on food additives and contaminants of 2 MUg kg-1 and the maximum level recommended by the U.S. Food and Drug Administration (FDA) for protection of human consumption (2-4 mg L-1). PMID- 25558989 TI - Optofluidic approaches for enhanced microsensor performances. AB - Optofluidics is a relatively young research field able to create a tight synergy between optics and micro/nano-fluidics. The high level of integration between fluidic and optical elements achievable by means of optofluidic approaches makes it possible to realize an innovative class of sensors, which have been demonstrated to have an improved sensitivity, adaptability and compactness. Many developments in this field have been made in the last years thanks to the availability of a new class of low cost materials and new technologies. This review describes the Italian state of art on optofluidic devices for sensing applications and offers a perspective for further future advances. We introduce the optofluidic concept and describe the advantages of merging photonic and fluidic elements, focusing on sensor developments for both environmental and biomedical monitoring. PMID- 25558991 TI - Nanomaterials-based optical techniques for the detection of acetylcholinesterase and pesticides. AB - The large amount of pesticide residues in the environment is a threat to global health by inhibition of acetylcholinesterase (AChE). Biosensors for inhibition of AChE have been thus developed for the detection of pesticides. In line with the rapid development of nanotechnology, nanomaterials have attracted great attention and have been intensively studied in biological analysis due to their unique chemical, physical and size properties. The aim of this review is to provide insight into nanomaterial-based optical techniques for the determination of AChE and pesticides, including colorimetric and fluorescent assays and surface plasmon resonance. PMID- 25559001 TI - Performance comparison of cross-like Hall plates with different covering layers. AB - This paper studies the effects of the covering layers on the performance of a cross-like Hall plate. Three different structures of a cross-like Hall plate in various sizes are designed and analyzed. The Hall plate sensitivity and offset are characterized using a self-built measurement system. The effect of the P-type region over the active area on the current-related sensitivity is studied for different Hall plate designs. In addition, the correlation between the P-type covering layer and offset is analyzed. The best structure out of three designs is determined. Besides, a modified eight-resistor circuit model for the Hall plate is presented with improved accuracy by taking the offset into account. PMID- 25558996 TI - Simultaneous automatic electrochemical detection of zinc, cadmium, copper and lead ions in environmental samples using a thin-film mercury electrode and an artificial neural network. AB - In this study a device for automatic electrochemical analysis was designed. A three electrodes detection system was attached to a positioning device, which enabled us to move the electrode system from one well to another of a microtitre plate. Disposable carbon tip electrodes were used for Cd(II), Cu(II) and Pb(II) ion quantification, while Zn(II) did not give signal in this electrode configuration. In order to detect all mentioned heavy metals simultaneously, thin film mercury electrodes (TFME) were fabricated by electrodeposition of mercury on the surface of carbon tips. In comparison with bare electrodes the TMFEs had lower detection limits and better sensitivity. In addition to pure aqueous heavy metal solutions, the assay was also performed on mineralized rock samples, artificial blood plasma samples and samples of chicken embryo organs treated with cadmium. An artificial neural network was created to evaluate the concentrations of the mentioned heavy metals correctly in mixture samples and an excellent fit was observed (R2 = 0.9933). PMID- 25559004 TI - Quantifying recording quality in in vivo striatal recordings. AB - The striatum mediates a variety of functions including movement, decision-making, motivation, and reward learning. In vivo recording is a powerful technique that allows for the interrogation of these striatal functions while an animal is awake and behaving. Here, we describe equipment needed and general setup for performing in vivo electrophysiology experiments, data processing, and quantification of recording quality. While this protocol is focused on striatal recordings, concepts should translate to other structures as well. PMID- 25559002 TI - Non-isotopic RNA In Situ Hybridization on Embryonic Sections. AB - This unit describes methods for non-isotopic RNA in situ hybridization on embryonic mouse sections. These methods can be used to follow the spatiotemporal dynamics of gene expression in an embryonic tissue of interest. They involve the use of labeled (e.g., digoxygenin, FITC) antisense riboprobes that hybridize to a specific mRNA in the target tissue. The probes are detected using an alkaline phosphatase-conjugated antibody recognizing the label and a chromogenic substrate. This method can be used to: (1) assess the expression of a single gene within a tissue, (2) compare the expression profiles of two genes within a tissue, or (3) compare the distribution of a transcript and protein within a tissue. While this approach is not quantitative, it provides a qualitative assessment of the precise cell types where a gene is expressed, which is not easily achievable with other more quantitative methods such as quantitative PCR. PMID- 25559006 TI - Avoidance behavior: a free-operant lever-press avoidance task for the assessment of the effects of safety signals. AB - This protocol details a free-operant avoidance paradigm that has been developed to evaluate the relative contribution of different sources of reinforcement of avoidance behavior that may play an important role in the development and maintenance of human anxiety disorders. The task enables the assessment of the effects of safety cues that signal a period free from danger on lever-press avoidance behavior. Avoidance behavior trained using this protocol has been shown to be sensitive to both behavioral and pharmacological manipulations and has been optimized so that it takes approximately 1 month for rats to perform at high levels of stable avoidance responding. PMID- 25559007 TI - To stress or not to stress: a question of models. AB - Stress research is a rapidly evolving field that encompasses numerous disciplines ranging from neuroscience to metabolism. With many new researchers migrating into the field, navigating the hows and whys of specific research questions can sometimes be enigmatic given the availability of so many models in the stress field. Additionally, as with every field, there are many seemingly minor experimental details that can have dramatic influences on data interpretation, although many of these are unknown to those not familiar with the field. The aim of this overview is to provide some suggestions and points to guide researchers moving into the stress field and highlight relevant methodological points that they should consider when choosing a model for stress and deciding how to structure a study. We briefly provide a primer on the basics of endpoint measurements in the stress field, factors to consider when choosing a model for acute stress, the difference between repeated and chronic stress, and importantly, influencing variables that modulate endpoints of analysis in stress work. PMID- 25559008 TI - Hand-to-mouth contacts result in greater ingestion of feces than dietary water consumption in Tanzania: a quantitative fecal exposure assessment model. AB - Diarrheal diseases kill 1800 children under the age of five die each day, and nearly half of these deaths occur in sub-Saharan Africa. Contaminated drinking water and hands are two important environmental transmission routes of diarrhea causing pathogens to young children in low-income countries. The objective of this research is to evaluate the relative contribution of these two major exposure pathways in a low-income country setting. A Monte Carlo simulation was used to model the amount of human feces ingested by children under five years old from exposure via hand-to-mouth contacts and stored drinking water ingestion in Bagamoyo, Tanzania. Child specific exposure data were obtained from the USEPA 2011 Exposure Factors Handbook, and fecal contamination was estimated using hand rinse and stored water fecal indicator bacteria concentrations from over 1200 Tanzanian households. The model outcome is a distribution of a child's daily dose of feces via each exposure route. The model results show that Tanzanian children ingest a significantly greater amount of feces each day from hand-to-mouth contacts than from drinking water, which may help elucidate why interventions focused on water without also addressing hygiene often see little to no effect on reported incidence of diarrhea. PMID- 25559003 TI - Imaging the Insertion of Superecliptic pHluorin-Labeled Dopamine D2 Receptor Using Total Internal Reflection Fluorescence Microscopy. AB - A better understanding of mechanisms governing receptor insertion to the plasma membrane (PM) requires an experimental approach with excellent spatial and temporal resolutions. Here we present a strategy that enables dynamic visualization of insertion events for dopamine D2 receptors into the PM. This approach includes tagging a pH-sensitive GFP, superecliptic pHluorin, to the extracellular domain of the receptor. By imaging pHluorin-tagged receptors under total internal reflection fluorescence microscopy (TIRFM), we were able to directly visualize individual receptor insertion events into the PM in cultured neurons. This novel imaging approach can be applied to both secreted proteins and many membrane proteins with an extracellular domain labeled with superecliptic pHluorin, and will ultimately allow for detailed dissections of the key mechanisms governing secretion of soluble proteins or the insertion of different membrane proteins to the PM. PMID- 25559005 TI - Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake, behaving rats. AB - Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion, and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of components required to sample and analyze dopamine concentration changes in awake rats with FSCV. PMID- 25559009 TI - Effects of daily almond consumption on cardiometabolic risk and abdominal adiposity in healthy adults with elevated LDL-cholesterol: a randomized controlled trial. AB - BACKGROUND: Evidence consistently shows that almond consumption beneficially affects lipids and lipoproteins. Almonds, however, have not been evaluated in a controlled-feeding setting using a diet design with only a single, calorie matched food substitution to assess their specific effects on cardiometabolic risk factors. METHODS AND RESULTS: In a randomized, 2-period (6 week/period), crossover, controlled-feeding study of 48 individuals with elevated LDL-C (149+/ 3 mg/dL), a cholesterol-lowering diet with almonds (1.5 oz. of almonds/day) was compared to an identical diet with an isocaloric muffin substitution (no almonds/day). Differences in the nutrient profiles of the control (58% CHO, 15% PRO, 26% total fat) and almond (51% CHO, 16% PRO, 32% total fat) diets were due to nutrients inherent to each snack; diets did not differ in saturated fat or cholesterol. The almond diet, compared with the control diet, decreased non-HDL-C (-6.9+/-2.4 mg/dL; P=0.01) and LDL-C (-5.3+/-1.9 mg/dL; P=0.01); furthermore, the control diet decreased HDL-C (-1.7+/-0.6 mg/dL; P<0.01). Almond consumption also reduced abdominal fat (-0.07+/-0.03 kg; P=0.02) and leg fat (-0.12+/-0.05 kg; P=0.02), despite no differences in total body weight. CONCLUSIONS: Almonds reduced non-HDL-C, LDL-C, and central adiposity, important risk factors for cardiometabolic dysfunction, while maintaining HDL-C concentrations. Therefore, daily consumption of almonds (1.5 oz.), substituted for a high-carbohydrate snack, may be a simple dietary strategy to prevent the onset of cardiometabolic diseases in healthy individuals. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov; Unique Identifier: NCT01101230. PMID- 25559011 TI - Evaluation of effectiveness and cost-effectiveness of a clinical decision support system in managing hypertension in resource constrained primary health care settings: results from a cluster randomized trial. AB - BACKGROUND: Randomized control trials from the developed world report that clinical decision support systems (DSS) could provide an effective means to improve the management of hypertension (HTN). However, evidence from developing countries in this regard is rather limited, and there is a need to assess the impact of a clinical DSS on managing HTN in primary health care center (PHC) settings. METHODS AND RESULTS: We performed a cluster randomized trial to test the effectiveness and cost-effectiveness of a clinical DSS among Indian adult hypertensive patients (between 35 and 64 years of age), wherein 16 PHC clusters from a district of Telangana state, India, were randomized to receive either a DSS or a chart-based support (CBS) system. Each intervention arm had 8 PHC clusters, with a mean of 102 hypertensive patients per cluster (n=845 in DSS and 783 in CBS groups). Mean change in systolic blood pressure (SBP) from baseline to 12 months was the primary endpoint. The mean difference in SBP change from baseline between the DSS and CBS at the 12th month of follow-up, adjusted for age, sex, height, waist, body mass index, alcohol consumption, vegetable intake, pickle intake, and baseline differences in blood pressure, was -6.59 mm Hg (95% confidence interval: -12.18 to -1.42; P=0.021). The cost-effective ratio for CBS and DSS groups was $96.01 and $36.57 per mm of SBP reduction, respectively. CONCLUSION: Clinical DSS are effective and cost-effective in the management of HTN in resource-constrained PHC settings. CLINICAL TRIAL REGISTRATION URL: http://www.ctri.nic.in. Unique identifier: CTRI/2012/03/002476. PMID- 25559010 TI - Role of heme in cardiovascular physiology and disease. PMID- 25559013 TI - Implementation of the third universal definition of myocardial infarction after coronary artery bypass grafting: a survey study in Western Europe. AB - BACKGROUND: Diagnosing a postoperative myocardial infarction in patients undergoing coronary artery bypass grafting is challenging, as the normally used criteria are more difficult to interpret. The rate of implementation of the consensus-based new diagnostic criteria for postoperative myocardial infarction proposed by the third universal definition of myocardial infarction is unknown. Therefore, the primary objective of this study was to address the implementation of the third universal definition of postoperative myocardial infarction following coronary artery bypass grafting. METHODS AND RESULTS: We conducted a web-based survey by sending 4 waves of invitations via e-mail to cardiothoracic surgeons in 12 Western European countries. Of the 302 participating cardiothoracic specialists, from 182 different centers, 213 (71%) were aware that troponin is the preferred biomarker and 112 (37%) knew that using a cut-off level of >10 times the 99th percentile is recommended. Overall, 90 (30%) participants (strongly) agreed with implementation of this cut-off level in their clinical practice. Troponin was used in clinical practice by 149 (49%) of the participants. In total, 117 (89%) of the 131 participants with a local guideline confirmed ECG changes as a diagnostic criterion in that guideline. ST segmental changes (75, 64%) were used more often for diagnosing postoperative myocardial infarction than Q waves (64, 55%) or new left bundle branch blocks (34, 29%). CONCLUSIONS: Cardiac biomarkers and ECG changes were not used in concordance with the third universal definition, and only a minority had a positive attitude toward implementation of the proposed cut-off level for troponin in their clinical practice. PMID- 25559012 TI - Incidence and risk factors of ventricular fibrillation before primary angioplasty in patients with first ST-elevation myocardial infarction: a nationwide study in Denmark. AB - BACKGROUND: We aimed to investigate the incidence and risk factors for ventricular fibrillation (VF) before primary percutaneous coronary intervention (PPCI) among patients with ST-segment elevation myocardial infarction (STEMI) in a prospective nationwide setting. METHODS AND RESULTS: In this case-control study, patients presenting within the first 12 hours of first STEMI who survived to undergo angiography and subsequent PPCI were enrolled. Over 2 years, 219 cases presenting with VF before PPCI and 441 controls without preceding VF were enrolled. Of the 219 case patients, 182 (83%) had STEMI with out-of-hospital cardiac arrest due to VF, and 37 (17%) had cardiac arrest upon arrival to the emergency room. Medical history was collected by standardized interviews and by linkage to national electronic health records. The incidence of VF before PPCI among STEMI patients was 11.6%. Multivariable logistic regression analysis identified novel associations between atrial fibrillation and alcohol consumption with VF. Patients with a history of atrial fibrillation had a 2.80-fold odds of experiencing VF before PPCI (95% CI 1.10 to 7.30). Compared with nondrinkers, patients who consumed 1 to 7 units, 8 to 14 units, or >15 units of alcohol per week had an odds ratio (OR) of 1.30 (95% CI, 0.80 to 2.20), 2.30 (95% CI, 1.20 to 4.20), or 3.30 (95% CI, 1.80 to 5.90), respectively, for VF. Previously reported associations for preinfarction angina (OR 0.46; 95% CI 0.32 to 0.67), age of <60 years (OR 1.75; 95% CI 1.20 to 2.60), anterior infarction (OR 2.10; 95% CI 1.40 to 3.00), preprocedural thrombolysis in myocardial infarction flow grade 0 (OR 1.65; 95% CI 1.14 to 2.40), and family history of sudden death (OR 1.60; 95% CI 1.10 to 2.40) were all associated with VF. CONCLUSION: Several easily assessed risk factors were associated with VF occurring out-of-hospital or on arrival at the emergency room before PPCI in STEMI patients, thus providing potential avenues for investigation regarding improved identification and prevention of life-threatening ventricular arrhythmias. PMID- 25559014 TI - Effect of cardiogenic shock hospital volume on mortality in patients with cardiogenic shock. AB - BACKGROUND: Cardiogenic shock (CS) is associated with significant morbidity, and mortality rates approach 40% to 60%. Treatment for CS requires an aggressive, sophisticated, complex, goal-oriented, therapeutic regimen focused on early revascularization and adjunctive supportive therapies, suggesting that hospitals with greater CS volume may provide better care. The association between CS hospital volume and inpatient mortality for CS is unclear. METHODS AND RESULTS: We used the Nationwide Inpatient Sample to examine 533 179 weighted patient discharges from 2675 hospitals with CS from 2004 to 2011 and divided them into quartiles of mean annual hospital CS case volume. The primary outcome was in hospital mortality. Multivariate adjustments were performed to account for severity of illness, relevant comorbidities, hospital characteristics, and differences in treatment. Compared with the highest volume quartile, the adjusted odds ratio for inpatient mortality for persons admitted to hospitals in the lowest-volume quartile (<=27 weighted cases per year) was 1.27 (95% CI 1.15 to 1.40), whereas for admission to hospitals in the low-volume and medium-volume quartiles, the odds ratios were 1.20 (95% CI 1.08 to 1.32) and 1.12 (95% CI 1.01 to 1.24), respectively. Similarly, improved survival was observed across quartiles, with an adjusted inpatient mortality incidence of 41.97% (95% CI 40.87 to 43.08) for hospitals with the lowest volume of CS cases and a drop to 37.01% (95% CI 35.11 to 38.96) for hospitals with the highest volume of CS cases. Analysis of treatments offered between hospital quartiles revealed that the centers with volumes in the highest quartile demonstrated significantly higher numbers of patients undergoing coronary artery bypass grafting, percutaneous coronary intervention, or intra-aortic balloon pump counterpulsation. A similar relationship was demonstrated with the use of mechanical circulatory support (ventricular assist devices and extracorporeal membrane oxygenation), for which there was significantly higher use in the higher volume quartiles. CONCLUSIONS: We demonstrated an association between lower CS case volume and higher mortality. There is more frequent use of both standard supportive and revascularization techniques at the higher volume centers. Future directions may include examining whether early stabilization and transfer improve outcomes of patients with CS who are admitted to lower volume centers. PMID- 25559015 TI - Association of fluid retention with anemia and clinical outcomes among patients with chronic kidney disease. AB - BACKGROUND: Observational studies have demonstrated an association between anemia and adverse outcomes in patients with chronic kidney disease (CKD). However, randomized trials failed to identify a benefit of higher hemoglobin concentrations, suggesting that the anemia-outcome association may be confounded by unknown factors. METHODS AND RESULTS: We evaluated the influence of fluid status on hemoglobin concentrations and the cardiovascular and renal outcomes in a prospective cohort of 326 patients with stage 3 to 5 CKD. Fluid status, as defined by overhydration (OH) level measured with bioimpedance, was negatively correlated with hemoglobin concentrations at baseline (r=-0.438, P<0.001). In multivariate regression analysis, OH remained an independent predictor of hemoglobin, second only to estimated glomerular filtration rate. Patients were stratified into 3 groups: no anemia (n=105), true anemia (n=82), and anemia with excess OH (n=139) (relative OH level >=7%, the 90th percentile for the healthy population). During a median follow-up of 2.2 years, there was no difference in cardiovascular and renal risks between patients with true anemia and those with no anemia in the adjusted Cox proportional hazards models. However, patients with anemia with excess OH had a significantly increased risk of cardiovascular morbidity and mortality and CKD progression relative to those with true anemia and those with no anemia, respectively. CONCLUSIONS: Fluid retention is associated with the severity of anemia and adverse cardiovascular and renal outcomes in patients with CKD. Further research is warranted to clarify whether the correction of fluid retention, instead of increasing erythropoiesis, would improve outcomes of CKD-associated anemia. PMID- 25559017 TI - Self-assembled core-shell nanoparticles for combined chemotherapy and photodynamic therapy of resistant head and neck cancers. AB - Combination therapy enhances anticancer efficacy of both drugs via synergistic effects. We report here nanoscale coordination polymer (NCP)-based core-shell nanoparticles carrying high payloads of cisplatin and the photosensitizer pyrolipid, NCP@pyrolipid, for combined chemotherapy and photodynamic therapy (PDT). NCP@pyrolipid releases cisplatin and pyrolipid in a triggered manner to synergistically induce cancer cell apoptosis and necrosis. In vivo pharmacokinetic and biodistribution studies in mice show prolonged blood circulation times, low uptake in normal organs, and high tumor accumulation of cisplatin and pyrolipid. Compared to monotherapy, NCP@pyrolipid shows superior potency and efficacy in tumor regression (83% reduction in tumor volume) at low drug doses in the cisplatin-resistant human head and neck cancer SQ20B xenograft murine model. We elucidated the in vitro/vivo fate of the lipid layer and its implications on the mechanisms of actions. This study suggests multifunctional NCP core-shell nanoparticles as a versatile and effective drug delivery system for potential translation to the clinic. PMID- 25559018 TI - Approach to the treatment of primary anterior shoulder dislocation: A review. AB - Glenohumeral joint dislocation is common among younger, active patients. Anterior dislocation is the most common direction of instability following a traumatic event. Due to a high rate of recurrence following primary traumatic anterior shoulder dislocation, an evidence-based approach is necessary to determine the best treatment regime for a patient presenting with this problem. A history, physical examination, and radiographic imaging can help guide treatment recommendations by determining the extent of soft tissue damage following dislocation. Controversies in the treatment of the first-time dislocator include the length and position of immobilization following dislocation, and the role of initial surgical stabilization. This article outlines the treatment options for the first-time glenohumeral dislocator, with an emphasis on the available evidence in the literature. Where applicable, the criteria known as the Strength of Recommendation Taxonomy were used to summarize the strength of evidence available for recommendations. PMID- 25559016 TI - Influence of sex on genetic regulation of "drinking in the dark" alcohol consumption. AB - The ILSXISS (LXS) recombinant inbred (RI) panel of mice is a valuable resource for genetic mapping studies of complex traits, due to its genetic diversity and large number of strains. Male and female mice from this panel were used to investigate genetic influences on alcohol consumption in the "drinking in the dark" (DID) model. Male mice (38 strains) and female mice (36 strains) were given access to 20% ethanol during the early phase of their circadian dark cycle for four consecutive days. The first principal component of alcohol consumption measures on days 2, 3, and 4 was used as a phenotype (DID phenotype) to calculate QTLs, using a SNP marker set for the LXS RI panel. Five QTLs were identified, three of which included a significant genotype by sex interaction, i.e., a significant genotype effect in males and not females. To investigate candidate genes associated with the DID phenotype, data from brain microarray analysis (Affymetrix Mouse Exon 1.0 ST Arrays) of male LXS RI strains were combined with RNA-Seq data (mouse brain transcriptome reconstruction) from the parental ILS and ISS strains in order to identify expressed mouse brain transcripts. Candidate genes were determined based on common eQTL and DID phenotype QTL regions and correlation of transcript expression levels with the DID phenotype. The resulting candidate genes (in particular, Arntl/Bmal1) focused attention on the influence of circadian regulation on the variation in the DID phenotype in this population of mice. PMID- 25559019 TI - Tricin derivatives as anti-inflammatory and anti-allergic constituents from the aerial part of Zizania latifolia. AB - Methanol extract of Zizania latifolia was partitioned with EtOAc, n-BuOH, and H2O. From the EtOAc layers, a new flavonolignan along with a known flavone and three known flavonolignans, tricin (1), salcolin A (2), salcolin B (3), and salcolin C (4), were isolated through repeated silica gel and ODS column chromatography. The chemical structure of the new flavonolignan was determined to be tricin-4'-O-[erythro-beta-guaiacyl-(7"-O-methyl)-glyceryl] ether and was named salcolin D (5) based on physicochemical and spectroscopic data, including FT-NMR and ESI-MS. All compounds were isolated for the first time from this plant. Compounds 2-5, tricin derivatives, all exhibited higher anti-inflammatory and anti-allergy activities than tricin. In particular, salcolin D (5) was shown to have the strongest inhibitory activity against LPS-induced NO production in RAW 264.7 cells as well as beta-hexosaminidase release in IgE-sensitized RBL-2H3 cells. These results suggest that the presence of tricin derivatives conveys allergy and inflammation treatment ability to Z. latifolia. PMID- 25559022 TI - Projecting a bright future. PMID- 25559020 TI - Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors. AB - Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-epsilon-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity. PMID- 25559021 TI - Production of inulinase, fructosyltransferase and sucrase from fungi on low-value inulin-rich substrates and their use in generation of fructose and fructo oligosaccharides. AB - Owing to applications in the food and nutraceutical industries, inulinases, fructosyltransferases and sucrases have gained considerable attention in recent times. Twenty-five fungal strains were screened for production of these enzymes on three different media formulated using inulin-rich plant extracts prepared from asparagus root, dahlia tuber and dandelion root extract. Culture filtrates of the fungi were examined for hydrolytic activities. Fungi belonging to genus Aspergillus, A. niger GNCC 2655 (11.3 U/ml), A. awamori MTCC 2879 (8.2 U/ml), A. niger ATCC 26011 (7.9 U/ml) secreted high titers of inulinase followed by Penicillium sp. NFCCI 2768 (2.6 U/ml) and Penicillium citrinum MTCC 1256 (1.1 U/ml). High sucrase activity was noticed in A. niger GNCC 2613 (113 U/ml) and A. awamori MTCC 2879 (107.8 U/ml). Analysis of end products of inulinase action by HPLC revealed that most of the enzymes were exo-inulinases liberating fructose exclusively from inulin. Five fungi, P. citrinum MTCC 1256, Penicillium rugulosum MTCC 3487, Penicillium sp. NFCCI 2768, A. fumigatus GNCC 1351 and A. niger ATCC 26011 however, produced a mixture of endo- and exo-inulinases liberating oligosaccharides (GF3 and GF2) along with fructose. High inulinase/sucrase yielding strains were evaluated for extracellular and intracellular hydrolytic and transfructosylating activities and intracellular enzyme profiles were found to be considerably different in terms of titers and end products. PMID- 25559023 TI - The role of the community nurse in care provision for people with multiple sclerosis. AB - Multiple sclerosis (MS) is a degenerative neurological condition that is often diagnosed in young adults in their 20s and 30s and is more common in women than in men. The long-term and unpredictable nature of the condition poses significant challenges for care delivery. The UK has one of the highest incidences of MS in the world, and care delivery for people with long-term conditions such as MS in the UK is changing: whereas previously it predominantly took place from a hospital setting, it now more commonly occurs in a primary care setting. In addition, patients and carers are recognised as equal partners in the planning and delivery of care. This article explores the approaches used by community nurses providing care to patients and families in a multiagency context. PMID- 25559024 TI - The image of community nursing: implications for future student nurse recruitment. AB - Young people's perceptions of nursing and, in particular, community nursing, do not reflect the realities of the profession. Community nursing needs to promote a realistic and positive image to young people who may consider nursing as a future career pathway. Strategies to increase awareness and understanding of community nursing roles are urgently required to halt the dissonance between the political drivers influencing changes in community care services, the advancing complexities of nursing roles, and the stereotypical imagery of nursing that continues to influence public thinking and interpretation of roles. The article draws on research that investigated the views of 40 young people from four schools in the West Midlands regarding nursing as a profession. PMID- 25559025 TI - Role of the community matron in advance care planning and 'do not attempt CPR' decision-making: a qualitative study. AB - The community matron (CM) is often the key worker caring for patients with chronic, life-limiting, long-term conditions, but these patients are not always recognised as palliative cases. This study explored the experiences of CMs with regard to advance care planning (ACP) and 'do not attempt cardiopulmonary resuscitation' (DNACPR) decision-making to understand whether or not they felt adequately prepared for this aspect of their role, and why. Qualitative data were generated from six CMs using a broad interpretive phenomenological approach. Face to-face recorded interviews were analysed using template analysis. The study found that although participants faced complex ethical situations around ACP and DNACPR almost on a daily basis, none had received any formal training despite the emphasis on training in national and local guidelines. Participants often struggled to get their patients accepted on to the Gold Standards Framework. The research found variability and complexity of cases to be the main barriers to clear identification of the palliative phase. PMID- 25559026 TI - Harnessing technology for the improved management of diabetes and community-based care. PMID- 25559027 TI - The Flexible Care Service: a third-sector service for older people with mental health needs. AB - Demographic patterns indicate that by 2030, one in five people in England will be over 65. Together with the fact that as people age they are more likely to suffer from comorbidities, it is of paramount importance that local services are designed to meet the needs of individual older people. The Flexible Care Service is a resource for older people with mental health problems. Through the use of client case studies, the Department of Health's 'six Cs' (care, compassion, competence, communication, courage and commitment) are used as a framework to demonstrate how a third-sector service such as Flexible Care can offer a person centred approach in order to meet the diverse needs of individual clients. The framework is also used to demonstrate the high level of skills needed by flexible carers in order to provide this support. PMID- 25559028 TI - Court-authorised deprivation of liberty. AB - The United Kingdom Supreme Court judgment in Cheshire West and Chester Council v P in 2014 introduced a more inclusive 'acid test' for determining the objective element of a deprivation of liberty in cases concerning people who lack decision making capacity. The case made clear that adults and young people who lack capacity could be deprived of their liberty in care settings other than hospitals and care homes, including the person's own home. A deprivation of liberty that occurs in a setting other than a hospital or care home must be authorised by a Court. This article explains the revised process for applying for Court authorisation of a deprivation of liberty where it occurs in supported living, Shared Lives placements or the incapable person's own home. PMID- 25559029 TI - Coronary heart disease: self-care, communication and quality of life. AB - Aysha Mendes discusses coronary heart disease, the UK's biggest killer, and describes the range of roles that nurses play in prevention, treatment and support. PMID- 25559030 TI - A letter to the editor re: 'avoiding burnout syndrome in palliative care'. PMID- 25559031 TI - Buffering burnout among staff in palliative care: a pledge for 2015. PMID- 25559033 TI - The love affair with antibiotics. PMID- 25559035 TI - Two new coumarin glycosides from Herpetospermum caudigerum. AB - Phytochemical investigation on the seeds of Herpetospermum caudigerum afforded two new coumarin glycosides A and B (1 and 2), together with a known compound herpetolide A (3). Their structures were determined by spectroscopic methods, including 2D NMR techniques. Compound 3 exhibited cytotoxicity against HepG2 cells with IC50 value of 6.47 MUg/ml. Compound 2 showed anti-hepatitis B virus activity with HBsAg secretion by 33.1% at 200 MUg/ml. PMID- 25559034 TI - MicroRNA and messenger RNA profiling reveals new biomarkers and mechanisms for RDX induced neurotoxicity. AB - BACKGROUND: RDX is a well-known pollutant to induce neurotoxicity. MicroRNAs (miRNA) and messenger RNA (mRNA) profiles are useful tools for toxicogenomics studies. It is worthy to integrate MiRNA and mRNA expression data to understand RDX-induced neurotoxicity. RESULTS: Rats were treated with or without RDX for 48 h. Both miRNA and mRNA profiles were conducted using brain tissues. Nine miRNAs were significantly regulated by RDX. Of these, 6 and 3 miRNAs were up- and down regulated respectively. The putative target genes of RDX-regulated miRNAs were highly nervous system function genes and pathways enriched. Fifteen differentially genes altered by RDX from mRNA profiles were the putative targets of regulated miRNAs. The induction of miR-71, miR-27ab, miR-98, and miR-135a expression by RDX, could reduce the expression of the genes POLE4, C5ORF13, SULF1 and ROCK2, and eventually induce neurotoxicity. Over-expression of miR-27ab, or reduction of the expression of unknown miRNAs by RDX, could up-regulate HMGCR expression and contribute to neurotoxicity. RDX regulated immune and inflammation response miRNAs and genes could contribute to RDX- induced neurotoxicity and other toxicities as well as animal defending reaction response to RDX exposure. CONCLUSIONS: Our results demonstrate that integrating miRNA and mRNA profiles is valuable to indentify novel biomarkers and molecular mechanisms for RDX-induced neurological disorder and neurotoxicity. PMID- 25559036 TI - Anxiety and depression symptoms in the 2 years following diagnosis of breast or gynaecologic cancer: prevalence, course and determinants of outcome. AB - PURPOSE: The purposes of this study are to examine the course and prevalence of anxiety and depression over 24 months in women with newly diagnosed breast and gynaecologic cancer and, controlling for demographic and clinical confounders, to test the role of neuroticism and psychiatric history in determining outcome 6, 12, 18 and 24 months post-diagnosis. METHODS: Participants completed the Hospital Anxiety and Depression Scale-anxiety subscale and Centre for Epidemiological Studies Depression Scale on an 8-weekly basis from diagnosis until 96 weeks. Changes over time were analyzed with repeated measures ANOVA. Hierarchical linear regression, adjusted a priori for age, chemotherapy and radiation treatment, living alone, education and tumour stream were used to predict anxiety and depression. RESULTS: Participants were 105 women (66 breast, 39 gynaecologic). Rates of anxiety (18.1 %) and depression (33.3 %) were highest at diagnosis. Average rates of anxiety and depression were 5.9 and 22.4 %, respectively. Average scores of anxiety and depression were highest at diagnosis, with improvement at 8 and 40 weeks, respectively, subsequently maintained. Morbidity at diagnosis was particularly acute among women with a treatment history of anxiety/depression or with high neuroticism. These three variables were the best and only predictors over 24 months. CONCLUSIONS: Women are most vulnerable to anxiety and depression at diagnosis, with improvement over time. Morbidity rates are lower than reported elsewhere. Women with high neuroticism and a psychiatric history are at greatest risk for future morbidity after adjusting for confounders. Early identification of these women plus heightened surveillance or early referral to psychosocial services may protect against longer-term morbidity. PMID- 25559037 TI - Is there a role for survivorship care plans in advanced cancer? AB - PURPOSE: The Institute of Medicine (2006) has recommended that cancer survivors completing treatment receive a survivorship care plan (SCP). The survivorship needs in advanced cancer have been overlooked and understudied. The potential role of SCPs for survivors with advanced or metastatic cancer is unknown and was explored in this study. METHODS: We conducted two focus groups of survivors with advanced or metastatic cancer. Participants reviewed a sample JourneyForwardTM SCP modified for advanced cancer. Sessions were audiotaped and transcribed; transcripts and field notes were evaluated using inductive content analysis. RESULTS: Sixteen survivors with metastatic cancer participated: 12 (75 %) were female, 15 (94 %) were white, and median age was 66 (range 55-80); 9 participants had breast cancer, 4 colon, 2 prostate, and 1 ovarian cancer. Participants believed that an SCP would be most helpful after initial diagnosis and treatment, but not as helpful once the cancer progressed. They thought a "cancer care plan" focusing solely on the current management would be better to concisely summarize the treatment plan and time frame for the next segment of care for those with advanced cancer. Most participants endorsed the need to have written information to reinforce verbal information received during medical visits since it was difficult to remember information provided. Participants expected their oncologist to assume primary responsibility for coordination of the care plan, but anticipated an important supportive role for primary care providers. To this end, they emphasized the need for better communication between providers. CONCLUSIONS: A cancer care plan developed by the oncologist, similar to an SCP but more focused on current management, may be more useful for survivors with advanced cancer. Exploring this topic in larger groups of more diverse survivors with advanced cancer will help to elucidate the details a written plan of care should contain, and how to promote effective coordination between oncology and primary care providers. IMPLICATIONS FOR CANCER SURVIVORS: There are many transitions of care along the cancer journey. A written plan of care, similar to an SCP, may be useful for survivors with advanced cancer. PMID- 25559038 TI - Nutrition, hydration, and patient's preferences at the end of life. PMID- 25559040 TI - Study of carrier concentration in single InP nanowires by luminescence and Hall measurements. AB - The free electron carrier concentrations in single InP core-shell nanowires are determined by micro-photoluminescence, cathodoluminescence (CL) and Hall effect measurements. The results from luminescence measurements were obtained by solving the Fermi-Dirac integral, as well as by analyzing the peak full width at half maximum (FWHM). Furthermore, the platform used for Hall effect measurements, combined with spot mode CL spectroscopy, is used to determine the carrier concentrations at specific positions along single nanowires. The results obtained via luminescence measurements provide an accurate and rapid feedback technique for the epitaxial development of doping incorporation in nanowires. The technique has been employed on several series of samples in which growth parameters, such as V/III-ratio, temperature and dopant flows, were investigated in an optimization procedure. The correlation between the Hall effect and luminescence measurements for extracting the carrier concentration of different samples were in excellent agreement. PMID- 25559041 TI - Expression and characterization of a novel recombinant version of the secreted human mucin MUC5AC in airway cell lines. AB - Molecular manipulation and expression of mucins, large glycoproteins that provide the structural framework of mucus, are challenging due to mucins' size and numerous domains, including variable number tandem repeat (VNTRs) regions that are sites of O-glycosylation. Only individual human mucin domains have been expressed in mammalian cells. We produced recombinant versions of MUC5AC, a major secreted mucin in the respiratory tract, encoding the N-terminus, C-terminus, N- and C-termini together, and N- and C-termini interspersed with two native tandem repeat sequences (N+2TR+C) in both tracheal and bronchial cell lines. The latter protein contains all of the functional domains required for the biosynthesis and secretion of glycosylated mucin. The N-terminus protein was found in monomeric and higher molecular mass forms suggesting that secreted MUC5AC may form a branched netlike structure analogous to that described for MUC2. At the C terminus, proteins underwent cleavage, polymerization, and glycosylation. Thus, they appear to undergo pivotal processing steps as predicted for native MUC5AC, which is analogous to that for other individual recombinant mucin domains. Secretion occurred when cells were grown on transwell filter inserts but not on plastic, indicating that the extracellular environment likely plays a role in mucin processing. The secreted N+2TR+C protein differed in molecular mass from the intracellular form, indicating that additional processing occurred. These recombinant proteins, expressed in different backgrounds, can potentially address the role of different mucin domains on MUC5AC processing and function as well as the role of MUC5AC in health and disease. PMID- 25559042 TI - Two-dimensional titanium carbide for efficiently reductive removal of highly toxic chromium(VI) from water. AB - Two dimensional (2-D) Ti3C2Tx nanosheets are obtained by etching bulk Ti3C2Tx powders in HF solution and delaminating ultrasonically, which exhibit excellent removal capacity for toxic Cr(VI) from water, due to their high surface area, well dispersibility, and reductivity. The Ti3C2Tx nanosheets delaminated by 10% HF solution present more efficient Cr(VI) removal performance with capacity of 250 mg g(-1), and the residual concentration of Cr(VI) in treated water is less than 5 ppb, far below the concentration (0.05 ppm) of Cr(VI) in the drinking water standard recommended by the World Health Organization. This kind of 2-D Ti3C2Tx nanosheet can not only remove Cr(VI) rapidly and effectively in one step from aqueous solution by reducing Cr(VI) to Cr(III) but also adsorb the reduced Cr(III) simultaneously. Furthermore, these reductive 2-D Ti3C2Tx nanosheets are generally explored to remove other oxidant agents, such as K3[Fe(CN)6], KMnO4, and NaAuCl4 solutions, by converting them to low oxidation states. These significantly expand the potential applications of 2-D Ti3C2Tx nanosheets in water treatment. PMID- 25559039 TI - Technetium-99m and rhenium-188 complexes with one and two pendant bisphosphonate groups for imaging arterial calcification. AB - The first (99m)Tc and (188)Re complexes containing two pendant bisphosphonate groups have been synthesised, based on the mononuclear M(v) nitride core with two dithiocarbamate ligands each with a pendant bisphosphonate. The structural identity of the (99)Tc and stable rhenium analogues as uncharged, mononuclear nitridobis(dithiocarbamate) complexes was determined by electrospray mass spectrometry. The (99m)Tc complex showed greater affinity for synthetic and biological hydroxyapatite, and greater stability in biological media, than the well-known but poorly-characterised and inhomogeneous bone imaging agent (99m)Tc MDP. It gave excellent SPECT images of both bone calcification (mice and rats) and vascular calcification (rat model), but the improved stability and the availability of two pendant bisphosphonate groups conferred no dramatic advantage in imaging over the conventional (99m)Tc-MDP agent in which the bisphosphonate group is bound directly to Tc. The (188)Re complex also showed preferential uptake in bone. These tracers and the biological model of vascular calcification offer the opportunity to study the biological interpretation and clinical potential of radionuclide imaging of vascular calcification and to deliver radionuclide therapy to bone metastases. PMID- 25559043 TI - Distinct and dramatic water dissociation on GaP(111) tracked by near-ambient pressure X-ray photoelectron spectroscopy. AB - Water adsorption and dissociation on a GaP(111) crystal surface are investigated using near-ambient pressure X-ray photoelectron spectroscopy (NAP XPS) in a wide range of pressures (~10(-10)-5 mbar) and temperatures (~300-773 K). Dynamic changes in chemical evolution at the H2O/GaP(111) interface are reflected in Ga 2p3/2, O 1s, and P 2p spectra. In the pressure-dependent study performed at room temperature, an enhancement of surface Ga hydroxylation and oxidation with an increase in H2O pressure is observed. In the temperature-dependent study performed at elevated pressures, two distinct regions can be defined in which drastic changes occur in the surface chemistry. Below 673 K, the surface Ga hydroxylation and oxidation progress continuously. However, above 673 K, a large scale conversion of surface O-Ga-OH species into non-stoichiometric Ga hydroxide along with oxidation of surface P atoms occurs through an intermediate state. The NAP XPS technique enabled us to experimentally track the chemistry at the H2O/GaP interface under near-realistic conditions, thereby providing evidence to compare with recent theoretical efforts to improve the understanding of water-splitting mechanisms and photo-corrosion on semiconductor surfaces. PMID- 25559044 TI - Behavior matters: the relevance, impact, and reach of behavioral medicine. AB - BACKGROUND/PURPOSE: Growing evidence suggests behavioral interventions that target a few key behaviors may be effective at improving population-level health outcomes; health status indicators; social, economic, and physical environments; personal capacity; and biological outcomes. A theoretical framework that targets both social and cognitive mechanisms of behavioral interventions is outlined as critical for understanding "ripple effects" of behavioral interventions on influencing a broad range of outcomes associated with improved health and well being. METHODS/RESULTS: Evidence from randomized controlled trials is reviewed and demonstrates support for ripple effects-the effects that behavioral interventions have on multiple outcomes beyond the intended primary target of the interventions. These outcomes include physical, psychological, and social health domains across the lifespan. CONCLUSIONS: Cascading effects of behavioral interventions have important implications for policy that argue for a broader conceptualization of health that integrates physical, mental, and social well being outcomes into future research to show the greater return on investment. PMID- 25559045 TI - Incidence of ischemic colitis in treated, commercially insured hypertensive adults: a cohort study of US health claims data. AB - BACKGROUND: Ischemic colitis (IC) incidence rates (IRs) among treated hypertensive patients are poorly understood, and existing literature on the subject is sparse. Antihypertensive drugs may raise the risk of developing IC. Novel antihypertensive agents-such as the direct renin inhibitor aliskiren-have not been assessed for IC risk. OBJECTIVES: The aims of this study were to evaluate (1) the IRs of probable IC (pIC) in treated hypertensive adults, with a focus on aliskiren-treated patients; (2) the antihypertensive therapies used; and (3) the IRs of pIC in non-hypertensive adults. METHODS: This study selected hypertensive and non-hypertensive patients (N = 2,356,226 each) from a US health plan claims database. pIC was defined as diagnosis of IC within 3 months after colonoscopy, recto-sigmoidoscopy, or colectomy. IRs were calculated per 100,000 person-years (PYs) with 95% confidence intervals (CIs) and stratified by antihypertensive regimen. RESULTS: IRs of pIC in hypertensive and non hypertensive subjects were 18.6 (95% CI 17.6-19.8) and 4.0 (95% CI 3.4-4.7), respectively. The non-hypertensive cohort consisted of younger patients who may have been less prone to developing IC. The overall (i.e., all antihypertensive regimens combined) monotherapy IR per 100,000 PYs was 17.5 (95% CI 16.2-18.8), the overall dual-combination regimen IR per 100,000 PYs was 19.5 (95% CI 17.37 21.83), and the overall triple-plus combination regimen IR per 100,000 PYs was 27.7 (95% CI 22.72-33.38). CONCLUSION: Study results indicate that the treated hypertensive patients may have a higher risk of pIC compared with non hypertensive populations. The quantity of antihypertensive agents prescribed may contribute to IC more than treatment duration. PMID- 25559046 TI - Schistosomiasis transmission and control in China. AB - In the last 60 years, great progress has been made in controlling and preventing schistosomiasis in China. However, due to the ecosystem changes caused by the construction of the Three Gorges Dams and the South-north Water Conversion Project, the effects of climate change, the scarcity of a highly sensitive surveillance and response system, schistosomiasis is still considered as a major public health problem and is listed among the top infectious diseases in the country prioritized for control and elimination. Based on the epidemiological pattern of schistosomiasis and ecological characteristics of the vector snail, endemic areas of schistosomiasis in China were categorized into three types: (i) plain region with waterway networks, (ii) mountainous and hilly regions, and (iii) marshland and lake regions. China aims to reach the criteria of transmission control threshold of less than 1% in the lake and marshland provinces and reach transmission interruption threshold in hilly provinces of Sichuan and Yunnan by the end of 2015. The purpose of this article is to use the deterministic model proposed in our earlier study in (Chen et al., 2010) to simulate the schistosomiasis infection data from other lake and marshland provinces, including Hunan, Jiangxi and Anhui. Our simulations demonstrate that the model can reasonably mimic the schistosomiasis infection data from these lake and marshland provinces. Thus, similar control and prevention measures can be designed and proposed for these provinces. We will also try to use the model to simulate the schistosomiasis infection data from Sichuan and Yunnan provinces in the mountainous and hilly regions where cattle farming is not as popular and important as in the lake and marshland provinces and find out that different control and prevention strategies are required. PMID- 25559047 TI - Modelling influenza A(H1N1) 2009 epidemics using a random network in a distributed computing environment. AB - In this paper we propose the use of a random network model for simulating and understanding the epidemics of influenza A(H1N1). The proposed model is used to simulate the transmission process of influenza A(H1N1) in a community region of Venezuela using distributed computing in order to accomplish many realizations of the underlying random process. These large scale epidemic simulations have recently become an important application of high-performance computing. The network model proposed performs better than the traditional epidemic model based on ordinary differential equations since it adjusts better to the irregularity of the real world data. In addition, the network model allows the consideration of many possibilities regarding the spread of influenza at the population level. The results presented here show how well the SEIR model fits the data for the AH1N1 time series despite the irregularity of the data and returns parameter values that are in good agreement with the medical data regarding AH1N1 influenza virus. This versatile network model approach may be applied to the simulation of the transmission dynamics of several epidemics in human networks. In addition, the simulation can provide useful information for the understanding, prediction and control of the transmission of influenza A(H1N1) epidemics. PMID- 25559048 TI - Vaginal cytokines do not correlate with postmenopausal vulvovaginal symptoms. AB - OBJECTIVES: Exploratory pilot study to determine the correlation between postmenopausal vulvovaginal symptoms and vaginal cytokine levels. METHODS: Postmenopausal women (n = 34) not using menopausal hormone therapy and presenting with or without symptoms of vulvovaginal irritation were screened. Each participant underwent a vaginal examination and screening for vaginitis. A cervicovaginal lavage (CVL) with sterile saline and a peripheral blood sample were obtained. Main outcome measures were assessed by Luminex(r) X-map method on the Bio-Plex(r) platform. Main outcome measures were cervicovaginal and serum interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, TNF-alpha, GM-CSF, MIP-1-alpha and RANTES level. Cervicovaginal cytokines were adjusted to total protein concentration [pg/mcg protein]. RESULTS: Twenty-six postmenopausal women were enrolled (symptomatic: n = 15; asymptomatic: n = 11). There were no significant differences between groups: age, age at menopause, vaginal pH and all CVL and serum cytokines (IL-4, IL-5, IL-10, IL-12, IL-13, TNF-alpha, GM-CSF, MIP-1-alpha and RANTES). GM-CSF was the most abundant vaginal cytokine (symptomatic: 146.5 +/ 165.6 pg/mcg protein; asymptomatic: 146.0 +/- 173.5 pg/mcg protein; p = 0.99). CONCLUSIONS: Postmenopausal vulvovaginal symptoms did not correlate with vaginal inflammatory marker. There was no difference in serum or CVL cytokines between symptomatic and asymptomatic postmenopasual women. Vaginal symptoms after menopause are not related to the vaginal cytokine changes associated with loss of estrogen. PMID- 25559049 TI - Stigma, lack of knowledge and prevalence maintain HIV risk among Black Africans in New Zealand. AB - OBJECTIVE: The AfricaNZ Health project aimed explore HIV risks in Black African communities in NZ with a view to informing HIV infection prevention and health promotion programs. METHODS: AfricaNZ Health was completed in two phases. The first developed desk estimates of the resident Black African population in New Zealand, and Africans living with HIV. The second comprised two arms: an anonymous survey administered at African community events and a series of focus groups around the country. RESULTS: High levels of knowledge and positive attitudes about HIV were more often found in older than younger age groups. Condom use was higher in the younger group than in older age groups. Traditional attitudes still inform some beliefs about HIV. Stigma about HIV and anyone at risk for HIV remains very high among Africans. Western sexual identity constructs are not meaningful. CONCLUSIONS: A culturally informed strategy for risk and stigma reduction is urgently needed. IMPLICATIONS: The existing prevention and care infrastructure, informed by MSM experiences, must address increased risk to Black African new settlers, but this is not a reason to discriminate or further stigmatise an already vulnerable population. PMID- 25559050 TI - Characterization and evaluation of the efficiency of SiO2/tetra-alpha-(2,4-di tert-butylphenoxy)-phthalocyaninato zinc nanocomposite as photosensitizers for oxidation of 2,4,6-trichlorophenol. AB - A photosensitizer tetra-alpha-(2,4-di-tert-butylphenoxy)-phthalocyaninato zinc [ZnPc(OAr)4] was successfully encapsulated in SiO2 nanoparticle by the microemulsion method. The photosensitized composite nanoparticle was able to degrade 2,4,6-trichlorophenol (TCP) in aqueous solution. Under visible light irradiation, the nanoparticles efficiently generated reactive oxygen species; 95.4% of TCP was degraded after 270 min of reaction. Some aromatic compounds and aliphatic carboxylic acids were detected by mass spectrometry as the reaction intermediates. The results were different from those of previously reported photocatalytic reactions, in which valence band holes or hydroxyl radicals functioned as the main oxidants. The photosensitizing composite nanoparticle is potentially applicable to the oxidation of phenol. PMID- 25559052 TI - News from the International Council on Women's Health Issues. PMID- 25559051 TI - Maternal health practice: a mismatch of knowledge and expectations. PMID- 25559053 TI - Physical education in secondary schools located in low-income communities: Physical activity levels, lesson context and teacher interaction. AB - OBJECTIVES: Physical education (PE) plays an important role in contributing to students' physical activity (PA); however, moderate-to-vigorous PA (MVPA) within PE is lower than recommended. Little is known about the PA levels of students from disadvantaged schools within PE. This study aimed to describe: (i) the PA levels of students from disadvantaged secondary schools during PE lessons, (ii) the lesson context and teacher interactions occurring during PE, and (iii) the associations between teacher, school or PE lesson characteristics with student physical activity levels in PE. DESIGN: Cross-sectional study of 100 Grade 7 PE lessons across 10 secondary schools. METHODS: System for observing fitness instruction time (SOFIT) was used to assess student PA, lesson context, and teacher interaction. Teacher and school characteristics were collected via survey. Mean proportion of lesson time was used to describe PA, lesson context and teacher interaction. Associations between each outcome variable and each characteristic were examined using 2-sample t-tests, ANOVAs and linear regression. RESULTS: Thirty-nine percent of PE lesson was spent in MVPA, and less than 10% spent in VA. Lessons in schools in urban areas included significantly more MVPA than rural areas (P=0.04). Male teachers and more experienced teachers conducted lessons with significantly more VA than female and less experienced teachers (P=0.04 and 0.02). MVPA was also higher in lessons conducted by more experienced teachers. CONCLUSIONS: PA during PE lessons within disadvantaged secondary schools is below international recommendations. Male teachers, more experienced teachers and schools in urban regions teach more active lessons. PMID- 25559055 TI - Can a mathematical model predict an individual's trait-like response to both total and partial sleep loss? AB - Humans display a trait-like response to sleep loss. However, it is not known whether this trait-like response can be captured by a mathematical model from only one sleep-loss condition to facilitate neurobehavioural performance prediction of the same individual during a different sleep-loss condition. In this paper, we investigated the extent to which the recently developed unified mathematical model of performance (UMP) captured such trait-like features for different sleep-loss conditions. We used the UMP to develop two sets of individual-specific models for 15 healthy adults who underwent two different sleep-loss challenges (order counterbalanced; separated by 2-4 weeks): (i) 64 h of total sleep deprivation (TSD) and (ii) chronic sleep restriction (CSR) of 7 days of 3 h nightly time in bed. We then quantified the extent to which models developed using psychomotor vigilance task data under TSD predicted performance data under CSR, and vice versa. The results showed that the models customized to an individual under one sleep-loss condition accurately predicted performance of the same individual under the other condition, yielding, on average, up to 50% improvement over non-individualized, group-average model predictions. This finding supports the notion that the UMP captures an individual's trait-like response to different sleep-loss conditions. PMID- 25559054 TI - Hospital-associated infections in small animal practice. AB - Hospital-associated infections (HAIs) occur in veterinary hospitals of all types and sizes, and their frequency is likely to increase. Urinary tract infections, pneumonia, bloodstream infections, surgical site infections, and infectious diarrhea are the HAIs most frequently identified in veterinary medicine. A hospital infection control program, consisting of an infectious disease control officer, written protocols, and staff training, is critical to reducing HAIs and promoting patient, staff, and client health. Infection control protocols (plans) should include discussion of hand hygiene and use of personal protective equipment, cleaning and disinfection, patient management, with-in hospital surveillance, and antimicrobial stewardship. PMID- 25559056 TI - Preliminary investigation of gait initiation and falls in multiple sclerosis. AB - OBJECTIVE: To examine the relationship between gait initiation, fall history, and physiological fall risk in individuals with multiple sclerosis (MS) during both cognitive distracting and nondistracting conditions. DESIGN: Single time point cross-sectional analysis. SETTING: University research laboratory. PARTICIPANTS: Ambulatory individuals (N=20) with MS ranging in age from 28 to 76 years. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Gait initiation time was quantified as the time to toe-off of the first step after an auditory cue. Gait initiation was performed with and without a concurrent cognitive challenge of reciting alternating letters of the alphabet. Additionally, participants underwent a test of fall risk using the Physiological Profile Assessment (PPA) and provided a self-report of the number of falls in the previous 3 months. RESULTS: Gait initiation times ranged from .67 to 1.12 seconds during the single task condition and .73 to 1.84 seconds during the cognitive challenge condition. PPA scores ranged from -.80 to 3.87. Participants reported a median of 0.0 falls (interquartile range, 0.0-2.75) in the previous 3 months. There was a significant correlation between PPA score and gait initiation times only in the cognitive distraction condition (rho=.50). There was also a correlation between cognitive distraction gait initiation times and fall history (rho=.60). CONCLUSIONS: The observations provide preliminary evidence that gait initiation during cognitive challenge may represent a target for fall prevention strategies in MS. PMID- 25559057 TI - Dutch multifactor fatigue scale: a new scale to measure the different aspects of fatigue after acquired brain injury. AB - OBJECTIVES: To develop the Dutch Multifactor Fatigue Scale (DMFS), a new scale to assess the nature and impact of fatigue and coping with fatigue in the chronic phase after acquired brain injury (ABI) and to analyze the psychometric properties of this scale in a mixed group of patients with ABI. DESIGN: Cross sectional survey study. SETTING: Academic rehabilitation center. PARTICIPANTS: A mixed sample of patients with ABI (N=134). For the development of the DMFS: community-dwelling adults with stroke (n=9) and traumatic brain injury (n=5). For analyses of the psychometric properties of the DMFS: community-dwelling adults with ischemic stroke (n=55), hemorrhagic stroke (n=22), traumatic brain injury (n=35), or other ABIs (n=22), all at least 6 months after brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: DMFS, Hospital Anxiety and Depression Scale, Checklist Individual Strength, and Dutch Personality Questionnaire. RESULTS: Exploratory and confirmatory factor analyses on data of 134 patients showed that the final DMFS consisted of 5 factors (explaining 55% of the variance): Impact of fatigue, Mental fatigue, Signs and Direct consequences of fatigue, Physical fatigue, and Coping with fatigue. All subscales of the DMFS showed sufficient to good reliability, good convergent validity with an existing fatigue scale, and good divergent validity with measures of mood and self-esteem. CONCLUSIONS: The DMFS is believed to improve the diagnostic process of fatigue in the chronic phase after ABI. As it measures several factors of fatigue after brain injury, therapeutic indications can be targeted to patients' needs. PMID- 25559058 TI - Effect of species-specific sound stimulation on the development and hatching of broiler chicks. AB - 1. Previous research has reported that chicken embryos develop a functionary auditory system during incubation and that prenatal sound may play an important role in embryo development and alter the hatch time. In this study the effects of prenatal auditory stimulation on hatch process, hatch performance, the development of embryo and blood parameters were investigated. 2. Four batches of Ross 308 broiler breeder eggs were incubated either in control or in sound stimulated groups. The sound-stimulated embryos were exposed to a discontinuous sound of species-specific calls by means of a speaker at 72 dB for 16 h a day: maternal calls from d 10 to d 19 of incubation time and embryo/chick calls from d 19 until hatching. The species-specific sound was excluded from the control group. 3. The onset of hatch was delayed in the sound-stimulated group compared to the controls. This was also supported by comparison of the exact hatching time of individual focal chicks within the two groups. However, the sound-stimulated embryos had a lower hatchability than the control group, mainly due to significantly increased numbers of late deaths. 4. The embryos exhibited a similar growth pattern between the sound-stimulated group and the control group. Although sound exposure decreased body weight at d 16, no consistent effect of sound on body weight at incubation stage was observed. Species-specific sound stimulation also had no impact on chick quality, blood values and plasma corticosterone concentrations during hatch. PMID- 25559059 TI - Population trends in rates of coronary revascularization. PMID- 25559060 TI - Inadequate physical activity and health care expenditures in the United States. AB - This study estimates the percentage of health care expenditures in the non institutionalized United States (U.S.) adult population associated with levels of physical activity inadequate to meet current guidelines. Leisure-time physical activity data from the National Health Interview Survey (2004-2010) were merged with health care expenditure data from the Medical Expenditure Panel Survey (2006 2011). Health care expenditures for inactive (i.e., no physical activity) and insufficiently active adults (i.e., some physical activity but not enough to meet guidelines) were compared with active adults (i.e., >=150minutes/week moderate intensity equivalent activity) using an econometric model. Overall, 11.1% (95% CI: 7.3, 14.9) of aggregate health care expenditures were associated with inadequate physical activity (i.e., inactive and insufficiently active levels). When adults with any reported difficulty walking due to a health problem were excluded, 8.7% (95% CI: 5.2, 12.3) of aggregate health care expenditures were associated with inadequate physical activity. Increasing adults' physical activity to meet guidelines may reduce U.S. health care expenditures. PMID- 25559062 TI - Prevalence of sexual dysfunction among female patients followed in a Brasilia Cohort of early rheumatoid arthritis. AB - OBJECTIVE: To determine the prevalence of sexual dysfunction in women diagnosed with early rheumatoid arthritis (RA) (less than one year of symptoms at the time of diagnosis), as well as to evaluate the possible association between sexual dysfunction with AR activity and functional disability. METHODS: Cross-sectional study assessing women diagnosed with early RA, accompanied per protocol in the Brasilia Cohort, Hospital Universitario de Brasilia. Demographics, disease activity index (Disease Activity Score 28 - DAS 28) and functional disability questionnaire (Health Assessment Questionnaire - HAQ), were obtained by direct interviews. The Female Sexual Function Index (FSFI) was used, questionnaire which contains 19 items that assess six domains: sexual desire, sexual arousal, vaginal lubrication, orgasm, sexual satisfaction and pain. RESULTS: 68 patients studied, of whom 54 (79.4%) reported sexual activity in the last four weeks. The participants were 49.7+/-13.7 (mean+/-SD) years old and the majority were married (61.4%). The mean DAS 28 was 3.6+/-1.5 and the mean HAQ was 0.7. The prevalence of sexual dysfunction (FSFI <=26) was 79.6%. There was no association of disease activity or of functional disability with the occurrence of sexual dysfunction in the female patients evaluated. CONCLUSION: The prevalence of sexual dysfunction found in this study was higher than that reported in the literature in healthy women. A knowledge of the extent of the problem is needed to provide adequate therapeutic options for these patients. PMID- 25559063 TI - [Autoantibodies in systemic sclerosis and their clinical correlation in patients from a Midwestern region of Brazil]. AB - INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disease of autoimmune nature characterized by the triad of vascular injury, autoimmunity (cellular and humoral) and tissue fibrosis. Autoantibodies do not seem to be simply epiphenomena, but are involved in disease pathogenesis. It is believed that the SSc-specific autoantibodies are responsible both for amplifying immune response and targeting cell types that are relevant in the pathophysiology of SSc. OBJECTIVES: To correlate the profile of the following specific autoantibodies: anti-centromere (ACA), anti-topoisomerase I (topo I) and anti-RNA polymerase III (RNAP III) with clinical and laboratory manifestations observed in 46 patients with SSc in the Midwest region of Brazil. METHODS: The occurrence of specific autoantibodies in 46 patients with SSc was investigated, correlating the type of autoantibody with clinical and laboratory manifestations found. RESULTS: Among all patients evaluated, we found a predominance of females (97.8%), mean age 50.21 years old, Caucasian (50%), limited cutaneous SSc (47.8%), time of diagnosis between 5-10 years (50%), and disease duration of 9.38 years. According to the specific autoantibody profile, 24 patients were ACA-positive (52.2%), 15 were positive for anti-topo I (32.6%), and 7 showed positive anti-RNAP III (15.2%). The anti-topo I autoantibody correlated with diffuse scleroderma, with greater disease severity and activity, with worse quality of life measured by the SHAQ index, with a higher prevalence of objective Raynaud's phenomenon and digital pitting scars of fingertips. The ACA correlated with limited scleroderma, with earlier onset of disease, as well as higher prevalence of telangiectasias. The anti- RNAP III correlated with diffuse scleroderma, with a higher occurrence of subjective Raynaud's phenomenon and muscle atrophy. There was no association between the positivity for anti-topo I, ACA and anti-RNAP III antibodies and other variables related to laboratory abnormalities, as well as Rodnan skin score and skin, vascular, musculoskeletal, gastrointestinal, cardiopulmonary and renal manifestations. CONCLUSIONS: The clinical subtype of the disease and some clinical manifestations in SSc may correlate positively with the presence of specific autoantibodies. PMID- 25559061 TI - Personalized preventive medicine: genetics and the response to regular exercise in preventive interventions. AB - Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to exercise and to translate them into useful clinical and public health applications. PMID- 25559064 TI - Development of stabilized Paclitaxel nanocrystals: In-vitro and in-vivo efficacy studies. AB - OBJECTIVE: The aim of the study was to develop stable Paclitaxel nanocrystals (PTX/NCs) for enhanced oral delivery of Paclitaxel (PTX) by circumventing its difficult solubilization properties and rapid metabolism. METHODS: Preparation of nanocrystals (NCs) was carried out using high pressure homogenizer (MicrofluidizerTM) without using any organic solvent. Effect of various process and formulation parameters on development and stability of nanocrystals (NCs) were investigated. Particle characteristics, stability studies, in-vitro cellular studies and oral pharmacokinetics in male Wistar rats were examined. RESULTS: It was found that different stabilizer used had different effect on size reduction and stability. Surfactants (Tween 80) and low molecular weight synthetic polymer sodium poly styrene sulfonate (PSS) found more suitable and efficient compared to high molecular weight polymers glycol chitosan (GC) and sodium alginate (SA). In vitro cytotoxicity and cell cycle arrest studies on MCF7 and MDA-MB breast cancer cell lines revealed that PTX/NCs retained the activity even after processing at high pressure and also NCs were more potent and efficacious than PTX solution. The oral in-vivo pharmacokinetic studies demonstrated that PTX/NCs exhibit significant increase in AUC0-t, Cmax, MRT and decrease in Tmax, compared to plain PTX crystals. The increase in AUC was almost 9-10 fold compared to plain PTX crystals. CONCLUSION: Altogether study showed that PTX/NC can be a clinically relevant drug delivery system for oral chemotherapy as it can remarkably increases the pharmacological effect by increasing oral bioavailability. PMID- 25559065 TI - Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects. AB - PURPOSE: The aim of this study was to investigate the potential drug-drug interaction between Bencycloquidium bromide (BCQB) and paroxetine, and between BCQB and roxithromycin. METHODS: Two studies were conducted on healthy male Chinese volunteers. Study A was an open-label, two-period, one-sequence crossover study (n=21). Each participant received a single nasal spray dose of BCQB 180MUg on day 1. After a 7-day wash-out period, subjects received 20mg of paroxetine from day 8 to 17, and were co-administered 20mg of paroxetine and BCQB 180MUg on day 18. In study B, participants (n=12) were randomly assigned to two groups. In period I, group A received BCQB 180MUg on day 1, followed by the same dose four times daily from day 4 to 10, then, on day 11 a single dose of 150mg roxithromycin with BCQB 180MUg were co-administered. In parallel, group B received a single dose of roxithromycin 150mg on day 1, followed by 300mg of roxithromycin from day 4 to 10, then, on day 11 a single dose of BCQB 180MUg with roxithromycin 300mg were co-administered. After a wash-out time of 7days the respective treatments of each group (A and B) were swapped in period II. Blood samples were collected for pharmacokinetic analysis. Statistical comparison of pharmacokinetic parameters was performed to identify a possible drug interaction between treatments. Tolerability was evaluated by recording adverse events. RESULTS: Study A: Geometric mean AUC0-36 for BCQB alone and co-administered with paroxetine were 474.3 and 631.3pgh/ml, respectively. The geometric mean ratio (GMR) of AUC0-36 was 1.33 (1.13-1.46), 90% C.Is, and was out the predefined bioequivalence interval (90% C.Is, 0.80-1.25). Geometric mean Cmax were 187.0 and 181.2pg/ml. Study B: The GMR of AUC0-36 was 0.98 (0.90-1.07), 90% C.Is for BCQB, and the GMR of AUC0-72 was 0.98 (0.87-1.11), 90% C.Is for roxithromycin. Both GMRs were within the predefined bioequivalence interval (90% C.Is, 0.80-1.25). Other pharmacokinetic parameters were within the predefined interval. No serious adverse events were reported and no significant clinical changes were observed in laboratory test results, vital signs and ECGs in any of the studies. All treatments were well tolerated. CONCLUSION: The co-administration of BCQB with paroxetine showed a moderate increase in BCQB exposure, but was not clinically relevant. Also, no drug interaction was found between BCQB and roxithromycin. PMID- 25559066 TI - Depth profile of a time-reversal focus in an elastic solid. AB - The out-of-plane velocity component is focused on the flat surface of an isotropic solid sample using the principle of time reversal. This experiment is often reproduced in the context of nondestructive testing for imaging features near the surface of the sample. However, it is not clear how deep the focus extends into the bulk of the sample and what its profile is. In this paper, this question is answered using both numerical simulations and experimental data. The profiles of the foci are expressed in terms of the wavelengths of the dominant waves, based on the interpretation of the Lamb's problem and the use of the diffraction limit. PMID- 25559068 TI - Clinical practice models in nursing education: implication for students' mobility. AB - BACKGROUND: In accordance with the process of nursing globalization, issues related to the increasing national and international mobility of student and qualified nurses are currently being debated. Identifying international differences and comparing similarities for mutual understanding, development and better harmonization of clinical training of undergraduate nursing students is recommended. AIMS: The aim of the study was to describe and compare the nature of the nursing clinical practice education models adopted in different countries. METHODS: A qualitative approach involving an expert panel of nurses was adopted. The Nominal Group Technique was employed to develop the initial research instrument for data collection. Eleven members of the UDINE-C network, representing institutions engaged in the process of professional nursing education and research (universities, high schools and clinical institutes), participated. Three data collection rounds were implemented. An analysis of the findings was performed, assuring rigour. RESULTS: Differences and homogeneity are reported and discussed regarding: (a) the clinical learning requirements across countries; (b) the prerequisites and clinical learning process patterns; and (c) the progress and final evaluation of the competencies achieved. CONCLUSIONS: A wider discussion is needed regarding nursing student exchange and internalization of clinical education in placements across European and non-European countries. A clear strategy for nursing education accreditation and harmonization of patterns of organization of clinical training at placements, as well as strategies of student assessment during this training, are recommended. There is also a need to develop international ethical guidelines for undergraduate nursing students gaining international experience. PMID- 25559067 TI - Changes in work affect in response to lunchtime walking in previously physically inactive employees: A randomized trial. AB - Physical activity may regulate affective experiences at work, but controlled studies are needed and there has been a reliance on retrospective accounts of experience. The purpose of the present study was to examine the effect of lunchtime walks on momentary work affect at the individual and group levels. Physically inactive employees (N = 56; M age = 47.68; 92.86% female) from a large university in the UK were randomized to immediate treatment or delayed treatment (DT). The DT participants completed both a control and intervention period. During the intervention period, participants partook in three weekly 30-min lunchtime group-led walks for 10 weeks. They completed twice daily affective reports at work (morning and afternoon) using mobile phones on two randomly chosen days per week. Multilevel modeling was used to analyze the data. Lunchtime walks improved enthusiasm, relaxation, and nervousness at work, although the pattern of results differed depending on whether between-group or within-person analyses were conducted. The intervention was effective in changing some affective states and may have broader implications for public health and workplace performance. PMID- 25559069 TI - Outcomes following childhood arterial ischaemic stroke: a Delphi Consensus on what parents want from future research. AB - AIM: Currently there are few population-based data on the outcomes of stroke in childhood, and no data on what parents want from such research. We conducted a Delphi Consensus Process among parents of children (n = 26) who had suffered an arterial ischaemic stroke to investigate which research outcomes they think are most important to follow up, and what methods of assessment they would find most acceptable. METHODS: A postal Delphi Consensus Process was conducted. RESULTS: The Delphi panel reached consensus that motor, cognitive and communication outcomes are the most important outcome domains to assess. They strongly preferred home visits over hospital visits or telephone interview. The majority were happy with assessment visits lasting up to 1.5 h. Ongoing concerns for panel members related to the cause of the original stroke, the risk of recurrence and the long term outcome for their child. INTERPRETATION: Future outcome studies should preferably assess outcomes at home and focus on children's motor, cognitive and communication abilities. There is an ongoing need to clarify issues with regards to the likely cause of children's strokes and their risk of recurrence. PMID- 25559070 TI - Host-pathogen interactions during porcine reproductive and respiratory syndrome virus 1 infection of piglets. AB - Porcine reproductive and respiratory syndrome (PRRS) is a major disease affecting pigs worldwide and resulting in considerable economic losses. While PRRS is a global phenomenon, the causative viruses PRRSV-1 (first detected in Europe) and PRRSV-2 (isolated in North America) are genetically and biologically distinct. In addition, the disease outcome is directly linked to co-infections associated with the porcine respiratory disease complex and the host response is variable between different breeds of pigs. It is therefore warranted when studying the pathogenesis of PRRS to consider each viral genotype separately and apply careful consideration to the disease model studied. We here review the respiratory pig model for PRRSV-1, with a focus on a recent set of studies conducted with carefully selected virus strains and pigs, which may serve as both a baseline and benchmark for future investigation. PMID- 25559074 TI - The Swedish duty hour enigma. AB - BACKGROUND: The Swedish resident duty hour limit is regulated by Swedish and European legal frameworks. With a maximum average of 40 working hours per week, the Swedish duty hour regulation is one of the most restrictive in the world. At the same time, the effects of resident duty hour limits have been neither debated nor researched in the Swedish context. As a result, little is known about the Swedish conceptual framework for resident duty hours, their restriction, or their outcomes: we call this "the Swedish duty hour enigma." This situation poses a further question: How do Swedish residents themselves construct a conceptual framework for duty hour restrictions? METHODS: A case study was conducted at Karolinska University Hospital, Stockholm--an urban, research-intensive hospital setting. Semi-structured interviews were carried out with 34 residents currently in training in 6 specialties. The empirical data analysis relied on theoretical propositions and was conducted thematically using a pattern-matching technique. The interview guide was based on four main topics: the perceived effect of duty hour restrictions on (1) patient care, (2) resident education, (3) resident well being, and (4) research. RESULTS: The residents did not perceive the volume of duty hours to be the main determinant of success or failure in the four contextual domains of patient care, resident education, resident well-being, and research. Instead, they emphasized resident well-being and a desire for flexibility. CONCLUSIONS: According to Swedish residents' conceptual framework on duty hours, the amount of time spent on duty is not a proxy for the quality of resident training. Instead, flexibility, organization, and scheduling of duty hours are considered to be the factors that have the greatest influence on resident well-being, quality of learning, and opportunities to attain the competence needed for independent practice. PMID- 25559076 TI - Low-Budget Instrumentation of a Conventional Leg Press to Measure Reliable Isometric-Strength Capacity. AB - Maximum strength and rate of force development (RFD) are 2 important strength characteristics for everyday tasks and athletic performance. Measurements of both parameters must be reliable. Expensive isokinetic devices with isometric modes are often used. The possibility of cost-effective measurements in a practical setting would facilitate quality control. The purpose of this study was to assess the reliability of measurements of maximum isometric strength (Fmax) and RFD on a conventional leg press. Sixteen subjects (23 +/- 2 y, 1.68 +/- 0.05 m, 59 +/- 5 kg) were tested twice within 1 session. After warm-up, subjects performed 2 times 5 trials eliciting maximum voluntary isometric contractions on an instrumented leg press (1- and 2-legged randomized). Fmax (N) and RFD (N/s) were extracted from force-time curves. Reliability was determined for Fmax and RFD by calculating the intraclass correlation coefficient (ICC), the test-retest variability (TRV), and the bias and limits of agreement. Reliability measures revealed good to excellent ICCs of .80-.93. TRV showed mean differences between measurement sessions of 0.4-6.9%. The systematic error was low compared with the absolute mean values (Fmax 5-6%, RFD 1-4%). The implementation of a force transducer into a conventional leg press provides a viable procedure to assess Fmax and RFD. Both performance parameters can be assessed with good to excellent reliability allowing quality control of interventions. PMID- 25559075 TI - Effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice. AB - Previous studies have shown that sigma-1 receptor chaperone (Sig-1R) ligands can regulate pain-related behaviors, and Sig-1R itself can regulate MU-opioid receptor functions as well as signal transduction. Even though (+/-)-pentazocine has been used clinically for the treatment of pain through opioid receptors, (+) pentazocine is known to be a selective Sig-1R agonist. To the best of our knowledge, there is no information available regarding the involvement of Sig-1R agonistic action in the antinociceptive effects of (+/-)-pentazocine. Therefore, the present study was designed to investigate the effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice. Both and (-)-pentazocine induced biphasic antinociceptive effects as measured by the warm-plate test. The early phase, but not the delayed phase, of the antinociceptive effects induced by (-)-pentazocine, which are mediated by the activation of MU-opioid receptors, were suppressed by pretreatment with (+)-pentazocine. These results suggest that the innate antinociceptive action of (+/-)-pentazocine could be marginally reduced by the effects of (+)-pentazocine, but (+)-pentazocine can suppress the antinociceptive effects of (-)-pentazocine at certain time points. PMID- 25559071 TI - Picornavirus RNA polyadenylation by 3D(pol), the viral RNA-dependent RNA polymerase. AB - Poly(A) tails are functionally important features of all picornavirus RNA genomes. Some viruses have genomes with relatively short poly(A) tails (encephalomyocarditis virus) whereas others have genomes with longer poly(A) tails (polioviruses and rhinoviruses). Here we review the polyadenylation of picornavirus RNA as it relates to the structure and function of 3D(pol). Poliovirus 3D(pol) uses template-dependent reiterative transcription mechanisms as it replicates the poly(A) tails of viral RNA (Steil et al., 2010). These mechanisms are analogous to those involved in the polyadenylation of vesicular stomatitis virus and influenza virus mRNAs. 3D(pol) residues intimately associated with viral RNA templates and products regulate the size of poly(A) tails in viral RNA (Kempf et al., 2013). Consistent with their ancient evolutionary origins, picornavirus 3D(pol) and telomerase reverse transcriptase (TERT) share structural and functional features. Structurally, both 3D(pol) and TERT assume a "right-hand" conformation with thumb, palm and fingers domains encircling templates and products. Functionally, both 3D(pol) and TERT use template-dependent reiterative transcription mechanisms to synthesize repetitive sequences: poly(A) tails in the case of picornavirus RNA genomes and DNA telomeres in the case of eukaryotic chromosomes. Thus, picornaviruses and their eukaryotic hosts (humans and animals) maintain the 3' ends of their respective genomes via evolutionarily related mechanisms. PMID- 25559077 TI - Individuals with severe mental illnesses have improved eating behaviors and cooking skills after attending a 6-week nutrition cooking class. AB - OBJECTIVE: This study assessed current meal planning/cooking behaviors and dietary intake of individuals with severe mental illnesses and determined differences after a 6-week nutrition education cooking class. METHOD: Eighteen individuals with severe mental illnesses participated in a 6-week nutrition education cooking class and completed pre- and posttest 24-hr recalls and a postretrospective survey. Paired samples t tests were used. RESULTS: Participants met their calories needs, but they consumed high amounts of sodium and fat and low amounts of fiber. Significant increases in calcium, vitamin D, grains, and fruit occurred from pre- to posttest (p < .05). Self-efficacy in cooking and grocery shopping skills improved. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Participants desire nutrition education programming that includes simple messages, hands-on cooking demonstrations, and health-related incentives. More research is needed to determine how nutrition education programs lead to sustained knowledge and behavior change within this specialized population. PMID- 25559078 TI - Resident and proprietor perspectives on a recovery orientation in community-based housing. AB - OBJECTIVE: Stable housing is a fundamental human right, and an important element for both mental health recovery and social inclusion among people with serious mental illness. This article reports findings from a study on the recovery orientation of structured congregate community housing services using the Recovery Self-Assessment Questionnaire (RSA) adapted for housing (O'Connell, Tondora, Croog, Evans, & Davidson, 2005). METHODS: The RSA questionnaires were administered to 118 residents and housing providers from 112 congregate housing units located in Montreal, Canada. RESULTS: Residents rated their homes as significantly less recovery-oriented than did proprietors, which is contrary to previous studies of clinical services or Assertive Community Treatment where RSA scores for service users were significantly higher than service provider scores. Findings for both groups suggest the need for improvement on 5 of 6 RSA factors. While proprietors favored recovery training and education, and valued resident opinion and experience, vestiges of a traditional medical model governing this housing emerged in other findings, as in agreement between the 2 groups that residents have little choice in case management, or in the belief among proprietors that residents are unable to manage their symptoms. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study demonstrates that the RSA adapted for housing is a useful tool for creating recovery profiles of housing services. The findings provide practical guidance on how to promote a recovery orientation in structured community housing, as well as a novel approach for reaching a common understanding of what this entails among stakeholders. (PsycINFO Database Record PMID- 25559079 TI - Transitory and storage starch metabolism: two sides of the same coin? AB - The industrially important polymer, starch, is manufactured through a complex process involving multiple isoforms of several different enzymes. These contribute to alter the structure of starch which, in turn, affects its downstream industrial use. This review compares recent advances in our knowledge of starch metabolism in leaves and storage organs. Starch granule initiation and formation, enzyme complexes involved in starch metabolism and control of flux in starch synthesis and degradation are examined. PMID- 25559080 TI - Additivity or cooperativity: which model can predict the influence of simultaneous incorporation of two or more functionalities in a ligand molecule? AB - Predicting how binding affinity responds to ligand structural modifications in structure-activity relationship studies (SAR) is a major challenge in medicinal chemistry. This is particularly true when two or more of these modifications are carried out simultaneously. In this study, we present binding affinity data from several series of thermolysin inhibitors in which simultaneous structural modifications were investigated to determine whether they are cooperative or additive. Data revealed that, while additivity is at work in some cases, cooperativity is more commonly demonstrated. Cooperativity and additivity were then correlated with ligand descriptors, such as the spacing and the topological features of the modified groups, in a manner that may provide guidance as to when each model should be utilized. Cooperativity was particularly associated with contiguous groups and small unbranched hydrophobic side chain. Additivity, on the other hand, was associated with moderately distant hydrophobic group combinations and side chain branching. Such correlations can improve the predictability of SAR studies and can provide a starting point for additional investigations that may lead to further significant enhancements in the current scoring functions. PMID- 25559082 TI - Hippocampal theta sequences reflect current goals. AB - Hippocampal information processing is discretized by oscillations, and the ensemble activity of place cells is organized into temporal sequences bounded by theta cycles. Theta sequences represent time-compressed trajectories through space. Their forward-directed nature makes them an intuitive candidate mechanism for planning future trajectories, but their connection to goal-directed behavior remains unclear. As rats performed a value-guided decision-making task, the extent to which theta sequences projected ahead of the animal's current location varied on a moment-by-moment basis depending on the rat's goals. Look-ahead extended farther on journeys to distant goals than on journeys to more proximal goals and was predictive of the animal's destination. On arrival at goals, however, look-ahead was similar regardless of where the animal began its journey from. Together, these results provide evidence that hippocampal theta sequences contain information related to goals or intentions, pointing toward a potential spatial basis for planning. PMID- 25559081 TI - Marinesco-Sjogren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS. AB - Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SIL1, mutated in Marinesco-Sjogren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress-prone fast fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sil1 allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus-mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival. PMID- 25559084 TI - beta-(1 -> 3)-Glucanolytic yeasts from Brazilian grape microbiota: production and characterization of beta-glucanolytic enzymes by Aureobasidium pullulans 1WA1 cultivated on fungal Mycelium. AB - A total of 95 yeast strains were isolated from the microbiota of different grapes collected at vineyards in southern Brazil. The yeasts were screened for beta-(1 > 3)-glucanases using a newly developed zymogram method that relies upon the appearance of clearance zones around growing colonies cultured on agar botryosphaeran medium and also by submerged fermentation on nutrient medium containing botryosphaeran, a (1 -> 3),(1 -> 6)-beta-d-glucan. Among 14 beta-(1 -> 3)-glucanase-positive yeasts identified, four strains produced the highest beta glucanolytic activities and were evaluated for enzyme production on cellobiose, botryosphaeran, and mycelial biomass from Botryosphaeria rhodina (MAMB-05). Yeast strain 1WA1 produced the highest beta-(1 -> 3)-glucanase and beta-glucosidase activities and was identified by molecular characterization as Aureobasidium pullulans. The physicochemical properties of the crude beta-glucanolytic enzyme preparation were characterized, and the preparation was used to hydrolyze several beta-d-glucans (laminarin, botryosphaeran, lasiodiplodan, pustulan, and curdlan). The production and physicochemical properties of the beta-glucanolytic preparation enable its potential applications in wine enology and production of prebiotics through hydrolysis of beta-d-glucans. PMID- 25559085 TI - Schistosome infection aggravates HCV-related liver disease and induces changes in the regulatory T-cell phenotype. AB - Schistosome infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co-infections with hepatitis C virus (HCV), schistosomes accentuate disease progression and we hypothesized that expanding schistosome-induced Treg populations change their phenotype and could thereby suppress beneficial anti-HCV responses. We therefore analysed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono-infected (HCV), schistosome-co-infected (Sm/HCV) and infection-free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and Helios(pos) Treg were not elevated in Sm/HCV individuals, but frequencies of GrzB(+) Treg were significantly increased. Simultaneously, GrzB(+) CD8(+) T cells were not suppressed in co-infected individuals. This study demonstrates that in Sm/HCV co-infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important prerequisite for successful HCV treatment as co-infected individuals respond poorly to interferon therapy. PMID- 25559083 TI - Inferred metagenomic comparison of mucosal and fecal microbiota from individuals undergoing routine screening colonoscopy reveals similar differences observed during active inflammation. AB - The mucosal microbiota lives in close proximity with the intestinal epithelium and may interact more directly with the host immune system than the luminal/fecal bacteria. The availability of nutrients in the mucus layer of the epithelium is also very different from the gut lumen environment. Inferred metagenomic analysis for microbial function of the mucosal microbiota is possible by PICRUSt. We recently found that by using this approach, actively inflamed tissue of ulcerative colitis (UC) patients have mucosal communities enriched for genes involved in lipid and amino acid metabolism, and reduced for carbohydrate and nucleotide metabolism. Here, we find that the same bacterial taxa (e.g. Acinetobacter) and predicted microbial pathways enriched in actively inflamed colitis tissue are also enriched in the mucosa of subjects undergoing routine screening colonoscopies, when compared with paired samples of luminal/fecal bacteria. These results suggest that the mucosa of healthy individuals may be a reservoir of aerotolerant microbial communities expanded during colitis. PMID- 25559086 TI - Neutron scattering studies of the hydration structure of Li+. AB - New results derived from the experimental method of neutron diffraction and isotopic substitution (NDIS) are presented for the hydration structure of the lithium cation (Li(+)) in aqueous solutions of lithium chloride in heavy water (D2O) at concentrations of 6, 3, and 1 m and at 1.5 m lithium sulfate. By introducing new and more-accurate data reduction procedures than in our earlier studies (I. Howell and G. W. Neilson, J. Phys: Condens. Matter, 1996, 8, 4455 4463), we find, in the first hydration shell of Li(+), ~4.3(2) water molecules at 6 m, 4.9(3) at 3 m, 4.8(3) at 1 m in the LiCl solutions, and 5.0(3) water molecules in the case of Li2SO4 solution. The general form of the first hydration shell is similar in all four solutions, with the correlations for Li-O and Li-D sited at 1.96 (0.02) A and 2.58 (0.02) A, respectively. The results resemble those presented in 1996, in terms of ion-water distances and local coordination, but the hydration number is significantly lower for the case at 1 m than the 6.5 (1.0) given at that time. Thus, experimental and theoretical results now agree that lithium is hydrated by a small number of water molecules (4-5) in the nearest coordination shell. PMID- 25559087 TI - A review of the potential role of nano-enabled drug delivery technologies in amyotrophic lateral sclerosis: lessons learned from other neurodegenerative disorders. AB - Amyotrophic lateral sclerosis (ALS) has a multitude of factors implicated in its etiology. The complex neuro-etiology and the restrictive nature of the blood brain barrier (BBB) have significantly hindered the drug therapy of ALS. Riluzole, a moderately performing drug, is the only agent approved for treating ALS. However, several promising nanocarrier approaches are surfacing that can provide more efficient drug delivery. In addition, biologicals such as stem cells are able to carry neurotrophic factors to their target site, providing motor neurons with the benefits of both, stem cells and neurotrophic factors. This review examines the current drug delivery strategies investigated for optimally treating ALS and related neurodegenerative disorders. Examples include cerium oxide nanoparticles in Alzheimer's disease, odorranalectin, and lactoferrin coupled PEG-PLGA nanoparticles for urocortin transportation in Parkinson's disease that can also be employed in ALS to bypass the BBB and increase drug bioavailability. A concise incursion into the progress (and lack thereof) made in ALS clinical trials is also discussed. Nanocarriers can potentially eliminate the challenges of poor drug bioavailability in ALS as they have been proven to cross the BBB and reach target sites while minimizing systemic side-effects. Nanocarrier-based delivery of ALS drugs is an area that requires much needed investigation. PMID- 25559089 TI - Going for broke: targeting the human cancer pseudokinome. AB - Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The human protein kinase superfamily (the kinome) encodes approximately 50 'pseudokinases', which were initially predicted to be incapable of dynamic cell signalling when compared with canonical enzymatically active kinases. This assumption was supported by bioinformatics, which showed that amino acid changes at one or more key loci, making up the nucleotide-binding site or phosphotransferase machinery, were conserved in multiple vertebrate and non vertebrate pseudokinase homologues. Protein kinases are highly attractive targets for drug discovery, as evidenced by the approval of almost 30 kinase inhibitors in oncology, and the successful development of the dual JAK1/2 (Janus kinase 1/2) inhibitor ruxolitinib for inflammatory indications. However, for such a large (>550) protein family, a remarkable number have still not been analysed at the molecular level, and only a surprisingly small percentage of kinases have been successfully targeted clinically. This is despite evidence that many are potential candidates for the development of new therapeutics. Indeed, several recent reports confirm that disease-associated pseudokinases can bind to nucleotide co-factors at concentrations achievable in the cell. Together, these findings suggest that drug targeting using either ATP-site or unbiased ligand discovery approaches should now be attempted using the validation technology currently employed to evaluate their classic protein kinase counterparts. In the present review, we discuss members of the human pseudokinome repertoire, and catalogue somatic amino acid pseudokinase mutations that are emerging as the depth and clinical coverage of the human cancer pseudokinome expand. PMID- 25559088 TI - Induced pluripotent stem cell-derived vascular smooth muscle cells: methods and application. AB - Vascular smooth muscle cells (VSMCs) play a major role in the pathophysiology of cardiovascular diseases. The advent of induced pluripotent stem cell (iPSC) technology and the capability of differentiating into virtually every cell type in the human body make this field a ray of hope for vascular regenerative therapy and understanding of the disease mechanism. In the present review, we first discuss the recent iPSC technology and vascular smooth muscle development from an embryo and then examine different methodologies to derive VSMCs from iPSCs, and their applications in regenerative therapy and disease modelling. PMID- 25559090 TI - Rehabilitation of memory following brain injury (ReMemBrIn): study protocol for a randomised controlled trial. AB - BACKGROUND: Impairments of memory are commonly reported by people with traumatic brain injuries (TBI). Such deficits are persistent, debilitating, and can severely impact quality of life. Currently, many do not routinely receive follow up appointments for residual memory problems following discharge. METHODS/DESIGN: This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based memory rehabilitation programme. Three hundred and twelve people with a traumatic brain injury will be randomised from four centres. Participants will be eligible if they had a traumatic brain injury more than 3 months prior to recruitment, have memory problems, are 18 to 69 years of age, are able to travel to one of our centres and attend group sessions, and are able to give informed consent. Participants will be randomised in clusters of 4 to 6 to the group rehabilitation intervention or to usual care. Intervention groups will receive 10 weekly sessions of a manualised memory rehabilitation programme, which has been developed in previous pilot studies. The intervention will include restitution strategies to retrain impaired memory functions and compensation strategies to enable participants to cope with their memory problems. All participants will receive a follow-up postal questionnaire and an assessment by a research assistant at 6 and 12 months post-randomisation. The primary outcome is the Everyday Memory Questionnaire at 6 months. Secondary outcomes include the Rivermead Behavioural Memory Test-3, General Health Questionnaire-30, health related quality of life, cost-effectiveness analysis determined by the EQ-5D and a service use questionnaire, individual goal attainment, European Brain Injury Questionnaire (patient and relative versions), and the Everyday Memory Questionnaire-relative version. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the Everyday Memory Questionnaire at 6 months will be used to estimate the effect of the group memory rehabilitation programme. DISCUSSION: The study will hopefully provide robust evidence regarding the clinical and cost-effectiveness of a group-based memory rehabilitation intervention for civilians and military personnel following TBI. We discuss our decision-making regarding choice of outcome measures and control group, and the unique challenges to recruiting people with memory problems to trials. TRIAL REGISTRATION: ISRCTN65792154; Date: 18 October 2012. PMID- 25559092 TI - Anticipated climate and land-cover changes reveal refuge areas for Borneo's orang utans. AB - Habitat loss and climate change pose a double jeopardy for many threatened taxa, making the identification of optimal habitat for the future a conservation priority. Using a case study of the endangered Bornean orang-utan, we identify environmental refuges by integrating bioclimatic models with projected deforestation and oil-palm agriculture suitability from the 1950s to 2080s. We coupled a maximum entropy algorithm with information on habitat needs to predict suitable habitat for the present day and 1950s. We then projected to the 2020s, 2050s and 2080s in models incorporating only land-cover change, climate change or both processes combined. For future climate, we incorporated projections from four model and emission scenario combinations. For future land cover, we developed spatial deforestation predictions from 10 years of satellite data. Refuges were delineated as suitable forested habitats identified by all models that were also unsuitable for oil palm - a major threat to tropical biodiversity. Our analyses indicate that in 2010 up to 260,000 km(2) of Borneo was suitable habitat within the core orang-utan range; an 18-24% reduction since the 1950s. Land-cover models predicted further decline of 15-30% by the 2080s. Although habitat extent under future climate conditions varied among projections, there was majority consensus, particularly in north-eastern and western regions. Across projections habitat loss due to climate change alone averaged 63% by 2080, but 74% when also considering land-cover change. Refuge areas amounted to 2000-42,000 km(2) depending on thresholds used, with 900-17,000 km(2) outside the current species range. We demonstrate that efforts to halt deforestation could mediate some orang-utan habitat loss, but further decline of the most suitable areas is to be expected given projected changes to climate. Protected refuge areas could therefore become increasingly important for ongoing translocation efforts. We present an approach to help identify such areas for highly threatened species given environmental changes expected this century. PMID- 25559093 TI - The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review. AB - BACKGROUND: Tissue factor (TF) is a key element for normal gestation, especially in the first trimester. TF levels are hence raised in pregnancy, producing an adaptive hypercoagulable state. Potentiated hypercoagulability however, is associated with disorders of pregnancy such as pre-eclampsia but the results of TF and its inhibitor, tissue factor pathway inhibitor (TFPI), measurement, in pre eclampsic women are ambiguous and the data conflicting. This review covers the current knowledge status of the role of TF assessment in pregnancy with a focus on its diagnostic utility. METHODS: A review of the literature using the following key words: tissue factor, thrombosis, inflammation, pregnancy, preeclampsia. RESULTS: The published literature shows raised and unchanged TF levels in various studies of pre-eclampsia along with equally conflicting data for TFPI. The various study designs and methods used in these studies makes valid comparison difficult. Meta analysis of 34 randomized trials showed that low-dose aspirin in early phases of gravidity (starting from the 16th week or earlier) significantly reduces the incidence of preeclampsia. CONCLUSIONS: Overall, the results of the literature search together with knowledge of the structure and biological effects of TF, suggest that measuring the level of plasma TF/TFPI is not ideal for determining the actual levels of TF in the uteroplacental circulation. The current view that endothelial dysfunction is the trigger for preeclampsia, suggests that aspirin may be an effective prophylaxis. Further research will be necessary: measuring the expression of tissue factor on monocytes using flowcytometry and comparing the development of this expression during normal pregnancy and pregnancy complicated by preeclampsia, for example. Another possibility is immunohistochemical determination of the level of TF expression directly in placental tissue. PMID- 25559091 TI - Protective variant for hippocampal atrophy identified by whole exome sequencing. AB - We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. PMID- 25559094 TI - The effect of continuous positive airway pressure therapy on the prevalence of masked hypertension in obstructive sleep apnea patients. AB - BACKGROUND AND AIM: Obstructive sleep apnea (OSA) is a common cause of secondary arterial hypertension. Masked hypertension (MH) is defined as normal office blood pressure and abnormal results in 24 h ambulatory blood pressure monitoring (ABPM). The aim of this study was to evaluate the effect of CPAP therapy on the prevalence of MH in patients with OSA. METHODS: 43 patients (40 men) were included, average age 54.2+/-10.5 years. All underwent sleep study (PG or PSG) with a diagnosis of OSA indicated for CPAP treatment, average apnea-hypopnea index (AHI) 60.6+/-23.6. Patients were treated with CPAP for one year. Ambulatory blood pressure monitoring was performed before and after one year of treatment. RESULTS: Masked hypertension was initially present in 25 (58.1%) and in 26 (60.5%) patients after one year of CPAP therapy. However, there was a statistically significant improvement in BP for all evaluated intervals of ABPM with the exception of systolic pressure during the daytime. CONCLUSIONS: Masked hypertension was very prevalent in these patients with OSA. The CPAP treatment for one year however had no affect on prevalence of masked hypertension although there was a positive effect of CPAP treatment on blood pressure for all assessed intervals of ABPM with the exception of systolic BP during daytime. PMID- 25559095 TI - The effect of HSAB on stereoselectivity: copper- and gold-catalyzed 1,3 phosphatyloxy and 1,3-halogen migration relay to 1,3-dienes. AB - The origin of stereodivergence between copper- and gold-catalyzed cascade 1,3 phosphatyloxy and 1,3-halogen migration from alpha-halo-propargylic phosphates to 1,3-dienes is rationalized with density functional theory (DFT) studies. Our studies reveal the significant role of the relative hardness/softness of the metal centers in determining the reaction mechanism and the stereoselectivity. The relative harder Cu(I/III) center prefers an associative pathway with the aid of a phosphate group, leading to the (Z)-1,3-dienes. In contrast, the relative softer Au(I/III) center tends to undergo a dissociative pathway without coordination to a phosphate group, resulting in the (E)-1,3-dienes, where the E type of transition state is favored due to the steric effect. Our findings indicate the intriguing role of hard-soft/acid-base (HSAB) theory in tuning the stereoselectivity of metal-catalyzed transformations with functionalized substrates. PMID- 25559096 TI - Patient-reported outcome measures for use in gynaecological oncology: a systematic review. AB - BACKGROUND: Patient-reported outcome measures (PROMs) are used to assess the impact of health care on a patient's health. Within the gynaecological oncology setting, multiple PROMs have been adopted but no assessment has been made in terms of their psychometric qualities and robustness. OBJECTIVES: To undertake a systematic review to identify the most psychometrically robust and appropriate PROM used in the gynaecological oncology setting. SEARCH STRATEGY: A search of the bibliographic database of the Oxford PROM group, plus nine additional databases, was carried out along with citation-tracking and hand searches. SELECTION CRITERIA: Studies examining the psychometric properties of outcome measures tested in gynaecological cancer populations were selected by three blinded reviewers. DATA COLLECTION AND ANALYSIS: Studies were independently assessed and data extracted. Analysis included an appraisal of the psychometric properties and functionality of the included PROMs to guide recommendations. MAIN RESULTS: Eighteen PROMs tested in gynaecological oncology settings were identified. These were categorised into seven areas of focus, and the most psychometrically robust tools were identified: (1) generic (no recommendation); (2) general cancer (EORTC QLQ-C30 and FACT-G); (3) pelvic cancer (QUEST GY); (4) ovarian cancer (EORTC QLQ-OV28); (5) cervical cancer (EORTC QLQ-CX24); (6) endometrial cancer (EORTC QLQ-EN 24); and (7) vulval cancer (FACT-V). AUTHOR'S CONCLUSIONS: Seven PROMs were recommended for use in six gynaecological populations. No single tool was identified that had been tested in all disease groups. Some showed promise, but a lack of conceptual clarity about the core outcomes and the rationale for use will require further testing using well constructed studies. PMID- 25559097 TI - Novel technique for characterizing prostate cancer utilizing MRI restriction spectrum imaging: proof of principle and initial clinical experience with extraprostatic extension. AB - BACKGROUND: Standard magnetic resonance imaging (MRI) of the prostate lacks sensitivity in the diagnosis and staging of prostate cancer (PCa). To improve the operating characteristics of prostate MRI in the detection and characterization of PCa, we developed a novel, enhanced MRI diffusion technique using restriction spectrum imaging (RSI-MRI). METHODS: We compared the efficacy of our novel RSI MRI technique with standard MRI for detecting extraprostatic extension (EPE) among 28 PCa patients who underwent MRI and RSI-MRI prior to radical prostatectomy, 10 with histologically proven pT3 disease. RSI cellularity maps isolating the restricted isotropic water fraction were reconstructed based on all b-values and then standardized across the sample with z-score maps. Distortion correction of the RSI maps was performed using the alternating phase-encode technique. RESULTS: 27 patients were evaluated, excluding one patient where distortion could not be performed. Preoperative standard MRI correctly identified extraprostatic the extension in two of the nine pT3 (22%) patients, whereas RSI MRI identified EPE in eight of nine (89%) patients. RSI-MRI correctly identified pT2 disease in the remaining 18 patients. CONCLUSIONS: In this proof of principle study, we conclude that our novel RSI-MRI technology is feasible and shows promise for substantially improving PCa imaging. Further translational studies of prostate RSI-MRI in the diagnosis and staging of PCa are indicated. PMID- 25559098 TI - Plant-based solutions for veterinary immunotherapeutics and prophylactics. AB - An alarming increase in emergence of antibiotic resistance among pathogens worldwide has become a serious threat to our ability to treat infectious diseases according to the World Health Organization. Extensive use of antibiotics by livestock producers promotes the spread of new resistant strains, some of zoonotic concern, which increases food-borne illness in humans and causes significant economic burden on healthcare systems. Furthermore, consumer preferences for meat/poultry/fish produced without the use of antibiotics shape today's market demand. So, it is viewed as inevitable by the One Health Initiative that humans need to reduce the use of antibiotics and turn to alternative, improved means to control disease: vaccination and prophylactics. Besides the intense research focused on novel therapeutic molecules, both these strategies rely heavily on the availability of cost-effective, efficient and scalable production platforms which will allow large-volume manufacturing for vaccines, antibodies and other biopharmaceuticals. Within this context, plant based platforms for production of recombinant therapeutic proteins offer significant advantages over conventional expression systems, including lack of animal pathogens, low production costs, fast turnaround and response times and rapid, nearly-unlimited scalability. Also, because dried leaves and seeds can be stored at room temperature for lengthy periods without loss of recombinant proteins, plant expression systems have the potential to offer lucrative benefits from the development of edible vaccines and prophylactics, as these would not require "cold chain" storage and transportation, and could be administered in mass volumes with minimal processing. Several biotechnology companies currently have developed and adopted plant-based platforms for commercial production of recombinant protein therapeutics. In this manuscript, we outline the challenges in the process of livestock immunization as well as the current plant biotechnology developments aimed to address these challenges. PMID- 25559099 TI - Linking electronic health records with community-level data to understand childhood obesity risk. AB - BACKGROUND: Environmental and socioeconomic factors should be considered along with individual characteristics when determining risk for childhood obesity. OBJECTIVES: To assess relationships and interactions among the economic hardship index (EHI) and race/ethnicity, age and sex in regard to childhood obesity rates in Wisconsin children using an electronic health record dataset. METHODS: Data were collected using the University of Wisconsin (UW) Public Health Information Exchange database, which links electronic health records with census-derived community-level data. Records from 53,775 children seen at UW clinics from 2007 to 2012 were included. Mixed-effects modelling was used to determine obesity rates and the interaction of EHI with covariates (race/ethnicity, age, sex). When significant interactions were determined, linear regression analyses were performed for each subgroup (e.g. by age groups). RESULTS: The overall obesity rate was 11.7% and significant racial/ethnic disparities were detected. Childhood obesity was significantly associated with EHI at the community level (r = 0.62, P < 0.0001). A significant interaction was determined between EHI and both race/ethnicity and age on obesity rates. CONCLUSIONS: Reducing economic disparities and improving environmental conditions may influence childhood obesity risk in some, but not all, races and ethnicities. Furthermore, the impact of EHI on obesity may be compounded over time. Our findings demonstrate the utility of linking electronic health information with census data to rapidly identify community-specific risk factors in a cost-effective manner. PMID- 25559100 TI - Exploration of cyanine compounds as selective inhibitors of protein arginine methyltransferases: synthesis and biological evaluation. AB - Protein arginine methyltransferase 1 (PRMT1) is involved in many biological activities, such as gene transcription, signal transduction, and RNA processing. Overexpression of PRMT1 is related to cardiovascular diseases, kidney diseases, and cancers; therefore, selective PRMT1 inhibitors serve as chemical probes to investigate the biological function of PRMT1 and drug candidates for disease treatment. Our previous work found trimethine cyanine compounds that effectively inhibit PRMT1 activity. In our present study, we systematically investigated the structure-activity relationship of cyanine structures. A pentamethine compound, E 84 (compound 50), showed inhibition on PRMT1 at the micromolar level and 6- to 25 fold selectivity over CARM1, PRMT5, and PRMT8. The cellular activity suggests that compound 50 permeated the cellular membrane, inhibited cellular PRMT1 activity, and blocked leukemia cell proliferation. Additionally, our molecular docking study suggested compound 50 might act by occupying the cofactor binding site, which provided a roadmap to guide further optimization of this lead compound. PMID- 25559101 TI - Disorder-to-order transition in the CyaA toxin RTX domain: implications for toxin secretion. AB - The past decade has seen a fundamental reappraisal of the protein structure-to function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many proteins that contain intrinsically disordered regions. This trait is exhibited by RTX (Repeat in ToXin) motifs found in more than 250 virulence factors secreted by Gram-negative pathogenic bacteria. We have investigated several RTX-containing polypeptides of different lengths, all derived from the Bordetella pertussis adenylate cyclase toxin, CyaA. Using a combination of experimental approaches, we showed that the RTX proteins exhibit the hallmarks of intrinsically disordered proteins in the absence of calcium. This intrinsic disorder mainly results from internal electrostatic repulsions between negatively charged residues of the RTX motifs. Calcium binding triggers a strong reduction of the mean net charge, dehydration and compaction, folding and stabilization of secondary and tertiary structures of the RTX proteins. We propose that the intrinsically disordered character of the RTX proteins may facilitate the uptake and secretion of virulence factors through the bacterial secretion machinery. These results support the hypothesis that the folding reaction is achieved upon protein secretion and, in the case of proteins containing RTX motifs, could be finely regulated by the calcium gradient across bacterial cell wall. PMID- 25559103 TI - Using CellProfiler for Automatic Identification and Measurement of Biological Objects in Images. AB - Visual analysis is required to perform many biological experiments, from counting colonies to measuring the size or fluorescence intensity of individual cells or organisms. This unit outlines the use of CellProfiler, a free, open-source image analysis tool that extracts quantitative information from biological images. It includes a step-by-step protocol for automated analysis of the number, color, and size of yeast colonies growing on agar plates, but the methods can be adapted to identify and measure many other types of objects in images. The flexibility of the software allows experimenters to create pipelines of adjustable modules to fit different biological experiments and to generate accurate measurements from dozens or even hundreds of thousands of images. PMID- 25559102 TI - Complexity of naturally produced polybrominated diphenyl ethers revealed via mass spectrometry. AB - Polybrominated diphenyl ethers (PBDEs) are persistent and bioaccumulative anthropogenic and natural chemicals that are broadly distributed in the marine environment. PBDEs are potentially toxic due to inhibition of various mammalian signaling pathways and enzymatic reactions. PBDE isoforms vary in toxicity in accordance with structural differences, primarily in the number and pattern of hydroxyl moieties afforded upon a conserved core structure. Over four decades of isolation and discovery-based efforts have established an impressive repertoire of natural PBDEs. Based on our recent reports describing the bacterial biosyntheses of PBDEs, we predicted the presence of additional classes of PBDEs to those previously identified from marine sources. Using mass spectrometry and NMR spectroscopy, we now establish the existence of new structural classes of PBDEs in marine sponges. Our findings expand the chemical space explored by naturally produced PBDEs, which may inform future environmental toxicology studies. Furthermore, we provide evidence for iodinated PBDEs and direct attention toward the contribution of promiscuous halogenating enzymes in further expanding the diversity of these polyhalogenated marine natural products. PMID- 25559104 TI - Parallel protein detection by solid-phase proximity ligation assay with real-time PCR or sequencing. AB - Proximity ligation assays are a group of protein detection techniques in which reagents with affinity for target proteins, typically antibodies, are coupled to short strands of DNA. DNA-modified affinity reagents are combined in assays constructed such that the coordinated binding of individual target molecules or complexes of interacting proteins by two or more of the reagents, followed by DNA ligation and/or polymerization reactions, gives rise to amplifiable DNA reporter strands. Proximity ligation assays have been shown to exhibit excellent sensitivity in single and multiplexed protein assays for individual or interacting proteins, both in solution and in situ. This unit describes procedures for developing solid-phase proximity ligation assays for soluble proteins using either real-time PCR or DNA sequencing as the readout. In addition, critical steps for assay optimization are discussed. PMID- 25559105 TI - ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide. AB - This unit describes Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq), a method for mapping chromatin accessibility genome-wide. This method probes DNA accessibility with hyperactive Tn5 transposase, which inserts sequencing adapters into accessible regions of chromatin. Sequencing reads can then be used to infer regions of increased accessibility, as well as to map regions of transcription-factor binding and nucleosome position. The method is a fast and sensitive alternative to DNase-seq for assaying chromatin accessibility genome-wide, or to MNase-seq for assaying nucleosome positions in accessible regions of the genome. PMID- 25559106 TI - BioTAP-XL: Cross-linking/Tandem Affinity Purification to Study DNA Targets, RNA, and Protein Components of Chromatin-Associated Complexes. AB - In order to understand how chromatin complexes function in the nucleus, it is important to obtain a comprehensive picture of their protein, DNA, and RNA components, as well as their mutual interactions. This unit presents a chromatin cross-linking approach (BioTAP-XL) that utilizes a special BioTAP-tagged transgenic protein bait along with mass spectrometry to identify protein complex components, and high-throughput sequencing to identify RNA components and DNA binding sites. Full protocols are provided for Drosophila cells and for human cells in culture, along with an additional protocol for Drosophila embryos as the source material. A key element of the approach in all cases is the generation of control data from input chromatin samples. PMID- 25559107 TI - RNA Interference in Caenorhabditis elegans. AB - RNAi has become an essential tool in C. elegans research. This unit describes procedures for RNAi in C. elegans by microinjecting with dsRNA, feeding with bacteria expressing dsRNA, and soaking in dsRNA solution, as well as high throughput methods for RNAi-based screens. PMID- 25559108 TI - Label-free biomedical imaging of lipids by stimulated Raman scattering microscopy. AB - Advances in modern optical microscopy have provided unparalleled tools to study intracellular structure and function, yet visualizing lipid molecules within a cell remains challenging. Stimulated Raman Scattering (SRS) microscopy is a recently developed imaging modality that addresses this challenge. By selectively imaging the vibration of chemical moieties enriched in lipids, this technique allows for rapid imaging of lipid molecules in vivo without the need for perturbative extrinsic labels. SRS microscopy has been effectively employed in the study of fat metabolism, helping uncover novel regulators of lipid storage. This unit provides a brief introduction to the principle of SRS microscopy, and describes methods for its use in imaging lipids in cells, tissues, and whole organisms. PMID- 25559109 TI - Interest in Smoking Cessation Related to a Smoke-Free Policy Among Homeless Adults. AB - Homeless adults have among the highest rates of cigarette smoking. Few studies have explored the potential of smoke-free policies as facilitators of smoking cessation or harm reduction among sheltered homeless adults. We focused on clients of a homeless shelter in San Diego, California. The facility prohibited smoking indoors and outdoors within five blocks of the building, and permitted smoking during four smoking breaks during the day in designated smoking zones away from the building. Current and former smokers who were residents of the facility were interviewed on smoking behaviors and attitudes toward these policies. Of the 170 ever smokers, 75.3% were current smokers. The average daily cigarette consumption was 6.6 cigarettes per day (SD 4.3). More than half of the participants (57.8%) attempted to quit smoking in the past year. Of the current smokers, three-fourths agreed that the facility policies were associated with their reduced consumption, and about half agreed that the policies were associated with either making a quit attempt or getting ready to quit completely. Sixty percent agreed that further restrictions on smoking, beyond the current policies, would be associated with increased interest in quitting smoking completely. Less than 10% agreed that they were unhappy to stay in the facility because of the policies. Findings suggest that smoke-free policies may not influence occupancy rates in shelters serving clientele with high rates of cigarette smoking. Smoke-free policies in homeless service settings present an important and un-tapped opportunity to reduce smoking behaviors among homeless adults. PMID- 25559110 TI - Glove Changing Habits in Mobile Food Vendors in New York City. AB - The aim of this study was to determine how often mobile food cart vendors in New York City (NYC) changed gloves after exchanging money, which is required by the current NYC health code as one of various measures to prevent foodborne illness. A total of 100 carts (10 carts in 10 zones) throughout Manhattan were observed. In the majority (56.9%, n = 1,026) of the 1,804 money exchanges, food cart vendors did not change their gloves. Not changing gloves after exchanging money was widespread regardless of food type served (46.6% for breakfast to 63.7% for lunch), and across all 10 zones. Not changing gloves after touching money may result in indirect transmission of agents of disease and pose health risks for consumers. PMID- 25559112 TI - Probing local bias-induced transitions using photothermal excitation contact resonance atomic force microscopy and voltage spectroscopy. AB - Nanomechanical properties are closely related to the states of matter, including chemical composition, crystal structure, mesoscopic domain configuration, etc. Investigation of these properties at the nanoscale requires not only static imaging methods, e.g., contact resonance atomic force microscopy (CR-AFM), but also spectroscopic methods capable of revealing their dependence on various external stimuli. Here we demonstrate the voltage spectroscopy of CR-AFM, which was realized by combining photothermal excitation (as opposed to the conventional piezoacoustic excitation method) with the band excitation technique. We applied this spectroscopy to explore local bias-induced phenomena ranging from purely physical to surface electromechanical and electrochemical processes. Our measurements show that the changes in the surface properties associated with these bias-induced transitions can be accurately assessed in a fast and dynamic manner, using resonance frequency as a signature. With many of the advantages offered by photothermal excitation, contact resonance voltage spectroscopy not only is expected to find applications in a broader field of nanoscience but also will provide a basis for future development of other nanoscale elastic spectroscopies. PMID- 25559113 TI - Consolidating memories. AB - Our own experiences, as well as the findings of many studies, suggest that emotionally arousing experiences can create lasting memories. This autobiographical article provides a brief summary of the author's research investigating neurobiological systems responsible for the influence of emotional arousal on the consolidation of lasting memories. The research began with the finding that stimulant drugs enhanced memory in rats when administered shortly after training. Those findings suggested the possibility that endogenous systems activated by arousal might influence neural processes underlying memory consolidation. Subsequent findings that adrenal stress hormones activated by learning experiences enhance memory consolidation provided strong evidence supporting this hypothesis. Other findings suggest that the enhancement is induced by stress hormone activation of the amygdala. The findings also suggest that the basolateral amygdala modulates memory consolidation via its projections to brain regions involved in processing different aspects and forms of memory. This emotional-arousal-activated neurobiological system thus seems to play an important adaptive role in insuring that the strength of our memories will reflect their emotional significance. PMID- 25559111 TI - Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project. AB - INTRODUCTION: Focal therapy can offer the middle ground for treatment between active surveillance and radical therapy in patients with low- and intermediate risk prostate cancer. Factors that prohibit focal therapy from being standard of care are numerous. Several consensus projects have been conducted to position the utilization of imaging and trial design in focal therapy. However, the literature is still scarce on patient follow-up after focal therapy. For these reasons, an international multidisciplinary consensus project was established in order to reach consensus about a uniform follow-up protocol after focal therapy. OBJECTIVE: To standardize patient follow-up after focal therapy. MATERIALS AND METHODS: A literature study was performed, and a questionnaire was constructed. The questionnaire was sent out to 76 participants (70 % urologists, 28 % radiologists and 2 % biomedical engineers) in three consecutive rounds according to the Delphi method. In each round, the panelists were presented with the results of the previous round. Participants each had the opportunity to adapt, delete or add questions. The topics discussed pertaining to follow-up after focal therapy were as follows: (1) general,(2) biopsies, (3) PSA, (4) digital rectal examination (DRE), (5) imaging, (6) quality of life (QoL) and (7) registration and pooling of data. The project was concluded with a face-to-face meeting in which final conclusions were formulated. RESULTS: The follow-up after focal therapy should be a minimum of 5 years. The following modalities should be included in assessing post-treatment outcomes: multiparametric MRI (mpMRI), biopsies, assessment of erectile function, QoL, urinary symptoms and incontinence. A systematic 12-core TRUS biopsy combined with 4-6 targeted biopsy cores of the treated area and any suspicious lesion(s) should be performed after 1 year, and thereafter only when there is suspicion on imaging. The ideal way to perform targeted biopsies is to use TRUS-MRI fusion technology. PSA should be performed for research purposes, in the first year, every 3 months, and after the first year, every 6 months. mpMRI is the optimal imaging modality for follow-up after focal therapy. On a 1.5T scanner, an endorectal coil is strongly advised by the panel, whereas on a 3T machine, it is optional, however, it will improve image quality. The following sequences should be included: T2WI, DWI including high b values of >1,000 and ADC maps of DWI, DCE and T1WI. Imaging should be performed at 6 months and at 1 year following treatment; after the first year post-treatment, it should be performed every year until 5 years following treatment. All data should ideally be pooled in a common global database. CONCLUSION: Focal therapy is a relatively new form of treatment for prostate cancer. In order to include focal therapy as a standard of care treatment, consistent follow-up is necessary. By implementing the results of this consensus study, focal therapy users will be able to provide important and standardized outcome data. PMID- 25559114 TI - Information processing as a paradigm for decision making. AB - For decades, the dominant paradigm for studying decision making--the expected utility framework--has been burdened by an increasing number of empirical findings that question its validity as a model of human cognition and behavior. However, as Kuhn (1962) argued in his seminal discussion of paradigm shifts, an old paradigm cannot be abandoned until a new paradigm emerges to replace it. In this article, we argue that the recent shift in researcher attention toward basic cognitive processes that give rise to decision phenomena constitutes the beginning of that replacement paradigm. Models grounded in basic perceptual, attentional, memory, and aggregation processes have begun to proliferate. The development of this new approach closely aligns with Kuhn's notion of paradigm shift, suggesting that this is a particularly generative and revolutionary time to be studying decision science. PMID- 25559116 TI - Childhood antecedents and risk for adult mental disorders. AB - Progress in treating and preventing mental disorders may follow from research that integrates development, genetics, and neuroscience. This review first delineates how longitudinal research has identified three particular groups of disorders shown to differ on the basis of symptom trajectories and risk-factor profiles. In the next section, the review describes how research on genetic contributions to psychopathology has elucidated the nature of risk for two groups of disorders, the neurodevelopmental and psychotic disorders. In the third section, the review describes how research on environmental contributions to psychopathology has targeted early temperament, its associated perturbations in information-processing functions, and its relations to a third group of disorders, the emotional disorders. For all three groups of disorders, such integrative research has generated ideas about novel interventions. The hope is that over the coming decade such ideas will lead to novel treatments that alter the trajectory of risk in developmental psychopathology. PMID- 25559118 TI - Rapid separation of seed gliadins by reversed-phase ultra performance liquid chromatography (RP-UPLC) and its application in wheat cultivar and germplasm identification. AB - To separate gliadin from wheat flour, a novel and stability-indicating reversed phase ultra performance liquid chromatography (RP-UPLC) method is established and optimized. A comparative analysis of routine capillary electrophoresis (CE), reversed-phase high-performance liquid chromatography (RP-HPLC), and RP-UPLC was performed and the results showed that the resolution and efficiency of RP-UPLC were significantly higher than those of CE and RP-HPLC. Characteristic RP-UPLC patterns of different bread wheat variety and related species were readily identified. These results demonstrated that our RP-UPLC procedure resulted in significant improvements in sensitivity, speed, and resolution, and thus is highly useful in wheat cultivar and germplasm identification. PMID- 25559115 TI - The evolutionary roots of human decision making. AB - Humans exhibit a suite of biases when making economic decisions. We review recent research on the origins of human decision making by examining whether similar choice biases are seen in nonhuman primates, our closest phylogenetic relatives. We propose that comparative studies can provide insight into four major questions about the nature of human choice biases that cannot be addressed by studies of our species alone. First, research with other primates can address the evolution of human choice biases and identify shared versus human-unique tendencies in decision making. Second, primate studies can constrain hypotheses about the psychological mechanisms underlying such biases. Third, comparisons of closely related species can identify when distinct mechanisms underlie related biases by examining evolutionary dissociations in choice strategies. Finally, comparative work can provide insight into the biological rationality of economically irrational preferences. PMID- 25559119 TI - Sleep Duration, Kidney Function, and Their Effects on Cerebral Small Vessel Disease in Elderly Hypertensive Patients. AB - BACKGROUND: Short sleep duration has been shown to be associated with cardio/cerebrovascular disease. White matter hyperintensities (WMH) have been associated with an increased risk of stroke. In addition to high ambulatory blood pressure (BP), chronic kidney disease (CKD) is a risk for WMH. In this study, we investigated the relationships among sleep duration, CKD, and WMH in elderly hypertensives. METHODS: Ambulatory BP monitoring and brain magnetic resonance imaging were performed in 514 Japanese elderly hypertensives (mean age 72.3 years, males 37%). WMH cases were further divided into deep subcortical white matter lesion or periventricular hyperintensity (PVH). CKD (n = 193) was defined as estimated glomerular filtration rate less than 60 ml/min/1.73 m(2). RESULTS: According to sleep duration (<7.5, >=7.5 to <9.5, and >=9.5 hour per night), significant associations of sleep duration were observed with WMH and PVH. In the regression analysis including age, gender, smoking, antiplatelet agents use, 24 hour systolic BP, nondipper, white coat hypertension and CKD, short sleep duration was significantly positively associated with WMH and PVH when subjects with mid-range sleep duration were used as a reference group. A significant interaction was found between short sleep duration and CKD for PVH. In the non CKD group, short sleep duration had strong significant positive associations with WMH and PVH. CONCLUSIONS: In the present study, short sleep duration was a positive significant determinant for WMH and PVH in elderly hypertensives. Sleep duration might serve as a strong determinant for white matter lesions especially in those without CKD. PMID- 25559120 TI - Silicone rubber encapsulation for an endoscopically implantable gastrostimulator. AB - Gastrointestinal stimulator implants have recently shown positive results in treating obesity. However, the implantation currently requires an invasive surgical procedure. Endoscopy could be used to place the gastric stimulator in the stomach, hence avoiding the riskier surgery. The implant then needs to go through the oesophagus and be located inside the stomach, which imposes new design constraints, such as miniaturization and protecting the electronic circuit against the highly acidic environment of the stomach. We propose to protect the implant by encapsulation with silicone rubber. This paper lists the advantages of this method compared to the more usual approach of a hermetic enclosure and then presents a method to evaluate the underwater adhesive stability of six adhesive/substrate couples, using repeated lap-shear tests and an elevated temperature to accelerate the ageing process. The results for different adhesive/substrate couples tested, presented on probability plots, show that FR4 and alumina substrates with MED4-4220 silicone rubber are suitable for a first implantable prototype. We then compare these with the predicted lifetimes of bonds between historical standard silicone rubber DC3140 and different substrates and describe the encapsulation of our gastrostimulator. PMID- 25559121 TI - Three new compounds isolated from the seeds of Vaccaria segetalis. AB - Two new capsaicin analogs, N-(3-methoxy-4-hydroxyphenethyl)-tetracosanamide (1) and N-(3,4-dihydroxyphenethyl)-tetracosanamide (2), along with one new flavonoidal glycoside pinnatifin E (3) were isolated from the ethanolic extract of the seeds of Vaccaria segetalis. Their structures were elucidated on the basis of spectroscopic methods including 1D, 2D NMR, MS, and other spectroscopic techniques, as well as by comparison with the relevant literatures. All compounds were evaluated for their coagulation Factor Xa inhibition activities. PMID- 25559117 TI - Diffusion tensor imaging for understanding brain development in early life. AB - The human brain rapidly develops during the final weeks of gestation and in the first two years following birth. Diffusion tensor imaging (DTI) is a unique in vivo imaging technique that allows three-dimensional visualization of the white matter anatomy in the brain. It has been considered to be a valuable tool for studying brain development in early life. In this review, we first introduce the DTI technique. We then review DTI findings on white matter development at the fetal stage and in infancy as well as DTI applications for understanding neurocognitive development and brain abnormalities in preterm infants. Finally, we discuss limitations of DTI and potential valuable imaging techniques for studying white matter myelination. PMID- 25559122 TI - Effects on repolarization using dynamic QT interval monitoring in long-QT patients following left cardiac sympathetic denervation. AB - BACKGROUND: Videoscopic left cardiac sympathetic denervation (LCSD) is an adjunct therapy for reduction of arrhythmia-induced events in patients with long-QT syndrome (LQTS). LCSD reduces LQTS-triggered breakthrough cardiac events. The temporal effects of QTc changes post-LCSD have not been studied. METHODS: We utilized continuous QTc monitoring on 72 patients with LQTS. We evaluated acute and long-term QTc changes in comparison to 12-lead ECG-derived QTc values prior to surgery, 24 hours postsurgery, and at follow up >=3 months. RESULTS: Seventy two patients underwent LCSD at our institution (46% male, mean age at LCSD was 14 +/- 10 years). The mean baseline, pre-LCSD QTc was 505 +/- 56 ms, which had decreased significantly at >=3 months post-LCSD to 491 +/- 40 ms (P = 0.001). QTc monitoring revealed that the majority of the cohort (53/72; 74%) had a transient increase >30 ms in QTc from baseline, with an average maximum increase of 72 +/- 30 ms. Resolution within 10 ms of baseline or less occurred in 57% (30/53) at 24 hours post-LCSD. CONCLUSIONS: Although LQTS patients may have a paradoxically increased QTc post-LCSD, the effects are transient in most patients. Importantly, no patients experienced any arrhythmias in the postoperative setting related to this transient rise in QTc. PMID- 25559125 TI - First iron and cobalt(II) hexabromoclathrochelates: structural, magnetic, redox, and electrocatalytic behavior. AB - Template condensation of dibromoglyoxime with n-butylboronic acid on the corresponding metal ion as a matrix under vigorous reaction conditions afforded iron and cobalt(ii) hexabromoclathrochelates. The paramagnetic cobalt clathrochelate was found to be a low-spin complex at temperatures below 100 K, with a gradual increase in the effective magnetic moment at higher temperatures due to the temperature 1/2<->3/2 spin crossover and a gap caused by the structure phase transition. The multitemperature X-ray and DSC studies of this complex and its iron(ii)-containing analog also showed temperature structural transitions. The variation of an encapsulated metal ion's radius, electronic structure and spin state caused substantial differences in the geometry of its coordination polyhedron; these differences increase with the decrease in temperature due to Jahn-Teller distortion of the encapsulated cobalt(ii) ion with an electronic configuration d(7). As follows from CV and GC data, these cage iron and cobalt complexes undergo both oxidation and reduction quasireversibly, and showed an electrocatalytic activity for hydrogen production in different producing systems. PMID- 25559126 TI - Role of phospholipids of subunit III in the regulation of structural rearrangements in cytochrome c oxidase of Rhodobacter sphaeroides. AB - Subunit III of cytochrome c oxidase possesses structural domains that contain conserved phospholipid binding sites. Mutations within these domains induce a loss of phospholipid binding, coinciding with decreased electron transfer activity. Functional and structural roles for phospholipids in the enzyme from Rhodobacter sphaeroides have been investigated. Upon the removal of intrinsic lipids using phospholipase A2, electron transfer activity was decreased 30-50%. Moreover, the delipidated enzyme exhibited turnover-induced, suicide inactivation, which was reversed by the addition of exogenous lipids, most specifically by cardiolipin. Cardiolipin exhibited two sites of interaction with the delipidated enzyme, a high-affinity site (Km = 0.14 MUM) and a low-affinity site (Km = 26 MUM). Subunit I of the delipidated enzyme exhibited a faster digestion rate when it was treated with alpha-chymotrypsin compared to that of the wild-type enzyme, suggesting that lipid removal induces a conformational change to expose the digestion sites further. Upon reaction of subunit III of the enzyme with a fluorophore (AEDANS), fluorescence anisotropy showed an increased rotational rate of the fluorophore in the absence of lipids, indicating increased flexibility of subunit III within the enzyme's tertiary structure. Additionally, Forster resonance energy transfer between AEDANS and a fluorescently labeled cardiolipin revealed that cardiolipin binds in the v-shaped cleft of subunit III in the delipidated enzyme and that it moves closer to the active site in subunit I upon a change in the redox state of the enzyme. In conclusion, these results show that the phospholipids regulate events occurring during electron transfer activity by maintaining the structural integrity of the enzyme at the active site. PMID- 25559124 TI - Effects of an Organizational Linkage Intervention on Inter-Organizational Service Coordination Between Probation/Parole Agencies and Community Treatment Providers. AB - Weak coordination between community correctional agencies and community-based treatment providers is a major barrier to diffusion of medication-assisted treatment (MAT)--the inclusion of medications (e.g., methadone and buprenorphine) in combination with traditional counseling and behavioral therapies to treat substance use disorders. In a multisite cluster randomized trial, experimental sites (j = 10) received a 3-h MAT training plus a 12-month linkage intervention; control sites (j = 10) received the 3-h training alone. Hierarchical linear models showed that the intervention resulted in significant improvements in perceptions of interagency coordination among treatment providers, but not probation/parole agents. Implications for policy and practice are discussed. PMID- 25559127 TI - A study of HIV positive undocumented African migrants' access to health services in the UK. AB - Newly immigrated persons, whatever their origin, tend to fall in the lower socioeconomic levels. In fact, failure of an asylum application renders one destitute in a large proportion of cases, often resulting in a profound lack of access to basic necessities. With over a third of HIV positive failed asylum seekers reporting no income, and the remainder reporting highly limited resources, poverty is a reality for the vast majority. The purpose of the study was to determine the basic social processes that guide HIV positive undocumented migrant's efforts to gain health services in the UK. The study used the Grounded Theory Approach. Theoretical saturation occurred after 16 participants were included in the study. The data included reflections of the prominent factors related to the establishment of a safe and productive life and the ability of individuals to remain within the UK. The data reflected heavily upon the ability of migrants to enter the medical care system during their asylum period, and on an emerging pattern of service denial after loss on immigration appeal. The findings of this study are notable in that they have demonstrated sequence of events along a timeline related to the interaction between the asylum process and access to health-related services. The results reflect that African migrants maintain a degree of formal access to health services during the period that they possess legal access to services and informal access after the failure of their asylum claim. The purpose of this paper is to examine the basic social processes that characterize efforts to gain access to health services among HIV positive undocumented African migrants to the UK. The most recent estimates indicate that there are a total of 618,000 migrants who lack legal status within the UK. Other studies have placed the number of undocumented migrants within the UK in the range of 525,000-950,000. More than 442,000 are thought to dwell in the London metropolitan area. Even in cases where African migrants enter the UK legally, they often face considerable difficulty in their quest to gain legal employment due to barriers inherent to the system that grants work permits. With over a third of HIV positive failed asylum seekers reporting no income, and the remainder reporting highly limited resources, poverty is a reality for the vast majority. PMID- 25559128 TI - MUFOLD-DB: a processed protein structure database for protein structure prediction and analysis. AB - BACKGROUND: Protein structure data in Protein Data Bank (PDB) are widely used in studies of protein function and evolution and in protein structure prediction. However, there are two main barriers in large-scale usage of PDB data: 1) PDB data are highly redundant in terms of sequence and structure similarity; and 2) many PDB files have issues due to inconsistency of data and standards as well as missing residues, so that automated retrieval and analysis are often difficult. DESCRIPTION: To address these issues, we have created MUFOLD-DB http://mufold.org/mufolddb.php, a web-based database, to collect and process the weekly PDB files thereby providing users with non-redundant, cleaned and partially-predicted structure data. For each of the non-redundant sequences, we annotate the SCOP domain classification and predict structures of missing regions by loop modelling. In addition, evolutional information, secondary structure, disorder region, and processed three-dimensional structure are computed and visualized to help users better understand the protein. CONCLUSIONS: MUFOLD-DB integrates processed PDB sequence and structure data and multiple computational results, provides a friendly interface for users to retrieve, browse and download these data, and offers several useful functionalities to facilitate users' data operation. PMID- 25559130 TI - A topological study of repetitive co-activation networks in in vitro cortical assemblies. AB - To address the issue of extracting useful information from large data-set of large scale networks of neurons, we propose an algorithm that involves both algebraic-statistical and topological tools. We investigate the electrical behavior of in vitro cortical assemblies both during spontaneous and stimulus evoked activity coupled to Micro-Electrode Arrays (MEAs). Our goal is to identify core sub-networks of repetitive and synchronous patterns of activity and to characterize them. The analysis is performed at different resolution levels using a clustering algorithm that reduces the network dimensionality. To better visualize the results, we provide a graphical representation of the detected sub networks and characterize them with a topological invariant, i.e. the sequence of Betti numbers computed on the associated simplicial complexes. The results show that the extracted sub-populations of neurons have a more heterogeneous firing rate with respect to the entire network. Furthermore, the comparison of spontaneous and stimulus-evoked behavior reveals similarities in the identified clusters of neurons, indicating that in both conditions similar activation patterns drive the global network activity. PMID- 25559131 TI - The year in cardiology 2014: peripheral circulation. AB - In 2014, the debate on the indication of revascularization in case of asymptomatic carotid disease continued, while another one regarding the use of surgery vs. stenting addressed some new issues regarding the long-term cardiac risk of these patients. Renal arteries interventions trials were disappointing, as neither renal denervation nor renal artery stenting was found associated with better blood pressure management or outcome. In contrast, in lower-extremities artery disease, the endovascular techniques represent in 2014 major alternatives to surgery, even in distal arteries, with new insights regarding the interest of drug-eluting balloons. Regarding the aorta, the ESC published its first guidelines document on the entire vessel, emphasizing on the role of every cardiologist for screening abdominal aorta aneurysm during echocardiography. Among vascular wall biomarkers, the aorta stiffness is of increasing interest with new data and meta-analysis confirming its ability to stratify risk, whereas carotid intima-media thickness showed poor performances in terms of reclassifying patients into risk categories beyond risk scores. Regarding the veins, new data suggest the interest of D-dimers and residual venous thrombosis to help the decision of anti-coagulation prolongation or discontinuation after the initial period of treatment for deep vein thrombosis. PMID- 25559132 TI - The year in cardiology 2014: arrhythmias and device therapy. AB - This review looks back at important and clinically relevant new developments in the fields of invasive electrophysiology and device therapy in 2014. Many findings do not only apply to pure electrophysiologists, but also to every clinical cardiologist's practice. The authors have extracted the key findings of studies with potential guideline impact and put those into a clinical perspective. Looking back at the achievements of 2014 may instil enthusiasm for further scientific endeavours in the years to come! PMID- 25559129 TI - Evidence-based clinical practice guidelines for management of colorectal polyps. AB - BACKGROUND: Recently in Japan, the morbidity of colorectal polyp has been increasing. As a result, a large number of cases of colorectal polyps that are diagnosed and treated using colonoscopy has now increased, and clinical guidelines are needed for endoscopic management and surveillance after treatment. METHODS: Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Ten specialists for colorectal polyp management extracted the specific clinical statements from articles published between 1983 and September 2011 obtained from PubMed and a secondary database, and developed the CQs and statements. Basically, statements were made according to the GRADE system. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. RESULTS: The professional committee created 91CQs and statements for the current concept and diagnosis/treatment of various colorectal polyps including epidemiology, screening, pathophysiology, definition and classification, diagnosis, treatment/management, practical treatment, complications and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumor/carcinoma). CONCLUSIONS: After evaluation by the moderators, evidence-based clinical guidelines for management of colorectal polyps have been proposed for 2014. PMID- 25559133 TI - The year in cardiology 2014: valvular heart disease. PMID- 25559134 TI - The year in cardiology 2014: imaging. PMID- 25559136 TI - The year in cardiology 2014: prevention. PMID- 25559135 TI - The year in cardiology 2014: coronary intervention. PMID- 25559137 TI - The year in cardiology 2014: acute coronary syndromes. PMID- 25559138 TI - Electronic transport regimes through an alkoxythiolated diphenyl-2,2'-bithiophene based molecular junction diodes: critical assessment of the thermal dependence. AB - The detailed understanding of electronic transport through a single molecule or an ensemble of self-assembled molecules embedded between two metallic leads is still a matter of controversy. Multiple factors influence the charge transport in the molecular junction, with particular attention to be given to the band states of the electrodes, molecular orbital energies, bias potential and importantly molecule-electrode electronic coupling. Moreover it is not trivial to disentangle molecular contributions from other possible conduction pathways directly coupling the opposite electrodes. We here investigate the electronic transport properties of an ensemble molecular junction embedding an alkylthiol derivative of a diphenol substituted bithiophene (DPBT) by means of current vs. voltage and temperature dependent measurements. We explored different junction configurations using: micropores (Au//DPBT//Au and Au//DPBT-polymer conductor//Au) and conductive-atomic force microscopy (c-AFM). In all cases, we found a transition voltage V(T) of ~0.35 V. The consistent presence of a similar V(T) in all the tested configurations is a strong, but not conclusive, indication of a molecular signature in the charge transport, which we assessed and confirmed by temperature dependent measurements. We found a transition from an incoherent resonant tunneling at low biases and close to room temperature, where transport is thermally activated with an activation energy of ~85 meV, to a coherent tunneling at voltages higher than V(T). Unlike many other molecular junctions reported in the literature, resonant conditions commonly attributed to a hopping transport regime can be found already at room temperature and very low biases for a molecule only ~1.5 nm long. This paper is the first report to clearly show temperature activated transport through a short and not fully conjugated molecule. Moreover, we could clearly identify a regime at low temperatures and low bias where the transport mechanism is controlled by the thermal conductivity of the metal electrodes rather than the molecule. PMID- 25559139 TI - Multiferroic behavior of templated BiFeO3-CoFe2O4 self-assembled nanocomposites. AB - Self-assembled BiFeO3-CoFe2O4 nanocomposites were templated into ordered structures in which the ferrimagnetic CoFe2O4 pillars form square arrays of periods 60-100 nm in a ferroelectric BiFeO3 matrix. The ferroelectricity, magnetism, conductivity, and magnetoelectric coupling of the ordered nanocomposites were characterized by scanning probe microscopy. The insulating BiFeO3 matrix exhibited ferroelectric domains, whereas the resistive CoFe2O4 pillars exhibited single-domain magnetic contrast with high anisotropy due to the magnetoelasticity of the spinel phase. Magnetoelectric coupling was observed in which an applied voltage led to reversal of the magnetic pillars. PMID- 25559140 TI - A review of vitamin B12 in dermatology. AB - Vitamin B12, also known as cobalamin, is a water-soluble vitamin that is important in the hematological and nervous systems, and it has a complex relationship with the skin. Altered cobalamin levels can lead to dermatological manifestations, which may indicate a deficiency or excess of this vitamin. The biochemistry and metabolism of cobalamin is complex, and diseases can be associated with alterations of this metabolic pathway. The cutaneous manifestations of cobalamin deficiency include hyperpigmentation (most commonly); hair and nail changes; and oral changes, including glossitis. Additionally, several dermatologic conditions, including vitiligo, aphthous stomatitis, atopic dermatitis, and acne are related to cobalamin excess or deficiency. The cutaneous complications of cobalamin therapy include acne, rosacea, and allergic site reactions, or anaphylaxis with cobalamin injections. As cobalt is a component of cobalamin, patients with cobalt sensitivity have been reported to have cutaneous manifestations when receiving cobalamin replacement therapy. PMID- 25559141 TI - Site and chirality selective chemical modifications of boron nitride nanotubes (BNNTs) via Lewis acid-base interactions. AB - The pristine BNNTs contain both Lewis acid (boron) and Lewis base (nitrogen) centers at their surface. Interactions of ammonia and borane molecules, representatives of Lewis base and acid as adsorbates respectively, with matching sites at the surface of BNNTs, have been explored in the present DFT study. Adsorption energies suggest stronger chemisorption (about 15-20 kcal mol(-1)) of borane than ammonia (about 5-10 kcal mol(-1)) in both armchair (4,4) and zigzag (8,0) variants of the tube. NH3 favors (8,0) over the (4,4) tube, whereas BH3 exhibits the opposite preference, indicating some chirality dependence on acid base interactions. A new feature of bonding is found in BH3/AlH3-BNNTs (at the edge site) complexes, where one hydrogen of the guest molecule is involved in three-center two-electron bonding, in addition to dative covalent bond (N: -> B). This interaction causes a reversal of electron flow from borane/alane to BNNT, making the tube an electron acceptor, suggesting tailoring of electronic properties could be possible by varying strength of incoming Lewis acids. On the contrary, BNNTs always behave as electron acceptor in ammonia complexes. IR, XPS and NMR spectra show some characteristic features of complexes and can help experimentalists to identify not only structures of such complexes but also the location of the guest molecules and design second functionalizations. Interaction with several other neutral BF3, BCl3, BH2CH3 and ionic CH3(+) acids as well as amino group (CH3NH2 and NH2COOH) were also studied. The strongest interaction (>100 kcal mol(-1)) is found in BNNT-CH3(+) complexes and H-bonds are the only source of stability of NH2COOH-BNNT complexes. PMID- 25559142 TI - Notes on Zika virus--an emerging pathogen now present in the South Pacific. PMID- 25559143 TI - Co-composting of invasive Acacia longifolia with pine bark for horticultural use. AB - The feasibility of commercial-scale co-composting of waste biomass from the control of invasive Acacia species with pine bark waste from the lumber industry, in a blend ratio of 60:40 (v:v), was investigated and compared with previous research on the composting of Acacia without additional feedstock, to determine the potential process and end-product quality benefits of co-composting with bark. Pile temperatures rose rapidly to >70 degrees C and were maintained at >60 degrees C for several months. Acacia and bark biomass contained a large fraction of mineralizable organic matter (OM) equivalent to approximately 600 g kg(-1) of initial OM. Bark was more recalcitrant to biodegradation compared with Acacia, which degraded at twice the rate of bark. Therefore, incorporating the bark increased the final amount of compost produced compared with composting Acacia residues without bark. The relatively high C/N ratio of the composting matrix (C/N=56) and NH3 volatilization explained the limited increases in NH4+-N content, whereas concentrations of conservative nutrient elements (e.g. P, K, Ca, Mg, Fe) increased in proportion to OM mineralization, enriching the compost as a nutrient source for horticultural use. Nitrogen concentrations also increased to a small extent, but were much more dynamic and losses, probably associated with N volatilization mechanisms, were difficult to actively control. The physicochemical characteristics of the stabilized end-product, such as pH, electrical conductivity and OM content, were improved with the addition of bark to Acacia biomass, and the final compost characteristics were suitable for use for soil improvement and also as horticultural substrate components. PMID- 25559144 TI - Tumor necrosis factor-alpha promotes survival and phenotypic maturation of poly(I:C)-treated dendritic cells but impairs their Th1 and Th17 polarizing capability. AB - BACKGROUND AIMS: Toll-like receptor (TLR)-3 synthetic agonist polyinosinic polycytidylic acid (poly(I:C)) is a promising agent for dendritic cell (DC)-based anti-tumor vaccines because of its ability to induce a strong maturation of DCs, but such an effect is followed by stimulation of DC apoptosis. Tumor necrosis factor (TNF)-alpha may promote the survival of poly(I:C)-stimulated DCs, but it is not known in detail how this combination affects the maturation and polarization capacity of monocyte-derived (Mo)DCs. METHODS: Immature MoDCs, generated from human monocytes, were treated with different concentrations of poly(I:C) combined with TNF-alpha, and the effect on survival, phenotype, production of cytokines, allostimulatory and Th polarization capacity was assessed after 24 and 48 h. RESULTS: We showed that TNF-alpha inhibited the dose dependent pro-apoptotic effect of poly(I:C). However, TNF-alpha also decreased poly(I:C)-induced production of interleukin (IL)-12 and IL-23 by MoDCs, which correlated with their diminished capacity to stimulate cellular proliferation, interferon-gamma and IL-17 production by allogeneic CD4(+)T cells in co-culture. Such an effect was more pronounced after 24 h and could not be restored by CD40 ligation. In the presence of CD40L, TNF-alpha even stimulated IL-10 production and immunoglobulin-like transcript 3 expression by poly(I:C)-matured DCs, which correlated with their increased capacity to induce IL-10 production by CD4(+)T cells. CONCLUSION: Even though TNF-alpha could promote the survival of poly(I:C) matured MoDCs, it also suppresses key anti-tumor functions of these cells, which could have important implications when considering this, already suggested, protocol for the DC-based anti-tumor therapy. PMID- 25559146 TI - Preoperative exercise facilitates abundant bone marrow collection in patients with type 2 diabetes for mononuclear cell therapy. AB - BACKGROUND AIMS: Traditional bone marrow (BM) collection is inadequate for separation of abundant mononuclear cells (MNCs). We aimed to investigate the effects of preoperative exercise on BM collection in patients with type 2 diabetes mellitus (T2DM). METHODS: Sixty patients with T2DM were randomly assigned to either a control group or an exercise group (n = 30 each). The patients in the exercise group exercised before the collection. All patients underwent routine surgical care. The collected BM volume, operation duration, collecting speed, puncture times and pain scores were recorded. BM samples were tested before and after MNCs separation for CD34+ flow cytometry and whole blood cell count. RESULTS: The collected BM volumes were significantly larger and collection speed was faster in the exercise group (379.77 +/- 4.93 mL and 1.40 +/ 0.14 mL/s) than those in the control group (356.67 +/- 15.36 mL and 0.89 +/- 0.16 mL/s, P = 0.00 for both). Puncture times were significantly less and pain scores were lower in the exercise group (2.07 +/- 0.25 and 2.67 +/- 1.56) than those in the control group (2.50 +/- 0.63 and 3.43 +/- 1.76, P = 0.00 and 0.02, respectively). CD34+ cells and whole blood cell count variables were comparable in the 2 groups. CONCLUSIONS: Preoperative exercise facilitates BM collection by increasing collected volume, improving collecting speed, relieving patients' pains and ensuring MNC quality. PMID- 25559147 TI - An exploratory study of the effects of occupational exposure to physical demands on biomarkers of cartilage and muscle damage. AB - Biomarkers of tissue damage, derived from tissues commonly injured as a result of occupational physical demands, may be of use for future prediction of work related musculoskeletal disorders (WMSDs). This exploratory study assessed whether selected biomarkers are likely to be sensitive to the level of occupational physical demands. Twenty-four participants were recruited to form two groups, with relatively high and low levels of WMSD risk. Serum levels of Cartilage Oligomeric Matrix Protein (COMP), Interleukin-6 (IL6), and Creatine Kinase (CK)--which respectively indicate cartilage damage, muscle use, and muscle damage--were obtained,. Six blood samples were obtained before and after work on Monday, Wednesday, and Friday of one working week. Additionally, a self-report measure of risk factor exposure, the Hollmann Index, was used to, and did, confirm group differences in WMSD risk. COMP levels varied significantly over time, but not between groups. IL6 levels were greater in the high-risk group at all time points and varied significantly over time and between groups. CK levels did not vary significantly over time or between groups. IL6 successfully differentiated between the high and low risk groups, suggesting potential use in the occupational domain. Prospective studies are needed, though, to associate biomarker levels/changes with WMSD risk. PMID- 25559148 TI - IUPS and the future of physiology. PMID- 25559145 TI - Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood derived endothelial colony forming cells. AB - BACKGROUND AIMS: Human cord blood (CB) is enriched in circulating endothelial colony forming cells (ECFCs) that display high proliferative potential and in vivo vessel forming ability. Because Notch signaling is critical for embryonic blood vessel formation in utero, we hypothesized that Notch pathway activation may enhance cultured ECFC vasculogenic properties in vivo. METHODS: In vitro ECFC stimulation with an immobilized chimeric Notch ligand (Delta-like1(ext-IgG)) led to significant increases in the mRNA and protein levels of Notch regulated Hey2 and EphrinB2 that were blocked by treatment with gamma-secretase inhibitor addition. However, Notch stimulated preconditioning in vitro failed to enhance ECFC vasculogenesis in vivo. In contrast, in vivo co-implantation of ECFCs with OP9-Delta-like 1 stromal cells that constitutively expressed the Notch ligand delta-like 1 resulted in enhanced Notch activated ECFC-derived increased vessel density and enlarged vessel area in vivo, an effect not induced by OP9 control stromal implantation. RESULTS: This Notch activation was associated with diminished apoptosis in the exposed ECFC. CONCLUSIONS: We conclude that Notch pathway activation in ECFC in vivo via co-implanted stromal cells expressing delta-like 1 promotes vasculogenesis and augments blood vessel formation via diminishing apoptosis of the implanted ECFC. PMID- 25559149 TI - The basis of translational physiology: from molecules to humans, a wide arc of scientific inquiry. PMID- 25559150 TI - Integrative and adaptive responses. PMID- 25559152 TI - Evolutionary physiology of bone: bone metabolism in changing environments. AB - Bone evolved to serve many mechanical and physiological functions. Osteocytes and bone remodeling first appeared in the dermal skeleton of fish, and subsequently adapted to various challenges in terrestrial animals occupying diverse environments. This review discusses the physiology of bone and its role in mechanical and calcium homeostases from an evolutionary perspective. We review how bone physiology responds to changing environments and the adaptations to unique and extreme physiological conditions. PMID- 25559151 TI - Aging and the muscle-bone relationship. AB - Aging-induced declines in muscle size and quality are thought to contribute to catabolic alterations in bone, but changes in bone with age also profoundly alter its response to muscle-derived stimuli. This review provides an overview of some of the alterations that occur in muscle and bone with aging, and discusses the cellular and molecular mechanisms that may impact these age-associated changes. PMID- 25559155 TI - GLP-1: a mediator of the beneficial metabolic effects of bariatric surgery? AB - There has been increasing interest in the role that gut hormones may play in contributing to the physiological changes produced by certain bariatric procedures, such as Roux-en-Y gastric bypass and sleeve gastrectomy. Here, we review the evidence implicating one such gut hormone, glucagon-like peptide-1, as a mediator of the metabolic benefits of these two procedures. PMID- 25559153 TI - Sex-based differences in skeletal muscle kinetics and fiber-type composition. AB - Previous studies have identified over 3,000 genes that are differentially expressed in male and female skeletal muscle. Here, we review the sex-based differences in skeletal muscle fiber composition, myosin heavy chain expression, contractile function, and the regulation of these physiological differences by thyroid hormone, estrogen, and testosterone. The findings presented lay the basis for the continued work needed to fully understand the skeletal muscle differences between males and females. PMID- 25559156 TI - Programming and inheritance of parental DNA methylomes in vertebrates. AB - 5-Methylcytosine (5mC) is a major epigenetic modification in animals. The programming and inheritance of parental DNA methylomes ensures the compatibility for totipotency and embryonic development. In vertebrates, the DNA methylomes of sperm and oocyte are significantly different. During early embryogenesis, the paternal and maternal methylomes will reset to the same state. Herein, we focus on recent advances in how offspring obtain the DNA methylation information from parents in vertebrates. PMID- 25559157 TI - Digestive adaptations of aerial lifestyles. AB - Flying vertebrates (birds and bats) are under selective pressure to reduce the size of the gut and the mass of the digesta it carries. Compared with similar sized nonflying mammals, birds and bats have smaller intestines and shorter retention times. We review evidence that birds and bats have lower spare digestive capacity and partially compensate for smaller intestines with increased paracellular nutrient absorption. PMID- 25559154 TI - In vivo fluorescence microscopy: lessons from observing cell behavior in their native environment. AB - Microscopic imaging techniques to visualize cellular behaviors in their natural environment play a pivotal role in biomedical research. Here, we review how recent technical advances in intravital microscopy have enabled unprecedented access to cellular physiology in various organs of mice in normal and diseased states. PMID- 25559158 TI - Cost-effectiveness of interferon-gamma release assay for systematic tuberculosis screening of healthcare workers in low-incidence countries. AB - BACKGROUND: Tuberculosis (TB) is one of the important occupationally acquired infectious diseases in low-incidence countries. Delays in TB diagnosis and treatment among healthcare workers (HCWs) result in costly large-scale TB contact screening among patients and other HCWs. AIM: To assess the cost-effectiveness of TB screening for HCWs using interferon-gamma release assays (IGRAs) compared with tuberculin skin test (TST) and chest x ray (CXR). METHODS: Markov models were constructed using a hospital payer perspective. The target populations were a hypothetical cohort of 30-year-old HCWs at the time of employment, and a hypothetical cohort of HCWs working on a high-risk ward until 60 years of age. Six strategies were modelled: TST, QuantiFERON-TB Gold In-Tube (QFT), T-SPOT.TB (T-SPOT), TST followed by QFT, TST followed by T-SPOT, and CXR. The main outcome measure of effectiveness was quality-adjusted life-years (QALYs). Costs and QALYs gained per person screened were calculated. FINDINGS: QFT was the most cost effective strategy at the 'willingness to pay' level of US$ 50,000/QALYs gained (at the time of employment: US$ 334.91, 21.071 QALYs; on a high-risk ward: US$ 1050.32, 20.968 QALYs; values for 2012). Cost-effectiveness was sensitive to latent TB infection (LTBI) rate and bacillus Calmette-Guerin vaccination rate. TST followed by QFT was more cost-effective than QFT when the LTBI rate was <0.026 at the time of employment and <0.08 on a high-risk ward. CONCLUSION: Systematic TB screening using QFT is cost-effective for screening HCWs, and is recommended in low-incidence countries. PMID- 25559159 TI - Response to Grayson's letter to the editor: 'Response to K. Page et al., 'Costing the Australian National Hand Hygiene Initiative''. PMID- 25559160 TI - The role of personality variables in predicting attitudes toward people with intellectual disability: An Australian perspective. AB - BACKGROUND: Personality dimensions such as openness and agreeableness have been found to be associated with prejudice levels towards several minority groups. Yet these variables have been mostly ignored by existing research into attitudes towards people with intellectual disability (PWID), which has primarily focused on contact and demographic variables. The current study investigated the relationship between personality dimensions and attitudes toward PWID. METHODS: An online survey was completed by 466 adult participants recruited through a variety of sources. The survey consisted of a well-validated attitude survey, the Big Five inventory, contact related and demographic questions. RESULTS: The hypothesis that higher levels of the personality dimensions openness and agreeableness would be significantly associated with positive attitudes towards PWID was supported. However the effect was relatively weak and the strongest predicting factor of positive attitudes was increased quality of contact with PWID. More positive attitudes were also associated with females, more highly educated and younger participants. CONCLUSIONS: Results provide support for an integrated (including person and situational factors) theoretical approach to attitudes research in this field. Practically, results support programmes that stimulate and promote quality interactions between PWID and the wider community. PMID- 25559162 TI - Everything should be as simple as possible, but this will still be complex: a reply to various commentaries on IPEBA. PMID- 25559161 TI - Novel expression and characterization of a light driven proton pump archaerhodopsin 4 in a Halobacterium salinarum strain. AB - Archaerhodopsin 4 (AR4), a new member of the microbial rhodopsin family, is isolated from Halobacterium species xz515 in a Tibetan salt lake. AR4 functions as a proton pump similar to bacteriorhodopsin (BR) but with an opposite temporal order of proton uptake and release at neutral pH. However, further studies to elucidate the mechanism of the proton pump and photocycle of AR4 have been inhibited due to the difficulty of establishing a suitable system in which to express recombinant AR4 mutants. In this paper, we report a reliable method for expressing recombinant AR4 in Halobacterium salinarum L33 with a high yield of up to 20mg/l. Experimental results show that the recombinant AR4 retains the light driven proton pump characteristics and photo-cycling kinetics, similar to that in the native membrane. The functional role of bacterioruberin in AR4 and the trimeric packing of AR4 in its native and recombinant forms are investigated through light-induced kinetic measurements, two-dimensional solid-state NMR experiments, dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR). Such approaches provide new insights into structure-function relationships of AR4, and form a basis for other archaeal rhodopsins. PMID- 25559163 TI - Lichen planopilaris with foreign-body granuloma. PMID- 25559164 TI - Effects of dietary probiotic supplementation on LXRalpha and CYP7alpha1 gene expression, liver enzyme activities and fat metabolism in ducks. AB - 1. The objective of this study was to investigate the effects of dietary probiotic supplementation on liver X receptor alpha (LXRalpha) and cholesterol 7alpha-hydroxylase (CYP7alpha1) mRNA levels, protein enzymatic activities and fat metabolism in Cherry Valley Pekin ducks. 2. A total of 750 one-day-old Cherry Valley Pekin ducks were randomly divided into 5 groups with three replicates of 50 ducks each in a completely randomised experiment. Each group was fed on a basal diet supplemented with 0, 500, 1000, 1500 or 2000 mg probiotics/kg. 3. Body rate and feed conversion ratio were highest and abdominal subcutaneous fat % was lowest at 1000 mg probiotic/kg. 4. The mRNA levels of LXRalpha and CYP7alpha1 in liver tissue was estimated by RT-PCR; serum triglyceride (TG) and total cholesterol (TC) concentrations were measured by ELISA. 5. The expression levels and enzyme activity of LXRalpha and CYP7alpha1 increased in conjunction with decreases in TG and TC concentrations following probiotic supplementation to a maximum at 1000 mg probiotics/kg and decreased thereafter. 6. It is concluded that dietary probiotics can enhance LXRalpha and CYP7alpha1 enzyme activities in the liver and reduce lipid concentrations and fat deposition in ducks. PMID- 25559165 TI - Commentary: taking a deep breath before reflecting on differential response. AB - Although there are certainly limitations to each and every research and evaluation project in child welfare, as with other fields of study, understanding DR as a CPS reform has been fostered through many thoughtful and rigorous studies that have employed random control trial evaluation designs. For each assumption addressed in this commentary, we have raised a few questions. For all interested in CPS reform, other questions arise because child protection and child welfare professionals are trying to encourage more scientific ways of thinking as a means of engendering improvements: 1. Has the research on DR spotlighted the inadequacy of CPS interventions, either AR or IR? A high percentage of CPS responses are short-term. Is it reasonable to expect significant differences between AR and IR families and improvements in the CPS population, given that families often present with problems characterized as intractable but the intensity of the CPS response, coupled with limited service availability and accessibility, may not be sufficient to meet family needs? 2. Has the DR research, which has mainly focused on AR families, also highlighted the glaring absence of quality research in what is effective in producing positive outcomes for families that receive traditional child abuse and neglect investigations? 3. Does the implementation of DR move the CPS field ahead in terms of making better triage decisions, identifying especially those that require CPS involvement as compared to those who will benefit from but might not absolutely need intervention? Is 'triage' an explicit assumption of the DR innovation? Is it an implicit assumption of DR, however defined? If triage is not part of the research, does the ability of child protection to respond both differentially and also correctly to cases needing most, some, or no attention remain unknown? Until there is a reliable and valid way for determining for which families services are most urgently needed, are many reforms in CPS at risk of not producing the outcomes desired? 4. Are there other unintended consequences of either accepting or rejecting DR that might not have been considered? Our current perspective is to state the obvious and point out that rarely are scientifically or "evidence-based" changes in practice achieved or discredited in a decade or two, much more a scant few years. Breathing deeply from time to time, and even pausing for reflection once in awhile, are useful habits for taking on long-range and difficult human endeavors. PMID- 25559167 TI - Time trends in physical activity from 1982 to 2012 in Finland. AB - The aim of this study was to examine population trends from 1982 to 2012 in Finland for leisure time physical activity (LTPA), commuting physical activity (CPA), occupational physical activity (OPA), and total physical activity. Furthermore, time trends in physical activity by educational levels and body mass index (BMI) categories were explored. Data were collected in independent cross sectional population surveys, implemented every 5 years from 1982 to 2012. The data comprised 21,903 men and 24,311 women. Participants underwent a health examination and filled in questionnaires. Information on LTPA, CPA, and OPA was used both separately and combined to create an index of total physical activity. Between 1982 and 2012, high LTPA has increased in men (from 21% to 33%) and women (from 12% to 27%). High CPA and high OPA have decreased in men (from 17% to 12% and from 48% to 36%, respectively) and women (from 30% to 20% and from 26% to 21%, respectively). Total physical activity has remained fairly stable. Differences by education and BMI have increased, particularly for LTPA. Marked changes in physical activity have taken place over time. Differences in LTPA and OPA have grown wider across educational groups and BMI categories. PMID- 25559166 TI - Effect of Medicare's nonpayment for Hospital-Acquired Conditions: lessons for future policy. AB - IMPORTANCE: In 2008, Medicare implemented the Hospital-Acquired Conditions (HACs) Initiative, a policy denying incremental payment for 8 complications of hospital care, also known as never events. The regulation's effect on these events has not been well studied. OBJECTIVE: To measure the association between Medicare's nonpayment policy and 4 outcomes addressed by the HACs Initiative: central line associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), hospital-acquired pressure ulcers (HAPUs), and injurious inpatient falls. DESIGN, SETTING, AND PARTICIPANTS: Quasi-experimental study of adult nursing units from 1381 US hospitals participating in the National Database of Nursing Quality Indicators (NDNQI), a program of the American Nurses Association. The NDNQI data were combined with American Hospital Association, Medicare Cost Report, and local market data to examine adjusted outcomes. Multilevel models were used to evaluate the effect of Medicare's nonpayment policy on never events. EXPOSURES: United States hospitals providing treatment for Medicare patients were subject to the new payment policy beginning in October 2008. MAIN OUTCOMES AND MEASURES: Changes in unit-level rates of HAPUs, injurious falls, CLABSIs, and CAUTIs after initiation of the policy. RESULTS: Medicare's nonpayment policy was associated with an 11% reduction in the rate of change in CLABSIs (incidence rate ratio [IRR], 0.89; 95% CI, 0.83-0.95) and a 10% reduction in the rate of change in CAUTIs (IRR, 0.90; 95% CI, 0.85-0.95), but was not associated with a significant change in injurious falls (IRR, 0.99; 95% CI, 0.99 1.00) or HAPUs (odds ratio, 0.98; 95% CI, 0.96-1.01). Consideration of unit-, hospital-, and market-level factors did not significantly alter our findings. CONCLUSIONS AND RELEVANCE: The HACs Initiative was associated with improvements in CLABSI and CAUTI trends, conditions for which there is strong evidence that better hospital processes yield better outcomes. However, the HACs Initiative was not associated with improvements in HAPU or injurious fall trends, conditions for which there is less evidence that changing hospital processes leads to significantly better outcomes. PMID- 25559168 TI - Prognostic value of tumor necrosis at CT in diffuse large B-cell lymphoma. AB - OBJECTIVE: To determine the prognostic value of tumor necrosis at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: This retrospective study included 51 patients with newly diagnosed DLBCL who had undergone both unenhanced and intravenous contrast enhanced CT before R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone) chemo-immunotherapy. Presence of tumor necrosis was visually and quantitatively assessed at CT. Associations between tumor necrosis status at CT and the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI) factors were assessed. Cox regression analysis was used to determine the prognostic impact of NCCN-IPI scores and tumor necrosis status at CT. RESULTS: There were no correlations between tumor necrosis status at CT and the NCCN-IPI factors categorized age (rho=-0.042, P=0.765), categorized lactate dehydrogenase (LDH) ratio (rho=0.201, P=0.156), extranodal disease in major organs (phi=-0.245, P=0.083), Ann Arbor stage III/IV disease (phi=-0.208, P=0.141), and Eastern Cooperative Oncology Group (ECOG) performance status (phi=0.015, P=0.914). In the multivariate Cox proportional hazards model, only tumor necrosis status at CT was an independent predictive factor of progression free survival (P=0.003) and overall survival (P=0.004). CONCLUSION: The findings of this study indicate the prognostic potential of tumor necrosis at CT in newly diagnosed DLBCL. PMID- 25559169 TI - Evaluation of the relationship between T1rho and T2 values and patella cartilage degeneration in patients of the same age group. AB - OBJECTIVE: The aim of this study was to investigate the association between the T1rho and T2 values and the progression of cartilage degeneration in patients of the same age group. MATERIALS AND METHODS: Sagittal T1rho and T2 mapping and three-dimensional (3D) gradient-echo images were obtained from 78 subjects with medial knee osteoarthritis (OA). The degree of patella cartilage degeneration was classified into four groups using MRI-based grading: apparently normal cartilage, mild OA, moderate OA, and severe OA group. We measured the T1rho and T2 values (ms) in the regions of interest set on the full-thickness patella cartilage. Then, we analyzed the relationship between the T1rho and T2 values and the degree of patella cartilage degeneration. RESULTS: There were no significant differences in age among the four groups. Both the T1rho and T2 values showed a positive correlation with the degree of OA progression (rho=0.737 and rho=0.632, respectively). By comparison between the apparently normal cartilage and the mild OA groups, there were significant differences in the T1rho mapping, but not in the T2 mapping. CONCLUSIONS: Our study confirmed that T1rho and T2 mapping can quantitatively evaluate the degree of patella cartilage degeneration in patients within the same age group. PMID- 25559170 TI - Suppression of human macrophage-mediated cytotoxicity by transgenic swine endothelial cell expression of HLA-G. AB - BACKGROUND: Xenotransplantation is an appealing alternative to human allotransplantation because of a worldwide shortage of organs. One of the obstacles for xenografts is cellular rejection by the innate immune system, comprised of NK cells, monocytes, and macrophages. In this study the inhibitory function of HLA-G1, a MHC Ib molecule, on macrophage-mediated cytotoxicity was examined. Furthermore, this study also evaluates the suppressive effect of cytokine production by macrophages. METHODS: The expression of inhibitory receptors that interact with HLA-G1, immunoglobulin-like transcript 2 (ILT2), ILT4 and KIR2DL4 (CD158d) on in vitro generated macrophages were examined by flow cytometry. Complementary DNA (cDNA) of HLA-G1, HLA-E and human beta2 microglobulin (hbeta2m) were prepared and transfected into swine endothelial cells (SECs). The expression of the transgenic genes was evaluated by flow cytometry, and macrophage-mediated SEC cytolysis was assessed using the macrophages. RESULTS: In vitro generated macrophages expressed not only ILT2 and ILT4 but CD158d as well. The transgenic HLA-G1 on SECs indicated significant suppression in macrophage-mediated cytotoxicity, which was equivalent to that of transgenic HLA-E. Furthermore, the results on real time PCR and ELISA revealed that transgenic HLA-G1 induces the anti-inflammatory cytokines, such as IL-10 and TGF-beta, and suppresses iNOS mRNA expression, indicating that transgenic HLA-G1 has suppressive effects in a broad range of transplant rejection. CONCLUSION: These results indicate that generating HLA-G1 transgenic pigs can protect porcine grafts from macrophage-mediated cytotoxicity. PMID- 25559171 TI - Fish protein hydrolysates: application in deep-fried food and food safety analysis. AB - Four different processes (enzymatic, microwave-intensified enzymatic, chemical, and microwave-intensified chemical) were used to produce fish protein hydrolysates (FPH) from Yellowtail Kingfish for food applications. In this study, the production yield and oil-binding capacity of FPH produced from different processes were evaluated. Microwave intensification significantly increased the production yields of enzymatic process from 42% to 63%. It also increased the production yields of chemical process from 87% to 98%. The chemical process and microwave-intensified chemical process produced the FPH with low oil-binding capacity (8.66 g oil/g FPH and 6.25 g oil/g FPH), whereas the microwave intensified enzymatic process produced FPH with the highest oil-binding capacity (16.4 g oil/g FPH). The FPH from the 4 processes were applied in the formulation of deep-fried battered fish and deep-fried fish cakes. The fat uptake of deep fried battered fish can be reduced significantly from about 7% to about 4.5% by replacing 1% (w/w) batter powder with FPH, and the fat uptake of deep-fried fish cakes can be significantly reduced from about 11% to about 1% by replacing 1% (w/w) fish mince with FPH. Food safety tests of the FPH produced by these processes demonstrated that the maximum proportion of FPH that can be safely used in food formulation is 10%, due to its high content of histamine. This study demonstrates the value of FPH to the food industry and bridges the theoretical studies with the commercial applications of FPH. PMID- 25559172 TI - Photochemical transformation of tetrabromobisphenol A under simulated sunlight irradiation: Kinetics, mechanism and influencing factors. AB - A systematic study on photolysis of tetrabromobisphenol A (2,2',6,6'-tetrabromo 4,4'-isopropylidendiphenol, TBBPA) in water was investigated under simulated sunlight irradiation. The results showed that the photolysis of TBBPA followed apparent pseudo-first-order kinetics. The photolysis rate constants (k) changed from 2.80 * 10(-2) to 0.70 * 10(-2)min(-1) with the concentrations of TBBPA varying from 0.1 to 10 mg L(-1). Increasing humic acid (HA) concentration from 0 100 mg L(-1) led to the decrease of k from 2.53 * 10(-2) to 0.39 * 10(-2)min(-1), which was due to the competitive adsorption for photons between HA and TBBPA molecules. The photolysis rate was faster at near-neutral conditions (pH=6 and 7) than that in either acidic or basic conditions. Electron spin resonance (ESR) and reactive oxygen species (ROS) scavenging experiments indicated that TBBPA underwent self-sensitized photooxidation via ROS (i.e., OH, (1)O2 and O2(-)), and the process was mainly controlled by O2(-). After irradiation of 180 min, about 35.0% reduction of TOC occurred accompanied with approximate 99.1% of TBBPA removed. The detection of products (i.e., Br(-), bisphenol A, 2,6-dibromophenol, 2-bromophenol and phenol) revealed that the main photolytic pathways of TBBPA were debromination and breakage of C-C bond. PMID- 25559173 TI - Impact of biochar and root-induced changes on metal dynamics in the rhizosphere of Agrostis capillaris and Lupinus albus. AB - Rhizosphere interactions are deemed to play a key role in the success of phytoremediation technologies. Here, the effects of biochar and root-induced changes in the rhizosphere of Agrostis capillaris L. and Lupinus albus L. on metal (Cd, Pb and Zn) dynamics were investigated using a biotest on a 2mm soil layer and a sequential extraction procedure (Tessier's scheme). In the bulk soil, the application of 5% biochar significantly reduced the exchangeable pool of metals primarily due to a liming effect which subsequently promoted the metal shift into the carbonate-bound pool. However, metals were re-mobilized in the rhizosphere of both A. capillaris and L. albus due to root-induced acidification which counteracted the liming effect of biochar. As a result, the concentrations of metals in roots and shoots of both plants were not significantly reduced by the application of biochar. Although the study should be considered a worst-case scenario because experimental conditions induced the intensification of rhizosphere processes, the results highlight that changes in rhizosphere pH can impact the effectiveness of biochar to immobilize metals in soil. Biochar has thus a potential as amendment for reducing metal uptake by plants, provided the acidification of the rhizosphere is minimized. PMID- 25559174 TI - Blood parameters as biomarkers of cadmium and lead exposure and effects in wild wood mice (Apodemus sylvaticus) living along a pollution gradient. AB - Small mammal populations living on contaminated sites are exposed to various chemicals. Lead (Pb) and cadmium (Cd), two well-known nonessential trace metals, accumulate in different organs and are known to cause multiple adverse effects. To develop nonlethal markers in ecotoxicology, the present work aimed to study the relationships between blood parameters (hematocrit, leukocyte levels and granulated erythrocyte levels) and Cd and Pb concentrations in the soil and in the liver and kidneys of wood mice (Apodemus sylvaticus). Individuals were trapped along a pollution gradient with high levels of Cd, Pb and zinc (Zn) contamination. The results indicated that hematological parameters were independent of individual characteristics (age and gender). Blood parameters varied along the pollution gradient, following a pattern similar to the accumulation of Cd in the organs of the wood mice. No relationship was found between the blood parameters studied and Pb concentrations in the organs or in the environment. The hematocrit and leukocyte number decreased with increasing concentrations of Cd in the kidneys and/or in the liver. Moreover, the hematocrit was lower in the animals that were above the thresholds (LOAELs) for Cd concentrations in the liver. These responses were interpreted as a warning of potential negative effects of Cd exposure on the oxygen transport capacity of the blood (e.g., anemia). The present results suggest that blood parameters, notably hematocrit, may offer a minimally invasive biomarker for the evaluation of Cd exposure in further ecotoxicological studies. PMID- 25559175 TI - Removal of colloidal biogenic selenium from wastewater. AB - Biogenic selenium, Se(0), has colloidal properties and thus poses solid-liquid separation problems, such as poor settling and membrane fouling. The separation of Se(0) from the bulk liquid was assessed by centrifugation, filtration, and coagulation-flocculation. Se(0) particles produced by an anaerobic granular sludge are normally distributed, ranging from 50 nm to 250 nm, with an average size of 166+/-29 nm and a polydispersity index of 0.18. Due to its nanosize range and protein coating-associated negative zeta potential (-15 mV to -23 mV) between pH 2 and 12, biogenic Se(0) exhibits colloidal properties, hampering its removal from suspension. Centrifugation at different centrifugal speeds achieved 22+/-3% (1500 rpm), 73+/-2% (3000 rpm) and 91+/-2% (4500 rpm) removal. Separation by filtration through 0.45 MUm filters resulted in 87+/-1% Se(0) removal. Ferric chloride and aluminum sulfate were used as coagulants in coagulation-flocculation experiments. Aluminum sulfate achieved the highest turbidity removal (92+/-2%) at a dose of 10(-3) M, whereas ferric chloride achieved a maximum turbidity removal efficiency of only 43+/-4% at 2.7*10(-4) M. Charge repression plays a minor role in particle neutralization. The sediment volume resulting from Al2(SO3)4 treatment is three times larger than that produced by FeCl3. PMID- 25559176 TI - Predicting equilibrium vapour pressure isotope effects by using artificial neural networks or multi-linear regression - A quantitative structure property relationship approach. AB - We aim at predicting the effect of structure and isotopic substitutions on the equilibrium vapour pressure isotope effect of various organic compounds (alcohols, acids, alkanes, alkenes and aromatics) at intermediate temperatures. We attempt to explore quantitative structure property relationships by using artificial neural networks (ANN); the multi-layer perceptron (MLP) and compare the performances of it with multi-linear regression (MLR). These approaches are based on the relationship between the molecular structure (organic chain, polar functions, type of functions, type of isotope involved) of the organic compounds, and their equilibrium vapour pressure. A data set of 130 equilibrium vapour pressure isotope effects was used: 112 were used in the training set and the remaining 18 were used for the test/validation dataset. Two sets of descriptors were tested, a set with all the descriptors: number of(12)C, (13)C, (16)O, (18)O, (1)H, (2)H, OH functions, OD functions, CO functions, Connolly Solvent Accessible Surface Area (CSA) and temperature and a reduced set of descriptors. The dependent variable (the output) is the natural logarithm of the ratios of vapour pressures (ln R), expressed as light/heavy as in classical literature. Since the database is rather small, the leave-one-out procedure was used to validate both models. Considering higher determination coefficients and lower error values, it is concluded that the multi-layer perceptron provided better results compared to multi-linear regression. The stepwise regression procedure is a useful tool to reduce the number of descriptors. To our knowledge, a Quantitative Structure Property Relationship (QSPR) approach for isotopic studies is novel. PMID- 25559177 TI - A generic biotic ligand model quantifying the development in time of Ni toxicity to Enchytraeus crypticus. AB - Biotic ligand models (BLMs) predicting metal toxicity for a fixed exposure time are available, but it is uncertain how to extrapolate predictions to a dynamic environment with time-variable exposure. Three BLM-based models were developed to describe change of Ni toxicity to Enchytraeus crypticus in time. These models assumed that: (a) biotic ligand binding constants of Ni and competing cations (K(NiBL) and K(CBL)) and the fraction of biotic ligands occupied by Ni to produce 50% mortality (f50) are fixed with time, (b) K(NiBL) and K(CBL) remain constant while f50 varies with time, and (c) K(NiBL), K(CBL), and f50 are all time dependent. Model (a) successfully described the 7-d toxicity of Ni but failed in explaining Ni toxicity at longer exposure times. Both models (b) and (c) well described Ni toxicity, within a factor of 2, at varying solution chemistries and different exposure times. This shows that the acute BLM cannot directly be applied for predicting chronic metal toxicity and that some BLM parameters may vary with time. Our findings provide plausible explanations for differences in mechanisms of acute and chronic toxicity, offering a framework for incorporating toxicokinetic and toxicodynamic processes in describing Ni toxicity in time. PMID- 25559178 TI - In vivo delivery of siRNA to the brain by carbosilane dendrimer. AB - Nanotechnology offers a new platform for therapeutic delivery of antiretrovirals to the central nervous system (CNS). Nanoformulated antiretroviral drugs offer multifunctionality, that is, the ability to package multiple diagnostic and therapeutic agents in the same nanocompose, along with the added provisions of site-directed delivery, delivery across the blood-brain-barrier (BBB), and controlled release of therapeutics. We studied the viability of dendrimers and dendriplexes in human primary astrocytes, as well as their uptake by these astrocytes. Functional validation was performed by using specific siRNA against HIV-1 Nef to interfere to HIV-1 infectivity. A high efficiency in Nef silencing, reducing HIV-1 infectivity was observed in astrocytes treated with dendriplexes compared with control or siRandom treated astrocytes. More interestingly, we studied the biodistribution of the second generation of carbosilane dendrimer loaded with FITC (2G-(SNMe3I)11-FITC) in vivo, in BALB/c mice. Dendriplexes were inoculated into BALB/c mice by the retro-orbital venous plexus, and their localization was determined after 1 and 24h post-injection. Dendriplexes were detected inside the brain by a sensitive imaging system of fluorescent imaging in vivo (IVIS Lumina), and by confocal microscopy analysis of sections of OCT embedded tissues. The 2G-(SNMe3I)11-FITC dendrimer transported efficiently siRNA into the brain, crossing the BBB. Moreover, this dendrimer successfully delivered and transfected siRNA to HIV-infected human primary astrocytes and achieved gene silencing without causing cytotoxicity. These results highlight the potential of this nanoformulation in the treatment of neurological disorders. PMID- 25559180 TI - Julia von Blume: sorting through the trans-Golgi. PMID- 25559181 TI - TUNEL vision spots apoptotic cells. PMID- 25559179 TI - The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice. AB - Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder caused by the deficiency of the enzyme beta-glucuronidase (Gusb(-/-)) and results in glycosaminoglycan (GAG) accumulation. Skeletal abnormalities include stunted long bones and bone degeneration. GAGs have been hypothesized to activate toll-like receptor 4 (Tlr4) signaling and the complement pathway, resulting in upregulation of inflammatory cytokines that suppress growth and cause degeneration of the bone. Gusb(-/-) mice were bred with Tlr4- and complement component 3 (C3) deficient mice, and the skeletal manifestations of the doubly- and triply deficient mice were compared to those of purebred Gusb(-/-) mice. Radiographs showed that purebred Gusb(-/-) mice had shorter tibias and femurs, and wider femurs, compared to normal mice. No improvement was seen in Tlr4, C3, or Tlr4/C3 deficient Gusb(-/-) mice. The glenoid cavity and humerus were scored on a scale from 0 (normal) to +3 (severely abnormal) for dysplasia and bone irregularities, and the joint space was measured. No improvement was seen in Tlr4, C3, or Tlr4/C3 deficient Gusb(-/-) mice, and their joint space remained abnormally wide. Gusb(-/ ) mice treated neonatally with an intravenous retroviral vector (RV) had thinner femurs, longer legs, and a narrowed joint space compared with untreated purebred Gusb(-/-) mice, but no improvement in glenohumeral degeneration. We conclude that Tlr4- and/or C3-deficiency fail to ameliorate skeletal abnormalities, and other pathways may be involved. RV treatment improves some but not all aspects of bone disease. Radiographs may be an efficient method for future evaluation, as they readily show glenohumeral joint abnormalities. PMID- 25559182 TI - Celebrating the first 60 years of The Journal of Cell Biology. PMID- 25559183 TI - Accessorizing and anchoring the LINC complex for multifunctionality. AB - The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of outer and inner nuclear membrane Klarsicht, ANC-1, and Syne homology (KASH) and Sad1 and UNC-84 (SUN) proteins, respectively, connects the nucleus to cytoskeletal filaments and performs diverse functions including nuclear positioning, mechanotransduction, and meiotic chromosome movements. Recent studies have shed light on the source of this diversity by identifying factors associated with the complex that endow specific functions as well as those that differentially anchor the complex within the nucleus. Additional diversity may be provided by accessory factors that reorganize the complex into higher-ordered arrays. As core components of the LINC complex are associated with several diseases, understanding the role of accessory and anchoring proteins could provide insights into pathogenic mechanisms. PMID- 25559184 TI - Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans interaction. AB - The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. In this paper, using a photoactivatable probe to control Rac1 activity at AJs, we addressed the relationship between Rac1 and the dynamics of vascular endothelial cadherin (VE-cadherin). We demonstrated that Rac1 activation reduced the rate of VE-cadherin dissociation, leading to increased density of VE-cadherin at AJs. This response was coupled to a reduction in actomyosin-dependent tension across VE-cadherin adhesion sites. We observed that inhibiting myosin II directly or through photo-release of the caged Rho kinase inhibitor also reduced the rate of VE-cadherin dissociation. Thus, Rac1 functions by stabilizing VE-cadherin trans-dimers in mature AJs by counteracting the actomyosin tension. The results suggest a new model of VE-cadherin adhesive interaction mediated by Rac1-induced reduction of mechanical tension at AJs, resulting in the stabilization of VE-cadherin adhesions. PMID- 25559187 TI - Differential effects of IL-15 on the generation, maintenance and cytotoxic potential of adaptive cellular responses induced by DNA vaccination. AB - IL-15 is an important cytokine for the regulation of lymphocyte homeostasis. However, the role of IL-15 in the generation, maintenance and cytotoxic potential of antigen specific T cells is not fully understood. Because the route of antigenic delivery and the vaccine modality could influence the IL-15 requirement for mounting and preserving cytotoxic T cell responses, we have investigated the immunogenicity of DNA-based vaccines in IL-15 KO mice. DNA vaccination with SIV Gag induced antigen-specific CD4(+) and CD8(+) T cells in the absence of IL-15. However, the absolute number of antigen-specific CD8(+) T cells was decreased in IL-15 KO mice compared to WT animals, suggesting that IL-15 is important for the generation of maximal number of antigen-specific CD8(+) T cells. Interestingly, antigen-specific memory CD8 cells could be efficiently boosted 8 months after the final vaccination in both WT and KO strains of mice, suggesting that the maintenance of antigen-specific long-term memory T cells induced by DNA vaccination is comparable in the absence and presence of IL-15. Importantly, boosting by DNA 8-months after vaccination revealed severely reduced granzyme B content in CD8(+) T cells of IL-15 KO mice compared to WT mice. This suggests that the cytotoxic potential of the long-term memory CD8(+) T cells is impaired. These results suggest that IL-15 is not essential for the generation and maintenance of adaptive cellular responses upon DNA vaccination, but it is critical for the preservation of maximal numbers and for the activity of cytotoxic CD8(+) T cells. PMID- 25559186 TI - TRP channel-associated factors are a novel protein family that regulates TRPM8 trafficking and activity. AB - TRPM8 is a cold sensor that is highly expressed in the prostate as well as in other non-temperature-sensing organs, and is regulated by downstream receptor activated signaling pathways. However, little is known about the intracellular proteins necessary for channel function. Here, we identify two previously unknown proteins, which we have named "TRP channel-associated factors" (TCAFs), as new TRPM8 partner proteins, and we demonstrate that they are necessary for channel function. TCAF1 and TCAF2 both bind to the TRPM8 channel and promote its trafficking to the cell surface. However, they exert opposing effects on TRPM8 gating properties. Functional interaction of TCAF1/TRPM8 also leads to a reduction in both the speed and directionality of migration of prostate cancer cells, which is consistent with an observed loss of expression of TCAF1 in metastatic human specimens, whereas TCAF2 promotes migration. The identification of TCAFs introduces a novel mechanism for modulation of TRPM8 channel activity. PMID- 25559185 TI - Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins. AB - Nuclear organization has been implicated in regulating gene activity. Recently, large developmentally regulated regions of the genome dynamically associated with the nuclear lamina have been identified. However, little is known about how these lamina-associated domains (LADs) are directed to the nuclear lamina. We use our tagged chromosomal insertion site system to identify small sequences from borders of fibroblast-specific variable LADs that are sufficient to target these ectopic sites to the nuclear periphery. We identify YY1 (Ying-Yang1) binding sites as enriched in relocating sequences. Knockdown of YY1 or lamin A/C, but not lamin A, led to a loss of lamina association. In addition, targeted recruitment of YY1 proteins facilitated ectopic LAD formation dependent on histone H3 lysine 27 trimethylation and histone H3 lysine di- and trimethylation. Our results also reveal that endogenous loci appear to be dependent on lamin A/C, YY1, H3K27me3, and H3K9me2/3 for maintenance of lamina-proximal positioning. PMID- 25559189 TI - An eukaryotic translation initiation factor, AteIF5A-2, affects cadmium accumulation and sensitivity in Arabidopsis. AB - Cadmium (Cd) is one of the most toxic elements and can be accumulated in plants easily; meanwhile, eIF5A is a highly conserved protein in all eukaryotic organisms. The present work tried to investigate whether eIF5A is involved in Cd accumulation and sensitivity in Arabidopsis (Arabidopsis thaliana L.) by comparing the wild-type Columbia-0 (Col-0) with a knockdown mutant of AteIF5A-2, fbr12-3 under Cd stress conditions. The results showed that the mutant fbr12-3 accumulated more Cd in roots and shoots and had significantly lower chlorophyll content, shorter root length, and smaller biomass, suggesting that downregulation of AteIF5A-2 makes the mutant more Cd sensitive. Real-time polymerase chain reaction revealed that the expressions of metal transporters involved in Cd uptake and translocation including IRT1, ZIP1, AtNramp3, and AtHMA4 were significantly increased but the expressions of PCS1 and PCS2 related to Cd detoxification were decreased notably in fbr12-3 compared with Col-0. As a result, an increase in MDA and H2 O2 content but decrease in root trolox, glutathione and proline content under Cd stress was observed, indicating that a severer oxidative stress occurs in the mutant. All these results demonstrated for the first time that AteIF5A influences Cd sensitivity by affecting Cd uptake, accumulation, and detoxification in Arabidopsis. PMID- 25559188 TI - Liposomal vaccines incorporating molecular adjuvants and intrastructural T-cell help promote the immunogenicity of HIV membrane-proximal external region peptides. AB - An HIV vaccine capable of inducing high and durable levels of broadly neutralizing antibodies has thus far proven elusive. A promising antigen is the membrane-proximal external region (MPER) from gp41, a segment of the viral envelope recognized by a number of broadly neutralizing antibodies. Though an attractive vaccine target due to the linear nature of the epitope and its highly conserved sequence, MPER peptides are poorly immunogenic and may require display on membranes to achieve a physiological conformation matching the native virus. Here we systematically explored how the structure and composition of liposomes displaying MPER peptides impacts the strength and durability of humoral responses to this antigen as well as helper T-cell responses in mice. Administration of MPER peptides anchored to the surface of liposomes induced MPER-specific antibodies whereas MPER administered in oil-based emulsion adjuvants or alum did not, even when combined with Toll-like receptor agonists. High-titer IgG responses to liposomal MPER required the inclusion of molecular adjuvants such as monophosphoryl lipid A. Anti-MPER humoral responses were further enhanced by incorporating high-Tm lipids in the vesicle bilayer and optimizing the MPER density to a mean distance of ~10-15 nm between peptides on the liposomes' surfaces. Encapsulation of helper epitopes within the vesicles allowed efficient "intrastructural" T-cell help, which promoted IgG responses to MPER while minimizing competing B-cell responses against the helper sequence. These results define several key properties of liposome formulations that promote durable, high titer antibody responses against MPER peptides, which will be a prerequisite for a successful MPER-targeting vaccine. PMID- 25559191 TI - Resident perspectives on duty hour limits and attributes of their learning environment. AB - BACKGROUND: Residents are stakeholders in the debate surrounding duty hour restrictions, yet few studies have assessed their perspective on their programs' efforts to comply with them. OBJECTIVES: This paper explores learners' perceptions of the attributes of their programs in relation to duty hour compliance, and looks for evidence whether residents view duty hour limits as important to patient safety. METHODS: A grounded-theory framework was used to analyze learners' comments about programs' compliance with US duty hour limits. Data were collected by ACGME in 2011, using resident consensus lists of program strengths and opportunities for improvement generated prior to accreditation site visits. The data set for this analysis encompasses 112 core and 69 subspecialty programs where these lists mentioned duty hours. RESULTS: The analysis compared programs where residents viewed duty hour compliance as a strength, and programs where it was identified as an opportunity for improvement. Programs in the first group were characterized by clinical efficiency, responsiveness to problems, and a collegial environment that contributed to residents' ability to meet clinical and learning goals within the restrictions. These attributes were lacking in the second group, and residents also commented on onerous duty hour reporting. Learners did not associate duty hour compliance with patient safety, and the few comments in this area centred almost exclusively on the presence or absence of supervision when junior residents first assumed clinical duties. CONCLUSION: The findings have practical implications for programs that wish to enhance their learning and patient care environment, and suggest areas for future research. PMID- 25559192 TI - Are adult attachment styles categorical or dimensional? A taxometric analysis of general and relationship-specific attachment orientations. AB - One of the long-standing debates in the study of adult attachment is whether individual differences are best captured using categorical or continuous models. Although early research suggested that continuous models might be most appropriate, we revisit this issue here because (a) categorical models continue to be widely used in the empirical literature, (b) contemporary models of individual differences raise new questions about the structure of attachment, and (c) methods for addressing the types versus dimensions question have become more sophisticated over time. Analyses based on 2 samples indicate that individual differences appear more consistent with a dimensional rather than a categorical model. This was true with respect to general attachment representations and attachment in specific relationship contexts (e.g., attachment with parents and peers). These findings indicate that dimensional models of attachment style may be better suited for conceptualizing and measuring individual differences across multiple levels of analysis. PMID- 25559193 TI - The dispositional basis of attitudes: A replication and extension of Hepler and Albarracin (2013). AB - As a departure from traditional situational perspectives, researchers have given increased attention to the dispositional basis of attitudes. Recently, Hepler and Albarracin (2013) introduced a construct that they called "dispositional attitude" and provided validity evidence for a new scale--the Dispositional Attitude Measure (DAM). Although the DAM was introduced as a "new" approach for assessing the dispositional component of attitudes, there is considerable conceptual similarity between it and the Neutral Objects Satisfaction Questionnaire (NOSQ; Judge & Bretz, 1993; Weitz, 1952). In a series of 4 studies, we attempt to replicate the predictive validity of the DAM and empirically examined the distinctiveness of the DAM from the NOSQ. Our findings suggest that the DAM does not consistently predict attitudes (e.g., attitudes toward fictional consumer products, attitudes toward common objects, job satisfaction) after the NOSQ is controlled. As a whole, our results suggest that the DAM and NOSQ assess the same underlying construct and both are valid measures of the dispositional basis of attitudes. PMID- 25559190 TI - Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors. AB - Renin-angiotensin system overactivity, upregulation of postsynaptic NMDA receptor function, and increased reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) are hallmarks of angiotensin II (AngII)-induced hypertension, which is far more common in young males than in young females. We hypothesize that the sex differences in hypertension are related to differential AngII-induced changes in postsynaptic trafficking of the essential NMDA receptor GluN1 subunit and ROS production in PVN cells expressing angiotensin Type 1a receptor (AT1aR). We tested this hypothesis using slow pressor (14-day) infusion of AngII (600 ng/kg/min) in mice, which elicits hypertension in males but not in young females. Two-month-old male and female transgenic mice expressing enhanced green fluorescent protein (EGFP) in AT1aR containing cells were used. In males, but not in females, AngII increased blood pressure and ROS production in AT1aR-EGFP PVN cells at baseline and following NMDA treatment. Electron microscopy showed that AngII increased cytoplasmic and total GluN1-silver-intensified immunogold (SIG) densities and induced a trend toward an increase in near plasmalemmal GluN1-SIG density in AT1aR-EGFP dendrites of males and females. Moreover, AngII decreased dendritic area and diameter in males, but increased dendritic area of small (<1 um) dendrites and decreased diameter of large (>1 um) dendrites in females. Fluorescence microscopy revealed that AT1aR and estrogen receptor beta do not colocalize, suggesting that if estrogen is involved, its effect is indirect. These data suggest that the sexual dimorphism in AngII-induced hypertension is associated with sex differences in ROS production in AT1aR-containing PVN cells but not with postsynaptic NMDA receptor trafficking. PMID- 25559194 TI - Individual differences in activation of the parental care motivational system: assessment, prediction, and implications. AB - We report on the development, validation, and utility of a measure assessing individual differences in activation of the parental care motivational system: The Parental Care and Tenderness (PCAT) questionnaire. Results from 1,608 adults (including parents and nonparents) show that the 25-item PCAT measure has high internal consistency, high test-retest reliability, high construct validity, and unique predictive utility. Among parents, it predicted self-child identity overlap and caring child-rearing attitudes; among nonparents, it predicted desire to have children. PCAT scores predicted the intensity of tender emotions aroused by infants, and also predicted the amount of time individuals chose look at infant (but not adult) faces. PCAT scores uniquely predicted additional outcomes in the realm of social perception, including mate preferences, moral judgments, and trait inferences about baby-faced adults. Practical and conceptual implications are discussed. PMID- 25559195 TI - Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression. AB - To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) transposon mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC. PMID- 25559198 TI - The Effects of Low-Level Laser Therapy on Pain Associated With Tendinopathy: A Critically Appraised Topic. AB - CLINICAL SCENARIO: Tendinopathies plague many active individuals, causing pain and reducing sport activity by decreasing range of motion and strength. There are many modalities that have been used to treat pain associated with chronic inflammation, such as ultrasound, moist heat packs, and electrical stimulation. Low-level laser therapy (LLLT) is one such modality. Potential benefits of managing pain associated with tendinopathies have been investigated using LLLT. Cellular respiration and metabolism are thought to be increased by LLLT acting on the mitochondrial cytochromes. The effects LLLT may have on cellular activity could increase blood flow to progress the healing process by reducing the pain spasm cycle. The purpose of this critically appraised topic is to identify the clinical effectiveness of LLLT on pain associated with tendinopathy and to identify the parameters used to achieve statistically and clinically relevant pain outcomes. FOCUSED CLINICAL QUESTIon: What is the effect of LLLT on pain associated with tendinopathy? CLINICAL BOTTOM LINE: Although LLLT significantly decreases pain from baseline, its use may be no better than placebo or traditional treatments such as ultrasound, moist heat packs, electrical stimulation, or therapeutic exercise to reduce pain associated with tendinopathy. Total accumulated joules across the treatment sessions may need to be taken into account as a parameter. PMID- 25559199 TI - New paradigms for metabolic modeling of human cells. AB - Abnormalities in cellular functions are associated with the progression of human diseases, often resulting in metabolic reprogramming. GEnome-scale metabolic Models (GEMs) have enabled studying global metabolic reprogramming in connection with disease development in a systematic manner. Here we review recent work on reconstruction of GEMs for human cell/tissue types and cancer, and the use of GEMs for identification of metabolic changes occurring in response to disease development. We further discuss how GEMs can be used for the development of efficient therapeutic strategies. Finally, challenges in integration of cell/tissue models for simulation of whole body functions as well as integration of GEMs with other biological networks for generating complete cell/tissue models are presented. PMID- 25559197 TI - Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance. AB - Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naive immune cells. To identify such mechanisms, gut microbes and naive immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis. PMID- 25559200 TI - Advances and current limitations in transcript-level control of gene expression. AB - Gene expression control is critical to increase production of recombinant proteins, fine-tune metabolic pathways and reliably express synthetic pathways. The importance of transcriptional control seems to be most important in eukaryotic systems. In this review, we highlight recent developments in the field of transcriptional engineering with an emphasis on the opportunities and challenges. We discuss the engineering of 'parts' that influence transcriptional throughput including promoters, terminators, and transcription factors as well as the genetic context of the expression cassette. While great strides have been made in the area, the robustness of these parts has been largely untested. This review highlights the importance of considering robustness in biological systems and the limitations that current synthetic parts possess. PMID- 25559201 TI - Proposal for novel metabolic pathway of highly toxic dimethylated arsenics accompanied by enzymatic sulfuration, desulfuration and oxidation. AB - The International Agency for Research on Cancer (IARC) has concluded that dimethylarsinic acid [(CH3)2AsO(OH), DMA(V)], a main metabolite of inorganic arsenic, is responsible for carcinogenesis in urinary bladder and lung in rodents, and various modes of carcinogenic action have been proposed. One theory concerning the mode of action is that the biotransformation of dimethylarsinous acid [(CH3)2AsOH, DMA(III)] from DMA(V) plays an important role in the carcinogenesis by way of reactive oxygen species (ROS) production. Furthermore, dimethylmonothioarsinic acid [(CH3)2AsS(OH), DMMTA(V)], a metabolite of DMA(V), has also been noted because of its higher toxicity. However, the metabolic mechanisms of formation and disappearance of DMA(III) and DMMTA(V), and their toxicity are not fully understood. Thus, the purpose of the present study was to clarify the mechanism of metabolic formation of DMMTA(V) and DMA(V) from DMA(III). The in vitro transformation of arsenicals by treatment with liver homogenate from rodents and sulfur transferase was detected by HPLC-ICP-MS and HPLC-tandem MS. DMMTA(V) is produced from DMA(III) but not DMA(V) by cellular fractions from mouse liver homogenates and by rhodanese from bovine liver in the presence of thiosulfate, a sulfur donor. Not only DMMTA(V) thus produced but also DMA(III) are re-converted into DMA(V) by an in vitro addition of S9 mix. These findings indicate that the metabolic process not only of DMA(III) to DMA(V) or DMMTA(V) but also of DMMTA(V) to DMA(V) consists of a complicated mode of interaction between monooxygenase including cytochrome P450 (CYP) and/or sulfur transferase. PMID- 25559202 TI - Effectiveness of score card-based antenatal risk selection, care pathways, and multidisciplinary consultation in the Healthy Pregnancy 4 All study (HP4ALL): study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Promotion of healthy pregnancies has gained high priority in the Netherlands because of relatively unfavorable perinatal outcomes. In response, a nationwide study, 'Healthy Pregnancy 4 All' (HP4ALL), has been initiated. Part of this study involves systematic and broadened antenatal risk assessment (the Risk Assessment substudy). Risk selection in current clinical practice is mainly based on medical risk factors. Despite the increasing evidence for the influence of nonmedical risk factors (social status, lifestyle or ethnicity) on perinatal outcomes, these risk factors remain highly unexposed. Systematic risk selection, combined with customized care pathways to reduce or treat detected risks, and regular and structured consultation between community midwives, gynecologists and other care providers such as social workers, is part of this study. METHODS/DESIGN: Neighborhoods in 14 municipalities with adverse perinatal outcomes above national and municipal averages are selected for participation. The study concerns a cluster randomized controlled trial. Municipalities are randomly allocated to intervention (n = 3,500 pregnant women) and control groups (n = 3,500 pregnant women). The intervention consists of systematic risk selection with the Rotterdam Reproductive Risk Reduction (R4U) score card in pregnant women at the booking visit, and referral to corresponding care pathways. A risk score, based on weighed risk factors derived from the R4U, above a predefined threshold determines structured multidisciplinary consultation. Primary outcomes of this trial are dysmaturity (birth weight < p10), prematurity (birth <37 weeks), and efficacy of implementation. DISCUSSION: The 'HP4ALL' study introduces a systematic approach in antenatal health care that may improve perinatal outcomes and, thereby, affect future health status of a new generation in the Netherlands. TRIAL REGISTRATION: Dutch Trial Registry ( NTR-3367) on 20 March 2012. PMID- 25559196 TI - High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. AB - Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. PMID- 25559204 TI - Synthetic modification of hydroxychavicol by Mannich reaction and alkyne-azide cycloaddition derivatives depicting cytotoxic potential. AB - Here we report the design, synthesis and lead optimization of hydroxychavicol (1) a high yielding metabolite ubiquitously present in the Piper betel leaves with the significant cytotoxic activity. This is the first report to describe the synthetic strategies of two distinct series of hydroxychavicol by Mannich reaction (2-10) and alkyne-azide cycloaddition (11-20). Furthermore, all the synthesized derivatives along with parent compound were evaluated for their in vitro cytotoxic and antiproliferative potential in several distinct cancers cell lines. Among all, the Mannich reaction derived molecules 6, 8 and 10 displayed more potent cytotoxic activities with IC50 value in a range from 3 to 9 MUM, which were 7-10 fold more potent than 1 against five human cancer cell lines viz. HL-60, Mia PaCa-2, MCF-7, HEP G2 and SK-N-SH. Our results describe an efficient synthetic approach used to evaluate the structure activity relationship of 1 and its derivative in search of potential new anticancer agents. PMID- 25559203 TI - Precision and agreement of corneal power measurements obtained using a new corneal topographer OphthaTOP. AB - PURPOSE: To evaluate repeatability and reproducibility of anterior corneal power measurements obtained with a new corneal topographer OphthaTOP (Hummel AG, Germany) and agreement with measurements by a rotating Scheimpflug camera (Pentacam HR, Oculus, Germany) and an automated keratometer (IOLMaster, Carl Zeiss Meditec, Germany). METHODS: The right eyes of 79 healthy subjects were prospectively measured three times with all three devices. Another examiner performed three additional scans with the OphthaTOP in the same session. Within one week, the first examiner repeated the measurements using the OphthaTOP. The flat simulated keratometry (Kf), steep K (Ks), mean K (Km), J0, and J45 were noted. Repeatability and reproducibility of measurements were assessed by within subject standard deviation (Sw), repeatability (2.77 Sw), coefficient of variation (CoV), and intraclass correlation coefficient (ICC). Agreement between devices was assessed using 95% limits of agreement (LoA). RESULTS: Intraobserver repeatability and interobserver and intersession reproducibility of all measured parameters showed a 2.77 Sw of 0.29 diopter or less, a CoV of less than 0.24%, and an ICC of more than 0.906. Statistically significant differences (P<0.001) were found between the parameters analyzed by the three devices, except J0 and J45. The mean differences between OphthaTOP and the other two devices were small, and the 95% LoA was narrow for all results. CONCLUSIONS: The OphthaTOP showed excellent intraobserver repeatability and interobserver and intersession reproducibility of corneal power measurements. Good agreements with the other two devices in these parameters were found in healthy eyes. PMID- 25559205 TI - Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor. AB - A series of novel 2-amino-4-pyrazolecyclopentylpyrimidines have been prepared and evaluated as IGF-1R tyrosin kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 2- amino ring, 4-pyrazolo moieties and size of fused saturated ring with the central pyrimidine core. A stepwise optimization by combination of active fragments led to discovery of compound 6f and 6k, two structures with IGF-1R IC50 of 20 nM and 10 nM, respectively. 6f was further profiled for its anti cancer activity across various cell lines and pharmacokinetic studies in Sprague Dawley rats. PMID- 25559206 TI - Anticoagulant and antithrombotic evaluation of native fucosylated chondroitin sulfates and their derivatives as selective inhibitors of intrinsic factor Xase. AB - Fucosylated chondroitin sulfate (FCS), a structurally unusual glycosaminoglycan, has distinct anticoagulant properties, and is an especially strong inhibitor of the intrinsic factor Xase (anti-Xase). To obtain a highly selective inhibitor of human Xase, we purified six native FCSs with various sulfation patterns, prepared a series of FCS derivatives, and then elucidated the relationship between the structures and the anticoagulant activities of FCSs. FCSs 1-3 containing higher Fuc2S4S exhibit stronger AT-dependent anti-IIa activities, whereas 4-6 containing more Fuc3S4S produce potent HCII-dependent anti-IIa activities. Saccharides containing a minimum of 6-8 trisaccharide units, free carboxyl groups, and full fucosylation of GlcA may be required for potent anti-Xase activity, and approximately six trisaccharide units and partial fucosylation of GlcA may contribute to potent HCII-dependent activity. Decreasing of the molecular weights markedly reduces their AT-dependent anti-IIa activities, and even eliminates human platelet and factor XII activation. Furthermore, in vitro and in vivo studies suggested that fractions of 6-12 kDa may be very promising compounds as putative selective intrinsic Xase inhibitors with antithrombotic action, but without the consequences of major bleeding and factor XII activation. PMID- 25559207 TI - Synthesis and biological evaluations of novel endomorphin analogues containing alpha-hydroxy-beta-phenylalanine (AHPBA) displaying mixed MU/delta opioid receptor agonist and delta opioid receptor antagonist activities. AB - A novel series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues was synthesized, incorporating chiral alpha-hydroxy-beta-phenylalanine (AHPBA), and/or Dmt(1)-Tic(2) at different positions. Pharmacological activity and metabolic stability of the series was assessed. Consistent with earlier studies of beta-amino acid substitution into endomorphins, multiple analogues incorporation AHPBA displayed high affinity for MU and delta opioid receptors (MOR and DOR, respectively) in radioligand competition binding assays, and an increased stability in rat brain membrane homogenates, notably Dmt-Tic (2R,3S)AHPBA-Phe-NH2 (compound 26). Intracerebroventricular (i.c.v.) administration of 26 produced antinociception (ED50 value (and 95% confidence interval) = 1.98 (0.79-4.15) nmol, i.c.v.) in the mouse 55 degrees C warm-water tail-withdrawal assay, equivalent to morphine (2.35 (1.13-5.03) nmol, i.c.v.), but demonstrated DOR-selective antagonism in addition to non-selective opioid agonism. The antinociception of 26 was without locomotor activity or acute antinociceptive tolerance. This novel class of peptides adds to the potentially therapeutically relevant collection of previously reported EM analogues. PMID- 25559208 TI - Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series. AB - From a recently identified antileishmanial pharmacophore, a structure-activity relationship study was conducted by introducing various aminated, phenoxy or thiophenoxy moieties at position 4 of the 8-nitroquinolin-2(1H)-one scaffold, using SNAr reactions. Thus a series of 47 derivatives was synthesized and evaluated in vitro on the promastigote stage of Leishmania donovani. In parallel, the cytotoxicity of the active molecules was tested on the human HepG2 cell line. The results we obtained showed that the introduction of a substituent at position 4 of the antileishmanial pharmacophore can either lead to inactive or active derivatives, depending on the nature of the substituent. Aminated moieties appear as very unfavorable toward antileishmanial activity, while phenoxy or thiophenoxy moieties were shown to maintain the in vitro antileishmanial profile, especially when the phenyl ring of these moieties was substituted at the para or ortho position by a halogen atom (except fluorine), a trifluoromethyl group or a methyl group. Most of these derivatives showed a lack of solubility in the culture media which hindered the in vitro determination of both their cytotoxicity and activity against the intracellular amastigoste stage of L. donovani. PMID- 25559209 TI - TLR2-dependent amelioration of allergic airway inflammation by parasitic nematode type II MIF in mice. AB - In our previous studies, the recombinant type II macrophage migration inhibitory factor homologue (rAs-MIF) secreted from Anisakis simplex suppressed experimental inflammation mouse model through IL-10 production and CD4(+)CD25(+)Foxp3(+) T cell recruitment. Also, TLR2 gene expression was significantly increased following rAs-MIF treatment. To know the relation between TLR2 and amelioration mechanisms of rAs-MIF, we induced allergic airway inflammation by ovalbumin and alum with or without rAs-MIF under TLR2 blocking systems [anti-TLR2-specific antibody (alpha-mTLR2 Ab) treatment and using TLR2 knockout mice]. As a result, the amelioration effects of rAs-MIF in allergic airway inflammation model (diminished inflammation and Th2 response in the lung, increased IL-10 secretion, CD4(+)CD25(+)Foxp3(+) T-cell recruitment) were diminished under two of the TLR2 blocking model. The expression of TLR2 on the surface of lung epithelial cell was significantly elevated by rAs-MIF treatment or Pam3CSK (TLR2-specific agonist) treatment, but they might have some competition effect on the elevation of TLR2 expression. In addition, the elevation of IL-10 gene expression by rAs-MIF treatment was significantly inhibited by alpha-mTLR2 Ab or Pam3CSK pretreatment. In conclusion, anti-inflammatory effects of the rAs-MIF on OVA-induced allergic airway inflammation might be closely related to TLR2. PMID- 25559210 TI - Advances in translational bioinformatics facilitate revealing the landscape of complex disease mechanisms. AB - Advances of high-throughput technologies have rapidly produced more and more data from DNAs and RNAs to proteins, especially large volumes of genome-scale data. However, connection of the genomic information to cellular functions and biological behaviours relies on the development of effective approaches at higher systems level. In particular, advances in RNA-Seq technology has helped the studies of transcriptome, RNA expressed from the genome, while systems biology on the other hand provides more comprehensive pictures, from which genes and proteins actively interact to lead to cellular behaviours and physiological phenotypes. As biological interactions mediate many biological processes that are essential for cellular function or disease development, it is important to systematically identify genomic information including genetic mutations from GWAS (genome-wide association study), differentially expressed genes, bidirectional promoters, intrinsic disordered proteins (IDP) and protein interactions to gain deep insights into the underlying mechanisms of gene regulations and networks. Furthermore, bidirectional promoters can co-regulate many biological pathways, where the roles of bidirectional promoters can be studied systematically for identifying co-regulating genes at interactive network level. Combining information from different but related studies can ultimately help revealing the landscape of molecular mechanisms underlying complex diseases such as cancer. PMID- 25559211 TI - Neuron-specific enolase correlates to laboratory markers of haemolysis in patients on long-term circulatory support. AB - OBJECTIVES: Neuron-specific enolase (NSE) is used as a diagnostic tool in neuropathies, cerebral diseases or traumata and for some tumours. Furthermore, it is also expressed by erythrocytes and platelets and has been linked to haemolysis ex vivo as a laboratory issue. Chronic haemolysis is frequently associated with mechanical circulatory support by ventricular assist device (VAD) or total artificial heart (TAH). Therefore, we compared NSE with indicators of haemolysis in VAD and TAH patients. METHODS: We included 599 data sets of 97 patients who underwent VAD or TAH implantation. NSE, haptoglobin (HAPT), haemopexin (HPX), free haemoglobin (frHB), lactate dehydrogenase activity (LDH), platelet counts and total bilirubin (TBIL) in plasma were analysed. Further, all major cerebral events were assessed. RESULTS: NSE correlated to frHB (rs = 0.553) and to LDH (rs = 0.695). An inverse correlation was found with HAPT (rs = -0.484) and HPX (rs = 0.398). Thirty-two patients suffered neurological events. Within the time frame of 1 day before to 4 days after a neurological event, correlations of NSE to HAPT (rs = -0.540) and HPX (rs = -0.611) in negative and to frHB (rs = 0.757), LDH (rs = 0.862) and TBIL (rs = 0.549) in positive direction were established (all P < 0.05). Furthermore, haemolysis was graded into three groups for severe, moderate or no or only slight haemolysis. NSE values differed correspondingly between these groups (P < 0.001). CONCLUSION: NSE correlates to laboratory parameters indicative of haemolysis in VAD and TAH patients. Our data suggest an influence of intravascular haemolysis on NSE. Therefore, the parameter should be used with caution when it is used to assess cerebral damage. PMID- 25559212 TI - Kleine-Levin syndrome in 120 patients: differential diagnosis and long episodes. AB - OBJECTIVE: Kleine-Levin syndrome is a rare disease characterized by recurrent episodes of hypersomnia with behavioral and cognitive disturbances. We aimed at describing the diagnosis procedure, risk factors, and severe forms. METHODS: In consecutive patients referred for suspected Kleine-Levin syndrome, we detailed differential diagnoses, and atypical and secondary cases, compared typical patients with healthy subjects, and examined the characteristics of patients with prolonged (>30 days) episodes. RESULTS: Among 166 referred patients, 120 had typical primary Kleine-Levin syndrome (syndrome secondary to brain diseases; n = 4, atypical syndrome, n = 7; differential diagnoses that were mostly psychiatric, n = 29; incomplete information, n = 6). The prevalence in France was 1.8 per million. The patients were often male (64%) and had more frequent birth and developmental abnormalities (45%) than controls (despite normal karyotypes), and most (80%) had teenage onset, with no difference between patients with prolonged (n = 34) and short (n = 85) episodes. In patients with prolonged episodes, the durations of the first episode (32 +/- 33 vs 11 +/- 6 days) and subsequent episodes were longer (mean episode duration = 23 +/- 19 vs 10 +/- 3 days) and the disease course tended to be longer (9 +/- 6 vs 6 +/- 4 years). During episodes, patients with prolonged episodes had shorter sleep time, higher levels of anxiety, increased agitation, and more feelings of disembodiment and amnesia. Between episodes, they were more tired, needed more naps, fell asleep more rapidly, and had higher anxiety/depression scores. INTERPRETATION: Mental disorders are frequent differential diagnoses of Kleine-Levin syndrome. One-third of patients have prolonged (>1 month) episodes with more frequent immediate and long-term consequences of the disease, prompting therapeutic trials. PMID- 25559213 TI - Highly selective salicylketoxime-based estrogen receptor beta agonists display antiproliferative activities in a glioma model. AB - Estrogen receptor beta (ERbeta) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes alpha and beta are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ERbeta selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ERbeta-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease. PMID- 25559215 TI - Offender recidivism: an international dilemma. PMID- 25559214 TI - Applying the ideal cardiovascular health metrics to couples: a cross-sectional study in primary care. AB - BACKGROUND: There is little research on overall cardiovascular (CV) health among couples. Our aim was to examine concordance levels for CV health among couples, using the American Heart Association ideal health metrics, and to investigate if the CV health of an individual is associated with that of his or her partner. HYPOTHESIS: There is a positive association between the overall cardiovascular health of an individual and that of his/her partner. METHODS: The Mitchelstown Study is a community-based cohort study of middle-aged Irish adults. Potential couples were identified as 2 study participants living at the same address. This list was cross-referenced with self-reported marital status and telephone number in the electronic patient record. Information on CV health metrics (smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose) was collected using standardized methods. Participants were categorized as ideal, intermediate, or poor for each of the metrics and for overall CV health. The 0- to 14-point CV health metrics score was compared within couples using linear regression. RESULTS: Of 2047 participants, 191 potential couples were identified. We excluded 6 sibling pairs, 1 divorced couple, and 3 couples who self-reported being single. The analysis includes 181 couples. There were significant associations between partners for smoking, diet, blood pressure, cholesterol, and glucose (P < 0.05). No couple had ideal CV health (ie, both partners with 7 ideal metrics). Most couples (n = 127, 69%) were concordant for poor CV health. There was a significant relationship between partners for the CV health metrics score (P < 0.05). CONCLUSIONS: Our results suggest an individual's CV health is associated with that of his or her partner. Therefore, prevention strategies targeting couples and families may be appropriate. PMID- 25559216 TI - External validation of the paediatric risk of malignancy index. AB - OBJECTIVE: This study aimed to validate the paediatric risk of malignancy index (PRMI), as previously published. DESIGN: External validation study. SETTING: Academic hospital: Radboud University Medical Center. POPULATION: Female paediatric patients under the age of 18 years diagnosed with, or treated for, an adnexal mass between January 1999 and October 2013. METHODS: Information was collected on diagnosis, presenting symptoms, and signs and imaging characteristics. The PRMI was calculated for each patient. Sensitivity, specificity, and positive and negative predictive values were calculated, and the results were visualised using a receiver operating characteristic curve (ROC curve). MAIN OUTCOME MEASURES: Histological diagnosis, discriminative performance using the area under the curve (AUC) of the ROC curve and sensitivity and specificity. RESULTS: Seventy-eight patients were included, with a median age of 12 years. A malignant mass was found in 17 patients (21.8%). The PRMI with a cut off value of 7 resulted in a sensitivity of 70.1% (95% CI 44.1-89.6%) and a specificity of 85.3% (95% CI 73.8-93.0%). The area under the ROC curve was 0.868 (95% CI 0.756-0.980). CONCLUSIONS: The PRMI showed less discriminative capacity than originally published, but its performance was still good; however, further prospective validation studies are needed to define whether the model is useful in daily clinical practice. PMID- 25559217 TI - Feasibility of ulnar artery for cardiac catheterization: AJmer ULnar ARtery (AJULAR) catheterization study. AB - BACKGROUND: The ulnar artery is rarely selected for cardiac catheterization despite the expanding use of the transradial access (TRA). We tried to compare default transulnar access (TUA) with TRA in terms of feasibility and safety. MATERIALS AND METHODS: This was a prospective, open label, single center, observational study. We analyzed a total of 410 patients with normal Allen's test, who were then scheduled for coronary angiography through TUA with ad hoc PCI if necessary. Procedures were performed by a single operator who had an adequate transradial experience (>=150 transradial coronary procedures per year) but not trained in transulnar procedures. We analyzed observed findings with a retrospective cohort of patients undergoing TRA angiography under a previous study done at our center. We also performed selective ulnar arteriography of 200 patients, through radial route, to predict the bottlenecks of TUA. OBSERVATIONS: There is no statistically significant difference among the number of attempts made till the successful puncture, the total procedure time and the total fluoroscopy time for either radial or ulnar access angiography by an experienced operator (P > 0.05). However, the time taken in arterial access is statistically significant in the initial learning curve for the same (P < 0.05). On the contrary, the arterial access time, the total procedure time, and the total fluoroscopy time, all are statistically significant for the inexperienced operator (P < 0.05). There is a negligible incidence of nonmaneuverable anatomic obstruction in the real-world scenario in TUA, and so fear of the same should not impede the use of this route. Vasospasm in the use of this route is also not different from the radial route, with the experience of the operator. CONCLUSIONS: For an experienced operator, TUA is a safe and also an effective alternative to TRA in terms of feasibility and safety. PMID- 25559218 TI - Is the new variant RHDV replacing genogroup 1 in Portuguese wild rabbit populations? AB - The Lagovirus rabbit hemorrhagic disease virus (RHDV), a member of the family Caliciviridae, severely affects European rabbit (Oryctolagus cuniculus) populations by causing rabbit hemorrhagic disease (RHD). RHDV is subdivided in six genogroups but, more recently, a new RHDV variant with a unique genetic and antigenic profile emerged. We performed a study in rabbits found dead in the field during 2013 and 2014 in Portugal to determine the prevalence of this new variant versus the classical RHDV. Fifty-seven liver samples were screened for the presence of RHDV and positive samples were genotyped. All cases of RHDV infection were caused by the new variant. The only former genogroup circulating in Portugal, G1, was not detected. We hence conclude that the new RHDV variant is replacing G1 in Portugal, probably due to a selective advantage. This sudden and rapid replacement emphasizes the necessity of continued monitoring of wild rabbit populations. PMID- 25559219 TI - Analysis of exosome purification methods using a model liposome system and tunable-resistive pulse sensing. AB - Exosomes are vesicles which have garnered interest due to their diagnostic and therapeutic potential. Isolation of pure yields of exosomes from complex biological fluids whilst preserving their physical characteristics is critical for downstream applications. In this study, we use 100 nm-liposomes from 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol as a model system as a model system to assess the effect of exosome isolation protocols on vesicle recovery and size distribution using a single-particle analysis method. We demonstrate that liposome size distribution and zeta-potential are comparable to extracted exosomes, making them an ideal model for comparison studies. Four different purification protocols were evaluated, with liposomes robustly isolated by three of them. Recovered yields varied and liposome size distribution was unaltered during processing, suggesting that these protocols do not induce particle aggregation. This leads us to conclude that the size distribution profile and characteristics of vesicles are stably maintained during processing and purification, suggesting that reports detailing how exosomes derived from tumour cells differ in size to those from normal cells are reporting a real phenomenon. However, we hypothesize that larger particles present in most purified exosome samples represent co-purified contaminating non-exosome debris. These isolation techniques are therefore likely nonspecific and may co-isolate non-exosome material of similar physical properties. PMID- 25559220 TI - Digital data acquisition and processing. AB - A flow cytometer is made up of many different subsystems that work together to measure the optical properties of individual cells within a sample. The data acquisition system (also called the data system) is one of these subsystems, and it is responsible for converting the electrical signals from the optical detectors into list-mode data. This unit describes the inner workings of the data system, and provides insight into how the instrument functions as a whole. Some of the information provided in this unit is applicable to everyday use of these instruments, and, at minimum, should make it easier for the reader to assemble a specific data system. With the considerable advancement of electronics technology, it becomes possible to build an entirely functional data system using inexpensive hobbyist-level electronics. This unit covers both analog and digital data systems, but the primary focus is on the more prevalent digital data systems of modern flow cytometric instrumentation. PMID- 25559222 TI - Semi-automated object tracking methods in biological imaging. AB - Time-lapse imaging is a rich data source offering potential kinetic information of cellular activity and behavior. Tracking and extracting measurements of objects from time-lapse datasets are challenges that result from the complexity and dynamics of each object's motion and intensity or the appearance of new objects in the field of view. A wide range of strategies for proper data sampling, object detection, image analysis, and post-analysis interpretation are available. Theory and methods for single-particle tracking, spot detection, and object linking are discussed in this unit, as well as examples with step-by-step procedures for utilizing semi-automated software and visualization tools for achieving tracking results and interpreting this output. PMID- 25559221 TI - Light Sheet Fluorescence Microscopy (LSFM). AB - The development of confocal microscopy techniques introduced the ability to optically section fluorescent samples in the axial dimension, perpendicular to the image plane. These approaches, via the placement of a pinhole in the conjugate image plane, provided superior resolution in the axial (z) dimension resulting in nearly isotropic optical sections. However, increased axial resolution, via pinhole optics, comes at the cost of both speed and excitation efficiency. Light sheet fluorescent microscopy (LSFM), a century-old idea made possible with modern developments in both excitation and detection optics, provides sub-cellular resolution and optical sectioning capabilities without compromising speed or excitation efficiency. Over the past decade, several variations of LSFM have been implemented each with its own benefits and deficiencies. Here we discuss LSFM fundamentals and outline the basic principles of several major light-sheet-based imaging modalities (SPIM, inverted SPIM, multi view SPIM, Bessel beam SPIM, and stimulated emission depletion SPIM) while considering their biological relevance in terms of intrusiveness, temporal resolution, and sample requirements. PMID- 25559224 TI - Whole blood measurement of histone modifications linked to the epigenetic regulation of gene expression. AB - Rapid progress is being made to understand the regulatory mechanisms that underlie the epigenetic control of gene expression through histone modification. It is now recognized that this plays a major role in normal development and disease. This unit describes the application of flow cytometry to the study of epigenetic mechanisms by combining labeling of individual histone modifications and phenotypic markers, and it also discusses practical issues to optimize staining. The focus is on normal blood and samples from leukemia patients, but it can also be applied to cells grown in tissue culture. PMID- 25559223 TI - Quantification of Th1 and Th17 Cells with Intracellular Staining Following PMA/Ionomycin Stimulation. AB - Cytokine-producing cells are at the center of the adaptive immune responses, and quantifying these cells is an important aspect to build understanding of the immune response. In particular, Th1 and Th17 cells have been implicated in the pathogenesis of such diseases as inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. Quantification of Th1 and Th17 cells can provide important information in research of these diseases and other Th1- and Th17-mediated immune disorders. In vitro stimulation of cells followed by surface and intracellular staining, presented here, has the advantage of detecting the cytokines directly instead of relying exclusively on surrogate surface markers which, although showing enrichment for the effector T cells, are not specific markers for the cytokine-producing cells. PMID- 25559225 TI - Application of click chemistry conditions for 5-bromo-2'-deoxyuridine determination through Fenton and related reactions. AB - Mixtures of ascorbate and copper used in certain click chemistry experimental conditions act as oxidizing agents, catalyzing the formation of reactive oxygen species through Fenton and related reactions. Hydroxyl radicals act as chemical nucleases, introducing DNA strand breaks that can be exploited for BrdU immunostaining in place of acid denaturation. This procedure is readily applicable to high content analysis and flow cytometry assays, and provides results comparable to click chemistry EdU cycloaddition and classical BrdU immunodetection. Importantly, this approach allows preservation of labile epitopes such as phosphoproteins. This unit describes an optimized method that successfully employs Fenton chemistry for simultaneous detection of phosphoproteins and BrdU in intact cells. PMID- 25559226 TI - Review of lithium effects on immune cells. AB - One of the remarkable discoveries in the field of psychopharmacology from late 1940s is Lithium (Li) that reminds of old but still gold. It continues to be a distinctive mood stabilizer that matches various standards recommended for mood stabilizers. Apart from this Li is also known to affect immune cell functions. Lithium response and regulations of different immune cells in bipolar patients, related immune disorders are not well defined. Here, we provide an overview of literature with regard to Li's effects on different immune cells. However, the use of Li is currently limited to bipolar disorders and there is no empirical evidence for immune cell disorders. The objective of this article is to provide the evaluations of Li responses towards the different immune cells based on the existing studies. Further, more studies are needed to understand the mechanistic basis and heterogeneous responses of Li's effect in bipolar, also unravel relative immune disorders. PMID- 25559227 TI - Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies. AB - Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment for ulcerative colitis and asthma. Model simulations revealed important differences between plasma and tissues, when evaluated for drug disposition and target suppression. Target concentrations at tissue sites and type (soluble vs membrane-bound), tissue-site binding, and binding affinity are all major determinants of BAb disposition and subsequently target suppression. For the presented case studies, higher doses and/or frequent dosing regimens are required to achieve 80 % target suppression in site specific tissue (the more relevant matrix) as compared to plasma. Site specific target-mediated models may serve to guide the selection of first-in human doses for new BAbs. PMID- 25559228 TI - Chronic obstructive pulmonary disease hospitalisations and mortality in Victoria: analysis of variations by socioeconomic status. AB - OBJECTIVE: This paper analysed chronic obstructive pulmonary disease (COPD) hospitalisations, unplanned readmissions and deaths in Victoria to identify associations with socioeconomic status (SES). METHODS: The data was taken from the Victorian Admitted Episodes Dataset, the Victorian Health Information Surveillance System, the Victorian Burden of Disease Study and the Australian Bureau of Statistics' Index of Relative Socioeconomic Disadvantage. RESULTS: COPD separations have a greater variation by SES than all separations. The average age standardised separation rate (10.43) for the top percentile Local Government Areas (LGA) was 5.8 times that of the bottom percentile LGAs (1.80). The top percentile group was the lowest SES group (effect size = 0.93). There were significant negative correlations between the age-standardised COPD separation rates and SES across LGAs (r = -0.60) and Regions (r = -0.89). Analysis of readmissions (r = -0.49), mortality data (r = -0.51) and the burden of disease data (r = -0.39) also showed significant inverse associations between COPD and SES. CONCLUSIONS AND IMPLICATIONS: Victorians living in the most disadvantaged areas have a greater burden from COPD, highlighting a need to prioritise public health services interventions to improve outcomes. PMID- 25559229 TI - Cervical Expression of Elafin and SLPI in Pregnancy and Their Association With Preterm Labor. AB - PROBLEM: Elafin and secretory leukocyte peptidase inhibitor (SLPI) are unique among antimicrobial peptides (AMPs). This study aimed to determine the expression levels of these AMPs at the cervix during pregnancy and to investigate their association with preterm labor. METHOD OF STUDY: Cervical epithelial cells were swabbed from normal pregnant women to evaluate the physiological expression of elafin and SLPI. Cross-sectional analysis was conducted to compare cervical expression levels for SLPI and elafin among three women's groups, controls (n = 26), women with threatened preterm labor who delivered at term (t-TPL, n = 23) and TPL who ended in preterm labor (p-TPL, n = 19). RESULTS: Elafin and SLPI proteins were detected in the squamous and glandular cells of the cervix. Cervical SLPI expression levels increased over the course of pregnancy, whereas elafin levels remained unchanged. Cervical mRNA expression levels of elafin and SLPI were significantly higher in p-TPL compared with t-TPL and control groups. CONCLUSION: Constitutive expression of elafin and SLPI in cervical cells during pregnancy suggests their essential roles in local tissue homeostasis and immune defense. The elevations in cervical elafin and SLPI expression in the women with preterm delivery might reflect the local response to the pathogen invasion into the cervix preceding preterm labor. PMID- 25559230 TI - Hepatocellular carcinoma: diagnostic performance of multidetector CT and MR imaging-a systematic review and meta-analysis. AB - PURPOSE: To perform a systematic review and meta-analysis of the diagnostic performance of computed tomography (CT) and magnetic resonance (MR) imaging as noninvasive modalities for evaluating hepatocellular carcinoma (HCC) in patients with chronic liver disease. MATERIALS AND METHODS: A search of the MEDLINE, EMBASE, and Cochrane Library databases was performed to identify studies providing per-patient or per-lesion diagnostic accuracies of multidetector CT and MR imaging for HCCs in patients with chronic liver disease. Studies published from January 2000 to December 2012 that used a reference standard based on histopathologic findings and/or findings at follow-up were included. Summary estimates of diagnostic accuracy were obtained by using a random-effects model with further exploration with meta-regression and subgroup analyses. RESULTS: Forty studies (six on multidetector CT, 22 on MR imaging, and 12 on both CT and MR imaging) were included. The studies evaluated a total of 1135 patients with multidetector CT and 2489 patients with MR imaging. The overall per-patient sensitivity of MR imaging was 88% (95% confidence interval [CI]: 83%, 92%), with a specificity of 94% (95% CI: 85%, 98%). The overall per-lesion sensitivity of MR imaging was higher than that of multidetector CT when the paired data of the 11 available studies were pooled (80% vs 68%, P = .0023). Gadoxetic acid-enhanced MR imaging showed significantly higher per-lesion sensitivity than MR imaging performed with other contrast agents (87% vs 74%, P = .03). Per-lesion sensitivity was significantly lower for HCCs smaller than 1 cm than that for HCCs 1 cm or larger (P < .001 for CT, P = .02 for MR imaging) and for those in explanted livers (P = .04 for CT, P < .001 for MR imaging). CONCLUSION: MR imaging showed higher per-lesion sensitivity than multidetector CT and should be the preferred imaging modality for the diagnosis of HCCs in patients with chronic liver disease. PMID- 25559231 TI - Dynamic Contrast-enhanced MR Imaging Curve-type Analysis: Is It Helpful in the Differentiation of Prostate Cancer from Healthy Peripheral Zone? AB - PURPOSE: To evaluate the performance and interobserver agreement of qualitative dynamic contrast material enhanced magnetic resonance (MR) imaging curve analysis as described in the Prostate Imaging Reporting and Data System (PI-RADS) for the differentiation of prostate cancer (PCa) from healthy prostatic tissue in the peripheral zone (PZ). MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant institutional review board-approved retrospective analysis included 120 consecutive pretreatment dynamic contrast enhanced (DCE) MR imaging PCa examinations. Regions of interest (ROIs) were placed in 251 spots, including 95 (37.8%) in healthy PZ tissue and 156 (62.2%) in PCa, by using detailed histologic-multiparametric MR correlation review. Three radiologists reviewed the DCE time curves and assessed qualitative curve types as described in PI-RADS: type 1 (progressive), type 2 (plateau), or type 3 (washout). Receiver operating characteristic curve analysis was used to assess accuracy in differentiating PCa from healthy tissue on the basis of curve type, and kappa was calculated to assess interobserver agreement. RESULTS: Receiver operating characteristic curves were similar for all observers, but mean areas under the receiver operating characteristic curve were poor (0.58 +/- 0.04 [standard deviation] to 0.63 +/- 0.04). No differences in accuracy were seen for varying DCE time resolution and imaging length. Observer agreement in assessment of type 3 versus types 1 or 2 curves was substantial (0.66 < kappa < 0.79), better for PCa ROIs than for healthy-tissue ROIs. The agreement between type 1 and type 2 curves was moderate to substantial (0.49 < kappa < 0.78). CONCLUSION: Qualitative DCE MR imaging time-curve-type analysis performs poorly for differentiation of PCa from healthy prostatic tissue. Interobserver agreement is excellent in assessment of type 3 curves but only moderate for type 1 and 2 curves. PMID- 25559232 TI - Collateral vessels in proximal middle cerebral artery occlusion: the ENDOSTROKE study. AB - PURPOSE: To determine the impact of collateral vessel status on clinical and imaging outcomes in patients undergoing endovascular therapy (EVT) for proximal middle cerebral artery (MCA) occlusion. MATERIALS AND METHODS: There were 160 patients with proximal MCA occlusion at six centers in this institutional review board-approved multicenter EVT registry. Angiograms were analyzed at a blinded core laboratory, and collateral vessel status was assessed by using the American Society of Interventional and Therapeutic Neuroradiology (ASITN)/Society of Interventional Radiology (SIR) collateral vessel grading system, while reperfusion was assessed by using the Thrombolysis in Cerebral Infarction (TICI) scale. Good outcome was defined as a modified Rankin Scale score of 0-2 at follow up. Binary logistic regression analysis was performed by using parameters with P < .2 in univariate analysis. RESULTS: Good clinical outcome was attained in 62 (39%) of the 160 patients, and TICI 2b-3 reperfusion was achieved in 94 (59%) patients. Nineteen patients had ASITN/SIR collateral vessel grades of 0 or 1, 63 patients had a grade of 2, and 78 patients had grades of 3 or 4. Better collateral vessels were associated with higher reperfusion rates (21%, 48%, and 77% for ASITN/SIR grades of 0 or 1, 2, and 3 or 4, respectively; P < .001), a higher proportion of infarcts smaller than one-third of the MCA territory (32%, 48%, and 69% for ASITN/SIR grades of 0 or 1, 2, and 3 or 4, respectively; P < .001), and a higher proportion of good clinical outcome (11%, 35%, and 49% for ASITN/SIR grades of 0 or 1, 2, and 3 or 4, respectively; P = .007). At multivariable analysis, collateral vessel status independently predicted reperfusion, final infarct size, and clinical outcome. Within an onset-to treatment time (OTT) of 0-3 hours, collateral vessel status predicted final infarct size and reperfusion. Within an OTT of 3-6 hours, it additionally predicted clinical outcome, with 53% of patients with ASITN/SIR grades of 3 or 4 having a good outcome, as compared with 0% of patients with grades of 0 or 1 and 27% of patients with a grade of 2 (P = .008). CONCLUSION: In this patient population, collateral vessel status independently predicted the pivotal outcome parameters of reperfusion, infarct size, and clinical outcome. These data underscore the utility of patient selection for EVT on the basis of collateral vessel status. PMID- 25559233 TI - Automated Quantification of Right Ventricular Fat at Contrast-enhanced Cardiac Multidetector CT in Arrhythmogenic Right Ventricular Cardiomyopathy. AB - PURPOSE: To evaluate an automated method for the quantification of fat in the right ventricular (RV) free wall on multidetector computed tomography (CT) images and assess its diagnostic value in arrhythmogenic RV cardiomyopathy (ARVC). MATERIALS AND METHODS: This study was approved by the institutional review board, and all patients gave informed consent. Thirty-six patients with ARVC (mean age +/- standard deviation, 46 years +/- 15; seven women) were compared with 36 age- and sex-matched subjects with no structural heart disease (control group), as well as 36 patients with ischemic cardiomyopathy (ischemic group). Patients underwent contrast material-enhanced electrocardiography-gated cardiac multidetector CT. A 2-mm-thick RV free wall layer was automatically segmented and myocardial fat, expressed as percentage of RV free wall, was quantified as pixels with attenuation less than -10 HU. Patient-specific segmentations were registered to a template to study fat distribution. Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic value of fat quantification by using task force criteria as a reference. RESULTS: Fat extent was 16.5% +/- 6.1 in ARVC and 4.6% +/- 2.7 in non-ARVC (P < .0001). No significant difference was observed between control and ischemic groups (P = .23). A fat extent threshold of 8.5% of RV free wall was used to diagnose ARVC with 94% sensitivity (95% confidence interval [CI]: 82%, 98%) and 92% specificity (95% CI: 83%, 96%). This diagnostic performance was higher than the one for RV volume (mean area under the ROC curve, 0.96 +/- 0.02 vs 0.88 +/- 0.04; P = .009). In patients with ARVC, fat correlated to RV volume (R = 0.63, P < .0001), RV function (R = -0.67, P = .001), epsilon waves (R = 0.39, P = .02), inverted T waves in V1-V3 (R = 0.38, P = .02), and presence of PKP2 mutations (R = 0.59, P = .02). Fat distribution differed between patients with ARVC and those without, with posterolateral RV wall being the most ARVC-specific area. CONCLUSION: Automated quantification of RV myocardial fat on multidetector CT images is feasible and performs better than RV volume in the diagnosis of ARVC. Online supplemental material is available for this article. PMID- 25559234 TI - Mammographic breast density: comparison of methods for quantitative evaluation. AB - PURPOSE: To evaluate the results from two software tools for measurement of mammographic breast density and compare them with observer-based scores in a large cohort of women. MATERIALS AND METHODS: Following written informed consent, a data set of 36 281 mammograms from 8867 women were collected from six United Kingdom centers in an ethically approved trial. Breast density was assessed by one of 26 readers on a visual analog scale and with two automated density tools. Mean differences were calculated as the mean of all the individual percentage differences between each measurement for each case (woman). Agreement in total breast volume, fibroglandular volume, and percentage density was assessed with the Bland-Altman method. Association with observer's scores was calculated by using the Pearson correlation coefficient (r). RESULTS: Correlation between the Quantra and Volpara outputs for total breast volume was r = 0.97 (P < .001), with a mean difference of 43.5 cm(3) for all cases representing 5.0% of the mean total breast volume. Correlation of the two measures was lower for fibroglandular volume (r = 0.86, P < .001). The mean difference was 30.3 cm(3) for all cases representing 21.2% of the mean fibroglandular tissue volume result. Quantra gave the larger value and the difference tended to increase with volume. For the two measures of percentage volume density, the mean difference was 1.61 percentage points (r = 0.78, P < .001). Comparison of observer's scores with the area-based density given by Quantra yielded a low correlation (r = 0.55, P < .001). Correlations of observer's scores with the volumetric density results gave r values of 0.60 (P < .001) and 0.63 (P < .001) for Quantra and Volpara, respectively. CONCLUSION: Automated techniques for measuring breast density show good correlation, but these are poorly correlated with observer's scores. However automated techniques do give different results that should be considered when informing patient personalized imaging. ((c)) RSNA, 2015 Clinical trial registration no. ISRCTN 73467396. PMID- 25559235 TI - Repeated Hepatic Resection versus Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma after Hepatic Resection: A Propensity Score Matching Study. AB - PURPOSE: To compare the long-term outcomes of repeated hepatic resection and radiofrequency (RF) ablation for recurrent hepatocellular carcinoma (HCC) by using propensity score matching. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. Thirty-nine patients who underwent repeated hepatic resection and 178 who underwent RF ablation for recurrent HCC (mean tumor size +/ standard deviation, 1.8 cm +/- 0.7) between November 1994 and December 2012 were included in the study. Patients ranged in age from 24 to 85 years (mean, 54.9 years). Men ranged in age from 25 to 85 years (mean, 54.8 years), and women ranged in age from 24 to 76 years (mean, 55.4 years). A 1:2 repeated hepatic resection group-RF ablation group matching was done by using propensity score matching. The overall survival (OS) and disease-free survival (DFS) were compared before and after propensity score matching. Complications were assessed. RESULTS: Before matching, OS rates at 1, 3, 5, and 8 years were 88.8%, 88.8%, 83.9%, and 56.3%, respectively, with repeated hepatic resection and 98.9%, 82.5%, 71.0%, and 58.3% for RF ablation. DFS rates at 1, 3, and 5 years were 66.1%, 48.5%, and 43.1% for repeated hepatic resection and 70.1%, 40.8%, and 30.0% for RF ablation. After matching, the OS rates at 1, 3, 5, and 8 years were 98.7%, 85.7%, 72.1%, and 68.6%, respectively, and the DFS rates at 1, 3, and 5 years were 71.8%, 45.1%, and 39.4% in the RF ablation group (n = 78). Neither the OS nor DFS rate was significantly different between the two groups before matching (P = .686 and P = .461) and after matching (P = .834 and P = .960). The postoperative mortality rate was 2.6% in the repeated hepatic resection group and 0% in the RF ablation group. CONCLUSION: The long-term OS and DFS were not significantly different between repeated hepatic resection and RF ablation for patients with recurrent HCC after hepatic resection. PMID- 25559236 TI - Pharmaceutical HIV prevention technologies in the UK: six domains for social science research. AB - The development of pharmaceutical HIV prevention technologies (PPTs) over the last five years has generated intense interest from a range of stakeholders. There are concerns that these clinical and pharmaceutical interventions are proceeding with insufficient input of the social sciences. Hence key questions around implementation and evaluation remain unexplored whilst biomedical HIV prevention remains insufficiently critiqued or theorised from sociological as well as other social science perspectives. This paper presents the results of an expert symposium held in the UK to explore and build consensus on the role of the social sciences in researching and evaluating PPTs in this context. The symposium brought together UK social scientists from a variety of backgrounds. A position paper was produced and distributed in advance of the symposium and revised in the light this consultation phase. These exchanges and the emerging structure of this paper formed the basis for symposium panel presentations and break-out sessions. Recordings of all sessions were used to further refine the document which was also redrafted in light of ongoing comments from symposium participants. Six domains of enquiry for the social sciences were identified and discussed: self, identity and personal narrative; intimacy, risk and sex; communities, resistance and activism; systems, structures and institutions; economic considerations and analyses; and evaluation and outcomes. These are discussed in depth alongside overarching consensus points for social science research in this area as it moves forward. PMID- 25559237 TI - Reduced retinal nerve fibre layer thickness in children with severe obesity. AB - BACKGROUND: Some optic nerve diseases are silent and insidious. Recently, reduced thickness of retinal nerve fibre layer (RNFL) has been associated with increasing body mass index in adults. OBJECTIVES: To investigate the association of childhood obesity with RNFL measured by optical coherence tomography imaging. METHODS: Ninety-seven children aged 5-14 years classified according to standard deviation score of body mass index (SDS-BMI) were included. Parameters of metabolic risk, adipocytokines (leptin, adiponectin) and interleukin-6 were analyzed. All subjects underwent a comprehensive ophthalmologic examination with direct ophthalmoscopy. Evaluation of RNFL with optical coherence tomography of the head of the nerve was performed. RESULTS: RNFL thickness on the average and inferior, superior and nasal quadrants were decreased in severely obese children (SDS-BMI > 4) with respect to the other groups. However, no statistically significant association was found between the different groups of children and RNFL thickness in the temporal quadrant. There was a significant inverse correlation of RNFL thickness with adiposity indices (P = 0.016), leptin (P = 0.029) and interleukin-6 (P = 0.030) in overweight and obese children. CONCLUSIONS: These findings suggest that adiposity and obesity-related inflammatory factors may be associated with the loss of retinal ganglion cells in children. PMID- 25559238 TI - Association between dietary whole grain intake and risk of mortality: two large prospective studies in US men and women. AB - IMPORTANCE: Higher intake of whole grains has been associated with a lower risk of major chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease (CVD), although limited prospective evidence exists regarding whole grains' association with mortality. OBJECTIVE: To examine the association between dietary whole grain consumption and risk of mortality. DESIGN, SETTING, AND PARTICIPANTS: We investigated 74 341 women from the Nurses' Health Study (1984 2010) and 43 744 men from the Health Professionals Follow-Up Study (1986-2010), 2 large prospective cohort studies. All patients were free of CVD and cancer at baseline. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for total mortality and mortality due to CVD and cancer according to quintiles of whole grain consumption, which was updated every 2 or 4 years by using validated food frequency questionnaires. RESULTS: We documented 26 920 deaths during 2 727 006 person-years of follow-up. After multivariate adjustment for potential confounders, including age, smoking, body mass index, physical activity, and modified Alternate Healthy Eating Index score, higher whole grain intake was associated with lower total and CVD mortality but not cancer mortality: the pooled HRs for quintiles 1 through 5, respectively, of whole grain intake were 1 (reference), 0.99 (95% CI, 0.95-1.02), 0.98 (95% CI, 0.95-1.02), 0.97 (95% CI, 0.93-1.01), and 0.91 (95% CI, 0.88-0.95) for total mortality (P fortrend < .001); 1 (reference), 0.94 (95% CI, 0.88-1.01), 0.94 (95% CI, 0.87-1.01), 0.87 (95% CI, 0.80-0.94), and 0.85 (95% CI, 0.78-0.92) for CVD mortality (P fortrend < .001); and 1 (reference), 1.02 (95% CI, 0.96-1.08), 1.05 (95% CI, 0.99-1.12), 1.04 (95% CI, 0.98-1.11), and 0.97 (95% CI, 0.91-1.04) for cancer mortality (P fortrend = .43). We further estimated that every serving (28 g/d) of whole grain consumption was associated with a 5% (95% CI, 2%-7%) lower total morality or a 9% (95% CI, 4% 13%) lower CVD mortality, whereas the same intake level was nonsignificantly associated with lower cancer mortality (HR, 0.98; 95% CI, 0.94-1.02). Similar inverse associations were observed between bran intake and CVD mortality, with a pooled HR of 0.80 (95% CI, 0.73-0.87; P fortrend < .001), whereas germ intake was not associated with CVD mortality after adjustment for bran intake. CONCLUSIONS AND RELEVANCE: These data indicate that higher whole grain consumption is associated with lower total and CVD mortality in US men and women, independent of other dietary and lifestyle factors. These results are in line with recommendations that promote increased whole grain consumption to facilitate disease prevention. PMID- 25559239 TI - Plasma phospholipids, non-esterified plasma polyunsaturated fatty acids and oxylipids are associated with BMI. AB - The obese lipid profile is associated with increased free fatty acids and triacylglycerides. Currently, little is known about the plasma lipid species associated with obesity. In this study, we compared plasma lipid fatty acid (FA) profiles as a function of BMI. Profiling phospholipid (PL) FAs and their respective oxylipids could predict which obese individuals are more likely to suffer from diseases associated with chronic inflammation or oxidative stress. We investigated the relationship between BMI and plasma PL (PPL) FA composition in 126 men using a quantitative gas chromatography analysis. BMI was inversely associated with both PPL nervonic and linoleic acid (LA) but was positively associated with both dihomo-gamma-linolenic and palmitoleic acid. Compared to lean individuals, obese participants were more likely to have omega-6 FAs, except arachidonic acid and LA, incorporated into PPLs. Obese participants were less likely to have EPA and DHA incorporated into PPLs compared to lean participants. Non-esterified plasma PUFA and oxylipid analysis showed omega-6 oxylipids were more abundant in the obese plasma pool. These omega-6 oxylipids are associated with increased angiogenesis (i.e. epoxyeicosatrienoates), reactive oxygen species (i.e. 9-hydroxyeicosatetraenoate), and inflammation resolution (i.e. Lipoxin A4). In summary, BMI is directly associated with specific PPL FA and increased omega-6 oxylipids. PMID- 25559240 TI - The free fractions of circulating docosahexaenoic acid and eicosapentenoic acid as optimal end-point of measure in bioavailability studies on n-3 fatty acids. AB - The high complexity of n-3 fatty acids absorption process, along with the huge amount of endogenous fraction, makes bioavailability studies with these agents very challenging and deserving special consideration. In this paper we report the results of a bioequivalence study between a new formulation of EPA+DHA ethyl esters developed by IBSA Institut Biochimique and reference medicinal product present on the Italian market. Bioequivalence was demonstrated according to the criteria established by the EMA Guideline on the Investigation of Bioequivalence. We found that the free fractions represent a better and more sensitive end-point for bioequivalence investigations on n-3 fatty acids, since: (i) the overall and intra-subject variability of PK parameters was markedly lower compared to the same variability calculated on the total DHA and EPA fractions; (ii) the absorption process was completed within 4h, and the whole PK profile could be drawn within 12-15 h from drug administration. PMID- 25559241 TI - Asymmetric synthesis of 3-azide-4-fluoro-l-phenylalanine. AB - The asymmetric synthesis of N-Fmoc-protected 3-azide-4-fluoro-l-phenylalanine as a photoactive phenylalanine analog has been achieved by Schollkopf's alkylation. PMID- 25559242 TI - Time-dependence of 137Cs activity concentration in wild game meat in Knyszyn Primeval Forest (Poland). AB - Wild game meat samples were analysed from the region of the Podlasie province (Knyszyn Primeval Forest). (137)Cs content in meat was determined by gamma spectrometry in 2003 (33 samples), 2009 (22 samples) and 2012 (26 samples). The samples were collected in the autumn of 2003, 2009 and 2012 and were compared with data from 1996. Mean concentrations of (137)Cs in the respective years were as follow: 42.2 Bq kg(-1), 33.7 Bq kg(-1) and 30.5 Bq kg(-1), respectively. On the basis of mean values of (137)Cs in the meat samples of red deer (Cervus elaphus), roe deer (Capreolus capreolus) and wild boars (Sus scrofa) between 1996/2012, the effective half-life of (137)Cs was determined for specific species. For red deer equaled 8.9 years, for roe deer 11.6 years while for wild boar it exceeded the physical half-life and equaled 38.5 years. Mean value CR obtained for all three species equaled 1.7 +/- 1.5 out of 102 measurements in animals muscles. PMID- 25559243 TI - Preventive effect of yuzu and hesperidin on left ventricular remodeling and dysfunction in rat permanent left anterior descending coronary artery occlusion model. AB - Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, alpha-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium. PMID- 25559245 TI - Diagnostic accuracy of computed tomography angiography for the detection of coronary artery disease in patients referred for transcatheter aortic valve implantation. AB - OBJECTIVES: We aimed to investigate the diagnostic accuracy of a standardized computed tomography angiography (CTA) for the identification of significant coronary artery disease (CAD) in patients evaluated for transcatheter aortic valve implantation (TAVI). BACKGROUND: The diagnostic performance of CTA for the detection of CAD in patients with aortic stenosis referred for TAVI has thus far not been validated. METHODS: A consecutive series of 475 patients (194 male, mean age: 82 +/- 6 years) with CTA data sets obtained during the routine diagnostic work-up before TAVI were included. A total of 6,603 coronary segments in 1,899 coronary arteries >= 1.5 mm in diameter and 271 grafts were evaluated for the presence of significant CAD defined as >= 50% luminal narrowing. Results were compared with invasive coronary angiography as the standard of reference. RESULTS: Prevalence of significant CAD was 57% (270/475), and 5,925 coronary segments (90%) and 257 bypass grafts (95%) were evaluable by CTA. In the per patient analysis, sensitivity (Se), specificity, and positive and negative predictive values (NPV) were 98, 37, 67 and 94%, respectively. CTA showed satisfactory ability to exclude significant CAD in the following subgroups: (1) patients (221/475) without prior known CAD (Se: 97%, NPV: 97%), (2) patients (13/475) without prior known CAD and absent coronary calcification (NPV: 100%) and (3) bypass grafts (Se: 97%, NPV: 99%). CONCLUSIONS: Comprehensive evaluation of a pre-TAVI CTA could prove to be a useful rule-out test for significant CAD in selected subgroups of patients. PMID- 25559244 TI - Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer. AB - BACKGROUND: Epigallocatechin-3-gallate (EGCG) has been demonstrated to inhibit cancer in experimental studies through its antioxidant activity and modulations on cellular functions by binding specific proteins. We demonstrated previously that EGCG upregulates the expression of microRNA (i.e. miR-210) by binding HIF 1alpha, resulting in reduced cell proliferation and anchorage-independent growth. However, the binding affinities of EGCG to HIF-1alpha and many other targets are higher than the EGCG plasma peak level in experimental animals administered with high dose of EGCG, raising a concern whether the microRNA regulation by HIF 1alpha is involved in the anti-cancer activity of EGCG in vivo. RESULTS: We employed functional genomic approaches to elucidate the role of microRNA in the EGCG inhibition of tobacco carcinogen-induced lung tumors in A/J mice. By analysing the microRNA profiles, we found modest changes in the expression levels of 21 microRNAs. By correlating these 21 microRNAs with the mRNA expression profiles using the computation methods, we identified 26 potential targeted genes of the 21 microRNAs. Further exploration using pathway analysis revealed that the most impacted pathways of EGCG treatment are the regulatory networks associated to AKT, NF-kappaB, MAP kinases, and cell cycle, and the identified miRNA targets are involved in the networks of AKT, MAP kinases and cell cycle regulation CONCLUSIONS: These results demonstrate that the miRNA-mediated regulation is actively involved in the major aspects of the anti-cancer activity of EGCG in vivo. PMID- 25559247 TI - The absorbed dose to blood from blood-borne activity. AB - The radiation absorbed dose to blood and organs from activity in the blood is relevant for nuclear medicine dosimetry and for research in biodosimetry. The present study provides coefficients for the average absorbed dose rates to the blood from blood-borne activity for radionuclides frequently used in targeted radiotherapy and in PET diagnostics. The results were deduced from published data for vessel radius-dependent dose rate coefficients and reasonable assumptions on the blood-volume distribution as a function of the vessel radius. Different parts of the circulatory system were analyzed separately. Vessel size information for heart chambers, aorta, vena cava, pulmonary artery, and capillaries was taken from published results of morphometric measurements. The remaining blood not contained in the mentioned vessels was assumed to reside in fractal-like vascular trees, the smallest branches of which are the arterioles or venules. The applied vessel size distribution is consistent with recommendations of the ICRP on the blood-volume distribution in the human. The resulting average absorbed dose rates to the blood per nuclear disintegration per milliliter (ml) of blood are (in 10( 11) Gy.s(-1).Bq(-1).ml) Y-90: 5.58, I-131: 2.49, Lu-177: 1.72, Sm-153: 2.97, Tc 99m: 0.366, C-11: 4.56, F-18: 3.61, Ga-68: 5.94, I-124: 2.55. Photon radiation contributes 1.1-1.2.10(-11) Gy.s(-1).Bq(-1).ml to the total dose rate for positron emitters but significantly less for the other nuclides. Blood self absorption of the energy emitted by beta-particles in the whole blood ranges from 37% for Y-90 to 80% for Tc-99m. The correspondent values in vascular trees, which are important for the absorbed dose to organs, range from 30% for Y-90 to 82% for Tc-99m. PMID- 25559246 TI - Improved antiparasitic activity by incorporation of organosilane entities into half-sandwich ruthenium(II) and rhodium(III) thiosemicarbazone complexes. AB - A series of ferrocenyl- and aryl-functionalised organosilane thiosemicarbazone compounds was obtained via a nucleophilic substitution reaction with an amine terminated organosilane. The thiosemicarbazone (TSC) ligands were further reacted with either a ruthenium dimer [(eta(6-i)PrC6H4Me)Ru(MU-Cl)Cl]2 or a rhodium dimer [(Cp*)Rh(MU-Cl)Cl]2 to yield a series of cationic mono- and binuclear complexes. The thiosemicarbazone ligands, as well as their metal complexes, were characterised using NMR and IR spectroscopy, and mass spectrometry. The molecular structure of the binuclear ruthenium(ii) complex was determined by single-crystal X-ray diffraction analysis. The thiosemicarbazones and their complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine sensitive (NF54) and chloroquine-resistant (Dd2) Plasmodium falciparum strains, displaying activities in the low micromolar range. Selected compounds were screened for potential beta-haematin inhibition activity, and it was found that two Rh(iii) complexes exhibited moderate to good inhibition. Furthermore, the compounds were screened for their antitrichomonal activities against the G3 Trichomonas vaginalis strain, revealing a higher percentage of growth inhibition for the ruthenium and rhodium complexes over their corresponding ligand. PMID- 25559248 TI - High-level expression and one-step purification of a soluble recombinant human interleukin-37b in Escherichia coli. AB - Interleukin (IL)-37 is a novel member of the IL-1 cytokine family. However, as a result of lacking efficient method to generate relatively large quantity of IL 37, little is known of its functions in man. In the present study, the recombinant human IL-37b containing a C-hexahistidine tag was expressed in Escherichia coli (E. coli). The expression level of IL-37b in E. coli was very high after induction with IPTG. Furthermore, IL-37b protein was largely found in the soluble fraction. The expressed protein was readily purified by one-step immobilized metal-ion affinity chromatography using Ni(2+)-nitrilotriacetic acid agarose. The purified IL-37b appeared as a single band on SDS-PAGE and the purity was more than 97%. The yield was 90mg IL-37b from 1l of bacterial culture. Western blotting and N-terminal sequencing confirmed the identity of the purified protein. The purified IL-37b inhibited significantly the release of tumor necrosis factor-alpha and IL-1beta in lipopolysaccharide-activated THP-1 cells. Thus, this method provides an efficient way to obtain an active IL-37 with high yield and high purity. PMID- 25559249 TI - Neuromuscular and athletic performance following core strength training in elite youth soccer: Role of instability. AB - Cross-sectional studies revealed that inclusion of unstable elements in core strengthening exercises produced increases in trunk muscle activity and thus potential extra stimuli to induce more pronounced performance enhancements in youth athletes. Thus, the purpose of the study was to investigate changes in neuromuscular and athletic performance following core strength training performed on unstable (CSTU) compared with stable surfaces (CSTS) in youth soccer players. Thirty-nine male elite soccer players (age: 17 +/- 1 years) were assigned to two groups performing a progressive core strength-training program for 9 weeks (2-3 times/week) in addition to regular in-season soccer training. CSTS group conducted core exercises on stable (i.e., floor, bench) and CSTU group on unstable (e.g., Thera-Band(r) Stability Trainer, Togu(c) Swiss ball) surfaces. Measurements included tests for assessing trunk muscle strength/activation, countermovement jump height, sprint time, agility time, and kicking performance. Statistical analysis revealed significant main effects of test (pre vs post) for trunk extensor strength (5%, P < 0.05, d = 0.86), 10-20-m sprint time (3%, P < 0.05, d = 2.56), and kicking performance (1%, P < 0.01, d = 1.28). No significant Group * test interactions were observed for any variable. In conclusion, trunk muscle strength, sprint, and kicking performance improved following CSTU and CSTS when conducted in combination with regular soccer training. PMID- 25559250 TI - Perceived workplace health support is associated with employee productivity. AB - PURPOSE: To examine the relationship between perceived workplace health support and employee productivity. DESIGN: A quantitative cross-sectional study. SETTING: Washington State agencies. SUBJECTS: A total of 3528 employees from six state agencies were included in this analysis. MEASURES: Perceived workplace health support was assessed by two questions that queried respondents on how often they felt supported by the workplace for healthy living and physical activity. The Work Productivity and Activity Impairment Questionnaire was used to measure health-related absenteeism and presenteeism in the past 7 days. ANALYSIS: Multivariate linear regression was used to estimate the mean differences in productivity by levels of perceived health support. RESULTS: Most participants were between 45 and 64 years of age and were predominantly non-Hispanic white. Presenteeism varied significantly by the level of perceived workplace health support, with those who felt least supported having higher presenteeism than those who felt most supported. The difference in presenteeism by perceived workplace support remained significant in models adjusting for sociodemographic and health characteristics (mean difference: 7.1% for support for healthy living, 95% confidence interval: 3.7%, 10.4%; 4.3% for support for physical activity, 95% confidence interval: 1.7%, 6.8%). Absenteeism was not associated with perceived workplace health support. CONCLUSION: Higher perceived workplace health support is independently associated with higher work productivity. Employers may see productivity benefit from wellness programs through improved perceptions of workplace health support. PMID- 25559251 TI - An evaluation of the Well at Dell health management program: health risk change and financial return on investment. AB - PURPOSE: To investigate the effectiveness of the Well at Dell comprehensive health management program in delivering health care and productivity cost savings relative to program investment (i.e., return on investment). DESIGN: A quasi experimental design was used to quantify the financial impact of the program and nonexperimental pre-post design to evaluate change in health risks. SETTING: Ongoing worksite health management program implemented across multiple U.S. locations. SUBJECTS: Subjects were 24,651 employees with continuous medical enrollment in 2010-2011 who were eligible for 2011 health management programming. INTERVENTION: Incentive-driven, outcomes-based multicomponent corporate health management program including health risk appraisal (HRA)/wellness, lifestyle management, and disease management coaching programs. MEASURES: Medical, pharmacy, and short-term disability pre/post expenditure trends adjusted for demographics, health status, and baseline costs. Self-reported health risks from repeat HRA completers. Analysis: Propensity score-weighted and multivariate regression-adjusted comparison of baseline to post trends in health care expenditures and productivity costs for program participants and nonparticipants (i.e., difference in difference) relative to programmatic investment. RESULTS: The Well at Dell program achieved an overall return on investment of 2.48 in 2011. Most of the savings were realized from the HRA/wellness component of the program. Cost savings were supported with high participation and significant health risk improvement. CONCLUSION: An incentive-driven, well-managed comprehensive corporate health management program can continue to achieve significant health improvement while promoting health care and productivity cost savings in an employee population. PMID- 25559255 TI - Editor's desk: the vision and direction issue. AB - The past is prologue in dramatic story telling as well as in creating a sustainable strategy in a field of study or a profession. PMID- 25559252 TI - The impact of incentives on intrinsic and extrinsic motives for fitness-center attendance in college first-year students. AB - PURPOSE: A criticism of incentives for health behaviors is that incentives undermine intrinsic motivation. The objective of this study was to determine the impact of monetary incentive provision on participation motives for exercise in first-year college students at a northeastern public university. DESIGN: Randomized-controlled trial. SETTING: Public university in the Northeastern United States. SUBJECTS: One hundred seventeen first-year college students. INTERVENTION: Participants were randomized to one of three conditions: a control condition receiving no incentives for meeting fitness-center attendance goals; a discontinued-incentive condition receiving weekly incentives during fall semester 2011, and no incentives during spring semester 2012; or a continued-incentive condition receiving weekly incentives during fall semester, and incentives on a variable-interval schedule during spring semester. MEASURES: The Exercise Motivation Inventory 2 measured exercise participation motives at baseline, end of fall semester, and end of spring semester. Fitness-center attendance was monitored by using ID-card check-in/check-out records. ANALYSIS: Repeated measures analyses using linear mixed models with first-order autoregressive covariance structures were run to compare motive changes in the three conditions. RESULTS: Participation motives of Enjoyment and Revitalization associated with intrinsic motivation did not decrease significantly over time in any of the conditions, F(4, 218) = 2.25, p = .065 and F(4, 220) = 1.67, p = .16, respectively. CONCLUSION: Intrinsically associated participation motives for exercise did not decrease with incentive provision. Therefore, incentives may encourage fitness-center attendance without negatively impacting participation motives for exercise. PMID- 25559256 TI - What is the ROI for workplace health promotion? It really does depend, and that's the point. AB - A recent systematic review of the literature on the financial impact of workplace health promotion found that 46 of 47 programs saved money, 41 saved more than they cost, and that the returns on investment varied greatly based on the quality of the study methodology, year of publication, sample size, scope of the program, direct or indirect measurement of savings and costs, and several other factors. A close examination of the methodology of the single study that reported net financial loss illustrates the complexity of drawing conclusions from summaries of the literature without also examining the details. Next steps in advancing studies of the financial impact of workplace health promotion programs include developing a scale to measure methodology quality that is appropriate for workplace health promotion programs, and engaging independent third parties to evaluate programs. PMID- 25559259 TI - Heterolytic activation of dihydrogen molecule by hydroxo-/sulfido-bridged ruthenium-germanium dinuclear complex. Theoretical insights. AB - Heterolytic activation of dihydrogen molecule (H2) by hydroxo-/sulfido-bridged ruthenium-germanium dinuclear complex [Dmp(Dep)Ge(MU-S)(MU-OH)Ru(PPh3)](+) (1) (Dmp = 2,6-dimesitylphenyl, Dep = 2,6-diethylphenyl) is theoretically investigated with the ONIOM(DFT:MM) method. H2 approaches 1 to afford an intermediate [Dmp(Dep)(HO)Ge(MU-S)Ru(PPh3)](+)-(H2) (2). In 2, the Ru-OH coordinate bond is broken but H2 does not yet coordinate with the Ru center. Then, the H2 further approaches the Ru center through a transition state TS2-3 to afford a dihydrogen sigma-complex [Dmp(Dep)(HO)Ge(MU-S)Ru(eta(2)-H2)(PPh3)](+) (3). Starting from 3, the H-H sigma-bond is cleaved by the Ru and Ge-OH moieties to form [Dmp(Dep)(H2O)Ge(MU-S)Ru(H)(PPh3)](+) (4). In 4, hydride and H2O coordinate with the Ru and Ge centers, respectively. Electron population changes clearly indicate that this H-H sigma-bond cleavage occurs in a heterolytic manner like H2 activation by hydrogenase. Finally, the H2O dissociates from the Ge center to afford [Dmp(Dep)Ge(MU-S)Ru(H)(PPh3)](+) (PRD). This step is rate determining. The activation energy of the backward reaction is moderately smaller than that of the forward reaction, which is consistent with the experimental result that PRD reacts with H2O to form 1 and H2. In the Si analogue [Dmp(Dep)Si(MU-S)(MU-OH)Ru(PPh3)](+) (1Si), the isomerization of 1Si to 2Si easily occurs with a small activation energy, while the dissociation of H2O from the Si center needs a considerably large activation energy. Based on these computational findings, it is emphasized that the reaction of 1 resembles well that of hydrogenase and the use of Ge in 1 is crucial for this heterolytic H-H sigma-bond activation. PMID- 25559257 TI - Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. AB - Foxp3(+) regulatory T cells (Treg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (Tconv cells) and Treg cells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only Tconv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Treg cells was essential for lineage homeostasis and stability. Mice lacking Pten in Treg cells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Treg cells led to reduced expression of the interleukin-2 (IL-2) receptor alpha subunit CD25, accumulation of Foxp3(+)CD25(-) cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Treg cells is critical for maintaining their homeostasis, function and stability. PMID- 25559260 TI - MgO-decorated few-layered graphene as an anode for li-ion batteries. AB - Combustion of magnesium in dry ice and a simple subsequent acid treatment step resulted in a MgO-decorated few-layered graphene (FLG) composite that has a specific surface area of 393 m(2)/g and an average pore volume of 0.9 cm(3)/g. As an anode material in Li-ion batteries, the composite exhibited high reversible capacity and excellent cyclic performance in spite of high first-cycle irreversible capacity loss. A reversible capacity as high as 1052 mAh/g was measured during the first cycle. Even at the end of the 60th cycle, more than 83% of the capacity could be retained. Cyclic voltammetry results indicated pseudocapacitance behavior due to electrochemical absorption and desorption of lithium ions onto graphene. An increase in the capacity has been observed during long-term cycling owing to electrochemical exfoliation of graphene sheets. Owing to its good thermal stability and superior cyclic performance with high reversible capacities, MgO-decked FLG can be an excellent alternative to graphite as an anode material in Li-ion batteries, after suitable modifications. PMID- 25559258 TI - Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. AB - The interplay between effector T cells and regulatory T cells (Treg cells) is crucial for adaptive immunity, but how Treg cells control diverse effector responses is elusive. We found that the phosphatase PTEN links Treg cell stability to repression of type 1 helper T cell (TH1 cell) and follicular helper T cell (TFH cell) responses. Depletion of PTEN in Treg cells resulted in excessive TFH cell and germinal center responses and spontaneous inflammatory disease. These defects were considerably blocked by deletion of interferon-gamma, indicating coordinated control of TH1 and TFH responses. Mechanistically, PTEN maintained Treg cell stability and metabolic balance between glycolysis and mitochondrial fitness. Moreover, PTEN deficiency upregulates activity of the metabolic checkpoint kinase complex mTORC2 and the serine-threonine kinase Akt, and loss of this activity restores functioning of PTEN-deficient Treg cells. Our studies establish a PTEN-mTORC2 axis that maintains Treg cell stability and coordinates Treg cell-mediated control of effector responses. PMID- 25559261 TI - Orthology-driven mapping of bidirectional promoters in human and mouse genomes. AB - BACKGROUND: The presence of bidirectional promoters in all vertebrate species suggests that the promoters may be maintained in orthologous positions. Therefore the identification of the comprehensive orthologous mapping of this type promoter across species can facilitate elucidation of regulatory mechanisms controlling bidirectional gene expression. However, the lack of annotation for many transcribed regions in the genome can impact the orthology designation of these promoters. Human and mouse are among genomes that have been relatively well annotated. Thus we used them as models to study the orthologous patterns of bidirectional promoters. RESULTS: We developed a method to annotate these regulatory regions by confirming the orthology of the genes found on each side of the promoters. In this manuscript we report the cross-species comparisons between human and mouse genomes, where the bidirectional promoter sets regulating UCSC Known Genes and spliced EST annotations were mapped from human to mouse and vice versa. We validate hundreds of orthologous bidirectional promoters through the presence of orthologous flanking gene annotations in the second species. We also show that regulatory activity of these orthologous promoters confers similar gene expression profiles in 21 tissues of human and mouse. In particular, more than one third of human bidirectional promoters annotated from spliced EST annotations regulate ncRNA, of which over 90% are lncRNAs. CONCLUSIONS: Although evolutionary conservation shows a weaker signature in promoters than coding regions, our technique of mapping of orthologous genes shows that most bidirectional promoter arrangements are conserved across human and mouse genomes, suggesting a critical function. In addition, the similar expression patterns of the orthologous gene sets indicate that the regulatory mechanisms remain largely conserved as well. PMID- 25559263 TI - Changes in hearing threshold between 28 and 42 weeks of age in babies born at under 30 weeks of gestation. AB - AIM: This study aimed to describe changes in hearing thresholds in babies born below 30 weeks of gestation at 28-42 weeks of postconceptional age, detect differences between gestational ages and explore the prevalence of hearing impairment. METHODS: The threshold of brainstem auditory evoked response (BAER) was obtained longitudinally at 28-42 weeks of postconceptional age in 71 babies born at 23-29 weeks of gestation. RESULTS: The BAER threshold was 28 decibels above normal hearing level (dB nHL) at 28 weeks of postconceptional age and decreased to 13 dB nHL at 39-42 weeks. The threshold was slightly higher in babies born at 23-26 weeks of gestation than in those born at 27-29 weeks at most postconceptional ages studied. From 28 to 36 weeks, the threshold decreased at 0.98 dB/week. At term, BAER threshold elevation (>20 dB nHL) occurred in 12 (16.9%) of the 71 babies. CONCLUSION: The hearing threshold of babies born at 23 29 weeks of gestation decreased from 28 dB at 28 weeks of postconceptional age to 13 dB at 42 weeks. There were no major differences between gestational ages. During the preterm period, the threshold changed at around 1 dB/week. At term, one in six babies had hearing impairment. PMID- 25559264 TI - Aortic stenosis is largely a boney affair. PMID- 25559265 TI - Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease. AB - Anderson disease (ANDD) or chylomicron retention disease (CMRD) is a rare, hereditary lipid malabsorption syndrome associated with mutations in the SAR1B gene that is characterized by failure to thrive and hypocholesterolemia. Although the SAR1B structure has been resolved and its role in formation of coat protein II (COPII)-coated carriers is well established, little is known about the requirement for SAR1B during embryogenesis. To address this question, we have developed a zebrafish model of Sar1b deficiency based on antisense oligonucleotide knockdown. We show that zebrafish sar1b is highly conserved among vertebrates; broadly expressed during development; and enriched in the digestive tract organs, brain, and craniofacial skeleton. Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes. Transgenic expression analysis revealed that Sar1b is required for growth of exocrine pancreas and liver. Furthermore, we found abnormal differentiation and maturation of craniofacial cartilage associated with defects in procollagen II secretion and absence of select, neuroD-positive neurons of the midbrain and hindbrain. The model presented here will help to systematically dissect developmental roles of Sar1b and to discover molecular and cellular mechanisms leading to organ-specific ANDD pathology. Key messages: Sar1b depletion phenotype in zebrafish resembles Anderson disease deficits. Sar1b deficiency results in multi-organ developmental deficits. Sar1b is required for dietary cholesterol uptake into enterocytes. PMID- 25559266 TI - Activation of the peroxisome proliferator-activated receptor gamma counteracts sepsis-induced T cell cytotoxicity toward alloantigenic target cells. AB - Sepsis still emerges as a major cause of patient death in intensive care units. Therefore, new therapeutic approaches are mandatory. Because during sepsis progression cytotoxic T lymphocytes (CTLs) can be activated in an autoimmune fashion contributing to multiorgan damage, it remains unclear whether CTLs are activated toward alloantigenic cells. This is important for patients receiving an immunosuppressive therapy to permit organ transplantation and, thus, known to be at high risk for developing sepsis. Therefore, we analyzed whether sepsis activates CTL toward alloantigenic target cells and whether this can be inhibited by PPARgamma activation, known to block T helper cell responses. To mimic septic conditions, CTLs were isolated from cecal ligation and puncture-operated mice. CTL cytotoxicity was analyzed following a direct alloantigenic activation regime or following classical ex vivo splenocyte-driven activation in a cytotoxicity assay. With this readout, we found that CTL derived from septic mice enhanced cytotoxicity toward alloantigenic target cells, which was lowered by in vivo and ex vivo PPARgamma activation. With CTL derived from T cell-specific PPARgamma knockout mice, PPARgamma activation was ineffective, pointing to a PPARgamma dependent mechanism. In vivo and ex vivo PPARgamma activation reduced Fas and granzyme B expression in activated CTL. KEY MESSAGE: In the sepsis CLP mouse model, CTLs are activated toward alloantigenic target cells. Sepsis-mediated alloantigenic CTL activation is blocked in vivo by PPARgamma activation. PPARgamma deletion or antagonization restored rosiglitazone-dependent inhibition of CTL cytotoxicity. PPARgamma inhibits the expression of Fas and granzyme B in CTLs. PMID- 25559267 TI - Dynamics of retinal injury after acute optic neuritis. AB - OBJECTIVE: We set out to assess the dynamics of retinal injury after acute optic neuritis (ON) and their association with clinical visual outcomes. METHODS: Thirty-one consecutive patients with acute ON were prospectively analyzed over a 6-month follow-up period. Each month, we used optical coherence tomography (OCT) to assess the thickness of peripapillary retinal nerve fiber layer (pRNFL) and segmented macular layers, as well as high-contrast visual acuity, low-contrast visual acuity (LCVA), color visual acuity (CVA), and visual fields (VF). RESULTS: In this prospective study, we found that 6 months after clinical onset, ON eyes suffered a reduction in pRNFL (-45.3 MUm) and macular thickness (-17.3 MUm). Macular atrophy was due to the decrease of macular RNFL thickness (-7.8 MUm) and that of the ganglion cell layer and inner plexiform layer (GCIP, -11.3 MUm), whereas the thickness of the outer retinal layers increased slightly. The macular RNFL and GCIP thickness decreased in parallel, yet it always occurred more rapidly and more severely for the GCIP. The change in the GCIP thickness in the first month predicted the visual impairment by month 6; a decrease >= of 4.5 MUm predicted poor LCVA (sensitivity of 93% and specificity of 88%), and a decrease of >= 7 MUm predicted poor VF and CVA (sensitivity of 78% and 100% and specificity of 63% and 66%, respectively). INTERPRETATION: Retinal axonal and neuronal damage develops quickly after ON onset. Assessment of ganglion cell layer thickness by OCT after ON onset can be used as an imaging marker of persistent visual disability. PMID- 25559269 TI - Revealing the interactions between pentagon-octagon-pentagon defect graphene and organic donor/acceptor molecules: a theoretical study. AB - Defect engineering and the non-covalent interaction strategy allow for dramatically tuning the optoelectronic features of graphene. Herein, we theoretically investigated the intrinsic mechanism of non-covalent interactions between pentagon-octagon-pentagon (5-8-5) defect graphene (DG) and absorbed molecules, tetrathiafulvalene (TTF), perfluoronaphthalene (FNa), tetracyanoquinodimethane (TCNQ) and 2,3,5,6-tetrafluoro-7,7,8,8 tetracyanoquinodimethane (F4TCNQ), through geometry, distance, interaction energy, Mulliken charge distribution, terahertz frequency vibration, visualization of the interactions, charge density difference, electronic transition behaviour, band structure and density of state. All the calculations were performed using density functional theory including a dispersion correction (DFT-D). The calculated results indicate that the cyano- (CN) group (electron withdraw group) in TCNQ and F4TCNQ, rather than the F group, gain the electron from DG effectively and exhibit much stronger interactions via wavefunction overlap with DG, leading to a short non-covalent interaction distance, a large interaction energy and a red-shift of out-of-plane terahertz frequency vibration, changing the bands near the Fermi level and enhancing the infrared (IR) light absorption significantly. The enhancement of such IR absorbance offering a broader absorption (from 300 to 1200 nm) will benefit light harvesting in potential applications of solar energy conversion. PMID- 25559271 TI - Negative life events predict performance on an executive function task in young adults with developmental disabilities. AB - BACKGROUND: Recent research with typically developing children indicates that chronic stress can be detrimental to the development of executive function. This study extends this work to individuals with developmental disabilities and examines the longitudinal relationship between an indicator of chronic stress, negative life events, and performance on a task of executive function within a group of 30 individuals with early identified developmental disabilities. METHODS: Multilevel modelling was used to analyse the relationship between cumulative negative life events and response time on a Flanker task. RESULTS: As hypothesized, individuals who had experienced more cumulative negative life events in their families demonstrated longer response time, an indicator of less efficient executive function. CONCLUSIONS: The association between cumulative negative life events and executive function for children with developmental disabilities suggests the prominent role of the environment for development in this domain. These findings also suggest the importance of providing services, resources, and interventions that will help families adaptively cope with stressful circumstances. PMID- 25559268 TI - An investigation of factors contributing to higher levels of placebo response in clinical trials in neuropathic pain: a systematic review and meta-analysis. AB - BACKGROUND: In new drug development in neuropathic pain (NeP), randomized, double blind, placebo-controlled trials (PCTs) with long treatment durations in a parallel-group design are recommended for confirmatory trials. OBJECTIVE: This study was conducted to identify potential factors contributing to elevated placebo response in parallel-group PCTs for oral drugs with at least a 4-week treatment duration. METHODS: A literature search was conducted through MEDLINE and EMBASE, and was supplemented with data from ClinicalTrials.gov and US/Japanese regulatory approval review information. Using the 30 or 50 % responder rate (RR), logistic regression analyses were performed to investigate the relationship between the degree of placebo response and several potential influencing factors. RESULTS: The search identified 71 trials (n = 6,126). The estimated 50 % RRs (95 % confidence intervals) in the placebo group were as follows: peripheral neuropathic pain (P-NeP) 23 % (21, 26 %); central neuropathic pain (C-NeP) 14 % (10, 19 %); postherpetic neuralgia (PHN) 19 % (15, 24 %); painful diabetic peripheral neuropathy (pDPN) 26 % (23, 29 %); posttraumatic peripheral neuropathic pain (PT) 15 % (10, 20 %). From the logistic regression analyses, it was found that there was a significant association between placebo response (50 % RR and 30 % RR) and NeP classification (P < 0.05). Associations between placebo response and several factors were seen in univariate logistic regression analyses of 50 % RR. Multivariate analyses showed that age and baseline pain intensity in PHN, and treatment duration, trial design (fixed dose/flexible-dose) and baseline pain intensity in pDPN, were associated with placebo response, suggesting that a reduced placebo response correlated with increasing age and baseline pain intensity, and a higher placebo response correlated with a longer treatment period and flexible dosing regimen. A similar pattern observed in the analysis of 50 % RR was suggested in the analysis of 30 % RR, with the exception of treatment duration. In addition, investigations of trials with at least a 12-week treatment duration in pDPN found associations with the number of patients per site, patient enrolment rate, proportion of male patients and baseline pain intensity, suggesting that a higher placebo response correlated with an increasing number of patients per site, and a reduced placebo response correlated with increasing patient enrolment rate and proportion of male patients and baseline pain intensity. CONCLUSION: The results of this study suggest that NeP condition, trial design, and demographic and baseline characteristics may contribute to elevated placebo response in clinical trials in patients with NeP. In addition, the magnitude of placebo response and the effect of treatment duration are greater in pDPN than in PHN. These facts should be considered when planning and conducting confirmatory trials in NeP. PMID- 25559270 TI - Oncostatin m, an inflammatory cytokine produced by macrophages, supports intramembranous bone healing in a mouse model of tibia injury. AB - Different macrophage depletion strategies have demonstrated a vital role of macrophages in bone healing, but the underlying molecular mechanisms are poorly understood. Here, with the use of a mouse model of tibia injury, we found that the cytokine oncostatin M [OSM or murine (m)OSM] was overexpressed during the initial inflammatory phase and that depletion of macrophages repressed mOSM expression. In Osm(-/-) mice, by micro-computed tomography and histology we observed a significant reduction in the amount of new intramedullar woven bone formed at the injured site, reduced number of Osterix(+) osteoblastic cells, and reduced expression of the osteoblast markers runt-related transcription factor 2 and alkaline phosphatase. In contrast, osteoclasts were normal throughout the healing period. One day after bone injury, Stat3, the main transcription factor activated by mOSM, was found phosphorylated/activated in endosteal osteoblastic cells located at the hedge of the hematoma. Interestingly, we observed reduced activation of Stat3 in Osm(-/-) mice. In addition, mice deficient in the mOSM receptor (Osmr(-/-)) also had reduced bone formation and osteoblast number within the injury site. These results suggest that mOSM, a product of macrophages, sustains intramembranous bone formation by signaling through Osmr and Stat3, acting on the recruitment, proliferation, and/or osteoblast differentiation of endosteal mesenchymal progenitor cells. Because bone resorption is largely unaltered, OSM could represent a new anabolic treatment for unconsolidated bone fractures. PMID- 25559272 TI - Androgen receptor-positive mucoepidermoid carcinoma: case report and literature review. AB - Androgen receptor (AR) is usually expressed in salivary duct carcinoma (SDC), but only infrequently in other carcinoma types including mucoepidermoid carcinoma (MEC). The clinicopathological characteristics of AR-positive MEC remain to be clarified. Here we report a case of AR-positive MEC. A 76-year-old man presented with a growing painless tumor of the right parotid. The resected tumor was a high grade tumor with necroses. Since the tumor was positive for AR, GCDFP-15, and HER2, SDC was first suspected, but it was also positive for CK5/6 and P63, and negative for S-100 protein and alpha-smooth muscle actin. In addition, scattered mucous secreting tumor cells were found in the tumor nests, and they were positive for Alcian blue. A diagnosis of AR-positive MEC was finally made. The patient died of the tumor 5 years after the surgery. The present case may expand the histopathological spectrum of high-grade MEC. PMID- 25559273 TI - Tumor budding is an independent prognostic factor for prediction of lymph node metastasis in oral squamous cell carcinoma. AB - OBJECTIVE: Despite the enormous advances in diagnostic and management modalities of oral squamous cell carcinoma (OSCC), the mortality rates have remained stagnant with a 5-year survival rate of <50% challenging the available methods of prognostic assessment. Presence of tumor budding has been associated with aggressive behavior and is correlated with lymph node metastasis, recurrence, distant metastasis, and decreased survival in several cancers. However, the prognostic significance of this apparently simple to evaluate parameter is sparse in OSCC. METHODS: A total of 75 cases of surgically excised OSCC were analyzed for tumor budding along with other clinicopathologic parameters. Tumor budding was graded as high and low intensity based on presence and absence of >=10 or <10 budding foci in hematoxylin and eosin-stained sections. An association between the clinicopathological parameters, lymph node metastases with the budding index was examined using univariate and multivariate analyses. RESULTS: Tumor budding was evident in 89% of cases with around 45.3% of the cases demonstrated high intensity budding. High-intensity tumor budding was significantly associated with lymph node metastasis and depth of invasion. Multivariate analysis demonstrated that tumor budding and depth of invasion were significant independent predictors for lymph node metastasis. CONCLUSION: Tumor budding is frequently encountered histologic marker in OSCC. High-intensity tumor budding is a strong independent prognostic factor for prediction of lymph node metastasis. PMID- 25559276 TI - Community tuberculosis education: lessons learned in Tanna Island, Vanuatu. PMID- 25559274 TI - Structure of N-formimino-L-glutamate iminohydrolase from Pseudomonas aeruginosa. AB - N-Formimino-l-glutamate iminohydrolase (HutF), from Pseudomonas aeruginosa with a locus tag of Pa5106 ( gi|15600299 ), is a member of the amidohydrolase superfamily. This enzyme catalyzes the deamination of N-formimino-l-glutamate to N-formyl-l-glutamate and ammonia in the histidine degradation pathway. The crystal structure of Pa5106 was determined in the presence of the inhibitors N formimino-l-aspartate and N-guanidino-l-glutaric acid at resolutions of 1.9 and 1.4 A, respectively. The structure of an individual subunit is composed of two domains with the larger domain folding as a distorted (beta/alpha)8-barrel. The (beta/alpha)8-barrel domain is composed of eight beta-strands flanked by 11 alpha helices, whereas the smaller domain is made up of eight beta-strands. The active site of Pa5106 contains a single zinc atom that is coordinated by His-56, His-58, His-232, and Asp-320. The nucleophilic solvent water molecule coordinates with the zinc atom at a distance of 2.0 A and is hydrogen bonded to Asp-320 and His 269. The alpha-carboxylate groups of both inhibitors are hydrogen bonded to the imidazole moiety of His-206, the hydroxyl group of Tyr-121, and the side chain amide group of Gln-61. The side chain carboxylate groups of the two inhibitors are ion-paired with the guanidino groups of Arg-209 and Arg-82. Computational docking of high-energy tetrahedral intermediate forms of the substrate, N formimino-l-glutamate, to the three-dimensional structure of Pa5106 suggests that this compound likely undergoes a re-faced nucleophilic attack at the formimino group by the metal-bound hydroxide. A catalytic mechanism of the reaction catalyzed by Pa5106 is proposed. PMID- 25559277 TI - Resident duty hours around the globe: where are we now? AB - Safe and appropriate health care, especially in urgent or emergency situations, is the expectation of the public throughout the developed world. Achieving this goal requires appropriate levels of medical and other staff, appropriate training, and sensible working hours. Too often the brunt of such care, especially in out-of-hours situations, is borne by medical residents, who--to make matters worse--are frequently poorly supervised by more senior and experienced staff. Many jurisdictions have been alerted to this problem and are striving to correct it. However, the variation in attempts to restrict the actual hours worked by residents to "safe" levels is enormous, and all too often there is no consensus as to what should be put in place to achieve safe patient care. This paper sets out the current position for Europe, North America, and Australia. PMID- 25559278 TI - The value of magnetic resonance imaging in catheter ablation of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Catheter ablation is now a recognized treatment for those with symptomatic AF refractory to drug therapy. Innovations in magnetic resonance imaging (MRI) have empowered clinicians to improve ablation efficacy while reducing the risk of complications. It is demonstrated that late gadolinium enhancement MRI has additional advantages over modalities such as echocardiography and computed tomography, due to its ability to assess the structural remodeling directly. As a result, MRI has become an indispensable imaging tool to personalize the AF ablation strategy, assess the efficacy and potential complications of AF ablation, and guide the repeat procedure. PMID- 25559279 TI - Endothelial dysfunction in advanced liver disease. PMID- 25559281 TI - Health promotion and disease prevention strategies for today's physicians. AB - The majority of preventable diseases in both developed and developing countries could be strategically controlled by effectively implementing existing health promotion and disease prevention (HPDP) interventions. An important juncture for the implementation of risk-reduction strategies is the point of interaction between health care providers and patients during their scheduled visits. This article targets strategies for physicians to effectively implement HPDP interventions in a clinical setting. The factors that improve delivery of HPDP interventions are discussed briefly. We subsequently introduce and discuss the conceptual framework for enhanced patient education, which is based on the information-motivation-behavioral skills model and the health belief model. The article also describes an adapted patient-practitioner collaborative model for HPDP. This adapted model may serve as a blueprint for physicians to effectively execute HPDP interventions during clinical encounters. The recommended models and our conceptual frameworks could have limitations which need to be field tested. PMID- 25559280 TI - Hepatic iron in African Americans who underwent liver biopsy. AB - BACKGROUND: Primary iron overload in African Americans has been reported predominantly from autopsy studies. METHODS: We characterized hepatic iron phenotypes in 83 African Americans who underwent liver biopsy during the interval 1990 to 1995. We tabulated pathology report form data, iron grades in hepatocytes (0-4) and Kupffer cells (0-3) and abnormal liver histology. Increased iron was defined as hepatocyte or Kupffer iron grades >= 2, respectively. Heavy iron was defined as hepatocyte iron grade 3 or 4. Primary iron overload was defined as the presence of grade 3 or 4 hepatocellular iron in the absence of evidence of chronic alcohol effect, viral hepatitis, steatosis, unexplained inflammation, chronic erythrocyte transfusion or chronic ingestion of iron supplements. RESULTS: There were 37 men and 46 women (mean age: 53 +/- 15 [SD] years). We observed heavy ethanol consumption, 12.0%; viral hepatitis, 26.5%; steatosis without heavy ethanol consumption, 43.4%; inflammation, 45.6%; fibrosis, 26.2% and bridging fibrosis/cirrhosis, 29.4%. Logistic regression on bridging fibrosis/cirrhosis revealed positive associations with heavy ethanol consumption (P = 0.0410) and viral hepatitis (P = 0.0044). The 22 patients (26.5%) with increased iron had greater mean age, proportion of men and heavy ethanol consumption. Five patients had heavy iron staining, among whom were 3 women (mean age: 54 years) with primary iron overload. Two of the 3 women had cirrhosis and diabetes mellitus. CONCLUSIONS: Among 83 adult African Americans who underwent liver biopsy, 3.6% had hepatic iron phenotypes consistent with primary iron overload. PMID- 25559282 TI - It is well established that affected intracellular signaling is associated with carcinogenesis, cancer progression and tumor sensitivity to currently existing therapeutic approaches. PMID- 25559283 TI - MDR1 polymorphisms and idiopathic nephrotic syndrome in Slovak children: preliminary results. AB - BACKGROUND: The role of the multidrug resistance-1 (MDR1 or ABCB1) gene polymorphisms 1236T>C, 2677T>G, and 3435T>C was studied in relation to susceptibility, demographics, and pathological characteristics, as well as their role in the therapeutic response (TR) to prednisone treatment in children with idiopathic nephrotic syndrome (INS). MATERIAL/METHODS: The polymorphisms were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method in 46 children with INS and in 100 healthy controls. Different genetic models (codominant, dominant, recessive, and overdominant) were used for testing of associations between polymorphisms and phenotypes. RESULTS: Statistical analysis showed a significantly increased chance of TR in children carrying 3435TC genotype (OR=5.13, 95% CI=1.18-22.25; overdominant model). Moreover, INS patients under 6 years of age had significantly decreased frequencies of MDR1 1236CC (7.7% vs. 35%, p=0.029) or 2677GG (3.8% vs. 30.0%, p=0.033) genotypes. We also observed that patients with minimal change in disease and patients under 6 years of age at the onset of INS were initial responders more frequently when compared with children with focal segmental glomerulosclerosis and patients >=6 years old at the onset (p=0.0001, p=0.027, respectively). CONCLUSIONS: These data suggest that prednisone TR may be influenced by histology, age at the onset of INS, and MDR1 3435T>C polymorphism. The MDR1 1236T>C and 2677T>G polymorphisms were significantly associated with age at onset. Larger multicenter studies and studies across other ethnic groups are needed to elucidate the contradictory implications of MDR1 polymorphisms with INS in children. PMID- 25559284 TI - Pioglitazone may impair L-DOPA anti-parkinsonian efficacy in the MPTP-lesioned macaque: results of a pilot study. AB - In this pilot study, pioglitazone, an agonist of the peroxisome proliferator activated receptor gamma (PPAR-gamma) used in the treatment of diabetes mellitus, was administered to dyskinetic parkinsonian macaques. Pioglitazone alleviated L DOPA-induced dyskinesia, but impaired L-DOPA anti-parkinsonian efficacy. These results suggest caution when administering pioglitazone to patients with advanced Parkinson's disease. PMID- 25559285 TI - The strength of habit. PMID- 25559286 TI - PIP2-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6. AB - Among critical aspects of voltage-gated potassium (Kv) channels' functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore. This communication, called coupling, might be transmitted directly through interactions between these domains and, as recently proposed, indirectly through interactions with phosphatidylinositol-4,5 bisphosphate (PIP2), a minor lipid of the inner plasma membrane leaflet. Here, we show how the two components of coupling, mediated by protein-protein or protein lipid interactions, both contribute in the Kv7.1 functioning. On the one hand, using molecular dynamics simulations, we identified a Kv7.1 PIP2 binding site that involves residues playing a key role in PIP2-dependent coupling. On the other hand, combined theoretical and experimental approaches have shown that the direct interaction between the segments of the VSD (S4-S5) and the pore (S6) is weakened by electrostatic repulsion. Finally, we conclude that due to weakened protein-protein interactions, the PIP2-dependent coupling is especially prominent in Kv7.1. PMID- 25559287 TI - Afatinib efficacy against squamous cell carcinoma of the head and neck cell lines in vitro and in vivo. AB - Epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in squamous cell carcinoma of the head and neck (SCCHN). In addition to EGFR, other ErbB family members are expressed and activated in SCCHN. Afatinib is an ErbB family blocker that has been approved for treating patients with EGFR-mutated nonsmall cell lung cancer. We sought to determine the efficacy of afatinib in preclinical models and compare this to other EGFR-targeted agents. Afatinib efficacy was characterized in a panel of ten SCCHN cell lines and found to be most effective against cell lines amplified for EGFR. Afatinib had lower IC(50) values than did gefitinib against the same panel. Two EGFR-amplified cell lines that are resistant to gefitinib are sensitive to afatinib. Cetuximab was not found to have a synergistic effect with afatinib either in vitro or in vivo. Both afatinib and cetuximab were effective in tumor xenograft model. Afatinib is an effective agent in SCCHN especially in models with EGFR amplification. PMID- 25559288 TI - A rapid screening system evaluates novel inhibitors of DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk neuroblastoma. AB - After extensive research on radiochemotherapy, 5-year survival rates of children with high risk neuroblastoma still do not exceed 50%, owing to adverse side effects exemplified by doxorubicin-induced cardiomyopathy. A promising new approach is the combination of conventional therapies with specific modulation of cell signaling pathways promoting therapeutic resistance, such as inhibition of aberrant kinase activity or re-expression of silenced tumor suppressor genes by means of chromatin remodeling. In this regard, we established a system that allows to identify potential drug targets as well as to validate respective candidate inhibitors in high-risk neuroblastoma model cell lines. Cell culture, drug exposure, shRNA-mediated knockdown and phenotype analysis are integrated into an efficient and versatile single well-based protocol. By utilizing this system, we assessed RG108, SGI-1027 and nanaomycin A, three novel DNA methyltransferase inhibitors that have not been tested in neuroblastoma cell lines so far, for their potential of synergistic anti-tumor activity in combination with doxorubicin. We found that, similarly to azacytidine, SGI-1027 and nanaomycin A mediate synergistic growth inhibition with doxorubicin independently of N-Myc status. However, they display high cytotoxicity but lack global DNA demethylation activity. Secondly, we conducted a lentiviral shRNA screen of F-box proteins, key regulators of protein stability, and identified Fbxw11/beta-TrCP2 as well as Fbxo5/Emi1 as potential therapeutic targets in neuroblastoma. These results complement existing studies and underline the reliability and versatility of our single well-based protocol. PMID- 25559289 TI - Effectiveness and safety of post-induction phase bevacizumab treatment for patients with non-small-cell lung cancer: results from the ARIES observational cohort study. AB - Data from randomized, controlled trials suggest that post-induction phase (IP) treatment with bevacizumab may benefit patients with advanced non-small-cell lung cancer (NSCLC). Real-world clinical practice, however, can involve variable use and patterns of treatment in broader patient populations. To assess the effect of bevacizumab on post-IP overall survival (OS) following IP chemotherapy + bevacizumab, analyses were conducted in patients enrolled in the Avastin((r)) Registry--Investigation of Effectiveness and Safety (ARIES) observational cohort study (OCS) who received post-IP bevacizumab. ARIES was a large, prospective OCS of patients who received chemotherapy in combination with bevacizumab for the first-line treatment of NSCLC. This unplanned, post hoc analysis included patients who received chemotherapy and bevacizumab and who did not have progressive disease through the completion of IP treatment. A dichotomous analysis compared outcomes in patients who did and did not receive bevacizumab before a landmark date of day 30 post IP. A cumulative exposure analysis used a time-dependent Cox regression model to assess the effect of cumulative post-IP bevacizumab exposure on post-IP OS. In the dichotomous analysis, the duration of post-IP OS was significantly longer in patients who received post-IP bevacizumab; median post-IP OS was 15.6 vs. 11.3 months, respectively (hazard ratio [HR] = 0.80; 95 % confidence interval 0.71-0.91; P < 0.001). The cumulative exposure analysis observed that each additional cycle of cumulative bevacizumab exposure decreased the HR for post-IP OS by 2.7 %, on average. In conclusion, post-IP bevacizumab exposure was associated with improved post-IP OS in patients with advanced NSCLC who were enrolled in the ARIES OCS. PMID- 25559291 TI - How functionalist and process approaches to behavior can explain trait covariation. AB - Factors identified in investigations of trait structure (e.g., the Big Five) are sometimes understood as explanations or sources of the covariation of distinct behavioral traits, as when extraversion is suggested to underlie the covariation of assertiveness and sociability. Here, we detail how trait covariation can alternatively be understood as arising from units common to functionalist and process frameworks, such as self-efficacies, expectancies, values, and goals. Specifically, the expected covariation between 2 behavioral traits should be increased when a specific process variable tends to indicate the functionality of both traits simultaneously. In 2 empirical illustrations, we identify a wide array of specific process variables associated with several Big Five-related behavioral traits simultaneously, and which are thus likely sources of their covariation. Many of these, such as positive interpersonal expectancies, self regulatory skills, and preference for order, relate similarly to a broad range of trait perceptions in both studies, and across both self- and peer-reports. We also illustrate how this understanding of trait covariation provides a somewhat novel explanation of why some traits are uncorrelated. As we discuss, a functionalist understanding of trait covariation as arising through functionalist or process variables has implications for many basic issues in personality psychology, such as how personality traits should be measured, mechanisms for personality stability and change, and the nature of personality traits more generally. PMID- 25559292 TI - Correction to verdonck and tuerlinckx (2014). AB - Reports an error in "The Ising Decision Maker: A binary stochastic network for choice response time" by Stijn Verdonck and Francis Tuerlinckx (Psychological Review, 2014[Jul], Vol 121[3], 422-462). An inaccurate assumption in Appendix B (provided in the erratum) led to an oversimplified result in Equation 18 (the diffusion equations associated with the microscopically defined dynamics). The authors sincerely thank Rani Moran for making them aware of the problem. Only the expression of the diffusion coefficient D is incorrect, and should be changed, as indicated in the erratum. Both the cause of the problem and the solution are also explained in the erratum. (The following abstract of the original article appeared in record 2014-31650-006.) The Ising Decision Maker (IDM) is a new formal model for speeded two-choice decision making derived from the stochastic Hopfield network or dynamic Ising model. On a microscopic level, it consists of 2 pools of binary stochastic neurons with pairwise interactions. Inside each pool, neurons excite each other, whereas between pools, neurons inhibit each other. The perceptual input is represented by an external excitatory field. Using methods from statistical mechanics, the high-dimensional network of neurons (microscopic level) is reduced to a two-dimensional stochastic process, describing the evolution of the mean neural activity per pool (macroscopic level). The IDM can be seen as an abstract, analytically tractable multiple attractor network model of information accumulation. In this article, the properties of the IDM are studied, the relations to existing models are discussed, and it is shown that the most important basic aspects of two-choice response time data can be reproduced. In addition, the IDM is shown to predict a variety of observed psychophysical relations such as Pieron's law, the van der Molen-Keuss effect, and Weber's law. Using Bayesian methods, the model is fitted to both simulated and real data, and its performance is compared to the Ratcliff diffusion model. (PsycINFO Database Record (c) 2015 APA, all rights reserved). PMID- 25559290 TI - Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy. AB - We aimed to assess the prognostic role of pretreatment neutrophilia, lymphocytopenia, and neutrophil to lymphocyte ratio (NLR) in patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs) for late relapsing (>5 years) metastatic renal cell carcinoma (mRCC). Data were collected from 13 Italian centers involved in the treatment of metastatic RCC. Late relapse was defined as >5 years after initial radical nephrectomy. One hundred fifty-one patients were included in this analysis. Among them, MSKCC risk score was favorable in 68 %, intermediate in 29 %, and poor in 3 %. Fifty-six patients (37 %) had NLR >=3 at the start of VEGFR-TKI therapy (group A), while 95 had lower NLR (63 %, group B). The median overall survival (OS) was 28.8 months in group A and 68.7 months (95 % confidence interval (CI) 45.3-NA) in group B (p < 0.001). The median progression-free survival (PFS) was 15.8 months in group A and 25.1 months in group B (p = 0.03). At multivariate analysis, MSKCC risk group and NLR were independent prognostic factors for both OS and PFS. Pretreatment NLR is an independent prognostic factor for patients with late relapsing mRCC treated with first-line VEGFR-TKIs. A better characterization of baseline immunological impairment may optimize the management of this RCC subpopulation. PMID- 25559293 TI - Letter to editor concerning "symptomatic epidural hematoma after lumbar decompression surgery" by Kao FC et al (2014) Eur Spine J. doi:10.1007/s00586-014 3297-8. PMID- 25559294 TI - Characterization of the behavior of a novel low-stiffness posterior spinal implant under anterior shear loading on a degenerative spinal model. AB - PURPOSE: Dynamic implants have been developed to address potential adjacent level effects due to rigid instrumentation. Rates of revision surgeries may be reduced by using improved implants in the primary surgery. Prior to clinical use, implants should be rigorously tested ex vivo. The objective of our study was to characterize the load-sharing and kinematic behavior of a novel low-stiffness spinal implant. METHODS: A human cadaveric model of degenerative spondylolisthesis was tested in shear. Lumbar functional spinal units (N = 15) were tested under a static 300 N axial compression force and a cyclic anterior shear force (5-250 N). Translation was tracked with a motion capture system. A novel implant was compared to three standard implants with shear stiffness ranging from low to high. All implants were instrumented with strain gauges to measure the supported shear force. Each implant was affixed to each specimen, and the specimens were tested intact and in two progressively destabilized states. RESULTS: Specimen condition and implant type affected implant load-sharing and specimen translation (p < 0.0001). Implant load-sharing increased across all degeneration-simulating specimen conditions and decreased across the three standard implants (high- to low-stiffness). Translation increased with the three standard implants (trend). The novel implant behaved similarly to the medium stiffness implant (p > 0.2). CONCLUSIONS: The novel implant behaved similarly to the medium-stiffness implant in both load-sharing and translation despite having a different design and stiffness. Complex implant design and specimen-implant interaction necessitate pre-clinical testing of novel implants. Further in vitro testing in axial rotation and flexion-extension is recommended as they are highly relevant loading directions for non-rigid implants. PMID- 25559295 TI - Coccygectomy for coccygeal spicule: a study of 33 cases. AB - PURPOSE: To report the results of coccygectomy for coccygeal spicule. METHODS: We report the results of a retrospective series of 33 patients who underwent coccygectomy for coccygeal spicule. There were 31 women and 2 men. The mean age was 42 +/- 12 years (range 23-62). There was a pit in the skin overlying the spicule in 14 cases and the spicule was bulky in 8 cases. In three cases, weight loss had preceded the occurrence of the coccygodynia. The coccyx was rigid or had very reduced mobility (less than 5 degrees ) in 25 cases and normal mobility (between 5 degrees and 20 degrees of flexion) in 8 cases. All the patients had initially been managed conservatively with injections targeted on the spicule. As they did not obtain sufficient relief, they were offered surgery. Ten patients were followed up for more than 72 months, 10 patients for 48-66 months, and 13 for 30-42 months. The outcome analysis involved functional criteria only. RESULTS: Twenty-six patients (79%) had a very satisfactory outcome and 7 (21%) an unsatisfactory outcome. When asked 'Would you have the surgery again?', only one patient answered in the negative. CONCLUSIONS: Surgical treatment for coccygeal spicules that are causing coccygodynia and are resistant to conservative treatment gives satisfactory outcomes, similar to those obtained from surgery for instability of the coccyx. PMID- 25559297 TI - De novo assembly and discovery of genes that are involved in drought tolerance in Tibetan Sophora moorcroftiana. AB - Sophora moorcroftiana, a Leguminosae shrub species that is restricted to the arid and semi-arid regions of the Qinghai-Tibet Plateau, is an ecologically important foundation species and exhibits substantial drought tolerance in the Plateau. There are no functional genomics resources in public databases for understanding the molecular mechanism underlying the drought tolerance of S. moorcroftiana. Therefore, we performed a large-scale transcriptome sequencing of this species under drought stress using the Illumina sequencing technology. A total of 62,348,602 clean reads were obtained. The assembly of the clean reads resulted in 146,943 transcripts, including 66,026 unigenes. In the assembled sequences, 1534 transcription factors were identified and classified into 23 different common families, and 9040 SSR loci, from di- to hexa-nucleotides, whose repeat number is greater than five, were presented. In addition, we performed a gene expression profiling analysis upon dehydration treatment. The results indicated significant differences in the gene expression profiles among the control, mild stress and severe stress. In total, 4687, 5648 and 5735 genes were identified from the comparison of mild versus control, severe versus control and severe versus mild stress, respectively. Based on the differentially expressed genes, a Gene Ontology annotation analysis indicated many dehydration-relevant categories, including 'response to water 'stimulus' and 'response to water deprivation'. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes pathway analysis uncovered some important pathways, such as 'metabolic pathways' and 'plant hormone signal transduction'. In addition, the expression patterns of 25 putative genes that are involved in drought tolerance resulting from quantitative real-time PCR were consistent with their transcript abundance changes as identified by RNA-seq. The globally sequenced genes covered a considerable proportion of the S. moorcroftiana transcriptome, and the expression results may be useful to further extend the knowledge on the drought tolerance of this plant species that survives under Plateau conditions. PMID- 25559296 TI - Current smoking is associated with worse cognitive and adaptive functioning in serious mental illness. AB - OBJECTIVE: Cigarette smoking is highly prevalent among people with bipolar disorder or schizophrenia. Few studies have examined whether smoking history is associated with adaptive functioning among individuals diagnosed with these serious mental illnesses. METHOD: In a large relatively homogenous cohort of patients with either bipolar disorder (n=363) or schizophrenia (n=400), we investigated the association between cigarette smoking status, intensity, and cumulative exposure and performance on a comprehensive battery of neurocognitive, functional capacity, and informant-rated functional measures. The associations were adjusted for variation in sociodemographic indicators, psychopathologic symptoms, and substance use. RESULTS: There was an average of 12 pack years of smoking across the sample. People with schizophrenia reported double the rate of current smoking compared to patients with bipolar disorder. Adjusting for demographic covariates, current smokers had worse composite cognitive functioning and poorer functional outcome than past or never smokers. There were no significant differences between never and past smokers, and these effects were evident in both bipolar disorder and schizophrenia. CONCLUSION: Current smokers with either schizophrenia or bipolar disorder evidence worse cognitive and adaptive functioning functional outcome, even when demographic covariates are considered. PMID- 25559299 TI - Effects of stellate ganglion block on cardiovascular reaction and heart rate variability in elderly patients during anesthesia induction and endotracheal intubation. AB - STUDY OBJECTIVE: To investigate the effects of stellate ganglion block (SGB) on cardiovascular response and heart rate (HR) variability in elderly patients during anesthesia induction and endotracheal intubation. DESIGN: A randomized, double-blinded, and placebo-controlled study. SETTING: University-affiliated teaching hospital. PARTICIPANTS: Eighty elderly patients (American Society of Anesthesiologists grades I and II) receiving elective surgery during general anesthesia. INTERVENTIONS: Right stellate ganglion injection (SGB) was performed in all patients using 10 mL of 1% lidocaine or normal saline. MEASUREMENTS: Systolic blood pressure (BP), diastolic BP, HR, and calculated rate pressure product. HR variability at the following time points: conscious status before induction (T0); immediately before intubation (T1); immediately after intubation (T2); and 1, 3, and 5 minutes postintubation (T3, T4, and T5). MAIN RESULTS: No significant differences in BP and HR were observed between the 2 groups. Rate pressure product values significantly increased in the control group compared with baseline and SGB group values. Low-frequency power (LF) and LF/high frequency power (HF) significantly increased, and HF and normalized units of HF significantly decreased in the control group compared with baseline values. LF, normalized units of LF, and LF/HF in the SGB group significantly decreased compared with those of the control group. CONCLUSION: SGB protects the myocardium and effectively suppresses stress responses during anesthesia induction and tracheal intubation in elderly patients. PMID- 25559300 TI - Medical physics is beautiful. PMID- 25559301 TI - Hepatic hydatid disease fistulized to the skin surface. PMID- 25559302 TI - The pain and the pus. PMID- 25559303 TI - Comparison of Transcutaneous Electrical Nerve Stimulation and Cryotherapy for Increasing Quadriceps Activation in Patients With Knee Pathologies. AB - CLINICAL SCENARIO: Proper neuromuscular activation of the quadriceps muscle is essential for maintaining quadriceps (quad) strength and lower-extremity function. Quad activation (QA) failure is a common characteristic observed in patients with knee pathologies, defined as an inability to voluntarily activate the entire alpha-motor-neuron pool innervating the quad. One of the more popular techniques used to assess QA is the superimposed burst (SIB) technique, a force based technique that uses a supramaximal, percutaneous electrical stimulation to activate all of the motor units in the quad during a maximal, voluntary isometric contraction. Central activation ratio (CAR) is the formula used to calculate QA level (CAR = voluntary force/SIB force) with the SIB technique. People who can voluntarily activate 95% or more (CAR = 0.95-1.0) of their motor units are defined as being fully activated. Therapeutic exercises aimed at improving quad strength in patients with knee pathologies are limited in their effectiveness due to a failure to fully activate the muscle. Within the past decade, several disinhibitory interventions have been introduced to treat QA failure in patients with knee pathologies. Transcutaneous electrical nerve stimulation (TENS) and cryotherapy are sensory-targeted modalities traditionally used to treat pain, but they have been shown to be 2 of the most successful treatments for increasing QA levels in patients with QA failure. Both modalities are hypothesized to positively affect voluntary QA by disinhibiting the motor-neuron pool of the quad. In essence, these modalities provide excitatory afferent stimuli to the spinal cord, which thereby overrides the inhibitory afferent signaling that arises from the involved joint. However, it remains unknown whether 1 is more effective than the other for restoring QA levels in patients with knee pathologies. By knowing the capabilities of each disinhibitory modality, clinicians can tailor treatments based on the rehabilitation goals of their patients. Focused Clinical Question: Is TENS or cryotherapy the more effective disinhibitory modality for treating QA failure (quantified via CAR) in patients with knee pathologies? PMID- 25559298 TI - Ancient human microbiomes. AB - Very recently, we discovered a vast new microbial self: the human microbiome. Our native microbiota interface with our biology and culture to influence our health, behavior, and quality of life, and yet we know very little about their origin, evolution, or ecology. With the advent of industrialization, globalization, and modern sanitation, it is intuitive that we have changed our relationship with microbes, but we have little information about the ancestral state of our microbiome, and we therefore lack a foundation for characterizing this change. High-throughput sequencing has opened up new opportunities in the field of paleomicrobiology, allowing us to investigate the evolution of the complex microbial ecologies that inhabit our bodies. By focusing on recent coprolite and dental calculus research, we explore how emerging research on ancient human microbiomes is changing the way we think about ancient disease and how archaeological studies can contribute to a medical understanding of health and nutrition today. PMID- 25559304 TI - Bilateral nonunion of the sacrum in a long-term paraplegic patient treated with trans-sacral bar and spinopelvic fixation. AB - The incidence of fragility fractures of the pelvis is sharply increasing in accordance with growing life expectancy in developed countries. Numerous conditions may compromise bone density and quality, and paraplegia due to spinal cord injury is one of them. As screw anchorage is often problematic in poor bone stock, spinopelvic dissociation demands a type of osteosynthesis, which is less dependent on the density of trabecular bone. We present a case of a paraplegic 45 year-old man, with non-displaced bilateral nonunion of the sacrum. The patient was treated with trans-sacral bar and spinopelvic fixation. Rapid relief from pain and functional recovery was achieved with complete bone healing 1 year after the operation. PMID- 25559306 TI - Inhibition of protein aggregation and amyloid formation by small molecules. AB - For decades, drug after drug has failed to slow the progression of Alzheimer's disease in human trials. How compounds reducing fibril formation in vitro and toxicity in transgenic mice and flies bind to the Abeta toxic oligomers, is unknown. This account reviews recent drugs mainly targeting Abeta, how they were identified and report their successes from in vitro and in vivo experimental studies and their current status in clinical trials. We then focus on recent in vitro and simulation results on how inhibitors interact with Abeta monomers and oligomers, highly desirable knowledge for predicting new efficient drugs. We conclude with a perspective on the future of the inhibition of amyloid formation by small molecules. PMID- 25559307 TI - What protein folding teaches us about biological function and molecular machines. AB - Protein folding was the first area of molecular biology for which a systematic statistical-mechanical analysis of dynamics was developed. As a result, folding is described as a process by which a disordered protein chain diffuses across a high-dimensional energy landscape and finally reaches the folded ensemble. Folding studies have produced countless theoretical concepts that are generalizable to other biomolecular processes, such as the functional dynamics of molecular assemblies. Common themes in folding and function include the dominant role of excluded volume, that a balance between energetic roughness and geometrical effects guides dynamics, and that folding/functional landscapes are relatively smooth. Here, we discuss how insights into protein folding have been applied to investigate the functional dynamics of biomolecular assemblies. PMID- 25559308 TI - Hierarchical construction of a mechanically stable peptide-graphene oxide hybrid hydrogel for drug delivery and pulsatile triggered release in vivo. AB - The design of hydrogels with controllable drug-release properties remains challenging. Here we report a hydrogel made of hierarchical graphene oxide sheets and peptide assemblies for on-demand drug release. The hydrogel possesses high drug-sustainability and the release of drugs can be precisely and remotely controlled through external stimuli. PMID- 25559309 TI - Migration processes and self-rated health among marriage migrants in South Korea. AB - BACKGROUND: Research on migrant health mostly examines labor migrants, with some attention paid to the trauma faced by refugees. Marriage migrants represent an understudied vulnerable population in the migration and health literature. OBJECTIVES: Drawing on a Social Determinants of Health (SDH) approach, we use a large Korean national survey and stratified multivariate regressions to examine the link between migration processes and the self-rated health of Korea's three largest ethnic groups of marriage migrants: Korean-Chinese, Vietnamese, and Han Chinese. RESULTS: We find that post-migration socioeconomic status and several social integration factors are associated with the health of marriage migrants of all three groups. Specifically, having more social relationships with Koreans is associated with good health among marriage migrants, while having more social relationships with co-ethnics is associated with worse health. Marriage migrants' perceived social status of their natal and marital families is a better predictor of their health than more objective measures such as their education attainment and that of their Korean husbands. The post-migration social gradients among all ethnic groups demonstrate a dose-response effect of marital family's social standing on marriage migrants' health, independent of their own education and the social standing of their natal families. Lastly, we find some ethnicity-specific predictors such as the association between higher educational level and worse health status among the Vietnamese. This variability by group suggests a more complex set of SDH occurred during the marriage migration processes than a basic SDH framework would predict. CONCLUSION: Using a new immigrant destination, South Korea, as an example, we conclude that migration and health policies that reduce ethnicity-specific barriers and offer integration programs in early post migration stages may offer a pathway to good health among marriage migrants. PMID- 25559310 TI - Identification of sensory attributes that drive the likeability of Korean rice wines by American panelists. [Corrected]. AB - Six commercial Korean rice wines were described their sensory profiles by trained American panelists, and assessed acceptances by American subjects to identify the drivers of liking and disliking factors. Thirteen statistically different descriptive attributes were defined for Korean rice wines: aromas (apple, pear, earthy, peach, nutty, yeasty, honey), flavor (yeasty, nutty), taste (sweet, sour, bitter), and aftertaste (apricot). Samples A and F were characterized as sweet taste and fruity attributes, and sample C was characterized as being pear flavor and bitter taste. Sample B exhibited a strong earthy aroma, determined as the aroma of ginseng. The American subjects could not identify ginseng aroma due to their lack of experience in ginseng. Samples D and E were described as nutty and yeasty. In consumer test, consumer preference was skewed to sample A, for which the consumer preference revolved around the sweet, sour, and fruity characteristics of the sample by the principal component analysis. Few consumers expressed preference toward samples D and E, as evidenced by the lowest consumer acceptance ratings. Partial least squares regression revealed that the key liking factors of Korean rice wines were sweet, sour, and apricot flavors. Fruity characteristics (peach, apple, and pear) were also positively correlated with overall acceptance. The key disliking factors were yeasty and nutty characteristics. American subjects regarded Korean rice wine as belonging to the wine category, prompting them to grant the highest rank to sample A, which has similar characteristics to semisweet white wine. PMID- 25559312 TI - CO2 dose-response functions for wheat grain, protein and mineral yield based on FACE and open-top chamber experiments. AB - Data from three Swedish open-top chamber and four German FACE experiments were combined to derive response functions for elevated CO2 (eCO2) effects on Cd, Zn, Mn, protein, grain yield, grain mass and grain number of wheat. Grain yield and grain number were increased by ~6% and ~7%, respectively, per 100 ppm CO2; the former effect was linked to plant nitrogen status. Grain mass was not influenced by eCO2, whereas Cd concentration was reduced. Unlike Zn, Mn and protein, effects on Cd yield were not related to effects on grain yield. Yields of Mn, Zn and (weakly) protein were positively affected by eCO2. For protein, grain yield, grain mass and grain number, the results were consistent among the FACE and OTC experiments. A key conclusion was that yields of essential nutrients were enhanced (Mn > Zn > protein), although less than grain yield, which would not be expected from a simple dilution model. PMID- 25559311 TI - Validation of an obstetric comorbidity index in an external population. AB - OBJECTIVES: An obstetric comorbidity index has been developed recently with superior performance characteristics relative to general comorbidity measures in an obstetric population. This study aimed to externally validate this index and to examine the impact of including hospitalisation/delivery records only when estimating comorbidity prevalence and discriminative performance of the obstetric comorbidity index. DESIGN: Validation study. SETTING: Alberta, Canada. POPULATION: Pregnant women who delivered a live or stillborn infant in hospital (n = 5995). METHODS: Administrative databases were linked to create a population based cohort. Comorbid conditions were identified from diagnoses for the delivery hospitalisation, all hospitalisations and all healthcare contacts (i.e. hospitalisations, emergency room visits and physician visits) that occurred during pregnancy and 3 months pre-conception. Logistic regression was used to test the discriminative performance of the comorbidity index. MAIN OUTCOME MEASURES: Maternal end-organ damage and extended length of stay for delivery. RESULTS: Although prevalence estimates for comorbid conditions were consistently lower in delivery records and hospitalisation data than in data for all healthcare contacts, the discriminative performance of the comorbidity index was constant for maternal end-organ damage [all healthcare contacts area under the receiver operating characteristic curve (AUC) = 0.70; hospitalisation data AUC = 0.67; delivery data AUC = 0.65] and extended length of stay for delivery (all healthcare contacts AUC = 0.60; hospitalisation data AUC = 0.58; delivery data AUC = 0.58). CONCLUSIONS: The obstetric comorbidity index shows similar performance characteristics in an external population and is a valid measure of comorbidity in an obstetric population. Furthermore, the discriminative performance of the comorbidity index was similar for comorbidities ascertained at the time of delivery, in hospitalisation data or through all healthcare contacts. PMID- 25559313 TI - Abdominal oxygen saturation for monitoring return of spontaneous circulation in out-of-hospital cardiac arrest using near infrared spectrophometry. AB - AIM: We used near-infrared spectrophotometry to assess the initial and final abdominal and cerebral saturations during cardiopulmonary resuscitation (CPR) of patients with out-of-hospital cardiac arrest to determine if there is a correlation between increase in these saturation values and return of spontaneous circulation. MATERIALS AND METHODS: We evaluated 34 patients with out-of-hospital cardiac arrest without witnesses brought to our emergency department. Abdominal and cerebral saturations were measured using near-infrared spectrophotometry from the start of CPR. Cardiopulmonary resuscitation was performed for a maximum of 30 minutes. The effect of abdominal saturations in patients with or without spontaneous circulation restored through CPR was then assessed. RESULTS: Thirty four patients (17 males + females) with a mean age of 63.06 +/- 11.66 years were included in the study. A significant correlation was determined between increase in abdominal saturations measured at the start and end of CPR and the return of spontaneous circulation (P < .001). A good positive correlation was also identified between abdominal saturation and return of spontaneous circulation. CONCLUSION: Patients with increased abdominal and cerebral saturation values have a higher survival rate after appropriate CPR. This noninvasive measurement system and monitoring of patients during CPR may be a good method of predicting return of spontaneous circulation and assessing abdominal perfusion. PMID- 25559314 TI - Diagnosis of appendicitis by bedside ultrasound in the ED. AB - BACKGROUND: Computed tomography (CT) has largely become standard of care for diagnosing appendicitis at the expense of increased patient radiation exposure, cost, and time to surgical intervention. To date, there are very limited data on the accuracy of bedside ultrasound (BUS) for the diagnosis of appendicitis in adults. OBJECTIVE: The objective of this study is to evaluate test characteristics of BUS for diagnosis of acute appendicitis in the emergency department. METHODS: Data were prospectively collected on 97 cases of suspected appendicitis, which had BUS performed by trained residents with attending supervision between August 2011 and November 2013. All BUS interpretation and additional diagnostic imaging were left to the discretion of the physician or surgical consultants. A blinded ultrasound fellowship-trained physician reviewed all images after clinical treatment. Bedside ultrasound findings and patient outcomes were reported. RESULTS: A total of 97 adult cases underwent diagnostic ultrasound scans for suspected appendicitis. Of 97 cases, 34 had acute appendicitis by surgery/pathology report. Twenty-four BUS were positive for acute appendicitis and 11 were nondiagnostic. Of 24 positive ultrasounds, 23 had appendicitis on pathology report. There was 1 false-positive result, yielding a sensitivity of 67.65% (95% confidence limits, 49.5%-82.6%) and a specificity of 98.41% (95% confidence limits, 91.4%-99.7%). Of 23 positive BUS, 12 cases went to the Operating Room without an abdominal CT yielding a 12% reduction in CT utilization. If all positive BUS went to the OR without a CT scan, this would yield a 24% reduction in CT utilization. CONCLUSIONS: Bedside ultrasound may be an appropriate initial test to evaluate patients with suspected acute appendicitis in the emergency department. PMID- 25559315 TI - Anticancer agent-based marine natural products and related compounds. AB - Marine natural products constitute a huge reservoir of anticancer agents. Consequently during the past decades, several marine anticancer compounds have been isolated, identified, and approved for anticancer treatment or are under trials. In this article the sources, structure, bioactivities, mode of actions, and analogs of some promising marine and derived anticancer compounds have been discussed. PMID- 25559316 TI - Relationships between membrane water molecules and Patman equilibration kinetics at temperatures far above the phosphatidylcholine melting point. AB - The naphthalene-based fluorescent probes Patman and Laurdan detect bilayer polarity at the level of the phospholipid glycerol backbone. This polarity increases with temperature in the liquid-crystalline phase of phosphatidylcholines and was observed even 90 degrees C above the melting temperature. This study explores mechanisms associated with this phenomenon. Measurements of probe anisotropy and experiments conducted at 1M NaCl or KCl (to reduce water permittivity) revealed that this effect represents interactions of water molecules with the probes without proportional increases in probe mobility. Furthermore, comparison of emission spectra to Monte Carlo simulations indicated that the increased polarity represents elevation in probe access to water molecules rather than increased mobility of relevant bilayer waters. Equilibration of these probes with the membrane involves at least two steps which were distinguished by the membrane microenvironment reported by the probe. The difference in those microenvironments also changed with temperature in the liquid crystalline phase in that the equilibrium state was less polar than the initial environment detected by Patman at temperatures near the melting point, more polar at higher temperatures, and again less polar as temperature was raised further. Laurdan also displayed this level of complexity during equilibration, although the relationship to temperature differed quantitatively from that experienced by Patman. This kinetic approach provides a novel way to study in molecular detail basic principles of what happens to the membrane environment around an individual amphipathic molecule as it penetrates the bilayer. Moreover, it provides evidence of unexpected and interesting membrane behaviors far from the phase transition. PMID- 25559318 TI - Partially induced transition from horizontal to vertical orientation of helical peptides at the air-water interface and the structure of their monolayers transferred on the solid substrates. AB - To apply the Langmuir-Blodgett (LB) technique as a platform for investigating the fundamental properties of amphiphilic peptides (APs), we have investigated the structure of LB films using the APs. To vertically orient the helical APs like transmembrane proteins in the membrane, the primary structure of the APs was designed to have two domains: a hydrophilic domain (three amino acids) and a hydrophobic domain (ca. 20 amino acids). However, we are still far from having full control of their orientation. This study reports the contribution of the subphase temperature to the change in the orientation of helical APs. When the surface pressure-area isotherm of AP was observed at the subphase temperature at 41.5 degrees C, the isotherm exhibited a plateau, implying that a phase transition of the monolayer at the air-water interface occurred. Circular dichroism (CD) spectra of the monolayers transferred on the solid substrates revealed that the orientation of the helices changed at the pressure, where the plateau of the isotherm was observed. This change was not observed at 21.5 degrees C, i.e., the horizontal alignment of helixes was maintained. Atomic force microscopy (AFM) was used to systematically investigate the surface structure of the monolayers transferred at different surface pressures. A structural model of the monolayer that did not contradict with the results obtained by the three different techniques (the isotherm, CD spectroscopy, and AFM) was derived, and it was concluded that the horizontally oriented helices partially changed their orientation to vertical upon compression in the plateau region of the isotherm. PMID- 25559317 TI - Molecular basis of endosomal-membrane association for the dengue virus envelope protein. AB - Dengue virus is coated by an icosahedral shell of 90 envelope protein dimers that convert to trimers at low pH and promote fusion of its membrane with the membrane of the host endosome. We provide the first estimates for the free energy barrier and minimum for two key steps in this process: host membrane bending and protein membrane binding. Both are studied using complementary membrane elastic, continuum electrostatics and all-atom molecular dynamics simulations. The predicted host membrane bending required to form an initial fusion stalk presents a 22-30 kcal/mol free energy barrier according to a constrained membrane elastic model. Combined continuum and molecular dynamics results predict a 15 kcal/mol free energy decrease on binding of each trimer of dengue envelope protein to a membrane with 30% anionic phosphatidylglycerol lipid. The bending cost depends on the preferred curvature of the lipids composing the host membrane leaflets, while the free energy gained for protein binding depends on the surface charge density of the host membrane. The fusion loop of the envelope protein inserts exactly at the level of the interface between the membrane's hydrophobic and head-group regions. The methods used in this work provide a means for further characterization of the structures and free energies of protein-assisted membrane fusion. PMID- 25559319 TI - Abstracts of the IBRA Conference on Surgery of the Head, 6th International Orthognathic Surgery Forum, February 14-15, 2014, Interlaken, Switzerland. PMID- 25559320 TI - The Apple Snail Pomacea maculata (Caenogastropoda: Ampullariidae) as the intermediate host of Stomylotrema gratiosus (Trematoda: Stomylotrematidae) in Brazil: the first report of a mollusc host of a Stomylotrematid Trematode. AB - Trematodes belonging to the family Stomylotrematidae are intestinal parasites of birds. Despite the worldwide distribution and diversity of host species, the first intermediate host remains unknown. For a survey of parasites of Pomacea maculata , snails were collected from the municipality of Sao Vicente Ferrer, state of Maranhao, northeastern Brazil. In the present study, the xiphidiocercariae shed from these snails were used in the experimental infection of the water bug Belostoma plebejum. The insect mortality was observed 30 days post-infection, and the metacercariae recovered in the body cavity of B. plebejum were identified as Stomylotrema gratiosus. This is the first report of an ampullariid snail as intermediate host of stomylotrematid trematodes. PMID- 25559321 TI - Compensating for the impact of non-stationary spherical air cavities on IMRT dose delivery in transverse magnetic fields. AB - With the development of the 1.5 T MRI linear accelerator and the clinical introduction of the 0.35 T ViewRayTM system, delivering intensity-modulated radiotherapy (IMRT) in a transverse magnetic field becomes increasingly important. When delivering dose in the presence of a transverse magnetic field, one of the most prominent phenomena occurs around air cavities: the electron return effect (ERE). For stationary, spherical air cavities which are centrally located in the phantom, the ERE can be compensated by using opposing beams configurations in combination with IMRT. In this paper we investigate the effects of non-stationary spherical air cavities, centrally located within the target in a phantom containing no organs at risk, on IMRT dose delivery in 0.35 T and 1.5 T transverse magnetic fields by using Monte Carlo simulations. We show that IMRT can be used for compensating ERE around those air cavities, except for intrafraction appearing or disappearing air cavities. For these cases, gating or plan re-optimization should be used. We also analyzed the option of using IMRT plans optimized at 0 T to be delivered in the presence of 0.35 T and 1.5 T magnetic field. When delivering dose at 0.35 T, IMRT plans optimized at 0 T and 0.35 T perform equally well regarding ERE compensation. Within a 1.5 T environment, the 1.5 T optimized plans perform slightly better for the static and random intra- and interfraction air cavity movement cases than the 0 T optimized plans. For non-stationary spherical air cavities with a baseline shift (intra- and interfraction) the 0 T optimized plans perform better. These observations show the intrinsic ERE compensation by equidistant and opposing beam configurations for spherical air cavities within the target area. IMRT gives some additional compensation, but only in case of correct positioning of the air cavity according to the IMRT compensation. For intrafraction appearing or disappearing air cavities this correct positioning is absent and gating or plan re-optimization should be used. PMID- 25559323 TI - The Relationship Between Hypersexual Behavior, Sexual Excitation, Sexual Inhibition, and Personality Traits. AB - The term hypersexuality was introduced to describe excessive sexual behavior associated with a person's inability to control his or her sexual behavior. The main aim of the present study was to investigate the impact of different personality traits on the degree of hypersexual behavior as measured by the Hypersexual Behavior Inventory (HBI). A further aim was to evaluate the association between sexual inhibition and excitation [as described in the Dual Control Model (DCM)] and hypersexual behavior. A sample of 1,749 participants completed an internet-based survey comprised the HBI, the short form of the Sexual Inhibition/Sexual Excitation Scales (SIS/SES-SF) as well as more general personality measures: the Behavioral Inhibition System/Behavioral Activation System-scales (BIS/BAS-scales) and a short version of the Big Five Inventory (BFI 10). Using the recommended HBI cut-off, 6.0 % (n = 105) of the present sample could be categorized as hypersexual, which is comparable to the results of previous studies about the prevalence of hypersexual behavior in the general population. The results provided strong support for the components of the DCM sexual excitation and inhibition-to explain hypersexual behavior, irrespective of gender and sexual orientation. Some of the general personality traits also showed significant relationships with hypersexual behavior. Taken together, the results of the present study provide further support for the relevance of research about the relationships between sexual problems and disorders, the DCM, and personality variables. PMID- 25559322 TI - Deprotonated purine dissociation: experiments, computations, and astrobiological implications. AB - A central focus of astrobiology is the determination of abiotic formation routes to important biomolecules. The dissociation mechanisms of these molecules lend valuable insights into their synthesis pathways. Because of the detection of organic anions in the interstellar medium (ISM), it is imperative to study their role in these syntheses. This work aims to experimentally and computationally examine deprotonated adenine and guanine dissociation in an effort to illuminate potential anionic precursors to purine formation. Collision-induced dissociation (CID) products and their branching fractions are experimentally measured using an ion trap mass spectrometer. Deprotonated guanine dissociates primarily by deammoniation (97%) with minor losses of carbodiimide (HNCNH) and/or cyanamide (NH2CN), and isocyanic acid (HNCO). Deprotonated adenine fragments by loss of hydrogen cyanide and/or isocyanide (HCN/HNC; 90%) and carbodiimide (HNCNH) and/or cyanamide (NH2CN; 10%). Tandem mass spectrometry (MS(n)) experiments reveal that deprotonated guanine fragments lose additional HCN and CO, while deprotonated adenine fragments successively lose HNC and HCN. Every neutral fragment observed in this study has been detected in the ISM, highlighting the potential for nucleobases such as these to form in such environments. Lastly, the acidity of abundant fragment ions is experimentally bracketed. Theoretical calculations at the B3LYP/6-311++G(d,p) level of theory are performed to delineate the mechanisms of dissociation and analyze the energies of reactants, intermediates, transition states, and products of these CID processes. PMID- 25559325 TI - Going full circle: validation of P-body dispersion in hepatitis C virus-infected patients. PMID- 25559324 TI - STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection. AB - BACKGROUND & AIMS: The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naive patients with HCV genotype-1 infection. METHODS: Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naive patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg. PMID- 25559327 TI - HCC and liver disease risks in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance. PMID- 25559326 TI - Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS 9620 in the Woodchuck model of chronic hepatitis B. AB - BACKGROUND & AIMS: New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV). METHODS: After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n = 7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules. RESULTS: GS-9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620 treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8(+) T cell, NK cell, B cell and interferon response transcriptional signatures. CONCLUSIONS: The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients. PMID- 25559329 TI - Reply to: HCC and liver disease risk in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance. PMID- 25559328 TI - A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection. PMID- 25559330 TI - Electrochemical lithiation performance and characterization of silicon-graphite composites with lithium, sodium, potassium, and ammonium polyacrylate binders. AB - Poly(acrylic acid) (PAH), which is a water soluble polycarboxylic acid, is neutralized by adding different amounts of LiOH, NaOH, KOH, and ammonia (NH4OH) aqueous solutions to fix neutralization degrees. The differently neutralized polyacid, alkali and ammonium polyacrylates are examined as polymeric binders for the preparation of Si-graphite composite electrodes as negative electrodes for Li ion batteries. The electrode performance of the Si-graphite composite depends on the alkali chemicals and neutralization degree. It is found that 80% NaOH neutralized polyacrylate binder (a pH value of the resultant aqueous solution is ca. 6.7) is the most efficient binder to enhance the electrochemical lithiation and de-lithiation performance of the Si-graphite composite electrode compared to that of conventional PVdF and the other binders used in this study. The optimum polyacrylate binder highly improves the dispersion of active material in the composite electrode. The binder also provides the strong adhesion, suitable porosity, and hardness for the composite electrode with 10% (m/m) binder content, resulting in better electrochemical reversibility. From these results, the factors of alkali-neutralized polyacrylate binders affecting the electrode performance of Si-graphite composite electrodes are discussed. PMID- 25559332 TI - The Effect of Holy Qur'an Recitation on Anxiety in Hemodialysis Patients: A Randomized Clinical Trial. AB - Kidney disease and its related psychological costs have significantly increased in recent years. The aim of this study was to investigate the impact of Qur'an recitation on anxiety in hemodialysis patients. Sixty hemodialysis patients were randomized to either Qur'an recitation or a control group. Spielberger's State Trait Anxiety Inventory (STAI) was completed by patients at baseline and 1 month afterward. The intervention involved listening to the recitation of the Qur'an in traditional cantillation voice. The control group received no intervention. The data were analyzed using Student's t test and general linear models. Recitation of the Qur'an was effective in reducing anxiety in the intervention group, decreasing STAI score at baseline from 128.5 (SD = 13.0) to 82.1 (SD = 11.3), compared to the control group which experienced no change in anxiety scores from baseline to follow-up (118.3, SD = 14.5, vs. 120.1, SD = 14.4, respectively. Between-subject comparison at follow-up, after adjusting for baseline differences, indicated a significant reduction in anxiety in the intervention versus the control group (F = 15.5, p = 0.0002, Cohen's d = 1.03). Listening to the Holy Qur'an being recited is an effective intervention for anxiety in patients undergoing hemodialysis in Iran. PMID- 25559331 TI - Protein sector analysis for the clustering of disease-associated mutations. AB - BACKGROUND: The importance of mutations in disease phenotype has been studied, with information available in databases such as OMIM. However, it remains a research challenge for the possibility of clustering amino acid residues based on an underlying interaction, such as co-evolution, to understand how mutations in these related sites can lead to different disease phenotypes. RESULTS: This paper presents an integrative approach to identify groups of co-evolving residues, known as protein sectors. By studying a protein family using multiple sequence alignments and statistical coupling analysis, we attempted to determine if it is possible that these groups of residues could be related to disease phenotypes. After the protein sectors were identified, disease-associated residues within these groups of amino acids were mapped to a structure representing the protein family. In this study, we used the proposed pipeline to analyze two test cases of spermine synthase and Rab GDP dissociation inhibitor. CONCLUSIONS: The results suggest that there is a possible link between certain groups of co-evolving residues and different disease phenotypes. The pipeline described in this work could also be used to study other protein families associated with human diseases. PMID- 25559334 TI - Assessment of RIT2 rs12456492 association with Parkinson's disease in Mainland China. AB - A recent meta-analysis of genome-wide association studies in Parkinson's disease (PD) has identified the rs12456492 variant in RIT2 as a new susceptibility loci. Because the characteristics of this locus in a Han Chinese population from mainland China was still unknown, we performed a case-control replication study in this population and investigated RIT2 rs12456492 variant in a large cohort of Chinese Han individuals. In total, 933 subjects comprising 460 PD patients and 473 control subjects were genotyped. We found a significant difference in the distributions of genotype and allele between PD and control groups (genotype p = 0.008, allele p = 0.007, odds ratio = 1.296, 95% confidence interval = 1.075 1.563). This study replicates the association between rs12456492 variant and risk of developing PD in a Han Chinese population. PMID- 25559333 TI - Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia. AB - Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Here, we examine factors that may lead aging to sensitize microglia. Aged rats exhibited higher corticosterone levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These elevated hippocampal corticosterone levels were associated with increased hippocampal 11beta-hydroxysteroid dehydrogenase type 1 protein expression, the enzyme that catalyzes glucocorticoid formation and greater hippocampal glucocorticoid receptor (GR) activation. Intracisternal administration of mifepristone, a GR antagonist, effectively reduced immune-activated proinflammatory responses, specifically from hippocampal microglia and prevented Escherichia coli-induced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention significantly reduced total hippocampal GR expression. These data strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia. PMID- 25559336 TI - Sulfur dioxide activation: a theoretical investigation into dual S?O bond cleavage by three-coordinate molybdenum(III) complexes. AB - Cummins et al. have observed that 3 equiv of Mo(N[R]Ar)3 (R = C(CD3)2CH3, Ar = 3,5-C6H3Me2) are required for dual S?O bond cleavage within a SO2 molecule. Using density functional theory calculations, this theoretical study investigates a mechanism for this SO2 cleavage reaction that is mediated by MoL3, where L = NH2 or N[(t)Bu]Ph. Our results indicate that an electron transfers into the SO2 ligand, which leads to Mo oxidation and initiates SO2 coordination along the quartet surface. The antiferromagnetic (AF) nature of the (NH2)3Mo-SO2 adduct accelerates intersystem crossing onto the doublet surface. The first S?O bond cleavage occurs from the resulting doublet adduct and leads to formation of L3Mo?O and SO. Afterward, the released SO molecule is cleaved by the two remaining MoL3, resulting in formation of L3Mo?S and an additional L3Mo?O. This mononuclear mechanism is calculated to be strongly exothermic and proceeds via a small activation barrier, which is in accordance with experimental results. An additional investigation into a binuclear process for this SO2 cleavage reaction was also evaluated. Our results show that the binuclear mechanism is less favorable than that of the mononuclear mechanism. PMID- 25559335 TI - APOE epsilon4 moderates amyloid-related memory decline in preclinical Alzheimer's disease. AB - The apolipoprotein E (APOE) E4 allele and high levels of beta-amyloid (Abeta) are associated with episodic memory decline and risk for Alzheimer's disease. However, there is debate about independent or interactive effects of E4 on Abeta related memory decline in healthy older adults. Healthy older adults with high Abeta burden (n = 84) enrolled in Australian Imaging, Biomarkers, and Lifestyle Study were included in this study. Cognition was measured using the computerized Cogstate Brief Battery at baseline, 18-, 36-, and 54-month follow-ups. Mini Mental State Examination and Clinical Dementia Rating scales were also administered at baseline and each follow-up timepoint. Relative to Abeta+ E4 noncarriers (n = 36), Abeta+ E4 carriers (n = 48) showed significantly faster decline on memory tasks, which was by convention, moderate in magnitude (d = 0.40 0.47). Abeta positivity coupled with APOE E4 was associated with moderately increased decline in memory over a 54-month assessment period, suggesting that, in the preclinical stages of Alzheimer's disease, the manifestation of memory decline in older adults with high Abeta is exacerbated by the presence of APOE E4. PMID- 25559337 TI - Thermoelectric efficiency of (1 - x)(GeTe) x(Bi2Se0.2Te2.8) and implementation into highly performing thermoelectric power generators. AB - Here we report for the first time on a complete simulation assisted "material to module" development of a high performance thermoelectric generator (TEG) based on the combination of a phase change material and established thermoelectrics yielding the compositions (1 - x)(GeTe) x(Bi(2)Se(0.2)Te(2.8)). For the generator design our approach for benchmarking thermoelectric materials is demonstrated which is not restricted to the determination of the intrinsically imprecise ZT value but includes the implementation of the material into a TEG. This approach is enabling a much more reliable benchmarking of thermoelectric materials for TEG application. Furthermore we analyzed the microstructure and performance close to in-operandi conditions for two different compositions in order to demonstrate the sensitivity of the material against processing and thermal cycling. For x = 0.038 the microstructure of the as-prepared material remains unchanged, consequently, excellent and stable thermoelectric performance as prerequisites for TEG production was obtained. For x = 0.063 we observed strain phenomena for the pristine state which are released by the formation of planar defects after thermal cycling. Consequently the thermoelectric performance degrades significantly. These findings highlight a complication for deriving the correlation of microstructure and properties of thermoelectric materials in general. PMID- 25559338 TI - Cognitive shifting and externalising problem behaviour in intellectual disability and autism spectrum disorder. AB - BACKGROUND: Behavioural problems are frequently reported in residential care for people with an intellectual disability (ID) in particular when they are additionally diagnosed with autism spectrum disorder (ASD). There are indications that impairment in cognitive shifting may be associated with problem behaviour. The objectives of this study were (1) to examine the relationship of cognitive shifting and severity of ASD symptoms with externalising problem behaviour in individuals with ID, with and without ASD, and (2) to examine whether a diagnosis based on shifting impairment is more predictive of externalising problem behaviour than an ASD diagnosis. METHOD: Participants consisted of adolescents and young adults with mild ID, with and without ASD (n = 41). Pearson intercorrelations were computed to explore the relationship between shifting impairment and severity of ASD symptoms on the one hand and ratings of externalising problem behaviour on the other hand. t-Tests were performed to analyse differences in externalising problem behaviour. RESULTS: Unlike ASD symptom severity, shifting scores were found to be associated with externalising problem behaviour, but only if shifting was measured using rating scales and not when using neuropsychological tasks. Externalising problem behaviour scores significantly differed when groups were classified according to shifting impairment (impaired vs. non-impaired) but not when they were classified according to ID and ASD diagnoses. CONCLUSIONS: It is proposed to use a cognition based approach when analysing problem behaviour, thus concentrating not so much on ID and ASD diagnosis and their corresponding symptoms, but rather placing the focus on cognitive symptoms. PMID- 25559339 TI - An N-terminal region of a Myb-like protein is involved in its intracellular localization and activation of a gibberellin-inducible proteinase gene in germinated rice seeds. AB - The expression of the gene for a proteinase (Rep1) is upregulated by gibberellins. The CAACTC regulatory element (CARE) of the Rep1 promoter is involved in the gibberellin response. We isolated a cDNA for a CARE-binding protein containing a Myb domain in its carboxyl-terminal region and designated the gene Carboxyl-terminal Myb1 (CTMyb1). This gene encodes two polypeptides of two distinctive lengths, CTMyb1L and CTMyb1S, which include or exclude 213 N terminal amino acid residues, respectively. CTMyb1S transactivated the Rep1 promoter in the presence of OsGAMyb, but not CTMyb1L. We observed an interaction between CTMyb1S and the rice prolamin box-binding factor (RPBF). A bimolecular fluorescence complex analysis detected the CTMyb1S and RPBF complex in the nucleus, but not the CTMyb1L and RPBF complex. The results suggest that the arrangement of the transfactors is involved in gibberellin-inducible expression of Rep1. PMID- 25559340 TI - Quantitative methods for prediction of the effect of cytochrome P450 gene polymorphisms on substrate drug exposure. PMID- 25559341 TI - Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro((r))): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. AB - Mipomersen (Kynamro((r))), a second-generation 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO), inhibits the synthesis of apolipoprotein B (apoB) and is indicated in the US as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH) at a dose of 200 mg subcutaneously (SC) once weekly. The pharmacokinetic (PK) properties of mipomersen are generally consistent across all species studied, including mouse, rat, monkey, and humans. After SC administration, mipomersen is rapidly and extensively absorbed. It has an apparent plasma and tissue terminal elimination half-life of approximately 30 days. Mipomersen achieves steady-state tissue concentrations within approximately 4-6 months of once-weekly dosing. It does not exhibit PK-based drug-drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs. Furthermore, mipomersen does not prolong the corrected QT (QTc) interval. There have been no ethnic- or gender-related differences in PK observed. In clinical trials, both as a single agent and in the presence of maximal lipid-lowering therapy, mipomersen has demonstrated significant dose-dependent reductions in all measured apoB-containing atherogenic lipoproteins. Overall, mipomersen has well characterized PK and pharmacodynamic properties in both animals and humans, and is an efficacious adjunct treatment for patients with HoFH. PMID- 25559342 TI - Clinical pharmacokinetics and pharmacodynamics of clopidogrel. AB - Acute coronary syndromes (ACS) remain life-threatening disorders, which are associated with high morbidity and mortality. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in the response to clopidogrel treatment, in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19, which affect the pharmacokinetics of clopidogrel. While the US Food and Drug Administration has issued a boxed warning for CYP2C19 poor metabolizers because of potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability, and how they are interrelated, is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence the pharmacokinetics and pharmacodynamics of clopidogrel and how they mechanistically contribute to inter-individual differences in the response to clopidogrel treatment.